PMID- 21779637 TI - Work, social support and leisure protect the elderly from functional loss: EPIDOSO study. AB - OBJECTIVE: To identify risk factors for functional capacity loss in elderly people. METHODS: Epidoso (Epidemiology of the Elderly) cohort study with elderly people living in Sao Paulo (Southeastern Brazil). A total of 326 participants in the first interview (1991-1992) who were independent or had mild dependence (one or two activities of daily living) were selected. Those who presented functional loss in the second (1994-1995) or third interviews (1998-1999) were compared to those who did not present it. The incidence of functional loss was calculated according to sociodemographic variables, life habits, cognitive status, morbidity, hospitalization, self-rated health, tooth loss, social support and leisure activities. Crude and adjusted relative risks with 95% confidence intervals were estimated through bivariate and multiple analyses with Poisson regression. The criterion for the inclusion of the variables in the model was p < 0.20 and for exclusion, p > 0.10. RESULTS: The incidence of functional loss was 17.8% (13.6; 21.9). The risk factors in the final model were: age group 70-74 years RR=1.9 (0.9;3.9); age group 75-79 years RR=2.8 (1.4;5.5); age group 80 years or older RR=5.4 (3.0;9.6); score in the mini-mental state examination <24 RR=1.8 (1.1;2.9); asthma RR=2.3 (1.3;3.9); hypertension RR=1.7 (1.1;2.6); and diabetes RR=1.7 (0.9;3.0). The protective factors were: paid work RR=0.3 (0.1;1.0); monthly relationship with friends RR=0.5 (0.3;0.8); watching TV RR=0.5 (0.3;0.9); and handcrafting RR=0.7 (0.4;1.0). CONCLUSIONS: The prevention of functional loss should include adequate control of chronic diseases, like hypertension, asthma and diabetes, as well as cognitive stimulation. Work, leisure and relationships with friends should be valued due to their protective effect. PMID- 21779638 TI - Living conditions of people with psychotic disorders living in slums in Santos, Southeastern Brazil. AB - OBJECTIVE: To describe the living conditions and sociability among people with severe mental disorders living in slums. METHODOLOGICAL PROCEDURES: A qualitative study was carried out among adults living in slums in the central region of Santos, Southeastern Brazil, conducted in 2004-2006. Ethnographic observations were made in four slum properties, and in-depth semi-structured interviews were conducted with eight women who were living with individuals with psychotic disorders. The analysis method used was qualitative, based on anthropology. ANALYSIS OF RESULTS: The slum properties presented specific characteristics regarding sociability. The difficulties with psychotic patients came from breakage of the minimal rules. In one of the slum properties, one resident acted as a caregiver for the patients and kept closely in touch with the healthcare services. Despite day-to-day contact with such patients, the participants did not have any information about such disorders and believed that the patients were mad, nervous or mentally weak. They believed that such individuals should live in places other than the slum property. CONCLUSIONS: The population living in these slum properties did not deal with the individuals with psychotic disorders any differently from the general population, because of lack of knowledge, discrimination and stigmatization. The living conditions were poor for everyone, without any difference for the residents with psychotic disorders, except for those living in the collective residence with a greater number of patients, which was organized around them and was economically dependent on their benefits. PMID- 21779639 TI - Hospitalization for primary care-sensitive conditions in regional health districts in Southern Brazil. AB - OBJECTIVE: To compare rates of hospitalization for primary care-sensitive conditions in the major municipalities of regional health districts. METHODS: An ecological study was carried out with both male and female subjects aged 20 to 59 years in the major municipalities of regional health districts in the state of Rio Grande do Sul, Southern Brazil, between 1995 and 2007. Hospitalization data were obtained from the database of the Brazilian Health Care System (Datasus). Rates by Poisson regression with robust variance were analyzed. Rates for each municipality were compared to those of the remainder of the Rio Grande do Sul state excluding the major municipalities of each district. RESULTS: There was a reduction in the rates of hospitalization for primary care-sensitive conditions in all municipalities, with the exception of Porto Alegre (1.01) and Osorio (1.02). Among larger municipalities, the greatest reductions were observed in Santa Maria (0.92) and Pelotas (0.93). Rates in medium-sized municipalities showed a decrease towards the end of the study period. Among small municipalities, only Lajeado and Frederico Westphalen showed rates lower than those of the rest of the state in 2007. The highest rates were found in the smallest municipalities. CONCLUSIONS: There was a trend towards a reduction in hospitalizations in almost all municipalities, possibly due to the expansion of primary health care that took place even prior to the implementation of the Family Health Program and changes in management. The high rates of hospitalization in small municipalities suggest that hospitalization for primary care-sensitive conditions may be a means of justifying an idle supply of hospital beds. PMID- 21779640 TI - Risks and controversies in the social construction of the concept of healthy food: the case of soy. AB - Controversies and risks in the social construction of the concept of healthy food are discussed, using soybean as the object of study. Studies concerning the impacts of soy on human health and the effects of its cultivation on the social environmental domain were reviewed to analyze the political context of the discussion surrounding soy and the socio-environmental repercussions of its cultivation. Based on the sociology of scientific knowledge and the environmental sociology, we identified a thin line between healthy and risky food, which is vulnerable to different reflexively constructed influences. It is important to broaden the concept of healthy food to healthy alimentation and to consider its cultural and social-environmental dimension. PMID- 21779641 TI - Regulatory Impact Analysis: a new tool for better regulation at ANVISA. AB - Regulatory Impact Analysis, which is recommended to regulatory departments, aims to improve regulatory quality by providing information about the costs and benefits of regulation as well as solutions to current issues to enhance the decision-making process. This article discusses the importance of Regulatory Impact Analysis in the context of the National Agency for Sanitary Surveillance performance as well as the agency's current phase of regulation improvement and strengthening. Also, the main definitions related to the regulatory field as well as some international case experiences are presented. PMID- 21779642 TI - [Political agenda for strengthening and developing universal systems of social security]. PMID- 21779643 TI - [Institutional development program of the Brazilian National Health System]. PMID- 21779644 TI - [Eliminating vertical transmission of HIV and syphilis in Sao Paulo State, Southeastern Brazil]. PMID- 21779646 TI - [To improve the visibility of Brazilian papers in obstetrics and gynecology]. PMID- 21779647 TI - [Analysis of VDR gene polymorphism Fok1 in infertile women with endometriosis]. AB - PURPOSE: to evaluate the frequency of VDR gene polymorphism Fok1 in infertile women with endometriosis and Control and its relation to the disease. METHODS: a case-control study that included 147 infertile women with endometriosis and 154 fertile women without endometriosis as Control. Fok1 polymorphism (rs10735810, T2C), which promotes a T/C exchange in exon 2 of the VDR gene, was identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP), that involves the combination of amplification by PCR and digestion with restriction endonuclease. The chi2 test was used to compare allele and genotype frequencies between groups. All p-values were two-tailed and a p-value < 0.05 was considered statistically significant. RESULTS: the TT, TC and CC genotype frequencies of VDR Fok1 polymorphism were 44.2%, 46.9% and 8.9% in infertile women with endometriosis and 41.6%, 50% and 8.4% in the Control Group. No significant difference was found (p=0.8), even when the patients were subdivided according to the stage of endometriosis (p=0.3 for minimal and mild endometriosis and p=0.2 for moderate and severe endometriosis). Alleles T and C were present, respectively, in 67.6% and 32.3% of infertile women with endometriosis (p=0.8), in 63.5% and 36.5% of women with minimal/mild endometriosis (p=0.5), in 72.5% and 27.5% of women with moderate/severe endometriosis (p=0.2), and in 66.6% and 33.4% of the Control Group. No statistically significant difference was found among any groups and the Control. CONCLUSION: the results suggest that VDR gene polymorphism Fok1 does not confer genetic susceptibility to endometriosis associated infertility in the Brazilian population. PMID- 21779648 TI - [Correlation between complaints of stress urinary incontinence and the one-hour pad test in postmenopausal women]. AB - OBJECTIVE: to correlate complaints of stress urinary incontinence and the results of a one-hour pad test in pre- and postmenopausal women. METHODS: cross-sectional study conducted on 60 postmenopausal volunteers divided into two groups: one consisting of 34 women with involuntary loss of urine due to stress incontinence and the other consisting of 26 women without involuntary loss of urine. A control group of 15 premenopausal women with normal menstrual cycles and no urinary complaints was also used. All women underwent clinical and laboratory analysis as well as the one-hour pad test. Patients were considered to be incontinent when sanitary pad weight post-test was more than 1 g. Data were submitted to descriptive statistics, parametric ANOVA, post-hoc Tukey test and Pearson's correlation. RESULTS: all postmenopausal women presented with stress urinary incontinence during the pad test, both those with urinary loss (4 g) and with no previous loss (3.5 g). A strong correlation was observed between urinary loss and time since menopause (r=0.8; p<0.01) and body mass index (r=0.7; p=0.01). Premenopausal women were continent during the pad test (0.4 g). CONCLUSIONS: the results of the one-hour pad test showed that all postmenopausal women exhibited stress urinary incontinence, including those without urine loss on effort. Urine loss was correlated with time since menopause and body mass index. PMID- 21779649 TI - [Associated factors of lymphedema in breast cancer patients]. AB - PURPOSE: to determine the prevalence of lymphedema and its associated factors in breast cancer patients. METHODS: Two hundred and fifty women that had undergone more than six months of breast cancer treatment and were being treated at an oncology reference hospital in Juiz de Fora, Minas Gerais, Brazil. They were interviewed and submitted to physical evaluation. Data from the patients' medical records regarding the treatment of breast cancer, the extent of axillary intervention and the tumor were analyzed. Lymphedema was diagnosed when the difference between both upper limbs was 2 cm or more by perimetry. The groups of women with and without lymphedema were compared regarding the possible risk factors, and central tendency, dispersion, and prevalence were measured, with a significance level of 95%. RESULTS: One hundred and twelve women (44.8%) presented lymphedema. A significant difference was found between the groups of women with and without lymphedema regarding the median numbers of removed lymph nodes (p=0.02); presentation of superficial lymphatic thrombosis in the arm ipsilateral to the surgery (p<0.01); local application of radiotherapy, use of chemotherapy (p<0.01 for both); removal of the cuticles of the ipsilateral hand with pliers, and weightlifting after the treatment (p<0.01 and p=0.05, respectively). CONCLUSIONS: the association between lymphedema and the mentioned factors requires an interdisciplinary approach to this condition. It is of paramount importance that health teams and patients become aware of the prevention and treatment of lymphedema, a condition often undervalued. PMID- 21779650 TI - [Gestational and neonatal outcomes in women with positive screening for diabetes mellitus and 100g oral glucose challenge test normal]. AB - PURPOSE: to determine the prevalence of adverse gestational and neonatal outcomes in women with a positive screening and negative diagnosis for gestational diabetes mellitus (GDM). METHODS: a retrospective descriptive cross-sectional study was conducted from 2000 to 2009 on 409 women with positive screening for GDM. The maternal variables studied were: age, body mass index, history of cesarean section, macrosomia or diabetes mellitus in a previous pregnancy and a personal or family history of diabetes mellitus and chronic arterial hypertension. The neonatal variables studied were: polyhydramnios, gestational age at birth, prematurity, cesarean delivery, large for gestational age (LGA) newborn, macrosomia, Apgar score, neonatal respiratory distress syndrome, hypoglycemia and hyperbilirubinemia. Uni- and multivariate descriptive analyses were first performed regarding risk factors and neonatal outcome and the prevalences and respective 95% confidence intervals were determined. RESULTS: the route of delivery was cesarian section in 255 cases (62.3%), preterm birth occurred in 14.2% of cases and 19.3% of the newborns were LGA. The risk factors correlated with LGA newborns were overweight or obesity, maternal age and a history of macrosomia in a previous pregnancy. CONCLUSIONS: a high rate of LGA newborns was observed in the population with positive risk factors or altered fasting glycemia on the occasion of the first prenatal visit, even when the glycemia curve was normal, with cesarean rates above those habitually observed in populations considered to be of low risk. Pregnant women with these characteristics represent a differential group. PMID- 21779651 TI - [Dietary intake of pregnant women and maternal weight gain after nutritional counseling]. AB - PURPOSE: to determine the dietary consumption of pregnant women, by assessing the intake of macronutrients and micronutrients, and to verify the maternal weight gain during pregnancy. METHODS: a retrospective study conducted from June 2002 to June 2008 with pregnant women who received nutritional counseling during prenatal care at a university hospital, grouped according to anthropometric nutritional status classified by pregestational body mass index (BMI). The dietary intake was analyzed according to the information obtained in food frequency interviews, performed at the first evaluation of pregnant women in the service of nutrition to obtain data about eating habits, and the intake of macronutrients and micronutrients was calculated. The pregnant women received nutritional counseling, and the maternal weight gain was investigated. RESULTS: a total of 187 pregnant women who received nutritional counseling were analyzed. Twenty three (12.2%) were underweight, 84 (45.0%) normal weight, 37 (19.8%) overweight, and 43 (23.0%) obese. The underweight pregnant women had lower consumption of lipids when compared to the normal weight group (101.4 versus 137.3 g; p=0.043). The average iron intake was higher in normal weight pregnant women (14.6 mg/d) compared to the overweight (12.2 mg/d) or obese (10.9 mg/d; p<0.001) groups. The average intake of folate was higher in normal weight pregnant women compared to obese ones (336.5 ug/d versus 234.5 ug/d; p=0.002). Excessive maternal weight gain was significantly (p=0.009) more frequent in overweight (56.7%) and obese (39.5%) pregnant women compared to underweight (17.4%) and normal weight (31.0%) women. CONCLUSIONS: The maternal weight gain above recommended levels was associated with overweight and obesity. The dietary intake of pregnant women differs according to maternal anthropometric nutritional status, with a lower daily intake of iron in overweight and obese women and a lower intake of folate in obese ones, a fact that reinforces the importance of prenatal vitamin supplementation. PMID- 21779652 TI - [Prenatal screening for toxoplasmosis and factors associated with seropositivity of pregnant women in Goiania, Goias]. AB - PURPOSE: to estimate the prevalence and risk factors associated with seropositivity for Toxoplasma gondii in pregnant women. METHODS: a cross sectional retrospective study based on the records of women screened for toxoplasmosis by the Pregnancy Protection Program in 2008, living in Goiania (GO). These records were connected to records from the database of the National Information System on Live Births from the State of Goias. The process occurred in three phases, with 10,316 records being paired for analysis, among the 12,846 initial records. The following variables were evaluated in this process: woman's name, age, date of birth, estimated date of delivery, date of infant birth and household information. Anti-Toxoplasma gondii antibodies were detected with the Q Preven Toxo IgG and IgMin tests in dried blood samples collected on filter paper. The chi2 test and chi2 test for trend were used for data analysis, and the odds ratio (OR) was used to estimate the chance of association between exposure and outcome. RESULTS: the prevalence of infection was 67.7%, with 0.7% of the samples presenting anti-Toxoplasma gondii IgM and IgG reagents. Out of these, only three did not undergo confirmatory testing in venous blood. The median interval between the screening and the new collection of venous blood was of 12.5 days, and from screening to confirmatory test and avidity it was of 20 days. The variables associated with exposure were: age 20-30 years, OR=1.6 and >=31 years, OR=1.8; brown skin color, OR=1.4, and black skin color, OR=1.6; and education of 8-11 years, OR=0.7, and >=12 years of education, OR=0.6. CONCLUSION: a high prevalence of infection was estimated among the studied pregnant women. The associated factors that were found found should be considered during prenatal care, along with educational activities for the prevention of infection and assessment of serological status of seronegative pregnant women. PMID- 21779653 TI - [Dunnigan-type familial partial lipodystrophy: attention to precocious diagnosis]. AB - Dunnigan-type familial partial lipodystrophy (FPLD) is an autosomal dominant disease that results from heterozygous missense mutations in LMNA, the gene that encodes nuclear lamin A/C. FPLD is characterized by a progressive disappearance of subcutaneous adipose tissue in the limbs, gluteal region, abdomen and trunk, beginning at the time of or after puberty, and excessive amount of fat in the face, chin, labia majora, and intra-abdominal region, leading to a Cushingoid appearance and increased muscularity phenotype. Affected women are particularly predisposed to insulin resistance and its complications, including features of polycystic ovary syndrome. To emphasize the importance of an early FPLD diagnosis, which is necessary to prevent serious metabolic disturbances, we report a woman diagnosed at about 50 years of age. Increased muscularity and significant labia majora fat deposit made the diagnosis possible by gynecologists. PMID- 21779654 TI - Chemical composition and natural durability of juvenile and mature heartwood of Robinia pseudoacacia L. AB - The aim of this study was to characterize the properties of juvenile and mature heartwood of Robinia pseudoacacia L. (black locust). The content, the composition, and subcellular localization of heartwood extractives were studied in 14 old-grown trees from forest sites in Germany and Hungary, as well as in 16 younger trees of four clone types. Heartwood extractives (methanol and acetone extraction) were analysed by HPLC-chromatography. UV microspectrophotometry was used to localize the extractives in the wood cell walls. The natural durability of juvenile and mature heartwood was analysed according to the European standard EN 350-1. Growth analyses, as well as the chemical analyses, showed that in Robinia the formation of juvenile wood is restricted to the first 10-15 years of cambial growth. In the heartwood high contents of phenolic compounds and flavonoids were present, which were in high concentrations in the cell walls of the axial parenchyma and of the vessels. In the juvenile heartwood, the content of these extractives is significantly lower than in the mature heartwood. In agree, the juvenile heartwood had a lower resistance to decay by Coniophora puteana (brown rot fungus) and Coriolus versicolor (white rot fungus) compared to the mature. PMID- 21779655 TI - Study of the antiproliferative potential of seed extracts from Northeastern Brazilian plants. AB - This study assessed the antiproliferative and cytotoxic potential against tumor lines of ethanolic seed extracts of 21 plant species belonging to different families from Northeastern Brazil. In addition, some underlying mechanisms involved in this cytotoxicity were also investigated. Among the 21 extracts tested, the MTT assay after 72 h of incubation demonstrated that only the ethanolic extract obtained from Myracrodruon urundeuva seeds (EEMUS), which has steroids, alkaloids and phenols, showed in vitro cytotoxic activity against human cancer cells, being 2-fold more active on leukemia HL-60 line [IC(50) value of 12.5 (9.5-16.7) MUg/mL] than on glioblastoma SF-295 [IC(50) of 25.1 (17.3-36.3) MUg/mL] and Sarcoma 180 cells [IC(50) of 38.1 (33.5-43.4) MUg/mL]. After 72h exposure, flow cytometric and morphological analyses of HL-60-treated cells showed that EEMUS caused decrease in cell number, volume and viability as well as internucleosomal DNA fragmentation in a dose-dependent way, suggesting that the EEMUS triggers apoptotic pathways of cell death. PMID- 21779656 TI - Morpho-anatomical features of underground systems in six Asteraceae species from the Brazilian Cerrado. AB - In the Brazilian Cerrado (neotropical savanna), the development of bud-bearing underground systems as adaptive structures to fire and dry periods can comprise an important source of buds for this ecosystem, as already demonstrated in the Brazilian Campos grasslands and North American prairies. Asteraceae species from both woody and herbaceous strata have subterranean organs that accumulate carbohydrates, reinforcing the adaptive strategy of these plants to different environmental conditions. This study aims to analyse the morpho-anatomy of underground systems of six species of Asteraceae (Mikania cordifolia L.f. Willd., Mikania sessilifolia DC, Trixis nobilis (Vell.) Katinas, Pterocaulon alopecuroides (Lam.) DC., Vernonia elegans Gardner and Vernonia megapotamica Spreng.), to describe these structures and to verify the occurrence and origin of shoot buds, and to analyse the presence of reserve substances. Individuals sampled in Cerrado areas in Sao Paulo State showed thick underground bud-bearing organs, with adventitious or lateral roots and presence of fructans. Xylopodium was found in all studied species, except for Trixis nobilis, which had stem tuber. The presence of fructans as reserve, and the capacity of structures in the formation of buds indicate the potential of herbaceous species of Asteraceae in forming a viable bud bank for vegetation regeneration in the Brazilian Cerrado. PMID- 21779657 TI - Effects of environmental conditions associated to the cardinal orientation on the reproductive phenology of the cerrado savanna tree Xylopia aromatica (Annonaceae). AB - The Brazilian cerrado has undergone an intense process of fragmentation, which leads to an increase in the number of remnants exposed to edge effects and associated changes on environmental conditions that may affect the phenology of plants. This study aimed to verify whether the reproductive phenology of Xylopia aromatica (Lam.) Mart. (Annonaceae) differs under different light conditions in a cerrado sensu stricto (a woody savanna) of southeastern Brazil. We compared the reproductive phenology of X. aromatica trees distributed on east and south cardinal faces of the cerrado during monthly observations, from January 2005 to December 2008. The east face had a higher light incidence, higher temperatures and canopy openness in relation to south face. X. aromatica showed seasonal reproduction at both faces of the cerrado, but the percentage of individuals, the synchrony and duration of phenophases were higher at the east face. The study demonstrated the influence of the environmental conditions associated to the cardinal orientation of the cerrado faces on the phenological pattern of X. aromatica. Similar responses may be observed for other species, ultimately affecting patterns of floral visitation and fruit production, which reinforces the importance of considering the cardinal direction in studies of edge effects and fragmentation. PMID- 21779659 TI - Managing glaucoma in developing countries. PMID- 21779660 TI - [Central corneal thickness and its correlations with other ocular biometric data in patients with congenital glaucoma]. AB - PURPOSE: To study the distribution of the central corneal thickness and its correlations with other biometric data in patients with congenital glaucoma. METHODS: Patients had been divided into two groups: group "A", composed of patients with congenital glaucoma, being subdivided in two sub-groups: with Haab striae (A1) and without Haab striae (A2), and group"B" that represented the controls. RESULTS: The group A presented corneal diameter between 11 and 15.5 mm, with mean of 14.13 mm and standard deviation (SD) of 1.28, while group B presented values between 11.5 and 12.5 mm, with average of 12.01 mm SD of 0.09 (t=-8.9723 and p=1.5083 in level 0.05). Glaucomatous patients presented greater mean values of axial diameter (t=-6.46315, p=9.2498 with level of significance of 0.05), and smaller mean keratometry in relation to the controls. The A1 sub-group presented mean central corneal thickness of 539 +/- 46 um, the A2 presented 571 +/- 56 um, and Group B 559 +/- 28 um (t=0.43746 and p=0.66291). The correlation between corneal and axial diameters was positive in both groups. The correlation between corneal diameter and mean keratometric values was negative in both groups. CONCLUSIONS: Patients with congenital glaucoma presented greater mean of axial dia meter and smaller mean keratometric values compared to the controls. No statistical significant difference of the central corneal thickness was demonstrated. Corneal and axial diameters were correlated positively. Corneal diameter was correlated negatively with the mean keratometry. It was not possible to establish correlations between the central corneal thickness and other biometric data. PMID- 21779661 TI - HLA class I haplotypes and progression of primary open-angle glaucoma. AB - PURPOSE: To verify if patients with primary open-angle glaucoma with HLA class I haplotypes (A9-B12, A2-B40, A1-B8) associated with this disease may have a greater rate of progression than patients who do not present these haplotypes. METHODS: Anatomical and functional glaucoma evaluation (cup-to-disc ratio and visual field) of 25 patients (six of them with one of the haplotypes associated with glaucoma) followed at the Glaucoma Outpatient Clinic of the University Hospital, Ribeirao Preto School of Medicine, Sao Paulo University (HCFMRP-USP) for ten years after typing of their HLA antigens in order to compare with their previous condition. RESULTS: A greater increase of the cup-to-disc ratio was observed in patients with HLA haplotypes associated with primary open-angle glaucoma predisposition. However, no significant differences in functional damage progression or in retinal nerve fibers loss were detected between them and other patients with glaucoma. CONCLUSION: The present results indicate an association of class I HLA haplotypes with progression of anatomic alterations of the optic nerve head in glaucomatous patients. PMID- 21779662 TI - [Vision measurement in candelas: description of a psychophysical technique to quantify luminous intensity]. AB - PURPOSE: To develop a method and a device for vision measurement in candela (cd). Vision measurement studies are important to all visual sciences. METHODS: It is a theoretical and experimental study. The details of psychophysical method and device calibration were described. Preliminary tests were performed on volunteers. RESULTS: It is a simple psychophysical test and results are expressed in International System of Units. With this technical description it will be possible to reproduce the experiment in others research centers. CONCLUSION: The results measured in luminous intensity (cd) are an option for visual studies. These results allow to extrapolate measurements for mathematical models and to simulate data for individual aberrometry effects. PMID- 21779663 TI - [Ocular surface and hepatitis C]. AB - PURPOSE: To evaluate the outcomes of the tests used for dry eye diagnosis in patients with hepatitis C virus, and to verify if there is any relationship between the duration of illness and intensity of ocular surface changes. METHODS: 25 patients with hepatitis C virus without treatment, and 29 patients with negative serologic tests for hepatitis C virus were selected. Biomicroscopy, tear film crystallization test, tear film break-up time, evaluation of the corneal staining with 1% fluorescein sodium, Schirmer I test, ocular surface staining with 1% rose bengal and esthesiometry were performed in both groups. RESULTS: In the Schirmer I test, the group of patients with hepatitis C displayed lower values in both eyes (OR p=0.0162; OS p=0.0265). For the tear film break-up time, there was a lower score in the group with hepatitis C, but it was statistically significant only in the left eye (p=0.0007). Regarding the ocular surface damage, the rose bengal staining test showed a higher average in the hepatitis group in both eyes (right p=0.0008; left p=0.0034). There was a difference in the average esthesiometry between the groups, being the average lower in infected patients (OR p=0.0006; OS p=0.0015). There was no linear association between time of hepatitis C infection and intensity observed in dry eye tests. CONCLUSIONS: Hepatitis C virus infection causes dry eye. Further researches are necessary to establish the physiopathology and the relationship with Sjogren syndrome. PMID- 21779664 TI - [Application of corrective formula for intraocular pressure changes in patients that underwent LASIK]. AB - PURPOSE: To compare the intraocular pressure (IOP) pre and post LASIK, correlating it to changes in central corneal thickness (CCT) and average simulated keratometry (K), as well as verifying the results of a corrective formula previously proposed. METHODS: Longitudinal prospective study conducted in outpatients that underwent to LASIK. Patients underwent complete ophthalmic examination, previously and 2 months after the surgery. Intraocular pressure was evaluated with Goldmann applanation tonometer between 9 am and 11 am, average simulated keratometry was evaluated using corneal topography and central corneal thickness was measured with ultrasound pachymetry, been considered the average of three measurements. Two patients were excluded due to surgery or eye disease, and previous use of topical steroids over the past three months. The surgeries were performed according to standard procedures. The formula [real IOP = IOP measured + (540 - ECC)/71 + (43 - K)/2.7 + 0.75 mmHg] proposed for correcting intraocular pressure was used. RESULTS: Fifteen eyes of eight patients were evaluated, age ranged from 24 to 46 years (mean: 31.37 +/- 7.27). There was a statistically significant difference between the measurements of intraocular pressure, central corneal thickness and average simulated keratometry pre and post-LASIK. (p=0.0001). It was observed that each 1D corrected underestimated the IOP 1.06 +/ 0.59 mmHg (0.11 a 1.89 mmHg). The use of the corrective formula lead to 80% of eyes within 2.50 mmHg of preoperative intraocular pressure. Although, the two sets of data are statistically different (p=0.0266). CONCLUSIONS: Post LASIK eyes presented lower intraocular pressure than preoperatively. Intraocular pressure was moderately correlated to central corneal thickness and weakly correlated to average simulated keratometry. With the use of the corrective formula, we were able to determine that 80% were within 2.50 mmHg of the preoperative intraocular pressure. PMID- 21779665 TI - Intraocular pressure and ocular perfusion during hemodialysis. AB - AIM: To evaluate the intraocular pressure and ocular perfusion pressure during a hemodialysis. METHODS: Sixty-seven eyes from thirty-five patients were evaluated at the beggining of hemodialysis, 2 hours and 4 hours after initiation. Intraocular pressure was evaluated using a Tonopen. Systolic and diastolic arterial pressures were measured with a manual sphygmomanometer. The ocular perfusion pressure was estimated by measuring the difference between 2/3 of the mean arterial pressure and the intraocular pressure values. Generalized estimating equations were used to evaluate the difference between the repeated measurements using the appropriate correction for inter-eye dependency. RESULTS: There was no statistically significant difference in ocular perfusion pressure, in intraocular pressure (p=0.93) and in systolic arterial pressure (p=0.92) at the three time points (p=0.69). But, when analyzing the extreme values, some patients exhibited lower diastolic perfusion pressures at all time points. CONCLUSION: Our results did not support the view that significant changes in ocular perfusion pressure and intraocular pressure occur during hemodialysis session. However, we observed that some patients exhibited lower diastolic perfusion pressures, which could be a poor prognostic factor for glaucoma patients. PMID- 21779666 TI - Comparative analysis of the nuclear lens opalescence by the Lens Opacities Classification System III with nuclear density values provided by Oculus Pentacam: a cross-section study using Pentacam Nucleus Staging software. AB - PURPOSE: To compare the clinical classification of cataract using the Lens Opacities Classification System (LOCS) III with the mean values of lens density provided by the Pentacam Scheimpflug System in nuclear cataracts. METHODS: One hundred and one eyes from 101 patients with age-related nuclear cataract were submitted to clinical examination for lens grading score using LOCS III. According to LOCS III, nuclear opalescence was divided in six groups. Patients were evaluated by the Pentacam Scheimpflug System for the mean lens density using the Pentacam lens densitometry program (PLDP), the Pentacam Nucleus Staging (PNS) mean value and the PNS cataract grading score. RESULTS: A positive correlation between the mean values of lens density and LOCS III classification, considering groups 1 to 5, could be noticed with PLDP and PNS mean value. The mean values between the groups were similar using the PLDP and the PNS mean value. However, when the PNS cataract grading score was evaluated, there was low correspondence with LOCS III classification. CONCLUSION: Pentacam Scheimpflug device offers an objective measure of the lens nuclear density on nuclear cataracts. PLDP and the PNS mean value were both useful to evaluate age-related nuclear cataract up to LOCS III group 5. PMID- 21779667 TI - [Comparison between amniotic membrane with and without epithelium as a support for human limbal epithelial cells cultured ex vivo]. AB - PURPOSE: To evaluate the efficacy and ultrastructural aspects of human limbal epithelial cells cultured on amniotic membrane (AM) with and without epithelium. METHODS: Limbal epithelial cell cultures were established from cadaveric cor neo scleral rim explants derived from 6 different donors. The explants from each donor were placed under 3 different groups: on human preserved AM with epithelium (Group 1), AM deepithelialized with trypsin (Group 2) and control (Group 3). The epithelial cell migration was evaluated under phase contrast microscopy. After 15 days, the amniotic membrane with cells cultures were removed and submitted to scanning and transmission electron microscopy to check for epithelial migration and adhesion. RESULTS: All epithelial cell cultures from the controls grew over the botton of the culture plate wells until reaching confluence. Epithelial cultures grew over all but one denuded amniotic membrane. In the group amniotic membrane with epithelium, epithelial cell growing was observed only in 1 well. CONCLUSIONS: Using this model, denuded amniotic membrane appeared to be the best substrate for epithelial cell migration and adhesion comparing to amniotic membrane with epithelium. Removal of amniotic membrane epithelial seems to be an important step for establishing limbal epithelial cell culture on amniotic membrane. PMID- 21779668 TI - Cytokeratin expression in corneal dystrophies. AB - PURPOSE: To identify an immunohistochemical pattern of epithelial markers in granular, lattice and Avellino corneal dystrophies. METHODS: Twenty-two corneal buttons, diagnosed as lattice (17), Avellino (4) and granular (1) underwent immunohistochemical studies of cytokeratins (CKs) on paraffin-embedded sections (group I). Monoclonal antibodies for pan-CK (AE1/AE3) and CKs 3/12, 5/6, 8, 18 and 19 were used. Twenty-two normal corneas were used as the control (group II). RESULTS: Six lattice and 2 Avellino cases of group I stained positively with anti CK 3/12 in corneal epithelium and areas of corneal stroma deposits. One of these cases of lattice was positive for anti-pan-CK (AE1/AE3) also in the epithelium and areas of corneal stroma deposits with a similar pattern. None of the controls (group II) revealed any staining in corneal stroma. All disease and control cases (groups I and II) revealed positive staining in corneal epithelium. CONCLUSION: AE1/AE3 and CK 3/12 anti-CK positive markers in the stromal deposits of lattice and Avellino dystrophies may suggest an epithelial genesis of the disease. PMID- 21779669 TI - [Efficacy of fibrin tissue adhesive in the attachment of autogenous conjuntival graft on primary pterygium surgery]. AB - PURPOSE: To compare the efficacy of conjunctival autograft surgery with the attachment to the scleral bed using fibrin tissue adhesive or mononylon 10-0 suture after resection of primary pterygium. METHODS: A comparative, prospective and randomized clinical trial was performed in 47 eyes of 47 patients with primary medial located pterygium. Group 1 (adhesive) was composed by 21 patients that underwent conjunctival autograft closure with fibrin tissue adhesive (QuixilTM) and Group 2 (suture) was composed by 26 patients that underwent pterygium surgery with mononylon 10-0 (Ethicon((r))) suture (suture group) after pterygium excision. All surgeries were performed by the same surgeon. Patients were assessed on the preoperative period and on the 1(st), 14(th) and 21(st) postoperative days. They were followed-up with a questionnaire of ocular discomfort and by the surgical time spent, ocular hyperemia, complications and recurrence signals, being the recurrence also evaluated at the 6th postoperative month. Data were submitted to statistical analysis. A value of p<0.005 was considered statistically significant. RESULTS: The average surgical time was 19.05 +/- 6.12 minutes in group 1 (glue) and 48.15 +/- 7.13 minutes in the group 2 (suture) (p<0.001). The ocular discomfort scale analysis showed a lower score in the 1(st) (p<0.005), 7(th) (p<0.001) and 21(th) (p<0.001) postoperative days in group 1. Ocular hyperemia was less intense in all periods of this study in group 1 (p<0.001). Complications were one in each group and both were managed with clinical treatment until the 21(th) postoperative day. There was one recurrence in group 1 and two in group 2 until the 6(th) postoperative month. CONCLUSION: In the surgical management of primary pterygium, fibrin tissue adhesive attached the conjunctival autograft, decreased the surgical time and diminished the conjunctival hyperemia and ocular discomfort with similar recurrences on the postoperative period, compared to fixation with mononylon 10.0 suture, proving to be an excellent option for conjunctival autograft attachment in primary pterygium surgery. PMID- 21779670 TI - Infectious keratitis in patients undergoing Boston Type 1 keratoprosthesis (Boston KPro) procedure: case series. AB - Description of two cases of infectious keratitis in patients after Boston Type 1 keratoprosthesis (Boston KPro) implantation. The first case refers to a patient that had the device indicated due to limbal deficiency secondary to severe dry eye who presented a fungal infection by Aerobasidium pullulans that was successfully treated with amphotericin B eye drops. The second case reports a patient with Boston KPro implantation due to previous corneal transplant rejection showing bacterial keratitis in the fourth postoperative month. The etiologic agent was identified as Streptococcus sp and topical treatment with vancomycin was effective. The importance of postoperative surveillance in Boston KPro eyes is discussed. PMID- 21779671 TI - [Bilateral cavernous sinus non-Hodgkin's lymphoma as the presenting sign of acquired immunodeficiency syndrome: case report]. AB - Case report of bilateral cavernous sinus syndrome due to primary non-Hodgkin lymphoma of the central nervous system in a patient infected by the human immunodeficiency virus. A 51-year-old male patient infected by the human immunodeficiency virus but without antiretroviral treatment developed paralysis of the V and VI cranial nerves. Imaging studies were obtained to investigate an orbital apex and a cavernous sinus syndrome. A computerized tomography scan of the orbit was normal but a high-resolution magnetic resonance imaging demonstrated bilateral enlargement of the cavernous sinus. Although primary lymphoma of the central nervous system is a rare condition, it should be considered in the differential diagnosis in immunocompromised patients who develop ocular motility abnormalities and imaging signs suggestive of infiltrative cavernous sinus lesions. PMID- 21779672 TI - [Anterior uveitis in the absence of scleritis in a patient with rheumatoid arthritis: case report]. AB - Rheumatoid arthritis is the most common collagenosis and affects almost 0.6% of Brazilian population. It is an important cause of articular deformities. The main ocular manifestation of rheumatoid arthritis is dry eyes (secondary Sjogren's syndrome), followed by scleritis, peripheral ulcerative keratitis and uveitis. The aim of this paper is to present a case of anterior uveitis in the absence of scleritis in a patient with rheumatoid arthritis, a very rare presentation in this type of patient. Female patient, 55 years old, with rheumatoid arthritis, presenting suddenly ocular pain and low vision in the right eye. Her exam showed anterior chamber reaction with hypopion, peripheral corneal keratitis and intraocular pressure of 32 mmHg. She was diagnosed with hypertensive anterior uveitis and peripheral corneal keratitis and treated with systemic and topical corticosteroids, topical antibiotic, topic and systemic ocular hypotensive and mydriatic drops. Anterior uveitis is common in rheumatological diseases, especially in those seronegative arthropathies related to HLA B27. In this paper we present a patient with rheumathoid arthritis and anterior uveitis in the absence of scleritis, a rare presentation in actual medical literature. PMID- 21779673 TI - [Scleral injury caused by needling revision with adjunctive mytomicin-C: case report]. AB - A 70-year-old female patient underwent cataract and glaucoma surgery on her left eye in 1996. Eleven years later, we performed two bleb needling revisions with adjunctive mytomicin-C, in order to decrease an uncontrolled intraocular pressure of 32 mmHg. After the second needling, she developed severe overfiltration, with flat anterior chamber, choroidal effusion, and impending corneal decompensation. Conservative treatment with cycloplegic and corticosteroid eye drops, acetazolamide and therapeutic contact lenses was unsuccessfully tried. Anterior chamber reformation was successively tried with air, 4% ophthalmic viscosurgical device and 1% sodium hyaluronate, with only temporary results. Compressive sutures above the overfiltering bleb were applied, unsuccessfully. In order to avoid additional corneal endothelium damage, a surgical bleb revision was performed and revealed a large area of ciliary body and choroidal exposure under the conjunctiva. It was covered by a donor scleral patch graft providing successful resolution. Nevertheless, we had to reintroduce hypotensive eyedrops. While bleb needling is a relatively safe and effective procedure, ophthalmologists should be aware of the possibility of potentially serious complications, such as in this case report. PMID- 21779674 TI - The genetic and molecular basis of congenital cataract. AB - Congenital cataracts are one of the most treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of 1 to 6 cases per 10,000 live births. Approximately fifty percent of all congenital cataract cases may have a genetic cause. All three types of Mendelian inheritance have been reported for cataract; however, autosomal dominant transmission seems to be the most frequent. The transparency and high refractive index of the lens are achieved by the precise architecture of the fiber cells and the homeostasis of the lens proteins in terms of their concentration, stability, and supramolecular organization. Research on hereditary congenital cataract led to the identification of several classes of candidate genes that encode proteins such crystallins, lens specific connexins, aquaporine, cytoskeletal structural proteins, and developmental regulators. The purpose of this study was to review the literature on the recent advances made in understanding the molecular genetic basis of congenital cataracts. PMID- 21779675 TI - Antiangiogenic drugs and advanced proliferative diabetic retinopathy. AB - Advanced diabetic retinopathy with tractional retinal detachment or persistent vitreous hemorrhage often requires surgical treatment with pars plana vitrectomy. Despite advances in vitrectomy, surgery for complications of diabetic retinopathy can be a challenge and may be impaired by intense fibrovascular proliferation. Antiangiogenic drugs have been used for the treatment of diabetic retinopathy because of their inhibitory action on vascular endothelial growth factor. In this review, we discuss aspects related to the adjuvant use of these drugs in vitrectomy for complications of diabetic retinopathy. Bevacizumab shows beneficial effects regarding the surgical technique facilitation, but its long term benefit still needs to be studied. PMID- 21779676 TI - Optic neuropathy and cat scratch disease. PMID- 21779677 TI - Improvement of a PCR test to diagnose infection by Mansonella ozzardi. AB - INTRODUCTION: Mansonelliasis is caused by Mansonella ozzardi. It is widespread in the Amazon region, with a high prevalence. The common exam of thick blood smears stained with Giemsa shows low efficacy levels and has been an obstacle to diagnosing individuals with low blood parasitemia. METHODS: In order to increase diagnosis efficacy, the PCR technique was improved. RESULTS AND CONCLUSIONS: PCR demonstrated the best performance, with sensitivity and negative predictive values (NPV) of 100%, followed by blood filtration through membrane filters, which showed a sensitivity of 88.9% and a NPV of 84.6%, when compared to thick blood smears. PMID- 21779678 TI - [Larvicidal activity of a crude enzyme extract of the fungus Duddingtonia flagrans on first-stage larvae of Angiostrongylus vasorum]. AB - INTRODUCTION: Angiostrongylus vasorum is a nematode parasite of domestic dogs and potentially of humans. METHODS: This study aimed to observe the predatory activity in vitro of a crude enzyme extract of the fungus Duddingtonia flagrans on first-stage larvae of A. vasorum in laboratory conditions on 2% water-agar. RESULTS: At the end of the experiment, the percentage reductions observed for A. vasorum L1 were 53.5% (24h) and 71.3% (48h). CONCLUSIONS: Crude enzyme extract of the fungus D. flagrans destroyed the L1 in vitro and can be used as a biological control for this nematode. PMID- 21779679 TI - [Control of visceral leishmaniasis in the town of Porteirinha, state of Minas Gerais, Brazil, from 1998 to 2003]. AB - INTRODUCTION: In the town of Porteirinha, State of Minas Gerais, 23 human cases of visceral leishmaniasis (VL) in 1998 and 1999 were recorded. METHODS: A study was conducted involving the triad of action recommended for the control of VL. Patients were treated and serologically positive dogs were euthanized quarterly. The pyrethroid insecticide alpha-cypermethrin was applied in the neighborhoods where human cases were recorded. RESULTS: A reduction in canine seroprevalence and sand flies occurred following the implementation of control measures, reflecting in a reduction in human cases of VL. CONCLUSIONS: The results show the efficiency of such control measures when used in association. PMID- 21779680 TI - [Destruction of Strongyloides venezuelensis infective larvae by fungi Duddingtonia flagrans, Arthrobotrys robusta and Monacrosporium sinense]. AB - INTRODUCTION: Strongyloides venezuelensis has been used as a model for studying human strongyloidosis. METHODS: This study aimed to compare the ability of predatory nematophagous fungi Duddingtonia flagrans (AC001), Arthrobotrys robusta (I-31) and Monacrosporium sinense (SF53) and on infective larvae (L3) of Strongyloides venezuelensis in laboratory conditions on 2% water-agar medium. RESULTS: At the end of the experiment, the percentage reductions of Strongyloides venezuelensi L3 were: 93% (AC001), 77.2% (I-31) and 65.2% (SF53). CONCLUSIONS: The nematophagous fungi were able to capture and destroy the L3 in vitro and can be used as biological controllers of Strongyloides venezuelensi. PMID- 21779681 TI - A first case of protease codon 35 amino acid insertion in a HIV-1 subtype B sequence detected in the Bauru region, state of Sao Paulo, Brazil: case report. AB - Amino acid insertions in the protease have rarely been described in HIV-infected patients. One of these insertions has recently been described in codon 35, although its impact on resistance remains unknown. This study presents a case of an HIV variant with an insertion in codon 35 of the protease, described for the first time in Bauru, State of Sao Paulo, Brazil, circulating in a 38-year-old caucasian male with asymptomatic HIV infection since 1997. The variant isolated showed a codon 35 insertion of two amino acids in the protease: a threonine and an aspartic acid, resulting in the amino acid sequence E35E_TD. PMID- 21779682 TI - Fatal Brazilian spotless fever caused by Rickettsia rickettsii in a dark-skinned patient. AB - Brazilian spotted fever (BSF) is the most important and frequent rickettsial disease in Brazil. A fatal case of BSF is reported in a 32-year-old black man, who died of irreversible shock after five days of fever, severe headache and abdominal pain with no rash. Spleen, kidney and heart samples collected at autopsy were positive for Rickettsia rickettsii by PCR and sequencing. The authors emphasize the need for a high index of diagnostic suspicion for spotted fever in black patients. Absence of a skin rash should not dissuade clinicians from considering the possibility of BSF and initiating empirical therapy. PMID- 21779683 TI - Recurrent herpes simplex infections: laser therapy as a potential tool for long term successful treatment. AB - Herpes simplex virus types 1 and 2 are the main infectious agents associated with oral and genital ulcerations. These infections are now widely recognized as sexually transmitted diseases. Among treatment options, low-level laser therapy (LLLT) has shown promising clinical results as a longer-lasting suppression therapy. Two clinical cases are described with recurrent labial herpes for which LLLT was used. Following treatment, both patients remained symptom free during the 17-month clinical follow-up period. PMID- 21779684 TI - [Familiar outbreak of botulism at Ceara state, Brazil: case report]. AB - Report of a family outbreak of botulism food poisoning involving a death, where gaps in the completion of medical records were identified. The study aimed to describe the pathology and emphasize to health professionals the need to provide adequate information relevant to epidemiological investigation of compulsory notification diseases. PMID- 21779685 TI - Magnetic resonance of the liver in acute schistosomiasis. PMID- 21779686 TI - Editor's note. PMID- 21779687 TI - [Homeopathic strategies: the Homeopathic League of Rio Grande do Sul in the 1940s and 1950s]. AB - Although the period following 1930 has been considered an era in which homeopathy lost ground within academia, homeopaths nevertheless were advocating for their proposals in a variety of spaces. One such instance was represented by the Homeopathic League of Rio Grande do Sul, founded in 1941, which published a journal until the 1970s, set up three free dispensaries to serve the population in Porto Alegre, and played an active role in political discussions through a group of homeopaths who endeavored to disseminate and expand homeopathic practice. An analysis of the League's Boletim de Homeopatia provides insight into homeopaths' strategies for expanding their role in Porto Alegre, capital of Rio Grande do Sul. PMID- 21779688 TI - Disfiguring disease, degeneration and climate in Colombia, 1880-1920. AB - This text aims to unite two neglected areas of study in Colombian medical historiography: disfiguring disease and the concept of climate. It seeks to show how physicians in the late nineteenth and early twentieth centuries in Colombia associate a clinical semiology of disfiguring disease with the influence of certain climatic and hereditary conditions. Characterizing disfiguring disease associated with climate implies revising the way in which, at the close of the nineteenth century, medical discourse constructed etiological explanations using the applied rationalism of the period. Thus, the ideal pathological terrain was both the body of the patient and the territory he or she inhabited. PMID- 21779689 TI - [Medical supervision of sports by the Sao Paulo State Department of Physical Education: relations between sports and medicine in the 1930s and 1940s]. AB - The article analyzes medical evaluations of athletes conducted in the early years of the Sao Paulo State Department of Physical Education's (DEF-SP) medical office, founded in 1935 to promote medical supervision of 'exercise and sports' in the state. Through sports medicine supervision, and influenced by eugenicist scientific reasoning, the DEF-SP endeavored to promote more hygienic sports habits that would mold physical types suited for certain modalities of sports. We also observed that in these early years of sports medicine in Sao Paulo, efforts were made to define the characteristics of a Brazilian physical type. PMID- 21779690 TI - [Molding soldiers, forming citizens: doctor Eduardo Augusto Pereira de Abreu, the Paraguayan War, and physical education in Brazil]. AB - The article discusses Eduardo Augusto Pereira de Abreu's Estudos higienicos sobre a educacao fisica, intelectual e moral do soldado (Hygienic studies on the physical, intellectual, and moral education of soldiers), published in 1867. Marked by the experience of the Paraguayan War, this was one of the first works that endeavored explicitly to conjoin medical and military concerns and to establish a clear link between molding a soldier and forming a citizen, both ready to defend the fatherland. Placing heavy emphasis on the practice of physical activities tied in with civism, robustness, and good health, the book both anticipated and influenced subsequent debates in Brazil on the importance of physical education. PMID- 21779691 TI - [The creation of chairs in tropical medicine in Peru and Brazil]. AB - At the 5th Latin American Congress of Medicine, held in Lima, Peru, in 1913, the idea was put forth to establish chairs in Tropical Medicine at medical schools in Latin America. Through reference to the involvement of Julian Arce and Carlos Chagas, physicians devoted to the study of tropical medicine, the article analyzes this proposal and examines the process by which the teaching of the specialty became institutionalized in Peru and Brazil. The focus is specifically on the inaugural classes given by both professors, the former speaking before the University of San Marcos Faculty of Medicine in 1916 in Lima and the latter, before the Rio de Janeiro Faculty of Medicine in 1926. The present study hopes to contribute to a deeper understanding of the distinct meanings assigned to tropical medicine in Brazil and Peru. PMID- 21779692 TI - Between black and miscegenated population groups: sickle cell anemia and sickle cell trait in Brazil in the 1930s and 1940s. AB - The article examines medical and scientific studies of sickle cell anemia published in Brazil in the 1930s and 1940s, when the vast majority of physicians and scientists believed that miscegenation played a significant role in the epidemiology of the disease in the country. Special focus is placed on hematologist Ernani Martins da Silva, of the Oswaldo Cruz Institute, who conducted blood analyses around the interior of Brazil with the purpose of classifying miscegenated and pure population groups based on the presence of sickle cells and the racial distribution of blood groups. The article explores the ambivalences stemming from associations between sickle cell anemia and the 'black race' during this period. PMID- 21779693 TI - [Chloroquine resistance and the search for antimalarial drugs from the 1960s to 1980s]. AB - In 1961, the World Health Organization (WHO) recognized that strains of Plasmodium are resistant to chloroquine, which consequently stimulated R&D programs aimed at finding new synthetic drugs to replace this substance in the fight against malaria. The article analyzes the process of scientific research into the production of antimalarial drugs from the 1960s to the 1980s in both the Brazilian and international contexts, especially the USA and China. The dynamics specific to each country and the interests tied to questions of international relations engendered points of agreement and of disagreement, with WHO playing a key role. PMID- 21779694 TI - Malaria epidemics in Europe after the First World War: the early stages of an international approach to the control of the disease. AB - The severity and endemicity of malaria declined gradually in Europe until WWI. During and after the war, the number of malaria cases increased substantially and peaked in 1922-1924. This prompted the Hygiene Commission of the League of Nations to establish a Malaria Commission in 1923 to define the most efficient anti-malaria procedures. Additionally, between 1924 and 1930 there were several international meetings and collaborations concerning malaria, which involved the main institutes of parasitology and the Rockefeller Foundation. The Commission reports, the guidelines for anti-malaria campaigns and the scientific programs which came out of these meetings and collaborations are analyzed in the present paper. PMID- 21779695 TI - Fear of the sertao: malaria and the Rondon Commission (1907-1915). AB - The article analyzes the relationships between disease, knowledge, and settlement of the Brazilian territory within the context of the Strategic Telegraph Commission from Mato Grosso to Amazonas, more famously known as the Rondon Commission. From 1907 to 1915, the commission traversed broad regions of what are now the states of Mato Grosso, Rondonia and Amazonas as part of its endeavor to set up telegraph lines that would link these regions to the country's main cities. Over time, the malaria, endemic to the places visited by the commission, forced it to abandon some of its goals and delay achievement of others. The article focuses on how the disease impacted the work of the commission and highlights creation of a sanitary service intended primarily to control malaria. PMID- 21779696 TI - Studies of avian malaria and Brazil in the international scientific context (1907 1945). AB - The article explores Brazilian investigators' contributions to research on the protozoan causative agent of malaria. Focusing on the work of Henrique Aragao and Wladimir Lobato Paraense, it underscores the importance of avian malaria in elucidating human malaria and treatment options, and also examines the network of scientific relations forged by these researchers, their shared research agendas, exchange of information with other researchers, and role within the international context of scientific discoveries. PMID- 21779697 TI - [A method called Pinotti: medicated salt, malaria, and international health (1952 1960)]. AB - The article analyzes the creation, acceptance, and abandonment of a means of fighting malaria known as the Pinotti method: kitchen salt mixed with chloroquine. The early 1950s brainchild of Brazilian malariologist Mario Pinotti, this method was intended to both prevent and treat malaria. Chloroquine-medicated salt was tested during the first half of that decade and used in Brazil from 1959 through 1961 as part of a malaria eradication campaign coordinated by the World Health Organization. The method won recognition on the world health stage, drew criticism, and underwent testing in other countries until the mid-1960s. We argue that Brazil's abandonment of the method was primarily due to the political decline of its creator, which began in 1960. PMID- 21779698 TI - [The Rondon Commission, diseases, and politics: "Regiao do Madeira: Santo Antonio," by Joaquim Augusto Tanajura - another view of the Alto Madeira in 1911]. AB - Physician Joaquim Augusto Tanajura (1878-1941), head of health services for the Rondon Commission from 1909 to 1912, wrote a paper about the first scientific journeys sponsored by the Oswaldo Cruz Institute. Entitled "Regiao do Madeira: Santo Antonio," it was published in the newspaper Jornal do Commercio de Manaos on June 5, 1911, at a time when rediscovery of Brazil's sertoes had just begun and indictments were starting to be lodged about the state of abandonment and disease in which the interior of the country lay. Through Doctor Tanajura's article, the present text analyzes both the engagement of members of the Rondon Commission in local political dynamics and the era's controversies about construction of the image of the sertao and its inhabitants. PMID- 21779699 TI - Breakthroughs towards a malaria vaccine. AB - Since the 1960s, the scientist Ruth Nussenzweig, C.V. Starr Professor at New York University School of Medicine, has been working to develop an antimalarial vaccine. In her testimony, she traces some of the stages through which her research has passed. At the beginning of her studies, most scientists held that it would be impossible to develop such a vaccine. However, a different opinion had been expressed in a paper on avian malaria written some forty years earlier by a British researcher and his collaborators from India. The immunization principle developed by this group was irradiation of sporozoites in order to deactivate the parasite that causes malaria. Ruth Nussenzweig revived and expanded upon this line of research, which now underpins her efforts to devise an antimalarial vaccine for human use. PMID- 21779701 TI - [Knowing the origins of the Brazilian psychiatric reform: the French and Italian experiences]. PMID- 21779700 TI - Health, colonialism, and development: an interview with historian Randall Packard. Interview by Gilberto Hochman, Jaime Benchimol and Magali Romero Sa. AB - Interview with Randall Packard, William H. Welch Professor of the History of Medicine at The Johns Hopkins University and co-editor of the Bulletin of the History of Medicine. Speaking about his academic career, his activities as an editor, and his main works, Professor Packard addresses the topics of health and disease in the history of Africa; the relation between disease eradication programs and the ideology of development; the malaria eradication program; medicine, international health, and colonialism; academic production in the history of medicine in the Anglo-Saxon world; and the dynamics of scientific publishing in the field of the history of medicine. PMID- 21779702 TI - [The Republic and scientific practices]. PMID- 21779703 TI - [Roquette-Pinto and well-tempered positivism]. PMID- 21779705 TI - Pulmonary impairment in rheumatoid arthritis. PMID- 21779706 TI - Analysis of the applicability of different pain questionnaires in three hospital settings: outpatient clinic, ward and emergency unit. AB - OBJECTIVE: To assess the applicability of pain assessment instruments in three hospital settings. METHODOLOGY: This study comprised 60 patients with musculoskeletal pain cared for at the Conjunto Hospitalar de Sorocaba: orthopedic ward, Rheumatology outpatient clinic, and orthopedic emergency unit. QUESTIONNAIRES: Brief Pain Inventory (BPI); McGill Pain Questionnaire (MPQ); Visual Analogue Scale for pain (VAS). RESULTS: In the emergency unit, the male sex predominated, the mean age being 35 years. In the outpatient clinic, 18 men (mean age, 42 years) and two women (mean age, 55 years) were interviewed. In the orthopedic ward, men predominated (mean age, 30.7 years). In the orthopedic emergency unit and ward, the duration of application was shorter for VAS and longer for MPQ. The VAS duration of application was the shortest and did not differ in the three settings. In the orthopedic ward and emergency unit, patients preferred the BPI, and, at the ward, the VAS was the second option. In the outpatient clinic, the patients preferred BPI (80%), followed by MPQ, while the interviewers were equally divided between those same questionnaires. In the orthopedic emergency unit, the interviewers preferred the BPI (40%), and the remaining interviewers were equally divided between the other two instruments. There was more agreement than disagreement between the preferences of patients and interviewers. CONCLUSION: The multidimensional instruments for pain assessment have limitations regarding their applicability in daily health care activities. PMID- 21779707 TI - Skeletal and cardiac muscles involvement in systemic sclerosis. AB - Patients with systemic sclerosis (SSc) can have muscle involvement in the form of myositis or non-infl ammatory myopathy. The muscle involvement can be associated with left ventricular dysfunction (LVD) in patients with SSc, resulting in worse prognosis. Eighty-seven patients of the Hospital de Clinicas of the Universidade Federal do Parana, diagnosed with SSc, were assessed regarding the presence of skeletal muscle manifestations and their relation with LVD. A 42.5% prevalence of muscle involvement was observed in the patients studied, as well as a positive correlation with the diffuse form of the disease. Excluding other causes of LVD, three of the four patients with ejection fraction below the normal reference value had alteration of the muscle strength, atrophy and/or serum creatine phosphokinase (CPK) elevation. PMID- 21779708 TI - Autoantibody profile and clinical correlation in a group of patients with systemic sclerosis in southern Brazil. AB - OBJECTIVES: To assess the manifestations of systemic sclerosis (SSc), with an emphasis on the analysis of autoantibodies and their clinical correlations, in a population of patients followed up at the SSc Outpatient Clinics of the Hospital de Clinicas of the Universidade Federal do Parana. METHODOLOGY: Cross-sectional study with 96 patients followed up at the SSc Outpatient Clinics of the hospital between September 2007 and September 2009. RESULTS: Most patients were of the female sex, in their forties or fifties, and the median time of disease was ten years. The limited cutaneous form of SSc was more prevalent. The analysis of the autoantibodies showed the association of anticentromere antibody (ACA) with the following: the limited form of SSc; more advanced age at the time of diagnosis; longer disease time; longer interval between the appearance of the Raynaud's phenomenon (RyP) and the first non-RyP symptom; systemic arterial hypertension (SAH); and cardiac conduction blocks. The antitopoisomerase-1 antibody (ATA-1, previously called anti-Scl-70) was more common in the presence of the diffuse form of SSc, active disease, and digital ulcers. The anti-RNA polymerase III antibody (anti-Pol III) correlated with the diffuse form of SSc, disease activity, and synovitis. CONCLUSIONS: This study emphasizes and confirms the important role of autoantibodies in assessing patients with SSc, allowing the correlation between the autoimmune profile of patients with SSc and specific manifestations of the disease. PMID- 21779709 TI - Pulmonary changes on high-resolution computed tomography of patients with rheumatoid arthritis and their association with clinical, demographic, serological and therapeutic variables. AB - BACKGROUND: Extra-articular manifestations are found in up to 50% of the patients with rheumatoid arthritis (RA). OBJECTIVE: To assess the prevalence of pulmonary changes on high-resolution computed tomography (HRCT) in patients with RA and their association with demographic, clinical, serological and therapeutic variables. METHOD: Seventy-one patients with RA were assessed regarding their age at RA onset, duration of disease, gender, tobacco use, presence of rheumatoid nodules, secondary Sjogren's syndrome, rheumatoid factor, presence of anti-CCP and antinuclear factor, respiratory complaints, use of medications, and pulmonary changes on HRCT. RESULTS: HRCT changes were identified in 55% of the patients, the most common being the presence of ground glass opacities, parenchymal bands, traction bronchiectasis, and honeycombing. None of the clinical variables studied associated with the HRCT findings, except for duration of the disease, which was longer in patients with pulmonary nodules and reticular lesions (ground-glass opacity). CONCLUSIONS: There is a high prevalence of HRCT changes in patients with RA, which do not associate with clinical, serological, therapeutic and demographic variables, except for duration of disease. PMID- 21779710 TI - Assessment of quality of life, muscle strength and functional capacity in women with fibromyalgia. AB - OBJECTIVE: To assess the quality of life, muscle strength and functional capacity in women with fibromyalgia (FM). PATIENTS AND METHODS: Cross-sectional study carried out with 31 female volunteers (age range, 35 to 60 years), paired in two groups (16 with FM, and 15 in the control group). Both groups underwent the following assessments: one-repetition maximum (1RM) of knee flexors and extensors; quality of life (application of the SF-36 questionnaire); 6-minute walk test (6MWT); pinch strengths (tripod, pulp-to-pulp, and key) and handgrip strength. RESULTS: A significant difference between the groups was observed in the following variables: handgrip strength; pulp-to-pulp and tripod pinch strength of both hands; and the 1RM test of knee flexors and extensors in both limbs (P < 0.05). Only the key pinch showed no statistical difference between groups for both limbs (P > 0.05). The 6MWT also showed a statistical difference between the groups (P < 0.01). The SF-36 showed that women with FM have reduced functional capacity, increased bodily pain, and worsened general health status (P < 0.05). CONCLUSION: The results revealed, in women with FM, a reduction in the following: muscle strength in the upper and lower limbs; the distance walked in the 6MWT; and quality of life. PMID- 21779711 TI - Autoimmune rheumatic diseases and their association with killer immunoglobulin like receptor genes. AB - Killer Immunoglobulin-like Receptor (KIR) genes express as receptors that activate or inhibit Natural Killer (NK) cells. The NK cells are part of the innate immune response and, through their KIR receptors, they identify target cells that have modified or different HLA (Human Leukocyte Antigen) molecules, inducing their lysis. The KIR receptors result from the expression of KIR genes (19q13.14) on the cell membrane of NK cells, which are polymorphic, and form haplotypes. The diversity of the frequency of KIR haplotypes in certain populations suggests that some individuals have different levels of protection against some diseases. The balance between cell inhibition and activation enables the NK cell to help the organism in immunological surveillance. In addition, there is evidence of the association of activating KIR genotypes with an increased risk for autoimmune disease. PMID- 21779712 TI - Drugs for the management of osteoporosis: a review. AB - Osteoporosis is characterized by low bone mass with micro architectural deterioration of bone tissue leading to enhance bone fragility, thus increasing the susceptibility to fracture. Osteoporosis is an important public health problem leading to an increased risk of developing spontaneous and traumatic fractures. In India osteoporotic fractures occur more commonly in both sexes, and may occur at a younger age than in the western countries. Although exact numbers are not available, based on available data and clinical experience, 36 million Indians may be affected by osteoporosis by 2013. This would be associated with enormous costs and considerable consumption of health resources. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in markets. At present most drugs available in the markets decrease bone loss by inhibiting bone resorption, but the upcoming therapies may increase bone mass by directly increasing bone mass as is the case of parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, selective estrogen receptor modulators and inhibitors of RANK pathway but sufficient calcium and vitamin D are a prerequisite. Newer osteoclast targeted agents like cathepsin K and c-src kinase are under clinical development. The therapies which target osteoblasts include the agents acting through the Wnt beta catenin signaling pathway like Dkk-1 inhibitors and sclerostin antagonists. To further improve pharmacological interventions and therapeutical choices in this field, improvement of knowledge is very necessary. PMID- 21779713 TI - Antimalarials and cholesterol profile of patients with systemic lupus erythematosus. AB - A beneficial influence of antimalarials on lipid profile of systemic lupus erythematosus (SLE) patients has been recently claimed. In this cross-sectional study, we evaluated the effect of chloroquine on cholesterol levels of a Brazilian population with SLE. Sixty patients were studied, 95% females. Mean age was 48.7 years (SD 13.3 years). Overweight or obesity was documented in 27 cases (45%). Thirty-four patients (56.6%) were using chloroquine in standard dosage, while 33 (55%) were on corticosteroids. Hypercholesterolemia was present in 26 patients (43.3%), while low HDL cholesterol levels were seen in 18 cases (30%). Normal cholesterolemia was documented equally in users and non-users of antimalarials (P > 0.20). After adjustment for statin and corticosteroid intake by multivariate analysis, cholesterol and HDL-cholesterol levels did not significantly differ in users or non-users of chloroquine (P > 0.05). There was no association of chloroquine intake with low body mass index (P = 0.314). Our findings suggest that antimalarial intake by itself does not distinguish cholesterol profiles in SLE patients. PMID- 21779714 TI - Poncet's arthritis: case report. AB - Poncet's disease is a rare clinical condition, characterized by polyarticular impairment in a patient diagnosed with tuberculosis, with no evidence of direct bacillary invasion of the joints, constituting reactive arthritis. We report a case of a 56-year old, white male from the city of Porto Alegre, with evidence of additive polyarthritis of the large joints, investigated for five years, and with no defined diagnosis. The patient had undergone unilateral nephrectomy five years before, and the anatomicopathological exam of the specimen revealed renal tuberculosis. The current tuberculin test was strongly reactive (PPD = 20 mm). Analysis of the synovial fluid showed no direct bacillary invasion. Tuberculostatic treatment was initiated and clinical remission occurred after two months. The diagnosis of Poncet's arthritis was established. PMID- 21779715 TI - Paraneoplastic vesiculobullous dermatomyositis with synchronic prostate and tongue tumors: case report. AB - Dermatomyositis is an inflammatory myopathy with skin manifestations. In the adult over the age of 50 years, it can be associated with malignant neoplasias, being, thus, a signal of malignancy. OBJECTIVE: To show the association of dermatomyositis of atypical presentation with two synchronous tumors, usually not related to that. CASE REPORT: We report the case of a 72-year-old male, who developed dermatomyositis, initially with only classic skin findings, which progressed to vesiculobullous lesions, and, months later, to myopathy. After extensive investigation, prostate adenocarcinoma was diagnosed. After treatment of the cancer and administration of glucocorticoid, the disease went into remission. During gradual glucocorticoid withdrawal, dermatomyositis recurred, and the new investigation revealed the presence of squamous cell carcinoma of the tongue. After treating this neoplasia, complete remission occurred, even after total corticoid withdrawal. CONCLUSION: This is a rare case involving less usual dermatomyositis presentation forms, relating to the cutaneous-muscle findings and the association with prostate and tongue tumors (tumors never reported together). This case demonstrates the importance of a careful investigation, searching for neoplasias, when approaching such patients. PMID- 21779716 TI - Bisphosphonate-related osteonecrosis of the jaws. AB - Bisphosphonates are potent inhibitors of bone resorption, and are used in the treatment of osteoporosis and other diseases that cause bone mass loss, such as Paget's disease, bone metastases, and multiple myeloma, to prevent pathological fractures. Since 2003, avascular osteonecrosis of the jaw has been associated with the use of bisphosphonates, mainly intravenous. According to the literature, the occurrence of osteonecrosis of the jaw has ranged from 0.8% to 12% of the patients on bisphosphonates, most of them on prolonged use. Physicians and odontologists should be aware of that potential complication in dental treatment. PMID- 21779719 TI - Neuroimaging in Alzheimer's disease: current role in clinical practice and potential future applications. AB - 'Alzheimer's disease is the most common cause of dementia and its prevalence is expected to increase in the coming years. Therefore, accurate diagnosis is crucial for patients, clinicians and researchers. Neuroimaging techniques have provided invaluable information about Alzheimer's disease and, owing to recent advances, these methods will have an increasingly important role in research and clinical practice. The purpose of this article is to review recent neuroimaging studies of Alzheimer's disease that provide relevant information to clinical practice, including a new modality: in vivo amyloid imaging. Magnetic resonance imaging, single photon emission computed tomography and 18F-fluorodeoxyglucose positron emission tomography are currently available for clinical use. Patients with suspected Alzheimer's disease are commonly investigated with magnetic resonance imaging because it provides detailed images of brain structure and allows the identification of supportive features for the diagnosis. Neurofunctional techniques such as single photon emission computed tomography and 18F-fluorodeoxyglucose-positron emission tomography can also be used to complement the diagnostic investigation in cases of uncertainty. Amyloid imaging is a non-invasive technique that uses positron emission tomography technology to investigate the accumulation of the beta-amyloid peptide in the brain, which is a hallmark of Alzheimer's disease. This is a promising test but currently its use is restricted to very few specialized research centers in the world. Technological innovations will probably increase its availability and reliability, which are the necessary steps to achieve robust clinical applicability. Thus, in the future it is likely that amyloid imaging techniques will be used in the clinical evaluation of patients with Alzheimer's disease. PMID- 21779718 TI - Long-term potentiation and long-term depression: a clinical perspective. AB - Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke. PMID- 21779720 TI - Future developments in brain-machine interface research. AB - Neuroprosthetic devices based on brain-machine interface technology hold promise for the restoration of body mobility in patients suffering from devastating motor deficits caused by brain injury, neurologic diseases and limb loss. During the last decade, considerable progress has been achieved in this multidisciplinary research, mainly in the brain-machine interface that enacts upper-limb functionality. However, a considerable number of problems need to be resolved before fully functional limb neuroprostheses can be built. To move towards developing neuroprosthetic devices for humans, brain-machine interface research has to address a number of issues related to improving the quality of neuronal recordings, achieving stable, long-term performance, and extending the brain machine interface approach to a broad range of motor and sensory functions. Here, we review the future steps that are part of the strategic plan of the Duke University Center for Neuroengineering, and its partners, the Brazilian National Institute of Brain-Machine Interfaces and the Ecole Polytechnique Federale de Lausanne (EPFL) Center for Neuroprosthetics, to bring this new technology to clinical fruition. PMID- 21779721 TI - Metabolism and brain cancer. AB - Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer. PMID- 21779722 TI - Insights into Alzheimer disease pathogenesis from studies in transgenic animal models. AB - Alzheimer disease is the most common cause of dementia among the elderly, accounting for ~60-70% of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing p-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5% of patients with Alzheimer disease have familial Alzheimer disease--that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble b amyloid oligomers in disease pathogenesis, as well as of the relationship between p-amyloid and Tau pathologies. PMID- 21779723 TI - Animal models of intellectual disability: towards a translational approach. AB - Intellectual disability is a prevalent form of cognitive impairment, affecting 2 3% of the general population. It is a daunting societal problem characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. Intellectual disability is a clinically important disorder for which the etiology and pathogenesis are still poorly understood. Moreover, although tremendous progress has been made, pharmacological intervention is still currently non-existent and therapeutic strategies remain limited. Studies in humans have a very limited capacity to explain basic mechanisms of this condition. In this sense, animal models have been invaluable in intellectual disability investigation. Certainly, a great deal of the knowledge that has improved our understanding of several pathologies has derived from appropriate animal models. Moreover, to improve human health, scientific discoveries must be translated into practical applications. Translational research specifically aims at taking basic scientific discoveries and best practices to benefit the lives of people in our communities. In this context, the challenge that basic science research needs to meet is to make use of a comparative approach to benefit the most from what each animal model can tell us. Intellectual disability results from many different genetic and environmental insults. Taken together, the present review will describe several animal models of potential intellectual disability risk factors. PMID- 21779724 TI - Sudden unexpected death in epilepsy: an important concern. AB - Epilepsy is one of the most common neurologic problems worldwide. Unfortunately, individuals with epilepsy are at higher risk of death than the general population, and sudden unexpected death in epilepsy is the most important direct epilepsy-related cause of death. In this review article, our research group focused on the risk factors, mechanisms and preventative measures obtained from clinical and experimental studies on sudden unexpected death in epilepsy. PMID- 21779726 TI - [The biological effect of high glucose on human periodontal ligament fibroblast]. AB - PURPOSE: The investigate the effect of high glucose on proliferation, total protein synthesis, alkaline phosphatase (ALP) activities, collagen-I(Col-I) and osteocalcin(OCN) secretion of human periodontal ligament fibroblast(hPDLF) in vitro and the regulative function of insulin in this process. METHODS: Glucose of different concentration (5.5,15,25,35and 45mmol/L) was used to culture hPDLF and insulin was used for each group as treatment control. 24 hrs after administration, cell proliferation was detected by cell counting kit (CCK-8), total protein synthesis, ALP activities, Col-I and OCN secretion were investigated. Data was analyzed with SPSS 13.0 soft ware package. RESULTS: Glucose of low concentration had no effect on biological function of hPDLF, but glucose of high concentration could inhibit proliferation, total protein synthesis, ALP activities, Col-I and OCN secretion of hPDLF significantly in a concentration-dependent manner. This effect could be blocked by insulin. CONCLUSIONS: High glucose could inhibit biological function of hPDLF and such effect could be blocked by insulin. PMID- 21779727 TI - [The effect of different concentrations of fluoride on the expression of Smad2/3 in ameloblast of rat incisor]. AB - PURPOSE: To investigate the effect of different concentrations of fluoride on the expression of Smad2/3 which is a specific intracellular signal transduction molecule of TGF-beta, and to explore the mechanism of dental fluorosis in rat. METHODS: Forty Wistar rats were randomly divided into 3 groups.HE and immunohistochemistry were used to detect the changes of the ameloblasts and the expression of Smad2/3 in rat incisors. MetaMorph microscope images analysis system and SPSS12.0 software package were used to analyze the images and data. RESULTS: Typical symptoms of dental fluorosis were found in the fluoride group. The expression of Smad2/3 in the ameloblasts in the experimental group was significantly lower than that in the control group (P<0.01); but the difference was not significant between the low-dose group and high-dose group(P>0.05). CONCLUSIONS: By inhibiting the expression of Smad2/3 in ameloblasts, fluoride affects the differentiation and development of enamel,leading to the occurrence of dental fluorosis in rat. PMID- 21779725 TI - The role of the cerebellum in schizophrenia: from cognition to molecular pathways. AB - Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia. PMID- 21779728 TI - [Isolation, cultivation and induced-mineralization of dental pulp cells from goat deciduous teeth in vitro]. AB - PURPOSE: To isolate and cultivate dental cells from goat deciduous teeth ,and explore changes of its biological characters before and after induced mineralization. METHODS: Pulp cells were cultivated with modified tissue block enzymolytic method, cell lineage in the second passage with SAB methods was checked out. Induced-mineralized cultivation was adopted in the fourth passage, some examinations were used to compare with normal cultivated cells: cell proliferative capality, mineralized ability test, cell morphology change, protein(OCN) expression level, related osteogenic genes(ALP,COL-I,OCN,OPN) expression. RESULTS: Modified tissue block enzymolytic method could culture better pulp cells derived from goat deciduous teeth. Immunohistochemical staining showed that pulp cells were from mesenchyma. MTT method showed that induced mineralization pulp cells proliferated more slowly than un-induced cells. Compared with uninduced-mineralization cells, induced-mineralization cells had stronger ALP activity and Alizarin red staining rate, its proteins(OCN) and mineralized genes(ALP,OCN) expression were significantly upregulated. CONCLUSIONS: Pulp cells can be cultivated derived from goat exfoliated deciduous teeth with modified tissue block enzymolytic method. Fourteen days after continuous induced-mineralization culture , pulp cells derived from the goat deciduous teeth might own the potential in differentiating to osteoblast and form bone-like tissue. PMID- 21779729 TI - [Preliminary study of osteoblastic effect in different contents of calcium silicate bioceramics]. AB - PURPOSE: Using beta-TCP as the control, two kinds of bioceramics were prepared to determine whether and studied bioceramics could promote new bone formation in vitro, which will lay a foundation to further study the mechanism of new bone formation. METHODS: Osteoblast-like cells from calvaria of neonatal Sprague Dawley rats (24h old) were purified and then used in this study. MTT assay demonstrated that the extracts of three kinds of materials could promote cell proliferation. Cell periods were determined by FCM. Alkaline phosphatase(ALP) activity was detected to illustrate the contents of ALP in the supernatant. SEM was used to observe cell attachment on the disc. SPSS 17.0 software package was used for data analysis. RESULTS: According to MTT assay, the amounts of cell treated extracts were increased with the growth of CS contents. The result of cell periods showed that the DNA in the period of G0/G1 of cell-treated containing CS extracts were much higher than those of beta-TCP. And at the same point, the amounts of ALP raised with the increase of CS contents in a time dependent way. SEM results found that cell attachment on the surface of discs of containing CS was better than that of pure beta-TCP.There was no significant difference between 50wt% CS and 100wt% CS. CONCLUSIONS: The abilities of cell proliferation and differentiation were increased with the growth of CS contents. The biological qualities of containing CS materials were better than those of beta-TCP. PMID- 21779730 TI - [Computational-fluid-dynamical analysis of the flow field of forearm flap with four types of venous anastomotic techniques]. AB - PURPOSE: Using the computational fluid dynamics to analyse the alteration of flow field of free forearm flap with 4 different venous anastomotic techniques, and to preliminarily explore its clinical significance. METHODS: Three dimensional geometric models of radial forearm flap with 4 types of anastomotic techniques between radial vein and recipient vessels were established by Pro/E (Wildfire 4.0) as follow: type I(matched anastomosis), type II(stump anastomosis), type III (angular anastomosis) and type IV(end-to-side anastomosis). Then the established geometric models were transferred to the SC/Tetra 8.0 software for mesh generation and calculation. Porous model was applied to the flap to simulate capillary structure as before, inlet velocity of radial artery was set as 20mm/s and outlet pressure of recipient vein as 0 Pa. By comparing pressure and velocity distribution on different cross sections of blood vessels, hemodynamic feature of the flap with 4 types of anastomotic techniques was studied, focusing on the alternation of flow field of drainage system of the flap, especially at the anastomotic sites. The data was analysed using SAS8.0 software package for ANOVA. RESULTS: The pressure on the four sections of the flap circulatory system was significantly higher in type I compared with type II, III and IV (F=40.99,P<0.001). Type II presented with vortex in the anastomotic site, and type III,IV with smooth flow. Type IV had an absorption effect at the anastomotic site. The pressure loss of the flap circulation was maximal in the radial vein of vascular pedicle(F=97.00,P<0.001). CONCLUSIONS: Type III and IV are considered appropriate techniques to deal with caliber discrepancy of recipient site. Theoretically, reasonable reduction of the vascular pedicle length and choice of the concomitant radial vein with wider radius for anastomosis can effectively decrease the resistance of circulation in the flap. PMID- 21779731 TI - [Expression of IL-6 in cyclosporin A-induced gingival overgrowth]. AB - PURPOSE: To estimate the role of IL-6 in cyclosporin A(CsA)-induced gingival overgrowth(GO) and collect the evidence of pathomechanism for CsA-induced GO. METHODS: Gingival fibroblasts and epithelial cells were treated with CsA of three different concentrations (600ng/mL, 800ng/mL, and 1000ng/mL) with different time (48h, 72h). After cell stretched preparation, the secretion of IL-6 was analyzed by ELISA while expression of IL-6 was analyzed by immunohistochemistry (ABC). SAS 6.0 software package was used for statistical analysis. RESULTS: The growth speed of gingival epithelial cells in the group treated with CsA was significantly faster than the control group (P<0.05). The IL-6 expression of gingival epithelial cells and fibroblasts had no significance difference, but changed depending on the concentration and treated time with CsA. During the first 24h, there was no significant difference between the experimental and control groups of gingival fibroblasts, while after stimulation of 1000ng/mL CsA for 24h or longer, the secretion of IL-6 in gingival fibroblasts was significantly higher than the control group (P<0.05). CONCLUSIONS: IL-6 is not the main cytokine of gingival epithelial cells, IL-6 in CsA-induced GO probably secreted by the gingival fibroblasts; the effect of CsA on the secretion of IL-6 in the gingival epithelial cells and gingival fibroblasts is associated with the time and concentrations of CsA. PMID- 21779732 TI - [Evaluation of the coronal leakage of fiber posts using different adhesive approaches]. AB - PURPOSE: To test and compare the marginal leakage of radicular dentin cemented with three resin cements. METHODS: Nine extracted maxillary incisors after endodontically treated were divided into 3 groups(n=3).Fiber posts were inserted using three resin cements: One-Step Plus/DuoLink (OD),ParaCore Automix (PA) and RelyXTM Unicem(RU).All teeth were subjected to thermocycling for 5000 cycles. All teeth were stained in 0.1% basic fuchsin for 24h and then longitudinally sectioned into four parts.Coronal leakage was evaluated. SAS 6.0 software package was used for Kruskal-Wallis test. RESULTS: Different resin cements significantly affected the coronal leakage of fiber posts(P<0.001). CONCLUSION: The system RU, which represents a new simplified self-adhesive protocol, performs the best sealing capacity. PMID- 21779733 TI - [The ultrastructural study of bonding interface between two adhesive systems and three types of dental hard tissue]. AB - PURPOSE: To compare of the morphological ultrastructure of the 7th generation self-etching adhesive Adper Easy One and two-step total etch adhesive Adper Singlebond 2 after being bonded with the composite resin. METHODS: Buccal and lingual box-like holes were made in 20 isolated human molars (5mm in diameter, 3mm in depth), and cuted to pieces from surface of middle part of root (5mm in length, 3mm in width). They were equally divided into 2 groups with 10 root slices and 10 crowns each. The cavities of crown and root pieces were respectively bonded with adhesives of Adper Singlebond 2 and Adper Easy One, and were vertically cuted open from the midline after filling with composite resin to get 20 specimens in each group. Ten specimens of root and crown were randomly selected from each group for 5000 times of thermocycling, and the remaining specimens were soaked in distilled water at room temperature for 1 month. Then all the specimens were polished with sand paper, fixed dehydrated, vacuum dried and sprayed, and the bonding interfaces of the filling edge of profile were scanned by scanning electron microscope(SEM). RESULTS: SEM photos showed that in the group of total etching Adper Singlebond 2 bonding placed at room temperature, the enamel, cementum and the resin bonded closely with the adhesive after thermocycling. In the group of self etching Adper Easy One bonding placed at room temperature, the adhesive bonded to the enamel, small cracks were occasionally seen, and resin penetration blend within the resin in dentinal tubules, and enamel bonded well to the cementum. The specimens after thermocycling bonded enamel loosely with distinct cracks,while the dentinal tubules and resin penetration integrated and cementum bonded well to the dentin. CONCLUSIONS: Ultra micro structure observation by SEM shows that Adper Singlebond 2 total etch adhesive has better bonding to enamel than the self-etching adhesive Adper Easy One, but the bonding to dentin and cementum has no significant difference. PMID- 21779734 TI - [Study on the microstructure and ESR dosimetry of tetracycline-stained teeth with SEM observation and ESR measurement]. AB - PURPOSE: To compare the microstructure and ESR dosimetry between tetracycline stained teeth and normal teeth by means of scanning electron microscopy (SEM) and electron spin resonance (ESR) dosimeter. METHODS: Ten first or second premolars of tetracycline-stained teeth and ten normal teeth extracted for adult orthodontic persons were collected. The enamel on the surface and the dentine on the cross section of both type of teeth were observed with SEM. The ESR signal of teeth components (enamel and dentine) was evaluated by X-band ESR spectroscopy. RESULTS: Compared with normal teeth, the enamel of tetracycline-stained teeth was of porosity and the enamel prisms were irregular. The dentinal tubules and dentinal matrix also showed obvious difference between the two type of teeth. The X-band ESR spectrum of tetracycline-stained teeth was different from normal teeth. CONCLUSION: The microstructure and the native radicals have significant effect on the tetracyclines deposited in the teeth. PMID- 21779735 TI - [Expression of ERK and nm23-H1 in tongue squamous cell carcinoma and its relation with invasion and metastasis]. AB - PURPOSE: To reveal the relations between expression of extracellular signal regulated kinase (ERK) and nm23-H1 and tumor invasion and metastasis in tongue squamous cell carcinoma (TSCC). METHODS: The expression of ERK and nm23-H1 at protein level was examined in 74 cases of TSCC by strep avidin-biotin complex (SABC) immunohistochemical technique. SPSS10.0 software package was used for data analysis. RESULTS: The expression of ERK was positively related to TNM clinical stage and cervical lymph node metastasis. The expression of nm23-H1 was negatively related to TNM clinical stage and cervical lymph node metastasis. The expression of ERK had a negative correlation with the expression of nm23-H1. TSCC cases with ERK(+)/nm23-H1(-) revealed significant higher tendency to cervical lymph node metastasis than those with ERK(-)/nm23-H1(+). CONCLUSION: The expression of ERK and nm23-H1 is correlated with invasion and cervical lymph node metastasis in TSCC. PMID- 21779736 TI - [Clinical application of heterogeneous acellular dermal matrix in the surgical treatment of oral submucous fibrosis]. AB - PURPOSE: The aim of this study was to evaluate the clinical effect of heterogeneous acellular dermal matrix in the surgical treatment of advanced oral submucous fibrosis (OSF). METHODS: There were eight patients who had undergone surgical treatment of trismus caused by OSF. Surgery was performed under general anaesthesia given through a nasoendotracheal tube using a fibreoptic bronchoscope. All the fibrous bands on the buccal mucosa were incised and bluntly dissected to stretch the mouth opening. Based on the defect, heterogeneous acellular dermal matrix graft was applied directly on the bilateral wounds. A tie over dressing technique was used to hold the graft firmly to its bed.The sutures and dressing material were removed on the tenth to fourteenth day after the operation. All the patients were asked to stretch the mouth opening 3 times daily and were followed up for at least 6 months. A modality of medical treatment including multiple micronutrient supplements and steroid injection therapy were carried out if necessary. The changes in the interincisal distances (IDs) were analyzed in the preoperative, intraoperative, and postoperative stages. The data was analyzed with SPSS16.0 software package for one-way ANOVA. RESULTS: The overall success rate was 100% without any or only partial graft loss. There were no immunologic reactions or significant complications.The mean preoperative, intraoperative, and final follow-up interincisal distances were 12.04, 35.46, and 29.33 mm, respectively. Evaluation of the changes in the IDs revealed statistically significant differences between the values recorded at the different stages.(P<0.05). CONCLUSIONS: Heterogeneous acellular dermal matrix may be a valuable biomaterial for repairing oral mucosal defects after surgery on the fibrous bands in patients with advanced OSF through covering and protecting wound surface early,which shortens the healing time of wound, decreases relapse of fibrosis and improve the restricted mouth opening. PMID- 21779737 TI - [Expression of RANKL/OPG in male mandible of different ages]. AB - PURPOSE: To investigate the relationship between male osteoporosis and the expression of receptor activator of NF-kappaB ligand(RANKL) and osteoprotegerin(OPG)-mRNA in male mandible at different ages. METHODS: Between May 2008 and January 2009, bone tissues of the mandible were collected as the experimental material from 46 patients suffering from jaw facial deformity and extraction. The patients with periodontist, systemic disorder and smoking as well as drinking were excluded.They were divided into three groups: young group, whose age was 10-29 years old ;middle age group, whose age was 30-59 years old; aged group, whose age was 60-89 years old. The expression of RANKL mRNA and OPG mRNA was examined by real-time PCR. The data was analyzed using ANOVA followed by least significant difference (LSD) test with SPSS16.0 software package. RESULTS: (1)Compared with the young group, RANKL mRNA level in mandible was 2.1-fold and 5.3-fold higher in the middle age and aged groups, respectively, whereas OPG mRNA level was 3.3-fold and 4.8-fold higher in middle age and aged groups, respectively. RANKL and OPG were positively correlated with age.(2)The ratio of RANKL/OPG in middle age group was lower than that of young group and old group,respectively. CONCLUSIONS: (1)The expression of RANKL and OPG increases with age remarkably.(2)Bone formation of the mandible is activated in middle aged group. The formation is over absorption.(3)Bone formation of the mandible in aged group is at low level. Bone absorption exceeds bone formation. PMID- 21779738 TI - [Clinical use of beta-tricalcium phosphate ceramics with patient's own bone in maxillary elevation with osteotome]. AB - PURPOSE: To evaluate the clinical value of using the patient's autogenous bone mixed with beta-tricalcium phosphate ceramics(beta-TCP) for maxillary sinus lift with simultaneous implantation. METHODS: Patients with loss of posterior teeth and bone height of maxillary sinus floor between 4-10mm underwent internal sinus floor elevation, the proportion of bone to beta-TCP was 1:1 and the mixture was inserted into the sinus floor. All cases had simultaneously placed ITI implants.The final crown fabrication was taken 4-6 months after implanting. RESULTS: Twenty-one implants were inserted in 16 cases, the mean increase height was 4.2mm(2-6mm). There was clinical complaint of maxillary sinus inflammation in 1 case within 2 weeks, but the symptoms disappeared after antibiotic therapy. The remaining of 20 implants had no obvious complications. All implants had loaded for 32 months and were stable and well osseointegration on X-ray film. CONCLUSIONS: Maxillary sinus elevation with simultaneous implantation is an easy procedure. Implants can be stable for a long time. PMID- 21779739 TI - [Treatment of growing Class II division 1 patients with varying degrees of anteroposterior and vertical dysplasias]. AB - PURPOSE: To evaluate the difference of treatment on growing patients with Class II division 1 using various anteroposterior and vertical skeletal dysplasias. METHODS: Twenty-eight moderate to severe Class II division 1 malocclusion patients with Class I molar and canineocclusion after treatment were selected. The subjects were divided into 3 groups based on the initial ANB and FMA angles. Pre-treatment and post-treatment cephalograms were evaluated for soft and hard tissues changes after treatment. The data was analyzed using SPSS 12.0 software package. RESULTS: ANB angle decreased in all three groups. Changes of ANB angle in group 2 and group 3 were greater than group 1(P<0.01). SNA angle decreased significantly in group 3(P<0.01). SNB angle increased significantly in group 1(P<0.01) and group 2(P<0.05). All groups had great maxillary incisors retraction and similar changes in mandibular incisor positions.Soft tissue index showed no significant difference among three groups before and after treatment(P>0.05). But nasolabial angle(P<0.05), soft tissue convexity(P<0.05) and Z angle(P<0.01) changed significantly in group 3. CONCLUSIONS: Conventional orthodontic therapy successfully corrects Class II division 1 malocclusions in growing patients with the improvement of soft and hard tissues.The patients who initially have the most severe skeletal dysplasias can have the greatest changes in profile. PMID- 21779740 TI - [Clinical observation of acupuncture and massage therapy for temporomandibular joint disorders]. AB - PURPOSE: To explore simple and effective treatment method for temporomandibular joint disorders by investigating 96 temporomandibular joint disorder patients using electroacupuncture pulse stimulation and massage therapy. METHODS: Ninety six patients with temporomandibular joint disorder including 54 patients with myofacial pain and 42 patients with external pterygoid muscle spasm, were invloved and then divided into electroacupuncture group and massage combined with electroacupuncture group equally and randomly, with 48 cases in each group. Patients in the electroacupuncture group only received electroacupuncture pulse stimulation therapy alone at the acupoints in the affected sides, including Shangguan, Xiaguan, Jiache, Tinggong and Hegu acupoint. Patients in the massage combined with electroacupuncture group underwent both electroacupuncture pulse stimulation and massage therapy. Acupoints stimulated in the two groups were same. The therapeutic effect in the two groups was compared using SPSS11.0 software package. RESULTS: The therapeutic effect of massage combined with electroacupuncture pulse stimulation therapy was more effective than electroacupuncture pulse stimulation therapy alone, especially for the patients at early stage of myofacial pain. CONCLUSIONS: Electroacupuncture pulse stimulation combined with massage therapy has a good therapeutic effect on early temporomandibular joint disorders. PMID- 21779741 TI - [Clinical observation of screw and cement-retained implant-supported restoration of fixed bridges]. AB - PURPOSE: To compare the prosthetic outcome of screw- and cement-retained implant supported restorations of the fixed bridges. METHODS: A total of 185 Straumann implants were placed in the alveolar bone of 68 partially edentulous patients from Jan. 2006 to Dec. 2007. All of them were 2 to 6 units of combination crowns with Straumann system. Then they were followed up for 3 years. In each group, the retention, influence on hard and soft tissues, passive fitting and rupture strength of the ceramic layer were evaluated. The data was analyzed with SPSS12.0 software package. RESULTS: There were more advantages of retention and the rupture strength of the ceramic layer in the cement-retained group, while there was less influence on the hard and soft tissues, and more facility of maintenance and reparation in the screwed-retained group. The difference between the two groups was statistically not significant (P>0.05). CONCLUSIONS: The clinical outcomes of implant restorations are satisfactory, either screw-retained or cement-retained. Cement retention is used in 2 to 3 unit combination crowns, while screw retention is more suitable for complicated cases. PMID- 21779742 TI - [Antifungal susceptibility test of genotypes of Candida albicans from patients with atrophic or erosive oral lichen planus]. AB - PURPOSE: To study the antifungal susceptibility of genotypes of Candida albicans from patients with atrophic or erosive oral lichen planus and provide evidence for the treatment of candidiasis. METHODS: Polymerase chain reaction(PCR) was adopted to analyze 101 Candida albicans which were isolated from atrophic or erosive oral lichen planus.Microdilution broth method was carried out for antifungal susceptibility test. SPSS16.0 software package was used for Chi-square test. RESULTS: A total of 101 strains of Candida albicans were divided into three types, 39 were genotype A strains,17 genotype B stains and 45 genotype C stains.Strains of genotype A were significantly more resistant to 5 fluorocytosine than strains of genotypes B and C(P<0.05). Strains of genotype B were significantly more resistant to fluconazole than strains of genotype A(P<0.05). Strains of genotype C were significantly more resistant to itraconazole than strains of genotype A(P<0.05).None of the strains of genotypes B and C presented drug resistance to nystatin. There was no significant difference among genotypes A,B and C(P>0.05). CONCLUSIONS: There is a correlation between Candida albicans genotypes and antifungal susceptibility. The use of antifungal agent should be based on the genotypes and antifungal susceptibility test of Candida albicans. For the treatment of candidiasis in patients with atrophic or erosive oral lichen planus, the value of nystatin should be addressed. PMID- 21779743 TI - [A short term clinical evaluation of IPS e.max Press all-ceramic crowns]. AB - PURPOSE: The aim of this study was to evaluate the clinical effect of IPS e.max Press crowns. METHODS: A total of 127 IPS e.max Press crowns was placed in forty one patients from 2007 to 2009. The crowns were evaluated with a modified USPHS criteria for color match, marginal discoloration, fracture, secondary caries, marginal adaptation and gingival health for a period of 12 to 42 months, with a mean of 28 months after insertion. A,B,C and D ratings were assigned. RESULTS: 94.49% of the crowns were rated as A and 5.51% rated as B for color match and marginal adaptation. 1.57% of the crowns was detected with marginal discoloration and one crown(0.79%) was detected with veneer chipping. No secondary caries was detected, and 93.70% of the crowns were rated as A, 4.72% rated as B and 1.58% rated as C for gingival health. CONCLUSION: IPS e.max Press crowns exhibit excellent clinical performance over a mean evaluation period of 28 months. PMID- 21779744 TI - [Measurement of the height and width of residual alveolar crests in low-set maxillary sinus patients with missing upper molar]. AB - PURPOSE: Using spiral computed tomography and Simplant software to measure the width and height of residual alveolar crest of agomphious upper molar region at different levels around bottom of low-set maxillary sinus. To evaluate the impact of sex, age, agomphious duration, and cause of tooth extraction on the width and height of residual alveolar crest. METHODS: Forty-three patients with missing uppers molar and residual alveolar bone height being 4 to 6mm showed by panoramic radiographs were scanned by spiral computed tomography. 3D model of the alveolar crest and maxillary sinus were reconstructed using the images from CT scan and Simplant software. The height and width of the residual alveolar crest of agomphious upper molar region at different levels around bottom of maxillary sinus were measured. The data was analyzed with SPSS16.0 software package for Student's t test, analysis of variance(ANOVA) and Kruskal-Wallis H test. RESULTS: (1)The mean distance between the top of residual alveolar crest and the floor of sinus was (5.26+/-0.58)mm. (2)The difference between the width of internal bone wall and that of external bone wall at different levels above the bottom of maxillary sinus was significant(P<0.01), except for agomphious upper second molar at 3.75mm. (3)The height of residual crest and width of sinus floor decreased remarkably with age and agomphious duration(P<0.01) while the width of sinus lateral walls didn't change so much with them(P>0.05). (4)Height of residual crest of the tooth extracted due to periodontitis was obviously lower than that of the tooth extracted due to residual root(crown) or crown fracture(P<0.01). CONCLUSIONS: The height and width of residual crest change significantly with age, agomphious duration and causes of tooth extraction. However, the width of lateral walls above sinus floor do not change so much with those factors. The internal wall of maxillary sinus floor is wider than the external wall at agomphious molar. This anatomic feature may be taken into consideration during implantation. The site and direction of implant can be adjusted equally according to the age, agomphious duration and causes of tooth extraction, so that maxillary sinus augmentation can be avoided in part of patients with low-set maxillary sinus. PMID- 21779745 TI - [Evaluation of the application of tooth/JIAD(KOM) implant-supported restoration]. AB - PURPOSE: To investigate the effect of tooth/implant -supported restoration. METHODS: Twenty patients were divided into 2 groups randomly. In the group A, ten patients received tooth/implant supported restoration and in the group B, ten patients received implant only restoration. The absorption rate of bone tissue, the change of soft tissue, the survival rate of the implant and the degree of patients' satisfaction were collected during the follow-up three years after treatment. The data was analyzed by SPSS 14.0 software package for Student's t test. RESULTS: The survival rate of the implants in the 2 groups was 100%. The bone tissue absorption rate in the group A was (1.0+/-0.28)mm and (1.0+/-0.23)mm in the group B, the difference was not significant(P>0.05). No significant difference was found in bone absorption, change of soft tissue and degree of patients' satisfaction. CONCLUSION: Short-term success can be achieved to use tooth/implant-supported restoration for implant without any physical mobility. PMID- 21779746 TI - [Investigation on noncarious hard tissue lesions of teeth in teachers of one university in Shanghai municipality]. AB - PURPOSE: To investigate the condition of four kinds of noncarious hard tissue lesions of the teeth in teachers of one university in Shanghai municipality and provide guidance about oral health care. METHODS: The table and the standard on oral health survey authorized by WHO were adopted, condition of four kinds of noncarious hard tissue lesions of teeth in 776 teachers of East China University of Science was investigated and analyzed using SPSS16.0 software package. RESULTS: The average wedge-shaped defect teeth was 5.54+/-3.87, the incidence was 30.41%, caries incidence of the first bicuspid was the highest(29.52%). The incidence of tetracycline pigmentation teeth was 3.09%, the incidence of enamel hypoplasia was 2.06%, and the incidence of dental fluorosis was 1.55%. CONCLUSIONS: The average wedge-shaped defect teeth is higher than the data over the country, the incidence of dental textural anomaly is lower. The behaviors of oral health care of university teachers in Shanghai municipality remains to be further strengthened. PMID- 21779747 TI - [Clinical evaluation of implant anchorage with segmental arch technique on the elongated teeth and tilted teeth]. AB - PURPOSE: To evaluate the clinical efficiency of implant anchorage combined with segmental arch technique. METHODS: Segmental arch technique of the micro-implant and adjacent teeth was used, ideal space for the superstructure of the implant was gained. RESULTS: The implant anchorage with segmental arch technique methods decreased the therapeutic process efficiency and made enough space for superstructure of the implant. CONCLUSIONS: Implant anchorage with segmental arch technique can undertake the vertical anchorage force efficiently, depress the molar safely and make enough space for superstructure of implants. PMID- 21779748 TI - [Study on the teaching mode and quality management of orthodontic education in undergraduates]. AB - Orthodontic teaching, especially in undergraduates is the most difficult part in dental education, not only on the aspect of theoretical teaching covering a wide range of disciplines in limited teaching hours, but also their application in clinical practice. With the aim of training qualified dental practitioner with global competitiveness, improving the quality of training curriculum, the Orthodontic Department of Shanghai Jiao Tong University College of Stomatology has persisted in researching and reforming the teaching system. This paper described the current situation of orthodontic teaching and the concept of quality management. Our thought on the teaching mode and quality management of orthodontic training was also discussed. PMID- 21779749 TI - [Treatment of 37 cases with panfacial fracture]. AB - PURPOSE: To report the treatment experience of panfacial fracture. METHODS: Thirty-seven patients with panfacial fracture were treated with rigid internal fixation combined with intermaxillary or craniomaxillary traction. The fracture was repositioned in the order of "from fixed to mobile and from simple to complex". RESULTS: Thirty-four cases achieved satisfactory results, with good recovery of occlusion and normal oral function. CONCLUSIONS: Panfacial fracture can be managed successfully and conveniently through a small facial incision, in the order of "from fixed to mobile and from simple to complex", combined with intermaxillary traction. PMID- 21779750 TI - Dlx2 over-expression: a possible mechanism for first branchial arch malformation. AB - The first branchial arch malformation (FBAM) is a rare congenital defect associated with anomalous development of the first and second branchial arches. Cause of FBAM still remains unknown, and is thought in most cases to be multifactorial, involving both genetic and enviromental factors. Dlx2 as a member of the Dlx homeobox gene family, plays a crucial role in the development of the first branchial arch. The tissues regulated mainly by Dlx2 are coincident with the tissues mainly involved in FBAM. Dlx2 over-expression generated by electroporation transfection can disturb the migration and differentiation of cranial neural crest cells (CNCCs), which migrate to the branchial arches and in turn give rise to much of the facial skeleton and connective tissues. Furthermore, Dlx2 over-expression can be found in the first branchial arch spontaneous mutant mice. So we hypothesize that Dlx2 over-expression mutation causes FBAM due to an increase in cell-cell adhesion and inhibiting the migration of CNCC to the first branchial arch in the early stage, or migrating to an incorrect position and can't differentiate into normal tissues. What an exact role of Dlx2 over-expression in FBAM remains to be investigated and Dlx2 over expression transgenic mouse will be a nice model for further research in FBAM. PMID- 21779751 TI - [Parotid major duct cyst: a case report]. AB - Parotid gland cyst can be congenital or acquired, which is rarely seen in clinic. Cysts in the main duct of the parotid gland are especially rare. We reported a 37 year-old man who presented with a painless mass on the right cheek. Superficial parotidectomy was performed and histopathologic examination of the specimen revealed a main parotid duct cyst. The clinical features, diagnosis, and treatment of the case were discussed and the relevant literatures were reviewed. PMID- 21779753 TI - Enapranil-induced angioedema in a 2-year-old infant: case report. PMID- 21779755 TI - [Inflammatory dermatoses]. AB - The seven basic patterns of inflammatory dermatoses according to Ackerman can be applied to infectious dermatoses. However, it should be borne in mind that infection caused by one agent may induce differing patterns according to the stage of disease. Dermatophytosis and the arthropod reaction belong to perivascular dermatoses with spongiosis. Secondary syphilis and acrodermatitis chronica atrophicans regularly show a lichenoid infiltrate with interface dermatitis, whereas epidermal involvement is typically absent in erythema migrans, virus exanthema and bacillary angiomatosis. Lupus vulgaris, atypic mycobacteriosis, lepra, actinomycosis, cutaneous leishmaniosis and erysipelas belong to the nodular and diffuse dermatoses. In the group of vasculitides, septic vasculitis is induced by a biological agent, and the pattern of vesicular dermatitis is reflected by infections with herpes viruses, impetigo contagiosa and staphylococcal scalded-skin syndrome. Follicular dermatitis shows a pattern of furuncles and carbuncles which are mainly caused by bacteria or fungi. PMID- 21779754 TI - After-hyperpolarization currents and acetylcholine control sigmoid transfer functions in a spiking cortical model. AB - Recurrent networks are ubiquitous in the brain, where they enable a diverse set of transformations during perception, cognition, emotion, and action. It has been known since the 1970's how, in rate-based recurrent on-center off-surround networks, the choice of feedback signal function can control the transformation of input patterns into activity patterns that are stored in short term memory. A sigmoid signal function may, in particular, control a quenching threshold below which inputs are suppressed as noise and above which they may be contrast enhanced before the resulting activity pattern is stored. The threshold and slope of the sigmoid signal function determine the degree of noise suppression and of contrast enhancement. This article analyses how sigmoid signal functions and their shape may be determined in biophysically realistic spiking neurons. Combinations of fast, medium, and slow after-hyperpolarization (AHP) currents, and their modulation by acetylcholine (ACh), can control sigmoid signal threshold and slope. Instead of a simple gain in excitability that was previously attributed to ACh, cholinergic modulation may cause translation of the sigmoid threshold. This property clarifies how activation of ACh by basal forebrain circuits, notably the nucleus basalis of Meynert, may alter the vigilance of category learning circuits, and thus their sensitivity to predictive mismatches, thereby controlling whether learned categories code concrete or abstract information, as predicted by Adaptive Resonance Theory. PMID- 21779757 TI - Birth size and breast cancer risk among young California-born women. AB - OBJECTIVE: Evaluate the risk of breast cancer associated with birth size among young California-born women. METHODS: Invasive breast cancer cases diagnosed 1988 2004 among women born in California during the 1960s were identified from the California Cancer Registry. Breast cancer cases (n = 3,712) were linked to their California birth records. Controls (n = 8,615) were randomly selected from California birth records for women, frequency matched to cases by birth year. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated from unconditional logistic regression. RESULTS: The adjusted OR for breast cancer associated with the highest category of birth weight (>=4,000 g) was 1.12 (95% CI 0.89-1.41), p-trend = 0.02. The adjusted OR for the highest category of birth length (>20 inches) was 1.13 (95% CI 1.02-1.25), p-trend = 0.02. These relationships appeared to be confined to cases with estrogen receptor positive (ER+) tumors (p-trend <=0.01) or progesterone receptor positive (PR+) tumors (p trend <=0.02). No significant associations were found among cases with ER or PR negative tumors. CONCLUSIONS: Our results confirm previous findings of elevated breast cancer risk associated with increases in birth size. These risks may be confined to ER+ and PR+ tumors, highlighting the potential mechanistic role of sex steroid hormonal pathways. PMID- 21779756 TI - Coexistence of obstructive sleep apnoea and metabolic syndrome is independently associated with left ventricular hypertrophy and diastolic dysfunction. AB - PURPOSE: This study was conducted to investigate the impact of the severity of obstructive sleep apnoea (OSA) and metabolic syndrome (MS) on left ventricular (LV) hypertrophy and LV diastolic function. METHODS: Echocardiography for evaluation of LV hypertrophy (defined by relative wall thickness (RWT) and LV mass index (LVMI)) and for diastolic function (defined by the early rapid/atrial filling velocity (E/A ratio)) was performed on 660 OSA patients. RESULTS: In patients with both MS and severe OSA, LVMI and RWT were significantly higher and the E/A ratios were significantly lower compared to patients with neither MS nor severe OSA. Multivariate analysis after adjustment for other descriptive variables demonstrated that (1) coexistent MS and severe OSA was independently associated with increased LVMI and RWT and (2) severe OSA, MS and coexistence of both disorders were independently associated with a decreased E/A ratio. Significant interaction between MS and severe OSA was not observed with respect to LVMI and RWT, but was observed for the E/A ratio. CONCLUSIONS: Coexistent severe OSA and MS can exacerbate LV concentric hypertrophy. However, not only the coexistence of these two disorders, but also either severe OSA or MS can impair LV diastolic function. PMID- 21779758 TI - Association of circulating VacA-neutralizing antibodies with gastric cancer and duodenal ulcer. AB - OBJECTIVE: To study the association between anti-VacA antibodies and pre neoplastic lesions (IM), gastric cancer (GC), and duodenal ulcer (DU). METHODS: A case-control study that included 347 patients, 90 with IM, 60 with GC, 52 with DU, and 145 with non-atrophic gastritis was conducted. For the analysis, a polytomous logistic regression models were used. Anti-VacA antibodies were identified in sera from these patients, either by Western blot assay (WB), using antigens produced by H. pylori s1m1 strain, or by neutralization assay challenging HeLa cells with H. pylori VacA s1m1 cytotoxin. RESULTS: Results of the WB assay showed no association between WB-anti-VacA antibodies and gastroduodenal diseases. In contrast, when antibodies that neutralize VacA cytotoxic activity were studied, a significant association was found with IM (OR 2.7, 95% CI 1.4-5.1) and DU (OR 2.3, 95% CI 1.1-4.9) and an even stronger association with GC (OR 3.9, 95% CI 1.8-8.5). A significant association with histological subtypes of GC (diffuse and intestinal) and of IM (complete and incomplete) was also found. In addition, the association showed a significant dose-response effect in the case of GC, but not of DU or IM. These associations did not change substantially after adjustment for confounding factors. MAIN CONCLUSION: This study showed that VacA-neutralizing antibodies are significantly associated with gastroduodenal diseases, especially GC, and that they might be used as risk markers of GC and DU. PMID- 21779759 TI - Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse: comparison with Fibroscan((r)). AB - BACKGROUND: Accurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan((r)) procedure. METHODS: One hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000((r))), and Fibroscan((r)) was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis. RESULTS: Elastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan((r)) method. Moreover, both ARFI and Fibroscan((r)) values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis. CONCLUSIONS: Transient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan((r)) method. PMID- 21779760 TI - The staphylococcal nuclease prevents biofilm formation in Staphylococcus aureus and other biofilm-forming bacteria. AB - The staphylococcal nuclease, encoded by the nuc1 gene, is an important virulence factor of Staphylococcus aureus. However, the physiological role of the nuclease has not been fully characterized. The current study observed that biofilm development could be prevented in staphylococcal nuclease-producing strains of S. aureus; however, when the nuc1 gene was knocked out, the ability to form a biofilm significantly increased. Scanning electron and confocal scanning laser microscopy were used to evaluate the role of the nuc1 gene in biofilm formation. Moreover, the nuc1 gene product, staphylococcal nuclease, and recombinant NUC1 protein were found to have a visible effect on other biofilm-forming bacteria, such as Pseudomonas aeruginosa, Actinobacillus pleuropneumoniae, and Haemophilus parasuis. The current study showed a direct relationship between staphylococcal nuclease production and the prevention of biofilm development. The findings from this study underscore the important role of staphylococcal nuclease activity to prevent biofilm formation in S. aureus. They also provided evidence for the biological role of staphylococcal nucleases in other organisms. PMID- 21779761 TI - Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels. AB - Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, I(K1) and I(KATP), in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ~ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited I(KATP) > I(K1). We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP(2)-Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP(2) is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP(2) and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP(2) increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP(2) lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels. PMID- 21779762 TI - Refractory dispersion promotes conduction disturbance and arrhythmias in a Scn5a (+/-) mouse model. AB - Accentuated right ventricular (RV) gradients in action potential duration (APD) have been implicated in the arrhythmogenicity observed in Brugada syndrome in studies assuming that ventricular effective refractory periods (VERPs) vary in concert with APDs. The present experiments use a genetically modified mouse model to explore spatial heterogeneities in VERP that in turn might affect conduction velocity, thereby causing arrhythmias. Activation latencies, APDs and VERPs recorded during programmed S1S2 protocols were compared in RV and left ventricular (LV) epicardia and endocardia of Langendorff-perfused wild-type (WT) and Scn5a (+/-) hearts. Scn5a (+/-) and WT hearts showed similar patterns of shorter VERPs in RV than LV epicardia, and in epicardia than endocardia. However, Scn5a (+/-) hearts showed longer VERPs, despite shorter APD(90)s, than WT in all regions examined. The pro- and anti-arrhythmic agents flecainide and quinidine increased regional VERPs despite respectively decreasing and increasing the corresponding APD(90)s particularly in Scn5a (+/-) RV epicardia. In contrast, Scn5a (+/-) hearts showed greater VERP gradients between neighbouring regions, particularly RV transmural gradients, than WT (9.1 +/- 1.1 vs. 5.7 +/- 0.5 ms, p < 0.05, n = 12). Flecainide increased (to 21 +/- 0.9 ms, p < 0.05, n = 6) but quinidine decreased (to 4.5 +/- 0.5 ms, p < 0.05, n = 6) these gradients, particularly across the Scn5a (+/-) RV. Finally, Scn5a (+/-) hearts showed greater conduction slowing than WT following S2 stimuli, particularly with flecainide administration. Rather than arrhythmogenesis resulting from increased transmural repolarization gradients in an early, phase 2, reentrant excitation mechanism, the present findings implicate RV VERP gradients in potential reentrant mechanisms involving impulse conduction slowed by partial refractoriness. PMID- 21779763 TI - Antioxidant capacity and phenolics content of apricot (Prunus armeniaca L.) kernel as a function of genotype. AB - Fourteen apricot genotypes grown under similar cultural practices in Trans Himalayan Ladakh region were studied to find out the influence of genotype on antioxidant capacity and total phenolic content (TPC) of apricot kernel. The kernels were found to be rich in TPC ranging from 92.2 to 162.1 mg gallic acid equivalent/100 g. The free radical-scavenging activity in terms of inhibitory concentration (IC(50)) ranged from 43.8 to 123.4 mg/ml and ferric reducing antioxidant potential (FRAP) from 154.1 to 243.6 FeSO(4).7H(2)O MUg/ml. A variation of 1-1.7 fold in total phenolic content, 1-2.8 fold in IC(50) by 2,2 diphenyl-1-picrylhydrazyl (DPPH) assay and 1-1.6 fold in ferric reducing antioxidant potential among the examined kernels underlines the important role played by genetic background for determining the phenolic content and antioxidant potential of apricot kernel. A positive significant correlation between TPC and FRAP (r=0.671) was found. No significant correlation was found between TPC and IC(50); FRAP and IC(50); TPC and physical properties of kernel. Principal component analysis demonstrated that genotypic effect is more pronounced towards TPC and total antioxidant capacity (TAC) content in apricot kernel while the contribution of seed and kernel physical properties are not highly significant. PMID- 21779765 TI - Symptomatic heterotopic ossification: seven years after patella fracture. AB - We describe a case of heterotopic ossification (HO) of the lateral patella becoming symptomatic after 7 years following horizontal patella fracture. The patient presented peripatellar pain in full knee flexion and kneeling position. We resected the ossification, and the patient was immediately relieved from pain and was mobilised under full weight bearing with no limitation of knee flexion. The patient was able to return to his previous level of daily activities with no further episodes of pain. To our knowledge, this is the first case of heterotopic peripatellar ossification becoming symptomatic 7 years after a patellar fracture to be reported in the literature. PMID- 21779764 TI - Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia. AB - Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3(-/-) (knockout) and ephrin-B3(+/+) (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3(-/ ) compared to ephrin-B3(+/+) mice. However, prominent post-ischemic neurogenesis in ephrin-B3(-/-) mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3(-/-) mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3(+/+) animals, infarct size in ephrin-B3(-/-) mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3(-/-) mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3 mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke. PMID- 21779766 TI - Anterior knee dislocation with ipsilateral open tibial shaft fracture: a 5-year clinical follow-up of a professional athlete. AB - Traumatic dislocation of the knee joint is an uncommon complex, multiple ligamentous injury resulting from a high-energy trauma. Significant lack of functions can be seen because of both early and late complications of these injuries such as popliteal artery disruption, peroneal nerve injury, persistent instability and posttraumatic arthritis. Therefore, the emergency surgery is necessary due to possibility of neurovascular compromise and limb loss. Controversies over operative versus closed immobilization of traumatic complex, multiple ligamentous knee injury are still debated. We report a case of traumatic anterior dislocation of the right knee with an ipsilateral tibial shaft fracture in association with right popliteal artery occlusion of a professional athlete who was returned to his sports activity by surgical treated tibia fracture and conservative treatment of the knee dislocation. PMID- 21779767 TI - Automated segmentation of blood-flow regions in large thoracic arteries using 3D cine PC-MRI measurements. AB - PURPOSE: Quantitative analysis of vascular blood flow, acquired by phase-contrast MRI, requires accurate segmentation of the vessel lumen. In clinical practice, 2D cine velocity-encoded slices are inspected, and the lumen is segmented manually. However, segmentation of time-resolved volumetric blood-flow measurements is a tedious and time-consuming task requiring automation. METHODS: Automated segmentation of large thoracic arteries, based solely on the 3D-cine phase contrast MRI (PC-MRI) blood-flow data, was done. An active surface model, which is fast and topologically stable, was used. The active surface model requires an initial surface, approximating the desired segmentation. A method to generate this surface was developed based on a voxel-wise temporal maximum of blood-flow velocities. The active surface model balances forces, based on the surface structure and image features derived from the blood-flow data. The segmentation results were validated using volunteer studies, including time-resolved 3D and 2D blood-flow data. The segmented surface was intersected with a velocity-encoded PC MRI slice, resulting in a cross-sectional contour of the lumen. These cross sections were compared to reference contours that were manually delineated on high-resolution 2D-cine slices. RESULTS: The automated approach closely approximates the manual blood-flow segmentations, with error distances on the order of the voxel size. The initial surface provides a close approximation of the desired luminal geometry. This improves the convergence time of the active surface and facilitates parametrization. CONCLUSIONS: An active surface approach for vessel lumen segmentation was developed, suitable for quantitative analysis of 3D-cine PC-MRI blood-flow data. As opposed to prior thresholding and level-set approaches, the active surface model is topologically stable. A method to generate an initial approximate surface was developed, and various features that influence the segmentation model were evaluated. The active surface segmentation results were shown to closely approximate manual segmentations. PMID- 21779768 TI - Evaluation of portable CT scanners for otologic image-guided surgery. AB - PURPOSE: Portable CT scanners are beneficial for diagnosis in the intensive care unit, emergency room, and operating room. Portable fixed-base versus translating base CT systems were evaluated for otologic image-guided surgical (IGS) applications based on geometric accuracy and utility for percutaneous cochlear implantation. METHODS: Five cadaveric skulls were fitted with fiducial markers and scanned using both a translating-base, 8-slice CT scanner (CereTom((r))) and a fixed-base, flat-panel, volume CT (fpVCT) scanner (Xoran xCAT((r))). Images were analyzed for: (a) subjective quality (i.e., noise), (b) consistency of attenuation measurements (Hounsfield units) across similar tissue, and (c) geometric accuracy of fiducial marker positions. The utility of these scanners in clinical IGS cases was tested. RESULTS: Five cadaveric specimens were scanned using each of the scanners. The translating-base, 8-slice CT scanner had spatially consistent Hounsfield units, and the image quality was subjectively good. However, because of movement variations during scanning, the geometric accuracy of fiducial marker positions was low. The fixed-base, fpVCT system had high spatial resolution, but the images were noisy and had spatially inconsistent attenuation measurements, while the geometric representation of the fiducial markers was highly accurate. CONCLUSION: Two types of portable CT scanners were evaluated for otologic IGS. The translating-base, 8-slice CT scanner provided better image quality than a fixed-base, fpVCT scanner. However, the inherent error in three-dimensional spatial relationships by the translating-based system makes it suboptimal for otologic IGS use. PMID- 21779770 TI - Hysteroscopic tubal catheterization under laparoscopy for proximal tubal obstruction. AB - PURPOSE: The purpose of this study was to investigate the fertility outcomes of infertile patients having proximal tubal obstruction treated with hysteroscopic tubal catheterization (HCT) for recanalization under diagnostic laparoscopy. METHODS: From January 2000 to December 2008, diagnostic laparoscopy was used to assess the tubal status of 61 patients with unilateral or bilateral proximal tubal obstruction, as confirmed by hysterosalpingography. Among them, 35 patients with tubal obstruction confirmed by chromopertubation under laparoscopy subsequently underwent HCT. The pregnancy outcomes and success rates of recanalization were investigated. RESULTS: In the 35 patients with confirmed tubal obstruction, HCT was performed in 54 fallopian tubes. The success rate of recanalization was 25.9% (14/54) per tube and 37.1% (13/35) per patient. Of the patients in whom tubal patency was restored, 4 achieved pregnancy, including 1 tubal pregnancy and 1 miscarriage. Among the 61 patients, excluding 14 who underwent in vitro fertilization-embryo transfer (IVF-ET) after laparoscopy, 13 were pregnant (27.7%), 9 gave live births, 1 had tubal pregnancy, and 3 had miscarriages. CONCLUSIONS: HCT under laparoscopy is an option for couples with tubal infertility who do not prefer IVF-ET. PMID- 21779769 TI - Serum nitric oxide concentrations in patients with multiple sclerosis and patients with epilepsy. AB - Nitric oxide (NO), a neurotransmitter and a free radical, has been purported to be involved in numerous neurological diseases. We investigated the serum nitric oxide concentration in 30 patients with multiple sclerosis (MS), in 30 patients with epilepsy and in 30 control subjects. The aim was also to determine whether a statistically significant difference in serum NO concentrations exists between the groups of interest. The total serum nitric oxide concentration was measured using the Griess reaction after reducing nitrates to nitrites with elemental zinc. In the group multiple sclerosis, the mean NO concentrations were X +/- SEM = 31.02 +/- 1.79 MUmol/l, in the control group X +/- SEM = 25.31 +/- 1.44 MUmol/l and in the group epilepsy X +/- SEM = 22.51 +/- 1.28 MUmol/l. Student's t test showed a statistically significant difference between subjects with multiple sclerosis and the control group (p = 0.013), as well as between the groups multiple sclerosis and epilepsy (p = 0.0002). This data confirms that NO may play an important role in the pathogenesis of multiple sclerosis, whereas its role in epilepsy still remains unclear. PMID- 21779771 TI - Learning experience using the double-console da Vinci surgical system in gynecology: a prospective cohort study in a University hospital. AB - PURPOSE: To report our preliminary experience with robotic-assisted laparoscopy in a variety of gynecological surgeries in a teaching hospital. METHOD: A total of 33 patients who underwent robotic-assisted laparoscopic procedures for gynecological diseases were included in the study. All surgeries were performed using the double-console da Vinci surgical system. Patient's demographics, surgical procedures, operative time, perioperative complications, conversion rate, hospital stay and estimated blood loss were prospectively collected. RESULTS: All procedures were completed robotically except three (9%): two cases were converted to laparotomy and one case was converted to vaginal surgery. The mean age was 47 +/- 11 and mean BMI was 23 kg/m2. Mean time taken for docking the robot was 22 min. Mean operative time was 152 min. Mean anesthesia time was 196 min. Mean hemoglobin drop was 2 g/dL. Four complications occurred: one transitory ischemic attack, one port-site hernia managed through trocar incision, one periumbilical hematoma managed conservatively and one vaginal cuff hematoma who required laparoscopy. The mean hospital stay was 4 days. CONCLUSION: With the use of robotic technology, surgeons are able to offer minimally invasive surgery to a larger percentage of patients. Double console system seems a promising tool in surgical education, improving both resident training and participation in surgeries. A shorter adaption to robotics could be expected in teams with previous experience with standard laparoscopy, however, a stepwise start with simpler cases is the key to achieve a safe adaption to robotic surgery. PMID- 21779772 TI - Endometrial cancer: prognostic significance of risk classification based on pre intraoperative findings. AB - PURPOSE: The aim of this study was to determine whether a pre-intraoperative prognostic classification of endometrial cancer (EC) patients may accurately predict prognosis. METHODS: Prognostic factors achievable before and during surgery (histotype, grade, myoinvasion, cervical spread, abdominal spread) were utilized to classify patients in low-risk (endometrial adenocarcinoma, grade 1-2, myoinvasion <50%, no evidence of abdominal spread), and in intermediate/high risk (serous papillary and clear cell, grade 3, myoinvasion >50%, cervical invasion, abdominal spread). Risk classification obtained pre-intraoperatively was compared with the classification obtained from definitive surgical-pathological assessment in 130 consecutive patients with EC treated with surgery. RESULTS: Pre intraoperative risk assessment correctly identified risk classification in 125 (96%) patients; sensitivity, specificity, PPV and NPV were 98%, 94%, 94%, and 98%, respectively. Median follow-up was 38 months (range 6-93), and 14 (10%) patients relapsed (median time 14 months, range 3-60). Relative risk of relapse was higher in intermediate/high-risk patients with both classifications (pre intraoperative RR 3.37, CI 0.99-11.5; surgical-pathological RR 4.56, CI 1.2 17.3). As regards survival 11 patients have died, 6 due to endometrial cancer and 5 due to intercurrent disease. Five-years DFS according to pre-intraoperative assessment was 89% and 71% for low-risk and intermediate high-risk patients (p = 0.028), respectively; according to definitive assessment was 91% and 70% for low risk and intermediate/high-risk patients (p = 0.009), respectively. CONCLUSION: This classification, giving an accurate risk and prognostic estimate with parameters routinely utilized in clinical practice, may help the surgeon when undertaking the decision to perform limited or extended surgical staging according to tumor and patient characteristics. PMID- 21779773 TI - 3-D ultrasound imaging of a prenatally diagnosed Beckwith-Wiedemann syndrome. PMID- 21779774 TI - Robotic-assisted laparoscopic myomectomy versus abdominal myomectomy: a comparative analysis of surgical outcomes and costs. AB - OBJECTIVE: To compare clinical and effectiveness outcomes between robotic assisted laparoscopic myomectomy (RALM) and abdominal myomectomy (AM). STUDY DESIGN: Records were reviewed for the first 27 RALM procedures at our institution. Age, BMI, insurance status, race, uterine size, and operative indication were used to select comparable patients who had undergone AM. Clinical and efficiency outcomes were compared stratifying for uterine size, specimen weight, and matched propensity scores. RESULTS: IV hydromorphone use was significantly lower for RALM (P < 0.01), with no significant differences in blood loss or complications. RALM patients had significantly shorter hospital stays; however, total hospital charges were higher (P < 0.0001). This likely reflects longer operating room time (P < 0.0001), which was magnified as specimen size increased (P < 0.0001). CONCLUSION: RALM patients require less IV hydromorphone, have shorter hospital stays, and have generally equivalent clinical outcomes compared with AM patients. Additionally, as specimen size increased, the operative efficiency of RALM decreased compared with AM. PMID- 21779775 TI - Effects of a clinical pathway 3 years after implementation in breast surgery. AB - PURPOSE: The aim of the present study is to evaluate the effects of the implementation of clinical pathways into routine practice of breast surgery. MATERIALS AND METHODS: We implemented a clinical pathway for breast surgery in 2006 and analysed for the following 3 years its path in respect to hospital stay, total costs per case, readmission rate, and patients' satisfaction. RESULTS: The mean hospital stay decreased significantly from 4.5 days in 2006 to 3.7 days in 2007 and revealed 3.4 days in 2008. This is a decrease by 24.4% for the duration of hospital stay. The total cost per case between 2006 and 2007 showed a significant decrease of 23.4%. The total costs increased by 13.4% in 2008. Readmission rate was under 5% and remained constant. Patients' satisfaction remained constant, whereby more than 90% of the expected good results were attained. CONCLUSIONS: There is substantial evidence that clinical pathways lead to various improvements in clinical care in surgery. We show a constantly significant effect on duration of hospital stay without any increase in the number of readmissions. In our view, it is not only an economic benefit which prevails here, but also especially a transparency of treatment which leads to higher compliance, better outcome and a shorter length of stay. PMID- 21779776 TI - Comparative study of oxidative stress in maternal blood with that of cord blood and maternal milk. AB - OBJECTIVE: Oxidative stress has been implicated in pregnancy-induced hypertension and preeclampsia. There is still some debate over whether this is confined to the placenta or occurs in the maternal circulation. This study was designed to investigate this question by comparing parameters of oxidative stress in samples of maternal blood and cord blood taken from normotensive and hypertensive pregnant women. A further aim was to compare these parameters in maternal milk from the two populations. STUDY DESIGN: Forty-six hypertensive (31 preeclamptic and 15 chronic hypertensive) and 60 normotensive pregnant women were recruited. Antecubital blood was collected from each woman before and after delivery, cord blood just after delivery, and maternal milk for the first 3 days postpartum. Total antioxidant capacity, total peroxides and sulphydryl concentration were measured and total antioxidant capacity calculated for each specimen. RESULTS: For all specimens (maternal blood plasma, cord blood plasma, maternal milk) total antioxidant capacity and sulphydryl concentration were significantly lower in the hypertensive women than in the normotensive, while total peroxide and oxidative stress index were significantly higher. CONCLUSION: These results support the association between hypertension in pregnancy and oxidative stress and the view that this occurs throughout the maternal circulation. They show further that oxidative stress may be transmitted from mother to newborn in maternal milk. Supplementation with antioxidants could, in view of our findings, possibly provide protection to the mother and fetus and also, through transmission in maternal milk, to the newborn. PMID- 21779777 TI - Clinical manifestations of pregnancy in patients with Takayasu arteritis: experience from a single tertiary center. AB - OBJECTIVES: Takayasu arteritis predominantly affects young women of reproductive age; therefore, the management of pregnancies with this disease is of great importance in clinical obstetrics. However, only a limited number of such cases have been reported in the English literature. Our aim in this study was to investigate the clinical features of pregnant women with Takayasu arteritis managed at a tertiary center in Japan. METHODS: We conducted a retrospective study of 26 pregnancies (18 deliveries) in 10 women with Takayasu arteritis, who were managed at Kyushu University Hospital between 1996 and 2010. Data were collected retrospectively by reviewing the maternal medical records. RESULTS: The mean age of these patients at delivery was 29.3 +/- 5.2 years. Six patients had lesions above and below the diaphragm, and four patients showed isolated supradiaphragmatic disease. Echocardiography was performed in all patients, and aortic regurgitation was observed in six. Five pregnancies resulted in spontaneous abortion, and three pregnancies were legally terminated at the patients' request. The remaining 18 pregnancies resulted in live births. Of the 18 live babies born, growth restriction was observed in 2 babies. Superimposed pregnancy-induced hypertension was observed in two cases, and other severe complications, such as cerebral hemorrhage or cardiac failure did not occur. CONCLUSION: Although Takayasu arteritis is a potentially severe condition during pregnancy, successful pregnancy is possible if extreme caution is followed. Blood pressure should be strictly controlled and the delivery should be planned for favorable maternal and fetal outcomes. PMID- 21779778 TI - Cytogenetic, Y chromosome microdeletion, sperm chromatin and oxidative stress analysis in male partners of couples experiencing recurrent spontaneous abortions. AB - PURPOSE: Etiology in majority of couples experiencing recurrent spontaneous abortions (RSA) is still unknown. The aim of the study was to find the role of cytogenetic abnormalities, Y chromosome microdeletion, oxidative stress (OS) and sperm DNA fragmentation in male partners of couples experiencing RSA. METHODS: Forty-eight couples with history of RSA and 20 fertile controls were included in the study. The study subjects were divided into male partners of RSA couples with abnormal sperm parameters (SA) (N = 16), male partners of RSA couples with normal sperm parameters (NS) (N = 32) and age-matched fertile controls with normal sperm parameters (FC) (N = 20). RESULTS: One of 48 men (2%) showed 46, XY (1qh-) chromosomal complement. None of the cases including FC showed deletion in any of the 3 AZF loci on Y chromosome long arm. Sperm count was found be significantly lower in SA cases as compared to group NS cases (P < 0.0001) and FC (P < 0.005). Sperm forward motility was found to be significantly (P < 0.05) lower in SA cases as compared to NS and FC. Male partners of RSA couples with abnormal sperm parameters had higher reactive oxygen species (ROS) levels (P < 0.005) and sperm DNA damage (P < 0.0001), however, in male partners of RSA couples with normal sperm parameters had only increased (P < 0.0001) sperm DNA damage. CONCLUSION: Other than chromosomal anomalies, sperm DNA fragmentation and seminal OS may be the underlying pathology in RSA, thus screening for seminal ROS levels and DNA fragmentation has diagnostic and prognostic capabilities. PMID- 21779779 TI - Cervical gland area: a new sonographic marker in predicting preterm delivery. AB - PURPOSE: Preterm delivery is one of the important causes of morbidity and mortality in newborns. Nowadays, a new sonographic marker is suggested for prediction of preterm delivery which is termed "Cervical Gland Area" (CGA). Absence of normal mucosal glands of the cervix can be utilized as a predictor in preterm delivery. This study was performed to evaluate the role of absence of CGA for the prediction of preterm delivery <37 weeks. METHODS: Trans-vaginal ultrasonography was performed on 600 pregnant women at 16-19 weeks of gestational age. Cervical gland area and cervical length were evaluated. Women with cervical length <25 mm were conducted to cerclage and excluded from the study. Age, number of pregnancies and history of previous preterm deliveries were recorded in questionnaires. The date of delivery was recorded. Statistical analysis was performed by version 18 SPSS and P value <0.05 was significant. RESULTS: Spontaneous preterm delivery was seen in 6.7% of all women. There was no significant difference in age, cervical length, the number of pregnancies and history of previous preterm deliveries between term pregnancies and preterm cases. CGA was detected in 77.1% of term pregnancies comparing with 55% in preterm group; which was significantly different (P value = 0.002). CONCLUSIONS: Non detection of CGA at second trimester ultrasonography is a predictor of preterm delivery. PMID- 21779780 TI - Ovarian interstitial blood flow changes assessed by transvaginal colour Doppler sonography: predicting ovarian endometrioid cyst-induced injury to ovarian interstitial vessels. AB - PURPOSE: To evaluate the blood flow changes and their relationships to microvessel density (MVD) and thrombospondin-1 (TSP-1) by transvaginal colour Doppler sonography (TV-CDS) in the ovarian interstitium to predict ovarian interstitial microvascular injury in the pathological process of ovarian endometrial cysts (OEC). METHODS: TV-CDS was preoperatively performed to detect blood flow changes in 60 patients with 76 ovarian endometrioid cysts, and flow classification and resistance indices (RI) values were recorded for analysis. Ovarian interstitial specimens with blood flow signals were collected for postoperative pathologic examination. TSP-1 protein was evaluated by immunohistochemistry and Western blot, TSP-1 mRNA by reverse transcriptase polymerase chain reaction, microvessels by CD34 antibody, and MVD by image analysis. Thirty age-matched patients with benign ovarian tumours served as controls. RESULTS: Blood flow, most of star-shaped, within ovarian interstitial arteries in the OEC group was diminished; however, arterial spectra exhibited a high-resistance flow manifesting a significantly higher RI compared with that of the control group (P < 0.01). In ovarian interstitial specimens, there were significantly (P < 0.01) lower CD34-MVD and higher TSP-1 protein and mRNA in the OEC group than in the controls. CD34-MVD and TSP-1 showed remarkably negative correlation (rs = -0.76, P < 0.01). RI values correlated negatively with MVD values (rs = -0.91, P < 0.01), but positively with TSP-1 (rs = 0.81, P < 0.01), while flow classification correlated positively with MVD values (rs = 0.66, P < 0.01), but negatively with TSP-1 (rs = -0.54, P < 0.01). CONCLUSIONS: Changes in CD34-MVD and TSP-1 reflected ovarian interstitial microvascular injury of OEC, pathologically supported the findings of blood flow changes within ovarian interstitial arteries, and prospectively predicted OEC-induced ovarian interstitial vessel injury. This has important clinical value: early treatment, instead of allowing the cyst to become bigger, is of great importance for OEC patients, because a greater number of functional tissue blood vessels would be destroyed as the disease progresses. PMID- 21779781 TI - Does progression through the stages of physical addiction indicate increasing overall addiction to tobacco? AB - RATIONALE: With physical addiction to tobacco, abstinence triggers a desire to smoke. As physical addiction advances, the desire to smoke changes in quality and intensity from wanting, to craving, to needing. A prior study in adolescents suggested that this progression signifies increasing addiction. OBJECTIVE: We sought to determine if the sequential appearance of wanting, craving and needing provides an indication of the intensity of other markers of tobacco addiction including psychological and behavioral indicators. METHODS: A web-based survey was completed by 422 smokers ages 18-78 years. Subjects were assigned to one of four qualitatively distinct stages of physical addiction based on their most advanced symptom: 1-none, 2-wanting, 3-craving, or 4-needing. Using linear Chi square and ANOVA, we determined if higher stages were associated with higher levels of tobacco addiction on more than a dozen measures. RESULTS: 16.8% of subjects were in stage 1, 26.1% in stage 2, 17.1% in stage 3 and 40.0% in stage 4. Each step up in stage was associated with higher levels of addiction as measured by the Fagerstrom Test for Nicotine Dependence, the Hooked on Nicotine Checklist, the Autonomy over Tobacco Scale, and higher levels of psychological dependence, duration of tobacco use, frequency of tobacco use, daily cigarette consumption, and 10 additional measures. CONCLUSIONS: In this cross-sectional study, each sequential stage of physical addiction was associated with higher levels of every indicator of addiction. The data suggest that the stages of progression of physical addiction provide a global indication of the severity of tobacco addiction. PMID- 21779783 TI - Expression and immunohistochemical localization of TMEM16A/anoctamin 1, a calcium activated chloride channel in the mouse cochlea. AB - Sound transduction in the cochlea depends on the unique high concentrations of K(+) in the endolymph. The production and maintenance of high K(+) concentrations are accompanied by Cl(-) cycling. In this study, we report on an investigation of the expression and localization of TMEM16A/anoctamin 1 (ANO1), a recently cloned Ca(2+)-activated Cl(-) channel, in the mouse cochlea by Western blot and immunhistochemistry. The ANO1 protein was identified in the cochlea by Western blotting. The immunoreactivity was found in stria vascularis as a line and in the organ of Corti as three plaques. The cellular localization of ANO1 was examined by means of double-labeling experiments with anti-claudin 11, a marker for basal cells of the stria vascularis. The results demonstrated that ANO1 colocalized with claudin 11, indicating its expression in basal cells. We also examined ANO1 localization in the organ of Corti by double- and triple-labeling techniques with anti-myosin VI, a marker for hair cells, and anti-synaptophysin, a marker for olivocochlear efferent nerve endings under hair cells. The results clearly showed that ANO1 is colocalized with synaptophysin, but not with myosin VI, indicating that ANO1 is localized at medial olivocochlear efferent nerve endings under outer hair cells. These results suggest that ANO1 may be specifically involved in synaptic transmission from medial olivocochlear efferent nerve endings to outer hair cells in the organ of Corti, as well as Cl(-) cycling in basal cells of the stria vascularis. PMID- 21779782 TI - Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice. AB - RATIONALE: The neuroprotective agent riluzole has antidepressant-like properties in humans, but its mechanisms of action are unclear. Despite the increasing utility of transgenic and knockout mice in addressing such issues, previous studies aimed at characterizing biochemical mechanisms have been conducted in rats. OBJECTIVES: We sought to optimize an oral riluzole administration protocol with antidepressant-like consequences in C57BL/6 mice, a common background strain in genetically modified mice. METHODS: Riluzole (6-60 MUg/ml) was dissolved in tap water and replaced regular drinking water for up to 3 weeks; sensitivity to tail suspension, forced swimming, and the locomotor response to extinction training in a model of "incentive disengagement" were tested. Peripheral and central effects of long-term 60-MUg/ml treatment were also evaluated. RESULTS: Riluzole had dose-dependent antidepressant-like effects in the forced swim test, and like chronic fluoxetine, exerted antidepressant-like actions in an adaptation of the "incentive disengagement" model at the highest concentration tested. This 60-MUg/ml concentration also restored hippocampal brain-derived neuroptrophic factor (BDNF) expression after chronic corticosteroid exposure and increased glutamate glial transporter 1 (GLT-1, or EAAT2) expression without significantly affecting baseline locomotor activity, thymus and adrenal gland weights, or blood serum corticosterone. The lowest 6-MUg/ml concentration increased locomotor activity, potentially consistent with an anxiolytic-like effect. CONCLUSIONS: Riluzole's therapeutic potential for treating mood disorders may involve GLT-1 and BDNF, and we suggest this protocol could be used to further characterize its precise long-term biochemical mechanisms of action in animal models of depression. PMID- 21779784 TI - Effect of aliskiren in patients with heart failure according to background dose of ACE inhibitor: a retrospective analysis of the Aliskiren Observation of Heart Failure Treatment (ALOFT) trial. AB - AIMS: To compare the effect of the direct renin inhibitor aliskiren on neurohumoral activity in heart failure patients treated with low-dose and high dose ACE inhibitor. METHODS: A retrospective analysis of the ALOFT trial. Comparison of the effects of 6 months treatment with aliskiren (versus placebo) in patients receiving = recommended-dose (n = 81). Neurohumoral measures included B type natriuretic peptide (BNP), NT proBNP, plasma renin activity and urinary aldosterone excretion. RESULTS: Patients in each ACE inhibitor-dose group were generally similar (those in the >= recommended ACE inhibitor-dose had higher baseline blood-pressures and LVEF and were more often female and diabetic). In the =recommended ACE inhibitor-dose sub-group were: placebo -19% (-46 to +22%) and aliskiren -46% (-22 to -62%); interaction p-value 0.94. The pattern of results for other neurohumoral markers was similar. CONCLUSIONS: Aliskiren causes neurohumoral suppression in heart failure, even in patients treated with >=recommended-dose of ACE inhibitor. PMID- 21779785 TI - The value of human chorionic gonadotropin stimulation test in predicting ovarian response during in-vitro fertilization. AB - PURPOSE: To assess the predictive value of human Chorionic Gonadotropin (hCG) theca-stimulation test for ovarian reserve in women undergoing in-vitro fertilization (IVF) treatments. METHODS: 39 women were included in the study. All participants received a single hCG 10000 IU injection on cycle day 2-3. Serum levels of estradiol, testosterone, androstenedione and 17-OH progesterone were measured prior to the injection and on days 1, 3 and 7 following the injection. hCG-induced hormone levels were compared with ovarian response during the subsequent IVF cycle. RESULTS: There were 11 good responders (>10 oocytes) and 22 low responders (<3 oocytes). Before hCG stimulation serum E2 levels were higher in low responders compared to good responders (370.3 +/- 443 vs. 138.3 +/- 54 pmol/ml). Following hCG stimulation, day 3 androstendione levels showed an increase in good responders compared to low responders. The ratio between day 3 androstendione and day 0 estradiol was significantly different between the two groups (p = 0.03). ROC analysis of this test revealed area = 0.837 (good prediction), which was much better than day 3 FSH (area = 0.635, poor prediction). CONCLUSIONS: These preliminary results demonstrate the potential use of the hCG theca stimulation test in differentiating between good and poor responders. Larger series are needed for further verification of the test in routine clinical application. PMID- 21779786 TI - Assessment of sperm chromatin condensation and ploidy status using flow cytometry correlates to fertilization, embryo quality and pregnancy following in vitro fertilization. AB - PURPOSE: Sperm flow cytometry (SFC) was used to evaluate the association of sperm chromatin condensation and ploidy with fertilization, embryo development, pregnancy and abortion rates following IVF. METHODS: Conventional semen analysis was performed in one hundred fifty men, as well as SFC analysis, after acridine orange and propidium iodide staining, for the evaluation of sperm maturity and ploidy respectively. Conventional IVF was performed in all couples. RESULTS: Couples with low percentages of mature spermatozoa presented with lower fertilization rates (p < 0.005), lower rates of grade A embryos (p < 0.003) and lower pregnancy rates (p < 0.006), compared to couples with high percentages of mature spermatozoa. Couples with low total aneuploidy rates presented with higher fertilization rates (p < 0.007), higher rates of grade A embryos (p < 0.004) and higher pregnancy rates (p < 0.003), compared to couples with high total aneuploidy rates. CONCLUSIONS: Sperm chromatin condensation and ploidy constitute critical parameters for the evaluation of semen samples before IVF and for the identification of cases in need of ICSI application. PMID- 21779787 TI - Quantitation of plasma circulating DNA using quantitative PCR for the detection of hepatocellular carcinoma. AB - Circulating DNA is a potential biomarker for tumor diagnosis and prognosis. This study was aimed to quantify the circulating DNA in plasma from patients with hepatocellular carcinoma (HCC) using quantitative PCR and evaluate its potential clinical value. Blood samples were collected from 72 patients with HCC, 37 with liver cirrhosis or chronic hepatitis and 41 healthy volunteers. Plasma DNA was extracted and quantified by a real-time quantitative PCR method. The diagnostic and prognostic value of plasma DNA analysis for HCC was evaluated. DNA levels in the HCC plasma (median: 173 ng/mL) were significantly higher than those in the healthy controls (9 ng/mL) or control benign patients (46 ng/mL) (P < 0.001). The area under the receiver-operation characteristic (ROC) curve (AUC) assessing plasma DNA was 0.949 for healthy controls and 0.874 for control patients. Plasma DNA detection could discriminate HCC from normal controls with 90.2% sensitivity and 90.3% specificity at the cut-off value of 18.2 ng/mL. Combined ROC analyses using plasma DNA and serum AFP revealed an elevated AUC of 0.974 with 95.1% sensitivity and 94.4% specificity in discriminating HCC from normal controls. The plasma DNA levels were positively associated with tumor size (P = 0.012), and were significantly elevated in HCC patients with intrahepatic spreading or vascular invasion (P = 0.035). The overall survival time of patients with high plasma DNA levels showed a shortened tread when compared with that of patients with low plasma DNA concentrations (P = 0.071). Plasma DNA may be a valuable noninvasive tool for the detecting and predicting the metastasis potential of HCC; and the prognostic value of plasma DNA needed further investigation. PMID- 21779788 TI - HGF/c-Met overexpressions, but not met mutation, correlates with progression of non-small cell lung cancer. AB - Hepatocyte Growth Factor (HGF) and its receptor c-Met are suggested to play an important role in progression of solid organ tumors by mediating cell motility, invasion and metastasis. Overexpression of HGF and c-Met have been shown in non small-cell lung cancer (NSCLC). However, their role in tumor progression is not clearly defined. The aim of this study is to determine the role of HGF/c-Met pathway and its association with invasion related markers and clinicopathologic parameters in NSCLC. Immunohistochemical analysis was performed on 63 paraffin embedded NSCLC tumor sections. The expressions of invasion related markers such as Matrix Metalloproteinases (MMPs) 2 and 9, Tissue Inhibitor Metalloproteinase (TIMP) 1 and 3 and RhoA were also examined. Co-expression of HGF/c-Met was significantly associated with lymph node invasion and TIMP-3 and RhoA overexpressions. There were positive correlation between TIMP-3 overexpression and advanced stage and negative correlation between RhoA overexpression and survival. DNA sequencing for Met mutations in both nonkinase and tyrosine kinase (TK) domain was established. A single nucleotide polymorphism (SNP) in sema domain and two SNPs in TK domain of c-Met were found. There was no statistically significant correlation between the presence of c-Met alterations and clinicopathologic parameters except shorter survival time in cases with two SNPs in TK domain. These results suggest that HGF/c-Met might exert their effects in tumor progression in association with RhoA and probably with TIMP-3. The blockade of the HGF/c-Met pathway with RhoA and/or TIMP-3 inhibitors may be an effective therapeutic target for NSCLC treatment. PMID- 21779789 TI - Team players against headache: multidisciplinary treatment of primary headaches and medication overuse headache. AB - Multidisciplinary approaches are gaining acceptance in headache treatment. However, there is a lack of scientific data about the efficacy of various strategies and their combinations offered by physiotherapists, physicians, psychologists and headache nurses. Therefore, an international platform for more intense collaboration between these professions and between headache centers is needed. Our aims were to establish closer collaboration and an interchange of knowledge between headache care providers and different disciplines. A scientific session focusing on multidisciplinary headache management was organised at The European Headache and Migraine Trust International Congress (EHMTIC) 2010 in Nice. A summary of the contributions and the discussion is presented. It was concluded that effective multidisciplinary headache treatment can reduce headache frequency and burden of disease, as well as the risk for medication overuse headache. The significant value of physiotherapy, education in headache schools, and implementation of strategies of cognitive behavioural therapy was highlighted and the way paved for future studies and international collaboration. PMID- 21779790 TI - Phylogenetic perspectives of nitrogen-fixing actinobacteria. AB - It was assumed for a long time that the ability to catalyze atmospheric nitrogen (diazotrophy) has a narrow distribution among actinobacteria being limited to the genus Frankia. Recently, the number of nitrogen fixation (nifH) genes identified in other non-Frankia actinobacteria has dramatically increased and has opened investigation on the origin and emergence of diazotrophy among actinobacteria. During the last decade, Mycobacterium flavum, Corynebacterium autotrophicum and a fluorescent Arthrobacter sp. have been reported to have nitrogenase activity, but these studies have not been further verified. Additional reports of nitrogen fixation by Agromyces, Microbacterium, Corynebacterium and Micromonospora isolated from root nodules of leguminous and actinorhizal plants have increased. For several actinobacteria, nitrogen fixation was demonstrated by the ability to grow on nitrogen-free medium, acetylene reduction activity, 15N isotope dilution analysis and identification of a nifH gene via PCR amplification. Moreover, the analyses of draft genome sequences of actinobacteria including Slackia exigua, Rothia mucilaginosa and Gordonibacter pamelaeae have also revealed the presence of nifH-like sequences. Whether these nifH sequences are associated with effective nitrogen fixation in these actinobacteria taxa has not yet been demonstrated. These genes may be vertically or horizontally transferred and be silent sequences. These ideas merit further investigation. This minireview presents a phylogenetic comparison of nitrogen fixation gene (nifH) with the aim of elucidating the processes underlying the evolutionary history of this catalytic ability among actinobacteria. PMID- 21779791 TI - The adult galactosemic phenotype. AB - BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 +/- 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 +/- 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults. PMID- 21779792 TI - Gastrointestinal disturbances and their management in miglustat-treated patients. AB - Miglustat (Zavesca(r)) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat. PMID- 21779793 TI - Cellulase production by Aspergillus japonicus URM5620 using waste from castor bean (Ricinus communis L.) under solid-state fermentation. AB - The activity of beta-glucosidase (betaG), total cellulase (FPase) and endoglucanase (CMCase), produced by Aspergillus japonicus URM5620, was studied on solid-state fermentation using castor bean meal as substrate. The effect of the substrate amount, initial moisture, pH, and temperature on cellulase production was studied using a full factorial design (2(4)). The maximum betaG, FPase, and CMCase activity was 88.3, 953.4, and 191.6 U/g dry substrate, respectively. The best enzyme activities for all three enzymes were obtained at the same conditions with 5.0 g of substrate, initial moisture 15% at 25 degrees C and pH 6.0 with 120 h of fermentation. The optimum activity for FPase and CMCase was found at pH 3.0 at an optimum temperature of 50 degrees C for FPase and of 55 degrees C for CMCase. The cellulases were stable in the range of pH 3.0-10.0 at 50 degrees C temperature. The enzyme production optimization demonstrated clearly the impact of the process parameters on the yield of the cellulolytic enzymes. PMID- 21779794 TI - Embossing of a screw thread and TCP granules enhances the fixation strength of compressed ACL grafts with interference screws. AB - PURPOSE: Fixation of soft tissue grafts with interference screws relies on the friction of the graft between the screw and the bone tunnel. The goal of this study was to precondition such grafts by mechanical compression in order to reduce anticipated and undesired viscoelastic adaptation of the graft to screw pressure. Further, the otherwise slippery graft surface was modified with impressed tricalcium phosphate granules (TCP) to improve friction and mechanical hold. METHODS: Fresh flexor digitorum tendons from young bovines were used to create bundles with a diameter of 8-9 mm and were divided into 10 groups to compare the pullout strength and bone damage in a variety of construct scenarios. Specifically, the effects of graft precompression to reduce preimplantation graft diameter were investigated. Further the effects of impressing TCP granules and/or a screw thread into the tendon surface during the compression process were studied. RESULTS: In sawbone tests, radial graft compression allowed for a smaller bone tunnel (7 mm), but resulted in a significantly lower pullout strength of 174 N (95% CI: 97, 250), compared with controls [315 N (204, 426)]. In contrast, TCP coated [402 N (243, 561)], screw embossed grafts [458 N (302, 614)], and the combination of TCP and embossing [409 N (274, 543)] achieved higher pullout strengths when compared to the standard technique. In porcine bone, untreated grafts using an 8 mm screw pulled out at 694 +/- 93 N, significantly higher loads were required to pullout compressed grafts with or without TCP coating (870 +/- 74 and 878 +/- 131 N), yet fixed with a 7 mm screw. CONCLUSION: Modification of the tendon graft surface has a large influence on the biomechanical performance of interference screw fixation and results in less bone damage inflicted during insertion to a smaller tunnel diameter, while simultaneously achieving superior pullout strength. PMID- 21779795 TI - Mechanical assessment of two different methods of tripling hamstring tendons when using suspensory fixation. AB - PURPOSE: To investigate two different methods of suture fixation and tendon behaviour when using an Endobutton and a tripled tendon. METHODS: Thirty bovine tendons and foam blocks were randomly allocated to three groups: group 1: The tendon was doubled through 40-mm Endobutton; group 2: Tripled tendon--whip stitched with No. 2 Ultrabraid, passed through an Endobutton and third limb secured to the loop via seven knots; and group 3: Tripled tendon--whip-stitched with No. 2 Fibreloop and fixed as group 2. A tunnel matching the graft diameter was drilled through the block. The graft was passed through the tunnel and fixed with an interference screw. The constructs were cycled at 1 Hz from 10 to 50 N for 10 cycles followed by 50-250 N at 1 Hz for 500 cycles. Load-to-failure test was then carried out at a rate of 20 mm/min. A custom digital image capture technique was used to measure and calculate displacement, strain and stress. Statistical analysis was carried out using Kruskal-Wallis test and paired t test. RESULTS: There was no statistical significant difference between ultimate tensile strength (UTS) (P = 0.35) and yield load (0.41) between the 3 groups. The mean displacement of the third tendon limb in group 2 was 4.8 mm and in group 3, 1.5 mm. Displacement was not statistically significant (P = 0.07). The mean stress in the third limb versus the doubled portion of tendon in group 2 was 0.4 +/- 0.02 versus 4.8 +/- 0.52 MPa and in group 3, 0.5 +/- 0.03 versus 5.2 +/- 0.52 MPa. CONCLUSIONS: In this biomechanical study, there was no mechanical difference in the overall properties between a doubled and tripled tendon graft. Significant cyclic elongation occurred in the third limb of the tripled tendon in comparison with the doubled portioned. Further work is needed to determine whether these mechanical findings translate to clinical practice. Caution should be used when tripling hamstring grafts. In particular, tripling small grafts provides no biomechanical advantage immediately and possibly long term, thus potentially increasing the risk of failure. PMID- 21779796 TI - An anatomical three-dimensional study of the posteromedial corner of the knee. AB - PURPOSE: For many years, the anatomy of the medial knee corner has been reported. However, it is not exactly clear how all these structures function together. The purpose of this study is to identify and try to understand the relationship between the posteromedial corners of the knee using three-dimensional visualization techniques. MATERIALS AND METHODS: This study comprises of 10 knees from adult corpses. Images were acquired from the dissection of different layers of the posteromedial compartment of the knee using a camera Nikon D40 and AF-S Nikkor 18-55 mm (Nikon Corp., Japan) placed on a slide bar. The pair of images was processed using Callipyan 3D or Anabuilder software (Ana builder, France) that transforms the two different images of the same structure with the intrapupillary distance proportion into one anaglyphic image. RESULTS: During knee dissection, pictures were taken and transformed into three-dimensional images that become more realistic with the use of special glasses. The images were made during the dissection of the three layers of the posteromedial compartment of the knees. CONCLUSIONS: Posteromedial corner ligament structures are quite complex and are not always clearly described in the literature. Three dimensional images of these structures can help better understanding its anatomy. PMID- 21779797 TI - Arsenic trioxide induces human pulmonary fibroblast cell death via the regulation of Bcl-2 family and caspase-8. AB - Arsenic trioxide (ATO; As(2)O(3)) can induce apoptotic cell death in various cancer cells including lung cancer cells. However, little is known about the toxicological effects of ATO on normal primary lung cells. In this study, we investigated the cellular effects of ATO on human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition and death. ATO inhibited HPF cell growth with an IC(50) of approximately 30-40 MUM at 24 h and induced cell death accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). Thus, HPF cells were considered to be very resistant to ATO insults. ATO increased the expression of p53 protein and decreased that of Bcl-2 protein. This agent activated caspase-8 but not caspase-3 in HPF cells. Z-VAD (a pan-caspase inhibitor; 15 MUM) did not significantly decrease cell growth inhibition, death and MMP (DeltaPsi(m)) loss by ATO. Moreover, administration of Bax or casase-8 siRNA attenuated HPF cell death by ATO whereas p53 or caspase-3 siRNAs did not affect cell death. In conclusion, HPF cells were resistant to ATO and higher doses of ATO induced the growth inhibition and death in HPF cells via the regulation of Bcl-2 family and caspase-8. PMID- 21779798 TI - Comparative molecular characterization of the regucalcin (RGN) gene in rainbow trout (Oncorhynchus mykiss) and maraena whitefish (Coregonus marena). AB - The Ca(2+)-binding protein regucalcin (RGN) is crucial for the regulation of Ca(2+) ion homeostasis and signal transduction of cells. It is involved in the regulation of Ca(2+)-dependent protein kinases and Ca(2+) pump enzymes in cell membranes. Comparative transcriptome analysis in healthy fish of two aquacultured rainbow trout (Oncorhynchus mykiss) lines (BORN, TCO) varying in susceptibility to environmental stress identified significant differences in the expression of the RGN gene. Therefore, we firstly determined the full genomic DNA and cDNA sequence of RGN gene from rainbow trout and comparatively investigated the complete cDNA sequence in another salmonid fish dedicated for local aquaculture, the maraena whitefish (Coregonus marena). The sequence coding region translates for proteins of 298 and 299 amino acids (aa), respectively, indicating a high conservation of RGN proteins (95.7% aa identity) between the two related salmonids. In the second place, we generated RGN gene expression profiles after pathogen (Aeromonas salmonicidae subsp. salmonicida) and temperature (8 and 23 degrees C) challenge in the two rainbow trout lines using salmon microarrays and quantitative RT-PCR. The profiles not only verified initially detected gene expression differences, they also display a tissue specific gene expression in dependence from the stressor and time. The differences in gene expression support our assumption that RGN might play a role in recovery of rainbow trout after environmental stress. PMID- 21779799 TI - Neglected role of cAMP receptor protein monomer. AB - Lac operon transcription activation through CRP dimer depends on cAMP second messenger. The formation of CRP homodimers is mediated by protein-protein interactions between the monomers. Cyclic AMP ligand binding brings CRP dimer to an active state via conformational changes. Molecular modeling studies in our lab showed the importance of monomer in transcription activation through its pre existing conformational state. Until now CRP experiments were carried out at protein concentrations higher than that of CRP dimer dissociation value making all CRP monomers dimer and ignore the importance of CRP monomer in allosteric activation. Labeling CRP monomers with fluorophores exterminate using excess protein concentration and allow monitoring CRP monomer behavior. CRP monomer exchange accelerates in the presence of non specific DNA whereas the exchange is inhibited in the presence of specific DNA and cAMP ligand. Degree of subunit exchange depends on the stability of CRP dimer. Cyclic AMP forms a single molecule from two monomers and addition of specific DNA further stabilizes CRP dimer and decreases monomer exchange. On the other hand, addition of non specific DNA increases CRP monomer exchange and may explain the mechanism of CRP monomer removal and dissociation of CRP dimer:cAMP:DNA complex. The exchange behavior of CRP in the presence of different factors implies importance of monomer in transcription complex association and dissociation. PMID- 21779800 TI - The increased expression of DEC1 gene is related to HIF-1alpha protein in gastric cancer cell lines. AB - Overexpression of differentiated embryo chondrocyte 1 (DEC1) has been reported to contribute to the cellular differentiation, proliferation, and apoptosis of various cancers. Our previous studies have shown that DEC1 was highly expressed in gastric cancer (GCa) tissues. However, there is no report about the expression of DEC1 in GCa cell lines until now. In this study, We evaluated the mRNA and protein expression of DEC1 and hypoxia-inducible factor 1alpha (HIF-1alpha) under normoxic and hypoxic conditions in six GCa cell lines: BGC-823, MGC80-3, MKN1, AGS, FU97 and SGC-7901. An HIF-1alpha protein inhibitor was used to analyze the association of DEC1 and HIF-1alpha expression. Under normoxia, the mRNA expression of both HIF-1alpha and DEC1 was moderate, whereas the protein expression of DEC1 was higher than that of HIF-1alpha. Hypoxia induced the mRNA expression of DEC1 and the protein expression of HIF-1alpha and DEC1 in a time dependent manner but had no effect on the mRNA expression of HIF-1alpha. Furthermore, inhibition of HIF-1alpha protein expression resulted in a significant decrease in both the mRNA and protein expression of DEC1. Taken together, DEC1 expression is correlated with HIF-1alpha protein in GCa cell line, blockage of HIF-1alpha protein led to reduced DEC1 expression. The efficacy of inhibiting HIF-1alpha and DEC1 expression should be tested in clinical trials as possible treatment for GCa. PMID- 21779801 TI - Molecular characterization and expression analysis of a glycine-rich RNA-binding protein gene from Malus hupehensis Rehd. AB - Members of the plant glycine-rich RNA-binding protein (GR-RBP) family play diverse roles in regulating RNA metabolism for various cellular processes. To understand better their function at the molecular level in stress responses, we cloned a GR-RBP gene, MhGR-RBP1, from Malus hupehensis. Its full-length cDNA is 558 bp long, with a 495-bp open reading frame, and it encodes 164 amino acids. The deduced amino acid sequence contains an RNA-recognition motif (RRM) at the amino terminal and a glycine-rich domain at the carboxyl terminal; these are highly homologous with those from other plant species. Multiple alignment and phylogenetic analyses show that the deduced protein is a novel member of the plant GR-RBP family. To characterize this gene, we also applied a model for predicting its homology of protein structure with other species. Both organ specific and stress-related expression were detected by quantitative real-time PCR and semi-quantitative RT-PCR, indicating that MhGR-RBP1 is expressed abundantly in young leaves but weakly in roots and shoots. Transcript levels in the leaves were increased markedly by drought, hydrogen peroxide (H(2)O(2)), and mechanical wounding, slightly by salt stress. Furthermore, the transcript is initially up- and down-regulated rapidly within 24 h of abscisic acid (ABA) treatment. After 24 h of ABA and jasmonic acid (JA) treatments with different concentrations, the transcript levels of MhGR-RBP1 were significantly repressed. These results suggest that MhGR-RBP1 may be involved in the responses to abiotic stresses, H(2)O(2), ABA, or JA. PMID- 21779802 TI - Variation in the IGF2 gene promoter region is associated with intramuscular fat content in porcine skeletal muscle. AB - Intramuscular fat (IMF) and subcutaneous fat (back fat-BF) are two of the major fat depots in livestock. A QTN located in the insulin-like growth factor 2 gene (IGF2) has been associated with a desirable reduction in BF depth in pigs. Given that the lipid metabolism of intramuscular adipocytes differs from that of subcutaneous fat adipocytes, this study aimed to search for genetic variation in the IGF2 gene that may be associated with IMF, as well as BF, in diverse pig breeds. Four proximal promoter regions of the IGF2 gene were characterised and the association of IGF2 genetic variation with IMF and BF was assessed. Six promoter SNPs were identified in four promoter regions (P1-P4; sequence coverage 945, 866, 784 and 864 bp, respectively) in phenotypically diverse F1 cross populations. Three promoter SNPs were subsequently genotyped in three pure breeds (Pietrain = 98, Duroc = 99 and Large White = 98). All three SNPs were >95% monomorphic in the Pietrain and Duroc breeds but minor alleles were at moderate frequencies in the Large White breed. These SNPs were linked and one was located in a putative transcription factor binding site. Five haplotypes were inferred and three combined diplotypes tested for association with IMF and BF in the Large White. As expected haplotype 1 (likely in LD with the beneficial QTN allele) was superior for BF level. In contrast, the heterozygote diplotype of the most common haplotypes (1 and 2) was associated with higher IMF and marbling scores compared to either homozygote. Gene expression analysis of divergent animals showed that IGF2 was 1.89 fold up-regulated in muscle with higher compared to lower IMF content. These findings suggest that genetic variation in the promoter region of the IGF2 gene is associated with IMF content in porcine skeletal muscle and that greater expression of the IGF2 gene is associated with higher IMF content. PMID- 21779803 TI - Renin-angiotensin system polymorphisms in relation to hypertension status and obesity in a Tunisian population. AB - Essential hypertension (HTA) is the clinical expression of a disordered interaction between the genetic, physiological, and biochemical systems that under usual conditions maintain cardiovascular homeostasis. We studied the effects of the angiotensinogen M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of HTA and to evaluate the relationship between these polymorphisms and obesity. We performed AGT, ACE and AGTR genotyping in 142 hypertensive patients and 191 control subjects using PCR-RFLP methods and PCR, respectively. The three polymorphisms were significantly associated with HTA. Individuals carrying the mutated TT of AGT, DD of ACE and CC of AT1R genotypes had an 1.67 (P = 0.032), 3.09 (P < 0.001) and 3.45 (P < 0.001)-fold increased risk of HTA. After adjustment for sex, smoking, diabetes, dyslipidemia, BMI, triglycerides and DD, TT and CC genotypes, BMI was independent risk factor of HTA (OR = 3.14; P < 0.001). An association of BMI with ACE gene polymorphism (P = 0.035), whereas no association with AGT and AT1R gene polymorphisms was obtained. The proportion of hypertensives is as high as 21.8 and 13.4% in the overweight and the obese DD group. The present study implies that the genotyping for the variants of RAS gene could in the future become an important part of the clinical process of risk identification for HTA. PMID- 21779804 TI - Molecular characterization, tissue expression, polymorphism and association of porcine LCK gene. AB - Lymphocyte-specific protein tyrosine kinase (LCK) is an important reproduction related gene. In this study, the full-length cDNA sequence of porcine LCK gene was cloned through the rapid amplification of cDNA ends (RACE) method. The porcine LCK gene encodes a protein of 509 amino acids which shares high homology with the LCK of nine species: giant panda (97%), dog (97%), cattle (96%), sheep (95%), rabbit (95%), human (96%), rat (94%), mouse (94%) and horse (94%). This novel porcine gene was assigned to GeneID: 100233188. The phylogenetic analysis revealed that the porcine LCK gene has a closer genetic relationship with the LCK gene of dog. This gene is structured in twelve exons and eleven introns as revealed by computer-assisted analysis. The tissue transcription profile analysis indicated that the porcine LCK gene is generally but differentially expressed in the detected tissues including large intestine, spleen, lung, muscle, fat, liver, heart, kidney and ovary. PCR-Alu I-RFLP was established to detect an A/G substitution at the position of 1127-bp of mRNA and eight pig breeds displayed obvious genotype and allele frequency differences at this mutation locus. Association of this single-nucleotide polymorphism with litter size traits was assessed in Large White (n = 100) and Landrace (n = 100) pig populations, and results demonstrated that this polymorphic locus was significantly associated with the litter size of all parities in Large White sows and Landrace sows (P < 0.01). Therefore, LCK gene could be an useful candidate gene in selection for increasing litter size in pigs. These data serve as a foundation for further insight into this novel porcine gene. PMID- 21779805 TI - Heat stress activates ER stress signals which suppress the heat shock response, an effect occurring preferentially in the cortex in rats. AB - Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2alpha phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress. PMID- 21779806 TI - Molecular characterization of growth differentiation factor 9 and its spatio temporal expression pattern in gibel carp (Carassius auratus gibelio). AB - Growth differentiation factor 9 (GDF9) is a member of the transforming growth factor beta (TGF-beta) superfamily with a key role in regulating follicle development. In this study, the GDF9 full-length genomic DNA and cDNA were isolated and characterized from the gibel carp ovary using rapid-amplification of cDNA ends (RACE) and LD-PCR. The full-length genomic DNA and cDNA sequences of GDF9 are 3979 and 2044 bp which code 428 amino acid residues with a specific RKKR protease cleavage site of TGF-beta superfamily. Sequence analysis showed that gibel carp was similar to zebrafish and other fish species. Spatio-temporal expression analysis using real-time quantitative PCR revealed that GDF9 mRNA was largely expressed in ovary and testis. GDF9 is mainly present at stage I follicles indicating its important role in early follicles development. The same result was obtained in immunohistochemistry localization of GDF9 protein. Within the follicle, the follicle layer cells were barely expressed whereas GDF9 mRNA was mostly expressed in the oocytes. Supplemented with human chorionic gonadotropin (hCG) in isolated follicles, the expression of GDF9 mRNA was increased firstly and then decreased. The results of this study indicated that GDF9 gene played a role in fish during development of follicles, especially in the early stage follicles. PMID- 21779807 TI - Molecular aspects on the interaction of isatin-3-isonicotinylhydrazone to deoxyribonucleic acid: model for intercalative drug-DNA binding. AB - Isatin-3-isonicotinylhydrazone was synthesized and characterized. The interaction of native calf thymus DNA with isatin-3-isonicotinylhydrazone (IINH) in 10 mM Tris-HCl aqueous solutions at neutral pH 7.4 has been investigated by spectrophotometric, circular dichroism (CD), melting temperature (T ( m )), spectrofluorimetric, and viscometric techniques. It is found that IINH molecules could intercalate between base pairs of DNA as are evidenced by: hypochromism in UV absorption band of IINH, induced CD spectral changes, sharp increase in specific viscosity of DNA, and increase in the fluorescence of methylene blue (MB)-DNA solutions in the presence of increasing amounts of IINH, which indicates that it is able to release the intercalated MB completely. The binding constants of IINH-DNA complex at four different temperatures (277, 288, 298, and 310 K) were calculated to be 4.7 * 10(4), 2.2 * 10(4), 1.75 * 10(4) and 1.1 * 10(4) M( 1), respectively. Furthermore, the enthalpy and entropy of the reaction between IINH and CT-DNA showed that the reaction is enthalpy-favored and entropy- disfavored (?H = -30.187 kJ mol(-1); ?S = -20.46 J mol(-1)K(-1)) which are other evidences to indicate the IINH is able to be intercalated in the DNA base pairs. PMID- 21779809 TI - The metal-coordinated Casiopeina IIIEa induces the petite-like phenotype in Saccharomyces cerevisiae. AB - The Casiopeinas(r) are mixed chelate copper (II) complexes and promising antineoplastics agents against cancer cells and tumors in vitro and in vivo. However, the action mode of these compounds is poorly characterized. In this work the effect of the antineoplastic Casiopeina IIIEa on the metabolism and ultrastructure of the yeast Saccharomyces cerevisiae was investigated. Exposure of cells growing in rich or in low-iron medium to 5 MUM of the compound decreased duplication time and reduced oxygen consumption. Those cells formed smaller colonies when growing in a non-fermentable carbon source and low-iron medium, and under the light microscope, multiple folds were observed along the plasma membrane accompanied with a reduction in the diameter of the yeast. These observations were confirmed under the electron microscope, which also revealed a slight reduction of the mitochondrial size. A correlation was found with smaller colonies exhibiting lower rates of oxygen consumption, and yeast labelled with fluorescent MitoTracker(TM) consistently exhibited reduced mitochondrial activity. It appears that Casiopeina IIIEa gives rise to smaller yeast and petite like colonies by reducing the mitochondrial respiratory activity without significantly affecting the mitochondrial structure. PMID- 21779810 TI - Isolation and identification of endophytic and mycorrhizal fungi from seeds and roots of Dendrobium (Orchidaceae). AB - The seed germination of orchids under natural conditions requires association with mycorrhizal fungi. Dendrobium nobile and Dendrobium chrysanthum are threatened orchid species in China where they are considered medicinal plants. For conservation and application of Dendrobium using symbiosis technology, we isolated culturable endophytic and mycorrhizal fungi colonized in the protocorms and adult roots of two species plants and identified them by morphological and molecular analyses (5.8S and nrLSU). Of the 127 endophytic fungi isolated, 11 Rhizoctonia-like strains were identified as Tulasnellales (three strains from protocorms of D. nobile), Sebacinales (three strains from roots of D. nobile and two strains from protocorms of D. chrysanthum) and Cantharellales (three strains from roots of D. nobile), respectively. In addition, species of Xylaria, Fusarium, Trichoderma, Colletotrichum, Pestalotiopsis, and Phomopsis were the predominant non-mycorrhizal fungi isolated, and their probable ecological roles in the Dendrobium plants are discussed. These fungal resources will be of great importance for the large-scale cultivation of Dendrobium plants using symbiotic germination technology and for the screening of bioactive metabolites from them in the future. PMID- 21779812 TI - Dynamics of indigenous lactic acid bacteria populations in wine fermentations from La Rioja (Spain) during three vintages. AB - Diversity of lactic acid bacteria (LAB) species has been analyzed for three consecutive years (2006, 2007, and 2008) during alcoholic and malolactic fermentations of Tempranillo wine in a winery at La Rioja. The results showed differences in malolactic fermentation duration, and in both diversity of LAB species and diversity of Oenococcus oeni genotypes. O. oeni was shown to be the predominant species (73% of total isolates). Monitoring the different strains of O. oeni using pulsed-field gel electrophoresis of chromosomal DNA digested with SfiI and ApaI allowed detection of a total of 37 distinct genotypes, most of them comprised at least two isolates. Six appeared in more than one vintage, one of them being present in the three studied years. Moreover, four genotypes were indistinct of the strains isolated from the air of this same winery in 2007 vintage. The frequency of participation of each genotype varied from year to year, thus dominant genotypes at one year were minority or not present at another year. This suggests that distinct indigenous O. oeni strains are better adapted to the different winery conditions every year. Predominant genotypes that appeared in more than one vintage and lead to quality wines with low histamine contents could be considered as interesting for selecting of new malolactic starter cultures. PMID- 21779811 TI - High consistency between replicate 454 pyrosequencing analyses of ectomycorrhizal plant root samples. AB - In this methodological study, we compare 454 sequencing and a conventional cloning and Sanger sequencing approach in their ability to characterize fungal communities PCR amplified from four root systems of the ectomycorrhizal plant Bistorta vivipara. To examine variation introduced by stochastic processes during the laboratory work, we replicated all analyses using two independently obtained DNA extractions from the same root systems. The ITS1 region was used as DNA barcode and the sequences were clustered into OTUs as proxies for species using single linkage clustering (BLASTC: lust) and 97% sequence similarity cut-off. A relatively low overlap in fungal OTUs was observed between the 454 and the clone library datasets - even among the most abundant OTUs. In a non-metric multidimensional scaling analysis, the samples grouped more according to methodology compared to plant. Some OTUs frequently detected by 454, most notably those OTUs with taxonomic affinity to Glomales, were not detected in the Sanger dataset. Likewise, a few OTUs, including Cenococcum sp., only appeared in the clone libraries. Surprisingly, we observed a significant relationship between GC/AT content of the OTUs and their proportional abundances in the 454 versus the clone library datasets. Reassuringly, a very good consistency in OTU recovery was observed between replicate runs of both sequencing methods. This indicates that stochastic processes had little impact when applying the same sequencing technique on replicate samples. PMID- 21779813 TI - Phase I/II study of intraoperative radiotherapy for early breast cancer in Japan. AB - BACKGROUND: Intraoperative radiotherapy (IORT) is under evaluation in breast conserving surgery. We have begun our study with the first step being a phase I II study. This study was designed to identify the recommended dose and to test the feasibility of and tolerance to IORT in Japanese patients (UMIN000000918). METHODS: A phase I study was designed using a scheme of dose escalation from 19 to 20 to 21 Gy. We designed the phase II study to use the recommended dose. The primary endpoint was early toxicity. Secondary endpoints were efficacy for a long period and late toxicity. Inclusion criteria included the following: (1) T < 2.5 cm, (2) age >50 years, (3) surgical margin >1 cm, (4) intraoperative pathologically free margins, and (5) sentinel node negative. Partial resection was performed with at least a 1 cm margin around the tumor. Radiation was delivered directly to the mammary gland with the use of a Mobetron((r)). The toxicity was evaluated with the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. RESULTS: Nine patients were enrolled for the phase I study. All patients tolerated and we therefore recommend 21 Gy. The following 23 patients were enrolled in a phase II study and received 21 Gy. After a median follow-up of 26.0 months, their toxicities within 3 months included deep connective tissue fibrosis (G1 23/26, G2 2/26), hematoma (G1 9/26), infection in the musculoskeletal soft tissue (G1 4/26), and soft tissue necrosis (G2 3/26). There have been no local recurrences. CONCLUSIONS: The first group of Japanese female patients treated with IORT showed very good tolerability in the phase I/II study. PMID- 21779814 TI - Clinicopathological features of gastric metastasis from breast cancer in three cases. AB - The common sites for metastases from breast cancer are lymph nodes, bone, lung, liver, and brain. Gastrointestinal (GI) metastasis is rarely found or diagnosed in patients with breast cancer. This report presents three cases of gastric metastasis from breast cancer. Case 1 was a 42-year-old female diagnosed with gastric metastasis after mastectomy with axillary lymph node dissection for invasive lobular carcinoma of the left breast. Case 2 was a 54-year-old female who was diagnosed to have invasive lobular carcinoma of the left breast with systemic bone and gastric metastasis. Case 3 was a 54-year-old female who was diagnosed to have bilateral invasive ductal carcinoma of the breast with simultaneous bone and gastric metastasis. The immunohistochemical statuses for estrogen receptor, progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15 (GCDFP-15) between the primary and gastric metastatic lesions were all well matched. All three cases were treated with systemic chemotherapy, hormone therapy or both, without surgical intervention for gastric lesions. Two patients with disseminated disease died 27 and 58 months after diagnosis of gastric metastasis, while one patient without organ metastasis is still alive at 56 months after diagnosis. It is important to make a correct diagnosis by distinguishing gastric metastasis from breast cancer in order to select the optimal initial treatment for systemic disease of breast cancer. PMID- 21779815 TI - Biomarkers: optimizing treatment guidance in heart failure. AB - Heart failure is a frequent and life-threatening syndrome which is not only the result of myocardial injury or hemodynamic overload as commonly perceived, but appears to be the result of an interplay among genetic, neurohormonal, inflammatory, and biochemical factors, collectively referred to as biomarkers. Biomarkers can become risk factors in case their therapeutic modification results in an improvement of clinical outcomes. Among those markers identified in patients with heart failure, a number appears to have direct clinical relevance in aiding diagnosis, risk stratification, monitoring therapy, and treating to targets in order to improve clinical outcomes. These include brain natriuretic peptides (e.g., BNP, NT-proBNP), inflammatory markers (e.g., hsCRP), neurohormones (e.g., aldosterone), cardiorenal markers (e.g., cycstatin C), and novel markers (e.g., galectin-3). While their utility to indicate risk is mostly well established, there are less data to establish that a treatment using biomarkers as a guidance results in better outcomes than a more generalized intensified treatment of patients with heart failure. Future directions may involve larger platforms that facilitate to simultaneously analyze hundreds of biomarkers and may help to tailor heart failure therapy on a single patient basis, considering the specific pathogenesis and prognosis. Also from a therapeutic perspective there are data that a single intervention such as aldosterone blockade may affect multiple biomarkers at the same time. Taken together the data indicate that biomarkers are evolving into a valuable addendum to the diagnostic and therapeutic armamentarium. PMID- 21779816 TI - Is there an additional benefit of serial NT-proBNP measurements in patients with stable chronic heart failure receiving individually optimized therapy? AB - BACKGROUND: The role of serial NT-proBNP measurements in patients suffering from chronic systolic heart failure (CHF) who already receive individually optimized pharmacotherapy is still unresolved. METHODS: NT-proBNP was assessed at baseline and at 6 months follow-up in 504 stable CHF patients treated with individually optimized pharmacotherapy. After assessment of clinical stability at 6 months, patients were followed up for at least 1 year. The combined primary endpoint was defined as death, hospitalization due to cardiac reasons or heart transplantation in 1-year follow-up. We stratified our patients according to two principles: first, a percent change of value (CV) between the first and second measurement of NT-proBNP and secondly, the transformed logarithm of NT-proBNP measured at 6 months. RESULTS: During the follow-up period of 1 year, 50 patients (9.9%) reached the combined primary endpoint. Stratification according to percentage CV was less accurate in predicting endpoint-free survival compared to a classification in categories of lnNT-proBNP measured at 6 months (ROC AUC = 0.615; 95% CI 0.525-0.70 vs. ROC AUC = 0.790; 95% CI 0.721-0.856, respectively). When entered into proportional hazard regression analysis, lnNT-proBNP measured at 6 months remained an independent predictor of the combined primary endpoint with an associated HR of 2.53 (95% CI 1.385-4.280). CONCLUSION: To date, this is the largest analysis of serial NT-proBNP measurements in patients with CHF receiving individually optimized medical therapy. These data suggest that a single NT-proBNP measurement after 6 months in stable clinical conditions may have higher predictive value than stratification of change in serial measurements. PMID- 21779817 TI - Impact of a centralized osteoporosis coordinator on post-fracture osteoporosis management: a cluster randomized trial. AB - We conducted a cluster randomized trial evaluating the effect of a centralized coordinator who identifies and follows up with fracture patients and their primary care physicians about osteoporosis. Compared with controls, intervention patients were five times more likely to receive BMD testing and two times more likely to receive appropriate management. INTRODUCTION: To determine if a centralized coordinator who follows up with fracture patients and their primary care physicians by telephone and mail (intervention) will increase the proportion of patients who receive appropriate post-fracture osteoporosis management, compared to simple fall prevention advice (attention control). METHODS: A cluster randomized controlled trial was conducted in small community hospitals in the province of Ontario, Canada. Hospitals that treated between 60 and 340 fracture patients per year were eligible. Patients 40 years and older presenting with a low trauma fracture were identified from Emergency Department records and enrolled in the trial. The primary outcome was 'appropriate' management, defined as a normal bone mineral density (BMD) test or taking osteoporosis medications. RESULTS: Thirty-six hospitals were randomized to either intervention or control and 130 intervention and 137 control subjects completed the study. The mean age of participants was 65 +/- 12 years and 69% were female. The intervention increased the proportion of patients who received appropriate management within 6 months of fracture; 45% in the intervention group compared with 26% in the control group (absolute difference of 19%; adjusted OR, 2.3; 95% CI, 1.3-4.1). The proportion who had a BMD test scheduled or performed was much higher with 57% of intervention patients compared with 21% of controls (absolute difference of 36%; adjusted OR, 4.8; 95% CI, 3.0-7.0). CONCLUSIONS: A centralized osteoporosis coordinator is effective in improving the quality of osteoporosis care in smaller communities that do not have on-site coordinators or direct access to osteoporosis specialists. PMID- 21779818 TI - Interpretation and use of FRAX in clinical practice. AB - The introduction of the WHO FRAX(r) algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware and are the focus of this review INTRODUCTION: The International Osteoporosis Foundation (IOF) and the International Society for Clinical Densitometry (ISCD) appointed a joint Task Force to develop resource documents in order to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met in November 2010 for 3 days to discuss these topics which form the focus of this review. METHODS: This study reviews the resource documents and joint position statements of ISCD and IOF. RESULTS: Details on the clinical risk factors currently used in FRAX are provided, and the reasons for the exclusion of others are provided. Recommendations are made for the development of surrogate models where country-specific FRAX models are not available. CONCLUSIONS: The wish list of clinicians for the modulation of FRAX is large, but in many instances, these wishes cannot presently be fulfilled; however, an explanation and understanding of the reasons may be helpful in translating the information provided by FRAX into clinical practice. PMID- 21779820 TI - The effect of food on the acute toxicity of silver nitrate to four freshwater test species and acute-to-chronic ratios. AB - Acute silver toxicity studies were conducted with and without food for four common freshwater test species: Daphnia magna, Ceriodaphnia dubia, Pimephales promelas (fathead minnow-FHM), and Oncorhynchus mykiss (rainbow trout-RBT) in order to generate acute-to-chronic ratios (ACR). The studies were conducted similarly (i.e., static-renewal or flow-through) to chronic/early-life stage studies that were previously performed in this laboratory. The acute toxicity (EC/LC50 values) of silver without food ranged from 0.57 MUg dissolved Ag/l for C.dubia to 9.15 MUg dissolved Ag/l for RBT. The presence of food resulted in an increase in EC/LC50 values from 1.25* for RBT to 22.4* for C. dubia. Invertebrate food type was also shown to effect acute silver toxicity. Food did not affect EC/LC50s or ACRs as greatly in fish studies as in invertebrate studies. ACRs for both invertebrate species were <1.0 when using acute studies without food but were 1.22 and 1.33 when using acute studies with food. ACRs for FHMs ranged from 4.06 to 7.19, while RBT ACRs ranged from 28.6 to 35.8 depending on whether food was present in acute studies. The data generated from this research program should be useful in re-determining a final ACR for silver in freshwater as well as in risk assessments. PMID- 21779821 TI - Growth, morphology, ammonium uptake and nutrient allocation of Myriophyllum brasiliense Cambess. under high NH4+ concentrations. AB - The effects of high NH(4)(+) concentration on growth, morphology, NH(4) (+) uptake and nutrient allocation of Myriophyllum brasiliense were investigated in hydroponic culture. The plants were grown under greenhouse conditions for 4 weeks using four levels of NH(4)(+) concentration: 1, 5, 10 and 15 mM. M. brasiliense grew well with a relative growth rate of c.0.03 day(-1) at NH(4)(+) concentration up to 5 mM. At the higher NH(4)(+) concentrations the growth of the plants was stunted and the plants had short roots and few new buds, especially when grown in 15 mM NH(4)(+) where the submerged leaves were lost and there were rotten roots and submerged stems. To avoid NH(4)(+) toxicity, the plants may have a mechanism to prevent cytoplasmic NH(4)(+) accumulation in plant cells. The net uptake of NH(4)(+) significantly decreased and the total N significantly increased in the plants treated with 10 and 15 mM NH(4)(+), respectively. The plant may employ NH(4)(+) assimilation and extrusion as a mechanism to compensate for the high NH(4)(+) concentrations. However, the plants may show nutrient deficiency symptoms, especially K deficiency symptoms, after they were exposed to NH(4)(+) concentration higher than 10 mM. The present study provides a basic ecophysiology of M. brasiliense that it can grow in NH(4)(+) enriched water up to concentrations as high as 5 mM. PMID- 21779822 TI - Using nestling feathers to assess spatial and temporal concentrations of mercury in bald eagles at Voyageurs National Park, Minnesota, USA. AB - Bald eagles (Haliaeetus leucocephalus) have been utilized as a biosentinel of aquatic ecosystem health in the Great Lakes Region since the early 1960s. Bald eagle populations have been monitored at Voyageurs National Park (VNP), Minnesota, since 1973. For the past 20 years, researchers have collected feathers from nestling bald eagles to assess their dietary exposure to mercury (Hg) on Rainy, Kabetogama, and Namakan lakes in VNP. Mercury is an environmental pollutant with both natural and anthropogenic sources, and negatively affects many species of wildlife. In a previous study, geometric mean concentrations of Hg in feathers of nestling bald eagles were greater at VNP (20 mg/kg Dry Weight (DW)) than in nestling feathers from other Great Lakes subpopulations (~7 mg/kg DW), for the period 1985-1989. Current geometric mean concentrations have declined by 77.4% since 1989 at VNP. While all samples from 1985 to 1989 had detectable concentrations of Hg, 10% of current samples had concentrations below the reportable detection limit (0.001 mg/kg DW, n = 180). The major lakes at VNP are impounded, and Hg concentrations also declined greatly after the lake level stabilization order by the International Joint Commission was implemented in 1999. Mercury concentrations in feathers of nestling bald eagles from 1989 to 2010 ranged from ND (<0.001) to 34.97 mg/kg DW. The highest single concentration in a nestling was from Namakan Lake in 2010. The five-year geometric means for Rainy, Kabetogama, and Namakan lakes for 2006-2010 were 6.08, 1.07, and 5.56 mg/kg DW (n = 28, n = 32, n = 27) respectively. Although Hg concentrations in feathers of nestlings greatly declined after the change in water level management in 1999 and are lower than 1989 concentrations, recent samples suggest a gradual increase. Continued monitoring of nestling feather concentrations will be essential to assess this increase, to determine the source of Hg, to determine if there are changes to methylation potential, and to evaluate and optimize water level management. PMID- 21779823 TI - Update on environmental risk factors for attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurobehavioral disorder affecting 5% to 10% of children. Although considered to be a highly familial disorder, ADHD heritability estimates of 60% to 80% highlight the considerable role that environmental factors may still play in disorder susceptibility. Proposed ADHD environmental risk factors include prenatal substance exposures, heavy metal and chemical exposures, nutritional factors, and lifestyle/psychosocial factors. This paper reviews the literature published in 2010 investigating the association between environmental risk factors and ADHD or related symptomatology. Sources of risk factor exposure and the proposed mechanism by which each exposure is linked to ADHD-related neurobehavioral changes are also reported. Methodologic limitations of the current literature are discussed, and guidelines for future study are proposed. An improved understanding of the role that environmental factors play in ADHD etiology is critical to future ADHD prevention efforts. PMID- 21779825 TI - Propranolol for infantile hemangiomas: strawberry matters? PMID- 21779819 TI - Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo controlled study. AB - In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated. INTRODUCTION: This study evaluated the efficacy and safety of bazedoxifene for the treatment of postmenopausal osteoporosis over 5 years. METHODS: A total of 4,216 postmenopausal women with osteoporosis were enrolled in this 2-year extension of a 3-year, randomized, double-blind, placebo-controlled, phase 3 trial. In the core study (N = 7,492), subjects received bazedoxifene 20 or 40 mg/day, raloxifene 60 mg/day, or placebo. The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40 mg were transitioned to bazedoxifene 20 mg after 4 years. Five-year findings are reported for bazedoxifene 20 and 40/20 mg and placebo. Endpoints included incidence of new vertebral fractures (primary) and non-vertebral fractures, and changes in bone mineral density (BMD) and bone turnover markers. RESULTS: At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20 mg (4.5%) and 40/20 mg (3.9%) versus placebo (6.8%; P < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women (n = 1,324; femoral neck T-score <=-3.0 and/or >= 1 moderate or severe or >= 2 mild vertebral fracture[s]), bazedoxifene 20 mg reduced non-vertebral fracture risk versus placebo (37%; P = 0.06); combined data for bazedoxifene 20 and 40/20 mg reached statistical significance (34% reduction; P < 0.05). Bazedoxifene significantly increased BMD and reduced bone turnover versus placebo (P < 0.05) and was generally safe and well tolerated. CONCLUSIONS: The findings support a sustained anti-fracture effect of bazedoxifene on new vertebral fractures in postmenopausal osteoporotic women and on non-vertebral fractures in the higher-risk subgroup of women. PMID- 21779824 TI - Dietary and nutritional treatments for attention-deficit/hyperactivity disorder: current research support and recommendations for practitioners. AB - Evidence for dietary/nutritional treatments of attention-deficit/hyperactivity disorder (ADHD) varies widely, from double-blind, placebo-controlled trials to anecdotal. In guiding patients, clinicians can apply the SECS versus RUDE rule: treatments that are Safe, Easy, Cheap, and Sensible (SECS) require less evidence than those that are Risky, Unrealistic, Difficult, or Expensive (RUDE). Two nutritional treatments appear worth general consideration: Recommended Daily Allowance/Reference Daily Intake multivitamin/mineral supplements as a pediatric health intervention not specific to ADHD and essential fatty acids, especially a mix of eicosapentaenoic acid, docosahexaenoic acid, and gamma-linolenic acid as an ADHD-specific intervention. Controlled studies support the elimination of artificial food dyes to reduce ADHD symptoms, but this treatment may be more applicable to the general pediatric population than to children with diagnosed ADHD. Mineral supplementation is indicated for those with documented deficiencies but is not supported for others with ADHD. Carnitine may have a role for inattention, but the evidence is limited. Dimethylaminoethanol probably has a small effect. Herbs, although "natural," are actually crude drugs, which along with homeopathic treatments have little evidence of efficacy. Consequences of delayed proven treatments need consideration in the risk-benefit assessment of dietary/nutritional treatments. PMID- 21779826 TI - Benzothiadiazole (BTH) activates sterol pathway and affects vitamin D3 metabolism in Solanum malacoxylon cell cultures. AB - Benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH), a particularly efficient inducer of systemic acquired resistance (SAR), was developed as an immunizing agent to sensitize various crop species against pathogen infections. Recent works highlighted its activating effect on different metabolic pathways, concerning both primary and secondary metabolites. In this study, we investigated the effect of BTH treatment on sterol levels and vitamin D(3) metabolism in Solanum malacoxylon cultures. Calli of S. malacoxylon were incubated in Gamborg B5 liquid medium alone or added with 50 MUM BTH for different times (one, two or three cycles of light). Histocytochemical investigations performed on our experimental system using 3,3'-diaminobenzidine (DAB) for hydrogen peroxide (H(2)O(2)) detection and phloroglucinol for lignin staining showed that BTH causes H(2)O(2) accumulation and lignin deposition in treated calli. Gas chromatographic analysis of principal cell membrane sterols (beta-sitosterol, campesterol, stigmasterol) showed that BTH transiently increases their cellular levels. Callus cultures were found to contain also cholesterol, 7 dehydrocholesterol, the putative precursor of vitamin D(3), and the hydroxylated metabolites 25-hydroxyvitamin D(3) [25(OH)D(3)] and 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. BTH treatment enhanced 7-dehydrocholesterol while reduced cholesterol. HPLC analysis of sample extracts showed that BTH does not affect the cell content of vitamin D(3), though results of ELISA tests highlighted that this elicitor moderately enhances the levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3) metabolites. In conclusion, BTH treatment not only causes cell wall strengthening, a typical plant defence response, as just described in other experimental models, but in the same time increases the cellular level of the main sterols and 7-dehydrocholesterol. PMID- 21779827 TI - Microtubule configurations and nuclear DNA synthesis during initiation of suspensor-bearing embryos from Brassica napus cv. Topas microspores. AB - In the new Brassica napus microspore culture system, wherein embryos with suspensors are formed, ab initio mimics zygotic embryogenesis. The system provides a powerful in vitro tool for studying the diverse developmental processes that take place during early stages of plant embryogenesis. Here, we studied in this new culture system both the temporal and spatial distribution of nuclear DNA synthesis places and the organization of the microtubular (MT) cytoskeleton, which were visualized with a refined whole mount immunolocalization technology and 3D confocal laser scanning microscopy. A 'mild' heat stress induced microspores to elongate, to rearrange their MT cytoskeleton and to re enter the cell cycle and perform a predictable sequence of divisions. These events led to the formation of a filamentous suspensor-like structure, of which the distal tip cell gave rise to the embryo proper. Cells of the developing pro embryo characterized endoplasmic (EMTs) and cortical microtubules (CMTs) in various configurations in the successive stages of the cell cycle. However, the most prominent changes in MT configurations and nuclear DNA replication concerned the first sporophytic division occurring within microspores and the apical cell of the pro-embryo. Microspore embryogenesis was preceded by pre-prophase band formation and DNA synthesis. The apical cell of the pro-embryo exhibited a random organization of CMTs and, in relation to this, isotropic expansion occurred, mimicking the development of the apical cell of the zygotic situation. Moreover, the apical cell entered the S phase shortly before it divided transversally at the stage that the suspensor was 3-8 celled. PMID- 21779828 TI - Patient satisfaction and clinical results 10 years after modified open thoracoplasty for pectus deformities. AB - PURPOSE: Indications for surgical treatment for patients with pectus excavatum and carinatum are psychosocial issues, pulmonary or cardiac limitations or pain. When surgery is indicated in our institution, patients are treated with a modified thoracoplasty according to the Ravitch technique. In order to stabilize pectus excavatum, an allogenic bone strut is transplanted which does not require removal. PATIENT AND METHODS: Seventy-one patients with a mean age of 17 years who were treated for pectus deformities between 1997 and 2007 were evaluated retrospectively. RESULTS: The average period of follow-up was 5.3 years. Sixty six percent of the patients suffered from pectus excavatum, 34% from pectus carinatum. One osseous revision had to be performed after overcorrection of pectus carinatum into pectus excavatum. Six minor complications occurred. At follow-up, the mean patient satisfaction score was 4.3 (scale 1-5). The Manchester Scar Scale resulted in 96% cosmetically well-healed scars. Clinically, 93% of the surgical results were rated good. CONCLUSIONS: This study retrospectively shows that this modification of the Ravitch approach is a safe and effective treatment option for pectus deformities with long-term satisfactory results for the patients without the need for bar removal. PMID- 21779829 TI - Laparoscopic sigmoid resection for diverticular disease has no advantages over open approach: midterm results of a randomized controlled trial. AB - PURPOSE: Elective laparoscopic sigmoid resection (LSR) for symptomatic diverticular disease is supposed to have significant short-term advantages compared to open surgery (open sigmoid resection (OSR)). This opinion is rather based on inferences from trials on colonic resections for malignant diseases or minor laparoscopic surgery. This randomized controlled trial was conducted to compare quality of life as well as morbidity and clinical outcome after LSR vs. OSR following a midterm follow-up period. METHODS: Patients presenting with a symptomatic sigmoid diverticular disease stage II/III (Stock/Hansen) were randomly allocated to LSR or OSR in a prospective multicenter trial. Endpoints included the quality of life assessed with a standardized questionnaire, postoperative mortality, and complications within the follow-up of 12 months after operation. RESULTS: A total of 143 patients randomized between 2005 and 2008 in 12 centers could be analyzed. The recruitment was aborted for nonachievement of the planned sample size. Seventy-five patients were allocated to LSR, and 68 received OSR. Nine operations were converted to OSR (9%) and analyzed as intention to treat. Groups were comparable for age, gender, body mass index, comorbidity, and indication for surgery. Operation time was longer for LSR (p < 0.001). Quality of life did not differ between LSR and OSR, either during the early postoperative course or after 12 months (p = 0.172). Also, mortality and morbidity, including subgroups of major and minor morbidity, were compared. CONCLUSION: LSR was not superior to OSR regarding postoperative quality of life and incidence of complications in this trial. PMID- 21779830 TI - The versatility of the pedicled vertical rectus abdominis myocutaneous flap in oncologic patients. AB - PURPOSE: The vertical rectus abdominis muscle (VRAM) flap is considered a safe and simple option to cover defects of the trunk and proximal thigh. Detailed long time follow-up studies in oncologic patients including complications and donor site morbidity are rare. In this study, complications and donor site morbidity were analysed. METHODS: Data of 78 consecutive patients with oncologic disease, having received VRAM flaps, were analysed retrospectively. Patients with soft tissue sarcomas (n = 38), radiation ulcers (n = 18), carcinoma (n = 10), wound healing difficulties after tumour resection (n = 8), breast reconstruction after ablation (n = 3) and malignant melanoma (n = 1) were included. Statistics concerning patients' satisfaction, the occurrence of wound-healing difficulties, incisional herniation, loss of abdominal wall strength in correlation to operative and (neo)adjuvant treatment and patients' history were performed. The mean follow-up time was 5.5 years. RESULTS: No complete flap loss was observed. A body mass index over 30 was positively correlated with wound-healing difficulties; radiation had no negative effect. A contralateral cutaneous pedicle could reduce the risk of lymphoedema in groin defect patients. Incisional hernia was present in 13%. Strength endurance of the abdominal wall was reduced compared to an age-matched control. Most patients were satisfied with the postoperative result. CONCLUSIONS: VRAM flaps are reliable tools for defect coverage in the oncologic patient to prevent chronic ulceration, lymphangitis or more severe complications like septic rupture of femoral vessels and hip disarticulation. Donor site morbidity is tolerable, and patients' satisfaction is high. PMID- 21779831 TI - Morbidity and Mortality conference as part of PDCA cycle to decrease anastomotic failure in colorectal surgery. AB - BACKGROUND AND AIMS: Morbidity and Mortality meetings are an accepted tool for quality management in many hospitals. However, it is not proven whether these meetings increase quality. It was the aim of this study to investigate whether Morbidity and Mortality meetings as part of a PDCA cycle (Plan, Do, Check, Act) can improve the rate of anastomotic failure in colorectal surgery. MATERIALS AND METHODS: From January 1, 2004, to December 31, 2009, data for all anastomotic failures in patients operated on for colorectal diseases in the Department of Surgery (Klinikum Friedrichshafen, Germany) were prospectively collected. The events were discussed in Morbidity and Mortality meetings. On the basis of these discussions, a strategy to prevent anastomotic leaks and a new target were defined (i.e. 'Plan'). This strategy was implemented in the following period (i.e. 'Do') and results were prospectively analysed. A new strategy was established when the results differed from the target, and a new standard was defined when the target was achieved (i.e. 'Check, Act'). RESULTS: The year 2004 was set as the base year. In 2005 and 2006, new strategies were established. Comparing this period with the period of strategy conversion (2007-2009), we found a significant decrease in the anastomotic failure rate in colorectal surgery patients (5.7% vs 2.8%; p = 0.05), whereas the risk factors for anastomotic failure were unchanged or unfavourable. CONCLUSIONS: If Morbidity and Mortality meetings are integrated in a PDCA cycle, they can decrease anastomotic failure rates and improve quality of care in colorectal surgery. Therefore, the management tool 'PDCA cycle' should be considered also for medical issues. PMID- 21779832 TI - Meta-analysis of anatomic resection versus non-anatomic resection for hepatocellular carcinoma: are they comparing apples with oranges? PMID- 21779833 TI - Urothelial carcinoma. PMID- 21779834 TI - Minimally invasive percutaneous nephrolithotomy under peritubal local infiltration anesthesia. AB - OBJECTIVES: To evaluate the feasibility and safety of performing minimally invasive percutaneous nephrolithotomy (MPCNL) under peritubal local infiltration anesthesia. PATIENTS AND METHODS: From December 2007 to December 2009, 88 patients with upper urinary calculi underwent MPCNL with ultrasonography (US) guided renal access in the lateral decubitus flank position under peritubal local infiltration anesthesia. All patients were informed about the possibility of experiencing short periods of discomfort or pain and completed visual analog pain scale (VAS) questionnaires during the intra-operation and at 4, 24, and 48 h postoperatively. Postoperative narcotic usage was recorded at 24 and 48 h postoperatively. RESULTS: Eighty-two patients (93.2%, 82/88) underwent MPCNL under local anesthetic infiltration, 6 patients were converted to general anesthesia (2.2%, 2/88) or epidural anesthesia (4.4%, 4/88) because of serious pain or discomfort. The average VAS scores intra-operation and at 4, 24, and 48 h postoperatively were 3.1, 3.0, 2.4, and 2.1, respectively. Six patients (7.3%, 6/82) and 2 patients (2.4%, 2/82) were administered pethidine (75 mg) at 24 and 48 h postoperatively, respectively. The stone clearance rate was 88.3% (91/103) before discharge with MPCNL mono-therapy. The mean operative time was 89 min (range 56-145 min). CONCLUSION: MPCNL under peritubal local infiltration anesthesia is well-tolerated and feasible alternative to the same procedure under general or epidural anesthesia. PMID- 21779835 TI - Is it suitable to eliminate bone scan for prostate cancer patients with PSA <= 20 ng/mL? AB - PURPOSE: We evaluated the relationship between bone metastasis (BM) and clinical or pathological variables, including the serum prostate-specific antigen (PSA) concentration. METHODS: This retrospective study included 579 consecutive patients with newly diagnosed prostate cancer (Pca) who underwent a bone scan study at our institution between 2002 and 2010. We used receiver operating characteristics curves to evaluate accuracy of bone metastasis between serum PSA 10 and 20 ng/mL. RESULTS: A positive bone scan result was found in 83 men (14.3%) with PCa. However, 27 men (4.6%) with serum PSA between 10 and 20 ng/mL, 29/579 men (5.0%) with GS <= 7, and 21/83 (25.3%) with serum PSA <= 20 ng/mL and Gleason score (GS) <= 7 had positive bone scans. In the logistic regression analyses, clinical T stage (odds ratio [OR] = 3.26; 95% CI, 2.29-4.33; P = 0.021), GS (OR = 3.41; 95% CI, 2.91-4.63; P = 0.019), and serum PSA (OR = 8.37; 95% CI, 3.91 19.21; P < 0.001) were predictive factors of detecting the BM. When the serum PSA concentration <=20 ng/mL and GS <= 7, AUC value of bone scans for the detection of BM was 0.640 (P = 0.020; 95% CI, 0.563-0.717). With serum PSA at 10 ng/mL and GS <= 7, the AUC values of bone scans were 0.828 (P < 0.001; 95% CI, 0.773 0.883). CONCLUSIONS: Bone scans might be necessary in men with serum PSA between 10 and 20 ng/mL. New guidelines for eliminating bone scans in patients with newly diagnosed Pca are needed, especially in Asians. PMID- 21779837 TI - Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells. AB - Silibinin, a flavonolignan isolated from the milk thistle plant (Silybum marianum), possesses anti-neoplastic properties. In vitro and in vivo studies have recently shown that silibinin inhibits the growth of colorectal cancer (CRC). The present study investigates the mechanisms of silibinin-induced cell death using an in vitro model of human colon cancer progression, consisting of primary tumor cells (SW480) and their derived metastatic cells (SW620) isolated from a metastasis of the same patient. Silibinin induced apoptotic cell death evidenced by DNA fragmentation and activation of caspase-3 in both cell lines. Silibinin enhanced the expression (protein and mRNA) of TNF-related apoptosis inducing ligand (TRAIL) death receptors (DR4/DR5) at the cell surface in SW480 cells, and induced their expression in TRAIL-resistant SW620 cells normally not expressing DR4/DR5. Caspase-8 and -10 were activated demonstrating the involvement of the extrinsic apoptotic pathway in silibinin-treated SW480 and SW620 cells. The protein Bid was cleaved in SW480 cells indicating a cross-talk between extrinsic and intrinsic apoptotic pathway. We demonstrated that silibinin activated also the intrinsic apoptotic pathway in both cell lines, including the perturbation of the mitochondrial membrane potential, the release of cytochrome c into the cytosol and the activation of caspase-9. Simultaneously to apoptosis, silibinin triggered an autophagic response. The inhibition of autophagy with a specific inhibitor enhanced cell death, suggesting a cytoprotective function for autophagy in silibinin-treated cells. Taken together, our data show that silibinin initiated in SW480 and SW620 cells an autophagic-mediated survival response overwhelmed by the activation of both the extrinsic and intrinsic apoptotic pathways. PMID- 21779836 TI - Preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. AB - PURPOSE: To assess the patient and identify the risk factors for infectious complications in conjunction with urological procedures and suggest a model for classification of the procedures. METHOD: Review of literature, critical analysis of data and tentative model for reducing infectious complications. RESULTS: Risk factors are bound to the patient and to the procedure itself and are associated with the environment where the healthcare is provided. Assuming a clean environment and sterile operation field, a five-level assessment ladder related to the patient and type of surgery is useful, considering: (1) the ASA score, (2) the general risk factors, (3) the individual endogenous and exogenous risk factors, (4) the class of surgery and the potential bacterial contamination burden and (5) the level of severity and difficulty of the surgical intervention. A cumulative approach will identify the level of risk for each patient and define preventive measures, such as the type of antibiotic prophylaxis or therapeutic measures before surgery. There are data suggesting that the higher the ASA score, the higher is the risk of infectious complication. Age, dysfunction of the immune system, hypo-albuminaemia/malnutrition and overweight, uncontrolled blood glucose level and smoking are independent general risk factors, whilst bacteriuria, indwelling catheter treatment, urinary tract stone disease, urinary tract obstruction and a history of urogenital infection are specific urological risk factors. There is inconclusive evidence for most other reported risk factors. The level of contamination of the surgical field is of utmost importance as are the procedure-related factors, and the sum of these have to be reflected on for the subsequent perioperative management of the patient. CONCLUSIONS: It is essential to identify and control risk factors to minimize infectious complications in conjunction with urological procedures. Our knowledge is limited and clinical research and quality registries analysing risk factors must be undertaken. We propose a working basis for assessment of patients' risk factors and classification of urological procedures. PMID- 21779838 TI - Recurrent laryngeal nerve palsy in benign thyroid disease: can surgery make a difference? AB - The association between a pre-operative recurrent laryngeal nerve (RLN) palsy and thyroid disease is usually suggestive of locally advanced malignant thyroid disease by invasion of the nerve. However, the risk of benign thyroid disease causing paralysis to the nerve is extremely rare and has been scarcely reported. The aims of this paper are to analyse the experience of patients presenting with RLN palsy and benign multinodular goitre (MNG), evaluate the mechanisms of pathogenesis and determine if thyroid surgery may be of benefit for these patients. A retrospective review was conducted of five patients presenting to the Otorhinolaryngology Head and Neck Surgery Department at Guy's and St Thomas' NHS Foundation Trust Hospital between 2000 and 2009. All patients were evaluated with fibre-optic laryngoscopy, ultrasound-guided fine needle aspiration cytology and computerised tomography. All patients underwent total or completion thyroidectomy and a handheld nerve stimulator (Xomed-Medtronics Vari-Stim III((r))) was used at the end of the procedure to check the integrity of the RLN. Post-operatively all patients were followed up for at least 12 months with fibre-optic laryngoscopy. Five females with an age range between 32 and 81 years presented with RLN palsy and benign MNG. All patients underwent total or completion thyroidectomies with preservation of the affected nerves. Two patients recovered the function of the nerves. All patients were confirmed to have benign multinodular goitres on histological analysis. RLN palsy in the presence of benign disease is rare. Patients should be carefully evaluated to confirm the palsy and exclude malignant disease prior to surgery. Surgery should be undertaken to remove the MNG, confirm the diagnosis and preserve the affected nerve. There is a significant chance that some of these patients will recover the function of the nerve. PMID- 21779839 TI - The association between surgical site infection and previous operation in oral cavity cancer patients. AB - We investigated the post-operative surgical site infection (SSI) rate in oral cavity cancer patients who had previous operation in the oral cavity region and compared it with that of patients without previous operation. We retrospectively reviewed over 1,000 chart records of oral cavity cancer patients from January 2004 to November 2010 and relevant data were collected. Statistical methods included descriptive statistics, bivariate analyses, and a multiple logistic regression model for investigating the relevant factors of post-operative SSI. A total of 894 patients were enrolled in the final analyses. The overall post operative SSI rate was 20.8%. Previous history of operation was identified in 173 patients (19.4%). There was no significant difference in post-operative SSI rate between the patients with previous operation and those without (22.5 vs. 20.4%, P = 0.601). Previous operation in the oral cavity region was not associated with increased post-operative SSI rate in oral cavity cancer patients. PMID- 21779840 TI - Association of adenoid hyperplasia and bacterial biofilm formation in children with adenoiditis in Taiwan. AB - The adenoid is a bacterial reservoir that contributes to chronic otolaryngologic infections. Staphylococcus aureus (S. aureus) is a common pathogen in the adenoid. The increase of antibiotic resistance in S. aureus has become an important issue in public health. The aim of this study was to compare adenoid hyperplasia and biofilm formation in children with S. aureus adenoiditis in Taiwan. The patients were divided into methicillin-resistant and methicillin sensitive S. aureus groups according to the S. aureus obtained from adenoid tissue after antibiotic susceptibility testing. Adenoid hyperplasia was assessed by lateral cephalometry, and the severity of sinusitis was evaluated by Water's view. Microbiological investigation of available S. aureus isolates was performed by in vivo morphological observation and an in vitro bacterial biofilm assay. Sixty isolates of S. aureus were identified in 283 children (21.2%) after adenoidectomy, of which 21 (35%) were methicillin-resistant S. aureus (MRSA). The severity of adenoid hyperplasia and extensive biofilm formation were more prominent in patients infected with methicillin-resistant S. aureus than in those infected with methicillin-sensitive S. aureus (MSSA). The primary outcome of this study was to provide evidence that S. aureus constituted a significant portion of the adenoidal pathogens. The secondary outcome of this study was that MRSA adenoiditis may be associated with adenoid hyperplasia and biofilm formation. PMID- 21779841 TI - Analysis of prognostic factors for postoperative bleeding after tonsillectomy. AB - Postoperative bleeding is the most frequent surgical complication after tonsillectomy and may be associated with increased mortality rate. We have, therefore, analyzed factors associated with and prognostic for bleeding after tonsillectomy. The 2,254 patients who underwent tonsillectomy under general anesthesia at our institution from January 2005 to December 2009 were divided into bleeding and non-bleeding groups, and their demographic and clinical characteristics were compared. Age, administration of steroid immediately after general anesthesia, absence of administration of non-steroidal anti-inflammatory drugs, and the surgeon's experience were significantly associated with bleeding. In contrast, gender, chief complaints, performance of associated surgery, and type of anesthetic were not associated with postoperative bleeding. Hemorrhage after tonsillectomy was associated with the administration of steroids and with the non-administration of non-steroidal anti-inflammatory drugs. PMID- 21779842 TI - Potential cognitive endophenotypes in multigenerational families: segregating ADHD from a genetic isolate. AB - Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association. PMID- 21779843 TI - alpha-L-rhamnosidase of Aspergillus terreus immobilized on ferromagnetic supports. AB - alpha-L-rhamnosidase from Aspergillus terreus was covalently immobilized on the following ferromagnetic supports: polyethylene terephthalate (Dacron-hydrazide), polysiloxane/polyvinyl alcohol (POS/PVA), and chitosan. The powdered supports were magnetized by thermal coprecipitation method using ferric and ferrous chlorides, and the immobilization was carried out via glutaraldehyde. The activity of the Dacron-hydrazide (0.53 nkat/MUg of protein) and POS/PVA (0.59 nkat/MUg of protein) immobilized enzyme was significantly higher than that found for the chitosan derivative (0.06 nkat/MUg of protein). The activity-pH and activity-temperature profiles for all immobilized enzymes did not show difference compared to the free enzyme, except the chitosan derivative that presented higher maximum temperature at 65 degrees C. The Dacron-hydrazide derivative thermal stability showed a similar behavior of the free enzyme in the temperature range of 40-70 degrees C. The POS/PVA and chitosan derivatives were stable up to 60 degrees C, but were completely inactivated at 70 degrees C. The activity of the preparations did not appreciably decrease after ten successive reuses. Apparent K (m) of alpha-L-rhamnosidase immobilized on magnetized Dacron-hydrazide (1.05 +/- 0.22 mM), POS/PVA (0.57 +/- 0.09 mM), and chitosan (1.78 +/- 0.24 mM) were higher than that estimated for the soluble enzyme (0.30 +/- 0.03 mM). The Dacron hydrazide enzyme derivative showed better performance than the free enzyme to hydrolyze 0.3% narigin (91% and 73% after 1 h, respectively) and synthesize rhamnosides (0.116 and 0.014 mg narirutin after 1 h, respectively). PMID- 21779844 TI - Violacein and related tryptophan metabolites produced by Chromobacterium violaceum: biosynthetic mechanism and pathway for construction of violacein core. AB - Violacein is a natural violet pigment produced by several gram-negative bacteria, including Chromobacterium violaceum, Janthinobacterium lividum, and Pseudoalteromonas tunicata D2, among others. This pigment has potential medical applications as antibacterial, anti-trypanocidal, anti-ulcerogenic, and anticancer drugs. The structure of violacein consists of three units: a 5 hydroxyindole, an oxindole, and a 2-pyrrolidone. The biosynthetic origins of hydrogen, nitrogen, and carbon in the pyrrolidone nucleus were established by feeding experiments using various stable isotopically labeled tryptophans (Trps). Pro-S hydrogen of CH(2) at the 3-position of Trp is retained during biosynthesis. The nitrogen atom is exclusively from the alpha-amino group, and the skeletal carbon atoms originate from the side chains of the two Trp molecules. All three oxygen atoms in the violacein core are derived from molecular oxygen. The most interesting biosynthetic mechanism is the 1,2-shift of the indole nucleus on the left side of the violacein scaffold. The alternative Trp molecule is directly incorporated into the right side of the violacein core. This indole shift has been observed only in violacein biosynthesis, despite the large number of natural products having been isolated. There were remarkable advances in biosynthetic studies in 2006-2008. During the 3 years, most of the intermediates and the complete pathway were established. Two independent processes are involved: the enzymatic process catalyzed by the five proteins VioABCDE or the alternative nonenzymatic oxidative decarboxylation reactions. The X-ray crystallographic structure of VioE that mediates the indole rearrangement reaction was recently identified, and the mechanism of the indole shift is discussed here. PMID- 21779845 TI - A new Bacillus megaterium whole-cell catalyst for the hydroxylation of the pentacyclic triterpene 11-keto-beta-boswellic acid (KBA) based on a recombinant cytochrome P450 system. AB - The use of cytochromes P450 for the regio- and stereoselective hydroxylation of non-activated carbon atoms in biotechnological applications reflects an efficient and cost-effective alternative in comparison to classical organic chemistry. The prokaryotic cytochrome P450 CYP106A2 from Bacillus megaterium ATCC 13368 hydroxylates a variety of 3-oxo-Delta4 steroids and recently it was identified to carry out a one-step regioselective allylic hydroxylation of the diterpene abietic acid. The anti-inflammatory pentacyclic triterpene 11-keto-beta-boswellic acid (KBA) was found to be a further substrate of CYP106A2, being the first report of a pentacyclic triterpene conversion by a prokaryotic P450. The reaction products were analyzed by HPLC and the corresponding kinetic parameters were investigated. Structure determination of the main product by NMR revealed a 15alpha-hydroxylation of this substrate. In order to overcome the inability of a recombinant P450 whole-cell system in E. coli for the uptake of acids with terpene structure, we developed for the first time an expression system for cytochromes P450 in B. megaterium (strains MS941 and ATCC 13368). Interestingly, CYP106A2 was only successfully expressed in the plasmid-less B. megaterium strain MS941 but not in ATCC13368. This recombinant system, with the co-expressed heterologous redox chain of the P450, bovine adrenodoxin reductase (AdR), and bovine adrenodoxin (Adx), was applied for the whole-cell conversion of KBA. The formation of 15alpha-hydroxy-KBA was increased 15-fold in comparison with the naturally CYP106A2-expressing B. megaterium strain ATCC 13368. PMID- 21779846 TI - Pseudomonas putida esterase contains a GGG(A)X-motif confering activity for the kinetic resolution of tertiary alcohols. AB - An esterase from Pseudomonas putida JD1 (PPE) was successfully cloned, actively expressed in Escherichia coli, and characterized. It was discovered that PPE is more active towards short-chain esters, hydrolyzed delta-valerolactone, and epsilon-caprolactone and was most active at 37 degrees C and pH 8. After purification to homogeneity by Ni-NTA-assisted affinity chromatography, the kinetic parameters K(M) and k(cat) were determined for p-nitrophenyl acetate and butyrate, respectively, showing better catalytic efficiency for hydrolysis of the acetate residue. Investigation of the protein sequence revealed not only the classical catalytic triad for carboxylesterases, additionally the interesting GGG(A)X-motif, which is associated to activity towards tertiary alcohols, was found. Indeed, enzymatic activity was shown for a set of different tertiary alcohols with enantioselectivities up to E = 20, suggesting PPE to be a promising biocatalyst. In addition, PPE also hydrolyzed 4-hydroxyphenyl acetate, the product of a Baeyer-Villiger monooxygenase-catalyzed oxidation of 4 hydroxyacetophenone with a specific activity of 34.36 U/mg suggesting a physiological role in P. putida JD1. PMID- 21779847 TI - The cytotoxicity and anticancer mechanisms of alterporriol L, a marine bianthraquinone, against MCF-7 human breast cancer cells. AB - Alterporriol L, a new bianthraquinone derivative, was isolated from a marine fungus Alternaria sp. ZJ9-6B. The cytotoxic activity and anticancer mechanisms of alterporriol L towards breast cancer cells lines were detected using MTT assay, immunofluorescence, and flow cytometry. Simultaneously, the changes in morphological properties of cells were detected before and after treatment with alterporriol L by atomic force microscope (AFM) at a nanometer scale. MTT assay showed that alterporriol L could effectively inhibit the growth and proliferation, and there was a dose-dependent manner of cell death. Moreover, the alterporriol L could induce cancer cell apoptosis or necrosis. Furthermore, the reactive oxygen species, mitochondrial membrane potential, and cytosolic free calcium level were changed after treatment with alterporriol L, suggesting that alterporriol L played vital roles in breast cancer cells through destroying the mitochondrial. And all these alterations are in accord with changes of morphology detected by AFM, which suggested that the AFM is a useful tool to detect the morphological changes of the cancer cells. PMID- 21779848 TI - Arginine-vasopressin and corticosteroids in septic shock: engaged but not yet married! PMID- 21779849 TI - Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality. AB - PURPOSE: To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients. METHODS: This retrospective study included severe septic shock patients treated with supplementary AVP. To test the association between concomitant AVP/hydrocortisone use and mortality, a multivariate regression and Cox model (adjusted for admission year, initial AVP dosage and the Sepsis-related Organ Failure Assessment score before AVP) as well as a propensity score-based analysis were used. In both models, intensive care unit (ICU) and 28-day mortality served as outcome variables. RESULTS: One hundred fifty-nine patients were included. Hydrocortisone was administered to 76 (47.8%) at a median daily dosage of 300 (200-300) mg. In the multivariate logistic regression model, concomitant use of AVP and hydrocortisone was associated with a trend towards lower ICU (OR, 0.51; CI 95%, 0.24-1.08; p = 0.08) and 28-day (HR, 0.69; CI 95%, 0.43-1.08; p = 0.11) mortality. The probability of survival at day 28, as predicted by the regression model, was significantly higher in patients treated with concomitant AVP and hydrocortisone compared to those receiving AVP without hydrocortisone (p = 0.001). In a propensity score-based analysis, ICU (45 vs. 65%; OR, 0.69; CI 95% 0.38-1.26; p = 0.23) and 28-day mortality (35.5 vs. 55%; OR, 0.59; CI 95%, 0.27 1.29; p = 0.18) was not different between patients treated with (n = 40) or without concomitant hydrocortisone (n = 40). CONCLUSION: Concomitant AVP and hydrocortisone therapy may be associated with a survival benefit in septic shock. An adequately powered, randomised controlled trial appears warranted to confirm these preliminary, hypothesis-generating results. PMID- 21779850 TI - Erythropoietic neuroprotection: Holy Grail or potential to fail? PMID- 21779852 TI - Prediction of pandemic influenza. PMID- 21779851 TI - Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. AB - PURPOSE: Recombinant human erythropoietin (rhEPO) attenuated ischemia/reperfusion (I/R) injury-induced spinal cord damage. Since carbamylated EPO derivatives are stated to be devoid of rhEPO side effects, we tested the hypothesis that a newly developed carbamylated EPO-FC fusion protein (cEPO-FC) would compare favorably with rhEPO. METHODS: Anesthetized and mechanically ventilated pigs randomly received cEPO-FC (50 MUg kg(-1)), rhEPO (5,000 IU kg(-1)) or vehicle (n = 9 per group) 30 min prior to 30 min of aortic occlusion and over the 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80-120% of baseline values by esmolol, nitroglycerin, and adenosine-5' triphosphate (ATP). During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Spinal cord function was assessed by motor evoked potentials (MEP) and lower limb reflexes. Tissue damage was evaluated using hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Plasma levels of interleukin-6, tumor necrosis factor-alpha, and 8-isoprostanes were measured as markers of systemic inflammation and oxidative stress. RESULTS: While only cEPO-FC restored MEP amplitude to values close to pre-occlusion levels, both cEPO-FC and rhEPO comparably restored lower limb reflexes and reduced the percentage of damaged neurons. Infiltration of mononuclear inflammatory cells was moderate without intergroup difference; positive TUNEL staining was barely detectable in any group. I/R injury increased blood cytokine levels without intergroup difference, whereas both cEPO-FC and rhEPO significantly lowered 8-isoprostane levels. CONCLUSIONS: In a porcine model of aortic balloon occlusion-induced spinal cord I/R injury, cEPO-FC and rhEPO comparably protected against ischemic spinal cord dysfunction and neuronal damage. This effect coincided with attenuated oxidative stress. PMID- 21779853 TI - Late adverse reactions to intravascular iodine based contrast media: an update. AB - DEFINITION: Late adverse reactions (LAR) to contrast media (CM) are defined as reactions occurring 1 h to 1 week after exposure. NEED FOR REVIEW: In view of more prospective studies of LAR and new data about their pathophysiology, the Contrast Medium Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) reviewed the literature on LAR and updated their guidelines. CLINICAL FEATURES AND PATHOLOGY: LAR after CM include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. Skin reactions are well-documented LAR to CM with an incidence of approximately 2%-4% after nonionic monomers. LAR are commoner by a factor of three to four after nonionic dimers. The commonest skin reactions are maculopapular rashes, erythema and skin swelling. These reactions are T cell-mediated immune reactions, and the diagnosis may be confirmed using skin tests (patch or delayed reading intradermal). The main risk factors for LAR are a previous reaction to contrast medium, a history of allergy, and interleukin-2 treatment. Most skin reactions are mild or moderate and self-limiting. MANAGEMENT: Management is symptomatic and similar to the management of other drug-induced skin reactions. To reduce the risk of repeat reactions avoidance of the relevant CM and any cross-reacting agents identified by skin testing is recommended. PMID- 21779854 TI - Longitudinal study of bone mineral density in children with idiopathic hypercalciuria. AB - Children with idiopathic hypercalciuria (IH) may have a reduced bone mineral density (BMD), which could impact on bone health in adulthood. There is currently no strong evidence for a preferred treatment of such children. The aim of our study was to evaluate the BMD z-score before and after treating children and adolescents with IH with potassium citrate and thiazides. The study consisted of a historical cohort of 80 pediatric patients who were evaluated between October 1989 and November 2010. Bone scanning and densitometry measurements were made with dual-emission X-ray absorptiometry. Lumbar-spine BMD (g/cm(2)) and BMD z score were evaluated before and after treatment. The t test and Mann-Whitney U test were used for statistical analysis. Forty-three boys and 37 girls were followed for a median time of 6.0 years. Median calcium excretion before and after treatment was 5.0 and 2.6 mg/kg/24 h, respectively. The BMD z-score changed significantly from -0.763 +/- 0.954 (mean +/- SD) to -0.537 +/- 0.898 (p < 0.0001) before and after treatment, respectively. The BMD z-score of the patients improved with treatment, suggesting a beneficial effect and potential need for treatment. However, the lack of a control group points to the need for future studies to corroborate this outcome. PMID- 21779855 TI - Impact of magnetic resonance imaging on decision making for thoracolumbar traumatic fracture diagnosis and treatment. AB - INTRODUCTION: The role of magnetic resonance imaging (MRI) has recently been enhanced in the diagnosis of thoracolumbar fractures due to its ability to examine soft tissue injury. MATERIAL AND METHODS: We conducted a prospective study to analyze the usefulness of MRI in fracture diagnosis and its influence on treatment decision making. Thirty-three patients were enrolled after suffering an acute traumatic thoracolumbar fracture. Osteoporotic or pathologic fractures were excluded. Fractures were initially classified using X-ray and CT scan following the AO classification. Afterward, a selective MRI protocol was performed with T1 and T2-weighted FS/STIR sequences. Subsequently, fractures were classified according to the TLICS system and reclassified following the AO system. Analysis was performed before and after MRI, focusing on: diagnostic changes, occult fractures and differences in treatment decision making. RESULTS: Thirty patients (15 males, 15 females) with an average age of 39.9 years were studied. Forty-one fractures were initially diagnosed using plain X-rays and CT scans, while MRI diagnosed 50 fractures and 9 vertebral contusions. MRI modified our diagnosis in 40% of our patients (discovering 18 occult injuries), the classification of fracture pattern in 24% of the fractures (mostly upgrading type A to type B patterns) and the therapeutic management in 16% of our patients. CONCLUSIONS: MRI seems to be a useful tool in the evaluation of thoracolumbar acute fractures, as it allows a better visualization of the posterior complex integrity and of the levels involved, offering additional information compared to traditional diagnostic tools. PMID- 21779856 TI - Vertebral growth modulation by hemicircumferential electrocoagulation: an experimental study in pigs. AB - INTRODUCTION: This experimental study in pigs was aimed at evaluating spinal growth disorders after partial arrest of the vertebral epiphyseal plates (EP) and neurocentral cartilages (NCC). Unilateral and multisegmental single or combined lesions of the physeal structures were performed by electrocoagulation throughout a video-assisted thoracoscopical approach. MATERIALS AND METHODS: Thirty 4-week old domestic pigs (mean weight 16 kg) were included in the experiments. The superior and inferior epiphyseal plates of T5 to T9 vertebra were damaged in ten animals by hemicircumferential electrocoagulation (group I). In other ten pigs (group II), right NCC at the same T5-T9 levels were damaged. Ten other animals underwent combined lesions of the ipsilateral hemiepiphyseal plates and NCC at the T5-T9 levels. A total of 26 animals could be evaluated after 12 weeks of follow-up using conventional X-rays, CT scans and histology. RESULTS: The pigs with hemicircumferential EP damage developed very slight concave non-structured scoliotic deformities without vertebral rotation.(mean 12 degrees Cobb; range10 16 degrees ). Some of the damaged vertebra showed a marked wedgening with unilateral development alteration of the vertebral body, including the adjacent discs The animals with damage of the NCC developed mild scoliotic curves (mean 19 degrees Cobb; range 16-24 degrees ) with convexity opposite to the damaged side and loss of physiological kyphosis. The injured segments showed an asymmetric growth with hypoplasia of the pedicle and costovertebral joints at the damaged side. The pigs undergoing combined EP and NCC lesions developed minimal non structured curves, ranging from 10 to 12 degrees Cobb. In these animals there was a lack of growth of a vertebral hemibody and disc hypoplasia at the damaged segments. Both damage of the NCC and the EP affect the height of the vertebral body. No spinal stenosis was found in any case. In most cases, the adjacent superior and inferior vertebral EP to damaged segments had a compensatory growth that maintained the straight spinal shape. CONCLUSIONS: In summary, unilateral direct lesion of the EP by hemicircumferential thoracoscopic electrocoagulation modifies vertebral growth, but is not able to induce true scoliostic curves in pigs. Only animals with damaged NCC developed mild scoliotic curves of lordotic type. This work rediscovers and emphasizes the decisive role of the neurocentral cartilage in the ethiopatogeny of idiopathic scoliosis. PMID- 21779857 TI - Beneficial effects of aerobic training in adolescent patients with moderate idiopathic scoliosis. AB - AIM AND METHODS: The major aim of this study was to determine whether after 6 weeks of aerobic training adolescent idiopathic scoliosis (AIS) girls who suffer from mild scoliotic curvatures (n = 6) behaved in a similar way than healthy controls (n = 6) in different biochemical, anthropometric, and cardio respiratory parameters. RESULTS: The maximal power output and the power output achieved at the anaerobic threshold (AT), during the maximal exercise test, were significantly increased in both experimental groups, when compared with resting conditions. The training program caused significant changes in body composition (i.e., a decrease in body fat %) only in the scoliotic group. Regarding the cardio respiratory measurements, VO(2max) was increased by 17% in AIS group and 10% in the healthy group. CONCLUSIONS: Our results suggest that physical activity should be encouraged in scoliotic girls with mild curvatures. PMID- 21779858 TI - Titanium and tantalum as mesenchymal stem cell scaffolds for spinal fusion: an in vitro comparative study. AB - INTRODUCTION: In the last few years, great interest has been focused on tissue engineering as a potential therapeutic approach for musculoskeletal diseases. The role of metallic implants for spinal fusion has been tested in preclinical and clinical settings. Titanium and tantalum have excellent biocompatibility and mechanical properties and are being used in this situation. On the other hand, the therapeutic role of mesenchymal stem cells (MSC) is extensively explored for their multilineage differentiation into osteoblasts. OBJECTIVES: In vitro comparison of titanium and tantalum as MSCs scaffolds. MATERIAL AND METHODS: In the present study, we have compared the in vitro expansion capacity, viability, immunophenotype (both explored by flow cytometry) and multi-differentiation ability of MSC cultured in the presence of either titanium or tantalum fragments. The adherence of MSC to either metal was demonstrated by electron microscopy. RESULTS: Both metals were able to carry MSC when transferred to new culture flasks. In addition, our study shows that culture of MSC with titanium or tantalum improves cell viability and maintains all their biological properties, with no significant differences regarding the metal employed. CONCLUSION: This would support the use of these combinations for clinical purposes, especially in the spinal fusion and reconstruction setting. PMID- 21779859 TI - The relevance of intramedullary high signal intensity and gadolinium (Gd-DTPA) enhancement to the clinical outcome in cervical compressive myelopathy. AB - PURPOSE: We prospectively investigated whether high intramedullary SI and contrast [gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA)] enhancement in magnetic resonance imaging (MRI) are associated with postoperative prognosis in cervical compressive myelopathy (CCM) patients. METHODS: Seventy-four patients with ventral cord compression at one or two levels underwent anterior cervical discectomy and fusion (ACDF) for CCM between March 2006 and June 2009. The mean follow-up period was 39.7 months (range, 12.7-55.7 months). The cervical cord compression ratio and clinical outcomes were measured using Japanese Orthopedic Association (JOA) scores for cervical myelopathy. Patients were classified into three groups based on the SI change in T2WI, T1-weighted images (T1WI), and contrast (Gd-DTPA) enhancement. RESULTS: The mean preoperative and postoperative JOA scores were 10.5 +/- 2.9 and 15.0 +/- 2.1 (P < 0.05), respectively. The mean recovery ratio of the JOA score was 70.9 +/- 20.2%. There were statistically significant differences in postoperative JOA and recovery ratio among three groups. However, post-surgical neurological outcomes were not associated with age, symptom duration, preoperative JOA, and cord compression. CONCLUSIONS: We found that intramedullary SI change is a poor prognostic factor and the intramedullary contrast (Gd-DTPA) enhancement on preoperative MRI should be viewed as the worst predictor of surgical outcomes in cervical myelopathy. Contrast (Gd-DTPA) enhancement and postoperative MRI are useful for identifying the prognosis of patients with poor neurological recovery. PMID- 21779860 TI - Cloning, expression, and characterization of Schistosoma japonicum tegument protein phosphodiesterase-5. AB - The tegument proteins of schistosomes are regarded as potential vaccine candidates and drug targets to control schistosomiasis. Nucleotide pyrophosphatase/phosphodiesterase-5 (NPP-5), which belongs to a multigene family of nucleotide pyrophosphatase/phosphodiesterases (NPPs), is important in the hydrolysis of pyrophosphate or phosphodiester bonds in nucleotides and their derivatives. In the present study, SjNPP-5, identified as one of the tegument proteins of Schistosoma japonicum in our previous proteomic studies, was cloned on a fragment of 1,371 bp and expressed as a recombinant protein of 69 kDa. Real time RT-PCR analysis showed that SjNPP-5 was up-regulated at 21-42 days, and the expression level in 42-day-old male worms was almost nine times higher than that in females. Western blot analysis revealed that rSjNPP-5 had good antigenicity. Immunofluorescence analysis found that SjNPP-5 was a membrane-associated antigen mainly distributed on the surface of the male adult worm of S. japonicum. BALB/c mice vaccinated with rSjNPP-5 three times showed a 29.90% worm reduction (P < 0.05) and a 26.21% egg count reduction (P > 0.05). Immunization with rSjNPP-5 induced a mixed Th1/Th2 response in which Th1 was dominant. The response was characterized by a reduced IgG1/IgG2a ratio and elevated production of cytokines IFN-gamma and IL-4. This study suggested that SjNPP-5 may be important in schistosome development, and further investigations are required to fully understand the function of this molecule. PMID- 21779861 TI - First report on susceptibility of wild Aedes aegypti (Diptera: Culicidae) using Carapa guianensis (Meliaceae) and Copaifera sp. (Leguminosae). AB - Oils of Carapa guianensis and Copaifera spp. are well known in the Amazonian region as natural insect repellent, and studies have reported their efficiency as larvicide against some laboratory mosquito species. However, in wild populations of mosquitoes, these oils have not yet been evaluated. Thus, the objective of this study was to investigate their efficiency as larvicide in wild populations of Aedes aegypti with a history of exposure to organophosphate. The susceptibility of larvae was determined under three different temperatures, 15 degrees C, 20 degrees C, and 30 degrees C. For each test, 1,000 larvae were used (late third instar and early fourth instar-four replicates of 25 larvae per concentration). Statistical tests were used to identify significant differences. The results demonstrated that as the laboratory A. aegypti, the wild populations of A. aegypti were also susceptible to C. guianensis and Copaifera sp. oils. The lethal concentrations for Copaifera sp. ranged from LC(50) 47 to LC(90) 91 (milligrams per liter), and for C. guianensis, they were LC(50) 136 to LC(90) 551 (milligrams per liter). In relation to different temperature, the effectiveness of the oils on larvae mortality was directly related to the increase of temperature, and better results were observed for temperature at 25 degrees C. The results presented here indicate the potential larvicidal activity of C. guianensis and species of Copaifera, in populations of A. aegypti from the wild. Therefore, the results presented here are very important since such populations are primarily responsible for transmitting the dengue virus in the environment. PMID- 21779862 TI - ELISA and some biochemical tests of heterophyidae infection in laboratory animals. AB - Heterophyiasis is an important food-borne parasitic zoonosis in Egypt, among the inhabitants living around brackish-water lakes especially fishermen, and it is a common human parasite in the Nile Delta. The experiment was done on two laboratory animals (rats and dogs), and the time of sample collection was done periodically at 6, 9, 15, 21, and 28 days post-infection to evaluate different tests required. Whole blood was collected with heparin or ethylenediamine tetra acetic acid as anticoagulant to help in the hematological studies such as red blood cells count (RBCs), white blood cells count, packed cell volume (PCV), and hemoglobin (Hb). Only marked increase in the total leuckocytic count was recorded while RBCs, PCV, and Hb were decreased in most of the results obtained. Total protein and globulin decreased while albumin and A/G ratio increased. Liver enzymes showing marked increase in aspartate aminotransferase and increase in alanine aminotransferase in dogs and rats denoting that liver has a role in the response to that infection. Kidney-function tests, urea, and creatinine showed slight increase at 6 days post-infection (d.p.i.). After preparation of different Ag (antigen) from different collected helminthes, the protein content of each was determined. The sera of infected animals were collected to find antibodies in their blood against the parasite using enzyme-linked immunosorbent assay and using crude heterophyid antigen collected from their intestines after scarification. The worms washed, homogenized, and then centrifuged to collect supernatant fluid as antigens. The results indicated that antibody starts to appear at 9 d.p.i. and increases till 21 and 28 d.p.i. and detection depends on antigen concentration. PMID- 21779863 TI - Enhancing the acaricide effect of thymol on larvae of the cattle tick Rhipicephalus microplus (Acari: Ixodidae) by solubilization in ethanol. AB - The aim of the present work was to propose a new method of solubilizing thymol for use as an acaricide and to evaluate the resulting product's efficacy on Rhipicephalus microplus larvae. Two experiments were performed, both employing the larval packet test to evaluate the potential of the solutions formulated. In the first experiment, R. microplus larvae were exposed to three new formulations: formulation 1-distilled water (70%) + ethanol (30%) + thymol (10.0 mg/ml); formulation 2-distilled water (50%) + ethanol (50%) + thymol (10.0 mg/ml); and formulation 3-distilled water (55%) + ethanol (40%) + DMSO (5%) + thymol (10.0 mg/ml). A control was prepared for each formulation (same formulations except thymol), and another control group was formed where the larvae did not receive any treatment. From the results obtained in the first experiment, the formulation with the best performance and cost-benefit relation was chosen and was tested at concentrations of 2.5, 5.0 and 10.0 mg/ml on larvae of this tick. In the first experiment, the mortality of the groups treated with thymol was greater than 95% for all three formulations, with significant differences (p < 0.05) in comparison with the control groups, where the mortality was under 1%. In the second experiment, formulation 2 was selected because of its better cost-benefit relation, and the mortality rates were 94.0%, 96.5% and 99.9% for the concentrations of 2.5, 5.0 and 10.0 mg/ml, respectively, demonstrating that thymol dissolved in ethanol has high acaricide activity on cattle tick larvae. PMID- 21779864 TI - Temperature and the development and survival of infective Toxocara canis larvae. AB - The influence of temperature on the development and survival of Toxocara canis larvae was investigated under laboratory conditions, in water at 15, 20, 25, 30 and 35 degrees C and at room temperature 22 degrees C +/- 1 degrees C. T. canis eggs were able to develop to the larvated stage at all the tested temperatures. Development rate increased with temperature. Linear regression of development rate against temperature predicted a lower development threshold of 11.8 degrees C. Eggs survived cooling to 1 and -2 degrees C for 6 weeks, and could develop to the infective, larvated stage when transferred to higher temperatures, but their development rates were then retarded compared with non-chilled eggs. Larvated eggs remained viable after 7 weeks of incubation across the tested temperature range, with the highest percentage viability (47%) obtained at 25 degrees C. Development of eggs to the infective larval stage required, on average, 121 degree days between 20 degrees C and 30 degrees C. Results provide a basis for predicting variation in the infectivity of eggs in the environment over time in different climates. PMID- 21779866 TI - Validity of goniometric elbow measurements: comparative study with a radiographic method. AB - BACKGROUND: A universal goniometer is commonly used to measure the elbow's ROM and carrying angle; however, some authors question its poor intertester reliability. QUESTIONS/PURPOSES: We (1) assessed the validity of goniometric measurements as compared with radiographic measurements in the evaluation of ROM of the elbow and (2) determined the reliability of both. METHODS: The ROM and carrying angle of 51 healthy subjects (102 elbows) were measured using two methods: with a universal goniometer by one observer three times and on radiographs by two independent examiners. Paired t-test and Pearson's correlation were used to compare and detect the relationship between mean ROM. The maximal error was calculated according to the Bland and Altman method. RESULTS: The intraclass correlation coefficients (ICC) ranged from 0.945 to 0.973 for the goniometric measurements and from 0.980 to 0.991 for the radiographic measurements. The two methods correlated when measuring the total ROM in flexion and extension. The maximal errors of the goniometric measurement were 10.3 degrees for extension, 7.0 degrees for flexion, and 6.5 degrees for carrying angle 95% of the time. We observed differences for maximum flexion, maximal extension, and carrying angle between the methods. CONCLUSION: Both measurement methods differ but they correlate. When measured with a goniometer, the elbow ROM shows a maximal error of approximately 10 degrees . CLINICAL RELEVANCE: The goniometer is a reasonable and simple clinical tool, but for research protocols, we suggest using the radiographic method because of the higher level of precision required. PMID- 21779867 TI - Reverse total shoulder arthroplasty: editorial comment. PMID- 21779868 TI - Human embryonic stem cell-derived neurons establish region-specific, long-range projections in the adult brain. AB - While the availability of pluripotent stem cells has opened new prospects for generating neural donor cells for nervous system repair, their capability to integrate with adult brain tissue in a structurally relevant way is still largely unresolved. We addressed the potential of human embryonic stem cell-derived long term self-renewing neuroepithelial stem cells (lt-NES cells) to establish axonal projections after transplantation into the adult rodent brain. Transgenic and species-specific markers were used to trace the innervation pattern established by transplants in the hippocampus and motor cortex. In vitro, lt-NES cells formed a complex axonal network within several weeks after the initiation of differentiation and expressed a composition of surface receptors known to be instrumental in axonal growth and pathfinding. In vivo, these donor cells adopted projection patterns closely mimicking endogenous projections in two different regions of the adult rodent brain. Hippocampal grafts placed in the dentate gyrus projected to both the ipsilateral and contralateral pyramidal cell layers, while axons of donor neurons placed in the motor cortex extended via the external and internal capsule into the cervical spinal cord and via the corpus callosum into the contralateral cortex. Interestingly, acquisition of these region-specific projection profiles was not correlated with the adoption of a regional phenotype. Upon reaching their destination, human axons established ultrastructural correlates of synaptic connections with host neurons. Together, these data indicate that neurons derived from human pluripotent stem cells are endowed with a remarkable potential to establish orthotopic long-range projections in the adult mammalian brain. PMID- 21779869 TI - Adipose tissue mass and location affect circulating adiponectin levels. AB - AIMS/HYPOTHESIS: Plasma levels of adiponectin are inversely associated with body mass. We hypothesised that adipose tissue distribution and body composition influences adiponectin levels. METHODS: We assessed plasma adiponectin concentrations and dual-energy X-ray absorptiometry (DEXA) measurements of body composition among 2,820 participants from the Dallas Heart Study. RESULTS: Among both women and men, adiponectin levels were higher in whites than in either Hispanics or African-Americans (for women: median 9.99 MUg/ml [25th,75th percentile 7.11, 13.77] vs 7.56 MUg/ml [5.05, 9.98] vs 6.39 MUg/ml [4.37, 9.41], respectively, p < 0.0001; for men: 6.43 MUg/ml [4.66, 9.19] vs 5.55 MUg/ml [3.64, 7.50] vs 5.03 MUg/ml [3.39, 7.28], p < 0.0001). In univariate analysis, each individual component of body mass was inversely associated with adiponectin. After multivariate analysis, adiponectin levels were found to be positively associated with lower extremity fat, whether expressed in absolute mass (for women: beta = 0.055, p < 0.0001; for men: beta = 0.061, p < 0.0001), or as a relative proportion (for women: beta = 0.035, p < 0.0001; for men: beta = 0.034, p < 0.0001). This association was consistent across ethnicities. Conversely, adiponectin was negatively correlated with truncal fat, both in absolute (for women: beta = -0.039, p < 0.0001; for men: beta = -0.044, p < 0.0001) and relative terms (for women: beta = -0.027, p < 0.0001; for men beta = -0.033, p < 0.0001). At the extreme of body mass, higher degrees of lower extremity and truncal adiposity were associated with higher levels of adiponectin. CONCLUSIONS/INTERPRETATION: These data suggest that the location of adipose depots differentially influences circulating adiponectin concentrations-a finding observed across ethnicity and sex. Gross measures of body mass alone do not adequately account for adiponectin levels. This supports a role of adiponectin as a mediator of the positive effects of lower extremity adiposity on improvements in insulin sensitivity. PMID- 21779870 TI - Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. AB - AIMS/HYPOTHESIS: The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic beta cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR islets suggesting an epigenetic mechanism. Exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) analogue, given in the newborn period increases Pdx1 expression and prevents the development of diabetes in the IUGR rat. METHODS: IUGR was induced by bilateral uterine artery ligation in fetal life. Ex 4 was given on postnatal days 1-6 of life. Islets were isolated at 1 week and at 3-12 months. Histone modifications, PCAF, USF1 and DNA methyltransferase (Dnmt) 1 binding were assessed by chromatin immunoprecipitation (ChIP) assays and DNA methylation was quantified by pyrosequencing. RESULTS: Phosphorylation of USF1 was markedly increased in IUGR islets in Ex-4 treated animals. This resulted in increased USF1 and PCAF association at the proximal promoter of Pdx1, thereby increasing histone acetyl transferase (HAT) activity. Histone H3 acetylation and trimethylation of H3K4 were permanently increased, whereas Dnmt1 binding and subsequent DNA methylation were prevented at the proximal promoter of Pdx1 in IUGR islets. Normalisation of these epigenetic modifications reversed silencing of Pdx1 in islets of IUGR animals. CONCLUSIONS/INTERPRETATION: These studies demonstrate a novel mechanism whereby a short treatment course of Ex-4 in the newborn period permanently increases HAT activity by recruiting USF1 and PCAF to the proximal promoter of Pdx1 which restores chromatin structure at the Pdx1 promoter and prevents DNA methylation, thus preserving Pdx1 transcription. PMID- 21779872 TI - The disparity between long-term survival in patients with and without diabetes following a first myocardial infarction did not change between 1989 and 2006: an analysis of 6,776 patients in the Northern Sweden MONICA Study. AB - AIMS/HYPOTHESIS: Long-term survival after myocardial infarction (MI) has improved in the population, but data on diabetic patients is lacking. We analysed survival for up to 18 years after a first MI in patients with or without diabetes. METHODS: The Northern Sweden MONICA Myocardial Infarction Registry was linked to the Cause-of-Death Registry for a total of 6,776 patients, 25-64 years of age, with a first MI during 1989-2006. Prehospital deaths were included. Follow-up ended on 30 August 2008. RESULTS: Sixteen per cent had diabetes. Median follow-up time was 6.8 years, and the study included 50,667 patient-years. One third of the non-diabetic patients died vs half of the diabetic patients. Median survival for non-diabetic men was 227 months and for diabetic men 123 months. Corresponding figures for the non-diabetic and diabetic women were 222 and 81 months respectively. Men with diabetes had an age-adjusted HR for all-cause mortality of 1.56 (95% CI 1.39, 1.79) vs men without diabetes. Mortality risk was higher among diabetic women, HR 1.97 (1.62, 2.39) (diabetes * sex interaction, p = 0.03). Survival increased for three consecutive cohorts and was higher in non-diabetic patients for all durations of follow-up and in all three cohorts. The interaction of diabetes x cohort was not significant over time (p = 0.5) and HRs did not differ either. CONCLUSIONS/INTERPRETATION: Long-term survival after a first MI is markedly lower in diabetic patients, especially among women, over an 18-year observation time. Although survival has improved in diabetic patients, the effect of diabetes upon mortality has not diminished. PMID- 21779871 TI - Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome. AB - AIMS/HYPOTHESIS: Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2 driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. METHODS: We generated a model of the metabolic syndrome by backcrossing KKAy ( + ) with Apoe ( -/- ) mice (KKAy ( + ) Apoe ( -/- )) and studied the role of CCR2 in this model system. RESULTS: KKAy ( + ) Apoe ( -/- ) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe ( -/- ) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CONCLUSIONS/INTERPRETATION: CCR2 driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome. PMID- 21779873 TI - Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program. AB - AIMS/HYPOTHESIS: Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. METHODS: We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. RESULTS: We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype * treatment interactions at 1 year. CONCLUSIONS/INTERPRETATION: In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year. PMID- 21779874 TI - Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. AB - AIMS/HYPOTHESIS: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. METHODS: Male mice (C57BL/6J) were habituated to a corn-oil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF + F), ad libitum; (3) cHF with calorie restriction (CR; cHF + CR); and (4) cHF + F + CR. Mice fed a chow diet were also studied. RESULTS: We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Delta(12,15) prostaglandin J(2) and protectin D1. CONCLUSIONS/INTERPRETATION: White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome. PMID- 21779875 TI - The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure. AB - Some anticancer chemotherapeutics, such as anthracyclines and oxaliplatin, elicit immunogenic apoptosis, meaning that dying cancer cells are engulfed by dendritic cells and tumor antigens are efficiently presented to CD8+ T cells, which control residual tumor cells. Immunogenic apoptosis is characterized by pre-apoptotic cell surface exposure of calreticulin (CRT), which usually resides into the endoplasmic reticulum. We investigated the ability of the n3-polyunsaturated fatty acid docosahexaenoic acid (22:6n3, DHA) to induce pre-apoptotic CRT exposure on the surface of the human PaCa-44 pancreatic and EJ bladder cancer cell lines. Cells were treated with 150 MUM DHA for different time periods, and, by immunoblot and immunofluorescence, we showed that DHA induced CRT exposure, before the apoptosis-associated phosphatidylserine exposure. As for the known immunogenic compounds, CRT exposure was inhibited by the antioxidant GSH, the pan caspase zVAD-FMK, and caspase-8 IETD-FMK inhibitor. We provide the first evidence that DHA induces CRT exposure, representing thus a novel potential anticancer immunogenic chemotherapeutic agent. PMID- 21779876 TI - Prognostic impact of B-cell density in cutaneous melanoma. AB - Studies on the prognostic importance of tumor-infiltrating lymphocytes have mainly focused on T cells, while little is known about the role of tumor infiltrating B lymphocytes. We investigated the prevalence of CD20(+) B cells by immunohistochemistry in primary melanoma samples of 106 patients and analyzed in relation to clinicopathological parameters and patients' survival. The majority of samples contained a significant amount of B lymphocytes, predominantly dispersed in the stroma surrounding tumor deposits (mean peritumoral and intratumoral densities: 178.7 +/- 156.1 vs. 4.9 +/- 6.9 cells/mm2, respectively). B cells organized in follicle-like aggregates were also observed in 26% of the samples. B-cell density correlated with that of activated (CD25(+) or OX40(+)) T lymphocytes. Infiltration by CD20(+) lymphocytes did not correlate with tumor thickness, while the presence of B-cell aggregates was observed more frequently in thick melanomas. On the other hand, B-cell infiltration was more pronounced in nonmetastatic or lymph node metastatic tumors, compared to visceral metastatic ones. Accordingly, high number of these cells provided significant survival advantage (P = 0.0391 and P = 0.0136 for intra- and peritumoral infiltration, respectively). Furthermore, combination of peritumoral B-cell density with the number of activated T lymphocytes identified patient subgroups with different disease outcome, which was most favorable in the case of high density, while very poor in the case of low density of both cell types. Multivariate survival analysis identified tumor thickness and CD20(+)/OX40(+) cell density combination as significant independent prognostic factors. Taken together, our results show correlation between low number of CD20(+) B lymphocytes and melanoma progression, indicating a possible role of tumor-infiltrating B cells in antitumoral immune response. It was also reflected in better outcome of the disease since the density of B lymphocytes alone as well as in combination with that of activated T cells proved of prognostic importance in patients with malignant melanoma. PMID- 21779877 TI - A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment. AB - IL-17A, produced by Th17 cells, may play a dual role in antitumor immunity. Using the GL261-glioma model, we investigated the effects of Th17 cells on tumor growth and microenvironment. Th17 cells infiltrate mouse gliomas, increase significantly in a time-dependent manner similarly to Treg and do not express Foxp3. To characterize the direct effects of Th17 cells on GL261 murine gliomas and on tumor microenvironment, we isolated IL-17-producing cells enriched from splenocytes derived from naive (nTh17) or glioma-bearing mice (gTh17) and pre stimulated in vitro with or without TGF-beta. Spleen-derived Th17 cells co expressing IL-17, IFN-gamma and IL-10, but not Treg marker Foxp3, were co injected intracranially with GL261 in immune-competent mice. Mice co-injected with GL261 and nTh17 survived significantly longer than gTh17 (P < 0.006) and gliomas expressed high level of IFN-gamma and TNF-alpha, low levels of IL-10 and TGF-beta. In vitro IL-17 per se did not exert effects on GL261 proliferation; in vivo gliomas grew equally well intracranially in IL-17 deficient and wild-type mice. We further analyzed relationship between Th17 cells and Treg. Treg were significantly higher in splenocytes from glioma-bearing than naive mice (P = 0.01) and gTh17 produced more IL-10 than IFN-gamma (P = 0.002). In vitro depletion of Treg using PC61 in splenocytes from glioma-bearing mice causes increased IL-17/IFN-gamma cells (P = 0.007) and decreased IL-17/IL-10 cells (P = 0.03). These results suggest that Th17 polarization may be induced by Treg and that Th17 cells in gliomas modulate tumor growth depending on locally produced cytokines. PMID- 21779878 TI - [Development of morbidity and mortality in ANCA-associated vasculitis]. AB - The outcome of ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis (AAV) has been significantly improved due to the combined use of cyclophosphamide (CYC) and glucocorticosteroids. Recent studies demonstrated a normalization of life expectancy for several subgroups of AAV patients. Mortality is highest in the first year after diagnosis and infections are the most frequent cause of death. Older age and renal failure are associated with worse outcome. The use of Pneumocystis jiroveci prophylaxis and subsequent activity-adapted GC dose reduction (target: below 10 mg per day) can substantially reduce the risk of severe infections. Late sequelae of CYC medication, such as cystitis and malignancy should be recognized and can be minimized by the usage of uroprotection with mesna and avoidance of high cumulative CYC doses. PMID- 21779880 TI - Intravascular fasciitis: report of an intraoral case and review of the literature. AB - Intravascular fasciitis (IF) is an unusual variant of nodular fasciitis. It is characterized by intraluminal, intramural, and extramural involvement of small to large arteries or veins. Only three cases involving the oral cavity have been reported previously in the literature. Here we present an additional case of oral IF arising in the submucosa of the upper lip of a 20-year old female. Microscopic examination showed a well-circumscribed, nodular proliferation of spindle cells arranged in intersecting fascicles. Occasional multinucleated giants cells also were noted. The tumor was present within the lumen of an intermediate-sized artery and extended into adjacent smaller vessels, thereby creating a multinodular appearance. Extramural extension into the surrounding connective tissue also was observed. Among the 31 cases of IF reported thus far (including the present case), the majority (n = 23) arose in individuals in the 1st through 3rd decades, with a 1.4:1 male:female ratio. The most common sites of involvement were the head and neck (n = 11) and upper extremity (n = 11), followed by the lower extremity (n = 6) and trunk (n = 3). Conservative excision is standard treatment, although local recurrence has been reported in three cases. It is important for the pathologist to be aware of this lesion in order to avoid misdiagnosis as a sarcoma with angioinvasion. PMID- 21779879 TI - The multifaceted roles of autophagy in tumors-implications for breast cancer. AB - Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment. PMID- 21779881 TI - [Sagittal deformity. Basic principles of surgical strategies]. AB - There is a large body of literature supporting the importance of restoring sagittal balance to the spine. The main message is this: regardless of the specific surgical strategy and treatment or pathology, rebalancing results in a positive patient outcome. Complex deformity patients need to be evaluated with attention to the global balance and the operative planning and strategy must be adapted accordingly. Spinal fusions are not always considered within the framework of sagittal balance. Unsuccessful outcome including continued pain, adjacent level disease, accelerated degenerative changes of the spine, pseudarthrosis and hip and knee changes, may then ensue. Certainly, those patients need to be re-evaluated with attention to the global balance of the spine. The reason for the outcome may be sagittal imbalance and osteotomy techniques as well as fusion extension may be needed. The postoperative outcome can only be improved when the sagittal balance is already considered in the planning and treatment strategy during initial correction surgery. Concerning sagittal balance a paradigm shift seems to occur. PMID- 21779882 TI - [Restoration of sagittal balance in treatment of thoracic and lumbar vertebral fractures]. AB - Posttraumatic kyphosis (PTK) is a possible consequence of a missed fracture, a wrong indication for conservative therapy or an inadequate surgical technique but PTK can also be a complication after adequate surgery. Avoidance of PTK is of importance because subsequent surgical therapy can be extensive. A thorough planning as well as surgical experience with anterior and posterior revision cases is necessary. The various types of osteotomy which allow correction of local as well as global deformities should also be mastered. Knowledge of the principles of sagittal balance and spinopelvic parameters are indispensable in the treatment of PTK. Our experience and results from the literature show that a good long-term outcome with limited complications can only be achieved when considering the biomechanical principles as well as restoration of sagittal balance. PMID- 21779883 TI - The use of fruiting synchrony by foraging mangabey monkeys: a 'simple tool' to find fruit. AB - Previous research has shown that a considerable number of primates can remember the location and fruiting state of individual trees in their home range. This enables them to relocate fruit or predict whether previously encountered fruit has ripened. Recent studies, however, suggest that the ability of primates to cognitively map fruit-bearing trees is limited. In this study, we investigated an alternative and arguably simpler, more efficient strategy, the use of synchrony, a botanical characteristic of a large number of fruit species. Synchronous fruiting would allow the prediction of the fruiting state of a large number of trees without having to first check the trees. We studied whether rainforest primates, grey-cheeked mangabeys in the Kibale National Park, Uganda, used synchrony in fruit emergence to find fruit. We analysed the movements of adult males towards Uvariopsis congensis food trees, a strongly synchronous fruiting species with different local patterns of synchrony. Monkeys approached within crown distance, entered and inspected significantly more Uvariopsis trees when the percentage of trees with ripe fruit was high compared to when it was low. Since the effect was also found for empty trees, the monkeys likely followed a synchrony-based inspection strategy. We found no indication that the monkeys generalised this strategy to all Uvariopsis trees within their home range. Instead, they attended to fruiting peaks in local areas within the home range and adjusted their inspective behaviour accordingly revealing that non-human primates use botanical knowledge in a flexible way. PMID- 21779884 TI - [First line therapy for local advanced or metastatic urothelial cell carcinoma: randomized phase II study to investigate the combination of vinflunine with gemcitabine and vinflunine with carboplatin in patients unfit for cisplatin therapy with advanced or metastatic urothelial cell carcinoma (JASINT-1 - AB 38/11) of AUO]. PMID- 21779885 TI - [The portrayal of tuberculosis in the motion picture "Robert Koch--Bekampfer des Todes". How do movies shape knowledge about diseases in urology and medicine?]. AB - Popular media have an immediate effect on an audience of millions. They are the base of social learning through the times. Therefore they deserve greater attention from professionals. The Nazi propaganda for example created an elaborate system, which made use of new technologies of the twentieth century, especially radio broadcasting and the movies. Escapism should be produced. Up to now those movies are shown on TV or in the cinema often without reference to their origin and intention which were later on regarded as harmless. As a consequence, "propaganda" is maintained in a very distinguished way. In 1945, the Allies first banned the showing of films made during the Nazi era and confiscated important documents. Those films regarded as "harmless" were soon released to the public again, but in the 1950s some 250 politically dubious films were still under lock and key. Interestingly, they often can be received via the Internet from other countries especially the USA. It only became clear over time that the propagandistic aims that found expression in some 1,100 films needed to be examined more carefully. PMID- 21779886 TI - Simultaneous bilateral subtrochanteric fractures following risedronate therapy. PMID- 21779887 TI - Long-term treatment of invasive sinus, tracheobroncheal, pulmonary and intracerebral aspergillosis in acute lymphoblastic leukaemia. AB - A 59-year-old male with acute lymphoblastic leukemia developed sinus, tracheobroncheal, pulmonary, and intracerebral aspergillosis. All lesions except the intracerebral aspergillosis healed after combination antifungal treatment. Long-term voriconazole--but not posaconazole--therapy induced partial regression of the cerebral manifestations. At the time of writing, 3.5 years after the initial diagnosis, the patient is working half-time and suffers from a possible voriconazole-induced polyneuropathy. PMID- 21779888 TI - Assessment of two immobilized lipases activity and stability to low temperatures in organic solvents under ultrasound-assisted irradiation. AB - Both stability and catalytic activity of two commercial immobilized lipases were investigated in the presence of different organic solvents in ultrasound-assisted system. In a general way, for Novozym 435, the use of ethanol as solvent led to a loss of activity of 35% after 10 h of contact. The use of iso-octane conducted to a gradual increase in lipase activity in relation to the contact time, reaching a maximum value of relative activity of 126%. For Lipozyme RM IM, after 5 h of exposure, the enzyme presented no residual activity when ethanol was used as solvent. The solvents tert-butanol and iso-octane showed an enhancement of about 20 and 17% in the enzyme activity in 6 h of exposure, respectively. Novozym 435 and Lipozyme IM presented high stability to storage after treatment under ultrasound-assisted system using n-hexane and tert-butanol as solvents. PMID- 21779889 TI - Anaerobic co-digestion of dairy manure with mulched switchgrass for improvement of the methane yield. AB - The owners of farm-scale anaerobic digesters are relying on off-farm wastes or energy crops as a co-digestion feedstock with animal manure in order to increase their production of methane and thus revenues. Switchgrass represents an interesting feedstock for Canadian digesters owners as it is a high-yielding low maintenance perennial crop, well adapted to northern climate. Methane potential assays in batch tests showed methane production of 19.4 +/- 3.6, 28.3 +/- 1.7, 37.3 +/- 7.1 and 45.7 +/- 0.8 L kg(-1), for raw manure, blended manure, manure and mulched switchgrass, manure and pretreated switchgrass, respectively. Two 6-L lab-scale anaerobic digesters were operated for 130 days in order to assess the benefit of co-digesting switchgrass with bovine manure (digester #2), at a 20% wet mass fraction, compared with a manure-only operation (digester #1) The digesters were operated at an hydraulic retention time of 37 +/- 6 days and at loads of 2.4 +/- 0.6 and 2.6 +/- 0.6 kg total volatile solids (TVS) L(-1) day(-1) for digesters #1 (D1) and #2 (D2), respectively. The TVS degradation reached 25 and 39%, which resulted in a methane production of 1.18 +/- 0.18 and 2.19 +/- 0.31 L day(-1) for D1 and D2, respectively. The addition of 20% on a wet mass ratio of switchgrass to a manure digester increased its methane production by 86%. The co-digestion of switchgrass in a 500 m(3) manure digester could yield up to 10.2 GJ day(-1) of purified methane or 1.1 MWh day(-1) of electricity. PMID- 21779890 TI - Improving cultivation processes for recombinant protein production. AB - An new cascade control system is presented that reproducibly keeps the cultivation part of recombinant protein production processes on its predetermined track. While the system directly controls carbon dioxide production mass and carbon dioxide production rates along their setpoint profiles in fed-batch cultivation, it simultaneously keeps the specific biomass growth rates and the biomass profiles on their desired paths. The control scheme was designed and tuned using a virtual plant environment based on the industrial process control system SIMATIC PCS 7 (Siemens AG). It is shown by means of validation experiments that the simulations in this straightforward approach directly reflect the experimentally observed controller behaviour. Within the virtual plant environment, it was shown that the cascade control is considerably better than previously used control approaches. The controller significantly improved the batch-to-batch reproducibility of the fermentations. Experimental tests confirmed that it is particularly suited for cultivation processes suffering from long response times and delays. The performance of the new controller is demonstrated during its application in Escherichia coli fed-batch cultivations as well as in animal cell cultures with CHO cells. The technique is a simple and reliable alternative to more sophisticate model-supported controllers. PMID- 21779891 TI - The effect of temperature and pH gradients on Lactobacillus rhamnosus gene expression of stress-related genes. AB - In this study, Lactobacillus rhamnosus, a renowned probiotic, was cultivated in fluctuating environment. Base gradients caused by a pH control in an industrial process and temperature gradients caused by uneven heating were simulated with a scale-down method. A pH gradient was created in a plug flow reactor (PFR). Expression of pH stress-related genes (atpA, aldB, cfa, groEL, hrcA and pstS) were studied as a relative gene expression study using ldhD as a reference gene. Expression measurements were carried out with the TRAC method. The responses of groEL, hrcA and atpA genes to temperature and pH changes were observed. The expression of phosphate uptake system-related pstS gene was induced almost linearly in the chemostat cultivation experiments when the base gradient in the PFR was increased. Correlations between the results from gene expression studies and freeze stability or acid stress survival were studied. However, by measuring the expression of these genes, we were not able to predict eventual freeze stability or survival from the acid stress test. PMID- 21779892 TI - Prospective motion correction improves diagnostic utility of pediatric MRI scans. AB - A new technique for prospectively correcting head motion (called PROMO) during acquisition of high-resolution MRI scans has been developed to reduce motion artifacts. To evaluate the efficacy of PROMO, four T1-weighted image volumes (two with PROMO enabled, two uncorrected) were acquired for each of nine children. A radiologist, blind to whether PROMO was used, rated image quality and artifacts on all sagittal slices of every volume. These ratings were significantly better in scans collected with PROMO relative to those collected without PROMO (Mann Whitney U test, P < 0.0001). The use of PROMO, especially in motion-prone patients, should improve the accuracy of measurements made for clinical care and research, and potentially reduce the need for sedation in children. PMID- 21779893 TI - Comments on hippocampal sclerosis in children younger than 2 years. PMID- 21779894 TI - Reconstruction nailing for ipsilateral femoral neck and shaft fractures. AB - The surgical management of ipsilateral fractures of the femoral neck and shaft presents a difficult and challenging problem for the orthopaedic surgeon. The purpose of the present study was to report the mid-term results and complications in a series of patients who sustained ipsilateral femoral neck and shaft fractures and treated in our trauma department with a single reconstruction nail for both fractures. Eleven patients were included in the study with an average age of 46.4 years. The mean follow-up was 47 months (range, 15-75 months). There were no cases of a missed diagnosis at initial presentation. The mean time to union was 4.5 months for the neck fracture and 8.2 months for the shaft. There were no cases of avascular necrosis of the femoral head or non-union of the neck fracture. The mean Harris Hip Score was (85 +/- 4.3). Complications included two cases of shaft fracture non-union and one case of peroneal nerve palsy. Heterotopic ossification at the tip of the greater trochanter was evident in two cases without causing any functional deficit. The current study suggests that reconstruction nailing produces satisfactory clinical and functional results in the mid-term. The complications involved only the femoral shaft fracture and were successfully treated with a single operative procedure. PMID- 21779895 TI - What skeletons tell us. The story of human paleopathology. AB - Human skeletal paleopathology provides important insight regarding the antiquity of some diseases and their distribution in past human groups. The history of human skeletal paleopathology extends back more than 150 years. Rudolf Virchow published reports on the subject, and research on paleopathology has provided critical data on important topics such as the origin of syphilis. With the development of powerful new research tools, human paleopathology will continue to be a source of data on the development of disease and its effect on human biological and cultural development. PMID- 21779897 TI - [Surgical treatment of ankle fractures as an outpatient procedure. A safe and resource-efficient concept?]. AB - BACKGROUND: In many European countries, patients requiring surgical treatment of ankle fractures are generally hospitalized for an average of 8-11 days. This anecdotal concept is largely based on the premise that the inpatient monitoring of soft tissue conditions may lead to a decreased complication rate. The present study was designed to test the hypothesis that the surgical care of isolated ankle fractures as an outpatient procedure represents a safe and feasible concept which is not associated with an increased complication rate. METHODS: A retrospective analysis was performed of a prospective database during a 5-year period (01/01/2005-12/31/2009) at a US academic level 1 trauma center with an institutional protocol of outpatient surgery for isolated ankle fractures. All fractures were classified according to the AO/OTA system. Outcome parameters consisted of the rate of postoperative complications and frequency of unplanned surgical revisions outpatient isolated versus inpatient isolated with surgical fixation of ankle isolated fractures. RESULTS: Among 810 consecutive patients with ankle fractures during the study period, 476 met the inclusion criteria. Of these, 256 patients (53.8%) were treated as outpatients. The average length of stay of patients who were admitted as inpatients was 1.5+/-0.8 days (range 1-5 days). The age distribution was in a similar range for inpatients and outpatients (39+/-14.1 vs 35+/-12.8 years), and the injury severity based on the AO/OTA fracture classification revealed a similar distribution of fracture patterns in both groups. The rate of postoperative complications (9.1 vs 3.1%) and of unplanned surgical revisions (3.6 vs 1.2%) was significantly increased in the hospitalized group, compared to patients with ambulatory surgery (P<0.05). CONCLUSION: The surgical treatment of isolated ankle fractures as an outpatient procedure represents a safe and resource-efficient concept which is not associated with an increased complication rate. Cultural differences in the domestic environment of individual patients may have to be taken into consideration. PMID- 21779896 TI - Anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization. AB - IL-17-induced joint inflammation is associated with increased angiogenesis. However, the mechanism by which IL-17 mediates angiogenesis is undefined. Therefore, the pathologic role of CXCL1 and CXCL5 was investigated in arthritis mediated by local expression of IL-17, employing a neutralizing antibody to each chemokine. Next, endothelial chemotaxis was utilized to examine whether endothelial migration was differentially mediated by CXCL1 and CXCL5. Our results demonstrate that IL-17-mediated disease activity was not affected by anti-CXCL1 treatment alone. In contrast, mice receiving anti-CXCL5 demonstrated significantly reduced clinical signs of arthritis, compared to the mice treated with IgG control. Consistently, while inflammation, synovial lining thickness, bone erosion and vascularization were markedly reduced in both the anti-CXCL5 and combination anti-CXCL1 and 5 treatment groups, mice receiving anti-CXCL1 antibody had clinical scores similar to the control group. In contrast to joint FGF2 and VEGF levels, TNF-alpha was significantly reduced in mice receiving anti-CXCL5 or combination of anti-CXCL1 and 5 therapies compared to the control group. We found that, like IL-17, CXCL1-induced endothelial migration is mediated through activation of PI3K. In contrast, activation of NF-kappaB pathway was essential for endothelial chemotaxis induced by CXCL5. Although CXCL1 and CXCL5 can differentially mediate endothelial trafficking, blockade of CXCR2 can inhibit endothelial chemotaxis mediated by either of these chemokines. These results suggest that blockade of CXCL5 can modulate IL-17-induced inflammation in part by reducing joint blood vessel formation through a non-overlapping IL-17 mechanism. PMID- 21779898 TI - [Open stabilization and primary hip arthroplasty in geriatric patients with acetabular fractures: combination of minimally invasive techniques]. AB - Fractures of the acetabulum after low-energy trauma in geriatric patients suffering from osteoporosis are increasing in number and significance due to demographic changes. The results of current therapeutic principles though tend to be poor in this population, while risk and treatment-related morbidity of surgical or conservative approaches are substantial.The treatment of geriatric patients can be challenging, not only because of their often complex medical history. They essentially need rapid functional restoration and return to their familiar environment to avoid general decline unlike younger patients for whom rather the long-term perspective is crucial. This article critically discusses the current literature and reports on first experiences with a new surgical concept in six geriatric patients aged 82-91 years: the combination of an anterior minimally invasive approach for open reduction and internal fixation of the acetabulum combined with an anterior minimally invasive (AMIS(r)) approach to the hip for total hip arthroplasty with promising short-term results. PMID- 21779899 TI - [IT-based clinical pathway as a routine tool in trauma surgery]. AB - BACKGROUND: Today clinical pathways are established as a basis for the operational and organizational structure of surgical, interventional and conservative treatment in many hospitals. In our study we evaluate the establishment and systematic applicability of IT-based clinical pathways in a tertiary care facility. METHODS: We evaluate and compare the treatment of coxarthrosis with hip joint endoprosthesis either following an IT-based clinical pathway or without clinical pathway. RESULTS: All patients who had received a hip joint endoprosthesis from 1 January 2006 to 31 October 2009 were included. The duration of stay is significantly longer in the group without pathway. Furthermore there was a significant increase in the documentation of wound inspection after surgery in the "pathway patients". The preoperative urinalysis was done significantly more often in the pathway group. CONCLUSION: IT-based clinical pathways are applicable for routine use in trauma departments. For certain surgical procedures they are a suitable management device, even in a tertiary care facility. Clinical pathways lead to an improved operational structure of medical treatment and moreover to a complete and continuous documentation through the electronic file. PMID- 21779901 TI - [Foot trauma]. PMID- 21779900 TI - [Problems and controversies in the treatment of ankle fractures]. AB - Ankle fractures are the most frequent injuries of a load-bearing joint. Their treatment belongs to the daily routine in trauma surgery. However, despite an increased understanding of the mechanism of injury and relatively straightforward fixation techniques, the medium- to long-term results are often less than satisfactory. The following article therefore explicitly focusses on unsolved problems and controversies in the treatment of ankle fractures in the light of the current literature. These include the therapeutic and prognostic relevance of frequently used classification systems, criteria for the indication for surgery, frequent hazards in internal fixation, the question of whether and how to fix the posterior malleolus, and the detection and treatment of syndesmotic instability. Furthermore, trauma surgeons face the increasing incidence of ankle fractures in the elderly. The presence of osteoporosis, diabetes mellitus and neuropathic osteoarthropathy represents a special challenge. PMID- 21779902 TI - Direct metal laser sintering (DMLS) of a customized titanium mesh for prosthetically guided bone regeneration of atrophic maxillary arches. AB - This study describes a protocol for the direct manufacturing of a customized titanium mesh using CAD-CAM procedures and rapid prototyping to augment maxillary bone and minimize surgery when severe atrophy or post-oncological deformities are present. Titanium mesh and particulate autogenous plus bovine demineralised bone were planned for patient rehabilitation. Bone augmentation planning was performed using the pre-op CT data set in relation to the prosthetic demands, minimizing the bone volume to augment at the minimum necessary for implants. The containment mesh design was used to prototype the 0.6 mm thickness customized titanium mesh, by direct metal laser sintering. The levels of regenerated bone were calculated using the post-op CT data set, through comparison with the pre-op CT data set. The mean vertical height difference of the crestal bone was 2.57 mm, while the mean buccal-palatal dimension of thickness difference was 3.41 mm. All planned implants were positioned after an 8 month healing period using two-step implant surgery, and finally restored with a partial fixed prosthesis. We present a viable and reproducible method to determine the correct bone augmentation prior to implant placement and CAD-CAM to produce a customized direct laser-sintered titanium mesh that can be used for bone regeneration. PMID- 21779903 TI - Assessing the effectiveness of robot facilitated neurorehabilitation for relearning motor skills following a stroke. AB - A growing awareness of the potential for machine-mediated neurorehabilitation has led to several novel concepts for delivering these therapies. To get from laboratory demonstrators and prototypes to the point where the concepts can be used by clinicians in practice still requires significant additional effort, not least in the requirement to assess and measure the impact of any proposed solution. To be widely accepted a study is required to use validated clinical measures but these tend to be subjective, costly to administer and may be insensitive to the effect of the treatment. Although this situation will not change, there is good reason to consider both clinical and mechanical assessments of recovery. This article outlines the problems in measuring the impact of an intervention and explores the concept of providing more mechanical assessment techniques and ultimately the possibility of combining the assessment process with aspects of the intervention. PMID- 21779904 TI - Erratum to: Inhibitory effect of hot-water extract of quince (Cydonia oblonga) on immunoglobulin E-dependent late-phase immune reactions of mast cells. PMID- 21779906 TI - Retracted article: The complete nucleotide sequences of serotype 'O' and 'A' Indian vaccine strains of foot-and-mouth disease virus. PMID- 21779905 TI - Integrating science into management of ecosystems in the Greater Blue Mountains. AB - Effective management of large protected conservation areas is challenged by political, institutional and environmental complexity and inconsistency. Knowledge generation and its uptake into management are crucial to address these challenges. We reflect on practice at the interface between science and management of the Greater Blue Mountains World Heritage Area (GBMWHA), which covers approximately 1 million hectares west of Sydney, Australia. Multiple government agencies and other stakeholders are involved in its management, and decision-making is confounded by numerous plans of management and competing values and goals, reflecting the different objectives and responsibilities of stakeholders. To highlight the complexities of the decision-making process for this large area, we draw on the outcomes of a recent collaborative research project and focus on fire regimes and wild-dog control as examples of how existing knowledge is integrated into management. The collaborative research project achieved the objectives of collating and synthesizing biological data for the region; however, transfer of the project's outcomes to management has proved problematic. Reasons attributed to this include lack of clearly defined management objectives to guide research directions and uptake, and scientific information not being made more understandable and accessible. A key role of a local bridging organisation (e.g., the Blue Mountains World Heritage Institute) in linking science and management is ensuring that research results with management significance can be effectively transmitted to agencies and that outcomes are explained for nonspecialists as well as more widely distributed. We conclude that improved links between science, policy, and management within an adaptive learning-by-doing framework for the GBMWHA would assist the usefulness and uptake of future research. PMID- 21779907 TI - The grapevine-infecting vitiviruses, with particular reference to grapevine virus A. AB - A number of vitiviruses infect grapevine, arguably the most important fruit crop, and the host from which they derive their genus name. In contrast to most grapevine viruses, the etiological role of these viruses is unclear, albeit that they are associated with several well-known--and a number of emerging--diseases of grapevine. Here, we review the genus Vitivirus, with special reference to its most omnipresent member, grapevine virus A. We discuss the latest taxonomic status of the genus, as well as the genome and genomic organisation, replication mechanism, and genetic variability of GVA, and we also present the latest research progress with vitivirus-based vectors; the identification of a new vitivirus, GVE, the discovery of VIGG, a unique GVA-induced host protein, the molecular characterisation of hitherto unknown or puzzling genetic elements in the GVA genome, and the latest developments in vitivirus diagnostics. PMID- 21779908 TI - Molecular and biological characterization of a new Brazilian begomovirus, euphorbia yellow mosaic virus (EuYMV), infecting Euphorbia heterophylla plants. AB - To date, no begomovirus has been fully characterized from Euphorbia heterophylla, a widely distributed weed, in Brazil. Here, we show the occurrence of a new begomovirus on E. heterophylla plants showing bright yellow mosaic. The bipartite viral genome was cloned from 10 samples, and all clones are almost identical to each other (95.6-98.8% nucleotide sequence identity). The DNA-A sequences shared a maximum nucleotide sequence identity of 87.3% with euphorbia mosaic Peru virus (EuMPV) and thus were classified as belonging to a novel begomovirus species, tentatively named Euphorbia yellow mosaic virus (EuYMV). The EuYMV DNA-B sequences share a maximum nucleotide sequence identity of 56.2% with a euphorbia mosaic virus (EuMV) isolate from Mexico. Phylogenetic analysis demonstrated that this new virus belongs to a different lineage than EuMV isolates from Central America. PMID- 21779909 TI - Co-expression of multiple target proteins in plants from a tobacco mosaic virus vector using a combination of homologous and heterologous subgenomic promoters. AB - To co-express multiple target proteins, we engineered a single-component chimeric tobacco mosaic virus (TMV)-based vector containing homologous and heterologous capsid protein subgenomic RNA promoters. Delivery of this vector into Nicotiana benthamiana plants via agroinfiltration resulted in co-expression of two reporter genes within a single cell. Furthermore, co-expression of a host-specific antisense RNA or a silencing suppressor protein from this vector augmented the accumulation of green fluorescent protein or a vaccine antigen, hemagglutinin from avian influenza virus A/Vietnam/1194/04. These findings suggest that this chimeric vector utilizing the homologous and heterologous subgenomic TMV promoters has a potential for high-level production of multiple therapeutic proteins including monoclonal antibodies. PMID- 21779910 TI - Virological and serological characterization of SRV-4 infection in cynomolgus macaques. AB - The nature of SRV-4 infection in cynomolgus macaques remains unclear to date. Here, we report the monitoring of 24 cynomolgus monkeys that were naturally infected with SRV-4 for virus isolation, proviral load and antibody. The results indicated that the SRV-4 antibody status was statistically correlated to environmental temperature. PMID- 21779911 TI - Avian reovirus S1133-induced DNA damage signaling and subsequent apoptosis in cultured cells and in chickens. AB - In this study, intracellular signaling in ARV S1133-mediated apoptosis was investigated. A microarray was used to examine the gene expression profiles of cells upon ARV S1133 infection and ARV-encoded pro-apoptotic protein sigmaC overexpression. The analysis indicated that in the set of DNA-damage-responsive genes, DDIT-3 and GADD45alpha were both upregulated by viral infection and sigmaC overexpression. Further investigation demonstrated that both treatments caused DNA breaks, which increased the expression and/or phosphorylation of DNA damage response proteins. ROS and lipid peroxidation levels were increased, and ARV S1133 and sigmaC caused apoptosis mediated by DNA damage signaling. ROS scavenger NAC, caffeine and an ATM-specific inhibitor significantly reduced ARV S1133- and sigmaC-induced DNA breaks, DDIT-3 and GADD45alpha expression, H2AX phosphorylation, and apoptosis. Overexpression of DDIT-3 and GADD45alpha enhanced the oxidative stress and apoptosis induced by ARV S1133 and sigmaC. In conclusion, our results demonstrate the involvement of the DNA-damage-signaling pathway in ARV S1133- and sigmaC-induced apoptosis. PMID- 21779912 TI - Gene transfer as a strategy to achieve permanent cardioprotection I: rAAV mediated gene therapy with inducible nitric oxide synthase limits infarct size 1 year later without adverse functional consequences. AB - The ultimate goal of prophylactic gene therapy is to confer permanent protection against ischemia. Although gene therapy with inducible nitric oxide synthase (iNOS) is known to protect against myocardial infarction at 3 days and up to 2 months, the long-term effects on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the iNOS gene (rAAV/iNOS), which enables long-lasting transgene expression. The ability of rAAV/iNOS to direct the expression of functional iNOS protein was confirmed in COS-7 cells before in vivo gene transfer. Mice received injections in the anterior LV wall of rAAV/LacZ or rAAV/iNOS; 1 year later, they underwent a 30-min coronary occlusion (O) and 4 h of reperfusion (R). iNOS gene transfer resulted in elevated iNOS protein expression (+3-fold vs. the LacZ group, n = 6; P < 0.05) and iNOS activity (+4.4-fold vs. the LacZ group, n = 6; P < 0.05) 1 year later. Infarct size (% of risk region) was dramatically reduced at 1 year after iNOS gene transfer (13.5 +/- 2.2%, n = 12, vs. 41.7 +/- 2.9%, n = 10, in the LacZ group; P < 0.05). The infarct-sparing effect of iNOS gene therapy at 1 year was as powerful as that observed 24 h after ischemic preconditioning (six 4-min O/4-min R cycles) (19.3 +/- 2.3%, n = 11; P < 0.05). Importantly, compared with the LacZ group (n = 11), iNOS gene transfer (n = 10) had no effect on LV dimensions or function for up to 1 year (at 1 year: FS 34.5 +/- 2.0 vs. 34.6 +/- 2.6%, EF 57.0 +/- 2.0 vs. 59.7 +/- 2.9%, LVEDD 4.3 +/- 0.1 vs. 4.2 +/- 0.2 mm, LVESD 2.8 +/- 0.1 vs. 2.9 +/- 0.2 mm) (echocardiography). These data demonstrate, for the first time, that rAAV-mediated iNOS gene transfer affords long-term, probably permanent (1 year), cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy. PMID- 21779913 TI - Electromechanical effects of the direct renin inhibitor (aliskiren) on the pulmonary vein and atrium. AB - Activation of the atrial renin-angiotensin system plays an important role in the pathophysiology of atrial fibrillation (AF). The pulmonary vein (PV) and left atrium (LA) are important trigger and substrate for the genesis of AF. We investigate the effects of a direct renin inhibitor, aliskiren, on the PV and LA arrhythmogenic activity and the underlying electromechanical mechanisms. Conventional microelectrodes were used to record action potentials and contractility in isolated rabbit PVs and LA tissues before and after the administration of aliskiren (0.1, 1, 3 and 10 MUM). By the whole-cell patch clamp and indo-1 fluorimetric ratio techniques, ionic currents and intracellular calcium transient were studied in isolated single PV and LA cardiomyocyte before and after the administration of aliskiren (3 MUM). Aliskiren (0.1, 1, 3 and 10 MUM) reduced PV firing rate in a concentration-dependent manner (6, 10, 14 and 17%) and decreased PV diastolic tension, which could be attenuated in the presence of 100 MUM L-N(G)-Nitroarginine Methyl Ester (L-NAME). Aliskiren induced PV automatic rhythm exit block causing slow and irregular PV activity with variable pauses. Aliskiren increased PV and LA contractility, which could be abolished by pre-treating with 0.1 MUM ryanodine. Aliskiren (3 MUM) decreased L type calcium currents, but increased reverse-mode of Na( + )/Ca(2+ ) exchanger currents, intracellular calcium transients, and sarcoplasmic reticulum calcium content in PV and LA cardiomyocytes. Pretreatment with renin, losartan or angiotensin II did not alter the effect of aliskiren on sarcolemmal calcium flux. In conclusion, aliskiren reduces PV arrhythmogenic activity with a direct vasodilatory property and has a positive inotropic effect on cardiomyocytes. These findings may reveal the anti-arrhythmic and anti-heart failure potentials of aliskiren. PMID- 21779914 TI - Intracellular [Na(+)] modulates synergy between Na(+)/Ca (2+) exchanger and L type Ca (2+) current in cardiac excitation-contraction coupling during action potentials. AB - Excitation-contraction coupling (ECC) in cardiac myocytes involves triggering of Ca(2+) release from the sarcoplasmic reticulum (SR) by L-type Ca channels, whose activity is strongly influenced by action potential (AP) profile. The contribution of Ca(2+) entry via the Na(+)/Ca(2+) exchanger (NCX) to trigger SR Ca(2+) release during ECC in response to an AP remains uncertain. To isolate the contribution of NCX to SR Ca(2+) release, independent of effects on SR Ca(2+) load, Ca(2+) release was determined by recording Ca(2+) spikes using confocal microscopy on patch-clamped rat ventricular myocytes with [Ca(2+)](i) fixed at 150 nmol/L. In response to AP clamps, normalized Ca(2+) spike amplitudes (DeltaF/F (0)) increased sigmoidally and doubled as [Na(+)](i) was elevated from 0 to 20 mmol/L with an EC(50) of ~10 mmol/L. This [Na(+)](i)-dependence was independent of I (Na) as well as SR Ca(2+) load, which was unchanged under our experimental conditions. However, NCX inhibition using either KB-R7943 or XIP reduced DeltaF/F (0) amplitude in myocytes with 20 mmol/L [Na(+)](i), but not with 5 mmol/L [Na(+)](i). SR Ca(2+) release was complete before the membrane repolarized to -15 mV, indicating Ca(2+) entry into the dyad (not reduced extrusion) underlies [Na(+)](i)-dependent enhancement of ECC. Because I (Ca,L) inhibition with 50 mmol/L Cd(2+) abolished Ca(2+) spikes, our results demonstrate that during cardiac APs, NCX enhances SR Ca(2+) release by synergistically increasing the efficiency of I (Ca,L)-mediated ECC. PMID- 21779916 TI - Metastatic pulmonary calcification in chronic renal failure. AB - Metastatic pulmonary calcification can be caused by a number of diseases, most common being end-stage renal disease. Most of the patients are asymptomatic, and imaging with computed tomography is useful in making a diagnosis. Demonstration of pulmonary and chest wall vessel calcification is characteristic. We report a case of a 60-year-old patient with chronic renal failure on dialysis, presenting with gradual onset dyspnea, who showed metastatic pulmonary calcification on chest imaging. PMID- 21779915 TI - Neuroprotection and regeneration by extracellular metallothionein via lipoprotein receptor-related proteins. AB - Metallothionein has a well-documented protective and proregenerative effect in the mammalian brain, particularly following physical trauma and ischemia or during the onset of neurodegenerative disease. A range of mechanisms have been established for this, including metallothionein's metal binding properties and its ability to scavenge free radicals. In recent years it has become apparent that metallothionein is present in the extracellular compartment of the central nervous system and that it can interact with cell surface receptors of the lipoprotein-receptor-related protein family, including lipoprotein-receptor related protein 1 (LRP1) and megalin. These interactions activate intracellular pathways which are consistent with many of the observed effects of metallothionein in the central nervous system, including its effects on neurons, glial cells, and cells of the immune system. The evidence describing the release, receptor interactions, and subsequent physiological consequences of metallothionein is discussed in this review. PMID- 21779918 TI - Fungus balls due to Candida tropicalis. PMID- 21779917 TI - The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. AB - BACKGROUND/AIMS: The association between thyroid hormones and arterial stiffness is unclear. In this study, we investigated, for the first time in a large cohort of euthyroid peritoneal dialysis patients, the relationship between thyroid hormone levels and arterial stiffness. METHODS: Fifty-seven patients were enrolled. Serum TSH, free T3 and free T4 levels were measured by chemiluminescence immunoassay method. Pulse wave analysis [augmentation index (AIx) and subendocardial viability ratio (SEVR)] were measured to assess arterial stiffness. RESULTS: Mean age was 49 +/- 12.3 years, and 56.1% were female. Mean TSH, fT3 and fT4 levels were 1.97 +/- 0.99 mIU/ml, 2.80 +/- 0.42 pg/ml and 1.22 +/- 0.16 ng/dl, respectively. Mean AIx and SEVR were 22.3 +/- 11.3 and 136 +/- 21%, respectively. AIx was negatively correlated with residual urine volume (r = 0.372, P: 0.03) and fT3 levels (r = -0.382, P: 0.005). SEVR was correlated only with TSH level (r = -0.394, P: 0.003). In linear regression analysis adjusted for age, gender, history of diabetes and cardiovascular disease and residual diuresis, fT3 level (t = -3.949, P < 0.001) remained associated with AIx. Only TSH level (t = -2.409, P: 0.02) was related to SEVR. CONCLUSION: Low serum fT3 level is associated with arterial stiffness, and high TSH level within the normal range is related to lower SEVR in euthyroid PD patients. PMID- 21779919 TI - Risk factors for depressive symptoms in a large population on chronic hemodialysis. AB - Despite their significant influence on the quality of life, depressive symptoms are not usually included as a clinical parameter in the evaluation of hemodialysis patients. We aimed to identify depressive symptoms and associated risk factors in a large group of individuals with end-stage renal disease (ESRD) on chronic hemodialysis. This was a cross-sectional study of 400 consecutive patients. Cases were analyzed according to the presence/absence of depressive symptoms. All individuals were investigated by interview, and all variables were measured concurrently. Depressive symptoms were evaluated by the Beck Depression Inventory (BDI-II >=16) and sleep quality by the Pittsburgh Sleep Quality Index (PSQI > 5). Among the 400 patients (59% male), depressive symptoms were present in 77 (19.3%). Depressive symptoms were more common in women and were independently associated with poor sleep quality (P = <0.005), unemployment (P = 0.001), diabetes (P = 0.02), hypoalbuminemia (P = 0.01), low education (P = 0.03), and pruritus (P = 0.04). Women with ESRD on chronic hemodialysis are at increased risk of depression. Furthermore, unemployment and the presence of diabetes, hypoalbuminemia, low education, and pruritus are significantly associated with depressive symptoms. Depressive symptoms are also independently associated with poor quality sleep and studies about the effects of sleep hygiene therapy on depressive symptoms are warranted. PMID- 21779920 TI - The effects of long-term medical treatment combined with clean intermittent catheterization in children with neurogenic detrusor overactivity. AB - OBJECTIVES: To assess whether conservative treatment of pediatric patients with neurogenic detrusor overactivity (NDO) results in lower bladder pressure and increased expected bladder volume (EBV), we investigated the clinical and urodynamic effects of long-term intravesical oxybutynin instillation compared with a standard treatment of oral anticholinergic medication in patients with clean intermittent catheterization (CIC). METHODS: A retrospective study was performed including 21 patients suffering from myelomeningocele and NDO. Initially, all patients were treated with oral anticholinergics and CIC. Ten of the 21 patients showed a sufficient response to the treatment and were included in group I (anticholinergics and CIC). The other 11 patients responded poorly to the initial treatment or developed side effects to oral medication. These patients were included in group II and treated with intravesical oxybutynin and CIC. The two groups were compared using clinical, sonographic and urodynamic examinations performed prior to starting treatment and repeated on an annual basis. Changes from baseline were analyzed with the Mann-Whitney U test. RESULTS: Ten patients in group I and 11 in group II were investigated. Two of the 11 patients in group II stopped the treatment. The mean starting age was 8.1 (+/- 6.6) years in group I and 12.5 (+/- 4.5) years in group II. The mean follow-up time was 7.1 (+/- 5.5) years in group I and 3.6 (+/- 1.8) years in group II. Bladder capacity increased from 173 (+/- 99) to 371 (+/- 115) ml in group I and from 245 (+/- 133) to 370 (+/- 156) ml in group II. Six of the 10 patients in group I and 6/9 patients in group II reached normal EBV. Three of the 10 subjects in group I and 6/9 in group II had bladder compliance values >10 ml/cm H(2)O. At final follow-up, the overall rate of urinary tract infections was equal. Social continence was achieved in 6/10 in group I and 7/9 in group II. Altogether, 19/21 patients responded to conservative management. CONCLUSIONS: In children with NDO, conservative medical treatment combined with CIC is feasible and provides an improved pattern of bladder function, which could help avoid bladder surgery. PMID- 21779921 TI - Sexual function outcome following photoselective vaporisation of the prostate. AB - INTRODUCTION: There is little reported on sexual functional outcome following photoselective vaporisation of the prostate using the 120 W lithium triborate laser. OBJECTIVE: The objective of this study was to evaluate changes in sexual function at 3 and 12 months following PVP. MATERIAL AND METHODS: The primary outcome measures were changes in voiding parameters and changes in erectile function in the international index of erectile function (IIEF-5). Change in erectile function was defined as mild (<5 IIEF points) or major (>=5 points). RESULTS: Results found that 75% of men had an IIEF-5 < 17 at baseline. At 3 months, the mean post-operative IIEF-5 score was unchanged compared to baseline (P = 0.13). A major decline in erectile function was seen in 12.4 and 24% of men at 3 and 12 months, respectively, and a major improvement in erectile function was seen in 8.3 and 6% at 3 and 12 months, respectively. There was no correlation in change in erectile function with urinary function, quality of life and loss of emission on orgasm. Loss of emission on orgasm was reported in 65% of respondents. CONCLUSION: Significant changes in erectile function are observed following PVP although a cause and effect relationship remains unclear. PMID- 21779922 TI - Exploring of new Y-chromosome SNP loci using Pyrosequencing and the SNaPshot methods. AB - The single nucleotide polymorphisms on the Y chromosome (Y-SNP) have been considered to be important in forensic casework. However, Y-SNP loci were mostly population specific and lacked biallelic polymorphisms in the Asian population. In this study, we developed a strategy for seeking and genotyping new Y-SNP markers based on both Pyrosequencing and the SNaPshot methods. As results, 34 new biallelic markers were observed to be polymorphic in the Chinese Han population by estimation of allele frequencies of 103 candidate's Y-SNP loci in DNA pools using Pyrosequencing technology. Then, a multiplex system with 20 Y-SNP loci was genotyped using the SNaPshotTM multiplex kit. Twenty Y-SNP loci defined 56 different haplotypes, and the haplotype diversity was estimated to be 0.9539. Our result demonstrated that the strategy could be used as an efficient tool to search and genotype biallelic markers from a large amount of candidate loci. In addition, 20 Y-SNP loci constructed a multiplex system, which could provide supplementary information for forensic identification. PMID- 21779923 TI - Differences in investigations of sudden unexpected deaths in young people in a nationwide setting. AB - BACKGROUND: Inherited disease may be causative in many young sudden unexpected death cases. Autopsy is essential in the counselling of the bereaved, as the family of the victim may be at risk too. In a nationwide setting operating under the same set of laws, we hypothesized that regional differences exist in the investigation of young persons dying suddenly and unexpectedly. METHODS AND RESULTS: All deaths in persons aged 1-35 years in Denmark in 2000-2006 were included. Death certificates were read independently by two physicians. External examination as well as autopsy status was retrieved. Significant regional differences were found regarding external examinations and autopsy frequencies. Ratios of conducted external examinations varied between 63% and 93% (p = 0.004). Autopsy ratios varied between 60% and 88% (p = 0.001). In urban areas, external examinations and autopsies were more often conducted than in rural areas. In East Denmark, there were more external examinations resulting in a forensic autopsy, and there was a higher overall autopsy rate compared to West Denmark. CONCLUSION: Despite operating under the same set of laws, we document significant regional differences in forensic investigations of young persons suffering a sudden unexpected death. This is probably not unique for Denmark although no data exist to confirm that. The results are worrying and call for a revision of the way these deaths are handled. Mandatory autopsy in sudden unexpected death in young persons is warranted as a thorough investigation of the death may help the clinician in guidance of the relatives in relation to hereditary diseases. PMID- 21779924 TI - Prevention of partner violence by focusing on behaviors of both young males and females. AB - Historically, the political context of partner physical aggression policy and research has focused on protection of physically victimized women and mandated interventions for male batterers. This emphasis is understandable when one considers the injuries and deaths of women by men. However, physical aggression against partners among teens is a very different phenomenon than battering. Intimate partner violence (IPV) in the form of physical aggression, the focus of this review, often starts in junior high school, and approximately 35% of male and female senior high school students report engaging in IPV. The specific trajectory of IPV varies by sample, but IPV appears to decrease in the late teens or early 20s. IPV is generally reported by both males and females, and not attributable to self-defense. IPV is significantly stable in couples who remain together, but stability appears lower if partners change. Given the importance of physical aggression by both males and females, prevention and early intervention programs need to address relationship factors, and targeted prevention and early intervention would be prudent with young high-risk couples. Decades of intervention programs for batterers have not proven very successful, and IPV appears easier to prevent than treat. Thus, emphasis on prevention of IPV seems both timely and promising. This review is intended for diverse audiences including educational administrators, policy makers, and researchers. It reviews issues such as who and when to target for IPV prevention programs, and it summarizes data relevant to these issues. PMID- 21779925 TI - 1H, 13C, 15N and 31P chemical shift assignments of a human Xist RNA A-repeat tetraloop hairpin essential for X-chromosome inactivation. AB - Initiation of X-chromosome inactivation in female mammals depends on the non coding RNA Xist. We have solved the NMR structure of a 14-nucleotide hairpin with a novel AUCG tetraloop fold from a Xist A-repeat that is essential for silencing. The (1)H, (13)C, (15)N and (31)P chemical shift assignments are reported. PMID- 21779926 TI - 1H, 15N and 13C backbone chemical shift assignment of the titin A67-A68 domain tandem. AB - Single molecules of the giant protein titin extend across half of the muscle sarcomere, from the Z-line to the M-line, and have roles in muscle assembly and elasticity. In the A-band titin is attached to thick filaments and here the domain arrangement occurs in regular patterns of eleven called the large super repeat. The large super-repeat itself occurs eleven times and forms nearly half the titin molecule. Interactions of the large super-repeats with myosin are consistent with a role in thick filament assembly. Here we report backbone assignments of the titin A67-A68 domain tandem (Fn-Ig) from the third super repeat (A65-A75) completed using triple resonance NMR experiments. PMID- 21779927 TI - The middle suprarenal artery arising from the superior mesenteric artery. AB - We observed a rare case of the middle suprarenal artery branching out from the superior mesenteric artery in a 78-year-old male. This atypical artery enters the right suprarenal gland that was also supplied by the superior and the inferior suprarenal arteries as usual. In embryonic stages, vasculature of the vitelline system and the gonadal system is differentially organized. The superior mesenteric artery has been generally thought to be pure vitelline, since there has been no evidence that the superior mesenteric artery supplies other organs than digestive. We then speculate that the present middle suprarenal artery is a remnant of the embryonic gonadal artery from the superior mesenteric artery, whereas a stem artery to the testis disappeared. Surgeons should take notice of the middle suprarenal artery when operations are conducted around the superior mesenteric artery. PMID- 21779928 TI - Computer-assisted anatomic dissection (CAAD): evolution, methodology and application in intra-pelvic innervation study. AB - OBJECTIVE: Classic anatomical methods have limitations in micro determination of nerve fibre location. Furthermore, the precise detection of the nerve fibres nature is not possible by means of dissection. The combination of immunohistochemistry and three-dimensional reconstruction could be used to resolve these limitations of morphological sciences. Our aim is to describe the evolution of computer-assisted anatomic dissection (CAAD), which is an original method applied to study the distribution of intra-pelvic nerves in anatomic research. MATERIALS AND METHODS: Serial transverse sectioning of the pelvic region in rabbit, human fetus, infant and adult cadaver was performed. Sections were immuno-histochemically stained and digitized with a high optical resolution scanner. Photoshop 7 software was used in regrouping of the adult cadaver sections then a tri-dimensional reconstruction was achieved using WinSurf software. RESULTS: The 3D reconstruction of the immuno-histochemically stained histologic sections of the pelvis allowed for precise structural identification of the prostate and its innervations (in fetus, infant and adult). In addition, we reconstructed the entire intra-pelvic organs with accurate demonstration of the location of both adrenergic and cholinergic pathways. Moreover, we performed a virtual dissection of each of the pelvic structures with description of the exact location of the inferior hypogastric plexus, as well as the nature and the distribution of its fibres. CONCLUSION: The CAAD is an original method in anatomic research, which illustrates the fact that descriptive anatomy is still a dynamic science. This method allows for a 3D presentation of the intra-organic innervation, the nature of the nerve fibres, and the distribution of receptors and their neurotransmitters. This technique improves the understanding of the complex anatomic regions such as the pelvis from both surgical and educational point of view. PMID- 21779929 TI - Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non-squamous non-small cell lung cancer receiving gefitinib or erlotinib. AB - A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR. PMID- 21779930 TI - Autologous hematopoietic stem cell transplantation in multiple myeloma and lymphoma: an analysis of factors influencing stem cell collection and hematological recovery. AB - Autologous stem cell transplantation is standard treatment for newly diagnosed younger patients with multiple myeloma and for relapsed or refractory Hodgkin or non-Hodgkin lymphoma. Patient characteristics influencing the yield from stem cell collection and time from transplant to platelet recovery were retrospectively analyzed in 630 consecutive patients, attempting to define adequate amounts of CD34+ cells to collect and reinfuse; 509/630 patients (81%) mobilized the requested CD34+ cell number. Factors influencing the harvest yield were age (P < 0.001) and gender, where 85% of men and 78% of women (P < 0.02) attained the requested stem cell amount. Time to platelet recovery was significantly faster for multiple myeloma patients compared to all other diagnoses (14.6 days compared to 19.8, P < 0.0001). Multiple myeloma patients were older than lymphoma patients but received stem cell transplant up-front as opposed to second line therapy for other patient groups. Multivariate analysis revealed that the most important factor influencing platelet recovery was diagnosis, followed by the amount of reinfused CD34+ cells (P < 0.001, P < 0.05). Blood group O+ had the fastest platelet recovery, whereas blood group A harvested the highest cell amounts. In conclusion, we demonstrate a significant importance of the number of reinfused CD34+ cells on the time to platelet recovery. PMID- 21779932 TI - Sphincter of Oddi-preserving and T-tube-free laparoscopic management of extrahepatic bile duct calculi. AB - BACKGROUND: The current management of choledocholithiasis remains a controversial topic. Popular options for treatment include preoperative endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (EST) followed by laparoscopic cholecystectomy (LC), or LC and laparoscopic common bile duct exploration (LCBDE) with T-tube decompression. Some concerns suggest that sphincterotomy has significant long-term complications as a result of sphincter of Oddi (SO) dysfunction, and T-tube decompression is historically associated with many complications and discomfort. The purpose of this study was to demonstrate our simple, safe techniques of LCBDE without a T-tube and with an intact SO. METHODS: Between April 2006 and July 2009, a total of 44 selected patients with common bile duct (CBD) stones underwent laparoscopic exploration at our institution. Of 44 laparoscopic choledochotomies, primary choledochorrhaphy was performed on patients with preoperatively installed endoscopic retrograde biliary drainage (ERBD) tubes (n = 10, 22.73%) or endonasobiliary drainage (ENBD) tubes (n = 10, 22.73%) and on patients with intraoperative biliary drainage C tubes (n = 9, 20.45%) or pigtail J biliary drainage tubes (n = 15, 34.09%). RESULTS: The mean operating time for the ENBD, ERBD, J-tube, and C-tube groups were 97.8, 96.2, 102.1, and 98.7 min, respectively. There were no conversions to open surgery, and no intraoperative complications were experienced in any group. CBD clearance was achieved in 43 patients (97.73%). The mean lengths of follow-up for the ENBD, ERBD, J-tube, and C-tube groups were 27.0, 26.7, 23.8, and 30.4 months, respectively; and none of the patients developed major biliary complications including recurrent stones. CONCLUSIONS: Laparoscopic primary closure with internal and external biliary drainage tubes is safe and an effective alternative to T-tube placement, especially for younger patient groups able to endure bile duct exploration. Sphincter of Oddi function is well preserved to prevent recurrent bile duct stones and bile duct cancer. Procedures are safe with great feasibility. PMID- 21779933 TI - Multi-city assessment of lifetime pregnancy involvement among street youth, Ukraine. AB - Although street youth are at increased risk of lifetime pregnancy involvement (LPI), or ever becoming or getting someone pregnant, no reports to date describe the epidemiology of LPI among systematically sampled street youth from multiple cities outside of North America. The purpose of our assessment was to describe the prevalence of and risk factors associated with LPI among street youth from three Ukrainian cities. We used modified time-location sampling to conduct a cross-sectional assessment in Odesa, Kyiv, and Donetsk that included citywide mapping of 91 public venue locations frequented by street youth, random selection of 74 sites, and interviewing all eligible and consenting street youth aged 15-24 years found at sampled sites (n = 929). Characteristics of youth and prevalence of LPI overall and by demographic, social, sexual, and substance use risk factors, were estimated separately for males and females. Adjusted odds ratios (AORs) were calculated with multivariable logistic regression and effect modification by gender was examined. Most (96.6%) eligible youth consented to participate. LPI was reported for 41.7% of females (93/223) and 23.5% of males (166/706). For females, LPI was significantly elevated and highest (>70%) among those initiating sexual activity at <=12 years and for those reporting lifetime anal sex and exchanging sex for goods. For males, LPI was significantly elevated and highest (>40%) among those who reported lifetime anal sex and history of a sexually transmitted infection. Overall, risk factors associated with LPI were similar for females and males. Among the total sample (females and males combined), significant independent risk factors with AORs >=2.5 included female gender, being aged 20-24 years, having five to six total adverse childhood experiences, initiating sex at age <=12 or 13-14 years, lifetime anal sex, most recent sex act unprotected, and lifetime exchange of sex for goods. Among street youth with LPI (n = 259), the most recent LPI event was reported to be unintended by 63.3% and to have ended in abortion by 43.2%. In conclusion, our assessment documented high rates of LPI among Ukrainian street youth who, given the potential for negative outcomes and the challenges of raising a child on the streets, are in need of community-based pregnancy prevention programs and services. Promising preventive strategies are discussed, which are likely applicable to other urban populations of street-based youth as well. PMID- 21779934 TI - Host genetic variants and hepatitis B virologic features in HBeAg-negative hepatitis B carriers with long-term biochemical remission. AB - PURPOSE: A significant portion of HBeAg-negative chronic hepatitis B patients have persistently normal serum alanine aminotransferase levels (PNALT). We thus investigated host genetic variants and virological features in HBeAg-negative hepatitis B carriers. METHODS: Baseline clinical and virological features of 133 HBeAg-negative hepatitis B carriers (77 with PNALT and 56 with chronic hepatitis activity) with follow-up for more than 5 years were investigated. Three single nucleotide polymorphisms (SNPs) located within or around human leukocyte antigen (HLA)-DPA1, HLA-DPB1, and interleukin (IL) 28B loci were genotyped. RESULTS: The genotype frequencies of these SNPs were comparable between hepatitis B carriers with PNALT and those with chronic hepatitis. Compared with hepatitis B carriers with PNALT, those with chronic hepatitis had significantly higher baseline serum HBV-DNA levels (4.96 vs. 4.04 log10 IU/ml, P = 0.001). Baseline serum HBV-DNA level > 2000 IU/ml (OR, 8.42; 95% CI, 2.74-25.90, P < 0.001) were the only independent factor associated with chronic hepatitis activity. Changes of serum HBV-DNA in 30 hepatitis B carriers with PNALT had showed a significant reduction of viral load from baseline to last visit (mean difference of paired HBV-DNA levels: -0.78 log10 IU/ml, 95% CI: -1.57 to -0.013, P = 0.047). In contrast, no significant reduction of viral load was found in 28 patients with chronic hepatitis. CONCLUSIONS: The results indicate that lower baseline serum HBV-DNA level and viral load reduction over time are associated with long-term biochemical remission in HBeAg-negative hepatitis B carriers. PMID- 21779935 TI - Comment on Gow, A.J., Watson, R., Whiteman, M. & Deary, I.J. (2011). A stairway to heaven? Structure of the Religious Involvement Inventory and Spiritual Well Being Scale. Journal of Religion & Health doi: 10.1007/s10943-010-9375-2. PMID- 21779936 TI - Introduction to the special issue "Probiotic bacteria and human gut microbiota". PMID- 21779937 TI - Chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway. AB - Chlamydiae are obligate intracellular bacteria that cause variety of human diseases. Chlamydia-infected host cells are profoundly resistant to apoptosis induced by many different apoptotic stimuli. The inhibition of apoptosis is thought to be an important immune escape mechanism allowing chlamydiae to productively complete their obligate intracellular growth cycle. Infection with chlamydiae can activate the Raf/MEK/ERK pathway. Because the survival pathway can modulate apoptosis, we used MEK-specific inhibitor U0126 and Raf-specific inhibitor GW5074 to examine the role of Raf/MEK/ERK pathway in chlamydial antiapoptotic activity. Apoptosis was induced by staurosporine (STS) and detected by morphology, DNA fragmentation, caspase-3 activation, and poly (ADP-ribose) polymerase cleavage. Inhibition of the pathway sensitized Chlamydia-infected cells to STS-mediated cell apoptosis. The data indicate that chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway. PMID- 21779938 TI - Biofilm and siderophore effects on secondary waste water disinfection. AB - The efficiency of ultraviolet (UV) light disinfection of wastewater effluent using a large-scale pilot system was studied. The relationship between biofilm and siderophore production and UV doses received by Pseudomonas aeruginosa strain ATCC 15442 was determined. UV decreased pyoverdine production and enhanced biofilm production. Consequently external factors conditioned by both pyoverdine and biofilm may affect the UV effect on bacterial disinfection. PMID- 21779939 TI - Gastrointestinal colonization rates for human clinical isolates of Aeromonas veronii using a mouse model. AB - A variety of environment-associated gastrointestinal infections have been associated with the Aeromonas group of bacteria which contain both non-virulent strains as well as virulent strains within a particular species. This study monitors the colonization rates of colon tissue in a mouse-streptomycin dose/response model involving isolates of Aeromonas veronii biovar sobria obtained from human clinical specimens. The ability to successfully colonize mouse colon tissues by the human clinical isolates was then compared with the rates achieved in a previous study of Aeromonas isolates obtained from environmental drinking water samples. Results suggest that strains of Aeromonas isolated from drinking water environmental samples contain pathogenic and virulence capabilities similar to those seen in Aeromonas veronii clinical isolates from human infections. PMID- 21779940 TI - Potential errors in the volume of distribution estimation of therapeutic proteins composed of differently cleared components. AB - The volume of distribution at steady state (Vss) of therapeutic proteins is usually assessed by non-compartmental or compartmental pharmacokinetic (PK) analysis wherein errors may arise due to the elimination of therapeutic proteins from peripheral tissues that are not in rapid equilibrium with the sampling compartment (usually blood). Here we explored another potential source of error in the estimation of Vss that is linked to the heterogeneity of therapeutic proteins which may consist of components (e.g. glycosylation variants) with different elimination rates. PK simulations were performed with such hypothetical binary protein mixtures where elimination was assumed to be exclusively from the central compartment. The simulations demonstrated that binary mixtures containing a rapid-elimination component can give rise to pronounced bi-phasic concentration time profiles. Apparent Vss observed with both non-compartmental and 2 compartmental PK analysis, increased with increasing fraction as well as with increasing elimination rate k ( 10 ) of the rapid-elimination component. Simulation results were complemented by PK analysis of an in vivo study in cynomolgus monkeys with different lots of lenercept, a tumor necrosis factor receptor-immunoglobulin G1 fusion protein, with different heterogeneities. The comparative Vss data for the three lenercept lots with different amounts of rapidly cleared components were consistent with the outcome of our simulations. Both lots with a higher fraction of rapidly cleared components had a statistically significant higher Vss as compared to the reference lot. Overall our study demonstrates that Vss of a therapeutic protein may be overestimated in proteins with differently eliminated components. PMID- 21779941 TI - Experiences of sleep paralysis in a sample of Irish university students. AB - BACKGROUND: Sleep paralysis (SP) is characterised by an inability to move voluntarily for a period on going to sleep or on waking. It is also associated with hallucinations, and often with fear. This study seeks to explore the experience of SP in an Irish university sample. METHODS: A cross-sectional survey design was employed, with a validated scale for the assessment of SP being distributed to 2,500 students. A total of 418 responded, of whom 83 reported having experienced SP. RESULTS: The most commonly reported and most intense hallucinations were falling, sensed presence, visual hallucination, pressure on the body and belief might be dying. Fear was also commonly experienced. Bivariate analyses showed an association between fear and several hallucination types. CONCLUSION: SP in university students often includes experience of hallucinations. These, in turn, are associated with frequent and intense fear. PMID- 21779942 TI - Capacity building: benchmark for production of meat with low levels of bacterial contamination in local slaughterhouses in Somaliland. AB - The objective of the study was to investigate and assess the impact of trainings on the levels of meat contamination produced from local livestock slaughter facilities in the North-West region of Somalia (Somaliland). The investigation considered slaughter facilities where workers had been trained or not. The survey was carried out in four local slaughter facilities. A pre-tested questionnaire on abattoir hygiene and food safety standards was administered to International Aid Organizations, government officials, abattoir workers and supervisors. In addition, a total of 320 surface meat swab samples were collected from randomly selected small ruminant carcasses slaughtered from four purposefully selected local slaughter facilities. The samples were analyzed at Analabs laboratories in Nairobi, Kenya, for total viable counts, total coliforms count and presence of Salmonella species. Meat contamination risk factors associated with hygiene practices based on training offered or not was identified. It was noted that slaughter facilities where abattoir workers had not received trainings on minimum meat hygiene standards and quality assurance systems of good hygiene practices and sanitary standard operating procedures produced carcasses with high levels of bacterial contamination in comparison with those where workers had received the said trainings. The laboratory results were in agreement with poor hygiene meat handling practices and lack of compliance with minimum meat hygiene and food safety standards in Berbera and Burao local livestock slaughter facilities where personnel had not been trained. PMID- 21779944 TI - Action-effect binding by observational learning. AB - The acquisition of bidirectional action-effect associations plays a central role in the ability to intentionally control actions. Humans learn about actions not only through active experience, but also through observing the actions of others. In Experiment 1, we examined whether action-effect associations can be acquired by observational learning. To this end, participants observed how a model repeatedly pressed two buttons during an observation phase. Each of the buttonpresses led to a specific tone (action effect). In a subsequent test phase, the tones served as target stimuli to which the participants had to respond with buttonpresses. Reaction times were shorter if the stimulus-response mapping in the test phase was compatible with the action-effect association in the observation phase. Experiment 2 excluded the possibility that the impact of perceived action effects on own actions was driven merely by an association of spatial features with the particular tones. Furthermore, we demonstrated that the presence of an agent is necessary to acquire novel action-effect associations through observation. Altogether, the study provides evidence for the claim that bidirectional action-effect associations can be acquired by observational learning. Our findings are discussed in the context of the idea that the acquisition of action-effect associations through observation is an important cognitive mechanism subserving the human ability for social learning. PMID- 21779943 TI - Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study. AB - The purpose of this study was to investigate the prevalence of tubular damage in short-term (less than five years) type 2 diabetes mellitus (T2DM) patients and to explore the correlation between tubular markers and their relationship with renal indices at different stages of diabetic nephropathy. A group of 101 short-term T2DM patients and 28 control subjects were recruited. Tubular markers, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D: glucosaminidase (NAG), and kidney injury molecule 1 (KIM-1), as well as urinary albumin excretion were measured in voided urine. Glomerular filtration rate (GFR) was estimated via Macisaac's formula. The patients were further categorized into three groups, namely, the normoalbuminuria, microalbuminuria, and macroalbuminuria groups, according to their urine albumin/creatinine ratio (UACR). Urinary tubular markers were compared and their correlations with renal indices [UACR and estimated GFR (eGFR)] were analyzed among the different diabetic groups. Compared with the control group, Urinary NGAL [median (IQR)][83.6(41.4-138.7) MUg/gcr vs. 32.9(26.1-64.5) MUg/gcr], NAG [13.5(8.7-17.9) U/gcr vs. 7.6(6.5-13.0) U/gcr] and KIM-1 [120.0(98.4-139.9) ng/gcr vs. 103.1(86.8 106.2) ng/gcr] in the T2DM were all markedly increased. For all patients, urinary NGAL had stronger positive correlations with UACR than NAG (R = 0.556 vs. 0.305, both P < 0.05). In addition, only urinary NGAL showed a negative correlation with eGFR (R = -0.215, P < 0.05). Urinary KIM-1, however, showed no significant difference among the three T2DM groups and did not correlate with either UACR or eGFR. As UACR increased from the normoalbuminuria to the last macroalbuminuria group, all of the markers increased. However, only the concentrations of NGAL were statistically different among the three diabetic groups. The correlation between the tubular markers and their relationships with the renal indices differed markedly among the three T2DM groups. In conclusion, these results suggest that tubular damage is common in short-term T2DM patients. Urinary NGAL may be a promising early marker for monitoring renal impairment in short-term T2DM patients. PMID- 21779945 TI - Global and local vision in natural scene identification. AB - The results of previous studies have suggested that to optimize the decoding of visual information, global contents of a scene are analyzed before local features (global precedence hypothesis). Evidence supporting this hypothesis has been provided for identification of characters, faces, hybrid stimuli, and simple objects. In the present study, we examined identification of high- and low-pass filtered natural pictures. Despite the radical differences in the type of information conveyed by global and local features, confident and accurate identification was achieved on the basis of either kind of information when an intermediate range of spatial frequencies was preserved. The present data are consistent with the notion of global precedence in scene identification. PMID- 21779946 TI - A fast region-based active contour model for boundary detection of echocardiographic images. AB - This paper presents the boundary detection of atrium and ventricle in echocardiographic images. In case of mitral regurgitation, atrium and ventricle may get dilated. To examine this, doctors draw the boundary manually. Here the aim of this paper is to evolve the automatic boundary detection for carrying out segmentation of echocardiography images. Active contour method is selected for this purpose. There is an enhancement of Chan-Vese paper on active contours without edges. Our algorithm is based on Chan-Vese paper active contours without edges, but it is much faster than Chan-Vese model. Here we have developed a method by which it is possible to detect much faster the echocardiographic boundaries. The method is based on the region information of an image. The region based force provides a global segmentation with variational flow robust to noise. Implementation is based on level set theory so it easy to deal with topological changes. In this paper, Newton-Raphson method is used which makes possible the fast boundary detection. PMID- 21779947 TI - Effect of display magnification on perceived growth of liver lesions on computed tomography. AB - Our goal was to investigate the effect of displayed image magnification on perception of the size of hepatic lesions on abdominal computed tomography (CT) scans. Institutional review board approval and informed observer consent were obtained. Three experienced radiologists reviewed 90 CT image pairs in one session. Each image pair demonstrated a solitary, well-defined hypodense hepatic lesion measuring greater than 1 cm obtained at two points in time. The image pairs were presented three times in random order, once with the left image magnified, once with the right image magnified, and once with neither image magnified. The radiologists were asked to determine on which image the lesion was smaller or if there was no difference. The responses were analyzed statistically. The proportion of correct responses increased significantly as the difference in lesion size increased (p < 0.001). The percent of correct responses was higher when neither CT image was magnified. Magnification of one image decreased the accuracy of the readers' performance, especially at smaller differences, both of which were statistically significant (p < 0.001). Thus, accuracy of detecting lesion size differences was degraded when the images were presented at differing magnification. This should be kept in mind when evaluating serial CT scans for growth or regression of tumors and other lesions. PMID- 21779948 TI - Anesthetic management of patients with an anterior mediastinal mass: continuing professional development. AB - PURPOSE: Many cases have been reported of hemodynamic and airway collapse induced by general anesthesia in patients with an anterior mediastinal mass. We examined the literature for predictors of perioperative risk, guidelines for preoperative investigations, and strategies for management of the patient with a mediastinal mass. PRINCIPAL FINDINGS: In patients with an anterior mediastinal mass, symptoms may range from none to severe and may include orthopnea, stridor, cyanosis, jugular vein distension, or superior vena cava syndrome. In limited case series, incidences of serious complications up to 20% were noted, but these are primarily pediatric studies with unclear relevance to adults. There is a paucity of evidence providing guidance on quantifying risk and planning the safe conduct of anesthesia. In the largest adult case series to date, intraoperative complications were associated only with the preoperative presence of a pericardial effusion. Postoperative complications were predicted by severe symptoms at presentation, tracheal compression of > 50%, and a mixed obstructive restrictive picture on pulmonary function testing. Low-risk patients tolerate conventional general anesthesia with neuromuscular blockade and positive pressure ventilation. Those at intermediate or high risk are best managed with the maintenance of spontaneous ventilation, at least initially. Cardiopulmonary bypass remains the option of last resort. CONCLUSIONS: It appears prudent to avoid general anesthesia when possible for patients at the highest risk. When general anesthesia is required, a comprehensive plan must be formulated preoperatively with the surgical team. Cardiopulmonary bypass requires time for implementation, so it should be considered early and appropriate preparations should be made prior to the initiation of anesthesia. PMID- 21779949 TI - Cost implications of ACGME's 2011 changes to resident duty hours and the training environment. AB - BACKGROUND: In July 2011, the Accreditation Council for Graduate Medical Education (ACGME) will implemented stricter duty-hour limits and related changes to the training environment. This may affect preventable adverse event (PAE) rates. OBJECTIVES: To estimate direct costs under various implementation approaches, and examine net costs to teaching hospitals and cost-effectiveness to society across a range of hypothetical changes in PAEs. DESIGN: A decision analytical model represented direct costs and PAE rates, mortality, and costs. DATA SOURCES: Published literature and publicly available data. TARGET POPULATION: Patients admitted to hospitals with ACGME-accredited programs. TIME HORIZON: One year. PERSPECTIVES: All teaching hospitals, major teaching hospitals, society. INTERVENTION: ACGME's 2011 Common Program Requirements. OUTCOME MEASURES: Direct annual costs (all accredited hospitals), net cost (major teaching hospitals), cost per death averted (society). RESULTS OF BASE-ANALYSIS: Nationwide, duty-hour changes would cost $177 million annually if interns maintain current productivity, vs. up to $982 million if they transfer work to a mixture of substitutes; training-environment changes will cost $204 million. If PAEs decline by 7.2-25.8%, net costs to major teaching hospitals will be zero. If PAEs fall by 3%, the cost to society per death averted would be -$523,000 (95% confidence interval: -$1.82 million to $685,000) to $2.44 million ($271,000 to $6.91 million). If PAEs rise, the policy will be cost-increasing for teaching hospitals and society. RESULTS OF SENSITIVITY ANALYSIS: The total direct annual cost nationwide would be up to $1.34 billion using nurse practitioners/physician assistants, $1.64 billion using attending physicians, $820 million hiring additional residents, vs. 1.42 billion using mixed substitutes. LIMITATIONS: The effect on PAEs is unknown. Data were limited for some model parameters. CONCLUSION: Implementation decisions greatly affect the cost. Unless PAEs decline substantially, teaching hospitals will lose money. If PAEs decline modestly, the requirements might be cost-saving or cost-effective to society. PMID- 21779950 TI - B and T lymphocyte attenuator regulates the development of antigen-induced experimental conjunctivitis. AB - PURPOSE: To investigate the roles that B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) play in the development of antigen-induced experimental conjunctivitis (EC). METHODS: BALB/c mice were immunized with ragweed (RW) in alum. Ten days later, the mice were challenged with RW in eye drops. After 24 hours, the conjunctivas, blood and spleens were collected for histological analysis, measurement of serum immunoglobulin (Ig) levels, and both flow cytometric analysis and cytokine assays, respectively. The mice were injected intraperitoneally with anti-BTLA antibody, anti-HVEM antibody or control antibody during either induction phase or effector phase. RESULTS: Induction phase treatment with anti-BTLA antibody but not anti-HVEM antibody significantly increased conjunctival eosinophil infiltration. Treatment with either antibody during the effector phase did not affect conjunctival eosinophil infiltration. Anti-BTLA antibody treatment during the induction phase reduced the B cell compartment and increased the CD11b-positive cell compartment in splenocytes. Additionally, anti-BTLA treatment upregulated IL-4 and IL-10 production of splenocytes stimulated by RW. CONCLUSIONS: BTLA regulated the development of EC possibly by downregulating Th2 cytokine production and adjusting the compartments of immunocompetent cells. The regulation of EC by BTLA may be mediated by BTLA ligands other than HVEM. PMID- 21779951 TI - Metastatic bladder transitional cell carcinoma presenting as a vascularised cutaneous right arm lesion. AB - A 65-year-old man presented to the emergency department with a 3-week history of a fast-growing and painful mass in his right antecubital fossa. He felt otherwise well. Four months earlier, he had undergone a radical cystectomy for transitional cell carcinoma (TCC) of the bladder (grade 3, stage pT1). Two months after the cystectomy, at another hospital, he was diagnosed with, and treated for, a pseudoaneurysm in his right antecubital fossa. Duplex ultrasonography of the presenting lesion revealed a highly vascularised mass with no pseudoaneurysm. Histological and immunohistochemical analysis preceded a diagnosis of cutaneous metastatic TCC. Whole-body CT revealed widespread metastases. This is the first reported case of a highly vascularised cutaneous lesion being the presenting feature of metastatic bladder TCC. PMID- 21779952 TI - Traumatic extremity amputation in a Nigerian setting: patterns and challenges of care. AB - PURPOSE: We aimed to determine the epidemiological pattern and highlight challenges of managing traumatic amputation in our environment. METHOD: This was a ten-year retrospective study of all the patients with traumatic extremity amputation seen in Ebonyi State University Teaching Hospital and Federal Medical Centre Abakaliki from January 2001 to December 2010. RESULT: There were 53 patients with 58 amputations studied. There was a male to female ratio of 3:1 and the mean age was 32.67 +/- 1.54 years. Amputations were more prevalent in the rainy season. Road traffic accident was the predominant causative factor and accounted for about 57% of amputations. A majority of the patients (81.4%) had no pre-hospital care and none of the amputated parts received optimum care. Three patients underwent re-attachment of amputated fingers and one was successful. Wound infection (in 56.6% of patients) was the most common complication observed. Overall mortality was 7.5% and all were due to complications of amputations. CONCLUSION: Appropriate injury prevention mechanisms based on the observed patterns are needed. Educational campaigns for prevention should be intensified during the rainy season and directed toward young men. Measures aimed at improving pre-hospital care of patients and optimum care of amputated parts is an important aspect to be considered in any developmental programme of replantation services in the sub-region. PMID- 21779953 TI - Gait abnormalities in multiple sclerosis: pathogenesis, evaluation, and advances in treatment. AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by episodic decline in various neurologic functions. Gait dysfunction in MS is distinguished by decreased gait speed, walking endurance, step length, cadence and joint motion, as well as increased metabolic cost of walking and increased variability of gait. Standardized clinical, timed, and patient-based measures can identify MS patients with gait dysfunction, and observational gait analysis, instrumented walkways, or three-dimensional gait analysis can help determine which problem underlies their gait dysfunction to help direct effective treatment. Exercise may ameliorate all types of gait dysfunction. In addition, gait dysfunction due to weakness may be alleviated by orthoses or functional electrical stimulation; gait dysfunction due to spasticity may be relieved by oral, intrathecal, or intramuscular medications. Assistive devices and balance training may reduce gait dysfunction from imbalance, and dalfampridine may accelerate gait in people with MS who walk slowly. PMID- 21779954 TI - HIV risk behaviors of male and female jail inmates prior to incarceration and one year post-release. AB - Individuals cycling in and out of the criminal justice system are at high risk for contracting HIV/AIDS. Most infections are contracted in the community, not during incarceration, but little is known about the profile of risk behaviors responsible for this elevated infection rate. This study investigated pre incarceration and post-release HIV risk behaviors in a longitudinal study of 542 male and female inmates in a Northern Virginia jail. Although there was a significant decrease in risky behavior from pre-incarceration to post incarceration, participants reported high levels of unprotected sexual activity and risky IV drug behaviors at both time points, emphasizing the need for prevention programming among this at-risk population. Gender differences in participants' pre-incarceration and post-release HIV risk behaviors suggest the need for gender-specific interventions to reduce overall HIV risk. Identifying specific HIV risk behaviors of jail inmates is vital to improve treatment and intervention efforts inside and outside of correctional settings. PMID- 21779956 TI - Risk evaluation, prophylaxis, and treatment of tumor lysis syndrome: consensus of an Italian expert panel. AB - INTRODUCTION: Tumor lysis syndrome (TLS) is a life-threatening complication in patients with hematological disease and/or solid tumors that results from rapid, large-scale tumor necrosis occurring spontaneously, or more commonly, as a result of chemotherapy. TLS is characterized by metabolic and electrolyte imbalances that include hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Identification of risk groups as well as early detection of TLS is crucial for the establishment of appropriate strategies of prophylaxis and treatment. METHODS: A review of the peer-reviewed literature on TLS between 1990 and 2011 was conducted via a systematic search of the PubMed database using the keywords "TLS" [AND] "management," "risk evaluation," "prophylaxis," and "treatment." An expert opinion-based approach was used to review the national and international recommendations and guidelines on the topic. RESULTS: The PubMed search produced 90 results, all of which were evaluated. These studies, together with a recent international consensus panel provided recommendations for evaluating the risk of TLS and providing prophylaxis. Five algorithms are presented that consider all of the factors when assessing the risk for neoplastic disease in general, and specifically for leukemia and lymphoma. CONCLUSION: The present report provides clinicians with an easily consultable tool to guide the evidence-based management of this oncohematological emergency. PMID- 21779957 TI - The reduction of reactive oxygen species formation by mitochondrial alternative respiration in tomato basal defense against TMV infection. AB - The role of mitochondrial alternative oxidase (AOX) and the relationship between systemic AOX induction, ROS formation, and systemic plant basal defense to Tobacco mosaic virus (TMV) were investigated in tomato plants. The results showed that TMV inoculation significantly increased the level of AOX gene transcripts, ubiquinone reduction levels, pyruvate content, and cyanide-resistant respiration (CN-resistant R) in upper, un-inoculated leaves. Pretreatment with potassium cyanide (KCN, a cytochrome pathway inhibitor) greatly increased CN-resistant R and reduced reactive oxygen species (ROS) formation, while application of salicylhydroxamic acid (SHAM, an AOX inhibitor) blocked the AOX activity and enhanced the production of ROS in the plants. Furthermore, TMV systemic infection was enhanced by SHAM and reduced by KCN pretreatment, as compared with the un pretreated TMV counterpart. In addition, KCN application significantly diminished TMV-induced increase in antioxidant enzyme activities and dehydroascorbate/total ascorbate pool, while an opposite change was observed with SHAM-pretreated plants. These results suggest that the systemic induction of the mitochondrial AOX pathway plays a critical role in the reduction of ROS to enhance basal defenses. Additional antioxidant systems were also coordinately regulated in the maintenance of the cellular redox homeostasis. PMID- 21779958 TI - Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. AB - The aim of this study was to investigate the efficacy of idebenone on neurological function as assessed by ICARS and FARS neurological rating scales in pediatric Friedreich's ataxia (FRDA) patients. Sixty-eight pediatric patients were enrolled in an open-label extension study (IONIA-E) where patients received idebenone (Catena((r)), 150 mg film-coated tablets) at a weight-adjusted dose of 1,350/2,250 mg/day for 12 months after patients had completed a double-blind, randomized, placebo-controlled study (IONIA) receiving either idebenone at a weight-adjusted dose of 450/900 or 1,350/2,250 mg/day or placebo for 6 months. Changes in ICARS and FARS total scores and subscores were recorded for the 12 month IONIA-E study and for the 18-month combined IONIA and IONIA-E study period. Data analyzed by a mixed-model repeated-measures ANCOVA relative to baseline resulted in least square means for the change in ICARS for the IONIA-E study of +0.98 points (SEM 0.73; p = 0.180), indicating a trend for worsening. However, combined with the IONIA study the change was -1.03 +/- 0.68 points (p = 0.132), indicating a trend for improvement in neurological function over the 18-month period. Importantly, patients who received idebenone 1,350/2,250 mg/day over this period significantly improved in neurological function (change in ICARS: -3.02 +/ 1.22, p = 0.014). The improvement in neurological function over time was best seen when the posture and stance subscore was excluded from the analysis. Comparable data were obtained with the FARS. The findings of the open-label IONIA E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurological function and improving fine motor skills and speech. PMID- 21779959 TI - Increasing histamine neurotransmission in Gilles de la Tourette syndrome. PMID- 21779961 TI - Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg). AB - PURPOSE: To prospectively evaluate the association of vitamin/mineral supplementation with cancer, cardiovascular, and all-cause mortality. METHODS: In the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), which was recruited in 1994-1998, 23,943 participants without pre-existing cancer and myocardial infarction/stroke at baseline were included in the analyses. Vitamin/mineral supplementation was assessed at baseline and during follow-up. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After an average follow-up time of 11 years, 1,101 deaths were documented (cancer deaths = 513 and cardiovascular deaths = 264). After adjustment for potential confounders, neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer, cardiovascular, or all-cause mortality. However, baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality (HR: 0.52; 95% CI: 0.28, 0.97) and all-cause mortality (HR: 0.58; 95% CI: 0.38, 0.88). In comparison with never users, baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality (HR: 1.74; 95% CI: 1.09, 2.77) and all-cause mortality (HR: 1.58; 95% CI: 1.17, 2.14). CONCLUSIONS: Based on limited numbers of users and cases, this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality. The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a "sick-user effect," which researchers should be cautious of in future observational studies. PMID- 21779960 TI - [Measurement of glaucoma-specific functionality with the GQL-15 and correlation with parameters of visual function]. AB - INTRODUCTION: Glaucoma is one of the leading causes of irreversible blindness worldwide and can have a significant impact on patient quality of life and vision related functioning. The Glaucoma Quality of Life 15 (GQL-15) questionnaire is a disease-specific instrument to evaluate and quantify functional impairment of patients with glaucoma. This study evaluated the German version of the GQL-15 including correlations with perimetric parameters. METHODS: A German version of the GQL-15 containing 15 items was developed and evaluated in 98 patients with glaucoma in different stages of the disease. The GQL-15 results were correlated with the perimetric parameters mean deviation (MD) and pattern standard deviation (PSD) of the better and worse eye. Classical and probabilistic test analyses (Rasch model) were performed. RESULTS: The mean GQL-15 value was 77.3 +/- 21.7 (SD) and most items of the GQL-15 correlated significantly with the MD of the worse eye (r = -0.416; p = 0.0014) and the better eye (r = -0.304; p = 0.02). There was also a highly significant correlation between glaucoma-specific QoL and visual acuity. A short version containing nine items yielding a higher psychometric performance can also be used. CONCLUSIONS: The German version of the GQL-15 is a potent instrument to evaluate impairment in vision-specific functioning of patients with glaucoma. The GQL-15 values are better correlated with the sensitivity of the eye with the more severe glaucomatous damage. The data can help for a better understanding of individual patient impairment to improve medical advice and therapy of patients with glaucoma. PMID- 21779962 TI - The relationship between stress-induced myocardial ischemia and coronary artery atherosclerosis measured by hybrid SPECT/CT camera. AB - OBJECTIVE: The coronary artery calcium (CAC) score and myocardial perfusion imaging can now be detected simultaneously using a hybrid SPECT/CT camera. However, there has been little evaluation on the relationship between stress induced ischemia and coronary artery calcification in a Japanese population. The aim of this study was to investigate the relationship between these parameters and to elucidate the diagnostic value of the CAC score as an adjunct to myocardial perfusion imaging (MPI) for the assessment of coronary artery disease (CAD) in an intermediate-risk population. METHODS: We retrospectively analyzed 105 patients (63% men, mean age 71 years) with CAD or suspected CAD who underwent MPI using SPECT/CT. CAC scanning was performed using a SPECT/CT camera. RESULTS: There was a significant difference in the CAC score between patients with ischemia (n = 42) and those without ischemia (n = 63) (1353 +/- 1524 vs. 332 +/- 554, p < 0.01). The frequency of ischemic MPI determined by summed difference score tended to be higher in patients with high CAC (CAC = 0; 0.8 +/- 1.3 vs. CAC > 1000; 3.0 +/- 2.0). Higher age is related roughly with higher CAC score with no statistical significance (r(2) = 0.1) (<60 years old; 200 +/- 692, vs. >80 years old; 1258 +/- 1546, ns). The location of calcification was not related to the ischemic area. In a population with a predominately intermediate likelihood of CAD, a calcium score of zero has a possibility of excluding inducible ischemia on MPI. In part, ischemic MPI is associated with a high likelihood of subclinical atherosclerosis as detected by CAC. CONCLUSION: Hybrid SPECT/CT might be useful for diagnostic assessment and coronary artery with known or suspected CAD. PMID- 21779963 TI - A model of proto-anti-codon RNA enzymes requiring L-amino acid homochirality. AB - All living organisms encode the 20 natural amino acid units of polypeptides using a universal scheme of triplet nucleotide "codons". Disparate features of this codon scheme are potentially informative of early molecular evolution: (i) the absence of any codons for D-amino acids; (ii) the odd combination of alternate codon patterns for some amino acids; (iii) the confinement of synonymous positions to a codon's third nucleotide; (iv) the use of 20 specific amino acids rather than a number closer to the full coding potential of 64; and (v) the evolutionary relationship of patterns in stop codons to amino acid codons. Here I propose a model for an ancestral proto-anti-codon RNA (pacRNA) auto aminoacylation system and show that pacRNAs would naturally manifest features of the codon table. I show that pacRNAs could implement all the steps for auto aminoacylation: amino acid coordination, intermediate activation of the amino acid by the 5'-end of the pacRNA, and 3'-aminoacylation of the pacRNA. The anti codon cradles of pacRNAs would have been able to recognize and coordinate only a small number of L-amino acids via hydrogen bonding. A need for proper spatial coordination would have limited the number of chargeable amino acids for all anti codon sequences, in addition to making some anti-codon sequences unsuitable. Thus, the pacRNA model implies that the idiosyncrasies of the anti-codon table and L-amino acid homochirality co-evolved during a single evolutionary period. These results further imply that early life consisted of an aminoacylated RNA world with a richer enzymatic potential than ribonucleotides alone. PMID- 21779964 TI - Exercise-induced intraventricular obstruction in a child with near syncope and chest pain during exercise. AB - We report the case of a 10-year-old girl with two episodes of light-headedness and chest pain during exercise. She had an unremarkable clinical record, physical examination, ECG, and echocardiogram. Noninvasive ischemia tests were positive, but coronary angiography was normal. Exercise stress echocardiogram revealed an exercise-induced intra-left-ventricular obstruction with a peak gradient of 78 mmHg and replicated her symptoms. After starting beta-blocker therapy her clinical status improved and no residual obstruction was detected. The authors review this unsuspected clinical condition, seldom reported in the adult population and, to our knowledge, never before in a child. PMID- 21779965 TI - Exercise-induced myocardial ischemia in a case of anomalous origin of the left main coronary artery from the noncoronary sinus of valsalva. AB - We report a case of anomalous origin of the left main coronary artery (LCA) from the noncoronary sinus of valsalva (LCANCS) in a young healthy patient who presented with syncope and cardiopulmonary arrest during exercise. The enhanced computed tomography showed acute angle take-off (AAT) of LCA, and the exercise stress thallium-201 myocardial scintigraphy demonstrated a large defect at the LCA perfusion region. We propose that the coexistence of AAT and resulting ischemia causes sudden cardiac death during exercise in the patients with LCANCS. PMID- 21779966 TI - Congenital subclavian steal syndrome associated with heterotaxy syndrome and atrioventricular septal defect. AB - An infant under follow-up evaluation since the fetal stage was detected to have subclavian steal syndrome (SSS) associated with heterotaxy syndrome and atrioventricular septal defect. Such a complex association has not been reported previously. Congenital SSS occurs as a result of a subclavian artery originating from the main pulmonary artery through the ductus instead of the aortic arch. In rare cases, as in the reported case, it may occur due to proximal segment atresia of the left subclavian artery. PMID- 21779967 TI - Accuracy of Doppler-derived estimation of pulmonary vascular resistance in congenital heart disease: an index of operability. AB - Pulmonary vascular resistance (PVR) is a critical and essential parameter during the assessment and selection of modality of treatment in patients with congenital heart disease (CHD) accompanied by pulmonary arterial hypertension (PAH). Cardiac catheterization is the "gold standard" but is an invasive method for PVR measurement. A noninvasive and reliable method for estimation of PVR in children has been a major challenge and most desirable during past decades, especially for those who need repeated measurements. In a prospective study and among consecutive patients who were referred for cardiac catheterizations, PVR was calculated as the ratio of the transpulmonary pressure gradient (?P) to the amount of the pulmonary flow (QP) accordingly for 20 patients with CHD and high PAH. Subsequently and noninvasively, PVR was assessed for these patients by a Doppler echocardiography-derived index defined as the ratio of the tricuspid regurgitation velocity (TRV(m/s)) to the velocity time integral (VTI(cm)) of the right-ventricular outflow tract (RVOT). There was a good correlation between PVR measured at catheterization (PVR(cath)) and TRV/VTI(m) ratio; the mean of three measurements of VTI (VTI(m)) with R (2) = 0.53 (p = 0.008). In addition, a TRV/VTI(m) value of 0.2 provided a sensitivity of 71.4% and a specificity of 100% for PVR >6 Woods units (WU) as well as sensitivity of 90% and specificity of 90% for a PVR equal to 8 WU. PVR value between 6 and 8 WU by catheterization has been considered as a cut-off point for intervention in children with left-to-right shunts and PAH. In conclusion, Doppler-derived TRV/VTI(m) ratio is a reliable index that may be helpful as a supplementary diagnostic tool for the selection of modality of treatment and follow-up of patients with PAH and increased PVR. PMID- 21779968 TI - Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. AB - The use of unlicensed and off-label medicines in children is common because trials in children have not usually been performed during the drug development process. Consequently, the information available to paediatricians may not always be as detailed or as robust as that available when prescribing a medicine that is licensed for an approved indication. This has led to concerns that children may be receiving drugs at dosages that either lack efficacy or present safety problems. The latter in particular has received a great deal of attention. In this narrative review, we have evaluated the use of off-label and unlicensed medicines in children and whether and how frequently this predisposes to adverse drug reactions. PMID- 21779969 TI - Dopamine agonists and ischemic complications in Parkinson's disease: a nested case-control study. AB - BACKGROUND: It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied. OBJECTIVE: Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD. METHODS: We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified. RESULTS: The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists. CONCLUSIONS: This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization. PMID- 21779971 TI - The ethics of biobanking: key issues and controversies. PMID- 21779970 TI - Transcriptome analysis of probiotic Lactobacillus casei Zhang during fermentation in soymilk. AB - Lactobacillus casei Zhang is a widely recognized probiotic bacterium, which is being commercially used in China. To study the gene expression dynamics of L. casei Zhang during fermentation in soymilk, a whole genome microarray was used to screen for differentially expressed genes when grown to the lag phase, the late logarithmic phase, and the stationary phase. Comparisons of different transcripts next to each other revealed 162 and 63 significantly induced genes in the late logarithmic phase and stationary phase, of which the expression was at least threefold up-regulated and down-regulated, respectively. Approximately 38.4% of the up-regulated genes were associated with amino acid transport and metabolism notably for histidine and lysine biosynthesis, followed by genes/gene clusters involved in carbohydrate transport and metabolism, lipid transport and metabolism, and inorganic ion transport and metabolism. The analysis results suggest a complex stimulatory effect of soymilk-based ecosystem on the L. casei Zhang growth. On the other hand, it provides the very first insight into the molecular mechanism of L. casei strain for how it will adapt to the protein-rich environment. PMID- 21779972 TI - The international transferability of human capital in nursing. AB - This study examines the transferability of foreign human capital in nursing using the 1988-2004 National Sample Survey of Registered Nurses (NSSRN). In contrast with theoretical predictions and previous studies, this research finds evidence that foreign nursing education commands a higher return than U.S. education, even after controlling for a rich set of covariates. Consistent with the literature, the estimates illustrate foreign experience earns a lower return than domestic experience in nursing. Analysis across subsamples reveals the counter-intuitive foreign education premium is driven by foreign nurses educated in English speaking countries and those working in hospitals. These estimates suggest future research should take into account the heterogeneity in the returns on foreign education across occupations. PMID- 21779973 TI - Usefulness of psyllium in rehabilitation of obstructed defecation. AB - BACKGROUND: Rehabilitation is the first therapeutic step of obstructed defecation, after failure of conservative therapy with high-fiber diet and laxatives. This study evaluates the usefulness of psyllium, a bulk-forming agent, when used during rehabilitation of obstructed defecation. METHODS: Between January 2008 and December 2010, 45 patients affected by obstructed defecation were included in the study. Two randomized groups were selected. Group 1 (21 women; age range 25-67 (mean, 51.8) years) continued to consume a high-fiber diet (approximately 30 g fiber per day) during rehabilitation. Group 2 (24 women; age range 46-71 (mean, 59.8) years) consumed only psyllium (3.6 g * 2/day; Psyllogel((r)) Fibra, Nathura, Montecchio Emilia, Italy) during the rehabilitative cycle. After a preliminary clinical evaluation, including the obstructed defecation syndrome (ODS) score, patients underwent defecography and anorectal manometry as well as rehabilitative treatment according to the "multimodal rehabilitative program" for obstructive defecation. At the end of the program, patients were reassessed by clinical evaluation and anorectal manometry. Post-rehabilitative ODS scores were used for an arbitrary schedule of patients divided into three classes: Class I, good (score <= 4); Class II, fair (score > 4 to <= 8); Class III, poor (score > 8). RESULTS: The number of bowel movements per week did not increase significantly after rehabilitation. Both groups had a significantly better Bristol stool form scale score (Group 1: P < 0.034; Group 2: P < 0.02). The overall mean ODS score from Groups 1 and 2 showed significant improvement after treatment (P < 0.001). Twenty-eight patients (82.3%) were Class I (good results) without significant differences between groups. Nine women were symptom-free. Significant differences were found between pre-rehabilitative and post-rehabilitative manometric data from the straining test (P < 0.001) and duration of maximal voluntary contraction (Group 1: P < 0.004; Group 2: P < 0.02). A significant difference was found between the pre-rehabilitative and post rehabilitative conscious rectal sensitivity threshold (CRST) in Group 2 women (P < 0.02). The Group 2 women who underwent volumetric rehabilitation (11 patients) had significantly lower post-rehabilitative CRST values than pre-rehabilitative values (P < 0.002); the length of volumetric rehabilitation was also significantly shorter in Group 2 patients (P < 0.04) than in Group 1 patients. CONCLUSIONS: After rehabilitation of obstructed defecation, some patients became symptom-free and many had an improved ODS score. Psyllium is helpful for volumetric rehabilitation: patients who consumed psyllium had lower post rehabilitative CRST values than subjects were on high-fiber diet. PMID- 21779974 TI - Proximal colonic atresia: is right hemicolectomy inevitable? AB - PURPOSE: Proximal colonic atresia often results in a marked discrepancy of the atretic ends presenting a technical challenge for restoration of bowel continuity. We review our series of colonic atresia patients with particular reference to the techniques for restoring bowel continuity. METHODS: Case notes of all patients diagnosed with colonic atresia and admitted to our unit between 1997 and 2011 were reviewed. RESULTS: There were 13 patients with a median gestational age of 39 weeks. Location of the atresia was ascending colon (n = 1), hepatic flexure (n = 9), proximal transverse colon (n = 2) and sigmoid colon (n = 1). The primary procedure was: primary anastomosis (n = 1), right hemicolectomy followed by ileo-colic anastomosis (n = 2), right hemicolectomy and stoma formation (n = 3). Six patients underwent stoma formation, of which five subsequently had a right hemicolectomy at a later procedure. In total, 10/12 patients required right hemicolectomy to facilitate restoration of bowel continuity. Median time to full feeds was 11 days (4-46). Median follow up time was 11 months (22 days-5.6 years). CONCLUSION: A temporising stoma does not reduce the discrepancy in the calibre of the atretic ends in proximal colonic atresia. Right hemicolectomy and ileo-colic anastomosis should therefore be considered at the initial surgery. PMID- 21779975 TI - Involvement of IL-10 gene promoter polymorphisms in the susceptibility for childhood asthma. AB - Asthma and atopy have a complex background that may result from the interaction of genes and the environment. Interleukin (IL)-10 is known to play various roles in immune-regulating and anti-inflammatory responses. The aim of this study was to evaluate the possible effect of the IL-10 promoter polymorphisms on susceptibility to childhood asthma. We recruited 333 patients with atopic asthma, 55 with nonatopic asthma, and 248 normal controls. We performed a genetic association study of three genetic polymorphisms (IL-10 -1082A>G, IL-10 -819T>C, and IL-10 -592A>C) of the IL-10 promoter. There was no difference between atopic asthma, nonatopic asthma, and normal controls with respect to allele, genotype, or haplotype frequencies of these IL-10 polymorphisms. However, the -1082A>G polymorphism and ATA haplotype in the IL-10 promoter gene were associated with airway hyper responsiveness (AHR) and the -819T>C, -592A>C, and ATA and ACC haplotypes were also shown to be related to serum eosinophil cationic protein (ECP). Our results suggest that the polymorphisms within the IL-10 promoter may have a disease-modifying effect in the asthmatic airway. PMID- 21779976 TI - Ventriculoperitoneal shunt malfunction from cerebrospinal fluid eosinophilia in children: case-based update. AB - INTRODUCTION: Malfunction of cerebrospinal shunts is common and is due to multiple etiologies ranging from obstruction due to infiltrated brain tissue to mechanical disconnection. DISCUSSION: We review the differential diagnosis and recommended evaluation and treatment for cerebrospinal fluid (CSF) eosinophilia. ILLUSTRATIVE CASE: We report a child who, following the use of an antibiotics impregnated ventricular catheter, developed sterile ventriculoperitoneal shunt malfunction thought to be due to profound CSF eosinophilia. Following removal of the catheter, the eosinophilia spontaneously resolved, and at long-term follow up, the patient has a functioning non-antibiotic impregnated shunt catheter. CONCLUSIONS: Patients presenting with signs of shunt malfunction but without signs of CSF infection and with a raised CSF eosinophilia should be suspicious for cellular obstruction of their shunt system, i.e., sterile shunt malfunction. PMID- 21779977 TI - Microsurgical resection of deep-seated lesions using transparent tubular retractor: pediatric case series. AB - BACKGROUND: To facilitate effective resection of deep-seated brain lesions without causing significant trauma to the overlying cortex, the authors used a transparent plastic tubular retractor to approach these lesions. METHODS: Between July 2009 and January 2011, we used an 11-mm diameter transparent plastic tubular retractor in combination with a frameless stereotactic navigation system to remove 18 deep lesions. RESULTS: Gross total resection of the lesions was achieved in 14 of 18 patients, and subtotal removal occurred in four patients. Effective resection of lesions was achieved in all patients through small size craniotomy window and small cortical incision. The histopathologic diagnosis was established in all 18 patients: 3 hematomas, 3 cavernous angioma, 7 low-grade glioma, 2 dysembryoplastic neuroepithelial tumor, 1 choroid plexus papilloma, 1 abscess, and 1 meningioma. CONCLUSION: Microsurgery using a transparent tubular retractor guided by a neuronavigation system facilitated accurate and effective removal of these deep-seated brain lesions. PMID- 21779978 TI - Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54. AB - Certain aminoglycosides are capable of inducing "translational readthrough" of premature termination codons (PTCs). However, toxicity and relative lack of efficacy deter treatment with clinically available aminoglycosides for genetic diseases caused by PTCs, including cystic fibrosis (CF). Using a structure-based approach, the novel aminoglycoside NB54 was developed that exhibits reduced toxicity and enhanced suppression of PTCs in cell-based reporter assays relative to gentamicin. We examined whether NB54 administration rescued CFTR protein and function in clinically relevant CF models. In a fluorescence-based halide efflux assay, NB54 partially restored halide efflux in a CF bronchial epithelial cell line (CFTR genotype W1282X/F508del), but not in a CF epithelial cell line lacking a PTC (F508del/F508del). In polarized airway epithelial cells expressing either a CFTR-W1282X or -G542X cDNA, treatment with NB54 increased stimulated short circuit current (I (SC)) with greater efficiency than gentamicin. NB54 and gentamicin induced comparable increases in forskolin-stimulated I (SC) in primary airway epithelial cells derived from a G542X/F508del CF donor. Systemic administration of NB54 to Cftr-/- mice expressing a human CFTR-G542X transgene restored 15-17% of the average stimulated transepithelial chloride currents observed in wild-type (Cftr+/+) mice, comparable to gentamicin. NB54 exhibited reduced cellular toxicity in vitro and was tolerated at higher concentrations than gentamicin in vivo. These results provide evidence that synthetic aminoglycosides are capable of PTC suppression in relevant human CF cells and a CF animal model and support further development of these compounds as a treatment modality for genetic diseases caused by PTCs. PMID- 21779979 TI - Rethinking immigrant tuberculosis control in Canada: from medical surveillance to tackling social determinants of health. AB - Current tuberculosis control strategies in Canada rely exclusively on screening and surveillance of immigrants. This is consistent with current public health discourse that attributes the high burden of immigrant tuberculosis to the exposure of immigrants to infection in their country of origin. The effectiveness of control strategies is questionable given the evidence that many immigrants are at higher risk of tuberculosis reactivation because of risk factors such as poverty, malnutrition and overcrowded housing. This paper argues that the absence of policies that address poverty-related disadvantages among immigrants makes these populations more vulnerable to the reactivation of their tuberculosis long after they have been exposed in their countries of birth. Policies for tuberculosis prevention in the Aboriginal population attend to their poverty and other social determinants of health. Effective health prevention policy for tuberculosis within the immigrant population must take similar direction. PMID- 21779980 TI - A survey of APC mutations in Quebec. AB - This is an 11-year survey of molecular analysis of APC germline mutations for the province of Quebec done at the Molecular Pathology Unit of the Jewish General Hospital which offers genetic testing for hereditary forms of colorectal cancer for the whole of Quebec province. We report on 47 unique mutations seen in 66 families affected with familial adenomatous polyposis. Of these unique mutations, 60% are short indels, 28% are point mutations, and 6% are whole exon deletions. The absence of founder mutations and the variety of mutations encountered reinforce the value of RNA-based testing and the need for gene dosage techniques such as multiplex ligation-dependent probe amplification. PMID- 21779981 TI - Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery. AB - Phosphoinositide-dependent kinase-1 (PDK1) is a critical enzyme in the PI3K/AKT pathway and to the activation of AGC family protein kinases, including S6K, SGK, and PKC. Dysregulation of this pathway plays a key role in cancer cell growth, survival and tumor angiogenesis. As such, inhibitors of PDK1 offer the promise of a new therapeutic modality for cancer treatment. Fragment based drug screening has recently become a viable entry point for hit identification. In this work, NMR spectroscopy fragment screening of PDK1 afforded novel chemotypes as orthogonal starting points from HTS screening hits. Compounds identified as hits by NMR spectroscopy were tested in a biochemical assay, and fragments with activity in both assays were clustered. The Pfizer compound file was mined via substructure and 2D similarity search, and the chemotypes were prioritized by ligand efficiency (LE), SAR mining, chemical attractiveness, and chemical enablement of promising vectors. From this effort, an isoquinolone fragment hit, 5 (IC(50) 870 MUM, LE = 0.39), was identified as a novel, ligand efficient inhibitor of PDK1 and a suitable scaffold for further optimization. Initially in the absence of crystallographic data, a fragment growing approach efficiently explored four vectors of the isoquinolone scaffold via parallel synthesis to afford a compound with crystallographic data, 16 (IC(50) 41.4 MUM, LE = 0.33). Subsequent lead optimization efforts provided 24 (IC(50) 1.8 MUM, LE = 0.42), with greater than fivefold selectivity against other key pathway kinases. PMID- 21779982 TI - The expression of p33(ING1), p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer. AB - The purpose of this study was to investigate the expressions of tumor inhibitor of growth (ING1) gene p33ING1, p53, and autophagy-related gene Beclin1 in human non-small cell lung cancer (NSCLC), and the correlation between their expressions with clinical pathological features and clinical significance. The research can provide new ideas and experimental evidence for early diagnosis and biotherapy for NSCLC in the future. The human NSCLC tissues and surrounding non-cancerous tissues were collected from surgical operation. The expressions of mRNA or protein of p33ING1, p53, and Beclin1 were detected by using of reverse transcription polymerase chain reaction or Western blot in these tissues. The results were used to analyze the relationships between these gene expressions with the developing of NSCLC and clinical pathological features. The expressions of mRNA or protein of p33ING1 and Beclin1 in NSCLC tissues were significantly lower than that in surrounding noncancerous tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in well- and middle-differentiated NSCLC tissues were lower than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in presence of lymph nodes metastasis were lower than those in absence of lymph nodes metastasis (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in patients of pathological stage (stages I-II) were higher than those in pathological stage (stages III-IV) (p < 0.05). But the expression of protein of mutant-type p53 in NSCLC tissues was significantly higher than that in surrounding non-cancerous tissues (p < 0.05). The expressions of protein of mutant-type p53 in well- and middle-differentiated NSCLC tissues were higher than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of protein of mutant-type p53 in presence of lymph nodes metastasis were higher than those in absence of lymph nodes metastasis (p < 0.05). The expressions of protein of mutant-type p53 in patients of pathological stage (stages I-II) were lower than those in pathological stage (stages III-IV) (p < 0.05). These expression changes of p33ING1, p53, and autophagy-related Beclin1 genes were associated with tumor cell differentiation, lymph nodes metastasis, and pathological stage of NSCLC. But these expression changes of these three genes were not associated with gender, age, size of primary carcinoma, histological type of NSCLC (p > 0.05). The expression of mRNA of p53 and Beclin1 were correlated with p33ING1 mRNA expression in NSCLC tissues (p < 0.05). The activity changes of tumor inhibitor of growth, autophagy, and apoptosis may be related to the emergence and the development of NSCLC. The combined detection of p33ING1, p53, and Beclin1 genes and proteins will be helpful for early diagnosis and prognosis judgment for NSCLC, and can provide experimental evidence for biotherapy of NSCLC. PMID- 21779985 TI - Phase separation of a binary liquid in anodic aluminium oxide templates: a structural study by small angle neutron scattering. AB - The radial nanostructure of the binary liquid triethylamine/water confined in 60 nm diameter independent cylindrical pores of anodic aluminium oxide membranes is studied by small angle neutron scattering. It is shown that composition inhomogeneities are present in the confined mixtures well below the bulk critical point. An analysis of the neutron scattering form factor reveals the existence of an adsorbed water layer of a few nanometers at the liquid/alumina interface, coexisting with a TEA-rich phase in the core. PMID- 21779986 TI - Epigenetic features that regulate IgH locus recombination and expression. AB - Precisely regulated rearrangements that yield imprecise recombination junctions are hallmarks of antigen receptor gene assembly. At the immunoglobulin heavy chain (IgH) gene locus this is initiated by rearrangement of a D (H) gene segment to a J (H) gene segment to generate DJ(H) junctions, followed by rearrangement of a V (H) gene segment to the DJ(H) junction to generate fully recombined VDJ alleles. In this review we discuss the regulatory features of each step of IgH gene assembly and the role of epigenetic mechanisms in achieving regulatory precision. PMID- 21779987 TI - Accessing and selecting genetic markers from available resources. AB - The history of genetic markers accurately partitions the progression of molecular genetics into three phases: the RFLP (restriction fragment length polymorphism), microsatellite and SNP (single nucleotide polymorphism) eras. This chapter focuses predominately on the current workhorse, the SNP, though briefly covers the former two and overviews current online databases and portals that act as central repositories as well as hubs to further detailed information. Central gene or disease-based searches are considered and then followed through systematically. PMID- 21779988 TI - Linkage analysis. AB - Linkage analysis is used to map genetic loci using observations on relatives. It can be applied to both major gene disorders (parametric linkage) and complex diseases (model-free or non-parametric linkage), and it can be based on either a relatively small number of microsatellite markers or a denser map of single nucleotide polymorphisms (SNPs). We describe the methods commonly used to map loci influencing disease susceptibility or a quantitative trait. Application of these methods to simulated but realistic datasets is illustrated in some detail using the program Merlin. We provide some guidance on the best methods to use in different situations and on the interpretation of output. PMID- 21779989 TI - Association mapping. AB - Association mapping seeks to identify marker alleles present at significantly different frequencies in cases carrying a particular disease or trait compared with controls. Genome-wide association studies are increasingly replacing candidate gene-based association studies for complex diseases, where a number of loci are likely to contribute to disease risk and the effect size of each particular risk allele is typically modest or low. Good study design is essential to the success of an association study, and factors such as the heritability of the disease under investigation, the choice of controls, statistical power, multiple testing and whether the association can be replicated need to be considered before beginning. Likewise, thorough quality control of the genotype data needs to be undertaken prior to running any association analyses. Finally, it should be kept in mind that a significant genetic association is not proof positive that a particular genetic locus causes a disease, but rather an important first step in discovering the genetic variants underlying a complex disease. PMID- 21779990 TI - The ForeSee (4C) approach for integrative analysis in gene discovery. AB - The development of high-throughput experimental techniques has made measurements for virtually all kinds of cellular components possible. Effective integration and analysis of this diverged information to produce insightful knowledge is central to biological study today. In this chapter, we present a methodology for building integrative analytical workbenches using the workflow technology. We focus on the field of gene discovery through the combined study of transcriptomics, genomics and epigenomics, although the methodology is generally applicable to any omics-data analysis for biomarker discovery. We illustrate the application of the methodology by presenting our study on the identification of aberrant genomic regions, genes and/or their regulatory elements with their implications for breast cancer research. We also discuss the challenges and opportunities brought by the latest development of the next generation sequencing technology. PMID- 21779991 TI - R statistical tools for gene discovery. AB - A wide assortment of R tools are available for exploratory data analysis in high dimensional settings and are easily applicable to data arising from population based genetic association studies. In this chapter we illustrate the application of three such approaches, namely conditional inference trees, random forests, and logic regression. Through applications to simulated data, we explore the relative utility of each approach for uncovering underlying association between genetic polymorphisms and a quantitative trait. PMID- 21779992 TI - In silico PCR analysis. AB - In silico PCR analysis is a useful and efficient complementary method to ensure primer specificity for an extensive range of PCR applications from gene discovery, molecular diagnosis, and pathogen detection to forensic DNA typing. In silico PCR, SNPCheck, and Primer-BLAST are commonly used web-based in silico PCR tools. Their applications are discussed here in stepwise detail along with several examples, which aim to make it easier for the intended users to apply the tools. This virtual PCR method can assist in the selection of newly designed primers, identify potential mismatches in the primer binding sites due to known SNPs, and avoid the amplification of unwanted amplicons so that potential problems can be prevented before any "wet bench" experiment. PMID- 21779993 TI - In silico analysis of the exome for gene discovery. AB - Here we describe a bioinformatic strategy for extracting and analyzing the list of variants revealed from an exome sequencing project to identify potential disease genes. This in silico method filters out the majority of common SNPs and extracts a list of potential candidate protein-coding and non-coding RNA (ncRNA) genes. The workflow employs Galaxy, a publically available Web-based software, to filter and sort sequence variants identified by capture-based target enrichment and sequencing from exomes including selected ncRNAs. PMID- 21779994 TI - In silico knowledge and content tracking. AB - This chapter gives a brief overview of text-mining techniques to extract knowledge from large text collections. It describes the basis pipeline of how to come from text to relationships between biological concepts and the problems that are encountered at each step in the pipeline. We first explain how words in text are recognized as concepts. Second, concepts are associated with each other using 2*2 contingency tables and test statistics. Third, we explain that it is possible to extract indirect links between concepts using the direct links taken from 2*2 table analyses. This we call implicit information extraction. Fourth, the validation techniques to evaluate a text-mining system such as ROC curves and retrospective studies are discussed. We conclude by examining how text information can be combined with other non-textual data sources such as microarray expression data and what the future directions are for text-mining within the Internet. PMID- 21779995 TI - Application of gene ontology to gene identification. AB - Candidate gene identification deals with associating genes to underlying biological phenomena, such as diseases and specific disorders. It has been shown that classes of diseases with similar phenotypes are caused by functionally related genes. Currently, a fair amount of knowledge about the functional characterization can be found across several public databases; however, functional descriptors can be ambiguous, domain specific, and context dependent. In order to cope with these issues, the Gene Ontology (GO) project developed a bio-ontology of broad scope and wide applicability. Thus, the structured and controlled vocabulary of terms provided by the GO project describing the biological roles of gene products can be very helpful in candidate gene identification approaches. The method presented here uses GO annotation data in order to identify the most meaningful functional aspects occurring in a given set of related gene products. The method measures this meaningfulness by calculating an e-value based on the frequency of annotation of each GO term in the set of gene products versus the total frequency of annotation. Then after selecting a GO term related to the underlying biological phenomena being studied, the method uses semantic similarity to rank the given gene products that are annotated to the term. This enables the user to further narrow down the list of gene products and identify those that are more likely of interest. PMID- 21779996 TI - Phenotype mining for functional genomics and gene discovery. AB - In gene prediction, studying phenotypes is highly valuable for reducing the number of locus candidates in association studies and to aid disease gene candidate prioritization. This is due to the intrinsic nature of phenotypes to visibly reflect genetic activity, making them potentially one of the most useful data types for functional studies. However, systematic use of these data has begun only recently. 'Comparative phenomics' is the analysis of genotype phenotype associations across species and experimental methods. This is an emerging research field of utmost importance for gene discovery and gene function annotation. In this chapter, we review the use of phenotype data in the biomedical field. We will give an overview of phenotype resources, focusing on PhenomicDB--a cross-species genotype-phenotype database--which is the largest available collection of phenotype descriptions across species and experimental methods. We report on its latest extension by which genotype-phenotype relationships can be viewed as graphical representations of similar phenotypes clustered together ('phenoclusters'), supplemented with information from protein protein interactions and Gene Ontology terms. We show that such 'phenoclusters' represent a novel approach to group genes functionally and to predict novel gene functions with high precision. We explain how these data and methods can be used to supplement the results of gene discovery approaches. The aim of this chapter is to assist researchers interested in understanding how phenotype data can be used effectively in the gene discovery field. PMID- 21779997 TI - Conceptual thinking for in silico prioritization of candidate disease genes. AB - Prioritization of most likely etiological genes entails predicting and defining a set of characteristics that are most likely to fit the underlying disease gene and scoring candidates according to their fit to this "perfect disease gene" profile. This requires a full understanding of the disease phenotype, characteristics, and any available data on the underlying genetics of the disease. Public databases provide enormous and ever-growing amounts of information that can be relevant to the prioritization of etiological genes. Computational approaches allow this information to be retrieved in an automated and exhaustive way and can therefore facilitate the comprehensive mining of this information, including its combination with sets of empirically generated data, in the process of identifying most likely candidate disease genes. PMID- 21779998 TI - Web tools for the prioritization of candidate disease genes. AB - Despite increasing sequencing capacity, genetic disease investigation still frequently results in the identification of loci containing multiple candidate disease genes that need to be tested for involvement in the disease. This process can be expedited by prioritizing the candidates prior to testing. Over the last decade, a large number of computational methods and tools have been developed to assist the clinical geneticist in prioritizing candidate disease genes. In this chapter, we give an overview of computational tools that can be used for this purpose, all of which are freely available over the web. PMID- 21779999 TI - Comparative view of in silico DNA sequencing analysis tools. AB - DNA sequencing is an important tool for discovery of genetic variants. The task of detecting single-nucleotide variants is complicated by noise and sequencing artifacts in sequencing data. Several in silico tools have been developed to assist this process. These tools interpret the raw chromatogram data and perform a specialized base-calling and quality-control assessment procedure to identify variants. The approach used to identify variants differs between the tools, with some specific to SNPs and other for Indels. The choice of a tool is guided by the design of the sequencing project and the nature of the variant to be discovered. In this chapter, these tools are compared to facilitate the choice of a tool used for variant discovery. PMID- 21780000 TI - Mutation surveyor: an in silico tool for sequencing analysis. AB - DNA sequencing is widely used for DNA diagnostics and functional studies of genes of interest. With significantly increased sequencing outputs, manual reading of sequence results can impede an efficient and accurate analysis. Mutation Surveyor is a useful in silico tool developed by SoftGenetics that assists the detection of sequence variations within Sanger sequencing traces. This tool can process up to 400 lanes of data at a time with high accuracy and sensitivity. It can effectively detect SNPs and indels in their homozygous or heterozygous states as well as mosaicism. In this chapter, we describe the general application of Mutation Surveyor for DNA sequencing analysis and its unique features. PMID- 21780001 TI - In silico searching for disease-associated functional DNA variants. AB - Experimental analyses of disease-associated DNA variants have provided significant insights into the functional implications of sequence variation. However, such experiment-based approaches for identifying functional DNA variants from a pool with a large number of neutral variants are challenging. Computational biology has the opportunity to play an important role in the identification of functional DNA variants in large-scale genotyping studies, ultimately yielding new drug targets and biomarkers. This chapter outlines in silico methods to predict disease-associated functional DNA variants so that the number of DNA variants screened for association with disease can be reduced to those that are most likely to alter gene function. To explore possible relationships between genetic mutations and phenotypic variation, different computational methods like Sorting Intolerant from Tolerant (SIFT, an evolutionary-based approach), Polymorphism Phenotyping (PolyPhen, a structure based approach) and PupaSuite are discussed for prioritization of high-risk DNA variants. The PupaSuite tool aims to predict the phenotypic effect of DNA variants on the structure and function of the affected protein as well as the effect of variants in the non-coding regions of the same genes. To further investigate the possible causes of disease at the molecular level, deleterious nonsynonymous variants can be mapped to 3D protein structures. An analysis of solvent accessibility and secondary structure can also be performed to understand the impact of a mutation on protein function and stability. This chapter demonstrates a 'real-world' application of some existing bioinformatics tools for DNA variant analysis. PMID- 21780002 TI - In silico prediction of transcriptional factor-binding sites. AB - The recognition of transcription factor binding sites (TFBSs) is the first step on the way to deciphering the DNA regulatory code. A large variety of computational approaches and corresponding in silico tools for TFBS recognition are available, each having their own advantages and shortcomings. This chapter provides a brief tutorial to assist end users in the application of these tools for functional characterization of genes. PMID- 21780003 TI - In silico prediction of splice-affecting nucleotide variants. AB - It appears that all types of genomic nucleotide variations can be deleterious by affecting normal pre-mRNA splicing via disruption/creation of splice site consensus sequences. As it is neither pertinent nor realistic to perform functional testing for all of these variants, it is important to identify those that could lead to a splice defect in order to restrict experimental transcript analyses to the most appropriate cases. In silico tools designed to provide this type of prediction are available. In this chapter, we present in silico splice tools integrated in the Alamut (Interactive Biosoftware) application and detail their use in routine diagnostic applications. At this time, in silico predictions are useful for variants that decrease the strength of wild-type splice sites or create a cryptic splice site. Importantly, in silico predictions are not sufficient to classify variants as neutral or deleterious: they should be used as part of the decision-making process to detect potential candidates for splicing anomalies, prompting molecular geneticists to carry out transcript analyses in a limited and pertinent number of cases which could be managed in routine settings. PMID- 21780004 TI - In silico tools for qPCR assay design and data analysis. AB - qPCR instruments are supplied with basic software packages that enable the measurement of fluorescent changes, calculations of quantification cycle (Cq) values, the generation of standard curves and subsequent relative target nucleic acid quantity determination. However, detailed assessments of the technical parameters underlying Cq values and their translation into biological meaningful results require validation of these basic calculations through further analyses such as qPCR efficiency correction, normalization to multiple reference genes, averaging and statistical tests. Some instruments incorporate some of these features, while others offer additional tools to complement the basic running software, in many cases providing those that are described below. In this chapter, there is a detailed description of some of these programs and recommended strategies for the design of robust qPCR assays. Some of the packages available for validation of the resulting Cq data and detailed statistical analysis are described. PMID- 21780005 TI - RNA structure prediction. AB - The prediction of RNA structure can be a first important step for the functional characterization of novel ncRNAs. Especially for the very meaningful secondary structure, there is a multitude of computational prediction tools. They differ not only in algorithmic details and the underlying models but also in what exactly they are trying to predict. This chapter gives an overview of different programs that aim to predict RNA secondary structure. We will introduce the ViennaRNA software package and web server as a solution that implements most of the varieties of RNA secondary structure prediction that have been published over the years. We focus on algorithms going beyond the mere prediction of a static structure. PMID- 21780006 TI - In silico prediction of post-translational modifications. AB - Methods for predicting protein post-translational modifications have been developed extensively. In this chapter, we review major post-translational modification prediction strategies, with a particular focus on statistical and machine learning approaches. We present the workflow of the methods and summarize the advantages and disadvantages of the methods. PMID- 21780008 TI - Actual evidence for neuromonitoring-guided intensive care following severe traumatic brain injury. AB - Therapeutic interventions following severe traumatic brain injury (TBI) are substantially influenced by complex and interwoven pathophysiological cascades involving both, local and systemic alterations. Our main duty is to prevent secondary progression of the primary damage. This, in turn, obliges us to actively search and identify secondary insults related, for example, to hypoxia, hypotension, uncontrolled hyperventilation, anaemia, and hypoglycaemia. During pharmacological coma we must rely on specific cerebral monitoring which is indispensable in unmasking otherwise occult changes. In addition, extended neuromonitoring (SjvO2, ptiO2, microdialysis, transcranial Doppler sonography, electrophysiological studies, direct brain perfusion measurement) can be used to define individual pathological ICP levels which, in turn, will support our decision making. Extended neuromonitoring expands the limited knowledge derived from ICP and CPP values, thereby allowing us to adequately adapt the type, extent and speed of different therapeutic interventions. A more individualised and flexible treatment concept depends on extended neuromonitoring. The present review addresses current evidence in favour of extended neuromonitoring used to guide treatment options aimed at improving intensive care treatment of patients with severe TBI. With increasing experience gained by the use of extended neuromonitoring in clinical routine we may expect that the evidence obtained within the individual patient will translate to convincing evidence on a larger scale for the entire study population. PMID- 21780007 TI - In silico protein motif discovery and structural analysis. AB - A wealth of in silico tools is available for protein motif discovery and structural analysis. The aim of this chapter is to collect some of the most common and useful tools and to guide the biologist in their use. A detailed explanation is provided for the use of Distill, a suite of web servers for the prediction of protein structural features and the prediction of full-atom 3D models from a protein sequence. Besides this, we also provide pointers to many other tools available for motif discovery and secondary and tertiary structure prediction from a primary amino acid sequence. The prediction of protein intrinsic disorder and the prediction of functional sites and SLiMs are also briefly discussed. Given that user queries vary greatly in size, scope and character, the trade-offs in speed, accuracy and scale need to be considered when choosing which methods to adopt. PMID- 21780009 TI - [Patient, user, client]. PMID- 21780011 TI - Microsutures traction device for small vessel anastomosis. PMID- 21780010 TI - The Stillbirth Collaborative Research Network neuropathologic examination protocol. AB - We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations. PMID- 21780012 TI - Selective fascicular coaptation of free functioning gracilis transfer for restoration of independent thumb and finger flexion following Volkmann ischemic contracture. AB - Children are prone to developing moderate to severe Volkmann ischemic contracture following a supracondylar fracture of the humerus or its treatment. Given the variable extent of forearm muscle damage, tendon transfers and tenodeses are often unavailable. To address these contractures, intensive hand therapy and a free functioning muscle transfer are required. Despite functional improvement following free muscle transplantation, reconstructed patients with severe Volkmann ischemic contracture tend to have persistent difficulty with fine motor activities owing to the losses of intrinsic muscle function and independence of thumb and finger flexion. The authors demonstrate how selective coaptation of separate fascicular territories of the gracilis nerve branches to the branches of the anterior interosseous nerve that innervate flexor pollicis longus and flexor digitorum profundus may be performed to establish a degree of independent thumb and finger flexion with a single free gracilis transfer. This technical refinement as well as its long-term outcomes in a series of three patients is presented. PMID- 21780013 TI - Reverse second and third dorsal metacarpal artery fasciocutaneous flaps for repair of distal- and middle-segment finger soft tissue defects. AB - The present study evaluated the clinical efficacy of reverse second and third dorsal metacarpal artery fasciocutaneous flaps for repair of distal- and middle segment finger soft tissue defects. A total of 14 patients with distal- and middle-segment finger soft tissue defects complicated by exposure of the phalanx or tendon were repaired using second and third dorsal metacarpal artery fasciocutaneous flaps ranging between 2.0 cm * 4.5 cm and 3.0 cm * 7.0 cm. All of the skin flaps survived after surgery. Follow-up data during a 6- to 40-month period showed that the flaps exhibited a satisfactory appearance. They were not fat or clumsy, with a 2-point discrimination of 5 to 9 mm, and there was good recovery of finger function. The donor site was able to be directly sutured without dermoplasty. Pigmented linear surgical streaks appeared in the donor site. The second and third dorsal metacarpal artery fasciocutaneous flaps provide a good approach for the repair of distal- and middle-segment finger soft tissue defects and functional reconstruction because of convenient dissection, little trauma, sufficient use of the dorsal metacarpal artery, large harvested area of the flap, and a good dissection range. PMID- 21780014 TI - First experiences with simultaneous skeletal and soft tissue reconstruction of noma-related facial defects. AB - Noma victims suffer from a three-dimensional facial soft-tissue loss. Some may also develop complex viscerocranial defects, due to acute osteitis, chronic exposure, or arrested skeletal growth. Reconstruction has mainly focused on soft tissue so far, whereas skeletal restoration was mostly avoided. After successful microvascular soft tissue free flap reconstruction, we now included skeletal restoration and mandibular ankylosis release into the initial step of complex noma surgery. One free rib graft and parascapular flap, one microvascular osteomyocutaneous flap from the subscapular system, and two sequential chimeric free flaps including vascularized bone were used as the initial steps for facial reconstruction. Ankylosis release could spare the temporomandibular joint. Complex noma reconstruction should include skeletal restoration. Avascular bone is acceptable in cases with complete vascularized graft coverage. Microsurgical chimeric flaps are preferable as they can reduce the number and complexity of secondary operations and provide viable, infection-resistant bone supporting facial growth. PMID- 21780015 TI - Surgical aspects of a lower face, mandible, and tongue allotransplantation. AB - Face transplantation is a novel treatment for the reconstruction of massive facial defects. To date 13 cases have been performed. The technical aspects of a composite lower face transplantation including the tongue, floor of the mouth, and most of the mandible are detailed. The transplantation was performed in August 2009 in an HIV-positive, postoncologic patient. A preparatory surgery for nerve identification was performed. Facial composite tissue was procured after cardiac cessation. Revascularization was performed to the right subclavian artery with an internal shunt between the internal carotid arteries. At 16 months posttransplantation the patient is swallowing, without evidence of malignancy recurrence or HIV replication. PMID- 21780016 TI - Exploration of the intravascular stenting method for sub 1-mm vessels. AB - The intravascular stenting (IVaS) method was published by Narushima and Koshima in 2008. This method involves using a monofilament nylon stent to make the anastomosis of small vessels easier. The aim of this study was to explore the IVaS technique to determine its advantages, disadvantages, and usefulness for inexperienced microsurgeons and also for more experienced practitioners during difficult anastomoses. The study was approved by the Catholic University of Louvain Animal Experimentation Ethics Committee. The study was done on 20 Wistar rats; each rat acting as his own control. Group 1 had an anastomosis done with the IVaS technique on the femoral artery. Group 2 had a classic end-to-end anastomosis without a stent. All anastomoses were performed by the same trainee surgeon with 4 months experience in microsurgery. The diameter of the external artery, distance between the double clamp forceps, stent length, number of sutures, stent preparation, and installation time and suture time were all measured. Anastomotic patency was verified using O'Brien's Patency test. The rats were anesthetized 1 week later to reassess the patency of the vessels. While the anastomotic time was shorter in the stent group, the preparation time was longer and so the total time to perform the anastomosis in both groups was the same. All vessels were patent at the completion of the anastomosis. At 1 week, patency rates were identical (83.3%) in both groups. The study shows an improvement in suturing time in the IVaS group. The time saved is equivalent to the time required for preparation and installation of the stent. At 7 days, the Patency test was identical for the two groups (83.3%). IVaS technique is a useful method of vessels anastomosis especially for junior surgeons. The reason why the patency rate was not 100% at 1 week may be because of excessive manipulation of the stent causing thrombosis in the IVaS group and imperfections in suturing technique by a trainee surgeon. Different aspects of the method are open for discussion such as consideration of the stent size and execution of the anastomosis. The IVaS technique helps in the execution of anastomosis in microsurgery and allows for more precise suturing. Care, however, must be taken in its execution and manipulation so as to avoid any lesions of the intima of the vessels. PMID- 21780017 TI - Is it possible to do a microvascular anastomosis with an ordinary video camera? Experimental study. AB - An alternative method of magnification for microvascular anastomosis was analyzed using an ordinary video camera and compared with the traditional method under microscope. For this study 20 rats were divided in two groups of 10 each: control group (microscope-assisted [M]) and experimental group (video-assisted [V]). Magnification was accomplished by a surgical microscope in group M, whereas a video system composed of low-cost camera, audiovisual cable, and analogue television in group V. In both groups, the right femoral artery was severed and sutured with interrupted simple stitches. The criteria examined were: patency, vessel diameter, amount of sutures, anastomosis time, and histologic features. There were no differences between both groups in patency rate and vessel diameter. The video-assisted microanastomosis is a time-consuming procedure as compared with the microscope-assisted anastomosis, to a certain extent due to lack of stereoscopic image and technical inability with the video system as well. There was a smaller quantity of sutures in group V. Higher foreign body tissue reaction was found in group M, consequent to greater amount of suture material. In conclusion, video-assisted microanastomosis is possible with the present video system but is not as safe as conventional microanastomosis. PMID- 21780018 TI - Chemical and mechanical alternatives to leech therapy: a systematic review and critical appraisal. AB - Although leech therapy is a well-established, effective method of relieving venous congestion, it is associated with complications such as wound infection and leech migration. To minimize these risks, efforts to reproduce their effects have been developed and investigated. A search string using (chemical OR mechanical OR alternative) AND (Leeches OR HIRUDO MEDICINALIS) in Boolean format was used across the major electronic databases to cover the past 10 years. Selected references were subsequently validated against critical appraisal frameworks and classified and evaluated against a framework of hierarchies of evidence. Out of 95 retrieved studies, 25 articles were selected after content appraisal. Of these, 12 articles were methodologically and statistically robust. The heterogeneity noted in the studies precluded meta-analysis of the results. The studies infer evidence at Grade B level that current device prototypes show proof of concept by providing suction and chemical anticoagulation following a surgically created wound. Although progress had been made to replicate leech action, there are still areas to address in future research. This article represents the current state of play in clinical translation of these concepts, providing efficacious devices without the drawbacks of traditional leech therapy. PMID- 21780019 TI - Primary suture-less closure of gastroschisis using negative pressure dressing (wound vacuum). AB - INTRODUCTION: Primary suture-less closure of gastroschisis using negative pressure dressing (wound vacuum) involves the application of an initial preformed Silo with subsequent bedside suture-less closure of the defect using negative pressure dressing. The advantages of this gentle approach are the simple bedside closure without intubation, paralysis or ventilation as well as reduced risk of barotrauma, abdominal compartment syndrome, acidosis, bowel infarction and necrotizing enterocolitis. This study is a report of the technique we used for gastroschisis closure at our institute. METHODS: The medical records of 15 newborns who underwent primary suture-less closure of gastroschisis using a negative pressure dressing (wound vacuum) technique between March 2008 and February 2010 were retrospectively reviewed. Outcome criteria such as time on ventilation, time to initiating feeds, time to full feeds, time to discharge from NICU and complications were recorded. RESULTS: The median follow-up was 234 days (range: 13-528 days). The time on ventilation was (n = 8: no ventilation; n = 3: 1 day; n = 2: 2-5 days; n = 2: > 5 days). The median time to initiating feeds was 13 days (range: 6-61 days), the median time to full feeds was 20 days (range: 12 91 days) and the median time to discharge was 24 days (range: 21-131 days). 2 patients had a tiny umbilical hernia at last follow-up. CONCLUSION: Primary suture-less closure of gastroschisis using a negative pressure dressing (wound vacuum) technique is easily reversible, does not need intubation/ventilation, avoids a trip to the operating room (OR), has minimal to no complications and provides good cosmetic results. PMID- 21780020 TI - Significance of image-defined risk factors for surgical complications in patients with abdominal neuroblastoma. AB - INTRODUCTION: Neuroblastoma (NB) is one of the most common malignant tumors in infancy. The commonly used International Neuroblastoma Staging System is not suitable for determining the surgical risks. To address this, we aimed to evaluate the correlation between so-called image-defined risk factors (IDRFs) and the surgical risks in abdominal neuroblastoma. MATERIAL AND METHODS: We evaluated 60 cases who underwent surgical intervention and examined the pre-surgical radiological imaging to look for IDRFs and surgical complications in children with abdominal neuroblastoma. RESULTS: The MRI- and CT-scans showed a total of 122 IDRFs in 39 cases. Complete resection was carried out in 50%, partial excision in 32%, and biopsy in 18% of cases. Total resection was possible in 100% of cases with no IDRF. Where IDRFs were present, total resection was only possible in 26% of cases (p<0.0001). We found a highly significant, negative correlation between the number of IDRFs and the possibility of performing complete resection of NB (p<0.0001). 7 (11.6%) complications were detected, all in patients who showed at least one IDRF previously. CONCLUSION: Our findings indicate that IDRFs are useful indicators for predicting surgical risk and surgical outcome and thus should be taken into account when planning surgery. PMID- 21780021 TI - A case of congenital prepubic sinus. PMID- 21780022 TI - [Two-stage traumatic rupture of the arteria ovarica after high energy trauma]. AB - INTRODUCTION: Rupture of the Arteria ovarica is a rare but life-threatening injury and occurs primarily in pregnancy. Most previously described ruptures of the Arteria ovarica were in the early postpartum period and in women who were older than 45 years. We report on a two-stage rupture of the Arteria ovarica after a high energy trauma, which has not previously been described in the literature. PATIENT AND METHOD: A 66-year-old female patient was admitted to the emergency room after a car accident. Initial treatment was performed in a regional hospital. Initial clinical and radiological examinations were without any pathologies and the patient was discharged home after ambulatory treatment. Six days later, the patient was referred to our hospital because of increasing headache. A computed tomography of the head showed a subdural haematoma. A follow up CT scan after three days showed no further progression of the haematoma. RESULTS AND CONCLUSIONS: During the hospital stay, the patient developed abdominal pain, nausea and cardiovascular decompensation. An ultrasound of the abdomen showed free fluids, while a performed CT scan of the abdomen confirmed an arterial bleeding from a pseudoaneurysm of the left ovarian artery. An emergency operation was performed. Postoperative management included ICU monitoring, diuresis control and blood transfusion. The patient was discharged home after 19 days in a good condition. The indication for performing a CT scan and primary hospitalisation after a high energy trauma should be applied generously. PMID- 21780023 TI - [Josef Leiter - world renowned Vienna instrument maker]. PMID- 21780024 TI - [Cell death and its role in immunopathogenesis of infectious diseases]. AB - Cell death is still a matter of debate and scientific opinions have been challenged and are not uniform due to complexity of this issue. Recent research has brought some new evidence about the very subtle border between programmed cell death and necrosis. The concept of their mutual independence, broadly accepted for decades, is now significantly challenged. Lack of unified terminology led to the establishment of the Nomenclature Committee on Cell Death (NCCD) which provides recommendations for clear definition of distinct cell death programs. It also appeals for consistent application of this nomenclature in scientific literature. In this work, some keystone knowledge addressing three specific programmed cell death types - apoptosis, autophagic cell death, and pyroptosis which is recognized as a controversial cell death scenario on the border between programmed cell death and necrosis, is reviewed. These cell death scenarios are discussed in the context of pathogenesis of infectious diseases. PMID- 21780025 TI - [Proteus mirabilis isolated from urine, resistance to antibiotics and biofilm formation]. AB - BACKGROUND: In the rather rare urinary pathogen Proteus mirabilis resistance to antibiotics and ability to form biofilm were studied. MATERIAL AND METHODS: The strains Proteus mirabilis were isolated from urine samples from ambulatory and hospitalized patients diagnosed with urinary tract infection (UTI) between April 2008 and April 2010. Resistance to antibiotics was investigated using a disk diffusion antimicrobial susceptibility test. Biofilm formation was demonstrated by modified Christensen method. RESULTS: Two hundred and thirteen of P. mirabilis strains were tested. Eighty-two (38.5 %) strains were resistant to ampicillin, 49 (23.0 %) to cefalotin, 83 (39.0 %) to sulfamethoxazole/trimetoprim, 75 (35.2 %) to ciprofloxacin, 95 (44.6 %) to oxolinic acid, 54 (25.4 %) to gentamicin, and 72 (33.8 %) to chloramphenicol. There was significantly lower resistance to cefotaxime - 8 strains (3.8 %), ceftazidime - 8 (3.8 %), amoxicillin/clavulanic acid 17 (8.0 %) and aztreonam - 8 (3.8 %). No resistance to imipenem as well as to meropenem was found. Eight P. mirabilis strains were found to produce extended spectrum beta-lactamase (ESBL). From the total of 213 strains tested, 28 (13.1 %) were able to form a biofilm. CONCLUSIONS: P. mirabilis was found to be more frequent in urine of men and older patients. Biofilm formation in urinary P. mirabilis strains was relatively low. The strains showed higher resistance to beta-lactams and quinolones; in the other cases, resistance was low. PMID- 21780026 TI - [Cyclospora cayetanensis - the rare causal agent of diarrhoeal diseases]. AB - Cyclospora cayetanensis a casual agent of diarrhoeal diseases, was detected in 6 out of 3 097 patients between February 2009 and March 2010 using standard parasitological methods. Five cases were imported from the endemic countries. One patient was the first case with no travel history in the Czech Republic. PMID- 21780027 TI - [Gastric MALT lymphoma - a case report]. AB - Gastrointestinal tract is the most commonly (40 %) affected site of the extranodal forms of primary non-Hodgkin's lymphomas. Almost half of them are indolent lymphomas, mainly MALT lymphomas. The development of MALT lymphoma temporarily depends on antigen stimulation of Helicobacter pylori. More than 90 % of MALT lymphoma patients are positive for Helicobacter pylori antibodies, but the positivity of biopsy is present in only 60 % of them. Antibiotic therapy in Helicobacter pylori infection may lead to complete regression of the localized primary gastric lymphoma of the MALT type without any anti-tumour therapy. The aim of the case report is to present the disease in the context of possible antibiotic therapy of the tumour. PMID- 21780028 TI - [Disseminated infection with Mycobacterium avium in a patient with newly diagnosed HIV infection]. AB - In the Czech Republic, mycobacteriosis is relatively rare. The low incidence probably reflects high BCG coverage rates in the Czech population. Globally, the importance of BCG vaccine has been increasing, as a result of acquired immunodeficiencies, particularly HIV infection. The presented case report describes the course of disseminated mycobacteriosis in a Vietnamese asylum seeker with newly diagnosed advanced HIV infection. In HIV patients, disseminated mycobacteriosis, most frequently caused by members of Mycobacterium avium complex (MAC), is mostly manifested in the last stage, AIDS, with extremely severe immunodeficiency, or in immune reconstitution inflammatory syndrome (IRIS), shortly after initiation of antiretroviral therapy. From the beginning, the patient's condition was complicated by multiple simultaneous severe opportunistic infections which, together with gradually progressing atypical mycobacteriosis, resulted in overall exhaustion of the organism. The adverse prognosis of these infections is significantly influenced by prolonged diagnosis based on culture detection of slow-growing mycobacteria. In the above patient, the lethal course was contributed to by resistance to commonly used antitubercular drugs which was only detected post mortem due to time-consuming susceptibility tests. PMID- 21780029 TI - [Toxoplasmosis - the most common errors in diagnosis and treatment]. AB - In common practice, toxoplasmosis may be a source of frequent diagnostic and therapeutic dilemmas. Three case reports are presented, illustrating the most frequent 'non-standard" situations resulting in erroneous interpretation of findings and therapeutic decisions. The first case was false or non-specific positivity of antibodies of several classes, leading to a heavy mental burden and wrong prenatal therapy in a pregnant patient. In the second case, persistent low IgG avidity was not interpreted in the context of other results, leading to a hasty decision to terminate the pregnancy. The third case report describes a wrong combination of therapy resulting in the development of numerous adverse effects in a young patient with repeated abortions. PMID- 21780030 TI - [Laboratory diagnosis of pseudoparasites, artifacts and parasitic delusions]. AB - Common practice in a diagnostic parasitology laboratory involves distinguishing parasitic organisms from various artifacts. Artifacts mean pseudoparasites, supposed parasites and parasitic delusions. Pseudoparasites include undigested leftovers or coincidentally or purposely ingested nonparasitic organisms or their parts. Supposed parasites are wild organisms which were incorrectly identified as the components of faeces. In parasitic delusions, it is impossible to find any kind of parasites while patients describe imaginary parasites in detail. All the above categories of nonparasitic findings including case reports are described and discussed in the article. PMID- 21780031 TI - [Exogenous Cushing's syndrome as a serious side-effect of therapy with ritonavir an inhaled fluticasone]. AB - Inhalation of fluticasone is usually devoid of systemic side-effects. The authors describe a case of a young HIV positive woman treated concomitantly with fluticasone and inhibitors of HIV protease ritonavir and lopinavir in which developed a serious endocrine side-effect - an iatrogenic Cushing's syndrome. Plasma concentration of cortisol < 5.5 nmol/l was very low (norm 250-650 nmol/l) and plasmatic ACTH was even not detectable. The administration of fluticasone and both inhibitors of HIV protease was stopped and substitution therapy with decreasing dose of hydrocortisone was initiated. Twenty weeks later resolved both clinical and laboratory symptoms of Cushing's syndrome, and the substitution therapy with hydrocortisone was terminated. Two years later became the patient pregnant and gave birth to a healthy child. PMID- 21780032 TI - [Renal colic in pregnancy and lactation: diagnostic and therapeutic approaches]. AB - BACKGROUND: Renal colics due to urinary stones are also common in women of childbearing age whether pregnant or not. AIM: Through a review of literature, we evaluated diagnostic and therapeutic approaches in renal colic in pregnancy and lactation. METHODS: Review of literature. RESULTS: The clinical diagnosis is sometimes difficult requiring additional medical imaging based on ultrasound. Other radiological investigations using X-rays are formally forbidden. The prescription of analgesic treatment during pregnancy and lactation must take into account mainly the teratogenic risk in addition to maternal risk by altering drug pharmacokinetics during pregnancy. CONCLUSION: During pregnancy, NSAIDs are prohibited because of their teratogenicity effect. Salicylates and opiates should be used with care, especially in cases of threat of confinement. Paracetamol remains the treatment of choice. Salicylates and corticosteroids should be used with caution during lactation. PMID- 21780033 TI - [Uncommon cervicobrachial neuralgia: about 17 cases]. AB - BACKGROUND: Cervicobrachial neuralgia (CBN) is frequent in out patient clinic as well in general medicine as in rheumatology. Even though cervical disc degeneration and osteophytosis constitute the most frequent etiology of such a trouble, the practitioner must be aware of much more serious underlying cause. AIM: To investigate the epidemiology, clinical features, aetiologies and paraclinical characteristics of uncommon CBN. METHODS: Retrospective chart review about 17 cases of uncommon CBN among the 84 cases of CBN hospitalized at the rheumatology department of the Charles Nicolle Hospital during a 16-years-period [1990-2005]. RESULTS: There were 11 men and 6 women with a mean age of 63 years [33y-81y]. All patients presented a CBN since in average five months [2 months- 24 months]. Neck stiffness was noted in 60% of cases and a neurological impairment in 47% of cases. X-ray radiographs of cervical spine were normal in five cases. In the remaining cases, they showed lytic images (six cases), disk space narrowing with vertebral erosions (two cases) and vertebral fracture (three cases). Further investigations concluded that the CBN was due to a Pancoast'syndrome in five cases, an infectious spondylitis in three cases, cervical bone metastasis in two cases, a syringomyelia in two cases, a neuroma in one case, a thoracic outlet syndrome in one case and an erosive spondylarthropathy in a patient presenting chronic renal failure managed by hemodialysis. CONCLUSION: In comparison with common CBN, our patients presenting symptomatic CBN were characterised by an inflammatory and refractory pain. The more frequent recourse to modern imaging is justified. PMID- 21780034 TI - [Permanent cardiac pacing: about 234 patients]. AB - BACKGROUND: Permanent cardiac pacing remains the only effective treatment for chronic, symptomatic bradycardia. In recent years, the role of implantable pacing devices has expanded substantially. AIM: To compare the situation of patients with critical brady arrhythmias before and after pacing focusing on indication for pacemaker implantation, frequency of re intervention and early and late complications. METHODS: Retrospective study performed over 24 years between 1984 and 2007 at the department of cardiology of Farhat Hached hospital. A total of 234 patients were included, and the database was formed by the patients' files and the protocols of implantation. RESULTS: The mean age of patients was 69.5 years. The most frequently reported signs and symptoms before implantation of pace maker were dizzy spells and syncope respectively in 53% and 29.1% of patients. Among the electrocardiographic alterations leading to an indication of pacemaker implantation, atrio-ventricular blocks were the most numerous at 74.4% followed by sinus node disease at 17.1%. Early complications were represented essentially by haematoma and infection of the pocket of pacemaker respectively at 2.9% for each one. After a mean follow up of 6.8 years, 88 patients (45.3%) still free of symptoms. Late complications include lead dislodgement and pacemaker syndrome at 2% for each one. CONCLUSION: The results of our study demonstrates that even the rate of complications following pacemaker implantation is not high, the follow-up of patients should be fast, complete, safe, and clear, and should include sufficient documentation. PMID- 21780035 TI - [Long term evolution of corticodependant and corticoresistant Crohn's disease patients treated by azzathioprine]. AB - BACKGROUND: Immunosupressors, particularly azathioprine, represents the therapeutic alternative in patients with corticodependant or corticoresistant Crohn's disease. The prescription of azathioprine in Tunisia is common, but there is not Tunisian studies evaluating the long term results of this drug in Crohn's disease patients. AIMS: To evaluate the long term results of azathioprine treatment with determination of rates of relapses, surgery and need to corticosteroids in patients with corticodependant or corticoresistant Crohn's disease, and to look for predictive factors to theses events. METHODS: A retrospective study on 12 years including all patients treated by azathioprine for corticodependant or corticoresistant Crohn's disease. We excluded the cases of follow up less than 6 months. RESULTS: We studied 56 patients (46 corticodependant and 10 corticoresistant). Induction of remission was obtained in 89% of the cases. Concerning the long term results, the relapse rate was 60% of patients treated with azathioprine, with actuarial rates of 38% at one year, 65% at 5 years and 75% at 10 years. Need for corticosteroid treatment was estimated at 42% and need for surgical treatment was estimated at 24%. The only predictive factor for relapse was duration of treatment by azathioprine more than 36 months, with sensitivity of 93% and specificity of 50%. CONCLUSION: Although an excellent result of azathioprine in induction remission, long term results showed deterioration of results of treatment. Physicians must be followed up Crohn's disease patients in order to rapidly detect and treat the clinical relapses of the disease. PMID- 21780036 TI - [Lung cancer with venous thrombo-embolism: clinical characteristics]. AB - BACKGROUND: Lung cancer is the most common malignancy diagnosed in patients with venous thrombo-embolism (VTE). AIM: To investigate clinical, biological, radiological features and survival of lung cancer patients with VTE. METHODS: Retrospective case-control study investigating biologic, clinical course and survival of 25 patients lung cancers with VTE (Group M) and 50 lung cancers without VTE (group T). RESULTS: The frequency of the VTE was 5.88% with 2.58% pulmonary embolism (PE). The mean age was 58 years +/- 9.8 in group M and 57.9 years +/- 9.6 in group T. No significant difference concerning medical or surgical history for both groups was found. The dyspnea and chest pain were at equal frequency (63.6%). Regarding the clinical probability of the PE, it was no significant differences between the two groups. A rate of D-dimer > 0.7MUg/l was more frequent among group M (75% vs 20%; p = 0.054). The most common histological type was nonsmall cell lung cancer (88%). A stage IV was significantly more frequent in group M (86.4% vs. 52.3%; p = 0.007). The mean period of survival in Group M was 10.6 +/- 1.2 month and 20.2 + 1.8 month in group T; p = 0.38. CONCLUSION: The VTE associated to lung cancer is under diagnosed. Prospective studies are needed to establish more adapted scores. PMID- 21780037 TI - [Association between oxidative stress parameters and inflammation markers according to the gravity of the acute coronary syndrome]. AB - BACKGROUND: Cardiovascular disease is the consequence of appearance and development of atherosclerosis lesions of associated with a inflammatory complication. AIM: To elucidate a possible association between several inflammation and oxidative stress markers according to the severity of coronary artery disease. METHODS: This study was carried on 93 coronary subjects with: unstable angina (UA; n=42); stable angina (SA; n=15) and acute myocardial infarction (AMI; n=36) and 140 control subjects to whom lipidic, oxidative and inflammatory parameters were determined. RESULTS: In addition to a moderate hyperhomocysteinemia observed in the coronary artery disease, a significant higher levels of the oxidized LDL (ox-LDL) were found among these patients (p< 0.001). A positive correlation was found between the markers of the inflammation and the gravity of the acute coronary syndrome. One note a significant increase of the rate of ox-LDL and high sensitive CRP to AMI by reports in UA and SA (p=0.00, and p=0.001 respectively) which is linked to an elevation of the plasmatic concentration of the total homocysteine. CONCLUSION: This study suggests an association between the markers of the inflammation and oxidative parameters in the acute coronary syndrome. PMID- 21780038 TI - [Genital prolapse in young women: a study of risk factors]. AB - AIM: To determine the risk factors for genital prolapse in a group of 33 young women less than 45 years old. METHODS: We studied 33 young women who had been operated for genital prolapse, whereas the control group consisted of women operated for benign gynaecologic disorders. RESULTS: In the study group the number of pregnancies and deliveries, the babies'weight, the positive family history of prolapse were heavier than in the control group. The women with prolapse had more often chronic pulmonary diseases, asthma, as well as operations for abdominal hernias. The mode of delivery, be it a cesarean section or the use of forceps, and the active second stage of labor had no effect whatever on the occurring of genital prolapse in young women. CONCLUSION: Our data support the suggestion that multiparity, babies weight and congenital factors are responsible for a higher rate of genital prolapse in young women. PMID- 21780039 TI - Management of meconium aspiration syndrome with highfrequency oscillatory ventilation. AB - BACKGROUND: High-frequency oscillatory ventilation (HFOV) has been advocated for use to improve lung inflation while potentially decreasing lung injury. There were few data on the early use of HFOV in hypoxemic term neonates. AIM: To evaluate the effectiveness of HFOV, used as the initial mode of ventilation, in neonates with severe meconium aspiration syndrome (MAS). METHODS: In a tertiary care paediatric intensive care unit, 17 term neonates with severe MAS were managed with HFOV, used as the initial mode of ventilation, and prospectively evaluated. Ventilator settings, blood gases, oxygenation index (OI) and alveolar arterial oxygen difference (P(A-a)O2) were prospectively recorded during HFOV treatment and compared at the multiple time intervals. RESULTS: Target ventilation was easily achieved with HFOV. Initiation of HFOV caused a significant decrease in FIO2, achieved as early as 1 hour (from 0.93 +/- 0.11 to 0.78 +/- 0.25; p=0.031) and the improvement was sustained during the 1-32 hours period. There were a significant decreases in P (A-a) O2 and OI, respectively, at 4 hours (from 562.5 +/- 71.7 to 355.4 +/- 206 mm Hg; p=0.03) and 8 hours (from 23.3+/-17 to 14.6+/-16.3; p=0.04), that were sustained up to 16 and 40 hours . Three neonates (17.6%) developed pneumothorax on HFOV. One patient required oxygen support at 28 days. No significant others complications associated with HFOV were detected. Sixteen infants (94 %) were successfully weaned from HFOV and 15 (88%) survived to hospital discharge. CONCLUSION: Use of HFOV as the initial mode of ventilation in neonates with severe MAS is an effective strategy. PMID- 21780040 TI - Carbapenem-resistant Acinetobacter baumannii producing the carbapenemase OXA-23 in Tunisia. AB - BACKGROUND: AIM: To analyze the mechanisms of resistance to carbapenems among imipenem resistant A. baumannii recovered from different wards at Charles Nicolle Hospital. METHODS: From January to December 2007, 50 carbapenem-resistant A. baumannii isolates were recovered from hospitalized patients. MICs were performed by agar dilution method and interpreted according to CLSI guidelines. Metallo beta-lactamase production was evaluated using imipenem-EDTA disk synergy test. PCR and DNA sequencing targeting blaOXA genes were performed and pulsed field gel electrophoresis was used for epidemiologic study. RESULTS: Most of the isolates were obtained from patients hospitalized in surgery (62%) and Intensive Care Units (22%). All strains showed high level of resistance to ticarcillin (MIC50 > 2048MUg/ml), ticarcillin-clavulanic acid (MIC50 >1024MUg/ml), aztreonam (MIC50 = 512MUg/ml), ceftazidim (MIC50 = 512MUg/ml), imipenem (MIC50 = 512MUg/ml), meropenem (MIC50 =128MUg/ml) and cefepime (MIC50 = 256MUg/ml). Metallo-beta lactamase production was negative for all isolates. The co-existence of blaOXA-51 like/ blaOXA-23-like was detected in 82% (n= 41). The genes blaOXA- 24-like and blaOXA-58-like were not found in any isolate. All isolates harboured a blaOXA-51 like gene. Sequencing confirmed the presence of blaOXA-23 and blaOXA-69 genes. Eight distinct patterns were observed (A: 41 isolates, B: 1 isolate, C: 1 isolate, D: 1 isolate, E: 1 isolate, F: 2 isolates, G: 1 isolate, H: 2 isolates). CONCLUSION: Production of OXA-23 was the important mechanism of resistance to carbapenem among A. baumannii. Strengthening of prevention measures are required to control further spread of carbapenemases in Tunisia. PMID- 21780041 TI - Primary lumbar hernia : analysis of three cases. AB - BACKGROUND: Lumbar hernia is relatively rare; it is due to a defect of the posterior abdominal wall. AIM: To report three new cases of lumbar hernia and insist of the modalities of treatment. CASES REPORT: There are 2 women and one man. Mean age was 78 years. The mean symptom was lumbar mass. All patients had open surgery (by lumbar incision). The post operative course was uneventful. CONCLUSION: Primary lumbar hernias are rare. Earlier diagnosis of non complicated hernia should be of primary importance to avoid some serious complication. The only curative treatment is surgery and must be done as soon as the diagnosis was made. PMID- 21780042 TI - [Bronchiectasis and ulcerative colitis]. PMID- 21780043 TI - [Primary thyroid lymphoma]. PMID- 21780044 TI - [A rare cause of genital bleeding in prepubertal girl]. PMID- 21780045 TI - [Supernumerary cervical rib presenting as vertebral fracture]. PMID- 21780046 TI - Bilateral fontal sinus mucocele. PMID- 21780047 TI - Mycoplasma pneumoniae associated with severe autoimmune hemolytic anemia in a child with homozygous beta-thalassemia. PMID- 21780048 TI - [A rare cause of bowel obstruction in children: the superior mesenteric artery syndrome]. PMID- 21780049 TI - [Dysphagia: an unusual presentation of mediastinal and peripancreatic tuberculosis]. PMID- 21780050 TI - Lymphedema and lipedema - an overview of conservative treatment. AB - Lymphedema and lipedema are chronic progressive disorders for which no causal therapy exists so far. Many general practitioners will rarely see these disorders with the consequence that diagnosis is often delayed. The pathophysiological basis is edematization of the tissues. Lymphedema involves an impairment of lymph drainage with resultant fluid build-up. Lipedema arises from an orthostatic predisposition to edema in pathologically increased subcutaneous tissue. Treatment includes complex physical decongestion by manual lymph drainage and absolutely uncompromising compression therapy whether it is by bandage in the intensive phase to reduce edema or with a flat knit compression stocking to maintain volume. PMID- 21780051 TI - Perioperative management and "Fast-Track" therapy in vascular medicine. AB - Perioperative risk in vascular medicine is particularly high due to the increased prevalence of cardiovascular comorbidity. Therefore, it is of the utmost importance that during periprocedural management the patient remains in good general condition and that the patient is mobilized as soon as possible. Along with implementation of minimally-invasive techniques and endovascular procedures, networking and cooperation between the surgeon, anesthesiologist, physiotherapist and the nursing team can lead to an optimization of perioperative mobilization. The Fast-Track concept represents uncharted territory in the field of vascular surgery and it can provide advantages, particularly in relation to multimorbidity in the field of vascular medicine. The Fast-Track concept was introduced by Danish surgeon Henrik Kehlet and was originally intended to be implemented in general surgery. When compared to conventional management, this method offers better medical results, lower costs and other advantages for the patient: besides a better perioperative condition a reduction of postoperative complications and reduction of overall in-hospital stay was achieved. Therefore, the next logical step was to introduce and adapt this concept to other fields of operative medicine. This paper represents a systematic review on the actual experience of the fast-track concept in vascular surgery. PMID- 21780052 TI - Trends in amputations in people with hospital admissions for peripheral arterial disease in Germany. AB - BACKGROUND: Using the information of the federal statistics, a detailed description of the hospitalisation rate for amputation in Germany was possible for the first time, and trends since 2005 can be reported. PATIENTS AND METHODS: Detailed lists of all amputations coded as minor amputations (OPS 5 - 864) and major amputations (OPS 5 - 865) performed in 2005 and 2008, divided into the 4th and 5th number of the OPS-code, were provided by the Federal Statistical Office. RESULTS: Despite an increase in total number of hospitalized patients suffering from peripheral arterial disease and neurovascular disease there is a relevant decrease in age adjusted major amputation rates per 100.000 population in Germany from 27.0 in 2005 to 25.1 in 2008 in males and from 19.7 in 2005 to 17.1 in 2008 in females. Overall minor amputation rates do not show such a decrease but increased in males (from 47.4 in 2005 to 53.7 in 2008) und remained unchanged in females (23.1 in 2005 and 23.1 in 2008). In the 6th and 7th decade of life males have approximately four times higher major and minor amputation rates than females. CONCLUSIONS: Hospitalisation rate for major amputation in Germany decreased in the recent years whereas hospitalisation rate for minor amputation did not. PMID- 21780053 TI - Neovascularisation after surgery for recurrent saphenofemoral incompetence: does surgical dissection technique matter? AB - BACKGROUND: The effect of the type of surgery on neovascularisation in the groin is unknown. The aim of the present study was to compare three different surgical techniques used for recurrent saphenofemoral incompetence in view of their effect on neovascularisation in the groin at short- and long-term follow-up after surgery. PATIENTS AND METHODS: 36 consecutive patients undergoing surgery for recurrent saphenofemoral incompetence were randomised. 12 patients underwent sharp dissection with knife or scissors and excision and ligation of scar tissue using absorbable suture material; 12 had dissection with electrocoagulation and 12 dissection with ultrasound (Ultracision Harmonic Scalpel). Clinical outcome was assessed using the venous clinical severity score and venous disability score, and the saphenofemoral junction was evaluated by means of duplex sonography three months and seven years after the operation respectively. If neovascularisation was present, the maximal diameter of new refluxing veins in the groin was measured. RESULTS: There was no statistically significant difference between the three surgical techniques. Duplex ultrasound showed neovascularisation with an average maximal diameter (+/- standard error) of the newly formed refluxing vessel of respectively 2.00 (+/- 0.63) mm, 1.00 (+/- 0.45) mm and 0.50 (+/- 0.50) mm after three months and 4.29 (+/- 1.41) mm, 3.32 (+/- 0.90) mm and 3.00 (0.83) mm after seven years (no significant difference between groups). After seven years no reflux was detected in 8/36 patients, no varicose veins were found in 14/36 patients. The patients were less symptomatic than before our redo operation and no one needed reoperation within the seven years. CONCLUSIONS: Dissection techniques in the groin did not influence the clinical and sonographic result at 3 months and at 7 years after redo surgery for recurrent varicose veins. PMID- 21780054 TI - Clinical relevance of musical murmurs in color-coded duplex sonography of peripheral and visceral vessels. AB - BACKGROUND: Musical murmurs (MMs) are Doppler phenomena which sound like high frequency musical sounds. They reflect high and turbulent flow within relevant stenoses and were first described in degenerated bioprosthetic valves and later in intracranial vessels and were associated either with high-grade arterial stenosis, small collateral arteries or carotid cavernous fistulas. Objective of this article is to illustrate the spectrum of imaging of MMs observed in renal, intestinal and peripheral vessels. PATIENTS AND METHODS: Four experienced vascular ultrasound laboratories had been asked to report their cases with documented musical tones in color coded duplex sonography (CCDS) within a two year observational period (2008 and 2009). Documented Doppler findings and corresponding clinical data were analyzed. RESULTS: MMs were found in 18 patients with an incidence of 0.05 % and were observed in high grade stenosis in hemodialysis access (n = 5), in post-biopsy arteriovenous fistulas after renal transplantation (n = 3), in renal transplant artery (n = 1) and vein (n = 3), stenoses in peripheral (n = 2) and intestinal arterial disease (n = 2), and in peripheral veins (n = 2). CONCLUSIONS: The so called musical murmurs are a rare but potentially relevant finding in CCDS. They are caused by a variety of underlying pathologies with different clinical implications, however correct interpretation is mandatory since urgent therapy might be necessary. PMID- 21780055 TI - Renal ablation in patients with end-stage renal disease. AB - BACKGROUND: Transarterial catheter embolization of the kidneys (TAE) is a minimally invasive, image-guided procedure. In this study outcome and TAE-related complications of the patients who underwent TAE of the kidneys were evaluated retrospectively. PATIENTS AND METHODS: Between August 2003 and August 2009, 11 patients underwent selective percutaneous transarterial renal embolization for end stage renal disease associated with uncontrolled hypertension, nephrotic syndrome, bleeding or malignancy. TAE of renal arteries was performed using different embolization agents. RESULTS: Successful renal embolization was possible in all 21 kidneys. All patients became anuric. Non-target embolization was not detectable. Nevertheless, all patients developed some degree of postembolization symptoms including nausea, vomiting, fever or pain. A typical finding after embolization was an increase in the C-reactive protein. CONCLUSIONS: Renal embolization is rarely done but should be considered as an alternative to surgical nephrectomy in patients with end stage renal disease due to the lesser invasiveness. Our study confirms the safety and effectivity of percutaneous renal embolization in patients with ESRD. We were able to control the hypertension, nephrotic syndrome, and bleeding caused by ESRD. PMID- 21780056 TI - Gadofosveset enhanced MR phlebography for detecting pelvic and deep vein leg thrombosis. AB - BACKGROUND: Deep venous thrombosis is mainly diagnosed by ultrasound today. In some instances diagnosis is challenging and magnetic resonance angiography could be an attractive alternative. Gadofosveset is a blood pool contrast agent with some favourable properties for this purpose. PATIENTS AND METHODS: We investigated eight patients with proven deep venous thrombosis by Gadofosveset enhanced MR phlebography. We performed a 3D gradient-echo sequence with an overall measurement time of 9 minutes and 6 seconds. One minute after injection of Gadofosveset in a concentration of 0.12 ml/kg body weight images were acquired. Thrombi were visualised by their lack of luminal contrast filling. RESULTS: Thrombi were visualised in all patients. In one patient with extended thrombosis a previously undiagnosed ovarian adenocarcinoma was detected additionally. CONCLUSIONS: Deep venous thromboses in lower extremities can be visualised reliably by performing MR phlebography with blood pool contrast agent Gadofosveset. Visualisation of the complete venous system is feasible. This investigation method may be performed in patients difficult to investigate with ultrasound or may be used for planning interventional procedures. PMID- 21780057 TI - Hand ischemia caused by solitary humeral exostosis irritating the brachial artery. AB - A 39-year-old woman presented with ischemia of the left hand. Angiography revealed thrombosis of forearm arteries. Surgical intervention was unsuccessful. CT angiography revealed an exostosis on the distal humerus close to the brachial artery which we believe was the cause of repetitive minor trauma to the brachial artery leading to embolic occlusion of the radial and ulnar arteries. Early diagnosis of the underlying cause is the key to successful treatment of hand ischemia. For patients without risk factors for arterial occlusive disease, imaging of bony structures must be performed in order not to miss the likely cause of an insidious repetitive vascular trauma. PMID- 21780058 TI - Cavernous transformation of the portal vein in nephrotic syndrome. AB - We report a 19-year-old man with thrombosis of the portal vein associated with a nephrotic syndrome. A computed tomography showed obstruction of the portal vein with prominent collaterals and cavernous transformation. This case is noteworthy as a report of nephrotic syndrome accompanied by extensive abdominal venous thrombosis and was cured successfully. PMID- 21780059 TI - Pulmonary emboli due to venous aneurysm of extremities. AB - Venous aneurysms are uncommon but they can have devastating consequences, including pulmonary embolism, other thromboembolic events and death. We report six cases of venous aneurysm of the extremities, in which the first sign of presence was acute pulmonary embolism. Surgical resection is recommended whenever possible. Our experience suggests that prophylactic surgery is cautiously recommended for low-risk patients with venous aneurysms of the abdomen and strongly recommended for extremity deep and superficial venous aneurysms for their potential risk of developing thromboembolic complications despite adequate anticoagulation. Other venous aneurysms should be excised only if they are symptomatic or enlarging. PMID- 21780060 TI - Redo sternotomy for extra-anatomical correction of aortic coarctation and mitral repair in an adult after failed endovascular treatment. AB - Recently, extra-anatomical bypass surgery has been widely used in complicated adult aortic coarctation cases with concomitant intracardiac repair. Stent implantation has been widely used for primary aortic coarctation as well. The procedure has been shown to be effective with long term follow ups. However, failed stent implantations like stent fracture and dislodgement may complicate the clinical status and subsequent surgical procedure. Extra-anatomic bypass can provide effective results and lower morbidity in cases with concomitant intracardiac problems and stent failure. Here we present an adult aortic coarctation patient who had undergone a Bentall operation and two unsuccessful stent implantations for recurrent aortic coarctation. The patient then got an extra-anatomic bypass for aortic coarctation and concomitant mitral valve commissurotomy through median sternotomy. PMID- 21780061 TI - Cystic medial necrosis Erdheim-Gsell. PMID- 21780063 TI - [New concepts in human oncology: is it possible to use them in veterinary medicine as well?]. AB - In human oncology, novel targeted therapy focusing on monoclonal antibodies and tyrosine kinase inhibitors has become an attractive anticancer strategy. The introduction of antiangiogenetic drugs and metronomic chemotherapy has also increased the therapeutic arsenal. Chemotherapy still plays a key role in the treatment of many tumors affecting dogs and cats. However, novel anticancer strategies (including tyrosine kinase inhibitors and monoclonal antibodies, as well as antiangiogenetic treatments) are becoming relevant in veterinary medicine, too. The goal of this review is to describe new therapeutic strategies for cancer treatment in veterinary medicine, including less well-known chemotherapeutic drugs. PMID- 21780064 TI - [Systematic sanitation of dairy herds with mastitis caused by Staphylococcus aureus]. AB - Several strategies are known for sanitizing dairy herd problems caused by Staphylococcus (S.) aureus. They mostly consist of general management measures but specific decision-making at an individual animal level has not been described. A sanitation program in the form of a process chart developed by the Bern Clinic for Ruminants was undertaken in 10 dairy herds with this problem. In an affected herd the cows were divided into 3 groups: healthy, suspect, infected. Three milk samples (MS), taken at two-week intervals were cultivated. The cows were grouped according to the culture results. To measure the success of the sanitation program, the key figures "theoretical tank somatic cell count" (target < 150,000 SCC/ml) and "percentage of cows over limit" (limit: 150'00 SCC/ml, target < 20 %) were used. These were compared with the corresponding key figures from dairy herds, which were followed-up by the Bern Clinic for Ruminants (control herds). The problem herd sanitation program lasted between 2 and 21 months. A total of 1598 MS were analyzed, of which 241 (15 %) were S. aureus positive (15 %). At the end of the sanitation the key figures between problem herds and control herds were similar. The sanitation program has proved to be practical. The detection of S. aureus positive cows proved to be reliable and the udder health of the herd could be significantly improved. PMID- 21780065 TI - Prevalence of dog erythrocyte antigen 1.1 in dogs in Switzerland evaluated with the gel column technique. AB - Canine blood typing has become an established and essential laboratory test due to the rising demand for safe and efficient blood transfusions. The most immunogenic and clinically important blood type is DEA 1.1. Little is known about DEA 1.1 frequencies or special characteristics among different canine breeds. 304 dogs were tested for DEA 1.1. DEA 1.1-typing was performed using a commercial gel column technique (ID-Gel Test Canine DEA 1.1, DiaMed, Cressier, Switzerland). Fifty-three percent of all tested dogs reacted positive for DEA 1.1, whereas 49 % of the mixed breeds tested DEA 1.1-positive. All Bernese mountain dogs (n = 22) and Rottweilers (n = 9) tested positive for DEA 1.1, while all Boxers (n = 8), Flat-Coated Retrievers (n = 9), and Border Collies (6) tested negative for DEA 1.1. The prevalence of DEA 1.1 in dogs in Switzerland was found to be comparable to that reported from other countries. The tested breeds were found to differ considerably in the frequency of DEA 1.1. This knowledge is useful for selection of blood donors. However, DEA 1.1 blood typing of donor and recipient prior to transfusion and cross matching in sensitized dogs is unavoidable. PMID- 21780067 TI - [The workplace-caused inability to work]. PMID- 21780068 TI - [Yield calculation of an item of capital expenditure]. PMID- 21780071 TI - Percheron artery syndrome: variability in presentation and differential diagnosis. AB - INTRODUCTION: Synchronous bilateral paramedian thalamic stroke (SBPTS), usually equated to Percheron artery infarction, is considered to be uncommon and difficult to diagnose clinically. Its characterization is based on the original description plus a few small series. AIM: To characterize SBPTS clinically by collecting cases and identifying the key difficulties for an early diagnosis. PATIENTS AND METHODS: Six cases at our centre plus another 115 located by systematic literature search and critical reading of articles fulfilled the criteria for SBPTS. An analysis was made of the variables age, gender, vascular risk factors, aetiology, alterations and fluctuations of consciousness, need for intubation, cognitive-behavioural disorders, pupillary changes, other neurological focal disorders and brainstem involvement on imaging studies. RESULTS: Of note in our series were disorders of consciousness (n=5), their fluctuations (n=3) and the diagnostic delay (seven days, with MRI in four patients). In only one case was a bilateral thalamic lesion seen on the initial CT. Joint analysis of all the cases showed a mean age of 61 years, a predominance of men (58%), the presence of vascular risk factors in 77%, a mainly cardioembolic aetiology (34% among those that were specified), sensory involvement in 75% (intubation in 7% and fluctuations in 16.5%), cognitive behavioural disorders in 43%, oculomotor in 73%, pupillary in 31%, other in 67% and specified brainstem lesion in 37%. CONCLUSIONS: The SBPTS syndrome has a variable presentation with a low sensitivity on the initial CT, requiring brain MRI for typification. This explains the diagnostic difficulty and the fact that its frequency is probably underestimated. PMID- 21780072 TI - [Predisposing factors affecting drop-out rates in preventive treatment in a series of patients with migraine]. AB - INTRODUCTION: The drop-out rate among patients receiving preventive treatment for migraine is higher than 30%. This situation is not very widely known and the risk factors that lead patients to drop out from treatment have yet to be identified. AIM: To evaluate some of the factors that can predispose patients to drop out of preventive treatment. PATIENTS AND METHODS: We conducted a prospective study of patients suffering from migraine who required preventive treatment for the first time with one of what are considered the top three first-choice drugs, i.e. a beta-blocker (nadolol), a neuromodulator (topiramate) or a calcium antagonist (flunarizine). Two groups were established according to whether patients dropped out of treatment or not. Different demographic and clinical variables were analysed and compared in the two groups. RESULTS: Of 800 patients with migraine who required preventive treatment for the first time, the drop-out rate was 19.7%. In the drop-out group, the variables 'age', 'number of seizures', 'number of seizures prior to preventive treatment' and 'side effects' showed significant differences with those from the group of patients who did not drop out of preventive treatment. CONCLUSIONS: The drug used as preventive treatment, the side effects, a younger age and a lower number of seizures before starting the preventive treatment favoured higher drop-out rates. Whether the migraine was episodic or chronic, the presence of medication abuse and the drugs used to treat the seizures were not related with dropping out of preventive treatment. PMID- 21780073 TI - [The use of noninvasive brain stimulation in childhood psychiatric disorders: new diagnostic and therapeutic opportunities and challenges]. AB - Novel diagnostic and therapeutic approaches based on noninvasive brain stimulation offer some promise in the field of childhood psychiatric disorders. There are two primary methods of noninvasive brain stimulation currently available: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Both noninvasive neuromodulation techniques appear to rely on modulating brain plasticity and thus open new hopes in the treatment of brain circuit and plasticity disorders. Since many childhood psychiatric disorders involve disturbances in the timing or mechanisms of plasticity within frontostriatal circuits, and the developing brain shows a greater capacity of brain plasticity, noninvasive brain stimulation might induce greater benefits in this population than in adults. Although the utilization of TMS and tDCS remains limited in children, there is enough evidence for their rational, safe use in this population. In this paper, we review the principles of noninvasive brain stimulation and the diagnostic and therapeutic applications in child-hood psychiatric disorders in order to inform its development into safe and reliable diagnostic and effective therapeutic approaches in pediatric psychiatry. PMID- 21780074 TI - [Intracranial meningiomas: II. Diagnosis and treatment]. AB - INTRODUCTION: Meningiomas are the most frequent group of intracranial tumours. In most cases, they are histologically benign tumours, although the fact that they may be located in anatomical areas that are difficult to reach with surgical techniques often means that their treatment must be complemented with oncological therapies. AIMS: To update our current knowledge about the diagnostic techniques and therapeutic options available for intracranial meningiomas, so as to have the latest information on this subject. DEVELOPMENT: The study involves a review of the literature that covers aspects related to the different complementary diagnostic techniques and the alternative methods of treatment. CONCLUSIONS: Magnetic resonance imaging, in all its different sequences, is the preferred diagnostic technique, since it allows 100% intracranial meningiomas to be diagnosed. Although surgery is the preferred treatment technique in most cases, radiotherapy, in its different modes, is an essential therapeutic tool, both as a complement to surgery and as the first choice. PMID- 21780075 TI - [Neurosciences and the ravings of the Soviet era. Spanish Republican physicians, a set of privileged witnesses]. AB - This study analyses the links between the Russian and Soviet neurosciences and their Spanish counterpart, especially with regard to the experiences of the Spanish Republican physicians exiled in the USSR. The Russian neurosciences, which date back to the second half of the 19th century, followed a path that ran parallel to the discipline throughout the rest of Europe and finally displayed signs of being influenced by the German and French schools. Important figures include Alexei Kojevnikov and Vladimir Bekhterev in neurology, Sergei Korsakov in psychiatry, Ivan Pavlov and his disciple Piotr Anojin in neurophysiology, Lev Vygotsky and Alexander Luria in neuropsychology, and Nikolai Burdenko in neurosurgery. When the Bolsheviks came to power, they brought with them a progressive conception of health care, which was modified during the Stalinist era to serve political interests, above all in the case of psychiatry. During the first third of the 20th century, Spanish scientists became interested in Pavlov's reflexology and the Soviets took a similar interest in Spanish histology. Among the 4500 Spanish Republicans who emigrated to the USSR because of the Spanish Civil War, there were several dozen physicians who were privileged witnesses of the madness that shook the science and the health care of that period. Relevant names worth citing here from the field of the neurosciences include Juan Planelles and Ramon Alvarez-Buylla in neurophysiology, Federico Pascual and Florencio Villa Landa in psychiatry, Angel Escobio and Maria Perez in neurology, Julian Fuster in neurosurgery and Manuel Arce in neuroimaging. PMID- 21780077 TI - [Refractory nonconvulsive status epilepticus]. PMID- 21780079 TI - Compliance with guidelines for patients with bladder cancer: variation in the delivery of care. AB - BACKGROUND: Clinical practice guidelines for the management of patients with bladder cancer encompass strategies that minimize morbidity and improve survival. In the current study, the authors sought to characterize practice patterns in patients with high-grade non-muscle-invasive bladder cancer in relation to established guidelines. METHODS: Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data were used to identify subjects diagnosed with high grade non-muscle-invasive bladder cancer between 1992 and 2002 who survived at least 2 years without undergoing definitive treatment (n = 4545). The authors used mixed-effects modeling to estimate the association and partitioned variation of patient sociodemographic, tumor, and provider characteristics with compliance measures. RESULTS: Of the 4545 subjects analyzed, only 1 received all the recommended measures. Approximately 42% of physicians have not performed at least 1 cystoscopy, 1 cytology, and 1 instillation of immunotherapy for a single patient nested within their practice during the initial 2-year period after diagnosis. After 1997, only use of radiographic imaging (odds ratio [OR], 1.19; 95% confidence interval [95% CI], 1.03-1.37) and instillation of immunotherapy (OR, 1.67; 95% CI, 1.39-2.01) were found to be significantly increased. Surgeon attributable variation for individual guideline measures (cystoscopy, 25%; cytology, 59%; radiographic imaging, 10%; intravesical chemotherapy, 45%; and intravesical immunotherapy, 26%) contributes to this low compliance rate. CONCLUSIONS: There is marked underuse of guideline-recommended care in this potentially curable cohort. Unexplained provider-level factors significantly contribute to this low compliance rate. Future studies that identify barriers and modulators of provider-level adoption of guidelines are critical to improving care for patients with bladder cancer. PMID- 21780080 TI - Functionalization of a protein surface with per-O-methylated beta-cyclodextrin. AB - Per-O-methylated beta-cyclodextrin (CD) bearing an iodoacetamide group at the 6 position was synthesized to functionalize protein surfaces. Bovine serum albumin (BSA) was quantitatively modified with the CD derivative by the S(N) 2 reaction of iodoacetamide with a cysteine residue (Cys34) on the BSA surface. The resultant CD-functionalized BSA (BSA-CD) spontaneously dimerized upon addition of an anionic tetraarylporphyrin (TPPS) through the supramolecular 1:2 complexation between TPPS and CD on the protein surface. The BSA-CD/TPPS complex further complexed with ferric protoporphyrin IX (hemin) in the hydrophobic pockets of albumin to form a hemin/BSA-CD/TPPS ternary complex in which static fluorescence quenching occurred owing to intramolecular electron transfer from the photoexcited TPPS to hemin. PMID- 21780082 TI - Cancer Immunotherapy Trials Network launches effort to generate new research: focus on agents that improve cancer patients' immune systems. PMID- 21780083 TI - Organizations hope new fund accelerates cancer vaccine research. PMID- 21780084 TI - EEG power and coherence during preschoolers' performance of an executive function battery. AB - The current study investigated a set of abilities collectively referred to as executive function (EF). Substantial improvement in EF ability occurs between 3 and 6 years of age (e.g., Carlson [2005] Developmental Neuropsychology, 28(2):595 616). This improvement is thought to reflect changes in brain development, especially in areas of prefrontal cortex and frontal cortex, which occur during this time period (e.g., Luu & Posner [2003] Brain 126:2119-2120). Little work has examined preschoolers' cortical activity during EF tasks, despite the frequent use of performance on such tasks as indirect measures of (pre)frontal functioning. The current study measured continuous EEG activity in 104 preschool aged children as they completed a battery of EF tasks. Changes from baseline to task performance in EEG activity (power, coherence) were used as predictors of EF ability. Results indicated that changes from baseline to task engagement in EEG coherence, but not EEG power, were significantly related to performance on the EF battery in our sample. PMID- 21780085 TI - The impairment of one-trial passive avoidance learning in chicks caused by prenatal aluminum exposure. AB - Prenatal aluminum exposure may affect the development of the embryo and alter the capacity for learning and memory in adults. The chick embryo is a good experimental model to study the effect of prenatal toxin exposure on cognitive defects in offspring, because it eliminates maternal confounding variables. In the present study, we applied a one-trial passive avoidance-learning task in day old chicks to examine the effects of prenatal aluminum chloride injections (2, 20, and 200 mM in 200 ul per egg, daily over a period of 4 successive days) on memory consolidation. The data suggest that chicks injected with aluminum chloride (20 mM) daily from E12 to E15 had significantly impaired short-term memory, intermediate-term memory, and long-term memory (LTM) after training (p < .05) but chicks injected with aluminum chloride (2 mM) had impaired LTM only. PMID- 21780086 TI - National Patient Navigation Leadership Summit (NPNLS): measuring the impact and potential of patient navigation. PMID- 21780087 TI - Measuring the impact and potential of patient navigation: proposed common metrics and beyond. AB - In March 2010, the American Cancer Society hosted the National Patient Navigation Leadership Summit. The Summit organizers invited cancer clinicians, researchers, practicing public health and measurement experts, funders, and patient navigators to develop a national consensus on common outcomes to solidify the scientific evidence and efficacy of patient navigation. The goal of the Summit was to develop and propose core metrics to measure outcomes of navigation on individuals as well as populations across the continuum. It is the sincere hope of the editors, funders, authors, and workgroup members that this supplement and the proposed measures provide a roadmap for the development, implementation,and evaluation of patient navigation programs. PMID- 21780088 TI - History and principles of patient navigation. PMID- 21780089 TI - The role of patient navigators in eliminating health disparities. AB - Despite many important efforts to increase equity in the US health care system, not all Americans have equal access to health care-or similar health outcomes. With the goal of lowering costs and increasing accessibility to health care, the nation's new health care reform legislation includes certain provisions that expand health insurance coverage to uninsured and underinsured populations, promote medical homes, and support coordination of care. These provisions may help narrow existing health care disparities. Many of the most vulnerable patients, however, may continue to have difficulty accessing and navigating the complex US health care delivery system. This article explores the unique role that patient navigation can play in improving health outcomes for racial and ethnic minorities, as well as other underserved populations, in the context of a changing healthcare environment. Patient navigators can not only facilitate improved health care access and quality for underserved populations through advocacy and care coordination, but they can also address deep-rooted issues related to distrust in providers and the health system that often lead to avoidance of health problems and non-compliance with treatment recommendations. By addressing many of the disparities associated with language and cultural differences and barriers, patient navigators can foster trust and empowerment within the communities they serve. Specific patient navigator activities are discussed, and metrics to evaluate program efforts are presented. PMID- 21780090 TI - Assessing the impact of patient navigation: prevention and early detection metrics. AB - BACKGROUND: The lack of comparable metrics to evaluate prevention and early detection patient navigation programs impeded the ability to identify best practices. METHODS: The Prevention and Early Detection Workgroup of the Patient Navigation Leadership Summit was charged with making recommendations for common clinical metrics specific to the prevention and early detection phase of the cancer care continuum. The workgroup began with a review of existing literature to characterize variability in published navigation metrics; then developed a list of priority recommendations that would be applicable to the range of navigation settings (clinical, academic, or community-based). RESULTS: Recommendations for researchers and program evaluators included the following: 1) Clearly document key program characteristics; 2) Use a set of core data elements to form the basis of your reported metrics; and 3) Prioritize data collection using methods with the least amount of bias. CONCLUSIONS: If navigation programs explicitly state the context of their evaluation and choose from among the common set of data elements, meaningful comparisons among existing programs should be feasible. PMID- 21780091 TI - Metrics for evaluating patient navigation during cancer diagnosis and treatment: crafting a policy-relevant research agenda for patient navigation in cancer care. AB - BACKGROUND: Racial and ethnic minorities as well as other vulnerable populations experience disparate cancer-related health outcomes. Patient navigation is an emerging health care delivery innovation that offers promise in improving quality of cancer care delivery to these patients who experience unique health-access barriers. Metrics are needed to evaluate whether patient navigation can improve quality of care delivery, health outcomes, and overall value in health care during diagnosis and treatment of cancer. METHODS: Information regarding the current state of the science examining patient navigation interventions was gathered via search of the published scientific literature. A focus group of providers, patient navigators, and health-policy experts was convened as part of the Patient Navigation Leadership Summit sponsored by the American Cancer Society. Key metrics were identified for assessing the efficacy of patient navigation in cancer diagnosis and treatment. RESULTS: Patient navigation data exist for all stages of cancer care; however, the literature is more robust for its implementation during prevention, screening, and early diagnostic workup of cancer. Relatively fewer data are reported for outcomes and efficacy of patient navigation during cancer treatment. Metrics are proposed for a policy-relevant research agenda to evaluate the efficacy of patient navigation in cancer diagnosis and treatment. CONCLUSIONS: Patient navigation is understudied with respect to its use in cancer diagnosis and treatment. Core metrics are defined to evaluate its efficacy in improving outcomes and mitigating health-access barriers. PMID- 21780092 TI - Survivorship navigation outcome measures: a report from the ACS patient navigation working group on survivorship navigation. AB - Survivorship navigation is a relatively new concept in the field of patient navigation but an important one. This article highlights the essential functions of the survivorship navigator and defines core outcomes and measures for navigation in the survivorship period. Barriers to access to care experienced by patients during active cancer treatment can continue into the post-treatment period, affecting quality follow-up care for survivors. These barriers to care can be particularly acute for non-English speakers, immigrants, the uninsured, the underinsured, and other vulnerable populations. The survivorship navigator can help reduce barriers and facilitate access to survivorship care and services through communication and information exchange for patients. Survivorship navigation may improve appropriate health care utilization through education and care coordination, potentially improving health outcomes and quality of life of survivors while reducing cost to the health care system. Survivorship navigators can also educate survivors on how to improve their overall wellness, thereby directly impacting the health of a growing population of cancer survivors. PMID- 21780093 TI - Navigation and palliative care. AB - Patient navigation represents an opportunity to further the integration of palliative care with standard cancer care. This article defines palliative and hospice care and describes some of the current challenges of integrating palliative care into other forms of care. It also considers outcomes that navigation might be expected to improve for patients receiving palliative care or enrolled in hospice. These outcomes include symptom relief; communication efficacy; transitions of care; and access to palliative care, hospice, and bereavement care for families. Although these outcomes may not have been specifically assessed in patients in cancer navigation programs, they represent important outcomes for patients receiving palliative care and their families. It is recognized that the types of outcomes that are important to track for patients and families receiving palliative care should be consistent with outcomes at other stages of illness. PMID- 21780094 TI - Patients, family caregivers, and patient navigators: a partnership approach. AB - BACKGROUND: Navigation services may be strengthened by establishing a partnership between the patient, family/caregiver, and the navigator. Involvement of a patient's familial or social network in the navigation process would allow patient navigators to spend more time and resources with the subset of patients who do not have support from family and friends. The Partnership Approach evolves from combining the strength of a patient's existing social support and network with the delivery of navigation services. METHODS: To develop this novel approach, the Family and Caregiver Workgroup was convened at the American Cancer Society's National Leadership Summit. Individuals were asked to serve in this group due to their interest, research, or experience in family and caregiver issues. RESULTS: By the end of the Summit, the workgroup had achieved 3 major outcomes: 1) enhancement of current patient navigation services by building a partnership between the patient, family or primary caregivers, and navigators; 2) identification of a set of core functions that a family/caregiver could perform in a partnership; and 3) consensus on a set of metrics to use with caregivers and patients. Five major domains were selected to measure patient and/or caregiver outcomes: quality of life, satisfaction with care, social support, distress, and caregiver burden. Metrics appropriate for each domain were recommended. CONCLUSIONS: Integration of these domains and scales in current navigation services is needed to develop future research. Evidence from such research would help determine whether the Partnership Approach contributes to improved patient and caregiver outcomes. PMID- 21780095 TI - Patient-reported outcome measures suitable to assessment of patient navigation. AB - BACKGROUND: Patient-reported outcomes (PROs) are measures completed by patients to capture outcomes that are meaningful and valued by patients. To help standardize PRO measures in patient navigation research and program evaluation, the Patient-Reported Outcomes Working Group (PROWG) was convened as part of the American Cancer Society's National Patient Navigator Leadership Summit. METHODS: The PROWG consisted of clinicians, researchers, and program managers from a variety of perspectives who developed a set of recommended PRO measures across the cancer continuum (ie, screening, diagnostic follow-up, treatment, survivorship, end of life) as well as those useful for assessing family caregivers. Measures were recommended based on face validity, responsiveness to navigation, reliability, and construct validity in relevant populations. Other considerations included readability, existence of multiple language versions, the existence of norm groups, and respondent burden. RESULTS: The PROWG reached consensus on measures for use in the domains of treatment adherence; perceived barriers to care; satisfaction with cancer care; satisfaction with patient navigation services; working alliance with patient navigator; perceived knowledge/competence/self-efficacy; functional assessment/symptom burden; global quality of life; specific quality-of-life symptoms (eg, depression, anxiety); and perceived cultural competency of the navigator. In domains where validated measures were found lacking, recommendations were made for areas of needed scale development. CONCLUSIONS: These measures should guide research and programmatic evaluation of patient navigation. PMID- 21780096 TI - Establishing common cost measures to evaluate the economic value of patient navigation programs. AB - BACKGROUND: Patient navigation is an intervention aimed at reducing barriers to health care for underserved populations as a means to reduce cancer health disparities. Despite the proliferation of patient navigation programs across the United States, information related to the economic impact and sustainability of these programs is lacking. METHODS: After a review of the relevant literature, the Health Services Research (HSR)-Cost workgroup of the American Cancer Society National Patient Navigator Leadership Summit met to examine cost data relevant to assessing the economic impact of patient navigation and to propose common cost metrics. RESULTS: Recognizing that resources available for data collection, management, and analysis vary, 5 categories of core and optional cost measures were identified related to patient navigator programs, including program costs, human capital costs, direct medical costs, direct non-medical costs, and indirect costs. CONCLUSIONS: Information demonstrating economic as well as clinical value is necessary to make decisions about sustainability of patient navigation programs. Adoption of these common cost metrics are recommended to promote understanding of the economic impact of patient navigation and comparability across diverse patient navigation programs. PMID- 21780097 TI - Molecular model of human heparanase with proposed binding mode of a heparan sulfate oligosaccharide and catalytic amino acids. AB - Heparan sulfate is abundantly present in the extracellular matrix. As other glycosaminoglycans, it is synthesized in the Golgi apparatus and then exposed on the cell surface. The glucuronidase activity of human heparanase plays a major role in the structural remodeling of the extracellular matrix, which underlies cell migration, hence tumor invasion. Heparanase is therefore a major target for anti-cancer treatment. Several inhibitors of its enzymatic activity have been synthesized. However, their design is limited by the absence of experimental structure of the protein. Homology modeling is proposed based on the structure of the endoxylanase from Penicillium simplicissimum co-crystallized with a series of xylan oligosaccharide. The new heparanase model is consistent with the few experimental data suited for the validation of such work. Furthermore, the presence of natural substrates in the template structure allowed us to propose a binding model for a hydrolyzed heparin sulfate pentasaccharide. Several lysine residues have been identified to play a key role in binding to the anionic polysaccharide substrate. In addition, two phenylalanine residues are also potentially important for the interaction with the substrate. The enzymatic mechanism investigated in the light of this new model allows for the proposal of several amino acids that can influence the protonation state of the nucleophile and the proton donor. PMID- 21780098 TI - Pharmacokinetic parameters from 3-Tesla DCE-MRI as surrogate biomarkers of antitumor effects of bevacizumab plus FOLFIRI in colorectal cancer with liver metastasis. AB - Bevacizumab (BV) is an antivascular endothelial growth factor antibody. When administered with other chemotherapeutic drugs, BV-combined regimens prolong survival of colorectal cancer patients. We conducted a phase II trial to confirm the pharmacokinetic parameters from 3-Tesla dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as surrogate biomarkers of BV + FOLFIRI regimen efficacy in colorectal cancer with liver metastases. DCE-MRI was performed before treatment, on the seventh day after first treatment and every 8 weeks thereafter using a 3-Tesla MRI system. DCE-MRI parameters-area under the contrast concentration versus time curve at 90 and 180 s (AUC90 and AUC180, respectively) after contrast injection, and volume transfer constant of contrast agents (K(trans) and K(ep) ) were calculated from liver metastases. Fifty-eight liver metastases were analyzed. Univariate analysis revealed that a decrease in K(trans) ratios (DeltaK(trans) ), K(ep) ratios (DeltaK(ep) ), AUC90 ratios (DeltaAUC90) and AUC180 ratios (DeltaAUC180) correlated with higher response (all p < 0.0001) and longer time to progression (TTP) (DeltaK(trans) : p = 0.001; DeltaK(ep) : p = 0.004; DeltaAUC90: p = 0.006; DeltaAUC180: p < 0.0001). Multivariate analysis showed that DeltaAUC180 was correlated with higher response (p = 0.009), and DeltaK(trans) and DeltaAUC180 were correlated with longer TTP (DeltaK(trans) : p = 0.001; DeltaAUC180: p = 0.024). DeltaK(trans) and DeltaAUC180 are pharmacodynamic biomarkers of the blood perfusion of BV + FOLFIRI. Our data suggest that DeltaK(trans) and DeltaK(ep) can predict response to chemotherapy at 1 week. Changes in 3-Tesla DCE-MRI parameters confirmed the potential of these biomarkers of blood perfusion as surrogate predictors of response and TTP. PMID- 21780099 TI - Liver cancer and non-Hodgkin lymphoma in hepatitis C virus-infected patients: results from the DANVIR cohort study. AB - Hepatitis C virus (HCV)-infection can cause hepatocellular carcinoma (HCC) and most likely non-Hodgkin lymphoma (NHL). No studies have compared the risk of these cancers between patients with chronic and cleared HCV-infection. The aim of this study was to estimate the 10-year risk of HCC and NHL in HCV-infected patients and to compare the risk of these cancers between HCV-infected patients and the general population in Denmark and between patients with chronic and cleared HCV-infection. Nationwide cohorts were used: 11,975 HCV-infected patients in the DANVIR cohort and 71,850 individuals from an age- and gender-matched general population cohort. Within DANVIR, 4,158 patients with chronic HCV infection and 2,427 patients with cleared HCV-infection were studied. The 10-year risks of HCC and NHL in HCV-infected patients were 1.0% [95% confidence interval (CI): 0.8-1.3%] and 0.1% (95% CI: 0.1-0.2%), respectively. Compared to the general population, HCV-infected patients had a 62.91-fold increased risk of HCC (95% CI: 28.99-136.52), a 29.97-fold increased risk of NHL during the first year of follow-up (95% CI: 6.08-147.84), and a 1.26-fold increased risk of NHL after the first year (95% CI: 0.36-4.41). Chronic HCV-infection was associated with a 4.71-fold increased risk of HCC (95% CI: 1.67-13.32) compared to cleared HCV infection; 5 and 0 events of NHL occurred in patients with chronic and cleared HCV-infection, respectively. HCC-risk is increased substantially in HCV-infected patients compared to the general population. Chronic as opposed to cleared HCV infection increases the risk of HCC and perhaps NHL. PMID- 21780100 TI - Upregulation of prostate-derived Ets factor by luteolin causes inhibition of cell proliferation and cell invasion in prostate carcinoma cells. AB - Luteolin is a polyphenolic flavone and has antitumor activity for many cancers. The prostate-derived Ets factor (PDEF), a novel epithelium-specific Ets transcription factor, acts as an androgen-independent transcriptional activator of the prostate-specific antigen (PSA) promoter. We determined the antitumor function of luteolin via upregulation of PDEF gene expression in human prostate carcinoma LNCaP cells. Results from flow cytometry and (3) H-thymidine incorporation assays revealed that luteolin treatments attenuated cell proliferation and arrested the cell cycle at the G1/S phase. High concentration of luteolin (30 MUM) induced cell apoptosis. Immunoblot assays and enzyme linked immunosorbent assay revealed that luteolin treatment upregulated PDEF but downregulated androgen receptor (AR) gene expression, which decreased PSA gene expression in LNCaP cells. Results of immunoblot and transient gene expression assays revealed that luteolin treatments at proapoptosis dosage, enhanced gene expression of PDEF, B-cell translocation gene 2 (BTG2), N-myc downstream regulated gene 1 (NDRG1) and Maspin. Transient gene expression assays indicated that cotransfection of the PDEF expression vector enhanced the promoter activities of the BTG2, NDRG1 and Maspin genes. Stable overexpression of PDEF significantly induced BTG2, NDRG1 and Maspin gene expression, which markedly attenuated in vitro cell proliferation and invasion of LNCaP cells. The modulatory effect of luteolin on BTG2, NDRG1 and Maspin gene expression were attenuated when PDEF was knocked-down. These results suggest that luteolin blocks PSA gene expression by downregulation of AR expression. The enhancement of PDEF expression, which induced BTG2, NDRG1 and Maspin gene expression, could account for the function of luteolin for antiproliferation and anti-invasion in LNCaP cells. PMID- 21780101 TI - P-glycoprotein binds to ezrin at amino acid residues 149-242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma. AB - Overexpression of the mdr1 gene encoding P-glycoprotein (Pgp) exerts a major role in reducing the effectiveness of cytotoxic therapy in osteosarcoma. The interaction between actin and Pgp has been shown to be instrumental in the establishment of multidrug resistance (MDR) in human tumor cells. The cytoskeleton linker ezrin exerts a pivotal role in maintaining the functional connection between actin and Pgp. We investigated the role of ezrin in a human multidrug-resistant osteosarcoma cell line overexpressing Pgp and compared it to its counterpart that overexpresses an ezrin deletion mutant. The results showed that Pgp binds at amino acid residues 149-242 of the N-terminal domain of ezrin. The interaction between ezrin and Pgp occurs in the plasma membrane of MDR cells, where they also co-localize with the ganglioside G(M1) located in lipid rafts. The overexpression of the ezrin deletion mutant entirely restored drug susceptibility of osteosarcoma cells, consistent with Pgp dislocation to cytoplasmic compartments and abrogation of G(M1) /Pgp co-localization at the plasma membrane. Our study provides evidence that ezrin exerts a key role in MDR of human osteosarcoma cells through a Pgp-ezrin-actin connection that is instrumental for the permanence of Pgp into plasma membrane lipid rafts. We also show for the first time that Pgp-binding site is localized to amino acid residues 149-242 of the ezrin Band 4.1, Ezrin/Radixin/Moesin (FERM) domain, thus proposing a specific target for future molecular therapy aimed at counteracting MDR in osteosarcoma patients. PMID- 21780103 TI - Carbidopa abrogates L-dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression. AB - The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ~2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression. PMID- 21780102 TI - Use of nonsteroidal anti-inflammatory drugs and risk of basal cell carcinoma in the United States Radiologic Technologists study. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk of colorectal and other cancers, but the association with basal cell carcinoma (BCC) is unclear. Previous epidemiological studies have been small in size, conducted in especially vulnerable populations, or have not accounted for solar ultraviolet exposure, a major risk factor for BCC. In the United States Radiologic Technologists cohort, we followed subjects to assess NSAID use on risk of first incident BCC. We included Caucasian participants who responded to both second and third questionnaires (administered from 1994 to 1998 and 2003 to 2005, respectively), and who reported no cancer at the time of the second questionnaire, N = 58,213. BCC, constituent risk factors (e.g., eye color, complexion, hair color) and sun exposure history were assessed through self administered survey. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Of the 58,213 people in the study population, 2,291 went on to develop BCC. Any NSAID use was not associated with subsequent incidence of BCC (HR = 1.04, 95% CI: 0.92-1.16) after adjusting for age, sex and estimated lifetime summer sun exposure. Neither association was observed when stratified by NSAID type (aspirin and other NSAIDs), nor did dose response patterns emerge by frequency of use (average days per month). Further analyses did not reveal interaction with sex, birth cohort, smoking, alcohol consumption, sun exposure, occupational radiation exposure or personal risk factors for BCC. In this large nationwide study, we observed no association between NSAID use and subsequent BCC risk. PMID- 21780104 TI - alpha1-3/4 fucosylation at Asn 241 of beta-haptoglobin is a novel marker for colon cancer: a combinatorial approach for development of glycan biomarkers. AB - Aberrant glycosylation has been observed in many types of cancer, but the mechanism of glycosylation change is still poorly understood. To elucidate relationships between glycosylation and colon cancer progression, we analyzed glycosylation status of beta-haptoglobin (beta-Hp) obtained from 46 cancer patients, 14 inflammatory bowel disease patients and 38 normal subjects. Aleuria aurantia lectin reactivity with cancer beta-Hp was much higher than in the other two study groups. These results were confirmed by lectin blotting and microarray assay using other lectins directed to fucosyl residues. Levels of such glycans were correlated with stage of colon cancer progression. Reactivity with fucosylated glycans was eliminated by treatment with alpha1-3/4 fucosidase but not alpha1-6 fucosidase, indicating that enhanced lectin reactivity with the fucose moiety of colon cancer beta-Hp is due to Fucalpha1-3/4GlcNAc. Moreover, site-specific glycan occupancy was determined by sequential LC/MS analysis. Mass spectrometric analysis showed that fucosylation of beta-Hp was higher in colon cancer patients than in other subjects. In particular, fucosylation at Asn 241 of beta-Hp in sera of colon cancer patients was clearly higher than in the other groups, and the ratio of fucosylated glycopeptides containing Asn 241 decreased greatly after treatment with alpha1-3/4 fucosidase. In conclusion, the level of alpha1-3/4 fucosyl epitope at Asn 241 of beta-Hp is potentially useful as a novel marker for colon cancer. PMID- 21780105 TI - Proviral loads of human T-lymphotropic virus Type 1 in asymptomatic carriers with different infection routes. AB - High human T-lymphotropic virus Type 1 (HTLV-1) proviral DNA load (PVL) has been reported to be one risk factor for the development of adult T-cell leukemia/lymphoma (ATL). ATL is also believed to develop in HTLV-1 carriers who acquire infection perinatally. ATL cells have been reported to frequently harbor defective provirus. In our study, PVLs for three different regions of HTLV-1 provirus (5'LTR-gag, gag and pX) were measured in 309 asymptomatic carriers with different infection routes. PVLs for the pX region in 21 asymptomatic carriers with maternal infection was significantly higher than in 24 carriers with spousal infection. Among 161 carriers with relatively high pX PVLs (equal to or greater than 1 copy per 100 peripheral blood mononuclear cells), 26 carriers (16%) had low gag PVL/pX PVL (less than 0.5) and four (2%) had low 5'LTR-gag PVL/pX PVL (less than 0.5). Low gag PVL/pX PVL ratio, which reflects deficiency and/or polymorphism of HTLV-1 proviral DNA sequences for the gag region, was also associated with maternal infection. These data suggest that HTLV-1 carriers with maternal infection tend to have high PVLs, which may be related to provirus with deficiency and/or the polymorphism of proviral DNA sequences. In addition, there is a possibility that this ratio may be used as a tool to differentiate the infection routes of asymptomatic HTLV-1 carriers, which supports the need for a large scale study. PMID- 21780106 TI - High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. AB - Galectin-1 is implicated in making tumor cells immune privileged, in part by regulating the survival of infiltrating T cells. Galectin-1 is strongly expressed in activated pancreatic stellate cells (PSCs); however, whether this is linked to tumor cell immune escape in pancreatic cancer is unknown. Galectin-1 was knocked down in PSCs isolated from pancreatic tissues using small interfering RNA (siRNA), or overexpressed using recombinant lentiviruses, and the PSCs were cocultured with T cells. CD3(+) , CD4(+) and CD8(+) T cell apoptosis was detected by flow cytometry; T cell IL-2, IL-4, IL-5 and INF-gamma production levels were quantified using ELISA. Immunohistochemical analysis showed increased numbers of PSCs expressed Galectin-1 (p < 0.01) and pancreatic cancers had increased CD3(+) T cell densities (p < 0.01) compared to normal pancreas or chronic pancreatitis samples. In coculture experiments, PSCs that overexpressed Galectin-1 induced apoptosis of CD4(+) T cells (p < 0.01) and CD8(+) T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4(+) T cell (p < 0.01) and CD8(+) T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-gamma, p < 0.01). However, the knockdown of PSC Galectin-1 had the opposite effect on Th1 and Th2 cytokine secretion. Our study suggests that the overexpression of Galectin-1 in PSCs induced T cell apoptosis and Th2 cytokine secretion, which may regulate PSC dependent immunoprivilege in the pancreatic cancer microenvironment. Galectin-1 may provide a novel candidate target for pancreatic cancer immunotherapy. PMID- 21780107 TI - Diagnostic performance of one-step nucleic acid amplification for intraoperative sentinel node metastasis detection in breast cancer patients. AB - The purpose of this prospective multicenter study was to assess one-step nucleic acid amplification (OSNA) for intraoperative sentinel lymph node (SLN) metastasis detection in breast cancer patients, using final histology as the reference standard. OSNA results were also compared to intraoperative histology SLN evaluation and to standard clinicopathological risk markers. For this study, fresh SLNs were cut in four blocks, and alternate blocks were used for OSNA and histology. CK19 mRNA copy number was categorized as strongly positive, positive or negative. Positive histology was defined as presence of macrometastasis or micrometastasis. When discrepancies occurred, the entire SLNs were subjected to histological studies and the node lysates to additional molecular studies. Five hundred three SLN samples from 233 patients were studied. Mean time to evaluate two SLNs was 40 min. Sensitivity per patient was 91.4% (95% CI, 76.9-98.2%), specificity 93.3% (95% CI, 88.6-96.6%), positive likelihood ratio 13.7 and negative likelihood ratio 0.1. Sensitivity was 63.6% for frozen sections and 47.1% for touch imprint cytology. Both methods were 100% specific. Positive histology and positive OSNA were significantly associated with highest clinical stage, N1 status and vascular invasion; and OSNA results correlated with HER2/neu status and benefited patients with negative histology. These findings show that OSNA assay can allow detection of SLN metastasis in breast cancer patients intraoperatively with a good sensitivity, thus minimizing the need for second surgeries for axillary lymph node detection. PMID- 21780108 TI - Clinicopathologic factors associated with HER2-positive gastric cancer and its impact on survival outcomes--a systematic review. AB - With the availability of a therapeutic target and an effective agent in trastuzumab, a systematic examination of the literature to investigate the role of human epidermal growth factor 2 (HER2) as a prognostic factor for survival and its association with clinicopathologic markers may improve treatment. An electronic search of the MEDLINE and PubMed databases (January 1990 to January 2011) was undertaken to identify translational studies that correlated HER2 with clinicopathologic markers and/or survival outcome. This review included 49 studies totaling 11,337 patients. Forty-four percent of patients had Stage I/II, and 56% had Stage III/IV disease. Immunohistochemistry was most commonly used to assess HER2 expression, identifying a median rate of 18% (range, 4-53%) of gastric cancer demonstrating HER2 overexpression. In patients with and without HER2 overexpression, the median 3-year disease-free survival rate was 58% (range, 50-88%) and 86% (range, 62-97%), respectively. Of the 35 studies reporting the impact of HER2 overexpression on survival, 20 studies (57%) reported no difference in overall survival, two studies (6%) reported significantly longer overall survival in patients with HER2 overexpression and 13 studies (37%) reported significantly poorer overall survival in patients with HER2 overexpression. The median overall survival and 5-year survival rate was 21 (range, 10-57) months and 42%, and 33 (range, 13-80) months and 52% in patients with and without HER2 overexpression, respectively. HER2 overexpression appears to be associated with poorer survival and with intestinal-type gastric cancer in this group of patients for whom majority undergone curative gastrectomy. PMID- 21780109 TI - Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. AB - The nuclear bile acid receptor/farnesoid X receptor (FXR; NR1H4) is involved in bile acid homeostasis, cell proliferation and apoptosis and has been linked to intestinal carcinogenesis in mice. Aim of this study was to analyze FXR expression in human normal intestinal mucosa and colon carcinoma. We achieved systematic mapping of FXR expression of human intestinal mucosa and analysis of 75 human colon carcinomas using FXR immunohistochemistry on formalin-fixed, paraffin-embedded tissue. FXR expression gradually decreased from terminal ileum to the sigmoid colon with strongest expression in the terminal ileum (p < 0.001). FXR expression in carcinomas was reduced compared to peritumoral nonneoplastic mucosa (p < 0.000). Loss of FXR expression was significantly correlated with grading in tumors of the right colon (p = 0.008). FXR expression in tumor and normal tissue showed an inverse correlation with stage. FXR expression in tumor was inversely correlated with clinical outcome. No association was found with patients' age and sex. In nonneoplastic mucosa FXR expression concurred with low expression of Ki-67. In carcinomas, no association was found between FXR expression and Ki-67 and cyclin D1, respectively. Development of colon carcinoma in humans is associated with reduced FXR expression independent of site and may reflect an impaired defense against potentially carcinogenic bile acids along their intestinal gradient. In contrast to normal colon mucosa, FXR expression in carcinomas is not associated with low proliferation. Colon carcinomas with FXR expression seem to be associated with lower stage and a more favourable outcome compared to FXR negative carcinomas. PMID- 21780110 TI - Long-lasting immunoprotective and therapeutic effects of a hyperstable E7 oligomer based vaccine in a murine human papillomavirus tumor model. AB - Cervical cancer and many other anogenital and oropharyngeal carcinomas are strongly associated with high-risk human papillomavirus (HPV) persistent infections. HPV E7 oncoprotein is the major viral transforming factor, emerging as a natural candidate for immunotherapy, since it is constitutively expressed in HPV-induced cancer cells. We have previously shown that E7 can self-assemble into soluble and homogeneous spherical oligomers, named E7 soluble oligomers (E7SOs). These are highly resistant to thermal denaturation, providing an additional advantage given the demand for highly stable vaccine formulations. Here, we present a new chemically stabilized form of the E7SOs (E7SOx) and analyzed its effect in a murine HPV-tumor model. Vaccination of female mice with low doses of E7SOx combined with a CpG-rich oligonucleotide (ODN) as adjuvant elicits a strong long-lasting protection against E7-expressing tumor cells, preventing tumor outgrowth after rechallenge 90-days later. Therapeutic experiments showed that E7SOx/ODN vaccination significantly delays tumor growth and extends the time of survival of the treated mice in a dose-dependent manner. These proof-of-principle preclinical experiments denote the potential applicability of our E7SOx-based vaccine to the treatment of cervical cancer and other mucosal HPV-related neoplastic lesions. In addition to thermal, chemical and proteolysis stability, the combined recombinant and chemical modification nature of the E7SOx vaccine candidate, results in low-cost, of particular interest in developing countries, where most of the cervical cancer cases occur and the most affected population is at reproductive age. PMID- 21780112 TI - Novel insights in basic and applied stem cell therapy. AB - The achievement of novel findings in stem cell research were the subject of the meeting organized by Stem Cell Research Italy (SCR Italy) and by the International Society for Cellular Therapy-Europe (ISCT). Stem cell therapy represents great promise for the future of molecular and regenerative medicine. The use of several types of stem cells is a real opportunity to provide a valid approach to curing several untreatable human diseases. Before it is suitable for clinical applications, stem cell biology needs to be investigated further and in greater detail. Basic stem cell research could provide exact knowledge regarding stem cell action mechanisms, and pre-clinical research on stem cells on an in vivo model of disease provides scientific evidence for future human applications. Applied stem cell research is a promising new approach to handling several diseases. Along with tissue engineering, it offers a new and promising discipline that can help to manage human pathologies through stem cell therapy. All of these themes were discussed in this meeting, covering stem cell subtypes with their newest basic and applied research. PMID- 21780111 TI - Lack of association between common UGT2B nonsynonymous single-nucleotide polymorphisms and breast cancer in populations of African ancestry. PMID- 21780114 TI - Prognostic significance of osteopontin in hepatocellular carcinoma: a meta analysis. AB - Osteopontin (OPN) has been implicated in tumor development and progression for several years. However, the prognostic value of OPN overexpression in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta analysis to assess the relationship between OPN overexpression and clinical outcome of HCC. A meta-analysis of seven studies (1,158 patients) was carried out to evaluate the association between OPN and overall survival (OS) and disease free survival (DFS) in HCC patients. The correlation between OPN and tumor vascular invasion or other invasion-related parameters was also assessed. Data were synthesized with random effect model of DerSimonian and Laird, hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Our analysis results indicated that high OPN expression predicted poor OS (HR: 1.37, 95% CI: 1.21-1.55) and DFS (HR: 1.62, 95% CI: 1.24 2.11) of HCC. OPN overexpression tended to be associated with the presence of tumor vascular invasion (OR: 1.93, 95% CI: 0.97-3.84) and advanced tumor grade (OR: 1.74, 95% CI: 0.95-3.18). By this study, we conclude that OPN overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis. PMID- 21780113 TI - PED/PEA-15 controls fibroblast motility and wound closure by ERK1/2-dependent mechanisms. AB - Cell migration is dependent on the control of signaling events that play significant roles in creating contractile force and in contributing to wound closure. We evaluated wound closure in fibroblasts from mice overexpressing (TgPED) or lacking ped/pea-15 (KO), a gene overexpressed in patients with type 2 diabetes. Cultured skin fibroblasts isolated from TgPED mice showed a significant reduction in the ability to recolonize wounded area during scratch assay, compared to control fibroblasts. This difference was observed both in the absence and in the presence of mytomicin C, an inhibitor of mitosis. In time-lapse experiments, TgPED fibroblasts displayed about twofold lower velocity and diffusion coefficient, as compared to controls. These changes were accompanied by reduced spreading and decreased formation of stress fibers and focal adhesion plaques. At the molecular level, TgPED fibroblasts displayed decreased RhoA activation and increased abundance of phosphorylated extracellular signal regulated kinase 1/2 (ERK1/2). Inhibition of ERK1/2 activity by PD98059 restored RhoA activation, cytoskeleton organization and cell motility, and almost completely rescued wound closure of TgPED fibroblasts. Interestingly, skin fibroblasts isolated from KO mice displayed an increased wound closure ability. In vivo, healing of dorsal wounds was delayed in TgPED and accelerated in KO mice. Thus, PED/PEA-15 may affect fibroblast motility by a mechanism, at least in part, mediated by ERK1/2. PMID- 21780115 TI - Src family kinases regulate renal epithelial dedifferentiation through activation of EGFR/PI3K signaling. AB - Dedifferentiation, a process by which differentiated cells become mesenchymal like proliferating cells, is the first step in renal epithelium repair and occurs in vivo after acute kidney injury and in vitro in primary culture. However, the underlying mechanism remains poorly understood. In this report, we studied the signaling events that mediate dedifferentiation of proximal renal tubular cells (RPTC) in primary culture. RPTC dedifferentiation characterized by increased expression of vimentin concurrent with decreased expression of cytokeratin-18 was observed at 24 h after the initial plating of freshly isolated proximal tubules and persisted for 72 h. At 96 h, RPTC started to redifferentiate as revealed by reciprocal expression of cytokeratin-18 and vimentin and completed at 120 h. Phosphorylation levels of Src, epidermal growth factor receptor (EGFR), AKT (a target of phosphoinositide-3-kinase (PI3K)), and ERK1/2 were increased in the early time course of culture (<72 h). Inhibition of Src family kinases (SFKs) with PP1 blocked EGFR, AKT, and ERK1/2 phosphorylation, as well as RPTC dedifferentiation. Inhibition of EGFR with AG1478 also blocked AKT and ERK1/2 phosphorylation and RPTC dedifferentiation. Although inactivation of the PI3K/AKT pathway with LY294002 inhibited RPTC dedifferentiation, blocking the ERK1/2 pathway with U0126 did not show such an effect. Moreover, inhibition of SFKs, EGFR, PI3K/AKT, but not ERK1/2 pathways abrogated RPTC outgrowth and SFK inhibition decreased RPTC proliferation and migration. These findings demonstrate a critical role of SFKs in mediating RPTC dedifferentiation through activation of the EGFR/PI3K signaling pathway. PMID- 21780117 TI - The impact of decreased bead count to determine concentrations of amyloid beta1 42, total-tau, and phosphorylated-tau181 in human cerebrospinal fluid using xMAP technology. AB - Alzheimer's disease is the leading cause of human dementia. The lack of diagnostic tests and limited therapeutic options has driven the search for endogenous biomarkers. The INNO-BIA AlzBio3 assay is a multiplex flow-based immunoassay measuring Abeta42, tau, and p-tau in cerebrospinal fluid (CSF). This study assesses assays performance under varying bead count (BC) parameters. Original method validation parameters at 100 BC were acceptable. Reanalyses performed at 3, 10, 25, and 50 BCs were compared to 100 BC data by ANOVA, Bland Altman analysis, evaluation of concordance correlation coefficients, and frequency distribution of coefficient of variation (CV) ranges. Method validation characteristics were acceptable with 100 BCs. Equivalency for 25 and 50 versus 100 BCs was demonstrated, but not for 3 and 10 BCs. A general trend of decreasing agreement between decreasing BCs and the 100 BC reference resulted in decreases in concordance coefficients rho(c) . The frequency of CV values greater than 20% increased with decreasing BCs, and CV values of 5% or less decreased with decreased BCs. Statistical analyses demonstrate that BCs of 3 and 10 are not equivalent with the reference and should not be used as a basis for determination of Abeta42, tau, and p-tau concentration in human CSF. PMID- 21780116 TI - Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells. AB - Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda 7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3 mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients. PMID- 21780118 TI - Secure and effective gene vector of polyamidoamine dendrimer pharmaceutically modified with anionic polymer. AB - The purpose of this study was to develop a new type of gene vector, polyamidoamine (PAMAM) dendriplex pharmaceutically modified, based on electrostatic interactions, by various anionic polymers. The gamma-polyglutamic acid (gamma-PGA)/PAMAM dendriplex and the alpha-PGA/PAMAM dendriplex formed a stable complex, although alpha-polyaspartic acid and heparin released pDNA from the complex. The addition of anionic polymer decreased the zeta-potential, although it did not greatly affect the size of the complex. As a result of an in vitro gene expression study of mouse melanoma cells, we found that the gamma PGA/PAMAM dendriplex showed high gene expression comparable to the PAMAM dendriplex, although the alpha-PGA/PAMAM dendriplex showed lower gene expression. Tail vein injection of the gamma-PGA/PAMAM dendriplex into mice also led to high gene expression in the spleen and lung. The gamma-PGA/PAMAM dendriplex showed no cytotoxicity and no agglutination, although severe cytotoxicity and agglutination were observed in the PAMAM dendriplex. Thus, we discovered that complexes of pDNA, PAMAM dendrimers, and gamma-PGA showed higher gene expression in vitro and in vivo, and markedly lower toxicity. This complex is valuable and is expected to be a safe and effective gene vector. PMID- 21780119 TI - Demonstrating the stability of albinterferon alfa-2b in the presence of silicone oil. AB - Silicone oil is often used to decrease glide forces in prefilled syringes and cartridges, common primary container closures for biopharmaceutical products. Silicone oil has been linked to inducing protein aggregation (Diabet Med 1989;6:278; Diabet Care 1987;10:786-790), leading to patient safety and immunogenicity concerns. Because of the silicone oil application process (Biotech Adv 2007;25:318-324), silicone oil levels tend to vary between individual container closures. Various silicone oil levels were applied to a container closure prior to filling and lyophilization of an albumin and interferon alfa-2b fusion protein (albinterferon alfa-2b). Data demonstrated that high silicone oil levels in combination with intended and stress storage conditions had no impact on protein purity, higher order structure, stability trajectory, or biological activity. Subvisible particulate analysis (1-10 um range) from active and placebo samples from siliconized glass barrels showed similar particle counts. Increases in solution turbidity readings for both active and placebo samples correlated well with increases in silicone oil levels, suggesting that the particles in solution are related to the presence of silicone oil and not large protein aggregates. Results from this study demonstrate that silicone oil is not always detrimental to proteins; nevertheless, assessing the impact of silicone oil on a product case-by-case basis is still recommended. PMID- 21780120 TI - Impact of heat treatment on the physical properties of noncrystalline multisolute systems concentrated in frozen aqueous solutions. AB - The purpose of this study was to elucidate the effect of heat treatment on the miscibility of multiple concentrated solutes that mimic biopharmaceutical formulations in frozen solutions. The first heating thermal analysis of frozen solutions containing either a low-molecular-weight saccharide (e.g., sucrose, trehalose, and glucose) or a polymer (e.g., polyvinylpyrrolidone and dextran) and their mixtures from -70 degrees C showed a single transition at glass transition temperature of maximally freeze-concentrated solution (T(g) ') that indicated mixing of the freeze-concentrated multiple solutes. The heat treatment of single solute and various polymer-rich mixture frozen solutions at temperatures far above their T(g) ' induced additional ice crystallization that shifted the transitions upward in the following scan. Contrarily, the heat treatment of frozen disaccharide-rich solutions induced two-step heat flow changes (T(g) ' splitting) that suggested separation of the solutes into multiple concentrated noncrystalline phases, different in the solute compositions. The extent of the T(g) ' splitting depended on the heat treatment temperature and time. Two-step glass transition was observed in some sucrose and dextran mixture solids, lyophilized after the heat treatment. Increasing mobility of solute molecules during the heat treatment should allow spatial reordering of some concentrated solute mixtures into thermodynamically favorable multiple phases. PMID- 21780121 TI - Effects of normothermic hepatic ischemia-reperfusion injury on the in vivo, isolated perfused liver, and microsomal disposition of chlorzoxazone, a cytochrome P450 2E1 probe, in rats. AB - In vitro studies have shown that the activities of cytochrome P450 (P450) enzymes may be altered after hepatic ischemia-reperfusion (IR) injury. Here, we investigated the effects of 1 h of partial ischemia, followed by 3 (IR3) or 24 (IR24) h of in vivo reperfusion, on the in vivo, isolated perfused rat liver (IPRL), and microsomal disposition of chlorzoxazone (CZX) and its cytochrome P450 2E1 (CYP2E1)-mediated metabolite, 6-hydroxychlorzoxazone (HCZX), in rats. Although IR3 caused a 30% reduction in the in vivo clearance of CZX, the area under the plasma concentration-time curve of HCZX was not affected. IPRL experiments showed that IR3, in addition to a 30% reduction in the clearance of CZX, causes a 70% decrease in the biliary clearance of HCZX. Microsomal data revealed a 50% decline in the intrinsic clearance of HCZX formation due to an IR3 induced significant decline in maximum velocity. Although IR3 did not affect the microsomal CYP2E1 protein, it caused approximately 30% reduction in the cytochrome P450 reductase activity. IR24 did not have any effect on the disposition of CZX or HCZX. In conclusion, metabolism of xenobiotics and endogenous compounds that are substrates for CYP2E1, and possibly other P450 isoenzymes, may be reduced shortly after surgical procedures that require transient interruption of the hepatic blood flow. PMID- 21780122 TI - A convenient method to measure blood-plasma concentration ratio using routine plasma collection in in vivo pharmacokinetic studies. AB - A practical time-saving method of determination of equilibrium blood-plasma concentration ratio is described. The method is based on the analysis of compound plasma concentrations in regular blood sample and the blood sample diluted with blank plasma. Since only plasma concentrations are analyzed, the method can be conveniently applied in routine pharmacokinetic studies with minimal additional work for obtaining blood-plasma ratio. The method can also be easily used in in vitro experiment. The results obtained by suggested method are in good agreement with that obtained by common in vitro measurements of blood-plasma ratio. PMID- 21780123 TI - Editorial: human genome information. PMID- 21780124 TI - Outcomes of elderly patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal cancer peritoneal carcinomatosis. AB - BACKGROUND: The combined treatment of cytoreductive surgery (CRS) and perioperative chemotherapy (PIC) for colorectal peritoneal carcinomatosis (PC) is a rigorous surgical treatment most suited for fit and young patients. With technical maturity and improved perioperative care, we examined the outcomes of elderly patients undergoing CRS and PIC for colorectal PC. METHODS: All consecutive patients treated in two tertiary centers for PC of colorectal cancer who were 70 years of age or older at the time of surgery were included. Data on patient characteristics, concomitant diseases, operation details, perioperative course, and follow-up were retrieved from medical charts. Primary outcomes were perioperative morbidity and mortality. Secondary outcomes were disease-free and overall survival. RESULTS: Twenty-four patients (11 male) were included in this study (mean age 73.5 years). In eight patients major complications occurred. In six patients the postoperative course was complicated by minor adverse events. There was no perioperative mortality. Median overall survival was 35 months with a 6, 12, and 18 months survival rate of 94%, 83%, and 68%, respectively. CONCLUSIONS: CRS and PIC for colorectal PC may be safely performed with acceptable morbidity in selected elderly patients. When considering patients for surgery, performance status, and the disease extent should be used as eligibility criteria rather than age. PMID- 21780125 TI - REGIV as a potential biomarker for peritoneal dissemination in gastric adenocarcinoma. AB - BACKGROUND: This study examined the clinical significance of regenerating islet derived family member 4 (REGIV) in surgically resected gastric tumors. The potential of REGIV as a biomarker in gastric cancer was also assessed including its predictive value for prognosis and recurrence after surgery. METHODS: Immunohistochemistry was performed to assess the clinical significance of REGIV expression status in surgically resected specimens. The quantitative genetic diagnostic method, transcription-reverse transcription concerted reaction (TRC) that targeted REGIV mRNA was applied for prediction of peritoneal recurrence in gastric cancer. RESULTS: Positive immunostaining for REGIV was observed in 85 cases (52.5%), and correlated significantly with diffuse type histopathology (P = 0.001), advanced T stage (P = 0.022), and frequent peritoneal recurrence (P = 0.009). Multivariate analysis identified advanced T stage (P < 0.001) and REGIV expression (P = 0.034) as independent prognostic factors for peritoneal recurrence-free survival. Overexpression of REGIV protein was evident in the majority of peritoneal tumors (93.8%). REGIV mRNA assessed by TRC could be a predictive marker for peritoneal recurrence after curative operation. CONCLUSIONS: REGIV overexpression is common in primary gastric tumors and a potentially suitable marker of diffuse type histopathology and peritoneal dissemination. Overexpression of REGIV mRNA, assessed by the TRC method, is a potentially suitable marker of peritoneal recurrence after curative resection. PMID- 21780126 TI - Mesothelin expression correlates with prolonged patient survival in gastric cancer. AB - PURPOSE: Mesothelin expression is found in normal mesothelium, and cancerous mesothelin has been recently reported in ovarian and pancreas cancer. The clinicopathological implications of mesothelin expression have been discussed with respect to antitumor immunological mechanisms. However, there is no information on mesothelin expression in gastric cancer. The purpose of the current study is to identify the clinical significance of mesothelin in gastric cancer. EXPERIMENTAL DESIGN: A total of 212 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were enrolled in this study. Mesothelin was detected immunohistochemically and visualized by ABC method. Intensity of cancerous mesothelin was divided into two categories (0-50%: negative group and 51-100%: positive group). RESULTS: Mesothelin expression was detected in the cellular membrane. In accordance with the previous evaluation, patients were divided into two groups [mesothelin-positive group: 124 (59%) and mesothelin-negative group: 88 (41%)]. The mesothelin-positive group had significantly more nodal involvement and significantly deeper tumor invasion than the mesothelin-negative group (P < 0.05). However, by analysis confined to the 117 advanced gastric cancer patients, the 5-year survival rate of the mesothelin positive group was 55%, which was significantly better than that of the mesothelin-negative group. Multivariate analysis revealed that mesothelin expression is one of the independent prognostic factors of gastric cancer. CONCLUSION: Cancerous mesothelin expression in gastric cancer may be a useful tool to predict patient survival. PMID- 21780127 TI - Indication for relumpectomy--a useful scoring system in cases of invasive breast cancer. AB - BACKGROUND AND OBJECTIVES: In two-thirds of breast cancer patients undergoing reoperation no residual tumor will be found. A scoring system for selection of patients who might benefit from relumpectomy is proposed. METHODS: This study is based on 293 patients with invasive breast cancer undergoing reoperation due to margins of <2 mm. Eighteen parameters were evaluated by univariate and multivariate stepwise logistic regression. RESULTS: Univariate analysis identified nine parameters associated with a residual invasive tumor: surgical margins; lobular histological type; grade 3; multifocality; positive lymph modes; non-fine needle localization (FNL) versus FNL lumpectomy; vascular/lymphatic invasion; age <50 years; and tumor size >=3 cm. Multivariate stepwise logistic regression study identified six out of nine parameters associated with a higher probability of finding a residual invasive tumor: margins <1 mm, multifocality, tumor size >=3 cm, positive lymph nodes, age <50 years, and lumpectomy without previous FNL. Odds of these factors were used for scoring. CONCLUSIONS: For patients with surgical margins <2 mm and a score of <4, the probability of finding a residual invasive tumor is 0%, while the probability of finding a microfocus of <2 mm of invasive carcinoma is 3.2% and of finding residual DCIS is up to 10%. PMID- 21780128 TI - The relationship between RGS5 expression and cancer differentiation and metastasis in non-small cell lung cancer. AB - BACKGROUND: Regulator of G-protein signaling 5 (RGS5), a tissue-specific signal regulating molecular, plays important roles in the development of vasculature. Recently, we have found that the mRNA level of RGS5 was oppositely related with tumor metastasis in non-small cell lung cancer (NSCLC). However, the distribution of RGS5 in NSCLC and its significance need further study. We therefore investigated the expression of RGS5 in NSCLC, as well as its relationship with clinicopathologic parameters. METHODS: Tumor tissues from 51 NSCLC patients were analyzed and expression of RGS5 in tumor tissues was examined by immunohistochemistry. Chi-square test (or Fisher's exact test), Breslow test and multivariate Cox regression model were performed for statistical analysis. RESULTS: RGS5 were highly expressed in 47% (24/51) of NSCLC specimens. Expression of RGS5 was associated with tumor cell differentiation in NSCLC and low expression of RGS5 was strongly associated with cancer vasculature invasion and lymph node metastasis in NSCLC. Patients with high RGS5 expression in NSCLC had a prolonged progression free survival (15.0 months (95%CI: 6.1-23.9) vs. 6.0 months (95%CI: 1.3-10.7), P = 0.030). CONCLUSION: RGS5 might be involved in cancer differentiation and metastasis in NSCLC. And it might be a candidate prognostic marker for PFS in NSCLC. PMID- 21780129 TI - Relationship of interleukin-8 gene polymorphisms with hepatocellular carcinoma susceptibility and pathological development. AB - BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and the second leading cause of death from cancer in Taiwan. Interleukin-8 (IL-8) is an angiogenic chemokine with important roles in the development and progression of many human malignancies including HCC. This study investigates the effects of single-nucleotide polymorphisms (SNPs) in the IL-8 gene on the susceptibility and clinicopathological characteristics of HCC. METHODS: One hundred thirty-one HCC patients and 340 control subjects were analyzed for four IL-8 SNPs (-251 T/A, +781 C/T, +1633 C/T, and +2767 A/T) using PCR-RFLP genotyping analysis. RESULTS: After adjusting for other confounders, results show that individuals with the IL 8 +781 T/T polymorphic genotype had a significantly lower risk of developing HCC than those with the wild-type (C/C) genotype (AOR = 0.346; 95% CI: 0.132-0.909). Multiple regression analysis showed that the presence of T/A or A/A at IL-8 -251 may indicate higher potential risk of hepatitis B infection (AOR = 2.847; 95% CI: 1.083-8.656). Additionally, these four IL-8 SNPs did not associate with liver related clinicopathological markers in serum. CONCLUSIONS: Genetic polymorphism at IL-8 +781 is an important factor in determining susceptibility to HCC in the Taiwanese population. PMID- 21780130 TI - Multidrug resistance reversal effect of DMC derived from buds of Cleistocalyx operculatus in human hepatocellular tumor xenograft model. AB - BACKGROUND: Multidrug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. 2',4'-Dihydroxy-6'-methoxy 3',5'-dimethylchalcone (DMC) isolated from the buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), was investigated for its reversal effects on cancer cell MDR. RESULTS: A human hepatocellular tumor xenograft model was established with the BEL-7402/5-FU cell line. Combined 5-fluorouracil (5-FU) and DMC (40 mg kg(-1) ) treatment significantly elevated tumor inhibition rate to 72.2%. DMC could also increase 5-FU concentrations in tumor tissues and increase caspase-3 activity. Also, combined therapy resulted in enhanced tumor apoptotic and reduced proliferative activities relative to 5-FU alone. Examining body weight and other signs of unwanted toxicity of the different treatment groups revealed no significant signs of adverse effects. CONCLUSION: All results suggested that DMC reverses 5-FU resistance, with a benign side effects profile. PMID- 21780131 TI - Effect of genotype and environment on the concentrations of starch and protein in, and the physicochemical properties of starch from, field pea and fababean. AB - BACKGROUND: The effects of genotype and environment and their interaction on the concentrations of starch and protein in, and the amylose content and thermal and pasting properties of starch from, pea and fababean are not well known. RESULTS: Differences due to genotype were observed in the concentrations of starch and protein in pea and fababean, in the onset temperature (To) and peak temperature (Tp) of gelatinization of fababean starch, and in the pasting, trough, cooling and final viscosities of pea starch and fababean starch. Significant two-way interactions (location * genotype) were observed for the concentration of starch in fababean and the amylose content, To, endothermic enthalpy of gelatinization (DeltaH) and trough viscosity of fababean starch. Significant three-way interactions (location * year * genotype) were observed for the concentration of starch in pea and the pasting, trough, cooling and final viscosities of pea starch. CONCLUSION: Differences observed in the concentrations of starch and protein in pea and fababean were sufficient to be of practical significance to end-users, but the relatively small differences in amylose content and physicochemical properties of starch from pea and fababean were not. PMID- 21780132 TI - Determination of optimum harvest maturity and physico-chemical quality of Rastali banana (Musa AAB Rastali) during fruit ripening. AB - BACKGROUND: A series of physico-chemical quality (peel and pulp colours, pulp firmness, fruit pH, sugars and acids content, respiration rate and ethylene production) were conducted to study the optimum harvest periods (either week 11 or week 12 after emergence of the first hand) of Rastali banana (Musa AAB Rastali) based on the fruit quality during ripening. RESULT: Rastali banana fruit exhibited a climacteric rise with the peaks of both CO(2) and ethylene production occurring simultaneously at day 3 after ripening was initiated and declined at day 5 when fruits entered the senescence stage. De-greening was observed in both of the harvesting weeks with peel turned from green to yellow, tissue softening, and fruits became more acidic and sweeter as ripening progressed. Sucrose, fructose and glucose were the main sugars found while malic, citric and succinic acids were the main organic acids found in the fruit. CONCLUSION: Rastali banana harvested at weeks 11 and 12 can be considered as commercial harvest period when the fruits have developed good organoleptic and quality attributes during ripening. However, Rastali banana fruit at more mature stage of harvest maturity taste slightly sweeter and softer with higher ethylene production which also means the fruits may undergo senescence faster than fruit harvested at week 11. PMID- 21780133 TI - Wheat- and barley-based diets with or without additives influence broiler chicken performance, nutrient digestibility and intestinal microflora. AB - BACKGROUND: To our knowledge, there is scant literature on comparative broiler response to cereal diets high in soluble non-starch polysaccharides without or with enzyme, prebiotic, probiotic or synbiotic supplementation. In the present study, the effects of a wheat- and barley-based diet with or without supplemental xylanase plus beta-glucanase, inulin, Enterococcus faecium or inulin plus Enterococcus faecium, on bird performance, digesta viscosity, nutrient digestibility and intestinal microflora were compared to a maize-based diet. RESULTS: In comparison to a maize-based diet, the wheat- and barley-based diet reduced (P < 0.05) body weight gain and feed intake, but did not affect to the feed-to-gain ratio. Apparent digestibility of crude fat and various fatty acids were decreased (P < 0.05) as well as apparent metabolisable energy corrected to zero nitrogen retention content. There was an increase (P < 0.05) in the viscosity of jejunal digesta and in the caecal numbers of Escherichia coli and lactobacilli, and a decrease in the ileal numbers of E. coli and lactobacilli. Performance parameters and nutrient digestibility were not affected (P > 0.05) by dietary inclusion of the additives used, with the exception that exogenous enzyme improved (P < 0.05) the apparent digestibility of crude fat and decreased the viscosity of jejunal digesta. Enzyme and Enterococcus faecium supplementation increased intestinal lactic acid bacteria, whereas inulin addition reduced the number of E. coli (P < 0.05). Addition of inulin-Enterococcus faecium decreased E. coli and increased bifidobacteria numbers in the caeca. CONCLUSION: Enzyme supplementation to a wheat- and barley-based diet significantly improved the apparent digestibility of dietary fat. All four additives had a beneficial effect on the intestinal microflora of broilers. PMID- 21780134 TI - Induction of mud crab (Scylla paramamosain) tropomyosin and arginine kinase specific hypersensitivity in BALB/c mice. AB - BACKGROUND: Shellfish hypersensitivity is among the most common food allergies. The allergens tropomyosin (TM) and arginine kinase (AK) from mud crab (Scylla paramamosain) were purified to homogeneity. BALB/c female mice were sensitized with TM and AK by intragastric administration. Mice treated with normal saline served as the negative control (NC) group. RESULTS: Compared with NC group, mice that were treated with TM and AK developed reduced activity; meanwhile, their scratching behavior and specific-IgE level were increased. Specific-CD4 + T cells were significantly elevated in the splenocyte cultures of the mice upon TM and AK stimulation. However, compared with the positive control group (ovalbumin, OVA), there was no significant difference. The expression of IL-4 in culture cells stimulated by TM, AK, and OVA group showed significant differences from the NC group, respectively. CONCLUSION: These results indicated that a BALB/c mouse model for sensitization to TM and AK from mud crab was successfully established, and the Th2 response was observed, displaying increased immunoglobulin E levels, together with the production of interleukin 4 and allergic symptoms. PMID- 21780135 TI - Polyunsaturated fatty acid levels in rat tissues after chronic treatment with dietetic oils. AB - BACKGROUND: The essential fatty acids can be helpful in the prevention of several pathologies. The purpose of this study was to quantify the major n-3 and n-6 fatty acids in tissues of rats fed with flaxseed oil and with a dietetic oil in order to evaluate how their chronic supplementation could influence the correspondent in vivo levels and to study the effectiveness of the dietetic oil compared to flaxseed oil. RESULTS: Fatty acids were successfully extracted from biological samples, subjected to derivatization procedure and analysed by high performance liquid chromatography with UV detection under gradient elution mode. The developed method showed good linearity, precision and accuracy, with recoveries ranging from 89% to 92%. Animals treated with flaxseed and dietetic oils showed enhanced levels of n-3 fatty acids compared to control groups, with significantly higher levels of eicosapentaenoic acid and docosahexaenoic acid in the brain and in the adipose tissue of the dietetic group compared to the flaxseed group. CONCLUSION: The obtained data underline that the tested oils can effectively enhance the tissue levels of n-3 fatty acids and therefore they could be successfully used in the dietetic treatment of lipid-related diseases. PMID- 21780136 TI - Enhancing aspalathin stability in rooibos (Aspalathus linearis) ready-to-drink iced teas during storage: the role of nano-emulsification and beverage ingredients, citric and ascorbic acids. AB - BACKGROUND: The effects of citric and ascorbic acids on the stability of aspalathin in rooibos (Aspalathus linearis) ready-to-drink (RTD) formulations containing fermented rooibos extract (FR), aspalathin-enriched green rooibos extract (GR) and aspalathin-enriched green rooibos extract ascorbic acid solubilisate (GR-solubilisate) were investigated during storage (12 weeks at 25 degrees C). RESULTS: Storage of iced tea formulations containing FR and GR extracts reduced their flavonoid content. The aspalathin content of FR iced tea without citric or ascorbic acid was reduced to undetectable levels by week 8 of storage. Addition of citric acid resulted in improved stability of aspalathin, but ascorbic acid did not impart additional stability. Iso-orientin and orientin were less affected than aspalathin, presumably owing to partial conversion of aspalathin to these flavones. Similar results were obtained for GR iced tea formulations. Improved stability of aspalathin was noted in iced tea containing GR-solubilisate with or without citric acid. Lower pH was shown to favour stability, especially for fermented rooibos iced teas. CONCLUSION: Citric and ascorbic acids contribute to the stability of rooibos flavonoids during storage. Differences in stability between formulations are not due to pH differences but may be related to the matrix. PMID- 21780137 TI - Usefulness of tissue Doppler imaging-myocardial performance index in the evaluation of diastolic dysfunction and heart failure with preserved ejection fraction. AB - BACKGROUND: In heart failure with preserved ejection fraction (HFPEF), physiological abnormalities are not solely restricted to diastolic function. Because the tissue Doppler imaging (TDI)-derived myocardial performance index (MPI) offers the advantage of recording systolic and diastolic tissue velocity simultaneously in the same cardiac cycle, this study aimed to determine whether TDI-MPI is an informative index for assessing HFPEF, compared with conventional echo parameters. HYPOTHESIS: In patients with HFPEF, TDI-MPI would be an independent predictor for adverse cardiac events. METHODS: Among 408 patients who had diastolic dysfunction without heart failure (HF) or HFPEF, cardiac function was evaluated by mitral flow (MF) or TDI-MPI. During the median follow-up of 32 months, clinical outcomes, which were defined as the composite of cardiovascular death and admission for HF, were assessed. RESULTS: Mean MF and TDI-MPI were significantly greater in the HFPEF group. TDI-MPI rather than MF had a significant correlation with N-terminal pro-brain natriuretic peptide level. The area under the receiver operating characteristic curve of TDI-MPI for the detection of HFPEF was 0.86. With regard to clinical outcomes, 31 events were identified during follow-up periods. On a multivariate analysis, TDI-MPI >0.66 was the best prognostic predictor of events and provided incremental predictive value. CONCLUSIONS: Compared to MF-MPI, TDI-MPI may be a more useful parameter for the evaluation of patients with HFPEF. PMID- 21780139 TI - Diversity analysis of type I ketosynthase in rhizosphere soil of cucumber. AB - Fusarium wilt [Fusarium oxysporum (Sch1.) f.sp. cucumerinum Owen.] is a major soil-borne disease of cucumber worldwide, and can cause huge yield losses. Biological control of Fusarium wilt of cucumber has received considerable attention. Many bacteria, particularly actinomycetes, are known to produce secondary metabolites synthesized by Polyketide synthases (PKSs) with a diverse range of biological activities. Ketosynthase (KS) gene diversity was analyzed in samples which were collected from rhizosphere soil of both diseased cucumber and healthy cucumber in Dalian, China. The phylogenetic analysis amino acid (AA) sequences indicated that the KS genes in the rhizosphere soil samples were clustered into diverse seven clades, including Sorangium cellulosum, Anabaena variabilis, Nostoc punctiforme, Xanthobacter autotrophicus, Streptomyces, myxobacteria and uncultured bacteria. Among seven major clades in the phylogenetic tree, two clades were peculiar to rhizosphere soil of diseased cucumber and one was peculiar to healthy cucumber. Among the 182 cloned KS genes, 147 KS genes were clustered with the uncultured bacteria group. Most of the KS genes showed about 80% similarity at the AA level to sequences known in GenBank. These results revealed the great diversity and novelty of KS genes in rhizosphere soil of cucumber. PMID- 21780138 TI - Effect of phosphodiesterase type 5 inhibition on microvascular coronary dysfunction in women: a Women's Ischemia Syndrome Evaluation (WISE) ancillary study. AB - BACKGROUND: Microvascular coronary dysfunction (MCD) is associated with symptoms and signs of ischemia, and also adverse outcomes in women without macrovascular obstructive coronary artery disease (M-CAD). Although MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined. HYPOTHESIS: Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women. METHODS: The subjects were 23 symptomatic women (age 54 +/- 11 y) participating in an ancillary study of the Women's Ischemia Syndrome Evaluation with baseline CFR <=3.0 (Doppler flow wire and intracoronary adenosine) and without M-CAD. Coronary flow reserve was remeasured 45 minutes after PDE-5 inhibition (100 mg oral sildenafil). The primary measure of interest was change in CFR adjusted for baseline variables. RESULTS: The relationship between log(2)-transformed CFR post PDE-5 inhibition (adjusted) and baseline was different from the line of identity (slope: 0.55 vs 1.0, P = 0.008; intercept: 0.73 vs 0.0, P = 0.01), indicating that PDE-5 inhibition improves CFR and the lower the baseline CFR, the greater the response. Among women with baseline CFR <=2.5 (n = 11), CFR increased from 2.1 +/- 0.2 to 2.7 +/- 0.6 (P = 0.006). For women with baseline CFR >2.5 (n = 12), CFR did not change (3.1 +/- 0.3 to 3.0 +/- 0.6; P = 0.70). CONCLUSIONS: For women with symptoms and signs of ischemia and no M-CAD, PDE-5 inhibition is associated with acute improvement in CFR, and the effect concentrates among those with CFR <=2.5. If these acute effects are sustained, then PDE-5 inhibition would provide a rational strategy for management of MCD in symptomatic women without M CAD. The longer-term effects warrant study in a randomized trial using a sustained-acting PDE-5 inhibitor. PMID- 21780140 TI - Purification and characterization of a protease produced by Bacillus megaterium RRM2: application in detergent and dehairing industries. AB - An alkaline serine protease produced by Bacillus megaterium RRM2 isolated from the red alga, Kappaphycus alvarezii (Doty) Doty ex Silva was studied for the first time and the same analyzed for the production of protease in the present study. Identification of the bacterium was done on the basis of both biochemical analysis and by 16S rDNA sequence analysis. The extracellular protease obtained from B. megaterium RRM2 was purified by a three-step process involving ammonium sulphate precipitation, gel filtration (Sephadex G100) and Q-Sepharose column chromatography. The purity was found to be 30.6-fold with a specific activity of 3591.5 U/mg protein with a molecular weight of 27 kDa. The metal ions Ca(2+), Mg(2+), K(+) and Na(+) marginally enhanced the activity of the purified enzyme while Hg(2+), Cu(2+), Fe(2+), CO(2+) and Zn(2+), had reduced the activity. The enzyme was found to be active in the pH range of 9.0-10.0 and remained active up to 60 degrees C. Phenyl Methyl Sulfonyl Fluoride (PMSF) inhibited the enzyme activity, thus, confirming that this enzyme is an alkaline serine protease. Likewise, DTT also inhibited the enzyme thus confirming the disulfide nature of the enzyme. The enzyme exhibited a high degree of tolerance to Sodium Dodecyl Sulphate (SDS). The partially purified protease when used as an additive in the commercial detergents was found to be a suitable source for washing clothes especially those stained with blood. Further, it showed good dehairing activity within a short duration in goat skin without affecting its collagen component. PMID- 21780141 TI - Transesterification of used edible and non-edible oils to alkyl esters by Aspergillus sp. as a whole cell catalyst. AB - Aspergillus sp. (MTCC 5436), isolated from contaminated clarified butter was used as a whole cell catalyst for transesterification of oils from different sources. The strain was observed to be tolerant and grow in 90% oil as carbon source. Oils of Jathropa, karanj and spent cottonseed were used as carbon sources in the study. The product, alkyl ester, was characterized and quantified using (1) H NMR. The strain was observed to facilitate transesterification in an oil:minimal medium with the ratio of 70:30 resulting in a 98% conversion of oil to ethyl esters within 48 h at 28 degrees C and 120 rpm. The physico-chemical characteristics of the ethyl ester (>98%) at 70% oil as carbon source were similar to the standards specified for biodiesel as per standards of American Society for Testing and Materials (ASTM) and Bureau of Indian Standards (BIS), India. PMID- 21780142 TI - Cloning and characterization of the gene for the iron-sulfur subunit of succinate dehydrogenase from the violet root rot fungus, Helicobasidium mompa. AB - The sdhB gene, encoding the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (Sdh, EC 1.3.99.1), has been cloned from the violet root rot fungus, Helicobasidium mompa, and characterized. The promoter region contains a CCAAT box, TATA-like box, and CT-rich region. The gene is interrupted by eight introns and is predicted to encode a polypeptide of 291 amino acid residues. The putative amino acid sequence of the encoded product of sdhB gene from H. mompa shows high homology to the other known sdhB genes and is 79% identical to the Ip subunit of SdhB of Uromyces fabae. Three cysteine-rich clusters associated with the iron-sulfur centers involved in electron transport were particularly well conserved. One of these clusters contains a critical histidine residue implicated in carboxin sensitivity in the basidiomycetes. Only one copy of the gene was present in the genome of H. mompa, and reverse transcription (RT)-PCR analysis of mRNA expression showed that the sdhB gene was transcribed in potato dextrose broth. PMID- 21780143 TI - Production of 2,3-butanediol from glucose by GRAS microorganism Bacillus amyloliquefaciens. AB - In the current study, a GRAS (Generally Recognized As Safe) strain of Bacillus amyloliquefaciens producing 2,3-butanediol (2,3-BD) designated as B10-127 was isolated in our lab. The strain B10-127 produced 2,3-BD effectively under the condition of 20% glucose (quality concentration), showed a high-glucose tolerance. The effects of initial glucose concentration, temperature, pH and agitation on 2,3-BD production were investigated in this work and the proper parameters were identified. Accordingly, the fed-batch culture of B10-127 in larger scales (5 l) showed a remarkable 2,3-BD producing potency. The maximum 2,3 BD concentration reached 92.3 g/l at 96 h with a 2,3-BD productivity of 0.96 g/l h. To our knowledge, the results were new records on 2,3-BD fermentation by Bacillus, which shown an excellent candidate for the microbial fermentation of 2,3-BD on an industrial scale. PMID- 21780145 TI - Surveillance of single-cell behavior in different subpopulations of Ralstonia pickettii AR1 during growth and polyhydroxybutyrate production phases by flow cytometry. AB - Most bacterial strains accumulate intracellular polyhydroxybutyrate (PHB) granules as an energy reservoir, in response to fluctuations in their microenvironment. Flow cytometry was applied for the analysis of single cells of Ralstonia pickettii AR1 in response to changes in the culture conditions. Two parameters, the PHB production-related FL2 and side scatter (SSC) parameters, were used to monitor, distinguish and characterize different subpopulations in the growth and PHB production phases. A high SSC level was observed in the mid log exponential growth phase. When the nitrogen source reached a limiting level, the SSC started to decrease, in contrast to the intracellular PHB granules related FL2 parameter. The results show that ammonium limitation is a critical and important factor for the accumulation of reserve compounds. Four subpopulations were observed and distinguished upon entrance of the cells into the exponential growth phase. When the cells entered the late exponential growth or early stationary phase, two subpopulations had disappeared and only two, different subpopulations were dominant. One of the subpopulations with changed SSC and PHB production activity switched to another subpopulation that was only active in PHB production in the stationary phase. The whole cells of R. pickettii AR1 tended to form a homogeneous population at the end of the stationary phase. In fact, the changes in the subpopulations of a single strain are related to different physiological states of the cells. The observation of different subpopulations suggests that each subpopulation shows a specific response to changes in the surrounding microenvironment, nutrients and limiting factors. PMID- 21780144 TI - The small molecular mass antifungal protein of Penicillium chrysogenum--a mechanism of action oriented review. AB - The beta-lactam producing filamentous fungus Penicillium chrysogenum secretes a 6.25 kDa small molecular mass antifungal protein, PAF, which has a highly stable, compact 3D structure and is effective against a wide spectrum of plant and zoo pathogenic fungi. Its precise physiological functions and mode of action need to be elucidated before considering possible biomedical, agricultural or food technological applications. According to some more recent experimental data, PAF plays an important role in the fine-tuning of conidiogenesis in Penicillium chrysogenum. PAF triggers apoptotic cell death in sensitive fungi, and cell death signaling may be transmitted through two-component systems, heterotrimeric G protein coupled signal transduction and regulatory networks as well as via alteration of the Ca(2+) -homeostasis of the cells. Possible biotechnological applications of PAF are also outlined in the review. PMID- 21780146 TI - Cloning and transcription analysis of the Candida rugosa propionyl-CoA dehydrogenase gene and its expression in Pichia pastoris. AB - The propionyl-CoA dehydrogenase (PACD) gene was cloned from Candida rugosa by the cDNA RACE technique. The full cDNA of the PACD gene has a length of 1408 bp, which contains a complete open reading frame (ORF) of 1329 bp, coding for 442 amino acids. The cDNA of PACD was cloned into the expression plasmid pPIC9K and transformed into Pichia pastoris GS115. The recombinant protein was purified by Ni-NTA affinity chromatography, and its size was observed to be approximately 49 kDa as estimated by SDS-PAGE. Anti-His antibodies were used to characterise the recombinant PACD by western-blot analysis. The recombinant protein retained the activity of catalysing propionyl-CoA to acryloyl-CoA. The results of dot-blotting hybridisation using a PACD cDNA probe indicated that the PACD mRNA level was modified at different stages: mRNA levels were low for the first 36 h, then increased through 48 h and eventually reached a stable level. These results indicate that propionate induction could significantly activate PACD mRNA expression. Information from this study will be helpful in elucidating the metabolic pathway for 3-hydroxypropionic acid production in C. rugosa. PMID- 21780147 TI - Bacterial communities in the gut of the freshwater copepod Eudiaptomus gracilis. AB - Eudiaptomus gracilis is the most abundant member of the zooplankton, plays a key role in the food web of Lake Balaton (Hungary). In the present study the composition of bacterial communities of this copepod was investigated based on cultivation and molecular cloning. The cultivated bacterial strains from the gut homogenate samples of Eudiaptomus gracilis belonged to four different clades: Firmicutes, Actinobacteria, Bacteriodetes and Proteobacteria. Clone library showed high species diversity, Firmicutes, Actinobacteria, Proteobacteria, representatives of Deinococcus-Thermus lineage and Cyanobacteria were detected. The isolated strains were very effective in degradation of different biopolymers. Many of the detected bacteria are known as opportunistic human or fish pathogens (Pseudomonas spp., Aeromonas spp., Chryseobacterium sp. and Staphylococcus sp.). PMID- 21780148 TI - Identification and characterization of gushing-active hydrophobins from Fusarium graminearum and related species. AB - Fungal infection of barley and malt, particularly by the Fusarium species, is a direct cause of spontaneous overfoaming of beer, referred to as gushing. We have shown previously that small fungal proteins, hydrophobins, act as gushing inducing factors in beer. The aim of our present study was to isolate and characterize hydrophobins from a gushing-active fungus, Fusarium graminearum (teleomorph Gibberella zeae) and related species. We generated profile hidden Markov models (profile HMMs) for the hydrophobin classes Ia, Ib and II from the multiple sequence alignments of their known members available in public domain databases. We searched the published Fusarium graminearum genome with the Markov models. The best matching sequences and the corresponding genes were isolated from F. graminearum and the related species F. culmorum and F. poae by PCR and characterized. One each of the putative F. graminearum and F. poae hydrophobin genes were expressed in the heterologous host Trichoderma reesei. The proteins corresponding to the genes were purified and identified as hydrophobins and named GzHYD5 and FpHYD5, respectively. Concentrations of 0.003 ppm of these hydrophobins were observed to induce vigorous beer gushing. PMID- 21780149 TI - Application of response surface analysis for biodegradation of azo reactive textile dye using Aspergillus foetidus. AB - This paper reports the application of experimental design methodology for the optimization of decolourization of azo reactive textile dye Remazol Red RR and reduction of chemical oxygen demand (COD) using fungal isolate Aspergillus foetidus. Response surface methodology (RSM), involving central composite design matrix in three most important input variables; temperature, pH and initial dye concentration was employed. A total of 20 experiments were conducted in the study towards the construction of a quadratic model. This demonstrated the benefits of approach in achieving excellent predictions, while minimizing the number of experiments required. Very high regression coefficient between the variables and the responses indicated excellent evaluation of experimental data. Under optimized conditions fungal isolate was capable to decolourize Remazol Red RR up to 86.21% and COD reduction up to 55.43% was achieved during the experimental setup. Enzymatic activity indicated excellent outcome under the optimal process conditions. The experimental values agreed with the predicted ones, indicating suitability of the model and success of RSM approach in optimizing the process. PMID- 21780150 TI - GC content-independent amino acid patterns in bacteria and archaea. AB - Every organism can be characterized by the amino acid composition of its proteome. So far it was assumed that these compositions are determined by the GC content of the DNA or, in some cases, by extreme lifestyles, like thermophily or halophily. Here, we focussed our analysis on eight amino acids, each of which is encoded by both, GC and AT rich codons, to identify finer amino acid patterns beyond the GC dominance. We investigated the conceptually translated proteomes of 1029 bacterial and archaeal strains with sequenced genomes for amino acid composition. Using correspondence analysis, we found that phylogenetic groups within bacteria and archaea generally can be discriminated from other groups due to their amino acid composition. In some cases, single organisms, e.g. Treponema pallidum strains or Mycoplasma penetrans, are characterized by extreme amino acid compositions. We assume that our data could provide a basis for a new approach to analyze evolution of bacterial and archaeal groups. Furthermore, for single organisms, the detailed knowledge of the amino acid composition of the entire proteome encoded in the genome could lead to a better understanding, important for pharmaceutical or biotechnological applications. We recommend that information about amino acid compositions should be provided in databases, comparable to the GC content of genomes. PMID- 21780151 TI - 40-O -[2-Hydroxyethyl]rapamycin modulates human dendritic cell function during exposure to Aspergillus fumigatus. AB - 40-O -[2-Hydroxyethyl]rapamycin (RAD), a novel derivative of the immunosuppressive drug rapamycin, was analyzed for its immunomodulatory influence during the interaction of human monocyte-derived dendritic cells (moDC) with Aspergillus fumigatus. RAD is clinically used to prevent graft-versus -host disease as well as solid organ and bone marrow transplant rejection. However, it may constitute a risk factor for the development of opportunistic infections, such as invasive aspergillosis which is mainly caused by the most common airborne fungal pathogen A. fumigatus. moDC were generated in the presence or absence of RAD. In this setting, RAD had various modulating effects on the immune function of DC. A decrease of pro- and anti-inflammatory cytokines (IL-12, TNF-alpha, CCL20, IL-10) was observed. Furthermore, RAD reduced the expression of innate immunity receptors (TLR2, TLR4, dectin-1), impaired the maturation capacity of moDC observed through the reduction of costimulatory factors (CD40, CD80, CD83, CD86), and impaired their capacity to phagocytose and damage A. fumigatus. These data demonstrate that RAD influences the differentiation of DC. RAD modulates the cytokine response of DC to A. fumigatus and reduces their ability to kill germ tubes. Thus, RAD treatment might affect the risk of invasive aspergillosis independently of its capacity of blocking T cell activation. PMID- 21780152 TI - Development of loop-mediated isothermal amplification method for rapid detection of Streptococcus iniae, the causative agent of streptococcicosis in fish. AB - Streptococcus iniae is a major pathogen that causes sever economic losses in tilapia aquaculture. A set of four specific primers was designed by targeting lctO gene. With Bst DNA polymerase, the target DNA can be clearly amplified for 60 min at 64 degrees C in a simple water bath. The sensitivity of the LAMP assay for the detection of S. iniae is about 12.4 cells per reaction in both of pure cultures and added fish tissues cultures. LAMP products could be judged with agar gel or naked eye after addition of SYBR Green I. There were no cross-reactions with other bacterial strains indicating high specificity of the LAMP. The LAMP method was also applied to detect S. iniae-infected tilapia tissues effectively. The LAMP assay reported here indicates the potential usefulness of the technique as a valuable simple, rapid alternative procedure for the detection of S. iniae during streptococcicosis monitoring of cultured fish. PMID- 21780153 TI - Adaptive response of single and binary Pseudomonas aeruginosa and Escherichia coli biofilms to benzalkonium chloride. AB - The main goal of this work was to examine whether the continuous exposure of single and binary P. aeruginosa and E. coli biofilms to sub-lethal benzalkonium chloride (BC) doses can induce adaptive response of bacteria. Biofilms were formed during 24 h and then put continuously in contact with BC for more 5 days. The six-day-old adapted biofilms were then submitted to BC challenge, characterized and inspected by SEM. Both single and binary adapted biofilms have clearly more biomass, polysaccharides and proteins and less activity even though the number of cells was identical. After BC treatment, adapted biofilms maintained their mass and activity. SEM examination revealed that those adapted biofilms had a slimier and denser matrix that became thicker after BC treatment. Continuous exposure of bacteria to antimicrobials can lead to development of biofilms encompassing more virulent and tolerant bacteria. This adaptive resistance can be the result of a phenotypic adaptation, a genetic acquired resistance or both. Instead of eradicating biofilms and kill microorganisms, the use of a disinfectant can, favour biofilm formation and tolerance. This must be a genuine concern as it can happen in clinical environments, where the use of antimicrobials is unavoidable. PMID- 21780154 TI - Endocrine and testicular changes induced by olanzapine in adult Wistar rats. AB - Olanzapine is an atypical antipsychotic drug that has been increasingly used in acute treatment of, and therapeutic support for, schizophrenia, bipolar disorder and other psychoses. Considering that olanzapine acts on the dopaminergic receptor and this receptor is detected in germ cells, the present study aims to investigate the effects of treatment with different doses of olanzapine on spermatogenesis, plasma testosterone and weight of androgen-dependent organs in rats. Results showed reduced plasma testosterone levels, and reduced testis, epididymis and prostate weights. Histopathologic and histomorphometric analysis of spermatogenesis indicated testicular degeneration. Furthermore, germ cell desquamation, syncytial multinucleated cells, Sertoli cell vacuolization and presence of necrotic and apoptotic germ cells wwew observed. Olanzapine treatment in rats promoted endocrinological changes and lesions in the testis, leading to a disturbance in spermatogenesis. PMID- 21780155 TI - A chiral liquid chromatography method for the simultaneous determination of oxcarbazepine, eslicarbazepine, R-licarbazepine and other new chemical derivatives BIA 2-024, BIA 2-059 and BIA 2-265, in mouse plasma and brain. AB - Recently, in silico models have been developed to predict drug pharmacokinetics. However, before application, they must be validated and, for that, information about structurally similar reference compounds is required. A chiral liquid chromatography method with ultraviolet detection (LC-UV) was developed and validated for the simultaneous quantification of BIA 2-024, BIA 2-059, BIA 2-265, oxcarbazepine, eslicarbazepine (S-licarbazepine) and R-licarbazepine in mouse plasma and brain. Compounds were extracted by a selective solid-phase extraction procedure and their chromatographic separation was achieved on a LiChroCART 250-4 ChiraDex column using a mobile phase of water-methanol (92:8, v/v) pumped at 0.7 mL/min. The UV detector was set at 235 nm. Calibration curves were linear (r(2) >= 0.996) over the concentration ranges of 0.2-30 ug/mL for oxcarbazepine, eslicarbazepine and R-licarbazepine; 0.2-60 ug/mL for the remaining compounds in plasma; and 0.06-15 ug/mL for all the analytes in brain homogenate. Taking into account all analytes at these concentration ranges in both matrices, the overall precision did not exceed 9.09%, and the accuracy was within +/-14.3%. This LC-UV method is suitable for carrying out pharmacokinetic studies with these compounds in mouse in order to obtain a better picture of their metabolic pathways and biodistribution. PMID- 21780156 TI - Ultrastructural analysis of spermiogenesis in Rhacophorus arboreus (Amphibia, Anura, Rhacophoridae). AB - The spermatozoa of the Japanese green tree frog, Rhacophorus arboreus (Amphibia, Anura, Rhacophoridae), have a characteristic corkscrew-shaped head and a thick tail that extends perpendicular to the longitudinal axis of the head. We examined the process of spermatogenesis in Rh. arboreus, particularly spermiogenesis, using light and transmission electron microscopy. Spermiogenesis was categorized into the early, mid, and late stages based on the spermatid morphology and their location within the cyst. Early spermatids had a round nucleus and two independent flagella that elongated from a pair of parallel centrioles. The centrioles became embedded in centriolar adjunct material and attached to the nucleus. Then, the flagella were covered with a mantle-like cytoplasm that contained many microtubules. An acrosome appeared on the pointed side of the slightly elongated nucleus. Mid spermatids had an elongated rod-like head. As the nucleus elongated, the chromatin fibers became thicker and were arranged parallel to the elongation axis. An elongated acrosome was attached helically along the lateral side of the elongated nucleus. The biflagellate spermatids transformed into monoflagellate spermatids with two axonemes through a process in which the plasma membrane of each flagellum expanded. Late spermatids had a coiled or corkscrew-shaped head. An acrosome was located on the inside of the coiled cone composed of a nucleus. Parallel microtubules were connected in rows, and then became crystallized in the tail. The present report contains the first morphological description of spermatogenesis in Rhacophorus and suggests that spermiogenesis evolved to adapt to the fertilization environment. PMID- 21780157 TI - The synarcual cartilage of batoids with emphasis on the synarcual of Rajidae. AB - Comparison of embryonic specimens with juvenile and mature specimens of other skates indicates that the relative developmental sequence of events is maintained among several taxa within larger clades. However, there is a fundamental difference between the pattern of chondrification and the pattern of calcification in skates. Early in ontogeny a short synarcual surrounds the first free vertebral centrum. Additional neural arch segments are incorporated from anterior to posterior and the relative length of the synarcual cartilage to total length of the body normalizes early. A secondary direction of chondrification, from ventral to dorsal, is also present. Juveniles and subadults show that synarcual calcification is relatively late compared to the calcification of other regions of the skeleton and proceeds from lateral to medial. Comparison with extinct taxa also indicates that there is a decrease in vertebral centrum involvement with the synarcual cartilage over the evolutionary history of the clade. Results from exploratory analyses of morphospace and taxonomy reveal that phylogeny explains part, but not all, of the data on the synarcual in Rajidae. There is evidence of individual and ontogenetic variation among all species of skates examined, however, phylogenetically informative variation prevails. Comparison with other batoids demonstrates a trend where the number of vertebral centra flanked by the synarcual cartilage decreases among more derived taxa indicating a high degree of convergent morphology among batoids with potential functional significance. PMID- 21780158 TI - Comparison of cranial form and function in association with diet in natricine snakes. AB - The skull of squamates has many functions, with food acquisition and ingestion being paramount. Snakes vary interspecifically in the frequency, size, and types of prey that are consumed. Natural selection should favor phenotypes that minimize the costs of energy acquisition; therefore, trophic morphology should reflect a snake's primary prey type to enhance some aspect of feeding performance. I measured 19 cranial variables for six natricine species that vary in the frequency with which they consume frogs and fish. Both conventional and phylogenetically corrected analyses indicated that fish-eating snakes have relatively longer upper and lower jaw elements than frog-eating snakes, which tended to have broader skull components. I also compared the ratio of the in lever to the out-lever lengths of the jaw-closing mechanism [jaw mechanical advantage (MA)] among species. Fish-eating snakes had significantly lower MAs in the jaws than did the frog-eating snakes. This result suggests that piscivores have faster closing jaws and that the jaws of frog-eating snakes have higher closing forces. Cranial morphology and the functional demands of prey capture and ingestion appear to be associated with primary prey type in natricine snakes. PMID- 21780159 TI - Stem-like and non-stem human pancreatic cancer cells distinguished by morphology and metastatic behavior. AB - We report here that XPA1 human pancreatic cancer cells are dimorphic. After injection in the spleen, XPA1 cells isolated from the primary tumor in the spleen were predominantly round; while cells isolated from the resulting liver metastasis and ascites were comprised of both round- and spindle-shaped cell types. Cancer cells previously grown in the spleen and re-implanted in the spleen developed large primary tumors in the spleen only. Cancer cells isolated from liver metastasis and re-transplanted to the spleen resulted in a primary tumor in the spleen and liver metastasis. Cancer cells derived from ascites and re transplanted to the spleen developed primary tumors in the spleen and distant metastasis in the liver, lung, and diaphragm in addition to ascites formation. Spindle and round cells were differentially labeled with fluorescent proteins of different colors. After co-injection of the two cell types in the spleen, cells were isolated from the primary tumors, liver metastasis, and ascites and analyzed by color-coded fluorescence microscopy and fluorescence-activated cell sorting (FACS). No significant differences between the percentages of spindle-shaped and round cancer cells in the primary tumor and the liver metastasis were observed. However, spindle-shaped cancer cells were enriched in the ascites. One hundred percent of the spindle-shaped and round cancer cells expressed CD44, suggesting that morphology and metastatic behavior rather than CD44 expression can distinguish the stem-like cells of the XPA1 pancreatic cancer cell line. The spindle-shaped cancer cells had the greater capability for distant metastasis and ascites formation, suggesting they are stem-like cells, which can be readily targeted for therapy. PMID- 21780160 TI - Three-dimensional co-culture facilitates the differentiation of embryonic stem cells into mature cardiomyocytes. AB - The cardiomyocyte (CM) differentiation of embryonic stem cells (ESCs) is routinely cultured as two-dimensional (2D) monolayer, which doesn't mimic in vivo physiological environment and may lead to low differentiated level of ESCs. Here, we develop a novel strategy that enhances CM differentiation of ESCs in collagen matrix three-dimensional (3D) culture combined with indirect cardiac fibroblasts co-culture. ESCs were cultured in hanging drops to form embryoid bodies (EBs) and then applied on collagen matrix. The EBs were indirectly co-cultured with cardiac fibroblasts by the hanging cell culture inserts (PET 1 um). The molecular expressions and ultrastructural characteristics of ESC-derived CMs (ESCMs) were analyzed by real time RT-PCR, immunocytochemistry, and Transmission Electron Microscopy (TEM). We found that the percentage of beating EBs with cardiac fibroblasts co-culture was significantly higher than that without co-culture after differentiation period of 8 days. Type I collagen used as 3D substrates enhanced the late-stage CM differentiation of ESCs and had effect on ultrastructural mature of ESCMs in late-stage development. The combined effects of 3D and co-culture that mimic in vivo physiological environment further improved the efficiency of CM differentiation from ESCs, resulting in fiber-like structures of cardiac cells with organized sarcomeric structure in ESCMs. This novel 3D co-culture system emphasizes the fact that the ESC differentiation is actively responding to cues from their environment and those cues can drive phenotypic control, which provides a useful in vitro model to investigate CM differentiation of stem cells. PMID- 21780161 TI - Magnesium deficiency suppresses cell cycle progression mediated by increase in transcriptional activity of p21(Cip1) and p27(Kip1) in renal epithelial NRK-52E cells. AB - Lack of magnesium suppresses cell growth, but the molecular mechanism is not examined in detail. We examined the effect of extracellular magnesium deficiency on cell cycle progression and the expression of cell cycle regulators in renal epithelial NRK-52E cells. In synchronized cells caused by serum-starved method, over 80% cells were distributed in G1 phase. Cell proliferation and percentage of the cells in S phase in the presence of MgCl(2) were higher than those in the absence of MgCl(2) , suggesting that magnesium is involved in the cell cycle progression from G1 to S phase. After serum addition, the expression levels of p21(Cip1) and p27(Kip1) in the absence of MgCl(2) were higher than those in the presence of MgCl(2) . The exogenous expression of p21(Cip1) or p27(Kip1) increased the percentage in G1 phase, whereas it decreased that in S phase. The mRNA levels and promoter activities of p21(Cip1) and p27(Kip1) in the absence of MgCl(2) were higher than those in the presence of MgCl(2) . The phosphorylated p53 (p-p53) level was decreased by MgCl(2) addition. Pifithrin-alpha, a p53 inhibitor, decreased the p-p53, p21(Cip1) and p27(Kip1) levels, and the percentage in G1 phase in the absence of MgCl(2) . Rotenone, a mitochondrial respiratory inhibitor, decreased ATP content and increased the p-p53 level in the presence of MgCl(2) . Together, lack of magnesium may increase p21(Cip1) and p27(Kip1) levels mediated by the decrease in ATP content and the activation of p53, resulting in the suppression of cell cycle progression from G1 to S phase in NRK-52E cells. PMID- 21780162 TI - Suppression of the PI3K subunit p85alpha delays embryoid body development and inhibits cell adhesion. AB - Phosphatidylinositol-3-kinases (PI3Ks) exert a variety of signaling functions in eukaryotes. We suppressed the PI3K regulatory subunit p85alpha using a small interfering RNA (Pik3r1 siRNA) and examined the effects on embryoid body (EB) development in hanging drop culture. We observed a 150% increase in the volume of the treated EBs within 24 h, compared to the negative controls. Fluorescence Activated Cell Sorting (FACS) assays showed that this increase in volume is not due to increased cellular proliferation. Instead, the increase in volume appears to be due to reduced cellular aggregation and adherence. This is further shown by our observation that 40% of treated EBs form twin instead of single EBs, and that they have a significantly reduced ability to adhere to culture dishes when plated. A time course over the first 96 h reveals that the impaired adherence is transient and explained by an initial 12-hour delay in EB development. Quantitative PCR expression analysis suggests that the adhesion molecule integrin beta1 (ITGB1) is transiently downregulated by the p85alpha suppression. In conclusion we found that suppressing p85alpha leads to a delay in forming compact EBs, accompanied by a transient inability of the EBs to undergo normal cell-cell and cell-substrate adhesion. PMID- 21780163 TI - Urodynamic findings in young men with chronic lower urinary tract symptoms. AB - AIM: To assess frequency of urodynamic abnormalities in young men with chronic lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: We assessed 456 men (18-40 years old) with chronic LUTS. Those with the history of urogenital malignancies, neurological disease, urethral stricture or trauma, acute UTI, congenital urological disease, and diabetes mellitus were excluded. Patients were classified by special urodynamic diagnosis. RESULTS: Mean patient age was 25.8 +/- 5.9 years old and the mean symptom duration was 12.3 +/- 3.2 months. Urodynamic studies showed bladder neck dysfunction in 96 of cases (21%), dysfunctional voiding in 69 (15.1%), detrusor overactivity in 62 (13.6%), small cystometric capacity in 49 (10.7%), and acontractile detrusor in 48 (10.5%), underactive detrusor in 11 (2.4%), low compliance in 18 (3.9%), detrusor overactivity plus acontractile detrusor in 6 (1.3%), low compliance plus small cystometric capacity in 5 (1.0%), detrusor overactivity plus small cystometric capacity together with low compliance in 4 (0.8%), low compliance plus Underactive detrusor in 3 (0.6%) and normal urodynamics in 85 (18.6%). Mean Q(max) in patients with bladder neck dysfunction, dysfunctional voiding, underactive detrusor, acontractile detrusor, underactive detrusor plus low compliance, and acontractile detrusor plus detrusor overactivity were lower than those of the other groups. Mean postvoid residues in patients with underactive detrusor, and underactive detrusor plus low compliance, were higher than those in the remaining groups. Positive four-glass test in patient with normal urodynamic was greater than those in the remaining groups. CONCLUSION: A few clinical symptoms or noninvasive tests were useful in young men with chronic LUTS; hence, urodynamics are advised to make the correct diagnosis in this regard. PMID- 21780164 TI - Can maximum urethral closure pressure (MUCP) be used to predict outcome of surgical treatment of stress urinary incontinence? AB - AIMS: The outcome of surgery for stress urinary incontinence (SUI) can be unpredictable. Urethral pressure measurements, including measurement of maximum urethral closure pressure (MUCP) can form part of the investigation of women prior to SUI surgery and some studies have suggested that women with higher MUCP may have a better surgical outcome. This study aims to determine whether outcome of SUI surgery is related to pre-operative MUCP. METHODS: All patients undergoing colposuspension or TVT in a large European city between 1998 and 2002 were included. All women underwent pre-operative urodynamics, including measurement of urethral pressure profile; urodynamic data, including MUCP, were determined. Surgical outcome was measured using the ICIQ-FLUTS questionnaire, which was mailed to allow for a minimum follow-up period of 3 years. Surgical outcome was measured by assigning patients to one of three post-operative Stress Urinary Incontinence (SUI) groups. Group 1 (No incontinence), Group 2 (< 1 incontinence episode per day), Group 3 (> 1 incontinence episode per day). Independent statistical analysis was undertaken using STATA(r) software and a two-way ANOVA (Analysis of Variance) test to determine the relationship between pre-operative MUCP and post-operative SUI group. RESULTS: A total of 463 postal questionnaires were mailed, with a response rate of 62%, allowing for those who had died or moved away. Of the 285 responders, 218 had undergone colposuspension and 66 had a TVT. Median age, length of follow up and MUCP were 54 years (range 23-81), 77 months (range 47 to 107) and 45 cmH(2) O (range 5 to 105) respectively. Difference in MUCP between the two operation groups (colposuspension and TVT) was not significant (p > 0.19). No significant difference in preoperative MUCP was demonstrated between the three SUI groups, with mean MUCP in the three SUI groups of 50, 45 and 43 cmH(2) 0 respectively, confirming that patients with higher MUCP were not more likely to be in a lower post-operative SUI group (F(2, 237) = 3.42, p < 0.04). CONCLUSION: Our data demonstrate that women with higher preoperative MUCP do not have a better surgical outcome following stress incontinence surgery. PMID- 21780165 TI - Distribution of interstitial cells of Cajal and expression of nitric oxide synthase after experimental bladder outlet obstruction in a rat model of bladder overactivity. AB - AIMS: Recent studies have showed that interstitial cells (ICs) are widely distributed in the genitourinary tract and have suggested their involvement in spontaneous electrical activity and muscle contraction. Nitric oxide (NO) is thought to play a role in bladder overactivity related with bladder outlet obstruction (BOO). The purposes of this study were to investigate the effect of bladder overactivity induced by BOO on ICs and nitric oxide synthase (NOS) isoforms in rat urinary bladder. METHODS: Female Sprague-Dawley rats (230-240 g, n = 40) were divided into two groups: control (group Con, n = 20) and partial BOO (group BOO, n = 20). After 4 weeks, urodynamic studies measuring contraction interval and contraction pressure were done. The cellular localization of cKit immunoreactive ICs and the expression of endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined by Western blot and immunohistochemistry in the rat urinary bladder. RESULTS: Filling cystometry studies demonstrated a reduced interval between voiding contractions and an increased voiding pressure in BOO bladders. The contraction interval time (2.9 +/- 0.35 min) was significantly decreased in the BOO group compared to the control (6.1 +/- 0.05; P < 0.05). The population of ICs was increased in the suburothelial and muscle layers in BOO bladders. ICs had a close contact with each other and neighboring nNOS expressing cells. CONCLUSIONS: These results demonstrated an increased population of ICs in the BOO rat model and suggest that the functional change of ICs and NOS isoforms may contribute to the pathophysiology of bladder overactivity induced by BOO. PMID- 21780166 TI - Magnetic resonance imaging following InterStim(r): an institutional experience with imaging safety and patient satisfaction. AB - AIMS: We retrospectively assessed patient safety and satisfaction after magnetic resonance imaging (MRI) in patients with an InterStim(r) unit. METHODS: The records of all patients implanted with InterStim(r) between 1998 and 2006 were reviewed. Nine of these patients underwent MRI following InterStim(r) implantation. The patients' neurologists requested the MRI exams for medical reasons. Both 0.6 Tesla (T) and 1.5 T machines were used. Patient safety, interference of implanted pulse generator (IPG) with radiological interpretation, and patient satisfaction were assessed in these patients. RESULTS: The first patient in the series had IPG failure following MRI. For this patient, the voltage amplitude was set to zero, the IPG was turned off, and the IPG magnetic switch was left on. The patient underwent MRI uneventfully; however, the IPG did not function upon reprogramming. The IPG magnetic switch was turned off for the eight subsequent patients, all of whom underwent MRI safely. In addition, all of their IPGs functioned appropriately following reprogramming. Of the 15 MRIs performed, the lumbar spine was imaged in eight studies, the pelvis was imaged in one study, and the remaining examinations involved imaging the brain or cervical spine. Neither the IPG nor the sacral leads interfered with MRI interpretation. None of the eight patients perceived a change in perception or satisfaction following MRI. CONCLUSIONS: Although we don't advocate the routine use of MRI following InterStim(r) implantation, our experience suggests MRI may be feasible under controlled conditions and without adverse events. PMID- 21780167 TI - Patient-reported outcomes and urinary continence five years after the tension free vaginal tape operation. AB - AIMS: To evaluate patient-reported outcomes and continence rates 5 years after the tension-free vaginal tape (TVT) operation and to compare these with subjective and objective cure rates. METHODS: A total of 101 patients underwent clinical and urodynamic assessment and completed the Incontinence Outcome Questionnaire (IOQ) 5 years after the retropubic TVT operation. The IOQ results were compared with the subjective and objective cure rates. RESULTS: At 5 years 85% of patients had a negative clinical stress test. Based on clinical stress test, stable cystometry to >=300 ml and residual volume <=100 ml, the physician assessment of cure was 80%. Patient-reported outcome showed improvement in incontinence symptoms in 86% of patients. Eighty-three percent of patients were satisfied with the results and 92% would recommend the operation to others. The results of the IOQ correlated more with patient-reported than with physician assessed cure rates. CONCLUSION: Patient report high rates of satisfaction 5 years after the TVT operation. PMID- 21780168 TI - Non-invasive techniques in the diagnosis of bladder storage disorders. AB - AIMS: To review clinical studies thus have been conducted to develop non-invasive diagnostic tools in the storage phase of the micturition cycle. METHODS: Pub Med and Web of Science searches were carried out. The search covered the published data of non-invasive diagnostic techniques for detrusor overactivity (DO) and/or low compliance bladder in patients with urinary storage symptoms. The patho physiological and clinical relevance of these methods were addressed. Diagnostic accuracy of these techniques was scrutinized. RESULTS: Eighteen studies were included in the review. Ultrasonography and biomarkers were the most investigated techniques in the diagnosis of storage disorders. Assessment of diagnostic accuracy was possible in four studies. The heterogeneity in data reporting was too high to conduct a meta-analysis. Ultrasonographic parameters and cut-off values have been developed to define DO; such as bladder wall thickness (BWT), detrusor wall thickness and bladder weight. The likelihood ratio of vaginal ultrasonography in measurement of BWT was good. Guidelines are currently developing to standardize the methodologies applied in these techniques. Laboratory biomarkers of DO are gaining more attention recently, but their specificity for DO should be carefully defined. Near infrared spectroscopy (NIRS) is potential non-invasive diagnostic method that is able to detect the DO episodes in real time. However, a solution needs to be found for motion artifacts in this technique. CONCLUSION: Non-invasive diagnostic techniques for storage disorders show limited progress with some limitations. Yet these techniques still cannot replace the standard filling cystometry in standard clinical practice. PMID- 21780169 TI - The influence of ejaculation and abstinence on urinary flow rates. AB - AIMS: To investigate the relationship between urinary flow rate and ejaculation in healthy young men. METHODS: Young men were voluntarily enrolled in the study. All subjects were healthy, and sexually active, without neurological diseases, genital, or urethral surgery and they were not under any medications. Subjects were evaluated with ultrasound, uroflowmetry, and post-void residual urine (PVR) measurement. All subjects were followed for 22 days (T) with daily uroflowmetry, and were instructed to ejaculate only on specific days (0, 6 and 22) during the study period. On days 0, 6 and 22 uroflow measurements were performed between 2 and 6 hr following ejaculation. Uroflowmetry parameters before and after ejaculation and during abstinence were compared. Data presented a non-normal distribution and the non-parametric Wilcoxon-match-paired test and Kruskal-Wallis test were used for statistical analysis. RESULTS: 18 subjects (mean age 27.4 years) completed the study. A total of 414 uroflow charts were collected. A statistical significant increase in Qmax was observed after ejaculation (T-1 Qmax: 22.7 +/- 5.4 vs. T0 Qmax: 25.7 +/- 8, P = 0.002; T5 Qmax 23.2 +/- 5.4 vs. T6 Qmax 25.4 +/- 8, P = 0.031; T21 Qmax 21 +/- 4.8 vs. T22 Qmax 24.5 +/- 7.9, P = 0.031). Sexual abstinence resulted in a progressive, statistically significant decline in Qmax rates (T0 Qmax 25.7 +/- 8 vs. T5 23.2 +/- 5.4 P = 0.035; T6 Qmax 25.4 +/- 8 vs. T21 Qmax 21 +/- 4.8, P = 0.01). PVR did not change during the study period. CONCLUSIONS: Our results suggest that in young healthy men micturition might be influenced by ejaculation. Our findings, if confirmed in larger series of patients with LUTS, should support that sexual status and activity could represent an important confounding factor in the interpretation of uroflowmetry traces. PMID- 21780170 TI - Anal sphincter fatigue: is the mechanism peripheral or central? AB - AIMS: Striated muscles of continence appear to exhibit marked fatigue during voluntary efforts. This is counterintuitive considering the high proportion of slow twitch muscle fibers. One explanation is that fatigue is due to central, rather than peripheral mechanisms. Here we examined the contribution of reduced voluntary activation (central fatigue) to the decline in anal sphincter (AS) and elbow flexor muscle force during voluntary contractions. METHODS: Ten healthy subjects participated. Fatigue was induced using 10 maximal voluntary contractions sustained for 20 s. During each fatiguing contraction, transcranial magnetic stimulation (TMS) was delivered over the motor cortex at 5 s intervals. Central fatigue was assessed using the superimposed twitch force elicited by TMS. Peripheral fatigue was measured using brachial plexus (elbow flexors) or sacral plexus (AS) stimulation during contraction and at rest. RESULTS: Ability to maximally activate AS (75.9%) was less than for the elbow flexors at baseline (91.6%). Voluntary activation declined in both muscles, but the decline was greater in AS (AS 28%; elbow flexors 12%). There was no change in the amplitude of the twitch evoked by peripheral nerve stimulation in either muscle. CONCLUSIONS: AS exhibits a greater decline in voluntary activation during fatiguing contractions than elbow flexor muscles. This is not accompanied by peripheral changes, which implies central mechanisms are responsible. Thus, we conclude that AS is susceptible to central fatigue during maximal voluntary activations. We propose this may be a protective mechanism to conserve contractile potential of the anal sphincter for function. PMID- 21780171 TI - Parturition events and risk of urinary incontinence in later life. AB - AIMS: To examine the association between specific events during vaginal deliveries and urinary incontinence later in life. METHODS: A retrospective cohort study of 1,521 middle-aged and older women with at least one vaginal delivery who were long-term members of an integrated health delivery system. Age, race/ethnicity, current incontinence status, medical, surgical history, pregnancy and parturition history, menopausal status, hormone replacement, health habits, and general health were obtained by questionnaire. Labor and delivery records, archived since 1948, were abstracted by professional medical record abstractors to obtain parturition events including induction, length of labor stages, type of anesthesia, episiotomy, instrumental delivery, and birth weight. The primary dependent variable was current weekly urinary incontinence (once per week or more often) versus urinary incontinence less than monthly (including no incontinence) in past 12 months. Associations of parturition events and later incontinence were assessed in multivariate analysis with logistic regression. RESULTS: The mean age of participants was 56 years. After adjustment for multiple risk factors, weekly urinary incontinence significantly associated with age at first birth (P = 0.036), greatest birth weight (P = 0.005), and ever having been induced for labor (OR = 1.51; 95%CI = 1.06-2.16, P = 0.02). Risk of incontinence increased from OR = 1.35 (95%CI = 0.92-1.97, P = 0.12) for women with one induction to OR = 2.67 (95%CI = 1.25-5.71, P = 0.01) for women with two or more inductions (P = 0.01 for trend). No other parturition factors were associated with incontinence. CONCLUSIONS: Younger age at first birth, greatest birth weight, and induction of labor were associated with an increased risk of incontinence in later life. PMID- 21780172 TI - Factors influencing women's participation in urogynecology research in the UK and USA. AB - AIMS: To explore factors influencing willingness to participate in urogynecology trials and explore associations between demographics, quality of life score (ICIQ SF), and willingness to participate. METHODS: The Bladder Clinic Questionnaire (BCQ) was developed, piloted, and validated. The BCQ and ICIQ-SF were distributed to women attending urogynecologists in tertiary referral centers in the UK and USA. The BCQ collected demographic data and data on previous involvement in research and posed eight research scenarios. Women were asked to record their willingness to participate on a Likert scale, collapsed for analysis into "any yes," "unsure," or "any no," giving a BCQ score between 0 and 16 (higher scores indicating greater willingness). RESULTS: Two hundred sixty-seven UK women and 200 US women returned completed questionnaires. Median BCQ score differed between UK and US women (11 [0-16] vs. 10 [0-16]; P = 0.004); median ICIQ score was similar (9 [0-21] vs. 9 [0-20]). ICIQ score was higher in UK women willing to participate in two scenarios: standard operation versus new operation (P = 0.007), and new operation versus new operation (P = 0.001). UK women were uniformly more willing to take part in all scenarios involving established treatments. CONCLUSION: We identified cultural differences in willingness to participate and differences depending on type of intervention proposed which supports the growing evidence that detailed pilot work is required during planning of intervention studies. PMID- 21780173 TI - Does patient activity level affect 24-hr pad test results in stress-incontinent women? AB - AIM: Standardization of the 24-hr pad test procedure would increase its validity as an objective measure of urinary incontinence. Our aim was to establish whether patient activity levels affect pad test results in stress-incontinent women, and if so, to develop a standard activity level during the testing period. METHODS: In this prospective observational study, 25 women with pure stress urinary incontinence (SUI) completed two 24-hr pad tests and documented their daily activities during a "normally active" and "minimally active" day. Activity level was compared with pad weight gain and the number of leakage episodes due to activity according to a patient activity diary (diarized activity leakage episodes) using non-parametric tests. RESULTS: There was a significant difference between the "normally active" and "minimally active" days for median pad weight gain (9.9 g vs. 5.2 g, P < 0.05) and diarized activity leakage episodes (2 vs. 1, P < 0.05). When the days were re-categorized, there was a significant difference between "mild activity" and "moderate activity" days for median pad weight gain (4.85 g vs. 7.1 g, P < 0.05) and diarized activity leakage episodes (0 vs. 2, P < 0.05). CONCLUSION: Increased patient activity levels increase the degree of leakage as measured by 24-hr pad weight gain therefore patients with SUI should perform the 24-hr pad test with standardized activity instructions. In scientific research, we recommend that women perform minimal physical activity, as this decreases the variation of activity. This approach will enhance the function of the 24-hr pad test as a severity measure between patients with SUI. PMID- 21780174 TI - Which treatments do children with newly diagnosed non-organic urinary incontinence receive? An analysis of 3,188 outpatient cases from Germany. AB - AIMS: Objectives of this study were to examine the administrative incidence of urinary incontinence in children and to assess related outpatient health services utilization in this cohort. METHODS: Data of a statutory health insurance company were analyzed and outpatients from 1 to 18 years of age with a first recorded ICD 10 code for non-organic urinary incontinence during a 1-year-period (2007) were identified. For this cohort, the prescription of desmopressin, antispasmodics, non-selective monoamine reuptake inhibitors, alarm devices, and incontinence pads in the quarter of the first diagnosis and in the following one (i.e., 6 months) was evaluated with respect to age and gender. RESULTS: 3,188 patients (59.4% male; mean age 6.8 years) matched the inclusion criteria, of whom 25.4% were under 5 years old. 7.9% were prescribed desmopressin, 7.4% received urinary antispasmodics, and 7.0% were treated with alarm devices. For 77.9% of patients, no specific incontinence-related treatments were prescribed. We found considerable differences in treatment patterns between age groups, with patients >= 7 years receiving desmopressin more frequently than alarm devices. Regarding gender differences, the proportion of males treated with alarm devices (prevalence ratio [PR] 1.46; 95% confidence interval [95%CI] 1.11-1.92) and at least one specific treatment (PR 1.19; 95%CI 1.04-1.35) remained statistically significantly higher, even after adjusting for age. CONCLUSIONS: In our study, we found evidence that treatment modalities only partly comply with the current guidelines for treatment of children and adolescents with non-organic urinary incontinence. Therefore, the dissemination of current guidelines remains a major educational goal. PMID- 21780175 TI - Activation of the striated urethral sphincter to maintain continence during dynamic tasks in healthy men. AB - AIMS: Function of the striated urethral sphincter (SUS) in men is debated. Current evidence is limited to electromyographic (EMG) recordings made with concentric needle electrodes in supine. Understanding of SUS function requires investigation of SUS EMG activity using new recording techniques in dynamic tasks. The aim of this study was to evaluate timing and amplitude of SUS EMG at rest and during dynamic tasks that challenge continence by increasing intra abdominal pressure (IAP). METHODS: Investigative study of five healthy men aged 25-39 years. Measurements included SUS, anal sphincter (AS), and transversus abdominus (TrA) EMG, and IAP (recorded with a nasogastric pressure catheter). Participants performed four tasks that challenged postural control in standing (single and repetitive arm movement, stepping and load catching). RESULTS: IAP amplitude and SUS activity were linearly correlated during repetitive arm movement (R(2): 0.67-0.88). During stepping SUS EMG onset preceded the IAP increase, but followed it with rapid arm movements. When the trunk was loaded unpredictably onset of SUS generally followed the increase in IAP. The modest sample size meant only younger men were tested. Future studies might investigate healthy older men or those with certain pathologies. CONCLUSIONS: Data show that SUS activity increases proportionally with IAP. This provided evidence that SUS contributes to continence when IAP is increased, and that postural control of the trunk involves activation of this muscle. PMID- 21780176 TI - A galenical of traditional Chinese herbal mixture (THC-002) reduces expression of tachykinin peptides within urethras of spontaneously hypertensive rats. AB - AIMS: We investigated expression of tachykinin peptides neurokinin A, neurokinin B, and substance P within urethras of spontaneously hypertensive rats (SHRs) and determined if a traditional Chinese herbal mixture, THC-002, decreased them. METHODS: Ten- and 40-week-old male SHRs were randomly separated into three groups (n = 12 each). Rats of one group were given orally 20 ml 0.9% NaCl solution per kg body weight daily for 1 week. One hour later, each received a similar volume of water. Rats in the second group were also given saline. One hour later, each received 20 mg THC-002 per kg body weight. The third group was untreated. The urethras were removed and separated into prostatic and non-prostatic regions and analyzed by real-time reverse transcription polymerase chain reaction (n = 6) and immunohistochemistry (n = 6). RESULTS: In 40-week-old untreated SHRs, neurokinin B mRNA and protein, and substance P mRNA in prostatic urethras were significantly higher compared to the 10-week-old ones. Neurokinin A mRNA and protein, and substance P protein of the 40-week-old saline-loaded prostatic urethras were significantly higher compared to the 40-week-old untreated ones. In 40-week-old untreated SHRs, the non-prostatic urethral neurokinin B protein was significantly higher compared to the 10-week-old ones. In 40-week-old, saline-loaded SHRs, neurokinin A protein of the non-prostatic urethras was significantly higher compared to 40-week-old the untreated ones. In 40-week-old SHRs, THC-002 significantly decreased the expression of the urethral tachykinins, except for non-prostatic urethral neurokinin A mRNA. CONCLUSIONS: Aging and saline-loading increased the expression of urethral tachykinin mRNAs and peptides. THC-002 partially decreased them. PMID- 21780178 TI - Cardiac 123I-meta-iodobenzylguanidine scintigraphy and lewy body pathology in a patient with amyotrophic lateral sclerosis and parkinsonism-dementia complex of Kii, Japan. PMID- 21780177 TI - Improving voiding efficiency in the diabetic rat by a 5-HT1A serotonin receptor agonist. AB - AIMS: Serotonin affects micturition in the normal rat through actions not only on ascending and descending spinal pathways and supraspinal centers but also on the lumbosacral spinal cord level. The selective 5-HT1A receptor agonist, 8-OH DPAT((R)-(+)-8-hydroxy-2-(di-n-propylamino) tetralin), reversed detrusor sphincter dyssynergia (DSD) in the spinal cord injury (SCI) rat. Rats with experimental diabetes mellitus (DM) have been shown to have both bladder and urethral dysfunction during reflex voiding. We therefore examined the effects of 8-OH-DPAT on micturition in DM rats. METHODS: Female Sprague-Dawley rats were used. DM was induced by an intraperitoneal injection of streptozotocin (STZ, 65 mg/kg) and a cystometric study was performed 8 weeks post-injection. External urethral sphincter electromyography (EUS-EMG) was also measured. The 5-HT1A antagonist WAY-100635(N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2 phenylpropanamide) was administered after each 8-OH-DPAT dose-response. RESULTS: Compared to controls, DM rats had a higher bladder capacity, residual volume, and a lower voiding efficiency. In DM rats, 8-OH-DPAT (3-1,000 ug/kg, i.v.) induced significant dose-dependent increases in micturition volume, and decreases in residual volume, resulting in increases in voiding efficiency. During the micturition, there was a dose-dependent increased phasic EUS activity correlated with the improved voiding efficiency. WAY-100635 (300 ug/kg, i.v.) reversed the 8 OH-DPAT-induced changes. CONCLUSIONS: Both the bladder voiding efficiency and the periodic EUS activity were decreased in DM rats. 5-HT1A receptor agonism promoted periodic EUS activity, thereby improving voiding efficiency. Whether or not these results may have implications for the future treatment of voiding dysfunction in DM patients remains to be studied. PMID- 21780180 TI - Wearing-off scales in Parkinson's disease: critique and recommendations. AB - Wearing-off occurs in the majority of patients with Parkinson's disease after a few years of dopaminergic therapy. Because a variety of scales have been used to estimate wearing-off, the Movement Disorder Society commissioned a task force to assess their clinimetric properties. A systematic review was conducted to identify wearing-off scales that have either been validated or used in Parkinson's patients. A scale was designated "Recommended" if it had been used in clinical studies beyond the group that developed it, if it had been specifically used in Parkinson's disease reports, and if clinimetric studies had established that it is valid, reliable, and sensitive. "Suggested" scales met 2 of the above criteria, and those meeting 1 were "Listed." We identified 3 diagnostic and 4 severity rating scales for wearing-off quantification. Two questionnaires met the criteria to be Recommended for diagnostic screening (questionnaires for 19 and 9 items), and 1 was Suggested (questionnaire for 32 items). Only the patient diaries were Recommended to assess wearing-off severity, with the caveat of relatively limited knowledge of validity. Among the other severity assessment tools, the Unified Parkinson Disease Rating Scale version 3 and the version revised from the Movement Disorders Society were classified as Suggested, whereas the Treatment Response Scale was Listed. PMID- 21780181 TI - Brain region-selective cellular redistribution of mGlu5 but not GABA(B) receptors following methamphetamine-induced associative learning. AB - Alterations in receptor expression and distribution between cell surface and cytoplasm are means by which psychostimulants regulate neurotransmission. Metabotropic glutamate receptor group I, subtype 5 (mGluR5) and GABA(B) receptors (GABA(B) R) are critically involved in the development and expression of stimulant-induced behaviors, including conditioned place preference (CPP), an index of drug-seeking. However, it is not known if psychostimulant-induced CPP alters the trafficking of these receptors. To fill this gap, this study used methamphetamine (Meth)-induced CPP in rats to ascertain if receptor changes occur in limbic brain regions that regulate drug-seeking, the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP). To do so, ex vivo tissue was assessed for changes in expression and surface vs. intracellular distribution of mGluR5 and GABA(B) Rs. There was a decrease in the surface to intracellular ratio of mGluR5 in the mPFC in Meth-conditioned rats, commensurate with an increase in intracellular levels. mGluR5 levels in the NAc or the VP were unaltered. There were no changes for GABA(B) R in any brain region assayed. This ex vivo snapshot of metabotropic glutamate and GABA receptor cellular distribution following induction of Meth-induced CPP is the first report to determine if these receptors are differentially altered after Meth-induced CPP. The results suggest that this Meth treatment paradigm likely induced a compensatory change in mGluR5 surface to intracellular ratio such that the surface remains unaltered while an increase in intracellular protein occurred. PMID- 21780183 TI - Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age +/- SD, 58.3 +/- 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain. PMID- 21780179 TI - Impact of apathy on health-related quality of life in recently diagnosed Parkinson's disease: the ANIMO study. AB - The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (<0.89 [lower HRQOL] vs >=0.89 [reference]) was examined using multiple logistic regression analysis, adjusting for sociodemographic and clinical variables. We consecutively recruited 557 patients (60.3% men) with a mean age of 68.8 +/- 9.7 years. Apathy was diagnosed in 291 (52.2%) and was related to problems in each of the EuroQoL dimensions. Apathetic PD patients showed EuroQol-5D index scores significantly lower than those without apathy (0.64 vs 0.83). In an adjusted model, apathetic PD patients were 2.49 times more likely to have lower HRQOL than nonapathetic patients (odds ratio, 2.49; 95% confidence interval, 1.49-4.15, P < 0.01). Apathy is very common in those with recently diagnosed PD and is one of the major clinical determinants of HRQOL in this disease. It should be one of the primary concerns among clinicians who provide treatment to individuals affected by PD. PMID- 21780182 TI - Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. AB - BACKGROUND: Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. METHODS: This was a double-blind, single centre study, which included participants with MCI, aged >= 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. RESULTS: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 umol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01). CONCLUSION: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia. PMID- 21780184 TI - Donepezil, but not galantamine, blocks muscarinic receptor-mediated in vitro and in vivo responses. AB - We have found that galantamine, but not donepezil, reversed isolation rearing induced deficits of prepulse inhibition (PPI) via an activation of muscarinic M1 receptors. To explain this difference, the present study examined the effects of these acetylcholinesterase inhibitors on muscarinic receptor-mediated responses in in vitro and in vivo systems. Ca(2+) -imaging study showed that donepezil, but not galantamine, blocked a muscarinic agonist carbachol-induced increase in intracellular Ca(2+) levels in SH-SY5Y cells. Moreover, a microdialysis study showed that intraperitoneal administration of donepezil, but not galantamine, attenuated a preferential M1 receptor agonist Ndesmethylclozapine-induced increase in dopamine release in mouse cerebral cortex. These results suggest that donepezil, but not galantamine, has an ability to block muscarinic receptor function and imply that the differential effects may be responsible for the difference in the effects on isolation rearing-induced deficits of PPI between these drugs. Synapse, 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21780185 TI - Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study. AB - OBJECTIVE: Positron emission tomography (PET) studies performed with [(11) C]raclopride have consistently reported lower binding to D(2/3) receptors and lower amphetamine-induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D(2/3) antagonist radiotracers such as [(11) C]raclopride is the failure to provide information that is specific to D(2/3) receptors configured in a state of high affinity for the agonists (i.e., D(2/3) receptors coupled to G-proteins, D(2/3 HIGH) ). As the endogenous agonist DA binds with preference to D(2/3 HIGH) relative to D(2/3 LOW) receptors (i.e., D(2/3) receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D(2/3 HIGH) receptors in cocaine dependence. Thus, we measured the available fraction of D(2/3) (HIGH) receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D(2/3) antagonist and agonist PET radiotracers [(11) C]raclopride and [(11) C]NPA. METHODS: [(11) C]raclopride and [(11) C]NPA binding potential (BP) (BP(ND) ) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D(2/3 HIGH) receptors, i.e., % R(HIGH) available = D(2/3 HIGH) /(D(2/3 HIGH) + D(2/3 LOW) ) was then computed as the ratio of [(11) C]NPA BP(ND) /[(11) C]raclopride BP(ND) . RESULTS: No differences in striatal [(11) C]NPA BP(ND) (HC = 1.00 +/- 0.17; CD = 0.97 +/- 0.17, P = 0.67) or available % R(HIGH) (HC = 39% +/- 5%; CD = 41% +/- 5%, P = 0.50) was observed between cocaine abusers and matched controls. CONCLUSIONS: The results of this [(11) C]NPA PET study do not support alterations in D(2/3 HIGH) binding in the striatum in cocaine dependence. PMID- 21780186 TI - Heterogeneous voltage dependence of interneuron resonance in the hippocampal stratum radiatum of adult rats. PMID- 21780187 TI - Redistribution of astrocytic glutamine synthetase in the hippocampus of chronic epileptic rats. AB - Glutamine synthetase (GS) is an astrocytic enzyme, which catalyzes the synthesis of glutamine from glutamate and ammonia. In the central nervous system, GS prevents glutamate-dependent excitotoxicity and detoxifies nitrogen. Reduction in both expression and activity of GS was reported in the hippocampus of patients with temporal lobe epilepsy (TLE), and this reduction has been suggested to contribute to epileptogenesis. In this study, we characterized hippocampal GS expression in the pilocarpine model of TLE in Wistar rats by means of stereology and morphometric analysis. Neither the GS positive cell number nor the GS containing cell volume was found to be altered in different hippocampal subregions of chronic epileptic rats when compared with controls. Instead, redistribution of the enzyme at both intracellular and tissue levels was observed in the epileptic hippocampus; GS was expressed more in proximal astrocytic branches, and GS expressing astrocytic somata was located in closer proximity to vascular walls. These effects were not due to shrinkage of astrocytic processes, as revealed by glial fibrillary acidic protein staining. Our results argue for GS redistribution rather than downregulation in the rat pilocarpine model of TLE. The potential contribution of increased GS perivascular affinity to the pathogenesis of epilepsy is discussed as well. PMID- 21780188 TI - Fear of emotion as a moderator between PTSD and firefighter social interactions. AB - Despite high levels of exposure to stress, questions remain regarding how social interactions and beliefs about emotion interact to influence posttraumatic stress disorder (PTSD) in firefighters. United States urban firefighters (N = 225) completed the Interpersonal Support Evaluation List, the Unsupportive Social Interactions Inventory, the Affective Control Scale, and the Posttraumatic Stress Disorder Checklist. Each independent variable predicted PTSD beyond variance accounted for by demographic variables. Additionally, fear of emotion emerged as the strongest individual predictor of PTSD and a moderator of the relation between social interactions and PTSD symptoms. These findings emphasize the importance of beliefs about emotion both in how these beliefs might influence the expression of PTSD symptoms, and in how the social networks of trauma survivors might buffer distress. PMID- 21780189 TI - The child behavior checklist PTSD scale: screening for PTSD in young children with high exposure to trauma. AB - The objective of this study was to examine the validity of the Child Behavior Checklist (CBCL) Posttraumatic Stress Disorder (PTSD) subscale to screen for PTSD in children attending an inner-city early childhood mental health center. Using various measures, we assessed 51 preschool-age children with high exposure to trauma receiving outpatient child-parent psychotherapy for PTSD. We compared 15 items on the CBCL, a proposed subscale indicative of PTSD, to the UCLA-PTSD Index and to clinical diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) and the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (rev. ed.; DC:0-3; Zero to Three, 2005). Using the DC:0-3 criteria, 24% of the children were diagnosed with PTSD, but only 4% using the DSM-IV. The CBCL-PTSD subscale did not reach significant sensitivity or specificity to be a valuable screening tool for PTSD in this population. PMID- 21780190 TI - Behavioral and molecular genetics of dissociation: the role of the serotonin transporter gene promoter polymorphism (5-HTTLPR). AB - We evaluated the role of the serotonin transporter gene promoter polymorphism (5 HTTLPR) in the etiology of dissociation. Adult twin pairs (N = 184 pairs; mean age 33.0 years, SD = 10.8) completed measures for dissociation and trauma. The DNA samples were genotyped for 5-HTTLPR adjusted for rs25531 alleles. Behavioral genetic analyses showed that genetic factors explained 45% of the variance in dissociative symptoms, while 55% of the variance was explained by unique environment and measurement error. Participants with the SS genotype of 5-HTTLPR reported more dissociative symptoms compared to participants with the other genotypes (p = .02), and they showed more pathological dissociative symptoms than the other participants (p = .04) when they reported more depressive symptoms and when they had experienced trauma. PMID- 21780191 TI - Case report on the use of cognitive processing therapy-cognitive, enhanced to address heavy alcohol use. AB - There is a high rate of co-occurring alcohol dependence (AD) in individuals with posttraumatic stress disorder (PTSD). Cognitive processing therapy (CPT) is an effective treatment for individuals diagnosed with PTSD. CPT-Cognitive (CPT-C) is a modified form of CPT. This case report describes a 12-week course of CPT-C treatment, enhanced to address heavy alcohol use, in a combat veteran with PTSD and co-occurring AD. By treatment end, the veteran demonstrated clinically significant improvement in both PTSD symptoms and alcohol-related problems and sustained these gains 12-weeks posttreatment. The results indicate promise for the use of CPT-C, enhanced for heavy alcohol use, for individuals diagnosed with PTSD and AD. PMID- 21780192 TI - Pilot study on traumatic grief treatment program for Japanese women bereaved by violent death. AB - This pilot study aimed to refine a treatment approach for traumatic grief due to violent loss. Our Traumatic Grief Treatment Program, a modification of Shear's complicated grief treatment (Shear et al., 2005), comprises psychoeducation, in vivo exposure, imaginal exposure, discussion of memories about and imaginal conversation with the deceased. Thirteen of 15 Japanese women suffering from posttraumatic stress disorder (PTSD) due to traumatic grief completed 12 to 16 weekly individual sessions based on their therapists' recommendations. Assessment scales included the Inventory of Complicated Grief, the Impact of Event Scale Revised, and the Center for Epidemiologic Studies Depression Scale. There was significant reduction in symptom severity at treatment end, and symptom levels remained low throughout the 12-month follow-up period. Based on Jacobson's Reliable Change Index, 46% showed change on all 3 measures. These findings suggest that our treatment model may be feasible for treating traumatic grief with PTSD in non-Western settings. PMID- 21780193 TI - Simultaneous chiral separation of methylamphetamine and common precursors using gas chromatography/mass spectrometry. AB - Methylamphetamine, ephedrine, and pseudoephedrine were derivatized using trifluoroacetic anhydride and enantiomers of each were analyzed using gas chromatography coupled to mass spectrometry (GC/MS) fitted with a gamma cyclodextrin (ChiraldexTM G-PN) chiral column. A temperature-programmed method was developed and optimized and the results compared with those obtained using a previously published isothermal GC method applied to GC/MS analysis. Trifluoroacetylated 3-(trifluoromethyl)phenethylamine hydrochloride was used as an internal standard, and mass fragmentation patterns are proposed for all derivatives analyzed. Qualitative validation of the optimized chromatographic conditions was completed in accordance with the guidelines published by the United Nations Office on Drugs and Crime (UNODC). Under conditions of repeatability and reproducibility, the method gave relative retention times with a relative standard deviation of less than 0.02% for all six analytes of interest. This surpasses the UNODC's acceptance criteria of 2% for validation of qualitative precision. Ephedrine and pseudoephedrine are common precursors in the clandestine manufacture of methylamphetamine. Seizures of illicit methylamphetamine therefore often contain mixtures of these optically active compounds. The simultaneous enantioseparation of these compounds to produce a profile would provide valuable information to law enforcement agencies regarding the provenance of a methylamphetamine seizure. PMID- 21780194 TI - E-selectin rs5361 and FCGR2A rs1801274 variants were associated with increased risk of gastric cancer in a Chinese population. AB - Host immune responses are critical steps for carcinogenesis. Single nucleotide polymorphisms (SNPs) in immunoregulatory genes may influence gastric cancer risk. We performed a genotyping analysis for immunoregulatory genes in 311 gastric cancer cases and 425 controls from a Chinese population. We found that there were significant differences of E-selectin variant rs5361 (A>C) and FCGR2A variant rs1801274 (T>C) between cases and controls (P = 0.022 and P = 0.0001, respectively). Logistic regression analysis indicated that genotype of E-selectin rs5361AC increased the risk of gastric cancer significantly (P = 0.026, adjusted Odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.13-7.12). C allele of E selectin rs5361 showed a significant increased frequency in cases (P = 0.023). However, the E-selectin variant did not affect the protein expression. E-selectin protein was observed not only in tumor interstitial vascular endothelial cells, but also in gastric cancer cells at primary and metastatic sites. The protein was associated with clinicopathological characteristics of gastric cancer, such as age (P = 0.008), tumor size (P = 0.027), differentiation (P = 0.000), and tumor node-metastasis (TNM) stage (P = 0.006). CT and CC + CT genotypes of FCGR2A variant rs1801274 increased gastric cancer risk (P = 0.000, adjusted OR = 1.92, 95%CI = 1.36-2.72; P = 0.003, adjusted OR = 1.68, 95%CI = 1.20-2.35, respectively). Interleukin-4 receptor (IL-4R) variant rs2107356 presented negative correlations to E-selectin variant rs5361 and FCGR2A variant rs1801274 (P = 0.035 and P = 0.023) in conferring susceptibility to gastric cancer. We concluded E-selectin variant rs5361 and FCGR2A variant rs1801274 were significantly associated with gastric cancer risk. Expression of E-selectin protein would promote progression of gastric cancer. PMID- 21780195 TI - Total syntheses of bryostatins: synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment. AB - Herein, we report the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. Ring-closing metathesis was utilized to form the 31-membered ring macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty in forming the C16-C17 olefin at a late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment, containing both the ring B and C subunits. PMID- 21780196 TI - Synthesis of tri- or tetrasubstituted pyrimidine derivatives through the [5+1] annulation of enamidines with either N,N-dimethylformamide dialkyl acetals or orthoesters and their application in a ring transformation of pyrimidines to pyrido[2,3-d]pyrimidin-5-one derivatives. AB - The [5+1] annulation of enamidines, which were prepared from functionalized silanes, organolithium compounds and two nitriles, with N,N-dimethylformamide dialkyl acetals as the C1 unit is described, leading to the synthesis of tri- and tetrasubstituted pyrimidine derivatives under catalyst- and solvent-free reaction conditions. Furthermore, the [5+1] annulation of enamidines by using orthoesters as the C1 unit is described, in which catalytic amounts of ZnBr(2) catalyze the annulation to produce polysubstituted pyrimidines under toluene or xylene reflux conditions. Moreover, the combination of a reductive ring-opening reaction with [Mo(CO)(6)] and a subsequent intramolecular cyclization with tBuOK effectively causes a skeletal transformation from the pyrimidines containing an isoxazolyl and an ethoxy substituent to form pyrido[2,3-d]pyrimidin-5-one frameworks in excellent yield. PMID- 21780197 TI - Crystal structures and repair studies reveal the identity and the base-pairing properties of the UV-induced spore photoproduct DNA lesion. AB - UV light is one of the major causes of DNA damage. In spore DNA, due to an unusual packing of the genetic material, a special spore photoproduct lesion (SP lesion) is formed, which is repaired by the enzyme spore photoproduct lyase (Spl), a radical S-adenosylmethionine (SAM) enzyme. We report here the synthesis and DNA incorporation of a DNA SP lesion analogue lacking the phosphodiester backbone. The oligonucleotides were used for repair studies and they were cocrystallized with a polymerase enzyme as a template to clarify the configuration of the SP lesion and to provide information about the base-pairing properties of the lesion. The structural analysis together with repair studies allowed us to clarify the identity of the preferentially repaired lesion diastereoisomer. PMID- 21780198 TI - Self-assembly of nanosized 0D clusters: CdS quantum dot-polyoxotungstate nanohybrids with strongly coupled electronic structures and visible-light-active photofunctions. AB - Nanohybrids of CdS-polyoxotungstate with strongly coupled electronic structures and visible-light-active photofunctions can be synthesized by electrostatically derived self-assembly of very small CdS quantum dots, or QDs, (particle size ~ 2.5 nm) and polyoxotungstate nanoclusters (cluster size ~1 nm). The formation of CdS-polyoxotungstate nanohybrids is confirmed by high-resolution transmission electron microscopy, elemental mapping, and powder X-ray diffraction analysis. Due to the strong electronic coupling between two semiconductors, the CdS polyoxotungstate nanohybrids show a narrow bandgap energy of around 1.9-2.7 eV, thus reflecting their ability to harvest visible light. Time-resolved photoluminescence experiments indicate that the self-assembly between nanosized CdS and polyoxotungstate is very effective in increasing the lifetime of holes and electrons, thus indicating an efficient electron transfer between two component semiconductors. The hybridization results not only in a significant improvement in the photostability of CdS QD but also in the creation of visible light-induced photochromism. Of particular importance is that the present nanohybrids show visible-light-driven photocatalytic activity to produce H(2) and O(2) , which is superior to those of the unhybridized CdS and polyoxotungstate. The self-assembly of nanometer-level semiconductor clusters can provide a powerful way of optimizing the photoinduced functionalities of each component (i.e., visible-induced photochromism and photocatalysis) by means of strong electronic coupling. PMID- 21780199 TI - Synthesis, electronic, and electro-optical properties of emissive solvatochromic phenothiazinyl merocyanine dyes. AB - Phenothiazinyl merocyanine dyes with variable substitution patterns on the peripheral benzene ring were synthesized in good yields by Knoevenagel condensation of the corresponding phenothiazinyl aldehydes and N-methylrhodanine or indan-1,3-dione. The electronic properties were investigated by cyclic voltammetry, absorption, electro-optical absorption, and emission spectroscopy. All these merocyanines reveal reversible redox behavior that stems from the phenothiazinyl-centered oxidation to give stable radical cations. The redox potentials strongly correlate with Hammett sigma(p) parameters. All merocyanines reveal large Stokes shifts. They also display a pronounced emissive solvatochromism, which is caused by large dipole moment changes upon excitation from the ground to the excited state. These findings are supported by solvatochromism studies and time-dependent DFT computations. PMID- 21780200 TI - Synthesis and modification of silicon nanosheets and other silicon nanomaterials. AB - Silicon nanomaterials and nanostructures exhibit different properties from those of bulk silicon materials based on quantum confinement effects. They are expected to lead to the development of new applications of silicon, in addition to wide use in semiconductor devices. Aside from industrial interest, intriguing issues of academic interest still remain with respect to the origins of their characteristic properties. Zero- and one-dimensional crystalline silicon nanomaterials have been synthesized, to date, by using many methods and there has been rapid progress in size control and modification procedures. However, there have been only a few examples of silicon nanomaterials with atomic-order thickness akin to carbon nanomaterials, such as two-dimensional silicon nanosheets. Moreover, mass production of silicon nanomaterials with relatively low cost is not easily achievable, due to the typically severe conditions required for fabrication, such as high temperature and ultralow pressure. Recently, we have developed a soft synthetic method for silicon nanosheets with chemical surface modification in a solution process. This review provides methods for the synthesis and modification of silicon nanosheets and other silicon nanomaterials with examples of their potential applications. PMID- 21780201 TI - Novel reactivity of N-bridged diiron phthalocyanine in the activation of C-H bonds: hydroacylation of olefins as an example of the efficient formation of C-C bonds. PMID- 21780202 TI - High-efficiency tris(8-hydroxyquinoline)aluminum (Alq3) complexes for organic white-light-emitting diodes and solid-state lighting. AB - Combinations of electron-withdrawing and -donating substituents on the 8 hydroxyquinoline ligand of the tris(8-hydroxyquinoline)aluminum (Alq(3)) complexes allow for control of the HOMO and LUMO energies and the HOMO-LUMO gap responsible for emission from the complexes. Here, we present a systematic study on tuning the emission and electroluminescence (EL) from Alq(3) complexes from the green to blue region. In this study, we explored the combination of electron donating substituents on C4 and C6. Compounds 1-6 displayed the emission tuning between 478 and 526 nm, and fluorescence quantum yield between 0.15 and 0.57. The compounds 2-6 were used as emitters and hosts in organic light-emitting diodes (OLEDs). The highest OLED external quantum efficiency (EQE) observed was 4.6%, which is among the highest observed for Alq(3) complexes. Also, the compounds 3-5 were used as hosts for red phosphorescent dopants to obtain white light-emitting diodes (WOLED). The WOLEDs displayed high efficiency (EQE up to 19%) and high white color purity (color rendering index (CRI~85). PMID- 21780203 TI - X-ray and solution structures of Cu(II) GHK and Cu(II) DAHK complexes: influence on their redox properties. AB - The Gly-His-Lys (GHK) peptide and the Asp-Ala-His-Lys (DAHK) sequences are naturally occurring high-affinity copper(II) chelators found in the blood plasma and are hence of biological interest. A structural study of the copper complexes of these peptides was conducted in the solid state and in solution by determining their X-ray structures, and by using a large range of spectroscopies, including EPR and HYSCORE (hyperfine sub-level correlation), X-ray absorption and (1)H and (13)C NMR spectroscopy. The results indicate that the structures of [Cu(II)(DAHK)] in the solid state and in solution are similar and confirm the equatorial coordination sphere of NH(2), two amidyl N and one imidazole N. Additionally, a water molecule is bound apically to Cu(II) as revealed by the X ray structure. As reported previously in the literature, [Cu(II)(GHK)], which exhibits a dimeric structure in the solid state, forms a monomeric complex in solution with three nitrogen ligands: NH(2), amidyl and imidazole. The fourth equatorial site is occupied by a labile oxygen atom from a carboxylate ligand in the solid state. We probe that fourth position and study ternary complexes of [Cu(II)(GHK)] with glycine or histidine. The Cu(II) exchange reaction between different DAHK peptides is very slow, in contrast to [Cu(II)(GHK)], in which the fast exchange was attributed to the presence of a [Cu(II)(GHK)(2)] complex. The redox properties of [Cu(II)(GHK)] and [Cu(II)(DAHK)] were investigated by cyclic voltammetry and by measuring the ascorbate oxidation in the presence of molecular oxygen. The measurements indicate that both Cu(II) complexes are inert under moderate redox potentials. In contrast to [Cu(II)(DAHK)], [Cu(II)(GHK)] could be reduced to Cu(I) around -0.62 V (versus AgCl/Ag) with subsequent release of the Cu ion. These complete analyses of structure and redox activity of those complexes gave new insights with biological impact and can serve as models for other more complicated Cu(II)-peptide interactions. PMID- 21780204 TI - Interplay of chemical microenvironment and redox environment on thiol-disulfide exchange kinetics. AB - The interplay between the chemical microenvironment surrounding disulfides and the redox environment of the media on thiol-disulfide exchange kinetics was examined by using a peptide platform. Exchange kinetics of up to 34 cysteine containing peptides were measured in several redox buffers. The electrostatic attraction/repulsion between charged peptides and reducing agents such as glutathione was found to have a very pronounced effect on thiol-disulfide exchange kinetics (differences of ca. three orders of magnitude). Exchange kinetics could be directly correlated to peptide charge over the entire range examined. This study highlights the possibility of finely and predictably tuning thiol-disulfide exchange, and demonstrates the importance of considering both the local environment surrounding the disulfide and the nature of the major reducing species present in the environment for which their use is intended (e.g., in drug delivery systems, sensors, etc). PMID- 21780205 TI - Experimental and theoretical characterization of the aromatization, epimerization, and fragmentation reactions of bi-2H-azirin-2-yls prepared from 1,4-diazidobuta-1,3-dienes. AB - 1,4-Diazidobuta-1,3-dienes (Z,Z)-10, 17, and 21 were photolyzed and thermolyzed to yield the pyridazines 13, 20, and 23, respectively. To explain these aromatic final products, the generation of highly strained bi-2H-azirin-2-yls 12, 19, and 22 and their valence isomerization were postulated. In the case of meso- and rac 22, nearly quantitative formation from diazide 21, isolation as stable solids, and complete characterization were possible. On the thermolysis of 22, aromatization to 23 was only a side reaction, whereas equilibration of meso- and rac-22 and fragmentation, which led to alkyne 24 and acetonitrile, dominated. Prolonged irradiation of 22 gave mainly the pyrimidine 25. The change of the configuration at C-2 of the 2H-azirine unit was observed not only in the case of bi-2H-azirin-2-yls 22 but also for simple spirocyclic 2H-azirines 29 at a relatively low temperature (75 degrees C). The fragmentation of rac-22 to give alkyne 24 and two molecules of acetonitrile was also studied by high-level quantum chemical calculations. For a related model system 30 (methyl instead of phenyl groups), two transition states TS-30-31 of comparable energy with multiconfigurational electronic states could be localized on the energy hypersurface for this one-step conversion. The symmetrical transition state complies with the definition of a coarctate mechanism. PMID- 21780206 TI - Cyclopropyl carbinol rearrangement for benzo-fused nitrogen ring synthesis. AB - A synthetic method that relies on gold-catalysed cyclopropyl carbinol rearrangement of 2-tosylaminophenyl cyclopropylmethanols to prepare 2,3-dihydro 1H-benzo[b]azepines and 2-vinylindolines efficiently is reported. The reactions were shown to be chemoselective, with secondary and tertiary alcohol substrates exclusively providing benzo-fused five- and seven-membered ring products, respectively. The ring-forming process was also found to proceed in moderate to excellent yields under mild conditions only in the presence of the gold and silver catalyst combination. The mechanism is thought to involve activation of the alcohol by the (p-CF(3)C(6)H(4))(3)PAuCl/AgOTf (Tf = triflate) catalyst, resulting in ionization of the starting material. The tertiary carbocationic intermediate generated in situ in this manner then triggers ring-opening of the cyclopropane moiety and trapping by the tethered aniline group to give the 2,3 dihydro-1H-benzo[b]azepine. Cyclopropane ring fragmentation of the secondary carbocationic analogue, on the other hand, results in diene formation followed by subsequent intramolecular hydroamination to afford the 2-vinylindoline. PMID- 21780207 TI - C3-symmetric Pt3Pd3 purine vases based on a metal coordination motif involving the pyrimidinic N1 and N3 sites. PMID- 21780208 TI - Chemical synthesis, crystal structure and enzymatic evaluation of a dinucleotide spore photoproduct analogue containing a formacetal linker. AB - Spore photoproduct (SP) is the exclusive DNA photodamage product found in bacterial endospores. Its photoformation and repair by a metalloenzyme spore photoproduct lyase (SPL) composes the unique SP biochemistry. Despite the fact that the SP was discovered almost 50 years ago, its crystal structure is still unknown and the lack of structural information greatly hinders the study of SP biochemistry. Employing a formacetal linker and organic synthesis, we successfully prepared a dinucleotide SP isostere 5R-CH(2) SP, which contains a neutral CH(2) moiety between the two thymine residues instead of a phosphate. The neutral linker dramatically facilitates the crystallization process, allowing us to obtain the crystal structure for this intriguing thymine dimer half a century after its discovery. Further ROESY spectroscopic, DFT computational, and enzymatic studies of this 5R-CH(2) SP compound prove that it possesses similar properties with the 5R-SP species, suggesting that the revealed structure truly reflects that of SP generated in Nature. PMID- 21780209 TI - Supplementation with a flavanol-rich lychee fruit extract influences the inflammatory status of young athletes. AB - Flavanol-rich lychee fruit extract (FRLFE) is a processed lychee fruit extract that is higher in flavanols (monomers, dimers and trimers) than its unprocessed counterpart. FRLFE exerts antioxidant activities in vitro and is expected to protect against inflammation and tissue damage. However, the physiological effects of FRLFE intake have not been explored in vivo. The aim of this study was to examine the effects of FRLFE supplementation on inflammation and tissue damage in young athletes during intense physical training. Twenty healthy male long distance runners at a university were randomly assigned to receive FRLFE or placebo in a double-blind manner. Blood and serum parameters associated with inflammation, tissue damage and oxidative stress were evaluated before (pre training), during (mid-training) and after (post-training) a 2-month training period. Some parameters, including the white blood cell count, were significantly modified by FRLFE supplementation. Compared with the placebo group, the change in the serum interleukin-6 level between pre- and mid-training were significantly lower in the FRLFE group, while the change in the transforming growth factor-beta level between pre- and post-training was significantly greater in the FRLFE group. These findings suggest that FRLFE supplementation may suppress inflammation or tissue damage caused by high-intensity exercise training. PMID- 21780211 TI - The inhibitory effect of Duchesnea chrysantha extract on the development of atopic dermatitis-like lesions by regulating IgE and cytokine production in Nc/Nga mice. AB - Duchesnea chrysantha belongs to the Rosaceae family and has been used traditionally for the treatment of various diseases in Korea and other parts of East Asia. This study examined the antiinflammatory effect of Duchesnea chrysantha extract (DcE) on atopic dermatitis in vitro and in vivo. DcE inhibited the production of IL-6, IL-8 and MCP-1 in THP-1 cells and the release of IL-6 and MCP-1 in EoL-1 cells after treatment with house dust mite extract. In the in vivo experiment, Nc/Nga mice were sensitized to DNCB and then orally and dorsally administered DcE (50 mg/kg in PBS) for 3 weeks. The DcE administration significantly reduced the skin severity score when compared with the control group and inhibited the thickening of the epidermis and infiltration of inflammatory cells into the dermis. In addition, the serum IgE levels decreased markedly in the DcE-treated mice when compared with the control group. The synthesis of IL-5, IL-13, MCP-1 and eotaxin was also decreased in splenocytes of the DcE-treated group, while IFN-gamma was increased in the Dc-administered group. These results may indicate that DcE attenuates the development of atopic dermatitis-like lesions by lowering the IgE and inflammatory cytokine levels, and that it is useful in drug development for the treatment of atopic dermatitis. PMID- 21780210 TI - Digallic acid from Pistascia lentiscus fruits induces apoptosis and enhances antioxidant activities. AB - The antioxidant and apoptotic activities of digallic acid, isolated from the fruits of Pistascia lentiscus, were investigated. The study demonstrated that digallic acid possessed pro-apoptotic effects, as shown by provoking DNA fragmentation of K562 cells. It also revealed a significant antioxidant potential and effective scavenging activity against 2,2-diphenyl-1-picrylhdrazyl (DPPH.) and O2.- radicals, and reduced cupric ions. We conclude that this integrated approach to apoptotic and antioxidant assessment may be useful to maximize the beneficial effects associated with using P. lentiscus derivatives as medicinal and dietary compounds. PMID- 21780212 TI - Acetyl- and butyryl-cholinesterase inhibitory activities of mansorins and mansonones. AB - Cholinesterase (ChE) inhibitory activities of three coumarins (mansorins A-C) and five naphthoquinones (mansonone C, E, G and H) were evaluated to determine the relationships between the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects and the core structures of these compounds. Among the tested compounds, mansonone E exhibited the highest ChE inhibitory activities, with IC50 values in the low micromolar levels. In addition to revealing the ChE inhibitory activities of naphthoquinones for the first time, the results also revealed structure-activity relationship information that could be useful for further modification. Furthermore, the study also supports the hypothesis that mansonones are the active component in Thespesia populnea, a plant that previously has been shown to enhance memory activity in an in vivo study. PMID- 21780213 TI - Flanking domain stability modulates the aggregation kinetics of a polyglutamine disease protein. AB - Spinocerebellar Ataxia Type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases that are all characterized by progressive neuronal dysfunction and the presence of neuronal inclusions containing aggregated polyQ protein, suggesting that protein misfolding is a key part of this disease. Ataxin-3, the causative protein of SCA3, contains a globular, structured N-terminal domain (the Josephin domain) and a flexible polyQ-containing C-terminal tail, the repeat-length of which modulates pathogenicity. It has been suggested that the fibrillogenesis pathway of ataxin-3 begins with a non-polyQ-dependent step mediated by Josephin domain interactions, followed by a polyQ-dependent step. To test the involvement of the Josephin domain in ataxin-3 fibrillogenesis, we have created both pathogenic and nonpathogenic length ataxin-3 variants with a stabilized Josephin domain, and have both stabilized and destabilized the isolated Josephin domain. We show that changing the thermodynamic stability of the Josephin domain modulates ataxin-3 fibrillogenesis. These data support the hypothesis that the first stage of ataxin-3 fibrillogenesis is caused by interactions involving the non-polyQ containing Josephin domain and that the thermodynamic stability of this domain is linked to the aggregation propensity of ataxin-3. PMID- 21780214 TI - Thiol-exchange in DTSSP crosslinked peptides is proportional to cysteine content and precisely controlled in crosslink detection by two-step LC-MALDI MSMS. AB - The lysine-specific crosslinker 3,3'-dithiobis(sulfosuccinimidylpropionate) (DTSSP) is commonly used in the structural characterization of proteins by chemical crosslinking and mass spectrometry and we here describe an efficient two step LC-MALDI-TOF/TOF procedure to detect crosslinked peptides. First MS data are acquired, and the properties of isotope-labeled DTSSP are used in data analysis to identify candidate crosslinks. MSMS data are then acquired for a restricted number of precursor ions per spot for final crosslink identification. We show that the thiol-catalyzed exchange between crosslinked peptides, which is due to the disulfide bond in DTSSP and known to possibly obscure data, can be precisely quantified using isotope-labeled DTSSP. Crosslinked peptides are recognized as 8 Da doublet peaks and a new isotopic peak with twice the intensity appears in the middle of the doublet as a consequence of the thiol-exchange. False-positive crosslinks, formed exclusively by thiol-exchange, yield a 1:2:1 isotope pattern, whereas true crosslinks, formed by two lysine residues within crosslinkable distance in the native protein structure, yield a 1:0:1 isotope pattern. Peaks with a 1:X:1 isotope pattern, where 0 < X < 2, can be trusted as true crosslinks, with a defined proportion of the signal [2X/(2 + X)] being noise from the thiol exchange. The thiol-exchange was correlated with the protein cysteine content and was minimized by shortening the trypsin incubation time, and for two molecular chaperone proteins with known structure all crosslinks fitted well to the structure data. The thiol-exchange can thus be controlled and isotope-labeled DTSSP safely used to detect true crosslinks between lysine residues in proteins. PMID- 21780215 TI - Hydrogen-deuterium exchange in vivo to measure turnover of an ALS-associated mutant SOD1 protein in spinal cord of mice. AB - Mutations of cytosolic Cu/Zn superoxide dismutase 1 (SOD1) in humans and overexpression of mutant human SOD1 genes in transgenic mice are associated with the motor neuron degenerative condition known as amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease). Gain-of-function toxicity from the mutant protein expressed in motor neurons, associated with its misfolding and aggregation, leads to dysfunction and cell death, associated with paralyzing disease. Here, using hydrogen-deuterium exchange in intact mice in vivo, we have addressed whether an ALS-associated mutant protein, G85R SOD1-YFP, is subject to the same rate of turnover in spinal cord both early in the course of the disease and later. We find that the mutant protein turns over about 10-fold faster than a similarly expressed wild-type fusion and that there is no significant change in the rate of turnover as animals age and disease progresses. PMID- 21780220 TI - MRI-guided ablation of breast cancer: where do we stand today? AB - The treatment of patients with localized breast cancer has changed considerably over the past few decades. The next challenge is to use image-guided minimally invasive tumor ablation techniques. The fact that MRI is the most accurate imaging modality for visualization and delineation of breast tumor margins in three dimensions and provides MRI-based temperature mapping, makes it particularly applicable for monitoring during minimally invasive ablation techniques. The overall result of the studies performed on MRI-guided minimally invasive tumor ablation studies are varying, with reported total tumor ablation rates ranging between 20% and 100%. Strict selection of patients, consensus on the treatment zone margin and optimization of MR-imaging, should make MRI-guided breast cancer tumor ablation a useful tool in clinical practice. PMID- 21780222 TI - Automated regional wall motion abnormality detection by combining rest and stress cardiac MRI: correlation with contrast-enhanced MRI. AB - PURPOSE: To correlate an automated regional wall motion abnormality (RWMA) detection method based on combined rest and dobutamine-stress cardiac MRI with the assessment of myocardial infarction from contrast-enhanced MRI (CE-MRI), and to demonstrate that adding stress data improves the detection of scar segments compared with rest data alone. MATERIALS AND METHODS: An automated RWMA detection method was built based on a statistical model of normokinetic myocardium from 41 healthy volunteers. The method was adapted to detect changes in RWMA from rest to stress. Twelve patients with myocardial infarction were included in the experiment. The correlation with CE-MRI was performed on two measurements: infarct transmurality and scar detection. RESULTS: Compared with infarct transmurality, the probability of normokinetic motion decreased progressively as infarct transmurality increased. These probability values were 0.59 for non-scar segments, for <25% transmurality was 0.4 (SE=0.04), for 25-50% was 0.33 (SE=0.03), for 50-75% was 0.21 (SE=0.03) and for >=75% was 0.10 (SE=0.03). For scar tissue detection, adding stress data significantly improved the performance (P<0.001, confidence interval=99.9%). The sensitivity, specificity, and accuracy increased by 34%, 30%, and 32%, respectively. The area under the receiver operating characteristics curve was 0.63 when rest-only data was used, but it was improved to 0.87 when stress data was added. CONCLUSION: The presented automated RWMA assessment was capable of detecting wall motion improvements from rest to stress. The method correlated well with infarct transmurality from CE-MRI. Detection of scar regions was more accurate when rest and stress data were combined compared with rest data alone. PMID- 21780221 TI - Implementation of multi-echo-based correlated spectroscopic imaging and pilot findings in human brain and calf muscle. AB - PURPOSE: To implement a spatially encoded correlated spectroscopic imaging (COSI) sequence on 3 Tesla (T) MRI/MR spectroscopy scanners incorporating four echoes to collect four phase-encoded acquisitions per repetition time (TR), and to evaluate the performance and reliability of this four-dimensional (4D) multi-echo COSI (ME COSI) sequence in brain and calf muscle. MATERIALS AND METHODS: Typical scan parameters for the 4D datasets were as follows: repetition time = 1500 ms, 2000 Hz bandwidth, 8 * 8 spatial encoding, one average, 64 Deltat(1) increments and the scan duration was 25 min. The performance and test-retest reliability of ME COSI were evaluated with phantoms and in the occipitoparietal brain tissues and calf of six healthy volunteers (mean age = 32 years old). RESULTS: Regional differences in concentrations of lipids, creatine (Cr), choline (Ch), and carnosine (Car) were observed between spectra from voxels located in tibial marrow, tibialis anterior, and soleus muscle. Diagonal and cross-peak resonances were identified from several brain metabolites including N-acetyl aspartate (NAA), Ch, Cr, lactate (Lac), aspartate (Asp), glutathione (GSH), and glutamine?glutamate (Glx). Coefficients of variation (CV) in metabolite ratios across repeated measurements were <15% for diagonal and <25% for cross-peaks observed in vivo. CONCLUSION: The ME-COSI sequence reliably acquired spatially resolved 2D Correlated Spectroscopy (COSY) spectra demonstrating the feasibility of differentiating spatial variation of metabolites in different tissues. Multi echo acquisition shortens scan duration to clinically feasible times. PMID- 21780223 TI - Zoom imaging for rapid aortic vessel wall imaging and cardiovascular risk assessment. AB - PURPOSE: To demonstrate the utility of a "reduced field-of-view" (zoom imaging) technique to accelerate free-breathing, ECG-triggered, turbo-spin-echo black blood sequences, which have been previously described to detect subclinical aortic atherosclerosis. MATERIALS AND METHODS: Fifteen healthy volunteers underwent MRI of the thoracic and abdominal aorta. Imaging with the conventional full field-of-view sequence was compared with zoom imaging. Total scan time, image quality (i.e., contrast-to-noise ratio and vessel wall sharpness) and vessel wall thickness were analyzed. A subgroup of 10 volunteers also underwent acceleration of imaging using sensitivity encoding (SENSE) for comparison. RESULTS: Zoom imaging significantly reduced imaging time from a mean of 41 +/- 9 min (conventional imaging) to 15 +/- 0.5 min (P<0.01). There was no difference in image quality between conventional and zoom imaging with respect to CNR (10.1 +/- 6 versus 10.1 +/- 6) or vessel wall sharpness (38 +/- 4% versus 39 +/- 4%). Furthermore, Bland Altman plots showed excellent agreement in vessel wall thickness measurements using the two methods. In comparison, SENSE not only reduced CNR but also resulted in underestimation of vessel wall thickness compared with the conventional sequence. CONCLUSION: Zoom imaging allows accurate and time-efficient imaging of the abdominal and thoracic aorta for cardiovascular risk prediction. In this application, it is preferable to SENSE. PMID- 21780224 TI - A new approach towards improved visualization of myocardial edema using T2 weighted imaging: a cardiovascular magnetic resonance (CMR) study. AB - PURPOSE: To compare T2-weighted cardiovascular magnetic resonance (CMR) imaging with AASPIR (asymmetric adiabatic spectral inversion recovery) and STIR (short T1 inversion recovery) for myocardial signal intensity, image quality, and fat suppression. MATERIALS AND METHODS: Forty consecutive patients (47 +/- 16 years old) referred by cardiologists for CMR-based myocardial tissue characterization were scanned with both STIR and AASPIR T2-weighted imaging approaches. Signal intensity of left ventricular myocardium was normalized to a region of interest generating a signal-to-noise ratio (SNR). In six patients with regional edema on STIR the contrast-to-noise ratio (CNR) was assessed. Two independent observers used a scoring system to evaluate image quality and artifact suppression. Six healthy volunteers (three males, 32 +/- 7 years) were recruited to compare fat suppression between AASPIR and STIR. RESULTS: SNR of AASPIR was greater than STIR for basal (128 +/- 44 vs. 83 +/- 40, P < 0.001), mid- (144 +/- 65 vs. 96 +/- 39, P < 0.01), and apical (145 +/- 59 vs. 105 +/- 35, P < 0.05) myocardium. Improved image quality and greater suppression of artifacts was demonstrated with AASPIR. In patients with regional edema, CNR increased by 49% with AASPIR, while SNR of pericardial fat did not differ (44 +/- 39 vs. 33 +/- 30, P > 0.05). CONCLUSION: Our findings support the implementation of an AASPIR-based approach for T2 weighted imaging due to improved pericardial fat suppression, image quality, and artifact suppression with greater CNR and SNR. PMID- 21780225 TI - Comparison of enhancement characteristics between invasive lobular carcinoma and invasive ductal carcinoma. AB - PURPOSE: To compare enhancement characteristics between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) on contrast enhanced MRI of the breast and to observe the magnitude of eventual differences as these may impair the diagnostic value of breast MRI in ILC. MATERIALS AND METHODS: We performed an analysis of enhancement characteristics on biphasic breast MRI in a series of 136 patients (103 IDC, 33 ILC) using an in-house developed application for pharmacokinetic modeling of contrast enhancement and a commercially available CAD application that evaluated the contrast-enhancement versus time curve. RESULTS: Pharmacokinetic analysis showed that the most enhancing voxels in IDC had significantly higher K(trans) -values than in ILC (P < 0.01). No difference in v(e) -values was noted between groups. Visual assessment of contrast enhancement versus time curves revealed wash-out curves to be less common in ILC (48% versus 84%). However, when using the CAD-application to assess the most malignant looking curve, the difference was blotted out (76% versus 86%). CONCLUSION: ILC enhances slower than IDC but peak enhancement is not significantly less. The use of a CAD-application may help to determine the most malignant looking contrast-enhancement versus time curve, and hence facilitates lesion classification. PMID- 21780226 TI - Improving detection of siderotic nodules in cirrhotic liver with a multi-breath hold susceptibility-weighted imaging technique. AB - PURPOSE: To evaluate the role of abdominal susceptibility-weighted imaging (SWI) in the detection of siderotic nodules in cirrhotic liver. MATERIALS AND METHODS: Forty patients with pathologically identified liver cirrhosis and 40 age/sex matched normal controls underwent T1-, T2-, T2*-weighted imaging and SWI at 3T. Two radiologists prospectively analyzed all magnetic resonance imaging (MRI) studies. Siderotic nodules detected by each imaging technique were counted for comparison. The conspicuity of siderotic nodules was assessed using a scale from 1 to 3 (1, weak; 2, moderate; 3, prominent). RESULTS: The number of siderotic nodules detected by SWI (3863) was significantly greater than that of T1-weighted imaging (262, P < 0.001), T2-weighted imaging (842, P < 0.001), and T2*-weighted imaging (2475, P < 0.001). No suspected siderotic nodules were detected in normal controls by any imaging technique. CONCLUSION: SWI appears to provide the most sensitive method to detect siderotic nodules in cirrhotic liver. PMID- 21780227 TI - Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI. AB - PURPOSE: To compare the diagnostic accuracy of contrast-enhanced computed tomography (CE-CT), contrast-enhanced ultrasonography (CE-US), superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), and gadoxetic acid enhanced MRI (Gd-EOB-MRI) in the evaluation of colorectal hepatic metastases. MATERIALS AND METHODS: In all, 111 patients with colorectal cancers were enrolled in this study. Of the 112 metastases identified in 46 patients, 31 in 18 patients were confirmed histologically and the remaining 81 in 28 patients were confirmed by follow-up imaging. CE-CT, CE-US, SPIO-MRI, and Gd-EOB-MRI were evaluated. Mean (of three readers, except for CE-US) area under the receiver operating characteristic curve (A(z) ), sensitivities, and positive predictive values (PPV) were calculated. Each value was compared to the others by variance z-test or chi square test with Bonferroni correction. RESULTS: For all lesions, mean A(z) and sensitivity of Gd-EOB-MRI (0.992, 95% [56/59]) were significantly greater than those of CE-CT (0.847, 63% [71/112]) and CE-US (0.844, 73% [77/106]). For lesions <=1 cm, mean A(z) and sensitivity of Gd-EOB-MRI (0.999, 92% [22/24]) were significantly greater than those of CE-CT (0.685, 26% [13/50]) and CE-US (0.7, 41% [18/44]). Mean A(z) (95% CI) of SPIO-MRI for all lesions (0.966 [0.929 0.987]) and lesions <= 1 cm (0.961 [0.911-0.988]) were significantly greater than those of CE-CT and CE-US. Mean sensitivity of SPIO-MRI for lesions <=1 cm (63%, 26/41) was significantly greater than that of CE-CT. CONCLUSION: Gd-EOB-MRI and SPIO-MRI were more accurate than CE-CT and CE-US for evaluation of liver metastasis in patients with colorectal carcinoma. PMID- 21780228 TI - 31P MR spectroscopic imaging detects regenerative changes in human liver stimulated by portal vein embolization. AB - PURPOSE: First, to evaluate hepatocyte phospholipid metabolism and energetics during liver regeneration stimulated by portal vein embolization (PVE) using proton-decoupled (31)P MR spectroscopic imaging ((31)P-MRSI). Second, to compare the biophysiologic differences between hepatic regeneration stimulated by PVE and by partial hepatectomy (PH). MATERIALS AND METHODS: Subjects included six patients with hepatic metastases from colorectal cancer who were scheduled to undergo right PVE before definitive resection of right-sided tumor. (31)P-MRSI was performed on the left liver lobe before PVE and 48 h following PVE. Normalized quantities of phosphorus-containing hepatic metabolites were analyzed from both visits. In addition, MRSI data at 48 h following partial hepatectomy were compared with the data from the PVE patients. RESULTS: At 48 h after PVE, the ratio of phosphomonoesters to phosphodiesters in the nonembolized lobe was significantly elevated. No significant changes were found in nucleoside triphosphates (NTP) and Pi values. The phosphomonoester (PME) to phosphodiester (PDE) ratio in regenerating liver 48 h after partial hepatectomy was significantly greater than PME/PDE 48 h after PVE. CONCLUSION: (31)P-MRSI is a valid technique to noninvasively evaluate cell membrane metabolism following PVE. The different degree of biochemical change between partial hepatectomy and PVE indicates that hepatic growth following these two procedures does not follow the same course. PMID- 21780230 TI - Nonenhanced extracranial carotid MR angiography using arterial spin labeling: improved performance with pseudocontinuous tagging. AB - PURPOSE: To compare pulsed arterial spin labeling (PASL) and pseudocontinuous arterial spin labeling (PCASL) for nonenhanced extracranial carotid MR angiography (MRA). MATERIALS AND METHODS: Parametric signal equations for PASL and PCASL MRA were formulated and compared. Volunteer imaging (n=7) at 1.5 Tesla was performed to compare the methods over a broad range of repetition and labeling times. Empirical results were compared with theoretical predictions. The feasibility of the optimal method was investigated in patients (n=2) with sonographically documented carotid artery disease. RESULTS: In volunteers, PCASL provided significantly improved signal than PASL (range: 32-255% improvement; P<0.01), and better supported the use of long labeling times and short repetition times. Excellent agreement between theory and experiment was found (intraclass correlation coefficient=0.966; P<0.001). PCASL provided excellent depiction of the carotid arteries in initial patient studies. CONCLUSION: Compared with pulsed tagging, pseudocontinuous tagging provides improved performance for nonenhanced extracranial carotid MRA and warrants further clinical investigation. PMID- 21780229 TI - MRI of trabecular bone using a decay due to diffusion in the internal field contrast imaging sequence. AB - PURPOSE: To characterize the DDIF (Decay due to Diffusion in the Internal Field) method using intact animal trabecular bone specimens of varying trabecular structure and porosity, under ex vivo conditions closely resembling in vivo physiological conditions. The DDIF method provides a diffusion contrast which is related to the surface-to-volume ratio of the porous structure of bones. DDIF has previously been used successfully to study marrow-free trabecular bone, but the DDIF contrast hitherto had not been tested in intact specimens containing marrow and surrounded by soft tissue. MATERIALS AND METHODS: DDIF imaging was implemented on a 4.7 Tesla (T) small-bore, horizontal, animal scanner. Ex vivo results on fresh bone specimens containing marrow were obtained at body temperature. Control measurements were carried out in surrounding tissue and saline. RESULTS: Significant DDIF effect was observed for trabecular bone samples, while it was considerably smaller for soft tissue outside the bone and for lipids. Additionally, significant differences were observed between specimens of different trabecular structure. CONCLUSION: The DDIF contrast is feasible despite the reduction of the diffusion constant and of T(1) in such conditions, increasing our confidence that DDIF imaging in vivo may be clinically viable for bone characterization. PMID- 21780231 TI - Novel peptide targeting integrin alphavbeta3-rich tumor cells by magnetic resonance imaging. AB - PURPOSE: To investigate the targeting activity of the peptide (named P1c) derived from connective tissue growth factor (CTGF) to alphavbeta3-rich tumor cells. MATERIALS AND METHODS: P1c was synthesized and conjugated with ultrasuperparamagnetic iron oxide particles (USPIOs) coated with meso-2,3 dimercaptosuccinic acid (DMSA). The specific binding activity of P1c-USPIOs to alphavbeta3 was verified by solid phase binding assay. The combination of P1c USPIOs with a human primary liver cancer cell (Bel 7402) with alphavbeta3 positive expression and uptake of P1c-USPIOs by cells was investigated by Prussian blue staining, transmission electron microscopy (TEM), and magnetic resonance imaging (MRI). The targeting activity of the probe in vivo was also evaluated using a small-animal tumor model by MRI. RESULTS: The cell uptake of P1c-USPIOs was observed in a dose-dependent manner, whereas no significant particle uptake was found in the plain USPIOs group. The differences on T2* weighted imaging were also found by MRI and the signal intensity (SI) was statistically reduced after coculture of Bel 7402 cells with P1c-USPIOs at a concentration of 20-80 MUg/mL compared with plain USPIOs (P < 0.05). The in vivo study showed that the signal reduction was distributed mainly in the periphery and some central areas of the tumor. The tumor-to-muscle CNR (contrast-to-noise ratio) at 12 hours after the administration of the P1c-USPIOs was statistically significantly different compared to those at 0 hour, 1 hour, or the plain USPIO group (P < 0.05). CONCLUSION: The peptide P1c might be a good candidate as a targeting carrier for drugs or tracers. PMID- 21780232 TI - A framework for generalized reference image reconstruction methods including HYPR LR, PR-FOCUSS, and k-t FOCUSS. AB - PURPOSE: To investigate the relationships among highly constrained back projection (HYPR)-LR, projection reconstruction focal underdetermined system solver (PR-FOCUSS), and k-t FOCUSS by showing how each method relates to a generalized reference image reconstruction method. That is, the generalized series model employs a fixed reference image and multiplicative corrections-that model is extended here to consider reference images more broadly, both in image space and in transform spaces (x-t and x-f spaces), and that can evolve with iteration. MATERIALS AND METHODS: Theoretical relationships between the methods were derived. Computer simulations were done to compare HYPR-LR to one iteration of PR-FOCUSS. The generalized reference approaches applied in the x-t or x-f domain were compared using computer simulation, five cardiac cine imaging datasets, and six myocardial perfusion datasets. RESULTS: PR-FOCUSS and HYPR-LR gave comparable errors, with PR-FOCUSS slightly outperforming HYPR-LR. The baseline image is important to the performance of k-t FOCUSS and x-t FOCUSS, as demonstrated by results from cardiac cine imaging. For cardiac perfusion reconstructions with the use of a temporal average image as the baseline image, k t FOCUSS gave lower errors than x-t FOCUSS. CONCLUSION: HYPR-LR and PR-FOCUSS are closely related: both work for radial sampling and use reference images in the x t domain; HYPR-LR is an approximate implementation of the generalized reference framework, while PR-FOCUSS is a conjugate gradient implementation of the generalized reference framework. The superiority of generalized reference approaches applied in the x-t or x-f domain was sensitive to the characteristics of the acquired data and to the baseline image used. PMID- 21780233 TI - Developing optimized fMRI protocol for clinical use: comparison of different language paradigms. AB - PURPOSE: To compare the potential of five functional magnetic resonance imaging (fMRI) language paradigms in activating language areas in Persian-speaking volunteers in order to optimize these tasks for clinically useful protocol. MATERIALS AND METHODS: 16 healthy right-handed Persian-speaking volunteers were studied. Each individual performed five tasks during the fMRI scan: word generation (WG), object naming (ON), word reading (WR), word production (WP), and reverse word reading (RWR). The ability of each task to activate classical language areas was assessed using group analysis. In addition, the lateralization index (LI) for each subject-task was calculated and compared. RESULTS: We found that WP, RWR, and WG robustly activated language-related areas in the dominant hemisphere. ON and WR failed to sufficiently delineate these activation areas. Highest activation intensities in the frontal lobe (including Broca's area) were seen with WP, whereas RWR showed the highest LI among all examined tasks. CONCLUSION: Our results demonstrated that the Persian version of WG and newly presented WP and RWR tasks can be reliably used for localization of language related areas in Persian speakers. This type of language evaluation may be used in presurgical planning of neurosurgical procedures in the Persian population. We recommend application of WP and RWR in future researches establishing the optimized protocol for other language speakers. PMID- 21780234 TI - Model-based nonlinear inverse reconstruction for T2 mapping using highly undersampled spin-echo MRI. AB - PURPOSE: To develop a model-based reconstruction technique for T2 mapping based on multi-echo spin-echo MRI sequences with highly undersampled Cartesian data encoding. MATERIALS AND METHODS: The proposed technique relies on a nonlinear inverse reconstruction algorithm which directly estimates a T2 and spin-density map from a train of undersampled spin echoes. The method is applicable to acquisitions with single receiver coils but benefits from multi-element coil arrays. The algorithm is validated for trains of 16 spin echoes with a spacing of 10 to 12 ms using numerical simulations as well as human brain MRI at 3 Tesla (T). RESULTS: When compared with a standard T2 fitting procedure using fully sampled T2-weighted images, and depending on the available signal-to-noise ratio and number of coil elements, model-based nonlinear inverse reconstructions for both simulated and in vivo MRI data yield accurate T2 estimates for undersampling factors of 5 to 10. CONCLUSION: This work describes a promising strategy for T2 weighted MRI that simultaneously offers accurate T2 relaxation times and properly T2-weighted images at arbitrary echo times. For a standard spin-echo MRI sequence with Cartesian encoding, the method allows for a much higher degree of undersampling than obtainable by conventional parallel imaging. PMID- 21780235 TI - Clinical functional MRI of sensorimotor cortex using passive motor and sensory stimulation at 3 Tesla. AB - PURPOSE: To establish a passive motor paradigm for clinical functional MRI (fMRI) that could be beneficial for patients with motor or attention deficits who are not able to perform active motor tasks. MATERIALS AND METHODS: A novel standardized sensorimotor fMRI protocol was applied in 16 healthy volunteers at 3 Tesla (T) using active and passive motor tasks as well as sensory stimulation of hands and feet. Data analysis was carried out individually using a dynamic thresholding routine. RESULTS: Active motor tasks yielded time efficient and robust blood-oxygen-level-dependent (BOLD) signals in primary motor cortex. Noteworthy, it was possible to achieve equal activation levels within identical anatomical localization for passive and active motor tasks with these paradigms. CONCLUSION: Patients unable to perform active movements can benefit from paradigms with passive motor and sensory stimulation. Therefore, we recommend these paradigms for functional somatotopic mapping of the central region at 3T in clinical routine. PMID- 21780236 TI - Fully automatic geometry planning for cardiac MR imaging and reproducibility of functional cardiac parameters. AB - PURPOSE: To establish operator-independent, fully automated planning of standard cardiac geometries and to determine the impact on interstudy reproducibility of cardiac functional parameters. MATERIALS AND METHODS: Cardiac MR imaging was done in 50 patients referred for left-ventricular function assessment. In all patients, first standard manual planning was performed followed by automatic planning (AUTO1) and repeat automatic planning (AUTO2) after repositioning the patient to investigate interstudy reproducibility. Cardiac functional parameters were assessed and cine scans were visually graded on a 4-point scale from nondiagnostic to excellent. RESULTS: Overall success rate of AUTO was 94% with good to excellent geometry planning in >94% of cine standard views. Comparing manual versus fully automated planning, a high agreement of cardiac functional parameters (Lin's concordance correlation coefficient, 0.91 to 0.99) with minimal percent bias (0.24 to 3.84%) was found. In addition, a high interstudy reproducibility of automatic planning was demonstrated (Lin's concordance correlation coefficient, 0.89 to 0.99; percent bias, 0.38 to 5.04%; precision, 3.46 to 9.09%). CONCLUSION: Fully automated planning of cardiac geometries could reliably be performed in patients showing a variety of cardiovascular pathologies. Standard cardiac geometries were precisely replicated and functional parameters were highly accurate. PMID- 21780237 TI - MR properties of brown and white adipose tissues. AB - PURPOSE: To explore the MR signatures of brown adipose tissue (BAT) compared with white adipose tissue (WAT) using single-voxel MR spectroscopy. MATERIALS AND METHODS: (1) H MR STEAM spectra were acquired from a 3 Tesla clinical whole body scanner from seven excised murine adipose tissue samples of BAT (n=4) and WAT (n=3). Spectra were acquired at multiple echo times (TEs) and inversion times (TIs) to measure the T1, T2, and T2-corrected peak areas. A theoretical triglyceride model characterized the fat in terms of number of double bonds (ndb) and number of methylene-interrupted double bonds (nmidb). RESULTS: Negligible differences between WAT and BAT were seen in the T1 and T2 of fat and the T2 of water. However, the water fraction in BAT was higher (48.5%) compared with WAT (7.1%) and the T1 of water was lower in BAT (618 ms) compared with WAT (1053 ms). The fat spectrum also differed, indicating lower levels of unsaturated triglycerides in BAT (ndb=2.7, nmidb=0.7) compared with WAT (ndb=3.3, nmidb=1.0). CONCLUSION: We have demonstrated that there are several key MR-based signatures of BAT and WAT that may allow differentiation on MR imaging. PMID- 21780238 TI - Evaluation of adipose tissue volume quantification with IDEAL fat-water separation. AB - PURPOSE: To validate iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) for adipose tissue volume quantification. IDEAL allows MRI images to be produced only from adipose-containing tissues; hence, quantifying adipose tissue should be simpler and more accurate than with current methods. MATERIALS AND METHODS: Ten healthy controls were imaged with 1.5 Tesla (T) Spin Echo (SE), 3.0T T1-weighted spoiled gradient echo (SPGR), and 3.0T IDEAL-SPGR. Images were acquired from the abdomen, pelvis, mid-thigh, and mid calf. Mean subcutaneous and visceral adipose tissue volumes were compared between the three acquisitions for each subject. RESULTS: There were no significant differences (P>0.05) between the three acquisitions for subcutaneous adipose tissue volumes. However, there was a significant difference (P=0.0002) for visceral adipose tissue volumes in the abdomen. Post hoc analysis showed significantly lower visceral adipose tissue volumes measured by IDEAL versus 1.5T (P<0.0001) and 3.0T SPGR (P<0.002). The lower volumes given by IDEAL are due to its ability to differentiate true visceral adipose tissue from other bright structures like blood vessels and bowel content that are mistaken for adipose tissue in non-fat suppressed images. CONCLUSION: IDEAL measurements of adipose tissue are equivalent to established 1.5T measurement techniques for subcutaneous depots and have improved accuracy for visceral depots, which are more metabolically relevant. PMID- 21780239 TI - The impact of voluntary health insurance on health care utilization and out-of pocket payments: new evidence for Vietnam. AB - Vietnam aims to achieve full coverage of health insurance in 2015. An increasing type of health insurance in Vietnam is voluntary health insurance. Although there are many studies on the implementation of voluntary health insurance in Vietnam, little is known on the causal impact of voluntary health insurance. This paper measures the impact of voluntary health insurance on health care utilization and out-of-pocket payments using Vietnam Household Living Standard Surveys in 2004 and 2006. It was found out that voluntary health insurance helps the insured people increase the annual outpatient and inpatient visits by around 45% and 70%, respectively. However, the effect of voluntary health insurance on out-of-pocket expenses on health care services is not statistically significant. PMID- 21780240 TI - Skin care behaviors among melanoma survivors. AB - INTRODUCTION: Clinical recommendations for survivors of melanoma generally include skin care behaviors, including regular physician and skin self examination to identify any recurrences or second primary disease early, as well as sun protection. We measured skin care behaviors in a population-based sample of melanoma survivors. METHODS: Melanoma survivors were approached through the regional National Cancer Institute-funded cancer registry (Surveillance, Epidemiology, and End Results) and recruited to this study with a response rate of approximately 75%, for a total sample of n = 313. RESULTS: The sample was 99% Caucasian, 56% female, 44% male, 81% married, 62% college educated, and 48% with an income over 70 K annually, with an average age of 56 years. Over the last 7 days, a total of 45% reported wearing sunscreen, 59% reported wearing long sleeves, 80% reported wearing pants, 35% reported wearing something on the head, and 36% stayed in available shade. Skin self-examination behaviors were reported at relatively low frequencies, with only 22% performing a thorough check on skin. A total of 88% of survivors reported that their physician checked their skin in the past few years by having all clothes removed. A multivariate analysis using logistic regression indicated that perceived risk was positively related to having the skin checked by a medical provider but no other skin protection behaviors. Gender effects were also detected for wearing sunscreen and wearing a hat or scarf. DISCUSSION: Data indicate that melanoma survivors are performing sun protection behaviors to a moderate extent. Future studies can address barriers to consistent use of these behaviors in melanoma survivors. PMID- 21780241 TI - Effectiveness of QUICATOUCH: a computerised touch screen evaluation for pain and distress in ambulatory oncology patients in Newcastle, Australia. AB - OBJECTIVE: To describe the change in pain and distress over time to demonstrate the effectiveness of the QUICATOUCH program in an outpatient oncology population. METHODS: Descriptive study of the first 29 months of the QUICATOUCH program (13 736 assessments for 5775 patients). A longitudinal cohort design was used to examine the patients with three or more assessments (8129 assessments for 1778 patients). Effectiveness of this complex intervention (repeated assessment, clinician report and referral to speciality psycho-oncology service) was examined using: reduction in proportion over threshold for pain and distress, predictors of mean pain and distress scores and comparison of the number of new patients treated by the psycho-oncology service during the study and in the preceding 29 months. RESULTS: Pain and distress declined during the study. The risk of being over threshold at endpoint was reduced for pain (odds ratio (OR) 0.70, confidence interval (CI) 95% 0.60-0.81) and for distress (OR 0.58 CI 95% 0.49-0.68) with baseline as referent level. Three variables predicted the mean pain: clinic type, current radiotherapy treatment and distress score; and five predicted mean distress: time, gender, clinic type, age and pain score. There was an increase of 40% (533v747) in new patients treated by the psycho-oncology service. CONCLUSIONS: The QUICATOUCH assessment for pain and distress was implemented into usual clinical practice with reasonable coverage of patients for modest cost. It was effective in monitoring the patients over time, contributed to a reduction in pain and distress, whilst appropriately increasing the number of new patients reaching psychological treatment as part of the clinical service. PMID- 21780242 TI - Regulation of early Xenopus development by the PIAS genes. AB - Originally identified as cytokine inhibitors, protein inhibitors of activated STAT (PIAS) are shown to regulate activities of a plethora of proteins and influence diverse processes such as immune response, cancer formation, and cell cycle progression. However, the roles of PIAS during vertebrate embryogenesis are less understood. In this study, we report isolation and initial characterization of all four PIAS genes from Xenopus laevis. The Xenopus PIAS genes are expressed throughout early development and have overlapping and distinct expression patterns, with, for example, high levels of PIAS2 in the notochord and strong expression of PIAS4 in the neural and neural crest derivatives. Overexpression of PIAS disrupts mesoderm induction and impairs body axis formation. PIAS proteins have differential ability to regulate signals from the growth factors activin, bone morphogenetic protein 4 (BMP4), and Wnt8. Our data suggest that Xenopus PIAS play important roles in mesodermal induction and patterning during early frog development. PMID- 21780243 TI - Differential regional expression of multiple ADAMs during feather bud formation. AB - The expression of seven members of the ADAM family was investigated by in situ hybridization in the developing feather buds of chicken. The expression profiles of the ADAMs in the cells and tissues of the feather buds differ from each other. ADAM9, ADAM10, and ADAM17 are expressed in the epidermis of the feather bud, whereas ADAM23 expression is restricted to the bud crest, with a distribution similar to that of sonic hedgehog. ADAM13 is not only expressed in the epidermis, but also in restricted regions of the dermis. Both ADAM12 and ADAM22 are expressed in the dermis of the feather bud, with an opposite mediolateral and anteroposterior polarity. Furthermore, the mRNAs of all investigated ADAMs show regional differences in their expression, for example, in the neck and in the roots of the leg and wing. These results suggest that ADAMs play a variety of roles during avian feather bud formation. PMID- 21780245 TI - New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects. AB - The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. PMID- 21780244 TI - Transforming growth factor Beta2 is required for valve remodeling during heart development. AB - Although the function of transforming growth factor beta2 (TGFbeta2) in epithelial mesenchymal transition (EMT) is well studied, its role in valve remodeling remains to be fully explored. Here, we used histological, morphometric, immunohistochemical and molecular approaches and showed that significant dysregulation of major extracellular matrix (ECM) components contributed to valve remodeling defects in Tgfb2(-/-) embryos. The data indicated that cushion mesenchymal cell differentiation was impaired in Tgfb2(-/-) embryos. Hyaluronan and cartilage link protein-1 (CRTL1) were increased in hyperplastic valves of Tgfb2(-/-) embryos, indicating increased expansion and diversification of cushion mesenchyme into the cartilage cell lineage during heart development. Finally, Western blot and immunohistochemistry analyses indicate that the activation of SMAD2/3 was decreased in Tgfb2(-/-) embryos during valve remodeling. Collectively, the data indicate that TGFbeta2 promotes valve remodeling and differentiation by inducing matrix organization and suppressing cushion mesenchyme differentiation into cartilage cell lineage during heart development. PMID- 21780246 TI - Influence of anti-inflammatory administration in collagen maturation process during orthodontic tooth movement. AB - Bone formation is essential to orthodontic tooth movement and bone is formed by collagen. To analyze the collagen maturation process on bone matrix neoformed under nonsteroidal and steroidal treatment during orthodontic tooth movement by polarized microscopy, male Wistar rats (n = 90) were randomly divided into three groups (n = 30): C (control), NSAID (potassium diclofenac) and SAID (disodic phosphate dexamethasone). The animals of the C group received 0.9% saline solution; NSAID group received 5 mg/kg potassium diclofenac (CATAFLAM(r)); and SAID group received 2 mg/kg phosphate dissodic dexamethasone (DEXANIL(r)). Animals were sacrificed 3, 7 or 14 days after the placement of orthodontic appliances and the upper first molars were processed histologically and stained with picrosirius. Bone formation was evaluated under polarized light microscopy and 4.5 Image Pro-Plus(r) software calculated the percentage of immature/mature collagen present in the groups. On the third days after force application, SAID and NSAID groups showed greater proportion of immature collagen than C group. On the seventh and fourteenth days, there was a lower proportion of mature collagen only in the SAID group (P < 0.001). These data demonstrate that dexamethasone delays the collagen maturation process in established bone matrix. PMID- 21780247 TI - Preservation, development, and hatching of resting eggs in the freshwater rotifer Brachionus calyciflorus pallas. AB - The resting eggs of Brachionus calyciflorus produced under laboratory by manipulating various environmental conditions were subjected to preservation for long-term storage. Preservation strategies included as storing freshly collected resting eggs, dry resting eggs, and storing at 4 degrees C. Results showed that the resting eggs preserved by drying as they were able to maintain the viability without much variation in the hatchability. The scanning electron micrographs clearly depicted the surface damage as well as change in the shape and surface topography due to the storage. The resting eggs thus stored were traced for their normal embryonic development, during which as many as 11 stages were traced and time taken for each stage of development was observed. Microscopic observations revealed that the first four stages represented the development of embryo and thereafter around 16-18 h extrution of neonate from egg occurred. At 18-19 h of development the characteristic of anterior and posterior spines appeared in the neonate. Just released neonate, after 4-5 h of development reached adult stage. Overall the hatching and embryonic development of the resting eggs preserved by "drying" were normal and hence this method could be adopted for long-term storage. PMID- 21780248 TI - Observation particle morphology of colloidal system by conventional SEM with an improved specimen preparation technique. AB - On the basis of our previous report that polymer emulsion with different viscosity can be investigated by conventional scanning electron microscopy (SEM), we have developed an improved specimen preparation technique for obtaining particle morphology and size of colloidal silver, collagen, glutin, and polymer microspheres. In this study, we expect to provide a means for charactering the three-dimensional surface microstructure of colloidal particles. Dilution of the samples with appropriate volatile solvent like ethanol is effective for SEM specimen preparation. At a proper ratio between sample and ethanol, the colloidal particles are dispersed uniformly in ethanol and then deposited evenly on the substrate. Different drying methods are studied to search a proper drying condition, in which the small molecule solvent is removed without destroying the natural particle morphology. And the effects of ethanol in the specimen preparation process are described by analyzing the physicochemical properties of ethanol. The specimen preparation technique is simple and can be achieved in common laboratory for charactering the particle morphology of colloidal system. PMID- 21780249 TI - Investigations on the leaf anatomy and ultrastructure of grapevine (Vitis vinifera) under heat stress. AB - Leaf anatomical and ultrastructural responses of "Razegui" and "Muscat Italia" grapevine cultivars to high temperatures were studied under controlled conditions (T > 36 degrees C), based on photonic and electron microscopy. Histological studies performed on leaves from heat-stressed and control grapevines revealed thicker leaf blades under high temperature conditions. Environmental scanning electron microscopy of leaf surfaces from both cultivars allowed observing sinuate epidermal cells on the leaves of grapevines cultivated under heat stress and irregular giant oblong pores on their adaxial surface. When observed by transmission electron microscopy, leaf cross sections in grapevines cultivated under high temperature conditions exhibited folded cuticle and cell wall on the adaxial epidermis layer. Therefore, significantly greater cell wall thicknesses were measured under heat stress than control conditions in both cultivars. Regarding chloroplasts, they were more globular in shape under heat stress compared with control conditions and had disorganized thylakoids with a reduced thickness of grana stacking. The size of starch granule decreased, while the number of plastoglobules increased with heat stress, indicating a reduced carbon metabolism and a beginning of senescence within the 3-month heat stress period. This study confirms widespread adaptive properties in two grapevine cultivars in response to high temperature stress. PMID- 21780250 TI - Morphology and histochemistry of the intramandibular glands in Attini and Ponerini (Hymenoptera, Formicidae) species. AB - An understanding of the internal morphology of the ant mandible is important in explaining the relationship between the exocrine system and the behavioral and phylogenetic characteristics of different subfamilies of Formicidae. In this study, we investigated the occurrence of intramandibular glands in ants from the Ponerini (Ponerinae) and Attini (Myrmicinae). These ants possess glands from classes I and III, and secretory epithelial cells with a reservoir. The intramandibular glands show a distinct histology in the studied species, varying in their location, degree of development, and chemical content. Using this information, it is possible to hypothesize that the glands from different tribes produce different substances, which may indicate a variety of functions, depending on the chemical nature of the cellular constituents. A cladistic analysis using the characters of the intramandibular glands separated both tribes, suggesting that structural differences in the intramandibular glands may contribute to future phylogenetic studies of the Formicidae. PMID- 21780251 TI - Growth factors, CD34 positive cells, and fibrin network analysis in concentrated growth factors fraction. AB - An interesting clinical option for optimizing healing tissue is the use of platelet concentrate. Platelets contain high quantities of growth factors, among these TGF-beta1 and VEGF, which are known to be implicated in tissue regeneration. CGF is produced by processing blood samples with a special centrifuge device; three layers are formed: top acellular plasma (PPP), middle CGF and bottom red blood cells (RBC) layers. Given that to date there are no data concerning the biological characteristic of CGF, the aim of this study was to evaluate the presence of TGF-beta1 and VEGF in CGF and also in PPP and RBC layers. In addition, since circulating stem cells are recruited from blood to injured tissue for healing we also evaluated the presence of CD34 positive cells. Our data show the presence of TGF-beta1 and VEGF in CGF and RBC layers. In addition, we show CD34 positive cells in CGF. PMID- 21780252 TI - The mitochondrial electron transport chain is dispensable for proliferation and differentiation of epidermal progenitor cells. AB - Tissue stem cells and germ line or embryonic stem cells were shown to have reduced oxidative metabolism, which was proposed to be an adaptive mechanism to reduce damage accumulation caused by reactive oxygen species. However, an alternate explanation is that stem cells are less dependent on specialized cytoplasmic functions compared with differentiated cells, therefore, having a high nuclear-to-cytoplasmic volume ratio and consequently a low mitochondrial content. To determine whether stem cells rely or not on mitochondrial respiration, we selectively ablated the electron transport chain in the basal layer of the epidermis, which includes the epidermal progenitor/stem cells (EPSCs). This was achieved using a loxP-flanked mitochondrial transcription factor A (Tfam) allele in conjunction with a keratin 14 Cre transgene. The epidermis of these animals (Tfam(EKO)) showed a profound depletion of mitochondrial DNA and complete absence of respiratory chain complexes. However, despite a short lifespan due to malnutrition, epidermal development and skin barrier function were not impaired. Differentiation of epidermal layers was normal and no proliferation defect or major increase of apoptosis could be observed. In contrast, mice with an epidermal ablation of prohibitin-2, a scaffold protein in the inner mitochondrial membrane, displayed a dramatic phenotype observable already in utero, with severely impaired skin architecture and barrier function, ultimately causing death from dehydration shortly after birth. In conclusion, we here provide unequivocal evidence that EPSCs, and probably tissue stem cells in general, are independent of the mitochondrial respiratory chain, but still require a functional dynamic mitochondrial compartment. PMID- 21780253 TI - Synergistic anticancer activity of curcumin and catechin: an in vitro study using human cancer cell lines. AB - The most practical approach to reduce morbidity and mortality of cancer is to delay the process of carcinogenesis by usage of anticancer agents. This necessitates that safer compounds are to be critically examined for anticancer activity especially, those derived from natural sources. A spice commonly found in India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa and the major active component is a phytochemical termed curcumin. Green tea is one of the most popular beverages used worldwide, produced from the leaves of evergreen plant Camellia sinensis and the major active ingredients are polyphenolic compounds known as catechins. In this study, synergistic anticancer activity of curcumin and catechin was evaluated in human colon adenocarcinoma HCT 15, HCT 116, and human larynx carcinoma Hep G-2 cell lines. Although, both curcumin or catechin inhibited the growth of above cell lines, interestingly, in combination of both these compounds highest level of growth control was observed. The anticancer activity shown is due to cytotoxicity, nuclear fragmentation as well as condensation, and DNA fragmentation associated with the appearance of apoptosis. These results suggest that curcumin and catechin in combination can inhibit the proliferation of HCT 15, HCT 116, as well as Hep G-2 cells efficiently through induction of apoptosis. PMID- 21780257 TI - Cyano groups as probes of protein microenvironments and dynamics. PMID- 21780258 TI - Metastable linkage isomerism in [Ni(Et4dien)(NO2)2]: a combined thermal and photocrystallographic structural investigation of a nitro/nitrito interconversion. PMID- 21780254 TI - Association of candidate genes with phenotypic traits relevant to anorexia nervosa. AB - This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein, we investigate alternative phenotypes associated with AN. In 1762 females, using regression analyses, we examined the following: (i) lowest illness-related attained body mass index; (ii) age at menarche; (iii) drive for thinness; (iv) body dissatisfaction; (v) trait anxiety; (vi) concern over mistakes; and (vii) the anticipatory worry and pessimism versus uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes. PMID- 21780259 TI - Active oxygen on a Au/TiO2 catalyst: formation, stability, and CO oxidation activity. PMID- 21780260 TI - Smart foams: switching reversibly between ultrastable and unstable foams. PMID- 21780261 TI - Softening and hardening of macro- and nano-sized organic cocrystals in a single crystal transformation. PMID- 21780262 TI - X-ray photolysis to release ligands from caged reagents by an intramolecular antenna sensitive to magnetic resonance imaging. PMID- 21780263 TI - Total synthesis of paecilospirone. PMID- 21780264 TI - Concise syntheses of strychnine and englerin A: the power of reductive cyclizations triggered by samarium iodide. PMID- 21780265 TI - Synthesis of angularly fused aromatic compounds from alkenyl enediynes by a tandem radical cyclization process. PMID- 21780266 TI - Characterization of the isochromen-4-yl-gold(I) intermediate in the gold(I) catalyzed glycosidation of glycosyl ortho-alkynylbenzoates and enhancement of the catalytic efficiency thereof. PMID- 21780267 TI - Versatile fabrication of intact three-dimensional metallic butterfly wing scales with hierarchical sub-micrometer structures. PMID- 21780268 TI - Tris(thiocyanate) ruthenium(II) sensitizers with functionalized dicarboxyterpyridine for dye-sensitized solar cells. PMID- 21780269 TI - N-heterocyclic carbene catalyzed umpolung of Michael acceptors for intermolecular reactions. PMID- 21780273 TI - SNAP dendrimers: multivalent protein display on dendrimer-like DNA for directed evolution. AB - Display systems connect a protein with the DNA encoding it. Such systems (e.g., phage or ribosome display) have found widespread application in the directed evolution of protein binders and constitute a key element of the biotechnological toolkit. In this proof-of-concept study we describe the construction of a system that allows the display of multiple copies of a protein of interest in order to take advantage of avidity effects during affinity panning. To this end, dendrimer like DNA is used as a scaffold with docking points that can join the coding DNA with multiple protein copies. Each DNA construct is compartmentalised in water-in oil emulsion droplets. The corresponding protein is expressed, in vitro, inside the droplets as a SNAP-tag fusion. The covalent bond between DNA and the SNAP-tag is created by reaction with dendrimer-bound benzylguanine (BG). The ability to form dendrimer-like DNA straightforwardly from oligonucleotides bearing BG allowed the comparison of a series of templates differing in size, valency and position of BG. In model selections the most efficient constructs show recoveries of up to 0.86 % and up to 400-fold enrichments. The comparison of mono- and multivalent constructs suggests that the avidity effect enhances enrichment by up to fivefold and recovery by up to 25-fold. Our data establish a multivalent format for SNAP-display based on dendrimer-like DNA as the first in vitro display system with defined tailor-made valencies and explore a new application for DNA nanostructures. These data suggest that multivalent SNAP dendrimers have the potential to facilitate the selection of protein binders especially during early rounds of directed evolution, allowing a larger diversity of candidate binders to be recovered. PMID- 21780274 TI - Imaging an ionic liquid adlayer by scanning tunneling microscopy at the solid|vacuum interface. PMID- 21780275 TI - The use of gadolinium in patients with contrast allergy or renal failure requiring coronary angiography, coronary intervention, or vascular procedure. AB - Coronary artery angiography remains an important procedure for the assessment of coronary arteries. It requires injection of iodinated contrast for the opacification of coronary arteries. Severe allergy to iodine contrast and renal insufficiency are two main problems with iodine-based contrast media. Gadolinium (Gd) has different chemical structure with no cross reactivity with iodine-based contrast media in patients with iodine allergy. The use of Gd is commonly used in contrast-enhanced magnetic resonance imaging for image enhancement, making it a potential alternative in patients in whom iodine is contraindicated. The aim of this manuscript is to review the available literature on the use of Gd in patients with contraindication to iodine contrast due to allergy or in patients with severe renal failure requiring coronary or vascular procedures. PMID- 21780276 TI - Radial artery perforation after coronary intervention: is there a role for covered coronary stent? AB - We report a case of right radial artery perforation observed after successful stenting of left anterior descending artery through right radial access. This was noticed immediately after completion of the procedure, when the patient described right forearm pain and we noticed swelling of the right forearm. She was treated by a prolonged guiding catheter positioning proximal to the perforated segment, external compression by sphygmomanometer cuff followed by prolonged balloon inflation across the perforation. All these measures failed to stop the bleeding. Complete reconstruction of the perforation was achieved by PTFE covered coronary stent. To our knowledge, this is the first case to be managed utilizing this approach. PMID- 21780277 TI - Percutaneous closure of a large iatrogenic fistula between the inferior vena cava and the pulmonary vein in a child. AB - We hereby describe a complex late postoperative veno-venous fistula in a child, successfully treated by an interventional percutaneous procedure. It is a unique complication of diaphragmatic hernia surgery that has never been reported before: a late postoperative iatrogenic fistula, between the inferior vena cava and the right lower pulmonary vein, discovered in a 6-year-old boy operated at the age of 4 months for a right diaphragmatic hernia. The right to left shunt was completely and uneventfully suppressed by a percutaneous procedure separating the systemic venous return from the pulmonary venous return with an Amplatzer Vascular Plug II. PMID- 21780278 TI - Stent sizing by coronary computed tomographic angiography: comparison with conventional coronary angiography in an experienced setting. AB - OBJECTIVES: The goal was to compare stent sizing by coronary computed tomographic angiography (CCTA) with that deployed in an experienced setting based upon conventional coronary angiography (CA). BACKGROUND: Stent sizing is currently performed by visual estimation, with infrequent guidance by intravascular ultrasound. CCTA permits quantitative determination of stent length (Stent L) and diameter (Stent D). METHODS: Projected L (CTA-Stent L) and D (CTA-Stent D) were determined from CCTA obtained in 248 patients with 352 lesions undergoing percutaneous coronary intervention within 4 months of the CCTA, and were compared to the Stent-L and Stent-D of the actually deployed stents. The effects of lesion modification and calcified plaque were also evaluated. RESULTS: There were significant correlations between CTA-Stent L and Stent L (r = 0.656, P < 0.0001) and between CTA-Stent D and Stent D (r = 0.40, P < 0.001). Median predicted CTA Stent L was slightly longer (20 mm vs. 18 mm, P < 0.0001) and predicted CTA-Stent D was slightly smaller (3.0 mm vs. 3.2 mm, P < 0.0001) than Stent-L and Stent-D, respectively. The differences were unchanged in stents with lesion modification by pre-dilation or intracoronary nitroglycerin. CTA Stent-L and CTA Stent-D increased significantly with increasing calcium (P < 0.0001 and P = 0.019, respectively). CONCLUSIONS: (1) There are significant correlations between CCTA and CA based stent sizing in an experienced setting. (2) CCTA projects slightly longer and slightly smaller diameter stents than those deployed during PCI irrespective of lesion modification; the small differences are unlikely to have clinical significance. (3) CCTA may offer a noninvasive alternative to intravascular ultrasound for stent planning. PMID- 21780279 TI - Successful removal of an entrapped rotablation burr by extracting drive shaft sheath followed by balloon dilatation. AB - Burr entrapment is a rare but serious complication during rotational atherectomy (RA). Although emergent surgical removal is a reliable option for this complication, surgical removal is invasive and takes several hours. Balloon inflation just proximal to the burr was the previously-reported nonsurgical option for burr removal. However, this method needed large guide catheter lumen (>=8 Fr). We present a case of 67-year-old male on chronic hemodialysis. During RA for severe stenosis of the right coronary artery, the RA burr was entrapped. We cut off the drive shaft, the drive shaft sheath, and the RA wire together near the advancer, and then we removed the drive shaft sheath. After removing the drive shaft sheath, the 2.5 mm balloon easily entered the 7-Fr guide catheter. We inflated that balloon to a pressure of 18 atm. The burr was easily removed immediately after balloon deflation. Removal of the drive shaft sheath following balloon dilatation is a new, nonsurgical bailout method for a burr that becomes entrapped during RA. Since removal of the drive shaft sheath following balloon dilatation can be applied to 7 Fr as well as 6 Fr guide systems, this method may be of considerable benefit when operators use 7 Fr or 6 Fr systems. PMID- 21780280 TI - Intentionally induced swirling flow may improve the hemodynamic performance of coronary bifurcation stenting. AB - OBJECTIVES AND BACKGROUND: Bifurcation stenting represents a challenge for the high rate of restenosis that has close correlations with local hemodynamics. This study sought to test the hypothesis that by intentionally inducing swirling flow the hemodynamic performance of bifurcation stenting can be improved. METHODS: The hemodynamics of bifurcation stenting with and without swirling flows were numerically simulated and compared. RESULTS: The results revealed that swirling flow significantly suppressed flow disturbance of blood at the bifurcation and WSS at two critical regions, the outer wall of the bifurcation ostium and the floor wall opposite the branching, was enhanced. CONCLUSIONS: This study therefore suggests that intentionally inducing swirling flow might be a good strategy in bifurcation stenting. PMID- 21780281 TI - Resistance mechanism to carboxylic acid amide fungicides in the cucurbit downy mildew pathogen Pseudoperonospora cubensis. AB - BACKGROUND: Pseudoperonospora cubensis, the causal oomycete agent of cucurbit downy mildew, is responsible for enormous crop losses in many species of Cucurbitaceae, particularly in cucumber and melon. Disease control is mainly achieved by combinations of host resistance and fungicide applications. However, since 2004, resistance to downy mildew in cucumber has been overcome by the pathogen, thus driving farmers to rely only on fungicide spray applications, including carboxylic acid amide (CAA) fungicides. Recently, CAA-resistant isolates of P. cubensis were recovered, but the underlying mechanism of resistance was not revealed. The purpose of the present study was to identify the molecular mechanism controlling resistance to CAAs in P. cubensis. RESULTS: The four CesA (cellulose synthase) genes responsible for cellulose biosynthesis in P. cubensis were characterised. Resistant strains showed a mutation in the CesA3 gene, at position 1105, leading to an amino acid exchange from glycine to valine or tryptophan. Cross-resistance tests with different CAAs indicated that these mutations lead to resistance against all tested CAAs. CONCLUSION: Point mutations in the CesA3 gene of P. cubensis lead to CAA resistance. Accurate monitoring of these mutations among P. cubensis populations may improve/facilitate adequate recommendation/deployment of fungicides in the field. PMID- 21780282 TI - Ethyl formate plus methyl isothiocyanate--a potential liquid fumigant for stored grains. AB - BACKGROUND: Methyl bromide is being phased out for use on stored commodities, as it is listed as an ozone-depleting substance, and phosphine is the fumigant widely used on grains. However, phosphine resistance occurs worldwide, and phosphine fumigation requires a long exposure period and temperatures of >15 degrees C. There is an urgent requirement for the development of a fumigant that kills insects quickly and for phosphine resistance management. This paper reports on a new fumigant formulation of 95% ethyl formate plus 5% methyl isothiocyanate as an alternative fumigant for stored grains. RESULTS: The formulation is stable for at least 4 months of storage at 45 degrees C. A laboratory bioassay with the formulation showed that it controlled all stages of Sitophilus oryzae (L.), Sitophilus granarius (L.), Tribolium castaneum (Herbst), Rhyzopertha dominica (F.), Trogoderma variabile Ballion and Callosobruchus maculatus (Fabricius) in infested wheat, barley, oats and peas at 80 mg L(-1) for 5 days, and in canola at both 40 mg L(-1) for 5 days and 80 mg L(-1) for 2 days at 25+/-2 degrees C. After an 8-14 day holding period, residues of ethyl formate and methyl isothiocyanate in wheat, barley, peas and canola were below the experimental permit levels of 1.0 and 0.1 mg kg(-1). However, fumigated oats needed an 18 day holding period. CONCLUSIONS: The findings suggest that the ethyl formate plus methyl isothiocyanate formulation has potential as a fumigant for the control of stored-grain insect pests in various commodities. PMID- 21780283 TI - ZnO hollow-sphere nanofilm-based high-performance and low-cost photodetector. AB - The first high-performance ZnO hollow-sphere nanofilm-based photodetector is constructed by 'water-oil interfacial self-assembly' of polystyrene (PS)/ZnO core/shell nanospheres and subsequent thermal treatment. The versatile growth substrate, general fabrication strategy, and high performance including excellent sensitivity, high spectral selectivity, and fast response times show the current work to be a new paradigm in the preparation of hollow-sphere nanofilm-based photodetectors. PMID- 21780284 TI - A new high-throughput method utilizing porous silica-based nano-composites for the determination of partition coefficients of drug candidates. AB - We show that highly porous silica-based nanoparticles prepared via micro-emulsion and sol-gel techniques are stable colloids in aqueous solution. By incorporating a magnetic core into the porous silica nano-composite, it is found that the material can be rapidly separated (precipitated) upon exposure to an external magnetic field. Alternatively, the porous silica nanoparticles without magnetic cores can be equally separated from solution by applying a high-speed centrifugation. Using these silica-based nanostructures a new high-throughput method for the determination of partition coefficient for water/n-octanol is hereby described. First, a tiny quantity of n-octanol phase is pre-absorbed in the porous silica nano-composite colloids, which allows an establishment of interface at nano-scale between the adsorbed n-octanol with the bulk aqueous phase. Organic compounds added to the mixture can therefore undergo a rapid partition between the two phases. The concentration of drug compound in the supernatant in a small vial can be determined by UV-visible absorption spectroscopy. With the adaptation of a robotic liquid handler, a high-throughput technology for the determination of partition coefficients of drug candidates can be employed for drug screening in the industry based on these nano-separation skills. The experimental results clearly suggest that this new method can provide partition coefficient values of potential drug candidates comparable to the conventional shake-flask method but requires much shorter analytical time and lesser quantity of chemicals. PMID- 21780285 TI - Affinity capillary electrophoresis and quantum mechanical calculations applied to the investigation of hexaarylbenzene-based receptor binding with lithium ion. AB - In this study, two complementary approaches, affinity capillary electrophoresis (ACE) and quantum mechanical density functional theory (DFT) calculations, have been employed for quantitative characterization and structure elucidation of the complex between hexaarylbenzene (HAB)-based receptor R and lithium ion Li(+) . First, by means of ACE, the apparent binding constant of LiR(+) complex (K LiR +) in methanol was determined from the dependence of the effective electrophoretic mobilities of LiR(+) complex on the concentration of lithium ions in the 25 mM Tris/50 mM chloroacetate background electrolyte (BGE) using non-linear regression analysis. Prior to regression analysis, the effective electrophoretic mobilities of the LiR(+) complex were corrected to reference temperature 25 degrees C and constant ionic strength 25 mM. The apparent binding constant of the LiR(+) complex in the above methanolic BGE was evaluated as logK LiR + = 1.15+/-0.09. Second, the most probable structures of nonhydrated LiR(+) and hydrated LiR(+).3H(2)O complexes were derived by DFT calculations. The optimized structure of the hydrated LiR(+).3H(2)O complex was found to be more realistic than the nonhydrated LiR(+) complex because of the considerably higher binding energy of LiR(+).3H(2)O complex (500.4 kJ/mol) as compared with LiR(+) complex (427.5 kJ/mol). PMID- 21780286 TI - One-step isolation of gamma-oryzanol from rice bran oil by non-aqueous hydrostatic countercurrent chromatography. AB - The value-added gamma-oryzanol was purified in one step from crude rice bran oil (RBO) using a preparative hydrostatic countercurrent chromatography (hydrostatic CCC) method, operating in the dual mode. The fractionation was performed using a non-aqueous biphasic solvent system consisting of heptane-acetonitrile-butanol (1.8:1.4:0.7, v/v/v), leading rapidly to the target compounds. Transfer of the analytical CCC method to large-scale isolation was also carried out yielding a high quantity-high purity fraction of gamma-oryzanol. In addition, a fraction of hydroxylated triterpene alcohol ferulates (polar gamma-oryzanol) was clearly separated and obtained. Furthermore, a fast HPLC-APCI(+/-)-HRMS method was developed and applied for the identification of gamma-oryzanol as well as the polar gamma-oryzanol in RBO and the resulting fractions. The purity of gamma oryzanol fraction was estimated as 97% based on HPLC-APCI-HRMS analysis. PMID- 21780287 TI - Nonionic surfactant enhanced semipermanent coatings for capillary electrophoresis of inorganic anions without use of organic additives. AB - Separation of inorganic anions by capillary electrophoresis (CE) is usually conducted in co-electroosmotic mode due to the large electrophoretic mobilities of inorganic anions. Semipermanent surfactant coatings have been shown to be effective for CE of inorganic anions due to their strong capability of electroosmotic flow (EOF) manipulation. However, semipermanent coatings often suffer from their unsatisfactory stability. In addition, organic solvent additives are usually required to adjust the selectivity, which also aggravate the degradation of coating. In this work, a novel semipermanent coating consisting of cationic Gemini surfactant 18-10-18 and nonionic surfactant Tween 20 was developed to separate inorganic anions in CE. This coating is easy to prepare and more stable than pure Gemini coating. The introduction of nonionic surfactant in the coating not only suppresses the reversed EOF but can also adjust the selectivity of separation. Good separations of six model anions were achieved, the separation efficiency was as high as 65040-169700 plates/m and the RSDs of the migration times were less than 0.5 and 2.5% for run-to-run and day-to day assays, respectively. Calibration curves were linear in the range of 0.05-5.0 mM; the detection limits ranged from 20 to 50 MUM. More importantly, no organic solvents are required in the background buffer to achieve the satisfactory separations. This guarantees the coating stability and makes the method greener than most of other methods for CE of inorganic anions. PMID- 21780288 TI - Magnetic solid-phase extraction based on magnetic carbon nanotube for the determination of estrogens in milk. AB - In this work, a novel method for the fabrication of magnetic carbon nanotubes based on 'aggregation wrap' was proposed. When carbon nanotubes and magnetic nanoparticles were vortically mixed in a solvent, the magnetic nanoparticles were wrapped into the carbon nanotube bundles that formed during the aggregation process, leading to the formation of magnetic carbon nanotubes. Thus, the resultant material can be separated from the solvent rapidly and conveniently by a magnet. Our investigation demonstrated that the 'aggregation wrap' mechanism for the preparation of magnetic composite is also applicable to other self aggregated micro/nanomaterials, including graphene, graphite, C(60), etc. To testify the feasibility of the magnetic composites in sample preparation, the resultant magnetic carbon nanotubes were applied as sorbents for magnetic solid phase extraction (MSPE) of estrogens in milk samples. Under optimized conditions, a rapid, convenient and efficient method for the determination of estrogens in milk samples was established by the combination of MSPE with high-performance liquid chromatography with fluorescence detector. The linearity range of the proposed method was 5-2000 MUg/L with correlation coefficients (R) of 0.9983 0.9994. The limit of detection (LOD) for three estrogens ranged from 1.21 to 2.35 MUg/L. The intra- and inter-day relative standard deviations (RSDs) were <9.3%. The reproducibility of the MSPE with different batches of magnetic carbon nanotubes was acceptable with RSD values <3.6%. PMID- 21780289 TI - Novel Pirkle-type quinine 3,5-dinitrophenylcarbamate chiral stationary phase implementing click chemistry. AB - A new Pirkle-anion exchange hybrid-type chiral stationary phase (CSP-1) has been synthesized by immobilizing 10,11-didehydroquinine 3,5-dinitrophenylcarbamate onto 3-azidopropyl silica gel using click chemistry (1,3-dipolar Huisgen cycloaddition). This chiral selector and CSP contain a strong pi-accepting 3,5 dinitrophenyl residue besides the pi-basic quinoline group and an ionizable tertiary amino group. In concert with ion pairing it offers pi-donor-pi-acceptor interactions resulting in an enhancement of the selectivity toward specific pi donating analytes such as aryloxypropionic acids and profens. A representative set of these analytes has been investigated under various chromatographic conditions (polar-organic, reversed- and normal-phase) leading to base-line enantioseparations with selectivity (alpha) values up to 1.8. Control experiments with related quinine tert-butylcarbamate phase grafted onto the surface either by thioether (Chiralpak QN-AX) or 1,2,3-triazole linker revealed the impact of the additional aromatic moiety in the chiral selector motif. PMID- 21780290 TI - PET imaging of CXCR4 receptors in cancer by a new optimized ligand. PMID- 21780291 TI - Chiral silver amides as effective catalysts for enantioselective [3+2] cycloaddition reactions. AB - Asymmetric [3+2] cycloaddition of alpha-aminoester Schiff bases with substituted olefins is one of the most efficient methods for the preparation of chiral pyrrolidine derivatives in optically pure form. In spite of its potential utility, applicable substrates for this method have been limited to Schiff bases that bear relatively acidic alpha-hydrogen atoms. Here we report a chiral silver amide complex for asymmetric [3+2] cycloaddition reactions. A silver complex prepared from silver bis(trimethylsilyl)amide (AgHMDS) and (R)-DTBM-SEGPHOS worked well in asymmetric [3+2] cycloaddition reactions of alpha-aminoester Schiff bases with several olefins to afford the corresponding pyrrolidine derivatives in high yields with remarkable exo- and enantioselectivities. Furthermore, alpha-aminophosphonate Schiff bases, which have less acidic alpha hydrogen atoms, also reacted with olefins with high exo- and enantioselectivities. The stereoselectivities of the [3+2] cycloadditions with maleate and fumarate suggested that the reaction proceeded by means of a concerted mechanism. An NMR spectroscopic study indicated that complexation of AgHMDS with the bisphosphine ligand was not complete, and that free AgHMDS, which did not show any significant catalytic activity, existed in the catalyst solution. This means that significant ligand acceleration occurred in the current reaction system. PMID- 21780292 TI - Alkylation effects on the energy transfer of highly vibrationally excited naphthalene. AB - The energy transfer of highly vibrationally excited isomers of dimethylnaphthalene and 2-ethylnaphthalene in collisions with krypton were investigated using crossed molecular beam/time-of-flight mass spectrometer/time sliced velocity map ion imaging techniques at a collision energy of approximately 300 cm(-1). Angular-resolved energy-transfer distribution functions were obtained directly from the images of inelastic scattering. The results show that alkyl substituted naphthalenes transfer more vibrational energy to translational energy than unsubstituted naphthalene. Alkylation enhances the V->T energy transfer in the range -DeltaE(d)=-100~-1500 cm(-1) by approximately a factor of 2. However, the maximum values of V->T energy transfer for alkyl-substituted naphthalenes are about 1500~2000 cm(-1), which is similar to that of naphthalene. The lack of rotation-like wide-angle motion of the aromatic ring and no enhancement in very large V->T energy transfer, like supercollisions, indicates that very large V->T energy transfer requires special vibrational motions. This transfer cannot be achieved by the low-frequency vibrational motions of alkyl groups. PMID- 21780293 TI - Synthesis and nanostructures of cyclic triphenylene trimers having long alkyl and alkoxy side-chains. PMID- 21780294 TI - One-pot multimolecular macrocyclization for the expedient synthesis of macrocyclic aromatic pentamers by a chain growth mechanism. AB - POCl(3)-mediated one-pot macrocyclization allows the highly selective formation of five-residue macrocycles that are rigidified by internally placed intramolecular hydrogen bonds. Mechanistic investigation by using tailored competition experiments and kinetic simulation provides a comprehensive model, supporting a chain-growth mechanism underlying the one-pot formation of aromatic pentamers, whereby the successive addition of a bifunctional monomer unit onto either another monomer or the growing oligomeric backbone is faster than other types of bimolecular condensations involving oligomers longer than monomers. DFT calculations at the B3LYP/6-31G* level reveal the five-residue pentamer to be the most stable with respect to alternative four-, six-, and seven-residue macrocycles. These novel mechanistic insights may become useful in analyzing other macrocyclization, oligomerization, and ploymerization reactions. PMID- 21780295 TI - Inhibition of amyloid beta aggregation and cytotoxicity by photodegradation using a designed fullerene derivative. PMID- 21780299 TI - Dynamic microvascular responses with a high speed TiVi imaging system. AB - TiVi technology presents a high resolution, low speed methodology for imaging microcirculation. Recently, the TiVi system was adapted to produce a high speed system capable of analysing dynamic responses from human tissues at a frame rate of 30 frames per second. We present results based on this system by investigating dynamic responses such as arterial pulsations both from a controlled flow model and in vivo tissue sites. We also quantify the effects of sympathetic vasomotion, a biological effect which is evident in many tissue sites, and show that the effects of arterial pulsations and vasomotion on the resulting TiVi time traces are easily determined. PMID- 21780300 TI - Cross-polarization optical coherence tomography for early bladder-cancer detection: statistical study. AB - The capabilities of cross-polarization optical coherence tomography (CP OCT) for early bladder-cancer detection are assessed in statistical study and compared with the traditional OCT. Unlike the traditional OCT that demonstrates images only in copolarization, CP OCT acquires images in cross-polarization and copolarization simultaneously. 116 patients with localized flat suspicious lesions in the bladder were enrolled, 360 CP OCT images were obtained and analyzed. CP OCT demonstrated sensitivity 93.7% (vs. 81.2%, <0.0001), specificity 84% (vs. 70.0%, <0.001) and accuracy 85.3% (vs. 71.5%, <0.001) in detecting flat malignant bladder lesions, which is significantly better than with the traditional OCT. Higher diagnostic efficacy of CP OCT in detecting early bladder cancer is associated with the ability to detect changes in epithelium and connective tissues. PMID- 21780301 TI - Wavelength swept amplified spontaneous emission source for high speed retinal optical coherence tomography at 1060 nm. AB - The wavelength swept amplified spontaneous emission (ASE) source presented in this paper is an alternative approach to realize a light source for high speed swept source optical coherence tomography (OCT). ASE alternately passes a cascade of different optical gain elements and tunable optical bandpass filters. In this work we show for the first time a wavelength swept ASE source in the 1060 nm wavelength range, enabling high speed retinal OCT imaging. We demonstrate ultra rapid retinal OCT at a line rate of 170 kHz, a record sweep rate at 1060 nm of 340 kHz with 70 nm full sweep width, enabling an axial resolution of 11 MUm. Two different implementations of the source are characterized and compared to each other. The last gain element is either a semiconductor optical amplifier or an Ytterbium-doped fibre amplifier enabling high average output power of >40 mW. Various biophotonic imaging examples provide a wide range of quality benchmarks achievable with such sources. PMID- 21780302 TI - Reflectance measurement using digital camera and a protecting dome with built in light source. AB - The reflectance of the skin reveals the chemical and physical changes of the skin as well as many metabolic changes. The reflectance measurement is an important method for medical diagnosis, follow-up and screening. This article concentrates on designing and validating an imaging system, based on a digital camera. The proposed system can measure the reflectance of the skin with high spatial and currently four channel spectral resolution, in the range of 450 nm to 980 nm. The accuracy of the system is determined by imaging a colour checker board and comparing the obtained values with both given values and spectrometer measurements. The diffuse interreflections of both, the integrating sphere and the lighting dome of the imaging system, is compensated with a correction factor. The accuracy of the proposed system is only slightly weaker than the spectrometer. The imaging system characteristics are independent of the camera characteristics. PMID- 21780304 TI - 14-3-3 proteins regulate retinal axon growth by modulating ADF/cofilin activity. AB - Precise navigation of axons to their targets is critical for establishing proper neuronal networks during development. Axon elongation, whereby axons extend far beyond the site of initiation to reach their target cells, is an essential step in this process, but the precise molecular pathways that regulate axon growth remain uncharacterized. Here we show that 14-3-3/14-3-3sigma proteins-adaptor proteins that modulate diverse cellular processes including cytoskeletal dynamics play a critical role in Xenopus retinal ganglion cell (RGC) axon elongation in vivo and in vitro. We have identified the expression of 14-3-3/14-3-3sigma transcripts and proteins in retinal growth cones, with higher levels of expression occurring during the phase of rapid pathway extension. Competitive inhibition of 14-3-3/14-3-3sigma by expression of a genetically encoded peptide, R18, in RGCs resulted in a marked decrease in the length of the initial retinotectal projection in vivo and a corresponding decrease in axon elongation rate in vitro (30-40%). Furthermore, 14-3-3/14-3-3sigma (R1) co-localized with Xenopus actin depolymerizing factor (ADF)/cofilin (XAC) in RGC growth cones. Inhibition of 14-3-3/14-3-3sigma function with either R18 or morpholinos reduced the level of inactive pXAC and increased the sensitivity to collapse by the repulsive cue, Slit2. Collectively, these results demonstrate that14-3-3/14-3 3sigma participates in the regulation of retinal axon elongation, in part by modulating XAC activity. PMID- 21780305 TI - Enhanced expression of tubulin-specific chaperone protein A, mitochondrial ribosomal protein S27, and the DNA excision repair protein XPACCH in the song system of juvenile male zebra finches. AB - Recent evidence suggests that sexual dimorphisms in the zebra finch song system and behavior arise due to factors intrinsic to the brain, rather than being solely organized by circulating steroid hormones. The present study examined expression of 10 sex chromosome genes in the song system of 25-day-old zebra finches in an attempt to further elucidate these factors. Increased expression in males was confirmed for nine of the genes by real-time qPCR using cDNA from individual whole telecephalons. In situ hybridization at the same age revealed specific, male-enhanced mRNA for three of the nine genes in one or more song control nuclei. These genes encode tubulin-specific chaperone A, mitochondrial ribosomal protein S27, and a DNA repair protein XPACCH. Based on what is currently known about these proteins' functions and their localization to particular components of the song circuit, we hypothesize that they each may be involved in specific aspects of masculinization. PMID- 21780306 TI - In vivo injectable gels for tissue repair. AB - The desire to reduce healthcare costs while improving outcomes drives minimally invasive methods to replacing traditional surgical procedures. Various treatments that would previously have needed open-type surgeries can be carried out using endoscopes, catheters, and needles. These advantages have become especially obvious for tissue engineering and regenerative medicine with in vivo gel injectable nanomaterials. In this review, the state of the art in this rapidly developing field is given. This is done by contrasting functional evaluation in vitro with in vivo followed by describing (1) synthetic materials, (2) the body's own polymers, (3) polymers in nature, (4) self-assembled peptides, and (5) new innovations and combinations. With increased understanding of the relationship between material characteristics and the outcome in vivo more rational design criteria are emerging. PMID- 21780303 TI - Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. AB - The blood-brain barrier (BBB) is formed primarily to protect the brain microenvironment from the influx of plasma components, which may disturb neuronal functions. The BBB is a functional unit that consists mainly of specialized endothelial cells (ECs) lining the cerebral blood vessels, astrocytes, and pericytes. The BBB is a dynamic structure that is altered in neurologic diseases, such as stroke. ECs and astrocytes secrete extracellular matrix (ECM) proteins to generate and maintain the basement membranes (BMs). ECM receptors, such as integrins and dystroglycan, are also expressed at the brain microvasculature and mediate the connections between cellular and matrix components in physiology and disease. ECM proteins and receptors elicit diverse molecular signals that allow cell adaptation to environmental changes and regulate growth and cell motility. The composition of the ECM is altered upon BBB disruption and directly affects the progression of neurologic disease. The purpose of this review is to discuss the dynamic changes of ECM composition and integrin receptor expression that control BBB functions in physiology and pathology. PMID- 21780307 TI - A brief history of 'new psychoactive substances'. PMID- 21780308 TI - Characterization of flagellar cysteine-rich sperm proteins involved in motility, by the combination of cellular fractionation, fluorescence detection, and mass spectrometry analysis. AB - Mammalian sperm proteins undergo thiol group (SH) oxidation to form disulfides bonds (S?S) as they travel through the epididymis during cell maturation. Disulfide bonds are involved in chromatin condensation and tail organelle stabilization. In this work, we used a fluorescent thiol-selective labeling agent, monobromobimane (mBBr), to study the protein thiol status of rat sperm during maturation. Fluorescence signal decrease along the epididymal trip, more evidently in the head, but also in the tail, indicates that both sub cellular regions participate in the thiol changes. The sources of the fluorescence signal are sulfhydryls sperm proteins labeled by mBBr (mBBr-spp). Initial attempts to identify the mBBr-spp labeled were detected in the initial-caput, but not in the distal cauda-segment of the epididymis in sodium dodecyl sulfate (SDS)-PAGE analysis. This phenomenon could be due to protein resistance to solubilization. For this reason, disulfide bond reduction was accomplished by sodium dodecyl sulfate plus dithiothreitol treatment to recover the mBBr signal in SDS-PAGE. Under this protocol, a major 27 kDa protein band displays a strong signal. Protein identification by mass spectrometry and sequence database searching correlated this protein with the outer dense fiber 1 (ODF1). The mBBr specifically bound to N-terminal domain cysteine of ODF1. The mBBr reduces rat sperm motility, quantitatively and qualitatively, and the effects are dose dependent, without significantly increasing the percentage of dead sperm. Thus, we found that ODF1 is highly responsible for mBBr fluorescence detection in the sperm tail, and the motility inhibition by the fluorescence marker indicates that ODF1 N-terminal domain are related to sperm motility. (c) 2011 Wiley-Liss, Inc. PMID- 21780309 TI - Bacillus anthracis tubulin-related protein Ba-TubZ assembles force-generating polymers. AB - Pathogenicity of Bacillus anthracis depends on the faithful inheritance of plasmid pXO1, in a process that requires the plasmid encoded tubulin-related protein Ba-TubZ. Here we show, using heterologous expression in Schizosaccharomyces pombe, that Ba-TubZ assembles into a dynamic polymer in the absence of other B. anthracis proteins and can generate force capable of deforming the fission yeast nuclear envelope. The polymer bundles contain 27 +/- 15 protofilaments/MUm assuming that each protofilament spans the entire length. Thinner appearing buckled and thicker appearing straight filaments of Ba-TubZ were both capable of inducing nuclear envelope deformation. Unlike the related protein Bt-TubZ from Bacillus thuringiensis, which undergoes treadmilling upon expression in fission yeast, Ba-TubZ polymers did not undergo detectable treadmilling. Instead, in fluorescence recovery after photobleaching experiments, it displayed a different turnover behavior characterized by moderate fluorescence recovery along the entire length of the polymer. Modeling Ba-TubZ bundles as Euler-Bernoulli beams that buckle under compressive loads when pushed against the nuclear envelope allowed us to estimate that Ba-TubZ generates forces in the order of 1-10 nN. We propose that polymerization based filament elongation and force generation might aid faithful segregation of the virulence plasmid. PMID- 21780310 TI - The effects of periodized concurrent and aerobic training on oxidative stress parameters, endothelial function and immune response in sedentary male individuals of middle age. AB - The vascular endothelium plays a key role in arterial wall homeostasis by preventing atherosclerotic plaque formation. A primary causal factor of endothelial dysfunction is the reactive oxygen species. Aerobic exercise is ascribed as an important adjuvant therapy in endothelium-dependent cardiovascular disease. However, little is known about the effects of concurrent (aerobic + strength) training on that. For a comparison of the effects of aerobic and concurrent physical training on endothelial function, oxidative stress parameters and the immunoinflammatory activity of monocytes/macrophages, 20 adult male volunteers of middle age were divided into a concurrent training (CT) programme group and an aerobic training group. The glutathione disulphide to glutathione ratio (GSSG/GSH) and plasma lipoperoxide (LPO) levels, as well as flow-mediated dilation (FMD), monocyte/macrophage functional activity (zymosan phagocytosis), body lipid profiles, aerobic capacity (maximal oxygen uptake) and strength parameters (one-repetition maximum test), were measured before and after the exercise training programmes. The CT exhibited reduced acute effects of exercise on the GSSG/GSH ratio, plasma LPO levels and zymosan phagocytosis. The CT also displayed improved lipid profiles, glycaemic control, maximal oxygen uptake and one-repetition maximum test values. In both the aerobic training and the CT, training improved the acute responses to exercise, as inferred from a decrease in the GSSG/GSH ratios. The aerobic sessions did not alter basal levels of plasma LPO or macrophage phagocytic activity but improved FMD values as well as lipid profiles and glycaemic control. In summary, both training programmes improve systemic redox status and antioxidant defences. However, the aerobic training was more efficient in improving FMD in the individuals studied. PMID- 21780311 TI - Multiplexed magnetic labeling amplification using oligonucleotide hybridization. PMID- 21780312 TI - Advanced organic optoelectronic materials: harnessing excited-state intramolecular proton transfer (ESIPT) process. AB - Recently, organic fluorescent molecules harnessing the excited-state intramolecular proton transfer (ESIPT) process are drawing great attention due to their unique photophysical properties which facilitate novel optoelectronic applications. After a brief introduction to the ESIPT process and related photo physical properties, molecular design strategies towards tailored emission are discussed in relation to their theoretical aspects. Subsequently, recent studies on advanced ESIPT molecules and their optoelectronic applications are surveyed, particularly focusing on chemical sensors, fluorescence imaging, proton transfer lasers, and organic light-emitting diodes (OLEDs). PMID- 21780313 TI - Ion flow crossing over a polyelectrolyte diode on a microfluidic chip. AB - Key evidences are reported for the rectification mechanism of an aqueous ion diode based on polyelectrolytic plugs on a microfluidic chip by monitoring the ion flow crossing over the junction. The ion flow penetrating the polyelectrolyte junction is visualized by employing a fluorescent chemodosimeter, rhodamine B hydrazide and the pH-dependent dye, carboxy-fluorescein. How hysteresis phenomena, exhibited through the nonlinear behavior of the polyelectrolyte diode, are affected by a variety of parameters (e.g., switching potential, scan rate, and electrolyte concentration) is also investigated. The insights and knowledge from this study provide a crucial foundation for ion control at the iontronic diode in the aqueous phase, leading to more advanced aqueous organic computing devices and more diverse applications for microfluidic logic devices. PMID- 21780317 TI - Consensus document. Recommendations on assessing proteinuria during the diagnosis and follow-up of chronic kidney disease. AB - The presence of persistently elevated urinary concentrations of protein or albumin is considered a sign of kidney damage. The diagnosis and staging of chronic kidney disease (CKD) is nowadays based upon the presence of signs of kidney damage together with the estimation of the glomerular filtration rate.The presence of either proteinuria or albuminuria identifies a group of patients with higher risk of CKD progression and higher cardiovascular risk. Treatment with angiotensin converting enzyme inhibitors or angiotensin-receptor blockers,for instance, decreases both the progression of CKD and the incidence of cardiovascular events and death in patients with CKD and proteinuria. Thus, proteinuria is currently considered a therapeutic target by itself. Despite of the importance of detecting and monitoring proteinuria in the diagnosis and follow-up of CKD, there is not a consensus among the clinical practice guidelines published by different scientific societies on the diagnostic cut-off levels, on different sampling procedures,on the units used in laboratory reports or just on whether it should be defined in terms of albumin or proteinuria. The goal of this document, created by the consensus of the Spanish Society of Clinical Biochemistry and Molecular Pathology(SEQC, representing its spanish acronym) and the Spanish Society of Nephrology (S.E.N.), is to recommend to medical and laboratory clinicians appropriate guidelines for the detection and monitorization of proteinuria as a marker of CKD in adults and children. These recommendations result from searching,evaluating and summarizing current scientific evidence published in the last years. PMID- 21780318 TI - Air pollution in China, with Junfeng (Jim) Zhang by Ashley Ahearn. AB - Air pollution in China, one of the world's oldest civilizations, reflects a combination of traditional and modern-day factors. Severe air pollution in Chinese cities is the result of rapid industrialization, urbanization, and growth in vehicle use. At the same time, traditional indoor burning of solid fuels such as coal and dung presents acute, severe exposures to pollutants including particulate matter, carbon monoxide, arsenic, and mercury. In this podcast, Junfeng (Jim) Zhang tells host Ashley Ahearn about some of the factors that make air pollution a significant problem in China. PMID- 21780319 TI - Frederick Soddy--pioneer in radioactivity. PMID- 21780320 TI - MAGEC2 is a sensitive and novel marker for seminoma: a tissue microarray analysis of 325 testicular germ cell tumors. AB - Melanoma-associated gene C2 (MAGEC2) is a recently identified cancer testis antigen expressed in normal testicular and placental tissue. It has been detected in some human carcinomas, but its expression in primary testicular germ cell tumors is unknown. Immunohistochemistry was used to study MAGEC2 protein in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. MAGEC2 expression was compared with POU5F1 (OCT3/4), SOX2, SOX17, KIT and TNFRSF8 (CD30). The mouse monoclonal anti-MAGEC2 antibody (clone LX-CT10.5) revealed a nuclear MAGEC2 expression with little or no background staining. MAGEC2 expression was found in 238 of 254 seminomas (94%), but not in embryonal carcinomas (n=89). POU5F1 (OCT3/4) was positive in 97% of seminomas and all embryonal carcinomas. In contrast, KIT was positive in 94% of seminoma but also in 8% of embryonal carcinomas. TNFRSF8 (CD30) and SOX2 were negative in seminoma and positive in embryonal carcinoma (96 and 90%, respectively). SOX17 was positive in 94% of seminoma and negative in embryonal carcinoma. We conclude that MAGEC2 allows a reliable distinction of seminoma from embryonal carcinomas. Therefore, MAGEC2 represents an additional tool for the differential diagnosis of testicular germ cell tumors. PMID- 21780321 TI - Tethered cord. PMID- 21780322 TI - Refining probability: a simple concept to be considered when interpreting interictal epileptiform discharges in EEG. PMID- 21780323 TI - [Naturopathy consultation. Flaccid paralyses]. PMID- 21780324 TI - [Recurrent anterior shoulder dislocation--always take along some handcuffs?]. PMID- 21780325 TI - Electron transfer in reaction centers of Rhodopseudomonas sphaeroides. II. Free energy and kinetic relations between the acceptor states Q(-)A Q(-)B and QAQ(2 )B. AB - Thermodynamic equilibria and electron transfer kinetics involving the quinone acceptor complex in reaction centers from Rhodopseudomonas sphaeroides were investigated. We focussed on reactions involving the two-electron states QA Qn and QAQ~-, described by the scheme DQAQa~-D +X,~~A- , ~~a- ~k~ .~D+ "r~~ AK~'La2- - k~2~ k~lk O~ (2)D+~D The equilibrium partitioning between QA Q n and QAQ 2n- was determined spectroscopically from either the concentration of oxidized cytochrome c or the concentration of semiquinone after successive flashes of light.At pH < 9.5, QAQ2n - is stabilized relative to QAQn, while for pH > 9.5, QAQB is energetically favored.The reduction of QA, to form QAQ~, is not associated with a protonation step (pK< 8). However, the reduction of Q~, to form the final state QAQ~-, is accompanied by an uptake of a proton (pK >/10.7). The preferential interaction of a proton with QAQ2n - provides the driving force for the forward electron transfer.The shift toward the photochemically inactive state QAQa with increasing pH may serve as a feedback mechanism in photosynthetic organisms to limit the rise in intracellular pH. The electron-transfer rate constants were determined from the observed kinetics and the equilibria between the states QAQ2n - and QA Q n. The forward rate constant z-.A~2n~ was approximately proportional to the proton concentration, whereas kta2A~ depended only weakly on pH. The recombination kinetics of D +QAQ2n- was biphasic. The slow rate agreed with the predicted charge recombination via the intermediate state D +QAQff; the fast rate may be due to the recombination from a separate (conformational) state. The results of this work were combined with those of a previous study on reactions involving the one-electron precursor states QAQa and QAQn(Kleinfeld, D., Okamura, M.Y., and Feher, G. (1984) Biochim. Biophys. Acta 766, 126-140). The overall sequence for the protonation of the reaction center in response to successive reductions of the accept or complex involves the uptake of one proton for each electron transferred to QB- This sequential uptake initiates the formation of a proton gradient across the cell membrane. PMID- 21780326 TI - Damping of oscillations in the semiquinone absorption in reaction centers after successive flashes determination of the equilibrium between Q(-)AQB and QAQ(-)B. AB - A quantitative model for the damping of oscillations of the semiquinone absorption after successive light flashes is presented. It is based on the equilibrium between the states Q(A)-Q(B) and Q(A) Q(-B). A fit of the model to the experimental results obtained for reaction centers from Rhodopseudomonas sphaeroides gave a value of alpha = [Q(A)-Q(B)I/(IQ(A)-Q(Bl)+ [Q(A)Q(-B)I) = 0.065 +/- 0.005 (T= 21 degrees C, pH 8). PMID- 21780327 TI - Cardiovascular devices; classification of electrocardiograph electrodes. Final rule. AB - The Food and Drug Administration (FDA) is classifying the electrocardiograph electrode, intended to acquire and transmit the electrical signal at the body surface to a processor that produces an electrocardiogram (ECG) or vectorcardiogram, into class II (special controls). FDA is also exempting this device from the premarket notification requirement. PMID- 21780328 TI - Rare complication after mitral valve replacement due to infective endocarditis. AB - A 27-year-old woman who had undergone mitral valve replacement for infective endocarditis developed a significant paravalvular leak. Percutaneous transcatheter obliteration of the defect using an Amplatzer Vascular Plug III was undertaken, with an excellent clinical outcome. PMID- 21780329 TI - Does medication adherence lower Medicare spending among beneficiaries with diabetes? PMID- 21780330 TI - [IV. Hungarian PET/CT Multidisciplinary Consensus Conference -- position statement]. PMID- 21780331 TI - A trial using rechargeable batteries to run mosquito light traps. PMID- 21780332 TI - Seasonal oviposition of Culex quinquefasciatus in proprietary belowground stormwater treatment systems in an urban area of southern California. PMID- 21780333 TI - Tree holes as larval habitats for Aedes aegypti in public areas in Aguaray, Salta province, Argentina. PMID- 21780334 TI - Summary of AHRQ's comparative effectiveness review of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers added to standard medical therapy for treating stable ischemic heart disease. AB - BACKGROUND: Standard therapies for the management of stable ischemic heart disease (IHD) partially reduce the risk of a future acute coronary syndrome. Among patients with chronic heart failure or previous myocardial infarction and left ventricular dysfunction, a large body of evidence supports the benefits of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs) and, in heart failure, combined therapy with these agents. In contrast, there is less certainty regarding outcomes of ACE inhibitors and ARBs for people with stable IHD who have preserved left ventricular function and no signs or symptoms of heart failure. To compile and synthesize findings derived from research on this specific population, the Agency for Healthcare Research and Quality (AHRQ) commissioned and, in October 2009, published a systematic review and meta-analysis on the benefits and harms of ACE inhibitors and ARBs. OBJECTIVES: To (a) familiarize health care professionals with AHRQ's 2009 systematic review on ACE inhibitors and ARBs for people with stable IHD and preserved left ventricular function, (b) provide commentary and encourage consideration of the clinical and managed care applications of the review findings, and (c) identify limitations to the existing research on the benefits and harms of ACE inhibitors and ARBs. SUMMARY: Six trials meeting eligibility criteria provided moderate to strong evidence that, compared with standard therapies alone, ACE inhibitors significantly lower the risks of total mortality, cardiovascular mortality, nonfatal myocardial infarction (MI), stroke, and other clinical outcomes. However, study participants on ACE inhibitors had higher incidences of withdrawals due to adverse events, including syncope, cough, and hyperkalemia. Only 1 trial (TRANSCEND) met eligibility criteria for comparing standard therapies alone versus an ARB (telmisartan). No significant differences were observed for individual clinical endpoints across groups in TRANSCEND, although the composite measure (cardiovascular mortality, nonfatal MI, and stroke) was significantly lower for telmisartan compared with placebo; like ACE inhibitors, ARB therapy increased the risk of hyperkalemia. Only 1 trial (ONTARGET) was identified that compared an ACE inhibitor (ramipril) with an ARB (telmisartan), and this trial showed that ramipril and telmisartan have similar efficacy, similar risks of harms, and therefore a similar balance of benefits to harms. ONTARGET showed that the risk reduction for all clinical endpoints was similar across the 3 treatment arms (ramipril, telmisartan, and combination therapy with ramipril and telmisartan). Combination therapy in ONTARGET was associated with a greater number of total study discontinuations, including discontinuations due to hypotension and syncope. Telmisartan compared with ramipiril had lower rates of cough and angioedema and a higher rate of hypotensive symptoms; there was no difference between ramipril and telmisartan in the rate of syncope. This summary of the AHRQ review also describes the benefits and harms of ACE inhibitors and ARBs in patients who recently had, or were scheduled to have, a revascularization procedure and in different patient subpopulations. PMID- 21780335 TI - Prostitutes as a threat to national honor in Habsburg-occupied Serbia during the Great War. PMID- 21780336 TI - Cross-dressing in a Russian Orthodox monastery: the case of Mariia Zakharova. PMID- 21780337 TI - Of female chastity and male arms: the Balkan "man-woman" in the age of the world picture. PMID- 21780338 TI - Dr. John Lancelot Todd, 1876-1949. PMID- 21780339 TI - Introduction. Challenges in managing acne patients. PMID- 21780340 TI - Rethinking treatment of acne in the severe patient. AB - Managing acne continues to be a challenge. The data presented here provide a rationale for rethinking our approach to the use of oral antibiotics in moderate to-severe acne and suggest strategies that favor combination regimens that limit the use of oral antibiotics. PMID- 21780341 TI - Acne in patients with skin of color. PMID- 21780342 TI - Importance of vehicles in acne therapy. AB - Topiucal drug therapy is an intuitively sound approach to the management of skin diseases. Depositing medication at the site of disease involvement is potentially effective and reduces systemic exposure. Topical drugs are absorbed usually by passive diffusion. In clinical practice, the choice of an optimized formulation that will be effective and well tolerated is essential. Data confirm that patient adherence with therapy leads to better outcomes and lower long-term treatment costs, while poor adherence is directly linked to poor treatment outcomes and and patient dissatisfaction. Local cutaneous irritation, which may be linked to components of the formulation and/or to the active drug itself, is a common cause of non-adherence. Well-designed drugs are important in the management of acne vulgaris and acne rosacea. Formulators have sought to improve treatment efficacy and tolerability by several different techniques, such as delayed release of the active drug, fixed combinations of two different molecules, or incorporating ingredients into the formulation vehicle that improve epidermal barrier function and offset the irritating effects of the active drugs. PMID- 21780343 TI - Oxybutynin dependence: a case presentation. PMID- 21780344 TI - Raynaud's phenomenon in a patient with schizophrenia and obsessive-compulsive disorder: a case report. PMID- 21780345 TI - [Social rehabilitation among schizophrenics. Bio-social approach to improve QOL]. PMID- 21780346 TI - [On future cooperation with psychiatric technology]. PMID- 21780347 TI - [The meaning of psychotherapy to a psychiatrist--its relationship with diagnosis and physical and drug therapy]. PMID- 21780348 TI - [Education of clinical psychologists]. PMID- 21780349 TI - [Collaboration with psychologists--on future prospect]. PMID- 21780350 TI - Pricing and competition in the private dental market in Finland. AB - OBJECTIVE: To investigate how the prices were set in private dental care, which factors determined prices and whether the recent National Dental Care Reform had increased competition in the dental care market in Finland. DESIGN: A questionnaire to all full time private dentists (n = 1,121) in the ten largest cities. Characteristics of the practice, prices charged, price setting, perceived competition and expectations for the practices were requested. The response rate was 59.6%. Correlation analysis (Pearson's) was used to study relationships between the prices of different treatment items. Linear regression analysis was used to study determinants of the price of a one surface filling. RESULTS: Most dentists' fee schedules were based on the price of a one surface filling and updated annually. Changes in practice costs calculated by the dentists' professional association and information on average prices charged on dental treatments in the country influenced pricing. High price levels were associated with specialisation, working in a group practice, working close to many other practices or in a town with a dental school. Less than half of the respondents had faced competition in dental services and price competition was insignificant. CONCLUSIONS: Price setting followed traditional patterns and private markets in dental services were not found to be very competitive. PMID- 21780351 TI - Geographical accessibility to dental care in the Japanese elderly. AB - OBJECTIVE: The current research aims to clarify the factors relevant to elderly people's access to dental care in Japan, particularly focusing on geographical accessibility. METHODS: The sample was taken from among the Japanese elderly, aged 65 and over, who responded to a postal survey conducted in 2003 (n = 2,192). Six types of geographical accessibility to the dental clinics were calculated using Geographic Information Systems. Logistic regression analysis was conducted using 'having a regular dentist' as a dependent variable and geographical accessibility as an explanatory variable. RESULTS: The results showed an association between having a regular dentist and geographical accessibility only for females. In the univariate model, distance to the closest dental clinics (OR = 0.62 (95% CI: 0.43-0.90)), number of dental clinics at the school district level (OR = 1.14 (95% CI: 1.03-1.26)), number of dental clinics at the municipality level (OR = 1.02 (95% CI: 1.00-1.05)), and density distribution of dental clinics (OR = 1.56 (95% CI: 1.11-2.19)) showed significant relations with having a regular dentist. After controlling for demographic, socioeconomic, and health related variables, only the density distribution of dental clinics showed significant relations at the 5% level, although distance and number of dental clinics kept a marginal significance. CONCLUSION: The current study verifies that geographical accessibility correlates with access to dental care among women, and that there were large gender differences concerning the issue of geographical access. PMID- 21780352 TI - Socioeconomic inequality in self-reported oral health status: the experience of Thailand after implementation of the universal coverage policy. AB - OBJECTIVES: This study aimed to quantify the extent to which socioeconomic related inequality in self-reported oral health status among Thais is present after the country implemented the Universal Coverage policy and to decompose the determinants and their associations with inequality in self-reported oral health status in particular with the worse condition. DESIGN AND METHOD: The study employed a concentration index to measure socioeconomic-related inequality in self-reported oral health status, and the decomposition method to identify the determinants and their associations with inequality in oral health-related measures. Data from 32,748 Thai adults aged 15-75 years from the nationally representative Health &Welfare Survey and Socio-Economic Survey 2006 were used in analyses. RESULTS: Reports of worse oral health status of the lower socioeconomic status group were more common than their higher socioeconomic-status counterparts. The concentration index (equaling -0.208) corroborates the finding of pro-poor inequality in self-reported worse oral health. Decomposition analysis demonstrated certain demographic-, socioeconomic-, and geographic characteristics are particularly associated with poor-rich differences in self-reported oral health status among Thai adults. CONCLUSIONS: This study demonstrated socioeconomic-related inequality in oral health is discernable along the entire spectrum of socioeconomic status. Inequality in perceived oral health status among Thais is present even while the country has virtually achieved universality of health coverage. The study also indicates population subgroups, particularly the poor, should receive consideration for improving oral health status as revealed by underlying determinants. PMID- 21780353 TI - Oral health status and inequalities among ambulant older adults living in central Chile. AB - OBJECTIVE: To assess the oral health status and treatment needs of older adults, living in the Valparaiso Region of Chile. BASIC RESEARCH DESIGN: A random sample of 354 older adults, aged 60 years or older, living independently in the community were examined orally by calibrated examiners and underwent a structured oral health interview. Data collection extended from October 2006 to June 2007. RESULTS: This was a largely dentate population (80%) with a mean DMFT score of 21.6 (s.d. 5.7). While about 28% of the dentate sample had all their restorative needs unmet, 30.8% had all of their restorative needs met. Regarding periodontal health, 3.3% had sound periodontum; complex periodontal therapy (CPI 3-4) was needed by 43.1% of the sample. CONCLUSION: This study represents one of the largest data collections in oral health among older adults living in Chile. Participants seemed to have better oral health status than previously reported. Of particular relevance is the reduction of the decayed component and the increased number of sound teeth in the present sample. Participants also presented lower need for advance periodontal treatment. Yet, inequalities were apparent in the proportion of unmet restorative needs. Strategies to develop oral health care programmes focused on improving access to and use of preventive services for older adults are critical. Further research is indicated to get a more complete picture of the factors that shape the oral health of Chilean older adults. PMID- 21780354 TI - Relationship between dental anxiety, general anxiety level and depression in patients attending a university hospital dental clinic in Turkey. AB - OBJECTIVE: To evaluate the relationship between dental anxiety, general anxiety and depression levels in patients attending a university hospital dental clinic in Turkey. BASIC RESEARCH DESIGN: A cross sectional study. PARTICIPANTS: 250 first visit patients seeking dental treatment. MAIN OUTCOME MEASURES: Modified Dental Anxiety Scale (MDAS), Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were used to assess the dental anxiety, general anxiety and depression level in these patients. RESULTS: The mean MDAS, BAI, and BDI scores were 10.5, 9.4, and 10.7, respectively. The prevalence of dental anxiety was found to be 20.8% (52/250) at the cut-off point > or = 15 and 6.8% (17/250) at the cut-off point > or = 19 according to MDAS score evaluation. MDAS and BAI scores were significantly higher in women (p < 0.001 and p < 0.01, respectively). BDI and BAI scores were significantly higher in MDAS cut-off point of 15 (p < 0.05 and p < 0.001, respectively). When the cut-off point was taken as 19, age and BAI scores were significantly higher in MDAS > or = 19 (p < 0.05, p < 0.001 and p = 0.477, respectively) but there was no association with BDI. There was significant correlation between MDAS scores and age, BDI and BAI mean scores (r = - 0.166, p < 0.01; r = 0.148, p < 0.05; r = 0.273, p < 0.01 respectively). CONCLUSIONS: Dental anxiety was positively correlated with patients' general anxiety level and was higher in women and at younger age. PMID- 21780355 TI - Mesial migration and loss of first molars among young adolescents in Kuwait. AB - OBJECTIVE: Our aim was to determine the prevalence of and factors associated with mesial migration and/or loss of first molars in 13-14-year-old school children in Kuwait. METHODS: A population-based sample of 1,583 eighth grade students of mean age 13.23 +/- 0.42 yrs, representing about 7% of the target population, were selected using multistage cluster sampling methods. Information on nationality, family income, and number of siblings was collected through subject and family interview. Any mesial migration or loss of first molars as well as visible caries was recorded in a well lit classroom. RESULTS: The prevalence of mesial migration and/or loss was 11.4%. Almost 70% of this occurred only in the mandible, and the majority (75.7%) had only one tooth affected (p < 0.01). Although the prevalence differed with residential geographical regions (p < 0.01), there were no gender differences (p > 0.05). The prevalence also differed with family income (p < 0.05), increased (p < 0.05) with increasing number of siblings, and was higher (p < 0.001) in subjects with presence of caries lesions (22.2%) than in those without (9.6%). CONCLUSIONS: About 12% of current age cohorts of school children in Kuwait are likely to experience mesial migration and/or loss of one or more first molars. The conditions are associated with presence of untreated caries lesions. Private school attendance and high as well as low family income are associated with a decreased level of mesial migration and/or loss of one or more first molars. Increased number of siblings is a risk factor. PMID- 21780356 TI - Use of Haavikko's method to assess dental age in Chinese children. AB - OBJECTIVE: To investigate the accuracy and precision of Haavikko's method in estimating dental age (DA) in healthy Chinese children, and evaluate the agreement between DA and dental age in the left mandibular quadrant (DALM), in order to simplify Haavikko's method by using only the developing teeth in the left half of the mandible. METHOD: Six hundred and thirteen panoramic photographs of healthy Chinese children were reviewed retrospectively. DA and DALM were calculated using Haavikko's method, but DALM included only the developing teeth in the left mandible. A paired t-test was used to compare the difference between chronological age (CA) and DA, DA and DALM. Correlation coefficients were calculated. Intra-examiner and inter-examiner variation were also evaluated using Cohen's Kappa value. RESULTS: Intra-examiner and inter-examiner Kappa values were 0.90 and 0.84 respectively, indicating a high reliability of Haavikko's method in this study group. The mean difference between DA and CA of the samples was 0.14 years. The correlation coefficient between the two was 0.93. For DA and DALM, the mean difference was 0.05 years, and the correlation coefficient was 0.99. CONCLUSIONS: Haavikko's method has a high degree of accuracy and precision when applied in this Chinese population. DALM may be used instead of DA to estimate dental ages. PMID- 21780358 TI - The relationship between self-reported oral health, self-regulation, proactive coping, procrastination and proactive attitude. AB - OBJECTIVES: This cross-sectional study investigated the relationship between self regulation, proactive coping, procrastination and proactive attitude, perceived oral health and self-reported oral-health behaviours. METHODS: The study sample consisted of 198 first year medical students. The questionnaire included information about socio-demographic factors, behavioural variables, self-reported oral health status, proactive coping (proactive coping subscale of the Proactive Coping Inventory), procrastination (Procrastination Scale) and proactive attitude (Proactive Attitude Scale). RESULTS: Significant differences were found on self regulation, proactive coping, procrastination and proactive attitude scales between participants who rated their gingival condition as very good/excellent and those who evaluated it as being poor, very poor or normal (p < 0.05). Results revealed significant differences in procrastination level among individuals who never visit their dentist and those who visit their dentist for check-up or for tooth cleaning and scaling (p = 0.001) or when treatment is needed or when in pain (p < 0.05). In multiple linear regression analyses, proactive coping was associated with toothbrushing frequency and reason for dental visiting. CONCLUSIONS: The result suggested that procrastination and proactive coping are important determinants of perceived oral health and self-reported oral-health behaviours. PMID- 21780357 TI - Relationship between bone fragility of the mandibular inferior cortex and tooth loss related to periodontal disease in older people. AB - OBJECTIVE: The purpose of this study was to evaluate the relationship between bone fragility of the mandibular inferior cortex and tooth loss in older adults by accounting for periodontal disease and bone metabolism markers. RESEARCH DESIGN: A total of 177 subjects aged 77 years participated in this study. We counted the number of remaining teeth. The mandibular cortex condition was examined using the mandibular inferior cortex classification (MICC) on dental panoramic radiographs. The mandibular inferior cortex was detected on both sides of the mandible, distally from the mental foramen (C1, normal; C2, mild/moderate erosion; C3, severe erosion). Multiple linear regression analysis was performed to assess the relationship between the mandibular cortex condition with the MICC and the number of remaining teeth after controlling for confounding factors such as gender, the percentage of sites with > or = 4 mm clinical attachment levels, and serum osteocalcin levels. RESULTS: The mean +/- SD number of remaining teeth of MICC C1, C2 and C3 were 20.7 +/- 7.5, 14.6 +/- 8.1 and 4.0 +/- 0.0 for males, and MICC C1, C2, and C3 were 21.7 +/- 7.6, 17.2 +/- 8.0, and 16.2 +/- 10.4 for females. The MICC was significantly associated with the number of remaining teeth using multiple linear regression analysis (beta = -0.21, p = 0.031). CONCLUSION: This study suggests that there is a relationship between bone fragility of the mandibular inferior cortex and tooth loss related to periodontal disease. PMID- 21780359 TI - Is there a correlation between dental caries and body mass index-for-age among adolescents in Iran? AB - AIM: Obesity in adolescents is a public health problem and is steadily increasing in many countries. The aim of this study was to investigate the association between age-and gender-specific body mass index (BMI-for-age) and dental caries among adolescents aged 12 -15 years in Rafsanjan, Iran. MATERIALS AND METHODS: Following ethical approval, 747 students aged 12-15 years were randomly selected from 12 state and private secondary schools in Rafsanjan, Iran. The DMFT index (following World Health Organization criteria) was used to assess the subjects' previous and existing dental caries experience. The BMI (Body Mass Index) percentile was calculated using BMI-for-age criteria as underweight (< 5th percent), normal-weight (5th-85th percent), at risk of being overweight (> 85th and < 95th percent) and overweight (> or = 95th percent). RESULTS: Of 353 males and 394 females examined, 7.5% were underweight, 72.8% were normal-weight, 13.8% were at risk of being overweight, and 5.9% were overweight. The mean DMFT was 2.83. There was no significant difference between DMFT scores amongst the BMI-for age groups (underweight = 2.91, normal-weight = 2.92, at risk of overweight = 2.54, overweight = 2.34, p > 0.05). However, males were more likely to have caries than females (11% of males were caries-free, in comparison to 20.6% of females; p < 0.05). CONCLUSION: Almost one in five adolescents (19.7%) examined were deemed to be at risk of being overweight, or were classified as overweight. There was no association between DMFT scores and BMI-for-age scores. PMID- 21780360 TI - Nigerian dentists' knowledge of the current guidelines for preventing infective endocarditis. AB - OBJECTIVE: This study assessed Nigerian dentists' knowledge of current guidelines for the prevention of infective endocarditis. MATERIAL AND METHODS: A self administered questionnaire surveyed a cross-section of Nigerian dentists gathering information on respondent demographics, awareness of the American Heart Association current guidelines on preventing infective endocarditis and sources of knowledge regarding that guidance. Respondents indicated: a) whether or not they would prescribe antibiotics before dental treatment in 10 cardiac conditions, b) if antibiotic prophylaxis was reasonable before 10 dental procedures in an endocarditis high-risk patient, and c) a prescription for oral antibiotics for an endocarditis high-risk non-allergic adult about to undergo a dental procedure. RESULTS: Respondents numbered 173 and 41% were aware of the guidelines. Most commonly the sources of this knowledge were undergraduate/postgraduate education. Overall, the correct responses for the 10 cardiac conditions was very low (33%), ranging from 94% for prosthetic heart valves (94.2%) down to 4% for previous coronary artery bypass (3.5%). For clearly invasive procedures, 80% to 96% of respondents indicated that a prophylactic antibiotic was reasonable. For clearly non-invasive procedures, 89% to 92% indicated that antibiotics were not reasonable. Correct antimicrobial agent, dose and timing of administration were prescribed by 89%, 9%, and 57% respectively. CONCLUSIONS: A low level of knowledge of the current guidelines was found among Nigerian dentists. Although, most prescribed the correct antimicrobial agent, the numbers prescribing correct dose and time of administration were quite low. Therefore, attempts should be made to teach the current guidelines in Nigerian undergraduate/postgraduate dental education. PMID- 21780361 TI - A new index to measure tooth wear--methodolgy and practical advice. AB - A new tooth wear index, designed to measure stages of tooth wear in enamel and dentine is presented. The index measures the lateral spread of wear in enamel and the depth of tooth wear in dentine. The index scores enamel loss at 5 levels and 6 levels in dentine and provides a more sensitive index for monitoring the progression of wear than older indices. The protocols and methods of the index are described and incorporate refinements based on the combined experiences of two independent studies conducted on adults and children. The findings of both studies are summarised and recommendations are made for future studies which investigate the prevalence of tooth wear in adults or children. PMID- 21780362 TI - Review of report of workshop on "Effective Use of Fluoride in Asia". PMID- 21780363 TI - A review on hydrogen production: methods, materials and nanotechnology. AB - In recent years hydrogen production and storage has attracted a lot of attention in both academia and industry due to its variety of applications in energy sector. Hydrogen is recognized as one of the most important components of the next generation clean energy technology. Within the whole cycle of the use of hydrogen energy, hydrogen production is considered as the key element of the upcoming hydrogen economy. Since the first production method invented for hydrogen on a smaller scale by dissolving iron in the acid vitriol in the 15th century, many improvements have been made to make the production viable and more cost effective. It is known that "nano" is playing its role in many technologies from medicine to material science and it has its say even in the production of hydrogen energy with continuous improvements in materials and methodologies. In this review we attempt to list various methods of producing hydrogen from different sources of materials followed by the description of most recent developments in the materials prospective. We explain the role of nanotechnology in making the hydrogen production technology a viable and cost effective process. The chemical reaction cycle, mechanism and configurations of various methods of hydrogen production are elaborated. PMID- 21780364 TI - Gold revolution--gold nanoparticles for modern medicine and surgery. AB - Nanotechnology is a new and exciting branch of science which offers enormous potential for development of medicine and surgery. Gold nanoparticles (GNP) is just one of a variety of nano products which will be available for physician of the future. GNP will give us more effective treatments and diagnosis. We are able to conjugate GNP with peptides, drugs, and other molecules to gain astonishing effects. High quality, non-invasive imaging will inevitably lead to astonishing accuracy diagnostic tools with effective use during surgery. The same principles may be used in the future for drug delivery and thermal treatment of cancer. Detailed DNA detection and regulation may become everyday use technology, in medicine with support from GNP based tools. Bacterial diagnostics and nerve repair are relatively poorly researched areas of application of GNP with possibly astonishing therapeutic effects. Non-invasive clearance of arteriosclerotic plagues with GNP shows a great prospect for further development of minimally invasive surgery. However, before all of those tools will become available for clinicians, in depth toxicology research as well as transitional research and design have to be done to ensure safe clinical practice with maximal benefit for patients. PMID- 21780365 TI - Preparation and evaluation of magnetic nanoparticles for cell labeling. AB - Cell labeling and tracking are becoming increasingly important in the fields of stem cell transplantation. To track the migration and distribution of the implanted cells is critical for understanding the beneficial effects of stem cell therapy. The aim of this study is to synthesize new superparamagnetic nanoparticles and investigate the feasibility of magnetic labeling of bone marrow mesenchymal stem cells (MSCs). Monodisperse hydrophobic magnetite (Fe3O4) nanoparticles were prepared through high temperature decomposition of Fe(acac)3 and a long-chain alcohol. The nanoparticles were further modified with a bipolar surfactant, 2,3-dimercaptosuccinic acid (DMSA) and then transformed into water soluble iron oxide nanoparticles (WION). The magnetic particles showed uniform size (10 nm), high efficiency and stability in MSCs labeling. The labeled cells were cultured until passage 8, there is no reduction in magnetic tropism and the percentage of labeled cells. The results of MTT proliferation assay and flow cytometry analysis show that the WION are biocompatible. The labeling process does not cause cell death and apoptosis, and has no side effect on growth capacity of the cells. In conclusion, the successful and stable labeling of MSCs and the efficient magnetic tropism indicate that this WION can be used for tracking of MSCs in future MSCs-based stem cell therapy. PMID- 21780366 TI - Single-domain antibody bioconjugated near-IR quantum dots for targeted cellular imaging of pancreatic cancer. AB - Successful targeted imaging of BxPC3 human pancreatic cancer cells is feasible with near-IR CdTeSe/CdS quantum dots (QDs) functionalized with single-domain antibody (sdAb) 2A3. For specific targeting, sdAbs are superior to conventional antibodies, especially in terms of stability, aggregation, and production cost. The bright CdTeSe/CdS QDs were synthesized to emit in the diagnostic window of 650-900 nm with a narrow emission band. 2A3 was derived from llama and is small in size of 13 kDa, but with fully-functional recognition to the target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a possible biomarker as a therapeutic target of pancreatic cancer. For compelling imaging, optical may be the most sensible among the various imaging modalities, regarding the sensitivity and cost. This first report on sdAb-conjugated near-IR QDs with high signal to background sensitivity for targeted cellular imaging brings insights into the development of optical molecular imaging for early stage cancer diagnosis. PMID- 21780367 TI - A new chimeric drug delivery nano system (chi-aDDnS) composed of PAMAM G 3.5 dendrimer and liposomes as doxorubicin's carrier. In vitro pharmacological studies. AB - Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems due to the combination process of nanobiomaterials and can offer advantages as drug carriers. The role of the release modulator from the liposomal system is undertaken by the dendrimer molecules leading to new pharmacokinetic and, probably, pharmacological properties of the chimeric system. In this work, a conventional DOPC/DPPG liposomal system and a new chi-aDDnS composed of liposomes (DOPC/DPPG) incorporating PAMAM G3,5 has been developed, Doxorubicin (Dox) was loaded in the systems and the final formulations were lyophilized. The physicochemical (spectroscopic and calorimetric) investigation concerning the chi-aDDnS, revealed a strong interaction between both lipophilic and hydrophilic parts of the liposomal membrane and the dendrimer, with the induction of multiple energetic states. These states are probably the basis of higher Dox encapsulation and slower release rate compared to the respective conventional liposome. These results, in conjunction with the increase in TI observed in two investigated cancer cell lines (i.e., MB231 and MCF7), compared to the respective conventional liposomal system and to the free Dox, make this new chi-aDDnS the basic candidate for further in vivo investigations. PMID- 21780368 TI - The role of NADPH oxidase in multi-walled carbon nanotubes-induced oxidative stress and cytotoxicity in human macrophages. AB - Recent studies suggest reactive oxygen species (ROS) induced in mammalian cells exposed to multi-walled carbon nanotubes (MWCNTs) could mediate the cytotoxicity. This study was conducted to determine the mechanisms responsible for MWCNTs induced ROS production in human primary macrophages. Our results showed that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 100 microg/ml MWCNTs for 12 h. Concomitantly, MWCNTs induced membrane translocation of the NADPH oxidase subunits p47phox and p67phox, a signature event for NADPH oxidase activation. Pre incubation with apocynin, a selective inhibitor of NADPH oxidase, prevented both membrane translocation of p47phox and superoxide production. Treatment with MWCNTs also resulted in an increased cytotoxicity in human primary macrophages that was significantly attenuated by both apocynin and antioxidants. These findings demonstrate that MWCNTs activate NADPH oxidase in human macrophages, which may contribute to ROS generation in MWCNTs treated-macrophages. PMID- 21780369 TI - Zinc oxide nanoparticle induced genotoxicity in primary human epidermal keratinocytes. AB - Zinc oxide (ZnO) nanoparticles are widely used in cosmetics and sunscreens. Human epidermal keratinocytes may serve as the first portal of entry for these nanoparticles either directly through topically applied cosmetics or indirectly through any breaches in the skin integrity. Therefore, the objective of the present study was to assess the biological interactions of ZnO nanoparticles in primary human epidermal keratinocytes (HEK) as they are the most abundant cell type in the human epidermis. Cellular uptake of nanoparticles was investigated by scanning electron microscopy using back scattered electrons imaging as well as transmission electron microscopy. The electron microscopy revealed the internalization of ZnO nanoparticles in primary HEK after 6 h exposure at 14 microg/ml concentration. ZnO nanoparticles exhibited a time (6-24 h) as well as concentration (8-20 microg/ml) dependent inhibition of mitochondrial activity as evident by the MTT assay. A significant (p < 0.05) induction in DNA damage was observed in cells exposed to ZnO nanoparticles for 6 h at 8 and 14 microg/ml concentrations compared to control as evident in the Comet assay. This is the first study providing information on biological interactions of ZnO nanoparticles with primary human epidermal keratinocytes. Our findings demonstrate that ZnO nanoparticles are internalized by the human epidermal keratinocytes and elicit a cytotoxic and genotoxic response. Therefore, caution should be taken while using consumer products containing nanoparticles as any perturbation in the skin barrier could expose the underlying cells to nanoparticles. PMID- 21780370 TI - Hyaluronic acid-bound letrozole nanoparticles restore sensitivity to letrozole resistant xenograft tumors in mice. AB - Letrozole is a potent aromatase inhibitor and superior to other defined selective estrogen receptor modulators such as tamoxifen in treating hormone-responsive postmenopausal breast cancer patients. Patients who receive this drug may become insensitive to the effects of estrogen deprivation induced by letrozole. Letrozole has known side effects on bone metabolism due to systemic ablation of estrogen production. The purpose of this study was to examine the therapeutic efficacy of hyaluronic acid-bound letrozole nanoparticles (HA-Letr-NPs) in restoring sensitivity to letrozole-resistant (LTLT-Ca) cells. To target letrozole to LTLT-Ca cells, hyaluronic acid-bound letrozole nanoparticles were prepared by nanoprecipitation using biodegradable PLGA-PEG co-polymer. Binding specificity of HA to CD44 on the cell surface was analyzed in vitro using FITC-CD44 Ab and CD44 siRNA by flow cytometry. Effects on in vitro cytotoxicity and aromatase enzymatic activity of HA-Letr-NPs were performed in MCF-7 breast cancer cells, MCF-7 cells over-expressing aromatase (MCF-7/Aro), and LTLT-Ca cells resistant to letrozole. Preclinical efficacy of HA-Letr-NPs was examined in mice using LTLT-Ca xenograft tumors. HA-Letr-NPs were restricted to a maximum size of 100 nm. The in vitro drug release assay showed that the highest released concentration of letrozole occurred after 23 hours at 37 degrees C in phosphate-buffered saline. HA-Letr-NPs on MCF-7/Aro and LTLT-Ca cells showed an IC50 of 2 microM and 5 microM, respectively. HA-Letr-NPs were more efficacious in inhibiting tumor growth, reducing in vitro cellular and in vivo tumor aromatase enzyme activity more than the corresponding Letr-NPs or letrozole. HA-Letr-NPs restored and maintained a prolonged sensitivity and targeted delivery of letrozole in letrozole-resistant tumors in vivo. PMID- 21780371 TI - Magnetic resonance imaging contrast agent: cRGD-ferric oxide nanometer particle and its role in the diagnosis of tumor. AB - To construct tumor-targeted nanometer particles as a negative magnetic resonance imaging (MRI) contrast agent. Ultra-small superparamagnetic iron oxide (USPIO) nanometer particles were prepared by one-step chemical precipitation. The covalent bond between cyclic RGD (cRGD) containing an Arg-Gly-Asp sequence targeting integrin-alphavbeta3, and USPIO was conducted by chemical crosslinking. The physico-chemical property of cRGD-USPIO was detected. Prussian blue staining was applied to detect the specific binding capacity of cRGD-USPIO and USPIO to human pulmonary adenocarcinoma A549 cells and human umbilical vein endothelial cells. Subsequently, A549 xenografts in nude mice were established, and intravenous injections of USPIO and cRGD-USPIO into the vena caudalis were performed. The enhancement of cRGD-USPIO against tumor MRI signal was evaluated. The mean hydrodynamic diameter of cRGD-USPIO was 43.97 +/- 10.10 nm and the size of the ferric oxide core was 5-10 nm. The specific saturation magnetization was 59.94 A x m2 x Kg(-1). The cell conjugation assay results indicated that the positive staining of the cRGD-USPIO group was significantly enhanced. The in vivo MRI diagnosis indicated that the cRGD-USPIO tumor signal was significantly reduced compared to that of the USPIO group (P < 0.01). The targeted superparamagnetic iron oxide nanometer particle can be a novel MRI negative contrast agent for more specific tumor early diagnosis. PMID- 21780372 TI - Positive patterning of ferritin and fibronectin molecules on silicon by the atomic force microscopic anodic oxidation technique. AB - Oxide dots fabricated on silicon (111) by the Atomic Force Microscopy (AFM) anodic oxidation technique was used for the patterning of two different proteins namely, ferritin and fibronectin. Si surfaces were oxidized by the SC1 process and then modified with octadecyltrichlorosilane (OTS) for passivation. Oxide dots were fabricated by applying a bias voltage between the AFM probe and the silicon surface. Furthermore, surface functionalization of oxide dots was achieved through gamma-aminopropyltriethoxysilane (gamma-APTES) and glutaraldehye modification to establish a covalent bond between aldehydes and amino groups of protein molecules. Topographies after each modification steps were monitored by AFM. We were able to achieve positive patterning of ferritin molecules up to an average density of 6 x 10(9)/cm2 on gamma-APTES-covered dots, while 9 x 10(8)/cm2 of ferritin molecules remained on the OTS surface. In contrast to this observation, fibronectin molecules were patterned successfully only on oxide dots, and we did not observe any fibronectin molecules on the OTS surface. PMID- 21780373 TI - Fullerene-C60 incorporated in liposome exerts persistent hydroxyl radical scavenging activity and cytoprotection in UVA/B-irradiated keratinocytes. AB - The aim of this study is to examine antioxidant activity of fullerene-C60 (C60) incorporated in liposome (LpsmFlln, a diameter of 75.6 nm). LpsmFlln is water soluble, and composed of hydrogenated lecithin of 89.7%, glycine soja sterol of 10% and C60 of 0.3%. Hydroxyl radicals (*OH), generated from UVA- or UVB irradiated H2O2, were scavenged by LpsmFlln but not by C60-lacking Lpsm as assessed by ESR, showing that the active principle is C60 as scanty as 1/415 weight versus LpsmFlln; the *OH amount (% of non-additive control) was decreased, LpsmFlln-dose-dependently, and for 0.5% LpsmFlln (C60-eq.:16.7 microM) to 34.1% or 78.3% upon irradiation with UVA (12 J/cm2) or UVB (500 mJ/cm2), respectively, showing the superiority for UVA to UVB in terms of the *OH scavenging of LpsmFlln. Cell viability of human skin keratinocytes HaCaT decreased to 41.1% upon UVA-irradiation at 10 J/cm2, but retained to 60.6% with 0.025% LpsmFlln (C60 eq.: 0.84 microM) together with prevention of cell-morphological degeneration, in contrast to scarce effects of C60-lacking Lpsm. The scavenging activity for Fenton reaction-generated *OH, detected by DMPO/ESR, was 96.2% or 72.2% (% of no additive control) at 1 min and decreased time-dependently to 24.8% or 28.3% at 12 min with 16.7 microM L-ascorbic acid (Asc) or Trolox, respectively, whereas 0.5% LpsmFlln (C60-eq:16.7 microM, the same concentration as for Asc) diminished *OH by 90.9% at 1 min and 91.5% even at 12 min, demonstrating the superiority of LpsmFlln to Asc or Trolox in terms of persistence of *OH-scavenging ability. Repressive efficacy on beta-carotene discoloration (% of control) for 60 min was in the order, based on the same molar or weight concentration: 1.3%:3.34 microM Asc < 25.0%:0.1% Lpsm < 36.3%:0.1% LpsmFlln (C60-eq.:3.34 microM) < 57.2%:3.34 microM Trolox, indicating the preventive effect of LpsmFlln against beta-carotene oxidation. Thus, LpsmFlln was demonstrated for an antioxidant ability characteristic of long-term persistence, and is attributed to fullerene-C60 but scarcely to Lpsm in all the tests examined, and is expected as the skin protecting agent against oxidative stress. PMID- 21780375 TI - Detection of bioconjugated quantum dots passivated with different ligands for bio applications. AB - Bioconjugation of quantum dots has resulted in a significant increase in resolution of biological fluorescent labeling. This intrinsic property of quantum dots can be utilized for sensitive detection of target analytes with high sensitivity; including pathogenic bacteria and cancer monitoring. The quantum dots and quantum dot doped silica nanoparticles exhibit prominent emission peaks when excited at 400 nm but on conjugation to model rabbit antigoat antibodies exhibit diminished intensity of emission peak at 600 nm. It shows that photoluminescence intensity of conjugated quantum dots and quantum dot doped silica nanoparticles could permit the detection of bioconjugation. Samples of conjugated and unconjugated quantum dots and quantum dot doped silica nanoparticles were subjected to enzyme linked immunosorbent assay for further confirmation of bioconjugation. In the present study ligand exchange, bioconjugation, fluorescence detection of bioconjugated quantum dots and quantum dot doped silica nanoparticles and further confirmation of bioconjugation by enzyme linked immunosorbent assay has been described. PMID- 21780374 TI - Bovine serum albumin driven interfacial growth of selenium-gold/silver hybrid nanomaterials. AB - Selenium (Se) nanorods (NRs) capped with BSA were used as precursor to synthesize Se-Au/Ag hybrid nanocrystals (NCs). Aqueous Au/Ag ions in the presence of fixed amount of purified dried Se NRs were reduced by ascorbic acid at 80 degrees C to generate respective nucleating centres which subsequently grew on the capped BSA hot spots. The hybrid NCs thus obtained were characterized by SEM, TEM, and EDS analysis while their synthesis was monitored simultaneously by UV-visible absorbance due to the surface plasmon resonance of Au and Ag nanoparticles (NPs). In both cases, a gradual decrease in the absorbance of Au/Ag NPs with respect to reaction time was observed which indicated a diminishing number density of such particles in colloidal aqueous phase. SEM and TEM analyses then explained the presence of Au NPs in self assembled ball shaped aggregates and their selective adsorption on Se NRs, whereas no self aggregated balls of Ag NPs were observed and they always grew on the Se NRs. The results were discussed on the basis of different routes followed by the Au and Ag nucleating centres to produced hybrid nanomaterials. PMID- 21780376 TI - Mesoporous Co3O4 for low temperature CO oxidation: effect of calcination temperatures on their catalytic performance. AB - Mesoporous Co3O4 particles are prepared by using mesoporous silica KIT-6 (with double gyroid Ia-3d symmetry) as a hard-template and Co(No3)2 x 6H2O as an inorganic precursor. In the former section, we investigate the effect of the calcination temperatures at which the Co salts are converted into Co3O4 inside the mesopores on the textural parameters of the products. The results of N2 adsorption-desorption analysis indicates that the calcination temperatures do not obviously affect the textural parameters such as the surface areas and pore volumes. However, when the calcination temperature reaches 800 degrees C, the mesostructural ordering is dramatically decreased, resulting in the reduction of the surface areas and pore volumes. After 800 degrees C calcination, the formation of large Co3O4 grains is partially confirmed on the particle surface by SEM observation. The grain size is much larger than the mesopore size of the original KIT-6, meaning the crystal growth is continuously occurred by breaking the rigid silica frameworks. In the latter section, we discuss the effect of the calcination temperatures and textural parameters on the catalytic activity for CO oxidation by both steady state and kinetic measurements. All mesoporous Co3O4 particles show a high catalytic activity, for example, -72 degrees C for sample calcined at 450 degrees C. Only 10 degrees C difference in T50 (the temperature of 50% conversion of CO) is found between the samples with the highest and lowest catalytic activity. The values of activation energy (Ea) and pre-exponential factor (A) per unit area are almost the same between two samples calcined at 450 degrees C and 800 degrees C. It is demonstrated that calcination process can not alter the essential catalytic property of mesoporous Co3O4 particles. PMID- 21780377 TI - CdSe@CdS core-shell quantum dot-polymer multilayer sensitized TiO2 for photovoltaics. AB - Colloidal CdSe@CdS core-shell quantum dots (QDs) have been prepared and exploited as inorganic dyes to sensitize a large-band-gap TiO2 layer for QD-sensitized solar cells. The sensitized films were prepared by alternating the layer-by-layer deposition of water-soluble semiconductor QDs and polycations over mesoscopic TiO2 films. The multilayer build-up, monitored by UV-vis spectroscopy shows an increase in the film absorbance with the number of adsorbed CdSe@CdS layers. The photoluminescence (PL) and photoelectrochemical properties of the multilayers were investigated. The photovoltaic performance of QD-sensitized solar cells is strongly dependent on the film structure and component. The incorporation of the electron mediators of [Co(Phen)3]2+ during the deposition process remarkably enhanced the photocurrent intensity in comparison to that in case of QD/polyelectrolyte multilayers. PMID- 21780378 TI - Facile preparation of Ag-coated TiO2 nanobelts and their photocatalytic activities. AB - This article describes facile preparation of Ag nanoparticles coated on TiO2 nanobelts and their visible-light photocatalysis activity toward the degradation of Rhodamine B. An Ag complex was adsorbed onto the TiO2 nanobelts by impregnation of the nanobelts into an [Ag(NH3)2]NO3 aqueous solution, and subsequently the Ag precursor was reduced at room temperature by a glucose solution to form Ag nanoparticle-coated TiO2 nanobelts. The visible-light photodegradation of Rhodamine B on such nanocomposite was studied and showed much higher photocatalytic activity than commercial P-25 TiO2 nanoparticles and pure TiO2 nanobelts. Using a seeding preparation procedure through dropwise addition of fresh aqueous solution of NH2NH2 and AgNO3 alternately, larger Ag particles on TiO2 nanobelts were obtained. PMID- 21780379 TI - Fabrication and interfacial electronic structure studies on polypyrrole/TiO2 nano hybrid systems for photovoltaic aspects. AB - The progress in studying the interfacial electronic structures of the developing new class of hybrid organic/inorganic material systems have envisaged a new dimension into the field of photovoltaics, which could be of great help in understanding the nature of charge transfer in them. In this regard, electropolymerization of pyrrole monomers have been carried out at room temperature on the surface of TiO2 working electrodes (assisted by UV radiations) and their interfacial electronic structure has been studied as a function of the applied photo anodic potentials. The formation of polypyrrole deposits has been ensured using FT-IR and Raman spectroscopy. Surface analysis of the hybrid matrix revealed the tendency of polymer molecules to cover up the spherical surface of TiO2 nanoparticles that could help in improving the light absorption rate. Signals (bands) corresponding to pyrrole molecules observed in the ultraviolet photoelectron spectroscopy measurements have been correlated with the polaronic states formed and identified to shift as a function of the applied photo anodic potentials, revealing the decrease in work function of the hybrid system to take place (confirmed using cyclic voltammetry measurements). The decreasing trend in the work function elucidates the adjustment in electronic structure of the system (hybrid materials possessing smaller work functions are generally preferred for photovoltaic studies). The aforementioned behavioural aspects have been reasoned with the increase in overpotential values for polarization, from the decrease in up-take rate of the anionic dopant, which increases the current density values, thereby modifying the conductivity of the systems. PMID- 21780380 TI - Highly flexible frontside-illuminated dye-sensitized solar cells using three dimensional network TiO2 nanowires. AB - Here we report a highly flexible frontside-illuminated dye-sensitized solar cell (FIDSSC) using Ti foils as the substrates. The laser-drilled microhole arrays (LDMAs) on Ti foil substrates as the photoanode provided an efficient pathway for the diffusion of liquid electrolyte, which would be particularly favorable for frontside illumination of FIDSSC designs. The three-dimensional (3D) network TiO2 nanowires (NWs) were directly grown on the Ti substrate with LDMAs via a simple hydrothermal method. Platinized Ti sheet was used as the counter electrode in the FIDSSC. The mechanical properties of the novel structured device were measured. It was shown that as-synthesized large-scale 3D network TiO2 NWs with a diameter of about 20-30 nm and a length of about 6 microm can prevent crack from generating efficiently when bended to an extreme angle of 120 degree. Furthermore, we demonstrated that the effects of the different bending angles on the performance of the 3D network TiO2 NWs-based FIDSSCs were slight, indicating NWs preferable advantages for the fabrication of flexible DSSCs. The results showed that the FIDSSC achieved an efficiency of 0.72% under front illumination of AM 1.5 simulated one sun light (100 mWcm(-2)). PMID- 21780381 TI - The role of aggregation of ferrite nanoparticles on their magnetic properties. AB - We have studied the magnetic properties of aggregates of Mn0.5Zn0.5Gd(x)Fe(2-x)O4 ferrite nanoparticles, with x = 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.18, 0.20. The scanning electron microscopy micrographs show significant aggregation of the nanoparticles in all samples. Zero field cooled and field cooled magnetization measurements were conducted on all samples from 400 K down to 5 K. Most zero field cooled curves were found to exhibit the usual behavior but with wide peaked regions. For some x values, the field cooled magnetization was found to increase slowly with decreasing temperature, and becomes nearly constant at low temperatures. The measurements of magnetization versus applied magnetic field were conducted on all samples at 5 K and 305 K in the field range from -15000 to 15000 Oe. At 305 K the magnetization for all samples was observed to saturate, while at 5 K the magnetization did not reach saturation for some values of x. The saturation magnetization values were suggested to be proportional to the size of particles. These results were discussed and suggested to be due to the inter-particle dipolar and exchange interactions between the particles in the aggregates, the large particle size distribution and the surface magnetization effects. PMID- 21780382 TI - Microstructural enhancement of high coercivity L1(0)-FePt films for next generation magnetic recording media. AB - The effects of substrate Ar-ion milling and Ta adhesion layer on the microstructural and magnetic properties of L1(0)-FePt films prepared on Si, SiO2, and glass substrates were investigated. It was discovered that the relatively large in-plane surface roughness of CrRu/MgO/FePt films deposited on Si substrates was due to the deformation of the CrRu layer when the composition was heated to 550 degrees C. More than an order of magnitude improvement for the in plane surface roughness was achieved when substrate Ar-ion milling or Ta adhesion layer was incorporated into the process. While the Ta adhesion layer proved to be detrimental to the (200) growth of the CrRu layer, optimal FePt film properties with coercivity values larger than 2 Tesla and out-of-plane roughness less than 1 nm were achieved when only substrate Ar-ion milling was implemented. PMID- 21780383 TI - Microstructure and magnetic property of M-type SrRe(x)Fe(12-x)O19 by sol-gel method. AB - Magnetoplumbite-type (M-type) SrRE(x)Fe(12-x)O19 (RE = La and Ce, x = 0-1.0) powders were prepared by a citric acid sol-gel technique and subsequent heat treatment. The crystal structure, grain size and magnetic properties were investigated by X-ray Diffraction (XRD), Scanning Electron Microscope (SEM) and vibrating sample magnetometer (VSM). The XRD patterns show that SrRE(x)Fe(12 x)O19 (RE = La and Ce) are mainly hexagonal magnetic plumbite structure, and the average grain size of 30-40 nm was calculated using the Scherer's equation based on the XRD spectrum. Substitution of Fe ion by the rare earth La ion causes a significant decrease in intrinsic coercivity (Hc) and a slight decrease in saturation magnetization (Ms) as shown in the magnetization hysteresis loops. However, the Hc rises gradually in a small wave pattern with the increase of doping content of the rare earth Ce. The relation between the crystal structure and magnetic properties was also studied in this work. PMID- 21780384 TI - Template assisted electrochemical growth of cobalt nanowires: influence of deposition conditions on structural, optical and magnetic properties. AB - The influence of electrodeposition potential, pH, composition and temperature of the electrolytic bath on the structure of cobalt nanowires arrays electrodeposited into anodic aluminum oxide (AAO) porous membranes is reported. XRD, SEM, and TEM analysis were employed to characterize structural (crystal phase, crystallographic texture, and grain size), and morphological nanowire properties. It was confirmed that at pH 2 the electrodeposition potential has not influence on the preferred crystallographic orientation of the electrochemically grown Co nanowires. At pH 4 the electrodeposition potential controls the growth of cobalt nanowires along some preferential crystallographic planes. The electrolytic pH bath modulates the fcc or hcp phase exhibited by the cobalt nanowires. Single crystalline nanowires with a hcp phase strongly oriented along the (2021) crystallographic plane were obtained at pH 4 and at -1.1 V (vs. Ag/AgCl), a result not previously reported. High electrolytic bath temperatures contributed to improve the single crystalline character of the cobalt nanowires. The presence of chloride anion in the electrolytic bath also influenced on the structural properties of the resulting cobalt nanowires, improving their crystallinity. The optical reflectance of the samples shows a structure in the UV blue region that can be assigned to the two-dimensional morphology arising in the shape of the almost parallel nanowires. Magnetic measurements showed that different electrodeposition potentials and electrolytic bath pH lead to different magnetic anisotropies on the nanowire array samples. PMID- 21780385 TI - Degradation and failure of field emitting carbon nanotube arrays. AB - It has been observed experimentally that the collective field emission from an array of Carbon Nanotubes (CNTs) exhibits fluctuation and degradation, and produces thermal spikes, resulting in electro-mechanical fatigue and failure of CNTs. Based on a new coupled multiphysics model incorporating the electron-phonon transport and thermo-electrically activated breakdown, a novel method for estimating accurately the lifetime of CNT arrays has been developed in this paper. The main results are discussed for CNT arrays during the field emission process. It is shown that the time-to-failure of CNT arrays increases with the decrease in the angle of tip orientation. This observation has important ramifications for such areas as biomedical X-ray devices using patterned films of CNTs. PMID- 21780386 TI - Direct current conductivity of carbon nanofiber-based conductive polymer composites: effects of temperature and electric field. AB - Polymer composites based on high density polyethylene (HDPE) and carbon nanofiber (CNF) were fabricated by melt compounding. The dependences of electrical conductivity of HDPE-CNF composites on filler concentration, temperature, and applied electric field were investigated. The results showed that the conductivity of the HDPE-CNF composites follows the scaling law of percolation theory. Increasing temperature caused a sharp increase in the resistivity of HDPE CNF composites near the melting temperature of HDPE, yielding a positive temperature coefficient (PTC) effect of resistance. The potential mechanisms involved in the PTC effect of such composites were analyzed. An investigation of the effect of electric field on the conductivity of HDPE-CNF composites revealed the presence of tunneling conduction. The tunneling conductivity increased with increasing filler content because of high tunneling frequency, and decreased with rising temperature as a result of gap widening between conducting CNF fillers. PMID- 21780387 TI - Optimization of tribological and mechanical properties of nanocomposites of polyurethane/poly(vinyl acetate)/CaCO3. AB - Properties of samples containing polyurethane (PU), poly(vinyl acetate) (PVAc) and nanosize particles of calcium carbonate (CaCO3) are correlated with concentrations of these components. Interphase phenomena in PU/PVAc/CaCO3 nanohybrids have been studied before, we focus here on wear and scratch resistance. In addition to polymer blends containing CaCO3, the effects of adding CaCO3 with grafted PVAc, and CaCO3 with grafted silane and PVAc in varying ratios are also evaluated. For blends that do not contain the filler, a hypothesis explaining the concentration dependence of friction called the Bump Model is advanced and supported by the experimental results. In particular, we explain how creating a blend containing only 10% of a second polymer results in a dramatic drop of friction of the majority polymer. In single scratch testing, above 3% the filler displays 'its own' resistance to scratching. Chemical modification of the filler results in shallower residual depths--a consequence of improved interaction of the filler with the polymeric matrix. In sliding wear determination, strain hardening is seen for blends as well as for filler containing composites. In tensile testing, addition of an unmodified filler increases the elongation at break and thus lowers the brittleness; the effect is even larger for chemically modified fillers. PMID- 21780388 TI - Mechanical, thermal and morphological characterization of polycarbonate/oxidized carbon nanofiber composites produced with a lean 2-step manufacturing process. AB - In this study we report the advantages of a 2-step method that incorporates an additional process pre-conditioning step for rapid and precise blending of the constituents prior to the commonly used melt compounding method for preparing polycarbonate/oxidized carbon nanofiber composites. This additional step (equivalent to a manufacturing cell) involves the formation of a highly concentrated solid nano-nectar of polycarbonate/carbon nanofiber composite using a solution mixing process followed by melt mixing with pure polycarbonate. This combined method yields excellent dispersion and improved mechanical and thermal properties as compared to the 1-step melt mixing method. The test results indicated that inclusion of carbon nanofibers into composites via the 2-step method resulted in dramatically reduced ( 48% lower) coefficient of thermal expansion compared to that of pure polycarbonate and 30% lower than that from the 1-step processing, at the same loading of 1.0 wt%. Improvements were also found in dynamic mechanical analysis and flexural mechanical properties. The 2 step approach is more precise and leads to better dispersion, higher quality, consistency, and improved performance in critical application areas. It is also consistent with Lean Manufacturing principles in which manufacturing cells are linked together using less of the key resources and creates a smoother production flow. Therefore, this 2-step process can be more attractive for industry. PMID- 21780389 TI - Hybrid AlGaN/GaN-ZnO-nanowire gas sensors. AB - The potential of AIGaN/GaN heterostructures integrated with zinc oxide (ZnO) nanowires for gas sensing applications is demonstrated. Single crystal ZnO nanowires, serving as sensing probes, were selectively grown between two ohmic electrodes of AIGaN/GaN two dimensional electron gas heterostructures by thermal oxidation of sputtered zinc films in air. Electron diffraction and transmission electron microscopy showed the ZnO-nanowires to be crystalline structures oriented in the [001] direction. The fabricated structures were used to detect ethanol, acetone and methanol in a nitrogen background. The results indicate that the hybrid AIGaN/GaN-ZnO nanowires gas sensors are operable over a broad range of temperatures and could potentially be integrated with devices for wireless environmental monitoring. PMID- 21780390 TI - Luminescent dye-doped KAP nanorods obtained by template assisted crystallization. AB - Luminescent nanorods of potassium acid phthalate (KAP) doped with rhodamine 6G (Rh 6G) dye molecules were grown by template assisted crystallization. Pores with diameters ranging from tens of nanometers to few micrometers were obtained in polycarbonate foils after heavy-ion irradiation and subsequent chemical etching of the damage trails along the ion trajectories. Crystallization from solution was employed for filling of the pores with the dye-doped KAP rods. These nanostructures were characterized using scanning electron microscopy, optical absorption spectroscopy and photoluminescence detection. X-ray diffraction was used for structural analysis. The luminescence of the dye-doped rods undergoes a redshift when the diameter of the structures decreases. This shift is probably caused by increasing dye concentration in the rods with decreasing pore diameter. The luminescence originating from the Rh 6G presence is up-converted due to the second-harmonic generation in KAP. PMID- 21780391 TI - Electrospun polyethylene oxide (PEO) nanofibers containing cyclodextrin inclusion complex. AB - In this study, we obtained functional electrospun nanofibers containing stable fragrance/flavor molecule facilitated by cyclodextrin inclusion complexation. Menthol was used as a model fragrance/flavor molecule and we have electrospun poly(ethylene oxide) (PEO) nanofibers containing cyclodextrin-menthol inclusion complexes (CD-menthol-IC). We used two different solvent systems; water and water:ethanol and three types of CDs; alpha-CD, beta-CD and gamma-CD in order to find the optimal performance for the stabilization of menthol at high temperatures. We observed that the solvent system used for electrospinning process and the types of CDs (alpha-CD, beta-CD and gamma-CD) are very important to obtain CD-menthol-IC which ultimately determines the durability and temperature stability of menthol in the PEO nanofibrous web. We found out that it is better to use water rather than the water:ethanol solvent system for the inclusion complexation and additionally beta-CD and gamma-CD are most favorable choices since they are able to form complexation with menthol in the water solvent system. Despite the high volatility nature of menthol, our results demonstrated that the stability and temperature release of menthol was sustained to a very high and a broad temperature range (100 degrees C-250 degrees C) for PEO nanowebs containing CD-menthol-IC whereas the PEO nanofibers without CD and without CD-menthol complex could not preserve menthol even during storage. In brief, the results are very encouraging and open up for a variety of new exciting possibilities for the development of multi-functional electrospun nanofibers containing cyclodextrin inclusion complexes. PMID- 21780392 TI - Base-selective adsorption of nucleosides to pore-engineered nanocarbon, carbon nanocage. AB - Selective molecular recognition is an important subject in supramolecular science as well as in practical applications such as sensing, drug delivery, and biomedical processes. In this research we have investigated adsorption behavior of nucleosides (adenosine, guanosine, and thymidine) onto various porous supports. When compared with mesoporous silica, porous carbons exhibit superior adsorptive performance. We serendipitously observed a pronounced selectivity between purine-base and pyrimidine-base nucleosides by carbon naonocage. These findings are useful for design of materials for applications in adsorption-based separations and as column stationary phases for separation of costly and important biomolecules. PMID- 21780393 TI - Synthesis and characterization of poly(butylene oxide) grafted carbon nanofibers. AB - The grafting of polybutylene oxide onto purified and functionalized carbon nanofibers is reported. Grafting was possible after the insertion of 2 (formyloxy)ethyl 2-bromo-2-methylpropanoate onto the carbon nanofibers. The polymerization of tetrahydrofuran was mediated by copper(I) bromide and 1,1,4,7 pentamethyl diethylenetriamine. The polymer-grafted carbon nanofibers were characterized by Raman spectrsocopy, Transmission Electron Microscopy, and Thermogravimetric Analysis. TEM images of CNF-COOH (A), CNF-PBO (B), completely open tip of CNF-COOH, and coated tip of CNF-PBO (D) are shown in the left panel. The right panel depicts the distribution of bromine (blue), and carbon (red) atoms inside and in the vicinity of CNF-Br (as obtained by Electron Energy Loss Spectroscopy). The bottom shows the actual doped CNF. Preliminary data showed that these modified fibers have potential applications as smart (electrorheological) fluids. PMID- 21780394 TI - Enhanced reaction kinetics and impact strength of cyanate ester reinforced with multiwalled carbon nanotubes. AB - In this work, the effect of multiwalled carbon nanotubes on the properties of a unique, low viscosity bisphenol E cyanate ester (BECy) resin is characterized during various stages of nanocomposite preparation. The effect of surface functionalization, with nanotubes containing hydroxyl groups (OH CNTs) and carboxylic acid groups (COOH CNTs), on the rheological, cure, thermal, and impact properties of the nanocomposite properties are also examined. Based on rheology measurements prior to cure, the unfunctionalized nanotube suspensions are found to exhibit the highest viscosity and the most dramatic shear thinning behavior. Cure characterization using differential scanning calorimetry (DSC) reveals that the nanotubes catalyze the cure of BECy and the OH CNTs exhibiting the most dramatic catalytic effect. The DSC data is well described by an nth order autocatalytic model. The impact strength of fully cured BECy is found to increase by 91% and 63% upon incorporation of 1 wt% COOH and OH CNTs, respectively. While incorporation of 1 wt% unfunctionalized nanotubes results in an 8 degrees C decrease in the glass transition temperature (T(g)) of BECy, chemical functionalization greatly mitigates the magnitude of the reduction. PMID- 21780395 TI - Deep and alignment free patterned etching of GaN surface using an atomic force microscope. AB - Successful deep and alignment-free patterned etching on GaN using atomic force microscope (AFM) local oxidation followed by in-situ chemical etching is demonstrated. Oxide ridges are grown on GaN on an AFM by applying positive sample bias at 80% humidity, with the oxidation reaction expedited by UV light. The oxide ridges are then etched by HCl solution, leaving troughs in the GaN surface. A dripping strategy for the in-situ chemical etching is recommended that allows deep, alignment-free multiple AFM oxidation/etching works on the GaN surface without any need of substrate removal from the AFM platform. Repeated etching followed by AFM oxidation on a spot on a GaN surface resulting in a hole as deep as 800 nm was also demonstrated. Further, a preliminary evaluation of the porosity of the AFM-grown oxide indicates that the oxide ridges grown on GaN at an AFM cantilever moving speed of 300 nm/s are porous in structure, with an estimated porosity of 86%, which porosity could be reduced if longer resident time of the AFM cantilever on the target oxidation region was used. PMID- 21780396 TI - A new insight on the preparation of stabilized alpha-nickel hydroxide nanoparticles. AB - Nickel hydroxide can provide an outstanding cathode material in alkaline secondary batteries, however the progressive decrease of the charge capacity as a function of the number of oxidation/reduction cycles is a challenging problem to be solved. New improvements on the electrochemical properties of electrode materials can be achieved by exploiting the much better performance of alpha nickel hydroxide. Such materials were obtained in a stable form by sol-gel method and characterized by thermogravimetric analyses, UV-Vis spectroscopy, X-ray diffractometry, scanning and transmission electron microscopy, cyclic voltammetry and electrochemical quartz crystal microbalance techniques. The results revealed not only the formation of the alpha-Ni(OH)2 phase, but also a much better electrochemical reversibility and stability as compared with similar materials obtained by electrochemical precipitation method. PMID- 21780397 TI - Morphology and polymorphic phase changes of calcium carbonate micro/nanocrystals using fruit extracts. AB - This study reveals the morphology and polymorphic phase changes of calcium carbonate crystals into a mixture of calcite and aragonite micro/nanocrystals of interesting morphology at room temperature by a simple reaction with fruit extracts of Tamarindus indica and Emblica officinalis respectively by mixing CaCO3 solutions with their corresponding extracts. The control experiments were carried out to establish the plausible role of tartaric acid from Tamarindus indica and ascorbic acid from Emblica officinalis in this regard. The quantitative determination of CaCO3 phases was done based on the use of intensities obtained from corresponding XRD spectrum. The molar % of aragonite was found to be more in case of TA and AA rather than TI and EO respectively, however the calcite was observed to be the predominant phase in all four reactions. Interestingly, the TI changes the rhombohedral morphology of calcite to elongated rods, whereas EO induces a great polymorphic phase change. PMID- 21780398 TI - Study on morphology and characterization of poly(mphenylene isophtalamide)/multi walled carbon nanotubes composite nanofibers by electrospinning. AB - Electrospinning technique is the main method of preparing polymer nanofiber simply, directly and continuously at present. In this work, electrospinning blend solution was prepared by in-situ polymerization using acid-modified multi-walled carbon nanotubes (MWNTs), m-phenylenediamine (MPD) and isophthaloyl chloride (IPC). And then composite nanofibers were prepared by electrospinning. MWNTs played an important role in nanofiber's properties. The effects of MWNTs on the morphology and characterization of the MWNTs/PMIA composite nanofibers were investigated. Scanning electron microscopy (SEM), thermal gravimetric analyzer (TGA), and X-ray diffraction (XRD) were utilized to characterize the MWNTs/PMIA nanofibers morphology and properties. The experimental results indicated that the nanofibers diameter decreased and solution dynamic viscosity increased with increasing MWNTs contents. XRD data demonstrated that PMIA composite nanofibers had the same crystal type as the pure PMIA nanofiber, and crystallinity was improved with increasing MWNTs loading. Transmission electron microscopy (TEM) was used to confirm MWNTs aligned along the axis of composite nanofibers. PMID- 21780399 TI - A numerical demonstration of discontinuous directional motion at the nanometre scale. AB - Classical molecular dynamics simulations have been employed to investigate the behaviour of a relatively complex assembly of carbon nanotubes embedded into a CF4 liquid phase submitted to heating and cooling cycles. The assembly is formed by two concentric capsule-like carbon nanotubes, the smaller of which located in the interior of the larger one, which has a partially open end. The carbon nanotubes have radii such that the distance between their cylindrical walls, though keeping attrition negligible, does not permit the passage of chemical species from one side of the inner capsule to the other. CH4 molecules in liquid phase are confined between the capped end of the outer nanotube and the inner capsule. On the other side, CF4 molecules can access the volume available between the inner capsule and the outer nanotube through its open end. When temperature is raised, the confined CH4 molecules undergo the liquid-gas transition. The consequent volume expansion pushes the inner capsule in the direction of the open end of the outer nanotube, which determines the rapid ejection of the CF4 molecules. This generates a thrust that allows the motion of the whole assembly in the direction opposite to ejection. When temperature is decreased and CH4 molecules return in the liquid phase, the system slowly recovers the initial configuration. The whole cycle of operation is fully reversible and allows the assembly to directionally move into the liquid phase. PMID- 21780400 TI - Synthesis and characterization of Fe doped CeO2 nanoparticles for pigmented ultraviolet filter applications. AB - Iron doped CeO2 nanoparticles with doping concentrations between 0 and 30 mol% were synthesized by the co-precipitation method for potential application as a pigmented ultraviolet filtration material. Each sample was calcined in air and in argon. The iron solubility limit in the CeO2 lattice was found to be between 10 and 20 mol%. Raman spectroscopy results revealed that both iron doping and argon calcination increase the concentration of oxygen vacancies in the CeO2 lattice. Iron doping causes a blue-shift of the absorbance spectrum, which can be linked to the decreased crystallite size, as obtained by XRD peak broadening using the Scherrer formula. The undoped samples showed weak ferromagnetic behaviour whereas the doped samples were all paramagnetic. PMID- 21780401 TI - Micropatterning of porphyrin nanotubes thin film using focused laser writing. AB - We report an effective process to create micropatterns on a thin film of porphyrin nanotubes PNTs on Si substrate using focused laser beam. The optical properties of the newly synthesized porphyrin nanotubes are investigated and micropatterning is demonstrated using laser fabrication, an increasingly important tool in various fields of research. We made use of this laser cutting method to create interesting and useful two-dimensional patterned structures. The shapes and sizes of the structures created can be controlled by varying the power of the laser, angle of incident of the focused laser beam, the relative speed with which the laser beam traverse through the film and the magnification of objective lens used. PMID- 21780402 TI - Electrochemical behaviors of double-walled carbon nanotubes encapsulating ferrocene. AB - Electrochemical properties of a novel nanohybrid material, ferrocene-filled double-walled carbon nanotubes (Fc@DWNTs), have been successfully investigated for the first time by preparing different kinds of Fc@DWNTs modified glassy carbon electrodes. One pair of surface-confined redox waves corresponding to the couple of Fc/Fc+ is obtained, indicating Fc encapsulated in DWNTs retains electrochemical activity. Significantly differing from those of ferrocene-filled single-walled carbon nanotubes (Fc@SWNTs), Fc@DWNTs shows a specific electrochemical behavior, typically exhibiting thin-layer electrochemical characteristics at low scan rates, whereas diffusion-confined characteristics at high scan rates. The results indicate that the novel nanohybrid material possessing excellent electrochemical properties may have possible applications in constructing specific chemical and biological sensors. PMID- 21780403 TI - One-step and rapid synthesis of composition-tunable and water-soluble ZnCdS quantum dots. AB - ZnCdS quantum dots have been successfully prepared at room temperature in aqueous solution with sodium hexametaphosphate as stabilizer and thioacetamide as the source of S. The photoluminescence (PL) spectra and UV-Vis absorption spectra of the ZnCdS quantum dots were determined on the basis of the initial Cd/Zn mole ratio (Cd/Zn = 8/0, 7/1, 6/2, 5/3, 4/4, 3/5, 2/6, 1/7 and 0/8) and the concentration of thioacetamide. The emission peaks first showed a red shift and then a blue shift with the increasing initial Zn concentration, which provided the evidence of formation of CdS/ZnCdS core/shell and ZnCdS alloyed quantum dots. The ZnCdS quantum dots were compared with CdS (ZnS) quantum dots doped with Zn2+ (Cd2+). The samples have also been characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray photoelectron spectra (XPS). PMID- 21780404 TI - Photophysical and complexation studies of chloro-aluminum phthalocyanine with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. AB - A variety of nanostructures are being investigated as functional drug carriers for treatment of a wide range of diseases, most notably cardiovascular defects, autoimmune diseases, and cancer. The aim of this present contribution is to evaluate potentially applicable nanomaterials in the diagnosis and treatment of cancer due to their photophysical and photobiological properties and complexation behavior. The delivery systems consisted of chloro-aluminum phthalocyanine associated with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. The preparation of the complex and its stoichiometry in an ethanol/buffer (3:1) solution were studied by spectroscopic techniques, which were defined as 1:2. The inclusion complex in the nanometer scale was observed on the basis of changes to the spectroscopic properties. The singlet oxygen production and complex photophysical parameters were determined by measuring luminescence at 1270 nm and by steady state and time resolved spectroscopic, respectively. The preparation of the complex was tested and analyzed with regard to cellular damage by visible light activation. The inclusion complex showed a higher singlet oxygen quantum yield compared with other systems and other photoactive dyes. There was also a reduction in the fluorescence quantum yield compared with the results obtained for zinc phthalocyanine in organic medium. The results reported clearly that the inclusion complex chloro-aluminum phthalocyanine/cyclodextrin showed some changes in its spectroscopy properties leading to better biodistribution and biocompatibility with a potential application in photodynamic therapy, especially in the case of neoplasy. Additionally, it also has non-oncological applications as a drug delivery system. PMID- 21780405 TI - Synthesis of hollow ZrO2 mesopores microspheres with strong adsorption capability by the yeast bio-template route. AB - In this work, cage-like ZrO2 and hollow ZrO2 microspheres with high surface area and strong adsorption capability were successfully synthesized by microwave- ethanol-thermal method using yeasts as bio-template. XRD, SEM, EDS and BET were used to characterize the products. The results show that these micropheres have a size of about 2-3 microm and are composed by ZrO2 particles of 30-40 nm. The maximum specific surface area of them can reach to 384.780 m2/g and there are presences of the inhomogeneous mesopores. Moreover, the template can be removed and tetragonal phase ZrO2 can be obtained without using calcinations, which greatly simplifies the experimental procedure. We also studied the adsorption capability of cage-like ZrO2 and hollow ZrO2 microspheres to methyl orange, the highest adsorption percent was up to 99.5%. The adsorption isotherm conforms to Freundlich equation. PMID- 21780406 TI - Utilization of ZnO nanocones for the photocatalytic degradation of acridine orange. AB - A facile aqueous solution process was used to synthesize well-crystalline ZnO nanocones at 60 degrees C by using zinc nitrate hexahydrate and sodium hydroxide. The morphological, structural and optical properties of the synthesized ZnO nanocones were investigated by using field emission scanning electron microscopy (FESEM) attached with energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM) equipped with high-resolution (HRTEM), X-ray diffraction (XRD) pattern, Fourier transform infrared (FTIR) spectroscopy and UV-Vis. spectroscopy measurements. The structural and optical properties of the as-synthesized nanocones confirmed a pure and well crystalline product possessing wurtzite hexagonal phase. The as-synthesized ZnO nanocones were used as photocatalyst for the efficient photocatalytic degradation of acridine orange. The acridine orange was almost completely degraded within 105 minutes. This research demonstrates that the simply synthesized ZnO nanostructures could be efficient photocatalyst for the photocatalytic degradation of various organic dyes and chemicals. PMID- 21780407 TI - Thermal stability of the peak emission wavelength in multilayer InAs/GaAs QDs capped with a combination capping of InAlGaAs and GaAs. AB - The effect of rapid thermal annealing (RTA) on the optical properties of a 10 layer stacked InAs/GaAs quantum dot (QD) heterostructure where the QDs are overgrown with a combination of quaternary InAlGaAs and GaAs capping have been investigated. TEM micrographs showed that the shape of the QDs is preserved for annealing temperatures up to 800 degrees C. The peak emission wavelength of the investigated heterostructures remains stable on annealing at temperatures upto 750 degrees C, which is unusual in QD samples. This phenomenon is attributed due to the suppression of the strain-enhanced intermixing in such structures. One of the reasons behind such suppression is the strain driven phase separation of Indium from the overgrown quaternary alloy, which maintains an In rich region across the QD periphery thereby checking the out-diffusion of Indium from the dots. The overlapping vertical strain from the under lying dot layers in the QD stack also maintains a strain relaxed state at the QD base, thereby preventing the material mixing at the base of the pyramidal QDs. This stability of wavelength is of paramount importance in optoelectronic devices where the design is based on the emission wavelength of the active region. PMID- 21780408 TI - Preparation of ethenylene-silica hollow spheres with a single-layer of mesopores using a chiral amphiphile. AB - A chiral cationic low-molecular-weight amphiphile, derived from L-phenylalanine, was synthesized. It can gel benzene, toluene and chlorobenzene and cause viscous liquids in deionized water and tetrahydrofuran. Ethenylene-silica hollow nanospheres with a single-layer of pore channels in their shells were prepared using the self-assemblies of this amphiphile as templates. Small angle X-ray diffraction pattern indicated that the pore channels did not arrange in a high degree of order. The formation of this hierarchical porous structure was studied by taking TEM images after different reaction time. It was found that the morphologies of the amphiphile-ethenylene-silica assemblies changed gradually during the sol-gel transcription process. Moreover, silica hollow spheres were also prepared using this amphiphiles. PMID- 21780409 TI - In situ synthesis of ordered mesoporous silica materials embedded in cotton fiber and their CO2 capture properties. AB - Mesoporous silica/cotton fiber composite materials have been prepared in situ by using pluronics P123 (EO20PO70EO20) as template, tetraethyl orthosilicate as silica source and degreasing cotton as supporter. In order to avoid the hydrolysis of cotton fiber in a strong acidic media during the hydrothermal treatment, two kinds of methods were used to control the acidity of the reaction media. One was to adjust the pH to 5 after self-assembly in a strong acidic media; the other was a two-step route containing the pre-hydrolysis of TEOS and self-assembly in a weak acidic media. The resulting shaped composite materials presented the morphology of cotton fiber, and the silica particles mainly covered the surfaces of cotton fibers. These silica particles possessed a slightly ordered pore structure or a well ordered SBA-15 structure according to the difference in the synthetic methods. After modification with tetraethylenepentamine, these shaped composite materials exhibited considerable CO2 adsorption capacity. The use of cotton fiber has the advantages of shaping the powdery materials, dispersing the silica particles and avoiding the formation of moisture and sticky solid surfaces by overloaded tetraethylenepentamine. PMID- 21780410 TI - Preparation, characterization, and photoelectric properties of an electrostatically self-assembled film based on tungstophosphoric acid and a binuclear Ru(II) complex. AB - An electrostatically self-assembled film based on tungstophosphoric acid (PTA) and a binuclear Ru(II) complex RuL was prepared and characterized by UV-vis absorption spectroscopy and cyclic voltammetry. A linear increase in the UV-vis absorbance with the number of deposited layers indicated that the film deposition was uniform and reproducible. The cyclic voltammogram demonstrated that PTA and the binuclear Ru(II) complex assembled in the film were redox active with surface confined characteristics. The photoelectrochemical properties and mechanism of photocurrent generation have also been studied. A five-layer (PTA/RuL)5 film on the ITO was found to exhibit a large cathodic photocurrent density of 5.32 microA/cm2 while irradiated with polychromatic light (730 nm > lambda > 325 nm) at an applied potential of -0.3 V versus saturated calomel electrode. The photocurrent action spectrum was in agreement with metal-to-ligand charge transfer (MLCT) band of RuL in the absorption spectrum, which indicated that the photocurrent was generated based on MLCT excitation of the RuL in the film. It is noteworthy that the incident monochromatic photon-to-current conversion efficiency was calculated to be 1.1% at a wavelength of 450 nm. PMID- 21780411 TI - Electrical and magnetic properties of nanocrystalline BiFeO3 prepared by high energy ball milling and microwave sintering. AB - A new synthesis route with high energy ball milling and microwave sintering is used to obtain nanocrystalline BiFeO3 with improved dielectric and magnetic properties. Electrical and magnetic properties are compared with a conventionally sintered microcrystalline BiFeO3. It is found that the dielectric constant is increased more than one order of magnitude, electrical resistivity by six orders of magnitude and remnant polarization value is increased by 4-5 times for nanocrystalline BiFeO3 in comparison to conventionally sintered microcrystalline BiFeO3. Nanocrystalline BiFeO3 is seen to have ferromagnetic behavior whereas microcrystalline BiFeO3 is known to be antiferromagnetic. PMID- 21780412 TI - Comparison study on the antibacterial activity of nano- or bulk-cerium oxide. AB - Due to the unique physical and chemical properties, nanosized cerium oxide (n CeO2) has attracted considerable interest in many fields of research. The potential, the growing use and the mass production of n-CeO2 have stimulated research on their potential impact on the environment and human health. However, the toxicological definition for CeO2 nanoparticles (NPs) is still quite controversial. In the present work, we evaluated the antibacterial activity of CeO2 NPs sized ca. 7 nm (7-CeO2), ca. 25 nm (25-CeO2) and their bulk counterpart (b-CeO2), using gram-negative Escherichia coli (E. coli). Our results suggest that all the three types of CeO2 particles have antibacterial activity, and both the NPs are more toxic than b-CeO2. The rise in intracellular ROS level induced by direct contact of particles with the surface of E. coli was involved in the mechanism for the antibacterial activity of CeO2 NPs. Exposure to 25-CeO2 could also impair the integrity of the outer membrane within E. coli cells. Due to agglomeration and negligible effect on membrane integrity, 7-CeO2 did not exhibit greater antibacterial activity than 25-CeO2. PMID- 21780413 TI - The effect of substrate type on SiC nanowire orientation. AB - beta-SiC nanowires were synthesized on different monocrystalline substrates: Si (001), Si (111), 3C-SiC (001), 4H-SiC (0001), 6H-SiC (0001). The SiC nanowire growth was carried out using a Chemical Vapor Deposition method, with silane and propane diluted in hydrogen (3%) as precursors. The deposition was performed at atmospheric pressure and at 1100 degrees C, after dewetting of the Ni catalyst, which had been previously evaporated onto the substrate, to induce 1D growth according to a VLS process. The crystal structure of the nanowires, as determined by X-ray diffraction and High Resolution Transmission Electron Microscopy, corresponds to 3C-SiC polytype growing along a (111) direction, irrespective of the substrate. The occurrence of (111) stacking faults was observed, partly reduced for samples grown on 3C-SiC substrate. The growth on (111) substrate allowed to achieve a good vertical alignment of the nanowires, as investigated by Scanning Electron Microscopy. High Angle Annular Dark Field imaging and Energy Dispersive X-Ray spectroscopy were performed to study the catalyst particle on top of the wires and showed the formation of a nickel-silicon alloy. PMID- 21780414 TI - The effect of gold colloid on the fluorescence spectrum from Safranine T: a physical mechanism based on resonance light scattering. AB - The non-monotonic change of fluorescence intensity from Safranine T was observed experimentally by adding gold colloids to the Safranine T aqueous solution. Increasing the content of gold colloids leads to the fluorescence emission peak red shift and increases first and then decreases. We believe that one of the important reasons of the fluorescence changing and shifting is due to the resonance light scattering from gold nanoparticles which is stimulated by the fluorescence of Safranine T and is tunable by the shell thickness of the ST that coated around the gold particles. PMID- 21780415 TI - Carbon nanofiber reinforced aluminum matrix composite fabricated by combined process of spark plasma sintering and hot extrusion. AB - Spark plasma sintering and hot extrusion processes have been employed for fabricating carbon nanofiber (CNF)-aluminum (Al) matrix bulk materials. The Al powder and the CNFs were mixed in a mixing medium of natural rubber. The CNFs were well dispersed onto the Al particles. After removal of the natural rubber, the Al-CNF mixture powders were highly densified. From the microstructural viewpoint, the composite materials were observed by optical, field-emission scanning electron, and high-resolution transmission electron microscopies. The CNFs were found to be located on every grain boundary and aligned with the extrusion direction of the Al-CNF bulk materials. Some Al carbides (Al4C3) were also observed at the surface of the CNFs. This carbide was created by a reaction between the Al and the disordered CNF. The CNFs and the formation of Al4C3 play an important role in the enhancement of the mechanical properties of the Al-CNF bulk material. The CNFs can also be used for engineering reinforcement of other matrix materials such as ceramics, polymers and more complex matrices. PMID- 21780416 TI - Liquid-phase synthesis of cobalt oxide nanoparticles. AB - Various liquid-phase syntheses of CoO and Co3O4 nanoparticles have been studied. The experiments focus on two synthesis routes: the coprecipitation and the sol gel methods combined with thermal decomposition. The effect of synthesis route, the type of precursors (cobalt nitrate/chloride) and precipitation agent (carbonate, hydroxide, oxalic acid, and ammonia), the chemical compositions, pH, application of surfactants (PDMS, Triton X-100, NaDS, NaDBS, TTAB, ethyl acetate, citric acid), and the heat treatments on the properties of particles were investigated. The particle size and distribution have been determined by dynamic light scattering (DLS). The phases and the morphology of products have been analysed by XRD and SEM. The coprecipitation technique is less able to shape the particles than sol-gel technique. PDMS can be applied efficiently as surfactant in preparation methods. The finest particles (around 85 nm) with narrow polydispersity (70-100 nm) and spherical shape could be achieved by using sol-gel technique in medium of 1-propanol and ethyl acetate. PMID- 21780417 TI - Brownian relaxation of interacting magnetic nanoparticles in a colloid subjected to a pulsatile magnetic field. AB - We have investigated and modeled the effect of interaction among magnetic particles and the magnitude and duration of external applied magnetic field on Brownian relaxation in a colloidal suspension. In the case of interacting magnetic particles, Brownian relaxation depends on the interparticle dipole dipole interaction, which slows down the overall Brownian relaxation process of magnetic particles in the colloidal suspension. The individual magnetic particle experiences torque when a pulsatile magnetic field is applied. The torque due to the external field randomizes the particle rotation similar to that of the thermal energy. A faster Brownian relaxation is observed when individual magnetic particles are magnetized for a short duration. Magnetizing the magnetic particle for a longer duration suppress the rotational motion hence the effect of torque on Brownian relaxation. PMID- 21780418 TI - Silane coupling agent structures on carbon nanofibers. AB - Carbon nanofibers (CNFs) are considered ideal materials for reinforcing polymers due to their excellent mechanical properties, among others. In order to obtain composites of optimal properties the clue is to enhance the interaction between reinforcement (CNFs) and polymer matrix. Surface modification of CNFs with silane coupling agents (SCAs) has revealed as one of the most interesting methods. The silanization process has been carried out mixing at room temperature and for one minute the hydrolysed silane with CNFs. We have use four different SCAs: 3 aminopropyltriethoxyxilane (APS), 3-aminopropyltrimethoxysilane (AMMO), N-(2 aminoethyl)-3-(aminopropyltrimethoxysilane) (DAMO), and 3 glycidoxypropyltrimethoxysilane (GLYMO), in order to elucidate the SCA-CNFs interaction and the silane structures formed on CNFs surface. XPS and FTIR-ATR techniques have pointed out that each silane adsorbs on CNFs surface through chemical bonding, forming multilayers. Silane nature determines the structure taken on CNFs surface. APS and AMO silanes adsorb taking vertical structures on CNFs surface, while DMO and GMO adsorb on CNFs taking horizontal structures, stabilized by zwitterions formed through H-bonds with hydroxyl groups from CNFs surface. PMID- 21780419 TI - Hyperthermia induced by magnetic nanoparticles improves the effectiveness of the anticancer drug cis-diamminedichloroplatinum. AB - The cytotoxic enhancement of cisplatin by magnetic fluid hyperthermia (MFH) was investigated in human colon adenocarcinoma cells (Caco-2). A nanoparticle platform based on iron oxide functionalized with carboxymethyl dextran was employed to produce heat at the nanoscale. To assess the synergistic effect of hyperthermia and the anticancer drug cis-Diamminedichloroplatinum, commonly known as cisplatin (CIS), cell viability was measured 24, 48, and 72 hours after three different combined hyperthermia and CIS exposure sequences. These included CIS incubation prior to hyperthermia or magnetic fluid hyperthermia, CIS exposure only during hyperthermia or MFH, and additional CIS incubation following hyperthermia or MFH. Additional incubation of CIS after hyperthermia treatment appears to be more effective than prior CIS incubation for both hyperthermia treatments. Viability data also indicated that MFH combined with CIS is significantly more effective than hot water hyperthermia at the same temperature. A CIS concentration an order of magnitude lower than the calculated IC50 was found to be very effective in reducing cell viability. Such dramatic differences suggest that MFH may enhance the passive transport of CIS. PMID- 21780420 TI - Charge transfer directed growth and morphology regulation of silver nanoparticles. AB - We demonstrate the control of silver nanoparticle growth in electroless deposition by utilizing surfaces of varying conductivity. Nanoscopic wires can be developed on non-conductive substrates, whereas nanoloops and microspheres are produced on surfaces of weak and high conductivity, respectively. Our observations reveal that the morphologies of electroless deposition can be regulated by the charge transfer through substrates, which indicates the important role of a redox reaction potential and a size-dependent chemical potential as the driving force behind this directed growth. PMID- 21780421 TI - Electrodeposition-based construction of random arrays of Pt nanoparticles on glassy carbon electrode (GCE) towards methanol oxidation application. AB - An eletrodeposition of random arrays of Pt nanoparticles, supported on glassy carbon electrode (GCE), is reported. It has been shown that such arrays exhibited good catalytic activity with respect to methanol oxidation in an acidic medium and longer deposition time produced more Pt nanoparticles on GCE leading to larger effective catalytic area and higher catalytic current. It was found that the process of methanol oxidation was controlled by the diffusion of methanol and the Pt nanoparticles formed stable film on GCE surface and also exhibited stable catalytic performance towards methanol oxidation. PMID- 21780422 TI - Preparation of nanoporous SiO2 particles and their application in drug release control. AB - Nanoporous SiO2 particles which have different pore size and volume were prepared from a colloidal mixture of nano-sized silica particles by a spray heating method. The prepared nanoporous SiO2 particles were employed as a drug carrier to investigate the release behaviors of methylene blue (MB) as a model drug for a selected period of time. The concentration of released MB from the porous particles was measured by a UV-Vis spectroscopy with respect to time. The release of MB from the porous particles was maintained for 400 hours and the maximum amount of the released MB was 0.8 mg at 1.56 cm3/g of pore volume. As pore volume of the nanoporous particles increased, the release rate of MB increased. PMID- 21780423 TI - Mucoadhesive and pH-sensitive thiolated Eudragit microspheres for oral delivery of Pasteurella multocida antigens containing dermonecrotoxin. AB - In this study, cysteine was conjugated to the Eudragit to have mucoadhesive and pH-sensitive properties. Pasteurella multocida dermonecrotoxin (PMT) is a major virulence factor as a causative agent of atrophic rhinitis (AR) in swine and, therefore, inactivated P. multocida was used as a candidate vaccine in the current study. PMT-loaded thiolated Eudragit microspheres (TEMS) prepared using W/O/W emulsion-solvent evaporation method were characterized to assess their efficacy in oral vaccination. PMT-loaded TEMS were observed as spherical shapes with smooth surfaces and average particle sizes were 5.2 +/- 0.55 microm. The loading efficiency of PMT in the TEMS was about 75.3%. A significantly higher percentage of PMT from PMT-loaded TEMS was released at pH 7.4 than at pH 1.5. Murine macrophage stimulated with PMT-loaded TEMS facilitated a gradual secretion of tumor necrosis factor-alpha and nitric oxide as immune stimulatory mediators in a time dependent manner, suggesting that the released PMT from PMT-loaded TEMS had immune stimulating activity of AR vaccine in vitro. PMID- 21780424 TI - Apta-biosensors for nonlabeled real time detection of human IgE based on carbon nanotube field effect transistors. AB - In this study, we demonstrated the aptamer-based biosensor (apta-biosensor) using CNT-FET devices for label free detection of allergy diagnosis by IgE detection. In order to detect the IgE, two kinds of receptor (monoclonal IgE antibody and anti-IgE aptamer)-modified CNT-FET devices were fabricated. The binding event of the target IgE onto receptors was detected by monitoring the gating effect caused by the charges of the target proteins. Since the CNT-FET biosensors were used in buffer solution, it was crucial to use small-size receptors like aptamers than whole antibodies so that the charged target IgE could approach the CNT surface within the Debye length distance to give a large gating effect. The results show that CNT-FET biosensors using monoclonal IgE antibody had very low sensitivity (minimum detectable level 1000 ng/mL), while those based on anti-IgE aptamer could detect 50 ng/mL. Moreover, the aptamer-modified CNT-FET herein could successfully block non-target proteins and could selectively detect the target protein in an environment similar to human serum electrolyte. Therefore, aptamer based CNT-FET devices enable the production of label-free ultrasensitive electronic biosensors to detect clinically important biomarkers for disease diagnosis. PMID- 21780425 TI - Label-free detection of leptin antibody-antigen interaction by using LSPR-based optical biosensor. AB - In the recent research, the development of optical biosensing devices has been focused on finding new method and technologies to exploit the optical properties of noble metal nanostructure, especially localized surface plasmon resonance (LSPR). In this study, we fabricated a LSPR-based label-free optical biosensor with the multi-spot gold-capped nanoparticle array (MG-NPA) biochip based on the deposition of a thin gold (Au) film on the silica nanoparticles layer with the simple process. The MG-NPA biochip used the silica nanoparticles as the core and a thin Au film as a shell on the surface. This structure can excite the LSPR signal easily with the high reproducibility. The anti-leptin antibody was immobilized on the surface of MG-NPA biochip, which could recognize only leptin antigen. The leptin antibody-antigen interaction was performed by the introduction of different concentration (1 pg/mL-100 microg/mL) of leptin antigen solutions for 1 h. The detection limit was found to be 100 pg/mL by using the anti-leptin antibody immobilized MG-NPA biochip. This LSPR-based label-free optical biosensor employing the MG-NPA biochip brings several advantages such as low cost, easy to fabricate, using a simple optical system and can be applied in a wide immunoassay with the similar antibody-antigen model. PMID- 21780426 TI - Electrochemical detection of biomolecule with mixed self-assembled monolayers of ferrocene-undecanethiol. AB - Thiol self-assembled monolayers (SAMs) have been widely used as a modification method to immobilize biomolecules to gold surfaces. However, the additional layers of SAM and biomolecules make electron transfer difficult, leading to a large overpotential in electrical signal. Electron transfer mediation is the most popular solution to overcome the problem of the overpotential for an electrochemical biosensor. We introduced mixed SAMs of mercapto-dodecanoic acid (MDA) and ferrocene-undecanthiol. Ferrocene-undecanthiol acts as an electron transfer mediator and MDA is used for immobilization of biomolecule. The electron transferability of mixed SAMs is affected by pH, kinds of electrolytes, and the composition of the thiol molecule. We optimized the carboxyl acid and ferrocene molecule ratio which is a crucial factor in the performance of mixed SAMs and electrochemically detected the avidin. The detection limit was 2.0 microg/mL of avidin concentration. PMID- 21780427 TI - Detection of beta-amyloid (1-42) on protein array based on electrical detection technique using scanning tunneling microscopy. AB - In this study an immuno-array for Abeta42 based on scanning tunneling microscopy (STM) was developed using conjugated gold nanoparticle (Au-NP) and antibody (Ab) complex. Fragmented monoclonal Ab against Abeta42 was allowed to immobilize on the Au-dot arrays followed by its target protein Abeta42 and Au NP and Ab complex. The surface structure of Au-NP and Ab complex on Au-dots was investigated with Atomic Force Microscopy and the current profile of fabricated immunosensing element was investigated with STM. The power spectrum derived from the current profile was found to be increasing with higher concentrations of Abeta42 having a detection limit of 100 fg/ml. The proposed technique can be a promising method to construct the highly sensitive and efficient protein chip of immunosensors arrays. PMID- 21780428 TI - Fabrication of nanoconcave surface for cell immobilization in cell-based chip. AB - Nanostructured surface such as nanoconcave shape can be utilized as a bioplatform to immobilize cells. In this study, we present fabrication of Au-coated nanoconcave surface and some possibility of cell immobilization. Long-range ordered periodic patterns with concave shape were formed on aluminum substrate by electrochemical anodization process. The morphology and topography of nanoconcave surface was investigated by atomic force microscopy and scanning electron microscopy. The pore-pore distance and the pore depth of nanoconcave pattern were measured at 105 +/- 5 nm and 30 +/- 2 nm, respectively. After Au deposition, the pore depth within Au-coated concave surface was 15 +/- 2 nm. The topography of HeLa cells immobilized on the nanoconcave surface was observed by AFM combined with confocal microscopy. The result expected that the Au-coated nanoconcave surface may be used as new culture substrate for cells immobilization in cell based chip. PMID- 21780429 TI - Label-free detection of DNA hybridization using pyrene-functionalized single walled carbon nanotubes: effect of chemical structures of pyrene molecules on DNA sensing performance. AB - We investigate the effect of functional groups of pyrene molecules on the electrical sensing performance of single-walled carbon nanotubes (SWNTs) based DNA biosensor, in which pyrenes with three different functional groups of carboxylic acid (Py-COOH), aldehyde (Py-CHO) and amine (Py-NH2) are used as linker molecules to immobilize DNA on the SWNT films. UV/Visible absorption spectra results show that all of the pyrene molecules are successfully immobilized on the SWNT surface via pi-pi stacking interaction. Based on fluorescence analysis, we show that the amide bonding of amine terminated DNA via pyrene containing carboxylic groups is the most efficient to immobilize DNA on the nanotube film. The electrical detection results show that the conductance of Py-COOH modified SWNT film is increased upon DNA immobilization, followed by further increase after hybridization of target DNAs. It indicates that the pyrene molecules with carboxylic acid groups play an important role to achieve highly efficient label-free detection by nondestructive and specific immobilization of DNAs. PMID- 21780430 TI - Nanoscale fabrication of myoglobin monolayer on self-assembled DTSSP for bioelectronic device. AB - The fabrication method of nanoscale myoglobin monolayer using chemical linker is introduced in this study because control of amount and orientation of protein immobilized on electronic device is one of main issues to be solved for the realization of biomolecular electronic device. Myoglobin, metalloprotein, is selected as active material due to its electrochemical property. To immobilize myoglobin on Au surface, 3,3-dithiobis (sulphosuccinimidyl propionate) (DTSSP) is utilized as a chemical linker. The optimum amount of protein is investigated by surface plasmon resonance (SPR). SPR and scanning tunneling microscope (STM) results confirm the nano scale protein layer formed on DTSSP self assembled monolayer (SAM) on Au surface. Protein layer on Au surface using DTSSP as chemical linker was more stable than random adsorption without linker as aspect of redox character due to the fact that myoglobin immobilized with chemical linker did not lose its redox property after long usages. PMID- 21780431 TI - Detection of DNA-hybridization using a near-field scanning microwave microscope. AB - A near-field scanning microwave microscope (NSMM) is used to detect sequence specific hybridization between surface-immobilized and free DNA single strands. Hybridization between target (free) and capture (immobilized) sequences leads to changes in the reflection coefficient (S11) which are measured by the NSMM. These changes are caused by hybridization-induced modification of the dielectric constant profile of the DNA film. NSMM instrumentation does not require labeling of target sequences with fluorophores or other tagging groups. The physical basis of reflection coefficient changes underpinning the NSMM approach is discussed. PMID- 21780432 TI - Influence of charge densities of randomly sulfonated polystyrene surfaces on cell attachment and proliferation. AB - Attachment and proliferation of NIH-3T3 fibroblast cells on random polymer surfaces, polystyrene sulfonated acid (PSSAx) with five different degrees of sulfonation (x = 0%, 5%, 10%, 15% and 33%) and on a tissue culture polystyrene (TCPS) surface were studied. The surface properties, wettability and roughness were measured by water-contact angle and atomic force microscopy measurement. The wettability and surface roughness increased with increasing the content of sulfonic acid groups on the surfaces. The number of cells attached on the surface after seeding increased with increasing x and reached to the maximum value on PSSA15. The cell proliferation also increased with increasing x. However, cell proliferation was slow down on PSSA33 in comparison to PSSA10 and PSSA15 surfaces after 48 h culture. PMID- 21780433 TI - The fabrication of protein nano arrays using 3-dimensional plastic nanopillar patterns. AB - A plastic nanopillar array was used as the basis for development of a cheap, spatially patterned immobilization method that was applied to nano biochips. A plastic nanopillar array (diameter: 500 nm, height: 1.2 microm) was fabricated using poly(urethane acrylate) (PUA) by simple and fast UV-curable soft lithography. Antibodies were immobilized on top of the nanopillar structure due to the 'lotus effect'; the aqueous solution containing proteins could only contact the top portion of the nanopillar array due to the hydrophobicity of the surface. This phenomenon was verified by atomic force microscopy and confocal microscopy. Optimal conditions were investigated to effectively generate a clear protein pattern on the nanopillar array. The immunoreaction capability of captured antibodies immobilized on the nano pattern was validated using various concentrations of complimentary antibodies. PMID- 21780434 TI - Influence of diquat on growth and death of HepG2 cells using quartz crystal and micro CCD camera. AB - Diquat is widely used agent which produces toxicity in human and implicated as an environmental toxicity. HepG2 cell was cultured onto an indium tin oxide (ITO) surface of quartz crystal modified a collagen film. In this paper, we investigated the physical properties and the morphological change of the HepG2 cells cultured onto the ITO electrode of the quartz crystal sensor with micro CCD camera. The resonance responses of the quartz crystal and the morphological change were directly monitored. After seeding the cells and diquat injection into the chamber, the resonance frequency and the resonance resistance were obtained with real time morphologies. From the resonance characteristics and the series of morphologies, we could know the diquat to be death and weakening of the cells. PMID- 21780435 TI - Adriamycin-incorporated nanoparticles of deoxycholic acid-conjugated dextran: antitumor activity against CT26 colon carcinoma. AB - In this study, we prepared adriamycin (ADR)-encapsulated nanoparticles using deoxycholic acid-conjugated dextran (DexDA). Its antitumor activity was evaluated using CT 26 tumor cells in vitro and in vivo. ADR-incorporated DexDA nanoparticles have spherical shapes and their particle sizes were ranged about 50 200. Their particle sizes were changed according to the preparation conditions, i.e., the higher substitution degree (DS) of deoxycholic acid (DA) and higher drug feeding ratio induced increased particle size and zeta potential. Furthermore, the higher DS of DA and higher drug feeding ratio induced increased drug contents and loading efficiency of drug. The higher DS of DA and higher drug feeding ratio induced decreased drug release rate. Futhermore, acidic pH of release media accelerated the drug release rate compared to alkaline pH. At in vitro cytotoxicity test using CT26 tumor cells, the nanoparticles showed higher antitumor activity than free ADR. In fluorescence microscopic observation, nanoparticles were properly entered into tumors cells and maintained in the cells compared to ADR itself. At in vivo animal tumor model using CT-26 cells, nanoparticles resulted in survivability increase of mice even though free ADR showed higher effectiveness to inhibit tumor growth. These results suggested that ADR-incorporated DexDA nanoparticles are promising vehicles for anti-tumor drug delivery. PMID- 21780436 TI - An integrated microfluidic device for rapid cell lysis and DNA purification of epithelial cell samples. AB - In this paper, we describe the design and fabrication of a microfluidic device for cell lysis and DNA purification, and the results of device tests using a real sample of buccal cells. Cell lysis was thermally executed for two minutes at 80 degrees C in a serpentine type microreactor (20 microL) using an Au microheater with a microsensor. The DNA was then mixed with other residual products and purified by a new filtration process involving micropillars and 50-80 microm microbeads. The entire process of sample loading, cell lysis, DNA purification, and sample extraction was successfully completed in the microchip within five minutes. Sample preparation within the microchip was verified by performing a SY158 gene PCR analysis and gel electrophoresis on the products obtained from the chip. The new purification method enhanced DNA purity from 0.93 to 1.62 after purification. PMID- 21780437 TI - Shape-dependent cytotoxicity of polyaniline nanomaterials in human fibroblast cells. AB - The toxicity of polyaniline (PANI) nanomaterials with four different aspect ratios on human lung fibroblast cells was investigated by cell viability assay, cytotoxicity assay, apoptosis/necrosis measurement, and reactive oxygen species production. The toxicity increased with decreasing aspect ratio of PANI nanomaterials. In contrast, the highest aspect ratio PANI nanomaterials showed similar results with bulk PANI materials. The adverse effect of PANI nanomaterials was also concentration- and time-dependent. Low aspect ratio PANI nanomaterials induced more necrosis and more reactive oxygen species than others. These results provide new understanding of shape-dependent toxicity of nanomaterials. PMID- 21780438 TI - ATP regeneration system using E. coli ATP synthase and Gloeobacter rhodopsin and its stability. AB - Great efforts in using non-photosynthetic bacteria as light-utilizing bacteria for producing biomaterials have been developed recently as increasing interest in renewable resources such as light energy. With respect to producing bio-materials industrially such as food ingredients and amino acids, huge amount of adenosine 5'-triphosphate (ATP) is required. In this work, we developed a bio-ATP-synthesis system using ATP synthase of Escherichia coil as a biocatalyst and a microbial rhodopsin which is from primitive cyanobacteria, Gloeobacter violaceus. Gloeobacter rhodopsin (GR) is a light-driven proton pump. Besides electro chemical gradient produced by cellular respiration system, GR produces a proton gradient using light illumination which is used in additional driving force of synthesizing ATP by ATP synthase. Inverted membrane vesicle was prepared so that it could be incorporated with both of GR and ATP synthase and produced ATP in the exterior side of the vesicle in the presence of light. Since inverted membrane vesicle does not contain precursors for ATP, we added ADP and inorganic phosphate (P(i)). Then, we measured the amounts of ATP produced by ATP synthase in the presence of light. As the average value of 6 samples, 4.79 x 10(-2) micromole of ATP produced for 1 microg of GR per minute. Also, we measured again after 7 days and 65 days, respectively, in order to check the stability of the bio-ATP synthesis system. Amount of ATP produced decayed double-exponentially and an expected value of half-life of the system was 1.5 days and 39.7 days. Our results demonstrate that ATP was regenerated successfully by using GR and ATP synthase. However, the stability of ATP synthase should be increased to use this system industrially in the near future. PMID- 21780439 TI - Nanostructured films as a novel substrate for chondrocytes growth. AB - We fabricated a large area silica nano-particle monolayer on glass substrates for the cell growth by the Langmuir-Blodgett technique. A thin film of 300 nm sized mono-dispersed silica particles was constructed on the air-water interface and transferred onto a glass substrate. Chondrocytes were cultured on nano-structured substrates and bare glass substrates for 8 days. The characterizations of chondrocytes on nano-structured substrate were conducted on 3rd and 6th day using confocal laser microscopy and with MTT assay for 8 days. The chondrocytes cultured on nano-structured substrate showed podia like spike and their size was larger than that formed on bare glass substrate. The metabolic activity of chondrocytes on nano-structured substrate was lower than that on bare glass substrate at early-stage, but it was recovered after 4 days. PMID- 21780440 TI - Aptamer biosensors for label-free colorimetric detection of human IgE based on polydiacetylene (PDA) supramolecules. AB - In this study, we demonstrate an aptamer-based biosensor (apta-biosensor) using PDA liposomes for label-free detection of allergy diagnosis by hIgE detection. In order to detect the target hIgE, the surface of PDA liposome were functionalized with hIgE antibody and anti-hIgE aptamer as a receptor, and the target hIgE onto the receptors was detected by the change of fluorescence signal. The hIgE antibody-modified PDA liposome biosensor had a serious problem that the immune reaction between receptor and target could not powerfully affect the change of florescence signal on PDA liposome. In order to solve this problem, the anti-hIgE aptamer which was far smaller than whole antibody was introduced as the receptor for the PDA liposome system. An aptamer-based PDA liposome biosensor was able to measure a quantity of target protein with various concentrations and at this time the detection limit was 141 ng/mL of the hIgE concentration. These results enabled diagnosis of allergy disease by an aptamer-based PDA liposome biosensor because real allergic patients showed high concentration of hIgE in serum (greater than 290 ng/mL). Therefore, we suggest that aptamer-modified PDA supramolecules as promising candidates for development of label-free colorimetric biosensors. PMID- 21780441 TI - The color tuning of PS-b-P2VP lamellar films with changing the alkyl chain length of 1-iodoalkanes. AB - Photonic crystals with tunability in the visible or near-infrared region have drawn increasing attention for controlling and processing light for the active components of future display. We prepared polystyrene-b-poly(2-vinyl pyridine) (PS-b-P2VP) lamellar films which is hydrophobic block-hydrophilic polyelectrolyte block polymer of 57 kg/mol-b-57 kg/mol. The lamellar stacks, which is alternating layer of hydrophilic and hydrophobic moiety of PS-b-P2VP, are obtained by exposing the spin coated film under chloroform vapor. The band gaps of the lamellar films interestingly varied after immersion into the quaternizing solvents containing 5 wt% of iodomethane, iodoethane, 1-iodobutane, 1 iodopentane, 1-iodohexane and 1-iodooctane solubilized in n-hexane. The iodoalkanes reacted with pyridine groups in PS-b-P2VP and generated the alkyl pyridinium salts readily. The degree of quaternization, alkyl chain length of iodoalkane and the salt water concentration affects the spacing of layer structure of PS-b-P2VP. The iodomethane and iodohexane produced similar band gaps and salt concentration dependence. These results are very much dependent on the hydrophobic-hydrophilic characters of PS-b-P2VP lamellar surface. PMID- 21780442 TI - Synthesis and characterization of new dithienosilole-based copolymers for polymer solar cells. AB - A series of dithienosilole-based copolymers, poly [(4,4'-bis(2-hexyl)dithieno[3,2 b:2',3'-d]silole)-2,6-diyl-alt-(2,1,3-benzothiadiazole)-5,5'-diyl] (P1), poly[(4,4'-bis(2-hexyl)dithieno[3,2-b:2',3'-d]silole)-2,6-diyl-alt-(2,2' bithiazole)-5,5'-diyl] (P2), poly[(4,4'-bis(2-hexyl)dithieno[3,2-b:2',3' d]silole)-2, 6-diyl-alt-(10 -methyl-phenothiazine)-3,7-diyl](P3), poly[(4,4' bis(2-hexyl)dithieno[3,2-b:2',3'-d]silole)-2,6-diyl-alt-(4,7-bis(2-thienyl)-9,10 anthracene)-5,5'-diyl] (P4) were synthesized by the Pd-catalyzed Stille polymerization method. Electron-deficient benzothiadiazole and bithiazole units and electron-rich phenothiazine and anthracene moieties were incorporated into the polymer backbone to obtain the broad absorption spectrum and to improve the hole-transporting characteristics, respectively. The polymer solar cell (PSC) was fabricated with a layered structure of ITO/PEDOT:PSS/polymer:C71-PCBM (1:3)/LiF/Al. The best performance of PSC was obtained at P3:C71-PCBM which reaches a power conversion efficiency (PCE) of 1.18%, with a short circuit current density (J(sc)) of 4.75 mA/cm2, an open circuit voltage (V(oc)) of 0.71 V, and a fill factor (FF) of 0.35 under AM 1.5G irradiation (100 mW/cm2). PMID- 21780443 TI - Optical and electrical properties of merocyanine dye LB films by various time of UV irradiation and heat treatment. AB - The Langmuir-Blodgett (LB) technique provides many possibilities for the control of film thickness, dimensions, and molecular structures on the nanometer scale. Various kinds of dye molecules have been found to form the J-aggregation which has been used as sensitizers of silver halide photography for long time. In recent years, they attract attention as model systems for investigating the ultra fast exciton dynamics, materials for ultra-fast nonlinear optical devices, fluorescence probes for mitochondrial membranes. We fabricated the merocyanine dye LB films with arachidic acid (AA). In order to observe the J-aggregation of the merocyanine dye LB films, CdCl2 and KHCO3 solutions were added in subphase. From the optical absorption spectra of the mixed dye LB films (6Me-Ds:AA = 1:2) at different layers, the optical absorption peak was about 520 nm. However, the optical absorption peak of the LB films was shifted to 600 nm, when CdCl2 and KHCO3 solutions were added. This is the consequence result to the J-aggregation of the merocyanine dye. We also investigated the optical absorption peak of the LB films according to various time at 60 degrees C and 275 nm UV. We measured the STM morphology of the merocyanine dye LB film (1 layer) before UV irradiation and heat treatment. The morphology size of the LB film on HOPG was 5 nm. The roughness and molecular size were about 66.163 pm and 0.176 nm, respectively. The J-aggregation of this type was also accompanied by large morphological changes. We analyze the morphology and electrical properties of the LB films by the scanning tunneling microscopy (STM). PMID- 21780444 TI - Fabrication of fluorescence tunable electrospun conjugated polycarbazole fibers containing gold nanoparticles. AB - In this report, we demonstrate a novel way to tune the fluorescence property of electrospun conjugated polymer fibers. The basic strategy is to use a soluble precursor polymer with gold nanoparticles for electrospinning, which is then cross-linked by applying potential cycles in an electrochemical cell. Electroactive carbazole units in electrospun precursor polymer fibers were converted to conjugated polymer fibers. Since the conjugated polymer fibers can be formed, the fluorescence from the conjugated polymer fibers can be tuned by the rate of the conversion and doping of the fibers. Furthermore, the quenching of the fluorescence, which overlaps with the plasmon band of the gold nanoparticles, was observed. The quenching of the fluorescence properties of the fibers was dependent on the amount of gold nanoparticles inside the fibers. PMID- 21780445 TI - Organic microchemical performance of solvent resistant polycarbosilane based microreactor. AB - We report the successful fabrication of preceramic polymer allylhydridopolycarbosilane (AHPCS) derived microchannels with excellent organic solvent resistance and optical transparency via economic imprinting process, followed by UV and post thermal curing process at 160 degrees C for 3 h. The microchemical performance of the fabricated microreactors was evaluated by choosing two model micro chemical reactions under organic solvent conditions; syntheses of 2-aminothiazole in DMF and dimethylpyrazole in THF, and compared with glass-based microreactor having identical dimensions and batch system with analogy. It is clear that AHPCS derived microreactor showed excellent solvent resistance and chemical stability compare with glass derived microreactor made by high cost of photolithography and thermal bonding process. The novel preceramic polymer derived microreactors showed reliable mechanical and chemical stability and conversion yields compare with that of glass derived microreactors, which is very promising for developing an integrated microfluidics by adopting available microstructuring techniques of the polymers. PMID- 21780446 TI - Photocurrent imaging of nanocrystal quantum dots on single-walled carbon nanotube device. AB - Semiconductor nanocrystal quantum dots (NQDs) are considered an attractive candidate for use in optoelectronic applications due to the ease of band gap control provided by varying the particle size. To increase the efficiency of NQDs when practically applied in devices, researchers have introduced the concept of coupling of NQDs to one-dimensional nanostructures such as single-walled carbon nanotubes (SWCNTs), which have a ballistic conducting channel. In the present study, NQDs of CdSe core and CdSe/ZnS are used as light absorbing building blocks. SWCNTs and functionalized NQDs are non-covalently coupled using pyridine molecules in order to maintain their electronic structures. To measure the electrical signals from the device, a NQDs-SWCNT hybrid nanostructure is fabricated as a field-effect transistor (FET) using the dielectrophoresis (DEP) method. A confocal scanning microscope was used to scan the devices using a diffraction-limited laser spot and the photocurrent was recorded as a function of the position of the laser spot. To improve the performance of detecting small electronic signal with high signal-to-noise ratio we used a lock-in technique with an intensity-modulated laser. In this paper, we have demonstrated that detection of local photoconductivity provides an efficient means to resolve electronic structure modulations along NQDs-SWCNT hybrid nanostructures. PMID- 21780447 TI - Aptamer based electrochemical sensor system for protein using the generation/collection mode of scanning electrochemical microscope (SECM). AB - To detect the target molecules, aptamers are currently focused on and the use of aptamers for biosensing is particularly interesting, as aptamers could substitute antibodies in bioanalytical sensing. So this paper describes the novel electrochemical system for protein in sandwich manner by using the aptamers and the scanning electrochemical microscope (SECM). For protein detection, sandwich system is ideal since labeling of the target protein is not necessary. To develop the electrochemical protein sensor system, thrombin was chosen as a target protein since many aptamers for it were already reported and two different aptamers, which recognize different positions of thrombin, were chosen to construct sandwich type sensing system. In order to obtain the electrochemical signal, the glucose oxidase (GOD) used for labeling the detection aptamers since it has large amount of stability in aqueous solution. One aptamer was immobilized onto the gold electrode and the other aptamer for detection was labeled with GOD for generation of the electric signal. Thrombin was detected in sandwich manner with aptamer immobilized onto the gold electrode and the GOD labeled aptamer. The enzymatic signal, generated from glucose addition after the formation of the complex of thrombin, was measured. The generation-collection mode of SECM was used for amperometric H2O2 detection. PMID- 21780448 TI - Characteristics of ZnO films prepared by atomic layer deposition for transparent electronic devices. AB - Recently, nanostructured zinc oxide (ZnO) for many different applications in micro- and opto-electronic devices has been studied intensively. However, its structural and electrical properties still require improvements for ZnO-based transparent electronics. In this study, we fabricated ZnO films (thicknesses from 30 to 70 nm) on glass substrates using atomic layer deposition (ALD) and investigated the film properties in relation with substrate temperatures. The processing window (thermal ALD window) of self-limiting growth was observed at 110-190 degrees C. In our thermal ALD window, the average growth rate of ZnO films was 0.26 nm/cycle, and the (002) orientation became dominant with increasing substrate temperatures. For all growth temperatures, ZnO films have shown n-type conductivity. At 170 degrees C, ZnO with good electrical properties of carrier concentration (1.3 x 10(19) cm(-3)), mobility (18 cm2/Vs), and resistivity (2.7 x 10(-2) omegacm) was successfully obtained. PMID- 21780449 TI - The structure and the percolation behavior of a mixture of carbon nanotubes and molecular junctions: a Monte Carlo simulation study. AB - The structure and the percolation behavior of the composite of carbon nanotubes (CNTs), CNT molecular junctions and polymers are studied using Monte Carlo (MC) simulations. We model a CNT as a rigid rod composed of hard spheres. "X" and "Y" molecular junctions of CNTs are constructed by joining four and three segments of CNTs, respectively. The model system consists of CNTs mixed with either "X" or "Y" molecular junctions. The system is equilibrated using Monte Carlo simulations and the equilibrated configurations are used to locate the clusters of connected molecules via a recursive algorithm. The fraction (P(perc)) of configurations with a percolating cluster is then estimated for a given total volume fraction (phi(t)) of molecules. When P(perc) reaches 0.5, phi(t) of the system is considered a percolation threshold concentration (phi(c)). The percolation behavior is found to be sensitive to the aspect ratio of CNTs and the concentration and the shape of molecular junctions. phi(c) is decreased with an increase in the aspect ratio of CNTs. As the mole fraction of molecular junctions is increased, phi(c) is decreased significantly, which suggests that molecular junctions could enhance the electric conductivity of CNT-polymer composites. X junctions are found to construct a percolating network more effectively than Y junctions. More interestingly, even though molecular junctions change the percolation behavior significantly, the site-site pair correlation functions of CNTs hardly show any difference as the mole fraction of molecular junctions is increased. This implies that the percolation of CNTs is determined by the subtle many-body correlation of CNTs that is not captured by the site-site pair correlation functions. PMID- 21780450 TI - Interaction of TEMAHf precursor with OH-terminated Si (001) surface: a first principles study. AB - We performed a first principles study to investigate the interaction of tetrakis ethylmethylaminohafnium (4[(C2H5)(CH3)N]Hf, TEMAHf) precursors with an OH terminated Si (001) surface that is the initial stage of atomic layer deposition (ALD). When TEMAHf reacted on the OH-terminated Si surface, there were two reaction mechanisms. One was the reaction with one -OH, and the other was the reaction with two -OH's. When TEMAHf reacted with an -OH on the Si (001) surface, an ethylmethylamine ((C2H5)(CH3)NH, EMA) was produced as a by-product and the trikis-ethylmethylaminohafnium group (3[(C2H5)(CH3)N]Hf) was attached to the O atom of the -OH. There were five reaction sites for TEMAHf to react with two OH's to form the dikis-ethylmethylaminohafnium group (2[(C2H5)(CH3)N]Hf): Inter dimer, intra-dimer, inter-row, cross-dimer, and cross-row. The reaction with two OH's on the inter-dimer, intra-dimer, and inter-row sites were more favorable than the reaction with one -OH. Since the inter-dimer reaction was the most favorable, the energy barrier on the inter-dimer site for the reaction of the trikis-ethylmethylaminohafnium group with -OH to form the dikis ethylmethylaminohafnium group was calculated, and the result was 0.19 eV. An extra energy of 0.25 eV was needed to remove EMA from the surface. Four TEMAHf's reacted with the surface and these reactions were exothermic by -7.77 eV, and the calculated Hf coverage of the first-half ALD cycle was 1.67 x 10(14)/cm2. PMID- 21780451 TI - In-situ synchrotron radiation photoemission spectroscopy study of the initial atomic layer deposition of Al2O3 film on Si(001) substrate. AB - In-situ synchrotron radiation photoemission spectroscopy and X-ray photoemission spectroscopy have been used to investigate the initial stages of Al2O3 growth on a Si(001) substrate by atomic layer deposition (ALD). The core level spectra of Si 2p, O 1s, and Al 2p as well as the valence band spectra were measured at every half reaction in the trimethylaluminum (TMA)-H2O ALD process. The line shape changes and binding energy shifts of the core level spectra reveal that Al2O3 is predominantly formed with a small amount of Si oxide in the initial stages without the formation of Al silicate. All core level spectra were alternately shifted toward higher and lower binding energies sides at every half ALD reaction. This can be explained by the band bending effect induced by different chemical species on the surface during the TMA-H2O ALD reaction. The valence band spectra showed that four cycles of ALD reactions were necessary to complete the electronic structure of the Al2O3 film with a valence band offset of 3.73 eV. PMID- 21780452 TI - Molecular-scale investigation of tolane disulfide self-assembled monolayers on Au(111) using scanning tunneling microscopy. AB - Molecular-scale surface structures of self-assembled monolayers (SAMs) formed by the spontaneous adsorption of tolane disulfides (TDS) on Au(111) in a 1 mM mixed solution of ethanol/N, N'-dimethylformamide (9:1) were examined using scanning tunneling microscopy (STM). The STM study revealed that TDS SAMs formed after a 24 h immersion at room temperature were composed of two-dimensional (2D) ordered phases with inhomogeneous surface morphologies and no clear domain boundaries. However, after 2 h immersion at 50 degrees C, uniform 2D ordered domains with clear domain boundaries were observed, which could be described as c(3 x square root of 3) structures with centered rectangular unit cell. Interestingly, a unique intermediate ordered phase with a low surface coverage was also observed. After a longer immersion for 24 h at 50 degrees C, only the uniform c(3 x square root of 3) domains were observed with a corrugation that may have reflected surface reconstruction of the Au(111) surfaces. From this study, we found that 2D ordered TDS SAMs with large and uniform domains on Au(111) can be obtained by controlling the solution temperature and immersion time. PMID- 21780453 TI - Bias stress effects on different dielectric surfaces of pentacene thin-film transistors. AB - In this paper, it was demonstrated that pentacene thin-film transistors (TFTs) were fabricated with an organic adhesion layer between an organic semiconductor and a gate insulator. In order to form polymeric film as an adhesion layer, a vapor deposition polymerization (VDP) process was introduced to substitute for the usual spin-coating process. Field effect mobility, threshold voltage, and on/off current ratio in pentacene TFTs with a 15 nm thick organic adhesion layer were about 0.4 cm2/Vs, -1 V, and 10(6), respectively. We also demonstrated that threshold voltage strongly depends on the stress time when a gate voltage has been applied for bias stress test. We suggest that a polyimide adhesion layer fabricated by the VDP method can be applied to realize organic TFTs with long term stability because of lower threshold voltage shifts due to reduced charge trapping at the interface between the pentacene semiconductor and the polyimide layer. PMID- 21780454 TI - Identification of p53 gene by using CdSe/ZnS conjugation and hybridization. AB - Recently Quantum Dots (QDs) have been of great interest due to their unique optical properties such as size-dependent, symmetric, narrow, and stable emissions, allowing for prolonged observation and multiplexing. We have prepared oligonucleotide conjugated to QD as a probe to detect p53 tumor suppressor gene related to hereditary cancer. QDs with carboxyl functional group have been conjugated to thiol-modified oligo nucleotides, which have been used as a hybridization probe for p53 gene. Target gene was added and hybridized with the QD bound probe. The conjugation of QD and thiolated oligonucleotide was stained by gel electrophoresis using Etrium Bromide (EtBr) as intercalating dye. Fluorescence resonance energy transfer (FRET) has been observed between QD and intercalating dye (Propidium Iodide) after hybridization of target and probe. FRET efficiency was increased with the increase of dye and DNA concentration. This shows the possibility of specific detection of low concentration of unlabeled complimentary DNA via quantum dots. PMID- 21780455 TI - Synthesis and characterization of lead selenide nanocrystal quantum dots and wires. AB - Lead chalcogenide nanocrystalline materials offer possibilities of improving the efficiency of various optoelectric/thermoelectric applications, especially in solar cells, by generating more carriers with incoming photons, or by extending the bandgap toward the infra-red region. In this work, we suggest the synthetic approach of creating extended PbSe structures which shows better performances when incorporated into an electric device. Firstly, we synthesized monodisperse cubic-structured single-crystalline lead selenide nanocrystal quantum dots using lead acetate and oleic acid in non-coordinating solvent without additional surfactants. Also, single-crystal cubic PbSe nanowires were synthesized in a mixture of surfactants such as trioctylphosphine and phenyl ether. Morphologies of wires and dots were precisely controlled via reaction temperature and the surface ligands. Phenyl ether was found to facilitate the oriented attachment. Further, current-voltage characteristics of drop-casted 2D arrays of nanocrystalline materials were examined. PMID- 21780456 TI - Synthesis and electro-optical properties of carbazole-substituted pyrene derivatives. AB - Mono and dicarbazole-substituted pyrene derivatives, 9H-carbazol-9-ylpyrene (MCzP) and 1,6-di(9H-carbazol-9-yl)pyrene (DCzP), with dual-purpose function as a blue emitting and charge transporting layer in organic light emitting diodes, were synthesized and characterized. These series of molecules consisted of an electron donating (D) carbazole and an electron accepting (A) pyrene in D-A and D A-D shapes. Non-doped blue electroluminescent devices with the configurations of ITO (150 nm)/alpha-NPD (30 nm)/DCzP (40 nm)/LiF (1 nm)/Al (150 nm) (D1) and ITO (150 nm)/2-TNATA (15 nm)/alpha-NPD (20 nm)/DCzP (40 nm)/BCP (15 nm)/Alq3 (10 nm)/LiF (1 nm)/Al (120 nm) (D2) were fabricated. D1 and D2 devices showed blue emission at 492 nm and 488 nm, and maximum luminance of 840 and 7560 cd/m2 obtained at 13 V and 15 V, respectively. PMID- 21780457 TI - Highly efficient blue light-emitting diodes based on diarylanthracene/triphenylsilane compounds. AB - New host materials have been designed and synthesized, (4-(10-(naphthalen-2 yl)anthracen-9-yl)phenyl)triphenylsilane (ANPTPS) and (9,9-dimethyl-7-(10 (naphthalen-2-yl)anthracen-9-yl)-9H-fluoren-2-yl)triphenylsilane (ANFTPS), and photophysical characteristics investigated to determine suitability as candidates for blue light-emitting materials. To explore the electroluminescent properties, multilayered OLEDs were fabricated with the device structure of ITO/NPB/Host (ANPTPS and ANFTPS): 8% Dopant (PFVtPh and PCVtPh)/Bphen/Liq/Al. By using a host (ANPTPS) and a dopant (PFVtPh) as the emitting layer, high-efficiency blue OLEDs were fabricated with a maximum luminance of 3991 cd/cm2 at 8.0 V, a luminous efficiency of 5.99 cd/A at 20 mA/cm2, a power efficiency of 3.11 lm/W at 20 mA/cm2, an external quantum efficiency of 4.13% at 20 mA/cm2, and CIEx, y coordinates of (x = 0.15, y = 0.18) at 8.0 V. PMID- 21780458 TI - Effects of metallic absorption and the corrugated layer on the optical extraction efficiency of organic light-emitting diodes. AB - The absorption of a metallic cathode in OLEDs is analyzed by using FDTD calculation. As the light propagates parallel to the layer, the intensity of E(z) polarization decreases rapidly. The intensity at 2.0 microm from the dipole is less than a quarter of that at 0.5 microm. The strong absorption by a cathode can be a critical factor when considering the increase of optical extraction by means of bending the optical layers. The calculation indicates that the corrugation of layers helps the guided light escape the guiding layer, but also increases the absorption into a metallic cathode. The final optical output power of the corrugated OLED can be smaller than that of the flat OLED. On the contrary, the corrugated structure with a non-absorptive cathode increases the optical extraction by nearly two times. PMID- 21780459 TI - Synthesis of a new conjugated polymer composed of pyrene and bithiophene units for organic solar cells. AB - An alternating conjugated copolymer composed of pyrene and bithiophene units, poly(DHBT-alt-PYR) has been synthesized. The synthesized polymer was found to exhibit good solution processibility and thermal stability, losing less than 5% of their weight on heating to approximately 370 degrees C. The synthesized polymer showed its maximum absorption and peak PL emission at 401 and 548 nm, respectively. The optical band gap energy of the polymer was determined by absorption onset to be 2.64 eV. Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of the polymer was determined to be -5.48 and -2.84 eV by cyclic voltametry (CV) and the optical band gap. The polymer photovoltaic devices were fabricated with a typical sandwich structure of ITO/PEDOT:PSS/active layer/LiF/Al using poly(DHBT-alt-PYR) as an electron donor and C60-PCBM or C70-PCBM as electron acceptors. The open circuit voltage, short circuit current and fill factor of the device using C70 PCBM as an acceptor were 0.75 V, 3.80 mA/cm2 and 0.28, respectively, and the maximum power conversion efficiency of the device was 0.80%. PMID- 21780460 TI - Optimization of selective emitter fabrication method for solar cells using a laser grooving. AB - In this paper, screen-printing laser grooved buried contact (LGBC) method was applied, which is compatible with the existing screen-printed solar cell equipment and facilities. Experiments were performed in order to optimize short circuit current (I(sc)), open circuit voltage (V(oc)) and fill factor of high efficiency solar cells. To enhance I(sc), V(oc) and efficiency, heavy doping was performed at low sheet resistance in the laser grooved region of the cell. In contrast, light doping was carried out at a high sheet resistance in the non laser grooved region. To increase fill factor, porous silicon found on the wafer after dipping in an HF solution to remove SiN(x), was cleared. The fabricated screen-printing LGBC solar cell using a 125 mm x 125 mm single crystalline silicon wafer exhibited an efficiency of 17.2%. The results show that screen printing LGBC method can be applied for high efficiency solar cells. PMID- 21780461 TI - Modification of silicon substrate using low-energy proton beam for selective growth of CNTs. AB - A 3 keV low-energy proton beam was used to irradiate a silicon substrate for selective modification. The water contact angle measurement, chemical etching test with HF and the auger electron spectroscopy were used to investigate the chemical properties and the material composition of the proton beam-irradiated silicon substrate. The proton beam-irradiated silicon substrate was covered with a silicon oxide layer of about 60-70 angstroms due to the incorporation of oxygen molecules after exposure to ambient air. The silicon oxide layer produced by the proton beam was highly resistant to HF treatment which typically used to remove the silicon oxide on a substrate, and the surface of it was more hydrophilic than the native silicon oxide removed silicon surface with Si-H surface group. For the selective growth of carbon nanotubes (CNTs), the silicon oxide pattern was easily fabricated via proton beam irradiation when the silicon substrate was covered with a shadow mask. The Fe-Mo bimetallic catalysts for the growth of CNTs were adsorbed onto the silicon oxide layer, which is more hydrophilic than the silicon surface. The CNTs were grown on the patterned substrate using a chemical vapor deposition method, and it was confirmed by scanning electron microscopy. PMID- 21780462 TI - AM radio circuit using printed electronic components. AB - In this paper, printing technologies have been employed to print the resonant circuit and detection circuit for an amplitude modulation system (AM radio), which consists of a printed inductor, capacitor, resistor and diode on plastic foils for using as an AM radio circuit. To test the printed inductor, capacitor, resistor and diode as components of AM radio, we selected 640 KHz, the strongest AM frequency in Sunchon City, Korea and monitored the audio signal by replacing each component by a corresponding printed one. As a result the 640 KHz AM radio signals were detected. PMID- 21780463 TI - Enhanced photocurrent generation of binary self-assembled monolayers of di-(3 aminopropyl)-viologen and methylviologen on indium tin oxide. AB - The binary self-assembled monolayers (SAMs) of di-(3-aminopropyl)-viologen (DAPV) and methylviologen (MV) molecules on indium tin oxide (ITO) were prepared by dipping the DAPV SAMs/ITO substrates into MV solution. The DAPV-MV SAM films were characterized by UV-vis. absorption spectroscopy, Rutherford backscattering spectroscopy, and cyclic voltammetry. Optical band gap, lowest unoccupied molecular orbital, and highest occupied molecular orbital of DAPV-MV SAMs were measured to be 1.6, -4.3, and -5.9 eV, respectively. We found that although DAPV SAMs have a quantum yield of 0.11%, the binary SAM films have a good quantum yield of 2.30%, which was 20 times higher than that of DAPV SAMs on ITO. This result may be due to the higher adsorption property of the binary SAMs for the light in visible range compared to that of DAPV SAMs. From this study, we demonstrated that the photocurrent generation systems with a high quantum yield can be obtained by the functional binary SAMs. PMID- 21780464 TI - Fabrication of ordered hollow ZnO-NiO oxide arrays. AB - We have combined colloidal templating and pulsed laser deposition (PLD) to fabricate arrays of ordered two-dimensional hollow ZnO-NiO mixed oxides. The underlying principle involved in producing colloidal templates by a spin-coating method has been investigated with the use of radial distribution functions. To deposit mixed oxide in a facile manner, we have designed and fabricated a novel PLD target, which has an alternating sequence of pie-shaped ZnO and NiO pieces. Structural characterizations reveal a surface morphology of protruding nano crystallites, which consist of wurtzite ZnO and rock salt NiO. The electrical properties have been discussed from the viewpoint of junction effects. PMID- 21780465 TI - Secondary ion mass spectrometry study of thermal diffusion of Au nanoparticles in porous SiO2 matrices. AB - Migration of Au nanoparticles by thermal diffusion into porous SiO2 matrix substrates has been studied using secondary ion mass spectroscopy (SIMS). When the samples having four different porosities were annealed at T = 410 K for 1.5 h, no noticeable variations in the thermal diffusion of Au nanoparticles were observed. All the measured diffusion coefficients of Au particles, were an order of 10(-15) cm2/s at 300-410 K in a very limited interfacial region. Regardless of their porosities, the pores must be discontinuous, which acts as a diffusion barrier to block the continuous diffusion of Au particles. PMID- 21780466 TI - Synthesis and properties of siloxane-containing hybrid hydrogels with alpha,omega functionalized macromers. AB - Siloxane-containing transparent hybrid hydrogels, coupled with high oxygen permeability and moderate equilibrium water content (EWC), were successfully obtained through free radical bulk copolymerization of hydrophobic and hydrophilic monomers. Due to obvious incompatibility of hydrophobic tris(trimethylsiloxy)-3-methacrryloxypropylsilane (TRIS) and hydrophilic 2 hydroxyehtyl methacrylate (HEMA) or N-vinyl pyrrolidone (NVP) monomers, alpha,omega-methacrylate terminated poly(dimethyl siloxane) (PDMS) macromer was employed as a compatibilizer in the formulations, resulting in high optical transmittance (> 90% at 400 nm) of the hybrid hydrogels. Although properties such as EWC and oxygen permeability of the hybrid hydrogels could be tailored over a wide range, the formulations with the PDMS macromer could not increase both EWC and oxygen permeability of the hybrid hydrogels without sacrificing one of them. For controlling these two properties simultaneously, an amphiphilic alpha,omega methacrylate terminated PEO-PDMS-PEO triblock copolymer was synthesized as a surface-active macromer, and showed its usefulness in controlling phase separation and improving oxygen permeability and EWC, at the same time, of the hybrid hydrogels. PMID- 21780467 TI - New blue phosphorescent iridium complexes containing phenylpyridine and triazole ligands: synthesis and luminescence studies. AB - The synthesis and luminescence of iridium(III) complexes containing new phenylpyridine (C(see test for symbol)N) ligands, 4-Me-4'-F-ppy, 4-Me-4'-CF3-ppy and 4-OMe-4'-CF3-ppy, were studied. These ligands were designed for development of the blue light-emitting iridium complexes by introducing the electron withdrawing group (F, CF3) and the electron-donating group (Me, OMe) at the para positions of the phenyl and pyridine ligand rings, respectively. As an ancillary ligand, trzl-CMe3 was employed where trzl-CMe3 represents 2-(5-tert-butyl-2H 1,2,4-triazol-3-yl)pyridine. The resulting iridium complexes, Ir(4-Me-4'-F ppy)2(trzl-CMe3), Ir(4-OMe-4'-CF3-ppy)2 (trzl-CMe3) and Ir(4-Me-4'-CF3-ppy)2(trzl CMe3) exhibited the blue emission at 472, 484 and 494 nm in CH2Cl2 solution, respectively. Ir(4-Me-4'-F-ppy)2(trzl-CMe3) showed the most hypsochromic shift in photoluminescence (PL) among the complexes prepared herein. In the electroluminescence (EL) spectra, Ir(4-Me-4'-F-ppy)2(trzl-CMe3) and Ir(4-Me-4' CF3-ppy)2(trzI-CMe3) exhibited the luminescence peak at 437 nm and 496 nm, respectively. In the aspect of blue emission color purity, Ir(4-Me-4'-F ppy)2(trzl-CMe3) had the CIE coordinates of (0.176, 0.143), very close to the saturated standard blue emission. PMID- 21780468 TI - Nano barcoding cell-based biosensor using fluorophor-embedded silica nanotubes. AB - A simple and reliable drug screening method was developed using peptide hydrogel cell beads coded by quantum dot-embedded silica nanotubes. Very long silica nanotubes were fabricated upon a nanoporous alumina template using sol-gel techniques. The physical shapes of the nanotubes were measured by TEM (Transmission Electron Microscope). Green and red quantum dots embedded in silica nanotubes were applied to peptide hydrogel cell beads as coding materials. This was confirmed by confocal microscopy that examined fluorescence levels and quantum dot shapes. The peptide hydrogel cell beads coded with silica nanotubes were loaded into a PDMS single chamber in order to assess the effect of doxorubicin on HMEC and MCF-7 cells, which was measured in hydrogel cell beads by live and dead cell staining using coding materials. As a result, MCF-7 cancer cells were more affected by doxorubicin than HMEC; however, doxorubicin induced HMEC cell death at a relatively high concentration (> 5 microg/ml). PMID- 21780469 TI - Surface-enhanced Raman scattering of dopamine on self-assembled gold nanoparticles. AB - Dopamine, a potent neurotransmitter in the brain, influences a variety of motivated behaviors and plays a major role in Parkinson's disease. In this study, the Raman signal of dopamine was detected on a fabricated nanoparticle immobilized glass surface by surface-enhanced raman spectroscopy (SERS). Amine modified glass was prepared by the self-assembly of amine-terminated silane on substrate, followed by the deposition of gold nanoparticles. The gold nanoparticles deposited on the glass surface were functionalized by anti-dopamine or dopamine. The antigen-dopamine was captured by antibody-assembled gold substrate and detected by SERS. The optical properties and morpology of the glass substrate with immobilized gold nanoparticles were analyzed by scanning electron microscopy and UV-VIS absorption spectroscopy. The Raman spectrum of dopamine displayed broad bands at 1267, 1331, 1158, 1478, 1578 and 1584 cm(-1). The strongest peaks in the spectra (at 1267 and 1478 cm(-1)) were identified as phenolic carbon-oxygen and phenyl C=C stretches, respectively. A working curve of the SERS signal constructed from cathecol ring vibration versus antigen-dopamine concentration was obtained at 1478 cm(-1), and the non-optimized detection limit for anti-dopamine surface antigen was as low as 1 ng/ml. These results suggest that SERS-based immunosensor can be a promising tool for the detection and screening of neurotransmitters. PMID- 21780470 TI - A study on white organic light-emitting diodes co-doped with red fluorescent and blue phosphorescent dopants. AB - White organic light-emitting diodes (WOLEDs) have drawn increasing attention due to their potential use in various applications such as solid-state lighting and backlight of liquid crystal displays and full-color OLEDs of red, green, and blue pixel. N,N'-dicabazolyl-3,5-benzene (mCP), the host material, was co-doped with Iridium (III) bis[(4,6-difluorophenyl)-pyridinato-N,C2']-picolinate (FIrpic), which functions not only as phosphorescent sensitizer but also blue emitter, and (2Z,2'Z)-3,3'-[4,4"-bis (dimethylamino)-1,1':4',1"-terphenyl-2',5'-diyl]bis (2 phenylacrylonitrile) (ABCV-P), which is a red fluorescent material. The fabricated device structures were as follows: (device A) Indium tin oxide (ITO)/N,N'-bis-(1-naphyl)-N,N'-diphenyl-1,1'-biphenyl-4,4'-diamine (NPB)/(mCP)/mCP:ABCV-P (1%)/4,7-diphenyl-1,10-phenanthroline (Bphen)/lithium quinolate (Liq)/aluminum (Al), (device B) ITO/NPB/mCP/mCP:FIrpic (8%)/Bphen/Liq/Al and (device C) ITO/NPB/mCP/mCP:FIrpic:ABCV-P (8%, 1%)/Bphen/Liq/Al, respectively. Phosphorescent FIrpic harvesting both singlet and triplet excitions not only emitted blue light but also transferred energy to fluorescent ABCV-P. The maximum luminance efficiency, external quantum efficiency, and luminance of white light device were measured to be 5.95 cd/A, 2.45% and 2500 cd/m2, respectively. The white device gave practically white light with the Commision Internationale de l'Eclairage (CIE(xy)) coordinate of (0.44, 0.49) which was close to warm white color (CIE(xy) = 0.45, 0.45). PMID- 21780471 TI - Nanoporous silica membranes fabricated using multiwalled carbon nanotubes. AB - Nanoporous silica membranes were fabricated using 3-aminopropyltriethoxysilane (APS) and acyl chloride-functionalized multiwalled carbon nanotubes (MWCNTs). The amine groups of silane reacted with the functional groups (e.g., acid chloride) that were attached to the sidewall of the MWCNTs. The APS that was grafted to the sidewall of the MWCNTs was polymerized in order to coat the MWCNTs wall through heating. The thickness of the silica layer on the surface of the MWCNTs was controlled by adjusting the growth time of the SiO2 layer. Approximately 20 nm sized pores were formed through the removal of the MWCNTs using a simple thermal process, but some traces of the MWCNTs still remained. The porous properties of the nanoporous silica membrane were analyzed from the nitrogen adsorption desorption isotherms that were obtained using a surface area and porosimetry analyzer. The structure and composition of the silane-modified MWCNTs were characterized using scanning electron microscopy, energy dispersive spectroscopy and transmission electron microscopy. PMID- 21780472 TI - A triazine bridged p-phenylenevinylene polymer film for biomolecular patterning. AB - Photo-reaction by UV irradiation of a highly fluorescent s-triazine bridged p phenylenevinylene polymer resulted in micro and submicron fluorescent pattern because carbonyl group (C=O) was generated from vinylene group (C=C) through the photo-oxidation. This fluorescent pattern could be used for micro scale cell patterning as well as submicron scale biomolecules patterning such as proteins. When exposed to a solution containing biomolecules, the polymeric patterns were selectively coated with biomoleucles, to result in biomolecular patterns. In particular, the UV exposed area of the poly[4,6-bis(phenoxy)-2-diphenylamino-s triazine]co(2, 5-bis(trimethylsily)-1,4-phenylenevinylene) (DTSPV) patterns was highly selective toward fluorescein isothiocyanate (FITC) conjugated-collagen. These studies provide an exciting opportunity for tissue engineering and fundamental understanding of the mechanisms of cellular adhesion, proliferation, and differentiation. PMID- 21780473 TI - Fabrication of nano-structured SPR chip for sensitivity enhancement. AB - We used the Langmuir-Blodgett (LB) method for preparation of large area, defect free monolayer silica particle film as a template for the fabrication of nano structure Au pattern on a conventional Au substrate for Surface Plasmon Resonance (SPR). Well organized, trigonal pyramid shaped Au nano-structures were able to construct on 34 separate chips in one fabrication process. The dimensions of trigonal pyramid nano-structures were precisely controlled by changing the particle size of the silica LB template. The nano-structure Au patterned SPR chips provides the enhancement of sensitivity in SPR analysis. The sensitivity enhancement of nano-structure patterned chips was evaluated by comparison with conventional flat Au chips. The nano-structure patterned substrate demonstrated a sensitivity enhancement up to 120% compared to a conventional SPR chip when ethanol solution was used as an analyte. PMID- 21780474 TI - Effects of colloidal nanosilica on the rheological properties of epoxy resins filled with organoclay. AB - The rheological properties of epoxy resins filled with organoclay and colloidal nanosilica were investigated by employing a parallel plate rheometer in flow mode at 25 degrees C. Shear thickening and shear thinning behaviors were observed in the epoxy resins filled with a mixture of organoclay and colloidal nanosilica. Minima were observed in the relaxation time of the systems consisting of epoxy resins filled with organoclay and colloidal silica as the content of colloidal nanosilica was increased. It seems that the colloidal nanosilica increased the mobility of the filled epoxy resins and reduced the interactions between the silicate layers in the systems. PMID- 21780475 TI - Selective binding and detection of magnetic labels using PHR sensor via photoresist micro-wells. AB - We have developed a novel platform for selective binding of magnetic labels on planar Hall resistance sensor (PHR) for biosensing applications. The photoresist (PR) micro wells were prepared on the PHR sensor junctions to trap the magnetic bead at specified locations on the sensor surface and thin layer of Au was sputtered in the PR wells immobilize bimolecular. The Au surface is functionalized with single-stranded oligonucleotide and further biotin was used to immobilize streptavidin coated magnetic labels (Dynabeads Myone 1.0 microm, Invitrogen Co.). After removal of the PR wells on the sensor surface the non specific binding magnetic labels were successfully removed and only the chemically bounded magnetic labels were remained on the Au surface for detection of biomolecules using PHR sensor. We controlled the number of magnetic labels on the PHR sensor surface by using different sizes of the PR well on the junctions. The specifically bounded magnetic labels were successfully detected by characterizing the individual PHR sensor junctions. This technique enables the complete control over the magnetic labels for selective binding of biomolecules on the sensor surface for increasing the sensitivity of the PHR sensor as well as removal of the non specific bindings on the sensor surface. PMID- 21780476 TI - Low temperature synthesis of single crystalline iron hydroxide and oxide nanorods in aqueous media. AB - An easy aqueous 'one-pot' synthesis route for the fabrication of single crystalline uniform iron hydroxide (beta-FeOOH) nanorods at low temperature is reported. beta-FeOOH nanorods with diameters of 5-37 nm and lengths up to 45-185 nm were obtained by varying the reaction parameters. Addition of ethanol was found to be crucial to control the aspect ratio. After calcination at 250 degrees C for 2 h the as-obtained beta-FeOOH nanorods was converted to alpha-Fe2O3 nanorods. To the best of our knowledge, beta-FeOOH nanorods having diameter less than 6 nm is reported for the first time. PMID- 21780477 TI - A complete green protocol: wrapping of multiwall carbon nanotubes with silver nanoparticles. AB - Silver nanoparticles have been wrapped on multiwall carbon nanotubes though a green synthesis approach that has advantages over other conventional methods that involve chemical agents associated with environmental toxicity and damage of carbon nanotubes. Acacia was used as a green stabilizer for multiwall carbon nanotubes as well as a stabilizer and reducing agent for silver nanoparticles. Generation of silver-decorated multiwall carbon nanotubes was confirmed by UV-Vis spectrophotometry and X-ray diffraction. Generation of silver nanoparticles (5-10 nm) wrapped on MWCNTs was confirmed by field emission scanning electron microscopy and transmission electron microscopy. PMID- 21780479 TI - 5-Isobutyryl-2-phenylpyridine-derived iridium complexes for red phosphorescent light-emitting diodes. AB - For the development of efficient red materials in organic light emitting diodes, a series of cyclometalated iridium complexes with 5-isobutyryl-2-arylpyridine derived ligands were synthesized. Complexes 1-4 exhibited red phosphorescence with quantum yields of 0.16-0.48 in degassed CH2Cl2. An OLED device employing iridium complex 3 as a dopant exhibited the best performance with a maximum luminance of 35500 cd/m2 at 14 V and luminance and power efficiencies of 15.5 cd/A and 6.23 Im/W at 20 mA/cm2, respectively. In the device employing complex 2 as the dopant, the maximum luminance was 6300 cd/m2 at 14 V and the maximum luminance efficiency and power efficiencies were 5.23 cd/A and 3.16 Im/W at 5.2 V, respectively, with CIE coordinates of (0.66, 0.32) at 9.0 V, close to the saturated red emission. PMID- 21780478 TI - Preparation of poly(4-vinylphenol)/titanium dioxide composite and its application as a gate dielectric for organic thin-film transistors. AB - Organic-inorganic composites can provide a unique feature combining superior dielectric properties of inorganic materials and solution processing capability of organic materials. In this study, poly(4-vinylphenol) (PVP) and titanium dioxide (TiO2) composite was prepared by mixing TiO2 nanoparticles in the PVP solution. In order to avoid severe gate-leakage currents in organic thin-film transistors (OTFTs) with such a composite gate dielectric layer, poly(oxyethylene)(20)-sorbitane monooleate was used as a surfactant for uniform dispersion of TiO2 particles. The dispersion stability of TiO2 nanoparticles in the composite solutions was confirmed by observing its sedimentation time in the composite solutions. The composite dielectric film, fabricated by means of simple spin-coating, provided an enhanced dielectric property and contributed to reducing the threshold voltage of OTFT, without augmenting the gate-leakage current. These results demonstrate that the fabricated composite dielectric film is essentially eligible for low-voltage operating OTFTs. PMID- 21780480 TI - Enhancement of photoconversion efficiency of ZnO nanorod-based dye-sensitized solar cells in presence of ZrO2 thin energy barrier. AB - In order to enhance the power conversion efficiency of ZnO nanorods-based dye sensitized solar cells (DSSCs), ZrO2 thin energy barriers were formed on ZnO nanorods using a sol-gel method. In DSSCs, the short-circuit current was substantially increased, and the dark current was significantly reduced in the presence of the ZrO2 layer. Due to suppressed recombination in the presence of the ZrO2 layer, 81.3% increment of power conversion efficiency is achieved compared to those without ZrO2 layer. PMID- 21780481 TI - Built-in voltage in organic light-emitting diodes with a use of Li2O/Al cathode. AB - An effect of bilayer cathode Li2O/Al system was studied in Alq3 based organic light-emitting diodes with a variation of Li2O layer thickness from 0 to 10 nm. The device was made in a structure of ITO/(TPD)/Alq3/Li2O/Al. Current density luminance-voltage (J-L-V) characteristics and a built-in voltage of the device were measured at ambient conditions. Built-in voltage in the device is generated due to a difference of work functions between the anode and cathode. From the J-L V characteristics of the device, we observed an increase in luminance and current efficiency by more than 100 times and 2 times, respectively, for the device with 0.5 nm thick Li2O layer. The measured built-in voltage shows that the device with 0.5 nm thick Li2O layer has relatively higher built-in voltage compared to the others. Since the higher value of built-in voltage corresponds to the lower value of electron barrier height in cathode, the improvement in the efficiency for the device with 0.5 nm thick Li2O layer is thought to be due to a lowering of the electron barrier height. PMID- 21780482 TI - Improved light extraction efficiency of InGaN-based multi-quantum well light emitting diodes by using a single die growth. AB - We have demonstrated that the light extraction efficiency of the InGaN based multi-quantum well light-emitting diodes (LEDs) can be improved by using a single die growth (SDG) method. The SDG was performed by patterning the n-GaN and sapphire substrate with a size of single chip (600 x 250 microm2) by using a laser scriber, followed by the regrowth of the n-GaN and LED structures on the laser patterned n-GaN. We fabricated lateral LED chips having the SDG structures (SDG-LEDs), in which the thickness of the regrown n-GaN was varied from 2 to 6 microm. For comparison, we also fabricated conventional LED chips without the SDG structures. The SDG-LEDs showed lower operating voltage when compared to the conventional LEDs. In addition, the output power of the SDG-LEDs was significantly higher than that of the conventional LEDs. From optical ray tracing simulations, the increase in the thickness and sidewall angle of the regrown n GaN and LED structures may enhance photon escapes from the tilted facets of the regrown n-GaN, followed by the increase in light output power and extraction efficiency of the SDG-LEDs. PMID- 21780483 TI - High efficiency phosphorescent blue organic light-emitting diodes using double emitting layer. AB - We have demonstrated a highly efficient blue phosphorescent organic light emitting diodes (PHOLED) using iridium (111) bis[(4,6-di-fluoropheny)-pyridinato N,C2] picolinate doped in double emitting layers (D-EML), N,N-dicarbazolyl-3,5 benzene (mCP) and p-bis (triphenylsilyly)benzene (UGH2). D-EML layers were employed to broaden the exciton formation zone and confine excitons. The optimized blue PHOLEDs having mCP/UGH2 as D-EML with a thickness of 200/100 A, exhibited a peak external quantum efficiency of 11.44%, power efficiency of 16.8 Im/W, luminous efficiency of 23.14 cd/A, and Commission Internationale de l'Eclairage coordinates of (0.17, 0.33). PMID- 21780484 TI - Nonvolatile write-once-read-many times memory devices based on the composites of poly(4-vinylphenol)/Vulcan XC-72. AB - We fabricated write-once-read-many times (WORM) type organic memory devices in 8 x 8 cross-bar structure. The active material for organic based WORM memory devices is mixture of both poly(4-vinyphenol) (PVP) and Vulcan XC-72s. From the electrical characteristics of the WORM memory devices, we observed two different resistance states, low resistance state and high resistance state, with six orders of ON/OFF ratio (I(ON)/I(OFF) - 10(6)). In addition, the WORM memory devices were maintained for longer than 50000 seconds without any serious degradation. PMID- 21780485 TI - In situ catalytic activity of CuO nanosheets synthesized from a surfactant lamellar template. AB - CuO nanosheets approximately 0.8 nm thick were synthesized under ambient conditions within a few hours using a surfactant lamellar mesophase as a soft template. In aqueous media, metal ions and anionic surfactants form a lamellar mesophase. In the lamellar layers, metal ions can crystallize without structural collapse. Highly ordered CuO nanosheet/surfactant lamellar layers formed in an aqueous solution can be easily delaminated by washing with water. The use of the delaminated CuO nanosheet catalyst instead of traditional metallic catalysts resulted in a reduction reaction of 4-nitrophenol with NaBH4 that obeyed zero order kinetics. This indicates in situ conversion of CuO to Cu in the reaction solution. Cu in situ reduced by BH4- acted as a catalyst relaying electrons for the reduction of 4-NP. The catalytic reaction was investigated by UV-vis spectroscopy, and the reduction and crystalline structures of the nanosheets were analyzed by UV-vis spectroscopy and X-ray diffraction. These results indicate CuO nanosheets to be an attractive alternative to metal catalysts in reactions involving hydrogen. PMID- 21780486 TI - Photoelectrochemical polymerization of thiophene on self-assembled RuL2(NCS)2/di(3-aminopropyl)viologen on indium thin oxide. AB - Polythiophene layers were formed on self-assembled monolayers (SAMs)/indium tin oxide (ITO) using photoelectrochemical polymerization. The SAMs on ITO was prepared using Ru(4,4'-dicarboxylic acid-2,2'-bipyridine)2(NCS)2 and di(3 aminopropyl)viologen. The photoelectrochemically polymerized polythiophene layers on SAMs/ITO were characterized using UV-vis. absorption spectroscopy, atomic force microscopy, scanning electron microscopy, and cyclic voltammetry. The polymer layers have thickness of 360 nm, a dense surface morphology, optical gap of 2.38 eV, highest occupied molecular orbital of -5.2 eV and lowest unoccupied molecular orbital of -2.82 eV. In photoelectrochemical cells, the polythiophene on SAMs/ITO electrode showed a photocurrent of 5 microA/cm2. PMID- 21780487 TI - Nanodomain development of semifluorinated diblock copolymeric thin films via solvent vapor annealing. AB - The effect of solvent vapor annealing on the morphological change of poly(ethylene oxide)-b-poly(1H,1H dihydrofluorooctyl methacrylate) (PEO-b-PFOMA) micellar thin films has been studied. The time development of the nanodomain structure in PEO(5k)-b-PFOMA(10k) thin films was investigated with the vapor treatment of perfluoroalkanes. The block copolymeric thin film was initially cast from chloroform which is a good solvent for PEO. The as-cast film which has disordered morphology can be changed to ordered cylindrical morphology and at last to highly ordered morphology consisting of PEO spherical domains and PFOMA continuous phase by varying the annealing time. PMID- 21780488 TI - Microfabrication of SiN membrane nanosieve using anisotropic reactive ion etching (ARIE) with an Ar/CF4 gas flow. AB - We have designed, fabricated, and characterized a low-stressed silicon nitride (SiN) membrane nanosieve (100 microm x 100 microm) using an anisotropic reactive ion etching (ARIE) combining with gas mixture, thus maintaining compatibility with the complementary metal-oxide semiconductor integrated circuit (CMOS IC) processes. The holes pattern of this nanosieve membrane was precisely controlled under 30 nm diameter by the electron beam writing. By employing mainly anisotropic reactive ion etching plus diffusion to the depth direction, the etch holes size was controlled to be the same with patterns on the e-beam resist (ER). This nanosieve membrane has proper mechanical strength withstanding up to one bar of transmembrane pressure. And it can endure harsh treatments such as high temperature up to 800 degrees C. In addition, it is inert to a number of strong chemicals including the piranha (H2SO4 + H2O2) solution, highly-concentrated potassium hydroxide (KOH), hydrogen fluoride (HF), hydrogen chloride (HCI), and nitric acid (HNO3). PMID- 21780489 TI - Fabrication of silicon nanowire for detecting p-amyloid (1-42) by nanoimprint lithography. AB - Ultraviolet nanoimprint lithography (UV-NIL) is a high volume and cost-effective patterning technique with sub-10 nm resolution. It has great potential as a candidate for next generation lithography. Using UV-NIL, nanowire patterns were successfully fabricated on a four-inch silicon-on-insulator (SOI) wafer under moderate conditions. The fabricated nanowire patterns were characterized by FE SEM. Its electrical properties were confirmed by semiconductor parameter analysis. Monoclonal antibodies against beta-amyloid (1-42) were immobilized on the silicon nanowire using a chemical linker. Using this fabricated silicon nanowire device, beta-amyloid (1-42) levels of 1 pM to 100 nM were successfully determined from conductance versus time characteristics. Consequently, the nanopatterned SOI nanowire device can be applied to bioplatforms for the detection of proteins. PMID- 21780490 TI - Polypyrrole/titanium oxide nanotube arrays composites as an active material for supercapacitors. AB - The authors present the first reported use of vertically oriented titanium oxide nanotube/polypyrrole (PPy) nanocomposites to increase the specific capacitance of TiO2 based energy storage devices. To increase their electrical storage capacity, titanium oxide nanotubes were coated with PPy and their morphologies were characterized. The incorporation of PPy increased the specific capacitance of the titanium oxide nanotube based supercapacitor system, due to their increased surface area and additional pseudo-capacitance. PMID- 21780491 TI - Water meniscus-directed organization of liquid-ordered domains in lipid monolayer. AB - We report on a spatial organization process of liquid-ordered (l(o)) domains in a lipid monolayer into a two dimensional array on structurally patterned substrates. The curvature of a lipid monolayer which strongly obeys the water meniscus at an air-water interface is manipulated to create two different, curved and flat, zones during the water evaporation in the structural patterns. Due to the high bending rigidity, l(o) domains are diffused into the flat region to avoid the elastic deformation. The Helfrich-type thermodynamic criterion for coarsening of l(o) domains was first presented and confirmed through experimental results obtained in various patterns. Our topographic system will be very useful for understanding a fundamental concept as well as a quantitative criterion for curvature-driven organization of l(o) domains in biological membranes. PMID- 21780492 TI - Anthracene derivatives substituted with phenyl or pentafluorophenyl for organic thin film transistors. AB - Four anthracene derivatives (TIPSAntP, TIPSAntFP, TIPSAntPA and TIPSAntFPA) containing phenyl or pentafluorophenyl have been synthesized by using Suzuki coupling or Sonogashira cross-coupling reactions. DSC measurement showed that TIPSAntP and TIPSAntFP were crystalline and thermally stable to 300 degrees C under nitrogen atmosphere, comparing to TIPSAntPA and TIPSAntFPA with acetylene. From cyclic voltammetry measurement, it can be observed that all compounds were electrochemically stable in the voltage range of -2.0-2.0 V. The obtained data revealed that fluorinated phenyl groups could decrease HOMO as well as LUMO levels of the compounds. UV-vis absorption and fluorescent emission spectra of them showed red shift in solid film state in comparison to their solution state, revealing that the molecular packing formed in solid state. Further proofs for the study of the packing order of crystals by X-ray analysis showed that phenyl groups provided TIPSAntP and TIPSAntPA planar conjugated unit along the anthracene core and favorable face-to-face interactions between their neighboring molecules. Fluorinated phenyl groups were twisted to the anthracene core and formed interleaved layer packing in TIPSAntFP. Preliminary device results were achieved from TIPSAntP and TIPSAntPA with p-type mobility of 10(-5) and 10(-6) cm2N x s, respectively, and n-type mobility for TIPSAntFP as 10(-7) cm2/V x s. PMID- 21780493 TI - Alignment of SWNTs by protein-ligand interaction of functionalized magnetic particles under low magnetic fields. AB - Carbon nanotubes (CNTs) have attracted considerable attention for applications using their superior mechanical, thermal and electrical properties. A simple method to controllably align single-walled CNTs (SWNTs) by using magnetic particles embedded with superparamagnetic iron oxide as an accelerator under the magnetic field was developed. The functionalization of SWNTs using biotin, interacted with streptavidin-coupled magnetic particles (micro-to-nano in diameter), and layer-by-layer assembly were performed for the alignment of a particular direction onto the clean silicon and the gold substrate at very low magnetic forces (0.02-0.89 T) at room temperature. The successful alignment of the SWNTs with multi-layer film was observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). By changing the orientation and location of the substrates, crossed-networks of SWNTs-magnetic particle complex could easily be fabricated. We suggest that this approach, which consists of a combination of biological interaction among streptavidin-biotin and magnetite particles, should be useful for lateral orientation of individual SWNTs with controllable direction. PMID- 21780494 TI - A simple method for fabricating a Mach-Zehnder type waveguide using sol-gel derived photopatternable hybrid materials for optical biosensors. AB - In this work, we report on a simple method to fabricate a Mach-Zehnder type waveguide pattern using photopatternable sol-gel organic-inorganic hybrid materials. The refractive indices and propagation losses of the gel films were measured using the prism coupling method. The refractive indices of the resulting films were significantly influenced by the 3-trimethoxysilylpropylmethacrylate (TMSPM) concentration, and the average propagation loss was 0.32-0.52 dB/cm at the wavelength of 632.8 nm. The waveguides were fabricated using spin-coating and a photolithography technique. The Y-branch and straight pattern of the Mach Zehnder waveguide were well-defined and had high transparency (> 97%) in the visible region. The average thickness of the gel films was 10 microm, and the average width of the Mach-Zehnder pattern was 10 microm. The structural and optical properties of the fabricated patterns were analyzed using scanning electron microscopy (SEM), atomic force microscopy (AFM), near-infrared (IR) spectroscopy, and ultraviolet (UV)-visible spectroscopy. PMID- 21780495 TI - Selective separation of fluorescent-magnetic nanoparticles with different magnetite-doping levels. AB - Fluorescent-labeled magnetic nanoparticles were explored as a biomedical agent for selective magnetic separation. By adjusting the loading volume of citrate stabilized magnetites during a sol-gel reaction with silicon alkoxide, magnetites were simultaneously embedded into both the surface and inside the silica matrix, consequently leading to magnetic nanoparticles with different doping levels of magnetites. For endowing them with multifunctional tools in biomedical fields, magnetic nanoparticles were further encapsulated with silica thin layer labeled with fluorescent organic dyes (such as Alexa Fluor 488 and 594). Fluorescent magnetic nanoparticles with different magnetism successfully displayed the differential separation of fluorescence spectra under an external magnetic field. PMID- 21780496 TI - Theoretical study of iridium complexes with phenylpyridine based ligands and phosphines. AB - Recently, iridium complexes with phenylpyridine based ligands and phosphines, Ir(C(see text for symbol)N)2 (PPh3)(CN), [(C(see text for symbol)N) = dfppy, dfMeppy] are reported as blue phosphorescent OLED materials. These iridium complexes have novel blue color and emit light at 441 nm to 439 nm. However, these complexes have low external quantum efficiency because they exhibit less MLCT than iridium complexes with phenylpyridine, and some other ancillary ligands. To improve quantum efficiency of iridium complexes with phenylpyridine based ligands and phosphines, a time dependent density functional theory (TDDFT) study of these phosphors was performed. Using these results, this paper discusses how the ancillary ligand influences the emission peak, as well as the metal to ligand charge transfer (MLCT) transition efficiency. PMID- 21780497 TI - Patterned immobilization of biomolecules on a polymer surface functionalized by radiation grafting. AB - Patterned graft polymerization of a functional monomer on a hydrophobic polymer surface was proposed for biomolecule patterning. A poly(vinylidene fluoride) (PVDF) film surface was selectively activated by ion implantation through a pattern mask and acrylic acid (AA) was then graft polymerized onto the activated regions of the PVDF surfaces. The peroxide concentration on the implanted surface depended on the fluence, which had a considerable effect on the grafting degree of AA. Afterwards, amine-functionalized biotin and probe DNA were immobilized on the poly(acrylic acid)-grafted regions of the PVDF surfaces. Specific binding of biotin with streptavidin and hybridization of probe DNA with complimentary DNA proved successful protein and DNA patterning and well-defined 50 microm dot-type patterns of the streptavidin and DNA were obtained. These results confirmed the potential of this strategy for patterning of various biomolecules. PMID- 21780498 TI - Highly ordered poly(thiophene)s prepared in mesoporous silica nanoparticles. AB - Nanostructured PEDOT was synthesized using mesoporous silica as a nano-template. The polymerization of thiophene monomers was performed with an oxidant and mesoporous silica nanoparticles. The silica particles took essential role in absorbing monomers and oxidant molecules, and growth of polymers inside their pores. As prepared polymer/silica composite was treated with HF solution to remove silica template to result in 1D wire structure and mesh type porous 3D structures from SBA-15 and KIT-6 template, respectively. The average size of the poly(thiophene) wires was 10 15 nm, which was matched well to the pores size of the silica templates, as determined from an electron microscopy. At optimized condition, the room temperature electrical conductivities of the PEDOT grown from SBA-15 and KIT-6 template were similar as 1.1 and 1.0 S/cm, respectively. However, the evolution of the PEDOT conductivity versus temperature was different depending on the templates. These results gave a unique chance to tailor made 3 dimensional structure as well as properties of conductive polymer. PMID- 21780499 TI - Top emitting organic light emitting diodes with opaque metal grid electrodes by transfer technique. AB - The opaque metal grid electrodes are introduced to fabricate top emitting organic light emitting diodes (TOLEDs) through metal transfer technique. To transmit the lights, micrometer-sized patterns of aluminum (Al) were utilized as top cathodes in OLEDs and Al mirrors were also deposited at the other side of transparent substrates to reflect the lights emitted at the bottom sides. Although the only 50% of brightness compared to bottom emitting OLEDs (BOLEDs) could be achieved theoretically, the actual devices showed more than 70% based on the compressive effects during the metal transfer process. Since the resolution of human eyes recognizes these micrometer-sized grid structures as one pixel, TOLEDs can be simply fabricated without significant loss of efficiency. PMID- 21780500 TI - Moisture-induced hysteresis of pentacene thin film transistors with cross-linked poly(4-vinylphenol) gate dielectrics. AB - The time variable electrical characteristics of pentacene thin-film transistors (TFTs) with poly(4-vinylphenol) gate dielectrics were investigated under various relative humidity conditions and the effect of moisture on the hysteresis behavior of the pentacene TFTs was studied. One possible cause of the hysteresis behavior is the presence of inherent hydroxyl groups in bulk or surface of the polymeric dielectric, which make the gate dielectric polar, but the hysteresis behavior of the pentacene TFTs was found to depend strongly on the relative humidity and to increase with an increase of the moisture in the surrounding atmosphere. With a time-scalable investigation, it was also found that the adsorption of moisture onto the pentacene layer is the main reason for the hysteresis even with the -OH rich polymeric dielectric. The hysteresis behavior was found to be significantly reduced by suppression of moisture or other moisture-induced impurities, such as the encapsulation of the devices with glass. PMID- 21780501 TI - Producing soft molds of different feature size from a single template. AB - Molds having physical dimensions different from those on a template, can be obtained from a single template in a predictable way by stretching an elastomeric mold. Stretching results in a reduction of the pitch for line and space patterns. The duty ratio that is the ratio of line width to pitch can also be reduced independently of the change in the pitch. For two dimensional patterns, the feature shape and size can be altered. The ability to produce any number of different molds from one template should provide an easy route to optimize the feature size and shape in optics inexpensively. PMID- 21780502 TI - Nanoparticle formulation for controlled release of capsaicin. AB - Capsaicin might be an effective pharmacological agent for the treatment of discogenic back pain due to its effect on pain control neuronal degeneration. Therefore, capsaicin-loaded nano- and micro-particles for sustained release were formulated by nano-precipitation or oil-in-water single emulsion solvent evaporation/extraction method. First, the capsaicin-loaded PLGA nanoparticles were prepared by nano-precipitation method. By increasing the volume of oil-water ratio from 1:2 to 1:5, slight changes in size from 162 +/- 3 nm to 153 +/- 3 nm and in drug loading efficiency from 25% to 20% were observed, whereas the drug release period was significantly changed from 11 days for 1:2 to 5 days for 1:5 ratio. To get a more sustained release, a modified single emulsion method was applied with three kinds of biocompatible polymers (PLLA, PLGA, and PCL). Among them, PLLA particles showed a much sustained release profile than PLGA or PCL ones with the similar size. For PLLA particles, particles size and drug encapsulation efficiency increased as the oil/water ratio decreased, and the bigger particles showed the slower release profiles as well as the higher drug loading efficiency, thus about 1 month release was obtained with 800 nm particles. In conclusion, formulation for the controlled release of capsaicin from 1 week to 1 month was prepared by using biocompatible nanoparticles. PMID- 21780503 TI - Characterization and stability of liposome-enveloped trypsin/Fe3O4 for drug delivery and drug release behavior. AB - Liposome encapsulating Fe3O4 (liposome complexes) has been prepared for targeting a drug to a specific organ, as well as for MRI (magnetic resonance imaging) contrast agents. The objective of the present work was to investigate the Fe3O4 properties and the effects of chitosan concentration on the characteristics of chitosan-coated liposome complexes. They were characterized by DLS, FT-IR, XRD, VSM, UV-Vis spectrometer, TEM and phase-contrast microscopy. The average liposome complex size was approximately 500 nm, with individual Fe3O4 nanoparticle sizes of 10 nm. The drug incorporation efficiency of trypsin in liposome complexes was 65-69%, the drug release was sustained and the incorporated drugs had the magnetization properties of the liposome complexes. Incorporation of chitosan into the liposome bilayer decreased trypsin release from the liposome complexes due to an increased rigidity of the liposome membrane structure. Chitosan-coated liposome complexes showed a higher stability when compared with the stability of non-coated liposome complexes. PMID- 21780504 TI - Acetabularia rhodopsin I is a light-stimulated proton pump. AB - We cloned an intronless, nuclear-encoded opsin gene from an EST library of Acetabularia acetabulum. Acetabularia rhodopsin I (ARI) encodes a protein of 246 amino acids with molecular weight of 27 kDa. ARI was reconstituted in the Xenopus oocyte expression system to characterize its electrophysiological properties utilizing the two-electrode voltage-clamping technique. Oocytes where ARI cRNA was injected displayed outward directed currents in response to light. The maximum action spectrum of ARI was detected at 520 nm green light. Light stimulated ARI current amplitude was altered by the protons, but not by the other ions in recording solutions, suggesting that the algal rhodopsin is a light stimulated proton pump. Typical proton-mediated outward current elicited by 520 nm light was characterized with two phases of non-inactivating outward current following initial transient current. Taken together, we here reported cloning of a novel Acetabularia opsin gene which was characterized to be a proton-pump stimulated by light. PMID- 21780505 TI - Fabrication and characteristics of vertical type organic light emitting transistor using novel blue host material. AB - Vertical type organic light emitting transistor can perform as electroluminescence device as well as driving transistor. As the light emitting transistor containing vertical deposited configuration can control its own luminescence intensity, the device circuit can be simplified. In the present work, we have fabricated vertical type organic light emitting transistors consisting of Al(source)/C60/Al(gate)/C60/Bphen/TAT:FIrpic/CuPc/ITO(drain)/glass(substrate). TAT(9,10-bis(3",5"-diphenylbiphenyl-4'-yl)anthracene) and FIrpic were used as blue host material and phosphorescent dopant material, respectively. Relatively high radiance and on-off ratio were observed in the device using LiAl metal as source and gate electrodes. PMID- 21780506 TI - Detection of the effect of environmental toxicants on the synthetic peptide modified neural cell chip. AB - A cell based chip was designed to differentiate and to detect the effects of environmental chemicals on the neurite outgrowth in PC12 cell. To fabricate platform of cell chip, gold surfaces were modified by RGD based synthetic oligopeptide. Nanoscale controlled self-assembled peptide layer was investigated by Atomic Force Microscopy (AFM). On the fabricated cell chip, PC12 cell was immobilized and the differentiation of neurite outgrowth in PC12 cells was done by neurite growth factor (NGF). Differentiation of PC12 cell was confirmed by immunofluorescence study. Further the differentiation and the length of neurite was confirmed by confocal microscopy study. Voltammetry behavior of the neurite induced PC12 and the electrochemical behavior of the environmental toxicants effect on the neurite outgrowth was measured by cyclic voltammetry (CV). Self assembled layer mediated cell immobilization technique and voltammetric signal analysis system can be applied to construct the neural cell chip for the detection of large number of environmental toxins and various neurotoxicants. PMID- 21780507 TI - Synthesis and properties of poly(4-vinylpyridine-co-styrene) with pendant azobenzonitrile moieties. AB - A new ionic polymer, poly(4-vinylpyridine-co-styrene) [PVPS] with pendant azobenzonitrile moieties was prepared by the polymeric reaction of PVPS and 4-[4 (8-bromooctyloxy)phenylazo]benzonitrile. The polymer structure was characterized by various instrumental methods to have a PVPS backbone system with the designed azobenzonitrile moieties. The electrochemical and electro-optical properties were studied. The polymer showed two oxidation and reduction response properties in a polymer unit and two electrochemical processes were included in the irreversible redox steps. The plot of the oxidation current density of polymer versus the scan rate showed approximately a linear relationship in the range of 30 mV/sec 150 mV/sec. The exponent of scan rate, when we apply power law to our data, was found to be 0.35. The absorption spectrum showed a characteristic absorption peak at 365 nm. PMID- 21780508 TI - Fabrication and characterization of solid oxide fuel cell electrolyte films by electron beam vapor deposition. AB - Thin films of SDC for SOFC electrolyte were prepared using electron beam deposition technique. The influence of annealing temperature, substrate temperature and e-beam gun power on the structure and surface morphology of the thin films was examined. It was found that the SDC thin films annealed at 800 degrees C consisted of a single cubic phase and the main crystal structure of the thin films represented those of evaporated electrolyte powders. The crystal orientation of the SDC films increased with substrate temperature and decreased with e-beam gun power. The higher XRD peak intensity was observed for the SDC films deposited on NiO-YSZ substrate compared with those on SiO2 substrate due to the polycrystalline structure of the NiO-YSZ substrate. A good adhesion to the substrate and a columnar structure were observed by the fractured cross-sectional view of the SDC films on NiO-YSZ anode substrate. Electrical conductivity of SDC film with 5 microm thickness was observed to be 2.31 x 10(-3) Sm(-1) at 800 degrees C. PMID- 21780509 TI - Synthesis and characterization of stannane-terminated poly(silole-co-germole) for the evaluation of luminescent polymeric light-emitting diode. AB - Codehydrocoupling (with various inorganic hydrides) followed by stannane-capping (with Ph2SnHCI) of 1,1-dihydrotetraphenylsilole (1) and 1,1 dihydrotetraphenylgermole (2) (9:1 mol ratio) produces electroluminescent stannane-terminated poly(silole-co-germole)s (3) in high yield. The polymerization yield and molecular weight with Selectride increase in the order L Selectride < N-Selectride < K-Selectride. The molecular weights increase in the order L-Selectride < Red-Al < N-Selectride < K-Selectride < Super-Hydride. The copolymer 3, a good candidate for PLED fabrication, emits at 523 nm and are electroluminescent at 521 nm. The fluorescence quantum yield of 3 in toluene is (1.61 +/- 0.29) x 10(-2). The emission color is green. The maximum brightness of the device is 3,750 cd/m2 with a luminous power efficiency of 0.67 Im/W. PMID- 21780510 TI - Parratt-based and model-independent X-ray reflectivity fitting procedure for nanoscale thin film characterization. AB - A general-purpose fitting procedure is presented for X-ray reflectivity data. The Parratt formula was used to fit the low-angle region of the reflectivity data and the resulting electron density profile (continuous base EDP or cbEDP) was then divided into a series of electron density slabs of width 1 angstroms (discrete base EDP or dbEDP), which is then easily incorporated into the Distorted Wave Born Approximation (DWBA). An additional series of density slabs of resolution limited width are overlapped to the dbEDP, and the density value of the each additional slab is allowed to vary to further fit the data model-independently using DWBA. Because this procedure combines the Parratt formula and the model independent DWBA fitting, each fitting method can always be employed depending on the type of thin film. Moreover, it provides a way to overcome the difficulties when both fitting methods do not work well for certain types of thin films. Simulations show that this procedure is suitable for nanoscale thin film characterization. PMID- 21780511 TI - Characterization of crystalline structure and morphology of NiO thin films. AB - We investigated the relation of sputtering powers with structural and morphological properties of nickel oxide (NiO) thin films. NiO thin films were fabricated by using an rf-reactive sputtering method on Si(100) substrates with a Ni target in a partial pressure of oxygen and argon. The films were deposited by various rf-sputtering powers from 100 to 200 W at room temperature. The phases and crystalline structures of the deposited films were investigated by using grazing incident X-ray diffraction (XRD). The thickness and surface morphology of the films were investigated by using a field emission-scanning electron microscopy (FE-SEM). The different sputtering conditions drastically affected the crystallinity and the surface morphology of NiO thin films. A combined analysis of the data obtained from X-ray diffraction and SEM images demonstrates that the preferred orientation of NiO films tends to grow from (111) to (200) direction as increasing the sputtering power, which can be explained by in terms of the surface energy along the indexing plane in an fcc structure. As increasing the rf power, lattice constants decreased from 4.26 to 4.20 angstroms and samples became high-quality crystals. Under our experimental condition, NiO films prepared at 150 W with 20% partial pressure of oxygen and 7 cm distance from the sample to the target show the best quality of the crystal. PMID- 21780512 TI - Synthesis of mesoporous anatase TiO2 nanotubes by a hydrothermal treatment and their use in solid-state dye-sensitized solar cells. AB - Mesoporous anatase TiO2 nanotubes (NTs) with the diameter of about 7 12 nm and the length of several hundred nanometers were synthesized by a hydrothermal method on commercial TiO2 particles in NaOH followed by HCI washing. The samples were characterized by X-ray diffraction (XRD), transmitting electron microscopy (TEM), and Brunauer-Emmet-Teller (BET) measurements. The hydrothermal treatment temperature at 130 degrees C was shown to affect not only the extent of particle to-sheet conversion, and thus the resulting structures of the NTs, but also the anatase-to-rutile transformation. The surface area of the NTs was 200 m2g(-1). This value was much higher in comparison to TiO2 nanoparticles of 50 m2g(-1). It was also found that the NT photoelectrodes had a pronounced impact on the performance of solar cells as compared to nanoparticle ones. This was probably due to lead to a significantly higher specific dye loading and, for certain hydrothermal treatments, resulting in a doubling of the solar cell efficiency (in our case from 2.84% to 4.03% of AM 1.5 conditions). PMID- 21780513 TI - New deep blue emitting materials based on indenopyrazine core with high thermal stability. AB - New deep blue emitting materials 2,8-bis(3,5-diphenylphenyl)-6,6,12,12-tetraethyl 6,12-dihydrodiindeno[1,2-b:1',2'-e]pyrazine (DPP-EPY) and 2,8-bis(3',5' diphenylbiphenyl-4-yl)-6,6,12,12-tetraethyl-6,12-dihydrodiindeno[1,2-b:1',2' e]pyrazine (DPBP-EPY) were synthesized through introduction of m-terphenyl or triphenylbenzene bulky side groups in a new indenopyrazine core. These materials all showed high thermal stability and highly reduced intermolecular interaction. DPP-EPY and DPBP-EPY showed PL maxima of 456 nm and 460 nm in deep blue region and narrow PL spectra with full-width at half-maximum (FWHM) of 46 nm and 52 nm, respectively. As a result of making non-doped OLED devices using these synthesized materials as emitting layers, DPP-EPY showed EL spectrum of 452 nm, very narrow FWHM of 46 nm, luminance efficiency of 1.04 cd/A with current density of 10 mA/cm2 and CIE coordinate of (0.161, 0.104), creating a deep blue OLED close to the National Television System Committee (NTSC) blue standard. PMID- 21780514 TI - Fabrication and characteristics of fullerene-perylene dyad based organic photovoltaic cell. AB - Fullerene is an acceptor material which is used most usually in organic photovoltaic cell. By the way, the reduction of electron mobility and the phase separation of conducting polymer and fullerene in the actual bulk heterojunction photovoltaic cell limit further improvement of device performance. In order to overcome the problems, fabrication of hybrid planar mixed heterojunction cells and synthesis of donor-acceptor dyad have been studied. In the present work, we have synthesized fullerene-perylene dyad to improve the fullerene based photovoltaic cell. In order to explore the properties of the synthesized material, the measurements of absorption spectrum and energy level were carried out. We have investigated the energy conversion efficiency of organic photovoltaic cell consisting of ITO/PEDOT-PSS/MEH-PPV:fullerene-perylene dyad/Al. PMID- 21780515 TI - Synthesis of new fluorene-based copolymers containing an anthracene derivative and their applications in polymeric light-emitting diodes. AB - We report the synthesis of copolymers containing fluorene and highly soluble anthracene derivatives, of general formula, poly{9,9'-bis-(4-octoloxy-phenyl) fluorene-2,7-diyl-co-9,10-bis-(decy-1-ynyl)-anthracene-2,6-diyl}s (PFAnts). The PFAnts were synthesized via Suzuki coupling and the feed ratios of the anthracene derivative (Ant) were 1, 5, 10, 30, and 50 mol % of the total amount of monomer. PFAnts showed well-defined high molecular weights and were more soluble in conventional organic solvents. The photoluminescence spectra of PFAnts shifted to longer wavelengths with increases in Ant proportion and the PFAnts emitted various colors varying from greenish-blue to orange. The highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels trended toward enhanced hole and electron recombination balance as the Ant proportion increased, due to the better electron-accepting ability of the anthracene moiety compared to the fluorene moiety. Polymeric light-emitting diodes with the configurations ITO/PEDOT:PSS(40 nm)/polymer(60 nm)/Ca(10 nm)/Al(100 nm) (Device A) and ITO/PEDOT:PSS(40 nm)/polymer(60 nm)/Balq(40 nm)/LiF(1 nm)/Al(100 nm) (Device B) were fabricated using the polymers as emissive layers. Especially, Device B with PFAnt01 exhibited the highest measured maximum brightness of 1760 cd/m2 at 14 V, a maximum current efficiency of 1.66 cd/A, and a maximum external quantum efficiency of 0.70%. PMID- 21780516 TI - The surgeon and the law on patient's rights for minors. AB - The law of August 22nd, 2002 concerning patients' rights (LPR) gave a new dimension to the relationship between the physician and the patient. According to this law, it is up to the physician to judge if a patient is able to exercise his own rights or if the patient needs assistance from a representative. In the particular case of the patient being a minor, this often leads to a difficult situation because of the absence of validated criteria to evaluate the capacity of judgment of a minor patient. The triangular relationship physician-patient parents might be hampered when the parents are involved in a divorce. In daily practice, there are many questions concerning the physicians' attitude towards the rights of the minor patient, particularly in cases of medical intervention. By means of case histories, we describe several problematic situations: the right of free choice of the physician, the right of the minor to obtain informational privacy, obtaining consent for a medical intervention. In cases where there is a divorce, the situation is even more difficult. Solutions are provided to act as effectively as possible in the minors' interests and to offer support to the physician. Note: According to article 388 of the Belgian Civil Code a minor is a person, either male or female, who has not attained the age of 18 years. PMID- 21780517 TI - Superficial venous disease treatment--is there still a role for open surgery in 2011? AB - The treatment of superficial venous disease (commonly described as varicose veins by the general public) has remained relatively constant over the past 100 years until the refinements of endovenous treatments such as sclerotherapy and more recently, the development of endovenous ablation. This has radically changed the treatment profile of this disease with treatments easily administered and well tolerated even in those patients who would not be considered fit for open surgery previously. With the advent of day surgery and improved general and local anaesthetic techniques, venous surgery has forged a path towards the end goal of outpatient treatment with no requirement for inpatient stay. The end goal of all superficial venous surgery is an improvement in quality of life, and with such new treatments reducing the impact of the actual intervention, such gains are easier to make. This review assesses and presents the current literature describing superficial venous disease treatments covering all treatment modalities. With endovenous treatment, true ambulatory treatment is available, providing high quality treatment at speed and convenience for patients. PMID- 21780518 TI - Role of intra-operative touch imprint cytology in the treatment of breast cancer. AB - OBJECTIVES: A prospective study was carried out to evaluate the role of intra operative touch imprint cytology (TIC) in the assessment of sentinel lymph node (SLN) involvement for staging and treatment of early-stage, clinically node negative breast carcinoma. METHODS: Forty-five patients with early-stage, clinically node-negative breast cancer underwent a SLN biopsy with intra operative TIC. The SLN was bisected if its width was less than 4 mm or sliced every 2 mm if it was more than 4 mm. The imprint specimens were stained with haematoxylin and eosin (H&E). Rapid immunochemistry (IH) was performed in case of equivocal cytological result. Permanent sections were evaluated with H&E and IH staining. The results of TIC were compared to histopathological results. RESULTS: The sensitivity, specificity and overall accuracy of TIC on a node basis were 65.5%, 96.3%, 85.5%, respectively. When calculated according to the size of SLN metastasis, the sensitivity of TIC for overt metastasis was 84.6%, while it was 62.5% for micrometastasis and 37.5% for sub-micrometastasis. The mean size of nodal metastasis was 5.08 mm and 1.25 mm for true positive and false negative results, respectively (P = 0.0236). Because of intra-operative TIC, 76.5% of the patients who needed further axillary lymph node dissection (ALND) could undergo this during the same operating time. CONCLUSIONS: TIC is a rapid and reliable method for the intra-operative assessment of metastatic sentinel node involvement in patients with early-stage, clinically node-negative breast carcinoma. Despite a low sensitivity comparable to frozen section (FS) in detecting micro- and sub micrometastases, the technique offers the advantage of full tissue preservation for subsequent histological analysis. PMID- 21780519 TI - Morbidity after closure of a defunctioning loop ileostomy. AB - PURPOSE: A low pelvic anastomosis is associated with a substantial risk of leakage. A defunctioning stoma (DS) reduces the clinical anastomotic leak rate and the need for re-operation, but stoma closure has its own risk of morbidity and mortality. This study aims to audit morbidity and mortality after loop ileostomy (LI) closure. PATIENTS AND METHODS: The medical records of 197 consecutive patients who underwent closure of a defunctioning LI between August 2003 and July 2008 were reviewed. Postoperative morbidity and mortality were recorded. RESULTS: Transverse closure of the enterotomy was performed in 149 patients (75.6%), segmental enterectomy with hand-sewn end-to-end anastomosis in 26 (13.2%) and stapled side-to-side anastomosis in 22 (11.2%). Overall postoperative morbidity and mortality were 32.0% and 0.5%, respectively. The surgical complication rate was 30.5%, including prolonged ileus (11.2%), small bowel obstruction (4.1%), anastomotic leak (3.0%) and wound infection (4.6%). Surgical complications were more frequent in male patients (p = 0.005). Prolonged ileus was more frequent when the interval to stoma reversal exceeded 12 weeks (14.3% versus 3.5% ; p = 0.02). The incidence of complications was not influenced by the closure technique. Nineteen patients (9.6%) required re-operation for anastomotic leak (n = 8), wound infection (n = 1), small bowel obstruction (n = 3) and incisional herniation (n = 7). CONCLUSION: LI closure is associated with clinically relevant morbidity and mortality. This association should be taken into account in the context of a routine DS policy and should be part of the patient's information. PMID- 21780520 TI - Breast duct endoscopy: ductoscopy from a diagnostic to an interventional procedure and its future perspective. AB - OBJECTIVE: Breast duct endoscopy is increasingly used for evaluation of intraductal disease. We present a new rigid instrument for ductoscopy that allows intraductal biopsy and the removal of small lesions. METHODS: Overall, 102 women with breast cancer or pathologic nipple discharge were included in the analysis. All ductoscopies were performed with a rigid gradient index micro-endoscope (phi 0.7 mm) in combination with a special device for intraductal vacuum assisted biopsy. Ductoscopy, ductal lavage and intraductal biopsy were correlated with ductal cytology and histopathology of the resection specimen. RESULTS: Gradient index ductoscopy provided high resolution images of the breast ducts and identified additional intraductal lesions in 45% of the patients with breast cancer. The accuracy of ductal lavage, ductoscopy and mammography in the detection of an extensive intraductal component was 14%, 65% and 50%, respectively. Intraductal vacuum assisted biopsy yielded diagnostic material in 92% of 38 patients with nipple discharge and papillomatous lesions. Histology of the resection specimen confirmed the diagnosis in all cases including 2 in situ carcinoma and 2 invasive ductal carcinoma. CONCLUSIONS: Ductoscopy is a useful supplement for the standard radiological workup of breast cancer especially in patients with extensive intraductal carcinoma. Ductoscopic vacuum assisted biopsy is an effective technique for intraductal tissue sampling and allows ablation of small lesions. This technique provides new perspectives for interventional therapy of intraductal tumours. PMID- 21780521 TI - Assault induced stab injuries: epidemiology and actual treatment strategy. AB - OBJECTIVES: To investigate and analyse epidemiology, demographics and patterns of presentation of assault induced stab injuries in a main Belgian trauma centre. To evaluate surgical management, complications and postoperative follow-up of the stab wound victims. METHODS: One hundred and seventy assaulted patients, hospitalised because of stab injuries from January 2000 to June 2007 are studied retrospectively. RESULTS: Ninety-five percent of the assaults occurred on men and the mean age of the patients was 31.1 +/- 9.7 years. Ethnic minorities represent 77% of the patients hospitalised for assaults and 26.5% of all patients proved to be under toxic influence, predominantly from alcohol (21.8%). A decline of admissions of patients with stab injuries during the period 2002-2004 is recorded. However, the incidence doubled in the next two-year period. A weekend peak and circadian rhythm is apparent with more than 20% of the patients admitted between 4 and 6 am. The trunk is most frequently stabbed (54.5%) resulting in a laparotomy rate of 51%. One third of the patients who underwent thoraco-abdominal surgery revealed diaphragmatic injuries. Seventy-five percent of the patients left the hospital in a good condition while 2.4% had neuromuscular lesions. Two patients had serious vascular complications during follow-up. During the study period, no mortality was recorded. CONCLUSIONS: Stab wounds were recorded mainly in young and middle-aged men from ethnic minorities, whereas almost 27% were under the influence of drugs. A conservative approach was generally used resulting in a low laparotomy and thoracotomy rate without affecting mortality. Neuromuscular lesions are important long-term complications of stab injuries. PMID- 21780522 TI - Nuclear mapping in parathyroidectomy: the impact on operative time. AB - BACKGROUND: Precise intraoperative localization and identification of hyperactive parathyroid tissue remains one of the most challenging tasks for surgeons performing parathyroidectomies. Among a few adjuvant methods tested recently, a novel technique called nuclear mapping may become a real breakthrough in parathyroid surgery. It is based on intraoperative detection of radioactivity after previous intravenous administration of 99mTc Sestamibi, which is accumulated in hyperactive parathyroid tissue. The purpose of this study was to assess the impact of nuclear mapping on operative time in parathyroidectomy. METHODS: The study was conducted as a retrospective univariable and multivariable analysis of clinical factors potentially influencing the operative time in a group of 27 patients undergoing parathyroidectomy. RESULTS: Univariable analysis revealed that nuclear mapping was associated with significant reduction in operative time (79.4 +/- 62.2 min vs. 135.8 +/- 49.2 min; p = 0.0186); whereas, bilateral neck exploration, partial sternotomy and reoperative neck prolonged the procedure by mean 70.7 +/- 12.9 min (p = 0.0035); 100,9 +/- 50.36 min (p = 0.0154) and 73.3 +/- 22.8 min (p = 0.0081), respectively. Multivariable analysis using a multiple regression model identified nuclear mapping, sternotomy and reoperative neck as independent variables significantly influencing the duration of parathyroidectomy. CONCLUSIONS: Nuclear mapping is an efficient intraoperative adjuvant technique facilitating localization of hyperactive parathyroid tissues in vivo and instantly confirming their identity ex vivo. It guides the surgeon throughout the parathyroidectomy and is associated with significant reduction in operative time. PMID- 21780523 TI - Restaging the mediastinum in non-small cell lung cancer after induction therapy: non-invasive versus invasive procedures. AB - OBJECTIVE: Nodal status after induction therapy in patients with stage III non small cell lung cancer (NSCLC) is an independent prognostic factor for survival. Prognosis is poor in patients with persisting mediastinal lymph node involvement. METHODS: From February 2000 to September 2007, restaging for NSCLC was performed in 25 patients (23 men, 2 women) by computed tomography (CT), positron emission tomography (PET) as well as repeat mediastinoscopy. Initial proof of N2 or N3 disease was obtained by mediastinoscopy. RESULTS: The non-invasive restaging modalities CT and PET had a rather low accuracy of 64% and 72%, respectively. Repeat mediastinoscopy performed better with an accuracy of 84%. CONCLUSION: Histological proof of mediastinal involvement after induction therapy in NSCLC is necessary to select those patients who will benefit from surgical resection. When a first mediastinoscopy has been performed to obtain pathological proof of N2 or N3 disease, repeat mediastinoscopy proves to be more accurate than CT or PET scanning for mediastinal restaging. PMID- 21780524 TI - Radiofrequency-assisted liver resection: higher incidence of infectious complications? AB - AIM: To evaluate clinical experience with radiofrequency (RF)-assisted liver resection in non-cirrhotic and non-cholestatic patients with metastatic liver disease. METHODS: A group of consecutive patients who underwent RF-assisted liver resection for metastatic liver disease was prospectively followed. RESULTS: Between July 2005 and April 2008, 95 liver RF-assisted liver resections were performed, 71 of them for metastatic liver disease. The mean hospital stay was 14 (range 5-40) days. The mean operation time was 141 (range 64-233) minutes. The mean duration of RF coagulation was 10 (range 9-12) minutes. A total of 37 complications in 24 (33%) patients were recorded, including 12 (16.9%) infected collections in resection line that had to be drained percutaneously. The 30-day postoperative mortality was zero. CONCLUSION: This study indicates that RF assisted resection may have a benefit in decreasing peroperative blood loss and the number of blood transfusions. Nevertheless, an increased incidence of infectious complications and pleural effusions that required evacuation was noted. PMID- 21780525 TI - Complicated right-sided Bochdalek hernia in an adult. AB - Bochdalek hernias on the right side of the diaphragm are very rarely diagnosed in adults. We report a case of a 52-year-old female patient, who presented to the emergency department with acute intestinal obstruction. Plain and cross-sectional imaging identified a large right-sided Bochdalek hernia containing small bowel loops and the right colon. A laparoscopic approach was performed. The herniated intestinal loops and the right colon were reduced into the abdominal cavity. The diaphragmatic defect was closed using clips with reinforcement by a prosthetic polypropylene mesh. A mini median laparotomy was performed to ensure the viability of the bowel and a few stitches were inserted on superficial lesions of the serosa. The recovery was uneventful and the patient was discharged from the hospital 6 days after admission. Nine months later the patient is doing well. PMID- 21780526 TI - Intestinal intussusception as a complication of typhoid fever. AB - Typhoid fever is a severe febrile illness caused by Salmonella typhi. Although ileal perforation and bleeding are seen more frequently, intestinal intussusception is a very rare complication of typhoid fever. A male patient was admitted to hospital due to abdominal distension and pain. Abdominal computerised tomography revealed ileal intussusception. The patient underwent exploratory laparotomy. Ileal intussusception was determined and segmental ileal resection was performed. Examination of the resected ileal segment revealed multiple ulcerous lesions that led to intussusception. The postoperative course was uneventful. The operative treatment is the subject of debate because of insufficient evidence. We recommend segmental bowel resection because of the underlying pathology. PMID- 21780527 TI - Giant biliary cystadenoma: a case report. AB - Biliary cystadenoma is a very rare benign cystic tumour of the liver. Fewer than 150 cases have been described in the literature so far. The authors present a case of a 29-year-old female with a giant intrahepatic biliary cystadenoma who presented with abdominal pain and obstructive jaundice. The patient was treated with left hepatectomy and now 12 months after the surgery she is in good condition with no signs of recurrence of the disease. Clinical presentation of biliary cystadenoma is not specific. Diagnosis is based on imaging methods, mainly ultrasound and CT scan. However, it is often misdiagnosed. For treatment, radical resection is advocated because a biliary cystadenoma is considered to be a premalignant lesion. The prognosis of biliary cystadenoma after complete resection is excellent. Nevertheless, there is a risk of recurrence or malignant transformation after incomplete resection. PMID- 21780528 TI - Tailgut cyst. A case report. AB - Tailgut cysts, also called retro-rectal cystic hamartomas or mucin-secreting cysts, are uncommon vestigial masses. They can become complicated with infection or neoplastic degeneration. Surgery is the only treatment. We report here a case of a tailgut cyst in a 60-year-old female, that was discovered 10 years ago but not investigated. PMID- 21780529 TI - Perineal pilonidal sinus after an antero-posterior resection of rectum: case report. AB - INTRODUCTION: Pilonidal sinus is common in sacroiliac region and occasionally occurs in the interdigital web space. METHOD: We describe an unusual case of an acquired implantation pilonidal sinus involving the perineal wound which occurred after an anteroposterior resection of the rectum. RESULT/DISCUSSION: This patient was successfully treated by excision of the sinuses. Recognition and treatment of this condition may cure the patient with a persistent post operative perineal sinus. PMID- 21780530 TI - Surgeons and the Collegium Medicum Antverpiense: professionalisation of surgical practice in 17th century Antwerp. PMID- 21780531 TI - The relationship of alcohol problems to the risk for unidirectional and bidirectional intimate partner violence among a sample of blue-collar couples. AB - Understanding how each partner's alcohol problems may contribute to the risk of male-to-female only, female-to-male only, or bidirectional partner violence is important for the prevention and treatment of these problems. Multinomial regression analysis was conducted using data from 848 blue-collar couples. Findings suggest that male alcohol problems are linked to male-to-female and bidirectional partner violence but not with female-to-male partner violence. Female alcohol problems do not appear to be related to any type of partner aggression. Each partner's level of impulsivity was associated with bidirectional partner violence. Male impulsivity was associated with male-to-female violence, and female impulsivity was associated with female-to-male violence. Prevention of male alcohol problems and promotion of nonconfrontational conflict-solving techniques may help reduce partner aggression among couples in the general household population. PMID- 21780532 TI - Affective, behavioral, and social-cognitive dysregulation as mechanisms for sexual abuse revictimization. AB - Using a sample of 1117 female college students, this study examined emotional, behavioral, and social-cognitive mechanisms of sexual abuse revictimization. It was hypothesized that numbing, alexithymia, alcohol problems, mistrust, and adult attachment dimensions would mediate the relationship between childhood sexual abuse (CSA) and adult sexual abuse (ASA). Aside from the close adult attachment dimension, the results indicated that all of the hypothesized mediators were associated with CSA. However, only alcohol problems and mistrust met the necessary conditions of mediation. The results with respect to mistrust are especially unique in that it is one of the first empirical demonstrations of a social-cognitive mechanism for sexual abuse revictimization. Thus, these results enhance our understanding of interpersonal mediators of the relationship between CSA and ASA and provide a new direction for future research. PMID- 21780533 TI - Beliefs and attributions of partner violence perpetrators: the physical and psychological violence of adolescent males. AB - Partner violence is a crime of national concern. Understanding the cognitions of adolescent males who perpetrate partner violence is critical to develop appropriate interventions. One hundred and thirty-two partnered undergraduate males were assessed on gender beliefs, relationship beliefs, and partner attributions. More than 80% of males endorsed psychological or physical violence perpetration in the past year. Adolescent males who perpetrated psychological or physical partner violence were more likely to endorse hostile beliefs about women, negative partner attributions, and unrealistic relationship beliefs, as compared with nonviolent adolescents. Further, the relationship belief that partners cannot change and hostile partner attributions significantly predicted the frequency of psychological partner violence. The relationship belief disagreement is destructive predicted the frequency of physical partner violence, controlling for the influence of psychological violence. Clinical implications and future directions are discussed. PMID- 21780534 TI - In vino silentium? Individual, situational, and alcohol-related factors in reporting violence to the police. AB - This study identifies the individual, situational, and alcohol-related factors associated with reporting violent victimization to the police. Factors positively associated with reporting included older age and incident severity (the assailant's use of a weapon, incurring injury that required attendance at an emergency department). Factors negatively associated with reporting included higher educational qualifications, assault in the nighttime economy (NTE), and drinking more than two alcoholic drinks immediately prior to victimization. It is possible that drinkers engage in "moratorium" on reporting violence in the NTE. Recognizing and reducing the acceptability of violence in the NTE may help reduce incidence of alcohol-related violence. Organizations that use police records of violence to inform practice and policy should account for uneven distributions in reporting behavior when analyzing trends in violence. PMID- 21780535 TI - Women and men's use of coercive control in intimate partner violence. AB - This study examined the relationship between coercive control and intimate partner violence (IPV) for men and women and for targets and perpetrators. One hundred and seventy-two participants (85 men, 87 women) recruited from three samples reported on their own and their partner's behavior. IPV was measured using the Revised Conflict Tactics Scale (CTS2). Coercive control was measured using modified items from the Psychological Maltreatment of Women Inventory (PMWI). Coercive control was associated with IPV, and this relationship was similar for men and women across the three samples. In fact, coercive control was predominantly reciprocal in nature, with women and men reporting both receiving and perpetrating controlling behaviors. Overall, coercive controlling behaviors were characteristic of individuals within violent relationships, regardless of their physical abuse status. The experience of violence, rather than gender, was the best predictor of coercive control. PMID- 21780536 TI - The effect of poor parenting on male and female dating violence perpetration and victimization. AB - This study examines the effects of poor parenting on dating violence perpetration and victimization among approximately 900 males and females from the National Longitudinal Survey of Adolescent Health (Add Health). Results revealed that more physical abuse and low parental warmth were linked to greater substance use and higher rates of delinquency. In addition, low parental warmth, more neglect, and greater delinquency had positive direct effects on dating violence perpetration, whereas more physical abuse, low parental warmth, and increased delinquency were all positively associated with dating violence victimization. Finally, delinquency mediated the link between low parental warmth and dating violence perpetration and victimization. The results provide some support for both social learning theory and an antisocial orientation perspective. PMID- 21780537 TI - Children placed in out-of-home care: risk factors for involvement with the juvenile justice system. AB - In previous research, child maltreatment has been associated with several negative outcomes, including delinquency. This study uses administrative data to examine risk factors, including the severity and chronicity of maltreatment, for juvenile justice involvement among children, ages 7 to 17, who were placed in out of-home care in Florida (N = 13,212). The results of multivariate Cox regression analysis indicated that among specific types of maltreatment, sexual abuse was associated with the risk of faster placement only in a detention center. Additionally, findings from this study suggest that maltreatment chronicity but not maltreatment severity increases the chances of earlier involvement with the juvenile justice system among children who were placed in an out-of-home care. Implications of these findings are discussed. PMID- 21780538 TI - Behind the cycle of violence, beyond abuse history: a brief report on the association of parental attachment to physical child abuse potential. AB - Although the concept of a cycle of violence presumes that the transmission of violence is expressed directly across generations, the role of the overall quality of the parent-child relationship may ultimately be more influential in later parenting behavior. This study investigated whether mothers' poorer attachment to their parents was associated with their current increased child abuse potential and dysfunctional disciplinary style independent of a personal history of child abuse. A sample of 73 at-risk mothers raising children with behavior problems reported on their parental attachment, abuse potential, dysfunctional parenting style, and personal abuse history. An at-risk sample, rather than a sample of identified abuse victims or perpetrators, was studied to better examine the potential continuity or discontinuity from history of abuse to current abuse risk, allowing consideration of those who may break the cycle versus those who potentially initiate abuse in the absence of a personal history. Findings indicate that poor attachment significantly predicted both dysfunctional parenting practices and elevated child abuse potential, controlling for personal child abuse history. Such results highlight the importance of the overall quality of the relationship between the parent and child in potentially shaping future abuse risk. Findings are discussed in terms of continuity or discontinuity in the cycle of violence and future directions for research on attachment in relation to the development of later child abuse risk. PMID- 21780539 TI - Physical violence against children reported to the police: discrepancies between register-based data and child victim survey. AB - This study examines the reporting and not reporting of child victimization to the police. The study focuses on comparing the police reports of child victimization to the Finnish Child Victim Survey (FCVS) to find out the kind of violence that is reported to the police and the kind that is not. A total number of 242 police reports of 12-year-old victims of physical violence were collected from the Finnish Police Information System. These reports were compared to the 12-year-old children's victimization experiences in the FCVS. Discrepancies between these two data can be found in the victim's gender, the relationship between the victim and the suspect, and the location of the assault. Physical violence against girls committed by mothers is not reported as often as physical violence against boys committed by men. PMID- 21780540 TI - Variations in amino acid neurotransmitters in some brain areas of adult and young male albino rats due to exposure to mobile phone radiation. AB - BACKGROUND AND OBJECTIVES: Mobile phone radiation and health concerns have been raised, especially following the enormous increase in the use of wireless mobile telephony throughout the world. The present study aims to investigate the effect of one hour daily exposure to electromagnetic radiation (EMR) with frequency of 900 Mz (SAR 1.165 w/kg, power density 0.02 mW/cm2) on the levels of amino acid neurotransmitters in the midbrain, cerebellum and medulla of adult and young male albino rats. MATERIALS AND METHODS: Adult and young rats were divided into two main groups (treated and control). The treated group of both adult and young rats was exposed to EMR for 1 hour daily. The other group of both adult and young animals was served as control. The determination of amino acid levels was carried out after 1 hour, 1 month, 2 months and 4 months of EMR exposure as well as after stopping radiation. RESULTS: Data of the present study showed a significant increase in both excitatory and inhibitory amino acids in the cerebellum of adult and young rats and midbrain of adult animals after 1 hour of EMR exposure. In the midbrain of adult animals, there was a significant increase in glycine level after 1 month followed by significant increase in GABA after 4 months. Young rats showed significant decreases in the midbrain excitatory amino acids. In the medulla, the equilibrium ratio percent (ER%) calculations showed a state of neurochemical inhibition after 4 months in case of adult animals, whereas in young animals, the neurochemical inhibitory state was observed after 1 month of exposure due to significant decrease in glutamate and aspartate levels. This state was converted to excitation after 4 months due to the increase in glutamate level. CONCLUSION: The present changes in amino acid concentrations may underlie the reported adverse effects of using mobile phones. PMID- 21780541 TI - The effect of formoterol on airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice. AB - OBJECTIVES: Aim for this study was to investigate the effect of long-acting beta2 adrenoceptor agonist formoterol on airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice. MATERIALS AND METHODS: Forty female BABL/c mice were randomly divided into four groups with 10 mice in each. Mice in group A were treated with saline as control, and mice in group B, group C and group D were sensitized by intraperitoneal injection of 10 microg alum precipitated chicken egg ovalbumin (OVA) to establish asthmatic model, but group C were pretreated with formoterol and group D were pretreated with dexamethasone. All mice were killed 24 hours after the final OVA challenging. The left lung tissue sections were stained with periodic acid Schiff (PAS) for identification of goblet cell hyperplasia. Immunohistochemistry was used to identify the protein of Muc5ac. The right lung was isolated for detecting Muc5ac mRNA by the method of real-time fluorescence quantitative reverse transcription Polymerase Chain Reaction (real-time qRT-PCR). RESULTS: The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly higher in group B than those in group A [(163.63 +/- 16.68) vs. (0.46 +/- 0.16), (77.36 +/- 5.05) % vs. (0.03 +/- 0.01) % (10.31 +/- 0.73) vs. (1.00 +/- 0.13), (0.64 +/- 0.03) vs. (0.19 +/- 0.03) respectively, all P < 0.05]. The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly lower in group C than those in group B [(52.04 +/- 4.60) vs (163.63 +/- 16.68), (30.05 +/ 3.72) % vs. (77.36 +/- 5.05) %, (1.64 +/- 0.14) vs. (10.31 +/- 0.73), (0.26 +/- 0.01) vs (0.64 +/- 0.03) respectively, all P < 0.05] The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly lower in group D than those in group B [(63.41 +/- 6.39) vs. (163.63 +/- 16.68), (38.52 +/- 3.83)% vs. (77.36 +/- 5.05) %, (1.72 +/- 0.10) vs. (10.31 +/- 0.73), (0.31 +/- 0.01) vs. (0.64 +/- 0.03) respectively, all P < 0.05]. For mentioned above, no significant differences were found between group C and group D [(52.04 +/- 4.60) vs. (63.41 +/- 6.39), (30.05 +/- 3.72) % vs. (38.52 +/- 3.83) %, (1.64 +/- 0.14) vs. (1.72 +/- 0.10), (0.26 +/ 0.01) vs. (0.31 +/- 0.01) respectively, all P < 0.05]. CONCLUSIONS: This study demonstrates that the long-acting beta2-receptor agonist formoterol may inhibit airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice. PMID- 21780542 TI - Diabetes mellitus: biochemical, histological and microbiological aspects in periodontal disease. AB - Relationship between diabetes mellitus (DM) and periodontal disease has been the subject of many studies that underline that diabetic patients are two/three times more susceptible to have an increased risk of periodontal disease, especially when metabolic control is inadequate. In this review the authors analyze, in diabetic patient, biochemical, histological and microbiological aspects of periodontal disease. Recent studies reported the results obtained in not diabetic patients, both periodontopatic and not: in periodontopatic subjects, the value of glycated hemoglobin was higher. As regards type 2 DM has a positive relationship between periodontal inflammation and glycemia, with good probabilities of disease development. Some Authors showed how the hygiene and the professional/domiciliary control could support a reduction of the glycate hemoglobin and, therefore, of the periodontal disease. The glucose accumulation in the crevicular fluid, noticed in pockets with a depth >4 mm, causes an increase of spirochetes and bacteria. Some research reported that scarcely controlled patients show high levels of interleukin-1beta (IL-1beta). This alteration together with the prolonged expression of tumor necrosis factor (TNF) could represent a mechanism used by bacteria to cause a major damage during the inflammation process, sometimes favoured by immunological defects, due to the mobilization of lymphocytes subpopulations. By measuring the values of TNF-a, fibrinogen, high sensitive capsule reactive protein (hs-CRP), IL-4, IL-6, IL-8, IL-10, at the beginning of non-surgical periodontal therapy and it has been after 3 months of treatment, noticed a relevant reduction only of TNF-a and fibrinogen. Concerning vascular alteration, vascular endothelium growing factor (VEGF) could play a major role in the tissues ischemia. The VEGF should determine the tissue ischemia, the angiogenesis and the alteration of glucose haematic level, in patients affected by microvasculopathies due to diabetes and to periodontal diseases. Particularly, the angiogenesis should favor the chronic inflammation, caused by increasing concentration of cytokines and other pro-inflammatory factors. PMID- 21780543 TI - A randomized clinical trial to compare the efficacy of different doses of intravaginal misoprostol with intracervical dinoprostone for cervical ripening and labor induction. AB - OBJECTIVES: To compare the efficacy of 25 vs. 50 microg of intravaginal misoprostol vs. intracervical dinoprostone for cervical ripening and labor induction. MATERIALS AND METHODS: 210 women with Bishop's score <6 were randomized into 3 groups of 70 each to receive 6 hourly doses of either 25 or 50 microg of intravaginal misoprostol or 0.5 mg intracervical dinoprostone to maximum of 3 doses and outcome parameters were compared. RESULTS: Induction to vaginal delivery interval was significantly lower (p < 0.05) for 50 microg (13.8 +/- 6.62 hours) as compared to 25 microg misoprostol (16.4 +/- 7.34 hours) or dinoprostone group (16.3 +/- 7.49 hours). Maximum improvement (p < 0.05) in Bishop's score and minimum oxytocin requirement (p < 0.05) was seen with misoprostol 50 microg. No significant difference was observed for women delivering vaginally within 24 hours (93.8 vs. 89.7 vs. 85.4%), patients delivering after one dose (24.3 vs. 21.4 vs. 20%), cesarean deliveries, fetal outcome, complications like hyperstimulation and fetal heart abnormalities for the 50 vs. 25 microg misoprostol vs. dinoprostone group. CONCLUSION: Intravaginal misoprostol 50 microg administered 6 hourly appears to be most effective as it has least induction to delivery time, has maximum improvement in Bishop's score, least oxytocin requirement without any increase in complication rate. PMID- 21780544 TI - Clinical outcome of levonorgestrel intra-uterine system in idiopathic menorrhagia. AB - AIMS: To evaluate the efficacy, acceptability and side effects of levonorgestrel intrauterine system in patients with idiopathic menorrhagia. METHODS: A prospective, non-randomized clinical study in which 42 women between the age of 35-55 years complaining of menorrhagia with or without irregular cycle were recruited during one year period. The women were followed up at 3, 6, 12, 24 and 36 months after insertion. RESULTS: The reduction in mean blood loss was found to be statistically significant with a p value of < 0.001 for all the follow-up periods. CONCLUSION: The present study projects levonorgestrel intrauterine system as an effective patient friendly device with a high degree of compliance and worth considering as a viable alternative to surgery for the management of menorrhagia due to dysfunctional uterine bleeding in developing countries like India. PMID- 21780545 TI - Organ-confined prostate carcinoma radiation brachytherapy compared with external either photon- or hadron-beam radiation therapy. Just a short up-to-date. AB - Both low dose rate (LDR) permanent either 1251 or 103Pd seed implant and high dose rate (HDR) 1921r temporary implant are an excellent way to release high dose of ionizing radiations to cancerous lesions while significantly sparing the surrounding healthy tissues. Therefore, the radiation brachytherapy, among the established treatment options of organ-confined prostate carcinoma--interstitial radiofrequency, high intensity focused ultrasound, cryotherapy--has gained large acceptance in the last decades. The LDR permanent interstitial radioactive seed implantation is often used as monotherapy for low risk prostate carcinoma whereas the HDR temporary implant may useful to treat intermediate-to-high risk prostate tumors as a radiation boost to combined external beam radiation therapy (EBRT). On the other hand, with recent refinement of EBRT techniques--either three dimensional conformal- or intensity-modulated radiotherapy, cyber-knife radiosurgery with even 4D-high resolution image-guided tracking--high doses of X rays may be precisely delivered to prostate malignant lesions without increasing toxicity for surrounding normal structures. Also hadron therapy is an increasingly successful technique that allows the release of effective energy of protons (H+), neutrons or carbon ions (6(12)C) to the limited extent of the cancerous target site, thus destroying malignant lesion with millimetric precision--just as bloodless surgery--while less damaging the neighbouring healthy tissues. Looking to the near future, even more effective oncotherapy modality appears to be the use of antiprotons because of their highly confined energy deposition at well defined body dept around the annihilation point in contact with protons of the ordinary matter, so targeting only a very limited body volume. PMID- 21780546 TI - Antibacterial and antifungal efficacy of fatty acid methyl esters from the leaves of Sesuvium portulacastrum L. AB - OBJECTIVES: The fatty acid methyl esters (FAME extract) from Sesuvium (S.) portulacastrum was studied for its fatty acid composition and antimicrobial activity against human pathogenic microorganisms. MATERIALS AND METHODS AND RESULTS: The gas chromatographic analysis of FAME extract revealed the presence of palmitic acid with the highest relative percentage (31.18%), followed by oleic acid (21.15%), linolenic acid (14.18%) linoleic acid (10.63%), myristic acid (6.91%) and behenic acid (2.42%). The saturated fatty acids were higher than the unsaturated fatty acids. FAME extract showed the highest antibacterial and anticandidal activities and moderate antifungal activity against the tested microorganisms. The highest mean zone of inhibition (16.3 mm) and the lowest MIC (0.25 mg/ml) and MBC (0.5 mg/ml) values were recorded against Bacillus subtilis. The lowest mean zone of inhibition (8.8 mm) and the highest MIC (8 mg/ml) and MFC (16 mg/ml) values were recorded against Aspergillus fumigatus and Aspergillus niger. CONCLUSIONS: The results of the present study justify the use of S. portulacastrum in traditional medicine and the FAME extract can be used as a potential antimicrobial agent against the tested human pathogenic microorganisms. PMID- 21780547 TI - Antibacterial properties of the skin mucus of the freshwater fishes, Rita rita and Channa punctatus. AB - OBJECTIVES: The skin mucus of Rita rita and Channa punctatus was investigated to explore the possibilities of its antibacterial properties. MATERIALS AND METHODS: Skin mucus was extracted in acidic solvents (0.1% trifluoroacetic acid and 3% acetic acid) and in triple distilled water (aqueous medium). The antibacterial activity of the mucus extracts was analyzed, using disc diffusion method, against five strains of bacteria--the Gram-positive Staphylococcus aureus and Micrococcus luteus; and the Gram negative Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi. RESULTS: In both Rita rita and Channa punctatus, the skin mucus extracted in acidic solvents as well as in aqueous medium show antibacterial activity against Staphylococcus aureus and Micrococcus luteus. Nevertheless, the activity is higher in acidic solvents than that in aqueous medium. The acidic mucus extracts of Rita rita, show antibacterial activity against Salmonella typhi as well. CONCLUSIONS: The results suggest that fish skin mucus have bactericidal properties and thus play important role in the protection of fish against the invasion of pathogens. Fish skin mucus could thus be regarded as a potential source of novel antibacterial components. PMID- 21780548 TI - Mosquito larvicidal and ovicidal activity of Cardiospermum halicacabum Linn. (family: Sapindaceae) leaf extract against Culex quinquefasciatus (Say.) and Aedes aegypti (Linn.) (Diptera: Culicidae). AB - OBJECTIVE: To investigate the larvicidal and ovicidal efficacy of different extracts of Cardiospermum halicacabum L. against Culex quinquefasciatus Say and Aedes aegypti L. (Diptera: Culicidae). MATERIALS AND METHODS: Larvicidal efficacy of the crude leaf extracts of Cardiospermum halicacabum with five different solvents like benzene, hexane, ethyl acetate, methanol and chloroform was tested against the early third instar larvae of Culex (C.) quinquefasciatus and Aedes (A.) aegypti. The ovicidal activity was determined against two mosquito species to various concentrations ranging from 100-600 ppm under the laboratory conditions. RESULTS: The benzene, hexane, ethyl acetate, methanol and chloroform leaf extract of Cardiospermum halicacabum was found to be more effective against C. quinquefasciatus than A. aegypti. The LC50 values were 174.24, 193.31, 183.36, 150.44, 154.95 ppm and 182.51, 200.02, 192.31, 156.80, 164.54 ppm respectively. Among five solvent tested the methanol and benzene crude extract was found to be most effective for ovicidal activity against two mosquito species. The extract of methanol and benzene exerted 100% mortality at 300 ppm against C quinquefasciatus. A. aegypti attained the complete ovicidal activity at 400 ppm for the extract of methanol only. CONCLUSIONS: From the results it can be concluded the crude extract of Cardiospermum halicacabum was a potential for controlling C. quinquefasciatus and A. aegypti mosquitoes. PMID- 21780549 TI - Antidepressant-like effect of aqueous extract of Channa striatus fillet in mice models of depression. AB - BACKGROUND AND OBJECTIVES: Channa (C.) striatus (Malay-Haruan), is a fresh water snakehead fish, consumed as a rejuvenating diet in post-parturition period in local Malay population. The aqueous extract of C. striatus fillet (AECSF) was reported to act through serotonergic receptor system in a previous study. There is no scientific report on neuropharmacological effects of C. striatus. Based on these data, the antidepressant-like effect of C. striatus was evaluated in mice models of depression. MATERIALS AND METHODS: AECSF was prepared by steaming the fillets as described previously. Antidepressant activity was studied in male ICR mice using forced swimming test (FST) and tail suspension test (TST). Open-field test was used to evaluate any psychomotor stimulant activity. AECSF was administered intraperitoneally at the concentrations of 30%, 40% and 50% w/v at the dosage of 10 ml/kg. Amitriptyline (10 mg/kg) was used as positive control. RESULTS: All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly reduced the immobility time (p < 0.001) in FST and TST. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly (p < 0.001) reduced locomotor activity in a dose-dependent manner in open-field test. CONCLUSIONS: AECSF produced significant reduction of immobility time in both FST and TST. Amitriptyline produced a significant reduction of immobility time in both FST and TST similar to previous findings. The AECSF produced a dose dependent decrease in locomotor activity in the open-field test. This hypolocomotion effect indicated the absence of any psychomotor stimulant activity thereby supporting the antidepressant-like effect of the AECSF. The pharmacological mechanisms of the observed antidepressant-like effect and hypolocomotion effect are not understood from our study. Hence, further studies are required. PMID- 21780550 TI - Alpha-glucosidase inhibitory activity and lipid-lowering mechanisms of Moringa oleifera leaf extract. AB - OBJECTIVES AND MATERIALS AND METHODS: Medicinal plants constitute an important source of potential therapeutic agents for diabetes and hyperlipidemia. The purpose of present study was to investigate the effect of leaf extract of Moringa oleifera on inhibition of alpha-glucosidase and pancreatic alpha-amylase related to diabetes mellitus. Moreover, the study was also determined in vitro bile acid binding capacity as well as inhibition of cholesterol micellization, pancreatic lipase, and cholesterol esterase activity. RESULTS: The phytochemical analysis indicated that total phenolic, flavonoid, and condensed tannin contents in the extract were 45.21 +/- 0.96 mg gallic acid equivalents/g extract, 15.39 +/- 0.58 mg catechin equivalents/g extract, and 4.90 +/- 0.20 catechin equivalents/g extract, respectively. In addition, the extract contained a specific inhibitor of intestinal sucrase than intestinal maltase with IC50 value of 0.78 +/- 0.21 mg/ml, whereas it slightly inhibited pancreatic alpha-amylase and pancreatic cholesterol esterase. However, the extract had no inhibitory activity against pancreatic lipase. Furthermore, taurodeoxycholic acid, taurodeoxycholic acid, and glycodeoxycholic acid were bound to the extract (1 mg/ml) with a degree of 26.90 +/- 0.37%, 21.78 +/- 0.68%, and 22.59 +/- 1.02%, respectively. Finally, the extract (10 mg/ml) markedly inhibited the formation of cholesterol micelle about 40.22 +/- 2.64%. CONCLUSION: Our results indicated that the leaf extract of Moringa oleifera may be used for the control of blood glucose and lipid concentration and prevention of hyperglycemia and hyperlipidemia. PMID- 21780551 TI - Saccharomyces boulardii: a summary of the evidence for gastroenterology clinical practice in adults and children. AB - Probiotics are viable, nonpathogenic microorganisms (bacteria or yeast) which when administered in adequate amounts, confer a health benefit on the host. At this time, Saccharomyces boulardii is the only yeast commonly used in clinical practice. Literature on this probiotic is wide and even more data become available each year. Thus, it could be problematic for a physician summarize all the best information deriving from basic research and clinical studies. With the aim to help physicians in the use of Saccharomyces boulardii, this paper focuses on the available evidences for its efficacy and safety in different diseases in adult and pediatric patients in order to provide a practical guidance for gastroenterology clinical practice. Indications and dosage for several gastrointestinal diseases for a correct use of this probiotic are provided, and recent insights on its mechanisms of action and possible future clinical application are also discussed. PMID- 21780552 TI - Physical characteristics, pharmacological properties and clinical efficacy of the ketoprofen patch: a new patch formulation. AB - OBJECTIVE: The mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs), to which ketoprofen belongs, is based on their cyclo-oxigenase (COX) inhibiting action, concerning both subtype COX-1 constitutive isoform and COX-2 inducible isoform. Ketoprofen administration may be carried out by oral and parenteral routes as well as by topical application, which includes transdermic patch use. Following a synthetic description of the results obtained by several investigators on ketoprofen use, the Authors present a new formulation of the ketoprofen patch obtained by the so called DermaLight Technology. MATERIALS AND METHODS: According to such a technique, the active principle is dissolved in oil components and dispersed inside an anhydrous polymeric matrix made up of styrene isoprene-styrene (SIS), which is an elastic and flexible material that provides a gentle adhesion to the skin, maintains an elevated ketoprofen concentration and induces a strong thrust that favours the crossing of the skin by the drug; in addition, the patch is fit to be applied to the various areas of the body, including the joints. RESULTS: Patch adhesiveness reduces skin irritation due to multiple applications and to long-term use, as the DermaLight Technology minimises keratinocytes exfoliation. In pharmacokinetic studies carried out on pigs ketoprofen has been demonstrated to reach deep tissues, where the drug was detected in much higher concentrations, with respect to plasma levels, 12 hours following its application. Experimental studies carried out on rats have shown that ketoprofen patch significantly reduces the edema induced by chronic inflammation. The ulcerogenic effect of ketoprofen patch is then compared with that shown by oral administration of the drug. UD50 values of ketoprofen patch were 49.9 mg/kg and 48.9 mg/kg for the stomach and the small intestine, respectively, whereas UD50 values of oral ketoprofen were 3.6 mg/kg and 3.7 mg/kg, respectively. CONCLUSIONS: The Authors conclude by stating that ketoprofen patch is both a good alternative and a safe modality of administration, with special reference to patients who are prone to gastrointestinal disorders. PMID- 21780553 TI - Ewing's sarcoma of the mobile spine. AB - OBJECTIVES: To evaluate the role of enbloc resection on the oncological outcome of patients with Ewing's sarcoma of the mobile spine treated with systemic multiagent chemotherapy combined with radiation therapy. While the role of chemotherapy and radiation therapy is well known and accepted in the treatment of Ewing sarcoma, there is no consensus on the role of enbloc resection in those tumors occurring in the mobile spine and, therefore, it can be difficult to conclude the decision making process, particularly if to achieve a tumor-free margin resection functionally relevant structures should be sacrificed. The study design of this work was the retrospective analysis of a series of 27 cases of Ewing sarcoma of the mobile spine homogeneously treated. METHODS: Twenty-seven patients with primary ES of the mobile spine were treated from 1979 to 2008 by the same multidisciplinary team. All the patients presented with pain. Motor deficits were present in 6 patients. All the patients were submitted to multiagent protocols of chemotherapy (always) and radiotherapy (alternative to surgery or associated to). Surgery was performed in 17 cases both for functional purpose (7 cases: intralesional piecemeal excision) both for curative purpose (10 cases: enbloc resection, resulting characterized by marginal/wide or intralesional margins). Patients were observed for a minimum of 2 years or until death. The mean follow-up time was 65 months (median 28 months; ranging 2 to 218 months). Neurological function, local recurrence, distant relapse, and treatment related complications were evaluated. RESULTS: Three periods were considered according to the evolution of therapeutic strategies. Four patients were treated in the period 1979 to 1982. All were submitted to chemotherapy (REA-2) and radiation therapy (RT). Two of them were submitted to intralesional excision. All these patients died 2 to 29 months later without significant difference in the two groups. In the period 1983 to 1990 all patients were treated with chemotherapy (REN-1/2) and RT. Two were submitted to intralesional excision and had a worse evolution as died of the disease at 2 and 11 months follow up, while the patients who did not received surgery evolved more favourably: 1 died of the disease 57 months after the end of the treatment, 3 are continuously disease free at 130, 190, 290 months. The sixteen patients treated in the period 1991 to 2008 received chemotherapy (REN-3 and ISG-SSG) and RT, combined with intralesional excision in 3, with enbloc with intralesional margins in 4, enbloc with tumor free margins (wide or marginal) in 6. Only one patient submitted to tumor-free margin enbloc resection had local recurrence and died 29 months after the treatment (biopsy was performed by open approach), the other surviving continuously disease free at 17 to 193 months follow-up (av. 76 months). All the patients submitted to intralesional excision and to enbloc resection resulting in margin violation had the same prognosis, as died of the disease 10 to 63 months after the treatment. Only one of the 3 patients who had no surgery died of the disease 8 months after the treatment, the other surviving 9 and 49 months follow up. Among the seven patients who had neurological symptoms at the occurrence, just those with no metastasis and who underwent enbloc resection are alive. CONCLUSIONS: The current study seems to demonstrate that tumor-free margin enbloc resection provides better local control and longer survival, while the results after intralesional margin resection or piecemeal excision combined with chemotherapy and RT is less effective than chemotherapy and RT alone. PMID- 21780554 TI - Cagliari University Hospital (CUH) protocol for immediate alloplastic breast reconstruction and unplanned radiotherapy. A preliminary report. AB - INTRODUCTION: Alloplastic breast reconstruction necessitating postmastectomy radiotherapy (PMRT) is at increased risk for complications such as capsular contracture, infection, extrusion, and poor cosmetic results. However, often the indication for PMRT is not decided until a permanent histological examination with review of the permanent sections is carried out, and the expander has already been inserted. Techniques described to face this issue (delayed-immediate reconstruction and Memorial Sloan Kettering Cancer Center protocol) both have disadvantages. MATERIALS AND METHODS: The protocol we suggest is based on (1) reconstruction with tissue expander placement at the time of mastectomy; (2) complete tissue expansion during postoperative chemotherapy; (3) radiotherapy, as suggested by oncologists; (4) two or three fat grafting session, according to Coleman's technique, 4-6 months after RT; (5) exchange of the tissue expander for a permanent implant approximately 3 months after the completion of fat grafting. Ten patients were treated according to these guidelines. RESULTS: Results at 15 months have been encouraging, with no grade 3-4 Baker's capsular contracture. DISCUSSION: Although the group of patients treated according to our CUH Protocol for immediate implant-based breast reconstruction and radiotherapy is small, and follow-up is short; nevertheless, results are encouraging. PMID- 21780555 TI - Isolation of Aggregatibacter aphrophilus from a patient with acute appendicitis. AB - OBJECTIVES: Acute appendicitis is a common surgical emergency. The etiology and pathophysiology of appendicitis have been well investigated. Aggregatibacter aphrophilus is a fastidious gram-negative coccobacilli. Detection of this organism in clinical samples and its differentiation from Haemophilus aphrophilus or from Aggregatibacter actinomycetemcomitans in routine microbiology settings could be difficult. METHODS: In this rare case, we report the isolation of Aggregatibacter aphrophilus from the appendix of a 14-year-old boy presented with acute appendicitis. The genotypic method using 16S rRNA sequencing was used for identification of the organism at species level. CONCLUSION: This case highlights the importance of detecting fastidious and rare microorganisms such as Aggregatibacter aphrophilus that could be associated with acute appendicitis. PMID- 21780556 TI - Acute renal failure and hypercalcemia as onset in splenic lymphoma. AB - Hypercalcemia is a rare metabolic disorder in course of B cell lymphoma. The mechanism of hypercalcemia in patients with malignancy may include the increased extrarenal production of vitamin D from tumoral cells or neighboring macrophages, i-PTH or PTHrP from tumoral cells. In this case we reported a 34 years old caucasian woman with acute renal failure and hypercalcemia as onset of splenic lymphoma in absence of abnormal levels of serum vitamin D and PTHrP. Because of dramatic recovery of renal function and hypercalcemia after splenectomy, we can speculate that main mechanism of hypercalcemia is related to vitamin D production from neighboring lymphoma macrophages. PMID- 21780557 TI - Can we define a role for perisentinel lymph-nodes on breast cancer disease? AB - BACKGROUND: The development of sentinel lymph node biopsy in breast cancer disease and the increasing of using adjuvant systemic therapy provide a rational reduction of axillary dissection in patients with Sentinel Lymph Nodes free from breast cancer cells. The aim of our study was to assess the state of the perisentinel lymph nodes removed and how these nodes can provide further information about the status of the axillary lymph nodes. MATERIALS AND METHODS: We have analysed data about 319 patients undergoing surgery for benign and malignant breast disease from January 2007 to July 2010; 134 cases were subjected to the sentinel lymph node biopsy; 29 cases of these patients had the presence of perisentinel lymph nodes at histological examination. Before the intervention, we have used colloidal albumin marked with 99mtc to select the sentinel lymph node; during the intervention, we identified by probe the ipercaptant lymph node, consequently we removed and sent it to histological extemporaneous definitive examination. RESULTS: In 134 Sentinel Lymph Nodes examined, 15 resulted positive for breast cancer cells at extemporaneous examination. In these cases, we decided to proceed with an axillary dissection in the same operative session, with the discovery of axillary lymph nodes metastases in 3 cases on 15 (20%). The positive predictive value of sentinel lymph node in case of positivity was 0.2. 8 cases (6,7% of the lymph nodes sentinel biopsy made) were negative to extemporaneous examination and positive to definitive histological examination for presence of micrometastasis. In 8 axillary dissection, 3 patients were positive for the presence of metastasis. We have analysed with the test "t-student" these data divided on age and the value of Ki-67. Then we calculated the predictive positive and negative value (patients with negative sentinel lymph node: Mean age (+/- sd) =61.93 +/- 13.8 years, ki-67=10.87 +/- 5.78; patients with positive sentinel lymph node: Age mean (+/- sd) = 64 +/- 12 36 years, ki-67=14.08 +/- 8.005). The study showed no statistically significant differences between the positive and negative sentinel lymphnodes about the age (p=0.58) and the Ki-67 (p=0.184). In the 29 cases in which the sentinel lymph node was negative at extemporaneous histological examination and in which were removed the perisentinel lymph nodes, resulted negative at definitive histological examination, the negative predictive value was equal to 1. CONCLUSIONS: The method of sentinel lymph node has demonstrated to be a reproducible, reliable and safe technique. The positivity of sentinel lymph node at final examination (micrometastasis, cells isolated) in case of extemporaneous examination negative for breast cancer cells, determines specifical considerations on surgical indication to axillary dissection. We think that in selected cases (age, biological characteristic of cancer) in which perisentinel lymph nodes were removed and free from breast cancer cells, may not be indicated in case of sentinel node positivity the axillary dissection. PMID- 21780558 TI - Cardiological assessment of cardiac patients undergoing non-cardiac surgery (usefulness of surveys). AB - AIM OF THE STUDY: The aim of the study was to considerate the effective usefulness of preoperative stress test and echocardiography in adult patients with coronary artery disease, undergoing non-cardiac surgery. MATERIALS AND METHODS: In the last three years, 200 patients aged 58-85, affected by stable ischemic pathology, undergoing non cardiac surgery, and treated with oral drugs, were enrolled for an assessment orotocol including anamnesis, objective examination, blood pressure, RCG, blood chemistry analysis, and was performed a cardiac risk evaluation. A second 50 patients control cohort of the same class was subjected to the same tests, and preoperative and exercise stress test. RESULTS: All patients showed a good hemodynamic compensation and a quick recovery, and the group of 200 patients for whom the risk was closed without further investigation has concluded the process on average three days before the group underwent echocardiography and exercise stress test. DISCUSSION: The clinical evaluation of cardiac patients waiting for non-cardiac surgery, performed through anamnesis, examinations and the ECGs, is the cornerstone of cardiac risk stratification. It also important the type of surgery, as well as some priority conditions like certain neoplastic: diseases, where it seems appropriate to speed up the diagnostic program. CONCLUSIONS: When patients are hemodynamically stable and their conditions controlled by appropriate therapy, it is sufficient to perform first-level tests for the preoperative stratification of cardiovascular risk. It's recommended to perform echocardiogram and stress test when the first level tests are abnormal, when there is a worsening of the conditions prior to admission, or when the patient is not hemodynamically stable. PMID- 21780559 TI - [Carotid endarterectomy: evaluation of a "combined" technique of general anesthesia]. AB - INTRODUCTION: The literature suggests several techniques to ensure the optimal anesthetic procedure for carotid surgery. The aim of our study is to combine, in the carotid endarterectomy, a model of general anesthesia with the loco-regional anesthesia in order to test the safety of the method, the eventual brain damage and hemodynamic stability. We also wanted to test whether the immediate postoperative analgesia was adequate. MATERIAL AND METHODS: Seventy eight (78) patients were enrolled in the study (from 60 to 75 years), ASA II-III, candidates for unilateral carotid endarterectomy in a period from June 2008 to January 2009. During the procedure data about perioperative neurologic and hemodynamic complications were collected. At the end of the surgical treatment the pain at the awakening moment through verbal numerical scale VNS was estimated. Data are presented as mean values +/- sd and validated using the chi2 test, when required. Significance was accepted at a value of P < or = 0.05. RESULTS: 85% of patients reported a VNS between 1 and 2 and 10% equal to 3-5. In the study 95% of patients (P<0.05) appreciated the technique and only 3 patients reported their dissatisfaction. There was no mortality and in 5 patients a postoperative morbidity was registered. DISCUSSION: The study demonstrated the advantages in combining loco-regional anesthesia (valid monitoring of neurological and hemodynamic stability) with general anesthesia (complete airways control and patient comfort) during carotid surgery. PMID- 21780560 TI - [Macromastia surgical therapy]. AB - AIM: Macromastia is a social health problem that causes high discomfort in the patients. Goals of reduction mammaplasty are to alleviate physical emotional and psychosocial problems and to restore a conical shaped breast, maintaining scars as short as possible. We report our approach for reduction mammaplasty with superior pedicle. MATERIALS OF STUDY: Our method combines advantages of round block with vertical scar, using a dermal flap that is fixed to the new mammary crease. We analyzed skin and glandular resection customizing the mammaplasty. RESULTS: The dermal flap works against the weight of residual tissue, maintaining the crease at the desired position with natural result. Benefits are an excellent projection, short scar, suitable reshaping and patient satisfaction. DISCUSSION AND CONCLUSIONS: This technique can be used for mild to severe hypertrophy with various degrees of ptosis. It results in a successful aesthetic outcome with minimal scarring suitable breast remodelling and natural long-lasting projection. PMID- 21780561 TI - Hepatic cirrhosis and groin hernia: binomial or dichotomy? Our experience with a safe surgical treatment protocol. AB - Hepatitis B and C are endemic in the Campania region of Italy, and as a result there are many patients with hepatitis-related cirrhosis. The medical community is therefore faced with a series of issues which must be dealt with and which are especially relevant to various areas of surgery. Abdominal wall hernias occur very frequently in cirrhotic patients, and hepatic cirrhosis has always been the harbinger of a negative outcome in patients undergoing inguinal hernia repair. The aim of this study, conducted on 52 cirrhotic patients who underwent inguinal hernioplasty, was to evaluate the effectiveness and safety of surgical treatment when certain parasurgical measures are used. These measures and the notes we inserted in our surgical protocol include the following: short-term antibiotic prophylaxis, perioperative infusion of concentrated platelets, not opening the hernia sac, application of human fibrin glue, elastic compression. All patients were treated according to the same protocol and the data was analysed using the statistics software EPI INFO 3.5. PMID- 21780562 TI - An unusual localization of intraosseus schwannoma: mandibular localization and new pathogenetic prospectives. AB - AIM: The aim of the study is to give an explanation on the Intra-osseous Schwanoma etio-pathogenesis, based on the isto-pathological findings presented by the Authors. MATERIAL OF STUDY: In a 40 years old patient with pain on the territory innervated by the third right trigeminal branch, OPT showed a like ground-glass area that involved the mandible with the mandibular canal disappearance and dental roots resorption. They removed the lesion with preservation of the vascular-neural beam on which the lesion were extremely attached; the histological examination confirmed the diagnosis of intra-osseous Schwannoma. Immunohistochemically the Schwannoma labelled with antibodies to S 100, Vimentin, Osteopontin and Osteonectin. RESULST: The clinical and radiological follow-up after one year since the surgery, using OPT showed an improvement of bone formation and the disappearance of the pain. DISCUSSION: Schwannoma rarely presents as an intraosseous mass, comprising less than 1% of all bone tumors with a strong predilection for the mandible. Data like the expression of osteopontin are believed to be distinctive feature of other schwannian cell tumors such as the granular cell tumor. Such data might explain the prevalence of mandibular location among the rare intraosseous schwannomas and might point out that the calcified shwannoma of the skull is similar to an hamartomatous lesion. PMID- 21780563 TI - [Surgical management of a voluminous abdominal paraganglioma and review of the literature]. AB - The Authors report a case of a voluminous abdominal paraganglioma and a review of the literature on the surgical management of paragangliomas. CASE REPORT: A 58 years old woman was admitted to our Institution with acute endocrine impairment and simultaneous intestinal necrosis resulting from the mass effect of the tumor on the mesenteric vessels. Clinical and biochemical preoperative work up posed the suspect of paraganglioma. Previous intensive care treatment, the patient, underwent surgical resection of the tumor and left hemicolectomy, with immediate remission of both endocrine and abdominal syndromes. Histological examination confirm the preoperative clinical hypothesis. Paragangliomas are rare tumors of the extra-adrenal chromaffin tissue. A paraganglioma may be discovered in the absence of any symptom. When symptomatic, the clinical findings are related to the hypersecretion of catecholamines or to the compression of several anatomical structures from a growing mass. Combined acute syndromes of hormonal impairment and contemporaneous mass effect, as in our case, are exceptional. The diagnosis of the secreting forms may be obtained on the basis of biochemical dosage of serum and urinary catecholamines and metanephrines. The assessment of malignancy for paragangliomas is not always feasible. Several imaging, cytological and histological parameters have been proposed as predictors of malignancy, but the only element widely accepted is the existence of distant metastasis. Surgery represents the treatment of choice for paragangliomas. Benign forms, catecholamine secreting forms and tumors compressing neighbouring anatomical structures can be treated surgically with success. In general, an accurate follow up after complete resection must be considered. PMID- 21780564 TI - Emphysematous cellulitis of the left thigh caused by sigmoid diverticulum perforation. AB - Necrotizing fasciitis and gas gangrene of the lower extremities are two life threating emergencies and are the most common causes of gas presence in the lower extremity. Rarely the gas presence is secondary to a perforated viscus and especially the colon. Large bowel diverticula are a quiet common disease in western countries and their prevalence increases with age. Also, the possibility of complications is greater in older patients. However, perforated colonic diverticulum seldom presents only with the presence of gas in the lower extremity. We report a case of emphysematous cellulitis of the left thigh caused by a sigmoid diverticulum perforation in a patient with peritoneal carcinomatosis. PMID- 21780565 TI - Choledocholithiasis and endo-laparoscopic rendezvous. Analysis of 59 consecutive cases. AB - BACKGROUND: Choledocholithiasis is a real problem of major clinical importance. The incidence of cholelithiasis is 10-20%. MATERIALS: We have examined 2907 patients treated with videolaparoscopic cholecystectomy (VLC) between January 2001 and September 2009. 214 cases (7.4%) were affected by choledocolithiasis; among these, 59 consecutive cases were treated by rendezvous, 151 cases by sequential treatment (ERCP-ES before VLC), 3 cases by extraction with Dormia's basket, and 1 case by ERCP-ES after VLC. RESULTS: The complications were one biliary fistula and three hemorrhages (one from the cystic artery, one from the hepatic area and one from trocar's site). The mean hospital stay was 1.38 +/- 0.83 days for the rendezvous group vs 4 53 +/- 0.74 days in the sequential treatment group (p<0.004). The satisfaction scores were 6.6 +/- 1.39 versus 5.7 +/- 0.96 (p<0.004). CONCLUSIONS: The rendezvous procedure reduces hospital stay and has a greater compliance (only one treatment). We can use this option in the management of cases where preoperative ERCP-ES has failed. PMID- 21780566 TI - Desmoplastic fibroblastoma of the thigh. A case report. AB - Desmoplastic fibroblastoma (DF) is an extremely rare benign soft tissue tumor, prevalent in adult men, mostly arising in deep regions of extremities. The tumor presents with a slowly growing and no recurrence or metastases after surgical excision. Histologically, DF is characterized by a collagenous stroma that contains spindle- and stellated-shaped fibroblastic cells positive for vimentin. Differential diagnosis with locally aggressive soft tissue tumors could be difficult. This case report deals with the clinical pathological and immunoistochemical features of a DF of the left thigh in a 63-years old man. PMID- 21780567 TI - [Colonic metastasis from primary carcinoma of the lung. Case report]. AB - Lung cancer is the most common cause of cancer-related death in both men and women in Western countries. About one-half of patients with lung cancer have metastatic disease at the time of initial diagnosis. Metastasis to the gastrointestinal tract from primary lung cancer has rarely been described. The most common metastatic site is the small bowel whereas large bowel secondary lesions are very rare. The majority of patients are referred to a surgeon only after the intestinal secondary lesion becomes symptomatic posing a threat to the patient's life. Although the outcome is still unfavourable, the development of chemotherapy and of surgical techniques allows aggressive treatment when facing a single intestinal metastasis from lung cancer. We report on a case of a patient who came to our observation for a neoplastic stenosis of the descending colon with a single liver secondarism. Histology proved both lesions to be metastases of primitive adenocarcinoma of the lung. PMID- 21780568 TI - Surgical treatment of metastases from cutaneous melanoma to the small intestine and the spleen. Case reports and review of the literature. AB - Cutaneous melanoma is found in the head and neck in 15% of patients, in the limbs in 22%, in the trunk in 40% and in occult sites in 16%. There is usually an interval of at least 3 years between the diagnosis of primary melanoma and the identification of metastases. Primary melanoma metastasizes most frequently to the lymph nodes (73.6% cases) and the lungs (71.3% cases). The small intestine and the spleen are the sites of 36.5% and 30.6% respectively of the gastrointestinal metastases from melanoma. The cases reported provide evidence of the effect radical resection in patients with gastrointestinal metastases can have on survival. The cases and a review of the literature suggest that a careful and multidisciplinary follow-up is of crucial importance since it is the only means of identifying metastases when they can be still cured with surgical treatment. PMID- 21780569 TI - Appendiceal mucocele. A case report and literature review. AB - Appendiceal mucocele is a rare disease (0.3% of all appendectomy) and is characterized by the accumulation of mucoid material in the appendiceal lumen. Etiopathogenesis can be inflammatory or neoplastic. Four entities can be distinguished on the basis of histopathologic epithelial characteristics: simple appendiceal mucocele (AM), mucocele with epithelial hyperplasia, cystadenoma and cystadenocarcinoma; the last two subgroups represent neoplastic forms. Dissemination of neoplastic cells and mucoid material in abdominal cavity, caused by appendiceal perforation, clinically results in pseudomyxoma peritonei which is the dramatic evolution in 10-15% of cases. Clinically it can remain either asymptomatic for long time or it can manifest with abdominal pain that can be associated with the presence of a palpable mass. The most common clinical manifestation is pain in the right iliac fossa. Preoperative diagnosis is rare, while it is more frequently intraoperative. Therapy is fundamentally surgical: appendectomy is curative for simple AM, for AM with epithelial hyperplasia and for cystadenoma with intact appendiceal base; cecum resection is indicated for cystadenoma with larger base of implantation; right hemicolectomy has been the elective treatment in case of cystadenocarcinoma for several years although Gonzalez-Moreno and Sugarbaker have recently demonstrated its validity as definitive treatment only if it is performed in order to obtain complete cytoreduction, if there is lymph node involvement, or if histopathological examination indicates non-mucinous type. We report the case of a 60-year-old woman that presented with cystic neoformation in the right iliac fossa, that was preoperatively considered deriving from the ovary. We intraoperatively found the presence of appendiceal mucocele that histological examination defined as mucinous cystadenoma. PMID- 21780570 TI - [Anal Masson's tumor]. AB - The Authors report on an extremely rare case of anal Masson's tumour and has described clinical and histological considerations. Is important the surgical resection of the lesion because this tumour is similar to angiosarcoma. PMID- 21780571 TI - [Air pollutants emissions of locomotives in China railways in recent 33 years]. AB - Although railway has played a great role in transportation in China, there has been no any study on air pollutants emissions of locomotives until now. Based on the annual statistical data collected by the Chinese Railway Statistic Center, using the emission factor method derived from fuel consumption, the air pollutants emissions of locomotives during 1975-2007 were calculated, and their emission intensities and dynamic characteristics were analyzed. The results show that the emissions of soot, SO2, CO and CnHm from steam and diesel locomotives in china decreased from 3510.6 thousand, 399.7 thousand, 846.0 thousand and 845.3 thousand ton in 1975 to 78.7 thousand, 11.4 thousand, 36.7 thousand and 26.4 thousand ton in 2007, indicating a decrease of 107.0 thousand, 12.1 thousand, 25.3 thousand and 25.6 thousand ton per year, respectively. However, the emissions of NO,showed an increase trend from 34.8 thousand ton in 1975 to 98.3 thousand ton in 2007 with an increase rate of 2.0 thousand ton per year. The emission intensities of soot, SO2, CO and CnHm decreased significantly from 686.2, 78.1, 165.4 and 165.2 g/(hundred converted ton-km) in 1975 to 5.4, 0.8, 2.5 and 1.8 g/(hundred converted ton-km) in 2007, respectively. The emission intensity of NOx fluctuated in the range of 5.0-8.0 g/(hundred converted ton-km). Air pollutants emissions of locomotives accounted for very little of the total emissions in China, and the emission intensities decreased persistently. It shows that railway transportation is a perfect way of saving energy and reducing emission in the sector of transportation. PMID- 21780572 TI - [Atmospheric pollution characteristic during fireworks burning time in spring festival in Quanzhou suburb]. AB - Atmospheric pollution characteristics during fireworks burning time in 2009 Spring Festival in Quangzhou suburb were studied. Particulate aerosol has been monitored and collected using real-time monitor and middle-volume sampler during fireworks burning time. The objectives of this study were to identify the contents and distributing characteristics of particles, polycyclic aromatic hydrocarbon (PAHs) and water-soluble ions and to discuss sources of these pollutants. The results showed that PM2.5 and PM10 were increased significantly during fireworks burning time. The highest concentration of particles presented time of 00:57-01:27 on New Year's Eve, which the average concentration of PM2.5 and PM10 were reached 1102.43 microm(-3) and 1610.22 microg x m(-3) in 30 min. The concentration of particle- and gas-PAHs were 54.18 ng x m(-1) and 47.10 ng x m(-3), respectively, during fireworks burning time in New Year's Eve, which were higher than that in the normal day. It can be judged by the diagnostic ratios that the primary source of PAHs in Quanzhou suburb were the combustion of coal, biomass and the exhaust emission from diesel vehicles in this region. Results of water-soluble ions indicated that fireworks burning were the main reason to lead to higher concentration of these ions during Spring Festival. Moreover, pollution gases of NOx and SO2 that were origined from fireworks burning, coal combustion and exhaust emission from motor vehicle were supplied precursors to form secondary pollutants, such as NO3- and SO4(2-). PMID- 21780573 TI - [Indoor air pollution in the Nam Co and Ando Regions in the Tibetan Plateau]. AB - Concentrations and variations of fine particulate matter (PM2.5) and carbon monoxide (CO) within tents from the Nam Co and Ando regions were observed at summer 2009, in order to understand the concentrations and variations of PM2.5 and CO in these tents (or in rooms) and their main affect factors, as well as the exposure of different residents. The result indicates that the twenty-four hour average concentrations of PM2.5 and CO (V/V) in the tents without chimney are 1.272 mg x m(-3) and 5.035 x 10(-6), which are significantly higher than those of tents installed chimneys (0.097 mg x m(-3) and 0.089 x 10(-6)). Diurnal variations of PM2.5 and CO are similar and show multiple peaks, which is different with those in the eastern rural areas of China and closely connected with the behaviors of the residents within the tents. Generally, women and children spend three or four hours longer in tents than other family members every day. Children have the highest exposure of 0.972 mg x m(-3) and 0.132 x 10( 6) for PM2.5 and CO, respectively. Therefore, although the outdoor air in the Tibetan Plateau is very clean, the air of the Tibetan tents are seriously polluted and mainly caused by yak dung combustion. PMID- 21780574 TI - [Mass size distributions and existing forms of sulfate and nitrate and atmospheric environment in Beijing]. AB - In order to understand the formations and the concentrations of the secondary sulfate and nitrate of PM10 in Beijing. From May 2008 to April 2009, MOUDI has been used to collect the PM10 samples in Beijing atmospheric environment and the ion chromatography has been used to analyze the inorganic water-soluble components of the PM10 samples. The results showed that the mass size distributions of soluble sulfate and nitrate of PM10 in Beijing were single-mode distribution and the peak rang was from 0.32 microm to 0.56 microm, and the primary formation ways was the chemical reaction in the gas phase. The results of partial correlation analysis indicated that the primary formations of sulfate and nitrate of PM10 in Beijing was (NH4)2SO4, NH4NO3, NaNO3, KNO3 and Ca(NO3)2. The mass concentration of secondary (NH4)2SO4 and NH4NO3 were (17.0 +/- 8.2) microg/m3 and (8.8 +/- 3.3) microg/m3 respectively, which accounted for (14.7 +/- 3.6)% and (7.6 +/- 2.2)% of PM10 respectively. The sum of them accounted for (22.3 +/- 4.3)% of PM10. PMID- 21780575 TI - [Emission inventory of greenhouse gases from agricultural residues combustion: a case study of Jiangsu Province]. AB - Burning of agricultural crop residues was a major source greenhouse gases. In this study, the proportion of crop straws (rice, wheat, maize, oil rape, cotton and soja) in Jiangsu used as household fuel and direct open burning in different periods (1990-1995, 1996-2000, 2001-2005 and 2006-2008) was estimated through questionnaire. The emission factors of CO2, CO, CH4 and NO20 from the above six types of crop straws were calculated by the simulated burning experiment. Thus the emission inventory of greenhouse gases from crop straws burning was established according to above the burning percentages and emission factors, ratios of dry residues to production and crop productions of different periods in Jiangsu province. Results indicated that emission factors of CO2, CO, CH4 and N2O depended on crop straw type. The emission factors of CO2 and CH4 were higher for oil rape straw than the other straws, while the maize and the rice straw had the higher N2O and CO emission factor. Emission inventory of greenhouse gases from agricultural residues burning in Jiangsu province showed, the annual average global warming potential (GWP) of six tested crop straws were estimated to be 9.18 (rice straw), 4.35 (wheat straw), 2.55 (maize straw), 1.63 (oil rape straw), 0.55 (cotton straw) and 0. 39 (soja straw) Tg CO2 equivalent, respectively. Among the four study periods, the annual average GWP had no obvious difference between the 1990-1995 and 2006-2008 periods, while the maximal annual average GWP (23.83 Tg CO2 equivalent) happened in the 1996-2000 period, and the minimum (20.30 Tg CO2 equivalent) in 1996-2000 period. PMID- 21780576 TI - [Phytoplankton productivity and its influencing factors in Dianshan Lake]. AB - To understand the relationship between the spatial-temporal variations of phytoplankton primary productivity and its environmental factors in Dianshan Lake, monthly survey was carried out from April, 2009 to March, 2010, with the method of white and black bottles. The result shows that seasonal variation of primary productivity (calculated according to carbon, following the same) is summer [0.95 g x (m3 x d)(-1)] > winter [0.83 g x (m3 x d)(-1)] > spring [0.77 g x (m3 x d)(-1)] > autumn [0.62 g x (m3 x d)(-1). From the flat distribution, primary productivity is higher in northern and southern parts than that in east and west, with no significant differences in each point (p > 0.05). From the vertical distribution, phytoplankton light availability is an important limiting factor. Primary production of 0. 3 m underwater is higher than that of 0.5 m. However, primary production of 0.3 m level in summer is lower because of light inhibition. Seasonal changes in primary productivity may be due to phytoplankton community structure and replacement of the dominant species. There are significantly positive correlation between Chlorophyll a (Chl-a) and phytoplankton density with primary productivity (p < 0.01), and Chl-a has better correlation with primary productivity. Phytoplankton biomass shows a positive reaction to its productivity and may preliminary provide a reference for the number of phytoplankton. PMID- 21780577 TI - [Primary productivity evaluation based on underwater light distribution in Chaohu Lake]. AB - According to the in situ measured data on 32 sampling sites in Chaohu Lake in June 2009, underwater light distribution was explored, as well as, the euphotic depth was calculated in these waters. Furthermore, primary productivity was evaluated with chlorophyll-a concentration. The results indicate that: the underwater light intensity power decayed with the depth, and at the depth of 1 m it decreased to only 0.07%-15.17% compared with that at water surface. In general, underwater light intensity was higher in the west and northeast lake at different water depth, on the contrary, it presented lower in northwest and east central waters. At the same time, the euphotic depths ranged from 0.64 m to 2.33 m (mean 1.2 m) in Chaohu Lake. The maximum value was presented in the southwest lake; however, the euphotic depth was relatively lower in the northwest and east central parts. Primary production values which were calculated by VGPM model were divided into three levels from 1363.77 mg/(m2 x d) to 7349.37 mg/m2 x d). Among these, Level 1 [0-2500 x mg/(m2 x d)] was mainly distributed in eastern waters and scattered in western region, and the total area was 312.66 km2; Level 2 [2500 5000 mg/(m2 x d)] located in the west and northeast and occupied 47.12% of the area (353.42 km2); simultaneously, Level3 [5000-7500 mg/(m2 x d)] with area of 83.92 km2 was distributed in the northwest and a small area in the central north. PMID- 21780578 TI - [Spatio-temporal variation of nitrogen, phosphorus in different period in Three Gorges Reservoir after its impoundment]. AB - It is very important to investigate the change of nutrient in Three Gorges Reservoir for analyzing the influence after normal storage and proposing reasonable management methods. The water quality parameters were determined monthly from March in 2008 to February in 2009. Six horizontal monitoring sites and one vertical site were set in Three Gorges Reservoir. The period was separated into two different periods with taking account of the water level after the Three Gorges Reservoir storaged water, which were October-February and March September respectively. Then, the spatial-temporal variation characteristics of nutrient and environmental features in different periods were studied with the water quality data. The results showed that there were no significant differences of water quality parameters except DO in different periods. There were also no significant differences of the vertical distribution of hydrology, water quality indexes among the three observed levels. The concentration of DO in high water level (8.29 mg/L)was higher than that in low water level (7.49 mg/L) and the mean of saturation degree of DO was 83.5%. Total nitrogen (TN), NH4+ -N, total phosphorus (TP) values were 1.42-2.23 mg/L, 0.15-0.36 mg/L, 0.08-0.14 mg/L respectively, and plane of nutrition in high water level was higher than that in low water level. The main factor influenced the concentrations of TN, NH4+ -N and TP were rainfall runoff process. Significantly positive correlation was observed by correlation analysis between nutrients fluxes and the flux at the section Cun Tan. The fluxes of TN, NH4+ -N, TP were 368.4, 97.2, 29.5 thousands tons respectively, and the non-point pollution accounts for more than 55.5%. PMID- 21780579 TI - [Simulation and application of the agricultural non-point source pollutants in drainage ditch]. AB - Drainage ditch system is the transitional zone between yield in the field and receiving waters for agricultural non-point source pollutants. Based on the brief analysis of the migration and transformation process of agricultural non-point source pollutants in drainage ditch system, the one-dimensional transport model of agricultural non-point source pollutants in drainage ditch system was constructed on the basis of the equation of continuity of flow and pollutants migration transform. Taking the Di Yi drainage ditch system, in the Qing-Tong-Xia irrigation district at the Yellow River upstream, as an example, combining with actual situation, the drainage discharge and concentration of nitrate nitrogen and total phosphorus were simulated by this model. The results show that the simulated drainage discharge accords with measured data approximately and Nash Suttcliffe coefficient is 0.82, the simulated concentration of nitrate nitrogen and total phosphorus in farmland drainage was reasonable. PMID- 21780580 TI - [Study on the effect of total phosphor removing by constructed submerged hydrophyte bed for urban landscape river]. AB - A kind of modularized and air adjustable constructed submerged plant bed (CSPB) was used to restore the eutrophic water. This CSPB helps hydrophytes to grow up under poor conditions, like frequently changed water depth, blurred water transparency, algae bloom and duckweed rampant in summer, which are not suitable for growing water plants naturally. The experiments in Waihuan River of Tianjin show that total phosphor (TP) reduces 30%-40% in growing season and 7%-20% in winter when the detention time is 5.48 days. The variation between the concentration of TP and the detention time follows the first-order kinetic equation, the correlation coefficients (R2) is above 0.9. The attenuation coefficients k of the kinetic equation changes with the water temperature. When the water temperature is quite low or quite high, the value of k is not significantly changed with the temperature of water. While when the temperature is in a moderate range, an increase of water temperature leads to a rapid increase of k value. PMID- 21780581 TI - [Characteristic analysis of the adsorption/desorption of nitrogen and phosphorus in the sediments of Taihu Lake]. AB - The adsorption isotherms curves of 90 simples were studied in Taihu Lake through the experiment of adsorption/desorption. And the relation between the equilibrium concentrations, NAP, adsorption efficiency and corresponding parameter in interstitial water and sediment has been analyzed, in order to analyze the "source" and "collection" of Taihu. The results showed that the isotherms curves of nitrogen and phosphorus in the sediment had significant correlations in the range of the concentrations of experiment. The average equilibrium concentrations of nitrogen and phosphorus are 1.10 mg/L and 0.11 mg/L respectively. The average of NAP of nitrogen and phosphorus are 23.55 mg/kg and 11.72 mg/kg respectively. The NAP of nitrogen and phosphorus are higher in the area of serious pollution. The average adsorption efficiency of nitrogen and phosphorus are 23.14 L/kg and 102.09 L/kg respectively. Significant correlations were found between the equilibrium concentrations of adsorption/desorption of nitrogen and phosphous and corresponding parameter in interstitial water or sediment. Overall the sediment is the "source" of the nitrogen and phosphorus. PMID- 21780582 TI - [Effect of hyacinth mulching on rice (Oryza sativa L.) uptake and utilization of nitrogen]. AB - Nitrogen is the most important element for rice growth, and hyacinth can absorb large quantities of nitrogen and accumulate in their tissues. The field experiment was conducted to investigate the effects of hyacinth mulching on rice nitrogen (N) concentration, uptake, efficiency and allocation at different growth stages. Taked Yun 2645 as a material, the nitrogen uptake and utilization of rice were evaluated under two different levels of N input: low (LN, 120 kg x hm(-2)) and normal N (NN, 240 kg x hm(-2)) in 2009. Main results showed that: (1) Compared with AMB, hyacinth mulching significantly increased N concentration in rice plant over the season, hyacinth mulching significantly increased nitrogen accumulation in rice plant, and the increasing rate was gradual addition from mid tillering to heading, but from heading to maturity the increasing rate was gradual decline. (2) Hyacinth mulching had no obvious effect on nitrogen allocation pattern in leaves and stems of rice over the season, significantly decreased nitrogen allocation pattern in spikes. (3) Except mid-tillering, hyacinth mulching resulted in the significant decrease in N use efficiency for biomass (NUEp) over the season and in N use efficiency for grain yield (NUEg) at grain maturity, but no effect was observed on nitrogen harvest index (NHI). (4) Nitrogen concentration and accumulation at most growth stages of rice increased with increasing N supply (p < 0.05 or 0.01), but NUEp and NUEg showed the opposite trends. 1(5) nteractions between hyacinth mulching x N were not observed for N uptake and utilization. Hyacinth mulching increased N concentration and N uptake, decreased NUEp and NUEg at most growth stages of rice. PMID- 21780583 TI - [Purification effects of large-area planting water hyacinth on water environment of Zhushan Bay, Lake Taihu]. AB - Using water hyacinth and other fast-growing and high biomass of floating plants to purify polluted water has become an efficient and effective ecological restoration method at present. Effects of nutrients adsorption and water purification of planting water hyacinth on water quality in Zhushan Bay were studied. The results indicated that no anoxia was observed in water hyacinth planting areas because of wave disturbance and strong water exchange. Concentrations of TN and TP in water hyacinth planting areas were higher than that in the outside of stocking area (the content ranged 3.03-7.45 mg/L and 0.15 0.38 mg/L, respectively), and the content changes ranged 3.37-8.02 mg/L and 0.15 0.36 mg/L,respectively. The higher concentration of TN and TP in water indicated the water body was heavily polluted. Water hyacinth roots have a strong ability to adsorb suspended solids and algae cells, the concentration of Chl-a in stocking areas was higher than that in stocking fringe and outside, the maximum Chlorophyll in the stocking region in August was 177.01 mg/m3, and at the same time the concentrations in planting fringe and outside were 101.53 mg/m3 and 76.96 mg/m, respectively. Higher Chl-a content on water hyacinth roots indicated that water hyacinth had strong blocking effects on algae cells, and demonstrated it had a great purification effects on eutrophicated water, and it also provides a basis for the larger polluted water bodies purification in using water hyacinth. PMID- 21780584 TI - [Heavy metal accumulation during last hundred years and its assessment of potential ecological risk in the coastal wetland of Qi'ao Island, Pearl River Estuary of China]. AB - The processes of fine sediment transport and deposition can record some relative anthropogenic information in estuarine environments. Grain size analysis of the sediment core collected from coastal wetland of Qi'ao Island in the Pearl River Estuary of China show that the sediment is mainly composed by clayey silt, and the mean grain size, contents of clay and silt increase upward gradually. Chronology analysis show that the sedimentation rate above 59 cm is about 4.15 cm x a(-1), and 0.97 cm x a(-1) beneath 59 cm. Heavy metal analysis indicate that the contents of the each heavy metal increased slowly with a slight intensity of potential ecological risk; however, from 1966 to 1992, the heavy metal contents increased obviously because of the quick social-economy development around the Pearl River Estuary area, and the order of polluting degree of these heavy metals in core sediment is Cd > Ni > Pb > Cu > Cr > Zn. The potential ecological risk intensity of Cd increased from slight risk before 1966 to strong risk since 1992, and the potential ecological risk intensities other heavy metal are slight risk; the potential ecological risk index is weak level. The variations of core sediment heavy metal contents and its ecological risk assessments along the vertical profile reveal the interaction processes and intent of anthropogenic influences from the areas around the Pearl River Estuary and the catchments. PMID- 21780585 TI - [Heavy metals in the surface sediment of the dumping ground outside Jiaozhou Bay and their potential ecological risk]. AB - Based on the monitoring data of heavy metals (Cr, Hg, Cd, Pb, Zn, Cu) in the surface sediment of the dumping ground outside Jiaozhou Bay from 2003 to 2008, the distribution patterns, factors controlling the distribution, and the potential ecological risks of heavy metals were studied with the data in 2007-08, and the fluctuation trends of heavy metals in the surface sediment over the 6 years were also discussed. The average concentrations of heavy metals Cr, Hg, Cd, Pb, Zn, Cu in the surface sediment were 29.47, 0.065, 0.105, 1.145, 9.63, 3.355 microg/g, respectively. Except for Cr, the concentration of heavy metals was high in the central dumping area while low outside the dumping ground, suggesting that the dredged material dumped was the main source of heavy metals. Organic carbon content in the surface sediment had a significant positive correlation with heavy metals except for Cr. Based on the results of ecological risk assessment, Hg had a medium potential ecological risk, while the other heavy metals had low potential ecological risk. The overall risk index (RI) of the heavy metals was 100.50, which was considered as a level of low potential ecological risk. The average concentration of heavy metals showed a decreasing trend over the 6 years, except Hg. In conclusion, the quality of surface sediment in term of heavy metals in the dumping ground outside Jiaozhou Bay is relatively good. PMID- 21780586 TI - [Distribution of heavy metals in waters and pollution assessment in thallium contaminated area of Yunfu, Guangdong]. AB - Distribution of Thallium(T1), Cadmium( Cd), Chromium (Cr), Lead (Pb), Nickel (Ni), Arsenic (As), Copper (Cu), Zinc (Zn) in water and sediments of Yunfu pyrite mine area was studied. The environmental risk assessment was conducted systematically using Sediment Quality Guidelines (SQGs) and Hakanson potential ecological risk index. The results indicated that concentration range of Tl in stream water was 0.19-65.25 microg/L, which is higher than the environmental quality standards for surface water. Concentration ranges of Tl, Zn, As, Cd, Pb in sediments were 5.89-63.0 mg/kg, 1215-5754 mg/kg, 208.4-1327 mg/kg, 4.20-17.5 mg/kg, 282-13,770 mg/kg. According to Sediments Quality Guidelines, sediments was moderately to severe level of pollution since concentrations of Tl, Cd, Cr, Pb, Ni, As, Cu, Zn were much higher than LEL (lowest effect level) values, and the concentrations of Pb, As, Zn were higher than SEL (severe effect level) values, the others were partly higher than SEL values, which may result in severe negative biota effects in the watersheds. Compared to soil background values of Guangdong province, the metals in stream sediment showed strong to severe strong ecological risk, and the ecological risk of heavy metals in the descending order of Tl, Cd, As, Pb, Cr, Ni, Zn and Cu. Besides, the sediments were severe contained by toxic element thallium and cadmium. Besides, the mainly ecological risk of heavy metal is thallium. More emphasis should be placed on thallium and cadmium control and disposal in PMID- 21780587 TI - [Health risk assessment of heavy metals in drinking water based on field measurement of exposure factors of Chinese people]. AB - This study was carried out in Biyang County, located in the junction of Yangtze river and Huaihe river. Drinking water samples of 20 sites in urban and rural areas in this county were collected to measure 14 heavy metals by ICP/MS. About 2 500 subjects with different age and sex were selected to measure exposure factors. Time-activity of drinking water by ingestion and dermal contact of each individual subject during the last three days were kept in dairy in detail by questionnaires. Intake of drinking water from direct and indirect consumption of water and time duration of dermal contact to water in each individual subject were kept in record based on real time measurements. Human health risks were assessed and sensitivity of exposure factors and uncertainty of risks were also analyzed. The results showed that the average drinking water intake rate of male and female are 2276 mL/d, 2265 mL/d in urban adults and 2464 mL/d, 2170 mL/d in rural adults respectively. Body surface area of male and female are 1.806 m2, 1.641 m2 in urban adults and 1.747 m2, 1.617 m2 in rural adults respectively. The contents of 14 heavy metals in this study area are all below the national drinking water standards. Cancer risks from exposure to As are ranged from 2.5 x 10(-6) to 5.2 x 10(-6) through ingestion and 1.1 x 10(-7) to 2.3 x 10(-7) through dermal exposure. Non-cancer risks are ranged from 2.1 x 10(-7) to 1.7 x 10(-6) through ingestion and 1.0 x 10(-8) to 6.0 x 10(-8) through dermal exposure. Non cancer risks in rural population are 2.1 times to 5.6 times to the risks in urban populations. However all the risks are below the acceptable level. The sensitivity of various exposure factors including drinking water intake rate, dermal exposure time and body surface area are 71.5%. This indicates that exposure factors play a very important role in health risk assessment. Health risks in this research based on real measurement of exposure factors are about 0.94 time to 6.33 times higher than the risks based on the references of the data from the exposure factors handbooks in other countries. This study showed that the accuracy of health risk assessment could be improved a lot by the real measurements of exposure factors. Attentions should be attached to exposure factor investigation to decrease uncertainty of health risk assessment. PMID- 21780588 TI - [Spatial and temporal variation of Fe and Mn in the stormwater wetland]. AB - To study the purification mechanism and biogeochemical cycle of wetlands, the concentration of Fe/Mn and oxidation reduction potential (ORP) in the pore water were monitored in situ on the Wuhan Zoo stormwater wetland from 2004 to 2006. The results showed that the water level of the wetland was changed from -10 cm to 30 cm, and the range of ORP was-120-220 mV. The elements of sulfur, iron and manganese were the main oxidation and reduction systems in the wetland. The ranges of total Fe, Mn and Fe2+ concentration were 0.60-2.35, 0.75-1.89 and 0.20 1.25 mg x L(-1), respectively. The concentrations of total Fe, Mn and Fe2+ were higher in spring and summer than that in autumn and winter, while the sulfate concentration was on the contrary and the ratio of Fe2+/Fe was slightly various in different seasons. From the surface of 10 cm to 50 cm underground, ORP and pH was decreased, whereas the concentrations of total Fe, Mn and Fe2+ were increased (except for the surface water). Through the correlation analysis, it was showed that the correlation of ORP and total Mn and Fe2+ was negative and significant, while there was no significant correlation between ORP and total Fe (R = -0.169, p < 0.0001). The order of the correlation coefficient was total Mn, Fe and Fe2+ in turn. Therefore, the systems of sulfur, iron and manganese were the important component of the oxidation and reduction system for stormwater wetland. PMID- 21780589 TI - [Disinfection efficiency for outlet water from biological activated carbon process by different disinfecting modes]. AB - Lab-scale tests were designed to treat the leak of bacteria from BAC process. Water samples from outlet of BAC pool in Xujing Waterworks in Shanghai were disinfected by NaClO and NH2Cl disinfectant to compare the disinfection efficiency. Heterotrophic bacteria in disinfected water were cultivated and counted and halo hydrocarbons were detected by GC. To keep the disinfecting efficacy [lg(N0/N)] over 2 under the water temperature of 30 degrees C, NaClO should have an initial concentration more than 1.84 mg/L total chlorine and contact with bacteria for about 30 minutes. As to NH2Cl disinfection, the initial concentration should be more than 2.20 mg/L total chlorine and contacting time should be prolonged to about 90 minutes. The production of CHCl3 ranged from 4.97 to 7.10 microg/L and CCl4 ranged from 0.01 to 0.71 microg/L in NaClO disinfection tests with a initial disinfecting concentration in the range of 1.53-2.42 mg/L total chlorine values. In NH2Cl disinfecting tests, CHCl3 ranged from 4.43 to 5.55 microg/L and CCl4 ranged from 0.01 to 0.64 microg/L when initial disinfecting concentration limited in the range of 2.10-2.86 mg/L total chlorine values. All was below the state drinking water standard. The results showed that the disinfection process can be divided into fast step and slow step. NaCl0 has higher disinfecting efficiency on bacteria than NH2Cl, but neither can reach 100% effectivity. Meanwhile the risk of producing halo hydrocarbon over standard was proved to be negligible. PMID- 21780590 TI - [Membrane fouling mechanism and control strategy for the pilot-scale submerged PVC-UF membrane process]. AB - In this paper, Lujing water supply plant in Jiangsu was selected to carry out the investigation in order to understand the constitutes of the membrane fouling, comment on the membrane cleaning methods and obtain the proper cleaning sequences. In the experiments, water quality of the raw water was measured; membrane characteristics of the plant and membrane cleaning methods were thoroughly analyzed. The results indicated that the hydrophobic acids (HOA) and hydrophilic matters (HIM) are the major components in the raw water, 40.34% and 28.48% respectively in mass fraction. EEM's results also demonstrated that aromatic protein II are the main constitutes in the DOMs. In addition, the turbidity can reach around 0.1 NTU and the DOM can be removed partially by the PVC-UF membrane process during the water production. The constitutes of those emulations demonstrated that inorganic ions and NOM were both contributed to the membrane fouling. Ca and Si were the major inorganic contributors; aromatic protein II, SMP and fulvic acid were the major organic ones. According to SEM observation the sequence of the membrane cleaning should be HCl first, then NaOH. PMID- 21780591 TI - [Direct removal of typical endocrine disruptors from heavily polluted river water by ozonation]. AB - Ozone was applied to study the removal of conventional pollutants and typical endocrine disrupters (EDs), including bisphenol A (BPA), 4-n-nonylphenol(NP), 4 tert-octylphenol (OP), estrone (E1), estradiol (E2), 17alpha-estradiol (17alpha E2), estriol (E3) and ethinylestradiol (EE2) , from heavily polluted river water. The O3 dose was designed at 28 mg x L(-1) for 30 min and 42 mg x L(-1) for 80 min. Pollutants in terms of chemical oxygen demand (COD) and ammonia nitrogen can not be removed efficiently, ranged from 3% to 7%. The colority of the black water was quickly reduced in the first 5 minutes, while the turbidities increased first and then decreased gradually. It showed that three EDs with relatively high level including BPA, OP and EE2 could be removed efficiently in thirty minutes. Concentrations of E3 increased first then decreased to be lower than the detection limit. Removal efficiencies of E1 and E2 were 41%-70% and 62%-85% respectively. Extension of ozone exposure time can not improve the efficiency of EDs removal any more. PMID- 21780592 TI - [Study on the influence of bioclogging on permeability of saturated porous media by experiments and models]. AB - This paper studied on the influence of bioclogging on permeability of saturated porous media. Laboratory hydraulic tests were conducted in a two-dimensional C190 sand-filled cell (55 cm wide x 45 cm high x 1.28 cm thick) to investigate growth of the mixed microorganisms (KB-1) and influence of biofilm on permeability of saturated porous media under condition of rich nutrition. Biomass distributions in the water and on the sand in the cell were measured by protein analysis. The biofilm distribution on the sand was observed by confocal laser scanning microscopy. Permeability was measured by hydraulic tests. The biomass levels measured in water and on the sand increased with time, and were highest at the bottom of the cell. The biofilm on the sand at the bottom of the cell was thicker. The results of the hydraulic tests demonstrated that the permeability due to biofilm growth was estimated to be average 12% of the initial value. To investigate the spatial distribution of permeability in the two dimensional cell, three models (Taylor, Seki, and Clement) were used to calculate permeability of porous media with biofilm growth. The results of Taylor's model showed reduction in permeability of 2-5 orders magnitude. The Clement's model predicted 3%-98% of the initial value. Seki's model could not be applied in this study. Conclusively, biofilm growth could obviously decrease the permeability of two dimensional saturated porous media, however, the reduction was much less than that estimated in one dimensional condition. Additionally, under condition of two dimensional saturated porous media with rich nutrition, Seki's model could not be applied, Taylor's model predicted bigger reductions, and the results of Clement's model were closest to the result of hydraulic test. PMID- 21780593 TI - [Simulation study on reductive attenuation of nitrobenzene by Fe2+ in subsurface environment]. AB - Experiments were conducted to investigate reductive attenuation of nitrobenzene (NB) by Fe2+ in subsurface environment and influences of hydrochemical constituents such as water hardness, SO4(21), NO3- and Cl-. Experimental results indicated that concentration of Fe2+ and NB both had influences on NB reduction. The highest reducing efficiency obtained while n(Fe2):n(NB) was 5.88:1 under the condition of pH 6.8 and 10 degrees C. The deoxidization efficiency of NB was up to 57.63% over 48 h. Mg2+ and CO3(2-) could inhibit the reduction of NB, and the reduction efficiency reached 51.05% and 49.96% in 48 h while Mg2+ was 150 mg/L and CO3(2-) was 50 mg/L, respectively; the inhibition was enhanced with increasing of Mg2+ and CO3(2-) concentration, and the deoxidization efficiency of NB was 6.98% only while Mg2+ was 800 mg/L. SO4(21), NO3- and Cl- have small influence on NB reduction, the deoxidization efficiency was less than 50% in 48 h. HCO3- can accelerate the reaction, and the reduction efficiency was up to 60% in 8h. These baseline relationships provide a way to quantitatively evaluate the extent of natural attenuation in contaminated site. PMID- 21780594 TI - [Reclaimed water quality control for landscape with GFH + BF treatment system]. AB - In order to control reclaimed water quality for landscape, GFH + BF treatment system was studied. In the experiment, GFH effluent was the inlet water of artificial lake, and BF was used as core process for contaminants removal and lake water supplying. The results showed that GFH could reduce TP, DOM and N very effectively, the removal rates of TP, NH4+ -N, NO2- -N, DOC, UV254 and color were 89.8%, 23.3%, 58.7%, 17.6%, 26.1% and 41.2%, respectively. After GFH effluent flowing into artificial lake, the concentrations of TP and NH4+ -N increased slightly. NO2- -N and NO3- -N were nitrogen source for the growth of cyanobacteria and the removal rates were 68.3% and 84.9% , respectively. Bank filtration removed 33.0% TP, 39.5% NH4+ -N, 42.2% NO3- -N, 26.0% TN, 24.5% DOC, 12.1% UV254 and 33.0% color for landscape water. In conclusion, "GFH + BF" treatment system reduced contaminants greatly from reclaimed water and landscape water, and lake water cycle was achieved, which could avoid eutrophication of landscape effectively. PMID- 21780595 TI - [Treatment of high-concentration butyl-acrylate-production wastewater by A three phase biological fluidized bed reactor]. AB - The butyl-acrylate-production wastewater was treated by a three-phase biological fluidized bed reactor. The influences of acrylic acid concentrations, p toluenesulfonic acid concentrations, volumic load and hydraulic retention time on pollutants removal efficiencies were investigated. It was indicated that the reactor was suitable for the treatment of butyl-acrylate-production wastewater at a high loading rate. Acrylic acid of 100 mg/L or p-toluenesulfonic acid of 50 mg/L in the influent can inhibit the unacclimated microorganisms in the fluidized bed reactor. The inhibition effects were eliminated after an acclimation of two weeks. Acrylic acid and p-toluenesulfonic acid could be removed completely at COD loading rates up to 11.56-13.56 kg/(m3 x d). The effluent COD could satisfy the demand of Class II in Chinese Integrated Wastewater Discharge Standard (GB 8978 1996) at COD loading rates up to 8.86 kg/(m3 x d) when influent COD concentration is below 2000 mg/L. When the influent COD concentration was increased to 9550 11,800 mg/L(acrylic acid of 6244 mg/L and p-toluenesulfonic acid of 1000 mg/L), the effluent COD was 271-360 mg/L, which satisfied the demand of Class III in Chinese Integrated Wastewater Discharge Standard (GB 8978-1996) at COD loading rates of 7.96-9.83 kg/(m3 x d). PMID- 21780596 TI - [Desorption behaviors of 4-nitrophenol on hyper-cross-linked polymer resin NDA 701]. AB - Desorption behaviors of loaded 4-nitrophenol (4-NP) on hyper-cross-linked polymer resin NDA-701 were studied. The molar ratio of NaOH and 4-NP desorbed (M(NAOH/4 NP)) selection experiments were carried out at two different reaction temperature(303 K and 333 K). Desorption kinetics characteristic of4-NP on NDA 701 in the batch and fixed-bed mode were examined at different reaction temperature and M(NaOH/4-NP) values. The results showed that optimal M(NaOH/4-NP) values were 1.2 and 100% 4-NP could be desorbed from NDA-701 at two different temperature. When the M(NaOH/4-NP) was lower than 1.2, the desorption efficiency increases with the increase of temperature, but the function of temperature decrease with increasing of M(NaH/4-NP) values for desorption ratio. The information indicated that desorption thermodynamic characteristic of NDA-701 was controlled by M(NaOH/4-NP) values. Desorption kinetics in the alkaline system can be well described by pseudo-second-order kinetic model, and desorption rate is increased with the increase of desorption temperatures, the k2 value increase from 0.010 g x (mmol x min)(-1) to 0.035 g x (mmol x min)(-1) when desorption temperature increase from 303 K to 333 K. Nevertheless, higher M(NaOH/4-NP) values could not promote desorption rate if only M(NaOH/4-NP) value was larger than the optimal molar ratio of NaOH and 4-NP. When M(NaOH/4-NP) values increase from 1.2 to 5.0, the k2 value increase from 0.038 g x (mmol x min)(-1) to 0.044 g x (mmol x min)(-1) merely at 333 K. the results indicated that desorption kinetic characteristic of NDA-701 was controlled by temperature. NDA-701 can be completely recovered using 2 times Bed Volume of 2% NaOH solution at the temperature of 333 K, comparing with field application, implying that more energy and cost can be saved in comparison with the actual desorption process in the industry. PMID- 21780597 TI - [Effect of sulfide to nitrate ratios on the strains coupling nitrogen removal from wastewater and hydrogen sulfide removal from biogas]. AB - Two strains Pseudomonas fluorescens and Pseudomonas aeruginosa were isolated from the reactors coupling nitrogen removal from wastewater and hydrogen sulfide removal from biogas. It was investigated that sulfide to nitrate ratios had effects on the simultaneous removal of sulfide and nitrate of the two strains under the conditions of pH 7.0, temperature 30 degrees C, anaerobic, cultured for 2 days. The results showed that the nitrate-nitrogen removal rate of Pseudomonas aeruginosa was higher than that of Pseudomonas fluorescens under the same conditions. The sulfide-sulfur removal rates of the two strains had little difference. The best molar n(S)/n(N) of sulfide and nitrate removal rates of Pseudomonas fluorescens and Pseudomonas aeruginosa were 5/2-5/3, 5/3-5/4, respectively. Pseudomonas fluorescens could transform NO3- -N into NO2-N fast, its principal NOx- -N not removed was NO2- -N, especially at the low initial concentration of NOx- -N. The NOx- -N not removed was NO3- -N by Pseudomonas aeruginosa. The best molar n(S)/n(N) of sulfur as reaction outcome of sulfide sulfur were 5/4, 5/3 by Pseudomonas fluorescens and Pseudomonas aeruginosa, respectively. PMID- 21780598 TI - [Study on toxicity of phenol to anaerobic granular sludge]. AB - To understand the toxicity of phenol to anaerobic granular sludge, the changes of specific methanogenic activity (SMA), extracellular polymeric substance (EPS) constituents and coenzyme F420 concentration of anaerobic granular sludge at various phenol concentrations were investigated. Meanwhile, Fourier transform infrared spectrometry was used to analyze the structure of EPS. The results show that the phenol has little effect on anaerobic granular sludge when the concentration of phenol is less than 100 mg/L. When the phenol concentration increases from 100 mg/L to 400 mg/L, the special methanogenic activity (SMA) decreases from 173.4 mL/(g x d) to 57.6 mL/(g x d), coenzyme F420 concentration decreases from 0.14 micromol/g to 0.08 micromol/g, and EPS concentration, which is represented by TOC, decreases from 33.1 mg/g to 15.0 mg/g, when the SMA and the concentration of coenzyme F420 and EPS in the blank test are 259.6 mL/(g x d), 0.154 micromol/g and 38.5 mg/g respectively. The analysis of molecular structure of EPS with Fourier transform infrared spectrometry shows that it has big effect on molecular structure of EPS when the phenol concentration is 800 mg/L. PMID- 21780599 TI - [Spatial and temporal variability of soil C/N ratio in Songnen Plain maize belt]. AB - The C/N ratio of soils is a sensitive indicator of soil quality, and an indicator for assessing carbon and nitrogen nutrition balance of soils. Its variation is significant in reflecting the carbon and nitrogen cycling of soils. Based on field investigation, sample collection and analysis, and application of geostatistics and GIS technology, spatial and temporal variation of C/N ratio was analyzed and studied from 1980 to 2005 in Songnen Plain maize belt. The results indicated that the mean value of C/N ratio is 10.56 and 12.30 in 1980 and 2005, respectively. Spatial correlation distance of soil C/N ratio in two periods is 196.3 km and 51.1 km, showing a decreasing trend, which indicated that farming management factors were enhancing. In the past 25 years, 84.88% of soil C/N ratio was on rise with the highest value in the west of the study area, but parts of Dehui County and Jiutai County decreased. As for different land use types, soil C/N ratios in the upland, paddy land, forest and woodland and grassland showed upward trends, with the highest increase from 10.03 +/- 1.12 in 1980 to 12.61 +/- 0.87 in 2005 in grassland and higher in upland and paddy land than the national average. The increasing soil C/N ratio illustrated that soil carbon increased faster than nitrogen. To maintain the steady growth of soil C/N ratio, it is suggested that the return of carbon be paid more attention when the input of nitrogen, such as incorporating crop residues into soil and inputting more organic fertilizers into soils for future farming practices. PMID- 21780600 TI - [Relationship between longevity and soil environment in Xiayi County, Henan Province, China]. AB - Based on field investigation and laboratory analysis, exploration was done of distribution of macro and micro elements in the soils and distribution of longevity population in Xiayi County, Henan Province, China, and relationship between the spatial variation of the distribution of soil elements and the distribution of the longevity population. It was found that longevity population was distributed in a belt running across Xiayi county from northeast to southwest. In the northeast part, the longevity rate (over 95 years old) reached 187 per million and while in the northwest part, it was only 83. The concentrations of heavy metals such as Cd, Cr, Cu, Ni, Pb, Zn in Xiayi soils were (0.177 +/- 0.057), (63.9 +/- 7.48), (23.6 +/- 5.63), (29.5 +/- 3.80), (21.8 +/- 3.37) and (64.80 +/- 8.81) mg x kg(-1), respectively, all up to the criteria for grade II soils in the National Standard for Soil Environment Quality of China; Moreover, the soils in longevous areas were rich in Cr, Zn, K and Mg. K and Mg in Xiayi soils were 1.30 and 1.79 as times as high as the background value of Henan Province and 1.21 and 2.62 times that of the country, respectively. In Liji, Huodian and Zhongfeng where the centenarian rate was relatively low, the soils were low in Cu, Se and Zn, but high in Na. The findings clearly indicate that the soil rich in Cr, Zn, K and Mg and free of any heavy metal pollution is a major contributor to the longevity in the area, while uneven distribution of Se, Zn, Cu and Na in the soil is the key factor affecting the distribution of longevity population in Xiayi County. PMID- 21780601 TI - [Chemical speciation of rare metals in three natural soils of China]. AB - Soil profile samples of isohumosol, primosol, and ferrosol were obtained in relatively clean areas of China. Concentrations and chemical speciation of rare metals [e.g., Ag (Silver), Bi (Bismuth), In (Indium) and Sn (Tin)] were determined, in which sequential extraction was used to fraction metals. Vertical distributions of elemental enrichment ratios (ERs) were used to study the anthropogenic influence. The mobility of metals was characterized by the sum of exchangeable form and carbonate-bound form. Average concentrations of Ag, Bi, In and Sn in the A horizon were (0.14 +/- 0.01), (0.49 +/- 0.09), (0.050 +/- 0.01), and (2.8 +/- 0.9) mg x kg(-1), respectively. The ERs were close to 1. Average distributions of metal speciation were: Ag, residual (65.8%) > H202-extractable organically bound (H2O2-Org) (25.9%) > Amorphous metal oxide-bound (am-MeOx) (4.2%) > Metal-organic complex-bound (Me-Org) approximately Crystalline Fe oxide bound (cr-FeOx) (2.0%); Bi, residual (29.2%) > H2O2-Org (27.1%) > cr-FeOx (22.7%) > am-MeOx (18.8%) > Me-Org (1.0%) > carbonate-bound (0.9%) > easily reducible metal oxide-bound (re-MeOx) (0.3%); In, residual (67.8%) > cr-FeOx (17.0%) > am MeOx (6.8%) > H2O2-Org (6.0%) > carbonate-bound (1.4%) > Me-Org (1.0%); Sn, residual (58.1%) > am-MeOx (23.0%) > cr-FeOx (15.6%) > H2O2-Org (1.8%) > Me-Org (1.1%) > exchangeable approximately carbonate-bound (0.2%). the results indicated that the exogenous elements enrichment was deficiency to minimal, and the concentrations of the rare metals were close to background values of soil in studied areas. Rare metals were stable in soils. The mobility of metals was in the order In > Bi > Sn > Ag. PMID- 21780602 TI - [Characteristics of heavy metal elements and their relationship with magnetic properties of river sediment from urban area in Lanzhou]. AB - The contents of As, Co, Cr, Cu, Ni, Pb, V and Zn in the surface sediments from 8 rivers in urban area in Lanzhou were monitored by ecological risk which was assessed by the potential ecological Hakanson index, and the index of geoaccumulation (Igeo), sediment enrichment factor (R), and environmental magnetism. The results showed that: (1) the potential ecological risk of heavy metals of As, Co, Ni, V in surface sediments from 8 rivers were low, which belonged to low ecological risk. But the risk of heave metals Cr, Pb, Zn in surface sediments from Yuer river was high, which belonged to middle ecological risk, and in downstream of Yuer river, the element of Cu belonged to high ecological risk. (2) The rivers in Lanzhou could be divided into four groups according to the heavy mental pollution degree: first type, such as Paihong river, Shier river, Yuer river and Shuimo river, called downstream concentrate type; second type, such as Qili river, called upstream concentrate type; third type, such as Luoguo river and Dasha river, called less affected type; fourth type, Lanni river, which polluted heavily in up and downstream; (3) The correlation analysis between magnetic parameters and element contents show that the parameters which mainly reflect the concentration of the magnetic minerals (X, SIRM, Ms) have close association with Cr, Ni, Pb, Zn, Cu, So we can infer that the magnetic minerals in deposits samples mainly came from electroplating effluent, motor vehicle emission, and domestic sewage. SIRM/X shows a strong correlation with Cr, Ni, Pb, Zn, indicating the distribution of anthropogenic particulates. (4) The magnetic minerals(X, SIRM, Ms) have a strong correlation with the geoaccumulation (Igeo) than potential ecological risk index and enrichment factor (R). These results suggest a possible approach for source identification of magnetic material in pollution studies and the validity of using magnetic measurements to mapping the polluted area. PMID- 21780603 TI - [Spatial distribution and environmental risk of As and Pb from street dust in non ferrous metals smelting areas]. AB - ArcGIS analysis was applied to study the content level and the spatial distribution characteristics of As and Pb in street dust of Huludao city. Geoaccumulation Indexes and Potential Ecological Risk Index technique were applied to assess the ecological risk of As and Ph. The average contents of As and Pb were 33.10 mg x kg(-1) and 533.2 mg x kg(-1), which was 4 and 25 times as high as the background value respectively. The trends for Pb and As were similar with higher concentrations near Huludao Zinc Plant (HZP). The ecological risk of As and Pb contamination in street dust were serious, and the accumulation of Pb in street dust was higher than the As. PMID- 21780604 TI - [Immobilization of heavy metal Pb2+ with geopolymer]. AB - A series of geopolymers were synthesized by mixing metakaolinite, water glass, sodium hydroxide and water, and the lead ion solidification experiments were performed with the geopolymer. Then, the immobilization efficiency was characterized by monitoring the leaching concentration and compressive strength of solidified products. Additionally, the structure and properties of the solidified products were studied by X-ray diffraction (XRD), scan electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Furthermore, based on the analysis of immobilization efficiency, microstructure and mineral structure, the difference between geopolymer and cement on the performance of immobilizing heavy metals was discussed. The results of lead ion immobilization experiments showed that over 99.7% of heavy metal was captured by the geopolymer as the doping concentration of lead ion was less than 3%. Meanwhile, the compressive strength of the solidified product ranged from 40 MPa to 50 MPa. Furthermore, by using the same Pb2+ concentration, the geopolymer showed higher compressive strength and lower leaching concentration compared to the cement. Because lead ion participated in constitution of structure of geopolymer, or Pb2+ was adsorbed by the aluminium ions on the geopolymeric skeleton and held in geopolymer. However, cement mainly solidified lead ion by physical encapsulation and adsorption mechanism. Therefore, both from the compressive strength and leaching concentration and from the microstructure characterization as well as the mechanism of the geopolymerization reaction, the geopolymer has more advantages in immobilizing Pb2+ than the cement. PMID- 21780605 TI - [Removal of volatile organic compounds in soils by soil vapor extraction (SVE)]. AB - An experiment study has been carried out to investigate effects of the diameter of soil columns, the size of soil particulate and different contaminants on efficiency of simulated soil vapor extraction (SVE). Experiments with benzene, toluene, ethylbenzene and n-propylbenzene contaminated soils showed that larger bottom area/soil height (S/H) of the columns led to higher efficiency on removal of contaminants. Experiments with contaminated soils of different particulate size showed that the efficiency of SVE decreased with increases in soil particulate size, from 10 mesh to between 20 mesh and 40 mesh and removal of contaminants in soils became more difficult. Experiments with contaminated soils under different ventilation rates suggested that soil vapor extraction at a ventilation rate of 0.10 L x min(-1) can roughly remove most contaminants from the soils. Decreasing of contaminants in soils entered tailing stages after 12 h, 18 h and 48 h for benzene, toluene and ethylbenzene, respectively. Removal rate of TVOCs (Total VOCs) reached a level as high as 99.52%. The results of the experiment have indicated that molecule structure and properties of the VOCs are also important factors which have effects on removal rates of the contaminants. Increases in carbon number on the benzene ring, decreases in vapor pressure and volatile capability resulted in higher difficulties in soil decontamination. n propylbenzene has a lower vapor pressure than toluene and ethylbenzene which led to a significant retard effect on desorption and volatilization of benzene and ethylbenzene. PMID- 21780606 TI - [Dynamic changes of physicochemical properties in phenanthrene-contaminated soil under wheat and clover intercropping]. AB - Soil physicochemical properties play an important role in the efficiency of phytoremediation and soil arability after phytoremediation. Soil pot experiments were conducted to investigate the dynamic changes of physicochemical properties in phenanthrene (a representative of polycyclic aromatic hydrocarbons) contaminated soil under wheat and clover intercropping. The results showed that plants improved the pH values of phenanthrene-polluted soil with a maximum variation pH of 0.61. The difference in pH between wheat/clover intercropping and wheat/clover single cropping was not significant. Soil organic matter, total nitrogen, available nitrogen, total phosphorus, available phosphorus, cation exchange capacity and available potassium decreased over the experiment period due to biodecomposition and plant root absorption. The intercropping of wheat and alfalfa accelerated the consumption of the above-mentioned nutrients. And the decrease percentages ranged from 5.24% to 57.85%, more than those of wheat or alfalfa only planted with decrease percentages between 6.29% and 39.09%. In particular, soil available nitrogen and availiable phosphorus decreased more than the other nutrients with a maximum reduction percentage of 57.85%. Therefore, the application of nitrogen and phosphorus must be paid more attention during phytoremediation of polycyclic aromatic hydrocarbon-contaminated soil in the wheat and alfalfa intercropping system. PMID- 21780607 TI - [Biological responses of maize seedlings to single and combined stress of cadmium and phenanthrene]. AB - Maize (Zea mays L.) pot-culture experiments were conducted in this study for exploring the biological responses of maize seedlings to single and joint stress of Cadmium (Cd) and phenanthrene. The results showed that single-Cd treatment with Cd concentration ranging from 0 to 50 mg/kg had no significant influences on the above-ground biomass, root biomass, and the soluble protein of maize seedlings; with the increase of Cd concentrations, the maize leaf SOD activities appeared as an increasing-decreasing trend, while the POD, CAT, APX activities increased persistently. The APX is very sensitive to Cd stress, which increased 38% than control treatment at lower Cd treatment (1 mg/kg). The accumulation of O2-* is one of the main cause of single-Cd toxicity. Under the Cd-phenanthren combined stress, the SOD activity increased at lower Cd concentration (1 mg/kg) , which can reached to 1.66 times of control treatment, and decreased when Cd concentration becomes high. The SOD activity is a sensitive index in response to the Cd-phenanthren combined pollution. Unlike SOD activity, the activities of POD, CAT and APX were obviously induced by combined pollution of Cd and phenanthren; but these enzyme activities decreased when compared with the single Cd stress, which suggested that the combined toxicity of Cd and phenanthrene is stronger than the single-Cd stress. And the accumulation of O2-* and *OH is one of the main cause of Cd-phenanthrene combined toxicity. PMID- 21780608 TI - [Ecotoxicity of synthetical musks on wheat (Triticum aestivum) based on seed germination]. AB - With soil culture the ecotoxicological effects of galaxolide (HHCB) and tonalide (AHTN) on the germination of wheat (Triticum aestivum) seeds were investigated. And the influence of these two synthetical musks on the wheat germination rate, inhibition rate of root elongation and inhibition rate of shoot elongation were studied. The results showed that there were no obvious dose-effect relationship between wheat germination rate and concentrations of these two synthetical musks. Lower dose (HHCB < or = 150 mg x kg(-1), AHTN < or = 200 mg x kg(-1)) could accelerate the germination of wheat. Under the test concentrations of synthetical musks, the wheat germination rates treated with HHCB and AHTN were 77.78%-95.56% and 84.44%-97.78%, respectively. There were good dose-effect relationship between inhibition rate of root elongation (or inhibition rate of shoot elongation) and synthetical musks concentrations. The EC50 of HHCB and AHTN based on shoot were 155.84 mg x kg(-1) and 290.58 mg x kg(-1), and were 215.66 mg x kg(-1) and 323.10 mg x kg(-1) based on root from linear model. The EC50 of wheat sensitive positions showed that the toxicity of HHCB was stronger than AHTN. PMID- 21780609 TI - [Bioconcentration and translocation of Cu and Zn by Brassica sinensis L. planted in high Cu and Zn contaminated pig manure-applied soils]. AB - In recent years, Cu and Zn have been widely used in pig fodders in large-scale animal feeding, causing Cu and Zn contamination in soils and effecting plants in land application of pig manure. It is of great concern to the world that pig manure is used in the dose greater than the organic fertilizer criterion. It is very important to clarify bioconcentration and translocation of Cu and Zn in vegetables in order to assess human health risk of these heavy metals accumulated in soil and to safely produce vegetables. Bioconcentration and translocation of Cu and Zn by Brassica sinensis L. planted in pig manure-applied soils were studied using pot experiments. Pig manure with great concentrations of Cu and Zn (Cu = 1114.7 mg x kg(-1), Zn = 1496.8 mg x kg(-1)) were applied to soils at six rates, i.e., 0, 25, 50, 100, 200 and 500 t x hm(-2). The results indicate that the concentration of Zn was greater than that of Cu in both aboveground and underground parts of B. sinensis. Both Cu and Zn concentrations in the underground part were greater than those in upper-ground for every treatment. There were significant differences for both Cu and Zn concentrations in shoots between CK and the treatment with application rate above 50 t x hm(-2). Bioconcentration factor of Cu in B. sinensis increased with pig manure application rate from 0.11 to 0.17, while that of Zn decreased from 0.47 to 0.11. The proportion of Cu and Zn transported from roots to shoots decreased 25% and 38% with the increase of pig manure application, respectively. It indicates that pig manure application can reduce bioconcentration of Zn in B. sinensis, and build up Cu accumulation which leads to human health risk. The ratio of Zn:Cu in every part of B. sinensis decreased with manure application rate increment. This result prompted that uptake and translocation capacity discrepancy of Cu and Zn decreased with manure application rate increment in B. sinensis. PMID- 21780610 TI - [Effect of long-term application of nitrogen fertilizer on the diversity of nitrifying genes (amoA and hao) in paddy soil]. AB - The aim of this study was to determine the effect of long-term (16 years) application of nitrogen fertilizer on the diversity of nitrifying genes (amoA and hao) in paddy soil on the basis of long-term paddy field experimental station (started in 1990) located in Taoyuan, with the molecular approaches of PCR, constructing libraries and sequencing. The fertilizer was urea and no fertilizer was as control. The Shannon index showed that long-term application of nitrogen fertilizer made the diversity of amoA gene descend while no effect on the diversity of hao gene. The LIBSHUFF statistical analyses demonstrated that both amoA and hao libraries of CK and N treatments were significantly different from each other and the rarefaction curves of libraries failed to meet the plateaus indicating that there were lots kinds of genes haven't been detected. The results of blasting with GenBank and the phylogenetic tree showed that the amoA genes detected in our study had a similarity with the uncultured gene of amoA, which showed some similar to Nitrosospira. Otherwise, the hao genes cloned showed a relationship to the genes of cultured bacteria such as Silicibacteria, Nitrosospira and Methylococcus, and the hao genes found in the N treatment dominated in alpha-Proteobacteria. These results suggest that long-term fertilization of nitrogen had significant impacts on the diversity or community of amoA and hao genes. PMID- 21780611 TI - [Diversity and bacteria community structure of activated carbon used in advanced drinking water treatment]. AB - Two granular activated carbon (GAC) samples with 1.5 a and 5 a age were collected, Bacterial genome DNA was extracted for the 16S rDNA gene amplification, and then a bacterial 16S rDNA gene clone library was constructed. After the phylogenetic analysis of 16S rDNA sequences, bacterial diversity and community structure of two activated carbon biofilm sample were studied. The results showed the bacteria in GAC with 5 a age could be divided into 11 groups, which were as follows alpha-Proteobacteria (26.5%), beta-Proteobacteria (16.3%), delta-Proteobacteria (16.3%), Planctomycetes (12.2%), Gemmatimonadetes (6.1%), Acidobacteria (4.1%), Nitrospira (2.0%), gamma-Proteobacteria (2.0%), Bacteroidetes (2.0%), Actinobacteria (2.0%), Unclassified Bacteria (10.2%). The bacteria in GAC with 1.5 a age could be divided into 10 groups, which were as follows alpha-Proteobacteria (21.6%), Planctomycetes( 10.8%), Bacteroidetes (10.8%), beta-Proteobacteria (9.0%), Acidobacteria (9.0%), Nitrospira (7.2%), detla-Proteobacteria (7.2%), Unclassified Proteobacteria (5.4%), Gemmatimonadetes (3.6%), Unclassified Bacteria (14.4%). The results revealed a variety of bacterial divisions on the studied GAC biofilm. Proteobacteria had the highest share in the two total clones, and alpha- and beta-Proteobacteria were on a dominant position. A relatively high proportion of delta-Proteobacteria was observed in the biofilm of GAC with 5 a age, and Nitrospira was in a minor proportion. However, a totally converse condition appeared in GAC with 1.5 a age. Two pathogenic bacteria, Afipia and Chryseobacterium, were detected in analyzed GACs, which implies a potential microbial risk in water supply. PMID- 21780612 TI - [Evaluation and choice of PCR-DGGE primers in analyzing the microbial community structure of activated sludge in traditional Chinese medicine wastewater]. AB - In the study of traditional Chinese medicine wastewater, it was discussed for the effect of different sets of 16S rDNA universal primers on DGGE fingerprinting and microbial community diversity of aerobic and anaerobic activated sludge from one traditional Chinese medicine wastewater treatment. The genome DNA of activated sludge was isolated, and eleven sets of primers were used to amplify the four variable regions of 16S rDNA, the resolution of DGGE fingerprinting and community diversity was analyzed. The results indicated that community diversity with different sets of universal primers by DGGE was obviously different. Separated patterns of the V3 and V6-V8 regions were better than of V1-V3 and V3-V5. In the DGGE profiles, bands and diversity from V3 were most, bands and diversity from V3 V5 and V6-V8 were a little worse than those of V3. According to the length of targeted sequence and the resolution of DGGE fingerprinting, V6-V8 (B968F/B1401R) are recommended to be used to do the DGGE analysis. Mix I341F/I534R and B341F/B534R PCR product equally to make DGGE analysis can get more community diversity information. PMID- 21780613 TI - [Biodegradation of methyl tert-butyl ether by stabilized immobilized Methylibium petroleiphilum PM1 cells and its biodegradation kinetics analysis]. AB - Methylibium petroleiphilum PM1, which is capable of degrading methyl tert-butyl ether (MTBE) , was immobilized in calcium alginate gel beads. Several methods were explored to increase the strength of these gel beads. The central composite design analysis indicated that the introduction of 0.2 mol x L(-1) Ca2+ into the crosslinking solution, 1.38 mmol x L(-1) Ca2+ into the growth medium and 0.1% polyethyleneimine (PEI) as the chemical crosslinking agent could increase the stability of the Ca-alginate gel beads with no loss of biodegradation activity. The stabilized immobilized cells could be used 400 h continuously with no breakage and no bioactivity loss. Examination of scanning electron microscope demonstrated that a membrane surrounding the gel beads was formed and the cells could grow and breed well in the stabilized calcium alginate gel beads. Kinetic analysis of the gel bead-degradation indicated that the rate-limiting step was biochemical process instead of intraparticle diffusion process. The diameter of 3 mm affected the biodegradability less while high concentration of PEI induced much more serious mass transfer restraint. PMID- 21780614 TI - [Isolation and identification of imazethapyr degradable actinomyces S181 and its degradation characteristics]. AB - A selection of actinomyces that could degrade imazethapyr was conducted to provide actinomyces source for bioremediation of soil contaminated by imazethapyr. A strain of actinomyces was isolated from the samples of soil where imazethapyr had been applied for a long-term by use of bottle enriched culture and named S181. The strain had strong ability to degrade imazethapyr and could grow using mazethapyr as the sole nitrogen. The strain was related and shared characteristics to genus Streptomyces omiyaensis according to the physiological and biochemical properties as well as 16S rRNA sequence analysis. The influencing factors (temperature, pH, concentration and inoculum) were studied with fungus growth mass and degradation ratio as indexes. The results showed that the optimal degradation ratio occurred at the condition of inoculation ratio of 3%, 200 mg x L(-1) imazethapyr, at 30 degrees C and pH 7.0. Under these conditions, 84% imazethapyr had been degraded by S181 in medium Gao 1 without nitrogen after 5 days. PMID- 21780615 TI - [Influence of buffer solutions on the performance of microbial fuel cell electricity generation]. AB - Microbial fuel cell (MFC) is a potential green technology due to its application in wastewater treatment and renewable energy generation. Phosphate buffer solution (PBS) has been commonly used in MFC studies to maintain a suitable pH for electricity generating bacteria and/or to increase the solution conductivity. However, it has some drawbacks using PBS in MFC: One is that the addition of a high concentration of phosphate buffer in MFCs is expensive, especially for the application in wastewater treatment; the other is that phosphates can contribute to the eutrophication conditions of water bodies if the effluents are discharged without the removal of phosphates. By adding PBS buffer as the comparison, the study investigated the effect of borax buffer and in the absence of buffer on the performance of electrical power, coulomb efficiency and effluent pH. 200 mmol/L PBS was the best, conductivity was 1.973 mS/cm,the maximum power density was 36.4 mW/m2 and the maximum coulomb efficiency was 2.92%, effluent pH was almost at (7.00 +/- 0.05). 100 mmol/L borax buffer solution, conductivity was 1.553 mS/cm; the maximum power density was 26.2 mW/m2 coulomb efficiency of 6.26%, which was 2.14 times to PBS and greatly increased the electron recovery efficiency with the effluent pH was (7.35 +/- 0.05). While free buffer solution conductivity was 0.314 mS/cm, maximum power density was 27.64 mW/m2; coulomb efficiency was 2.82% and the effluent pH of approximately 7.43. The electrolyte which in absence of buffer solution conductivity was 1/6 of adding PBS buffer, 1/5 of borax buffer, while its power density lower 8.76 mW/mr2 than adding PBS and higher 1.24 mW/m2 than borax buffer. The results showed that adding the suitable concentration of borax buffer may improve the electron recovery efficiency and under batch conditions, MFC run successfully without adding buffer solution to MFC. PMID- 21780616 TI - [Eco-efficiency of Jiaozuo industry sectors]. AB - Jiaozuo city was taken as a representative industry city and its industry energy consumption and industry emissions such as wastewater,solid waste, SO2, dust and so on were selected as corresponding environmental loads. The contribution rate to the environmental loads and eco-efficiencies of Jiaozuo industry sectors were analyzed quantitatively. The results show that, the industry sector with the highest energy eco-efficiency is Mining and Processing of Ferrous Metal Ores (FMM), 43.19 x 10(4) yuan x tce(-1), and its contribution rate is 0.003%; the one with the highest wastewater-related eco-efficiency is Manufacture of Transport Equipment (TRM), 3.58 x 10(4) yuan x t(-1), and its contribution rate is 0.0001%; the one with the highest solid waste-related eco-efficiency is Manufacture of Special Purpose Machinery( SMM), 323.22 x 10(4) yuan x t(-1), and its contribution rate is 0.005%; the one with the highest SO2 emission-related eco efficiency is Manufacture of Special Purpose Machinery (SMM), 19.74 x 10(4) yuan x kg(-1), and its contribution rate is 0.0001%; the one with the highest dust emission-related eco-efficiency is Manufacture of Rubber (RUM), 6.75 x 10(4) yuan x kg(-1), and its contribution rate is 0.001%. It can be seen that the industry sector with high value of eco-efficiency always contributes less to its environmental load, which results that the industry sectors with high eco efficiencies only play a weak role in leading the overall industry eco efficiency. A succinct distance index (SDI) was proposed to estimate the differences between Jiaozuo and China average for their eco-efficiency of every industrial sector. The values of SDI range from -1 to 63.45, and the absolute value of SDI with positive value is much greater than that with negative value, which indicates that the values of eco-efficiencies for the advanced industry sectors of Jiaozuo city are much higher than those for China's industry sectors average. PMID- 21780617 TI - [Increasing efficacy of recanalization of infarction-associated coronary artery by means of pharmacological agent imitating pre- and postconditioning phenomenon (review of literature)]. AB - Analyzing the literature data shows that the formation of the necrosis focus in patients presenting with acute myocardial infarction (AMI) is mainly completed within 2-4 hours from the moment of the development of coronary thrombosis. A positive effect of throm bolytic therapy and coronary angioplasty observed at later terms is apparently associated with restoration ofcoronaryperfusion in the periinfarction zone. The protecting effect of adenosine in acute myocardial infarction (AMI) does not probably depend upon the size of the infarction focus but is due to decreased incidence of the development of the no-reflow phenomenon. The protective effect on nicotinamide seen in patients with AMI is probably associated with improved coronary perfusion in the periinfarction zone. Opioids and cannabioids imitate the pre- and postconditioning phenomenon. Hence, these compounds after cl employed in comprehensive therapy ofAMI. PMID- 21780618 TI - [Metabolic and surgical predictors of restenoses and thromboses of biological grafts in the infrainguinal position]. AB - The present study was aimed at revealing metabolic and surgical predictors of restenoses and thromboses of biological grafts "KemAngioprosthesis" in the infrainguinal position in the remote postoperative period. A total of 65patients (54.2% of the whole group) with primarily functioning bioprostheses underwent dispensary follow-up (consisting of comprehensive analysis of the haemostasis system, blood plasma lipid spectrum, findings of duplex scanning of the prosthesis and anastomosis zones). Based on the laboratory findings (fibrinogen, index of atherogenicity, cholesterol), the patients were subdivided into two groups: Group One (n=27) consisted ofpatients with normal values, and Group Two (n=38) was composed of those with one or more parameters exceeding the norm. Fifteen Group Two patients were found to have stenoses of the anastomosis zones. Based on the results ofthe study we determined a clear relationship between the development of complications and impairments in the system of haemostasis and lipid metabolism. All patients from Group Two whose the remote postoperative period was complicated by stenoses of anastomoses showed hypercholesterolemia, dyslipidemia, and platelet hyperaggregation, regardless of the terms of the development of the complication. Once stenoses developed within 3-to-18 months postoperatively, the levels offibrinogen and soluble fibrin monomeric complexes were elevated. Analysing surgical predictors of restenoses showed that the technique of establishing either an "end-to-end-" or "end-to-side" anastomosis exerted no influence on the incidence rate of restenoses in the remote postoperative period. PMID- 21780619 TI - [Role of the infection and inflammation in atherosclerosis development (literature review)]. AB - ecent researches have shown that the atherosclerosis is a chronic inflammatory disease. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Inflammatory and immune mechanisms, employing monocytes, innate receptors, cytokines are suggested to be involved in atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs). TLRs are expressed in the cardiovascular system and could thus be a key link between cardiovascular diseases and the immune system. Stimulation ofthese receptors results in the activation of a diversity of intracellular signal transduction pathways and the production of pro-inflammatory cytokines, which ultimately can contribute to atherosclerotic lesion development. Thus, bacterial endotoxin is a potential source of vascular inflammation and may be an important risk factor for atherosclerosis. Many prospective studies have shown independent associations between myocardial infarction and C-reactive protein, interleukin-6, fibrinogen, von Willebrandfactor, fibrin D-dimerand tissue plasminogen activator antigen. Numerous researches antiinflammatory therapies at an atherosclerosis, are inconsistent enough, however they allow to hope for success, in preventive maintenance and treatment cardiovascular events. PMID- 21780620 TI - [Assessing the prognostic significance of morphometric parameters of vascular wall inflammation for remote results of reconstructive operations in the aortoiliac zone in patients with atherosclerosis obliterans]. AB - The study was aimed at assessing the relationship between the activity (including the inflammatory one) of the atherosclerotic process in the zone ofarterial reconstruction in patients under-going surgery on the aortoiliac arterial segment and long-term thrombotic reocclusions. The study comprised a total offorty-nine patients, with the postoperative follow-up period amounting to 5 years. We carried out morphological studies of the aortic wall in the zone of the proximal anastomosis and the walls of the common femoral arteries in the zone of distal anastomoses. It was determined that the presence of morphometric sign of inflammation and atherosclerotic deformity in the preparations of the aortic and arterial walls was accompanied and followed by increased incidence of long-term thrombotic complications in the reconstruction zone with more pronounced progression of the thrombotic process in the arteries of the peripheral bed distal to the reconstruction site. PMID- 21780621 TI - Importance of the arterial pressure value for doppler assessment of carotid stenoses. AB - Many centres appear to perform carotid endarterectomy solely based on the findings of duplex scanning. There are two fundamental methods aimed at assessing the stenosis degree during an altrasonographic study, i. e., planimetric examination and Doppler altrasonography. Doppler ultrasonographic criteria have an independentsignificance when the assessment of the stenosis degree in the ultruasonographic B-mode is complicated. However, the currently available guidelines on haemodynamic assessment of the stenosis degree are solely based on the parameters of local blood flow without taking into consideration the state of central haemodynamics. The present study has shown that blood flow in the region ofstenosis of the internal carotid arteries (ICAs) depends not only on the stenosis degree but on the value of systemic arterial pressure (AP) at examination. Based on the obtained findings, we worked out Doppler ultrasonographic criteria for ICA stenosis degree "by the area" corrected for the value of systemic AP. It was determined that using pulse AP increases their prognostic eficiency. PMID- 21780622 TI - [Annual Congress of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE - 2010) September 2nd-6th, 2010 Valencia, Spain]. AB - The article reviews the materials presented at the Annual Congress of the Cardiovascular and Interventional Radiological Society of Europe held on September 2"-6'", 2010 in Valencia, Spain. The participants discussed the basic results of research studies on such currently important trends of interventional radiology as carotid stenting, transcatheter embolization, endovascular prosthetic repair of the aorta and its branches, angioplasty of the crural arteries in diabetic foot syndrome, prevention of pulmonary artery thromboembolism, peripheral interventions on lower-limb arteries, interventions on biliary ducts in mechanical jaundice, transjugular intrahepatic stenting, embolization of uterine arteries in uterine myoma, venous interventions, etc. PMID- 21780623 TI - [Effect of revascularization of on therapeutic outcomes of treatment for lower limb chronic critical ischaemia in neuroischaemic form of diabetic foot syndrome]. AB - The article deals with diabetic foot syndrome defined as a multidisciplinary problem. A reconstructive vascular operation in critical ischaemia on the background of diabetic foot syndrome is herein shown to be an efficient and justified intervention. Revascularization makes it possible to carry out sparing resections on the foot, to appropriately cope with the events of lower-limb critical ischaemia, and to reliably decrease the rate of high amputations. PMID- 21780624 TI - [Comparative characteristics of the open and endovascular methods of treatment for carotid artery stenoses]. AB - The article is dedicated to the problem concerning treatment for stenoses of the extracranial portions of carotid arteries. From March 2004 to November 2009 at the Department of Vascular Surgery No 2 of the N. A. Semashko Central Clinical Hospital No 2 we treated a total of 364 patients presenting with stenotic lesions of the extracranial portion of the carotid arteries. Of these, 176 patients underwent revascularization of the carotid basin: 120 patients endured open carotid endarterectomy (CEAE), 56 patients sustained carotid angioplasty and stenting (CAS), with a total of 128 CEAE and 67 CAS interventions performed. The following conclusion was made: with high skill of surgeons and broad experience in carrying out revascularization of the carotid basin, the CEAE and CAS procedures possess comparable efficacy and safety with CEAE possessing reliable advantage in terms of the parameters of the patient's quality of life. PMID- 21780625 TI - [Improving recanalization of deep veins and the "outcomes" of venous thromboembolic complications in prolonged therapy with enoxaparin]. AB - OBJECTIVE: The study was aimed at comparing efficacy and safety of two diferent approaches to initial anticoagulant therapy: a standard approach (non fractionated heparin [NFH]for not less than 5 days followed by changing over to warfarin) and an alternative one, i. e., prolongation of treatment with therapeutic doses of enoxaparinfor up to one month with switching to warfarin, also assessing the effect of initial anticoagulant therapy on the "outcomes" of venous thromboembolic complications (VTECs) during 12 months of treatment. MATERIAL AND METHODS: We followed up a total ofone hundred and eleven patients after endured episodes of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE). Group One patients (n=80) received the standard therapy (NFH for not less than 5 days followed by changing over to warfarin). For Group Two patients (n=31), NFH was replaced by therapeutic doses of enoxaparin (1 mg/kg each 12 hours) for at least 30 days, with the patients then transferred to warfarin according to the standard regimen. Ultrasonographic duplex scanning of limb vessels was performed at baseline, 1, 3, 6 and 12 months after initiation of therapy. The patients were followed up for 12months. The following end points were taken into account: DVT/PATE relapses, haemorrhagic complications. RESULTS: Improved patency ofdeep veins one month after initiation of treatment was observed in the both groups, however efficacy of enoxaparin turned out to be superior to that of the standard therapy in relation to a decreased number of occlusive thrombosis of veins - 9 versus 41 (p=0.005). Commencing from month two of treatment patients from the both groups began taking warfarin, however the number of occlusive thromboses of deep veins during 12 months of treatment was considerably lower as compared with that in the enoxaparin group, i. e. I versus 21 (p=0.013) after 3 months; with 1 vs 11 (p=0.009) after 6 months, and 0 vs 8 (p=0.013) after 12 months. The rate of DVT relapses and haemorrhagic complications during the first month of treatment was similar in the both groups. Startingfrom month two of therapy there were no DVT relapses in the enoxaparin group. Conclusions. Enoxaparin within the first month of treatment in patients having developed VTEC, with similar DVT complication rate, appeared to be superior to the standard therapy with NFH and warfarin in achieving recanalization of occlusively thrombosed veins, with its advantages in improving patency of deep veins preserving within 12 months. The use of enoxaparin was also associated with lower rate of DVT relapses during 12 months of treatment. PMID- 21780626 TI - [First experience in stenting iliofemoral segment veins]. AB - The authors share herein their first experience gained in stenting for stenosing and occlusive lesions of the iliac-femoral segment veins, reporting the outcomes of treating a total of thirteen patients subjected to balloon angioplasty and stenting of iliac veins for chronic venous obstruction. While treating non thrombotic venous lesions, stenting was successfully performed in 100% of the patients concerned. Inpost-thrombotic lesions therapeutic outcomes were successful in 9 (75%) patients. No immediate postoperative complications were observed. The remote results were followed up in eleven out of the 13 patients. Patency within the terms up to 16 months amounted to 81.1%. Clinical improvement was noted in 12 (92.3%) patients. According to the VCSS scale, there was a reliable decrease in the intensity of chronic venous insufficiency manifestations along all parameters. The integral index decreased from 6.56+/-0.71 to 4.45+/ 0.65 (t=3.82, p<0.002). The malleolar volume decreased from 275.3+/-6.7 to 241.6+/-6.1mm (t=12.3, p<0.001). Hence, angioplasty and stent-grafting of iliofemoral veins turned out to be a minimally invasive, safe, and highly efficient therapeutic modality. The efficacy of the procedure was confirmed by a considerable improvement of the limb's condition and good remote results concerning patency of the reconstructed segments of the venous bed. Endovascular methods may be considered as a promising modality of treatment for this patient cohort. PMID- 21780627 TI - [Regional venous hypertension as a factor of compensation for microcirculatory impairments in chronic obliterating diseases of lower-limb arteries (state of the art)]. AB - A thorough analysis of the literature and own data confirmed a lively interest of vascularsurgeons in alterations in venous haemodynamics in patients presenting with chronic obliterating diseases oflower-limb arteries. The presence of close relationships between impaired arterial and venous blood flow and a compensatory pattern of the development of venous hypertension in the ischaemia zone was proved. This should be taken into consideration during conservative therapy of patients sufferingfrom chronic obliterating diseases of lower-limb arteries, and while working out novel types of surgical interventions, as well as for more adequate interpretation of pathophysiological peculiarities of the existing disease. PMID- 21780628 TI - [Assessment of brain protection by means of cerebral oximetry incarotid endarterectomy]. AB - Presented herein are the results of cerebral oximetry in the assessment of the indication for brain protection during operations of carotid endarterectomy in a total of forty-eight patients presenting with carotid artery stenoses. It was determined that cerebral oximetry gives an insight into the degree of efficacy of the collateral blood flow along both hemispheres, and by virtue of its integral approach to the assessment of cerebral blood flow is an important criterion in determining the indications for brain protection during carotid endarterectomy. PMID- 21780629 TI - [Neurological status and quality of life in patients with degree IV chronic cerebral ischaemia after endured carotid endarterectomy]. AB - The study was aimed at evaluating the dynamics of the neurological status and quality of life (QOL) in patients after endured carotid endarterectomy (CEA) with previously sustained ischaemic stroke (IS). MATERIALS AND METHODS: At the Department of Vascular Surgery of the B. V. Petrovsky Russian Research Centre of Surgery under the Russian Academy of Medical Sciences, from 2001 to 2009 we treated a total of ninety-six patients after endured IS. CEA was performed in fifty-one patients (Group I), and the control group patients underwent conservative treatment (Group II). QOL was assessed by means of the Medical Outcomes Study Short Form - 36 (SF-36) questionnaire and the Bartel scale (predominantly in order to determine life activity). Initially, patients from the both groups had had equally low baseline QOL scores. After one year we carried out a repeat survey using the same SF-36, Bartel scale, and examination by the neurologist. Relapses of cerebral circulatory impairments were registered in two (3.9%) Group I patients and in three (6.6%) Group II subjects (p>0.05). Total mortality rate in Group I amounted to 1 (1.9%) case and in Group II - 2 (4.4%) lethal cases (p>0.05). According to the findings of the SF-36 questionnaire, restoration of the lostfunctions was observed in eleven (22%) Group I patients and in five (11.6%) Group II patients. Partial restoration was seen in seventeen (34%) Group I patients and in twelve (27.9%) Group H subjects. The neurological status was noted to have preserved in twenty- three (46%) Group I patients and in twenty-six (60.5%) Group II patients (p>0.05). Both in Group I and Group II patients, positive dynamics of the neurological status was observed among those being in the early restoration period (p<0.05). CONCLUSION: CEA performed in the early restoration period in patients with endured IS appeared to promote improved neurological status, extending physical activity, improving QOL, and is thus an efficient means of preventing relapses of cerebrovascular circulatory impairments. PMID- 21780630 TI - [Experience with a fresh aortic homograft employed in a patient with acute dissection of the ascending portion of the aorta and Marfan syndrome]. AB - The article deals with a case report concerning successful implantation of a fresh aortic homograft for correction of a life-threatening complication of Marfan syndrome, i.e., acute dissection of the ascending portion of the aorta, accompanied and followed by discussing possibilities and prospects of using homografts in cardiosurgical practice and the problems encountered by multimodality-hospital services in the settings of yet increasing widening expanding use of donor organs and tissues. PMID- 21780631 TI - [Objective criteria for the invasive nature of a mini-approach in aortofemoral reconstructions. A prospective study]. AB - The authors carried out a prospective study of the invasive nature ofaortofemoral reconstruction performed via the standard routine laparotomy (StLT, Group I, n 10) and minilaparotomy (MLT, Group II, n = 10). It was determined that the objective criteria for the invasive degree of the intervention were less pronounced in the group of the patients operated on through the MLT, with the main differences manifesting themselves to a greater extent in the early postoperative period. Despite statistically significant differences of the creatinphosphokinase (CPK) level as a marker of a parietal injury (562 U/I in Group 1, 243 U/I in Group II, P = 0.005), the concentration of Cortisol increased dramatically during the operation (by 288 and 162%, respectively) with a statistically insignificant deference between the groups (P = 0.08). Alterations in the vegetative status (determined by cardiointervalography) in the intraoperative period were ofa variously directed variable character, not differing between the groups. However, normalization ofthese parameters in the postoperative period occurred more rapidly in MLT. Group IH patients were noted to restore earlier the function of the gastrointestinal trapt with a less pronounced pain syndrome tested by the visual analogue scale, especially on postoperative days 2 and 4 (p<0.01 and. Hence, reconstruction of the infrarenal aorta through the MLT is characterized by a lesser invasive nature, with the above mentioned differences being more pronounced in the early postoperative period, since the main intraoperative factors of the invasion depend to a lesser extent on the approach size. PMID- 21780632 TI - [Experience with thoracoscopic sympathectomy in distal lesions of lower-limb arteries]. AB - We studied the results outcomes of thoracoscopic sympathectomy in 107patients with distal lesions of lower-limb arteries. The best results in the early postoperative period were observed in patients with Raynaud's disease and syndrome, reaching 100% efficacy. Due to implementation of novelties, we managed to preserve the efficiency of sympathectomy in 90% of patients with this pathology in the remote period. In patients with obliterating endarteritis and atherosclerosis, the efficacy of the operation was regarded as a possibility to preserve the supporting function of the extremity. In the postoperative period this goal was achieved in 73.2% and 62.5% of patients, respectively, while in the remote period in 62% and 25%, respectively. PMID- 21780633 TI - [Endovascular occlusion of posttraumatic suprarenal aortic pseudoaneurysm]. AB - Presented in the article is a case report regarding successful treatment of a posttraumatic false aneurysm localizing in the immediate proximity to the superior mesenteric artery, which was isolated by the Amplatzer Duct Occluder II, with the disks diameter measuring 6 mm to allow closure of the patent ductus arteriosus. PMID- 21780634 TI - [Successful outcome of treatment for a ruptured abdominal aortic aneurysm accompanied by inguinal hernia: a clinical case report]. AB - The article deals with a clinical case report concerning surgical management of a male patient presenting with a ruptured abdominal aortic aneurysm. The postoperative period was complicated by strangulation of inguinal hernia inadvertently neglected during prior surgery, however then treated successfully by tension-free hernioplasty, with due conclusions eventually drawn. PMID- 21780635 TI - [Outcomes of reconstructive operations in gerontological patients with diabetic foot syndrome]. AB - The authors share herein their experience in treating a total of two hundred and forty-six patients presenting with an ischaemic form of diabetic foot syndrome on the background of secondary to occlusion ofmajor arteries. The patients'average age amounted to 74 years. According to the findings of ultrasonographic angioscanning and radiopaque aorto- arteriography, 62.3 % of the patients were diagnosed as having bilateral lesions of the arterial bed and only 37.7 % of the patients had lesions of the major vessels on one side. Reconstructive operations on the aortoiliac-femoral zone were performed in sixty-nine (28 %) patients, distal reconstruction in one hundred and twenty-seven (52 %) patients, multi storey reconstructions in eighteen (7 %), and prolundoplasty in thirty-two (13 %) patients. Direct revascularization of lower extremities made it possible to save the supporting foot in 89 % of the patients undergoing proximal reconstructions and in 83 % of the patients subjected to distal reconstructions, as well as to decrease the rate of high amputations to 11 %. PMID- 21780636 TI - [Revacularizing operations in patients with atherosclerotic lesions of the superficial femoral artery]. AB - Intermittent claudication appears to be the main symptom of peripheral artery disease encountered in 10% of the population over 70 years old. Occlusive stenotic lesions of the femoropopliteal segment (FPS) predominate in the structure of limb artery disease, in connection with which the most frequently performed operations are infrainguinal revascularization procedures. Older-age group patients are known to have a variety of concomitant pathologies such as coronary artery disease (CAD), diabetes mellitus (DM), etc. Decreasing the incidence rate of perioperative complications and mortality, as well as the scope of anaesthesiological support and duration of in-hospital treatment in such patients is possible at the expense of diminishing the operative wound and may be achieved by means of minimally invasive interventions. The review contains the literature data concerning various types of infrainguinal interventions in patients presenting with femoropopliteal occlusion: balloon angioplasty and stenting, femoropopliteal bypass grafting, remote endarterectomy, etc. Special mention should be made of treating the patients with critical ischaemia. The problem of choosing between surgical and endovascular treatment for occlusive stenotic damage to the superficial femoral artery is featured insufficiently in the present-day literature. Therefore, further studies should be conducted. PMID- 21780637 TI - [Role of long-term potentiation in mechanism of the conditioned learning]. AB - The review analyzes the fundamental problem of study of the neuronal mechanisms underlying processes of learning and memory. As a neuronal models of these phenomena there was considered one of the cellular phenomena that has characteristics similar with those in the process of "remembering"--such as the long-term potentiation (LTP). LTP is easily reproduced in certain synapses of the central nervous system, specifically in synapses of hippocampus and amygdala. As to the behavioral model of learning, there was used the conditioned learning, in frames of which production of the context-dependent/independent conditioned reaction was considered. Analysis of literature data has allowed showing that various stages of LTP produced on synapses of hippocampus or amygdala can be comparable with certain phase of the process of learning. Based on the exposed material the authors conclude that plastic changes of synapses of hippocampus and amygdala can represent the morphological substrate of some kinds of learning and memory. PMID- 21780638 TI - [Participation of vertebrate forebrain activating systems in organization of the wakefulness--sleep cycle]. AB - The article considers mechanisms of diencephalic-telencephlic interactions in regulation of the wakefulness-sleep cycle in various classes of vertebrates. In such interactions a special role is played by the dopaminergic systems that perform neurosecretory function at the level of diencephalon and neurotransmitter function at the level of telencephalon. Concepts of A. I. Karamyan and A. L. Polenov about the stage pattern of development of CNS and neurosecretory systems are presented as well as the interconnection of dopaminergic and glutamatergic neurotransmitter system in the mammalian neostriatum in the wakefulness-sleep cycle is considered. Comparison of dynamics of expression of the dopamine metabotropic receptors and of the glutamate ionotropic receptors in neostriatum showed unidirectional changes of D1 and AMPA on the background of the 6-h sleep deprivation as well as of D2 and NMDA on the background of postdeprivative sleep. The corticofugal direction of glutamate impulsation and its relatively fast actions allow admitting its triggering action on generation of the sleep-inducing processes in the underlying brain parts. PMID- 21780639 TI - [Antiapoptotic effect of alpha-tocopherol at micro- and nanomolar concentrations on cells of neuronal line PC12 according to data of flow cytometry]. AB - By the method of flow cytometry it has been shown that alpha-tocopherol at micromolar concentrations produces antiapoptotic effect on the PC12 neuronal line cells exposed to the toxic agent hydrogen peroxide at various terms of incubation with it. At the same time, alpha-tocopherol at nanomolar concentrations had protective (antiapoptotic) effect only after the long (18 h) preincubation of the PC12 cells with it prior to exposure to hydrogen peroxide. This seems to indicate that the alpha-tocopherol effect at these concentrations is mediated by a signal transduction system. PMID- 21780640 TI - [Activity and properties of fructose bisphosphatase of turbellarian Phagocata sibirica]. AB - Activity and properties of fructose bisphosphatase (FBPase) was studied in the free-living turbellarian Phagocata sibirica. All subcellular fractions of P. sibirica (12 000 g cytosol, 105 000 g cytosol, mitochondria, and microsomes) have the FBPase activity. There was studied dependence of the FBPase reaction rate on the substrate concentration. For realization of the enzyme activity, the high affinity to substrate and presence of bivalent cations (Mg2+ or Mn2+) are necessary. The was studied the effect of various effectors as well as of monovalent (Na+, K+, Li+, and NH4+) and bivalent (Zn2+ and Cu2+) cations. PMID- 21780641 TI - [Comparison of photodynamic effect with respect to human and rabbit erythrocytes]. AB - Parameters of photoinduced lysis are studied for human and rabbit erythrocytes (photosensibilizer--Radachlorin, the light source--Shuttle HeNe lazer, lambda = 633 nm). The higher sensitivity to irradiation is revealed for rabbit erythrocytes. Treatment of erythrocytes with trypsin showed the surface proteins in human cells to produce a protective effect. Trypsynization of rabbit erythrocytes produced the opposite action--the rate of photohemolysis increased. Results of the study indicate the differences in sensitivity to the photoinduced lysis of erythrocytes of different species and participation of erythrocytes proteins in the effect of photohemolysis. PMID- 21780642 TI - [Functional role of hypothalamic D1 and D2 receptors in organization of some forms of behavior of the common frog]. AB - Dopamine is one of the most ancient, widely spread neurotransmitters that performs a great number of neuromodulator effects in the vertebrate CNS. For the last few years there considerably increases an interest in study of functional role of this neurotransmitter in regulation of various forms of behavior of poikilothermal vertebrates. The present work deals with study of the role of the dopaminergic system, specifically of the hypothalamic dophaminergic system in providing some behavioral frog reactions. We studies behavior of the animals in the "open field" before and after administration to them of antagonists of D1 (SCH 23390) and D2 (haloperidol) receptors as well as of animals with destructed anterior and posterior parts of hypothalamis. Administration of SCH 23390 to intact frogs caused a statistically significant decrease of the number of exploratory reactions and goal-oriented jumps, whereas haloperidol only moderately increased the number of the above reactions. Destruction of the posterior part of hypothalamus inhibited essentially all kinds of activity, while destruction of the anterior part suppressed them completely. Antagonists of D1 and D2 receptors of dopamin little changed the initial motor and emotional activity of the operated animals. The obtained data are discussed in the light of evolutionary origin of D1 and D2 receptors in the vertebrate subphylum and allow concluding that D1 and D2 receptors of hypothalamic dophamin of the common frog are located predominantly in the anterior hypothalamic areas and that their effect on behavior can be mediated and is associated with other brain neurotransmitter systems in such brain structures as lateral hypothalamus, locus coereleus, and striatum that provide different aspects of wakefulness. PMID- 21780643 TI - [Interaction of neuronal NOS and catecholamines in regulation of expression of proteins of apoptosis by vasopressinergic hypothalamic neurons]. AB - The work studied vasopressinergic neurons of hypothalamic supraoptic and paravenricular nuclei of the wild type mice and the neuronal nitric oxide synthase (nNOS) gene knockouted mice at a decrease of the brain catecholamine (CA) level caused by administration of the blocker of activity of tyrosine hydroxylase alpha-methyl-paratyrosine (alpha-MPT) and at the CA level decrease on the background of functional activity of the vasopressinergic neurons caused by dehydration of animals. There were analyzed changes in the number of neurons in both magnocellular hypothalamic nuclei expressing proapoptotic proteins caspase-8 and caspase-9, p53, and antiapoptotic protein Bcl-2. The disturbance of the CA ergic innervation was shown to be a strong damaging factor leading to apoptosis of neurons regardless of the presence of nNOS in the cells. However, at disturbance of the CA-ergic innervation due to the 5-day mouse dehydration, no death of neurons by apoptosis was revealed. Thus, it is possible that functional activation prevents the hypothalamic vasopressinergic neurons from death at a decrease of the CA level in brain. The main difference of the nNOS gene knockouts is the absence of activation of the Bcl-2 expression under all used actions. This confirms our suggestion about interaction of CA and NO in triggering of expression of the antiapoptotic protein Bcl-2. PMID- 21780644 TI - [Role of oxytocin in activation of spontaneous electrical activity of uterine body and uterine tubes in non-pregnant rats]. AB - The work studies effects of various doses of oxytocin (0.01, 0.1, 1 and 10 microg/kg) on duration of discharges of spontaneous electrical activity and frequency of spikes in various parts of uterine tubes and of uterine body of non pregnant rats. Under these conditions, changes in these parameters for ovarian parts of the uterine tubes had similar character unlike those in cervical parts of the tubes and in the middle part of the uterine body, so the latter parts can be grouped together owing to peculiarities of their changes. The longest duration of genesis of electric discharges has been shown for the ovarian part of uterine tubes at a concentration of 10 microg/kg of oxytocin. Morphological experiments revealed that among all studies areas the ovarian parts of uterine tubes were characterized by the highest amount of atypical cells that have the maximally pronounced functional activity. PMID- 21780645 TI - [Comparative study of effects of cortical nucleus of amygdala and pyriform cortex on activity of bulbar respiratory neurons in cats]. AB - Comparative microelectrophysiological study of character and peculiarities of effects of the cortical nucleus of amygdala and of the periamygdalar area of pyriform cortex on impulse activity was performed on the same single functionally identified respiratory medullar neurons. A high reactivity of bulbar respiratory neurons on stimulation is established in both studied limbic structures. There is established the qualitatively different character of their response reactions at stimulation of the cortical amygdala nucleus and the periamygdalar cortex. The cortical amygdala nucleus has been shown to produce on the activity of medullar respiratory neurons both facilitating and inhibitory action with predominance of the activating one (without topographical orderliness). The effect of periamygdalar cortex at stimulation of various parts was characterized by topographic differentiation. The suppressing reactions of neurons in the majority of cases were recorded at stimulation of the rostral area of periamygdalar cortex, whereas the excitatory reactions--at stimulation of its caudal part. Functional organization of respiratory control of the studied limbic system structures is discussed. PMID- 21780646 TI - [On generators of wing beating rate during flight and sound production in some insect species]. PMID- 21780647 TI - [Combination-sensitive neurons in the central nucleus of inferior colliculus of the house mouse Mus musculus]. PMID- 21780648 TI - [Quantum processes in evolution of regulation of living system (mathematical modelling)]. AB - We have developed an imitation model of the appearance of regulation of physiological functions of protocell at the initial stages of evolution of living system. It is based on suggestion of the appearance of signal function in spontaneously formed products of partial hydrolysis of the protocell polypeptides, based on which there appear the regulatory molecules--quanta of regulation. For construction of the model, the mathematical apparatus of final automats and of genetic algorithm is used. The model has demonstrated the positive role of involvement of regulatory peptides in the system of regulation of protocell functions to provide its viability under the changing envelopment conditions. PMID- 21780649 TI - [Perspectives of the treatment of rheumatic diseases in the beginning of the XXI century]. AB - Prevalence of immunoinflammatory diseases in general population is about 10%. Rheumatic diseases, first of all rheumatoid arthritis (RA), are among most prevalent immunoinflammatory diseases. In the first decade of the XXI century great progress was achieved in definition of the mechanisms of RA onset and in development of new approaches to its treatment. The article provides information about novel drugs which are effectively used not only in RA but also in other imunoinflammatory diseases. PMID- 21780650 TI - [Methotrexate-induced changes in the concentration of antibodies to mutaded citrullinated vimentin in blood serum of patients with rheumatoid arthritis]. AB - AIM: To study effects of methotrexate on the titer of antibodies to mutated citrullinated vimentin (anti-MCV) and ascertain possibility of using this marker for control of treatment results and choice of individual effective dose of the drug. MATERIAL AND METHODS: A 12-month trial included 76 patients with verified rheumatoid arthritis (RA). Methotrexate per os was given in a dose 7.5-10 mg/week to 44 (57.9%) patients, 25 patients received no basic therapy. Anti-MCV (IU/ml) were detected with commercial chemicals made in Germany (ORGENTEC). RESULTS: RA patients given methotrexate doses 7.5 and 10 mg/week and untreated with basic anti-inflammatory drugs showed no significant differences by basic clinical and device parameters, level of anti-MCV at primary examination and 12 months later. CONCLUSION: Anti-MCV titer cannot be used for control of efficacy of methotrexate treatment in doses 75 and 10 mg/week, choice of individual effective doses. PMID- 21780651 TI - [Ten-year risk of cardiovascular complications in patients with rheumatoid arthritis]. AB - AIM: To compare 10-year risk of cardiovascular complications (CVC) assessed by Adult Treatment Panel III (ATP III) and Reynolds Risk Score (RRS); to specify contribution of C-reactive protein (CRP) to development of CVC in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: The trial included 116 RA patients (100 females and 16 males) and 85 healthy subjects (63 females and 22 males) under 55 years of age free of clinical symptoms of cardiovascular diseases. RA duration and activity were the same in men and women. The patients and controls were matched by age, incidence of standard risk factors (RF). The 10 year risk of CVC development was estimated by two scales--ATP III and RRS. Total cholesterin, HDLP cholesterin were measured with standard enzyme tests, concentration of CRP was assessed by highly sensitive immune nephelometry. RESULTS: The 10-year risk of CVC was higher in RA patients both by ATP III (1.8 - 1;10%) and RRS (2.6 - 2; 7)% compared to the controls (1 - 1;3)% and (1.2 - 1;4)% (p < 0.05). In male RA patients RRS is higher than in females - 7 (3.5; 12)% and 2 (1;2)%, respectively (p < 0.001). Re-calculation from the scale ATP III to RRS has changed the risk in 17 (17%) females and 7 (44%) males with RA. As a result, the number of RA patients with a low CVC risk decreased, with a moderate risk rose 2 times, with a high risk was the same. RRS dependence on the disease duration, RA activity (DAS28) was not registered. RA patients showed a positive correlation of RRS with thickness of the intima-media complex of the carotid arteries (r = 0.44; p < 0.001). CONCLUSION: Introduction of a new prognostic scale RRS allows isolation of groups of patients with moderate and high CVC risk and timely medication of such patients. PMID- 21780652 TI - [Cardiovascular risk factors in psoriatic and rheumatoid arthritis]. AB - AIM: To study the role of conventional and new factors of cardiovascular risk in development of atherosclerosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PA). MATERIAL AND METHODS: Sixty patients with psoriatic arthritis, 414 RA patients and 79 healthy controls entered the trial. All of them had no manifestations of cardiovascular diseases. Screening was made of the leading risk factors of cardiovascular diseases and cardiovascular complications, thickness of the complex intima-media (TIM) of the carotid arteries, vascular wall stiffness were measured, vasoregulatory function of the endothelium, markers of endothelial damage were examined. RESULTS: Patients with psoriatic and rheumatoid arthritis were found to have increased TIM of the carotid arteries, high incidence of atherosclerotic plaques, increased stiffness, damage of the vascular wall, affected endothelial vasoregulation. These alterations were associated with high arthritis activity, systemic manifestations, seropositivity by rheumatoid factor (in RA), presence of entesitis, uveitis and dactilitis (in psoriatic arthritis), dislipidemia, arterial hypertension (AH). CONCLUSION: To determine cardiovascular risk in patients with arthritis, it is necessary to consider not only standard risk factors (dislipidemia and AH), but also severity of systemic inflammation, arterial stiffness, endothelial damage and ability of the vascular wall to relax reflecting endothelial dysfunction. PMID- 21780653 TI - [Current knowledge about pathogenesis and treatment of arterial hypertension in rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease with a proved high risk of cardiovascular diseases (CVD). An increase of this risk is mainly due to accumulation of conventional factors of CVD development (arterial hypertension - AH), dislipidemia, et cet). Causes of high prevalence of AH in RA, the role of chronic inflammation, effects of antirheumatic drugs with potentially hypertensive effects are outlined and recommendations on AH prevention and treatment in RA patients are given. PMID- 21780654 TI - [Standardization of methotrexate administration in routine rheumatological practice]. AB - The review is devoted to administration of methotrexate--a basic anti inflammatory drug--in rheumatoid arthritis. Some issues of practical use of this drug are still disputable. Recommendations of international experts and information on standardization for patients are considered. PMID- 21780655 TI - [Arterial stiffness in patients with systemic sclerosis]. AB - AIM: To study arterial stiffness (AS) in patients with systemic sclerosis (SS). MATERIAL AND METHODS: A total of 38 SS patients (36 females and 2 males over 40 years of age) entered the study. They met the following criteria: clinical symptoms of coronary heart disease, atherosclerosis of peripheral vessels, other severe chronic diseases in exacerbation. The control group consisted of 28 healthy matched volunteers. AS was measured with Tensioclinic (Tensiomed, Hungary) arteriograph which demonstrated changes in arterial bed in SS patients. RESULTS: Arterial overrigidity and accelerated reflection of the pulse wave have a strong impact on elevation of the central arterial pressure. High blood pressure in the ascending aorta overloads the left ventricle and promotes development of its hypertrophy, deteriorates diastolic relaxation and, finally, damages pump function of the heart. Moreover, chronic elevation of the central arterial pressure is the end component in formation of the vicious circle of a further increase of the cardiovascular risk and the marker of target organ affection. CONCLUSION: Increased vascular stiffness in SS patients suggests increased cardiovascular risk in these patients. Prospective studies of this risk are needed. PMID- 21780656 TI - [Pleiotropic effects of statins in systemic sclerosis]. AB - AIM: To study anti-inflammatory and angioprotective properties of statins in patients with systemic sclerosis (SS). MATERIAL AND METHODS: Fifty SS patients enrolled in the trial were divided into two groups: the study group included 30 patients who received standard therapy and atorvastatin in a dose 10-40 mg/day, the control group (n = 20) received standard therapy alone. The blood of the patients was studied with enzyme immunoassay for concentrations of highly sensitive C-reactive protein (hs-CRP), IL-6, VCAM-1, E-selectin, WF antigen, VEGF A, VEGF-R2. The tests were made before the treatment and after 12 months of the treatment. RESULTS: The levels of hs-CRP, IL-6, VCAM-1, E-selectin, WF antigen, VEGF-A and VEGF-R2 were significantly higher in the study group than in healthy donors. The controls also had elevated levels of the above substances except IL-6 and VEGF-A which elevated but not significantly. A 12-month treatment in the study group resulted in a significant lowering of hs-CRP, IL-6, WF antigen, E selectin, VEGF-A and VEGF-R2, the number of patients with elevated IL-6, WF antigen, VEGF-R2 also reduced while in the controls the parameters did not change. CONCLUSION: Atorvastatin has anti-inflammatory and angioprotective effects in SS patients. PMID- 21780657 TI - [Systemic lupus erythematosus in men: difficulties of diagnosis and specific features of clinical picture]. AB - AIM: To characterize specific clinical features of systemic lupus erythematosus (SLE) in male patients. MATERIAL AND METHODS: A total of 146 male patients with verified SLE diagnosis were examined in the Research Institute of Rheumatology. RESULTS: Literature and original data on SLE clinical characteristics in men were analysed. Diagnostic search and variants of SLE in male patients are described. CONCLUSION: To upgrade knowledge on SLE clinical characteristics, further prospective trials should be made. PMID- 21780658 TI - [Some aspects of pathogenesis of ankylosing spondylitis]. AB - Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease of the spine (spondylitis) and sacroiliac joints (sacroileitis) associated in many cases with inflammatory affection of the peripheral joints (arthritis), entesises (entesitis), eyes (uveitis), intestine (enteritis) and aortic root (aortitis). AS is considered now as a prototype of diseases from the group of seronegative spondyloarthritis. AS is a hereditary disease. Predisposition to AS (90%) is associated with genetic factors the key gene of which is HLA-B27. As pathogenesis of AS is not still verified, three hypotheses are considered basing on HLA-B27 biology. The role of environmental factors involved in AS development (tension in enteses and infection) are discussed. PMID- 21780659 TI - [Main factors of gender dimorphism of gout (estrogens and diuretics vs alcohol and genetics)]. AB - The article analyses factors underling gender dimorphism of gout, gender epidemiological differences. Discussion covers the role of estrogens and menopause, alcohol, diuretics, gender-associated genetic characteristics in gout genesis. PMID- 21780660 TI - [Efficacy of combined treatment of patients with severe obstructive sleep apnea and arterial hypertension of the second and third degree]. AB - AIM: To assess efficacy of two- and three-component antihypertensive treatment (AHT) in patients with severe sleep apnea and arterial hypertension (AH) of the second and third degree in combination with CPAP therapy (continuous positive air pressure) and without it. MATERIAL AND METHODS: A total of 58 patients aged 55.5 +/- 9.6 years participated in the study. Clinical blood pressure (BP) before treatment was 172.0 (170.7-175.9)/100.0 (98.5-104.2) mm Hg, apnea/ hypopnea index was 26.3 episodes an hour. The patients received amlodipin in combination with walsartan in a dose 5-10/160 mg with addition of 25 mg hydrochlorothiaside if target BP was not achieved. This treatment was followed for 3 weeks by CPAP therapy. Monitoring was made of clinical BP, central BP, target mean 24-h pressure. RESULTS: Despite a significant reduction of systolic arterial pressure/diastolic arterial pressure (by 30/14 mm Hg) as a result of antihypertensive treatment, this reduction was lower than in such patients without obstructive sleep apnea (by data from other investigators). CPAP-therapy reduced the number of resistant patients from 58 to 31%, patients with masked AH- from 19 to 11%, cases of arrhythmia--from 69 to 47%. CONCLUSION: Multicomponent pathophysiologically sound AHT in hypertensive patients with severe obstructive sleep apnea was effective in less than 42% cases. The maximal effect was achieved in combined treatment with CPAP-therapy. PMID- 21780661 TI - [Transplantation of hemopoietic stem cells in autoimmune diseases]. AB - Transplantation of stem hemopoietic cells is a new trend in the treatment of some autoimmune diseases.Large international trials made in the last 12 years in the USA, Europe, Russia, China were devoted to evaluation of efficacy of this method. Basing on the results of these trials, experts of the Russian Cooperative Cell Therapy Group and N.I. Pirogov National Medicosurgical Center have developed a conception of high-dose immunosuppressive therapy with transplantation of stem hemopoietic cells in autoimmune diseases. Main positions of the conception and its perspectives are discussed. PMID- 21780662 TI - [Optimization of the control of blood pressure. What contribution can be obtained from use of combinations of fixed doses of ace inhibitors and calcium channel blockers?]. AB - Basing on the results of large trials investigating efficacy of combined use of angiotensin-converting enzyme inhibitors (as a rule, perindopril) and calcium channel blockers (as a rule, amlodipin), the article analyses variety of mechanisms of their combined action, effects on dynamics of blood pressure, heart rate variability. The above combined treatment significantly reduces frequency of cardiovascular complications, improves the course of diabetes mellitus in its combination with arterial hypertension, renal function in patients with chronic renal failure and arterial hypertension. It is important to use fixed doses of the above drugs. PMID- 21780663 TI - [Efficacy of pharmacological inhibition of intestinal saccharases in patients with diabetes mellitus type 2 and/or visceral obesity]. AB - Inhibitors of intestinal enzymes regulate carbohydrate metabolism reducing glycemic index, glycemic load of food and postprandial glycemia which is a prognostic factor of DM2-related cardiovascular complications and death. This class of drugs was proposed for DM2 treatment in 1970s but still holds perspectives. The article gives a detailed description of the mechanism of action, efficacy and safety of inhibitors of alpha-glucosidase and alpha-amilase in experimental and clinical controlled trials. PMID- 21780664 TI - [Antimicrobial activity of bacteriocin S760 produced by Enterococcus faecium strain LWP760]. AB - Antimicrobial activity of bacteriocin S760 (enterocin) produced by Enterococcusfaecium strain LWP760 was studied. Bacteriocin S760 is a cationic, hydrophobic, and heat stable peptide with the molecular weight of 5.5 kDa and pl of 9.8. Enterocin S760 is shown to inhibit in vitro the growth both of sensitive and resistant to antibacterials gramnegative and grampositive bacteria of 25 species. MICs of the bacteriocin S760 vary between 0.05-1.6 mg/l for Escherichia coli 0157:H117, Salmonella typhimurium, Salmonella enteritidis, Campylobacter jejuni, Yersinia enterocolitica, Yersinia pseudotuberculosis, Listeria monocytogenes and Clostridium perfringens, that are main food-borne pathogens, and from 0.4-1.6 mg/l for Streptococcus pyogenes, Streptococcus pneumoniae and Corynebacterium diphteriae. It is also active against antibioticresistant strains of Staphylococcus aureus, Enterobacter cloacae, Acinetobacter baumannii (with MICs of 0.05-3 mg/l), Klebsiella pneumoniae (with MICs of 6 mg/l), Pseudomonas aeruginosa (with MICs of 0.4-25 mg/1), as well against fungi belonging to species of Candida albicans, Candida krusei and Aspergillus niger (with MICs of 0.1-0.2 mg/l). Enterocin S760 is a novel antimicrobial agents useful in medicine, veterinary and food industry. PMID- 21780665 TI - [Therapeutic efficacy of Triazavirin, a novel Russian chemotherapeutic, against influenza virus A (H5N1)]. AB - Therapeutic activity of Triazavirin against experimental influenza A was studied on albino mice intranazally infected with influenza virus A/Chicken/Kurgan/Russia/02/05 (H5N1) vs. reference drugs (Oseltamivir, Remantadin and Arbidol). The study showed that in a therapeutic dose of 1 mg/kg Triazavirin was efficient in protection of the animals from death. Its protective therapeutic efficacy (36.7+/-1.7%) was close to that of Oseltamivir (50.0+/-0.0%), comparable with that of Remantadin (38.3+/-1.7%) and higher than that of Arbidol (11.7+/ 1.7%). During the whole observation period (up to the terminal phase) Triazavirin inhibited the influenza virus A accumulation in the lungs of the infected albino mice by more than 3 lg. PMID- 21780666 TI - [Comparative study of hepatoprotective action of remaxol, reamberin and ademethionine in liver injury induced by antituberculosis drugs (experimental study)]. AB - The hepatoprotective activity of remaxol, reamberin and ademethionine was studied on a model of the liver injury induced by antituberculosis drugs. The study included 30 male uninbred albino rats. The following antituberculosis drugs were used: isoniazid (50 mg/kg) subcutaneously + rifampicin (250 mg/kg) intragastrically + pyrazinamide (45 mg/kg) intragastically (by the procedure of Yu. I. Slivka, 1989). Remaxol, reamberin and ademethionine were administered 1.5 hour prior to the antituberculosis drugs. The treatment course was 14 days. It was shown that remaxol, reamberin and ademethionin were able to correct the structural and functional disorders in the liver due to the use of the antituberculosis drugs. By the impact on the biochemical indices, evident of the liver function condition, remaxol showed the maximum effect. The effect of ream berin was somewhat lower and the results of the ademethionine use were less significant. Remaxol had also a distinct effect as for lowering the level of the structural injuries in the liver, evident from recovery of the organ histoarchitectonics, less extended carbohydrate, albuminous and fatty degeneration, more active intracellular regeneration. It was noted that ademethionine had an insignificant effect on necrobiosis. Moreover, there was once detected a large necrosis focus, evident of possible stimulation of the liver tissue alteration by the drug. PMID- 21780667 TI - [Antibioticograms of Vibrio cholerae non-01/non-0139 strains isolated from humans within 1968-2009]. AB - Analysis of the antibioticograms of the Vibrio cholerae non-01/non-0139 strains showed that in the cultures isolated in the Rostov Region in 1968--1975 there were present markers of resistance to ampicillin (7%), kanamycin (15.8%), rifampicin (3.5%) and trimetoprim/sulfamethoxazole (14%). Among the strains isolated in the Ukraine in 1975 14% was resistant to ampicillin. More than a half of the strains isolated in Uzbekistan in 1990 and 2000-2001, in the Arkhangelsk Region in 1999-2000 and in the Kalmykia in 1999-2005 was antibiotic resistant. In the above regions the strains were resistant to ampicillin (12.5-44.4%), kanamycin (11-55%), rifampicin (1.9-12.5%) and trimetoprim/sulfamethoxazole (25 62.5%). Among the cultures isolated in Uzbekistan in 1990 and 2000-2001 25 and 7.8% were resistant to furazolidone and 31.25% was resistant to streptomycin (1990). All the cultures isolated in the Rostov Region in 2005-2009 were resistant to ampicillin, 50% was resistant to ceftazidim, 57% was resistant to streptomycin and furazolidone, 7.2% was resistant to kanamycin and 14% was resistant to trimetoprim/sulfamethoxazole. The studies revealed an increase of the extent of the V.cholerae non-01/non-0139 resistance spectrum within 1968 2009, simultaneous presence of up to 5 diverse resistance markers and a variety of their combinations, that requires the use of antibacterials for the treatment of the diseases due to the vibrios in strict compliance with the pathogen antibioticogram and their early replace by more efficient drugs. PMID- 21780668 TI - [Immunomodulators in combined therapy of patients with chronic hepatitis]. AB - The efficacy of the use of triple schemes in combined therapy of chronic virus hepatitis was estimated and its safety was monitored. The problems of therapy of mixed hepatitis in drug addicts are discussed. Immunotropic agents, increasing the efficacy of the standard therapy of chronic affections of the liver, are suggested to be used as the third remedy in the combined therapy. PMID- 21780669 TI - [Modern antifungals in therapy of nosocomial mycosis in oncologic patients]. AB - Rational position of voriconazole in the treatment of oncologic inpatients was shown and the criteria of its use in the algorithms of the therapy and prophylaxis of nosocomial fungal infections were developed. The clinical trial enrolled 50 patients with oncologic pathologies. The patients were divided into two groups of possible invasive candidiasis risk. The patients of one group were treated with fluconazole (Diflucan) and those of the other group were treated with voriconazole (Vifend). The spectrum of the hospital fungal flora was determined and susceptibility of 310 clinically important opportunistic fungi was investigated. All the isolates of Candida albicans and C.tropicalis were susceptible to amphotericin B, fluconazole and voriconazole and 79 and 50% of the isolates were susceptible to intraconazole respectively. As for the C.krusei isolates, 67% was susceptible to amphotericin B, 50% was susceptible to fluconazole, 100% was susceptible to voriconazole and none of the strains was susceptible to intraconazole. By the clinical efficacy voriconazole was superior to fluconazole and comparable with amphotericin B, while superior to it by the number of the side effects and by the cost of the treatment course. It was concluded that voriconazole should be considered as the main agent in the antifungal therapy of oncologic patients. PMID- 21780670 TI - [Clinical and economic expedience of ertapenem therapy of complicated urinary tract infection]. AB - Clinical and economic investigation of various antibiotics use in the treatment of complicated urinary tract infection (CUTI) was performed under the Russian economic environment. The drugs of comparison were ertapenem, ceftriaxone and levofloxacin. Direct costs and their structure were shown, and the cost efficiency was calculated. Alternative analysis and one-side susceptibility analysis were performed. In complicated urinary tract infections when the major pathogens were Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis it was clinically and economically reasonable to start the treatment with ceftriaxone or ertapenem, while levofloxacin could be an alternative strategy. When the effects of the acquired resistance on the treatment effectiveness were evaluated (SIS model) it was shown that the pathogens susceptibility to ertapenem was preserved for a significantly longer time than that to ceftriaxone or levofloxacin (60 months). Such a parameter may serve as an additional evidence of the reasonable use of ertapenem as the starting treatment of CUTI. PMID- 21780671 TI - [Circular dichroism in study of drug chirality]. AB - Verapamyl substance and market verapamyl were investigated with circular dichroism. It was shown that circular dichroism provided rapid and highly efficient determination of the optic isomers and could be recommended as a method for control of drug quality. PMID- 21780672 TI - [Estimate of hypothetical toxicity of drug combinations exemplified by two injection antibiotics]. PMID- 21780673 TI - [Developmental features of the brain bioelectrical activity in children with remote consequences of a perinatal lesion of the CNS. II. EEG typology in normal and mental disorders]. AB - This research represents EEG - investigation by children with remote consequences of perinatal CNS pathology. Its described the different EEG types in normal and mental disorders in children. Its showed a early EEG - markers of abnormal ontogenesis in longitudinal study. The data obtained gives to prevent a negative dynamic of mental and speech development (learning disability, motor alalia, autism). PMID- 21780674 TI - [Possibility of using biofeedback for amplitude training of ERP's independent components]. AB - The aim of this study was to investigate the possibility of voluntary training for independent component of event-related potentials in modified two-stimuli Go/NoGo test by the method of biofeedback. Subjects were 10 healthy people which were asked to increase amplitude of P3b component of event-related potentials from Go stimulus. This component is generated in parietal area and is thought to be connected with action engagement. The study consisted of three sessions including tuning (determining of mean amplitude), training and placebo. Amplitude of P3b component did not change significantly during training and placebo sessions comparing to tuning session while amplitude of SPD component significantly decreased in both sessions. This component is separated in event related potentials from Go stimulus and its source according to "sLORETA" is localized in parahippocampus. Obtained results allow determining further approaches to research the possibility of using biofeedback for correction of ERPs' components. PMID- 21780675 TI - [The nonlinear parameters of interference EMG of two day old human newborns]. AB - Temporal structure of interference electromyogram (iEMG) was studied in healthy two days old human newborns (n = 76) using the non-linear parameters (correlation dimension, fractal dimension, correlation entropy). It has been found that the non-linear parameters of iEMG were time-dependent because they were decreasing within the first two days of life. Also, these parameters were sensitive to muscle function, because correlation dimension, fractal dimension, and correlation entropy of iEMG in gastrocnemius muscle differed from the other muscles. The non-linear parameters were proven to be independent of the iEMG amplitude. That model of early ontogenesis may be of potential use for investigation of anti-gravitation activity. PMID- 21780676 TI - [Baroreceptor reflex and arterial rigidity in schoolchildren]. AB - In this work there is shown a variability of heart rate and time delay of pulse wave of main arteries in schoolchildren.There is used the function of ordinary coherence of HR and DPW (time delay of pulse wave). This function reflects the rate of statistical linear relation of two processes in heart and blood vessels. A high tone of sympathetic part of vegetative nervous activity in schoolchildren increases CO (cardeiac out), shortens the hard connection phase of HR and DPW and results in a new system characteristic--arterial rigidity. There are presented results of passive orthostatic test and pharmacological tests on activation of sympathetic part of vegetative nervous activity in schoolchildren with heart rate problems. PMID- 21780677 TI - [Internal reference frame for representation and storage of visual information during standing]. AB - The participation of different afferent systems in organization of internal reference frame was studied. For this was chosen the task of visual comparison that executed in different experimental conditions: in upright standing, with inclined body or head in frontal plane and availability or non-availability visual information about external environment. Results showed that dominant orientation of referent stimulus (minimal value of mean error and minimal variability of responses) was connected with body position, mainly head position but not with gravity and visual vertical even when visual environment was available. It means that for creating the internal representing of vertical CNS mainly uses proprioceptive information about longitudinal axis of body. PMID- 21780678 TI - [Dependence of anticipatory changes of hand muscle activity and grip force on the height of the fall during catching of the object]. AB - Timing of changes of hand muscle activity and grip force before the impact of the object that fell from different height into the cup held between thumb and index fingers of sitting subject was studied in three variants of experiment: 1) the subject has seen the fall of the object, 2) the subject has not seen the movement of the object but has initiated the fall, 3) the subject has no information about the object fall. In the third variant changes of muscle activity and grip force has occurred in response to the impact of the falling object. In the second variant changes of muscle activity and grip force preceded the impact the falling object by 200-280 MC and this time interval that did not depend on the height of the fall. In the first variant of experiment changes of the muscle activity and grip force has occurred in 150 ms after the start of fall independently of the height of the fall when the height was 30-50 cm. When the height of the fall was 70-105 cm the changes has preceded the impact by the time interval that did not depend on the height of fall. Thus when the height of fall was small the time of the start of the changes of muscle activity and grip force was related to the start of the fall, but when the height was large the start of changes was related to the presumed impact of falling object. PMID- 21780679 TI - [The problem of information value in microvascular networks]. AB - The methodology of quantitative estimation of information value in microvascular networks is proposed for the first time with the use of wavelet analysis of skin blood flow oscillations registrated by laser Doppler flowmetry at 30 healthy persons and 56 patients after hand injuries and diseases. It includes calculation of relative indices for the information preservation, the predomination of preserved information and the efficacy of information. The most deviation from multistable information regimen happened after formation of resonance oscillations: the general quantity of information decreased but the preservation of predominated information increased. The preservation of trophic myogenic information predominated after reduction of sympathetic influences. With the increase in the number of information channels the quantity of information increased but its preservation varied. Sensory peptidergic nerve fibres were activated during local heating to 34 degrees C at dorsal forearm skin. This information was the most effective at the beginning of heating during the growth of blood flow to the plateau level. Blood flow oscillations represented in wavelet spectrum serve as operators build on the basis of effective information. These oscillations play not only hemodynamic role but are the bearers of information in microvascular networks. PMID- 21780680 TI - [The dynamics of histograms of difference between successive RR intervals of ECG during 24 hours as index of the balanced state of neurogenic influences on the heart rate]. AB - The quantitative parameters of neurogenic influences on the heart rate is offered: the dispersion of histograms of differences between successive RR intervals of ECG, the number of zero differences and the value of sum of differences between successive RR intervals. PMID- 21780681 TI - [Response of arterial blood haemoglobin saturation to short-term intermittent normobaric hypoxia in humans]. AB - The paper presents experimental data supporting a hypothesis that the changes of arterial blood haemoglobin saturation during breathing the hypoxic gas mixture (10-13% O2) can be fitted by exponential function. The formal description of the saturation curves allowed verifying their stages and evaluating interindividual variability. It is suggested that the parameters of exponents can be used when estimating an individual hypoxic resistance of a human organism. PMID- 21780682 TI - [Concentration of light hydrocarbons in exhaled air depending on the risk factors of metabolic disorder]. AB - In this study we investigated the effect of risk factors of metabolic syndrome on the content of light hydrocarbons (C2-C3) in exhaled air. We used a gas chromatograph with a short multi-channel column. As a result, sex differences in concentrations of light hydrocarbons presented in exhaled air were found. In addition, such factors as smoking and diabetes mellitus type 2 in relatives reflect on the exhaled C2-C3 compounds only in women. But the overweight correlates with the exhaled acetone (C3) only in men. Thus, the fact that the metabolic changes caused by the presence of risk factors of metabolic syndrome lead to changes in gas composition of exhaled air and can be registered and used for early diagnosis has been ascertained. PMID- 21780683 TI - [Acoustical estimation of impact of single dive in closed-type breathing apparatus on human ventilatory lung function]. AB - Diving renders negative influence on human respiratory system especially when oxygen breathing apparatus is used. Spirometry indexes, traditionally used to estimate ventilator lung function, have poor sensitivity to toxic effect of hyperbaric hyperoxia. The objective is to study possibility of revealing minimum impairments of lung ventilator function in oxygen divers by analysis of forced expiratory tracheal noise duration. 48 divers were studied before and after single shallow water dive in oxygen closed-type breathing apparatus. A significant drop of FVC, FEV1 over the group as a whole was found after dive however being in the limits of norm. The significant increase of individual forced expiratory tracheal noise duration, exceeding the natural variability limit (19.6%, p < 0.05), was found in 10 subjects (20.8%). Three of them during dive had respiratory symptoms characteristic for initial manifestations of pulmonary oxygen poisoning. The asymptomatic reversible increase of forced expiratory tracheal noise duration in the rest 7 divers was interpreted as a sign of hidden phase of hyperbaric hyperoxia effect. PMID- 21780684 TI - [Influence of the human blood serum on contractility and beta-adrenoreactyvity of the isolated human myocardium]. AB - On strips of the isolated myocardium of right hearts auriculum of the 43 patients with ischemic illness of heart and 9 patients with heart diseases of various ethyology at statement venous canule during aorto-coronary shunting, estimated influence of adrenaline (10(-9)-10(-4) g/ml) on amplitude caused by electrostimulus (1H, 5ms, 25-30 V) contractions, and also inotropic and adrenomodulation activity of serum blood (in dilution 1 : 10000, 1: 1000, 1 : 500, 1: 100, 1 : 50, 1: 10 and 1 : 5) nonpregnant women. Direct dependence of amplitude of contraction on size of fraction of of blood emission on Teyholts is revealed. It means, that strips of right auriculum myocardium reflect contractility of a left ventriculum myocardium. Adrenaline in concentration 10( 7)-10(-6) g/ml dependent of dose raised amplitude of the caused contraction not influencing it in concentration of 10(-9) and 10(-8) g/ml (the constant of dissotiation has 2 x 10(-7) g/ml), that as a whole, speaks about decrease in efficiency of activation beta-AP. Blood Serum in dissolutions 1 : 10000-1 : 50 did not influence on amplitude of contraction, and in dissolutions 1 : 10 and 1 : 5 strengthened it, that speaks presence in blood the endogenous activator of myocyte contractility (EAMC). Serum showed beta-adrenomodulation activity that speaks presence in it endogenous sensitizer of beta-adrenoreceptors (ESBAR) and endogenous blocker of beta-adrenoreceptors (EBBAR). In particular, in experiences with adrenaline in subthreshold concentration (10(-8) g/ml) serum showed ESBAR activity (in dissolutions 1 : 1000, 1 : 500, 1 : 100 and 1 : 50), and in experiences with adrenaline in as much as possible effective concentration (10( 6) g/ml) serum showed ESBAR-activity (in dissolutions 1 : 50 and 1 : 10) and EBBAR-activity (in dissolutions 1:500) Hence, containing in blood serum endogenous modulators of beta-adrenoreactivity - ESBAR and EBBAR can modulate efficiency of beta-adrenoreceptors activation of human cardiomyocytes. It speaks about perspectivity of application of ES BAR analogues in cardiology. PMID- 21780685 TI - [Intensity of lipid peroxidation and antioxidant protection system indices during re-adaptation period after long-term space flights at the international space station]. AB - In the blood serum of seventeen members of crews which participated in 14 orbital expeditions to the International Space Station with the duration of 125 to 217 days, during the pre-flight period and on the day of landing on the 1st, 7th and 14th days of the rehabilitation period (RP) the content of LPO products was determined, namely diene conjugates (DC), malon dialdehyde (MDA), shiffbases (SB) and the main lipid oxidant - tocopherol (TP). The group of astronauts who made landing in the Space Shuttle spacecraft (8 persons) and the group of astronauts who accomplished space mission in the Soyus TM spacecraft (9 persons) demonstrated a decrease in DC and MDA levels with a rise in TF concentration in the course of the rehabilitation period. Changes in the group of the American spacecraft astronauts were more pronounced. LPO inhibition during the rehabilitation period is recognized [treated] as an adequate reaction to the stress caused by re-adaptation to the ground conditions. Also are discussed probable mechanisms of intergroup differencies in LPO intensity degree: biomembrane phase state changing under the influence of overloads during de orbiting and stress response intensity during landing in different types of spacecraft. PMID- 21780686 TI - [Variability of urine proteome of healthy persons during 105-daily isolation]. AB - Human proteome is very plastic, it changes under the influence of various biological factors. It is of big interest to find out how specific factors of an environment, including a long-term isolation affect on urine proteome. The study was conducted during the experiment with 105-day isolation. In the present investigation we collected urine samples from 6 healthy volunteers (26-41 years old). The physical activity, daily rhythms and diet were controlled. Urine samples were fractionated on magnetic beads MB-HIC C8 (MB - hydrophobic interaction chromatography) with ClinProt robot (Bruker Daltonics) prior to MALDI TOF mass spectrometer analysis with Autoflex III TOF/TOF (Bruker Daltonics), working in a positive linear mode. 117 peaks have been obtained in each spectrum of urine. We have shown that even during isolation and under controlled conditions of life a high variability of urine proteome of healthy personas (36 protein MC-peaks in the urine, on average) are revealed. PMID- 21780687 TI - [A comparison of rate human lipid profile changes at moderate altitude]. AB - The paper studies antiatherogenic changes of serum lipid profile in various conditions, namely: 1) the mountain and climatic treatment on Caucasian resorts, 2) periodic hypobaric therapy, 3) trekking in mountains with regular cold tests (the Tibetan yoga gTum-mo). We made the comparison of rate of change of serum total cholesterol, high (HDL), low (LDL) and very low density (VLDL) lipoproteins, and also triglycerides by use of exponential model of changes of lipid profile. By application of new computing algorithm it was proved that the maximal rate of antiatherogenic changes of serum lipid profile (decrease in the total cholesterol and in LDL, increase in HDL) is characteristic for a combination of three conditions: 1) moderate altitude hypoxia, 2) moderate physical activities and 3) special exercises for increase of cold tolerance (the Tibetan yoga gTum-mo). PMID- 21780689 TI - [Hemostasis system indices in the course of a 105-day hermo chamber isolation experiment]. AB - The present paper deals with studying of hemostasis system indices in the course of the experiment with a 105-day isolation in a hermo chamber. The following values were determined: activated partial thromboplastin time, prothrombin time (PT), prothrombin index (PI), international normalized ratio [relationship] (INR), thrombin time, fibrinogen concentration, soluble fibrin-monomer complexes, D-dimer, plasminogen (PG), activity of antithrombin III, protein C, alpha2 antiplasmin. According to the experiment results, isolation is accompanied by PT prolongation (PI decreasing, INR increasing) which conserves up to the 7th day of the aftereffect period, as well as by PG concentration decreasing. Changes are likely to be connected with peculiarities of reduced motion activity conditions, compensatory physical activity influence, protein and lipid metabolism characteristics changing. PMID- 21780688 TI - [Cardiovascular effects of nerve growth factor analytical review. Part 2]. AB - In the second part of the review discusses the features of the influence ofNGFon the functional activity of the cardiovascular system, as well as signaling pathways by which activated NGF TrkA and p75(ntr) receptors regulate the functional state of endothelial and vascular smooth muscle cells and cardiomyocytes. In addition, the review observes the theoretical perspectives of agonists and antagonists of TrkA and p75(ntr) receptors for the treatment of various diseases of the heart and blood vessels. PMID- 21780690 TI - [Bioimpedance spectroscopy parameters of suspensions of young and old erythrocytes]. AB - The bioimpedance spectroscopy (BIS) parameters of the suspensions of young and old erythrocytes were studied. The separation of the erythrocytes by age was made by density gradient. The BIS parameters: extracellular (Re) and intracellular (Ri) fluid resistance, characteristic frequency (Fchar), cell membranes capacitance (Cm) and Alpha parameter of concentrate suspensions of young and old erythrocytes were measured on the BIA analyzer ABC-01 "Medass" in the frequency range 5-500 kHz. It was found that Re (300.4 +/- 30.0 Ohm and 261.2 +/- 21.8 Ohm for old and young respectively, p < 0.05), Ri (86.6 +/- 9.1 Ohm and 73.4 +/- 7.3 Ohm for old and young respectively, p < 0.001) and Alpha (0.305 +/- 0.003 and 0.302 +/- 0.001 for old and young respectively, p < 0.05) of the old erythrocytes suspensions were higher, than of the young one, and Fchar (308.3 +/- 42.0 kHz and 347.4 +/- 48.0 kHz for old and young respectively, p <0.05) and Cm (99.3 +/- 10.1 pF and 112.8 +/- 6.3 pF for old and young respectively, p < 0.01) of the old erythrocytes were lower, than of the young one. The found differences between electrical properties of the suspensions of young and old erythrocytes were obviously determined by the alterations of the red blood cells during aging (growth of intracellular hemoglobin concentration, erythrocytes rapprochement because of diminishing of surface negative charge, increase of red blood cell sphericity and cell membrane permeability for ions). Thus the BIS parameters are related to the erythrocyte aging. PMID- 21780691 TI - [Physiological and psychophysiological indices dynamics in operators with three shift working day in different working conditions]. AB - It was shown that intense operator work in pulp and paper industry (bleachers and chlorinators) with changes in shift time (day, evening, night) causes fatigue. The fatigue in operators was indicated by increasing number of errors in sensomotor coordination test and coordination index, and among chlorinators it was accompanied by deterioration of state of health. Manifestations of 24 hours' rhythm of physiological functions were detected by changes in body temperature (among bleachers), heart rate, blood pressure and sensomotor coordination indices (all operators). Harmful chemical substances (chlorine and chlorine dioxide) in the air negatively influence psychophysiological status among clorinators. PMID- 21780692 TI - A review of the use of red mud as adsorbent for the removal of toxic pollutants from water and wastewater. AB - Red mud (an aluminium industry waste) has received wide attention as an effective adsorbent for water pollution control, showing significant adsorption potential for the removal of various aquatic pollutants. In this review, an extensive list of red-mud-based adsorbents has been compiled and their adsorption capacities (maximum uptake value of the adsorbent for the pollutant or adsorbate being removed) for various aquatic pollutants (metal ions, dyes, phenolic compounds, inorganic anions) are presented. The review provides a summary of recent information obtained using batch studies and deals with the adsorption mechanisms involved. It is evident from the literature survey that red mud has been found to be efficient for the removal of various aquatic pollutants, especially arsenic and phosphate. However, there is still a need to investigate the practical utility of these adsorbents on a commercial scale. PMID- 21780693 TI - Chemical reduction kinetics of nitrate in aqueous solution by Mg/Cu bimetallic particles. AB - Synthesized magnesium/copper (Mg/Cu) bimetallic particles have shown good potential for use in the reduction of nitrate from aqueous solutions. This study was conducted to investigate the main factors affecting the kinetics of nitrate reduction by Mg/Cu particles (<100 microm) in uncontrolled reaction conditions. The Mg/Cu bimetallic particles removed the majority of the various nitrate concentrations tested (50, 100, 150, 200 and 300 mg L(-1)) within a short period. The time required for the removal of 90.6% of the NO3(-) from a 100 mg L(-1) solution was about 20 min using 2 gL(-1) bimetallic Mg/Cu at an initial solution pH of 6. The activation energy (Ea) for nitrate reduction by Mg/Cu over the temperature range of 5 to 60 degrees C was 14.21 kJ mol(-1). The experimental results of the kinetic analysis from batch studies indicated that a higher initial nitrate concentration yielded a greater reaction-rate constant and the denitrification rate increased with increase Mg/Cu dosage. PMID- 21780694 TI - Oxidation of X-ray compound ditrizoic acid by ferrate(VI). AB - Iodinated X-ray contrast media (ICM) such as diatrizoic acid (DTZA) is used in large amounts in hospitals to enhance imaging of organs and blood vessels during radiography. Due to its persistence and non-biodegradability, it is found in treated water, sewage effluent, surface waters, and aquatic environments. This paper presents the kinetics of the oxidation of DTZA by ferrate(VI) (Fe(VI)O4(2 ), Fe(VI)) as a function of pH (7.1-9.6) at 25 degrees C in order to determine the effectiveness of Fe(VI) to remove DTZA from water. The reaction was determined to be first-order with respect to concentrations of Fe(VI) and DTZA. The rate of the reaction was found to be pH dependent and the rate decreased nonlinearly as the pH increase from 7.1 to 9.6. The speciation of Fe(VI) (HFeO4( ) and FeO4(2-)) was used to explain the rate dependence on pH. The calculated rate constant of Fe(VI) with DTZA at pH 7.0 was compared with nitrogen-containing pollutants and is briefly discussed. PMID- 21780695 TI - Role of non-ionic surfactants and plant oils on the solubilization of organochlorine pesticides by oil-in-water microemulsions. AB - Screening low-cost, high efficacy and environmentally safe surface active agents is critical for achieving successful surfactant-enhanced remediation (SER) of soil contaminated with hydrophobic organic compounds. This study reports the solubilization of organochlorine pesticides (DDT or gamma-HCH) in oil-in-water (Winsor I) microemulsions (microE) composed of non-ionic surfactant (Tween 80 or Triton X-100), plant oil (linseed oil or soybean oil), and the cosurfactant (1 pentanol). Results show that the cosurfactant to surfactant ratio (C/S ratio, w/w) is the major factor influencing the microemulsion formation, and C/S ratios of 1:3 and 1:6 are superior to 1:1 for microemulsion formation. 66.9-95.6% and 51.9-80.9% of DDT solubilization enhancements were achieved by microemulsions based respectively on Tween 80 or Triton X-100 as compared to their respective surfactant solution alone, indicating the higher solubilizing capacities of microemulsion systems. The solubilization of gamma-HCH also increased by 40.6 57.5% in microemulsion formed with Tween 80 and 43.0-65.8% in microemulsion formed with Triton X-100, compared with that in corresponding surfactant solutions only. Further studies revealed that both cosurfactant content and oil content could influence the solubilizing capacity of microemulsions system, and higher solubilizing capacity could be obtained when more cosurfactant or oil were emulsified in microemulsion system. Between the two, oil content is more influential than cosurfactant content. The present results affirm the effective role of microemulsions formed with Tween 80 and Triton X-100 in enhancing the solubilization of DDT and gamma-HCH which would facilitate remediation of soils contaminated with these compounds. PMID- 21780696 TI - Characterization and removal of specific organic constituents in an UASB trickling-filter system treating domestic wastewater. AB - This paper presents the characterization of specific organic constituents (carbohydrates, proteins and lipids) in raw sewage and in the anaerobic and aerobic effluents of a demo-scale (500 inhabitants) UASB- trickling-filter system. The evaluation of such parameters was carried out for two operating conditions, either without sludge recirculation (experiment I) from the trickling filter to the UASB reactor or with sludge recirculation (experiment II), for sludge thickening and stabilization, in the anaerobic reactor. The results showed that the contribution of acetic acid, carbohydrates, proteins and lipids amounted for approximately 70% of the total COD fed to the UASB during experiment I, whereas during experiment II these constituents amounted for only around 40% of the total COD. Although very high BOD and COD overall removal efficiencies were observed for the treatment system (around 90% and 80%, respectively), it was possible to infer that these efficiencies were mainly related to the removal of carbohydrates and lipids (around 80% removal), and of other non-identified constituents. The removal of proteins was much lower (around 50% removal), and the relative contribution of proteins to the total COD increased along the treatment course, being responsible for most of the residual COD of the treatment units. In the present system configuration, the UASB reactor played a major role in the removal of carbohydrates, whereas the trickling filter was very effective in the removal of lipids. The return of aerobic sludge for thickening and stabilization in the UASB reactor did not affect its performance. PMID- 21780697 TI - Autotrophic ammonium removal from reject water: partial nitrification and anammox in one-reactor versus two-reactor systems. AB - Removal of total nitrogen from anaerobically digested sludge reject water by a fully autotrophic process in either one- or two-reactor systems was compared. Autotrophic nitrogen removal is currently most often applied in the one-reactor system primarily in the DEMON configuration. The two-reactor systems had a similar nitrogen removal rate to the one-reactor systems. It was evident that the limiting step was partial nitrification. Increase in partial nitrification can be difficult in a one-reactor system, where the overall conditions, such as the oxygen concentration or substrate concentrations, would progress to full nitrification. The partial nitrification of the two-reactor system may be improved by adjusting key parameters: the un-ionized form of the substrates, the oxygen concentration or the solids residence time. The impact of two process configurations on the operational stability and process performance was presented based on two cases--DEMON and the SHARON-ANAMMOX process. PMID- 21780698 TI - Analysis of organic compounds in an urban wastewater treatment plant effluent. AB - In the present work we fractioned the effluent water from an urban sewage treatment plant (USTP) of Ribarroja (Valencia, Spain) using the conventional protocol based on DAX8 and XAD4 resins. The fractions were analyzed by elemental analysis, FT-IR, 1H-NMR, COSY-NMR, HSQC-NMR, FAB+-MS and also by derivatization with bis(trimethylsilyl)trifluoroacetamide with 10% of trimethylchlorosilane. The four fractions obtained have common spectroscopic features and individual compounds indicating that the fractioning procedure is inefficient at separating different families of compounds. Gas chromatography/mass spectrometry (GC-MS) analysis of the derivatized fractions allowed identification of many individual compounds. The main classes of organic compounds present in the effluent are saccharides, amino acids, fatty acids, hydroxyacids, aromatic compounds and steroids. Also we were able to identify in the effluent the emerging pollutants paracetamol and ketoprofen - two best-selling antiinflammatory drugs used in humans. PMID- 21780699 TI - Synergetic catalytic performance of TiO2/MCM-41 for ozone-assisted photocatalytic degradation of gaseous acetaldehyde. AB - This paper presents the preparation and characterization of TiO2/MCM-41 catalysts with different amounts of TiO2 loading or calcination at various temperatures. The activities of the samples were investigated under UV, ozone and UV-zone by the comparison of acetaldehyde degradation. The results showed that the application of photocatalytic ozonation (UV-ozone) produced the highest efficiency for acetaldehyde removal, indicating that a synergistic effect occurred when photocatalysis and ozonation are carried out simultaneously. The synergistic catalytic performance depended significantly on the composition of catalysts used. The TiO2/MCM-41 catalysts were superior to single TiO2 and MCM-41 with respect to the ozone-assisted photocatalytic oxidation of gaseous acetaldehyde, and the activity of the catalyst TiO2/MCM-41, with TiO2:MCM-41 = 5:10, is the highest one among these prepared catalysts. The improvement was attributed to the synergetic effect between adsorption, ozonation and catalytic reaction. PMID- 21780700 TI - Effective separation and sensitive determination of cyanuric acid, melamine and cyromazine in environmental water by reversed phase high-performance liquid chromatography. AB - A new method for the simultaneous determination of cyanuric acid (CA), melamine (MM) and cyromazine (CM) in different water samples was developed by using reversed phase high-performance liquid chromatography diode-array detection (RP HPLC-DAD). The conditions of HPLC were investigated and optimized. A KROMASIL C18 column (250 x 4.6 mm ID, 5 microm) was used for the RP-HPLC using gradient elution with a mobile phase composed of 0.1 mM KH2PO4-K2HPO4 buffer solution (pH = 7.3) and methanol (75:25, v/v). The conditions for HPLC were investigated and optimized. Under optimal conditions, the linearity was satisfactory in the range of 0.04-10.00 microg/mL with a correlation coefficient of 0.999, and the method limits of detection (LODs) of the proposed method were 0.02 microg/mL for CA and CM, and 0.01 microg/mL for MM. The recoveries were: 96.0-116.0% with relative standard deviations (RSDs) of 0.9-5.7% for CA, 94.3-115.0% with RSDs of 1.5-5.3% for MM, and 91.0-112.0% with RSDs (n = 6) of 1.0-4.9% for CM. The proposed method can permit the detection of CA and CM at levels as low as 0.07 microg/mL and MM at levels as low as 0.03 microg/mL in environmental water samples. PMID- 21780701 TI - Removal of lead and yellow 44 acid dye in single and binary component systems by raw Posidonia oceanica and the cellulose extracted from the raw biomass. AB - This study examined the sorption behaviour of Pb(II) and C.I. Acid Yellow 44 on Posidonia oceanica, an abundant Mediterranean biomass. A comparison with sorption onto cellulose extracted from the raw material was carried out to identify those site characteristics that play a predominant role in the adsorption of both dye and metal ions. Kinetic and equilibrium studies were performed for single and binary component systems, and the experimental data were analyzed by a non-linear method. The pseudo second-order kinetic model was successfully applied for both dye and metal retention onto sorbents in single and binary systems. Both sorbents were found to be more effective for lead than for Yellow 44 removal. However, lead sorption was more effective on raw P. oceanica suggesting that the metal ions are sorbed into the whole available biomass sites (cellulose and lignin). An opposite behaviour was reported for Yellow 44 sorption, which was found to be more effective on the extracted cellulose than raw P. oceanica. This finding proves that the only available sites for dye sorption are the cellulosic ones. The binary component experimental studies indicated competition between dye and lead for the available sites of raw P. oceanica. However, this competition was found to be less prevalent for sorption by cellulose extracted from raw P. oceanica suggesting that, in binary component systems, the cellulosic sites are equally available for both pollutants, the only limiting parameter being the size of the molecular sorbate. Langmuir and Freundlich isotherms were used to fit the experimental data using the non-linear method for parameter determination. PMID- 21780702 TI - Study of arsenic(III) and arsenic(V) removal from waters using ferric hydroxide supported on silica gel prepared at low pH. AB - Removal of As(III) and As(V) species using ferric hydroxide supported on silica gel was studied. Laboratory reagent quality silica gel was used as to avoid uncertainties that may be caused by impurities. Ferric hydroxide precipitation was realized at various pH values and a relatively low pH 6.0 was chosen because, at this pH, the highest arsenic removal capacity and removal efficiency were obtained and clear supernatant solution was observed. It was also shown by arsenic speciation analysis at trace level that As(III) is adsorbed onto ferric hydroxide partly without oxidation to As(V); this has been a controversial point in the literature. The effects on arsenic removal of some parameters such as pH, flow rate and matrix ions were investigated. In the batch method, initial pH change of the solution did not significantly affect the arsenic removal efficiencies for As(III) and As(V) in the pH range of 3.1-9.7. This was attributed to the decreases of the initial pH values to around 5 at equilibrium. The column capacities of 1.32 mg As(III)/g sorbent and 1.21 mg As(V)/g sorbent were found for initial concentration of 1.00 mg/L arsenic. Batch capacities were 16.2 mg As(III)/g sorbent and 17.7 mg As(V)/g sorbent for initial arsenic concentration of 100 mg/L. The method was applied successfully to the removal of As(III) and As(V) from drinking water, geothermal water and mineral water. PMID- 21780703 TI - Lead sorption-desorption from organic residues. AB - Sorption and desorption are mechanisms involved in the reduction of metal mobility and bioavailability in organic materials. Metal release from substrates is controlled by desorption. The capacity of coffee husk and pulp residues, vermicompost and cow manure to adsorb Pb2+ was evaluated. The mechanisms involved in the sorption process were also studied. Organic materials retained high concentrations of lead (up to 36,000 mg L(-1)); however, the mechanisms of sorption varied according to the characteristics of each material: degree of decomposition, pH, cation exchange capacity and percentage of organic matter. Vermicompost and manure removed 98% of the Pb from solution. Lead precipitated in manure and vermicompost, forming lead oxide (PbO) and lead ferrite (PbFe4O7). Adsorption isotherms did not fit to the typical Freundlich and Langmuir equations. Not only specific and non-specific adsorption was observed, but also precipitation and coprecipitation. Lead desorption from vermicompost and cow manure was less than 2%. For remediation of Pb-polluted sites, the application of vermicompost and manure is recommended in places with alkaline soils because Pb precipitation can be induced, whereas coffee pulp residue is recommended for acidic soils where Pb is adsorbed. PMID- 21780704 TI - Synthesis and characterization of pillared stevensites: application to chromate adsorption. AB - The purpose of this work was to study the synthesis of pillared interlayered clays from Moroccan stevensite called locally 'Ghassoul'. This clay has been intercalated with cetyltrimethylammonium surfactant (CTA-Stv) and aluminium hydroxypolycation (Al13-Stv). Characterization studies were performed using XRF, XRD, FTIR and DTA/TG analysis. Basal spacing values of Al13-Stv and CTA-Stv increased respectively from 13.5 A for natural stevensite to 17.5 and 17.6 A with increasing Al13(7+)/clay and CTA+/clay ratios. The DTA/TG results showed that Al13-Stv has a relatively high thermal stability compared with CTA-Stv. A quasi irreversible intercalation by exchanging the interlayer inorganic cations with voluminous pillars Al13(7+) or CTA+ was observed. Batch adsorption of chromate anions from aqueous solutions was investigated and the results showed that both pillared clays had great affinity for the chromate compared with untreated stevensite. The Dubinin-Kaganer-Radushkevich (DKR) model was selected to describe the adsorption isotherms. The maximum adsorption capacities for natural stevensite, Al13-Stv and CTA-Stv are 13.7, 75.4 and 195.6 mmol/kg, respectively. PMID- 21780705 TI - Non-isothermal modelling of H2S removal in a biofilter. AB - In this study the biodegradation of H2S in the air in a biofilter is modelled in the non-isothermal operating condition. For this purpose, using conservation laws of heat and mass transfer and considering the physical and chemical phenomena occurring in a biofilter, the governing equations in non-isothermal, isothermal, steady, and unsteady-state operations are obtained and solved numerically. The model results are compared with the available experimental data and also with the results of the isothermal model. The comparisons are made both in steady and unsteady-state situations. The results show that considering the heat effects on the modelling of a biofilter improves the accuracy of the model results. Furthermore, the effects of some operating parameters on the removal efficiency of biofilter are investigated. PMID- 21780706 TI - Development of bamboo-derived sorbents for mercury removal in gas phase. AB - Activated carbon sorbents were synthesized from bamboo precursors by carbonization in an inert atmosphere followed by physiochemical activation with carbon dioxide and finally acidulation in hydrochloric acid. Bamboo strips with and without the epidermal tissue (bark) were used. The morphology and specific surface area changes due to the treatment were analysed. The adsorption characteristics of these sorbents after each stage of treatment were also analysed and the data were correlated to the changes in the physical characteristics of the sorbents. Kinetic studies were conducted on these samples. The adsorption equilibrium and kinetics of elemental mercury adsorption on these carbons were evaluated at room temperature. Elemental mercury uptake at different sorbent loading and initial elemental mercury concentrations were examined. The adsorption rate constants and the mass transfer constants were estimated for the sorbents prepared under different conditions. Adsorption isotherms of the elemental mercury on these activated carbons were determined and correlated with Langmuir and Freundlich adsorption isotherm equations. It was found that the overall process was mass transfer controlled and that the adsorption equilibrium could be described by a linear isotherm for the concentrations used in this study. PMID- 21780707 TI - Preparation of Ag-M (M: Fe, Co and Mn)-ZSM-5 bimetal catalysts with high performance for catalytic oxidation of ethyl acetate. AB - The catalytic combustion of ethyl acetate has been investigated in a series of mono-metal silver and bimetal Ag-M (M: Fe, Co and Mn)-modified HZSM-5 zeolites. The objective was to find a catalyst with high superior activity, selectivity towards deep oxidation product and stability. The catalyst activity was measured under excess oxygen condition in a fixed bed reactor operated at gas hourly space velocity (GHSV) = 30000 h(-1), reaction temperature between 150 and 450 degrees C and ethyl acetate inlet concentration of 1000 ppm. Both Fe-Ag-ZSM-5 and Co-Ag-ZSM 5 catalysts exhibited high activity in the oxidation of ethyl acetate. The sequences of catalytic activity and catalytic stability were as follows: Fe-Ag ZSM-5 > Co-Ag-ZSM-5 > Mn-Ag-ZSM-5 > Ag-ZSM-5 > HZSM-5. Total conversion of ethyl acetate was achieved at above 250 degrees C. The catalysts were characterized by inductively coupled plasma atomic emission spectroscopy, X-ray diffraction, transmission electron microscopy, scanning electron microscopy and X-ray photoelectron spectroscopy. PMID- 21780708 TI - Conditions for energy generation as an alternative approach to compost utilization. AB - Very strict limits constrain the current possibilities for compost utilization in agriculture and for land reclamation, thus creating a need for other compost utilization practices. A favourable alternative can be compost utilization as a renewable heat source - alternative fuel. The changes of the basic physical chemical parameters during the composting process are evaluated. During the composting process, energy losses of 920 kJ/kg occur, caused by carbohydrate decomposition (loss of 12.64% TOC). The net calorific value for mature compost was 11.169 kJ/kg dry matter. The grain size of compost below 0.045 mm has the highest ash content. The energetic utilization of compost depended on moisture, which can be influenced by paper addition or by prolonging the time of maturation to six months. PMID- 21780709 TI - Behaviour of molecular weight distribution for the liquid fraction of pig slurry treated by anaerobic digestion. AB - Pig slurry was treated in an upflow anaerobic sludge blanket (UASB) reactor. To maintain a stable operation, the organic loading rate (OLR) applied to the system was increased stepwise by decreasing the dilution ratio of the pig slurry. Finally, during the last operational stage, no dilution was applied to the influent. The reactor maintained a soluble chemical oxygen demand (CODs) removal efficiency of 82% when OLRs lower than 1.73 g CODs l(-1) d(-1) were applied, although its efficiency fell to 55% when operated at 2.48 g CODs l(-1) d(-1). System performance was not affected by the presence of free ammonia (concentrations up to 375 mg NH3 l(-1)). The distribution of the different molecular weight fractions changed significantly during anaerobic digestion. Proteins contained in the fractions higher than 10,000 Daltons are less degraded than those belonging to the lower fractions. An important percentage of both COD and BOD5 in the effluent were observed in the lowest fraction, probably caused by the presence of volatile fatty acids (VFA). PMID- 21780710 TI - The synthesis of TiO2 and TiO2-Pt and their application in the removal of Cr (VI). AB - The deposition of noble metal on titanium dioxide (TiO2) has been considered as an effective strategy to improve the activity of TiO2. In this paper, TiO2 nanoparticles were prepared via a sol-gel route, followed by heat treatment at elevated temperatures. TiO2-Pt catalyst was prepared by deposition of platinum (Pt) on the surface of as-prepared TiO2 nanoparticles. TiO2 and TiO2-Pt were characterized by X-ray diffraction, transmission electron microscopy, Raman spectroscopy, ultraviolet-visible differential reflectance spectra and infrared spectroscopy. TiO2 and TiO2-Pt were used as heterogeneous catalysts for the removal of Cr (VI) under ultraviolet-light illumination. TiO2 prepared at low temperature had smaller particle size and higher specific surface area, and consequently had higher activity on the removal of Cr (VI). The Pt deposited on the surface of TiO2 favoured the separation of photo-produced electrons (e-) and holes (h+), inhibited the recombination of e- and h+, and enhanced Cr (VI) removal. However, its blocking of active sites also inhibited the removal of Cr (VI). The deposition of 1% (wt.%) Pt to TiO2 produced the optimum activity for the removal of Cr (VI). A lower pH favoured the adsorption of Cr (VI) on the surface of TiO2, and correspondingly enhanced the removal of Cr (VI). PMID- 21780711 TI - Catalytic degradation of picric acid by heterogeneous Fenton-based processes. AB - The efficiency of goethite, magnetite and iron powder (Fe0) in catalysing the Fenton-based oxidation of picric acid (PA) in aqueous solution was studied. The effect of pH, hydrogen peroxide concentration, and catalyst type and dosage on treatment efficacy was investigated. The adsorption of PA from aqueous solution by heterogeneous catalysts was also examined. The results demonstrated negligible PA removal in H2O2/alpha-FeOOH and H2O2/Fe3O4 systems independent of process pH, and hydrogen peroxide and catalyst dosage. The PA adsorption effects of both iron oxides turned out to be insignificant for all studied pH values and catalyst dosages. The H2O2/Fe0 system proved efficient at degrading PA, but only under acidic conditions (pH 3). The results indicated that, due to rather fast leaching of ferrous ions from the iron powder surface, PA degradation was carried out mainly by the classic Fenton oxidation mechanism in the bulk solution. The adsorption of PA onto the iron powder surface may also contribute to the overall efficiency of PA degradation. PMID- 21780712 TI - Removal of o-nitrobenzoic acid by adsorption on to a new organoclay: montmorillonite modified with HDTMA microemulsion. AB - A new organoclay, consisting of montmorillonite modified by a hexadecyl trimethyl ammonium (HDTMA) microemulsion, was synthesized, characterized and used as an adsorbent for the removal of o-nitrobenzoic acid from aqueous solution. Adsorption kinetics, isotherms and effects of operating variables, such as adsorbent dosage, ionic strength and initial solution pH, were also investigated. The results of Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) analysis and BET surface area determination indicated that HDTMA molecules had entered into the interlayer of the montmorillonite. The optimized experimental conditions for the adsorption of o-nitrobenzoic acid by montmorillonite modified by HDTMA microemulsion were 0.5 g adsorbent dosage, 0.4 mL of 0.1 mol lbL(-1) CaCl2 solution, initial solution pH of 6.0 and contact time of 6 h. The adsorption isotherms of o-nitrobenzoic acid fitted the Langmuir model well (R2 = 0.9880). The adsorption kinetics data fitted the pseudo-second-order equation (R2 = 0.9999). These above results indicate that montmorillonite modified by an HDTMA microemulsion can be used as adsorbent for o-nitrobenzoic acid because of its high adsorption capacity and low cost. PMID- 21780713 TI - Sorption of sunset yellow dye by weak base anion exchanger-kinetic and equilibrium studies. AB - The sorption equilibrium and kinetics of Sunset Yellow dye in aqueous solutions on the weak base anion exchange resin Amberlite FPA51 were examined in this paper. The influences of phase contact time, solution pH, initial dye concentration and temperature were studied by the batch method. The amounts of dye sorbed at equilibrium changed from 9.9 to 48.7 mg/g with increasing initial dye concentration in the range 100-500 mg/L. The experimental data were analysed by the Langmuir, Freundlich, Temkin and Dubinin-Radushkevich models of adsorption. The maximum monolayer capacity was 130.6 mg/g. The sorption free energy was equal to 14.6 kJ/mol and revealed the nature of the ion exchange mechanism in this system. The kinetic data were modelled using the pseudo-first order, pseudo-second-order (types 1-5) and intraparticle diffusion equations. The experimental data were well described by types 1-3 of the pseudo-second-order kinetic model. PMID- 21780714 TI - Nurses win local power. PMID- 21780715 TI - Advisory role gained on clinical senates. PMID- 21780716 TI - Call to revisit HCA regulation. PMID- 21780717 TI - Your guide to the proposals for the NHS. PMID- 21780718 TI - "Nursing showed its power in the saga of the health reforms". PMID- 21780719 TI - "Leaders without a cause could end up like rogue teachers". PMID- 21780720 TI - "Cottage industry could end delayed discharge misery". PMID- 21780721 TI - Medication errors in care homes. AB - BACKGROUND: The Care Homes' Use of Medicines Study (Alldred et al, 2009) found medication administration errors occur during drug rounds in care homes. AIM: This study aimed to establish if there were differences in administration error rates: between tablets and capsules and other formulations; and between tablets and capsules dispensed in monitored dosage systems and those given out in the manufacturer's original packaging. METHOD: Clinical pharmacists observed two drug rounds of care home residents in 55 care homes. They compared the error rates of different formulations and monitored dosage systems. RESULTS: Formulations that are not tablets and capsules, for example inhaled therapy, are particularly at risk of being administered incorrectly. CONCLUSION: Care home staff need greater support and training to administer formulations that are not tablets or capsules. PMID- 21780722 TI - Tackling insulin maladministration. PMID- 21780723 TI - Addressing ketamine bladder syndrome. AB - The rise in ketamine misuse means more health professionals will need to diagnose, refer and treat ketamine bladder syndrome. Prevention and raising awareness of the problem among multidisciplinary teams will help limit damage to the bladder as well as making treatment and management more effective. PMID- 21780725 TI - Learning to rise. PMID- 21780724 TI - Palliative care in Parkinson's disease. AB - Parkinson's disease is a progressive, neurodegenerative condition with no known cure. People with the condition can have complex palliative care needs similar to those of cancer patients. This article describes the four stages of Parkinson's disease, and illustrates how nurses can apply the principles of palliative care to support and care at each stage. PMID- 21780726 TI - Influence of a peracetic acid-based immersion on indirect composite resin. AB - The aim of this study was to evaluate the influence of immersion in a 0.2% peracetic acid-based disinfectant on the three-point flexural strength, water sorption and water solubility of an indirect composite resin. Specimens were produced according to ISO 4049:2000 specifications and were divided in two groups: Control group, with no disinfection and Disinfected group, with three 10 min immersions in the peracetic acid intercalated with 10 min immersions in sterile distilled water. All evaluations were conducted in compliance with ISO specifications. Three-point flexural strength, water sorption and solubility of indirect composite resin before and after immersion showed no statistical significant differences (p > 0.05) and met ISO standard requirements. Immersion in peracetic acid solution showed no influence in indirect composite resin tested properties. PMID- 21780727 TI - Repair versus replacement of defective composite restorations in dental schools in Germany. AB - The aim of this paper was to review the current teaching of repairs to direct composite restorations in dental schools in Germany, last surveyed ten years ago. Based on an 83% response rate, the findings indicate that most, but not all, dental schools included teaching of repair techniques; however marked variations were found to exist regarding clinical indications and repair techniques of the teaching. It is suggested that certain aspects of the existing teaching in some schools should be reviewed, specifically the lack of use of a bonding agent and the issue of flowable composites to complete repairs. PMID- 21780728 TI - Modified technique for retaining silicone auricular prosthesis: a case report. AB - Prosthetic rehabilitation of auricular defects can be a demanding procedure due to a broad variety of clinical presentations and a wide array of treatment options. The retention of auricular prostheses is a major factor influencing the successful outcome of rehabilitative treatment following cancer surgery or trauma. Auricular prostheses have been retained by methods including implants, adhesives and spectacle frames but the choice of repair ultimately depends on patient factors, amount of soft tissue loss, and location of the auricular defect. This article describes a newer technique of using resin template for silicone auricular prosthesis, for better retention and orientation. Moreover it is cost effective and aesthetically acceptable for patients who decline or need to postpone implant retained prosthesis reconstruction. PMID- 21780729 TI - Management of a patient suffering with Cherubism with dental implants. AB - Cherubism is a rare non-neoplastic, fibro-osseous hereditary disorder characterized by bilateral expansion of the maxilla and mandible producing a characteristic facial appearance. It can affect the facial and dental growth of the individual and often results in gross aesthetic and functional deficiencies. The teeth may also be displaced or submerged and these problems can often compromise successful restorative rehabilitation. This paper describes the restorative management of an adult patient with Cherubism involving a fixed implant retained mandibular restoration. The care utilized 3D planning software and implant insertion guides to facilitate an early loading protocol and the use of optimum bone quality/volume areas. PMID- 21780730 TI - Radiographic evaluation of healing tissues of early-failing implants after therapy: a case report. AB - Aside from clinical evaluation, the interpretation of radiographic images is one of the most frequently applied diagnostic procedures in patients with oral implants. Radiology is an important part of treatment with tissue-integrated prostheses, both at the pre-operative stage to obtain full assessment of the bony host and at the post- operative stage to assess the clinical result. Radiographic examination of peri-implant tissues is an essential diagnostic prerequisite for the evaluation of success and failure of oral implants. A case of peri-implant radiolucency detected 3 months after surgical placement is presented. A remarkable regression of the radiolucency was noticed after a successful anti infective therapy. The aim was to stress the role of oral radiology in exploring peri-implant bone defects. At this point, appropriate intervention might save early-failing implants from complete loss of osseointegration. PMID- 21780732 TI - A study on the practical applicability of the rule of golden rectangle in dental aesthetics. AB - Maxillary central incisors are of critical value in the aesthetics of a smile. The Golden Rectangle ratio concept may play an important role in selecting the optimum width and length of this tooth. The aim of the study was to investigate the existence of this ratio among individuals with natural dentition and to validate its role in aesthetic oral rehabilitation. The clinical crown length of the maxillary left central incisor (CI) and combined crown width of the maxillary left and right CI of 70 subjects were measured. The crown width to crown length ratio was calculated and compared with the Golden Rectangle ratio and statistically analysed. Eighty percent of the subjects varied within 2 standard deviations of the ratio of 1.618. No statistically significant influence of gender on the ratio was observed. Golden rectangle was found to have a significant relationship with aesthetic appearance of maxillary central incisors. PMID- 21780731 TI - Two-body wear resistance of some indirect composite resins. AB - The aim of this study was to evaluate two-body wear of five indirect composites and compare them with enamel. Signum, belleGlass HP, SR Adoro, Dialog, GC Gradia and enamel were formed into cylinders (n = 10). Two-body abrasive wear rates were determined using a porcelain disk and a pin on disk apparatus. The height and weight loss of the specimens were measured by stereomicroscope and digital scale. The data were subjected to analysis of variance and Tukey HSD tests to determine significant differences (alpha = 0.05). GC Gradia showed significantly less wear resistance than the other materials. Enamel was more resistant than any of the tested composites. Within the limitations of this study it can be concluded that the type of resin, filler size and method of polymerization could have affect the two-body abrasion resistance of indirect composites. PMID- 21780733 TI - A provider unit with multiple nurse planners in a multifaceted organization: making it work. AB - The accredited provider unit in a large academic medical center includes 26 nurse planners spread across the institution. The provider unit, its structure, and its relationship to the rest of the organization are discussed. The selection, orientation, and ongoing competence of nurse planners are addressed. Operations and communication strategies are featured. PMID- 21780734 TI - Improving feedback to students online: teaching tips from experienced faculty. AB - BACKGROUND: As nurses seek to advance their education through online courses, considering best practices in feedback is especially important. Rich and rapid feedback has long been considered a best teaching practice, but how to provide this feedback in an online course environment is not always clear. This study was conducted to identify how experienced faculty provide feedback to online students. METHODS: This descriptive exploratory study surveyed faculty about their approach to feedback with broad exploratory questions and a validation survey. The sample included faculty in four different states who benchmark online educational best practices. RESULTS: Content analysis was used to evaluate data, with 15 themes emerging. These themes were organized into three categories: using best available tools; having a system; and creating a feedback-rich environment. CONCLUSION: The findings support and extend the guidelines for best practices in online education, including a focus on multisource feedback opportunities during course design. PMID- 21780735 TI - Establishing a virtual learning environment: a nursing experience. AB - The use of virtual worlds has exploded in popularity, but getting started may not be easy. In this article, the authors, members of the corporate nursing education team at University Health Network, outline their experience with incorporating virtual technology into their learning environment. Over a period of several months, a virtual hospital, including two nursing units, was created in Second Life(r), allowing more than 500 nurses to role-play in a safe environment without the fear of making a mistake. This experience has provided valuable insight into the best ways to develop and learn in a virtual environment. The authors discuss the challenges of installing and building the Second Life(r) platform and provide guidelines for preparing users and suggestions for crafting educational activities. This article provides a starting point for organizations planning to incorporate virtual worlds into their learning environment. PMID- 21780736 TI - To lift or not to lift: patient-handling practices. AB - Musculoskeletal injury is common among nurses as a result of lifting and handling patients. In response to musculoskeletal injuries, safe patient-handling programs are being instituted to decrease the risk of injuries and resulting impaired function. This study was designed to identify patient-handling practices in clinical practice. This qualitative study used 128 hours of observations of patient-handling practices and interviews of 32 nursing staff who discussed these practices. Findings demonstrated five factors impact nurses' judgment regarding the best way to move patients: complexity of everyday care, patient treatment goals, time, knowledge, and equipment issues. PMID- 21780737 TI - Yoga to treat nonspecific low back pain. AB - Low back pain is common and poses a challenge for clinicians to find effective treatment to prevent it from becoming chronic. Chronic low back pain can have a significant impact on an employee's ability to remain an active and productive member of the work force due to increased absenteeism, duty restrictions, or physical limitations from pain. Low back pain is the most common cause of work related disability among employees younger than 46 years. Advancing technology and less invasive surgical procedures have not improved outcomes for employees who suffer from low back pain. Most continue to experience some pain and dysfunction after conventional treatments such as injections and surgery. An alternative treatment that could reduce nonspecific chronic low back pain would benefit both employees and employers. Exercising and remaining active are part of most guidelines' routine care recommendations but are not well defined. PMID- 21780738 TI - Isolation of nematicidal compounds from Tagetes patula L. yellow flowers: structure-activity relationship studies against cyst nematode Heterodera zeae infective stage larvae. AB - Bioassay-guided isolation studies on the extracts of yellow flowers of Tagetes patula L. against the Heterodera zeae were carried out to identify phytochemicals lethal to this economically important cyst nematode. In vitro investigation of a polar extract and fractions showing activity led to the isolation of phenolic compounds (flavonoids and phenolic acids). In the nonpolar extract, a few fatty acids, their methyl esters, and thiophenes (including alpha-terthienyl) were detected. In studies of compounds obtained commercially, alpha-terthienyl and gallic and linoleic acids showed 100% mortality at concentrations of 0.125% after 24 h. Assessment of structure-activity relationships revealed that an increase in the number of hydroxyl groups in phenolic acids increased the activity; with fatty acids, activity depended on chain length and the number and position of double bonds. Crude extracts of the flowers of different colors also have promising activity. PMID- 21780739 TI - Radiocarbon (14C) diurnal variations in fine particles at sites downwind from Tokyo, Japan in summer. AB - The radiocarbon ((14)C) of total carbon (TC) in atmospheric fine particles was measured at 6 h or 12 h intervals at two sites, 50 and 100 km downwind from Tokyo, Japan (Kisai and Maebashi) in summer 2007. The percent modern carbon (pMC) showed clear diurnal variations with minimums in the daytime. The mean pMC values at Maebashi were 28 +/- 7 in the daytime and 45 +/- 16 at night (37 +/- 15 for the overall period). Those at Kisai were 26 +/- 9 in the daytime and 44 +/- 8 at night (37 +/- 12 for the overall period). This data indicates that fossil sources were major contributors to the daytime TC, while fossil and modern sources had comparable contributions to nighttime TC in the suburban areas. At both sites, the concentration of fossil carbon as well as O(3) and the estimated secondary organic carbon increased in the daytime. These results suggest that fossil sources around Tokyo contributed significantly to the high daytime concentration of secondary organic aerosols (SOA) at the two suburban sites. A comparison of pMC and the ratio of elemental carbon/TC from our particulate samples with those from three end-member sources corroborates the dominant role of fossil SOA in the daytime. PMID- 21780740 TI - Integrated online system for a pyrosequencing-based microbial source tracking method that targets Bacteroidetes 16S rDNA. AB - Genotypic microbial source tracking (MST) methods are now routinely used to determine sources of fecal contamination impacting waterways. We previously reported the development of a pyrosequencing-based MST method that assigns contamination sources based on shared operational taxonomic units (OTUs) between fecal and environmental bacterial communities. Despite decreasing sequencing costs, pyrosequencing-based MST approaches are not used in routine water quality monitoring studies due in large part to difficulties in handling massive data sets and difficulties in determining sources of fecal contamination. In the studies presented here we describe the development of an online MST tool, PyroMiST ( http://env1.gist.ac.kr/~aeml/MST.html) that uses total bacterial or Bacteroidetes 16S rDNA pyrosequencing reads to determine fecal contamination of waterways. The program cd-hit was used for OTU assignment and a Perl script was used to calculate the number of shared OTUs. The analyses require only a small number of pyrosequencing reads from environmental samples. Our results indicate that PyroMiST provides a user-friendly web interface for pyrosequence data that significantly reduces analysis time required to determine potential sources of fecal contamination in the environment. PMID- 21780741 TI - Impact of Ni(OH)(2) platelike particles on lamellar surfactant mesophases and the orientation of their mixtures under elongational flow. AB - This article describes the behavior under elongational flow of mixtures of lamellar fragments and platelike colloidal particles. Mixtures of a dialkyl chain cationic surfactant, DHTAC (15 wt %), and the nonionic surfactant Brij 97 (0.5 wt %) form dispersions of lamellar phase fragments, and these were studied in the presence of smaller platelike colloidal particles of Ni(OH)(2) stabilized with sodium polyacrylate. Small-angle neutron scattering was used to follow the changes in the lamellar phase fragments in the mixture under elongational flow. The addition of a small fraction of the Ni(OH)(2) dispersion resulted in significantly increased viscosity and reduced the structure and size of the lamellar fragments, and this effect was further enhanced because of the flow induced alignment. The behavior of the mixture under elongational flow is described, and the induced orientation is discussed in terms of order parameters at the different positions using spatially resolved small-angle scattering. The effect of flow rate on the orientational alignment in the mixture is also described. PMID- 21780742 TI - A prodrug approach for improving antituberculosis activity of potent Mycobacterium tuberculosis type II dehydroquinase inhibitors. AB - The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities. PMID- 21780743 TI - Fabrication and characterization of rare-earth-doped nanostructures on surfaces. AB - This article presents a simple and practical means to produce rare-earth-based nanostructures, as well as a combined characterization of structure and optical properties in situ. A nanosphere lithography strategy combined with surface chemistry enables the production of arrays of beta-NaYF(4):Yb,Er nanorings inlaid in an octadecyltrichlorosilane matrix. These arrays of nanorings are produced over the entire support, such as a 1 cm(2) glass coverslip. The dimension of nanorings can be varied by changing the deposition conditions. A home constructed, multifunctional microscope integrating atomic force microscopy, near field scanning optical microscopy, and far-field optical microscopy and spectroscopy is utilized to characterize the nanostructures. This in situ and combined characterization is important for rare-earth-containing nanomaterials in order to correlate local structure with upconversion photoluminescence. Knowledge gained from the investigation should facilitate materials design and optimization, for instance, in the context of photovoltaic devices and biofluorescent probes. PMID- 21780744 TI - Low fluorine content CO2-philic surfactants. AB - The article addresses an important, and still unresolved question in the field of CO(2) science and technology: what is the minimum fluorine content necessary to obtain a CO(2)-philic surfactant? A previous publication (Langmuir 2002, 18, 3014) suggested there should be an ideal fluorination level: for optimization of possible process applications in CO(2), it is important to establish just how little F is needed to render a surfactant CO(2)-philic. Here, optimum chemical structures for water-in-CO(2) (w/c) microemulsion stabilization are identified through a systematic study of CO(2)-philic surfactant design based on dichain sulfosuccinates. High pressure small-angle neutron scattering (HP-SANS) measurements of reversed micelle formation in CO(2) show a clear relationship between F content and CO(2) compatibility of any given surfactant. Interestingly, high F content surfactants, having lower limiting aqueous surface tensions, gamma(cmc), also have better performance in CO(2), as indicated by lower cloud point pressures, P(trans). The results have important implications for the rational design of CO(2)-philic surfactants helping to identify the most economic and efficient compounds for emerging CO(2) based fluid technologies. PMID- 21780745 TI - Role of bacterial biomass in the sorption of Ni by biomass-birnessite assemblages. AB - Birnessites precipitated by bacteria are typically poorly crystalline Mn(IV) oxides enmeshed within biofilms to form complex biomass-birnessite assemblages. The strong sorption affinity of bacteriogenic birnessites for environmentally important trace metals is relatively well understood mechanistically, but the role of bacterial cells and extracellular polymeric substances appears to vary among trace metals. To assess the role of biomass definitively, comparison between metal sorption by biomass at high metal loadings in the presence and absence of birnessite is required. We investigated the biomass effect on Ni sorption through laboratory experiments utilizing the birnessite produced by the model bacterium, Pseudomonas putida. Surface excess measurements at pH 6-8 showed that birnessite significantly enhanced Ni sorption at high loadings (up to nearly 4-fold) relative to biomass alone. This apparent large difference in affinity for Ni between the organic and mineral components was confirmed by extended X-ray absorption fine structure spectroscopy, which revealed preferential Ni binding to birnessite cation vacancy sites. At pH >= 7, Ni sorption involved both adsorption and precipitation reactions. Our results thus support the view that the biofilm does not block reactive mineral surface sites; instead, the organic material contributes to metal sorption once high-affinity sites on the mineral are saturated. PMID- 21780746 TI - Force-driven polymer translocation through a nanopore: an old problem revisited. AB - We consider DNA translocation through a pore in a planar membrane. The pore is so narrow that only one DNA segment can fit in. Assuming that the biasing force f acts inside the pore only, and that the DNA monomer number N is asymptotically large, we modify the previously developed treatment of the stretched part of the pre-translocated polymer by introducing the concept of "iso-flux trumpet". We show that friction of a moving chain in the trumpet, although it determines the speed of the process, provides only a marginal fraction of overall dissipation in the process. The dominant dissipation turns out to be due to irreversible entropic squeezing of the chain into the small pore. We also discover that because of the role of the membrane a much larger amount of heat of order k(B)T per monomer gets transferred from the heat bath on the post-translocation side to that on the pre-translocation side. PMID- 21780749 TI - Subshell fitting of relativistic atomic core electron densities for use in QTAIM analyses of ECP-based wave functions. AB - Scalar-relativistic, all-electron density functional theory (DFT) calculations were done for free, neutral atoms of all elements of the periodic table using the universal Gaussian basis set. Each core, closed-subshell contribution to a total atomic electron density distribution was separately fitted to a spherical electron density function: a linear combination of s-type Gaussian functions. The resulting core subshell electron densities are useful for systematically and compactly approximating total core electron densities of atoms in molecules, for any atomic core defined in terms of closed subshells. When used to augment the electron density from a wave function based on a calculation using effective core potentials (ECPs) in the Hamiltonian, the atomic core electron densities are sufficient to restore the otherwise-absent electron density maxima at the nuclear positions and eliminate spurious critical points in the neighborhood of the atom, thus enabling quantum theory of atoms in molecules (QTAIM) analyses to be done in the neighborhoods of atoms for which ECPs were used. Comparison of results from QTAIM analyses with all-electron, relativistic and nonrelativistic molecular wave functions validates the use of the atomic core electron densities for augmenting electron densities from ECP-based wave functions. For an atom in a molecule for which a small-core or medium-core ECPs is used, simply representing the core using a simplistic, tightly localized electron density function is actually sufficient to obtain a correct electron density topology and perform QTAIM analyses to obtain at least semiquantitatively meaningful results, but this is often not true when a large-core ECP is used. Comparison of QTAIM results from augmenting ECP-based molecular wave functions with the realistic atomic core electron densities presented here versus augmenting with the limiting case of tight core densities may be useful for diagnosing the reliability of large-core ECP models in particular cases. For molecules containing atoms of any elements of the periodic table, the production of extended wave function files that include the appropriate atomic core densities for ECP-based calculations, and the use of these wave functions for QTAIM analyses, has been automated. PMID- 21780747 TI - Quantitative glycoproteomic analysis of optimal cutting temperature-embedded frozen tissues identifying glycoproteins associated with aggressive prostate cancer. AB - Prostate cancer is the most common malignancy in men in the United States, and one in seven men with prostate cancer dies of the disease. A major issue of prostate diagnosis is that there is no good method to reliably distinguish aggressive prostate cancer from nonaggressive prostate cancer. This leads to significant unnecessary suffering among prostate cancer patients and massive unnecessary health care expenditures. In this study, we aim to identify glycoproteins associated with aggressive prostate cancer using optimal cutting temperature (OCT)-embedded frozen tissues obtained from patients with known clinical outcome. To eliminate the interference of mass spectrometric analysis by the compounds in OCT and identify extracellular proteins that are likely to serve as biomarkers in body fluids, we employed glycoproteomic analysis using solid phase extraction of glycopeptides, which allowed the immobilization of glycopeptides to solid support and removal of OCT from sample proteins before releasing the glycopeptides from the solid support for mass spectrometry analysis. Tumor tissues were cryostat microdissected from four cases of aggressive and four cases of nonaggressive prostate tumors, and glycopeptides were isolated and labeled with iTRAQ reagents before the samples were analyzed with LTQ Orbitrap Velos. From the aggressive prostate cancer tissues, we identified the overexpression of three glycoproteins involved in an extracellular matrix remodeling and further examined two glycoproteins, cathepsin L and periostin, using Western blot and immunohistochemistry analyses. This is the first proteomic study to identify proteins potentially associated with aggressive prostate cancer using OCT-embedded frozen tissues. Further study of these proteins will be needed to understand the roles of extracellular matrix proteins in cancer progression and their potential clinical utility in improving diagnosis of aggressive prostate cancer. PMID- 21780750 TI - Emission and excitation spectra of Ce3+ and Pr3+ ions in hexafluoroelpasolite lattices. AB - The emission and excitation spectra of Ce(3+) and Pr(3+) doped into the cubic host Cs(2)NaYF(6) have been recorded at room temperature and ~10 K using synchrotron radiation. The two 5d(1) T(2g) states of Ce(3+) have been located from the excitation spectra, whereas the E(g) state is placed above the host band gap. Decay measurements of the 5d(1) -> 4f(1) Ce(3+) emission, and spectra collected using selective excitation, indicate the occupation of more than one type of site by Ce(3+) in this host lattice. By contrast, the location of features in the 4f(1)5d(1) -> 4f(2) emission of Pr(3+) is independent of the excitation wavelength. Assignments are presented for some of the 4f(1)5d(1) levels and for the Pr(3+)-F(-) charge transfer band. The 5d emission lifetimes for Ce(3+) and Pr(3+) in the Cs(2)NaYF(6) host are 42 and 29 +/- 1 ns, respectively, and are not temperature-dependent. PMID- 21780751 TI - Bond energies, reaction volumes, and kinetics for sigma- and pi-complexes of MoCO5L. AB - The photosubstitution reactions of molybdenum hexacarbonyl with sigma and pi donor ligands were investigated using photoacoustic calorimetry and computational methods in a series of linear alkane solvents (pentane, hexane, heptane, octane, decane, and dodecane). The results show that reaction volumes make a significant contribution to the photoacoustic signal and must be considered during thermodynamic calculations based on photoacoustic measurements. The enthalpies of CO substitution by an alkane solvent and subsequent substitution by each Lewis base were determined. Corresponding Mo-L bond energies (kcal mol(-1)) were calculated: L = linear alkanes (13), triethylsilane (26), 1-hexyne (27), 1-hexene (27), and benzene (17). The relative energies are in agreement with computational results. The experimental reaction volume for CO substitution by alkane was positive (15 mL mol(-1)) and negative or close to zero for alkane substitution by a Lewis base (for example, -11 mL mol(-1) for triethylsilane and 3.6 mL mol(-1) for benzene). The errors in the experimental and computational reaction volumes are large and often comparable to the reaction volumes. An improved calibration of the methods as well as a better understanding of the underlying physics involved is needed. For the Lewis bases reported in this study, the second-order rate constants for the displacement of a coordinated alkane are less than diffusion control (5 * 10(6)-4 * 10(7) M(-1) s(-1)) and decrease monotonically with the alkane chain length. The rate constants correlate better with steric effects than with bond energies. An interchange mechanism is consistent with the results. PMID- 21780752 TI - Tuning manganese dopant spin interactions in single GaN nanowires at room temperature. AB - Control of electron spins in individual magnetically doped semiconductor nanostructures has considerable potential for quantum information processing and storage. The manipulations of dilute magnetic interactions have largely been restricted to low temperatures, limiting their potential technological applications. Among the systems predicted to be ferromagnetic above room temperature, Mn-doped GaN has attracted particular attention, due to its attractive optical and electrical properties. However, the experimental data have been inconsistent, and the origin of the magnetic interactions remains unclear. Furthermore, there has been no demonstration of tuning the dopant exchange interactions within a single nanostructure, which is necessary for the design of nanoscale spin-electronic (spintronic) devices. Here we directly show for the first time intrinsic magnetization of manganese dopants in individual gallium nitride nanowires (NWs) at room temperature. Using high-resolution circularly polarized X-ray microscopy imaging, we demonstrate the dependence of the manganese exchange interactions on the NW orientation with respect to the external magnetic field. The crystalline anisotropy allows for the control of dilute magnetization in a single NW and the application of bottom-up approaches, such as in situ nanowire growth control or targeted positioning of individual NWs, for the design of networks for quantum information technologies. PMID- 21780753 TI - Microwave-assisted domino access to C2-chain functionalized furans from tertiary propargyl vinyl ethers. AB - Tertiary propargyl vinyl ethers armed with an electron-withdrawing group (amide or ester) at the tertiary propargylic position have been efficiently transformed into trisubstituted C(2)-chain functionalized furans. The metal-free domino transformation involves a microwave-assisted tandem [3,3]-propargyl Claisen rearrangement/5-exo-dig O-cyclization reaction. The manifold can be performed in a one-pot fashion from the primary components (1,2-ketoester/1,2-ketoamide or tertiary propargyl alcohols). PMID- 21780754 TI - Cyclization reaction for the synthesis of polysubstituted naphthalenes in the presence of Au(I) precatalysts. AB - Au(I)-catalyzed cyclization of alkenyl carbonyl compounds leading to a variety of substituted naphthalenes has been developed. This process exploits a dual function of the Au(I) catalyst: (1) the oxophilic nature of the Au(I) catalyst, counterintuitive to the pi-acidic reactivities generally associated with Au catalysts, and (2) olefin isomerization supported by the outcome of isotope scrambling experiments. It cannot be completely excluded that TfOH is a true operative catalyst in this protocol. In view of the practicality, the unnecessity of isomerically pure starting material in this reaction is particularly attractive and valuable. PMID- 21780756 TI - Pyrrolinone-pyrrolidine oligomers as universal peptidomimetics. AB - Peptidomimetics 1-3 were prepared from amino acid-derived tetramic acids 7 as the key starting materials. Calculations show that preferred conformations of 1 can align their side-chain vectors with amino acids in common secondary structures more effectively than conformations of 3. A good fit was found for a preferred conformation of 2 (an extended derivative of 1) with a sheet/beta-turn/sheet motif. PMID- 21780757 TI - Computational design of a beta-peptide that targets transmembrane helices. AB - The design of beta-peptide foldamers targeting the transmembrane (TM) domains of complex natural membrane proteins has been a formidable challenge. A series of beta-peptides was designed to stably insert in TM orientations in phospholipid bilayers. Their secondary structures and orientation in the phospholipid bilayer was characterized using biophysical methods. Computational methods were then devised to design a beta-peptide that targeted a TM helix of the integrin alpha(IIb)beta(3). The designed peptide (beta-CHAMP) interacts with the isolated target TM domain of the protein and activates the intact integrin in vitro. PMID- 21780758 TI - Directional emission from plasmonic Yagi-Uda antennas probed by angle-resolved cathodoluminescence spectroscopy. AB - Optical nanoantennas mediate optical coupling between single emitters and the far field, making both light emission and reception more effective. Probing the response of a nanoantenna as a function of position requires accurate positioning of a subwavelength sized emitter with known orientation. Here we present a novel experimental technique that uses a high-energy electron beam as broad band point dipole source of visible radiation, to study the emission properties of a Yagi Uda antenna composed of a linear array of Au nanoparticles. We show angle resolved emission spectra for different wavelengths and find evidence for directional emission of light that depends strongly on where the antenna is excited. We demonstrate that the experimental results can be explained by a coupled point dipole model which includes the effect of the dielectric substrate. This work establishes angle-resolved cathodoluminescence spectroscopy as a powerful technique tool to characterize single optical nanoantennas. PMID- 21780759 TI - Modeling nitrous oxide production during biological nitrogen removal via nitrification and denitrification: extensions to the general ASM models. AB - Nitrous oxide (N(2)O) can be formed during biological nitrogen (N) removal processes. In this work, a mathematical model is developed that describes N(2)O production and consumption during activated sludge nitrification and denitrification. The well-known ASM process models are extended to capture N(2)O dynamics during both nitrification and denitrification in biological N removal. Six additional processes and three additional reactants, all involved in known biochemical reactions, have been added. The validity and applicability of the model is demonstrated by comparing simulations with experimental data on N(2)O production from four different mixed culture nitrification and denitrification reactor study reports. Modeling results confirm that hydroxylamine oxidation by ammonium oxidizers (AOB) occurs 10 times slower when NO(2)(-) participates as final electron acceptor compared to the oxic pathway. Among the four denitrification steps, the last one (N(2)O reduction to N(2)) seems to be inhibited first when O(2) is present. Overall, N(2)O production can account for 0.1-25% of the consumed N in different nitrification and denitrification systems, which can be well simulated by the proposed model. In conclusion, we provide a modeling structure, which adequately captures N(2)O dynamics in autotrophic nitrification and heterotrophic denitrification driven biological N removal processes and which can form the basis for ongoing refinements. PMID- 21780760 TI - Polyelectrolyte-functionalized graphene as metal-free electrocatalysts for oxygen reduction. AB - Poly(diallyldimethylammonium chloride), PDDA, was used as an electron acceptor for functionalizing graphene to impart electrocatalytic activity for the oxygen reduction reaction (ORR) in fuel cells. Raman and X-ray photoelectron spectroscopic measurements indicate the charge transfer from graphene to PDDA. The resultant graphene positively charged via intermolecular charge-transfer with PDDA was demonstrated to show remarkable electrocatalytic activity toward ORR with better fuel selectivity, tolerance to CO posing, and long-term stability than that of the commercially available Pt/C electrode. The observed ORR electrocatalytic activity induced by the intermolecular charge-transfer provides a general approach to various carbon-based metal-free ORR catalysts for oxygen reduction. PMID- 21780761 TI - Characterization of dibenzo[a,l]pyrene-trans-11,12-diol (dibenzo[def,p]chrysene) glucuronidation by UDP-glucuronosyltransferases. AB - Dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene) is a highly carcinogenic polycyclic aromatic hydrocarbon (PAH) that has been identified in tobacco smoke and is found in our environment due to incomplete combustion of organic matter. Its metabolites are known to form stable DNA adducts in bacteria and mammalian cells, and can lead to tumors in animal models. Glucuronidation of major metabolites of DB[a,l]P by the uridine-5'-diphosphate glucuronosyltransferase (UGT) family of enzymes is an important route of detoxification of this pro carcinogen. The focus of the current study was to characterize the glucuronidation of the pro-carcinogenic enantiomers DB[a,l]P-(+)-trans-11S,12S diol and DB[a,l]P-(-)-trans-11R,12R-diol. Glucuronidation assays with HEK293 cell lines overexpressing individual human UGT enzymes demonstrated that UGTs 1A1, 1A4, 1A7, 1A8, 1A9, 1A10, and 2B7 glucuronidated one or both DB[a,l]P-trans-11,12 diol enantiomers. Three glucuronide conjugates were observed in activity assays with UGTs 1A1 and 1A10, while two glucuronides were formed by UGTs 1A7, 1A8, and 1A9, and one glucuronide was made by UGT1A4 and UGT2B7. Enzyme kinetic analysis indicated that UGT1A9 was the most efficient UGT at forming both the (+)-DB[a,l]P 11-Gluc and (-)-DB[a,l]P-11-Gluc products, while UGTs 1A1 and 1A10 were the most efficient at forming the (+)-DB[a,l]P-12-Gluc product (as determined by k(cat)/K(M)). Incubations with human liver microsomes showed the formation of three diastereomeric glucuronide products: (+)-DB[a,l]P-11-Gluc, (+)-DB[a,l]P-12 Gluc, and (-)-DB[a,l]P-11-Gluc, with an average overall ratio of 31:32:37 in four liver specimens. Human bronchus and trachea tissue homogenates demonstrated glucuronidation activity against both DB[a,l]P-trans-11,12-diol enantiomers, with both tissues producing the (+)-DB[a,l]P-11-Gluc and (+)-DB[a,l]P-12-Gluc with little or no formation of (-)-DB[a,l]P-11-Gluc. These results indicate that multiple UGTs are involved in the stereospecific glucuronidation of DB[a,l]P trans-11,12-diol in a pattern consistent with their expression in respiratory tract tissues and that glucuronidation may be an important first-line detoxification mechanism of DB[a,l]P metabolites. PMID- 21780762 TI - Label-free probing of G-quadruplex formation by surface-enhanced Raman scattering. AB - In this work, we establish the use of surface-enhanced Raman scattering (SERS) as a label-free analytical technique for the direct detection of G-quadruplex formation. In particular, we demonstrate that SERS analysis allows the evaluation of the relative stability of G quadruplexes that differ for the number of G tetrads and investigate several structural features of quadruplexes, such as the orientation of glycosidic bonds, the identification of distortions in the sugar phosphate backbone, and the degree of hydrogen-bond solvation. Herein, the fluctuation of the SERS spectra, due to the specific interaction of vibrational modes with the SERS-active substrate, is quantitatively analyzed before and after quadruplex formation. The results of this study suggest a perpendicular orientation of the quadruplexes (with or without the 3'-tetra end linker) with respect to the silver colloidal surface, which opens new perspectives for the use of SERS as a label-free analytical tool for the study of the binding mode between quadruplexes and their ligands. PMID- 21780763 TI - Highly efficient hydrogen-bonding catalysis of the Diels-Alder reaction of 3 vinylindoles and methyleneindolinones provides carbazolespirooxindole skeletons. AB - Carbazolespirooxindole derivatives were synthesized in a high-yielding, atypically rapid, stereocontrolled Diels-Alder reaction catalyzed by a C(2) symmetric bisthiourea organocatalyst. Simple precursors and mild conditions were used to construct carbazolespirooxindole derivatives with high enantiopurity and structural diversity under H-bonding catalysis. The practical approach recycles the organocatalyst and solvent. This simple and efficient operational procedure will allow diversity-oriented syntheses of this intriguing class of compounds. PMID- 21780764 TI - N-heterocyclic carbene stabilized dichlorosilylene transition-metal complexes of V(I), Co(I), and Fe(0). AB - Reactions of N-heterocyclic carbene stabilized dichlorosilylene IPr.SiCl(2) (1) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) with (eta(5) C(5)H(5))V(CO)(4), (eta(5)-C(5)H(5))Co(CO)(2), and Fe(2)(CO)(9) afford dichlorosilylene complexes IPr.SiCl(2).V(CO)(3)(eta(5)-C(5)H(5)) (2), IPr.SiCl(2).Co(CO)(eta(5)-C(5)H(5)) (3), and IPr.SiCl(2).Fe(CO)(4) (4), respectively. Complexes 2-4 are stable under an inert atmosphere, are soluble in common organic solvents, and have been characterized by elemental analysis and multinuclear ((1)H, (13)C, and (29)Si) NMR spectroscopy. Molecular structures of 2-4 have been determined by single crystal X-ray crystallographic studies and refined with nonspherical scattering factors. PMID- 21780765 TI - Two new methods of synthesis for the perbromate ion: chemistry and determination by LC-MS/MS. AB - Historically, the synthesis of perbromate ion through conventional oxidation routes has proven elusive. Herein, we report perbromate ion formation through the reaction of hypobromite and bromate ions in an alkaline sodium hypobromite solution. Formation was established via LC-MS/MS analysis of the bromate and perbromate ions in the reaction solutions over a 13-day period. Furthermore, it was discovered that the perbromate ion was also formed as a result of the electrospray ionization process. Selective reduction of the bromate ion prior to analysis was used to confirm the two formation pathways. PMID- 21780766 TI - DNA cleavage activity of Fe(II)N4Py under photo irradiation in the presence of 1,8-naphthalimide and 9-aminoacridine: unexpected effects of reactive oxygen species scavengers. AB - The DNA cleavage activity of the iron(II) complex of the ligand N,N-bis(2 pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) was investigated in the presence of the chromophores 1,8-naphthalimide (NI) and 9-aminoacridine (AA) under photo irradiation at 355 and 400.8 nm and compared to the activity of the complex without the chromophores. Whereas in most cases no synergistic effect of the added chromophores on DNA cleavage efficiency was observed, it was found that for Fe(II)N4Py, in combination with NI under irradiation at 355 nm, the DNA cleavage activity was increased. Surprisingly, it was found that the addition of reactive oxygen species (ROS) scavengers gave rise to significantly increased DNA cleavage efficiency, which is a highly counterintuitive observation since ROS are needed to achieve DNA cleavage. A hypothesis is put forward to explain, at least partly, these results. It is proposed that the addition of scavengers inhibits quenching of (3)NI*, thus making photo-induced electron transfer between (3)NI* and Fe(III)N4Py more efficient. This results in reduction of Fe(III)N4Py to Fe(II)N4Py, which can then react with ROS giving rise to DNA cleavage. Hence the role of the scavengers is to maintain a close to optimal concentration of ROS. The present study serves as an illustration of the care that needs to be exercised in interpreting the results of experiments using standard ROS scavengers, since especially in complex systems such as presented here they can give rise to unexpected phenomena. In the presence of 1,8-naphthalimide or 9 aminoacridine, ROS scavengers can increase the DNA cleavage efficiency of Fe(II)N4Py complex under photo irradiation. PMID- 21780767 TI - Diffusion of organic solutes in squalane. AB - The translational diffusion constants, D, of 26 hydrocarbons have been determined in squalane (2,6,10,15,19,23-hexamethyltetracosane) at room temperature using capillary flow techniques. These new data and previously published room temperature D values for the same solutes in some (or all) of the n-alkanes n C(6)-n-C(16) constitute a study of solute diffusion in media spanning a 100-fold change in viscosity; at 23 degrees C, eta = 0.31 cP for n-C(6), 3.2 cP for n C(16), and 30 cP for squalane. The D values in the n-alkanes and squalane show deviations from the Stokes-Einstein relation, D = k(B)T/(6pietar); the values of r, a solute's hydrodynamic radius, decrease as the viscosity increases. The deviations increase as the solute size decreases and are analyzed by fitting the diffusion constants to the modified Stokes-Einstein equation, D/T = A(SE)/eta(p). Fits involving the n-alkane-only and combined n-alkane-squalane D values give comparable results with values of p < 1 that increase as the solute size increases; p = 1 for the Stokes-Einstein limit. The deviations from Stokes Einstein behavior also are discussed in terms of the relative sizes of the solutes, the n-alkanes, and squalane. PMID- 21780768 TI - Connection between the isobaric thermal expansion coefficient with the Zeno-line and critical-point parameters for liquids. AB - We have found the expression which connects the values of volumetric thermal expansion coefficients under low temperatures and pressures with the critical point and Zeno-line parameters. The calculations based on this expression for different substances (NH(3), CO(2), hexane, Hg, and Cs) are in good agreement with experimental data at relatively low temperatures. PMID- 21780769 TI - Understanding the effect of the counterion on the reverse-phase ion-pair high performance liquid chromatography (RPIP-HPLC) resolution of heparin-related saccharide anomers. AB - Reverse-phase ion-pair high-performance liquid chromatography (RPIP-HPLC) is an increasingly popular chromatographic technique for the separation of charged compounds, including oligosaccharides derived from the glycosaminoglycans (GAGs) heparin and heparan sulfate (HS). This family of heparin disaccharides has been shown to be useful compounds to probe the details of the RPIP-HPLC separation mechanism, the aspects of which are still being debated. In this manuscript, the effects of ion-pairing reagent (IPR) concentration, counterion, and mobile phase pH on the quality of the RPIP-UPLC separation were examined with particular emphasis on how these factors impact the separation of the disaccharide anomers. These results highlight the role of the IPR counterion and demonstrate that the resolution of the disaccharide anomers can be minimized by conducting the separation at low pH, simplifying chromatographic analysis and improving resolution. The results presented herein can also provide insights into strategies for developing more sensitive and efficient reverse-phase separations for other charged analytes including larger GAG oligosaccharides. PMID- 21780770 TI - The nuclear transport machinery recognizes nucleoplasmin-histone complexes. AB - The nuclear transport of the chromatin remodeling protein nucleoplasmin and chromatin building histones is mediated by importins. Nucleoplasmin (NP) contains a classical bipartite nuclear localization signal (NLS) that is recognized by the importin alpha/beta heterodimer, while histones present multiple NLS-like motifs that are recognized by importin beta family members for nuclear targeting. To explore the possibility of a cotransport of histones and their chaperone NP to the nucleus, we have analyzed the assembly of complexes of NP/histones with importins by means of fluorescence anisotropy, centrifugation in sucrose gradients, and isothermal titration calorimetry. Data show that importin alpha DeltaIBB (a truncated form of importin alpha lacking the autoinhibitory N terminal domain) and histones (linker, H5, and nucleosomal core, H2AH2B) can simultaneously bind to NP. Analysis of the binding energetics reveals an enthalpy driven formation of high affinity ternary, NP/Deltaalpha/H5 and NP/Deltaalpha/H2AH2B, complexes. We find that different amount of importin alpha molecules can be loaded on NP/histone complexes dependent on the histone type, linker or core, and the amount of bound histones. We further demonstrate that NP/H5 complexes can also incorporate importin alpha/beta, thus forming quaternary NP/histones/alpha/beta complexes that might represent a putative coimport pathway for nuclear import of histones and their chaperone protein NP, enhancing the histone import efficiency. PMID- 21780771 TI - Phylogenetic diversity and metabolic potential of activated sludge microbial communities in full-scale wastewater treatment plants. AB - The activated sludge process is an essential process for treating domestic and industrial wastewaters in most wastewater treatment plants (WWTPs). This process consists of a mixture of general and special microorganisms in a form of a complex enrichment population. Thus, the exploration of activated sludge microbial communities is crucial to improve the performance of activated sludge process. In this study, we investigated the phylogenetic diversity and metabolic potential of activated sludge microbial communities in full-scale WWTPs. Four 16S rRNA gene clone libraries were constructed from activated sludge samples. In all samples, Proteobacteria was the most abundant phylogenetic group, followed by Bacteroidetes and Firmicutes. The dominance of Proteobacteria was further demonstrated by denaturing gradient gel electrophoresis (DGGE) and terminal restriction fragment length polymorphism (T-RFLP). Some specific genera, e.g., Nitrosomonas, Thauera, and Dechloromonas, which significantly correlate with the functions and performance of wastewater treatment, were abundant in all samples. A large number of unclassified sequences were found in the library, suggesting that a wide variety of novel species may inhabit complex activated sludge communities. The structures of the bacterial community did not differ significantly among samples. All samples utilized the vast majority of 31 carbon sources of an EcoPlate (Biolog), suggesting that activated sludge microbial communities possess high metabolic potential and equivalent functions required for wastewater treatment. PMID- 21780772 TI - Pathogenic bacteria in sewage treatment plants as revealed by 454 pyrosequencing. AB - This study applied 454 high-throughput pyrosequencing to analyze potentially pathogenic bacteria in activated sludge from 14 municipal wastewater treatment plants (WWTPs) across four countries (China, U.S., Canada, and Singapore), plus the influent and effluent of one of the 14 WWTPs. A total of 370,870 16S rRNA gene sequences with average length of 207 bps were obtained and all of them were assigned to corresponding taxonomic ranks by using RDP classifier and MEGAN. It was found that the most abundant potentially pathogenic bacteria in the WWTPs were affiliated with the genera of Aeromonas and Clostridium. Aeromonas veronii, Aeromonas hydrophila, and Clostridium perfringens were species most similar to the potentially pathogenic bacteria found in this study. Some sequences highly similar (>99%) to Corynebacterium diphtheriae were found in the influent and activated sludge samples from a saline WWTP. Overall, the percentage of the sequences closely related (>99%) to known pathogenic bacteria sequences was about 0.16% of the total sequences. Additionally, a platform-independent Java application (BAND) was developed for graphical visualization of the data of microbial abundance generated by high-throughput pyrosequencing. The approach demonstrated in this study could examine most of the potentially pathogenic bacteria simultaneously instead of one-by-one detection by other methods. PMID- 21780773 TI - Heterogeneity of the electron-trapping kinetics in CdSe nanoparticles. AB - The kinetics of electron trapping in CdSe nanoparticles are examined from 0.5 ps to 1.8 ns. The ensemble kinetics fit a slow power law, but two-dimensional measurements show that the decay of each nanoparticle is exponential. A model is proposed in which defect sites provide a gateway for surface trapping and are randomly distributed on the surface. The electric field from the particle's dipole moment creates the observed heterogeneity in rates. PMID- 21780774 TI - Long-term effects of titanium dioxide nanoparticles on nitrogen and phosphorus removal from wastewater and bacterial community shift in activated sludge. AB - The expanding use of titanium dioxide nanoparticles (TiO(2) NPs) in a wide range of fields raises concerns about their potential environmental impacts. However, investigations of the potential effects of TiO(2) NPs on biological nitrogen and phosphorus removal and bacterial community in activated sludge are sparse. This study evaluated the influences of TiO(2) NPs on biological nutrient removal in the anaerobic-low dissolved oxygen (0.15-0.50 mg/L) sequencing batch reactor. It was found that 1 and 50 mg/L TiO(2) NPs had no acute effects on wastewater nitrogen and phosphorus removal after short-term exposure (1 day). However, 50 mg/L TiO(2) NPs (higher than its environmentally relevant concentration) was observed to significantly decrease total nitrogen (TN) removal efficiency from 80.3% to 24.4% after long-term exposure (70 days), whereas biological phosphorus removal was unaffected. Denaturing gradient gel electrophoresis profiles showed that 50 mg/L TiO(2) NPs obviously reduced the diversity of microbial community in activated sludge, and fluorescence in situ hybridization analysis indicated that the abundance of nitrifying bacteria, especially ammonia-oxidizing bacteria, was highly decreased after long-term exposure to 50 mg/L TiO(2) NPs, which was the main reason for the serious deterioration of ammonia oxidation. Further study revealed that 50 mg/L TiO(2) NPs inhibited the activities of ammonia monooxygenase and nitrite oxidoreductase after long-term exposure, but had no significant impacts on the activities of exopolyphosphatase and polyphosphate kinase, and the transformations of intracellular polyhydroxyalkanoates and glycogen, which were consistent with the observed influences of TiO(2) NPs on biological nitrogen and phosphorus removal. PMID- 21780775 TI - Label-free optical characterization methods for detecting amine silanization driven gold nanoparticle self-assembly. AB - Fluorescence lifetime correlation spectroscopy (FLCS) is presented as a single step label-free detection method for probing the amine silanization-driven spontaneous 3D self-assembly of freestanding gold nanoparticles (GNPs) in solution. Unlike the conventional methods of studying self-assembly, for example, UV-vis spectroscopy and electron microscopy, FLCS utilizes the intrinsic gold fluorescence. The significance of this approach is to amalgamate the measurement of optical and hydrodynamic size properties simultaneously to achieve a more coherent description of the self-assembly pathway. GNP self-assembly has two stage kinetics. Electrostatic interaction drives the initial amine silanization, and this is followed by siloxane bond formation between hydrolyzed ethoxy groups of GNP-attached APTES, resulting in the formation of micrometer-sized superstructures. The self-assembly has resulted in a 5-fold increase in the fluorescence lifetime (FL), and the FLCS study has shown an 8- to 10-fold increase in the diffusion coefficient using the pure diffusion model. This result is consistent with the transmission electron microscopy (TEM) observation, which shows a few hundred fold increase in the diameter due to assembly formation by the GNPs. PMID- 21780776 TI - Remarkable potential of the alpha-aminophosphonate/phosphinate structural motif in medicinal chemistry. PMID- 21780777 TI - Integrating silicon nanowire field effect transistor, microfluidics and air sampling techniques for real-time monitoring biological aerosols. AB - Numerous threats from biological aerosol exposures, such as those from H1N1 influenza, SARS, bird flu, and bioterrorism activities necessitate the development of a real-time bioaerosol sensing system, which however is a long standing challenge in the field. Here, we developed a real-time monitoring system for airborne influenza H3N2 viruses by integrating electronically addressable silicon nanowire (SiNW) sensor devices, microfluidics and bioaerosol-to-hydrosol air sampling techniques. When airborne influenza H3N2 virus samples were collected and delivered to antibody-modified SiNW devices, discrete nanowire conductance changes were observed within seconds. In contrast, the conductance levels remained relatively unchanged when indoor air or clean air samples were delivered. A 10-fold increase in virus concentration was found to give rise to about 20-30% increase in the sensor response. The selectivity of the sensing device was successfully demonstrated using H1N1 viruses and house dust allergens. From the simulated aerosol release to the detection, we observed a time scale of 1-2 min. Quantitative polymerase chain reaction (qPCR) tests revealed that higher virus concentrations in the air samples generally corresponded to higher conductance levels in the SiNW devices. In addition, the display of detection data on remote platforms such as cell phone and computer was also successfully demonstrated with a wireless module. The work here is expected to lead to innovative methods for biological aerosol monitoring, and further improvements in each of the integrated elements could extend the system to real world applications. PMID- 21780778 TI - Concerted complex assembly and GTPase activation in the chloroplast signal recognition particle. AB - The universally conserved signal recognition particle (SRP) and SRP receptor (SR) mediate the cotranslational targeting of proteins to cellular membranes. In contrast, a unique chloroplast SRP in green plants is primarily dedicated to the post-translational targeting of light harvesting chlorophyll a/b binding (LHC) proteins. In both pathways, dimerization and activation between the SRP and SR GTPases mediate the delivery of cargo; whether and how the GTPase cycle in each system adapts to its distinct substrate proteins were unclear. Here, we show that interactions at the active site essential for GTPase activation in the chloroplast SRP and SR play key roles in the assembly of the GTPase complex. In contrast to their cytosolic homologues, GTPase activation in the chloroplast SRP SR complex contributes marginally to the targeting of LHC proteins. These results demonstrate that complex assembly and GTPase activation are highly coupled in the chloroplast SRP and SR and suggest that the chloroplast GTPases may forego the GTPase activation step as a key regulatory point. These features may reflect adaptations of the chloroplast SRP to the delivery of their unique substrate protein. PMID- 21780779 TI - Interactions between spheroidal colloidal particles. AB - Using Derjaguin's approximation, we have evaluated the interaction energy associated with van der Waals, electrostatic, depletion, and capillary forces between colloidal spheroids. If the interaction range between spheroids is distinctly smaller than the lengths of their principal axes, then simple pair potentials that depend on particle distance and orientation can be derived. Attractive interactions between adjacent spheroids favor their parallel alignment. Parallel spheroids can be arranged into a variety of densely packed configurations. All of these configurations turn out to have the same lattice energy. We discuss the implications of this degeneracy with respect to the stability of photonic crystals consisting of spheroids. PMID- 21780780 TI - Diarylethene-containing cyclometalated platinum(II) complexes: tunable photochromism via metal coordination and rational ligand design. AB - The synthesis, characterization, electrochemistry, photophysics and photochromic behavior of a new class of cyclometalated platinum(II) complexes [Pt(C(?)N)(O(?)O)] (1a-5a and 1b-5b), where C(?)N is a cyclometalating 2-(2' thienyl)pyridyl (thpy) or 2-(2'-thienothienyl)pyridyl (tthpy) ligand containing the photochromic dithienylethene (DTE) unit and O(?)O is a beta-diketonato ligand of acetylacetonato (acac) or hexafluoroacetylacetonato (hfac), have been reported. The X-ray crystal structures of five of the complexes have also been determined. The electrochemical studies reveal that the first quasi-reversible reduction couple, and hence the nature of lowest unoccupied molecular orbital (LUMO) of the complexes, is sensitive to the nature of the ancillary O(?)O ligands. Upon photoexcitation, complexes 1a-3a and 1b-3b exhibit drastic color changes, ascribed to the reversible photochromic behavior, which is found to be sensitive to the substituents on the pyridyl ring and the extent of pi conjugation of the C(?)N ligand as well as the nature of the ancillary ligand. The thermal bleaching kinetics of complex 1a has been studied in toluene at various temperatures, and the activation barrier for the thermal cycloreversion of the complex has been determined. Density functional theory (DFT) calculations have been performed to provide an insight into the electrochemical, photophysical and photochromic properties. PMID- 21780781 TI - Binaphthol-derived bisphosphoric acids serve as efficient organocatalysts for highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient olefins. AB - A variety of chiral bisphosphoric acids derived from binaphthols have been evaluated for enantioselective 1,3-dipolar cycloaddition reactions, revealing that the feature of the linker in the catalysts exerted great impact on the stereoselectivity. Among them, the oxygen-linked bisphosphoric acid 1a provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of aldehydes and alpha-amino esters, and various electron deficient dipolarophiles such as maleates, fumarates, vinyl ketones, and esters. This reaction actually represents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidines with excellent optical purity. Theoretical calculations with DFT method on the formation of azomethine ylides and on the transition states of the 1,3-dipolar cycloaddition step showed that the dipole and dipolarophile were simultaneously activated by the bifunctional chiral bisphosphoric acids through the formation of hydrogen bonds. The effect of the bisphosphoric acids on reactivity and stereochemistry of the three-component 1,3-dipolar cycloaddition reaction was also theoretically rationalized. The bisphosphoric acid catalyst 1a may take on a half-moon shape with the two phosphoric acid groups forming two intramolecular hydrogen bonds. In the case of maleates, one phosphate acts as a base to activate the 1,3-dipole, and simultaneously, the two hydroxyl groups in the catalyst 1a may respectively form two hydrogen bonds with the two ester groups of maleate to make it more electronically deficient as a much stronger dipolarophile to participate in a concerted 1,3-dipolar cycloaddition with azomethine ylide. However, in the cases involving acrylate and fumarate dipolarophiles, only one hydroxyl group forms a hydrogen bond with the ester functional group to lower the LUMO of the C-C double bond and another one is remained to adjust the acidity and basicity of two phosphoric acids to activate the dipole and dipolarophile more effectively. PMID- 21780782 TI - Noncovalent trapping and stabilization of dinuclear ruthenium complexes within a coordination cage. AB - A dinuclear ruthenium complex, [(eta(5)-indenyl)Ru(CO)(2)](2), was noncovalently enclathrated within a self-assembled coordination cage. In the cavity, rapid cis trans isomerization and ligand exchange between the terminal and bridging carbonyls were suppressed, and only the carbonyl-bridged cis configuration was observed by X-ray crystallographic analysis. PMID- 21780783 TI - Effect of polyelectrolyte architecture and size on macroion-dye assemblies. AB - This study describes the influence of polyelectrolyte building block nature on the formation of supramolecular polyelectrolyte-dye nanoparticles self-assembled through electrostatic interactions of the oppositely charged building units and pi-pi interactions in-between dye molecules ("electrostatic self-assembly"). The anionic azo dye Acid Red 26 (Ar26) is combined with cationic polyamidoamine dendrimers of generations G0, G2, G4, G6, and G8 and linear polycations polylysine (PolyLys) and polyallylamine hydrochloride (PAH). Light scattering reveals defined supramolecular particles with hydrodynamic radii R(H) = 15 nm to R(H) = 50 nm for slight excess of G2-G8 dendrimers. G0 does not yield stable assemblies. Linear polyelectrolytes form assemblies with hydrodynamic radii from R(H) = 20 nm to R(H) = 200 nm. Thermodynamic measurements by isothermal titration calorimetry (ITC) show that all macroions bind dye molecules up to about charge stoichiometry, and assembly formation is predominantly enthalpically driven. Differences in dye-dye interactions are related to structural features by analyzing endothermic heats of aggregate disruption through excess macroion addition. A simple model connects thermodynamic parameters with the internal assembly structure. PMID- 21780784 TI - Reactivity differences between alpha,beta-unsaturated carbonyls and hydrazones investigated by experimental and theoretical electron density and electron localizability analyses. AB - It is still a challenge to predict a compound's reactivity from its ground-state electronic nature although Bader-type topological analyses of the electron density (ED) and electron localizability indicator (ELI) give detailed and useful information on electron concentration and electron-pair localization, respectively. Both ED and ELI can be obtained from theoretical calculations as well as high-resolution X-ray diffraction experiments. Besides ED and ELI descriptors, the delocalization index is used here; it is likewise derived from theoretical calculations as well as from experimental X-ray results, but in the latter case, demonstrated here for the first time. We investigate alpha,beta unsaturated carbonyl and hydrazone compounds because resonance exhibited by these compounds in the electronic ground-state determines their reactive behavior. The degree of resonance as well as the reactivity contrast are quantified with the electronic descriptors. Moreover, competitive mesomeric substituent effects are studied using the two biologically important compounds acrolein and acrylamide. The reactivity differences predicted from the analyses are in line with the known reactivity of these compounds in organic synthesis. Hence, the capability of the ED and ELI for rationalizing and predicting different and competing substituent effects with respect to reactivity is demonstrated. PMID- 21780785 TI - Conjugate addition-initiated Nazarov cyclization. AB - A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization. PMID- 21780786 TI - Lyotropic self-assembly of high-aspect-ratio semiconductor nanowires of single crystal ZnO. AB - Lyotropic nanowire dispersions are attractive precursors for semiconductor device fabrication because they permit the alignment control of active nanomaterials. The reliable production of nanowire-based mesophases, however, is very challenging in practice. We show that appropriately functionalized high-aspect ratio nanowires of single-crystal ZnO spontaneously form nematic phases in organic and aqueous media. These systems show isotropic, biphasic, and nematic phases on increasing concentration, in reasonable agreement with Onsager's theory for rigid rods interacting via excluded volume. Suspensions were readily processed to produce films with large-area monodomains of aligned nanowires. Imprints of the director field in quiescently dried films display a propensity for bend deformation in the organic mesophase versus splay deformation in the aqueous case, suggesting that system elasticity may be tuned via surface functionalization. These results provide critical insight for the utilization of semiconductor nanowires as novel mesogens and further enable the use of solution based routes for fabricating optoelectronic devices. PMID- 21780787 TI - Doping metal-organic frameworks for water oxidation, carbon dioxide reduction, and organic photocatalysis. AB - Catalytically competent Ir, Re, and Ru complexes H(2)L(1)-H(2)L(6) with dicarboxylic acid functionalities were incorporated into a highly stable and porous Zr(6)O(4)(OH)(4)(bpdc)(6) (UiO-67, bpdc = para-biphenyldicarboxylic acid) framework using a mix-and-match synthetic strategy. The matching ligand lengths between bpdc and L(1)-L(6) ligands allowed the construction of highly crystalline UiO-67 frameworks (metal-organic frameworks (MOFs) 1-6) that were doped with L(1) L(6) ligands. MOFs 1-6 were isostructural to the parent UiO-67 framework as shown by powder X-ray diffraction (PXRD) and exhibited high surface areas ranging from 1092 to 1497 m(2)/g. MOFs 1-6 were stable in air up to 400 degrees C and active catalysts in a range of reactions that are relevant to solar energy utilization. MOFs 1-3 containing [Cp*Ir(III)(dcppy)Cl] (H(2)L(1)), [Cp*Ir(III)(dcbpy)Cl]Cl (H(2)L(2)), and [Ir(III)(dcppy)(2)(H(2)O)(2)]OTf (H(2)L(3)) (where Cp* is pentamethylcyclopentadienyl, dcppy is 2-phenylpyridine-5,4'-dicarboxylic acid, and dcbpy is 2,2'-bipyridine-5,5'-dicarboxylic acid) were effective water oxidation catalysts (WOCs), with turnover frequencies (TOFs) of up to 4.8 h(-1). The [Re(I)(CO)(3)(dcbpy)Cl] (H(2)L(4)) derivatized MOF 4 served as an active catalyst for photocatalytic CO(2) reduction with a total turnover number (TON) of 10.9, three times higher than that of the homogeneous complex H(2)L(4). MOFs 5 and 6 contained phosphorescent [Ir(III)(ppy)(2)(dcbpy)]Cl (H(2)L(5)) and [Ru(II)(bpy)(2)(dcbpy)]Cl(2) (H(2)L(6)) (where ppy is 2-phenylpyridine and bpy is 2,2'-bipyridine) and were used in three photocatalytic organic transformations (aza-Henry reaction, aerobic amine coupling, and aerobic oxidation of thioanisole) with very high activities. The inactivity of the parent UiO-67 framework and the reaction supernatants in catalytic water oxidation, CO(2) reduction, and organic transformations indicate both the molecular origin and heterogeneous nature of these catalytic processes. The stability of the doped UiO 67 catalysts under catalytic conditions was also demonstrated by comparing PXRD patterns before and after catalysis. This work illustrates the potential of combining molecular catalysts and MOF structures in developing highly active heterogeneous catalysts for solar energy utilization. PMID- 21780789 TI - Varietal thiols in wine: discovery, analysis and applications. PMID- 21780788 TI - A simple method for the determination of enantiomeric excess and identity of chiral carboxylic acids. AB - The association between an achiral copper(II) host (1) and chiral carboxylate guests was studied using exciton-coupled circular dichroism (ECCD). Enantiomeric complexes were created upon binding of the enantiomers of the carboxylate guests to the host, and the sign of the resultant CD signal allowed for determination of the configuration of the studied guest. The difference in magnitudes and shapes of the CD signals, in conjunction with linear discriminant analysis (LDA), allowed for the identity of the guest to be determined successfully. A model was created for the host-guest complexes which successfully predicts the sign of the observed CD signal. Further, Taft parameters were used in the model, leading to rationalization of the observed magnitudes of the CD signals. Finally, the enantiomeric excess (ee) of unknown samples of three chiral carboxylic acid guests was determined with an average absolute error of +/-3.0%. PMID- 21780792 TI - Catalysis-based and protecting-group-free total syntheses of the marine oxylipins hybridalactone and the ecklonialactones A, B, and C. AB - Concise and protecting-group-free total syntheses of the marine oxylipins hybridalactone (1) and three members of the ecklonialactone family (2-4) were developed. They deliver these targets in optically pure form in 14 or 13 steps, respectively, in the longest linear sequence; five of these steps are metal catalyzed and four others are metal-mediated. The route to either 1 or 2-4 diverges from the common building block 22, which is accessible in 7 steps from 2[5H]furanone by recourse to a rhodium-catalyzed asymmetric 1,4-addition reaction controlled by the carvone-derived diene ligand 35 and a ring-closing alkene metathesis (RCM) catalyzed by the ruthenium indenylidene complex 17 as the key operations. Alternatively, 22 can be made in 10 steps from furfural via a diastereoselective three-component coupling process. The further elaboration of 22 into hybridalactone as the structurally most complex target with seven contiguous chiral centers was based upon a sequence of cyclopropanation followed by a vanadium-catalyzed epoxidation, both of which were directed by the same free hydroxy group at C15. The macrocyclic scaffold was annulated to the headgroup by means of a ring-closing alkyne metathesis reaction (RCAM). In response to the unusually high propensity of the oxirane of the targeted oxylipins for ring opening, this transformation had to be performed with complexes of the type [(Ar(3)SiO)(4)Mo=CPh][K.OEt(2)] (43), which represent a new generation of exceedingly tolerant yet remarkably efficient catalysts. Their ancillary triarylsilanolate ligands temper the Lewis acidity of the molybdenum center but are not sufficiently nucleophilic to engage in the opening of the fragile epoxide ring. A final semireduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene completed the total synthesis of (-)-1. The fact that the route from the common fragment 22 to the ecklonialactones could follow a similar logic showcased the flexibility inherent to the chosen approach. PMID- 21780790 TI - Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. AB - Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described. PMID- 21780793 TI - Condensed tannins and flavonoids from the forage legume sulla (Hedysarum coronarium). AB - The condensed tannin concentrations and composition and the characterization of the phenolic constituents in the leaves of the forage legume sulla (Hedysarum coronarium), a biennial forage legume found in temperate agricultural regions, were studied. The colorimetric butanol-HCl assay was used for the quantitation of the seasonal condensed tannin concentrations in the leaves of sulla. Fractionation of extracts on Sephadex LH-20 using step elution with aqueous methanol, followed with aqueous acetone or gradient elution with water, aqueous methanol, and aqueous acetone, gave condensed tannin and flavonoid fractions. The chemical characteristics of the purified condensed tannin fractions were studied by acid-catalyzed degradation with benzyl mercaptan and electrospray ionization mass spectrometry (ESI-MS). Thiolysis revealed that epigallocatechin was the major extender unit (15-75%) while gallocatechin was the major terminal unit (50 66%), thus indicating the extractable sulla condensed tannin fraction as the prodelphinidin type. Condensed tannin oligomers to polymers obtained from Sephadex LH-20 gradient fractions ranged between 2.9 and 46 mDP. The homo- and heterogeneous oligomer ions in condensed tannin gradient fractions detected by ESI-MS ranged from 2 to 10 DP and are consistent with the values obtained by thiolysis (2.9-6.9 DP). Lower molecular weight phenolics, including flavonoids and phenolic acids, were characterized by liquid chromatography atmospheric pressure chemical ionization mass spectrometry (LC-APCI/MS) and ESI/MS/MS on a linear ion trap. The flavonoids extracted with aqueous acetone and methanol from sulla leaves and identified included kaempferol, rutin, quercetin-7-O-alpha-L rhamnosyl-3-O-glucosylrhamnoside, quercetin-3-O-alpha-L-rhamnosyl-7-O-glucoside, kaempferol-3-O-beta-D-glucoside-dirhamnoside, genistein-7-O-beta-D-glucosyl-6"-O malonate, formononetin-7-O-beta-D-glucoside-6"-O-malonate, and afrormosin and the phenolic acid chlorogenic acid. PMID- 21780794 TI - Botrytone, a new naphthalenone pentaketide produced by Botrytis fabae, the causal agent of chocolate spot disease on Vicia faba. AB - A strain of Botrytis fabae isolated from faba bean (Vicia faba L.) plants displaying clear chocolate spot disease symptoms produced phytotoxic metabolites in vitro. The phytotoxins isolated from the culture filtrate organic extract were characterized by spectroscopic and optical methods. A new naphthalenone pentaketide, named botrytone, was isolated and characterized as (4R)-3,4-dihydro 4,5,8-trihydroxy-1(2H)-naphthalenone together with other well-known closely related naphthalenones such as regiolone and cis- and trans-3,4-dihydro-2,4,8 trihydroxynaphthalen-1(2H)-ones. When tested on leaves of the host plant, with the cis- and trans-3,4-dihydro-2,4,8-trihydroxynaphthalen-1(2H)-ones assayed in mixture, regiolone demonstrated the highest level of phytotoxicity together with cis- and trans-3,4-dihydro-2,4,8-trihydroxynaphthalen-1(2H)-ones. Botrytone showed moderate phytotoxic activity at 1 mg/mL and was still phytotoxic at 0.5 mg/mL. PMID- 21780795 TI - Designing a new Diels-Alderase: a combinatorial, semirational approach including dynamic optimization. AB - A computationally inexpensive design strategy involving 'semirational' screening for enzymatic catalysis is presented. The protocol is based on well-established computational methods and represents a holistic approach to the catalytic process. The model reaction studied here is the Diels-Alder, for which a successful computational design has recently been published (Siegel, J. B. et al. Science 2010, 329, 309-313). While it is a leap forward in the field of computational design, the focus on designing only a small fraction of the active site gives little control over dynamics. Our approach explicitly incorporates mutagenesis and the analysis of binding events and transition states, and a promising enzyme-substrate candidate is generated with relatively little effort. We estimate catalytic rate accelerations of up to 105. PMID- 21780796 TI - Argon solvent effects on optical properties of silver metal clusters. AB - Argon gas at a high pressure (~80 bar) has been expanded using a miniaturized pulsed valve at room temperature, producing a supersonic beam of cold, large argon droplets. Atoms of silver are subsequently embedded into the droplet using the pick-up technique. The resulting Ag(n)Ar(droplet) distribution was analyzed using multiphoton laser ionization time-of-flight mass spectrometry. Besides bare metal clusters, snowballs of silver monomers and dimers encapsulated in up to 50 argon atoms have been observed. The influence of the solvent on the optical absorption of the solute was studied for embedded Ag(8) using resonant two-photon ionization in the ultraviolet. A redshift and broadening of the Ag(8)Ar(droplet) optical spectrum compared to that measured in pure [Federmann et al., Eur. Phys. J. D 1999, 9, 11] and Ar-doped helium droplets [Diederich et al., J. Chem. Phys.2002, 116, 3263] was observed, which is attributed to the interaction with the larger Ar matrix environment. PMID- 21780797 TI - Enhanced catalytic activity on titanosilicate molecular sieves controlled by cation-pi interactions. AB - A new class of heterogeneous catalytic systems utilizing cation-guest interactions was designed based on microporous titanosilicate molecular sieves. Introducing heavier alkali metal cations on ion-exchange sites of the framework resulted in a significant enhancement of the catalytic activity for oxidation of cyclohexene and styrene, whereas such an enhancement was not observed in oxidation of cyclohexane without pi systems. Distinct relationships between the catalytic activities and intermolecular interaction energies which were determined by IR spectroscopic and computational approaches clearly evidenced the predominance of the cation-pi interaction in this catalytic system. PMID- 21780798 TI - Long-distance FRET analysis: a Monte Carlo simulation study. AB - A new method for extending the utilizable range of Forster resonance energy transfer (FRET) is proposed and tested by the Monte Carlo technique. The obtained results indicate that the efficiency of FRET can be significantly enhanced at a given distance if the energy transfer takes place toward multiple acceptors that are closely located on a macromolecule instead of a single acceptor molecule as it is currently used in FRET analysis. On the other hand, reasonable FRET efficiency can be obtained at significantly longer distances than in the case of a single acceptor. Randomly distributed and parallel orientated acceptor transition moments with respect to the transition moment of the donor molecule have been analyzed as two extreme cases. As expected, a parallel orientation of donor and acceptor transition moments results in a more efficient excitation energy transfer. This finding could be used to directly reveal the assembly/deassembly of large protein complexes in a cell by fluorescence microscopy. PMID- 21780799 TI - Preparation and characterization of a tetrabutylammonium graphite intercalation compound. AB - The intercalation of tetrabutylammonium (TBA) cations into graphite by cation exchange from a sodium-ethylenediamine graphite intercalation compound yields a single-phase first-stage product, C(44)TBA, with a gallery expansion of 0.47 nm. The gallery dimension requires an anisotropic "flattened" cation conformation. PMID- 21780800 TI - Structure-activity relationship and molecular mechanisms of ethyl 2-amino-6-(3,5 dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and its analogues. AB - Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells. Here we expand its scope and demonstrate that 5 can synergize with both vincristine and paclitaxel in three different MDR cell lines (HL60/DNR, K562/HHT300, and CCRF-CEM/VLB100). We also demonstrate that 5 has potent cytotoxicity in the NCI-60 panel of cell lines with an average IC(50) of 1.04 MUM. In addition, 5 has a unique mechanism of action in comparison with standard agents in the NCI database based on COMPARE analysis. Further structure-activity relationship study led to the development of a more potent analogue, compound 7d, with an IC(50) of 640 nM in HL60/MX2. Additionally, one enantiomer of 5 is 13 fold more active than the less active enantiomer. Taken together, our study has led to the discovery of a series of analogues that selectively target drug resistant cancer cells with the potential for the treatment of drug-resistant cancers. PMID- 21780801 TI - Comment on "Remanufacturing and energy savings". PMID- 21780802 TI - Raman analysis of mode softening in nanoparticle CeO(2-delta) and Au-CeO(2-delta) during CO oxidation. AB - Oxygen vacancy levels are monitored during the oxidation of CO by CeO(2-delta) nanorods and Au-CeO(2-delta) nanorods, nanocubes, and nanopolyhedra by using Raman scattering. The first-order CeO(2) F(2g) peak near 460 cm(-1) decreases when this reaction is fast (fast reduction and relatively slow reoxidation of the surface), because of the lattice expansion that occurs when Ce(3+) replaces Ce(4+) during oxygen vacancy creation. This shift correlates with reactivity for CO oxidation. Increases in the oxygen deficit delta as large as ~0.04 are measured relative to conditions when the ceria is not reduced. PMID- 21780803 TI - Dynamic calibration approach for determining catechins and gallic acid in green tea using LC-ESI/MS. AB - Catechins and gallic acid are antioxidant constituents of Camellia sinensis, or green tea. Liquid chromatography with both ultraviolet (UV) absorbance and electrospray ionization mass spectrometric (ESI/MS) detection was used to determine catechins and gallic acid in three green tea matrix materials that are commonly used as dietary supplements. The results from both detection modes were evaluated with 14 quantitation models, all of which were based on the analyte response relative to an internal standard. Half of the models were static, where quantitation was achieved with calibration factors that were constant over an analysis set. The other half were dynamic, with calibration factors calculated from interpolated response factor data at each time a sample was injected to correct for potential variations in analyte response over time. For all analytes, the relatively nonselective UV responses were found to be very stable over time and independent of the calibrant concentration; comparable results with low variability were obtained regardless of the quantitation model used. Conversely, the highly selective MS responses were found to vary both with time and as a function of the calibrant concentration. A dynamic quantitation model based on polynomial data-fitting was used to reduce the variability in the quantitative results using the MS data. PMID- 21780804 TI - Temperature dependence measurements and structural characterization of trimethyl ammonium ionic liquids with a highly polar solvent. AB - We report the synthesis and characterization of a series of an ammonium ionic liquids (ILs) containing acetate, dihydrogen phosphate, and hydrogen sulfate anions with a common cation. To characterize the thermophysical properties of these newly synthesized ILs with the highly polar solvent N,N-dimethylformamide (DMF), precise measurements such as densities (rho) and ultrasonic sound velocities (u) over the whole composition range have been performed at atmospheric pressure and over wide temperature ranges (25-50 degrees C). The excess molar volume (V(E)) and the deviation in isentropic compressibilities (Deltakappa(s)) were predicted using these temperature dependence properties as a function of the concentration of ILs. The Redlich-Kister polynomial was used to correlate the results. The ILs investigated in the present study included trimethylammonium acetate [(CH(3))(3)NH][CH(3)COO] (TMAA), trimethylammonium dihydrogen phosphate [(CH(3))(3)NH][H(2)PO(4)] (TMAP), and trimethylammonium hydrogen sulfate [(CH(3))(3)NH][HSO(4)] (TMAS). The intermolecular interactions and structural effects were analyzed on the basis of the measured and the derived properties. In addition, the hydrogen bonding between ILs and DMF has been demonstrated using semiempirical calculations with help of Hyperchem 7. A qualitative analysis of the results is discussed in terms of the ion-dipole, ion pair interactions, and hydrogen bonding between ILs and DMF molecules and their structural factors. The influence of the anion of the protic IL, namely, acetate (CH(3)COO), dihydrogen phosphate (H(2)PO(4)), and hydrogen sulfate (HSO(4)), on the thermophysical properties is also provided. PMID- 21780805 TI - A molecular mechanics approach to modeling protein-ligand interactions: relative binding affinities in congeneric series. AB - We introduce the "Prime-ligand" method for ranking ligands in congeneric series. The method employs a single scoring function, the OPLS-AA/GBSA molecular mechanics/implicit solvent model, for all stages of sampling and scoring. We evaluate the method using 12 test sets of congeneric series for which experimental binding data is available in the literature, as well as the structure of one member of the series bound to the protein. Ligands are "docked" by superimposing a common stem fragment among the compounds in the series using a crystal complex from the Protein Data Bank and sampling the conformational space of the variable region. Our results show good correlation between our predicted rankings and the experimental data for cases in which binding affinities differ by at least 1 order of magnitude. For 11 out of 12 cases, >90% of such ligand pairs could be correctly ranked, while for the remaining case, Factor Xa, 76% of such pairs were correctly ranked. A small number of compounds could not be docked using the current protocol because of the large size of functional groups that could not be accommodated by a rigid receptor. CPU requirements for the method, involving CPU minutes per ligand, are modest compared with more rigorous methods that use similar force fields, such as free energy perturbation. We also benchmark the scoring function using series of ligands bound to the same protein within the CSAR data set. We demonstrate that energy minimization of ligands in the crystal structures is critical to obtain any correlation with experimentally determined binding affinities. PMID- 21780807 TI - Combined application of cheminformatics- and physical force field-based scoring functions improves binding affinity prediction for CSAR data sets. AB - The curated CSAR-NRC benchmark sets provide valuable opportunity for testing or comparing the performance of both existing and novel scoring functions. We apply two different scoring functions, both independently and in combination, to predict the binding affinity of ligands in the CSAR-NRC data sets. One reported here for the first time employs multiple chemical-geometrical descriptors of the protein-ligand interface to develop Quantitative Structure Binding Affinity Relationships (QSBAR) models. These models are then used to predict binding affinity of ligands in the external data set. Second is a physical force field based scoring function, MedusaScore. We show that both individual scoring functions achieve statistically significant prediction accuracies with the squared correlation coefficient (R(2)) between the actual and predicted binding affinity of 0.44/0.53 (Set1/Set2) with QSBAR models and 0.34/0.47 (Set1/Set2) with MedusaScore. Importantly, we find that the combination of QSBAR models and MedusaScore into consensus scoring function affords higher prediction accuracy than any of the contributing methods achieving R(2) values of 0.45/0.58 (Set1/Set2). Furthermore, we identify several chemical features and noncovalent interactions that may be responsible for the inaccurate prediction of binding affinity for several ligands by the scoring functions employed in this study. PMID- 21780808 TI - Swimmer risk of gastrointestinal illness from exposure to tropical coastal waters impacted by terrestrial dry-weather runoff. AB - This study used molecular methods to measure concentrations of four enteric viruses (adenovirus, enterovirus, norovirus GI, and norovirus GII) and fecal source tracking markers (human, ruminant, and pig Bacteroidales) in land-based runoff from 22 tropical streams on O'ahu, Hawai'i. Each stream was sampled twice in the morning and afternoon during dry weather. Viruses and human Bacteroidales were widespread in the streams. Watershed septic tank densities were positively associated with higher occurrence of human Bacteroidales and norovirus. There were no associations between occurrence of viruses and fecal indicator concentrations. Virus concentrations and previously reported culturable Salmonella and Campylobacter were used as inputs to a quantitative microbial risk assessment (QMRA) model to estimate the risk of acquiring gastrointestinal (GI) illness from swimming in tropical marine waters adjacent to discharging streams. Monte Carlo methods were used to incorporate uncertainties in the dilution of stream discharge with seawater, swimmer ingestion volumes, pathogen concentrations, and dose-response parameters into the model. Median GI illness risk to swimmers from exposure to coastal waters adjacent to the 22 streams ranged from 0 to 21/1000. GI illness risks from viral exposures were generally orders of magnitude greater than bacterial exposures. Swimming adjacent to streams positive for norovirus or adenovirus resulted in the highest risks. The median risk adjacent to each stream was positively, significantly correlated to the concentration of Clostridium perfringens in the stream. Although a number of important assumptions were made to complete the QMRA, results suggest land-based runoff in the tropics as a potential source of GI illness risk, with pathogens coming from both human and nonhuman nonpoint sources including septic tanks. PMID- 21780806 TI - Total synthesis of bryostatin 7 via C-C bond-forming hydrogenation. AB - The marine macrolide bryostatin 7 is prepared in 20 steps (longest linear sequence) and 36 total steps with five C-C bonds formed using hydrogenative methods. This approach represents the most concise synthesis of any bryostatin reported, to date. PMID- 21780809 TI - Reactions of the bis(dialkylphosphino)methane complexes Pd2X2(MU-R2PCH2PR2)2 (X = halogen, R = Me or Et) with H2S, S8, COS, and CS2; detection of reaction intermediates. AB - The Pd(2)X(2)(dmpm)(2) complexes [X = Cl (1a), Br (1b), I (1c); dmpm = bis(dimethylphosphino)methane. In all the dipalladium complexes mentioned in this paper, the dmpm, depm, and dppm ligands (unless stated otherwise) are bridging, but for convenience the MU-symbol is omitted.] react with H(2)S to yield H(2) and the bridged-sulfido complexes Pd(2)X(2)(MU-S)(dmpm)(2) (2a-c), of which 2a and 2b are structurally characterized. With 1a, two rapid reversible equilibria are observed by NMR spectroscopy below -30 degrees C, and two reaction intermediates are detected; both are likely hydrido(mercapto) species. Reaction of 1a with 1 equiv of elemental sulfur also yields 2a. The reaction of 1a with COS results in the initial formation of Pd(2)Cl(2)(MU-COS)(dmpm)(2) (3) that undergoes decarbonylation to yield 2a and Pd(2)Cl(2)(MU-CO)(dmpm)(2) (4), which is also formed via reversible insertion of the CO into the Pd-Pd bond of 1a. The solid state molecular structure of the previously reported complex Pd(2)Cl(2)(MU CS(2))(dmpm)(2) (5), together with solution NMR data for 3 and 5, reveal that the bridging heterocumulene ligands coordinate in an eta(2)-C,S fashion. Analogous findings were made for the corresponding Pd(2)X(2)(depm)(2) complexes [X = Cl (1a'), Br (1b'), I (1c'); depm = bis(diethylphosphino)methane], although no MU COS species was detected. The Pd(2)X(2)(MU-S)(depm)(2) complex was structurally characterized. Differences in the chemistry of the previously studied, corresponding dppm systems (dppm = bis(diphenylphosphino)methane) are discussed. PMID- 21780811 TI - Comprehensive thermochemistry of W-H bonding in the metal hydrides CpW(CO)2(IMes)H, [CpW(CO)2(IMes)H](*+), and [CpW(CO)2(IMes)(H)2]+. Influence of an N-heterocyclic carbene ligand on metal hydride bond energies. AB - The free energies interconnecting nine tungsten complexes have been determined from chemical equilibria and electrochemical data in MeCN solution (T = 22 degrees C). Homolytic W-H bond dissociation free energies are 59.3(3) kcal mol( 1) for CpW(CO)(2)(IMes)H and 59(1) kcal mol(-1) for the dihydride [CpW(CO)(2)(IMes)(H)(2)](+) (where IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol 2-ylidene), indicating that the bonds are the same within experimental uncertainty for the neutral hydride and the cationic dihydride. For the radical cation, [CpW(CO)(2)(IMes)H](*+), W-H bond homolysis to generate the 16-electron cation [CpW(CO)(2)(IMes)](+) is followed by MeCN uptake, with free energies for these steps being 51(1) and -16.9(5) kcal mol(-1), respectively. Based on these two steps, the free energy change for the net conversion of [CpW(CO)(2)(IMes)H](*+) to [CpW(CO)(2)(IMes)(MeCN)](+) in MeCN is 34(1) kcal mol( 1), indicating a much lower bond strength for the 17-electron radical cation of the metal hydride compared to the 18-electron hydride or dihydride. The pK(a) of CpW(CO)(2)(IMes)H in MeCN was determined to be 31.9(1), significantly higher than the 26.6 reported for the related phosphine complex, CpW(CO)(2)(PMe(3))H. This difference is attributed to the electron donor strength of IMes greatly exceeding that of PMe(3). The pK(a) values for [CpW(CO)(2)(IMes)H](*+) and [CpW(CO)(2)(IMes)(H)(2)](+) were determined to be 6.3(5) and 6.3(8), much closer to the pK(a) values reported for the PMe(3) analogues. The free energy of hydride abstraction from CpW(CO)(2)(IMes)H is 74(1) kcal mol(-1), and the resultant [CpW(CO)(2)(IMes)](+) cation is significantly stabilized by binding MeCN to form [CpW(CO)(2)(IMes)(MeCN)](+), giving an effective hydride donor ability of 57(1) kcal mol(-1) in MeCN. Electrochemical oxidation of [CpW(CO)(2)(IMes)](-) is fully reversible at all observed scan rates in cyclic voltammetry experiments (E degrees = -1.65 V vs Cp(2)Fe(+/0) in MeCN), whereas CpW(CO)(2)(IMes)H is reversibly oxidized (E degrees = -0.13(3) V) only at high scan rates (800 V s( 1)). For [CpW(CO)(2)(IMes)(MeCN)](+), high-pressure NMR experiments provide an estimate of DeltaG degrees = 10.3(4) kcal mol(-1) for the displacement of MeCN by H(2) to give [CpW(CO)(2)(IMes)(H)(2)](+). PMID- 21780812 TI - Online reverse phase-high-performance liquid chromatography-fluorescence detection-electrospray ionization-mass spectrometry separation and characterization of heparan sulfate, heparin, and low-molecular weight-heparin disaccharides derivatized with 2-aminoacridone. AB - A high-resolution online reverse-phase-high-performance liquid chromatography (RP HPLC)-fluorescence detector (Fd)-electrospray ionization-mass spectrometry (ESI MS) separation and structural characterization of disaccharides prepared from heparin (Hep), heparan sulfate (HS), and various low-molecular-weight (LMW)-Hep using heparin lyases and derivatization with 2-aminoacridone (AMAC) are described. A total of 12 commercially available Hep/HS-derived unsaturated disaccharides were separated and unambiguously identified on the basis of their retention times and mass spectra. The constituent disaccharides of various samples, including unfractionated Hep/HS, fast-moving and slow-moving Hep components, and several marketed products, were characterized. Furthermore, for the first time, the saturated trisulfated disaccharide belonging to the nonreducing end of Heps was detected as being approximately 2% in unfractionated samples and ~15-21% in LMW-Heps prepared by nitrous acid depolymerization. No desalting of the commercial products prior to enzymatic digestion or prepurification steps to eliminate any excess of AMAC reagent or interference from proteins, peptides, and other sample impurities before RP-HPLC-Fd-ESI-MS injection were necessary. This method has applicability for the rapid differentiation of pharmaceutical Heps and LMW-Heps prepared by means of different depolymerization processes and for compositional analysis of small amounts of samples derived from biological sources by using the highly sensitive fluorescence detector. PMID- 21780810 TI - Structure and dynamics of highly PEG-ylated sterically stabilized micelles in aqueous media. AB - Molecular assemblies of highly PEG-ylated phospholipids are important in many biomedical applications. We have studied sterically stabilized micelles (SSMs) of self-assembled DSPE-PEG2000 in pure water and isotonic HEPES-buffered saline solution. The observed SSM sizes of 2-15 nm largely depend on the solvent and the lipid concentration used. The critical micelle concentration of DSPE-PEG2000 is 10 times higher in water than in buffer, and the viscosity of the dispersion dramatically increases with the lipid concentration. To explain the experimentally observed results, we performed atomistic molecular dynamics simulations of solvated SSMs. Our modeling revealed that the observed assemblies have very different aggregation numbers (N(agg) ~ 90 in saline solution and N(agg) < 8 in water) because of very different screening of their charged PO4(-) groups. We also demonstrate that the micelle cores can inflate and their coronas can fluctuate strongly, thus allowing storage and delivery of molecules with different chemistries. PMID- 21780813 TI - Autocatalytic O2 cleavage by an OCO3 trianionic pincer Cr(III) complex: isolation and characterization of the autocatalytic intermediate [Cr(IV)]2(MU-O) dimer. AB - Synthetic and kinetic experiments designed to probe the mechanism of O(2) activation by the trianionic pincer chromium(III) complex [(t)BuOCO]Cr(III)(THF)(3) (1) (where (t)BuOCO = [2,6 ((t)BuC(6)H(3)O)(2)C(6)H(3)](3-), THF = tetrahydrofuran) are described. Whereas analogous porphyrin and corrole oxidation catalysts can become inactive toward O(2) activation upon dimerization (forming a MU-oxo species) or product inhibition, complex 1 becomes more active toward O(2) activation when dimerized. The product from O(2) activation, [(t)BuOCO]Cr(V)(O)(THF) (2), catalyzes the oxidation of 1 via formation of the MU-O dimer {[(t)BuOCO]Cr(IV)(THF)}(2)(MU-O) (3). Complex 3 exists in equilibrium with 1 and 2 and thus could not be isolated in pure form. However, single crystals of 3 and 1 co-deposit, and the molecular stucture of 3 was determined using single-crystal X-ray crystallography methods. Variable (9.5, 35, and 240 GHz) frequency electron paramagnetic resonance spectroscopy supports the assignment of complex 3 as a Cr(IV)-O-Cr(IV) dimer, with a high (S = 2) spin ground state, based on detailed computer simulations. Complex 3 is the first conclusively assigned example of a complex containing a Cr(IV) dimer; its spin Hamiltonian parameters are g(iso) = 1.976, D = 2400 G, and E = 750 G. The reaction of 1 with O(2) was monitored by UV-visible spectrophotometry, and the kinetic orders of the reagents were determined. The reaction does not exhibit first-order behavior with respect to the concentrations of complex 1 and O(2). Altering the THF concentration reveals an inverse order behavior in THF. A proposed autocatalytic mechanism, with 3 as the key intermediate, was employed in numerical simulations of concentration versus time decay plots, and the individual rate constants were calculated. The simulations agree well with the experimental observations. The acceleration is not unique to 2; for example, the presence of OPPh(3) accelerates O(2) activation by forming the five-coordinate complex trans-[(t)BuOCO]Cr(III)(OPPh(3))(2) (4). PMID- 21780814 TI - Effect of interfacial water transport resistance on coupled proton and water transport across Nafion. AB - Dynamic and steady-state water flux, current density, and resistance across a Nafion 115 membrane-electrode-assembly (MEA) were measured as functions of temperature, water activity, and applied potential. After step changes in applied potential, the current, MEA resistance, and water flux evolved to new values over 3000-5000 s, indicating a slow redistribution of water in the membrane. Steady state current density initially increased linearly with increasing potential and then saturated at higher applied potentials. Water flux increases in the direction of current flow resulting from electro-osmotic drag. The coupled transport of water and protons was modeled with an explicit accounting for electro-osmotic drag, water diffusion, and interfacial water transport resistance across the vapor/membrane interface. The model shows that water is dragged inside the membrane by the proton current, but the net water flux into and out of the membrane is controlled by interfacial water transport at the membrane/vapor interface. The coupling of electro-osmotic drag and interfacial water transport redistributes the water in the membrane. Because water entering the membrane is limited by interfacial transport, an increase in current depletes water from the anode side of the membrane, increasing the membrane resistance there, which in turn limits the current. This feedback loop between current density and membrane resistance determines the stable steady-state operation at a fixed applied potential that results in current saturation. We show that interfacial water transport resistance substantially reduces the impact of electro-osmotic drag on polymer electrolyte membrane fuel cell operation. PMID- 21780815 TI - 2D-ELDOR study of heterogeneity and domain structure changes in plasma membrane vesicles upon cross-linking of receptors. AB - 2D electron-electron double resonance (2D-ELDOR) with the "full Sc-" method of analysis is applied to the study of plasma membrane vesicles. Membrane structural changes upon antigen cross-linking of IgE receptors (IgE-FcepsilonRI) in plasma membrane vesicles (PMVs) isolated from RBL-2H3 mast cells are investigated, for the first time, by means of these 2D-ELDOR techniques. Spectra of 1-palmitoyl-2 (16-doxyl stearoyl) phosphatidylcholine (16-PC) from PMVs before and after this stimulation at several temperatures are reported. The results demonstrate a coexistence of liquid-ordered (L(o)) and liquid-disordered (L(d)) components. We find that upon cross-linking, the membrane environment is remodeled to become more disordered, as shown by a moderate increase in the population of the L(d) component. This change in the relative amount of the L(o) versus L(d) components upon cross-linking is consistent with a model wherein the IgE receptors, which when clustered by antigen to cause cell stimulation, lead to more disordered lipids, and their dynamic and structural properties are slightly altered. This study demonstrates that 2D-ELDOR, analyzed by the full Sc- method, is a powerful approach for capturing the molecular dynamics in biological membranes. This is a particular case showing how 2D-ELDOR can be applied to study physical processes in complex systems that yield subtle changes. PMID- 21780816 TI - Subcellular resolution mapping of endogenous cytokine secretion by nano-plasmonic resonator sensor array. AB - Local extracellular signaling is central for cellular interactions and organizations. We report a novel sensing technique to interrogate extracellular signaling at the subcellular level. We developed an in situ immunoassay based on giant optical enhancement of a tunable nano-plasmonic-resonator array fabricated by nanoimprint lithography. Our nanoplasmonic device significantly increases the signal-to-noise ratio to enable the first time submicrometer resolution quantitative mapping of endogenous cytokine secretion. Our study shows a markedly high local interleukin-2 (IL-2) concentration within the immediate vicinity of the cell which finally validates a decades-old hypothesis on autocrine physiological concentration and spatial range. This general sensing technique can be applied for a broad range of cellular communication studies to improve our understanding of subcellular signaling and function. PMID- 21780817 TI - Profiling and association mapping of grain metabolites in a subset of the core collection of Chinese rice germplasm (Oryza sativa L.). AB - In this study, metabolic profiles of a set of 48 rice germplasms from the Chinese core collection were obtained by gas chromatography and time-of-flight mass spectrometry (GC-TOF-MS). Forty-one metabolites were identified and relatively quantified according to the internal standard (IS). Wide ranges of variations for all metabolites were observed among rice accessions. The maximum/minimum ratios varied from 4.73 to 211.36. The metabolites were categorized into seven groups based on their chemical characteristics. Clustering analysis and a correlation network showed that most of the metabolites had variations among rice accessions in the same direction. Using 218 molecular markers, association mapping was conducted to identify the chromosomal loci influencing the concentrations of identified metabolites. Twenty markers were identified associating with the concentrations of 29 metabolites [-lg(P) > 3]. Allelic effects were investigated in detail in two markers (RM315 and RM541) as examples. PMID- 21780819 TI - Development of interatomic ReaxFF potentials for Au-S-C-H systems. AB - We present fully reactive interatomic potentials for systems containing gold, sulfur, carbon, and hydrogen, employing the ReaxFF formalism. The potential is designed especially for simulating gold-thiol systems and has been used for studying cluster deposition on self-assembled monolayers. Additionally, a large number of density functional theory calculations are reported, including molecules containing the aforementioned elements and adsorption energetics of molecules and atoms on gold. PMID- 21780818 TI - Evaluation of 99mTc-labeled cyclic RGD peptide with a PEG4 linker for thrombosis imaging: comparison with DMP444. AB - DMP444 is a (99m)Tc-labeled cyclic RGD peptide, which has been evaluated in preclinical canine deep vein thrombosis (DVT) and pulmonary embolism (PE) models, and in patients with DVT and PE by SPECT (single photon emission computed tomography). Clinical data indicated that DMP444 is useful for imaging DVT, but it had limited utility for imaging PE in patients. To understand its clinical findings, we prepared a new radiotracer P4-DMP444 by replacing the lipophilic 6 aminocaproic acid (CA) in DMP444 with a highly water-soluble PEG(4) (15-amino 4,7,10,13-tetraoxapentadecanoic acid) linker. The objective of this study was to explore the impact of PEG(4) on biological properties (biodistribution, excretion kinetics, and capability to image thrombi) of (99m)Tc radiotracer. We also used canine DVT and PE models to perform imaging studies with/without the heparin pretreatment. These studies were specifically designed to explore the impact of heparin treatment on thrombosis uptake of P4-DMP444. It was found that replacing the CA linker with PEG(4) could enhance the radiotracer clearance kinetics from blood and normal organs in both rats and dogs. The fact that P4-DMP444 and DMP444 share very similar thrombosis uptake in both DVT and PE models suggests that the PEG(4) linker has little effect on GPIIb/IIIa binding affinity of cyclic RGD peptide. Even though P4-DMP444 had less accumulation than DMP444 in the blood, heart, lungs, and muscle over the 2 h study period in both rats and dogs, the difference in PE/lung and DVT/muscle ratios is marginal, suggesting that one PEG(4) linker is not sufficient to dramatically change the contrast between thrombus and background. It is very important to note that the heparin treatment of dogs with DVT and PE resulted in dramatic decrease in accumulation of P4 DMP444 in fresh thrombi. On the basis of these results, we believe that DMP444 and P4-DMP444 are excellent radiotracers for imaging both DVT and PE, and should be used in patients without antithrombosis treatment at the time of imaging. PMID- 21780820 TI - Diplonine, a neurotoxin isolated from cultures of the fungus Stenocarpella maydis (Berk.) Sacc. that induces diplodiosis. AB - Diplodiosis is a neuromycotoxicosis of cattle and sheep caused by ingestion of maize infected with the ear-rot fungus Stenocarpella (= Diplodia ) maydis . Apart from ataxia, paresis, and paralysis, the toxin is responsible for stillbirths and neonatal losses characterized by the presence of spongiform degeneration in the white matter of the brain in the offspring of dams exposed to infected maize cobs. In the present study a toxin, named diplonine, which induced neurological signs in guinea pigs resembling some of those occurring in cattle and sheep, was isolated from S. maydis cultures. Purification of diplonine was achieved by methanol extraction followed by chromatographic separation on silica gel and RP 18 stationary phases. The structure and relative configuration of diplonine were defined by analysis of NMR and MS data as (S)-2-amino-2-[(1R,2S)-1-hydroxy-2 methylcyclopropyl]acetic acid or the (S)-2-amino-2-[(1S,2R)-diastereomer. PMID- 21780821 TI - Aerobic oxidative kinetic resolution of secondary alcohols with naphthoxide-bound iron(salan) complex. AB - The first general method for iron-catalyzed aerobic oxidative kinetic resolution of secondary alcohols was achieved with good to high enantiomeric differentiation (k(rel) = 7-50). Although iron(salan) complex 1 does not catalyze alcohol oxidation, the naphthoxide-bound iron(salan) complex does. PMID- 21780822 TI - Efficient synthesis of diborylalkenes from alkenes and diboron by a new PSiP pincer palladium-catalyzed dehydrogenative borylation. AB - The efficient synthesis of various diborylalkenes such as 1,1-, trans-1,2-, and cyclic 1,2-diborylalkenes from alkenes and diboron was achieved for the first time. Selective preparation of di- and monoborylalkenes was also realized by the appropriate choice of reaction conditions. The reaction was found to proceed via a new mechanism of dehydrogenative borylation through a monoborylpalladium complex bearing an anionic PSiP-pincer ligand as a key intermediate, which realized the efficient borylation without sacrificial hydroboration or hydrogenation of the alkene. PMID- 21780823 TI - Formation of protein/surfactant adsorption layer at the air/water interface as studied by dilational surface rheology. AB - The dynamic dilatational surface elasticity of mixed solutions of globular proteins (beta-lactoglobulin (BLG) and bovine serum albumin (BSA)) with cationic (dodecyltrimethylammonium bromide (DTAB)) and anionic (sodium dodecyl sulfate (SDS)) surfactants was measured as a function of the surfactant concentration and surface age. If the cationic surfactant concentration exceeds a certain critical value, the kinetic dependencies of the dynamic surface elasticity of BLG/DTAB and BSA/DTAB solutions become nonmonotonous and resemble those of mixed solutions of proteins with guanidine hydrochloride. This result indicates not only the destruction of the protein tertiary structure in the surface layer of mixed solution but also a strong perturbation of the secondary structure. The corresponding kinetic dependencies for protein solutions with added anionic surfactants are always monotonous, thereby revealing a different mechanism of the adsorption layer formation. One can assume that the secondary structure is destroyed to a lesser extent in the latter case and hinders the formation of loops and tails at the interface. The increase of the solution's ionic strength by the addition of sodium chloride results in stronger changes of the protein conformations in the surface layer and the appearance of a local maximum in the kinetic dependencies of the dynamic surface elasticity in a relatively narrow range of SDS concentration. PMID- 21780824 TI - Exploiting metal-organic coordination polymers as highly efficient immobilization matrixes of enzymes for sensitive electrochemical biosensing. AB - We report on the exploitation of metal-organic coordination polymers (MOCPs) as new and efficient matrixes to immobilize enzymes for amperometric biosensing of glucose or phenols. A ligand, 2,5-dimercapto-1,3,4-thiadiazole (DMcT), two metallic salts, NaAuCl(4) and Na(2)PtCl(6), and two enzymes, glucose oxidase (GOx) and tyrosinase, are used to demonstrate the novel concept. Briefly, one of the metallic salts is added into an aqueous suspension containing DMcT and one of the enzymes to trigger the metal-organic coordination reaction, and the yielded MOCPs-enzyme biocomposite (MEBC) is then cast-coated on an Au electrode for biosensing. The aqueous-phase coordination polymerization reactions of the metallic ions with DMcT are studied by visual inspection as well as some spectroscopic, microscopic, and electrochemical methods. The thus-prepared glucose and phenolic biosensors perform better in analytical performance (such as sensitivity and limit of detection) than those prepared by the conventional chemical and/or electrochemical polymerization methods and most of the reported analogous biosensors, as a result of the improved enzyme load/activity and mass transfer efficiency after using the MOCPs materials with high adsorption/encapsulation capability and unique porous structure. For instance, the detection limit for catechol is as low as 0.2 nM here, being order(s) lower than those of most of the reported analogues. The enzyme electrode was also used to determine catachol in real samples with satisfactory results. The emerging MOCPs materials and the suggested aqueous-phase preparation strategy may find wide applications in the fields of bioanalysis, biocatalysis, and environmental monitoring. PMID- 21780825 TI - Enhancement of the catalytic activity of a 27 kDa subtilisin-like enzyme from Bacillus amyloliquefaciens CH51 by in vitro mutagenesis. AB - AprE51 from Bacillus amyloliquefaciens CH51 is a 27 kDa subtilisin-like protease with fibrinolytic activity. To enhance the catalytic activity of AprE51, two residues, Gly-169 and Ser-101, which, according to the three-dimensional structural model of subtilisin, are located in the P1 substrate-binding site and S3 subsite, respectively, were mutated by site-directed mutagenesis. Results of the mutational analysis showed that substitution of alanine for Gly-169 increased the fibrinolytic activity 1.4-fold. All four Ser-101 mutations, that is, replacements with arginine, leucine, lysine, and tryptophan, also increased the fibrinolytic activity up to 3.9-fold. The S101W mutant with a bulky side chain was more active than mutants with a positively charged or nonpolar small side chains. The fibrinolytic activity of the S101W mutant was further increased by error-prone polymerase chain reaction. The AprE51-6 mutant (S101W/G169A/V192A) had stronger fibrinolytic activity than the S101W mutant. Purified AprE51-6 had a 2.5-fold higher k(cat) and a 2.3-fold lower K(m), which resulted in a 6-fold increase in catalytic efficiency (k(cat)/K(m)) relative to that of wild-type AprE51. In addition, AprE51-6 showed a relatively broader pH range and increased thermostability as compared to AprE51. PMID- 21780826 TI - Gas phase structures, energetics, and potential energy surfaces of disilacyclohexanes. AB - The molecular structures of 1,4-, 1,3-, and 1,2-disilacyclohexanes (denoted as 14, 13, and 12, respectively) were investigated by means of gas electron diffraction (GED). Each molecule was found to possess a chair as the most stable conformation in the gas phase, the point group being C(2h), C(s), and C(2), respectively. Experimental GED structures are in good agreement with theoretical calculations (MP2/cc-pVTZ and B3LYP/cc-pVTZ). A qualitative ring strain analysis suggests 14 to be the most stable and 12 the least stable of the parent disilacyclohexanes. Relative energy calculations with the G4 model chemistry protocol, on the other hand, predict 13 to be the most stable isomer, 5.9 and 14.2 kcal/mol more stable than 14 and 12, respectively. The enhanced stability of 13 compared to 14 is in agreement with an analysis on endocyclic bond lengths and bond polarities. The heats of formation (G4 calculations) are predicted to be 12.3, -18.1, and -3.9 kcal/mol for 14, 13, and 12, respectively. The potential energy surface (PES) and the lowest energy path for the chair-to-chair inversion have been calculated for each isomer. In addition to the two chair forms in each case and some half-chair or sofa-like transition states (four in the case of 14, and two in the case of 13), there are two twist forms found as stationary points on the PES of 14, six twist and six boat forms on the PES of 13, and four twist and six boat forms on the PES of 12. PMID- 21780827 TI - Kirkendall effect and lattice contraction in nanocatalysts: a new strategy to enhance sustainable activity. AB - Core-shell nanoparticles increasingly are found to be effective in enhancing catalytic performance through the favorable influence of the core materials on the active components at the surface. Yet, sustaining high activities under operating conditions often has proven challenging. Here we explain how differences in the components' diffusivity affect the formation and stability of the core-shell and hollow nanostructures, which we ascribe to the Kirkendall effect. Using Ni nanoparticles as the templates, we fabricated compact and smooth Pt hollow nanocrystals that exhibit a sustained enhancement in Pt mass activity for oxygen reduction in acid fuel cells. This is achieved by the hollow-induced lattice contraction, high surface area per mass, and oxidation-resistant surface morphology--a new route for enhancing both the catalysts' activity and durability. The results indicate challenges and opportunities brought by the nanoscale Kirkendall effect for designing, at the atomic level, nanostructures with a wide range of novel properties. PMID- 21780828 TI - Aldehyde PEGylation kinetics: a standard protein versus a pharmaceutically relevant single chain variable fragment. AB - The mPEG-aldehyde PEGylation with two different PEG sizes and two proteins was experimentally determined with respect to yield, conversion, and selectivity. The kinetic behavior of these PEGylation reactions was simulated using a numerically solved set of differential equations. We show that the assumption of an inactivation of mPEG-aldehyde is crucial for the simulation of the overall PEGylation and that the inactivation is pH-dependent. We further demonstrate that ideal PEGylation parameters such as pH, temperature, reaction time, and protein concentration need to be chosen carefully depending on the protein and PEG size. In terms of selectivity and yield, we show that the reaction should be stopped before the highest mono-PEG concentration is reached. Moreover, room temperature and a slightly acidic pH of approximately 6 are good starting points. In conclusion, selectivity can be optimized choosing a shorter reaction time and a reduced reaction temperature. PMID- 21780829 TI - Supramolecular gelation of a polymeric prodrug for its encapsulation and sustained release. AB - A polymeric prodrug, PEGylated indomethacin (MPEG-indo), was prepared and then used to interact with alpha-cyclodextrin (alpha-CD) in their aqueous mixed system. This process could lead to the formation of supramolecular hydrogel under mild conditions and simultaneous encapsulation of MPEG-indo in the hydrogel matrix. For the formed supramolecular hydrogel, its gelation kinetics, mechanical strength, shear-thinning behavior and thixotropic response were investigated with respect to the effects of MPEG-indo and alpha-CD amounts by dynamic and steady rheological tests. Meanwhile, the possibility of using this hydrogel matrix as injectable drug delivery system was also explored. By in vitro release and cell viability tests, it was found that the encapsulated MPEG-indo could exhibit a controlled and sustained release behavior as well as maintain its biological activity. PMID- 21780830 TI - Vectorial transport of fexofenadine across Caco-2 cells: involvement of apical uptake and basolateral efflux transporters. AB - Fexofenadine is a nonsedative antihistamine that exhibits good oral bioavailability despite its zwitterionic chemical structure and efflux by P-gp. Evidence exists that multiple uptake and efflux transporters play a role in hepatic disposition of fexofenadine. However, the roles of specific transporters and their interrelationship in intestinal absorption of this drug are unclear. This study was designed to elucidate vectorial absorptive transport of fexofenadine across Caco-2 cells involving specific apical uptake and efflux transporters as well as basolateral efflux transporters. Studies with cellular models expressing single transporters showed that OATP2B1 expression stimulated uptake of fexofenadine at pH 6.0. Apical uptake of fexofenadine into Caco-2 cells was decreased by 45% by pretreatment with estrone 3-sulfate, an OATP inhibitor, at pH 6.0 but not at pH 7.4, indicating that OATP2B1 mediates apical uptake of fexofenadine into these cells. Examination of fexofenadine efflux from preloaded Caco-2 cells in the presence or absence of (i) the MRP inhibitor MK-571 and (ii) the P-gp inhibitor GW918 showed that apical efflux is predominantly mediated by P gp, with a small contribution by MRP2, whereas basolateral efflux is predominantly mediated by MRP3. These results also showed that while OSTalphabeta is functionally active in the basolateral membrane of Caco-2 cells, it does not play a role in the export of fexofenadine. MK-571 decreased the absorptive transport of fexofenadine by 17%. However, the decrease in absorptive transport by MK-571 was 42% when P-gp was inhibited by GW918. The results provide a novel insight into a vectorial transport system mainly consisting of apical OATP2B1 and basolateral MRP3 that may play an important role in delivering hydrophilic anionic and zwitterionic drugs such as pravastatin and fexofenadine into systemic circulation upon oral administration. PMID- 21780832 TI - Kinetic growth of self-formed In2O3 nanodots via phase segregation: Ni/InAs system. AB - Highly compact In(2)O(3) nanodots with uniform size were synthesized by a novel approach via direct annealing of Ni/InAs samples at temperatures over 250 degrees C. The In(2)O(3) nanodots were formed by solid diffusion between nickel and indium arsenide (InAs) and phase segregation via a catalyst-assisted kinetic process. By controlling the annealing time and ambient conditions, the size and density of In(2)O(3) nanodots can be controlled. From photoluminescence (PL) measurements, two distinct peaks located at ~430 and ~850 nm, corresponding to 2.9 and 1.5 eV for In(2)O(3) nanodots, can be observed. The peaks originate from radioactive recombination centers such as oxygen vacancies or indium interstitials inside In(2)O(3) nanodots. The periodic array of Ni microdiscs with diameters and interdisc spacing of ~5 and ~10 MUm on InAs substrate surface prepared by a photolithography process demonstrated the precise control of In(2)O(3) nanodots at a specific position. Applications for precisely locating optoelectronic nanodevices in combination with electronic nanodevices are envisioned. PMID- 21780831 TI - Chitosan is a surprising negative modulator of cytotoxic CD8+ T cell responses elicited by adenovirus cancer vaccines. AB - Adjuvants modulate protective CD8(+) T cell responses generated by cancer vaccines. We have previously shown that immunostimulatory cytosine-phosphodiester guanine (CpG) oligodeoxynucleotide (ODN) significantly augments tumor protection in mice given adenovirus cancer vaccines. Here, we examined the impact of chitosan, another candidate vaccine adjuvant, on protection conferred by adenovirus cancer vaccines. Unexpectedly, immunization of mice with adenovirus cancer vaccines in combination with chitosan provided little protection against tumor challenge. This directly correlated with the reduced detection of Ag specific CD8(+) T cells, interferon-gamma (IFN-gamma) production, and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since the frequency did not change regardless of whether chitosan was delivered. In mammalian cell lines, chitosan did not interfere with adenovirus transgene expression. However, infection of primary murine bone marrow-derived dendritic cells with adenovirus complexed with chitosan significantly reduced viability, transgene expression, and upregulation of major histocompatability (MHC) class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, which could prevent CD8(+) T cell activation from occurring in vivo. These surprising data demonstrate for the first time that chitosan vaccine formulations can negatively impact the induction of CD8(+) T cell responses via its effect on dendritic cells, which is clinically important since consideration of chitosan as an adjuvant for vaccine formulations is growing. PMID- 21780833 TI - In vivo labeling of B16 melanoma tumor xenograft with a thiol-reactive gadolinium based MRI contrast agent. AB - Murine melanoma B16 cells display on the extracellular side of the plasma membrane a large number of reactive protein thiols (exofacial protein thiols, EPTs). These EPTs can be chemically labeled with Gd-DO3A-PDP, a Gd(III)-based MRI contrast agent bearing a 2-pyridinedithio chemical function for the recognition of EPTs. Uptake of gadolinium up to 10(9) Gd atoms per cell can be achieved. The treatment of B16 cells ex vivo with a reducing agent such as tris(2 carboxyethyl)phosphine (TCEP) results in an increase by 850% of available EPTs and an increase by 45% of Gd uptake. Blocking EPTs with N-ethylmaleimide (NEM) caused a decrease by 84% of available EPTs and a decrease by 55% of Gd uptake. The amount of Gd taken up by B16 cells is therefore dependent upon the availability of EPTs, whose actual level in turn changes according to the extracellular redox microenvironment. Then Gd-DO3A-PDP has been assessed for the labeling of tumor cells in vivo on B16.F10 melanoma tumor-bearing mice. Gd-DO3A PDP (or Gd-DO3A as the control) has been injected directly into the tumor region at a dose level of 0.1 MUmol and the signal enhancement in MR images followed over time. The washout kinetics of Gd-DO3A-PDP from tumor is very slow if compared to that of control Gd-DO3A, and 48 h post injection, the gadolinium enhancement is still clearly visible. Therefore, B16 cells can be labeled ex vivo as well as in vivo according to a common EPTs-dependent route, provided that high levels of the thiol reactive probe can be delivered to the tumor. PMID- 21780834 TI - Determination of structures, stabilities, and electronic properties for bimetallic cesium-doped gold clusters: a density functional theory study. AB - The equilibrium geometric structures, stabilities, and electronic properties of bimetallic Au(n)Cs (n = 1-10) and pure gold Au(n) (n <= 11) clusters have been systematically investigated by using density functional theory with meta generalized gradient approximation. The optimized geometries show that one Au atom capped on Au(n-1)Cs structures and Cs atom capped Au(n) structures for different sized Au(n)Cs (n = 1-10) clusters are two dominant growth patterns. Theoretical calculated results indicate that the most stable isomers have three dimensional structures at n = 4 and 6-10. Averaged atomic binding energies, fragmentation energies, and second-order difference of energies exhibit a pronounced even-odd alternations phenomenon. The same even-odd alternations are found in the highest occupied-lowest unoccupied molecular orbital gaps, vertical ionization potential, vertical electron affinity, and hardnesses. In addition, it is found that the charge in corresponding Au(n)Cs clusters transfers from the Cs atom to the Au(n) host in the range of 0.851-1.036 electrons. PMID- 21780836 TI - Smart design of stripe-patterned gradient surfaces to control droplet motion. AB - The motion of droplets under the influence of lithographically created anisotropic chemically defined patterns is described and discussed. The patterns employed in our experiments consist of stripes of alternating wettability: hydrophobic stripes are created via fluorinated self-assembled monolayers, and for hydrophilic stripes, the SiO(2) substrate is used. The energy gradient required to induce the motion of the droplets is created by varying the relative widths of the stripes in such a way that the fraction of the hydrophilic area increases. The anisotropic patterns create a preferential direction for liquid spreading parallel to the stripes and confine motion to the perpendicular direction, giving rise to markedly higher velocities as compared to nonstructured surface energy gradients. Consequently, the influence of the distinct pattern features on the overall motion as well as suggestions for design improvements from an application point of view are discussed. PMID- 21780835 TI - Nanoscale water condensation on click-functionalized self-assembled monolayers. AB - We have examined the nanoscale adsorption of molecular water under ambient conditions onto a series of well-characterized functionalized surfaces produced by Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC or "click") reactions on alkyne-terminated self-assembled monolayers on silicon. Water contact angle (CA) measurements reveal a range of macroscopic hydrophilicity that does not correlate with the tendency of these surfaces to adsorb water at the molecular level. X-ray reflectometry has been used to follow the kinetics of water adsorption on these "click"-functionalized surfaces, and also shows that dense continuous molecular water layers are formed over 30 h. For example, a highly hydrophilic surface, functionalized by an oligo(ethylene glycol) moiety (with a CA = 34 degrees ) showed 2.9 A of adsorbed water after 30 h, while the almost hydrophobic underlying alkyne-terminated monolayer (CA = 84 degrees ) showed 5.6 A of adsorbed water over the same period. While this study highlights the capacity of X-ray reflectometry to study the structure of adsorbed water on these surfaces, it should also serve as a warning for those intending to characterize self assembled monolayers and functionalized surfaces to avoid contamination by even trace amounts of water vapor. Moreover, contact angle measurements alone cannot be relied upon to predict the likely degree of moisture uptake on such surfaces. PMID- 21780837 TI - Determination of the N-glycosylation patterns of seed proteins: applications to determine the authenticity and substantial equivalence of genetically modified (GM) crops. AB - Methods have been developed to determine the N-glycosylation pattern of proteins at the single-seed level in two different biological systems. These were the well characterized and widely consumed storage protein phaseolin from several species of Phaseolus (bean) and the alpha-amylase inhibitor from the same Phaseolus species expressed transgenically in pea. The N-glycosylation pattern of the alpha amylase inhibitor expressed transgenically in pea was different from that of the inhibitor present in common bean (P. vulgaris), the species of origin of the gene. However, multivariate analysis showed that the differences in N-glycan patterns between the alpha-amylase inhibitors from common bean and pea were less than those between the inhibitors from common bean and two related bean species, lima bean (Phaseolus lunatus) and tepary bean (Phaseolus acutifolius). PMID- 21780838 TI - Examining troughs in the mass distribution of all theoretically possible tryptic peptides. AB - This work describes the mass distribution of all theoretically possibly tryptic peptides made of 20 amino acids, up to the mass of 3 kDa, with resolution of 0.001 Da. We characterize regions between the peaks of the distribution, including gaps (forbidden zones) and low-populated areas (quiet zones). We show how the gaps shrink over the mass range and when they completely disappear. We demonstrate that peptide compositions in quiet zones are less diverse than those in the peaks of the distribution and that by eliminating certain types of unrealistic compositions the gaps in the distribution may be increased. The mass distribution is generated using a parallel implementation of a recursive procedure that enumerates all amino acid compositions. It allows us to enumerate all compositions of tryptic peptides below 3 kDa in 48 min using a computer cluster with 12 Intel Xeon X5650 CPUs (72 cores). The results of this work can be used to facilitate protein identification and mass defect labeling in mass spectrometry-based proteomics experiments. PMID- 21780839 TI - Hybrid resonant organic-inorganic nanostructures for optoelectronic applications. PMID- 21780840 TI - Carbaboranes as pharmacophores: properties, synthesis, and application strategies. PMID- 21780841 TI - Effect of substrate inhibition and cooperativity on the electrochemical responses of glucose dehydrogenase. Kinetic characterization of wild and mutant types. AB - Thanks to its insensitivity to dioxygen and to its good catalytic reactivity, and in spite of its poor substrate selectivity, quinoprotein glucose dehydrogenase (PQQ-GDH) plays a prominent role among the redox enzymes that can be used for analytical purposes, such as glucose detection, enzyme-based bioaffinity assays, and the design of biofuel cells. A detailed kinetic analysis of the electrochemical catalytic responses, leading to an unambiguous characterization of each individual steps, seems a priori intractable in view of the interference, on top of the usual ping-pong mechanism, of substrate inhibition and of cooperativity effects between the two identical subunits of the enzyme. Based on simplifications suggested by extended knowledge previously acquired by standard homogeneous kinetics, it is shown that analysis of the catalytic responses obtained by means of electrochemical nondestructive techniques, such as cyclic voltammetry, with ferrocene methanol as a mediator, does allow a full characterization of all individual steps of the catalytic reaction, including substrate inhibition and cooperativity and, thus, allows to decipher the reason that makes the enzyme more efficient when the neighboring subunit is filled with a glucose molecule. As a first practical illustration of this electrochemical approach, comparison of the native enzyme responses with those of a mutant (in which the asparagine amino acid in position 428 has been replaced by a cysteine residue) allowed identification of the elementary steps that makes the mutant type more efficient than the wild type when cooperativity between the two subunits takes place, which is observed at large mediator and substrate concentrations. A route is thus opened to structure-reactivity relationships and therefore to mutagenesis strategies aiming at better performances in terms of catalytic responses and/or substrate selectivity. PMID- 21780843 TI - Total synthesis of landomycin A, a potent antitumor angucycline antibiotic. AB - The first total synthesis of landomycin A, the longest and most potent antitumor angucycline antibiotic, has been achieved in 63 steps and 0.34% overall yield starting from 2,5-dihydroxybenzoic acid, 3,5-dimethylphenol, triacetyl d-glucal, and d-xylose, with a convergent linear sequence of 21 steps. PMID- 21780842 TI - N-heterocyclic carbene and Bronsted acid cooperative catalysis: asymmetric synthesis of trans-gamma-lactams. AB - An efficient enantioselective approach to form trans-gamma-lactams in up to 99% yield, 93% ee, and >20/1 dr using unactivated imines has been developed. The cyclohexyl-substituted azolium and the weak base sodium o-chlorobenzoate are most suitable for this transformation. Notably, the process involves cooperative catalysis by an N-heterocyclic carbene and a Bronsted acid. PMID- 21780844 TI - Chemical characterization of a procyanidin-rich extract from sorghum bran and its effect on oxidative stress and tumor inhibition in vivo. AB - The present study was to characterize a procyanidin-rich extract (PARE) from sorghum ( Sorghum bicolor (L.) Moench) bran and assess its biological activities. The procyanidin oligomers were separated and identified by normal-phase HPLC equipped with fluorescence (FLD) and mass spectrometry (MS) detectors. In addition, the effects of PARE on oxidative stress in mice induced by D-galactose as well as tumor inhibition in C57BL/6J mice bearing Lewis lung cancer were investigated. Administration of D-galactose significantly (p < 0.05) lowered the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). This was accompanied by a significant (p < 0.05) increase in malondialdehyde (MDA) levels in both liver and serum. Administration of PARE (150 mg/kg) significantly (p < 0.05) reversed the d-galactose-induced oxidative stress by enhancing the activities of antioxidant enzymes. Furthermore, PARE administration inhibited tumor growth and metastasis formation by suppressing vascular endothelial growth factor (VEGF) production. The results suggested that PARE had antioxidant and antitumor activities. PMID- 21780845 TI - Enhancing the electrical conductivity of carbon-nanotube-based transparent conductive films using functionalized few-walled carbon nanotubes decorated with palladium nanoparticles as fillers. AB - This work demonstrates the processing and characterization of the transparent and highly electrically conductive film using few-walled carbon nanotubes (FWCNTs) decorated with Pd nanoparticles as fillers. The approach included functionalizing the FWCNTs, immersing them in an aqueous solution of palladate salts, and subsequently subjecting them to a reduction reaction in H(2). Field-emission scanning electron microscopy and transmission electron microscopy images showed that the functionalized FWCNTs (f-FWCNTs) were decorated with uniform and homogeneous Pd nanoparticles with an average diameter of 5 nm. A shift of the G band to a higher frequency in the Raman spectra of the Pd-decorated f-FWCNTs (Pd@f-FWCNTs) illustrates that the p-type doping effect was enhanced. X-ray photoelectron spectroscopy and energy-dispersive X-ray spectroscopy showed that PdCl(2) was the primary decoration compound on the f-FWCNTs prior to the reduction reaction and that Pd nanoparticles were the only decorated nanoparticles after H(2) reduction. The contact resistance between the metallic materials and the semiconducting CNTs in FWCNTs, controlled by the Schottky barrier, was significantly decreased compared to the pristine FWCNTs. The decrease in contact resistance is attributed to the 0.26 eV increase of the work function of the Pd@f-FWCNTs. Extremely low sheet resistance of 274 ohm/sq of the poly(ethylene terephthalate) substrates coated with Pd@f-FWCNTs was attained, which was 1/25 the resistance exhibited by those coated with FWCNTs, whereas the same optical transmittance of 81.65% at a wavelength of 550 nm was maintained. PMID- 21780846 TI - Inhibition of azoxymethane-induced preneoplastic lesions in the rat colon by a cooked stearic acid complexed high-amylose cornstarch. AB - This study evaluated a novel stearic acid complexed high-amylose cornstarch (SAC) for the prevention of preneoplastic lesions in the colon of azoxymethane (AOM) treated Fisher 344 rats fed resistant starches at 50-55% of the diet for 8 weeks. Uncooked SAC (r-SAC) diet was compared with raw normal-cornstarch diet (r-CS) or raw high-amylose cornstarch diet (r-HA), and water-boiled CS (w-CS) was compared with w-HA and w-SAC, respectively. w-SAC markedly reduced mucin-depleted foci (MDF) numbers compared with w-HA or w-CS. r-HA significantly decreased aberrant crypt foci (ACF) numbers compared with r-CS or r-SAC. Increased cecum weight and decreased cecum pH were observed in the SAC or HA groups. The highest amounts of total or individual short-chain fatty acids (SCFAs) in cecum and of butyrate or propionate in feces were observed in the AOM-treated w-SAC group. This study revealed the effectiveness of a novel resistant starch in inhibiting colonic preneoplastic lesions and the importance of high-moisture cooking on the suppression of colon carcinogenesis by this resistant starch. PMID- 21780847 TI - Differences in DNA condensation and release by lysine and arginine homopeptides govern their DNA delivery efficiencies. AB - Designing of nanocarriers that can efficiently deliver therapeutic DNA payload and allow its smooth intracellular release for transgene expression is still a major constraint. The optimization of DNA nanocarriers requires thorough understanding of the chemical and structural characteristics of the vector nucleic acid complexes and its correlation with the cellular entry, intracellular state and transfection efficiency. L-lysine and L-arginine based cationic peptides alone or in conjugation with other vectors are known to be putative DNA delivery agents. Here we have used L-lysine and L-arginine homopeptides of three different lengths and probed their DNA condensation and release properties by using a multitude of biophysical techniques including fluorescence spectroscopy, gel electrophoresis and atomic force microscopy. Our results clearly showed that although both lysine and arginine based homopeptides condense DNA via electrostatic interactions, they follow different pattern of DNA condensation and release in vitro. While lysine homopeptides condense DNA to form both monomolecular and multimolecular complexes and show differential release of DNA in vitro depending on the peptide length, arginine homopeptides predominantly form multimolecular complexes and show complete DNA release for all peptide lengths. The cellular uptake of the complexes and their intracellular state (as observed through flow cytometry and fluorescence microscopy) seem to be controlled by the peptide chemistry. The difference in the transfection efficiency of lysine and arginine homopeptides has been rationalized in light of these observations. PMID- 21780848 TI - The non-surgical and surgical treatment of tarsal navicular stress fractures. AB - Stress fractures of the tarsal navicular, first described in 1970, were initially thought to be rare injuries. Heightened awareness and increased participation in athletics has resulted in more frequent diagnosis and more aggressive treatment. The vascular supply of the tarsal navicular results in a relatively avascular zone in the central one-third, which experiences severe compressive forces during explosive manoeuvers such as jumping and sprinting. Repetitive activities can result in stress reactions or even fracture. Patients often initially complain of vague midfoot pain localized to the medial border of the foot. The pain is usually exacerbated by activity and relieved with rest. The diagnosis of tarsal navicular stress fracture is challenging because of the high false negative rate of plain radiographs. Additional diagnostic testing with bone scan, CT and MRI are often required for diagnosis. The proper treatment of tarsal navicular stress fractures has become a topic of debate as surgical intervention for these injuries has increased. In a recent meta-analysis, Torg et al. found that 96% of tarsal navicular stress fractures treated with non-weight-bearing (NWB) conservative treatment for 5 weeks went on to successful outcomes. However, only 44% of patients treated with weight-bearing (WB) conservative treatment had successful outcomes. Surgical treatment resulted in successful outcome in 82% of patients. Interestingly, the meta-analysis also found that fracture type did not correlate with outcomes, regardless of treatment. The meta-analysis also found no difference in time to return to activity between patients treated surgically and those who underwent NWB conservative treatment. The recent literature indicates that patients are undergoing surgery or are receiving WB conservative management as a first-line treatment option with the expectation that they will return to their activity more quickly. Although surgical treatment seems increasingly common, the results statistically demonstrate an inferior trend to conservative NWB management. Conservative NWB management is the standard of care for initial treatment of both partial and complete stress fractures of the tarsal navicular. WB conservative treatment and surgical intervention are not recommended. PMID- 21780850 TI - The pleasure and displeasure people feel when they exercise at different intensities: decennial update and progress towards a tripartite rationale for exercise intensity prescription. AB - The public health problem of physical inactivity has proven resistant to research efforts aimed at elucidating its causes and interventions designed to alter its course. Thus, in most industrialized countries, the majority of the population is physically inactive or inadequately active. Most theoretical models of exercise behaviour assume that the decision to engage in exercise is based on cognitive factors (e.g. weighing pros and cons, appraising personal capabilities, evaluating sources of support). Another, still-under-appreciated, possibility is that these decisions are influenced by affective variables, such as whether previous exercise experiences were associated with pleasure or displeasure. This review examines 33 articles published from 1999 to 2009 on the relationship between exercise intensity and affective responses. Unlike 31 studies that were published until 1998 and were examined in a 1999 review, these more recent studies have provided evidence of a relation between the intensity of exercise and affective responses. Pleasure is reduced mainly above the ventilatory or lactate threshold or the onset of blood lactate accumulation. There are pleasant changes at sub-threshold intensities for most individuals, large inter-individual variability close to the ventilatory or lactate threshold and homogeneously negative changes at supra-threshold intensities. When the intensity is self selected, rather than imposed, it appears to foster greater tolerance to higher intensity levels. The evidence of a dose-response relation between exercise intensity and affect sets the stage for a reconsideration of the rationale behind current guidelines for exercise intensity prescription. Besides effectiveness and safety, it is becoming increasingly clear that the guidelines should take into account whether a certain level of exercise intensity would be likely to cause increases or decreases in pleasure. PMID- 21780852 TI - Trained humans can exercise safely in extreme dry heat when drinking water ad libitum. AB - Guidelines to establish safe environmental exercise conditions are partly based on thermal prescriptive zones. Yet there are reports of self-paced human athletic performances in extreme heat. Eighteen participants undertook a 25-km route march in a dry bulb temperature reaching 44.3 degrees C. The mean (+/- s) age of the participants was 26.0 +/- 3.7 years. Their mean ad libitum water intake was 1264 +/- 229 mL . h(-1). Predicted sweat rate was 1789 +/- 267 mL . h(-1). Despite an average body mass loss of 2.73 +/- 0.98 kg, plasma osmolality and serum sodium concentration did not change significantly during exercise. Total body water fell 1.47 kg during exercise. However, change in body mass did not accurately predict changes in total body water as a 1:1 ratio. There was a significant relationship (negative slope) between post-exercise serum sodium concentration and changes in both body mass and percent total body water. There was no relationship between percent body mass loss and peak exercise core temperature (39 +/- 0.9 degrees C) or exercise time. We conclude that participants maintained plasma osmolality, serum sodium concentration, and safe core temperatures by (1) adopting a pacing strategy, (2) high rates of ad libitum water intake, and (3) by a small reduction in total body water to maintain serum sodium concentration. Our findings support the hypothesis that humans are the mammals with the greatest capacity for exercising in extreme heat. PMID- 21780849 TI - Neuroendocrine-immune interactions and responses to exercise. AB - This article reviews the interaction between the neuroendocrine and immune systems in response to exercise stress, considering gender differences. The body's response to exercise stress is a system-wide effort coordinated by the integration between the immune and the neuroendocrine systems. Although considered distinct systems, increasing evidence supports the close communication between them. Like any stressor, the body's response to exercise triggers a systematic series of neuroendocrine and immune events directed at bringing the system back to a state of homeostasis. Physical exercise presents a unique physiological stress where the neuroendocrine and immune systems contribute to accommodating the increase in physiological demands. These systems of the body also adapt to chronic overload, or exercise training. Such adaptations alleviate the magnitude of subsequent stress or minimize the exercise challenge to within homeostatic limits. This adaptive capacity of collaborating systems resembles the acquired, or adaptive, branch of the immune system, characterized by the memory capacity of the cells involved. Specific to the adaptive immune response, once a specific antigen is encountered, memory cells, or lymphocytes, mount a response that reduces the magnitude of the immune response to subsequent encounters of the same stress. In each case, the endocrine response to physical exercise and the adaptive branch of the immune system share the ability to adapt to a stressful encounter. Moreover, each of these systemic responses to stress is influenced by gender. In both the neuroendocrine responses to exercise and the adaptive (B lymphocyte) immune response, gender differences have been attributed to the 'protective' effects of estrogens. Thus, this review will create a paradigm to explain the neuroendocrine communication with leukocytes during exercise by reviewing (i) endocrine and immune interactions; (ii) endocrine and immune systems response to physiological stress; and (iii) gender differences (and the role of estrogen) in both endocrine response to physiological stress and adaptive immune response. PMID- 21780851 TI - Repeated-sprint ability - part I: factors contributing to fatigue. AB - Short-duration sprints (<10 seconds), interspersed with brief recoveries (<60 seconds), are common during most team and racket sports. Therefore, the ability to recover and to reproduce performance in subsequent sprints is probably an important fitness requirement of athletes engaged in these disciplines, and has been termed repeated-sprint ability (RSA). This review (Part I) examines how fatigue manifests during repeated-sprint exercise (RSE), and discusses the potential underpinning muscular and neural mechanisms. A subsequent companion review to this article will explain a better understanding of the training interventions that could eventually improve RSA. Using laboratory and field-based protocols, performance analyses have consistently shown that fatigue during RSE typically manifests as a decline in maximal/mean sprint speed (i.e. running) or a decrease in peak power or total work (i.e. cycling) over sprint repetitions. A consistent result among these studies is that performance decrements (i.e. fatigue) during successive bouts are inversely correlated to initial sprint performance. To date, there is no doubt that the details of the task (e.g. changes in the nature of the work/recovery bouts) alter the time course/magnitude of fatigue development during RSE (i.e. task dependency) and potentially the contribution of the underlying mechanisms. At the muscle level, limitations in energy supply, which include energy available from phosphocreatine hydrolysis, anaerobic glycolysis and oxidative metabolism, and the intramuscular accumulation of metabolic by-products, such as hydrogen ions, emerge as key factors responsible for fatigue. Although not as extensively studied, the use of surface electromyography techniques has revealed that failure to fully activate the contracting musculature and/or changes in inter-muscle recruitment strategies (i.e. neural factors) are also associated with fatigue outcomes. Pending confirmatory research, other factors such as stiffness regulation, hypoglycaemia, muscle damage and hostile environments (e.g. heat, hypoxia) are also likely to compromise fatigue resistance during repeated-sprint protocols. PMID- 21780853 TI - Randomized study of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy. AB - OBJECTIVE: The aim of this research is to determine efficacy and safety of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy. METHODS: A 16-week, open-label, randomized, active-controlled, parallel-group trial was carried out. Subjects were randomized (1:1) to repaglinide 1 mg t.i.d. (maximum dose, 4 mg t.i.d.) or repaglinide plus metformin 1 mg/500 mg t.i.d. (maximum dose, 4 mg/500 mg t.i.d.). Eligible subjects (18 - 75 years old) had type 2 diabetes, A1C > 8.5%, BMI <= 35 kg/m(2), and were naive to oral antidiabetes agents. RESULTS: The primary outcome was A1C reduction. Secondary end points included fasting plasma glucose (FPG), 2 h postprandial glucose (PPG), and 7-point plasma glucose. Baseline characteristics (repaglinide/metformin, n = 218; repaglinide-only, n = 214) were similar between groups. Mean A1C reduction (+/- SD) was 4.51 +/- 1.64% (combination) and 4.05 +/- 1.59% (monotherapy). Estimated mean treatment difference for repaglinide/metformin versus repaglinide-only was -0.30% (95% CI 0.49 to -0.11; p < 0.01). Combination treatment demonstrated significant improvements versus monotherapy in FPG, 7-point plasma glucose, and lunchtime and dinnertime 2-h PPG (all p < 0.05). Hypoglycemia rates were 2.04 (combination) versus 1.35 (monotherapy) events/subject-year (p = 0.058). Adverse events were comparable between groups. CONCLUSIONS: Repaglinide plus metformin and repaglinide alone provided significant improvements in glycemic control and were well tolerated in Chinese patients naive to treatment with oral antidiabetes agents. Combination therapy with repaglinide plus metformin showed superiority to repaglinide monotherapy in this population. Limitations of this study are that subjects were newly diagnosed and had high mean baseline A1C, which may affect generalizability of results. PMID- 21780854 TI - Correlation between fetal heart rate reactivity and mortality and severe neurological morbidity in extremely low birth weight infants. AB - OBJECTIVE: To determine the correlation between specific fetal heart rate (FHR) abnormalities and the incidence of death, severe (grade 3-4) intraventricular hemorrhage (IVH) and periventricular echogenicity (PVE) in extremely low birth weight infants (ELBW) within the first 4 days after birth. METHODS: The study included live-born ELBW infants <= 30 weeks' gestation who were born in 2000-2007 at Kaplan Medical Center, Rehovot, Israel, and, who had FHR monitoring during the 24 h before delivery and cranial ultrasound during the first 4 days of life. FHR pattern was analyzed for the presence of baseline rate, reactivity, variability and decelerations. RESULTS: 96 infants with mean birth weight 757 +/- 150 g and mean gestational age 25.8 +/- 1.5 weeks were included. By 4 days of life, 23/96 (24%) died, 17/96 (18%) developed severe IVH and 31/96 (32%) had PVE. Absence of reactivity was significantly associated with increase in both death (p = 0.02, OR 3.45, 95% CI: 1.22-9.47 and severe IVH (p = 0.029, OR 3.33, 95% CI: 1.25-10) but not with PVE. Other FHR parameters were not associated with adverse outcome. CONCLUSION: These results suggest that FHR reactivity may be of value in predicting short-term outcome in ELBW infants. This may be helpful in counseling parents with imminent extremely preterm birth. PMID- 21780855 TI - Development and haematotoxicological evaluation of doped hydroxyapatite based multimodal nanocontrast agent for near-infrared, magnetic resonance and X-ray contrast imaging. AB - Multimodal molecular imaging provides both anatomical and molecular information, aiding early stage detection and better treatment planning of diseased conditions. Here, we report development and nanotoxicity evaluation of a novel hydroxyapatite nanoparticle (nHAp) based multimodal contrast agent for combined near-infrared (NIR), MR and X-ray imaging. Under optimised wet-chemical conditions, we achieved simultaneous doping of nHAp (size ~50 nm) with indocyanine green and Gd(3+) contributing to NIR contrast (~750-850 nm), paramagnetic behaviour and X-ray absorption suitable for NIR, MR and X-ray contrast imaging, respectively. Haematocompatibility studies using stem cell viability, haemolysis, platelet activation, platelet aggregation and coagulation time analysis indicated excellent compatibility of doped nHAp (D-nHAp). Further, the immunogenic function studies using human lymphocytes (in vitro) showed that D nHAp caused no adverse effects. Collectively, our studies suggest that D-nHAp with excellent biocompatibility and multifunctional properties is a promising nanocontrast agent for combined NIR, MR and X-ray imaging applications. PMID- 21780856 TI - Patency, flow, and endothelialization of the sutureless Excimer Laser Assisted Non-occlusive Anastomosis (ELANA) technique in a pig model. AB - OBJECT: The purpose of this study was to assess flow, patency, and endothelialization of bypasses created with the sutureless Excimer Laser Assisted Non-occlusive Anastomosis (SELANA) technique in a pig model. METHODS: In 38 pigs, a bypass was made on the left common carotid artery (CCA), using the right CCA as a graft, with 2 SELANAs. Bypass flow was measured using single-vessel flowmetry. The pigs were randomly assigned to 1 of 12 survival groups (1, 2, 3, 4, 5, 6, 7, and 10 days; 2 and 3 weeks; and 3 and 6 months). One extra animal underwent the procedure and then was killed after 1 hour of bypass patency to serve as a control. Angiography was performed just before the animals were killed, to assess bypass patency. Scanning electron microscopy and histological studies were used to evaluate the anastomoses after planned death. RESULTS: The mean SELANA bypass flow was not significantly different from the mean flow in the earlier ELANA (Excimer Laser Assisted Non-occlusive Anastomosis) pig study at opening and follow-up. Overall SELANA bypass patency (87%) was not significantly different from the ELANA patency of 86% in the earlier study. Complete SELANA endothelialization was observed after 2-3 weeks, compared with 2 weeks in the earlier ELANA study. CONCLUSIONS: The SELANA technique is not inferior to the current ELANA technique regarding flow, patency, and endothelialization. A pilot study in patients is a logical next step. PMID- 21780857 TI - Glioblastoma with dural tail. PMID- 21780858 TI - Prevalence and natural history of pineal cysts in adults. AB - OBJECT: We reviewed our experience with pineal cysts to define the natural history and clinical relevance of this common intracranial finding. METHODS: The study population consisted of 48,417 consecutive patients who underwent brain MR imaging at a single institution over a 12-year interval and who were over 18 years of age at the time of imaging. Patient characteristics, including demographic data and other intracranial diagnoses, were collected from cases involving patients with a pineal cyst. We then identified all patients with pineal cysts who had been clinically evaluated at our institution and who had at least 6 months of clinical and imaging follow-up. All inclusion criteria for the natural history analysis were met in 151 patients. RESULTS: Pineal cysts measuring 5 mm or larger in greatest dimension were found in 478 patients (1.0%). Of these, 162 patients were male and 316 were female. On follow-up MR imaging of 151 patients with pineal cyst at a mean interval of 3.4 years from the initial study, 124 pineal cysts remained stable, 4 increased in size, and 23 decreased in size. Cysts that were larger at the time of initial diagnosis were more likely to decrease in size over the follow-up interval (p = 0.004). Patient sex, patient age at diagnosis, and the presence of septations within the cyst were not significantly associated with cyst change on follow-up. CONCLUSIONS: Follow-up imaging and neurosurgical evaluation are not mandatory for adults with asymptomatic pineal cysts. PMID- 21780859 TI - Family and personal medical history and risk of meningioma. AB - OBJECT: Little is known about the epidemiology of meningioma, the most frequently reported primary brain tumor in the US. The authors undertook a case-control study to examine the relationship between family and personal medical history and meningioma risk. METHODS: The authors compared the personal and first-degree family histories of 1124 patients with meningioma (age range 20-79 years) in Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area, and 8 Houston counties between May 1, 2006, and February 26, 2010, and the histories of 1000 control individuals who were frequency-matched for age, sex, and geography. RESULTS: The patients were more likely than the controls to report a first-degree family history of meningioma (OR 4.4, 95% CI 1.6-11.5), and there was an even stronger association in younger cases. The patients were less likely than controls to report immune conditions including allergy (OR 0.6, 95% CI 0.5-0.7) but were more likely to report a history of thyroid cancer (OR 4.7, 95% CI 1.02 21.5) or leukemia (OR 5.4, 95% CI 1.2-24.1) (most after radiotherapy). Among women, patients were more likely than controls to report hormonally related conditions--uterine fibroid tumors (OR 1.2, 95% CI 1.0-1.5), endometriosis (OR 1.5, 95% CI 1.5-2.1), and breast cancer (OR 1.4, 95% CI 0.8-2.3). CONCLUSIONS: The influence of genetics, the immune system, and radiation near the head on meningioma risk is suggested in the authors' findings; the role of hormones is intriguing but requires further study. PMID- 21780860 TI - Genu of corpus callosum as a prognostic factor in diffuse axonal injury. AB - OBJECT: Previous studies have shown a relationship between a patient's stage of diffuse axonal injury (DAI) and outcome. However, few studies have assessed whether a specific lesion or type of corpus callosum injury (CCI) influences outcome in patients with DAI. The authors investigated the effect of various DAIs and CCIs on outcome in patients with traumatic brain injury (TBI). METHODS: The authors retrospectively reviewed 78 consecutive patients with DAI who were seen between May 2004 and March 2010. Outcome was evaluated using the Extended Glasgow Outcome Scale (EGOS) 1 year after TBI. Patients with single DAIs had only 1 of the 3 lesions (lobar, CC, or brainstem). Patients with dual DAIs had 2 of these lesions, and those with triple DAIs had all of these lesions. Furthermore, the authors defined single, dual, and triple CCIs by using 3 lesions (genu, body, splenium) in the same way among patients with single (CC) DAIs. Univariate and multivariate logistic regression analyses were performed to evaluate the relationships between these lesions and outcome in patients with DAI. RESULTS: Fifty patients had single DAIs: 34 in the lobar area, 11 in the CC, and 5 in the brainstem. Twenty had dual DAIs, and 8 had triple DAIs. Of the 11 CCIs, 9 were single and 2 were dual CCIs. Among these lesions, only those in the genu were related to disability. The authors dichotomized patients into those with and without genu lesions, regardless of other injuries. Multinomial logistic regression analysis showed that a genu lesion (OR 18, 95% CI 2.2-32; p = 0.0021) and a pupillary abnormality (OR 14, 95% CI 1.6-24; p = 0.0068) were associated with disability (EGOS <= 6) in patients with DAI. CONCLUSIONS: Regardless of the number of lesions, the existence of a genu lesion suggested disability 1 year after TBI in patients with DAI. PMID- 21780861 TI - Risk of progression of degenerative lumbar scoliosis. AB - OBJECT: In this paper the authors' goal was to determine the factors associated with the progression of degenerative lumbar scoliosis (DLS). METHODS: Twenty seven patients (3 men and 24 women; mean age 64.9 years) with more than 10 degrees of lumbar scoliosis at baseline were monitored for a mean period of 10 years. The radiological evaluation included measurement of the scoliosis angle using the Cobb method, the direction of the scoliosis, the relationship between the intercrest line and the L-5 vertebra, lateral listhesis, segmental angle, distance from the center of the sacral line to the apical vertebra, degenerative listhesis anteriorly or posteriorly or both, and lordosis angle. In addition, the lateral osteophyte difference, disc index, and severity of osteoporosis were measured. The pain and disability outcomes were assessed using the visual analog scale and the Oswestry Disability Index (ODI) relative to severity of the angle of scoliosis. RESULTS: The mean initial and final scoliosis angles were 14 degrees +/- 5.4 degrees and 25 degrees +/- 8.5 degrees , respectively. The initial disc index at the L-3 vertebra (Spearman rho = 0.7, p < 0.001), the sum of the segmental wedging angles above and below the L-3 vertebra (rho = 0.6, p < 0.001), and the initial disc index at the apical vertebra (rho = 0.6, p < 0.001) were correlated with the last follow-up angle of the scoliosis. By contrast, there was no statistically significant correlation between the initial segmental angles at L2-3 and L3-4 and the final follow-up scoliosis angle (rho = 0.2, p = 0.67; and rho = 0.1, p = 0.22; respectively). When the authors separated the patients into 3 groups according to the sum of the segmental angles above and below L-3 (< 5 degrees , 5 degrees to 10 degrees , and > 10 degrees ), they found that 3 (42.9%) of 7, 8 (66.7%) of 12, and 6 (75.0%) of 8 patients in the 3 groups showed increases of greater than 10 degrees in scoliosis angle. The mean distance from the center of the sacral line to the apical vertebra was 36.0 +/- 9.7 mm, and the distance correlated with the measurement of the last follow-up angle of the scoliosis (rho = 0.6, p < 0.001). The mean angle of the scoliosis was significantly greater when the intercrest line passed through the L-5 or L4-5 disc space than when the line passed through the L-4 vertebral body (31.4 degrees +/- 7.9 degrees vs 21.8 degrees +/- 6.7 degrees , p = 0.01). The ODI correlated with the measurement of the angle of the scoliosis (rho = 0.6, p < 0.001). Age, sex, osteoporosis, the direction of the scoliosis, listhesis of coronal and sagittal planes, the lateral osteophyte difference, and the vertebral body index did not correlate with curve progression. CONCLUSIONS: The findings of this study demonstrated that the progression of DLS was affected by the relationship between the intercrest line and the L-5 vertebra. When L-5 was deep seated, progression of DLS was found. Asymmetrical change in the disc space above and below the L-3 or apical vertebra may also be an important predictor of curve progression. PMID- 21780862 TI - Biomechanical comparison of lumbar total disc arthroplasty, discectomy, and fusion: effect on adjacent-level disc pressure and facet joint force. AB - OBJECT: With the increasing advocacy for total disc replacement (TDR) as a potential alternative to fusion in the management of lumbar degenerative disc disease, intradiscal pressures (IDPs) and facet joint stresses at the adjacent levels of spine have generated considerable interest. The purpose of this study was to compare adjacent-level IDPs and facet joint stresses among TDR, discectomy, and fusion. METHODS: Ten fresh human cadaveric lumbar specimens (L2 S1) were subjected to an unconstrained load in axial torsion, lateral bending, flexion, and extension by using multidirectional flexibility test. Four surgical treatment modes-control (disc intact), discectomy, TDR, and fusion-were tested in sequential order at L4-5. During testing, the IDPs and facet forces following each treatment were calculated at the adjacent vertebral levels (L3-4 and L5-S1). RESULTS: Intradiscal pressures and facet force pressures were similar between the intact condition and the TDR reconstruction at the L3-4 and L5-S1 levels under all loading conditions (p > 0.05). Compared with the intact and TDR groups, the discectomy and fusion groups had higher IDPs at the L3-4 and L5-S1 levels under all loading conditions (p < 0.05). No significant difference in the facet force pressure was noted among the intact, discectomy, and TDR groups at the L3-4 and L5-S1 levels under any loading conditions (p > 0.05). However, the facet force pressure produced for fusion was significantly higher than the mean values obtained for the intact, discectomy, and TDR groups at the L3-4 and L5-S1 levels under all loading conditions (p < 0.05). CONCLUSIONS: Lumbar TDR maintained adjacent-level IDPs and facet force pressures near the values for intact spines, whereas adjacent-level IDPs tended to increase after discectomy or fusion and facet forces tended to increase after fusion. PMID- 21780863 TI - An anterior approach to spinal pathology of the upper thoracic spine through a partial manubriotomy. AB - Surgical pathology in the region of the upper thoracic spine (T1-4) is uncommon compared with other regions of the spine. Often times posterior and posterolateral approaches can be used, but formal anterior decompression often requires a low anterior cervical approach combined with a sternotomy, which yields significant perioperative morbidity. The authors describe a modified low anterior cervical dissection combined with a partial manubriotomy that they have used to successfully access and decompress anterior pathology of the upper thoracic spine. Their modified approach spares the sternoclavicular joints and leaves the sternum intact, decreasing the morbidity associated with these added procedures. PMID- 21780864 TI - Disruption of tracheobronchial airway growth following postnatal exposure to ozone and ultrafine particles. AB - This study examined airway structure changes in adult rats after a long recovery period due to sub-chronic juvenile exposure to ozone and ultrafine particles that have a high organic fraction. Neonatal male Sprague-Dawley rats were exposed during lung development to 3 cycles of 0.5 ppm ozone from postnatal day 7 through 25. Two different exposure patterns were used: 5-day exposure per week (Ozone52) or 2-day exposure per week (Ozone25) with or without co-exposure to ultrafine particles (OPFP5252, OPFP5225). Airway architecture was evaluated at 81 days of age, after 56 days of continued development beyond the exposure period in filtered air (FA). By analyzing CT images from lung airway casts, we determined airway diameter, length, branching angle, and rotation angle for most conducting airways. Compared with the FA control group, the Ozone52 group showed significant decreases in airway diameter in generations larger than 10 especially in the right diaphragmatic lobe and in airway length in distal generations, while changes in airway structure due to the Ozone25 exposure were not appreciable. Interaction effects of ozone and ultrafine particle exposures were not significant. These results suggest that airway alterations due to postnatal ozone exposure are not limited to the distal region but occur extensively from the middle to distal conducting airways. Further, alterations due to early ozone exposure do not recover nearly 2 months after exposure has ceased demonstrating a persistent airway structural change following an early life exposure to ozone. PMID- 21780865 TI - Early hyperglycemia following alloxan administration in vivo is not associated with altered hepatic mitochondrial function: acceptable model for type 1 diabetes? AB - Alloxan and oxidative stress, which have been detected in livers of laboratory animals shortly after in vivo alloxan administration, cause in vitro mitochondrial dysfunction, thus questioning alloxan diabetes as an acceptable model for type 1 diabetes, a model that cannot legitimately be used to investigate mitochondrial metabolism in a diabetic state. In the current study, the blood glucose concentration increased in the drug-treated group of Sprague Dawley rats (compared with the placebo group) 45 or 60 min after alloxan treatment, whereas at 30 min the blood glucose concentration was unchanged. State 4, state 3, respiratory control, efficiency of oxidative phosphorylation, and mitochondrial ATP synthase activity, assayed using glutamate plus malate, pyruvate plus malate, or succinate as a substrate, were not negatively altered during the entire study. These results indicated that early increases of blood glucose concentration, after in vivo alloxan administration, did not lead to liver mitochondrial dysfunction, suggesting that alloxan diabetes can be used for the study of liver mitochondrial respiration in a diabetic state. PMID- 21780866 TI - Preparation, characterization and tissue distribution of brucine stealth liposomes with different lipid composition. AB - OBJECTIVE: To improve the therapeutic index of brucine, the novel stealth liposomes (SLS-n), composed of naturally unsaturated and hydrogenated soy phosphatidylcholines, with significant difference of phase transition temperature, were developed to encapsulate brucine. METHODS: Brucine-loaded stealth liposomes with different lipid compositions were prepared and characterized for their entrapment efficiency (EE), particle size, zeta potential and in vitro drug release profile. Tissue distribution after intravenous administration of different brucine formulations was further compared in tumor bearing mice. RESULTS: Compared with the conventional stealth liposomes composed of SPC (SLS-s) or HSPC (SLS-h), EE and zeta potential of SLS-n were increased slightly, and the size was decreased slightly. The results of drug release showed that SLS-n were more stable than SLS-s. After intravenous administration, tumor AUC in SLS-s, SLS-n and SLS-h treated animals were 1.33, 1.72 and 2.59-fold higher than in mice treated with the same dose of free brucine, respectively. Compared with brucine solution, administration of SLS-s and SLS-n could significantly decrease brucine concentration in brain, but administration of SLS h resulting in significantly increased (2.75-fold) concentration in 10 min. CONCLUSION: Since brucine has severe central nervous system toxicity, our study indicated that SLS-n could considerably improve the therapeutic index of brucine. PMID- 21780867 TI - Childhood obesity and walking: guidelines and challenges. AB - The development and maintenance of excess body mass in many children is partly attributable to levels of physical activity that are lower than the recommended 60 minutes/day. Walking is a recommended form of physical activity for obese children, due to its convenience and perceived ease of adoption. Unfortunately, studies that have used objective physical activity assessment continue to report low step counts and levels of physical activity in obese children. This may be due to physiological and/or biomechanical factors that make walking more difficult for obese children. The purpose of this review is to highlight the current recommended and measured levels of physical activity for children and to discuss the physiological and biomechanical challenges of walking for obese children that may help explain why these children are not meeting physical activity goals. PMID- 21780869 TI - Psychological control by parents is associated with a higher child weight. AB - OBJECTIVE: In this examination of the association between parenting style and child weight, the neglected concept of 'psychological control' has been added to the generally accepted parenting dimensions 'support' and 'behavioural control'. Also explored is whether the potential association between parenting and child weight is moderated by socio-demographic variables (child's age/ethnicity, and parent's education level). METHODS: A cross-sectional study was performed among 1,665 parent-child dyads. The children's mean age was 8 years. Their height and weight were measured to calculate their body mass index (BMI). Parents completed a questionnaire to measure the three parenting dimensions. Based on these dimensions, five parenting styles were defined: the authoritative, permissive, authoritarian, neglecting and rejecting parenting style. Child BMI z-scores were regressed on parenting style, adjusting for parental BMI, child ethnicity, and parent's education level. RESULTS: Rejecting parenting, characterized by high psychological control, low support and low behavioural control, is the only parenting style significantly related to child BMI z-scores (beta = 0.074, p < 0.001). The positive association was not moderated by socio-demographic variables. CONCLUSIONS: By adding the dimension of psychological control to the concept of parenting, this study has further elucidated the mechanisms whereby parenting may affect child weight. Demonstrating that 'rejecting parenting' is associated with a higher child weight, emphasizes the need for longitudinal studies in which parenting style is measured three-dimensionally. Potential mediating effects of parental feeding style and children's eating style, as well as age moderation, should be included in these studies. PMID- 21780868 TI - Maternal correlates of preschool child eating behaviours and body mass index: a cross-sectional study. AB - To the authors' knowledge, this is the first study to evaluate maternal child feeding practices, maternal parenting characteristics and mother-child interactions as cross-sectional predictors of child eating and/or weight within the one sample. Maternal pressure for her child to eat was a significant positive correlate of fussiness and a negative correlate of enjoyment. Maternal parenting warmth was associated negatively with child BMIz, while mother-child dysfunctional interaction was associated positively with child BMIz. Our findings suggest that childhood obesity research may be better informed by evaluating not just what mothers do (feeding practices) but also how they parent (parenting behaviours and interactions with their child). Longitudinal studies are needed to identify causal influences of parenting on preschool child eating and weight. PMID- 21780870 TI - Parental status and childhood obesity in Australia. AB - The overall aim of this study was to examine obesogenic factors in children from single and dual parent families. Data from the Longitudinal Study of Australian Children (LSAC) (8,717 children) were analyzed to examine the differences in children's activity levels, dietary intake and BMI according to parental status and determine the likelihood of childhood overweight and obesity in a single parent household. There were higher rates of overweight and obesity in girls aged four to nine whose parents were single (OR 1:60). Children in single-parent households watched more television, ate more food high in fat and sugar and less fresh fruit and vegetables than children from dual-parent households. The findings suggested that an additive effect of dietary and activity variables may contribute to the higher rates of overweight and obesity in Australian children, and that girls from single-parent households may be particularly at risk. PMID- 21780871 TI - Passing the baton: reflections on publishing in Ophthalmic Epidemiology. PMID- 21780872 TI - Population-based survey of active trachoma in 11 districts of Burundi. AB - PURPOSE: To establish that trachoma is a public health problem in Burundi, and to provide baseline data on the prevalence of active trachoma and unclean faces prior to the commencement of trachoma elimination activities in endemic districts. METHODS: For each of 11 pilot districts, eight collines (hills) (estimated population generally 1000-8000) were selected at random using a population-proportional-to-size technique; from each selected colline, one sous colline (of which there are generally 3-5 per colline) was selected at random by simple random draw. In each selected sous-colline, all available 1-9-year-old children were examined for clinical signs of trachoma, and for signs of an unclean face (defined as eye discharge, nose discharge and/or presence of one or more flies on the face during the time taken to examine the eyes). RESULTS: A mean of 230 children were examined per sous-colline (range 44-600); in all, 20,659 children were examined in 90 sous-collines of 11 districts. (In one district, 10 rather than eight sous-collines were selected.) In three contiguous districts (Buhiga, Nyabikere and Muyinga) in the country's north-east, the prevalence of the sign "trachomatous inflammation-follicular" (TF) in 1-9-year olds was >10%. In nine districts, the prevalence of unclean faces was >10%. CONCLUSION: Trachoma is a public health problem in Burundi. Implementation of trachoma control activities is indicated in at least Buhiga, Nyabikere and Muyinga. Further work should be carried out to establish the likely backlog of unoperated trachomatous trichiasis. PMID- 21780873 TI - The epidemiology of trachoma in the five northern districts of Sierra Leone. AB - PURPOSE: In 2008, a trachoma prevalence survey was conducted in the five northern districts of Sierra Leone to determine if and where specific components of the SAFE strategy (Surgery, Antibiotics, Face washing, Environmental change) should be initiated. METHODS: A cross-sectional survey at district level was implemented using two-stage random cluster sampling: probability proportionate sampling was used to select villages in the first stage and compact segment sampling of households in the second stage. Both eyes of 16,780 individuals were examined using the World Health Organization simplified trachoma grading system. Data were also collected on village- and household-level behavior and environmental factors related to trachoma. RESULTS: Prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years was highest in Kambia at 3.52% (95% Confidence Interval (CI): 2.28-4.75%), while the prevalence of trachomatous trichiasis (TT) in persons over 15 years of age was highest in Port Loko at 0.27% (95% CI: 0.03 0.50%). Across all districts, the percentage of households reporting washing children's faces less than once per day was very low, while latrine coverage and accessible and safe water sources were not highly prevalent. CONCLUSIONS: In all districts but Koinadugu, TT prevalence was greater than the WHO elimination threshold, indicating the need for 1,016 TT surgeries to prevent blindness. District TF prevalence rates did not warrant mass antibiotic distribution. Although not required given the low prevalence of TF, we recommend the construction of 35,941 household latrines and provision of water sources within a 30-minute walk roundtrip for 17,551 households to bring Sierra Leone closer to reaching Millennium Development Goal 7. PMID- 21780874 TI - Microbial keratitis in East Africa: why are the outcomes so poor? AB - PURPOSE: Microbial keratitis (MK) is a major cause of blindness in Africa. This study reports the epidemiology, causative organism, management and outcome of MK in people admitted to a large referral hospital in Northern Tanzania, and explores why the outcomes are so poor for this condition. METHODS: A retrospective review of all admissions for MK during a 27-month period. Information was collected on: demographics, history, examination, microbiology, treatment and outcome. RESULTS: A total of 170 patients with MK were identified. Presentation was often delayed (median 14 days), and more delayed if another health facility was visited first (median 21 days). Appropriate intensive antibiotic treatment was prescribed in 19% before admission. Lesions were often severe (41% >5mm). Filamentary fungi were detected in 25% of all specimens (51% of specimens with a positive result). At discharge, 66% of affected eyes had a visual acuity of less than 6/60. Perforations developed in 30% and evisceration was necessary in 8%. Perforation was associated with large lesions and visiting another health facility. HIV infection was diagnosed in 16% of individuals tested, which is approximately twice the prevalence found in the wider population. CONCLUSIONS: Microbial keratitis is a significant clinical problem in this region, which generally has a very poor outcome. Delayed presentation is a critical issue. Fungal keratitis is a prominent cause and there is an indication that HIV may increase susceptibility. Prompt recognition and appropriate treatment in primary/secondary health facilities and rapid referral when needed may reduce the burden of blindness from this disease. PMID- 21780875 TI - Cataract prevalence varies substantially with assessment systems: comparison of clinical and photographic grading in a population-based study. AB - PURPOSE: Cataract is the major cause of blindness worldwide yet there is no consensus on its assessment and definition. This study compares age-related cataract prevalence derived from two commonly used methods: clinical assessment using the Lens Opacity Classification System (LOCS III) and photographic grading using the Wisconsin Cataract Grading System (Wisconsin System). METHODS: The Singapore Malay Eye Study is a population-based study of 3,280 Singapore Malays aged 40-80 years. Presence of nuclear, cortical and posterior sub-capsular cataract was assessed clinically during slit-lamp examination using LOCS III, and via slit-lamp and retro-illumination photographic grading using the Wisconsin System. Analyses were conducted to determine agreement in cataract prevalence estimates between the two grading Systems and approaches. RESULTS: Poor agreement was found between severity levels of the two grading scales for all three cataract types. Using currently accepted cut-offs to define nuclear (>= 4 on both LOCS III and Wisconsin System), cortical (>= 2 in LOCS III, >= 25% in Wisconsin) and PSC (>= 2 in LOCS III, >= 5 % in Wisconsin) cataract, the LOCS III overestimated the prevalence of significant cataract as compared to the Wisconsin System, with nuclear cataract prevalence, 27.5% (LOCS III) versus 17.0% (Wisconsin System), cortical cataract prevalence, 27.9% versus 7.0% and posterior sub-capsular cataract prevalence, 7.8% versus 5.1%. CONCLUSION: The prevalence of cataract in a population varies substantially by measurement methods, with systematically different estimates found using the two most frequent cataract grading systems. This study re-emphasizes the need for global standards to assess and define cataract for epidemiologic and clinical studies. PMID- 21780876 TI - Follow-up survey of cataract surgical coverage and barriers to cataract surgery at Nkhoma, Malawi. AB - PURPOSE: Nkhoma Eye Hospital, Malawi provides high volume, high quality free cataract surgery to people in its catchment region of Central-Malawi. However, a previous survey in 2000 indicated that only 1 in 7 people with bilateral blindness from cataract had received surgery in a 10-mile radius of Nkhoma. METHODS: We conducted a population-based survey in 2006 in the 32 villages within a 10-mile radius of Nkhoma Hospital in people aged >= 40 years in order to investigate the cataract surgical coverage (CSC) and barriers to cataract surgery. RESULTS: The prevalence of blindness (visual acuity [VA] <3/60 in better eye) in 835 people aged >= 40 was 1.3% (95% CI 0.5-2.1), of which 36.4% was due to cataract. Overall, the CSC was 83.3%, and for eyes (VA<3/60) was 66.0%. The CSC was lower in females compared to males (73.3% vs. 100.0%. P < 0.001). The most common barrier to surgery was cost (58%). CONCLUSION: Our results demonstrate a 5-fold increase in coverage in the 6 years, primarily by increasing efficiency of the service provider and providing a community screening and referral service. Supporting the ophthalmic personnel with appropriate infrastructure and management has been central to this shift. Implementing an active case finding and referral mechanism has enabled this unit to provide regular high volume cataract surgery. There is a need to understand the factors influencing perceptions about cost as a barrier in this community and the disparity between need and access to services for women. PMID- 21780877 TI - Understanding barriers to cataract surgery among older persons in rural China through focus groups. AB - PURPOSE: To utilize focus groups (FGs) to identify barriers to cataract surgery specific to older persons in rural Guangdong, China. METHODS: Three focus groups in separate locations were carried out for persons aged 60 years and above with best-corrected vision <= 6/18 due to cataract, either accepting or refusing surgery. Participants also ranked responses to questions about acceptance of surgery among the elderly. FG transcripts were coded independently by two investigators using qualitative data management software. RESULTS: Twenty participants had a mean age of 72.7 +/- 6.1 years, 14 (70.0%) were women and 17 (85.0%) were blind (best-corrected vision <= 6/60) in at least one eye. Cost was ranked by two of three groups as the main barrier to surgery, and all groups listed reducing cost as the best strategy to increase surgical uptake. Many respondents planned to use China's New Cooperative Medical Scheme (NCMS) health insurance to pay for surgery. Participants showed poor understanding of cataract, but ranked educational interventions low as methods of increasing uptake. Though opinions of local service quality were poor, respondents did not see quality as an important barrier to accepting service. Participants frequently depended on family members to pay for surgery. CONCLUSIONS: Contrary to some previous reports, cost may be an important barrier to cataract surgery in rural China, which NCMS may help to alleviate. Educational interventions to increase knowledge about cataract are needed, but may face skepticism among patients. Strategies to promote cataract surgery should target the entire family. PMID- 21780878 TI - Dose-response effect of black maca (Lepidium meyenii) in mice with memory impairment induced by ethanol. AB - Previous studies have shown that black variety of maca has beneficial effects on learning and memory in experimental animal models. The present study aimed to determine whether the hydroalcoholic extract of black maca (BM) showed a dose response effect in mice treated with ethanol 20% (EtOH) as a model of memory impairment. Mice were divided in the following groups: control, EtOH, ascorbic acid (AA) and 0.125, 0.25, 0.50 and 1.00 g/kg of BM plus EtOH. All treatments were orally administered for 28 days. Open field test was performed to determine locomotor activity and water Morris maze was done to determine spatial memory. Also, total polyphenol content in the hydroalcoholic extract of BM was determined (0.65 g pyrogallol/100 g). Mice treated with EtOH took more time to find the hidden platform than control during escape acquisition trials; meanwhile, AA and BM reversed the effect of EtOH. In addition, AA and BM ameliorated the deleterious effect of EtOH during the probe trial. Correlation analyses showed that the effect of BM a dose-dependent behavior. Finally, BM improved experimental memory impairment induced by ethanol in a dose-response manner due, in part, to its content of polyphenolic compounds. PMID- 21780879 TI - The effect of intrapartum clindamycin on vaginal group B streptococcus colony counts. AB - OBJECTIVE: To determine the temporal relationship between intrapartum clindamycin and vaginal Group B Streptococcus (GBS) colony counts. METHODS: In this prospective observational study, women with GBS-positive, clindamycin-sensitive, antenatal rectovaginal cultures, intrapartum vaginal cultures were collected just before the first clindamycin dose (T(0)) and then every 2 h for 8 h or until delivery. Colony counts were quantified using serial dilution. Results were standardized as percent of initial colony count and analyzed using sequential Friedman tests. RESULTS: Twenty-one women had positive intrapartum vaginal GBS cultures at T(0). With T(0) colony counts standardized to 100%, subsequent percents-of-baseline fell rapidly and significantly by T(2) and fell further at each subsequent point, reaching 0% by T(6). For 12 women cultured for the full 8 hours, the decline in GBS was significant at p < 0.001. CONCLUSIONS: Vaginal GBS colony counts fall rapidly after intrapartum clindamycin administration, similar to declines after penicillin. This represents a possible mechanism for efficacy of chemoprophylaxis. PMID- 21780881 TI - Can cultural values help explain the positive aspects of caregiving among Chinese American caregivers? AB - This study used an adaptation of the caregivers' stress model to examine the positive aspects of caregiving with 113 Chinese American family caregivers who provided care to their elderly relatives. The hierarchical multiple regression analysis indicated that combination of caregiver background characteristics, stressors, and cultural values had direct effects on positive aspects of caregiving. Unlike previous studies in which cultural values were not measured, this study found that cultural values helped explain positive aspects of caregiving. Specifically, cultural values, caregiver's health, and caregiver's age predicted positive aspects of caregiving. Service implications are discussed based upon the findings. PMID- 21780882 TI - Quality of relationships between care recipients and their primary caregivers and its effect on caregivers' burden and satisfaction in Israel. AB - Research on the impact of quality of relationships between primary caregivers and their care recipients on burden and satisfaction with caregiving is still rare. The sample included 335 dyads of primary caregivers and care recipients who were cognitively intact. Face-to-face interviews were conducted at the respondents' homes using structured questionnaires. No significant correlation between caregiving burden and caregiving satisfaction was found. Quality of relationship was the most significant variable in explaining both caregiving burden and caregiving satisfaction, yet different sets of additional variables were found to explain each of the outcomes. Interventions should address quality of relationships in order to reduce burden and increase caregiving satisfaction. PMID- 21780883 TI - Wisdom from life's challenges: qualitative interviews with low- and moderate income older adults who were nominated as being wise. AB - Previous wisdom research tended to focus on cognitive and intellectual aspects, highly educated professionals and/or prominent subjects, and wisdom as the outcome not process. In this study, based on in-depth interviews of 18 low- and moderate income older adults who were nominated as being wise by their aging service providers, we explored the ways challenging life experiences and coping may have contributed to the development of their wisdom, their ideas/beliefs about the qualities of wisdom, and the ways they may be practicing wisdom in daily life. Their emphasis on interconnectedness and interdependence, forgiveness and patience, and gratitude appears to represent self-transcendental qualities of wisdom. Social work practice and research implications are discussed. PMID- 21780884 TI - Social work and transitions of care: observations from an intervention for older adults. AB - Making the transition from hospital to home can be challenging for many older adults. This article presents practice perspectives on these transitions, based on a social work intervention for older adults discharged from an acute care setting to home. An analysis of interviews with clinical social workers who managed 356 cases (n = 3) and a review of their clinical notes (n = 581) were used to identify salient themes relevant to care transitions. Concepts developed and discussed identify the role of surprises after discharge, an expanded view of the client system, and relationship building as instrumental in carrying out effective care transitions. PMID- 21780885 TI - Integration of supportive psychotherapy with case management for older adults with borderline personality disorder. AB - This article attempts to demonstrate how supportive psychotherapy may serve as a companion therapeutic modality for case management activities with older adult clients suffering with borderline personality disorder (BPD). Justification for this approach is provided and techniques and interventions are identified. Three case examples demonstrating the modalities integration are provided. PMID- 21780887 TI - Impact of IL-28B polymorphism on outcome in patients with hepatitis C after liver transplantation. PMID- 21780889 TI - Rectification of miscalculation of adalimumab costs. PMID- 21780890 TI - Dexlansoprazole MR for the management of gastroesophageal reflux disease. AB - Dexlansoprazole modified release (MR; DexilantTM), the R-enantiomer of lansoprazole, was approved in the USA in 2009 for the management of erosive esophagitis and nonerosive reflux disease. Dexlansoprazole MR has a unique dual delayed-release delivery system that was designed to address unmet needs that may accompany the use of single-release proton pump inhibitors (PPIs), specifically, their short plasma half-life and requirement for meal-associated dosing. The delivery technology of dexlansoprazole MR is designed to release the drug in two separate pH-dependent phases, the first in the proximal duodenum and the second in the more distal small intestine. This extends plasma concentration and pharmacodynamic effects of dexlansoprazole MR beyond those of single-release PPIs and allows for dosing at any time of the day without regard to meals. This added convenience, along with excellent healing of esophagitis and symptom relief, substantiate its use in patients with gastroesophageal reflux disease requiring PPI treatment. PMID- 21780891 TI - Reducing the risk of gastroduodenal ulcers with a fixed combination of esomeprazole and low-dose acetyl salicylic acid. AB - Low-dose acetyl salicylic acid (ASA) for preventing cardiovascular and cerebrovascular events is now one of the most frequently prescribed medications in some Western countries. However, it is associated with significant morbidity and mortality as a consequence of the development of gastric and duodenal ulcers and their complications. Recent randomized controlled trials in patients who are at moderately increased risk of ulcers have shown that the proton pump inhibitor esomeprazole (the S-isomer of racemic omeprazole) reduces the gastroduodenal ulcer incidence by approximately 70-85% and the gastrointestinal bleeding risk by as much as 90%. Case-control studies also indicate that the risk of ulcer bleeding is less in low-dose ASA users who concomitantly take a proton pump inhibitor. This article reviews the pharmacology of the component agents and the evidence for efficacy of the combination of esomeprazole and low-dose ASA. PMID- 21780892 TI - Advances in hepato-pancreato biliary surgery. AB - The Americas Hepato-Pancreato Biliary Association (AHPBA) Annual 2011 Meeting provided a forum for discussion of multidisciplinary advances surrounding six tracks including the liver, biliary system, liver transplantation, pancreas, imaging and biomedical engineering and general hepato-pancreato biliary (HPB) surgical disease. The meeting and postgraduate courses attracted the largest ever attendance and participation in the AHPBA annual meeting, including field leaders and participants from across North, Central and South America who interchanged clinical and scientific knowledge, and discussed advances in technology, care and outcomes for treatment of HPB diseases. The AHPBA Foundation, established in 2010, announced progress toward support of meritorious research in HPB disease and enrichment of educational programs. HPB fellowship graduates were recognized, marking successful establishment of the AHPBA as an important body guiding HPB education and training in the USA and the Americas. PMID- 21780893 TI - The role of rifaximin therapy in patients with irritable bowel syndrome without constipation. AB - Alterations in gut flora may play an important role in the pathophysiology of bowel symptoms, especially in patients with irritable bowel syndrome (IBS). If so, antibiotics that affect gut flora may offer a novel approach for the management of patients with IBS. Here, we discuss the results of two identically designed, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) of a poorly absorbed antibiotic, rifaximin, in patients with IBS. In these studies, 1260 patients (females 76.1 and 72.1%, respectively) who had IBS without constipation were randomized to receive either rifaximin 550 mg or placebo, three times daily for 2 weeks. Subsequently, daily symptoms were assessed and patients were followed up for 10 weeks. The primary outcome measure - adequate relief of global IBS symptoms during the first 4 weeks after treatment - was met in significantly more patients who received rifaximin than placebo (p < 0.001). In addition, more patients in the rifaximin group than in the placebo group (p < 0.001) reported an adequate relief of bloating, and an improvement in abdominal pain and stool consistency - secondary outcome measures. The incidence of adverse events with rifaximin was similar to placebo, and the drug was well tolerated. In summary, a 2-week course of rifaximin provided significant relief of IBS symptoms, as well as bloating and abdominal pain. PMID- 21780894 TI - Autoimmune and gastrointestinal dysfunctions: does a subset of children with autism reveal a broader connection? AB - A large number of autoimmune disorders have a gastrointestinal (GI) dysfunction component that may interplay with genetic, hormonal, environmental and/or stress factors. This narrarive review investigates possible links between autism, immune system abnormalities and GI symptoms in a subgroup of children with autism. A literature search on Medline (1950 to September 2010) was conducted to identify relevant articles by using the keywords 'autism and gastrointestinal' (71 publications) and 'autism and immune' (237 publications), cross-referencing and general searching to evaluate the available literature on the immunological and GI aspects of autism. Sufficient evidence exists to support that a subgroup of children with autism may suffer from concomitant immune-related GI symptoms. PMID- 21780895 TI - Clinical and immunological features of celiac disease in patients with Type 1 diabetes mellitus. AB - Celiac disease (CD) is one of the most frequent autoimmune disorders occurring in Type 1 diabetes mellitus (T1DM). The prevalence of CD in T1DM varies from 3 to 16%, with a mean prevalence of 8%. The clinical presentation of CD in T1DM is classified as symptomless in approximately half of cases, but a more accurate analysis often discloses a wide array of symptoms suggestive of CD. Both T1DM and CD show the same genetic background and an abnormal small intestinal immune response with inflammation and a variable grade of enteropathy. Serological screening for CD should be performed in all T1DM patients by means of antibodies to tissue transglutaminase at T1DM onset. T1DM patients found to be celiacs must be treated by a gluten-free diet. Potential CD cases (especially when asymptomatic) should be kept on a gluten-containing diet with a careful clinical and antibody follow-up, since many of them will not develop villous atrophy. PMID- 21780896 TI - Regulatory T cells in gastrointestinal tumors. AB - Regulatory T cells (Tregs) have the ability to suppress the activity of most other lymphoid cells, as well as dendritic cells through cell-cell contact dependent mechanisms, which have not yet been fully defined. Tregs are a key component of a functional immune system and Treg deficiency is associated with severe autoimmunity and allergies. However, Tregs specific for tumor-associated antigens are present in cancer patients and Tregs accumulate in many types of solid tumors, where they probably act to promote tumor escape from cytotoxic immune responses. Indeed, some studies even show a negative correlation between Treg infiltration and survival of the patient. Several studies indicate an active recruitment of Tregs to the tumor site and the mechanisms of Treg accumulation are starting to be better understood as a result of more detailed analysis of their adhesion molecule and chemokine receptor expression. In addition, in gastrointestinal tumors there is an increase in tumor-associated Tregs, but intriguingly, Treg infiltration into colorectal adenocarcinomas is associated with improved prognosis. In this article, we will review the proposed mechanisms of immune suppression by tumor-associated Tregs, how the tumor microenvironment favors immune evasion and Treg induction, the tumor-homing mechanisms of Tregs and how Tregs affect progression of gastric and colorectal tumors. PMID- 21780897 TI - Current understanding of insulin resistance in hepatitis C. AB - Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-alpha-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field. PMID- 21780898 TI - Mycophenolate mofetil as a rescue therapy for autoimmune hepatitis patients who are not responsive to standard therapy. AB - Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology that is responsive to steroid and azathioprine treatment in more than 80% of patients after 3 years of treatment. There are few alternative treatment options for individuals with AIH who are unresponsive to steroids and azathioprine, and research on this is limited to open-label studies of a variety of immunosuppressive agents that involve only small numbers of patients. Mycophenolate mofetil is one of the most frequently used alternative agents for the treatment of AIH patients not responsive to standard therapy. In this article, we review and summarize currently available data regarding the use of mycophenolate mofetil as an alternative treatment option for patients with AIH. PMID- 21780899 TI - Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions. AB - In recent years, acute-on-chronic liver failure has been recognized as a specific clinical form of liver failure associated with cirrhosis. The syndrome refers to an acute deterioration of liver function and subsequently of other end organs over a period of weeks following a precipitating event in a patient with previously well- or reasonably well-compensated cirrhosis. These precipitating events include either an indirect (e.g., variceal hemorrhage, sepsis) or a direct (e.g., drug-induced) hepatotoxic factor. The short-term mortality for this condition is more than 50%. At present, considerable efforts are ongoing to better characterize the syndrome, to gain further insight into its pathophysiology and to optimize therapy. This article aims to highlight the current concepts of these various aspects. PMID- 21780900 TI - Molecular classification and clonal differentiation of hepatocellular carcinoma: the step forward for patient selection for liver transplantation. AB - Liver transplantation is a successful treatment for hepatocellular carcinoma (HCC). However, advanced stages are not selected for transplant, based on the United Network for Organ Sharing selection criteria's. Nowadays, molecular biology-based techniques constitute an excellent option to better understand HCC origin differentiation and biological behavior. Moreover, microarray technology is a powerful tool to address a variety of tumor tissues at molecular level and is actively used for the discovery of biomarkers in cancer research. This article will discuss published data in the field of HCC origin differentiation and its potential impact on outcomes following liver transplantation. Although preliminary results are presented, these findings encourage the use of gene expression profiling microarrays for studying HCC biology and behavior and ultimately optimizing treatment success. PMID- 21780902 TI - Surgical crown lengthening in a population with human immunodeficiency virus: a retrospective analysis). AB - BACKGROUND: Individuals with human immunodeficiency virus (HIV) have an increased risk of developing health problems, including some that are life threatening. Today, dental treatment for the population with a positive HIV diagnosis (HIV+) is comprehensive. There are limited reports on the outcomes of intraoral surgical therapy in patients with HIV, such as crown lengthening surgery (CLS) with osseous recontouring. This report investigates the outcome of CLS procedures performed at an urban dental school in a population of individuals with HIV. Specifically, this retrospective clinical analysis evaluates the healing response after CLS. METHODS: Paper and electronic records were examined from the year 2000 to the present. Twenty-one individuals with HIV and immunosuppression, ranging from insignificant to severe, underwent CLS. Pertinent details, including laboratory values, medications, smoking history/status, and postoperative outcomes, were recorded. One such surgery is described in detail with radiographs, photographs, and a videoclip. RESULTS: Of the 21 patients with HIV examined after CLS, none had postoperative complications, such as delayed healing, infection, or prolonged bleeding. Variations in viral load (<48 to 40,000 copies/mL), CD4 cell count (126 to 1,260 cells/mm(3)), smoking (6 of 21 patients), platelets (130,000 to 369,000 cells/mm(3)), and neutrophils (1.1 to 4.5 * 103 /mm(3)) did not impact surgical healing. In addition, variations in medication regimens (highly active anti-retroviral therapy [18]; on protease inhibitors [1]; no medications [2]) did not have an impact. CONCLUSIONS: The results of this retrospective analysis show the absence of postoperative complications after CLS in this population with HIV. Additional investigation into this area will help health care practitioners increase the range of surgical services provided to this group of patients. PMID- 21780903 TI - Prospective study in periodontal maintenance therapy: comparative analysis between academic and private practices. AB - BACKGROUND: This prospective study aims to evaluate and compare the periodontal status, periodontitis progression, tooth loss, and influence of predictable risk variables of two periodontal maintenance therapy programs over a 12-month period. METHODS: A total of 288 individuals diagnosed with chronic moderate-to-advanced periodontitis, who had finished active periodontal treatment, were evaluated in a public academic environment (AG) (n = 138), as well as in a private clinic (PG) (n = 150). A full-mouth periodontal examination was performed at baseline and at quadrimestral recalls, evaluating plaque index, probing depth, clinical attachment level, furcation involvement, bleeding on probing (BOP), and suppuration. Individuals' social, demographic, and biologic data, as well as compliance with recalls, were recorded. The effect of variables of interest and confounders were tested by univariate and multivariate analysis. RESULTS: The PG demonstrated lower rates of periodontitis progression and tooth loss than did the AG. After adjusting for confounders, the risk variables of BOP (P = 0.047), smoking (P = 0.003), and diabetes (P = 0.028) for the PG and smoking (P = 0.047) for the AG showed a negative influence on periodontal status. CONCLUSIONS: In both groups, the periodontal maintenance therapy minimized the negative effect of the risk variables. However, PG showed significantly less progression of periodontitis and tooth loss compared to AG. PMID- 21780904 TI - Bacterial leakage in implants with different implant-abutment connections: an in vitro study. AB - BACKGROUND: Two-piece implants present gaps and cavities between the implant and the abutment, and these hollow spaces can act as a trap for bacteria. The aim of the present in vitro study was to evaluate the migration of two different microbial species from the inside to the outside of the implant-abutment assembly in three different connection types. METHODS: A total of 30 implants (10 implants per group) were used. The implants presented a screwed trilobed connection (group 1), a cemented connection (group 2), and an internal conical connection (group 3). The inner parts of five implants, per group, were inoculated with Pseudomonas aeruginosa suspension and the remaining five implants, per group, with Aggregatibacter actinomycetemcomitans. The penetration of bacteria into the surrounding solution was determined by the observation of turbidity of the broth. RESULTS: In group 1, bacterial contamination was found in six of 10 implants. In group 2, no contaminated samples were found. In group 3, bacterial contamination was found in one implant of 10. Statistically significant differences were detected between group 1 versus group 3 (P <0.05) and between group 1 versus group 2 (P <0.01), whereas no significant differences were found when comparing group 2 versus group 3 (P >0.05). CONCLUSION: The present study confirms previous results about the hermeticity of the cement-retained implant-abutment assembly, the very low permeability to bacteria of the conical implant-abutment connection, and the high prevalence of bacterial penetration of screw-retained implant abutment assemblies. PMID- 21780905 TI - Cellular response to efficient dUTPase RNAi silencing in stable HeLa cell lines perturbs expression levels of genes involved in thymidylate metabolism. AB - dUTPase is involved in preserving DNA integrity in cells. We report an efficient dUTPase silencing by RNAi-based system in stable human cell line. Repression of dUTPase induced specific expression level increments for thymidylate kinase and thymidine kinase, and also an increased sensitization to 5-fluoro-2'-deoxyuridine and 5-fluoro-uracil. The catalytic mechanism of dUTPase was investigated for 5 fluoro-dUTP. The 5F-substitution on the uracil ring of the substrate did not change the kinetic mechanism of dUTP hydrolysis by dUTPase. Results indicate that RNAi silencing of dUTPase induces a complex cellular response wherein sensitivity towards fluoropyrimidines and gene expression levels of related enzymes are both modulated. PMID- 21780906 TI - Synthesis of cyclobutane nucleosides. AB - 2-(6-Chloropurinyl)-3-benzoyloxymethylcyclobutanone can be prepared by reaction of 6-chloropurine with 3-benzoyloxymethyl-2-bromocyclobutanone. The N-alkylation gave both N-9 and N-7 regioisomers. Both regioisomers upon hydride reduction followed by aminolysis gave the corresponding adenine nucleoside analogues. However, the N-7 series led to the hypoxanthine analogues as byproducts. PMID- 21780907 TI - Binding studies of a novel antitumor palladium(II) complex to calf thymus DNA. AB - The interaction of new 1, 10-phenanthrolineoctyldithiocarbamatopalladium (II) nitrate with DNA from calf thymus was investigated at 300 and 310 K in a Tris-HCl buffer of pH 7.0 medium containing 20 mM sodium chloride. This water soluble, square planar Pd(II) complex has been synthesized and spectroscopic (electronic, infrared, and nuclear magnetic resonance) and elemental analysis of the complex are discussed. This complex shows greater growth inhibitory activity against human tumor cell line K562 than cisplatin. Results of UV-visible studies show that the complex exhibits cooperative binding with DNA and denatures the DNA at an extremely low concentration (~11.98 MUM). Fluorescence studies reveal that the mode of binding of this complex with DNA seems to be intercalation. The results of sephadex G-25 column show that the binding of metal complex with DNA is so strong that it does not readily break. Several binding and thermodynamic parameters are also described. They may shed light on the mechanisms of interaction of this agent with DNA, which should be quite different from that of cisplatin. PMID- 21780908 TI - Design and synthesis of novel carbocyclic versions of 2'-spirocyclopropyl ribonucleosides as potent anti-HCV agents. AB - The discovery of 2'-spirocyclopropyl-ribocytidine as a potent inhibitor of RNA synthesis by NS5B (IC(50) = 7.3 MUM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of carbocyclic versions of 2'-spiropropyl-nucleosides from cyclopentenol 6. Spirocyclopropylation of enone 7 was completed by using (2-chloroethyl) dimethylsulfonium iodide and potassium t-butoxide to form the desired intermediate 9a. The synthesized nucleoside analogues, 18, 19, 26, and 27, were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. The synthesized cytosine nucleoside 19 showed moderate anti-HCV activity (IC(50) = 14.4 MUM). PMID- 21780909 TI - Novel mutations in the human HPRT gene. AB - Inherited mutation of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT), gives rise to Lesch-Nyhan Syndrome (LNS) or HPRT-related gout. Here, we report five novel independent mutations in the coding region of the HPRT gene from five unrelated male patients manifesting different clinical phenotypes associated with LNS: exon 2: c.133A > G, p.45R > G; c.35A > C, p.12D > A; c.88delG; exon 7: c.530A > T, p.177D > V; and c.318 + 1G > C: IVS3 + 1G > C splice site mutation. PMID- 21780910 TI - Trimethylsilyl trifluoromethanesulfonate-promoted reductive 2'-O-arylmethylation of ribonucleoside derivatives. AB - Arylmethyl groups such as benzyl, p-methoxybenzyl, and 1-pyrenylmethyl groups were introduced to the 2'-O-position of nucleosides by reductive etherification. Combining corresponding aromatic aldehydes with 2'-O-trimethylsilylnucleoside derivatives in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) resulted in moderate to good yields of the 2'-O-arylmethyluridine derivatives, whereas the corresponding cytidine and adenosine derivatives were obtained in low yields. The reaction of ribonucleosides with aliphatic aldehydes did not proceed smoothly. Anomerization of the uridine derivatives by TMSOTf was observed in CH(2)Cl(2), toluene, and CH(3)CN, but was completely suppressed when the reactions were conducted in 1,4-dioxane. PMID- 21780911 TI - Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy. AB - Very small embryonic-like stem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing for autologus stem cell therapy mainly because of their small size. The present study was conducted on human umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained after separation of mononuclear cells from human BM (n=6), to test this hypothesis. The results show that VSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCs during Ficoll-Hypaque density separation. These cells are very small in size (3-5 MUm), have high nucleo cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotent markers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitative polymerase chain reaction (Q-PCR) studies. Interestingly, a distinct population of slightly larger, round hematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the "buffy" coat, which usually gets banked or used during autologus stem cell therapy. Immunohistochemical studies on the umbilical cord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and many fibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4. These VSELs with nuclear Oct-4, detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughout life, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as produce larger progenitor stem cells, viz. HSCs or MSCs, which follow differentiation trajectories depending on the somatic niche. Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs, whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division of VSELs. The results of the present study may help explain low efficacy reported during adult autologous stem cell trials, wherein unknowingly progenitor stem cells are injected rather than the pluripotent stem cells with maximum regenerative potential. PMID- 21780912 TI - World report on disability. PMID- 21780913 TI - A novel liver retraction technique for lateral lobe of the liver during laparoscopic surgery using silicone disk. AB - For safe and effective laparoscopic surgery it is important to maintain a favorable view of the operative field. However, the use of a conventional liver retractor needs an additional wound and carries a risk for liver injury during surgery. We developed a novel retraction technique for the lateral lobe of the liver using a silicone disk (Hakko Co. Ltd.) during laparoscopic surgery. We used a silicone disk that consists of a silicone rubber membrane inside a flexible ring and four monofilament threads. The disk can be inserted into the abdomen under the pneumoperitoneum through a 12-mm port and is located at the dorsal side of the lateral lobe of the liver. The threads are withdrawn through the abdominal wall, two threads close to the infraxiphoid space and the other two threads bilaterally below the costal arch. Thus, the lateral lobe of the liver is safely raised to the ventral side and covered with a silicone membrane. We introduced this technique for various laparoscopic operations, such as gastrectomy, gastroplasty, and fundoplication. There were no complications related to the procedure. This retraction technique is easy, results in less liver damage, and provides an excellent operative view around the esophageal hiatus. The silicone membrane covering the lateral lobe reduces the risk of liver injury during surgery using laparoscopic forceps to a low level. PMID- 21780914 TI - Utilization of screening mammography among middle-aged and older women. AB - AIMS: This study examines patterns of screening mammogram use, investigating the relationship of screening with demographic, health status, and healthcare factors. METHODS: Data from 1242 women aged ?41 were obtained from a random sample of mailed surveys to community households in an eight-county region in Central Texas in 2010. The dependent variable was the timing of the participants' most recent screening mammography (in the past 12 months, between 1 and 2 years, or >2 years). Predictor variables included demographic, health status, and healthcare access factors. Multinomial logistic regression identified variables associated with screening mammography practices. RESULTS: The majority of women reported having at least one mammogram during their lifetime (93.0%) and having a mammography within the past 2 years (76.2%). Participants who reported not having a routine checkup in the past 12 months (odds ratio [OR] 0.12, p<0.001), having a lapse of insurance in the past 3 years (OR 2.95, p<0.05), and living in a health provider shortage area (OR 1.42, p<0.05) were less likely to be screened within the past 2 years. CONCLUSIONS: Routine healthcare plays a major role in preventive screening, which indicates screening mammography practices can be enhanced by improving participation in routine checkups with medical providers, continuity of insurance coverage, and women's access to healthcare. Interventions to encourage screening mammography may be particularly needed for women who have experienced a lapse in insurance or have not had a checkup in the past year. PMID- 21780915 TI - Three genetic polymorphisms of homocysteine-metabolizing enzymes and risk of coronary heart disease: a meta-analysis based on 23 case-control studies. AB - Many epidemiological studies have explored the relationships between three genetic polymorphisms of genes encoding homocysteine-metabolizing enzymes (methionine synthase [MTR] A2756G, methionine synthase reductase [MTRR] A66G, and N(5),N(10)-methylenetetrahydrofolate reductase [MTHFR] A1298C) and risk of coronary heart disease (CHD), but no conclusive results were obtained. Therefore, we performed a meta-analysis of 23 case-control studies. Odds ratio (OR) and 95% confidence interval (95% CI) were used to examine the strength of the associations. Among those primary studies, 22 studies were for Europeans, and one study focused on the MTR A2756G polymorphism in Asians. The results of combined analyses of the MTR A2756G polymorphism suggested that the G allele was associated with increased risk of CHD and myocardial infarction (MI) especially for Europeans (GG vs. AA for CHD: OR [95% CI]=1.63 [1.18-2.25], p(z)( test)=0.001, p(heterogeneity)=0.274; GG+AG vs. AA for MI: OR [95% CI]=1.44 [1.08 1.93], p(z)(-test)=0.014, p(heterogeneity)=0.611). In addition, the G allele was also associated with higher risk CHD based on population-based case-control studies (PCC) (GG vs. AA: OR [95% CI]=1.75 [1.24-2.49], p(z)(-test)=0.002, p(heterogeneity)=0.316). The results suggested that the MTRR A66G polymorphism was not associated with risk of CHD for Europeans (AA vs. GG: OR [95% CI]=1.07 [0.59-1.94], p(z)(-test)=0.831, p(heterogeneity)<0.01). The results suggested that the C allele of the MTHFR A1298C polymorphism might be associated with the increased risk of MI for Europeans (CC vs. CA+AA: OR [95% CI]=1.37 [1.03-1.84], p(z)(-test)=0.033, p(heterogeneity)=0.668). However, when subgroup analyses for sources of controls were performed, conflicting results were obtained. The results suggested that the C allele was associated with decreased risk of CHD based on hospital-based case-control studies, but associated with increased risk of CHD based on PCC. This meta-analysis suggests that MTR A2756G polymorphism, but not MTRR A66G and MTHFR A1298C, is associated with risk of CHD for Europeans. Because of limitations and potential bias, more well-designed studies with larger sample size, especially focused on Asians and Africans, should be performed in the future. PMID- 21780916 TI - Analyzing multicomponent receptive fields from neural responses to natural stimuli. AB - The challenge of building increasingly better models of neural responses to natural stimuli is to accurately estimate the multiple stimulus features that may jointly affect the neural spike probability. The selectivity for combinations of features is thought to be crucial for achieving classical properties of neural responses such as contrast invariance. The joint search for these multiple stimulus features is difficult because estimating spike probability as a multidimensional function of stimulus projections onto candidate relevant dimensions is subject to the curse of dimensionality. An attractive alternative is to search for relevant dimensions sequentially, as in projection pursuit regression. Here we demonstrate using analytic arguments and simulations of model cells that different types of sequential search strategies exhibit systematic biases when used with natural stimuli. Simulations show that joint optimization is feasible for up to three dimensions with current algorithms. When applied to the responses of V1 neurons to natural scenes, models based on three jointly optimized dimensions had better predictive power in a majority of cases compared to dimensions optimized sequentially, with different sequential methods yielding comparable results. Thus, although the curse of dimensionality remains, at least several relevant dimensions can be estimated by joint information maximization. PMID- 21780917 TI - Tear osmolarity measurements in dry eye related to primary Sjogren's syndrome. AB - BACKGROUND: To evaluate the tear osmolarity in patients with dry eye syndrome related to primary Sjogren's Syndrome (SS). MATERIALS AND METHODS: Twenty eyes of 10 patients with dry eye and primary SS (Group 1) and 20 eyes of 20 subjects who do not have dry eye syndrome (Group 2) were included in this cross-sectional study. In all eyes, ophthalmic examination was performed in the same order: International Ocular Surface Disease Index survey, visual acuity assessment, conjunctival hyperemia scoring, tear osmolarity measurement with TearLab(TM) Osmolarity System, tear film break-up time assessment, corneal fluorescein staining scoring, ocular surface Lissamine Green staining scoring, anesthetized Schirmer test. Dry eye severity was graded according to Dry Eye Workshop (DEWS) classification system. RESULTS: Four eyes with grade 1, four eyes with grade 2, seven eyes with grade 3, and five eyes with grade 4 dryness, according to DEWS system, were included. The mean tear osmolarity value was 301.9 +/- 11.40 mOsm/L (range: 290-328) in Group 1, and 294.85 +/- 8.33 mOsm/L (range: 283-311) in Group 2 (p = 0.03). In Group 1, tear osmolarity values were positively correlated with OSDI scores (r(18) = 0.55, r(2) = 0.31, p = 0.01), DEWS classification grades (r(18) = 0.73, r(2) = 0.54, p < 0.01), temporal and total corneal staining scores (r(18) = 0.67, r(2) = 0.44, p < 0.01, and r(18) = 0.51, r(2) = 0.26, p = 0.02, respectively), temporal conjunctival staining scores (r(18) = 58, r(2) = 0.34, p < 0.01); and negatively correlated with anesthetized Schirmer test results (r(18) = -0.62, r(2) = 0.38, p < 0.01) and TFBUT (r(18) = -0.50, r(2) = 0.25, p = 0.02). CONCLUSIONS: Tear osmolarity values were found to be greater in patients with dry eye syndrome related to primary SS compared to control subjects, and positively correlated with the severity of dry eye. PMID- 21780918 TI - Effect of sub-atmospheric oxygen on the culture of rabbit limbal epithelial cells. AB - PURPOSE: To investigate the effect of sub-atmospheric oxygen tensions on the maintenance and expansion of limbal epithelial cells in vitro. MATERIALS AND METHODS: Limbal epithelial cells were isolated from rabbit corneas and cultured in 21%, 14%, 8%, and 2% oxygen in a co-culture system with Mitomycin C growth arrested 3T3 fibroblasts. The colony forming efficiency, proliferative ability, and cell cycle distribution of cells cultured in these different oxygen tensions were determined, and semi-quantitative RT-PCR was used to detect expression of putative limbal epithelial stem cell markers, such as ABCG2 and p63alpha. RESULTS: Of the four different oxygen tensions studied, 14% and 2% supported the highest and lowest colony forming efficiency values, respectively. A greater proportion of cells were found in S and G2/M phases of the cell cycle in primary 14% and 8% oxygen cultures compared to atmospheric controls. Differentiation was promoted at oxygen tensions of 8% and below. Cells with a differentiated phenotype and limited proliferative capacity were observed in 2% oxygen. Semi quantitative RT-PCR analysis showed that the putative limbal epithelial stem cell markers ABCG2 and p63alpha were expressed in 21%, 14%, and 8% oxygen, with a trend of lower expression in 8% oxygen being observed. CONCLUSIONS: Limbal epithelial cells are sensitive to in vitro changes in oxygen tension. A sub atmospheric oxygen tension of 14% promoted the maintenance and expansion of cells with limbal epithelial stem cell characteristics in a feeder co-culture system and is, therefore, recommended for the culture of rabbit limbal epithelial cells. This may also have relevance for the culture of human limbal epithelial stem cells for therapeutic application. PMID- 21780919 TI - A reconstituted telomerase-immortalized human corneal epithelium in vivo: a pilot study. AB - PURPOSE: Telomerase-immortalized human corneal epithelial cells have been reported to stratify and differentiate in vitro similar to native tissue. The purpose of this study was to assess the ability of a telomerase-immortalized human corneal epithelial cell line to generate a full thickness epithelium in vivo in athymic mice. METHODS: Telomerized corneal epithelial cells were transduced with a retroviral vector encoding the herpes simplex thymidine kinase gene. Efficacy of the thymidine kinase suicide gene was confirmed using a live/dead assay. The epithelium was mechanically removed from athymic nude mice and remaining cells were treated with mitomycin C to prevent re epithelialization. Telomerized corneal epithelial cells were seeded onto the denuded cornea and allowed to adhere for 4 and 24 hours. Cellular attachment was assessed using a fluorescent cell tracker. Stratification and differentiation were assessed after 7 days using phalloidin and a mouse monoclonal antibody to K3. RESULTS: Telomerized corneal epithelial cells were visualized across the denuded stromal surface at 4 and 24 hours, with multi-layering evident at the latter time point. No epithelium was present in the non-treated eye. After 7 days post-transplantation cells stratified into a multilayered epithelium, with positive K3 expression in basal and suprabasal cells. Treatment with ganciclovir induced significant loss of viability in vitro. CONCLUSIONS: The findings in this pilot study demonstrate that telomerized corneal epithelial cells possess the capacity to reconstitute a stratified corneal epithelium in vivo. The introduction of thymidine kinase allowed for the successful induction of cell death in proliferating cells in vitro. Collectively, these data suggest that a telomerase-immortalized corneal epithelial cell line transduced with thymidine kinase represents a potential model for studying differentiation and epithelial niche interactions in vivo with potential applications in tissue engineering. PMID- 21780920 TI - Antioxidant status and oxidative stress in primary open angle glaucoma and pseudoexfoliative glaucoma. AB - PURPOSE: The aim of this study was to establish the antioxidant status and oxidative stress in patients with primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEG). METHODS: Serum levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) as indicators of antioxidant status; and total oxidant status (TOS), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) as indicators of oxidative stress were measured from the blood samples of patients with POAG (n = 23), PEG (n = 24) and healthy control subjects (n = 19) by spectrophotometry. RESULTS: Mean TAC level was 0.6 +/- 0.1 mmol/L in the POAG group; 0.5 +/- 0.1 mmol/L in the PEG group and 1.2 +/- 0.3 mmol/L in the control group (p = 0.001). Mean SOD level was 13 +/- 0.5 mg/L in the POAG group, 11.6 +/- 0.2 mg/L in the PEG group and 9.4 +/- 0.6 mg/L in the control group (p = 0.001). Mean TOS level was 19.6 +/- 2.6 MUmol/L in the POAG group, 21.2 +/- 4.2 MUmol/L in the PEG group and 15.1 +/- 7 MUmol/L in the control group (p = 0.001). Mean NO level was 74.3 +/- 14.4 umol/L in the POAG group, 66.1 +/- 8.1 umol/L in the PEG group and 62.3 +/- 13.5 umol/L in the control group (p = 0.005). Mean PC level was 641.5 +/- 102.5 nmol/mg in the POAG group, 988.3 +/- 214.7 nmol/mg in the PEG group and 654.4 +/- 150.7 nmol/mg in the control group (p = 0.001). Mean MDA level was 1.9 +/- 0.2 umol/L in the POAG group, 1.7 +/- 0.4 umol/L in the PEG group and 1.1 +/- 0.2 umol/L in the control group (p = 0.001). CONCLUSION: The findings of the present study are potentially of significance and add to the growing body of evidence for oxidative stress in POAG and PEG. Decreased antioxidant defense and increased oxidative stress system may play an important role in the pathogenesis of POAG and PEG. PMID- 21780921 TI - Ultra high-field magnetic resonance imaging of a glaucoma microstent. AB - PURPOSE: The aim of the present study was to use 7.1T magnetic resonance imaging (MRI) to determine the correct anatomical position of a non-metallic glaucoma microstent following implantation in rabbit eyes. MATERIALS AND METHODS: In an in vitro experiment three microstents (made from silicone, polyurethane, and nickel titanium) were embedded in a standard vial filled with agar. In a second series of experiments a prefabricated polyurethane microstent connecting the anterior chamber with the suprachoroidal space (SCS) was implanted in rabbit eyes (n = 12). High-resolution images were acquired ex vivo (n = 6) and in vivo (n = 6) on an ultra high-field MRI unit using a 2-channel coil with four coil elements and T2-weighted turbo spin-echo sequences. Finally, the eyes were dissected and processed for histology. RESULTS: Artifact-free MR imaging of silicone and polyurethane microstents was achieved in vitro, with slightly higher contrast for silicone stents. Image quality for the nickel titanium stent was greatly reduced due to artifacts. MRI examination of rabbit eyes ex vivo and in vivo following polyurethane microstent implantation presented no problems in terms of the size and placement of the coil. The sequences showed good image quality; the full length of the microstent was visualized in cross-section and longitudinal section, and correct anatomical placement was demonstrated from the anterior chamber into the SCS. These findings were verified by histology. CONCLUSIONS: The excellent image quality obtained with both of the non-metallic materials generates detailed information about microstent placement, including the surrounding tissues. High-resolution MRI can be used to monitor the anatomical position of a microstent after glaucoma surgery in animal experiments and is therefore a valuable tool for documenting experimental research findings ex vivo and in vivo. PMID- 21780922 TI - Ocular pulse amplitude in patients with asymmetric primary open-angle glaucoma. AB - AIM: To evaluate ocular pulse amplitude (OPA) using the dynamic contour tonometer (DCT) in patients with asymmetric primary open-angle glaucoma (POAG) and asymmetric intra-ocular pressure (IOP). METHODS: The participants consisted of 48 patients (96 eyes) with asymmetric POAG. Three measurements of IOP and OPA were taken using DCT. The diagnosis of asymmetry required a difference of glaucomatous visual field loss greater than 6 dB in the global index MD and a difference of 5 mmHg in IOP measured by Goldmann tonometry between the more affected and the contra-lateral eye. All participants underwent full ophthalmologic clinical assessment including ultrasonic pachymetry and biometric measurements. Exclusion criteria were corneal diseases or scars, topical or systemic glaucomatous medications, and previous ocular surgery. RESULTS: No difference (p = 0.142) was found between the axial length measurements of the better eyes group (22.95 +/- 0.91 mm) and worse eyes group (22.85 +/- 0.97 mm). There was a statistically significant difference (p = 0.011) between the central corneal thickness values of the better eyes group (537.08 +/- 29.54 MUm) and worse eyes group (534.40 +/- 29.87 MUm). The OPA values of the better eyes group (3.32 +/- 1.14 mmHg) were significantly lower (p = 0.001) than those obtained in the worse eyes group (3.83 +/- 1.27 mmHg). When correcting the OPA readings by the IOP there was no statistical difference between groups (p = 0.996). CONCLUSION: Higher OPA values were found in eyes with higher IOP levels and advanced glaucoma's lesions in asymmetric hypertensive POAG patients. However, after the OPA correction by the IOP levels there was no more statistical difference between eyes. PMID- 21780923 TI - Effects of single intravitreal rhEPO injection on light-induced retinal injury in rats. AB - PURPOSE: To observe the effects of a single intravitreal rhEPO injection on light induced retinal damage in rats and to explore the possible mechanisms. METHODS: Male Sprague-Dawley rats were randomly divided into a normal group, a control group (PBS intravitreal injection), and a number of treatment groups (intravitreal rhEPO injection at 0.625, 1.25, 2.5, 5, 10, or 20 U). After dark adaptation for 24 h, rats were exposed to white light (2800 lx) for 5 h. Based on the effects of rhEPO on the ERG-b wave, an optimal dose (5U) was chosen for further experiments that included histopathological examination and outer nuclear layer (ONL) counting at 5 and 10 days after light exposure. Cell apoptosis and proteins (caspase-3, bcl-xL) were also examined at 3 days. Some cell signaling related proteins (AKT, ERK1/2 and STAT5) were also analyzed. In another experiment, rats received intravitreal injection of rhEPO (5U) at 30 min after light exposure. ERG and morphological changes were examined at 3 days after light exposure. RESULTS: ERG-b wave amplitudes are well preserved in rats receiving 2.5, 5, or 10 U rhEPO, in comparison with the PBS control. The dose-effect relationship was bell-shaped, with the maximum effect at 5 U. Less apoptotic cells were in the ONL in the 5U group. The rats receiving 5 U rhEPO at 30 min after light exposure also had higher b-wave amplitude. Caspase-3 expression was down-regulated and Bcl-xL was up-regulated in the rhEPO group. Phosphorylated ERK(1,2) was reduced in the rhEPO group. CONCLUSION: A single intravitreal injection of rhEPO can postpone photoreceptor light damage in rats. The optimal dose was 5 U in this study. The effective time window was from 24 h prior to light exposure to 5 h after. RhEPO may be involved in the regulation of the expression of Caspase-3 and Bcl-xL. The possible cell signal transduction maybe through the ERK1/2 pathway. PMID- 21780924 TI - High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: implications for diabetic retinopathy. AB - PURPOSE: The following study was designed to investigate early biosynthetic and ultrastructural changes that alter functional properties of the basement membrane (BM) and affect vascular permeability in diabetic retinopathy. MATERIALS AND METHODS: To determine whether altered matrix synthesis affects cell monolayer permeability, rat retinal endothelial cells (RRECs) were grown for 4 days to confluency in normal (N, 5 mM) or high glucose (HG, 30 mM) medium on transwell inserts and subjected to an in vitro cell monolayer permeability assay. Inserts were cut out and viewed under a transmission electron microscope to assess extracellular matrix (ECM) accumulation and cell morphology. In parallel cell cultures, fibronectin and collagen IV protein expression were determined using Western Blot analysis. RESULTS: Electron microscopic analysis of cells exposed to short-term HG showed no difference in inter-endothelial cell tight junctions (TJs) or in the number of vesicles or coated pits compared to those of normal cells. However, ECM accumulation underlying HG cells was significantly increased compared to that of cells grown in N medium (139 +/- 7% of control, p = 0.04), with areas of focal thickening. Western blot analysis showed increased fibronectin and collagen IV expression (152 +/- 24% of control, p = 0.01; 146 +/- 16% of control, p = 0.02, respectively) in cells grown in HG compared to those grown in N medium. Cell monolayers grown in HG exhibited increased permeability to FITC-dextran compared to cells grown in N medium (134 +/- 15% of control, p = 0.02). CONCLUSIONS: High glucose-induced excess ECM accumulation and altered composition underlies structural and functional changes that allow increased permeability. This finding provides evidence for the first time that the thickened vascular basement membrane contributes to the development of excess permeability seen in diabetic retinopathy. PMID- 21780925 TI - Gene expression changes in retinal Muller (glial) cells exposed to elevated pressure. AB - PURPOSE: Retinal Muller (glial) cells undergo "reactive gliosis", a stress response that is accompanied by changes in their morphology and upregulation of various cellular markers. Reactive gliosis is seen in many retinal diseases and conditions; however, it is not known whether it is a common, stereotypic response or the nature of the response varies with the type of retinal stress. To address this question, we have examined gene expression changes in Muller cells exposed to elevated pressure. MATERIALS AND METHODS: Rat Muller cells (rMC-1) were exposed to elevated pressure, and RNA was extracted and analyzed using Affymetrix GeneChip microarrays to identify pressure-responsive genes. RESULTS: Analysis of microarray data showed that at 6 h, 186 genes had > 1.5-fold change with FDR < 0.01. Of these, 62 genes were up-regulated while 124 genes were down-regulated. At 24 h, 73 genes changed > 1.5-fold. Of these, 37 genes were up-regulated while 36 genes were down-regulated. Ingenuity canonical pathway analysis showed that several signaling and metabolic pathways were significantly changed in Muller cells under high pressure. In addition, among up- and down-regulated genes, we identified eight genes-areg, bmp4, cyp1b1, gpnmb, herc2, msh2, heph, and selenbp1, that have been directly or indirectly associated with elevated intraocular pressure. Two genes, areg and gpnmb, further showed time-dependent changes in mRNA and protein expression. CONCLUSION: The results show that Muller cells in vitro respond to elevated pressure by differential regulation of expressed genes. The transcriptional profile is different from that seen with hypoxia, which indicates that Muller cells respond differentially to different microenvironmental changes in the retina. PMID- 21780926 TI - Intravitreal injection of commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser photocoagulation. AB - PURPOSE: To evaluate the short-term effect of a single intravitreal injection of commercially available ketorolac tromethamine (KT) in eyes with diabetic macular edema refractory to laser photocoagulation. METHODS: Prospective interventional case series. Twenty five patients with diabetic macular edema refractory to laser photocoagulation received a single intravitreal injection of commercially available KT (Toradol(r)), in a dose of 3000 ug. Examination included assessment of ETDRS-best corrected visual acuity (BCVA), measurement of intraocular pressure and high resolution imaging by optical coherence tomography, preoperatively and 7, 15, and 30 days postoperatively. RESULTS: In the follow up visits at 7, 15 and 30 days, BCVA had improved five or more letters in 20% (95% confidence interval, 7.7-38.9%), 16% (95% confidence interval, 5.3-34.2%) and 28% (95% confidence interval, 13.2-47.7%) respectively. An improvement in macular thickness was also observed, although it has not been statistically significant. CONCLUSION: This pilot study showed that a single intravitreal injection of 3000 ug of commercial KT led to a short-term improvement of visual acuity in approximately 30% of eyes with diabetic macular edema refractory to laser photocoagulation. PMID- 21780927 TI - Staphylococcus aureus necrotizing fasciitis involving eyelids and periorbita. PMID- 21780928 TI - One-stage reconstruction technique for large congenital eyelid coloboma. AB - PURPOSE: To determine the functional and cosmetic outcome of using skin graft from prepuce (after circumcision) to reconstruct eyelids in congenital lid coloboma. PATIENT & METHODS: Four male infants with large eyelid coloboma and marked exposure keratopathy were included. All the patients were selected from the outpatient clinic of Tanta University Eye Hospital, Egypt from March 2006 till August 2009. One-stage reconstruction was used to repair the defect. For upper eyelid coloboma, sliding tarsoconjunctival flap with a free skin graft from of skin of prepuce (after circumcision) was done.For lower lid coloboma, conjunctival dissection with reflection over the cornea with use of a free skin graft from prepuce. RESULTS: All infants had large unilateral defect, 3 upper lids and 1 lower lid. The cosmetic and functional outcome of using skin of the prepuce was satisfactory with good color match in all cases. Also functional and cosmetic results of tarsoconjunctival sliding flap was excellent. All the cases were followed up for a period ranged from 7 to 36 months. CONCLUSION: Tarsoconjunctival rotational flap and the use of skin of prepuce are very helpful and seems to be an adequate method of reconstruction of large eyelid defect in male patients when the usual donor sites for skin grafts are not available as in infants. PMID- 21780929 TI - Solitary orbital myofibroma: clinical, radiographic, and histopathologic findings. A report of two cases. AB - This describes a non-interventional case series of 2 patients, aged 7 and 9 years referred to Oculoplastic Unit, both for evaluation of a gradually enlarging, painless, mass of the cheek. CT scan of the first case revealed left orbital floor destruction from a well-defined intraosseous mass. The second was a round circumscribed orbital floor tumor without bone destruction. Histological diagnosis of myofibroma was rendered in both cases. Solitary myofibromas are rare in the orbit. Their rapid growth and bony destruction can mimic malignant tumors. Complete excision with close follow-up is the preferred treatment. Solitary myofibroma should be considered in the differential diagnoses of fibrous tumors with bone destruction in the orbit. PMID- 21780930 TI - Angiomatous meningioma of orbit mimicking as malignant neoplasm: a case report and literature review. AB - Angiomatous meningioma is a rare and distinct meningioma variant characterised with predominance of microvascularcomponent.There are few reported cases in literature with limited information on ophthalmic manifestations and radiological findings. There is no consistent feature reported so far of this neoplasm to aid in its diagnosis. Authors report an interesting case of Angiomatous Meningioma presenting as an aggressively expanding orbital mass lesion with adjacent bony destruction mimicking a malignant neoplasm. PMID- 21780931 TI - Extraocular muscle involvement in MALT lymphomas. AB - We report 3 cases of extraocular muscle involvement by MALT (mucosa-associated lymphoid tissue) lymphoma. The first case was a 68-year-old woman who presented with mild proptosis of the left eye and diplopia caused by a lymphoma in the medial rectus. The other two cases presented with ptosis caused by a lymphoma in the most anterior aspect of the levator muscle. MALT lymphoma may involve extraocular muscles, either as a primary or secondary presentation. Although localization of orbital lymphoma in extraocular muscles is rare, this possibility should be considered in the differential diagnosis with other conditions involving extraocular musculature. PMID- 21780932 TI - Spiradenocarcinoma of the eyelid: a case report. AB - A 84-year-old-woman presented a painless eyelid mass in her right eyelid. A biopsy was made and the anatomopathologic study showed a spiradenoma with malignant changes. The patient rejected any kind of treatment in spite of the prognosis of the lesion. Radiological and pathological features of this infrequent eyelid tumour are discussed. PMID- 21780933 TI - Undifferentiated high-grade pleomorphic sarcoma in a blind eye with a silicone prosthesis implant: a clinico-pathologic study. AB - PURPOSE: To describe a rare case of an orbital undifferentiated sarcoma arising in an eviscerated eye socket with a silicone implant. METHODS: The clinical and histopathological findings of the case are reviewed and presented. RESULTS: A patient who had undergone post-traumatic evisceration of the right eye and a silicone prosthesis implant 8 years earlier, presented to our observation with a painful eye, on which a brownish, bleeding mass, measuring 1 cm in diameter, was evident. After removal of the silicone prosthesis, the mass was found to arise from the scleral socket. Histopathological analysis demonstrated a malignant tumor composed of markedly pleomorphic cells with a high mitotic rate. An undifferentiated high-grade pleomorphic sarcoma was diagnosed. Complete right orbital exenteration was performed and the patient underwent radiotherapy CONCLUSIONS: This is the first report of an undifferentiated high-grade pleomorphic sarcoma arising from a scleral socket with a silicone implant. PMID- 21780935 TI - Exploring the links between personality traits and motivations to play online games. AB - The present study explores the links between personality traits and motivations to play online games. We identified the underlying dimensions of motivations to play online games, examined how personality traits predict motivation, and investigated how personality traits predict online gaming behavior (i.e., playing time and preference for game genres). Factor analyses identified five motivational factors: relationships, adventure, escapism, relaxation, and achievement. The regression analyses indicated that two personality traits, extraversion and agreeableness, predicted various motivations; however, personality traits did not affect the playing time and game genre preference. PMID- 21780934 TI - Acute presentation of cavernous hemangioma of the orbit. AB - Cavernous hemangioma of the orbit typically presents as a slow-growing tumor with gradual onset of symptoms. Acute onset of clinical signs and symptoms, are a rare feature. We present the case of a 40-year-old female, who developed sudden onset of clinical symptoms. MRI evidence of intralesional hemorrhage was confirmed by histopathology. PMID- 21780936 TI - Does an admission booklet improve patient safety? AB - BACKGROUND: The quality of admission clerking to psychiatry wards will influence initial management of patients suffering from mental illness. Incomplete clerking may put patient safety at risk. AIMS: We sought to assess the completeness of clerking to general adult psychiatry wards and to evaluate whether the introduction of an admission booklet would improve clerking. METHOD: We analysed the completeness of clerking to general adult psychiatric wards by trainee doctors. Using an audit approach, the first phase assessed completeness of clerking when trainee doctors used continuation sheets to document the clerking in a free-hand manner. Thereafter, we developed a standardised admission booklet to document the clerking and assessed completeness of clerking in the second phase. RESULTS: The admission booklet significantly improved the completeness of clerking. Notable improvements were seen in multiple components of history taking and initial management, particularly in documenting risk to self and others. CONCLUSIONS: Improving clerking by use of an admission booklet can lead to more informed management decisions particularly in regard to the patients' physical health and clinical risk management. This may consequently improve patient safety and help trainees communicate important aspects of the case to seniors and the wider multi-disciplinary team. PMID- 21780938 TI - Negotiating depression treatment with older adults: primary care providers' perspectives. AB - BACKGROUND: Primary care occupies a strategic position in the evaluation and treatment of depression in late life, yet many older patients do not initiate or adhere to treatments available in primary care. AIM: To explore how primary care providers describe the process of discussing depression care with older adults. METHOD: Semi-structured interviews conducted with 15 providers involved with intervention studies of depression management for older adults. We used the constant comparative method to identify themes related to negotiating the treatment of depression with older adults. RESULTS: Providers felt that older patients often attribute depression to non-medical causes. They talked about the challenges and described the need to 'convince' them of the medical model of depression. CONCLUSION: How primary care physicians surmise patients' views of depression may influence the discussion of depression in practice. As medication is most often provided for depression treatment, some may feel compelled to convince their patients of biomedical explanations while others may avoid treating depression altogether. PMID- 21780939 TI - Mental health issues in fetal alcohol spectrum disorder. AB - BACKGROUND: High numbers of individuals with Fetal Alcohol Spectrum Disorders (FASD) have been described as having mental health problems. AIMS: This article summarizes research about mental health problems in FASD and considers related developmental and environmental issues. METHOD: A computer-based literature search was conducted in the databases Medline, PsycINFO, Google Scholar, Academic Search Complete, and Education Resources Information Centre for articles addressing the prevalence and types of mental health issues in individuals affected by FASD. RESULTS: High rates of mental disorders within the FASD and prenatal alcohol exposure (PAE) population were found to be consistently reported for both internalizing and externalizing disorders. Moreover, problems that emerge in childhood may reflect a convergence of genetic, environmental, and neurophysiological factors that persist into adulthood. CONCLUSIONS: Researchers are beginning to document the impacts of PAE on later mental health development. Further longitudinal study is needed to determine whether there is an increasing severity of mental health deficits and consequences with age, and whether any such changes reflect increasingly deteriorating environmental factors or brain based factors. Additionally, research is needed to design interventions to better address the unique mental health needs of this population. PMID- 21780940 TI - Mortality among infants born with orofacial clefts in a single cleft network. AB - OBJECTIVE: To determine mortality rate and cause of death in infants born with orofacial clefts. METHODS: Retrospective case note review of all children with orofacial clefts within the East of England Cleft Network who have died. RESULTS: Between 2002 and 2010, of 638 children born with orofacial clefts, 23 died at a median age of 5 months (range, 1 day to 4 years). The overall mortality rate was 36 per 1000 cleft births. A total of 21 deaths were in the isolated cleft palate group, with a calculated death rate of 68.1 per 1000. One child each from the cleft lip and the cleft lip and palate groups died. Of the children who died, 21 (91%) had other structural abnormalities. Of these children, 19 (83%) died before their first birthday. The causes of death were mainly due to associated congenital anomalies (61%) and infection (17%). CONCLUSIONS: Children born with cleft palate have a 15-fold increase in mortality compared with the regional East of England infant mortality rate and at least a 10-fold increase when compared with other clefts. Pediatricians should be involved in the care of these complicated patients. PMID- 21780941 TI - Increasing clinical presence of mobile communication technology: avoiding the pitfalls. AB - Mobile communication technologies are employed in many diverse areas of healthcare delivery to provide improved quality and efficiency of communication and facilitate increased rapidity of data or information transfer. Mobile phones enable healthcare professionals to possess a portable platform from which to provide many healthcare-related applications and are a popular means to directly communicate with colleagues and patients. As involvement of mobile communication technology in healthcare delivery continues to rapidly expand, there are also important considerations of relevance to patient safety and security as a result. Here, we review the previous evidence of reported clinical risks associated with mobile communication technology, such as electromagnetic interference, confidentiality and data security, distraction/noise, infection control, and cross contamination. In conclusion, although mobile phones provide much putative potential improvement to healthcare delivery, further evaluation and research are required to both inform and protect health professionals and users of such technology in the healthcare environment and provide the evidence base to support the provision of clear and comprehensive guidelines. PMID- 21780943 TI - A call for safer utilization of radio frequency identification in the e-health era. AB - The main purpose of this study was to investigate the perceptions of the electromagnetic interference (EMI) caused by radio frequency identification (RFID) with medical devices among hospitals as well as to call the attention of medical institutions to the development of RFID applications. A survey sponsored by the Department of Health of Taiwan was conducted and the target subjects were every hospital in Taiwan (486 in total). The survey topics included testing of RFID interference with medical devices and perceptions of safety issues of RFID. The main targets of the survey were the Chief Information Officers (CIOs) or the main person responsible for RFID systems in each hospital. Of the original 486 questionnaires mailed, 273 were returned. A return rate of 56.17% was obtained. The survey results revealed that only six hospitals had carried out tests on interference by RFID with medical devices, and the results of these tests indicated that RFID does not interfere with medical devices. A majority of hospitals understood that RFID may interfere with medical devices but did not think that this would seriously harm patients. The application of RFID in the healthcare industry is certainly promising; however, EMI issues must be appropriately handled. This study asserts that most hospitals do not understand or pay insufficient attention to the issue of RFID interference with patient safety or medical devices. In addition, most hospitals believe that the problem of RFID should be resolved by RFID vendors. Therefore, this study argues that medical institutions should develop more understanding of RFID issues and that more attention should be given to the potential problems of RFID interference when developing RFID applications. PMID- 21780942 TI - Feasibility and impact of telemonitor-based depression care management for geriatric homecare patients. AB - OBJECTIVE: The objective of this study was to test the feasibility, acceptability, and preliminary clinical outcomes of a method to leverage existing home healthcare telemonitoring technology to deliver depression care management (DCM) to both Spanish- and English-speaking elderly homebound recipients of homecare services. MATERIALS AND METHODS: Three stand-alone, nonprofit community homecare agencies located in New York, Vermont, and Miami participated in this study. Evidence-based DCM was adapted to the telemonitor platform by programming questions and educational information on depression symptoms, antidepressant adherence, and side effects. Recruited patients participated for a minimum of 3 weeks. Telehealth nurses were trained on DCM and received biweekly supervision. On-site trained research assistants conducted in-home research interviews on depression diagnosis and severity and patient satisfaction with the protocol. RESULTS: An ethnically diverse sample of 48 English- and Spanish-only-speaking patients participated, along with seven telehealth nurses. Both patients and telehealth nurses reported high levels of protocol acceptance. Among 19 patients meeting diagnostic criteria for major depression, the mean depression severity was in the "markedly severe" range at baseline and in the "mild" range at follow up. CONCLUSIONS: Results of this pilot support the feasibility of using homecare's existing telemonitoring technology to deliver DCM to their elderly homebound patients. This was true for both English- and Spanish-speaking patients. Preliminary clinical outcomes suggest improvement in depression severity, although these findings require testing in a randomized clinical trial. Implications for the science and service of telehealth-based depression care for elderly patients are discussed. PMID- 21780944 TI - Constitutive expression of short hairpin RNA in vivo triggers buildup of mature hairpin molecules. AB - RNA interference (RNAi) has become the cornerstone technology for studying gene function in mammalian cells. In addition, it is a promising therapeutic treatment for multiple human diseases. Virus-mediated constitutive expression of short hairpin RNA (shRNA) has the potential to provide a permanent source of silencing molecules to tissues, and it is being devised as a strategy for the treatment of liver conditions such as hepatitis B and hepatitis C virus infection. Unintended interaction between silencing molecules and cellular components, leading to toxic effects, has been described in vitro. Despite the enormous interest in using the RNAi technology for in vivo applications, little is known about the safety of constitutively expressing shRNA for multiple weeks. Here we report the effects of in vivo shRNA expression, using helper-dependent adenoviral vectors. We show that gene-specific knockdown is maintained for at least 6 weeks after injection of 1 * 10(11) viral particles. Nonetheless, accumulation of mature shRNA molecules was observed up to weeks 3 and 4, and then declined gradually, suggesting the buildup of mature shRNA molecules induced cell death with concomitant loss of viral DNA and shRNA expression. No evidence of well-characterized innate immunity activation (such as interferon production) or saturation of the exportin-5 pathway was observed. Overall, our data suggest constitutive expression of shRNA results in accumulation of mature shRNA molecules, inducing cellular toxicity at late time points, despite the presence of gene silencing. PMID- 21780945 TI - Recombinant FIXFc: a novel therapy for the royal disease? AB - INTRODUCTION: Hemophilia B, the deficiency or complete absence of coagulation factor IX (FIX), affects an estimated 80,000 people throughout the world. Some of these individuals are managed with prophylaxis, which involves the intravenous infusion of FIX concentrate two to three times weekly to prevent bleeding. Because FIX prophylaxis remains underutilized, patients with hemophilia B are at risk for bleeding that may be severe and potentially life- or limb-threatening, and they may experience arthropathy resulting from recurrent hemarthroses. AREAS COVERED: This review focuses on recent advances in therapeutic protein fusion technology as they apply to FIX deficiency. The National Library of Medicine Medline database was searched for articles containing the term 'Fc fusion proteins'. EXPERT OPINION: Genetically engineered recombinant FIX fused to the Fc portion of immunoglobulin significantly extends FIX half-life, thereby decreasing the frequency of prophylactic infusions. This in turn may increase the adoption of, and adherence to, prophylaxis, leading to better outcomes for hemophilia B patients. PMID- 21780947 TI - PPARgamma disease gene network and identification of therapeutic targets for prostate cancer. AB - Peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear hormone receptor superfamily. Recently published reports demonstrate the importance of a direct repeat 2 (DR2) as a PPARgamma-responsive element in addition to the canonical direct repeat 1 (DR1) Peroxisome proliferator response elements (PPREs). However, a comprehensive and systematic approach to constructing de novo disease-specific gene networks for PPARgamma is lacking, especially one that includes PPARgamma target genes containing either DR1 or DR2 site within their promoter region. Here, we computationally identified 1154 PPARgamma direct target genes and constructed the PPARgamma disease gene network, which revealed 138 PPARgamma target genes that are associated with 65 unique diseases. The network shows that PPARgamma target genes are highly associated with cancer and neurological diseases. Thirty-eight PPARgamma direct target genes were found to be involved in prostate cancer and two key (hub) PPARgamma direct target genes, PRKCZ and PGK1, were experimentally validated to be repressed upon PPARgamma activation by its natural ligand, 15d-PGJ(2) in three prostrate cancer cell lines. We proposed that PRKCZ and PGK1 could be novel therapeutic targets for prostate cancer. These investigations would not only aid in understanding the molecular mechanisms by which PPARgamma regulates disease targets but would also lead to the identification of novel PPARgamma gene targets. PMID- 21780948 TI - Variability comparison of simultaneous brain near-infrared spectroscopy and functional magnetic resonance imaging during visual stimulation. AB - Brain near-infrared spectroscopy (NIRS) is emerging as a potential alternative to functional magnetic resonance imaging (fMRI). To date, no study has explicitly compared the two techniques in terms of measurement variability, a key parameter dictating attainable statistical power. Here, NIRS and fMRI were simultaneously recorded during event-related visual stimulation. Inter-subject coefficients of variation (CVs) for peak response amplitude were considerably larger for NIRS than fMRI, but inter-subject CVs for response latency and intra-subject CVs for response amplitude were overall comparable. Our results may represent an optimistic estimate of the CVs of NIRS measurements, as optode positioning was guided by structural MRI, which is normally unavailable. We concluded that fMRI may be preferable to NIRS for group comparisons, but NIRS is equally powerful when comparing conditions within participants. The discrepancy between inter- and intra-subject CVs is likely related to variability in head anatomy and tissue properties, which may be better accounted for by emerging NIRS technology. PMID- 21780949 TI - From struma ovarii to Hashimoto disease--an unusual diagnosis of primary hypothyroidism: case report. AB - CAPSULE: Authors report a case of a 52-year-old woman after struma ovarii with chronic lymphocytic inflammation excision. Finally thyroxin treatment was started and patient's hypothyroidism symptoms diminished. CASE SUMMARY: Struma ovarii is a type of mature teratoma in which thyroid tissue forms the main component. In most cases struma ovarii is composed of normal thyroid tissue while lymphocytic thyroiditis in struma ovarii occurs very rarely. The authors report a case of a 52-year-old woman after ovarian tumor excision. In histopatholgical examination struma ovarii with chronic lymphocytic inflammation was diagnosed. Additional studies revealed a typical ultrasonographic picture of Hashimoto disease in the thyroid gland and an increased concentration of thyroglobulin antibodies. A final diagnosis of Hashimoto disease was confirmed. Initially, thyroid gland function was normal but 11 months after surgery, supplementation therapy with thyroxin was administered. In this case, an early diagnosis of Hashimoto disease resulted from excision of struma ovarii with chronic lymphocytic inflammation. It induced early thyroxin treatment and allowed to reduce hypothyroidism symptoms. PMID- 21780950 TI - Establishment of polycystic ovary syndrome-derived human embryonic stem cell lines. AB - BACKGROUND: Recently, human embryonic stem cells (hESCs) of some genetic diseases have been established, but little research has been done on polycystic ovary syndrome (PCOS)-derived hESCs. The establishment of PCOS-derived hESCs provides a biological basis for exploring the pathogenesis, gene mapping and gene therapy of PCOS. METHODS: Discarded fresh embryos were collected and cultured until the blastocyst stage, and then inner cell masses (ICM) were isolated by mechanical methods and incubated in the mixed feeder layer containing human stem cell medium. hESCs were identified whether to maintain normal karyotype and pluripotency by alkaline phosphates (AKP), stage-specific embryonic antigen-4 (SSEA-4), NANOG, SOX2 and TRA-1-60, octamer binding protein 4(OCT-4), and in vivo and in vitro differentiation. RESULTS: Of the 11 passaged ICM, nine showed adherent growths within 48 h with an adherence rate of 81.8% (9/11). Five PCOS derived hESCs were established and all of them have the characteristics of pluripotent differentiation. One was from 2PN embryo which was retarded in the cleavage stage, one was from 1PN embryo and others were from 0PN embryo. They were named p-hES-1, p-hES-2, p-hES-3, p-hES-4, p-hES-5, respectively. CONCLUSION: We provide biological models for studying the pathogenesiss of PCOS. PMID- 21780951 TI - A case of an ectopic prolactinoma. AB - A 34-year-old female presented to our clinic with a 1.5 year history of secondary amenorrhea and galactorrhea. Prolactin (PRL) level was found to be 151.89 ng/ml. Pituitary imaging was reported to be normal. An examination of the patient revealed that PRL level was still high so the dose of cabergoline was further increased and subsequently, bromocriptine was added to the treatment. There was no reduction in PRL levels in controls. A scanning was performed to look for an ectopic focus. Abdominal computerized tomography revealed a heterogenous mass lesion originating from the uterus. Octreotide scintigraphy was performed and we observed an involvement consistent with the mass in the uterus. The patient underwent abdominal total hysterectomy. PRL dropped to 0.4 ng/ml the next day after the operation. The pathology result was a low-grade malignant mesenchymal tumor. Prolactin was found to be immunohistochemically negative. However, galactorrhea disappeared postoperative and PRL levels are still low. Elevated levels of PRL, resistant to bromocriptine and cabergoline, rapidly returned to normal after hysterectomy, which obviously indicates that hyperprolactinemia was associated with the myoma of the uterus. PMID- 21780952 TI - High mortality explained by mildly elevated blood pressure in Scandinavian adolescent conscripts: a plea for early drug treatment? PMID- 21780953 TI - Association between habitual sleep duration and blood pressure and clinical implications: a systematic review. AB - Elucidation of the association between short sleep duration and elevated blood pressure has implications for assessing and managing hypertension in adults. OBJECTIVE: To assess the relationship between sleep duration and blood pressure, and its role in the etiology of hypertension. METHODS: On a systematic search from MEDLINE, EMBASE, CINAHL, PEDro, PsychINFO and grey literature were included articles with participants over 18 years, reported sleep duration, measured blood pressure or diagnosed hypertension, and the relationship between sleep duration and blood pressure was analyzed. RESULTS: Of 2522 articles initially identified, 11 studies met the inclusion criteria. Sample sizes ranged from 505 to 8860 (aged >= 20-98 years). Five studies (aged >= 58-60 years) determined that sleep duration and blood pressure were unrelated. In younger adults, five studies reported an association between short sleep duration and hypertension before adjustment for confounding variables; only the findings from one study remained significant after adjustment. Two studies supported a sex association; women who sleep less than 5-6 h nightly are at greater risk of developing hypertension. CONCLUSION: Sleep duration and blood pressure are associated in both women and adults under 60 years. Controlled studies are needed to elucidate confounding factors and the degree to which sleep profiles could augment diagnosis of hypertension and sleep recommendations to prevent or manage hypertension. PMID- 21780954 TI - Prevalence and risk factors associated with syphilis in a cohort of HIV positive individuals in Brazil. AB - Individuals with syphilis have higher chance of having HIV, and syphilis' genital ulcers increases HIV transmission rate. Nevertheless, there are few well documented studies about HIV and syphilis co-infection and its risk factors. The study was based on 2262 HIV infected individuals from South Brazilian HIV cohort, which began in 1991, and this analysis included individuals who were included in the cohort until November 2008. Inclusion criteria were having CD4 + T cell count and viral load at baseline, and syphilis serology tests (venereal disease research laboratory [VDRL] > 1:64 or a positive VDRL plus a positive treponemal test). A total of 1012 patients were included; 580 were men (57%); mean age at HIV diagnosis was 33 years; 591 (58%) had previous diagnosis of AIDS; most of the individuals acquired HIV from sexual contact (47.9% heterosexual and 31.7% men who had sex with men [MSM]); and 759 (75%) were on antiretroviral therapy. The prevalence of syphilis was 20.5% (208). After multivariate analysis, being male (2.01; 95% CI, 1.23-3.27; p = 0.005) and MSM (1.91; 95% CI, 1.25-2.90; p = 0.002) were significantly associated to HIV and syphilis co-infection. Males and MSM were associated with higher risk of this co-infection. Our findings may reflect that this particular population is still engaging in unprotected sexual intercourse, and efforts should be made to better target this specific group as they might perpetuate these infections. PMID- 21780955 TI - The infant feeding choices and experiences of women living with HIV in Kinshasa, Democratic Republic of Congo. AB - HIV transmission through breastfeeding is a significant public health challenge. While breastfeeding provides important nutrition, and results in reduced morbidity and mortality, there is a risk of HIV transmission through breastfeeding. International prevention of mother-to-child transmission (PMTCT) guidelines recommend exclusive breastfeeding for six months among HIV-infected women on antiretroviral therapy. Promoting exclusive feeding has proved difficult in settings where mixed feeding is a cultural norm. Understanding the factors that influence HIV infected women's infant feeding choices and practices is critical to promoting adherence to PMTCT guidelines. We conducted in-depth interviews with 40 HIV+ pregnant and post-partum women in Kinshasa, Democratic Republic of Congo to understand their infant feeding experiences. Interviews were conducted in Lingala, and transcribed and translated into French for analysis. Deductive and inductive codes were applied, and matrices were created to facilitate cross-case analysis. Women had limited understanding of the specific mechanisms through which their infant feeding practices influenced HIV transmission risk. Clinical staff was the primary source of women's knowledge of HIV mother-to-child-transmission. Among the 24 post-partum women in the sample, seven women adhered to exclusive breastfeeding and two women to exclusive formula feeding for at least six months. Women's beliefs and awareness about HIV transmission through breastfeeding, as well as the information and support from clinical staff and other members of their support networks positively influenced their exclusive feeding. Common barriers to exclusive feeding included financial constraints, breast health problems, misinformation about HIV transmission, local norms, and prior feeding experiences. Health care workers play a key role in providing correct information on PMTCT and supporting women's infant feeding choices to adhere to guidelines of exclusive infant feeding. Optimizing provider patient communication and creating a supportive environment surrounding infant feeding is critical. PMID- 21780956 TI - Why some MSM present late for HIV testing: a qualitative analysis. AB - Although initiatives are under way in the UK to diagnose HIV infection early, late presentation is still a major issue and often results in serious health complications for the individual and has implications for society, including high costs and increased rates of transmission. Intervention strategies in the UK have aimed at increasing testing opportunities but still a significant proportion of those with HIV infection either decline testing or continue to test late. The main objective of this study is to identify ideas and themes as to why testing was not carried out earlier in men who have sex with men (MSM) who presented with late HIV infection. Semi-structured interviews were carried out with MSM presenting late with a CD4 cell count of <200. A structured framework approach was used to analyse the data collected and generate ideas as to why they did not seek testing earlier. Seventeen MSM were interviewed and four main themes were identified: psychological barriers, including fear of illness and dying, stigma surrounding testing for HIV and in living with a positive diagnosis, perceived low risk for contracting HIV despite participants reporting having a good understanding of HIV and its transmission and strong views that a more active approach by healthcare services, including general practice, is necessary if the uptake of HIV testing is to increase. Late presentation with HIV infection continues to be a problem in the UK despite government initiatives to expand opportunities for testing. Recurring themes for late testing were a low perceived risk for HIV infection and a fear of HIV and a positive diagnosis. Population targeted health promotion alongside a more proactive approach by healthcare professionals and making HIV testing more convenient and accessible may result in earlier testing. PMID- 21780957 TI - Hope, HIV and health: a prospective study. AB - In this study we examined the impact of trait hope on the health of 16 HIV+ individuals. In 2006, hopefulness was assessed with a comprehensive measure derived from an integrative theory of hope. At this time, we also collected self reported health data as well as blood samples that provided an index of immunological status (CD4). Subsequently, at 8, 24, and 48 months we obtained follow-up CD4 levels. To rule out a potential confound, we computed and found, no significant correlations between self-reports of hope or heath, and blind ratings of illness denial provided by a case manager. Total hope scores as well as hope sub-scores were significantly correlated with various dimensions of self-reported health as well as CDC established CD4 classification levels, both concurrently and prospectively. PMID- 21780959 TI - FERTILITY 2011, 5th-7th January 2011, Dublin, 7th biennial conference of the UK Fertility Societies: the Association of Clinical Embryologists, British Fertility Society and the Society for Reproduction & Fertility. Also participating: Irish Clinical Embryologists Association (ICE) and the Irish Fertility Society (IFS). PMID- 21780958 TI - Functional disability and psychological well-being in later life: does source of support matter? AB - OBJECTIVES: This study explored the buffering effects of instrumental and emotional support from different sources against the impact of increasing functional disability on depression and life satisfaction. METHODS: Random effects modeling was utilized with data from a nationwide longitudinal study in Taiwan. A total of 6722 observations from 2856 elders over a seven-year period served as subjects of this study. RESULTS: The results suggested that instrumental support from family members and formal organizations as well as emotional support from families, friends and formal organizations was significantly associated with better psychological well-being among the elderly in Taiwan. In addition, receiving instrumental support from family members and formal organizations can moderate the linkage between increasing functional disability and depression. CONCLUSION: The results emphasize the importance of encouraging a partnership between natural helpers and health care professionals. A good integration between formal and informal networks could more effectively meet the needs of the frail older adults and their families. This study also calls for more attention to the cultural competence of health care policy and service delivery. PMID- 21780960 TI - A pilot study on the use of tracking technology: feasibility, acceptability, and benefits for people in early stages of dementia and their informal caregivers. AB - OBJECTIVES: Caregivers and clinicians may be confronted with the dilemma whether to allow people in early stages of dementia to go outside independently with the risk of getting lost, or to limit their autonomy and mobility. Newly available technology may offer a solution. This pilot study is focused on the feasibility, acceptability, and effectiveness of a three-month use of Global Positioning System (GPS) by care receivers and caregivers. METHOD: Numbers and percentages of participants with positive responses to self-report questions were calculated. Differences between the pre- and post-test scores of role-overload and worry were tested with paired t-tests and effect-sizes were calculated. RESULTS: Of the 33 dyads of care receivers and caregivers, 28 remained in the study (dropout rate 15%). The majority of the caregivers was able to use the technology and integrate the use into their daily routines and would recommend the use of GPS. Almost half of the participants with dementia experienced more freedom and were less worried when they were outside unaccompanied, a quarter mentioned that they were more outside independently and a fifth that they had less conflicts with their caregiver after three months. Caregivers showed a trend to feel less worried, especially caregivers who could reach their relative using the telephone connection. No changes in caregivers' feelings of role-overload were found. CONCLUSION: The GPS device used in this study seems to be promising for people in early stages of dementia and their informal caregivers. A next step is to carry out a randomized controlled trial. PMID- 21780961 TI - Cognitive and affective correlates of decisional balance regarding screening mammography in older women. AB - Participation in screening mammography remains suboptimal. This research aimed to improve understanding of ways to facilitate screening mammography attendance. One hundred and forty-two women from Gold Coast, Australia, aged 50-75, participated in the study. Social cognitive variables were assessed as potential predictors of mammography attendance. Most participants (79%) were maintaining regular screening mammography. Greater knowledge of breast cancer was the strongest predictor of decisional balance in favor of attending screening. Women who had relapsed from screening had significantly lower breast cancer worry than those contemplating attending for the first time. The results were consistent with previous research and point to factors screening services could consider to increase uptake. PMID- 21780962 TI - Effects of a comprehensive educational group intervention in older women with cognitive complaints: a randomized controlled trial. AB - OBJECTIVE: This study presents a new comprehensive educational group intervention that offers psycho-education about cognitive aging and contextual factors (i.e., negative age stereotypes, beliefs, health, and lifestyle), focuses on skills and compensatory behavior, and incorporates group discussion. Its effects were investigated in community-dwelling older women who report normal age-related cognitive complaints. METHODS: A randomized controlled trial with an experimental and waiting-list control condition was carried out in a sample of 50 women aged 60-75 years. As the main problem of these individuals were perceived cognitive deficits without actual cognitive decrements, metacognition served as the primary outcome measure. OBJECTIVE: cognitive functioning and psychological well-being were secondary outcome measures. A double baseline and a follow-up assessment were carried out. RESULTS: Participants in the experimental condition reported significantly fewer negative emotional reactions toward cognitive functioning (U = 164.500, p = 0.004). The reported effect size (delta = -0.473) could be interpreted as large. CONCLUSIONS: This new comprehensive educational group intervention reduces negative emotional reactions toward cognitive functioning, which seems a prerequisite for improved subjective cognitive functioning and well being. It can potentially contribute the well-being of an important and large group of older adults. PMID- 21780963 TI - Regional heterogeneity of right atrial repolarization. Monophasic action potential mapping in swine. AB - OBJECTIVES: To establish a set of reference values for regional dispersion of repolarization of the right atrium in the in situ heart of pigs and to see if the global dispersion of repolarization could be estimated from regional mapping. DESIGN: Monophasic action potential (MAP) were sequentially recorded from 28 ? 3 sites in seven different regional areas of the right atrium: lateral, anterior and posterior wall, septum, sinoatrial node (SAN), appendage, and near the tricuspid annulus (TA) in 10 healthy pigs using the CARTO mapping system. RESULTS: The activation time (AT), MAP duration (MAPd) and end of repolarization time (EOR) of the whole right atrium were 68 +/- 7, 239 +/- 20 and 270 +/- 23 ms, respectively. There were no significant differences on MAPd and EOR among the seven regional areas, nor between each of the regional and global values. The global dispersions of the MAPd and EOR were 75 +/- 19 and 103 +/- 13 ms, which were significantly greater than those obtained from any of the seven regional areas and those between two remote regions, SAN vs. TA and SAN vs. appendage regions. CONCLUSIONS: The data of regional and global dispersion of repolarization in healthy pigs can serve as reference values for evaluation of increased dispersion of repolarization. The global dispersions of MAPd and EOR in the right atrium were poorly estimated from regional mapping, suggesting the importance of global mapping in evaluating the dispersion of atrial repolarization. PMID- 21780964 TI - HIV-related risk behaviors among kathoey (male-to-female transgender) sex workers in Bangkok, Thailand. AB - Based on combined methods, this study investigated substance use and HIV risk behaviors among kathoey sex workers (KSWs) in Bangkok, Thailand. The study found that only half of the KSW participants reported having been tested for HIV, and that except for one participant, all others had not seen health care providers in the past 12 months. About one third of the participants reported having engaged in unprotected anal sex with customers in the past six months. Almost all participants reported alcohol use, as well as having had sex with customers under the influence of alcohol. The prevalence of marijuana and ecstasy use in the past 12 months was high (32 and 36%, respectively); as was for ketamine (20%) and non injecting methamphetamine (yaba) use (10%). A multiple regression analysis showed that the participants who were post-operative status, had used illicit drugs, or had been abused by their father and brothers were less likely to use condoms for anal sex with customers. Three quarters of the participants sent money to their families and 35% of the participants expressed their willingness to engage in unsafe sex when customers offer extra money. The qualitative interviews revealed that many identified as girl or kathoey in early age and had been exposed to transphobia and violence from father and brothers. Some reported support for gender transition from their mothers. More than half of the participants currently had difficulties in living as kathoey, such as challenges in the job market and relationship with family members. Family obligation for sending money and the Buddhist concept of karma were discussed in relation to risk behaviors among KSWs. The study provided implications for facilitating HIV testing and developing future HIV prevention intervention programs for KSWs in Thailand. PMID- 21780965 TI - Exploring positive adjustment in HIV positive African women living in the UK. AB - Research into living with HIV/AIDS has to date mainly focused on quality of life and there is little on the adjustment process for this group. The numbers of African women living with HIV/AIDS in the UK is growing and yet little is known about the adjustment experience for these women. This study explored aspects of positive adjustment to living with HIV/AIDS among a sample of African women living in London, UK. Transcripts of semi-structured interviews with 12 women were analysed using interpretative phenomenological analysis (IPA). Two superordinate themes emerged inductively from the data: positive changes in coping (subthemes: positive interpretation of their situation and positive behavioural changes) and positive growth since the HIV diagnosis (subthemes: changes in the value of life and, changes in goals and opportunities). While these women acknowledged the negative impact of living with HIV/AIDS, all participants mentioned changes in health behaviours to help regain mastery of their lives and comparing with others better-off and worse-off was used to enhance self-esteem and view their situation positively. The data show evidence for Taylor's Cognitive Adaptation Theory. PMID- 21780966 TI - Streptococcus mutans and Streptococcus sobrinus biofilm formation and metabolic activity on dental materials. AB - OBJECTIVES: To examine potential correlations between streptococcal biofilm formation and lactate production in streptococcal biofilms formed on the surface of dental materials with different surface characteristics. MATERIALS AND METHODS: Samples of a glass-ionomer cement (Ketac Molar) and a ceramic (Empress 2) were incubated with whole saliva and suspensions of Streptococcus mutans ATCC 25175 or Streptococcus sobrinus ATCC 33478 for initiating single-species biofilm formation for either 4 or 24 h. The relative amount of adherent, viable cells was determined using a Resazurin and a MTT assay. Metabolic activity was assessed by quantifying lactate production with a modification of the commercial Clinpro Cario L-Pop kit. RESULTS: Both assays identified similar S. sobrinus biofilm formation on the two substrata; for S. mutans, the MTT test showed significantly fewer streptococci on the glass-ionomer cement than on the ceramic. Concerning metabolic activity, for S. sobrinus, significantly higher lactate production was observed for biofilms formed on the glass-ionomer cement in comparison to the ceramic, whereas similar values were identified for S. mutans. CONCLUSIONS: Within the limitations of the study, the results suggest that the pure amount of adherent streptococci does not a priori indicate the metabolic activity of the cariogenic bacteria organized in the respective biofilm. Thus, comparisons between the relative amount of adherent streptococci and their metabolic activity may allow for an improved understanding of the effect of dental material surfaces on the formation and metabolic activity of streptococcal biofilms. PMID- 21780967 TI - Detection and characterization of a new astrovirus in chicken and turkeys with enteric and locomotion disorders. AB - In the present paper, we report the unexpected discovery of a new virus in samples from chicken and turkey flocks with clinical disorders such as tenosynovitis, enteric problems, or runting and/or stunting-like conditions. Since 1987, several virus isolation attempts on samples from these flocks resulted in the same macroscopic characteristic lesions in embryonated specific pathogen free eggs, being mortality with bright-red discolouration of legs and wing-tips, a swollen dark-red liver and oedema. Initial work suggested the presence of an agent with characteristics of a non-enveloped RNA virus. Further work, which is described in this paper, showed that the isolated strains formed a new group of avian nephritis viruses, which is genetically and antigenically distinct from known avian astroviruses. Inoculation of a representative strain (isolate 19) of this new group of avian nephritis viruses, provisionally named avian nephritis virus-3, in specific pathogen free layer chicks resulted in diarrhoea, runting and stunting, and even mortality. PMID- 21780968 TI - Microhardness change of enamel due to bleaching with in-office bleaching gels of different acidity. AB - OBJECTIVE: The aim of this study was to assess the enamel microhardness treated with three in-office bleaching agents, containing 35% hydrogen peroxide with different acidity. MATERIALS AND METHODS: Bovine incisors were divided into three groups that received the following bleaching agents: Whiteness HP, Total Bleach and Opalescence Xtra. Three gel applications/10-min each, totaling 30-min of bleaching treatment, were made on the teeth and activated with a blue LED (1000 mW/470 nm) combined to a LASER (120 mW/795 nm) device (Easy Bleach-Clean Line). Vickers hardness (VH) was evaluated at baseline and after the bleaching procedure. The values of Hardness loss [HNL] (% reduction) were calculated. The two-sample t-test was used for comparison of the HNL of the three bleaching products (5% level of significance). RESULTS: The Opalescence Xtra, which had the lowest pH value (pH = 4.30), showed a significant increase of HNL when compared with Total Bleach bleaching agent, which had the highest pH value (pH = 6.62). CONCLUSIONS: The 35% hydrogen peroxide bleaching agents resulted in a reduction in surface enamel microhardness and bleaching with the most acid agent resulted in a significant enamel hardness loss compared to the less acid agent (4.30 vs 6.62). Strategies proposed to reduce the enamel loss after bleaching treatment may include the use of daily fluoride therapy, mouth rinsing (fluoride, milk and sodium bicarbonate solution), fluoride/bicarbonate dentifrices without abrasives, do not toothbrush immediately after bleaching, fluorides and calcium add to bleaching agents. PMID- 21780969 TI - Three-dimensional analysis of the pulp cavity on surface models of molar teeth, using X-ray micro-computed tomography. AB - AIM: The purpose of this study was to investigate the scanning and segmentation precision of surface models of molars for the detection of small volumes, such as the reduced pulp cavity; formation of mineral deposits; detection of narrow root canals and to improve the clinical and morphological understanding of the number of root canals and their configuration. METHODS: Eighteen human molars were scanned using X-ray micro-computed tomography. The reconstruction of the surface models had a precision of <1 voxel, using three-dimensional software and quantitative color mapping. In order to relate the measurements to changes over time the size of the pulp chambers was classified in two well-defined groups. RESULTS: The mineral deposits were more evenly distributed in small pulp chambers than in large, but complete root canal calcification was never observed. No difference was observed in the material with respect to the presence of intra radicular connections. In upper molars, a second mesiobuccal canal (mb(2)) frequency of 91% was found. The difference in length between the first mesiobuccal canal (mb(1)) and mb(2) was <1 mm. The number of root canals could be related to the number of root cones. CONCLUSION: In summary, three-dimensional surface models were made with a high precision; an increased accumulation of mineral deposits was noted in molars with small pulp chambers and combined with the consistent pattern of intra-radicular connections, the potential endodontic treatment complexity is underlined in such cases. Finally, an improved understanding of root canal prevalence was reached, when merging well-defined definitions on root morphology and clinical classification systems. PMID- 21780970 TI - Ranulas: possible signs for HIV/AIDS? 1 year Ugandan descriptive study. AB - INTRODUCTION: Certain oral manifestations signal progression of HIV disease among HAART naive patients or an increase in the plasma HIV-1 RNA levels for those on treatment. Ranulas may be one of those manifestations. Therefore, this study describes the clinical features of patients who presented with ranulas including their demographics, HIV sero-status and the CD4 CD8 cell counts for those who were HIV positive. METHODS: A prospective study on ranulas was undertaken at Mulago national referral hospital and St Mary's hospital Lacor covering the period December 2008 to November 2009. RESULTS: Fifty-seven cases participated in the study: 38.6% male and 61.4% female. Out of the study group, 73.7% were HIV positive. This was statistically significant (Chi = 12.789, df = 1, p = 0.001). In relation, to CD4 cell count, 23.8% had <200 cells/mm(3), 35.7% between 200-500 cells/mm(3) and 40.5% more than 500 cells/mm(3). The CD4-to-CD8 ratio ranged from 0.02-0.98 with an average of 0.31 +/- 0.23, median and mode of 0.27 and 0.32, respectively. CONCLUSIONS: It is felt that ranulas may be one of the oral manifestations of worsening immunity in HIV/AIDS disease. Therefore, more research is needed to establish if it should be included among known oral manifestations of the disease. PMID- 21780971 TI - Concomitant hypodontia and hyperodontia: an analysis of nine patients. AB - INTRODUCTION: Congenital absence of tooth germs and presence of supernumerary teeth (CHH) are anomalies which are classified as embryologically determined disorders. Both disorders can occur together (CHH), but relatively rarely. OBJECTIVE: The aim of the present study was to present and analyze nine cases collected during the past 24 years, where congenitally missing teeth occurred with supernumerary teeth in the same patient. MATERIALS AND METHODS: Dental records, radiographs and casts of nine patients, six boys and three girls (aged 9 29 years, mean age: 19 years) were examined. All the family members of the patients were also investigated regarding the presence of tooth disorders. RESULTS: The boys showed hypo-hyperodontia twice as often as the girls (6:3). Congenital absence of tooth germs was more common than the presence of supernumerary teeth (25:11). CAP were not present in the other family members. CONCLUSIONS: The full diagnosis of hypo-hyperodontia is only possible on the basis of radiographic examination, because some teeth may remain unerupted or missing. The results of this study showed that concomitant hypo-hyperodontia is rare and sex-related, with predominance of hypodontia. The genetic influence seems unclear. PMID- 21780972 TI - Chronological and subjective age differences in flourishing mental health and major depressive episode. AB - Mental health is more than the absence of psychopathology, but few studies use positive mental health along with a measure of past year major depressive episode (MDE). This study addresses this gap by investigating the association of MDE and flourishing mental health (FMH) with chronological age and subjective (felt and ideal) age. Data are from the Midlife in the United States random digit dialing sample of adults ages 25 to 74, collected in 1995 (n = 3032). Rates of MDE were lowest, and FMH highest, among the three oldest age cohorts (45-54, 55-64, 65-74 years). Subjective age was linked with chronological age; with age, adults tend to feel younger, and want to be an age that is younger, than their actual age. As predicted by the model of subjective age as an adaptive strategy, feeling younger was related to a lower risk of MDE and a higher risk of FMH. However, wanting to be younger was related to a lower risk of FMH and unrelated to MDE. PMID- 21780973 TI - Effect of NaF and TiF(4) varnish and solution on bovine dentin erosion plus abrasion in vitro. AB - OBJECTIVES: This in vitro study aimed to analyze the effect of TiF(4) compared to NaF varnishes and solutions, to protect against dentin erosion associated with abrasion. MATERIALS AND METHODS: Bovine dentin specimens were pre-treated with NaF-Duraphat (2.26% F), NaF/CaF(2)-Duofluorid (5.63% F), experimental-NaF (2.45% F), experimental-TiF(4) (2.45% F) and placebo varnishes; NaF (2.26% F) and TiF(4) (2.45% F) solutions. Controls remained untreated. The erosive pH cycling was performed using a soft drink (pH 2.6) 4 * 90 s/day and the toothbrushing-abrasion 2 * 10 s/day, in vitro for 5 days. Between the challenges, the specimens were exposed to artificial saliva. Dentin tissue loss was measured profilometrically (MUm). RESULTS: ANOVA/Tukey's test showed that all fluoridated varnishes (Duraphat, 7.5 +/- 1.1; Duofluorid, 6.8 +/- 1.1; NaF, 7.2 +/- 1.9; TiF(4), 6.5 +/ 1.0) were able to significantly reduce dentin tissue loss (40.7% reduction compared to control) when compared to placebo varnish (11.2 +/- 1.3), control (11.8 +/- 1.7) and fluoridated (NaF, 9.9 +/- 1.8; TiF(4), 10.3 +/- 2.1) solutions (p < 0.0001), which in turn did not significantly differ from each other. CONCLUSION: All fluoridated varnishes, but not the solutions, had a similar performance and a good potential to reduce dentin tissue loss under mild erosive and abrasive conditions in vitro. Risk patients for erosion and abrasion, especially those with exposed dentin, should benefit from this clinical preventive measure. Further research has to confirm this promising result in the clinical situation. PMID- 21780974 TI - Influence of extra- and intra-oral application of CPP-ACP and fluoride on re hardening of eroded enamel. AB - OBJECTIVES: This in-situ study aimed to investigate the potential of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) creme and fluoride mouth rinse to re-harden erosively softened enamel and to evaluate the influence of an intra-oral or extra-oral application. METHODS: Ten volunteers performed five experimental series. Per series, four bovine enamel samples were extra-orally softened by immersion in Sprite light((r)) (2 min) and subsequently worn intra orally for 5 min in intra-oral appliances. Thereafter, samples were treated (3 min) with either 250 ppm AmF/SnF(2) solution (Meridol) (series 1 and 3) or CPP ACP creme (Tooth Mousse) (series 2 and 4). Application of the substances was performed extra-orally (series 1 and 2) or intra-orally (series 3 and 4). Untreated specimens served as control (series 5). The appliances were worn for 4 h afterwards. Knoop microhardness (KHN) measurement was performed at baseline, after softening and after completing of the respective run. Data were statistically analyzed by ANOVA and Bonferroni/Dunn post-hoc test. RESULTS: No significant difference in baseline microhardness was observed, while immersion in Sprite light reduced the microhardness significantly. Significant re-hardening after intra-oral exposure occurred in all series, but baseline microhardness was not achieved. Microhardness in series 2 was significantly higher than that in series 1 and 5. No significant differences in KHN were detected between series 3, 4 and 5. The re-hardening DeltaKHN (final microhardness - microhardness after erosion) was not significant different in all five series. CONCLUSION: Intra-oral application of CPP-ACP creme or fluoride solution provides no benefit regarding re-hardening of erosively softened enamel. PMID- 21780946 TI - Apixaban with antiplatelet therapy after acute coronary syndrome. AB - BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.). PMID- 21780975 TI - Co-expression of Ki-67 and p53 protein in ameloblastoma and keratocystic odontogenic tumor. AB - OBJECTIVES: The purpose of this study was to evaluate the cell proliferation and p53 protein expression in ameloblastomas (ABs), keratocystic odontogenic tumor (KCOT) and dentigerous cyst (DC). METHOD: The immunohistochemistry were carried out for Ki-67 and p53 protein expression by using MIB-1 clone and DO-7 clone, respectively, in ABs (n = 23), KCOT (n = 32), DC (n = 30), normal oral mucosa (NOM) (n = 12) and fetal oral mucosa (FOM) (n = 10). RESULTS: Both the Ki-67 LI Labeling index (LI) and p53 LI was significantly higher in ABs than KCOT, DC, NOM and FOM. The Ki-67 LI and p53 LI was significantly higher in KCOT as compared to DC. Ki-67 LI and p53 LI was observed in descending order in ABs, KOCT, FOM, NOM and DC. There was significant correlation between Ki-67 expression and p53 expression in ABs, KCOT, DC and NOM. The densely stained p53 positive cells were noted higher in ABs than KCOT. The very few densely p53 positive cells were noted in DC, NOM and FOM. CONCLUSION: The results suggest that the p53 protein expression does not necessarily imply an association with malignant disease and/or p53 gene mutation, but a tendency to be expressed in an increasing quantitative and qualitative manner, as the biologic behavior of odontogenic cyst or tumors becomes more aggressive. p53 over-expression may promote cell proliferation in odontogenic lesions. Thus, it can be stipulated that Ki-67 and p53 protein expression can be used as a prognostic marker in odontogenic lesions. PMID- 21780976 TI - A three-dimensional analysis of the perceived proportions of maxillary anterior teeth. AB - OBJECTIVE: The proportions of the anterior dentition, which is important for excellent esthetics, have been extensively studied, but there have been no 3 dimensional interpretations. This study was conducted to compare real tooth sizes and perceived tooth sizes between different genders and populations and to analyze the effects of 3-dimensional tooth position and alignment. MATERIALS AND METHODS: Complete dental stone casts were prepared for a total of 139 subjects (50 males and 44 females from Korea and 46 females from Japan). Using 3 dimensional scanning and reconstructions, virtual models were constructed and the widths, lengths and rotations of maxillary anterior teeth were measured. Parameters related to the arch form were measured orthographically. Descriptive statistics and ANOVA were performed to determine the differences among the three groups. A regression model was created to interpret the values of 2-dimensional perceived widths with 3-dimensional measurements and other parameters. RESULTS: This study observed differences in the average mesiodistal perceived and real dimensions of the maxillary central incisors between Japanese and Korean females, as well as differences in lateral incisor/central incisor ratios and canine/lateral incisor ratios in the perceived 2-dimensional measurements. There were no differences in individual tooth rotations between groups. The r(2) values of the regression model decreased from the central incisors to the canine. CONCLUSIONS: Several differences were found between Japanese and Korean females and the regression models that used real dimensions, rotations and arch form parameters as independent factors were not sufficient to explain the perceived widths of anterior teeth in the study samples. PMID- 21780977 TI - Self-rated health as a moderator of the relation between functional impairment and depressive symptoms in older adults. AB - OBJECTIVES: The purpose of this study was to examine the relation between functional impairment, self-rated health, and depressive symptoms. Independently, self-rated health and functional impairment each contribute to depressive symptoms; however, it remains unknown how these variables are related to depression in combination. It was hypothesized that self-rated health would moderate the relation between functional impairment and depressive symptoms in a sample of older adults. METHOD: A community sample of adults aged 60 and above was recruited from primary care clinics (n = 106); 98 of these participants had usable data. Participants completed self-report questionnaires that assessed depressive symptoms, functional impairment, and self-rated physical health. RESULTS: Self-rated health moderated the relation between functional impairment and depressive symptoms. For participants with poor self-rated health, greater functional impairment was associated with greater depressive symptoms. CONCLUSION: It appears that patient perceptions of health may be protective against depressive symptoms for those with functional impairment. PMID- 21780978 TI - Multi-locus sequence typing and plasmid profile characterization of avian pathogenic Escherichia coli associated with increased mortality in free-range layer flocks. AB - Avian pathogenic Escherichia coli strains originating from 10 free-range layer flocks were characterized by multi-locus sequence typing and plasmid profile analysis to investigate their phylogenetic relationship and diversity, respectively. In addition to colibacillosis, all flocks tested positive for antibodies against avian metapneumovirus (aMPV) during production, and six of the flocks were concurrently affected by histomonosis. Accumulated average mortality for flocks concurrently affected by colibacillosis and histomonosis made up 17.4%, while the average mortality for E. coli-infected flocks was 16.5%. A total of eight different sequence types (STs) and 47 different plasmid profiles were demonstrated among the E. coli isolates. Within each flock between one and four different STs and between three and 13 different plasmid profiles were demonstrated. A statistical significant difference in STs and plasmid profile diversity of the population of E. coli was not demonstrated between flocks affected by histomonosis compared with histomonosis-free flocks. Only minor clonal diversity was demonstrated for each flock, and in all but one flock colibacillosis started before antibodies against aMPV were detected. All isolates, except two, carried plasmids greater than 100 kb, but only a single plasmid replicon type, IncFIB, was demonstrated, suggesting plasmids representing this type might represent a common pathogenicity factor for the different STs of E. coli. Within each flock a clonal tendency was observed, indicating that only certain clones of E. coli possess a significant pathogenic potential. These clones act as primary rather than secondary pathogens, resulting in colibacillosis without predisposing factors, including histomonosis and aMPV. PMID- 21780979 TI - The effect of different power outputs of carbon dioxide laser on bonding between zirconia ceramic surface and resin cement. AB - OBJECTIVE: The purpose of this in vitro study was to evaluate the influence of different power outputs of a carbon dioxide (CO2) laser on shear bond strength of resin cement to zirconium dioxide-based ceramic. MATERIALS AND METHODS: Fifty zirconium dioxide core specimens (10 mm diameter and 2 mm thickness) were produced and they were embedded in the centers of auto-polymerizing acrylic resin blocks. Ten specimens served as control and no surface treatment was applied. Subsequently specimens were randomly divided into four groups, each containing 10 specimens for surface treatment with CO2 laser with different output power; laser treated with 2 W (Group 2 W), 3 W (Group 3 W), 4 W (Group 4 W) and finally 5 W (Group 5 W). Fifty composite resin discs were fabricated and cemented with adhesive resin cement to the specimen surfaces. A universal test machine was used for shear bond strength test at a crosshead speed 1 mm/min. Data were statistically analyzed by one-way analyses of variance (ANOVA) with Post-Hoc Tukey tests (alpha = 0.05). RESULTS: It was found that the shear bond strength values were affected by power outputs of laser (p < 0.05). Highest shear bond strength values were obtained with group 2 W (21.0 +/- 2.7). Lowest values were obtained with group 5 W (14.4 +/- 1.6). CONCLUSION: The current study revealed that there was a relationship between laser output power and shear bond strength for zirconium dioxide ceramics. However, output power of the laser and the energy level is a critical factor on micromechanical retention. PMID- 21780980 TI - Influence of refractive index on optical parameters of experimental resin composites. AB - OBJECTIVE: Color characteristics of the experimental resin composites were determined to know the influence of different refractive index (RI) on optical parameters. MATERIALS AND METHODS: Four experimental light-cured resin composites of the same shade but with different RI were used. The colorimetric values of the specimens were measured against black and white backgrounds using spectrophotometry. The results were converted to CIE L*a*b* color-space values. The chroma (C*ab), color difference (DeltaE), translucency parameter (TP) and opacity (OP, opposite property of TP) values were calculated. Surface gloss (GS) of the specimen was also measured. RESULTS: The L* coordinate, a* coordinate and DeltaE*ab values increased as the difference in RI increased. The OP and GS values increased and the TP values decreased as the refractive-index difference increased. The L* and C*ab values increased as the value of the RI increased. The TP, OP and GS values were highly correlated with the RI value. The TP value decreased and the OP and GS values increased, as the RI value increased. CONCLUSIONS: Refractive index of resin composites is important when thinking about improving the color appearance of esthetic restorations. PMID- 21780981 TI - An assessment of brief group interventions to increase condom use by heterosexual crack smokers living with HIV infection. AB - The purpose of this study was to assess the efficacy of brief group interventions, the positive choices intervention (PCI) and a standard intervention (SI), to increase condom use and intention to use condoms and to change condom use attitudes and beliefs. The design of the study was a randomized comparative trial. Participants were 347 heterosexual African American crack cocaine users living with HIV infection. Data were collected at intake and at three and nine months after intake. Behavioral and sociocognitive data were collected. Although both brief interventions achieved positive results, there were significant differences in outcomes between the interventions groups. The mean number of sex partners was significantly lower in the PCI group at three months. The proportion of those assigned to the PCI reporting sex with a paid partner significantly decreased, while the proportion disclosing their serostatus to their partners increased. There were no significant differences on these measures in the SI group. Significant time effects were found on measures of condom use, condom use attitudes, and self-efficacy beliefs. These measures significantly increased from intake to one month for both groups. One significant time-by-group effect was found. The measure of situational self-efficacy significantly increased in the PCI group, but not the SI group. Results also showed significant time-by-time effects. Mean condom use, intention to use condoms, attitudes, and condom use self-efficacy beliefs showed significant difference between three and nine months. However, there was no clear pattern of change. Findings suggest that brief group interventions designed to reduce HIV can help heterosexual drug users living with HIV infection increase condom use and intention to use condoms and change condom use attitudes and beliefs. A significant time-by-group effect was observed only for situational self-efficacy, suggesting limited additional efficacy of the PCI intervention. Given similar positive findings between groups, more research is needed to determine which components of brief interventions produce changes in motivations and risk behaviors. PMID- 21780982 TI - Path analysis of exercise treatment-induced changes in psychological factors leading to weight loss. AB - Physical activity may affect weight loss largely through psychological pathways associated with eating changes, especially in obese individuals whose caloric expenditure through exercise is typically small. Direct testing of this is, however, lacking. Previously sedentary adults (N = 114; 77% female; M(age) = 43.3 years), with a minimum body mass index (BMI) of 35 kg/m2 (M (BMI) = 42.0 kg/m2), participated in a 24-week treatment of cognitive-behavioural exercise support and nutrition information. A path model based on tenets of social cognitive and self efficacy theory was constructed. It was expected that improvements in self efficacy, physical self-concept, body satisfaction and mood associated with the exercise treatment would predict changes in self-regulation and increased physical activity. It was also hypothesised that improvements in self-efficacy and self-regulation for appropriate eating would transfer from these relationships and predict weight loss. After three theoretically viable paths were added based on modification indices, structural equation modelling indicated a good fit with the data, chi2(16) = 20.53, p = 0.20; RMSEA = 0.05; SRMR = 0.06; CFI = 0.97; TLI = 0.95. Associations of psychological effects linked to exercise programme participation with predictors of appropriate eating and weight loss were found, and may inform theory, research and treatments. PMID- 21780983 TI - Extensive composite molar restorations: 3 years clinical evaluation. AB - Abstract Objective. To evaluate the clinical performance of extensive direct composite restorations in molars after 1 and 3 years and to find out the importance of extent of the restorations and other factors related to their performance. Materials and methods. Seventy-four patients with a molar tooth in need of a restoration covering at least three surfaces and one cusp were selected. Patient-related factors were registered and the tooth was prepared and restored by using a nano-filled composite. A topographic system for classification of extensive posterior restorations was developed. At baseline, the operator recorded a clinical evaluation, using modified USPHS-criteria. After 1 and 3 years, an independent observer evaluated the restorations. Post-operative problems arising during the observation period were registered. Results. A change in clinical score from baseline to the 1 and 3 year recall was recorded for all clinical criteria. A total of nine restorations were graded as unacceptable after 3 years (3-year survival rate of 87.7% and a mean annual failure rate of 4.2%). Except for gender (p = 0.022), none of the patient-related factors investigated (age, caries risk, extension of the restoration and presence of cervical enamel) had a significant influence on the survival of the restorations. Conclusions. Extensive direct posterior composite restorations showed an acceptable clinical performance after 3 years. Men had a significantly greater restoration failure rate than women. PMID- 21780984 TI - HIV infection as a predictor of methadone maintenance outcomes in Chinese injection drug users. AB - This paper's design is descriptive and correlational based on retrospective self report survey data collected in Kunming city, China. The study investigated the difference between a group of Chinese HIV positive (N=36) and negative (N=131) opioid dependent adults maintained on methadone treatment. Comparisons were based on their quality of life (QOL), methadone treatment adherence, adverse symptom occurrence related to methadone treatment, and HIV-related behavior changes. No significant differences were found between the two groups in age, methadone maintenance dose, methadone adherence, sex desire, and drug craving level. Participants who were HIV positive reported significantly lower scores on physical health and total health-related qualify of life. They also reported greater engagement in injection related risk behavior before methadone treatment than those who tested HIV negative. For both groups, sexual and injection risk behavior significantly decreased following initiation of methadone treatment. A regression model revealed that those infected with HIV, associated significantly with higher likelihood of reporting constipation and lack of appetite, and higher frequency of reporting abdominal pain and nausea than HIV negative patients. The primary implication of these findings is that HIV positive persons in methadone treatment may require more focused services to meet their special HIV care and substance treatment needs. PMID- 21780985 TI - Occupational balance as used in occupational therapy: a concept analysis. AB - Occupational balance is a frequently used concept in occupational therapy, but it is complex and differences in content exist. Further knowledge would be valuable for scholars, practitioners, and measurement development. Concept analysis is a way to clarify concepts. The present concept analysis used Walker and Avant's procedure for analysing the concept of occupational balance, with 43 articles included in the analysis. The results showed that occupational balance can be defined as the individual's perception of having the right amount of occupations and the right variation between occupations. Three perspectives of occupational balance were identified: in relation to occupational areas, in relation to occupations with different characteristics, and in relation to time use. The knowledge gained may guide the use of the concept, and some suggestions are made for its use and for further research. PMID- 21780986 TI - rTMS stimulation to induce plastic changes at the language motor area in a patient with a left recidivant brain tumor affecting Broca's area. AB - INTRODUCTION: Extent of resection is one of the most powerful predictors of outcome in surgery of gliomas. Tumors located within areas governing eloquence may impede a total tumor resection. Functional plasticity may be induced by therapeutic means, such as cortical stimulation with repetitive transcranial magnetic stimulation (rTMS). Thus, rTMS is a potential tool to induce an improvement of functions of eloquence menaced by brain tumors. MATERIAL AND METHODS: We report a case of a 59-year-old woman operated for a left sided precentral oligodendroglioma with awake intraoperative stimulation, whose tumor could not be completely removed because it affected areas governing language. Nine months later the tumor progressed and the motor language functions worsened. We submitted the patient to rTMS directed to Broca's area, next to the anterior pole of the tumor, with the aim of improving motor language function before a new tumor resection attempt. We performed 12 daily sessions of theta-burst rTMS followed by intensive language rehabilitation for 10 minutes, and 5 different aspects of language were measured before, immediately after and 10 minutes after each session. RESULTS: Repetition and nomination worsened immediately after each rTMS session, and improved after 10 min of rehabilitation. However, basal values improved globally along the experiment. Also, the impact of rTMS on motor language was increasingly less along the procedure. CONCLUSIONS: rTMS induces changes in Broca's area and this effect can be potentially used to improve language function in tumors located at or close to eloquent cortical areas. PMID- 21780987 TI - Leisure activities preference of Israeli Jewish children from secular versus Orthodox families. AB - AIMS: To compare daily activity preferences of Israeli Jewish Orthodox and secular children in order to better understand the relationship between children's religious background and their participation patterns. METHODS: Participants were 45 Orthodox and 45 secular Israeli Jewish children, aged 6-10.6 years. MAJOR FINDINGS: In most PAC scales, the secular children showed a significantly lower preference than the Orthodox children to participate in activities. In both groups, activity preferences were impacted by age and gender. Among the secular group, mother's education level was correlated with a lower preference to participate in active physical activities. PRINCIPAL CONCLUSIONS: Family religiosity may impact on children's daily activity preferences. Occupational therapists should consider these socio-environmental factors in order to better integrate a child's religious and cultural identity into therapeutic interventions and assist the child in finding a meaningful occupational experience. PMID- 21780988 TI - Exploring the relationship between white matter microstructure and working memory functioning following stroke: a single case study of computerized cognitive training. AB - Cognitive impairment is a well-known consequence of acquired brain injuries, including stroke. Computerized cognitive training (CCT) is a rehabilitation approach intended to enhance cognitive functioning. It is unclear whether CCT leads to generalized cognitive improvements in daily life functioning, or if the subjects improve performance only on the exercises involved in the training. The current study explores whether fractional anisotropy (FA), a measure of white matter microstructure, may serve as an indirect biological indicator of enhanced neuropsychological functioning, particularly working memory, following CCT. The findings suggest a possible relationship between changes in FA measures and working memory. PMID- 21780989 TI - Stronger evidence for own-age effects in memory for older as compared to younger adults. AB - Three studies examined whether younger and older adults better recall information associated with their own than information related to another age group. All studies compared young and older adults with respect to incidental memory for previously presented stimuli (Studies 1 and 2: everyday objects; Study 3: vacation advertisements) that had been randomly paired with an age-related cue (e.g., photo of a young or an old person; the word "young" or "old"). All three studies found the expected interaction of participants' age and age-associated information. Studies 1 and 2 showed that the memory bias for information arbitrarily associated with one's own as compared to another age group was significant for older adults only. However, when age-relevance was introduced in a context of equal importance to younger and older adults (information about vacations paired either with pictures of young or older adults), the memory bias for one's own age group was clearly present for both younger and older adults (Study 3). PMID- 21780990 TI - Using versions of the trail making test as alternate forms. AB - Alternate forms of neuropsychological instruments are often made parallel by developing tests with similar numbers of items, formats, and psychometric properties. The present study offers an alternative approach by examining three different trail-making tests that could potentially be used as alternate forms. Over a 3-week period, the Trail Making Test of the Delis-Kaplan Executive Functioning System (DK-TMT), Comprehensive Trail Making Test (CTMT), and Connections Task (CT) were individually administered to 154 undergraduate psychology students in each of six possible orders. Consistent with hypotheses, the three tests share the same underlying factors of sequencing and shifting as alternatives to one- and three-factor models; statistical evidence is provided to support that the two-factor solution is invariant regardless of test order. These findings support the notion that three different trail-making tests can be administered without discernable practice effects, increasing the flexibility of a serial neuropsychological assessment battery. PMID- 21780991 TI - The effect of prophylaxis on pediatric HIV costs. AB - The objective of this study was to determine and compare the cost to treat HIV(+) and HIV(-) pediatric patients both before and after HIV prophylaxis became the standard of care. Retrospective chart review of a pediatric HIV/AIDS specialty clinic's medical charts was conducted for clinical and healthcare utilization data on 125 children diagnosed from 1986 to 2007. Mean HIV-related costs were compared using bootstrapped t-tests for children born in the pre-prophylaxis (1979-1993) and prophylaxis eras (1994-2007). Patients were also stratified into two categories based on death during the follow-up period. Lastly, national cost savings were estimated using mean costs, national number of at-risk births, and national perinatal HIV transmission rates in each era. For HIV(+) children, mean annual per patient treatment cost was $15,067 (95% CI: $10,169-$19,965) in the pre-prophylaxis era (n = 40) and $14,959 (95% CI: $9140-$20,779) in the prophylaxis era (n = 14); difference not statistically significant (p > 0.05). For HIV(-) children, mean annual per patient treatment cost was $204 (95% CI: $219-$627) for the pre-prophylaxis era (n = 2) and $427 (95% CI: $277-$579) for the prophylaxis era (n = 69); difference statistically significant (p < 0.05). A projected cost-savings of $16-23 million annually in the USA was observed due to the adoption of prophylaxis treatment guidelines in pediatric HIV care. The prophylaxis era of pediatric HIV treatment has been successful in decreasing perinatal HIV transmission and mortality, as reflected by clinical trials and national cost-savings data, and emphasizes the value of the rapid adoption of evidence-based practice guidelines. PMID- 21780992 TI - Evidence for dissociable representations for body image and body schema from a patient with visual neglect. AB - The existence of independent and dissociable representations of the body within the brain for perception (body image) and action (body schema) is currently under debate. Although demonstrations in which fake limbs are incorporated into the body image but not body schema are commonplace, such findings can be explained due to the strength of the illusion rather than autonomous representations. The current study, however, offers striking evidence in favor of a clear dissociation in a patient with visual neglect, such that different fake limbs were incorporated into the body image and body schema simultaneously. PMID- 21780993 TI - HIV among out-of-school youth in Eastern and Southern Africa: a review. AB - The overall decline of the HIV epidemic in Sub-Saharan Africa conceals how the HIV burden has shifted to fall on areas that have been more difficult to reach. This review considers out-of-school youth, a category typically eluding interventions that are school-based. Our review of descriptive studies concentrates on the most affected region, Southern and Eastern Africa, and spans the period between 2000 and 2010. Among the relatively small but increasing number of studies, out-of-school youth was significantly associated with risky sexual behavior (RSB), more precisely with early sexual debut, high levels of partner concurrency, transactional sex, age-mixing, low sexually transmitted infection (STI)/HIV risk perception, a high lifetime number of partners, and inconsistent condom use. Being-in-school not only raises health literacy. The in school (e.g., age-near) sexual network may also be protective, an effect which the better-studied (and regionally less significant) variable of educational attainment cannot measure. To verify such double effect of being-in-school we need to complement the behavioral research of the past decade with longitudinal cohort analyses that map sexual networks, in various regions. PMID- 21780994 TI - Cerebral hemorrhage treated with NovoSeven in acute promyelocytic leukemia. PMID- 21780995 TI - Three different expression patterns of T-bet in angioimmunoblastic T-cell lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) exhibits a multifaceted clinical picture and distinct architectural patterns that correlate with disease progression and the number of neoplastic cells. In this study we investigated the expression of the transcription factor T-bet and correlated it with the architectural patterns in 29 cases of AITL. Double immunolabelings for T-bet, CD20, CD3 or PD1 revealed the following patterns: predominant T-bet expression by neoplastic T-cells (A), by aggregates of small B-cells (B) or by B-immunoblasts (C). The majority of cases of AITL pattern II showed a T-bet expression pattern B (6/8 cases), while the majority of those with pattern III exhibited the T-bet pattern A (11/21 cases). We propose that T-bet expression by B-cells represents a T-cell independent immune response trying to cope with opportunistic infections, while T-bet expression by neoplastic T-cells is linked to the introduction of a Th17 response responsible for the immunologic derangements characteristic of AITL. PMID- 21780996 TI - Therapeutic Toll-like receptor agonists directly influence mouse and human T cell lymphoma cell viability and cytokine secretion. PMID- 21780997 TI - Feasibility of autologous hematopoietic stem cell transplant in patients aged >=70 years with multiple myeloma. AB - Abstract We retrospectively analyzed the outcomes of all consecutive patients with myeloma (n = 84) aged >=70 years who had received autologous hematopoietic stem cell transplant (auto HCT) between July 1999 and June 2010 at our institution. The median age at auto HCT was 72 years, the median number of prior therapies was 2.5 and the median time from diagnosis to auto HCT was 10.2 months. The conditioning regimen consisted of melphalan at 140 mg/m(2) in 10%, 180 mg/m(2) in 25% and 200 mg/m(2) in 65% of patients. The day-100 non-relapse mortality was 3%. The overall response rate at day 100 was 85% (complete response 18%, very good partial response 12%, partial response 55%). After a median follow up of 25 months among surviving patients, the estimated progression-free survival and overall survival at 5 years were 27% and 67%, respectively. The incidence of grade II-IV toxicity, response rate and survival were similar across three melphalan dose levels. These results indicate that high-dose melphalan plus auto HCT is safe and feasible for patients with multiple myeloma aged >=70 years and age alone should not be an exclusion criterion for auto HCT. PMID- 21780998 TI - Clinicopathologic features and outcome of acute erythroid leukemia based on 2008 revised World Health Organization classification. AB - We report 67 patients with acute erythroid leukemia (erythroleukemia) based on the World Health Organization (WHO) 2008 classification. Reviewing the clinicopathologic features, cytogenetics and outcomes, the characteristics of erythroleukemia resembled myelodysplastic syndromes (MDS). Patients with poor performance status, advanced anemia and poor-risk cytogenetics had significantly inferior outcomes. The International Prognostic Scoring System (IPSS) for MDS is useful to differentiate the prognosis of erythroleukemia. PMID- 21781001 TI - Erratum. PMID- 21781000 TI - Enhanced brain responsiveness during active emotional face processing in obsessive compulsive disorder. AB - OBJECTIVES. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. METHODS. We assessed 21 OCD patients and 21 healthy controls with fMRI during an emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. RESULTS. OCD patients showed significantly greater activation of "face processing" regions including the amygdala, fusiform gyrus and dorsolateral prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected significant correlations between patients' clinical symptom severity and both task-related region activation and network functional connectivity. CONCLUSIONS. The results suggest that OCD patients may show enhanced brain responsiveness during emotional face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction. This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity. PMID- 21781002 TI - Clinical metabolomics and urinary NGAL for the early prediction of chronic kidney disease in healthy adults born ELBW. AB - BACKGROUND: Clinical metabolomics is a recent "omic" technology which is defined as a global holistic overview of the personal metabolic status (fingerprinting). This technique allows to prove metabolic differences in different groups of people with the opportunity to explore interactions such as genotype-phenotype and genotype-environment type, whether normal or pathological. AIM: To study chronic kidney injury 1) using urine metabolomic profiles of young adults born extremely low-birth weight (ELBW) and 2) correlating a biomarker of kidney injury, urinary neutrophil gelatinase-associated lipocalin (NGAL), in order to confirm the metabolomic injury profile. METHOD: Urine samples were collected from a group of 18 people (mean: 24-year-old, std: 4.27) who were born with ELBW and a group of 13 who were born at term appropriate for gestational age (AGA) as control (mean 25-year-old, std: 5.15). Urine samples were analyzed by (1)H nuclear magnetic resonance spectroscopy, and then submitted to unsupervised and supervised multivariate analysis. Urine NGAL (uNGAL) was measured using ARCHITECT (ABBOTT diagnostic NGAL kit). RESULTS: With a multivariate approach and using a supervised analysis method, PLS-DA, (partial least squares discriminant analysis) we could correlate ELBW metabolic profiles with uNGAL concentration. Conversely, uNGAL could not be correlated to AGA. CONCLUSIONS: This study demonstrates the relevance of the metabolomic technique as a predictive tool of the metabolic status of exELBW. This was confirmed by the use of uNGAL as a biomarker which may predict a subclinical pathological process in the kidney such as chronic kidney disease. PMID- 21781003 TI - Metabolomic analysis of bronchoalveolar lavage fluid in preterm infants complicated by respiratory distress syndrome: preliminary results. AB - OBJECTIVE: Metabolomics is a technique used to non-invasively determine a snapshot of the current metabolic status of an organism by analyzing intact tissue or bio-fluids. The aim of the present preliminary study was to analyze metabolic profiles in preterm infants complicated by respiratory distress syndrome (RDS) trough bronchoalveolar lavage fluid (BALF) measurement. METHODS: Twelve BALF samples collected at birth prior surfactant, post-surfactant during mechanical ventilation and at extubation time-points, were analyzed by proton nuclear magnetic resonance spectroscopy and Gas chromatography-Mass Spectrometry (GC-MS). RESULTS: GC-MS analysis identified 25 metabolites of whom 10 had a known molecular structure. They were: undecane, decanoic acid, dodecanoic acid, hexadecanoic acid, octadecanoic acid, hexadecanoic acid methyl ester, 9 octadecanoic acid, tetracosanoic acid, myristic acid, phosphate. These metabolites were over-expressed in BALF collected during mechanical ventilation after surfactant administration. CONCLUSIONS: The present preliminary data suggest that metabolic profile in BALF of RDS infants is becoming possible opening a new cue of metabolomics as promising tool in management of sick premature infants. PMID- 21781004 TI - Interleukin-6 reduces NMDA-induced Ca2+ overload via prevention of Ca2+ release from intracellular store. AB - A mechanism for neuroprotection of interleukin-6 (IL-6) via reduction of intracellular Ca2+ overload induced by N-methyl-D-aspartate (NMDA) was explored. Cerebellar granule neurons (CGNs) from postnatal 8-day infant rats were chronically exposed to IL-6 for 8 days. Confocal laser scanning microscope was used to measure dynamic changes of intracellular Ca2+ fluorescence intensity. NMDA triggered an acute and sustaining enhancement of intracellular Ca2+ fluorescence intensity in the cultured CGNs, whereas NMDA stimulation of the neurons that had been exposed to IL-6 reduced the intracellular Ca2+ fluorescence intensity relative to that of non-IL-6-pretreated neurons. Ethylene glycol bis(aminoethylether) tetraacetate (EGTA), a chelator of extracellular Ca2+, decreased the intracellular Ca2+ overload triggered by NMDA. The component of intracellular Ca2+ overload after EGTA treatment was prevented by IL-6 chronic exposure. Cotreatment with dantrolene sodium (DAN) and 2 aminoethoxydiphenylborate (2-APB), blockers of ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP3R), respectively, also decreased the intracellular Ca2+ overload triggered by NMDA. However, the component of intracellular Ca2+ overload after DAN and 2-APB treatment was only slightly but not significantly diminished by IL-6. These results suggest that IL-6 has a neuroprotective effect against NMDA-induced intracellular Ca2+ overload, and that the effect is implemented primarily via a suppression of Ca2+ release from the intracellular Ca2+ store. PMID- 21781005 TI - Effects of gamma radiation on fungi infected rice (in vitro). AB - PURPOSE: This work focuses on the effect of gamma radiation on seed born fungi (in vitro) on Oryza sativa (Swarna, Initial Evaluation Trial-5656). MATERIALS AND METHODS: The responses of fungi to gamma radiation (0-4.2 kGy; 0.12 kGy/h) were studied in individual cultures of major seed-borne fungi including Alternaria alternata, Aspergillus flavus, Trichoderma viride and Curvularia geniculata. RESULTS: The inactivation of individual fungal-viability was noted between 1.0 2.0 kGy for A. alternata and A. flavus and 0.5-1.0 kGy for T. viride and C. geniculata. Complete inhibition was observed at <2.5 kGy. Formations of multiple germ tubes were noted in A. alternata and A. flavus at 2 kGy and 2.5 kGy, respectively. A. flavus required a higher dose to reduce viability to 10% (D(10)) value in comparison to other selected fungi. CONCLUSIONS: Different fungi exhibited different radiosensitivity. The dose range of 2-2.5 kGy was effective in killing all selected fungi. The fungi showing a higher D(10) value exhibited multiple germ tubes. PMID- 21781006 TI - Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7. AB - Menaquinone-7 (MK-7) is part of a family of vitamin K that are essential co factors for the enzyme gamma-glutamyl carboxylase, which is involved in the activation of gamma-carboxy glutamate (Gla) proteins in the body. Gla proteins are important for normal blood coagulation and normality of bones and arteries. The objective of this study was to examine the potential toxicity of synthetic MK 7 in BomTac:NMRI mice and in Sprague-Dawley rats. In an acute oral toxicity test, mice were administered a single oral dose of 2000 mg/kg body weight (limit dose) and no toxicity was observed during the 14-day observation period. In the subchronic oral toxicity test in rats, animals were administered MK-7 for 90 days by gavage at the following doses: 0 (vehicle control, corn oil), 2.5, 5, and 10 mg/kg body weight/day. All generated data, including clinical observations, ophthalmology, clinical pathology, gross necropsy, and histopathology, revealed no compound-related toxicity in rats. Any statistically significant findings in clinical pathology parameters and/or organ weights noted were considered to be within normal biological variability. Therefore, under the conditions of this experiment, the median lethal dose (LD(50)) of MK-7 after a single oral administration in mice was determined to be greater than the limit dose level of 2000 mg/kg body weight. The no observed adverse effect level (NOAEL) of MK-7, when administered orally to rats for 90 days, was considered to be equal to 10 mg/kg body weight/day, the highest dose tested, based on lack of toxicity during the 90-day study period. PMID- 21781008 TI - Inhibition of cardiac oxidative and endoplasmic reticulum stress-mediated apoptosis by curcumin treatment contributes to protection against acute myocarditis. AB - Curcumin is used anecdotally as an herb in traditional Indian and Chinese medicine. In the present study, the effects and possible mechanism of curcumin in experimental autoimmune myocarditis (EAM) rats were further investigated. They were divided randomly into a treatment and vehicle group, and orally administrated curcumin (50 mg/kg/day) and 1% gum arabic, respectively, for 3 weeks after myosin injection. The results showed that curcumin significantly suppressed the myocardial protein expression of inducible nitric oxide synthase (iNOS) and the catalytic subunit of nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase. In addition, curcumin significantly decreased myocardial endoplasmic reticulum (ER) stress signaling proteins and improved cardiac function. Furthermore, curcumin significantly decreased the key regulators or inducers of apoptosis. In summary, our results indicate that curcumin has the potential to protect EAM by modulating cardiac oxidative and ER stress-mediated apoptosis, and provides a novel therapeutic strategy for autoimmune myocarditis. PMID- 21781007 TI - Lysosomal membrane permeabilization contributes to elemene emulsion-induced apoptosis in A549 cells. AB - Elemene is a broad-spectrum antitumor agent. In the present study, lysosomal membrane permeabilization (LMP) was detected after short elemene emulsion- exposure (12 h) that preceded a decrease of the mitochondrial membrane potential and DNA damage (24 h) in A549 cells. At later time points (36 h) elemene emulsion caused the appearance of A549 cells with apoptotic features, including apoptotic morphology, phosphatidylserine exposure, and caspase-3 activation. A significant increase in protein expression for cathepsin D was also observed utilizing Western blot analysis after exposure to elemene emulsion for 12 h. The present study showed that elemene emulsion induced the increased levels of reactive oxygen species (ROS) and depletion of glutathione (GSH) in A549 cells. Cells treated with pepstatin A, an inhibitor for cathepsin D, showed a significant inhibition in DNA damage, mitochondrial membrane permeabilization, caspase-3 activation, and phosphatidylserine exposure. These results demonstrated that apoptosis induced by elemene emulsion in A549 cells is mediated in part through LMP and lysosomal protease cathepsin D. PMID- 21781009 TI - Cellular uptake mechanisms and responses to NO transferred from mono- and poly-S nitrosated human serum albumin. AB - Endogenous S-nitrosated human serum albumin (E-Mono-SNO-HSA) is a large molecular weight nitric oxide (NO) carrier in human plasma, which has shown many beneficial effects in different animal models. To construct more efficient SNO-HSA preparations, SNO-HSA with many conjugated SNO groups has been prepared using chemical modification (CM-Poly-SNO-HSA). We have compared the properties of such a preparation to those of E-Mono-SNO-HSA. Cellular uptake of NO from E-Mono-SNO HSA partly takes place via low molecular weight thiol, and it results in cytoprotective effects by induction of heme oxygenase-1. By contrast, transfer of NO from CM-Poly-SNO-HSA into the cells is faster and more pronounced. The influx mainly takes place by cell-surface protein disulfide isomerase. The considerable NO inflow results in apoptotic cell death by ROS induction and caspase-3 activation. Thus, increasing the number of SNO groups on HSA does not simply intensify the cellular responses to the product but can also result in very different effects. PMID- 21781010 TI - Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: a case series and review. AB - Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer in the Caucasian population and its incidence is increasing worldwide. Although surgical procedures show a high cure rate with acceptable morbidity, non-surgical, pharmacotherapeutic approaches have been regarded as appropriate alternatives, and/or first-line treatments, in selected cases. Imiquimod (IQ) is a synthetic imidazoquinoline amine that locally enhances, through cytokine induction, both innate and acquired immune pathways, resulting in immunomodulating, antiviral and antitumor effects. Topical IQ 5% cream is approved by the FDA and the European Union for the treatment of small superficial BCCs (<2.0 cm); however, published data highlight the possibility of successful outcomes in larger lesions. We report three patients, each one presenting with a large BCC and successfully treated with IQ 5% cream. Although our cases and those from the literature do not rise to the level of evidence, IQ may be a reliable, efficacious and safe non surgical option for selected cases of large superficial BCCs. Histological examination should occur at baseline and at the end of treatment along with clinical and dermatoscopic examination at least monthly during the course of the treatment and every 6 months for 2 years following the treatment. PMID- 21781011 TI - Treatment of localized non-segmental vitiligo with intradermal 5-flurouracil injection combined with narrow-band ultraviolet B: a preliminary study. AB - BACKGROUND: Several treatment modalities had been used for the treatment of vitiligo but the optimal treatment has not yet been identified. AIM: To evaluate the efficacy and safety of intradermal injection of 5-flurouracil (5-FU) combined with narrow-band ultraviolet B (NB-UVB) as a treatment option for vitiligo. PATIENTS AND METHODS: The study included 60 vitiligo patients with overall symmetrical lesions affecting less than 30% of body surface area. For each patient, one side of the body was treated with NB-UVB alone (control side) while the other side was treated with NB-UVB therapy in addition to intradermal injection of 5-FU (50 mg/ml), 0.01-0.02 ml per injection with 1 cm apart in skin of vitiligo, every 2 weeks for 4 months. RESULTS: The overall repigmentation was significantly higher in the 5-FU side compared with control side in all body parts (p < 0.001) except for the acral lesions where the difference was not significant (p = 0.561). No systemic side effects of 5-FU were detected, and the majority of the patients reported pain during injections. CONCLUSIONS: Intradermal 5-FU injection in combination with NB-UVB could be considered as a simple, safe, tolerable and cheap technique for treatment of vitiligo. It shortens the duration of NB-UVB therapy and improves the outcome, repigmentation. Longer follow-up is needed. PMID- 21781012 TI - A comparative evaluation of combination therapy of fluconazole 1% and urea 40% compared with fluconazole 1% alone in a nail lacquer for treatment of onychomycosis: therapeutic trial. AB - This is a randomized, double-blind study enrolling 70 patients with onychomycosis of the finger and toenails. Clinical and mycological efficacies as well as measures of safety were assessed monthly for a maximum of 6 months of treatment. The treatment regimens were: fluconazole 1% and fluconazole 1% with urea 40%. These results indicated topical treatment of onychomycosis with a combination of fluconazole 1% and urea 40% was more effective (82.8%) than fluconazole 1% (62.8%) nail lacquer alone in treatment of dermatophytic onychomycosis. Fluconazole was well tolerated and side effects were negligible. At the end of therapy and the end of the 6-month follow-up, fluconazole 1% and urea 40% demonstrated statistically significant superiority in clinical and mycological responses compared with fluconazole 1% alone. PMID- 21781013 TI - A look into the future: improving diabetes care by 2015. AB - Insulin initiation, which was traditionally the province of specialists, is increasingly undertaken by primary care. However, significant barriers to appropriate and timely initiation still exist. Whilst insulin is recognized as providing the most effective treatment in type 2 diabetes, it is also widely considered to be the most challenging and time consuming. This editorial identifies that the organization of existing healthcare services, the challenges faced by patients, and the treatments themselves contribute to suboptimal insulin management. In order to improve future diabetes care, it will be necessary to address all three problem areas: (1) re-think the best use of existing human and financial resources to promote and support patient self-management and adherence to treatment; (2) empower patients to participate more actively in treatment decision making; and (3) improve acceptance, persistence and adherence to therapy by continuing to refine insulin therapy and treatment regimens in terms of safety, simplicity and convenience. The principles discussed are also applicable to the successful management of any chronic medical illness. PMID- 21781014 TI - In vitro disintegration studies of weekly generic and branded risedronate sodium formulations available in Canada. AB - OBJECTIVE: The aim of this study was to evaluate the in vitro disintegration of the five newly available Canadian generic risedronate 35 mg tablets compared to the innovator (branded) product, ACTONEL * *ACTONEL is a registered trade name of Warner Chilcott Company, LLC. (risedronate sodium) 35 mg. RESEARCH DESIGN AND METHODS: Tablets were inspected for colour and appearance. Disintegration times were determined using United States Pharmacopeia 33 (USP33-NF 28) methods. Disintegration onset time was also evaluated. RESULTS: The mean disintegration onset time values for the generic risedronate 35 mg tablets ranged from 2 to 29 seconds, and the mean disintegration completion times ranged from 81 to 260 seconds. The mean disintegration onset and completion time values for the ACTONEL 35 mg tablets were 23 and 43 seconds respectively. Four out of the five generic tablets tested had shorter disintegration onset times than the branded product; two of the generic tablet products had very fast disintegration onset times i.e. 2-3 seconds. Disintegration completion time for all five generic products tested was longer than that observed for the branded product; two generic products had disintegration completion time values five to six times longer than the branded product. CONCLUSIONS: Differences in the in vitro disintegration times were observed between the generic risedronate 35 mg tablets commercially available in Canada and the branded product, ACTONEL. The rapid disintegration onset times of two generic products may be important as this could increase the possibility of drug exposure in both the mouth and the esophagus during swallowing, resulting in unwanted localized irritation. However, it should be noted that an in vitro/in vivo correlation has not been established. Until such studies are completed it may be important to be aware of such in vitro disintegration differences when evaluating patients with newly presenting upper gastrointestinal complaints upon being switched from the branded product to generic formulations. PMID- 21781015 TI - The value to patients of reducing lesion severity in plaque psoriasis. AB - Plaque psoriasis is associated with significant psychosocial, quality-of-life, and economic burden. The objective of this study was to quantify the value to patients of reducing the severity and size of plaque psoriasis lesions. Subjects included individuals with a self-reported diagnosis of plaque psoriasis from a nationally representative US household panel. Subjects completed a web-based conjoint analysis survey and chose between hypothetical treatments in a series of questions. Each alternative was defined by lesion severity, percentage of body surface area (BSA) covered by lesions, type of treatment, injection discomfort or pain (if treatment included injections), risk of serious lung infection, and monthly out-of-pocket cost. 28,200 panelists were invited to participate. 18,330 responded, 503 qualified, and 419 completed the survey. Mean age was 54.5 years and 52% were female. 64% (35%) of patients reported psoriasis severity as mild or mild to moderate (moderate to very severe). Patients were willing to pay $486.73 out-of-pocket per month to eliminate severe lesions covering 25% BSA on the arms and legs and $444.80 out-of-pocket per month to eliminate moderate lesions covering 4% BSA on the face. Individuals with plaque psoriasis are willing to pay substantial amounts to reduce lesion severity and percentage of BSA covered by lesions. PMID- 21781016 TI - Impact of body mass index on retention rates of anti-TNF-alfa drugs in daily practice for psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease which often requires life-long treatment. OBJECTIVE/AIM: Our objective was to assess the role of the body mass index (BMI) on the retention rates of anti-TNF-alfa therapies in patients with moderate to severe plaque psoriasis. MATERIAL AND METHODS: Retrospective observational study of psoriasis patients included in local databases of three public Italian hospitals. All patients, who received anti-TNF alfa treatment in referral centers, were included. Only patients with at least 1 year follow-up were considered eligible. The outcome was the conservation of the treatment at 1 and 2 years of follow-up. RESULTS: 194 patients were enrolled. 307 treatment courses with a minimum follow-up of 12 months and 263 with a follow-up of 24 months were analyzed. The proportion of patients receiving the same treatment at months 12 and 24 was 67.43% and 42.21%, respectively. The proportion steadily decreased with increased values of BMI. CONCLUSIONS: The overall efficacy of TNF-alfa inhibitors diminishes with time. The BMI affects the long term survival rate of anti-TNF-alfa in psoriatic patients. A high BMI can be considered a potential predictor of drug discontinuation. PMID- 21781017 TI - Regulation of small GTPases at epithelial cell-cell junctions. AB - Small GTPases of the Rho family (RhoA, Rac1, and Cdc42) and the Ras family GTPase Rap1 are essential for the assembly and function of epithelial cell-cell junctions. Through their downstream effectors, small GTPases modulate junction formation and stability, primarily by orchestrating the polymerization and contractility of the actomyosin cytoskeleton. The major upstream regulators of small GTPases are guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Several GEFs and a few GAPs have been localized at epithelial junctions, and bind to specific junctional proteins. Thus, junctional proteins can regulate small GTPases at junctions, through their interactions with GEFs and GAPs. Here we review the current knowledge about the mechanisms of regulation of small GTPases by junctional proteins. Understanding these mechanisms will help to clarify at the molecular level how small GTPases control the morphogenesis and physiology of epithelial tissues, and how they are disregulated in disease. PMID- 21781018 TI - Human primary bronchial epithelial cells respond differently to titanium dioxide nanoparticles than the lung epithelial cell lines A549 and BEAS-2B. AB - We have compared the cellular uptake and responses of five preparations of nanocrystalline titanium dioxide (TiO(2)) between normal human bronchial epithelial (NHBE) cells and epithelial cell lines (A549 and BEAS-2B). The P25 nanoparticles, containing both anatase and rutile modifications, induced reactive oxygen species (ROS) and secretion of the neutrophil chemoattractant IL-8 in all three cell types used. Pure anatase and rutile particles provoked differential IL 8 response in A549 and no response in BEAS-2B cells despite similar formation of ROS. The pure TiO(2) modifications also provoked release of the inflammatory mediators: IL-6, G-CSF and VEGF, in NHBE cells but not in the two cell lines. We conclude that the responsiveness of lung epithelial cells is strongly dependent on both the physicochemical properties of TiO(2) nanoparticles and the type of responder cells. The differential pro-inflammatory responsiveness of primary lung epithelial cells compared with immortalized cell lines should be considered in the assessment of adverse reactions to inhaled nanoparticles. PMID- 21781019 TI - Immobilization of silver in polypropylene membrane for anti-biofouling performance. AB - In this study, a method was developed to immobilize silver onto polypropylene (PP) membrane surfaces for improved anti-biofouling performance. A commercial PP membrane was first grafted with the thiol functional groups, and then silver ions were immobilized onto the PP membrane surface through coordinating with the thiol groups. The immobilized silver was found to be very stable, with only ~1.1% of the immobilized silver being leached out during a leaching test. The surface of the modified membrane (PPS-Ag) was examined with ATR-FTIR and XPS analysis, which verified the successful grafting of the thiol groups and the coordination of silver ions on the membrane surface. The surface properties of the membrane were also characterized by SEM, AFM and water contact angle measurements. The PPS-Ag membrane was found to have a smoother and more hydrophilic surface than the PP membrane. Both Gram-negative bacteria, Escherichia coli, and Gram-positive bacteria, Staphylococcus aureus, were used to evaluate the antibacterial and anti biofouling performance of the PPS-Ag membrane. From disk diffusion experiments, the PPS-Ag membrane exhibited the capability of inhibiting the growth of both the Gram-negative and Gram-positive bacteria tested. The anti-biofouling performance of the membrane was assessed by immersion in a mixed suspension of E. coli and S. aureus and filtration tests. The PPS-Ag membrane showed a stable and significantly enhanced anti-biofouling performance as compared with the PP membrane. The results in this study demonstrate that biofouling of a PP membrane can be sufficiently overcome through immobilizing silver onto the membrane surface. PMID- 21781020 TI - The prevalence and correlations of medical student burnout in the pre-clinical years: a cross-sectional study. AB - Burnout is a psychological syndrome of emotional exhaustion, depersonalization, and impaired personal accomplishment induced by repeated workplace stressors. Current research suggests that physician burnout may have its origins in medical school. The consequences of medical student burnout include both personal and professional distress, loss of empathy, and poor health. We hypothesized that burnout occurs prior to the initiation of the clinical years of medical education. This was a cross-sectional survey administered to third-year medical students at the Mount Sinai School of Medicine (MSSM) in New York, New York (a traditional-style medical school with a marked division between pre-clinical and clinical training occurring at the beginning of the third year). Survey included an instrument used to measure job burnout, a sleep deprivation screen, and questions related to demographic information, current rotation, psychiatric history, time spent working/studying, participation in extracurricular activities, social support network, autonomy and isolation. Of the 86 medical students who participated, 71% met criteria for burnout. Burnt out students were significantly more likely to suffer from sleep deprivation (p = 0.0359). They were also more likely to disagree with the following statements: "I have control over my daily schedule" (p = 0.0286) and "I am confident that I will have the knowledge and skills necessary to become an intern when I graduate" (p = 0.0263). Our findings show that burnout is present at the beginning of the third year of medical school, prior to the initiation of the clinical years of medical training. Medical student burnout is quite common, and early efforts should be made to empower medical students to both build the knowledge and skills necessary to become capable physicians, as well as withstand the emotional, mental, and physical challenges inherent to medical school. PMID- 21781021 TI - Physical activity, social support, and depression: possible independent and indirect associations in persons with multiple sclerosis. AB - The present study examined the pattern of associations among physical activity, social support, mobility disability, perceived stress, and depressive symptoms in relapsing-remitting MS (RRMS). Persons (N = 218) with RRMS completed a battery of questionnaires that was sent and returned through the United States Postal Service (USPS). Bivariate correlation analysis indicated that physical activity and social support were both inversely associated with depressive symptoms (r's = -0.288 and -0.386, p <= 0.05, respectively). Multiple linear regression analysis indicated that physical activity (beta = -0.21, p = 0.002) and social support (beta = -0.37, p = 0.0001) were independently associated with depressive symptoms. Path analysis confirmed that the associations between physical activity and social support with depressive symptoms were indirect via mobility disability and perceived stress. Collectively, the evidence indicates that physical activity and social support are independently and indirectly associated with depression via mobility disability and perceived stress in relapsing-remitting MS. This supports the design of interventions and programs that target physical activity and social support for reducing depressive symptoms among persons with MS. PMID- 21781022 TI - Chitooligosaccharides decreases plasma lipid levels in healthy men. AB - Chitosan, which is derived from chitin, has drawn much attention due to its low toxicity and potential use in medical and pharmaceutical applications. The biological activities of chitosan have been shown to depend on its molecular weight (MW) and degree of deacetylation. In this study, we investigated whether oral chitooligosaccharides, which are easily absorbed into the body, can reduce the plasma level of lipid in smokers and non-smokers because smoking is a high risk factor for cardiovascular diseases. All healthy men (11 smokers and 8 non smokers) consumed 500 mg of chitooligosaccharides in water twice daily before a meal (breakfast and dinner) over a 6-week period. Total cholesterol and low density lipoprotein cholesterol levels were significantly decreased in both the smoker group and non-smoker group when compared with baseline. These results suggest that low MW chitooligosaccharides would be an effective dietary supplement for lowering cholesterol level. PMID- 21781023 TI - The effects of a plant proteinase inhibitor from Enterolobium contortisiliquum on human tumor cell lines. AB - Supplementary to the efficient inhibition of trypsin, chymotrypsin, plasma kallikrein, and plasmin already described by the EcTI inhibitor from Enterolobium contortisiliquum, it also blocks human neutrophil elastase (K(iapp)=4.3 nM) and prevents phorbol ester (PMA)-stimulated activation of matrix metalloproteinase (MMP)-2 probably via interference with membrane-type 1 (MT1)-MMP. Moreover, plasminogen-induced activation of proMMP-9 and processing of active MMP-2 was also inhibited. Furthermore, the effect of EcTI on the human cancer cell lines HCT116 and HT29 (colorectal), SkBr-3 and MCF-7 (breast), K562 and THP-1 (leukemia), as well as on human primary fibroblasts and human mesenchymal stem cells (hMSCs) was studied. EcTI inhibited in a concentration range of 1.0-2.5 MUM rather specifically tumor cell viability without targeting primary fibroblasts and hMSCs. Taken together, our data indicate that the polyspecific proteinase inhibitor EcTI prevents proMMP activation and is cytotoxic against tumor cells without affecting normal tissue remodeling fibroblasts or regenerative hMSCs being an important tool in the studies of tumor cell development and dissemination. PMID- 21781024 TI - New antimicrobial frontiers. AB - New antimicrobials able to counteract bacterial resistance are needed to maintain the control of infectious diseases. The last 40 years have seen the systematic tailoring and refinement of previously identified antibiotics, to produce a multitude of semi-synthetic derivatives that share their mechanism of action with the original molecules. The major limit of this approach is the emergence of multi- and cross-resistant bacterial strains, favoured by the selective pressure inherent to the targeting of specific enzymes. The most promising new strategies aim to the development of molecules that, targeting essential bacterial structures instead of specific enzymatic activities, achieve infection control without enforcing a selective pressure on bacteria. This review, based on the consultation of the up-to-date literature, deals with antimicrobial peptides and some antivirulence factors. PMID- 21781025 TI - Recent progress in the development of natural ent-kaurane diterpenoids with anti tumor activity. AB - The ent-kaurane diterpenoids are widely distributed in China, some of which have high natural abundance in plants of Isodon, Pteris, Gnaphalium, Diplospora, Croton and some other species. These compounds exhibit significant anti-tumor, antibacterial and anti-inflammatory activities, which have attracted the attention of medicinal chemists. This review focuses on the recent advances in the research of derivatives, anti-tumor activity, mechanism of action, and structure-activity relationships of ent-kaurane diterpenoids. All of these will show the potential in the development of new antitumor agents in natural products. PMID- 21781026 TI - Recent advances in semisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: an update (2008 2010). AB - Podophyllotoxin, one of the well-known naturally occurring aryltetralin lignans, has been used as the lead-compound for the preparation of potent anticancer agents, such as etoposide, teniposide, and etopophos. In our previous review, we described the advances of podophyllotoxin derivatives from 2003 and 2007. In recent years, an increased number of interesting research work has been carried out on the podophyllotoxins. As a continuation, the present review summarizes and highlights the update advances of podophyllotoxin derivatives from 2008 and 2010 in regard to semisynthesis, biosynthesis, biological activities, mode of action and structure-biological activity relationship. PMID- 21781027 TI - Polymer membrane and cell models for drug discovery. AB - This paper reviews the functional polymer membrane and membrane based cell drug evaluation models for drug discovery. Based on the characteristics of biological membranes in vivo, chemical modification methods of synthetic membrane, including blending and surface modification are explored to mitigate the membrane fouling and improve biocompatibility. Different membrane-based cell models used in drug investigation and related trouble shooting are analyzed in detail. Specific attention is given to the current studies on ADME/Tox of drugs using membrane based in vitro models of cells including Caco-2, hepatocytes or renal cells, which can be used to evaluate the feasibility of polymer membrane in drug investigation. The progress toward solving present bottlenecks of the facilitated cell models are supposed to provide great benefits to drug discovery in pharmaceutical industry. PMID- 21781028 TI - Microarray-based technology for glycomics analysis. AB - In the post-genomic era, glycomics (the functional study of carbohydrates in living organisms) has come into the forefront of biological research because the interactions of glycoconjugates with proteins not only occur widely in biological processes of cells but also initiate infection of host cells by bacteria and viruses. Microarrays have been reportedly successful in carbohydrate-protein interaction as well as cellular surface glycan profiling. This review provides an overview of recent progress in the development of microarray-based techniques for glycomic studies. The fabrication, application and challenge/bottleneck of glycan/lectin microarrays have been summarized and discussed. PMID- 21781030 TI - Reflecting on stem cell differentiation. BioSpotlight. PMID- 21781032 TI - Profile of Robert Clarke. Interviewed by Kristie Nybo, Ph.D. PMID- 21781034 TI - A STED-y route to commercialization. PMID- 21781037 TI - Beyond ancient microbial DNA: nonnucleotidic biomolecules for paleomicrobiology. AB - Identifying the causes of past epidemics depends on the specific detection of pathogens in buried individuals; this field of research is known as paleomicrobiology, an emerging field that has benefited from technological advances in microbiology. For almost 15 years, the detection, identification, and characterization of microbes in ancient environmental and human specimens emerged on the basis of ancient DNA (aDNA) analyses. aDNA limitations due to potential contamination by modern DNA and altered aDNA led to the development of alternative methods for the detection and characterization of nonnucleotidic biomolecules, including mycolic acids (of ancient mycobacteria) and proteins. Accordingly, immunohistochemistry, immunochromatography, and enzyme-linked immunosorbent assay techniques have been developed for the specific detection of microbes from ancient human and environmental specimens. Protein analysis by mass spectrometry, a standard for ancient animal identification, has also recently emerged as a technique for ancient mycobacteria detection, while immuno-PCR is yet another promising technique. As with aDNA, strict protocols must be enforced to ensure authenticity of the data. Here we review the analysis of nonnucleotidic biomolecules from ancient microbes and the ability of these analyses to complement aDNA analyses, which opens new opportunities for identification of ancient microbes as well as new avenues to potentially resolve controversies regarding the cause of some historical pandemics and study the coevolution of microbes and hosts. PMID- 21781038 TI - Label-free detection of surface markers on stem cells by oblique-incidence reflectivity difference microscopy. AB - Conventional fluorescence microscopy is routinely used to detect cell surface markers through fluorophore-conjugated antibodies. However, fluorophore conjugation of antibodies alters binding properties such as strength and specificity of the antibody in often uncharacterized ways. Here we present a method using an oblique-incidence reflectivity difference (OI-RD) microscope for label-free, real-time detection of cell surface markers, and apply it to analysis of stage-specific embryonic antigen 1 (SSEA1) on stem cells. Mouse stem cells express SSEA1 on their surfaces, and the level of SSEA1 decreases when the cells start to differentiate. In this study, we immobilized mouse stem cells and non stem cells (control) on a glass surface as a microarray and reacted the cell microarray with unlabeled SSEA1 antibodies. By monitoring the reaction with an OI RD microscope in real time, we confirmed that the SSEA1 antibodies bind only to the surface of the stem cells and not to the surface of non-stem cells. From the binding curves, we determined the equilibrium dissociation constant (Kd) of the antibody with the SSEA1 markers on the stem cell surface. Thus, the OI-RD microscope can be used to detect binding affinities between cell surface markers and unlabeled antibodies bound to the cells; this information could be useful for determination of stem cell stages. PMID- 21781039 TI - Thickness profiling of formaldehyde-fixed cells by transmission-through-dye microscopy. AB - Conventional light microscopy techniques are poorly suited for imaging the vertical cell dimension. This can be accomplished using transmission-through-dye (TTD) imaging, in which cell thickness is directly converted into image intensity in the presence of extracellular dye with strong absorption. We have previously described applications of TTD to living cells using the dye Acid Blue 9 (AB9) to generate contrast. In this work, we investigated the possibility of extending TTD to chemically fixed cells. This would depend on preservation of cell impermeability to the dye; by using a method based on fluorescence quenching, we found that formaldehyde-fixed cells remain impermeable to AB9. Fixation enables imaging of cell surfaces in the presence of high concentrations of AB9, bringing the vertical resolution to several nanometers per pixel; that is at least an order of magnitude better than resolution achievable with live cells. TTD images collected with high-NA objectives are often contaminated by Becke lines resulting from intracellular organelles, and we show how to distinguish them from features on the cell surface. Quantification of cell thickness and volume on fixed cells is also possible during the early stages of fixation; this can be useful, for example, for measuring volume kinetics following rapid introduction of a stimulus. PMID- 21781040 TI - Chemically-induced affinity star restriction specificity: a novel TspGWI/sinefungin endonuclease with theoretical 3-bp cleavage frequency. AB - The type IIS/IIC restriction endonuclease TspGWI recognizes the sequence 5'-ACGGA 3', cleaving DNA 11/9 nucleotides downstream. Here we show that sinefungin, a cofactor analog of S-adenosyl methionine, induces a unique type of relaxation in DNA recognition specificity. In the presence of sinefungin, TspGWI recognizes and cleaves at least 12 degenerate variants of the original recognition sequence that vary by single base pair changes from the original 5-bp restriction site with only a single degeneracy per variant appearing to be allowed. In addition, sinefungin was found to have a stimulatory effect on cleavage at these nondegenerate TspGWI recognition sites, irrespective of their number or the DNA topology. Interestingly, no fixed "core" could be identified among the new recognition sequences. Theoretically, TspGWI cleaves DNA every 1024 bp, while sinefungin-induced activity cleaves every 78.8 bp, corresponding to a putative 3 bp long recognition site. Thus, the combination of sinefungin and TspGWI represents a novel frequent cutter, next only to CviJI/CviJI*, that should prove useful in DNA cloning methodologies. PMID- 21781041 TI - Nonradioactive method to detect native single-stranded G-tails on yeast telomeres using a modified Southern blot protocol. AB - Because of their low abundance and short length, telomeric single-stranded extensions have not traditionally been assessed by Southern blot analysis. Instead, most methods have relied on hybridizing radioactively labeled oligonucleotide probes to electrophoresed DNA within agarose gels. Here we describe a rapid and nonradioactive Southern blot-derived method to transfer and detect telomeric single-stranded G-rich overhangs (G-tails) under nondenaturing (native) conditions, using Saccharomyces cerevisiae DNA. Restriction enzyme digested chromosomal DNA is separated by agarose gel electrophoresis, transferred onto a charged membrane by electroblotting under nondenaturing conditions, and probed with a digoxigenin (DIG)-labeled oligonucleotide. Compared with the prolonged film exposure required to detect radioactive probes, detection of short single-strand G-tails with this method takes mere minutes. Furthermore, following detection of the single-stranded G-tails, the DNA on the membrane can be denatured and reprobed using conventional hybridization and detection methods. PMID- 21781042 TI - YGFP: a spectral variant of GFP. AB - We describe YGFP, a slow bleaching green fluorescent protein (GFP) with unique spectral properties. YGFP is derived from an Escherichia coli codon-optimized synthetic gfp mutant 2 derivative. In addition to the GFP-mut 2 changes, it also carries S202F and T203I substitutions. YGFP can be used as a substitute for yellow fluorescent protein (YFP) in experiments in which two or more fluorescent proteins are fused to different cellular protein components, expanding the ability to study multiple labeled proteins in a cell at once. PMID- 21781043 TI - Arsenic poisoning. PMID- 21781046 TI - Profile of Larry J. Young. Shaping the social brain. Interview by Kristie Nybo. PMID- 21781048 TI - Copy number variants: mapping the genome's 'land mines'. PMID- 21781049 TI - Cloning: enzyme quality. PMID- 21781050 TI - Portable magnetic tweezers device enables visualization of the three-dimensional microscale deformation of soft biological materials. AB - We have designed and built a magnetic tweezers device that enables the application of calibrated stresses to soft materials while simultaneously measuring their microscale deformation using confocal microscopy. Unlike previous magnetic tweezers designs, our device is entirely portable, allowing easy use on microscopes in core imaging facilities or in collaborators' laboratories. The imaging capabilities of the microscope are unimpaired, enabling the 3-D structures of fluorescently labeled materials to be precisely determined under applied load. With this device, we can apply a large range of forces (~1-1200 pN) over micron-scale contact areas to beads that are either embedded within 3-D matrices or attached to the surface of thin slab gels. To demonstrate the usefulness of this instrument, we have studied two important and biologically relevant materials: polyacrylamide-based hydrogel films typical of those used in cell traction force microscopy, and reconstituted networks of microtubules, essential cytoskeletal filaments. PMID- 21781051 TI - High-content imaging of neutral lipid droplets with 1,6-diphenylhexatriene. AB - Neutral lipid droplets (LDs) are dynamic lipid storage organelles found in all eukaryotic cells from yeast to mammals and higher plants. LDs are important to many physiological processes that include basic cellular maintenance, metabolism, and diverse medical pathologies. LD accumulation has been studied extensively by a range of methods, but particularly by microscopy with several fluorescent dyes extensively used for qualitative and quantitative imaging. Here, we compared established LD stains Nile Red and BODIPY 493/503 to the 4', 6-diamidino-2 phenylindole (DAPI)-range dye 1,6-diphenyl-1,3,5-hexatriene (DPH; excitation/emission lambdamax=350 nm/420 nm) using high-content image analysis. HeLa cells treated with oleic acid or vehicle were used to compare staining patterns between DPH and Nile Red as well as DPH and the LD protein adipophilin. DPH, Nile Red, and BODIPY 493/503 were compared as assay reagents in oleic acid dose-response experiments. Treatment of MCF-7 cells with sodium butyrate was used as a second cellular system for high-content analysis of LD formation. In this experimental context, we demonstrate the compatibility of DPH with GFP, a technical limitation of Nile Red and BODIPY 493/503 dyes. These data show that DPH has comparable sensitivity and specificity to that of Nile Red. Z'-factor analysis of dose-response experiments indicated that DPH and BODIPY 493/503 are well suited for quantitative analysis of LDs for high-throughput screening (HTS) applications. PMID- 21781052 TI - A fluorescent GTP analog as a specific, high-precision label of microtubules. AB - Fluorescent imaging of cytoskeletal structures permits studies of both organization within the cell and dynamic reorganization of the cytoskeleton itself. Traditional fluorescent labels of microtubules, part of the cytoskeleton, have been used to study microtubule localization, structure, and dynamics, both in vivo and in vitro. However, shortcomings of existing labels make imaging of microtubules with high precision light microscopy difficult. In this paper, we report a new fluorescent labeling technique for microtubules, which involves a GTP analog modified with a bright, organic fluorophore (TAMRA, Cy3, or Cy5). This fluorescent GTP binds to a specific site, the exchangeable site, on tubulin in solution with a dissociation constant of 1.0+/-0.4 uM. Furthermore, the label becomes permanently incorporated into the microtubule lattice once tubulin polymerizes. We show that this label is usable as a single molecule fluorescence probe with nanometer precision and expect it to be useful for modern subdiffraction optical microscopy of microtubules and the cytoskeleton. PMID- 21781053 TI - TLM-Converter: reorganization of long time-lapse microscopy datasets for downstream image analysis. AB - Automated microscopy enables in vivo studies in developmental biology over long periods of time. Time-lapse recordings in three or more dimensions to study the dynamics of developmental processes can produce huge data sets that extend into the terabyte range. However, depending on the available computational resources and software design, downstream processing of very large image data sets can become highly inefficient, if not impossible. To address the lack of available open source and commercial software tools to efficiently reorganize time-lapse data on a desktop computer with limited system resources, we developed TLM Converter. The software either fragments oversized files or concatenates multiple files representing single time frames and saves the output files in open standard formats. Our application is undemanding on system resources as it does not require the whole data set to be loaded into the system memory. We tested our tool on time-lapse data sets of live Drosophila specimens recorded by laser scanning confocal microscopy. Image data reorganization dramatically enhances the productivity of time-lapse data processing and allows the use of downstream image analysis software that is unable to handle large data sets of >=2 GB. In addition, saving the outputs in open standard image file formats enables data sharing between independently developed software tools. PMID- 21781054 TI - Self-assembly cloning: a rapid construction method for recombinant molecules from multiple fragments. AB - Enzyme-free cloning (EFC) can rapidly produce an in-frame fusion gene with multiple fragments. To practically apply EFC, we investigated the extent and sequence of complementary staggered overhangs necessary to direct self-assembly of multiple fragments as well as a size limitation of the constructed DNA molecule. Six-base pair overhangs with 50% GC content were sufficient to direct self-assembly. A functional plasmid that exceeded 10 kb, which includes an in frame fusion domain, was efficiently constructed from four PCR fragments in one step by our improved method. PMID- 21781055 TI - Zeocin for selection of bleMX6 resistance in fission yeast. AB - Complementation of auxotrophic nutrient deficiencies in minimal media is widely used for selection of exogenous gene introduction to fission yeast. However, only a limited number of such selection markers are available. Antibiotic resistance markers are good alternatives, but they typically work well in complete rich medium but not in minimal defined Edinburgh minimal medium (EMM). It would be ideal if both the auxotrophic and antibiotic resistance markers can be used together for molecular genetic analysis. Here we describe the use of Zeocin in Pombe minimal glutamate (PMG) media for selection and maintenance of bleMX6 resistance with a LEU2 auxotrophic marker in fission yeast. PMID- 21781056 TI - Intrathecal levels of vitamin D and IgG in multiple sclerosis. AB - BACKGROUND: Intrathecal synthesis of IgG is a hallmark of multiple sclerosis (MS). Vitamin D may modulate B-cell function and dampen the synthesis of IgG. OBJECTIVE: To investigate the relation between vitamin D levels in cerebrospinal fluid and serum and intrathecal synthesis of IgG. METHODS: 25-hydroxyvitamin D (25(OH)D) and IgG were assessed in cerebrospinal fluid and serum in 40 patients with MS. RESULTS: There was no significant correlation between the IgG index and 25(OH)D levels in cerebrospinal fluid or serum. The levels of 25(OH)D in cerebrospinal fluid and serum did not differ between patients with and without intrathecal synthesis of IgG. There was a non-significant trend towards a positive correlation between the concentrations of 25(OH)D and IgG in the cerebrospinal fluid, but not in serum. CONCLUSION: Physiological variation in vitamin D does not exert a major impact on intrathecal synthesis of IgG in MS. PMID- 21781057 TI - Correlation between crossed cerebellar diaschisis and clinical neurological scales. AB - BACKGROUND: A common consequence of unilateral stroke is crossed cerebellar diaschisis (CCD), a decrease in regional blood flow (CBF) and metabolism (CMRglu) in the cerebellar hemisphere contralateral to the affected cerebral hemisphere. Former studies indicated a post-stroke time-dependent relationship between the degree of CCD and the clinical status of acute and sub-acute stroke patients, but no study has been performed in post-stroke patients. OBJECTIVES: The objective of this investigation was to evaluate the quantitative correlation between the degree of CCD and the values of clinical stroke scales in post-stroke patients. MATERIALS AND METHODS: We measured with positron emission tomography (PET) regional CBF and CMRglu values in the affected cortical regions and the contralateral cerebellum in ten ischaemic post-stroke patients. Based on these quantitative parameters, the degree of diaschisis (DoD) was calculated, and the DoD values were correlated with three clinical stroke scales [Barthel Index, Orgogozo Scale and Scandinavian Neurological Scale (SNS)]. RESULTS: There were significant linear correlations between all clinical stroke scales and the CCD values (Barthel Index and Orgogozo Scale: P < 0.001, for both CBF and CMRglu; SNS: P = 0.007 and P = 0.044; CBF and CMRglu, respectively). CONCLUSIONS: The findings indicate that DoD can be used as a quantitative indicator of the functional impairments following stroke, i.e. it can serve as a potential surrogate of the severity of the damage. PMID- 21781058 TI - Paraneoplastic autoimmune multiorgan syndrome: 20 years after. AB - The purpose of this review is to provide insight and clarification in the quandary of classification and delineate clinical and histological features and pathophysiology of paraneoplastic pemphigus. This is a paraneoplastic disease of epithelial autoimmunity and adhesion originally described by Dr. Anhalt in 1990. Paraneoplastic pemphigus represents only one manifestation of the heterogeneous autoimmune syndrome in which patients, in addition to small airways occlusion, may display a spectrum of at least five clinical variants of the mucocutaneous disease [i.e. pemphigus-like, pemphigoid-like, erythema multiforme-like, graft versus-host disease-like, and lichen planus-like, termed paraneoplastic autoimmune multiorgan syndrome (PAMS)]. There is a need for the expanded, inclusive classification of diverse mucocutaneous and respiratory presentations of PAMS. Multiple specific effectors of humoral and cellular autoimmunity mediating epithelial damage have been identified. An update of advances in clinical and basic research on PAMS and in management and overall prognosis of PAMS is provided. PMID- 21781059 TI - Human T-lymphotropic virus 1 (HTLV-1) infection--dermatological implications. AB - Human T-lymphotropic virus type 1 (HTLV-1) is a type C retrovirus primarily endemic to Japan, Central and South America, the Middle East, regions of Africa, and the Caribbean. Currently, an estimated 10-20 million people worldwide are infected with this virus. Although the majority of infected individuals remain asymptomatic, HTLV-1 is the causative agent of a number of disorders, notably adult T-cell leukemia/lymphoma (ATLL) and a progressive demyelinating neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to ATLL and HAM/TSP, HTLV-1 has been associated with a spectrum of skin disorders, such as infective dermatitis associated with HTLV-1, crusted scabies, and leprosy. The understanding of the interaction between virus and host response has improved markedly, but there are still few treatment options. PMID- 21781060 TI - Floppy tumor on the shoulder. PMID- 21781061 TI - Toe-tip purpura. PMID- 21781062 TI - The incidence of leukotrichia in segmental vitiligo: implication of poor response to medical treatment. AB - BACKGROUND: In vitiligo, the melanocyte of the hair follicle is one of the major sources for repigmentation. Segmental vitiligo seems to be often associated with white hairs. However, in the case of small vellus hairs, it is often difficult or impossible to detect hair color. Thus, the real incidence of leukotrichia in segmental vitiligo has not been known. MATERIALS AND METHODS: In this study, we investigated the existence of white hairs in the lesional skin of 82 patients with segmental vitiligo. When it was difficult to detect hair color with the naked eye or a magnifier, a digital microscope with 30* magnification was used. RESULTS: Interestingly, all 82 patients showed leukotrichia in segmental vitiligo independent of age and disease duration. Some patients had more than 90% white hairs in the lesional skin, and they showed poor response to medical treatment. CONCLUSIONS: Based on our results, a very high percentage of patients with segmental vitiligo may be associated with leukotrichia. Many white hairs in segmental vitiligo may contribute to the lack of response with medical treatment. The examination of hair color with a digital microscope may be very useful for the prediction of treatment outcome and decision of treatment modalities. PMID- 21781063 TI - Photoprotection against the UVB-induced oxidative stress and epidermal damage in mice using leaves of three different varieties of Lepidium meyenii (maca). AB - BACKGROUND: Skin exposure to ultraviolet (UV) B radiation leads to epidermal damage and generation of reactive oxygen species. The photoprotective effect of extracts of three varieties of leaves (red, yellow, and black) from maca (Lepidium meyenii), a plant from the Peruvian highlands, was assessed in mouse skin exposed to UVB radiation. MATERIALS AND METHODS: The hydroalcoholic extracts of three varieties of maca leaves were applied topically to the dorsal skin of young-adult male mice prior to exposition to UVB radiation. RESULTS: The three varieties had UVA/UVB absorptive properties and presented antioxidant activity, being highest with red maca, followed by black and yellow maca. The three varieties of maca leaves prevented the development of sunburn cells, epidermal hyperplasia, leukocytic infiltration, and other alterations produced by UVB radiation. Mice treated with black maca showed the highest superoxide dismutase levels, and mice treated with black and yellow maca showed higher catalase levels in skin, whereas red maca protected the skin and liver against significant increases in the lipid peroxidation activity observed in the unprotected animals. CONCLUSION: The presence of significant antioxidant activity and the inhibition of lipid peroxidation suggest that the observed protection could be partly attributable to this mechanism. PMID- 21781064 TI - Spectrum of autoimmune blistering dermatoses in Tunisia: an 11-year study and a review of the literature. AB - BACKGROUND: Autoimmune bullous dermatoses (ABD) are a rare but significant group of cutaneous disorders posing great diagnostic and therapeutic challenges to the treating dermatologist. Few surveys have been carried out to describe the whole spectrum of ABD in a region. OBJECTIVE: To determine the clinicoepidemiological features of various ABD. METHODS: We retrospectively recruited all ABD cases seen during an 11-year period (1997-2007). RESULTS: One hundred and seventy-four patients were involved (16.3 cases/year). Pemphigus was observed to be the most common ABD (53%), with the majority being pemphigus vulgaris (61%) vs. 36% of pemphigus foliaceus (Tunisian pemphigus). DISCUSSION: Most epidemiological surveys have focused on a single or just one group of ABD. In our series, pemphigus foliaceus was relatively more prevalent than in occidental data. The frequencies of subepidermal immunobullous dermatoses in our study were in agreement with those in the literature. PMID- 21781065 TI - Dermoscopic evaluation of erythema associated with pressure ulcers. AB - OBJECTIVE: To assess dermoscopic findings of "non-blanchable erythema" in stage I pressure ulcers and to determine their characteristics. METHODS: Dermoscopic examinations using DermLite((r)) II pro of redness over a bony prominence that did not resolve within 30min of pressure relief or if a positional change was impossible for three days. RESULTS: Characteristic dermoscopic findings of redness in stage I pressure ulcers included petechial dots and telangiectatic streaks while other discolorations disappeared by diascopy. These dermoscopic features were seen in 9 of 10 cases. In one case, purpura that persisted under dermoscope compression was observed. Likewise, petechial dots and telangiectatic streaks were detected in three cases with redness surrounding stage II pressure ulcers. CONCLUSION: The "non-blanchable erythema" in pressure ulcers consists of petechial dots, telangiectatic streaks and purpura that persist after compression by the dermoscope and these characteristics are helpful for dermoscopically diagnosing pressure ulcers. PMID- 21781066 TI - CD26/dipeptidyl-peptidase IV and adenosine deaminase serum levels in psoriatic patients treated with cyclosporine, etanercept, and psoralen plus ultraviolet A phototherapy. AB - OBJECTIVE: The aim of this study is to determine serum levels of soluble forms of CD26/dipeptidyl-peptidase IV (DPP-IV) and adenosine deaminase (ADA), thought to be markers of T-cell activation, and changes in their levels in response to cyclosporine, etanercept, and psoralen plus ultraviolet A (PUVA) treatments with respect to disease activity. METHODS: This study is designed as a prospective clinical study with a control group and three months of follow-up. The study included 41 patients with psoriasis and 41 healthy controls that were older than 18years of age. There were three different treatment groups: PUVA (n=15), cyclosporine (n=15), and etanercept (n=11). To determine disease severity of patients with psoriasis, psoriasis area and severity index (PASI) scores were calculated. RESULTS: Only mean serum ADA levels were different between patients with psoriasis [mean1+/-standard deviation (SD)=13.9+/-3.3U/ml] and control group (mean+/-SD=12+/-3.5U/ml). Mean serum ADA levels were significantly higher before treatment than after treatment (mean+/-SD=12.4+/-3.4U/ml). Contrarily, following three months of therapy, mean serum CD26 levels increased significantly from 777.7+/-214.6 to 835.3+/-203ng/ml (P<0.05) and mean serum DPP-IV activity increased significantly from 12.1+/-4 to 15.9+/-4.2nmol/min (P<0.05). There was no correlation between ADA and CD 26/DPP-IV with PASI values. CONCLUSIONS: The results show that ADA might be a useful marker indicating disease activity and T cell activation. As significant changes were observed in serum CD26/DPP-IV before and after treatment, we think CD26/DPP-IV might play a role in psoriasis pathogenesis, which should be clarified by further studies. PMID- 21781068 TI - Sensitive skin in the American population: prevalence, clinical data, and role of the dermatologist. AB - INTRODUCTION: Sensitive skin is a complex dermatological condition, defined by abnormal sensory symptoms. The aim of this epidemiological survey was to assess the prevalence of sensitive skin and collect data on sensitive skin in the US population. METHODS: A phone survey was conducted in the USA by a poll institute in 2007. A sample was drawn from a representative national cohort of the American population at least 18years of age through the quota method. Data on demographic characteristics, environmental and climatic factors, skin characteristics, dermatological disorders, cosmetics use, and visits to the dermatologist were collected. RESULTS: Of 994 subjects who answered (495 men and 499 women), 44.6% declared having "sensitive" or "very sensitive" skin. Women were more concerned than men (50.9% vs. 38.2%, P<0.0001). There was no significant difference related to geographic localization, age, or ethnic distribution. Subjects with sensitive skin had mainly dry (34.5%) or mixed skin (35.7%), fair phototypes, dermatological disorders, higher skin reactivity to cosmetics and various environmental factors in comparison with subjects who stated having only a "slightly" sensitive or not sensitive skin. The dermatologist had a strong influence on subjects with "sensitive" or "very sensitive" skin through the prescription of skin care products. CONCLUSION: This study, based on a representative sample of the American population, reveals a high prevalence of sensitive skin in the USA. Sensitive skin is mainly associated with dry skin, fair phototype, reactivity to climatic and environmental factors, and cosmetics. American dermatologists seem largely involved in the care of this condition. PMID- 21781067 TI - Greater expression of TC21/R-ras2 in highly aggressive malignant skin cancer. AB - BACKGROUND: TC21 plays an important role in highly aggressive tumor formation, and it was overexpressed in several human cancers, including breast cancer, oral squamous cell carcinoma (SCC), and esophageal SCC. In light of this, we explored the expression of TC21 in overall skin cancers in order to evaluate the relationship between TC21 and malignant skin tumors. METHODS: We examined six normal skin tissues and 18 malignant skin tumor tissues, including six malignant melanomas (MM), six SCCs, and six basal cell carcinomas (BCCs) using western blotting for the expression of TC21. In another set, 16 specimens of MM, 16 SCC, and 16 BCC were analyzed for the expression of TC21 using immunohistochemical staining. To evaluate the amount of expression of TC21, the Raytest TINA software was used for western blotting and a histochemical score (HSCORE) was used for immunohistochemical evaluation. RESULTS: The western blotting and immunohistochemistry showed that TC21 was expressed in all malignant skin tumors and not in normal skin tissues. The relative protein expression was an average of 0.004 in normal skin, 1.042 in MM, 0.621 in SCC, and 0.485 in BCC. In immunohistochemistry, HSCORE for normal skin was an average of 0.05, MM was 2.42, SCC was 2.11, and BCC was 1.22. CONCLUSIONS: This article is the first study demonstrating expression of TC21 in human skin malignant tumors and suggests that TC21 is more expressed in highly aggressive skin tumors. PMID- 21781069 TI - Birt-Hogg-Dube syndrome in a patient with localized fibrofolliculomas and a novel mutation in the FLCN gene. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is characterized by skin fibrofolliculomas (FF), multiple lung cysts, spontaneous pneumothorax, and renal cancer. Cutaneous lesions are usually distributed over the face, neck, and upper trunk. The presence of FF confined to a circumscribed region of the skin has rarely been reported. CASE REPORT: A 64-year-old woman presented with a 20-year history of asymptomatic skin lesions located on the neck. Multiple skin-colored papules with a clinical plaque-like appearance were confined to the right side of the neck. Histopathological findings were typical for FF, and BHDS was suspected. The novel heterozygous mutation p.Val126SerfsX4 was identified in exon 5 of the FLCN gene. Colonoscopy, abdominal ultrasound, and abdominal thoracic scan revealed no associated pathologies, except for benign renal and hepatic cysts. DISCUSSION: To date, only two cases of localized FF in BHDS have been reported. Mutation analysis was not performed, but the authors considered the lesions to represent a localized variant of BHDS and speculated that this unusual form of the disease may be associated with a lack of visceral involvement as no signs of systemic disease were detected. CONCLUSIONS: We identified the novel germline mutation p.Vall26SerfsX4 as responsible for this aspect of the patient's phenotype, which suggests that alterations in the FLCN gene are also responsible for localized forms of BHDS. Moreover, the localized distribution of skin lesions may be related to a less severe form of the disease. PMID- 21781070 TI - Lipoid proteinosis in two families. PMID- 21781071 TI - Botulinum toxin historical aspects: from food poisoning to pharmaceutical. AB - BACKGROUND: In the history of medicine, unexpected coincidences indicated the development of new treatment options. OBJECTIVE: One of the most peculiar ones concerns the finding of botulinum toxin, and this should be familiar to physicians using the drug. METHODS: A survey through the history of the "fat poison" has been performed. RESULT: A poison turned to one of the most popular drugs in aesthetic medicine. CONCLUSION: Depending on the dose, a substance may be poisonous or not. PMID- 21781072 TI - Chromoblastomycosis: a clinical and molecular study of 18 cases in Rio de Janeiro, Brazil. AB - BACKGROUND: Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis caused by dematiaceous fungi. METHODS: We described epidemiological data, clinical presentation, and treatment of 18 cases of CBM diagnosed in Rio de Janeiro, Brazil. Diagnosis was obtained by mycological, histopathological findings demonstrating typical muriform cells with confirmation of isolated by DNA sequencing of the ribosomal internal transcribed spacer. RESULTS: The majority of patients were male (72.2%) ranging from 39 to 83 years old, farm laborers and construction workers. The duration of disease varied from four months to 32 years. The most common presentations were verrucous form in ten (55.6%) patients, followed by tumoral in three (16.7%) patients, primarily of moderate (55.6%) and severe (38.9%) intensity. Lower (44.4%) and upper limbs (33.3%) were the most affected sites. Fonsecaea pedrosoi isolated from 14 (77.8%), and Cladophialophora carrionii isolated from one case (5.6%). Fifteen patients (83.3%) were treated. Six patients (40%) received oral itraconazole 200-400 mg/day, five patients (33.3%) received oral itraconazole 200-400 mg/day combined with fluconazole 200 mg/day, and four (26.7%) patients were submitted to surgery. The duration of therapy varied from 12 to 48 months. Cure rate was 80% (12/15). No relapse was observed after two years of follow-up. CONCLUSIONS: Success was due to attending a center with specialized clinical care, laboratory support, and pharmaceutical care. PMID- 21781073 TI - The protective melanocytic nevus sign: a new finding. PMID- 21781074 TI - A case of extensive erosive and bullous erythema elevatum diutinum in a patient diagnosed with human immunodeficiency virus (HIV). PMID- 21781075 TI - A novel finding in atopic dermatitis: film-producing Staphylococcus epidermidis as an etiology. PMID- 21781076 TI - Phacomatosis pigmentokeratotica associated with compound melanocytic nevus of the conjunctiva. PMID- 21781077 TI - Etanercept therapy in a hepatitis B virus (HBV)-positive psoriatic patient developing a monoclonal gammopathy of undetermined significance. PMID- 21781078 TI - Long-term follow-up of metil aminolevulinate (MAL)-PDT in difficult-to-treat cutaneous Bowen's disease. AB - Bowen's disease (BD) is a form of intraepidermal squamous cell carcinoma, which is clinically characterized by gradually enlarging, well-demarcated erythematous plaques with irregular borders and surface crusting or scaling, affecting primarily the elderly. BD often presents with lesions difficult to treat with standard therapy as surgery, cryosurgery, or 5-fluorouracil (5-FU) for the risk of significantly poor cosmetic outcome, failure rate, and adverse events, related mainly to the age of the patients. Topical PDT with methyl aminolevulinate (MAL) represents a valid and approved therapy for BD lesions in many cases, especially for lesions located at poor healing sites or for large patches of disease, due to its high efficacy coupled with good tolerability and tissue-sparing attitude. In this study, we sought to investigate the efficacy, safety, and cosmetic outcome of MAL-PDT in a series of patients with BD lesions which were challenging to treat for clinical, surgical, and patient-related reasons, such as size of the lesion, difficult surgical approach for anatomical sites, or age of patients and request of the best cosmetic result. We also performed a long-term follow-up to assess recurrence rates and eventual late-onset adverse events. PMID- 21781079 TI - Effectiveness of medium-dose ultraviolet A1 phototherapy in localized scleroderma. AB - BACKGROUND: Recently, ultraviolet (UV) A1 phototherapy has been suggested as an effective treatment for localized scleroderma (LS); however, the optimal dose of UVA1 still has not been determined. OBJECTIVE: We aimed to evaluate the therapeutic effectiveness of medium-dose (30 J/cm(2) ) UVA1 phototherapy and to show that 13MHz ultrasound is a valuable tool for assessing the results of UVA1 phototherapy in LS. METHODS: Thirty-five patients with LS were treated with medium-dose (30J/cm(2) ) UVA1. In total, 30-45 treatments and 900-1350J/cm(2) cumulative UVA1 doses were evaluated by clinical scoring in all patients. In 14 patients, skin thickness was also determined by 13MHz ultrasound examination. RESULTS: In all patients, medium-dose UVA1 therapy softened sclerotic plaques, and marked clinical improvement was observed in 29 of 35 (82. 85%) patients. Ultrasound measurements showed that skin thickness was significantly reduced. No side effects were observed during or after treatment. CONCLUSION: Medium-dose UVA1 phototherapy is a highly effective, safe, and well-tolerated therapeutic modality for treatment of all types of LS. A 13MHz ultrasound probe may be used for evaluating UVA1 phototherapy results. PMID- 21781080 TI - The impact of stratifying initial dose of corticosteroids by severity of pemphigus vulgaris on long-term disease severity. AB - BACKGROUND: Pemphigus vulgaris (PV) is a life-threatening disease affecting skin and mucous membranes. The "epitope spreading" theory posits that uncontrolled PV can gradually worsen because of exposure of cellular antigens to the immune system. To this end, high-dose systemic corticosteroids have been advocated as first-line treatment for patients with PV to achieve disease control. OBJECTIVE: To determine whether the initial dose of prednisone stratified by disease severity affects long-term disease severity. METHODS: A retrospective study was conducted on 58 patients with PV with at least five years of follow-up from diagnosis. Patients were categorized into three groups according to the initial dose of prednisone treatment. Parameters analyzed included age, gender, disease severity at baseline and follow-up, hospitalizations, prednisone doses and adjuvant therapy at follow-up, and remission rate. RESULTS: Ten patients received initial low-dose prednisone or were treated initially without systemic CS, 19 patients received intermediate-dose prednisone, and 29 received high-dose prednisone. Disease severity at presentation correlated directly with initial prednisone doses. The duration of the first hospitalization and number of hospitalization days during the five-year follow-up period were significantly lower in the group treated with initial low-dose prednisone and similar for the groups treated with intermediate and high doses. CONCLUSIONS: Disease severity of PV at presentation is a good predictor of the clinical course. Stratifying initial prednisone dose according to PV disease severity at presentation is appropriate. PMID- 21781081 TI - Successful treatment of Rowell syndrome using oral cyclosporine A. AB - BACKGROUND: To present and discuss successful treatment of Rowell syndrome with low dose orally administered cyclosporine in a male patient with refractory course of disease. METHODS: A 63-year-old male patient presented with a five-week history of widespread, severely pruritic erythematous skin changes that were first seen on the back. Within a few weeks, skin rashes extended to the whole body recessing the face. Because treatment with topical and orally administered corticosteroids was ineffective, we began an immunosuppressive therapy using cyclosporine. Treatment was initiated with an orally administered dosage of 100mg/day and subsequent dose reduction to 50mg/day after 14 days. RESULT: After four weeks of treatment, all clinical signs were resolved; only postinflammatory hyperpigmentation persisted for several weeks. Treatment-related side effects included arterial hypertension that could be controlled with antihypertensive drugs. CONCLUSION: Primarily described in 1963, Rowell syndrome represents the combination of cutaneous lupus erythematosus and erythema multiforme in a single individual. Controversial discussion concerning the genuine character of the disease is still going on, and even the existence of this entity remains unclear. Several therapeutic regimes are known, including corticosteroids, methotrexate, or dapsone. To the best of our knowledge, this is the first report of successful treatment of Rowell syndrome with low doses of cyclosporine. Orally administered low-dose cyclosporine seems to be a potent alternative treatment option for patients with Rowell syndrome refractory to standard therapies. PMID- 21781082 TI - Use of frozen poloxamer as a base for Itchy skin conditions, including irritant contact dermatitis. PMID- 21781083 TI - Simultaneous diagnosis of mycosis fungoides and dermatofibrosarcoma protuberans in a young patient: is it just a coincidence? PMID- 21781084 TI - An unusual case of cutaneous hyaline-vascular Castleman's disease with multicentric involvement and systemic symptoms. PMID- 21781085 TI - Acquired eruptive vellus hair cysts. PMID- 21781086 TI - Serum level of sCD30 molecule but not sCD30L in patients with psoriasis is reduced by Goeckerman's therapy. PMID- 21781092 TI - Aquifer recharge and recovery: groundwater recharge systems for treatment, storage, and water reclamation. PMID- 21781093 TI - Distribution, organization and innervation of gastric MALT in conventional piglet. AB - Mucosa-associated lymphoid tissue (MALT) is the initial inductive site for mucosal immunity. It is present in the different layers of the mucosal wall and consists of organized lymphoid tissue which may occur as isolated or aggregated lymphoid follicles (LFs) and interfollicular areas. It is present in many organs, including the pig stomach. Gastric MALT has been intensely studied in experimentally infected pigs but few data are available in healthy, non gnotobiotic or germ-free animals. In the present study we described the gastric MALT in conventional piglets in the cardiac mucosa of the gastric diverticulum, in the pyloric mucosa, and in the sites of transition from cardiac to oxyntic and from cardiac to pyloric mucosa by means of histological and immunohistochemical stains. The majority of LFs were located in the cardiac mucosa and in the transition from the cardiac to the oxyntic mucosa. Here the LFs were mainly located in the submucosa and reached the mucosa; we called these submucosal lymphoid follicles (SLFs). In the pyloric mucosa and in the transition sites from the cardiac to the pyloric mucosa, LFs were located in the mucosa; we called these mucosal lymphoid follicles (MLFs). In SLFs, a compartmental organization of T and B lymphocytes was present; by contrast, in the MLFs, the T and B cells were intermingled, suggesting the possibility of different roles for the two types of follicles. In the epithelium overlying the lymphoid tissue, numerous T lymphocytes and some cells immunoreactive to cytokeratin-18 were observed. Following the application of the fluorescent tracer DiI into the SLFs of the diverticulum, enteric neurones located in the submucosal plexus were labelled, confirming the interplay between the immune and the enteric nervous system. PMID- 21781094 TI - Autonomic-somatic communications in the human pelvis: computer-assisted anatomic dissection in male and female fetuses. AB - Sphincter continence and sexual function require co-ordinated activity of autonomic and somatic neural pathways, which communicate at several levels in the human pelvis. However, classical dissection approaches are only of limited value for the determination and examination of thin nerve fibres belonging to autonomic supralevator and somatic infralevator pathways. In this study, we aimed to identify the location and nature of communications between these two pathways by combining specific neuronal immunohistochemical staining and three-dimensional reconstruction imaging. We studied 14 normal human fetal pelvic specimens (seven male and seven female, 15-31 weeks' gestation) by three-dimensional computer assisted anatomic dissection (CAAD) with neural, nitrergic and myelin sheath markers. We determined the precise location and distribution of both the supra- and infralevator neural pathways, for which we provide a three-dimensional presentation. We found that the two pathways crossed each other distally in an X shaped area in two spatial planes. They yielded dual innervation to five targets: the anal sphincter, levator ani muscles, urethral sphincter, corpus spongiosum and perineal muscles, and corpora cavernosa. The two pathways communicated at three levels: proximal supralevator, intermediary intralevator and distal infralevator. The dorsal penis/clitoris nerve (DN) had segmental nitrergic activity. The proximal DN was nNOS-negative, whereas the distal DN was nNOS positive. Distal communication was found to involve interaction of the autonomic nitrergic cavernous nerves with somatic nitrergic branches of the DN, with nitrergic activity carried in the distal part of the nerve. In conclusion, the pelvic structures responsible for sphincter continence and sexual function receive dual innervation from the autonomic supralevator and the somatic infralevator pathways. These two pathways displayed proximal, intermediate and distal communication. The distal communication between the CN and branches of the DN extended nitrergic activity to the distal part of the cavernous bodies in fetuses of both sexes. These structures are important for erectile function, and care should therefore be taken to conserve this communication during reconstructive surgery. PMID- 21781095 TI - Molecular phylogeny of the subfamily Amphistichinae (Teleostei: Embiotocidae) reveals parallel divergent evolution of red pigmentation in two rapidly evolving lineages of sand-dwelling surfperch. AB - Pigment evolution was reconstructed in the subfamily Amphistichinae, a six species clade of the surfperches, family Embiotocidae. Assignment was confirmed for all species within the subfamily, but low levels of differentiation were found among species within the subfamily, suggesting a recent radiation. The new phylogeny differs from previous hypotheses by the placement of the spotfin surfperch Hyperprosopon anale at the base of the subfamily, while still preserving the calico surfperch Amphistichus koelzi and the redtailed surfperch Amphistichus rhodoterus as sister species. Phenotypically, A. rhodoterus, A. koelzi and the silver surfperch Hyperprosopon ellipticum express high levels of red pigmentation. The barred surfperch, Amphistichus argenteus and the walleye surfperch Hyperprosopon argenteum express little to no red pigment, while basal H. anale expresses an intermediate amount of red pigment. Red pigmentation is proposed to have experienced parallel divergent evolution in each genus within the subfamily. PMID- 21781096 TI - Effects of immunostimulants on ranched southern bluefin tuna Thunnus maccoyii: immune response, health and performance. AB - Ranched southern bluefin tuna Thunnus maccoyii were fed baitfishes supplemented with vitamins (predominantly E and C) or vitamins and immunostimulants, nucleotides and beta-glucans, over 12 weeks after transfer and monitored for enhancement in immune response, health and performance through their 19 week grow out period. Fish from two different tows were sampled separately at three different sampling points: at transfer to grow-out pontoons, at 8 weeks post transfer and at harvest, 19 weeks post-transfer. Lysozyme activity was enhanced during vitamin supplementation compared to control fish. Performance (i.e. survival, condition index and crude fat), health (i.e. blood plasma variables including pH, osmolality, cortisol, lactate and glucose) and alternative complement activity were not commonly improved through diet supplementation. There were some tow-specific improvements in performance through vitamin supplementation including survival, selected parasite prevalence and intensity, and alternative complement activity. Immunostimulant supplementation also showed a tow-specific improvement in plasma cortisol level. Tow-specific responses may suggest that life history, previous health condition and husbandry can affect the success of vitamin and immunostimulant enhancement of immune response, health and performance of ranched T. maccoyii. PMID- 21781097 TI - Feeding ecology of early marine phase Atlantic salmon Salmo salar post-smolts. AB - Dietary analyses of Atlantic salmon Salmo salar post-smolt stomachs collected from 2001 to 2005 in Penobscot Bay, Maine, U.S.A., have yielded insights into the feeding ecology of early marine phase post-smolts from different rearing origins. Most stomachs contained only one or two prey types, suggesting active prey selection. Post-smolts that lived in the river longer (i.e. from naturally reared and parr-stocked origins) were smaller and consumed more fishes than invertebrates compared to larger post-smolts that emigrated immediately post stocking (i.e. from smolt-stocked origins). Naturally reared S. salar consumed c. 84% fishes and 16% crustaceans and parr-stocked S. salar consumed 64% fishes and 34% crustaceans. Stocked smolts consumed 48% fishes and 40% crustaceans. Differences in the type and quantity of consumed prey may be indicative of behavioural differences among rearing origins that influence post-smolt survival. PMID- 21781098 TI - Surface trawl survey for U.S. origin Atlantic salmon Salmo salar. AB - A surface trawl survey (2001-2005) in Penobscot Bay, Maine, U.S.A., and the nearshore Gulf of Maine waters was conducted to investigate early marine dynamics of a hatchery-dependent Atlantic salmon Salmo salar population from a severely modified river system. Data generated were used to evaluate the effect of stocking location and time on migration success and to describe the migratory pathways and environments that post-smolts traverse. Significant differences in early migration success were detected among different stocking groups, but subsequent marine survival was independent of stocking group. While the post smolt population was primarily composed of hatchery origin smolt-stocked fish, other life-stage stocking strategies (i.e. parr stocking) represented a higher proportion of the population than previously assumed. Catch distribution suggests evidence of an initial marine migratory pathway out of the dynamic Penobscot Bay environment. The hypothesized benefits of a predator refuge based on the co occurring species complex is considered minimal for emigrating post-smolts given a mismatch in the size overlap among species and low abundance of other co occurring diadromous populations. These data can be used to modify current management actions to optimize S. salar recovery and inform future research agendas. PMID- 21781099 TI - Chimaera opalescens n. sp., a new chimaeroid (Chondrichthyes: Holocephali) from the north-eastern Atlantic Ocean. AB - A new species of chimaeroid, Chimaera opalescens n. sp., was described from 31 type specimens caught in the north-eastern Atlantic Ocean at 950-1400 m depth. This species differed from all its congeners by the combination of the following characters: body uniformly pale brown to bronze, iridescent on fresh specimens; unpaired fins brown to purple, uniformly coloured or with pale or whitish edges; iris black; claspers tripartite and divided for a third of their length, not extending beyond the pelvic fins in adults; dorsal spine equal to or shorter than first dorsal fin; ventral caudal lobe equal to or deeper than dorsal caudal lobe. Comparison of DNA sequences of the CO1 gene with those of related species supported C. opalescens n. sp. as a distinct species. Specimens of C. opalescens n. sp. were previously misidentified as Chimaera monstrosa, a species sharing a similar geographical distribution. Chimaera opalescens n. sp. lives in deeper water and is a larger-bodied species than C. monstrosa. The two species were newly exploited by deep-sea fisheries and confused under a single landing name. PMID- 21781100 TI - A new endemic cyprinid species from the Danube drainage. AB - Populations of endemic Croatian dace were found to belong to two different species, one of which is first described in this study. Telestes karsticus sp. nov. differed morphologically from Telestes polylepis in the total count of lateral line scales, number of gill rakers and the shape of the posterior margin of the anal fin. Morphological differences were corroborated with mtDNA analyses (with p-distance between T. polylepis and T. karsticus sp. nov. ranging between 3.2 and 4.1%; and the number of substitutions between 37 and 47). The newly described species is geographically very localized. It has been recorded from only four localities around Velika Kapela and Mala Kapela mountains in Croatia. PMID- 21781101 TI - The interactions of abiotic and biotic factors influencing perch Perca fluviatilis and roach Rutilus rutilus populations in small acidified boreal lakes. AB - Four small, acidified boreal lakes, all sustaining populations of perch Perca fluviatilis, roach Rutilus rutilus and pike Esox lucius, were studied in four successive years. Three lakes were moderately acidified (mean pH of 5.61-5.83), while the fourth was more acidic (mean pH of 5.16) and had a sparse population of R. rutilus. Perca fluviatilis density was higher in this lake (1004 ha(-1)) than in the other three (355-717 ha(-1)), where R. rutilus dominated in terms of numbers (981-2185 ha(-1)). Large, potentially predatory, P. fluviatilis were most abundant in the lake with clearest water, and these seemed to have a negative effect on P. fluviatilis density. Perca fluviatilis mean mass was negatively correlated with R. rutilus biomass and was highest in the most acidic lake with the sparse R. rutilus and the highest P. fluviatilis density. Perca fluviatilis mass correlated positively with pH in two lakes (with the highest fish biomass), suggesting that low pH affected P. fluviatilis mass negatively. Perca fluviatilis growth correlated positively with summer (July to August) air temperature in the lake with sparse R. rutilus, thus differing from P. fluviatilis and R. rutilus growth in the other three lakes. The mean age of P. fluviatilis was generally lower than that of R. rutilus and was lowest in the two lakes with the highest fish biomass, indicating that adult mortality was affected by density-induced factors. PMID- 21781102 TI - Temporal changes in blood variables during final maturation and senescence in male sockeye salmon Oncorhynchus nerka: reduced osmoregulatory ability can predict mortality. AB - This study is the first to characterize temporal changes in blood chemistry of individuals from one population of male sockeye salmon Oncorhynchus nerka during the final 6 weeks of sexual maturation and senescence in the freshwater stage of their spawning migration. Fish that died before the start of their historic mean spawning period (c. 5 November) were characterized by a 20-40% decrease in plasma osmolality, chloride and sodium, probably representing a complete loss of osmoregulatory ability. As fish became moribund, they were further characterized by elevated levels of plasma cortisol, lactate and potassium. Regressions between time to death and plasma chloride (8 October: P < 0.001; 15 October: P < 0.001) indicate that plasma chloride was a strong predictor of longevity in O. nerka. That major plasma ion levels started to decline 2-10 days (mean of 6 days) before fish became moribund, and before other stress, metabolic or reproductive hormone variables started to change, suggests that a dysfunctional osmoregulatory system may initiate rapid senescence and influence other physiological changes (i.e. elevated stress and collapsed reproductive hormones) which occur as O. nerka die on spawning grounds. PMID- 21781103 TI - Factors influencing infection patterns of trophically transmitted parasites among a fish community: host diet, host-parasite compatibility or both? AB - Parasite infection patterns were compared with the occurrence of their intermediate hosts in the diet of nine sympatric fish species in a New Zealand lake. Stomach contents and infection levels of three gastrointestinal helminth species were examined from the entire fish community. The results highlighted some links between fish host diet and the flow of trophically transmitted helminths. Stomach contents indicated that all but one fish species were exposed to these helminths through their diet. Host feeding behaviour best explained infection patterns of the trematode Coitocaecum parvum among the fish community. Infection levels of the nematode Hedruris spinigera and the acanthocephalan Acanthocephalus galaxii, however, were not correlated with host diets. Host specificity is thus likely to modulate parasite infection patterns. The data indicate that host diet and host-parasite compatibility both contribute to the distribution of helminths in the fish community. Furthermore, the relative influence of encounter (trophic interactions between prey and predator hosts) and compatibility (host suitability) filters on infection levels appeared to vary between host-parasite species associations. Therefore, understanding parasite infection patterns and their potential impacts on fish communities requires determining the relative roles of encounter and compatibility filters within and across all potential host-parasite associations. PMID- 21781104 TI - Molecular cloning and expression analysis of heat-shock protein 70 in orange spotted grouper Epinephelus coioides following heat shock and Vibrio alginolyticus challenge. AB - In this study, the complementary (c)DNA encoding heat-shock protein 70 (Hsp70) of orange-spotted grouper Epinephelus coioides (OsgHsp70) was cloned. OsgHsp70 was 2206 bp and encoded 652 amino acids with predicted molecular mass of 70.89 kDa and theoretical isoelectric point of 5.48. Three Hsp70 family signatures, bipartite nuclear localization signal sequence (NLS) and cytoplasmic characteristic motif (EEVD) were observed in the OsgHsp70, which shared high similarity in amino-acid sequences with the Hsp70 gene of other vertebrates. The results indicated that the OsgHsp70 is a member of the heat-shock protein 70 family. The Hsp70 messenger (m)RNA expressions were quantified by real-time PCR following heat shock, bacterial infection and immunization with formalin-killed Vibrio alginolyticus, a kind of bacterial pathogen that causes septicaemia. Hsp70 mRNA expression in gill, kidney, spleen, thymus gland, muscle and total-blood samples increased at first and then decreased gradually following heat shock. A similar time-dependent pattern was observed following V. alginolyticus pathogen challenge, in which Hsp70 mRNA expression peaked at 24 h after live bacterial infection and 3 days after dead bacterial vaccination. The results indicated that the Hsp70 gene was inducible and involved in the fish immune response. PMID- 21781105 TI - Water chemistry and its effects on the physiology and survival of Atlantic salmon Salmo salar smolts. AB - The physiological effects of episodic pH fluctuations on Atlantic salmon Salmo salar smolts in eastern Maine, U.S.A., were investigated. During this study, S. salar smolts were exposed to ambient stream-water chemistry conditions at nine sites in four catchments for 3 and 6 day intervals during the spring S. salar smolt migration period. Plasma chloride, plasma glucose, gill aluminium and gill Na(+)- and K(+)-ATPase levels in S. salar smolts were assessed in relation to ambient stream-water chemistry during this migration period. Changes in both plasma chloride and plasma glucose levels of S. salar smolts were strongly correlated with stream pH, and S. salar smolt mortality occurred in one study site with ambient stream pH between 5.6 and 5.8 during the study period. The findings from this study suggest that physiological effects on S. salar smolts are strongly correlated with stream pH and that in rivers and streams with low dissolved organic carbon (DOC) concentrations the threshold for physiological effects and mortality probably occurs at a higher pH and shorter exposure period than in rivers with higher DOC. Additionally, whenever an acidification event in which pH drops below 5.9 coincides with S. salar smolt migration in eastern Maine rivers, there is potential for a significant reduction in plasma ions of S. salar smolts. PMID- 21781106 TI - Home range use and movement patterns of the yellow moray eel Gymnothorax prasinus. AB - This study investigated the movement patterns of yellow moray eels Gymnothorax prasinus using acoustic telemetry. Gymnothorax prasinus were found to use multiple sites within a localized area or home range. PMID- 21781107 TI - The feeding response of Pseudophycas barbata to multisensory prey cues in a low light environment. AB - The nocturnal southern bastard cod Pseudophycis barbata was found to utilize chemo- and mechanosensory systems when hunting for prey under low light conditions. The sensory system used depended on whether prey produced a hydrodynamic signal. PMID- 21781108 TI - Behavioural responses of prey fishes to habitat complexity and predation risk induce bias in minnow trap catches. AB - The effects of predation risk and habitat complexity on the efficiency of minnow traps to catch northern redbelly dace Chrosomus eos in laboratory experiments were investigated. Trap efficiency significantly decreased in the presence of vegetation and predators. These results suggest that the various antipredator behaviours used by prey fishes can affect trap efficiency. PMID- 21781109 TI - Euthanization methods influence cytokine mRNA expression levels in age 0 year Oncorhynchus mykiss. AB - Significant differences in cytokine transcription were found between Oncorhynchus mykiss euthanized using the pharmacological agents MS-222 v. benzocaine and also when contrasting death induced by carbon dioxide asphyxiation v. physical methods (cervical dislocation). This study highlights the need to consider the potentially confounding effect of euthanization method on gene expression data. PMID- 21781110 TI - New records of coastal fishes in the northern Rio de Janeiro State, Brazil, with comments on the biogeography of the south-western Atlantic Ocean. AB - The distribution limits in the Atlantic of Callorhinchus callorynchus (Callorhinchidae) and Odontesthes argentinensis (Atherinopsidae) are extended northwards to 22 degrees 22' S and 22 degrees 31' S, respectively, whereas that of Lile piquitinga (Clupeidae) is extended southwards to 22 degrees 22' S. Their occurrence in the north of Rio de Janeiro State is discussed. Remarks on the osteology of O. argentinensis, and morphometric and meristic data of L. piquitinga, are also provided. PMID- 21781114 TI - L-type voltage-dependent calcium channels facilitate acetylation of histone H3 through PKCgamma phosphorylation in mice with methamphetamine-induced place preference. AB - The present study investigated regulation of histone acetylation by L-type voltage-dependent calcium channels (VDCCs), one of the machineries to provide Ca(2+) signals. Acetylation of histone through the phosphorylation of protein kinase Cgamma (PKCgamma) in the development of methamphetamine (METH)-induced place preference was demonstrated in the limbic forebrain predominantly but also in the nucleus accumbens of alpha1C subunit knockout mice. Chronic administration of METH produced a significant place preference in mice, which was dose dependently inhibited by both chelerythrine (a PKC inhibitor) and nifedipine (an L-type VDCC blocker). Protein levels of acetylated histone H3 and p-PKCgamma significantly increased in the limbic forebrain of mice showing METH-induced place preference, and it was also significantly attenuated by pre-treatment with chelerythrine or nifedipine. METH-induced place preference was also significantly attenuated by deletion of half the alpha1C gene, which is one of the subunits forming Ca(2+) channels. Furthermore, increased acetylation of histone H3 was found in specific gene-promoter regions related to synaptic plasticity, such as Nrxn, Syp, Dlg4, Gria1, Grin2a, Grin2b, Camk2a, Creb, and cyclin-dependent kinase 5, in wild-type mice showing METH-induced place preference, while such enhancement of multiple synaptic plasticity genes was significantly attenuated by a deletion of half the alpha1C gene. These findings suggest that L-type VDCCs play an important role in the development of METH-induced place preference by facilitating acetylation of histone H3 in association with enhanced expression of synaptic plasticity genes via PKCgamma phosphorylation following an increase in the intracellular Ca(2+) concentration. PMID- 21781115 TI - Functional characterization of vesicular excitatory amino acid transport by human sialin. AB - Sialin, the protein coded by SLC17A5, is responsible for membrane potential (Deltapsi)-driven aspartate and glutamate transport into synaptic vesicles in addition to H+/sialic acid co-transport in lysosomes. Rodent sialin mutants harboring the mutations associated with Salla disease in humans did not transport aspartate and glutamate whereas H+/sialic acid co-transport activity was about one-third of the wild-type protein. In this study, we investigate the effects of various mutations on the transport activities of human sialin. Proteoliposomes containing purified heterologously expressed human sialin exhibited both Deltapsi driven aspartate and glutamate transport activity and H+/sialic acid co-transport activity. Aspartate and glutamate transport was not detected in the R39C and K136E mutant forms of SLC17A5 protein associated with Salla disease, whereas H+/sialic acid co-transport activity corresponded to 30-50% of the recombinant wild-type protein. In contrast, SLC17A5 protein harboring the mutations associated with infantile sialic acid storage disease, H183R and Delta268SSLRN272 still showed normal levels of Deltapsi-driven aspartate and glutamate transport even though H+/sialic acid co-transport activity was absent. Human sialin carrying the G328E mutation that causes both phenotypes, and P334R and G378V mutations that cause infantile sialic acid storage disease showed no transport activity. These results support the idea that people suffering from Salla disease have been defective in aspartergic and glutamatergic neurotransmissions. PMID- 21781117 TI - The action of Semaphorin7A on thalamocortical axon branching. AB - Developing axons form extensive branches to make synaptic contacts with their target cells. Despite the important role of axon branching in neural circuit formation, its underlying molecular mechanism is still largely unknown. In this study, we investigated the involvement of Semaphorin7A (Sema7A) in thalamocortical (TC) axon branching. In situ hybridization demonstrated that sema7a was expressed specifically in layer 4, the TC recipient layer, when TC axons form extensive arbors. A similar protein expression pattern was observed by immunohistochemistry with an anti-Sema7A antibody. The effect of Sema7A on axon branching was investigated in dissociated cell cultures from embryonic rat thalamus. TC axon branching increased dramatically on Sema7A-coated dishes. We further studied the activity of Sema7A in vivo using loss- and gain-of-function analyses. The number of vesicular glutamate transporter 2-positive puncta was markedly reduced in the Sema7A-deficient cortex. In contrast, their number increased significantly when Sema7A was over-expressed in layer 4 cells by in utero electroporation. Taken together, these findings suggest that Sema7A acts as a positive regulator for TC axon branching and/or pre-synaptic puncta formation. PMID- 21781116 TI - A monoclonal antibody against synthetic Abeta dimer assemblies neutralizes brain derived synaptic plasticity-disrupting Abeta. AB - Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid beta-protein (Abeta) play an important role in Alzheimer's disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS) stable Abeta dimers may be the basic building blocks of Alzheimer's disease associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Abeta dimers, we have used synthetic disulfide cross-linked dimers (free of Abeta monomer or fibrils) to generate conformation-specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Abeta dimers, but do not bind to Abeta monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype-matched control antibody, ameliorated the plasticity-disrupting effects of Abeta extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant Abeta assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies. PMID- 21781119 TI - Antioxidant mechanism of isoflavone metabolites in hydrogen peroxide-stimulated rat primary astrocytes: critical role of hemeoxygenase-1 and NQO1 expression. AB - The brain is highly vulnerable to oxidative stress, thus controlling oxidative stress is considered to be an important therapeutic target for neurodegenerative diseases. In this study, we found that two isoflavone metabolites (tectorigenin and glycitein) inhibited hydrogen peroxide-induced reactive oxygen species (ROS) generation and subsequent cell death in rat primary astrocytes. The isoflavone metabolites increased the expression of phase II antioxidant enzymes, such as hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and pre treatment of cells with their specific inhibitors or small interfering RNA (siRNA) reversed the antioxidant and cytoprotective effects of isoflavones. The results suggest that the antioxidant/cytoprotective effects of isoflavone metabolites are at least because of increased HO-1 and NQO1 expression. Further mechanistic studies revealed that isoflavones increase the binding of transcription factors [nuclear factor-E2-related factor 2 (Nrf2) and c-Jun] to the antioxidant response element (ARE) on HO-1 and NQO1 promoters. Down regulation of Nrf2 and/or c-Jun using dominant-negative mutants (DNMs) or siRNA diminished the expression of HO-1 and NQO1, suggesting that Nrf2 and c-Jun are key transcription factors modulating HO-1/NQO1 expression. Moreover, PI3 kinase and mitogen-activated protein kinase (MAPK) signaling pathways were shown to be involved in HO-1 and/or NQO1 expression by isoflavones. Our data collectively suggest that HO-1 and NQO1 play a critical role in antioxidant effects of isoflavone metabolites in rat brain astrocytes. PMID- 21781118 TI - Delta9-THC increases endogenous AHA1 expression in rat cerebellum and may modulate CB1 receptor function during chronic use. AB - To characterize the long-term effects of adolescent marijuana abuse, we performed a proteomic analysis of cerebellar extracts from adult female rats with and without ovariectomy that were treated with Delta9-THC for 40 days during adolescence. Six proteins were found to significantly differ among the four treatment groups, with Delta9-THC and ovariectomy (OVX) decreasing the mitochondrial proteins, pyruvate carboxylase and NADH dehydrogenase, whereas the levels of putative cytosolic molecular chaperones NM23B, translationally controlled tumor protein, DJ-1 and activator of heat-shock 90kDa protein ATPase homolog 1 (AHA1) were increased. We further analyzed the effects of AHA1, a HSP90 co-chaperone, on CB1R and CB2R trafficking and signaling in transfected HEK293T and Neuro-2A cells. In HEK293T cells, AHA1 over-expression enhanced plasma membrane levels of CB1R and increased CB1R-mediated effects on cAMP levels and on MAPK phosphorylation. AHA1 over-expression also enhanced cell surface levels of endogenous CB1R and the effects of Delta9-THC on the cAMP levels in Neuro-2A cells. In contrast, over-expression of AHA1 did not affect the subcellular localization and signaling of CB2R. Our data indicate that chronic Delta9-THC administration in adolescence altered the endogenous levels of specialized proteins in the cerebellum, such as AHA1, and that this protein can change CB1R cell surface levels and signaling. PMID- 21781120 TI - Cerebral ischemic pre-conditioning enhances the binding characteristics and glutamate uptake of glial glutamate transporter-1 in hippocampal CA1 subfield of rats. AB - Glial glutamate transporter-1 (GLT-1) is the predominant subtype of glutamate transporters which are responsible for the homeostasis of extracellular glutamate. Our previous studies have shown that up-regulation in GLT-1 protein expression matches brain ischemic tolerance induced by cerebral ischemic preconditioning (CIP). To specify the role of functional changes of GLT-1 in the induction of brain ischemic tolerance by CIP, the present study was undertaken to examine changes in the binding properties of GLT-1 (including maximum binding and affinity for glutamate) and in GLT-1 mediated glutamate uptake, using L-3H glutamate assay in the rat hippocampus. The results indicated that CIP was able to increase the maximum binding and affinity, and uptake of GLT-1 for glutamate in hippocampal CA1 subfield either with or without the presence of the subsequent severe brain ischemic insult. Simultaneously, accompanied with the above changes, CIP significantly reduced the delayed neuronal death (DND) in this region induced by lethal global cerebral ischemia. It could be concluded that up-regulation in the maximum binding and affinity and glutamate uptake of GLT-1 contributed to the neuronal protection of CIP against global cerebral ischemic insult. PMID- 21781121 TI - Oral mucosa model based on a collagen-elastin matrix. AB - BACKGROUND AND OBJECTIVE: The collagen-elastin matrix (Matriderm((r))) is used to treat deep and full-thickness burns and was recently described as a suitable scaffold for tissue engineering. The aim of the present study was to investigate the biocompatibility of Matriderm((r)) for gingival use through creation of an oral mucosa model ex vivo. MATERIAL AND METHODS: Gingival fibroblasts and keratinocytes were cultured. A dermal area on the base of the collagen-elastin matrix was repopulated with fibroblasts. After 14 days, keratinocytes were seeded on this dermal area to engineer a multilayered mucosa. Analysis of the architecture was performed using light and electron microscopy. Immunohistochemical detection of collagen IV and cytokeratin was carried out. RESULTS: Based on this scaffold we generated a multilayered oral mucosa-like structure. Histological, immunohistochemical and electron microscopic analysis of the dermal/epidermal junction showed a typical basement membrane and hemidesmosomal structures. Neighboring keratinocytes formed desmosomes in the epidermal sections. Cytokeratin was detectable in all epidermal layers. These experiments revealed that the collagen-elastin matrix was highly biocompatible with gingival cells under ex vivo conditions. CONCLUSION: Employing tissue engineering techniques with dermal and epidermal cells from the gingiva, a multilayered oral mucosa was generated and characterized with respect to biocompatibility for Matriderm((r)). The results indicate that Matriderm((r)) is suitable for the ex vivo growth of gingival tissue cells and is a useful scaffold with possible applications in periodontal therapy. PMID- 21781122 TI - The plant-specific family of DNA-binding proteins containing three HMG-box domains interacts with mitotic and meiotic chromosomes. AB - * The high mobility group (HMG)-box represents a DNA-binding domain that is found in various eukaryotic DNA-interacting proteins. Proteins that contain three copies of the HMG-box domain, termed 3 * HMG-box proteins, appear to be specific to plants. The Arabidopsis genome encodes two 3 * HMG-box proteins that were studied here. * DNA interactions were examined using electrophoretic mobility shift assays, whereas expression, subcellular localization and chromosome association were mainly analysed by different types of fluorescence microscopy. * The 3 * HMG-box proteins bind structure specifically to DNA, display DNA bending activity and, in addition to the three HMG-box domains, the basic N-terminal domain contributes to DNA binding. The expression of the two Arabidopsis genes encoding 3 * HMG-box proteins is linked to cell proliferation. In synchronized cells, expression is cell cycle dependent and peaks in cells undergoing mitosis. 3 * HMG-box proteins are excluded from the nuclei of interphase cells and localize to the cytosol, but, during mitosis, they associate with condensed chromosomes. The 3 * HMG-box2 protein generally associates with mitotic chromosomes, while 3 * HMG-box1 is detected specifically at 45S rDNA loci. * In addition to mitotic chromosomes the 3 * HMG-box proteins associate with meiotic chromosomes, suggesting that they are involved in a general process of chromosome function related to cell division, such as chromosome condensation and/or segregation. PMID- 21781123 TI - Variability of parvovirus B19 genotype 2 in plasma products with different compositions in the inactivation sensitivity by liquid-heating. AB - BACKGROUND AND OBJECTIVES: Our previous report showed that parvovirus B19 genotype 1 in different solutions derived from plasma preparations showed different heat-sensitivity patterns during liquid-heating. In this study, we similarly examined B19 genotype 2. MATERIALS AND METHODS: Two plasma samples one containing B19 genotype 1 and the other genotype 2 DNA were used. Four process samples collected immediately before the heat treatment step in the manufacture of albumin, immunoglobulin, haptoglobin and antithrombin preparations were spiked with B19 and subsequently treated at 60 degrees C for 10 h. A low pH immunoglobulin solution was also spiked with B19 and treated at room temperature for 14 days. Infectivity was then measured. RESULTS: B19 genotype 2, similar to genotype 1, showed three patterns of inactivation: (i) a rapid inactivation in the albumin and immunoglobulin preparations, (ii) a slow inactivation in the haptoglobin preparation and (iii) only limited inactivation in the antithrombin preparation. Its sensitivity in the low pH immunoglobulin solutions also resembled that of genotype 1. CONCLUSION: Both genotypes 1 and 2 of B19 varied in sensitivity to liquid-heating and low pH among different plasma preparations. PMID- 21781124 TI - Iron studies and red cell transfusion in cardiothoracic and orthopaedic surgical patients: a retrospective audit at a tertiary hospital. AB - BACKGROUND AND OBJECTIVES: Preoperative diagnosis and treatment of anaemia are important to minimize adverse postoperative outcomes. This audit reviewed red cell transfusion practice, degree of anaemia, iron deficiency anaemia (IDA) and chronic disease or anaemia of inflammation (AI) in cardiothoracic and orthopaedic surgical patients who had available iron studies. MATERIALS AND METHODS: A total of 178 consecutive cardiothoracic and orthopaedic surgical patients with available iron studies were retrospectively reviewed. RESULTS: Of patients, 36.5% had preoperative iron studies. However, 63.2% males and 45.3% females with postoperative iron studies presented with anaemia; 38.5% patients with preoperative iron studies had AI; 21.5% IDA; 23.1% normal. For patients with iron studies requested within the first two postoperative intervals (<= 5 days and 6 <= 10 days) 73.8% and 63.6%, respectively, had AI; few had classical IDA or were normal, and 51.5% patients transfused postsurgery had a discharge Hb >= 110 g/l. Restricting the discharge Hb to 90 or 100 g/l may have eliminated postsurgical transfusion in 14.8-42.6% patients. CONCLUSION: Iron studies were more commonly requested postoperatively despite many being anaemic at admission. A higher proportion of patients with postoperative iron studies had AI, and few had classical IDA or normal iron parameters, suggesting a transient inflammatory effect of surgery. This may mask underlying IDA or normal iron parameters and affect treatment. Preadmission assessment, including iron status, should be emphasized allowing diagnosis and correction of presurgical anaemia with treatment modalities other than red cell transfusion. In the postsurgical setting, consideration of a restrictive transfusion regimen sufficient to alleviate a patient's clinical symptoms would ensure that this valuable resource is appropriately used. PMID- 21781125 TI - Risk-based decision-making for blood safety: preliminary report of a consensus conference. PMID- 21781126 TI - ABO-mismatched transfusions are not over-represented in febrile non-haemolytic transfusion reactions to platelets. AB - ABO-mismatched plasma and platelet (PLT) transfusion have been associated with worse outcomes, including haemolysis and other reactions, compared to recipients of ABO-identical products. The immune complexes that form in a mismatched transfusion have been demonstrated to stimulate pyrogenic cytokine release in vitro. Comparing ABO identical vs. ABO mismatched PLT transfusions, we found no significant difference in the ABO compatibilities between the PLT doses implicated in causing febrile non-haemolytic transfusion reactions (FNHTR) in 162 recipients and both the baseline PLT donor/recipient ABO compatibility (P = 0.67) or the PLTs issued in the 30 days preceding the FNHTR (P = 0.92). ABO-mismatched PLT transfusions do not appear to be aetiological agents of FNHTR in a population routinely receiving both ABO-identical and ABO-mismatched transfusions. PMID- 21781128 TI - Symposium on Nonhuman Primate Models for AIDS. Introduction. PMID- 21781129 TI - Development of a pigtail macaque model of sexually transmitted infection/HIV coinfection using Chlamydia trachomatis, Trichomonas vaginalis, and SHIV(SF162P3). AB - BACKGROUND: Sexually transmitted infections (STIs) are associated with an increased risk of HIV infection. To model the interaction between STIs and HIV infection, we evaluated the capacity of the pigtail macaque model to sustain triple infection with Trichomonas vaginalis, Chlamydia trachomatis, and SHIV(SF162P3). METHODS: Seven SHIV(SF162P3) -infected pigtail macaques were inoculated with T. vaginalis only (n = 2), C. trachomatis only (n = 1), both T. vaginalis and C. trachomatis (n = 2), or control media (no STI; n = 2). Infections were confirmed by culture and/or nucleic acid testing. Genital mucosa was visualized by colposcopy. RESULTS: Characteristic gynecologic signs were observed for both STIs, but not in control animals. Manifestations were most prominent at days 7-10 post-infection. STIs persisted between 4 and 6 weeks and were cleared with antibiotics. CONCLUSIONS: These pilot studies demonstrate the first successful STI-SHIV triple infection of pigtail macaques, with clinical presentation of genital STI symptoms similar to those observed in humans. PMID- 21781130 TI - High-throughput single-nucleotide polymorphism discovery and the search for candidate genes for long-term SIVmac nonprogression in Chinese rhesus macaques (Macaca mulatta). AB - BACKGROUND: Genetic differences between Indian and Chinese rhesus macaques contribute to the phenotypic variance of clinical trials, including infection with SIVmac. The completion of the rhesus genome has facilitated the discovery of several thousand markers. METHODS: We developed a genome-wide SNP map for rhesus macaques containing 3869 validated markers with an average distance of 0.88 Mb and used the program VarLD to identify genomic areas with significant differences in linkage disequilibrium (LD) between Indian-derived and Chinese rhesus macaques. RESULTS: Forty-one statistically significant differences in LD between Chinese and Indian-origin rhesus were detected on chromosomes 1, 4, 5 and 11. The region of greatest LD difference was located on the proximal end of chromosome one, which also contained the genes ELAVL4, MAST2 and HIVEP3. CONCLUSION: These genomic areas provide entry to more detailed studies of gene function. This method is also applicable to the study of differences in biomarkers between regional populations of other species. PMID- 21781131 TI - Reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus. AB - BACKGROUND: Tuberculosis (TB) and AIDS together present a devastating public health challenge. Over 3 million deaths every year are attributed to these twin epidemics. Annually, ~11 million people are coinfected with HIV and Mycobacterium tuberculosis (Mtb). AIDS is thought to alter the spontaneous rate of latent TB reactivation. METHODOLOGY: Macaques are excellent models of both TB and AIDS. Therefore, it is conceivable that they can also be used to model coinfection. Using clinical, pathological, and microbiological data, we addressed whether latent TB infection in rhesus macaques can be reactivated by infection with simian immunodeficiency virus (SIV). RESULTS: A low-dose aerosol infection of rhesus macaques with Mtb caused latent, asymptomatic TB infection. Infection of macaques exhibiting latent TB with a rhesus-specific strain of SIV significantly reactivated TB. CONCLUSIONS: Rhesus macaques are excellent model of TB/AIDS coinfection and can be used to study the phenomena of TB latency and reactivation. PMID- 21781132 TI - SIV-infected Chinese-origin rhesus macaques express specific MHC class I alleles in either elite controllers or normal progressors. PMID- 21781134 TI - Long-term effect of a simple nest-box on the reproductive efficiency and other life traits of an Aotus lemurinus lemurinus monkey colony: an animal model for malaria research. AB - BACKGROUND: The long-term effect of a PVC pipe nest-box on the reproductive efficiency and other life traits of an Aotus monkey-breeding colony have not been characterized. METHODS AND RESULTS: We analyzed laboratory records of the Gorgas Memorial Institute (GMI) Aotus monkey colony in Panama for the period 1999-2010 and found a 273% increase in the annual mean life births in the following 7 years after the introduction of a PVC pipe nest-box in 2002, as well as increases in the mean body mass and survival of laboratory-bred monkeys. Other life traits such as inter-birth interval, parity, birth sex distribution, mortality, and longevity were also determined. CONCLUSIONS: The use of a PVC pipe nest-box significantly improved the reproductive efficiency and other life traits of the GMI Aotus breeding colony. PMID- 21781135 TI - Prevalence and impact of rhinitis in asthma. SACRA, a cross-sectional nation-wide study in Japan. AB - BACKGROUND: Asthma and rhinitis are common co-morbidities everywhere in the world but nation-wide studies assessing rhinitis in asthmatics using questionnaires based on guidelines are not available. OBJECTIVE: To assess the prevalence, classification, and severity of rhinitis using the Allergic Rhinitis and its Impact on Asthma (ARIA) criteria in Japanese patients with diagnosed and treated asthma. METHODS: The study was performed from March to August 2009. Patients in physicians' waiting rooms, or physicians themselves, filled out questionnaires on rhinitis and asthma based on ARIA and Global Initiative for Asthma (GINA) diagnostic guides. The patients answered questions on the severity of the diseases and a Visual Analog Scale. Their physicians made the diagnosis of rhinitis. RESULTS: In this study, 1910 physicians enrolled 29,518 asthmatics; 15,051 (51.0%) questionnaires were administered by physician, and 26,680 (90.4%) patients were evaluable. Self- and physician-administered questionnaires gave similar results. Rhinitis was diagnosed in 68.5% of patients with self administered questionnaires and 66.2% with physician-administered questionnaires. In this study, 994 (7.6%) patients with self-administered and 561 (5.2%) patients with physician-administered questionnaires indicated rhinitis symptoms on the questionnaires without a physician's diagnosis of rhinitis. Most patients with the physician's diagnosis of rhinitis had moderate/severe rhinitis. Asthma control was significantly impaired in patients with a physician's diagnosis of rhinitis for all GINA clinical criteria except exacerbations. There were significantly more patients with uncontrolled asthma as defined by GINA in those with a physician's diagnosis of rhinitis (25.4% and 29.7%) by comparison with those without rhinitis (18.0% and 22.8%). CONCLUSION: Rhinitis is common in asthma and impairs asthma control. PMID- 21781136 TI - Development and validation of a tissue cage model of acute inflammation in the cat. AB - Four cylindrical silicon tissue cages (TC, internal volume: 6.7 +/- 0.11 cm(3)) were inserted subcutaneously in 29 young healthy cats. A mild inflammatory reaction was induced by intracaveal injection of 1 mL of a 2%lambda-carrageenan solution. TC exudate was subsequently sampled at predetermined times (up to 120 h) to measure exudate leucocyte counts and the concentrations of protein and eicosanoids. TC remained in situ for 9-10 months and were well tolerated. Leucocyte counts peaked at 34 h (50.1 +/- 57.6 * 10(3) cells/mm(3) ) and returned towards baseline after 72 h. Protein concentration increased from 26.2 +/- 2.7 g/L to a peak of 35.9 +/- 6.0 g/L at 12 h before returning to baseline at 48 h. Exudate prostaglandin (PG)E(2) concentration peaked at 24 h (11.7 +/- 13.7 ng/mL) and returned to baseline by 120 h. Repeated collection of fluid from noninjected cages did not increase transudate PGE(2). Ketoprofen (2 mg/kg, subcutaneously) suppressed exudate PGE(2) at 24 h. The carrageenan-stimulated TC model is an ethical and novel means of investigating soft tissue inflammation in the cat, in which exudate PGE(2) acts as surrogate marker of cyclooxygenase-2 activity. This model will facilitate the investigation of in vivo pharmacokinetics and pharmacodynamics of anti-inflammatory drugs in this species. PMID- 21781137 TI - Co-administration of rectal BCG and autoclaved Leishmania major induce protection in susceptible BALB/c mice. AB - We examined the protective effect of autoclaved Leishmania major (ALM) vaccine in combination of either rectal or subcutaneous BCG on susceptible BALB/c mice. One month after BCG vaccination, BALB/c mice were immunized subcutaneously twice with ALM + alum at 3 weeks intervals. Three weeks after booster injection, 5 * 10(5) stationary phase L. major promastigotes were inoculated subcutaneously in one footpad. Immunological evaluation at before and post infectious challenge showed strong proliferative responses in the spleen cells of the rectal immunized group after stimulating with parasite lysate. High level of interferon gamma was induced in the spleen, and significant increase in the serum ratio of IgG2a/IgG1 was observed only in rectal immunized group. Rectal immunized mice showed comparable nitric oxide production and iNOS induction in peritoneal macrophages (P <= 0.05). The obtained results in rectal BCG vaccinated group showed no mortality but low parasite burden in the liver and spleen. In conclusion, the results of our study indicated that co-administration of rectal BCG and ALM induced protective type 1 immune responses against L. major infection. This safe and effective mucosal vaccine could be useful in prevention of human leishmaniasis infections. PMID- 21781138 TI - Comparative virulence of Pyrenophora teres f. teres from Syria and Tunisia and screening for resistance sources in barley: implications for breeding. AB - AIMS: The aim of this study is to investigate the pathogenic diversity and virulence groups among Pyrenophora teres f. teres isolates, sampled from Syria and Tunisia, and to identify the most effective source of resistance in barley that could be used in breeding programmes to control net blotch in both countries. METHODS AND RESULTS: One hundred and four isolates of P. teres f. teres were collected from barley in different agroecological zones of Tunisia and Syria. Their virulence was evaluated using 14 barley genotypes as differential hosts. The UPGMA clustering identified high pathogenic variability; the isolates were clustered onto 20 pathotypes that were sheltered under three virulence groups, with high, intermediate and low disease scores. According to susceptibility/resistance frequencies and mean disease ratings, CI05401 cultivar ranked as the best differential when inoculated with the Syrian isolates. However, CI09214 cultivar was classified as the best effective source of resistance in Tunisia. CONCLUSIONS: All P. teres f. teres isolates were differentially pathogenic. CI09214 and CI05401 cultivars were released as the most effective sources of resistance in Syria and Tunisia. SIGNIFICANCE AND IMPACT OF THE STUDY: National and international barley breeding programmes that seek to develop resistance against P. teres f. teres in barley should strongly benefit from this study. This resistance cannot be achieved without the proper knowledge of the pathogen virulence spectrum and the sources of host resistance. PMID- 21781139 TI - Effects of temperature and diet on development and interspecies competition in Aedes aegypti and Aedes albopictus. AB - We asked whether climate change might affect the geographic distributions of Aedes aegypti (L.) and Aedes albopictus (Skuse) (Diptera: Culicidae). We tested the effects of temperature, diet and the presence of congeneric species on the performance of immature stages of these two aedine species in the laboratory. Mosquitoes in three different species-density combinations were reared at four constant temperatures (20 degrees C, 25 degrees C, 30 degrees C, 35 degrees C) on low- or high-level diets. Of the four temperatures tested, mortality increased only at 35 degrees C in both species. Mortality was higher on the high level diet than on the low-level diet at 35 degrees C, but not at other temperatures. The presence of congeneric species had a significant positive effect on mortality in Ae. albopictus, but not in Ae. aegypti. Both species developed more quickly at higher temperatures within the range of 20-30 degrees C; development was not enhanced at 35 degrees C. Population growth of Ae. albopictus was more stable, regardless of diet and temperature; that of Ae. aegypti varied more according to these two factors. These species-specific attributes may help to explain the latitudinal distribution of the mosquitoes and degree of species dominance where they are sympatric. PMID- 21781140 TI - Nepetalactones from essential oil of Nepeta cataria represent a stable fly feeding and oviposition repellent. AB - The stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), is one of the most serious pests to livestock. It feeds mainly on cattle and causes significant economic losses in the cattle industry. Standard stable fly control involving insecticides and sanitation is usually costly and often has limited effectiveness. As we continue to evaluate and develop safer fly control strategies, the present study reports on the effectiveness of catnip (Nepeta cataria L.) oil and its constituent compounds, nepetalactones, as stable fly repellents. The essential oil of catnip reduced the feeding of stable flies by >96% in an in vitro bioassay system, compared with other sesquiterpene-rich plant oils (e.g. amyris and sandalwood). Catnip oil demonstrated strong repellency against stable flies relative to other chemicals for repelling biting insects, including isolongifolenone, 2-methylpiperidinyl-3-cyclohexen-1-carboxamide and (1S,2'S)-2-methylpiperidinyl-3-cyclohexen-1-carboxamide. The repellency against stable flies of the most commonly used mosquito repellent, DEET, was relatively low. In field trials, two formulations of catnip oil provided >95% protection and were effective for up to 6 h when tested on cattle. Catnip oil also acted as a strong oviposition repellent and reduced gravid stable fly oviposition by 98%. PMID- 21781141 TI - Expression of heat shock proteins and subolesin affects stress responses, Anaplasma phagocytophilum infection and questing behaviour in the tick, Ixodes scapularis. AB - We characterized the effects of subolesin and heat shock protein (HSP) expression on Ixodes scapularis Say (Acari: Ixodidae) stress responses to heat shock and feeding, questing behaviour and Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae) infection. Ticks and cultured tick cells were analysed before and after subolesin, hsp20 and hsp70 gene knock-down by RNA interference. The results of these studies confirm that HSPs are involved in the tick cell response to heat stress and that subolesin and HSPs are both involved in the tick response to blood-feeding stress and A. phagocytophilum infection. Subolesin and hsp20 are involved in the tick protective response to A. phagocytophilum infection and hsp70 expression may be manipulated by the pathogen to increase infectivity. Importantly, these results demonstrate that subolesin, hsp20 and hsp70 expression also affect tick questing behaviour. Overall, this research demonstrates a relationship between hsp and subolesin expression and tick stress responses to heat shock and blood feeding, A. phagocytophilum infection and questing behaviour, thereby extending our understanding of the tick-host-pathogen interface. PMID- 21781142 TI - Emotional distance to so-called difficult patients. AB - PURPOSE: To explore nurses' relationships with patients they regard as being difficult. How do nurses feel about such patients and relate to them, and what are the consequences for nurse and patient? DESIGN AND METHODS: A qualitative study inspired by hermeneutic phenomenology was conducted. The data were obtained through participant observation and interviewing in a home nursing unit in a Danish municipality. During an initial 3 month period, eighteen participant observations were conducted with 12 nurses during their visits to 96 patients. During the following 3 months, 12 more participant observations were made with three nurses visiting 50 patients. Four of these patients whom the three nurses found difficult were selected and six interviews conducted with these patients. Eleven interviews were conducted with five nurses. Patients' case records were studied and four meetings with the staff were arranged to discuss the findings. Data collection lasted 18 months in all. FINDINGS: Three strategies were identified: persuasion, avoidance (emotional distance), and compromise. Interestingly, in the relationship with a particular patient, the avoidance strategy did not necessarily represent the terminal stage, since a nurse could revert to the compromise strategy. Some of the nurses experienced painful emotions regarding these interactions. CONCLUSIONS: The avoidance strategy (emotional distance) resulted in important social and health problems of some patients not being recognized, and some nurses using it expressed the fear of losing contact with their emotional lives. The compromise strategy gave possibilities for dialogue. STUDY LIMITATIONS: The focus was mainly on the nurses and their perspectives. It would be interesting to study in greater detail the perspectives of the patients. PMID- 21781143 TI - Plasma corticotrophin response to desmopressin in patients with Cushing's disease correlates with the expression of vasopressin receptor 2, but not with that of vasopressin receptor 1 or 3, in their pituitary tumours. AB - OBJECTIVES: Most patients with Cushing's disease (CD) respond to corticotrophin releasing hormone (CRH) or desmopressin with increased corticotrophin (ACTH) and cortisol levels. Although the vasopressin receptor subtype located on normal corticotrophs is the V3 receptor (V3R), desmopressin is a selective V2 receptor (V2R) agonist and it is unclear whether corticotrophinomas exhibit aberrant V2R expression. Furthermore, no studies have determined the relationship between the in vivo response of CD patients to desmopressin and vasopressin receptor expression, or between the response to CRH and CRH receptor (CRHR) expression. Therefore, the aim of this study was to investigate the expression of vasopressin receptors (V1R, V2R, and V3R) and CRHR on corticotroph tumours and its possible relation to the in vivo response. DESIGNS: A prospective study of 29 patients with CD. METHODS: Patients underwent desmopressin and CRH stimulation tests before surgery. The expression of vasopressin receptors and CRHR on corticotrophinomas was determined by immunocytochemistry. RESULTS: Most of the corticotrophinomas exhibited abundant expression of V1R, V3R, and CRHR, whereas the expression of V2R varied greatly and was lower in macroadenomas than in microadenomas. Both the percentage increment of ACTH and net area under the curve (AUC) of ACTH in the desmopressin stimulation test were found to be correlated with tumour volume. After adjustment for tumour volume, a positive correlation was found between the percentage increment of ACTH and the degree of V2R expression, but not between that of V1R or V3R. No relationship between the level of expression of CRHR on tumour tissues and the percentage increment or netAUC of ACTH to CRH was observed in CD patients. CONCLUSIONS: We concluded that V2R was expressed on corticotrophinomas and that the level of its expression correlated well with the ACTH response to desmopressin in CD patients, although abundant expression of V1R and V3R was also found in almost all corticotroph tumours. Further studies are needed to elucidate the role of these receptors in the pathogenesis of CD. PMID- 21781144 TI - Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat. AB - OBJECTIVE: Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negatively associated with body mass index. These appetite-regulating hormones may have opposing effects on mood and stress pathways. Women with anorexia nervosa (AN), hypothalamic amenorrhoea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contributes to the development of depression and/or anxiety in these disorders. We investigated the relationship between leptin and ghrelin levels and symptoms of depression, anxiety and perceived stress in women across the weight spectrum. DESIGN: Cross-sectional. PATIENTS: 64 women: 15 with AN, 12 normal-weight with HA, 17 overweight or obese (OB) and 20 normal-weight in good health (HC). MEASUREMENTS: Fasting serum leptin and plasma ghrelin levels were measured. Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Perceived Stress Scale were administered. RESULTS: Leptin levels were inversely associated with HAM-D, HAM-A and Perceived Stress scores. The negative relationships between leptin and severity of symptoms of both depression and anxiety remained significant after controlling for body fat or weight. There was no relationship between ghrelin and symptoms of depression or anxiety. Although ghrelin levels were positively associated with the degree of perceived stress, this relationship was not significant after controlling for body fat or weight. CONCLUSIONS: Leptin may mediate depressive symptoms across the weight spectrum. Further investigation of the role of leptin in modulating mood will be important. PMID- 21781145 TI - Decreased serum vascular endothelial growth factor-D levels in metastatic patients with differentiated thyroid carcinoma. AB - OBJECTIVE: Vascular endothelial growth factor-D (VEGF-D) has been identified as one of the lymphangiogenic growth factors involved in metastatic diffusion. The aim of this study is to evaluate the serum VEGF-D levels in patients with differentiated thyroid cancer at different conditions of disease. DESIGN AND PATIENTS: We studied prospectively the VEGF-D plasma levels in 96 subjects affected by differentiated thyroid cancer. The patients were divided into three groups according to the clinical and biochemical findings: patients with no evidence of disease (Cured), patients with pathological (>1 ng/ml) stimulated thyroglobulin (Tg) (Path-Tg/rhTSH) levels only after rhTSH and patients with elevated basal Tg levels (Path-Tg/LT4). RESULTS: The serum VEGF-D concentrations in patients of group Cured were not different from the controls, while group Path Tg/rhTSH showed baseline serum VEGF-D levels significantly lower than group Cured and controls (P < 0.001 and P < 0.01, respectively). Moreover, the patients of group Path-Tg/LT4 showed median serum cytokine concentrations at baseline not significantly different from the patients of group Path-Tg/rhTSH. The rhTSH stimulation did not modify the difference in serum VEGF-D levels in patients of group Cured and group Path-Tg/rhTSH. CONCLUSIONS: Our data demonstrate that the VEGF-D serum levels are reduced in patients with metastases of differentiated thyroid cancer, regardless of the degree of metastatic spread. It is possible that some other molecule produced by the tumoral tissue could affect the VEGF-D physiologically produced of from different tissues, thus conducting to a decrease in the VEGF-D found in blood of patients with evidence of metastatic differentiated thyroid cancer. PMID- 21781146 TI - Arrhythmogenic pulmonary vein myocardium in heart failure. PMID- 21781147 TI - An expression of love--midwives' experiences in the encounter with lesbian women and their partners. AB - AIM: This paper is a report of a descriptive study of midwives' lived experiences of caring for lesbian women and their partners. BACKGROUND: A growing body of qualitative studies describes lesbian women's experiences of maternity care. Studies about midwives' caring experiences in the encounter are needed to improve care for lesbian women and their partners. METHOD: A qualitative study, using a phenomenological-hermeneutical method influenced by Ricoeur was conducted. Eleven midwives were recruited by snowball method. Interviews were conducted in 2009 and participants were encouraged to share events in their midwifery practice encountering lesbian women. FINDINGS: The midwives described the lesbian love relationship as strong and caring, but including elements of difference which could make the couple vulnerable. It was important for midwives to acknowledge their own attitudes and culturally sensitive non-verbal communication; also to consider the co-mother's needs and role as different compared with those of fathers. Although caring for lesbian couples was seen as unproblematic, midwives described experiences of ambivalence or anxiety in the encounter and they had noticed that some couples had had negative experiences with maternity care. CONCLUSION: Studies are required to map content, consequences and coping strategies regarding the ambivalent or uncertain caring situations and to assess a co-mother's particular role and needs during pregnancy, labour and the postnatal period to provide tailored care for lesbian couples. PMID- 21781148 TI - Nurses' perceptions of an electronic patient record from a patient safety perspective: a qualitative study. AB - AIMS: The overall aim of this study was to explore nurses' perceptions of using an electronic patient record in everyday practice, in general ward settings. This paper reports on the patient safety aspects revealed in the study. BACKGROUND: Electronic patient records are widely used and becoming the main method of nursing documentation. Emerging evidence suggests that they fail to capture the essence of clinical practice and support the most frequent end-users: nurses. The impact of using electronic patient records in general ward settings is under explored. METHOD: In 2008, focus group interviews were conducted with 21 Registered Nurses. This was a qualitative study and the data were analysed by content analysis. At the time of data collection, the electronic patient record system had been in use for approximately 1 year. FINDINGS: The findings related to patient safety were clustered in one main category: 'documentation in everyday practise'. There were three sub-categories: vital signs, overview and medication module. Nurses reported that the electronic patient record did not support nursing practice when documenting crucial patient information, such as vital signs. CONCLUSIONS: Efforts should be made to include the views of nurses when designing an electronic patient record to ensure it suits the needs of nursing practice and supports patient safety. Essential patient information needs to be easily accessible and give support for decision-making. PMID- 21781149 TI - Losartan and amlodipine on myocardial structure and function: a prospective, randomized, clinical trial. AB - AIMS: To compare the effects of losartan and amlodipine on myocardial structure and function in hypertensive patients with Type 2 diabetes and left ventricular hypertrophy. METHODS: After a 4-week placebo period, patients were randomized to losartan 50 mg (n = 90) or amlodipine 5 mg (n = 91) for 12 months, with a doubling of the dose in patients who did not respond after 4 weeks. Blood pressure was measured in the clinic every month, while conventional echocardiography and acoustic densitometry (integrated backscatter analysis) were performed at the end of the placebo period and after 12 months of treatment. RESULTS: Both drugs reduced systolic/diastolic blood pressure to a comparable extent. Losartan significantly reduced left ventricular mass index (-19%, P < 0.001), interventricular septal thickness (-16.6%, P < 0.01) and left ventricular posterior wall thickness in diastole (-13.7%, P < 0.01). Amlodipine also decreased such measurements (-10%, P < 0.01 for left ventricular mass index, 9.3%, P < 0.05 for interventricular septal thickness in diastole and -10.1%, P < 0.05 for posterior wall thickness in diastole), but to a lesser extent than losartan. Both drugs significantly increased the ratio of peak filling velocity at early diastole to that at atrial contraction (E/A ratio) and decreased isovolumetric relaxation time: +13.7% and -8.5% with losartan,(both P < 0.01), and +7.9% and -4.9%, with amlopidine (both P < 0.05). Losartan, but not amlodipine, significantly reduced the relative integrated backscatter compared to baseline of the intraventricular septum (-10%, P < 0.01), and of the left ventricular posterior wall (-12%, P < 0.01), while increasing the cyclic variation of integrated backscatter of both the intraventricular septum (+35%, P < 0.001) and the left ventricular posterior wall (+32%, P < 0.001). CONCLUSIONS: Losartan provided a greater attenuation of left ventricular hypertrophy than amlodipine, seemingly as a result of a greater reduction of myocardial fibrosis. PMID- 21781150 TI - Acute hepatic injury following treatment of a long-acting insulin analogue overdose necessitating urgent insulin depot excision. AB - BACKGROUND: A 26-year-old man with Type 1 diabetes presented with an overdose of 4800 units of the long-acting insulin analogue, glargine (Lantus). Glucose supplementation of approximately 800 g/day was associated with acute hepatic injury. METHODS: On day 4, a depot of insulin was excised from the patient's abdominal wall; this was followed by a reduction in his glucose requirements and improvement in liver function. CONCLUSIONS: This report highlights the risk of acute hepatic injury during the treatment of insulin overdose and the importance of careful glucose supplementation. It also demonstrates how earlier excision of an insulin depot could potentially prevent this problem and hasten recovery. PMID- 21781151 TI - Reduction in glycated albumin can predict change in HbA1c: comparison of oral hypoglycaemic agent and insulin treatments. AB - AIM: To investigate whether the change in glycated albumin 3 weeks after initiating anti-diabetes treatment (oral hypoglycaemic agent or insulin) could predict the corresponding change in HbA(1c) 3 months later in Korean patients with Type 2 diabetes. METHODS: A total of 140 patients were enrolled into two groups: group I (insulin-based; n = 100) and group II (oral hypoglycaemic agent based; n = 40). Both glycated albumin and HbA(1c) levels were measured as 'glucose control markers' during hospitalization. Glycated albumin was measured again at 3 weeks (first visit) after the initial measurement, and HbA(1c) was measured at 3 months (second visit) after the initial measurement.. The change in glucose control marker was defined as 100 * (follow-up glucose control marker- hospital glucose control marker)/hospital glucose control marker. RESULTS: In both groups, the change in glycated albumin at the first visit and in HbA(1c) at the second visit showed a moderate linear relationship (r = 0.735; P < 0.01). In group II (r = 0.778; P < 0.01), a slightly stronger linear relationship was demonstrated than in group I (r = 0.738; P < 0.001); however, there was no statistically significant difference between the two groups. A correlation coefficient between the change in glycated albumin and HbA(1c) was not affected by sex, age, BMI, haemoglobin, serum creatinine or albumin. CONCLUSION: The reduction in glycated albumin 3 weeks after the initiation of treatment corresponded with the reduction in HbA(1c) 3 months after starting treatment in both the group treated with a oral hypoglycaemic agent and the insulin-treated group of Korean patients with Type 2 diabetes. PMID- 21781152 TI - Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. AB - AIMS: To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA(1c) 53-86 mmol/mol (7.0-10.0%)] by metformin and sulphonylurea combination treatment. METHODS: A multi-centre, 24-week, randomized, double-blind, parallel group study in 1058 patients comparing linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA(1c) after 24 weeks. RESULTS: At week 24, the linagliptin placebo-corrected HbA(1c) adjusted mean change from baseline was -7 mmol/mol (-0.62%) [95% CI -8 to -6 mmol/mol (-0.73 to -0.50%); P < 0.0001]. More participants with baseline HbA(1c) >= 53 mmol/mol (>= 7.0%) achieved an HbA(1c) < 53 mmol/mol (<7.0%) with linagliptin compared with placebo (29.2% vs. 8.1%, P< 0.0001). Fasting plasma glucose was reduced with linagliptin relative to placebo (-0.7 mmol/l, 95% CI 1.0 to -0.4; P<0.0001). Improvements in homeostasis model assessment of beta-cell function were seen with linagliptin (P<0.001). The proportion of patients who reported a severe adverse event was low in both groups (linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7 and 10.3% of the linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups, respectively. No significant weight changes were noted. CONCLUSIONS: In patients with Type 2 diabetes, adding linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated. Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea. PMID- 21781153 TI - Family history of diabetes and effectiveness of lifestyle counselling on the cardio-metabolic risk profile in individuals at high risk of Type 2 diabetes: 1 year follow-up of the FIN-D2D project. AB - AIMS: To investigate whether a positive family history of diabetes is associated with the effectiveness of lifestyle counselling on cardio-metabolic risk factors and glucose tolerance status in a 1-year follow-up in a cohort of Finnish men and women at high risk for Type 2 diabetes. METHODS: Altogether, 10,149 individuals who had high risk of Type 2 diabetes participated in the implementation programme of the national diabetes prevention programme at baseline. One-year follow-up data were available for 2798 individuals without diabetes. Family history of diabetes was based on self-report. Lifestyle interventions were individual or groups sessions on lifestyle changes. The effectiveness of lifestyle intervention was measured as changes in cardiovascular risk factors, glucose tolerance status and incidence of Type 2 diabetes. RESULTS: Family history was associated with the effectiveness of lifestyle intervention in men, but not in women. During the 1 year follow-up, body weight, BMI, systolic blood pressure, total cholesterol, LDL cholesterol and score for 10-year risk for fatal cardiovascular disease (SCORE) decreased and glucose tolerance status improved more in men without a family history of diabetes than in men with a family history of diabetes. Of the participating men and women, 10% and 5% developed Type 2 diabetes, respectively. Family history was not related to the incidence of Type 2 diabetes in either gender. CONCLUSIONS: Men without a family history of diabetes were more successful in responding to lifestyle counselling with regard to cardio-metabolic measurements and glucose tolerance than those with a family history of diabetes. Similar results were not seen in women. In keeping with findings from earlier studies, the prevention of Type 2 diabetes is not influenced by a family history of diabetes. PMID- 21781154 TI - Undiagnosed diabetes in the over-60s: performance of the Association of Public Health Observatories (APHO) Diabetes Prevalence Model in a general practice. AB - AIM: The Association of Public Health Observatories (APHO) Diabetes Prevalence Model has been interpreted to suggest that a substantial number of people with diabetes are 'missed'. An affluent suburb of Newcastle upon Tyne has a low known diabetes prevalence. We aimed to determine the true prevalence of diabetes in the practice population aged over 60 years and compare our prevalence estimate with that of the Association of Public Health Observatories Diabetes Prevalence Model (18.0%; uncertainty limit 10.7-27.7%). At baseline, the known prevalence of diabetes in this group was 7.4%. METHODS: All individuals aged 60 years and over registered with one general practice in Newcastle-upon-Tyne, not known to have diabetes (n = 1375), were invited for a standard oral glucose tolerance test and measurement of HbA(1c). Standard World Health Organization cut points for fasting and post-challenge glucose on oral glucose tolerance test or HbA(1c) >= 48 mmol/mol (6.5%) were used to identify diabetes. RESULTS: Five hundred and eighty four individuals (42.5%) attended for screening. Using oral glucose tolerance test criteria, 4.5% were identified with undiagnosed diabetes. Using HbA(1c), 3.1% had undiagnosed diabetes. The estimated prevalence of total diabetes for the practice population aged 60 years and older is 11.8 (10.5-13.2%) and 10.3 (9.3 11.6) for oral glucose tolerance test and HbA(1c) criteria, respectively. CONCLUSIONS: The prevalence of diabetes in those aged 60 years and older registered with this practice is lower than the point estimate of the Association of Public Health Observatories Diabetes Prevalence Model, but within its uncertainty limits. Application of the Association of Public Health Observatories model must take into account its uncertainty limits. PMID- 21781155 TI - Are arterial and venous samples clinically equivalent for the estimation of pH, serum bicarbonate and potassium concentration in critically ill patients? AB - AIMS: To assess the comparability of venous and arterial samples for pH, bicarbonate and potassium measurements in critically ill patients. METHODS: Simultaneous arterial and venous samples from 206 critically ill patients were analysed in duplicate. Coefficients of variation and 95% limits of agreement were calculated for arterial and venous samples. Bland-Altman plots were constructed to assess agreement between sampling sites. RESULTS: The median (range) of arterial pH, bicarbonate concentrations, potassium concentrations and glucose concentrations were 7.40 (7.01-7.56), 25 (9-41) mmol/l, 4.2 (3.1-6.8) mmol/l and 7.4 (3.0-13.5) mmol/l, respectively. Coefficients of variation for arterial and venous pH were both 0.1%, with bias (95% limits of agreement) of -0.01 (-0.03 to 0.01) for arterial and -0.01 (-0.02 to 0.01) for venous samples. The bias (95% limits of agreement) between arterial and venous samples was 0.03 (-0.02 to 0.08). Coefficients of variation for arterial and venous bicarbonate results were 0.8 and 0.7%, respectively, with bias (95% limits of agreement) of 0 (-0.5 to 0.5) mmol/l for both sample types. The bias (95% limits of agreement) between venous and arterial samples was 0 (-1.3 to 1.3) mmol/l. Coefficients of variation for arterial and venous potassium samples were 0.8 and 1.1%, respectively, with bias (95% limits of agreement) of 0 (-0.1 to 0.1) for both sample types. The bias (95% limits of agreement) between venous and arterial samples was 0.1 (-0.4 to 0.6) mmol/l. CONCLUSIONS: A venous blood sample, analysed on a blood gas machine, is sufficiently reliable to assess pH, bicarbonate and potassium concentrations in critically ill patients, suggesting that venous sampling alone is appropriate in the management of diabetic ketoacidosis. PMID- 21781156 TI - Development of fulminant Type 1 diabetes with thrombocytopenia after influenza vaccination: a case report. AB - BACKGROUND: Fulminant Type 1 diabetes was originally reported as idiopathic Type 1 diabetes. Involvement of viral infections in the pathogenesis of fulminant T1D has been suggested, but the development of fulminant Type 1 diabetes after influenza vaccination has not been reported. CASE REPORT: We report a case of fulminant Type 1 diabetes with thrombocytopenia following influenza vaccination. A 54-year-old man was admitted to hospital with hyperglycaemia and diabetic ketosis. Seven days before admission, he received a seasonal influenza vaccine for the prevention of influenza infection. On admission, blood glucose was 29 mmol/L and HbA1c 40 mmol/mol (5.9%). Fasting and 2-h C-peptide immunoreactivity were <0.0333 nmol/L and 0.0999 nmol/L, respectively. Anti-GAD and anti-IA-2 antibodies were negative, so no autoimmunity seemed to participate in the etiology. ELISPOT assay also showed no association with T cell-mediated autoimmunity. HLA genotypes were consistent with susceptibility to fulminant Type 1 diabetes. After the abrupt onset of diabetes, he showed mild thrombocytopenia, which has been observed for approximately 5 years after diabetes development. CONCLUSION: This is the first description of fulminant Type 1 diabetes after influenza vaccination. Our observation raises the possibility that influenza vaccination might trigger this condition via the TLR7 pathway. PMID- 21781157 TI - I(Ks) blockade in border zone arrhythmias from guinea-pig ventricular myocardium submitted to simulated ischemia and reperfusion. AB - I(Ks) blockade might be a promising way to treat tachyarrhythmia because of the accumulation of activated potassium channels. However, I(Ks) blockade during ischemia/reperfusion has not been investigated. Thus, the electrophysiological effects of two I(Ks) blockers, chromanol 293B (10 MUm) and HMR 1556 (1 MUm), were assessed in an in vitro model of border zone between normal and ischemic/reperfused right ventricular myocardium from guinea-pigs, and classic electrophysiological parameters and the incidence of arrhythmias were studied. HMR 1556 and chromanol 293B exhibited slight conventional class III effects on action potential duration in the normal zone (NZ) (APD(90) : -2 +/- 5%, not significant (NS); +6 +/- 3%, NS; and +5 +/- 1%, P < 0.05, respectively, in control, HMR 1556, and chromanol 293B groups) but failed to oppose its decrease after 30 min of simulated ischemic superfusion (APD(90) : -52 +/- 5%, P < 0.01; 64 +/- 5%, P < 0.01; and -61 +/- 3%, P < 0.01, respectively, in control, HMR 1556, and chromanol 293B groups), leading to repolarization dispersion between normal and ischemic zones. Chromanol 293B and HMR 1556 prolonged APD(90) during reperfusion, respectively, by +11 +/- 1%, P < 0.01 and +25 +/- 4%, P < 0.01 in the NZ and by +13 +/- 3%, NS and +31 +/- 2%, P < 0.01 in the simulated ischemic zone. Both compounds exhibited neutral arrhythmogenic effects during ischemia or reperfusion. Thus, I(Ks) blockade was neutral on the occurrence of ventricular arrhythmias during ischemia and reperfusion in guinea-pig ventricular tissue. PMID- 21781158 TI - Decision-making under conditions of uncertainty-what can we learn from palivizumab? PMID- 21781159 TI - Effect of caesarean section on brain maturation. AB - The rates of caesarean section (CS) are increasing worldwide. The short-term effects of CS in the newborn have been described and long-term reported risks of alterations of pathophysiology include altered microflora, increased risk of childhood asthma and childhood-onset type I diabetes mellitus. There has been emphasis on the respiratory morbidity related to the timing of elective CS. More recently, a population study demonstrated dose-dependent effect of each week of gestation on the need for special education. This highlights the importance of intrauterine brain development towards the end of pregnancy and hitherto largely unexplored possible effects on neurodevelopment if it is interrupted. CONCLUSION: The timing of CS is important not only because delivery before 39 weeks can increase respiratory morbidity, but also owing to the fact that ongoing intrauterine brain maturation could be significant for future neurodevelopment. PMID- 21781160 TI - The effect of atenolol on NT-proBNP and troponin in asymptomatic cats with severe left ventricular hypertrophy because of hypertrophic cardiomyopathy: a pilot study. AB - BACKGROUND: Atenolol often is used empirically in cats with hypertrophic cardiomyopathy (HCM) before the onset of heart failure, although evidence of efficacy is lacking. Cardiac biomarkers play a critical role in the early detection of subclinical cardiac disease, in the prediction of long-term prognosis, and in monitoring the response to therapy in humans. HYPOTHESIS: Circulating concentrations of the biomarkers N-terminal pro-B type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) will decrease after chronic administration of atenolol PO to cats with severe HCM but no signs of heart failure. ANIMALS: Six Maine Coon or Maine Coon cross cats with severe HCM. METHODS: Cats were treated with atenolol (12.5 mg PO q12 h) for 30 days. No cat had left ventricular dynamic outflow tract obstruction caused by systolic anterior motion of the mitral valve. The concentrations of NT-proBNP and cTnI were assayed before and on the last day of drug administration. RESULTS: There was no statistically significant change in NT-proBNP (median before, 394 pmol/L; range, 71-1,500 pmol/L; median after, 439 pmol/L; range, 24-1,500 pmol/L; P = .63) or in cTnI (median before, 0.24 ng/mL; range, 0.10-0.97 ng/mL; median after, 0.28 ng/mL; range, 0.09-1.0 ng/mL; P = .69) after administration of atenolol. CONCLUSIONS: Atenolol administration did not decrease NT-proBNP or cTnI concentrations in cats with severe left ventricular hypertrophy caused by hypertrophic cardiomyopathy. These results suggest that atenolol did not decrease myocardial ischemia and myocyte death in these cats. A larger clinical trial is warranted to verify these findings. PMID- 21781161 TI - A novel movement disorder in related male Labrador Retrievers characterized by extreme generalized muscular stiffness. AB - OBJECTIVES: To describe the clinical phenotype of a new motor disorder in Labrador Retrievers. ANIMALS AND METHODS: Case series study. Seven young male Labrador Retrievers presented for evaluation of stiff gait. RESULTS: All affected dogs had generalized muscular stiffness, persistent at rest and resulting in restricted joint movements. They showed a forward flexed posture, festinating gait, and bradykinesia. Signs developed between 2 and 16 months of age and tended to stabilize in adulthood. Needle electromyogram in the conscious state showed continuous motor unit activity in resting epaxial and proximal limb muscles. This activity was abolished by general anesthesia. Muscle and nerve histopathology was normal. In 2 dogs necropsied, astrocytosis was evident throughout the spinal cord gray matter, reticular formation and caudate nuclei. Decreased neuronal counts were selectively found in the spinal cord Rexed's lamina VII, but not in VIII and IX. Pedigree analysis showed that the affected dogs were from 5 related litters. CONCLUSIONS AND CLINICAL IMPORTANCE: This new hypertonicity syndrome in Labrador Retrievers is unique because of the selective distribution of the histological lesions, the lack of progression in adulthood, and its exclusive occurrence in male dogs. Pedigree analysis suggests an X-linked hereditary disease, although other modes of inheritance cannot be ruled out with certainty. We hypothesize that altered output from basal nuclei and reticular formation together with motor neuron disinhibition caused by a decreased number of spinal cord interneurons leads to the muscular stiffness. PMID- 21781162 TI - Synovial fluid D-dimer concentration in foals with septic joint disease. AB - BACKGROUND: Increased synovial fibrinolytic activity (detected by increases in synovial D-Dimer concentrations) has been observed in different joint diseases in humans and adult horses, presumably in order to minimize fibrin deposition within the joint and thus avoid its detrimental effects. OBJECTIVE: To investigate fibrinolytic pathway activation in joint sepsis in foals by measuring synovial D Dimer concentrations. ANIMALS: Eighteen septic foals with septic joints, 9 septic foals without septic joints, 9 systemically healthy foals with septic joint, and 3 controls are included. METHODS: Prospective observational clinical study of foals admitted for septic arthritis. Synovial D-Dimer concentration and routine synovial fluid analysis were performed. Diagnosis of joint sepsis was made whenever synovial total nucleated cell count was >30,000 cells/MUL, synovial total protein >4 g/dL, and neutrophil percentage of >80%, or synovial fluid culture resulted positive. Results were compared among groups by general lineal models. RESULTS: Synovial D-Dimer concentration was significantly (P < .001) higher in the foals with septic joints compared with foals without joint disease (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Septic joint disease is associated with a marked increase of synovial D-Dimer concentration (marked activation of the fibrinolytic activity) within the affected joint. Although further studies are needed, the measurement of synovial D-Dimer concentration may be considered a complementary diagnostic marker of septic joint disease. PMID- 21781163 TI - Retrospective evaluation of urethral bovine cross-linked collagen implantation for treatment of urinary incontinence in female dogs. AB - BACKGROUND: Transurethral collagen injections are an alternative treatment for canine urinary incontinence. There is controversy regarding the long-term effectiveness of collagen and the impact urethral coaptation and injection site have on outcome. HYPOTHESIS/OBJECTIVES: To evaluate outcome and client satisfaction after urethral collagen injections, and correlation between degree of urethral coaptation and collagen placement with outcome. ANIMALS: Thirty-six procedures on 31 dogs, 10 with ureteral ectopia. METHODS: Retrospective review of records and video evaluation of injection procedures. Follow-up communication with owners was performed between 1 and 56 months after bovine cross-linked collagen implantation to evaluate duration of continence, need for additional medical therapy, and owner satisfaction. Continence score was evaluated before and after the procedure, and after additional medical therapy, if needed. Injection location and degree of urethral coaptation was assessed with respect to duration of continence. RESULTS: Dogs had a significant increase in continence score after the procedure. Mean (SD) duration of continence in dogs without addition of medication was 16.4 (15.2) months, and 5.2 (4.3) months in dogs needing additional medical therapy. No significant difference was found with respect to degree of coaptation. Median client satisfaction with the procedure was 100%. CONCLUSIONS AND CLINICAL IMPORTANCE: Transurethral collagen implantation may be a viable option for treatment of female dogs with urethral sphincter mechanism incompetence, particularly after medical failure. Duration and degree of improvement are variable. Client satisfaction was excellent despite lack of complete continence in some dogs, and highlights the importance of discussing outcome expectations with owners. PMID- 21781164 TI - Systemic effects of a prolonged continuous infusion of ketamine in healthy horses. AB - BACKGROUND: Ketamine as continuous rate infusion (CRI) provides analgesia in hospitalized horses. OBJECTIVE: Determine effects of prolonged CRI of ketamine on gastrointestinal transit time, fecal weight, vital parameters, gastrointestinal borborygmi, and behavior scores in healthy adult horses. ANIMALS: Seven adult Thoroughbred or Thoroughbred cross horses, with permanently implanted gastric cannulae. METHODS: Nonblinded trial. Random assignment to 1 of 2 crossover designed treatments. Ketamine (0.55 mg/kg IV over 15 minutes followed by 1.2 mg/kg/h) or lactated Ringer's solution (50 mL IV over 15 minutes followed by 0.15 mL/kg/h) treatments. Two hundred 3 * 5 mm plastic beads administered by nasogastric tube before drug administration. Every 2 hours vital parameters, behavior scores recorded, feces collected and weighed, and beads retrieved. Every 6 hours gastrointestinal borborygmi scores recorded. Study terminated upon retrieval of 180 beads (minimum 34 hours) or maximum 96 hours. Nontransit time data analyzed between hours 0 and 34. RESULTS: No significant (P < .05) differences detected between treatments in vital signs or gastrointestinal borborygmi. Significant (P = .002) increase in behavior score during ketamine infusion (0.381) from hours 24-34 compared with placebo (0). Ketamine caused significant delay in passage of 25, 50, and 75% of beads (ketamine = 30.6 +/- 5.3, 41.4 +/- 8.4, 65.3 +/- 13.5 hours versus placebo = 26.8 +/- 7.9, 34.3 +/- 11.1, 45.8 +/- 19.4 hours), and significant (P < .05) decrease in fecal weight from hours 22 (12.6 +/- 3.2 versus 14.5 +/- 3.8 kg) through 34 (18.5 +/- 3.9 versus 12.8 +/- 6.4 kg) of infusion. CONCLUSIONS AND CLINICAL IMPORTANCE: Ketamine CRI delayed gastrointestinal transit time in healthy horses without effect on vital parameters. PMID- 21781165 TI - Cardiac magnetic resonance in the differentiation of neoplastic and nonneoplastic pericardial effusion. AB - BACKGROUND: Cardiac magnetic resonance (CMR) is the imaging modality of choice for cardiac tumors in people. Although neoplastic pericardial effusion (PE) carries a poor prognosis, benign idiopathic pericardial effusion does not. Definitive diagnosis is critical for surgical intervention, but currently available diagnostic techniques such as echocardiography and pericardial fluid cytology often are inconclusive. HYPOTHESIS/OBJECTIVE: Describe CMR findings associated with PE and determine whether CMR aids in differentiation of benign and neoplastic causes of PE. ANIMALS: Eight client-owned dogs with PE diagnosed by transthoracic echocardiography (TTE). METHODS: CMR was performed with a 1.5 T, including dark blood, steady-state free procession cine, pre- and postcontrast T1 weighted imaging, and delayed inversion recovery prepped imaging. RESULTS: CMR confirmed a cardiac mass and supported suspected tumor type in 4 dogs with suspected hemangiosarcoma. In 1 equivocal TTE case, CMR did not demonstrate a mass, but neoplasia was later diagnosed. In another equivocal case, CMR did not demonstrate a mass but showed findings consistent with a pericardiocentesis complication. In 1 dog without evidence of cardiac neoplasia, abdominal magnetic resonance imaging identified presumptive hepatic and splenic metastases. On reevaluation of the original CMR study, the 2 equivocal cases that were interpreted as tumor negative were reassessed as tumor positive. CONCLUSIONS AND CLINICAL IMPORTANCE: CMR did not substantially improve diagnosis of cardiac tumors compared with TTE in these 8 cases, but it yielded useful descriptive information regarding extent, anatomic location, and potential tumor type and confirmed that CMR requires extensive additional training for tumor identification. PMID- 21781166 TI - Distribution of flunixin meglumine and firocoxib into aqueous humor of horses. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used systemically for the treatment of inflammatory ocular disease in horses. However, little information exists regarding the ocular penetration of this class of drugs in the horse. OBJECTIVE: To determine the distribution of orally administered flunixin meglumine and firocoxib into the aqueous humor of horses. ANIMALS: Fifteen healthy adult horses with no evidence of ophthalmic disease. METHODS: Horses were randomly assigned to a control group and 2 treatment groups of equal sizes (n = 5). Horses assigned to the treatment groups received an NSAID (flunixin meglumine, 1.1 mg/kg PO q24h or firocoxib, 0.1 mg/kg PO q24h for 7 days). Horses in the control group received no medications. Concentrations of flunixin meglumine and firocoxib in serum and aqueous humor and prostaglandin (PG) E(2) in aqueous humor were determined on days 1, 3, and 5 and aqueous : serum ratios were calculated. RESULTS: Firocoxib penetrated the aqueous humor to a significantly greater extent than did flunixin meglumine at days 3 and 5. Aqueous : serum ratios were 3.59 +/- 3.32 and 11.99 +/- 4.62% for flunixin meglumine and firocoxib, respectively. Ocular PGE(2) concentrations showed no differences at any time point among study groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Both flunixin meglumine and firocoxib penetrated into the aqueous humor of horses. This study suggests that orally administered firocoxib penetrates the aqueous humor better than orally administered flunixin meglumine at label dosages in the absence of ocular inflammation. Firocoxib should be considered for the treatment of inflammatory ophthalmic lesions in horses at risk for the development of adverse effects associated with nonselective NSAID administration. PMID- 21781167 TI - Multisystem cranial polyneuritis and ganglionitis in a dog. PMID- 21781168 TI - Treatment of aseptic dogs with hemorrhagic gastroenteritis with amoxicillin/clavulanic acid: a prospective blinded study. AB - BACKGROUND: Antibiotics generally are recommended to treat hemorrhagic gastroenteritis (HGE). Inappropriate use of antibiotics may promote risk of antimicrobial resistance and unnecessary adverse drug reactions. The necessity of antimicrobial therapy in dogs with HGE has not been demonstrated. OBJECTIVE: The purpose of this prospective, placebo-controlled, blinded study was to evaluate whether treatment with amoxicillin/clavulanic acid improves the clinical course and outcome of HGE in dogs that show no signs of sepsis. ANIMALS: The study included 60 dogs diagnosed with HGE between 2007 and 2009 at the Clinic of Small Animal Medicine, LMU University of Munich, Germany. The inclusion criterion was the presence of acute hemorrhagic diarrhea (<3 days). Dogs pretreated with antibiotics, with signs of sepsis, or diagnosed with any disease known to cause bloody diarrhea were excluded from the study. METHODS: Patients were randomly divided into treatment (amoxicillin/clavulanic acid for 7 days) and placebo groups. To evaluate treatment efficacy, severity of clinical signs (based on a newly developed HGE index), duration of hospitalization, and mortality rate were compared between the 2 groups. RESULTS: Fifty-three of 60 dogs completed the study. No significant difference between treatment groups concerning mortality rate, dropout rate, duration of hospitalization, or severity of clinical signs, either on any individual day or over the course of disease, was observed. CONCLUSIONS AND CLINICAL IMPORTANCE: In some dogs with HGE that show no signs of sepsis, antibiotics may not change the case outcome or time to recovery. PMID- 21781169 TI - Serum and bronchoalveolar lavage fluid endothelin-1 concentrations as diagnostic biomarkers of canine idiopathic pulmonary fibrosis. AB - BACKGROUND: Diagnosis of canine idiopathic pulmonary fibrosis (IPF) is challenging. Endothelin-1 (ET1) is a biomarker of IPF in humans, but whether ET1 can detect and differentiate IPF from other canine respiratory diseases is unknown. OBJECTIVE: To evaluate whether measurement of the concentration of ET1 in serum and bronchoalveolar lavage fluid (BALF) can be used to distinguish canine IPF from chronic bronchitis (CB) and eosinophilic bronchopneumopathy (EBP). ANIMALS: Twelve dogs with IPF, 10 dogs with CB, 6 dogs with EBP, 13 privately owned healthy West Highland White Terriers (WHWT), and 9 healthy Beagle dogs. METHODS: Prospective, case control study. ET1 concentration was determined by ELISA in serum and in BALF. RESULTS: No significant difference in serum ET1 concentration was detected between healthy Beagle dogs and WHWT. Serum ET1 concentration was higher in dogs with IPF (median interquartile range; 2.32 pg/mL, 2.05-3.38) than healthy Beagle dogs (1.28, 1.07-1.53; P < .001), healthy WHWT (1.56, 1.25-1.85; P < .001), dogs with EBP (0.94 0.68-1.01; P = .001), and dogs with CB (1.54 0.74-1.82; P = .005). BALF ET1 concentration was below the detection limit in healthy WHWT and in dogs with CB, whereas it was measurable in all dogs with IPF. A cut-off serum concentration of 1.8 pg/mL had a sensitivity of 100% and a specificity of 81.2% for detection of IPF, with an area under the receiver operating characteristic curve of 0.818. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum ET1 can differentiate dogs with IPF from dogs with EBP or CB. ET1 can be detected in BALF of dogs with IPF. PMID- 21781170 TI - Class II major histocompatibility complex expression and cell size independently predict survival in canine B-cell lymphoma. AB - BACKGROUND: Class II major histocompatibility complex (MHC) is an independent predictor of outcome in human B-cell lymphoma. We assessed class II expression together with other markers for their impact on prognosis in canine B-cell lymphoma. HYPOTHESIS: Low class II MHC expression, large cell size, and expression of CD34 will predict a poorer outcome in canine B-cell lymphoma. Expression of CD5 and CD21 on tumor cells also may be associated with outcome. ANIMALS: One hundred and sixty dogs with cytologically confirmed lymphoma. METHODS: Patient signalment, treatment type, and flow cytometry characteristics were analyzed for their influence on outcome. A multivariable predictive model of survival was generated using 2/3 of the patients and validated on the remaining 1/3 of the dataset. RESULTS: Class II MHC expression had a negative association with mortality and relapse. Treatment type also influenced relapse and mortality, whereas cell size and patient age was only associated with mortality. CD34, CD21, and CD5 expression was not associated with disease outcome. The constructed model performed variably in predicting the validation group's outcome at the 6-month time point. CONCLUSIONS AND CLINICAL IMPORTANCE: Low levels of class II MHC expression on B-cell lymphoma predict a poor outcome, as in human B-cell lymphoma. This finding has implications for the use of dogs to model human lymphomas. Class II expression, cell size, treatment, and age can be combined to predict mortality with a high level of specificity. PMID- 21781171 TI - Antimicrobial activity of gallium nitrate against Mycobacterium avium subsp. paratuberculosis in neonatal calves. AB - BACKGROUND: Mycobacterium avium subsp. paratuberculosis (MAP), the agent of Johne's disease in cattle, is a facultative intracellular bacterium that is dependent on ferric iron for its survival and replication. Gallium (Ga), a trivalent semimetal that shares many similarities with ferric iron and functions as an iron mimic has been shown to have in vitro antimicrobial activity against several microorganisms, including MAP. OBJECTIVES: (1) To investigate the antimicrobial activity of Ga in calves experimentally infected with MAP; and (2) to monitor for potential adverse effects of Ga on calf health. ANIMALS: Twelve Holstein calves. METHODS: Randomized blind controlled experiment. Beginning at 10 days of age (study day 1), the experimental calves (n = 6) were treated with 20 mg/kg gallium nitrate daily for 45 days. On study days 4 and 5, all calves were challenged with a PO dose of a live field strain MAP. Treated calves were monitored daily for adverse effects. Calves were euthanized on study day 100, and 29 tissue samples and 1 fecal sample were collected from each calf. Samples were cultured for MAP by MGIT liquid culture system, Herrold's Egg Yolk Medium culture, or both. RESULTS: No adverse effects were observed in the treated calves. Treatment was associated with a significant reduction in MAP tissue burden when compared with control calves (P = .017). CONCLUSIONS AND CLINICAL RELEVANCE: Chemoprophylactic treatment of calves with Ga before and during the period of high susceptibility decreased MAP tissue colonization in experimentally infected neonatal calves. PMID- 21781172 TI - Higher access-associated bacteremia but less hospitalization among Saudi compared with US hemodialysis outpatients. AB - Comparison of Saudi patients with chronic hemodialysis to an international benchmark was not performed before. We conducted a prospective surveillance study for all end-stage kidney disease patients served by the hemodialysis unit at King Abdulaziz Medical City (KAMC) in Riyadh, SA, between May 2008 and December 2009. US National Healthcare Safety Network (NHSN) definitions were used for comparison. Among 227 patients with adverse events, 55% were women and their age was 60.2 +/- 20.2 years. Events recorded included 339 all-cause hospitalizations, 302 outpatient start of intravenous antimicrobials, and 174 access-associated bacteremias. In comparison with NHSN, hospitalization rate per 100 patient-months was lower (8.6 vs. 10.7, p < 0.001), rates of both antimicrobial start (7.6 vs. 3.5, p < 0.001) and access-associated bacteremia (4.4 vs. 1.3, p < 0.001) were higher, and blood cultures were more likely to grow gram-negative rods (47.9% vs. 21.3%, p < 0.001). Similar to NHSN, permanent catheter was associated with highest, while arterio-venous fistula was associated with lowest event rates, irrespective of event type. KAMC had 2-4 times higher rates of access-associated bacteremia and antimicrobial start as well as a higher catheter prevalence (42% vs. 31%). The lower hospitalization may indicate good control of comorbidities at outpatient level or underutilization of inpatient services. PMID- 21781175 TI - Tumours of the oral cavity. PMID- 21781174 TI - Maternal depression related to infant's wheezing. AB - OBJECTIVE: To assess whether maternal psychological status is related to infant's wheezing. STUDY DESIGN: In a case-control study conducted in Paris in cases aged less than 36 months suffering from wheezing and matched healthy controls, mothers filled a standardized questionnaire on child's health and the State Trait Anxiety Inventory form Y-B and the Beck Depression Inventory short form. Cases underwent also routine clinical and biological assessments. The statistical analysis used the propensity score analysis to control for selection bias. RESULTS: Hundred and thirty-eight wheezers and hundred and nine controls participated in the study. After adjustment for confounders, maternal depressive symptoms at the period of the survey according to the Beck Inventory were more significantly found in the cases than in others (p < 0.01). A trend was found for maternal depression during pregnancy. Among the cases, 10.6% suffered from severe asthma, 84.8% took inhaled corticosteroids (ICs), 17.4% had positive specific immunoglobulin E (IgE) to allergens and 11.5% hypereosinophilia. The more the mother was depressed according to the Beck Inventory, the more the infant's asthma was severe (OR = 4.25, 95% CI: 1.14, 15.9 between severe infant's wheezing and severe maternal depression). No relationship was observed between mother's depressive symptoms and ICs taken by the infant, allergic sensitization or eosinophilia. CONCLUSION: Our findings support the hypothesis of a link between maternal depression and infant's wheezing and its severity early in life independent of allergic status. Consequences of our study include the need to assess depressive symptoms in mothers of infants with asthma. PMID- 21781173 TI - Increased plasma chymase concentration and mast cell chymase expression in venous neointimal lesions of patients with CKD and ESRD. AB - The underlying inflammatory component of chronic kidney disease may predispose blood vessels to intimal hyperplasia (IH), which is the primary cause of dialysis access failure. We hypothesize that vascular pathology and markers of IH formation are antecedent to arteriovenous (AV) fistula creation. Blood, cephalic, and basilic vein segments were collected from predialysis chronic kidney disease (CKD) patients with no previous AV access and patients with end-stage renal disease (ESRD). Immunohistochemistry was performed with antibodies against mast cell chymase, transforming growth factor-beta (TGF-beta) and interleukin-6 (IL 6), which cause IH. Plasma chymase was measured by ELISA. IH was present in 91% of CKD and 75% of ESRD vein segments. Chymase was abundant in vessels with IH, with the greatest expression in intima and medial layers, and virtually absent in the controls. Chymase colocalized with TGF-beta1 and IL-6. Plasma chymase concentration was elevated up to 33-fold in patients with CKD versus controls and was associated with increased chymase in vessels with IH. We show that chymase expression in vessels with IH corresponds with plasma chymase concentrations. As chymase inhibition attenuates IH in animal models, and we find chymase is highly expressed in IH lesions of patients with CKD and ESRD, we speculate that chymase inhibition could have therapeutic value in humans. PMID- 21781176 TI - Squamous cell carcinoma and precursor lesions: clinical presentation. PMID- 21781177 TI - Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. PMID- 21781178 TI - Squamous cell carcinoma and precursor lesions: prevention. PMID- 21781179 TI - Squamous cell carcinoma and precursor lesions: clinical pathology. PMID- 21781181 TI - Contemporary clinical management of oral squamous cell carcinoma. PMID- 21781180 TI - Squamous cell carcinoma and precursor lesions: diagnosis and screening in a technical era. PMID- 21781182 TI - Oral rehabilitation following treatment for oral cancer. PMID- 21781183 TI - Oral cancers: supportive care issues. PMID- 21781184 TI - An overview of the molecular pathology of head and neck cancer, and its clinical implications. PMID- 21781185 TI - Salivary tumours. PMID- 21781186 TI - Odontogenic tumors: a review. PMID- 21781187 TI - Soft tissue tumors and common metastases of the oral cavity. PMID- 21781188 TI - Consumer views on the potential use of mobile phones for the delivery of weight loss interventions. AB - BACKGROUND: The surge in the incidence of obesity and being overweight demands new options to extend the reach of weight-loss interventions. Mobile phones provide a medium for reaching large numbers of people in a cost-effective manner. The present study aimed to explore the potential for weight-loss interventions to be delivered via mobile phone. METHODS: A mixed methods approach was employed. A telephone survey was conducted with 306 randomly selected participants, and 10 focus groups were undertaken with 54 purposively selected participants. The telephone survey comprised questions exploring the nature and acceptability of any potential weight-loss programme that might be delivered via mobile phones. The focus groups were conducted to explore issues of acceptability in more depth than was possible in the survey. RESULTS: Two-thirds of participants reported support for a mobile phone weight-loss intervention, with greater levels of support amongst younger age groups and rural Maori (the indigenous population in New Zealand). Participants liked the idea of ready access to weight-loss information, and associated feedback and encouragement. The results suggest that interventions would need to include aspects of social support, use tailored and personalised content, and be practical and relevant so that they appeal to consumers. Appropriate methods of providing social support using a mobile phone require further exploration. CONCLUSIONS: Mobile phones may provide a novel but acceptable way to deliver a weight-loss intervention. They have the potential to be automatically personalised and tailored to the needs of the individual, at the same time as being delivered at a population level. PMID- 21781189 TI - Neuronal basis for evaluating selected action in the primate striatum. AB - Humans and animals optimize their behavior by evaluating outcomes of individual actions and predicting how much reward the actions will yield. While the estimated values of actions guide choice behavior, the choices are also governed by other behavioral norms, such as rules and strategies. Values, rules and strategies are represented in neuronal activity, and the striatum is one of the best qualified brain loci where these signals meet. To understand the role of the striatum in value- and strategy-based decision-making, we recorded striatal neurons in macaque monkeys performing a behavioral task in which they searched for a reward target by trial-and-error among three alternatives, earned a reward for a target choice, and then earned additional rewards for choosing the same target. This task allowed us to examine whether and how values of targets and strategy, which were defined as negative-then-search and positive-then-repeat (or win-stay-lose-switch), are represented in the striatum. Large subsets of striatal neurons encoded positive and negative outcome feedbacks of individual decisions and actions. Once monkeys made a choice, signals related to chosen actions, their values and search- or repeat-type actions increased and persisted until the outcome feedback appeared. Subsets of neurons exhibited a tonic increase in activity after the search- and repeat-choices following negative and positive feedback in the last trials as the task strategy monkeys adapted. These activity profiles as a heterogeneous representation of decision variables may underlie a part of the process for reinforcement- and strategy-based evaluation of selected actions in the striatum. PMID- 21781190 TI - Evaluating dopaminergic system contributions to cued pattern switching during bimanual coordination. AB - Switching between different coordinated movements has been shown to be slow, with delayed responses and even freezing deficits in individuals with Parkinson's disease (PD). While it is well accepted that the dopaminergic system responds to dopamine replacement to ameliorate overall slowness (bradykinesia) and other motor symptoms of PD, it is unknown whether the dopaminergic system can influence overall coordination between limbs and if this may be impacted by the availability of sensory feedback. In the current study, PD and healthy age matched control participants performed a rhythmic coordination task that required a cued voluntary switch between movement patterns (in-phase and anti-phase). PD participants performed the task first after overnight withdrawal ('off'), and subsequently after administration ('on') of dopamine replacement. Coordinated movements were performed while paced by an auditory metronome in two sensory conditions: 'no vision' or 'normal vision'. Measures of voluntary switch time and delayed responses revealed that PD 'off' required significantly more time than healthy participants to switch between movement patterns. Interestingly, PD 'off' demonstrated disrupted coordination, as revealed by mean (accuracy) and standard deviation (stability) of absolute error of relative phase. Dopamine replacement improved the time needed to switch and amount of delayed responses in PD participants, but had no influence on coordination itself. It is concluded that although modulation of the dopaminergic system improves the slowness during switching, coordination deficits may be the result of secondary impairments (possibly attention-related) that cannot be improved with dopamine replacement. PMID- 21781191 TI - Molecular and electrophysiological evidence for the expression of BK channels in oligodendroglial precursor cells. AB - Changes in intracellular Ca(2+) play a key role in regulating gene expression and developmental changes in oligodendroglial precursor cells (OPCs). However, the mechanisms by which Ca(2+) influx in OPCs is controlled remains incompletely understood. Although there are several mechanisms that modulate Ca(2+) influx, in many systems the large-conductance, voltage- and Ca(2+) -activated K(+) channel (BK channel) plays an important role in regulating both membrane excitability and intracellular Ca(2+) levels. To date, the role of the BK channel in the regulation of intracellular Ca(2+) in oligodendroglial lineage cells is unknown. Here we investigated whether cells of the oligodendroglial lineage express BK channels and what potential role they play in regulation of Ca(2+) influx in these cells. In oligodendrocytes derived from differentiated adult neural precursor cells (NPCs, obtained from C57bl6 mice) we observed outward currents that were sensitive to the BK channel blocker iberiotoxin (IbTx). Further confirmation of the expression of the BK channel was obtained utilizing other blockers of the BK channel and by confocal immunofluoresence labelling of the BK channel on oligodendroglia. Using Fura-2AM to monitor intracellular Ca(2+) , it was observed that inhibition of the BK channel during glutamate-induced depolarization led to an additive increase in intracellular Ca(2+) levels. Electrophysiological difference currents demonstrated that the expression levels of the BK channel decrease with developmental age. This latter finding was further corroborated via RT-PCR and Western blot analysis. We conclude that the BK channel is involved in regulating Ca(2+) influx in OPCs, and may potentially play a role during differentiation of oligodendroglial lineage cells. PMID- 21781192 TI - Blue light stress in retinal neuronal (R28) cells is dependent on wavelength range and irradiance. AB - The aim of our study was to elucidate the role of wavelength and irradiance in blue light retinal damage. We investigated the impact of blue light emitted from light-emitting diode (LED) modules with peaks at either 411nm (half bandwidth 17nm) or 470nm (half bandwidth 25nm) at defined irradiances of 0.6, 1.5 and 4.5W/m(2) for 411nm and 4.5W/m(2) for 470nm on retinal neuronal (R28) cells in vitro. We observed a reduction in metabolic activity and transmembrane potential of mitochondria when cells were irradiated at 411nm at higher irradiances. Furthermore, production of mitochondrial superoxide radicals increased significantly when cells were irradiated with 411nm light at 4.5W/m(2) . In addition, such irradiation caused an activation of the antioxidative glutathion system. Using vital staining, flow cytometry and western blotting, we were able to show that apoptosis only took place when cells were exposed to 411nm blue light at higher irradiances; necrosis was not observed. Enhanced caspase-3 cleavage product levels confirmed that this effect was dependent on light irradiance. Significant alterations of the above-mentioned parameters were not observed when cells were irradiated with 471nm light despite a high irradiance of 4.5W/m(2) , indicating that the cytotoxic effect of blue light is highly dependent on wavelength. The observed phenomena in R28 cells at 411nm (4.5W/m(2) ) point to an apoptosis pathway elicited by direct mitochondrial damage and increased oxidative stress. Thus, light of 411nm should act via impairment of mitochondrial function by compromising the metabolic situation of these retinal neuronal cells. PMID- 21781194 TI - Cell autonomous and cell-type specific circadian rhythms in Arabidopsis. AB - The circadian system of plants regulates a wide range of rhythmic physiological and cellular output processes with a period of about 24 h. The rhythms are generated by an oscillator mechanism that, in Arabidopsis, consists of interlocking feedback loops of several components including CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1) and CCA1 HIKING EXPEDITION (CHE). Over recent years, researchers have gained a detailed picture of the clock mechanism at the resolution of the whole plant and several tissue types, but little information is known about the specificities of the clock mechanism at the level of individual cells. In this paper we have addressed the question of cell-type-specific differences in circadian systems. Using transgenic Arabidopsis plants with fluorescence-tagged CCA1 to measure rhythmicity in individual leaf cells in intact living plants, we showed that stomatal guard cells have a different period from surrounding epidermal and mesophyll leaf cells. By comparing transcript levels in guard cells with whole plants, we identified differences in the expression of some oscillator genes that may underlie cell-specific differences in clock properties. In addition, we demonstrated that the oscillators of individual cells in the leaf are robust, but become partially desynchronized in constant conditions. Taken together our results suggest that, at the level of individual cells, there are differences in the canonical oscillator mechanism that has been described for plants. PMID- 21781193 TI - Common capacity-limited neural mechanisms of selective attention and spatial working memory encoding. AB - One characteristic feature of visual working memory (WM) is its limited capacity, and selective attention has been implicated as limiting factor. A possible reason why attention constrains the number of items that can be encoded into WM is that the two processes share limited neural resources. Functional magnetic resonance imaging (fMRI) studies have indeed demonstrated commonalities between the neural substrates of WM and attention. Here we investigated whether such overlapping activations reflect interacting neural mechanisms that could result in capacity limitations. To independently manipulate the demands on attention and WM encoding within one single task, we combined visual search and delayed discrimination of spatial locations. Participants were presented with a search array and performed easy or difficult visual search in order to encode one, three or five positions of target items into WM. Our fMRI data revealed colocalised activation for attention-demanding visual search and WM encoding in distributed posterior and frontal regions. However, further analysis yielded two patterns of results. Activity in prefrontal regions increased additively with increased demands on WM and attention, indicating regional overlap without functional interaction. Conversely, the WM load-dependent activation in visual, parietal and premotor regions was severely reduced during high attentional demand. We interpret this interaction as indicating the sites of shared capacity-limited neural resources. Our findings point to differential contributions of prefrontal and posterior regions to the common neural mechanisms that support spatial WM encoding and attention, providing new imaging evidence for attention-based models of WM encoding. PMID- 21781195 TI - The Arabidopsis MERISTEM DISORGANIZATION 1 gene is required for the maintenance of stem cells through the reduction of DNA damage. AB - In plants, stem cells reside in apical meristems, and provide the descendants required for post-embryonic growth and development throughout the life of a plant. To identify a novel factor required for the maintenance of stem cells, we isolated an Arabidopsis mutant, named meristem disorganization 1-1 (mdo1-1), that exhibits several developmental defects, such as abnormal phyllotaxy and plastochron, stem fasciation and retarded root growth. We found that the mutant plants fail to maintain stem cells, resulting in the differentiation or death of stem cells. The mutant plants also showed several phenotypes related to DNA damage, suggesting that the mutant cells are exposed constitutively to DNA damage even without external genotoxic stress. The growth defect and the hypersensitivity to DNA-damaging agents of mdo1-1 were enhanced significantly when combined with a lesion of the ATAXIA-TELANGIECTASIA MUTATED (ATM) gene, but not of the ATM/RAD3-RELATED (ATR) gene, suggesting that the function of the MDO1 gene is closely related to that of ATM kinase. The MDO1 gene encodes an unknown protein that is conserved in a wide variety of land plants. The results thus suggested that the MDO1 gene product is required for the maintenance of stem cells through a reduction in DNA damage. PMID- 21781196 TI - Barley mildew and its elicitor chitosan promote closed stomata by stimulating guard-cell S-type anion channels. AB - Stomatal closure is known to be associated with early defence responses of plant cells triggered by microbe-associated molecular patterns (MAMPs). However, the molecular mechanisms underlying these guard-cell responses have not yet been elucidated. We therefore studied pathogen-induced changes in ion channel activity in Hordeum vulgare guard cells. Barley mildew (Blumeria graminis) hyphae growing on leaves inhibited light-induced stomatal opening, starting at 9 h after inoculation, when appressoria had developed. Alternatively, stomatal closure was induced by nano-infusion of chitosan via open stomata into the sub-stomatal cavity. Experiments using intracellular double-barreled micro-electrodes revealed that mildew stimulated S-type (slow) anion channels in guard cells. These channels enable the efflux of anions from guard cells and also promote K(+) extrusion by altering the plasma membrane potential. Stimulation of S-type anion channels was also provoked by nano-infusion of chitosan. These data suggest that MAMPs of mildew hyphae penetrating the cuticle provoke activation of S-type anion channels in guard cells. In response, guard cells extrude K(+) salts, resulting in stomatal closure. Plasma membrane anion channels probably represent general targets of MAMP signaling in plants, as these elicitors depolarize the plasma membrane of various cell types. PMID- 21781197 TI - Arabidopsis ARP endonuclease functions in a branched base excision DNA repair pathway completed by LIG1. AB - Base excision repair (BER) is an essential cellular defence mechanism against DNA damage, but it is poorly understood in plants. We used an assay that monitors repair of damaged bases and abasic (apurinic/apyrimidinic, AP) sites in Arabidopsis to characterize post-excision events during plant BER. We found that Apurinic endonuclease-redox protein (ARP) is the major AP endonuclease activity in Arabidopsis cell extracts, and is required for AP incision during uracil BER in vitro. Mutant plants that are deficient in ARP grow normally but are hypersensitive to 5-fluorouracil, a compound that favours mis-incorporation of uracil into DNA. We also found that, after AP incision, the choice between single nucleotide or long-patch DNA synthesis (SN- or LP-BER) is influenced by the 5' end of the repair gap. When the 5' end is blocked and not amenable to beta elimination, the SN sub-pathway is abrogated, and repair is accomplished through LP-BER only. Finally, we provide evidence that Arabidopsis DNA ligase I (LIG1) is required for both SN- and LP-BER. lig1 RNAi-silenced lines show very reduced uracil BER, and anti-LIG1 antibody abolishes repair in wild-type cell extracts. In contrast, knockout lig4(-/-) mutants exhibit normal BER and nick ligation levels. Our results suggest that a branched BER pathway completed by a member of the DNA ligase I family may be an ancient feature in eukaryotic species. PMID- 21781198 TI - Hypoplastic root cementum and premature loss of primary teeth in Coffin-Lowry syndrome: a case report. AB - BACKGROUND: Coffin-Lowry syndrome (CLS) is a rare genetic disorder. The syndrome presents with psychomotor retardation, short stature, skeletal deformations, digit abnormalities, and distinctive facial features. Oral and dental findings in CLS are common and they include thick prominent lips, high palate, midline lingual furrow, hypodontia, microdontia, delayed eruption, and early tooth loss. Only one earlier case suggesting hypoplastic root cementum as cause for primary loss of teeth in CLS has been published. CASE REPORT: This case describes a 3 year-old boy with premature loss of primary incisors without preceding root resorption. In addition to the dental findings, the boy had several general signs and symptoms and the dental findings together with the other characteristics led to the clinical diagnosis of CLS, which later was genetically verified. Histological analysis of an extracted primary incisor showed hypoplastic root cementum. CONCLUSION: Hypoplastic root cementum may explain early tooth loss in CLS. As early loss of primary teeth is rare, especially when there is no previous root resorption, the individual is likely to seek dental care. Thus, the dentist may play an important role in assisting in the diagnosing of CLS. PMID- 21781200 TI - The effect of chewing exercise in preschool children on maximum bite force and masticatory performance. AB - BACKGROUND: Mastication is a developing function affected by various factors. There is a need for further research on methods of promoting masticatory function in young children. AIM: The aim of this study was to evaluate the effects of gum chewing exercise on the maximum bite force (MBF) and the masticatory performance of preschool children. DESIGN: The study population included 98 preschool children age 4-6years. MBF was measured by Occlusal Force-Meter((r)) , and masticatory performance values were evaluated by using the colour-changeable chewing gum. The examinations were performed four times with an interval of 4weeks. An exercise group of 70 subjects was instructed to chew the exercise gum twice daily for 5min during a 4-week period. The chewing gum used for this study was specially developed with the physical property of maintaining hardness during chewing. A control group of 28 subjects was instructed not to chew any gum during the study period. RESULTS: No significant differences were found between the exercise group and the control group in MBF and a* values at the start of the study. After 4weeks of chewing exercise, MBF and a* values were significantly increased in the exercise group compared with those of the control group. These increases were maintained for 4weeks after exercise had finished. CONCLUSIONS: Gum chewing exercise is effective to increase MBF and a* values of preschool children and the effects are maintained after exercise completion. PMID- 21781199 TI - Treatment outcomes and dental anxiety in 18-year-olds with MIH, comparisons with healthy controls - a longitudinal study. AB - BACKGROUND: In a previous study, 9-year-old children with severe Molar Incisor Hypomineralization (MIH) had undergone dental treatment of their first molars nearly ten times as often as children in a control group. They also showed more management problems (BMP) and fear and anxiety (DFA). AIM: To assess the long term outcomes of dental treatments, dental anxiety, and patients' satisfaction in adolescents with MIH. DESIGN: Sixty-seven patients, identical with those in the baseline study, were studied at age 18-years. The participants answered the Children's Fear Survey Schedule - Dental Subscale the Dental Visit Satisfaction Scale (DVSS). Data were compiled from the dental records concerning dental health, number of restorative treatments and BMP. RESULTS: Molar Incisor Hypomineralization group had a significantly higher DMFT, and had undergone treatment of their permanent first molars 4.2 times as often as the controls. BMP was still significantly more common in the MIH group. However, DFS was reduced in MIH group and increased in the control groups. The DVSS scores did not differ between the groups. Conclusions. Patients with severe MIH had a poorer dental health and were still more treatment consuming at age 18-years. However, their dental fear was now at the same level as the controls. PMID- 21781201 TI - Sleep, arousal and health-related quality of life in men and women with coronary artery disease. AB - AIM: To evaluate whether there are gender differences in insomnia, sleep quality, sleep efficiency (%), general arousal, disease-specific and health-related quality of life in patients with coronary artery disease, compared with an age- and gender-matched randomly selected group from the general population. BACKGROUND: There are gender difference effects of sleep disturbances in the general population, but this perspective among patients with coronary artery disease has been poorly analysed. DESIGN: In this prospective study, comparative, descriptive and model testing designs were used. METHOD: The patients with coronary artery disease, 556 men and 324 women aged 25-86, were compared with a matched population-based group. Data were collected by validated and reliability tested questionnaires. RESULTS: The prevalence of severe insomnia varied between 17-44% in all four groups. The severe insomniac coronary artery disease patients displayed a two- or threefold higher presleep arousal, had two hours shorter nocturnal sleep duration/night and were more limited in their physical exercise level than the population-based group. Gender differences in sleep quality, sleep efficiency (%) and general arousal disappeared with increased insomnia severity. CONCLUSIONS: Independent of gender, age and comorbidity, physical exercise, general arousal behaviour and delayed poststress recovery after mental stress were found to have a negative impact on the coronary artery disease patients' sleep quality and sleep efficiency (%), interfering with their health-related quality of life. The variables significantly explained 41% of the sleep quality outcome and 29% of the sleep efficiency (%). RELEVANCE TO CLINICAL PRACTICE: Insomnia because of hyperarousal behaviour can be an important factor in the development of an individual self-care management programme supported by a healthcare team. PMID- 21781203 TI - Vested interests in addiction research and policy. Alcohol industry use of social aspect public relations organizations against preventative health measures. AB - AIM: It has been proposed that alcohol industry 'social aspects/public relations' organizations (SAPROs) serve the agenda of lending credibility to industry claims of corporate responsibility while promoting ineffective industry-friendly interventions (such as school-based education or TV advertising campaigns) and creating doubt about interventions which have a strong evidence base (such as higher taxes on alcoholic beverages). This paper investigated whether submissions to Australia's National Preventative Health Taskforce (NPHT) from alcohol industry bodies regarding the Australian SAPRO, Drinkwise, have used this organization to demonstrate corporate responsibility while promoting industry friendly interventions. METHOD: Submissions to the Australian National Preventative Health Taskforce (NPHT) discussion paper Australia, the healthiest country by 2020 (n = 375) were examined to identify those with primary alcohol content. A thematic analysis of the resulting 33 submissions was conducted to determine which organization, institution or individual discussed Drinkwise. SETTING: Australia. FINDINGS: Nine of the 33 submissions discussed Drinkwise; all were submitted by the alcohol industry or its affiliates. Every industry submission referred to Drinkwise either as providing evidence of social responsibility or by suggesting the industry-friendly actions of Drinkwise as alternatives to those recommended by the NPHT report. CONCLUSIONS: Drinkwise has been used by the alcohol industry to create an impression of social responsibility while promoting interventions that maintain profits and campaigning against effective interventions such as higher taxes on alcohol. PMID- 21781204 TI - The 2011 Shiga toxin-producing Escherichia coli O104:H4 German outbreak: a lesson in genomic plasticity. PMID- 21781202 TI - Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials. AB - AIMS: Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. METHODS: A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated. RESULTS: Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. CONCLUSIONS: We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them. PMID- 21781205 TI - Detection of West Nile virus lineage 2 in mosquitoes during a human outbreak in Greece. AB - A human outbreak of West Nile virus (WNV) infections occurred in 2010 in central Macedonia, northern Greece. Most cases were observed close to four rivers forming a large Delta, a major Mediterranean wetland. WNV lineage 2 sequences were obtained from two pools of Culex pipiens mosquitoes trapped in sites where encephalitis cases occurred a few days before the trapping. The Greek strain showed the highest homology to Hungarian and South African strains, differing from the Russian WNV lineage 2 strain, which suggests that at least two lineage 2 strains have been introduced and established in Europe, causing severe disease to humans. PMID- 21781206 TI - Prevalence of antibodies to phleboviruses and flaviviruses in Peja, Kosovo. AB - In order to investigate the current and past activity of phlebovirus and flavivirus in Kosovo, a seroprevalence study among 200 blood donors was performed. Positive results were obtained for the phleboviruses TOSV and SFNV, and for a flavivirus of the Japanese Encephalitis group. No positive results for TBEV were observed. PMID- 21781207 TI - Association of bla(DHA-1) and qnrB genes carried by broad-host-range plasmids among isolates of Enterobacteriaceae at a Spanish hospital. AB - A collection of 30 DHA-1-Enterobacteriaceae producers was examined for the presence of qnr genes. PCR-based replicon typing, plasmid profile and Southern hybridisation analyses revealed that all isolates co-harboured bla(DHA-1) and qnrB genes on the same plasmid. All but one of these plasmids belonged to the L/M group. Genetic organization analyses of a randomly selected isolate revealed the co-localization of both genes on an IS26-composite transposon. As plasmids carrying both genes seem to have a high prevalence and a worldwide distribution, care should be taken when quinolones are used to treat infections caused by DHA-1 producers. PMID- 21781208 TI - Establishment of a matrix-assisted laser desorption ionization time-of-flight mass spectrometry database for rapid identification of infectious achlorophyllous green micro-algae of the genus Prototheca. AB - The possibility of using matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) for rapid identification of pathogenic and non-pathogenic species of the genus Prototheca has been recently demonstrated. A unique reference database of MALDI-TOF MS profiles for type and reference strains of the six generally accepted Prototheca species was established. The database quality was reinforced after the acquisition of 27 spectra for selected Prototheca strains, with three biological and technical replicates for each of 18 type and reference strains of Prototheca and four strains of Chlorella. This provides reproducible and unique spectra covering a wide m/z range (2000-20 000 Da) for each of the strains used in the present study. The reproducibility of the spectra was further confirmed by employing composite correlation index calculation and main spectra library (MSP) dendrogram creation, available with MALDI Biotyper software. The MSP dendrograms obtained were comparable with the 18S rDNA sequence-based dendrograms. These reference spectra were successfully added to the Bruker database, and the efficiency of identification was evaluated by cross-reference-based and unknown Prototheca identification. It is proposed that the addition of further strains would reinforce the reference spectra library for rapid identification of Prototheca strains to the genus and species/genotype level. PMID- 21781210 TI - The role of clinical wisdom in evidence-based practice? PMID- 21781209 TI - Eumycetoma caused by Diaporthe phaseolorum (Phomopsis phaseoli): a case report and a mini-review of Diaporthe/Phomopsis spp invasive infections in humans. AB - Diaporthe phaseolorum (syn. Phomopsis phaseoli) is a frequent fungal parasite of plants, present on all continents around the world. It has rarely been involved in human diseases. We report a case of eumycetoma with osteomyelitis of the forefoot caused by this fungus and diagnosed by molecular biology. The patient had positive HTLV-1 serology and was a farmer from French Guiana who walked barefoot. He was successfully treated with long-term oral itraconazole (400 mg/day). A review of the literature underlines the essential roles of plants and host immunosuppression in this infection and the favourable outcome with a triazole antifungal treatment. PMID- 21781211 TI - How has liberation theology influenced my practice? AB - In this paper, I would like to share with readers some concepts from liberation theology in relation to Christian nursing. First, I present liberation theology to explore its concepts and how they can shed light on Christian nursing. I introduce liberation theology and discuss the three concepts of relevance to Christian nursing: emancipatory knowing, contextual mindedness and socioeconomic inequality. Two case studies will be described to revisit the importance of building a rapport, learning the patient's story in a humble and respectful way, and addressing the social inequality and heath disparity of which we should be aware in a patient-nurse encounter. The possibility for collaboration between theologians and Christian nurses should be further explored in the future. PMID- 21781212 TI - Respecting dignity in care in diverse care settings: strategies of UK nurses. AB - This paper presents nurses' views of dignity issues in diverse UK health-care settings. A qualitative multisite case study was conducted at seven organizations: four National Health Service hospitals, two independent care providers and one mental health-care provider. The paper reports on the data from qualitative semistructured interviews (n = 51); the participants worked in a wide variety of care contexts. The data were analysed thematically and this paper reports on the theme 'strategies to respect dignity in care'. The subthemes were: recognizing vulnerability to dignity loss; enhancing privacy; improving communication between staff and patients/families and building relationships; improving the care environment; and addressing issues that matter to individuals. The findings indicate core elements to promoting dignity that apply across all care settings but suggest that nurses should identify and address dignity issues specific to their own practice areas. PMID- 21781213 TI - Examination of current handover practice: evidence to support changing the ritual. AB - Examining systems of nursing handover provides the opportunity to identify areas in need of improvement and modification. The aim of this study was to describe nursing handover practices for one organization and explore clinical nurses' opinions regarding the quality of the current shift-to-shift handover style. One hundred and fifty-three registered nurses employed in 23 wards in an acute tertiary hospital in Australia completed a survey. The survey collected information about demographic data, current methods and preferences for style of handover and opinions about the quality of nursing handover. This study found that existing handover practice is time-consuming, lacks patient involvement and essential information, and is varied in style. Only one ward (4.3%) conducted handover at the bedside. The majority (82%) expressed reluctance to change their current handover style. Modification of existing nursing handover is needed but might be challenging in view of the reluctance to change this ritual. PMID- 21781214 TI - Registered nurses' beliefs of the benefits of exercise, their exercise behaviour and their patient teaching regarding exercise. AB - Recommendations by experts have been in place for > 10 years encouraging every adult to participate in >= 30 min of daily moderate-intensity physical activity. Despite extensive research supporting the value of physical activity, only about one-third of all adults meet physical activity recommendations. Using Pender's Health Promotion Theory as the framework, this study was focused on the relationships between nurses' beliefs regarding the benefits of exercise, their exercise behaviour and their recommendation of exercise for health promotion or as part of a treatment plan. Results showed positive correlations between exercise benefits, physical activity and recommendation of exercise to patients. Nurses who believe in health promotion and embrace healthy behaviours are more likely to be positive role models and teach healthy behaviours to their patients. Recommendations for practice and future research are included. PMID- 21781215 TI - Safety of rapid rituximab infusion in adult cancer patients: a systematic review. AB - The purpose of this study is to critically appraise, synthesize and present the best available evidence related to the safety of rapid rituximab infusion in adult non-Hodgkin lymphoma and chronic lymphocytic leukaemia patients. Data are from published and unpublished studies from electronic databases, grey literature and reference lists. The studies that met the inclusion criteria were critically appraised by two independent reviewers for methodological validity using standardized critical appraisal instruments. Proportional meta-analysis based on DerSimonian-Laird weights using a random effects model was used for statistical pooling through Stats Direct. Heterogeneity is assessed using Cochran Q. When statistical pooling is not possible, the findings were presented in narrative summary. Rapid rituximab infusion is safe for non-Hodgkin lymphoma patients at a 90 min regimen. However, there is insufficient evidence to support rapid rituximab infusions for chronic lymphocytic leukaemia patients. PMID- 21781216 TI - Causes of illness-constraining and facilitating beliefs. AB - The aim of this study was to enhance knowledge about patients' beliefs related to different kinds of illnesses and to describe and understand their beliefs as they relate to their outlook on their illnesses. Fifty-two patients with various illness symptoms receiving integrative anthroposophic care answered an item in a questionnaire about their own thinking of the causes of their illness. The method used for analysis was qualitative content analysis. The result showed that from a patient's perspective a complex combination of causes led to illness. The most prominent causes were psychosocial factors, but personal attitudes, biological factors and chance were also mentioned. Beliefs act as either facilitating or constraining. The informants displayed more constraining than facilitating beliefs, which might prevent them from improving their health. Furthermore, the informants might improve their ability to deal with their illness by identifying their own personal internal resources. PMID- 21781217 TI - Personality traits of Australian nurses and doctors: challenging stereotypes? AB - This study compared temperament and character traits of Australian registered nurses and general practitioners. A cross-sectional quantitative design used the Temperament and Character Inventory. Total sample size was 426. Only main effects were detected. Nurses were higher in the temperament traits of Novelty Seeking and Reward Dependence, lower in the character traits of Self-Directedness and Cooperativeness but higher in Self-Transcendence compared with the sample of doctors. Differences in personality profiles between registered nurses and general practitioners might challenge existing stereotypes between these professions. Further exploration of traits exclusive to and shared among health professions would supplement a broad conceptualization of specialities and support the enhancement of appropriate training and career counselling. Awareness of one's temperament and character can lead to a clearer understanding of how they function in the workplace and might encourage reflection on and insight into the implications of their personality and career plans. PMID- 21781218 TI - When time matters: the reality of patient care in acute care settings. AB - Laitinen H, Kaunonen M, Astedt-Kurki P. International Journal of Nursing Practice 2011; 17: 388-395 When time matters: The reality of patient care in acute care settings The purpose of the study was to investigate the reality of patient care in acute care settings when the patients' stay in the hospital was relatively short. The study was conducted by using the grounded theory method with constant comparative analysis. The sample comprised patients (n = 43) participating, relatives and hospital staff. The data were collected by participant observation, including informal interviews in natural settings, and by reviewing participating patients' electronic patient records. The main findings are presented in three categories: patients' endurance, interface and broken interface (along with several subcategories). The study showed that even with time pressures, good health care was delivered. However, it also showed some challenging issues for improvement. The study concluded that it is crucial for caregivers to focus on interactive patient care. PMID- 21781219 TI - Individual face-to-face support and quality of life in patients with breast cancer. AB - Living with breast cancer significantly affects women's quality of life (QOL) creating a need for support that might persist throughout the breast cancer experience. The aim of this study was to assess the effect of individual face-to face support on women's QOL and identify factors associated with their QOL. A two group quasi-experimental design was used with a sample of 204 women who was assigned to the intervention (n = 112) or the control group (n = 92) in hospital after breast cancer surgery. Data of this study were collected 6 months after the surgery by structured questionnaires and analysed statistically using descriptive statistics and non-parametric tests. Factors predicting poor QOL were investigated using logistic regression models with enter-method. Women in the intervention group reported less arm symptoms and clinically better sexual functioning. Factors related to QOL were age, education, employment status, lymph node status, type of surgery, type of axillary surgery, received chemotherapy, hormonal therapy and ongoing therapy. Factors, predictive of poor QOL, included control group, age, education, type of surgery, type of axillary surgery, chemotherapy and ongoing therapy. Short-term face-to-face education and support intervention might have decreased arm symptoms and increased sexual functioning. Women with breast cancer should be offered systematic support and education, which is tailored to women's individual needs. PMID- 21781220 TI - Anxiety and depression levels of inpatients in the city centre of Kirsehir in Turkey. AB - The aim of this study was to determine the anxiety and depression levels of inpatients. A cross-sectional study was conducted in Kirsehir in the middle part of Turkey with a sample of 433 inpatients. As the data-gathering tools, a questionnaire form and Hospital Anxiety and Depression Scale (HADS) were used. Statistical analyses were performed using Kruskal-Wallis Variance analysis and Mann-Whitney U-test. The mean HADS-depression scores of patients were compared according to the clinics they were in, and the difference was found to be significant for HADS-depression (P < 0.01) scores. The mean HADS-anxiety score of participants was 9.07, and the mean HADS-depression scores was 8.88. Among the participants in this study, 44.3% had an anxiety disorder (HADS-anxiety score of >= 10) whereas the 73.7% showed depression (HADS-depression score of >= 7). Results indicate that support, counselling, and routine screening for anxiety and depression should be provided to inpatients. PMID- 21781221 TI - Living with haemodialysis: the experience of adolescents in Turkey. AB - This study explored how adolescents receiving haemodialysis for end-stage renal disease were affected by their diagnosis and treatment. A qualitative approach was used, with data collected through individual interviews with 18 adolescents aged 12-20. Data were analysed using content analysis method. Adolescents reported physical, psychological and social problems. Compliance related to diet and fluid restrictions were issues for the adolescents interviewed. Body image problems related to physical limitations and the fistula were described. Their regular school attendance was reduced by the illness and therapy, as were socialization and peer interactions. Adolescents felt different from their friends/peers and had negative feelings about their future. Nurses need to assess each adolescent to determine their responses and take action to assist the adolescents with the many issues they are likely to experience. Parents and siblings, who contribute significantly to the care of adolescents on haemodialysis, also require support. PMID- 21781222 TI - Developing healthy childhood behaviour: outcomes of a summer camp experience. AB - The purpose of this pilot study was to test the short-term effects of the Wellness Summer Camp (WSC) on changes in children's knowledge of healthy foods and healthy snacks, physical activity and eating behaviours, and self-perception of competence in school-age children. The WSC programme activities were developed based on age-appropriate developmental theory, including healthy behaviour developmental skills and reinforcement for effective behaviour choices and action patterns. A total of 18 children who participated in the 10 day WSC were evaluated using a pretest-posttest evaluation design. The results revealed that at post-intervention, children significantly improved their knowledge about healthy foods and healthy snacks. Based on paired t-test analyses, the mean posttest scores of healthy eating behaviours and self-perception of competence were statistically significantly higher than the mean pretest scores. The mean posttest score of physical activity also increased but not statistically significant. Introducing children to the WSC programme could help maximize their opportunities to build confidence and self-competence to improve their knowledge of healthy foods and healthy snacks as well as motivate them to engage in healthy behaviours. PMID- 21781223 TI - Hand hygiene compliance of nurses: a 5-unit observational study in North-Eastern Anatolia. AB - In five neonatal intensive care units (NICUs) in two cities, the hand hygiene applications of 72 nurses included in this observational study have been investigated. The research was conducted between February and June 2007. It was found that before entering the NICUs, majority of nurses have washed their hands but used much less alcohol-based antiseptics; more than half of the nurses did not use gloves, and 50 of them did not wash their hands before care and one-third of the nurses did not wash their hands after care after neonatal treatments. The results obtained from our research showed that most of the nurses paid more attention to hand washing before applying medical treatment. PMID- 21781224 TI - Validity and reliability of physical activity questionnaire for Japanese students. AB - BACKGROUND: Self-administered questionnaires about physical activity are useful for collecting data to develop public health policies. There is currently no validated physical activity questionnaire, however, for Japanese children and adolescents. The purpose of the present study was to evaluate the validity and reliability of self-administered, physical activity questionnaires for Japanese students. METHODS: Fifth- and eighth-grade students were asked to complete two questionnaires that estimated the intensity and time of moderate-to-vigorous physical activities in which they participated, and the frequency and duration spent performing sports activities. Students also wore triaxial accelerometers to compare their actual activity levels to their estimates, to investigate the validity and reliability of the questionnaires. RESULTS: The intensity and time spent performing moderate-to-vigorous physical activity that were estimated from the questionnaire were higher than those measured by accelerometry (9-161% of accelerometry). Questionnaire data were highly correlated with accelerometer data for eighth graders (Spearman correlation, 0.642-0.754), but the correlations were lower for fifth graders (<= 0.331). Furthermore, there was higher repeatability in the data collected from eighth graders (intraclass correlation, 0.625-0.645) than from fifth graders (0.136-0.194). CONCLUSIONS: Questionnaires may be useful in epidemiological studies for ranking physical activity levels of adolescents, such as a confounding factor for other lifestyle surveys, but these surveys are less accurate for younger children. PMID- 21781225 TI - Early activation and interferon-gamma production of tumor-infiltrating mature CD27 high natural killer cells. AB - Natural killer (NK) cells are known to be critically involved in the control of tumors through their direct cytotoxic function, but have also been proposed as an initial source of interferon (IFN)-gamma that primes subsequent adaptive tumor specific immune responses. Although mounting evidence supports the importance of NK cells in antitumor immune responses, the immunological characteristics of NK cells infiltrating the tumor microenvironment and the mechanisms that regulate this process remain unclear. In the present study, we found that NK cells infiltrate early developing MCA205 tumors, and further showed that mature CD27(high) NK cells were the predominant subpopulation of NK cells accumulating in the tumor microenvironment. The tumor-infiltrating NK cells displayed an activated cell surface phenotype and provided an early source of IFN-gamma. Importantly, we also found that host IFN-gamma was critical for NK cell infiltration into the local tumor site and that the tumor-infiltrating NK cells mainly suppressed tumor growth via the IFN-gamma pathway. This work implicates the importance of IFN-gamma as a positive regulatory factor for NK cell recruitment into the tumor microenvironment and an effective antitumor immune effector response. PMID- 21781226 TI - Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors. AB - Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (four patients). The most frequent adverse events (AE; >= 50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade >= 3 (>= 10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD. PMID- 21781228 TI - Role of interstitial cells of Cajal in the generation and modulation of motor activity induced by cholinergic neurotransmission in the stomach. AB - BACKGROUND: Interstitial cells of Cajal (ICC) are intimately linked to the enteric nervous system and a better understanding of the interactions between the two systems is going to advance our understanding of gut motor control. The objective of the present study was to investigate the role of ICC in the generation of gastric motor activity induced by cholinergic neurotransmission. METHODS: Gastric motor activity was evoked through activation of intrinsic cholinergic neural activity, in in vitro muscle strips by electrical field stimulation, in the in vitro whole stomach by distension and in vivo by fluoroscopy after gavaging the stomach with barium sulfate. The cholinergic activity was assessed as that component of the effect of the stimulus that was sensitive to atropine. These experiments were carried out in wild-type and Ws/Ws rats that have few intramuscular ICC (ICC-IM) in the stomach. KEY RESULTS: Under all three experimental conditions, cholinergic activity was prominent in both wild-type and W mutant rats providing evidence against the hypothesis that cholinergic neurotransmission to smooth muscle is primarily mediated by ICC-IM. Strong cholinergic activity in Ws/Ws rats was not due to upregulation of muscarinic receptors in ICC but possibly in smooth muscle of the antrum. CONCLUSIONS & INFERENCES: Pacemaker ICC play a prominent role in the expression of motor activity induced by cholinergic activity and our data suggest that cholinergic neurotransmission to ICC affects the pacemaker frequency. PMID- 21781227 TI - Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc. AB - Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. To study if termination of long-term androgen ablation and restoration of testosterone levels could suppress the growth of relapsed hormone-refractory prostate tumors, we implanted testosterone pellets in castrated nude mice carrying androgen receptor (AR) positive LNCaP 104-R2 cells, which relapsed from androgen-dependent LNCaP 104-S cells after long-term androgen deprivation. 104-R2 tumor xenografts regressed after testosterone pellets were implanted. Of 33 tumors, 24 adapted to elevation of testosterone level and relapsed as androgen-insensitive tumors. Relapsed tumors (R2Ad) expressed less AR and prostate-specific antigen. We then studied the molecular mechanism underlying the androgenic regulation of prostate cancer cell proliferation. Androgen suppresses proliferation of 104-R2 by inducing G(1) cell cycle arrest through reduction of S-phase kinase-associated protein 2 (Skp2) and c-Myc, and induction of p27(Kip1). 104-R2 cells adapted to androgen treatment and the adapted cells, R2Ad, were androgen-insensitive cells with a slower growth rate and low protein level of AR, high levels of c-Myc and Skp2, and low levels of p27(Kip1). Nuclear AR and prostate-specific antigen expression is present in 104-R2 cells but not R2Ad cells when androgen is absent. Overexpression of AR in R2Ad cells regenerated an androgen-repressed phenotype; knockdown of AR in 104-R2 cells generated an androgen-insensitive phenotype. Overexpression of Skp2 and c Myc in 104-R2 cells blocked the growth inhibition caused by androgens. We concluded that androgens cause growth inhibition in LNCaP 104-R2 prostate cancer cells through AR, Skp2, and c-Myc. PMID- 21781229 TI - Marathon of eponyms: 20 Treacher Collins syndrome. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognized relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarizes data about Treacher Collins syndrome. PMID- 21781230 TI - DNA methylation in oral squamous cell carcinoma: molecular mechanisms and clinical implications. AB - DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in the last few years. Of the all epigenetic modifications, methylation, which represses transcription of the promoter region of tumor suppressor genes leading to gene silencing, has been most extensively studied. Oral squamous cell carcinoma (OSCC) has long been known to be the endpoint of many genetic changes, not only genomic mutations but also abnormal epigenetic modifications, as such, promoter methylation, contribute to development of this tumors. Recent studies have shown that promoter methylation of tumor suppressor genes is an important factor in carcinogenesis of OSCC. Some of the main genes that frequently showed promoter methylation in OSCC are those that participate in diverse processes such as regulation of the cell cycle, DNA repair, proliferation, and apoptosis. The aim of this review is to assess the current state of knowledge regarding promoter methylation of diverse genes in OSCC. PMID- 21781231 TI - New treatment for faecal incontinence using zinc-aluminium ointment: a double blind randomized trial. AB - AIM: In a randomized double-blind study the therapeutic effect of a novel zinc aluminium ointment was compared with placebo in patients with faecal incontinence. METHOD: A randomized double-blind trial was performed. Patients who met the inclusion criteria were randomized to receive the ointment or a placebo. All were evaluated prior to and 3 weeks after ointment application, using the Wexner incontinence score and the Fecal Incontinence Quality of Life (FIQL) score. RESULTS: Fifty patients were randomized and six were lost to follow-up, leaving 24 in the treatment and 20 in the placebo group. The average ages were 61.3 and 60.7 years. The respective Wexner scores prior to intervention were 16.6 and 16.7. They decreased significantly after treatment to 8.5 and 13.1 (P<0.001 and P=0.002 respectively). There was a significant difference in the final scores, favouring the treatment group (P=0.001). The FIQL scores for the treatment group were also significantly better in all parameters compared with those of the placebo group. CONCLUSION: The study shows that the zinc-aluminium based ointment decreases faecal incontinence significantly compared with placebo. PMID- 21781232 TI - A novel three-dimensional dynamic anorectal ultrasonography technique for the assessment of perineal descent, compared with defaecography. AB - AIM: The purpose of the study was to describe a novel three-dimensional dynamic anorectal ultrasonography technique (dynamic 3-DAUS) for assessment of perineal descent (PD) and establishment of normal range values, comparing it with defaecography. Secondarily, the study compares the ability of the two techniques to identify various pelvic floor dysfunctions. METHOD: A prospective study was undertaken in 29 women (mean age 43 years) with obstructed defecation disorder. All patients underwent defaecography and dynamic 3-DAUS and the results were compared. Lee kappa coefficients (K) were used. RESULTS: On defaecography, PD > 3 cm was detected in 12 patients. On dynamic 3-DAUS, 10 of these patients had PD > 2.5 cm. Seventeen had normal PD on defaecography and PD <= 2.5 cm on dynamic 3 DAUS (K 0.85). Normal relaxation was observed in 10 patients and anismus in 14 with both techniques (K 0.65). Both techniques identified five patients without rectocele, two with grade I rectocele (K 0.89 and 1.00, respectively) and 10 with grade II and nine with grade III (K 0.72 and 0.77, respectively). Rectal intussusception was identified in six patients on defaecography. These were confirmed on dynamic 3-DAUS in addition to the identification of another seven cases indicating moderate agreement (K 0.46). Enterocele/sigmoidocele grade III was identified in one patient with both techniques, indicating substantial agreement (K 0.65). CONCLUSION: Dynamic 3-DAUS was shown to be a reliable technique for the assessment of PD and pelvic floor dysfunctions, identifying all disorders and confirming findings from defaecography. PMID- 21781233 TI - Human macroecology: linking pattern and process in big-picture human ecology. AB - Humans have a dual nature. We are subject to the same natural laws and forces as other species yet dominate global ecology and exhibit enormous variation in energy use, cultural diversity, and apparent social organization. We suggest scientists tackle these challenges with a macroecological approach-using comparative statistical techniques to identify deep patterns of variation in large datasets and to test for causal mechanisms. We show the power of a metabolic perspective for interpreting these patterns and suggesting possible underlying mechanisms, one that focuses on the exchange of energy and materials within and among human societies and with the biophysical environment. Examples on human foraging ecology, life history, space use, population structure, disease ecology, cultural and linguistic diversity patterns, and industrial and urban systems showcase the power and promise of this approach. PMID- 21781234 TI - Ethics of human genetic studies in sub-saharan Africa: the case of Cameroon through a bibliometric analysis. AB - Many ethical concerns surrounding human genetics studies remain unresolved. We report here the situation in Cameroon. OBJECTIVES: To describe the profile of human genetic studies that used Cameroonian DNA samples, with specific focus on i) the research centres that were involved, ii) authorship, iii) population studied, iv) research topics and v) ethics disclosure, with the aim of raising ethical issues that emerged from these studies. METHOD: Bibliometric Studies; we conducted a PubMed-based systematic review of all the studies on human genetics that used Cameroonian DNA samples from 1989 to 2009. RESULTS AND DISCUSSION: Fifty articles were identified, involving predominantly research centres from Europe (64%) and America (32%). Only 7 (14%) Cameroonian institutions and 14 (28%) Cameroonian authors were associated with these publications. At least 52% of publications were devoted to population genetics (variation/migration patterns) amongst 30 Cameroonian ethnic groups. Very few studies concerned public health related genetic issues and only 5 (10%) references were found for hemoglobinopathies like sickle cell anaemia. Almost all DNA samples are 'banked' outside of the African continent. Capacity building, rights to the genetic information and benefits to the individuals, communities and populations who contribute to these studies are addressed. CONCLUSIONS: 1) Our data suggests the need for a wider debate towards building capacity and addressing ethical issues related to human genomic research in sub-Saharan Africa and specifically in Cameroon; 2) National ethical guidelines and regulations concerning the collection, use and storage of human DNA are urgently needed in Cameroon. PMID- 21781236 TI - Gene therapy for haemophilia: a long and winding road. AB - BACKGROUND: Cure, or improvement of disease phenotype, has been a long-term goal in the treatment of haemophilia. An obvious strategy for achieving this goal is the use of gene therapy. OBJECTIVES: This paper summarises prior and current clinical trials of gene therapy for haemophilia A and B, and briefly describes additional strategies in pre-clinical development. RESULTS AND CONCLUSIONS: Approximately 50 human subjects with severe haemophilia A or B have been enrolled in seven different trials of gene therapy. These have used plasmids, retroviral, adenoviral, and AAV vectors, directed to autologous fibroblasts, skeletal muscle, liver, and other target cell types accessed by intravenous injection of vector. Four separate trials have used AAV vectors, three of these targeting liver. Data from animal models suggest that several different gene replacement strategies may eventually yield long-term expression of factor at therapeutic levels, and that in situ correction of gene defects in hepatocytes may eventually be a therapeutic option. PMID- 21781237 TI - Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. AB - While parenteral anticoagulants such as unfractionated and low molecular weight heparins and the oral vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have a number of limitations. Up until recently, vitamin K antagonists (e.g. warfarin) have been the only available oral anticoagulants. These drugs have a delayed onset of action, food and drug interactions, and variable pharmacokinetics/pharmacodynamics such that regular laboratory monitoring and dose adjustments are required to maintain the International Normalized Ratio (INR) in the therapeutic range. New oral anticoagulants that selectively inhibit either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban) have now gained approval in many countries for some clinical indications. Unlike warfarin, these drugs have a rapid onset of action and a relatively wide therapeutic range such that coagulation monitoring is not required. These agents are more convenient for patients and health care providers, but also have potential for improving clinical outcomes and being more cost-effective than existing agents. This will result in major changes in the way that thrombosis is managed, both with respect to prevention and treatment. The new oral inhibitors of thrombin and factor Xa, however, have limitations and the absence of a need for regular laboratory monitoring makes medication compliance extremely important for maintaining efficacy given their relatively short half lives. Furthermore there will be challenges in managing patients on these agents who develop recurrent thrombosis or major bleeding until methods to monitor and assess the levels of the new agents are readily available and specific antidotes are developed. PMID- 21781238 TI - Molecular mechanism of inside-out integrin regulation. AB - Integrins are cell surface adhesion and signaling receptors important for cell adhesion, survival and migration. Integrins are known to be regulated by signals from inside the cells. Such inside-out regulation modulates affinities of integrins for their extracellular matrix ligand and is critical for thrombosis, haemostasis and immune response. Talin and kindlin, two integrin binding proteins, have been shown to be important regulators of integrin function. In this review, we will focus on the molecular mechanism of integrin regulation that has emerged from recent structural, biochemical and genetic studies. PMID- 21781239 TI - Serpin structure, function and dysfunction. AB - Serpins have been studied as a distinct protein superfamily since the early 80s. In spite of the poor sequence homology between family members, serpins share a highly conserved core structure that is critical for their functioning as serine protease inhibitors. Therefore, discoveries made about one serpin can be related to the others. In this short review, I introduce the serpin structure and general mechanism of protease inhibition, and illustrate, using recent crystallographic and biochemical data on antithrombin (AT), how serpin activity can be modulated by cofactors. The ability of the serpins to undergo conformational change is critical for their function, but it also renders them uniquely susceptible to mutations that perturb their folding, leading to deficiency and disease. A recent crystal structure of an AT dimer revealed that serpins can participate in large scale domain-swaps to form stable polymers, and that such a mechanism may explain the accumulation of misfolded serpins within secretory cells. Serpins play important roles in haemostasis and fibrinolysis, and although each will have some elements specifically tailored for its individual function, the mechanisms described here provide a general conceptual framework. PMID- 21781241 TI - Novel platelet activation receptor CLEC-2: from discovery to prospects. AB - C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for the platelet activating snake venom rhodocytin. CLEC-2 elicits powerful platelet activation signals in conjunction with Src, Syk kinases, and phospholipase Cgamma2, similar to the collagen receptor glycoprotein (GP) VI/FcRgamma-chain complex. In contrast to GPVI/FcRgamma, which initiates platelet activation through the tandem YxxL motif immunoreceptor tyrosine-based activation motif (ITAM), CLEC-2 signals via the single YxxL motif hemi-ITAM. The endogenous ligand of CLEC-2 has been identified as podoplanin, which is expressed on the surface of tumour cells and facilitates tumour metastasis by inducing platelet activation. Studies of CLEC-2-deficient mice have revealed several physiological roles of CLEC-2. Podoplanin is also expressed in lymphatic endothelial cells as well as several other cells, including type I alveolar cells and kidney podocytes, but is absent from vascular endothelial cells. In the developmental stages, when the primary lymph sac is derived from the cardinal vein, podoplanin activates platelets in lymphatic endothelial cells by binding to CLEC-2, which facilitates blood/lymphatic vessel separation. Moreover, CLEC-2 is involved in thrombus stabilisation under flow conditions in part through homophilic interactions. However, the absence of CLEC-2 does not significantly increase bleeding tendency. CLEC-2 may be a good target protein for novel anti-platelet drugs or anti metastatic drugs having therapeutic and preventive effects on arterial thrombosis and cancer, the primary causes of mortality in developed countries. In this article, we review the mechanisms of signal transduction, structure, expression, and function of CLEC-2. PMID- 21781240 TI - The role of lectins and glycans in platelet clearance. AB - In recent years, it has become increasingly apparent that the life span of transfused platelets in circulation is regulated, at least in part, by glycan lectin mediated mechanisms. There is clear evidence that refrigerated platelets are cleared by glycan-lectin mediated clearance mechanisms. Acute platelet cooling clusters glycoprotein (GP) Ibalpha receptors bearing uncovered N acetylglucosamine (GlcNAc), and alpha(M) beta(2) integrins on hepatic macrophages recognise clustered GlcNAc to rapidly clear these platelets from circulation. With prolonged refrigeration GPIbalpha clustering bearing uncovered galactose increases, which mediates the removal of long-term refrigerated platelets via hepatic Ashwell-Morell receptors (AMR), originally named as asialoglycoprotein receptors. In contrast, little is known about the molecular mechanisms of transfused room temperature platelet clearance. This review examines the role of glycan-lectin mediated clearance of exogenous, that is transfused chilled platelet clearance and briefly addresses the current knowledge of stored platelet function, degradation and its relation to platelet clearance. PMID- 21781242 TI - How platelets safeguard vascular integrity. AB - The haemostatic role of platelets was established in the 1880s by Bizzozero who observed their ability to adhere and aggregate at sites of vascular injury. It was only some 80 years later that the function of platelets in maintaining the structural integrity of intact blood vessels was reported by Danielli. Danielli noted that platelets help preserve the barrier function of endothelium during organ perfusion. Subsequent studies have demonstrated further that platelets are continuously needed to support intact mature blood vessels. More recently, platelets were shown to safeguard developing vessels, lymphatics, as well as the microvasculature at sites of leukocyte infiltration, including inflamed organs and tumours. Interestingly, from a mechanistic point of view, the supporting role of platelets in these various vessels does not necessarily involve the well understood process of platelet plug formation but, rather, may rely on secretion of the various platelet granules and their many active components. The present review focuses on these nonconventional aspects of platelet biology and function by presenting situations in which platelets intervene to maintain vascular integrity and discusses possible mechanisms of their actions. We propose that modulating these newly described platelet functions may help treat haemorrhage as well as treat cancer by increasing the efficacy of drug delivery to tumours. PMID- 21781244 TI - Advances in our understanding of the molecular basis of disorders of platelet function. AB - Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury. Abnormalities of pathways involving glycoprotein (GP) mediators of adhesion (Bernard-Soulier syndrome, platelet-type von Willebrand disease) and aggregation (Glanzmann thrombasthenia) are the most studied and affect the GPIb IX-V complex and integrin alphaIIbbeta3, respectively. Leukocyte adhesion deficiency-III combines Glanzmann thrombasthenia with infections and defects of kindlin-3, a mediator of integrin activation. Agonist-specific deficiencies in platelet aggregation relate to mutations of primary receptors for ADP (P2Y(12)), thromboxane A(2) (TXA2R) and collagen (GPVI); however, selective abnormalities of intracellular signalling pathways remain better understood in mouse models. Defects of secretion from delta-granules are accompanied by pigment defects in the Hermansky-Pudlak and Chediak-Higashi syndromes; they concern multiple genes and protein complexes involved in secretory organelle biogenesis and function. Quebec syndrome is linked to a tandem duplication of the urokinase plasminogen activator (PLAU) gene while locus assignment to chromosome 3p has advanced the search for the gene(s) responsible for alpha-granule deficiency in the gray platelet syndrome. Defects of alpha-granule biosynthesis also involve germline VPS33B mutations in the ARC (arthrogryposis, renal dysfunction and cholestasis) syndrome. A mutation in transmembrane protein 16F (TMEM16F) has been linked to a defective procoagulant activity and phosphatidylserine expression in the Scott syndrome. Cytoskeletal dysfunction (with platelet anisotrophy) occurs not only in the Wiskott-Aldrich syndrome but also in filamin A deficiency or MYH9-related disease while GATA1 mutations or RUNX1 haploinsufficiency can affect expression of multiple platelet proteins. PMID- 21781243 TI - Regulating thrombus growth and stability to achieve an optimal response to injury. AB - An optimal platelet response to injury can be defined as one in which blood loss is restrained and haemostasis is achieved without the penalty of further tissue damage caused by unwarranted vascular occlusion. This brief review considers some of the ways in which thrombus growth and stability can be regulated so that an optimal platelet response can be achieved in vivo. Three related topics are considered. The first focuses on intracellular mechanisms that regulate the early events of platelet activation downstream of G protein coupled receptors for agonists such as thrombin, thromboxane A(2) and ADP. The second considers the ways in which signalling events that are dependent on stable contacts between platelets can influence the state of platelet activation and thus affect thrombus growth and stability. The third focuses on the changes that are experienced by platelets as they move from their normal environment in freely-flowing plasma to a very different environment within the growing haemostatic plug, an environment in which the narrowing gaps and junctions between platelets not only facilitate communication, but also increasingly limit both the penetration of plasma and the exodus of platelet-derived bioactive molecules. PMID- 21781245 TI - Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke. AB - Platelet adhesion, activation and aggregation on the exposed subendothelial extracellular matrix (ECM) are essential for haemostasis, but may also lead to occlusion of diseased vessels. Binding of the glycoprotein (GP)Ib-V-IX complex to immobilised von Willebrand factor (VWF) initiates adhesion of flowing platelets to the ECM, and thereby enables the collagen receptor GPVI to interact with its ligand and to mediate platelet activation. This process is reinforced by locally produced thrombin and platelet-derived secondary mediators, such as adenosine diphosphate (ADP) and thromboxane A(2) (TxA(2)). Together, these events promote a shift of beta1 and beta3 integrins from a low to a high affinity state for their ligands through 'inside-out' signalling allowing firm platelet adhesion and aggregation. Formed platelet aggregates are stabilised by fibrin formation and signalling events between adjacent platelets involving multiple platelet receptors, such as the newly discovered C-type lectin-like receptor 2 (CLEC-2). While occlusive thrombus formation is the principal pathogenic event in myocardial infarction, the situation is more complex in ischaemic stroke where infarct development often progresses despite sustained early reperfusion of previously occluded major intracranial arteries, a process referred to as 'reperfusion injury'. Increasing experimental evidence now suggests that early platelet adhesion and activation events, orchestrate a 'thrombo-inflammatory' cascade in this setting, whereas platelet aggregation and thrombus formation are not required. This review summarises recent developments in understanding the principal platelet adhesion receptor systems with a focus on their involvement in arterial thrombosis and ischaemic stroke models. PMID- 21781246 TI - HIT paradigms and paradoxes. AB - The current major problem with HIT is its overdiagnosis. This concept follows from the HIT central paradigm: HIT is caused by a subset of antibodies against platelet factor 4 (PF4)/heparin complexes that have strong platelet-activating properties. Prospective studies show that only a minority of sera containing such antibodies exhibit platelet-activating properties. Ironically, the earliest tests for HIT--platelet activation assays--remain today the most diagnostically useful, particularly the washed platelet assays. But the wider application of PF4 dependent immunoassays, and their much greater sensitivity for the larger subset of non-platelet-activating (and non-HIT-inducing) antibodies, has resulted in HIT overdiagnosis in many centres. Studies of anti-PF4/heparin immunization in diverse clinical situations have provided insights into the factors that influence the HIT immune response. Besides the conundrum of anticoagulant-induced thrombosis (including its potentiation of coumarin-induced microthrombosis), HIT evinces numerous other paradoxes: (i) it is a platelet-activating disorder with venous thrombosis as its predominant clinical manifestation; (ii) 'delayed-onset' (or 'autoimmune') HIT can lead to dramatic worsening of HIT-associated thrombosis despite cessation of heparin; (iii) partial thromboplastin time (PTT) monitoring of direct thrombin inhibitor treatment - and confounding of PTT monitoring by HIT associated consumptive coagulopathy - infers that the worst subset of HIT patients may fail this therapeutic approach; (iv) the highly sulfated pentasaccharide anticoagulant, fondaparinux, can (rarely) cause HIT yet appears to be an effective treatment for this disorder; and (v) the transience of the HIT immune response means that many patients with previous HIT can safely receive future heparin. PMID- 21781247 TI - Discovery of the cardiovascular system: from Galen to William Harvey. AB - The goal of this review is to examine the events that led to discovery of blood circulation. The Ancient Greeks, including Hippocrates and Galen viewed the cardiovascular system as comprising two distinct networks of arteries and veins. Galen claimed that the liver produced blood that was then distributed to the body in a centrifugal manner, whereas air or pneuma was absorbed from the lung into the pulmonary veins and carried by arteries to the various tissues of the body. Arteries also contained blood, which passed from the venous side via invisible pores in the interventricular septum and peripheral anastomoses. This was an open ended system in which blood and air simply dissipated at the ends of veins and arteries according to the needs of the local tissue. Blood was not seen to circulate but rather to slowly ebb and flow. This view would hold sway for 15 centuries until 1628 when William Harvey published his momentous 72-page book, On the Motion of the Heart and Blood in Animals. Harvey employed experiment and deductive logic to show that arteries and veins are functionally, if not structurally, connected in the lung and the peripheral tissues, and that blood circulates. The mechanical force of the heart replaced Galen's elusive attractive powers. Ultimately, Galenism would collapse under the weight of Harvey's evidence, and a new paradigm of blood circulation would prevail. PMID- 21781248 TI - Biology and physics of von Willebrand factor concatamers. AB - Structural specialisations enable von Willebrand factor (VWF) to assemble during biosynthesis into helical tubules in Weibel-Palade bodies (WPB). Specialisations include a pH-regulated dimeric bouquet formed by the C-terminal half of VWF and helical assembly guided by the N-terminal half that templates inter-dimer disulphide bridges. Orderly assembly and storage of ultra-long concatamers in helical tubules, without crosslinking of neighboring tubules, enables unfurling during secretion without entanglement. Length regulation occurs post-secretion, by hydrodynamic force-regulated unfolding of the VWF A2 domain, and its cleavage by the plasma protease ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). VWF is longest at its site of secretion, where its haemostatic function is most important. Moreover, elongational hydrodynamic forces on VWF are strongest just where needed, when bound to the vessel wall, or in elongational flow in the circulation at sites of vessel rupture or vasoconstriction in haemostasis. Elongational forces regulate haemostasis by activating binding of the A1 domain to platelet GPIbalpha, and over longer time periods, regulate VWF length by unfolding of the A2 domain for cleavage by ADAMTS13. Recent structures of A2 and single molecule measurements of A2 unfolding and cleavage by ADAMTS13 illuminate the mechanisms of VWF length regulation. Single molecule studies on the A1-GPIb receptor-ligand bond demonstrate a specialised flex-bond that enhances resistance to the strong hydrodynamic forces experienced at sites of haemorrhage. PMID- 21781249 TI - Role of intimate interactions between endothelial cells and the surrounding accessory cells in the maturation of blood vessels. AB - While blood vessels clearly have a fundamental role in supplying oxygen and nutrients, and transporting inflammatory cells throughout the body, they are also involved in organogenesis and maintenance. Blood vessels provide a niche that supports self-renewal of stem cell populations in normal organs. This role unfortunately also extends to the field of cancer biology; it has been suggested that cancer stem cells are located in perivascular regions supporting their proliferation. Through cell-to-cell interactions, arteries also have the important function of guiding appropriate migration of neurites. Therefore, analysis of the molecular mechanisms responsible for blood vessel formation and maintenance is important for developing strategies to regulate tissue regeneration. According to the usual concept of angiogenesis, it is widely accepted that homogeneous endothelial cells from preexisting vessels sprout and proliferate during angiogenesis. Recently, however, at least three different endothelial cell types designated tip, stalk and phalanx cells have been suggested to be involved in new blood vessel formation in sprouting angiogenesis. Given this endothelial cell heterogeneity, the involvement of a stem cell system in preexisting blood vessels is proposed. In addition, endothelial cells possess the capacity to differentiate into mesenchymal stem cells upon stimulation with growth factors, and pericytes show stem cell behaviour in their ability to differentiate into a variety of different histotypes. Moreover, under normal physiological conditions, haematopoietic stem cells differentiate into mural cells to provide blood vessel stability. These findings make it necessary to reconsider issues concerning the regulation of blood vessels by accessory cells situated around those vessels. PMID- 21781250 TI - Role of stem cells in cardiovascular biology. AB - This review article addresses the controversy as to whether the adult heart possesses an intrinsic growth reserve. If myocyte renewal takes place in healthy and diseased organs, the reconstitution of the damaged tissue lost upon pathological insults might be achieved by enhancing a natural occurring process. Evidence in support of the old and new view of cardiac biology is critically discussed in an attempt to understand whether the heart is a static or dynamic organ. According to the traditional concept, the heart exerts its function until death of the organism with the same or lesser number of cells that are present at birth. This paradigm was challenged by documentation of the cell cycle activation and nuclear and cellular division in a subset of myocytes. These observations raised the important question of the origin of replicating myocytes. Several theories have been proposed and are presented in this review article. Newly formed myocytes may derive from a pre-existing pool of cells that has maintained the ability to divide. Alternatively, myocytes may be generated by activation and commitment of resident cardiac stem cells or by migration of progenitor cells from distant organs. In all cases, parenchymal cell turnover throughout lifespan results in a heterogeneous population consisting of young, adult, and senescent myocytes. With time, accumulation of old myocytes has detrimental effects on cardiac performance and may cause the development of an aging myopathy. PMID- 21781251 TI - Nanoscale studies of protein-membrane interactions in blood clotting. AB - Most of the steps in the blood clotting cascade require clotting proteins to bind to membrane surfaces with exposed phosphatidylserine. In spite of the importance of these protein-membrane interactions, we still lack a detailed understanding of how clotting proteins interact with membranes and how membranes contribute so profoundly to catalysis. Our laboratories are using multidisciplinary approaches to explore, at atomic-resolution, how blood clotting protein complexes assemble and function on membrane surfaces. PMID- 21781252 TI - Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. AB - Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated activation of protein C. Recently, we conducted a multicentre, double-blind, randomized trial to evaluate the efficacy and safety of recombinant human soluble thrombomodulin (rhsTM, also known as ART-123) for the treatment of disseminated intravascular coagulation (DIC), and found that rhsTM therapy is more effective and safer than low-dose heparin therapy. Thus, in 2008, rhsTM (Recomodulin) was approved for the treatment of DIC in Japan. Here we re-evaluate the therapeutic basis of this drug from the view of its anticoagulant, anti inflammatory, and cytoprotective properties. Structurally, the extracellular portion of TM is composed of three domains: an N-terminal lectin-like domain (TM D1), followed by an epidermal growth factor (EGF)-like domain (TM-D2), and an O glycosylation-rich domain (TM-D3). TM-D2 and TM-D3 are important for the protein's anticoagulant cofactor activities, i.e. inhibition of thrombin and activation of protein C. TM-D1 plays an important role in attenuation of inflammatory responses, through inhibition of leukocyte adhesion to endothelial cells, inhibition of complement pathways, neutralization of lipopolysaccharide (LPS), and sequestration and degradation of pro-inflammatory high-mobility group box 1 protein (HMGB1). Thus, TM on the surface of endothelial cells prevents dissemination of pro-coagulant and pro-inflammatory molecules, and by doing so, allows these molecules to act locally at the site of injury. In patients with sepsis and DIC, TM expression is down-regulated, which may result in dissemination of pro-coagulant and pro-inflammatory molecules throughout the systemic circulation. Replacement with rhsTM may offer therapeutic value in such conditions. PMID- 21781253 TI - Tissue-type plasminogen activator-mediated plasminogen activation and contact activation, implications in and beyond haemostasis. AB - Due to its discovery as initiator of fibrinolysis and its well-studied activation by fibrin, tissue-type plasminogen activator (tPA) and the fibrinolytic system are generally associated with the dissolution of blood clots. However, it has been demonstrated over the years that (i) tPA can be activated by multiple proteins, (ii) plasmin has many substrates other than fibrin and (iii) tPA and plasmin have biological functions independent of fibrin and distinct from their role in blood clot lysis. We here review the data with respect to the activation of tPA by fibrin and its multiple other cofactors, in relation to tPA's role in pathophysiology, notably fibrinolysis and amyloidosis, with emphasis on Alzheimer's disease. We demonstrate a common structural element, termed cross beta structure, in misfolded proteins that is causal to tPA activation. The implications for protein misfolding diseases that are known to be associated with the deposition of amyloid and for diseases for which this has not (yet) been established are discussed. PMID- 21781254 TI - Innate immunity and coagulation. AB - Infection frequently elicits a coagulation response. Endotoxin triggers the formation of tissue factor initiating coagulation, down regulates anticoagulant mechanisms including the protein C pathway and heparin-like proteoglycans and up regulates plasminogen activator inhibitor. The overall physiological result of this is to promote coagulation through enhancing initiation, suppressing negative regulation and impairing fibrin removal. The response to infection also leads to tissue destruction. Nucleosomes and histones released from the injured cells trigger further inflammation, protection from the pathogen but further tissue injury leading to multi-organ failure. Such a complex response to infection presumably arises due to the role of coagulation in the control and clearance of the infectious agent. PMID- 21781256 TI - Toxins in thrombosis and haemostasis: potential beyond imagination. AB - Exogenous factors isolated from venoms of snakes and saliva of haematophagous animals that affect thrombosis and haemostasis have contributed significantly to the development of diagnostic agents, research tools and life-saving drugs. Here, I discuss recent advances in the discovery, structural and functional characterisation, and mechanism of action of new procoagulant and anti haemostatic proteins. In nature, these factors have evolved to target crucial 'bottlenecks' in the coagulation cascade and platelet aggregation. Several simple protein scaffolds are used to target a wide variety of target proteins and receptors exhibiting functional divergence. Different protein scaffolds have also evolved to target identical, physiologically relevant key enzymes or receptors exhibiting functional convergence. At times, exogenous factors bind to the same target protein, but at distinct sites, to differentially attenuate their functions exhibiting mechanistic divergence within the same family of proteins. The structure-function relationships of these factors are subtle and complicated but represent an exciting challenge. These studies provide ample opportunities to design highly specific and precise ligands to achieve desired biological target function. Although only a small number of them have been characterised to date, the molecular and mechanical diversities of these exogenous factors and their contributions to understanding molecular and cellular events in thrombosis and haemostasis as well as developing diagnostic and research tools and therapeutic agents, is outstanding. Based on the current status, I have attempted to identify future potential and prospects in this area of research. PMID- 21781255 TI - Exploration of the host haemostatic system by group A streptococcus: implications in searching for novel antimicrobial therapies. AB - The haemostatic system is heavily involved in the host response to infection. A number of host haemostatic factors, notably plasminogen and fibrinogen have been reported to bind and interact with various bacterial proteins. This review summarises the roles of host haemostatic factors such as plasminogen, factor V and fibrinogen in host defence against group A streptococcus infection and discusses the potential of targeting the host haemostatic system for therapeutic intervention against infectious diseases. PMID- 21781257 TI - von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. AB - von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is characterised by a prolonged bleeding time due to quantitative and/or functional deficits of von Willebrand factor (VWF), a huge multimeric protein. Given the large size and complexity of the protein, the many functions of VWF, for example, binding to collagen, to platelet GPIb, and to FVIII, the localisation of these binding sites in different VWF domains, as well as the dependence on a high molecular weight multimer structure for proper function, VWF is prone to quantitative and very heterogeneous structural and functional defects. Comprehensive clinical and laboratory phenotypic description of patients with VWD in correlation to the genotype has considerably increased our knowledge on this disorder and the physiology and pathophysiology of VWF. This article focuses on the phenotype/genotype relationship in VWD and the context of VWD types and subtypes with particular VWF domains. PMID- 21781258 TI - Immune tolerance induction in haemophilia: evidence and the way forward. AB - Given the inhibitor-associated morbidity resulting from limited effective treatment options, antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). First reported over 30 years ago, much of our current knowledge about ITI in haemophilia A and B was derived from small cohort studies and retrospective national and international ITI registries. More recently, prospective randomised ITI trials have been designed and initiated to answer outstanding questions related to the optimisation of current therapeutic strategy in haemophilia A. However, due to the low incidence of inhibitor development in haemophilia B compared to haemophilia A, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of FIX inhibitors. The lack of an effective strategy is particularly problematic given the even greater morbidity associated with the almost unique occurrence of allergic and anaphylactic reactions that often herald FIX antibody development, and further complicates attempts to eradicate FIX inhibitors. Ultimately, successful inhibitor prevention and eradication strategies for both diseases will emerge from the clinical translation of our evolving knowledge of immune stimulation and tolerance. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; it will also review the current consensus recommendations for ITI, as well as the emerging scientific body of immunological knowledge that may significantly impact the therapeutic and preventative strategies of the future. PMID- 21781259 TI - Management of acquired haemophilia A. AB - Acquired haemophilia A is an auto-immune disease caused by an inhibitory antibody to factor VIII. The pattern of bleeding varies but patients remain at risk of life threatening bleeding until the inhibitor has been eradicated. The cornerstones of management are; rapid and accurate diagnosis, control of bleeding, investigation for an underlying cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without significant bleeding. Despite an extensive literature, few controlled data are available and treatment guidelines are based on expert opinion. To treat bleeds recombinant factor VIIa and activated prothrombin complex concentrate are equally efficacious but both are superior to factor VIII or desmopressin. Immunosuppression should be started as soon as the diagnosis is made. Commonly used regimens are steroids alone or combined with cytotoxic agents. Rituximab is being used more widely but current evidence does not suggest that it improves outcomes or reduces side effects. PMID- 21781260 TI - Gynecological and obstetrical manifestations of inherited bleeding disorders in women. AB - Patients affected by bleeding disorders present a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding tendency to significant episodes. Women with inherited bleeding disorders are particularly disadvantaged since, in addition to suffering from general bleeding symptoms, they are also at risk of bleeding complications from regular haemostatic challenges during menstruation, pregnancy and childbirth. Moreover, such disorders pose important problems for affected women due to their reduced quality of life caused by limitations in activities and work, and alteration of their reproductive life. These latter problems include excessive menstrual bleeding or menorrhagia, miscarriage, bleeding complications during pregnancy and after delivery and their related complications such as acute or chronic anaemia. The management of these women is difficult because of considerable inter-individual variation. Moreover, reliable information on clinical management is scarce, only a few available long term prospective studies of large cohorts provide evidence-based guideline about diagnosis and treatment. PMID- 21781262 TI - Lessons from genome-wide association studies in venous thrombosis. AB - From the first genome wide association studies (GWAS) conducted on age-related macular degeneration back in 2005 until now, hundreds of studies have applied this strategy to identify novel genetic loci associated with hundreds of human diseases and related quantitative risk factors. While the GWAS revolution has just started to shift towards the next generation sequencing's burst, it is important to illustrate how the genetics research in venous thrombosis has benefit from the GWAS paradigm. PMID- 21781261 TI - The genetics of common variation affecting platelet development, function and pharmaceutical targeting. AB - Common variant effects on human platelet function and response to anti-platelet treatment have traditionally been studied using candidate gene approaches involving a limited number of variants and genes. These studies have often been undertaken in clinically defined cohorts. More recently, studies have applied genome-wide scans in larger population samples than prior candidate studies, in some cases scanning relatively healthy individuals. These studies demonstrate synergy with some prior candidate gene findings (e.g., GP6, ADRA2A) but also uncover novel loci involved in platelet function. Here, I summarise findings on common genetic variation influencing platelet development, function and therapeutics. Taken together, candidate gene and genome-wide studies begin to account for common variation in platelet function and provide information that may ultimately be useful in pharmacogenetic applications in the clinic. More than 50 loci have been identified with consistent associations with platelet phenotypes in >= 2 populations. Several variants are under further study in clinical trials relating to anti-platelet therapies. In order to have useful clinical applications, variants must have large effects on a modifiable outcome. Regardless of clinical applications, studies of common genetic influences, even of small effect, offer additional insights into platelet biology including the importance of intracellular signalling and novel receptors. Understanding of common platelet-related genetics remains behind parallel fields (e.g., lipids, blood pressure) due to challenges in phenotype ascertainment. Further work is necessary to discover and characterise loci for platelet function, and to assess whether these loci contribute to disease aetiologies or response to therapeutics. PMID- 21781263 TI - How to prevent, treat, and overcome current clinical challenges of VTE. AB - Venous thromboembolism (VTE) is most commonly initially treated with low molecular weight heparin (LMWH), fondaparinux, or unfractionated heparin, in combination with vitamin-K antagonists (VKA) for long-term treatment. VKA have some drawbacks, however, which has led to the development of new anticoagulants. Most of these new drugs can be administered orally, and have been investigated in several phase III clinical trials. The benefits of these anticoagulants include their stable therapeutic effect, reduced interactions with other medication and food, and, therefore, the reduced need for regular monitoring. The duration of anticoagulant treatment for VTE is usually 3-12 months, but depends on the balance between the risks of recurrent thrombosis, major bleeding, and the patient's preference. Clinical decision rules to assess the risk of recurrence to tailor the duration of anticoagulant treatment are being investigated. The beneficial aspects of novel anticoagulants may prolong the duration of treatment. VTE treatment should be adjusted in special patient groups, such as in cases of malignancy, renal failure, pregnancy, or obesity. In this review, the current and future aspects of the treatment of VTE are explored. PMID- 21781264 TI - Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I. AB - It has been well established that antiphospholipid antibodies and specifically those directed against beta 2 glycoprotein I (beta2GPI) are pathogenic for the development of thrombosis in the antiphospholipid syndrome (APS). Several groups have shown that anti-beta2GPI antibodies, in complex with beta2GPI, elicit effects on blood cells and coagulation-fibrinolysis proteins, which prime the arterial and venous vasculature for the development of thrombosis. However, much less is known about the mechanism initiating the production of autoantibodies against beta2GPI, a physiological abundant protein of blood. In the current review, novel findings are presented regarding the structure and oxidative post translational modifications of beta2GPI, which trigger the immune response. The majority of circulating beta2GPI exists in a form containing unpaired cysteines (free thiols), which constitutes the reduced form of beta2GPI. The free thiols exposed on beta2GPI are involved in the interaction with platelets and endothelial cells. We propose that this abundant pool of free thiols may serve as an antioxidant reservoir protecting cells or critical molecules from oxidative stress. Oxidation of beta2GPI confers an increase in its immunogenicity through a Th1 immunological mechanism. The clinical significance of these observations is that serum from patients with APS, assessed by a novel ELISA assay, have a significant increase in oxidised beta2GPI. These findings hold promise, not only for the delineation of the role of beta2GPI as an immunological target, but also for the development of improved diagnostic and prognostic assays for APS. PMID- 21781265 TI - Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. AB - Upshaw-Schulman syndrome (USS) is an extremely rare hereditary deficiency of ADAMTS13 activity, termed congenital TTP. The clinical signs are usually mild during childhood, often with isolated thrombocytopenia. But their symptoms become more evident when patients have infections or get pregnant. We identified 43 USS patients in Japan, who ranged in age from early childhood to 79 years of age. Analysing the natural history of these USS patients based on ADAMTS13 gene mutations may help characterise their clinical phenotypes. Severe neonatal jaundice that requires exchange blood transfusion, a hallmark of USS, was found in 18 of 43 patients (42%). During childhood, 25 of 43 patients were correctly diagnosed with USS without gender disparity. These 25 patients were categorised as having 'the early-onset phenotype'. Between 15 and 45 years of age, 15 were correctly diagnosed, and, interestingly, they were all female. The remaining three patients were male and were diagnosed when they were older than 45 years of age, suggesting that they were 'the late-onset phenotype'. Two of these three males developed sudden overt TTP when they were 55 and 63 years old, respectively. These two men had two different homozygous ADAMTS13 gene mutations, p.R193W/p.R193W and p.C1024R/p.C1024R, respectively. Both of which were not discovered in the US or Western countries. In vitro expression studies showed that these two proteins were consistently secreted into the culture medium but to a lesser extent and with reduced activity compared to the wild-type protein. Our results indicate that 'the late-onset phenotype' of USS is formed with ethnic specificity. PMID- 21781266 TI - Antithrombotic treatment for recurrent pregnancy loss? AB - BACKGROUND: Recurrent pregnancy loss (RPL) is a major issue for women's health. Acquired and heritable thrombophilias are associated with RPL, this association could reflect a general prothrombotic phenotype rather than a specific thrombophilia. Antithrombotic intervention has therefore been assessed for RPL. RESULTS: Two large randomised trials with untreated control groups showed no benefit from antithrombotic treatment with LMWH and low dose aspirin in women with RPL. These trials had insufficient power to exclude an effect in women with underlying thrombophilia, >= 3 losses, or late losses. CONCLUSIONS: Antithrombotic intervention should not be recommended for unexplained RPL in general. There may be specific groups such as those with an heritable thrombophilia, or with three or more losses, or second trimester losses that might benefit and where further trials are required. Further there is a need to consider the benefits of LMWH on implantation such as in women undergoing assisted conception therapy. PMID- 21781268 TI - Management of venous thromboembolism in patients with cancer. AB - Patients with cancer are at increased risk of venous thromboembolism (VTE). In these patients VTE is associated with substantial morbidity and complicates the clinical management of cancer. Emerging research indicates a probable detrimental effect of VTE on cancer survival. Although VTE may develop at any stage of cancer disease, the risk of VTE is particularly high in association with three clinical settings including surgery for cancer, use of a central vein catheter (CVC) and chemotherapy. Guidelines recommend post-operative prophylaxis (for at least 7-10 days) for patients undergoing elective cancer surgery. A prolonged prophylaxis (for upto four post-operative weeks) is recommended in cancer patients at high risk for VTE. The role of antithrombotic prophylaxis in the prevention of CVC related thrombosis remains controversial. The PROTECHT study has recently evaluated the benefit of antithrombotic prophylaxis in cancer patients receiving chemotherapy, showing a statistically significant 50% relative risk reduction in symptomatic thromboembolic events. The international guidelines currently agree in non-recommending routine prophylaxis in ambulatory patients who receive anticancer chemotherapy but suggest an individual risk-based evaluation. To better identify cancer patients at high risk for VTE, simple predictive models have been validated. Further intervention studies are currently on-going to explore the benefit of antithrombotic prophylaxis in individual high-risk groups of patients. The long-term treatment of cancer-related VTE is based on therapeutic doses of LMWH in preference to warfarin. The optimal duration of antithrombotic treatment in cancer patients remains to be fully defined. PMID- 21781269 TI - Atherothrombosis and the role of antiplatelet therapy. AB - Atherothrombosis remains a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across vascular beds, but when complicated by thrombosis can result in acute coronary syndrome, stroke, transient ischaemic attack and critical limb ischaemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous trials have examined the role of antiplatelet agents in primary and secondary prevention and several new antiplatelet drugs are under development. In secondary prevention, there is evidence of clear benefit of single and in some cases dual antiplatelet therapy in the prevention of recurrent cerebro-vascular complications. Dual antiplatelet therapy has emerged as the standard of care in acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent antiplatelet agents. Conversely, in chronic stable coronary disease, no benefit has yet been convincingly demonstrated from dual antiplatelet therapy. In cerebro-vascular disease, aspirin monotherapy remains the cornerstone of prevention of recurrent events, with clopidogrel or the combination of aspirin and dipyridamole being only modestly more efficacious. In primary prevention, the evidence for the routine use of aspirin or any other antiplatelet agent is mixed and suggests this should only be considered on an individual basis in high-risk groups where the thrombotic risk outweighs the risk of major bleeding complications. PMID- 21781267 TI - Tissue factor and cell signalling in cancer progression and thrombosis. AB - The close link between coagulation activation and clinical cancer is well established and recent progress has defined underlying molecular pathways by which tumour cells interact with the haemostatic system to promote cancer progression. Tumour type-specific oncogenic transformations cause constitutive and hypoxia-dependent upregulation of tissue factor (TF) in cancer cells, but TF expressed by vascular, stromal and inflammatory cells also contributes to the procoagulant character of the tumour microenvironment. A growing body of genetic and pharmacological evidence implicates signalling by protease activated receptors (PARs) and specifically by tumour cell-expressed TF-VIIa-PAR2 in the induction of an array of proangiogenic and immune modulating cytokines, chemokines and growth factors. Specific inhibition of this pathway results in attenuated tumour growth and angiogenesis. PARs are increasingly recognised as targets for proteases outside the coagulation system and emerging evidence indicates that alternative protease signalling pathways synergise with the coagulation system to promote tumour growth, angiogenesis and metastasis. The elucidation of new therapeutic targets in tumour-promoting protease signalling pathways requires new diagnostic approaches to identify patients that will benefit from tailored therapy targeting procoagulant or signalling aspects of the TF pathway. PMID- 21781270 TI - Improving reperfusion therapy for acute ischaemic stroke. AB - BACKGROUND: The first generation of clinical reperfusion treatment, intravenous (IV) fibrinolysis with tissue plasminogen activator (tPA), was a transformative breakthrough in stroke care, but is far from ideal. OBJECTIVES: TO survey emerging strategies to increase the efficacy and safety of cerebral reperfusion therapy. METHODS: Narrative review. RESULTS AND CONCLUSIONS: Innovative IV pharmacologic reperfusion strategies include: extending IV tPA use to patients with mild deficits; developing novel fibrinolytic agents (tenecteplase, desmetolplase, plasmin); using ultrasound to enhance enzymatic fibrinolysis; combination clot lysis therapies (fibrinolytics with GPIIb/IIIa agents or direct thrombin inhibitors); co-administration of MMP-9 inhibitors to deter haemorrhagic transformation; and prehospital neuroprotection to support threatened tissues until reperfusion. Endovascular recanalisation strategies are rapidly evolving, and include intra-arterial fibrinolysis, mechanical clot retrieval, suction thrombectomy, and primary stenting. Combined approaches appear especially promising, using IV fibrinolysis to rapidly initiate reperfusion, mechanical endovascular treatment to debulk large, proximal thrombi, and intra-arterial (IA) fibrinolysis to clear residual distal thrombus elements and emboli. PMID- 21781271 TI - Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. AB - Atrial fibrillation (AF) is the commonest sustained cardiac rhythm disorder, which is associated with a substantial risk of mortality and morbidity arising from stroke and thromboembolism. Extensive epidemiological evidence and robust data from clinical trials have shown that stroke and thromboembolism in AF can be prevented by oral anticoagulation (OAC). Despite this evidence and guidelines, appropriate thromboprophylaxis is still suboptimal, and this is partly due to the only OAC agent being available is the vitamin K antagonist class of drugs (e.g. warfarin) that has many limitations and disadvantages. With the availability of new OAC agents that avoid the disutility of the vitamin K antagonists, it is hoped that greater use of OAC would allow more effective thromboprophylaxis and have a great impact on preventing strokes related to AF. Additionally, stroke risk assessments need to evolve such that they are better at identifying the 'truly low risk' subjects who do not need antithrombotic therapy, whilst all other patients with >= 1 stroke risk factors can be considered for OAC. The availability of comprehensive stroke and bleeding risk assessments would enable us to make informed decisions in everyday clinical practice. The aim of the review article is to provide a state-of-the-art overview of the clinical epidemiology of stroke in AF, stroke (and bleeding) risk assessments and the current provision of thromboprophylaxis for patients with AF. PMID- 21781272 TI - Historical perspective and future direction of coagulation research. AB - Over the past 100 years, remarkable advances have been made in our understanding of the mechanisms of blood coagulation. Starting with the early clinical observations of rare patients with hereditary clotting disorders, our knowledge has increased in keeping pace with the introduction of new technologies: from simple laboratory tests to protein chemistry, to DNA technology, and to gene targeting technology. Advances in basic research have been successfully translated into improved methods for the diagnosis of bleeding disorders as well as thrombosis, and the development of recombinant clotting factors for replacement therapy in patients with haemophilia. New promising anticoagulants have also been developed for the treatment of thrombotic disorders. Based on the unique nature of blood coagulation research the close interactions and collaborations between basic scientists and clinicians have played a major role in these developments. It is anticipated that blood coagulation research will continue to play a leading role in promoting better care of the patients with bleeding disorders or thromboembolism. PMID- 21781273 TI - Historical perspective and future direction of thrombolysis research: the re discovery of plasmin. AB - Two issues have held the focus of thrombolysis research for over 50 years, namely, choosing between a plasminogen activator (PA) or plasmin as the best therapeutic agent and choosing between systemic or local administration. The original plasmin product of the 1950s was both ineffective and contaminated with PA, and catheter technology was not yet developed for routine clinical use. For decades, clinical practice has focused on PA and systemic administration, but today, PAs are often administered by catheter into thrombosed vessels, notably for peripheral arterial and graft occlusion and deep vein thrombosis, and increasingly for acute ischaemic stroke. Despite using catheter-delivered therapy, bleeding complications still occur, most severely expressed as symptomatic intracranial haemorrhage. New experimental data indicate that we should now reconsider plasmin as a viable, even preferable, thrombolytic agent. Plasmin requires catheter delivery to achieve thrombolysis, but this technical issue has been solved with modern technology and widespread presence of interventional suites. After local administration, plasmin will lyse thrombi; thereafter, any plasmin in the circulation will be rapidly neutralised. Pre clinical studies confirm that plasmin has marked haemostatic safety advantage over t-PA. After more than 50 years, the field has come full circle, and plasmin as the thrombolytic agent and catheter use for local delivery of agent may represent a step forward in thrombolytic therapy. PMID- 21781275 TI - Telocytes within human skeletal muscle stem cell niche. AB - Human skeletal muscle tissue displays specific cellular architecture easily damaged during individual existence, requiring multiple resources for regeneration. Congruent with local prerequisites, heterogeneous muscle stem cells (MuSCs) are present in the muscle interstitium. In this study, we aimed to characterize the properties of human muscle interstitial cells that had the characteristic morphology of telocytes (TCs). Immunocytochemistry and immunofluorescence showed that cells with TC morphology stained positive for c kit/CD117 and VEGF. C-kit positive TCs were separated with magnetic-activated cell sorting, cultured in vitro and expanded for study. These cells exhibited high proliferation capacity (60% expressed endoglin/CD105 and 80% expressed nuclear Ki67). They also exhibited pluripotent capacity limited to Oct4 nuclear staining. In addition, 90% of c-kit positive TCs expressed VEGF. C-kit negative cells in the MuSCs population exhibited fibroblast-like morphology, low trilineage differential potential and negative VEGF staining. These results suggested that c-kit/CD117 positive TCs represented a unique cell type within the MuSC niche. PMID- 21781276 TI - Enhanced suicidal erythrocyte death in mice carrying a loss-of-function mutation of the adenomatous polyposis coli gene. AB - Loss-of-function mutations in human adenomatous polyposis coli (APC) lead to multiple colonic adenomatous polyps eventually resulting in colonic carcinoma. Similarly, heterozygous mice carrying defective APC (apc(Min/+)) suffer from intestinal tumours. The animals further suffer from anaemia, which in theory could result from accelerated eryptosis, a suicidal erythrocyte death triggered by enhanced cytosolic Ca(2+) activity and characterized by cell membrane scrambling and cell shrinkage. To explore, whether APC-deficiency enhances eryptosis, we estimated cell membrane scrambling from annexin V binding, cell size from forward scatter and cytosolic ATP utilizing luciferin-luciferase in isolated erythrocytes from apc(Min/+) mice and wild-type mice (apc(+/+)). Clearance of circulating erythrocytes was estimated by carboxyfluorescein diacetate-succinimidyl-ester labelling. As a result, apc(Min/+) mice were anaemic despite reticulocytosis. Cytosolic ATP was significantly lower and annexin V binding significantly higher in apc(Min/+) erythrocytes than in apc(+/+) erythrocytes. Glucose depletion enhanced annexin V binding, an effect significantly more pronounced in apc(Min/+) erythrocytes than in apc(+/+) erythrocytes. Extracellular Ca(2+) removal or inhibition of Ca(2+) entry with amiloride (1 mM) blunted the increase but did not abrogate the genotype differences of annexin V binding following glucose depletion. Stimulation of Ca(2+) -entry by treatment with Ca(2+) -ionophore ionomycin (10 MUM) increased annexin V binding, an effect again significantly more pronounced in apc(Min/+) erythrocytes than in apc(+/+) erythrocytes. Following retrieval and injection into the circulation of the same mice, apc(Min/+) erythrocytes were more rapidly cleared from circulating blood than apc(+/+) erythrocytes. Most labelled erythrocytes were trapped in the spleen, which was significantly enlarged in apc(Min/+) mice. The observations point to accelerated eryptosis and subsequent clearance of apc(Min/+) erythrocytes, which contributes to or even accounts for the enhanced erythrocyte turnover, anaemia and splenomegaly in those mice. PMID- 21781279 TI - Identification of antibacterial mechanism of L-amino acid oxidase derived from Trichoderma harzianum ETS 323. AB - Although L-amino oxidase (LAAO; EC 1.4.3.2) has been reported to be a potent antibacterial agent, the mechanism responsible for its antibacterial activity has not been identified. The present study aimed to identify the mechanism responsible for the antibacterial activity of Th-LAAO, an LAAO recently isolated from the extracellular proteins of Trichoderma harzianum ETS 323, at the same time as elucidating the nature of this enzyme. The results obtained indicate that the enzyme activity and structure of Th-LAAO are stable at pH 6-8 and less stable at both pH 4-5.5 and pH 9. At pH 7.0, the optimum temperature for Th-LAAO was found to be 40 degrees C, comprising the temperature at which enzymatic activity is greatest, with enzymatic activity deceasing with further increases in temperature as a result of thermal denaturation of the enzyme, leading to partial denaturation at 50 degrees C. The results obtained by confocal microscopy and flow cytometry indicate that Th-LAAO interacts with bacteria to cause membrane permeabilization, and this interaction may be promoted by the amphipathic sequence in Th-LAAO and other cytotoxic LAAOs located at the N-terminus. The findings of increased exogenous H(2) O(2) production and reactive oxidative species accumulation in Th-LAAO-treated bacteria indicate that reactive oxidative species accumulation may trigger forms of cell damage, including lipid peroxidation and DNA strand breakage that results in bacterial growth inhibition. Taken together, the results indicate that the processes of bacterial interaction, membrane permeabilization and H(2)O(2) production are involved in the mechanism responsible for the antibacterial activity of Th-LAAO. PMID- 21781278 TI - Induced Pib Expression and Resistance to Magnaporthe grisea are Compromised by Cytosine Demethylation at Critical Promoter Regions in Rice. AB - Pib is a well-characterized rice blast-resistance gene belonging to the nucleotide binding site (NBS) and leucine-rich repeat (LRR) superfamily. Expression of Pib was low under non-challenged conditions, but strongly induced by the blast-causing fungal pathogen Magnaporthe grisea, thereby conferring resistance to the pathogen. It is generally established that cytosine methylation of the promoter-region often plays a repressive role in modulating expression of the gene in question. We report here that two critical regions of the Pib promoter were heavily CG cytosine-methylated in both cultivars studied. Surprisingly, induced expression of Pib by M. grisea infection did not entail its promoter demethylation, and partial demethylation by 5-azacytidine-treatment actually reduced Pib expression relative to wild-type plants. Accordingly, the blast disease-resistance was compromised in the 5'-azaC-treated plants relative to wild-type. In contrast, the disease susceptibility was not affected by the 5' azaC treatment in another two rice cultivars that did not contain the Pib gene, ruling out effects of other R genes and non-specific genotoxic effects by the drug-treatment as a cause for the compromised Pib-conditioned blast-resistance. Taken together, our results suggest that promoter DNA methylation plays a novel enhancing role in conditioning high-level of induced expression of the Pib gene in times of M. grisea infection, and its conferred resistance to the pathogen. PMID- 21781277 TI - Functional genetic variation in the Rev-Erbalpha pathway and lithium response in the treatment of bipolar disorder. AB - Bipolar disorder (BD) is characterized by disruptions in circadian rhythms such as sleep and daily activity that often normalize after lithium treatment in responsive patients. As lithium is known to interact with the circadian clock, we hypothesized that variation in circadian 'clock genes' would be associated with lithium response in BD. We determined genotype for 16 variants in seven circadian clock genes and conducted a candidate gene association study of these in 282 Caucasian patients with BD who were previously treated with lithium. We found that a variant in the promoter of NR1D1 encoding Rev-Erbalpha (rs2071427) and a second variant in CRY1 (rs8192440) were nominally associated with good treatment response. Previous studies have shown that lithium regulates Rev-Erbalpha protein stability by inhibiting glycogen synthase kinase 3beta (GSK3beta). We found that GSK3beta genotype was also suggestive of a lithium response association, but not statistically significant. However, when GSK3beta and NR1D1 genotypes were considered together, they predicted lithium response robustly and additively in proportion to the number of response-associated alleles. Using lymphoblastoid cell lines from patients with BD, we found that both the NR1D1 and GSK3beta variants are associated with functional differences in gene expression. Our findings support a role for Rev-Erbalpha in the therapeutic mechanism of lithium and suggest that the interaction between Rev-Erbalpha and GSK3beta may warrant further study. PMID- 21781280 TI - Cellular vacuolation induced by Clostridium perfringens epsilon-toxin. AB - The epsilon-toxin of Clostridium perfringens forms a heptamer in the membranes of Madin-Darby canine kidney cells, leading to cell death. Here, we report that it caused the vacuolation of Madin-Darby canine kidney cells. The toxin induced vacuolation in a dose-dependent and time-dependent manner. The monomer of the toxin formed oligomers on lipid rafts in membranes of the cells. Methyl-beta cyclodextrin and poly(ethylene glycol) 4000 inhibited the vacuolation. Epsilon toxin was internalized into the cells. Confocal microscopy revealed that the internalized toxin was transported from early endosomes (early endosome antigen 1 staining) to late endosomes and lysosomes (lysosomal-associated membrane protein 2 staining) and then distributed to the membranes of vacuoles. Furthermore, the vacuolation was inhibited by bafilomycin A1, a V-type ATPase inhibitor, and colchicine and nocodazole, microtubule-depolymerizing agents. The early endosomal marker green fluorescent protein-Rab5 and early endosome antigen 1 did not localize to vacuolar membranes. In contrast, the vacuolar membranes were specifically stained by the late endosomal and lysosomal marker green fluorescent protein-Rab7 and lysosomal-associated membrane protein 2. The vacuoles in the toxin-treated cells were stained with LysoTracker Red DND-99, a marker for late endosomes and lysosomes. A dominant negative mutant of Rab7 prevented the vacuolization, whereas a mutant form of Rab5 was less effective. These results demonstrate, for the first time, that: (a) oligomers of epsilon-toxin formed in lipid rafts are endocytosed; and (b) the vacuoles originating from late endosomes and lysosomes are formed by an oligomer of epsilon-toxin. PMID- 21781274 TI - Historical perspective and future directions in platelet research. AB - Platelets are a remarkable mammalian adaptation that are required for human survival by virtue of their ability to prevent and arrest bleeding. Ironically, however, in the past century, the platelets' hemostatic activity became maladaptive for the increasingly large percentage of individuals who develop age dependent progressive atherosclerosis. As a result, platelets also make a major contribution to ischemic thrombotic vascular disease, the leading cause of death worldwide. In this brief review, I provide historical descriptions of a highly selected group of topics to provide a framework for understanding our current knowledge and the trends that are likely to continue into the future of platelet research. For convenience, I separate the eras of platelet research into the "Descriptive Period" extending from ~1880-1960 and the "Mechanistic Period" encompassing the past ~50 years since 1960. We currently are reaching yet another inflection point, as there is a major shift from a focus on traditional biochemistry and cell and molecular biology to an era of single molecule biophysics, single cell biology, single cell molecular biology, structural biology, computational simulations, and the high-throughput, data-dense techniques collectively named with the "omics postfix". Given the progress made in understanding, diagnosing, and treating many rare and common platelet disorders during the past 50 years, I think it appropriate to consider it a Golden Age of Platelet Research and to recognize all of the investigators who have made important contributions to this remarkable achievement.. PMID- 21781281 TI - Importance of position 8 in MU-conotoxin KIIIA for voltage-gated sodium channel selectivity. AB - MU-Conotoxin KIIIA from Conus kinoshitai is a 16-residue peptide that acts as a potent pore blocker of several voltage-gated sodium channels (Na(v)). In order to obtain more selective blockers and to investigate the role of Trp at position 8, we substituted this residue with Arg, Gln and Glu. KIIIA and analogues were tested on a range of Na(v) expressed in Xenopus laevis oocytes. The rank order of potency for KIIIA was: rNa(v)1.4 >= rNa(v)1.2 > mNa(v)1.6 > rNa(v)1.3, with IC(50) values of 48 +/- 6 nm, 61 +/- 5 nm, 183 +/- 31 nm and 3.6 +/- 0.3 MUm, respectively, whereas no effect was seen on hNa(v)1.5 and hNa(v)1.8 at a concentration of 10 MUm. Replacement of Trp8 resulted in more selective blockers with a preference for neuronal sodium channels over the skeletal sodium channel. The activity on rNa(v)1.4 was reduced about 40-, 70- and 200-fold for [W8R]KIIIA, [W8Q]KIIIA and [W8E]KIIIA, respectively. All analogues showed a completely reversible block of rNa(v)1.2, as opposed to the partial reversibility of KIIIA. At saturating concentrations, complete block of rNa(v)1.2 was never achieved. The residual current was lower than 10%, except for [W8E]KIIIA. KIIIA had no effect on the voltage dependence of activation of rNa(v)1.2, whereas all analogues caused a depolarizing shift. Overall, this study shows that Trp8 is a key residue in the pharmacophore. Replacement of Trp8 enables more selective blockers to be obtained for neuronal sodium channels. Trp is a key determinant for the reversibility of block of rNa(v)1.2. PMID- 21781282 TI - A protein oxidase catalysing disulfide bond formation is localized to the chloroplast thylakoids. AB - In chloroplasts, thiol/disulfide-redox-regulated proteins have been linked to numerous metabolic pathways. However, the biochemical system for disulfide bond formation in chloroplasts remains undetermined. In the present study, we characterized an oxidoreductase, AtVKOR-DsbA, encoded by the gene At4g35760 as a potential disulfide bond oxidant in Arabidopsis. The gene product contains two distinct domains: an integral membrane domain homologous to the catalytic subunit of mammalian vitamin K epoxide reductase (VKOR) and a soluble DsbA-like domain. Transient expression of green fluorescent protein fusion in Arabidopsis protoplasts indicated that AtVKOR-DsbA is located in the chloroplast. The first 45 amino acids from the N-terminus were found to act as a transit peptide targeting the protein to the chloroplast. An immunoblot assay of chloroplast fractions revealed that AtVKOR-DsbA was localized in the thylakoid. A motility complementation assay showed that the full-length of AtVKOR-DsbA, if lacking its transit peptide, could catalyze the formation of disulfide bonds. Among the 10 cysteine residues present in the mature protein, eight cysteines (four in the AtVKOR domain and four in the AtDsbA domain) were found to be essential for promoting disulfide bond formation. The topological arrangement of AtVKOR-DsbA was assayed using alkaline phosphatase sandwich fusions. From these results, we developed a possible topology model of AtVKOR-DsbA in chloroplasts. We propose that the integral membrane domain of AtVKOR-DsbA contains four transmembrane helices, and that both termini and the cysteines involved in catalyzing the formation of disulfide bonds face the oxidative thylakoid lumen. These studies may help to resolve some of the issues surrounding the structure and function of AtVKOR-DsbA in Arabidopsis chloroplasts. PMID- 21781283 TI - DbMDR: a relational database for multidrug resistance genes as potential drug targets. AB - DbMDR is non-redundant reference database of multidrug resistance (MDR) genes and their orthologs acting as potential drug targets. Drug resistance is a common phenomenon of pathogens, creating a serious problem of inactivation of drugs and antibiotics resulting in occurrence of diseases. Apart from other factors, the MDR genes present in pathogens are shown to be responsible for multidrug resistance. Much of the unorganized information on MDR genes is scattered across the literature and other web resources. Thus, consolidation of such knowledge about MDR genes into one database will make the drug discovery research more efficient. Mining of text for MDR genes has resulted into a large number of publications but in scattered and unorganized form. This information was compiled into a database, which enables a user not only to look at a particular MDR gene but also to find out putative homologs based on sequence similarity, conserved domains, and motifs in proteins encoded by MDR genes more efficiently. At present, DbMDR database contains 2843 MDR genes characterized experimentally as well as functionally annotated with cross-referencing search support. The DbMDR database (http://203.190.147.116/dbmdr/) is a comprehensive resource for comparative study focused on MDR genes and metabolic pathway efflux pumps and intended to provide a platform for researchers for further research in drug resistance. PMID- 21781284 TI - Determination of noscapine's localization and interaction with the tubulin alpha/beta heterodimer. AB - Noscapine, the benzylisoquinoline alkaloid, 5-(4,5-Dimethoxy-3-oxo-1,3-dihydro isobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5 g]isoquinolin-6-ium, has been extensively used as a cough-suppressing medication with low toxicity. It has been recently shown to also have anti-cancer activity in mice and humans. In this work, using in silico analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the alpha and beta subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon noscapine binding, the conformational change in the tubulin heterodimer along with a potential long range allosteric effect on both the N and E sites is studied by means of molecular dynamics simulations. Noscapine is found to function as a tubulin stabilizing agent that interacts strongest with the lateral and longitudinal segments of the tubulin dimer, impacting the interaction between monomers in neighboring protofilaments. We infer that this may act as a depolymerization inhibitor of microtubules. As a result of this study, we have designed novel analogues of noscapine with the ultimate goal of finding agents with increased anti-tumor activity and lower inhibitory concentrations than that of noscapine. PMID- 21781286 TI - Melanoma response and resistance - taking it to the tumor bank. PMID- 21781285 TI - Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain. AB - OBJECTIVE: To describe the epidemiological and clinical characteristics of children hospitalized with 2009 pandemic influenza (pH1N1) in Madrid, Spain. PATIENTS/METHODS: We included patients less than 14 years of age admitted to one of 18 hospitals in Madrid, Spain, between May 1 and November 30, 2009 and diagnosed with pH1N1 by polymerase chain reaction. A retrospective chart review was conducted and data were compared by age, presence of high-risk medical conditions, and pediatric intensive care unit (PICU) admission. RESULTS: A total of 517 pH1N1 cases were included for final analysis. One hundred and forty-two patients (27.5%) had predisposing underlying illnesses, with immunosuppression (36 children, 7%) and moderate persistent asthma (34, 6.6%) being the most common ones. Patients with underlying medical conditions had longer hospital stays [median 5, interquartile range (IQR) 3-8 days, versus median 4, IQR 3-6, P < 0.001] and required intensive care (20.4% versus 5.9%, P < 0.001) and mechanical ventilation more frequently than previously healthy children. Globally, intensive care was required for 51 patients (10%) and invasive mechanical ventilation for 12 (2%). Pediatric intensive care unit admission was significantly associated with abnormal initial chest X-ray [Odds Ratio (OR) 3.5, 95% confidence interval (CI) 1.5-8.5], underlying neurological condition (OR 3.1, CI 1.2-7.5) and immunosuppression (OR 2.9, 1.2-6.8). Five patients (0.9%) died; two with severe neurological disease, two with leukemia, and one with a malignant solid tumor. CONCLUSIONS: Children with underlying medical conditions experienced more severe pH1N1 disease. Risk factors for admission to the PICU included underlying neurological conditions, immunosuppression and abnormal initial chest X-ray. PMID- 21781287 TI - Measuring outcome after wrist injury: translation and validation of the Swedish version of the patient-rated wrist evaluation (PRWE-Swe). AB - BACKGROUND: There is a need for outcome measurement instruments for evaluation of disability after trauma. The Patient-Rated Wrist Evaluation (PRWE) is a self administered region-specific outcome measuring instrument developed for use in evaluating disability and pain of the wrist. The aim of this study is to translate and to cross-culturally adapt the PRWE for use in a Swedish patient population. Moreover, we aim at investigating the PRWE in terms of validity, reliability and responsiveness. METHODS: We performed a translation and cross cultural adaptation of the PRWE to Swedish (PRWE-Swe), utilising the process recommended by the American Association of Orthopedic Surgeons. A total of 124 patients with an injury to the wrist were included in the study. They filled in the PRWE and the DASH questionnaires at two separate occasions. RESULTS: Reliability of the PRWE in terms of internal consistency (Cronbach's alpha 0.97) and test-retest stability (intraclass correlation coefficient 0.93) were excellent. Face validity and content validity were judged as good. Criterion validity assessed as the correlation between the PRWE and the DASH was also good (Spearman's rho = 0.9). Responsiveness measured by the standardized response mean (SRM) was good with an SRMPRWE of 1.29. CONCLUSION: This Swedish version of the PRWE is a short and easily understood self-administered questionnaire with good validity, reliability, and responsiveness. Our results confirm that the PRWE is a valuable tool in evaluating the results after treatment of a wrist injury. PMID- 21781288 TI - PubChem3D: Biologically relevant 3-D similarity. AB - BACKGROUND: The use of 3-D similarity techniques in the analysis of biological data and virtual screening is pervasive, but what is a biologically meaningful 3 D similarity value? Can one find statistically significant separation between "active/active" and "active/inactive" spaces? These questions are explored using 734,486 biologically tested chemical structures, 1,389 biological assay data sets, and six different 3-D similarity types utilized by PubChem analysis tools. RESULTS: The similarity value distributions of 269.7 billion unique conformer pairs from 734,486 biologically tested compounds (all-against-all) from PubChem were utilized to help work towards an answer to the question: what is a biologically meaningful 3-D similarity score? The average and standard deviation for the six similarity measures STST-opt, CTST-opt, ComboTST-opt, STCT-opt, CTCT opt, and ComboTCT-opt were 0.54 +/- 0.10, 0.07 +/- 0.05, 0.62 +/- 0.13, 0.41 +/- 0.11, 0.18 +/- 0.06, and 0.59 +/- 0.14, respectively. Considering that this random distribution of biologically tested compounds was constructed using a single theoretical conformer per compound (the "default" conformer provided by PubChem), further study may be necessary using multiple diverse conformers per compound; however, given the breadth of the compound set, the single conformer per compound results may still apply to the case of multi-conformer per compound 3-D similarity value distributions. As such, this work is a critical step, covering a very wide corpus of chemical structures and biological assays, creating a statistical framework to build upon.The second part of this study explored the question of whether it was possible to realize a statistically meaningful 3-D similarity value separation between reputed biological assay "inactives" and "actives". Using the terminology of noninactive-noninactive (NN) pairs and the noninactive-inactive (NI) pairs to represent comparison of the "active/active" and "active/inactive" spaces, respectively, each of the 1,389 biological assays was examined by their 3-D similarity score differences between the NN and NI pairs and analyzed across all assays and by assay category types. While a consistent trend of separation was observed, this result was not statistically unambiguous after considering the respective standard deviations. While not all "actives" in a biological assay are amenable to this type of analysis, e.g., due to different mechanisms of action or binding configurations, the ambiguous separation may also be due to employing a single conformer per compound in this study. With that said, there were a subset of biological assays where a clear separation between the NN and NI pairs found. In addition, use of combo Tanimoto (ComboT) alone, independent of superposition optimization type, appears to be the most efficient 3-D score type in identifying these cases. CONCLUSION: This study provides a statistical guideline for analyzing biological assay data in terms of 3-D similarity and PubChem structure-activity analysis tools. When using a single conformer per compound, a relatively small number of assays appear to be able to separate "active/active" space from "active/inactive" space. PMID- 21781289 TI - Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors. AB - BACKGROUND: Transgenic mouse tumor models have the advantage of facilitating controlled in vivo oncogenic perturbations in a common genetic background. This provides an idealized context for generating transcriptome-based diagnostic models while minimizing the inherent noisiness of high-throughput technologies. However, the question remains whether models developed in such a setting are suitable prototypes for useful human diagnostics. We show that latent factor modeling of the peripheral blood transcriptome in a mouse model of breast cancer provides the basis for using computational methods to link a mouse model to a prototype human diagnostic based on a common underlying biological response to the presence of a tumor. METHODS: We used gene expression data from mouse peripheral blood cell (PBC) samples to identify significantly differentially expressed genes using supervised classification and sparse ANOVA. We employed these transcriptome data as the starting point for developing a breast tumor predictor from human peripheral blood mononuclear cells (PBMCs) by using a factor modeling approach. RESULTS: The predictor distinguished breast cancer patients from healthy individuals in a cohort of patients independent from that used to build the factors and train the model with 89% sensitivity, 100% specificity and an area under the curve (AUC) of 0.97 using Youden's J-statistic to objectively select the model's classification threshold. Both permutation testing of the model and evaluating the model strategy by swapping the training and validation sets highlight its stability. CONCLUSIONS: We describe a human breast tumor predictor based on the gene expression of mouse PBCs. This strategy overcomes many of the limitations of earlier studies by using the model system to reduce noise and identify transcripts associated with the presence of a breast tumor over other potentially confounding factors. Our results serve as a proof-of concept for using an animal model to develop a blood-based diagnostic, and it establishes an experimental framework for identifying predictors of solid tumors, not only in the context of breast cancer, but also in other types of cancer. PMID- 21781290 TI - First report of field evolved resistance to agrochemicals in dengue mosquito, Aedes albopictus (Diptera: Culicidae), from Pakistan. AB - BACKGROUND: Agrochemicals have been widely used in Pakistan for several years. This exposes mosquito populations, particularly those present around agricultural settings, to an intense selection pressure for insecticide resistance. The aim of the present study was to investigate the toxicity of representative agrochemicals against various populations of Aedes albopictus (Skuse) collected from three different regions from 2008-2010. RESULTS: For organophosphates and pyrethroids, the resistance ratios compared with susceptible Lab-PK were in the range of 157 266 fold for chlorpyrifos, 24-52 fold for profenofos, 41-71 fold for triazofos, and 15-26 fold for cypermethrin, 15-53 fold for deltamethrin and 21-58 fold for lambdacyhalothrin. The resistance ratios for carbamates and new insecticides were in the range of 13-22 fold for methomyl, 24-30 fold for thiodicarb, and 41-101 fold for indoxacarb, 14-27 fold for emamectin benzoate and 23-50 fold for spinosad. Pair wise comparisons of the log LC50s of insecticides revealed correlation among several insecticides, suggesting a possible cross resistance mechanism. Moreover, resistance remained stable across 3 years, suggesting field selection for general fitness had also taken place for various populations of Ae. albopictus. CONCLUSION: Moderate to high level of resistance to agrochemicals in Pakistani field populations of Ae. albopictus is reported here first time. The geographic extent of resistance is unknown but, if widespread, may lead to problems in future vector control. PMID- 21781291 TI - Surveillance of vector populations and malaria transmission during the 2009/10 El Nino event in the western Kenya highlands: opportunities for early detection of malaria hyper-transmission. AB - BACKGROUND: Vector control in the highlands of western Kenya has resulted in a significant reduction of malaria transmission and a change in the vectorial system. Climate variability as a result of events such as El Nino increases the highlands suitability for malaria transmission. Surveillance and monitoring is an important component of early transmission risk identification and management. However, below certain disease transmission thresholds, traditional tools for surveillance such as entomological inoculation rates may become insensitive. A rapid diagnostic kit comprising Plasmodium falciparum circumsporozoite surface protein and merozoite surface protein antibodies in humans was tested for early detection of transmission surges in the western Kenya highlands during an El Nino event (October 2009-February 2010). METHODS: Indoor resting female adult malaria vectors were collected in western Kenya highlands in four selected villages categorized into two valley systems, the U-shaped (Iguhu and Emutete) and the V shaped valleys (Marani and Fort Ternan) for eight months. Members of the Anopheles gambiae complex were identified by PCR. Blood samples were collected from children 6-15 years old and exposure to malaria was tested using a circum sporozoite protein and merozoite surface protein immunchromatographic rapid diagnostic test kit. Sporozoite ELISA was conducted to detect circum-sporozoite protein, later used for estimation of entomological inoculation rates. RESULTS: Among the four villages studied, an upsurge in antibody levels was first observed in October 2009. Plasmodium falciparum sporozoites were then first observed in December 2009 at Iguhu village and February 2010 at Emutete. Despite the upsurge in Marani and Fort Ternan no sporozoites were detected throughout the eight month study period. The antibody-based assay had much earlier transmission detection ability than the sporozoite-based assay. The proportion of An. arabiensis among An. gambiae s.l. ranged from 2.9-66.7% indicating a rearrangement of the sibling species of the An. gambiae s.l complex. This is possibly an adaptation to insecticide interventions and climate change. CONCLUSION: The changing malaria transmission rates in the western Kenya highlands will lead to more unstable transmission, decreased immunity and a high vulnerability to epidemics unless surveillance tools are improved and effective vector control is sustained. PMID- 21781292 TI - Ganglioneuroblastoma of the posterior mediastinum: a case report. AB - INTRODUCTION: Ganglioneuroblastoma is a rare peripheral neuroblastic tumor that is derived from developing neuronal cells of the sympathetic nervous system, and is found mostly, but not exclusively, in babies and young children. CASE PRESENTATION: To the best of our knowledge, there have been no previously reported cases of ganglioneuroblastoma of the mediastinum from Pakistan. We present a case of ganglioneuroblastoma in an eight-year-old Pakistani Sindhi boy incidentally found to have a large posterior mediastinal mass that on biopsy initially looked like ganglioneuroma. He underwent successful excision of the mediastinal mass and remained stable post-operatively. Final pathology findings showed a ganglioneuroblastoma. He has remained free of symptoms on long-term follow-up. CONCLUSIONS: The rarity of this tumor along with its almost exclusive occurrence in the pediatric population necessitates a thorough investigation of patients presenting with a symptomatic mass. PMID- 21781293 TI - Atypical clinical presentation of a subset of patients with anti-RNA polymerase III--non-scleroderma cases associated with dominant RNA polymerase I reactivity and nucleolar staining. AB - INTRODUCTION: Anti-RNA polymerase III (RNAP III) antibodies are highly specific markers of scleroderma (systemic sclerosis, SSc) and associated with a rapidly progressing subset of SSc. The clinical presentation of anti-RNAP III positive patients, onset of Raynaud's phenomenon (RP) and SSc in unselected patients in a rheumatology clinic were evaluated. METHODS: Autoantibodies in sera from 1,966 unselected patients (including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) in a rheumatology clinic were screened by radioimmunoprecipitation. Anti-RNAP III positive sera were also tested by immunofluorescence antinuclear antibodies and anti-RNAP III ELISA. Medical records of anti-RNAP III positive patients were reviewed. RESULTS: Among 21 anti RNAP III positive patients, 16 met the American College of Rheumatology (ACR) SSc criteria at the initial visit but 5 did not; diagnoses were vasculitis, early polyarthritis, renal failure with RP, interstitial lung disease, and Sjogren's syndrome. The first two patients developed rapidly progressive diffuse SSc. An additional case presented with diffuse scleroderma without RP and RP developed two years later. Anti-RNAP III antibodies in these 6 cases of atypical clinical presentation were compared with those in 15 cases of typical (SSc with RP) cases. Anti-RNAP III levels by ELISA were lower in the former group (P = 0.04 by Mann Whitney test) and 3 of 6 were negative versus only 1 of 15 negative in the latter (P < 0.05 by Fisher's exact test). Three cases of non-SSc anti-RNAP III positive patients had predominant reactivity with RNAP I with weak RNAP III reactivity and had a strong nucleolar staining. Three anti-RNAP III patients, who did not have RP at the initial visit, developed RP months later. Scleroderma developed prior to RP in 5 out of 16 (31%) in the anti-RNAP III group, but this was rare in patients with other autoantibodies. The interval between the onset of RP to scleroderma was short in anti-RNAP III positive patients. CONCLUSIONS: Anti-RNAP III antibodies are highly specific for SSc; however, a subset of anti-RNAP III positive patients do not present as typical SSc. The interval between RP and scleroderma in this group is short, and 31% of patients developed scleroderma prior to RP in this group. Anti-RNAP III positive patients may not present as typical SSc and detecting anti-RNAP III may have predictive value. PMID- 21781294 TI - Hippobosca longipennis--a potential intermediate host of a species of Acanthocheilonema in dogs in northern India. AB - BACKGROUND: Hippobosca longipennis (the 'dog louse fly') is a blood sucking ectoparasite found on wild carnivores such as cheetahs and lions and domesticated and feral dogs in Africa, the Middle East and Asia, including China. Known as an intermediate host for Acanthocheilonema dracunculoides and a transport host for Cheyletiella yasguri, it has also been suggested that H. longipennis may be a vector for other pathogens, including Acanthocheilonema sp.? nov., which was recently reported to infect up to 48% of dogs in northern India where this species of fly is known to commonly infest dogs. To test this hypothesis, hippoboscid flies feeding on dogs in Ladakh in northern India were collected and subjected to microscopic dissection. RESULTS: A total of 12 infective larvae were found in 10 out of 65 flies dissected; 9 from the head, 2 from the thorax and 1 from the abdomen. The larvae averaged 2, 900 (+/- 60) MUm in length and 34 (+/- 5) MUm in width and possessed morphological features characteristic of the family Onchocercidae. Genetic analysis and comparison of the 18S, ITS-2, 12S and cox-1 genes confirmed the identity of the larvae as the Acanthocheilonema sp.? nov. reported in dogs in Ladakh. CONCLUSION: This study provides evidence for a potential intermediate host-parasite relationship between H. longipennis and the canine Acanthocheilonema sp.? nov. in northern India. PMID- 21781296 TI - Management of pain induced by exercise and mobilization during physical therapy programs: views of patients and care providers. AB - BACKGROUND: The expectations of patients for managing pain induced by exercise and mobilization (PIEM) have seldom been investigated. We identified the views of patients and care providers regarding pain management induced by exercise and mobilization during physical therapy programs. METHODS: We performed a qualitative study based on semi-structured interviews with a stratified sample of 12 patients (7 women) and 14 care providers (6 women): 4 general practitioners [GPs], 1 rheumatologist, 1 physical medicine physician, 1 geriatrician, 2 orthopedic surgeons, and 5 physical therapists. RESULTS: Patients and care providers have differing views on PIEM in the overall management of the state of disease. Patients' descriptions of PIEM were polymorphic, and they experienced it as decreased health-related quality of life. The impact of PIEM was complex, and patient views were sometimes ambivalent, ranging from denial of symptoms to discontinuation of therapy. Care providers agreed that PIEM is generally not integrated in management strategies. Care providers more often emphasized the positive and less often the negative dimensions of PIEM than did patients. However, the consequences of PIEM cited included worsened patient clinical condition, fears about physical therapy, rejection of the physical therapist and refusal of care. PIEM follow-up is not optimal and is characterized by poor transmission of information. Patients expected education on how better to prevent stress and anxiety generated by pain, education on mobilization, and adaptations of physical therapy programs according to pain intensity. CONCLUSION: PIEM management could be optimized by alerting care providers to the situation, improving communication among care providers, and providing education to patients and care providers. PMID- 21781295 TI - The efficacy and value of emergency medicine: a supportive literature review. AB - STUDY OBJECTIVES: The goal of this study was to identify publications in the medical literature that support the efficacy or value of Emergency Medicine (EM) as a medical specialty and of clinical care delivered by trained emergency physicians. In this study we use the term "value" to refer both to the "efficacy of clinical care" in terms of achieving desired patient outcomes, as well as "efficiency" in terms of effective and/or cost-effective utilization of healthcare resources in delivering emergency care. A comprehensive listing of publications describing the efficacy or value of EM has not been previously published. It is anticipated that the accumulated reference list generated by this study will serve to help promote awareness of the value of EM as a medical specialty, and acceptance and development of the specialty of EM in countries where EM is new or not yet fully established. METHODS: The January 1995 to October 2010 issues of selected journals, including the EM journals with the highest article impact factors, were reviewed to identify articles of studies or commentaries that evaluated efficacy, effectiveness, and/or value related to EM as a specialty or to clinical care delivered by EM practitioners. Articles were included if they found a positive or beneficial effect of EM or of EM physician provided medical care. Additional articles that had been published prior to 1995 or in other non-EM journals already known to the authors were also included. RESULTS: A total of 282 articles were identified, and each was categorized into one of the following topics: efficacy of EM for critical care and procedures (31 articles), efficacy of EM for efficiency or cost of care (30 articles), efficacy of EM for public health or preventive medicine (34 articles), efficacy of EM for radiology (11 articles), efficacy of EM for trauma or airway management (27 articles), efficacy of EM for using ultrasound (56 articles), efficacy of EM faculty (34 articles), efficacy of EM residencies (24 articles), and overviews and editorials of EM efficacy and value (35 articles). CONCLUSION: There is extensive medical literature that supports the efficacy and value for both EM as a medical specialty and for emergency patient care delivered by trained EM physicians. PMID- 21781298 TI - Errorless and errorful learning modulated by transcranial direct current stimulation. AB - BACKGROUND: Errorless learning is advantageous over trial and error learning (errorful learning) as errors are avoided during learning resulting in increased memory performance. Errorful learning challenges the executive control system of memory processes as the erroneous items compete with the correct items during retrieval. The left dorsolateral prefrontal cortex (DLPFC) is a core region involved in this executive control system. Transcranial direct current stimulation (tDCS) can modify the excitability of underlying brain functioning. RESULTS: In a single blinded tDCS study one group of young healthy participants received anodal and another group cathodal tDCS of the left DLPFC each compared to sham stimulation. Participants had to learn words in an errorless and an errorful manner using a word stem completion paradigm. The results showed that errorless compared to errorful learning had a profound effect on the memory performance in terms of quality. Anodal stimulation of the left DLPFC did not modulate the memory performance following errorless or errorful learning. By contrast, cathodal stimulation hampered memory performance after errorful learning compared to sham, whereas there was no modulation after errorless learning. CONCLUSIONS: Concluding, the study further supports the advantages of errorless learning over errorful learning. Moreover, cathodal stimulation of the left DLPFC hampered memory performance following the conflict-inducing errorful learning as compared to no modulation after errorless learning emphasizing the importance of the left DLPFC in executive control of memory. PMID- 21781300 TI - Correction: The role of particle size of particulate nano-zinc oxide wood preservatives on termite mortality and leach resistance. PMID- 21781299 TI - Pregnancy outcomes in women with repeated implantation failures after intracytoplasmic morphologically selected sperm injection (IMSI). AB - BACKGROUND: The purpose of this study was to compare laboratory and clinical outcomes of intracytoplasmic morphologically selected sperm injection (IMSI) and conventional intracytoplasmic sperm injection (ICSI) in couples with repeated implantation failures. METHODS: A total of 200 couples with at least two prior unsuccessful ICSI cycles were enrolled: 100 couples were submitted to IMSI and 100 were submitted to routine ICSI. For IMSI, spermatozoa were selected at 8400* magnification using an inverted microscope equipped with Nomarski (differential interference contrast) optics. For conventional ICSI, spermatozoa were selected at 400* magnification. Clinical outcomes were evaluated between the two groups. RESULTS: Study patients were comparable in age, number of treatment failures, aetiology of infertility, percentage of normal form assessed by MSOME (motile sperm organelle morphology examination), semen parameters, total number of oocytes collected, number of mature oocytes collected, total number of embryos transferred and number of high-quality embryos transferred. No statistically significant differences between the two groups were observed with regard to rates of fertilisation, implantation and pregnancy/cycle. Although not statistically significant, rates of miscarriage (IMSI:15.3% vs ICSI:31.7%), ongoing pregnancy (IMSI:22% vs ICSI:13%) and live births (IMSI:21% vs ICSI:12%) showed a trend towards better outcomes in the IMSI group. In addition, analysis of subpopulations with or without male factor showed similar results. CONCLUSIONS: Our results suggest that IMSI does not provide a significant improvement in clinical outcome compared to ICSI, at least in couples with repeated implantation failures after conventional ICSI. However, it should be noted that there were clear trends for lower miscarriage rates (~50% reduced) and higher rates of ongoing pregnancy and live births (both nearly doubled) within the IMSI group. Further confirmation as well as randomized large-scale trials are needed to confirm the beneficial effects of IMSI in couples with poor reproductive prognoses. PMID- 21781301 TI - Self-reported poor oral hygiene among in-school adolescents in Zambia. AB - BACKGROUND: Dental health is a neglected aspect of adolescent health globally but more so in low-income countries. Secondary analysis using the 2004 Zambia Global School-Based Health Survey (GSHS) was conducted in which we estimated frequencies of relevant socio-demographic variables and explored associations between selected explanatory variables and self-reported poor oral hygiene (not cleaning or brushing teeth) within the last 30 days of the completion of questionnaire. FINDINGS: Most of the 2257 respondents were males (53.9%) and went hungry (82.5%). More than 4 in 10 respondents drank alcohol (42.2%) while 37.2% smoked cannabis. Overall 10.0% of the respondents reported to have poor oral hygiene. Male respondents were 7% less likely to report to have poor oral hygiene compared to females. Compared to respondents who never drank alcohol, those who drank alcohol were 27% more likely to report to have poor oral hygiene. Respondents who smoked cannabis were 4% more likely to report to have poor oral hygiene compared to those who did not smoke cannabis. Finally, respondents who went hungry were 35% more likely to report to have poor oral hygiene compared to those who did not go hungry. CONCLUSIONS: Results from this study indicate that female gender, alcohol drinking, cannabis smoking, and going hungry were associated with self reported poor oral hygiene. The identification of these factors should guide the design and implementation of programs aimed to improve oral health among adolescents. PMID- 21781302 TI - Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/beta-catenin in SW480 human colon cancer cells. AB - BACKGROUND: Polysaccharides extracted from the Phellinus linteus (PL) mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL. METHODS: The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP) activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC) proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model. RESULTS: PL (125-1000 MUg/mL) significantly inhibited cell proliferation and decreased beta-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of beta-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in beta-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased. CONCLUSIONS: These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/beta-catenin signaling in certain colon cancer cells. PMID- 21781297 TI - Generation, analysis and functional annotation of expressed sequence tags from the ectoparasitic mite Psoroptes ovis. AB - BACKGROUND: Sheep scab is caused by Psoroptes ovis and is arguably the most important ectoparasitic disease affecting sheep in the UK. The disease is highly contagious and causes and considerable pruritis and irritation and is therefore a major welfare concern. Current methods of treatment are unsustainable and in order to elucidate novel methods of disease control a more comprehensive understanding of the parasite is required. To date, no full genomic DNA sequence or large scale transcript datasets are available and prior to this study only 484 P. ovis expressed sequence tags (ESTs) were accessible in public databases. RESULTS: In order to further expand upon the transcriptomic coverage of P. ovis thus facilitating novel insights into the mite biology we undertook a larger scale EST approach, incorporating newly generated and previously described P. ovis transcript data and representing the largest collection of P. ovis ESTs to date. We sequenced 1,574 ESTs and assembled these along with 484 previously generated P. ovis ESTs, which resulted in the identification of 1,545 unique P. ovis sequences. BLASTX searches identified 961 ESTs with significant hits (E value < 1E-04) and 584 novel P. ovis ESTs. Gene Ontology (GO) analysis allowed the functional annotation of 880 ESTs and included predictions of signal peptide and transmembrane domains; allowing the identification of potential P. ovis excreted/secreted factors, and mapping of metabolic pathways. CONCLUSIONS: This dataset currently represents the largest collection of P. ovis ESTs, all of which are publicly available in the GenBank EST database (dbEST) (accession numbers FR748230 - FR749648). Functional analysis of this dataset identified important homologues, including house dust mite allergens and tick salivary factors. These findings offer new insights into the underlying biology of P. ovis, facilitating further investigations into mite biology and the identification of novel methods of intervention. PMID- 21781303 TI - Cytoskeleton proteins previously considered exclusive to ganglion cells are transiently expressed by all retinal neuronal precursors. AB - BACKGROUND: Understanding the mechanisms governing cell fate specification remains one of the main challenges in the study of retinal development. In this context, molecular markers that identify specific cell types become crucial tools for the analysis and interpretation of these phenomena. In studies using the developing chick retina, expression of the mid-size neurofilament (NF-M) and a chick-specific microtubule associated protein recognized by the RA4 antibody (MAP(RA4)), have been broadly used to selectively identify ganglion cells and their committed precursors. However, observations in our laboratory suggested that the expression of these proteins may not be restricted to cells of the ganglion cell lineage. Because of its potential significance in the field, we pursued a detailed analysis of the expression of these two molecules in combination with an array of proteins that allowed precise identification of all retinal cell-type precursors throughout the development of the chick retina. RESULTS: Both, NF-M and MAP(RA4) proteins, showed a dynamic pattern of expression coincident with the progression of retinal cell differentiation. Both proteins were coexpressed spatially and temporally in postmitotic neuronal precursors throughout development. Expression of both proteins was seen in ganglion cell precursors and adult differentiated ganglion cells, but they were also transiently expressed by precursors of the photoreceptor, horizontal, bipolar and amacrine cell lineages. CONCLUSIONS: We have clearly demonstrated that, contrary to the generally accepted paradigm, expression of NF-M and MAP(RA4) proteins is not exclusive to ganglion cells. Rather, both proteins are transiently expressed by all neuronal retinal progenitors in a developmentally-regulated manner. In addition, MAP(RA4) and NF-M are the first molecules so far characterized that may allow unambiguous identification of postmitotic precursors from the pool of mitotically active progenitors and/or the differentiated cell population during retinogenesis. These results are of significant impact for the field of developmental biology of the retina, since they provide novel and important information for the appropriate design and interpretation of studies on retinal cell differentiation, as well as for the reinterpretation of previously published studies. PMID- 21781304 TI - Pulmonary fibrotic response to aspiration of multi-walled carbon nanotubes. AB - BACKGROUND: Multi-walled carbon nanotubes (MWCNTs) are new manufactured nanomaterials with a wide spectrum of commercial applications. To address the hypothesis that MWCNTs cause persistent pulmonary pathology, C57BL/6J mice were exposed by pharyngeal aspiration to 10, 20, 40 or 80 MUg of MWCNTs (mean dimensions of 3.9 MUm * 49 nm) or vehicle. Lungs were preserved at 1, 7, 28 and 56 days post- exposure to determine the potential regions and target cells for impact by MWCNT lung burden. Morphometric measurement of Sirius Red staining was used to assess the connective tissue response. RESULTS: At 56 days post-exposure, 68.7 +/- 3.9, 7.5 +/- 1.9 and 22.0 +/- 5.1 percent (mean +/- SE, N = 8) of the MWCNT lung burden were in alveolar macrophages, alveolar tissue and granulomatous lesions, respectively. The subpleural tissues contained 1.6% of the MWCNT lung burden. No MWCNTs were found in the airways at 7, 28 or 56 days after aspiration The connective tissue in the alveolar interstitium demonstrated a progressive increase in thickness over time in the 80 MUg exposure group (0.12 +/- 0.01, 0.12 +/- 0.01, 0.16 +/- 0.01 and 0.19 +/- 0.01 MUm for 1, 7, 28 and 56 days post exposure (mean +/- SE, N = 8)). Dose-response determined at 56 days post-exposure for the average thickness of connective tissue in alveolar septa was 0.11 +/- 0.01, 0.14 +/- .02, 0.14 +/- 0.01, 0.16 +/- 0.01 and 0.19 +/- 0.01 MUm (mean +/- SE, N = 8) for vehicle, 10, 20, 40 and 80 MUg dose groups, respectively. CONCLUSIONS: The distribution of lung burden was predominately within alveolar macrophages with approximately 8% delivery to the alveolar septa, and a smaller but potentially significant burden to the subpleural tissues. Despite the relatively low fraction of the lung burden being delivered to the alveolar tissue, the average thickness of connective tissue in the alveolar septa was increased over vehicle control by 45% in the 40 MUg and 73% in the 80 MUg exposure groups. The results demonstrate that MWCNTs have the potential to produce a progressive, fibrotic response in the alveolar tissues of the lungs. However, the increases in connective tissue per MUg dose of MWCNTs to the interstitium are significantly less than those previously found for single-walled carbon nanotubes (SWCNTs). PMID- 21781305 TI - The generation and evaluation of recombinant human IgA specific for Plasmodium falciparum merozoite surface protein 1-19 (PfMSP1 19). AB - BACKGROUND: Human immunoglobulin G (IgG) plays an important role in mediating protective immune responses to malaria. Although human serum immunoglobulin A (IgA) is the second most abundant class of antibody in the circulation, its contribution, if any, to protective responses against malaria is not clear. RESULTS: To explore the mechanism(s) by which IgA may mediate a protective effect, we generated fully human IgA specific for the C-terminal 19-kDa region of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19), a major target of protective immune responses. This novel human IgA bound antigen with an affinity comparable to that seen for an epitope-matched protective human IgG1. Furthermore, the human IgA induced significantly higher NADPH-mediated oxidative bursts and degranulation from human neutrophils than the epitope-matched human IgG1 from which it was derived. Despite showing efficacy in in vitro functional assays, the human IgA failed to protect against parasite challenge in vivo in mice transgenic for the human Fcalpha receptor (FcalphaRI/CD89). A minority of the animals treated with IgA, irrespective of FcalphaRI expression, showed elevated serum TNF-alpha levels and concomitant mouse anti-human antibody (MAHA) responses. CONCLUSIONS: The lack of protection afforded by MSP1 19-specific IgA against parasite challenge in mice transgenic for human FcalphaRI suggests that this antibody class does not play a major role in control of infection. However, we cannot exclude the possibility that protective capacity may have been compromised in this model due to rapid clearance and inappropriate bio distribution of IgA, and differences in FcalphaRI expression profile between humans and transgenic mice. PMID- 21781306 TI - Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. AB - BACKGROUND: The proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR), is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown. RESULTS: We investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (KXXK- X3-5--SGS) is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon gamma-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase. CONCLUSION: Collective data showed that DNA damage induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function. PMID- 21781307 TI - Integrated genomics of ovarian xenograft tumor progression and chemotherapy response. AB - BACKGROUND: Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. METHODS: In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARgamma agonist, Rosiglitazone, on SKOV-3 cell growth. RESULTS: These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARgamma, was significantly up regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARgamma with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARgamma is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. CONCLUSIONS: We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARgamma promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy. PMID- 21781308 TI - Ranking insertion, deletion and nonsense mutations based on their effect on genetic information. AB - BACKGROUND: Genetic variations contribute to normal phenotypic differences as well as diseases, and new sequencing technologies are greatly increasing the capacity to identify these variations. Given the large number of variations now being discovered, computational methods to prioritize the functional importance of genetic variations are of growing interest. Thus far, the focus of computational tools has been mainly on the prediction of the effects of amino acid changing single nucleotide polymorphisms (SNPs) and little attention has been paid to indels or nonsense SNPs that result in premature stop codons. RESULTS: We propose computational methods to rank insertion-deletion mutations in the coding as well as non-coding regions and nonsense mutations. We rank these variations by measuring the extent of their effect on biological function, based on the assumption that evolutionary conservation reflects function. Using sequence data from budding yeast and human, we show that variations which that we predict to have larger effects segregate at significantly lower allele frequencies, and occur less frequently than expected by chance, indicating stronger purifying selection. Furthermore, we find that insertions, deletions and premature stop codons associated with disease in the human have significantly larger predicted effects than those not associated with disease. Interestingly, the large-effect mutations associated with disease show a similar distribution of predicted effects to that expected for completely random mutations. CONCLUSIONS: This demonstrates that the evolutionary conservation context of the sequences that harbour insertions, deletions and nonsense mutations can be used to predict and rank the effects of the mutations. PMID- 21781309 TI - Attitudes and behaviour predict women's intention to drink alcohol during pregnancy: the challenge for health professionals. AB - BACKGROUND: To explore women's alcohol consumption in pregnancy, and potential predictors of alcohol consumption in pregnancy including: demographic characteristics; and women's knowledge and attitudes regarding alcohol consumption in pregnancy and its effects on the fetus. METHODS: We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations of alcohol consumption in pregnancy with participants' characteristics, knowledge and attitudes. RESULTS: The majority of women (89.4%) had consumed alcohol in the last 12 months. During their last pregnancy (n = 700), 34.1% drank alcohol. When asked what they would do if planning a pregnancy (n = 1103), 31.6% said they would consume alcohol and 4.8% would smoke. Intention to consume alcohol in a future pregnancy was associated with: alcohol use in the last pregnancy (adjusted OR (aOR) 43.9; 95% Confidence Interval (CI) 27.0 to 71.4); neutral or positive attitudes towards alcohol use in pregnancy (aOR 5.1; 95% CI 3.6 to 7.1); intention to smoke in a future pregnancy (aOR 4.7; 95% CI 2.5 to 9.0); and more frequent and higher current alcohol consumption. CONCLUSIONS: Women's past pregnancy and current drinking behaviour, and attitudes to alcohol use in pregnancy were the strongest predictors of alcohol consumption in pregnancy. Targeted interventions for women at higher risk of alcohol consumption in pregnancy are needed to change women's risk perception and behaviour. PMID- 21781310 TI - Neurophysiologic effects of spinal manipulation in patients with chronic low back pain. AB - BACKGROUND: While there is growing evidence for the efficacy of SM to treat LBP, little is known on the mechanisms and physiologic effects of these treatments. Accordingly, the purpose of this study was to determine whether SM alters the amplitude of the motor evoked potential (MEP) or the short-latency stretch reflex of the erector spinae muscles, and whether these physiologic responses depend on whether SM causes an audible joint sound. METHODS: We used transcranial magnetic stimulation to elicit MEPs and electromechanical tapping to elicit short-latency stretch reflexes in 10 patients with chronic LBP and 10 asymptomatic controls. Neurophysiologic outcomes were measured before and after SM. Changes in MEP and stretch reflex amplitude were examined based on patient grouping (LBP vs. controls), and whether SM caused an audible joint sound. RESULTS: SM did not alter the erector spinae MEP amplitude in patients with LBP (0.80+/-0.33 vs. 0.80+/-0.30 MUV) or in asymptomatic controls (0.56+/-0.09 vs. 0.57+/-0.06 MUV). Similarly, SM did not alter the erector spinae stretch reflex amplitude in patients with LBP (0.66+/-0.12 vs. 0.66+/-0.15 MUV) or in asymptomatic controls (0.60+/-0.09 vs. 0.55+/-0.08 MUV). Interestingly, study participants exhibiting an audible response exhibited a 20% decrease in the stretch reflex (p<0.05). CONCLUSIONS: These findings suggest that a single SM treatment does not systematically alter corticospinal or stretch reflex excitability of the erector spinae muscles (when assessed~10-minutes following SM); however, they do indicate that the stretch reflex is attenuated when SM causes an audible response. This finding provides insight into the mechanisms of SM, and suggests that SM that produces an audible response may mechanistically act to decrease the sensitivity of the muscle spindles and/or the various segmental sites of the Ia reflex pathway. PMID- 21781311 TI - Detection of HBV genotypes of tumor tissues and serum by a fluorescence polarization assay in north-western China's hepatocellular carcinoma patients. AB - BACKGROUND: The understanding of the distribution of hepatitis B virus genotypes and the occult hepatitis B virus infection in hepatocellular carcinoma may shed light into the prevention and treatment of hepatocellular carcinoma. The purpose of the study is to investigate hepatitis B virus genotypes distribution, the high risk genotypes and the occult infection in north-western China's hepatocellular carcinoma patients. METHODS: Hepatitis B virus genotypes A-D of hepatocellular carcinoma tumor tissues and serum samples in 268 north-western China hepatocellular carcinoma patients were detected by fluorescence polarization assay. The hepatitis B virus genotypes in serum and matched primary tumor tissue samples were compared. Hepatitis B surface antigen and alpha-fetoprotein in serum were detected. Occult hepatitis B virus infections were analyzed. The relationship between hepatitis B virus genotypes and clinicopathologic characteristics were analyzed statistically using SPSS v.10.0. RESULTS: Intrahepatic hepatitis B virus DNA was detected in 83.6% of 268 patients, whereas serum hepatitis B virus DNA was detected in 78.7%. The hepatitis B virus genotypes in serum were consistent with the results in matched tumor tissue. Intrahepatic hepatitis B virus genotype B and C were detected respectively in 11.6% and 54.5% of the patients. Mixed intrahepatic hepatitis B virus genotypes were detected in 13.4% of 268 patients. There was not mixed hepatitis B virus infection in Edmondonson grade I. The patients with mixed HBV genotypes exhibited statistically significant different Edmondson grade than the patients with single type HBV infection (p < 0.05). Hepatitis B surface antigens were positive in 77.2% of 268 patients. Hepatitis B virus genotype C was detected in 64.7% of occult infected patients. There was no significant differences of patients' ages and alpha-fetoprotein level in different groups of intrahepatic hepatitis B virus genotypes (p > 0.05). CONCLUSIONS: Hepatitis B virus genotype C was associated closely with the development of hepatocellular carcinoma and the occult hepatitis B virus infection in patients in north-western China. There was a relatively high prevalence of mixed hepatitis B virus infection in Edmondonson grade III-IV. PMID- 21781312 TI - Autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model. AB - BACKGROUND: This study tested the hypothesis that autologous transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can effectively attenuate acute pulmonary ischemia-reperfusion (IR) injury. METHODS: Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus intravenous transplantation of 1.5 * 106 autologous ADMSCs at 1h, 6h, and 24h following IR injury). The duration of ischemia was 30 minutes, followed by 72 hours of reperfusion prior to sacrificing the animals. Blood samples were collected and lungs were harvested for analysis. RESULTS: Blood gas analysis showed that oxygen saturation (%) was remarkably lower, whereas right ventricular systolic pressure was notably higher in group 2 than in group 3 (all p < 0.03). Histological scoring of lung parenchymal damage was notably higher in group 2 than in group 3 (all p < 0.001). Real time-PCR demonstrated remarkably higher expressions of oxidative stress, as well as inflammatory and apoptotic biomarkers in group 2 compared with group 3 (all p < 0.005). Western blot showed that vascular cell adhesion molecule (VCAM) 1, intercellular adhesion molecule (ICAM)-1, oxidative stress, tumor necrosis factor-alpha and nuclear factor-kappaB were remarkably higher, whereas NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 activities were lower in group 2 compared to those in group 3 (all p < 0.004). Immunofluorescent staining demonstrated notably higher number of CD68+ cells, but significantly fewer CD31+ and vWF+ cells in group 2 than in group 3. CONCLUSION: ADMSC therapy minimized lung damage after IR injury in a rodent model through suppressing oxidative stress and inflammatory reaction. PMID- 21781313 TI - Modifiable risk factors for overweight and obesity in children and adolescents from Sao Paulo, Brazil. AB - BACKGROUND: Brazil is currently experiencing a nutrition transition: the displacement of traditional diets with foods high in saturated fat, sodium, and cholesterol and an increase in sedentary lifestyles. Despite these trends, our understanding of child obesity in Brazil is limited. Thus, the aims of this study were (1) to investigate the current prevalence of overweight and obesity in a large sample of children and adolescents living in Sao Paulo, Brazil, and (2) to identify the lifestyle behaviors associated with an increased risk of obesity in young Brazilians. METHODS: A total of 3,397 children and adolescents (1,596 male) aged 7-18 years were randomly selected from 22 schools in Sao Paulo, Brazil. Participants were classified as normal weight, overweight, or obese based on international age- and sex-specific body mass index thresholds. Selected sociodemographic, physical activity, and nutrition behaviors were assessed via questionnaire. RESULTS: Overall, 19.4% of boys and 16.1% of girls were overweight while 8.9% and 4.3% were obese. Two-way analysis of variance revealed that the prevalence of overweight and obesity was significantly higher in boys and in younger children when compared to girls and older children, respectively (P < 0.05 for both). Logistic regression analysis revealed that overweight was associated with more computer usage, parental encouragement to be active, and light soft drink consumption after controlling for differences in sex, age, and parental education (P < 0.05 for all). Conversely, overweight was associated with less active transport to school, eating before sleep, and consumption of breakfast, full-sugar soft drinks, fried food and confectionery (P < 0.05 for all). CONCLUSIONS: Our results show that obesity in Sao Paulo children and adolescents has reached a level equivalent to that seen in many developed countries. We have also identified three key modifiable factors related to obesity that may be appropriate targets for future intervention in Brazilian youth: transport mode to school, computer usage, and breakfast consumption. PMID- 21781315 TI - Proviral HIV-genome-wide and pol-gene specific zinc finger nucleases: usability for targeted HIV gene therapy. AB - BACKGROUND: Infection with HIV, which culminates in the establishment of a latent proviral reservoir, presents formidable challenges for ultimate cure. Building on the hypothesis that ex-vivo or even in-vivo abolition or disruption of HIV gene/genome-action by target mutagenesis or excision can irreversibly abrogate HIV's innate fitness to replicate and survive, we previously identified the isoschizomeric bacteria restriction enzymes (REases) AcsI and ApoI as potent cleavers of the HIV-pol gene (11 and 9 times in HIV-1 and 2, respectively). However, both enzymes, along with others found to cleave across the entire HIV-1 genome, slice (SX) at palindromic sequences that are prevalent within the human genome and thereby pose the risk of host genome toxicity. A long-term goal in the field of R-M enzymatic therapeutics has thus been to generate synthetic restriction endonucleases with longer recognition sites limited in specificity to HIV. We aimed (i) to assemble and construct zinc finger arrays and nucleases (ZFN) with either proviral-HIV-pol gene or proviral-HIV-1 whole-genome specificity respectively, and (ii) to advance a model for pre-clinically testing lentiviral vectors (LV) that deliver and transduce either ZFN genotype. METHODS AND RESULTS: First, we computationally generated the consensus sequences of (a) 114 dsDNA-binding zinc finger (Zif) arrays (ZFAs or ZifHIV-pol) and (b) two zinc finger nucleases (ZFNs) which, unlike the AcsI and ApoI homeodomains, possess specificity to >18 base-pair sequences uniquely present within the HIV-pol gene (ZifHIV-polFN). Another 15 ZFNs targeting >18 bp sequences within the complete HIV-1 proviral genome were constructed (ZifHIV-1FN). Second, a model for constructing lentiviral vectors (LVs) that deliver and transduce a diploid copy of either ZifHIV-polFN or ZifHIV-1FN chimeric genes (termed LV- 2xZifHIV-polFN and LV- 2xZifHIV-1FN, respectively) is proposed. Third, two preclinical models for controlled testing of the safety and efficacy of either of these LVs are described using active HIV-infected TZM-bl reporter cells (HeLa-derived JC53-BL cells) and latent HIV-infected cell lines. CONCLUSION: LV-2xZifHIV-polFN and LV- 2xZifHIV-1FN may offer the ex-vivo or even in-vivo experimental opportunity to halt HIV replication functionally by directly abrogating HIV-pol-gene-action or disrupting/excising over 80% of the proviral HIV DNA from latently infected cells. PMID- 21781314 TI - Surgical management of stress urinary incontinence in women: safety, effectiveness and cost-utility of trans-obturator tape (TOT) versus tension-free vaginal tape (TVT) five years after a randomized surgical trial. AB - BACKGROUND: We recently completed a randomized clinical trial of two minimally invasive surgical procedures for stress urinary incontinence, the retropubic tension-free vaginal tape (TVT) versus the trans-obturator tape (TOT) procedure. At one year postoperatively, we were concerned to find that a significant number of women had tape that was palpable when a vaginal examination was undertaken. Because the risk factors for adverse outcomes of tape surgery are not clearly understood, we are unable to say whether palpable tapes will lead to vaginal erosions or whether they merge into vaginal tissue. We do not know whether patients go on to have further adverse consequences of surgery, leading to additional cost to patients and healthcare system. Our current study is a 5 year follow-up of the women who took part in our original trial. METHODS/DESIGN: All 199 women who participated in our original trial will be contacted and invited to take part in the follow-up study. Consenting women will attend a clinic visit where they will have a physical examination to identify vaginal erosion or other serious adverse outcomes of surgery, undertake a standardized pad test for urinary incontinence, and complete several health-related quality of life questionnaires (15D, UDI-6, IIQ-7). Analyses will compare the outcomes for women in the TOT versus TVT groups. The cost-effectiveness of TOT versus TVT over the 5 years after surgery, will be assessed with the use of disease-specific health service administrative data and an objective health outcome measure. A cost utility analysis may also be undertaken, based on economic modeling, data from the clinical trial and inputs obtained from published literature. DISCUSSION: This study is needed now, because TOT and TVT are among the most frequently conducted surgical procedures for stress urinary incontinence in Canada. Because stress urinary incontinence is so common, the impact of selecting an approach that causes more adverse events, or is less effective, will have a significant impact on individual quality of life, and societal and health care costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00234754. Registered October 2005. PMID- 21781317 TI - E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. AB - BACKGROUND: E7080 is an orally active multi-targeted kinase inhibitor whose targets include vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptors (PDGFR). It has been shown to inhibit tumor angiogenesis by targeting endothelial cells. A number of the targets of E7080 are also expressed on tumor cells and here we have looked at the direct effects of E7080 on tumor cell behavior. METHODS: Using a panel of human tumor cell lines we determined the effect of E7080 on cell proliferation, migration and invasion. Inhibition of FGFR and PDGFR signaling in the cells was measured. RESULTS: E7080 had little effect on tumor cell proliferation. However, it blocked migration and invasion at concentrations that inhibited FGFR and PDGFR signaling. Knock-down of PDGFR-beta in U2OS osteosarcoma cells also inhibited cell migration which, could not be further inhibited in the presence of E7080. Furthermore, E7080 could not inhibit the migration of a PDGFR negative cell line. CONCLUSION: E7080 does not significantly affect tumor cell proliferation but can inhibit their migration and invasion at concentrations that both inhibit its known targets and are achievable clinically. PMID- 21781316 TI - Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance. AB - BACKGROUND: High fat diet impairs nitric oxide (NO) bioavailability, and induces insulin resistance. The link between NO availability and the metabolic adaptation to a high fat diet is not well characterized. The purpose of this study was to investigate the effect of high fat diet on metabolism in mice with decreased (eNOS-/-) and increased (DDAH overexpressed) NO bioavailability. METHODS: eNOS-/- (n = 16), DDAH (n = 24), and WT (n = 19) mice were fed a high fat diet (HFD) for 13 weeks. Body weight, biochemical parameters, adipokines and insulin were monitored. The matrigel in vivo model with CD31 immunostaining was used to assess angiogenesis. Gene expression in adipose tissues was analyzed by microarray and Real Time PCR. Comparisons of the mean values were made using the unpaired Student t test and p < 0.05 were considered statistically significant. RESULTS: eNOS-/- mice gained less weight than control WT and DDAH mice. In DDAH mice, a greater increase in serum adiponectin and a lesser increment in glucose level was observed. Fasting insulin and cholesterol levels remained unchanged. The angiogenic response was increased in DDAH mice. In adipose tissue of DDAH mice, genes characteristic of differentiated adipocytes were down-regulated, whereas in eNOS-/- mice, genes associated with adipogenesis, fatty acid and triglyceride synthesis were upregulated. CONCLUSIONS: Our results indicate that increased NO availability attenuates some HFD induced alterations in metabolism and gene expression associated with insulin resistance. PMID- 21781318 TI - Evaluation of a clinical decision support tool for osteoporosis disease management: protocol for an interrupted time series design. AB - BACKGROUND: Osteoporosis affects over 200 million people worldwide at a high cost to healthcare systems. Although guidelines on assessing and managing osteoporosis are available, many patients are not receiving appropriate diagnostic testing or treatment. Findings from a systematic review of osteoporosis interventions, a series of mixed-methods studies, and advice from experts in osteoporosis and human-factors engineering were used collectively to develop a multicomponent tool (targeted to family physicians and patients at risk for osteoporosis) that may support clinical decision making in osteoporosis disease management at the point of care. METHODS: A three-phased approach will be used to evaluate the osteoporosis tool. In phase 1, the tool will be implemented in three family practices. It will involve ensuring optimal functioning of the tool while minimizing disruption to usual practice. In phase 2, the tool will be pilot tested in a quasi-experimental interrupted time series (ITS) design to determine if it can improve osteoporosis disease management at the point of care. Phase 3 will involve conducting a qualitative postintervention follow-up study to better understand participants' experiences and perceived utility of the tool and readiness to adopt the tool at the point of care. DISCUSSION: The osteoporosis tool has the potential to make several contributions to the development and evaluation of complex, chronic disease interventions, such as the inclusion of an implementation strategy prior to conducting an evaluation study. Anticipated benefits of the tool may be to increase awareness for patients about osteoporosis and its associated risks and provide an opportunity to discuss a management plan with their physician, which may all facilitate patient self-management. PMID- 21781319 TI - Developing a curriculum framework for global health in family medicine: emerging principles, competencies, and educational approaches. AB - BACKGROUND: Recognizing the growing demand from medical students and residents for more comprehensive global health training, and the paucity of explicit curricula on such issues, global health and curriculum experts from the six Ontario Family Medicine Residency Programs worked together to design a framework for global health curricula in family medicine training programs. METHODS: A working group comprised of global health educators from Ontario's six medical schools conducted a scoping review of global health curricula, competencies, and pedagogical approaches. The working group then hosted a full day meeting, inviting experts in education, clinical care, family medicine and public health, and developed a consensus process and draft framework to design global health curricula. Through a series of weekly teleconferences over the next six months, the framework was revised and used to guide the identification of enabling global health competencies (behaviours, skills and attitudes) for Canadian Family Medicine training. RESULTS: The main outcome was an evidence-informed interactive framework http://globalhealth.ennovativesolution.com/ to provide a shared foundation to guide the design, delivery and evaluation of global health education programs for Ontario's family medicine residency programs. The curriculum framework blended a definition and mission for global health training, core values and principles, global health competencies aligning with the Canadian Medical Education Directives for Specialists (CanMEDS) competencies, and key learning approaches. The framework guided the development of subsequent enabling competencies. CONCLUSIONS: The shared curriculum framework can support the design, delivery and evaluation of global health curriculum in Canada and around the world, lay the foundation for research and development, provide consistency across programmes, and support the creation of learning and evaluation tools to align with the framework. The process used to develop this framework can be applied to other aspects of residency curriculum development. PMID- 21781320 TI - Prevalence of COPD and its association with socioeconomic status in China: findings from China Chronic Disease Risk Factor Surveillance 2007. AB - BACKGROUND: Socioeconomic status is likely an independent risk factor for Chronic Obstructive Pulmonary Disease (COPD), but little research has been done in China to study this association in a nationwide sample. METHODS: We used data from the 2007 China Chronic Disease Risk Factor Surveillance of 49,363 Chinese men and women aged 15-69 years to examine the association between the prevalence of self reported physician diagnosed COPD and socioeconomic status defined by both educational level and annual household income. Multivariable logistic regression modelling was performed with adjustement for potential confounders. RESULTS: Both low educational attainment and low household income were independently associated with higher risk of physician-diagnosed COPD. Compared to subjects with high educational level, subjects with low educational level had a significantly increased risk of COPD (OR 1.67, 95%CI 1.32-2.13, p for trend< 0.001 for urban, OR 1.76, 95%CI 1.34-2.30, p for trend < 0.001 for rural) after adjusting for age, sex, smoking status, passive smoking and geographic regions. Similarly increased risk was observed for household income and COPD in urban (OR 1.64, 95%CI 1.28 2.09, P for trend< 0.001) but not rural areas. Among never smokers, low educational level and household income were still associated with a significant higher prevalence of COPD (OR 1.77, 95%CI 1.40-2.25, OR 1.31, 95%CI 1.05-1.62). Removal of those with asthma diagnosis did not alter the observed associations. CONCLUSIONS: Socioeconomic status is a risk factor for self-reported physician diagnosed COPD independently of current or passive smoking. Prospective studies are needed in China to better understand the association between socioeconomic status and COPD. PMID- 21781321 TI - Salmonella enterica ssp. arizonae infection in a 43-year-old Italian man with hypoglobulinemia: a case report and review of the literature. AB - INTRODUCTION: Salmonella enterica ssp. arizonae is an uncommon human pathogen with serious infections reported in immunocompromised hosts. In Europe, only a few cases have been described. Patients with this infection usually have a history of contact with reptiles or travel abroad. We present a case report of infection in a patient with hypoglobulinemia and a literature review. CASE PRESENTATION: We describe the case of a 43-year-old Caucasian Italian man with hypoglobulinemia who presented to our hospital with sepsis and diarrhea. A stool culture yielded S. enterica ssp. arizonae. Our patient was treated with oral ciprofloxacin and made a full recovery. We also present a review of the cases of S. enterica ssp. arizonae infections previously reported in Europe. CONCLUSIONS: The majority of infections from S. enterica ssp. arizonae occur in patients who are immunocompromised. Data from the literature suggests that it may be difficult to eradicate the bacteria and thus, prolonged antibiotic courses are often used. It would be advisable for clinicians to investigate for pre-existing immune dysfunction if S. enterica ssp. arizonae is isolated. In Italy, although there have only been a few cases, the likely route of transmission remains unclear and requires further surveillance. PMID- 21781322 TI - Phage display identifies two Caprine Arthritis Encephalitis Virus env epitopes. AB - Using phage display and IgG of a goat infected with Caprine Arthritis Encephalitis Virus (CAEV) we obtained families of 7 mer constrained peptides with consensus motifs LxSDPF/Y and SWN/KHWSY and mapped the epitopes mimicked by them at the Env 6-LISDPY-11 and 67-WNTYHW-72 sites of the mature gp135 amino acid sequence. The first epitope fell into the N-terminal immunogenic aa1 EDYTLISDPYGFS- aa14 site identified previously with a synthetic peptide approach; the second epitope has not been described previously. The first epitope is mostly conserved across CAEV isolates whereas the second newly described epitope is extremely conserved in Small Ruminant Lentiviruses env sequences. As being immunodominant, the epitopes are candidate targets for mimotope-mediated diagnosis and/or neutralization. PMID- 21781323 TI - To be at the right place at the right time. AB - AIM: To analyze the hypothesis of events or neighborhood interactions that is based upon recognizable structures of systems which possess a surface in a four dimensional space-time constellation {x, y, z, t}. To include the theory of hierarchic order of structures and aspects of thermodynamically open systems, especially entropy, structural entropy and entropy flow. HYPOTHESIS: Any structure is a space-time constellation that occupies a unique space in its environment. The environment can be a system too, and is assumed to be (nearly) constant. Structures can interact in their environment and create a new structure at a higher order level. Interacting structures that create a surface are called a system. Starting from the bottom, such a system is characterized by its inner structures, its surface function, and its neighborhood. Interaction with a neighboring system is called an event. An event can alter a system, create new systems or induce the decay of a system, dependent upon the surrounding lower level system (background). RESULTS: The hypothesis results in a uniform theory about matter, life, diseases, or behavior. Concrete applications permit the estimation of duration of life in man, for example the effect of solid cancer in man, or appearance of protozoans in sexual or asexual reduplication. In addition, it can successfully describe the development of the universe (small exceed of matter above antimatter at the big bang), or the increase of structures (and systems) with increasing time (development of intelligent systems). The three dimensional space possesses the lowest number of mandatory dimensions to implement such a system. PMID- 21781324 TI - The students' voice: Strengths and weaknesses of an undergraduate medical curriculum in a developing country, a qualitative study. AB - BACKGROUND: In medical education, feedback from students' is essential in course evaluation and development. Students at Faculty of Medicine, University of Colombo, Sri Lanka complete a five year medical curriculum comprising of five different streams. We aimed to evaluate the five year medical curriculum at the Faculty of Medicine, University of Colombo, Sri Lanka. METHODS: A qualitative research was conducted among recent graduates of the faculty. Students' opinions on strengths and weaknesses of the curriculum were collected via questionnaires, which were analysed and classified into common themes. A focus group discussion (FGD) based on these themes was conducted among two student groups, each comprising of a facilitator, two observers and nine students selected as a representative sample from questionnaire respondents. FGDs were conducted using a semi-structured set of open-ended questions to guide participants and maintain consistency between groups. The FGD evaluated the reasons behind students' perceptions, attitudes, emotions and perceived solution. Verbal and non-verbal responses were transcribed and analysed. RESULTS: Questionnaire response rate was 82% (153/186). Students highlighted 68 and 135 different responses on strengths and weaknesses respectively. After analysis of both questionnaire and FGD results the following themes emerged: a well organized module system, increased frequency of assessments, a good variety in clinical appointments, lack of specific objectives and assessments at clinical appointments, community and behavioural sciences streams beneficial but too much time allocation, lengthy duration of course, inadequate knowledge provided on pharmacology and pathology. CONCLUSION: We demonstrate how a brief qualitative method could be efficiently used to evaluate a curriculum spanning a considerable length of time. This method provided an insight into the students' attitudes and perceptions of the present faculty curriculum. Qualitative feedback from students highlighted certain key areas that need attention and also possible solutions as perceived by the students'. PMID- 21781325 TI - Evolution of small putative group I introns in the SSU rRNA gene locus of Phialophora species. AB - BACKGROUND: Group I introns (specifically subgroup IC1) are common in the nuclear ribosomal RNA genes of fungi. While most range in length from more than 200 to nearly 1800 nucleotides (nt) in length, several small putative (or degenerate) group I introns have been described that are between 56 and 81 nt. Although small, previously we demonstrated that the PaSSU intron in the rRNA small subunit gene of Phialophora americana isolate Wang 1046 is capable of in vitro splicing using a standard group I intron pathway, thus qualifying it as a functional ribozyme. FINDINGS: Here, we describe eight short putative group I introns, ranging in length from 63 to 75 nt, in the rRNA small subunit genes of Phialophora isolates, a fungal genus that ranges from saprobic to pathogenic on plants and animals. All contain putative pairing regions P1, P7, and P10, as well as a pairing region formed between the middle of the intron and part of the 3' exon. The other pairing regions common in the core of standard group I introns are absent. However, parts of the 3' exon may aid in the stabilization of these small introns. Although the eight putative group I introns were from at least three species of Phialophora, phylogenetic analysis indicated that the eight are monophyletic. They are also monophyletic with the small introns of two lichen forming fungi, Porpidia crustulata and Arthonia lapidicola. CONCLUSIONS: The small putative group I introns in Phialophora have common features that may represent group I introns at their minima. They appear to have a single origin as indicated by their monophyly in phylogenetic analyses. PMID- 21781326 TI - PromBase: a web resource for various genomic features and predicted promoters in prokaryotic genomes. AB - BACKGROUND: As more and more genomes are being sequenced, an overview of their genomic features and annotation of their functional elements, which control the expression of each gene or transcription unit of the genome, is a fundamental challenge in genomics and bioinformatics. FINDINGS: Relative stability of DNA sequence has been used to predict promoter regions in 913 microbial genomic sequences with GC-content ranging from 16.6% to 74.9%. Irrespective of the genome GC-content the relative stability based promoter prediction method has already been proven to be robust in terms of recall and precision. The predicted promoter regions for the 913 microbial genomes have been accumulated in a database called PromBase. Promoter search can be carried out in PromBase either by specifying the gene name or the genomic position. Each predicted promoter region has been assigned to a reliability class (low, medium, high, very high and highest) based on the difference between its average free energy and the downstream region. The recall and precision values for each class are shown graphically in PromBase. In addition, PromBase provides detailed information about base composition, CDS and CG/TA skews for each genome and various DNA sequence dependent structural properties (average free energy, curvature and bendability) in the vicinity of all annotated translation start sites (TLS). CONCLUSION: PromBase is a database, which contains predicted promoter regions and detailed analysis of various genomic features for 913 microbial genomes. PromBase can serve as a valuable resource for comparative genomics study and help the experimentalist to rapidly access detailed information on various genomic features and putative promoter regions in any given genome. This database is freely accessible for academic and non- academic users via the worldwide web http://nucleix.mbu.iisc.ernet.in/prombase/. PMID- 21781327 TI - AQUILA: assessment of quality in lower limb arthroplasty. An expert Delphi consensus for total knee and total hip arthroplasty. AB - BACKGROUND: In the light of both the importance and large numbers of case series and cohort studies (observational studies) in orthopaedic literature, it is remarkable that there is currently no validated measurement tool to appraise their quality. A Delphi approach was used to develop a checklist for reporting quality, methodological quality and generalizability of case series and cohorts in total hip and total knee arthroplasty with a focus on aseptic loosening. METHODS: A web-based Delphi was conducted consisting of two internal rounds and three external rounds in order to achieve expert consensus on items considered relevant for reporting quality, methodological quality and generalizability. RESULTS: The internal rounds were used to construct a master list. The first external round was completed by 44 experts, 35 of them completed the second external round and 33 of them completed the third external round. Consensus was reached on an 8-item reporting quality checklist, a 6-item methodological checklist and a 22-item generalizability checklist. CONCLUSIONS: Checklist for reporting quality, methodological quality and generalizability for case series and cohorts in total hip and total knee arthroplasty were successfully created through this Delphi. These checklists should improve the accuracy, completeness and quality of case series and cohorts regarding total hip and total knee arthroplasty. PMID- 21781328 TI - The meaning and measurement of implementation climate. AB - BACKGROUND: Climate has a long history in organizational studies, but few theoretical models integrate the complex effects of climate during innovation implementation. In 1996, a theoretical model was proposed that organizations could develop a positive climate for implementation by making use of various policies and practices that promote organizational members' means, motives, and opportunities for innovation use. The model proposes that implementation climate- or the extent to which organizational members perceive that innovation use is expected, supported, and rewarded--is positively associated with implementation effectiveness. The implementation climate construct holds significant promise for advancing scientific knowledge about the organizational determinants of innovation implementation. However, the construct has not received sufficient scholarly attention, despite numerous citations in the scientific literature. In this article, we clarify the meaning of implementation climate, discuss several measurement issues, and propose guidelines for empirical study. DISCUSSION: Implementation climate differs from constructs such as organizational climate, culture, or context in two important respects: first, it has a strategic focus (implementation), and second, it is innovation-specific. Measuring implementation climate is challenging because the construct operates at the organizational level, but requires the collection of multi-dimensional perceptual data from many expected innovation users within an organization. In order to avoid problems with construct validity, assessments of within-group agreement of implementation climate measures must be carefully considered. Implementation climate implies a high degree of within-group agreement in climate perceptions. However, researchers might find it useful to distinguish implementation climate level (the average of implementation climate perceptions) from implementation climate strength (the variability of implementation climate perceptions). It is important to recognize that the implementation climate construct applies most readily to innovations that require collective, coordinated behavior change by many organizational members both for successful implementation and for realization of anticipated benefits. For innovations that do not possess these attributes, individual-level theories of behavior change could be more useful in explaining implementation effectiveness. SUMMARY: This construct has considerable value in implementation science, however, further debate and development is necessary to refine and distinguish the construct for empirical use. PMID- 21781329 TI - Spontaneous and evolutionary changes in the antibiotic resistance of Burkholderia cenocepacia observed by global gene expression analysis. AB - BACKGROUND: Burkholderia cenocepacia is a member of the Burkholderia cepacia complex group of bacteria that cause infections in individuals with cystic fibrosis. B. cenocepacia isolate J2315 has been genome sequenced and is representative of a virulent, epidemic CF strain (ET12). Its genome encodes multiple antimicrobial resistance pathways and it is not known which of these is important for intrinsic or spontaneous resistance. To map these pathways, transcriptomic analysis was performed on: (i) strain J2315 exposed to sub inhibitory concentrations of antibiotics and the antibiotic potentiator chlorpromazine, and (ii) on spontaneous mutants derived from J2315 and with increased resistance to the antibiotics amikacin, meropenem and trimethoprim sulfamethoxazole. Two pan-resistant ET12 outbreak isolates recovered two decades after J2315 were also compared to identify naturally evolved gene expression changes. RESULTS: Spontaneous resistance in B. cenocepacia involved more gene expression changes and different subsets of genes than those provoked by exposure to sub inhibitory concentrations of each antibiotic. The phenotype and altered gene expression in the resistant mutants was also stable irrespective of the presence of the priming antibiotic. Both known and novel genes involved in efflux, antibiotic degradation/modification, membrane function, regulation and unknown functions were mapped. A novel role for the phenylacetic acid (PA) degradation pathway genes was identified in relation to spontaneous resistance to meropenem and glucose was found to repress their expression. Subsequently, 20 mM glucose was found to produce greater that 2-fold reductions in the MIC of multiple antibiotics against B. cenocepacia J2315. Mutation of an RND multidrug efflux pump locus (BCAM0925-27) and squalene-hopene cyclase gene (BCAS0167), both upregulated after chlorpromazine exposure, confirmed their role in resistance. The recently isolated outbreak isolates had altered the expression of multiple genes which mirrored changes seen in the antibiotic resistant mutants, corroborating the strategy used to model resistance. Mutation of an ABC transporter gene (BCAS0081) upregulated in both outbreak strains, confirmed its role in B. cenocepacia resistance. CONCLUSIONS: Global mapping of the genetic pathways which mediate antibiotic resistance in B. cenocepacia has revealed that they are multifactorial, identified potential therapeutic targets and also demonstrated that putative catabolite repression of genes by glucose can improve antibiotic efficacy. PMID- 21781330 TI - Resurrection of an ancestral 5S rRNA. AB - BACKGROUND: In addition to providing phylogenetic relationships, tree making procedures such as parsimony and maximum likelihood can make specific predictions of actual historical sequences. Resurrection of such sequences can be used to understand early events in evolution. In the case of RNA, the nature of parsimony is such that when applied to multiple RNA sequences it typically predicts ancestral sequences that satisfy the base pairing constraints associated with secondary structure. The case for such sequences being actual ancestors is greatly improved, if they can be shown to be biologically functional. RESULTS: A unique common ancestral sequence of 28 Vibrio 5S ribosomal RNA sequences predicted by parsimony was resurrected and found to be functional in the context of the E. coli cellular environment. The functionality of various point variants and intermediates that were constructed as part of the resurrection were examined in detail. When separately introduced the changes at single stranded positions and individual double variants at base-paired positions were also viable. An additional double variant was examined at a different base-paired position and it was also valid. CONCLUSIONS: The results show that at least in the case of the 5S rRNAs considered here, ancestors predicted by parsimony are likely to be realistic when the prediction is not overly influenced by single outliers. It is especially noteworthy that the phenotype of the predicted ancestors could be anticipated as a cumulative consequence of the phenotypes of the individual variants that comprised them. Thus, point mutation data is potentially useful in evaluating the reasonableness of ancestral sequences predicted by parsimony or other methods. The results also suggest that in the absence of significant tertiary structure constraints double variants that preserve pairing in stem regions will typically be accepted. Overall, the results suggest that it will be feasible to resurrect additional meaningful 5S rRNA ancestors as well as ancestral sequences of many different types of RNA. PMID- 21781331 TI - High yield expression in a recombinant E. coli of a codon optimized chicken anemia virus capsid protein VP1 useful for vaccine development. AB - BACKGROUND: Chicken anemia virus (CAV), the causative agent chicken anemia, is the only member of the genus Gyrovirus of the Circoviridae family. CAV is an immune suppressive virus and causes anemia, lymph organ atrophy and immunodeficiency. The production and biochemical characterization of VP1 protein and its use in a subunit vaccine or as part of a diagnostic kit would be useful to CAV infection prevention. RESULTS: Significantly increased expression of the recombinant full-length VP1 capsid protein from chicken anemia virus was demonstrated using an E. coli expression system. The VP1 gene was cloned into various different expression vectors and then these were expressed in a number of different E. coli strains. The expression of CAV VP1 in E. coli was significantly increased when VP1 was fused with GST protein rather than a His-tag. By optimizing the various rare amino acid codons within the N-terminus of the VP1 protein, the expression level of the VP1 protein in E. coli BL21(DE3)-pLysS was further increased significantly. The highest protein expression level obtained was 17.5 g/L per liter of bacterial culture after induction with 0.1 mM IPTG for 2 h. After purification by GST affinity chromatography, the purified full-length VP1 protein produced in this way was demonstrated to have good antigenicity and was able to be recognized by CAV-positive chicken serum in an ELISA assay. CONCLUSIONS: Purified recombinant VP1 protein with the gene's codons optimized in the N-terminal region has potential as chimeric protein that, when expressed in E. coli, may be useful in the future for the development of subunit vaccines and diagnostic tests. PMID- 21781333 TI - Characterization of chronic HCV infection-induced apoptosis. AB - BACKGROUND: To understand the complex and largely not well-understood apoptotic pathway and immune system evasion mechanisms in hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC) and HCV associated chronic hepatitis (CH), we studied the expression patterns of a number of pro-apoptotic and anti apoptotic genes (Fas, FasL, Bcl-2, Bcl-xL and Bak) in HepG2 cell line harboring HCV- genotype-4 replication. For confirmation, we also assessed the expression levels of the same group of genes in clinical samples obtained from 35 HCC and 34 CH patients. METHODS: Viral replication was assessed in the tissue culture medium by RT-PCR, quantitative Real-Time PCR (qRT-PCR); detection of HCV core protein by western blot and inhibition of HCV replication with siRNA. The expression level of Fas, FasL, Bcl-2, Bcl-xL and Bak was assessed by immunohistochemistry and RT PCR whereas caspases 3, 8 and 9 were assessed by colorimetric assay kits up to 135 days post infection. RESULTS: There was a consistent increase in apoptotic activity for the first 4 weeks post-CV infection followed by a consistent decrease up to the end of the experiment. The concordance between the changes in the expression levels of Fas, FasL, Bcl-2, Bcl-xL and Bak in vitro and in situ was statistically significant (p < 0.05). Fas was highly expressed at early stages of infection in cell lines and in normal control liver tissues followed by a dramatic reduction post-HCV infection and an increase in the expression level of FasL post HCV infection. The effect of HCV infection on other apoptotic proteins started very early post-infection, suggesting that hepatitis C modulating apoptosis by modulating intracellular pro-apoptotic signals. CONCLUSIONS: Chronic HCV infection differently modulates the apoptotic machinery during the course of infection, where the virus induces apoptosis early in the course of infection, and as the disease progresses apoptosis is modulated. This study could open a new opportunity for understanding the various signaling of apoptosis and in the developing a targeted therapy to inhibit viral persistence and HCC development. PMID- 21781332 TI - A survey of green plant tRNA 3'-end processing enzyme tRNase Zs, homologs of the candidate prostate cancer susceptibility protein ELAC2. AB - BACKGROUND: tRNase Z removes the 3'-trailer sequences from precursor tRNAs, which is an essential step preceding the addition of the CCA sequence. tRNase Z exists in the short (tRNase ZS) and long (tRNase ZL) forms. Based on the sequence characteristics, they can be divided into two major types: bacterial-type tRNase ZS and eukaryotic-type tRNase ZL, and one minor type, Thermotoga maritima (TM) type tRNase ZS. The number of tRNase Zs is highly variable, with the largest number being identified experimentally in the flowering plant Arabidopsis thaliana. It is unknown whether multiple tRNase Zs found in A. thaliana is common to the plant kingdom. Also unknown is the extent of sequence and structural conservation among tRNase Zs from the plant kingdom. RESULTS: We report the identification and analysis of candidate tRNase Zs in 27 fully sequenced genomes of green plants, the great majority of which are flowering plants. It appears that green plants contain multiple distinct tRNase Zs predicted to reside in different subcellular compartments. Furthermore, while the bacterial-type tRNase ZSs are present only in basal land plants and green algae, the TM-type tRNase ZSs are widespread in green plants. The protein sequences of the TM-type tRNase ZSs identified in green plants are similar to those of the bacterial-type tRNase ZSs but have distinct features, including the TM-type flexible arm, the variant catalytic HEAT and HST motifs, and a lack of the PxKxRN motif involved in CCA anti-determination (inhibition of tRNase Z activity by CCA), which prevents tRNase Z cleavage of mature tRNAs. Examination of flowering plant chloroplast tRNA genes reveals that many of these genes encode partial CCA sequences. Based on our results and previous studies, we predict that the plant TM-type tRNase ZSs may not recognize the CCA sequence as an anti-determinant. CONCLUSIONS: Our findings substantially expand the current repertoire of the TM-type tRNase ZSs and hint at the possibility that these proteins may have been selected for their ability to process chloroplast pre-tRNAs with whole or partial CCA sequences. Our results also support the coevolution of tRNase Zs and tRNA 3'-trailer sequences in plants. PMID- 21781334 TI - Differential gene expression analysis of in vitro duck hepatitis B virus infected primary duck hepatocyte cultures. AB - BACKGROUND: The human hepatitis B virus (HBV), a member of the hepadna viridae, causes acute or chronic hepatitis B, and hepatocellular carcinoma (HCC). The duck hepatitis B virus (DHBV) infection, a dependable and reproducible model for hepadna viral studies, does not result in HCC unlike chronic HBV infection. Information on differential gene expression in DHBV infection might help to compare corresponding changes during HBV infection, and to delineate the reasons for this difference. FINDINGS: A subtractive hybridization cDNA library screening of in vitro DHBV infected, cultured primary duck hepatocytes (PDH) identified cDNAs of 42 up-regulated and 36 down-regulated genes coding for proteins associated with signal transduction, cellular respiration, transcription, translation, ubiquitin/proteasome pathway, apoptosis, and membrane and cytoskeletal organization. Those coding for both novel as well as previously reported proteins in HBV/DHBV infection were present in the library. An inverse modulation of the cDNAs of ten proteins, reported to play role in human HCC, such as that of Y-box binding protein1, Platelet-activating factor acetylhydrolase isoform 1B, ribosomal protein L35a, Ferritin, alpha-enolase, Acid alpha glucosidase and Caspase 3, copper-zinc superoxide dismutase (CuZnSOD), Filamin and Pyruvate dehydrogenase, was also observed in this in vitro study. CONCLUSIONS: The present study identified cDNAs of a number of genes that are differentially modulated in in vitro DHBV infection of primary duck hepatocytes. Further correlation of this differential gene expression in in vivo infection models would be valuable to understand the little known aspects of the hepadnavirus biology. PMID- 21781335 TI - Over 95% of large-scale length uniformity in template-assisted electrodeposited nanowires by subzero-temperature electrodeposition. AB - In this work, we report highly uniform growth of template-assisted electrodeposited copper nanowires on a large area by lowering the deposition temperature down to subzero centigrade. Even with highly disordered commercial porous anodic aluminum oxide template and conventional potentiostatic electrodeposition, length uniformity over 95% can be achieved when the deposition temperature is lowered down to -2.4 degrees C. Decreased diffusion coefficient and ion concentration gradient due to the lowered deposition temperature effectively reduces ion diffusion rate, thereby favors uniform nanowire growth. Moreover, by varying the deposition temperature, we show that also the pore nucleation and the crystallinity can be controlled. PMID- 21781336 TI - Impedance of nanometer thickness ferromagnetic Co40Fe40B20 films. AB - Nanocrystalline Co40Fe40B20 films, with film thickness tf = 100 nm, were deposited on glass substrates by the magnetron sputtering method at room temperature. During the film deposition period, a dc magnetic field, h = 40 Oe, was applied to introduce an easy axis for each film sample: one with h||L and the other with h||w, where L and w are the length and width of the film. Ferromagnetic resonance (FMR), ultrahigh frequency impedance (IM), dc electrical resistivity (rho), and magnetic hysteresis loops (MHL) of these films were studied. From the MHL and r measurements, we obtain saturation magnetization 4piMs = 15.5 kG, anisotropy field Hk = 0.031 kG, and r = 168 mW.cm. From FMR, we can determine the Kittel mode ferromagnetic resonance (FMR-K) frequency fFMRK = 1,963 MHz. In the h||L case, IM spectra show the quasi-Kittel-mode ferromagnetic resonance (QFMR-K) at f0 and the Walker-mode ferromagnetic resonance (FMR-W) at fn, where n = 1, 2, 3, and 4. In the h||w case, IM spectra show QFMR-K at F0 and FMR-W at Fn. We find that f0 and F0 are shifted from fFMRK, respectively, and fn = Fn. The in-plane spin-wave resonances are responsible for those relative shifts.PACS No. 76.50.+q; 84.37.+q; 75.70.-i. PMID- 21781337 TI - Open versus laparoscopically-assisted oesophagectomy for cancer: a multicentre randomised controlled phase III trial - the MIRO trial. AB - BACKGROUND: Open transthoracic oesophagectomy is the standard treatment for infracarinal resectable oesophageal carcinomas, although it is associated with high mortality and morbidity rates of 2 to 10% and 30 to 50%, respectively, for both the abdominal and thoracic approaches. The worldwide popularity of laparoscopic techniques is based on promising results, including lower postoperative morbidity rates, which are related to the reduced postoperative trauma. We hypothesise that the laparoscopic abdominal approach (laparoscopic gastric mobilisation) in oesophageal cancer surgery will decrease the major postoperative complication rate due to the reduced surgical trauma. METHODS/DESIGN: The MIRO trial is an open, controlled, prospective, randomised multicentre phase III trial. Patients in study arm A will receive laparoscopic assisted oesophagectomy, i.e., a transthoracic oesophagectomy with two-field lymphadenectomy and laparoscopic gastric mobilisation. Patients in study arm B will receive the same procedure, but with the conventional open abdominal approach. The primary objective of the study is to evaluate the major postoperative 30-day morbidity. Secondary objectives are to assess the overall 30 day morbidity, 30-day mortality, 30-day pulmonary morbidity, disease-free survival, overall survival as well as quality of life and to perform medico economic analysis. A total of 200 patients will be enrolled, and two safety analyses will be performed using 25 and 50 patients included in arm A. DISCUSSION: Postoperative morbidity remains high after oesophageal cancer surgery, especially due to major pulmonary complications, which are responsible for 50% of the postoperative deaths. This study represents the first randomised controlled phase III trial to evaluate the benefits of the minimally invasive approach with respect to the postoperative course and oncological outcomes in oesophageal cancer surgery. TRIAL REGISTRATION: NCT00937456 (ClinicalTrials.gov). PMID- 21781338 TI - The efficacy of computer reminders on external quality assessment for point-of care testing in Danish general practice: rationale and methodology for two randomized trials. AB - BACKGROUND: Point-of-care testing (POCT) is increasingly being used in general practice to assist general practitioners (GPs) in their management of patients with diseases. However, low adherence to quality guidelines in terms of split test procedures has been observed among GPs in parts of the Capital Region in Denmark. Computer reminders embedded in GPs electronic medical records (ComRem) may facilitate improved quality control behaviour, but more research is needed to identify what types of reminders work and when. The overall aim of this study is to evaluate the efficacy of ComRem to improve GPs adherence to quality guidelines. This article describes the rationale and methods of the study that constitute this research project. METHODS/DESIGN: The study is conducted as two randomised controlled trials (RCTs) among general practices in two districts of the Capital Region in Denmark. These districts contain a total of 739 GPs in 567 practices with a total of 1.1 million patients allocated to practice lists. In the first RCT (RCT A), ComRem is compared to postal reminder letters. In the second RCT (RCT B), ComRem is compared to usual activities (no reminders) with a crossover approach. In both of these studies, outcomes are measured by the number of split tests received by the laboratory. CONCLUSIONS: This study will contribute to knowledge on the efficacy of ComRem in primary care. Because the study does not explore GPs' perceptions and experiences with regard to ComRem, we will subsequently conduct a qualitative survey focusing on these aspects. TRIAL REGISTRATIONS: Study A: ClinicalTrials.gov identifier: NCT01152151Study B: ClinicalTrials.gov identifier: NCT01152177. PMID- 21781339 TI - Direct synthesis of ultrafine tetragonal BaTiO3 nanoparticles at room temperature. AB - A large quantity of ultrafine tetragonal barium titanate (BaTiO3) nanoparticles is directly synthesized at room temperature. The crystalline form and grain size are checked by both X-ray diffraction and transmission electron microscopy. The results revealed that the perovskite nanoparticles as fine as 7 nm have been synthesized. The phase transition of the as-prepared nanoparticles is investigated by the temperature-dependent Raman spectrum and shows the similar tendency to that of bulk BaTiO3 materials. It is confirmed that the nanoparticles have tetragonal phase at room temperature. PMID- 21781340 TI - Role of wild ruminants in the epidemiology of bluetongue virus serotypes 1, 4 and 8 in Spain. AB - Although the importance of wild ruminants as potential reservoirs of bluetongue virus (BTV) has been suggested, the role played by these species in the epidemiology of BT in Europe is still unclear. We carried out a serologic and virologic survey to assess the role of wild ruminants in the transmission and maintenance of BTV in Andalusia (southern Spain) between 2006 and 2010.A total of 473 out of 1339 (35.3%) wild ruminants analyzed showed antibodies against BTV by both ELISA and serum neutralization test (SNT). The presence of neutralizing antibodies to BTV-1 and BTV-4 were detected in the four species analyzed (red deer, roe deer, fallow deer and mouflon), while seropositivity against BTV-8 was found in red deer, fallow deer and mouflon but not in roe deer. Statistically significant differences were found among species, ages and sampling regions. BTV RNA was detected in twenty-one out of 1013 wild ruminants (2.1%) tested. BTV-1 and BTV-4 RNA were confirmed in red deer and mouflon by specific rRT-PCR.BTV-1 and BTV-4 seropositive and RNA positive wild ruminants, including juveniles and sub-adults, were detected years after the last outbreak was reported in livestock. In addition, between the 2008/2009 and the 2010/2011 hunting seasons, the seroprevalence against BTV-1, BTV-4 and BTV-8 increased in the majority of provinces, and these serotypes were detected in many areas where BTV outbreaks were not reported in domestic ruminants. The results indicate that wild ruminants seem to be implicated in the dissemination and persistence of BTV in Spain. PMID- 21781341 TI - Kids in the city study: research design and methodology. AB - BACKGROUND: Physical activity is essential for optimal physical and psychological health but substantial declines in children's activity levels have occurred in New Zealand and internationally. Children's independent mobility (i.e., outdoor play and traveling to destinations unsupervised), an integral component of physical activity in childhood, has also declined radically in recent decades. Safety-conscious parenting practices, car reliance and auto-centric urban design have converged to produce children living increasingly sedentary lives. This research investigates how urban neighborhood environments can support or enable or restrict children's independent mobility, thereby influencing physical activity accumulation and participation in daily life. METHODS/DESIGN: The study is located in six Auckland, New Zealand neighborhoods, diverse in terms of urban design attributes, particularly residential density. Participants comprise 160 children aged 9-11 years and their parents/caregivers. Objective measures (global positioning systems, accelerometers, geographical information systems, observational audits) assessed children's independent mobility and physical activity, neighborhood infrastructure, and streetscape attributes. Parent and child neighborhood perceptions and experiences were assessed using qualitative research methods. DISCUSSION: This study is one of the first internationally to examine the association of specific urban design attributes with child independent mobility. Using robust, appropriate, and best practice objective measures, this study provides robust epidemiological information regarding the relationships between the built environment and health outcomes for this population. PMID- 21781342 TI - Identification of area-level influences on regions of high cancer incidence in Queensland, Australia: a classification tree approach. AB - BACKGROUND: Strategies for cancer reduction and management are targeted at both individual and area levels. Area-level strategies require careful understanding of geographic differences in cancer incidence, in particular the association with factors such as socioeconomic status, ethnicity and accessibility. This study aimed to identify the complex interplay of area-level factors associated with high area-specific incidence of Australian priority cancers using a classification and regression tree (CART) approach. METHODS: Area-specific smoothed standardised incidence ratios were estimated for priority-area cancers across 478 statistical local areas in Queensland, Australia (1998-2007, n = 186,075). For those cancers with significant spatial variation, CART models were used to identify whether area-level accessibility, socioeconomic status and ethnicity were associated with high area-specific incidence. RESULTS: The accessibility of a person's residence had the most consistent association with the risk of cancer diagnosis across the specific cancers. Many cancers were likely to have high incidence in more urban areas, although male lung cancer and cervical cancer tended to have high incidence in more remote areas. The impact of socioeconomic status and ethnicity on these associations differed by type of cancer. CONCLUSIONS: These results highlight the complex interactions between accessibility, socioeconomic status and ethnicity in determining cancer incidence risk. PMID- 21781343 TI - Electron transport in acetate-grown Methanosarcina acetivorans. AB - BACKGROUND: Acetate is the major source of methane in nature. The majority of investigations have focused on acetotrophic methanogens for which energy conserving electron transport is dependent on the production and consumption of H2 as an intermediate, although the great majority of acetotrophs are unable to metabolize H2. The presence of cytochrome c and a complex (Ma-Rnf) homologous to the Rnf (Rhodobacter nitrogen fixation) complexes distributed in the domain Bacteria distinguishes non-H2-utilizing Methanosarcina acetivorans from H2 utilizing species suggesting fundamentally different electron transport pathways. Thus, the membrane-bound electron transport chain of acetate-grown M. acetivorans was investigated to advance a more complete understanding of acetotrophic methanogens. RESULTS: A component of the CO dehydrogenase/acetyl-CoA synthase (CdhAE) was partially purified and shown to reduce a ferredoxin purified using an assay coupling reduction of the ferredoxin to oxidation of CdhAE. Mass spectrometry analysis of the ferredoxin identified the encoding gene among annotations for nine ferredoxins encoded in the genome. Reduction of purified membranes from acetate-grown cells with ferredoxin lead to reduction of membrane associated multi-heme cytochrome c that was re-oxidized by the addition of either the heterodisulfide of coenzyme M and coenzyme B (CoM-S-S-CoB) or 2 hydoxyphenazine, the soluble analog of methanophenazine (MP). Reduced 2 hydoxyphenazine was re-oxidized by membranes that was dependent on addition of CoM-S-S-CoB. A genomic analysis of Methanosarcina thermophila, a non-H2-utilizing acetotrophic methanogen, identified genes homologous to cytochrome c and the Ma Rnf complex of M. acetivorans. CONCLUSIONS: The results support roles for ferredoxin, cytochrome c and MP in the energy-conserving electron transport pathway of non-H2-utilizing acetotrophic methanogens. This is the first report of involvement of a cytochrome c in acetotrophic methanogenesis. The results suggest that diverse acetotrophic Methanosarcina species have evolved diverse membrane bound electron transport pathways leading from ferredoxin and culminating with MP donating electrons to the heterodisulfide reductase (HdrDE) for reduction of CoM S-S-CoB. PMID- 21781344 TI - The Active for Life Year 5 (AFLY5) school based cluster randomised controlled trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Low levels of physical activity, high levels of sedentary behaviour and low levels of fruit and vegetable consumption are common in children and are associated with adverse health outcomes. The aim of this paper is to describe the protocol for a cluster randomised controlled trial (RCT) designed to evaluate a school-based intervention that aims to increase levels of physical activity, decrease sedentary behaviour and increase consumption of fruit and vegetables in school children. METHODS/DESIGN: The Active for Life Year 5 (AFLY5) study is a school-based, cluster RCT that targets school children in Year 5 (age 9-10 years). All state junior/primary schools in the area covered by Bristol City and North Somerset Council are invited to participate; special schools are excluded. Eligible schools are randomised to one of two arms: intervention arm (receive the intervention 2011-2012) and control arm (receive the intervention after the final follow-up assessment, 2013-2014). The primary outcomes of the trial are levels of accelerometer assessed physical activity and sedentary behaviour and questionnaire assessed fruit and vegetable consumption. A number of secondary outcomes will also be measured, including body mass index, waist circumference and overweight/obesity. Outcomes will be assessed at baseline (prior to intervention when the children are in Year 4), at the end of intervention 'immediate follow-up' and '12 months long-term' follow-up. We will use random effects linear and logistic regression models to compare outcomes by randomised arm. The economic evaluation from a societal perspective will take the form of a cost consequence analysis. Data from focus groups and interviews with pupils, parents and teachers will be used to increase understanding of how the intervention has any effect and is integrated into normal school activity. DISCUSSION: The results of the trial will provide information about the public health effectiveness of a school-based intervention aimed at improving levels of physical activity, sedentary behaviour and diet in children. TRIAL REGISTRATION: ISRCTN50133740. PMID- 21781345 TI - Sustained productivity in recombinant Chinese hamster ovary (CHO) cell lines: proteome analysis of the molecular basis for a process-related phenotype. AB - BACKGROUND: The ability of mammalian cell lines to sustain cell specific productivity (Qp) over the full duration of bioprocess culture is a highly desirable phenotype, but the molecular basis for sustainable productivity has not been previously investigated in detail. In order to identify proteins that may be associated with a sustained productivity phenotype, we have conducted a proteomic profiling analysis of two matched pairs of monoclonal antibody-producing Chinese hamster ovary (CHO) cell lines that differ in their ability to sustain productivity over a 10 day fed-batch culture. RESULTS: Proteomic profiling of inherent differences between the two sets of comparators using 2D-DIGE (Difference Gel Electrophoresis) and LC-MS/MS resulted in the identification of 89 distinct differentially expressed proteins. Overlap comparisons between the two sets of cell line pairs identified 12 proteins (AKRIB8, ANXA1, ANXA4, EIF3I, G6PD, HSPA8, HSP90B1, HSPD1, NUDC, PGAM1, RUVBL1 and CNN3) that were differentially expressed in the same direction. CONCLUSION: These proteins may have an important role in sustaining high productivity of recombinant protein over the duration of a fed-batch bioprocess culture. It is possible that many of these proteins could be useful for future approaches to successfully manipulate or engineer CHO cells in order to sustain productivity of recombinant protein. PMID- 21781346 TI - Evaluating target silencing by short hairpin RNA mediated by the group I intron in cultured mammalian cells. AB - BACKGROUND: The group I intron, a ribozyme that catalyzes its own splicing reactions in the absence of proteins in vitro, is a potential target for rational engineering and attracted our interest due to its potential utility in gene repair using trans-splicing. However, the ribozyme activity of a group I intron appears to be facilitated by RNA chaperones in vivo; therefore, the efficiency of self-splicing could be dependent on the structure around the insert site or the length of the sequence to be inserted. To better understand how ribozyme activity could be modulated in cultured mammalian cells, a group I intron was inserted into a short hairpin RNA (shRNA), and silencing of a reporter gene by the shRNA was estimated to reflect self-splicing activity in vivo. In addition, we appended a theophylline-binding aptamer to the ribozyme to investigate any potential effects caused by a trans-effector. RESULTS: shRNA-expression vectors in which the loop region of the shRNA was interrupted by an intron were constructed to target firefly luciferase mRNA. There was no remarkable toxicity of the shRNA expression vectors in Cos cells, and the decrease in luciferase activity was measured as an index of the ribozyme splicing activity. In contrast, the expression of the shRNA through intron splicing was completely abolished in 293T cells, although the silencing induced by the shRNA-expressing vector alone was no different from that in the Cos cells. The splicing efficiency of the aptamer appended intron also had implications for the potential of trans-factors to differentially promote self-splicing among cultured mammalian cells. CONCLUSIONS: Silencing by shRNAs interrupted by a group I intron could be used to monitor self splicing activity in cultured mammalian cells, and the efficiency of self splicing appears to be affected by cell-type specific factors, demonstrating the potential effectiveness of a trans-effector. PMID- 21781347 TI - Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin phagocytosing macrophages on lymphocyte reactivity. METHODS: Thioglycolate elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9 d post-immunization. RESULTS: In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes. CONCLUSIONS: Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO. PMID- 21781348 TI - Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population. AB - BACKGROUND: Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. METHODS: We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. RESULTS: Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. CONCLUSIONS: The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD. PMID- 21781350 TI - Mn bioavailability by polarized Caco-2 cells: comparison between Mn gluconate and Mn oxyprolinate. AB - BACKGROUND: Micronutrient inadequate intake is responsible of pathological deficiencies and there is a need of assessing the effectiveness of metal supplementation, frequently proposed to rebalance poor diets. Manganese (Mn) is present in many enzymatic intracellular systems crucial for the regulation of cell metabolism, and is contained in commercially available metal supplements. METHODS: We compared the effects of two different commercial Mn forms, gluconate (MnGluc) and oxyprolinate (MnOxP). For this purpose we used the polarized Caco-2 cells cultured on transwell filters, an established in vitro model of intestinal epithelium. Since micronutrient deficiency may accelerate mitochondrial efficiency, the mitochondrial response of these cells, in the presence of MnGluc and MnOxP, by microscopy methods and by ATP luminescence assay was used. RESULTS: In the presence of both MnOxP and MnGluc a sustained mitochondrial activity was shown by mitoTraker labeling (indicative of mitochondrial respiration), but ATP intracellular content remained comparable to untreated cells only in the presence of MnOxP. In addition MnOxP transiently up-regulated the antioxidant enzyme Mn superoxide dismutase more efficiently than MnGluc. Both metal treatments preserved NADH and betaNADPH diaphorase oxidative activity, avoided mitochondrial dysfunction, as assessed by the absence of a sustained phosphoERK activation, and were able to maintain cell viability. CONCLUSIONS: Collectively, our data indicate that MnOxP and MnGluc, and primarily the former, produce a moderate and safe modification of Caco-2 cell metabolism, by activating positive enzymatic mechanisms, thus could contribute to long-term maintenance of cell homeostasis. PMID- 21781351 TI - Studies of a genetic variant in HK1 in relation to quantitative metabolic traits and to the prevalence of type 2 diabetes. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) within the gene encoding Hexokinase 1 (HK1) are associated with changes in glycated haemoglobin (HbA1c) levels. Our aim was to investigate the effect of HK1 rs7072268 on measures of glucose- and lipid-metabolism in a Danish non-diabetic population and combine the outcome of these analyses in a meta-analysis with previously published results. Furthermore, our aim was to perform a type 2 diabetes case-control analysis and meta-analysis with two previous case-control studies. METHODS: SNP rs7072268 was genotyped in 9,724 Danes. The quantitative trait study included 5,604 non diabetic individuals from the Inter99 cohort. The case-control study included 4,449 glucose tolerant individuals and 3,398 patients with type 2 diabetes. Meta analyses on quantitative traits included 24,560 Caucasian individuals and 30,802 individuals were included in the combined analysis of present and previous type 2 diabetes case-control studies. RESULTS: Using an additive model, we confirmed that the T-allele of rs7072268 associates with increased HbA1c of 0.6% (CI: 0.4 0.9), p = 3*10-7 per allele. The same allele associated with an increased area under the curve (AUC) for glucose of 5.0 mmol/l*min (0.1-10.0), p = 0.045 following an oral glucose tolerance test (OGTT) and increased fasting levels of cholesterol of 0.06 mmol/l (0.03-1.0), p = 0.001 and triglycerides of 2.0% (0.2 3.8), p = 0.03 per allele in the same study sample of non-diabetic individuals from the Inter99 cohort. However, the T-allele did not show any association with estimates of insulin release or insulin sensitivity neither in Inter99 nor in combined analyses. The prevalence of type 2 diabetes was increased among carriers of the rs7072268 T-allele both in the Danish study-population with an OR of 1.11 (1.02-1.21) and in a meta-analysis including the two additional sample sets with an OR of 1.06 (1.02-1.11). However, after Bonferroni correction the T-allele only remained associated to HbA1c and fasting cholesterol. CONCLUSIONS: The present study provides suggestive evidence of an association of the rs7072268 T-allele in HK1 with increased AUC glucose following an OGTT in non-diabetic individuals and a nominal association with type 2 diabetes prior to Bonferroni correction. The latter was confirmed in combined analyses involving 16,445 cases and 14,357 control subjects. PMID- 21781349 TI - Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine. AB - BACKGROUND: Globally, gastric cancer is the second most common cause of cancer related death, with the majority of the health burden borne by economically less developed countries. METHODS: Here, we report a genetic characterization of 50 gastric adenocarcinoma samples, using affymetrix SNP arrays and Illumina mRNA expression arrays as well as Illumina sequencing of the coding regions of 384 genes belonging to various pathways known to be altered in other cancers. RESULTS: Genetic alterations were observed in the WNT, Hedgehog, cell cycle, DNA damage and epithelial-to-mesenchymal-transition pathways. CONCLUSIONS: The data suggests targeted therapies approved or in clinical development for gastric carcinoma would be of benefit to ~22% of the patients studied. In addition, the novel mutations detected here, are likely to influence clinical response and suggest new targets for drug discovery. PMID- 21781352 TI - Auditory event-related potentials (P3) and cognitive changes induced by frontal direct current stimulation in alcoholics according to Lesch alcoholism typology. AB - Frontal lobe dysfunction is a hallmark of alcohol dependence. Recent studies have shown that a simple but powerful technique of cortical modulation--transcranial direct current stimulation (tDCS)--can induce significant cognitive changes. We therefore aimed to assess the clinical and electrophysiological (as indexed by P3) effects of tDCS of left dorsolateral prefrontal cortex (DLPFC) in different types of alcoholic patients according to Lesch's typology. We enrolled 49 alcoholic subjects, aged between 18 and 75 yr, during the subacute abstinence period to participate in this study. Subjects underwent event-related potential (ERP) registration of alcohol-related and neutral sounds before, during and after active tDCS (1 mA, 35 cm2, during 10 min) or sham procedure in a counterbalanced and randomized order. Frontal assessment battery (FAB) and five items of the Obsessive Compulsive Drinking Scale were applied at the beginning and at the end of each experimental session. ERP analysis showed an increase in the mean amplitude of P3 associated with alcohol-related sounds after tDCS. This effect was not seen for neutral sounds. This change was more pronounced in Lesch IV alcoholics. Secondary exploratory analysis showed a significant improvement of FAB performance after active tDCS compared to sham tDCS in Lesch IV alcoholics only. We showed clinical and electrophysiological evidence of tDCS-induced frontal activity enhancement that was specific for Lesch IV alcoholics. Given that frontal dysfunction may contribute to the loss of control over drinking behaviour, local increase in frontal activity induced by tDCS might have a beneficial clinical impact in the future. PMID- 21781353 TI - Spontaneous reversibility of damage to outer hair cells after sodium salicylate induced ototoxicity. AB - BACKGROUND: High sodium salicylate doses can cause reversible hearing loss and tinnitus, possibly due to reduced outer hair cell electromotility. Sodium salicylate is known to alter outer hair cell structure and function. This study determined the reversibility and cochlear recovery time after administration of an ototoxic sodium salicylate dose to guinea pigs with normal cochlear function. STUDY DESIGN: Prospective experimental investigation. METHODS: All animals received a single 500 mg sodium salicylate dose, but with different durations of action. Function was evaluated before drug administration and immediately before sacrifice. Cochleae were processed and viewed using scanning electron microscopy. RESULTS: Changes in outer hair cell function were observed to be present 2 hours after drug administration, with recovery of normal anatomy beginning after 24 hours. Subsequently, derangement and distortion of cilia reduced, with effects predominantly in row three. At 168 hours, cilia were near-normal but with mild distortions which interfered with normal cochlear physiology. CONCLUSIONS: Ciliary changes persisted for up to 168 hours after ototoxic sodium salicylate administration. PMID- 21781354 TI - Quality parenteral nutrition: an ideal mixed bag. AB - Professor Pennington was an advocate for quality in all aspects of nutrition support and its delivery, ensuring that the patient remained at the centre of all decisions, and that specialist artificial nutrition support was best managed by the multidisciplinary nutrition team and the education of the wider healthcare community. Within the conference theme of 'Quality', this commentary aims to outline drivers for and risks to aspects of quality in parenteral nutrition (PN) services. Quality is defined as a particular property or attribute associated with excellence; in the context of the provision of PN this can be translated to quality processes and standards in the assessment, prescription, preparation, administration and monitoring of PN. Quality products and services are delivered through the timely application of knowledge, competence, procedures and standards. Quality can be so easily compromised; inattention, ignorance and arrogance all play their part. PN is a high-risk therapy; the quality of its delivery should not be entirely dependent on the skills, knowledge and competence of those delivering this care but on accepted standards, procedures, communication, resource and infrastructure. Identification of key steps in the provision of PN and a review of the relevant patient safety data reveal points where safeguards can be put in place to ensure quality is not compromised. Full evaluation of standardisation, computerisation and competency-based training as risk-reduction strategies is required. PMID- 21781355 TI - Gastrostomy tube feeding in adults: the risks, benefits and alternatives. AB - Enteral feeding (or 'tube feeding') is a very common inpatient intervention to maintain nutritional status where the oral route is inadequate, unsafe or inaccessible. A proportion of patients will need to continue tube feeding in the community after their admission and will require a gastrostomy tube. Although gastrostomy insertion is relatively straightforward, it is not without complications in an often frail and vulnerable group of patients and a multidisciplinary approach is necessary to ensure that the procedure is appropriate. Some patients are better managed with careful assisted hand feeding or nasogastric tubes. Particular care needs to be taken in deciding whether patients with dementia should have a gastrostomy in view of data suggesting that this group of patients have a particularly poor prognosis after the procedure. Decisions regarding the provision of enteral nutrition at the end of life or where patients are not competent to make an informed judgement are particularly challenging and need to be made on a case-by-case basis. PMID- 21781356 TI - Aluminium exposure from parenteral nutrition in preterm infants and later health outcomes during childhood and adolescence. AB - Aluminium is the most common metallic element, but has no known biological role. It accumulates in the body when protective gastrointestinal mechanisms are bypassed, renal function is impaired, or exposure is high - all of which apply frequently to preterm infants. Recognised clinical manifestations of aluminium toxicity include dementia, anaemia and bone disease. Parenteral nutrition (PN) solutions are liable to contamination with aluminium, particularly from acidic solutions in glass vials, notably calcium gluconate. When fed parenterally, infants retain >75% of the aluminium, with high serum, urine and tissue levels. Later health effects of neonatal intravenous aluminium exposure were investigated in a randomised trial comparing standard PN solutions with solutions specially sourced for low aluminium content. Preterm infants exposed for >10 d to standard solutions had impaired neurologic development at 18 months. At 13-15 years, subjects randomised to standard PN had lower lumbar spine bone mass; and, in non randomised analyses, those with neonatal aluminium intake above the median had lower hip bone mass. Given the sizeable number of infants undergoing intensive care and still exposed to aluminium via PN, these findings have contemporary relevance. Until recently, little progress had been made on reducing aluminium exposure, and meeting Food and Drug Administration recommendations (<5 MUg/kg per d) has been impossible in patients <50 kg using available products. Recent advice from the UK Medicines and Healthcare regulatory Authority that calcium gluconate in small volume glass containers should not be used for repeated treatment in children <18 years, including preparation of PN, is an important step towards addressing this problem. PMID- 21781357 TI - Peri-operative nutritional management. AB - The metabolic response to surgical trauma is mainly characterised by an increase in BMR, a negative N balance, increased gluconeogenesis and increased synthesis of acute-phase proteins. These reactions aim at ensuring the availability of endogenous substrates for healing wounds while the synthesis of acute-phase proteins enhances the scavenging process and helps repair. However, if this process is excessive or continues for too long, it leads to a progressive depletion of body compartment with a consequent adverse outcome. Obviously, the severity of such depletion is magnified if the patient is starving or is already malnourished and the consumption of lean body mass is not compensated by an exogenous supply of nutrients. The nutritional control of this metabolic reaction represents the traditional rationale for nutritional support of surgical patients. Subsequent data have shown that the negative effects of starvation are not simply due to the starvation per se but due to the starving gut, and peri operative enteral nutrition has proven successful in blunting the metabolic response after injury and improving protein kinetics, net balance and amino acid flux across peripheral tissue and consequently in decreasing the complications. Finally, further clinical research has shown that many post-operative infections may result from immune suppression and that such state might be reversed to some degree by modulation of the immune response through specialised nutritional support in surgical patients, regardless of their nutritional status. This paper will focus on the updated evidence-based research on peri-operative nutrition (parenteral, enteral and immune-enhancing) in patients undergoing major surgery. PMID- 21781358 TI - Pre-operative nutrition and carbohydrate loading. AB - An optimal nutritional state is an important consideration in providing successful operative outcomes. Unfortunately, many aspects of surgery are not constructive to providing this. In addition, the metabolic and immune response to injury induces a catabolic state and insulin resistance, a known risk factor of post-operative complications. Aggressive insulin therapy post-operatively has been shown to reduce morbidity and mortality but similar results can be achieved when insulin resistance is lessened by the use of pre-operative carbohydrate loading. Consuming carbohydrate-containing drinks up to 2 h before surgery has been found to be an effective way to attenuate insulin resistance, minimise protein losses, reduce hospital stays and improve patient comfort without adversely affecting gastric emptying. Enhanced recovery programmes have employed carbohydrate loading as one of several strategies aimed at reducing post operative stress and improving the recovery process. Studies examining the benefits of these programmes have demonstrated significantly shorter post operative hospital stays, faster return to normal functions and lower occurrences of surgical complications. As a consequence of the favourable evidence they are now being implemented in many surgical units. Further benefit to post-operative recovery may be found with the use of immune-enhancing diets, i.e. supplementation with n-3 fatty acids, arginine, glutamine and/or nucleotides. These have the potential to boost the immune system, improve wound healing and reduce inflammatory markers. Research exploring the benefits of immunonutrition and solidifying the use of carbohydrate loading is ongoing; however, there is strong evidence to link good pre-operative nutrition and improved surgical outcomes. PMID- 21781359 TI - Jejunostomy after oesophagectomy: a review of evidence and current practice. AB - Patients undergoing oesophagectomy often have nutritional needs at the time of diagnosis and in the post-operative period. The aim of this article is to review the current literature and report on the author's experience of routine feeding jejunostomy insertion following oesophagectomy. The records of forty-eight consecutive patients undergoing oesphagectomy under the author's care were reviewed. Although the evidence of benefit of peri-operative feeding in patients undergoing oesophagectomy is limited, there is a clear need to establish a feeding route at the time of surgery. Oesophagectomy is associated with a mortality rate of 5-10% and a morbidity rate of 30-40% even in high-volume specialist centres. Over 50% of patients developing complications will require an alternative to oral feeding beyond 30 d. The enteral route is preferred in terms of safety and cost. A surgical feeding jejunostomy is associated with a low complication rate and a mortality rate of less than 1%. In forty-eight patients undergoing oesophagectomy the average weight loss at 6 months was 8.4 kg with only 8% regaining their pre-operative weight. Large reductions in weight at 6 months post-operatively were recorded irrespective of the development of post operative complications or early recurrent disease. Routine jejunostomy insertion is recommended to ensure adequate nutrition in patients who develop post operative complications and for those patients with long-term reduced appetite and poor oral intake. PMID- 21781360 TI - Management of acute intestinal failure. AB - Intestinal failure (IF) occurs when intestinal absorptive function is inadequate to maintain hydration and nutrition without enteral or parenteral supplements. It has been classified into three types depending on duration of nutrition support and reversibility. Type 1 IF is commonly seen in the peri-operative period as ileus and usually spontaneously resolves within 14 d. Type 2 IF is uncommon and is often associated with an intra-abdominal catastrophe, intestinal resection, sepsis, metabolic disturbances and undernutrition. Type 3 IF is a chronic condition in a metabolically stable patient, which usually requires long-term parenteral nutrition. This paper focuses on Types 1 and 2 IF (or acute IF) that are usually found in surgical wards. The objectives of this paper are to review the incidence, aetiology, prevention, management principles and outcome of acute IF. The paper discusses the resources necessary to manage acute IF, the indications for inter-hospital transfer and the practicalities of how to transfer and receive a patient with acute IF. PMID- 21781361 TI - Tracing the fate of dietary fatty acids: metabolic studies of postprandial lipaemia in human subjects. AB - Most postprandial studies have investigated the response of a single meal, yet the ingestion of sequential meals is more typical in a Western society. The aim of this review is to explain how natural and stable isotope tracers of fatty acids have been used to investigate the metabolism of dietary fat after single and multiple meals, with a focus on in vivo measurements of adipose tissue metabolism. When stable isotope tracers are combined with arteriovenous difference measurements, very specific measurements of metabolic flux across tissues can be made. We have found that adipose tissue is a net importer of dietary fat for 5 h following a single test meal and for most of the day during a typical three-meal eating pattern. When dietary fat is cleared from plasma, some fatty acids 'spillover' into the plasma and contribute up to 50% of postprandial plasma NEFA concentrations. Therefore, plasma NEFA concentrations after a meal reflect the balance between intracellular and extracellular lipolysis in adipose tissue. This balance is altered after the acute ingestion of fructose. The enzyme lipoprotein lipase is a key modulator of fatty acid flux in adipose tissue and its rate of action is severely diminished in obese men. In conclusion, in vivo studies of human metabolism can quantify the way that adipose tissue fatty acid trafficking modulates plasma lipid concentrations. This has implications for the flux of fatty acids to tissues that are susceptible to ectopic fat deposition such as the liver and muscle. PMID- 21781362 TI - Nutriproteomics: technologies and applications for identification and quantification of biomarkers and ingredients. AB - Nutrition refers to the process by which a living organism ingests and digests food and uses the nutrients therein for growth, tissue maintenance and all other functions essential to life. Food components interact with our body at molecular, cellular, organ and system level. Nutrients come in complex mixtures, in which the presence and concentration of single compounds as well as their interactions with other compounds and the food matrix influence their bioavailability and bioefficacy. Traditionally, nutrition research mainly concentrated on supplying nutrients of quality to nourish populations and on preventing specific nutrient deficiencies. More recently, it investigates health-related aspects of individual ingredients or of complete diets, in view of health promotion, performance optimisation, disease prevention and risk assessment. This review focuses on proteins and peptides, their role as nutrients and biomarkers and on the technologies developed for their analysis. In the first part of this review, we provide insights into the way proteins are currently characterised and analysed using classical and emerging proteomic approaches. The scope of the second part is to review major applications of proteomics to nutrition, from characterisation of food proteins and peptides, via investigation of health-related food benefits to understanding disease-related mechanisms. PMID- 21781363 TI - The potential role of epigenetic responses to diet in ageing. AB - Epigenetic changes may be causal in the ageing process and may be influenced by diet, providing opportunities to improve health in later life. The aim of this review is to provide an overview of several areas of research relevant to this topic and to explore a hypothesis relating to a possible role of epigenetic effects, mediated by sirtuin 1, in the beneficial effects of dietary restriction, including increased lifespan. Epigenetic features of ageing include changes in DNA methylation, both globally and at specific loci, which differ between individuals. A major focus of research on dietary influences on epigenetic status has been on nutrition in utero, because the epigenome is probably particularly malleable during this life-course window and because epigenetic marking by early exposures is a compelling mechanism underlying effects on lifelong health. We explore the potential of diet during adulthood, including the practice of dietary restriction, to affect the epigenetic architecture. We report progress with respect to deriving data to support our hypothesis that sirtuin 1 may mediate some of the effects of dietary restriction through effects on DNA methylation and note observations that resveratrol affects DNA methylation and other epigenetic features. Disentangling cause and effect in the context of epigenetic change and ageing is a challenge and requires better understanding of the underlying mechanisms and also the development of more refined experimental tools to manipulate the epigenetic architecture, to facilitate hypothesis-driven research to elucidate these links and thus to exploit them to improve health across the full life-course through dietary measures. PMID- 21781364 TI - Plant secondary metabolites and gut health: the case for phenolic acids. AB - Plant-based diets contain a plethora of secondary metabolites that may impact on health and disease prevention. Much attention has been focused on the potential bioactivity and nutritional relevance of several classes of phytochemicals such as flavonoids, carotenoids, phyto-oestrogens and glucosinolates. Less attention has been paid to simple phenolic acids that are widely found in fruit, vegetables, herbs, spices and beverages. Daily intakes may exceed 100 mg. In addition, bacteria in the gut can perform reactions that transform more complex plant phenolics such as anthocyanins, procyanidins, flavanones, flavonols, tannins and isoflavones into simple phenolic metabolites. The colon is thus a rich source of potentially active phenolic acids that may impact both locally and systemically on gut health. Both the small and large intestine (colon) contain absorption sites for phenolic acids but low post-prandial concentrations in plasma indicate minimal absorption early in the gastrointestinal tract and/or rapid hepatic metabolism and excretion. Therefore, any bioactivity that contributes to gut health may predominantly occur in the colon. Several phenolic acids affect the expression and activity of enzymes involved in the production of inflammatory mediators of pathways thought to be important in the development of gut disorders including colon cancer. However, at present, we remain largely ignorant as to which of these compounds are beneficial to gut health. Until we can elucidate which pro-inflammatory and potentially carcinogenetic changes in gene expression can be moderated by simple phenolic acids, it is not possible to recommend specific plant-based foods rich in particular phenolics to optimise gut health. PMID- 21781365 TI - Iodine concentration of organic and conventional milk: implications for iodine intake. AB - Iodine is required for adequate thyroid hormone production, which is essential for brain development, particularly in the first trimester of pregnancy. Milk is the principal source of iodine in UK diets, and while small studies in Europe have shown organic milk to have a lower iodine concentration than conventional milk, no such study has been conducted in Britain. In view of the increasing popularity of organic milk in the UK, we aimed to compare the iodine concentration of retail organic and conventional milk and to evaluate regional influences in iodine levels. Samples of organic milk (n 92) and conventional milk (n 80), purchased from retail outlets in sixteen areas of the UK (southern England, Wales and Northern Ireland), were analysed for iodine using inductively coupled plasma MS. The region of origin of the milk was determined from information on the label. Organic milk was 42.1 % lower in iodine content than conventional milk (median iodine concentration 144.5 v. 249.5 ng/g; P < 0.001). There was no difference in the iodine concentration of either conventional or organic milk by area of purchase. However, a difference was seen in iodine concentration of organic milk by region of origin (P < 0.001). The lower iodine concentration of organic milk has public-health implications, particularly in view of emerging evidence of iodine deficiency in UK population sub-groups, including pregnant women. Individuals who choose organic milk should be aware that their iodine intake may be compromised and should ensure adequate iodine intake from alternative sources. PMID- 21781366 TI - Persistent environmental reservoirs on farms as risk factors for Campylobacter in commercial poultry. AB - Campylobacter is the most common known source of human bacterial enteritis in the developed world and poultry is considered the main source. Broilers often become colonized with Campylobacter during rearing, and then contaminate the farm environment. The objective of this study was to identify Campylobacter-positive environmental reservoirs on farms, as these pose a risk to broiler flocks becoming colonized with Campylobacter. We considered the temporal aspects of exposure and colonization. A longitudinal study monitored six conventional rearing farms over 2 years. The broiler flocks, catchers' equipment, vehicles, shed surrounds, shed entrance, other equipment, farm entrance, other animals, puddles, dead birds, mains water and drinkers were systematically sampled 2-4 times per flock. A multivariable generalized estimating equation model was used to assess associations between contaminated environmental sites and colonized broiler flocks. The associations were adjusted for confounders and other known risk factors. To further assess temporality of contamination, the sequence of contamination of the different environmental sites and the flocks was established. Contaminated shed entrances and anterooms, contaminated drinkers and shedding of Campylobacter by other animals such as cattle, dogs, wildlife and rodents were significantly associated with positive flocks. The reservoir of 'other animals' was also the reservoir most commonly positive before the flock became colonized. The other sites usually became contaminated after the flock was colonized. PMID- 21781367 TI - An outbreak of sheep rabies in Shanxi province, China. AB - This study describes an outbreak of rabies in a flock of 110 sheep in Yangqu county, Shanxi province, China, in 2010. The flock, housed in a cave being used as a sheepfold, was attacked by a rabid dog, which resulted in 36 deaths over the following 2 days from the crushing and trampling caused by panic, and some 15 further deaths from rabies 2 weeks later. Rabies in the sheep was confirmed by the fluorescent antibody test (FAT) and RT-PCR. Rabies virus was isolated from the index dog brain and its N gene was partially sequenced (nucleotides 77-880). Results showed that the canine isolate (SXTYD01) was rabies virus with the N gene fragment 100% identical to that of the virus isolated from rabid sheep. This is the first confirmed sheep rabies outbreak in China. The clinical presentation of the disease is also described. PMID- 21781368 TI - Trends in primary-care consultations, comorbidities, and antibiotic prescriptions for respiratory infections in The Netherlands before implementation of pneumococcal vaccines for infants. AB - The burden of respiratory infections is mainly seen in primary healthcare. To evaluate the potential impact of new preventive strategies against respiratory infections, such as the implementation of pneumococcal conjugate vaccines for infants in 2006 in The Netherlands, we conducted a baseline retrospective cohort study of electronic primary-care patient records to assess consultation rates, comorbidities and antibiotic prescription rates for respiratory infections in primary care. We found that between 1995 and 2005, overall registered consultation rates for lower respiratory tract infections had increased by 42.4%, upper respiratory infections declined by 4.9%, and otitis media remained unchanged. Concomitantly, there was a steady rise in overall comorbidity (75.7%) and antibiotic prescription rates (67.7%). Since Dutch primary-care rates for respiratory infections changed considerably between 1995 and 2005, these changes must be taken into account to properly evaluate the effect of population-based preventive strategies on primary-care utilization. PMID- 21781369 TI - Modelling meningococcal meningitis in the African meningitis belt. AB - SUMMARYMeningococcal meningitis is a major public health problem in a large area of sub-Saharan Africa known as the meningitis belt. Disease incidence increases every dry season, before dying out with the first rains of the year. Large epidemics, which can kill tens of thousands of people, occur frequently but unpredictably every 6-14 years. It has been suggested that these patterns may be attributable to complex interactions between the bacteria, human hosts and the environment. We used deterministic compartmental models to investigate how well simple model structures with seasonal forcing were able to qualitatively capture these patterns of disease. We showed that the complex and irregular timing of epidemics could be caused by the interaction of temporary immunity conferred by carriage of the bacteria together with seasonal changes in the transmissibility of infection. This suggests that population immunity is an important factor to include in models attempting to predict meningitis epidemics. PMID- 21781370 TI - Early-life environment influencing susceptibility to cytomegalovirus infection: evidence from the Leiden Longevity Study and the Longitudinal Study of Aging Danish Twins. AB - Human cytomegalovirus (CMV) is a common herpesvirus establishing lifelong persisting infection, which has been implicated in immunosenescence and mortality in the elderly. Little is known about how and when susceptibility to CMV infection is determined. We measured CMV seroprevalence in two genetically informative cohorts. From the Leiden Longevity Study (LLS) we selected long-lived sib-pairs (n=844) and their middle-aged offspring and the offspring's partners (n=1452). From the Longitudinal Study of Aging Danish Twins (LSADT) 604 (302 pairs) same-sex monozygotic (MZ) and dizygotic (DZ) twins aged 73-94 years were included (n=302 pairs). Offspring of the long-lived LLS participants had significantly lower seroprevalence of CMV compared to their partners (offspring: 42% vs. partners: 51%, P=0.003). Of 372 offspring living with a CMV-positive partner, only 58% were infected. The corresponding number for partners was 71% (P<0.001). In the LSADT, MZ and DZ twins had high and similar CMV-positive concordance rates (MZ: 90% vs. DZ: 88%, P=0.51) suggesting that shared family environment accounts for the similarity within twin pairs. Our findings suggest that susceptibility to CMV infection--even under continuous within-partnership exposure--appears to be more strongly influenced by early-life environment than by genetic factors and adult environment. PMID- 21781371 TI - Evaluating interventions against Salmonella in broiler chickens: applying synthesis research in support of quantitative exposure assessment. AB - A scoping study and systematic review-meta-analyses (SR-MAs) were conducted to evaluate the effectiveness of various interventions for Salmonella in broiler chicken, from grow-out farm to secondary processing. The resulting information was used to inform a quantitative exposure assessment (QEA) comparing various control options within the context of broiler chicken production in Ontario, Canada. Multiple scenarios, including use of two separate on-farm interventions (CF3 competitive exclusion culture and a 2% lactose water additive), a package of processing interventions (a sodium hydroxide scald water disinfectant, a chlorinated post-evisceration spray, a trisodium phosphate pre-chill spray and chlorinated immersion chilling) a package consisting of these farm and processing interventions and a hypothetical scenario (reductions in between-flock prevalence and post-transport concentration), were simulated and compared to a baseline scenario. The package of on-farm and processing interventions was the most effective in achieving relative reductions (compared to baseline with no interventions) in the concentration and prevalence of Salmonella by the end of chilling ranging from 89.94% to 99.87% and 43.88% to 87.78%, respectively. Contaminated carcasses entering defeathering, reductions in concentration due to scalding and post-evisceration washing, and the potential for cross-contamination during chilling had the largest influence on the model outcomes under the current assumptions. Scoping study provided a transparent process for mapping out and selecting promising interventions, while SR-MA was useful for generating more precise and robust intervention effect estimates for QEA. Realization of the full potential of these methods was hampered by low methodological soundness and reporting of primary research in this area. PMID- 21781372 TI - Second-first language acquisition: analysis of expressive language skills in a sample of girls adopted from China. AB - In this study we investigated adopted Chinese girls' expressive English language outcomes in relation to their age at adoption, chronological age, length of exposure to English and developmental risk status at the time of adoption. Vocabulary and phrase utterance data on 318 girls were collected from the adoptive mothers using the Language Development Survey (LDS) (Achenbach & Rescorla, 2000). The girls, aged 18-35 months (M=26.2 months, SD=4.9 months), were adopted at ages ranging from 6.8 to 24 months (M=12.6 months, SD=3.1 months), and had been exposed to English for periods ranging from 1.6 to 27.6 months (M=13.7, SD=5.7). Findings suggest that vocabulary and mean length of phrase scores were negatively correlated with age at adoption but positively correlated with chronological age and length of exposure to English. Developmental risk status at the time of adoption was not correlated with language outcomes. The gap between their expressive language and that of same-age girls from the US normative sample was wider for children aged 18-23 months but was closed for children aged 30-35 months. About 16% of the children met the LDS criteria for delays in vocabulary and 17% met the LDS criteria for delays in mean length of phrase. Speech/language interventions were received by 33.3% of the children with delays in vocabulary and 25% with delays in phrase. PMID- 21781373 TI - Molecular and catalytic properties of an arginine kinase from the nematode Ascaris suum. AB - We amplified the cDNA coding for arginine kinase (AK) from the parasitic nematode Ascaris suum, cloned it in pMAL plasmid and expressed the enzyme as a fusion protein with the maltose-binding protein. The whole cDNA was 1260 bp, encoding 400 amino acids, and the recombinant protein had a molecular mass of 45,341 Da. Ascaris suum recombinant AK showed significant activity and strong affinity ( K(m)(Arg) = 0.126 mM) for the substrate L-arginine. It also exhibited high catalytic efficiency ( k(ca)/K(m)(Arg) = 352) comparable with AKs from other organisms. Sequence analysis revealed high amino acid sequence identity between A. suum AK and other nematode AKs, all of which cluster in a phylogenetic tree. However, comparison of gene structures showed that A. suum AK gene intron/exon organization is quite distinct from that of other nematode AKs. Phosphagen kinases (PKs) from certain parasites have been shown to be potential novel drug targets or tools for detection of infection. The characterization of A. suum AK will be useful in the development of strategies for control not only of A. suum but also of related species infecting humans. PMID- 21781374 TI - White-matter abnormalities in the right posterior hemisphere in generalized anxiety disorder: a diffusion imaging study. AB - BACKGROUND: Prior imaging studies have shown structural, functional and biochemical impairments in patients with generalized anxiety disorder (GAD), particularly in the right hemisphere. In this study we investigated, for the first time to the best of our knowledge, the white-matter microstructure organization in GAD. METHOD: A total of 12 patients with DSM-IV GAD and 15 matched healthy controls underwent a magnetic resonance imaging session of diffusion weighted imaging, exploring white-matter water molecules by the means of apparent diffusion coefficients (ADCs). Regions of interests were placed in the frontal, parietal, temporal and occipital lobes and in the splenium and genu of the corpus callosum, bilaterally. RESULTS: ADC measures were significantly greater in patients with GAD in the right splenium and right parietal cortex compared with healthy controls (p?0.002). No significant correlations between ADCs and age or clinical variables were found. CONCLUSIONS: We provide evidence that GAD is associated with disrupted white-matter coherence of posterior right hemisphere regions, which may partly sustain the impaired cognitive regulation of anxiety. Future diffusion imaging investigations are expected to better elucidate the communication between the parietal cortex and other right hemisphere regions in sustaining the cognitive processing of social and emotional stimuli in patients with GAD. PMID- 21781375 TI - Predictors of cosmetic surgery and its effects on psychological factors and mental health: a population-based follow-up study among Norwegian females. AB - BACKGROUND: There is limited information about psychological predictors of cosmetic surgery and how cosmetic surgery influences subsequent changes in mental health and overall appearance satisfaction. To date, there is a lack of studies examining this issue, whereby representative population samples are assessed at an age before cosmetic surgery is typically conducted and followed up after such surgery has commonly been performed. METHOD: We obtained data from a survey study following 1597 adolescent females from a representative Norwegian sample over a 13-year period. Participants provided information on cosmetic surgery, appearance satisfaction, mental health, risky sexual behavior, drug use and conduct problems at two time-points (overall response rate 67%). RESULTS: Of all participants, 78 (4.9%) reported having undergone cosmetic surgery, of whom 71 were operated on during the course of the study and seven before the first data collection. Symptoms of depression and anxiety [odds ratio (OR) 1.66, 95% confidence interval (CI) 1.07-2.57] and a history of deliberate self-harm (OR 2.88, 95% CI 1.46 5.68), parasuicide (OR 3.29, 95% CI 1.53-7.08) and illicit drug use (OR 2.46, 95% CI 1.07-5.82) predicted prospective cosmetic surgery. Moreover, those who underwent surgery during the course of the study experienced a greater increase than other females in symptoms of depression and anxiety (t=2.07, p=0.04) and eating problems (t=2.71, p<0.01). Patients' use of alcohol also increased more than among non-patients (t=2.47, p=0.01). CONCLUSIONS: A series of mental health symptoms predict cosmetic surgery. Cosmetic surgery does not in turn seem to alleviate such mental health problems. PMID- 21781376 TI - A practical approach to the early identification of antidepressant medication non responders. AB - BACKGROUND: The aim of the present study was to determine whether a combination of baseline features and early post-baseline depressive symptom changes have clinical value in predicting out-patient non-response in depressed out-patients after 8 weeks of medication treatment. METHOD: We analysed data from the Combining Medications to Enhance Depression Outcomes study for 447 participants with complete 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) ratings at baseline and at treatment weeks 2, 4 and 8. We used a multi-time point, recursive subsetting approach that included baseline features and changes in QIDS-SR16 scores from baseline to weeks 2 and 4, to identify non responders (<50% reduction in QIDS-SR16) at week 8 with a pre-specified accuracy level. RESULTS: Pretreatment clinical features alone were not clinically useful predictors of non-response after 8 weeks of treatment. Baseline to week 2 symptom change identified 48 non-responders (of which 36 were true non-responders). This approach gave a clinically meaningful negative predictive value of 0.75. Symptom change from baseline to week 4 identified 79 non-responders (of which 60 were true non-responders), achieving the same accuracy. Symptom change at both weeks 2 and 4 identified 87 participants (almost 20% of the sample) as non-responders with the same accuracy. More participants with chronic than non-chronic index episodes could be accurately identified by week 4. CONCLUSIONS: Specific baseline clinical features combined with symptom changes by weeks 2-4 can provide clinically actionable results, enhancing the efficiency of care by personalizing the treatment of depression. PMID- 21781377 TI - Change in psychosocial functioning and depressive symptoms during acute-phase cognitive therapy for depression. AB - BACKGROUND: Major depressive disorder (MDD) is highly prevalent, is recurrent, and impairs people's work, relationships and leisure. Acute-phase treatments improve psychosocial impairment associated with MDD, but how these improvements occur is unclear. In this study, we tested the hypotheses that reductions in depressive symptoms exceed, precede and predict improvements in psychosocial functioning. METHOD: Patients with recurrent MDD (n=523; 68% women, 81% Caucasian, mean age 42 years) received acute-phase cognitive therapy (CT). We measured functioning and symptom severity with the Social Adjustment Scale - Self Report (SAS-SR), Range of Impaired Functioning Tool (RIFT), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAMD) and Inventory for Depressive Symptomatology - Self-Report (IDS-SR). We tested cross-lagged correlations between functioning and symptoms measured at baseline and the beginning, middle and end of acute-phase CT. RESULTS: Pre- to post-treatment improvement in psychosocial functioning and depressive symptoms was large and intercorrelated. Depressive symptoms improved more and sooner than did psychosocial functioning. However, among four assessments across the course of treatment, improvements in functioning more strongly predicted later improvement in symptoms than vice versa. CONCLUSIONS: Improvements in psychosocial functioning and depressive symptoms correlate substantially during acute-phase CT, and improvements in functioning may play a role in subsequent symptom reduction during acute-phase CT. PMID- 21781378 TI - Effects of pomegranate extracts on cartilage, bone and mesenchymal cells of mouse fetuses. AB - Pomegranate is a rich source of polyphenols, which are believed to be responsible for the oestrogenic activities of extracts of this fruit in mice. One of these potential activities is the prevention of bone loss. The objectives of the present study were to determine the effects of pomegranate extract on chondrogenesis and osteogenesis in mouse embryos in vivo and limb bud cultures in vitro. A total of fifty pregnant Balb/c mice were given vehicle, pomegranate juice extract (PJE), pomegranate husk extract (PHE) or a mixture of husk and juice extract (PME). Their embryos were stained with alizarin red S and alcian blue, and the length of the femur, tibia and their ossification zones were measured on day 19 of gestation. Bone Ca content in pregnant mice was also measured. Mice treated with PJE showed an increase in bone Ca content. Dietary supplementation with all extracts significantly increased embryo femur length and osteogenesis index. Mesenchymal cells from fetal limb buds were cultured and exposed to 10, 100, 1000 and 10 000 MUg/ml of PJE, PHE or PME. The number of viable cells was greater in cultures exposed to the extracts than in control cultures. The number of cartilage nodules and their diameters were greater in extract-treated cell cultures, a finding which reflected increased cell proliferation and differentiation rates. In conclusion, the findings of the present study suggest that pomegranate is able to enhance bone formation. PMID- 21781379 TI - Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and increased sucrose intake in mice lacking gut microbiota. AB - The chemosensory components shared by both lingual and intestinal epithelium play a critical role in food consumption and the regulation of intestinal functions. In addition to nutrient signals, other luminal contents, including micro organisms, are important in signalling across the gastrointestinal mucosa and initiating changes in digestive functions. A potential role of gut microbiota in influencing food intake, energy homeostasis and weight gain has been suggested. However, whether gut microbiota modulates the expression of nutrient-responsive receptors and transporters, leading to altered food consumption, is unknown. Thus, we examined the preference for nutritive (sucrose) and non-nutritive (saccharin) sweet solutions in germ-free (GF, C57BL/6J) mice compared with conventional (CV, C57BL/6J) control mice using a two-bottle preference test. Then, we quantified mRNA and protein expression of the sweet signalling protein type 1 taste receptor 3 (T1R3) and alpha-gustducin and Na glucose luminal transporter-1 (SGLT-1) of the intestinal epithelium of both CV and GF mice. Additionally, we measured gene expression of T1R2, T1R3 and alpha-gustducin in the lingual epithelium. We found that, while the preference for sucrose was similar between the groups, GF mice consumed more of the high concentration (8 %) of sucrose solution than CV mice. There was no difference in either the intake of or the preference for saccharin. GF mice expressed significantly more T1R3 and SGLT-1 mRNA and protein in the intestinal epithelium compared with CV mice; however, lingual taste receptor mRNA expression was similar between the groups. We conclude that the absence of intestinal microbiota alters the expression of sweet taste receptors and GLUT in the proximal small intestine, which is associated with increased consumption of nutritive sweet solutions. PMID- 21781380 TI - Factors affecting vascular access complications in children undergoing congenital cardiac catheterization. AB - BACKGROUND: Complications at the vascular access sites are among the most common adverse events in congenital cardiac catheterization. The use of small-gauge catheters may reduce these events; however, other factors can contribute to the development of vascular complications. OBJECTIVES: To determine factors associated with the development of vascular access complications in children undergoing congenital cardiac catheterization. METHODS: We performed a prospective study of 403 patients who underwent diagnostic (62.5%) or interventional (37.5%) cardiac catheterization over a period of 6 months, and analysed the vascular complications during and immediately after the procedure. RESULTS: The most common access-related adverse event was transient loss of pulsation (17.6%). Other less common access-related adverse events included subcutaneous haematoma (2%), bleeding (3%), vessel tear (0.2%), and vein thrombosis (0.2%). Patients who had no access-related adverse events had significantly higher age and body weight compared with those who had one or more access problems. Among 81 patients who had vascular access established in unplanned access sites, 30 patients (37%) had lost pulsations. Among the 322 patients who had vascular access established in planned access sites, however, only 41 patients had lost pulsation (13%). In addition, patients who had lost pulsations had significantly longer puncture time compared to those who had normal pulsations (p value 0.01). CONCLUSION: Factors other than sheath size can contribute to access-related adverse events in children undergoing cardiac catheterization. Obtaining vascular access in unplanned access sites and longer puncture times increases the incidence of lost pulsations after catheterization. Younger age and smaller body weight are also associated with significant increase in access-related adverse events. PMID- 21781381 TI - The effect of poly(d,l-lactide-co-glycolide)-alendronate conjugate nanoparticles on human osteoclast precursors. AB - Nanoparticles (NPs) formed from polymers conjugated with bisphosphonates (BPs) allow the bone targeting of loaded drugs, such as doxorubicin, for the treatment of skeletal tumours. The additional antiosteoclastic effect of the conjugated BP could contribute to the inhibition of tumour-associated bone degradation. With this aim, we have produced NPs made of poly(d,l-lactide-co-glycolide) (PLGA) conjugated with alendronate (ALE). To show if ALE retained the antiosteoclastic properties after the conjugation with PLGA and the production of NPs, we treated human osteoclasts, derived from circulating precursors, with PLGA-ALE NPs and compared the effects on actin ring generation, apoptosis and type-I collagen degradation with those of free ALE and with NPs made of pure PLGA. PLGA-ALE NPs disrupted actin ring, induced apoptosis and inhibited collagen degradation. Unexpectedly, also NPs made of pure PLGA showed similar effects. Therefore, we cannot exclude that in addition to the observed antiosteoclastic activity dependent on ALE in PLGA-ALE NPs, there was also an effect due to pure PLGA. Still, as PLGA-ALE NPs are intended for the loading with drugs for the treatment of osteolytic bone metastases, the additional antiosteoclastic effect of PLGA-ALE NPs, and even of PLGA, may contribute to the inhibition of the disease-associated bone degradation. PMID- 21781382 TI - Chitosan/TPP-hyaluronic acid nanoparticles: a new vehicle for gene delivery to the spinal cord. AB - Gene delivery offers therapeutic promise for the treatment of neurological diseases and spinal cord injury. Several studies have offered viral vectors as vehicles to deliver therapeutic agents, yet their toxicity and immunogenicity, along with the cost of their large-scale formulation, limits their clinical use. As such, non-viral vectors are attractive in that they offer improved safety profiles compared to viruses. Poly(ethylene imine) (PEI) is one of the most extensively studied non-viral vectors, but its clinical value is limited y its cytotoxicity. Recently, chitosan/DNA complex nanoparticles have een considered as a vector for gene delivery. Here, we demonstrate that DNA nanoparticles made of hyaluronic acid (HA) and chitosan have low cytotoxicity and induce high transgene expression in neural stem cells and organotypic spinal cord slice tissue. Chitosan-TPP/HA nanoparticles were significantly less cytotoxic than PEI at various concentrations. Additionally, chitosan-TPP/HA nanoparticles with pDNA induced higher transgene expression in vitro for a longer duration than PEI in neural stem cells. These results suggest chitosan-TPP/HA nanoparticles may have the potential to serve as an option for gene delivery to the spinal cord. PMID- 21781383 TI - Mouse retinal progenitor cell dynamics on electrospun poly (epsilon caprolactone). AB - Age-related macular degeneration, retinitis pigmentosa and glaucoma are among the many retinal degenerative diseases where retinal cell death leads to irreversible vision loss and blindness. Working toward a cell-replacement-based therapy for such diseases, a number of research groups have recently evaluated the feasibility of using retinal progenitor cells (RPCs) cultured and transplanted on biodegradable polymer substrates to replace damaged retinal tissue. Appropriate polymer substrate design is essential to providing a three-dimensional environment that can facilitate cell adhesion, proliferation and post transplantation migration into the host environment. In this study, we have designed and fabricated a novel, ultra-thin electrospun poly(epsilon caprolactone) (PCL) scaffold with microscale fiber diameters, appropriate porosity for infiltration by RPCs, and biologically compatible mechanical characteristics. We have verified that our electrospun PCL scaffold supports robust mouse RPC proliferation, adhesion, and differentiation in vitro, as well as migration into mouse retinal explants. These promising results make PCL a strong candidate for further development as a cell transplantation substrate in retinal regenerative research. PMID- 21781384 TI - Mentors and other species. PMID- 21781385 TI - Mentoring in general practice: a real activity or a theoretical possibility? PMID- 21781386 TI - Should supervision be a part of continuing professional development for GPs? The Danish experience would suggest it should. PMID- 21781387 TI - General practice nurse education: introducing mentorship. PMID- 21781388 TI - Is there a value to case-based discussion? AB - Case-based discussion (CbD) is a workplace-based assessment which is used formatively to help develop a GP trainee's performance and which will also contribute to the judgement made on a trainee's competence at the end of their training. The views of GP trainers and trainee's in their final year of training were explored quantitively to identify if CbD was of value, its limitations and whether or not it could assess a trainee's performance. The results suggest as an isolated assessment it is not possible to fully assess performance. The feedback received by the trainee did encourage the learner to develop and an improvement in performance in subsequent assessments could be demonstrated. This, however, relied on the skills and confidence of the educator in giving feedback. Further work on the development of feedback skills need to be introduced for the benefits of this assessment to be maximised. PMID- 21781389 TI - What were the perceptions of primary care teams on learning from a single multidisciplinary simulation-based training intervention? AB - Medical emergencies in general practice are uncommon and their management requires good teamwork, communication and effective use of the available resources by the whole primary care team. To address this need the Montagu Clinical Simulation Centre developed and delivered a half-day simulation-based medical emergencies course for primary care teams (GPs, practice nurses and administrative staff). Each half-day course comprises two simulated medical emergencies, which are video-taped and then debriefed. The course was evaluated using a multi-level approach by seeking the staff's reactions to the course, their learning, the behaviour changes produced and the results for the organisation. We gained this information through self-reporting using end-of course and follow-up questionnaires. The immediate feedback was very positive, showing they had learnt the objectives set. We then surveyed all those who had attended training between 2003 and 2007. A follow-up questionnaire was developed and sent to the practice managers who then co-ordinated their completion and return using a pre-paid return envelope. The survey was carried out in two cohorts. The first set of follow-up questionnaires was sent out in September 2004 to all those that had attended up to the end of May 2004 and the second set sent out in May 2008 to those who had attended between June 2004 and May 2007. Of the 338 available to complete the follow-up questionnaire, 208 responded, giving a response rate of 62%. Eighty percent of practices had made changes to equipment, emergency protocols or training and 20% of the participants had been involved in managing a medical emergency since attending the course. Of those, 86% indicated that their management and confidence had improved, that they were better able to take a lead role, give instruction and delegate tasks as required. Based on the self-reported perceptions of learning, we believe that the lessons learnt have been translated into positive changes at a personal and practice level for all members of the primary care team. The participants valued the chance to train as a complete unit. We plan to evaluate simulation-based training in the workplace to see if this has a greater impact. PMID- 21781390 TI - Mentoring for NHS general practitioners: a prospective pilot study of an action learning approach. AB - BACKGROUND: Annual GP appraisal provides a standardised system to identify poorly performing or underperforming doctors as well as development needs. Mentoring is widely used for enhancing personal and professional development and might help address these needs. However, doubts have been expressed in the literature about the strength of the supporting evidence. The aim of this pilot study was to explore the possible benefits of using a specified 'action learning' approach to mentoring through a prospective study design. METHOD: Both mentors and mentees were recruited using open invitation through the local appraisal service. Mentees were allocated to either one-to-one or group sessions. Each participant received four sessions of mentoring. All sessions were evaluated using a learning needs log, visual plots and feedback forms. RESULTS: Fourteen GPs participated as mentees (via either self-referral or the appraisal process). Twelve completed the four sessions of action learning mentoring. The average duration of one-to-one sessions was 1 hour 45 minutes. Each group session was 3 hours long. Time between sessions varied from 7 to 30 days. The average number of days between each session was 17. Benefits were observed in several areas of personal and professional development. CONCLUSIONS: The mentoring intervention piloted in this study demonstrates a feasible approach to identifying and developing learning needs. Small numbers in the study make it difficult to attribute this specifically to the action learning approach taken. However, the framework presented was recognised as useful by the mentors. Future work will aim to identify if the approach is due to action learning specifically or the more general effect of counselling. PMID- 21781391 TI - Developing a tool for analysis of recorded appraisal discussions. AB - Appraisal in Wales is organised and quality assured through Cardiff University on behalf of the Local Health Boards. This has enabled the development of a standardised and consistent appraisal experience for GPs in Wales. Central to this is regular feedback to all GP appraisers from their line managers, their appraisal co-ordinator, about their work and especially the quality of the Form 4 document (the appraisal summary). Included is feedback about GP experience of the appraisal process, including the appraisal discussion. Presently there are no methods of directly assessing the quality of the appraisal discussion. The authors, who are both appraisal co-ordinators (ACs), have developed a method of assessing the quality of a recording of a real appraisal discussion. The information gathered from this assessment has been used in a facilitative style to feedback to the appraiser to acknowledge their skills in the appraisal discussion and to identify areas for development. This paper describes the work done to create an appraisal discussion assessment method (ADAM), and suggestions about how to use it. Using a Delphi approach, we have developed descriptors to aid formative assessment of the appraisal discussion. PMID- 21781392 TI - Five minutes to find your ideal match: speed dating in Banbury. PMID- 21781393 TI - Promoting reflection through research in general practice: a programme director's view. PMID- 21781394 TI - Enriching training for general practice: an evaluation of a pilot programme of general practice clinics in specialty training year 1. PMID- 21781395 TI - Can peer group review by trainer group make a robust and effective contribution to the reapproval process across London Deanery? PMID- 21781396 TI - Begin to get to grips with educational theory. PMID- 21781398 TI - Expanding provision of training places in general practice for the Severn School of Primary Care 2009-2010. PMID- 21781397 TI - Ten into one can go: gaining educational capacity through large group teaching in general practice. PMID- 21781399 TI - Not the reasons we hear as to why doctors decide to become GPS! PMID- 21781400 TI - Plasma enhancement of in vitro attachment of rat bone-marrow-derived stem cells on cross-linked gelatin films. AB - In this work, nitrogen, oxygen and air glow discharges powered by 50 Hz AC power supply are used for the treatment of type-A gelatin film cross-linked by a dehydrothermal (DHT) process. The properties of cross-linked gelatin were characterized by contact angle measurement, atomic force microscopy (AFM) and X ray photoelectron spectroscopy (XPS) analysis. The results showed that the water contact angle of gelatin films decrease with increasing plasma treatment time. The treatment of nitrogen, oxygen and air plasma up to 30 s had no effects on the surface roughness of the gelatin film as revealed by AFM results. The XPS analysis showed that the N-containing functional groups generated by nitrogen and air plasma, and O-containing functional groups generated by oxygen and air plasmas were incorporated onto the film surface, the functional groups were found to increase with increasing treatment time. An in vitro test using rat bone marrow-mesenchym-derived stem cells (MSCs) revealed that the number of cells attached on plasma-treated gelatin films was significantly increased compared to untreated samples. The best enhancement of cell attachment was noticed when the film was treated with nitrogen plasma for 15-30 s, oxygen plasma for 3 s, and air plasma for 9 s. In addition, among the three types of plasmas used, nitrogen plasma treatment gave the best MSCs attachment on the gelatin surface. The results suggest that a type-A gelatin film with water contact angle of 27-28 degrees and an O/N ratio of 1.4 is most suitable for MSCs attachment. PMID- 21781401 TI - Analysis of fluticasone propionate in induced sputum by mass spectrometry. AB - Although evaluation of induced sputum has shown promise as a marker of eosinophilic airway inflammation in asthmatic subjects, most studies, to date, do not adequately address the potential effect that inhaled corticosteroids may have on sputum eosinophilia. This study was designed to prospectively evaluate analysis of fluticasone propionate (FP) in whole sputum by mass spectrometry as a tool to determine recent administration of inhaled FP. Induced sputum of nonsmoking asthmatic subjects was prospectively analyzed 16-24 hours after witnessed administration of orally inhaled FP. FP was extracted from whole sputum via an acetonitrile protein precipitation followed by methylene chloride liquid extraction of the supernatant (AB 4000; AB Sciex). A portion of the reconstituted sample was analyzed by liquid chromatography tandem mass spectrometry using a triple quad tandem mass spectrometer. Results were compared with those from nonsmoking asthmatic subjects not receiving inhaled FP. Twenty-two asthmatic subjects on FP and 9 asthmatic subjects without FP underwent sputum induction 16 24 hours following witnessed administration of FP. Sufficient sputum for analysis was obtained from 30 of 31 subjects. FP was detected in 22 of 22 asthmatic subjects receiving FP (range, 29-133,000 pg/mL) and was undetectable in 8 of 8 subjects not receiving FP. The sensitivity and specificity of tandem mass spectrometry's ability to detect FP in sputum was 100% and 100%, respectively. Analysis of FP in induced sputum is a reliable method to verify recent administration of inhaled FP. Induced asthmatic sputum from one induction may be used to concomitantly assess sputum eosinophilia as well as recent administration of FP. PMID- 21781402 TI - The reality of adherence to rhinitis treatment: identifying and overcoming the barriers. AB - Medical advances have allowed many patients with chronic diseases to lead relatively normal lives, but disparity between patient perceptions of "normal" and therapeutically defined disease control contributes to lowered adherence to treatment. This disconnect is greatest in diseases such as allergic rhinitis (AR) in which patients experience varying symptom severity over time-from asymptomatic periods to episodes of severe illness. This study was designed to evaluate the concept of adherence as applied to patients with AR. We reviewed the published literature. Adherence (or nonadherence) is an active process involving decision making on the part of the patient. Poor adherence with therapy can be the major barrier to achieving disease control, and the "on again, off again" approach to AR treatment embraced purposely by some patients may contribute to symptom lability, disease exacerbations, and higher costs. Evidence from surveys suggests that although specific educational interventions can temporarily improve adherence, in the long term most patients eventually revert to their former behavior. The available data suggest a need to reappraise how we address adherence with therapy in patients with chronic diseases with variable symptoms such as AR. The question is not just whether patient behavior can conform to recommended treatment plans, but whether it should. Experience suggests that successful strategies will be brief, easy to use, and capable of being tailored to individual patients in diverse clinical settings. Increased flexibility with medications is a corollary, particularly when patients are relatively asymptomatic (i.e., considered in control). PMID- 21781403 TI - Biological terrorism and the allergist's office practice. AB - During the anthrax outbreak and threat in Trenton (2001), our allergy practice experienced increased visits from approximately 50 of our regular patients with symptoms they believed resulted from anthrax exposure. In all cases, their symptoms were caused by a combination of an exacerbation of their underlying allergic disease and anxiety because of possible exposure to anthrax. Our objective is to present an orderly approach to the allergist's outpatients presenting with possible exposure to a bioterrorist's agent. The 10 precepts of approach to the management of a biological casualty (index of suspicion, protect yourself, patient assessment, decontaminate, diagnose, treat, infection control, alert authorities, assist in investigation, and maintain proficiency) and the epidemiological characteristics of a biological attack are discussed. In table form, we compared the signs and symptoms of the most common outpatient consultations to an allergist's office practice (chronic rhinitis, asthma, food allergy, venom allergy, atopic dermatitis, drug allergy, chronic urticaria, acute urticaria, immunodeficiency, and anaphylaxis) with those of likely bioterrorism threats. Descriptions of smallpox, plague, tularemia, anthrax, viral hemorrhagic fevers, Q fever, brucellosis, Venezuelan equine encephalitis, glanders, and melioidosis are presented. Patients may readily mistake their allergic symptoms with those of infection with a bioterrorist's agent. At the same time, the allergist may be faced with one of his own chronic patients presenting with symptoms resembling their allergic disease but actually caused by one of the aforementioned pathogens. PMID- 21781404 TI - Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. AB - The use of epinephrine for anaphylaxis to subcutaneous allergen immunotherapy (SCIT) is the standard of care, but its use for mild systemic reactions (SRs) is somewhat controversial. The objective of this study is to determine the rate of SR to SCIT, the symptoms reported, and the response to intramuscular (i.m.) epinephrine over a 1 year period. This retrospective study was designed to evaluate SRs to SCIT to any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 773 subjects representing 14,707 visits, receiving approximately 28,000 injections over 1 year. Nurses were instructed to administer epinephrine (1:1000 v/v) 0.2 mL i.m. for signs or symptoms of a SR. SRs were graded using the universal grading system proposed by the World Allergy Organization (WAO) Joint Task Force for Grading SR to Immunotherapy. Thirty-one patients (4%) had 32 SRs, 22 (71%) female, average age 40 yr. Nineteen (61%) had a history of asthma; 7 (22.6%) had a history of a previous SR. SRs were reported on average 24 minutes after injection. Symptoms included: generalized pruritus, 34.4%; upper airway pruritus, 28.1%; cough, 25.0%; shortness of breath, 21.9%. Fourteen SRs were classified as Grade 1, thirteen Grade 2, two Grade 3, and three Grade 4. No Grade 5 or late phase reactions were reported. 29 (90.6%) reactions were treated with epinephrine, 27 (84.4%) glucocorticosteroid, and 30 (93.8%) H1 antihistamine. SRs occurred in 4% of patients receiving SCIT and all who received early intervention with epinephrine responded successfully. The WAO Grading system was useful. PMID- 21781405 TI - Epinephrine autoinjector availability among children with food allergy. AB - Epinephrine is the treatment of choice for anaphylaxis. Delay in administration of epinephrine is a known risk factor for food allergy reaction-related mortality; however, individuals with food allergy may not have epinephrine readily available. This study was designed to determine the percent of food allergic children that have an epinephrine autoinjector readily available and factors associated with epinephrine autoinjector carriage rates. Parents completed a questionnaire on food allergy and food allergy preparedness. Staff recorded whether an epinephrine autoinjector and medical alert bracelet was immediately available in clinic. Parental responses from 63 food-allergic children were included. Fifty-nine percent (37/63) had an epinephrine autoinjector present in the clinic, and 79% (50/63) reported receiving training in epinephrine autoinjector use. There was no correlation between epinephrine autoinjector presence in the clinic and parental report of having an epinephrine autoinjector available at all times (phi = 0.21). Epinephrine autoinjector training was associated with increased odds of having an epinephrine autoinjector immediately available (adjusted odds ratio, 8.74 [1.69, 45.04]). Fewer school aged children (>=5 years old) reportedly had their epinephrine autoinjector with them when eating lunch (25% [8/32] versus 42% [13/31]; p = 0.002) or snacks (28% [9/32] versus 37% [13/31]; p = 0.005) when compared with those <5 years old. Many children do not have their epinephrine autoinjectors readily available despite parental report. Epinephrine autoinjector training improved the odds of having an epinephrine autoinjector readily available. Continued patient education on the importance of having an epinephrine autoinjector easily accessible, especially when eating, is important. PMID- 21781406 TI - Outcomes and safety of drug provocation tests. AB - Drug provocation tests (DPTs) are considered the gold standard for identifying adverse drug reactions (ADRs). The aim of this study was to analyze DPT results and discuss severe systemic reactions associated with them. This was a retrospective analysis of 500 patients with ADRs who sought treatment and were submitted to DPTs when indicated between 2006 and 2010. We performed DPTs according to the European Network for Drug Allergy recommendations. Single-blind, placebo-controlled DPTs were performed with antibiotics, local anesthetics, and nonsteroidal anti-inflammatory drugs, as well as with other drugs. Patient characteristics, DPT results, and reactions were analyzed. The sample comprised 198 patients (80.8% of whom were female patients) submitted to 243 DPTs. Ages ranged from 9 to 84 years (mean, 39.9 years). The 243 DPTs were performed with local anesthetics (n = 93), antibiotics (n = 19), acetaminophen (n = 44), benzydamine (n = 33), COX-2 inhibitors (n = 26), dipyrone (n = 7), aspirin (n = 4), or other drugs (n = 17). The results of 4 tests (1.6%) were inconclusive, whereas those of 10 (4.1%) revealed positive reactions to antibiotics (2/19), COX 2 inhibitors (2/26), acetaminophen (3/44), and local anesthetics (3/93). Two severe reactions were observed: cephalexin-induced anaphylactic shock and bupivacaine-induced anaphylaxis without shock. Four patients (2.0%) reacted to the placebo before administration of the drug. Drug provocation tests are safe for use in clinical practice but they should be placebo-controlled and should be performed under the supervision of an allergist. To confirm a presumptive diagnosis and to manage allergies appropriately, it is crucial to perform DPTs. PMID- 21781407 TI - Asthma consultations with specialists: what do the pediatricians seek? AB - "Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma" includes guidelines for referral to an asthma specialist. Because most cases of asthma are managed by primary care physicians, we intended to explore the referral practices of pediatricians managing childhood asthma. This study was designed to identify important considerations by pediatricians while referring a child to an asthma specialist. An electronic survey was sent to 1200 graduated pediatricians enlisted in the Michigan Chapter, American Academy of Pediatrics directory. The questions explored asthma disease characteristics, physician preferences when referring children with asthma, and reasons and barriers for asthma consultations. All responses were collected anonymously. We received 240/1200 (20%) questionnaires. The majority of pediatricians considered referral to a specialist if a child had severe persistent asthma (201/236 [85.2%]) or had a single life-threatening asthma event (188/229 [82.1%]). The top two likely reasons of referral included poor asthma control (200/224 [89.3%]) and unclear diagnosis (139/224 [62.1%]). We found 74/219 (33.8%) preferred consultation to a pediatric pulmonologist when compared with 93/219 (42.5%) allergists. We found the minority of pediatricians "always" recommended referral to a specialist for the following reasons: allergy skin testing (30/222 [13.5%]), possible allergen immunotherapy (54/223 [24.2%]), and spirometry (26/221 [11.8%]). The major barrier for childhood asthma specialist consultations was issues with medical insurance coverage (137/205 [66.8%]). Allergists have to educate primary care providers about the importance of allergen control, role of allergen immunotherapy, and updating current asthma treatment guidelines when treating a child with allergic asthma. PMID- 21781408 TI - Serum OX40 ligand levels in asthmatic children: a potential biomarker of severity and persistence. AB - The costimulatory molecule OX40 and its ligand, OX40L, mediate key aspects of allergic airway inflammation in animal models of asthma, including eosinophilic airway inflammation, airway hyperresponsiveness, and T-helper type 2 (Th2) polarization. However, involvement of these molecules in Th2-dominated allergen induced childhood asthma remains unclear. Therefore, we sought to examine OX40L expression in pediatric asthma across disease activity and attack severity. Serum OX40L concentrations were measured by ELISA in 50 children with atopic asthma (during and in between acute attacks), and in 40 healthy children serving as controls. The median and mean (SD) serum OX40L levels (1487 and 1560 [543] pg/mL) were significantly higher in asthmatic children during acute attacks in comparison with children in between attacks (731 and 689 [321] pg/mL) and in comparison with controls (193 and 157 [60.3] pg/mL). OX40L values were higher among children who presented with acute severe asthma exacerbations than in children with mild or moderate asthma exacerbations. During stability, patients with severe persistent asthma had significantly higher levels when compared with patients with moderate or mild persistent asthma. A positive correlation could be elicited between OX40L levels during exacerbations and the corresponding values during remission. Serum OX40L levels correlated negatively with peak expiratory flow rate and positively with absolute eosinophil count. Up-regulation of OX40L may play a critical role in development of childhood atopic asthma and is in favor of asthma severity. OX40L may represent a useful biomarker of monitoring allergic inflammation. OX40L is one of the most promising targets of immune intervention for treatment of these diseases. PMID- 21781409 TI - Response to ecallantide treatment of acute attacks of hereditary angioedema based on time to intervention: results from the EDEMA clinical trials. AB - Hereditary Angioedema (HAE) is a rare, debilitating, genetic disorder characterized by acute attacks of edema without urticaria. Ecallantide, a direct plasma kallikrein inhibitor, is approved for treatment of acute HAE attacks. This article addresses the efficacy of ecallantide in the treatment of moderate-to severe attacks of HAE based on time to treatment. A post hoc integrated analysis of the EDEMA4 and EDEMA3-DB clinical trials was performed based on the time to patient's treatment, defined as the time from initial recognition of moderate-to severe symptoms to dosing (cohort, 0-2, >2-4, >4-6, >6-8, and >8 hours). Mean symptom complex severity (MSCS) score and treatment outcome score (TOS) were analyzed. Complete or near-complete resolution of symptoms was assessed at 4 and 24 hours. In this analysis, 70 patients received 30 mg of subcutaneous (s.c.) ecallantide and 73 patients received placebo. Change from baseline in MSCS score and TOS at 4 hours revealed significantly better response to ecallantide versus placebo for patients treated >2-4 (n = 46; p = 0.002; p = 0.003) or >4-6 (n = 47; p = 0.044; p = 0.043) hours after symptom onset. Fewer patients were treated within 2 hours of symptom onset; for these patients (n = 10; p = 0.752; p = 0.422) treatment did not achieve statistical significance. For overall response, complete or near-complete resolution was greatest within the 0- to 2-hour cohort (71.4%). As with other therapies for HAE early ecallantide therapy is optimal. Treatment with ecallantide within 6 hours of symptom onset leads to more rapid and sustained improvement of symptoms. PMID- 21781410 TI - A 64-year-old man with chronic obstructive pulmonary disease and an atypical rash. AB - A 64-year-old male patient with a 15-year history of chronic obstructive pulmonary disease presented with an atypical rash that was refractory to standard therapy. Pulmonary function tests confirmed an obstructive lung disease. Basic laboratory workup revealed conflicting information, leading to a diagnostic challenge discussed in this article. Ultimately, careful testing did reveal the diagnosis and the patient was treated accordingly. PMID- 21781412 TI - Community-based interventions to improve neonatal survival in low-resource settings. AB - As child mortality declines globally, neonatal mortality (death in the 1st month of life) has become an increasingly important cause of under-5 deaths. Emerging evidence showing the effectiveness of low-cost community-based interventions proves that expensive hospital interventions are not needed to make progress with newborn survival in low-income countries where the vast majority of deaths occur. This paper discusses the use of two approaches to community-based interventions: home visits by community health workers and participatory women's groups. Both are shown to reduce neonatal mortality but they might also have synergy when combined. Although further research is needed to explore contextual factors which might amplify or limit the degree of effect achievable, these interventions look very promising as a low-cost and sustainable approach towards Millennium Development Goal 4. PMID- 21781413 TI - Enteric protozoa and human potential. PMID- 21781414 TI - Effect of cryptosporidial and giardial diarrhoea on social maturity, intelligence and physical growth in children in a semi-urban slum in south India. AB - BACKGROUND: Early childhood diarrhoea is a major cause of infant morbidity and mortality in developing countries. Recurrent and persistent diarrhoea affect growth and cognition in children as young as 6 years. OBJECTIVES: To evaluate the effect of early childhood cryptosporidial and giardial diarrhoea on growth and development in children in a semi-urban slum in India. This is the first report of such assessment at 3 years of age. METHODS: This study was undertaken on 116 children who were part of an ongoing birth cohort study (n=452) of rotaviral and cryptosporidial diarrhoea between June and December 2005. Social quotients (SQ) assessed by the Vineland Social Maturity Scale, intelligence quotients (IQ) assessed by the Seguin Form Board Test, physical growth parameters and sociodemographic data in 84 children with a history of cryptosporidial or giardial diarrhoea were compared with those of 32 without diarrhoea. RESULTS: Children with a past history of giardial diarrhoea showed a trend towards lower SQ (p=0.09) and had significantly lower IQ (p=0.04) and increased wasting (p=0.04). Cryptosporidial diarrhoea was not associated with poor IQ, SQ or physical growth. CONCLUSION: This study demonstrates the long-term effect of protozoan diarrhoea, especially that caused by giardia, on both intelligence and physical growth in Indian children as early as 3 years of age and re-inforces the need for early detection and prevention of early childhood protozoan diarrhoea. PMID- 21781415 TI - Colorectal polyps: a frequently-missed cause of rectal bleeding in Egyptian children. AB - OBJECTIVES: Colorectal polyps are important causes of rectal bleeding but they have been infrequently reported in Egyptian children. The prevalence and characteristics of colorectal polyps in a consecutive cohort of Egyptian children with rectal bleeding are presented. METHODS: A total of 174 children aged 2-12 years [mean (SD) 6.4 (3.7)] with fresh rectal bleeding were enrolled prospectively. Rectal examination, laboratory investigations and fibre-optic colonoscopy were performed in all patients. RESULTS: The source of bleeding was diagnosed as colorectal polyps in 100 patients (57.4%) and was owing to other causes in 74. The interval between onset of symptoms and presentation ranged from 2 to 48 months [mean (SD) 18.3 (16)]. In patients with other causes, rectal bleeding was attributed to intestinal amoebiasis (42), diarrhoea/dysentery (18), severe constipation (2) and intestinal schistosomiasis (2). Polyps were solitary in 56 children (56%) and ranged from 2 to 5 in 34 (34%) and >5 in 10 (10%). Polyps were confined to the rectum in 68 children, were rectosigmoid in 20, in the descending colon in 8, and splenic flexure in 4. Polyps were juvenile in 84 children (84%), inflammatory in 10 (10%) and hyperplastic, schistosomal or adenomatous in 2 each (6%). Colonoscopic polypectomy was successful and arrested the bleeding in all cases. CONCLUSION: In Egyptian children, colorectal polyps are relatively common and an easily treatable cause of fresh rectal bleeding. They should be high on the list of differential diagnoses. PMID- 21781416 TI - Diagnostic accuracy of clinical signs used to identify electrolyte disturbances in children with diarrhoea. AB - BACKGROUND: No studies have assessed the diagnostic accuracy of clinical signs of electrolyte disturbances in children with dehydrating diarrhoea. AIMS: To assess the diagnostic accuracy and reliability of clinical signs previously reported to be associated with plasma sodium and potassium disturbances in children. METHODS: A cross-sectional analytical study of 476 children aged 6 weeks to 2 years, admitted to a rehydration unit in Cape Town, South Africa. The clinical signs were elicited on admission by one of 58 junior doctors. Operational definitions of clinical signs were provided, but no additional training was given. Admission plasma electrolyte levels were the reference standard. Likelihood ratios were the primary measures of diagnostic accuracy, with reliability expressed as weighted Kappa scores. RESULTS: Inter-observer agreement was generally poor, and confidence intervals were wide. None of the 18 signs studied had clinically meaningful diagnostic accuracy even for severe plasma sodium and potassium abnormalities. CONCLUSIONS: None of the clinical signs assessed were useful in clinical practice. Additional training would improve the accuracy of the signs. PMID- 21781417 TI - Longitudinal study of vitamin D status in the 1st 6 months of life. AB - Although hypovitaminosis D has been reported in the neonatal period and infancy, there is currently little information on the longitudinal changes in vitamin D status throughout early infancy. AIM: To estimate, in Al Ain, UAE, the prevalence of vitamin D deficiency and longitudinal changes and risk factors in infants between birth and 6 months of age. METHODS: Serum 25-OH-vitamin-D levels were measured after birth and 6 months later in 27 infants of mothers of Middle Eastern or Asian origin who were pregnant between the months of September and November 2007. RESULTS: At delivery, mean (SD) maternal serum 25-OH-vitamin-D level was 35.5 nmol/L (24.7); five mothers (22%, 95% CI 0.7-43) had adequate serum levels (>50 mmol/L), 11 (48%, 95% CI 27-70) insufficient levels (25-50 nmol/L) and seven (30%, 95% CI 13-53) deficient (<25 nmol/L) levels. Serum 25-OH vitamin-D levels were adequate in eight infants (30%, CI 14-50%), insufficient in 13 (48%, CI 28-60%) and deficient in six (22%, CI 8.5-42%). Despite recommendations, none had received any vitamin D supplementation since birth. Despite the high prevalence of hypovitaminosis D at birth and the lack of pharmacological supplementation, the number of infants with adequate levels at 6 months of age rose to 20 (87%, CI 66-97%). No infant had deficiency (CI 0-21%) and three (13%, CI 27-33%) had insufficiency. Adequate levels were detected in four infants who were partially breastfed [mean (SD) 108.5 (20.7) nmol/L] and in only 84% of the 19 exclusively breastfed infants [mean (SD) 96.2 (44.5) nmol/L] but the difference was not statistically significant. Although serum levels improved at 6 months, it occurred more slowly in exclusively breastfed infants. CONCLUSION: In the absence of vitamin D supplementation, guidelines for vitamin D supplementation in infancy still need to be followed because the mechanisms for normalisation are not clearly understood. PMID- 21781418 TI - Comparison of a rapid commercial test, Enterocheck WB((r)), with automated blood culture for diagnosis of typhoid fever. AB - BACKGROUND: Rapid diagnosis of typhoid fever is very important in the timely initiation of therapy. OBJECTIVES: To evaluate the sensitivity and specificity of the Enterocheck WB((r)) test. METHODS: In a prospective study, the sensitivity and specificity of Enterocheck WB((r)) that detects IgM antibodies to Salmonella typhi were compared with blood culture using BacT/Alert. RESULTS: Four hundred and fifty patients with suspected typhoid fever were assessed both by blood culture and Enterocheck WB((r)); 100 of them were either Enterocheck WB((r)) positive or blood culture-positive or both for S. typhi. Both tests were positive in 47 of the 100 patients. In 45 patients, Enterocheck WB((r)) was positive but blood culture was negative. In eight cases, Enterocheck was negative but blood culture was positive. Using blood culture as the gold standard, the sensitivity of Enterocheck WB((r)) was 85.5%, specificity 88.6%, negative predictive value 97.7% and positive predictive value 51.1%. CONCLUSION: The Enterocheck WB((r)) test can be performed at the bedside in 15 minutes and is a useful rapid method for diagnosis of typhoid fever. PMID- 21781419 TI - Adherence to tablet and liquid formulations of antiretroviral medication for paediatric HIV treatment at an urban clinic in Uganda. AB - BACKGROUND: Major obstacles remain in scaling up paediatric HIV treatment, including limited paediatric anti-retroviral drug options for resource-limited settings, challenges with adherence to liquid formulations and treatment fatigue with lifelong therapy. AIM: To determine levels of adherence to HAART in HIV infected children at 12, 24, 36 and 48 weeks of follow-up and to compare adherence levels before and after switching from syrup to fixed-dose combination (FDC)-tablet anti-retroviral formulations. METHODS: HIV-infected children aged between 6 months and 12 years were initiated on anti-retroviral therapy at Makerere University-Johns Hopkins University Care Clinic, Kampala. Good adherence to HAART was defined as taking >=95% of prescribed medications. Adherence levels were measured using pharmacy refill data, quarterly unannounced home-visit pill counts and caregiver self-reports. Data were analysed using STATA((r)) version 10.0. RESULTS: A total of 129 HIV-infected children were initiated on HAART with 14.7% on syrups and 85.3% on tablet formulations at enrollment. According to caregiver self-reporting, 99.2%, 100%, 100% and 99.2% achieved >=95% adherence at 12, 24, 36 and 48 weeks, respectively. Using pharmacy refill data, the proportions were 89.9%, 95.4%, 93.8% and 93.0% and for unannounced home visits were 89.8%, 92.4%, 88.9% and 86.2%, respectively. Median adherence to syrup formulations (97%, IQR 93-98) was significantly lower than for tablets (100%, IQR 97-100, p = 0.012, n = 28) using pharmacy refill data. Viral suppression correlated with home visit and pharmacy refill adherence data. CONCLUSION: The majority of children initiating HAART had good adherence when estimated by caregiver self-report and pharmacy refill data but lower adherence when measured by home-visit pill counts. Adherence to tablet formulation of HAART was significantly better than syrup formulation. Medication formulation did not significantly affect viral suppression. PMID- 21781420 TI - Management of harlequin ichthyosis in low-income countries. AB - Harlequin ichthyosis (HI) is a very rare severe form of autosomal recessive congenital ichthyosis, usually associated with stillbirth and early neonatal death. A newborn girl with HI is described. She presented in a critical condition with severe universalis hyperkeratosis, diffuse scales and deep erythematous fissures. She received preventive systemic antibiotics and hygienic nursing with skin and eye care, feeding and appropriate hydration. She was discharged at 28 days in good general condition. PMID- 21781421 TI - Cardiac echinococcosis associated with cerebrovascular occlusive disease and subcutaneous bullous eruptions and ulcers. AB - Cardiac involvement is an uncommon complication of echinococcosis. It is usually asymptomatic and may only be diagnosed incidentally. A 7-year-old boy was admitted with acute stroke and bullous and ulcerated skin lesions. He was diagnosed with cardiac echinococcosis complicated by systemic emboli to the central nervous system and superficial cutaneous arteries. In endemic areas, echinococcosis should be considered in the differential diagnosis of cardiac disease and unexplained cerebral embolism. PMID- 21781422 TI - Cranial nerve palsies in typhoid fever: report of three cases. AB - Neurological manifestations of enteric fever are well known. However, isolated cranial nerve palsies are rare. A 4-year-old boy and two girls aged 5 and 11 years with culture-proven typhoid fever are described, two of whom developed palatal palsy and the other sixth cranial nerve palsy. Following treatment, there was complete resolution of the cranial nerve palsies within 5-7 weeks. While palatal palsy is reported rarely, isolated sixth cranial nerve palsy associated with typhoid has not been reported previously. PMID- 21781423 TI - Fatal bronchiolitis obliterans complicating Stevens-Johnson syndrome following treatment with nimesulide: a case report. AB - Nimesulide is a frequently used non-steroidal anti-inflammatory drug with analgesic and antipyretic effects in children. In view of fatal adverse drug reactions, however, its safety has been questioned. A 5-year-old boy developed Stevens-Johnson syndrome following use of nimesulide which was later complicated by rapidly progressive fatal bronchiolitis obliterans. PMID- 21781424 TI - Organophosphate poisoning in a 12-day-old infant: case report. AB - A 12-day-old infant girl was admitted with increasing lethargy and respiratory distress. Initial treatment was for pneumonia but deterioration despite appropriate treatment prompted review of her diagnosis and consideration of organophosphate poisoning. There was a brisk response to atropine. To our knowledge, this is the youngest infant reported to have been exposed to poisoning by organophosphates. PMID- 21781425 TI - Acute disseminated encephalomyelitis (ADEM) after pertussis infection. AB - Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating disorder of the central nervous system which is usually precipitated by a viral infection or vaccination. A 3-month-old boy is reported who developed ADEM a week after full recovery from pertussis. MRI detected a high-intensity lesion extending from the pons to the mesencephalon, compatible with ADEM. Following the administration of intravenous immunoglobulins, the patient's clinical symptoms improved. This case report demonstrates that pertussis is capable of inducing an immune-mediated demyelinating disorder of the central nervous system. PMID- 21781426 TI - Steroid-unresponsive hypereosinophilic syndrome. AB - Hypereosinophilic syndrome in children is rare and is characterised by sustained over-production of eosinophils. An 11-year-old boy was diagnosed with hypereosinophilic syndrome as per standard criteria. He was treated initially with intravenous methylprednisolone, followed by oral prednisolone, to which he showed a limited response. The highest absolute eosinophil count was 27.0*10(9)/L. He was commenced on imatinib mesylate but, because of no response, he was switched to hydroxyurea combined with low-dose prednisolone to which he showed improvement with decreasing levels of eosinophils. PMID- 21781427 TI - Long-term immunity after hepatitis B vaccination. PMID- 21781428 TI - Improving the quality of general practice: from cottage industry to consortia. PMID- 21781429 TI - Is the recession also wreaking chaos in health? PMID- 21781430 TI - Do immunisation procedures match provider perception? A study from the South Carolina Pediatric Practice Research Network (SCPPRN). AB - OBJECTIVE: Immunisation coverage of children by 19 months of age in US primary care practices is below the desired goal of 80%. In order to improve this rate, primary care providers must first understand the specific processes of immunisation delivery within their office settings. This paper aims to identify key components in identifying strategies for quality improvement (QI) of immunisation delivery. METHODS: We surveyed a South Carolina Pediatric Practice Research Network (SCPPRN) representative for each of six paediatric practices. The surveys included questions regarding immunisation assessment, medical record keeping, opportunities for immunisation administration and prompting. Subsequently, research staff visited the participating practices to directly observe their immunisation delivery process and review patient charts in order to validate survey responses and identify areas for QI. RESULTS: Most survey responses were verified using direct observation of actual practice or chart review. However, observation of actual practice and chart review identified key areas for improvement of immunisation delivery. Although four practices responded that they prompted for needed immunisations at sick visits, only one did so. We also noted considerable variation among and within practices in terms of immunising with all indicated vaccines during sick visits. In addition, most practices had multiple immunisation forms and all administered immunisations were not always recorded on all forms, making it difficult to determine a child's immunisation status. CONCLUSIONS: For any QI procedure, including immunisation delivery, providers must first understand how the process within their practice actually occurs. Direct observation of immunisation processes and medical record review enhances survey responses in identifying areas for improvement. This study identified several opportunities that practices can use to improve immunisation delivery, particularly maintaining accurate and easy-to-locate immunisation records and prompting for needed immunisations during sick visits. PMID- 21781431 TI - Developing quality indicators for community services: the case of district nursing. AB - BACKGROUND: Quality indicators exist for the acute and primary care sectors in the National Health Service (NHS), but until recently little attention has been given to measuring the quality of community services. The innovative project described in this paper attempted to address that gap. OBJECTIVES: To produce a framework for developing quality indicators for Bristol Community Health services. To develop a set of initial indicators for Bristol Community Health services using the proposed framework. METHOD: After familiarising ourselves with community services and NHS policy, gathering the views of stakeholders and consulting the literature on quality indicators, we designed a framework for indicator development, using the 'test' case of the district nursing service. The long list of possible indicators came from best practice guidelines for wound, diabetes and end of life care, the three conditions most commonly treated by district nurses. To narrow down this list we surveyed and held workshops with district nurses, interviewed service users by telephone and met with commissioners and senior community health managers. RESULTS: The final set of quality indicators for district nurses included 23 organisational and clinical process and outcome indicators and eight patient experience indicators. These indicators are now being piloted, together with two potential tools identified to capture patient reported outcomes. CONCLUSION: Developing quality indicators for community services is time consuming and resource intensive. A range of skills are needed including clinical expertise, project management and skills in evidence-based medicine. The commitment and involvement of front-line professionals is crucial. PMID- 21781432 TI - An evaluation of a training placement in general practice for paramedic practitioner students: improving patient-centred care through greater interprofessional understanding and supporting the development of autonomous practitioners. AB - OBJECTIVES: To report the extent to which the placement of paramedic practitioner students (PPSs) in accredited general practice (GP) training practices supported their development as autonomous, patient-centred practitioners and fostered interprofessional learning. DESIGN: A case study method was used. Sources of data included semi-structured telephone interviews (eight PPSs, eight GP trainers), an online end of placement survey and placement and assessment documentation. Interview data were transcribed and analysed using the constant comparative method. SETTING: Accredited training practices in South East England. RESULTS: All respondents were positive that the placement provided a high-quality interprofessional learning environment which provided PPSs with learning opportunities based on assessed need, the support of experienced trainers and access to a wide range of patients and learning situations. The placement enabled PPSs to acquire the appropriate skills, knowledge and understanding to act as autonomous, patient-centred practitioners. CONCLUSIONS: The placement provides a sound model for expanding the skills of paramedic practitioners in order to meet the increasing demands for patient-centred, community based health care. It provided them with the skills to treat patients closer to home rather than automatically transporting them to hospital. PMID- 21781433 TI - Dealing with uncertainty in general practice: an essential skill for the general practitioner. AB - Many patients attending general practice do not have an obvious diagnosis at presentation. Skills to deal with uncertainty are particularly important in general practice as undifferentiated and unorganised problems are a common challenge for general practitioners (GPs). This paper describes the management of uncertainty as an essential skill which should be included in educational programmes for both trainee and established GPs. Philosophers, psychologists and sociologists use different approaches to the conceptualisation of managing uncertainty. The literature on dealing with uncertainty focuses largely on identifying relevant evidence and decision making. Existing models of the consultation should be improved in order to understand consultations involving uncertainty. An alternative approach focusing on shared decision making and understanding the consultation from the patient's perspective is suggested. A good doctor-patient relationship is vital, creating trust and mutual respect, developed over time with good communication skills. Evidence-based medicine should be used, including discussion of probabilities where available. Trainers need to be aware of their own use of heuristics as they act as role models for trainees. Expression of feelings by trainees should be encouraged and acknowledged by trainers as a useful tool in dealing with uncertainty. Skills to deal with uncertainty should be regarded as quality improvement tools and included in educational programmes involving both trainee and established GPs. PMID- 21781434 TI - A strategy for the implementation of a quality indicator system in German primary care. AB - BACKGROUND: The Quality and Outcomes Framework (QOF) has had a major impact on the quality of care in British general practice. It is seen as a major innovation amongst quality indicator systems and as a result various countries are looking at whether such initiatives could be used in their primary care. In Germany also the development of similar schemes has started. AIM: To propose a strategy indicating key issues for the implementation of a quality indicator scheme in German primary care. METHODS: Literature review with a focus on the QOF and German quality indicator literature. RESULTS: There are major differences between the German and British healthcare and primary care systems. The development of quality indicator systems for German general practice is in progress and there is a net force for the implementation of such systems. The following ten key factors are suggested for the successful implementation of such a system in German primary care: involvement of general practitioners (GPs) at all levels of the development, a clear implementation process, investment in practice information technology (IT) systems, an accepted quality indicator set, a quality indicator setting institution and data collection organisation, clear financial and non financial incentives, a 'practice registration' structure, an exception reporting mechanism, delegation of routine clinical data collection tasks to practice assistants, a stepped implementation approach and adequate evaluation processes. CONCLUSION: For the successful implementation of a quality indicator system in German primary care a number of key issues, as presented in this article, need to be taken into account. PMID- 21781435 TI - Delivering more with less? Making the NHS Health Check work in financially hard times: real time learning from Stoke-on-Trent. AB - BACKGROUND: The NHS Health Check Programme presents the opportunity to reduce death and ill health caused by cardiovascular diseases (CVDs). Owing to the current restructuring of health care in the UK, financial resources will in future be limited. It is important to develop cost-effective ways of delivering this programme. There are practical alternatives to strategies that advocate using existing data to pre-stratify patients and prioritise those aged between 50 and 74 years. METHOD: Data on patients eligible for a health check were retrospectively collected from two early implementer practice teams. The characteristics of attenders and non-attenders, such as demographic factors, consulting behaviour, clinical measures and lifestyle measures, were collected. Costs of two approaches to delivery (drop-in clinic with choice of booked appointment versus booked appointment alone) were compiled. RESULTS: Nearly half of all patients had accessed their GP or practice nurse with four or more appointments in the 12 months prior to their health check. There remained a margin of error between estimated CVD risk (calculated prior to the health check by the practice, using existing information) and actual CVD risk (calculated after a health check had been completed). Drop-in clinics with choice of booked appointment cost half the price of offering patients the option of booked appointments alone. DISCUSSION: The cost-effectiveness of drop-in clinics was achieved by a reduction in staffing costs through intensively offering health checks; this approach provides a practical solution to maintaining a population wide approach. Using existing data to pre-stratify patients is dependent on the quality and completeness of data used to estimate CVD risk. Concentrating efforts on 50 to 74 year olds may improve sensitivity to detect CVD but would reduce the chance of engaging with patients about their health at an earlier stage. Offering health checks opportunistically and using existing data no older than 12 months to complete a health check provide the potential for further cost savings. PMID- 21781437 TI - Study of ABCB1 multidrug resistance protein in a common orofacial malformation. AB - The onset of embryonic malformations is greatly determined by the intrauterine environment, conditioned by maternal lifestyle, diet, drugs and medication intake, in addition to both foetal and maternal genotypes. Maternal C677T MTHFR genotype has been identified as important factor in cleft lip with or without cleft palate (CL/P) etiology. In the present study we evaluated the possible interaction between maternal methylenetetrahydrofolate reductase (MTHFR) and foetal ABCB1 genotypes. ABCB1 gene codes for a drug-transport pump in charge to protect the cell by extruding a variety of harmful exogens, but with a reduced activity in a folate-restricted condition. Maternal 677T genotype is translated in a reduced folate availability for the developing embryo who consequently may becomes more exposed to external insults. A family based association analysis was performed to test the effect of ABCB1 polymorphisms in clefting, in the whole sample and in the stratified sample accordingly to maternal MTHFR genotype. No evidence of association between ABCB1 polymorphisms and CL/P was detected. This suggests that ABCB1 or ABCB1-MTHFR feto-maternal interaction could have no effect in orofacial clefting or could play a role in a limited number of cases. PMID- 21781438 TI - Evidence of an involvement of TFAP2A gene in non-syndromic cleft lip with or without cleft palate: an Italian study. AB - Unraveling of factors involved in multifactorial diseases is a great challenge. Different approaches can be contemplate and applied to a variety of congenital malformations. In the present investigation TFAP2A has been considered a good candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCLP) aetiology, basing on a sum of considerations. TFAP2A has been seen involved in orofacial development in mice; it is located in the NSCLP candidate region 6p24; it codes for a transcription factor which regulates expression of IRF6, a gene implied in NSCLP; finally, it is embroiled in the branchiooculofacial syndrome, that includes clefting as feature. A family based association analysis was performed with a sample study of 405 NSCLP triads. Evidence of association was obtained with both single marker and haplotype analyses, thus providing a support for TFAP2A in NSCLP aetiology. PMID- 21781439 TI - No association between polymorphisms in cubilin, a gene of the homocysteine metabolism and the risk of non-syndromic cleft lip with or without cleft palate. AB - Epidemiological studies have correlated lower maternal periconceptional levels of plasma folate and cobalamin with increased risk of delivering offspring presenting congenital malformations such as cleft lip with or without cleft palate (CL/P) or neural tube defects. A number of genetic studies aimed at correlating these biochemical levels or the occurrence of malformations with specific genetic defects or polymorphisms have been successfully performed. The cubilin gene (CUBN) codes for a carrier that plays a crucial role in cobalamin cell internalization. CUBN polymorphisms were previously found to be associated with spina bifida occurrence. In this work, a family-based association study was performed to test CUBN involvement in CL/P. A sample of 391 CL/P triads was investigated with three single nucleotide polymorphisms mapping on the cubilin gene. Association tests indicated no significant association between CL/P and marker alleles or marker haplotypes. No evidence of maternal effect and imprinting were obtained. These data suggest that CUBN is not involved in CL/P onset in the investigated Italian population. PMID- 21781440 TI - Evidence of LEF1 fetal-maternal interaction in cleft lip with or without cleft palate in a consistent Italian sample study. AB - Epithelial mesenchymal transformation is considered a cardinal process in orofacial development. Several molecular players appear to be involved in this delicate mechanism; the activation of LEF1 transcription factor by transforming growth factor beta 3 seems to be a key step for the correct flow of events. The failure of orofacial processes during embryonic development may provoke cleft lip and/or cleft palate malformations. The scope of the present investigation was to verify whether genetic variants at LEF1 could influence the risk of orofacial clefting. The approach was a family based association study involving a total of 512 Italian patients and their parents, 401 having cleft lip with or without cleft palate (CL/P) and 111 with cleft palate only (CPO). Haplotype association analysis provided moderate evidence of an association with clefting (p 0.01). A log-linear likelihood-based method was used to verify maternal and foetal maternal association. An association between the maternal genotype and the occurrence of CL/P was observed at two polymorphic loci, at rs10022956 (P = 0.0049) and rs10025431 (P = 0.0065) respectively, while a foetal-maternal effect modulating the risk of clefting was found at locus rs10025431 (P = 0.0071). These data further corroborate the importance of the mother's genotype with regard to susceptibility to malformations and early-onset diseases. PMID- 21781441 TI - Study of the 12q13 region in nonsyndromic cleft lip with or without cleft palate. AB - The 12q13 region has been suggested as a candidate locus for orofacial cleft by different investigators. In the present study we tested the region for linkage with non syndromic cleft lip with or without cleft palate in a collection of 39 Italian multigenerational families, using microsatellite markers. No evidence of linkage was detected between the marker map and NSCLP under different mode of inheritance nor with a nonparametric method. Formal level of linkage exclusion, were obtained for each point of the map. Genetic heterogeneity and the different impact of the candidate locus among populations could explain conflicting results obtained in different studies. PMID- 21781442 TI - Histomorphic-metric evaluation of an implant retrieved from human maxilla after 13 years. AB - Fixture fracture is the most catastrophic failure of implant components because it usually causes the loss of the implant. Nevertheless, the osseointegrated fractured implants represent a very useful opportunity to study in humans the effects of loading to the peri-implant bone microstructure. The aim of the present study was to evaluate the interplay between microstructure and function of the bone around an implant retrieved from human maxilla after 13 years. There was 1 fractured Dental Implant Line (sand blasted surface from a patient placed in the anterior region of the maxillary bone (2.1) after a bone augmentation procedure, and it was processed for histology. The specimen was analyzed under the scanning electron microscope (SEM), the confocal scanning laser microscope (CSLM) and brightfield light microscope (LM) equipped with circularly polarized light (CPL). The BIC rate of the implant retrieved after 13 years was (mean +/ SD) 68.7 +/- 3.7. The crestal bone down the implant platform damage appeared to be under modeling process. The transverse collagen fiber orientation (CFO) (mean +/-SD) under the lower flank of the threads was 20.4 +/- 3.5 x 10(4) pixel while the longitudinal CFO was 19.8 +/- 2.8 x 10(4) pixel (P>.05). In the inter-threads region the transverse CFO (mean +/-SD) was 15.0 +/- 4.0 x 10(4) pixel while the longitudinal CFO was 21.4 +/- 3.0 x 10(4) pixel (P>.05). The osteocytes numbers (mean +/-SD) was 130 ? 34. Under SEM with back scattered electrons (BSE) signal the peri-implant bone appears mainly lamellar and highly mature with several osteons organized in the implant inter-threads areas. The fracture of the implant was most probably correlated to a fatigue of the material mainly associated to a damage of the internal coil. Surprisingly, it was noted a lack of implant site specific CFO of the bone extracellular matrix facing the threaded dental implant notwithstanding the high level of BIC rate. PMID- 21781443 TI - Histomorphometric evaluation of an immediately loaded implant retrieved from human mandible after 2 years. AB - The aim of the present study was to evaluate the interplay between microstructure and function of the bone around an immediately loaded implant retrieved from human maxilla after 23 months due to fracture. A spiral implant of 3.3 mm x 15 mm was placed in a male 53 years old in the anterior region of the mandible bone (4.1) and it was processed for histology. The specimen was analyzed under the confocal scanning laser microscope (CSLM) and brightfield light microscope (LM) equipped with circularly polarized light (CPL). The BIC rate was 76.7 +/- 4.9 (mean +/-SD). Many cement lines indicates an high remodeling rate of the bone. The transverse collagen fiber orientation (CFO) (mean+/-SD) under the lower flank of the thread near the tread tip was 55.2 +/- 4.8 x 10(4) pixel while the longitudinal CFO was 45.8 +/- 2.3 x 10(4) pixel (P<.05). In the inter-threads region the transverse CFO (mean +/-SD) was 36.4 +/- 2.4 x 10(4) pixel while the longitudinal CFO was 65.6 +/- 6.5 x 10(4) pixel (P<.05). The osteocytes numbers (mean +/-SD) was 205 +/- 45 in the peri-implant bone and 144 +/- 53 in the native bone (P=.007). After 2-years of loading the SLA spiral implant was well osseointegrated but still surrounded by woven bone. The osteocytes density was significantly higher in the peri-implant bone than in the native bone. The transverse collagen fibers were significantly associated with the lower flank of the implant threads, while the longitudinal collagen fibers were more represented in the straight surface of the implant. The implant fracture was correlated to crestal bone resorbing and subsequent fatigue yielding. PMID- 21781444 TI - Analysis of MGMT promoter methylation status on intraoperative fresh tissue section from frameless neuronavigation needle biopsy of 25 patients with brain tumor. AB - Formalin fixation under conditions that adversely affected the quality of the DNA, or indeterminant assay, or extensive tumor necrosis can compromise the genetic analysis of a brain bioptic sample. The success of DNA extraction and Methyl Guanine Methyl Transferase (MGMT) promoter methylation testing could be improved by freezing of fresh tumor tissue at the moment of biopsy. To ensure an increased concentration of the DNA samples the withdrawal should be performed in an area with high probability of neoplastic cells. From May 2007 to January 2011 fifty-two frameless neuronavigation brain needle biopsy were performed at the Neurosurgery Unit of the "Arcispedale Santa Maria Nuova" City Hospital of Reggio Emilia. The "image-guided" neuronavigated protocol sampling provided withdrawal specimens highly correlated with neuroimaging characteristics of the lesions. In this study the Authors report the genetic analysis on 24 cases of freezing fresh tissue from brain needle bioptic sample starting from July 2008. The molecular determination of MGMT promoter was assessed with the Nested-Methylation Specific Polymerase Chain Reaction on fresh or cryopreserved needle bioptic tissue. The genetic characterization was feasible in all the bioptic samples. The MGMT promoter was methylated in eleven patients, including a brain infection. The diagnostic yield of brain biopsy could be increased by the neuronavigated trajectories and the intraoperative frozen sections. In the future the availability of the molecular-genetic characterization of a brain tumor before open surgery will provide important information for the optimal treatment. The MGMT promoter status analysis on needle bioptic fresh tissue could be available also for that patient not eligible for surgical remotion of the tumor. PMID- 21781445 TI - Detection of IDH1 mutations and the status of MGMT promoter on intraoperative fresh tissue section from frameless neuronavigation needle biopsy. Analysis on 17 patients with brain glial tumor ineligible for craniotomy and tumor resection. AB - It is well known that primary and secondary glioblastomas are histologically largely indistinguishable. Therefore, the detection of IDH1 mutations or the status of the MGMT promoter on a simple bioptic sample could be one of major diagnostic and prognostic importance for glial patients that complements clinical criteria for distinguishing secondary from primary glioblastomas and to predict a more favourable prognosis. Currently, biopsy is the method of choice to obtain tissue from intracranial lesions with uncertain neurodiagnostic findings or in deep locations, with a minimal invasive approach. The needle biopsy with frameless neuronavigation could provide a sampling with elevated diagnostic yield and high concentration of DNA, due to the "image-guided" computer assisted technique of needle insertion through the most neurodiagnostic representative tumor area. The freezing of fresh tumor tissue at biopsy could greatly improve the success of DNA extraction. The concentration of the DNA samples can also improved from a withdrawal in an area with high probability of neoplastic cells. The present study reports the results of 17 patients who had undergone frameless image-guided intracranial needle biopsy from April 2008 until July 2010 at Neurosurgery Unit of the "Arcispedale Santa Maria Nuova" of Reggio Emilia. For these patients the molecular determination of MGMT promoter was assessed with the Nested-Methylation Specific-Polymerase Chain Reaction and the screening of mutations in IDH1 e IDH2 genes was performer by polymerase chain reaction (PCR) and direct sequencing on fresh or cryopreserved needle bioptic tissue. PMID- 21781446 TI - Calcium sulfate stimulates pulp stem cells towards osteoblasts differentiation. AB - Calcium sulfate (CaS) is a highly biocompatible material and enhances bone formation in vivo. However, how CaS alters osteoblast activity to promote bone formation is poorly understood. To study how CaS can induce osteoblast differentiation in mesenchymal stem cells, the expression levels of bone related genes and mesenchymal stem cells marker were compared in normal osteoblasts and dental pulp stem cells, using real time Reverse Transcription-Polymerase Chain Reaction. Gene differentially expressed between the two cells type were the trascriptional factor RUNX2, osteopontin (SPP1), COL1A1 (collagen type 1alpha1) and alkaline phosphatase (ALPL). The obtained results demonstrated that CaS strongly influences the behavior of DPSCs in vitro enhancing proliferation, differentiation and deposition of matrix. PMID- 21781447 TI - Polylactide-polyglycolide resorbable plates stimulates adipose tissue-derived stem cells towards osteoblasts differentiation. AB - Polylactide, polyglycolide materials or devices have been utilized routinely during maxillofacial, craniofacial, and orthopaedic reconstructive surgical procedures.(1) These materials combine the benefits of rigid fixation with the advantages of biodegradation, avoiding the need for implant removal and minimizing the risk of other complications.(2) To study how polylactide, polyglycolide acids plates (PLPG plates) can induce osteoblast differentiation and proliferation in mesenchymal stem cells, the expression levels of bone related genes (RUNX2, SP7, ALPL, SPP1, COL1A1, COL3A1 and FOSL1) and mesenchymal stem cells marker (ENG) were measured in adipose derived stem cells (ADSCs) and normal osteoblast (NO) cultivated on PLPG plates after 15 and 30 days of treatment using real time Reverse Transcription-Polymerase Chain Reaction. Significantly differentially expressed genes among ADSCs and NO were SP7, ENG, FOSL1, RUNX, ALPL and SPP1 in the first 15 days of treatment and SP7, ENG FOSL1, COL3A1 COL1A1, SPP1 and ALPL after 30 days. The present study demonstrated that PLPG plates strongly influences the behavior of ADSCs in vitro by enhancing proliferation, differentiation and deposition of matrix. PMID- 21781448 TI - Assessment of pain associated with insertion torque of dental implants. A prospective, randomized-controlled study. AB - This study investigated pain experience following dental implant placement in relation to insertion torque using questionnaires. A total 80 implants were placed in 20 patients. Each patient received 4 implants at different times. One implant was inserted and, then, after 40 days was placed the second implant, after 80 days was placed the third implant and after 120 days was placed the fourth implant. At each time the peri-implant bone levels were evaluated on intraoral radiographs taken with the paralleling technique. The implants were placed with a dynamometric key at 35N, 50N, 65N, 85N. Patients were asked to evaluate their pain experience during surgery, 24 hours after surgery, and at 2 days, 4 days, 1, 2, and 4 weeks after surgery on special pain assessment forms. A separate form was used for each time point. Pain was assessed using a descriptive numerical rating scale of 0 to 10, with 0 indicative of no pain and 10 representing the worst pain imaginable. Patients were instructed that a score of 1 to 3 was indicative of mild pain, 4 to 6 was indicative of moderate pain, and 7 to 10 was indicative of severe pain. A significant correlation pain scores and insertion torque was found between group III and group IV vs group II and group I during surgery, at 24 hours, 2 days, 4 days, 1 week, 2 weeks p <= 0.05. No statistical difference was found between group I vs. group II during surgery, at 24 hours, 2 days, 4 days, 1 week, 2 weeks p >= 0.05. In conclusion, elevated insertion torque values produces pain and resoption of the crestal bone around the implants. PMID- 21781449 TI - Expansion of the alveolar bone crest with ultrasonic surgery device: clinical study in mandible. AB - The purpose of this paper was to document the application to the split-crest mandibular procedure in two stage in order to avoid cortical resorption due to periosteal detachment in buccal cortical bone of the alveolar crest. Twenty-two healthy patients with non-contributory past medical history (14 women and 8 men, all non-smokers, mean age 59 years, range 54-65 years) were included in this study. After buccal mucoperiosteal flap was followed by a sagittal corticotomy in the coronal area of the alveolar crest and a second sagittal corticotomy, but in a lower (basal) position and two vertical corticotomies in the buccal wall, using a ultrasonic surgery device (Surgysonic, Esacrom, Imola Italy). Adequate crest expansion was achieved without compromising cortical vascularisation by utilising a combination of scalpel, thin chisels and threaded osteotomes (Bone System, Milano, Italy). Postoperative results were assessed by panoramic and periapical radiographs. Ossification of the osteotomy lines was evident and could be observed as sites with increasing radiopacity on panoramic and periapical radiographs 3 months after implants insertion. No dehiscence of the mucosa was observed. No patient suffered from hypoaesthesia. The mean horizontal bone increase in coronal area was 5+/-3 mm. Mandibular ridge expansion using a split crest technique that included grafting the implant sites with a ultrasonic surgery device is a viable therapeutic alternative for implant placement in this patient population. PMID- 21781450 TI - Analysis and structural examination of screw loosening in oral implants. AB - Biological and technical failures of implants have already been reported. Mechanical factors are certainly of importance in implant failures, even if their exact nature has not yet been established. The abutment screw fracture or loosening represents a rare, but quite unpleasant failure. The aim of the present research is an analysis and structural examination of screw thread or abutment. In this study broken screws were excluded. A total of 58 screw thread loosening were observed, 5 Branemark, (Nobel Biocare, Gothenburg, Sweden) 4 Implant Innovation (Riverside Drive Palm Beach Gardens, FL, USA) and 7 Restore (Lifecore Biomedical, Chaska, Minnesota, USA) and 42 T.B.R. implant (Benax, Ancona, Italy). The loosened abutment screws were retrieved and analyzed under SEM. Many alterations and deformations were present in concavities and convexities of screw threads. PMID- 21781451 TI - Incidence of low risk human papillomavirus in oral cancer: a real time PCR study on 278 patients. AB - Squamous cell carcinoma is the most frequent malignant tumour of the oral cavity. It is widely known that tobacco and alcohol consumption are the major causes of the development of oral squamous cell carcinoma (OSCC). The human papilloma virus infection has also been postulated as a risk factor for squamous cell carcinoma, although conflicting results have been reported. The aim of this study is to evaluate the presence of high-risk and low-risk type human papillomavirus in a large sample of squamous cell carcinoma limited to the oral cavity by means of quantitative real-time polymerase chain reaction. Data were obtained from 278 squamous cell carcinoma limited to oral cavity proper. Sequencing revealed that 5 samples were positive for HPV type 16, 5 for HPV type 11, and 1 for HPV type 6. Human papillomavirus 11 was detected in 5 tumours out of the 278 examined. The prevalence rate for Human papillomavirus 11 was 1.8% (C.I. 0.7-3.9). The matched case-controls analysis indicated that the prevalence among controls did not significantly differ with respect to cases and that Human papillomavirus 11 alone did not correlate with squamous cell carcinoma. PMID- 21781452 TI - LOH at PDCD4, CTNNB1, and CASP4 loci contributes to stage progression of oral cancer. AB - Squamous cell carcinoma is the most frequent malignant tumor of the oral cavity. Markers of tumor progression that could help to define diagnosis, plan treatment and implement prognosis have still to be identified. Seven candidate markers for tumor progression were investigated using a loss of heterozygosity (LOH) assay. The sample was made up of 51 squamous cell carcinoma and adjacent normal tissues from the same patients. LOH at one, or more, markers was a relatively frequent event that was observed in 53% of tumors. The number of losses detected in each tumor was significantly associated with tumor severity. Significant association between UICC stage grouping and LOH was found for 3 gene loci: programmed cell death 4 (PDCD4), catenin beta 1 (CTNNB1), and caspase 4 (CASP4). No association between allelic loss and the occurrence of lymph node metastasis was found for any of the seven investigated loci. Overall, LOH contributes to tumor progression of oral SCC. A specific role for PDCD4, CTNNB1, and CASP4 was found. PMID- 21781453 TI - Double demonstration of oncogenic high risk human papilloma virus DNA and HPV-E7 protein in oral cancers. AB - Oncogenic HPVs are necessarily involved in cervical cancer but their role in oral carcinogenesis is debated. To detect HPV in oral cancer, 38 cases of formalin fixed-paraffin embedded OSCC were studied by both DNA genotyping (MY09/11 L1 consensus primers in combination with GP5-GP6 primer pair followed by sequencing) and immunohistochemistry (monoclonal Abs against capsid protein and HPV-E7 protein, K1H8 DAKO and clone 8C9 INVITROGEN, respectively). HPV-16 tonsil cancer was used as positive control. The overall prevalence of HPV infection in OSCCs was 10.5%. Amplification of DNA samples showed single HPV DNA infection in 3 cases (HPV16; HPV53; HPV70) and double infection in one case of cheek cancer (HPV31/HPV44). The overall HR-HPV prevalence was 7.5%. E-7 antigen was immunohistochemically detected in all HPV-positive cases. HPV+ OSCC cases showed an overall better outcome than HPV negative oral cancers, as evaluated by Kaplan Meier curves. HPVs exert their oncogenic role after DNA integration, gene expression of E5, E6 and E7 loci and p53/pRb host proteins suppression. This study showed that HPV-E7 protein inactivating pRb is expressed in oral cancer cells infected by oncogenic HPV other than classical HR-HPV-16/18. Interestingly HPV-70, considered a low risk virus with no definite collocation in oncogenic type category, gives rise to the expression of HPV-E7 protein and inactivate pRb in oral cancer. HPV-70, as proved in current literature, is able to inactivates also p53 protein, promoting cell immortalization. HPV-53, classified as a possible high risk virus, expresses E7 protein in OSCC, contributing to oral carcinogenesis. We have identified among OSCCs, a subgroup characterized by HPV infection (10.5%). Finally, we have proved the oncogenic potential of some HPV virus types, not well known in literature. PMID- 21781454 TI - Reciprocal altered expression of E-cadherin and P-cadherin in mucous membrane pemphigoid. AB - E- and P- cadherins are involved in the selective adhesion of epidermal cells. To gain insight into the role of cadherins on the acantholysis of keratinocytes and further investigate the pathogenesis of Mucous Membrane Pemphigoid, we examined the expression of P-cadherin and E-cadherin, in normal human oral mucosa, lesional and peri-lesional mucosa in MMP. Twenty-nine samples from paraffin embedded specimens of MMP were used for the study. Five specimens of healthy oral mucosa were evaluated as control group. To evaluate the E- and P-Cadherin expression, a mean percentage of positive cells was determined from the percentage of positive cells derived from the analysis of 100 cells in ten random areas at x400 magnification. It was observed that E-cadherin was weakly and discontinuously expressed on the epithelial layers of pemphigoid mucosa, while it was intensively expressed on all keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in MMP samples, although its expression is restricted to the basal cell layer in normal human skin. Statistical analyses showed that the percentage of E-cadherin positive cells in the epithelium of pemphigoid cases was significantly decreased compared with that in normal human mucosa. There was a significant increase in the percentage of P-cadherin positive cells in the epithelial layers of MMP compared with normal human mucosa. The present study showed that there is downregulation of E-cadherin expression and upregulation of P-cadherin expression in MMP mucosa, which may be involved in the pathogenesis of MMP. PMID- 21781455 TI - Expression of beta-catenin and gamma-catenin in maxillary bone regeneration. AB - beta- and gamma-catenin are components of catenin family involved in cadherin adhesion function. Recently it has been shown that this family is involved in other functions such as signaling and activation of transcription factors. The final goal of this study was to evaluate the role of beta- and gamma-catenin in bone cell physiology and bone regeneration. Formalin-fixed-paraffin embedded specimens of 15 human bone specimens after sinus lift were collected and examined by immunohistochemstry using primary antibodies against beta- and gamma-catenin. Staining intensity and cellular localization were evaluated. beta and gamma catenin showed a very high level of expression in human bone tissues. In particular catenins were expressed in cells with morphological findings of osteoblasts in the areas of new bone formation at the junction between mineralized and unmineralized tissue, between osteoid matrix and bone. Osteoclasts showed also positivity for catenins. Osteocytes, cells located in lacunae of mature mineralized bone with function of bone vitality maintenance, showed no expression for catenins. Specimens characterized by high amount of catenins in osteoblasts at 1 degrees month showed high grade of bone maturation at 3 degrees month. Data demonstrated an overall involvement of catenins in human bone tissues and in particular during bone regeneration process. The presence of staining for beta- and gamma-catenin particularly in osteoblasts demonstrates a significant role of catenins in functions, other than in cadherin interaction, such as signaling and activation of transcription factors during differentiation of bone tissues. PMID- 21781456 TI - Peri-tumoral inflammatory cell infiltration in OSCC: a reliable marker of local recurrence and prognosis? An investigation using artificial neural networks. AB - The presence of inflammatory reaction in peri-tumoural connective tissue is generally considered as a defense mechanism against cancer, but inflammation tissue in malignant transformation and early steps of oncogenesis has been recently proven to play a supporting and aggravating role in some carcinomas. Aims of this retrospective study were to evaluate in OSCCs the independent association of peri-tumoral inflammatory infiltrate (PTI) with local recurrence (LR) or survival outcome, and to verify whether PTI can be considered a marker of prognosis. Data from 211 cases of OSCC, only surgically treated between 1990 and 2000, were collected and retrospectively analyzed for PTI and the event LR (5 yrs follow-up at least) by means of univariate-multivariate and neural networks analyses. Patients (mean age 65.3 +/- 12.4 yrs, M/F = 2.98) showed presence of PTI in 68.2% (144/211): (+) in 27.0%, (++) in 25.6%, (+++) 15.6%; PTI was found reduced in 24.7% of cases and absent in 7.1%. In overall PTI+ve group (n=144), 66 were TNM Stage I, 33 Stage II, 45 Stage III, none Stage IV. LR (mean 6 +/- 4 months) was present in 87/211 (41.2%) patients, of which 43/144 (29.8%) in OSCCs with PTI [23 (+), 13 (++) and 7 (+++)] vs. 44/67 (65.7%) in OSCC with PTI -/+ or PTI-ve ones. By univariate analysis, PTI+ve cases showed a significant lower risk to have LR (p <0.0001; OR= 0.2297; CI= 0.1277:0.4134) vs PTI -/+ or -ve ones, especially among cases with higher PTI value (+++) (OR= 0.1718; CI= 0.0749:0.3939). Multivariate analyses (Logit model and neural networks) confirmed the same datum: presence of PTI was an independent predictive variable accounting for a better tumoural outcome without LR (Logit and neural networks values: OR' 0.226; CI= 0.113:0.454; ROC Area = 0.66, respectively). In terms of prognostic significance, elevated PTI was found to have an independent association with the poorest overall survival rate (P = 0.056). Our findings strongly suggest the importance to investigate routinely PTI in OSCCs, as useful marker of tumoral behavior and prognosis, and warrant further studies. PMID- 21781457 TI - Direct visualization of oral-cavity tissue fluorescence as novel aid for early oral cancer diagnosis and potentially malignant disorders monitoring. AB - Direct visualization of the oral tissue autofluorescence has been recently reviewed in several studies as a possible adjunctive tool for early recognition and diagnosis of potentially malignant and malignant oral disorders. The aims of this study were to assess: a) the value of a simple handheld device for tissue auto-fluorescence visualization of potentially malignant oral lesions; and b) the sensitivity, specificity and diagnostic accuracy of tested device, using histological examination as the gold standard. 175 consecutive patients, with at least one clinical oral lesion, were enrolled in the study. Clinical conventional inspections were performed for each patient by two blind operators. Then, oral biopsy and histological examination were performed. Pathologist was blind with respect to the autofluorescence results. The 175 histological assessments revealed no dysplasia, mild dysplasia, moderate/severe dysplasia and OSCC, in the 67.4%, 8.6%, 8%, 16% of cases, respectively. Oral lesions diagnosed as OSCC were found as positive under fluorescent light in the 96.4% of cases. Statistically significant correlation was observed between oral dysplastic lesions and the loss of tissue fluorescence (p-value=0.001). Low sensitivity values (60% and 71%) were recorded about the ability of the device in differentiating mild dysplasia vs. lack of dysplasia and moderate/severe dysplasia vs absence of dysplasia, respectively. The device tested in our study was found to not replace the histopathology procedure. However, we assessed its usefulness for oral tissue examination, especially within an oral medicine secondary care facility, before performing a biopsy and in monitoring oral lesions. PMID- 21781458 TI - Expression of sexual hormones receptors in oral squamous cell carcinoma. AB - Sexual hormones play an important role in expression of genes involved in a wide variety of biological and neoplastic processes. The information on Estrogen Receptors (ER) expression in non-target tissues is very few and, in particular, the studies in head and neck tumors are still controversial. Recent studies analyzed the role of Tamoxifen (TAM) on Oral Squamous Cell Carcinoma (OSCC) lines in relation to the presence/absence of ER. The purpose of the present study was to evaluate the expression of sexual hormones receptors mRNAs, in particular Estrogen Receptor alpha (ERalpha) and Androgen Receptor (AR) mRNA in OSCC tissues. The study group comprised 20 samples of OSCC, harvested from 20 otherwise healthy subjects (14 males and 6 females, mean age 58.2y, range 38-74). The control group was formed by 20 samples of normal mucosa harvested around the margins of the specimens (at least 1 cm from the lesion margins). Estrogens Receptor alpha (Era) and Androgen Receptor (AR) mRNA expressions were analyzed by RT-PCR carried out on total RNAs extracted from both cancerous and healthy tissues. Obtained data were evaluated by Shapiro-Walk normality test and compared by Student's t test. Results with p<0.05 were considered statistically significant. AR transcripts were less expressed in OSCC specimens than in healthy tissues, while levels of ERalpha transcripts significantly increased in tumor samples. These preliminary data show different expression patterns of AR and ERalpha mRNAs in malignant tissues of oral mucosa and could suggest an involvement of these sexual hormones in oral cancer. PMID- 21781459 TI - [Repair system engineering and the concept of sequential cytoprotection in treatment of burn]. AB - It has been an essential trend to understand and solve the difficult problems arising in the treatment process of burn with views of holistic theory. Recent researches have indicated that the driven factors and the termination signals of repair system engineering in treatment of burn are the unity of two opposite rather than two independent bodies with chronological order. Repair driven factors are germinated at the cost of systemic inflammatory response and even multiple organ damage. Inflammatory response is both a necessary procedure of burn repair and the pathological basis of multiple system dysfunction after burn. A comprehensive burn therapy nominated sequential cytoprotection (SCP) strategy has emerged in which the knowledge derived from basic research is translated to clinical practice stepwise, and it might play an important role in treatment of severe burn. Further multi-center randomized controlled clinical trials should be conducted in order to raise the level of SCP strategy in guideline of evidence based medicine. PMID- 21781460 TI - [Protective effect of ginsenoside Re on myocardial cells of neonatal SD rat subjected to hypoxia injury]. AB - OBJECTIVE: To investigate the protective effect of ginsenoside Re on myocardial cells of neonatal SD rat with hypoxia injury, and to explore its mechanism. METHODS: The primary passage of myocardial cells collected from neonatal SD rats were divided into A group (with ordinary treatment), B group [exposed to hypoxia (1% O2, 5% CO2, 94% N(2)) for 12 hours after being cultured for 48 hours], C group (pretreated with 80 g/L ginsenoside Re for 30 minutes after 48 hours of ordinary culture, then exposed to hypoxia for 12 hours), D group (received the same treatment as used in C group except for using 40 g/L ginsenoside Re), E group (received the same treatment as used in C group except for using 20 g/L ginsenoside Re) according to the random number table, with 6 samples in each group. Myocardial cell supernatants were collected for determination of content of lactate dehydrogenase (LDH) with enzyme linked immunosorbent assay. Fluorescence recovery after photobleaching technique was used to detect gap junction intercellular communication (GJIC). Result was observed by laser scanning confocal microscope. Data were processed with paired t test. RESULTS: (1) Compared with that in B group [(403 +/- 22) U/L], contents of LDH in E, D, and C groups were obviously decreased [(255 +/- 16), (241 +/- 13), (237 +/- 24) U/L, with t value respectively 5.1, 5.2, 8.3, P values all below 0.05]. (2) The fluorescence recovery rate in A group was (74.8 +/- 3.6)% 10 min after quenching, which was higher than that in B group [(13.2 +/- 5.6)%, t = 15.2, P < 0.01]. The fluorescence recovery rate in C, D, and E groups was respectively (39.5 +/- 2.9)%, (36.2 +/- 3.1)%, and (34.3 +/- 3.9)% 10 min after quenching, all higher than that in B group (with t value respectively -6.6, -41.9, 18.3, P values all below 0.05). CONCLUSIONS: Ginsenoside Re pretreatment, particularly with a dose of 20 g/L, can protect myocardial cells from hypoxia injury, and the effect may be attributable to inhibition of release of LDH and improvement of the GJIC function. PMID- 21781461 TI - [Early treatment of high-voltage electric burn wound in the limbs]. AB - OBJECTIVE: To summarize the experience of early treatment of high-voltage electric burn wounds in the limbs. METHODS: Fifty-four patients (50 males and 4 females, aged from 10 to 56 years) with high-voltage electric burn wounds in 97 limbs (67 upper limbs and 30 lower limbs) were hospitalized in our burn wards from January 2003 to December 2010. A total of 119 burn wounds in wrist-forearm, forearm-elbow-upper arm, shoulder-axillary region, ankle-foot, lower leg, around the knee, thigh-inguinal region were treated with incision for decompression within 10 days after burn. Under the premise of relatively stable systemic condition of the patients, certain surgical operations were performed as follows. (1) Sixteen limbs with 16 wounds were amputated, among them forearm amputation was performed for 5 upper limbs with necrosis, with preservation of elbow joints, and the residual wounds of the elbow and upper arm were repaired with pedicled latissimus dorsi musculo-cutaneous flaps; 1 upper limb with upper arm amputated, with preservation of shoulder joint, was repaired with pedicled latissimus dorsi musculo-cutaneous flap. (2) Ninety-five wounds were covered with various tissue flaps with abundant blood supply after early debridement, in which 3 brachial arteries, 1 vein, 1 brachial artery and vein were reconstructed in 5 wrist wounds, artery reconstruction was performed in elbow wound of 1 case with injured brachial artery. (3) Eight wounds were treated with free skin grafting. Wound healing conditions were observed and followed up. RESULTS: Wounds in 16 limbs healed after amputation and repair. Blood supply and (or) venous return of hands were restored in 5 wrist wounds after vessel reconstruction. After artery reconstruction, abundant blood supply was observed in 1 case with injured brachial artery and amputation was avoided. Necrosis occurred in distal parts of tissue flaps in 5 wounds after grafting, in which 2 wounds healed after removal of necrotic tissue followed by closure with suture, and 3 wounds healed after debridement and free skin grafting. Tissue flap infection occurred in wrist (5 wounds), elbow (1 wound), ankle-foot (2 wounds), and healed after debridement and suture. The other tissue flaps survived after grafting. Six wounds healed after skin grafting. Partial necrosis occurred in 2 wounds after skin grafting, and they were healed after second skin grafting. Thirty-seven patients were followed up for 6 to 12 months, the skin flaps survived with satisfactory appearance and texture. CONCLUSIONS: Early extensive compartment release through fasciectomies and escharectomies, early debridement, early vascular grafting, early wound coverage with contemporary reparative and reconstructive surgical techniques are rational options for the treatment of high-voltage electric burns in the limbs. PMID- 21781462 TI - [Activity of adenosine triphosphatase and the expression of ryanodine receptor 1 mRNA in local tissue of pressure ulcer at early stage in gracilis of rats]. AB - OBJECTIVE: To investigate changes in adenosine triphosphatase (ATPase) activity and expression of ryanodine receptor 1 (RyR1) mRNA in formation of pressure ulcer at early stage, and to analyze its mechanism. METHODS: Thirty-six male Sprague Dawley rats were divided into three groups according to the random number table as follows, with 12 rats in each group. (1) Ischemia-reperfusion (IR) for 3 times (3IR) group: unilateral gracilis of rats were loaded with 22.47 kPa pressure with a special pressure apparatus for 2.0 h to simulate ischemia, and unloaded for 0.5 h to simulate reperfusion. All rats were treated with above-mentioned manoeuvre for 3 times. (2) IR for 5 times (5IR) group: rats were treated with the same manoeuvre as that in 3IR group except for IR for 5 times. (3) CONTROL GROUP: gracilis of rats were subjected to a load of 0 kPa pressure. Rats in 3IR, 5IR groups were sacrificed, and then central part of pressured tissue was harvested for detection of activity of total ATPase, Ca(2+)-Mg(2+)-ATPase, and Na(+)-K(+) ATPase with spectrophotometer colorimetry, the level of malondialdehyde (MDA) with enzyme linked immunosorbent assay (ELISA), and the level of RyR1 mRNA with real-time fluorescence quantitative RT-PCR. The same part of gracilis muscle of rats in control group was harvested for determination of indexes as above. Data were processed with one-way analysis of variance. Pearson correlation analysis was respectively performed between total ATPase activity and MDA level, total ATPase activity and RyR1 mRNA expression level, and RyR1 mRNA expression level and MDA level. RESULTS: Activity of total ATPase, Ca(2+)-Mg(2+)-ATPase, Na(+) K(+)-ATPase in control group was respectively (1.629 +/- 0.004), (0.907 +/- 0.061), (0.697 +/- 0.083) U/mg, all significantly higher than those in 3IR group [(1.365 +/- 0.004), (0.784 +/- 0.020), (0.581 +/- 0.017) U/mg, with F value respectively 1707.0, 29.8, 15.2, P < 0.05 or P < 0.01] and 5IR group [(1.055 +/- 0.049), (0.619 +/- 0.016), (0.436 +/- 0.039) U/mg, with F value respectively 1107.0, 169.9, 65.7, P values all below 0.01], and the values of 3 indexes in 5IR group were obviously lower than those in 3IR group (with F value respectively 322.8, 341.7, 94.0, P values all below 0.01). The level of MDA in control group [(7.5 +/- 0.6) nmol/L] was lower than that in 3IR group [(9.9 +/- 0.6) nmol/L, F = 53.2, P < 0.01] and 5IR group [(13.7 +/- 1.3) nmol/L, F = 76.9, P < 0.01]. There was also statistical difference in MDA level between 3IR group and 5IR group (F = 82.9, P < 0.01). Expression level of RyR1 mRNA in control group (8.5 +/- 4.2), which was similar to that in 3IR group (3.3 +/- 2.1, F = 0.9, P > 0.05), was significantly higher than that in 5IR group (0.6 +/- 0.5, F = 23.6, P < 0.05); while the RyR1 mRNA expression level was lower in 5IR group than in 3IR group (F = 39.3,P < 0.05). Activity of total ATPase was negatively correlated with MDA level (r = -0.918, P < 0.01). Activity of total ATPase was positively correlated with RyR1 mRNA expression level (r = 0.713, P < 0.01). RyR1 mRNA expression level was negatively correlated with MDA level (r = -0.702, P < 0.01). CONCLUSIONS: Energy dysbolism may be an initial factor in the development of pressure ulcer at early stage. Calcium overload injury in pressure tissue can be identified by determination of RyR1 mRNA expression. PMID- 21781463 TI - [Modulatory effect of Rac1 protein on epidermal stem cells migration during wound healing]. AB - OBJECTIVE: To investigate modulatory role of Rac1 protein in epidermal stem cell (ESC) migration during wound healing, in order to provide a reference for enriching basic theory of wound healing and guiding clinical application. METHODS: Constitutively active mutant of Rac1 protein (Rac1Q61L) or dominant negative isoform of Rac1 protein (Rac1T17N) was transfected into ESC using a retroviral vector FUGW, and retroviral vector FUGW transfected into ESC in singles was used as blank control. The cells were divided into 3 parts according to the random number table and treated as follows. First, equal numbers of cells were inoculated into 24-well plates coated with collagen I (20 ug/mL), collagen IV (20 ug/mL) or fibronectin (10 ug/mL). Cells adhered to above matrices were quantitated using CytoTox 96 colorimetric kit. Second, 1000 cells adhered to collagen IV, after being stained with tetramethyl rhodamine isothiocyanate phalloidin, were collected for observation of cell morphology and comparison of spreading area under confocal laser scanning microscope. Third, ESC with density of 2 * 10(5) cells per well were placed in upper compartment of Transwell chamber, DK-SFM culture medium alone or that containing stromal cell derived factor 1 (SDF-1) was added into lower compartment of Transwell chamber. Migration of ESC was observed using inverted phase contrast microscope, and the result was denoted as migration rate. Lastly, ESC with density of 7.5 * 10(5) cells per well was inoculated into 6-well plates for 12 hours, and treated with 4 ug/mL mitomycin C for 2 hours. The remaining scratch width of monolayer was respectively measured 6 hours or 12 hours after scratching to calculate the percentage of remaining scratch width. Data were processed with t test. RESULTS: Compared with that of blank control, the number of Rac1Q61L-transfected cells adhered to collagen I was significantly increased (t = 5.302,P < 0.05), while the number of Rac1T17N-transfected cells adhered to collagen I, IV, and fibronectin were all obviously decreased (with t value respectively 13.741, 15.676, 8.256, P values all below 0.05). Confocal laser scanning microscope showed that spreading area of Rac1Q61L-transfected ESC (with laminate pseudopodia on edge) and Rac1T17N transfected ESC was respectively larger and smaller as compared with that of blank control. With SDF-1 effect, the migration rate of Rac1T17N-transfected ESC was decreased by 78.0% and Rac1Q61L-transfected ESC was increased by 43.4% as compared with that of blank control. Without SDF-1 effect, the migration rate of Rac1T17N-transfected ESC was decreased by 55.2%, while the migration rate of Rac1Q61L-transfected ESC was close to that of blank control. Six or 12 hours after scratching, the percentage of remaining scratch width in Rac1Q61L transfected ESC was lower as compared with that in blank control [(39 +/- 9)% vs. (43 +/- 5)%, (6 +/- 5)% vs. (18 +/- 7)%, with t value respectively 1.027, 4.389, with P value respectively above and below 0.05], while that in Rac1T17N transfected ESC [(81 +/- 9)%, (71 +/- 11)%, respectively] was obviously higher as compared with that in blank control (with t value respectively 11.386, 11.726, P values all below 0.05). CONCLUSIONS: Rac1 protein may control the migration of ESC by regulating its adhesion, spreading, and chemotaxis, and it plays an active role in wound healing accelerated by ESC. PMID- 21781464 TI - [Identification of biological characteristics of human keloid-derived stem cells]. AB - OBJECTIVE: To investigate the biological characteristics of human keloid-derived stem cells (KDSC) in order to further research its role in keloid pathogenesis. METHODS: Human keloid specimens were harvested to isolate and select KDSC by enzyme digestion and subculturing. Primary and (or) the third generation of KDSC were collected for identification of biological characteristics as follows. (1) After addition of mouse anti-human monoclonal fluorescent antibodies (CD29-PE, CD34-PE, CD44-FITC, CD90-FITC, CD45-PerCP), the expression of cell surface antigen phenotype (CD29, CD34, CD44, CD45, CD90) as well as cell cycle was analyzed by flow cytometry. (2) After addition of mouse anti-human cell keratin (CK19) monoclonal antibody and mouse anti-human vimentin monoclonal antibody, the expression level of CK19 and vimentin was respectively determined with immunocytochemical method. RT-PCR was used to detect the expression of Oct4. The multipotent differentiation capacity of the first generation KDSC was observed with osteogenic, chondrogenic and adipogenic nutrient media. RESULTS: After being subcultured, the sizes of cells were similar, and the majority of them were spindle-shaped with disorderly arrangement. The cells highly expressed typical surface markers of mesenchymal stem cells (such as CD29, CD44, and CD90, etc.) with low expression of hematopoietic stem cell surface markers (such as CD34, CD45, etc.). 67.66% of cells were in G0/G1 phase, 26.24% of cells were in G2/M phase, and 6.11% of cells were in S phase. Vimentin was positively expressed in KDSC while CK19 was negatively expressed. The expression of Oct4 was also positive. After being cultured in inducing differentiation media, the cells could differentiate into osteoblasts, chondrocytes, and adipocytes. CONCLUSIONS: Stem cells existing in human keloid, which are similar to mesenchymal stem cells, may play an important role in keloid pathogenesis. PMID- 21781465 TI - [Effect of local injection of recombinant hirudin on survival of skin flaps with venous congestion in a rabbit model]. AB - OBJECTIVE: To observe the effect of local injection of recombinant hirudin on survival of skin flaps with venous congestion in a rabbit model. METHODS: Eighteen healthy rabbits were enrolled and divided into heparin-treatment (HT), recombinant hirudin treatment (RHT) and control (C) groups according to the random number table, with 6 rabbits in each group. After intravenous anesthesia with 20 g/L pentobarbital sodium, model of skin flaps with venous congestion in the size of 6 cm * 3 cm was reproduced in the dorsal side of left ear of each rabbit, in which central artery of ear served as the only blood supply, and a pedicle of 1 cm in width including central vessel of ear and its accompanying nerves as the only venous return pathway. Each flap in RHT, HT, C groups was respectively given 1 mL recombinant hirudin (1 U), low-molecular-weight heparin (625 U), and isotonic saline via multi-point and homogenous injection, then they were sutured in site. Appearance and survival rate of the flaps were observed after operation. Specimens of the distal part of flaps were harvested for determination of thromboxane B2 (TXB2) on post operation day (POD) 1, 3, 5, 7. Data were processed with one-way analysis of variance and t test. RESULTS: Rabbit model of skin flaps with venous congestion was reproduced successfully. Obvious hair loss was observed in completely necrotic parts of flap in each group. Obvious edema was observed in all flaps with venous congestion at distal site. The color of flaps in HT and RHT groups were lighter as compared with that in C group, and apparent hematoma of flap was observed in 1 rabbit of RHT group, 2 rabbits of HT group, 4 rabbits of C group on POD 1. The survival rate of flap in HT and RHT groups was respectively (92.3 +/- 1.7)% and (94.8 +/- 1.9)%, both higher than that in C group [(77.9 +/- 1.2)%, F = 191.29, P < 0.05]. There was no statistical difference in survival rate of flap between HT group and RHT group (t = 2.75,P > 0.05). The content of TXB2 in HT and RHT groups on POD 3, 5 was respectively lower than that in C group (with t value from 6.68 to 30.55, P values all below 0.01), but there was no statistical difference between HT and RHT groups (with t value respectively 1.22, 6.44, P values all above 0.05). CONCLUSIONS: Local injection of low-molecular-weight heparin or recombinant hirudin can significantly ameliorate venous congestion of skin flap in rabbit ear, and improve its survival rate. PMID- 21781466 TI - [Advances in research on the prevalence and prevention of disabilities in China]. PMID- 21781467 TI - [Application of spatial autocorrelation method in epidemiology]. PMID- 21781468 TI - [A review of professional teaching of epidemiology in China]. PMID- 21781469 TI - [Consensus on the immunological defence of pertussis]. PMID- 21781470 TI - [Association between risk factors of cardiovascular diseases and osteoporosis in postmenopausal Chinese women]. AB - OBJECTIVE: To assess the relationship between cardiovascular risk factors and osteoporosis. METHODS: 2202 women aged 50 - 73 years were included in this cross sectional study from the communities in Guangzhou, from July 2008 to January 2010. Cardiovascular risk factors including age, years since menopause, physical activity, anthropometrics, body composition, blood pressure, fasting serum lipids, glucose and uric acid, intima-media thickness (IMT) of carotid artery were assessed. Ultrasonic bone density (speed of sound) at the radius and tibia were determined. Osteoporosis was defined as T-score <= -2.5. Common factors for the cardiovascular risk factors were extracted using the factor analysis method. RESULTS: Eight common factors representing obesity, lean mass, blood triglycerides and uric acid, cholesterol, age, blood pressure, IMT and physical activity were extracted. Data from the Multivariate logistic regression showed a dose-dependent association of greater scores of age and IMT factors and lower score of lean mass factor with the increased risk of osteoporosis at the radius and tibia. As compared with the bottom quartile, the OR (95%CI) of radius and tibia osteoporosis were 0.62 (0.44 - 0.88) and 0.62 (0.48 - 0.80) for lean mass factor, 4.02 (2.72 - 5.94) and 3.68 (2.81 - 4.82) for age factor, 1.41 (1.00 - 2.00) and 1.54 (1.19 - 2.00) for IMT factors, respectively. Moreover, greater blood pressure score was associated with higher risk of radius osteoporosis while the higher obese score, was correlated with the increased risk of tibia osteoporosis. CONCLUSION: The cardiovascular-related risk factors of greater IMT, obesity, blood pressure and lower lean mass scores were associated with increased osteoporosis risks while called for more concern among the Chinese women. PMID- 21781471 TI - [Study on the factors influencing steady transmission of leprosy in Qiubei county, China]. AB - OBJECTIVE: To explore the factors influencing the steady transmission of leprosy as indicated by new case detection rate in Qiubei county, Yunnan province, China despite the implementation of MDT for the last 25 years. METHODS: Information related to case-finding was collected. ELISA and PCR were applied to detect anti PGL-1 antibody in sera and Mycobacterium leprae in nasal secretions respectively, in leprosy patients, their household contacts and the general population. M. leprae by PCR was also detected from water in the highly endemic villages. VNTR typing was performed to explore the mode and chain of transmission of M. leprae. RESULTS: Prior to 2001, the proportion of new cases detected from the examination of household contacts of leprosy patients was low (number, compared to), while the proportion of patients whose identification was delayed by more than 2 years, was high (number, compared to). Qualities of these two indicators has been improved, along with the improvement of leprosy control program since 2001, but the detection rates has been steady at 4-5/100 000 during 1986 - 2010. The PGL-1 seropositivity rate was 20% - 30% in general population, with the peak rate (30%) detected in the teenage population in the endemic villages. In addition to the fact that M. leprae was detected in nasal secretion from patients, their contacts and from water, the M. leprae VNTR genotypes were found to be highly similar between skin biopsy and nasal secretion in untreated cases. Families with multi cases were clustered and located in the Northern part of the County, and the genotypes of M. leprae were identical within those families. The percentage of clusters was considerably higher in Northern rather than Southern parts of the County. CONCLUSION: Results from this molecular study demonstrated evidence that transmission of leprosy within the families and in the endemic-villages was severe. M. leprae were detected in waters from the endemic villages and others areas which might have a relation to the continued transmission of leprosy. PMID- 21781472 TI - [Historical comparisons on related features among newly registered leprosy patients in the endemic areas of Wenshan district, Yunnan province]. AB - OBJECTIVE: To analyze the current situation and prevalence of leprosy in Wenshan district, Yunnan province. METHODS: To collect various data on leprosy reported by the health workers at the county level. RESULTS: The number of newly registered patients did not decrease significantly in 1989, 1999 and 2009, respectively. The mean age of patients at detection was 33 - 35 years old. Time of delay between the disease onset and being diagnosed was shortened from 35.2 months in 1989 to 15.9 months in 2009. However, the proportion of patients with more than 12 months of delay still accounted for nearly 50%. The proportion of Grade II disability fluctuated between 15.2% - 17.7% and the proportion of child cases increased from 8.1% in 1989 to 13.1% in 2009. Clinics for skin diseases were the main locations for case detection. The proportion of new cases detected through 'active case finding' program accounted for 44.3% in 1999 and 42.6% in 2009, both higher than 17.7% in 1989. CONCLUSION: The situation of leprosy in Wenshan district, Yunnan province, was still serious and the reason for the occurrence of new cases was related to the fact that the infectious source of leprosy had not been under full control. PMID- 21781473 TI - [Seroepidemiology investigation of neutralizing antibody against enterovirus 71 among healthy people in Tianjin]. AB - OBJECTIVE: To investigate the latent infection caused by enterovirus 71 (EV71) among healthy people in Tianjin and to provide evidence on prevention and control hand-food and mouth diseases (HFMD). METHODS: 1611 sera specimens were collected from healthy people in Tianjin while EV71 antibody was detected by neutralization test, and then the results were analyzed statistically. RESULTS: For determining positivity, the cut-point was set at 1:4. The positive rate was 66.79% (1076/1611) for EV71 neutralizing antibody. The lowest positive rate was 32.71% in the 0 - 5 age group while the highest rate was 76.67% in the 16 - 25 age group. Significant difference was seen in the positive rates among different age groups. The lowest positive rate (59.05%) was seen in the city areas while the highest rate (72.35%) was seen in the surrounding counties. 5.71% of the people being tested showed their neutralizing antibody as >= 1:256. The difference was statistically significant on positive rates among different areas. We constructed logistic regression models with the EV71 neutralizing antibody positive rate as the dependent variable and age, sex, floating population, area etc. as independent variables. There appeared statistical significances in all the independent variables. CONCLUSION: Age seemed a risk factor for recessive infection of EV71, and the neutralizing antibody against EV71 might not be kept permanently. In order to prevent and control the HFMD, more attention should be paid to the areas where more floating population were resided. PMID- 21781474 TI - [Construction and application of both adolescent multi-domain risk behavior questionnaire and risk perception questionnaire]. AB - OBJECTIVE: According to the Domain Specific Theory (DST) in risk-taking, this study intended to construct adolescent risk-taking behavior questionnaire and risk perception questionnaire inferred many domains for studying the adolescent risk-taking behavior and risk perception. METHODS: With 422 middle school students in Yinchuan as subjects to develop the questionnaire. 2402 middle school students in Ningxia and Anhui were surveyed using the questionnaire. RESULTS: Exploratory factor analysis (EFA) indicated that both of the questionnaires contain four domains named society, recreation, safe and moral, and 33 items, which could explain 41.25% and 45.5% of the total variance respectively. The split-half reliability were 0.848, 0.890 and the coefficient of internal consistency were 0.900 and 0.938. The fit indices of confirmatory factor analysis (CFA) were as follows: chi(2)/df = 8.36 and 6.73, RMSEA = 0.066 and 0.054, NFI = 0.97 and 0.97, CFI = 0.97 and 0.97 separately. Gender difference in adolescent risk-taking behavior and risk perception were noticed, with F (1, 2288) = 56.256, P < 0.001, F (1, 2288) = 10.766, P = 0.05. The adolescent risk-taking behaviors increased with age, F (2, 2288) = 140.067, P < 0.001, while the risk perception decreased with age, F (2, 2288) = 54.900, P < 0.001. Adolescent on the highest score was in the social risk, followed by recreation, morality and safety. CONCLUSION: Our results showed the newly developed scales were reliable and valid enough to be applicable to measure the adolescent risk-taking behavior and risk perception. PMID- 21781475 TI - [Study on the change of urinary iodine of different salt concentrations among the target population in an intervention trial]. AB - OBJECTIVE: To analyze the change of urinary iodine in a cohort of intervention trial and to observe the role of different doses on salt iodization and related impact factors on nutritional condition of iodine. METHODS: Multistage cluster sampling was used to sample three townships in two counties for community intervention with different doses (15 +/- 5, 25 +/- 5, 35 +/- 5) mg/kg. RESULTS: Compared to the (35 +/- 5) mg/kg group, the urine iodine levels of three experimental townships were gradually declining in county B when time went on, and the (15 +/- 5) mg/kg group showed an obvious results, at 6, 12, 18 and 24 months, with the urine iodine level as 180.00, 186.10, 150.04, 191.28 ug/L respectively, which were in accordance with the WHO standard and reached to appropriate range (187.96 ug/L) at the 18 month. The townships at county Y under intervention had declined slightly, but the urine iodine levels did not reach the WHO standard. The thyroid volume declined from 3.65 ml to 3.40 ml in two counties and the difference between them was statistically significant. CONCLUSION: To some extent, reducing the iodine concentration in salt, had a role of lowering the urine iodine level and reducing the strumous rate. PMID- 21781476 TI - [The comparison of two different types of baseline data regarding the performance of aberration detection algorithm for infectious disease outbreaks]. AB - OBJECTIVE: To compare the performance of aberration detection algorithm for infectious disease outbreaks, based on two different types of baseline data. METHODS: Cases and outbreaks of hand-foot-and-mouth disease (HFMD) reported by six provinces of China in 2009 were used as the source of data. Two types of baseline data on algorithms of C1, C2 and C3 were tested, by distinguishing the baseline data of weekdays and weekends. Time to detection (TTD) and false alarm rate (FAR) were adopted as two evaluation indices to compare the performance of 3 algorithms based on these two types of baseline data. RESULTS: A total of 405 460 cases of HFMD were reported by 6 provinces in 2009. On average, each county reported 1.78 cases per day during the weekdays and 1.29 cases per day during weekends, with significant difference (P < 0.01) between them. When using the baseline data without distinguish weekdays and weekends, the optimal thresholds for C1, C2 and C3 was 0.2, 0.4 and 0.6 respectively while the TTD of C1, C2 and C3 was all 1 day and the FARs were 5.33%, 4.88% and 4.50% respectively. On the contrast, when using the baseline data to distinguish the weekdays and weekends, the optimal thresholds for C1, C2 and C3 became 0.4, 0.6 and 1.0 while the TTD of C1, C2 and C3 also appeared equally as 1 day. However, the FARs became 4.81%, 4.75% and 4.16% respectively, which were lower than the baseline data from the first type. CONCLUSION: The number of HFMD cases reported in weekdays and weekends were significantly different, suggesting that when using the baseline data to distinguish weekdays and weekends, the FAR of C1, C2 and C3 algorithm could effectively reduce so as to improve the accuracy of outbreak detection. PMID- 21781477 TI - [Snail habitats detection in the marshland of Eastern Dongting Lake Area, based on China-Brazil Earth Resources Satellite-02B CCD data]. AB - OBJECTIVE: To detect the snail habitats from the marshland of Eastern Dongting Lake Area, using the Remote Sensing (RS) and Geographic Information System (GIS) technology based on the China-Brazil Earth Resources Satellite-02B (CBERS-02B) CCD images. METHODS: According to the two typical traits of snail habitats in marshland including "water in summer and land in winter" and "no grass, no snails", the "water in summer and land in winter" region and the vegetation coverage region were calculated by RS image processing respectively. The two regions mentioned above were then overlapped to confirm the snail habitats through comparing with the data from field survey under spatial overlapping of Arcgis as the last step. RESULTS: In Eastern Dongting Lake area, the "water in summer and land in winter" region and vegetation coverage region were predicted based on the formula normalized difference water index (NDWI) > 0.01 and normalized difference vegetation index (NDVI) > 0.36, respectively. The snail habitat was determined by theme overlay of the two regions said above. The agreement rate between the prediction and the geospatial data of field survey was 93.55%, which demonstrated the final results were credible and reliable. CONCLUSION: CBERS-02B image could be used to detect the snail habitats and to monitor the changes of them, so as to find out the characteristics of distribution and the trends of diffusion. The snail index (discriminant 1 and 2) seemed to be suitable for the detection of snail habitats in the marshland of Lake area and used for the programs of snail control. PMID- 21781478 TI - [Spatio-temporal process and the influencing factors on influenza A (H1N1) pandemic in Changsha]. AB - OBJECTIVE: To analyze the spatio-temporal process on 2009 influenza A (H1N1) pandemic in Changsha and the influencing factors during the diffusion process. METHODS: Data were from the following 5 sources, influenza A (H1N1) pandemic gathered in 2009, Geographic Information System (GIS) of Changsha, the broad range of theorems and techniques of hot spot analysis, spatio-temporal process analysis and Spearman correlation analysis. RESULTS: Hot spot areas appeared to be more in the economically developed areas, such as cities and townships. The cluster of spatial-temporal distribution of influenza A (H1N1) pandemic was most likely appearing in Liuyang city (RR = 22.70, P < 0.01). The secondary cluster would include districts as Yuelu (RR = 6.49, P < 0.01), Yuhua (RR = 81.63, P < 0.01). Xingsha township appeared as the center in the Changsha county (RR = 2.90, P < 0.01) while townships as Yutangping (RR = 19.31, P < 0.01), Chengjiao (RR = 73.14, P < 0.01) and Longtian appeared as the center in the west of Ningxiang county (RR = 14.43, P < 0.01) and Wushan as the center in the Wangcheng county (RR = 13.84, P < 0.01). As time went on, the epidemic moved towards the eastern and more developed regions. Regarding factor analysis, population, the amount of students, geographic relationship and business activities etc. appeared to be the key elements influencing the transmission of influenza A (H1N1) pandemic. At the beginning of the epidemic, population density served as the main factor (r = 0.477, P < 0.05) but during the initial and fast growing stages, it was replaced by the size of students to serve as the important indicator (r = 0.831, P < 0.01; r = 0.518, P < 0.01). However, during the peak of the epidemics, the business activities played an important role (r = -0.676, P < 0.01). CONCLUSION: Groups under high risk and districts with high incidence rates were shifting, along with the temporal process of influenza A (H1N1) pandemic, suggesting that the protection measures need to be adjusted, according to the significance of influencing factors at different stages. PMID- 21781479 TI - [Genotyping of 210 Mycobacterium tuberculosis strains with Spoligotyping and MIRU VNTR among pediatric tuberculosis patients in Chongqing]. AB - OBJECTIVE: To evaluate the application of spacer oligonucleotide typing (Spoligotyping) and mycobacterial interspersed repetitive unit-variable-number tandem repeat (MIRU-VNTR) analysis in the molecular-epidemiological study of tuberculosis and to discuss the characteristics of pediatric Mycobacterium (M.) tuberculosis strains in Chongqing. METHODS: M. tuberculosis strains isolated and typed by Spoligotyping and MIRU-VNTR respectively, from the children patients in Chongqing and to compare the results from both methods, epidemiologically. RESULTS: By means of Spoligotyping, 210 clinical isolates were divided into 2 gene groups, displaying 44 genotypes. Among them, the biggest group was M. tuberculosis Beijing family, including 130 strains (61.90%), using the Spoligotyping. From the results of MIRU-VNTR, 24 loci showed different polymorphism and the HGI of different loci set (12 old loci, 15 basic loci and 24 loci set) increased accordingly. The subtle difference in HGI was originated from one locus ETR-B, which was included in the 24-locus system. The diversity of each loci and MIRU-VNTR set for non-Beijing genotype strains was higher than that of the Beijing genotype strains. CONCLUSION: In this study, it was preliminarily confirmed the existence of high polymorphism of M. tuberculosis while the Beijing Family was the main genotype and main prevalent strain in children of Chongqing area. Spoligotyping prior to 15-locus with ETR-B combination seemed more suitable for the massive epidemiological investigation of pediatric tuberculosis patients. PMID- 21781480 TI - [Investigation on the natural infectious status of hantaviruses among small mammals in Longquan city, Zhejiang province]. AB - OBJECTIVE: To investigate the situation of the natural infection of hantaviruses (HV) in small mammals and to provide evidence for the control and prevention of hemorrhagic fever with renal syndrome (HFRS) in Longquan area, Zhejiang province. METHODS: Small mammals were captured by night trap, and lung tissue samples were collected and stored in liquid nitrogen. HV antigens were detected by indirect immuno-fluorescence assay (IFA). The partial S genome segment sequences were amplified by RT-PCR. DNAStar program was used for editing and comparing the sequences. Phylogeny was analyzed through PAUP*4.0 software. RESULTS: 319 small animals were collected in Longquan, and 9 hantavirus antigen-positive samples were identified. The positive rate of hantavirus in Apodemus agrarius was 4.97%. Phylogenetic tree constructed by partial S segment (620 - 999 nt) showed that the 9 strains carried by A. agrarius from Longquan all belonged to HTNV, and had a closer evolutionary relationship with isolate Z251 from Zhejiang province. CONCLUSION: Our results indicated that the main host was A. agrarius and the infection rate of HTNV was high in Longquan area. PMID- 21781481 TI - [Polymorphism of Helicobacter pylori vacA, isolated in China]. AB - OBJECTIVE: To understand the polymorphism of Helicobacter pylori (H. pylori) vacA alleles in China. METHODS: A total of 119 H. pylori strains were isolated from different gastro-duodenal diseases in 7 different geographic regions in China. vacA and its alleles were identified according to the length of PCR products with DNA electrophoresis. The distributions of vacA alleles were statistically analyzed. The core fragment of vacA was sequentially analyzed by software MEGA4.0. RESULTS: The alleles in vacA dominantly belonged to s1a, m2 and i1 in the tested strains. The distribution appeared to be 97.5% (116/119), 68.9% (82/119) and 91.6% (109/119), respectively. The m1b allele appeared to be 26.1% (31/119). s1b and m1a were not found. The major vacA recombination was between s1a/m2/i1 and 62.2%, followed by s1a/m1b/i1 (25.2%, 30/119). No association was found between the distribution of s1a allele and the clinical outcome, as well as the geographical regions (P > 0.05). However, the distribution of m alleles showed significant difference both among the types of disease and the geographic regions (P < 0.01). The present of i alleles did not show significant differences among disease patterns, but had significant differences between different geographic groups (P < 0.01). Three clusters were identified among these 119 isolates according to the DNA sequence of vacA. CONCLUSION: s1a/m2/i1 appeared to be the main allele in H. pylori vacA isolates from China in this study. The distribution of m alleles in vacA was correlated both to the regions and the disease patterns. The presence of i allele was associated to the regions but not the disease patterns. PMID- 21781482 TI - [Identification of Haemaphysalis longicornis and Rhipicephalus microplus]. AB - OBJECTIVE: To establish a method combined morphology and molecular marker for identifying Haemaphysalis longicornis and Rhipicephalus microplus. METHODS: Ticks were collected from domestic animals and wild environment in epidemic area of Hubei and Henan provinces where cases of fever with thrombocytopenia syndrome were prevalent. We classified the ticks by morphology characteristics before 12S rDNA of ticks were amplified by PCR and subsequently sequenced. Phylogenetic tree was constructed by PAUP4.0. RESULTS: The ticks belonged to Haemaphysalis longicornis and Rhipicephalus microplus through observation and analysed by the morphological characteristics of the ticks. 12S rDNA was cloned and sequenced while data confirmed the morphological identification of the results. CONCLUSION: The method based on morphology that combined with molecular marker seemed a good method for the identification of ticks. PMID- 21781483 TI - [SIRT1 inhibits IL-1beta mRNA transcription in lipopolysaccharide tolerant THP-1 cells]. AB - OBJECTIVE: To explore the role of silent information regulation 2 homolog 1 (SIRT1) in the regulation of IL-1beta mRNA transcription in lipopolysaccharide (LPS) tolerant THP-1 cells. METHODS: THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype was used. Chromatin immunoprecipitation assay (ChIP) and real-time PCR were applied to quantify the binding of SIRT1 and histone H3 lys9/H4 lys16 acetylation to IL-1beta promoter. IL-1beta mRNA transcription was studied after knocking down the SIRT1. RESULTS: The binding of SIRT1 to IL-1beta promoter increased about 5 times in tolerant THP 1 cells (P < 0.05), which was accompanied by the low level of histone H3 lys9/H4 lys16 acetylation (P < 0.05, compared with normal cells). Knocking-down of SIRT1 increased the transcription of IL-1beta mRNA up to the level of 68% of normal cells (P < 0.05), which was accompanied by the increase of histone H3 lys9/H4 lys16 acetylation (P < 0.05). However, there was no significant difference of p65 lys310 acetylation between normal and tolerant cells. CONCLUSION: SIRT1 inhibited the IL-1beta mRNA transcription in tolerant THP-1 cells but had not related to p65 lys310 acetylation. However, it was related to IL-1beta promoter acetylation. PMID- 21781484 TI - [Effect of folic acid and DNA methyltransferase 1 on cervical cancer and its precancerous lesion]. AB - OBJECTIVE: To explore the effect of folic acid and DNA methyltransferase 1 (DNMT1) on cervical cancer and cervix precancerous lesion. METHODS: 100 patients with cervix squamous cell carcinoma (SCC), 101 patients with cervical intraepithelial neoplasm (CIN) and 109 patients with cervix inflammation (CI) diagnosed by histology were included in this study. Radioimmunoassay (RIA), polymerase chain reaction (PCR) and Western blot were used to detect the levels of serum folate, HPV16 infection and the expression of DNMT1 protein, respectively. RESULTS: The average levels of serum folate were (2.60 +/- 1.61) ng/ml, (3.14 +/- 2.08) ng/ml and (3.32 +/- 1.74) ng/ml, and the expression of DNMT1 protein were 2.40 +/- 0.99, 1.88 +/- 0.33 and 0.89 +/- 0.29 in the group of SCC, CIN and CI, respectively. The relationship of folate levels and DNMT1 protein expression showed inverse correlation (r = -0.186, P = 0.001). The results in our study indicated that there was an additive interaction between low level of serum folate and high-expression of DNMT1 protein related to the risk of CIN and SCC, with OR value as 2.50 (95%CI: 1.21 - 9.22) and 6.03 (95%CI: 2.79 - 21.72) respectively. The relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index (S) were 0.92, 0.36 and 2.59 in the CIN group while 2.47, 0.41 and 1.96 in the SCC group. CONCLUSION: The low level of serum folate and high expression of DNMT1 protein seemed to be associated with high risk of cervical cancer and its precancerous lesion. It suggested that there might be a synergistic action between serum folate and DNMT1 in the progression of cervix carcinogenesis. PMID- 21781485 TI - [Study on the relation between peripheral arterial disease and renal insufficiency in high risk cardiovascular patients]. AB - OBJECTIVE: This study was to examine the relation of peripheral arterial disease (PAD) and renal insufficiency in cardiovascular patients with high risk. METHODS: PAD, defined as an ankle brachial index (ABI) <= 0.9 in either leg and renal insufficiency, defined as an estimated creatinine clearance (CRCL) < 60 ml*min( 1)*1.73 m(-1) were evaluated in 5270 Chinese patients at high risk of CV. RESULTS: 2648 (50.2%) patients had an estimated CRCL < 60 ml*min(-1)*1.73 m(-1), while 746 (14.2%) patients having PAD defined ABI <= 0.9. ABI and CRCL were positively correlated (r = 0.217, P < 0.001). The prevalence of PAD in patients with renal dysfunction was significantly higher than those with normal renal function (19.9% vs. 8.3%, P < 0.001). The association of ABI <= 0.9 with CRCL was independent from potential confounders such as age, diabetes, hypertension, hypercholesterolemia, smoking, coronary artery disease and stroke history (OR = 0.98, 95%CI: 0.98 - 0.99, P < 0.001). CONCLUSION: Results from the present study demonstrated a remarkably high prevalence of PAD (defined as an ABI <= 0.9) among patients with renal dysfunction and at high risk. Even after adjustment for important confounders such as age, diabetes, and coronary artery and cerebro vascular diseases etc., persons with lower CRCL were still more likely to have an ABI <= 0.9. PMID- 21781486 TI - [Relationship between serum gamma-glutamyltransferase and the risk of metabolic syndrome]. AB - OBJECTIVE: To observe the relationship between serum gamma-glutamyltransferase (GGT) and the risk factors of metabolic syndrome (MS). METHODS: Between April and August 2010, a total of 4110 persons from the out-patient Department of Tianjin First Central Hospital, were divided into two groups, the less than and the older than 65-year-old groups. Items as body mass index (BMI), blood pressure, FPG, serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), aspartate aminotransferase (AST), GGT, serum high-density lipoprotein level (HDL C), serum low-density lipoprotein level (LDL-C) and uric acid (UA) were tested and data was analyzed by SPSS. All subjects were divided into normal and abnormal groups, according to the GGT level. RESULTS: 14.6 percent of the subjects in the younger groups and 24.3 percent in the older groups were diagnosed as MS. Significant differences were noticed among MS groups and normal groups, regarding items as BMI, diastolic, ALT, GGT, HDL-C, FPG, and UA (P < 0.05). There were significant differences between GGT normal group and abnormal group (P < 0.05). The GGT levels were significant positively related to the levels of BMI, diastolic, TC, TG, FPG and UA with Rs as 0.212, 0.226, 0.362, 0.200, 0.120 and 0.213 (P < 0.01), while negatively related to the HDL-C level (r = -0.23, P < 0.001). Data from the regression analysis demonstrated that diastolic, TG, FPG and UA were predictors for GGT (beta = 0.170, 0.293, 0.107, 0.094, P < 0.05). CONCLUSION: GGT levels were significantly related to the risk factors of metabolic syndrome. PMID- 21781487 TI - [Progress of hepatitis E vaccine]. PMID- 21781489 TI - [Current status of leukemia stem cell study]. PMID- 21781488 TI - [A review on the evaluation instruments for urban built environment related to physical activity]. PMID- 21781490 TI - [The inhibition effect of DFO alone and in combination with ATO on xenograft tumor growth of HL-60 cells in nude mice and its possible mechanism]. AB - OBJECTIVE: To investigate the effect of deferoxamine (DFO) and DFO in combination with arsenic trioxide (ATO) on inhibition of HL-60 cells xenograft tumor growth in nude mice and its mechanism. METHODS: Xenograft tumor model of HL-60 cell line in nude mice was established by inoculating HL-60 cells subcutaneously into nude mice. The tumor-bearing mice were randomly divided into four groups: 50 mg/kg DFO group (group I), 3 mg/kg ATO group (group II), combination group (50 mg/kg DFO + 1.5 mg/kg ATO (group III) and normal saline control group. The drugs were administered intraperitoneally from the day of inoculation (once a day for 10 days). The inhibitory effects on the tumor growth were compared. NF-kappaBp65 expression levels of the tumors were detected by immunohistochemistry (24h after the last administration). RESULTS: (1) Tumors growth could be observed in all of the nude mice on day 7 to day 8 after inoculation, 0.5 - 1.0 cm in diameter, and then grew rapidly; (2) Tumor weight of control group, group I, group II and group III were (2.62 +/- 0.54) g, (2.55 +/- 0.82) g, (2.34 +/- 0.79) g and (1.95 +/- 0.39) g respectively, and the growth inhibition rates in group I, group II and group III were 2.67%, 10.69% and 25.57% respectively. Both DFO alone and in combination with ATO could inhibit the growth of transplanted tumors, and the combination group exhibited more effects, with no vital organ damages in the tumor-bearing mice. (3) There was significant difference in mean value of NF kappaBp65 expression among the three experimental groups (P < 0.05), with a descending order of control group > group II, > group I > group III. CONCLUSION: (1) Both DFO and ATO have antitumor activities on tumor-bearing mice, and their combination has an obvious and significant effect. (2) DFO combined with ATO, is well tolerated with no significant adverse effects in the nude mice. (3) Both DFO and ATO can downregulate NF-kappaBp65 expression of transplanted tumors, especially for their combination. PMID- 21781491 TI - [Hepatitis B related hepatic cancer with Castleman and non-Hodgkin's lymphoma: a case report]. PMID- 21781492 TI - [The induced differentiation and apoptosis of THP-1 cells by anti-CD44 antibody and its mechanism]. AB - OBJECTIVE: To investigate the effects of anti-CD44 mAb A3D8 on the cell proliferation of human acute monocytic leukemia cell line THP-1 and its mechanism. METHODS: Cell proliferation was assayed with MTT method, the expression of CD33, CD15, CD11b, CD14, Annexin-V, caspase-3 and cell cycle with flow cytometry, and the expression of p-Akt, p-ERK, bcl-2 and p27kip1 with Western blot. RESULTS: A3D8 could remarkably inhibit the proliferation capacity of the THP-1 cells in a dosage- and time-dependent manner. THP-1 differentiation was observed when treated with A3D8 (2.0 ug/ml) for one to six days. Expression of CD33 (68.9 +/- 2.0 vs 39.3 +/- 1.5), CD15 (61.7 +/- 5.5 vs 12.9 +/- 2.6), CD11b (67.3 +/- 3.8 vs 14.0 +/- 2.0) and CD14 (83.0 +/- 5.7 vs 8.0 +/- 1.0) was significantly increased at day 4 compared with the control group (all P < 0.01). Cell cycle of the THP-1 cells was arrested in G(0)/G(1). Expression of the Annexin-V ?[(32.5 +/- 2.5)% vs (2.4 +/- 0.3)%?] and caspase-3 ?[(33.3 +/- 2.5)% vs (3.6 +/- 0.3)%?] was much higher than that in normal controls (all P < 0.01), and apoptosis was observed in THP-1 cells at day 5. Expression of p-Akt (0.24 +/- 0.06 vs 1.20 +/- 0.15), p-ERK (0.32 +/- 0.05 vs 1.24 +/- 0.09), and bcl-2 (0.11 +/- 0.05 vs 0.65 +/- 0.07) was much lower than that of the controls (all P < 0.01), while p27kip1 (1.08 +/- 0.09 vs 0.10 +/- 0.02) was significantly increased at day 4 (P < 0.05). CONCLUSION: Anti-CD44 antibody can induce the differentiation and apoptosis of THP-1 cell through inhibiting PI3K/AKt and ERK1/2 signaling pathway. PMID- 21781493 TI - [Construction of AML1-ETO eukaryotic expression vector and its effects on proliferation and differentiation of U937 cells]. AB - OBJECTIVE: To construct a pcDNA3.1-AML1-ETO expression vector and investigate its effects on proliferation and differentiation of U937 leukemic cells. METHODS: AML1-ETO gene was amplified by PCR from pCMV5-AML1-ETO and inserted into eukaryotic expression plasmid pcDNA3.1/V5-His-TOPO. The recombinant plasmid was transfected into U937 cells by Lipofectamin 2000. Individual clones selected with G418 were isolated. The integration and the expression levels of AML1-ETO in transfectants were determined by PCR, RT-PCR and Western blot analysis respectively. Trypan blue refusal staining method was used to detect the proliferation of U937 cells. Light microscope was applied to observe the morphologic changes of the cell. The expression of myeloid cell differentiation antigen was detected using flow cytometry. RESULTS: The recombinant pcDNA3.1-AML1 ETO was confirmed by enzyme digestion and sequencing. The highly expressing AML1 ETO subclone was established. AML1-ETO was expressed in U937 cells transfected with pcDNA3.1-AML1-ETO. The growth of the monoclonal cells was inhibited evidently (P < 0.05). The expression of CD11b in transfected group ?[(4.17 +/- 0.31)%?] was lower than that in empty plasmid transfected group and non transfected group ?[(11.40 +/- 0.17)% and (11.03 +/- 0.15)%?] respectively (P < 0.001). Transfected cells displayed morphology of less differentiation. The expression level of CDl1b was unchanged in transfected cells treated with TPA (P > 0.05). CONCLUSION: The eukaryotic expression vector for AML1-ETO gene was successfully constructed and expressed in U937. AML1-ETO inhibits the proliferation and differentiation of transfected cells. It provides the basis for further study of mechanisms of AML1-ETO in leukemogenesis. PMID- 21781494 TI - [Effects of hermap gene on p-STAT5 kinases in signal transduction pathway during erythroid differentiation]. AB - OBJECTIVE: To study the effects of hermap gene on kinases in erythroid signal transduction pathway and investigate the mechanism of hermap on erythroid differentiation. METHODS: The K562 cells expressing hermap and hermap-siRNA respectively were established for up- and down-regulating the expression of hermap gene. These K562 cells were then induced by Ara-C to erythroid differentiation and analyzed at 0, 24, 48, 72 and 96 h, respectively, for cell morphology and biphenylamine staining positive cells, determination of CD235a, CD36, kinases p-STAT5, p-Akt, p-MAPK and p-c-JUN by FCM; and quantification of hermap gene and gamma (Agamma,Ggamma) globin gene by FQ-PCR. RESULTS: With up regulating hermap gene and inducing by Ara-C, K562 cells were changing to low ratio of nucleus to cytoplasm, cytoplasm colour from basophilic to pinkish or amethyst tinge, increase of number of biphenylamine positive cells and expression of CD235a, CD36, gamma (Agamma,Ggamma) globin gene, hermap gene and p-STAT5 from 0 to 96 h. At 0, 24, 48, 72 and 96 h of culture, the positive rates of p-STAT5 cells were detected of 0.46%, 4.54%, 20.01%, 23.65% and 33.08%, respectively. This results demonstrated that there was a positive correlation between expression of p-STAT5 and hermap gene expression (P < 0.05). CONCLUSION: hermap gene can stimulate erythroid differentiation of Ara-C induced K562 cells mainly through JAK/STAT5 signal transduction pathway. PMID- 21781495 TI - [Effect of regulation of Y-box protein 1 by RNA interference on the doxorubicin induced mdr1 gene expression in K562 cells]. AB - OBJECTIVE: To investigate the effect of YB-1 on the transcription of induced mdr1 gene expression in K562 cells. METHODS: K562 cells were treated with doxorubicin (DOX) at different concentrations and times. Expression of mdr1 and YB-1 genes was examined by RT-PCR and P-glycoprotein (P-gp) by flow cytometry. Cyto/nuclear protein was extracted for YB-1 detection by Western blotting. The expression of YB-1 gene in K562 cells was inhibited by YB-1 gene specific RNA interference (RNAi), then the expression of mdr1 and P-gp in YB-1 gene silenced cells treated with DOX was detected. RESULTS: The mdr1 gene as well as its corresponding protein P-gp was highly expressed in DOX exposed K562 cells. DOX up-regulated the expression of YB-1 gene, and promoted YB-1 protein nuclear translocation. On YB-1 gene silenced, the expressions of mdr1 gene and P-gp were obviously down regulated in DOX treated K562 cells. CONCLUSION: Doxorubicin can induce the expression of mdr1 gene in K562 cells, which may result from the transcription of mdr1 gene by activated YB-1. PMID- 21781496 TI - [Effects of HO-1 gene expression on proliferation of imatinib resistant CML cells]. AB - OBJECTIVE: To investigate the effect of heme oxygenase-1 (HO-1) expression on cell growth and apoptosis in imatinib resistant chronic myeloid leukemia (CML) cells (K562/A02-IM), and explore the relationship between HO-1 gene and CML. METHODS: The expression of HO-1 in 20 drug-resistant CML patients was detected by RT-PCR. Different concentrations of hemin were used to induce HO-1 expression of K562/A02-IM, HO-1 expression at different time was detected by RT-PCR and Western blot analysis. Cell apoptosis was detected by Annexin V/PI staining, and MTT assay was used to detect viability of K562/A02-IM cells after induction or inhibition of HO-1 gene by hemin and zinc protoporphyrin (ZPP). RESULTS: RT-PCR showed that HO-1 was expressed in the bone marrow mononuclear cells (BMMNCs). When treated with hemin at different concentrations (0, 10, 20, 40 umol/L) for 16 h, the expression of HO-1 in K562/A02-IM was increased in a dose-dependent manner, and peaked at 20 umol/L of hemin for 16 h. The apoptosis rates were (17.61 +/- 0.01)%, (12.13 +/- 0.11)%, (7.94 +/- 0.03)% and (4.62 +/- 0.15)% at 0,10, 20 and 40 umol/L of hemin respectively for 16 h and were (14.7 +/- 0.05)%, (8.1 +/- 0.07)% and (16.3 +/- 0.13)% at 20 umol/L of hemin treatment for 8,16, and 24 h respectively. Hemin induced apoptosis of K562/A02-IM cells in a dose dependent manner. The expression of HO-1 was induced in K562/A02-IM cells in a dose-dependent manner, and the survival of K562/A02-IM cells was significantly increased as compared to that of control group. When HO-1 was inhibited by ZPP, the cells survival was sharply decreased compared to that of the control group (P < 0.05). CONCLUSION: HO-1 was expressed in the BMMNCs. It is a kind of molecules whose expression can be induced and can promote the growth of drug-resistant cells. Inhibition of HO-1 expression probably be used for the treatment of drug resistant CML. PMID- 21781497 TI - [Effect of bortezomib on the drug sensitivity of imatinib resistant K562/G01 cells]. AB - OBJECTIVE: To explore the effect of bortezomib (BOR) on the drug sensitivity of imatinib-resistant chronic myeloid leukemia cell line K562/G01 cell and its mechanism. METHODS: MTT assay was used to detect the inhibition effect of cell growth, flow cytometry to cell cycle, and real time-PCR to the expression of COX 2 and mdr1 mRNA. RESULTS: Combination of 10 and 20 nmol/L BOR with imatinib could significantly enhance the sensitivity of K562/G01 to imatinib, the reverse factor was 1.83 and 2.72-fold respectively. Cell cycle arrested at G(2)/M phase could be observed by flow cytometry on BOR treatment. The over-expression of COX-2 and mdr1 could be down-regulated by BOR. CONCLUSIONS: BOR can enhance the imatinib sensitivity of imatinib resistant K562/G01 cell. The mechanism may be related to cell cycle phase arrested at G2/M and down-regulation of COX-2 and mdr1 expression. PMID- 21781498 TI - [Anti GVHD effect of the induction of immune tolerance in rats embryo]. AB - OBJECTIVE: To investigate whether the fetal immune tolerance induction could replace the HLA typing for hematopoietic stem cell transplantation. METHODS: Immune tolerance of SD rats was induced by injecting host Wistar rats peripheral blood mononuclear cells into yolk sac of the embryo, afterward the mature male offsprings were used as donor. The host female recipients received lethal dose irradiation and bone marrow transplantation(BMT). The Wistar rats transplanted with bone marrow from donor and unrelated SD rats as well as the rats which received radiation alone were used as control. The survival, histopathologically GVHD, the mental status, food and water intake, coat characteristics, activities were observed. Forty days after BMT, autologous and allogenous skin transplantation between donor and recipient rats was performed to observe the engraftment of solid organ. RESULTS: The survival of the rats received bone marrow grafts from the immune tolerant donor was significantly longer than that of control groups (30 day survival rates were 86.7%, 6.7%, 0%, and 0% respectively), and there was no histopathologically GVHD observed, while in the sham group, the manifestations of GVHD was clearly visible. The skin engraftment rate between the host and the immune tolerant donor was significantly higher than that among non-related rats (84.6% and 0% respectively). CONCLUSION: The induction of immune tolerance in embryo can overcome the HLA barrier and provide a good donor for hematopoietic stem cell and solid organ transplantation. PMID- 21781499 TI - [Clinical significance of sequential monitoring minimal residual disease in childhood B-cell acute lymphoblastic leukemia]. AB - OBJECTIVE: To study the clinical significance of sequentially monitoring minimal residual disease (MRD) in childhood B-cell acute lymphoblastic leukemia (B-ALL). METHOD: Eighty one B-ALL cases were enrolled in the study from January 2004 to December 2009. Leukemia cell markers were detected by flow cytometry at diagnosis, then regularly followed-up. RESULTS: Of 81 cases, 80 achieved complete remission (CR) after induction therapy, 5-year event-free survival (EFS) was (76.80 +/- 5.70)%. Among them, the EFS was (89.40 +/- 5.90)% in standard risk group and (66.99 +/- 13.60)% in intermediate risk group. Eight cases were screened for leukemia markers for MRD monitoring and identified in 68; and 5-year EFS was (79.10 +/- 6.20)% and (62.50 +/- 15.10)% (P > 0.05, respectively). MRD detection at day 35 in induction therapy showed that 52 of 68 cases were MRD negative (leukemia cells < 0.01%), the 5-year EFS being (88.50 +/- 4.90)%, and 16 were MRD positive (leukemia cells >= 0.01%), the 5-year EFS being (42.10 +/- 20.10)% (P > 0.05). Univariate analysis confirmed that there was a correlation between MRD monitoring and risk stratification. MRD detection at day 55 showed that among the 52 day 35 MRD negative cases, 51 were still negative, 1 positive, among 16 day 35 MRD positive cases, 14 (87.50%) turned negative, 2 still positive. Of the 68 cases, 9 were MRD positive within one year after CR (3 relapsed), 4 MRD positive after one year (2 relapsed) and 55 MRD negative (4 relapsed) (P > 0.05). CONCLUSIONS: Sequential monitoring MRD can find out treatment outcome and adjust therapy in time. PMID- 21781500 TI - [A preliminary study on the influence of human plasma exosomes-like vesicles on macrophage Wnt5A-Ca2+ pathway]. AB - OBJECTIVE: To study the influence of human plasma exosomes-like vesicles on the regulatory function of macrophages. METHODS: The exosomes-like vesicles were purified from healthy donors plasma with a series of high-speed centrifugation and ultrafiltration. Macrophages were derived from cultured human blood monocytes. The molecular markers of macrophages were assayed by FACS. After cultured with exosomes-like vesicles, the changes of macrophages cytoplasma Ca(2+), and related genes and proteins were assayed by FACS, RT-PCR and Western Blot, respectively. RESULTS: After cultured with exosomes-like vesicles, mean fluorescent intensity (MFI) of macrophages cytoplasma Ca(2+) was increased. The vesicles enhanced macrophages to express cytokines genes, the expression of IL 1beta and TNF-alpha genes being increased by 0.85 and 1.69 times respectively at 2 h, and that of IL-6 gene 3.7 times compared with the control at 8 h. However, the vesicles inhibited the expression of macrophages IL-10 gene, had no influence on the Frizzled5 receptor expression and could induce CaMKII phosphorylation. CONCLUSIONS: Exosomes-like vesicles can up-regulat macrophages expression of inflammatory cytokines genes, and increase the secretion of inflammatory cytokines by activating the Wnt5A-Ca(2+) signaling pathway. PMID- 21781501 TI - [Effect of IFN-alpha combining with celecoxib on K562/A02 cells proliferation and its mechanism]. PMID- 21781502 TI - [Promotion of melatonin on the differentiation of human adipose-derived mesenchymal stem cell to endothelial cells]. PMID- 21781503 TI - [The apoptosis-inducing potential of L-asparaginase in acute myeloid leukemia cells]. PMID- 21781504 TI - [Effect of human bone marrow mesenchymal stem cells on proliferation of allogenic T lymphocytes and Treg subgroup]. PMID- 21781505 TI - [Effects of hyperbaric oxygen combined with adriamycin on K562/A02 cell cycles and tumor xenografts growth]. PMID- 21781506 TI - [Effect of ubiquitin in preserved whole blood on the cytokine secretion of peripheral blood mononuclear cells]. PMID- 21781507 TI - [c-CBL gene and myeloid malignancy]. PMID- 21781508 TI - [Treatment guidelines of chronic myeloid leukemia]. PMID- 21781509 TI - [Clinical features, diagnosis and treatment of 5 cases of primary pneumonic plague in Tibet in 2010]. AB - OBJECTIVE: To explore the clinical manifestations, the feature of chest X-ray, the clinical outcome, and the clinical treatments of severe pneumonic plague. METHODS: We observed the clinical course of primary pneumonic plague in 5 patients, who infected Yersinia pestis in Tibet during September 2010, including manifestations of chest X-ray, the antibiotic therapy, respiratory support and the prognosis. RESULTS: All of the 5 patients presented with high fever, bloody sputum and difficulty breathing. The chest X-ray showed signs consistent with necrotizing inflammation with multiple lobar involvement. Mass-like lesions might coalesce, and the "white lung" sign might appear. Three out of the 5 patients presented with hypoxemia. The results of reverse indirect hemagglutination assay (RIHA) in these patients were positive on the second day of the illness onset. All of these patients recovered after antibiotic therapy and other treatments. However, the absorption of lung lesions was very slow. CONCLUSIONS: Patients infected with primary pneumonic plague presented with rapid onset high fever and hemoptysis, and the lung injury was very severe. The positive result of RIHA was useful for early diagnosis of plague. Streptomycin should be the first choice for Yersinia pestis infection, but its optimal dose needed further study. Fluoroquinolones can be used as combination with Streptomycin. Nutritional support and symptomatic treatment, as well as non-invasive or invasive mechanical ventilation when needed, were important for the management of the disease. PMID- 21781510 TI - [Activity of macrolides and fluoroquinolones against intracellular Legionella pneumophila]. AB - OBJECTIVE: To evaluate the activity of macrolides and fluoroquinolones against Legionella pneumophila by intracellular susceptibility testing. METHODS: Minimum inhibitory concentration (MIC) was determined by standard agar dilution test according to the CLSI. For intracellular assays, legionella pneumonia was used to infect human monocytic cell line THP-1. Erythromycin, azithromycin, levofloxacin and moxifloxacin at 1 * MIC, 4 * MIC, 8 * MIC were added following phagocytosis. Number of viable bacteria was enumerated at 24 h on BCYE (buffered charcoal yeast extract) agar in duplicates using standard plate count method. The result was expressed as percentage inhibition. Mann-Whitney U test was used to determine the significant differences in mean percentage inhibition between agents. RESULTS: Percentage inhibition at 24 h were as follows: Erythromycin 1 * MIC (50.18 +/- 27.29)%, 4 * MIC (79.48 +/- 20.08)%, 8 * MIC (91.46 +/- 8.70)%; Azithromycin 1 * MIC (66.77 +/- 26.18)%, 4 * MIC (91.73 +/- 8.72)%, 8 * MIC (97.10 +/- 3.37)%; Levofloxacin 1 * MIC (99.84 +/- 0.25)%, 4 * MIC (99.99 +/- 0.02)%, 8 * MIC (99.99 +/- 0.01)%; Moxifloxacin 1 * MIC (99.90 +/- 0.10)%, 4 * MIC (99.99 +/- 0.03)%, 8 * MIC (99.99 +/- 0.03)%. The fluoroquinolones showed greater inhibitory activity than macrolides against legionella pneumophila(u = 1.0, 2.0, 5.0, P < 0.05). Levofloxacin and moxifloxacin had the same intracellular activity against legionella pneumophila (u = 190, 183, 217, P > 0.05). Azithromycin was more effective than erythromycin in inhibiting intracellular legionella pneumophila (u = 132, 125, 128, P < 0.05). CONCLUSIONS: The fluoroquinolones were more active than macrolides against legionella pneumophila. The intracellular activity of levofloxacin against legionella pneumophila appeared to be similar to moxifloxacin. Azithromycin was demonstrated to have superior activity against legionella pneumophila compared with erythromycin. PMID- 21781511 TI - [The in vitro and in vivo effects of adenovirus-mediated inhibitor of growth 4 and interleukin-24 co-expression on the radiosensitivity of human lung adenocarcinoma]. AB - OBJECTIVE: To study the radiosensitivity of the recombinant adenoviral vector (called Ad-ING4-IL-24) carrying and co-expressing inhibitor of growth 4 (ING4) and interleukin-24 (IL-24) to human lung adenocarcinoma and the underlying mechanisms. METHODS: The expression levels of ING4 and IL-24 were detected by Western blot. The growth-suppressing and apoptosis-inducing effect of Ad-ING4-IL 24 combined with radiotherapy on SPC-A-1 lung carcinoma cells were assessed by MTT assay and FCM respectively. The 25 nude mice were randomly divided into 5 groups of 5 mice ecah: PBS group, Ad group, Ad-ING4-IL-24 group, radiotherapy group and joint group (Ad-ING4-IL-24 combined radiotherapy). Mice in all groups except radiotherapy group were intratumorally injected every other day for 6 cycles. The short and long axes of the tumor were measured dynamically, tumor volume was calculated as: V = L * W(2/2), changes in tumor volume were graphed. The human lung carcinoma model was established with SPC-A-1 cells in nude mice. The ratios of tumor-suppression and q were calculated. The expression of Caspase 3, Bcl-2, Bax, VEGF in tumor samples were detected by immunohistochemistry. RESULTS: The expressions of ING4 and IL-24 were successfully expressed in SPC-A-1 cells. MTT assay and FCM showed that the levels of cell-growth inhibition and apoptosis induction in Ad-ING4-IL-24 combined with radiotherapy group [(86.2 +/- 0.8)%, (60.9 +/- 1.0)%] were higher than in Ad-ING4-IL-24 group [(49.8 +/- 0.3)%, (26.3 +/- 1.3)%] and in radiotherapy group [(44.4 +/- 2.2)%, (33.3 +/- 0.8)%] (ratio of cell-growth inhibition, F = 550.88, P < 0.01; ratio of induced apoptosis F = 614.08, P < 0.01). Ad-ING4-IL-24 combined with radiotherapy showed an enhanced radiosensitivity effect on human lung adenocarcinoma (q = 1.20). In Ad-ING4-IL-24 group, radiotherapy group and Ad-ING4-IL-24 combined with radiotherapy group, the weight inhibition ratio was 49.5% (5 nude mice), 35.4% (5 nude mice), 79.8% (5 nude mice) respectively. Ad-ING4-IL-24 combined with radiotherapy had a synergetic and enhanced radiosensitivity effect on inhibiting the growth of transplanted tumor (q = 1.18). According to immunohistochemistry, Ad-ING4-IL-24 was shown to up-regulate the expression of Bax and Caspase-3 but down-regulate the expression of Bcl-2 and VEGF. CONCLUSION: Ad-ING4-IL-24 had an enhanced radiosensitivity effect on human lung adenocarcinoma, and therefore acted as a radiotherapy sensitizer, which may be related to its effect on apoptosis-induction and antiangiogenesis. PMID- 21781512 TI - [Sildenafil therapy for pulmonary hypertension: a prospective study]. AB - OBJECTIVE: To explore the safety and efficacy of oral sildenafil therapy for pulmonary arterial hypertension (PAH), and to provide evidence for sildenafil treatment for Chinese patients with PAH. METHODS: In this 12-week, prospective, open-label, uncontrolled study, 56 patients with PAH were given oral sildenafil (25 mg, tid). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by 6 min walk (6MW) test. Secondary end points included changes in WHO class and cardiopulmonary hemodynamics. Clinical worsening was defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH, such as intravenous epoprostenol or oral bosentan. RESULTS: After 12 weeks, the compliance was good in 56 patients. Significant improvement was seen in NYHA heart function class and WHO class as compared to baseline (P < 0.01): from class IV to class III in 2, from class III to class II in 8 and to class I in 2 cases, and from class II to class I in 5 cases. No NYHA heart function class and WHO PAH function class deterioration were observed. Oral sildenafil increased 6MW distance, from (352 +/- 80) m to (396 +/- 78) m, with a change of (44 +/- 70) m (P < 0.01). Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, P < 0.01; cardiac index, P < 0.01; pulmonary vascular resistance, P < 0.01) at week 12 as compared with baseline. Mean right atrial pressure decreased (3 +/- 11) mm Hg (1 mm Hg = 0.133 kPa), mean pulmonary arterial pressure decreased (6 +/- 14) mm Hg, cardiac output increased (1.1 +/- 2.0) L/min, cardiac index increased (0.7 +/- 1.1) L*min(-1)*m( 2), and total pulmonary resistance decreased (490 +/- 831) Dys*s*cm(-5). Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients. CONCLUSIONS: Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension. PMID- 21781513 TI - [Superoxide dismutase gene polymorphisms and functional activity in chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore the association of genetic polymorphism of superoxide dismutase (SOD) and superoxide dismutase activity in chronic obstructive pulmonary disease. METHODS: A total of 114 patients with COPD (the COPD group) and 80 healthy volunteers (the control group) were enrolled in this study. Peripheral blood was taken and whole blood cell genomic DNA was extracted. The genetic polymorphisms of Mn-SOD (G5774A) and EC-SOD G (-4466)T genes were determined by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Peripheral blood plasma was collected and the functional activity of SOD was determined by a SOD kit. RESULTS: The distribution of the Mn-SOD genotype frequencies (GG, AG, AA) between the patients [27.2% (31/114), 53.5% (61/114) and 19.3% (22/114)] and the controls [46.3% (37/80), 37.5% (30/80) and 16.2% (13/80)] were significantly different (chi(2) = 7.681, P < 0.05). The A allele gene frequencies of the patients (46.1%, 105/228) were significant higher than those of the controls (35.0%, 56/160), and subjects with the A allele gene of Mn-SOD were more likely to have COPD [OR = 1.585, 95%CI (1.045 - 2.404), P < 0.05]. The AA and AG genotypes of Mn-SOD were correlated with the most severe COPD (chi(2) = 12.345, P < 0.01). The distribution of the EC SOD genotype frequencies (GG, GT, TT) was 76.3% (87/114), 22.8% (26/114), 0.9% (1/114) in the patients and 71.3% (57/80), 28.7% (23/80), 0% (0/80) in the controls. The allele gene frequencies of the EC-SOD (G, T) were 87.7% (200/228), 12.3% (28/228) in the patients and 85.6% (137/160), 14.4% (23/160) in the controls. There were no significant differences in the distribution of the different genotypes or allele gene frequencies between the patients and the controls in the EC-SOD genes (chi(2) = 0.631, P > 0.05; chi(2) = 0.36, P > 0.05). The SOD activity of COPD patients [(84 +/- 17) kU/L] was significant lower than that of the healthy controls [(109 +/- 15) kU/L]. CONCLUSIONS: Mn-SOD (G5774A) genetic polymorphism is related to the development of COPD. The Mn-SOD 5774A allele gene may be one of the predisposing genes for COPD. The AA and AG genotypes of Mn-SOD were correlated with the most severy COPD. The decrease of blood plasma SOD activity in COPD patients indicates a dysfunction of the oxidant/antioxidant defense system in the disease. PMID- 21781514 TI - [Correlation between the airway inflammations and levels of stromal cell-derived factor 1 in induced sputum of asthmatic patients]. AB - OBJECTIVE: To evaluate concentrations of stromal cell-derived factor 1 (SDF-1) and IL-17 in induced sputum supernatants from asthmatic patients before and after treatment with glucocorticosteroids. METHODS: Induced sputum was collected from 30 healthy controls and 99 patients with chronic persistent asthma from 2009 2010. Sputum samples were obtained before and after 4 week treatment with inhaled glucocorticosteroids. The sputum concentrations of SDF-1 and IL-17 were measured by ELISA. RESULTS: The FEV(1)% and the asthma control score of patients with severe asthma were decreased as compared with patients with moderate persistent and mild persistent asthma (F = 457.448 and 79.271, all P < 0.01). The concentrations of SDF-1, IL-17 and the percentage of eosinophils were increased in asthma group compared with control subjects (all P < 0.01), but the percentage of sputum neutrophils was lower than that in the healthy controls (P < 0.01). The percentage of sputum neutrophils and eosinophils and the level of SDF-1 and IL-17 in patients with severe persistent asthma were significantly higher than those in patients with mild persistent asthma (all P < 0.05). The percentage of sputum neutrophils and eosinophils were negatively correlated with FEV(1)% (r = -0.409 and -0.316, all P < 0.05). The levels of IL-17 and SDF-1 were positively correlated with the percentage of sputum neutrophils and eosinophils (all P < 0.01). The levels of IL-17 were positively correlated with the levels of SDF-1 (r = 0.872, P < 0.01). After glucocorticosteroid therapy, the percentage of eosinophils and neutrophils, the levels of IL-17 and SDF-1 decreased significantly in all patients (all P < 0.01), while the percentage of sputum neutrophils and the levels of IL-17 and SDF-1 in uncontrolled patients increased significantly compared with the controlled and partly controlled groups (all P < 0.05). CONCLUSIONS: SDF-1 and IL-17 may contribute to airway inflammation in asthma by chemotactic activity towards neutrophils. The concentration of SDF-1 may be used to evaluate the inflammation and the therapeutic effects. PMID- 21781515 TI - [The mechanism of airway inflammation in eosinophilic bronchitis and cough variant asthma]. AB - OBJECTIVE: To explore the characteristics of airway inflammatory cells, cytokines and inflammatory mediators in eosinophilic bronchitis (EB) and cough variant asthma (CVA) patients and to elucidate the underlying mechanism of distinct airway inflammation between EB and CVA. METHODS: This study included 15 patients with EB (EB group), 15 patients with cough variant asthma (CVA, CVA group), 14 patients with bronchial asthma (asthma group) and 14 healthy controls (healthy group). Percentage of eosinophils (EOS) in sputum induced by hypertonic saline was detected by FACS. The percentage of CD(69)(+) EOS stimulated by interleukin-5 (IL-5) and interferon gamma (IFN-gamma) was also detected by FACS. The expression of leukotriene C4 synthase (LTC4S) and prostaglandin-endoperoxide synthase-2 (PTGS2) mRNA in sputum was measured by real-time PCR and the concentration of leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) in sputum was measured by ELISA. RESULTS: The percentage of EOS in induced sputum was 15.8 +/- 3.2 (EB group), 13.0 +/- 2.7 (CVA group) and 11.6 +/- 4.5 (asthma group), respectively, which were significantly higher than 1.0 +/- 0.4 in the healthy group. The difference was significant and the t value was 16.31, 15.23 and 14.21 respectively (P < 0.05). After stimulated by IL-5 and IFN-gamma, the percentage of CD(69)(+) EOS in induced sputum was 1.5 +/- 0.4 and 1.5 +/- 0.5 (EB group), 1.4 +/- 0.4 and 1.4 +/- 0.3 (CVA group) and 1.42 +/- 0.72 and 1.37 +/- 0.46 (asthma group) respectively. There was no statistical significance between these 3 groups, but when compared with 0.4 +/- 0.2 and 0.4 +/- 0.1 in healthy group, the difference was significant (P < 0.05). The expression of IL-5 mRNA and protein in induced sputum of EB group, CVA group and asthma group were higher than the healthy group and the difference was all statistically different (P < 0.05), but there was no statistical significance between EB group, CVA group and asthma group. The expression of IFN-gamma mRNA and protein in induced sputum of each group was not different when compared with healthy group (P > 0.05). The concentration of PGE2 in induced sputum of EB group was(839 +/- 69) ng/L, which was higher than (33 +/- 8) ng/L of CVA group, (25 +/- 6) ng/L of asthma group and (24 +/- 8) ng/L of healthy group (all P < 0.01). There was no statistical difference between CVA group, asthma group and healthy group. The expression of PTGS2 in induced sputum of EB group increased significantly; when compared with CVA group, asthma group and healthy group, the difference was significant (all P < 0.01). The concentration of LTC4 in induced sputum of EB group, CVA group and asthma group was all higher than the healthy group (all P < 0.05). The expression of LTC4S mRNA of EB group, CVA group and asthma group was also higher than the healthy group (all P < 0.05). The expression of LTC4S mRNA and LTC4 in the EB group was higher than that in the CVA group and the asthma group (P < 0.05). The value of LTC4/PGE2 in the CVA group and the asthma group was higher than that in the EB group (t = 8.7 and 13.1, P < 0.05). CONCLUSION: These data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and CVA (or asthma) may be due to the results of differences in PGE(2) production and an imbalance between the production of bronchoconstrictor LTC(4) and bronchoprotective PGE(2) lipid mediators. PMID- 21781516 TI - [Inhibition of 1,25-(OH)2D3 on passively sensitized human airway smooth muscle cells]. AB - OBJECTIVE: To investigate the effects of 1,25-(OH)(2)D(3) on the proliferation of passively sensitized human airway smooth muscle cells (HASMCs) and their expressions of MMP-9 and a disintegrin and metalloprotease 33(ADAM33). METHODS: HASMCs were passively sensitized with 10% serum from asthmatic patients. MTT colorimetry assay was used to examine the effect of 1,25-(OH)(2)D(3) on cell proliferation at different concentrations (10(-10) mol/L, 10(-9) mol/L, 10(-8) mol/L, 10(-7) mol/L).By this way, its optimal inhibitory concentration was determined. And then the effects of 1,25-(OH)(2)D(3) at the optimal concentration on cell proliferation was examined by the same MTT assay and cell cycle analysis by flow cytometry. The expressions of MMP-9 and ADAM33 in HASMCs were studied by real-time quantitative RT-PCR and Western blotting analysis. RESULTS: (1) Inhibition of cell proliferation by 1,25-(OH)(2)D(3) was barely detectable at 10( 10) mol/L. But with the increasing concentration ranging from 10(-9) mol/L to 10( 7) mol/L, 1,25-(OH)(2)D(3) markedly inhibited the cell proliferation concentration-dependently and reached the maximum effect at the concentration of 10(-7) mol/L. Accordingly, 10(-7) mol/L was chosen as the optimal concentration of 1,25-(OH)(2)D(3) for the following study. (2) At the concentration of 10(-7) mol/L, 1,25-(OH)(2)D(3) inhibited the cell proliferation of passively sensitized HASMCs in a time-dependent manner and hampered the G(1)/S transition. (3) 1,25 (OH)(2)D(3) pretreatment attenuated the MMP-9 and ADAM33 protein levels in passively sensitized HASMCs by (63.4 +/- 3.6)% and (50.9 +/- 2.9)%, respectively (P < 0.01). (4) 1,25-(OH)(2)D(3) significantly inhibited the MMP-9 and ADAM33 mRNA levels in passively sensitized HASMCs by (52.2 +/- 2.5)% and (67.8 +/- 3.2)%, respectively (P < 0.01). CONCLUSION: 1,25-(OH)(2)D(3) has a direct inhibitory effect on passively sensitized HASMCs in vitro, including the inhibition of cell proliferation and the expressions of MMP-9 and ADAM33, which maybe associated with the beneficial role of 1,25-(OH)(2)D(3) in the prevention and therapy of asthmatic airway remodeling. PMID- 21781517 TI - [Interaction of protein kinase C-extracellular signal-regulated kinase 1/2 signal pathway in the process of plasminogen activator inhibitor-1 expression induced by nicotine in human umbilical vein endothelial cells]. AB - OBJECTIVE: To explore the role of protein kinase C (PKC)- extracellular signal regulated kinase (ERK)1/2 signal pathway in the process of plasminogen activator inhibitor-1 (PAI-1) protein and mRNA expression in cultured human umbilical vein endothelial cells (HUVECs) induced by nicotine. METHODS: HUVECs were cultured to examine the effect of nicotine on the expression of secreting PAI-1 in HUVECs on different experimental conditions. The expression of PAI-1 protein was measured by ELISA. PKC inhibitor staurosporine (STS) and ERK1/2 inhibitor PD98059 were used to detect PKC or ERK1/2 function on the expression of PAI-1 in HUVECs induced by nicotine. The PAI-1 mRNA expression was determined by RT-PCR. RESULTS: The expression level of PAI-1 protein in 100 umol/L nicotine treated group [(22.6 +/- 1.1) ug/L] increased significantly compared to the control group [(14.2 +/- 2.8) ug/L; q = 5.64, P < 0.05]. After stimulation with 100 umol/L nicotine for 0, 4, 6, 8, 12 and 24 h, the levels of PAI-1 protein increased over time and reached the peak at 12 h (F = 32.063, P < 0.05). The PAI-1 mRNA and protein expression in nicotine treated group [(1.32 +/- 0.20), (21.08 +/- 0.83) ug/L] increased significantly compared to the control group [(0.73 +/- 0.10), (13.39 +/- 0.93) ug/L; q = 8.43, 11.97, all P < 0.05].Compared with nicotine treated group, the PAI-1 mRNA and protein expression in nicotine and STS treated group [(1.07 +/- 0.10), (16.19 +/- 2.15) ug/L] decreased significantly(q = 5.61, 7.61, all P < 0.05), but still higher than the control group (q = 7.84, 4.36, all P < 0.05). In nicotine and PD98059 treated group, the PAI-1 mRNA and protein expression [(1.12 +/- 0.11), (17.52 +/- 1.72) ug/L] decreased significantly compared to the nicotine treated group(q = 4.68, 5.54, all P < 0.05), still higher than the control group (q = 8.77, 6.43, all P < 0.05). CONCLUSION: PKC-ERK1/2 signal pathway may play a partial role in the up-regulation of PAI-1 induced by nicotine in HUVECs. PMID- 21781518 TI - [The cluster and drug-resistant characteristics of Beijing genotype Mycobacterium tuberculosis in eastern rural China]. AB - OBJECTIVE: To investigate the distribution of Mycobacterium tuberculosis (MTB) Beijing genotype, which was isolated from tuberculosis (TB) patients registered in local TB dispensaries in Deqing and Guanyun county respectively within 1 year, as well as its drug-resistant phenotypic and genotypic profiles and genotyping features. METHODS: A total of 399 TB patients were enrolled from 2 counties. Of the 351 TB patients with MTB isolates available, 237 were male, and 114 were female; aged from 18 - 82 (46 +/- 35) years. The proportion method and DNA sequencing were used to define the susceptibility of the isolates to 4 first line anti-TB drugs and the related mutation. Beijing genotype MTB strains were identified by Spoligotyping, while the "cluster" strains and the "unique" strains were defined by IS6110 restriction fragment length polymorphism (RFLP). RESULTS: Beijing genotype MTB strains were identified in 243 of the 351 strains isolated, and the proportion of multi-drug resistance, mono-resistance to rifampin and isoniazid among Beijing genotype MTB was 18.5% (45/243), 43.2% (105/243) and 22.2% (54/243) respectively, all being significantly higher than the non-Beijing genotype MTB, 7.4% (8/108), 24.1% (26/108) and 12.0% (13/108) respectively. katG and rpoB mutations were observed more common among Beijing genotype MTB than among non-Beijing genotype MTB, 13.2% (32/243) and 4.6% (5/108) respectively, OR = 2.553, 95%CI: 1.031 - 6.324. The Beijing genotype MTB was more likely to be clustered than non-Beijing genotype MTB, 41.2% (100/243) and 11.1% (12/108) respectively, OR = 5.503, 95%CI: 2.851 - 10.622. CONCLUSIONS: In eastern rural China, TB patients infected with the Beijing genotype MTB may have a higher risk to develop isoniazid-or rifampin-resistance and multi-drug resistance. The disease is more likely due to recent transmission. PMID- 21781519 TI - [A survey on resistance to second-line drugs in patients with pulmonary tuberculosis in Shanghai, China]. AB - OBJECTIVE: To determine the pattern of resistance to second-line drugs (SLDs) in patients with tuberculosis (TB) in Shanghai, China. METHODS: All sputum culture positive patients detected at each district/county TB hospital/clinic in Shanghai during January to December 2009 were enrolled. First-line drug susceptibility testing was routinely performed for each clinical isolate. All clinical isolates with any resistance to first-line anti-TB drug were tested for second-line drug susceptibility. RESULTS: Of the 431 TB patients with any resistance to first-line anti-TB drugs included in this study, 27.8% (120/431) were resistant to any SLDs tested. The rank of drug resistance was as follows: ofloxacin (68/431, 15.8%) > kanamycin (37/431, 8.6%) > para-aminosalicylic acid (35/431, 8.1%) > capreomycin (28/431, 6.5%) > amikacin (23/431, 5.3%) > prothionamide (8/431, 1.9%). Mono resistance to SLD was the most predominant pattern. Among patients with resistance to SLD, the percentages of mono-resistance were 2/2, 20/36, 22/24 and 43/58 for rifampin-resistant group, isoniazid-resistant group, other-resistant group, and MDR group, respectively. CONCLUSION: The high prevalence of resistance to SLDs in TB patients suggests the necessity to strengthen the TB control program for drug-resistant TB in Shanghai. PMID- 21781520 TI - [Therapeutic efficacy analysis of bronchoscopic interventional therapy on severe tuberculous main bronchial stenosis complicated with unilateral atelectasis]. AB - OBJECTIVE: To observe the therapeutic efficacy of bronchoscopic interventional therapy on severe tuberculous main bronchial stenosis or atresia complicated with unilateral atelectasis. METHODS: Ninety patients with severe tuberculous main bronchial stenosis or atresia complicated with unilateral atelectasis, who had received bronchoscopic interventional therapy, were divided into group A and B according to whether stents had been implanted or not. Patients in group A had been treated with electrocautery, balloon dilatation and cryotherapy. Group B had been treated with metallic stent implantation on the basis of the above interventional management. In order to observe the effectiveness, the time needed for taking effect and restenosis rate were noted. The efficacy between patients with different disease courses, radiology, bronchoscopy and dyspnea index were evaluated before treatment and after the patients' conditions were stable. RESULTS: Three months after treatment, the good response rate and the total effective rate of group B were higher than those of group A, 97% vs 42% (chi(2) = 29.595, P < 0.05), 100% vs 81% (chi(2) = 6.060, P < 0.05), respectively. The time needed for taking effect in group B was significantly shorter than that in group A, 0.25 month vs 1.6 month. The dyspnea indexes of both groups were significantly improved after treatment, but the improvement of group B was more significant than that of group A (u = -2.478, P < 0.05). The disease course of patients with different therapeutic efficacy was evaluated, and the median disease course was 2 months in good response efficacy patients, 3.5 months in improved patients, and 5 months in ineffective patients; the difference being significant between ineffective and good response efficacy patients (u = -3.079, P < 0.01). The restenosis rate of group B was significantly higher than that of group A, 72% vs 32% (chi(2) = 9.090, P < 0.01). The median restenosis time was 4 months in group A, and 6 months in group B. Bronchoscopy follow-up 12 months after the initial effective treatment showed that the good response rate and the total effective rate of group B were better than those of group A, 60% vs 29% (chi(2) = 10.559, P < 0.01), 88% vs 60% (chi(2) = 10.261, P < 0.01, respectively), and the total effective rate of main bronchial atresia patients in group B was significantly higher than that in group A, 90% vs 50% (Fisher's exact test, P < 0.05). There was no significant difference in effectiveness between severe stenosis and atresia patients in group A and B. CONCLUSION: Electrocautery, balloon dilatation, cryotherapy and stent implantation were effective methods to treat severe tuberculous main bronchial stenosis or atresia complicated with unilateral atelectasis. Among them, the therapeutic efficacy was better and the symptoms improved more quickly in patients with stent implantation. The efficacy of stent implantation was better than that of conventional interventional therapy, but the incidence of restenosis was also higher. Following-up should be emphasized in this group of patients. Disease courses were associated with the therapeutic efficacy; longer disease course was related to worse therapeutic efficacy, and restenosis occurred earlier. So interventional therapy should be initiated earlier for bronchial tuberculosis with dyspnea, especially for that complicated by atelectasis. PMID- 21781521 TI - [Progress of cryorecanalization for airway disorders]. PMID- 21781522 TI - [Reciprocal regulation between microRNAs and DNA methylation in lung cancer]. PMID- 21781523 TI - [Clinical application of neurally adjusted ventilatory assist]. PMID- 21781524 TI - [Controversies and responses about anti-infection de-escalation therapy in clinical practice]. PMID- 21781525 TI - [Pay attention to comorbidities in chronic obstructive pulmonary disease]. PMID- 21781526 TI - [A pilot study of diaphragmatic function evaluated as predictors of weaning in chronic obstructive pulmonary disease patients]. AB - OBJECTIVE: To evaluate the predictive performance of neuro-mechanical coupling (NMC) and neuro-ventilatory coupling (NVC) in the weaning outcome in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sixteen patients were enrolled when the criteria for their first spontaneous breathing trial (SBT) was met. A 30-minute SBT was attempted, with the measurement of electrical activity of the diaphragm (Edi), NMC, NVC, NVC * NMC, index of rapid shallow breathing (f/Vt), airway occlusion pressure (P(0.1)) and f/Vt * P(0.1) at 0, 5 and 30 min. The receiver operating characteristic (ROC) curve was calculated to evaluate the predictive performance of each index. RESULTS: Successful weaning (S group) was observed in 6 patients while weaning failure (F group) in 10 patients. (1) The predictive capacity of Edi: at 30 min of SBT, Edi showed higher values in the F group (P < 0.05), the area under the ROC curves (AUC) was 0.817(P < 0.05). (2) The predictive capacity of NVC and NMC: at 5, 30 min of SBT, NVC and NMC showed higher values in the S group (P < 0.05); at 30 min of SBT NVC presented the largest AUC than any other time of SBT (0.822, P < 0.05), while the AUC of NMC was 0.800(P > 0.05). (3) The predictive capacity of NVC * NMC: at 30 min of SBT, the AUC of NVC * NMC was larger than NVC (0.864, P < 0.05), showing greater sensitivity (100.0%) and specificity (83.3%). (4) The predictive capacity of f/Vt and P(0.1): f/Vt and f/Vt * P(0.1) presented poor predictive performance in the failed patients. CONCLUSIONS: Edi, NVC and NVC * NMC were good predictor for the weaning outcome in patients with COPD. PMID- 21781527 TI - [Serum myostatin levels and malnutrition in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the prevalence and severity of malnutrition in patients with stable chronic obstructive pulmonary disease (COPD), analyze serum levels of myostatin, tumor necrosis factor alpha (TNFalpha) and C reactive protein (CRP), and investigate the relationship between serum myostatin and malnutrition in COPD. METHODS: Seventy-one patients with stable COPD and 60 age-matched healthy volunteers were recruited in this study. Pulmonary function was tested in all of the subjects and the severity of malnutrition was evaluated by a multiple parameter malnutritional index (MNI). Based on the MNI scores, patients with COPD were divided into group I (MNI >= 5 score) and group II (MNI < 5 score), the former represents the patients with severe or very severe malnutrition while the latter represents the patients with mild or without malnutrition. Serum concentration of myostatin, TNFalpha and CRP were measured by enzyme-linked immunosorbent assay. RESULTS: The MNI score was significantly elevated in patients with COPD [(7.75 +/- 3.86) score] compared with the controls [(1.13 +/- 0.96) score; P < 0.001], and 55 patients (77%) in COPD group I showed MNI >= 5 (9.30 +/- 3.01) score. Serum myostatin concentration was significantly elevated in COPD group I [(12.18 +/- 4.76) ug/L] than in COPD group II [(9.73 +/- 2.85) ug/L] and controls [(7.93 +/- 2.35) ug/L], with each P < 0.001. Serum TNFalpha concentration was also significantly elevated in patients with COPD compared with the controls (P < 0.001). Pearson correlation analysis showed that serum myostatin levels were significantly correlated with MNI scores (r = 0.438, P = 0.000) and TNFalpha levels (r = 0.234, P = 0.041) in COPD group (combined group I and II) while MNI scores were correlated inversely with BMI in COPD group (r = 0.530, P = 0.000). After stratified with subgroups, the correlation between myostatin levels and MNI scores was more significant and the correlation coefficient was higher (r = 0.464, P = 0.000) in COPD group I patients. Moreover, myostatin levels were inversely correlated with BMI (r = -0.287, P = 0.034) and forced expiratory volume in one second of the predicted value (r = -0.264, P = 0.049) in COPD group I patients. CONCLUSIONS: Malnutrition commonly and substantially exists in patients with COPD; serum myostatin concentration is significantly elevated and is correlated with the severity of malnutrition in the patients. The elevation of serum myostatin may contribute to malnutrition in COPD patients. PMID- 21781528 TI - [The correlation between chemotherapeutic efficacy and breast cancer susceptibility gene 1 and class IIIbeta-tubulin protein expression in non-small cell lung cancer patients]. AB - OBJECTIVE: To investigate the predictive value of breast cancer susceptibility gene 1 (BRCA1) and class IIIbeta-tubulin protein expression in tumor tissue for the efficacy of taxol and cisplatin combined chemotherapy (TP) in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. METHODS: A total of 92 stage IIIB/IV NSCLC patients were recruited with 87 patients evaluated. Bronchoscopy or lung puncture tumor biopsy samples were obtained with BRCA1 and class IIIbeta-tubulin protein expression examined immunohistochemically before chemotherapy. The patients were randomly assigned to be received 4 to 6 cycles of TP chemotherapy regiments and followed up until death or lost. Response rate (RR), overall survival (OS) and time to tumor progression (TTP) were assessed. RESULTS: Among the 87 evaluated patients, the positive expression rates of BRCA1 and class IIIbeta-tubulin were 57.5% (50/87) and 48.3% (42/87) respectively. There was no significant difference in clinical characteristics among patients with different positive expression rate. According to different expression of BRCA1 and class IIIbeta-tubulin, the patients were divided into four groups: group A (low expression of both BRCA1 and class IIIbeta-tubulin), group B (high expression of both BRCA1 and class IIIbeta-tubulin), group C (high expression of only BRCA1) and group D (high expression of only class IIIbeta-tubulin). The RR was higher in group A than other three groups (60.7%, 34.8%, 9/19 and 6/17 respectively). The OS and TTP were longer in group A than other three groups [OS: (539.4 +/- 17.6) days, (267.2 +/- 20.5) days, (325.6 +/- 24.1) days and (283.7 +/- 26.2) days respectively; TTP: (256.9 +/- 28.4) days, (143.8 +/- 17.6) days, (179.3 +/- 19.8) days and (152.6 +/- 23.5) days respectively]. There were no significant differences among the other three groups. CONCLUSIONS: The expression level of BRCA1 and class IIIbeta-tubulin in tumor tissue is probably a predictor for the efficacy of TP chemotherapy in NSCLC patients. TP chemotherapy is more suitable for the NSCLC patients with lower expression of both BRCA1 and class IIIbeta tubulin. Our study may provide a new sight for tailored chemotherapy in NSCLC patients. PMID- 21781529 TI - [The disease characteristics and risk factors of type 2 diabetes mellitus in pedigrees]. AB - OBJECTIVE: To explore the characteristics and risk factors of type 2 diabetes mellitus (T2DM) onset in pedigrees. METHODS: A total of 865 subjects were screened and diagnosed by oral glucose tolerance test (OGTT) based on American Diabetes Association (ADA) criteria. Type 1 diabetes mellitus (T1DM), maturity onset diabetes of the young (MODY) and chondriosome diabetes were excluded by clinical features and laboratory test of insulin and autoantibodies including glutamic acid decarboxylase antibody, insular cellular antibody and insulin autoantibody. A total of 182 pedigrees of T2DM were obtained. RESULTS: No gender difference was found in the prevalence of T2DM (42.59% in male and 48.18% in female respectively, P > 0.05), nor was the newly diagnosed rate (9.89% in male and 11.82% in female, P > 0.05). The onset age was (63.3 +/- 12.4) years old in the first generation [(64.4 +/- 12.5) years in male and (62.3 +/- 10.3) years in female], (47.1 +/- 8.7) years old in the second generation [(48.2 +/- 9.3) years in male and (46.1 +/- 8.1) years in female], (29.6 +/- 10.2) years old in the third generation [(28.9 +/- 9.5) years in male and (30.0 +/- 10.4) years in female]. Compared with normal glucose tolerance (NGT) subjects, newly diagnosed T2DM and impaired glucose regulation (IGR) subjects had higher prevalence of hypertension, hyperlipidemia and smoking but less physical activities. Statistical differences were shown in body weight five years before diagnosis, one years before diagnosis and at diagnosis in newly diagnosed T2DM [(68.4 +/- 12.4) kg, (69.5 +/- 11.0) kg and (69.1 +/- 9.6) kg] and IGR [(66.1 +/- 10.7) kg, (65.9 +/- 10.7) kg and (65.7 +/- 10.4) kg], when compared with NGT [(61.0 +/- 10.2) kg, (59.5 +/- 11.0) kg and (60.1 +/- 10.4) kg, all P < 0.05]. The same results were obtained with waist circumference and waist-hip ratio [(4.1 +/- 12.5) cm and 0.92 +/- 0.36 in newly diagnosed T2DM while (89.1 +/- 10.7) cm and 0.90 +/- 0.64 in IGR], when compared with NGT [(82.5 +/- 10.1) cm and 0.82 +/- 0.25], all P < 0.05. CONCLUSIONS: No gender difference was found in the onset characteristics of T2DM. High prevalence of obesity, hypertension, hyperlipidemia and smoking with less physical activities were associated with T2DM. PMID- 21781530 TI - [The efficacy and safety of transradial versus transfemoral approach for percutaneous coronary intervention in acute myocardial infarction]. AB - OBJECTIVES: To compare the safety and efficacy of radial artery access versus femoral artery access for percutaneous coronary intervention in acute myocardial infarction population. METHODS: From June 2004 to December 2006, 446 patients with acute myocardial infarction treated with percutaneous stenting were reviewed retrospectively. The radial artery approach was used in 242 patients, and the femoral artery approach in 204 patients. The success of the procedure, procedure duration, X-ray exposition, volume of contrast, incidence of major adverse cardiac events and complications were compared between the radial artery and femoral artery approach. RESULTS: Total procedure duration, X-ray exposition, the immediate success of the procedure and the proportion of patients with reperfusion time above 60min are higher in patients with radial artery acess than that with femoral artery access [(62.1 +/- 23.4) min vs (56.8 +/- 16.7) min, (2829.4 +/- 1365.2) mGY vs (2352.3 +/- 903.1) mGY, 4% vs 0.9% and 7.44% vs 2.94% respectively, all P < 0.05]. CONCLUSIONS: In non-selected patients with acute myocardial infarction treated with primary stent implantation, the success rate of the radial artery approach is lower than the femoral artery approach and could prolong the reperfusion time. It is suitable to change artery access immediately if abnormality is found via radial artery access. PMID- 21781531 TI - [The evaluation of left ventricular diastolic function by tissue Doppler echocardiography in essential hypertension]. AB - OBJECTIVE: To evaluate Left ventricular(LV) diastolic function in essential hypertension by conventional pulse-wave Doppler echocardiography (cPWD) and Doppler tissue imaging (DTI) and compare the two modalities. METHODS: Two hundred patients with essential hypertension were classified as NLVH subgroup (n = 160) and LVH subgroup (n = 40) based on left ventricular mass index (LVMI) with one hundred and sixty health subjects as control group. The mitral valve flow pattern (MVFP) was obtained.Early diastolic (E) and late velocities (A) were measured and E/A was calculated. DTI was used to obtain the left ventricular lateral wall early diastolic mitral annulus velocity (Em) and E/Em was calculated. RESULTS: Essential hypertension patients had LV diastolic dysfunction both by cPWD (higher E and lower E/A ratio) and DTI (lower Em and higher E/Em ratio) compared with healthy subjects [E: (0.88 +/- 0.18) cm/s vs (0.76 +/- 0.19) cm/s; E/A ratio: 0.86 +/- 0.28 vs 1.02 +/- 0.38; Em: (9.4 +/- 2.8) cm/s vs (11.9 +/- 3.8) cm/s; E/Em ratio: 7.9 +/- 2.7 vs 6.0 +/- 1.8: with all P value < 0.01]. Em was significantly reduced and E/Em was significantly elevated in LVH subgroup than NLVH subgroup [Em: (7.7 +/- 2.6) cm/s vs (9.9 +/- 2.8) cm/s, E/Em:9.6 +/- 3.6 vs 7.4 +/- 2.4, P < 0.05]. No significant difference was found in A and E/A between these two subgroups [(0.90 +/- 0.22) cm/s vs (0.87 +/- 0.17) cm/s; 0.80 +/- 0.34 vs 0.88 +/- 0.28, P > 0.05]. CONCLUSIONS: cPWD and DTI both had implications to detect diastolic dysfunction in non-hypertrophic stage hypertension. Em, E/Em could be more sensitive and precise to reflect the impairment of diastolic function in the progress of hypertension. PMID- 21781532 TI - [A comparative study of CT virtual endoscopy imaging and pathologies of lower alimentary tract mesenchymal tumors]. AB - OBJECTIVE: To study the pathological and immunohistochemical features of alimentary tract mesenchymal tumors and compare with computed tomographic virtue endoscopy (CTVE) imaging technology to evaluate the diagnostic value of CTVE in alimentary tract mesenchymal tumors. METHODS: Seventy-four pathological specimens of alimentary tract mesenchymal tumors were collected. The pathological features and the expression of CD(117), CD(34), SMA and S-100 were observed by immunohistochemical method with light microscope. The pathological types and characteristics were determined by pathologists and compared with CTVE imaging technology. RESULTS: In the 74 cases of alimentary tract mesenchymal tumors, 40 cases were diagnosed as stromal tumor with pathological and immunohistochemical methods(54.1%). Sixteen of them were malignant, accounting for 40% of the stromal tumor while 33 cases were diagnosed as leiomyoma (44.6%) and 1 case as schwannoma (1.4%). In the 74 GIMTs cases, 33 were jejunum GIMTs, 21 were ileum GIMTs and 20 were large intestine GIMTs. Immunohistochemistry assay in the 74 GIMTs cases showed that 51.4% GIMTs were positive for CD(117), approximately 36.5% were positive for CD(34), 62.2% were positive for smooth-muscle actin (SMA) and 1.4% were positive for S-100 protein. In the 74 GIMTs cases, 69 cases were diagnosed right in the accuracy for location with CTVE (93.2%) with 51 cases in small intestinal (94.4%) and 18 cases in large intestinal (90.0%). The sensitivity and the specificity of CTVE to distinguish benign from malignant stromal tumors by CTVE characteristics were 84.2% and 85.7% respectively. CONCLUSIONS: GIST is common in GIMTs and is often originated from the small intestinal. The immunohistochemistry has great value in diagnosing alimentary tract mesenchymal tumors. The CTVE imaging technology also has great value in diagnosing alimentary tract mesenchymal tumors which can show the localization, shape size and artery of the tumor clearly. The diagnostic sensitivity and specificity of CTVE are high to distinguish benign from malignant alimentary tract GISTs. CTVE plays an important role in guiding the clinical management of GISTs. PMID- 21781533 TI - [The efficacy and safety of second allogeneic hematopoietic stem cell transplantation for post-transplant hematologic malignancies relapse]. AB - OBJECTIVE: To investigate the safety and efficacy of second allogeneic hematopoietic stem cell transplantation for the relapsed hematologic malignancies. METHODS: The data of 25 relapsed patients received the second allogeneic transplantation as a salvage therapy in Institute of Hematology Peking University between October 1999 and March 2010 were analyzed retrospectively. Twenty-four patients relapsed at 8.8 (1 - 55) months after the first transplantation, except one received the second transplantation as prophylaxis therapy. They received the second transplantation after 3 (0.3 - 20) months' therapy. The median time between the 2 transplants was 10.6 (0.6 - 59.0) months. RESULTS: Most of the patients were given the conditioning regimen including total body irradiation (TBI, 700 - 779 cGy) or modified busulfan and cyclophosphamide (BUCY, BU 12 mg). All patients survived more than 30 days and achieved sustained white blood cell engraftment. Sinus obstructive syndrome, irradiation dermatitis and acute myocardial infraction were occurred in 3 patients and recoverable. Until January 31 in 2011, with a median observation period of 9.1 (2.0 - 131.1) months, 8 patients had been living with a overall survival (OS) of 30.9%. Twelve patients relapsed at a median 4.4 months and 10 died of it. The other 7 patients died of transplant related complications. The non-relapsed mortality was 35.1%. The disease status at the 2nd transplantation was the only factor which effected the OS (P = 0.009). CONCLUSIONS: The second allogeneic transplantation is a viable option for patients relapsing after the first transplantation. Reduced intensive conditioning regimen ensures the graft engraftment and reduces transplant related toxicity. PMID- 21781534 TI - [The effects of donor peripheral blood stem cell infusion in the prevention of relapse in high risk leukemia after haplotype hematopoietic stem cell transplantation]. AB - OBJECTIVE: To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation (HSCT), as well as its therapeutic effect and safety. METHODS: G CSF was given at 5 - 10 ug*kg(-1)*d(-1) to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT, and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graft-versus-host disease (GVHD), relapse rate of high risk leukemia and long-term survival were evaluate after PBSC infusion. RESULTS: A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12 - 60) months, 4 of them were >= degree III. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted, and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML), 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52.5%. CONCLUSION: The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia. PMID- 21781535 TI - [The clinical characteristics of early-onset versus late-onset types of myasthenia gravis]. AB - OBJECTIVE: To compare the clinical characteristics of early-onset and late-onset myasthenia gravis (MG). METHODS: A total of 819 MG patients admitted in our department during the same period were reviewed retrospectively. The patients with MG were divided into two groups by the age of onset, which were the early onset MG (< 49 years) and late-onset MG (>= 50 years). Several clinical features were compared in the two groups including the percentage, initial symptoms, MG types, the positive rates of neostigmine test and repetitive nerve stimulation, thyroid function and thymic abnormalities. RESULTS: The more common onset age of MG was 0 - 49 years (early-onset). In both groups the male and female ratio was closer to 1:1 with the extra ocular muscles weakness presented as the most frequent symptom and Type IIB presented as the most common type in both groups (41.51% and 51.37% respectively in early-onset and late-onset groups). Type I was more common in early-onset group while type IIB was more common in late-onset group (P < 0.05). There was no significant difference in the positive rates of neostigmine test and repetitive nerve stimulation between the two groups. The thyroid function abnormality ratio was higher in early-onset group. Hyperplastic thymus was common in early-onset group (67.57%) while both hyperplastic thymus and thymoma were common in late-onset group (48.68% and 47.37%). CONCLUSIONS: The clinical characteristics of early-onset and late-onset myasthenia gravis (MG) was different in MG type, the positive rate of thyroid function abnormalities and thymic pathologic type. PMID- 21781536 TI - [A meta analysis of tumor necrosis factor alpha blockers therapy for ulcerative colitis]. AB - OBJECTIVE: To pool the data of studies and evaluate the efficacy and safety of TNFalpha blocking agents in the treatment of ulcerative colitis (UC). METHODS: The randomized clinical trials (RCT) that compared the efficacy or safety of TNFalpha in the treatment of UC were researched from Pubmed, OVID, EMBASE, Cochrane library, CNKI, Wanfang data and VIP Chinese Scientific and Technologic Periodical Database. Statistical heterogeneity between trials was evaluated by Revman 5.0 and was considered to exist when P < 0.1. Heterogeneity of the included articles was tested, which was used to select proper effect model to calculate. Publication bias was investigated through visual inspection of funnel plots. RESULTS: Nine RCT including 1226 cases were analyzed. Eight hundred and six cases had received TNFalpha treatment and 420 cases had received placebo or glucocorticoid treatment. Compared with placebo or glucocorticoid groups, TNFalpha group achieved significantly higher rates of short-term clinical response, short-term clinical remission, long-term clinical response, long-term clinical remission and the total OR were 2.36 (95%CI 1.34 - 4.15), 2.42 (95%CI 1.22 - 4.81), 3.22 (95%CI 2.28 - 4.55) and 2.82 (95%CI 1.91 - 4.16) respectively. TNFalpha group was less likely to undergo colectomy than placebo group and the total OR was 0.31 (95%CI 0.20 - 0.48). TNFalpha could not improve the mucosal healing and quality of life. No significant difference was found in adverse effect between TNFalpha group and placebo or glucocorticoid group (OR = 1.07 (95%CI 0.55 - 2.09, P = 0.84)). The rate of serious adverse effect in TNFalpha group was less than placebo or glucocorticoid groups (OR = 0.65, 95%CI 0.48 - 0.89, P = 0.007). Inspection of the funnel plots for all dichotomous data measures had not revealed evidence of publication bias. CONCLUSIONS: Patients with moderately to severely active UC treated with TNFalpha have effective clinical response and clinical remission and are less likely to undergo colectomy than those receiving placebo or glucocorticoid. TNFalpha treatment is safe for UC but can not improve the mucosal healing and quality of life. Large-scale, high quality RCTs are needed to confirm or refuse the available evidence. PMID- 21781537 TI - [The expression and role of Toll receptor 4 in renal tubular epithelial cells in hepatitis B virus infection]. AB - OBJECTIVE: To explore the expression and role of Toll receptor 4 (TLR4) in human proximal tubular epithelial cell line HK-2, infected by HBV. METHODS: The serum of HBV DNA copies between 10(7) - 10(8)/ml was collected. Before and after infected by HBV DNA positive serum, the HK-2 cells' morphology and the expression of alpha-smooth muscle actin (alpha-SMA) were observed by microscopy and immunofluorescence, and the effects of different concentrations of lipopolysaccharides (LPS, TLR4-stimulating factor) and CLI-095 (TLR4 Inhibitor) on the proliferation rate of HK-2 cells were observed by MTT assays. After HBV serum and 10 ug/ml LPS and 5 ul/ml CLI-095 acted on HK-2 cells, TLR4 protein expression was measured by immunofluorescence and Western-blotting assay, and HBsAg and HBeAg in cell culture medium were detected by ELISA, and HBV DNA copies by fluorescence quantitative PCR. RESULTS: The longer HBV infected HK-2 cells, the more irregular of the cells' shape, the fewer number of the cells were left. But compared with HBV infected after 24 hours, alpha-SMA was more expressed after HBV infected 12 hours.After infected by HBV serum in 24 hours, HK-2 cells' proliferation rate was positively correlation in a dose range of LPS, but was negatively correlated with the CLI-095 (P < 0.05). The levels of HBsAg and HBeAg in cell culture medium were largest when the LPS concentration was at 10 ug/ml and CLI-095 at 5 ug/ml. The expression of TLR4 significantly increased in HK-2 cells treated with LPS compared with those with CLI-095, but HBV DNA levels and HBsAg and HBeAg expression levels were lower. CONCLUSIONS: HBV infection may promote cell transdifferentiation and cell injury. The stimulation of HK-2 infected with HBV by LPS may upregulate the expression of TLR4 and reduce the copies of HBV DNA. PMID- 21781538 TI - ["Qi-Huang" Culture in the context of anthropological perspective of medicine and health]. AB - The survey of the two Chinese characters "(qi)(huang)" from the perspective of anthropology of medicine and health show that the words represent a variety of meanings. All the TCM related contents, such as physicians, medical works and official position of medicine etc. can be represented by the word. "Qi-huang" culture contained the relevant medical works and the physicians who handed down Chinese medicine, such as Qibo, Bogao, Shaoshi, Leigong, Rongcheng etc., and the contents are more abundant. Previously, less study concerned the historical relics spread extensively in Xinmi City, Henan Province, such as Qibo Shan, Limu Tai, Fenghou Ding etc. "Qi-huang" culture not only remained in the history, but also are living vividly in the present medical civilization. "Qi-huang" culture is not confined within China, but has been spread to the whole world. PMID- 21781539 TI - [Survey on Qibo and his anecdotes]. AB - As an ancient physician, the name of Qibo was firstly found in Hung Di Nei Jing (Huangdi's internal canon). In official history, his name was firstly recorded in Shi Ji (Historical Records) by Si Maqian. According to the records in Tong Zhi and Lu Shi, Qibo might be a tribe headman being aware of medicine and health preservation in the period of three emperors. Ancient Qibo tribe located at the foot of Qishan in Shanxi Province. Qibo and his tribes lived in Zhouyuan at the foot of Qishan. During Huangdi's travel to the west, he guided Qibo and his tribe to Xinmi, Henan Province. According to Suwen and Lushi, Qibo studied medicine from an ancient famous physician, Jiudaiji. According to the forward of Dian Huang Di Ba Shi Yi Nan Jing by Wang Bo, it can be known that Nan Jing was handed down by Qibo to the latter generations. Except Nan Jing, the Huang Di Nei Jing, Huang Di Wai Jing, Huang Di Tai Su, Huang Di Qi Bo An Mo Jing, Qi Bo Zhen Jing, Qi Bo Jing Zang Lun, Huang Di Zong Nan Jing were also medical treatises written by Qibo. PMID- 21781540 TI - [On Qi-huang culture]. AB - Qi-Huang is a short name for TCM, Qi-huang culture, i.e. the culture of TCM. The textual investigation on Qibo's biography and his cadastral records, as well as his contribution to life science is the key to clarify the cultural origins of TCM. Lacking of historical data, the study on Qibo is difficult to be extended profoundly. It is necessary to cut in from the aspect of culture and start field study. According to the historical records and the cultural relics discovered and unearthed, the fragment of Qibo's life was explored. It is thought that Xinmi is one of the important origins of Qi-huang culture. So it is important to grasp the concept of culture to expound and extend the Qi-huang culture, as well as extract the figures of the culture, all these are so important to study Qibo. PMID- 21781541 TI - [Xuanyuan Qiu and Qi-huang relics around]. AB - Related archaeological research shows that the ancient stockade located in Fanzhuang Village, Quliang County, Xinmi City, Henan Province, is a Longshan Culture Site, which is conformed with the records about Xuanyuan Qiu in the historical materials. The time of Huangdi was equivalent to the early and middle period of Longshan culture. The ancient city of the stockade was at the Longshan culture period. Around Xuanyuan Qiu, large amount of Qi-huang relics were remained, such as, Juci Shan, Qibo Shan, Xitai Shan, Fenghou Ling, that were related to the ancient physicians Qibo, Guiquyu and Leigong etc. The place can be called the origin of TCM. PMID- 21781542 TI - [Xinmi, the cradle of TCM culture]. AB - As recorded in the history, Xinmi was surrounded by mountains and near Zhen and Wei rivers, where was of a very good living environment for ancient human being. Historical records and relics showed a successive development of culture from the period of three emperors, five kings to Xia, Shang and Zhou Dynasties. Nowadays, historical relics of medical saints in terms of Huangdi, Qibo, Fuxi, Leigong were preserved. So Xinmi can be called the cradle of TCM. PMID- 21781543 TI - [Ancient medical cultural and historical sites in Xinmi]. AB - Fuxi in the period of the three great emperors and Yandi, Huangdi, Zhurong in the period of five emperors had set their capitals in Xinmi in Henan Province, so did Kuai State and Mi State in Western Zhou Dynasty, as well as Zheng State in Spring Autumn Period. Large amount of culture relics of medicine were preserved. It can be deduced through the relics that Xinmi is one of the headstream of Chinese medicine. We should fully develop and utilize the Qi-huang culture resources in Xinmi to serve the development of the economy, culture and health care system in Xinmi. PMID- 21781544 TI - [On figures of Xinmi medical culture]. AB - Fuxi used to made "the nine needles", "taste hundreds of herbs", who was respectfully named after the ancestor of Chinese medicine. Abundant historical relics and folk culture were preserved in Xinmi, Henan. Compare to other regions in China, Fuxi culture in Xinmi is characterized by primitiveness, individualism, diversity, inheritability and civilite. PMID- 21781545 TI - [Human body structure in Su Wen]. AB - The ancient medical book Su Wen states that the human is a dual composition of physical and spiritual bodies. Thus, if only physical perspectives were applied to interpret its medical terms, confusion would result because of the misunderstanding of spiritual terms. The descriptions in Su Wen didn't show a complete anatomy system or at least at organ levels. The fragments of its context revealed proofs of gross anatomical studies with measurement in ancient China. Su Wen was not a special work for the circulatory route of the channels, so the anatomy terms used was simple. The anatomy position of the body couldn't be judged. The elementary superficial anatomy system formed, which can be traced from the superficial anatomy locations expounded in the book. PMID- 21781546 TI - [Textural research on the initiator of "new contracted warm disease"]. AB - Most scholars of the contemporary age thought that WANG Ji was the initiator of "new contracted warm disease". But no evidence was found in Shang Han Xuan Lu to support the viewpoint. New contracted warm disease was not mentioned in the book, even without significant narratives. It is the wrong quotation of Shang Han Xuan Lu by HE Lianchen in his book Chong Ding Guang Wen Re Lun, which is the root cause of the incorrect viewpoint. Therefore, the wrong statement spread among scholars. Actually, GUO Yong had proposed the theory of "new contracted warm disease" in the Southern Song Dynasty. This wrong statement should be corrected. PMID- 21781547 TI - [Development of Zhu Gong' thought on cold pathogenic diseases from Shanghan Baiwen to Huorenshu]. AB - Huorenshu (The Book of Huoren) is a famous work by physician Zhu Gong in Song Dynasty. Its early edition named Shanghan Baiwen (One Hundred Questions on Cold Pathogenic Diseases). It was reedited and printed for many times. The two early editions now exist are Shanghan Baiwen Jingluotu (One Hundred Questions on Cold Pathogenic Diseases and Meridian-collateral Diagram) printed in Yuan Dynasty and Chongjiaozheng Huorenshu (Corrected edition of Huorenshu) printed in Song Dynasty. Compared with the two editions, there are plenty of additions and deletions. These changes consider the convenience of searching, and reflect the development of Zhu Gong' thought on cold pathogenic diseases, though which implies the trend of development on Cold Pathogenic Diseases study during later Northern Song Dynasty. PMID- 21781548 TI - [Influence of "danxi theory" in Korea and Japan]. AB - "Danxi Theory" had deep influence on the traditional medicine in Korea and Japan. In Korea, the compilation of Yi Fang Lei Ju and Dong Yi Bao Jian referred to the medical works of ZHU Danxi and that of his students, the Korean doctors advocated the theory of ZHU Danxi's theory of "four injuries by qi, blood, phlegm and stagnation", and quoted large number of formulas and herbs from Dangxi's works into the above books. In Japan, Tashiro Sanki had came to China and studied medicine from Japanese monk Yue Hu, who was the disciple of YU Tianmin (a private disciple of ZHU Danxi). After returned to Japan he energetically initiated Danxi's theory and classified diseases to blood disease, qi disease and phlegm disease (water toxin) according to Danxi's theory of "four injuries by qi, blood, phlegm and stagnation". His student Manase Dosan set up a "Danxi Society" and spread Danxi Theory in Japan and therefore the unique medical system "Gose Ha shcool" was formed. His student Manase Gensaku, and Manase Gensaku's students Okamoto Genya, Nagasawa Doju and Hurubayashi Kengi spread and developed Danxi Theory, hich was popular in Japan for more than 200 years. It was proved that Danxi Theory had deep and far influence on the formation and development of overseas traditional medicine in Korea and Japan. PMID- 21781549 TI - [Developmental History of laparoscopic liver resection]. AB - Since 1991, the first laparoscopic liver resection (LLR) was reported by Reich, LLR had been applied and improved by different scholars like Wayand (1993), Ferzli (1995), Cherqui (2002), Descottes (2003). Zhou Weiping reported the first LLR in China in 1994. In 2004, after ten years development, LLR became more and more mature and international exchange happens. In 2006, indication and contraindications of LLR were formulated internationally, which promote the application and spread of LLR, especially after 2007. The advantages of LLR include minimal invasion, faster recovery and less complications, but shortages still exist, and the improvements relies on development of related techniques in terms of Laparoscopic ultrasound, LUS, liver dissecting sealer, electrocoagulation electrotome, parenchymatous organ dissection and in vitro simulator. Therefore LLR can get new progress. PMID- 21781550 TI - [Investigation on bookstore block-printed editions of Zheng He Ben Cao in Ming Dynasty]. AB - Many editions of Zheng He Ben Cao was published in Ming Dynasty. The bookstore block-printed editions recorded are Liu's Rixintang Edition in Zhengde year 14 (1519 AD), Yangxianchun Gui Renzai Edition and Jinling Tang's Fuchuntang Edition in Wanli year 6 (1578 AD). Rixintang Edition took Chenghua year 4 (1478 AD) Edition as source text and inherited the mistakes too. Guirenzai Version took Rixintang Version as source text, thereafter, Fuchuntang version took Guirenzai Version. Errors, missing, rough collation handed down from one version to another, thus in Fuchuntang Version, mistakes jumped out on each page. In order to attract more buyers, the bookstores erase the name Chong Xiu Zheng He Jing Shi Zheng Lei Bei Yong Ben Cao and change the name to Da Guan Ben Cao Gang Mu Quan Shu or Da Guan Ben Cao. PMID- 21781551 TI - [Zhao Kaimei, a outstanding bibliographer]. AB - Zhao Kaimei is a famous bibliographer in Ming Dynasty, who preserved and sorted Gu Jin Za Ju, carved a new plate for Song Ban Shang Han Lun. Scholars in Ming Qing Dynasties set a value on his contributions to preserve and inherit traditional culture of China. Qian Qianyi in Ming Dynasty drafted Zhao Kaimei's memorial tablet of gravestone, which open a window to know about Zhao Kaimei thoroughly. At the end of Qing Dynasty, Sun Yuxiu wrote Mai Wang Guan Shu Mu Ba that provided important information about the procedure of writing Zhao Kaimei's bibliography, the figures of the content, as well as the copiers. Mori Tachiyuki found that Qimei is Zhao Kaimei's first name in his old age. PMID- 21781552 TI - [Enhance the reconstruction skill in head and neck surgery and care for the quality of life]. PMID- 21781553 TI - [Repair and functional reconstruction in treatment of head and neck tissue defect]. PMID- 21781554 TI - [Reconstruction of oral and maxillofacial defects in the last three decades]. PMID- 21781555 TI - [Rehabilitation by hollow obturator prosthesis immediately after total maxillectomy for malignant tumor]. AB - OBJECTIVE: The feasibility and clinical effects of hollow obturator prosthesis for the repair of maxillofacial defect immediately after maxillectomy for cancer were assessed. METHODS: Thirteen patients with T3-4aN0M0 maxillary neoplasm were treated by the prostheses immediately after maxillectomy. According to the 3D-CT reconstruction of nasal sinus, the 3D stereoscopic prototype was constructed before the surgery. Simulating surgery with Surgicare 5.0 software and then the prosthesis 3D stereoscopic model was shaped. The prosthesis was made quickly and precisely with methacrylate resins according to the model and the print mold before surgery, with supplementary tooth at the bottom of prosthesis. In the surgery, the prosthesis was installed instantly after maxillectomy. The patients were followed up at 1, 3 and 6 month after the surgery, respectively. The facial features and the pronunciation clarity were examined and the questionnaires were carried out in the patients, with comparation by paired t-test. The hollow obturator prosthesis would be replaced by permanent prosthesis made of methacrylate resins at 6 month after the surgery. RESULTS: The hollow obturator prostheses were installed accurately and maxillofacial defects were repaired immediately after maxillectomy in the 13 patients. Postoperative follow-up showed there were significant differences in eyeball sagging (t = 4.67, P < 0.05), mid facial region collapse (t = 5.67, P < 0.05), and pronunciation clarity (t = 16.38, P < 0.05) between patients with and without prostheses. Questionnaires showed that all the patients were satisfied with the retention of prostheses, the improvement of appearance, the improvement of the symptom of water choking and speech definition. Six months after the surgery, the hollow obturator prostheses were replaced smoothly by permanent prostheses in 11 of the 13 patients. CONCLUSION: The precise and instant repair of maxillofacial defect by prosthesis after maxillectomy can improve survival quality of patient. PMID- 21781556 TI - [Microvascular free flap reconstructive options in patients with different types of maxillectomy defects]. AB - OBJECTIVE: To evaluate the efficacy of the distinct free flaps in reconstruction of different types of maxillectomy defects. METHODS: A retrospective reviews was performed of in 66 consecutive cases of reconstructions with free flaps for maxillary tumor ablation defects from October 1997 to June 2010. There were 43 patients who had recurrences after previous operations and 46 patients had accepted radiation therapy before. According to the classification of Brown's maxilla defect:10 cases were in class I, 13 in class II, 23 in class III and 20 in class IV. The reconstructive free flaps included 26 fibula flaps, 10 radial forearm flaps, 7 latissimus dorsi flaps, 7 rectus abdominis flaps, 7 anterolateral thigh perforator flaps, 5 deep inferior epigastric artery perforators, 2 latissimus dorsi/rib flaps and 2 iliac crest flaps. Postoperative features and functions were assessed in 29 patients. RESULTS: The overall free flap success rate was 93.9% (62/66). Three rectus abdominis flaps and one fibula flap failed. There were 29 patients who received postoperative function assessment. Sixty-two percent of the patients restored to taking regular diets, 24 (82.8%) patients had normal language communication ability, and 25 (86.2%) patients were satisfied with their feature. CONCLUSIONS: Radial forearm flap was recommended to reconstruct the class 1 defect, fibula flap to class 2 or class 3 and preformatted flap to class 4. PMID- 21781557 TI - [Reconstruction of hypopharyngeal circumferential and cervical esophageal defects with free jejunal interposition in 112 cases]. AB - OBJECTIVE: To investigate the results of reconstruction of hypopharyngeal circumferential and cervical esophageal defects with free jejunal transfer. METHODS: Retrospective review of 112 patients who underwent pharyngoesophageal reconstruction with free jejunal interposition. Analysis was confined to the patients with advanced hypopharyngeal, esophageal or recurrent laryngeal squamous cell cancer. Kaplan-Meier method was used to identify the accumulative survival rate. RESULTS: The free jejunal success rate was 94.6% (106/112). The pharyngocutaneous fistula rate and anastomoses narrow rate were 8.9% (10/112) and 12.5% (12/96) respectively. The perioperative mortality rate was 1.8% (2/112). Except 1 case of dead, 6 cases with flap failure and 2 cases with laryngeal preservation, other 103 cases had resumed oral feeding. CONCLUSIONS: The success rate of free jejunal transplantation is high and free jejunal interposition is an ideal reconstruction method for patients who have hypopharyngeal circumferential and cervical esophageal defects after tumor resection. PMID- 21781558 TI - [Application of free anterolateral thigh flap in head and neck surgery]. AB - OBJECTIVE: To evaluate the results of reconstruction by free anterolateral thigh flaps (ALT) after operation of head and neck tumors. METHODS: Forty-three cases underwent the reconstruction of postoperative defects with free anterolateral thigh flaps after head and neck cancer surgeries between November 2007 and June 2010 were reviewed. Ages of the patients ranged from 40 to 81 years, with a median of 56 years; 32 males and 11 females; 23 cases of oral carcinoma, 7 cases of tonsil carcinoma, 11 cases of hypopharyngeal carcinoma, and 2 cases of head skin cancer. TNM classified as follows: no case of distant metastasis; T1 9 cases; T2 17 cases; T3 11 cases; T4 6 cases. All patients were applied with ALT to restore swallowing and respiratory functions. The mean length of blood vessel pedicles of the ALT free flaps was 12.5 (8 - 18) cm. The flaps were 4 - 15 cm in width, 5 - 25 cm in length. RESULTS: In the 43 cases applied with ALT free flaps, 40 cases were successful and 3 cases unsuccessful. Two of the failed cases were reconstructed with pectoralis major flap. In 11 cases of hypopharyngeal carcinoma, except 3 cases with total laryngectomy, 8 cases (72.7%) had their laryngeal function been preserved. CONCLUSIONS: The successful rate of ALT free flaps is perfect. There were no serious complication in offered areas. The flap could be shaped into various forms. ALT free flap is an ideal flap to reconstruct the defect after surgery in some head and neck tumors. PMID- 21781559 TI - [Subjective visual horizontal in peripheral unilateral vestibular dysfunction]. AB - OBJECTIVE: To analyze the characteristics of subjective visual horizontal (SVH) and evaluate its clinical value for vestibular function in peripheral unilateral vestibular hypofunction (UVH). METHODS: Eighty-five patients with UVH (study group) and 39 normal persons (control group) accepted vestibular function tests, including SVH, subjective visual vertical (SVV) and caloric test by video nystagmography. The parameters of the angle of SVH and SVV, directional preponderance (DP) and unilateral weakness (UW) of caloric test were observed. The correlation between SVH/SVV, DP, UW and the course of disease were investigated respectively. SPSS 16.0 software was used to analyze the data. RESULTS: Reference range of SVH and SVV was from -2 degrees to 2 degrees in the control group. Among the 85 patients, 46 cases (54.1%) and 43 cases (50.6%) had the abnormal values of SVH and SVV respectively, with no statistical significance (chi(2) = 12.5, P = 0.481) by chi square test. Fifty-five cases (64.7%) with abnormal DP had no statistical significance when compared with SVH and SVV respectively (chi(2) values were 0.19 and 2.86, respectively, P value were 0.164, 0.067, respectively). In UVH, there were positive correlation between SVH, SVV and DP (r value was 0.939, 0.648, 0.658, all P < 0.05) respectively, but no correlation between UW and SVH or SVV (r value was 0.048, 0.085, all P > 0.05). According to the permutation and combination of the four parameters, positive or negative, three main groups could be defined [SVH(+)DP(+)UW(+), SVH(-)DP(+)UW(+), SVH(-)DP(-)UW(+); SVV(+)DP(+)UW(+), SVV(-)DP(+)UW(+), SVV(-)DP(-)UW(+)]. The course of disease in the three main groups was positively skewed distribution, with median of 5.0, 10.0, 15.0 d and 5.0, 9.5, 14.5 d respectively. By Kruskal Wallis Test, chi(2) value were 8.80 and 6.26, respectively(P value were 0.012, 0.040, respectively), with statistical significance between the above three main groups. CONCLUSIONS: The SVH value can evaluate the function of the otolithic. The angle of SVH and SVV are changing in the course of disease, SVH and SVV can be used as a guidance of the vestibular compensation evaluation. PMID- 21781560 TI - [Efficacy of high-resolution CT in differential diagnosis of chronic suppurative otitis media and cholesteatoma otitis media by soft-tissue shadows]. AB - OBJECTIVE: To evalute the efficacy of high-resolution CT(HRCT) in differential diagnosis and treatment of chronic suppurative otitis media and cholesteatoma otitis media by soft-tissue shadows. METHODS: HRCT scanning was performed in 120 cases, 153 ears, with chronic otitis suppurative media and cholesteatoma otitis media, of which original data were processed with multi-planar reconstruction (MPR) and maximum intensity projection (MIP), the characteristics of the soft tissue shadows' growth, window width or window leveling and bony destruction were respectively observed, as well as compared with the surgery findings. RESULTS: In 120 patients (153 ears), 109 ears were diagnosed as cholesteatoma otitis media, and 44 ears were diagnosed as chronic suppurative otitis media, among which 33 ears had granulation tissue and 11 ears had secretion. One hundred and seven ears were postoperatively diagnosed as cholesteatoma otitis media, among which 25 ears had granulation tissue. Among 46 ears of chronic suppurative otitis media, 35 ears had granulation tissue, and only 11 ears had secretion. A 98.6% diagnostic accuracy can be reached with HRCT in diagnosing cholesteatoma otitis media and chronic suppurative otitis media. The Youden's index was 0.98, 0.98 and 1.00 respectively with HRCT in diagnosing cholesteatoma, granulation tissue and secretion. CONCLUSIONS: Combination of the three different imaging methods, axial images, coronal MPR images and MIP images, can improve the efficacy of the HRCT diagnosis and definite chronic otitis media, which can be routinely used for surgery plan. PMID- 21781561 TI - [Clinical efficacy and safety of sublingual immunotherapy using standardized Dermatophagoides farinae extract for children with combined allergic rhinitis and asthma syndrome]. AB - OBJECTIVE: To study the clinical efficacy of sublingual immunotherapy using standardized Dermatophagoides farinae extract for children with combined allergic rhinitis and asthma syndrome. METHODS: Fifty-two children, from 4 to 14 years of age, with mite-sensitive combined allergic rhinitis and asthma syndrome were treated sublingually with standardized Dermatophagoides farinae extract. The clinical efficacy was evaluated by monthly follow-up visits. After treatment for 1 or 2 years using the standardized Dermatophagoides farinae extract, the asthma and rhinitis symptom scores, medication scores and adverse reactions before and after treatment were evaluated. SPSS 17.0 software was used to analyze the data. RESULTS: The allergic asthma symptom scores before treatment during the day were 3.22 +/- 0.66 and at night 2.05 +/- 0.57. After 1 year of treatment, the day and night scores (1.68 +/- 0.61, 0.94 +/- 0.32) respectively, were decreased significantly (q values were 15.25 and 13.78 respectively, all P < 0.01). After 2 years of treatment, the scores (0.61 +/- 0.28, 0.43 +/- 0.13) were also decreased significantly (q values were 10.29 and 6.07 respectively, all P < 0.01). The allergic rhinitis symptom scores and medication scores were 2.34 +/- 0.59 and 3.09 +/- 1.01 respectively before treatment and 1.21 +/- 0.46 and 1.89 +/- 0.64 after 1 year of treatment. The differences were significant (q values were 15.48 and 18.61 respectively, all P < 0.01). The allergic rhinitis symptom scores and medication scores were 1.02 +/- 0.37 and 1.49 +/- 0.38 after 2 years of treatment. There was no significant difference between 2 years of treatment and 1 year of treatment (q values were 2.53 and 2.78 respectively, all P > 0.05). There were no severe adverse events during the treatment, except for mild mouth cavity discomfort. CONCLUSIONS: Sublingual immunotherapy using standardized Dermatophagoides farinae extract is safe and effective in the treatment of children with combined allergic rhinitis and asthma syndrome. PMID- 21781562 TI - [Clinical features of non-allergic rhinitis and the therapeutic efficacy of combination of intranasal steroid and H1-antihistamine]. AB - OBJECTIVE: To investigate the basic clinical features of non-allergic rhinitis (NAR) in age, sex, incentives, and the effect of treatment with combined intranasal steroids and antihistamines. METHODS: One hundred consecutive NAR patients were included in this study and the age, gender, predisposing factors and clinical symptoms were analyzed. Combined intranasal steroids and antihistamines used for 8 weeks, the symptoms were recorded before and after treatment with visual analogue scale(VAS) score as the assessment of treatment effects. SPSS 17.0 software was used to analyze the data. RESULTS: Ninety-three NAR patients were adults, and the sex ratio was 1:1.2 (male:female), and the peak age incidence was between 30 - 39 years old. The main nasal symptoms were sneezing (96 cases), rhinorrhea (88 cases), nasal blockage (72 cases) and nasal itching (69 cases). The symptoms of eye and respiratory tract were always accompanied as eye itching (49 cases), tears (32 cases), congestion (22 cases), swelling (13 cases), cough (21 cases), suffocation (19 cases), chest compression (13 cases), wheezing (10 cases); Seventy-nine (79.0%) patients could indicate at least one kind of incentives, the temperature change (54 cases), dust (28 cases), irritating odor (21 cases) was the main incentive of NAR. Forty-seven patients completed the combined treatment of intranasal steroids and antihistamines, 38 (80.9%) patients were satisfied with the result with all symptoms relieved except wheezing (P < 0.05), but 36 patients had the NAR returned when they were exposed with the predisposing factors in the coming year; the remaining 9 (19.1%) patients failed the treatment. CONCLUSIONS: The clinical features of NAR were as follows: adult constituted the main patient population, women were slightly more than man but with no difference between genders; sneezing and nasal discharge were the main clinical symptoms, always more than 1 incentives. The combination of intranasal steroids and antihistamines could control the most of clinical symptoms. PMID- 21781563 TI - [Adenoid cystic carcinoma of maxillary sinus: diagnosis, treatment and prognostic factors]. AB - OBJECTIVE: To study the clinical characters, the outcomes of treatments and the factors affecting long-term treatment results of adenoid cystic carcinoma (ACC) of the maxillary sinus. METHODS: The clinical data of 80 patients with ACC of the maxillary sinus treated initially were analyzed retrospectively. Survival rate, local recurrence and distant metastasis were analyzed using Kaplan-Meier method. Prognosis factors were analyzed by Log-rank test and Cox regression. RESULTS: The 5-, 10- and 15-year cumulative overall survival rates were 65.2%, 37.1%, 26.3% respectively and 5-, 10-, and 15-year disease-free survival rates 50.7%, 30.7% and 24.5% respectively. The 5-, 10- and 15-year cumulative local control rates were 68.5%, 47.3% and 47.3% respectively and the cumulative distant metastasis rate were 32.8%, 48.8% and 48.8% respectively. Prognostic factors affecting survival included T stage, pathologic grade and the modes of treatment (P < 0.05). Patients with combined therapy composed of surgery and radiation had a better local control, compared with surgery or radiation alone (chi(2) = 18.33, P < 0.01), and surgery combined with postoperative radiation was prior to preoperative radiation combined with surgery (chi(2) = 6.64, P < 0.05). Patients treated with surgery combined with preoperative radiation, either with doses of >= 60 Gy or with negative margins, had a better local control, compared with doses < 60 Gy and with positive margins (chi(2) = 5.06, P < 0.05). The most of patients (62.8%) died of local recurrence. CONCLUSIONS: The most of failure was due to recurrence. Combined therapy composed of surgery and radiation improves the local control and survival in patients with ACC of the maxillary sinus, compared with surgery or radiation alone. Surgery combined with postoperative radiation provides the best overall survival and local control and should be the first choice of treatments. PMID- 21781564 TI - [The isolation, cultivation and identification of laryngeal mucosal mesenchymal stem cells]. AB - OBJECTIVE: To investigate the presence of mesenchymal stem cells (MSC) in laryngeal mucosa, and to seek for the method to isolate, cultivate and identify these cells. METHODS: Normal laryngeal mucosa was obtained from patients with laryngeal carcinoma during surgery, and the generating mesenchymal cells was obtained by digestive method. The cell growth curve was evaluated by 3-(4.5 methylthiazol-2yl)-2.5-diphenyltetrazolium bromide (MTT) assay. Colony forming cell assay was used to screen different morphologic colonies and evaluate clone formation ability. Flow cytometry was performed for the expression of the cells of the 4th passage surface marker profiles. Multiple differentiation potentials were confirmed by adipogenic, osteogenic and neural lineages induction. RESULTS: MTT assay and colony forming cell assay showed that laryngeal mucosa MSC had a relatively rapid proliferation capacity and a relatively high clone formation capacity (clone formation rate 7.1%). Flow cytometry analysis revealed that the laryngeal mucosa MSC were positive for CD29 (16.9%), CD44 (97.4%), CD90 (89.5%), CD105 (85.9%), CD146 (2.5%) and stro-1 (20.4%), but negative for CD34 (1.2%) and CD45 (0.8%). Laryngeal mucosa MSC undergone adipogenic, osteogenic and neural lineages induction were positive for oil red staining, alizarin red staining and S100 staining respectively, which suggested that laryngeal mucosa MSC could differentiate into adipogenic, osteogenic and neural lineages. CONCLUSION: This study demonstrated that MSC with rapid proliferative capacity and multiple differentiation potential could be obtained from lamina propria of laryngeal mucosa. PMID- 21781565 TI - [A guinea pigs model of otitis media with effusion caused by reversible Eustachian tube obstruction]. AB - OBJECTIVE: To develop a animal model for acute otitis media with effusion (OME). METHODS: In 22 guinea pigs, the left nasal orifice of Eustachian tube was approached via a transpalatal incision and obstructed with polyvinyl acetal material. Right ears were set as the control. Then all the ears were evaluated by otomicroscopy every day. Seven, 14 and 21 days after the intervention, six guinea pigs were killed for histologic study. RESULTS: Of the 22 guinea pigs included in this study, 20 ears (90.9%) were found to have effusion 3 - 7 days after the operation, two cases were excluded for purulent otorrhea 10 days postoperatively. The epithelium initially developed hyperplasia, and the submucosa showed vascular and lymphatic dilatations with inflammatory cells infiltration. None of the contralateral control ears had evidence of disease by otomicroscopic examination and histologic study. CONCLUSION: This experimental methods provoked reproducible pathologic characteristics similar to those for otitis media with effusion. PMID- 21781566 TI - [Methylation and expression of RUNX3 gene promoter in papillary thyroid carcinoma]. AB - OBJECTIVE: To study the relationship between status of methylation of human runt related transcription factor 3 (RUNX3) gene promoter in papillary thyroid carcinoma (PTC). METHODS: Methylation-specific PCR and immunohistochemical SP technique were used to detect the methylation of RUNX3 gene promoter and expression of its protein in 56 cases of PTC and their matched adjacent non carcinous epithelium (NCE). RESULTS: In NCE, there was no methylation of RUNX3 gene promoter, while in PTC the methylation rate was 35.7%(20/56), which was related to the tumor TNM stage, pathological grade and lymph node metastasis (P < 0.05). The positive rates of RUNX3 protein expression in NCE and PTC were 100.0% and 60.7%, respectively, with a significant difference (chi(2) = 27.378, P < 0.05). In PTC, the positive rates of RUNX3 protein expression in gradeI and grade II were 70.0% and 37.5%, respectively (P < 0.05); the rates were 46.7% and 76.9% in lymph node metastasis group and no metastasis group, respectively (P < 0.05). Moreover, there was a distinct correlation between methylation of RUNX3 gene promoter and expression of its protein (chi(2) = 21.62, P < 0.01). CONCLUSIONS: Methylation of promoter might be one of the important factors of inactivation of RUNX3 gene, and might play an important role in carcinogenesis and progression of PTC. PMID- 21781567 TI - [Facial nerve injury caused by foreign bodies in parotid and deep part of the neck:a case report]. PMID- 21781568 TI - [Surgical management of aspergillosis limited within the vocal cord: 2 cases report]. PMID- 21781569 TI - [A case report of endonasal meningoencephalocele complicated with abscess in brain and nasal cavity]. PMID- 21781570 TI - [Closure traumatic injury of the throat and trachea of a case]. PMID- 21781571 TI - [Laryngeal granulocyte sarcoma: a case report]. PMID- 21781572 TI - [A case of neurofibroma of vocal fold]. PMID- 21781573 TI - [Progress in studies on the surgical margins for pleomorphic adenoma of parotid gland]. PMID- 21781574 TI - [How to reconstruct the surgical defects of facial skin tumor with local flaps]. PMID- 21781575 TI - [Introduction to allergic rhinitis and its impact on asthma (ARIA) guidelines 2010 revision]. PMID- 21781576 TI - [To develop technique of ultrasound ablation, to promote minimal invasive surgery]. PMID- 21781577 TI - [Doppler flow imaging characteristics of blood supply of uterine fibroids on the therapeutic dosage of ultrasound ablation]. AB - OBJECTIVE: To explore the relationship between therapeutic dosage of ultrasound ablation in treatment of uterine fibroids and imaging characteristics of bloody supply of uterine fibroids by color Doppler ultrasound imaging. METHODS: One hundred and forty-two patients with 168 fibroids were treated by ultrasound ablation. Before treatment, bloody supply of fibroids were classified into grade 0 - 4 by ultrasonography. Three patients lost follow-up with contrast MRI exam within 1 month after treatment, so 165 fibroids were enrolled in this study. Bloody supplies were 9 fibroids in grade 0, 34 fibroids in grade 1, 35 fibroids in grade 2, 55 fibroids in grade 3 and 32 fibroids in grade 4. After 1 month treatment, the treated area without blood supply and ratio of ablation were measured by contrast MRI to evaluate the efficacy of thermal ablation and compare status of blood supple based different therapeutic dosage. According to International Reditherapy for Society (SIR) standard, adverse effect and score of pain were evaluated. RESULTS: (1) Ratio of ablation based: ratios of ablation were 79% in grade 0, 89% in grade 1, 92% in grade 2, 86% in grade 3, 71% in grade 4. It reached statistical difference when blood supply of grade 0 compared with those of grade 2 and 3 (P < 0.05) and blood supply of grade 4 compared with those of grade 1, 2, 3 (P < 0.05). (2) Factor of energy efficiency: factor of energy efficiency were 13.19 J/mm(3) in degree 0, 9.54 J/mm(3) in degree 1, 12.91 J/mm(3) in degree 2, 17.83 J/mm(3) in degree 3 and 28.10 J/mm(3) in degree 4. Factor of energy of ablation in degree 4 was significantly higher than those in degree 1, 2 and 3 blood supply (P < 0.05). It exhibit the positive relationship between blood supply and factor of energy of ablation (r = 0.354, P < 0.01). (3) Score of pain and adverse effect: nearly 85% (120/142) patients could tolerate this treatment very well. Those scores of pain were in range of 0 to 4. All patients did not extend their hospitalization and C to F of SIR standard was not recorded. CONCLUSION: blood supply of myoma measured by ultrasound could predict dosage of ultrasound ablation, it could help select indicated well patients. PMID- 21781578 TI - [Efficacy and safety of focused ultrasound ablation in treatment of submucosal uterine fibroids]. AB - OBJECTIVE: To evaluate the efficacy and safety of focused ultrasound ablation in the treatment of submucosal fibroids which broke into uterine cavity less than 50%. METHODS: From Oct. 2006 to Sept. 2009, 66 patients with 69 submucosal fibroids broke into uterine cavity less than 50% diagnosed by MRI in Chinese People's Liberation Army General Hospital were enrolled in this study. They were treated by ultrasound-guided focused ultrasound ablation in the outpatient department, which using the contrast enhanced ultrasonography to assess the efficacy after ablation immediately, to measure reduction of fibroids volume and record adverse effect before and after ultrasound ablation. At 3, 6, 12 and 24 months after treatment, ablation outcome and fibroids volumes were evaluated by contrast ultrasound. The changes of clinical symptom were evaluated by the symptom severity score (SSS) of the uterine fibroid quality-of-life instrument (UFS-QOL). RESULTS: The average volume of fibroids in 66 patients with 68 submucosal fibroids were (151 +/- 134) cm(3) before treatment and (114 +/- 104) cm(3) no enhanced regional after treatment. The ablation rate of target fibroids was (77 +/- 16)%. All patients completed this treatment successfully, they were followed up for 6 - 44 months, the median follow-up time was 24 months. No serious complication was observed. However, there were 52% (34/66) patients presented vaginal discharge after ablation, it disappeared gradually after 3 to 4 menstrual cycles. The SSS and the menstrual period symptom scores were significantly lower than that before ablation at the follow-up of 3, 6, 12 and 24 months, the rates were 20.9%, 38.0%, 45.1%, 47.1% and 42.0%, 63.8%, 64.2%, 68.8%, which all reached statistical difference (P < 0.05). The necrotic fibroids were absorbed gradually, the reduction rates of fibroid volume were 44.7%, 66.0%, 77.7% and 89.8%. CONCLUSION: It was safe and efficacy that focused ultrasound ablation was used in treatment of submucosal fibroids which broke into the uterine less than 50%. PMID- 21781579 TI - [Effect of oxytocin on uterine fibroids treated by ultrasound ablation]. AB - OBJECTIVE: To explore the effect of oxytocin on uterine fibroids treated by ultrasound ablation. METHODS: Eighty-two single points in 29 uterine fibroids from 26 patients were sonicated with magnetic resonance imaging guided by high intensity focused ultrasound before and after using oxytocin. The required total energy, sonication time required to reach 60 degrees C and the acoustic energy for increasing 1 degrees C of temperature at the single point before and after using oxytocin were compared. RESULTS: Before intravenous infusion of oxytocin, the average total sonication energy required to reach 60 degrees C was (5320 +/- 910) J and it took (21 +/- 20) seconds for sonicating a single point, the energy required for increasing 1 degrees C was (255 +/- 302) J. In contrast, after intravenous infusion of oxytocin, the average total sonication energy required to reach 60 degrees C was (2890 +/- 325) J, and it took (12 +/- 7) seconds for sonicating a single point, the energy required for increasing 1 degrees C was (126 +/- 94) J. Those three index all reached statistical difference (P = 0.002, P = 0.001, P = 0.002, respectively). CONCLUSION: It seemed that Oxytocin could significantly decrease the energy required for ablating uterine fibroids, shorten treatment time and improve the treatment efficiency. PMID- 21781580 TI - [Critique on commentary]. PMID- 21781581 TI - [Outcome and prognosis of isolated mild fetal ventriculomegaly in uterus]. AB - OBJECTIVE: To investigate outcome and prognosis of isolated mild fetal ventriculomegaly (IMV) of fetus in uterus. METHODS: From Jan. 2006 to Dec. 2009, 18 200 singleton pregnancy women from 20 weeks gestation underwent prenatal ultrasonography examination in Department of Obstetrics and Gynecology, Second Affiliated Hospital of Wenzhou Medical College. One hundred and forty-eight women with IMV (transverse diameter of the atrium of the lateral ventricle measuring between 10 and 15 mm with no other abnormalities) were studied prospectively, which were divided into two groups: 99 women with transverse diameter of the lateral ventricle of 10 - 11 mm in group A and 49 women with transverse diameter lateral ventricle of 12 - 15 mm in group B. The changes of ventriculomegaly and the associated intracranial and extracranial anomalies were observed regularly every 2 or 4 weeks until delivery. The development of neurological system was also followed up. RESULTS: (1) The overall incidence of IMV was 0.08% (148/18 200). The rate of bilateral ventriculomegaly were 20% (20/99) in group A and 51% (25/49) in group B, which reached statistical difference (P < 0.05). (2) Prognosis of fetus: 139 cases with 2 or more ultrasonographic examinations, IMV resolved throughout pregnancy in 41.7% (58/139), regressed in 7.9% (11/139), remained stable in 36.7% (51/139) and progressed in 13.7% (19/139). Five cases in group A and 11 cases in group B present progress, which reached significantly difference (P < 0.05). (3) One hundred and eleven cases infant were followed up for 5-12 months, the rate of psycho-motor developmental delay was 5.4% (6/111). The rate of neuro-developmental delay in progressed group (3/15) was higher than 2.5% (1/40) in resolved group, 0 (0/8) in regressed group and 4.2% (2/48) in remained stable group, which reached significantly difference (P < 0.05). CONCLUSIONS: About 85% of cases of IMV resolved, regressed or remained stable in utero would exhibited good prognosis. IMV with a transverse atrial size >= 12 mm or progression in utero was usually associated with a poor prognosis, which should be observed carefully. PMID- 21781582 TI - [Sex hormone-binding globulin of gestational diabetes mellitus pregnant women with well-controlled glucose and pregnancy outcomes]. AB - OBJECTIVE: To explore the relationship between sex hormone-binding globulin (SHBG) of gestational diabetes mellitus (GDM) pregnant women with well-controlled glucose and pregnancy outcomes. METHODS: Two hundred and fifty-one GDM pregnant women of 24 - 28 weeks in Shengjing Hospital of China Medical University were recruited from Mar. 2005 to Mar. 2010. Two hundred and sixteen cases of GDM with well-controlled glucose were defined as glycemic satisfied group, and they were treated by diet therapy (169 cases) or insulin therapy (47 cases). Thirty-five cases with unsatisfied glucose were defined as glycemic unsatisfied group. One hundred and ninety-two healthy pregnant women of 24 - 28 weeks were defined as healthy control group. Serum SHBG and homeostasis model analysis of insulin resistance (HOMA-IR) at 24 - 28 weeks and above 36 weeks were measured. GDM was diagnosed by "two-step" method according to the National Diabetes Data Group (NDDG) criteria. The pregnancy outcomes and complications of the three groups were recorded. RESULTS: (1) Comparison of pregnancy outcomes and complications:glycemic satisfied group was less likely to develop hypertensive disorders in pregnancy (10.6%), premature birth (8.3%), large for gestational age (LGA) (8.8%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%) compared to glycemic unsatisfied group (42.9%, 34.3%, 31.4%, 22.9% and 11.4%, respectively). And the difference was statistically significant (P < 0.05 or P < 0.01). There was no significant difference for incidence of polyhydramnios, pueperal infection, postpartum hemorrhage, neonatal hyperbilirubinemia between the two groups (P > 0.05). When compared to healthy control group (7.3%, 2.1%, 4.2%, 2.1% and 1.6%), no significant difference was found for incidence of premature birth (8.3%), pueperal infection (3.2%), postpartum hemorrhage (5.1%), neonatal asphyxia (3.7%) and neonatal hypoglycemia (2.3%, P > 0.05). (2) Comparison of results of 24 - 28 weeks and above 36 weeks: serum SHBG of glycemic satisfied group [(384 +/- 88), (457 +/- 48) nmol/L] was significantly higher than that of glycemic unsatisfied group [(313 +/- 45), (401 +/- 73) nmol/L]; HOMA-IR of glycemic satisfied group (5.3 +/- 1.1, 5.5 +/- 1.1) was significantly lower than that of glycemic unsatisfied group (7.0 +/- 1.3, 7.6 +/- 1.7; P < 0.01). Serum SHBG of glycemic satisfied group was significantly lower than that of healthy control group [(492 +/- 95), (565 +/- 40) nmol/L]; and HOMA-IR of glycemic satisfied group (5.3 +/- 1.1, 5.5 +/- 1.1) was significantly higher than that of healthy control group (3.6 +/- 0.6, 3.9 +/- 0.5; P < 0.01). FPG of glycemic satisfied group [(5.84 +/- 0.28), (5.16 +/- 0.13) mmol/L] was significantly lower than that of glycemic unsatisfied group [(6.13 +/- 0.16), (5.68 +/- 1.14) mmol/L;P < 0.01]. FINS of glycemic satisfied group [(20.4 +/- 2.1), (24.1 +/- 4.2) mmol/L] was significantly lower than that of glycemic unsatisfied group [(24.7 +/- 4.5), (29.9 +/- 2.7) mmol/L; P < 0.01]. (3) Correlation analysis. Between 24-28 weeks, SHBG was negatively correlated with HOMA-IR in the three groups (r = -0.952, P < 0.01); and SHBG was negatively correlated with HOMA-IR in glycemic satisfied group (r = -0.903, P < 0.01). CONCLUSIONS: Well-controlled glucose can not completely improve maternal and fetal outcomes of GDM pregnant women. High insulin resistance and low serum SHBG can influence pregnancy outcomes. PMID- 21781583 TI - [Detection of trisomy 21 by quantitative fluorescent PCR in clinical samples undergoing prenatal diagnosis for hereditary hearing loss]. AB - OBJECTIVE: To establish the genetic test technique of trisomy 21 concurrently conducts with prenatal diagnosis for hereditary hearing loss. METHODS: Fifty-four pregnant women who underwent prenatal diagnosis for hearing loss of their fetuses in Chinese People's Liberation Army General Hospital from March 2009 to May 2010 were enrolled in this study. All probands from the deaf families have confirmed the causative mutation for hearing loss in Genetic Testing Center in Chinese People's Liberation Army General Hospital. The mean age of 54 pregnant women is 31 years at pregnancy of 18 - 26 weeks, 5 cases > pregnancy of 23 weeks, 9 cases >= 35 years. All subjects did not conduct the serologic tests for trisomy 21 before. Fifteen to twenty ml amniotic fluid was drawn from 49 cases at pregnancy of 18 - 23 weeks and 5 cases > pregnancy of 23 weeks. One to two ml umbilical blood was drawn from 5 cases > pregnancy of 23 weeks. For 9 cases >= 35 years, amniotic fluid cell culture and karyotyping analysis were conducted concurrently. A multiple quantitative fluorescent (QF) PCR and six microsatellite markers were applied to diagnosis trisomy 21. The samples with peaks of 1:1:1 or 2:1 at two microsatellite markers can be diagnosed as trisomy 21. RESULTS: (1) Fifty-four fetuses were successfully conducted prenatal genetic diagnosis for hearing loss (included GJB2 and SLC26A4). Ten fetuses copied the exactly same genotypes as the probands. The other 44 cases fetuses did not copy the same genotypes as the probands and won't develop hearing loss. The hearing test showed normal hearing for the neonates. (2) All the 54 fetuses were excluded of trisomy 21 by QF-PCR and were verified after birth. Five fetuses with advanced maternal age were performed karyotyping analysis and showed normal. The diagnostic results of QF PCR can be obtained in 1-3 days without misdiagnosed. CONCLUSIONS: QF-PCR is an efficient, rapid and accurate technique for detection of trisomy 21 without increasing sample amount. It can be used for fetuses who were undertaken hearing loss gene test or other prenatal gene test. PMID- 21781584 TI - [Impact of colpocleisis on body image in women with severe pelvic organ prolapse]. AB - OBJECTIVE: To investigate the impact of colpocleisis on body image in women with severe pelvic organ prolapse (POP). METHODS: From Oct. 2005 to Feb. 2010, 60 POP patients with stage III and IV by POP quantitation system underwent total or partial colpocleisis. Patients received body image evaluation before and 1 year after operation. RESULTS: One year after operation, 52 (87%, 52/60) patients completed body image evaluation. Before and 1 year after operation, the ratio of answer "Not at all" of questions such as "Have you felt less physically attractive as a result of your vaginal prolapse?", "Have you been feeling less feminine as a result of your vaginal prolapse?", "Did you find it difficult to look at yourself naked?", "Have you been feeling less sexually attractive as a result of your vaginal prolapse?", "Have you felt dissatisfied with your body?" were 25% and 96% (P < 0.01), 21% and 96% (P < 0.01), 37% and 67% (P = 0.018), 29% and 96% (P < 0.01), 12% and 83% (P < 0.01), respectively, indicating significant improvement on body image after operation for patients treated by colpocleisis. CONCLUSION: Women underwent colpocleisis for severe POP could not decrease their body image as a result of the disability of vaginal intercourse. PMID- 21781585 TI - [Clinical analysis on the lymph nodes metastasis characters and their relation with the prognosis of the endometrial carcinoma patients]. AB - OBJECTIVE: To explore the lymph nodes (LN) metastasis characters of the endometrial carcinoma and its relation with the patients' prognosis. METHODS: A retrospective study was carried out on 227 cases of endometrial carcinoma who admitted to our department and underwent LN excision from Jul.2000 to Feb.2008. RESULTS: Among 227 cases who underwent pelvic LN excision, there were 22 cases (9.7%) presented LN metastasis. There were 12 cases with positive external iliac LN from 20 cases of patients with data in LN grouping. Para-aortic LN excision was carried out on 138 patients. There were 6 cases with positive para-aortic LN, 5 cases of them together with pelvic LN metastasis. Those patients with cervix involvement, annex metastasis, deep myometrium infiltration, grade 2-3 and negative estrogen receptor occurred pelvic LN metastasis more frequently than the others (P < 0.05). Among the 6 cases with positive para-aortic LN, there were 3 cases (3/6) with deep myometrium infiltration. For those whose para-aortic LN was negative, it was only 16.7% (22 cases). But there were no difference statistically between them (P > 0.05). There were significant difference in 3 years disease-free survival rate between patients with positive pelvic LN or negative pelvic LN [(81.8 +/- 8.2)% vs (97.4 +/- 1.2)%, P = 0.004]. While there were not significant difference in 3 years disease-free survival rate between patients with positive para-aortic LN or negative para-aortic LN [100% vs (96.7 +/- 1.6)%, P > 0.05]. Single factor analysis showed that the age more than 50 years, annex metastasis and pelvic LN metastasis related with the recurrence (P < 0.01). But cervix involvement, deep myometrium infiltration, para-aortic LN metastasis, pathology type, tumor grade and estrogen receptor did not relate with the recurrence (P > 0.05). Cox regression analysis showed that annex metastasis and the age of patients were independent risk factors affecting the recurrence (P = 0.011, P = 0.025). CONCLUSIONS: The most common site of pelvic LN metastasis is the external iliac LN for endometrial carcinoma patients. The patients with positive para-aortic LN always accompanied pelvic LN metastasis. Those patients with cervical involvement, annex metastasis, deep myometrium infiltration, poor differentiation and negative estrogen receptor be more likely exist pelvic LN metastasis. Pelvic LN metastasis may affect the prognosis of endometrial carcinoma patients. PMID- 21781586 TI - [Influence on pubertal reproductive function in female rats by immune challenge in early life]. AB - OBJECTIVE: To investigate the long-term programming effects on pubertal reproductive function by immunological challenge in early life. METHODS: Female Sprague-Dawley rats were administered by endotoxin (lipopolysaccharide, LPS) at a dosage of 50 ug/kg and saline intraperitoneally on postnatal day 3 and 5. Body weight was measured weekly. Puberty onset (vaginal opening) and oestrous cyclicity were monitored from postnatal day 30. At the age of 6 weeks, bilateral ovariectomy was performed. The histological and morphological change of the ovaries (the thickness of the theca interna and the number of different kinds of follicles) were observed and the immunoreactivity of the ovarian sympathetic nerve markers (low affinity receptor of nerve growth factor, p75NGFR) was evaluated by immune staining. RESULTS: Immunological challenge (exposed to LPS) in early life delayed vaginal opening significantly [LPS-treated (40.6 +/- 0.7) days versus controls (38.6 +/- 0.5) days, P < 0.05], decreased the percentage of normal oestrous cyclicity (LPS-treated 26.1% versus controls 66.8%, P < 0.05), decreased the total number of different types of follicles (primordial follicles: LPS-treated 610 +/- 47 versus controls 1181 +/- 57, P < 0.05; primary follicles: LPS-treated 624 +/- 41 versus controls 960 +/- 30, P < 0.05; preantral follicles: LPS-treated 183 +/- 16 versus controls 260 +/- 14, P < 0.05; antral follicles: LPS-treated 32 +/- 4 versus controls 79 +/- 7, P < 0.05) and increased the thickness of the theca interna [LPS-treated (15.8 +/- 0.4) um versus controls (11.4 +/- 0.3) um, P < 0.05]. The immunostaining of p75NGFR was obviously enhanced in the LPS-treated ovaries when compared with that of controls (P < 0.05). CONCLUSIONS: Immunological stress during early critical developmental windows could have long dysfunctional effects on the pubertal reproductive function. It delayed puberty onset, reduced the percentage of the normal oestrous cycles, decreased follicles reserve and increased the thickness of the theca interna which might involve the up-regulation of the local ovarian sympathetic nerve activity. PMID- 21781588 TI - [Critics and assessment for guidelines for the prevention of cardiovascular disease in women-2011 update]. PMID- 21781587 TI - [Effects of PD98059 and LY294002 on subcutaneous xenograft of human endometrial carcinoma in nude mice]. AB - OBJECTIVE: To investigate the effects of signal pathway inhibitors PD98059 and LY294002 on cell proliferation, apoptosis, expressions of phosphorylated extracellular signal-regulared kinase (p-ERK) and phosphorylated protein kinase B (p-Akt) in endometrial carcinoma xenografts. METHODS: Human endometrial carcinoma Ishikawa cells were cultured in vitro. The effects of PD98059 and LY294002 on proliferation, apoptosis, and cell cycle distribution of endometrial cancer cells were detected by monotetrazolium (MTT) assay and fluorescence-activated cell sorting technique. The models of xenografted tumor were established by the subcutaneous inoculation in 24 nude mice, and then they were randomly divided into 4 groups (n = 6), normal saline group, PD98059 group (PD group), LY294002 group (LY group) or PD98059 + LY294002 group (PD + LY group) by intraperitoneal injections, respectively. The anti-tumor efficacy was evaluated by measuring tumor volume and tumor growth status. The histopathological change of tumor specimens was observed using HE staining and terminal deoxynucleotidyl transferase-mediated dUTP-digoxigen in nick and labeling method (TUNEL) testing and the expression levels of p-ERK and p-Akt were detected by immunohistochemistry method. RESULTS: (1) The proliferation of Ishikawa cells were suppressed after treated by PD98059 and(or) Y294002, in which A(570) values of cells decreased showing both time-dependent and concentration-dependent manner (LY294002: F(group) = 9.801, P = 0.002; F(time) = 10.398, P = 0.001. PD98059: F(group) = 8.213, P = 0.015; F(time) = 6.839, P = 0.036). Cell cycle distribution analysis revealed that percentage of Ishikawa cells at G(0)/G(1) phase (F(time) = 35.049, P = 0.004; F(group) = 32.024, P < 0.01) increased and percentage of S phase cells (F(time) = 7.789, P = 0.049; F(group) = 30.132, P < 0.01) decreased significantly. The percentage of apoptotic cells increased significantly among PD group, LY group and PD + LY group, in which there were significant difference [(63.3 +/- 0.5)% vs (30.7 +/- 20.1)% vs (40.8 +/- 1.3)%; F = 621.059, P < 0.01]. (2) Compared with the control group, the increasing of transplanting tumor volume in the treated groups were obviously (F = 23.545, P < 0.01), and the inhibited rate of the tumor was higher in PD + LY group than that in PD group or LY group [(68 +/- 9)% vs (32 +/- 16)% or (38 +/- 17)%; F = 10.283, P < 0.05]. (3) HE staining shown that there were different degrees of necrosis for endometrial carcinoma cell in different groups. The apoptosis of tumor cells were significantly increased in treated groups by TUNEL testing [(13.7 +/- 1.5)%, (14.1 +/- 1.2)%, (29.0 +/- 1.8)%; F = 320.344, P < 0.01]. Immunohistochemistry results demonstrated that the expressions of p-ERK and p-Akt in treated groups were lower than that in control group, of which LY + PD group was the lowest one. CONCLUSION: The signal pathway inhibitors PD98059 and LY294002 could inhibit the growth of human endometrial carcinoma in vivo and in vitro, in which may induce cell apoptosis. PMID- 21781589 TI - [Current status of coronary revascularization in female patients]. PMID- 21781590 TI - [Clinical characteristics, treatments and outcome of diabetic patients with non ST elevation acute coronary syndromes in China]. AB - OBJECTIVE: To observe the clinical characteristics, treatment options and outcome of diabetic patients with non-ST elevation acute coronary syndromes (NSTEACS). METHODS: Consecutive patients admitted with NSTEACS from 38 centers in north China were enrolled. Medical histories, clinical characteristics, treatments and outcomes were evaluated and follow-up was made at 6, 12, and 24 months after their initial hospital admission. Cumulative event rates were compared between diabetic and non-diabetic patients. RESULTS: There were 420 diabetic patients out of 2294 NSTEACS patients (18.3%). Diabetic patients were older [(64.9 +/- 6.7) years vs. (62.3 +/- 8.6) years, P < 0.01], more often women (48.1% vs. 35.3%, P < 0.05) and were associated with higher baseline comorbidities such as previous hypertension, myocardial infarction, congestive heart failure and stroke than non diabetic patients. The incidence of antiplatelet therapy (92.1% vs. 95.0%, P < 0.05), coronary angiography (30.0% vs. 36.3%, P < 0.05) and revascularization (12.1% vs.18.8%, P < 0.05) was lower in patients with diabetes than non-diabetic patients. In hospital and 2-year mortality as well as the incidence of congestive heart failure and composite outcomes of myocardial infarction, stroke, congestive heart failure and death were substantially higher in diabetic patients compared with non-diabetic patients. Multivariate Cox regression analysis revealed that age >= 70 years, diabetes, previous myocardial infarction, previous congestive heart failure, systolic blood pressure less than 90 mm Hg (1 mm Hg = 0.133 kPa) and heart rate more than 100 bpm at admission were risk factors for 2-year death. CONCLUSION: In NSTEACS, diabetes is associated with higher rate of in-hospital and 2-year death, congestive heart failure and composite outcomes of myocardial infarction, stroke, congestive heart failure and death. Diabetes mellitus is a major independent predictor of 2-year mortality post NSTEACS. Status of antiplatelet therapy, coronary angiography and revascularization should be improved for diabetic patients with NSTEACS during hospitalization. PMID- 21781591 TI - [Current statin use for patients with atherosclerotic cardiovascular disease in 39 large Chinese hospitals]. AB - OBJECTIVE: To investigate the current statin use among high-risk patients with atherosclerotic cardiovascular diseases in Chinese large hospitals. METHODS: Clinical history and current medication were recorded in 11 783 patients with a history of atherosclerotic cardiovascular disease (CVD) from 39 highest-ranking hospitals in 10 Chinese cities. RESULTS: Indication for statin use was given for all screened patients and statin was not prescribed in up to 59.6% (7022) patients. For patients with statin use, medication time was shorter than their atherosclerotic CVD history in 1120 (23.5%) patients. The proportion of statin use among patients with ischemic stroke was 19.6%, among patients with coronary heart disease without ischemic stroke was 59.2%. CONCLUSION: Statin is underused in secondary prevention among patients with atherosclerotic CVD in China. There is a large gap between guideline recommended statin use and in practice. Thus, it remains a major challenge for healthcare professionals and policy makers to resolve this problem rapidly. PMID- 21781592 TI - [Relationship between fractional esterification rate of high density lipoprotein cholesterol and coronary artery disease]. AB - OBJECTIVE: To assess the relationship between fractional esterification rate of high density lipoprotein cholesterol (FER(HDL)) and coronary artery disease. METHODS: A total of 131 hospitalized patients underwent coronary angiography due to chest pain were included in the study and patients were divided into CAD group (n = 76) and non CAD group (n = 55) according to coronary angiogram. Clinical and laboratory data including biochemical laboratory, FER(HDL) and lipid subclasses were analyzed. RESULTS: The FER(HDL) value of CAD group was significantly higher than that of the non CAD group (21.70 +/- 8.73 vs. 18.65 +/- 6.26, P < 0.05). There was an increased trend of FER(HDL) with numbers of diseased coronary arteries, significant difference was evidenced between non CAD group and 3-vessel group (18.65 +/- 6.26 vs. 24.00 +/- 9.22, P < 0.05). FER(HDL) was positively correlated with TG (r = 0.647, P < 0.001), LDLb-C(r = 0.441, P < 0.001) and negatively correlated with HDL-C (r = -0.708, P < 0.001) and HDL(2)-C (r = 0.748, P < 0.001). CONCLUSION: Our data showed that the values of FER(HDL) were significantly increased in CAD patients and correlated with the severity of the CAD. PMID- 21781593 TI - [Status quo and factors influencing smoking cessation in cigarette smoking patients with coronary artery disease]. AB - OBJECTIVE: To investigate the status quo of smoking cessation and analyze factors influencing smoking cessation in cigarette smoking patients with coronary artery disease (CAD). METHOD: A total of 350 smoking patients with CAD was surveyed by questionnaire, logistic regression analysis was performed to analyze factors influencing smoking cessation. RESULTS: Incidence of smoking cessation was 57.1% (200/350) in this cohort. Patients were divided into two groups, the elderly (> 65 years old, n = 111) and the young group (<= 65 years old, n = 239). The smoking cessation rate in the elderly group is significantly higher than in the young group (71.2% vs. 50.6%, P < 0.001). Aged patients and patients with high cultural level are easier to give up smoking. Logistic analysis showed that age <= 65 years old (OR = 2.336, P = 0.004), low cultural level (OR = 1.310, P = 0.028), PCI (OR = 0.261, P < 0.001), coronary artery bypass graft (OR = 0.107, P = 0.004), total family income > 4000 RMB/month (OR = 1.828, P = 0.003) are risk factors for failed smoking cessation. There are 76 patients smoking again in current smokers, most due to lack of self-control (76.3%). Compared to the elderly group, there is a higher proportion of smoking again due to the need of daily communication and work in the young group. CONCLUSIONS: We still need to raise the awareness of smoking cessation for smoking patients with CAD. Following factors should be focused for tobacco control in CAD patients: younger age, lower cultural level, not treated with PCI or CABG, patients with smoking family members, higher body mass index and higher total family income. PMID- 21781594 TI - [Impact of acute smoking on artery function in healthy chronic smokers]. AB - OBJECTIVES: To explore the effect of acute smoking on vascular endothelial function, arterial stiffness and the possible underlying mechanisms. METHODS: We measured the endothelial function and arterial stiffness in 50 healthy chronic smokers before and after acute smoking with EndoPAT2000. The test was carried out on two separate finger tips. The endothelial function was evaluated by PAT ratio of the finger tip and systemic arterial stiffness was evaluated by augmentation index (AI). Plasma soluble intercellular adhesion molecule-1 (sICAM-1) and tissue plasminogen activator (tPA) before and 20 min after acute smoking were measured with enzyme linked immuno sorbent assay. RESULTS: The PAT ratio was decreased (1.87 +/- 0.40 vs. 1.73 +/- 0.28, P = 0.004) while AI was significantly increased after acute smoking (2.94% +/- 21.77% vs. 7.11% +/- 20.65%, P = 0.01). There was no significant changes in sICAM [(306.5 +/- 76.1) ug/L vs. (315.7 +/- 90.9) ug/L, P = 0.402], but tPA [7.87 (5.41 - 10.08) ug/L vs. 5.77 (3.77 - 9.68) ug/L, P < 0.01] was significantly decreased after smoking. CONCLUSIONS: Smoking could acutely affect endothelia function, arterial stiffness and deteriorate the activity of fibrinolytic system which could lead to coronary thrombosis in smokers. PMID- 21781595 TI - [Myocardial regeneration and repair of infarcted heart by a new composition isolated from Geum japonicum]. AB - OBJECTIVES: To isolate the cardiogenic fraction, which can enhance cardiogenic differentiation of bone marrow-derived mesenchymal stem cells (MSC) from Geum japonicum. The therapeutic effect of the isolated cardiogenic fraction was further tested in a rat myocardial infarction (MI) model. METHOD: Bioassay guided fractionation method was used for the isolation of the cardiogenic fraction, named as heart repair fraction (HRF). MI was induced by a permanent ligation of left anterior descending coronary artery. The rats exhibiting similarly decreased values of left ventricle ejection fraction (LVEF) and fraction shortening (LVFS) were used. The rats in test group (n = 10) were subject to HRF treatment (20 mg*kg(-1)*d(-1)) through gastric gavage daily for 4 weeks. Water alone (2 ml/d) was given through gastric gavage to rats in the control group (n = 10). The cardiac function was assessed by echocardiography at different time points. Masson trichrome staining was used for evaluation of the infarct size. Morphological and immunohistochemical studies were performed to investigate the HRF mediated myocardial regeneration. RESULTS: LVEF (66.2% +/- 6.9%) and LVFS (46.8% +/- 5.8%) were significantly increased two weeks post HRF treatment compared with the values (LVEF: 55.7% +/- 6.0% and LVFS: 36.4% +/- 5.2%) in control rats (all P < 0.01). The improved heart function was further restored 4 weeks post HRF treatment (P < 0.01). Furthermore, the treatment of acute MI with this HRF significantly reduced the infarct size (19.0% +/- 6.1%) compared with that (31.1% +/- 8.6%) in control rats (P < 0.01). Substantial regeneration of cardiomyocytes in infarcted region of the HRF treated heart was also observed that replaced a considerable part of the infarcted heart tissues resulting in remarkable reduction of the infarct size. CONCLUSION: The properties of this HRF isolated from Geum japonicum in stimulating substantial regeneration of myocardium in infarct region with consequently improved cardiac function appear to be new and represent a new approach for the treatment of MI. PMID- 21781596 TI - [Transplantation of bone marrow-derived endothelial progenitor cells preconditioned with ex vivo 17beta-estradiol enhances healing efficacy after acute myocardial infarction]. AB - OBJECTIVE: To investigate the therapeutic efficacy of intravenous implanted bone marrow-derived endothelial progenitor cells (BM-EPC) preconditioned with 17beta estradiol in ovariectomized mice model of acute myocardial infarction (AMI). METHODS: BM-EPC were cultured and identified from ovariectomized BALB/C mice tibia and femur. The ovariectomized BALB/C mice models of acute myocardial infarction (AMI) were established, and randomly divided into 17beta-estradiol + BM-EPC group (n = 6), BM-EPC group (n = 6) and control group (n = 6). Three days after AMI, BM-EPC pretreated with or without 17beta-estradiol was infused via tail vein. The equal volume of saline was infused in control group. Twenty-five days after infusion, left ventricular (LV) function and dimensions, capillary density and ratio of fibrosis area to LV area were measured. RESULTS: LV function and dimensions, capillary density and LV fibrosis were significantly improved in 17beta-estradiol + BM-EPC group than in control group [(LVDs: (3.09 +/- 0.05) mm vs. (3.27 +/- 0.10)mm, P < 0.05; LVDd: (4.18 +/- 0.07) mm vs. (4.31 +/- 0.05) mm, P < 0.05; FS: (33.0 +/- 3.8)% vs. (26.0 +/- 3.2)%, P < 0.05; capillary density: (1428 +/- 214)/mm2 vs. (1070 +/- 168)/mm2, P < 0.05; ratio of fibrosis: (38.8 +/- 4.9)% vs. (49.0 +/- 4.6)%, P < 0.05]. However, Above mentioned parameters were similar between BM-EPC group and control group (P > 0.05). CONCLUSIONS: BM-EPC preconditioned with 17beta-estradiol can enhance capillary density, decrease LV fibrosis and improve cardiac function in this mice model of AMI. PMID- 21781597 TI - [Evaluation on the relationship between pregnancy associated plasma protein-a and intravascular ultrasound detected culprit coronary plaque morphology in patients with unstable angina]. AB - OBJECTIVE: To assess the relationship between pregnancy associated plasma protein A (PAPP-A) and culprit coronary plaque morphology in patients with unstable angina (UA). METHODS: Sixty-eight UA patients undergoing diagnostic coronary angiography and intravascular ultrasound were included in this study. A sandwich enzyme-linked immunosorbent assay technique was used to assay the circulating PAPP-A. Plaque characteristics of culprit lesion were analyzed for UA patients with various PAPP-A levels. RESULTS: PAPP-A level was significantly higher in high-risk UA than in non-high-risk UA [(19.9 +/- 20.1) mIU/L vs. (6.9 +/- 5.7) mIU/L, P = 0.002]. Optimal threshold of PAPP-A to predict high-risk UA was determined as 11.0 mIU/L with a sensitivity of 78.6% and a specificity of 77.5%. Patients with higher PAPP-A level (>= 11.0 mIU/L) was associated with larger external elastic membrane cross-sectional area, plaque area and more plaque burden compared with patients with lower PAPP-A level (all P < 0.01). Positive remodeling, attenuated plaque and plaque rupture were significantly more often in patients with higher PAPP-A than in patients with lower PAPP-A level (all P < 0.01). PAPP-A >= 11.0 mIU/L (OR = 5.921, P = 0.014) and attenuated plaque (OR = 7.541, P = 0.038) were independent risk predictors for high-risk UA. CONCLUSIONS: PAPP-A was associated with instability of culprit plaque in UA patients. PAPP-A >= 11.0 mIU/L and attenuated plaque were independent predictors for high-risk UA. PMID- 21781598 TI - [Efficacy comparison between video-assisted minimally invasive radiofrequency ablation and catheter ablation in the treatment of persistent atrial fibrillation]. AB - OBJECTIVE: To compare the efficacy of the video-assisted minimally invasive radiofrequency ablation in comparison with catheter ablation for the treatment of persistent atrial fibrillation (AF). METHODS: A total of 172 patients [116 male, mean age (56 +/- 12) years] with persistent AF underwent ablation procedures during the last 4 years in our institute (83 patients underwent video-assisted minimally invasive radiofrequency ablation, group MIA and 89 patients underwent circumferential pulmonary vein linear ablation, group CA). Mean duration of preoperative AF was (72 +/- 68) months. Patients were follow-uped for a period of 1 to 3.6 years [mean (2.2 +/- 0.8) years]. RESULTS: There was no procedure related death. During follow-up, one patient died of encephalorrhagia in CA group, one patient died of sudden death in each group. At the end of the procedure, there were 67 sinus rhythm (39.0%), 4 pacing rhythm (2.3%), 29 atrial flutter or atrial tachycardia (16.9%) and 72 AF (41.9%). Before discharge, sinus rhythm was recorded in 53 patients (63.9%) of MIA group and in 78 patients (87.6%) of CA group; AF recorded in 24 patients (28.9%) of MIA group and in 4 patients (4.5%) of CA group (P < 0.01). At the latest follow-up, sinus rhythm was recorded in 65 patients (79.3%) of MIA group and in 54 patients (62.1%) of CA group; AF or atrial flutter was recorded in 14 patients (17.1%) of MIA group and in 24 patients (27.6%) of CA group (P = 0.028). The Kaplan-Meier survival analysis showed that the long-term efficacy of MIA is superior to CA in terms of incidence of free of AF, AF recurrence and antiarrhythmic drugs (P = 0.03, P = 0.028, P = 0.017, respectively). CONCLUSIONS: The video-assisted minimally invasive ablation was safe and effective, and had an optimistic long-term success rate for patients with long-lasting persistent AF. Thus, a randomized study comparing the long-term efficacy between the two procedures for patients with long-lasting persistent AF is warranted. PMID- 21781599 TI - [Fifteen-year evolving trends of etiology and prognosis in hospitalized patients with heart failure]. AB - OBJECTIVE: To investigate the etiological and prognostic changes of hospitalized patients with chronic heart failure. METHODS: This retrospective study analyzed 7319 hospitalized patients (male 62.07%) with validated primary discharge diagnosis of chronic heart failure in Chinese PLA General Hospital in Beijing from January 1, 1993 to December 31, 2007. Etiological characteristics, comorbidities and 30-day hospitalized mortality in the following three periods: 1993 - 1997 (n = 1623), 1998 - 2002 (n = 2444), and 2003 - 2007 (n = 3252) were compared. RESULTS: (1) The patient age increased [(56.0 +/- 17.5) years, (57.8 +/ 17.6) years and (62.7 +/- 15.5) years, P < 0.01] and hospital stay time decreased [(31.3 +/- 17.4) days, (22.7 +/- 14.1) days and (20.1 +/- 15.2) days, P < 0.01] from 1993 to 2007. (2) The common causes of heart failure were coronary heart disease, hypertension, rheumatic valvular heart disease and diabetes mellitus. From 1993 - 1998 to 2003 - 2007, the proportion of patients with coronary heart disease, hypertension and diabetes mellitus rose from 37.2%, 23.3% and 12.3% to 46.8%, 46.7% and 21.1%, respectively (all P < 0.05). Meanwhile the proportion of patients with rheumatic valvular heart disease fell from 35.2% to 16.6% (P < 0.05). (3) The main etiologies and comorbidities were atrial fibrillation, myocardial infarction, pneumonia, chronic obstructive pulmonary disease and renal failure. From 1993 - 1998 to 2003 - 2007, atrial fibrillation was the most common cause of heart failure, and the rate of myocardial infarction, pneumonia and renal failure rose from 11.0%, 8.9% and 5.2% to 14.7%, 14.5% and 9.1%, respectively (all P < 0.05) and the rate of COPD fell from 12.9% to 8.4% (P < 0.05). (4) The 30-day hospitalized mortalities in the three periods were 7.0%, 4.5% and 5.1%, respectively, and the mortalities in the 1998 - 2002 and 2003 - 2007 periods were lower than those of in the 1993 - 1998 period (all P < 0.05). The mortality related to coronary heart disease decreased significantly from 1993 to 2007 (9.3%, 5.0% and 3.8% in the three periods, respectively, P < 0.05). CONCLUSIONS: It is demonstrated that the primary diseases causing heart failure were coronary heart disease, hypertension, diabetes mellitus and rheumatic valvular heart disease, and the former three diseases exhibited a upward trend and the later one exhibited a downward trend. Moreover, the proportion of comorbidities in patients with heart failure increased over the study period. The 30-day hospital mortality exhibited a downward trend and decreased significantly in patients with coronary heart disease or myocardial infarction. PMID- 21781600 TI - [Effect of valsartan and carnitine on cardiomyocyte Calpain-1 and Bcl-xl expressions of dogs with chronic alcohol intake-induced cardiomyopathy]. AB - OBJECTIVE: To evaluate the effects of valsartan and carnitine on cardiomyocyte Calpain-1 and Bcl-xl expressions of dogs with chronic alcohol intake-induced cardiomyopathy. METHODS: Dogs were randomly assigned into 4 groups (n = 7 each): (1) alcohol fed (free access to 5%, 1(st) week; 10% 2(nd) week; 500 ml 25% bolus plus free access to 5% from 3 to 24 weeks, A); (2) alcohol + valsartan (5 mg*kg( 1)*d(-1), B); (3) alcohol + carnitine (300 mg*kg(-1)*d(-1), C); (4) Control (D). After six months, all animals were assessed for left ventricular (LV) function by echocardiography. The Bad and Bcl-xl protein expressions were evaluated by immunohistochemistry. The expression of Calpain-1 protein was determined with Western blot. Myocardial morphology was quantified on HE stained slices and under electron microscopy. The terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) was performed for apoptosis analysis. RESULTS: Compared with group D, LVEDD and LVESD were significantly increased while EF and FS significantly decreased in group A. In alcohol fed group, expressions of Bad and Calpain-1 protein were significantly increased while Bcl-xl protein expression was downregulated, all changes could be significantly attenuated by intervention with valsartan and carnitine (all P < 0.05). CONCLUSION: These data suggest that alcohol could promote cardiac myocyte apoptosis, reduce cardiac function and aggravate myocardial remodeling which valsartan and carnitine could reduce alcoholic cardiomyopathy by downregulating Calpain-1 and Bad protein expression and upregulating expression of Bcl-xl protein. PMID- 21781601 TI - [Effect of miRNA-199a on rat cardiac hypertrophy]. AB - OBJECTIVE: To investigate the role of miRNA-199a on cardiac hypertrophy. METHODS: (1) Male Sprague-Dawley rats were subjected to pressure overload induced by abdominal aortic constriction (AAC, n = 6) and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the change of microRNAs (miRNAs). (2) Neonatal rat ventricular myocytes were isolated from 2-day old Sprague-Dawley rats. The myocytes were divided into two groups: adenovirus miRNA-199a (Ad-miRNA 199a) or adenovirus vector (Ad-vector). They were transfected in cardiomyocytes for 48 h using Lipofectamine 2000. qRT-PCR was used to detect the change of myocardial hypertrophy markers alpha-myosin heavy chain (alphaMHC, myh6), beta myosin heavy chain (betaMHC, myh7) and atrial natriuretic peptide (ANP, Nppa). Software Axio Vision was used to detect the change of cardiomyocytes surface areas. (3) Neonatal rat ventricular myocytes were divided into two groups: antisense oligonucleotide-miRNA-199a (As-miRNA-199a) and scramble oligonucleotides (As-ctl). They were transfected to cardiomyocytes respectively for 48 h. qRT-PCR was used to detect the change of miRNA-199a. (4) Neonatal rat ventricular myocytes were divided into four groups: A: control (ctl), B: phenylephrine (PE), C: PE + As-ctl, D: PE + As-miRNA-199a. qRT-PCR was used to detect the change of myh6, myh7 and Nppa. Software Axio Vision was used to detect the change of cardiomyocytes surface areas. RESULTS: (1) qRT-PCR results showed that miRNA-1, miRNA-133, miRNA-181a and miRNA-499 were significantly decreased, while the miRNA-199a was significantly increased at 1 week post AAC hearts compared with the sham group. (2) qRT-PCR results showed that miRNA-199a and myh7 were increased and myh6 was decreased significantly in Ad-miRNA-199a group compared with Ad-vector group. The cardiomyocytes surface area was increased in Ad-miRNA-199a group detected by immunofluorescence. (3) qRT-PCR results showed that miRNA-199a was significantly decreased in As-miRNA-199a group compared with Ad-vector group. (4) The Nppa and myh7 were significantly increased and myh6 was decreased in cardiomyocytes stimulated by PE for 48 h. The cardiomyocytes surface area determined by immunofluorescence was increased in PE + As-miRNA-199a groups compared with PE + As-ctl groups. CONCLUSION: miRNA-199a may play a regulatory role in cardiac hypertrophy. PMID- 21781602 TI - [Effects of docosahexaenoic acid on sodium channel current and transient outward potassium channel current in rat ventricular myocytes]. AB - OBJECTIVE: To investigate the effects of docosahexaenoic acid (DHA) on sodium channel current (I(Na)) and transient outward potassium channel current (I(to)) in rat ventricular myocytes and to evaluate potential anti-arrhythmic mechanisms of DHA. METHODS: I(Na) and I(to) of individual ventricular myocytes were recorded by patch-clamp technique in whole-cell configuration at room temperature. Effects of DHA at various concentrations (0, 20, 40, 60, 80, 100 and 120 micromol/L) on I(Na) and I(to) were observed. RESULTS: (1) I(Na) was blocked in a concentration dependent manner by DHA, stably inactivated curves were shifted to the left, and recover time from inactivation was prolonged while stably activated curves were not affected by DHA. At -30 mV, I(Na) was blocked to (1.51 +/- 1.32)%, (21.13 +/- 4.62)%, (51.61 +/- 5.73)%, (67.62 +/- 6.52)%, (73.49 +/- 7.59)% and (79.95 +/- 7.62)% in the presence of above DHA concentrations (all P < 0.05, n = 20), and half-effect concentration (EC(50)) of DHA on I(Na) was (47.91 +/- 1.57)micromol/L. (2) I(to) were also blocked in a concentration-dependent manner by DHA, stably inactivated curves were shifted to the left, and recover time from inactivation was prolonged with increasing concentrations of DHA, and stably activated curves were not affected by DHA. At +70 mV, I(to) was blocked to (2.61 +/- 0.26)%, (21.79 +/- 4.85)%, (63.11 +/- 6.57)%, (75.52 +/- 7.26)%, (81.82 +/- 7.63)% and (84.33 +/- 8.25)%, respectively, in the presence of above DHA concentrations (all P < 0.05, n = 20), and the EC(50) of DHA on I(to) was (49.11 +/- 2.68)micromol/L. CONCLUSION: The blocking effects of DHA on APD and I(to) may serve as one of the anti-arrhythmia mechanisms of DHA. PMID- 21781603 TI - [Prevalence and clinical characteristics of orthostatic hypotension in the elderly and retired population]. AB - OBJECTIVE: To determine the prevalence and clinical characteristics of orthostatic hypotension (OH) in the elderly and retired population. METHODS: A total of 1174 elderly and retired people underwent health screening physical examination in Guangzhou military region were included. The orthostatic blood pressure and heart rate were measured in supine position after resting for more than 5 minutes and at 0 and 2 min after standing. Subjects were divided into OH positive group and OH negative group. Orthostatic hypotension was defined as 20 mm Hg (1 mm Hg = 0.133 kPa) or greater decrease in SBP and/or 10 mm Hg or greater decrease in DBP after standing. RESULTS: The prevalence of OH in this cohort was 25.6% at either 0 or 2 min after standing (21.6% or 20.7% respectively). Incidence of hypertension, myocardial infarction (MI), heart failure (HF), ischemic stroke and diabetes was significantly higher in OH positive group than in OH negative group (all P < 0.05), however, antihypertensive medication was similar between the two groups. CONCLUSIONS: Orthostatic hypotension is common in the elderly and retired population and is associated with increased risk of hypertension, diabetes mellitus and cardiovascular disease. PMID- 21781604 TI - [Association between the urinary microalbumin/creatinine ratio and cardiovascular risk factors among elderly community subjects]. AB - OBJECTIVE: To determine the value of the urinary microalbumin/creatinine ratio (UACR) and the relationship between UACR and traditional cardiovascular risk factors among elderly community subjects. METHODS: A representative population in Shanghai rural district aged more than 65 years who participated in the heart health survey of the key projects in the national science and technology pillar program in the eleventh five-year plan period of China were sampled via a clustered complex sampling method. A midstream collection from the first morning void collected was used to measure the urinary microalbumin, the urinary creatinine and the UACR. Baseline information including traditional cardiovascular risk factors were obtained by standard questionaire to analyze the distribution status of UACR in the population with or without the risk factors. RESULTS: (1) There were 1718 subjects (721 males) of (73.3 +/- 5.5) years included in this study. (2) The prevalence of with at least one cardiovascular risk factor was 78.00% in this cohort, the top there risk factors were dyslipidemia (61.06%), hypertension (44.59%) and diabetes (13.80%). (3) The median (the lower quartile-the upper quartile) of the UACR of the population without cardiovascular diseases and risk factors was 13.81 (6.03 - 26.51) ug/mg. The level of UACR was significantly higher in females than that in males [17.12 (7.28 - 33.28) ug/mg vs. 5.49 (2.92 - 9.76) ug/mg, P < 0.01]. (4) The level of UACR in population with hypertension, diabetes or dyslipidemia was 16.27 (6.65 - 42.00) ug/mg, 26.27 (10.92 - 76.65) ug/mg and 16.39 (6.98 - 41.03) ug/mg respectively, all exceeding that of the healthy group (P < 0.05 or P < 0.01). (5) The levels of UACR increased in proportion to the increase of cardiovascular risk factor numbers, the UACR of the population with 0, 1, 2, 3 and 4 cardiovascular risk factors were 13.81 (6.03 - 26.51) ug/mg, 15.76 (6.79 - 36.44) ug/mg, 13.82 (5.68 - 34.43) ug/mg, 16.47 (6.07 - 50.56) ug/mg and 18.63 (11.26 - 83.09) ug/mg, respectively. The population with 4 cluster of cardiovascular risk factors posed the higher level of UACR than that of population with 0 cardiovascular risk factors (P < 0.05). CONCLUSIONS: The three most common risk factors of cardiovascular diseases among the elderly community subjects aged more than 65 years are dyslipidemia, hypertension and diabetes, all of which are related to the elevation of UACR. PMID- 21781605 TI - [A case report of sinus of Valsalva aneurysm with rupture into the interventricular septum]. PMID- 21781606 TI - [Multivessel coronary disease in a patient with lipophagia granulomatosis]. PMID- 21781607 TI - [Very small embryonic-like stem cells: a new alternative of stem cell-based therapy after acute myocardial infarction]. PMID- 21781608 TI - [Cardiovascular protective effects and related mechanisms of n-3 polyunsaturated fatty acids]. PMID- 21781610 TI - [The importance of teaching training]. PMID- 21781611 TI - [Euroscore system validation for cardiac surgery in Cordoba city]. AB - BACKGROUND: We recommend the use of models to estimate mortality hospital risk in cardiac surgery (CC). The aim of this study was to validate a risk stratification system, widely used as the EuroSCORE (ES), in our institution. MATERIAL AND METHODS: We retrospectively analyzed the records of patients undergoing CC consecutively between January 2006 and November 2008. The ES was calculated retrospectively based on data from medical records. Mortality was considered until the time of discharge. In all patients, the ES was calculated by logistic and additive. To study the validity of the model, we analyzed their ability to calibration and discrimination through the goodness of fit test of Hosmer and Lemeshow and area under the ROC curve, respectively. RESULTS: 153 patients were included, mean age 64.1 +/- 9.5 years, 77.8% men. The CRM was 60.8%, 24.8% and 14.4% valvular surgery combined (bypass + valve). Overall mortality was 3.9%. The area under the curve of the logistic model was 0.87 and the Hosmer Lemeshow test was 0.84. The area under the curve of the additive model was 0.86 and the Hosmer Lemeshow test was p = 0.89. A score greater than 7 points is additive had a sensitivity of 66% and 91,5% specificity for predicting hospital mortality. CONCLUSION: The ES is a useful model and can be used to estimate the risk of hospital mortality in CC in the city of Cordoba. PMID- 21781612 TI - [Brain signaling mechanisms during neonatal sepsis]. AB - The brain and the immune system are the two major adaptive systems of the body. During an immune response the developing neonatal brain and the immune system "cross-talk" and this course of action is essential for maintaining homeostasis. Two pathway are involved in this intercommunication: the hypothalamic-pituitary adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence suggests that norepinephrine (NE) is a neurotransmitter/neuromodulator in different organs and tissues. Under stimulation, NE is released from the sympathetic nerve terminals in these organs and tissues .Through stimulation of specific receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2) adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response. PMID- 21781613 TI - [Splenic cystic lymphagioma]. AB - Splenic cystic lymphangioma is a very rare benign neoplasia characterized by cystic dilation of the lymphatic vessels of the splenic parenchyima. It may occur in the spleen only or in multiple organs. We describe the case of a 46 year-old female, with he diagnosis of splenic cystic lymphangioma. Its clinical manifestations include abdominal pain, especially in left upper quadrant pain, abdominal distension, loss of appetite. Physical examination showed no specific findings. Ultrasonography and CT scann imaging showed multiple cysts replacing the normal parenchyma of the spleen. We report herein the surgical significance of lymphangioma of the spleen from both diagnostic and also therapeutic aspects, and we discuss laparoscopic splenectomy as an effective procedure for an excision of a splenic tumor suspected to be benign. .Histologic study after splenectomy confirmed the diagnosis of cystic lymphangioma of the spleen. PMID- 21781614 TI - [Primary lung paraganglioma. A case report]. AB - Primary lung paragangliomas are rare. They are 1-2% of the paragangliomas, and most of them occur in patients of 43-61 years. They clinically appear as solitary tumors and are in general asymptomatic. These tumors show a nesting pattern (Zellballen) of chief polygonal cells locked by fibrovascular trabeculae with subtenticular cells. The main cells have uniform nuclei with granular eosinophilic cytoplasm, and they are positive for neuroendocrinal markers (Neuron Specific Enolase, sinaptofisine and cromogranine A). Sustentacular cells are positive for protein S-100 and neurofibrilar protein. A differential diagnosis with the carcinoid tumor can be very difficult. The surgical treatment is mandatory , specially high blood pressure and the chances of malignization. PMID- 21781615 TI - One Health: much more than a slogan. PMID- 21781616 TI - A review of the epidemiology and surveillance of viral zoonotic encephalitis and the impact on human health in Australia. AB - Human encephalitis in Australia causes substantial mortality and morbidity, with frequent severe neurological sequelae and long-term cognitive impairment. This review discusses a number of highly pathogenic zoonotic viruses which have recently emerged in Australia, including Hendra virus and Australian bat lyssavirus which present with an encephalitic syndrome in humans. Encephalitis surveillance currently focuses on animals at sentinel sites and animal disease or definitive diagnosis of notifiable conditions that may present with encephalitis. This is inadequate for detecting newly emerged viral encephalatides. Hospital based sentinel surveillance may aid in identifying increases in known pathogens or emergence of new pathogens that require a prompt public health response. PMID- 21781617 TI - One Health in NSW: coordination of human and animal health sector management of zoonoses of public health significance. AB - Zoonoses of public health significance may occur in wildlife, livestock or companion animals, and may be detected by the human or animal health sectors. Of particular public health interest are foodborne, arboviral and emerging zoonoses (known/unknown, endemic/exotic). A coordinated One Health approach to the management of zoonoses in NSW uses measures including: mutually agreed intersectoral procedures for detection and response; surveillance and notification systems for defined endemic and exotic diseases; joint meetings and exercises to ensure currency of response plans; and intersectoral communication during a response. This One Health approach is effective and ensures the interests of both the human health and animal health sectors are addressed. PMID- 21781618 TI - Discovering novel zoonotic viruses. AB - From the emergence of Hendra virus and Menangle virus in Australia to the global pandemics of severe acute respiratory syndrome and influenza viruses (both H5N1 and H1N1), there has been a surge of zoonotic virus outbreaks in the last two decades. Although the drivers for virus emergence remain poorly understood, the rate of discovery of new viruses is accelerating. This is due to a combination of true emergence of new pathogens and the advance of new technologies making rapid detection and characterisation possible. While molecular approaches will continue to lead the way in virus discovery, other technological platforms are required to increase the chance of success. The lessons learnt in the last 20 years confirm that the One Health approach, involving inclusive collaborations between physicians, veterinarians and other health and environmental professionals, will be the key to combating future zoonotic disease outbreaks. PMID- 21781619 TI - Hendra virus: what do we know? AB - Hendra virus infection is an emerging infectious disease that is not well understood. Most cases of Hendra virus infection have occurred in Queensland, with one case in a horse in NSW. Hendra virus infection has a high mortality rate in horses and humans and as cases could occur anywhere in Australia it is important to be ready for prompt action should an outbreak occur in NSW. This paper: reviews the current knowledge on Hendra virus infection including methods for preventing the disease; explains the animal health and human health response for an outbreak within NSW; and discusses possible future avenues for post exposure prophylaxis and prevention by vaccination. PMID- 21781620 TI - Influenza: One Health in action. AB - Influenza highlights the relevance of One Health, where experts in animal, human and environmental health combine to solve inter-related problems. Human disease due to pandemic (H1N1) 2009 influenza and avian and human disease due to influenza A/H5N1 are recent examples of new zoonoses with significant global impact. Management and prevention of influenza and other emerging infectious diseases requires the expansion and continuing support of collaborations between human and animal health experts at the clinical, diagnostic laboratory, public health, research and training levels. PMID- 21781621 TI - Bug breakfast in the bulletin: automated data extraction from general practice: influenza-like illness surveillance. PMID- 21781622 TI - Bug breakfast in the bulletin: dengue. PMID- 21781623 TI - Communicable Diseases Report, NSW, March and April 2011. PMID- 21781624 TI - A refresher on herpes zoster, current status on vaccination, and the role of the dermatologist. AB - BACKGROUND: Herpes zoster (HZ) and postherpetic neuralgia (PHN) have a significant impact on quality of life. PHN is often chronic and difficult to treat. Dermatologists have always been involved in making the diagnosis of these conditions and, most recently, teaching the need for early antiviral therapy. OBJECTIVE: With the introduction of a new vaccine, HZ and its difficult-to-treat complication PHN can be prevented or minimized. Preventive medicine is important and has been supported by dermatologists with sun safety programs. Patients receiving biologics are at increased risk of developing zoster. CONCLUSION: Dermatologists should embrace zoster vaccination and recommend routine vaccination of immunocompetent individuals > age 60 years, as well as patients of any age who are starting immunosuppressants, including biologics. Given that individuals over age 50 years are at risk for PHN and studies have shown that the vaccine's immunogenicity and safety are maintained in individuals age 50 to 59 years, vaccination in this age group may be considered. Some dermatologists may consider vaccinating their own patients, but most will likely recommend that vaccination be performed by their patients' primary care physicians. PMID- 21781625 TI - Support needed to involve psoriasis patients in treatment decisions: survey of dermatologists. AB - BACKGROUND: Little is known about the interaction between dermatologists and their patients in facilitating treatment decisions for psoriasis. PURPOSE: Our objective was to determine dermatologists' perceptions of the needs of psoriasis patients in treatment decisions. METHODS: Dermatologists were invited to complete an 18-item online survey on the treatment of psoriasis, including questions on decision-making roles, factors they considered important to patients in treatment decisions, and patients' needs for decision support. RESULTS: Seventy dermatologists completed the survey (15% response rate). The highest rated factors in decision making were access to physicians for discussion (86%) and information about the risks and benefits (80%); the latter was more frequently reported by those >= 50 years (p = .021). Treatment-specific factors of greatest importance were side-effect profile (87%) and cost (80%). Potential hindrances were patient misconceptions about disease, inadequate patient education materials, patient indecision, and inadequate physician time. CONCLUSION: Although dermatologists consider accessibility to dermatologists and information on treatment risk and benefits to be important in treatment decision making, they report time with patients and educational materials to be inadequate. LIMITATIONS: The small sample size may limit the generalizability of our findings. PMID- 21781626 TI - Fibroblast growth factor-binding protein facilitates the growth and migration of skin-derived precursors. AB - BACKGROUND: Fibroblast growth factors (FGFs) are important regulators of cell proliferation, migration, and differentiation during wound healing. FGF-binding protein (FGF-BP) plays a critical role in activating FGFs by releasing them from the extracellular matrix. Although previous studies have demonstrated a pivotal role for FGF-BP in wound healing and angiogenesis, little is known about the biologic effects of FGF-BP on skin stem cells that contribute to wound healing. OBJECTIVE: To investigate the effects of FGF-BP on the growth and migration of skin-derived precursors (SKPs). METHODS: FGF-BP was titrated to determine the optimal concentration that maximally stimulated cell proliferation. Cellular phenotype and telomerase activity were compared in the presence and absence of FGF-BP. The effect of FGF-BP on cell migration was observed by intravenously transplanting SKPs to adult mice. RESULTS: Cell proliferation was maximally stimulated by FGF-BP at a concentration of 10 ng/mL without changing the intrinsic characteristics of SKPs. Low levels of telomerase activity were detected, and FGF-BP decreased the rate at which telomerase activity was downregulated. In vivo, FGF-BP remarkably enhanced the migration of SKPs to skin lesion sites. CONCLUSION: FGF-BP exerts a positive effect on the growth and migration of SKPs, suggesting a potential role for SKPs in wound healing. PMID- 21781627 TI - Canadian guidelines for the management of plaque psoriasis: overview. AB - New clinical treatment guidelines for plaque psoriasis, written by a panel of 16 Canadian dermatologists, were recently published online. These Canadian Guidelines for the Management of Plaque Psoriasis are evidence based and free of any influence from corporate sponsors and have been endorsed by the Canadian Dermatology Association (CDA). The Guidelines offer treatment recommendations for mild and moderate to severe body psoriasis, as well as for psoriasis affecting specific areas of the skin, such as the facial, flexural, and genital areas; nails; scalp; and palms and soles. The present overview describes the genesis and contents of the Guidelines, which are available in full through the CDA at (English) or (French). PMID- 21781628 TI - 5-year review of a unique multidisciplinary nonmelanoma skin cancer clinic. AB - BACKGROUND: A multidisciplinary nonmelanoma skin cancer (NMSC) clinic is held weekly at our center, where all new patients are jointly assessed by dermatology/dermatopathology, radiation oncology, and plastic surgery. A new patient database was established in 2004. The purpose of this study was to provide a preliminary report on the patients seen in the NMSC clinic and the treatment recommendations rendered. METHODS: The new patient database was reviewed from January 2004 to December 2008, and patient demographics, tumor characteristics, and treatment recommendations were extracted. Cochran-Mantel Harnszel (CMH) testing and chi-square analysis were used to detect any associations or relationships between variables within the database. A p value of less than .05 was considered significant. RESULTS: During the 5-year study period, 2,146 new patients were seen in the NMSC clinic. The majority of patients presented with basal cell carcinoma (64%) or squamous cell carcinoma (22%), with a median tumor size of 1 to 2 cm (range 0 to > 9 cm). Tumors were located in the head and neck region (80%), extremities (14%), and torso (6%). Previous treatment included biopsy only (62%), surgery (20%), electrodesiccation and curettage (11%), topical imiquimod (3%), and radiotherapy (1%). Treatment recommendations included surgery (55%) (with either simple excision [31%] or excision with margin control under frozen-section guidance [24%]), radiotherapy (19%), topical imiquimod (10%), observation (7%), and electrodesiccation and curettage (4%). CONCLUSIONS: The NMSC clinic at our center sees a high volume of patients who benefit from the multidisciplinary assessment provided. Treatment recommendations were based on patient and disease characteristics as well as patient preference. PMID- 21781629 TI - Treatment of acral persistent papular mucinosis with electrocoagulation. AB - BACKGROUND: Acral persistent papular mucinosis is a rare localized form of lichen myxedematosus with few case reports and no documented therapeutic options. OBJECTIVE: To report full resolution of acral persistent papular mucinosis after electrocoagulation. METHODS: Case report of a 51-year-old white female diagnosed with an acral persistent papular mucinosis. The clinical and histopathologic features, treatment provided, and response to treatment are detailed. RESULTS: Acral persistent papular mucinosis presented as multiple asymptomatic normochromic papules on the wrists. Treatment with topical and intralesional steroids was unsatisfactory. Gentle electrocoagulation led to complete resolution of the lesions and negligible scarring. The favorable results remained for 6 months of follow-up, and no new lesions have emerged. CONCLUSION: Our case of acral persistent papular mucinosis was successfully treated with electrocoagulation and long-lasting, excellent cosmetic results. PMID- 21781630 TI - Multiple symmetric lipomatosis. AB - BACKGROUND: Multiple symmetric lipomatosis (MSL) is a relatively uncommon entity of unknown etiology characterized by symmetrically subcutaneous accumulation of nonencapsulated adipose tissue. Approximately 200 to 300 cases have been published. OBJECTIVES: The aims of this article are to report the case of a 58 year-old Brazilian patient with MSL and provide a comprehensive overview of the current concepts concerning this disease. METHODS: Our search yielded 28 articles on MSL, including case reports and reviews of the literature. RESULTS: MSL predominantly affects Mediterranean males with a history of chronic alcohol abuse. It is usually asymptomatic and may be associated with diabetes mellitus, hyperlipidemia, hyperuricemia, macrocytic anemia, and oral cancer. Surgical resection is the best treatment option. CONCLUSION: The case reported is a classic presentation of MSL; however, it is particularly uncommon owing to the association with immune thrombocytopenic purpura. This association has been described only once in the medical literature. PMID- 21781631 TI - Cryptococcus gattii infections with cutaneous involvement. PMID- 21781632 TI - Acne keloidalis nuchae is scar and keloid formation secondary to mechanically induced folliculitis. PMID- 21781633 TI - Black rubber sensitization by bicycle handgrips in a child with palmar hyperhidrosis. AB - Black rubber is mainly an occupational source of contact sensitization; however, several unusual causes of non-occupational black rubber allergy are reported in the literature. A 10-year-old nonatopic Turkish boy with palmar hyperhidrosis developed acute vesicular bilateral palmar dermatitis following 2 to 3 weeks of intensive use of a new bicycle. The handgrips of the bicycle were made of black rubber. Patch testing showed a strong positive reaction to N-isopropyl-N-phenyl-4 phenylenediamine (the main sensitizer in black rubber) and questionable papular reactions to pieces of the black rubber handgrip. Additional cross-sensitization was found to p-phenylenediamine. There was no previous contact with black rubber or with any material that would contain p-phenylenediamine (eg, black henna dye). In conclusion, this was an unusual pediatric case of non-occupational allergic contact dermatitis from N-isopropyl-N-phenyl-4-phenylenediamine in black rubber bicycle handgrips. The young age of the patient and the development of contact sensitization within a relatively short period were striking. The release of the sensitizer from black rubber and the skin penetration were possibly enhanced by continuous friction and the accompanying hyperhidrosis, suggesting that the black rubber bicycle handgrip was the primary source of sensitization. PMID- 21781634 TI - Alternative hair-dye products for persons allergic to para-phenylenediamine. AB - BACKGROUND: Finding alternative hair dyes for individuals allergic to para phenylenediamine (PPD) has been difficult. Newer permanent and demipermanent hair dyes that have replaced PPD with para-toluenediamine sulfate (PTDS) are now available. OBJECTIVE: We examined whether individuals allergic to PPD will tolerate PPD-free hair dyes containing PTDS. METHODS: A retrospective analysis of patch-test results since October 2006 was done and yielded 28 patients allergic to PPD who were also tested with a hair dye series. From January 2004 through October 2006, seven additional patients allergic to PPD were tested with PTDS but not the full dye series. Patch-test results were analyzed. The newer PTDS dyes were recommended for all PPD-positive PTDS-negative subjects starting in 2008, and these subjects were contacted to determine whether they tolerated the recommended hair-dye products. RESULTS: Of 28 PPD-allergic patients seen since October 2006, 16 (57.1%) tested negative to all other substances on the dye series. Eleven tested positive to PTDS; of these, several were also allergic to other substances in the hair dye series. There was only one patient who was allergic to ortho-nitro-PPD and not to PTDS. Of 7 additional PPD-allergic patients seen from 2004 through 2006, 4 (57.1%) tested negative to PTDS. In total, 20 of 35 individuals (57.1%) tested positive to PPD but negative to PTDS. Ten of 13 PPD-positive patients for whom PTDS hair dyes were recommended subsequently used a PTDS hair dye, and all tolerated these products. CONCLUSION: Fifty-seven percent of patients allergic to PPD in this study will likely tolerate newer permanent and demipermanent hair dyes based on PTDS. Most individuals not allergic to PTDS will also test negative to other substances in the dye series. All 10 patients who tested positive to PPD and negative to PTDS who subsequently used a PTDS dye free of PPD tolerated these products. Many individuals allergic to PPD will benefit from the newer PTDS-based products. PMID- 21781635 TI - Cutaneous reactions to transdermal therapeutic systems. AB - Transdermal therapeutic systems (TTSs) are commonly used to treat many diverse medical conditions. There are several advantages to this form of drug delivery; however, adverse cutaneous reactions are common. This review article provides an update on skin reactions due to TTSs containing medications newly available in TTS form, including buprenorphine, diclofenac, lidocaine, oxybutynin, rotigotine, methylphenidate, rivastigmine, teriparatide, and nicardipine. PMID- 21781636 TI - Safety and efficacy evaluation of TRUE TEST panels 1.1, 2.1, and 3.1 in children and adolescents. AB - BACKGROUND: The Thin-layer Rapid Use Epicutaneous (TRUE) Test has approval for adults. OBJECTIVE: To evaluate the efficacy and safety of TRUE Test panels 1.1, 2.1, and 3.1 in children and adolescents suspected of having allergic contact dermatitis (ACD). METHODS: An open-label prospective study was performed, analyzing 102 consecutive patients aged 6 to 18 years referred for suspected ACD, between December 2008 and October 2009. Patch tests were applied for 48 hours, and evaluations of skin reactions were conducted at days 3 and 7, with a follow up visit 3 weeks after the initial applications. RESULTS: The mean age of all enrolled subjects was 11.6 years, and subjects included 52% females and 48% males. Positive reactions noted in more than 10% of the children were to nickel sulfate (29.7%), p-tert-butylphenol formaldehyde resin (16.8%), wool alcohols (15.8%), fragrance mix (12.9%), and cobalt dichloride (12.9%). Of the 101 subjects, 77 (76.2%) tested positive to one or more of the 28 allergens. No meaningful differences were observed in the frequency or severity of adverse events; reports of burning and stinging following patch removal; or the frequency, intensity, or symptoms of persistent reactions when evaluated by age, sex, or race. CONCLUSION: Patch testing is efficacious and safe in the pediatric population. PMID- 21781637 TI - Contact sensitization in Chinese patients with hand eczema. AB - BACKGROUND: Contact sensitization is an important cause of hand eczema, a common disease that affects both daily and occupational life. OBJECTIVE: To describe contact allergens in Chinese patients with hand eczema and to analyze the association between allergens and occupational exposure. METHODS: Three hundred sixty-six patients with hand eczema underwent patch testing with a modified North American standard series between September 1989 and December 2009. RESULTS: Positive patch-test reactions were observed in 74% of patients. The most frequent allergens were p-phenylenediamine (22.7%), nickel sulfate (21.9%), fragrance mix (19.9%), ammoniated mercury (19.7%), and carba mix (17.8%). Nickel and fragrance allergy in women, and carba mix and chromate allergy in men, showed gender predilection, and 64.2% of patients developed hand eczema from occupational exposure. Positive reactions to p-phenylenediamine in hairdressers and to chromate in metalworkers and construction workers presented higher frequencies (p < .05). CONCLUSIONS: p-Phenylenediamine, nickel, fragrance, mercury, and rubber chemicals are common allergens in Chinese patients with hand eczema. Gender and occupation may cause different exposures; thus, allergens may vary. PMID- 21781638 TI - Occupational allergic contact dermatitis from methyl aminolevulinate. AB - Photodynamic therapy (PDT) is used to treat certain types of nonmelanoma skin cancer. Metvix cream applied topically in PDT is composed of the active substance methyl aminolevulinate and 14 excipients composing the vehicle. One case of occupational allergic contact dermatitis from methyl aminolevulinate is reported. A 49-year-old nurse's aide working in a PDT unit in the dermatology department developed a dermatitis involving the eyelids and fingers. The lesions began a few months after she started working in that unit. Patch tests were performed with the standard series (Spanish Group for Research into Dermatitis and Skin Allergies [GEIDAC]), cosmetics series, Metvix cream "as is," the Metvix vehicle supplied by the manufacturer, and some of the excipients separately (methyl para hydroxybenzoate [Nipagin M], propyl para-hydroxybenzoate [Nipasol M], isopropyl myristate, cetostearyl alcohol [Lanette N], and disodium edetate). After day-2, day-4, and day-7 readings, positive results were achieved only with Metvix cream "as is." Tests performed on a control group of 15 individuals were negative. Literature on cases of allergic contact dermatitis from methyl aminolevulinate is reviewed. It should be emphasized that the present case is the first occupational case reported so far. PMID- 21781639 TI - Shellac. AB - Shellac is a common ingredient in cosmetics such as mascaras, lipsticks, nail polish, and hairsprays. As an emerging contact allergen in patients with eyelid dermatitis and contact cheilitis, it was added to the 2009-2010 North American Contact Dermatitis Group screening panel. Consideration of this allergen should be given with patients who present with allergic contact dermatitis in areas where shellac-containing substances were applied. PMID- 21781640 TI - Violin bow-associated rubber allergy in a child. PMID- 21781642 TI - Persistent perianal dermatitis associated with mucosal hemorrhoidal prolapse. PMID- 21781641 TI - Allergic contact dermatitis in private practice: what are the main sensitizers? PMID- 21781643 TI - Is soybean patch testing a valid diagnostic tool for adult atopic dermatitis? A comparison of two methods. PMID- 21781644 TI - Allergic contact dermatitis due to carteolol, with good tolerance to betaxolol. PMID- 21781645 TI - Stoma dermatitis: prevalent but often overlooked--clarifications. PMID- 21781646 TI - Non-occupational allergic contact dermatitis from pyridoxine hydrochloride and ranitidine hydrochloride. PMID- 21781648 TI - Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers. AB - OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce renal complications in patients taking loop diuretics. This study investigated the pharmacokinetic/pharmacodynamic effects and safety profile of orally administered diclofenac sodium, ibuprofen and diclofenac epolamine topical patch (DETP) on furosemide in healthy adult subjects. METHODS: This open-label, randomized, 5-way crossover study was conducted in 40 subjects (aged 19 - 45 y). Diclofenac (75 mg taken orally twice daily), DETP (1.3% applied topically twice daily), or ibuprofen (800 mg taken orally thrice daily) was administered for 3 consecutive days, followed by co-administration with furosemide (given intravenously as 20 mg/2 min). Plasma furosemide and NSAID concentrations, urine furosemide, sodium and potassium concentrations and urine output were determined throughout the 24 h period following furosemide administration. RESULTS: Orally administered ibuprofen significantly increased furosemide AUC(0-t) (37%) and AUC(0-inf) (36%) and decreased total body CL (27%), R(max) (19%) and CLR (23%) geometric mean ratios compared with furosemide control. Oral and topical diclofenac had no pharmacokinetic effects on furosemide. Ibuprofen increased sodium excretion (Ae(0 24), 16%) and decreased sodium R(max) (15%), and oral diclofenac decreased urine output (Vu(0-24), 15%). DETP had no effect on furosemide pharmacodynamics; total systemic exposure to diclofenac during DETP treatment was < 1% that of oral diclofenac. Treatments were generally safe, with 25 subjects reporting a total of 112 adverse events. CONCLUSIONS: Pharmacodynamic effects were seen with oral diclofenac (urine output) and ibuprofen (urine sodium excretion). Furosemide also affected plasma and urine pharmacokinetic profiles. Pharmacologic effects of DETP on furosemide were not observed under these conditions. Additional research is warranted to delineate the potential interactions of other NSAIDs with furosemide and other loop diuretics. PMID- 21781649 TI - Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study. AB - OBJECTIVE: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized. MATERIALS AND METHODS: Patients (n = 12) with severe renal impairment (creatinine clearance CL(CR) < 30 ml/ min/1.73 m2; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CL(CR) > 80 ml/min/1.73 m2) were enrolled into an open-label, parallelgroup study. Single dose (500 MUg, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups. RESULTS: A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)), maximum plasma concentration (C(max))) and a small increase in elimination half-life (t(1/2)) of roflumilast (-1%; -6%; +19%, respectively) and roflumilast N-oxide ( %; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups. CONCLUSIONS: The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment. PMID- 21781650 TI - Pharmaco-epidemiologic study of the prescription of contraindicated drugs in a primary care setting of a university: a retrospective review of drug prescription. AB - BACKGROUND: The prescription of contraindicated drugs is a preventable medication error, which can cause morbidity and mortality. Recent data on the factors associated with drug contraindications (DCIs) is limited world-wide, especially in Malaysia. AIMS: The objectives of this study are 1) to quantify the prevalence of DCIs in a primary care setting at a Malaysian University; 2) to identify patient characteristics associated with increased DCI episodes, and 3) to identify associated factors for these DCIs. METHODS: We retrospectively collected data from 1 academic year using computerized databases at the Universiti Sains Malaysia (USM) from patients of USM's primary care. Descriptive and comparative statistics were used to characterize DCIs. RESULTS: There were 1,317 DCIs during the study period. These were observed in a cohort of 923 patients, out of a total of 17,288 patients, representing 5,339 DCIs per 100,000 patients, or 5.3% of all patients over a 1-year period. Of the 923 exposed patients, 745 (80.7%) were exposed to 1 DCI event, 92 (10%) to 2 DCI events, 35 (3.8%) to 3 DCI events, 18 (2%) to 4 DCI events, and 33 patients (3.6%) were exposed to 5 or more DCI events. The average age of the exposed patients was 30.7 +/- 15 y, and 51.5% were male. Multivariate logistic regression analysis revealed that being male (OR = 1.3; 95% CI = 1.1 - 1.5; p < 0.001), being a member of the staff (OR = 3; 95% CI = 2.5 - 3.7; p < 0.001), having 4 or more prescribers (OR = 2.8; 95% CI = 2.2 - 3.6; p < 0.001), and having 4 or more longterm therapeutic groups (OR = 2.3; 95%CI = 1.7 - 3.1; p < 0.001), were significantly associated with increased chance of exposure to DCIs. DISCUSSION AND CONCLUSIONS: This is the first study in Malaysia that presents data on the prevalence of DCIs. The prescription of contraindicated drugs was found to be frequent in this primary care setting. Exposure to DCI events was associated with specific socio-demographic and health status factors. Further research is needed to evaluate the relationship between health outcomes and the exposure to DCIs. PMID- 21781651 TI - A systematic review of available clinical evidence - filgrastim compared with lenograstim. AB - BACKGROUND: Filgrastim (Neu-pogen(r), Amgen) and lenograstim (Granocyte(r), Chugai Pharma) are chemically different granulocyte colony-stimulating factors (G CSFs). Based on receptor-binding studies and in vitro potency assessment, a clinical superiority of lenograstim versus filgrastim has been postulated together with potential cost savings favouring lenograstim over filgrastim. OBJECTIVES: To compare the clinical efficacy of filgrastim and lenograstim based on current Summaries of Product Characteristics (SPCs) for both products taking into account published clinical trials in patients and healthy volunteers. SEARCH STRATEGY AND SELECTION CRITERIA: PubMed and citation lists of published articles were used to identify clinical trials with direct comparisons of filgrastim and lenograstim. All available clinical information directly comparing filgrastim and lenograstim has been accepted for evaluation. DATA COLLECTION: A total of 16 studies compared filgrastim with lenograstim. Four studies had a randomized, parallel-group design, 4 had a cross-over design and 8 studies were uncontrolled. RESULTS: Available data do not suggest a clinically remarkable difference between filgrastim and lenograstim in chemotherapy-induced neutropenia and the mobilisation of peripheral blood progenitor cells (PBPC) in patients and healthy donors. CONCLUSIONS: Both G-CSFs are recommended for clinical use according to instructions in the respective SPCs; there is no reason to prefer lenograstim over filgrastim in any of the approved indications for both. Costs calculations need to consider the advent of biosimilar filgrastim in Europe. PMID- 21781652 TI - Pharmacokinetics of hydralazine, an antihypertensive and DNA-demethylating agent, using controlled-release formulations designed for use in dosing schedules based on the acetylator phenotype. AB - PURPOSE: The antihypertensive hydralazine has recently been repositioned as DNA demethylating for the epigenetic therapy of cancer. As the acetylator phenotype is the key determinant of its plasma levels, the dose of hydralazine needs to be adjusted for the acetylation status of patients. METHODS: The pharmacokinetics of orally administered hydralazine was evaluated in 26 healthy volunteers (13 slow and 13 fast acetylators) after a single dose of 182 mg administered as a controlled-release tablet. Plasma levels of hydralazine were analyzed in 85 cancer patients treated with this formulation at a dose of 83 mg/day and 182 mg/day for slow and fast acetylators, respectively. RESULTS: The C(max) and t(max) of hydralazine for fast acetylators were 208.4 +/- 56.9 SD ng/ml and 2.8 +/- 2.5 h, respectively. The corresponding results for slow acetylators were 470.4 +/- 162.8 ng/ml, and 4.4 +/- 3.1 h. Healthy volunteers who were fast acetylators had no clinically significant changes in blood pressure and heart rate or any other side-effect, however, slow acetylators had transient episodes of headache, tachycardia and faintness. Among 85 cancer patients that received either 182 mg or 83 mg of hydralazine daily, according to their acetylator status, the mean concentrations of hydralazine in plasma were 239.1 ng/ml and 259.2 ng/ml for fast and slow acetylators, respectively. These differences were not significantly different, p = 0.3868. CONCLUSIONS: The administration of dose adjusted controlled-release hydralazine according to the acetylation status of cancer patients yields similar levels of hydralazine. PMID- 21781653 TI - Comparative bioavailability of two sildenafil tablet formulations after single dose administration in healthy Thai male volunteers. AB - OBJECTIVE: To compare the rate and extent of absorption of two sildenafil tablet formulations (Tonafil(r), T.O. Chemicals (1979) Ltd., Thailand as a test formulation and Viagra(r), Pfizer Pty Limited., Australia as a reference formulation) in healthy Thai male volunteers after single-dose administration under fasting condition. METHODS: A randomized crossover study with a washout period of 2 weeks was conducted in 20 healthy Thai male volunteers. The volunteers received either 100 mg of the reference or test formulation. Blood samples were collected at 0, 0.16, 0.33, 0.67, 1, 1.5, 2, 2.5, 4, 6, 9 and 12 h after drug administration. The plasma sildenafil concentrations were determined using a validated high performance liquid chromatography method. The pharmacokinetic parameters of sildenafil were calculated from the observed plasma concentration-time profiles by using a non-compartmental model. RESULTS AND CONCLUSIONS: The geometric means, C(max), of the reference and the test formulations were 696.42 and 734.06 ng/ml. The mean values of the AUC(0-t) and AUC(0-inf) of the test formulation were 2,073.03 and 2,237.37 ng * h/ml, while those of the reference formulation were 1,950.26 and 2,078.06 ng * h/ml. The geometric mean ratios (%) and 90% confidence intervals (CI) of the test and reference products for the log transformed C(max), AUC(0-t) and AUC(0-inf) of sildenafil were 105.40% (95.0 - 116.95%), 106.30% (99.74 - 113.28%) and 107.67% (100.83 - 116.48%). These values were within 80 to 125% of the US-FDA and the Thai-FDA criteria and therefore it can be concluded that the test formulation was bioequivalent to the reference formulation both in terms of rate and extent of absorption after single-dose administration under fasting condition. PMID- 21781654 TI - The toxicity potential of pharmaceuticals found in the Douro River estuary (Portugal): assessing impacts on gonadal maturation with a histopathological and stereological study of zebrafish ovary and testis after sub-acute exposures. AB - Concerns associated with pharmaceuticals in aquatic systems demand the establishment of links between xenobiotics and their respective concentrations and impacts on aquatic organisms. Herein, effects of non-steroidal pharmaceuticals in the gonadal maturation of zebrafish (Danio rerio) were evaluated by histopathological and stereological analyses after 21 days of exposure. Carbamazepine, fenofibric acid, propranolol, sulfamethoxazole and trimethoprim were selected, considering their detection in the Douro estuary (Portugal). Exposures were performed with single compounds and mixtures, the exposure concentrations including environmental levels. Overall, quantitative analyses showed a decreasing trend for late maturation stages in male and female gametogenesis with parallel increases in immature gametes. In females, and at the highest concentration mixture, a significant switch between the volume densities of late/mature oocytes versus primary oocytes was observed. On the verge of statistical significance, oocyte atresia was higher in both mixtures (5.75 +/- 4.02% for MXA and 5.65 +/- 5.27% for MXB) versus control (2.21 +/- 1.88%), in accordance with the histological identification of large atretic areas in some fish. Unlike females, males showed significant effects with single exposures. Spermatozoa in controls totalled 53.25 +/- 7.13% of the testis volume, decreasing with carbamazepine (47.19 +/- 5.30%), fenofibric acid (46.36 +/- 4.30%), propranolol (37.22 +/- 2.38%) and sulfametoxazole (39.37 +/- 5.15%). An increase in spermatocyte percentage was noted with propranolol (40.13 +/- 7.36%) and sulfametoxazole (40.84 +/- 1.66%) versus control (30.93 +/- 6.53%). The changes in maturation dynamics did not impact the gonadosomatic index. The results show that pharmaceuticals from various therapeutic classes can disrupt the maturation dynamics of fish ovaries and testes. Further studies are justified to tackle the underlying mechanisms and to gauge the full extent of effects/risks. PMID- 21781656 TI - Editorial. PMID- 21781657 TI - Cytochrome P450-mediated activation of phenanthrene in genetically engineered V79 Chinese hamster cells. AB - V79 Chinese hamster cells genetically engineered for rat cytochromes P450 1A1, 1A2, 2B1 and human cytochromes P450 1A1, 1A2, 2A6, 2E1, and 3A4 are being applied in metabolism studies on polycyclic aromatic hydrocarbons. This study presents the results on phenanthrene as the prototypic polycyclic aromatic hydrocarbon possessing a bay region. Phenanthrene is of less importance regarding cytotoxicity and carcinogenicity as compared to e.g. benzo[a]pyrene or 7,12 dimethylbenz[a]anthracene. However, phenanthrene is more readily converted to metabolites which are exreted in higher amounts than those from any other polycyclic aromatic hydrocarbon. Therefore, its metabolites are of diagnostic value in epidemiological and occupational exposure studies. For this reason, it is worthwhile to understand the metabolism of phenanthrene in detail, e.g. allocating metabolites and cytochromes P450s. In accordance to previous observations cytochromes P450 1A1 and 1A2 were the most active forms towards phenanthrene. However, metabolite profiles differed between rat and human homologues of cytochromes P450, in particular for cytochrome P450 1A2. The predominant metabolite formed by rat cytochrome P450 1A2 was the K region trans 9,10-dihydrodiol, whereas human cytochrome P450 1A2 produced similar amounts of the trans-1,2-, trans-3,4- and trans-9,10-dihydrodiol. High amounts of trans-1,2 dihydrodiol, the metabolic precursor of the bay-region dihydrodiol epoxide, were also formed by human cytochrome P450 1A1 compared to its rat homologue. Unexpectedly, human cytochrome P450 2E1 showed a remarkable catalytic activity to metabolize phenanthrene to its trans-9,10-dihydrodiol. Utilizing recombinant CYPs in live V79 cells appears to be a valuable too yielding results important for the evaluation of exposure data and risk assessment for humans. PMID- 21781655 TI - Effects of in vivo chronic hydrocarbons pollution on sanitary status and immune system in sea bass (Dicentrarchus labrax L.). AB - Following the development of an experimental system to expose adult fish to low and stable concentration of pollutant over a prolonged period, the in vivo effects of hydrocarbons on sanitary status, i.e. the health status of fish with regard to chemical pollution, and immune system in sea bass, Dicentrarchus labrax were assessed. A total of 90 fish were acclimated for 15 days, then 45 fish were exposed to the water soluble fraction (WSF) of Arabian crude oil, similar to a complex pollution by hydrocarbons chronically observed in situ in estuaries, while the 45 other control fish sustained the same experimental conditions in clean seawater. After 21 days of exposure, 30 contaminated and control fish were sampled, then 30 other fish were collected after a 15 day recovery period in clean sea water. PAH concentrations in crude oil, WSF, muscles and bile were measured by gas chromatography coupled with mass spectrometry analysis. White blood cell counts and differential leucocyte counts were determined by classical haematology methods. Cell mortality and phagocytosis activity of leucocytes were analyzed by flow cytometry. Haemolytic alternative complement activity and stress parameters were analyzed in blood plasma by spectrophotometry. After a 21 day exposure period to a mixture of 41 parent/alkylated-PAHs (835 +/- 52/85 +/- 1 5 ng L(-1)). Fish flesh was contaminated by a bioconcentration of naphthalene very closed to the Reference Dose for Oral Exposure estimated by US-EPA's Integrated Risk Information System, causing a potential risk for human consumers. A leucopenia due to a lymphopenia, a rise in leucocyte mortality and a decrease in phagocytosis activity were noted in contaminated fish compared to controls. All these results may be explained by the damage to membrane cells integrity by uptake of PAHs and suggested an impairment of specific and nonspecific immune systems. After a 15 day recovery period, effects were reversible for sanitary status and an offset in immunity was noted by a significant increase in leucocytes in contaminated fish compared to controls. PMID- 21781658 TI - F-actin levels but not actin polymerization are affected by triphenyltin in HL-60 cells. AB - The toxin triphenyl tin (TPT), Sn(C(6)H(5))(+)(3) caused a rapid decrease in the F-actin content of promyelocytic human leukemia cells (HL-60) chemically differentiated to neutrophils. Prior incubation (2 min) of the cells with 10 MUM TPT did not modify the extent of actin polymerization inducible either by a receptor-mediated stimulus (chemotactic peptide fMLP) or by a direct activator of G proteins (AlF(-)(4)). The inorganic tin salts SnCl(2) and SnCl(4) did not affect F-actin content or production of HL-60 cells. Microfilament thiol groups were not reduced by exposure of cells to TPT, but even increased. When F-actin was exposed to 10 |GmM triphenyltin in a cell-free system, the depolymerizing effect was not detectable. Thus, TPT does not affect cytoskeletal protein directly but depends for its toxicity on some other induced change, probably ionic/osmotic in the intact cell. PMID- 21781659 TI - Mutagenicity and genotoxicity of the mycotoxin ochratoxin A. AB - Natural occurrence of the mycotoxin ochratoxin A in food commodities has been linked to endemic diseases in certain human populations, where a high incidence of nephropathy is observed (Balkan endemic nephropathy). The increase of renal disease is accompanied with a high risk for urinary tract tumours. Despite epidemiological and experimental evidence for the carcinogenicity of ochratoxin A the underlying mechanism needs to be established. The pivotal role of cytochrome P450 in the mutagenicity of ochratoxin A could be demonstrated in experiments with cell lines stably expressing the human cytochrome P450 enzymes. CYP1A1, 1A2, 2C10 and 3A4, which were able to activate the non-mutagenic ochratoxin A into mutagenic metabolites. In the cell lines the bacterial lacZ' gene was used as reporter gene for mutagenicity. Sequencing of the lacZ' gene resulted in the detection of large deletions. In addition, in metabolically competent rat hepatocytes an increase of single strand breaks could be observed by means of the DNA alkaline elution assay. These DNA alterations could be related to biotransformation processes, indicating extensive metabolism of ochratoxin A. The discrepancies found between microsomal and cellular metabolism leads to the conclusion that ochratoxin A mediated mutagenicity requires additional processing of cytochrome P450 derived metabolism. PMID- 21781660 TI - Inhibition of intercellular communication and induction of ethoxyresorufin-O deethylase activity by polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans in mouse hepa1c1c7 cells. AB - Inhibition of intercellular communication (IC) between hepa1c1c7 cells was used as a possible bioassay to predict tumor promoting potency of polyhalogenated aromatic hydrocarbons (PAHs). Relative potencies with regard to 2,3,7,8-TCDD to inhibit IC and to induce cytochrome P450IA1/2 (EROD) in these hepa1c1c7 cells were compared in order to investigate the possible role of the Ah receptor (AhR). For the PCDD/F and the co-planar PCB congeners relative potencies of both responses were within the same range. However, the mono-ortho PCBs, 2,3,3',4,4' PeCB, 2,3,4,4',5-PeCB, 2,3',4,4',5-PeCB and 2,3,3',4,4',5,5'-HxCB showed a 30 1300 times higher potency to inhibit IC compared to EROD induction activity. These potency differences were even more pronounced for the di-ortho PCBs, 2,2',5,5'-TeCB and 2,2',3,3',4,4'-HxCB. The data presented here indicate that for IC inhibition by these non-planar PCBs a non-AhR mediated mechanism, with a different structure-activity relationship may be responsible. Given the high IC inhibition potency of mono- and di-ortho PCBs and their abundancy in environmental mixtures, the mono- and di-ortho PCBs may contribute for a major part to the total tumor promoting potency of complex mixtures relevant to human exposure. Using the traditional TEF values, these compounds do not account for much toxic potency in a mixture, which may imply that the tumor promotion potential is not covered by the commonly derived TEF values. PMID- 21781661 TI - Toxicity of dichloropropanols in rat hepatocyte cultues. AB - Exposure of humans to dichloropropanols has been shown to result in fulminant hepatic necrosis. These compounds have also been shown to be hepatotoxic in rats. In this study, 1,3-dichloropropanol, but not 2,3-dichloropropanol, was shown to be toxic to 24 h cultures of rat hepatocytes. The toxicity was inhibited by pre treatment of cultures with a cytochrome P450 inhibitor and enhanced by prior depletion of cellular glutathione. In addition, at equimolar concentrations both isomers were shown to deplete glutathione, although the extent of depletion was greater with the 1,3-isomer. 1,3-Dichloropropanol also depleted ATP and reduced the mitochondrial membrane potential. The effects on ATP, glutathione and membrane potential could be inhibited by the cytochrome P450 inhibitor. It is concluded that the toxicity of 1,3-dichloropropanol is mediated by cytochrome P450 and involves depletion of glutathione and loss of mitochondrial function. PMID- 21781662 TI - Dietary alpha-tocopherol content modulates responses to moderate ethanol consumption. AB - Rats were fed with diets containing differing amounts of alpha-tocopherol for 21 days. For the latter 14 days of this period, one half of the rats also received ethanol (7% v/v) in the drinking water. Treatments did not alter the rate of weight gain between groups. Hepatic glutathione levels were depressed by ethanol treatment in rats receiving diets deficient in alpha-tocopherol or containing normal levels of the vitamin (50 ppm). However, this depression was not found in rats maintained on a high alpha-tocopherol diet (1000 ppm). The high alpha tocopherol diet also prevented the ethanol-induced inhibition of proteolytic activity within the liver. A dose-dependent reduction of rates of hepatic generation of reactive oxygen species was effected by this vitamin. Within the central nervous system, the only region showing an ethanol-induced lowering of glutathione levels, was the midbrain of rats receiving the alpha-tocopherol deficient diet. PMID- 21781663 TI - Development of a caffeine breath test to measure cytochrome P450-1A activity in birds. AB - Cytochrome P450-1A activity is induced by planar polyhalogenated diaromatic hydrocarbons, and is often used as a biomarker of exposure of wildlife to these compounds. P450-1A activity is usually measured ex vivo in liver tissue. The purpose of this study was to develop a less invasive breath test to measure P450 1A activity in birds. Such an assay would allow measurement of P450-1A activity without the need to kill birds, and on the same individual over time. Caffeine is specifically metabolized by P450-1A, and N-demethylation of (14)C-labelled caffeine to (14)CO(2) was used as indicator of whole-body P450-1A activity. The caffeine breath test (CBT) was performed by injecting (14)C-labelled caffeine i.v. and measuring the (14)C activity of respired (14)CO(2). The CBT was developed with domestic chickens (Gallus domesticus) using several (14)C-labelled caffeine isomers, and was also performed with three species of fish-eating birds in the North American Great Lakes. The CBT was an effective method for measuring P450-1A activity. Chickens treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) metabolized significantly more tri-labelled caffeine (1,3,7 [(14)C]trimethylxanthine) during the CBT than untreated chickens (p = 0.004). Tri labelled caffeine and 3-methyl-[(14)C]caffeine were effective substrates in the CBT. PMID- 21781664 TI - Selective drug efflux in multidrug-resistant immunoblastic B lymphoma cells with overexpressed P-glycoprotein. AB - Multidrug-resistant (MDR) sublines of the immunoblastic B lymphoma cell line were established by sequentially selecting in increasing concentrations of vincristine or adriamycin. The vincristine- and adriamycin-resistant cell lines, HOB1/VCR and HOB1/ADR, respectively, demonstrated resistance to a wide spectrum of chemotherapeutic agents including MDR drugs (Vinca alkaloids and anthracycline), antimicrotubule drugs (colchicine), and DNA-damaging agents (cisplatin and mitomycin C). The expression of human mdrl gene, as analyzed by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR), revealed a 10-15 fold overexpression in both drug-resistant cell lines. Drug accumulation analysis demonstrated reduced accumulation of vincristine but not adriamycin in HOB1/VCR and HOB1/ADR cell lines. Inhibition of vincristine resistance was observed in both cell lines by verapamil, associated with restoration of drug accumulation, suggesting that acquired resistance in these cells is mainly due to P glycoprotein. The drug accumulation was also examined in two series of previously characterized adriamycin-selected MDR colon adenocarcinoma cells and vincristin selected non-MDR lung cancer cells. These studies demonstrated that immunoblastic B lymphoma cells selected for vincristine or adriamycin resistance preferentially develop P-glycoprotein-mediated vincristine efflux which plays a pivotal role in vincristine resistance. In contrast, these cells did not elevate adriamycin efflux, suggesting an additional mechanism responsible for adriamycin resistance. PMID- 21781665 TI - CYP1A1-inducing potency in H4IIE cells and chemical composition of technical mixtures of polychlorinated biphenyls. AB - Polychlorinated biphenyls (PCBs) are present in environmental and tissue samples as complex mixtures of dioxin-like and non-dioxin-like congeners. Induction of cytochrome (CYP) P4501A1-catalyzed 7-ethoxyresorufin-O-deethylase (EROD) activity in H4IIE hepatoma cells is widely used as a simple in vitro bioassay for the dioxin receptor-mediated biological action of dioxin-like agonists. Since the results of the assay may be influenced indirectly by abundant non-dioxin-like PCBs, its application to the bioanalysis of complex PCB mixtures was studied. In the PCB mixtures Arochlor 1254 and Clophen A50, potent dioxin-like non-ortho PCBs and polychlorinated dibenzofurans (PCDFs) were found in minor amounts. However, the non-ortho PCBs accounted for most of the overall 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) equivalents based on EROD induction (EROD-TEQs). A comparison with a pattern of toxic equivalents (TEQs) based on toxic equivalency factors (I-TEFs) recently suggested in an international report revealed a much higher relative impact of mono-ortho PCBs on I-TEQs than on EROD-TEQs while total EROD-TEQs approximately coincided with total I-TEQs. It is concluded that the H4IIE bioassay is useful to assess total I-TEQs but does not reflect the individual contributions of PCB subgroups because of a higher evaluation of mono-ortho and di-ortho PCBs by I-TEFs. Based on individual EROD-TEFs, slightly higher mean EROD TEQs than those calculated by assuming additive behaviour of single PCBs were obtained. This finding suggests a minor synergistic influence of non-dioxin-like PCBs on the inducing potency of dioxin-like agonists in the H4IIE bioassay. PMID- 21781666 TI - Novel piperidine derivatives: inhibitory properties towards cytochrome P450 isoforms, and cytoprotective and cytotoxic characteristics. AB - The ability of a series of eight piperidine derivatives, substituted at positions 1, 3 and 4, to inhibit P450-dependent metabolism of specific substrates, is reported. Five different P450 isoforms (1A1, 1A2, 2B1, 2E1 and 3A1) in differentially induced rat liver microsomes were used for this purpose. From the results it is concluded that compound 2 was the most potent and moreover, highly selective inhibitor for P4502B1 with an IC(50) of 2.5 MUM. Compound 3 appeared to have high selectivity for P4501A1 but not for P4501A2 (IC(50)s 80 and > 1000 MUM, respectively). P4502B1 was found to be the most susceptible P450 isoform for inhibition by compounds 2, 3 and 6, while P4502E1 was largely insensitive to the inhibitory properties of all piperidine derivatives. A preliminary SAR study for the cytotoxicity, cytoprotective and P450 inhibitory properties of the piperidine derivatives, was also attempted. Using freshly isolated rat hepatocytes, the toxicity of the compounds was estimated and expressed as lactate dehydrogenase (LDH) leakage, lipid peroxidation (LPO) levels and GSH depletion. Considering the P450 inhibition and cytotoxicity results, compounds 2 and 3 were tested for possible protective activity against paracetamol-induced cytotoxicities. It was found that compound 2 protects completely against LDH leakage and LPO caused by paracetamol in rat hepatocytes isolated from beta-naphthoflavone (beta-NF) pretreated rats. It is concluded that the piperidine structures studied proved to be potentially valuable lead compounds for the design of potent and selective P450 inhibitors and for non-toxic cytoprotective agents as well. PMID- 21781667 TI - Inhibition of Mac-1-dependent leukocyte adhesion by Y-24180, an anti-inflammatory agent, in mice. AB - Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine), an antagonist of platelet activating factor (PAF), has been already clarified to suppress the expression of an adhesion molecule, Mac-1, on human neutrophils in the previous in vitro study. In the present paper, we examined the effect of Y-24180 on in vivo Mac-1 expression on mouse neutrophils using a lipopolysaccharide-induced leukocyte reduction model in which Mac-1-dependent infiltration of neutrophils was involved. Prophylactic oral administration of Y-24180 inhibited the induction of Mac-1-strongly positive neutrophils by intraperitoneal injection of lipopolysaccharide and prevented the reduction of leukocyte number. In contrast, WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 a][1,4]diazepine-2-yl]-1-(4-morpholinyl)-1-propanone), another PAF antagonist, showed little effect. PAF injection failed to induce the Mac-1-strongly positive neutrophils in peripheral blood and the reduction of circulating leukocytes, indicating that PAF was not concerned with the lipopolysaccharide-induced up regulation of Mac-1 expression and leukocyte reduction. Y-24180 inhibited the leukocyte infiltration also in the thioglycollate medium-induced peritonitis, which was mediated by Mac-1-dependent leukocyte adhesion. These results indicate that Y-24180 inhibits the leukocyte infiltration into the inflamed sites by suppressing Mac-1 expression on leukocytes in vivo and can contribute to the improvement of inflammatory diseases in which the Mac-1-dependent leukocyte adhesion is involved. PMID- 21781668 TI - Studies on the differential sensitivity between diabetic and non-diabetic human erythrocytes to monoacetyl dapsone hydroxylamine-mediated methaemoglobin formation in vitro. AB - Methaemoglobin generation by monoacetyl dapsone hydroxylamine in non-diabetic and diabetic erythrocytes was investigated in vitro. Methaemoglobin formation in purified haemoglobin isolated from both types of erythrocytes as well as haemolysates from both diabetic and non-diabetic erythrocytes did not differ. Prior to 18 h incubation with 10 and 20 mM glucose diabetic erythrocytes were significantly less sensitive to monoacetyl dapsone-induced methaemoglobinaemia. After pre-incubation the differential was lost although significant change in glutathione concentrations could not be shown between the two cell types. NADH diaphorase levels measured in diabetics and non-diabetics did not significantly differ. It is possible that diabetic cells display reduced hydroxylamine-mediated methaemoglobin generation due to differences in glutathione metabolism. PMID- 21781669 TI - Different age-related changes in NMDA and glycine receptors in the rat brain. AB - We investigated the age-related changes of N-methyl-d-aspartate (NMDA) and strychnine-insensitive glycine receptors in the brain from Fischer rats aged 3 weeks (immature), 6 months (adult), 12 months (mature), 18 months (middle-aged) and 24 months (aged) using receptor autoradiography. [(3)H]MK-801 and [(3)H]glycine were used to label the NMDA receptor and the glycine receptor, respectively. In immature rats, [(3)H]MK-801 binding showed a significant decline only in the nucleus accumbens, whereas [(3)H]glycine binding exhibited a significant increase in the frontal cortex, parietal cortex, striatum and thalamus as compared with young rats. In mature, middle-aged and aged rats, [(3)H]MK-801 binding showed no significant change in the brain. In contrast, [(3)H]glycine binding showed a conspicuous reduction in the striatum and hippocampal CA3 sector and thalamus from mature rats. Thereafter, the age-related reduction in [(3)H]glycine binding was observed in all brain areas of middle-aged and aged rats. These results demonstrate that the glycine receptor in the rat brain is far more susceptible to aging processes than the NMDA receptor. Furthermore, they suggest the conspicuous differences in the developmental pattern between NMDA and glycine receptors in the rat brain after birth. These findings suggest that glycine receptor in the brain is primarily and severely affected in aging processes and this may lead to age-related neurological deficits. PMID- 21781670 TI - Differences in binding of epidermal growth factor to liver membranes of TCDD resistant and TCDD-sensitive rats after a single dose of TCDD. AB - Epidermal growth factor (EGF) receptor has been implied as having a role in certain actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). After a single dose of TCDD, the receptor has been shown to be downregulated in several tissues including the liver. Two rat substrains, the Han/Wistar (Kuopio; H/W) rat and the Long-Evans (Turku AB; L-E) rat exhibit over a 1000-fold difference in their sensitivity to the lethal effect of TCDD. This large sensitivity difference was utilized in the current study to investigate whether or not a correlation exists between TCDD lethality and biochemical endpoints related to the hepatic EGF receptor. In the TCDD-sensitive L-E strain both the B(max) of the EGF receptor and the receptor protein as measured by Western blots, decreased dose and time dependently. Ten days after a lethal dose of TCDD (50 MUg/kg), the downregulation was 80%. In the resistant H/W strain, two non-lethal doses were used (50 and 500 MUg/kg), since the lethal dose is not known. These doses caused a downregulation already at 4 days after dosing, but no further decrease by day 10. The activity of phosphoenolpyruvate carboxykinase (PEPCK, the main gluconeogenetic enzyme in the liver and a proposed target of TCDD) decreased in H/W rats at least to the same extent as in L-E rats at both 4 and 10 days. It is concluded that EGF receptor downregulation is different in the two rat strains studied, despite the fact that a classical Ah receptor-regulated response (CYP1A1 induction) is similar. The results demonstrate that downregulation of the EGF receptor by TCDD is strain-dependent as well as dose- and time-dependent. PMID- 21781671 TI - Nephrosis aggravates HCl-ethanol-induced gastric lesions in rats. AB - This study was performed to evaluate the effect of nephrosis on gastric lesions in the rats. A single i.v. injection of daunomycin (12 mg/kg) into rats produced severe proteinuria and hypercholesterolemia on the 20th and 40th days after the administration. The severity of HCl-ethanol-induced gastric lesions was significantly greater in nephrotic rats than in control animals on the 20th and 40th days. The gastric mucosal blood flow on the 40th day was significantly lower in nephrotic rats. Pretreatment of normal rats with N(omega)-nitro-l-arginine or N(omega)-nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly aggravated the HCl-ethanol-induced gastric lesions and reduced the blood flow. When N(omega)-nitro-l-arginine methyl ester was given to nephrotic rats on the 40th day, it further increased the aggravation of the gastric lesions caused by nephrosis. These results suggest that the aggravation of HCl-ethanol-induced gastric lesions observed in nephrotic rats may be, at least in part, related to the decrease in the release of NO from endothelial cells. PMID- 21781672 TI - Comparison of effects of xenobiotics on extrahepatic and hepatic microsomal drug metabolizing enzymes in mice. AB - The content of microsomal protein is the same in both kidneys and small intestine, corresponding to 57% of the control value expressed as 100% in the untreated liver. The contents of P450 and cytochrome b(5), and the activity of NADPH-cytochrome c reductase in the kidney were higher than those in the small intestine, which were 17%, 22% and 41% of controls, respectively, in the former and 5%, 11% and 22% of controls in the latter. As compared with similar measurements made in the liver, the activities of substrate-metabolizing enzymes in these extrahepatic organs were very low. The activities of renal aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase, 7 methoxycoumarin O-demethylase and benzo(a)pyrene hydroxylase were 6%, 5%, 3%, 0.6% and 0.2% of controls, respectively. The activities of these enzymes in the small intestine were lower than those in the kidney or below the limits of detection. These results suggested that isoforms or their contents of P450 responsible for these substrate biotransformations are different among liver, kidneys and small intestine. Meantime, this study showed similar significant inductions by phenobarbital and rifampin of small intestinal and hepatic microsomal drug-metabolizing enzymes. In contrast, neither phenobarbital nor rifampin was capable of increasing renal microsomal enzymes, with the exception of benzo(a)pyrene hydroxylase which was induced by rifampin. These findings indicated that both liver and small intestine, but not kidneys contain the same phenobarbital- and rifampin-inducible P450 isoforms, cytochrome b(5) and NADPH cytochrome c reductase. In addition, CCl(4) could be bioactivated by CYP2E1 to free radicals in the kidney which caused destruction of microsomal enzymes. In mice pretreated with phenobarbital, CCl(4) also attenuated the increase in content of P450 in the small intestine, which appeared to be a result of induction by phenobarbital of CYP2E1. PMID- 21781673 TI - Doxorubicin alters Ca(2+) transients but fails to change Ca(2+) sensitivity of contractile proteins. AB - Doxorubicin produced a transient increase and a subsequent decrease in the amplitude of twitch contraction in myocytes isolated from guinea-pig heart and loaded with fura-2. These changes were associated with an increase and a subsequent decrease, respectively, in the amplitude of Ca(2+) transients (peak minus diastolic Ca(2+) concentrations). Doxorubicin increased the diastolic Ca(2+) concentration with a concomitant shortening of the diastolic myocyte length. The time to peak Ca(2+) transients and the time to peak twitch contraction increased in parallel. Doxorubicin failed to affect the Ca(2+) concentration-contraction curve in skinned fibers obtained from atrial muscle. We conclude that biphasic inotropic effects of doxorubicin result from biphasic changes in Ca(2+) transients, and that doxorubicin fails to alter Ca(2+) sensitivity of contractile proteins. These findings are consistent with the hypothesis that doxorubicin enhances Ca(2+) release and impairs Ca(2+) uptake by the sarcoplasmic reticulum. PMID- 21781674 TI - The effect of chronic cyclodiene insecticide treatment on some pharmacological actions of diazepam in rats. AB - The sedative and hypnotic effects of diazepam were tested in rats following chronic treatment with subconvulsive doses of the cyclodiene insecticides, endosulfan and aldrin. The anticonvulsant effect of diazepam was determined on picrotoxin-induced convulsions in insecticide-treated and control animals. Both endosulfan and aldrin promoted the convulsant action of picrotoxin indicating that the insecticides were able to show proconvulsant action following chronic administration. Interestingly, the protective effect of diazepam against picrotoxin-induced convulsions was greater in endosulfan- and aldrin-treated animals than in control animals. The sedative and hypnotic effects of diazepam were also increased in insecticide-treated animals. The mechanisms involved in the interaction were discussed with the support of the findings reported by the present and other investigators on the central and hepatic effects of chronic endosulfan and aldrin treatment. PMID- 21781675 TI - Alterations of striatal monoamine metabolites in young rats following pre- and postnatal lead exposure. AB - Dam rats were given lead (0, 0.58, 1.76, and 5.27 mmol/l) containing water ad lib from day 16 of gestation to weaning of the offspring on day 21 postpartum. The pups continued drinking the same lead containing water until the postnatal day 30. At the 30th day postpartum, the pups in each lead treated group were divided into four groups. The first group contains six male pups (PN30M). The second, third, and fourth groups contain six female pups (PN30F, PN60a, PN60b), respectively. The six female pups from control group formed the fifth group (PN60c). PN60a continued drinking the same lead-containing water until the postnatal day 60. PN60b were dosed with distilled water instead of lead containing water from the 30th day to the 60th day postpartum. PN60c began to expose to 5.27 mmol Pb/l from the 30th day to the 60th day postpartum. The rats in PN30M and PN30F were decapitated on the 30th day postartum, whereas PN60a, PN60b, and PN60c were decapitated on the 60th day postpartum. The contents of metabolites of monoamine neurotransmitters: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5 hydroxyin-doleacetic acid (5-HIAA) in striatum were determined using high performance liquid chromatography with electrochemical detection (HPLC-ECD). There were significant increases in the concentrations of HVA (1.58 +/- 0.30 vs. 1.17 +/- 0.12 ng/mg wet tissue in the 5.27 mmol Pb/l group of PN30M, p < 0.01; and 1.44 +/- 0.08 vs. 1.17 +/- 0.10 ng/mg wet tissue in the 5.27 mmol Pb/l group of PN60a, p < 0.05) and DOPAC (2.39 +/- 0.25, 2.47 +/- 0.28, 2.39 +/- 0.44 vs. 1.82 +/- 0.24 ng/mg wet tissue in three lead treated groups of PN60a, p < 0.05). The significant decreases in the concentration of MHPG (37.33 +/- 5.53, 32.02 +/- 6.87, 33.31 +/- 2.41 vs. 43.85 +/- 4.93 ng/mg wet tissue in the 0.58 mmol Pb/l group of PN60a, p < 0.05; in the 1.76 and the 5.27 mmol Pb/l group of PN60a, p < 0.01) and 5-HIAA (0.23 +/- 0.04 vs. 0.38 +/- 0.05 ng/mg wet tissue in the 5.27 mmol Pb/l group of PN30M, p < 0.05; 0.26 +/- 0.09 vs. 0.45 +/- 0.09 ng/mg wet tissue in the 5.27 mmol Pb/l group of PN30F, p < 0.05; 0.31 +/- 0.08 vs. 0.44 +/- 0.08 ng/mg wet tissue in the 5.27 mmol Pb/l group of PN60a, p < 0.05) were observed. No significant changes in the concentration of monoamine metabolites were observed either in rats of PN60b or PN60c. The results demonstrated the disturbances of monoamine metabolism in the striatum of developmental lead exposed rats. PMID- 21781676 TI - Developmental neurotoxicity of four ortho-substituted polychlorinated biphenyls in the neonatal mouse. AB - The objective of the present study was to investigate whether neonatal exposure to single PCB (polychlorinated biphenyl) congeners 2,4,4'-trichlorobiphenyl (IUPAC 28), 2,2',5,5'-tetrachlorobiphenyl (IUPAC 52), 2,3',4,4',5 pentachlorobiphenyl (IUPAC 118) and 2,3,3',4,4',5-hexachlorobiphenyl (IUPAC 156) when given as one single dose (0.7-14 MUmol/kg body weight per os) to 10-day-old male NMRI mice could induce persistent neurotoxic effects in the adult animal. Furthermore, to ascertain whether behavioural aberrations, both in spontaneous behaviour and in learning and memory function, were followed by changes in the cholinergic and/or the dopaminergic system. It was found that neonatal exposure to lightly chlorinated ortho-substituted PCBs, 2,4,4'-tri- and 2,2',5,5' tetrachlorobiphenyls, can induce persistent aberrations in spontaneous behaviour. Neonatal exposure to 2,2',5,5'-tetrachlorobiphenyl also affected learning and memory functions in the adult animal. In the animals showing a deficit in memory and learning function, the cholinergic nicotinic receptors in the cerebral cortex were affected. Exposure to 2,3',4,4',5-penta- and 2,3,3',4,4',5 hexachlorobiphenyl, mono-ortho congeners ('co-planar-like'), in the same dose range did not cause any significant change in the investigated behavioural variables, spontaneous and swim-maze behaviour. PMID- 21781677 TI - Mucosal nitric oxide is not responsible for the hemodynamic changes induced by nicotine in rat stomachs. AB - It has been shown that chronic nicotine treatment decreases gastric mucosal blood flow (GMBF). The mechanism for this action is still not defined. In this study, nicotine treatment (5, 25 or 50 MUg/ml drinking water) for 10 days dose dependently reduced the GMBF and volume of hemoglobin but increased ethanol induced gastric damage. These effects were potentiated by N(omega)-nitro-l arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor. l arginine but not the d-analog restored the actions of l-NAME, indicating that the selective action of l-NAME. However, the potentiating actions of l-NAME were significantly attenuated in the nicotine-pretreated rats. When the basal mucosal NO synthase (both iNOS and cNOS) activity and its second messenger cyclic GMP levels were measured, no difference was found between the nicotine and the non nicotine groups. Furthermore, high dose of l-arginine could not reverse the action of nicotine. These findings suggest that the adverse action of chronic nicotine treatment on GMBF and lesion formation is probably mediated through a NO independent mechanism. PMID- 21781678 TI - Silent cholinesterase gene in an Asian Indian family in Trinidad. AB - Cholinesterase activity was estimated in the serum of a Trinidadian female of Asian Indian descent. Her serum cholinesterase was pathologically low (0.17 U/ml) compared to the average reported for the population (10.59 +/- 2.77 U/ml), and her dibucaine number could not be estimated. In a pedigree study her sister displayed similar enzyme activity and cholinesterase was 0.09 U/ml. Cholinesterase could not be detected in the sera of both sisters using electrophoresis. Among three generations of the family studied, the silent variant of the cholinesterase gene could be segregated in offspring of the maternal uncle (normal cholinesterase phenotype) whose spouse's serum displayed an intermediate dibucaine number. The possible inheritance of the silent gene in the pedigree is discussed. PMID- 21781679 TI - Antiemetic activity of antioxidants against cisplatin-induced emesis in dogs. AB - Antioxidants such as glutathione, N-(2-mercaptopropionyl)glycine (MPG), vitamin E, vitamin C and a combination of vitamin E and vitamin C in different treatment schedules were evaluated for their antiemetic activity against cisplatin-induced emesis in dogs. While cisplatin-induced emesis was significantly reduced by all these agents, glutathione, MPG and combination of vitamin E and vitamin C produced maximum reduction. The antiemetic activity of antioxidants may be attributable to their ability to react with free radicals generated by cisplatin. The present study provides further evidence that free radicals play a role in cancer chemotherapy induced emesis and warrant clinical evaluation. PMID- 21781680 TI - Tumor promoters induce inhibition of gap junctional intercellular communication in mouse epidermal cells by affecting the localization of connexin43 and E cadherin. AB - The molecular and histological effects of tumor promoters on gap junctional intercellular communication (GJIC) were studied in three mouse epidermal cell types, representing different stages of tumor formation. GJIC was inhibited by most of the studied compounds (l-ethionine, d-limonene, o-anisidine, clofibrate, Aroclor 1260 and 1,1'-(2,2,2-trichloroethylidene)bis(4-chlorobenzene) (DDT)) except NaF and phenobarbital (PB). Whatever their effect on GJIC, most of the studied compounds increased the phosphorylation state of the gap junction protein expressed in these cells, connexin43 (Cx43), as shown by Western analysis. All agents with GJIC inhibiting capacity changed the intensity of the immunofluorescent staining of Cx43 on the membrane of the cells, whereas NaF and PB had no effect on Cx43 immunostaining. No association could be found between the type of change in Cx43 localization (changed membrane and/or cytosolic staining) and Cx43 phosphorylation or GJIC inhibition. Because the cell adhesion molecule E-cadherin also regulates GJIC, the effects of tumor promoters on E cadherin protein and localization were studied. No quantitative change could be observed in E-cadherin protein content of cells treated with any of the selected agents. However, all agents which decreased GJIC, affected E-cadherin immunostaining of the membrane, while PB and NaF had no effect. These results show that an association exists between inhibition of GJIC and localization of both connexin43 and E-cadherin protein, but not with Cx43 phosphorylation. PMID- 21781681 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans via mother's milk may cause developmental defects in the child's teeth. AB - Previous studies have shown developmental dental defects in rhesus macaques and rats experimentally exposed to dioxin. Now it was investigated if dioxin exposure from mother's milk in a normal breast-fed child population correlated with enamel hypomineralization of teeth that mineralize during the first 2 years of life. We studied 102 6-7-year-old Finnish children breast-fed for an average of 10.5 months. Milk samples were collected when the child was 4 weeks old. The concentrations of 17 most toxic polychlorinated dibenzo-p-dioxin and furan congeners were determined. The total exposure to dioxins was calculated from the concentrations in milk and the duration of breast feeding. Hypomineralization of the target teeth was found in 17 children. Both the frequency and severity of the lesions correlated with the total exposure. The results suggest that at the prevailing levels in human milk, dioxin may be an important cause of hypomineralization in the developing teeth of children. PMID- 21781682 TI - Inhibition by arsenite of anticancer drug cis-diamminedichloroplatinum(II) induced DNA repair and drug resistance in HeLa cells. AB - We have previously reported a cisplatin-resistant HeLa variant cell line (HeLa/CPR) which exhibited an enhancement in repairing cisplatin-DNA adducts (Chao, 1994, Mol. Pharmacol. 45, 1137-1144). In this study, using this cell line, we investigated the modification, by arsenite, of cisplatin-induced cytotoxicity and DNA repair in the resistant cell line. By a sublethal dose of arsenite, cytotoxicity of the resistant cells was enhanced by 2.5-fold, compared to 1.62 fold in the parental cells. Using enzyme-linked immunosorbent assay (ELISA) and a monoclonal antibody specific for cisplatin-DNA adducts, we found that the resistant cells showed a 5.15-fold decrease in the adduct formation compared to the parental cells. However, in the presence of arsenite, the resistant cells showed only a 1.47-fold decrease in the adduct formation, indicating a more than 3-fold modification. Using host cell reactivation of transfected plasmid DNA carrying cisplatin damage (an indirect detection of DNA repair), arsenite also revealed a ~2-fold modification of adduct formation in the resistant cells. In addition, the time-dependent potentiation of cytotoxicity by arsenite in both cell lines was parallel to the increase of adduct formation. These results indicate that arsenite is an effective modifier of cisplatin-induced resistance and enhanced DNA repair in HeLa/CPR cells. The results are consistent with the notion that the cisplatin-resistant phenotype in HeLa cells is mainly mediated by enhancement of DNA repair. PMID- 21781683 TI - Influence of pH changes on the actions of verapamil on vascular excitation contraction coupling. AB - We have previously shown that pH changes alter the cardiovascular responses to verapamil in rat, in vivo and in isolated rat heart. The current study investigated the influence of pH changes on the actions of verapamil on potassium or noradrenaline-stimulated contraction in rat tail arteries. The proximal 2-2.5 cm of ventral tail artery was bathed in and perfused initially (20-25 min) with physiological salt solution (pH 7.4) which was later made calcium-free at pH 7.4 (control), pH 7.2 (acidosis) or pH 7.67 (alkalosis). After equilibration each artery was exposed to verapamil following which the contractile responses to increasing concentrations of calcium were recorded. The patterns of responses in noradrenaline- or potassium-stimulated arteries were different. In normal conditions, the vasodilator effect of verapamil was predominant in potassium stimulated arteries but less in the noradrenaline-stimulated preparations. With pH changes the effect of verapamil was enhanced more in noradrenaline- than in potassium-stimulated arteries. It is postulated that pathology-induced changes in the character of calcium channels could alter the effect of calcium channel blockers. PMID- 21781684 TI - Reduced retention of cadmium in the liver of metallothionein-null mice. AB - The distribution of cadmium (Cd) in the organs of mice was studied using metallothionein (MT)-null transgenic mice. When mice were administered with Cd chloride at a single subcutaneous dose of 1.0 mg Cd/kg body weight, Cd accumulated mainly in the liver and kidney by 6 h after injection without any significant difference between the MT-null mice and control (C57BL/6J) mice. MT was not detected in these organs of MT-null mice both before and after Cd administration whereas MT was induced mainly in these organs of the control mice. There was a marked elimination of Cd from the liver of MT-null mice by 21 days after administration, compared with a relatively slow Cd elimination in the C57BL/6J mice. Under the condition that no significant liver or kidney damage was observed, MT was considered to play a significant role in the retention of Cd in the liver but not in the uptake of this metal. PMID- 21781685 TI - Neonatal exposure to 2,2',5,5'-tetrachlorobiphenyl causes increased susceptibility in the cholinergic transmitter system at adult age. AB - Polychlorinated biphenyls (PCBs) constitute a large category of chlorinated hydrocarbons that can have developmental neurotoxic effects. We have recently reported that neonatal exposure to a lightly chlorinated ortho-substituted PCB, 2,2',5,5'-tetrachlorobiphenyl, can induce persistent aberrations in spontaneous behaviour and also affect learning and memory functions in the adult animal. Furthermore, in the adult animal the cholinergic nicotinic receptors in cerebral cortex were affected. The present study presents further evidence that the developing cholinergic system can be sensitive to lightly chlorinated ortho substituted PCBs. Neonatal exposure of male NMRI mice on postnatal day 10 to 2,2',5,5'-tetrachlorobiphenyl (4.1 mg/kg body weight, per os) was shown to alter the response to a cholinergic agent, nicotine, at an adult age of 4 months, but not to d-amphetamine, an agent known to affect the dopaminergic system. PMID- 21781686 TI - Susceptibility of metallothionein-null mice to paraquat. AB - Using transgenic mice in which metallothionein (MT)-I and MT-II genes, we have studied a putative role of MT as a free radical scavenger against paraquat, a free radical generator. Male mice were injected s.c. with paraquat (PQ) at a single dose of 40 or 60 mg/kg of body weight (b.w.). Two of the six MT-null mice died within 16 h at the dose of 60 mg PQ/kg. b. w. PQ administration increased hepatic MT concentration in the normal mice (C57BL/6J), but not in the MT-null mice. The lipid peroxidation (LP) determined by thiobarbituric acid-reactive substance formation was increased by PQ in the liver of normal and MT-null mice, and the enhanced level was greater in the MT-null mice than in the C57BL/6J mice. Administration of PQ significantly increased blood urea nitrogen only in the MT null mice, indicating renal damage. Without paraquat administration, the hepatic concentration of non-protein sulphydryl compounds was less in the MT-null mice than in the C57BL/6J mice, and the basal level of LP was higher in the MT-null mice than in the C57BL/6J mice. The present results support the notion that MT plays an antioxidative role against paraquat insult under physiological conditions. PMID- 21781687 TI - Role of tachykinins in airway narrowing induced by cigarette smoke in guinea pigs. AB - To investigate the mechanism of the airway narrowing induced by cigarette smoke, anaesthetized guinea pigs were exposed to 200 puffs of smoke for 10 min. Airway narrowing was assessed by monitoring the total pulmonary resistance (R(L)). Plasma extravasation was determined by measuring the amount of Evans blue dye extravasated into the trachea and main bronchi. Exposure to cigarette smoke caused a marked airway narrowing and plasma extravasation. Pretreatment with the dual NK(1) and NK(2) receptor antagonist, FK224, abolished such airway narrowing and significantly inhibited the extravasation. While the NK(1) receptor antagonist, FK888, inhibited the extravasation, it had no effect on airway narrowing. Atropine partially inhibited airway narrowing without affecting extravasation. Results suggest that the airway narrowing induced by cigarette smoke is caused by tachykinins, and that a cholinergic pathway is involved. Thickening of the airway walls induced by NK(1) receptor-mediated extravasation may not be involved in such airway narrowing. PMID- 21781688 TI - Induction of heat shock protein HSP-70 in rat retrosplenial cortex following administration of dextromethorphan. AB - Dextromethorphan, a non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptor, is one of the most widely used non-opioid cough suppressants, and it is generally considered to be a safe drug. In this study, we have examined whether dextromethorphan is neurotoxic to rat cerebrocortical neurons. Induction of heat shock protein HSP-70, an indicator of cellular stress, was observed in the posterior cingulate and retrosplenial cortex of rat brain after a single administration of dextromethorphan (75 mg/kg). Furthermore, administration of dextromethorphan (75 mg/kg) caused vacuolization in the same regions. These results suggest that high doses of dextromethorphan could cause neuronal injury in the cerebrocortical neurons. PMID- 21781689 TI - The role of nicotinic receptors and calcium channels in mipafox induced inhibition of catecholamine release in bovine chromaffin cells. AB - Depolarization induced catecholamine release from chromaffin cells was decreased 28% by N,N'-diisopropyl diamido-phosphorofluoridate (mipafox), an organophosphorus compound (OP) causing neurotoxic effects, while secretion stimulated by nicotinic agonist was inhibited 65%. The reversibility of this effect and the fact that calcium-dependent secretion from digitonin-permeabilized cells was unaffected by mipafox suggest that this compound affects the ionic currents implicated in catecholamine release. Patch-clamp experiments showed that the activity of voltage-dependent calcium channels (VDCC) was inhibited 35% by mipafox being this effect reversible whereas only minor effects were detected on Na(+) and K(+) currents. Finally, we studied the effect of mipafox on nicotinic ionic currents in chromaffin cells. In this case, the OP was able to cause reversible inhibition reaching maximal effects of 50-60%. In conclusion, nicotinic receptors and VDCC should be considered as potential targets in order to understand the neurotoxicity of these chemicals. PMID- 21781690 TI - Selective induction of the CYP3A family by endosulfan and DNA-adduct formation in different hepatic and hepatoma cells. AB - Endosulfan, a chlorinated cyclodiene insecticide, is known to cause a significant enhancement of altered hepatic foci in rats and to be a potent inhibitor of gap junctional intercellular communication in vitro. Both of these features are common to many tumor promoters. However, long-term studies in rodents provide no evidence that it is carcinogenic or genotoxic. In the present study, endosulfan genotoxicity is evaluated and the formation of DNA adducts is investigated in three types of cultured hepatic cells (rodent, bird, and human). DNA-adduct formation in response to endosulfan treatment is measured by the (32)P postlabelling method. The results have shown a high genotoxicity of endosulfan only in rat and human cells. Therefore, to better understand these findings and because nothing is known about the xenobiotic-metabolizing enzymes involved in endosulfan metabolism, we have attempted to identify the cytochromes P450 induced, which can transform endosulfan into reactive intermediates capable of interacting with DNA. To examine if endosulfan induces CYP1A-, CYP2B-, or CYP3A family transcripts, we measured transcript levels by Northern blot and RT-PCR analyses. Endosulfan appears to selectively induce expression of the CYP3A gene family. It is a potent inducer of CYP3A1 mRNA in rat and is also shown, by RT PCR. to increase the CYP3A7 transcript level in Hep G2 human hepatoma cells. In contrast, in fetal quail hepatocytes, CYP3A is not expressed and no endosulfan DNA adducts are formed. PMID- 21781691 TI - The effect of trimethyltin on acetylcholine release in the guinea-pig trachea. AB - The purpose of the present work was to characterise the effects of trimethyltin on the release of acetylcholine from parasympathetic nerves and its effect on the postjunctional cholinergic stimulation of a smooth muscle. The guinea-pig trachea has been used as a model. Prejunctionally, trimethyltin (3.0 * 10(-3) M) significantly enhanced in a reversible manner the high K(+) (75 mM) evoked release of endogenous acetylcholine and [(3)H]acetylcholine. The evoked release of endogenous acetylcholine and [(3)H]acetylcholine was released from a pool of acetylcholine being independent of extraneuronal Ca(2+) in the presence, but not in the absence of trimethyltin. The effect of trimethyltin on the release was not inhibited by low Ca(2+) (0 mM and 1.0 * 10(-4) M) or by Ca(2+) channel blockers (verapamil, 1.0 * 10(-4) M, flunarizine, 1.0 * 10(-4) M, omega-conotoxin GVIA, 2.0 * 10(-7) M and omega-agatoxin, 2.0 * 10(-7) M). The present results also demonstrate that trimethyltin induce emptying of a non-vesicular, probably a cytoplasmic storage pool of acetylcholine, since AH5183 (2.0 * 10(-5) M), an inhibitor of the translocation of acetylcholine into synaptic vesicles, and alpha latrotoxin (1.0 * 10(-8) M), a toxin from black widow spider venom inducing vesicle depletion, had no inhibitory effects on the release of [(3)H]acetylcholine evoked by trimethyltin (3.0 * 10(-3) M). The release of [(3)H]acetylcholine was moreover enhanced by trimethyltin when the vesicular uptake of [(3)H]acetylcholine was inhibited by AH5183, probably as a result of a higher cytoplasmic concentration of [(3)H]acetylcholine. Trimethyltin also reduced the neuronal uptake of [(3)H]choline and this was probably due to a depolarising effect of trimethyltin on the cholinergic nerve terminals. A similar depolarisation induced by trimethyltin was observed during patch clamping of GH(4) C(1) neuronal cells. Postjunctionally, trimethyltin had no effect by itself or on the carbachol-induced smooth muscle contraction, indicating that trimethyltin did not have a general depolarising effect on smooth muscle cells or an effect on muscarinic receptors. Furthermore, the reduced electrical field induced contraction and the subsequent increase in the basal smooth muscle tension that was observed by addition of trimethyltin was activity-dependent, and was most probably due to emptying of a nervous non-vesicular storage pool of acetylcholine, followed by rapid hydrolysis of acetylcholine by acetyl- and pseudocholinesterases. PMID- 21781692 TI - Adenosinergic mechanisms in anticonvulsant action of diazepam and sodium valproate. AB - The effects of adenosine receptor agonists and antagonists were studied in pentylenetetrazole (PTZ)-induced seizures in rats. Animals were pretreated with the non-specific adenosine receptor antagonist, theophylline (50 and 100 mg/kg, i.p.), or the specific A(1) adenosine receptor antagonist, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), in a dose of 1 mg/kg, i.p., followed by 100% anticonvulsant doses of diazepam (4 mg/kg)/sodium valproate (300 mg/kg, i.p.). Subsequently, they were challenged with convulsant doses of PTZ i.e. 60 mg/kg, i.p. It was seen that while DPCPX could not reverse the protection of both the antiepileptic drugs, theophylline significantly reversed this protection, as assessed by percent incidence of seizures and change in latency parameters. In another set of experiments, the rats were pretreated with a combination of subanticonvulsant doses of adenosine (500 mg/kg) or specific adenosine A(1) receptor agonist, cyclopentyladenosine (CPA) and diazepam (0.5 and 1 mg/kg)/sodium valproate (150 mg/kg), prior to PTZ challenge. We observed a decrease in incidence and increase in latency of seizures following either combination. The protection observed was independent of the hypothermic and hypotensive effects of adenosine and CPA. These results indicate that though A(1) agonist enhances the protection of diazepam and sodium valproate, a direct involvement of adenosine A(1) receptor in anticonvulsant action of these drugs is doubtful. PMID- 21781693 TI - Kinetics of the inhibition of xanthine dehydrogenase and of the reversible and irreversible forms of xanthine oxidase by silibinin and bendazac. AB - Xanthine oxidase exists in vivo predominantly as a NAD(+)-dependent dehydrogenase form (xanthine dehydrogenase) which can be transformed into oxygen-dependent oxidase forms as a result of sulfhydryl oxidation (reversible xanthine oxidase) or proteolysis (irreversible xanthine oxidase). Xanthine oxidase has been hypothesized to be a potential source of oxygen-derived free radicals during reperfusion of ischemic tissues. Xanthine dehydrogenase was purified from rat liver and converted into reversible xanthine oxidase by heating at 37 degrees C and into irreversible xanthine oxidase by proteolysis with trypsin. Silibinin and bendazac are compounds used in therapeutics and to which free radical scavenging properties were ascribed. The effects of the compounds silibinin and bendazac on the different forms of the enzyme were studied. Silibinin inhibited all the forms of the enzyme but bendazac inhibited only reversible and irreversible xanthine oxidase. The inhibitions seem to be mixed non-competitive-competitive. The authors discuss the hypothesis that selective inhibitors of xanthine oxidase, preventing the interruption of uric acid formation, may have some advantage over the inhibitors of both xanthine dehydrogenase and xanthine oxidase in the treatment and prevention of situations such as ischemia and reperfusion syndromes. PMID- 21781694 TI - Change of a beneficial effect into an untoward effect by ischaemia: effect of quinidine-like drugs on vulnerability to ventricular fibrillation. AB - The effects of three quinidine-like drugs, disopyramide, lidocaine and flecainide were investigated in anaesthetized, open-chest pigs on vulnerability to ventricular fibrillation under normal conditions and under myocardial ischaemia conditions. Vulnerability to fibrillation was evaluated by electrical ventricular fibrillation threshold (VFT), measured with 100 ms duration diastolic impulses the intensity of which was increased by steps of 1.0 or 0.5 mA. Impulses were delivered at the rate of 180 beats . min(-1). The ventricles were subjected to pacing at the same rate before the VFT determination, particularly throughout periods of ischaemia of increasing duration (30, 60, 90, 120, 150 s), separated by appropriate intervals for reproducibility of the results. Monophasic action potential (MAP) duration and conduction time were monitored in the ischaemic area under pacing. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin. The three drugs were i.v. administered in clinical dose range (1.00 mg . kg(-1) plus 0.04 mg . kg(-1) . min(-1)). In the absence of ischaemia, they increased almost equally VFT (from about 7 to 10 mA), despite 25% prolongation of conduction time. But, none of them was able to impede the increasingly marked fall of VFT caused by ischaemia: at 30 s, they had already lost any capacity for raising VFT and, beyond this time, they even aggravated its fall which led to spontaneous fibrillation when VFT approached 0 mA. The faster fall of VFT shortened time to onset of fibrillation (20 24 fibrillations for the three drugs at 150 s as against 12 24 in control period), the ischaemia-induced reduction of MAP duration (by 20%) being also hastened and slowing of conduction enhanced, given the addition of the depressant effects of ischaemia and drugs on conduction. Consequently, the antifibrillatory properties normally manifested by the studied drugs are first suppressed, then inverted by ischaemia. PMID- 21781695 TI - Activation of functionally protective K(+) channels by methylmercury in rat alveolar macrophages. AB - Methylmercury (MeHg) is generally known as a neurotoxic heavy metal while its effect on alveolar macrophages is still rarely studied. In this paper, we attempted to use whole cell and cell-attached patch-clamp recording technique and fura-2 fluorescence measurement to elucidate the effects of MeHg on rat alveolar macrophages. The results showed that extracellular application of MeHg induced a transient outward current I(O)(MeHg), 10-20 s in duration, 100-1000 pA in amplitude at -40 mV associated with a marked increase in conductance. The reversal potential depended distinctly on the external K(+) concentration. Removal of external Ca(2+) as well as bath applied verapamil caused a depression of I(O)(MeHg), and intracellular dialysis with 5 mM EGTA completely abolished I(O)(MeHg). Heparin (5 mg/ml) applied by intracellular dialysis greatly accelerated a run-down of I(O)(MeHg) induced by pressure ejection of MeHg. K(+) channel blockers such as quinine, and 4-aminopyridine especially low concentrations of dequalinium and apamin, but not tetraethylammonium inhibited I(O)(MeHg). Cell-attached single-channel recordings with the pipette solution containing 145 mM KCl revealed that the activation of single-channel currents with a conductance of 12 pS could be induced by application of MeHg outside the patch. Since MeHg increased [Ca(2+)](i), in a concentration-dependent manner which was partially blocked by either verapamil or Ca(2+)-free medium containing 1 mM EGTA, it is concluded that MeHg activates a Ca(2+)-dependent K(+) conductance by an increase of [Ca(2+)](i) through an influx from outside the cells as well as mobilization from intracellular store. A possibility that this membrane hyperpolarizing K(+) current may exhibit a functioning modulator in response to the harmful cytotoxic increase in [Ca(2+)](i) caused by MeHg was tested. Accordingly, this working hypothesis is verified by an increase of MeHg induced cytotoxicity of cultured rat alveolar macrophages through a blockade of this Ca(2+)-activated K(+) channel by dequalinium. PMID- 21781696 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects retinol esterification in rat hepatic stellate cells and kidney. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic environmental contaminant, interferes with retinoid homeostasis. To elucidate the underlying mechanism, the activities of lecithin : retinol and acyl-CoA : retinol acyltransferase (LRAT and ARAT) were determined in liver, kidney, and hepatic parenchymal and nonparenchymal cell fractions from rats 7 days after a single oral dose of 10 MUg TCDD/kg body weight (b.w). Severely depressed LRAT activity in hepatic stellate cells, and greatly increased LRAT activity in kidneys, as well as decreased ARAT activity in stellate cells, were seen in TCDD-treated rats. Although the relevance of decreased ARAT activity under physiological conditions is not clear, the changed LRAT activities most likely contributes significantly to the TCDD-induced effects on tissue retinyl ester levels. It is intriguing that TCDD affects LRAT activity in hepatic stellate cells and kidney in opposite directions. The results suggest that effects of TCDD on retinyl ester tissue levels could be due to a specific interaction with retinoid metabolism. PMID- 21781697 TI - Involvement of superoxide anions in ozone-induced airway hyperresponsiveness in unanesthetized guinea pigs. AB - To evaluate the involvement of superoxide in ozone (O(3))-induced airway hyperresponsiveness, we studied the effects of superoxide dismutase (SOD), a scavenger of superoxide anion, and apocynin, an inhibitor of superoxide anion generating NADPH oxidase in phagocytes, on the airway responses induced by O(3) in unanesthetized guinea pigs. Airway responsiveness was measured by PC(200)Mch, the concentration required to produce a doubling in the baseline specific airway resistance to an inhaled methacholine aerosol, in spontaneously breathing animals. Before exposure to 3 ppm O(3) for 30 min, animals inhaled either SOD (5000 U/ml) or vehicle for 5 min. Although SOD did not affect PC(200)Mch in the air control group, this agent reduced the O(3)-induced airway hyperresponsiveness. Repeated administration of apocynin (12 mg/kg for 4 days) also attenuated the O(3)-induced airway hyperresponsiveness. These data suggest that superoxide may be involved in the pathogenesis of O(3)-induced airway hyperresponsiveness, possibly through the stimulation of superoxide anions release from bronchoalveolar phagocytes. The data also suggest a potential therapeutic role for antioxidants in oxidant injury by air pollutants. PMID- 21781698 TI - Toxicity of amphotericin B to analbuminemic rats. AB - Nagase analbuminemic rats (NAR), a strain derived from Sprague Dawley rats (SDR), are suitable to determine the in vivo effect of hyperlipidemia and analbuminemia on the toxicity of the antifungal agent amphotericin B (AB). Cholesterol content was increased in all plasma lipoprotein fractions when SDR serum was compared with NAR serum. Incubation of AB with plasma from animals of both strains and further isolation of plasma lipoprotein by ultracentrifugation, showed that, while in SDR approximately 40% of the injected AB was in the lipoprotein fraction, in NAR almost all (approximately 80%) AB was associated with lipoproteins, especially in the low density lipoprotein fraction. AB spectrophotometry showed differences in the extent of AB aggregation between SDR and NAR plasma fractions. The lack of albumin results in aggregation of the AB present in the infranatant fraction. In vivo, a strong reduction in lethality was observed for NAR when compared to SDR (LD 50% of 6.4 and 1.9 mg/kg respectively). The preferential distribution of AB in the plasma lipoprotein fraction seems to affect pharmacological parameters, with a consequent reduction of toxicity. PMID- 21781699 TI - Isozyme selective induction of mouse pulmonary superoxide dismutase by the exposure to mercury vapor. AB - Alterations in lung superoxide dismutase (SOD) isozymes after exposure of mice to mercury vapor were examined. Inhalation of mercury vapor (10 mg/m(3)) for 1 h by mice resulted in a higher accumulation of mercury in the kidney and lung compared to other organs, at 1 h after exposure. Under these conditions marked enhancement of protein content in bronchoalveolar fluid (BALF), attributed to lung injury, was observed. Exposure to mercury vapor caused a significant increase in the pulmonary Cu,Zn-SOD activity (1.32-fold at 48 h) whereas Mn-SOD activity was suppressed to 82% of the control level, suggesting different sensitivity to the metal inhalation. The selective induction of Cu,Zn-SOD protein (1.79-fold at 48 h) was confirmed by immunoblot analysis with polyclonal antibodies against these isozymes. These observations suggest that the selective induction of Cu,Zn-SOD at the translational level appears to occur as an initial defense against mercury promoted oxidative stress. PMID- 21781700 TI - The characteristics in the inhibitory effects of capsaicin on voltage-dependent K(+) currents in rat atrial myocytes. AB - The electrophysiological effects of capsaicin in rat atrial myocytes were examined. Measurement of contractile force was done in rat left atria. Whole-cell patch-clamp technique was primarily used to study the change in membrane potential and ionic currents. Capsaicin produced an initial rise and a sustained increase in contractile force in rat left atria. Capsaicin (10 MUM) caused a significant prolongation of atrial action potential. In voltage-clamp experiments, capsaicin (1-100 MUM) caused the reversible reduction in the amplitude of transient outward (I(TO)) and late outward (I(L)) K(+) currents in concentration- and voltage-dependent manners. The time course for inactivation of I(TO) was changed to the biexponential process after the application of capsaicin. Capsaicin failed to cause any significant shift in quasi-steady-state inactivation curve of I(TO). The EC(50) values for the inhibitory effects of capsaicin on I(TO) and I(L) were 5 and 20 MUM, respectively. Capsaicin also suppressed the amplitude of acetylcholine- or adenosine-induced K(+) current, i.e., I(K(ACh,Ado)). The EC(50) value for capsaicin-mediated inhibition of I(K(ACh,Ado)) is 50 MUM. The present findings suggest that in isolated rat atria, during capsaicin exposure, the capsaicin-mediated inhibition of these K(+) channels is one of the ionic mechanisms underlying the positive inotropic and chronotropic actions. PMID- 21781701 TI - Epithelium-linked smooth muscle hyperresponsiveness in ferret tracheae exposed to acrolein. AB - The effects of acrolein exposure on tissue uptake and airway responses to substance P (SP) and nitroprusside (NIP) were determined in excised ferret tracheae exposed for 60 min to a constant flow of air or 0.3 and 3.5 ppm acrolein air mixtures. Histological examination indicated that whereas the epithelium of an air-exposed trachea was intact with no apparent injury, acrolein-induced epithelium damage was more pronounced at 3.5 than at 0.3 ppm vapor concentration. The fractional uptake of acrolein into the tracheal tissue continually decreased during the 1 h of exposure and was found to be significantly concentration dependent at the 60 min measurement point. This suggests that the uptake process of acrolein in the mucosal layer is not linear and is dominated by irreversible reaction. In the absence of the neutral endopeptidase inhibitor, phosphoramidon, acrolein significantly increased the maximal response to SP. Pretreatment with phosphoramidon abolished the differential effect of acrolein on airway smooth muscle response to SP. Nitroprusside relaxed acrolein-exposed tracheal rings precontracted with carbachol to their baseline tone, but it induced relaxation of air-exposed tracheal rings below their initial resting tension, indicating the presence of endogenous as well as induced tone. Pretreatment with NIP also abolished the differential effect of acrolein on airway response to carbachol and modified the potency of this agonist. We conclude that acrolein-induced hyperresponsiveness of the underlying airway smooth muscle is linked to inactivation of neutral endopeptidase synthesis as well as to loss of epithelium derived relaxation factor. PMID- 21781702 TI - Neurotoxicity of 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) and effects on catecholamine homeostasis in SH-SY5Y cells. AB - We have investigated the potential neurotoxicity of the catecholamine depleting agent 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) in SH-SY5Y neuroblastoma cells. TMIQ induced a time and dose related inhibition of 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazoyl blue (MTT) reduction and an increase in lactate dehydrogenase release. After 72 h TMIQ (30 MUM) significantly (P < 0.05) inhibited MTT reduction, and significantly increased LDH release. TMIQ cytotoxicity was not prevented by the inclusion of monoamine oxidase inhibitors (clorgyline or deprenyl), antioxidants (alpha tocopherol or Trolox C) or the uptake(1) inhibitor imipramine. TMIQ also induced a dose dependent stimulation of [(3)H]noradrenaline (NA) uptake, with maximum at 100 MUM and EC(50) of 8 MUM. This stimulation of [(3)H]NA uptake was not prevented by the inhibition of protein kinase C, or activation of adenylate or guanylate cyclases. In addition, TMIQ significantly (P < 0.05) displaced [(3)H]nisoxetine binding from the uptake(1) recognition site with a K(i) of 71 +/ 8 MUM. However, as this interaction occurs at concentrations of TMIQ well above the EC(50) for [(3)H]NA uptake, it is unlikely to explain TMIQ stimulated NA uptake. Furthermore, TMIQ inhibited potassium evoked [(3)H]NA release from SH SY5Y cells, with an IC(50) of 490 MUM. Thus, TMIQ is cytotoxic to SH-SY5Y cells. However, the exact mechanism of toxicity requires further investigation, since it appears not to involve monoamine oxidase bioactivation, and is not mediated through membrane based free radical damage. Furthermore, although TMIQ inhibits mitochondrial Complex I (IC(50) = 1.5 mM) with potency apparently greater than MPTP (2.7 mM), mitochondrial respiration was unaffected. The present studies suggest that the mechanism of toxicity differs from that causing depletion of catecholamines and inhibition of tyrosine hydroxylase by TMIQ described in previous studies. PMID- 21781703 TI - The beta-adrenoceptors and catecholamine levels in lead poisoned rats. AB - To investigate beta-adrenoceptor dysfunction upon exposure to lead, we measured (a) beta-adrenoceptor density in brain, heart, blood vessels and lymphocytes and (b) plasma catecholamine levels in rats with lead poisoning. Wistar rats were given drinking water containing lead acetate (2% w/v) for a period of 60 days. The radioligand [(125)I]iodocyanopindolol was used for determining the density of beta-adrenoceptors in membrane fragments in vitro and a high performance liquid chromatography (HPLC) for measuring plasma catecholamine levels. Plasma norepinephrine levels were found to be significantly higher in lead-exposed rats than in control animals (4.69 +/- 0.58 MUg/l vs. 3.67 +/- 0.53 MUg/l, p < 0.01). In lead-exposed animals the density of beta-adrenoceptors in brain (36%), heart (68%), blood vessels (57%) and lymphocytes (48%) was significantly less than in controls (p < 0.001), whereas the K(d) did not vary between the two groups. We have found that beta-adrenoceptor dysfunction in lead-poisoned rats was brought about by a decline in beta-adrenoceptor density. PMID- 21781704 TI - Increased severity of gentamicin nephrotoxicity in aging rats is mediated by a reduced glomerular nitric oxide production. AB - The present experiments have been performed to assess whether the increased severity of gentamicin-induced nephrotoxicity in old animals could be mediated by a decreased production of nitric oxide. Aging rats (12 months) treated with gentamicin showed higher plasma creatinine and a higher reduction in creatinine clearance. After gentamicin treatment, glomerular nitrite production was higher in young than in old animals, whereas no differences in cortical gentamicin concentration were observed between young and aging animals. The increased severity of gentamicin-induced acute renal failure in old animals could be based on a decreased glomerular NO production after gentamicin treatment. PMID- 21781705 TI - Introduction to the workshop on variability in toxic response - human and environmental Rapporteurs' summary. PMID- 21781706 TI - Variability in toxic response - relevance to chemical safety and risk assessment at the global level. AB - The aim of control limits for exposure to chemicals in air, food, water, and consumer products is to protect the whole human population, including the most susceptible individuals and 'at risk' groups. The existence of susceptible individuals is a factor that must be taken into account when quantitative chemical risk assessments are being made, and should be covered in the risk characterization. Classically, when extrapolating data derived from animal experiments using homogeneous, healthy test species for human health risk assessment uncertainty factors are applied. For inter-species extrapolation an uncertainty factor of up to 10 is applied. While it is evident that this procedure provides reasonable protection for the great majority of the population there are outlyers who may not be protected under all conditions. Within a population, individual susceptibility is influenced by genetic and environmental factors. These have regional and national differences. Environmental factors that are important in many countries include 'life-style' (e.g. tobacco and alcohol consumption, diet), nutritional and health status. In the case of environmental protection similar considerations apply but the emphasis is on species rather than individuals. The International Programme on Chemical Safety, as the global programme on identifying and assessing chemical risks to human health and the environment in order to assist countries in effective management, is constantly advancing the basic science and methodology for making chemical risk assessment. PMID- 21781707 TI - Population heterogeneity and its impact on the risk management of food safety. AB - Successful risk management of possible toxicological effects of chemicals in food, including novel foods, requires diverse strategies. This paper concentrates on the advisability of introducing post marketing surveillance as a key stratagem in the risk management of selected foods and food chemicals. It is argued that this stratagem is particularly applicable to those occasions when the population at risk is relatively easily identified. A key element therefore in the successful use of post marketing surveillance in selected foods, requires those agencies responsible for risk management to introduce a more thorough analysis of population heterogeneity into their strategies. PMID- 21781708 TI - Outline on risk assessment programme of existing substances in the European Union. AB - Various programmes have been developed by national and international organisations to improve chemical safety of existing substances. The European Union Programme came into force on 4 June 1993. This programme gives a legal requirement that the manufacturer or the importer has to deliver data on substances produced or imported. The risk assessment process in the EU provides that every member state formally selects priority substances. To perform the risk characterisation for a priority substance, exposure assessment and the dose (concentration)-response (effect) assessment are conducted. Comparing the information on exposure to the effects identified by a hazard identification of the substance the risk assessor has to decide whether there is or there is no need for further information or testing or whether there is need for limiting the risks. The draft risk assessment report is sent to the OECD as European contribution to the programme on existing substances for discussion with OECD member countries. A final decision on the substance is performed by the member states of the European Union. PMID- 21781709 TI - The influence of human variability upon food safety legislation. AB - This paper considers the influence of human variations in the kinetics and dynamics of chemicals in food upon the formulation of food safety legislation. Legislation is designed to protect and benefit all and not solely specific groups or individuals within the population. A consideration of the adequacy of the safety factors used to calculate Acceptable Daily Intake (ADI) leads on to the discussion of those circumstances in which a part of the population may exceed the ADI for a particular chemical. The conclusion is that the ADI does take human variability into consideration and that current legislation is satisfactory and made more so through the surveillance of dietary additive and contaminant intakes in man. PMID- 21781710 TI - Risk evaluation: criteria arising from legal traditions and experience with quantitative risk assessment in the United States. AB - Making use of quantitative estimates of risk involves sometimes painful choices about risk control options and ethical and social policies for additional control and/or acceptance of remaining risks. Out of the history of these choices in the U.S., we have drawn four broad categories of risk control criteria: The first of these is entirely qualitative; the last three can be informed by different kinds of quantitative analyses. The analyses differ in the implications of variability and uncertainty, among other factors. These suggested criteria should not be seen as a kind of formula to be programmed into a computer in place of human decision making. Rather, we hope they will contribute to an evolving language that can accurately represent our advancing technical understanding of the facts and frankly and compassionately convey our maturing understanding of the relevant value questions. PMID- 21781711 TI - Assessments of priority substances under the Canadian Environmental Protection Act Variations in exposure and response. AB - Under the Canadian Environmental Protection Act (CEPA), assessments have been completed for 44 environmental contaminants on the first Priority Substances List. The principles developed for the assessment of risk to human health for Priority Substances under CEPA are outlined, with specific emphasis on variations in exposure and response. These include the estimation of total exposure from all media, the development of exposure potency indices for carcinogens in lieu of low dose risk estimates and incorporation of toxicokinetic and toxicodynamic data, where available, to modify traditionally adopted uncertainty factors for development of tolerable intakes, or concentrations, for non-neoplastic effects. PMID- 21781712 TI - Derivation of acceptable concentrations for the protection of aquatic organisms. AB - Derivation of quality standards to protect aquatic ecosystems demands a minimum set of toxicity data to allow the risk assessor to take some account of: (1) variable responses to toxicants; (2) variable environmental characteristics; (3) interactions between duration of exposure and effects; and (4) ecological significance of impacts. Extrapolation from limited experimental data to predict a concentration protective in diverse ecosystems can employ either statistical models (consistent but rather rigid and may not protect all species) or empirical factors (more flexible and possibly more protective, but require expert judgment in their application). However derived, quality standards must be tailored to the specific conditions of release and environmental fate which influence a chemical's impact in aquatic ecosystems. It must also be recognised that protection of all individuals and even of all aquatic species may not be achievable or necessary to maintain a healthy ecosystem. Some possible future advances in the determination of water quality standards are suggested. PMID- 21781713 TI - Variability: noise or information in ecotoxicology? AB - There can be considerable variability between species, and within species between genotypes, in responses to toxicants. This needs to be controlled in running ecotoxicity tests and taken into account in carrying out ecological risk assessments. This paper addresses these two aspects of the problem and describes the methodology involved in each. PMID- 21781714 TI - A comparison of the toxicity to laboratory mice and pipistrelle bats Pipistrellus pipistrellus of exposure to remedially-treated timber. AB - Many species of bats roost in roof spaces and can come into contact with pesticides used to treat roof timbers against rot. As part of a study to develop a test with laboratory mice which could be used to predict the likely toxicity of pesticides to bats, the toxic effects on pipistrelle bats Pipistrellus pipistrellus and laboratory mice (CFLP outbred-strain) of exposure to dieldrin treated timber were compared. Dose (amount of dieldrin applied to the wood surface) - response (mortality) studies demonstrated that pipistrelle bats were 30 times more sensitive to dieldrin-treated wood than laboratory mice. However, dieldrin residues in the brain and liver of animals which had been poisoned were significantly higher in bats than mice. These residue data suggest that bats may be inherently less sensitive to dieldrin poisoning than mice and so it is likely that the 30-fold greater sensitivity of bats than mice to dieldrin-treated timber was a result of greater rate of uptake, per gram body weight, of the active ingredient from the wood surface and/or slower clearance from the body. The importance of differences in exposure and the reliability of residue data as an indicator of differences in inherent sensitivity to a chemical are discussed in terms of their importance when considering inter-species variation in toxic response. PMID- 21781715 TI - Variability in susceptibility of the nervous system to toxic insult. AB - There is a marked variability in the susceptibility of different cell types in the nervous system to toxic insult. Some of this variation is associated with factors related to the specific functions of the cells, but some also reflects genetic differences in metabolism. It is important that the role of genetic polymorphisms are considered, along with the broader aspects of susceptibility to neurotoxins, in the development of certain neurological disorders. PMID- 21781716 TI - Variability in susceptibility - how big, how often, for what responses to what agents? AB - This paper surveys some recent available observations in humans on interindividual variability in exposure-related parameters, pharmacokinetics, and pharmacodynamics. Overall, I think two inferences are warranted. First, the drug and epidemiological literatures do contain information that can shed new light on the extent of variability in the doses associated with different non-cancer responses. These data are waiting to be systematically extracted and analyzed. Second, I think it is likely that with more systematic measurement and analysis of interindividual variability we are likely to find that there are systematic tendencies for some kinds of responses to some categories of agents to occur at more variable exposures/doses than others. If we gather and analyze additional data of this type, we may be able to recommend adaptive modifications to the ten fold safety factor tuned to these differences. PMID- 21781717 TI - Exposure factors that contribute to variability in toxic responses in man. AB - The route of exposure is an important determinant of the internal dose of a chemical in man and the expression of toxicity. Routes of exposure are inhalation via the lung and dermal penetration, and the degree of absorption and first pass metabolism vary between chemicals. Inter-individual differences in metabolism of both genetic and environmental cause contribute to variability in metabolic fate and toxic response. PMID- 21781718 TI - Influence of environmental and genetic factors on variation in human response to DNA damaging agents. AB - Exogenous DNA damaging agents must be considered in the context of endogenous reactive species which have the potential to damage DNA. Although a no-effect level for a DNA-damaging compound may not exist, it may be feasible to define a level where reducing exposure to the compound is no longer the most effective way of reducing human risk. Modifying environmental factors which affect human response to damage may be the better strategy. Although a number of rare human syndromes are associated with a reduced ability to repair DNA damage, it is not clear how wide is the range of genetic variation in repair capacity among normal individuals. Studies with DNA repair-deficient human syndromes indicate that processes other than mutation and DNA repair must be involved in the development of cancer, and these processes may represent new sources of variation in human response to genotoxic agents. PMID- 21781719 TI - Effects of genetic polymorphism and enzyme induction in the glutathione S transferase family on chemical safety and risk assessment. AB - Glutathione is important in the detoxication of many xenobiotic chemicals and in the bioactivation of some. The glutathione-S-transferases are a super-family of enzymes involved in conjugation of xenobiotics with glutathione. There are wide genetically determined inter-individual differences in the expression of the isoenzymes. These differences may have important implications for the toxicity of compounds such as polycyclic aromatic hydrocarbons and aflatoxins. PMID- 21781720 TI - Interindividual variability in metabolic activation in humans in vivo. AB - In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process. PMID- 21781721 TI - Inter-ethnic differences in xenobiotic metabolism. AB - The aim of safety assurance procedures is to determine a level of intake (the acceptable daily intake (ADI) or tolerable daily intake (TDI)) that is without adverse health effects in the human population. The majority of studies on inter ethnic differences in xenobiotic metabolism have concentrated in the incidence of expression of the poor metaboliser phenotype for a number of drug metabolising enzymes. Such ethnic differences can result in different incidences of individuals at higher risk, but this would not affect the safety assurance/risk assessment outcome unless poor metaboliser status was not recognised in the database used for the initial assessment and calculation of ADI or TDI. Of far greater importance are ethnic differences which result in population differences in the mean values, and/or the extent of variability within the population, for key kinetic parameters such as the internal dose or area under the plasma concentration time curve (AUC). There are few studies on inter-ethnic differences in sensitivity and most of these relate to in vivo differences for therapeutic/pharmacological agents, so that the reported data reflect both kinetic and dynamic variability. Inter-ethnic differences are limited in extent and well within the uncertainty factor of 10 used for human variability. PMID- 21781722 TI - Individual variability in human lung function responses to ozone exposure. AB - Ozone is a common photochemical air pollutant which is present in the ambient air of many urban areas at concentrations sufficient to produce acute respiratory effects in humans. Because individuals vary considerably in the magnitude of their responses to ozone exposure, it is difficult to estimate the number of individuals in a given population who are experiencing adverse effects. Consequently risk and benefits analysis for various regulatory scenarios cannot be carried out with precision. As an aid to risk assessment this paper presents a method of predicting the proportion of individuals in the population who experience a particular health effect. Risk equations predicting the proportion of individuals experiencing lung function decrements as a function of ozone concentration, duration of exposure, and age are presented. PMID- 21781723 TI - The immune response is subject to individual variability at all levels. AB - All the components of the immune system involved in recognition and memory and in the nature, vigour and distribution of responses to antigenic challenge may be affected by the genotype and phenotype of the exposed person. They are likely to be greatly influenced by the individual genotype as well as by phenotype effects, and so are likely to vary greatly between individuals, depending on constitutional factors and on any previous exposure of the individual. Although immune responses do follow conventional types of dose-response relationship, the end effect is greatly modified by prior sensitisation. There is a considerable range of individual responses in conditions involving the immune system, as is well shown in the variability of the common immunological disorders of asthma and contact dermatitis, although strong sensitisers may be able to overcome much of the difference in the responsitivity of the individual. PMID- 21781724 TI - Modulation of toxicity by dietary and environmental factors. AB - Both epidemiological and experimental evidence indicate that environmental factors may modulate chemical toxicity. Of these, dietary factors have been most thoroughly studied and shown to modulate a number of toxic processes including carcinogenesis. Total energy intake and specific nutrients (protein and specific amino acids, vitamins, and minerals) have been shown to be active in this regard as have a number of non-nutritive dietary factors, most notably phenolic and sulphur-containing compounds, and indoles. The mechanisms by which dietary factors might influence toxicity include effects on bioavailability, phase I or phase II metabolism, scavenging of reactive metabolites, induction of DNA repair processes, inhibition of cell proliferation, induction of differentiation or apoptosis and effects on the immune system. These factors are discussed with emphasis on dietary exposure to modulating factors. PMID- 21781725 TI - Fetal hemoglobin as a possible marker of susceptibility to working conditions for certain men exposed to industrial pollutants. AB - In 43 from 222 men (19.4%) employed in a coking plant a higher than normal concentration of fetal hemoglobin (HbF) was found, whereas an elevated level of HbF was detected in only two from 87 persons (2.3%) working in the cold rolling mill of the steel mill 'Huta Sendzimira', Krakow, Poland. Subjects employed in the coking mill worked in a much more polluted atmosphere than those in the cold rolling mill. It is speculated that synthesis of HbF may be a marker of the effect of unfavorable working conditions on some susceptible persons. PMID- 21781726 TI - Multiple chemical sensitivities: an overview. AB - At the present time multiple chemical sensitivities (MCS) is generally acknowledged to be a poorly understood clinical syndrome which is exhibited by individuals exposed to low levels of exposure to environmental agents that the general population tolerate quite well. A wide range of individual symptoms (typically multiple and related to neurologic, endocrine/metabolic, and immunological, often occurring simultaneously) are displayed by MCS patients. Questions concerning whether or not MCS is a real clinical condition, a form of psychiatric illness or a combination of both remain to be unambiguously clarified. PMID- 21781727 TI - Population approaches/sparse data analysis for human variability in kinetics and dynamics. AB - The application of sparse data analysis techniques, otherwise known as the population approach, to the assessment of pharmacokinetic and pharmacodynamic variability is reviewed. Using software that has recently become available it is now possible to analyse heterogeneous, sparse data from a variety of clinical trials, particularly during drug development. Therefore the pharmacokinetics and pharmacodynamics of a drug can be studied in the target population and this information can be used to guide dosage for optimal therapeutic benefit. PMID- 21781728 TI - In vitro testing for lung toxicity: a method for distinguishing between immune- and non-immune-mediated reactions to xenobiotics. AB - Knowledge of whether a given toxicant produces its effects through direct or immune mechanisms should prove useful in predicting variability of the toxic response. This paper presents preliminary findings from biochemical studies conducted in perfused and ventilated guinea-pig lung to examine the release of arachidonic acid metabolites and vasoactive intestinal polypeptide associated with various types of lung injury. Anaphylaxis provoked with ovalbumin challenge in sensitized lungs was associated with increases in products of both cyclo oxygenase (thromboxane A(2) prostaglandin E(2)) and lipoxygenase (leukotrienes B(4) and C(4)) metabolism. Xenobiotics that cause direct bronchial irritation (formaldehyde, acid water) produced increases only in cyclo-oxygenase activity. Anaphylactic bronchospasm was also associated with increased release of vasoactive intestinal polypeptide. These findings suggest that in vitro immune mediated bronchospastic reactions to xenobiotics might be distinguished on the basis of the arachidonic acid metabolites and/or VIP they release. PMID- 21781729 TI - Validity and reliability of in vitro systems in safety evaluation. AB - In vitro data could make an important contribution to the application of the proposed scheme for the subdivision of the usual 10-fold safety factors (used in risk assessment for inter-species and inter-individual differences) into two separate aspects of toxicokinetics and toxicodynamics. Whereas toxicokinetics (or delivery of the chemical to its site of action via the general circulation) is amenable to direct in vivo measurement, toxicodynamics (or the assessment of the sensitivity of the target tissue to the presence of the chemical) is open to in vitro investigation. Human risk assessment requires human data to be able to replace any of the default safety (or uncertainty) factors (Renwick, 1993). Because human tissues are of limited availability, it is likely that the main quantitative contribution of in vitro data will be to allow chemical specific inter-species differences in toxicodynamics to replace the proposed default value. Although in vitro data from human tissues could be used to define human variability in target organ sensitivity (toxicodynamics) this would require a large number of specimens and the variability detected in vitro should be representative of that present in vivo. PMID- 21781730 TI - Developmental changes of membrane electrical properties of rat skeletal muscle fibers produced by prenatal exposure to carbon monoxide. AB - The effects of prenatal exposure to 75 and 150 ppm of carbon monoxide (CO) were evaluated in vitro on the electrical parameters of extensor digitorum longus muscle of newborn rats, by means of computerized two intracellular microelectrode technique. Within the first 2 months of postnatal life the muscles from offspring of mothers exposed to 150 ppm CO showed lower values of resting chloride conductance (G(CI)) with respect to age-matched controls, but no significant differences were recorded after 80 days of life. Between 40-200 days of life, the extensor digitorum longus muscles from offspring of 150 ppm CO exposed rats showed a pharmacological response to a specific chloride channel modulator, the R (+)-enantiomer of 2-(p-chlorophenoxy)propionic acid (R-(+)-CPP), different from that of age-matched controls, but similar to that of normal developing rats aged 8-20 days. The prenatal exposure to 150 ppm CO also slightly delayed the developmental reduction of resting potassium conductance (G(K)); indeed higher values of G(K) were recorded with respect to controls until 60 days of postnatal life. In the offspring of 150 ppm CO treated rats a slight and reversible modification of the excitability parameters related to G(CI) were also observed along with a decreased sensitivity to tetrodotoxin. In the muscle from offspring of 75 ppm CO treated animals G(CI) and G(K) were not different with respect to controls, at any age; however the pharmacological modulation of G(CI) by R-(+) CPP was similar to that observed in the rats prenatally exposed 150 ppm CO. These results suggest that the prenatal exposure to mild concentrations of CO produces developmental alterations of the ion channels responsible for the passive and active membrane electrical properties of rat skeletal muscle fibers. PMID- 21781731 TI - Enhancement of acetylcholine release by homoanatoxin-a from Oscillatoria formosa. AB - The strain NIVA-CYA 92 of Oscillatoria formosa Bory ex Gormont produces phycotoxins with neurotoxic properties. Chemical analysis by gas chromatography/mass spectrometry of a water extract of lyophilized material of the organism showed the presence of only homoanatoxin-a. The mechanism of action of homoanatoxin-a on peripheral cholinergic nerves is so far not known. The neurotoxicity of O. formosa containing homoanatoxin-a was investigated in rat bronchi, rat brain synaptosomes and in GH(4)C(1) cells. The water extract of lyophilized material of the organism produced a concentration-dependent reversible increase in the release of [(3)H]acetylcholine from both K(+) (51 mM) depolarised and non-depolarised cholinergic nerves of the rat bronchial smooth muscle. The K(+)-evoked release of [(3)H]acetylcholine was enhanced by about 75% by a water extract from 15-20 mg/ml of lyophilized algal material. The enhanced release of [(3)H]acetylcholine was substantially reduced by the L-type Ca(2+) channel blocker verapamil (100 MUM) and not by the N-type Ca(2+)-channel blocker omega-conotoxin GVIA (1.0 MUM) or the P-type Ca(2+)-channel blocker omega agatoxin IV-A (0.2 MUM). Chelation of intra-cellular Ca(2+) by 1,2-bis (aminofenoxi)etan-N,N,N',N'-tetraacidic acid/acetoxymethyl (BAPTA/AM) (30 MUM) had no effect on the phycotoxin-induced release of [(3)H]acetylcholine, indicating that an extracellular pool of Ca(2+) was important for the action of the phycotoxin on the release of [(3)H]acetylcholine from peripheral cholinergic nerves. In rat brain synaptosomes the algal extract enhanced the influx of (45)Ca(2+) in a tetrodotoxin (1.0 MUM) and omega-conotoxin MVIIC (blocker of N-, P- and Q-type Ca(2+) channels) (1.0 MUM) insensitive manner. Patch-clamp studies showed that the phycotoxin opened endogenous voltage dependent L-type Ca(2+) channels in neuronal GH(4)C(1) cells. These Ca(2+) channels and the effect of the toxin on the channels were blocked by the L-type Ca(2+)-channel antagonist gallopamil (200 MUM). The present results suggest, therefore, that the investigated strain of O. formosa contains homoanatoxin-a, which enhances the release of acetylcholine from peripheral cholinergic nerves through opening of endogenous voltage dependent neuronal L-type Ca(2-) channels. PMID- 21781732 TI - In vitro quantitative determination of phospholipid adducts of chloroform intermediates in hepatic and renal microsomes from different rodent strains. AB - We have comparatively studied in vitro the oxidative and reductive pathways of chloroform metabolism in hepatic and renal microsomes of rodent strains used for carcinogenicity testing (B6C3F1 mice, Osborne Mendel and Sprague Dawley rats). To this aim we exploited the regioselective binding of phosgene to phospholipid (PL) polar heads and of dichloromethyl radical to PL fatty acyl chains, using a method based on the chemical transmethylation of PL adducts, followed by phase partitioning of the resulting products (De Biasi et al., 1992). The analysis of results let us to conclude at first that a (14)C label partitioning by 89.2 (+/ 6.5)% or 13.7 (+/-5.0)% in the aqueous phase is typical of the PL adduct with phosgene (PL-PHOS) or with dichloromethyl radical (PL-RAD), respectively. Metabolism of 0.1 mM CHCl(3) was mainly oxidative in all the samples, being hepatic microsomes more active than renal ones by about one order of magnitude and levels of CHCl(3)-derived PL adducts in B6C3F1 mouse liver microsomes higher than in rat samples. At 5 mM CHCl(3), total levels of PL adducts in renal microsomes reached levels almost similar to those found in liver microsomes. However, while B6C3F1 mouse kidney microsomes produced both reactive metabolites, similarly as the hepatic samples, Osborne Mendel rat kidney microsomes bioactivated CHCl(3) only reductiveiy, producing the radical. The relevance of this finding depends on the fact that phosgene is known to be the major cause of CHCl(3) toxicity, based on data with the rat liver and mouse liver and kidney, while nephrotoxicity in rats occurs with minimal production of COCl(2). Chloroform reductive bioactivation may therefore provide a reasonable explanation for the toxicity of chloroform to the rat kidney. The same finding may be of interest in elucidating the metabolic reasons of the chloroform-induced kidney tumors in Osborne Mendel rats. PMID- 21781733 TI - Risk assessment and management of new and existing chemicals. AB - An evaluation was made of the recently developed risk assessment methodologies for new and existing chemicals in the European Communities. The evaluation also included the methodologies to prioritize chemicals and procedures for risk management, i.e., the (draft) guidance document for the development of strategies for risk reduction. The way in which chemicals are prioritized is accepted with only very few comments. Clear progress has been made in the development and harmonization of risk assessment methodologies and the application of estimation methodologies. Nevertheless, improvements are necessary for the estimation of consumer and occupational exposure, the derivation, use and transparency of assessment factors for chemicals and classes of chemicals based on the mode of toxic action, environmental exposure models and their validation and relation with monitoring data. As far as risk management is concerned it was recommended to improve the integration of the myriad of directives and regulations, to clarify definitions, to provide clear guidance on the determination and weighing of advantages and implications of risk reduction measures and to develop tools, including voluntary agreements, to speed up the slow chemical-by-chemical approach. PMID- 21781734 TI - Effects of the Japanese herbal medicine 'Sho-saiko-to' as a cytokine inducer. AB - The herbal medicine, Sho-saiko-to (TJ-9), has been widely prescribed to chronic viral liver disease patients in Japan. This study examined the inductions of such sytokines as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF alpha), and granulocyte-colony stimulating factor (G-CSF), on some fractions of peripheral blood mononuclear cells (PBMC) by TJ-9 and each of its seven components. IL-1beta, TNF-alpha, and G-CSF were highly induced by scutellaria root and glycyrrhiza root on monocytes/macrophages. By repeating the same experiments using taxol (an LPS antagonist)-treated substances, authors confirmed that these inductions were not attributable to the presence of quite low LPS in TJ-9 solution, and the cytokine inductions are the specific effect of TJ-9. Because TJ-9's macrobiotic effect in liver cirrhosis patients has been proven statistically in an etiological study, TJ-9 could be a new important therapy in chronic liver diseases. PMID- 21781735 TI - Low-dose effects of paraoxon in adult mice exposed neonatally to DDT: changes in behavioural and cholinergic receptor variables. AB - This study revealed increased susceptibility in adult mice, exposed neonatally to a low dose of DDT (1,1,1-trichloro-2,2-bis( p-chlorofenyl)ethane), to develop changes in behaviour and cholinergic muscarinic receptors when exposed as adults to the organophosphorus insecticide paraoxon. 10-day-old NMRI male mice were given a single oral dose of DDT (0.5 mg/kg body weight). At the age of 5 months, paraoxon was administered by gavage as a single dose (0.7 or 1.4 mg/kg body weight) every 2nd day for 1 week. These doses caused approximately 15% and 45% inhibition of acetylcholinesterase respectively, 48 h after the last exposure. 24 h after the last paraoxon administration, a spontaneous motor activity test revealed no differences between any of the adult paraoxon-treated mice and their corresponding controls, though when the test was performed again 2 months later, mice exposed neonatally to DDT and given paraoxon as adults had developed changes in spontaneous behaviour. The density of muscarinic cholinergic receptors was significantly increased in this group. No significant changes were seen in either behaviour or muscarinic receptors in mice exposed neonatally to the vehicle and receiving paraoxon as adults and there were no significant differences in the muscarinic or nicotinic subpopulations investigated, between any of the treatment groups. These results show that a dose of paraoxon not having any effect in vehicle-treated animals can cause effects in animals neonatally exposed to DDT. PMID- 21781736 TI - Biochemical and immunotoxicological alterations following repeated gallium arsenide exposure and their recoveries by meso-2,3-dimercaptosuccinic acid and 2,3-dimercaptopropane 1-sulfonate administration in rats. AB - Efficacy of two analogues of British anti-lewisite (BAL), meso-2,3 dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane 1-suffonate (DMPS), in depleting arsenic and gallium concentration of blood and other soft tissues, in restoring altered blood, liver and renal biochemical variables and some immunlogical indices were investigated in male rats exposed to multiple doses of gallium arsenide (GaAs). The results indicate that exposure to gallium arsenide produced a significant inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity, an increase in urinary ALA excretion and blood zinc protoporphyrin level. Blood glutathione (GSH) contents also decreased on GaAs exposure. No influence of GaAs however, on serum transminase activity or hepatic GSH contents was noticed, although, renal alkaline phosphatase activity decreased significantly on GaAs exposure. Further, a marked influence of GaAs administration on immunological variables like relative thymus and spleen weight, spleen cellularity, antibody forming cell (AFC) response to sheep RBC and delayed type of hypersensitivity (DTH) was observed. These data indicate that multiple exposure to GaAs may produce an adverse effect on the haematopoietic, renal and immune system. Further, post exposure treatment with two thiols, meso-2,3 dimercaptosuccinic acid and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), DMPS proved more effective than DMSA in producing an effective reversal of altered immunological variables and reducing arsenic concentration of spleen, liver, kidney and blood. Biochemical variables, on the other hand, responded less favorably to the treatment of DMSA or DMPS except for a significant recovery in the activity of blood delta-aminolevulinic acid dehydratase (ALAD) following DMSA administration. The results suggest that DMPS could be an effective chelating drug for reversing most of the GaAs induced immunological alterations and reducing tissue arsenic burden. PMID- 21781737 TI - Lipopolysaccharide-induced platinum accumulation in the cerebral cortex after cisplatin administration in mice: Involvement of free radicals. AB - The relationship between the accumulation of platinum in the cerebral cortex following cisplatin administration and injury to the blood-brain barrier after lipopolysaccharide (LPS) treatment was investigated. The appearance of intravenously injected fluorescein in the brain was significantly increased 10-24 h after LPS treatment, the effect being dose-dependent. Platinum was detectable in the cerebral cortex of cisplatin-treated mice 24 h after LPS treatment, but not without LPS treatment. In mice pretreated with alpha-tocopherol, LPS administration did not significantly augment fluorescein penetration into the brain, whereas pretreatment with either allopurinol or ascorbic acid did not modify the LPS-induced increase in fluorescein penetration. In contrast, platinum in the cerebral cortex after cisplatin administration was still detectable in the allopurinol-, ascorbic acid-, and alpha-tocopherol-pretreated groups, and the levels of platinum in these groups were not significantly different from those in the group treated with LPS only. Administration of superoxide dismutase (SOD), but not of catalase, tended to inhibit the penetration of fluorescein. Both SOD and catalase significantly lowered platinum content in the cerebral cortex following cisplatin administration in mice treated with LPS. Thus, free radicals may injure the blood-brain barrier in mice challenged with LPS, and allow cisplatin to penetrate into the cerebral cortex, resulting in platinum accumulation. PMID- 21781738 TI - Evidence that A(2a) and not A(2b) purinoceptors are coupled to production of nitric oxide in the central regulation of blood pressure. AB - In a previous study we reported that nitric oxide (NO) partially mediates centrally the decrease of arterial blood pressure induced by adenosine A(2) subtype receptor stimulation. The present study confirms the earlier suggestion and shows that in adult male normotensive anaesthetized rats 5'-N ethylcarboxamidoadenosine (NECA), a non-selective adenosine receptor agonist, centrally injected induced a significant decrease of arterial blood pressure. Moreover, the observation that intracerebroventricular (i.c.v.) administration of N(omega)-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, +8-(3 chlorostyryl)-caffeine (CSC), antagonist of A(2a) receptors, did not reduce furthermore the hypotensive effect induced by NECA injection, demonstrated that NO is involved only via A(2a) and not via A(2b) adenosine subtype receptors in the central regulation of blood pressure. PMID- 21781739 TI - Species difference in the inhibition of pentobarbital metabolism by empenthrin. AB - Empenthrin, synthetic pyrethroid, prolonged the pentobarbital-induced sleeping time in mice, but not in rats, guinea pigs or hamsters. Empenthrin did not delay the clearance of pentobarbital from serum in dogs. In addition, empenthrin dose dependently inhibited in vitro metabolism of pentobarbital in mice, but not in rats, guinea pigs, hamsters or rabbits. Lineweaver-Burk plots indicated that the inhibition was competitive in mice. Microsomal fractions of recombinant yeast expressing human cytochrome P-450 (CYP)s were used to determine the inhibitory effect of empenthrin on pentobarbital metabolism in humans. CYP2B6 and CYP2D6 were responsible for biotransformation of pentobarbital to a pentobarbital alcohol identified as 5-ethyl-5-(1'-methyl-3'-hydroxybutyl) barbituric acid. The structure of pentobarbital fit the criteria for a CYP2D6 substrate on computational analysis. Empenthrin did not inhibit the pentobarbital metabolism catalyzed by these two CYPs. These findings suggest that the inhibition of pentobarbital metabolism by empenthrin in mice does not occur in other species including humans. PMID- 21781740 TI - Effects of beta-ODAP and its biosynthetic precursor on the electrophysiological activity of cloned glutamate receptors. AB - 3-N-Oxalyl-l-2,3-diaminopropanoic acid (beta-ODAP) induces neurolathyrism, a motor neuron disease. To elucidate the pathogenic mechanism of this process, the action of beta-ODAP on the excitatory amino acid (EAA) receptor-mediated currents was examined using cloned EAA receptors expressed in Xenopus oocytes. On the voltage-clamp recordings of an AMPA receptor (alpha (1)alpha (2) heterooligomer), beta-ODAP was a strong agonist on this receptor, the potency being almost the same as l-glutamate. On the other hand, beta-ODAP had little effect on the glutamate-evoked currents through the expressed NMDA receptor (NR1(A)/NR2A), but showed a weak inhibitory effect on the glycine-modulatory site. beta-ODAP may cause the neurodegenerative disease, neurolathyrism, mainly through the excitotoxic interaction with AMPA receptors. PMID- 21781741 TI - Effects of vinconate on neurotransmitter receptor systems in aged rat brain. AB - We investigated the effects of age and (+/-)-methyl-3-ethyl-2,3,3a,4-tetrahydro-1 H-indolo[3,2,1-de][1,5]naphthyridine-6-carboxylate hydrochloride (vinconate), an indolonaphthyridine derivative, on neurotransmitter receptor systems in the rat brain using quantitative receptor autoradiography. [(3)H]Quinuclidinyl benzilate (QNB), [(3)H]hemicholinium-3 (HC) and [(3)H]muscimol were used to label acetylcholine receptors, high-affinity choline uptake sites and gamma aminobutyric acid(A) (GABA(A)) receptors, respectively. [(3)H]QNB, [(3)H]HC and [(3)H]muscimol binding decreased in any brain areas of 24-month-old (aged) rats in comparison with 6-month-old (adult) animals. Chronic treatment with vinconate (10 and 30 mg/kg, i.p., once a day for 4 weeks) partly ameliorated the reduction in [(3)H]QNB, [(3)H]HC and [(3)H]muscimol biding in aged rat brains. This effect was especially noted in [(3)H]muscimol binding. The results suggest that vinconate may have beneficial effects on age-related changes in neurotransmitter receptor systems. PMID- 21781742 TI - Comparative study on the in vivo and in vitro antilipolytic effects of etofibrate, nicotinic acid and clofibrate in the rat. AB - The release of both glycerol and free fatty acids (FFA) into a medium by epididymal fat pad pieces from fed rats incubated in Krebs Ringer bicarbonate albumin buffer supplemented or not with epinephrine decreased more in the presence of etofibrate than in the presence of equimolecular doses of nicotinic acid or clofibrate. The first drug was the only one to stimulate the rate of fatty acid re-esterification when incubations were done under basal conditions. By 3 h after their acute oral administration all three drugs decreased plasma FFA levels, although the effect from etofibrate was largest, the drugs enhanced or decreased plasma glycerol levels depending on both the dose and the time after treatment. Plasma triglycerides also decreased at 3 h after oral drug administration, and this effect was similar with etofibrate and nicotinic acid but less with clofibrate. With the exception of a decrease at 7 h after the highest dose (1.2 mmol/kg) of either etofibrate or nicotinic acid (but not clofibrate), plasma cholesterol levels remained stable at 7 h after the respective treatments. Thus, the hypocholesterolemic effect of these drugs seems secondary to their hypotriglyceridemic effect, which would be a consequence of their respective antilipolytic actions, and follows an efficiency sequence of etofibrate, nicotinic acid and clofibrate. PMID- 21781743 TI - Selective inhibition of the mouse brain Mn-SOD by methylmercury. AB - Changes in mRNA levels, protein contents and enzyme activities for brain Cu,Zn- and Mn-SOD by methylmercury chloride (MMC) administration, were examined, over a period of 12 days in ICR male mice. After subcutaneous administration of MMC (10 mg/kg) to mice, brain mercury content reached a maximum at 2 days and remained at that level for at least 5 days. MMC exposure resulted in a time-dependent decrease in the Mn-SOD activity: the enzyme activity at 5 days after exposure to MMC was about 60% of control level whereas this exposure was without effect on the Cu,Zn-SOD activity, indicating differential sensitivity of SOD isozymes to the metal. However, levels of mRNA and protein synthesis for Mn-SOD were unaffected by MMC administration. The direct effect of MMC on the both SOD activities were further examined with purified enzyme preparations. After each SOD isozyme (10 U) was incubated with 0.2 mM MMC for 24 h at pH 7.8, the enzyme activities for Cu,Zn- and Mn-SOD were 90% and 37% of control, respectively. Incubations at a ratio of SOD to MMC (1 : 600) for 24 h resulted in a substantial decrease in the enzyme activity of the Mn form; this isozyme-selective inactivation was noted at alkaline pH. A combination of isoelectric focusing agarose gel electrophoresis (IEF-AGE) and synchrotron radiation X-ray fluorescence (SR-XRF) analysis revealed that Mn-SOD rather than Cu,Zn-SOD underwent modification. Furthermore, a decrease in native form of Mn-SOD protein after MMC exposure was confirmed by gel filtration chromatography. These results indicate that Mn-SOD, but not Cu,Zn-SOD, is susceptible to modification by MMC and the resulting alteration in structure appears to cause a loss of enzyme activities. PMID- 21781744 TI - Binding of the antiretroviral drug, d-aspartate-beta-hydroxamate on the NMDA receptor. AB - d-Aspartate-beta-hydroxamate (d-A beta H) exhibits antiretroviral properties in vitro and in vivo. It has glutamate agonist properties at the N-methyl-d aspartate (NMDA) receptor in neuronal cell cultures. This study characterizes its binding properties to the NMDA receptor by measuring its stimulating effect on N (1-(2-thienyl)[(3)H]cyclohexyl)piperidine ([(3)H]TCP) binding to the ionic channel in rat brain membranes. d-A beta H stimulated [(3)H]TCP binding in a dose dependent manner but to a lower extent than glutamate, suggesting only partial glutamate agonist properties. In the presence of antagonists of the different effector sites of the NMDA receptor the affinity of d-A beta H was competitively decreased by CGS-19755 and 7-chlorokynurenate and unaffected by arcaine. Among several d-A beta H analogues VHS.125 behaved as a full NMDA agonist, but l- or d glutamate gamma-monohydroxamate (d-GH or l-GH) were without effect. This study shows that d-A beta H has potential neurotoxic effects due to its direct interaction with the NMDA receptor and that analogues such as d-GH or l-GH may rather be used in humans. PMID- 21781745 TI - Induction of c-fos expression by tributyltin in PC12 cells: involvement of intracellular Ca(2+). AB - The effects of tributyltin on the expression of immediate early genes, c-fos and c-jun, were examined in PC12 cells using reverse transcription polymerase chain reaction analysis. Tributyltin at concentrations of more than 0.4 MUM induced the expression of c-fos after 15 min exposure. The induction of c-fos was accompanied with c-jun expression. Tributyltin-induced c-fos expression was abolished completely by actinomycin D, indicating it was due to transcriptional activation of the gene. Chelation of intracellular Ca(2+) suppressed the expression of c-fos markedly, while removal of external Ca(2+) did not. These results suggest that Ca(2+) mobilized from intracellular stores played a major role in the tributyltin induced transcriptional activation of c-fos in PC12 cells. PMID- 21781746 TI - CYP3A5 is the major cytochrome P450 3A expressed in human colon and colonic cell lines. AB - CYP3A is known to be expressed in liver, small intestine and colon. However, its isoform distribution (CYP3A4, 3A5 and 3A7) and inducibility have not been clearly elucidated in the colon. Therefore, we analyzed CYP3A in human colon and compared its expression and inducibility to the human colonic cell lines HT29 and Caco2, which were used as models. Patients suffered either from sigmoiditis or colonic adenocarcinoma. Patients as well as HT29 and Caco2 cells were treated with rifampicin. CYP3A protein expression was analyzed in the colon of patients and in the cells by immunoblot and by isoelectric focusing enabling separation of CYP3A isoforms, while mRNA expression was determined using specific reverse transcription-polymerase chain reaction. In both human colon and cells, CYP3A5 was the main isoform expressed at the protein and mRNA levels. Rifampicin treatment had no effect on CYP3A expression. HT29 and Caco2 cells exhibiting the same CYP3A expression and inducibility might therefore be useful in vitro models for studying xenobiotic metabolism in human colon. PMID- 21781747 TI - Preliminary evaluation of the toxicity and efficacy of novel 2,4-diamino-5 benzylpyrimidine-sulphone derivatives using rat and human tissues in vitro. AB - Four novel combined dapsone and trimethoprim analogues, K-120, K-150, K-138 and DRS-506, have been compared with dapsone in their methaemoglobin forming abilities as well as their anti-inflammatory properties using rat and human tissues in vitro. All four compounds formed consistently less methaemoglobin compared with dapsone in both the rat and human microsomes. Using human microsomes from five livers, K-120 was significantly less toxic than the other analogues in three of the five livers (P < 0.01). DRS-506 and K-138 both inhibited the human neutrophil respiratory burst to a significantly greater degree compared with dapsone at 0.5 mM (P < 0.01), while K-120 and K-150 showed no significant effect at 0.5 mM. At 1 mM, DRS-506, K-120 and K-138 were more potent than dapsone (P < 0.01), although K-150 appeared to increase the neutrophil activation. All four analogues caused a significant reduction in neutrophil adhesion to human umbilical vein cells at 0.1 mM. In view of its efficacy and low toxicity, K-120 shows considerable promise for future clinical evaluation. PMID- 21781748 TI - Human cytochrome P450 3A4 is involved in the biotransformation of the herbicide 2,4-dichlorophenoxyacetic acid. AB - 2,4-Dichlorophenoxyacetic acid (2,4-D) is one of the most frequently used herbicides and is an environmental pollutant. Evidence exists that 2,4-D exposure results in an increased risk for certain malignant disorders such as nasal carcinoma and soft tissue sarcoma in humans and animals. The involvement of cytochrome P450 3A4 (CYP3A4), the major form of monooxygenase enzyme in human liver, in the metabolism of 2,4-D was studied using microsomal fractions and whole cells of Saccharomyces cerevisiae expressing cytochrome P450 3A4. 2,4 Dichlorophenol (2,4-DCP) was identified as the only product of metabolism by TLC followed by NMR and IR spectroscopy and a turnover of 0.13 nmol 2,4-DCP/min/nmol P450 was observed. PMID- 21781749 TI - Pharmacokinetics of arginine butyrate in patients with hemoglobinopathy. AB - Recent reports have demonstrated improvement in the clinical status and hemoglobin levels with use of intravenous arginine butyrate in patients with homozygous beta-thalassemia and sickle cell disease. To allow optimalization of therapy, we conducted pharmacokinetic studies in nine patients, five with sickle cell disease and four with beta-thalassemia, treated with continuous intravenous infusion of arginine butyrate. The disappearance of the drug after discontinuation was characterized by a biphasic elimination with an initial rapid phase followed by a slower phase. Redistribution was noted in five of the patients after 11.2 +/- 4.0 min. The short half life was the result of both rapid clearance rate of 93.6 +/- 31.9 ml/kg/min and small Vc (0.21 +/- 0.26 l/kg) and Vss (0.31 +/- 0.37 l/kg). While preliminary results of the effectiveness of arginine butyrate are encouraging with a rise of gamma-globin mRNA and F reticulocytes in some patients, the rapid elimination of this agent will probably limit its current use to administration by continuous infusion. PMID- 21781750 TI - Strain differences in age-associated change in testosterone 6beta-hydroxylation in Wistar and Dark Agouti rats. AB - This study examines strain differences in testosterone (T)-hydroxylations between Wistar and Dark Agouti (DA) rats of both genders. The DA rat, an animal model, is a poor metabolizer of such drugs as debrisoquine, which are metabolized by cytochrome P450 (CYP) 2D. T-16alpha-, 2alpha-hydroxylations, which are linked to CYP2C11, were catalyzed at similar rates by the microsomes of both strains. In contrast, the liver microsomes from mature male DA rats catalyzed T-6beta hydroxylation, the CYP3A mediated activity, at higher rates (~ 2-fold) than Wistar rat liver microsomes did. There was no difference between immature male DA and Wistar rats for T-6beta-hydroxylation, indicating that the activity in male DA rat increases with maturation. Polyclonal antibodies raised against rat liver microsomal CYP3A2 and a CYP3A inhibitor, troleandomycin (TAO), effectively inhibited T-6beta-hydroxylation by liver microsomes from both strains of rats. The level of T-6beta- hydroxylation activity correlated well with the amount of CYP3A protein in the microsomes in mature as well as in immature male and female Wistar and DA rats. Northern blot analysis repeatedly indicated that the cellular contents of CYP3A2 mRNA are slightly (~ 20%) higher in the liver of mature DA rats than in that of mature Wistar rats. These results indicate that the increased levels of CYP3A are responsible for the increased T-6beta-hydroxylation activity and protein in DA rat. PMID- 21781751 TI - The influence of experimental hyperthyroidism on responsiveness in rabbit aortic smooth muscle. AB - This study investigated the responsiveness of hyperthyroid and control (euthyroid) rabbit aortic rings to vasoconstrictor agents. There was no significant difference between the responsiveness of hyperthyroid and control tissues to KCl. Maximum responses (E(m)) to noradrenaline and serotonin were reduced in hyperthyroid rabbit aortic rings compared to those euthyroid rings. The sensitivity (i.e., EC(50)) of hyperthyroid aortic rings to noradrenaline and serotonin compared to euthyroid controls was unchanged. The K(b) value of prazosin against 10(-6) M noradrenaline-induced contractions in eu- and hyperthyroid states was 1.97 +/- 0.59 . 10(-9) M and 1.92 +/- 0.79 . 10(-9) M, respectively. The K(b) value of methisergide against 10(-6) M serotonin-induced contractions in eu- and hyperthyroid states was 1.46 +/- 0.80 . 10(-9) M and 1.10 +/- 0.16 . 10(-9) M, respectively. These data indicate that vascular reactivity is altered in experimental hyperthyroidism and this alteration, if any, do not occur at the receptor level. PMID- 21781752 TI - The role of calcium in the tumor promoter-induced inhibition of gap junctional intercellular communication. AB - The effect of several tumor promoters (12-O-tetradecanoyl-phorbol-13-acetate (TPA); 1,1'-(2,2,2-trichloroethylidene)bis[4-chlorobenzene] (DDT); Aroclor1260, and clofibrate) on the inhibition of gap junctional intercellular communication (GJIC) and intracellular calcium concentration ([Ca(2+)](i)) was studied in a cell line consisting of initiated cells (3PC). In addition, the effect of different extracellular calcium concentrations ([Ca(2+)](e)) on the effects of tumor promoters on both GJIC and [Ca(2+)](i) were studied. Agents with GJIC inhibiting capacity increased [Ca(2+)](i). However, the increase of [Ca(2+)](i) did not (always) precede GJIC inhibition. The effect of tumor promoters on GJIC were similar under low (0.05 mM) and high (1.20 mM) Ca(2+)(e) conditions, while different effects on [Ca(2+)](i) were found. These results suggest that tumor promoters can inhibit GJIC and change [Ca(2+)](i), but that there is no direct relationship between these two processes. PMID- 21781753 TI - Isolation of a bovine full length cytochrome P450 (CYP3A) cDNA sequence and its functional expression in V79 cells. AB - From a bovine liver cDNA library in lambdaMaxl a 1870 bp cDNA was isolated using the human CYP3A4 cDNA as a probe. The cDNA-deduced amino acid sequence encoded a protein of 507 amino acids and exhibited homologies of 76, 72 and 64% with canine CYP3A12, human CYP3A4 and rat CYP3A1, respectively. Furthermore, a very high homology of 91.7% was observed with the deduced amino acid sequence of a partial CYP3A cDNA from dwarf goat. A striking observation was that both the bovine and the goat cDNA exhibit a 4 amino acid extension at the C-terminus, which is due to a frame-shifting insertion of 2 nt. The bovine CYP3A cDNA was cloned in a retroviral vector, transfected to V79 cells and cells were selected for cytochrome P450 expression. The expressed enzyme was shown to catalyze the 6beta hydroxylation of testosterone, which could also be observed in a V79 cell line expressing human CYP3A4. In the bovine CYP3A cell line, however, 6beta hydroxytestosterone was not found to be the major metabolite. This cell line additionally showed high levels of hydroxylase activity at the 2beta and 12beta position of testosterone. The cDNA-expressed testosterone hydroxylase activity could be inhibited with the specific CYP3A inhibitors, tiamulin and ketoconazole. PMID- 21781754 TI - A model for predicting ventilation rates in mammals. AB - The relationship between ventilation rate (1/min) and body weight (kg) in mammals was examined using regression techniques. The initial hypothesis of a single power function relationship was rejected. An additional model of the log-log relationship was developed which is piece-wise linear. Results showed the piece wise linear model gave a better overall fit to the data suggesting a complex relationship with body weight. The breakpoint in the function occurred at approximately 5 kg. Nonlinear regression of untransformed data gave a better fit than linear regression of the log-transformed data. PMID- 21781755 TI - Development of a V79 cell line expressing human cytochrome P450 2D6 and its application as a metabolic screening tool. AB - Expression of human cytochrome P450 (CYP) in heterologous cells is a means of specifically studying the role of these enzymes in drug metabolism. The complete cDNA encoding CYP2D6-VAL(374) was inserted into an expression vector containing the strong mycloproliferative sarcoma virus promotor in combination with the enhancer of the cytomegalovirus and stably expressed in V79 Chinese hamster cells. The presence of genomically integrated CYP2D6 cDNA was confirmed by polymerase chain reaction analysis. The protein expression was shown by Western blotting. Functional expression could be demonstrated by O-demethylation of dextromethorphan to dextrorphan in live cells. The enzymatic activity of 154 +/- 16 pmol min(-1) mg(-1) protein was comparable with dextromethorphan-O demethylation activities of human liver. The metabolism of two dopaminergic ergoline derivatives was investigated in whole recombinant V19 cells. Both lisuride and terguride were monodeethylated; in case of lisuride a correlation to the in vivo situation was demonstrated comparing poor and extensive metabolizers. PMID- 21781756 TI - Effect of antioxidants on cisplatin induced delay in gastric emptying in rats. AB - Cisplatin causes severe nausea and vomiting and also suppresses gastric emptying. Antioxidants have been shown to exert antiemetic effects against cisplatin induced emesis. In the present study, the effect of antioxidants-glutathione, N-2 (mercaptopropionyl)glycine (tiopronin), vitamin E, vitamin C and a combination of vitamin E and vitamin C was investigated against cisplatin induced delay in gastric emptying, in a rat model. Pretreatment with these antioxidants significantly reversed the cisplatin induced delay in gastric emptying. This effect of antioxidants may help in the improvement of other accompanying gastrointestinal symptoms such as abdominal discomfort and also contribute to their antiemetic efficacy against cytotoxic drugs. PMID- 21781757 TI - Bioactivation of benzocaine to a methaemoglobin-forming metabolite by rat and human microsomes in vitro. AB - Benzocaine-mediated methaemoglobin-generation was compared with that of dapsone in vitro. Direct incubation of benzocaine with washed human erythrocytes alone at up to 15 mM did not result in significant methaemoglobin formation (0.4 +/- 0.1%). With rat microsomes, dapsone-dependent methaemoglobin formation was almost two-fold that of benzocaine at 30 min (56.5 +/- 0.7% vs 31.6 +/- 2.4% P < 0.005)). Benzocaine-mediated methaemoglobin formation was significantly reduced in the presence of DDC (diethyldithiocarbamate) at the 10 (P < 0.005) and 20 (P < 0.025) min time points. At 30 min, cimetidine reduced benzocaine-mediated methaemoglobin from 34.4 +/- 8.7% to less than 3% (P < 0.005). The methaemoglobin forming capacity of dapsone was significantly inhibited at all three time points by both DDC (P < 0.005) and cimetidine (P < 0.005). Incubation of benzocaine with microsomes from five human livers showed that each liver produced methaemoglobin forming metabolites. No inhibitory effect was seen with DDC, although cimetidine caused a significant reduction (32.8 +/- 12.4% overall) in benzocaine-mediated methaemoglobin formation in the four livers tested. PMID- 21781758 TI - A role of nitric oxide in organophosphate-induced convulsions. AB - The effects of nitric oxide-regulating compounds on convulsions and mortality of rats administered i.p. with diisopropylfluorophosphate was investigated. l-N(G) nitroarginine methyl ester, a nitric oxide synthase inhibitor possessing an anticholinergic action, markedly attenuated the intensity of convulsions and significantly reduced the mortality rate. A similar result was obtained with anticholinergic procyclidine, an N-methyl-d-aspartate receptor antagonist. Noteworthy, l-N(G)-nitroarginine, another inhibitor of nitric oxide synthase, significantly attenuated the seizure intensity when administered in combination with atropine sulfate (5 mg/kg), though either l-N(G)-nitroarginine or atropine sulfate was inactive alone. It is suggested that nitric oxide may be a proconvulsant or a convulsion-promoting factor in anticholinesterase poisoning, and both the reduction of nitric oxide level and blockade of cholinergic systems may be required for more effective protection of seizures. PMID- 21781759 TI - Streptomyces spores from mouldy houses induce nitric oxide, TNFalpha and IL-6 secretion from RAW264.7 macrophage cell line without causing subsequent cell death. AB - The current view is that only bacterial lipopolysaccharide (LPS) and gamma interferon (IFNgamma) are able to alone activate macrophages to secrete nitric oxide (NO), probably a causative agent of cell death. Moreover, some cytokines and gram positive pathogens together with IFNgamma induce NO-production. Surprisingly, spores of Streptomyces sp., which are mesophilic gram-positive bacteria found in mouldy houses, stimulated RAW264.7 macrophages to produce pro inflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6), and induced the expression of inducible NO-synthase (iNOS) with a subsequent NO-production. However, the Streptomyces spores did not kill NO producing macrophages, as did both LPS and gram negative bacteria Pseudomonas fluorescens, strong inducers of cytokine- and NO-production. These results imply that Streptomyces sp., induced cytokine and NO-secretion, may play a role in the responses evoked by exposure to these microbes. Moreover, factors other than, or in addition to NO, are necessary for cytotoxicity in murine macrophages. PMID- 21781760 TI - Microassay of superoxide anion scavenging activity in vitro. AB - We have developed a photometric, platereader-based microassay for superoxide anion scavening activity in vitro. Superoxide anions were generated using a xanthine oxidase/hypoxanthine system and detected by following the reduction of ferricytochrome c at 550 nM. Inhibitory activity was assessed for superoxide dismutase (SOD) and the superoxide anion scavengers tiron and TEMPO together with a number of TEMPO derivatives. The initial rate of change in optical density (OD) at 550 nm, i.e., initial reaction rate, generated by xanthine oxidase (20 mU/ml)/hypoxanthine (100 MUM) coupled to ferricytochrome c (100 MUM) was effectively abolished by SOD (200 U/ml), tiron (10 mM) and TEMPO (0.3 mM), indicating the involvement of superoxide anions. TEMPO derivatives inhibited the initial reaction rate with the potency order: TEMPO > 4-hydroxy-TEMPO = 4-carboxy TEMPO. In contrast, 4-hydroxy-TEMPO, which lacks the free radical nitroxide function, was inactive up to 1 mM. PMID- 21781761 TI - Comparison of neuroprotective efficacy of competitive and non-competitive AMPA antagonists in vitro. AB - The neuroprotective efficacy of the most potent competitive alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7 sulfamoyl-benzo(F)quinoxaline (NBQX) and three recently developed 2,3 benzodiazepine non-competitive AMPA antagonists (GYKI 52466, 53405 and 53655) was investigated in primary cultures of rat telencephalic neurons. NBQX protected cultured neurons against AMPA (20 MUM for 21-23 h) induced toxicity with EC(50) of 0.5 MUM. In the same test GYKI 52466, 53405 and 53655 had EC(50) values of 10.6, 9.3 and 5.1 MUM, respectively. Thus we found the competitive antagonist NBQX to be ten times more effective neuroprotectant in vitro than the most potent non-competitive GYKI compound (GYKI 53655). PMID- 21781762 TI - Alteration of major cytokines produced by mitogen-activated peritoneal macrophages and splenocytes in T-2 toxin-treated male CD-1 mice. AB - Fusarium T-2 toxin has immunotoxic properties that may be related to the modulation of cytokine expression by cells of the immune system. Male CD-1 mice were used to study the effect of in vivo exposure to T-2 toxin on the alteration of interleukin (IL)-1alpha, tumor necrosis factor alpha (TNF), and IL-6 in lipopolysaccharide-stimulated peritoneal macrophages, and IL-2, IL-3, and interferon gamma (IFNgamma) in concanavalin A (Con A)-stimulated splenocytes. Mice were orally dosed with 0, 0.1, 0.5, and 2.5 mg T-2 toxin/kg body weight for 2 weeks on alternate days. Northern blot analysis of IL-1alpha, TNF, and IL-6 mRNA from activated peritoneal macrophages showed no significant differences between control and treated groups. Measurements of secreted protein by immunoassay demonstrated suppression of these cytokines in all treated groups, suggesting that T-2 toxin affects the translational or post-translational regulation of these cytokines from peritoneal macrophages. Levels of IL-2, IL-3, and IFNgamma mRNA from Con A-activated splenocytes were higher in all treated groups. The increases were significant for IL-2 and IFNgamma in the groups receiving low (0.1 mg/kg) and high (2.5 mg/kg) doses of T-2 toxin, and for IL-3 in the group receiving a medium (0.5 mg/kg) dose of this toxin (P <= 0.05). Results indicated that T-2 toxin given orally at low or medium doses induces transcription or increases mRNA stability of IL-2, IFNgamma, and IL-3. Protein levels of all three cytokines were also increased, indicating that T-2 toxin also increases translational/post-translational efficiency of IFNgamma, IL-2, and IL 3. Possible mechanisms in the immunosuppressive effects of T-2 toxin may involve endotoxemia resulting after the toxin administration, alteration of the stability of mRNA, or previously described effects of T-2 toxin on protein synthesis. PMID- 21781763 TI - Divergent effects of classical inducers on rat plasma and microsomal fraction paraoxonase and arylesterase. AB - The effects of three different enzyme-inducing agents (phenobarbital, 3 methylcholanthrene and rifampicin) on plasma and liver microsomal fraction paraoxonase and arylesterase were studied in rats. Although phenobarbital and 3 methylcholanthrene each increased the esterase activities in microsomal fraction, only 3-methylcholanthrene was capable to increase them in plasma. By contrast, the administration of rifampicin decreased both enzyme activities in liver and plasma. The results indicate that at least there exists two esterase activities in rat liver microsomes which hydrolyse both paraoxon and phenylacetate, but only one of them is released into the blood. PMID- 21781764 TI - A hierarchical approach to the evaluation of chemicals for estrogenic and other endocrine-disrupting properties. AB - The emergence of estrogenicity/endocrine-disruption as an important endpoint in the toxicological assessment of chemicals presents a series of problems to overcome before regulatory control of such agents can be enacted. A framework is presented by which progress in this endeavour can be expedited. A hierarchial approach to testing is proposed, together with consideration of the types of information required to transform test data into human risk estimations. The approach is based broadly on current methods for defining potential human carcinogens and mutagens, and if found acceptable, would dramatically accelerate regulatory progress on this subject. However, several questions must be answered, using focused data, before the approach can be endorsed or transferred into a regulatory context. The importance of early consideration of all aspects of this complex new toxicity, including the unexpected observation of synergism between synthetic estrogens, is emphasized. PMID- 21781765 TI - Ozone at high-pollution urban levels causes airway hyperresponsiveness to substance P but not to other agonists. AB - Ozone (O(3)) causes airway hyperresponsiveness, but few studies have evaluated this effect at urban concentrations. In this work dose-response curves to intravenous acetylcholine, histamine or substance P were performed in guinea pigs with or without previous exposure to O(3) (0.15, 0.3, 0.6 or 1.2 ppm for 4 h, 16 18 h before the studies). We found airway hyperresponsiveness to histamine, but not to acetylcholine, only after 1.2 ppm O(3). By contrast, airway hyperresponsiveness to substance P was developed at O(3) levels encountered in highly-polluted cities (0.3 ppm). These results suggest that excitatory non adrenergic non-cholinergic responses could be affected by air pollution, and that substance P is a useful pharmacological tool for evaluating the airway hyperresponsiveness induced by low O(3) concentrations. PMID- 21781766 TI - Behavioral effects of maternal exposure to an ortho-chlorinated or a coplanar PCB congener in rats. AB - Polychlorinated biphenyls (PCBs) are still of environmental concern. Neurotoxic effects were described after developmental exposure to PCB mixtures and single congeners. The purpose of the present experiment was to compare the behavioral effects of the coplanar congener 3,4,3',4'-tetrachlorobiphenyl with the ortho chlorinated 2,4,2',4'-tetrachlorobiphenyl. Female Wistar rats were exposed with a subtoxic dose of 1 mg/kg b.w. of 3,4,3',4'-tetrachlorobiphenyl, 2,4,2',4' tetrachlorobiphenyl or the vehicle during gestation from day 7 to 18. There were significant lower concentrations of 3,4,3',4'-TCB than of 2,4,2',4'-TCB in dams and offspring at gestational day 19. Decreases from gestational day 19 (F 19) to postnatal day 21 (PND 21) were only observed in the adipose from dams exposed to 2,4,2',4'-TCB. The following behavioral tests were conducted in the offspring: locomotor activity in the open field, spatial learning in the radial arm maze, catalepsy induced by the dopamine receptor blocker haloperidol, and passive avoidance learning at PND 25, PND 95, PND 180, and PND 220, respectively. Significant differences to the control group were detected in the 3,4,3',4' tetrachlorobiphenyl exposed offspring. There were increases in descent latencies in the catalepsy test and impairments of passive avoidance behavior. These behavioral effects were observed in the adult rats long after the termination of exposure when internal PCB levels were indistinguishable from those of controls. A mediation of the reported effects by alterations of dopaminergic processes or thyroid hormone levels is discussed. PMID- 21781767 TI - 2,3,7,8-Tetrafluorodibenzo-p-dioxin: a potent agonist of the murine dioxin receptor. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related polychlorinated aromatic hydrocarbons exert a pattern of toxicity related to their binding to a common receptor, the Ah (aryl hydrocarbon) or dioxin receptor. No information is available, however, on the toxicological properties of 2,3,7,8-tetrafluorodibenzo p-dioxin (TFDD). In our experiments, TFDD was found to act as a highly potent dioxin receptor agonist leading to a transient induction of cytochrome P450(CYP)1A1 mRNA and protein in receptor-proficient mouse Hepa-1 hepatoma cells treated with 10(-10) M TFDD. However, no significant induction of 7 ethoxyresorufin O-deethylase (EROD) activity was observable in TFDD-treated Hepa 1 cells or mouse hepatocytes in primary culture, suggesting an interference with the catalytic activity of CYP1A1. Parallel experiments with 10(-10) M TCDD showed a sustained induction of CYP1A1 mRNA and protein, and of EROD activity. When a reporter gene construct comprising a xenobiotic-responsive element (XRE) in 5' position was transfected in Hepa-1c-1c-7 cells, 5*10(-8) M TFDD and 5*10(-9) M TCDD induced transcription to a comparable extent. Both inducers were inactive when a mutant XRE with a guanine replaced by thymine was transfected. In metabolism studies in mouse liver homogenate, TFDD was rapidly degraded in the presence of an NADPH-regenerating system, and metabolism was enhanced in liver homogenate from beta-naphthoflavone-pretreated mice indicating that TFDD is metabolized in a CYP-catalyzed pathway. The open ring products dihydroxytetrafluororbiphenyl ether, and 1,2-difluoro-o-benzoquinone, probably derived from 1,2-difluorocatechol, were identified by GC-MS analysis of the incubation mixtures, whereas no phenolic metabolites/and or metabolites with an intact dioxin ring could be found. It is concluded that TFDD, in contrast to its chlorinated analogue, is metabolically unstable, and thus currently does not fulfill the criteria for the recommendation of a TCDD or toxicity equivalency factor (TEF). PMID- 21781768 TI - Dopamine D(1) antagonist SCH23390 attenuates self-administration of both cocaine and fentanyl in rats. AB - To investigate the role of dopamine D(1) receptors in the reinforcing effects of cocaine and fentanyl, the effect of the D(1) antagonist SCH23390 on intravenous self-administration of these drugs was investigated in rats using a progressive ratio (PR) reinforcement schedule, during which the rats received the first three injections under an FR1 schedule. Then the number of lever presses required to deliver an injection (lever press ratio) increased by three after every three further injections. The last lever press ratio completed by each rat during each 6 h session was designated the breaking point. Breaking point values increased dose-dependently during both cocaine (0.125-1.00 mg/kg per injection) and fentanyl (0.25-2.00 MUg/kg per injection) self-administration. Pretreatment with SCH23390 (0.01 mg/kg, s.c.) decreased breaking point values for both cocaine and fentanyl, reflecting a decrease in the reinforcing efficacy of the drugs. To determine whether the effect of SCH23390 was due to general suppression of the lever pressing response, the effect of SCH23390 (0.01 mg/kg, s.c.) on the performance of rats maintained by water-reinforcement was examined. SCH23390 suppressed performance only transiently, therefore general suppression appears to have little or no effect on the breaking point. These results suggest that dopamine D(1) receptors are involved in mediating the reinforcing effects of both the psychostimulant cocaine and the opiate fentanyl. PMID- 21781769 TI - Effect of nitric oxide synthesis modification on renal function in gentamicin induced nephrotoxicity. AB - We evaluated the effect of acute or chronic nitric oxide (NO) synthesis activation or inhibition in rats with gentamicin-induced acute renal failure. Rats received gentamicin 100 mg/kg per day for 6 days, or isotonic saline. Some animals of each group also received N(G)-monomethyl-l-arginine (l-NAME, 4 mg/kg per day) or l-arginine (1%) in the drinking water for 6 days (chronic NO synthesis modification). In another experimental set, animals were treated with gentamicin or saline for 6 days and glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured before and after the infusion of l-NAME (50 mg/h per kg) or l-arginine (60 mg/h per kg) (acute NO synthesis modification). Acute l NAME administration induced a decrease in GFR and RPF both in control and gentamicin treated animals. Chronic l-NAME treatment induced an impairment in GFR only in gentamicin-treated animals. Acute l-arginine administration did not modify renal function in any experimental group whereas chronic l-arginine administration improved renal function only in gentamicin-treated animals. Urinary excretion of N-acetyl-beta-d-glucosaminidase and alkaline phosphatase was increased by chronic treatment with l-NAME in both groups, whereas l-arginine had no effect. In conclusion, NO synthesis inhibition aggravates gentamicin-induced renal damage. However, chronic NO synthesis stimulation partially prevents against gentamicin nephrotoxicity, thus suggesting that increased renal NO synthesis during gentamicin-induced nephrotoxicity plays a protector role on renal function. PMID- 21781770 TI - Protective effects of lobenzarit against allyl alcohol-induced hepatotoxicity in mice and rats. AB - The protective effects of lobenzarit disodium against the toxicity of allyl alcohol were investigated in vitro using isolated rat hepatocytes and in vivo using mice. In mice, at i.p doses of 25, 50 and 100 mg/kg lobenzarit significantly decreased the activity of alanine amino transferase (ALT) in serum and the concentration of malondialdehyde (MDA) in liver homogenates, both of which were increased by allyl alcohol at a dose of 64 mg/kg. At concentrations of 0.2 and 0.3 mM, lobenzarit reduced the release of lactate dehydrogenase (LDH) and the levels of malondialdehyde (MDA) induced by 0.4 mM of allyl alcohol in isolated rat hepatocytes. However, lobenzarit did not increase the levels of reduced glutathione (GSH) depleted by allyl alcohol in any of the two experimental models. The protective effects of lobenzarit were dose- and concentration-dependent and they were most obvious when lobenzarit was administered 30 min before allyl alcohol. It is concluded that lobenzarit exerts the observed protective effects most likely by its antioxidant properties. PMID- 21781771 TI - Structure-dependent induction of CYP2B1/2 by 3-methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats. AB - The effects of eleven 3-methylsulfonyl (3-MeSO(2))-metabolites of polychlorinated biphenyl (PCB) congeners (which were reported to remain in Swedish mother's milk and Japanese Yusho patient's tissues) and their two structurally similar 3 MeSO(2)-PCBs on the hepatic drug-metabolizing enzyme activities were compared with those of phenobarbital (PB) and 3-methylcholanthrene (3-MC).The induction profile of the drug-metabolizing enzymes, CYP2B1 and CYP2B2 in the hepatic microsomes of rats treated with nine 3-MeSO(2) derivatives, namely 3-MeSO(2) 2,4',5-trichlorobiphenyl, 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (3-MeSO(2) 2,2',4',5-tetraCB), 3-MeSO(2)-2,2',5,5'-tetraCB, 3-MeSO(2)-2,3',4',5-tetraCB, 3 MeSO(2)-2,2',3',4',5-pentachlorobiphenyl (3-MeSO(2)-2,2',3',4',5-pentaCB), 3 MeSO(2)-2,2',4',5,5'-pentaCB, 3-MeSO(2)-2,2',3',4',5,5'-hexachlorobiphenyl (3 MeSO(2)-2,2',3',4',5,5'-hexaCB), 3-MeSO(2)-2,2',3',4',5,6-hexaCB and 3-MeSO(2) 2,2',4',5,5',6-hexaCB, was similar to that of rats treated with PB, but was different from that of rats treated with 3-MC. These findings indicate that 3 MeSO(2) metabolites derived from nine PCBs are PB-type inducers of microsomal drug-metabolizing enzymes. The relative inducing potencies of 3-MeSO(2) derivatives on the hepatic drug-metabolizing enzyme activities differed with the extent of chlorination and the positions of chlorine substituent on the phenyl rings. The results of present study show that the structure-CYP2B1/2 induction relationship exists for the 3-MeSO(2) derivatives studied. The inducing abilities of 3-MeSO(2)-2,2',4',5-tetraCB and 3-MeSO(2)-2,2',4',5,5'-pentaCB (2 MUmol/kg) on the content of cytochrome P450 were higher than those of 2,3',4,4',5-pentaCB (mono-ortho-substituted PCB) (80 MUmol/kg), 3,3',4,4'-tetraCB (coplanar PCB) (80 MUmol/kg) and 3,3',4,4',5-pentaCB (coplanar PCB) (0.5 MUmol/kg). The inducing effects of the administration of 3-MeSO(2)-2,2',4',5-tetraCB and 3-MeSO(2) 2,2',4',5,5'-pentaCB at 2 MUmol/kg on the contents of total cytochrome P450, CYP2B1 and CYP2B2 corresponded to those of PB at 431 MUmol/kg twice at a 24 h interval. It is noticeable that 3-MeSO(2)-2,2',4',5-tetraCB and 3-MeSO(2) 2,2',4',5,5'-pentaCB have highly potent PB-type inducing activity on drug metabolizing enzyme systems. PMID- 21781772 TI - Cisplatin-induced pica behaviour in rats is prevented by antioxidants with antiemetic activity. AB - Pica, eating of non-nutritive substances such as kaolin in rats has been suggested as an illness response behaviour, analogous to vomiting in species that have developed emetic reflex. We have recently demonstrated that antioxidants glutathione, N-(2- mercaptopropionyl)glycine (tiopronin), vitamin C and vitamin E exert antiemetic effect against cisplatin-induced emesis in dogs. In the present study, the effect of these antioxidants was investigated against pica model in rats. Pretreatment with these agents significantly inhibited the cisplatin induced enhanced kaolin intake. However, these agents failed to exert any significant improvement in the decreased food intake by cisplatin. The findings confirm the potential of these antioxidants as antiemetics against cancer chemotherapy induced vomiting, though they may not improve the anorexia. The experiments further support that pica in rats can be used as a good alternative rodent model to dogs and cats particularly for preliminary and rapid screening of antiemetic agents. PMID- 21781773 TI - Effects of single and repeated administration of endosulfan on behaviour and its interaction with centrally acting drugs in experimental animals: a mini review. AB - The organochlorine cyclodiene insecticide, endosulfan readily penetrates into the brain. The neurotoxic action of endosulfan has been attributed to its alpha isomer. Endosulfan sulphate which is a chief metabolite of endosulfan seems to contribute to its acute neurotoxic action which is manifested by clonic convulsions in experimental animals. Convulsant and proconvulsant effects of endosulfan are apparent after its chronic exposure at low dose levels. These effects have been attributed to its gamma-aminobutyric acid antagonistic action. Repeated exposure to low doses has resulted in behavioral changes too. Endosulfan induced hyper-excitability has been associated with its muscarinic receptor stimulating action. The insecticide has been shown to produce aggressive behaviour and learning impairment by activating serotonergic mechanism. A dopaminergic involvement has been suggested for endosulfan-induced hypermotoractivity and circling movement. Animals exposed chronically to low doses of the insecticide have responded more markedly than control animals to the pharmacological actions of diazepam, chlorpromazine, pentobarbital and ethanol. The findings reviewed here emphasize awareness that chronic occupational exposure to low doses of endosulfan may result not only in behavioral abberations but in hazardous interaction with centrally acting drugs too. PMID- 21781774 TI - Influence of methionine administration during chelation of cadmium by CaNa(3)DTPA and DMPS in the rat. AB - Influence of methionine administration was investigated in rats on the efficacy of calcium trisodium diethylenetriamine pentaacetate (CaNa(3)DTPA) and 2,3 dimercaptopropane-1 sulfonate (DMPS) in the treatment of cadmium intoxication. CaNa(3)DTPA, DMPS or methionine were quite effective in mobilizing cadmium from blood and all the tissues examined in cadmium pre-exposed animals. The combination of CaNa(3)DTPA and methionine was more efficient in reducing hepatic, renal and heart cadmium levels while that of DMPS and methionine was more efficient in lowering liver, kidney and brain cadmium levels than either of them alone. The combinations were also highly effective in enhancing the urinary and the fecal excretion of cadmium. The treatment with CaNa(3)DTPA, DMPS or methionine was quite effective in reversing cadmium inhibited tissue enzymes and alterations in blood and serum biochemical levels. The combined treatment with a chelator and methionine was more effective than the chelators alone in restoring cadmium induced changes in hepatic and renal transaminases. The treatment with CaNa(3)DTPA, DMPS or methionine appreciably decreased the depletion of endogenous zinc, copper and iron due to cadmium but the combined treatments were more efficient than the individuals in restoring the kidney and the brain copper levels only. The results show that the administration of methionine during chelation therapy may be beneficial in the treatment of cadmium intoxication. PMID- 21781775 TI - Cytotoxic effects of 2,6-di-tert-butyl-4-methylphenyl N-methylcarbamate (terbutol) herbicide on hepatocytes and mitochondria isolated from male rats. AB - The cytotoxic effects of 2,6-di-tert-butyl-4-methylphenyl N-methylcarbamate (terbutol) and its major metabolites were investigated in freshly isolated rat hepatocytes. Terbutol and its metabolite, especially 2,6-di-tert-butyl-4 methylphenyl carbamate (N-demethylterbutol), at a concentration of 1.0 mM resulted in a time dependent cell killing accompanied by losses of intracellular ATP, protein thiols, and glutathione (GSH) and the accumulation of oxidized GSH. Supplementation of the hepatocyte suspension with 5 mM N-acetylcysteine, a precursor of intracellular GSH, inhibited the cytotoxicity of N-demethylterbutol. In mitochondria isolated from rat liver, terbutol and its metabolites impaired respiration related to oxidative phosphorylation and the potency of their toxicity is associated with impairment of mitochondrial respiration. These results indicate that N-demethylterbutol is the most cytotoxic followed by terbutol and other metabolites, and that both the mitochondrial respiratory system and protein thiols are important targets for these compounds. PMID- 21781776 TI - 3-Chloro-2-hydroxypropylmercapturic acid and alpha-chlorohydrin as biomarkers of occupational exposure to epichlorohydrin. AB - Until now no urinary biomarker of exposure was available to assess human exposure to epichlorohydrin (ECH). For this purpose the urinary excretion of mercapturic acids and alpha-chlorohydrin (alpha-CH), which are potential metabolites of ECH in humans was investigated. This study was undertaken in a chemical plant in which ECH is used in the production of glycidyl ethers. Urine samples were collected from 19 persons at the beginning and at the end of work-shifts and at the morning after the last work-shift. Respiratory air concentrations of ECH were determined by personal air monitoring (PAM) and were found to range from<0.03 to 1.1 mg/m(3) (8 h-TWA, median 0.09, n=23). The determined respiratory exposure to ECH was in all cases below the current occupational exposure limit of 4 mg/m(3) for ECH (8 h-TWA-OEL). In one additional case a dermal exposure to an unknown amount of technical ECH was noted. Urinary metabolites were isolated by ethyl acetate extraction or by lyophilization and determined by GC-MS. In ethyl acetate extracts of acidified urine samples of workers with potential occupational exposure to ECH, 3-chloro-2-hydroxypropylmercapturic acid (CHPMA) was identified with GC-MS and the concentrations measured ranged from<0.05 (detection limit) to 5.35 mmol/mol creatinine. The increase of the CHPMA excretion during the work shifts, corrected for creatinine excretion, correlated well with the 8 h-TWA respiratory air concentrations of ECH (r(2)=0.94, n=7). For 8 individuals it was possible to assess an urinary half-life for the excretion of CHPMA (2.54+/-0.94 h). By extrapolating the relation between the ambient air concentrations of ECH and the urinary CHPMA excretions, an excretion of 6.2 mmol CHPMA/mol creatinine (tolerance levels of 95% C.I.: 5.1-7.3) is predicted if ECH exposure is at the level of the current OEL. The urinary excretion of two other known metabolites of ECH in rats, namely alpha-CH and 2,3-dihydroxypropylmercapturic acid (DHPMA) was also investigated. alpha-CH was identified in urine of workers exposed to low air concentrations of ECH but DHPMA could only be identified after the dermal exposure to technical ECH. In these latter samples CHPMA and alpha-CH were determined up to 167 and 6.3 mmol/mol creatinine, respectively. From this investigation it is concluded that urinary excretion of the mercapturic acid CHPMA is an appropriate biomarker of human exposure to ECH. A tentative biological exposure index (BEI) of 6 mmol CHPMA/mol creatinine for ECH during an 8 h work-shift is proposed. PMID- 21781777 TI - Cadmium induces the production of high molecular weight heparan sulfate proteoglycan molecules in cultured vascular endothelial cells. AB - The purpose of the present study is to clarify whether or not cadmium-induced production of heparan sulfate in vascular endothelial cells includes: (1) an increase in the number of heparan sulfate proteoglycan (HSPG) molecules; (2) a formation of longer chains of heparan sulfate; and (3) a binding of more heparan sulfate chains to core proteins. Bovine aortic endothelial cells were cultured and metabolically labeled with [(3)H]glucosamine and [(35)S]sulfate in the presence of cadmium chloride. Radiolabeled HSPGs were separated from more highly charged chondroitin or dermatan sulfate proteoglycans by ion-exchange chromatography and hydrodynamic size of HSPGs was characterized by gel filtration. Heparan sulfate chains were characterized by gel filtration after digestion with either papain or heparitinase. It was found that cadmium increases the incorporation of radioactive precursors into the high molecular weight subclass of HSPGs without a marked change of molecular weight of heparan sulfate chains (approximately 45 kDa). A sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [(35)S]methionine-labeled proteins after heparitinase digestion revealed that the endothelial cells actively produce a HSPG core with a high molecular weight (~400 kDa), probably a perlecan core and the accumulation was increased by cadmium. HSPGs produced by cadmium-treated endothelial cells enhanced the [(3)H]thymidine incorporation in vascular smooth muscle cells cultured in the presence of basic fibroblast growth factor. It was therefore suggested that vascular endothelial cells after exposure to cadmium produce more perlecan molecules and this alteration may contribute to the antithrombogenic property of vascular wall and the formation of atherosclerosis after exposure to the metal through increase in anticoagulant heparan sulfate chains and stimulation of vascular smooth muscle proliferation, respectively. PMID- 21781778 TI - Induction of estradiol 2-hydroxylase activity in MCF-7 human breast cancer cells by pesticides and carcinogens. AB - The induction of 17beta-estradiol (E2) 2-hydroxylase activity was investigated in MCF-7 human breast cancer cells using 2-[(3)H]E2 as the substrate in a radiometric assay. Treatment of MCF-7 cells with 10 MUM indole-3-carbinol (I3C) for 48 h caused a 3.5-fold induction of E2 2-hydroxylase activity, whereas, I3C at concentrations as high as 100 MUM did not induce CYP1A1 mRNA levels or immunoreactive protein. Thus, the induction of E2 2-hydroxylase activity using the radiometric assay was not dependent on induction of CYP1A1. E2 2-hydroxylase activity was also increased by I3C within 2 h after treatment suggesting in situ interactions with the cellular cytochrome P450 system. The time-dependent effects of various chlorinated pesticides, antiestrogens and mammary carcinogens on E2 2 hydroxylase activity were also investigated. p,p'-DDE, atrazine and the mammary carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) significantly decreased E2 2 hydroxylase activity after 2 h; whereas, only the latter two compounds decreased activity after 48 h. Both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the mammary carcinogen benzo[a]pyrene (BaP) induced E2 2-hydroxylase in MCF-7 cells after incubation for 48 h and this was also paralleled by induction of CYP1A1 protein. The antiestrogens ICI 164 384 and ICI 182 780 decreased E2 2-hydroxylase activity in MCF-7 cells after incubation for 48 h, whereas tamoxifen and 4 hydroxytamoxifen were inactive. The results indicate that chemical-induced modulation of E2 2-hydroxylase activity in MCF-7 cells is complex and does not predict their activity as mammary carcinogens. PMID- 21781779 TI - Prevention of ozone-induced airway hyperresponsiveness and epithelial injury by phosphodiesterase inhibitors in guinea pigs. AB - We investigated the effects of phosphodiesterase (PDE) inhibitors on ozone induced airway hyperresponsiveness (AHR) in guinea pigs. Theophylline (10-100 mg/kg), rolipram (1-100 mg/kg) and T-440 (1-100 mg/kg) were orally administered 30 min before ozone exposure (3 ppm, for 30 min). Ozone exposure caused an increase in airway responsiveness to methacholine aerosol, and log PC(10) (log transformed methacholine concentration causing a 10 cm H(2)O increase in pulmonary inflation pressure) in the control and ozone-exposed group was 4.43+/ 0.05 (n=6) and 3.26+/-0.15 (n=12), respectively. Theophylline at 100 mg/kg, 10 mg/kg rolipram and 10 mg/kg T-440 significantly inhibited AHR with log PC(10) value of 4.73+/-0.16 (n=7), 3.74+/-0.11 (n=7), 3.82+/-0.15 (n=6), respectively. On histological examination, epithelial damage in the trachea and peripheral airways was recognized after ozone exposure. At 100 mg/kg, rolipram, T-440 and theophylline caused complete inhibition of AHR, and prevented epithelial damage of the trachea and peripheral airways. These results indicate that PDE inhibitors prevent not only ozone-induced AHR but also airway epithelial injury by ozone. PMID- 21781780 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes an Ah receptor-dependent and ARNT-independent increase in membrane levels and activity of p60(Src). AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to affect various cellular activities including growth factor signal transduction, hormone responses, and cell differentiation. The purpose of this study was to examine more closely the very early effects of TCDD on protein tyrosine kinase activity, specifically p60(Src). We found that TCDD causes rapid changes in the plasma-microsomal membrane levels and activity of p60(Src) in Hepa 1c1c7, Hepa c4 cells, and SR3Y1 cells, a p60(v-Src) overexpressing cell line. Such cellular changes occur within 30 minutes after 10 nM TCDD treatment, as measured by Western blot analysis. TCDD's ability to increase p60(Src) levels was found to be: (1) dose-dependent, with an estimated EC(50) between 10(-10) and 10(-11) M TCDD; (2) Ah receptor (AhR)-dependent, since TCDD's effect was blocked by co-administration with 1 MUM alpha-naphthoflavone, an AhR antagonist; and interestingly (3) ARNT-independent, since TCDD's effect was observed in Hepa c4 cells, an ARNT(-) mutant cell line. Since ARNT is a heterodimerization partner of the AhR required for binding of the ligand-activated AhR to dioxin-responsive elements on DNA in the nucleus to transactivate genes controlled by the AhR, an alternative mechanism for TCDD's action is discussed which does not require ARNT. Along with increased membrane levels of p60(Src), we observed a corresponding increase in the activity of a 60 kDa protein tyrosine kinase using two different kinase detection assays. This effect of TCDD was also found to be AhR-dependent, ARNT-independent, and independent of de novo protein synthesis since cycloheximide was unable to completely abolish TCDD's effect. The present findings provide a potentially important mechanism by which TCDD can alter cell growth and differentiation. PMID- 21781781 TI - Disruption of sphingolipid metabolism and induction of equine leukoencephalomalacia by Fusarium proliferatum culture material containing fumonisin B(2) or B(3). AB - Fumonisin B(1), B(2), and B(3) are inhibitors of ceramide synthase, a key enzyme in the pathway for de novo sphingolipid biosynthesis. Corn, naturally contaminated with either predominantly fumonisin B(1) or pure fumonisin B(1), has been shown to cause equine leukoencephalomalacia (ELEM). It has been hypothesized that fumonisin-induced disruption of sphingolipid metabolism is an early event in the development of ELEM. Recently, it was shown that Fusarium proliferatum corn culture diets containing predominantly fumonisin B(2), but not diets which were predominantly fumonisin B(3), at 75 ppm (0.75 mg/kg BW/day) caused hepatotoxicity and ELEM. Analysis of free sphingoid bases and complex sphingolipids in serum, liver, and kidney, revealed that both the fumonisin B(2) and B(3) diets caused significant disruption of sphingolipid metabolism, however, the fumonisin B(2) culture material diet was significantly more effective than the fumonisin B(3) culture material diet at disrupting sphingolipid metabolism and in causing hepatotoxicity and clinical signs indicative of the onset of ELEM. A significant increase in the ratio of free sphinganine to free sphingosine in serum was first evident at day 4 and 11 with the fumonisin B(2) and B(3) diets, respectively. Increase in serum enzymes indicative of liver toxicity was first evident at day 34 in ponies fed the fumonisin B(2) diet and clinical signs (head shaking, gait problems, and muscle tremors) were first observed at day 48. Ponies fed the fumonisin B(3) diets showed no increase in serum enzymes or clinical signs for as long as 65 days when the study with fumonisin B(3) was stopped. The results support the conclusion fumonisin B(2) is more effective than fumonisin B(3) in disrupting sphingolipid metabolism and induction of ELEM and liver injury in ponies. PMID- 21781782 TI - Mercuric chloride toxicity in rat liver mitochondria and isolated hepatocytes. AB - The effects of mercuric chloride on isolated rat liver mitochondria and freshly isolated rat hepatocytes were investigated. Mercuric chloride (in the MUM range) depresses state 3 respiration, suggesting a strong effect at the level of the phosphorylation system. It also stimulates state 4 respiration and decreases mitochondrial membrane potential, suggesting an uncoupling action. In isolated hepatocytes, mercuric chloride causes a dose- and time-dependent cell death, accompanied by depletion of intracellular glutathione. Furthermore, mercuric chloride decreases intracellular ATP and ADP levels simultaneously with increasing AMP concentration, indicating fast hydrolysis of ATP without adequate rephosphorylation. From this study we can conclude that the bioenergetic lesion promoted by mercuric chloride seems to be sufficient to explain lethal hepatocyte injury. PMID- 21781783 TI - Fluorescent estimation on cytotoxicity of methylmercury in dissociated rat cerebellar neurons: its comparison with ionomycin. AB - To study the cellular basis of the neurotoxicity of methylmercury, the effects of methylmercury on dissociated rat cerebellar neurons were examined using a flow cytometer, a confocal laser microscope and three fluorescent dyes, fluo-3 for monitoring the changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) and for detecting live neurons, ethidium for assessing the neurons that are dead or have compromised membranes, and 5-chloromethylfluorescein (CMF) for estimating the cellular content of nonprotein thiols. Methylmercury at concentrations of 1 MUM or greater increased the [Ca(2+)](i) of almost all neurons. Prolonged exposure to methylmercury (3 and 10 MUM) produced a further increase in [Ca(2+)](i), in association with compromising membranes in some neurons. Thereafter, methylmercury induced blebs on membranes of some neurons with increased [Ca(2+)](i). Methylmercury at concentrations of 0.3 MUM or greater dose dependently decreased the cellular content of nonprotein thiols. Results suggest that methylmercury may induce the loss of membrane integrity through destabilized Ca(2+) homeostasis and oxidative stress in mammalian brain neurons. PMID- 21781784 TI - Bioactivation of lapachol responsible for DNA scission by NADPH-cytochrome P450 reductase. AB - The reduction of the naphthoquinone derivative, lapachol, which is responsible for its bioactivation was examined using microsomal preparations and NADPH cytochrome P450 reductase (P450 reductase). Phenobarbital (PB) pretreatment resulted in an induction of enzyme activities for cytochrome c reduction (1.54 times) and lapachol reduction (1.20 times) by hepatic microsomal preparation of rats. The specific activity of lapachol reduction by purified P450 reductase showed 56-fold higher than that by untreated liver microsomes. Addition of antibody against P450 reductase (2 mg of IgG/mg of protein) to the microsomal incubation mixture caused an immunoinhibition of cytochrome c (32%) and lapachol (19%) reduction activities, suggesting that P450 reductase catalyzes lapachol reduction. Generation of superoxide anion radical (1321 nmol/mg per min) in approximately equivalent amounts of with NADPH consumption (941 nmol/mg per min) was detected during metabolism of lapachol by P450 reductase. Electron spin resonance (ESR) experiments confirmed generation of superoxide anion radical and hydroxyl radical as these 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adducts. Incubation of lapachol with P450 reductase caused a cleavage of DNA which was reduced in the presence of Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase(1), and hydroxyl radical scavengers such as dimethyl sulfoxide (DMSO) and thiourea. Taken together, these results indicate that lapachol is bioactivated by P450 reductase to reactive species, which promote DNA scission through the redox cycling based generation of superoxide anion radical. PMID- 21781785 TI - The use of precision-cut rat lung slices for studying PGF(2alpha) metabolism. AB - The suitability of a dynamic lung slice culture system as an in vitro model for studying pulmonary metabolism of PGF(2alpha) was assessed. [(3)H]Prostaglandin F(2alpha) ([(3)H]PGF(2alpha)), a twenty carbon fatty acid that contains a five carbon ring and is known to be metabolized by lung in vivo, was incubated with precision-cut rat lung slices in 1.7 ml of Waymouth's buffer fortified with 10% fetal calf serum. At 0, 2, 4 and 8 h after addition of [(3)H]PGF(2alpha) (1.82 ng/MUCi), incubation was stopped and the contents of each vial were analyzed for [(3)H]PGF(2alpha) and its metabolites using reversed-phase HPLC with radiochemical detection. PGF(2alpha) was metabolized to 15-keto PGF(2alpha), 13,14-dihydro-15-keto PGF(2alpha), and two unknown minor polar metabolites. These results indicate that PGF(2alpha) was metabolized in lung slices pathways similar to those seen in vivo. Slice viability was assessed by protein synthesis and light microscopic examination of lung slices through 24 h of incubation. Protein synthesis was maintained and no tissue necrosis was observed over the entire 24 h incubation, indicating that the lung slices were viable for at least 24 h. These results indicate that the dynamic lung slice culture system is an appropriate in vitro model for studying the pulmonary metabolism of PGF(2alpha). PMID- 21781786 TI - Altered function, localization and phosphorylation of gap junctions in rat liver epithelial, IAR 20, cells after treatment with PCBs or TCDD. AB - Three different PCB-congeners 3,4,5,3',4'-pentachlorobiphenyl (IUPAC no. 126), 2,4,5,2',4',5'-hexachlorobiphenyl (IUPAC no. 153) and 2,4,5,3',4' pentachlorobiphenyl (IUPAC no. 118) were investigated for possible structure activity relationships in altering gap junction intercellular proteins. All tested PCB-congeners and TCDD decreased the gap junctional intercellular communication in IAR 20 cells, but at different treatment periods, suggesting different modes of action. The presence of the Cx43-P(2) band, a phosphorylated isoform of Cx43, was associated with a functional communication. A reduced Cx43 mRNA level was noted after 48 h of exposure with PCB 126, PCB 118 and TCDD. In summary, the non dioxin-like PCB 153 can decrease gap junctional intercellular communication rapidly by reducing the phosphorylated isoform of Cx43, whereas the dioxin-like PCB 126 and TCDD reduce the communication slowly by decreasing the mRNA level of Cx43, resulting in a reduced Cx43 protein level (which includes the P(2)-band). The mixed inducing PCB-congener, PCB 118, can act both as the dioxin like and the non dioxin-like PCBs in gap junction regulation. PMID- 21781787 TI - Changes in the hepatic glutathione peroxidase redox system produced by coplanar polychlorinated biphenyls in Ah-responsive and -less-responsive strains of mice: mechanism and implications for toxicity. AB - The alteration in hepatic glutathione peroxidase (GPx) produced by polychlorinated biphenyls (PCBs) was studied in vivo in aryl hydrocarbon (Ah) responsive C57BL and -less-responsive DBA strains of mice. 3,3',4,4',5 Pentachlorobiphenyl (PCB 126), one of the high-affinity ligands for the Ah receptor, significantly reduced Se-dependent GPx activity in C57BL mice, but not in DBA mice. A reduction in activity in C57BL mice was also observed following treatment with a high dose of 3,3',4,4'-tetrachlorobiphenyl with lesser affinity for the Ah receptor than PCB 126, but not by 2,2',5,5'-tetrachlorobiphenyl, a low affinity ligand. To assess the effects on GPx in the liver, the content of reduced glutathione (GSH), an obligate co-factor for GPx, and the activity of two enzymes, gamma-glutamyl transpeptidase (gamma-GTP) and glutathione reductase (GR), which play a role in supplying GSH were determined after PCB treatment. The results showed that although the hepatic activity of gamma-GTP and GR was affected differently by PCB 126, the content of GSH was slightly increased rather than reduced in both strains of mice. The activity of non-Se-dependent GPx, which is due to the catalysis by some isozymes of glutathione S-transferase (GST), was significantly increased only in C57BL mice by PCB 126 treatment. Immunoblot analysis demonstrated that the induction of the class theta GST, which is a potent reducer of peroxides (Hiratsuka et al., 1995. Biochem. Biophys. Res. Commun. 212, 743) reflects the enhancement of the above activity. These results suggest that (i) the PCB-induced reduction in Se-dependent GPx activity is mediated by a mechanism involving the Ah receptor; and (ii) a concomitant increase in the class theta GST partially rescues the Ah-responsive mice from coplanar PCB-induced oxidative stress. PMID- 21781788 TI - Retinoids in eggs and embryos of birds fed fish from the Great Lakes. AB - Retinoids were analyzed in 11-day chick embryos and eggs from white Leghorn hens (Gallus domesticus) fed environmentally-derived polychlorinated biphenyls (PCB) in carp (Cyprinus carpio) from Saginaw Bay. The yolks and the embryos contained all-trans-retinol, 3,4-didehydroretinol and retinyl esters. There was no significant difference in the total retinoid content in the yolks of 11-day incubated eggs among hens fed for 7 weeks diets containing 0.5-6.6 mg PCB/kg diet. However, the proportional amount of retinols in the high (6.6 mg) PCB group was significantly less than that in low (0.5 mg) PCB controls, while the amount of retinyl palmitate in the high PCB group was significantly greater than that in the controls. Retinoids in the embryos were not affected by any of the PCB levels fed to hens for 7 weeks prior to laying the eggs. The 50% reduction in the molar ratio of retinols to retinyl palmitate in the yolks of eggs as the result of the high PCB level fed to hens for 7 weeks can serve as an indicator for chronic exposure to PCB contamination at the level of 6.6 mg or higher PCB/kg diet. PMID- 21781789 TI - The effect of the spin trapping agent alpha-phenyl-n-tert-butyl nitrone on dexfenfluramine-induced serotonin depletion in rat brain. AB - Oxygen-free radical formation from either the parent compound amphetamine, its metabolites or drug-released serotonin (5-HT) has been implicated in the reduction of serotoninergic markers caused by amphetamine derivatives. Therefore, the present study investigated the effects of the spin-trapping agent alpha phenyl-tert-butyl nitrone (PBN) on the 5-HT-lowering action of dexfenfluramine (DF) in rats, compared with p-chloroamphetamine (PCA). PBN (150 mg/kg, i.p, divided in two doses) almost totally prevented the reduction of 5-HT in particularly sensitive regions of the rat brain (cortex and striatum) 1 and 7 days after DF (10 mg/kg, i.p.). It also provided complete protection against the acute 5-HT-depleting action of PCA (5 mg/kg, i.p.), reducing it at 7 days in striatum, although with the higher dose (300 mg/kg, divided in two doses) there was a tendency to antagonize the long-term effects in both regions. With DF, however, the antagonistic effect of PBN was associated with a marked reduction of the plasma and brain concentrations of the parent drug, but particularly its active metabolite dexnorfenfluramine (DNF). Thus, reduced brain availability of the total active drug (DF+DNF) may explain why PBN prevents the neurochemical effects of DF (but not PCA), including the long-term one which possibly depends on the extent of the initial 5-HT lowering. PMID- 21781790 TI - The genotoxicity of diaveridine and trimethoprim. AB - We examined the genotoxicity of diaveridine and trimethoprim in the bacterial umu test, the bacterial reverse mutation test, the in vitro chromosome aberration test, the in vivo rodent bone marrow micronucleus test in two species, and the in vivo comet assay in five mouse organs. Both compounds were negative in the umu test (Salmonella typhimurium TA1535/pSK1002) and in the reverse mutation tests (S. typhimurium TA100, TA98, TA97, TA102, and Escherichia coli WP2 uvrA/pKM101) in the presence and absence of S9 mix. Diaveridine induced structural chromosome aberrations in cultured Chinese hamster CHL cells in the absence of a metabolic activation system, but not in the presence of a liver S9 fraction. No clastogenic activity in CHL cells was detected for trimethoprim. Bone marrow micronucleus tests in mice and rats conducted on diaveridine by single- and triple-oral dosing protocols were negative. The comet assay revealed that a single oral administration of diaveridine significantly induced DNA damage in liver, kidney, lung, and spleen cells, but not in bone marrow cells. The significant increase in migration values of DNA was reproducible with dose-response relationship. We suggest that the liver detoxifies the compound before it reaches the bone marrow, and that is why it is negative in the in vivo bone marrow micronucleus test. We concluded that diaveridine is genotoxic to mammalian cells in vitro and in vivo. PMID- 21781792 TI - Conclusions and recommendations. PMID- 21781791 TI - Chronic ethanol promotes the neuronal differentiation of NG108-15 cells independently of toxin-sensitive G-proteins. AB - The ability of ethanol to promote neuronal differentiation of NG108-15 mouse neuroblastoma x rat glioma hybrid cells was investigated using morphological, biochemical and electrophysiological techniques. Ethanol concentration-(10-200 mM) and time-(1 h-3 days) dependently reduced cell proliferation, but increased acetylcholinesterase (AChE) activity and cell protein content. Chronic ethanol (200 mM) also time-dependently increased voltage-sensitive Ca(2+) currents in the cells. Similar effects were obtained with chronic treatment of the cells with the standard differentiating agents sodium butyrate or forskolin. Chronic treatment of NG108-15 cells with primary alcohols (0.1-200 mM) of varying chain length all reduced cell proliferation and increased cell protein content and AChE activity with the potency order butanol>propanol>ethanol>methanol. Chronic treatment of NG108-15 cells with cholera toxin (50 ng ml(-1)) or pertussis toxin (50 ng ml( 1)) did not induce differentiation of the cells, nor did it modify the effects of 50 or 200 mM ethanol on cell proliferation, AChE activity or cellular protein content. Chronic cholera toxin did however abolish agonist-stimulated adenylyl cyclase activity in the cells, whereas pertussis toxin abolished receptor mediated inhibition of adenylyl cyclase activity. Furthermore, inhibitors of protein kinase C (GF 109203X, 5 MUM), protein kinase A (H-89, 10 MUM) or Ca(2+)/calmodulin-dependent protein kinase II (KN-62, 3 MUM) all failed to modify the effects of 200 mM ethanol on cell proliferation, AChE activity and cellular protein content. These experiments indicate that chronic ethanol is able to promote neuronal differentiation of NG108-15 cells independently of toxin sensitive G-proteins and some protein kinases. PMID- 21781793 TI - Food allergy and intolerance: an international chemical safety perspective. AB - Chemical safety is concerned with the assessment of human health (and environmental) risks and their management. The safety of chemicals in food, present as normal constituents, intentional additives, contaminants or residues is part of chemical safety. Morbidity and mortality due to allergenic chemicals and allergic hypersensitization are being addressed on a global basis. As part of this, international efforts are being made to establish the prevalence of respiratory and dermal allergies in all countries and it is timely to extend this to food allergies. A number of international organizations are involved in the assessment of chemical risk and risk management. Information exchange is a vital part of these processes. The International Programme on Chemical Safety is an example of a cooperative programme of three organizations with close links and coordination with other bodies and organizations concerned with safe and sustainable use of chemicals. PMID- 21781794 TI - Mechanisms of gastrointestinal reactions to food. AB - Much of the genetic information that modulates mucosal immune responses was encoded several million years ago and has subsequently been subjected to modifications selected by the impact of microorganisms and food antigens. Confronted with these challenges, the intestinal immune system has developed two arms: (1) immune exclusion performed mainly by secretory IgA antibodies to inhibit colonization of pathogenic microorganisms and penetration of harmful antigens; and (2) down-regulatory mechanisms to avoid local and peripheral overreaction (hypersensitivity) towards innocuous substances. The latter phenomenon is called oral tolerance and apparently explains why most individuals show no adverse immune reactions food. When the mucosal barrier function is insufficient, tolerance to dietary antigens is abrogated in genetically susceptible individuals. This is most likely to occur during the vulnerable period after birth before the immunoregulatory network has been established. Breast-feeding appears to be immunologically important during this period, not only to substitute for the infant's lacking secretory antibodies but also because of its immune-modulating effects. PMID- 21781795 TI - Why are we not all allergic: basic mechanisms for tolerance development. AB - Harmless antigens encountered on the mucosal surface are normally tolerated in the sense that they do not induce inflammatory immune responses. Oral tolerance is the type of mucosal immune regulation that prevents inflammatory reactions to food proteins. However, parasites and invasive microorganisms at the mucosal surfaces must be recognised and dealt with in a proper manner. The immune system does so by cross-regulating the response where it either produces IgA to exclude invasion, IgE to fight parasites, or IgG to destroy the invasive organisms. Allergy is an anti-parasitic reaction to a misinterpreted but harmless antigen. This lack of tolerance induction is influenced by genetic factors controlling the amount of interleukin (IL)-4 produced initially in the immune response. IL-4 directs B-cells to produce IgE, induces naive T-cells to become IL-4 producing T helper cells (Th2 cells) and prevent other T-cells from entering into the IFN gamma-producing Th1 pathway. Long lasting Th2 clones lose their IL-12 responsiveness and can no longer be induced to produce IFN-gamma thus they are locked in an allergy inducing Th2 phenotype. Environmental factors play on the genetic background and influence the outcome of the immune response. Mucosal tolerance depends on an intact mucosal surface, is influenced by the age of the subject, and can be manipulated through antigen dose and place of entry. Immune manipulating therapy may be more successful in primary than in secondary prevention of allergy. PMID- 21781796 TI - Symptoms and manifestations of food allergy, with particular relevance to the gut. AB - Adverse reactions to ingested foods can cause a wide variety of symptoms, syndromes and diseases. Several different mechanisms may be implicated in organic (i.e. not psychologically based) reactions to foods, and these include IgE- and non-IgE-mediated immunological reactions-food allergies. Many specific conditions have now been recognised, and can be separated from the general body of food allergy/food intolerance disease; diagnostic criteria are recognised, and often a specific diagnostic test is available. For others, both to establish that reaction to food is involved, and to establish the foods implicated, diagnosis may require exclusion diet, open and/or double blind, placebo-controlled challenges, ideally monitored objectively. Manifestations of food allergy in the gut are described; and the relevance of digestive function, in relation to dose and distribution of allergens, is discussed. PMID- 21781797 TI - Food induced skin diseases. AB - Skin diseases due to an adverse reaction to food are urticaria, atopic dermatitis, oral allergy syndrome, dermatitis herpetiformis and protein induced contact dermatitis. The first three disorders will be discussed in more detail. Urticaria per se is a common skin reaction associated with various external and internal factors. Food as a causative factor is more frequently associated with acute than with chronic urticaria. The relation between food and atopic dermatitis is evident in young children with atopic dermatitis. The course of atopic dermatitis in adults is hardly influenced by food. The mechanism involved in urticaria may be immune-mediated, being IgE-mediated, or non-immune mediated, being pharmacologic or unknown. The mechanism involved in food-induced atopic dermatitis is based on the involvement of IgE antibodies and T lymphocytes. So far, it not known if and how (free or complexed with antibodies) food allergens enter the skin. It has been speculated that cutaneous T cell homing factors are involved. PMID- 21781798 TI - Food sensitivity and rheumatoid arthritis. AB - The majority of double-blind placebo-controlled trials have shown that 30-40% of rheumatoid arthritis (RA) patients can improve substantially by using an elimination diet to identify foods that precipitate symptoms and the avoiding of these foods. Some such patients have discontinued drug treatment and remained well for 12 years or more. Prior to the elimination diet, most patients had not recognised diet as a trigger for their symptoms, because the offending foods were eaten daily. (Foods eaten infrequently can also provoke sensitivity, resulting in episodic arthritis.) Additionally, many RA patients are sensitive to several foods, making a rigorous elimination diet essential for diagnosis. The pattern of response to an elimination diet (30-40% of RA patients respond well; response occurs within 10-21 days; benefits are maintained if offending foods are avoided) is markedly different from the pattern of response to a fast (almost all RA patients respond well; response occurs within 3-5 days; benefits are lost rapidly when a normal diet is resumed). Clearly fasting and the elimination diet have different therapeutic mechanisms. The effect of fasting may be mediated by the absence of dietary fat, leading to a shortage of pro-inflammatory prostaglandins and leukotrienes. The mechanism by which food sensitivity is involved in rheumatoid arthritis remains unknown, but weight loss is definitely not responsible for the improvement seen on an elimination diet. Some evidence implicates the gut flora. Food-sensitive RA patients may also show changes in immune parameters during an elimination diet, but no consistent universal change has yet been found. PMID- 21781799 TI - Symptoms and manifestations of food intolerance. AB - Food intolerance (FI) is a less defined and a more heterogenous diagnosis than food allergy. The characterization of symptoms during trials, and relationship to time, meal and events such as provocation, are cornerstones of the diagnosis, which is hampered by the complexity of mechanisms and individual conceptuality of illness. Most cases of food intolerance are seen in general practice or do not seek health care. Nevertheless, a substantial number of patients are refered to hospitals. Variation in frequency of diagnosis may be caused by differences in health care levels, dietary habits and age. General symptoms may occur alone or in combination with symptoms from one or more target organs. Even the double blind provocation may give both false positive and false negative results. Repeat examinations, open provocations or verification by a subsequent follow up on an elimination diet may be needed. Many patients are satisfied with an elimination diet given after provocation. The primary objective, however, is to exclude specific organic or psychosocial explanations, in a multidisciplinary approach to these patients. PMID- 21781800 TI - Food allergens. AB - A food allergen may be defined as a substance that reacts with IgE antibodies, induces allergic sensitisation or induces allergic reactions. Some allergens only induce allergic sensitisation but do not provoke symptoms, while others bind IgE but do not induce mast cell degranulation. There is no common structure that can predict whether a given antigen may be a strong food allergen. A complete food allergen, e.g. fish parvalbumin, is capable of stimulating the immune system to produce IgE antibodies, and degranulate mast cells upon subsequent contact. The reason(s) for why some patients with IgE to ovalbumin tolerate eggs, and why some react on one occasion but not on another, are mostly unclear, but may be related to changes in gut permeability induced by other food substances or by gastro intestinal inflammation prior to the allergen contact. IgE antibodies to fruit or vegetables often show cross-reactivity, due to carbohydrate structures. These cross-reactive glycans have been designated cross-reactive carbohydrate determinants (CCD). Anti-CCD antibodies are highly cross-reactive. The antibodies do not have clinical significant because CCD-containing foods are usually well tolerated by patients with IgE antibodies to CCD. These IgE antibodies may cause confusion in relation to allergy diagnosis. PMID- 21781801 TI - Allergenic cross-reactivity, food allergy and pollen. AB - Pollen-allergic patients frequently present oral allergy-like symptoms after ingestion of several kinds of plant foods. The majority of these reactions are due to three distinct cross-reactive structures that are present in birch pollen. Proteins that share common epitopes with Bet v 1, the major birch pollen allergen, occur in other kinds of tree pollen, apples, stone fruits, celery, carrots and nuts. Approximately 70% of patients who are allergic to birch pollen may experience symptoms after consumption of foods from these groups. In contrast to Bet v 1, two minor allergenic structures which sensitise ~10-20% of all pollen allergic patients are also present in grass and weed pollen, namely profilin and cross-reactive carbohydrate determinants. Profilins can induce symptoms to almost all kinds of plant foods, whereas the clinical relevance of IgE binding to ubiquitous carbohydrates of N-glycans from plants remains in doubt. The paper summarises the knowledge pertaining to the molecular features of these cross reactive structures and the characteristics of the cross-reactivity patterns and discusses aspects of diagnosis, management and routes of sensitisation. PMID- 21781802 TI - Genetics of food allergy. AB - Genetics of human diseases has passed through three main historical phases: (1) studies of formal genetics aimed at investigating mechanisms of inheritance using Mendelian models in population, family and twin surveys; (2) studies of associations between HLA antigens and diseases; and (3) direct mapping of genes through candidate gene or random genomic search approach. Very few data in each of these three phases are available for food allergy and intolerance. They are mostly confined to formal genetics studies of allergy in general and to HLA association studies in celiac diseases. The main reason for paucity of data in this important area of investigation is represented by the heterogeneity of the clinical entities grouped under the label of food allergy at the level of: (1) the clinical phenotype, because of the many diseases and end-organs interested; (2) pathophysiological variables involved, since several immunological and non immunological mechanisms can be invoked in different cases of food allergy and intolerance; and (3) the foods or their absorbed metabolites which induce symptoms. However, progress made in genetics of allergy can be in part extrapolated to the limited number of cases where an IgE-mediated mechanism has been demonstrated. The review of studies based on a more punctual definition of the allergic phenotype and of the candidate genes (regions) of allergy: (1) suggests that allergen recognition and specific IgE response, total IgE (and IgG4) polyclonal activation, up-regulation of inflammatory cells (mast cells and eosinophils mainly) and hyper-responsiveness of end-organs are possibly regulated by different genetic and environmental factors; and (2) calls particular attention on the following genomic regions: 5q31.1-33, 6p21.3, 11q13,14. Research on genetics of food allergy and intolerance is highly recommended because of its high prevalence and of the potential applicative value of results for preventive measures of dietary control in subjects at risk. Since 'food allergy and intolerance' does not represent an useful phenotype for genetic studies because of its heterogeneity, adequate strategies of gene mapping should be designed in study groups selected for defined variables with a well established role in the pathogenesis of the different clinical expressions of this common condition. PMID- 21781803 TI - The allergy march: from food to pollen. AB - There is epidemiological evidence, especially from longitudinal studies, that clinical manifestations of atopy as well as IgE antibodies against food and aeroallergens show a systematic sequence of events. The atopic march begins with food allergy associated gastrointestinal disorders and atopic dermatitis followed by respiratory allergies, i.e. asthma and atopic rhino-conjunctivitis. Detectable food antibodies, especially against egg and milk proteins, usually precede or accompany the early clinical symptoms and signs. Similarly, aeroallergen sensitization, first against indoor allergen antibodies, succeeded by outdoor allergen antibodies, precede the clinical manifestation of respiratory allergy. Early atopic events, either manifestation or sensitization can be used as risk markers or even predictors of atopic disorders to implement preventive measures. Early atopic dermatitis as well as elevated serum IgE antibodies against food allergens in the first two years of life in combination with a family history can be used as a predictor for aeroallergen sensitization. PMID- 21781804 TI - Factors predicting food allergy. AB - Prediction of food allergies has not been addressed systematically and to date studies have concentrated on prediction of allergic disorders in a general fashion. The current available data suggests that possibly the best predictor is the combined approach of taking into account the family history together with elevated cord blood IgE. Other indicators, such as cord blood lymphocyte responses and gamma-interferon production at birth, are also discussed. Although preliminary studies seem to be promising, only studies of an unselected population with long term follow-ups will be able to show whether or not these possible predictors are of value. PMID- 21781805 TI - General principles of epidemiology, as applied to studies of IgE-mediated food allergy. AB - Epidemiology is the study of the distribution of disease and of the factors which contribute to or determine the development of a disease. Descriptive studies measure the frequency of a disease whereas analytic studies are predominantly concerned with identifying determinants or causes. In any epidemiological study it is essential that the exact objectives are clearly understood in terms of definitions and diagnostic criteria for the condition under scrutiny. Rather than address all food-induced reactions and diseases, the issues raised by epidemiological studies of one main group of conditions with a common mechanism, IgE-mediated food allergy, are considered. Problems with population-based and hospital-based surveys include case definition, case ascertainment, calculations and presentation of results and small numbers with wide confidence limits. PMID- 21781806 TI - Public perception of food allergy. AB - Although studies that use the double-blind placebo-controled food challenge (DBPCFC) suggest that the prevalence of food allergy is about 2%, public belief in food allergy appears to be considerably higher. The study was undertaken to determine the magnitude and features of the American public's belief in food allergy by surveying a large, demographically balanced population. A simple question about food allergy was incorporated into a broad, self-reported, mailed consumer questionnaire. Demographically representative American households (5000) were surveyed by means of quota sample in 1989, 1992, and 1993. The response rate was 79, 75, and 74%, respectively. Of responding households, 16.2, 16.6, and 13.9%, respectively, of responding households reported an average of 1.17 household members with food allergy. Individuals reported to be allergic to foods were more likely to be female, particularly adult women. Male individuals with reported food allergy tended to be young, whereas no such skew was noted among female subjects. Geographic differences were observed in reported food allergy, with the highest rate in the Pacific region. Milk and chocolate were the individual foods most frequently implicated in food allergy. Trends were consistent over the time period studied. Perceived food allergy is widespread and persistent. The characteristics and demographic patterns of this belief are not reflective of known food allergy epidemiology derived from studies in which the DBPCFC is used. PMID- 21781807 TI - The frequency of food allergy in Australia and Asia. AB - A review of the development of food allergy in a birth cohort of 620 Australian infants at high risk for development of atopic disease has recently been completed. Extrapolating to a random community population showed that at the age of two, egg appears the most frequent food allergen (3.2%), while cow milk (2.0%), and peanut are of similar frequency (1.9%). The prevalence of hypersensitivity to wheat and soy appears similar to sesame seed, cashew nut, hazelnut and walnut, but allergy to fish, brazil nut and shell fish are uncommon. Despite a different methodology, reports from several Asian centres suggest a similar frequency of hypersensitivity to these foods in young children although hypersensitivity to shellfish and seafood was more common than for nuts, peanut and wheat, if seafoods are part of the staple infant diet. Rice hypersensitivity was rare in both Australia and Asian countries. PMID- 21781808 TI - Prevalence of intolerance to food additives. AB - Food additives have been implicated as aetiological factors in many different disease states. Concern arose from a suggested link with food additives and hyperactivity in children. They have also been implicated in many other disease states. This perception, often made by parents on behalf of their children, is not confirmed by double-blind placebo-controlled challenge studies. The discrepancy between public perception and the true prevalence of food additive reactions is great and this discrepancy between perception and confirmed reactions also exists with food-related symptoms. The discrepancy is much greater in the case of food additives than in foods. The mechanism of food additive reactions is not immunological and there is no in vivo or in vitro confirmatory test. PMID- 21781809 TI - Chemicals in food and allergy: fact and fiction. AB - The prevalence of the atopic diseases asthma, rhinitis and atopic eczema has increased in the past two to three decades. It is not unusual to read the statement that food additives and other chemicals in food increase the risk of allergy. From a theoretical standpoint chemicals in the diet may influence allergic sensitization and elicitation in different ways: (i) they may directly cause allergy because they are allergens or haptens; (ii) they may act as adjuvants facilitating allergy to other (dietary) components; (iii) they may modulate the immune system by direct immunotoxicity and in theory be able to change the balance from tolerance to IgE production; and (iv) they may trigger non-allergic intolerance reactions. With the present knowledge of chemicals in foods, the human exposure to these chemicals, and the described trends in this exposure, there is no supportive evidence confirming that chemicals in foods are contributing to the reported increase in the prevalence of atopic diseases. PMID- 21781810 TI - Food from genetically modified organisms and potential for food allergy. AB - Crops produced through genetic modification are beginning to reach the market and many genetically-modified crops are under development. Since genetic modification results in the introduction of new proteins into the food plant the safety of the newly introduced proteins must be assessed. The potential allergenicity of the newly introduced protein is a major consideration in that safety assessment. All allergens are proteins but only a few of the many proteins found in foods are allergenic. The assessment of the allergenicity of the newly introduced proteins should focus on the source of the gene, the sequence homology of the newly introduced protein to known allergens, the immunochemical reactivity of the newly introduced protein with IgE from the blood serum of individuals with known allergies to the source of the transferred genetic material, and the physicochemical properties of the newly introduced protein. PMID- 21781811 TI - Food allergy: predictive testing of food products. AB - Food allergy is a substantial cause of distress in humans. Several biotechnological techniques can be applied to reduce the antigenicity of food proteins to produce for instance hypoallergenic infant formulas. Biotechnological techniques synthesizing new proteins or new biological varieties for applications in food are also available. For such biotechnologically for derived protein products (novel foods), allergenicity may also pose a major concern. For safety reasons, it is of importance to evaluate the residual antigenicity of modified protein products, to screen for possible cross-reactivity to prevent reactions in previously sensitized individuals, and to test for sensitizing properties of new and/or modified protein products. Besides physico-chemical and immunochemical analyses, several in vitro and in vivo bioassays may be applied in studying the antigenic or allergenic properties of (new or modified) food proteins. In this paper, an overview of several available assays and new developments for determining the antigenic or allergenic properties of dietary proteins, as well as their possible applications and limitations is presented. Special attention is paid to the role of the gastro-intestinal tract physiology in food allergy and in the evaluation of the allergenic potential of food proteins and to the possible applications of animal models in food allergy research and in the evaluation of the allergenicity of food proteins. PMID- 21781812 TI - Cow-milk allergy. AB - Hereditary predisposition is the major denominator of allergy, and hypersensitivity reactions contribute to the expression of the genetic predisposition. The route of sensitization varies with age so that dietary antigens predominate in infancy. The immaturity of the immune system and the gastrointestinal barrier may explain the peak prevalence of food allergies at an early age. The treatment of choice for cow-milk allergy is complete avoidance of cow-milk antigens. The approach to control allergic inflammation by antigen elimination, however, has not been satisfactory. New approaches are urgently needed for the management of patients with cow-milk allergy. These may include: (i) immunotherapy to counteract the immunological dysfunction, and (ii) stabilisation of the gut mucosal barrier to strengthen endogenous defence mechanisms. PMID- 21781813 TI - Sensitisation through breast milk? AB - The benefit of breast feeding to prevent or delay the development of food allergy in infants is somewhat controversial. Although prolonged breast feeding has widely been recommended for infants at high risk of allergy, studies concerning the composition of human milk in atopic mothers are scarce. Human breast milk is not a stabile concept. We have previously found that the cellular composition of human milk is significantly different in mothers with a food allergic infant than in those with a healthy child. The number of monocytes, lymphocytes or eosinophils, was greatly elevated whereas the number of activated macrophages was decreased in the breast milk of mothers with a severely allergic infant. The high numbers of eosinophils could easily increase the permeability of the gut thereby increasing the absorption of dietary antigens, and thus enhance the development of food allergies. Breast feeding provide many advantages to the suckling infant. However, infants developing food allergic symptoms on exclusive breast feeding may benefit from changing to formula feeding to protect adequate growth and to prevent the development of a more severe allergic symptomatology. PMID- 21781814 TI - Prevention of food allergy. AB - Development of a food allergy appears to depend on both genetic factors and exposure-especially in early infancy-to food proteins. In prospective studies, the effect of dietary allergy prevention programmes has only been demonstrated in high-risk infants, i.e. infants with at least one first degree relative with documented atopic disease. High-risk infants feeding exclusively on breast milk and/or extensively hydrolysed formula (eHF) combined with avoidance of cow's milk proteins and solid foods during at least the first 4 months of life are found to have a significant reduction in the cumulative incidence of food allergy, especially cow's milk protein allergy/intolerance (CMPA/CMPI), in the first 4 years of life. As no studies have been conducted pertaining to the preventive effect of avoidance of milk and other foods after the age of 4-6 months, recommendation of preventive elimination diets beyond this age is empirically based. In order to reduce costs and to minimize the risks of stigmatisation and malnutrition, it is important to avoid unnecessary restrictive and prolonged diets. A diet period of 4-6 months appears to be sufficient in the majority of infants. At present, eHF are recommended as a substitute for cow's milk. A few high risk infants may benefit from a maternal diet during lactation, but there is no documented beneficial effect of maternal dieting during pregnancy. PMID- 21781815 TI - Labelling of potential allergens in food. AB - In order to avoid food that they cannot tolerate, consumers suffering from food allergy or intolerance need sufficient and correct, information about food products. Labelling requirements are not satisfactory in this regard. Registration of adverse reactions in Sweden show that out of 77 cases, 51 were a result of inadequate labelling, six cases were fatal and several others required hospitalization. International recommendations for the labelling of food (Codex Alimentarius, a joint WHO/FAO organization) do not require specification of ingredients in composite ingredients if the composite ingredient constitutes less than 25% of the food (25% rule). Some ingredients are declared by category names. Ingredients such as milk, eggs, nuts, peanuts, fish, cereals, etc., will not appear on the label in these cases. Amendments are being discussed with a view to providing allergic consumers with more adequate information. A lowered specification limit for declaring ingredients in composite ingredients is suggested, combined with the establishment of a list of certain specific potent allergenic ingredients that should always be specified if present. Although many measures are needed to improve the situation for the allergic consumer, appropriate labelling of each product is fundamental. Adequate labelling is an important prerequisite for secondary prevention, a necessary basis for other measures and in addition will increase knowledge, awareness and caution in food production. PMID- 21781816 TI - Prevalence of food allergy/intolerance in Europe. AB - Discussed in this paper is the prevalence of allergy and intolerance to foods in Europe. Prevalence of allergy to food additives is not included. A fully reliable estimate of the prevalence of food allergy/intolerance does not exist. Prevalence changes with age, as does the relative importance of the most common food allergens. The cumulative prevalence of allergy and intolerance to cow's milk during the first year of life is approximately 2%. The total prevalence of food allergy/intolerance in children is not as well documented. In 18-month-old infants the Danish estimate is 6.5%. The high prevalence of peanut allergy (0.5%) in British children is not reflected in the results from other European countries. Milk, egg, fish and oranges seem to be the most common causes of allergy and intolerance in European infants and children. Results from epidemiological studies combined with the knowledge on pollen and latex cross reactivity, systemic reactions to contact allergens and coeliac disease point to a prevalence of food allergy/intolerance in the adult European population of approximately 5%. A mild itch in the mouth and lactose intolerance are not included in this estimate which is a qualified guess. PMID- 21781817 TI - Cross-reactivity between natural rubber latex and food allergens. AB - Immediate-type hypersensitivity to latex is a growing problem, especially among health care workers (HCWs) and patients requiring long-term catheterization and multiple operations. The responsible allergens are latex proteins, which are found in raw latex, as well as in various latex-containing products. More than 200 polypeptides can be discerned in latex sap and of these, 60 proteins showed reactivity with IgE antibodies from patients with latex allergy. Several of these proteins have been characterized at the molecular level and their role in latex allergy has been elucidated. Latex allergy is often associated with hypersensitivity to certain fruits and vegetables like avocado, kiwi, banana, sweet pepper, and tomato. Several case reports demonstrate a potential for serious allergic reactions to foods in latex allergic patients. Nevertheless, comprehensive studies on the clinical significance and relevance of this co sensitization are missing. Although some of the latex allergens are ubiquitous plant proteins or share structural features with plant proteins, the molecular bases of these cross-reactivities have not yet been clarified. PMID- 21781818 TI - Clinical symptoms of food allergy/intolerance in children. AB - Food allergy is principally a problem in infancy and early childhood. Food allergy/intolerance may cause a broad spectrum of symptoms and signs in children, including generalized reactions, such as anaphylactic shock. Reactions are localized mainly in the gastrointestinal tract, but food allergy/intolerance may also cause local symptoms in other organs such as the skin and the respiratory tract. About 50-70% demonstrate cutaneous symptoms, 50-60% gastrointestinal symptoms, and 20-30% respiratory symptoms. Among young children with food allergy/intolerance the majority have two or more symptoms with symptoms occurring in two or more organ systems. The symptoms occur primarily within a few minutes after food exposure (immediate reactions), however delayed reactions in the skin, gastrointestinal tract and lungs may also occur. Among children with symptoms suggestive of food allergy/intolerance, the diagnosis can be confirmed by controlled elimination/challenge procedures only in about one third of the patients. A proper diagnosis is important in order to avoid unnecessary restrictive diets and risk of malnutrition. PMID- 21781819 TI - Environmental chemicals and food allergy/intolerance, a synopsis. PMID- 21781820 TI - Susceptibility and risk: an overview. AB - This symposium on susceptibility and risk was the third in a series designed to bring together experts from diverse disciplines to discuss contemporary issues in risk assessment. The topic in 1996 was especially challenging since susceptibility is influenced by a myriad of factors including environmental, genetic, social and political elements. The delineation of the relative contribution of various 'susceptibility' factors has major implications for risk management options that may be applied in a regulatory context (risk prevention and risk reduction) or by the individual (risk avoidance). Current approaches to account for susceptibility in risk assessments (e.g. application of an uncertainty factor) have frequently been challenged as to their scientific basis and thus need periodic re-examination or update to maintain a credible foundation for the assessment process. The goal of this symposium was to gain a better understanding of the dimensions of the problem and to explore the directions that the risk assessment process might follow to better quantify the contribution of susceptibility in risk calculations. PMID- 21781821 TI - Accounting for susceptibility in risk assessment: current practice and new directions. AB - Differences in susceptibility between individuals can lead to variability in response to chemical exposures which in turn modify the risk of illness. As a means of exploring the basis for such differences in susceptibility, a project was undertaken to determine what data were available on the range of response variability for several health effects: neurotoxicity, reproductive/developmental toxicity, pulmonary toxicity, and cancer. In addition, modeling approaches for characterizing response variability were examined and evaluated. The main goal of this effort was to determine whether human response variability was adequately accounted for in the current risk assessment procedures for human health effects. The conclusions of the project were that few data are available, both because variability has rarely been the primary focus of study, and because data are not usually reported in such a way that response variability can be determined. Several recommendations were made to facilitate better characterization of interindividual variability, including the study of variability in available human data (e.g. the NHANES database) and allowing greater access to raw data from epidemiologic studies. In addition, the identification of relevant biomarkers, improved understanding of sources of variability, interaction of chemical effects with other exposures or pre-existing disease, and retrospective evaluations of risk assessments were recommended. It is hoped that these recommendations will stimulate research on susceptibility and response variability and encourage the reporting of data in a way that facilitates analysis of interindividual variability in response. PMID- 21781822 TI - Human variability in susceptibility How big, how often, for what responses to what agents? AB - This paper first reviews in plain language some basic concepts and methods for estimating inter-individual variability in susceptibility from human data. A scale is offered to allow different variability findings to be understood and compared. Then the accumulated results of different variability analyses, information on how much variability has been observed and how often, is summarized in the form of a series of box plots. Data are presented on pharmacodynamic variability for various non-cancer effects, variability in susceptibility to infectious organisms, and variability in susceptibility to carcinogenesis by genetically-acting agents. PMID- 21781823 TI - Acquired risk factors and susceptibility to environmental toxicants. AB - Susceptibility to illness after exposure to environmental toxicants is determined by the interaction of numerous factors involving both constitutive and acquired traits. Constitutive susceptibility (risk) factors are the intrinsic traits determined by developmental stage, gender, and genetic makeup. Within a population, changes in constitutive risk factors tend to occur slowly, through aging, alterations in the birth or death rate, or by migration in or out of the population. Often overlooked is the effect of acquired susceptibility factors on susceptibility to environmental toxicants. Acquired susceptibility factors, which are related to the effects of living conditions, psychosocial factors, diet, behavior and access to medical care, may modify the effect of constitutive factors. Three examples demonstrate the interaction of acquired susceptibility factors with exposure and constitutive factors. The increased prevalence of asthma in children is suspected of having a strong environmental component but the underlying acquired susceptibility factors, if any, are difficult to identify because of the multifactorial nature of asthma and the use of surrogate risk factors such as parent's education. beta-Carotene is a dietary component which may modify acquired susceptibility. While numerous observational studies find that dietary beta-carotene reduces the risk of lung cancer in cigarette smokers, intervention studies do not support this role. Hepatitis B is an example of an infectious agent functioning as an acquired susceptibility factor. Hepatitis B synergistically increases the risk of hepatocellular carcinoma when accompanied by exposure to aflatoxin, a relationship that may be modified by constitutive risk factors, such as epoxide hydrolase capabilities. Acquired risk factors have the potential to greatly influence risk and their impact should be included in future studies of the health effects of environmental toxicants. PMID- 21781824 TI - Not to decide is to decide: ignoring susceptibility is not 'good science'. PMID- 21781825 TI - The use of information on susceptibility in risk assessment: state of the science and potential for improvement. AB - The aim of this paper is to evaluate the use of information on susceptibility or variability in risk assessment. Are we using it well? Are we not using it well or not at all? And finally, what can we do to improve the use of information on variability in risk assessment? The presentation is organized using the risk assessment paradigm developed by the National Research Council in 1983 (National Research Council, 1983. Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, DC.) which conceptualized risk assessment as consisting of four phases: hazard identification, dose response assessment, exposure assessment, and risk characterization. Because risk assessment procedures differentiate cancer risk from risk for systemic toxicity (i.e. non-cancer), cancer and noncancer risk assessment are discussed separately. PMID- 21781826 TI - Emerging technologies from the Human Genome Project for understanding susceptibility and risk. AB - The new technologies from the Human Genome Program provide exceptional opportunities for surveying and measuring human exposure, as well as determining susceptibility on an individual-by-individual basis. These new technologies will soon enable rapid screening of populations at risk, as well as the broader public, for a variety of genes known to be associated with increased risk. These include specific oncogenes, tumor suppressor genes and DNA repair enzymes. Use of these technologies also presents a number of ethical issues, both in screening and in use of the information about individuals. Overall, the use of rapid genotyping technologies will introduce a specificity and possible group identifiers that will present new challenges to the determination of risk within the EPA mandate. PMID- 21781827 TI - Eggshell skulls and loss of hair from fright: some moral and legal principles that protect susceptible subpopulations. AB - Some of the legislation authorizing the Environmental Protection Agency's (EPA) regulation of toxic substances, principles deeply embedded in our legal system, and some moral principles tend to support the claim that all of us, even the most susceptible, have equal standing to be protected from harms from toxic substances. Information about susceptible subpopulations should be part of risk assessment, either as default considerations or as a result of empirical research. Risk assessment is the step in a regulatory process where higher risks to sensitive subpopulations should be recognized regardless of the statute authorizing agency action. If we do not acknowledge susceptible subpopulations in risk assessment, this suggests that they do not have sufficient standing to be protected. Such a view would be unacceptable. However, because full protection for susceptible subpopulations might be costly, risk managers may have to be imaginative in finding regulatory options to provide these protections. PMID- 21781828 TI - Accounting for susceptibility in risk assessment: The need for full disclosure. AB - Many Environmental Laws create the unrealistic expectation that science can be used to determine 'safety'. The many uncertainties surrounding environmental risks, as well as individual, group and societal differences about what is considered 'safe', make it inevitable that policy decisions must be made. It is appropriate that such decisions be shaped by politics and social issues, as well as be informed by science and economics, but care should be taken to distinguish between policy and fact. Not much is known about the nature and magnitude of environmental susceptibilities. Credible environmental decisions require that scientists, risk assessors and decision-makers acknowledge this, and that they take care to distinguish policy calls from scientific fact. PMID- 21781829 TI - Human activities that may lead to high inhaled intake doses in children aged 6 13. AB - This paper focuses on possible activities of children aged 6-13 that may make them susceptible to high hourly intake doses of ozone (O(3)) air pollution. Data from an O(3) exposure modeling exercise indicates that relatively few hours can account for a significant amount of the total cumulative ozone intake dose (D(I)(T)) received in a year. While O(3) concentration levels affected the hourly intake dose (D(Ih)) more than breathing rate (V (E)), there was a distinct and significant relationship between V (E) and D(Ih) when hours in a year were stratified by concentration levels. By investigating the V (E) levels associated with high dose hours, it appears that activities with an hourly V (E) rate of between 25 and 45 l/min can lead to high intake doses of O(3). The exercise literature was reviewed to ascertain which activities could lead to that range of V (E)'s and be sustained by children for 1 h. A list of such activities was developed. If an analyst is interested only in modeling high D(Ih) hours for children aged 6-13, an efficient approach might be to focus on those activities and estimate D(I)(T) for the other hours in an aggregated manner. PMID- 21781831 TI - Genetic and acquired determinants of individual susceptibility: Introduction. PMID- 21781830 TI - Sociodemographic aspects of human susceptibility to toxic chemicals: Do class and race matter for realistic risk assessment? AB - Susceptibility is well-recognized as a potentially important aspect of health risk assessment, particularly for groups such as pregnant women and their fetuses, infants, children, the elderly, and the infirm, that are known or suspected to be more vulnerable to environmental insults. More recently, it has become apparent that economically disadvantaged groups are likely to be systematically both more exposed and more susceptible to environmental pollution. This article reviews the reasons why low-income communities and many racial minorities are at an increased risk because they are more susceptible to the adverse health effects of toxic chemicals. The scientific challenges of quantifying the magnitude of environmental health risks for these groups are discussed, emphasizing ramifications for risk assessment and risk management decisions. Problems incorporating susceptibility into risk-based decision making are identified, and specific actions are recommended to address these deficiencies. PMID- 21781832 TI - Genetic predisposition to environmental induced diseases. AB - It is argued that genetic predispositions to environmentally induced illness are common in the general population. Yet, despite this, recognition assessment of the nature and magnitude of such predispositions has generally not been the object of environmental health research. The case is made that major public health advances in the understanding of environmental contaminants on human populations needs to focus on those sizeable subgroups (usually individuals who are heterozygote carriers of more serious diseases) with identifiable genetic predispositions. PMID- 21781833 TI - Metabolic differences and their impact on human disease Sulfotransferase and colorectal cancer. AB - Gene-environment interaction is an important aspect of human cancer risk. Genetic polymorphisms in acetylation and N-oxidation have previously been described regarding their impact on the heterocyclic amine-induced risk for colon cancer. Here, we report that another enzyme involved in the metabolism of food-borne carcinogens, sulfotransferase (ST1A3 measured by 2-naphthol activity), may function as a potential protective factor for colon cancer in humans. Initially characterized in human liver and colon (Chou et al., 1995), TS-PST activity can also be measured in platelets. A simple microtiter-based colorimetric technique was developed for use in this case-control study. African-Americans had a higher mean ST activity than Caucasians (2.32+/-0.24 versus 1.77+/-0.09 nmols/min per mg cytosolic protein, P=0.036). Furthermore, the slow ST phenotype (ST<=1.53) was more frequently associated with colon cancer than controls (57 versus 40%, P=0.026). These data suggest that the ST1A3 isoform may play a role in the differential risk for colorectal cancer. PMID- 21781834 TI - Mouse models for breast cancer susceptibility. AB - Breast cancer is the most common form of malignancy in American women. Apart from age, a strong family history of breast cancer confers the highest known risk for neoplastic development by the various etiologic factors identified to date. Four genes have been identified (p53, BRCA1, BRCA2, ATM) that appear to confer substantial predispositions to human breast cancer. Gene targeting techniques have been used to create mice with specific defects in these genes. This review describes the status of these mice as models for breast cancer susceptibility and suggests future research directions which may increase our understanding of breast carcinogenesis. PMID- 21781835 TI - Genotypic differences in host immunoreactivity and their effect on the development of polycyclic hydrocarbon-induced tumors. AB - Polyaromatic hydrocarbons are ubiquitous environmental contaminants that are known primarily for their mutagenic and carcinogenic properties. In mice, when applied to the skin, they also act as antigenic substances, capable of initiating a cell-mediated immune response (contact hypersensitivity). Using dimethylbenz(a)anthracene (DMBA) as a prototype, studies from this laboratory have found that genetic polymorphisms, at the Ah receptor locus, the major histocompatibility complex and the Lps locus, control the magnitude of the cell mediated immune response to these carcinogenic compounds. Strains of mice that metabolize polyaromatic hydrocarbons well and can be immunized to them are less likely to develop cutaneous tumors when subjected to a polyaromatic hydrocarbon initiation, TPA-promotion cutaneous carcinogenesis protocol. It may thus be possible to assess individual susceptibility to polyaromatic hydrocarbon-induced tumors by characterizing one's ability to metabolize polyaromatic hydrocarbons and his or her immune response to these agents. PMID- 21781836 TI - The influence of susceptibility factors on the immune response to DNA. AB - Susceptibility to autoimmune disease results from genetic factors that determine the pattern of immune responsiveness to self as well as foreign antigens. These factors may influence the immune response to DNA, a complex macromolecule that can induce antibody responses in normal as well as aberrant immunity. In systemic lupus erythematosus, anti-DNA antibodies target conserved sites present on all DNA and appear to arise by a T dependent mechanism. In contrast, in normal humans, anti-DNA antibodies react to non-conserved sites on certain bacterial DNA and have features suggesting induction by a T independent mechanism. The activity of bacterial DNA reflects the presence of base sequence motifs centering on an unmethylated CpG core. Because of susceptibility factors in patients with systemic lupus erythematosus, bacterial DNA may drive a response crossreactive with self DNA instead of a response specific for the foreign antigen. PMID- 21781837 TI - Life stage and its impact on risk of environmentally-induced adverse effects: Introduction. PMID- 21781838 TI - Toxicant exposure and trace element metabolism in pregnancy. AB - A review of the literature provides support for the concept that maternal nutritional status has a significant influence on embryonic and fetal development. The consumption of 'poor' diets has been shown to be a risk factor for poor pregnancy outcome, while the provision of selected nutritional supplements prior to and during pregnancy has been associated with improved pregnancy outcome. Despite the above, it has been difficult to identify specific nutrient deficiencies as causative factors of abnormal development. One explanation for this failure is that embryo/fetal nutritional deficiencies can arise through a number of mechanisms in addition to a low maternal intake of a nutrient(s). Evidence is presented for the hypothesis that the developmental toxicity of a number of teratogens can be ascribed, in part, to their ability to induce alterations in the partitioning of essential trace elements between the maternal and fetal unit. An implication of the above hypothesis is that maternal diet can be an important modulator of the developmental toxicity of several agents. PMID- 21781839 TI - Age-related differences in sensitivity to organophosphorus pesticides. AB - Organophosphorus (OP) pesticides are used extensively throughout the world to control undesirable pest species. The primary mechanism of action for OP insecticides is inhibition of acetylcholinesterase (AChE), an enzyme dynamically involved in cholinergic neurotransmission. Extensive inhibition of AChE leads to accumulation of acetylcholine in the synapse, disruption of normal impulse flow and subsequent signs of toxicity, including autonomic dysfunction, involuntary movements, muscle fasciculations and a host of others. It is generally believed that young individuals are more sensitive to the neurotoxic effects of these agents relative to adults. Essentially all studies addressing age-related differences in sensitivity to these toxicants have examined responses to acute exposures, however, using acute toxicity (lethality) as the endpoint. As the biochemical mechanism of toxicity for this class of toxicants (inhibition of AChE) is well known and considering that low level, repeated exposures are of great concern to the general public, we propose that evidence of neurochemical alterations, especially when exposures occur during development and maturation, is a more relevant endpoint of toxicity than lethality for estimating susceptibility. This report briefly summarizes previous and ongoing work in our laboratory which examines the relative sensitivity to these toxicants between young and adult rats. PMID- 21781840 TI - Age-related susceptibility to immunotoxicants: animal data and human parallels. AB - There are numerous examples, of both the identical and different effects of animals exposure to toxic agents, which can be compared in both, exposed prenatal/neonatal animals and exposed adults. In some instances, although the chemical and its metabolites are stored for long periods in adipose tissue, adult exposure (short of acute poisoning) has little effect on the immune system (Johnson et al., 1986. An immunotoxicological evaluation of gamma-chlordane. Fundam. Appl. Toxicol. 6, 317-326), while exposure during gestation results in immunoteratology (Barnett, 1996. Developmental immunotoxicology. In: Smialowicz, R.J., Holsapple, M.P. (Eds.), Experimental Immunotoxicology, CRC Press, Boca Raton, FL, pp.47-62). With the heavily studied dioxins, both prenatal as well as adult exposure causes immunotoxicity, however, the effects are not always the same. Attempts to confirm these observations in humans have been hampered by a multitude of problems that are directly related to the exposure paradigm, such as lack of accurate exposure data, varying lengths of exposure, etc. as well as many variables that are simply related to differences in genetic makeup, lifestyle, socioeconomic status, etc. that are part of the human populations. A few studies have noted important trends in immune status that are correlated with levels of halogenated aromatic hydrocarbon exposures, however, even these fail to provide unequivocal answers regarding the relative risk of prenatal exposure. PMID- 21781841 TI - Differential susceptibility to inhaled pollutants: effects of demographics and diseases. AB - Inhaled pollutants and respiratory disease deserve particular attention at a conference focused on susceptibility and environmental risk. Inhaled air contains diverse biological, physical and chemical stressors which may cause upper and lower respiratory inflammation and exacerbate complex polygenic disorders such as asthma and sinusitis. This paper focuses on intrinsic susceptibility factors of demographics and diseases as well as genetic background. The National Health Information Survey shows that acute and chronic respiratory conditions are common at all ages, but their incidence and prevalence vary between age groups. Susceptibility is therefore not a fixed characteristic, but the aggregate effect of changing intrinsic factors such as age and disease. While ethnicity is often cited as a risk factor for disease prevalence or severity, recent research shows that measurable factors such as nasal ellipticity determine exposure-dose relationships, while the imperfect surrogate of ethnicity does not. Studies also show that exposure-dose relationships can be modified by recent exposures, and additional information is clearly needed in this area. We propose that evidence for the genetic contribution to pollutant susceptibility be sought in inter individual variation in responses of homogenous, well characterized individuals to short term controlled pollutant exposure. Future improvements in risk assessment models will be based on a precise identification of factors that determine exposure-dose relationships, and a mechanistic understanding of the reasons that a demographic factor or disease appears to confer altered susceptibility. PMID- 21781842 TI - Ambient particulate matter and respiratory and cardiovascular illness in adults: particle-borne transition metals and the heart-lung axis(,). AB - Epidemiological studies have consistently shown associations of exposure to ambient particulate matter (PM) with severe health effects, including mortality and hospitalization, in adults. From the standpoints of both relative risk and attributable risk, the public health burden of ambient PM exposure is potentially greatest in elderly adults with underlying cardiopulmonary illness. Recent experimental data suggest that PM-borne transition metals have toxicity that could be mechanistically relevant to PM-related epidemiological findings. These data may prove to be especially relevant in elderly adults with cardiopulmonary illness. At the same time, important uncertainties remain in the epidemiological and experimental databases, such that the true degree of correspondence between the two is not yet known. In our opinion, this combination of emerging experimental-epidemiological coherence and remaining uncertainty imparts high priority to further research into the health effects of PM-borne transition metals. This research should not be confined to the respiratory system. Rather, it should examine the entire heart-lung axis and should probably consider other body systems (e.g. the vascular system) as well. In this research, close interdisciplinary communication should be sustained and experimental and epidemiological approaches should be coordinated to the maximum feasible extent. PMID- 21781843 TI - Age-related susceptibility to hepatotoxicants. AB - Limited information is available regarding age-associated events that lead to differences in vulnerability to chemicals that injure the liver. For some agents, such as allyl alcohol, alterations in metabolic activation, by liver biotransformation enzymes, are responsible for age-associated changes in severity of liver damage. For other toxicants, such as carbon tetrachloride, there appears to be no relation between changes in activation/detoxification processes and the effects of aging on the extent of liver injury. With diquat, a rise in iron content seems to explain the increased toxicity observed in hepatocytes of old rats compared with those of young-adult rats. Additional research is needed to identify the mechanisms responsible for age-dependent differences in sensitivity to environmental chemicals. PMID- 21781844 TI - Freshwater cyanobacterium Microcystis aeruginosa (UTEX 2385) induced DNA damage in vivo and in vitro. AB - Microcystins are a family of potent hepatotoxins and liver tumor promoters produced by several genera of cyanobacteria including Microcystis, Nodularia, Anabena, Nostoc, etc. They are chemically very stable and represent a public health threat when they occur in water used for human consumption. We investigated the DNA damage effects of M. aeruginosa UTEX 2385 in mouse liver in vivo and also in mammalian cells in vitro. The DNA damage effect is compared with purified toxin microcystin-LR (MCLR) in non-hepatic cells viz. baby hamster kidney cells (BHK-21) and mouse embryo fibroblasts primary cells (MEF). Cell-free extracts of UTEX 2385 induced significant DNA fragmentation at 0.5, 1 and 2 LD(50) (32.7, 65.4 and 130.8 mg/kg, respectively) and it was also time dependent. M. aeruginosa UTEX 2385 and MCLR induced significant DNA fragmentation in BHK-21 and MEF cells at 100 and 1.0 MUg/ml concentration. Electrophoretic analysis revealed necrotic DNA damage by UTEX 2385 in vivo. Both the toxins caused smear in agarose gel electrophoresis indicating the necrotic DNA damage in MEF cells, whereas, multiple DNA fragments in BHK-21 cells. The DNA damage effect of the toxin is supported by data on hepatotoxicity in vivo and cytotoxicity in vitro. PMID- 21781845 TI - Modulating effects of thyroid state on the induction of biotransformation enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - In this study we investigated to what extent the induction of detoxification enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is modulated by concomitant TCDD-induced changes in thyroid state. Euthyroid (Eu) male Sprague-Dawley rats, surgically thyroidectomized (Tx) rats and Tx rats receiving substitution doses of 3,3',5-triiodothyronine (Tx+T3) or thyroxine (Tx+T4) by osmotic minipumps were treated with a single ip injection of 10 MUg TCDD/kg/bwt or with vehicle (corn oil). Three days after TCDD administration, rats were sacrificed and blood and livers were collected for analysis. Total hepatic cytochrome P450 (CYP) content was increased by ~50% by TCDD in all groups but was not affected by thyroid state. In Eu rats, TCDD increased CYP1A1/1A2 activity 90-fold, CYP1A1 protein content 52-fold and CYP1A1 mRNA levels ~5.8-fold. Similar findings were obtained in Tx, Tx+T3 and Tx+T4 rats except that TCDD-induced CYP1A1 activity was significantly decreased in Tx rats. NADPH cytochrome P450 reductase activity was not affected by TCDD but was decreased in Tx rats, which may explain the diminished TCDD-induced CYP1A1 activity in Tx rats. Hepatic p-nitrophenol UDP glucuronyltransferase (UGT) activity was induced ~4-fold by TCDD in Eu rats. Similar basal and TCDD-induced activities were observed in Tx+T3 and Tx+T4 rats, but TCDD-induced activities were significantly lower in Tx rats. TCDD did not have a significant effect on overall glutathione-S-transferase (GST) activity or hepatic GST 2-2, 3-3 or 4-4 protein levels but produced a marked increase in GST 1-1 protein levels. Thyroid state did not affect basal or TCDD-induced GST activity or subunit pattern. Iodothyronine sulfotransferase (ST) activity was not affected by TCDD treatment and was slightly but not significantly lower in Tx rats than in Eu, Tx+T3 and Tx+T4 rats. These results suggest that the changes in thyroid hormone levels associated with TCDD treatment have little modulating effects on the induction of hepatic detoxification enzymes in Sprague-Dawley rats exposed to this compound. PMID- 21781846 TI - Neurotoxic effects in adult mice neonatally exposed to 3,3'4,4'5 pentachlorobiphenyl or 2,3,3'4,4'-pentachlorobiphenyl. Changes in brain nicotinic receptors and behaviour. AB - The objective of the present study was to investigate whether neonatal exposure to single PCB congeners 3,3',4,4',5-pentachlorobiphenyl (IUPAC 126) (co-planar) and 2,3,3',4,4'-pentachlorobiphenyl (IUPAC 105) (mono-ortho 'co-planar like') when given as one single dose (0.14-14 MUmol/kg body weight per os) to 10 day old male NMRI mice could induce neurotoxic effects in the adult animal, as earlier seen for some ortho-substituted PCBs. Furthermore, to ascertain whether behavioural aberrations, both in spontaneous behaviour and in learning and memory function, were followed by changes in the cholinergic and/or the dopaminergic system, and whether behavioural changes could worsen with age. It was found that neonatal exposure to 3,3',4,4',5-pentachlorobiphenyl can induce persistent aberrations in spontaneous behaviour and that this derangement can grow worse with age. Furthermore, this exposure affected also learning and memory functions in the adult animal and in the animals showing this deficit, the cholinergic nicotinic receptors in the hippocampus were affected. Exposure to 2,3,3',4,4' pentachlorobiphenyl, at the same dose or higher, did not cause any significant change in the investigated behavioural variables, spontaneous and swim-maze behaviour. PMID- 21781847 TI - Gender dependent effects of cigarette smoke on hepatic and pulmonary xenobiotic metabolizing enzymes in rats. AB - The adult male and female rats were exposed to cigarette smoke (CS) 5 times a day, with 1 h intervals, for 3 days in a chamber where smoke and fresh air lead alternatively and were killed 16 h after the last treatments and hepatic and pulmonary monooxygenase (MO) activities (aniline-4-hydroxylase, AH; aminopyrine-N demethylase, AMND; 7-ethoxyresorufin-O-deethylase, EROD; p-nitroanisole-O demethylase, p-NAOD), lipid peroxidation (LP) and reduced glutathione (GSH) levels and glutathione-S-transferases (GSTs) activities toward several substrates (1-chloro-2,4-dinitrobenzene, CDNB; 1,2-dichloro-4-nitrobenzene, DCNB; ethacrynic acid, EAA; 1,2-epoxy-3-(p-nitrophenoxy)-propane, ENPP) were determined. CS significantly increased hepatic AMND, EROD and p-NAOD activities whereas it unaltered AH activity in both genders as compared with controls. In the lung, EROD and p-NAOD activities were also significantly increased by CS in both genders. Pulmonary AH activity, however, significantly increased in males but remained unchanged in females. Pulmonary AMND activity significantly increased in females but remained unaltered in males. A significant decrease was noted in the LP level of males, while that of females was unaltered by CS in the liver. Pulmonary GSH and LP, and hepatic GSH levels were significantly increased by CS in both genders. In males, GST activities toward CDNB and DCNB did not alter, whereas GST activities toward EAA and ENPP significantly increased and decreased, respectively, in the liver. In females, CS significantly increased hepatic GST activity toward DCNB but it was ineffective on the other hepatic GST activities. All pulmonary GST activities of males were significantly depressed by CS. In females, however, CS significantly increased pulmonary GST activities toward CDNB and DCNB but was ineffective on GST activities toward EAA and ENPP. These results suggest that gender related differences exist in the modulations of hepatic GST, and pulmonary MO and GST activities but not in those of hepatic MO activities, by CS in rats. PMID- 21781848 TI - Roles of nitric oxide and prostaglandins in the increased permeability of the blood-brain barrier caused by lipopolysaccharide. AB - We investigated the involvement of nitric oxide (NO) and prostaglandins (PGs) in the damage to the blood-brain barrier (BBB) induced by lipopolysaccharide (LPS), using fluorescein as a tracer in mice. Aminoguanidine, a competitive inhibitor of inducible NO synthase (iNOS), when administered s.c. at 5 mg/kg, but not 500 mg/kg, reduced significantly the increase in brain fluorescein level after its i.v. injection in LPS-treated mice. When 1000 mg/kg of l-arginine, a substrate of NOS, were co-administered with 5 mg/kg of aminoguanidine to LPS-treated mice, the inhibitory effect of aminoguanidine on the increased fluorescein level disappeared. N(G)-Nitro-l-arginine methyl ester (l-NAME), a non-isoenzyme selective NOS inhibitor, when administered s.c. at 5 mg/kg, only slightly reduced the LPS-induced increase in the brain fluorescein level. A pretreatment with dexamethasone, which suppressed the induction of both iNOS and cyclooxygenase 2 (COX-2), tended to decrease the brain fluorescein level in LPS-treated mice. Indomethacin, a COX inhibitor, at 5 mg/kg, but not 10 mg/kg, suppressed significantly the LPS-induced increase in the brain fluorescein level. These results involve that both the NO produced by iNOS and the PGs produced by COX contribute to enhance BBB permeability in LPS-administered mice. PMID- 21781849 TI - Effectiveness of procyclidine in combination with carbamate prophylactics against diisopropylfluorophosphate poisoning. AB - The protective effect of cholinolytics such as procyclidine and atropine, in combination with carbamate prophylactics, against diisopropylfluorophosphate poisoning was examined in mice. Doses of carbamates were optimized, based on the maximum sign-free dose, the time course of cholinesterase inhibition and the protective potential against diisopropylfluorophosphate poisoning. Centrally active physostigmine was more toxic than centrally-inactive pyridostigmine and the toxic signs of carbamates appeared to be closely related to the level of inhibition of brain cholinesterase activity. In combination with atropine, physostigmine was more effective than pyridostigmine in protecting mice intoxicated with diisopropylfluorophosphate. Moreover, centrally-active atropine sulfate was a more effective co-antidote to carbamates than centrally-inactive atropine methylnitrate. The most prominent protection was achieved with the combination of carbamates and procyclidine, a centrally-active cholinolytic showing anticonvulsion, which was also observed to prevent diisopropylfluorophosphate-induced convulsions (Kim et al., 1997). Taken together, it is suggested that procyclidine could be a possible substitute for atropine as an antidote to diisopropylfluorophosphate poisoning. PMID- 21781850 TI - The effect of water soluble cyanotoxin(s) produced by two species of Anabaena on the release of acetylcholine from the peripheral cholinergic nervous system of the rat airway. AB - A water extract of the lyophilised fresh-water alga Anabaena flos-aquae enhanced substantially the release of [(3)H]acetylcholine ([(3)H]acetylcholine and [(3)H]choline) from cholinergic nerves of rat bronchi. Parallel experiments performed with the related species Anabaena lemmermannii did not demonstrate this effect. The effect on the release of [(3)H]acetylcholine by A. flos-aquae extract was concentration dependent. The A. flos-aquae induced [(3)H]acetylcholine release was not reduced by exposure to a low concentration of Ca(2+), but omega conotoxin GVIA (1.0 MUM), a blocker of N-type Ca(2+) channels reduced the release of [(3)H]acetylcholine induced by the A. flos-aquae extract. Addition of verapamil in a concentration (1.0 MUM) specific for inhibition of L-type Ca(2+) channels had no effect on the neurotransmitter release. A reduction in the release was, moreover, observed with the intracellular Ca(2+) chelator BAPTA/AM (30 MUM) and with the Na(+) channel blocker tetrodotoxin (3.0 MUM). During patch clamp studies of GH(4)C(1) neuronal cells, which have L- and T-type Ca(2+) channels, but no Na(+) channels, it was shown that a water extract of A. flos aquae depolarised these cells and reduced, rather than enhanced, the influx of Ca(2+). Such an effect was not seen following exposure of GH(4)C(1) cells to water extracts of A. lemmermannii. In addition to its presynaptic activity, the water extract of A. flos-aquae showed an antimuscarinic effect by displacing [(3)H]QNB binding from muscarinic receptors in homogenates of rat bronchi. A similar but more potent effect was observed during experiments with water extract of A. lemmermannii. None of the respective water extracts showed any effects on cholinesterase activities in rat bronchial smooth muscle. The present observations suggest, therefore, that water extracts of A. flos-aquae may depolarise cells by activation of mono and divalent cation channels in cholinergic nerve cells. These channels are probably Na(+) channels and N-type, but not L- or T-type Ca(2+) channels. L- and T-type Ca(2+) channels were blocked in experiments with GH(4)C(1) cells and high concentrations of Ca(2+) channel blockers were necessary to reduce the effects of A. flos-aquae extract in cholinergic nerves in the airways. Furthermore, A. flos-aquae extract may also mobilise Ca(2+) from intracellular compartments. A. lemmermannii, on the other hand, does not contain components which alter mono and divalent cation-fluxes across cell membranes, but may rather have substances with more potent antagonistic effects on muscarinic cholinergic receptors than what is observed in experiments with A. flos-aquae. PMID- 21781851 TI - Methaemoglobin formation due to nitrite, disulfiram, 4-aminophenol and monoacetyldapsone hydroxylamine in diabetic and non-diabetic human erythrocytes in vitro. AB - Nitrite, monoacetyl dapsone hydroxylamine, 4-aminophenol and disulfiram-mediated methaemoglobin formation was studied in human diabetic and non-diabetic erythrocytes in vitro. Diabetic intact erythrocytes were significantly less sensitive compared with those of non-diabetics to haemoglobin oxidation caused by the hydroxylamine, nitrite and 4-aminophenol, but not disulfiram. In haemolysates, differential sensitivity did occur with disulfiram and was partially retained with 4-aminophenol and nitrite. The differences were lost with 4-aminophenol, nitrite and disulfiram in the presence of haemoglobin purified from the respective erythrocyte types. Diethyl maleate reduced methaemoglobin formation in non-diabetic intact erythrocytes with 4-aminophenol, the hydroxylamine and disulfiram, but not with nitrite. Overall, the differential sensitivity to methaemoglobin formation seen in diabetic compared with non diabetic erythrocytes, is probably linked to differences in the respective cells' cytosolic anti-oxidant systems. PMID- 21781852 TI - The role of prostanoids in ozone-induced changes in airway responsiveness: receptor activation-specific prostanoid release. AB - We studied the effect of in vivo ozone exposure (3 ppm, 2 h) on methacholine- and histamine-induced guinea pig tracheal smooth muscle contractions in vitro and the role of cyclooxygenase products in this process. After exposure to ozone, methacholine stimulation showed a functional hyperreactivity, whereas after stimulation with histamine a hyporeactivity was observed. These effects could be explained by the release of prostanoids. In a control situation an increase in PGF(2alpha), PGE(2) and PGD(2) release is observed after stimulation of the histaminergic receptor system. After ozone exposure the release of prostanoids was also enhanced (unstimulated, PGF(2alpha) and TxB(2); histamine, PGF(2alpha), PGE(2); methacholine, PGF(2alpha), TxB(2), 6-kPGF(1alpha), PGE(2)). This study shows that the prostanoid release is strongly dependent on the receptor system stimulated to induce smooth muscle contraction and the importance of prostanoids in ozone-induced changes in guinea pig tracheal smooth muscle reactivity. PMID- 21781853 TI - Expression of Hsp60, a stress protein, in human nasal septa cells after exposure to MTBE. AB - Human nasal septa epithelial cells (HNS) were exposed to low concentrations of methyl tert-butyl ether (MTBE). After an exposure of 24 h, the concentrations of heat shock proteins (Hsp) were determined after separation by gel electrophoresis and quantified with standardized Western blotting using densitometric imaging after background corrections. HNS cells showed an increase expression of the 60 kD molecular weight stress protein. The more commonly measured 70 kD Hsp appears to not increase in concentration after exposure to MTBE. This study revealed different expression patterns of Hsp to MTBE in nasal cells and showed that this applied technique might serve as a versatile screening tool to identify relevant environmental toxicants to nasal tissue. PMID- 21781854 TI - Interactions between selenium and group Va-metalloids (arsenic, antimony and bismuth) in the biliary excretion. AB - The interrelationship between the biliary excretion of exogenous group Va metalloids (arsenic, antimony and bismuth) and selenium, as well as endogenous glutathione has been studied in rats injected intravenously with sodium selenite and one of the group Va-metalloids. Arsenic, antimony and bismuth appeared in the bile of rats together with large amounts of non-protein thiols (NPSH, representing glutathione and its SH-containing degradation products) and, with the exception of bismuth, they caused choleresis. Significant interactions were observed in the hepatobiliary disposition between selenium and each of the group Va-metalloids, however, their outcomes were not uniform. When coadministered with sodium arsenite or arsenate, selenite enhanced the initial biliary excretion of arsenic 2- and 8-fold, respectively, without further increasing the concomitant excretion of NPSH or the choleretic effect of arsenicals. However, selenite augmented neither the excretion of antimony or bismuth, nor the simultaneous biliary release of NPSH. In turn, arsenite, arsenate and antimony potassium tartrate increased the initial biliary excretion of selenium more than 10-fold and enhanced the accumulation of selenium in blood (exclusively in the erythrocytes). In contrast, administration of bismuth ammonium citrate diminished both the biliary excretion and the erythrocytic accumulation of selenium, while causing retention of selenium in the blood plasma. In rats receiving arsenic or antimony with selenite, the time courses of the biliary excretion of these group Va-metalloids, selenium and NPSH were similar. It is hypothesised that incorporation of selenol metabolites of selenite into the glutathione complexes of arsenic and antimony, resulting in cholephilic ternary complexes, accounts for the arsenic- and antimony-induced augmentation of the hepatobiliary transport of selenium. However, additional chemical and/or dispositional mechanisms are thought to be responsible for the selenite-induced increase in biliary excretion of arsenic. PMID- 21781855 TI - Toxicity and sphinganine levels are correlated in rats fed fumonisin B(1) (FB(1)) or hydrolyzed FB(1). AB - Nixtamalization of Fusarium moniliforme culture material reduced, but did not eliminate, its toxicity to rats. Liver and kidney sphinganine concentration and sphinganine to sphingosine ratio of the animals fed diets containing water extracted (8 ppm fumonisin B(1) (FB(1))), nixtamalized (58 ppm hydrolyzed FB(1)), or unprocessed culture material (71 ppm FB(1)) were increased compared to those fed a diet lacking detectable fumonisins. Increases were generally correlated with the severity of hepatic and renal lesions and were highly correlated (P<0.0001) with body weight effects and serum chemical indications of hepatotoxicity. The findings are further evidence that inhibition of the enzyme ceramide synthase may be a key event in fumonisin toxigenesis. PMID- 21781856 TI - Ortho substituted polychlorinated biphenyls elevate intracellular [Ca(2+)] in human granulocytes. AB - The perturbation of Ca(2+)-homeostasis in human granulocytes exposed to ortho and non ortho substituted polychlorinated biphenyls (PCB) was investigated. Ortho substituted PCB congeners increased intracellular free calcium, [Ca(2+)]i, in a concentration-dependent manner. The increase in [Ca(2+)]i was inversely proportional to the total surface area of the ortho substituted congeners. The effect of ortho substituted PCB congeners was dependent upon external Ca(2+) and phospholipase C activation, except for a tetra-ortho substituted congener, 2,2',6,6'-TeCB, that was not phospholipase C-dependent. We suppose that PCBs activate phospholipase C which leads to the production of ins(1,4,5)P3. This will release Ca(2+) from intracellular stores and subsequently activation of Ca(2+) release activated Ca(2+) channels (CRAC) in the plasma membrane. It is also possible that PCBs activate CRAC in a more direct manner. Our findings show that ortho substituted PCB congeners stimulate [Ca(2+)]i elevation in human granulocytes, and this could in part account for the effects of PCB on the immune system. PMID- 21781857 TI - Effects of lead on neutrophil functions in occupationally exposed workers. AB - Chemotactic and intracellular killing activity of neutrophils were examined in 25 male lead-exposed workers from storage-battery plants and compared to 25 healthy males with no history of lead exposure. Lead exposure was assessed using blood lead levels measured by atomic absorption spectrophotometry and zinc protoporphyrin levels assayed by hematofluorometry. Chemotaxis was carried out in Boyden chambers using zymosan activated serum as chemotactic stimulus. Intracellular killing activity of neutrophils was measured using nitroblue tetrazolium reduction test, measured of 515 nm in spectrophotometry. In lead exposed workers a significant decrease in chemotaxis and random migration of neutrophils (p<0.001) was observed compared to controls. Intracellular killing activity of polymorphonuclear leukocytes have also seemed to be slightly but not significantly reduced. These results suggest that human chronic exposure to lead may diminish neutrophil function in man. PMID- 21781858 TI - Inhibitory effects of extracts from the marine alga Caulerpa taxifolia and of toxin from Caulerpa racemosa on multixenobiotic resistance in the marine sponge Geodia cydonium. AB - The invasive growth of the introduced green alga Caulerpa taxifolia, already affecting the richness and diversity of the littoral ecosystems, has become a major ecological problem in the Mediterranean Sea. Previously, we demonstrated that the water pollutant tributyltin induces apoptosis in tissue of the marine sponge Geodia cydonium at concentrations of 3 MUM and higher. Here we show that exposure of G. cydonium to low (non-toxic) concentrations of Caulerpa extract or purified caulerpin (10 MUg/ml) together with low doses of tributyltin (1 MUM; non toxic), results in a strong apoptotic effect. Evidence is presented that the enhancement of toxicity of tributyltin by Caulerpa extract is at least partially caused by inhibition of the multixenobiotic resistance (MXR) pump by the algal toxin. Caulerpa extract, as well as caulerpin, strongly enhance the accumulation of the test substrate of MXR, rhodamine B, in the gills of the mussel Dreissena polymorpha, used as a model system for testing MXR-inhibiting potential. PMID- 21781859 TI - Recovery from lead induced biochemical and immunological alterations following combined treatment with DMSA and calcium disodium EDTA in rats. AB - The therapeutic potential of meso 2,3-dimercaptosuccinic acid (DMSA) and calcium disodium ethylenediamine tetraacetic acid (CaNa(2)EDTA) alone or in combination in reducing levels of lead in blood and other soft organs and reversing lead induced biochemical and immunological alterations were investigated after chronic low level lead exposure. Lead exposure produced a significant adverse effect on few selected haematopoietic, nervous, testicular and immunological variables. Conventional 5-day treatment with both DMSA and CaNa(2)EDTA individually was effective in inducing elimination of lead but the recovery of the altered biochemical and clinical indices was moderate. When given in combination for 5 days, (DMSA was administered orally twice daily before intraperitoneal CaNa(2)EDTA administration) they were more effective in depleting body lead burden and providing recoveries in the altered biochemical parameters. Along with the rapid removal of lead from body stores after combined treatment, the immunological variables also recovered spontaneously. However, the altered CNS disorders remained practically unchanged following 5 days of chelation therapy. Lead induced testicular alterations also showed some recoveries after combined treatment. The results indicate that combined DMSA and CaNa(2)EDTA treatment could be more beneficial than individual treatment with any of these agents. PMID- 21781860 TI - In vitro toxicity of sodium nitroprusside to human endothelial ECV304 cells. AB - The cytotoxicity of sodium nitroprusside (SNP) to the human endothelial cell line, ECV304, was studied. The cytotoxicity of SNP was primarily related to the liberation of nitric oxide (NO). S-nitroso-N-acetyl-d-penicillamine (SNAP), an NO donor, was highly toxic. Other degradation products of SNP either exerted much less toxicity (i.e. cyanide and nitrite) or were non-toxic (i.e. ferricyanide and ferrocyanide). SNP induced multinucleation, inhibited cell proliferation, lowered the endogenous level of reduced glutathione (GSH), and induced apoptotic cell death. The plasma membrane was not the prime site of toxic action, as leakage of lactic acid dehydrogenase (LDH) occurred only at a relatively high concentration of SNP. Cells treated with non-toxic levels of the glutathione-depleting agents, 1-chloro-2,4-dinitrobenzene (CDNB), dl-buthionine-[S,R]-sulfoximine (BSO), and 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU), were hypersensitive to subsequent exposure to SNP. The GSH status of the cells was, therefore, a key factor in determining the cytotoxicity of SNP. PMID- 21781861 TI - The effect of 2,2'-substitution on the metabolism and toxicity of dapsone in vitro and in vivo. AB - The effect of 2,2'-substitution with fluorine, methyl or trifluoromethyl groups on the toxicity, metabolism and pharmacological activity of dapsone has been investigated in vitro and in vivo. There was marked inter-species variation in the bioactivation (N-hydroxylation) of the compounds, as determined by methemoglobin formation. However, the inclusion of fluorine significantly (P<0.01) reduced methemoglobin formation compared with dapsone in all species studied. All three analogs resulted in significantly (P<0.001) less methemoglobinemia than dapsone when given either intraperitoneally or intravenously to the male Wistar rat. Rapid plasma clearance of the analogs through increased lipophilicity and enhanced N-glucuronidation may account for the low toxicity compared with dapsone. Although trifluoromethyl substitution resulted in a loss of activity against respiratory burst in human neutrophils in an in vitro model, all three analogs retained pharmacological activity against Plasmodium berghei malaria in an in vivo mouse model. PMID- 21781862 TI - Food plant toxicants and safety Risk assessment and regulation of inherent toxicants in plant foods. AB - The ADI as a tool for risk management and regulation of food additives and pesticide residues is not readily applicable to inherent food plant toxicants: The margin between actual intake and potentially toxic levels is often small; application of the default uncertainty factors used to derive ADI values, particularly when extrapolating from animal data, would prohibit the utilisation of the food, which may have an overall beneficial health effect. Levels of inherent toxicants are difficult to control; their complete removal is not always wanted, due to their function for the plant or for human health. The health impact of the inherent toxicant is often modified by factors in the food, e.g. the bioavailability from the matrix and interaction with other inherent constituents. Risk-benefit analysis should be made for different consumption scenarios, without the use of uncertainty factors. Crucial in this approach is analysis of the toxicity of the whole foodstuff. The relationship between the whole foodstuff and the pure toxicant is expressed in the 'product correction factor' (PCF). Investigations in humans are essential so that biomarkers of exposure and for effect can be used to analyse the difference between animals and humans and between the food and the pure toxicant. A grid of the variables characterising toxicity is proposed, showing their inter-relationships. A flow diagram for risk estimate is provided, using both toxicological and epidemiological studies. PMID- 21781863 TI - Effects of SS320A, a new cysteine derivative, on the change in the number of goblet cells induced by bacterial endotoxin in rat tracheal epithelium. AB - We examined the effects of SS320A, a new cysteine derivative, on the change in the number of goblet cells induced by bacterial endotoxin in rat tracheal epithelium. Four types of goblet cell were characterized in tracheal epithelium according to their size and staining affinity with Alcian blue (AB)/periodic acid Schiff (PAS). Each rat was intratracheally given a single instillation of lipopolysaccharide (LPS) (2 mg/ml). The results showed that treatment with LPS increased the number of AB/PAS-positive cells that were recognizable as goblet cells in tracheal epithelium. On the other hand, LPS evoked acute lung inflammation related to neutrophil accumulation in the lung before the increase in goblet cells. SS320A (10-100 mg/kg, p.o.) and dexamethasone (10 mg/kg, p.o.) each significantly inhibited the increase in the number of goblet cells induced by LPS. On the other hand, ambroxol, bromhexine, l-cysteine ethyl ester and S carboxymethylcysteine, which are used as expectorants, had no inhibitory effects on the LPS-induced change in the number of goblet cells. SS320A slightly inhibited the lung injury based on a histological examination. These data suggest that SS320A may have a beneficial effect against mucus hypersecretion in respiratory disease. PMID- 21781864 TI - Regio- and stereoselectivity in the metabolism of benzo[c]phenanthrene mediated by genetically engineered V79 Chinese hamster cells expressing rat and human cytochromes P450. AB - Regio- and stereoselective metabolism mediated by cytochrome P450 (CYP) and metabolite-dependent cytotoxicity of benzo[c]phenanthrene (B[c]Ph) and its trans 3,4-dihydrodiol, the metabolic precursor of the carcinogenic fjord-region B[c]Ph 3,4-dihydrodiol 1,2-epoxides (B[c]PhDE), were investigated with V79 Chinese hamster cells genetically engineered for three rat and six human CYP isoforms. The order of the capabilities of the CYP isoforms to metabolize B[c]Ph was as follows: h1A1>r1A1>r1A2>h1B1>h1A2>r2B1>>h2E1>h2A6>h3A4. Regardless of the species, all individual CYP isoforms preferentially catalyzed the oxidation of B[c]Ph at the 5,6-position (K-region) except human CYP1A1 and human CYP1A2, which oxidized both the 5,6- and the 3,4-position with similar efficiency. While human CYP1A1, rat CYP1A1 and rat CYP1A2 formed almost exclusively the (-)-B[c]Ph-3R,4R dihydrodiol, human CYP1A2 produced both the (-)-3R,4R- and the (+)-3S,4S dihydrodiol enantiomers in a ratio of 2:1. Stereoselective activation of B[c]Ph, the (+/-)-B[c]Ph-3,4-dihydrodiol and its (-)-3R,4R-enantiomer to the fjord-region (-)-anti-B[c]PhDE occurred upon incubation with rat CYP1A1 and rat CYP1A2 as indicated by the formation of two stereoisomeric tetraols, the hydrolysis products of the labile anti-B[c]PhDE. The formation of tetraols in the culture medium was accompanied by a concentration-dependent increase in cytotoxicity indicating that this effect was mediated by the fjord-region (-)-anti-B[c]PhDE formed as reactive intermediate. All human and rat CYP-expressing V79 cell lines investigated did not show any significant capacity to metabolize the (+)-3S,4S dihydrodiol. The present study indicates that the human CYP isoforms 1A1 and 1B1 have complementary catalytic properties to activate B[c]Ph to its fjord-region B[c]PhDE, whereas other human isoforms play a minor role. Activation of B[c]Ph by human CYP1A1 and 1B1 is less efficient than by rat CYP1A1 or rat CYP1A2, but proceeds with similar stereoselectivity via the (-)-3R,4R-dihydrodiol to the strong carcinogen (-)-anti-B[c]PhDE with (R,S,S,R)-configuration. PMID- 21781865 TI - Macrophages influence gap junctional intercellular communication between smooth muscle cells in a co-culture model. AB - The present study demonstrates for the first time that cells cultured on pore membrane inserts (macrophages) modulate gap junctional intercellular communication (GJIC) between a second cell type (smooth muscle cells (SMC)) co cultured in Transwell-COL cell culture chambers. Unstimulated J774A.1 murine macrophages reduced GJIC between human SMC. Stimulation of J774A.1 cells by lipopolysaccharide (LPS) or interferon-gamma abrogated this modulation of GJIC. Unstimulated human monocyte-macrophages did not affect GJIC between human SMC. Upon stimulation of these monocyte-macrophages with LPS, a substantial increase in GJIC between co-cultured SMC was observed. Thus, activation of macrophages alters their interaction with co-cultured SMC. Since these results were obtained in an indirect co-culture system in which direct cell-cell contact is prevented, it is hypothesized that soluble factors released by macrophages may be involved in this modulation of GJIC between SMC. The possible nature of the responsible soluble factors is discussed in the context of atherosclerosis. PMID- 21781866 TI - Ah receptor-independent induction of CYP1A2 gene expression in genetically inbred mice. AB - Acenaphthylene is a tricyclic aromatic hydrocarbon which induces hepatic methoxyresorufin O-demethylase (MROD) activity and CYP1A2 mRNA levels in 2 week old male B6C3F1 mice. In the present study, this induction response was further investigated in genetically-inbred mice which differ in their aryl-hydrocarbon (Ah)-responsiveness. Acenapthylene (300 mg/kg) induced a 5- to 23-fold induction of MROD activity in Ah-nonresponsive (DBA and SJL) and responsive (C3H, C57/BL6, A/J, CBA and B6C3F1) mice. The highest induction response was observed in the DBA strain in which there was a 23- and 15-fold increase in activity in males and females, respectively. Acenaphthylene also caused a 2-fold increase in CYP1A2 mRNA and immunoreactive protein levels in 2 week-old DBA mice; however, this induction response was not observed in 6 week-old animals. For example, MROD activity in 6 week-old DBA mice was induced <2-fold by acenaphthylene, mainly as a consequence of increased basal CYP1A2 expression and MROD activity which, at the age of 6 weeks, approached levels induced by acenaphthylene in the 2 week-old mice. This was also observed by immunohistochemical staining with CYP1A2 antibodies of 2 and 6 week-old hepatic tissue from treated and control mice which also showed that CYP1A2 induction was dependent on the age of the animals. PMID- 21781867 TI - Inhibition of AMP deaminase by alkylsulfonate compounds. AB - Alkylsulfonate compounds act as potent allosteric inhibitors of AMP deaminase from bovine brain. The order of effectiveness as inhibitors was stearoyl->cetyl >myristoyl->lauryl->decylsulfonate. Laurylbenzene sulfonate was the most potent inhibitor of the enzyme. The I(0.5) values of alkylsulfonates, the concentrations required for 50% inhibition, were closely related to the hydrophobic parameter of the inhibitors, suggesting that the inhibitory sites of the enzyme for the binding of alkylsulfonates involve hydrophobic nature. Inhibition of AMP deaminase by alkylsulfonates and alkylbenzene sulfonate may serve for understanding the biological toxicity of this compounds as environmental pollutants. PMID- 21781868 TI - Highly toxic coplanar PCB126 reduces liver peroxisomal enzyme activities in rats. AB - The effect of the highly toxic coplanar PCB congener, 3,4,5,3',4' pentachlorobiphenyl (PCB126) on hepatic peroxisomes was studied in rats. The aim of this study was to investigate whether a toxic dose of the dioxin-like coplanar PCB modifies enzyme activities in peroxisomes where plays an important role in lipid metabolism. Treatment with PCB126, at a single i.p. administration of 25 mg/kg which evokes clear suppression of body weight gain, resulted in marked reduction (to about 40-50%) of catalase activity and peroxisomal fatty acyl-CoA beta-oxidizing system. Immunoblotting showed that expression of catalase was greatly reduced by the treatment in parallel with the activity. Light microscopy revealed a drastic reduction in granules possessing peroxidase activity, while electron microscopy demonstrated that no apparent morphological changes had taken place. Thus the reduction in catalase activity caused by PCB126 could be attributable to suppression of protein expression. The marked reduction of these peroxisomal enzyme activities might be related to hyperlipidemia caused by dioxin related compounds in rats and humans. PMID- 21781869 TI - Towards internationally acceptable standards for food additives and contaminants based on the use of risk analysis. AB - Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure to reach these goals. The interaction between risk assessors and risk managers is considered vital to this procedure. This paper reports the outcome of a meeting of risk assessors and risk managers on specific aspects of risk analysis and its application to international standard setting for food additives and contaminants. Case studies on aflatoxins and aspartame were used to identify the key steps of the interaction process which ensure scientific justification for risk management decisions. A series of recommendations were proposed in order to enhance the scientific transparency in these critical phases of the standard setting procedure. PMID- 21781870 TI - Modulation of rifampicin toxicity by 6 MFA, an interferon inducer obtained from fungus Aspergillus ochraceus. AB - The effect of 6 MFA (Sixth mycelial fraction of acetone), an interferon inducer obtained from fungus Aspergillus ochraceus, on rifampicin toxicity was studied in rats. Chronic oral administration of rifampicin (1 g/kg per day) for 30 days produced thrombocytopenia, hemolytic anaemia, transient leukopenia and increased nucleated cells in bone marrow and decreased weights of thymus and spleen significantly in male rats. Furthermore, chronic administration of rifampicin induced significant increase in cytochrome P-450 contents, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity in liver and bone marrow. Simultaneous administration of 6 MFA (100 mg/kg; i.p.) on alternate days for a period of 30 days prevented most of the adverse effects of rifampicin, mentioned earlier and also restored the hepatic architecture histologically. The LPO, cytochrome P 450 content, lymphocyte and bone marrow cell counts returned to normal level whereas SOD activity was further increased. The 6 MFA treatment enhanced the SRBC antibody litre in rifampicin-treated rats. Thus, beneficial effects of 6 MFA in the amelioration of mediated rifampicin toxicity observed in the present study may be through induction of interferons and their associated effects. PMID- 21781871 TI - Physiologically-based pharmacokinetic modeling of pyrene in the rat. AB - The objective of the present study was to develop a physiologically-based model to simulate the oral and i.v. pharmacokinetics of pyrene in the rat. The physiologically-based pharmacokinetic (PBPK) model for pyrene consisted of the following tissue compartments: liver, lungs, adipose tissue, slowly perfused tissues, and richly perfused tissues interconnected with arterial and venous blood pools. The tissue:blood partition coefficients required for the pyrene PBPK model were estimated by equilibrium dialysis. Using perfusion-limited descriptions for tissue uptake and previously determined in vitro-derived hepatic metabolism rate constants (V(max) and K(m)), the PBPK model predicted a faster clearance of pyrene than that suggested by the experimental data. The biological basis of PBPK model then provided an opportunity to refine the estimate of V(max), and to explore and uncover additional mechanistic determinants of pyrene disposition in vivo. Accordingly, the in vitro V(max) had to be lowered by about a factor of 10 to adequately simulate experimental data on pyrene pharmacokinetics. Further, the model simulations could be matched with the experimental data on tissue concentrations of pyrene only with the considerations of (i) diffusion-limited uptake in slowly perfused tissues and adipose tissue, and (ii) binding to proteins in metabolizing tissues (lungs and liver). The present study successfully integrated the available data on oral and i.v. pharmacokinetics of pyrene using a physiological model framework, and identified several mechanistic data gaps that should be addressed by future research efforts. PMID- 21781872 TI - Pharmacokinetic behavior of 4-nonylphenol in humans. AB - In this study, the pharmacokinetic behavior of 4-nonylphenol (NP) was investigated in human volunteers. In order to avoid analytical background problems, isotope labeled (13)C(6)-NP was synthesized. Both after intravenous and oral application, the elimination half-life of the parent compound from the blood was 2-3 h. Bioavailability after oral application (determined by oral and intravenous AUCs) was about 20%. NP seems to distribute into the lipid phase of the body within 2 h. Furthermore, levels of NP and 4-octylphenol (OP) in non occupationally exposed persons were investigated by analyzing human autopsy adipose tissue samples. NP concentrations ranged from 19 to 85 ng/g lipids, OP concentrations from 0.58 to 4.07 ng/g lipids. These values were both in the range of the analytical background contamination. No NP and OP ethoxylates (ethoxylate number 1,2) were found in any of the samples (detection limit of 10 ng/g lipids for NP ethoxylates and 0.5 ng/g lipids for OP ethoxylates). On the basis of the pharmacokinetic data from this study, actual adipose tissue concentrations were estimated to lie a factor of 50 below analytical background values. PMID- 21781873 TI - Effects of uranium ore dust on cultured human lung cells. AB - Effects of uranium ore dust on cell proliferation, lipid peroxidation and micronuclei formation were compared with silica (DQ12) and titanium oxide in normal human distal airway epithelial cells (NHDE), human lung cancer cells (A549) and human lung fibroblast cells. Cell proliferation was significantly inhibited with uranium ore dust and silica but not with titanium oxide. Lipid peroxidation was significantly enhanced only with uranium ore dust. Micronuclei formation was significantly stimulated with uranium ore dust in A549 and NHDE cells, but not in fibroblast cells. Silica stimulated micronuclei formation only in A549 cells. The results showed the outstanding effect of uranium ore dust on lipid peroxidation and micronuclei formation in human lung cells compared to silica and titanium dioxide. PMID- 21781874 TI - (1->3)-beta-d-Glucan stimulates nitric oxide generation and cytokine mRNA expression in macrophages. AB - Beta-glucans are known for their potent ability to induce nonspecific inflammatory reactions and are believed to play a role in bioaerosol-induced respiratory symptoms seen in both occupational and residential environments. Here, the ability of a (1->3)-beta-d-glucan (Curdlan) to stimulate nitric oxide generation and cytokine mRNA expression in rat alveolar macrophages (AMs) and the murine monocyte/macrophage cell line, RAW 264.7 was investigated. Exposure to (1 >3)-beta-d-glucan (20, 100 and 500 MUg/ml) induced a dose-dependent increase in the expression of inducible nitric oxide synthase mRNA and a release of nitric oxide into the culture medium in both rat AMs and RAW 264.7 cells. The mRNA expression of a number of other inflammatory mediators such as interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and cyclooxygenase-2 was also increased by the exposure to beta-glucan. The capability of (1->3)-beta-d-glucan (500 MUg/ml) to induce mRNA synthesis of these various mediators were comparable to that of endotoxin (1 MUg/ml). These results imply that (1->3)-beta-d-glucan stimulates the generation of nitric oxide, cytokines and prostaglandins in macrophages and suggest the possibility that this may contribute to bioaerosol induced respiratory symptoms seen in exposed individuals. PMID- 21781875 TI - Implication of cytochrome P-450 1A isoforms and the AH receptor in the genotoxicity of coal-tar fume condensate and bitumen fume condensates. AB - During the hot application of bitumen- or coal-tar-containing materials, fumes are emitted that contain polycyclic aromatic compounds. Although workers' exposure to these fumes is low, it might lead to health problems. No study has reported the metabolic pathways involved in the genotoxicity of coal tar or bitumen fume condensates (CTFC, BFCs). We have therefore studied the DNA adducts formed by incubation of CTFC or BFCs with liver microsomes from several type of mice and with yeast microsomes expressing individual human CYP enzymes. Our results demonstrates that: (1) the aryl hydrocarbon receptor (AHR) plays an important role in the biotransformation of BFCs and to a lesser extent of CTFC; (2) for CTFC, both cytochrome P450 (CYP) 1A isoforms are involved in the formation of genotoxic compounds, and the reactive metabolites formed via CYP 1A1, are substrates for epoxide hydrolase (mEH); (3) for BFCs, the genotoxicity is partially dependent upon CYP 1A1 and the reactive metabolites are not substrates for mEH; (4) CYP 1A isoforms are not exclusively responsible for the genotoxicity of the CTFC and BFCs as other CYPs and also enzymes of the [AH] gene battery, may play an important role. PMID- 21781876 TI - Global environmental pollutant substance vanadium activates mast cells and basophils at the late phase in the presence of hydrogen peroxide. AB - Vanadium is contained in fossil fuel such as coal, oil and sand oil and released in the air through the combustion. We studied the allergic and inflammatory potentials of vanadium as the factor of a recent increase of allergic disease. Vanadium oxide (V(2)O(5)) and orthovanadate (Na(3)VO(4)) released histamine from human basophils, rat mast cells and rat basophilic leukemia (RBL-2H3) cells in the presence of hydrogen peroxide (H(2)O(2)). Activation of RBL-2H3 cells by vanadium/H(2)O(2) was accompanied by leukotriene synthesis, increases of [Ca(2+)](i), multiple protein tyrosine phosphorylations and remarkable morphological changes. Pharmacological study suggests that vanadium/H(2)O(2) activates mast cells at the late phase, bypassing the early signaling components. Thus, vanadium can amplify the allergy in the presence of H(2)O(2) at the inflammation site in the global environment of industrial age. PMID- 21781877 TI - Cytochromes P-4501A, P-4503A and P-4502B in liver and heart of Mugil capito treated with CYP1A inducers. AB - Hepatic microsomes of Aroclor 1254-treated Mugil capito showed a single protein band detected in immunoblot with monoclonal antibody 1-12-3 to teleost (scup) CYP1A. The hepatic CYP1A like protein was induced with dose dependency after exposure of the fish to beta-naphthoflavone (BNF) as well as to Aroclor 1254. The induced mullet hepatic CYP1A protein was confined to a distinct fraction obtained by DE-52 anion exchange chromatography, and its relative content in that fraction increased in fish that were treated with higher doses of inducer. EROD (7 ethoxyresorufin O-deethylase) activity in hepatic microsomes from mullet treated with various doses of BNF correlated significantly (r(2)=0.81502, P<0.01) with CYP1A content. Treatment of the mullet with low dose of Aroclor 1254 (25 mg/kg) induced only traces of CYP1A in liver microsomes (5.1+/-4.8 mg/kg). However, in mullet treated with the high dose of Aroclor 1254 (100 mg/kg) there was a dramatic induction in CYP1A content (408+/-275 pmol/mg) and this hemoprotein comprised about 83% of the total P-450 content of liver microsomes. The total level of P-450, although induced in the liver tissue, was not induced in heart tissue of Aroclor 1254 treated mullet. On the other hand, P-4501A was induced in treated mullet to a level that comprised almost all of the cardiac P-450 content. EROD activity in the heart tissue of induced mullet was characterized by low V(max) and high K(m) values (K(m)=2.35 mM, V(max)=39.5 pmol/min per mg) compared to the values recorded for the enzyme from the liver (K(m)=1.0 mM, V(max)=288.0 pmol/min per mg). Cardiac CYP1A with low catalytic activity and repression of CYP types other then CYP1A in heart of CYP1A induced fish may be part of a mechanism aimed to preserve crucial levels of electron donors and molecular oxygen in cardiac muscle of fish exposed to CYP1A inducers. PMID- 21781878 TI - Evaluation of the estrogenic potency of nonylphenol in non-occupationally exposed humans. AB - In this study, the estrogenic potency of 4-nonylphenol (NP) was estimated and a risk calculation for non-occupationally exposed humans was performed. The daily intake of non-occupationally exposed persons was estimated to be less than 0.16 mg/day. Risk estimates were based on this daily intake and the relative potency of NP to 17beta-estradiol. Comparison of this intake with the NOAEL derived from a 90-day subchronic toxicity study in animals, results in a safety factor of about 20 000. A safety margin of 3000 can be derived when comparing the resulting NP blood concentrations (calculated upon pharmacokinetic studies) with 17beta estradiol levels in the blood of adult males. Risk estimations based on the daily intake of NP and the resulting organ concentrations (calculated upon the lipid content) compared with minimal estrogenic cell effect concentrations result in a safety factor in the range of 5000. In addition, the comparison of NP with genistein in human blood indicate a minor importance of nonylphenol. The results of this study show that the non-occupational exposure to NP does not pose an estrogenic health risk to humans. PMID- 21781879 TI - Mechanisms of cell death induced by nitric oxide and peroxynitrite in Calu-1 cells. AB - S-nitrosoglutathione (GSNO) is an important physiological redox form of nitric oxide (NO) and serves as an NO-releasing compound. 3-Morpholinosydnonimine hydrochloride (SIN-1) produces NO and superoxide anion (O(2)(.-)) which results in the formation of peroxynitrite (ONOO(-)). We investigate the cytotoxicity, cell death mechanisms and gene expression of NO and ONOO(-) in human lung epithelial cells show NO induced apoptosis and DNA genomic fragmentation. Whereas, ONOO(-) induced cell death more characteristic of necrosis than apoptosis. The concentrations of GSNO and SIN-1 required to cause death in 50% of cells were greater than 1 mM. Several gene products are important in controling the apoptotic and necrotic processes. Of these, bcl-2, bax and hsp 70 were studied. The level of expression of bcl-2 was dramatically decreased in cells treated with SIN-1 or GSNO, while the expression level of bax, the heterodimer of bcl-2, did not significant change. In addition, a roughly two-fold increase of hsp 70 was found in cells treated with SIN-1. There were no significant changes in hsp 70 levels in cells treated with GSNO. PMID- 21781880 TI - Distribution and pharmacokinetics of alkylphenolic compounds in primary mouse hepatocyte cultures. AB - In order to allow an interpretation of in vitro results on the estrogenic potency of 4-nonylphenol (NP) and 4-octylphenol (OP), their distribution and pharmacokinetics were investigated in primary mouse hepatocyte cultures. 10(-5) M NP and 10(-6)M OP were added to the hepatocyte cultures and incubated up to 48 h. The time course of parent NP and OP concentrations was followed with GC-MS both in the medium and in the cell fraction. Both NP and OP concentrations decreased rapidly in the cell cultures, indicating that the alkylphenols underwent a rapid metabolism. The concentrations in the cell fractions were 100 ng NP and 2-6 ng OP/mg cell protein after 2 h, declining to about 20 ng NP and 1-4 ng OP/mg cell protein, respectively, after 48 h. PMID- 21781881 TI - Quantitative low-dose assessment of seafood toxin, domoic acid, in the rat brain: application of physiologically-based pharmacokinetic (PBPK) modeling. AB - The purpose of this study was to construct a physiologically based pharmacokinetic model and demonstrate its ability to predict low-dose uptake of domoic acid, a seafood contaminant, in discrete areas of the rat brain. The model we used was derived from the generic PBPK model of our previous studies with 2,4 dichlorophenoxyacetic acid (Kim et al., 1994. Pharmacokinetic modeling of 2,4 dichlorophenoxyacetic acid (2,4-D) in rats and in rabbits brain following single dose administration. Toxicol. Lett. 74, 189; Kim et al., 1995. Development of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in discrete areas of the rabbit brain. Neurotoxicol. Teratol. 17, 111), to which physiological- and chemical-specific parameters for domoic acid were applied. It incorporates two body compartments along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and seven brain regions. Uptake of the blood-borne toxin is membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospinal fluid 'sink' mechanisms. This model generated predicted profiles of toxin level in brain and blood over a 1-h period that compared reasonably well with concentrations calculated from in vivo data of rats that had been given [(3)H]domoic acid intravenously (Preston and Hynie, 1991. Transfer constants for blood-brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid. Can. J. Neurol. Sci. 18, 39). This PBPK model should be an effective tool for evaluating the target doses that produce the potential neurotoxicity of domoic acid found in foods. PMID- 21781882 TI - Pantethine stimulates lipolysis in adipose tissue and inhibits cholesterol and fatty acid synthesis in liver and intestinal mucosa in the normolipidemic rat. AB - In vitro effects of pantethine on adipose tissue lipolysis and on both hepatic and intestinal cholesterol and fatty acid synthesis in normolipidemic rats are determined and related to their respective in vivo hypolipidemic effects after acute oral administration. At 3, 5, 7 and 24 h after a single high dose of pantethine to rats, free fatty acids (FFA), cholesterol and triglycerides levels decreased whereas plasma glycerol increased, the effect becoming significant at 7 h. The release of glycerol and FFA by epididymal fat pad pieces from rats was measured in Krebs Ringer bicarbonate-albumin buffer supplemented or not with epinephrine and several concentrations of pantethine (0, 10(-5), 10(-4), or 10( 3) M), and it turned out to be enhanced as pantethine concentration increased. Besides, when glucose was present in the medium, this drug lowered fatty acid re esterification in a dose-dependent manner, the effect being specially evident in the presence of epinephrine. In vitro synthesis of both cholesterol and fatty acids by slices of liver or intestinal epithelial cells was depressed as the concentration of pantethine increased in the medium. Thus, an inhibition of both cholesterolgenesis and lipogenesis seems to contribute to the hypocholesterolemic and hypotriglyceridemic effects of pantethine. On the other hand, the stimulation of lipolysis and the inhibition of fatty acid re-esterification on adipose tissue caused by pantethine must be counteracted by a high fatty acid oxidation in the liver which would explain the decrease in FFA and the increase in glycerol levels detected in the plasma of the pantethine-treated animals. PMID- 21781883 TI - Indices of mercury contamination during breast feeding in the Amazon Basin. AB - Mercury pollution, due to gold mining has spread through the Amazon ecosystem reaching the food chain and affecting the indigenous people of the region. We studied the mercury contamination of 47 mothers and infants and the role of breast feeding in indices of mercury body burden in both groups, by measuring hair and milk Hg levels. Total mercury concentration of breast milk ranged from 0.0 to 24.8 (5.85, 5.2 S.D.) ng/g. Calculated levels of mercury exposure of breast fed babies indicated that 53% were above tolerable daily intakes (0.5 MUg/kg body weight) recommended for adults by WHO. Mercury concentration in maternal hair was higher than in hair from breast-fed babies. Correlation analysis showed that mercury hair concentration in infants was significantly affected by maternal mercury contamination during pregnancy, but not during the post-natal breast-feeding period. The mercury concentration in milk was not significantly correlated with maternal or infant's hair Hg. A statistically significant correlation was found only between maternal and infant's hair mercury concentration (r=0.675; P=0.0001). PMID- 21781884 TI - Benzo(a)pyrene toxicokinetics in the cricket following injection into the haemolymph. AB - The metabolic disposition of (14)C-labelled benzo(a)pyrene (BP) in the cricket (Acheta domesticus) was investigated after injection into the haemolymph. (14)C BP was taken up rapidly by the nerve cord, malpighian tubules, reproductive organs, gut, and muscle:cuticle of the cricket. The elimination half-lives of (14)C-BP in these tissues ranged from 8.9 to 17.8 h. The haemolymph (14)C-BP concentration-time curve could be described by a one-compartment open pharmacokinetic model. (14)C-BP was metabolized by the cricket mainly to unconjugated and conjugated BP metabolites since very little unchanged (14)C-BP was found in the excreta at 48 h post-dosing. GLPC-MSD and HPLC/ES-MS analyses showed the presence of at least two BP metabolites in the excreta. The BP metabolites were identified tenatively as the diol derivatives of benzo(a)pyrene and benzo(a)pyrene quinone. PMID- 21781885 TI - Application of biomarkers for exposure and effect of polyhalogenated aromatic hydrocarbons in naturally exposed European otters (Lutra lutra). AB - In the serious decline of European otters (Lutra lutra) over the last decades, polychlorinated biphenyls (PCBs) are considered to be one of the major factors. As no experiments can be conducted with otters, an eco-epidemiological study was performed to derive no observed effect concentrations (NOECs) for PCBs in the otter. A strong negative correlation was found between hepatic vitamin A and polychlorinated biphenyl (PCB) concentrations expressed as TCDD-equivalents (TEQs), coinciding with a higher incidence of infectious diseases. The no-effect concentration for vitamin A reduction was 2 ng TEQ/g lipid, 10-fold reduction was already found in animals with 5 ng TEQ/g lipid. The TEQ-levels measured with a reporter gene assay based on chemical-activated luciferase expression (the CALUX assay) correlated well with the TEQ levels calculated based on non- and mono ortho PCB concentrations. The TEQ levels in blood and liver correlated well when expressed on a lipid basis. In living captive otters blood plasma TEQ levels (either measured based on gas chromatography (GC) or CALUX measurement) were lower than in the feral otters, and positively correlated with plasma total and free thyroid hormone but not with plasma retinol levels. Hepatic vitamin A concentration was found to be a physiologically relevant effect parameter. The NOEC for hepatic vitamin A reduction was translated into TEQ levels in fish and sediment. The CALUX response in 50-500 MUl blood plasma proved to be a sensitive non-destructive biomarker for quantification of internal TEQ levels. PMID- 21781886 TI - Effects of vegetables-fruit extracts and indole-3-carbinol on stearic acid modulated intercellular communication and cytochrome P450-IA activity. AB - Modulatory effects were investigated of extracts of a vegetables-fruit mixture and indole-3-carbinol (I3C) on stearic acid-modulated gap junctional intercellular communication (GJIC) and cytochrome P450-IA activity (EROD). In V79 cells, pure water and hexane extracts of a vegetables-fruit mixture and 25 MUg/ml I3C significantly protected against decreased GJIC caused by 10 MUM stearic acid. Furthermore, pure, 10* and 100* diluted vegetables-fruit extracts significantly maintained their capacity to induce EROD activity in Caco-2 cells, but only when these extracts were added to the cells in media already containing 500 MUM stearic acid for 48 h. Stearic acid itself did not induce EROD activity. I3C (10, 25, and 50 MUg/ml) clearly induced EROD activity in Caco-2 cells, irrespective of the order at which I3C and stearic acid were added to the cells. In conclusion, the present in vitro study showed that vegetables-fruit extracts and I3C modulate effects of stearic acid on intercellular communication and cytochrome P450-IA activity. PMID- 21781887 TI - Subacute toxicity of uranyl acetate in Swiss-Albino mice. AB - Subacute effects of uranyl acetate were investigated in laboratory mice (Mus musculus, Swiss-Albino). Uranyl acetate was administrated to mice during a period of 5 days with dietary consumption ad libitum. Effects of uranyl acetate on food and water consumption, body weight changes; plasma urea nitrogen (BUN), creatinine concentrations and activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assayed by time course experiment. Glutathione S-transferase (GST) and catalase (CAT) activities were also determined in liver tissues on day 5. Distribution of radioactivity in liver, kidney and brain was detected by scintillation spectrometry. The results indicated that uranyl acetate was accumulated in examined tissues, with highest accumulation being in brain. Some of the biochemical biomarkers (BUN, creatinine, ALP) were significantly increased (P<0.05) in the exposure group compared to control animals. Also, BUN and/or creatinine levels and/or ALT and AST activities significantly increased (P<0.01 or P<0.05) with UA exposure on day 3 and/or day 5 compared with results of day 1. PMID- 21781888 TI - Mechanism of pathophysiological effects of diesel exhaust particles on endothelial cells. AB - The suspension of diesel exhaust particles (DEP) inhibited endothelium-dependent relaxation (EDR). The mechanism of the impairment of EDR by DEP was investigated with cultured porcine endothelial cells (PEC) and NO synthase (NOS) cell free system. Incubation of PEC with DEP (50-150 MUg/ml) for 10-30 min did not induce cell damage. Bradykinin-induced endothelium-dependent relaxing factor (EDRF) release from PEC was bioassayed by cyclic GMP formation in RFL-6 cells. A 10-min preincubation of PEC with DEP (0.1-100 MUg/ml) inhibited EDRF release. NOS activity from rat cerebellum cytosol was measured either by the conversion of 3H l-arginine to (3)H-l-citrulline or the NO(2)(-) formation. A 10-min preincubation of NOS with DEP (0.1-100 MUg/ml) did not affect the formation of (3)H-l citrulline. In contrast, it inhibited NO(2)(-) formation. These results suggest that DEP neither induced cell damage nor inhibited EDRF release from PEC, but DEP scavenged NO to block its physiological action. PMID- 21781889 TI - Neuroactive compounds produced by bacteria from the marine sponge Halichondria panicea: activation of the neuronal NMDA receptor. AB - Previous studies revealed that the marine sponge Halichondria panicea habors symbiotic- and commensalic bacteria (Althoff et al., 1998. Marine Biol. 130, 529 536). In the present study the hypothesis was tested whether some of those bacteria synthesize neuroactive compounds. For the first time the effect of bacterial bioactive compounds on the neuronal ionotropic glutamate receptors [iGluR], subtype N-methyl-d-aspartate (NMDA) receptor, was checked. In cortical neurons from rats as cell system the supernatant of two bacterial cultures isolated from H. panicea proved to agonize the NMDA receptor. The response of the NMDA receptor to the bioactive compounds was determined by measuring the intracellular Ca(2+) level. The supernatants of cultures 697 and 698 were found to upregulate the intracellular Ca(2+) level. To validate the specificity of the effects, inhibition studies with Memantine and d-AP5 were performed. The two bacteria were identified by polymerase chain reaction-amplification of the 16S rDNA genes and subsequent sequencing; they displayed highest identity to Antarcticum vesiculatum and to Psychroserpens burtonensis, respectively. Based on these data first experimental evidence is presented indicating that bacteria associated with sponges display neuroactivity by agonizing the NMDA receptor. PMID- 21781890 TI - In vitro myelotoxicity of environmental contaminants. AB - Myelotoxicity of pesticides and algal toxins was detected in vitro by using the granulocyte-macrophage colony forming unit assay (CFU-GM), and the MTT test with SR-4987 cells, an established stromal cell line derived from a long term murine bone marrow culture, which may represent a suitable in vitro model for studying haematotoxicity. Comparison of the IC50s and NOELs obtained with the CFU-GM assay and those determined by testing the established stromal cells in the MTT cytotoxicity test indicate that inhibition of the proliferation of SR-4987 stromal cells is a sensitive in vitro endpoint for measuring myelotoxicity. It is suggested that this assay could be used as rapid and easy screening test for determining the haematotoxicity of environmental toxins. A comparison with results obtained with the MTT test on a non-differentiated cell line, 3T3-L1, was carried out to distinguish between non-specific interference with cell proliferation and specific toxicity on haemopoietic cells. PMID- 21781891 TI - Controlling persistent organic pollutants-what next? AB - Within the context of current international initiatives on the control of persistent organic pollutants (POPs), an overview is given of the scientific knowledge relating to POP sources, emissions, transport, fate and effects. At the regional scale, improvements in mass balance models for well-characterised POPs are resulting in an ability to estimate their environmental concentrations with sufficient accuracy to be of help for some regulatory purposes. The relevance of the parameters used to define POPs within these international initiatives is considered with an emphasis on mechanisms for adding new substances to the initial lists. A tiered approach is proposed for screening the large number of untested chemical substances according to their long-range transport potential, persistence and bioaccumulative potential prior to more detailed risk assessments. The importance of testing candidate POPs for chronic toxicity (i.e. for immunotoxicity, endocrine disruption and carcinogenicity) is emphasised as is a need for the further development of relevant SAR (structure activity relationship) models and in vitro and in vivo tests for these effects. Where there is a high level of uncertainty at the risk assessment stage, decision makers may have to rely on expert judgement and weight-of-evidence, taking into account the precautionary principle and the views of relevant stake-holders. Close co-operation between the various international initiatives on POPs will be required to ensure that assessment criteria and procedures are as compatible as possible. PMID- 21781892 TI - Kinetics of protein depletion in rat bronchoalveolar lavage fluid following in vitro exposure to nitrogen dioxide. AB - Upon inhalation, nitrogen dioxide (NO(2)), a strong oxidizing agent, first comes into contact and reacts with the fluids lining the airways of the respiratory tract. These respiratory tract lining fluids (RTLF) form a barrier between the inhaled toxic pollutant and the epithelium which protects the underlying tissue from inflammation. Proteins, mainly albumin, and antioxidants are the major components of the RTLF. Many studies have utilized human blood plasma to study the interaction of an extracellular fluid with ozone. In this study, we used bronchoalveolar lavage fluids (BALF) as a more specific surrogate for rat RTLF, and we utilized the native fluorescence as a marker to investigate the depletion kinetics of naturally-occurring protein following exposure to NO(2) in a controlled flow reactor system. We also studied the depletion kinetics of albumin in a buffered salt solution. The results indicated that: (1) the decay in fluorescence was linearly dependent on the concentration of NO(2), indicating that protein oxidation was first order with respect to NO(2) concentration in both BALF and in buffered albumin solution; (2) the depletion kinetics of protein in BALF was non-linear with respect to substrate concentration; (3) the rate of protein depletion was much slower in BALF than in a buffered solution of albumin, suggesting that the presence of antioxidants in BALF protected proteins from being oxidized by NO(2); and (4) whereas the addition of ascorbic acid to buffered albumin solution significantly attenuated albumin depletion, the addition of glutathione had no effect. This suggested that the reaction rate constant of ascorbic acid was considerably higher than that of glutathione. PMID- 21781893 TI - Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats. AB - Spontaneous motor activity and motor coordination were tested in adult female rats after treating with sodium fluoride at 20 or 40 mg/kg dose level daily for 60 days, using an activity chamber and a rota-rod apparatus, respectively. Total protein concentrations were determined in skeletal muscle, liver and serum of similarly treated animals. The activities of total cholinesterase and acetylcholinesterase were determined in blood and brain regions, respectively. Sodium fluoride treatment suppressed spontaneous motor activity. But no change was observed in the motor coordination of these animals. Tissue and serum protein concentrations were decreased. Cholinesterase activity was decreased in the blood and not in brain regions. A failure of sodium fluoride to impair motor coordination indicated that neuromuscular function required for a forced task was not deteriorated in these animals, although skeletal muscles were deprived of protein and blood cholinesterase activity was suppressed. A suppression of spontaneous motor activity suggests that fluoride has, by a central action, inhibited motivation of these animals to exhibit locomotor behavior. A cholinergic mechanism through a change in the activity of acetylcholinesterase may not account for this effect, since sodium fluoride treatment did not alter the activity this enzyme in brain regions. However, an involvement of monoamines may be proposed in view of previously reported finding that excessive fluoride intake has decreased the concentrations of 5-hydroxyindoleacetic acid and increased that of norepinephrine in rat brain. PMID- 21781894 TI - Cytotoxicity, production of reactive oxygen species and cytokines induced by different strains of Stachybotrys sp. from moldy buildings in RAW264.7 macrophages. AB - The ability of different strains of the fungus Stachybotrys, isolated from mold problem buildings, to induce cytotoxicity and production of important inflammatory mediators, i.e. nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in RAW264.7 macrophages were studied. Several strains of Stachybotrys sp. stimulated immediate increase in the ROS production and in 24-h exposure caused TNF-alpha and IL-6 release from these cells. However, none of the strains of Stachybotrys sp. was able to induce the expression of inducible nitric oxide synthase (iNOS) and subsequent production of NO in RAW264.7 cells. Moreover, there were significant differences in their ability to induce cytotoxicity in the macrophages. These results suggest that, in addition to direct cytotoxic effects of most Stachybotrys sp., some strains of Stachybotrys sp. stimulate production of inflammatory mediators, TNF-alpha and IL-6 which were associated with low cytotoxicity in RAW264.7 macrophages. PMID- 21781895 TI - Cadmium-induced time-dependent oxidative stress in liver of mice: a correlation with kidney. AB - In the present investigation a time-responsive oxidative stress, both in liver and kidney were carried out following cadmium (Cd) exposure. Cadmium was administered subcutaneously on each other day in normal saline solution. Mice were sacrificed on the 15th, 30th and 45th days post-exposure. For oxidative stress study different biochemical markers, e.g. lipid peroxidation (LPO), reduced glutathione (GSH) and glutathione S-transferase (GST) activity were considered. Time-responsive exponential increase in the lipid peroxidation and decrease in glutathione level and glutathione S-transferase activity occurred both in hepatic and renal tissues following cadmium treatment. Though both the organs responded in a similar fashion, their magnitude of response was found to be different. Body weight did not differ but relative liver and kidney weight were found to be significantly increased at different time points. The possible mechanism of time-dependent cadmium-induced toxic effects and relation between hepatic and renal biochemical response have been discussed. PMID- 21781896 TI - Effects of triphenyltin on growth and viability of K562 leukemia cells. AB - The effects of triphenyltin on growth and viability of K562 human leukemia cells were examined using a flow cytometer with fluorescent dyes, ethidium bromide, fluo-3-AM, and propidium iodide. Triphenyltin at concentrations ranging from 30 nM to 1 MUM inhibited the growth of K562 cells in a dose-dependent manner when the cells were incubated with triphenyltin at respective concentrations for 72 h. Triphenyltin at 100 nM slowed the rate of growth without affecting the viability. Triphenyltin at 300 nM or higher greatly decreased the viability of K562 cells. Triphenyltin at 300 nM increased the concentration of intracellular Ca(2+) and induced cell cycle arrest in G2/M phase and apoptosis in K562 cells. The concentration of triphenyltin inducing 50% inhibition of growth of K562 cells was lower than those of cisplatin, diphenyltin, monophenyltin, triethyltin and trimethyltin. However, tributyltin was equally toxic. Results suggest that there are several types of mechanisms for the inhibitory action of triphenyltin on the growth of K562 cells, being dependent on its concentration. PMID- 21781897 TI - Production of tetrodotoxin in puffer fish embryos. AB - It has been accepted that puffer fish accumulates tetrodotoxin through the food chain. This indicates that tetrodotoxin in puffer fish is exogenous. The present study, however, describes an endogenous origin of tetrodotoxin in puffer fish. For this purpose, the ovulated oocytes from puffer fish Fugu niphobles were artificially fertilized and cultivated. The toxin levels of embryos increased gradually with development until the time of hatching, suggesting that the increased toxin is a product of embryos. PMID- 21781898 TI - Methylmercury toxicity in dissociated rat brain neurons: modification by l cysteine and trimethylbenzylmercaptan and comparison with dimethylmercury and N ethylmaleimide. AB - The effects of methylmercury (MeHg) on dissociated rat cerebellar neurons were compared with those of MeHg conjugated with l-cysteine (MeHg-Cys conjugate), dimethylmercury (DiMeHg), N-ethylmaleimide (NEM) and ionomycin using a flow cytometer and two fluorescent dyes, fluo-3-AM and ethidium bromide. The efficacies of MeHg to increase intracellular concentration of Ca(2+) ([Ca(2+)]i) and to decrease cell viability were greatly reduced by conjugating MeHg with l cysteine. It was not due to a decreased lipophilic property of MeHg-Cys because the conjugation of MeHg with trimethylbenzylmercaptane, a lipophilic substance, also reduced the efficacies. It seems that the reactivity of MeHg to SH-groups is responsible for the MeHg-induced toxicity since NEM increased [Ca(2+)]i and decreased cell viability while DiMeHg did not significantly affect them. However, the toxicity of MeHg was not explained only by the reactivity of MeHg to SH groups since NEM-induced changes in fluo-3 and ethidium fluorescence were different from MeHg-induced ones. Ionomycin-induced changes in those fluorescence were also different although ionomycin decreased cell viability after increasing [Ca(2+)]i. Therefore, it is suggested that the mechanism of MeHg toxicity is more complicated than those of NEM and ionomycin. PMID- 21781899 TI - Chemosensitizers of the multixenobiotic resistance in amorphous aggregates (marine snow): etiology of mass killing on the benthos in the Northern Adriatic? AB - Periodically appearing amorphous aggregates, 'marine snow', are formed in the sea and if settled as mats on the sea bottom cause death of benthic metazoans. Especially those animals are killed which are sessile filter feeders, e.g. sponges, mussels, or Anthozoa. The etiology of the toxic principle(s) is not yet well understood. Gel-like marine snow aggregates occurred in the Northern Adriatic during summer 1997. Samples of these aggregates were collected during the period July to September and the outer as well as the inner zones were analyzed for (i) cell toxicity, and (ii) chemosensitizing activity of the multixenobiotic resistance (MXR) mechanism. Organic extracts were prepared and cell toxicity was determined using mouse lymphoma cells. The experiments revealed that the major activity is seen in the center of the mats of the gel-like aggregates; a growth inhibitory activity of up to 54% (correlated to 5 ml of snow sample) was determined. The same extracts were used to determine the inhibition of the P-glycoprotein (Pgp) extrusion pump which confers the multixenobiotic resistance. The analyses were performed with cells from the sponge Suberites domuncula and with gills from the clam Corbicula fluminea in situ. Both systems have been shown to express the Pgp extrusion pump. The data show that extracts from the outer zone of the gel-like aggregate samples display pronounced inhibitory activity on the MXR extrusion pump and hence act as chemosensitizers by reversing the MXP property. These findings indicate that gel-like aggregates contain compounds in the outer zone, chemosensitizer of the Pgp extrusion pump, which lower the level of protection of metazoan animals towards dissolved compounds in their surrounding milieu, and in the center toxic compounds which are-very likely-even in the absence of chemosensitizers hazardous for the invertebrates. PMID- 21781900 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses apoptosis and leads to hyperphosphorylation of p53 in rat hepatocytes. AB - Inhibition of apoptosis of preneoplastic cells is thought to represent a major mechanism of action of tumor promoters. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent promoter of liver carcinogenesis in rodents, suppressed apoptosis in rat hepatocytes pretreated in vitro with an apoptogenic dose of UV light. This effect, which was also observable in DNA fragmentation analysis, coincided with a pronounced inhibition of the p53 increase usually seen after UV irradiation of rat hepatocytes. Interestingly, TCDD also led to a very minor but consistent enhancement of DNA fragmentation and to a slight increase in p53. Furthermore, TCDD resulted in a dose-dependent increase in p53 phosphorylation in intact cells. The concentration-response curves of the effects of TCDD on p53 phosphorylation and aromatic hydrocarbon receptor (AhR)-dependent induction of cytochrome P450 1A1 activity were almost superimposable, suggesting that TCDD induces p53 phosphorylation via an AhR-linked kinase activity. In an extract prepared from rat liver homogenate, 1 nM TCDD also stimulated p53 phosphorylation. Since the tyrosine kinase c-src was previously shown by others to be activated upon binding of TCDD to the AhR, extracts were pretreated with anti-src-antibodies. This treatment almost completely abrogated the effect of TCDD on p53 phosphorylation suggesting a key role for AhR-associated c-src. This mode of action may result in the observed suppression of the p53 response to apoptogenic UV irradiation, and may contribute to the inhibition of apoptosis. PMID- 21781901 TI - Induction of a cytosolic 54 kDa protein in rat liver that is highly homologous to selenium-binding protein. AB - We have previously shown that a 54 kDa protein in rat liver is highly homologous to selenium-binding protein (SeBP) or acetaminophen-binding protein (APBP) in mice and is highly inducible by treatment with 3,3',4,4',5-pentachlorobiphenyl or 3-methylcholanthrene. In this study, we examine the effect of six typical inducers, 3-methylcholanthrene (MC), isosafrole (ISO), phenobarbital (PB), dexamethasone (DEX), clofibrate (CLO), pyrazole (PYR) and butylated hydroxytoluene (BHT), on the expression level of this 54 kDa protein. Male Wistar rats were given each inducer following a predetermined schedule. Among these inducers, the 54 kDa protein was inducible by MC and BHT. The response to MC and BHT was compared with that of NAD(P)H: quinone oxidoreductase and ethoxyresorufin O-deethylase activities. The induction mechanisms and physiological role of the 54 kDa protein are discussed in the light of our results. PMID- 21781902 TI - Effect of ozone on susceptibility to respiratory viral infection and virus induced cytokine secretion. AB - Airway epithelium is the primary target tissue for respiratory viruses as well as an important target of ozone (O(3)) toxicity. A change in the severity of viral airway infection may result from changes in epithelial cell susceptibility to infection, metabolic interference with viral replication, or altered production of immune regulatory molecules by the infected cells as a result of exposure to O(3). In this study we have investigated whether O(3) exposure alters the susceptibility of human airway epithelial cells to respiratory syncytial virus (RSV) infection, the production of infectious virus, and/or release of virus induced cytokines IL-6 and IL-8. The epithelial cell line BEAS-2B grown on collagen-impregnated filters was exposed to O(3) (0.5 ppm for 60 min) or filtered air immediately before or 24 h after infection with RSV. Cells exposed to O(3) before RSV infection released 44% less virus over 4 days of infection while O(3) exposure post RSV infection had no effect on virus production. O(3) exposure preceding RSV infection showed short term additive effects of these treatments on epithelial cell IL-6 and IL-8 production, a decrease in cytokines at 48 h, but did not affect long term cytokine production by RSV-infected cells. Furthermore, O(3) exposure did not affect long term cytokine production by cells with an established RSV infection at the time of exposure. These data suggest that O(3) does not adversely affect viral airway infection, at least not on the level of the host cell for viral replication. PMID- 21781903 TI - Inactivation of ochratoxin in ruminal fluid with variation of pH-value and fermentation parameters in an in vitro system. AB - Ochratoxin A which is degraded to ochratoxin alpha in the rumen may have negative effects on kidney function. However, the toxicity of ochratoxin alpha is significantly lower than of ochratoxin A. The objective of this study was to examine the effect of different ruminal parameters such as pH and fermentation on the inactivation of ochratoxin A. These studies were performed under in-vitro conditions by using the 'Hohenheimer gas test'.Incubation was carried out over a period of 48 h by incubating pure ochratoxin A with a mixture of ruminal fluid and a culture medium. The concentration of ochratoxin A was 200 MUg/l of ruminal fluid. Ochratoxine was determined by high performance liquid chromatography (HPLC)-fluorescence detection. The recovery rates for ochratoxin A and ochratoxin alpha were 70+/-6 and 53+/-4%, respectively. The ruminal degration rate of these toxins was affected by the relation of roughage and concentrate in the complete diet, i.e. in diets comprising of 40% roughage and 60% of concentrate the degradation rate was higher than in diets consisting of 100% concentrate. The relation of roughage to concentrate in the complete diets (n=4) had a significant effect on the half-life of the toxin that were measured. In this study, a shorter half-life for ochratoxin A was estimated when starch was added to the medium. pH had no significant effect on the degradation rate of ochratoxin A. PMID- 21781904 TI - Diesel particles induce nitric oxide production in murine alveolar macrophages and rat airways. AB - The acute adverse health effects among respiratory and cardiovascular patients have been associated with particulate air pollution, containing diesel particles (DP). The mechanisms of these effects are unknown, but they may involve inflammation. We investigated the effects of DP (30-3000 MUg/10(6) cells) on cell viability and production of nitric oxide (NO), interleukin-1 (IL-1), interleukin 6 (IL-6), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF alpha) in murine RAW 264.7 macrophage cultures in vitro. DP caused a dose- and time-dependent NO-production and was cytotoxic in murine RAW 264.7 macrophages. Cytotoxicity preceded the increases in NO production. DP had minimal effects on cytokine production. A single intratracheal instillation of DP 1 and 5 mg/rat increased NO production and protein concentration in bronchoalveolar lavage fluid, and caused pulmonary edema and hemorrhage. The present results indicate that DP can induce both NO production and cytotoxicity in the lower respiratory tract, which may contribute to the short-term adverse respiratory effects of these particles. PMID- 21781905 TI - Relative potencies of PAHs and PCBs based on the response of human cells. AB - P450 reporter gene system (RGS) utilizes a human hepatoma cell line stably transfected with a plasmid containing firefly luciferase linked to human CYP1A1 promoter sequences. Luciferase expression in these cells is used to detect and quantify compounds that activate the Ah receptor (AhR) and induce CYP1A1. In this study, concentration-response curves were used to determine the relative potencies and calculate induction equivalency factors (IEFs) for non-ortho and mono-ortho coplanar PCBs and high-molecular weight PAHs. Relative potencies of PCBs were: 3,4,4',5-TetraCB (81)>3,3',4,4',5-PentaCB (126)>3,3',4,4'-TetraCB (77)~2,3,4,4',5-PentaCB (114)>2,3',4,4',5-PentaCB (118)~2',3,4,4',5-PentaCB (123)>3,3',4,4',5,5'-HexaCB (169). In addition, two other mono-ortho congeners, 2,3,3',4,4'-PentaCB (105) and 2,3,3',4,4',5-HexaCB (156), did not induce luciferase in these cells. Relative potencies of the PAHs were: benzo[k]fluoranthene>dibenz[a,h]anthracene>benzo[b]fluoranthene~indeno[1,2,3 cd]pyrene>benzo[a]pyrene>chrysene~benzo[a]anthracene>benzo[g,h,i]perylene. Relative potencies of PAHs are similar to those of PCBs. PMID- 21781906 TI - Physiological microassay of plasma total antioxidant status in a model of endothelial dysfunction in the rat following experimental oxidant stress in vivo. AB - We have developed a photometric microassay for the assessment of total antioxidant status in plasma at physiological pH and temperature and applied it to evaluate experimental oxidant stress in vivo associated with endothelial dysfunction in vitro. Rat plasma or l-ascorbic acid inhibited the peroxidase mediated accumulation after 6 min at pH 7.4 and 37 degrees C of ABTS(+) (2,2' azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radical), measured at 405 nm, in a concentration-dependent manner. Plasma total antioxidant status, expressed as the ascorbate equivalent antioxidant concentration, was subsequently found to be significantly reduced in rats treated daily for 7 days in vivo with the oxidant compounds hydroquinone (50 mg/kg i.p.) and triethylenetetramine (100 mg/kg i.p.), either alone or in combination with the glutathione-depleting agent l-buthionine sulfoximine (50 mg/kg i.p). Furthermore, basal endothelial function in isolated aorta was impaired after hydroquinone or triethylenetetramine in a manner aggravated by l-buthionine sulfoximine. PMID- 21781907 TI - Structure-toxicity relationships for selected halogenated aliphatic chemicals. AB - Toxicity to the ciliate Tetrahymena pyriformis (log(IGC(50)(-1))) for 39 halogen substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log(IGC(50)(-1)) along with the hydrophobic term, logK(ow) (1-octanol/water partition coefficient) and the electrophilic parameter, E(lumo) (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure-activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohols. The relationship for the haloalkanes [log(IGC(50)(-1))=0.92 (logK(ow))-2.58; n=4, r(2)=0.993, s=0.063, f=276, Pr>f=0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log(IGC(50)(-1))=0.63(logK(ow))-1.18; n=19, r(2)=0.860, s=0.274, f=104, Pr>f=0.0001] was observed for the haloalcohols. No hydrophobicity-dependent model (r(2)=0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log(IGC(50)(-1))= 1.245(E(lumo))+0.73; n=15, r(2)=0.588, s=0.764, F=18.6, Pr>f=0.0009] was developed for the halonitriles. Additional analysis designed to examine surface response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log(IGC(50)(-1))=0.60(logK(ow)) 0.747(E(lumo))-0.37; n=34, r(2)=0.915, s=0.297, F=162, Pr>F=0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure-toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character. PMID- 21781908 TI - Modulation of hepatic cytochrome P450 activity and carcinogen bioactivation by black and decaffeinated black tea. AB - The principal objective of this study was to compare the ability of green, black and decaffeinated black tea to modulate hepatic expression of cytochromes P450 in the rat, and the consequences on the bioactivation of some food-borne carcinogens. Furthermore, these studies allow inferences to be drawn as to the contribution of caffeine and flavanols in the tea-mediated changes in cytochrome P450 expression. Black tea is prepared from fresh tea leaf following oxidation of flavanols by polyphenol oxidases and consequently has a low content of these compounds. All three types of tea enhanced lauric acid hydroxylation but in the case of decaffeinated black tea no statistical significance was attained. Green tea and black tea, but not decaffeinated black tea, stimulated the O dealkylations of methoxy-, ethoxy- and pentoxy-resorufin indicating upregulation of CYP1A and CYP2B. Immunoblot analysis revealed that green and black tea, but not decaffeinated black tea, elevated the hepatic CYP1A2 apoprotein levels. Hepatic microsomes from green and black tea-treated rats, but not those from the decaffeinated black tea-treated rats, were more effective than controls in converting IQ into mutagenic species in the Ames test. It is concluded that flavanols are not responsible for the effects of tea on the cytochrome P450 system, but caffeine could account for the increase in CYP1A2 and the consequent increase in the bioactivation of IQ. PMID- 21781909 TI - Could mitochondrial dysfunction play a role in manganese toxicity? AB - Individuals suffering from manganese toxicity exhibit several symptoms, including mitochondrial dysfunction, which are similar to those frequently observed in cases of Parkinson's disease. We review the literature concerning manganese toxicity and mitochondrial function, and propose a simple conceptual model of the aetiology of manganese toxicity which involves an interaction between inhibition of mitochondrial energy transduction, generation of free radicals and mutations of the mitochondrial genome. This conceptual model prompts a number of relatively simple experiments which would provide a test of the model. PMID- 21781910 TI - Preliminary in vitro toxicological evaluation of a series of 2 pyridylcarboxamidrazone candidate anti-tuberculosis compounds. AB - We have investigated the toxicity of a series of 2-pyridylcarboxamidrazones in vitro using a rat liver metabolism system as well as human erythrocytes and mononuclear leucocytes (MNL) as target cells. Of the seven derivatives and four precursors tested, only minimal (<2.3%) metabolism-mediated methaemoglobin was formed by two analogues. However, one of these, a naphthylidene 2 pyridylcarboxamidrazone derivative (compound III), was also directly toxic to human MNLs. This toxicity was partially attenuated by the rat metabolising system and incubation of diethyldithiocarbamate or cimetidine together with compound III and the rat metabolising system suppressed the metabolism-dependent detoxification. This indicated that cytochrome P-450-mediated biotransformation of compound III was preventing its direct toxicity to the MNL. Of the seven derivatives tested, six were low in toxicity to MNL directly and in the presence of a metabolising system. The two compounds which were the most potent anti mycobacterially, the dimethylpropyl and dimethylethyl benzylidene amidrazone derivatives, were also the least toxic to MNL and erythrocytes. This amidrazone series has shown promise for future development as antituberculosis drugs. PMID- 21781911 TI - Paracetamol hepatotoxicity and microsomal function. AB - The effect of paracetamol-induced hepatotoxicity in rats (650 mg/kg) on microsomal function was examined. Paracetamol treatment resulted in lowered Na(+),K(+)-ATPase activity in the microsomes with decrease in V(max) of the low affinity high V(max) component II. However, the temperature kinetics was not influenced significantly. The total phospholipid and cholesterol contents as well as lipid peroxidation in the microsomes were unchanged. However, content of acidic phospholipids: phosphatidylserine and phosphatidylinositol decreased by 50% with a reciprocal increase in the sphingomyelin content; the lysophosphoglyceride content increased by 12-fold. The microsomal membrane appeared to be more fluidized following paracetamol treatment. Paracetamol treatment also resulted in a significant reduction in the sulfhydryl groups content. PMID- 21781912 TI - Bioactivation of the cyanide antidote 4-aminopropiophenone (4-PAPP) by human and rat hepatic microsomal enzymes: effect of inhibitors. AB - The bioactivation of the cyanide antidote methaemoglobin former 4 aminopropiophenone (4-PAPP) was studied using rat and human microsomes. With rat liver and NADPH in single and two-compartment systems, dapsone and benzocaine were more potent methaemoglobin generators compared with 4-PAPP. In the single compartment studies, the order of potency of inhibition of 4-PAPP-mediated methaemoglobin formation was cimetidine (1.5 mM)>isoniazid (500 MUM)/diethyldithiocarbamate (DDC, 1 mM)>erythromycin (500 MUM). Human liver microsomal activation of 4-PAPP in the two-compartment system was partially inhibited by both DDC and cimetidine. These preliminary studies suggest that 4 PAPP may be metabolised by CYP 2C11, 2E1 and 3A in the rat and CYP 2C, 2E1 and probably 3A4 in man. PMID- 21781913 TI - The social aspects of food biotechnology: a European view. AB - The application of the modern biotechnology to food, notably through the use of GM, has raised concern amongst the European public. Values that underlie this public concern about food biotechnology, include perceptions of: trust, choice, need, and care for a sustainable society and natural balance. Recommendations are advocated for addressing these social aspects, in terms of improving consumer choice, promoting greater public involvement in decision making and achieving a sustainable society. A model of risk analysis for genetically modified organisms (GMOs) and genetically modified food that incorporates this social dimension, through the integration of risk analysis with a social impact analysis is proposed, in order to build greater popular trust into the decision making processes. PMID- 21781914 TI - Roles of cyclooxygenase and lipoxygenases in ochratoxin A genotoxicity in human epithelial lung cells. AB - The roles of constitutive prostaglandin-H-synthetase (PGHS) and lipoxygenases in ochratoxin A (OTA) genotoxicity, as reflected by DNA adduct formation, have been investigated in vitro: (1) in culture of human epithelial cells and (2) by incubation in presence of pig seminal vesicle microsomes. Indomethacin (0.1 MUM), which inhibits PGHS and significantly increases leukotriene C(4) production by enhancement of lipoxygenases, enhanced formation of OTA-DNA adducts tenfold. At highest dose of 10 MUM, indomethacin inhibited all pathways (PGHS and lipoxygenases) and thus prevented OTA-DNA adduct formation. Nordihydroguaiaretic acid, which inhibits lipoxygenases, suppressed OTA-DNA adduct formation. The OTA metabolites formed were analysed by HPLC. OTalpha, 4[R]- and 4[S]-hydroxy-OTA and a unidentified derivative were formed in control cells. After pre-incubation with indomethacin (0.1 MUM), further unidentified metabolites were obtained. They were similar to those obtained in presence of pig seminal vesicle microsomes. These data demonstrate that OTA is biotransformed into genotoxic metabolites via a lipoxygenase, whereas PGHS decreases OTA genotoxicity. PMID- 21781915 TI - Serine palmitoyltransferase inhibition reverses anti-proliferative effects of ceramide synthase inhibition in cultured renal cells and suppresses free sphingoid base accumulation in kidney of BALBc mice. AB - The purpose of this study was to determine the ability of the fungal serine palmitoyltransferase (SPT) inhibitor, myriocin, to prevent the anti-proliferative and cytotoxic effects of fumonisin B(1) in cultured pig kidney epithelial cells, LLC-PK(1). In an earlier study with LLC-PK(1) cells, beta-chloroalanine (a nonspecific SPT inhibitor) was found to inhibit the fumonisin-induced accumulation of free sphinganine by >90% but only partially reversed (50-60%) fumonisin's antiproliferative and cytotoxic effects. beta-Chloroalanine is not the ideal SPT inhibitor for this type of study because it also inhibits other pyridoxal 5'-phosphate-dependent enzymes. A potent and selective fungal SPT inhibitor (myriocin) was partially purified from liquid cultures of Isaria (=Cordyceps) sinclairii by a combination of organic extraction and column chromatography. The various fractions were bioassayed for their ability to inhibit fumonisin-induced sphinganine accumulation in LLC-PK(1) cells. The activity in partially purified material was compared to the activity of highly purified myriocin and the results expressed as myriocin equivalents. The estimated IC(50) and IC(95) for inhibition of fumonisin-induced sphinganine accumulation were approximately 1.8 and 22 nM, respectively. The IC(95) concentration of the fungal SPT inhibitor reversed the antiproliferative effects and prevented fumonisin-induced apoptosis after 48 h exposure to 50 MUM fumonisin B(1). The SPT inhibitor was also effective at reducing free sphinganine in vivo. Free sphinganine concentration was reduced 60% in kidney of mice injected i.p. with SPT inhibitor plus fumonisin B(1) when compared to fumonisin B(1) alone. The ability of SPT inhibition to reduce fumonisin B(1)-induced sphinganine accumulation in vivo may be useful in the development of therapeutic agents for treatment of animals suspected to have been exposed to toxic levels of fumonisin in feeds. PMID- 21781916 TI - Antagonism of methomyl-induced toxicosis by diphenhydramine in rats. AB - The efficacy of diphenhydramine in the prevention and treatment of methomyl induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD(50) of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl. PMID- 21781917 TI - Pharmacokinetics of acrylamide after oral administration in male rats. AB - Acrylamide (AMD) is a commonly used industrial chemical. However, it produces a dying back type of peripheral neuropathy in animals and man. This study was performed to investigate the pharmacokinetics of AMD after oral administration at 50 mg/g ([1-(14)C]AMD) in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid and radioactivity was detected in blood 5 min post-administration. The peak plasma concentration occurred 38 min after administration and was equivalent to 47 MUg/ml. The elimination pattern for plasma was fitted to a one-compartment model with 6 h half-life. However, in the blood the elimination pattern was fitted to a two-compartment model with 7.93 and 374 h for distribution and elimination phases, respectively. Tissue concentrations of radioactivity determined at 28 and 144 h post-administration differed substantially. After 28 h the highest activity was in the gastric content, followed by stomach, lung, bone marrow and skin, while after 144 h the order of total radioactivity was lung>bone marrow>esophagus. The activities in the rest of the organs in both experiments were very low. The excretion study revealed that the kidney is the major route of elimination and the majority of radioactivity in urine was excreted during the first 12 h. The feces contained approximately 10% of the administered dose after 144 h. This study indicated that AMD is rapidly absorbed from the rat's gastrointestinal tract, distributed and eliminated from the body. AMD bound but did not accumulate in the erythrocytes or the neural tissues. PMID- 21781918 TI - Cytotoxic effects of 2-butoxyethanol in vitro are related to butoxyacetaldehyde, an intermediate oxidation product. AB - Ethylene glycol ethers belong to a group of solvents with a wide spectrum of applications, particularly because of their compatibility to both hydrophilic and lipophilic systems. Especially ethylene glycol monobutyl ether (2-butoxyethanol, BE) is widely used as a key ingredient in many industrial and consumer cleaning products. Therefore, the risk of human exposure and toxicity by BE as well as its potential for environmental contamination have to be carefully evaluated. By using an established kidney epithelial cell line from the proximal tubule (opossum kidney cells), we investigated the effects of BE on viability, proliferative activity, volume and the organization of the intracellular cytoskeleton of the cells. The experiments were performed with freshly used BE and BE that had been stored at room temperature in the original packing for 3 months after use. After this period of storage the latter BE contained-besides butyraldehyde and n-butanol-0.5 vol% butoxyacetaldehyde (BAL) as measured by capillary gas chromatography and mass spectrometry. Freshly used BE did not cause a toxic effect in the in vitro assays at all concentrations tested (up to 1 mg/ml). In contrast, stored BE which contained BAL reduced cell viability and mitotic activity in a dose-dependent manner. The effective concentration of stored BE causing a 50% loss in cell viability (EC(50/24h)) was calculated to be 1 mg/ml. The toxic effect of stored BE also resulted in alterations of cell morphology and a depolymerization of actin-containing stress fibers. Moreover, administration of stored BE also caused a dose-dependent cell volume increase by the uptake of water, pointing to a necrotic process. In addition, synthesized BAL with a purity of 73.5% (gas chromatography) was also tested and caused an EC(50/24h) of 15 MUg/ml, which is a 70-fold lower concentration when compared with stored BE. The present study provides evidence that BE possesses only a low cytotoxic potential in vitro, whereas the corresponding BAL, an intermediate in the oxidation process of BE to butoxyacetic acid, has marked toxic effects. The occurrence of the aldehyde might explain the predominant hematological effects of BE observed in vivo. PMID- 21781919 TI - Sex differences in dizocilpine (MK-801) neurotoxicity in rats. AB - The sex differences in the clinical signs and the distribution of astrocytic glial fibrillary acidic protein (GFAP) induced by an N-methyl-d-aspartate antagonist, dizocilpine (MK-801), were examined. A single intraperitoneal injection of MK-801 (5 mg/kg body weight) caused a prolonged recumbency (35-40 h), leading to a severe loss of body weight in female rats, in contrast to a light effect in males, independent of age. Early salivation or lacrimation was also severe in females and delayed bloody lacrimation was observed in females only. The pretreatment with 17beta-estradiol (0.1 or 1.0 mg/kg body weight) made early signs worse in both sexes, but a remarkable mortality (20-40%) was observed in females only. The treatment with MK-801 greatly enhanced GFAP expression in retrospenial cortex of both sexes with a higher enhancement in females. The MK 801-induced expression of GFAP was further increased by the pretreatment with 17beta-estradiol (1 mg/kg body weight) in females. Overall, the expression of GFAP in the retrospenial cortex of rats treated with MK-801 appeared to be higher in females than males, somewhat in parallel with more severe clinical signs in females. The results indicate the higher sensitivity of female rats to MK-801 neurotixicity, and the possible involvement of 17beta-estradiol in the sex differences of the sensitivity. PMID- 21781920 TI - Organophosphate-induced brain injuries: delayed apoptosis mediated by nitric oxide. AB - The features of organophosphate-induced brain injuries were investigated. Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD(50)) of diisopropylfluorophosphate. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate (20 mg/kg), which are centrally inactive, were pre-treated intramuscularly to reduce the mortality and eliminate peripheral signs. Diisopropylfluorophosphate induced severe limbic seizures, and early necrotic and delayed apoptotic brain injuries. The necrotic brain injury was observed to be maximal as early as 1 h after diisopropylfluorophosphate treatment predominently in hippocampus and piriform/entorhinal cortices, showing a spongiform change (malacia) of neuropils in severe cases. In contrast, typical apoptotic (TUNEL positive) cells started to appear at 12 h in thalamus, and a mixed type in amygdala. Separately, nitrite/nitrate content in cerebrospinal fluid was found to significantly increase after 2 h, reaching a maximal level at 6 h. Pre-treatment with l-N(G)-nitroarginine, an inhibitor of nitric oxide synthase, reduced nitrite/nitrate content and, noteworthy, attenuated only apoptotic brain injury in all four brain regions without affecting seizure intensity and necrotic injury. Taken together, the delayed apoptotic injury of brain induced by diisopropylfluorophosphate poisoning in rats might be mediated in part through nitric oxide production. PMID- 21781921 TI - Inhibitory metabolite complex formation of methylenedioxymethamphetamine with rat and human cytochrome P450. Particular involvement of CYP 2D. AB - Methylenedioxymethamphetamine (MDMA or ecstasy) is a common recreational drug used at rave parties. Unfortunately, MDMA may have neurological effects and in some cases causes hepatotoxicity. MDMA binds to cytochrome P450 in rat and human hepatic microsomal preparations. Upon metabolic transformation of either the methylenedioxy or the methylamino function, it forms an inhibitory P450 metabolite complex. This inhibitory complex is formed predominantly with the P450 2D isozymes. This complex formation may account for the clinical toxicity observed upon ingestion of MDMA, particularly with other compounds normally metabolized by P450 2D6. PMID- 21781922 TI - Mechanism of acute inhalation toxicity of alkanes and aliphatic alcohols. AB - This study investigated the mechanism of non-specific toxicity of non-reactive volatile organic compounds by using data reported in the literature. Inhalation toxicity data, in terms of LC(50) for alcohols and alkanes in rodents, were examined in relation to their partitioning behaviour in the biological system. Regression analysis of the data showed that, after the elimination of the kinetic influence in the absorption process, lethal toxicity increases linearly with the octanol-air partition coefficient in a homologous series. Comparing this relationship with that for anaesthesia, it could be concluded that lethal toxicity of the test chemical series probably acts on the lipid bilayer plasma membrane through a non-specific biophysical mechanism similar to anaesthesia. The critical concentration hypothesis appears to be valid for lethal toxicity of the test series. It was also shown that toxicity data for the test series by other routes, namely oral, intraperitoneal and intravenous, give a similar toxicity partition relationship to that by inhalation. PMID- 21781923 TI - Induction of rat brain and liver cytochrome P450 1A1/1A2 and 2B1/2B2 isoenzymes by deltamethrin. AB - Deltamethrin, an alpha-cyano type II pyrethroid, administered orally (5, 10 and 15 mg/kg body weight for 7 consecutive days or at 5 mg/kg for further 15 and 21 days) to young albino Wistar rats (approximately 8 weeks old) produced a dose- and time-dependent increase in the activity of cytochrome P450-dependent 7 ethoxyresorufin-O-dealkylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) in rat liver and brain. However, significant induction in the enzyme activities was observed at higher doses or prolonged exposure. The magnitude of induction in rat liver microsomes was less at 15 mg/kg dose as compared to 10 mg/kg dose. Western blot analysis revealed a similar dose-related and time-dependent increase in the expression of P450 2B1/2B2 and 1A1 isoenzymes as indicated by the increased cross reactivity of liver microsomes isolated from deltamethrin-treated animals with anti-P450 2B1/2B2 and 1A1. Inhibition of EROD and PROD observed after in vitro addition of anti-P450 2B1/2B2 and 1A1/1A2 or organic inhibitors, metyrapone and alpha-naphthoflavone, to the brain and liver microsomes of deltamethrin pretreated animals (5 mg/kg*21 days), further provided support that the induction observed in the EROD and PROD activity in brain is due to the increased expression of P450 2B1/2B2 and 1A1/1A2, while, in the liver, isoenzymes other than these are also involved. PMID- 21781924 TI - Selective induction of apoptosis of renal proximal tubular cells caused by inorganic mercury in vivo. AB - A recent notion, that a variety of toxicants causing necrosis can lead to apoptosis as well, has been demonstrated with cultured cells, but not with in an vivo system. In the present study, we examined the induction of both apoptosis and necrosis in the kidneys of Wistar rats exposed to mercuric chloride (HgCl(2)). A single injection of HgCl(2) to rats at a dose of 4 mg/kg resulted in an increase in the renal DNA fragmentation evaluated as an occurrence of apoptosis, prior to urinary excretion of alkaline phosphatase (ALP) and renal morphological changes assessed as necrotic phenomena. The mercury-promoted DNA fragmentation was induced in a dose-dependent manner. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and morphological observation of the nuclei revealed that apoptotic cells caused by HgCl(2) were predominantly found in the proximal tubules, but not in the distal tubules, glomeruli or medullary tubules. When we confirmed the proximal tubular-selective apoptosis by inorganic mercury with a combined technique of TUNEL staining with synchrotron radiation X-ray fluorescence (SR-XRF) imaging, it was shown that the apoptotic cells localized in the proximal tubules did contain higher level of mercury. Thus these results indicate that the proximal tubular cells-dominant site-specific distribution of mercury appears to be associated with induction of renal apoptosis and necrosis. PMID- 21781925 TI - Behavioural and biochemical changes after simultaneous and post-treatment of vitamin A and D on cadmium toxicity. AB - In the present study, an investigation was undertaken to assess the protective efficacy in cadmium toxicity of vitamins administered simultaneously as well as post-treatment. Rats were treated with cadmium 1 mg/kg body weight (bw) powdered vitamin A chewable tablet 500 IU/kg bw/day and injectable vitamin D(3) (made into a suspension with gum tragacanth in 100 ml distilled water) 100 IU/kg bw/day, mixed with powdered pellet feed and fed to experimental animals. Spontaneous motor activity and Rota Rod Endurance time was recorded after both simultaneous (for 21 days) and post-treatment (42 days). Vitamin treated animals by themselves behaved like controls but attenuated the cadmium effect when given Cd simultaneously or as post-treatment. While the biochemical changes were assayed, vitamins which did not have any influence on their own, given simultaneously and as post-treatment, antagonized the cadmium effect on heart, liver tissues and serum. Both simultaneous and post-cadmium and -vitamin treatments significantly increased the activities of the enzymes aspartic amino transferase, alanine aminotransferase, acid phosphatase and alkaline phosphatase in tissues and serum. Simultaneous and post-vitamin treatment with Cd had an effect of bringing back the activity of the enzymes closer to control values. These data suggest that treatment with vitamin A and D can minimise the Cd effect when given to the population exposed to Cd. PMID- 21781926 TI - Phytoestrogens. State of the art. AB - A short overview of recent advances of phytoestrogen research is presented. Developments have particularly been made with regard to methods, food analyses, pharmacokinetics, receptor studies, mechanisms of action and effects on cancer. Most studies deal with isoflavones, but the interest in lignans is increasing as a result of a large rye project in the Nordic countries. The development of rapid time-resolved immunofluorescence assays in 20 MUl plasma samples for enterolactone, genistein and daidzein has resulted in the initiation of many prospective studies on cancer risk using blood bank material. PMID- 21781927 TI - Bioavailability of genistein, daidzein, and their glycosides in intestinal epithelial Caco-2 cells. AB - In this study information was obtained on bioavailability of genistein, daidzein and their glycosides in human intestinal epithelial Caco-2 cells grown on semi permeable filters. The integrity of Caco-2 monolayers was confirmed by transepithelial electrical resistance measurements and by determination of the permeability of the radioactive marker polyethylene glycol (PEG4000). After 6 h approximately 30-40% of genistein and daidzein added at the apical side was transported to the basolateral side and this level was maintained for 24 h, The glycosides were barely transported through the Caco-2 cells. No significant metabolism of genistein and daidzein in the Caco-2 cells occurred, whereas the glycosides were mainly metabolised to their respective aglycones. Obviously, our data indicates that Caco-2 cells contain an endogenous glycosidase activity. PMID- 21781928 TI - Phytoestrogens and menopause. PMID- 21781929 TI - The synthesis of 2-substituted isoflavones for immunoassay. AB - Details are given of the preparation of isoflavones derivatised so that they act as haptens in the development of immunoassays for large scale screening for phytoestrogens in biological fluid. A specifically designed new cyclisation reaction allowed the direct conversion of 2-acyloxydeoxybenzoins to the required isoflavones. PMID- 21781930 TI - Analysis of phyto-oestrogens by gas chromatography-mass spectrometry. AB - The metabolites of oestrogenic substances of plant origin, phyto-oestrogens, have been proposed as cancer-protective agents in Asian and vegetarian populations. The two principle classes of these weak oestrogens are isoflavonoids and mammalian lignans. The former is derived from soya-based foods and the latter from oilseeds, cereals and whole grains. Asian populations such as the Japanese have high plasma concentrations of the isoflavones, daidzein and genistein, whereas vegetarians excrete large quantities of the lignan enterolactone, in their urine. The concentrations of these compounds in biological samples and foods are usually determined by GC-MS, although other techniques such as HPLC and LC-MS have also been used. A simple, robust method employing isotope dilution GC MS will be described which could be applied to the determination of phyto oestrogens in biological samples and food matrices. Briefly, samples are hydrolysed with beta-glucuronidase, the aglycones extracted and the phyto oestrogen fraction isolated by chromatography on Sephadex LH20. This fraction is then derivatised for GC-MS by reaction with N,O-bistrimethylsilyl triflouroacetatamide to form trimethylsilyl derivatives. Using this technique we have determined the concentrations of the lignans, enterodiol and enterolactone, and the isoflavonoids, equol, daidzein and genistein, in the serum of men from Japan (n=42). The mean levels of daidzein and genistein in these men were 82.5 ng/ml (range 1.9-577) and 158.6 ng/ml (range 5.3-852), respectively. The majority of these men (57%) produced equol concentrations of >5 ng/ml, with a mean value of 26.7 ng/ml. Mean Levels of enterodiol and enterolactone were 0.6 and 9.4 ng/ml, respectively. The levels of daidzein and genistein produced from the hydrolysis of soya bean hulls, soya bean hypocotyl, dehulled soya beans, soya flour, soya grit and soya concentrates have also been determined by this method. Soya bean hypocotyl, for example, produces 2.1 mg/g of daidzein and 1.2 mg/g genistein, whereas some concentrates yield as much as 40% isoflavones. PMID- 21781931 TI - Toxopathology of gout induced in laying pullets by sodium bicarbonate toxicity. AB - A total of 60, 3-week-old, laying pullets were used in the present experiment. The exposed birds received excess sodium bicarbonate (SB) in their drinking water for 35 days at the levels of: 2 g/l (0.2%), 7.5 g/l (0.75%), 20 g/l (2%) and 40 g/l (4%). All birds were subjected to pathological and toxicological examination. Birds of the 0.75% and 2%-groups developed gross picture of visceral gout, while birds of 4%-group showed acute kidney damage without manifesting visceral urate deposition. Erythrocytic count, packed cell volume (PCV), and hemoglobin (Hb) levels were all increased in the exposed birds. There were dose-related increments in the serum level of sodium (Na(+)). Serum levels of chloride (Cl( )), and potassium (K(+)) were relatively decreased in some cases. Serum levels of uric acid were increased in a dose-related pattern. Blood pH of the treated birds was shifted toward the alkaline side. Microscopic examination revealed significant renal changes in birds manifesting visceral gout and these changes included urate deposits associated with tubular necrotic changes. Some birds in the third group (2%) developed urate granulomas (tophi) in their renal interstitium. It was concluded that development of gout in birds may be related to a state of metabolic alkalosis which is associated with significant changes of the electrolyte balance. PMID- 21781932 TI - Comparison of hematologic consequences and efficacy of p-aminophenones in mice. AB - Controlled methemoglobin (MHb) formation is one strategy employed to counter cyanide (CN) toxicity. Currently available MHb formers present certain drawbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophenone (PAPP), and two structurally-related p-aminophenones, p-aminoheptanoylphenone (PAHP) and p aminooctanoylphenone (PAOP). Although these three p-aminophenones have been shown previously to be efficacious as pretreatments against CN, a more complete understanding of their hematologic effects is lacking. In addition, because the active form of PAPP has been shown to be its N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP were also tested. Using a hemoximeter, blood samples obtained -2 to +180 min relative to intramuscular (i.m.) or intraperitoneal (i.p.) drug injections were evaluated. Sodium nitrite (NaNO(2)) and the appropriate solvents served as the positive and negative controls, respectively. Dose-, time-, route-, and compound-related effects were observed. MHb and sulfhemoglobin levels increased, whereas levels of those parameters related to oxygen-carrying capacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased. In general, the effects of PAHP and PAOP were longer lasting than those of PAPP and NaNO(2). Furthermore, PAPP and NaNO(2) were equally effective with either route of administration. Conversely, PAHP and PAOP showed larger effects when administered i.p. versus i.m. The animals treated with N-hydroxy metabolites of the p-aminophenones also showed similar changes in the hematological parameters measured. N-hydroxy PAPP was shown to be the most rapidly acting MHb-forming compound examined in this series. It could achieve therapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication. Although additional work is needed, these data provide information that will be useful for the successful development of improved anti-CN MHb formers. PMID- 21781933 TI - Cholinesterase activity as potential biomarker in two bivalves. AB - In this study, the pH, temperature and substrate specificity for cholinesterases (ChE) assay in two bivalves was optimized: the Spanish mussel Mytilus galloprovincialis and the Asiatic clam Corbicula fluminea. The optimal values found are pH 7, 25 degrees C, 2 mM of acetylthiocholine (ASCh) as substrate for M. galloprovincialis and pH 8, 25 degrees C, 5 mM propionylthiocholine (PrSCh) for C. fluminea. The apparent K(m) are 30 and 70 MUM for the two bivalves, respectively. In comparison with some other crustaceans and fishes, the levels of ChE activity were found to be low. The in vitro and in vivo sensitivities of the ChEs activity toward two well known pesticides: carbaryl and methylparathion (or its oxon derived form) are comparable to that observed in fishes but less than that found in crustaceans. Although further studies should be done, and other contaminants tested, the studied bivalves can be considered as interesting 'sentinel' species in the monitoring of the acute water contamination by pesticides. PMID- 21781934 TI - Streptomyces anulatus from indoor air of moldy houses induce NO and IL-6 production in a human alveolar epithelial cell-line. AB - Moisture associated microbial growth in buildings may cause respiratory symptoms such as pulmonary inflammation. We studied the effects of spores of Streptomyces anulatus, commonly found in moldy buildings, on the production of nitric oxide (NO), interleukin-6 (IL-6), interleukin-5 (IL-5), interleukin-4 (IL-4), and tumour necrosis factor alpha (TNFalpha), as well as cell viability in human alveolar II type epithelial cell line (A549). Cells were exposed in vitro to S. anulatus spores with and without interferon-gamma (IFNgamma) in vitro. Lipopolysaccharide (LPS) was used as a reference substance. S. anulatus alone, and in combination with IFNgamma induced NO and IL-6 production and decreased cell viability whereas IL-4, IL-5 or TNFalpha production were not affected. IFNgamma alone had a weaker but otherwise similar effect as S. anulatus on NO and IL-6 production and it potentiated the effects of S. anulatus. LPS did not induce NO or cytokine production, or affect cell viability in A549 cells. These data indicate that spores of S. anulatus induce the excretion of inflammatory mediators in respiratory epithelial cells, which may partly explain the adverse respiratory health effects experienced by individuals exposed to the indoor air of moldy houses. PMID- 21781935 TI - Flow cytometric analysis on tri-n-butyltin-induced increase in annexin V binding to membranes of rat thymocytes. AB - Effects of tri-n-butyltin chloride (TBT) on rat thymocytes were examined by using a flow cytometer and three fluorescent dyes (annexin V-FITC, ethidium bromide and fluo-3-AM) to further characterize its cytotoxic action. TBT at concentrations of 100 nM or greater, time- and dose-dependently increased the population of annexin V-positive live cells in the cell suspension. Most of cells became to be annexin V-positive within 60 min after the start of application of 300 nM TBT. Some of annexin V-positive live cells were further stained with ethidium, indicating that some of the cells were killed, in continued presence of TBT at 300 nM or greater. When the cells were exposed to 300 nM TBT only for 15 min, the population of annexin V-positive live cells increased after removal of TBT from incubation medium. TBT-induced increase in the population of annexin V-positive live cells was partly attenuated under Ca(2+)-free condition, although that was not the case for the dead cells. TBT at 30 nM or greater increased [Ca(2+)]i in a dose dependent manner. Triethyltin and trimethyltin even at 1 MUM did not increase the [Ca(2+)]i and the population of annexin V-positive live cells. The population of annexin V-positive live cells increased as the [Ca(2+)]i was increased by ionomycin, a calcium ionophore. Results suggest an involvement of Ca(2+) in some of TBT-induced cytotoxicity. PMID- 21781936 TI - Delayed effects of pre- and early-life time exposure to polychlorinated biphenyls on tadpoles of two amphibian species (Xenopus laevis and Rana temporaria). AB - This study examined the effects of polychlorinated biphenyls (PCBs) on the development of amphibians using Xenopus laevis and Rana temporaria as experimental animals. Amphibians were exposed at different life stages and via different routes to the technical mixtures Clophen A50 and Aroclor 1254 or to a non-ortho PCB congener (PCB 126). The effects of PCB exposure in amphibians, such as mortality, number and pattern of malformations, or body weight at the end of successful metamorphosis of tadpoles, depends on the route, the point of time of exposure during the complex life cycle of amphibians, and the length of the observation period. Retinoid concentrations were significantly altered in PCB dosed embryos. Presently used early-life time test systems such as the FETAX assay may underestimate toxic effects of compounds with long term response such as PCBs on amphibians. PMID- 21781937 TI - Influence of trolox derivative and N-acetylcysteine on surface charge density of erythrocytes in methanol intoxicated rats. AB - Methanol is oxidized in vivo to formaldehyde and then to formate and these processes are accompanied by free radicals generation. This paper reports the effect of antioxidants: trolox derivative (U-83836E) and N-acetylcysteine (NAC) on lipid peroxidation, surface charge density and hematological parameters of erythrocytes from rats intoxicated with methanol (3.0 g/kg body weight). Methanol administration caused increase in erythrocyte lipid peroxidation products and changes in surface charge density. Ingestion of methanol with U-83836E and NAC partially prevented these methanol-induced changes. This suggests that U83836E and NAC act as effective antioxidants and free radicals scavengers. They may have efficacy in protecting free radical damage to erythrocytes following methanol intoxication. PMID- 21781938 TI - Cardiovascular effects of subchronically low/high carbon monoxide exposure in rats. AB - This study was designed to determine whether subchronic CO exposure ranging from 15 to 530 ppm induced modifications in the rat cardiovascular system. We investigated the degree of resistance to an in vitro transient ischemia in the hearts exposed in vivo to different CO concentrations for 1-4 weeks. Subchronic CO exposure induced dose and/or time-dependent increases (hematocrit, cardiomegaly and coronary flow). We showed an increase in the ventricular tachycardia (VT) incidence with the passing weeks of exposure, which demonstrated the proarrhythmic activity of CO even in low doses (15 ppm). The contractile recovery decreased owing to a low (50 ppm) or high (530ppm) CO exposure after a 25-min ischemia period. This diminution seems to be dependent on the increased amplitude of ischemic contracture. The present study supports the hypothesis that subchronic CO exposure, even at low levels of CO, can produce cardiovascular changes and could explain the increased risk of myocardial infarction. PMID- 21781939 TI - Antibiotic production by the cyanobacteria Oscillatoria angustissima and Calothrix parietina. AB - The accumulation of antibiotic in the medium is temperature dependent and not in direct proportion to growth parameters. The cyanobacterial product suppressed growth of some natural isolates of cyanobacteria and green algae. It inhibits the growth rate and oxygen evolution of the green alga, Chlorella fusca. The antibiotic also inhibits the growth of bacteria and some fungi, especially the dermatophytes. Generally eukaryotic organisms were less sensitive than prokaryotic. Experimental mice were unaffected by the antibiotic. The Oscillatoria antibiotic does not structurally resemble to cyanobacterin. PMID- 21781940 TI - The role of 3-methylsulfonyl-2,2',4',5,5'-pentachlorobiphenyl, a metabolite of 2,2',4,5,5'-pentachlorobiphenyl, in the induction of hepatic microsomal drug metabolizing enzymes by 2,2',4,5,5'-pentachlorobiphenyl in rats. AB - After the administration of 2,2',4,5,5'-pentachlorobiphenyl (2,2',4,5,5'-pentaCB) to intact rats, the concentration of 2,2',4,5,5'-pentaCB in liver gradually decreased, whereas 3-methylsulfonyl (3-MeSO(2))-2,2',4',5,5'-pentaCB appeared in liver and remained detectable in liver for 6 weeks. A single injection of 2,2',4,5,5'-pentaCB (342 MUmol/kg) or 3-MeSO(2)-2,2',4',5,5'-pentaCB (0.5 MUmol/kg) caused a significant increase both in the contents of cytochromes P450 and b(5) and in the activities of aminopyrine N-demethylase and benzo[a]pyrene hydroxylase, and the increased enzyme contents and activities continued for 6 weeks after the administration. The extent of both the hepatic accumulation of 3 MeSO(2)-2,2',4',5,5'-pentaCB and the induction of the enzymes for 6 weeks after the administration of 2,2',4,5,5'-pentaCB was similar to that after the administration of 3-MeSO(2)-2,2',4',5,5'-pentaCB. 3-MeSO(2)-2,2',4',5,5'-pentaCB was considered to play a principal role in the induction of microsomal drug metabolizing enzymes by 2,2',4,5,5'-pentaCB. When 2,2',4,5,5'-pentaCB was injected i.p. into bile duct-cannulated rats, 3- and 4-MeSO(2)-2,2',4',5,5' pentaCBs were not detected in liver. In antibiotic-treated rats dosed with 2,2',4,5,5'-pentaCB, the concentrations of 3- and 4-MeSO(2)-2,2',4',5,5'-pentaCBs in liver were markedly reduced. These findings suggest that the process in which 3- and 4-MeSO(2) metabolites of 2,2',4,5,5'-pentaCB are formed involves the biliary secretion of some precursors which will be subjected to metabolism by intestinal microflora. The increasing effects of 2,2',4,5,5'-pentaCB both on the content of cytochrome P450 and on the activity of aminopyrine metabolizing enzyme in hepatic microsomes were not observed in the bile duct-cannulated rats, in which the phenobarbital treatment enabled the drug-metabolizing enzymes to be induced. In antibiotic-treated rats, the increases both in the cytochrome P450 content and in the aminopyrine N-demethylase activity after the administration of 2,2',4,5,5'-pentaCB were smaller than those observed in the intact rats. These findings provide the evidence that the induction of some drug-metabolizing enzymes by 2,2',4,5,5'-pentaCB is due not to the action of 2,2',4,5,5'-pentaCB itself but to its 3-methylsulfonyl metabolite, 3-MeSO(2)-2,2',4',5,5'-pentaCB. PMID- 21781941 TI - Basal and induced EROD activity in the chorioallantoic membrane during chicken embryo development. AB - The chorioallantoic membrane (CAM) is a highly vascularized tissue that takes part in the respiratory exchange of gases through the eggshell. Although the CAM may be exposed to environmental contaminants, its response to pollutants has not been studied. We examined the cytochrome P4501A (CYP1A)-catalyzed deethylation of 7-ethoxyresorufin (EROD) in the CAM during chicken embryo development. EROD was constitutively present and was inducible by the aryl hydrocarbon (Ah) receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Our results suggest the CAM as a first line of defence of the avian embryo against toxic compounds, but also as a target for CYP1A-activated chemicals. PMID- 21781942 TI - Proliferative response of peripheral blood lymphocytes and lymphocyte subpopulations in n-Hexane, toluen, and methyl ethyl ketone co-exposed workers. AB - To estimate the quantitative relation between chronic co-exposure to airborne n hexane, toluen, methyl ethyl ketone (MEK) and various markers of immune function such as proliferative response of peripheral blood lymphocytes and lymphocyte subpopulations, a group of workers employed in a shoe factory were examined and compared with the unexposed controls. A significant increase was observed in the proliferative response of the peripheral lymphocytes to 2.5 and 5 MUg PHA in the exposed group compared with that of the control group. There was no significant change in the percentage of circulating CD3(+), CD4(+), CD8(+), CD19(+), CD16(+) lymphocytes even in those workers with 3.3-fold higher mean levels of urine 2,5 hexanedione (2,5-Hxdn) and approximately twofold higher mean levels of urine hippuric acid (HA) as compared to controls. No difference was also observed between the mean granulocyte, monocyte, lymphocyte percentages of the groups, but a significant increase was observed in mean serum C3 level of the workers. Our results suggest that while lymphocyte subpopulations and leucocyte percentages are not affected, the proliferative response of the peripheral lymphocytes is stimulated after chronic co-exposure to n-hexane, toluen and MEK at the defined levels. PMID- 21781945 TI - Sirolimus--it doesn't deserve its bad Rap(a). PMID- 21781944 TI - Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study. AB - BACKGROUND & AIMS: Blood tests and transient elastography (FibroscanTM) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (FibroscanTM) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and FibroscanTM. Two experienced pathologists independently reviewed the liver biopsies (mean length=25+/-8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: FibroscanTM was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable FibroscanTM, FibroscanTM performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer(r) (0.86), Fibrotest(r) (0.84), Hepascore(r) (0.84), and interpretable FibroscanTM (0.84) to be the most accurate tests. The combination of Fibrotest(r), Fibrometer(r), or Hepascore(r) with FibroscanTM or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer(r)) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer(r) and Hepascore(r)) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of FibroscanTM was reduced due to uninterpretable results. Fibrotest(r), interpretable FibroscanTM, Fibrometer(r), and Hepascore(r) perform best and similarly for diagnosis of significant fibrosis and cirrhosis. PMID- 21781943 TI - High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. AB - BACKGROUND & AIMS: Dietary copper deficiency is associated with a variety of manifestations of the metabolic syndrome, including hyperlipidemia and fatty liver. Fructose feeding has been reported to exacerbate complications of copper deficiency. In this study, we investigated whether copper deficiency plays a role in fructose-induced fatty liver and explored the potential underlying mechanism(s). METHODS: Male weanling Sprague-Dawley rats were fed either an adequate copper or a marginally copper deficient diet for 4 weeks. Deionized water or deionized water containing 30% fructose (w/v) was also given ad lib. Copper and iron status, hepatic injury and steatosis, and duodenum copper transporter-1 (Ctr-1) were assessed. RESULTS: Fructose feeding further impaired copper status and led to iron overload. Liver injury and fat accumulation were significantly induced in marginal copper deficient rats exposed to fructose as evidenced by robustly increased plasma aspartate aminotransferase (AST) and hepatic triglyceride. Hepatic carnitine palmitoyl-CoA transferase I (CPT I) expression was significantly inhibited, whereas hepatic fatty acid synthase (FAS) was markedly up-regulated in marginal copper deficient rats fed with fructose. Hepatic antioxidant defense system was suppressed and lipid peroxidation was increased by marginal copper deficiency and fructose feeding. Moreover, duodenum Ctr-1 expression was significantly increased by marginal copper deficiency, whereas this increase was abrogated by fructose feeding. CONCLUSIONS: Our data suggest that high fructose-induced nonalcoholic fatty liver disease (NAFLD) may be due, in part, to inadequate dietary copper. Impaired duodenum Ctr-1 expression seen in fructose feeding may lead to decreased copper absorption, and subsequent copper deficiency. PMID- 21781946 TI - Influence of interferon-based therapy on liver fibrosis progression in HIV/HCV coinfected patients: a retrospective repeated liver biopsy analysis. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) coinfection is one of the leading causes of mortality in human immunodeficiency virus-infected patients. The current standard of care leads to cure only in a part of these patients. The course of the disease is determined by the rapidity of liver fibrosis progression (LFP). The influence of interferon on LFP in coinfected patients has yet not been evaluated by comparative liver biopsies. METHODS: We extracted data of patients who had serial liver biopsies from a hospital database. Histopathological findings were compared to factors possibly linked to fibrosis progression. Furthermore, we studied the impact of response to interferon treatment on fibrosis progression. RESULTS: Hundred and twenty-six patients were included, 68 had received anti-HCV treatment, and 58 had not. The median time between the first and the last biopsy was 4 years. Worsened fibrosis was observed in 35 of 58 (60%) untreated patients, and 22 of 50 (44%) patients in the nonresponder/relapser group, and in 5 out of 18 (28%) in the SVR group. Liver fibrosis evolution was significantly better in patients achieving a SVR than in untreated and NR/R patients (p<0.02, odds-ratio [95% CI] for improvement vs. stability vs. worsening=3.16 [1.24-8.07]). This result persisted after adjustment for known predictors of liver fibrosis progression, HBsAg, CD4, and alcohol consumption: adjusted odds ratio=2.89 [1.09-7.68], p=0.03. CONCLUSIONS: HCV treatment can stop fibrosis progression and induce its regression. Nonresponders to treatment may even have a fast fibrosis progression. It remains to be clarified if the same factors that induce nonresponse to treatment may also induce faster fibrosis progression. PMID- 21781947 TI - m-TOR inhibitors: what role in liver transplantation? AB - The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence. PMID- 21781948 TI - Deciphering transcriptional control mechanisms in hematopoiesis:the impact of high-throughput sequencing technologies. AB - One of the key challenges facing biomedical research is to extract biologically meaningful information from the ever-increasing scale and complexity of datasets generated through high-throughput approaches. Hematopoiesis represents one of the most experimentally tractable mammalian organ systems and, therefore, has historically tended to be at the forefront of applying new technologies within biomedical research. The combination of massive parallel sequencing technologies with chromatin-immunoprecipitation (ChIP-Seq) permits genome-scale characterization of histone modification status and identification of the complete set of binding sites for transcription factors. Because transcription factors have long been recognized as essential regulators of cell fate choice in hematopoiesis, ChIP-Seq technology has rapidly entered the arena of modern experimental hematology. Here we review the biological insights gained from ChIP Seq studies performed in the hematopoietic system since the earliest studies just 4 years ago. A surprisingly large number of different approaches have already been implemented to extract new biological knowledge from ChIP-Seq datasets. By focusing on successful insights from multiple different approaches, we hope to provide stimulating reading for anyone wanting to utilize ChIP-Seq technology within their particular research field. PMID- 21781949 TI - Reduced-intensity conditioning before allogeneic hematopoietic stem cell transplantation in patients over 60 years: a report from the SFGM-TC. AB - This retrospective multicenter report assessed the outcome of 600 patients with hematologic diseases older than 60 years who received reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo HSCT), with the specific aim to compare outcomes of patients between 60 and 65 years old (N = 493) with those older than 65 years (N = 107). Except for donor age, there were no significant differences between the groups regarding patients, diseases, and allo-HSCT characteristics. At time of RIC allo-HSCT, 276 patients (46%) were in complete remission. With a median follow-up of 22.8 and 23.7 months in the younger and the older groups, respectively, 2-year relapse, nonrelapse mortality, disease-free survival, and overall survival rates were similar in both groups (29.6% vs. 20.4%; 29.9% vs. 34.6%; 40.6% vs. 46.7%; 49.2% vs. 50.2%, respectively; P = NS for all comparisons). In a Cox multivariate analysis, after adjustment for disease and transplant factors, age per se was not an adverse factor for survival (relative risk = 1.08; 95% confidence interval, 0.81-1.44, P = .62). We conclude that in selected patients, RIC allo-HSCT could be offered to patients over 65 years old. PMID- 21781950 TI - Genome-wide profiling in AML patients relapsing after allogeneic hematopoietic cell transplantation. AB - Molecular pathogenesis of relapse after allogeneic hematopoietic cell transplantation is poorly understood. Data regarding relapse mechanisms after transplantation is scarcely available. We investigated genomic aberrations (GAs) in 21 patients undergoing related and unrelated HLA-matched transplantation in leukemic blasts before transplant and at relapse after transplantation. We found a higher number of GAs after transplantation, suggesting increased genomic instability during relapse. Two of 21 patients showed a large homozygous region spanning the whole HLA-locus on chromosome 6p in the relapse sample. In both patients sequence-based HLA typing of the blasts revealed a loss of the patient specific allele at the mismatched locus leading to homozygosity for the HLA haplotype shared by the patient and the donor. In addition, GAs were found in critical regions such as 12p13, 13q12.2, and 17p13. Our results suggest that escape from immunologic surveillance may be a relevant mechanism of relapse after transplantation in patients with GAs on chromosome 6p. A combination of continuous immunologic pressure mediated by donor T cells and clonal evolution of myeloid leukemia may result in acquired GAs after transplantation. PMID- 21781951 TI - Knowledge and interests of Romanian medical students in parasitology, tropical and travel medicine. AB - As travel has become easier and faster, the rate of tropical infections across the world is expected to increase; more students working abroad are going to encounter these diseases more often. Disorders of parasitic etiology play an important role in travel and tropical medicine. The aim of our study was to assess the preclinical students' knowledge regarding parasitic diseases, tropical and travel medicine in the broad context of their professional background. A total of 346 Romanian medical students completed a 13-item questionnaire on the above-mentioned topics. In order to allow for complex evaluation, the questionnaire also included items related to their extracurricular training as well as their future perspectives. The majority of the students (97.7%) declared they had prior knowledge (before studying parasitology) of malaria. Most of the responders (90.2%) knew that a journey in (sub)tropical regions requires adequate prophylactic measures. About a quarter of those interviewed (26.4%) would agree to practice tropical medicine after graduation. They were mainly interested in helping people from underdeveloped countries regardless of remuneration (52.7%). The majority of students (59.8%) wished to practice clinical medicine. It has been observed that fewer than 5% of the questioned students had ever read a scientific paper or book in the field of tropical medicine. English was the most commonly spoken foreign language (92.8%), and 99.1% of students had at least intermediate computer skills. Finally, 71.6% of students would choose to practice the specialty of travel medicine if it were available in Romania. The implementation of appropriate measures towards the globalization of medical teaching in Romanian universities should represent an important issue in this new millennium, in which borders between various nations are starting to fade; otherwise the next generations of physicians will lose the chance to gain wider experiences and share the international influences on health. PMID- 21781952 TI - Malaria in Turkey: successful control and strategies for achieving elimination. AB - Turkey is located in the middle of Asia, Africa and Europe, close to Caucasia, Balkans and Middle East in subtropical climate zone. Malaria has been known since the early ages of human history and it was one of the leading diseases in Anatolian history, as well. Today, chloroquine-sensitive Plasmodium vivax is the only agent of autochthonous malaria cases in Turkey. The other Plasmodium species identified are isolated from imported cases of malaria. The most common vector of malaria in Turkey is Anopheles sacharovi followed by An. superpictus, An. maculipennis and An. subalpinus. In 2009, pre-elimination stage of Malaria Program was started due to dramatic decline in the number of malaria cases in Turkey (Total, 84; 38 autochthonous cases only in 26 foci in south-eastern Anatolia, and 46 imported cases; incidence: 0.1/100,000). As there were no detected cases of new autochthonous malaria in the first 8 months of 2010, elimination stage was started. The role of the persistent policies and successful applications of the Ministry of Health, such as the strict control of the patients using anti-malarial drugs especially chloroquine, avoidance of resistant insecticides, facilitation of access to patients via Health Transformation Program (HTP), establishment of close contact with the patients' families, and improvement of reporting and surveillance system, was essential. In addition, improvement maintained in the motivations and professional rights of malaria workers, as well in the coordination of field studies and maintenance of a decline or termination in vector-to-person transmission were all achieved with the insistent policies of the Ministry of Health. Other factors that probably contributed to elimination studies include lessening of military operations in south-eastern Anatolia and the lowering of malaria cases in neighbouring countries in recent years. Free access to health services concerning malaria is still successfully conducted throughout the country. PMID- 21781953 TI - Prospects for malaria elimination in non-Amazonian regions of Latin America. AB - Latin America contributes 1-1.2 million clinical malaria cases to the global malaria burden of about 300 million per year. In 21 malaria endemic countries, the population at risk in this region represents less than 10% of the total population exposed worldwide. Factors such as rapid deforestation, inadequate agricultural practices, climate change, political instability, and both increasing parasite drug resistance and vector resistance to insecticides contribute to malaria transmission. Recently, several malaria endemic countries have experienced a significant reduction in numbers of malaria cases. This is most likely due to actions taken by National Malaria Control Programs (NMCP) with the support from international funding agencies. We describe here the research strategies and activities to be undertaken by the Centro Latino Americano de Investigacion en Malaria (CLAIM), a new research center established for the non Amazonian region of Latin America by the National Institute of Allergy and Infectious Diseases (NIAID). Throughout a network of countries in the region, initially including Colombia, Guatemala, Panama, and Peru, CLAIM will address major gaps in our understanding of changing malaria epidemiology, vector biology and control, and clinical malaria mainly due to Plasmodium vivax. In close partnership with NMCPs, CLAIM seeks to conduct research on how and why malaria is decreasing in many countries of the region as a basis for developing and implementing new strategies that will accelerate malaria elimination. PMID- 21781954 TI - Functional studies of single-nucleotide polymorphic variants of human glutathione transferase T1-1 involving residues in the dimer interface. AB - Glutathione transferase T1-1 catalyses detoxication and bioactivation processes in which glutathione conjugates are formed from endogenous and xenobiotic substrates, including alkylating agents and halogenated alkanes. Although the common null polymorphism of the human GSTT1 gene has been studied extensively, little is known about the consequences of GSTT1 single-nucleotide polymorphisms (SNPs). Here, we have examined the effects of two SNPs that alter amino acid residues in the dimer interface of the GST T1-1 protein and one that causes a conservative substitution in the core of the subunit. Variant proteins were expressed in an Escherichia coli strain in which the metabolism of ethylene dibromide to a glutathione conjugate leads to lacZ reversion mutations. We measured the kinetic properties of the enzymes with the characteristic substrate 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) and determined the specific activities with several other substrates. Circular dichroism spectroscopy was used to measure protein thermal denaturation profiles. Variant T104P, which has been reported as inactive, showed weak but detectable activity with each substrate. Variant R76S was expressed at lower levels and showed much-reduced thermal stability. The results are interpreted in the context of the three-dimensional structure of human GST T1-1. PMID- 21781955 TI - Oligomerization of plant FtsZ1 and FtsZ2 plastid division proteins. AB - FtsZ was identified in bacteria as the first protein to localize mid-cell prior to division and homologs have been found in many plant species. Bacterial studies demonstrated that FtsZ forms a ring structure that is dynamically exchanged with a soluble pool of FtsZ. Our previous work established that Arabidopsis FtsZ1 and FtsZ2-1 are capable of in vitro self-assembly into two distinct filament types, termed type-I and type-II and noted the presence of filament precursor molecules which prompted this investigation. Using a combination of electron microscopy, gel chromatography and native PAGE revealed that (i) prior to FtsZ assembly initiation the pool consists solely of dimers and (ii) during assembly of the Arabidopsis FtsZ type-II filaments the most common intermediate between the dimer and filament state is a tetramer. Three-dimensional reconstructions of the observed dimer and tetramer suggest these oligomeric forms may represent consecutive steps in type-II filament assembly and a mechanism is proposed, which is expanded to include FtsZ assembly into type-I filaments. Finally, the results permit a discussion of the oligomeric nature of the soluble pool in plants. PMID- 21781956 TI - Stoichiometry and thermodynamics of the interaction between the C-terminus of human 90kDa heat shock protein Hsp90 and the mitochondrial translocase of outer membrane Tom70. AB - A large majority of the 1000-1500 proteins in the mitochondria are encoded by the nuclear genome, and therefore, they are translated in the cytosol in the form and contain signals to enable the import of proteins into the organelle. The TOM complex is the major translocase of the outer membrane responsible for preprotein translocation. It consists of a general import pore complex and two membrane import receptors, Tom20 and Tom70. Tom70 contains a characteristic TPR domain, which is a docking site for the Hsp70 and Hsp90 chaperones. These chaperones are involved in protecting cytosolic preproteins from aggregation and then in delivering them to the TOM complex. Although highly significant, many aspects of the interaction between Tom70 and Hsp90 are still uncertain. Thus, we used biophysical tools to study the interaction between the C-terminal domain of Hsp90 (C-Hsp90), which contains the EEVD motif that binds to TPR domains, and the cytosolic fragment of Tom70. The results indicate a stoichiometry of binding of one monomer of Tom70 per dimer of C-Hsp90 with a K(D) of 360+/-30nM, and the stoichiometry and thermodynamic parameters obtained suggested that Tom70 presents a different mechanism of interaction with Hsp90 when compared with other TPR proteins investigated. PMID- 21781957 TI - Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract. AB - Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat GI tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the GI tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all GI tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the GI tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the GI tract. PMID- 21781958 TI - Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis. AB - The hypothalamic-pituitary-adrenal (HPA) axis is an important regulator of energy balance, immune function and the body's response to stress. Signaling networks governing the initial specification of corticotropes, a major component of this axis, are not fully understood. Loss of function studies indicate that Notch signaling may be necessary to repress premature differentiation of corticotropes and to promote proliferation of pituitary progenitors. To elucidate whether Notch signaling must be suppressed in order for corticotrope differentiation to proceed and whether Notch signaling is sufficient to promote corticotrope proliferation, we examined the effects of persistent Notch expression in Pomc lineage cells. We show that constitutive activation of the Notch cascade inhibits the differentiation of both corticotropes and melanotropes and results in the suppression of transcription factors required for Pomc expression. Furthermore, persistent Notch signaling traps cells in the intermediate lobe of the pituitary in a progenitor state, but has no effect on pituitary proliferation. Undifferentiated cells are eliminated in the first two postnatal weeks in these mice, resulting in a modest increase in CRH expression in the paraventricular nucleus, hypoplastic adrenal glands and decreased stress-induced corticosterone levels. Taken together, these findings show that Notch signaling is sufficient to prevent corticotrope and melanotrope differentiation, resulting in dysregulation of the HPA axis. PMID- 21781959 TI - Cell death and selective adhesion reorganize the dorsoventral boundary for zigzag patterning of Drosophila wing margin hairs. AB - Animal tissues and organs are comprised of several types of cells, which are often arranged in a well-ordered pattern. The posterior part of the Drosophila wing margin is covered with a double row of long hairs, which are equally and alternately derived from the dorsal and ventral sides of the wing, exhibiting a zigzag pattern in the lateral view. How this geometrically regular pattern is formed has not been fully understood. In this study, we show that this zigzag pattern is created by rearrangement of wing margin cells along the dorsoventral boundary flanked by the double row of hair cells during metamorphosis. This cell rearrangement is induced by selective apoptosis of wing margin cells that are spatially separated from hair cells. As a result of apoptosis, the remaining wing margin cells are rearranged in a well-ordered manner, which shapes corrugated lateral sides of both dorsal and ventral edges to interlock them for zigzag patterning. We further show that the corrugated topology of the wing edges is achieved by cell-type specific expression and localization of four kinds of NEPH1/nephrin family proteins through heterophilic adhesion between wing margin cells and hair cells. Homophilic E-cadherin adhesion is also required for attachment of the corrugated dorsoventral edges. Taken together, our results demonstrate that sequential coordination of apoptosis and epithelial architecture with selective adhesion creates the zigzag hair alignment. This may be a common mechanism for geometrically ordered repetitive packing of several types of cells in similarly patterned developmental fields such as the mammalian organ of Corti. PMID- 21781960 TI - The Drosophila larval visual system: high-resolution analysis of a simple visual neuropil. AB - The task of the visual system is to translate light into neuronal encoded information. This translation of photons into neuronal signals is achieved by photoreceptor neurons (PRs), specialized sensory neurons, located in the eye. Upon perception of light the PRs will send a signal to target neurons, which represent a first station of visual processing. Increasing complexity of visual processing stems from the number of distinct PR subtypes and their various types of target neurons that are contacted. The visual system of the fruit fly larva represents a simple visual system (larval optic neuropil, LON) that consists of 12 PRs falling into two classes: blue-senstive PRs expressing Rhodopsin 5 (Rh5) and green-sensitive PRs expressing Rhodopsin 6 (Rh6). These afferents contact a small number of target neurons, including optic lobe pioneers (OLPs) and lateral clock neurons (LNs). We combine the use of genetic markers to label both PR subtypes and the distinct, identifiable sets of target neurons with a serial EM reconstruction to generate a high-resolution map of the larval optic neuropil. We find that the larval optic neuropil shows a clear bipartite organization consisting of one domain innervated by PRs and one devoid of PR axons. The topology of PR projections, in particular the relationship between Rh5 and Rh6 afferents, is maintained from the nerve entering the brain to the axon terminals. The target neurons can be subdivided according to neurotransmitter or neuropeptide they use as well as the location within the brain. We further track the larval optic neuropil through development from first larval instar to its location in the adult brain as the accessory medulla. PMID- 21781961 TI - The Hippo pathway controls polar cell fate through Notch signaling during Drosophila oogenesis. AB - During Drosophila oogenesis, the somatic follicle cells form an epithelial layer surrounding the germline cells to form egg chambers. In this process, follicle cell precursors are specified into polar cells, stalk cells, and main-body follicle cells. Proper specification of these three cell types ensures correct egg chamber formation and polarization of the anterior-posterior axis of the germline cells. Multiple signaling cascades coordinate to control the follicle cell fate determination, including Notch, JAK/STAT, and Hedgehog signaling pathways. Here, we show that the Hippo pathway also participates in polar cell specification. Over-activation of yorkie (yki) leads to egg chamber fusion, possibly through attenuation of polar cell specification. Loss-of-function experiments using RNAi knockdown or generation of mutant clones by mitotic recombination demonstrates that reduction of yki expression promotes polar cell formation in a cell-autonomous manner. Consistently, polar cells mutant for hippo (hpo) or warts (wts) are not properly specified, leading to egg chamber fusion. Furthermore, Notch activity is increased in yki mutant cells and reduction of Notch activity suppresses polar cell formation in yki mutant clones. These results demonstrate that yki represses polar cell fate through Notch signaling. Collectively, our data reveal that the Hippo pathway controls polar cell specification. Through repressing Notch activity, Yki serves as a key repressor in specifying polar cells during Drosophila oogenesis. PMID- 21781962 TI - alpha1-Adrenergic drugs modulate differentiation and cell death of human erythroleukemia cells through non adrenergic mechanism. AB - Preliminary data showed that alpha1-adrenergic antagonists induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells. To test the hypothesis whether survival and differentiation of erythroleukemia cells are under control of alpha1-adrenergic signalling, we examined alpha1 adrenoceptor expression of erythroleukemia cells and compared the in vitro effects of alpha-adrenergic antagonists with those of agonists. We discovered that alpha1-adrenergic agonists suppress both erythroid differentiation and growth of erythroleukemia cells concomitant with lipofuscin accumulation, autophagy and necrotic cell death. alpha1-adrenergic agonists also inhibit the in vitro growth of physiologic hematopoietic progenitors obtained from umbilical cord blood with high selectivity for the erythroid lineage. Interestingly, the observed effects could not be related to alpha1-adrenoceptors, even though agonists and antagonists displayed opposing effects regarding cellular growth and differentiation of erythroleukemia cells. Our data suggest that the effects of alpha1-adrenergic drugs are related to a non-adrenoceptor binding site, controlling the fate of erythroid progenitor cells towards differentiation and cell death. Since the observed effects are not mediated through adrenoceptors, the physiologic relevance of our data remains unclear, so far. Nevertheless, the identification of the still unknown binding site(s) might disclose new insights into regulation of erythroid differentiation and cell death. PMID- 21781964 TI - Transcription of long hypothetical orfs in Trypanosoma cruzi: the epimastigote stage uses trans-splicing sites that generate short 5' UTRs. AB - We mapped the 5' UTR for five long hypothetical orfs from Trypanosoma cruzi; each one having a length of more than 10,000 bp. Our aim was to verify the constraints to the length of the 5' UTR and to identify the sites of alternative trans splicing in the epimastigote stage of three T. cruzi strains. We used reverse transcription PCR to amplify the 5' UTR and demonstrated the transcription of all selected genes as well as additional trans-splicing sites in two of these genes. We observed that the length of the 5' UTR in these genes has a limit, in contrast to previous reports that indicated a trend for longer genes to display a proportionally long 5' UTR. The maximum length of the 5' UTR for the long genes analyzed in the present work is approximately 3% of the orf and, on average, is 1% of the orf length. The poly-pyrimidine tracts used as trans-splicing signal are in the range of 17-53 bases within a distance of 6-59 nt to first spliced leader acceptor site. T. cruzi populations may use both signals differentially. We conclude that the limit for the 5' UTR length in long genes is determined primarily by the distance to neighboring genes. PMID- 21781963 TI - RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals. PMID- 21781965 TI - Enzymes of the ornithine-glutamate-proline pathway in the sheep abomasal nematode parasites Haemonchus contortus and Teladorsagia circumcincta. AB - A fully functional ornithine-glutamate-proline pathway was detected in L3 and adult Haemonchus contortus and Teladorsagia circumcincta, making the parasites capable of interconversion of these amino acids. Ornithine aminotransferase (OAT) (E.C. 2.6.1.13) was a reversible pyridoxal-5-phosphate (PLP)-dependent enzyme with an optimum pH 8.5. Hydroxylamine completely inhibited OAT activity in both parasites. For all five enzymes, substrate affinity was similar for each species and life cycle stage, the notable exceptions being the nearly 10-fold lower affinity for Delta(1)-pyrroline-5-carboxylate (P5C) of P5C reductase (E.C. 1.5.1.2) in adult T. circumcincta and about half for P5C for L3 H. contortus P5C dehydrogenase (E.C. 1.5.1.12). P5C synthase (E.C. 1.2.1.41) activity was similar with either NADPH or NADH as co-factor. Proline oxidase (E.C. 1.5.99.8) was a co factor independent enzyme with an optimal pH 8.5. Despite similarities to those in the host, enzymes of this pathway may still be useful as control targets if they differ antigenically, as a supply of proline is necessary for cuticle formation. PMID- 21781966 TI - Functional analysis of metal tolerance proteins isolated from Zn/Cd hyperaccumulating ecotype and non-hyperaccumulating ecotype of Sedum alfredii Hance. AB - The Zn/Cd hyperaccumulating ecotype (HE) of Sedum alfredii Hance can accumulate 24- and 28-fold higher leaf and stem Zn concentrations when compared with the non hyperaccumulating ecotype (NHE) of Sedum. Heterologous expression of a metal tolerance protein (MTP1) encoding gene from HE plants (SaMTP1) or the homologous gene from NHE plants (SnMTP1) suppressed Zn(2+) hypersensitivity in the Deltazrc1 yeast mutant. In plants, SaMTP1 localized to the tonoplast. Furthermore, MTP1 transcript level in the shoot of HE plants was more than 80-fold higher than that of NHE plants. The transcript level of SaMTP1 in shoot was up-regulated 1-fold by Zn(2+) while the expression of SnMTP1 was slightly inhibited. These data suggest that SaMTP1 can play an important role in Zn accumulation in HE plants. PMID- 21781968 TI - The evolution of the adipose tissue: a neglected enigma. AB - The complexity of the anatomical distribution and functions of adipose tissue (AT) has been rarely analyzed in an evolutionary perspective. From yeast to man lipid droplets are stored mainly in the form of triglycerides in order to provide energy during periods when energy demands exceed caloric intake. This simple scenario is in agreement with the recent discovery of a highly conserved family of proteins for fat storage in both unicellular and multicellular organisms. However, the evolutionary history of organs such as the fat body in insects, playing a role in immunity and other functions besides energy storage and thermal insulation, and of differently distributed subtypes of AT in vertebrates is much less clear. These topics still await a systematic investigation using up-to-date technologies and approaches that would provide information useful for understanding the role of different AT subtypes in normal/physiological conditions or in metabolic pathologies of humans. PMID- 21781967 TI - MicroRNA-19b downregulates insulin 1 through targeting transcription factor NeuroD1. AB - MiR-17-92 cluster miRNAs are disclosed to contribute to the development of multiple organs and tumorigenesis, but their roles in pancreas development remains unclear. In this study, we found that miR-19b, a member of miR-17-92, was highly expressed in the pancreatic progenitor cells, and miR-19b could target the 3' UTR of NeuroD1 mRNA to decrease its protein and mRNA levels. Functional analysis showed that miR-19b exerted little effect on the proliferation of pancreatic progenitors, whereas it inhibited the expression of insulin 1, but not insulin 2 in MIN6 cells. These results suggest that miR-19b can downregulate insulin 1 expression through targeting transcription factor NeuroD1, and thus regulate the differentiation and function of beta-cells. PMID- 21781969 TI - Variation in the reproductive potential of Schistocephalus infected male sticklebacks is associated with 11-ketotestosterone titre. AB - Parasites can impact host reproduction by interfering with host endocrine systems, but the adaptive nature of such effects is disputed. Schistocephalus solidus plerocercoids are parasites of three-spined sticklebacks Gasterosteus aculeatus that are often associated with impaired host reproduction. Here, we relate reproductive behavior and physiology to levels of the androgen 11 ketotestosterone (11KT) in naturally infected and non-infected male sticklebacks from two UK populations. In one population infected males harbored heavy infections and showed uniformly reduced 11KT titres and kidney spiggin (nesting glue protein) content compared to non-infected fish. However in a second population infection levels were more variable and males with smaller infections recorded 11KT and spiggin titres that overlapped those of non-infected fish; among infected males from this population 11KT and kidney spiggin also both correlated negatively with infection severity. Male reproductive behavior correlated closely with 11KT titre in both populations, and infected males with high 11KT levels exhibited normal reproductive behavior. Our results suggest that Schistocephalus infection per se does not block reproductive development in male sticklebacks, and that some male fish may have the ability to breed whilst infected. Our results are not consistent with the hypothesis that Schistocephalus adaptively castrates male hosts via endocrine disruption; rather they support the hypothesis that reproductive disruption is a side effect of the energetic costs of infection. PMID- 21781970 TI - Multiplex measurement of proinflammatory cytokines in human serum: comparison of the Meso Scale Discovery electrochemiluminescence assay and the Cytometric Bead Array. AB - Serum cytokine profiling is a powerful tool to link host immune defense with disease pathogenesis. Although several multiplex assays are commercially available, none has been rigorously validated in the context of chronic infectious disease (such as HIV infection). Here we compared the measurement of proinflammatory cytokines by two multiplex platforms: the Meso Scale Discovery (MSD) electrochemiluminescence assay and the Becton Dickinson Cytometric Bead Array (CBA) flow cytometric assay, using serum samples from HIV-infected and uninfected donors. We evaluated the ability of these assays to: a) quantify circulating levels of native cytokines (IL-6, IL-8, IL-10, TNF-alpha, IL-12p70, IL-1beta), and b) accurately recover known amounts of recombinant cytokines added to serum samples. Based on the standard curves, the sensitivity of the MSD system was only slightly better than the CBA. However, in serum the MSD platform consistently quantified levels of endogenous IL-12p70, TNF-alpha, and IL-10 that were undetectable by the CBA assay. The MSD assay was also more accurate as determined by an enhanced capacity to recover known concentrations of recombinant cytokines added to serum. Both assays performed equally well in quantifying IL-6 and IL-8, while neither assay quantified IL-1beta with accuracy and precision. Interestingly, HIV infection did not affect the performance of either assay. Overall, the MSD assay provided a more reliable assessment of the proinflammatory cytokines tested in the serum of healthy and HIV-infected individuals. PMID- 21781971 TI - The new violet laser dye, Krome Orange, allows an optimal polychromatic immunophenotyping based on CD45-KO gating. AB - BACKGROUND: Polychromatic immunophenotyping improves characterization of leukocyte subpopulations and their malignant counterparts. However, the lack of various fluorochrome-labeled monoclonal antibodies (MoAbs) hinders the formation of multi-color panels. CD45 appears to be an important MoAb for immunophenotyping of these cells. Plotted against the side scatter, CD45 provides immunological cell differentiation and the ability to recognize various normal and malignant leukocyte subpopulations. CD45 is commonly used and labeled with various fluorochromes and as a result, is incorporated in multi-color panels as a conjugate of less available fluorochromes, such as the violet laser dyes. However, these dyes (e.g. Pacific Orange/PO) often possess low fluorescence intensity, which may be too weak to differentiate between populations. The new organic dye Krome Orange (KO, emission at 528 nm) appears to be a more intense violet laser dye, serving as an alternative to PO. METHODS: Intensities of CD45 conjugated with FITC, PE, ECD, PE-Cy5, PE-Cy7, PO and KO were tested in different cell sources. Various lineage markers were sequentially back gated on CD45-KO to identify subpopulations. A 10-color MoAb panel for determination of aberrancies in small cell samples was composed to test specificity of CD45-KO. CONCLUSIONS: We showed in various fixed and unfixed cells from different sources that KO is a suitable fluorochrome with a significantly higher quantum yield than PO and is even brighter than other violet laser dyes (e.g. Pacific Blue). CD45-KO/SS enables us to distinguish and characterize various normal and malignant leukocyte subpopulations. By using a 10-color MoAb panel to screen on aberrancies, we showed that CD45-KO provides reliable immunophenotyping within small amounts of cells and thereby improves the quality of 10-color stainings. PMID- 21781972 TI - Rapid assessment of in vitro expanded human regulatory T cell function. AB - Human regulatory T cells (Treg) are able to actively suppress autoreactive immune responses. Phenotypically, they are broadly characterized as CD4+, CD25+, CD127(lo/-) and FoxP3+. CD45RA can be used to further differentiate the population into naive (CD45RA(+)) and induced (CD45RA-) Treg. The functional potential of Treg is routinely determined by assessing their ability to suppress T cell function in 3-5day proliferation assays. Since Treg are being explored for therapeutic use, a short-term functional assay could serve as a valuable tool for evaluating the potency of Treg. Therefore, an assay designed to measure Treg suppression of activation marker expression by responder T cells in 7 to 20h has been examined in this report. Using flow cytometry, expression of CD69 and CD154 on T cells, in response to stimulation with CD3/CD28 beads, was used as a measure of activation in the assay. Treg from healthy volunteers were sorted as CD4+CD25+CD127(lo/-)CD45RA+ cells with a BD FACSAriaTM II. The highly purified Treg were then expanded in vitro and their function was assessed in short term activation marker suppression assays using autologous PBMC as responder cells. The data suggest that this short term suppression assay could be a reliable surrogate for assessing Treg functional potential. PMID- 21781973 TI - PET imaging of cardiac hypoxia: opportunities and challenges. AB - Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at sub-pharmacological (>=pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically. PMID- 21781975 TI - Prediction of beta-turn types in protein by using composite vector. AB - Protein secondary structure prediction is an intermediate step in the overall process of tertiary structure prediction. beta-turns are important components of the secondary structure of a protein. Development of an accurate method of prediction of beta-turn types would be helpful for predicting the overall tertiary structure of proteins. In this work, we constructed a database of 2805 protein chains. Our work improved the previous input parameters and used the support vector machine algorithm to predict the beta-turn types; we obtained the overall prediction accuracy of 98.1%, 96.0%, 96.1%, 98.7%, 99.1%, 86.8%, 99.2% and 73.2% with the Matthews Correlation Coefficient values of 0.398, 0.460, 0.043, 0.463, 0.355, 0.172, 0.109 and 0.247, respectively, for types I, II, VIII, I', II', IV, VI and non-beta-turn, respectively. In addition, we also used same method to predict the beta-turn types in three databases of 426, 547 and 823 protein chains and found that our prediction results were better than other predictions. PMID- 21781974 TI - A crystallographic study of the role of sequence context in thymine glycol bypass by a replicative DNA polymerase serendipitously sheds light on the exonuclease complex. AB - Thymine glycol (Tg) is the most common oxidation product of thymine and is known to be a strong block to replicative DNA polymerases. A previously solved structure of the bacteriophage RB69 DNA polymerase (RB69 gp43) in complex with Tg in the sequence context 5'-G-Tg-G shed light on how Tg blocks primer elongation: The protruding methyl group of the oxidized thymine displaces the adjacent 5'-G, which can no longer serve as a template for primer elongation [Aller, P., Rould, M. A., Hogg, M, Wallace, S. S. & Doublie S. (2007). A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol. Proc. Natl. Acad. Sci. USA, 104, 814-818.]. Several studies showed that in the sequence context 5'-C-Tg-purine, Tg is more likely to be bypassed by Klenow fragment, an A-family DNA polymerase. We set out to investigate the role of sequence context in Tg bypass in a B-family polymerase and to solve the crystal structures of the bacteriophage RB69 DNA polymerase in complex with Tg-containing DNA in the three remaining sequence contexts: 5'-A-Tg G, 5'-T-Tg-G, and 5'-C-Tg-G. A combination of several factors-including the associated exonuclease activity, the nature of the 3' and 5' bases surrounding Tg, and the cis-trans interconversion of Tg-influences Tg bypass. We also visualized for the first time the structure of a well-ordered exonuclease complex, allowing us to identify and confirm the role of key residues (Phe123, Met256, and Tyr257) in strand separation and in the stabilization of the primer strand in the exonuclease site. PMID- 21781976 TI - Models of neurovascular coupling via potassium and EET signalling. AB - Functional hyperemia is an important metabolic autoregulation mechanism by which increased neuronal activity is matched by a rapid and regional increase in blood supply. This mechanism is facilitated by a process known as "neurovascular coupling"--the orchestrated communication system involving neurons, astrocytes and arterioles. Important steps in this process are the production of EETs in the astrocyte and the release of potassium, via two potassium channels (BK and KIR), into the perivascular space. We provide a model which successfully accounts for several observations seen in experiment. The model is capable of simulating the approximate 15% arteriolar dilation caused by a 60-s neuronal activation (modelled as a release of potassium and glutamate into the synaptic cleft). This model also successfully emulates the paradoxical experimental finding that vasoconstriction follows vasodilation when the astrocytic calcium concentration (or perivascular potassium concentration) is increased further. We suggest that the interaction of the changing smooth muscle cell membrane potential and the changing potassium-dependent resting potential of the KIR channel are responsible for this effect. Finally, we demonstrate that a well-controlled mechanism of potassium buffering is potentially important for successful neurovascular coupling. PMID- 21781977 TI - 3D current-voltage-time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study. AB - The number of mathematical models of cardiac cellular excitability is rapidly growing, and compact graphical representations of their properties can make new acquisitions available for a broader range of scientists in cardiac field. Particularly, the intrinsic over-determination of the model equations systems when fitted only to action potential (AP) waveform and the fact that they are frequently tuned on data covering only a relatively narrow range of dynamic conditions, often lead modellers to compare very similar AP profiles, which underlie though quite different excitable properties. In this study I discuss a novel compact 3D representation of the cardiac cellular AP, where the third dimension represents the instantaneous current-voltage profile of the membrane, measured as repolarization proceeds. Measurements of this type have been used previously for in vivo experiments, and are adopted here iteratively at a very high time, voltage, current-resolution on (i) the same human ventricular model, endowed with two different parameters sets which generate the same AP waveform, and on (ii) three different models of the same human ventricular cell type. In these 3D representations, the AP waveforms lie at the intersection between instantaneous time-voltage-current surfaces and the zero-current plane. Different surfaces can share the same intersection and therefore the same AP; in these cases, the morphology of the current surface provides a compact view of important differences within corresponding repolarization dynamics. Refractory period, supernormal excitability window, and extent of repolarization reserve can be visualized at once. Two pivotal dynamical properties can be precisely assessed, i.e. all-or-nothing repolarization window and membrane resistance during recovery. I discuss differences in these properties among the membranes under study, and show relevant implications for cardiac cellular repolarization. PMID- 21781978 TI - Kainate postconditioning restores LTP in ischemic hippocampal CA1: onset dependent second pathophysiological stress. AB - Postconditioning can be induced by a broad range of stimuli within minutes to days after an ischemic cerebral insult. A special form is elicited by pharmacological intervention called second pathophysiological stress. The present study aimed to evaluate the effects of low-dose (5 mg/kg) kainate postconditioning with onsets 0, 24 and 48 h after the ischemic insult on the hippocampal synaptic plasticity in a 2-vessel occlusion model in rat. The hippocampal function was tested by LTP measurements of Schaffer collateral-CA1 pyramidal cell synapses in acute slices and the changes in density of Golgi-Cox stained apical dendritic spines. Postconditioning 0 and 24 h after ischemia was not protective, whereas 48-h-onset postconditioning resulted in the reappearance of a normal spine density (>100,000 spines) 3 days after ischemia, in parallel with the long-term restoration of the damaged LTP function. Similar, but somewhat less effects were observed after 10 days. Our data clearly demonstrate the onset dependence of postconditioning elicited by a subconvulsant dose of kainate treatment in global ischemia, with restoration of the structural plasticity and hippocampal function. PMID- 21781979 TI - Role of superior laryngeal nerve and Fos staining following dehydration and rehydration in the rat. AB - Immunohistochemistry for Fos was used to determine the role of the superior laryngeal nerve in conscious rats following water deprivation and rehydration. Adult male rats were subjected to either unilateral superior laryngeal nerve section (SLNX) or sham surgery. Two weeks later rats from each surgical group were water deprived for 48 h or water deprived for 46 h and given access to water for 2 h prior to perfusion. Controls were allowed ad libitum access to water. Brains were processed for Fos using a commercially available antibody. Changes in plasma osmolality and hematocrit were not significantly different between SLNX and sham following any of the treatments. Water intake in rats was not significantly affected by SLNX. In the supraoptic nucleus (SON) of sham rats, water deprivation significantly increased Fos staining while water intake following dehydration prevented this increase. Water deprivation significantly increased Fos staining in the SON of SLNX rats. Following water intake after 46 h water deprivation in SLNX rats, Fos staining in the ipsilateral SON was significantly greater than the contralateral SON and significantly lower than 48 h water deprivation. In the nucleus of the solitary tract (NTS) of sham rats, both water deprivation and water intake produced significant increases in Fos staining bilaterally compared to euhydrated controls. In SLNX rats, water deprivation significantly increased Fos in both ipsilateral and contralateral NTS that was not different from sham rats. SLNX significantly decreased Fos staining in the ipsilateral NTS of rats given access to water after dehydration compared to the corresponding sham treated rats. Fos staining was not affected in the contralateral NTS of SLNX rats given access to water after dehydration. This suggests that the superior laryngeal nerve contributes to changes in Fos staining in the NTS and SON following water intake in dehydrated rats. PMID- 21781980 TI - Efficacy of fasting calorie restriction on quality of life among aging men. AB - Calorie restriction (CR) has been promoted to increase longevity. Previous studies have indicated that CR can negatively affect mood and therefore the effect of CR on mood and quality of life (QOL) becomes crucial when considering the feasibility of CR in humans. We conducted a three month clinical trial on CR (reduction of 300 to 500 kcal/day) combined with two days/week of Muslim sunnah fasting (FCR) to determine the effectiveness of FCR on QOL among aging men in Klang Valley, Malaysia. A total of 25 healthy Malay men (age 58.8+/-5.1 years), with no chronic diseases and a BMI of 23.0 to 29.9 kg/m2 were randomized to FCR (n=12) and control (n=13) groups. Body composition measurements and QOL questionnaires were ascertained at baseline, week 6 and week 12. QOL was measured using the Short-Form 36, sleep quality was determined using the Pittsburgh Sleep Quality Index, the Beck Depression Inventory II was used to measure mood and the Perceived Stress Scale was used to measure depression. The FCR group had a significant reduction in body weight, BMI, body fat percentage and depression (P<0.05). The energy component of QOL was significantly increased in FCR group (p<0.05). There were no significant changes in sleep quality and stress level between the groups as a result of the intervention. In conclusion, FCR resulted in body weight and fat loss and alleviated depression with some improvement in the QOL in our study and has the potential to be implemented on a wider scale. PMID- 21781981 TI - Serum amylase in bulimia nervosa and purging disorder: differentiating the association with binge eating versus purging behavior. AB - OBJECTIVE: Elevated serum amylase levels in bulimia nervosa (BN), associated with increased salivary gland size and self-induced vomiting in some patients, provide a possible marker of symptom severity. The goal of this study was to assess whether serum hyperamylasemia in BN is more closely associated with binge eating episodes involving consumption of large amounts of food or with purging behavior. METHOD: Participants included women with BN (n=26); women with "purging disorder" (PD), a subtype of EDNOS characterized by recurrent purging in the absence of objectively large binge eating episodes (n=14); and healthy non-eating disorder female controls (n=32). There were no significant differences in age or body mass index (BMI) across groups. The clinical groups reported similar frequency of self induced vomiting behavior and were free of psychotropic medications. Serum samples were obtained after overnight fast and were assayed for alpha-amylase by enzymatic method. RESULTS: Serum amylase levels were significantly elevated in BN (60.7+/-25.4 international units [IU]/liter, mean+/-sd) in comparison to PD (44.7+/-17.1 IU/L, p<.02) and to Controls (49.3+/-15.8, p<.05). CONCLUSION: These findings provide evidence to suggest that it is recurrent binge eating involving large amounts of food, rather than self-induced vomiting, which contributes to elevated serum amylase values in BN. PMID- 21781982 TI - Mineral intake independent from gastric irritation or pica by cell-dehydrated rats. AB - Gavage of 2 M NaCl (IG 2 M NaCl), a procedure to induce cell-dehydration-and water and 0.15 M NaCl intake in a two-bottle choice test-is also a potential gastric irritant. In this study, we assessed whether mineral intake induced by IG 2 M NaCl is associated with gastric irritation or production of pica in the rat. We first determined the amount of mineral solution (0.15 M NaCl, 0.15 M NaHCO3, 0.01 M KCl and 0.05 mM CaCl2) and water ingested in response to IG 2 M NaCl in a five-bottle test. Then, we used mineral solutions (0.01 M KCl and 0.15 M NaHCO3), whose intakes were significantly increased compared to controls, and water in three-bottle tests to test the gastric irritation hypothesis. The IG 2 M NaCl induced KCl and NaHCO3 intake that was not inhibited by gavage with gastric protectors Al(OH)3 or NaHCO3. IG 2 M NaCl or gavage of 0.6 N acetic acid induced mild irritation, hyperemia, of the glandular part of the stomach. A gavage of 50% ethanol induced strong irritation seen as pinpoint ulcerations. Neither ethanol nor acetic acid induced any fluid intake. Neither IG 2 M NaCl nor acetic acid induced kaolin intake, a marker of pica in laboratory rats. Ethanol did induce kaolin intake. These results suggest that IG 2 M NaCl induced a mineral fluid intake not selective for sodium and independent from gastric irritation or pica. PMID- 21781983 TI - Adoption of preventive measures during and after the 2009 influenza A (H1N1) virus pandemic peak in Spain. AB - OBJECTIVE: This study describes the preventive measures adopted by the Spanish population towards 2009 influenza A (H1N1) virus and their associated factors. METHOD: An anonymous computer-assisted telephone interview survey was conducted in Spain in December 2009 and February 2010. Respondents were asked about their perceptions of influenza A (H1N1) virus and the preventive measures adopted. Factors associated with the adoption of preventive measures were assessed by logistic regression analyses. RESULTS: Out of 4892 households approached, 1627 valid responses were obtained (response rate of 33.3%). The most commonly adopted preventive measures were respiratory hygiene and hand washing. Factors independently associated with the adoption of the preventive measures recommended by the Spanish Ministry of Health were female gender, higher educational level, size of municipality of residence >50,000 inhabitants, high perceived susceptibility to infection, high perceived effectiveness of the measures and high perceived usefulness of the information provided by the government. The presence of school-aged children in household was associated with purchasing masks and hand sanitizer. CONCLUSION: In addition to demographic factors, modifiable factors such as personal beliefs and expectations play a role in the adoption of preventive measures. PMID- 21781984 TI - Teleost fish interferons and their role in immunity. AB - Interferons (IFNs) are the hallmark of the vertebrate antiviral system. Two of the three IFN families identified in higher vertebrates are now known to be important for antiviral defence in teleost fish. Based on the cysteine patterns, the fish type I IFN family can be divided into two subfamilies, which possibly interact with distinct receptors for signalling. The fish type II IFN family consists of two members, IFN-gamma with similar functions to mammalian IFN-gamma and a teleost specific IFN-gamma related (IFN-gammarel) molecule whose functions are not fully elucidated. These two type II IFNs also appear to bind to distinct receptors to exert their functions. It has become clear that fish IFN responses are mediated by the host pattern recognition receptors and an array of transcription factors including the IFN regulatory factors, the Jak/Stat proteins and the suppressor of cytokine signalling (SOCS) molecules. PMID- 21781985 TI - Assessment of neurotoxicity of monocrotaline, an alkaloid extracted from Crotalaria retusa in astrocyte/neuron co-culture system. AB - Studies have shown cases of poisoning with plants from the genus Crotalaria (Leguminosae) mainly in animals. They induce damages in the central nervous system (CNS), which has been attributed to toxic effects of the pyrrolizidine alkaloid (PA) monocrotaline (MCT). Previously we demonstrated that both MCT and dehydromonocrotaline (DHMC), its main active metabolite, induce changes in the levels and patterns of expression of the main protein from astrocyte cytoskeleton, glial fibrillary acidic protein (GFAP). In this study we investigated the effect of MCT on rat cortical astrocyte/neuron primary co cultures. Primary cultures were exposed to 10 or 100 MUM MCT. The MTT test and the measurement of LDH activity on the culture medium revealed that after 24h exposure MCT was not cytotoxic to neuron/astrocyte cells. However, the cell viability after 72 h treatment decreased in 10-20%, and the LDH levels in the culture medium increased at a rate of 12% and 23%, in cultures exposed to 10 or 100 MUM MCT. Rosenfeld staining showed vacuolization and increase in cell body in astrocytes after MCT exposure. Immunocytochemistry and Western blot analyses revealed changes on pattern of GFAP and betaIII-tubulin expression and steady state levels after MCT treatment, with a dose and time dependent intense down regulation and depolarization of neuronal betaIII-tubulin. Moreover, treatment with 100 MUM MCT for 12h induced GSH depletion, which was not seen when cytochrome P450 enzyme system was inhibited indicating that it is involved in MCT induced cytotoxicity in CNS cells. PMID- 21781986 TI - Diagnostic performance of T-SPOT.TB for extrapulmonary tuberculosis according to the site of infection. AB - BACKGROUND: The clinical manifestations of extrapulmonary tuberculosis (E-TB) vary according to site of disease, so we tested the hypothesis that IFN-gamma producing T-cell responses also vary in parallel. Therefore we conducted a prospective, blinded, observational study to evaluate the diagnostic performance of blood T-SPOT.TB according to the various sites of E-TB. METHODS: From April 2008 to August 2010, all patients with suspected E-TB were enrolled at a tertiary hospital in an intermediate TB-burden country. Final diagnosis in patients with suspected E-TB was classified by clinical category. RESULTS: A total of 368 patients with suspected E-TB were enrolled; 196 (53%) were classified as having TB, including 119 (32%) with confirmed TB, 34 (9%) probable TB, and 43 (12%) possible TB; the remaining 172 (47%) were classified as not having TB. After excluding patients with possible TB, the T-SPOT.TB was more sensitive in patients with chronic forms of E-TB such as lymph node or osteoarticular TB (93%, 95% CI 83%-97%) than in patients with acute forms of E-TB such as TB meningitis or miliary TB (79%, 95% CI 66%-87%, P = 0.03). CONCLUSIONS: The diagnostic performance of the blood T-SPOT.TB differs among patients with various clinical manifestations of E-TB. PMID- 21781987 TI - Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza. AB - AIM: Explore the role of viral factors and immune response in patients with severe pandemic pdmH1N1 illness without significant co-morbidity. MATERIALS: Seven patients with pdmH1N1 influenza, bilateral chest X-rays infiltrates, requiring mechanical ventilator support were consecutively recruited. Seven age- and gender-matched healthy individuals served as controls. RESULTS: Four patients were viremic, two with the mutant D222G/N pdmH1N1.Microarray analyses of peripheral blood leukocytes suggested a marked granulocytes activation, but no up regulation of inflammatory cytokine mRNA. Patients with severe pdmH1NI had a marked systemic complement activation, and in contrast to the lack of cytokine mRNA up-regulation in blood leukocytes, plasma levels of a broad range of inflammatory mediators, including IP-10, and mediators involved in pulmonary remodelling were markedly elevated. Patients with mutant virus had particularly high IP-10 levels, and the most pronounced complement activation. CONCLUSIONS: In severe pdmH1N1, viremia was common and the D222G/N mutant was found in half of the viremic patients. Host immune response was characterized by strong activation of the innate immune system, including complement and granulocytes activation, increased serum levels of inflammation and pulmonary remodelling markers, possibly contributing to the observed tissue damage. However, few patients were included and further studies are needed to characterize the immune response in severe pdmH1N1 infection. PMID- 21781988 TI - Real-time profiling of NK cell killing of human astrocytes using xCELLigence technology. AB - We have conducted the first profiling of human Natural Killer (NK) cell mediated killing of astrocytes using xCELLigence technology. The sensitivity and applicability of xCELLigence was compared to lactate dehydrogenase (LDH) release and time-lapsed microscopy to validate the killing events. The xCELLigence technology uses electrical impedance measurements from adherent cells and converts into Cell Index (CI). NK cells did not register any Cell Index signal directly, therefore all changes in Cell Index are a direct measure of astrocyte responses. Astrocytes are insensitive to basal NK cells (non-activated NKs). Whereas NK cells activated by IL-2 prior to culture with targets rapidly kill astrocytes. This observation was supported by all methods of analysis. Using the xCELLigence we were able to monitor the longer term killing profile. This demonstrated that at all NK ratios, death was achieved if given long enough. In addition, the development of the killing phenotype was investigated by inducing lymphokine activated killing with IL-2 in the presence of the target astrocytes. In this paradigm of killing, the xCELLigence was the only assay suitable due to the prolonged time-course required for killing, which required 4-5 days to achieve maximal killing (100%). This suggested that the astrocytes can directly suppress the killing activity of the NK cells. These data highlight the sensitivity, applicability and profiling power of the xCELLigence system and support its use for further investigation of NK-killing of healthy and/or tumourogenic astrocytic cells. PMID- 21781989 TI - Development of a portable, high throughput biosensor system for rapid plant virus detection. AB - Biosensors based on living cells are characterized by high sensitivity, selectivity and rapid response times. A novel portable cell biosensor system for the detection of plant viruses, based on immobilized 'Vero' cells carrying on their membrane virus specific antibodies was developed and was designated as High Throughput Bioelectric Recognition Assay (BERA-HTP). BERA-HTP was tested for the detection of purified Potato virus Y (PVY), Cucumber mosaic virus (CMV) and Tobacco rattle virus (TRV) and of CMV and TRV in single, as well as in mixed infections in two different plant host species. The sensor was based on live, mammalian cells, the membrane of which has been artificially saturated with antibodies specific to different plant viruses. The attachment of PVY, CMV or TRV viral particles to the homologous electroinserted antibodies caused a virus specific change of the cell membrane electric potential that was not observed with virus-free samples or with heterologous viruses. Fluorescence microscopy observations showed that attachment of virus particles to the cell membrane bearing the homologous antibody, was associated with a decrease of [Ca(2+)]cyt. The perspective for the development of BERA-HTP as a portable, reliable and rapid (duration of assay for 96 samples: ~70 min) detection method of plant viruses in the field is discussed. PMID- 21781990 TI - Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signaling events. AB - Neutrophils are the most abundant leukocyte and have a short lifespan, dying by apoptosis approximately five days after leaving the bone marrow. Their apoptosis can be delayed at sites of inflammation to extend their functional lifespan, but inappropriate inhibition of apoptosis contributes to chronic inflammatory disease. Levels of the physiological iron chelator lactoferrin are raised at sites of inflammation and we have shown previously that iron-unsaturated lactoferrin inhibited human neutrophil apoptosis, but the mechanisms involved were not determined. Here we report that the anti-apoptotic effect of lactoferrin is dependent upon its iron saturation status as iron-saturated lactoferrin did not affect neutrophil apoptosis. We also show that the effect of lactoferrin is mediated at an early stage in apoptosis as it inhibited activation of sphingomyelinase, generation of ceramide, activation of caspase 8 and Bax and cleavage of Bid. Lactoferrin did not inhibit apoptosis induced by exogenous ceramide, supporting the proposal that it acts upstream of ceramide generation. We therefore conclude that raised lactoferrin levels are likely to contribute to chronic inflammation by delaying neutrophil apoptosis and that this is achieved by inhibiting proximal apoptotic signaling events. PMID- 21781991 TI - The N-end rule pathway: from recognition by N-recognins, to destruction by AAA+proteases. AB - Intracellular proteolysis is a tightly regulated process responsible for the targeted removal of unwanted or damaged proteins. The non-lysosomal removal of these proteins is performed by processive enzymes, which belong to the AAA+superfamily, such as the 26S proteasome and Clp proteases. One important protein degradation pathway, that is common to both prokaryotes and eukaryotes, is the N-end rule. In this pathway, proteins bearing a destabilizing amino acid residue at their N-terminus are degraded either by the ClpAP protease in bacteria, such as Escherichia coli or by the ubiquitin proteasome system in the eukaryotic cytoplasm. A suite of enzymes and other molecular components are also required for the successful generation, recognition and delivery of N-end rule substrates to their cognate proteases. In this review we examine the similarities and differences in the N-end rule pathway of bacterial and eukaryotic systems, focusing on the molecular determinants of this pathway. PMID- 21781992 TI - Recent advances in p97/VCP/Cdc48 cellular functions. AB - p97/VCP/Cdc48 is one of the best-characterized type II AAA (ATPases associated with diverse cellular activities) ATPases. p97 is suggested to be a ubiquitin selective chaperone and its key function is to disassemble protein complexes. p97 is involved in a wide variety of cellular activities. Recently, novel functions, namely autophagy and mitochondrial quality control, for p97 have been uncovered. p97 was identified as a causative factor for inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) and more recently as a causative factor for amyotrophic lateral sclerosis (ALS). In this review, we will summarize and discuss recent progress and topics in p97 functions and the relationship to its associated diseases. PMID- 21781993 TI - Ensemble neural activity of the frontal cortical basal ganglia system predicts reaction time task performance in rats. AB - The question pursued in this study was when neural activity appears in the cortico-basal ganglia system that could predict alternate behavioral responses in a reaction time (RT) task. In this protocol, rats first performed a nose poke to initiate a trial, depressed a lever when presented, and then released the lever after a tone cue. Multiple-channel, single-unit recordings (up to 62 units) were obtained simultaneously from the prefrontal cortex, the dorsal medial striatum, the globus pallidus, and the substantia nigra pars reticulata in a single rat during a session. Results indicated that (1) global alterations of neural activity appeared in clusters, which was associated with different behavioral components and observed in each of the targeted areas; (2) small independent subsets of neurons responded differently between error (lever was released before tone presentation) and correct trials (lever was released within 0.5s after tone onset) during these behavioral episodes; (3) significant correlations between RTs and single units activities were found in the early preparation phases of the task. The results reveal that complex early preparatory activity exists several seconds before the final movements in a RT task, which may determine executive functions leading to rapid decoding of alternate behavioral performances. PMID- 21781994 TI - Molecular targeting of atherosclerotic plaques by a stabilin-2-specific peptide ligand. AB - Many cells, including macrophages, accumulate in atherosclerotic lesions, destabilizing plaques and driving plaque disruption. Therefore, macrophages serve as useful targets for atherosclerosis treatment and imaging. Stabilin-2 is a transmembrane protein expressed predominantly in macrophages and endothelial cells. In the present study, we found that stabilin-2 was widely expressed in atherosclerotic plaques than in normal vessel walls, and was present not only in macrophages but also in endothelial and smooth muscle cells in plaques. We used phage display technology to identify peptides that specifically bound to stabilin 2. After four rounds of selection, the most commonly isolated peptide had the sequence CRTLTVRKC, and was named S2P. We confirmed that this peptide specifically bound to stabilin-2-expressing cells in vitro and sinus endothelial cells in the spleen and lymph nodes in vivo. A FITC-conjugated synthetic CRTLTVRKC peptide was shown to home to atherosclerotic plaques in Ldlr-/- mice and to co-localize with endothelial cells, macrophages, and smooth muscle cells in such plaques. S2P conjugated to hydrophobically modified glycol chitosan nanoparticles was efficiently delivered to atherosclerotic plaques. These results show that the CRLTLTVRKC peptide homes to plaques by targeting stabilin-2; the peptide shows promise as a drug delivery moiety for, and an aid to molecular imaging of, atherosclerosis and other inflammatory diseases. PMID- 21781995 TI - Physiological roles revealed by ghrelin and ghrelin receptor deficient mice. AB - Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neuroprotection. Furthermore, ghrelin could promote overall health and longevity by acting directly in the immune system and promoting an extended antigen repertoire. The development of mice lacking either ghrelin (ghrelin-/-) or its receptor (ghsr-/-) have provided a valuable tool for determining the relevance of ghrelin and its receptor in these multiple and diverse roles. In this review, we summarize the most important findings and lessons learned from the ghrelin-/- and ghsr-/- mice. PMID- 21781996 TI - PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis. AB - Vascular endothelial growth factor (VEGF), a specific pro-angiogenic peptide, has shown neuroprotective effects in the Parkinson's disease (PD) models, but the underlying mechanisms remain elusive. In this study, the neuroprotective properties of VEGF on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity in primary cerebellar granule neurons were investigated. Pretreatment of VEGF prevented MPP(+)-induced neuronal apoptosis in a concentration- and time-dependent manner. And this prevention was blocked by PTK787/ZK222584, a VEGF receptor-2 specific inhibitor. Both inhibition of the Akt pathway and activation of the extracellular signal-regulated kinase (ERK) pathway contribute to MPP(+)-induced neuronal apoptosis. VEGF reversed the inhibition of phosphoinositide 3-kinase (PI3-K)/Akt pathway caused by MPP(+), but further enhanced the activation of ERK induced by MPP(+). Interestingly, VEGF and PD98059 (an ERK kinase inhibitor) play a synergistic role in protecting neurons from MPP(+)-induced toxicity. Collectively, these findings suggest that the PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP(+)-induced neuronal apoptosis. This finding offers not only a new and clinically significant modality as to how VEGF exerts its neuroprotective effects but also a novel therapeutic strategy for PD by differentially regulating PD-associated signaling pathways. PMID- 21781997 TI - Development and clinical evaluation of multiple investigational monovalent DENV vaccines to identify components for inclusion in a live attenuated tetravalent DENV vaccine. AB - The Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health has been engaged in an effort to develop a safe, efficacious, and affordable live attenuated tetravalent dengue vaccine (LATV) for more than ten years. Numerous recombinant monovalent DENV vaccine candidates have been evaluated in the SCID-HuH-7 mouse and in rhesus macaques to identify those candidates with a suitable attenuation phenotype. In addition, the ability of these candidates to infect and disseminate in Aedes mosquitoes had also been determined. Those candidates that were suitably attenuated in SCID-HuH-7 mice, rhesus macaques, and mosquitoes were selected for further evaluation in humans. This review will describe the generation of multiple candidate vaccines directed against each DENV serotype, the preclinical and clinical evaluation of these candidates, and the process of selecting suitable candidates for inclusion in a LATV dengue vaccine. PMID- 21781998 TI - Next generation dengue vaccines: a review of candidates in preclinical development. AB - Dengue represents a major public health problem of growing global importance. In the absence of specific dengue therapeutics, strategies for disease control have increasingly focused on the development of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates are currently being evaluated in clinical trials and are described in detail in accompanying articles. In addition, there are a large variety of candidates in preclinical development, which are based on diverse technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some of the current preclinical candidates may become next generation dengue vaccines with superior product profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development. PMID- 21781999 TI - The pathogenesis of dengue. AB - Dengue is an important cause of childhood and adult morbidity in Asian and Latin American countries and its geographic footprint is growing. The clinical manifestations of dengue are the expression of a constellation of host and viral factors, some acquired, others intrinsic to the individual. The virulence of the virus plus the flavivirus infection history, age, gender and genotype of the host all appear to help shape the severity of infection. Similarly, the characteristics of the innate and acquired host immune response subsequent to infection are also likely determinants of outcome. This review summarises recent developments in the understanding of dengue pathogenesis and their relevance to dengue vaccine development. PMID- 21782000 TI - Oxidative stress by antimicrobial peptide pleurocidin triggers apoptosis in Candida albicans. AB - Pleurocidin (GWGSFFKKAAHVGKHVGKAALTHYL-NH(2)), found in skin mucous secretions of the winter flounder Pleuronectes americanus, is known to possess a high potency and broad-spectrum antimicrobial peptide without cytotoxicity. In this study, to investigate the impact of pleurocidin on apoptotic progress, we observed morphological and physiological changes in Candida albicans. In cells exposed to pleurocidin, intracellular reactive oxygen species (ROS) which is a major cause of apoptosis were increased, and hydroxyl radicals were especially a large part of ROS. The increase of ROS induced oxidative stress and mitochondrial membrane depolarization which causes release of pro-apoptotic factors. Using FITC-VAD-FMK staining, we confirmed activation of yeast metacaspases which lead to apoptosis and phosphatidylserine externalization at early stage apoptosis was observed using annexin V FITC. In addition, pleurocidin induced-apoptotic cells underwent apoptotic morphological changes, showing the reduced cell size (low FSC) and enhanced intracellular density (high SSC) in flow cytometry dot plots. Under the influence of oxidative stress, DNA and nuclei were fragmented and condensed in cells, and they were visualized by 4',6-diamidino-2-phenylindole (DAPI) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. These apoptotic phenomena represent that oxidative stress by inducing pleurocidin must be an important factor of the apoptotic process in C. albicans. PMID- 21782002 TI - Salicylate modulates Hsp70 expression in the explanted organ of Corti. AB - Heat shock protein 70 (Hsp70, Hspa1a) is known to play a protective role in the inner ear and in the nervous system. Our recent study demonstrated that the induction of Hsp70 by geldanamycin protected the auditory hair cells against ototoxic insult. Here, using the explanted organ of Corti (OC), we characterized the effect of sodium salicylate on the expression of Hsp70. Using the real-time RT-PCR; after 27 h in standard culture, we observed an increase in the Hsp70 transcript number. After 48 h in culture, the number of Hsp70 transcripts increased further, as compared to the freshly isolated tissues or explant cultured for 27 h. Three hours after the addition of 2.5mM sodium salicylate, the expression of Hsp70 mRNA increased significantly. Interestingly, Hsp70 protein level remained unaffected by the addition of salicylate, as shown by immunoblotting and Hsp70-ELISA. Confocal microscopy imaging demonstrated predominant localization of Hsp70 protein with or without salicylate exposure to the fibrocytes of spiral limbus. Our results suggest that in the OC, explanting process induces expression of Hsp70 in limbal fibrocytes and that this expression can be enhanced by salicylate but only on mRNA and not on the protein level. PMID- 21782003 TI - The different P200 effects of phonological and orthographic syllable frequency in visual word recognition in Korean. AB - The principal purpose of this study was to examine whether event-related potential (ERP) waveform amplitudes at around 200 ms are affected by first syllable frequency. Another purpose of this study was to investigate whether the source of the amplitude at around 200 ms is phonological syllable frequency or orthographic syllable frequency. The phonological first-syllable frequency and the orthographic first-syllable frequency of Korean pseudo-words were manipulated, and ERPs were collected during a go/no-go lexical decision task. The results of this study showed that the P200 waveform is sensitive to the frequency of the first phonological syllable; specifically, pseudo-words with higher phonological first-syllable frequency produced a lower P200 amplitude than those with lower phonological first-syllable frequency. The orthographic syllable frequency did not affect the P200 waveform. The present result implies that there may be different routes by which phonological syllables and orthographic syllables are processed during the early stage of the visual word recognition process. PMID- 21782004 TI - Galectin-3 is upregulated in activated glia during Junin virus-induced murine encephalitis. AB - Argentine haemorrhagic fever (AHF) is a systemic febrile syndrome characterized by several haematological and neurological alterations caused by Junin virus (JUNV), a member of the Arenaviridae family. Newborn mice are highly susceptible to JUNV and the course of infection has been associated with the viral strain used. Galectin-3 (Gal-3) is an animal lectin that has been proposed to play an important role in some central nervous system (CNS) diseases. In this study, we analysed Gal-3 expression at the transcriptional and translational expression levels during JUNV-induced CNS disease. We found that Candid 1 strain induced, with relatively low mortality, a subacute/chronic CNS disease with significant glia activation and upregulation of Gal-3 in microglia cells as well as in reactive astrocytes that correlated with viral levels. Our results suggest an important role for Gal-3 in viral-induced CNS disease. PMID- 21782005 TI - Isoflurane for spinal anesthesia in the rat. AB - Although isoflurane, a non-water soluble agent, has been known to block Na+ currents, its spinal anesthetic effect was not exposed. The aim of this experiment was to evaluate the local anesthetic effect of isoflurane in spinal anesthesia. After intrathecal injection of isoflurane on rats, the spinal anesthetic effect in motor function, proprioception and nociception were evaluated. Lidocaine, a common used local anesthetic, was used as control. Isoflurane acted like lidocaine and produced dose-related spinal blockades of motor function, proprioception and nociception. Although isoflurane [27.6 (25.4 30.0)] had less potency when compared with lidocaine [1.0 (0.9-1.1)] (P<0.001) in spinal anesthesia, it caused a much longer duration of spinal blockades than lidocaine at equianesthetic doses (P<0.001). Our results showed that when compared with lidocaine, isoflurane produced a less potency but much longer duration in spinal anesthesia. PMID- 21782001 TI - The AR dependent cell cycle: mechanisms and cancer relevance. AB - Prostate cancer cells are exquisitely dependent on androgen receptor (AR) activity for proliferation and survival. As these functions are critical targets of therapeutic intervention for human disease, it is imperative to delineate the mechanisms by which AR engages the cell cycle engine. More than a decade of research has revealed that elegant intercommunication between AR and the cell cycle machinery governs receptor-dependent cellular proliferation, and that perturbations in this process occur frequently in human disease. Here, AR-cell cycle interplay and associated cancer relevance will be reviewed. PMID- 21782006 TI - Orai1/CRACM1 overexpression suppresses cell proliferation via attenuation of the store-operated calcium influx-mediated signalling pathway in A549 lung cancer cells. AB - BACKGROUND: Orai1/CRACM1 is a principal component of the store-operated calcium channels. Store-operated calcium influx is highly correlated with inflammatory reactions, immunological regulation, and cell proliferation. Epidermal growth factor (EGF), which plays an important role in the regulation of cell proliferation, can activate store-operated calcium channels. However, the consequences of Orai1/CRACM1 overexpression in EGF-mediated lung cancer cells growth are not known. METHODS: To investigate the role of Orai1/CRACM1 in EGF mediated lung cancer cell proliferation, Orai1/CRACM1 plasmids were transfected into cells by lipofection. A cell proliferation assay, immunofluorescence staining, flow cytometry, and real-time polymerase chain reaction were employed to monitor cell proliferation. The calcium influx signals were investigated using a fluorescent-based calcium assay. RESULTS: Transfection of Orai1/CRACM1 plasmids resulted in the inhibition of EGF-mediated cell proliferation. ERK1/2 and Akt phosphorylation were inhibited by Orai1/CRACM1 overexpression. Expression of the cell cycle modulator p21 was induced in the Orai1/CRACM1-overexpressing cells, whereas the expression of cyclin D3 was reduced. Flow cytometry revealed that overexpression of Orai1/CRACM1 resulted in G0/G1 cell cycle arrest. Importantly, Orai1/CRACM1 overexpression significantly attenuated EGF-mediated store-operated calcium influx. In addition, application of 2-APB, a store-operated calcium channel inhibitor, resulted in the inhibition of EGF-mediated cancer cell proliferation. CONCLUSIONS: We conclude that Orai1/CRACM1 overexpression attenuates store-operated Ca(2+) influx that in turn blocks EGF-mediated proliferative signaling and drives cell cycle arrest. PMID- 21782007 TI - The effects of chronic tinnitus caused by acoustic trauma on social behaviour and anxiety in rats. AB - Tinnitus is associated with significant increases in anxiety disorders in humans, which is thought to affect social interaction; however, there has been only one previous study of the effects of tinnitus on social interaction in animals treated with salicylate and no previous study of the effects of tinnitus on anxiety in animals. In the present study, we used acoustic trauma to induce tinnitus in rats and investigated its effects on social interaction and anxiety in animals confirmed to have tinnitus. When social behaviours were grouped, we found that animals with tinnitus engaged in significantly more aggressive behaviours toward both tinnitus and sham control animals (P=0.03). When individual social behaviours were analysed without considering whether a tinnitus or sham animal was interacting with a member of its own treatment group, tinnitus animals were found to engage in significantly more anogenital investigation (P=0.01) and significantly less social grooming (P=0.003). When the data were analysed according to whether an animal was interacting with a member of its own group, tinnitus animals were found to bite sham animals significantly more than other tinnitus animals (P=0.005). Sham animals also bit tinnitus animals significantly more than other sham animals (P=0.02), as well as climbing away from them more (P=0.04), kicking (P=0.003), nudging them more (P=0.04), and sleeping with them more (P=0.02). By contrast, sham animals sniffed tinnitus animals significantly less than sham animals (P=0.05). There were no significant differences between the sham and tinnitus animals in performance in the elevated plus and elevated T maze tests of anxiety. However, tinnitus animals displayed a slight but significant increase in locomotor activity in the open field (P=0.04). These data suggest that tinnitus results in complex changes in social interaction in rats, which are not due simply to increases in anxiety. PMID- 21782008 TI - Some OH-PCBs are more potent inhibitors of aromatase activity and (anti-) glucocorticoids than non-dioxin like (NDL)-PCBs and MeSO2-PCBs. AB - Traditional risk assessment of potential endocrine-disruptive pollutants, including PCBs, focus mainly on the effects of parent compounds. Still, biotransformation results in systemic exposure to PCBs and their bioactive metabolites. In the present paper, the effects of twenty ultra-pure non-dioxin like (NDL) PCBs and their environmentally relevant hydroxy- (OH-) and methylsulfonyl- (MeSO(2)-) metabolites on aromatase activity and their glucocorticoid properties were investigated. Although most NDL-PCBs were inactive, PCB28 inhibited aromatase activity in human placenta microsomes with an IC(50) of 2.2MUM. Most of these NDL-PCBs were weak (ant-)agonist of the glucocorticoid receptor (GR). Interestingly, four OH-metabolites of the commonly found NDL-PCB180 were able to inhibit aromatase activity (LOECs in the low MUM range) and showed anti-glucocorticoid properties (LOECs in the low nM range), in a concentration-dependent manner. Further, four MeSO(2)-PCBs slightly inhibited aromatase activity and showed anti-glucocorticoid properties. Although, these effects were also associated with cytotoxicity, they were dependent on the position of the MeSO(2)-group on the biphenyl ring. Our results are the first to show that OH-PCBs are both anti-glucocorticoids and aromatase inhibitors. Taken together, these results for PCBs again support the common idea that risk assessment of the endocrine disruptive potential of PCBs should also include their metabolites. PMID- 21782009 TI - A cytoplasm-sensitive peptide vector cross-linked with dynein light chain association sequence (DLCAS) enhances gene expression. AB - We previously engineered a novel, non-viral, multifunctional gene vector (STR CH(2)R(4)H(2)C) containing stearoyl (STR) and a block peptide consisting of Cys (C), His (H), and Arg (R). STR-CH(2)R(4)H(2)C forms a nano-complex with pDNA and is stabilized by electronic interactions and disulfide cross linkages. In blood, pDNA, a cytosol-sensitive gene vector, is released from the complex into the cytosol. The current study aimed to make STR-CH(2)R(4)H(2)C capable of active nuclear localization. The dynein light chain association sequence (DLCAS) was disulfide cross-linked to STR-CH(2)R(4)H(2)C/pDNA through disulfide linkages, and the gene expression ability of this DLCAS cross-linked gene vector was evaluated. We examined the gene transfection efficiency of S-180 cells transfected with the STR-CH(2)R(4)H(2)C/DLCAS/pDNA complex. STR-CH(2)R(4)H(2)C/DLCAS/pDNA showed significantly higher and faster gene expression compared with STR CH(2)R(4)H(2)C/pDNA. We also evaluated the cellular uptake ability of STR CH(2)R(4)H(2)C/DLCAS/Cy5-labeled pDNA complex. STR-CH(2)R(4)H(2)C/DLCAS/pDNA showed significantly lower cellular uptake compared with STR-CH(2)R(4)H(2)C/pDNA. This result indicates that high gene expression of STR-CH(2)R(4)H(2)C/DLCAS/pDNA does not facilitate its cellular uptake. In addition, the gene expression of DLCAS/STR-CH(2)R(4)H(2)C/pDNA in S-180 cells pretreated with the tubulin polymerization inhibitor, nocodazole (NCZ), was significantly lower than that in the absence of NCZ. These results indicate that the high transfection efficiency of DLCAS/STR-CH(2)R(4)H(2)C/pDNA is dependent on intra-cellular transport utilizing the microtubule motor protein, dynein. Taken together, our results suggest that DLCAS-modified STR-CH(2)R(4)H(2)C may be a promising gene delivery system. PMID- 21782010 TI - Anti-osteoporosis activity of Cibotium barometz extract on ovariectomy-induced bone loss in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Recent research has confirmed that Cibotium barometz could inhibits osteoclast formation with no affect on BMM cell viability. However, the influence of Cibotium barometz on osteoporosis in animals is relatively unknown. The purpose of this study is to systemically investigate the effects of Cibotium barometz extract (CBE) on ovariectomy-induced osteoporosis in rats. MATERIALS AND METHODS: A total of Seventy-two 3-month-old female Sprague-Dawley rats were used and randomly divided into sham-operated group and five ovariectomized (OVX) groups: OVX with vehicle; OVX with 17beta estradiol (E2, 25 MUg/kg/day); OVX with CBE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of E2 or CBE began 4 weeks after the surgery and lasted for 16 weeks. Bone mass, bone turnover and strength were analyzed by DEXA, biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by MicroCT. RESULTS: CBE prevented total BMD decrease in the femur induced by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers, such as osteocalcin (OC), alkaline phosphatese (ALP), deoxypyridinoline (DPD), and urinary Ca and P excretions. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. CONCLUSIONS: The present study indicated that Cibotium barometz extract might be a potential alternative medicine for the prevention and treatment of postmenopausal osteoporosis. PMID- 21782011 TI - Influence of Paeonia lactiflora roots extract on cAMP-phosphodiesterase activity and related anti-inflammatory action. AB - BACKGROUND: Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in TCM. Research has shown baishao to have positive pharmacological actions, including, particularly, anti-inflammatory properties. In this paper we studied the influence of baishao extract on cAMP-phosphodiesterase (PDE) activity and related anti-inflammatory action to identify new pharmacologic action for its clinically widespread use. METHODS: PDE activity was calculated by cAMP change examined with HPLC, respiratory burst of neutrophils was detected with method of cytochrome C reduction, elastase release was indicated with the substrate reduction, rat arthritis model was caused by complete Freund's adjuvant, mouse capillary permeability model was made by acetic acid, and chemical constituents of baishao extract was identified by HPLC, mass spectroscopy and NMR spectrum. RESULTS: Baishao extract had significant inhibition on cAMP-PDE activity (p<0.01), had dose dependent restraint on neutrophils respiratory burst (p<0.001), had inhibition at low concentration and promotion at high concentration on elastase release (p<0.05), and had obvious restraint on local inflammation of animal model (p<0.01). Analysis of HPLC, mass spectroscopy and NMR spectrum showed baishao extract mainly had five components (identified as gallic acid, paeoniflorin sulfonate, albiflorin, paeoniflorin and benzoic acid), among which gallic acid had the largest inhibition on cAMP-PDE activity. CONCLUSION: The anti-inflammatory effects of baishao may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on cAMP-PDE. PMID- 21782012 TI - Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Baicalein, the active constituent derived from Scutellaria baicalensis Georgi., has previously been shown to significantly restore the effectiveness of beta-lactam antibiotics and tetracycline against methicillin-resistant Staphylococcus aureus (MRSA). With multiple therapeutic benefits, the antibacterial actions of baicalein may also be involved in overcoming other bacterial resistance mechanisms. The aim of the present study was to further investigate antibacterial activities of baicalein in association with various antibiotics against selected Staphylococcus aureus strains with known specific drug resistance mechanisms. MATERIAL AND METHODS: A panel of clinical MRSA strains was used for further confirmation of the antibacterial activities of baicalein. The effect of baicalein on inhibiting the enzymatic activity of a newly discovered MRSA-specific pyruvate kinase (PK), which is essential for Staphylococcus aureus growth and survival was also examined. RESULTS: In the checkerboard dilution test and time-kill assay, baicalein at 16 MUg/ml could synergistically restore the antibacterial actions of ciprofloxacin against the NorA efflux pump overexpressed SA-1199B, but not with the poor NorA substrate, pefloxacin. Moreover, synergistic effects were observed when baicalein was combined with ciprofloxacin against 12 out of 20 clinical ciprofloxacin resistant strains. For MRSA PK studies, baicalein alone could inhibit the enzymatic activity of MRSA PK in a dose-dependent manner. CONCLUSION: Our results demonstrated that baicalein could significantly reverse the ciprofloxacin resistance of MRSA possibly by inhibiting the NorA efflux pump in vitro. The inhibition of MRSA PK by baicalein could lead to a deficiency of ATP which might further contribute to the antibacterial actions of baicalein against MRSA. PMID- 21782013 TI - Sesquiterpene lactones from Gynoxys verrucosa and their anti-MRSA activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Because of its virulence and antibiotic resistance, Staphylococcus aureus is a more formidable pathogen now than at any time since the pre-antibiotic era. In an effort to identify and develop novel antimicrobial agents with activity against this pathogen, we have examined Gynoxys verrucosa Wedd (Asteraceae), an herb used in traditional medicine in southern Ecuador for the treatment and healing of wounds. MATERIALS AND METHODS: The sesquiterpene lactones leucodine (1) and dehydroleucodine (2) were extracted and purified from the aerial parts of Gynoxys verrucosa, and their structure was elucidated by spectroscopic methods and single-crystal X-ray analysis. The in vitro anti-microbial activity of Gynoxys verrucosa extracts and its purified constituents was determined against six clinical isolates including Staphylococcus aureus and Staphylococcus epidermidis strains with different drug resistance profiles, using the microtiter broth method. RESULTS: Compound 1 has very low activity, while compound 2 has moderate activity with MIC(50)s between 49 and 195 MUg/mL. The extract of Gynoxys verrucosa has weak activity with MIC(50)s between 908 and 3290 MUg/mL. CONCLUSIONS: We are reporting the full assignment of the (1)H NMR and (13)C NMR of both compounds, and the crystal structure of compound 2, for the first time. Moreover, the fact that compound 2 has antimicrobial activity and compound 1 does not, demonstrates that the exocyclic conjugated methylene in the lactone ring is essential for the antimicrobial activity of these sesquiterpene lactones. However, the weak activity observed for the plant extracts, does not explain the use of Gynoxys verrucosa in traditional medicine for the treatment of wounds and skin infections. PMID- 21782014 TI - Medicinal plants used in the management of chronic joint pains in Machakos and Makueni counties, Kenya. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicines play an important role in the management of chronically painful and debilitating joint conditions, particularly in the rural Africa. However, their potential use as sources of medicines has not been fully exploited. The present study was carried to find the medicinal plants traditionally used to manage chronic joint pains in Machakos and Makueni counties in Kenya. MATERIALS AND METHODS: To obtain this ethnobotanical information, 30 consenting traditional herbal medical practitioners were interviewed exclusively on medicinal plant use in the management of chronic joint pains, in a pre-planned workshop. RESULTS AND DISCUSSION: In this survey, a total of 37 plants belonging to 32 genera and 23 families were cited as being important for treatment of chronic joint pains. The most commonly cited plant species were Pavetta crassipes K. Schum, Strychnos henningsii Gilg., Carissa spinarum L., Fagaropsis hildebrandtii (Engl.) Milve-Redh. and Zanthoxylum chalybeum Engl. Acacia mellifera (Vahl) Benth., Amaranthus albus L., Balanites glabra Mildbr. & Schltr., Grewia fallax K. Schum., Lactuca capensis, Launaea cornuta (Oliv. & Hiern) O. Jeffrey, Lippia kituiensis Vatke, Pappea capensis Eckl. & Zeyh. and Pennisetum glaucum (L.) R. Br. are documented for the first time as being important in the management of chronic joint pains. CONCLUSIONS: The findings of this study show that a variety of medicinal plants are used in the management of chronic joint pains and the main mode of administration is oral. PMID- 21782015 TI - Inhibitory effect of Aralia continentalis on the cariogenic properties of Streptococcus mutans. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aralia continentalis has been used in traditional Korean medicine for dental diseases such as toothache, dental caries, periodontal disease and gingivitis, and also has been used for neuralgia, analgesia, sweating, and as an antirheumatic. AIM OF THE STUDY: The present study was designed to investigate the inhibitory effect of Aralia continentalis extract on cariogenic properties of Streptococcus mutans, which is one of the most important bacteria in the formation of dental caries and dental plaque. MATERIALS AND METHODS: The inhibitory effects of Aralia continentalis extract on the growth, acid production, water-insoluble glucan synthesis, and adhesion were investigated in Streptococcus mutans. The biofilm formation of Streptococcus mutans was determined by scanning electron microscopy (SEM) and safranin staining. RESULTS: The ethanol extract of Aralia continentalis showed concentration dependent inhibitory activity on the growth of Streptococcus mutans and significant inhibition of acid production at the concentrations of 0.25, 0.5, 1, 2 and 4 mg/ml compared to the control group. The synthesis of water-insoluble glucan by glucosyltransferase (GTFase) was decreased in the presence of 0.5-4 mg/ml of the extract of Aralia continentalis. The extract markedly inhibited Streptococcus mutans adherence to saliva-coated hydroxyapatite beads (S-HAs). The extract of Aralia continentalis has an inhibitory effect on the formation of Streptococcus mutans biofilms at the concentrations higher than 2mg/ml. CONCLUSIONS: These results suggest that Aralia continentalis may inhibit cariogenic properties of Streptococcus mutans, and also may support the scientific rationale that native inhabitants used the extract for the treatment of dental diseases. PMID- 21782016 TI - Reproduction and juvenile animal toxicology studies in the rat with a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL((r))) for the treatment of grass pollen allergy. AB - Pollinex((r)) Quattro Grass has been developed for the prevention or relief of allergic symptoms caused by pollen in both adults and children. Reproduction and juvenile animal toxicology studies have been performed. Subcutaneous injection on Day 14 prior to pairing and on Days 6 and 13 of gestation to pregnant rats at 2000SU/0.5 mL elicited no signs of maternal or embryo-foetal toxicity. Mating, fertility, fecundity and pup parameters were all unaffected by treatment. Once weekly subcutaneous administration at ascending doses of 300, 800, 2000 and 2000SU/0.5 mL followed by a 4 week non-dose period to juvenile rats from 3 weeks of age showed no signs of obvious toxicity. As in a previously performed adult animal toxicology study with the vaccine, not unexpected, but relatively minor, immuno-stimulatory effects were seen in this study along with injection site reaction which can largely be attributed to the presence of tyrosine in the formulation. PMID- 21782017 TI - Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs). AB - OBJECTIVES: Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. STUDY DESIGN: Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. RESULTS: Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to fetal transfer (P<0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. CONCLUSIONS: The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP transporters may be an important factor in fetal exposure to repaglinide. PMID- 21782018 TI - Marine organisms as a therapeutic source against herpes simplex virus infection. AB - Herpes simplex virus (HSV) is a member of the Herpesviridae family that causes general communicable infections in human populations throughout the world, the most common being genital and orolabial disease. The current treatments for HSV infections are nucleoside analogs such as acyclovir, valacyclovir and famciclovir. Despite the safety and efficacy, extensive clinical use of these drugs has led to the emergence of resistant viral strains, mainly in immunocompromised patients. To counteract these problems, alternative anti-HSV agents from natural products have been reported. Recently, a great deal of interest has been expressed regarding marine organisms such as algae, sponges, tunicates, echinoderms, mollusks, shrimp, bacteria, and fungus as promising anti HSV agents. This contribution presents an overview of potential anti-HSV agents derived from marine organisms and their promising application in HSV therapy. PMID- 21782019 TI - Ferrocenyl Schiff base as novel antioxidant to protect DNA against the oxidation damage. AB - The antioxidant capacities of ferrocenyl Schiff bases including o-(1 ferrocenylethylideneamino)phenol (OFP), m-(1-ferrocenylethylideneamino)phenol (MFP), and p-(1-ferrocenylethylideneamino)phenol (PFP) were evaluated in 2,2' azobis(2-amidinopropane hydrochloride) (AAPH), Cu(2+)/glutathione (GSH), and hydroxyl radical (()OH)-induced oxidation of DNA, and in trapping 2,2'-diphenyl-1 picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+(.)), respectively. OFP, MFP and PFP possessed similar activities to trap DPPH and ABTS+(.). All the ferrocenyl Schiff bases employed herein behaved as prooxidants in Cu(2+)/GSH- and (.)OH-induced oxidation of DNA except that OFP exhibited weak antioxidant activity in ()OH-induced oxidation of DNA. PFP, OFP and MFP can terminate about 15.2, 11.3, and 9.4 radical-chain propagations in AAPH-induced oxidation of DNA. Especially, the introduction of ferrocenyl group to Schiff base increased the antioxidant effectiveness more remarkably than benzene-related Schiff bases. PMID- 21782020 TI - Infant rhythms versus parental time: promoting parent-infant synchrony. AB - Traditional psychoanalytic theories of early development have been put into question by developmental psychology, and particularly by attachment theory. Psychopathology appears to be more linked to interpersonal relationship problems rather than to intra-psychic conflict, as hypothesized in Freudian drive theory. Establishing synchrony between parent and infant is probably one of the major tasks of the first year of life. Attachment theory appears to be an effective paradigm to understand how caregiver responses to stressful infant situations give way to different regulatory strategies, which impact on the effectiveness of the stress buffer systems and its physiological impact on emotion and stress regulation. This paper underlines the importance of synchronization between infant and caregiver; it highlights the key concept of attachment disorganization and of its relationship with sustained social withdrawal as a defence mechanism and an alarm signal when synchronization fails, and underlines the importance of early interventions promoting parent-infant synchrony. PMID- 21782021 TI - Good use and misuse of "genetic determinism". AB - After sequencing the human genome, scientists believed it would be possible to draw up a list of diseases, morphological characteristics and behavioral traits linked to each gene, but the post-genome era has shown that while links between genes and phenotypes, including behavioral phenotypes, do exist, they are more complex than was previously thought. There is no linear connection between genotype and brain and between brain and behavior; consequently, genomic and behavioral levels of organization are not isomorphous. There is no isomorphism because one gene plays many different roles, which means that the integrative processes needed for the development and functioning of an organism inevitably occurs in situations of non-linear multiple causality. Pleiotropy and epistasis, interactions between genes and the environment, alternative splicing and neuronal integration are all crucial mechanisms contributing to the many and varied aspects of brain-related genes. PMID- 21782022 TI - Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. AB - GPER/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone substituent in G15 could minimize key steric conflicts, present in G-1, that limit binding within the ERalpha ligand binding pocket. In this report, we identify low-affinity cross-reactivity of the GPER antagonist G15 to the classical estrogen receptor ERalpha. To generate an antagonist with enhanced selectivity, we therefore synthesized an isosteric G-1 derivative, G36, containing an isopropyl moiety in place of the ethanone moiety. We demonstrate that G36 shows decreased binding and activation of ERalpha, while maintaining its antagonist profile towards GPER. G36 selectively inhibits estrogen-mediated activation of PI3K by GPER but not ERalpha. It also inhibits estrogen- and G-1 mediated calcium mobilization as well as ERK1/2 activation, with no effect on EGF mediated ERK1/2 activation. Similar to G15, G36 inhibits estrogen- and G-1 stimulated proliferation of uterine epithelial cells in vivo. The identification of G36 as a GPER antagonist with improved ER counterselectivity represents a significant step towards the development of new highly selective therapeutics for cancer and other diseases. PMID- 21782023 TI - Heat shock factor binds to heat shock elements upstream of heat shock protein 70a and Samui genes to confer transcriptional activity in Bombyx mori diapause eggs exposed to 5 degrees C. AB - To understand the molecular mechanisms of how 5 degrees C-incubation activates mRNA expression of Hsp70a and Samui genes in Bombyx mori diapause eggs, we first searched the 5'-upstream regions of the Hsp70a and Samui genes for heat shock elements (HSEs) and found two regions [Hsp70aHSE-1 (-95 to -58) and -2 (-145 to 121), and SamuiHSE-1 (-84 to -55) and -2 (-304 to -290)] corresponding to HSEs (repeats of nGAAn and/or nTTCn). We cloned four cDNAs encoding heat shock factor (HSF)-a2 (627 amino acids), -b (685 aa), -c (682 aa) and -d (705 aa), which were produced by alternative splicing. When we exposed diapause eggs to 5 degrees C beginning at 2 day post-oviposition to break diapause, HSFd mRNA only increased after chilling for 6-8 days, a pattern very similar to those of Hsp70a and Samui mRNAs. To examine further whether HSFd binds to the respective HSEs, we carried out a gel shift assay using HSFd protein expressed in a cell-free system and the isolated HSEs; migration of the respective digoxigenin(DIG)-labeled HSE-1 and -2 of Hsp70a and Samui was retarded by addition of HSFd; the retarded bands disappeared after addition of the corresponding unlabeled HSE-1 and -2 as competitors, but were not affected by addition of the respective mutated unlabeled HSE-1 and -2. These results indicated that HSFd protein binds to the respective HSEs and may activate mRNA expression of Hsp70a and Samui genes upon exposure of diapause eggs to 5 degrees C. PMID- 21782024 TI - Progesterone blocks multiple routes of ion flux. AB - The administration of progesterone as a neuroprotective agent following traumatic brain injury has recently entered phase III clinical trials. Previous work has demonstrated that therapeutic concentrations of progesterone decrease excitotoxicity through direct inhibition of voltage-gated calcium channels, an action independent of the nuclear progesterone receptor. Here we report using cultured rat striatal neurons that these same concentrations of progesterone also block voltage-gated potassium channels, sodium channels and GABA(A) currents. The actions of progesterone act at the surface membrane of neurons in a steroid specific, voltage-independent, concentration-dependent manner. Notably, these broad actions of progesterone on ion channel and neurotransmitter receptor function mirror those of dihydropyridines, and indicate potential shared mechanisms of action, the prospective of additional therapeutic applications, and possibly, untoward effects. PMID- 21782025 TI - Improved isolation and purification of functional human Fas receptor extracellular domain using baculovirus-silkworm expression system. AB - To achieve an efficient isolation of human Fas receptor extracellular domain (hFasRECD), a fusion protein of hFasRECD with human IgG1 heavy chain Fc domain containing thrombin cleavage sequence at the junction site was overexpressed using baculovirus-silkworm larvae expression system. The hFasRECD part was separated from the fusion protein by the effective cleavage of the recognition site with bovine thrombin. Protein G column treatment of the reaction mixture and the subsequent cation-exchange chromatography provided purified hFasRECD with a final yield of 13.5mg from 25.0 ml silkworm hemolymph. The functional activity of the product was examined by size-exclusion chromatography analysis. The isolated hFasRECD less strongly interacted with human Fas ligand extracellular domain (hFasLECD) than the Fc domain-bridged counterpart, showing the contribution of antibody-like avidity in the latter case. The purified glycosylated hFasRECD presented several discrete bands in the disulphide-bridge non-reducing SDS-PAGE analysis, and virtually all of the components were considered to participate in the binding to hFasLECD. The attached glycans were susceptible to PNGase F digestion, but mostly resistant to Endo Hf digestion under denaturing conditions. One of the components exhibited a higher susceptibility to PNGase F digestion under non-denaturing conditions. PMID- 21782026 TI - Cloning, purification and characterization of a thermostable carboxylesterase from Anoxybacillus sp. PDF1. AB - The gene encoding a carboxylesterase from Anoxybacillus sp., PDF1, was cloned and sequenced. The recombinant protein was expressed in Escherichia coli BL21, under the control of isopropyl-beta-D-thiogalactopyranoside-inducible T7 promoter. The enzyme, designated as PDF1Est, was purified by heat shock and ion-exchange column chromatography. The molecular mass of the native protein, as determined by SDS PAGE, was about 26 kDa. PDF1Est was active under a broad pH range (pH 5.0-10.0) and a broad temperature range (25-90 degrees C), and it had an optimum pH of 8.0 and an optimum temperature of 60 degrees C. The enzyme was thermostable carboxylesterase, and did not lose any activity after 30 min of incubation at 60 degrees C. The enzyme exhibited a high level of activity with p-nitrophenyl butyrate with apparent K(m), V(max), and K(cat) values of 0.348 +/- 0.030 mM, 3725.8 U/mg, and 1500 +/- 54.50/s, respectively. The effect of some chemicals on the esterase activity indicated that Anoxybacillus sp. PDF1 produce an carboxylesterase having serine residue in active site and -SH groups in specific sites, which are required for its activity. PMID- 21782027 TI - Human multiprotein bridging factor 1 and Calmodulin do not interact in vitro as confirmed by NMR spectroscopy and CaM-agarose affinity chromatography. AB - The human multiprotein bridging factor 1 (hMBF1) has been established in different cellular types to have the role of transcriptional coactivator. It is also reported to be a putative Calmodulin (CaM) target, able to bind CaM in its calcium-free state, but little is known about the structural features and the biological relevance of this interaction. We applied NMR to investigate the interaction between the two proteins in solution and compared the results with those obtained with CaM-agarose affinity chromatography. No changes in 1H-15N HSQC spectrum of both apo-CaM and Ca2+-CaM upon addition of hMBF1 prove that the two proteins do not interact in vitro. These results were confirmed by CaM agarose affinity chromatography when operating under the same conditions. The discrepancy between present and previous experiments performed with CaM-agarose affinity chromatography depends on different experimental parameters suggesting that particular attention must be paid when CaM, or other immobilized proteins, are used to measure their affinity with putative partners. These results also imply that if an interaction between the two proteins exists in vivo, as reported for hMBF1 of endothelial cells, it might involve a posttranslational modified form of the proteins or it relies on other conditions imposed by the cellular environment. PMID- 21782028 TI - Molecular cloning and characterization of two isoforms of cyclophilin A gene from Venerupis philippinarum. AB - Cyclophilin A (CypA) is a ubiquitously distributed intracellular protein belonging to the immunophilin family, which is recognized as the cell receptor for the potent immunosuppressive drug cyclosporine A. In the present study, two isoforms of cyclophilin A gene (named as VpCypA1 and VpCypA2) were isolated and characterized from Venerupis philippinarum by RACE approaches. Both VpCypA1 and VpCypA2 possessed all conserved features critical for the fundamental structure and function of CypA, indicating that the two isoforms of cyclophilin A should be new members of CypA family. The expression of VpCypA2 mRNA in haemocytes was significantly up-regulated and the highest expression level was detected at 96 h post-infection with 7.7-fold increase compared with that in the blank group. On the contrary, the relative expression level of VpCypA1 mRNA was down-regulated rapidly at 6 h post-infection and reached 0.4-fold of the control group. They exhibited different expression profile and identical effect of immune modulation, which might suggest the two VpCypA isoforms exert their function in a manner of synergy. These results provide valuable information for further exploring the roles of cyclophilin A in the immune responses of V. philippinarum. PMID- 21782030 TI - Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease. AB - Apathy and depression are heterogeneous syndromes with symptoms that overlap clinically. This clinical overlap leads to problems with classification and diagnosis in clinical populations. No functional imaging study has attempted to separate brain regions altered in apathy from those altered in depression in a clinical population. Parkinson disease (PD) is a disorder in which apathy and depression co-exist in a single population. We evaluate the relationship between apathy, depression, and motor severity of disease in PD, focusing on the relationship between these factors and the amplitude of the low frequency fluctuation (ALFF) in the resting state. We first evaluated if the resting ALFF signal is a reliable measure for our clinical question. For this, we develop and introduce a cross validation approach we term the "Regional Mapping of Reliable Differences" (RMRD) method to evaluate reliability of regions of interest deemed "significant" by standard voxel-wise techniques. Using this approach, we show that the apathy score in this sample is best predicted by ALFF signal in the left supplementary motor cortex, the right orbitofrontal cortex, and the right middle frontal cortex, whereas depression score is best predicted by ALFF signal in the right subgenual cingulate. Disease severity was best predicted by ALFF signal in the right putamen. A number of additional regions are also statistically (but not reliably) correlated with our neuropsychological measures and disease severity. Our results support the use of resting fMRI as a means to evaluate neuropsychiatric states and motor disease progression in Parkinson disease, and the clinical and epidemiologic observation that apathy and depression are distinct pathological entities. Our finding that "significance" and "reliability" are dissociated properties of regions of interest identified as significant using standard voxel-wise techniques suggests that including reliability analyses may add useful scientific information in neurobehavioral research. PMID- 21782029 TI - Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone. AB - INTRODUCTION: Scanning properties and analytic methodology of the 5-HT2A receptor selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. METHODS: 64 11C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT2A receptors. RESULTS: Optimum analytic method was a 2 tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BPP and BPND) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 MUg to remain below 5% receptor occupancy. 11C MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age related decline in brain 5-HT2A receptors was 14.0+/-5.0% per decade, and higher in prefrontal regions. CONCLUSIONS: Our data confirm and extend support for 11C MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain. PMID- 21782031 TI - Mind wandering and attention during focused meditation: a fine-grained temporal analysis of fluctuating cognitive states. AB - Studies have suggested that the default mode network is active during mind wandering, which is often experienced intermittently during sustained attention tasks. Conversely, an anticorrelated task-positive network is thought to subserve various forms of attentional processing. Understanding how these two systems work together is central for understanding many forms of optimal and sub-optimal task performance. Here we present a basic model of naturalistic cognitive fluctuations between mind wandering and attentional states derived from the practice of focused attention meditation. This model proposes four intervals in a cognitive cycle: mind wandering, awareness of mind wandering, shifting of attention, and sustained attention. People who train in this style of meditation cultivate their abilities to monitor cognitive processes related to attention and distraction, making them well suited to report on these mental events. Fourteen meditation practitioners performed breath-focused meditation while undergoing fMRI scanning. When participants realized their mind had wandered, they pressed a button and returned their focus to the breath. The four intervals above were then constructed around these button presses. We hypothesized that periods of mind wandering would be associated with default mode activity, whereas cognitive processes engaged during awareness of mind wandering, shifting of attention and sustained attention would engage attentional subnetworks. Analyses revealed activity in brain regions associated with the default mode during mind wandering, and in salience network regions during awareness of mind wandering. Elements of the executive network were active during shifting and sustained attention. Furthermore, activations during these cognitive phases were modulated by lifetime meditation experience. These findings support and extend theories about cognitive correlates of distributed brain networks. PMID- 21782032 TI - Targeted gene expression profiling in European sea bass (Dicentrarchus labrax, L.) follicles from primary growth to late vitellogenesis. AB - A real-time PCR-based gene expression survey was performed on isolated European sea bass follicles from primary growth to late vitellogenesis. Expression levels of 18 transcripts with demonstrated relevance during oogenesis, encoding gonadotropin, thyrotropin, estrogen, androgen, and vitellogenin receptors, steroidogenesis-related as well as growth and transcription factors were measured. Primary oocytes showed high mRNA levels of insulin-like growth factors 1 and 2, bone morphogenetic protein 4, estrogen receptor 2b, androgen receptor b, and SRY-box containing gene 17 together with low transcript amounts of gonadotropin receptors. Follicles at the lipid vesicles stage (i.e., the beginning of the secondary growth phase) showed elevated mRNA amounts of follicle stimulating hormone receptor (fshr) and anti-Mullerian hormone. Early-to-mid vitellogenic follicles showed high mRNA levels of fshr and cytochrome P450, family 19, subfamily A, polypeptide 1a while mid-to-late vitellogenic follicles expressed increasing transcript amounts of luteinizing hormone/choriogonadotropin receptor, steroidogenic acute regulatory protein, and estrogen receptors 1 and 2a. The molecular data presented here may serve as a solid base for future studies focused on unraveling the specific mechanisms orchestrating follicular development in teleost fish. PMID- 21782033 TI - Antimicrobial peptides in the duodenum at the acute and convalescent stages in patients with diarrhea due to Vibrio cholerae O1 or enterotoxigenic Escherichia coli infection. AB - Patients with acute watery diarrhea caused by Vibrio cholerae O1 or enterotoxigenic Escherichia coli (ETEC) were analyzed for innate immune factors produced by the epithelium during the disease process. Duodenal biopsies were obtained from study participants at the acute (day 2) and convalescent (day 21) stages of disease. Levels of alpha-defensin (HD-5 and -6), beta-defensin (hBD-1 4), and cathelicidin (LL-37) mRNAs were determined by real-time qRT-PCR. hBD-2, HD-5, LL-37 peptides were analyzed in duodenal epithelium by immunomorphometry. Concentration of hBD-2 in stool was determined by ELISA. Specimens from healthy controls were also analyzed. hBD-2 mRNA levels were significantly increased at acute stage of diarrhea; hBD-2 peptide was detected in fecal specimens but barely in duodenal epithelium at acute stage. Immunomorphometry analysis showed that Paneth cells contain significantly higher amounts of HD-5 pre/propeptide at convalescence (P<0.01) and in healthy controls (P<0.001) compared to acute stage, LL-37 peptide levels also decreased at acute stage while mRNA levels remained unchanged. mRNA expression levels of the other antimicrobial peptides remained unchanged with higher levels of alpha-defensins than beta-defensins. V. cholerae induced an innate immune response at the acute stage of disease characterized by increased expression of hBD-2, and continued expression of hBD-1, HD-5-6, and LL 37. PMID- 21782036 TI - Classification and prioritization of usability problems using an augmented classification scheme. AB - Various methods exist for conducting usability evaluation studies in health care. But although the methodology is clear, no usability evaluation method provides a framework by which the usability reporting activities are fully standardized. Despite the frequent use of forms to report the usability problems and their context-information, this reporting is often hindered by information losses. This is due to the fact that evaluators' problem descriptions are based on individual judgments of what they find salient about a usability problem at a certain moment in time. Moreover, usability problems are typically classified in terms of their type, number, and severity. These classes are usually devised by the evaluator for the purpose at hand and the used problem types often are not mutually exclusive, complete and distinct. Also the impact of usability problems on the task outcome is usually not taken into account. Consequently, problem descriptions are often vague and even when combined with their classification in type or severity leave room for multiple interpretations when discussed with system designers afterwards. Correct interpretation of these problem descriptions is then highly dependent upon the extent to which the evaluators can retrieve relevant details from memory. To remedy this situation a framework is needed guiding usability evaluators in high quality reporting and unique classification of usability problems. Such a framework should allow the disclosure of the underlying essence of problem causes, the severity rating and the classification of the impact of usability problems on the task outcome. The User Action Framework (UAF) is an existing validated classification framework that allows the unique classification of usability problems, but it does not include a severity rating nor does it contain an assessment of the potential impact of usability flaws on the final task outcomes. We therefore augmented the UAF with a severity rating based on Nielsen's classification and added a classification for expressing the potential impact of usability problems on final task outcomes. Such an augmented scheme will provide the necessary information to system developers to understand the essence of usability problems, to prioritize problems and to tackle them in a system redesign. To investigate the feasibility of such an augmented scheme, it was applied to the results of usability studies of a computerized physician order entry system (CPOE). The evaluators classified the majority of the usability problems identically by use of the augmented UAF. In addition it helped in differentiating problems that looked similar but yet affect the user-system interaction and the task results differently and vice versa. This work is of value not only for system developers but also for researchers who want to study the results of other usability evaluation studies, because this scheme makes the results of usability studies comparable and easily retrievable. PMID- 21782034 TI - Signaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis. AB - Vitamin A, retinol, circulates in blood bound to serum retinol binding protein (RBP) and is transported into cells by a membrane protein termed stimulated by retinoic acid 6 (STRA6). It was reported that serum levels of RBP are elevated in obese rodents and humans, and that increased level of RBP in blood causes insulin resistance. A molecular mechanism by which RBP can exert such an effect is suggested by the recent discovery that STRA6 is not only a vitamin A transporter but also functions as a surface signaling receptor. Binding of RBP-ROH to STRA6 induces the phosphorylation of a tyrosine residue in the receptor C-terminus, thereby activating a JAK/STAT signaling cascade. Consequently, in STRA6 expressing cells such as adipocytes, RBP-ROH induces the expression of STAT target genes, including SOCS3, which suppresses insulin signaling, and PPARgamma, which enhances lipid accumulation. RBP-retinol thus joins the myriad of cytokines, growth factors and hormones which regulate gene transcription by activating cell surface receptors that signal through activation of Janus kinases and their associated transcription factors STATs. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21782035 TI - A review of causal inference for biomedical informatics. AB - Causality is an important concept throughout the health sciences and is particularly vital for informatics work such as finding adverse drug events or risk factors for disease using electronic health records. While philosophers and scientists working for centuries on formalizing what makes something a cause have not reached a consensus, new methods for inference show that we can make progress in this area in many practical cases. This article reviews core concepts in understanding and identifying causality and then reviews current computational methods for inference and explanation, focusing on inference from large-scale observational data. While the problem is not fully solved, we show that graphical models and Granger causality provide useful frameworks for inference and that a more recent approach based on temporal logic addresses some of the limitations of these methods. PMID- 21782038 TI - Homeobox gene expression in Brachiopoda: the role of Not and Cdx in bodyplan patterning, neurogenesis, and germ layer specification. AB - The molecular control that underlies brachiopod ontogeny is largely unknown. In order to contribute to this issue we analyzed the expression pattern of two homeobox containing genes, Not and Cdx, during development of the rhynchonelliform (i.e., articulate) brachiopod Terebratalia transversa. Not is a homeobox containing gene that regulates the formation of the notochord in chordates, while Cdx (caudal) is a ParaHox gene involved in the formation of posterior tissues of various animal phyla. The T. transversa homolog, TtrNot, is expressed in the ectoderm from the beginning of gastrulation until completion of larval development, which is marked by a three-lobed body with larval setae. Expression starts at gastrulation in two areas lateral to the blastopore and subsequently extends over the animal pole of the gastrula. With elongation of the gastrula, expression at the animal pole narrows to a small band, whereas the areas lateral to the blastopore shift slightly towards the future anterior region of the larva. Upon formation of the three larval body lobes, TtrNot expressing cells are present only in the posterior part of the apical lobe. Expression ceases entirely at the onset of larval setae formation. TtrNot expression is absent in unfertilized eggs, in embryos prior to gastrulation, and in settled individuals during and after metamorphosis. Comparison with the expression patterns of Not genes in other metazoan phyla suggests an ancestral role for this gene in gastrulation and germ layer (ectoderm) specification with co-opted functions in notochord formation in chordates and left/right determination in ambulacrarians and vertebrates. The caudal ortholog, TtrCdx, is first expressed in the ectoderm of the gastrulating embryo in the posterior region of the blastopore. Its expression stays stable in that domain until the blastopore is closed. Thereafter, the expression is confined to the ventral portion of the mantle lobe in the fully developed larva. No TtrCdx expression is detectable in the juvenile after metamorphosis. This expression of TtrCdx is congruent with findings in other metazoans, where genes belonging to the Cdx/caudal family are predominantly localized in posterior domains during gastrulation. Later in development this gene will play a fundamental role in the formation of posterior tissues. PMID- 21782037 TI - The National Lung Screening Trial's Endpoint Verification Process: determining the cause of death. AB - BACKGROUND: Randomized controlled trials (RCTs) evaluating cancer screening modalities usually employ cause-specific mortality as their primary endpoint. Because death certificate cause of death can be inaccurate, RCTs frequently use review committees to assign an underlying cause of death. We describe the National Lung Screening Trial's (NLST's) death review approach, the Endpoint Verification Process (EVP), which strives to minimize errors in assignment of cause of death due to lung cancer. METHODS: Deaths selected for review include those with a notation of lung cancer on the death certificate and those occurring among participants ever diagnosed with lung cancer. Other criteria that trigger death review include, but are not limited to, death within 6 months of a screen suspicious for lung cancer and death within 60 days of certain diagnostic evaluation procedures associated with a screen suspicious for lung cancer or a lung cancer diagnosis. EVP requires concordance on whether death was due to lung cancer. Deaths are first reviewed by the EVP chair. If concordance is not achieved, the death is next reviewed by an Endpoint Verification Team (EVT) member. If concordance between the chair- and member-assigned cause of death is not achieved, the death is next reviewed by a group of at least three EVT members. Cause of death is assigned at the step in which concordance was achieved, or if necessary, at the team review. CONCLUSIONS: NLST's EVP is designed to produce a highly accurate count of lung cancer deaths. PMID- 21782039 TI - Effect of overexpression of human SR-AI on oxLDL uptake and apoptosis in 293T cells. AB - Type I class A macrophage scavenger receptor (SR)-AI plays an important role in foam cell formation and in apoptosis in atherosclerosis, however the mechanism remains unclear. Therefore, we generated a pEGFP-C1-SR-AI plasmid construct for transient transfection of 293T human embryonic kidney cells and observed if SR-AI expression led: (i) to foam cell formation or apoptosis; and (ii) to expression of apoptosis-related genes Bcl-2 and Bak-1 in cells treated with oxidized low density lipoprotein (oxLDL). The pEGFP-C1 (empty vector) transfected cell line was used as a control. Transfection efficiency of each group was >90% and transfected cells expressed functional SR-AI protein. Binding and uptake of 3,3' dioctadecylindocarbocyanine-labeled oxLDL (DiI-oxLDL) were verified by flow cytometry; increases in the rate of oxLDL binding and uptake were observed in pEGFP-C1-SR-AI transfected 293T cells and incubation with oxLDL also led to increased apoptosis (~50%) compared with controls. A decrease in Bcl-2 and an increase in Bak-1 mRNA and protein expression were observed in pEGFP-C1-SR-AI transfected cells compared with controls. We conclude that transient over expression of SR-AI leads to an increase in oxLDL uptake and binding in a non macrophage cell line. In addition, over-expression of SR-AI induced non macrophage cell apoptosis via downregulation of Bcl-2 and upregulation of Bak-1 expression. We conclude that the 293T cell expression described here is a model for foam cell formation. These results may form the basis of further research into SR-AI structure and function (including lipoprotein uptake, apoptosis modulation and adhesion), which may give an insight into the progression of atherosclerosis in vivo. PMID- 21782040 TI - Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions. AB - Histamine plays major roles in allergic diseases and its action is mediated mainly by histamine H(1) receptor (H1R). We have demonstrated that histamine signaling-related H1R and histidine decarboxylase (HDC) genes are allergic diseases sensitive genes and their expression level affects severity of the allergic symptoms. Therefore, compounds that suppress histamine signaling should be promising candidates as anti-allergic drugs. Here, we investigated the effect of the extract from the bark of Albizia lebbeck (AL), one of the ingredients of Ayruvedic medicines, on H1R and HDC gene expression using toluene-2,4 diisocyanate (TDI) sensitized allergy model rats and HeLa cells expressing endogenous H1R. Administration of the AL extract significantly decreased the numbers of sneezing and nasal rubbing. Pretreatment with the AL extract suppressed TDI-induced H1R and HDC mRNA elevations as well as [(3)H]mepyramine binding, HDC activity, and histamine content in the nasal mucosa. AL extract also suppressed TDI-induced up-regulation of IL-4, IL-5, and IL-13 mRNA. In HeLa cells, AL extract suppressed phorbol-12-myristate-13-acetate- or histamine induced up-regulation of H1R mRNA. Our data suggest that AL alleviated nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through suppression of H1R and HDC gene transcriptions. Suppression of Th2-cytokine signaling by AL also suggests that it could affect the histamine-cytokine network. PMID- 21782041 TI - Thrombin plasticity. AB - Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20 years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to protease conformational transition. Understanding thrombin function in terms of 'plasticity' provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21782042 TI - Limb skeletal malformations - what the HOX is going on? AB - Synpolydactyly (SPD) is a rare congenital limb disorder caused by mutations in the HOXD13 gene, a homeobox transcription factor crucial for autopod development. The hallmarks of SPD are the webbing between the third and the fourth finger and the fourth and the fifth toe, with a partial or complete digit duplication in the syndactylous web. Different classes of HOXD13 mutations are involved in the pathogenesis of synpolydactyly, but an unequivocal genotype-phenotype correlation cannot always be achieved due to the lack of structure-function data of HOXD13. Mutations in DNA binding or polyalanine tract domains of HOXD13 result in predictable clinical outcomes. However, mutations outside of these domains cause a broad variety of clinical features that complicate the differential diagnosis. In this review, we summarize the different classes of HOXD13 mutations causing synpolydactyly phenotypes with respect to their underlying pathogenic mechanism of action. In addition, we emphasize the importance of the chicken embryo as an animal model system for the study of (limb) development and potential genotype phenotype correlations in SPD or other human malformation syndromes. PMID- 21782043 TI - Plant proteomics in Europe--COST action FA0603. PMID- 21782046 TI - The human histone H3 complement anno 2011. AB - Histones are highly basic, relatively small proteins that complex with DNA to form higher order structures that underlie chromosome topology. Of the four core histones H2A, H2B, H3 and H4, it is H3 that is most heavily modified at the post translational level. The human genome harbours 16 annotated bona fide histone H3 genes which code for four H3 protein variants. In 2010, two novel histone H3.3 protein variants were reported, carrying over twenty amino acid substitutions. Nevertheless, they appear to be incorporated into chromatin. Interestingly, these new H3 genes are located on human chromosome 5 in a repetitive region that harbours an additional five H3 pseudogenes, but no other core histone ORFs. In addition, a human-specific novel putative histone H3.3 variant located at 12p11.21 was reported in 2011. These developments raised the question as to how many more human histone H3 ORFs there may be. Using homology searches, we detected 41 histone H3 pseudogenes in the current human genome assembly. The large majority are derived from the H3.3 gene H3F3A, and three of those may code for yet more histone H3.3 protein variants. We also identified one extra intact H3.2-type variant ORF in the vicinity of the canonical HIST2 gene cluster at chromosome 1p21.2. RNA polymerase II occupancy data revealed heterogeneity in H3 gene expression in human cell lines. None of the novel H3 genes were significantly occupied by RNA polymerase II in the data sets at hand, however. We discuss the implications of these recent developments. PMID- 21782048 TI - Staining procedure for the detection of microcracks: application to ewe bone. AB - Microcracks are one of the determinants of the bone strength and their accumulation may contribute to increased fracture risk. They are detected after bulk staining with various dyes, including basic fuschin, calcein and xylenol orange. The duration of staining usually varies across types of bone and species. The ewe is a large animal with a bone remodeling similar to humans, used as an animal model in bone histomorphometry studies. The aim of the present study was to determine the optimal conditions for bulk staining with xylenol orange of ewe bone. Xylenol orange 5mM in 70% ethanol was applied to iliac crest and vertebral biopsies for 2 or 15 days or 1, 2 or 3 months. After embedding, sections of 40, 50 and 80 MUm thick were cut with either a precision diamond wire saw or a microtome. The staining was not visible after 2 or 15 days and was heterogeneous after 1 or 2 months. The quality of 40 and 50 MUm thick sections was not preserved compared with those of 80 MUm. Microcracks were suitably observed on ewe bone after bulk staining with xylenol orange for 3 months, in 80 MUm thick sections. We conclude that the staining procedures should differ when examining ewe or human bone. This may be due to differences in bone matrix composition. PMID- 21782045 TI - Histone acetyltransferase 1: More than just an enzyme? AB - Histone acetyltransferase 1 (HAT1) is an enzyme that is likely to be responsible for the acetylation that occurs on lysines 5 and 12 of the NH(2)-terminal tail of newly synthesized histone H4. Initial studies suggested that, despite its evolutionary conservation, this modification of new histone H4 played only a minor role in chromatin assembly. However, a number of recent studies have brought into focus the important role of both this modification and HAT1 in histone dynamics. Surprisingly, the function of HAT1 in chromatin assembly may extend beyond just its catalytic activity to include its role as a major histone binding protein. These results are incorporated into a model for the function of HAT1 in histone deposition and chromatin assembly. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly. PMID- 21782049 TI - Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. AB - OBJECTIVE: We systematically assessed bone mineral density (BMD), bone turnover markers (BTM), and fractures in a large cohort of patients with Indolent Systemic Mastocytosis (ISM). METHODS: Eighty-two patients (mean age 48 years, 37 women) with ISM were studied. BMD was measured by dual X-ray absorptiometry at the lumbar spine and proximal hip. The serum markers of bone turnover included bone specific alkaline phosphatase, C-telopeptides of type I collagen, and serum osteocalcin. Previous clinical fractures were registered and spine X-ray was obtained from all patients. RESULTS: Three women were excluded for concomitant diseases associated to osteoporosis. Osteoporosis according with the WHO classification (T-score<-2.5) was found in 16 patients (20.0%) (7 females and 9 men). Mastocytosis-related low BMD (Z-score at either the spine or the hip<-2) was found in 3 women (9%) and 13 men (28%). The BMD was generally lower at the spine than at the hip. No significant correlation was observed between serum tryptase levels and T or Z-score BMD. One or more moderate or severe vertebral fractures were found in 17 patients (12 men); in 11 of them Z-score values were> 2 or not valuable at the spine. No significant difference was found in the prevalence of mastocytosis-related low BMD and/or vertebral fractures between patients with or without skin involvement. Two patients had radiographic and densitometric osteosclerosis-like characteristics. In osteoporotic patients higher, normal or lower serum BTM were found, without correlations with serum tryptase levels, while in patients with osteosclerosis both BTM and serum tryptase values were particularly increased. CONCLUSIONS: Vertebral osteoporosis and fractures are frequent in patients with ISM. Spine X-ray and densitometric examination are warranted in all patients, also without skin involvement and particularly in males; Z-score other than T-score BMD must be evaluated. Patients with idiopathic osteoporosis should be evaluated for mast cell disease. Both high than low BTM can be observed in patients with osteoporosis while osteosclerosis is characterized by high bone turnover and serum tryptase levels. PMID- 21782050 TI - The effect of static bone strain on implant stability and bone remodeling. AB - Bone remodeling is a process involving both dynamic and static bone strain. Although there exist numerous studies on the effect of dynamic strain on implant stability and bone remodeling, the effect of static strain has yet to be clarified. Hence, for this purpose, the effect of static bone strain on implant stability and bone remodeling was investigated in rabbits. Based on Finite Element (FE) simulation two different test implants, with a diametrical increase of 0.15 mm (group A) and 0.05 mm (group B) creating static strains in the bone of 0.045 and 0.015 respectively, were inserted in the femur (group A) and the proximal tibia metaphysis (groups A and B respectively) of 14 rabbits to observe the biological response. Both groups were compared to control implants, with no diametrical increase (group C), which were placed in the opposite leg. At the time of surgery, the insertion torque (ITQ) was measured to represent the initial stability. The rabbits were euthanized after 24 days and the removal torque (RTQ) was measured to analyze the effect on implant stability and bone remodeling. The mean ITQ value was significantly higher for both groups A and B compared to group C regardless of the bone type. The RTQ value was significantly higher in tibia for groups A and B compared to group C while group A placed in femur presented no significant difference compared to group C. The results suggest that increased static strain in the bone not only creates higher implant stability at the time of insertion, but also generates increased implant stability throughout the observation period. PMID- 21782051 TI - Successful pregnancy in a Swyer syndrome patient with preexisting hypertension. AB - OBJECTIVE: To report a case of a successful pregnancy and delivery of a patient with 46,XY pure gonadal dysgenesis (Swyer syndrome) and preexisting chronic hypertension who underwent in vitro fertilization (IVF) and embryo transfer (ET). DESIGN: Case report and review of the literature. SETTING: 2nd Department of Obstetrics and Gynecology, University of Athens, Medical School, "Aretaieion" Hospital. Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery. PATIENT(S): A 35-year-old woman with Swyer syndrome and chronic idiopathic hypertension. INTERVENTION(S): Karyotype analysis due to primary amenorrhea; gonadectomy, hormone therapy, investigation of hypertension, IVF using donor oocytes, embryo transfer and caesarean delivery for fetal distress. MAIN OUTCOME MEASURE(S): Successful pregnancy and live birth. RESULT(S): We present a rare case of a successful pregnancy of a patient with Swyer syndrome accompanied by idiopathic chronic hypertension. CONCLUSION(S): A woman with Swyer syndrome, hypoplastic uterus, and chronic hypertension delivered a healthy newborn. PMID- 21782052 TI - Cryopreservation in assisted reproduction: milestones and future challenges. PMID- 21782053 TI - The principal variables of cryopreservation: solutions, temperatures, and rate changes. AB - OBJECTIVE: To describe several fundamental variables that influence ultimate survival of oocytes and embryos when they are cryopreserved. DESIGN: The literature describing fundamental and applied aspects of cryobiological variables that determine the responses of oocytes and embryos has been reviewed. CONCLUSION(S): When oocytes and embryos are to be cryopreserved, they are suspended in a solution of one of several low-molecular-weight solutes. The permeability of oocytes and embryos to these various low-molecular-weight compounds differs. These differences determine how these compounds are taken up by cells. That, in turn, influences how these compounds act to protect cells against damage when the cells are subjected to cryopreservation. Because of those protective effects, the compounds are referred to as cryoprotective additives. Another principal variable that influences oocyte and embryo survival is the rate at which the cells are cooled to subzero temperatures. After being stored for some time at -196 degrees C in liquid nitrogen, the cryopreserved oocytes and embryos are warmed to liquefy the medium. The rate at which the specimens are warmed is at least as important, if not more important, in determining the ultimate survival of the oocytes and embryos. The effects of these physical variables on cell survival also are described. PMID- 21782054 TI - Long-term life and partnership satisfaction in infertile patients: a 5-year longitudinal study. AB - OBJECTIVE: To describe the long-term effects of infertility on life and partnership satisfaction. DESIGN: Longitudinal cohort study. SETTING: A university outpatient andrology and gynecology infertility clinic. PATIENT(S): 275 men and 272 women treated for infertility between August 2000 and December 2001. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The Life Satisfaction Questionnaire (FLZ), the Partnership Questionnaire (PFB), and sociodemographic items at baseline (T1) and 5 years later (T2). RESULT(S): Compared with a representative sample, our male and female participants had higher Finance and Partnership scores and lower Health scores on the FLZ at T1. They also had markedly higher PFB scores, with the exception of Conflict Behavior. After 5 years (T2), 101 men and 113 women rated the Partnership and Sexuality FLZ subscales as well as all the PFB subscales statistically significantly lower than at baseline. Only the women rated the Self-esteem FLZ subscale lower than at baseline (T1). Participants who became parents had lower Leisure and Partnership FLZ subscale scores, and fathers had lower Finance FLZ subscale scores. CONCLUSION(S): Satisfaction declined over 5 years for both men and women, but only in the partnership-related domains. Women were more affected than men. The success of infertility treatment had only a minor influence on a couple's future satisfaction. PMID- 21782055 TI - Therapy of mantle cell lymphoma: new treatment options in an old disease or vice versa? PMID- 21782056 TI - Histopathology of mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a relatively rare lymphoma, accounting for less than 10% only of all lymphomas. Its morphology is quite homogeneous, but it varies strikingly in about 10% of the cases, making the diagnosis of MCL challenging for histopathologists. The definition of the disease was greatly influenced by the discovery of the translocation t(11;14)(q13,q32), which juxtaposes the cyclin D1 and the immunoglobulin heavy chain genes and is present in the vast majority of MCL cases. The introduction of monoclonal antibodies for the detection of cyclin D1 expression into the diagnostic procedure substantially improved the reproducibility and reliability of the pathological diagnosis. However, new challenges for histopathologists have arisen over the last years, among which are the detection of cyclin D1-negative MCL cases and clinically relevant prognostic subgroups. PMID- 21782057 TI - Molecular pathogenesis of mantle cell lymphoma: new perspectives and challenges with clinical implications. AB - Mantle cell lymphoma (MCL) is a B-cell neoplasia genetically characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of its target gene CCND1. The aggressive clinical behavior of this tumor has been considered to be influenced by its genetic and molecular pathogenesis that integrates an accumulation of many chromosomal aberrations associated with frequent alterations in cell cycle and DNA damage response mechanisms and activation of cell survival pathways. Recent studies aimed to define new chromosomal regions, target genes, and signaling pathways that may contribute to the pathogenesis of this tumor. A subset of patients presenting with a leukemic and non-nodal disease and following a more indolent clinical evolution seem to have some differences in their chromosomal and genomic profiles compared to patients with conventional MCL. The new studies are opening new perspectives on the pathogenesis of this lymphoma that may influence our clinical practice in the diagnosis and management of patients. PMID- 21782058 TI - The use of microarray technologies in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is characterized by adverse prognosis and the development of novel therapeutic approaches is essential to improve outcome. The introduction of gene expression profiling using DNA microarrays has significantly enhanced our understanding of the molecular pathogenesis of MCL, which is a prerequisite to the development of novel treatment strategies. Gene expression profiling can furthermore be applied to predict treatment response at diagnosis and thus can be used to assess a patient's individual risk profile. This review summarizes our current knowledge on the use of microarray technology in MCL. PMID- 21782059 TI - Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance. AB - The prognostic impact of minimal residual disease (MRD) has been demonstrated for several hematologic malignancies. While in acute lymphoblastic leukemias MRD assessment by polymerase chain reaction (PCR)-based methods has been established as an important tool for clinical risk assessment and is part of clinical management, data demonstrating a prognostic value of MRD in mantle cell lymphoma (MCL) were sparse and results from randomized trials have been published only recently. In the present review technical aspects of different MRD detection methods are discussed, as well as the prognostic relevance of MRD in the context of clinical trials in patients with MCL. Furthermore, recommendations are given for workflow and useful implication of MRD in future clinical trials design. PMID- 21782060 TI - Prognostic relevance of clinical risk factors in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) has only recently been recognized as a separate biologically defined lymphoma entity. Due to its low incidence, many reports on clinical prognostic factors are limited by small patient numbers. The MCL International Prognostic Index (MIPI) was developed using data of more than 400 patients treated within randomized trials of the European MCL Network. Based on the routinely available clinical prognostic factors age, performance status, lactate dehydrogenase (LDH), and white blood cell count, three MIPI risk groups were defined with different survival. The MIPI has been externally validated by several independent groups. It therefore may be used to report and compare risk profiles of MCL patient groups, to stratify randomization in clinical trials, to perform risk adjustment in epidemiological studies, and it might be implemented into risk-adapted treatment strategies. PMID- 21782061 TI - Is there a role for "watch and wait" in patients with mantle cell lymphoma? AB - Up to one third of patients with mantle cell lymphoma (MCL) may be observed for a period of months to years before developing indications for therapy. Importantly, observational studies suggest that this approach has no apparent negative impact on their overall survival. Although there is broad agreement on which patients require early therapy, identification of patients with less aggressive disease can be challenging. Clinical tools such as the Mantle Cell International Prognostic Index (MIPI) and Ki67 are effective at predicting survival but may not always correspond with indications for treatment. Research tools such as the proliferative signature are attractive but have yet to be evaluated in this context. Physicians, therefore, must make decisions regarding therapy based on the best available evidence. In the absence of evidence that treatment necessarily influences long-term survival, it may be reasonable to observe selected patients for a period of time prior to making definitive treatment related decisions. Collaborative efforts are required to better understand the pathophysiology of the disease and potentially identify patients amenable to "watch and wait." Similarly, patients with less aggressive MCL may be an ideal group in which to evaluate novel treatment approaches. PMID- 21782062 TI - Treatment of younger patients with mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an individualized entity that is well characterized at the molecular level and considered to be a disease of elderly patients. However, about half of patients are less than 65 years of age and may benefit from intensive therapies. Although MCL has been considered during the last three decades as an incurable disease with current chemotherapy regimens, in young patients recent intense chemo-immunotherapy (CIT) induction regimens including high-dose cytarabine with consolidation with autologous stem cell transplantation (ASCT) have increased significantly the outcome of patients with the disease; some may experience long-term survival free of disease and may even be cured. In addition, new drugs targeting some pathways, including molecular alterations of the disease, are being progressively incorporated into the therapeutic armamentarium of the disease and will certainly contribute to further improve prognosis. In the near future, more individualized approaches are foreseen that will take into account risk factors present at diagnosis, biomarkers representative of the molecular alterations, as well as quality of the response assessed by molecular residual diseases analysis. In this review, we discuss the current therapeutic approaches with classical CITs, the role of autologous and allogeneic stem cell transplantation, and the main new drugs that target major molecular pathways alterations of the disease, as well as their positioning during induction, consolidation, and maintenance in first-line treatment and in relapsing younger patients with MCL. PMID- 21782063 TI - Treatment of elderly patients with mantle cell lymphoma. AB - Treatment of elderly patients with a mantle cell lymphoma (MCL) is a challenge. High-dose cytarabine and autologous transplantation, both important components of the treatment in younger patients, are not feasible for most elderly patients. However, in fit elderly patients long progression-free survival and molecular remissions are possible. The regimen most commonly used is rituximab combined with an anthracycline-combination therapy, ie, R-CHOP. An alternative is rituximab combined with a purine analogue-containing regimen, ie, fludarabine with cyclophosphamide (R-FC). The results of a large randomized study comparing these two regimens are expected soon. Maintenance therapy with rituximab after induction improves progression-free survival. Relapse of lymphoma will occur in all patients, as cure of MCL is not yet achieved with standard therapy. Second line treatment regimens with reasonable results are described. Treatment of the frail elderly patient and of patients after first relapse should aim at reducing symptoms and maintaining quality of life. It therefore should be individualized, and benefits and possible side effects should be carefully balanced. It is advised to include patients with MCL in clinical trials to obtain a better understanding of the value of different treatment options and new developments. PMID- 21782065 TI - Allogeneic stem cell transplantation in mantle cell lymphoma: where are we now and which way should we go? AB - Despite the use of intensive chemotherapy regimens with or without autologous stem cell transplant (auto-SCT) support, the clinical course of mantle cell lymphoma (MCL) remains characterized by iterative relapses and is still an incurable disease. The impact of allogeneic stem cell transplantation (allo-SCT) in MCL emerged in the late 1990s when it was shown that myeloablative allo-SCT could potentially cure some relapsed/refractory MCL patients. This curative impact is sustained by a graft-versus-disease (GVD-MCL) effect. However, toxicity and mortality following myeloablative allo-SCT are too high and have limited its use for patients aged under 65 years at diagnosis. Reduced-intensity conditioning regimens (RIC-allo) entail lower toxicity and reduced transplant-related mortality (TRM), making allogeneic transplant a valid option for a larger MCL population. At present, RIC-allo should be considered a valid therapeutic option for relapsed MCL patients and innovative therapeutic strategies including RIC allo need to be investigated. Herein, the role of GVD-MCL and place of allo-SCT in MCL is discussed, taking into account the most recent literature, and several ways to improve RIC-allo in MCL that deserve to be explored are presented. PMID- 21782066 TI - Targeting DNA. PMID- 21782067 TI - Genitourinary emergencies in emergency medicine. PMID- 21782064 TI - Molecular targeted approaches in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good, but most patients relapse, resulting in a median survival of 5 to 7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second-generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress. PMID- 21782068 TI - Genitourinary (GU) complaints can be quite distressing for the patient, parent, or caretaker (and even, at times, for the health care provider!). Introduction. PMID- 21782069 TI - Scrotal emergencies. AB - An acute scrotum is defined as an acute painful swelling of the scrotum or its contents, accompanied by local signs or general symptoms. Early identification and skillful management of testicular torsion is critical, as it may threaten testicular viability and future fertility if not managed expediently and appropriately. The cremasteric reflex and testicular sonography are frequently used, yet imperfect, diagnostic tools in assessing for testicular torsion. Other emergent conditions include incarcerated inguinal hernia, Fournier's gangrene, and any form of genitourinary trauma until proven otherwise. This article reviews the evaluation and management of the acute scrotum in the emergency department. PMID- 21782070 TI - Penile emergencies. AB - The penis is a very sensitive organ and even minor injury or discomfort may cause a patient to seek emergency evaluation. Emergency practitioners must be most concerned with the entities that, if left untreated, can result in ischemia and necrosis of the penis, namely ischemic priapism, paraphimosis, and entrapment injury. Any penile trauma should be considered an emergency until proven otherwise. This article discusses emergent penile complaints in adults, with emphasis on the most serious and common conditions. PMID- 21782071 TI - Genitourinary trauma. AB - Injury to the genitourinary (GU) tract occurs in up to 10% of all traumas, with the kidneys being the most frequently affected. Trauma to different areas of the GU tract can be caused in a variety of ways, and the diagnostics and management of the injuries vary widely depending on the mechanism and location. Overall, fatalities from GU trauma are not common. However, significant morbidity can occur without prompt recognition and appropriate intervention. A basic understanding of urologic trauma is necessary for all emergency practitioners when caring for trauma patients. PMID- 21782072 TI - Urolithiasis in the emergency department. AB - Urolithiasis commonly presents to the emergency department with acute, severe, unilateral flank pain. Patients with a suspected first-time stone or atypical presentation should be evaluated with a noncontrast computed tomography scan to confirm the diagnosis and rule out alternative diagnoses. Narcotics remain the mainstay of pain management but in select patients, nonsteroidal anti inflammatories alone or in combination with narcotics provide safe and effective analgesia in the emergency department. Whereas most kidney stones can be managed with pain control and expectant management, obstructing kidney stones with a suspected proximal urinary tract infection are urological emergencies requiring emergent decompression, antibiotics, and resuscitation. PMID- 21782073 TI - Diagnosis and management of urinary tract infection and pyelonephritis. AB - Urinary tract infections (UTIs) are the most common bacterial infections treated in the outpatient setting and range in severity from minimally symptomatic cystitis to severe septic shock in a wide array of patients. Diagnosis of uncomplicated cystitis can be inferred from history and physical, and confirmed by urinalysis. Appropriate antimicrobial therapy should rapidly improve symptoms in all UTIs. Treatment can be further tailored according to severity of illness, analysis of individualized risk factors, and antimicrobial resistance patterns. This article discusses treatment options in light of bacterial resistance in the twenty-first century. PMID- 21782074 TI - Genitourinary imaging in the emergency department. AB - The emergency medicine (EM) specialist has a wide-ranging armamentarium of imaging modalities available for use in the patient with genitourinary complaints. This article covers the various imaging options, with a discussion of the advantages and disadvantages of each of these different modalities. Special emphasis is placed on point-of-care EM ultrasound performed by the EM specialist at the patient bedside. PMID- 21782075 TI - Renal failure: emergency evaluation and management. AB - Patients with altered renal function are frequently encountered in the emergency department (ED) and emergency physicians often play an important role in the evaluation and management of renal disease. Early recognition, diagnosis, prevention of further iatrogenic injury, and management of renal disease have important implications for long-term morbidity and mortality. This article reviews basic renal physiology, discusses the differential diagnosis and approach to therapy, as well as strategies to prevent further renal injury, for adult patients who present to the ED with renal injury or failure. PMID- 21782076 TI - Emergency department management of sexually transmitted infections. AB - Patients seeking treatment for sexually transmitted infections (STIs) account for a large number of emergency department (ED) visits per year. Despite the large volume of patients, STIs are often missed or treated inappropriately. Due to the high prevalence and incidence of STIs in the United States, it is important that emergency practitioners recognize symptoms consistent with STIs, and treat presumptively. This practice leads to overtreatment of STIs; however, when weighed against the public health risk and complications of untreated disease, empiric treatment is recommended. This article provides an overview of STIs encountered in the ED and recommendations for their treatment. PMID- 21782077 TI - Sexual assault. AB - Sexual assault is a problem that permeates all socioeconomic classes and impacts hundreds of thousands in the United States and millions worldwide. Most victims do not report the assault; those that do often present to an emergency department. Care must encompass the patients' physical and emotional needs. Providers must be cognizant regarding handling of evidence and possible legal ramifications. This article discusses the emergency medicine approach to history taking, physical examination, evidence collection, chain of custody, psychological and medical treatment, and appropriate follow-up. Special circumstances discussed include intimate partner violence, male examinations, pediatric examinations, suspect examinations, and drug-facilitated assaults. PMID- 21782078 TI - Genitourinary emergencies in the nonpregnant woman. AB - Lower abdominal and pelvic pains are common symptoms in women who present to the emergency department (ED). Once pregnancy has been ruled out, attention should focus on other potential life or fertility threats. Ultrasound remains the most helpful initial diagnostic modality. Time-sensitive and serious conditions, such as large ovarian masses or abnormal vaginal bleeding, need gynecologic consultation. Because many patients do not have access to primary care, ED physicians should be familiar with the treatment of sexually transmitted diseases. However, most nonpregnant women with pelvic complaints can safely be managed in the outpatient setting after ED evaluation. PMID- 21782079 TI - Pediatric urinary tract infections. AB - Urinary tract infections (UTIs) in children are commonly seen in the emergency department and pose several challenges to establishing the proper diagnosis and determining management. This article reviews pediatric UTI and addresses epidemiology, diagnosis, treatment, and imaging, and their importance to the practicing emergency medicine provider. Accurate and timely diagnosis of pediatric UTI can prevent short-term complications, such as severe pyelonephritis or sepsis, and long-term sequelae including scarring of the kidneys, hypertension, and ultimately chronic renal insufficiency and need for transplant. PMID- 21782080 TI - Pediatric genitourinary emergencies. AB - Pediatric medical complaints and differential diagnoses often vary from adults, requiring a specialized knowledge base and behavioral skill set. This article addresses a variety of congenital and acquired pediatric genitourinary disorders. Genitourinary emergencies include paraphismosis, priapism, serious infection, significant traumatic injury and gonadal torsion. PMID- 21782081 TI - Compromised corneal endothelium and cataract: how should we decide? PMID- 21782082 TI - Appropriate research design for studies of refractive surgery in children. PMID- 21782083 TI - Approach to cataract with persistent hyperplastic primary vitreous. AB - Persistent hyperplastic primary vitreous (PHPV) is a congenital anomaly in which the hyaloid vasculature persists beyond fetal life. In cases in which cataract is associated with PHPV, intraoperative bleeding is a potential complication during cataract surgery. The pars plana approach along with endocoagulation has been used in such cases. We describe an alternative approach using a Fugo plasma blade via an anterior route. This approach provides better control over the posterior capsulotomy along with minimal traction over the retina and, most important, hemostasis during surgery. PMID- 21782084 TI - Repositioning and scleral fixation of subluxated lenses using a T-shaped capsule stabilization hook. AB - We describe a T-shaped capsule stabilization hook (modified capsule expander [M CE]) used for repositioning and scleral fixation of the lens capsule of subluxated lenses. The 5-0 polypropylene device is flexible and attached to a curved needle. The contact portion is bent at 1.25 mm, and the end bifurcates in a T configuration to form a 3.75 mm footpad from which the capsular bag can be suspended. Modified capsule expanders were implanted in 4 eyes of 4 patients with subluxated cataractous lenses and provided excellent support and centration of the intraocular lens (IOL)-capsular bag complex. The IOLs remained well centered and stable. The corrected distance visual acuity improved to at least 20/20 in all patients after surgery. Thus, M-CEs were effective in fixating the lens capsule to the sclera in patients with significant zonular weakness. PMID- 21782085 TI - Accuracy of toric intraocular lens implantation in cataract and refractive surgery. AB - PURPOSE: To determine the accuracy of a commonly used 3-step procedure for toric pseudophakic and phakic intraocular lens (IOL) implantation. SETTING: University Eye Clinic, Maastricht University Medical Centre, Maastricht, The Netherlands. DESIGN: Cohort study. METHOD: In this analysis of toric IOL implantation, 6 preoperative images of the eye per patient and the surgery video were obtained using a digital imaging system. All 3 steps for toric IOL implantation were analyzed as follows: reference axis marking, alignment axis marking, and IOL alignment. In addition, vector analysis was used to calculate the errors in toric IOL alignment. RESULTS: Forty eyes (26 pseudophakic, 14 phakic) were analyzed. The mean errors in reference axis marking, alignment axis marking, and toric IOL alignment were 2.4 degrees +/- 0.8 (SD), 3.3 +/- 2.0 degrees, and 2.6 +/- 2.6 degrees, respectively. Together, these 3 errors led to a mean total error in toric IOL alignment of 4.9 +/- 2.1 degrees. Subgroup analysis showed no significant difference in mean error between pseudophakic IOL and phakic toric IOL alignment (P=.501). Vector analysis showed a mean angle or error of -2 +/- 8 degrees (pseudophakic IOLs) and 6 +/- 14 degrees (phakic IOLs). CONCLUSIONS: A commonly used 3-step ink-marker procedure to implant toric IOLs led to a mean error in IOL placement of approximately 5 degrees. The error was especially relevant in cases in which higher cylinder power IOLs were implanted. Orienting the toric IOL with great accuracy is necessary in all patients to achieve the best cylinder correction. PMID- 21782086 TI - Cataract surgery with toric intraocular lens implantation in patients with high corneal astigmatism. AB - PURPOSE: To evaluate the visual and refractive outcomes after toric intraocular lens (IOL) implantation in patients with high amounts of corneal astigmatism. SETTING: University Eye Clinic, Maastricht, The Netherlands; Oftalvist Centro Integral Ocular and Fundacion Oftalmologica del Mediterraneo, Valencia, Spain. DESIGN: Cohort study. METHODS: This study comprised eyes with cataract and more than 2.25 diopters (D) of corneal astigmatism who had toric Acrysof SN60T6, SN60T7, SN60T8, or SN60T9 IOL implantation. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, visual potential index (ratio of postoperative UDVA to postoperative CDVA), residual refractive cylinder, IOL misalignment, and surgically induced astigmatism (SIA) were evaluated. RESULTS: The mean follow-up in this study of 67 eyes (45 patients) was 6.3 months. Postoperatively, the mean UDVA was 0.61 +/- 0.26 (SD) and the mean CDVA, 0.81 +/- 0.21. The UDVA of 20/40 was better in 83% of eyes and 20/30 or better in 50% of eyes. The mean visual potential index was 0.78. The residual refractive cylinder was less than 0.75 D in 62% of eyes and less than 1.00 D in 81% of eyes. The mean IOL misalignment was 3.2 +/- 2.8 degrees. The mean SIA was -0.40 +/- 0.60 D with a superior incision and -0.19 +/- 0.78 D with a temporal incision (P=.034). CONCLUSION: Implantation of the toric IOL during cataract surgery was effective and safe in correcting high amounts of corneal astigmatism. PMID- 21782087 TI - Pharmacologic pupil dilation as a predictive test for the risk for intraoperative floppy-iris syndrome. AB - PURPOSE: To evaluate the effect of alpha1-adrenergic receptor antagonists (alpha1 ARAs) on pupil diameter and determine whether the diameter predicts intraoperative floppy-iris syndrome (IFIS). SETTING: Ophthalmology Section, Palermo University, Palermo, Italy. DESIGN: Prospective cohort study. METHODS: Male outpatients taking tamsulosin, alpha(1)-ARAs, or no alpha(1)-ARAs having phacoemulsification were recruited. Pupils were measured 1 month preoperatively, immediately preoperatively, and postoperatively under mesopic low (0.4 lux) and high (4.0 lux) illumination after pharmacologic dilation. The IFIS severity was graded. RESULTS: Each group comprised 50 patients. Pharmacologic dilation in both alpha(1)-ARA groups was statistically significantly less than in the no alpha1 ARA group 1 month preoperatively, immediately before surgery, and postoperatively (P=.001, P<.0005, and P<.0005, respectively). The IFIS incidence differed significantly between the tamsulosin and other alpha(1)-ARA groups and the no alpha1-ARA group (P<.0005 and P=.017, respectively) and between the tamsulosin group and the other alpha1-ARA group (P=.027). On regression analysis, the hazard ratio for overall IFIS incidence was 3.8 in the other alpha(1)-ARA group (P=.012) and 10.1 in the tamsulosin group (P<.0005). Pupil size was inversely related to IFIS incidence and severity (P<.0005). A dilated pupil of 7.0 mm or smaller had 73% sensitivity and 95% specificity for predicting IFIS (P=.0001). CONCLUSIONS: Pupil dilation was inhibited by alpha(1)-ARAs, in particular tamsulosin. For a pupil 7.0 mm or smaller, the risk for IFIS existed regardless of alpha(1)-ARAs treatment, which surgeons should take into consideration. PMID- 21782088 TI - Refractive change and stability after Descemet membrane endothelial keratoplasty. Effect of corneal dehydration-induced hyperopic shift on intraocular lens power calculation. AB - PURPOSE: To determine the refractive change and stability of the transplanted cornea after Descemet membrane endothelial keratoplasty (DMEK) through a 3.0 mm clear corneal incision. SETTING: Tertiary referral center. DESIGN: Cohort study. METHODS: Subjective and objective refractive data from pseudophakic eyes were obtained before and 3 and 6 months after DMEK. RESULTS: The study comprised 50 eyes, 7 were phakic and 43 pseudophakic. Six months postoperatively, the corrected distance visual acuity was 20/25 (0.8) or better in 38 eyes (74%). The mean increase in spherical equivalent at 6 months (N = 50) was +0.32 diopter (D) +/- 1.01 D (SD) (P=.0304) and in refractive cylinder, -0.48 +/- 1.02 D (P=.001). Although Scheimpflug imaging showed a stable anterior corneal curvature, the posterior curvature increased from 5.50 +/- 0.5 D preoperatively to 6.40 +/- 0.4 D at 6 months and pachymetry decreased from 672 +/- 82 MUm to 540 +/- 59 MUm, respectively (both N = 32) (both P=.000). CONCLUSIONS: After DMEK, a slight preoperative to postoperative refractive change and stabilization at 3 months occurred that may induce a hyperopic shift that was not the result of the negative lenticule effect of DSEK/DSAEK. Thus, in DMEK, the hyperopic shift may result from a reversal of a preceding myopic shift induced by stromal swelling in endothelial disease. If so, normal intraocular power nomograms apply for cataract surgery before or during DMEK. PMID- 21782089 TI - Efficacy, predictability, and safety of wavefront-guided refractive laser treatment: metaanalysis. AB - PURPOSE: To compare the efficacy, predictability, safety, and induced higher order aberrations (HOAs) between wavefront-guided and non-wavefront-guided ablations. SETTING: Division of Ophthalmology and Visual Sciences, University of Nottingham, Nottingham, United Kingdom. DESIGN: Metaanalysis. METHODS: The Cochrane Central Register of Controlled Trials, PubMED, and EMBASE were searched for randomized controlled trails. Trials meeting the selection criteria were quality appraised and data extracted by 2 independent authors. Measures of association were pooled quantitatively using metaanalytical methods. Comparison between wavefront-guided and non-wavefront-guided ablations was measured as pooled odds ratios (ORs) or weighted mean differences. The pooled ORs and 95% confidence intervals (CIs) were computed for efficacy, safety, and predictability. The weighted mean difference and 95% CIs were used to compare induced HOAs. RESULTS: Eight trials involving 955 eyes were included. After wavefront-guided LASIK, the pooled OR of achieving uncorrected distance visual acuity (UDVA) of 20/20 (efficacy) was 1.10 (95% CI, 0.66-1.83; P=.72), the pooled OR of achieving a result within +/- 0.50 diopter of intended target (predictability) was 1.03 (95% CI, 0.60-1.75; P=.92), and the weighted mean difference in induced HOAs was -0.09 (95% CI, -0.17 to -0.01; P=.04). No study reported loss of 2 or more lines of Snellen acuity (safety) with either modality. CONCLUSIONS: Metaanalysis showed no clear evidence of a benefit of wavefront guided over non-wavefront-guided ablations. However, there was a lack of standardized reporting of UDVA better than 20/20, which might mask an advantage in wavefront-guided treatment. With high preexisting HOAs, wavefront-guided has advantages over non-wavefront-guided treatment. PMID- 21782090 TI - Objective optical assessment of tear-film quality dynamics in normal and mildly symptomatic dry eyes. AB - PURPOSE: To evaluate and compare the tear-film dynamics in normal eyes and in eyes with mild dry-eye symptoms using a new noninvasive optical method based on a double-pass instrument. SETTING: Hospital Universitario Virgen de la Arrixaca, Murcia, Spain. DESIGN: Evaluation of diagnostic test or technology. METHODS: Dynamic recording of double-pass retinal images during unforced tear-film breakup was performed in eyes with mild dry-eye symptoms (study group) and in an asymptomatic control group. Series of consecutive retinal images were recorded every 0.5 seconds while the patient avoided blinking. Measurements were performed under low-light conditions to naturally increase pupil diameter and maximize the method's sensitivity. Additional clinical tests were performed for comparison and included tear breakup time (TBUT), Schirmer I tests, and a normalized questionnaire (McMonnies). From the retinal images, a quality metric, the intensity distribution index, was calculated. An objective TBUT value was estimated in each eye when the intensity distribution index surpassed a defined threshold value compared with the initial baseline. RESULTS: The study group comprised 20 eyes and the control group, 18 eyes. Symptomatic dry eyes had a typical exponential increase in the intensity distribution index with time. The objective TBUT values in the study group were comparable to the clinical TBUT estimates. CONCLUSIONS: The new objective optical method to evaluate the quality and stability of the tear film was sensitive in detecting mild symptoms of dry eye and differentiating from normal cases. The procedure may allow early detection and follow-up of patients' tear film-related complaints. PMID- 21782091 TI - Flattening of the cornea after collagen crosslinking for keratoconus. AB - PURPOSE: To identify preoperative parameters that may predict flattening of the keratoconic cornea after collagen crosslinking (CXL). SETTING: Institut fur Refraktive und Ophthalmo-Chirurgie (IROC), Zurich, Switzerland. DESIGN: Cohort study. METHODS: Patients with verified progressive primary keratectasia received standard corneal CXL. Factors such as corrected distance visual acuity (CDVA) and Scheimpflug tomography (Pentacam) were used to follow the evolution from preoperatively to 12 months after CXL. Statistical analysis included U tests and Spearman rank correlation tests to detect risk factors for flattening of the keratoconus. RESULTS: The study enrolled 151 eyes of 151 patients; more than 80% completed the 12-month follow-up. The flattening rate (flattening of the maximum curvature >1.00 diopter [D]) was 37.7%. A preoperative maximum keratometry (K) reading of more than 54.00 D was identified as the only significant risk factor for this effect (odds ratio, 1.88; 95% confidence interval, 1.01-3.51). A restriction to corneas with a maximum K value greater than 54.00 D would have resulted in a significant flattening in 51% of the cases. CONCLUSIONS: Statistically significant flattening occurred during 1 year after CXL in more than 50% of cases when the preoperative maximum K reading was more than 54.00 D. None of the other preoperative parameters evaluated (eg, age, sex, diagnosis, CDVA, corneal shape factors) had a statistically significant impact on corneal flattening after CXL. PMID- 21782092 TI - Computerized corneal tomography and associated features in a large New Zealand keratoconic population. AB - PURPOSE: To evaluate corneal tomographic features of keratoconus and associations between risk factors and disease phenotype in New Zealand. SETTING: Departments of Ophthalmology, University of Auckland and Auckland District Health Board, Auckland, New Zealand. DESIGN: Clinic-based, cross-sectional study. METHODS: The medical records and corneal tomography of patients attending a subspecialty service were reviewed. Data included age, sex, ethnicity, ocular history, family history, atopy, and eye rubbing. Orbscan II parameters included simulated keratometry, mean power, pachymetry, location of maximum power, anterior best-fit sphere (BFS) and posterior BFS. Morphology was categorized by the Rabinowitz topography classification. RESULTS: Final analyses included 532 eyes (266 patients; 144 men) with a mean age of 29.3 years +/- 11.56 (SD). Maori and Pacific patients were overrepresented (P=.0001). Family history of keratoconus was associated with a lower mean corneal power (P=.01) and greater pachymetry (P=.03). Comparing patients with family history and patients with atopy, showed differences in thinnest-point pachymetry (mean: family history, 340 +/- 15 MUm; atopy 381 +/- 8 MUm) (P=.0218). Keratoconus was classified as severe (58.3%) or moderate (33.8%) on mean keratometry. Axial keratometric maps were predominantly asymmetric bow-tie (29%), round (18%), or inferior steepening (17%). Anterior elevation maps were classified as spur (49.3%), island (24%), irregular ridge (15%), or other (11.3%). Eighteen patients (12.5%) had complete enantiomorphism. CONCLUSIONS: Advanced keratoconus was largely asymmetric and differences in tomographic phenotype were associated with differing etiologic risk factors. Maori and Pacific ethnicities were overrepresented in this population. PMID- 21782093 TI - Computerized Scheimpflug densitometry as a measure of corneal optical density after excimer laser refractive surgery in myopic eyes. AB - PURPOSE: To evaluate changes in anterior corneal optical density and the refractive index after photorefractive keratectomy (PRK) using a rotating Scheimpflug system. SETTING: Department of Ophthalmology, University Federico II, Naples, Italy. DESIGN: Comparative case series. METHODS: Anterior corneal optical density was evaluated with a rotating Scheimpflug system at baseline and 3 months and 12 months after PRK in eyes with a refractive error between -6.00 diopters (D) and -12.00 D (study group). A control group of unoperated eyes with the same refraction range was used to calculate corneal optical density and the Gladstone Dale constant in unoperated eyes using the Gladstone-Dale formula. In the study group, changes in the anterior corneal optical density were evaluated over time and variations in the anterior corneal refractive index were obtained using the Gladstone-Dale constant. RESULTS: The study group comprised 37 eyes and the control group, 200 eyes. In the study group, the mean anterior corneal optical density and refractive index, respectively, were 27.71 +/- 4.39 and 1.360 +/- 0.05 at baseline, 37.812 +/- 12.31 and 1.491 +/- 0.16 after 3 months (P<.001 compared with baseline), and 26.29 +/- 4.93 and 1.341 +/- 0.06 after 12 months (P=.03 compared with baseline). The mean corneal optical density in the control group was 27.71 +/- 4.31 (SD), and the resultant Gladstone-Dale constant was 0.013. CONCLUSION: An early increase and a subsequent reduction in anterior corneal optical density and the refractive index were present in myopic eyes during 1 year after PRK. PMID- 21782094 TI - Variations in corneal biomechanical parameters and central corneal thickness during the menstrual cycle. AB - PURPOSE: To assess variations in the biomechanical properties and central corneal thickness (CCT) throughout the female menstrual cycle. SETTING: Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin Israel. DESIGN: Case series. METHODS: Young healthy women were prospectively recruited. Every participant was assessed at the beginning of the menstrual cycle, at ovulation, and at the end of the cycle. At every time point, corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured with the Ocular Response Analyzer and the CCT was measured with an ultrasonic pachymeter. RESULTS: Twenty-two eyes of 22 women (mean age 19.5 years +/- 1.5 [SD]) were included. The CH was statistically significantly decreased at ovulation (10.1 mm Hg) compared with the beginning (11.1 mm Hg, P<.001) and the end (11.4 mm Hg, P<.001) of the cycle. The CRF was also significantly decreased at ovulation (9.8 mm Hg) compared with the beginning (10.6 mm Hg, P<.001) and the end (10.5 mm Hg, P<.001) of the cycle. The central cornea was thinnest at the beginning (535 MUm) and statistically significantly thicker at ovulation (542 MUm, P<.001) and at the end of the menstrual cycle (543 MUm, P<.001). CONCLUSIONS: The CCT and biomechanical parameters significantly varied during the menstrual cycle. The CH and CRF were temporarily decreased at ovulation. The cornea was thinnest at the beginning and thicker at ovulation and at the end of the cycle. Such corneal changes may be important to consider during screening of candidates for laser refractive surgery. PMID- 21782095 TI - Corneal endothelial cell loss in post-penetrating keratoplasty patients after cataract surgery: phacoemulsification versus planned extracapsular cataract extraction. AB - PURPOSE: To compare the changes in endothelial cell density (ECD) in post penetrating keratoplasty (PKP) patients after cataract extraction with phacoemulsification or planned extracapsular cataract extraction (ECCE). SETTING: Haydarpasa Numune Education and Research Hospital, Ophthalmology Clinic, Istanbul, Turkey. DESIGN: Clinical trial. METHODS: Eyes with hard nuclear cataract that had previous PKP were randomly assigned to have phacoemulsification or ECCE. Noncontact specular microscopy was performed preoperatively and 1, 3, and 6 months postoperatively. RESULTS: Twenty-six eyes of 26 patients were enrolled (14 phacoemulsification; 12 ECCE). Six months postoperatively, the mean corneal ECD was statistically significantly lower in the phacoemulsification group (1869.50 cells/mm(2) +/- 158.05 [SD]) than in the ECCE group (1996.00 +/- 127.96 cells/mm(2)) (P=.024). The mean percentage of endothelial cell loss at 6 months was 20.3% and 12.7%, respectively (P<.05). In both groups, there was no significant difference in the percentage hexagonality between preoperatively and postoperatively (P>.05). CONCLUSION: Extracapsular cataract extraction seemed to cause less endothelial cell damage than phacoemulsification in post-PKP patients with hard nuclear cataract. PMID- 21782096 TI - Effect of distraction on simulated anterior segment surgical performance. AB - PURPOSE: To determine the effect of distraction on anterior segment surgical performance using a virtual reality simulator in expert and novice surgeons. SETTING: Horizon Suite Simulation Centre, South Devon Foundation NHS Trust, Devon, England. DESIGN: Cohort study. METHODS: Expert and novice ophthalmic surgeons completed a standardized and validated surgical task 10 times on a virtual reality simulator (EyeSi). They then completed a cognitive task (arithmetic questions), after which they completed 10 attempts on the simulator module while also completing the cognitive task. RESULTS: For experts (n = 7), the distracting cognitive task had no statistically significant effect on operating scores. The rate of correctly answered questions decreased from 12.3 per minute +/- 2.1 (SD) while single tasking to 8.6 +/- 3.1 per minute while dual tasking (P=.018). For novices (n = 14), the distracting cognitive task had no effect on any operating score except a small reduction in the penalty odometer score. The rate of correctly answered questions decreased from 11.5 +/- 4.1 per minute while single tasking to 7.0 +/- 3.2 per minute while dual tasking (P=.001). CONCLUSION: A distractive cognitive task reduced the ability of novice surgeons and expert surgeons to deal with that cognitive task, although their simulated surgical performance was not overtly compromised. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21782097 TI - Six just-noticeable differences in retinal image quality in 1 line of visual acuity: toward quantification of happy versus unhappy patients with 20/20 acuity. AB - PURPOSE: To determine the number of just-noticeable differences in wavefront blur necessary to induce a 1-line loss of corrected distance visual acuity (CDVA). SETTING: Visual Optics Institute, College of Optometry, University of Houston, Houston, Texas, USA. DESIGN: Evidence-based manuscript. METHODS: The 3.0 mm wavefront error of a well-corrected average eye was scaled to yield 9 small steps of blur quantified in units of log visual Strehl (logVS). For each logVS value, 10 unique 3-line acuity charts were generated. Using a temporal forced-choice paradigm, subjects compared each test chart to a reference acuity chart and indicated which chart was blurrier. The difference between 80% and 50% on the psychometric function defined a just-noticeable difference. The CDVA was measured up to fifth-letter miss for several aberrated logMAR charts for 6 logVS values. The number of just-noticeable differences necessary to lose 1 line of acuity was defined as the change in logVS necessary to lose 1 line of acuity divided by the 1 just-noticeable difference in logVS. RESULTS: Linear regression showed that logVS = -2.98 * (logMAR acuity) - 0.31 (R(2) = 0.961). The mean just-noticeable difference was 0.049 logVS +/- 0.012 (SD), resulting in a mean of 6.1 just noticeable differences per line of logMAR acuity. CONCLUSIONS: The retinal image quality metric logVS was highly correlated with logMAR acuity. The 6 just noticeable differences in logVS before 1 line of acuity was lost may provide an objective explanation for the distinction between patients with 20/20 CDVA who are happy and patients with 20/20 CDVA who are unhappy and other aberration related clinical complaints when acuity is near normal. PMID- 21782098 TI - Simulation of flow field during irrigation/aspiration in phacoemulsification using computational fluid dynamics. AB - PURPOSE: To provide the details of the flow field in the anterior chamber during irrigation/aspiration (I/A) in phacoemulsification using computational fluid dynamics methods. SETTINGS: School of Mechanical Engineering, Shiraz University, Dr. Khodadoust Eye Hospital, Shiraz, Iran, and Clarkson University, Potsdam, New York, USA. DESIGN: Theoretical study. METHODS: A 3-dimensional model for the irrigating cannula, anterior chamber, capsular bag, and aspiration cannula was developed. The corresponding mathematic equations were solved numerically, and the details of the flow field were evaluated. The simulation was performed for coaxial and bimanual I/A systems with various flow rates. The pressure flow rate curve was evaluated, and the possibility of an unstable anterior chamber in different cases was assessed. RESULTS: The effects of flow turbulence on the corneal endothelium were lower for the coaxial handpiece. That is, inner placement of irrigation cannula tip lowered the effect of turbulence on the cornea. CONCLUSIONS: Assessment of the fluid dynamics of I/A using computational fluid dynamics provided details that cannot be obtained with the available experimental and analytic methods. PMID- 21782099 TI - One million cataract surgeries: Swedish National Cataract Register 1992-2009. AB - This review summarizes data collected by the Swedish National Cataract Register, which now contains data pertaining to more than a million cataract surgery procedures, representing 95.6% of the surgeries performed in Sweden during 1992 2009. During this period, the rate of cataract surgery rose from 4.47 to 9.00 per 1000 inhabitants. The mean patient age increased until 1999 but has slowly decreased since then. Preoperative visual acuity has risen steadily. The distribution between the sexes was stable until 2000, after which the proportion of women slowly decreased. Registration of subjective benefit has brought new knowledge regarding indications and expectations. An improved questionnaire, Catquest-9SF has been used since 2008. The outcome register generally shows good results from the surgery. Endophthalmitis has decreased from 0.10% to below 0.040%. PMID- 21782100 TI - Phacoemulsification with corneal astigmatism correction with the use of a toric intraocular lens in a case of megalocornea. AB - We report the case of a 49-year-old patient with megalocornea and coexisting corneal astigmatism. The corneal diameter in the right eye was 15.0 mm and in the left eye, 14.9 mm. In both eyes, a nuclear sclerotic cataract developed, with the tendency toward cortical mass swelling in the right eye. The aim of surgical treatment was to remove the cataract with simultaneous correction of corneal astigmatism by implanting an Acrysof toric intraocular lens (IOL). Intraocular lens stabilization was obtained by suturing it to an capsular tension ring (CTR) in the anterior chamber. The IOL-CTR complex was rotated into the lens capsule and aligned with the steep meridian of corneal astigmatism. The surgical technique provides a stable refractive and functional effect in patients with megalocornea and coexisting cataract and corneal astigmatism. PMID- 21782101 TI - Late-onset Klebsiella oxytoca flap-margin-related corneal ulcer following laser in situ keratomileusis. AB - A 45-year-old woman developed a spontaneous flap-margin-related corneal ulcer 11 years after the original laser in situ keratomileusis (LASIK) procedure. Two enhancements had been performed; the most recent was 3 years prior to presentation. Cultures were positive for a heavy growth of Klebsiella oxytoca. The ulcer responded clinically to topical treatment with fortified cefazolin. Eighteen days after presentation, the infiltrate had resolved and the cornea had fully epithelialized. To our knowledge, this is the first report of post-LASIK infectious keratitis caused by K oxytoca. PMID- 21782103 TI - Cross-action capsulorhexis forceps for coaxial microincision cataract surgery. PMID- 21782102 TI - Bilateral posterior subcapsular cataracts associated with long-term intranasal steroid use. AB - The use of systemic steroids has been established as a risk factor for the development of posterior subcapsular cataracts. In recent decades, the use of nasal topical steroids has increased in an effort to decrease systemic side effects. Current evidence of an association between nasal steroid use and cataract formation is contradictory. We present a case of rapid-onset bilateral posterior subcapsular cataracts in a young healthy patient with a history of long term nasal steroid use. PMID- 21782104 TI - Why 5 is better than 4. PMID- 21782105 TI - Consultation Section. Cataract surgical problem. PMID- 21782115 TI - Letter from the guest editor: breast cancer screening and diagnosis: state of the art. PMID- 21782116 TI - Magnetic resonance imaging and breast ultrasonography as an adjunct to mammographic screening in high-risk patients. AB - Screening mammography remains the standard of care for breast cancer screening of the general population and is likely to remain so in the foreseeable future. We discuss the current role of breast ultrasound and magnetic resonance imaging (MRI) in screening for breast cancer in the high-risk population. Breast ultrasound finds small cancers not seen on mammography particularly in women with dense breasts. Breast MRI has sensitivity significantly higher than that of mammography, breast ultrasound, or a combination of mammography and breast ultrasound. PMID- 21782117 TI - Automated whole-breast ultrasound: advancing the performance of breast cancer screening. AB - Screening has been successful in the early detection of some cancers, including cervical, colon, and breast. However, the success in mortality reduction by screening mammography has been limited in women with mammographically dense tissue. Magnetic resonance imaging has been used with success in the screening of high-risk women, but it is expensive. Also, its use in a screening program requires a contrast medium that has not been tested in humans or animals for long term safety in humans or animals for repeated biannual or annual injections. Ultrasound also has the potential to be an ideal screening tool because it is relatively inexpensive and requires no injected contrast or ionizing radiation. However, the relatively poor conspicuity of some cancers by hand scanning and the considerable radiologist time necessary limit its use. Automated whole-breast ultrasound (AWBU) allows the radiologist to read the images quickly, at a convenient time, while being free from doing the scan. Two-dimensional AWBU uses a cine loop of axial images, with <1 mm image spacing, which are read on a high resolution monitor to improve the conspicuity of small cancers. A blinded study of this system combined with screening mammography showed that adding AWBU both doubles overall cancer detection and triples the 1 cm-or-less invasive cancers found in dense-breasted women. As expected, mammography had a significantly greater detection rate of ductal carcinoma in situ than AWBU. As yet no clinical studies of other AWBU systems have been published. PMID- 21782118 TI - Breast tomosynthesis. AB - Digital mammography has been well-evaluated for the diagnosis of breast cancer. The scientific data show that mammography alone, especially in dense breast parenchyma, has its weaknesses. These weaknesses are due to the low contrast of tumors in comparison with the surrounding parenchyma and the overlying structures that mask tumors. The initial results from tomosynthesis studies show a tendency for better imaging and higher accuracy and lower recall rates with tomosynthesis. We present in this article a literature review of the development of breast tomosynthesis and follow it with case examples. PMID- 21782119 TI - Emerging techniques and molecular imaging in breast cancer. AB - The sensitivity of screening mammography is limited in the evaluation of dense breasts, with as few as 45% of cancers visible in extremely dense breasts. Supplementary imaging for improved sensitivity in women with dense breasts is necessary to overcome this limitation. Emerging technologies that advance the applications of digital mammography include digital breast tomosynthesis and dedicated breast cone-beam computed tomography. Molecular imaging goes beyond structural imaging. A functional imaging technique that provides information on the biology, physiology, and metabolic pathways of cancer might help to improve the sensitivity and specificity of breast cancer diagnosis, facilitate early assessment of treatment response, and help individualize therapy options for patients. Advanced magnetic resonance, nuclear medicine, and optical imaging techniques in the realm of molecular imaging will be explored in this article. PMID- 21782120 TI - Screening and diagnosis of breast cancer in low-resource countries: what is state of the art? AB - Breast cancer is the most common type of cancer in women worldwide; there has been a significant increase in the incidence of breast cancer in low-resource countries, with a disproportionately greater mortality rate compared to high resource countries attributed to a lack of public awareness of the disease, absence of organized screening programs, and lack of accessible and effective treatment options. Mammography is not a cost-effective or a feasible option for screening and early detection of breast cancer in low-resource countries. A triple test assessment approach of screening clinical breast examination, diagnostic breast ultrasound, and ultrasound-guided fine-needle aspiration cytology may be a feasible option for the early detection of breast cancer. PMID- 21782121 TI - Ductal carcinoma in situ: detection, diagnosis, and characterization with magnetic resonance imaging. AB - Ductal carcinoma in situ (DCIS) is a preinvasive malignancy that currently accounts for over 20% of newly diagnosed breast cancers in the US. This article reviews how clinical magnetic resonance imaging methods are being implemented for the detection, diagnosis and characterization of DCIS. Research strategies that are being pursued to help realize the full potential for magnetic resonance imaging to improve the outcomes of patients diagnosed with DCIS are discussed. PMID- 21782122 TI - Magnetic resonance imaging of the breast for cancer diagnosis and staging. AB - Gadolinium-enhanced breast magnetic resonance imaging (MRI) is optimally suited for the diagnosis and assessment of breast cancer. The complete breast MRI examination, which includes select nonenhanced sequences, yields abundant information about the nature and stage of disease. In this article, we will explore cancer diagnosis by examining the main imaging features of breast malignancy as well as the assessment of surrounding structures. We will then discuss current ideas in the use of breast MRI in breast cancer, including high risk screening, evaluation of extent of disease, role in surgical planning, and the use of MRI in the patient receiving neoadjuvant chemotherapy. Breast MRI plays an important role in the assessment of patients with breast malignancy-a role that is yet to be fully defined and used. By understanding the strengths and weakness of this imaging method in cancer evaluation, we hope to highlight the appropriate uses of the technique. PMID- 21782123 TI - Staging of breast cancer with ultrasound. AB - The prognosis of women with breast cancer depends on tumor size and regional lymph node status. Clinical assessment combined with imaging is important in the staging of primary breast cancer, particularly in a multidisciplinary setting where radiologists, pathologists, medical, surgical, and radiation oncologists work together to optimize patient care. Delineation of loco-regional (multifocal vs multicentric) disease is critical in surgical planning to enable a curative procedure with clear margins and good cosmetic outcome. Regional (ipsilateral axillary, infraclavicular, internal mammary, and supraclavicular) nodal information helps determine patient eligibility for neoadjuvant protocols and also aids in radiation planning. The role of high-resolution ultrasound in staging breast cancer is discussed in conjunction with mammography, and magnetic resonance imaging. PMID- 21782124 TI - Challenges and potential pitfalls in magnetic resonance imaging of more elusive breast carcinomas. AB - Breast cancer is a heterogeneous group of diseases caused by differences in the biological, clinical, radiologic, and pathologic features of the different types of invasive carcinoma in the breast. The majority of invasive breast carcinomas are the invasive ductal or no special-type (NST) carcinomas. The rest of the invasive carcinomas are either nonductal carcinoma subtypes or special-type carcinomas, making up 20%-30% of all invasive carcinomas. The latter group comprises very different and distinctive types of cancer with imaging characteristics and challenges that are unique to each subtype. The invasive lobular carcinoma is the most common type of the nonductal carcinomas and can be difficult to detect on imaging because of the distinct pattern of tumor growth in sheets of single file cells with minimal desmoplastic reaction. The mucinous carcinoma of the breast contains extracellular mucin, secreted by the tumor cells. The mucin within these tumors result in imaging features that overlap with benign breast lesions, and may lead to misdiagnosis. Other rare and aggressive breast cancers include metaplastic breast carcinoma and inflammatory breast carcinoma. Both diseases have a poorer prognosis than invasive ductal carcinoma. This article will focus on the rarer non-NST carcinoma of the breast that can be a challenge to assess with imaging, partially related to the unique biology of these cancers. PMID- 21782125 TI - Spectrum of diseases presenting as architectural distortion on mammography: multimodality radiologic imaging with pathologic correlation. AB - Architectural distortion is the third most-common appearance of breast cancer and often is a subtle finding on mammography. In this article, we review a variety of breast diseases that may present as architectural distortion on mammography; review the utility of correlative imaging, such as ultrasound and magnetic resonance; and review appropriate management for these diagnoses. Primary causes include breast cancer, ductal carcinoma in situ, radial scar, complex sclerosing lesion, and fat necrosis. Secondary etiologies include previous breast surgery, trauma, and infection. Familiarity with imaging findings presenting as distortion on multimodality imaging will optimize detection and management of this subtle yet-significant finding. PMID- 21782126 TI - Albuminuria and prognosis in CKD: truth be told. PMID- 21782127 TI - CKD treatment: time to alter the focus to albuminuria? PMID- 21782128 TI - Historical aspects of proteinuria. AB - Historical aspects in the investigation, evaluation, and management of patients with proteinuria, in large part, as they relate to patients with glomerulonephritis, are reviewed. This evaluation has been a long and complex process with many divergent and cross pathways. Although the history covers more than 2000 years, it is only in the past 2 centuries, with the more advanced experimental methods that have developed in science, that the growth has been exponential. With these advances, the knowledge between kidney structure and function evolved, and the subsequent links determined between physiology and pathology of kidney disease, and the clinical phenotypes of glomerular disease have revealed the overwhelming importance of proteinuria as both an indicator of kidney involvement and a marker of disease progression. PMID- 21782130 TI - Assessment of proteinuria. AB - Proteinuria is a strong predictor of adverse cardiovascular and kidney events, and an accurate assessment of proteinuria is important for the evaluation and management of CKD. Total urinary protein can be assessed using dipstick, precipitation, and electrophoresis methods. Urinary albumin, the predominant urinary protein in most proteinuric kidney diseases, can be assessed using an albumin-specific dipstick, immunochemical techniques, and size-exclusion high performance liquid chromatography. Urine albumin may be immune-reactive, immune unreactive, fragmented, and biochemically modified, and laboratory techniques have variable abilities to detect different types of albumin. Urine specimen for proteinuria assessment can either be obtained from a timed-collection or a spot urine sample. Spot urine protein- or albumin-to-creatinine ratios are preferred to a 24-hour urine sample in routine practice. Assessment of albuminuria rather than proteinuria is more clinically meaningful in patients with diabetic kidney disease, and proteinuria and albuminuria assessments both have a role in nondiabetic kidney disease and in general population screening. As measurement and sampling procedures for proteinuria assessment have yet not been standardized, it is important for physicians to be aware of different types of urinary proteins, albumins, laboratory techniques, and urine sampling methods. PMID- 21782131 TI - Albuminuria: is it time to screen the general population? AB - Albuminuria has been associated with increased risk of multiple adverse outcomes, including ESRD, acute kidney injury, cardiovascular disease, and death. Some clinicians advocate for population-based screening of this condition, as a means of identifying individuals at high risk for morbidity and mortality. Several factors influence the potential implementation of screening for albuminuria in the general population, including the type of test used, the threshold for albuminuria, the validity and prognostic value of testing, frequency of follow-up testing, and associated costs of screening. This review discusses the available literature addressing these issues, and suggests an approach to screening patients for albuminuria. PMID- 21782129 TI - Glomerular proteinuria: a complex interplay between unique players. AB - Protein leak in the urine is a harbinger of disruption of the glomerular filtration barrier. It also correlates with disease progression and development of ESRD. At present, therapies are aimed at decreasing proteinuria to decrease further damage to the filter and as a marker of remission. Understanding the mechanism of molecular events that lead to protein leak is vital to developing new therapeutic interventions. There has been tremendous progress over the last decade in identifying gene defects which result in hereditary proteinuric defects. This has led to identifying pathways by which these genes regulate the structure and function of the components of the filtration barrier, namely the podocytes, mesangial cells, endothelial cells, and the basement membrane. Using gene knockout mouse models, a role of tubular cells in regulating proteinuria is also emerging. In this review, we have attempted to present some of the prevailing understanding of the underlying mechanisms and physiology of proteinuria. PMID- 21782132 TI - Implications of proteinuria: CKD progression and cardiovascular outcomes. AB - In this review, we summarize the evidence for the associations of proteinuria with incident CKD, progression of kidney disease, development of kidney failure, as well as the association with surrogates of cardiovascular disease (CVD), clinical cardiovascular outcomes, and all-cause mortality. Results reveal that proteinuria is a powerful and independent risk factor for kidney and cardiovascular outcomes, and that these relationships are independent of the level of glomerular filtration rate. Furthermore, these associations are true in populations at high, medium, and low risk for kidney disease progression and development of CVD. We show data which demonstrate that the associations with CVD are present even at levels of proteinuria below current cutoffs for microalbuminuria, and that changes in proteinuria may be a useful predictor of future outcomes. Finally, we provide some theories as to why proteinuria may be a risk factor for development of CVD. PMID- 21782133 TI - Proteinuria in special populations: pregnant women and children. AB - Proteinuria is the hallmark of glomerular kidney disease. It is used diagnostically to follow disease progression and to determine response to therapy. Thus, it is necessary to have an understanding of the mechanisms of proteinuria and the limitations to its accurate assessment in special populations. In this article, we review 2 special populations--pregnant women and children--providing insight into their unique circumstances that require consideration when assessing proteinuria. PMID- 21782134 TI - Genetics of proteinuria: an overview of gene mutations associated with nonsyndromic proteinuric glomerulopathies. AB - Heritable causes of proteinuria are rare and account for a relatively small proportion of all cases of proteinuria affecting children and adults. Yet, significant contributions to understanding the mechanistic basis for proteinuria have been made through genetic and molecular analyses of a small group of syndromic and nonsyndromic proteinuric disorders which are caused by mutations encoding structural components of the glomerular filtration barrier. Technological advances in genomic analyses and improved accessibility to mutational screening at clinically approved laboratories have facilitated diagnosis of proteinuria in the clinical setting. From a clinical standpoint, it may be argued that a genetic diagnosis mitigates exposure to potentially ineffective and harmful treatments in instances where a clear genotype-phenotype correlation exists between a specific gene mutation and treatment nonresponsiveness. However, cautious interpretation of risk may be necessitated in cases with phenotypic heterogeneity (eg, variability in clinical or histological presentation). This review summarizes gene mutations which are known to be associated with proteinuric glomerulopathies in children and adults. PMID- 21782135 TI - Therapeutic approaches in lowering albuminuria: travels along the renin angiotensin-aldosterone-system pathway. AB - Achieving optimal blood pressure and albuminuria control is a major therapeutic treatment goal in patients with renal insufficiency. Angiotensin-converting enzyme-inhibitors (ACEIs) and angiotensin-receptor blockers (ARB) are the mainstay of therapy in these patients. However, despite these therapies many patients remain at high risk of renal or cardiovascular disease that shows a relationship with albuminuria. Various approaches have been tested to maximize the efficacy of ACEI and ARB. Increasing the dose of an ACEI or ARB beyond the maximal registered antihypertensive dose causes a distinct decrease in albuminuria without additional effects on blood pressure. The combination of an ACEI and ARB is another possibility to further reduce albuminuria. However, the alleged beneficial effects on hard renal and cardiovascular outcome are not unambiguously demonstrated. Adding a direct renin inhibitor to an ACEI or ARB has been shown to lower albuminuria in patients with and without diabetes. Long-term trials are currently under way to determine the effects of direct renin inhibition on clinical outcomes. Volume excess has been shown to blunt the blood pressure and albuminuria response to ACEI or ARB therapy. Intervening in volume status by means of restricting dietary sodium intake or diuretic therapy has convincingly been shown to lower blood pressure and albuminuria. Whether this strategy translates into a reduction in the risk of renal or cardiovascular events has not (yet) been investigated in prospective randomized trials. Various options are at hand which have been shown to maximize the blood pressure and albuminuria response to ACEI and ARB treatment. However, long-term studies supporting the benefits of these strategies on hard renal and cardiovascular outcomes are warranted. PMID- 21782137 TI - Bariatric surgery: an IDF statement for obese Type 2 diabetes. AB - The International Diabetes Federation Taskforce on Epidemiology and Prevention of Diabetes convened a consensus working group of diabetologists, endocrinologists, surgeons and public health experts to review the appropriate role of surgery and other gastrointestinal interventions in the treatment and prevention of Type 2 diabetes. The specific goals were: to develop practical recommendations for clinicians on patient selection; to identify barriers to surgical access and suggest interventions for health policy changes that ensure equitable access to surgery when indicated; and to identify priorities for research. Bariatric surgery can significantly improve glycaemic control in severely obese patients with Type 2 diabetes. It is an effective, safe and cost-effective therapy for obese Type 2 diabetes. Surgery can be considered an appropriate treatment for people with Type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially in the presence of other major co morbidities. The procedures must be performed within accepted guidelines and require appropriate multidisciplinary assessment for the procedure, comprehensive patient education and ongoing care, as well as safe and standardized surgical procedures. National guidelines for bariatric surgery need to be developed for people with Type 2 diabetes and a BMI of 35 kg/m(2) or more. PMID- 21782138 TI - International Diabetes Federation position statement on bariatric surgery for type 2 diabetes: implications for patients, physicians, and surgeons. PMID- 21782139 TI - The case of being in the wrong place at the wrong time: the consequences of undiagnosed anatomic anomalies. PMID- 21782140 TI - Conversion of laparoscopic adjustable gastric band to robot-assisted laparoscopic biliopancreatic diversion with duodenal switch. PMID- 21782141 TI - Introduction: proteinuric renal disease. PMID- 21782142 TI - Proteinuria: measurement and interpretation. AB - Proteinuria is a general term that describes the presence of any type of protein in the urine (e.g., albumin, globulins, mucoproteins, and Bence-Jones proteins); however, albumin is the predominate protein in urine in healthy dogs and cats as well as dogs and cats with renal disease. Proteinuria can arise from several different physiologic and pathologic causes, but persistent proteinuria associated with normal urine sediment is consistent with kidney disease. The urine dipstick colorimetric test is the usual first-line screening test for the detection of proteinuria, but false-positive reactions are common. When proteinuria of renal origin is suspected, the next diagnostic steps are quantitation and longitudinal monitoring via the urine protein/creatinine ratio. The recent availability of a species-specific albumin enzyme-linked immunosorbent assay technology that enables detection of low concentrations of canine and feline albuminuria has both increased diagnostic capability and stimulated discussion about what level of proteinuria/albuminuria is normal. Beyond being an important diagnostic marker, proteinuria is associated with kidney disease progression in both dogs and cats: the greater the magnitude of the proteinuria, the greater the risk of renal disease progression and mortality. Treatments that have attenuated proteinuria in dogs and cats have also been associated with slowed kidney disease progression and/or improved survival. For these reasons, screening for renal proteinuria and longitudinal assessment of renal proteinuria has recently received renewed interest. PMID- 21782136 TI - Off the beaten renin-angiotensin-aldosterone system pathway: new perspectives on antiproteinuric therapy. AB - CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria. PMID- 21782143 TI - Glomerular disease. AB - Glomerular diseases are a leading cause of chronic kidney disease in dogs but seem to be less common in cats. Glomerular diseases are diverse, and a renal biopsy is needed to determine the specific glomerular disease that is present in any animal. Familial glomerulopathies occur in many breeds of dogs. However, most dogs with glomerular disease have acquired glomerular injury that is either immune-complex mediated or due to systemic factors, both of which are believed to be the result of a disease process elsewhere in the body (i.e., neoplastic, infectious, and noninfectious inflammatory disorders). A thorough clinical evaluation is indicated in all dogs suspected of having glomerular disease and should include an extensive evaluation for potential predisposing disorders. Nonspecific management of dogs with glomerular disease can be divided into 3 major categories: (1) treatment of potential predisposing disorders, (2) management of proteinuria, and (3) management of uremia and other complications of glomerular disease and chronic kidney disease. Specific management of specific glomerular diseases has not been fully studied in dogs. However, it may be reasonable to consider immunosuppressive therapy in dogs that have developed a form of glomerulonephritis secondary to a steroid-responsive disease (e.g., systemic lupus erythematosus) or have immune-mediated lesions that have been documented in renal biopsy specimens. Appropriate patient monitoring during therapy is important for maximizing patient care. The prognosis for dogs and cats with glomerular disease is variable and probably dependent on a combination of factors. The purpose of this article is to discuss the general diagnosis and management of dogs with glomerular disease. PMID- 21782144 TI - Nephrotic syndrome in dogs: clinical features and evidence-based treatment considerations. AB - Nephrotic syndrome (NS), defined as the concurrent presence of hypoalbuminemia, proteinuria, hyperlipidemia, and fluid accumulation in interstitial spaces and/or body cavities, is a rare complication of glomerular disease in dogs, cats, and people. Affected animals frequently have markedly abnormal urine protein:creatinine ratios because of urinary loss of large amounts of protein; however, hypoalbuminemia-associated decreased plasma oncotic pressure is insufficient to explain fluid extravasation in most laboratory models, and, instead, either aberrant renal tubule retention of sodium with resultant increase in hydrostatic pressure or a systemic increase in vascular permeability may be the primary defects responsible for development of NS. Factors associated with NS in people (including "nephrotic-range" serum albumin concentration and urine protein concentration, and particular glomerular disease subtypes) have been assumed previously to also be important in dogs, although descriptions were limited to those patients included in case series of glomerular disease, and sporadic case reports. However, case-control comparison of larger cohorts of dogs with nephrotic versus nonnephrotic glomerular disease more recently suggests that predisposing factors and concurrent clinicopathologic abnormalities differ from those typically encountered in people with nephrotic syndrome, although case progression and negative effect on patient outcome are similar. This article briefly reviews major current theories and supporting evidence on the pathogenesis of NS, followed by an overview on the clinical features of this syndrome in dogs with glomerular disease. The authors also offer evidence-based and experience-based treatment recommendations that are based on minimizing the suspected dysregulation of the renin-angiotensin-aldosterone axis in affected dogs. PMID- 21782145 TI - Renal biopsy and pathologic evaluation of glomerular disease. AB - Presence of suspected primary glomerular disease is the most common and compelling reason to consider renal biopsy. Pathologic findings in samples from animals with nephritic or nephrotic glomerulopathies, as well as from animals with persistent subclinical glomerular proteinuria that is not associated with advanced chronic kidney disease, frequently guide treatment decisions and inform prognosis when suitable specimens are obtained and examined appropriately. Ultrasound-guided needle biopsy techniques generally are satisfactory; however, other methods of locating or approaching the kidney, such as manual palpation (e.g., in cats), laparoscopy, or open surgery, also can be used. Visual assessment of the tissue content of needle biopsy samples to verify that they are renal cortex (i.e., contain glomeruli) as they are obtained is a key step that minimizes the submission of uninformative samples for examination. Adequate planning for a renal biopsy also requires prior procurement of the fixatives and preservatives needed to process and submit samples that will be suitable for electron microscopic examination and immunostaining, as well as for light microscopic evaluation. Finally, to be optimally informative, renal biopsy specimens must be processed by laboratories that routinely perform the required specialized examinations and then be evaluated by experienced veterinary nephropathologists. The pathologic findings must be carefully integrated with one another and with information derived from the clinical investigation of the patient's illness to formulate the correct diagnosis and most informative guidance for therapeutic management of the animal's glomerular disease. PMID- 21782146 TI - The prevalence of microalbuminuria and proteinuria in cats with diabetes mellitus. AB - The prevalence of microalbuminuria (MA) and proteinuria was evaluated in 66 cats with diabetes mellitus (DM), 35 nondiabetic cats with other illness, and 11 healthy nondiabetic cats with use of the E.R.D.-HealthScreen Feline Urine Test. The MA prevalence was higher in the diabetic than in the nondiabetic sick and healthy control cats (70%, 39%, and 18% respectively, P < .0001). In addition, prevalence of proteinuria defined by a protein/creatinine ratio (UPC) > 0.4 was significantly higher in the diabetic cat than in the control cats (70%, 35%, and 9% respectively, P < .0001). There was a significant but weak correlation between the results of MA and UPC (P < .0001, r = 0.43). Our results showed that MA is common in cats with DM. Further studies are required to evaluate the prognostic value of the presence and the severity of MA in cats with DM. PMID- 21782147 TI - [Pyoderma gangrenosum: a report of 15 cases and review of the literature]. AB - BACKGROUND: Pyoderma gangrenosum is a condition that is included among the neutrophilic dermatoses. Given its low incidence, few studies have addressed its epidemiology or treatment. OBJECTIVE: To describe the epidemiological and clinical characteristics of patients with pyoderma gangrenosum along with our experience of treating the condition in a referral hospital in Malaga, Spain. MATERIAL AND METHODS: A retrospective, observational study was undertaken in the Department of Dermatology at Hospital Clinico Universitario Virgen de la Victoria in Malaga, Spain between January 2000 and December 2009 and included all patients diagnosed with pyoderma gangrenosum. RESULTS: The incidence of pyoderma gangrenosum in our reference population is 3.26 cases per million inhabitants per year. The most frequent concomitant systemic disease was ulcerative colitis (5 cases, 33%). In 4 patients with that disease, pyoderma gangrenosum appeared during a flare-up. In 80% of cases, patients were not referred to a dermatologist during the initial phase of pyoderma gangrenosum, and most referrals were from gastroenterology or general surgery (4 patients each, 52%). CONCLUSIONS: Patients with pyoderma gangrenosum are often referred to dermatologists by other specialists after a varying period of time has elapsed without achieving an accurate diagnosis. In these patients, especially those between 20 and 40 years of age, it is essential to rule out concomitant disease. Adalimumab is a good treatment option for pyoderma gangrenosum. PMID- 21782148 TI - Multipurpose smart hydrogel systems. AB - This paper represents the review of the last investigations in the field of smart polymeric hydrogels and our contribution to this matter. New hydrogel systems and nanocomposites based on acrylic monomers (acrylamide, acrylonitrile, acrylic acid, N-isopropylacrylamide etc.) with incorporated nanosized colloidal silver, hydroxyapatite and carbon nanotubes with a new set of properties have been obtained and examined. These systems can sharply change their characteristics when minor external physical (electric and magnetic fields, temperature etc.) or chemical (pH, ionic strength) stimuli are applied. Such stimulus-responsive polymeric systems are very promising from the standpoint of different medical applications, especially for the development of intelligent drug delivery systems. On the base of designed hydrogel iontophoretic transdermal therapeutic systems, endoprosthesis for the replacement of bone tissue and hydrogel burns coatings with immobilized mesenchymal cells were obtained and tested. PMID- 21782149 TI - Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. AB - KBG syndrome is characterized by intellectual disability associated with macrodontia of the upper central incisors as well as distinct craniofacial findings, short stature, and skeletal anomalies. Although believed to be genetic in origin, the specific underlying defect is unknown. Through whole-exome sequencing, we identified deleterious heterozygous mutations in ANKRD11 encoding ankyrin repeat domain 11, also known as ankyrin repeat-containing cofactor 1. A splice-site mutation, c.7570-1G>C (p.Glu2524_Lys2525del), cosegregated with the disease in a family with three affected members, whereas in a simplex case a de novo truncating mutation, c.2305delT (p.Ser769GlnfsX8), was detected. Sanger sequencing revealed additional de novo truncating ANKRD11 mutations in three other simplex cases. ANKRD11 is known to interact with nuclear receptor complexes to modify transcriptional activation. We demonstrated that ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized, suggesting that it plays a role in neural plasticity. Our results demonstrate that mutations in ANKRD11 cause KBG syndrome and outline a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function. PMID- 21782150 TI - Apoptosis induction and inhibition of hyperplasia formation by 2 [piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran in rat uterus. AB - OBJECTIVE: The study was undertaken to explore the antiproliferative mechanism of action of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) in estradiol-induced rat uterine hyperplasia. STUDY DESIGN: Adult ovariectomized rats received vehicle or estradiol alone (20 MUg/kg) or estradiol along with K-1 (100 or 200 MUg/kg) for 14 days. Uterine histomorphometric analysis and immunoblotting were performed. Caspase-3 activity and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining were performed to analyze the apoptotic potential of compound. RESULTS: Compound inhibited estradiol-induced uterine weight and histomorphometric changes pertaining to endometrial growth and down-regulated the expression of estrogen response element and activator protein 1 regulated genes and transcription factors. The compound significantly induced apoptosis, interfered with Akt activation, decreased X-linked inhibitor of apoptosis protein expression leading to an increased cleavage of caspase-9, caspase-3, poly(adenosine diphosphate-ribose) polymerase, increased Bax/Bcl2 ratio, and caspase-3 activity. CONCLUSION: K-1 inhibits endometrial proliferation via nonclassical estrogen receptor signaling mechanisms. It interfered with Akt activation and induced apoptosis via the intrinsic pathway and inhibited estradiol-induced hyperplasia formation in rat uterus. PMID- 21782151 TI - Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. AB - PURPOSE: To investigate the changes in aqueous inflammatory and angiogenic cytokine levels after intravitreal injection of triamcinolone or bevacizumab for reducing foveal thickness in diabetic macular edema (DME). DESIGN: Prospective, interventional case series. METHODS: Twenty-two eyes of 11 patients with bilateral DME and 6 eyes of 6 patients undergoing cataract surgery participated in this study. In each DME patient, 1 eye received an intravitreal injection of 4 mg triamcinolone acetonide and the other eye received 1.25 mg bevacizumab. Aqueous humor samples were obtained before and 4 weeks after the intravitreal injection in the DME group and before the surgery in the control group. Aqueous concentrations of interleukin (IL)-6, IL-8, interferon-induced protein (IP)-10, monocyte chemotactic protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, and vascular endothelial growth factor (VEGF) were measured by multiplex bead assay. RESULTS: Before the administration of the drugs, aqueous levels of IL-8, IP-10, MCP-1, and VEGF were significantly higher in the DME group than in the control group. After intravitreal injection, foveal thickness was more decreased in the triamcinolone acetonide (IVTA) group compared with the bevacizumab (IVBe) group. IL-6, IP-10, MCP-1, PDGF-AA, and VEGF were significantly decreased in the IVTA group, but only VEGF in the IVBe group. Aqueous levels of VEGF were more decreased in the IVBe group than in the IVTA group. CONCLUSIONS: These findings suggest that the pathogenesis of DME is not only related to VEGF dependency, but also to other mechanisms suppressed by corticosteroids. We suppose that these cytokines would have an important role in both the pathogenesis of DME and the underlying mechanism of intravitreal injections. PMID- 21782152 TI - Historical review of emergency tourniquet use to stop bleeding. AB - BACKGROUND: Although a common first aid topic, emergency tourniquets to stop bleeding are controversial because there is little experience on which to guide use. Absent an adequate historical analysis, we have researched development of emergency tourniquets from antiquity to the present. METHODS: We selected sources emphasizing historical development of tourniquets from books and databases such as PubMed. RESULTS: The history of the emergency tourniquet is long and disjointed, mainly written by hospital surgeons with little accounting, until recently, of the needs of forward medics near the point injury. Many investigators often are unaware of the breadth of the tourniquet's history and voice opinions based on anecdotal observations. CONCLUSIONS: Reporting the historical development of tourniquet use allowed us to recognize disparate problems investigators discuss but do not recognize, such as venous tourniquet use. We relate past observations with recent observations for use by subsequent investigators. PMID- 21782153 TI - Multidrug donor preconditioning protects steatotic liver grafts against ischemia reperfusion injury. AB - BACKGROUND: Graft dysfunction of steatotic livers (SL) still remains a major challenge in liver transplantation. Different mechanisms are thought to be involved in the impaired tolerance of SL to ischemia-reperfusion injury. Thus, different pharmacologic strategies may need to be combined to effectively protect SL and to reduce graft dysfunction after transplantation. Therefore, we analyzed the effectiveness of a multidrug donor preconditioning (MDDP) procedure to protect SL from cold ischemia-reperfusion injury. METHODS: Liver steatosis was induced by a high-carbohydrate, fat-free diet. A total of 24 Sprague-Dawley rats were divided into 3 groups (n = 8 each), including a control group with nonsteatotic livers (Con), a vehicle-treated SL group (SL-Con), and a SL group undergoing MDDP (SL-MDDP), including pentoxyphylline, glycine, deferoxamine, N acetylcysteine, erythropoietin, melatonin, and simvastatin. MDDP was applied before liver perfusion with 4 degrees C histidine-tryptophan-ketoglutarate (HTK) solution and organ harvest. After 24 hours of cold storage in HTK, postischemic reperfusion was performed in an isolated liver reperfusion model using 37 degrees C Krebs-Henseleit bicarbonate buffer. RESULTS: After 60 minutes of reperfusion, SL showed a significant reduction of bile flow as well as a marked increase of liver enzyme levels and apoptotic cell death compared with Con. This was associated with an increased malondialdehyde formation, interleukin-1 production, and leukocytic tissue infiltration. MDDP completely abolished the inflammatory response and was capable of significantly reducing parenchymal dysfunction and injury. CONCLUSIONS: MDDP decreases SL injury after cold storage and reperfusion. The concept of MDDP as a simple and safe preoperative regime, thus may be of interest in clinical use, expanding the donor pool from marginal donors. PMID- 21782154 TI - Guidelines of the French society of endocrinology for the management of thyroid nodules. AB - The present document is a follow-up of the clinical practice guidelines of the French Society of Endocrinology, which were established for the use of its members and made available to scientific communities and physicians. Based on a critical analysis of data from the literature, consensuses and guidelines that have already been published internationally, it constitutes an update of the report on the diagnostic management of thyroid nodules that was proposed in France, in 1995, under the auspices of the French National Agency for Medical Evaluation (l'Agence nationale d'evaluation medicale). The current guidelines were deliberated beforehand by a number of physicians that are recognised for their expertise on the subject, coming from the specialities of endocrinology (the French Thyroid Research Group) and surgery (the French Association for Endocrine Surgery), as well as representatives from the fields of biology, ultrasonography, cytology and nuclear medicine. The guidelines were presented and submitted for the opinion of the members of the Society at its annual conference, which was held in Nice from 7-10 October 2009. The amended document was posted on the website of the Society and benefited from additional remarks of its members. The final version that is presented here was not subjected to methodological validation. It does not claim to be universal in its scope and will need to be revised in concert with progress made in technical and developmental concepts. It constitutes a document that the Society deems useful for distribution concerning the management of thyroid nodules, which is current, efficient and cost effective. PMID- 21782157 TI - The effect of problem structure on problem-solving: an fMRI study of word versus number problems. AB - It has long been thought that word problems are more difficult to solve than number/equation problems. However, recent findings have begun to bring this broadly believed idea into question. The current study examined the processing differences between these two types of problems. The behavioral results presented here failed to show an overwhelming advantage for number problems. In fact, there were more errors for the number problems than the word problems. The neuroimaging results reported demonstrate that there is significant overlap in the processing of what, on the surface, appears to be completely different problems that elicit different problem-solving strategies. Word and number problems rely on a general network responsible for problem-solving that includes the superior posterior parietal cortex, the horizontal segment of the intraparietal sulcus which is hypothesized to be involved in problem representation and calculation as well as the regions that have been linked to executive aspects of working memory such as the pre-SMA and basal ganglia. While overlap was observed, significant differences were also found primarily in language processing regions such as Broca's and Wernicke's areas for the word problems and the horizontal segment of the intraparietal sulcus for the number problems. PMID- 21782156 TI - Effect of acute and continuous morphine treatment on transcription factor expression in subregions of the rat caudate putamen. Marked modulation by D4 receptor activation. AB - Acute administration of the dopamine D(4) receptor (D(4)R) agonist PD168,077 induces a down-regulation of the MU opioid receptor (MOR) in the striosomal compartment of the rat caudate putamen (CPu), suggesting a striosomal D(4)R/MOR receptor interaction in line with their high co-distribution in this brain subregion. The present work was designed to explore if a D(4)R/MOR receptor interaction also occurs in the modulation of the expression pattern of several transcription factors in striatal subregions that play a central role in drug addiction. Thus, c-Fos, FosB/DeltaFosB and P-CREB immunoreactive profiles were quantified in the rat CPu after either acute or continuous (6-day) administration of morphine and/or PD168,077. Acute and continuous administration of morphine induced different patterns of expression of these transcription factors, effects that were time-course and region dependent and fully blocked by PD168,077 co administration. Moreover, this effect of the D(4)R agonist was counteracted by the D(4)R antagonist L745,870. Interestingly, at some time-points, combined treatment with morphine and PD168,077 substantially increased c-Fos, FosB/DeltaFosB and P-CREB expression. The results of this study give indications for a general antagonistic D(4)R/MOR receptor interaction at the level of transcription factors. The change in the transcription factor expression by D(4)R/MOR interactions in turn suggests a modulation of neuronal activity in the CPu that could be of relevance for drug addiction. PMID- 21782155 TI - Serine proteases, serine protease inhibitors, and protease-activated receptors: roles in synaptic function and behavior. AB - Serine proteases, serine protease inhibitors, and protease-activated receptors have been intensively investigated in the periphery and their roles in a wide range of processes-coagulation, inflammation, and digestion, for example-have been well characterized (see Coughlin, 2000; Macfarlane et al., 2001; Molinari et al., 2003; Wang et al., 2008; Di Cera, 2009 for reviews). A growing number of studies demonstrate that these protein systems are widely expressed in many cell types and regions in mammalian brains. Accumulating lines of evidence suggest that the brain has co-opted the activities of these interesting proteins to regulate various processes underlying synaptic activity and behavior. In this review, we discuss emerging roles for serine proteases in the regulation of mechanisms underlying synaptic plasticity and memory formation. PMID- 21782159 TI - Magnetoencephalographic signatures of visual form and motion binding. AB - This study investigates neural magneto-encephalographic (MEG) correlates of visual form and motion binding. Steady-state visual evoked fields (SSVEF) were recorded in MEG while observers reported their bound or unbound perception of moving bars arranged in a square shape. By using pairs of oscillating vertical and horizontal bars, "frequency-tagged" at f1 and f2, we identified a region with enhanced sustained power at 2f1+2f2 intermodulation frequency correlated with perceptual reports. Intermodulation power is more important during perceptual form/motion integration than during the perceptual segmentation of the stimulus into individual component motions, indicating that intermodulation frequency power is a neuromarker of form/motion integration. Source reconstruction of cortical activities at the relevant frequencies further reveals well segregated activity in the occipital lobe at the fundamental of the stimulation, f1 and f2, widely spread activity at 2f1 and 2f2 and a focal activity in the medial part of the right precentral sulcus region at the intermodulation component, 2f1+2f2. The present findings indicate that motion tagging provides a powerful way of investigating the processes underlying visual form/motion binding non-invasively in humans. PMID- 21782160 TI - Dibutylsilylene-pentose bis-chelates: on the glycoses' binding sites for strongly Lewis-acidic centres. AB - Excess di(tert-butyl)silylene (DTBS) bis(trifluoromethanesulfonate) formed bis DTBS derivatives with the four aldopentoses (arabinose, lyxose, ribose and xylose). The structure of the bis-chelates was affected by the bulk of the DTBS groups and the requirement of flat silacycles in the case of five-membered chelate rings. These restrictions resulted in unusual cyclic bis-chelates for ribofuranose (kappaO(1,5),kappaO(2,3) bis-chelate) and lyxopyranose (kappaO(1,4),kappaO(2,3) bis-chelate of a twisted boat conformation). Most importantly, all aldopentoses formed bis-chelates of their open-chain aldehydo isomers. The bis-chelates of aldehydo-arabinose and -xylose were kappaO(2,3),kappaO(4,5)-bonded and thus exhibited five-membered chelate rings. The bis-chelates of aldehydo-lyxose and -ribose were kappaO(2,4),kappaO(3,5) bonded and resembled six-membered chelate rings. For lyxose, the aldehydo bis chelate was isolated as a solid. The molecular structures were assigned by a combined (1)H, (13)C, and (29)Si NMR spectroscopic approach, which was supported by X-ray analyses on crystals of the bis-DTBS chelates of kappaO(1,2),kappaO(3,5) bonded rac-xylofuranose, kappaO(1,5),kappaO(2,3)-bonded d-ribofuranose, and kappaO(2,4),kappaO(3,5)-bonded aldehydo-d-lyxose. PMID- 21782158 TI - The beginning of intracellular recording in spinal neurons: facts, reflections, and speculations. AB - Intracellular (IC) recording of action potentials in neurons of the vertebrate central nervous system (CNS) was first reported by John Eccles and two colleagues, Walter Brock and John Coombs, in Dunedin, NZL in 1951/1952 and by Walter Woodbury and Harry Patton in Seattle, WA, USA in 1952. Both groups studied spinal cord neurons of the adult cat. In this review, we discuss the precedents to their notable achievement and reflect and speculate on some of the scientific and personal nuances of their work and its immediate and later impact. We then briefly discuss early achievements in IC recording in the study of CNS neurobiology in other laboratories around the world, and some of the methods that led to enhancement of CNS IC-recording techniques. Our modern understanding of CNS neurophysiology directly emanates from the pioneering endeavors of the five who wrote the seminal 1951/1952 articles. PMID- 21782161 TI - Oligosaccharides in feces of breast- and formula-fed babies. AB - So far, little is known on the fate of oligosaccharides in the colon of breast- and formula-fed babies. Using capillary electrophoresis with laser induced fluorescence detector coupled to a mass spectrometer (CE-LIF-MS(n)), we studied the fecal oligosaccharide profiles of 27 two-month-old breast-, formula- and mixed-fed preterm babies. The interpretation of the complex oligosaccharide profiles was facilitated by beforehand clustering the CE-LIF data points by agglomerative hierarchical clustering (AHC). In the feces of breast-fed babies, characteristic human milk oligosaccharide (HMO) profiles, showing genetic fingerprints known for human milk of secretors and non-secretors, were recognized. Alternatively, advanced degradation and bioconversion of HMOs, resulting in an accumulation of acidic HMOs or HMO bioconversion products was observed. Independent of the prebiotic supplementation of the formula with galactooligosaccharides (GOS) at the level used, similar oligosaccharide profiles of low peak abundance were obtained for formula-fed babies. Feeding influences the presence of diet-related oligosaccharides in baby feces and gastrointestinal adaptation plays an important role herein. Four fecal oligosaccharides, characterized as HexNAc-Hex-Hex, Hex-[Fuc]-HexNAc-Hex, HexNAc-[Fuc]-Hex-Hex and HexNAc-[Fuc]-Hex-HexNAc-Hex-Hex, highlighted an active gastrointestinal metabolization of the feeding-related oligosaccharides. Their presence was linked to the gastrointestinal mucus layer and the blood-group determinant oligosaccharides therein, which are characteristic for the host's genotype. PMID- 21782163 TI - Turning point of age for semen quality: a population-based study in Chinese men. AB - OBJECTIVE: To explore the relationship between age and semen quality in Chinese men. DESIGN: Population-based cross-sectional study. SETTING: The Department of Reproductive Epidemiology and Social Science, Shanghai Institute of Planned Parenthood Research, People's Republic of China. PATIENT(S): Healthy 20- to 60 year-old men. INTERVENTION(S): Standard World Health Organization procedures (3rd ed.) for semen analysis. MAIN OUTCOME MEASURE(S): Semen volume, sperm concentration, total sperm number, progressive motility, vitality, and sperm morphology. RESULT(S): Statistical analysis results of 998 subjects showed that age was negatively correlated with progressive motility, vitality, and percentage of normal sperm. No declining trend was found between age and parameters semen volume, sperm concentration, or total sperm number. Rapidly progressive motility and percentage of normal sperm began to decrease slowly at age 30 years, and progressive motility began to decrease at age 40 years. Compared with the 20- to 29-year age group, the values of the latter three parameters showed significant differences in men aged >=35, >=45, and >=40 years. CONCLUSION(S): Increasing age mainly influences sperm motility, vitality, and normal morphology, but these parameters have turning points at different ages. Because of the large sample size, this information can be used to provide standard values for Chinese men, particularly in the age range 30-50 years. Further research would enroll a large sample of healthy 40- to 70-year olds to examine declining semen parameters in these age groups. PMID- 21782162 TI - Hospital admissions for asthma and acute bronchitis in El Paso, Texas: do age, sex, and insurance status modify the effects of dust and low wind events? AB - BACKGROUND: El Paso County (Texas) is prone to still air inversions and is one of the dust "hot spots" in North America. In this context, we examined the sub lethal effects of airborne dust and low wind events on human respiratory health (i.e., asthma and acute bronchitis) between 2000 and 2003, when 110 dust and 157 low wind events occurred. Because environmental conditions may not affect everyone the same, we explored the effects of dust and low wind within three age groups (children, adults, and the elderly), testing for effect modifications by sex and insurance status, while controlling for weather and air pollutants. METHODS: We used a case-crossover design using events matched with referent days on the same day-of-the-week, month, and year with conditional logistic regression to estimate the probability of hospital admission, while controlling for apparent temperature (lag 1), nitrogen dioxide, and particulate matter of 2.5MUm or less. RESULTS: Children (aged 1-17) were 1.19 (95% confidence interval: 1.00-1.41) times more likely to be hospitalized for asthma three days after a low wind event, and 1.33 (95% CI: 1.01-1.75) times more likely to be hospitalized for acute bronchitis one day after a dust event than on a clear day. Girls were more sensitive to acute bronchitis hospitalizations after dust events (1.83, 95% CI: 1.09-3.08) than boys, but less sensitive than boys to acute bronchitis hospitalizations after low wind events (0.68, 95% CI: 0.46-1.00). We found general trends with regard to dust and low wind events being associated with increased odds of hospitalization for asthma and bronchitis amongst all ages and adults (aged 18-64). Adults covered by Medicaid and adults without health insurance had higher risks of hospitalization for asthma and acute bronchitis after both low wind and dust events. CONCLUSIONS: Results suggest that there were respiratory health effects associated with dust and low wind events in El Paso, with stronger impacts among children and poor adults. Girls and boys with acute bronchitis were differentially sensitive to dust and low wind events. PMID- 21782164 TI - Embryonic imprinting perturbations do not originate from superovulation-induced defects in DNA methylation acquisition. AB - OBJECTIVE: To investigate whether superovulation disrupts maternal imprint acquisition in oocytes. DESIGN: Animal model. SETTING: Academic institute. ANIMAL(S): Spontaneously ovulated and superovulated mice. INTERVENTION(S): Low and high hormone dosage treatments were administered to females, and ovulated metaphase II oocytes were collected. MAIN OUTCOME MEASURE(S): Imprinted DNA methylation was analyzed at Snrpn, Kcnq1ot1, Peg3, and H19 in individual oocytes. RESULT(S): Examination of 125 individual oocytes derived from females subjected to low and high hormone treatments revealed normal imprinted methylation patterns that were comparable to oocytes derived from spontaneously ovulated females. CONCLUSION(S): Maternal imprint acquisition was not affected by superovulation. Given its aberrant effects during preimplantation development, superovulation must instead disrupt maternal-effect gene products that are required after fertilization for imprint maintenance. These results eliminate imprint acquisition per se as the initial stage of imprint loss and point to the importance of analyses on early embryos after procedures involving oocyte manipulation. PMID- 21782165 TI - Public perceptions of providing IVF services to cancer and HIV patients. AB - OBJECTIVE: To assess the attitudes of the general U.S. population toward the use of IVF to assist adults with a history of cancer or human immunodeficiency virus (HIV). DESIGN: Cross-sectional survey study. SETTING: Online. PATIENT(S): A total of 1,183 adult men and women across the U.S. INTERVENTION(S): Questionnaire consisting of multiple-choice and open-ended questions. MAIN OUTCOME MEASURE(S): Attitudes toward IVF for cancer and HIV patients. RESULT(S): A total of 82% supported IVF for cancer patients compared with 38% for HIV patients. The most common reasons for support was the anticipation of normal life expectancies and a belief in the universal right to have children, although nearly twice as many participants believed this to be a "right" for cancer patients than for HIV patients. Young respondent ages, higher educational attainment, Jewish religion, and a personal history of infertility were associated with higher likelihood of support. Lower education level, higher annual household income, and having children were predictors of discordance in support of IVF for cancer versus HIV patients. CONCLUSION(S): Despite advancements in the treatment of cancer and HIV, which have allowed patients to have longer life expectancies and improved chances of parenthood, there is significant disparity in the support of providing IVF to these patient groups. PMID- 21782166 TI - Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome. AB - OBJECTIVE: To compare the ovulation rate between raloxifene and clomiphene citrate (CC) in patients with polycystic ovary syndrome (PCOS). DESIGN: Double blind, randomized, superiority clinical trial. SETTING: Tertiary university hospital. PATIENT(S): Women with ovulatory dysfunction and PCOS based on the Rotterdam criteria. INTERVENTION(S): One of two oral treatments: 5 days of 100 mg/day of CC or R. MAIN OUTCOME MEASURE(S): Ovulation, based on follicle collapse on serial ultrasound and midsecretory serum progesterone concentration (>=3 ng/dL). RESULT(S): The women with PCOS (n = 82) were randomized to receive CC (n = 40) or raloxifene (n = 42). From these, 68 patients finished the trial according to the protocol (CC: n = 37; raloxifene: n = 31). There were no statistically significant differences between the groups in ovulation rates per an intention-to-treat analysis based on ultrasound alone (CC: 21 of 40 vs. raloxifene: 17 of 42) or on progesterone levels (CC: 16 of 40 vs. raloxifene: 11 of 42). No serious adverse events were observed in either group. CONCLUSION(S): No statistically significant difference in ovulation was observed between raloxifene and clomiphene citrate in patients with PCOS with ovulatory dysfunction. PMID- 21782167 TI - Oxygen consumption is a quality marker for human oocyte competence conditioned by ovarian stimulation regimens. AB - OBJECTIVE: To evaluate the effect of different ovarian stimulation protocols on oocyte respiration and to investigate the relationship between oocyte oxygen consumption and reproductive outcome. DESIGN: Prospective observational cohort study. SETTING: Infertility clinic in a university hospital. PATIENT(S): A total of 349 oocytes from 56 IVF treatment cycles in our oocyte donation program. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Average oocyte oxygen consumption rate in fmol/s. We correlated oxygen consumption values with ovarian stimulation features, fertilization, embryo quality on days 2 and 3, and implantation. RESULT(S): Differences in the measured oxygen consumption rates were found depending on which type of gonadotropins were used in the stimulation protocol. Higher consumption rates were found for oocytes that underwent normal fertilization compared with rates from nonfertilized or abnormal oocytes (odds ratio = 1.340; 95% confidence intervals = 1.037-1.732). Furthermore, higher oxygen consumption was observed for those oocytes which generated embryos that implanted compared with those that did not implant (6.21 +/- 0.849 fmol/s vs. 5.23 +/- 0.345 fmol/s. CONCLUSION(S): Measurement of oxygen consumption rates for individual oocytes before fertilization provides a noninvasive marker of oocyte quality and hence a quantitative assessment of the reproductive potential for the oocyte. PMID- 21782168 TI - A comparison of novice and experienced physicians performing hysteroscopic sterilization: an analysis of an FDA-mandated trial. AB - OBJECTIVE: To assess the placement rates for experienced users versus newly trained physicians using the new ESS 305 delivery catheter for the Essure microinsert hysteroscopic sterilization system. DESIGN: Multicenter prospective cohort study. SETTING: Seventy-six sites throughout the U.S. comprising community hospitals, teaching institutions, surgery centers, and office-based practices. PATIENT(S): A total of 578 women seeking hysteroscopic sterilization. INTERVENTION(S): Hysteroscopic sterilization with the ESS 305 device by either experienced or novice physicians. MAIN OUTCOME MEASURE(S): Successful bilateral placement of the Essure 305 device. RESULT(S): A total of 625 patients were recruited with 578 eligible cases performed by 37 newly trained and 39 experienced physicians: 562/578 (97.2%) overall had successful placement, with 98% successful placement rate versus 96.1% for experienced versus novice physicians, respectively. Mean procedural time was 9 minutes (+/-7 SD), with experienced physicians completing it on average quicker at 7.9 minutes (+/-5.8 SD) and novices completing it in 10.7 minutes (+/-8.3 SD). There was no significant association between successful placement with patient characteristics such as body mass index, surgical history, parity, or prior vaginal deliveries observed. CONCLUSION(S): The Essure procedure can be performed quickly and safely with high bilateral placement rates regardless of physician experience or patient characteristics. PMID- 21782169 TI - Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients. AB - The combination of trophectoderm biopsy, blastocyst vitrification, and single nucleotide polymorphism microarray-based technology for comprehensive chromosome screening results in high implantation and live birth rates that could contribute to the practical application of single embryo transfer for infertility patients. PMID- 21782170 TI - Study on self-tuning pole assignment speed control of an ultrasonic motor. AB - Ultrasonic motors have a heavy nonlinearity, which varies with driving conditions. The nonlinearity is a problem as an accurate motion actuator for industrial applications and it is important to eliminate the nonlinearity in order to improve the control performance. In general, complicated control strategies are used to deal with the nonlinearity of ultrasonic motors. This paper proposes a new speed control scheme for ultrasonic motors to overcome the nonlinearity employing a simplified self-tuning control. The speed control model which can reflect the main nonlinear characteristics is obtained using a system identification method based on the step response. Then, a pole assignment speed controller is designed. To avoid the influence of the motor's nonlinearity on the speed control performance, a control parameters' on-line self-tuning strategy utilizing the gain of the model is designed. The proposed control strategy is realized using a DSP circuit, and experiments prove the validity of the proposed speed control scheme. PMID- 21782171 TI - Informed consent in trauma: does written information improve patient recall of risks? A prospective randomised study. AB - Informed consent is vital to good surgical practice. Pain, sedative medication and psychological distress resulting from trauma are likely to adversely affect a patient's ability to understand and retain information thus impairing the quality of the consent process. This study aims to assess whether provision of written information improves trauma patient's recall of the risks associated with their surgery. 121 consecutive trauma patients were randomised to receive structured verbal information or structured verbal information with the addition of supplementary written information at the time of obtaining consent for their surgery. Patients were followed up post-operatively (mean 3.2 days) with a questionnaire to assess recall of risks discussed during the consent interview and satisfaction with the consent process. Recall of risks discussed in the consent interview was found to be significantly improved in the group receiving written and verbal information compared to verbal information alone (mean questionnaire score 41% vs. 64%), p=0.0014 using the Mann-Whitney U test. Patient satisfaction with the consent process was improved in the group receiving written and verbal information and 90% of patients in both groups expressed a preference for both written and verbal information compared to verbal information alone. Patients awaiting surgery following trauma can pose a challenge to adequately inform about benefits conferred, the likely post operative course and potential risks. Written information is a simple and cost-effective means to improve the consent process and was popular with patients. PMID- 21782172 TI - One-third tubular-hook-plate osteosynthesis for olecranon osteotomies in distal humerus type-C fractures: a preliminary report of results and complications. AB - INTRODUCTION: Distal humerus fractures are rare and challenging to treat. Anatomic reduction of the articular surface and stable osteosynthesis are mandatory for satisfactory results. The transolecranon approach allows superior visualisation of the joint. However, controversy exists regarding how best to fix the osteotomy. The purpose of the present study was to investigate the eligibility of a one-third tubular hook plate for osteosynthesis of olecranon osteotomies in distal humerus type-C fractures. PATIENTS AND METHODS: A consecutive series of 34 patients who were treated through an olecranon osteotomy and underwent fixation using a one-third tubular hook plate were identified. Thirty-one patients (17 females, 14 males) with a median age of 50 years (14-87, standard deviation (SD) 18.3) were available for a comprehensive assessment after a mean of 12.3 months (6-20, SD 3.7). Using the Arbeitsgemeinschaft fur Osteosynthesefragen (AO) classification, six (19.4%) fractures were categorised as type C2 and 25 (80.6%) were categorised as C3. Physical and radiological examinations were performed. The Mayo Elbow Performance Score (MEPS) and the Disabilities of the Arm, Shoulder and Hand score (DASH) were evaluated. RESULTS: Mean extension-flexion ROM was found to be 102 degrees (50-145 degrees , SD 25). Pronation and supination were only slightly compromised. The mean MEPS was 87.2 points (50-100, SD 12.4). Fourteen patients (45.2%) were rated as excellent, and 15 (48.4%) were rated as good. One patient was rated fair, and one patient was rated as poor, respectively. Mean DASH score was 24.4 points (0-65, SD 20.3). Complications regarding the osteotomy occurred in seven patients (22.5%). Revision surgery was necessary in five cases (16%). At follow-up, all osteotomies went on to union. Mild joint degeneration (Broberg I) was found in 10 patients (32.2%). Implant removal was carried out in 15 patients (48.4%). CONCLUSION: Based on this study, the osteosynthesis of olecranon osteotomies using a one third tubular hook plate can be regarded as a safe procedure with a low complication rate. The implant needed is widely available and cost-efficient, in contrast to specially designed plates or nails. PMID- 21782173 TI - Barriers to orthopaedic practice--why surgeons do not put into practice what they have learned in educational events. AB - BACKGROUND: All orthopaedic and trauma surgeons attend educational events throughout their careers. Many surgeons find that when they return to practice they are unable to put into effect those things that they have learned. METHODS: This study focussed on 708 surgeons from 2 different cultural backgrounds (developed and developing world) who attended 7 separate trauma Educational events. Surgeons were contacted by e-mail at least 6 weeks after the event and asked if they had encountered any Barriers, which had prevented them from putting into practice what they had learned at the event. If Barriers had been encountered they were asked to categorize them and state if they were able to overcome them. RESULTS: Barriers affect nearly every learner and learners are usually unable to overcome them. The study identified what barriers exist for implementation of acquired knowledge, how they vary with the degree of experience of the surgeon and his or her cultural background. CONCLUSION: The commonest barrier amongst all surgeons is not having contact with a suitable patient to treat with their new knowledge and skills. Inability to get access to equipment and facilities is a major barrier for many surgeons especially in the developing world. This has profound implications for organizers of educational events that will need to incorporate strategies into their educational planning to help surgeon learners avoid or overcome barriers. PMID- 21782174 TI - Neuromyelitis optica during pregnancy. PMID- 21782175 TI - Factors in the practice environment of nurses working in inpatient mental health: A partial least squares path modeling approach. AB - BACKGROUND: Developing a therapeutic relationship with consumers is considered as the central aspect of nursing work in mental health. The importance of this relationship stems from its association with enhanced patient care and improved patient outcomes. Factors within the practice environment may influence the nurse's ability to engage effectively in this relationship. OBJECTIVE: This study explored a model that added characteristics of the individual and practice environment to a central framework incorporating therapeutic commitment: a nurse's ability and willingness to engage in a therapeutic relationship. SETTING AND PARTICIPANTS: Data were collected at six mental health nursing units in five public general acute hospitals in New South Wales, Australia for 14 days per unit, between 2005 and 2006. All nurses in participating wards were invited to partake in the study. Seventy-six (51%) responses were analyzed. METHOD: The data were collected using a Nurse Survey inclusive of the Practice Environment Scale of the Nursing Work Index (NWI-PES), and the Mental Health Problems Perception Questionnaire (MHPPQ). A Unit Profile form was used concurrently to collect staffing, skill mix and patient turnover data. Partial least squares path modeling (PLS-PM) was chosen as the analytical method to test the model and identify the most influential factors. RESULTS: Experienced nurses who perceived themselves to be competent and supported were more likely to express a willingness to engage therapeutically with patients. Environmental factors associated with these perceptions included foundations of quality nursing care, opportunities to participate in hospital affairs and clinical supervision. Not all elements in the proposed model were supported. CONCLUSION: Positive hospital practice environments can improve the capacity of nurses working in mental health to engage therapeutically with patients. Specific approaches may include access to preceptorship, continued education and career development opportunities, together with clinical supervision, improved continuity of care, and the involvement of mental health nurses in the governance of the hospital. PMID- 21782176 TI - Influence of pericoronary adipose tissue on local coronary atherosclerosis as assessed by a novel MDCT volumetric method. AB - OBJECTIVE: Pericoronary adipose tissue (PCAT) may create a pro-inflammatory state, contributing to the development of coronary artery disease (CAD). We sought to evaluate the feasibility of a novel volumetric PCAT quantification method using a novel threshold based computed tomography approach. In addition we determined the relation between PCAT volumes and CAD. METHODS: In 51 patients (49.5+/-5.1 years, 64.8% male) who underwent 64-slice MDCT, we measured threshold based PCAT volumes using distance and anatomic-based methods. Using the most reproducible method, we performed the proximal 40-mm distance measurement in three groups as stratified by coronary plaque and high-sensitivity C-reactive protein (hs-CRP) levels: Group 1 (presence of coronary plaque, hs-CRP >2.0 mg/L); an intermediate group (Group 2, no plaque, hs-CRP >2.0 mg/L); and Group 3 (no plaque, hs-CRP<1.0 mg/L). We compared PCAT volumes to the presence of coronary plaque on a patient (n=51) and vessel (n=153) basis. On a subsegment basis (n=1224), we compared PCAT volume to the presence of plaque as well as plaque morphology. RESULTS: Distance-based PCAT volume measurements yielded excellent reproducibility with intra-observer intraclass correlation (ICC) of 0.997 and inter-observer ICC of 0.951. On a both a per-patient and per-vessel analysis, adjusted PCAT volume was greater in patients with plaque (Group 1) than without plaque (Groups 2 and 3, p<0.001). No difference in PCAT volume was seen between high and low hs-CRP groups without plaque (p=0.51). Adjusted PCAT volumes were higher in subsegments with plaque as compared without (p<0.001). Additionally, adjusted PCAT volume was greatest in subsegments with mixed plaque followed by non-calcified plaque, calcified plaque, and the lowest volume in segments with no plaque (p<0.001). CONCLUSION: In this proof-of-concept study, threshold based PCAT volume assessment is feasible and highly reproducible. PCAT volume is increased in patients and vessels with coronary plaques. Surrounding vessel subsegments with coronary plaque, particularly mixed plaques, have greatest PCAT volume and highlight the effect of local PCAT in the development of coronary atherosclerosis. PMID- 21782177 TI - Serum cystatin C is associated with early stage coronary atherosclerotic plaque morphology on multidetector computed tomography. AB - OBJECTIVE: Cystatin C, a novel marker of kidney function, has been reported to be a predictor of adverse cardiovascular outcomes in patients without established chronic kidney disease. However, the relationship between serum cystatin C concentrations and early stage coronary atherosclerotic plaque morphology among patients with preserved kidney function has not been fully evaluated. METHODS AND RESULTS: 405 outpatients with early coronary artery disease with estimated glomerular filtration rate (eGFR) >= 60ml/min/1.73m(2) and <50% stenosis on 64 slice CT coronary angiography were enrolled. Subjects were categorized into quartiles by serum cystatin C (quartile I: <= 0.88mg/L - quartile IV: >= 1.16mg/L). Plaques in coronary segments were categorized as calcified or noncalcified. Multiple linear regression analysis revealed that lower eGFR, higher age, increasing numbers of noncalcified and calcified plaques, lower high density lipoprotein cholesterol, and female gender were statistically significant predictors of increased cystatin C concentrations. The risk for presence of noncalcified plaques increased significantly with increasing quartiles of cystatin C. Compared with those in the lowest quartile, patients in each subsequent quartile were at steadily increased risk of having noncalcified plaque (quartile IV: OR 5.6; 95% CI 2.3-13.9, p-value <0.001). Both number of segments with calcified plaque and Agatston score were highly correlated with cystatin C concentrations (both p<0.001), but when adjusted for segments with noncalcified plaque and other risk factors, calcified plaque segments were no longer independently predictive. CONCLUSION: Higher serum cystatin C concentrations were correlated with early stage coronary atherosclerotic plaques among patients without established chronic kidney dysfunction. Noncalcified plaques increased with serum cystatin C concentrations, an association independent of eGFR and other cardiovascular risk factors. PMID- 21782178 TI - Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes. AB - INTRODUCTION: We previously reported increased expression of TLR4 on monocytes in thrombi from patients with acute coronary syndromes (ACS). In mice, myeloid related protein (MRP) 8 and MRP14, cytoplasmic proteins of neutrophils and monocytes, activate Toll-like receptor (TLR) 4 during sepsis. In human ACS, we investigated now whether the pro-inflammatory action of MRPs occurs through TLR4 in monocytes derived from thrombi. METHODS: Coronary thrombi and peripheral blood of 27 ACS patients were analyzed. CD14(+) monocytes were isolated and incubated with TLR2 ligand PM3SKA, TLR4 ligand lipopolysaccharide (LPS), MRP8, MRP14, or MRP8/14 heterocomplex. Anti-TLR4 antibodies (HTA125) were used to block TLR4 and polymyxin B (PMB) was employed to inhibit endotoxins. Before and after stimulation, the release of TNFalpha was measured by ELISA and the expression of TLR4 on CD14(+) monocytes was determined by flow cytometry. Further, selected pathways of downstream signaling were analyzed. RESULTS: MRP8 and MRP8/14 increased release of TNFalpha in cultures of CD14(+) monocytes, more in cells derived from thrombi compared with matched peripheral blood cells (p<0.001). LPS, MRP8, and MRP8/14, but much less PM3SKA and MRP14 alone, stimulated TNFalpha release, which can be inhibited by HTA125. MRP8/14 enhanced TLR4 expression on monocytes from thrombi (p<0.001), but not on monocytes from peripheral blood of the same patients. CONCLUSION: In ACS, MRP8 and MRP8/14 complex are specific ligands of TLR4, which induce the release of TNFalpha and probably other pro inflammatory agents from monocytes. This specific MRP8/14-dependent pathway with striking similarities to sepsis increasing expression of TLR4 in thrombi appears to be involved in the pathogenesis of coronary occlusion and may represent a novel therapeutic target in ACS. PMID- 21782179 TI - Initial stress in biomechanical models of atherosclerotic plaques. AB - Rupture of atherosclerotic plaques is the underlying cause for the majority of acute strokes and myocardial infarctions. Rupture of the plaque occurs when the stress in the plaque exceeds the strength of the material locally. Biomechanical stress analyses are commonly based on pressurized geometries, in most cases measured by in-vivo MRI. The geometry is therefore not stress-free. The aim of this study is to identify the effect of neglecting the initial stress state on the plaque stress distribution. Fifty 2D histological sections (7 patients, 9 diseased coronary artery segments), perfusion fixed at 100 mmHg, were segmented and finite element models were created. The Backward Incremental method was applied to determine the initial stress state and the zero-pressure state. Peak plaque and cap stresses were compared with and without initial stress. The effect of initial stress on the peak stress was related to the minimum cap thickness, maximum necrotic core thickness, and necrotic core angle. When accounting for initial stress, the general relations between geometrical features and peak cap stress remain intact. However, on a patient-specific basis, accounting for initial stress has a different effect on the absolute cap stress for each plaque. Incorporating initial stress may therefore improve the accuracy of future stress based rupture risk analyses for atherosclerotic plaques. PMID- 21782181 TI - Size-exclusion chromatography of perfluorosulfonated ionomers. AB - A size-exclusion chromatography (SEC) method in N,N-dimethylformamide containing 0.1 M LiNO(3) is shown to be suitable for the determination of molar mass distributions of three classes of perfluorosulfonated ionomers, including Nafion((r)). Autoclaving sample preparation is optimized to prepare molecular solutions free of aggregates, and a solvent exchange method concentrates the autoclaved samples to enable the use of molar-mass-sensitive detection. Calibration curves obtained from light scattering and viscometry detection suggest minor variation in the specific refractive index increment across the molecular size distributions, which introduces inaccuracies in the calculation of local absolute molar masses and intrinsic viscosities. Conformation plots that combine apparent molar masses from light scattering detection with apparent intrinsic viscosities from viscometry detection partially compensate for the variations in refractive index increment. The conformation plots are consistent with compact polymer conformations, and they provide Mark-Houwink-Sakurada constants that can be used to calculate molar mass distributions without molar mass-sensitive detection. Unperturbed dimensions and characteristic ratios calculated from viscosity-molar mass relationships indicate unusually free rotation of the perfluoroalkane backbones and may suggest limitations to applying two-parameter excluded volume theories for these ionomers. PMID- 21782182 TI - Simultaneous determination of tryptophan, kynurenine, kynurenic and xanthurenic acids in honey by liquid chromatography with diode array, fluorescence and tandem mass spectrometry detection. AB - A liquid chromatography method using diode array-fluorescence detection and atmospheric pressure chemical ionization mass spectrometry (LC-DAD-FLD and LC APCI-MS/MS) was developed to quantify the levels of tryptophan (TRP), kynurenine (KYN), kynurenic (KYNA) and xanthurenic (XA) acids in honey. This procedure involved isolating the compounds of interest via solid-phase extraction (SPE) with mixed-mode polymeric cartridges. Chromatographic separation of the analytes was performed in isocratic mode on a Synergi 4MU Hydro-RP 80 A (150*4.60 mm i.d.) analytical column at 30 degrees C. The mobile phase of 20mM ammonium formate (pH 4) and methanol was passed at a flow rate of 0.5 mL/min. In replicate sets of spiked honey samples, the average analyte recoveries ranged from 60 to 98% for TRP, 55 to 120% for KYN, 65 to 106.5 for KYNA and 56 to 114% for XA. Detection limits ranged from 4 to 36 MUg/kg for LC-DAD-FLD to 0.2 and 1.0 MUg/kg for LC APCI-MS/MS. A strong matrix effect was found when MS/MS was employed, necessitating calibration using the standard addition method on matrix-matched standards for each honey type. The method was used to quantify each of the compounds of interest in 17 honey samples of distinct botanical origins. PMID- 21782183 TI - Hydrosilated silica-based columns: the effects of mobile phase and temperature on dual hydrophilic-reversed-phase separation mechanism of phenolic acids. AB - The effects of mobile phase composition and of temperature on the retention behavior of phenolic acids were studied on 4 hydrosilated (type C silica) based columns in buffered aqueous acetonitrile, both in the aqueous normal phase (HILIC) and in the reversed-phase mobile phase range. The UDC cholesterol and the C18 bidentate columns show significant reversed phase and normal-phase retention mechanisms, whereas very weak retention in the reversed-phase mode was observed on the silica hydride and the Diamond hydride columns. The concentration effects of the aqueous acetate buffer over the full mobile phase (HILIC and RP) composition range can be described by a simple four-parameter equation. At increasing temperature, the retention times and peak widths decrease both in the aqueous normal phase and in the reversed phase mobile phase range. Linear van't Hoff log k versus 1/T plots were observed, indicating a single retention mechanism predominating in the highly organic (HILIC), like in highly aqueous (RP) mobile phase ranges. Besides the type of the stationary phase, the separation selectivity of phenolic acids strongly depends on temperature and on the mobile phase composition. From among the 4 hydrosilated columns compared in this work, the UDC cholesterol column has high temperature stability (up to 100 degrees C) and is most suitable for selective and efficient separations of phenolic acids both in the HILIC and in the RP modes. PMID- 21782184 TI - Ultrasonic/microwave assisted extraction and diagnostic ion filtering strategy by liquid chromatography-quadrupole time-of-flight mass spectrometry for rapid characterization of flavonoids in Spatholobus suberectus. AB - Spatholobus suberectus is a widely used herb in traditional medicine for the treatment of blood stasis syndrome and related diseases. In this work, a potential ultrasonic/microwave assisted extraction (UMAE) method was developed for efficient sample pretreatment, and a diagnostic ion filtering strategy with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) was established for rapid characterization of flavonoids in S. suberectus. The factors of UMAE influencing the extraction yield of flavonoids of S. suberectus were evaluated. The optimal conditions were determined as: microwave power of 300 W, extraction time of 450 s, 70% methanol as extraction solvent, solvent to solid ratio of 20 mL/g, ultrasound power of 50 W, extraction temperature of 80 degrees C, and one extraction cycle. Compared with commonly used extraction methods, UMAE showed higher efficiency and shorter extraction time for sample preparation. Subsequently, the major diagnostic ions and fragmentation pathways of flavonoids in Q-TOF-MS were summarized with available reference compounds. Using a new diagnostic ion filtering strategy, a rapid screening and identification of thirty eight compounds was achieved in real S. suberectus samples. The results of this study clearly demonstrate the potential of UMAE for efficient extraction and LC-Q TOF-MS for rapid and sensitive structural elucidation of flavonoids in S. suberectus, and open perspectives for similar studies on other medicinal herbs. PMID- 21782185 TI - A novel solid-phase microextraction using coated fiber based sol-gel technique using poly(ethylene glycol) grafted multi-walled carbon nanotubes for determination of benzene, toluene, ethylbenzene and o-xylene in water samples with gas chromatography-flame ionization detector. AB - In this study, poly(ethylene glycol) (PEG) grafted onto multi-walled carbon nanotubes (PEG-g-MWCNTs) were synthesized by the covalent functionalization of MWCNTs with hydroxyl-terminated PEG chains. For the first time, functionalized product of PEG-g-MWCNTs was used as selective stationary phase to prepare the sol gel solid-phase microextraction (SPME) fiber in combination with gas chromatography-flame ionization detector (GC-FID) for the determination of ultra trace levels of benzene, toluene, ethylbenzene and o-xylene (BTEX) in real water samples. The PEG-g-MWCNTs were characterized by Fourier transform infrared spectra and also thermo-gravimetric analysis, which verified that PEG chains were grafted onto the surface of the MWCNTs. The scanning electron micrographs of the fiber surface revealed a highly porous structure which greatly increases the surface area for PEG-g-MWCNTs sol-gel coating. This fiber demonstrated many inherent advantages, the main being the strong anchoring of the coating to the fused silica resulting from chemical bonding with the silanol groups on the fused silica fiber surface. The new PEG-g-MWCNTs sol-gel fiber is simple to prepare, robust, with high thermal stability and long lifetime, up to 200 extractions. Important parameters influencing the extraction efficiency such as desorption temperature and time, extraction temperature, extraction time, stirring speed and salt effect were investigated and optimized. Under the optimal conditions, the method detection limits (S/N=3) were in the range of 0.6-3 pg mL(-1) and the limits of quantification (S/N=10) between 2 and 10 pg mL(-1). The relative standard deviations (RSDs) for one fiber (repeatability) (n=5) were obtained from 4.40 up to 5.75% and between fibers or batch to batch (n=3) (reproducibility) in the range of 4.31-6.55%. The developed method was successfully applied to real water samples while the relative recovery percentages obtained for the spiked water samples at 20 pg mL(-1) were from 90.21 to 101.90%. PMID- 21782186 TI - Direct sensitive simultaneous determination of fluorinated benzoic acids in oil reservoir waters by ultra high-performance liquid chromatography-tandem mass spectrometry. AB - A direct ultra-high performance reverse-phase HPLC (UHPLC)--electrospray MS/MS method was developed for the simultaneous determination of 16 fluorinated benzoic acids (FBAs) in oil reservoir waters. The separation was achieved within 5 min in a non-linear gradient mode using a 1-ml sample aliquot. The method detection limits were in the lower ng/ml range (between 0.05 and 50 ng/ml, depending on the compound) owing to the use of the travelling-wave collision cell technology. The method developed was more sensitive, faster (by avoiding sample preconcentration and purification steps) and more robust than the GC/MS methods currently used in oil industries. The accuracy of the method was verified by comparison with GC/MS results. It was applied to the determination of FBAs in water samples coming from reservoir tracing campaigns. PMID- 21782187 TI - Injection profiles in liquid chromatography II: predicting accurate injection profiles for computer-assisted preparative optimizations. AB - In computer assisted optimization of liquid chromatography it has been known for some years that it is important to use experimental injection profiles, instead of rectangular ones, in order to calculate accurate elution bands. However, the incorrectly assumed rectangular profiles are still mostly used especially in numerical optimizations. The reason is that the acquisition of injection profiles, for each injection volume and each flow rate considered in a computer assisted optimization requires a too large number of experiments. In this article a new function is proposed, which enables highly accurate predictions of the injection profiles and thus more accurate computer optimizations, with a minimum experimental effort. To model the injection profiles for any injection volume at a constant flow rate, as few as two experimental injection profiles are required. If it is desirable to also take the effect of flow rate on the injection profiles into account, then just two additional experiments are required. The overlap between fitted and experimental injection profiles at different flow rates and different injection volumes were excellent, more than 90%, using experimental injection profiles from just four different injection volumes at two different flow rates. Moreover, it was demonstrated that the flow rate has a minor influence on the injection profiles and that the injection volume is the main parameter that needs to be accounted for. PMID- 21782188 TI - Determination of coumaphos, chlorpyrifos and ethion residues in propolis tinctures by matrix solid-phase dispersion and gas chromatography coupled to flame photometric and mass spectrometric detection. AB - A new analytical method has been developed and successfully evaluated in routine application for the quantitative analysis of a selected group of organophosphate pesticides (coumaphos, chlorpyrifos and ethion) which can be found at trace levels in propolis tinctures (ethanolic propolis extracts); a valuable commodity used as raw material in the food and pharmaceutical industries for which there have been few attempts for pesticide residue analysis reported in the literature. The proposed methodology is based on matrix solid phase dispersion (MSPD) using aluminum sulfate anh. a novel dispersant material and subsequent column chromatography clean-up in silica gel prior to gas chromatography (GC) with both flame photometric detector (FPD) and mass spectrometry (MS) detection used for the routine quantification and identification of the residues, respectively. The limits of detection, for coumaphos, chlorpyrifos and ethion were below 26.0 MUg/kg in FPD and 1.43 MUg/kg for MS detection. Mean recoveries were in the range of 85-123% with RSD values below 13%, which suggests that the proposed method is fit for the purpose of analyzing pesticides in propolis tinctures containing high concentration of polyphenolics. The method has been successfully applied in our laboratory for the last 2 year in the analysis of real propolis tinctures samples. PMID- 21782189 TI - Expanded separation technique for chlorophyll metabolites in Oriental tobacco leaf using non aqueous reversed phase chromatography. AB - An improved separation method for chlorophyll metabolites in Oriental tobacco leaf was developed. While Oriental leaf still gives the green color even after the curing process, little attention has been paid to the detailed composition of the remaining green pigments. This study aimed to identify the green pigments using non aqueous reversed phase chromatography (NARPC). To this end, liquid chromatograph (LC) equipped with a photo diode array detector (DAD) and an atmospheric pressure chemical ionization/mass spectrometer (APCI/MSD) was selected, because it is useful for detecting low polar non-volatile compounds giving green color such as pheophytin a. Identification was based on the wavelength spectrum, mass spectrum and retention time, comparing the analytes in Oriental leaf with the commercially available and synthesized components. Consequently, several chlorophyll metabolites such as hydroxypheophytin a, solanesyl pheophorbide a and solanesyl hydroxypheophorbide a were newly identified, in addition to typical green pigments such as chlorophyll a and pheophytin a. Chlorophyll metabolites bound to solanesol were considered the tobacco specific components. NARPC expanded the number of detectable low polar chlorophyll metabolites in Oriental tobacco leaf. PMID- 21782190 TI - Micelle to solvent stacking of two alkaloids in nonaqueous capillary electrophoresis. AB - This paper for the first time describes the development of micelle to solvent stacking (MSS) to nonaqueous capillary electrophoresis (NACE). In this proposed MSS-NACE, sodium dodecyl sulfate (SDS) micelles transport, release, and focus analytes from the sample solution to the running buffer using methanol as their solvent. After the focusing step, the focused analytes were separated via NACE. The focusing mechanism and influencing factors were discussed using berberine (BBR) and jatrorrhizine (JTZ) as model compounds. And the optimum condition was obtained as following: 50 mM ammonium acetate, 6% (v/v) acetic acid and 10 mM SDS in redistilled water as sample matrix, 50 mM ammonium acetate and 6% (v/v) acetic acid in pure methanol as the running buffer, -20 kV focusing voltage with 30 min focusing time. Under these conditions, this method afforded limits of detection (S/N=3) of 0.002 MUg/mL and 0.003 MUg/mL for BBR and JTZ, respectively. In contrast to conventional NACE, the concentration sensitivity was improved 128-153 fold. PMID- 21782191 TI - Facile analysis of short-chain fatty acids as 4-nitrophenyl esters in complex anaerobic fermentation samples by high performance liquid chromatography. AB - Short-chain fatty acids are crucial intermediates in the conversion of biomass to methane. Due to the complexity of raw biomass, volatile fatty acids (including n- and branched-chain compounds) as well as arylacetic and arylpropionic acids arise from digestion of carbohydrates, proteins and lipids. The development of a simple extraction procedure in combination with internal standardization and facile 4 nitrophenyl-labelling via oxalylchloride-generated acylchlorides enabled robust separation and quantification of the target compounds in crude biological samples like raw cattle manure and biogas fermenter contents. Detection limits of <100 MUM and error rates of less than 4% for the quantification of individual compounds in a concentration range up to 50 mM for non-diluted samples suggest that the novel method might be of general advantage for the routine quantification of short-chain fatty acids in complex biological samples including complex fermentation media. PMID- 21782192 TI - A complementary mobile phase approach based on the peak count concept oriented to the full resolution of complex mixtures. AB - Situations of minimal resolution are often found in liquid chromatography, when samples that contain a large number of compounds, or highly similar in terms of structure and/or polarity, are analysed. This makes full resolution with a single separation condition (e.g., mobile phase, gradient or column) unfeasible. In this work, the optimisation of the resolution of such samples in reversed-phase liquid chromatography is approached using two or more isocratic mobile phases with a complementary resolution behaviour (complementary mobile phases, CMPs). Each mobile phase is dedicated to the separation of a group of compounds. The CMPs are selected in such a way that, when the separation is considered globally, all the compounds in the sample are satisfactorily resolved. The search of optimal CMPs can be carried out through a comprehensive examination of the mobile phases in a selected domain. The computation time of this search has been reported to be substantially reduced by application of a genetic algorithm with local search (LOGA). A much simpler approach is here described, which is accessible to non experts in programming, and offers solutions of the same quality as LOGA, with a similar computation time. The approach makes a sequential search of CMPs based on the peak count concept, which is the number of peaks exceeding a pre-established resolution threshold. The new approach is described using as test sample a mixture of 30 probe compounds, 23 of them with an ionisable character, and the pH and organic solvent contents as experimental factors. PMID- 21782193 TI - Pressurized liquid extraction of ginger (Zingiber officinale Roscoe) with bioethanol: an efficient and sustainable approach. AB - To develop an efficient green extraction approach for recovery of bioactive compounds from natural plants, we examined the potential of pressurized liquid extraction (PLE) of ginger (Zingiber officinale Roscoe) with bioethanol/water as solvents. The advantages of PLE over other extraction approaches, in addition to reduced time/solvent cost, the extract of PLE showed a distinct constituent profile from that of Soxhlet extraction, with significantly improved recovery of diarylheptanoids, etc. Among the pure solvents tested for PLE, bioethanol yield the highest efficiency for recovering most constituents of gingerol-related compounds; while for a broad concentration spectrum of ethanol aqueous solutions, 70% ethanol gave the best performance in terms of yield of total extract, complete constituent profile and recovery of most gingerol-related components. PLE with 70% bioethanol operated at 1500 psi and 100 degrees C for 20 min (static extraction time: 5 min) is recommended as optimized extraction conditions, achieving 106.8%, 109.3% and 108.0% yield of [6]-, [8]- and [10] gingerol relative to the yield of corresponding constituent obtained by 8h Soxhlet extraction (absolute ethanol as extraction solvent). PMID- 21782194 TI - Assessment for the light-induced cis-trans isomerization of rhapontigenin and its glucoside rhaponticin by capillary electrophoresis and spectrometric methods. AB - The light-induced cis-trans isomerization of rhapontigenin (RHA) and its glucoside rhaponticin (RHA-Glc) were evaluated under ultraviolet (UV) light irradiation. A simple and rapid capillary electrophoresis method was developed for the kinetic study of four stilbenes (both cis and trans form of RHA and RHA Glc). These analyses were achieved by using beta-cyclodextrin (beta-CD) modified capillary zone electrophoresis with diode array detector (CZE-DAD). The method provided reliable separations with a short analysis time of 3 min. The purity of individual compound was checked by UV spectral comparisons with known standards, and further confirmed by (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy. Furthermore, the UV absorbance and the molar absoptivity (epsilon) values were determined by UV-vis spectrophotometer to be 36824 L mol(-1) cm(-1) at lambda(max) 324.5 nm for trans-RHA and 43894 L mol(-1) cm(-1) at lambda(max) 325 nm for trans-RHA-Glc in methanol/water mixture solution (50%, v:v), respectively. CZE, UV-vis and NMR spectroscopy studies provided similar conclusions by considering the influence of irradiation time and the influence of irradiation wavelength. PMID- 21782195 TI - Chromatographic characterization of hydrophilic interaction liquid chromatography stationary phases: hydrophilicity, charge effects, structural selectivity, and separation efficiency. AB - Fourteen commercially available particle-packed columns and a monolithic column for hydrophilic interaction liquid chromatography (HILIC) were characterized in terms of the degree of hydrophilicity, the selectivity for hydrophilic hydrophobic substituents, the selectivity for the regio and configurational differences in hydrophilic substituents, the selectivity for molecular shapes, the evaluation of electrostatic interactions, and the evaluation of the acidic basic nature of the stationary phases using nucleoside derivatives, phenyl glucoside derivatives, xanthine derivatives, sodium p-toluenesulfonate, and trimethylphenylammonium chloride as a set of samples. Principal component analysis based on the data of retention factors could separate three clusters of the HILIC phases. The column efficiency and the peak asymmetry factors were also discussed. These data on the selectivity for partial structural differences were summarized as radar-shaped diagrams. This method of column characterization is helpful to classify HILIC stationary phases on the basis of their chromatographic properties, and to choose better columns for targets to be separated. Judging from the retention factor for uridine, these HILIC columns could be separated into two groups: strongly retentive and weakly retentive stationary phases. Among the strongly retentive stationary phases, zwitterionic and amide functionalities were found to be the most selective on the basis of partial structural differences. The hydroxyethyl-type stationary phase showed the highest retention factor, but with low separation efficiency. Weakly retentive stationary phases generally showed lower selectivity for partial structural differences. PMID- 21782196 TI - Creation of coating surfaces possessing superhydrophobic and superoleophobic characteristics with fluoroalkyl end-capped vinyltrimethoxysilane oligomeric nanocomposites having biphenylene segments. AB - Fluoroalkyl end-capped vinyltrimethoxysilane oligomeric nanocomposites having biphenylene units [R(F)-(VM-SiO(2))(n)-R(F)/Ar-SiO(2)] were prepared by the sol gel reaction of the corresponding oligomer [R(F)-(VM)(n)-R(F)] with 4,4' bis(triethoxysilyl)-1,1'-biphenyl [Ar-Si(OEt)(3)] under alkaline conditions. R(F) (VM-SiO(2))(n)-R(F)/Ar-SiO(2) nanocomposites were applied to the surface modification of PMMA to exhibit not only a good oleophobicity imparted by fluorine but also a fluorescent emission ability on the surface. Methanol sol solutions of R(F)-(VM-SiO(2))(n)-R(F)/Ar-SiO(2) nanocomposites were effective for the surface modification of glass through the dipping technique to exhibit good oleophobicity with superhydrophobicity on the modified glass surface. On the other hand, 1,2-dichloroethane sol solutions enabled R(F)-(VM-SiO(2))(n)-R(F)/Ar SiO(2) nanocomposites to exhibit both superhydrophobic and superoleophobic characteristics on the modified surface through dipping the glass in these sol solutions. PMID- 21782197 TI - Looking good versus doing good: which factors take precedence when children learn about new tools? AB - We present two experiments exploring whether individuals would be persuaded to imitate the intentional action of an adult model whose actions suggest that the correct way to complete a task is with an inefficient tool. In Experiment 1, children ages 5-10years and a group of adults watched an adult model reject an efficient tool in favor of one that was inefficient, but claim it was "made for" the task. Results indicated low rates of imitation of the model's intentional choice until 9 and 10years of age. In Experiment 2, children ages 3-11years again watched a model reject a functional tool in favor of a nonfunctional one. This time, the demonstration took place on video. For half of the participants, the model from the video was present to offer a choice between the two tools (high pressure condition), and for the other half, she was absent (low-pressure condition). Children also completed a social desirability questionnaire to explore relationships between imitation choices and personality. Results indicated that rates of imitation were associated with higher scores on the social desirability scale among children ages 3-7years. Among 8- to 11-year-olds and especially among 9- and 10-year-olds - the decision to copy the model's intentional choice was more likely when the model was present than when she was absent. The findings reveal the contributions of age, personality, and social pressure to differences in imitation. PMID- 21782198 TI - Working memory components as predictors of children's mathematical word problem solving. AB - This study determined the working memory (WM) components (executive, phonological loop, and visual-spatial sketchpad) that best predicted mathematical word problem solving accuracy of elementary school children in Grades 2, 3, and 4 (N=310). A battery of tests was administered to assess problem-solving accuracy, problem solving processes, WM, reading, and math calculation. Structural equation modeling analyses indicated that (a) all three WM components significantly predicted problem-solving accuracy, (b) reading skills and calculation proficiency mediated the predictive effects of the central executive system and the phonological loop on solution accuracy, and (c) academic mediators failed to moderate the relationship between the visual-spatial sketchpad and solution accuracy. The results support the notion that all components of WM play a major role in predicting problem-solving accuracy, but basic skills acquired in specific academic domains (reading and math) can compensate for some of the influence of WM on children's mathematical word problem solving. PMID- 21782199 TI - Frontal lobe-mediated behavioral changes in amyotrophic lateral sclerosis: are they independent of physical disabilities? AB - OBJECTIVE: Several studies have indicated that frontal cognitive impairment is present in patients with amyotrophic lateral sclerosis (ALS). However, it remains to be elucidated whether the behavioral change is a direct consequence of ALS pathology or the measurements are confounded by the physical impairments. We examined frontal lobe-mediated behavioral dysfunction in daily living in patients with ALS by using the family- and self-rating forms of the Frontal Systems Behavior Scale (FrSBe) and assessed the relationship between the scores and motor impairments or ventilatory status. METHODS: We examined 24 patients with sporadic ALS, who were aged 65.7 +/- 10.5 years with mean disease duration of 2.3 +/- 1.7 years, Mini-Mental State Examination score of >= 24, normal Self-rating Depression Scale, no need of assistance in daily life, normal respiratory function, and normal arterial blood gas analytes. We examined the relationship between FrSBe scores and ALS Functional Rating Scale (ALSFRS), respiratory function, and arterial blood gas analytes. RESULTS: The scores of family- and self-rating FrSBe were significantly higher after onset of ALS than before onset, most notably in apathy. The family-rating FrSBe scores after onset were not correlated with ALSFRS, respiratory function, or arterial blood gas analytes. CONCLUSION: The frontal-lobe-related behavioral dysfunction is present after the onset of ALS, but is independent of physical impairments. PMID- 21782200 TI - Thoracoabdominal aortic aneurysm repair with patent gastroepiploic artery graft. PMID- 21782201 TI - In vitro photochemical and phototoxicological characterization of major constituents in St. John's Wort (Hypericum perforatum) extracts. AB - Extracts from St. John's Wort (SJW: Hypericum perforatum) have been used for the treatment of mild-to-moderate depression. In spite of the high therapeutic potential, orally administered SJW sometimes causes phototoxic skin responses. As such, the present study aimed to clarify the phototoxic mechanisms and to identify the major phototoxins of SJW extract. Photobiochemical properties of SJW extract and 19 known constituents were characterized with focus on generation of reactive oxygen species (ROS), lipid peroxidation, and DNA photocleavage, which are indicative of photosensitive, photoirritant, and photogenotoxic potentials, respectively. ROS assay revealed the photoreactivity of SJW extract and some SJW ingredients as evidenced by type I and/or II photochemical reactions under light exposure. Not all the ROS-generating constituents caused photosensitized peroxidation of linoleic acid and photodynamic cleavage of plasmid DNA, and only hypericin, pseudohypericin, and hyperforin exhibited in vitro photoirritant potential. Concomitant UV exposure of quercitrin, an SJW component with potent UV/Vis absorption, with hyperforin resulted in significant attenuation of photodynamic generation of singlet oxygen from hyperforin, but not with hypericin. In conclusion, our results suggested that hypericin, pseudohypericin, and hyperforin might be responsible for the in vitro phototoxic effects of SJW extract. PMID- 21782202 TI - Interactive map communication: pilot study of the visual perceptions and preferences of public health practitioners. AB - OBJECTIVES: To conduct a pilot study into the comprehension and visualisation preferences of geographic information by public health practitioners (PHPs), particularly in the context of interactive, Internet-based atlases. STUDY DESIGN: Structured human-computer interaction interviews. METHODS: Seven academia-based PHPs were interviewed as information service users based on a structured questionnaire to assess their understanding of geographic representations of morbidity data, and identify their visualisation preferences in a geographic information systems environment. RESULTS: Awareness of area-based deprivation indices and the Index of Multiple Deprivation 2007 health and disability domain was near-universal. However, novice users of disease maps had difficulties in interpreting data classifications, in understanding supplementary information in the form of box plots and histograms, and in making use of links between interactive tabular and cartographic information. Choices for colour plans when viewing maps showed little agreement between users, although pre-viewing comments showed preferences for red-blue diverging schema. CONCLUSIONS: PHPs new to geographic information would benefit from enhanced interpretive support documentation to meet their needs when using Internet-based, interactive public health atlases, which are rarely provided at such sites. Technical, software related support alone is insufficient. Increased interaction between PHPs and mapmakers would be beneficial to maximise the potential of the current growth in interactive, electronic atlases, and improve geographic information support for public health decision-making and informing the wider public. PMID- 21782203 TI - Three-dimensional hybrid model for predicting air-coupled generation of guided waves in composite material plates. AB - For contact-less, non-destructive testing (NDT) purposes using air-coupled ultrasonic transducers, it is often required to numerically simulate the propagation of ultrasonic waves in solid media, and their coupling through air with specific transducers. At that point, one could simulate the propagation in the air and then in the solid component, using a Finite Element (FE) model. However, when three-dimensional (3D) modeling becomes necessary, such a solution reveals to be extremely demanding in terms of number of degrees of freedom and computational time. In this paper, to avoid such difficulties, the propagation in air from an ultrasonic transmitter to a tested solid plate is modeled in 3D using a closed-form solution. The knowledge of the transducer characteristics (diameter, frequency bandwidth, efficiency in Pa/V) allows the spatial distribution and actual pressure (in Pa) of the acoustic field produced in the air to be predicted, for a given input voltage. This pressure field is applied in turn as a boundary condition in a 3D FE model, to predict the plate response (displacement and stress guided beams) for a given distance between the transmitter and the plate, and for a given angle of orientation of the transmitter with respect to the plate. The FE model is so restricted to modeling of the solid structure only, thus reducing very significantly the number of degrees of freedom and computational time. The material constituting the plate is considered to be an anisotropic and viscoelastic medium. To validate the whole modeling process, an air-coupled ultrasonic transducer is used and oriented at a specific angle chosen for generating one specific Lamb mode guided along a composite plate sample, and a laser probe measures the normal velocity at different locations on the surface of the plate. In the field of NDT, it is generally suitable to excite a pure Lamb mode in order to ease the interpretation of received signals that would represent waves scattered by defects. After a validation step, the numerical model is then used to investigate the effect of the material anisotropy on the purity of the incident guided mode. PMID- 21782204 TI - In vivo generated Citrus exocortis viroid progeny variants display a range of phenotypes with altered levels of replication, systemic accumulation and pathogenicity. AB - Citrus exocortis viroid (CEVd) exists as populations of heterogeneous variants in infected hosts. In vivo generated CEVd progeny variants (CEVd-PVs) populations from citrus protoplasts, seedlings and mature plants, following inoculation with transcripts of a single CEVd cDNA-clone (wild-type, WT), were studied. The CEVd PVs population in protoplasts was heterogeneous and became progressively more homogeneous in seedlings and mature plants. The infectivity and pathogenicity of selected CEVd-PVs was evaluated in citrus and herbaceous experimental hosts. The CEVd-PVs U30C, G128A and U182C were not infectious; G50A and 108U+ were infectious but reverted back to WT and 62A+, U129A and U278A were infectious, genetically stable and more severe than WT. The 62A+ and U278A and U129A accumulated at higher levels than WT in protoplasts and seedlings respectively. The effect of specific mutations on the predicted secondary structure of the CEVd PVs' RNA coupled with the infectivity and replication studies suggested complex structure-to-function relationships for CEVd. PMID- 21782205 TI - Herpes simplex virus 1 microRNAs expressed abundantly during latent infection are not essential for latency in mouse trigeminal ganglia. AB - Several herpes simplex virus 1 microRNAs are encoded within or near the latency associated transcript (LAT) locus, and are expressed abundantly during latency. Some of these microRNAs can repress the expression of important viral proteins and are hypothesized to play important roles in establishing and/or maintaining latent infections. We found that in lytically infected cells and in acutely infected mouse ganglia, expression of LAT-encoded microRNAs was weak and unaffected by a deletion that includes the LAT promoter. In mouse ganglia latently infected with wild type virus, the microRNAs accumulated to high levels, but deletions of the LAT promoter markedly reduced expression of LAT-encoded microRNAs and also miR-H6, which is encoded upstream of LAT and can repress expression of ICP4. Because these LAT deletion mutants establish and maintain latent infections, these microRNAs are not essential for latency, at least in mouse trigeminal ganglia, but may help promote it. PMID- 21782206 TI - Effect of chlorination on endotoxin activities in secondary sewage effluent and typical Gram-negative bacteria. AB - Wastewater reuse is a viable and attractive method to address water shortage problems. However, wastewater can have high endotoxin activity. Endotoxins are toxic inflammatory agents and are considered a risk factor for wastewater reuse. In this study, the effect of chlorination on endotoxin activity in secondary sewage effluent was evaluated by Limulus (Tachypleus tridentatus) Amebocyte Lysate assay. It was found that chlorination could not decrease endotoxin activity of secondary effluent effectively under the conditions employed in this study. Chlorination of a pure cultured Gram-negative bacterium (Escherichia coli), and a Gram-negative bacterium isolated from secondary sewage effluent, resulted in a significant increase in endotoxin activity, suggesting that the presence of Gram-negative bacteria contributed substantially to endotoxin activity, masking any potential reduction that may be attributable to chlorination. Furthermore, the activities of both free and cell-bound endotoxins in pure culture increased significantly during chlorination due to cell wall damage induced by chlorination. PMID- 21782207 TI - Evaluation of suitable chlorine bulk-decay models for water distribution systems. AB - Maintaining the chlorine residual is a major disinfection goal for many water distribution systems. A suitable general chlorine bulk-decay model is required for simulation of chlorine profiles in networks to assist disinfection planning/management efficiently. The first-order model is unsuitable due to inaccuracy and inability to represent rechlorination. Three potentially suitable, simple, reactant models were compared. The single-reactant model was found to be unsuitable, as it was inaccurate when restricted to using a single set of invariant parameters. The two-reactant model was more suitable than the variable rate-coefficient model, although both models were accurate under the same restriction. The two-reactant model was then calibrated against datasets consisting of multiple decay tests for five distinctly different waters. It accurately predicted data reserved for validation over the chlorine concentration range of 0-6 mg/L, using a single set of invariant parameters, and is therefore the simplest, generally suitable model for simulating chlorine profiles in distribution system networks. PMID- 21782208 TI - Performance evaluation of the UV/H2O2 process on selected nitrogenous organic compounds: reductions of organic contents vs. corresponding C-, N-DBPs formations. AB - The presence of various organic contaminants in water sources is of concern due to their direct threats to human health and potential to react with disinfectants to form carcinogenic byproducts including trihalomethanes, haloacetic acids and nitrosamines in finished water. This study applied both medium-pressure and low pressure ultraviolet light coupled with hydrogen peroxide (UV/H2O2) to evaluate its efficacy for degradation of selected nitrogenous organic compounds and corresponding disinfection byproduct (DBP) formation. Six organic compounds were chosen as target precursors based on their nitrogen contents and molecular structures. The results showed that higher oxidation capacity resulted in better reduction of organic matters and DBP formation potentials (DBPFPs). However, insufficient contact time and oxidant doses could lead to a rise of DBPFPs in the early stages of UV/H2O2 reactions. A greater percentage removal was achieved for organic carbon than organic nitrogen after UV/H2O2 treatment, especially for compounds with complicated structure such as diltiazem. During the UV/H2O2 treatment, the intermediate products include tertiary amine, dimethyl amine (DMA) or DMA-like structures, which are N-nitrosodimethylamine (NDMA) precursors after chlorination or chloramination. Furthermore, it was observed that using dissolved organic nitrogen and DMA to predict NDMAFP could lead to biased conclusions because of the complex nature of nitrogenous matters in aqueous environments. PMID- 21782209 TI - Impact of silver nanoparticles on natural marine biofilm bacteria. AB - There has been a recent increase in the use of silver nanoparticles (Ag NPs) in a wide range of consumer products due to their highly effective antimicrobial properties. However, Ag NPs give cause for concern since their wide use makes them likely to be released into aquatic ecosystems and potentially affect natural bacterial communities. In this study marine biofilms were grown in situ in a coastal site (Singapore Harbour) and exposed in the laboratory for a further 24h to 0-2000 MUg L-1 of well characterised Ag NPs. Increasing concentrations of Ag NPs caused a significant decrease in biofilm volume and biomass, and Ag uptake by biofilms per unit of volume was also dependent on concentration. Terminal fragment length polymorphisms and subsequent cluster and phylogenetic analysis showed the presence of major bacterial groups in biofilms irrespective of treatment with Ag NPs. This implies that even at the highest concentrations studied these taxonomic groups were not displaced. Nevertheless, biofilm succession was impeded on Ag NP treated biofilms, affecting the relative abundance of major bacterial groups in the biofilm community, with potential longer term effects on biofilm development and function. PMID- 21782210 TI - Organohalogen compounds and their metabolites in the blood of Japanese amberjack (Seriola quinqueradiata) and scalloped hammerhead shark (Sphyrna lewini) from Japanese coastal waters. AB - Information on accumulation of polychlorinated biphenyl metabolites (OH-PCBs) and hydroxylated polybrominated diphenyl ethers (OH-PBDEs) in the blood of marine fish is limited. The present study, we determined the residue levels and patterns of PCBs, OH-PCBs, PBDEs, OH-PBDEs and methoxylated PBDEs (MeO-PBDEs) in the blood collected from scalloped hammerhead shark (Sphyrna lewini) and Japanese amberjack (Seriola quinqueradiata), species of predatory fish at Japanese coastal waters. The predominant homologues found in Japanese amberjacks were mono- and di chlorinated OH-PCBs, and scalloped hammerhead sharks were octa-chlorinated OH PCBs. The predominant OH-PCB isomers were lower-chlorinated OH-PCBs such as 6OH CB2 and 2'OH-CB9 in Japanese amberjacks. This result suggests that exposure of Japanese amberjacks to lower-chlorinated OH-PCBs might be from the ambient aquatic environment. In scalloped hammerhead sharks, 4,4'diOH-CB202, 4OH-CB201 and 4OH-CB146 were the predominant isomers accounting for approximately 60% of the total OH-PCBs. The predominant MeO-PBDE isomers were 6MeO-BDE47 followed by 2'MeO-BDE68 in both species. As for OH-PBDE isomers, 6OH-BDE47 was predominant followed by 2'OH-BDE68 in Japanese amberjacks and scalloped hammerhead sharks. Residue levels of SigmaMeO-PBDEs and SigmaOH-PBDEs showed a significant positive correlation (p=0.029). This result suggests that MeO-PBDEs and OH-PBDEs share a common source or a metabolic pathway in fishes. Characteristic differences found in the profiles of OH-PCBs and OH-PBDEs in Japanese amberjack and scalloped hammerhead shark show the need for further studies on the differences in exposure profiles, metabolic capacities and toxic effects in fish. PMID- 21782211 TI - Uptake, depuration, and radiation dose estimation in zebrafish exposed to radionuclides via aqueous or dietary routes. AB - Understanding uptake and depuration of radionuclides in organisms is necessary to relate exposure to radiation dose and ultimately to biological effects. We investigated uptake and depuration of a mixture of radionuclides to link bioaccumulation with radiation dose in zebrafish, Danio rerio. Adult zebrafish were exposed to radionuclides ((54)Mn, (60)Co, (65)Zn, (75)Se, (109)Cd, (110m)Ag, (134)Cs and (241)Am) at tracer levels (<200 Bq g(-1)) for 14 d, either via water or diet. Radioactivity concentrations were measured in whole body and excised gonads of exposed fish during uptake (14 d) and depuration phases (47 d and 42 d for aqueous and dietary exposures respectively), and dose rates were modelled from activity concentrations in whole body and exposure medium (water or diet). After 14-day aqueous exposure, radionuclides were detected in decreasing activity concentrations: (75)Se>(65)Zn>(109)Cd>(110m)Ag>(54)Mn>(60)Co>(241)Am>(134)Cs (range: 175-8 Bq g(1)). After dietary exposure the order of radionuclide activity concentration in tissues (Bq g(-1)) was: (65)Zn>(60)Co>(75)Se>(109)Cd>(110m)Ag>(241)Am>(54)Mn>(134)Cs (range: 91-1 Bq g( 1)). Aqueous exposure resulted in higher whole body activity concentrations for all radionuclides except (60)Co. Route of exposure did not appear to influence activity concentrations in gonads, except for (54)Mn, (65)Zn, and (75)Se, which had higher activity concentrations in gonads following aqueous exposure. Highest gonad activity concentrations (Bq g(-1)) were for (75)Se (211), (109)Cd (142), and (65)Zn (117), and highest dose rates (MUGy h(-1)) were from (241)Am (aqueous, 1050; diet 242). This study links radionuclide bioaccumulation data obtained in laboratory experiments with radiation dose determined by application of a dosimetry modelling tool, an approach that will enable better linkages to be made between exposure, dose, and effects of radionuclides in organisms. PMID- 21782212 TI - Evaluation of different analysis and identification methods for Salmonella detection in surface drinking water sources. AB - The standard method for detecting Salmonella generally analyzes food or fecal samples. Salmonella often occur in relatively low concentrations in environmental waters. Therefore, some form of concentration and proliferation may be needed. This study compares three Salmonella analysis methods and develops a new Salmonella detection procedure for use in environmental water samples. The new procedure for Salmonella detection include water concentration, nutrient broth enrichment, selection of Salmonella containing broth by PCR, isolation of Salmonella strains by selective culture plates, detection of possible Salmonella isolate by PCR, and biochemical testing. Serological assay and pulsed-field gel electrophoresis (PFGE) can be used to identify Salmonella serotype and genotype, respectively. This study analyzed 116 raw water samples taken from 18 water plants and belonging to 5 watersheds. Of these 116, 10 water samples (8.6%) taken from 7 water plants and belonging to 4 watersheds were positive for a Salmonella specific polymerase chain reaction targeting the invA gene. Guided by serological assay results, this study identified 7 cultured Salmonella isolates as Salmonella enterica serovar: Alnaby, Enteritidis, Houten, Montevideo, Newport, Paratyphi B var. Java, and Victoria. These seven Salmonella serovars were identified in clinical cases for the same geographical areas, but only one of them was 100% homologous with clinical cases in the PFGE pattern. PMID- 21782213 TI - Mercury exposure and risks from dental amalgam in the US population, post-2000. AB - Dental amalgam is 50% metallic mercury (Hg) by weight and Hg vapour continuously evolves from in-place dental amalgam, causing increased Hg content with increasing amalgam load in urine, faeces, exhaled breath, saliva, blood, and various organs and tissues including the kidney, pituitary gland, liver, and brain. The Hg content also increases with maternal amalgam load in amniotic fluid, placenta, cord blood, meconium, various foetal tissues including liver, kidney and brain, in colostrum and breast milk. Based on 2001 to 2004 population statistics, 181.1 million Americans carry a grand total of 1.46 billion restored teeth. Children as young as 26 months were recorded as having restored teeth. Past dental practice and recently available data indicate that the majority of these restorations are composed of dental amalgam. Employing recent US population based statistics on body weight and the frequency of dentally restored tooth surfaces, and recent research on the incremental increase in urinary Hg concentration per amalgam-filled tooth surface, estimates of Hg exposure from amalgam fillings were determined for 5 age groups of the US population. Three specific exposure scenarios were considered, each scenario incrementally reducing the number of tooth surfaces assumed to be restored with amalgam. Based on the least conservative of the scenarios evaluated, it was estimated that some 67.2 million Americans would exceed the Hg dose associated with the reference exposure level (REL) of 0.3 MUg/m(3) established by the US Environmental Protection Agency; and 122.3 million Americans would exceed the dose associated with the REL of 0.03 MUg/m(3) established by the California Environmental Protection Agency. Exposure estimates are consistent with previous estimates presented by Health Canada in 1995, and amount to 0.2 to 0.4 MUg/day per amalgam-filled tooth surface, or 0.5 to 1 MUg/day/amalgam-filled tooth, depending on age and other factors. PMID- 21782214 TI - Trends of lead and zinc in resident and transplanted Flavocetraria nivalis lichens near a former lead-zinc mine in West Greenland. AB - This study investigated spatial and temporal trends of lead (Pb) and zinc (Zn) in resident and transplanted Flavocetraria nivalis lichens near the former Black Angel Mine in Maarmorilik, West Greenland. The objectives of the study were to evaluate resident and transplanted lichens for monitoring dust contamination and investigate trends in mine-related dust contamination near the mine. The mine operated between 1973 and 1990 and lichens were regularly sampled between 1986 and 2009. When the mine operated, elevated concentrations of Pb, Zn and other elements were observed in resident lichens up to 35 km from Maarmorilik. In the period after mine closure, Pb and Zn concentrations in resident lichens decreased with 1-11% and 0-6% per year, respectively. From 1996 to 2009, lichens were transplanted into the study area from an uncontaminated site and collected the following year. After 1 year, transplanted lichens showed elevated concentrations of Pb and Zn but contained consistently less Pb and Zn compared to resident lichens (24+/-23% and 63+/-37%, respectively). During the most recent sampling in 2009, transplanted lichens still showed significantly elevated Pb concentrations (up to a factor 270) within a distance of 20 km from Maarmorilik. Zinc concentrations were only significantly elevated at sites within 5 km from the mine. Time-series regression analyses showed no significant decreases in Pb and Zn in transplanted lichens at any of the sites during the period 1996-2009. In conclusion, our study showed that resident F. nivalis lichens could not be used to evaluate the recent annual dust contamination in Maarmorilik. Lichen transplants, however, were considered adequate for assessing spatial and temporal trends in Pb and Zn contamination from recently deposited dust. The continuous dispersal of contaminated dust in Maarmorilik almost 20 years after mine closure reveals a slow recovery from mining contamination in this arctic area. PMID- 21782215 TI - Contribution of Miscanthus x giganteus root exudates to the biostimulation of PAH degradation: an in vitro study. AB - Phytoremediation is considered as a promising and cost-effective method to enhance bioremediation of polluted soils. Exudation of plant root secondary metabolites similar to organic pollutants may induce the expression of microbial degradative enzymes and favour cometabolism of xenobiotics. We investigated the contribution of Miscanthus x giganteus root exudates in the biostimulation of PAH degradation. This perennial grass was chosen because of its capability to grow on polluted soils and its high biomass production for non-food purposes. First, the impact of cometabolism phenomena was evaluated on the selective enrichment of pyrene-degrading bacterial consortia. The identification of each isolated strains following incubation with pyrene only, "pyrene+phenanthrene", "pyrene+salycilate" or "pyrene+diesel fuel" showed a varying bacterial diversity and pyrene-degrading ability, depending on the co-substrate used. Then, a microplate assay was designed, based on the simultaneous measurement of bacterial consortia growth and degradation activity, in the presence of PAH and total root exudates. Results showed that i) the addition of root exudates was efficient for promoting bacterial growth, ii) but a selective enrichment of PAH-degraders compared to aliphatic ones could be clearly demonstrated, thereby conducing to an enhanced PAH catabolism. The identification of plant secondary metabolites showed the presence of a broad range of flavonoid-derived compounds that could play a role in cometabolic processes. Microplate assays with the two major molecules, quercetin and rutin, suggested a partial involvement of these compounds in biostimulation processes. Further investigations with the other identified secondary metabolites (apigenin, isovitexin, catechin, gallic and caffeic acid) should provide more information on the exudate-PAH cometabolic degradation phenomenon. PMID- 21782216 TI - Effects of PerClot(r) on the healing of full-thickness skin wounds in rats. AB - PerClot((r)) is a hemostatic material made of polysaccharide from modified starch and has been shown to assist in topical hemostasis. The principal goal in treating surgical and non-surgical wounds is the need for rapid closure of the lesion. This study investigated whether topical application of PerClot((r)) could improve impaired wound healing in Sprague-Dawley (SD) rats. Full-thickness skin wounds were created on the back of the rats. Immediately, PerClot((r)) was introduced into the wound bed, while wounds receiving starch or nothing served as controls. Wound closure was monitored using well-recognized wound-healing parameters: histological examination for inflammatory cells and fibroblast infiltration, newly formed capillaries, and collagen deposition. Meanwhile, transforming growth factor (TGF-beta1) was measured by immunochemistry. Wound closure was significantly accelerated by local application of PerClot((r)). Furthermore, PerClot((r))-treated wounds showed significantly increased fibroblast numbers at 5 days post-wounding, and newly formed capillaries at 7 days post-wounding, and collagen regeneration at 7 and 14 days post-wounding. The number of infiltrating fibroblasts expressing TGF-beta1 was significantly higher than that in the controls at 7 and 14 days post-wounding. PerClot((r)) can improve the wound healing and this effect might involve an increase in the activity of fibroblasts and increased release of TGF-beta1. PMID- 21782217 TI - Retroperitoneal histologic findings of patients with elevated serum alpha fetoprotein and pure seminoma at orchiectomy. AB - OBJECTIVES: To report the retroperitoneal histologic findings from a contemporary series of patients with pure seminoma at orchiectomy with an elevated serum alpha fetoprotein (AFP) level. These patients underwent treatment on the assumption that the lesion was nonseminomatous germ cell tumor (NSGCT). METHODS: We identified 22 patients from 1989 to 2009 with pure seminoma diagnosed at orchiectomy with an elevated serum AFP level (>15 ng/mL) either before or after orchiectomy. The retroperitoneal histologic and relapse data are reported. RESULTS: The median preorchiectomy and prechemotherapy serum AFP level was 248 ng/mL (interquartile range 48-4693) and 279 ng/mL (interquartile range 66-5311), respectively. The percentage of patients with clinical Stage I, II, and III disease was 5%, 50%, and 45%, respectively. The percentage of patients with a good, intermediate, and poor risk status according to the International Germ Cell Cancer Collaborative Group was 32%, 32%, and 36%, respectively. Of the 22 patients, 21 underwent induction chemotherapy followed by retroperitoneal lymph node dissection. Overall, 67% of patients had NSGCT elements in the retroperitoneum. The histologic findings were pure teratoma in 38%, malignant transformation in 14%, and viable NSGCT in 14%. Also, 59% had some component of teratoma in the retroperitoneum. Only 1 patient (5%) had any seminoma in the retroperitoneum, but this patient also had retroperitoneal teratoma. Of the 22 patients, 7 developed a relapse and received salvage chemotherapy. The actuarial relapse-free survival rate at 5 and 10 years was 76% and 61%, respectively, reflecting the high percentage of patients with Stage II-III disease. CONCLUSIONS: Pure seminoma at orchiectomy with an elevated serum AFP level portends a high likelihood of NSGCT elements in the retroperitoneum. PMID- 21782218 TI - Anastomosis during robot-assisted radical prostatectomy: randomized controlled trial comparing barbed and standard monofilament suture. AB - OBJECTIVE: To compare perioperative and functional outcomes after urethrovesical anastomosis (UVA) with barbed polyglyconate and monofilament poliglecaprone in robot-assisted radical prostatectomy (RARP). Barbed polyglyconate suture was first used for the UVA during RARP beginning in January 2010; safety and feasibility were previously demonstrated in 51 patients. METHODS: From May to September 2010, 64 patients meeting all the inclusion criteria participated in the present multisurgeon prospective, randomized, controlled trial and underwent posterior repair and UVA during RARP with either barbed polyglyconate (n=33) or monofilament poliglecaprone (n=31) suture. The primary outcomes were the anastomotic (UVA) and posterior reconstruction times. Secondary outcomes included cystogram leak, bladder neck reconstruction rate, and 6-week functional outcomes assessed by a self-administered validated patient questionnaire. RESULTS: Posterior reconstruction was performed within 3.3 minutes with the barbed suture versus 4.3 minutes with the monofilament poliglecaprone suture (23.3% reduction) and UVA within 10.1 versus 13.8 minutes, respectively (26.8% reduction). The absolute time difference for the 2-layer anastomosis was 4.7 minutes (a 26.0% reduction in the total anastomosis time). All other perioperative outcomes were equivalent between the 2 groups. Urinary functional outcomes, including the pad use and leakage rates, were equivalent at 6 weeks. CONCLUSION: Anastomosis during RARP with the V-Loc barbed suture can be performed safely and more efficiently than with standard monofilament suture. We demonstrated a 26% decrease in the anastomotic time with no increase in the adverse events, no instances of urinary retention and equivalent functional outcomes were measured with the self administered patient questionnaire. PMID- 21782219 TI - Interobserver reliability of the RENAL nephrometry scoring system. AB - OBJECTIVE: To determine the reliability of the RENAL nephrometry scoring system by studying its reproducibility among different observers. METHODS: We reviewed computed tomography or magnetic resonance imaging scans from 51 patients who underwent partial nephrectomy at our cancer center. Digitized axial and coronal images were available for all patients. Three surgeons independently scored the renal tumors using the RENAL nephrometry system. The scoring system had 5 components: R (tumor diameter), E (exophytic/endophytic), N (nearness to collecting system), A (anterior/posterior), and L (location in relation to polar lines). Interobserver variability was calculated for each of the 5 components using a frequency procedure and Kappa statistics. RESULTS: The reliability assessed by frequency procedure showed concordance among 3 observers in 94%, 76%, 66%, 80%, and 54% for the R, E, N, A, and L components, respectively. The corresponding kappa values for each of these 5 components were 0.95, 0.86, 0.76, 0.84, and 0.73, respectively. CONCLUSION: The RENAL nephrometry scoring system has good interobserver reliability. Quantifying the tumor location (L) was more challenging and the least reliable of the 5 components. This variation might affect the total nephrometry score and should be considered when using the system to compare different series of patients undergoing partial nephrectomy. PMID- 21782220 TI - Is the comparison of a left varicocele testis to its contralateral normal testis sufficient in determining its well-being? AB - OBJECTIVE: To determine whether a size difference between a left testis involved with a varicocele and the contralateral normal testis is sufficient in its size assessment. METHODS: We reviewed all pediatric scrotal ultrasounds at Helen DeVos Children's Hospital between 2001 and 2008. Sonographic testicular measurements were recorded for patients with clinically diagnosed left varicocele (n = 81 for "varicocele" group) and for patients with no specific pathologic findings (n = 184 for "normal" group). We first compared the sizes between left and right testes for all patients, then between the "varicocele" group and the "normal" group separately for left and right. RESULTS: There were no significant size differences between left and right testes for the "normal" group, whereas the left was significantly smaller than the contralateral right for the "varicocele" group (P = .0048 for length; P = .012 for volume) for all ages. For boys 16 years or older, both the left and contralateral right testes of "varicocele" boys were smaller than those of "normal" boys, adjusting for age (P for left = .026 for length and .059 for volume; for right P = .033 for length and .031 for volume). CONCLUSION: Our study confirms that the left testis in boys with varicocele is most often smaller than the contralateral right testis no matter the age. Compared with normal boys in late adolescence, the contralateral right testis is smaller in boys with varicocele. PMID- 21782221 TI - Laparoendoscopic single-site surgery extravesical repair of vesicovaginal fistula: early experience. AB - OBJECTIVE: To describe for the first time the technique of laparoendoscopic single-site surgery (LESS) for repair of vesicovaginal fistula (VVF). LESS has recently been described as an alternative to conventional laparoscopy for the treatment of various urologic pathologic features. METHODS: The present study included 5 female patients with supratrigonal VVF who presented with urinary leakage per vagina after obstetric and gynecologic procedures. Extravesical LESS repair of VVF was done using the TriPort and prebent instruments. The fistulas tracts were identified and excised extravesically using sharp dissection. The edge of the bladder was trimmed at the site of fistula tract. The vagina was closed in 1 layer with continuous 3-0 Vicryl sutures, and the urinary bladder was closed in 2 layers using 3-0 Vicryl sutures. An additional 5-mm extraport was added at suturing to allow triangulation and hand-free extracorporeal suturing. An omental flap was interposed between the bladder and vagina. The urinary bladder was drained by an indwelling urethral catheter for 3 weeks. RESULTS: The operative time was 198+/-27.7 minutes. The blood loss was 90+/-25 mL. No intraoperative or postoperative complications developed. No conversion to conventional laparoscopy or open surgery was necessary. The postoperative hospital stay was 2 days. No postoperative urinary leakage occurred. The follow up examination at 8+/-3.2 months showed complete continence and no recurrence of VVF. CONCLUSION: LESS extravesical repair of VVF is a technically feasible and effective procedure that adheres to the principles of transabdominal open surgical repair. The technique has significant low morbidity; however, it requires advanced laparoscopic skills. PMID- 21782222 TI - Ethnic differences in bladder cancer survival. AB - OBJECTIVE: To examine trends in bladder cancer survival among whites, blacks, Hispanics, and Asian/Pacific Islanders in the United States over a 30-year period. Racial disparities in bladder cancer outcomes have been documented with poorer survival observed among blacks. Bladder cancer outcomes in other ethnic minority groups are less well described. METHODS: From the Surveillance, Epidemiology and End Results cancer registry data, we identified patients diagnosed with transitional cell carcinoma of the bladder between 1975 and 2005. This cohort included 163,973 white, 7731 black, 7364 Hispanic, and 5934 Asian/Pacific Islander patients. We assessed the relationship between ethnicity and patient characteristics. Disease-specific 5-year survival was estimated for each ethnic group and for subgroups of stage and grade. RESULTS: Blacks presented with higher-stage disease than whites, Hispanics, and Asian/Pacific Islanders, although a trend toward earlier-stage presentation was observed in all groups over time. Five-year disease-specific survival was consistently worse for blacks than for other ethnic groups, even when stratified by stage and grade. Five-year disease-specific survival was 82.8% in whites compared with 70.2% in blacks, 80.7% in Hispanics, and 81.9% in Asian/Pacific Islanders. There was a persistent disease-specific survival disadvantage in black patients over time that was not seen in the other ethnic groups. CONCLUSION: Ethnic disparities in bladder cancer survival persist between whites and blacks, whereas survival in other ethnic minority groups appears similar to that of whites. Further study of access to care, quality of care, and treatment decision making among black patients is needed to better understand these disparities. PMID- 21782223 TI - Serum testosterone levels significantly correlate with nocturia in men aged 40-79 years. AB - OBJECTIVE: To investigate the association between serum sex hormone levels and lower urinary tract symptoms in men aged 40-79 years. METHODS: A cross-sectional study was conducted in 509 men (mean age 58 years). The serum total testosterone (TT), dihydrotestosterone, and estradiol levels were measured. The total prostate volume measured by transrectal ultrasonography and International Prostate Symptom Score (IPSS) questionnaire were obtained. Correlations were determined using univariate and multivariate regression analysis. RESULTS: The subjects with moderate to severe lower urinary tract symptoms (total IPSS>=8) were older, with a greater incidence of hypertension and diabetes, a larger prostate, and had lower serum TT levels. On the univariate analysis, the serum TT levels were negatively associated with the total IPSS, IPSS storage subscore, weak stream, and nocturia. After adjusting for age, hypertension, diabetes, and total prostate volume, only the serum TT level was significantly associated with nocturia (>2 times/night; P=.042), and men with serum TT levels in the greatest quartile had a 44% reduced risk of nocturia than in the lowest quartile (P=.037). CONCLUSION: In our relative healthy male cohort, most IPSS items showed no significant association with serum sex hormone levels, except for nocturia, which showed a negative correlation with the serum testosterone level. PMID- 21782224 TI - Effect of botulinum toxin on expression of nerve growth factor and transient receptor potential vanilloid 1 in urothelium and detrusor muscle of rats with bladder outlet obstruction-induced detrusor overactivity. AB - OBJECTIVE: To investigate the effects of botulinum toxin A (BoNT/A) on the expression of nerve growth factor (NGF) and transient receptor potential vanilloid 1 (TRPV1) in the urothelium and detrusor muscle of rats with partial bladder outlet obstruction (BOO)-induced detrusor overactivity. METHODS: Male Sprague-Dawley rats were allocated to a control group, a BOO group, or a BoNT/A treated BOO group. BoNT/A (1 U) was injected into the detrusor muscle simultaneously with the induction of BOO. The rats were assessed by cystometrography 3 weeks later. The bladder was then removed. Immunofluorescence staining and Western blotting was performed to localize and quantify the expression of NGF and TRPV1 in the urothelium and detrusor muscle. RESULTS: Cystometrography revealed induction of an unstable bladder in the BOO group and recovery of bladder stability after BoNT/A treatment. Expression of the NGF and TRPV1 proteins in the urothelium was significantly greater in the BOO group than in the control group and had decreased significantly with BoNT/A treatment in BOO induced rat. The expression of NGF in detrusor muscle was significantly greater in the BOO group than in the control group and subsequently decreased significantly with BoNT/A treatment in the BOO-induced rat. In contrast, TRPV1 expression in the detrusor muscle did not differ significantly among the 3 groups. CONCLUSION: Our experiments showed that detrusor wall injection of BoNT/A can modulate the expression of NGF and TRPV1, particularly in the urothelium, in accordance with recovery of bladder function. PMID- 21782225 TI - Rising incidence of acute prostatitis following prostate biopsy: fluoroquinolone resistance and exposure is a significant risk factor. AB - OBJECTIVE: To evaluate the frequency and potential risk factors for infection related complications after transrectal prostate biopsy and to propose adjustments in current antimicrobial prophylaxis recommendations. METHODS: During 2008-2010, 107 patients underwent transrectal ultrasound-guided biopsies of the prostate at our institution. Charts were reviewed for infection-related complications within 30 days of the procedure. Potential risk factors were evaluated, including age, diabetes mellitus, chronic constipation/diverticular disease, prior use of quinolones, enema and prostatitis, on the pathology report. For patients with acute prostatitis, urine and blood samples were assessed for bacteriology and antibiotic susceptibility. RESULTS: Of our 107 patients, acute prostatitis developed in 10 (9.3%). The most significant risk factor was prior use of a fluoroquinolone antimicrobial, with acute prostatitis developing in 7 (17.1%) of 41 patients who had used a fluoroquinolone compared with 3 (4.5%) of 66 patients who had not (P=.042). Patients who received an enema before the procedure were slightly less likely to develop prostatitis (P=.061). Of 8 positive specimens, the organisms isolated were Escherichia coli in 6, Klebsiella pneumoniae in 1, and Staphylococcus epidermidis in one. Isolated Gram-negative organisms were fluoroquinolone-resistant in 85.7% of samples. CONCLUSION: Prior fluoroquinolone intake is a significant risk factor behind a rising incidence of acute prostatitis after transrectal prostate biopsy. Identified pathogens are mostly Gram-negative organisms with a high rate of fluoroquinolone resistance. Alternative prophylaxis regimens for the biopsy procedure should be considered in patients with recent quinolone intake. PMID- 21782226 TI - Tailoring adjuvant radiotherapy for stage IB-IIA node negative cervical carcinoma after radical hysterectomy and pelvic lymph node dissection using the GOG score. AB - OBJECTIVE: The use of adjuvant radiotherapy for early stage node negative patients varies for different institutions. The recognized factors such as deep stromal invasion, lymph vascular space invasion, and size of tumor are the most common factors cited for adjuvant radiotherapy. Studies done have shown that this increases local control but may increase chronic toxicity rates. We report on our use of the GOG score to tailor our treatment decisions. METHODS: A review of all patients staged IB-IIA who underwent Type 3 Radical Hysterectomy and pelvic lymph node dissection (RH) from 1997 to 2007. The GOG score proposed by Delgado et al. was applied, and patients were stratified into 3 groups; <40: no adjuvant treatment, 40-120: Small Field RT (SmRT), and >120: Standard Field RT (StRT) RESULTS: A total of 126 patients matched these criteria. Sixty one patients underwent either SmRT or StRT. There were only 2 known relapses and one death due to inter current illness. The median follow up was 57 months and the 5 year Disease Free Survival was 98.2%. There were no documented Grade 3 or 4 chronic toxicities. There were significantly less (p=0.025) patients with lower limb lymphedema in the SmRT group compared to StRT. CONCLUSION: Our study confirms the utility of the GOG score to tailor radiotherapy for this cohort of patients. This has been proven to be high in efficacy and low in morbidity. PMID- 21782227 TI - The NF-kappaB pathway mediates lysophosphatidic acid (LPA)-induced VEGF signaling and cell invasion in epithelial ovarian cancer (EOC). AB - OBJECTIVES: Our previous report has implicated the involvement of VEGF-VEGFR-2 h signaling in LPA-induced EOC invasion. However, the mechanism by which LPA regulates VEGF and VEGFR-2 expression remains to be elucidated. In the present study, we systematically examined the signal transduction pathways activated by LPA and further evaluated whether LPA's effect on VEGF-VEGFR-2 signaling and EOC invasion was mediated by the activation of NF-kappaB pathway. METHODS: Using a signal transduction PathwayFinder PCR array, we examined the expression change of 86 key genes representing 18 signal transduction pathways in DOV13 and SKOV3 cells upon LPA (20 MUM) treatment. We also used quantitative PCR, Western blotting and ELISA to evaluate the effect of NF-kappaB pathway inhibition on VEGF(121), VEGF(165) and VEGFR-2 mRNA and protein expression/secretion with or without the presence of LPA (20 MUM) in SKOV3. Cell invasion under various treatment conditions was assessed by Matrigel invasion assay and MMP-2 secretion was detected by gelatin zymography. RESULTS: Our results showed that in both DOV13 and SKOV3, several of the NF-kappaB pathway components, such as TNF, are consistently activated by LPA stimulation. In addition, treatment with an NF kappaB pathway activation inhibitor, at 10 MUM, significantly decreased LPA induced VEGF(121), VEGF(165) and VEGFR-2 mRNA expression and VEGF secretion, as well as LPA-induced SKOV3 invasion (p<0.05). When combined with an EGFR inhibitor, NF-kappaB pathway inhibition exhibited a significantly stronger effect than used alone (p<0.05) on reducing LPA-induced VEGF secretion and cell invasion. Additionally, NF-kappaB inhibition also decreased LPA-induced MMP-2 secretion and MMP-1 expression (p<0.05). CONCLUSIONS: These results suggest that the NF-kappaB pathway plays an important role in LPA-induced VEGF signaling and EOC invasion and targeting this pathway may reveal potential therapeutic options for metastatic EOC. PMID- 21782228 TI - Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. AB - BACKGROUND: Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy. OBJECTIVES: We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development. METHODS: We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life. RESULTS: We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils (P = .034), and allergic rhinitis (P = .007). There was no association with the development of asthma or atopic dermatitis. CONCLUSIONS: Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease. PMID- 21782229 TI - Delayed hypersensitivity reactions caused by iodixanol: an assessment of cross reactivity in 22 patients. PMID- 21782230 TI - Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. AB - BACKGROUND: Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. OBJECTIVES: We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. METHODS: We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. RESULTS: We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV(1) and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC(20), 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4(+) T cells increased significantly. CONCLUSIONS: Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach. PMID- 21782231 TI - MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. AB - In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-kappaB to induce type I interferons. [corrected] We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade. PMID- 21782233 TI - Selective neurocognitive impairments in adolescents with major depressive disorder. AB - This study investigated whether major depression in adolescence is characterized by neurocognitive deficits in attention, affective decision making, and cognitive control of emotion processing. Neuropsychological tests including the Wechsler Abbreviated Scale of Intelligence, the Continuous Performance Test-Identical Pairs, the Attention Network Test, the Iowa Gambling Task, the Emotional Go-NoGo Task, and the Face Go-NoGo Task were administered to adolescents with Major Depressive Disorder (MDD) (n = 31) and psychiatric diagnosis free controls (n = 30). Findings indicated that compared with controls, depressed adolescents exhibited impaired sustained attention; a gender by group interaction on affective decision making such that depressed males tended to make less advantageous choices on the IGT; and an inverse pattern of correlations between depressive symptom counts and reaction time to affective stimuli, characterizing greater affective reactivity in depressed adolescents. Findings demonstrate that adolescents with MDD display selective neurocognitive impairments on tasks capturing 'cool' and 'hot' executive functioning. PMID- 21782234 TI - 3D in vitro bioengineered tumors based on collagen I hydrogels. AB - Cells cultured within a three-dimensional (3D) in vitro environment have the ability to acquire phenotypes and respond to stimuli analogous to in vivo biological systems. This approach has been utilized in tissue engineering and can also be applied to the development of a physiologically relevant in vitro tumor model. In this study, collagen I hydrogels cultured with MDA-MB-231 human breast cancer cells were bioengineered as a platform for in vitro solid tumor development. The cell-cell and cell-matrix interactions present during in vivo tissue progression were encouraged within the 3D hydrogel architecture, and the biocompatibility of collagen I supported unconfined cellular proliferation. The development of necrosis beyond a depth of ~150-200 MUm and the expression of hypoxia-inducible factor (HIF)-1alpha were demonstrated in the in vitro bioengineered tumors. Oxygen and nutrient diffusion limitations through the collagen I matrix as well as competition for available nutrients resulted in growing levels of intra-cellular hypoxia, quantified by a statistically significant (p < 0.01) upregulation of HIF-1alpha gene expression. The bioengineered tumors also demonstrated promising angiogenic potential with a statistically significant (p < 0.001) upregulation of vascular endothelial growth factor (VEGF)-A gene expression. In addition, comparable gene expression analysis demonstrated a statistically significant increase of HIF-1alpha (p < 0.05) and VEGF-A (p < 0.001) by MDA-MB-231 cells cultured in the 3D collagen I hydrogels compared to cells cultured in a monolayer on two-dimensional tissue culture polystyrene. The results presented in this study demonstrate the capacity of collagen I hydrogels to facilitate the development of 3D in vitro bioengineered tumors that are representative of the pre-vascularized stages of in vivo solid tumor progression. PMID- 21782235 TI - Controlling multipotent stromal cell migration by integrating "course-graining" materials and "fine-tuning" small molecules via decision tree signal-response modeling. AB - Biomimetic scaffolds have been proposed as a means to facilitate tissue regeneration by multi-potent stromal cells (MSCs). Effective scaffold colonization requires a control of multiple MSC responses including survival, proliferation, differentiation, and migration. As MSC migration is relatively unstudied in this context, we present here a multi-level approach to its understanding and control, integratively tuning cell speed and directional persistence to achieve maximal mean free path (MFP) of migration. This approach employs data-driven computational modeling to ascertain small molecule drug treatments that can enhance MFP on a given materials substratum. Using poly(methyl methacrylate)-graft-poly(ethylene oxide) polymer surfaces tethered with epidermal growth factor (tEGF) and systematically adsorbed with fibronectin, vitronectin, or collagen-I to present hTERT-immortalized human MSCs with growth factor and extracellular matrix cues, we measured cell motility properties along with signaling activities of EGFR, ERK, Akt, and FAK on 19 different substrate conditions. Speed was consistent on collagen/tEGF substrates, but low associated directional persistence limited MFP. Decision tree modeling successfully predicted that ERK inhibition should enhance MFP on collagen/tEGF substrates by increasing persistence. Thus, we demonstrated a two-tiered approach to control MSC migration: materials-based "coarse-graining" complemented by small molecule "fine-tuning". PMID- 21782236 TI - The treatment of bladder cancer in a mouse model by epigallocatechin-3-gallate gold nanoparticles. AB - (--)-Epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, was known to effectively inhibit formation and development of tumors. However, excessive uptake of EGCG was also known to cause cytotoxicity to normal cells. In this study, EGCGs that were physically attached onto the surface of nanogold particles (pNG) was confirmed by scanning electron microscopy. The anticancer activity of the EGCG-adsorbed pNG was investigated in C3H/HeN mice subcutaneously implanted with MBT-2 murine bladder tumor cells. EGCG-pNG was confirmed to inhibit tumor cell growing by means of cell apoptosis. The mechanism that EGCG pNG mediates tumor apoptosis was uncovered to activate the caspase cascade through the Bcl-family proteins in the mitochondrial pathway. Additionally, the mechanism that tumors were suppressed by injecting EGCG-pNG directly into the tumor site was determined to be through downregulation of VEGF, whereas that by oral administration of EGCG was through reversing immune suppression upon cancer progression. In this assessment, the prepared EGCG-pNG was confirmed to be more effective than free EGCG in inhibiting bladder tumor in model mice. PMID- 21782237 TI - Mechanisms of hepatocyte attachment to keratin biomaterials. AB - Keratin biomaterials support cellular adhesion, proliferation and migration, which have led to their exploitation in a variety of biomedical applications. The mechanism of cell adhesion to keratin biomaterials, however, is poorly understood. Therefore, the goal of this work was to investigate the mechanisms by which human hair keratin-based biomaterials facilitate cellular adhesion. Hepatocytes were used as a model cell type due to the abundance of published data on cell adhesion mechanisms and their relatively copious attachment to keratin substrates. The roles of beta(1)- and beta(2)-integrins and the hepatic asialoglycoprotein receptor (ASGPR) in hepatocyte adhesion to keratin substrates were studied using attachment assays with and without function blocking antibodies. Blocking of the hepatic integrin subunits did not decrease hepatocyte attachment to keratin. Furthermore, adhesion to keratin did not result in the formation of focal complexes or focal adhesions, nor did it produce an upregulation of phosphorylated-focal adhesion kinase. However, inhibition of hepatic ASGPR decreased the ability of hepatocytes to attach to keratin substrates, which is indicative of the role of this glycoprotein receptor in hepatocyte binding to keratin biomaterials. PMID- 21782238 TI - Self-assembled biodegradable amphiphilic PEG-PCL-lPEI triblock copolymers at the borderline between micelles and nanoparticles designed for drug and gene delivery. AB - Amphiphilic PEG-PCL-PEI triblock copolymers self-assemble into nano-scaled, positively charged, multifunctional carriers, suitable for drug and gene delivery. A set of block copolymers with varying hydrophilic/hydrophobic ratio (systematically altered at the borderline of micelle and particle forming polymers) was synthesized, characterized and assembled into carriers. A detailed structural characterization in the liquid state of these assemblies was carried out: carrier size was determined using dynamic light scattering, cryogenic scanning electron microscopy and atomic force microscopy. Nuclear magnetic resonance analyses elucidated carrier's core-shell structure. zeta-potential and thickness of the hydrophilic outer polymer shell were determined by laser Doppler anemometry. Subsequently the impact of carrier's structure on its features (stability and toxicity) was investigated. Polymers hydrophilic in nature formed small (<40 nm) micelle-like carriers, whilst hydrophobic polymers aggregated to larger particle-like assemblies (>100 nm). Monitoring carrier size as a function of initial polymer concentration clarified different assembly mechanisms. Shell thickness, colloidal stability and toxicity were found to depend on the length of the hydrophilic polymer block. Due to controllable size, charge, stability and toxicity, this class of novel carriers is a promising candidate for prospective co-delivery of drugs and nucleic acids. PMID- 21782239 TI - Which morphological scoring system is relevant in human embryo development? AB - OBJECTIVES: In the past several scoring systems were proposed for early human development aiming to assist in the identification of the best embryos. Scoring criteria are usually assessed at static developmental time points by microscopy. For almost every scoring system controversial results on its benefit can be found in the literature. With the introduction of time-lapse imaging static assessment of developmental parameters needs to be revised. The objective of this study was to critical review the strategy of static assessment by using an embryo monitoring system to study time-dependent variations of scoring criteria. STUDY DESIGN: Human oocytes were subjected to intracytoplasmic sperm injection and subsequently incubated in an embryo monitoring device. Images from individual oocytes were captured at given time intervals allowing a time-lapse analysis of early embryo development. MAIN OUTCOME MEASURES: Scoring of pronuclear morphology, early cleavage and embryo morphology up to day 3 of development was performed at standard time points and compared to the morphological fate present in time intervals prior and after standard assessment. RESULTS: Pronuclear morphology showed a high variability within very short time intervals. First cleavage can be observed at very early time points questioning the criterion "early cleavage". Embryo morphology can change within short time intervals and thus may be misleading if assessment is done at a static time point. CONCLUSIONS: Scoring of early embryo development has limitations if based on static observation only. Time-lapse imaging will lead to revised scoring systems emphasizing the need for a new look on embryological parameters. PMID- 21782240 TI - Cutaneous manifestations in CMML: Indication of disease acceleration or transformation to AML and review of the literature. AB - Our retrospective analysis explored the role of leukemia cutis (LC) in disease progression of chronic myelomonocytic leukemia (CMML). Of 108 patients with CMML, 11 patients (10.2%) had LC including its equivalent (2 patients). Four of these patients developed acute myeloid leukemia (AML) within 0-4 months. The remaining 7 patients demonstrated increased monocytes (<20% blasts), with 3 demonstrating extramedullary involvement. Overall survival from LC to disease progression was 7.8 months. Overall survival from diagnosis to the last follow-up in patients with LC was 28.2 months, shorter than patients without LC (44 months). LC and its equivalent could predict disease progression to AML. PMID- 21782241 TI - Advanced age and prognosis in chronic myeloid leukemia in the era of tyrosine kinase inhibitors. PMID- 21782242 TI - The role of regulatory T cells during the attenuation of graft-versus-leukemia activity following donor leukocyte infusion in mice. AB - We investigated how the graft-versus-leukemia (GVL) effect is attenuated in the tumor microenvironment using a murine model of non-myeloablative allo-HSCT (NM HSCT) plus delayed donor leukocyte infusion (DLI) in a haploidentical B6->F1 strain combination. In-line with aggravated leukemia growth, the proportions of effector T cells expressing IFN-gamma (Teffs) in spleen were reduced and attenuated GVL activity was found to be accompanied by a rebound in CD4(+)Foxp3(+) regulatory T cells (Tregs) in tumor-draining lymph nodes and tumor tissues. DLI-derived Tregs and Teffs may be potential indicators of presence of leukemic progression after DLI in this GVL model. PMID- 21782243 TI - Cinnamon extract ameliorates ionizing radiation-induced cellular injury in rats. AB - The present study aimed to investigate the protective role of cinnamon extract against inflammatory and oxidative injuries in gamma irradiated rats. Rats were subjected to fractionated doses of gamma radiation. Cinnamon extract were daily administrated before starting irradiation and continued after radiation exposure. The results obtained revealed that the administration of cinnamon extract to irradiated rats significantly ameliorated the changes induced in liver antioxidant system; catalase, superoxide dismutase and glutathione peroxidase activities as well as reduced glutathione concentration. The liver's lipid peroxidation and protein oxidation indices were significantly decreased when compared with their equivalent values in irradiated rats. Furthermore, the changes induces in xanthine oxidoreductase system were significantly diminished. In addition, the changes in liver nitric oxide contents, serum tumor necrosis factor alpha and C-reactive protein levels were markedly improved. In conclusion, the administration of cinnamon extract might provide substantial protection against radiation-induced oxidative and inflammatory damages. PMID- 21782244 TI - Protective effects of vitamins C and E against hepatotoxicity induced by methyl parathion in rats. AB - Male rats were given vitamins C+E, methyl parathion, or both daily via gavage for seven weeks. Body weight was decreased while liver weight increased significantly at the end of fourth and seventh weeks in the methyl parathion- and methyl parathion plus vitamin-treated groups. Serum total protein, albumin, triglyceride, low density lipoprotein-cholesterol (VLDL-cholesterol) levels decreased, and serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase (GGT), lactate dehydrogenase (LDH), and total cholesterol levels increased significantly in the methyl parathion- and the methyl parathion plus vitamin-treated rats. There was a statistically significant difference for all biochemical parameters when the methyl parathion plus vitamin-treated group was compared with methyl parathion treated group. In electron microscopic investigation, cytopathological alterations were observed in hepatocytes of the methyl parathion- and the methyl parathion plus vitamin-treated rats. As a result, methyl parathion-induced hepatotoxicity is reduced by vitamins C+E, but vitamins C+E did not provide complete protection. PMID- 21782245 TI - High-resolution 3T MR neurography of radial neuropathy. AB - The radial nerve is a continuation of the posterior cord of the brachial plexus and one of the major nerves that provide motor and sensory innervations to the forearm. MR imaging evaluation of the radial nerve pathology has been described in scattered case reports. Current high-field MR scanners enable high resolution and high contrast imaging of the peripheral nerves. This article reviews the 3 Tesla magnetic resonance neurography imaging of radial nerve anatomy and various pathologies affecting it with relevant case examples. PMID- 21782246 TI - Abnormal neural activities in first-episode, treatment-naive, short-illness duration, and treatment-response patients with major depressive disorder: a resting-state fMRI study. AB - BACKGROUND: Abnormality of limbic-cortical networks was postulated in depression. Using a regional homogeneity (ReHo) approach, we explored the regional homogeneity (ReHo) of the brain regions in patients with first-episode, treatment naive, short-illness-duration, and treatment-response depression in resting state to test the abnormality hypothesis of limbic-cortical networks in major depressive disorder (MDD). METHODS: Seventeen patients with treatment-response MDD and 17 gender-, age-, and education-matched healthy subjects participated in the resting-state fMRI scans. RESULTS: CONCLUSIONS: Our findings suggested the abnormality of limbic-cortical networks in first-episode, treatment-naive, short illness-duration, and treatment-response MDD patients, and added an expanding literature to the abnormality hypothesis of limbic-cortical networks in MDD. PMID- 21782247 TI - Age at onset of major depressive disorder in Han Chinese women: relationship with clinical features and family history. AB - BACKGROUND: Individuals with early-onset depression may be a clinically distinct group with particular symptom patterns, illness course, comorbidity and family history. This question has not been previously investigated in a Han Chinese population. METHODS: We examined the clinical features of 1970 Han Chinese women with DSM-IV major depressive disorder (MDD) between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models was used to determine the association between age at onset (AAO) with continuous, binary and discrete characteristic clinical features of MDD. RESULTS: Earlier AAO was associated with more suicidal ideation and attempts and higher neuroticism, but fewer sleep, appetite and weight changes. Patients with an earlier AAO were more likely to suffer a chronic course (longer illness duration, more MDD episodes and longer index episode), increased rates of MDD in their parents and a lower likelihood of marriage. They tend to have higher comorbidity with anxiety disorders (general anxiety disorder, social phobia and agoraphobia) and dysthymia. CONCLUSIONS: Early AAO in MDD may be an index of a more severe, highly comorbid and familial disorder. Our findings indicate that the features of MDD in China are similar to those reported elsewhere in the world. PMID- 21782248 TI - Validation of the Brazilian brief version of the temperament auto-questionnaire TEMPS-A: the brief TEMPS-Rio de Janeiro. AB - BACKGROUND: Over the last thirty years, Akiskal and collaborators have described and developed operationalized diagnostic criteria for five types of affective temperaments - cyclothymic, irritable, hyperthymic, depressive, and anxious. A 110-item, yes-or-no questionnaire, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-A), was specifically developed for measuring temperamental variation. The TEMPS-A was translated into more than 25 languages and cross-culturally valid versions are now available in Italian, French, German, Japanese, Turkish, Arabic, Polish, Hungarian, Spanish and Portuguese. Recent studies in the US and in Europe, however, have suggested that shorter versions of TEMPS-A can be just as efficient as the full ones while potentially enhancing the compliance of respondents. The main objective of the present study was to validate a brief Brazilian Portuguese version of TEMPS-A (brief TEMPS-Rio de Janeiro). METHODS: Our main sample consisted of 997 undergraduate students (female = 72.6%) from seven different universities located in the city of Rio de Janeiro, Brazil. An additional group of 167 healthy senior citizens (women = 83.8%) was recruited in senior community centers in the city of Rio de Janeiro, Brazil. All participants were asked to complete the 110-item, Brazilian translation of the full version of the TEMPS-A. RESULTS: An exploratory factor analysis (PCA type 2, Varimax rotation) vying for a five-factor solution yielded mixed results, with cyclothymic traits, physical symptoms of anxiety and preoccupation with the well-being of a family member loading together on the first factor. When a forced six-factor solution was attempted, cyclothymic, irritable, hyperthymic, and depressive were delineated as predicted by the theory. The original generalized anxious temperament was split into two sharply delimited components, a "worrying" subscale and an abbreviated anxious subscale, which included physical symptoms of anxiety and concerns with the well-being of relatives. Based on the tripartite model of anxiety and depression, we proposed that the abridged anxious subscale, which includes physical symptoms of anxiety, represents the "true" generalized anxious temperament, while the "worrying" subscale corresponds to the "general distress factor". The internal consistency of the six subscales thus identified was generally good, ranging from 0.67 (anxious subscale) to 0.81 (worrying subscale), with cyclothymic, irritable, depressive, and hyperthymic subscales exhibiting intermediate values (0.74, 0.74, 0.72, and 0.7, respectively). LIMITATIONS: The present study was based on a non clinical sample that does not reflect accurately the characteristics of the Brazilian population. The relative uniformity of the sample in terms of age and education precluded a more in-depth analysis of the influence of these highly relevant factors. Further, we did not assess convergent, divergent or test-retest validity. CONCLUSIONS: We believe that the brief Brazilian version of the TEMPS-A auto-questionnaire will provide Brazilian researchers and clinicians with a psychometrically sound instrument and thus contribute toward the creation of a worldwide research network dedicated to the investigation of affective temperaments. PMID- 21782249 TI - Examining the dimensionality of combat-related posttraumatic stress and depressive symptoms in treatment-seeking OEF/OIF/OND veterans. AB - BACKGROUND: This study examined the factor structure of two of the most commonly used screening measures of posttraumatic stress disorder and depression in 164 treatment-seeking veterans who served in Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND). METHODS: Exploratory factor analysis was used to assess the dimensionality of items from the Posttraumatic Stress Disorder Checklist-Military Version (PCL-M) and the Patient Health Questionnaire-9 (PHQ 9). Regression analyses were then conducted to examine associations between factor scores of the resulting factor solution and measures of alcohol use, cognitive coping, psychological resilience, social support, and healthcare utilization. RESULTS: A four-factor solution was found that consisted of clusters of symptoms reflecting reexperiencing/avoidance, detachment/numbing, hopelessness/depression, and bodily disturbance. Scores on the detachment/numbing factor were uniquely related to alcohol use, whereas scores on the hopelessness/depression factor was uniquely associated with emergency room visits. Compared to conventional PCL-M and PHQ-9 total scores, the four-factor solution explained 2 to 10% more variance in scores on measures of alcohol use, cognitive coping, psychological resilience, social support, and healthcare utilization. LIMITATIONS: This study was limited by a small sample size and cross sectional design. CONCLUSIONS: Combat-related posttraumatic stress disorder and depressive symptoms in treatment-seeking OEF/OIF/OND veterans may be better conceptualized by four dimensions of reexperiencing/avoidance, detachment/numbing, hopelessness/depression, and bodily disturbance symptoms. This symptom structure may provide greater utility when examining other outcomes of interest in this population. PMID- 21782250 TI - Introducing the concept of modern depression in Japan; an international case vignette survey. AB - AIM: Japanese psychiatrists have increasingly reported patients with depression that does not seem to fit the criteria of the ICD-10 and the DSM-IV, and which has recently been called modern type depression (MTD). We explored whether MTD is frequently seen in Japan and also in other countries, and if so, how patients with MTD are diagnosed and treated. METHODS: The questionnaires, with two case vignettes (traditional type depression (TTD) and MTD), were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated their opinions about each case's prevalence in their country, etiology, diagnosis, suicide risk, and treatment using Likert scales. RESULTS: Out of 247 responses (123 from Japan and 124 from other countries), two hundred thirty-nine valid responses were received. MTD was recognized in all participating countries, and especially in urban areas. Generally, the factor of personality was regarded as the most probable cause of MTD. Whereas about 90% of Japanese psychiatrists applied the ICD/DSM criteria to TTD, only about 60% applied the criteria to MTD. CONCLUSION: Our results indicate that Japan's MTD seems to be occurring in many other countries, and that the present ICD/DSM criteria may not be sufficient to diagnose MTD. Therefore, it could be an important candidate for a new international diagnostic criterion as a subtype of depression. A clear diagnostic framework and consensus on the interventions to treat MTD would be valuable. Further clinical, psychopathological and international epidemiological studies are needed to confirm our preliminary findings of MTD. PMID- 21782252 TI - The unique pathophysiology of early-onset severe preeclampsia: role of decidual T regulatory cells. AB - Immunological mechanisms play a pivotal role in the pathophysiology of preeclampsia. T regulatory cells (Treg cells, FoxP3(+)) suppress the cytotoxic T cell (CD8(+)) and natural killer (NK) cell response, thereby promoting immunological tolerance to the fetus. In peripheral blood, Treg cells are elevated during pregnancy, decrease throughout gestation, and are decreased in preeclampsia. To determine their role at the implantation site, we characterized the proportion of decidual Treg and CD8+ cells, and compared these with placental histology, villous sFlt expression, and chorionic trophoblast apoptotic index in normal and preeclamptic pregnancies. Decidua from first (n=5) and second (n=4) trimester terminations and chorioamniotic membranes, containing decidua, from term deliveries (n=14), early-onset (<= 34 weeks) (n=12), and late-onset (>34 weeks) (n=14) severe preeclampsia were evaluated. Immunohistochemistry for CD3, CD8, and FoxP3 was performed: CD8(+) and FoxP3(+) cells were calculated as a proportion of CD3(+) cells. Placental tissue was evaluated for villous hypermaturity and sFlt staining. Chorioamniotic membranes were evaluated, via TUNEL assay, for chorionic trophoblast apoptosis. Decidual Treg cells were seen to peak in second trimester and decrease with advancing gestational age and were lower in early-onset (0.46%) compared with late-onset severe preeclampsia (3.34%) and term pregnancies (5.21%). The proportion of CD8(+) cells was higher in cases of severe preeclampsia. Early-onset severe preeclamptic cases had the highest sFlt score, placental insufficiency score, and apoptotic index. Our data suggest that early-onset severe preeclampsia has a unique pathophysiology involving defective immunoregulatory pathways, potentially causing vascular and trophoblast damage at the implantation site. PMID- 21782251 TI - Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity. AB - OBJECTIVE: This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD: In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15 mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference>35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (>=25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months. RESULTS: Pioglitazone decreased depression symptom severity from a total IDS score of 40.3+/-1.8 to 19.2+/-1.8 at Week 12 (p<.001). Among partial responders (>=25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration=24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (-0.8+/-0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (-0.87+/ 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. LIMITATIONS: These data are limited by a small sample size and an open-label study design with no placebo control. CONCLUSION: Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated. PMID- 21782253 TI - The antagonist activity of lipid IVa on the stimulation by lipid A of TNF-alpha production from canine blood mononuclear cells. AB - Lipid A, the active component of lipopolysaccharide (LPS), exists in the outer membrane of Gram-negative bacteria and binds to the Toll-like receptor 4 (TLR4) and MD-2 complex. On the other hand, the synthetic precursor of Escherichia coli lipid A, tetraacylated lipid IVa, is an agonist for TLR4 and MD-2 complex in murine, equine and feline cells but is an antagonist for lipid A in human cells. The aim of the study was to examine the function of canine Toll-like receptor 4 (TLR4) and MD-2 complex on canine blood mononuclear cells (BMC), by analyzing lipid A- or lipid IVa-induction of TNF-alpha production from these cells in order to understand canine innate immune system. After 5-h culture of canine BMC with lipid A (lipid A culture) or lipid IVa (lipid IVa culture), the TNF-alpha, as determined by ELISA, had increased in the supernatants of the lipid A cultures in a dose-dependent manner, whereas the TNF-alpha was undetectable in supernatant of lipid IVa-treated cultures. The TNF-alpha was statistically significantly different between the lipid A and lipid IVa cultures (100 and 1000 ng/ml). TNF alpha production from canine BMC was inhibited, in a lipid IVa-dose-dependent manner, when the BMC were pre-cultured with lipid IVa for 60 min and then cultured with lipid A for 5h, while in control BMC cultures production if TNF alpha was unchanged. These results indicate that the TNF-alpha production stimulated by lipid A was competed out by pre-exposing the BMC to lipid IVa. Thus, lipid A is an agonist for TNF-alpha production in canine BMC, whereas lipid IVa appears to be an antagonist against this lipid A stimulation of canine BMC. PMID- 21782254 TI - Immunological and pathological responses of red deer resistant or susceptible genotypes, to experimental challenge with Mycobacterium avium subsp. paratuberculosis. AB - This study aimed to monitor the clinical, immunological and pathological changes in red deer for 49 weeks after experimental oral challenge with Mycobacterium avium subsp. paratuberculosis (MAP) and to assess the heritability of resistance in the offspring of two red stags. Eighteen young deer, which were bred from unselected hinds and sired by two stags resistant (R) or susceptible (S) to paratuberculosis, were challenged with MAP and monitored for 49 weeks. Biopsy samples of the jejunal lymph node were collected at Weeks 4 and 13 and at necropsy after euthanasia of clinically affected animals or when electively killed at Week 49. Three animals (two S and one R) developed clinical disease and were euthanised. The nine S offspring had significantly more severe lesions than the nine R offspring (Mantel-Haenszel Chi-square P=0.017). The average Lesion Severity Score (LSS) of R offspring was 5.9 (mild), and 7/9 had no or very mild lesions. In contrast, the LSS of S offspring averaged 11.7 (severe), and 7/9 had severe lesions. Most of the resistant, but not the susceptible, animals showed evidence of resolving lesions and a reduction in the number of MAP between 13 and 49 weeks after challenge. One R offspring appeared to completely cure itself, and progressed from mild culture-positive paratuberculosis lesions at Week 13 to having no signs of disease or infection 36 weeks later. This study showed significant heritable resistance/susceptibility to paratuberculosis and key differences in immunological responses in the first 3 months after challenge, indicating different paths to relative success or failure to control MAP. In general, R deer had higher IFN-gamma levels, low antibody titres and fewer MAP, while S deer had lower IFN-gamma levels, higher antibody and more MAP. PMID- 21782255 TI - Immunophenotype and gene expression profiles of cell surface markers of mesenchymal stem cells derived from equine bone marrow and adipose tissue. AB - Bone marrow and adipose tissue are the two main sources of mesenchymal stem cell (MSC). The aim of this work was to analyse the immunophenotype of 7 surface markers and the expression of a panel of 13 genes coding for cell surface markers in equine bone marrow and adipose tissue-derived MSCs obtained from 9 horses at third passage. The tri-lineage differentiation was confirmed by specific staining. Equine MSCs from both sources were positive for the MSC markers CD29 and CD90, while were negative for CD44, CD73, CD105, CD45 and CD34. The gene expression of these molecules was also evaluated by reverse transcriptase real time quantitative PCR along with the expression of 5 other MSC markers. Both populations of cells expressed CD13, CD29, CD44, CD49d, CD73, CD90, CD105, CD106, CD146 and CD166 transcripts. Significant differences in gene expression levels between BM- and AT-MSCs were observed for CD44, CD90, CD29 and CD34. Both cell types were negative for CD45 and CD31. The surface antigens tested revealed a similar phenotypic profile between horse and human MSCs, although specific differences in some surface antigens were noticed. PMID- 21782256 TI - The occurrence of velopharyngeal insufficiency in Pierre Robin Sequence patients. AB - OBJECTIVE: Children born with Pierre-Robin Sequence (PRS) have cleft palate, micrognathia, and macroglossia. After the repair of the cleft palate, velopharyngeal insufficiency (VPI) can occur in a subset of patients. We hypothesize that the need for the surgical correction of VPI in PRS children is no different than cleft palate only (CPO) patients. METHODS: A retrospective study of 21 children with non-syndromic PRS who were matched to 42 non-syndromic, CPO controls for age and sex. We reviewed incidence of VPI, the need for secondary speech surgery, and speech outcomes post-operatively. RESULTS: Secondary surgery to correct VPI was necessary in 3 of 21 (14.29%) PRS patients (2 Pharyngeal Flaps, 1 Z-plasty), vs. 10 of 42 (23.81%) CPO (9 Pharyngeal Flaps, 1 Z-plasty) controls. Mean age for VPI surgery for PRS vs. controls: 5.33 vs. 6.41 years, respectively. For final speech outcomes, 73.68% of PRS vs. 71.88% of controls showed no evidence of hypernasality, 89.47% of PRS patients vs. 93.75% of controls showed no evidence of hyponasality, and 76.47% of PRS patients vs. 78.13% of controls had normal velopharyngeal competence (p>0.90 for all three measures). CONCLUSION: Our findings suggest that children born with a Pierre Robin Sequence do not have a higher rate of post-operative VPI after cleft palate repair and are no more likely to require additional surgical intervention. PMID- 21782257 TI - Usefulness of dextranomer/hyaluronic acid copolymer in bronchoscopic treatment of recurrent tracheoesophageal fistula in children. AB - OBJECTIVE: Endoscopic repair of recurrent tracheoesophageal fistula (RTF) in infants who underwent surgery at birth for esophageal atresia (EA) is under investigation as an alternative to open surgery, which is technically challenging and associated with high morbidity. The aims of this paper are to present the experience of a single institution in treating RTF using a novel submucosal bronchoscopic injection of biocompatible dextranomer/hyaluronic acid (Dx/HA) copolymer, and to discuss the indications and limitations of this technique. METHODS: From 2000 to 2007, 6 children (2 boys; 4 girls) aged 1-48 months, weighing 2.5-18 kg were referred to our hospital for respiratory symptoms (pneumonia and failure to thrive) secondary to suspected RTF. All infants had undergone surgery at birth for EA with inferior tracheoesophageal fistula. Bronchoscopy revealed that five infants had RTF and one had a large remnant tracheal upper-pouch fistula. The bronchoscopic intervention was performed under general anesthesia, using a pediatric rigid bronchoscope with a 0 degrees telescope and telemonitoring. The fistula wall mucosa was gently abraded to promote adhesion, and Dx/HA was then injected at two points in the fistula submucosa to obtain a stable swelling of the wall and closure of the RTF. RESULTS: In two infants (aged 1 month and 18 months) complete resolution of the RTF was achieved following two separate procedures with a 1-month interval. In three children (aged 2, 18 and 25 months) complete closure of the fistula was not achieved; however, the partial closure was sufficient to address the respiratory symptoms and allow subsequent standard open thoracic surgery without requiring recovery in the intensive care unit. Complete resolution of respiratory symptoms was also obtained following a single endoscopic procedure with two Dx/HA injections in the child with residual pouch fistula. CONCLUSION: Bronchoscopic treatment of RTF with Dx/HA is a simple, minimally invasive, low-risk procedure that enables complete closure of RTF or reduction and resolution of respiratory symptoms, which in turn facilitates uncomplicated thoracic surgery. The technique also provides good results in remnant tracheal upper-pouch fistula. PMID- 21782258 TI - Comparison of a geriatric unit with a general ward in Mexican elders. AB - There is evidence that geriatric services may be more effective in handling problems of the elderly in acute care. We therefore studied a cohort of matched triplets (age, gender and admission diagnosis), to assess the effect of a geriatric service on elderly problems (falls, pressure ulcers, delirium and functional decline). This is a follow up study; comparing a geriatric unit with an internal medicine unit at two hospitals of the Mexican Institute of Social Security (IMSS) in Mexico City. Socio-demographic characteristics, functionality, emotional state, cognitive status, delirium, co-morbidities, diagnosis, number of medications, presence of pressure ulcers and falls, were assessed. We developed a composite variable as a global end-point, including: delirium, falls, mortality, pressure sores and functional decline. 70 patients were included in the geriatric services and 140 in the internal medicine unit. Mean age =72.5+/-7 years (+/ S.D.), and 52.9% were women. At baseline, only illiteracy, quality of life and the number of medications were statistically different between each group. Fully adjusted multiple logistic conditional regression model found an odds ratio of 0.27 (95% CI 0.1-0.7) for the presence of the composite variable, favoring the geriatric unit. Geriatric units in acute care may be beneficial in different frequent end points in elderly. PMID- 21782259 TI - Downward trend in the prevalence of hospitalisation for atherothrombotic disease. AB - BACKGROUND: The prevalence of hospitalised atherothrombotic disease affecting the coronary, cerebrovascular and peripheral vasculature is expected to increase due to improving survival, ageing and changing risk factor profiles. This study determined sex, age-standardised and age-specific (35-54, 55-69, 70-84years) prevalence of atherothrombotic disease and its association with diabetes and chronic kidney disease in Western Australian residents from 2000 to 2007. METHODS: In a cross-sectional and longitudinal study, person-linked hospitalisations for atherothrombotic disease were obtained using records from 1985. From 2000 to 2007, total and vasculature-specific prevalence of atherothrombotic disease (as a principal diagnosis) was calculated using a 15 year lead-in to determine prior disease and comorbidity. RESULTS: In 2007, 45,916 (8.6%) men and 22,782 (4.3%) women in Western Australia had established atherothrombotic disease and about 25% had diabetes, 10% had chronic kidney disease, and 5% had both. From 2000 to 2007 the estimated average annual change in age-standardised atherothrombotic disease prevalence was -0.6%/year (95% CI 0.8, -0.4) in men and -0.7%/year (95% CI -1.0, -0.4) in women. Similar modest declines were seen in age-standardised prevalence of monovascular and polyvascular atherothrombotic disease. The proportion of cases with diabetes increased by about 5%/year, the proportion having chronic kidney disease increased slowly in women (1.5%/year) and was stable in men, and the proportion with both comorbidities increased at about 9%/year. CONCLUSION: The age standardised prevalence of atherothrombotic disease requiring hospitalisation has been in marginal decline in Western Australia this decade, despite the proportion of affected persons with diabetes and/or chronic kidney disease steadily rising. PMID- 21782260 TI - Ethics, vanity and publications. PMID- 21782261 TI - Effect of eptifibatide on platelet-mediated inflammation in acute coronary syndromes. PMID- 21782262 TI - Herpes simplex virus infection and risk of atrial fibrillation: a nationwide study. AB - BACKGROUND: Currently, precise mechanisms of atrial fibrillation (AF) are uncertain but proved to be associated with inflammation. There has been no specific study to evaluate the risk of AF after diagnosis of herpes simplex virus (HSV) infection. METHODS: To investigate the relationship between HSV infection and the occurrence of AF, we used a nation-wide population-based dataset from Taiwan. A total of 15,180 patients with diagnosis of HSV infection were included in the study group from a 1,000,000 sampling cohort dataset between January 2000 and December 2003. Another 73,197 age-, gender-, and comorbidity-matched subjects without HSV infection were included in the control group. The log-rank test was performed to analyze the differences in accumulated AF-free survival rates between these 2 groups. Cox proportional hazard regressions were performed to evaluate the independent factor in determining the longitudinal hazard of AF. RESULTS: During a 3-year follow-up period, 240 patients from the study group (1.6%) and 801 patients from the comparison group (1.1%) had newly developed AF. The log-rank test showed that patients with HSV had significantly higher incidence of AF development than those without HSV (p<0.001). After Cox model adjustment for risk factors and comorbidities, HSV infection was independently associated with increased risk of AF development (hazard ratios [HR], 1.39; 95% confidence interval [CI], 1.2-1.60; p<0.0001). CONCLUSION: Our study concludes that HSV infection may be independently associated with an increased risk of future AF development. PMID- 21782263 TI - Treatment and referral decisions under different physician payment mechanisms. AB - This paper analyzes and compares the incentive properties of some common payment mechanisms for GPs, namely fee for service (FFS), capitation and fundholding. It focuses on gatekeeping GPs and it specifically recognizes GPs heterogeneity in both ability and altruism. It also allows inappropriate care by GPs to lead to more serious illnesses. The results are as follows. Capitation is the payment mechanism that induces the most referrals to expensive specialty care. Fundholding may induce almost as much referrals as capitation when the expected costs of GPs care are high relative to those of specialty care. Although driven by financial incentives of different nature, the strategic behaviors associated with fundholding and FFS are very much alike. Finally, whether a regulator should use one or another payment mechanism for GPs will depend on (i) his priorities (either cost-containment or quality enhancement) which, in turn, depend on the expected cost difference between GPs care and specialty care, and (ii) the distribution of profiles (diagnostic ability and altruism levels) among GPs. PMID- 21782265 TI - Cytochrome P450 monooxygenases: an update on perspectives for synthetic application. AB - Cytochrome P450 monooxygenases (P450s) are versatile biocatalysts that catalyze the regio- and stereospecific oxidation of non-activated hydrocarbons under mild conditions, which is a challenging task for chemical catalysts. Over the past decade impressive advances have been achieved via protein engineering with regard to activity, stability and specificity of P450s. In addition, a large pool of newly annotated P450s has attracted much attention as a source for novel biocatalysts for oxidation. In this review we give a short up-to-date overview of recent results on P450 engineering for technical applications including aspects of whole-cell biocatalysis with engineered recombinant enzymes. Furthermore, we focus on recently identified P450s with novel biotechnologically relevant properties. PMID- 21782264 TI - Psychiatric disorders and labor market outcomes: evidence from the National Comorbidity Survey-Replication. AB - This paper uses the National Comorbidity Survey-Replication to estimate effects of recent psychiatric disorder on employment, hours worked, and earnings. We employ methods proposed in Altonji et al. (2005a) which use selection on observable traits to provide information regarding selection along unobservable factors. Among males, disorder is associated with reductions in labor force participation and employment. When selection on observed characteristics is set equal to selection on unobserved characteristics, the magnitudes of these effects for males are 9 and 14 percentage point reductions for participation and employment, respectively. Among females, we find negative associations between disorder and labor force participation and employment, but these estimates are more sensitive to assumptions about selection. There are no effects of disorder on earnings or hours worked among employed individuals. PMID- 21782266 TI - Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: a prospective study. AB - BACKGROUND AND PURPOSE: To characterise the incidence, pattern and severity of post cranial radiotherapy somnolence and to identify factors predictive of frequency and severity. MATERIALS AND METHODS: Seventy consecutive patients receiving radical cranial irradiation were prospectively assessed for somnolence at baseline, during and up to 10weeks following radiotherapy using five variables scored on a visual analogue scale (VAS) and the Littman scale. Fatigue was measured using the FACT-G score and quality of life using the EORTC QLQC30+3 with the brain tumour module questionnaire. RESULTS: Ninety percent of patients experienced ?grade 1 somnolence (Littman score) and this correlated with VAS scores (r=0.456, p<0.001). The score increased from 3 to 12weeks (p<0.001) with a peak at the end of treatment and improvement 6weeks later. None of the patient, disease or treatment characteristics analysed were predictive for the development or the severity of somnolence. CONCLUSIONS: The majority of patients experience some degree of somnolence following radical radiotherapy for primary brain tumour and this follows a clear pattern during and after treatment. While there are no clear predictors of severity, the pattern described allows for provision of information for patients and carers to minimise the distress the syndrome may cause. PMID- 21782267 TI - Effect of increased load on scapular kinematics during manual wheelchair propulsion in individuals with paraplegia and tetraplegia. AB - Repetitive loading of the upper extremity musculature during activities like wheelchair propulsion can lead to fatigue of surrounding musculature causing irregular segment kinematics. The goal of this study was to determine the effect of increase in load on the kinematics of the scapula in users with paraplegia and tetraplegia. Data were collected on 18 participants (11 with paraplegia and 7 with tetraplegia) using an electromagnetic motion tracking system (100Hz) and force sensing pushrim (200Hz). The participants propelled under no load and loaded conditions at their customary propulsion velocity. On average a 60N increase in force was elicited with the experimental protocol. Users with tetraplegia showed significant increases (p<.05) in the rate of change of scapular angles in the upward/downward rotation and the retraction/protraction direction under the loaded conditions, whereas users with paraplegia only showed difference in the retraction/protraction rotation direction. Overall both user populations moved towards position of increased downward rotation, anterior tilt and protraction with increase in load hence increasing the risk of impingement. This experiment adds depth to our understanding of dynamic scapular kinematics during wheelchair propulsion under different loading conditions and differences in scapular control between users with paraplegia and tetraplegia. PMID- 21782268 TI - By 'default or design'? The expansion of the private health care sector in Madhya Pradesh, India. AB - OBJECTIVE: Despite an extensive tiered public healthcare system, India has one of the most privatized healthcare systems in world. There is no evidence suggesting that this privatization at anytime has been deliberate. So what has contributed to the private healthcare sector becoming so dominant in the setting? METHODS: We explore possible reasons for the rapid expansion of the private sector through in depth interviews with policy makers in the public and private sectors in Madhya Pradesh province, Central India. Interviews were analyzed using qualitative content analysis. RESULTS AND CONCLUSIONS: Public and private sector respondents concurred that the expansion of private sector had occurred by default; a passive privatization resulting from an underfunded and underperforming public health sector. Regulation by the public sector has lagged behind the development of a popular private healthcare market. Professional self-regulation functioned poorly, with professional bodies reported as being opportunistic. The private sector is fractured and heterogeneous making it more difficult to regulate. Further, the state has focused on regulating its own public sector, little attention has been paid to the expanding private sector. Income and career opportunities for qualified healthcare professionals are attractive in the private sector. India needs to invest more in the public health system, develop ways of reducing out of pocket expenses through integration of, regulation of and partnerships with segments of the private health sector. PMID- 21782269 TI - Adverse event rates as measures of hospital performance. AB - OBJECTIVES: Adverse event or complication rates are increasingly advocated as measures of hospital quality and performance. Objective of this study is to analyse patient-complexity adjusted adverse events rates to compare the performance of hospitals in Victoria, Australia. We use a unique hospital dataset that routinely records adverse events which arise during the admission. We identify hospitals with below or above average performance in comparison to their peers, and show for which types of hospitals risk adjusting makes biggest difference. METHODS: We estimate adverse event rates for 87,790 elective and 43,771 emergency episodes in 34 public hospitals over the financial year 2005/06 with a complementary log-log model, using patient level administrative hospital data and controlling for patient complexity with a range of covariates. RESULTS: Teaching hospitals have average risk-adjusted adverse event rates of 24.3% for elective and 19.7% for emergency surgical patients. Suburban and rural hospitals have lower rates of 17.4% and 17%, and 16.1% and 15.7%, respectively. Selected non-teaching hospitals have relatively high rates, in particular hospitals in rural and socially disadvantaged areas. Risk adjustment makes a significant difference to most hospitals. CONCLUSION: We find comparably high adverse events rates for surgical patients in Australian hospitals, possibly because our data allow identification of a larger number of adverse events than data used in previous studies. There are marked variations in adverse event rates across hospitals in Victoria, even after risk adjusting. We discuss how policy makers could improve quality of care in Australian hospitals. PMID- 21782270 TI - Evidence for Fisher's dominance theory: how many 'special cases'? AB - Dominance, its genetic basis and evolution has been at the heart of one of the most intense controversies in the history of genetics. For more than eighty years the existence of dominance modifiers, genetic elements controlling dominance recessivity interactions, has been suggested as a theoretical possibility, but the modifier elements themselves have remained elusive. A recent study of the self-incompatibility locus in flowering plants provided the first empirical evidence for such genetic elements: small non-coding RNAs that control dominance recessivity by mediating methylation of the promoter of the recessive allele. Theory has shown that several biological situations are favorable for the evolution of dominance modifiers. We argue that the elucidation of this mechanism of dominance opens up new research avenues that could lead to uncovering dominance modifiers in other genetic systems, such as genes controlling Batesian and Mullerian mimicry or host-parasite interactions, thereby shedding light on the generality of the proposed mechanism. PMID- 21782271 TI - New and old ways to control meiotic recombination. AB - The unique segregation of homologs, rather than sister chromatids, at the first meiotic division requires the formation of crossovers (COs) between homologs by meiotic recombination in most species. Crossovers do not form at random along chromosomes. Rather, their formation is carefully controlled, both at the stage of formation of DNA double-strand breaks (DSBs) that can initiate COs and during the repair of these DSBs. Here, we review control of DSB formation and two recently recognized controls of DSB repair: CO homeostasis and CO invariance. Crossover homeostasis maintains a constant number of COs per cell when the total number of DSBs in a cell is experimentally or stochastically reduced. Crossover invariance maintains a constant CO density (COs per kb of DNA) across much of the genome despite strong DSB hotspots in some intervals. These recently uncovered phenomena show that CO control is even more complex than previously suspected. PMID- 21782272 TI - Identification of residual metabolic-active areas within NSCLC tumours using a pre-radiotherapy FDG-PET-CT scan: a prospective validation. AB - It was recently described that high FDG-uptake areas pre-radiotherapy largely correspond with residual metabolic-active areas post-radiotherapy. Here, an independent prospective validation of these results was performed using an overlap-fraction (OF) calculation of various FDG-uptake based thresholds. Data from twelve patients treated at Radboud University Nijmegen Medical Center with lung cancer were analyzed. All patients underwent two FDG-PET-CT scans, one pre radiotherapy (pre-RT) and one approximately three months after treatment (post RT). Of the twelve analyzed patients, eight patients showed residual FDG uptake on the post-RT scan and were included for analysis. One of these patients had a residue that was not clearly distinguishable from the surrounding tissue due to FDG avid inflammation. Therefore, seven patients remained for further analysis. The mean volume of the residual metabolic-active areas post-RT was 14.6+/-10.0% (mean+/-SD) of the mean volume of the gross tumour volume (GTV) pre-RT. The residual metabolic-active areas largely corresponded with the pre-RT GTV (OF=93.7+/-7.2%). The pre-RT-scan threshold delineations of 34%, 40% and 50% of the SUV(max) had a large OF with the residual region, 86.9+/-8.3%, 77.4+/-8.1% and 67.9+/-6.8%, respectively. In this independent dataset, we confirmed that the location of residual FDG-uptake areas after radiotherapy corresponds with the high FDG-uptake areas pre-radiotherapy. Therefore, a pre-radiotherapy FDG-PET-CT scan can potentially be used for radiotherapy dose redistribution. PMID- 21782273 TI - Restoration of ecosystem services and biodiversity: conflicts and opportunities. AB - Ecological restoration is becoming regarded as a major strategy for increasing the provision of ecosystem services as well as reversing biodiversity losses. Here, we show that restoration projects can be effective in enhancing both, but that conflicts can arise, especially if single services are targeted in isolation. Furthermore, recovery of biodiversity and services can be slow and incomplete. Despite this uncertainty, new methods of ecosystem service valuation are suggesting that the economic benefits of restoration can outweigh costs. Payment for Ecosystem Service schemes could therefore provide incentives for restoration, but require development to ensure biodiversity and multiple services are enhanced and the needs of different stakeholders are met. Such approaches must be implemented widely if new global restoration targets are to be achieved. PMID- 21782274 TI - Climate change responses: forgetting frogs, ferns and flies? PMID- 21782276 TI - Endosymbionts and honey bee colony losses? PMID- 21782277 TI - Distribution, clinical features and treatment in Taiwanese patients with symptomatic primary immunodeficiency diseases (PIDs) in a nationwide population based study during 1985-2010. AB - Primary immunodeficiency diseases (PIDs) are a group of rare diseases with wide geographic and ethnic variations in incidence, prevalence, and distribution patterns. The aim of this study was to examine the distribution pattern and clinical spectrum of PIDs in Taiwan at a national referral institute. From 1985 to 2010, 215 patients from 183 families were diagnosed and grouped according to the updated classification of PIDs. Eighty-one (37.7%) patients had "other well defined immunodeficiency syndromes", followed by "predominantly antibody deficiencies" (54 patients; 25.1%), "T- and B-cell immunodeficiencies" (34; 15.8%), "congenital defects of phagocytes" (25; 20.2%), "complement deficiencies" (15; 7.0%), and "disease in immune dysregulation" (5; 2.3%). The last category included two patients with Chediak-Higashi syndrome, and one each with familial hemophagocytosis, IPEX, and hypogammaglobulinemia and albinism. One female had cold-induced auto-inflammatory disease. There were no cases of "defects in innate immunity". Pseudomonas and Streptococcus pneumoniae were the two most identified microorganisms in septicemia (42.7%; 44/103 episodes). Stem cell transplantation was successful in 13 of 22 patients, while 34 patients (15.8%) died. Molecular defects were identified in 109 individuals (from 90 families). There were relatively fewer cases of "predominantly antibody deficiencies" due to there being only a few patients with adult-onset PIDs, implying certainty bias rather than ethnic variation. Awareness of under-diagnosis among physicians rather than pediatricians is vital for timely diagnosis and consequently adequate treatment. PMID- 21782278 TI - Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. AB - BACKGROUND: Few prospective studies have evaluated the safety of dermatologic surgery. OBJECTIVE: We sought to determine rates of bleeding, infection, flap and graft necrosis, and dehiscence in outpatient dermatologic surgery, and to examine their relationship to type of repair, anatomic location of repair, antibiotic use, antiplatelet use, or anticoagulant use. METHODS: Patients presenting to University of Massachusetts Medical School Dermatology Clinic for surgery during a 15-month period were prospectively entered. Medications, procedures, and complications were recorded. RESULTS: Of the 1911 patients, 38% were on one anticoagulant or antiplatelet medication, and 8.0% were on two or more. Risk of hemorrhage was 0.89%. Complex repair (odds ratio [OR] = 5.80), graft repair (OR = 7.58), flap repair (OR = 11.93), and partial repair (OR = 43.13) were more likely to result in bleeding than intermediate repair. Patients on both clopidogrel and warfarin were 40 times more likely to have bleeding complications than all others (P = .03). Risk of infection was 1.3%, but was greater than 3% on the genitalia, scalp, back, and leg. Partial flap necrosis occurred in 1.7% of flaps, and partial graft necrosis occurred in 8.6% of grafts. Partial graft necrosis occurred in 20% of grafts on the scalp and 10% of grafts on the nose. All complications resolved without sequelae. LIMITATIONS: The study was limited to one academic dermatology practice. CONCLUSION: The rate of complications in dermatologic surgery is low, even when multiple oral anticoagulant and antiplatelet medications are continued, and prophylactic antibiotics are not used. Closure type and use of warfarin or clopidogrel increase bleeding risk. However, these medications should be continued to avoid adverse thrombotic events. PMID- 21782279 TI - Awareness, anxiety, compliance: community perceptions and response to the threat and reality of an influenza pandemic. AB - This study compared community response prior to and during the H1N1 2009 influenza pandemic using a cross-sectional phone survey of rural and metropolitan South Australia, conducted in 2007 and 2009. Awareness of pandemic influenza was significantly higher and anxiety lower in 2009 than in 2007. Reported seasonal influenza vaccine uptake increased from 51.7% in 2007 to 61.4% in 2009, but there was more interest in receiving pandemic vaccine in 2007 (87.5%) than in 2009 (57%). PMID- 21782280 TI - US university response to H1N1: a study of access to online preparedness and response information. AB - BACKGROUND: The recent outbreaks of severe acute respiratory syndrome, H5N1 (avian influenza), and, most recently, the novel H1N1 influenza pandemic of 2009 have raised awareness of the danger of new and emerging infections. Preparedness and response plans for such outbreaks are crucial, and given the centrality of the Internet as a source of information on university and college campuses, such plans should be made available at pandemic-dedicated university Web sites. The information on these sites must be comprehensive, accessible, and tailored to the specific circumstances of individual schools. METHODS: An Internet-based search was conducted in September 2009 to evaluate university Web sites for influenza specific information in a sample of 51 universities. Web sites were assessed by applying a set of key words and a list of 10 indicators used as measures of accessibility and comprehensiveness. RESULTS: Of the 51 universities evaluated, only 9 (17.6%) either had no influenza Web site or had a university influenza preparedness plan with no dedicated Web site. Only 6 (14.3%) of the schools with influenza specific Web sites had information for parents, with 23 (54.8%) providing information specifically for faculty and staff, and 24 (57.1%) providing information specifically to students. CONCLUSION: We found no guidelines for maximizing the access to and effectiveness of online pandemic communications at institutions of higher learning. Until such time as appropriate guidelines are developed, university authorities must carefully assess their needs, taking into account local, national, and international public health circumstances and resources; ease of access; comprehensiveness; and appropriately tailored strategies in their online communications. PMID- 21782281 TI - An unexpected increase in catheter-associated bloodstream infections at a children's hospital following introduction of the Spiros closed male connector. AB - BACKGROUND: Catheter-associated bloodstream infections (CA-BSIs) are associated with increased morbidity and mortality. Previous investigations have reported outbreaks of CA-BSI temporally associated with the use of needleless connector valves or similar devices. METHODS: We observed an unexpected increase in the rate of CA-BSI at our institution during August 2009. We used statistical process control and quality improvement methodology to identify the factor(s) associated with this increased rate of CA-BSI. RESULTS: We reviewed the overall hospital Shewhart U chart for CA-BSI, which indicated special cause variation with an unexpected cluster (6/9; 67%) of CA-BSIs localized to the oncology ward and the bone marrow transplant unit. An event-cause analysis review showed that 5 of these 9 infections were caused by Staphylococcus aureus. We discovered that the Spiros Closed Male Connector (ICU Medical, San Clemente, CA) had been introduced in these 2 units around the same time as the cluster of infections occurred. Based on this information, we discontinued the use of this device, and the CA-BSI rate and distribution of causative microorganisms returned to previous baseline values. CONCLUSION: This case study highlights the utility of statistical process control in the surveillance and investigation of CA-BSI. PMID- 21782282 TI - How many bacteria live on the keyboard of your computer? PMID- 21782283 TI - An unusual cause of continuous ambulatory peritoneal dialysis-associated outpatient peritonitis: Stenotrophomonas maltophilia. PMID- 21782284 TI - Infection or colonization and antimicrobial susceptibility of Enterococcus spp at a regional hospital in Queretaro, Mexico. PMID- 21782285 TI - Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease. AB - Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. PMID- 21782287 TI - Structural MRI changes detectable up to ten years before clinical Alzheimer's disease. AB - Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology. PMID- 21782288 TI - [Left atrial myxoma embolizing in the left appendage]. PMID- 21782289 TI - [Utility of the dead space fraction (Vd/Vt) as a predictor of extubation success]. AB - PURPOSE: To determine the value of Vd/Vt as a predictor of extubation failure in patients with mechanical ventilation admitted to the intensive care units. DESIGN: A prospective, observational cohort study conducted from 1 September 2010 to 1 March 2011. SETTING: General intensive care unit (G-ICU) of a third level university hospital. PATIENTS OR PARTICIPANTS: The study included patients on mechanical ventilation (MV) for over 12 hours, and who in the process of weaning were subjected to low-level pressure support. Exclusion criteria were age under 18 years, ventilation via tracheotomy and patients failing to cooperate for different reasons. During the study, 392 patients were admitted to the G-ICU; of these, 214 required MV. The weaning process was started in 154 cases. Fifty-four patients were excluded from the study, and 24 were not extubated from MV. A total of 76 patients were finally extubated and analyzed. VARIABLES OF INTEREST: Vd/Vt was calculated as the ratio (PaCO(2)-Pe CO(2))/PaCO(2), with the recorded parameters. RESULTS: Logistic regression analysis showed a significant association between the Vd/Vt and extubation failure, with OR=1.52 (95%CI 1.11 to 2.09, p=0.008). The area under the ROC curve with respect to the prediction of extubation failure according to the Vd/Vt value was 0.94 (95%CI 0.86 to 0.98, p<0.0001). CONCLUSIONS: Vd/Vt is a powerful predictor of extubation failure in patients on MV. PMID- 21782290 TI - [Comorbidity and multiple medication of patients with cardiac failure in emergency departments]. PMID- 21782291 TI - [The symptoms in family medicine are not symptoms of disease, they are symptoms of life]. AB - The symptoms in family medicine are not signs of disease, but "signs of life"; in the consultation "all patient life comes together with him". Every consultation is primarily a biopsicosocial problem: the person perceives a dysfunction or alteration in relation with himself and his context. To do a diagnosis only with physical symptoms, can be a mistake because these do not identify the real problem. The different types of symptoms are "entangled" or chained some in others: the symptoms can be fitted or inevitable; to be expressions of biochemical alterations, symbols for the patient, group context expressions, or kinds of facing the facts; and they depend on the previous psychological patient performance, the severity of the deficit of the psychological function associated with the disease, the residual skills, the adjustment and the confrontation of the functional limitations, the relation doctor-patient, as well as on the influence of the context. PMID- 21782286 TI - A genome-wide association study of aging. AB - Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 * 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10( 5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity. PMID- 21782293 TI - [Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry vs conventional methods in the identification of Candida non albicans]. AB - INTRODUCTION: Candida infection has become a major health problem worldwide. The epidemiology of Candidaemia has substantially changed by the emergence of the species Candida non-albicans. This variation is particularly important in the choice of prophylaxis and empirical treatment. The methods based on biochemical and molecular biology have limitations for the correct identification of Candida species. The aim of this study is to demonstrate the ability of the MALDI-TOF mass spectrometry for the identification of these species and compare it with the technology used today. METHODS: We included all isolates collected over 2 years (n=73) of Candida non-albicans from non-invasive samples. The identification was carried out by Vitek-2 systems YST and API CAUX. The MALDI-TOF identifications were made with Confidence Axima system (Shimadzu Corporation) using the Shimadzu Launchpad software and database SARAMIS (AnagnosTec GmbH). Discrepancies were resolved by SeptiFast LightCycler multiplex PCR, specific PCR C. glabrata and enzymatic digestion with BanI SADH fragment in isolates of C. parapsilosis. RESULTS: Of the 73 isolates of Candida non-albicans, the biochemical methods conclusively identified 67 to species level and 6 at the genus level. The MALDI TOF system obtained identifications at the species level in all cases. The correlation in the species of all isolates studied was 85.07%, reaching 94.52% when the correlation was made between the identification obtained by biochemical methods and the methods for the analysis of the discrepancies. In isolates of C. parapsilosis, MALDI-TOF system obtained an identification of C. orthopsilosis. In 3 of them it was confirmed by digestion with BanI SADH fragment. CONCLUSION: This study has demonstrated the use of mass spectrometry (MALDI-TOF system) to provide the microbiology laboratory with greater efficiency and reliability to identify isolates of Candida non-albicans to species level. It also shows its potential usefulness in identifying related species, such as C. parapsilosis, metapsilosis and orthopsilosis. PMID- 21782294 TI - Chemical synthesis and evaluation of 17alpha-alkylated derivatives of estradiol as inhibitors of steroid sulfatase. AB - Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17alpha-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17alpha-derivatives of E2. PMID- 21782295 TI - Instrument of Professional Attitude for Student Nurses (IPASN): a confirmatory factor analytic study. AB - The purpose of this study is to confirm the indentified factor structure of the Instrument of Professional Attitude for Student Nurses (IPASN) developed by Hisar et al. (2010). Confirmatory factor analysis (CFA) was performed using 1039 voluntary students from 23 schools which were randomly selected from institutions offering an undergraduate education in nursing in the 2009-10 academic year in Turkey. The CFA yielded high fit indices, thus confirming the factor structure of the IPASN with 28 items and 8 factors. The IPASN was found to be appropriate, both theoretically and statistically. Due to these results, it is recommended that the IPASN scale could be used in future studies in Turkey. It is also recommended that the scale could be adapted and used in other cultures. PMID- 21782296 TI - Radon measurements by nuclear track detectors in secondary schools in Oke-Ogun region, Nigeria. AB - Radon measurements were performed in secondary schools in the Oke-Ogun area, South-west, Nigeria, by solid state nuclear track detectors (SSNTDs). About seventy CR-39 detectors were distributed in 35 high schools of the Oke-Ogun area. The CR-39 detectors were exposed in the schools for 3 months and then etched in NaOH 6 N solution at 90 degrees C for 3 h. The tracks were counted manually at the microscope and the radon concentration was determined at the Radioactivity Laboratory, Department of Physics, University of Trieste, Trieste, Italy. The overall average radon concentration in the surveyed area was 45 +/- 27 Bq m(-3). The results indicate no radiological health hazard. The research also focused on parameters affecting radon concentrations such as the age of the building in relation to building materials and floor number of the classrooms. The results show that radon concentrations in ground floors are higher than in upper floors. PMID- 21782297 TI - Key role in the prevention of child neglect and abuse in Germany: continuous care by qualified family midwives. AB - OBJECTIVE: the aim of two related studies was an in-depth knowledge of psychosocially and health-related vulnerable families and the 'portfolio' of care that family midwives (FM) provide. Besides factors which influence acceptance and access from the mothers' perspective, the effectiveness of FM with regard to care, infant nutrition, and parent-child relationship as well as multidisciplinary collaboration were of interest, especially against the backdrop of Germany's national aim to strengthen prevention of neglect and abuse of infants. In addition, the reasons why families did not want FM care were explored. DESIGN: two FM model projects in Saxony-Anhalt (SA) and Lower Saxony (LS), Germany, were evaluated. Quantitative data were prospectively collected on 93% of vulnerable families being cared for by FM (SA) and regarding vulnerable families that declined FM care (LS). These data were complemented by problem focused interviews with 14 mothers and six social workers (LS). SETTING AND INTERVENTIONS: the 33 FM in SA and 11 FM in LS are community-based and visit vulnerable families from pregnancy up to the first birthday of the child, maximally. They provide health promotion, maternal and infant care, and multidisciplinary support geared towards early prevention of child neglect and abuse. PARTICIPANTS: from May 2006 until 2008 (SA) and from January 2008 until December 2009 (LS) 814 and 235 vulnerable families, respectively, were cared for by FM. Complete data on 734 families were analysed (SA) as were 30 questionnaires on 'non-compliant' families (LS). Problem-focused interviews were conducted with 14 mothers and 6 social workers (LS). MEASUREMENTS AND FINDINGS: many families exhibited a high vulnerability score of complex risk factors. Four vulnerability patterns were statistically extracted explaining 40% of the total variance. The highest frequencies of care activities related to infant care and nutrition, giving advice on the Mother-Child relationship, and psychosocial support. The Youth Welfare Services (YWS) were significant collaboration partners, especially regarding families whose child was taken out for safety reasons. By conclusion of care, significantly higher mean scores were observed regarding 'parent-child relationship' and 'maternal care for child' (compared to the outset of care) when mean duration of care was at least 6 months. The children who were taken out of their families had significantly lower scores in nutritional care, and were given solids at a significantly earlier time. From the mothers' perspective it was important to have early access to the FM and easy between-visits communication via phone calls, or text messages. They appreciated the physical and psychosocial care for the infant and herself, an uncomplicated transition from caseload midwifery, and collaboration among providers. Families who declined FM care wanted to stay with their self-chosen midwife, were afraid of external control, or felt they were able to cope without professional support. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: when families can access FM early on and home-visits are sustained, maternal competencies in caring for, and relating to, the child can potentially be strengthened. FM seem to fill a gap between standard care by caseload midwives ending at 8 weeks postpartum and YWS whose personnel is not skilled in the assessment of health-related problems, such as inadequate infant nutrition. As a relatively high percentage of the families were challenged by domestic violence, drug addiction, and teenage pregnancy, ongoing educational activities should address these topics. PMID- 21782298 TI - Trophically available metal--a variable feast. AB - Assimilation of trace metals by predators from prey is affected by the physicochemical form of the accumulated metal in the prey, leading to the concept of a Trophically Available Metal (TAM) component in the food item definable in terms of particular subcellular fractions of accumulated metal. As originally defined TAM consists of soluble metal forms and metal associated with cell organelles, the combination of separated fractions which best explained particular results involving a decapod crustacean predator feeding on bivalve mollusc tissues. Unfortunately TAM as originally defined has subsequently frequently been used in the literature as an absolute description of that component of accumulated metal that is trophically available in all prey to all consumers. It is now clear that what is trophically available varies between food items, consumers and metals. TAM as originally defined should be seen as a useful starting hypothesis, not as a statement of fact. PMID- 21782299 TI - Global DNA methylation in earthworms: a candidate biomarker of epigenetic risks related to the presence of metals/metalloids in terrestrial environments. AB - In this work, possible relationships between global DNA methylation and metal/metalloid concentrations in earthworms have been explored. Direct correlation was observed between soil and tissue As, Se, Sb, Zn, Cu, Mn, Ag, Co, Hg, Pb (p< 0.05). Speciation results obtained for As and Hg hint at the capability of earthworms for conversion of inorganic element forms present in soil to methylated species. Inverse correlation was observed between the percentage of methylated DNA cytosines and total tissue As, As + Hg, As + Hg + Se + Sb (beta = -0.8456, p = 0.071; beta = -0.9406, p = 0.017; beta = -0.9526, p = 0.012 respectively), as well as inorganic As + Hg (beta = -0.8807, p = 0.049). It was concluded that earthworms would be particularly helpful as bioindicators of elements undergoing in vivo methylation and might also be used to assess the related risk of epigenetic changes in DNA methylation. PMID- 21782300 TI - Effects of organic matter and ageing on the bioaccessibility of arsenic. AB - Arsenic-contaminated soils may pose a risk to human health. Redevelopment of contaminated sites may involve amending soils with organic matter, which potentially increases arsenic bioaccessibility. The effects of ageing on arsenic contaminated soils mixed with peat moss were evaluated in a simulated ageing period representing two years, during which arsenic bioaccessibility was periodically measured. Significant increases (p = 0.032) in bioaccessibility were observed for 15 of 31 samples tested, particularly in comparison with samples originally containing >30% bioaccessible arsenic in soils naturally rich in organic matter (>25%). Samples where percent arsenic bioaccessibility was unchanged with age were generally poor in organic matter (average 7.7%) and contained both arsenopyrite and pentavalent arsenic forms that remained unaffected by the organic matter amendments. Results suggest that the addition of organic matter may lead to increases in arsenic bioaccessibility, which warrants caution in the evaluation of risks associated with redevelopment of arsenic contaminated land. PMID- 21782302 TI - Innovation and the English National Health Service: a qualitative study of the independent sector treatment centre programme. AB - Over the past two decades, an international trend of exposing public health services to different forms of economic organisation has emerged. In the English National Health Service (NHS), care is currently provided through a quasi-market including 'diverse' providers from the private and third sector. The predominant scheme through which private sector companies have been awarded NHS contracts is the Independent Sector Treatment Centre (ISTC) programme. ISTCs were designed to produce innovative models of service delivery for elective care and stimulate innovation among incumbent NHS providers. This paper investigates these claims using qualitative data on the impact of an ISTC upon a local health economy (LHE) composed of NHS organisations in England. Using the case of elective orthopaedic surgery, we conducted semi-structured interviews with senior managers from incumbent NHS providers and an ISTC in 2009. We show that ISTCs exhibit a different relationship with frontline clinicians because they counteract the power of professional communities associated with the NHS. This has positive and negative consequences for innovation. ISTCs have introduced new routines unencumbered by the extant norms of professional communities, but they appear to represent weaker learning environments and do not reproduce cooperation across organisational boundaries to the same extent as incumbent NHS providers. PMID- 21782301 TI - Reduction in uptake by rice and soybean of aromatic arsenicals from diphenylarsinic acid contaminated soil amended with activated charcoal. AB - Activated charcoal (AC) amendment has been suggested as a promising method to immobilize organic contaminants in soil. We performed pot experiments with rice and soybean grown in agricultural soil polluted by aromatic arsenicals (AAs). The most abundant AA in rice grains and soybean seeds was methylphenylarsinic acid (MPAA). MPAA concentration in rice grains was significantly reduced to 2% and 3% in 0.2% AC treated soil compared to untreated soil in the first year of rice cultivation. In the second year, MPAA concentration in rice grains was significantly reduced to 15% in 0.2% AC treated soil compared to untreated soil. MPAA concentration in soybean seeds was significantly reduced to 44% in 0.2% AC treated soil compared to untreated soil. AC amendment was effective in reducing AAs in rice and soybean. PMID- 21782304 TI - Sex, stressful life events, and adult onset depression and alcohol dependence: are men and women equally vulnerable? AB - Higher rates of major depression (MD) among females, and of alcohol dependence (AD) among males, are among the most routinely reported findings in psychiatric epidemiology. One of the most often pursued explanations for sex differences in both disorders suggests that males and females have a differential vulnerability to stressors, which is manifested in sex-specific ways (MD for females, AD for males). However, existing evidence in support of this explanation is mixed. In the present study, we investigated sex differences in the association between stressful life events and MD and AD in a large national sample of adults in the United States (n = 32,744) using a prospective design. Logistic regression was used to estimate associations between stressful life events and both MD and AD; sex-specific effects of stress on MD and AD were evaluated by testing interaction terms between sex and stressors in the prediction of both outcomes. The number of stressful life events was predictive of first onset MD and AD. This was true for both males and females, and sex-by-stress interaction terms did not support the hypothesis that sex-specific responses to stressful life events lead to sex differences in first onset of MD and AD among adults. These results indicate the resistance of sex differences in MD and AD to simple explanations, and suggest the need for more nuanced models that incorporate both physiological and social aspects of vulnerability. PMID- 21782303 TI - Sex inequalities in physical and mental functioning of British, Finnish, and Japanese civil servants: role of job demand, control and work hours. AB - In general, women report more physical and mental symptoms than men. International comparisons of countries with different welfare state regimes may provide further understanding of the social determinants of sex inequalities in health. This study aims to evaluate (1) whether there are sex inequalities in health functioning as measured by the Short Form 36 (SF-36), and (2) whether work characteristics contribute to the sex inequalities in health among employees from Britain, Finland, and Japan, representing liberal, social democratic, and conservative welfare state regimes, respectively. The participants were 7340 (5122 men and 2218 women) British employees, 2297 (1638 men and 659 women) Japanese employees, and 8164 (1649 men and 6515 women) Finnish employees. All the participants were civil servants aged 40-60 years. We found that more women than men tended to have disadvantaged work characteristics (i.e. low employment grade, low job control, high job demands, and long work hours) but such sex differences were relatively smaller among employees from Finland, where more gender equal policies exist than Britain and Japan. The age-adjusted odds ratio (OR) of women for poor physical functioning was the largest for British women (OR = 2.08), followed by for Japanese women (OR = 1.72), and then for Finnish women (OR = 1.51). The age-adjusted OR of women for poor mental functioning was the largest for Japanese women (OR = 1.91), followed by for British women (OR = 1.45), and then for Finnish women (OR = 1.07). Thus, sex differences in physical and mental health was the smallest in the Finnish population. The larger the sex differences in work characteristics, the larger the sex differences in health and the reduction in the sex differences in health after adjustment for work characteristics. These results suggest that egalitarian and gender equal policies may contribute to smaller sex differences in health, through smaller differences in disadvantaged work characteristics between men and women. PMID- 21782305 TI - Evaluation of satisfaction of patients rehabilitated with zygomatic fixtures. AB - PURPOSE: The aim of this study was to evaluate the satisfaction of patients rehabilitated with zygomatic fixtures and prosthesis with immediate loading. MATERIALS AND METHODS: The study selected patients who were rehabilitated with zygomatic implants at the clinic of the Latin American Institute for Dental Research and Education (ILAPEO. Curitiba-PR. Brasil) between 2005 and 2009. The patients were asked to answer a control-questionnaire during their follow-up visits. Data were collected regarding the level of patient satisfaction, reason for dissatisfaction, number of post-operative clinical sessions, and the type of complication. Sixteen patients were selected: 10 females and 6 males. RESULTS: Half of the patients were completely satisfied while the other half were satisfied with some complaints. The complaints were related to hygiene, esthetics, phonetics, and discomfort during chewing. Regarding the post-operative evaluation, 50% of the patients were attended due to the prosthesis (62.5%) and the implant (37.5%). CONCLUSIONS: The treatment with zygomatic fixtures is predictable and reliable. The patients were satisfied both with implants and prosthesis. PMID- 21782306 TI - Diagnostic challenges of myoepithelioma arising from a minor salivary gland. PMID- 21782307 TI - Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan. AB - PURPOSE: A nationwide retrospective cohort study was conducted by the Japanese Society of Oral and Maxillofacial Surgeons to assess the occurrence of bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) during 2006 to 2008 and to elucidate the outcome and factors associated with remission of BRONJ. MATERIALS AND METHODS: A written questionnaire, including the clinical characteristics, management, and outcome of patients with BRONJ, was sent to 248 institutions certified as training facilities by the Japanese Society of Oral and Maxillofacial Surgeons in 2008. RESULTS: A total of 568 patients with BRONJ, including suspicious cases, were registered. Of these 568 patients, 263, including the maxilla in 81, the mandible in 160, and both in 22, met the working definition of BRONJ proposed by the American Association of Oral and Maxillofacial Surgeons. The patients included 219 women (83.3%) and 44 men (16.7%). Of these patients, 152 (57.8%) had received intravenous BPs, 104 (39.5%) had received oral BPs, and 7 (2.7%) had received both. The mean duration of administration until onset of BRONJ was 23.6 months for intravenous BPs and 33.2 months for oral BPs. BRONJ was stage 1 in 42 patients (16.0%), stage 2 in 187 (71.1%), stage 3 in 32 (12.2%), and unknown in 2. Of these patients, 34.2% had remission of BRONJ, 46.0% had persistent or progressive disease, and 19.7% died of malignancy or were lost to follow-up. Statistical analysis revealed that surgical treatment, including tooth extraction, sequestrectomy, and segmental mandibulectomy, contributed to the remission of BRONJ. In contrast, conservative treatment, concurrent anticancer drugs, poor oral hygiene, and the use of intravenous BPs did not. CONCLUSIONS: The relative ratio of BRONJ related to the use of oral BPs was greater in Japan than in the United States and European Union. Surgical treatment contributed to remission of BRONJ, and conservative treatment, concurrent anticancer drugs, poor oral hygiene, and intravenous BPs did not. PMID- 21782308 TI - Solid keratocystic odontogenic tumor--report of a nonaggressive case. PMID- 21782309 TI - An fMRI investigation of a novel analogue to the Trail-Making Test. AB - The Trail-Making Test (TMT) is a widely used neuropsychological measure that assesses visuomotor abilities and cognitive flexibility. For the TMT-A condition participants are required to locate and connect numbers (i.e. 1-2-3...) while in the TMT-B condition participants perform the set-shifting task of locating and connecting numbers and letters (i.e. 1-A-2-B...). The TMT-B condition has shown impairments in many clinical populations, particularly schizophrenia patients, but the neurobiological underpinning of the task can be difficult to discern given pragmatic obstacles in adapting the task for neuroimaging. In a behavioural testing experiment we demonstrated a close correspondence between performance on the standard TMT and a novel, computer programmed adaptation of the TMT (pcTMT). The pcTMT was designed for functional magnetic resonance imaging (fMRI) administration and neuroimaging data for this task were obtained in. A whole brain analysis revealed significantly greater activation during the pcTMT-B relative to the pcTMT-A in right inferior/middle frontal cortices, right precentral gyrus, left angular gyrus/left middle temporal gyrus. These results identify the regions that most likely underlie cognitive flexibility during the TMT and are candidate regions underlying the impairment of groups with poor set shifting abilities. PMID- 21782310 TI - [A cost analysis of DIEP flap in breast reconstruction]. AB - BACKGROUND: We postulate that the absence of a CPT code for DIEP (deep inferior epigastric perforator) free flap in breast reconstruction is in part responsible for the delayed adoption of this modern technique in France. In order to provide data to our regulating health agency, we determined the cost of this technique compared to a gold standard. We performed a cost-identification study, comparing costs of DIEP free flap versus latissimus dorsi pedicled flap with implant (LD+I) in secondary breast reconstruction following irradiation. METHODS: Over a 12 month period, direct medical and non-medical costs as well as indirect costs were recorded in both groups (DIEP and LD+I). RESULTS: In an academic department funded by the national health system, total cost of a secondary breast reconstruction by DIEP free flap was 10,671 +/- 3005? (n=57) versus 8218 +/- 2049? (n=18) for the LD+I group (P<0.05). Mean OR occupation time was 390 +/- 64minutes for DIEP versus 283 +/- 44minutes for LD+I (P<0.05). Mean hospital stay was 6 +/- 2 days for DIEP versus 5 +/- 2 days for LD+I (P>0.05). CONCLUSION: DIEP free flap technique offers a long lasting breast reconstruction at an reasonable expense compared to the LD+I (+22%). Furthermore, in an academic department, collaboration of two microsurgeons during DIEP flaps allows OR times to drop significantly and become competitive with LD+I. PMID- 21782311 TI - [The quality of information available on the internet about aortic aneurysm and its endovascular treatment]. AB - INTRODUCTION AND OBJECTIVES: To evaluate the readability, accessibility, usability, and reliability of information available on the Internet in the Spanish language about aortic aneurysm and its endovascular treatment, and to determine whether this information source provides comprehensible material that will enable patients to participate in decisions regarding their condition. METHODS: In November 2010, information from the Internet was compiled by entering the terms "aneurisma aorta" (aortic aneurysm) and "endoprotesis aorta" (aortic endoprosthesis) in the most widely used search engines: Google, Yahoo, and MSN/Bing. The first 30 pages provided by each search engine were analyzed. The Inflesz software was used to calculate the readability of the information retrieved and the LIDA instrument, a validated tool to evaluate the quality of health-related Web sites, was used to assess accessibility, usability, and reliability. RESULTS: The results for Web pages containing the terms aneurisma aorta and endoprotesis aorta indicated that the readability of the material retrieved was "somewhat difficult" based on the Flesch index within Microsoft Word (48.3 +/- 11.42 and 50.11 +/- 9.33, respectively; P = .87), Flesch-Szigriszt index (52.69 +/- 8.86, 49.31 +/- 7.24; P = .87), Fernandez-Huerta index (58.05 +/ 8.5, 54.44 +/- 7.19; P=.82), and Gunning-Fog index (22.03 +/- 2.05, 23.86+/ 1.59; P=.83), as well as the Inflesz grading scale (2.39 +/- 0.7, 2.08 +/- 0.64; P=.28). The LIDA values for accessibility (82.28 +/- 14.14, 77.77 +/- 12.64; P=.98), usability (72.28 +/- 16.67, 72.28 +/- 26.61; P=.08), and reliability (46.17 +/- 28.69, 56.38 +/- 16.17; P=.06) and the total score (70.22 +/- 16.85, 72.15 +/- 14.93; P=.52), yielded an evaluation of "moderate". CONCLUSIONS: The Internet information on aortic aneurysms and its endovascular treatment with aortic endoprostheses was deficient with regard to accessibility, usability, and reliability, and had the added difficultly of complicated readability. Our results suggest that readability indexes should be incorporated in the creation and improvement of Web sites providing medical information related to cardiovascular disease. PMID- 21782312 TI - Utstein-style audit of Protocol C: a non-standard resuscitation protocol for healthcare professionals. AB - INTRODUCTION: International guidelines for basic life support and defibrillation are identical for lay people and healthcare professionals. In 2002, a small meeting hosted by the Resuscitation Council (UK) debated recent advances in resuscitation science, along with the possibility of more demanding procedures for treating out of hospital cardiac arrest (OHCA) that could take advantage of the expertise available with professional use. The resulting algorithm known as Protocol C could not be tested in a randomized trial for reasons relating to consent, but was introduced by one ambulance service as an observational study. Results from a 2-year period from one city within the service area are presented, using the Utstein style of reporting to show the recommended 'comparator' group whilst also providing epidemiological data on the frequency of cardiac arrest within the community and the outcome of all resuscitation attempts. METHODS: Manual methods were used to collect data from 2009 and 2010 for cases of cardiac arrest treated by crews from the two ambulance stations within the city of Brighton and Hove. All transported patients were tracked individually through the hospital because no official method of data linkage is available. Outcome data were obtained for survival to hospital discharge, or to 30 days for the few who remained in hospital care for that duration. RESULTS: In the epidemiological analysis, 454 patients with OHCA were treated over 2 years, of whom 151 (33%) had sustained return of spontaneous circulation (ROSC) at hospital handover and 59 (13%) survived to discharge or for 30 days. Within the 'comparator' group of 79 patients, 47 (59%) achieved sustained ROSC to hospital handover and 24 (30%) survived. CONCLUSION: The use of Protocol C has been associated with rates of sustained ROSC to hospital and of survival to discharge that have reached the range of international best practice. The improvement noted in this observational study cannot be ascribed to the new protocol alone; any wider use should await randomized trials to test the impact of this single variable. Meanwhile, wider adoption of the Utstein system to compare results for treatment of OHCA will provide a potent stimulus for emergency services to seek ways of improving outcome. PMID- 21782313 TI - Infant chest compression depth needs further evaluation. PMID- 21782314 TI - Serum estradiol does not differentiate stress, mixed and urge incontinent women around menopause. A report from the Women's Health in the Lund Area (WHILA) study. AB - OBJECTIVE: To outline serum estradiol levels in perimenopausal women with stress, mixed or urge incontinence. We believe the majority of urgency symptoms in perimenopausal women to be caused by a pelvic floor dysfunction and a hypermobility of the bladder neck. If this is the case, there would be no difference in estradiol levels between the groups. STUDY DESIGN: SETTING: University hospital. In the observational Women's Health in the Lund Area study, a subset of 400/2221 women reporting urinary incontinence completed a detailed questionnaire regarding lower urinary tract symptoms and had their serum steroid hormone levels measured. Statistical analyses were made by Chi-square test, nonparametrical tests, ANOVA, multi- and univariate logistic regression analysis. RESULTS: Stress incontinence was reported by 196, mixed incontinence by 153 and urge incontinence by 43 women; in 369, serumestradiol values were available. Serum estradiol did not differ significantly between stress incontinent (median 49.5 pmo/l, range 2.63-875.4), urge incontinent (median 31.6 pmol/l, range 2.63 460.7) or mixed incontinent women (median 35.5 pmol/l, range 2.63-787.9, p=0.62). Logistic regression analysis correcting for age, parity, hormonal status, smoking, hysterectomy and BMI also failed to show any difference in estradiol levels between the groups (p=0.41-0.58). CONCLUSION: No significant differences in serum estradiol levels between stress, mixed or urge incontinent perimenopausal women could be demonstrated. PMID- 21782315 TI - The soluble, periplasmic domain of OmpA folds as an independent unit and displays chaperone activity by reducing the self-association propensity of the unfolded OmpA transmembrane beta-barrel. AB - OmpA is one of only a few transmembrane proteins whose folding and stability have been investigated in detail. However, only half of the OmpA mass encodes its transmembrane beta-barrel; the remaining sequence is a soluble domain that is localized to the periplasmic side of the outer membrane. To understand how the OmpA periplasmic domain contributes to the stability and folding of the full length OmpA protein, we cloned, expressed, purified and studied the OmpA periplasmic domain independently of the OmpA transmembrane beta-barrel region. Our experiments showed that the OmpA periplasmic domain exists as an independent folding unit with a free energy of folding equal to -6.2 (+/-0.1) kcal mol(-1) at 25 degrees C. Using circular dichroism, we determined that the OmpA periplasmic domain adopts a mixed alpha/beta secondary structure, a conformation that has previously been used to describe the partially folded non-native state of the full-length OmpA. We further discovered that the OmpA periplasmic domain reduces the self-association propensity of the unfolded barrel domain, but only when covalently attached (in cis). In vitro folding experiments showed that self association competes with beta-barrel folding when allowed to occur before the addition of membranes, and the periplasmic domain enhances the folding efficiency of the full-length protein by reducing its self-association. These results identify a novel chaperone function for the periplasmic domain of OmpA that may be relevant for folding in vivo. We have also extensively investigated the properties of the self-association reaction of unfolded OmpA and found that the transmembrane region must form a critical nucleus comprised of three molecules before undergoing further oligomerization to form large molecular weight species. Finally, we studied the conformation of the unfolded OmpA monomer and found that the folding-competent form of the transmembrane region adopts an expanded conformation, which is in contrast to previous studies that have suggested a collapsed unfolded state. PMID- 21782316 TI - Modulation of allosteric behavior through adjustment of the differential stability of the two interacting domains in E. coli cAMP receptor protein. AB - The communication mechanism(s) responsible for the allosteric behavior of E.coli cAMP binding receptor protein, CRP, is still a subject of intense investigation. As a tool to explore the communication mechanism, the mutations at various positions in the cAMP-binding (K52N, D53H, S62F and T127L) or the DNA- binding (H159L) domain or both (K52N/H159L) were generated. The sites and specific nature of side chain substitutions were defined by earlier genetic studies, the results of which show that these mutants have a similar phenotype i.e. they are activated without exogenous cAMP. Presently, no significant changes in the structures of WT and mutant CRPs have been observed. Hence, the pressing issue is to identify a physical parameter that reflects the effects of mutations. In this study, the stability of these various CRP species in the presence of GuHCl was monitored by three spectroscopic techniques, namely, CD, tryptophan fluorescence and FT-IR which could provide data on the stability of alpha-helices and beta-strands separately. Results of this study led to the following conclusions: 1. The alpha helices can be grouped into two families with different stabilities. Mutations exert a differential effect on the stability of helices as demonstrated by a biphasic unfolding curve for the helices. 2. Regardless of the locations of mutations, the effects can be communicated to the other domain resulting in a perturbation of the stability of both domains, although the effects are more significantly expressed in the stability of the helices. 3. Although in an earlier study [Gekko, et al. Biochemistry 43 (2004) 3844] we showed that cooperativity of cAMP binding is generally correlated to the global dynamics of the protein and DNA binding affinity, in this study we found that generally there is no clear correlation between functional energetics and stability of secondary structures. Thus, results of this study imply that modulation of allostery in CRP is entropic in nature. PMID- 21782317 TI - The simplest method for in vitro beta-cell production from human adult stem cells. AB - Diabetes mellitus is a challenging autoimmune disease. Biomedical researchers are currently exploring efficient and effective ways to solve this challenge. The potential of stem cell therapies for treating diabetes represents one of the major focuses of current research on diabetes treatment. Here, we have attempted to differentiate adult stem cells from umbilical cord blood-derived mesenchymal cells (UCB-MSC), Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) and amniotic epithelial stem cells (AE-SC) into insulin-producing cells. The serum free protocol developed in this study resulted in the differentiation of cells into definitive endoderm, pancreatic foregut, pancreatic endoderm and, finally, pancreatic endocrine cells, which expressed the marker genes SOX17, PDX1, NGN3, NKX6.1, INS, GCG, and PPY, respectively. Detection of the expression of the gap junction-related gene connexin-36 (CX36) using RT-PCR provided conclusive evidence for insulin-producing cell differentiation. In addition to this RT-PCR result, insulin and C-peptide protein were detected by immunohistochemistry and ELISA. Glucose stimulation test results showed that significantly greater amounts of C-peptide and insulin were released from differentiated cells than from undifferentiated cells. In conclusion, the methods investigated in this study can be considered an effective and efficient means of obtaining insulin-producing cells from adult stem cells within a week. PMID- 21782318 TI - Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA). AB - CONTEXT: The use of botulinum toxin A (BoNTA) in the treatment of lower urinary tract dysfunction has expanded in recent years and the off-licence usage list includes neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity (IDO), painful bladder syndrome (PBS), and lower urinary tract symptoms resulting from bladder outflow obstruction (BOO) or detrusor sphincter dyssynergia (DSD). There are two commonly used preparations of BoNTA: Botox (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA). OBJECTIVE: To compare the reported outcomes of onabotulinumtoxinA and abobotulinumtoxinA in the treatment of NDO, IDO, PBS, DSD, and BOO for adults and children. EVIDENCE ACQUISITION: We performed a systematic review of the published literature on PubMed, Scopus, and Embase in the English language reporting on outcomes of both BoNTA preparations. Review articles and series with <10 cases were excluded. The articles were graded for level of evidence and conclusions drawn separately for data with higher-level evidence. EVIDENCE SYNTHESIS: There is high-level evidence for the use of onabotulinumtoxinA and abobotulinumtoxinA in adults with NDO but only for abobotulinumtoxinA in children with NDO. Only onabotulinumtoxinA has level 1 evidence supporting its use in IDO, BOO, DSD, and PBS/interstitial cystitis. CONCLUSIONS: We identified good-quality studies that evaluated onabotulinumtoxinA for all the indications described above in adults; such was not the case with abobotulinumtoxinA. Although this does not imply that onabotulinumtoxinA is more effective than abobotulinumtoxinA, it should be a consideration when counselling patients on the use of botulinum toxin in urologic applications. The two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used. PMID- 21782320 TI - Patient acceptance of awake craniotomy. AB - OBJECTIVES: The aim of this study was to objectively assess the patients' acceptance for awake craniotomy in a group of neurosurgical patients, who underwent this procedure for removal of lesions in or close to eloquent brain areas. PATIENTS AND METHODS: Patients acceptance for awake craniotomy under local anesthesia and conscious sedation was assessed by a formal questionnaire (PPP33), initially developed for general surgery patients. The results are compared to a group of patients who had brain surgery under general anesthesia and to previously published data. RESULTS: The awake craniotomy (AC) group consisted of 37 male and 9 female patients (48 craniotomies) with age ranging from 18 to 71 years. The general anesthesia (GA) group consisted of 26 male and 15 female patients (43 craniotomies) with age ranging from 26 to 83 years. All patients in the study were included in the questionnaire analysis. In comparison to GA the overall PPP33 score for AC was higher (p=0.07), suggesting better overall acceptance for AC. The subscale scores for AC were also significantly better compared to GA for the two subscales "postoperative pain" (p=0.02) and "physical disorders" (p=0.01) and equal for the other 6 subscales. The results of the overall mean score and the scores for the subscales of the PPP33 questionnaire verify good patients' acceptance for AC. CONCLUSION: Previous studies have shown good patients' acceptance for awake craniotomy, but only a few times using formal approaches. By utilizing a formal questionnaire we could verify good patient acceptance for awake craniotomy for the treatment of brain tumors in or close to eloquent areas. This is a novel approach that substantiates previously published experiences. PMID- 21782319 TI - Bilateral sphenoorbital hyperostotic meningiomas with proptosis and visual impairment: a therapeutic challenge. Report of three patients and review of the literature. AB - OBJECTIVE: Bilateral hyperostotic sphenoorbital meningiomas are extremely uncommon. Due to extensive infiltration of the orbits and the frontotemporal skull base, often only a subtotal tumor resection is feasible. Thus far, no treatment algorithms have been suggested for this rare tumor entity. We report on the surgical management of 3 patients. METHODS: All 3 patients underwent a pterional approach for surgical resection. Surgery was performed in two stages, primarily treating the most affected side. Treatment consisted of microsurgical resection of the infiltrated sphenoid wing and orbital walls, intraorbital tumor removal and optic nerve decompression. Orbital wall reconstruction was performed using titanium mesh allografts. Radiation therapy was administered in 1 patient with residual tumor infiltration of the cavernous sinus. RESULTS: Our series includes 2 women (51 and 68 years old) suffering from simultaneous progressive bilateral loss of vision and proptosis and 1 woman (69 years old) who developed contralateral disease after surgical resection of a hyperostotic sphenoorbital meningioma 16 years earlier. After optic nerve decompression, vision improved in 2 cases after surgery. Initial visual deterioration was observed in 1 case but improved on longterm follow-up. The degree of proptosis was reduced in all treated eyes. CONCLUSION: In bilateral hyperostotic sphenoorbital meningiomas we propose staged surgery when clinical and radiological progression is observed. Subtotal tumor resection with the aim of optic nerve decompression and subsequent orbital reconstruction provides satisfactory results. The most affected eye should be treated first. In case of additional cavernous sinus infiltration, focal radiation therapy can be considered. PMID- 21782321 TI - Perfusion computer tomography helps to differentiate seizure and stroke in acute setting. PMID- 21782322 TI - A phase II study of neoadjuvant chemoradiotherapy with oxaliplatin and capecitabine for rectal cancer. AB - PURPOSE: This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy with the XELOX regimen in rectal cancer patients. PATIENTS AND METHODS: Twenty-five patients with histopathologically confirmed and locally advanced rectal cancer (T3/T4 or N+) were enrolled in the study. Radiotherapy of 5000 cGy was delivered in 25 fractions of 200 cGy five times per week for a total of 5 weeks. During the first, second, fourth and fifth weeks of radiotherapy, the patients also received the following chemotherapy: 50 mg/m2 oxaliplatin on day one and 850 mg/m2 capecitabine bid for 5 days. Surgery was scheduled 5-6 weeks after the completion of the preoperative chemoradiotherapy. Four weeks after the surgery, four more cycles of chemotherapy were administered every 3 weeks. The postoperative chemotherapy consisted of 130 mg/m2 oxaliplatin on day 1 and 1000 mg/m2 capecitabine bid from day 1 to day 14. The end points were the downstage rate, R0 resection rate, and sphincter preservation rate. RESULTS: Twenty-five patients received the neoadjuvant chemoradiotherapy. The overall regression rate was 85%, with a Grade 3/4 regression rate of 30% and a pathological complete response rate of 12%. Among the 17 patients with lower rectal cancer, thirteen (76%) were originally indicated for abdominal-perineal resection (APR). However, after the neoadjuvant chemoradiotherapy, the anus could be preserved in nine patients (53%). The most frequent toxicities of the chemoradiotherapy were diarrhea (64%) and hematological toxicity (60%), followed by nausea and vomiting (48%), urinary tract irritation (28%), and anal pain (24%). Grade 3 or 4 adverse events were relatively infrequent and presented as diarrhea (12%), myelosuppression (8%), and elevated transaminase (4%). Six cases also experienced long-term anal exudates after surgery. CONCLUSIONS: Neoadjuvant chemoradiotherapy using the XELOX regimen in rectal cancer patients obviously reduced the TNM staging and improved the pathological complete response rate. The therapy was well-tolerated and had mild adverse events and no serious perioperational complications. PMID- 21782323 TI - Gastric cancer stem-like cells possess higher capability of invasion and metastasis in association with a mesenchymal transition phenotype. AB - Cancer stem cells have been isolated from various types of cancer including leukemia and solid tumors. However, the methods for isolating gastric cancer stem like cells (GCSCs) have not been well established. As a consequence, the biological behavior and the significance of these cells to cancer progression remains to be clarified. In this study, we isolated and characterized GCSCs from a gastric cancer cell line SGC7901 and found their enhanced capabilities of invasion in vitro and metastasis in vivo. We further studied the expression of molecules related to epithelial-mesenchymal and invasion in GCSCs and found there were decreased E-cadherin, but increased vimentin and matrix metalloproteinase 2 (MMP-2), in these cells. Our results suggest that decreased E-cadherin and increased MMP-2 may be associated with the capacity of GCSCs to metastasize. PMID- 21782325 TI - Removal of methylene blue from aqueous solution by a solvothermal-synthesized graphene/magnetite composite. AB - In this study, we have demonstrated a facile one-step solvothermal method for the synthesis of the graphene nanosheet (GNS)/magnetite (Fe(3)O(4)) composite. During the solvothermal treatment, in situ conversion of FeCl(3) to Fe(3)O(4) and simultaneous reduction of graphene oxide (GO) into graphene in ethylene glycol solution were achieved. Electron microscopy study suggests the Fe(3)O(4) spheres with a size of about 200 nm are uniformly distributed and firmly anchored on the wrinkled graphene layers with a high density. The resulting GNS/Fe(3)O(4) composite shows extraordinary adsorption capacity and fast adsorption rates for removal of organic dye, methylene blue (MB), in water. The adsorption kinetics, isotherms and thermodynamics were investigated in detail to reveal that the kinetics and equilibrium adsorptions are well-described by pseudo-second-order kinetic and Langmuir isotherm model, respectively. The thermodynamic parameters reveal that the adsorption process is spontaneous and endothermic in nature. This study shows that the as-prepared GNS/Fe(3)O(4) composite could be utilized as an efficient, magnetically separable adsorbent for the environmental cleanup. PMID- 21782326 TI - Influence of flue gas SO2 on the toxicity of heavy metals in municipal solid waste incinerator fly ash after accelerated carbonation stabilization. AB - The influence of CO(2) content and SO(2) presence on the leaching toxicity of heavy metals in municipal solid waste incinerator (MSWI) fly ash was studied by examining the carbonation reaction of MSWI fly ash with different combinations of simulated incineration flue gases. Compared with raw ash, the leaching solution pH of carbonated ash decreased by almost 1 unit and the leaching concentrations of heavy metals were generally lower, with that of Pb decreasing from 19.45 mg/L (raw ash) to 4.08 mg/L (1# carbonated ash). The presence of SO(2) in the incineration flue gas increased the leaching concentrations of heavy metals from the fly ash to different extents after the carbonation stabilization reaction. The pH of the leaching solution was the main factor influencing the leaching concentrations of heavy metals. The increase in buffer capacity with the pH of carbonated ash caused an increase in heavy metal stability after the carbonation reaction. Accelerated carbonation stabilization of MSWI fly ash could reduce its long-term leaching concentrations (toxicity) of Cu, Pb, Se, and Zn. The leaching concentrations of heavy metals from carbonated ash also likely had better long term stability than those from raw ash. The presence of SO(2) in the incineration flue gas increased the proportion of exchangeable state species of heavy metals; slightly increased the long-term leaching toxicity of Cu, Pb, Se, and Zn; and reduced the long-term stability of these metals in the fly ash after the carbonation reaction. PMID- 21782324 TI - Rapid induction of apoptosis during Kinesin-5 inhibitor-induced mitotic arrest in HL60 cells. AB - Small molecule inhibitors of Kinesin-5 (K5Is) that arrest cells in mitosis with monopolar spindles are promising anti-cancer drug candidates. Clinical trials of K5Is revealed dose-limiting neutropenia, or loss of neutrophils, for which the molecular mechanism is unclear. We investigated the effects of a K5I on HL60 cells, a human promyelocytic leukemia cell line that is often used to model dividing neutrophil progenitors in cell culture. We found K5I treatment caused unusually rapid death of HL60 cells exclusively during mitotic arrest. This mitotic death occurred via the intrinsic apoptosis pathway with molecular events that include cytochrome c leakage into the cytoplasm, caspase activation, and Parp1 cleavage. Bcl-2 overexpression protected from death. We probed mitochondrial physiology to find candidate triggers of cytochrome c release, and observed a decrease of membrane potential (DeltaPsim) before mitochondrial outer membrane permeabilization (MOMP). Interestingly, this loss of DeltaPsim was not blocked by overexpressing Bcl-2, suggesting it might be a cause of Bax/Bak activation, not a consequence. Taken together, these results show that K5I induces intrinsic apoptosis during mitotic arrest in HL60 with loss of DeltaPsim as an upstream event of MOMP. PMID- 21782327 TI - Design and synthesis of immunoconjugates and development of competition inhibition enzyme-linked immunosorbent assay (CIEIA) for the detection of O isopropyl methylphosphonofluoridate (sarin): an organophosphorous toxicant. AB - Three haptens of the organophosphorus (OP) toxicant 'sarin' having different spacer arm were designed and synthesized. Haptens were conjugated with BSA (bovine serum albumin) and ovalbumin (OVA) for raising antibody and coating antigen. High antibody titer with higher specificity was obtained from 4-(4 (isopropoxy(methyl)phosphoryloxy)phenylamino)-4-oxobutanoic acid (hapten B) having reasonable long spacer arm. For the standard curve, an IC(50) (inhibitory concentration) of free antigen was found to be 0.415 MUg mL(-1) on the basis of indirect competitive ELISA. The study revealed that heterology in competition inhibition enzyme immunoassay (CIEIA) produced remarkable improvement in the sensitivity and specificity of the assay. Under the optimized conditions, the quantitative working range was found to be 0.19-1.56 MUg mL(-1) with a limit of detection (LOD) of 0.05 MUg mL(-1). The antibodies showed negligible cross reactivity (CR) with other OP toxicants and pesticides, which makes the assay suitable for the selective detection of sarin. PMID- 21782328 TI - Solid phase extraction of ultra traces mercury (II) using octadecyl silica membrane disks modified by 1,3-bis(2-ethoxyphenyl)triazene (EPT) ligand and determination by cold vapor atomic absorption spectrometry. AB - A facile and highly efficient method was developed for the preconcentration of the ultra trace amounts of mercury (II) ions. Octadecyl silica membrane disk was modified by the recently synthesized triazene ligand, 1,3-bis(2 ethoxyphenyl)triazene (EPT), and cold vapor atomic absorption spectrometry was used to determine the resultant preconcentrated Hg(II) ions. Solution studies with EPT and a series of metal ions were done in advance, and the results showed a strong affinity of EPT to the mercury ions. To perform solid phase extraction, various parameters such as pH of the sample, flow rates and the amount of the ligand were optimized. A linear calibration curve was obtained in the range of 0.02-1.90 MUg L(-1) with r(2) = 0.9990 (n = 8), and the limit of detection (LOD) based on three times the standard deviation of the blank was 10.6 ng L(-1). The relative standard deviation (RSD) for the determination of 0.1 MUg L(-1) Hg(II) found to be 2.9% while a RSD value of 1.1% was obtained for the determination of 1.0 MUg L(-1) Hg(II) (n = 8). The preconcentration and improvement factors were 380 and 74, respectively. The newly developed method was successfully applied to the determination of mercury ions in real water samples. PMID- 21782329 TI - Comparative analysis of PCDD/Fs in soil around waste incineration plants in China using CALUX bioassay and HRGC/HRMS. AB - In this study, the contamination of soil by PCDD/Fs and other dioxin-like chemicals in the vicinity of Municipal Solid Waste Incinerators (MSWIs) and Hazardous Waste Incinerators (HWIs) is estimated by the XDS-CALUX bioassay. The resulting CALUX-TEQ value is compared with the WHO-TEQ value obtained from HRGC/HRMS analysis, in order to validate the CALUX bioassay as suitable screening method for PCDD/Fs determination of soil samples. The results show that the CALUX TEQ and the WHO-TEQ values are significantly correlated (R = 0.87). The WHO-TEQ and CALUX-TEQ of soil samples collected from four waste incineration plants in China were in the range from 1.72 to 31.4 pg-TEQ/g and 1.71 to 44.2 pg-TEQ/g respectively, with a mean value of 6.09 pg-TEQ/g and 11.0 pg-TEQ/g. Considering the homologue patterns, a principal component analysis (PCA) and a hierarchical cluster analysis (HCA) of the PCDD/Fs in the soil samples, the emissions of MSWIs and HWIs were probably not the only source of PCDD/Fs. PMID- 21782330 TI - Effects of dissolved organic matter from the rhizosphere of the hyperaccumulator Sedum alfredii on sorption of zinc and cadmium by different soils. AB - Pot experiments were conducted to investigate the changes of the dissolved organic matter (DOM) in the rhizosphere of hyperaccumulating ecotype (HE) and non hyperaccumulating ecotype (NHE) of Sedum alfredii and its effects on Zn and Cd sorption by soils. After planted with HE, soil pH in the rhizosphere reduced by 0.5-0.6 units which is consistent with the increase of DOM. The hydrophilic fractions (51%) in DOM from the rhizosphere of HE (HE-DOM) was much greater than NHE-DOM (35%). In the presence of HE-DOM, Zn and Cd sorption capacity decreased markedly in the following order: calcareous clay loam>neutral clay loam>acidic silty clay. The sorption isotherms could be well described by the Freundlich equation (R(2)>0.95), and the partition coefficient (K) in the presence of HE-DOM was decreased by 30.7-68.8% for Zn and 20.3-59.2% for Cd, as compared to NHE-DOM. An increase in HE-DOM concentration significantly reduced the sorption and increased the desorption of Zn and Cd by three soils. DOM derived from the rhizosphere of the hyperaccumulating ecotype of S. alfredii could significantly reduce metal sorption and increase its mobility through the formation of soluble DOM-metal complexes. PMID- 21782331 TI - Visible light induced H2PO(4)(-) removal over CuAlO2 catalyst. AB - The delafossite CuAlO(2) is successfully used for the visible light driven H(2)PO(4)(-) reduction. It is prepared from the nitrates decomposition in order to increase the ratio of reaction surface per given mass. CuAlO(2) is a narrow band gap semiconductor which exhibits a good chemical stability with a corrosion rate of 1.70 MUmol year(-1) at neutral pH. The flat band potential (+0.25 V(SCE)) is determined from the Mott-Schottky characteristic. Hence, the conduction band, positioned at (-1.19 V(SCE)), lies below the H(2)PO(4)(-) level yielding a spontaneous reduction under visible illumination. The photocatalytic process is investigated under mild conditions and 30% conversion occurs in less than ~6h with a quantum efficiency of 0.04% under full light. The concentration decreases by a factor of 39% after a second cycle. The photoactivity follows a first order kinetic with a rate constant of 6.6 * 10(-2)h(-1). The possibility of identifying the reaction products via the intensity-potential characteristics is explored. The decrease of the conversion rate over illumination time is due to the competitive water reduction. PMID- 21782332 TI - CoMOR zeolite catalyst prepared by buffered ion exchange for effective decomposition of nitrous oxide. AB - Co contained MOR zeolite catalysts with high Co loadings were successfully synthesized by buffered ion exchange at pH 8, and were tested for N(2)O catalytic decomposition. The high exchange level of synthesized CoMOR(x)-BIE catalysts probably benefits from the maximizing hydroxycomplexes Co(OH)(+) ion in the buffered solution, which is more preferred for the ion exchange with the zeolites. It has been found that the novel CoMOR(x)-BIE catalysts exhibit excellent catalytic activities, which is attributed to the large population of isolated Co(2+) ions on ion exchange positions. The most active CoMOR(130)-BIE catalyst shows high resistance to the inhibition of oxygen, NO and water vapor. Furthermore, stability tests indicate that the CoMOR(130)-BIE catalyst has no obvious deactivation under simulated emission conditions after reaction for more than 100 h. This extraordinary durability could be related to its high Co(2+) content and low Bronsted acidity sites in the catalyst, which facilitate the stability of active isolated Co(2+) on ion exchange positions. Thus, the CoMOR(130)-BIE catalyst shows a great potential as a cost-effective catalyst for N(2)O elimination in future applications. PMID- 21782333 TI - Novel Cu (II) magnetic ion imprinted materials prepared by surface imprinted technique combined with a sol-gel process. AB - A novel Cu (II) magnetic ion-imprinted polymer (MIIP) was synthesized by surface imprinting technique combined with a sol-gel process. The adsorbent of Cu (II) MIIP shows higher capacity and selectivity than that of magnetic non-imprinted polymers (MNIP). Adsorption capacities of Cu (II)-MIIP and MNIP are 24.2 and 5.2mg/g for Cu (II) ions, respectively. The selectivity coefficients of the Cu (II)-MIIP for Cu (II)/Zn (II) and Cu (II)/Ni (II) are 91.84 and 133.92, respectively. Kinetics studies show that the adsorption process obeys pseudo second-order rate mechanism with an initial adsorption rate of 132.48 for Cu (II) MIIP and 2.41mgg(-1)min(-1) for MNIP. In addition, no obvious decrease was observed after up to five adsorption cycles, indicating that the Cu (II)-MIIP is of high stability. PMID- 21782334 TI - Effect of anthraquinone-2,6-disulfonate on the trichloroethene degradation by Dehalococcoides-containing consortium. AB - This paper reports the findings of an examination on the influence of anthraquinone-2,6-disulfonate (AQDS) on the degradation of trichloroethene (TCE) by Dehalococcoides-containing consortium (designated UC-1). Compared with the control, the results indicated that (i) in 100 MUmol/L AQDS, TCE was rapidly degraded. More ethene was produced, while less vinyl chloride (VC) was accumulated. AQDS might improve the activity of organisms in dechlorinating populations which resulted in more ethene being accumulated in the medium; (ii) in 500 MUmol/L AQDS, TCE was incompletely degraded. Presumably, 500 MUmol/L AQDS might have an inhibition effect on methanogens in the UC-1. The inhibition effect might influence the interactions among methanogens, Dehalococcoides species and other organisms in the UC-1. PMID- 21782335 TI - High performance activated carbon for benzene/toluene adsorption from industrial wastewater. AB - A coal-tar-derived mesophase was chemically activated to produce a high surface area (~3200 m(2)/g) carbon with a porosity made up of both micropores and mesopores. Its adsorption capacities were found to be among the highest ever reported in literature, reaching values of 860 mg/g and 1200 mg/g for the adsorption of benzene and toluene, respectively, and 1200 mg/g for the combined adsorption of benzene and toluene from an industrial wastewater. Such high values imply that the entire pore system, including the mesopore fraction, is involved in the adsorption process. The almost complete pore filling is thought to be due to the high relative concentrations of the tested solutions, resulting from the low saturation concentration values for benzene and toluene, which were obtained by fitting the adsorption data to the BET equation in liquid phase. The kinetics of adsorption in the batch experiments which were conducted in a syringe-like adsorption chamber was observed to proceed in accordance with the pseudo-second order kinetic model. The combined presence of micropores and mesopores in the material is thought to be the key to the high kinetic performance, which was outstanding in a comparison with other porous materials reported in the literature. PMID- 21782336 TI - Remotion of the antibiotic tetracycline by titania and titania-silica composed materials. AB - Removal of the antibiotic tetracycline (TC) by TiO(2) and the mesoporous binary system TiO(2)-SiO(2) have been studied in batch experiments by performing adsorption isotherms/kinetics and photodegradation kinetics under different conditions of pH, supporting electrolyte concentration, temperature, adsorbent amount, and TiO(2)-loading. On the one hand, the adsorption of TC on the studied materials is strongly dependent on pH, increasing as pH decreases. The adsorption mechanism, controlled by diffusion processes, is strongly related to electrostatic attractions and H-bond formations mainly between amide, carbonylic and phenolic groups of the antibiotic and the functional groups of TiO(2). The adsorption capacity at constant pH increases in the order TiO(2)=32 contiguous voxels). CONCLUSIONS: These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use. PMID- 21782356 TI - New Bruce-ladder multiplex PCR assay for the biovar typing of Brucella suis and the discrimination of Brucella suis and Brucella canis. AB - Rapid and specific identification of Brucella suis at the biovar level is necessary because some of the biovars that infect animals are pathogenic for humans. None of the molecular typing methods described so far are able to discriminate B. suis biovars in a single test and differentiation of B. suis from Brucella canis by molecular approaches can be difficult. This article describes a new multiplex PCR assay, Suis-ladder, for fast and accurate identification of B. suis at the biovar level and the differentiation of B. suis, B. canis and Brucella microti. An advancement of the original Bruce-ladder PCR protocol which allows the correct discrimination of all known Brucella species is also described. PMID- 21782357 TI - Identification and isolation of psittacid herpesvirus from psittacids in Brazil. AB - Psittacid herpesvirus (PsHV) was isolated from 41 birds kept in captivity in Belo Horizonte, Minas Gerais/Brazil using chicken embryo fibroblasts (CEF) cell cultures. For this study, leukocytes or cloacal swabs of live birds were used. Also, portions of liver, spleen or kidney from birds collected at necropsy were utilized for these tests. PCR tests confirmed the presence of PsHV in 100% of samples. Thirty-three of the PCR products were sequenced and the results disclosed a 99% and 100% identity when compared with other sequences PsHV-1 (AY372243.1 and AF261756.1), previously deposited in GenBank. In addition, histopathology was performed and 19 of the 29 birds contained random multifocal lymphoplasmacytic hepatitis with necrotic foci, suggestive of viral infection. Three samples were examined by electron microscopy to visualize the viral particles obtained from cell culture. The viral structures measured 269 nm in average, had envelopes with an icosahedral capsid and tegument, consistent with herpesvirus. Thus, a total of 41 isolates were obtained from PsHV cell cultivation in CEF, confirming the circulation of the virus between parrots kept in captivity in Belo Horizonte, and affirming the importance of further studies in this area. PMID- 21782358 TI - Porcine circovirus type 2 potentiates morbidity of Salmonella enterica serovar Choleraesuis in Cesarean-derived, colostrum-deprived pigs. AB - PROBLEM ADDRESSED: Porcine circovirus type 2 (PCV2) and Salmonella enterica subspecies enterica serovar Choleraesuis (S. Choleraesuis) are two leading causes of economic loss in the swine industry. Although S. Choleraesuis infection occurs concurrently with PCV2-associated disease in many swine herds, the pathogenesis of concurrent infection with PCV2 and S. Choleraesuis remains largely undefined. OBJECTIVE: We investigated the interactions between PCV2 and S. Choleraesuis in 20 Cesarean-derived, colostrum-deprived (CDCD) pigs randomly assigned to 4 groups (n=5 per group). METHODS AND APPROACH: Pigs in the dual-infected and PCV2 infected groups were inoculated intranasally with PCV2 at 5 weeks of age, and pigs in the dual-infected and S. Choleraesuis-infected groups were inoculated intranasally with S. Choleraesuis at 7 weeks of age. Pigs in the control group served as uninfected controls. RESULTS: After S. Choleraesuis inoculation, severe clinical signs, reduction of weight gain, and severe microscopic lung lesions were observed in dual-infected pigs compared to those in other groups. In addition, the pigs in the dual-infected group shed significantly (P=0.002) higher quantities of S. Choleraesuis in feces 12 days after S. Choleraesuis inoculation, and S. Choleraesuis was recovered from more tissues in this group 14 days after S. Choleraesuis inoculation. CONCLUSIONS: These results indicate that prior PCV2 infection potentiates the severity of clinical signs, lung lesions, and fecal shedding and tissue dissemination of S. Choleraesuis in infected pigs. Therefore, dual infection of pigs with PCV2 and S. Choleraesuis may increase clinical effects of salmonellosis in the field. PMID- 21782359 TI - Recombinant canine parvovirus-like particles express foreign epitopes in silkworm pupae. AB - The capsid structural protein VP2 of canine parvovirus (CPV) can self-assemble into highly organized virus-like particles (VLPs) and retain major immunoreactivity. In this study, different recombinant baculoviruses that expressed varying fusion proteins of the CPV VP2 protein with the T cell determinant and/or the linear virus-neutralizing epitope of rabies virus (RV) were generated. Infection with these baculoviruses changed BmN cell morphology and inhibited their proliferation as well as damaged silkworms and pupae. However, infection with these baculoviruses induced high levels of recombinant protein expression in silkworms and pupae. More importantly, these fusion proteins self-assembled VLPs with properties similar to CPV virions and retained their VP2-specific immunoreactivity, but some retained their RV-specific immunoreactivity. Interestingly, only one fusion protein, T-VP2, maintained its haemagglutination activity. These data indicated that these insertions and replacements in the loop 2 of VP2 did not interfere with the formation of VLP, and silkworms and pupae could act as a low-costing bioreactor for the production of heterologous proteins. Therefore, our findings may provide a new framework for the development of subunit vaccines against RV and CPV. PMID- 21782360 TI - Validation of transcutaneous bilirubin nomogram in identifying neonates not at risk of hyperbilirubinaemia: a prospective, observational, multicenter study. AB - BACKGROUND: Transcutaneous bilirubin (TcB) measurement is widely used as screening for neonatal hyperbilirubinaemia. AIMS: To prospectively validate TcB measurement using hour-specific nomogram in identifying newborn infants not at risk for severe hyperbilirubinaemia. STUDY DESIGN: prospective, observational, multicenter. SUBJECTS: 2167 term and late preterm infants born in 5 neonatal units in the Lazio region of Italy. METHODS: All neonates had simultaneous TcB and total serum bilirubin (TSB) measurements, when jaundice appeared and/or before hospital discharge. TcB and TSB values were plotted on a percentile-based hour-specific transcutaneous nomogram previously developed, to identify the safe percentile able to predict subsequent significant hyperbilirubinaemia defined as serum bilirubin >17 mg/dL or need for phototherapy. RESULTS: Fifty-five babies (2.5%) developed significant hyperbilirubinaemia. The 50th percentile of our nomogram was able to identify all babies who were at risk of significant hyperbilirubinaemia, but with a high false positive rate. Using the 75th percentile, two false negatives reduced sensitivity in the first 48 hours but we were able to detect all babies at risk after the 48th hour of age. CONCLUSIONS: This study demonstrates that the 75th percentile of our TcB nomogram is able to exclude any subsequent severe hyperbilirubinaemia from 48 h of life ahead. PMID- 21782361 TI - Parenting stress in mothers of preterm infants during early infancy. AB - OBJECTIVE: Mothers of preterm infants during the first year of life may experience stresses greater that those found in mothers of term infants. The aim of the study was to determine the levels of parenting stress and psychological well-being in mothers of very preterm babies in comparison to a control group of term mothers. METHODS: One hundred and five mothers who delivered 124 babies at <=30weeks gestation were recruited together with 105 mothers who delivered 120 babies at term. At 4months of age (corrected for prematurity for the preterm babies), the mothers completed the Parenting Stress Index Short Form, the Edinburgh Postnatal Depression Scale (EPDS), the Dyadic Adjustment Scale (DAS) and the Short Temperament Scale for Infants (STSI). The preterm and term groups were compared. RESULTS: Questionnaires were returned from 86 of the preterm mothers and 97 of the term mothers. The mean Total Stress score for the preterm and term groups was 67.0 and 63.79 respectively (P=0.32) with 17% of the preterm and 9% of the term group having high scores (P=0.135). There were no differences of the EPDS and the DAS between the groups. The temperament of the preterm infants was similar to the term infants. For both groups, scores on the EPDS, DAS and the STSI were independent predictors of Total Stress scores on multiple regression analysis. CONCLUSION: Parenting stress in mothers of preterm infants during early infancy does not appear to be greater than that in mothers of infants born at term. For both groups of mothers, depression symptoms, marital satisfaction and infant temperament were independent risk factors for high levels of parenting stress. PMID- 21782362 TI - Seminal quality and neutral alpha-glucosidase activity after sequential electroejaculation of chinchilla (Ch. lanigera). AB - The objectives of this study of seminal quality of chinchilla (Chinchilla lanigera) males were to evaluate (1) the use of neutral alpha-glucosidase (NAG) as a functional epididymal marker in this species, and (2) the effects of repetitive electroejaculation on sperm function and seminal NAG concentration. Semen was obtained by electroejaculation from sexually mature domestic Ch. lanigera males (n=6) once a week for six consecutive weeks, and evaluated to assess seminal volume and NAG activity, and sperm concentration and functional activity (motility, viability, membrane and acrosome integrity). Body weight was determined in all animals before each electroejaculation procedure. NAG activity was detected in all semen samples obtained, reaching a concentration of 55.4+/ 6.8MUU/mL. No significant variations were observed throughout the experimental period in any of the semen quality parameters evaluated. A reduction (P=0.001) in body weight was detected from the third week of experimentation and by the end of the experiments the animals lost a 7.2+/-0.9% of body weight. Overall, results in the present study confirm that NAG activity is detectable in chinchilla seminal plasma and that repetitive electroejaculation is not deleterious, on a short-term basis, to the semen characteristics. PMID- 21782363 TI - Assessing heat-adaptive behaviors among older, urban-dwelling adults. AB - OBJECTIVES: Health studies have shown that the elderly are at a greater risk to extreme heat. The frequency and intensity of summer heat waves will continue to increase as a result of climate change. It is important that we understand the environmental and structural factors that increase heat vulnerability, as well as examine the behaviors used by the elderly to adapt to hot indoor temperatures. STUDY DESIGN: From June 1 to August 31, 2009, residents in 29 homes in Detroit, MI, kept an hourly log of eight heat-adaptive behaviors: opening windows/doors, turning fans or the air conditioner on, changing clothes, taking a shower, going to the basement, the porch/yard, or leaving the house. Percentages of hourly behavior were calculated, overall and stratified by housing type and percent surface imperviousness. The frequency of behavior use, as a result of indoor and outdoor predetermined temperature intervals was compared to a reference temperature range of 21.1-23.8 degrees C. RESULTS: The use of all adaptive behaviors, except going to the porch or yard, was significantly associated with indoor temperature. Non-mechanical adaptations such as changing clothes, taking showers, and going outside or to the basement were rarely used. Residents living in high-rises and highly impervious areas reported a higher use of adaptive behaviors. The odds of leaving the house significantly increased as outdoor temperature increased. CONCLUSIONS: These findings suggest that the full range of heat adaptation measures may be underused by the elderly and public health interventions need to focus on outreach to these populations. PMID- 21782364 TI - Physical activity and 5-year changes in physical performance tests and bone mineral density in postmenopausal women: the Yokogoshi Study. AB - OBJECTIVE: The effect of physical activity on musculoskeletal health in older adults is not completely understood. The aim of this study was to determine the relationship between physical activity and 5-year changes in physical performance tests and bone mineral density (BMD) in postmenopausal women. STUDY DESIGN: The design was a 5-year cohort study. MAIN OUTCOME MEASURES: Subjects were 507 women (55-74 years old) living in a rural community in Japan. Physical activity assessed included housework, farm work, and moderate leisure-time physical activity within the previous week. Measurements at baseline included handgrip strength, walking time (timed "Up & Go" test) and BMD of the femoral neck and vertebrae. Five-year changes in these measures (outcome variables) were compared among groups with different levels of physical activity by analysis of covariance. RESULTS: Women who did not do housework performed worse in changes in handgrip strength (difference=2.22 kg, P=0.0201) and worse in changes in the walking time (difference=0.54 s, P=0.0072) than those who did housework alone. Women who spent at least 9h per week (median=24) doing farm work performed better in changes in handgrip strength (difference=0.28 kg, P=0.0334), but worse in changes in the walking time (difference=0.66 s, P<0.0001) than those who did not do farm work. However, leisure-time activity was not associated with changes in any outcome variable, and none of the physical activities predicted BMD changes. CONCLUSIONS: Engaging in housework and farm work are determinants of physical function in postmenopausal women, which may help them maintain independence in daily living. PMID- 21782365 TI - Complementary and alternative medicine (CAM) for sexual dysfunction and erectile dysfunction in older men and women: an overview of systematic reviews. AB - Older patients with sexual dysfunction (SD) and/or erectile dysfunction (ED) often use complementary and alternative medicine (CAM). The aim of this overview of systematic reviews is to critically evaluate the evidence for or against the effectiveness of CAM. Six electronic databases were searched to identify all relevant systematic reviews (SRs). Their methodological quality was assessed independently by two reviewers using the Oxman score. Four SRs met our inclusion criteria. They evaluated: acupuncture, ginseng, maca and yohimbine. The methodological quality of all of the SRs was good. However, the primary studies were often associated with considerable risk of bias. Cautiously positive conclusions were drawn for yohimbine and ginseng as treatment options for ED. For acupuncture and maca the evidence was insufficient for ED and SD respectively. It is concluded that there is some encouraging evidence but more and better studies are required to establish the value of CAM for SD and ED. PMID- 21782366 TI - Lesions of cortical GABAergic interneurons and acetylcholine neurons in xeroderma pigmentosum group A. AB - Xeroderma pigmentosum (XP) is a rare genetic disorder caused by inherited disturbances in the nucleotide excision repair system; patients with XP groups A (XP-A), B, D, and G were shown to have progressive neurological disturbances. Particularly, XP-A patients, which account for approximately half of Japanese XP patients, show severe neurological disorders, including mental retardation and epilepsy. Herein, we performed an immunohistochemical analysis of the number of GABAergic interneurons (GABAis), including calbindin-D28K, parvalbumin, and calretinin, in the cerebral cortex and acetylcholinergic neurons (AchNs) in the nucleus basalis of Meynert (NM) and in the pedunculopontine tegmental nucleus (PPN) in six autopsy cases of XP-A in order to investigate the relationships between mental dysfunction and GABAis and AchNs. The density and percentages of neurons that were immunoreactive for calbindin-D28K and parvalbumin were significantly reduced in the frontal and temporal cortices in XP-A cases, although the density of neurons that were immunoreactive for MAP2 did not differ from that in controls. Additionally, XP-A cases showed reduced AchNs in both the NM and the PPN. The observed reductions of cortical GABAis and AchNs may be involved in the mental disturbances, the higher occurrence of epilepsy, and/or the abnormalities in rapid eye movement sleep in patients with XP-A. PMID- 21782367 TI - Taxonomic characterisation of ceftazidime-resistant Brevundimonas isolates and description of Brevundimonas faecalis sp. nov. AB - Three ceftazidime-resistant strains isolated from the sewage water of a municipal hospital in Palma de Mallorca, Spain, were analysed phenotypically and genotypically to clarify their taxonomic positions. Sequence determinations and phylogenetic analyses of the 16S rRNA genes indicated that strains CS20.3(T), CS39 and CS41 were affiliated with the species of the alphaproteobacterial genus Brevundimonas, most closely related to B. bullata, B. diminuta, B. naejangsanensis and B. terrae. Additional sequences analyses of the ITS1 region of the rRNA operon and the genes for the housekeeping enzymes DNA gyrase beta subunit and RNA polymerase beta-subunit, genomic DNA-DNA hybridisation similarities, cell fatty acid profiles and physiological and biochemical characterizations supported the recognition of CS20.3(T) (CCUG 58127(T)=CECT 7729(T)) as a distinct and novel species, for which the name Brevundimonas faecalis sp. nov. is proposed. Strains CS39 and CS41 were ascribed to the species B. diminuta. PMID- 21782368 TI - Baclofen ester and carbamate prodrug candidates: a simultaneous chromatographic assay, resolution optimized with DryLab. AB - Baclofen exhibits insufficient CNS-availability when dosed systemically. Hence, prodrug candidates (methyl, ethyl, 1-propyl, 2-propyl and butyl 4-(tert butoxycarbonyl amino)-3-(4-chlorophenyl) butanoate) were synthesized aiming at CNS-levels appropriate for the treatment of spastic disorders. The characterization of some biopharmaceutically highly relevant physicochemical properties (LogP and aqueous solubility) and the evaluation of biophase levels represent one important component of the project. The overall research aim was to generate an HPLC optimized method using DryLab, a simulation software for the optimization of a RP-HPLC method, which was optimized using a simulation software (DryLab), for the simultaneous determination of baclofen and ten synthesized prodrug candidates. The chromatographic resolution predicted and obtained via the simulation is Rs >1.5 for all baclofen derivatives, as well as, with parent baclofen. The method was used to assay the prodrugs and determine their purities, solubility and lipophilicity parameters. The designed analytical method also permits the tracking of the new prodrug candidates' hydrolysis in vitro and in vivo. The determined physicochemical properties indicate for some of the compounds that they might be suitable for CNS-targeting which was exemplified by the detection of significant baclofen levels in rat brain tissues following an i.p. dose of ethyl carbamate (vs. ethyl ester, for which only traces of baclofen were detected). PMID- 21782369 TI - Characterization and relative response factor determination of process related impurity in Naproxen by nuclear magnetic resonance spectroscopy. AB - In the impurity profile of naproxen around 0.6% unknown polar impurity was detected by high performance liquid chromatography (HPLC). The product ion spectrum of the impurity and Naproxen was recorded in LCMS/MS and the fragmentation pattern of the impurity was observed to be similar to the fragmentation pattern of Naproxen with only a difference of two atomic mass units. The high resolution mass spectrum (HRMS) of the impurity displayed a protonated molecular ion at m/z 229.0863, which corresponds to the pseudomolecular formula C(14)H(13)O(3)(+). Based on LC/MS/MS, HRMS, 1D and 2D NMR data, the structure of the impurity was characterized as 2-(6-methoxynaphthalen-2 yl)acrylic acid. The acrylic acid impurity was synthesized in the laboratory and co injected in HPLC to confirm the retention time. RRF of the impurity was determined by (1)H NMR method and also by conventional HPLC slope method and the RRF values are found to be 6.11 and 5.64, respectively. The values are comparable and (1)H NMR method of RRF determination is complimentary and can be effectively used as an alternative method to conventional HPLC method especially in early stages of development when availability of impurity standards is not possible. PMID- 21782370 TI - Free-radical degradation of high-molecular-weight hyaluronan induced by ascorbate plus cupric ions. Testing of bucillamine and its SA981-metabolite as antioxidants. AB - High-molecular-weight hyaluronan (HA) samples were exposed to free-radical chain degradation reactions induced by ascorbate in the presence of Cu(II) ions - the so-called Weissberger's oxidative system. The concentrations of both reactants [ascorbate, Cu(II)] were comparable to those that may occur during an early stage of the acute phase of joint inflammation. The time-dependent changes of the viscosity of the HA solution in the absence of the substance tested were monitored by rotational viscometry. However, when the anti- or pro-oxidative effects of the antioxidants/drugs were investigated, their dose-dependency was also examined. Additionally, the anti-oxidative activities of these substances were screened by the well-established ABTS and DPPH decolorization assays. The actions of the disease-modifying anti-rheumatic drugs, namely bucillamine and D penicillamine, were compared to those of L-cysteine and of SA981, the oxidized metabolite of bucillamine. The results indicated that bucillamine was the most efficient scavenger of hydroxyl- and/or peroxyl-type radicals, even at the lowest drug concentration. In contrast, SA981 demonstrated no scavenging activity against the aforementioned free radicals. D-Penicillamine and L-cysteine showed a dual effect, i.e. a pronounced anti-oxidative effect was, after a given time period, followed by a significant pro-oxidative effect. PMID- 21782371 TI - Development and validation of a LC/MS/MS method for 6-keto PGF1alpha, a metabolite of prostacyclin (PGI2). AB - A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the quantitation of 6-keto PGF(1alpha) in human urine and plasma. Prostacyclin (PGI(2)) is a locally acting prostanoid, which mediates vasorelaxation and inhibition of platelet aggregation. 6-Keto PGF(1alpha) is the most-immediate metabolite of PGI(2). Samples were spiked with an internal standard (6-keto PGF(1alpha)-d(4)), purified by immuno-affinity chromatography and selected reaction monitoring (SRM) was performed. Analytical validation of the 6-keto PGF(1alpha) assay was performed in urine. This included an assessment of assay precision, recovery, stability, sensitivity and linearity. Urinary 6 keto PGF(1alpha) concentrations were also correlated to urinary 2,3-dinor-6-keto PGF(1alpha) (PGIM) concentrations using urine samples collected from 16 healthy volunteers. The mean concentration of 6-keto PGF(1alpha) in urine (mean +/- SD) was 92 +/- 51 pg/ml or 168 +/- 91 pg/mg creatinine. Overall, there was a statistically significant correlation between urinary 6-keto PGF(1alpha) and PGIM (r(2)=0.55, p <= 0.001; slope=2.7; y-intercept=130). However, PGIM was approximately 3-fold more abundant than 6-keto PGF(1alpha) in urine. In addition, 6-keto PGF(1alpha) concentrations were measured in EDTA plasma samples obtained from 7 healthy donors. The mean concentration of 6-keto PGF(1alpha) in plasma was 1.9 +/- 0.8 pg/ml (+/- SD). PMID- 21782372 TI - Lady-in-waiting. PMID- 21782374 TI - Minimum incision endoscopic radical prostatectomy: clinical and oncological outcomes at a single institute. AB - AIMS: The objective of this study was to investigate the clinical and oncological outcomes of prostatectomy patients undergoing minimum incision endoscopic radical prostatectomy (MIE-RP). METHODS: Between September 2005 and May 2010, 541 patients underwent MIE-RP with bilateral lymphadenectomy for clinically localized prostate cancer at Hirosaki University Hospital. The present retrospective study enrolled 375 patients who had not received neoadjuvant or adjuvant therapy. MIE RP was performed through a 6-cm suprapubic midline incision. A 30 degrees laparoscope was conveniently positioned on the head side of the patient for precise observation and monitoring. RESULTS: The median operating time was 119 min, and the estimated blood loss was 900 ml. The most frequent perioperative complication was leakage from the vesicourethral anastomosis (6.7%), and rectal injury occurred in 1.0%. Overall, 31.2% of the patients had a positive surgical margin, including 11.1% with pT2, 52.9% with pT3 and 100% with pT4 diseases. The post-operative median follow-up period was 40.5 months (range, 2-56.5 months). The 5-year PSA-free survival rate was 71.6%. In multivariate analysis, high-risk patients (according to the D'Amico risk criteria), pathological T stage and positive surgical margins were identified as independent predictors of PSA-free survival. The limitations of this study included a retrospective study, relatively short follow-up period and single-institution nature of the study. CONCLUSIONS: MIE-RP is a safe and minimally invasive procedure that may represent a reliable alternative to laparoscopic and robotic-assisted RP. PMID- 21782373 TI - Sentinel lymph node detection in patients with vulvar carcinoma; Feasibility of intra-operative mapping with technetium-99m-labeled nanocolloid. AB - AIMS: Sentinel lymph node (SLN) mapping appears to be feasible in patients with primary vulvar cancer. Previous protocols describe the injection of the technetium-99m-nanocolloid at least 3 h before surgery which involves two invasive procedures for the patient. In this study, we assessed the feasibility, safety, and accuracy of an intra-operative rather than preoperative SLN mapping in patients with primary vulvar cancer. METHODS: Patients with histologically confirmed squamous cell vulvar cancer and clinically FIGO stage Ib disease underwent intra-operative SLN mapping by intradermal injection of the nanocolloid around the tumor. SLN were identified and removed before a complete inguinofemoral lymphnode dissection was performed. Surgical and pathologic data on all patients were prospectively entered into a database. RESULTS: An SLN procedure was performed in 16 patients; 3 patients received unilateral lymphadenectomy, and 13 women underwent surgery on both groins. In all groins but 4 at least one SLN was clearly identified (detection rate 25/29, 86%). A median number of 2 SLN and 4 non-SLN per groin were removed. 3 of 16 patients (19%) had metastatic disease in the lymph nodes. There was no false negative SLN result. CONCLUSION: Intra-operative SLN detection seems feasible in patients with early stage vulvar cancer. More patients need to be enrolled in this ongoing study before this more convenient technique can be considered safe. PMID- 21782376 TI - [Acute valproic acid intoxication: interest of a treatment by extracoporeal elimination combined with L-carnitine]. AB - We present the case of a 24-year-old-female patient, who made an attempt to autolysis with valproic acid, benzodiazepines and neuroleptic. The valproic acid plasma level was very high (1437 MUg/mL), confirming it was a severe intoxication. She presents an acute encephalopathy with prolonged status epilepticus, a lactic metabolic acidosis and hematologic disorders such as bicytopenia. Treatment including L-carnintine and continuous veno-venous haemodialysis (CVVHD) was rapidly introduced to prevent the occurrence of cerebral oedema. The evolution was favourable despite the occurrence of a nosocomial ventilation acute lung injury. The patient had motor sequelae of cranial nerves following status epilepticus extended, which disappeared spontaneously after several days. PMID- 21782375 TI - Arthroscopic anterior cruciate ligament reconstruction with at least 2.5 years' follow-up comparing hamstring tendon autograft and irradiated allograft. AB - PURPOSE: To compare the clinical outcomes of arthroscopic anterior cruciate ligament (ACL) reconstruction with hamstring tendon autograft versus irradiated allograft. METHODS: All irradiated hamstring tendon allografts (gracilis and semitendinosus), which were sterilized with 2.5 Mrad of irradiation before distribution, were obtained from a single certified tissue bank. A total of 78 patients undergoing arthroscopic ACL reconstruction were prospectively randomized consecutively into 1 of 2 groups: autograft and irradiated allograft. The same surgical technique was used in all operations, which were performed by the same senior surgeon. Before surgery and at a mean of 42.2 months of follow-up, patients were evaluated by the same observer according to objective and subjective clinical evaluations. RESULTS: Of the patients, 67 (36 in autograft group and 31 in irradiated allograft group) were available for full evaluation. When the irradiated allograft group was compared with the autograft group at the final follow-up by the Lachman test, anterior drawer test, pivot-shift test, and KT-2000 arthrometer (MEDmetric, San Diego, CA) assessment, statistically significant differences were found (P = .00011, P = .00016, P = .008, and P = .00021, respectively). Most importantly, 86.1% of patients in the autograft group and only 32.3% in the irradiated allograft group had a side-to-side difference of less than 3 mm according to KT-2000 assessment. The rate of laxity (side-to-side difference >5 mm) with irradiated allograft (32.3%) was higher than that with autograft (8.3%). The anterior and rotational stabilities decreased significantly in the irradiated allograft group. According to the overall International Knee Documentation Committee rating, functional and subjective evaluations, and activity level testing, no statistically significant differences were found between the 2 groups. However, patients in the irradiated allograft group had a shorter operative time and a longer duration of postoperative fever. When the patients had a fever, the laboratory examination findings of all patients were almost normal (white blood cell count, normal; erythrocyte sedimentation rate, 8 to 20 mm/h; and C-reactive protein level, 4 to 11 mg/L). CONCLUSIONS: The clinical outcome of ACL reconstruction with hamstring tendon autograft was satisfactory, whereas the difference in instrumented laxity between the 2 groups was significant and the difference in functional test results was not significant. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 21782377 TI - A three-dimensional morphological reconstruction of uterine leiomyoma pseudocapsule vasculature by the Allen-Cahn mathematical model. AB - OBJECTIVE: To allow a morphological evaluation of pseudocapsule vasculature of uterine leiomyomas (ULs). DESIGN: Preliminary prospective study. SETTING: University-affiliated hospitals. PATIENTS: Ten women with symptomatic myomas warranting laparotomic hysterectomies. METHODS: Pseudocapsules of ULs were isolated from the surrounding myometrium, for a digital reconstruction of pseudocapsule vessels and analysis by three-dimensional structure applying the Allen-Cahn mathematical model. The images were converted in a matrix and an appropriate created software elaborated the images. The "nonlocal" Allen-Cahn mathematical model was applied to reduce the image noise and to regulate vessel outlines obtaining a "clean" image. MAIN OUTCOME MEASURES: The geometrical characteristics and morphology of vessel pseudocapsule network of ULs. RESULTS: The disarray in vascular architecture was evident from the absence of vessel parallelism and variable intervascular distances. An abnormal vascular branching of pseudocapsule was indicated by the different density of vessels per space and some vascular walls without interruption indicated vessel tortuosity. There were vascular spaces, which did not communicate with other vessels ("cul-de-sac" vessels). CONCLUSIONS: Pseudocapsule vasculature showed increase of tortuosity, disarray, abnormal branching and the presence of "cul-de-sac" vessels. Three dimensional reconstruction of leiomyoma pseudocapsule vasculature network, despite the benign nature of ULs, showed geometrical characteristics of malignant neoplasm vessels. PMID- 21782378 TI - Letter to the editor regarding the article by Jenderny et al. AB - Jenderny et al. demonstrated that NOV-002 treatment may be protected by cisplatin induced nephrotoxicity. However, Jenderny's article has some errors. These mistakes are checked and corrected. PMID- 21782379 TI - [Tuberculosis unit: case study of 10 years of activity (1999-2009)]. AB - INTRODUCTION: The Pulmonology Service of a Central Hospital in Lisbon created a Unit dedicated to the treatment of tuberculosis (TB). OBJECTIVES: Casuistic analysis and assessment of the predictive factors for in-hospital mortality, over a 10-years period. MATERIAL/METHODS: Retrospective study, from April 1999 to September 2009, through the Statistical Package for the Social Sciences application for binary logistic regression. RESULTS: In a total of 1917 patients, most were male (n=1450; 76%), Caucasian (76.6%), with an average age of 43+/-15.2 years, and 19.8% were immigrants. The retreatments were responsible for 26% of the hospitalizations. The presence of comorbidities was detected in 85.7%, particularly HIV infection (34.7%). The multidrug-resistant (MDR) and the extensively drug resistant (XDR) TB occurred in 6.6% and 6.8%, respectively. The average delay was 28.5+/-54.8 days, with the mortality rate at 8.6%. The mortality risk was more significant amongst men (OR 1.8; 95%CI 1.16-2.90; p<0.01), in patients with HIV infection (OR 3.7; 95%CI 2.47-5.49; p<0.001), and amongst those who presented MDR TB (OR 2.5; 95%CI 1.24-5.15; p<0.01) and XDR TB (OR 5.5; 95%CI 3.14-9.58; p<0.001). CONCLUSIONS: A high percentage of patients presented comorbidities, namely HIV infection. The main factors associated with mortality were HIV infection, XDR TB and MDR TB. PMID- 21782380 TI - Physiotherapy in critically ill patients. AB - Prolonged stay in Intensive Care Unit (ICU) can cause muscle weakness, physical deconditioning, recurrent symptoms, mood alterations and poor quality of life. Physiotherapy is probably the only treatment likely to increase in the short- and long-term care of the patients admitted to these units. Recovery of physical and respiratory functions, coming off mechanical ventilation, prevention of the effects of bed-rest and improvement in the health status are the clinical objectives of a physiotherapy program in medical and surgical areas. To manage these patients, integrated programs dealing with both whole-body physical therapy and pulmonary care are needed. There is still limited scientific evidence to support such a comprehensive approach to all critically ill patients; therefore we need randomised studies with solid clinical short- and long-term outcome measures. PMID- 21782381 TI - Comparison of corneal wetting properties of viscous eye lubricant and balanced salt solution to maintain optical clarity during cataract surgery. AB - PURPOSE: To compare the corneal wetting properties of balanced salt solution (BSS) and a viscous eye lubricant during cataract surgery. SETTING: Vienna Institute for Research in Ocular Surgery, Department of Ophthalmology, Hanusch Hospital, Vienna, Austria. DESIGN: Prospective randomized controlled study. METHODS: This randomized controlled subject- and examiner-masked study comprised patients scheduled for cataract surgery. The patients were randomly assigned to receive either BSS or hydroxypropyl methylcellulose (HPMC) 2% gel (Cornea_Protect). Fluorescein staining, optical clarity during surgery, application frequency, subjective grading of discomfort, and subjective dryness of the eye were assessed. RESULTS: One hundred one eyes of 97 patients (mean age 73.6 years; range 53 to 87 years) were included in the study. Mean grade of fluorescein staining was 9.46 +/- 3.64 (SD) and 9.76 +/- 3.27 (SD) in the BSS group and the HPMC 2% group, respectively (P=.67). Median grade of optical clarity during surgery was 2.0 in the BSS group and 1.0 in the HPMC 2% group, a statistically significant difference (P=.03). Median application frequency of BSS was 10 times higher than median application frequency of 1 time for HPMC 2%, a statistically significant difference (P<.001). CONCLUSIONS: Hydroxypropyl methylcellulose 2% provided significantly better optical clarity than BSS during cataract surgery. Because frequent irrigation is not needed and HPMC 2% provides a better view for the surgeon, the use of HPMC 2% results in increased comfort for the patient, especially under topical anaesthesia, and in a simpler and possibly safer surgical procedure. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosure is found in the footnotes. PMID- 21782382 TI - Prevention, diagnosis, and management of acute postoperative bacterial endophthalmitis. AB - This distillation of the peer-reviewed scientific literature on infection after cataract surgery summarizes background material on epidemiology, etiology, and pathogenesis, describes the roles of surgical technique and antibiotic prophylaxis in prevention, and discusses diagnostic and therapeutic interventions in cases of suspected endophthalmitis. PMID- 21782383 TI - Long-term corneal wavefront aberration variations after photorefractive keratectomy for myopia and myopic astigmatism. AB - PURPOSE: To analyze the higher-order corneal wavefront aberration during an 8 year follow-up after photorefractive keratectomy (PRK). SETTING: IRCCS Fondazione G.B. Bietti, Rome, Italy. DESIGN: Case series. METHODS: Patients having PRK using the Technolas 217C excimer laser platform were divided into 3 groups according to the preoperative refraction as follows: low myopia, high myopia, and astigmatism. The preoperative and 1-, 4-, 6-, and 8-year postoperative root mean square (RMS) values of coma, spherical aberration, and total higher-order aberrations (HOAs) were calculated with 3.5 mm and 6.0 mm simulated pupils. The mean preoperative and postoperative higher-order corneal wavefront aberration maps, point-spread functions, and radial modulation transfer functions (MTFs) were represented to describe the impact of PRK on the optical quality of the anterior cornea. RESULTS: The study enrolled 33 patients (66 eyes). Corneal spherical aberration was statistically significantly higher after PRK for simple myopia with 3.5 mm and 6.0 mm pupils (P<.05). The postoperative increase in coma was statistically significant in the high-myopia group with both pupil sizes (P<.05). Total RMS HOAs increased postoperatively with a 6.0 mm pupil in all groups (P<.05). The mean radial MTF was almost stable in all groups between preoperatively and postoperatively. CONCLUSIONS: Higher-order corneal wavefront aberrations stabilized 1 year after PRK to treat myopia or myopic astigmatism. The effect of induced corneal HOAs tended to increase after correction of high myopia with large pupils, although without degrading the image optical quality of the cornea over the long term. PMID- 21782384 TI - Incidence and long-term outcomes of toxic anterior segment syndrome at Aravind Eye Hospital. AB - PURPOSE: To determine the incidence and long-term outcomes of toxic anterior segment syndrome (TASS) at a single institution. SETTING: Aravind Eye Hospital, Pondicherry, India. DESIGN: Case series. METHODS: The records of all eyes developing TASS during a 1-year period after cataract surgery were retrospectively reviewed. Clinical outcomes, including corrected distance visual acuity (CDVA), intraocular pressure, and complications, were recorded at the 1 month and 6-month follow-up visits. RESULTS: Toxic anterior segment syndrome occurred in 60 eyes (0.22%) in 26 408 consecutive cataract surgeries. Although there were 2 identifiable clusters of TASS, 52% of cases were sporadic. The mean duration until resolution of severe iridocyclitis was 6.11 days +/- 2.19 (SD). Of the 24 eyes (40%) with a follow-up of at least 6 months (mean 11.24 +/- 2.3 months), 6 (24%) had atrophic iris changes, 1 (4%) had cystoid macular edema, 3 (12.5%) developed anterior capsule phimosis, and 4 (16%) had posterior capsule opacification (PCO). There was no statistically significant difference between the mean CDVA at 1 month (0.08 +/- 0.06 logMAR) (n = 60) and the mean final CDVA (0.11 +/- 0.1 logMAR, minimum 6 months; n = 24) (P=.42). CONCLUSIONS: Although it is impossible to generalize for all etiologies, this study found that TASS is uncommon but not rare, responded to intensive topical antiinflammatory medication, and was usually associated with a good visual outcome. Anterior capsule contraction and PCO were the principal delayed-onset complications beyond those present 1 month postoperatively. PMID- 21782385 TI - Attentional control as a moderator of the relationship between posttraumatic stress symptoms and attentional threat bias. AB - Attentional threat bias (ATB) has been suggested as one factor leading to maintenance and exacerbation of posttraumatic stress symptoms (PTSS). In the present study, attentional processes (i.e., facilitated engagement, difficulty disengaging) underlying the association between ATB and PTSS were examined. Additionally, attentional control (AC) was examined as a moderator of this relationship. Participants (N=97) completed a dot-probe task with two levels of stimulus-onset asynchrony (SOA: 150 and 500ms). Higher PTSS were associated with ATB when SOA was longer (i.e., 500ms), suggesting difficulty disengaging from threat stimuli. AC moderated the relationship between PTSS and ATB when SOA was shorter (i.e., 150ms), with participants high in PTSS and high in AC having disengaged and shifted attention from threat stimuli using top-down AC when the emotional valence of threat stimuli was less salient (i.e., shorter presentation duration). Findings implicate AC as a buffering mechanism against prolonged attentional engagement with threat-related stimuli among those with high PTSS. Current PTSD interventions may benefit from incorporating attention-based components. PMID- 21782386 TI - Aerodynamic evaluation of the postthyroidectomy voice. AB - OBJECTIVES/HYPOTHESES: Changes in vocal function before and after thyroidectomy were examined using aerodynamic and related assessments. Laryngeal airway resistance (R(law)) and phonation threshold pressure (PTP) were hypothesized to be sensitive to changes in laryngeal function that may occur after thyroidectomy separate from changes that may occur from endotracheal intubation alone. STUDY DESIGN: Prospective longitudinal clinical trial with comparison group. METHODS: Eighty patients were evaluated preoperatively, and 2 weeks and 3 months postoperatively to assess voice outcomes after thyroidectomy. In addition, 16 patients who underwent a nonneck operation were tested as a control group. Maximum phonation time (MPT), mean airflow, R(law), and PTP were determined at two vocal fundamental frequency (F0) levels (30% and 80% of the F0 range). RESULTS: No systematic differences were detected for MPT, mean airflow, or R(law) as a short-term or intermediate-term outcome of either surgical group. PTP decreased significantly over time for both groups of participants and at both F0 levels. F0 range decreased significantly at the short-term postsurgical assessment and covaried with the PTP results, thereby explaining some of the variability in the PTP data. CONCLUSIONS: Aerodynamic assessment did not reveal systematic changes in vocal function associated with thyroidectomy, although PTP decreased postoperatively for both surgical groups. This may be attributable in part to a learning effect or to postoperative reductions in F0 range. PMID- 21782387 TI - Mathematical analysis of the accordion grating illusion: a differential geometry approach to introduce the 3D aperture problem. AB - When an observer moves towards a square-wave grating display, a non-rigid distortion of the pattern occurs in which the stripes bulge and expand perpendicularly to their orientation; these effects reverse when the observer moves away. Such distortions present a new problem beyond the classical aperture problem faced by visual motion detectors, one we describe as a 3D aperture problem as it incorporates depth signals. We applied differential geometry to obtain a closed form solution to characterize the fluid distortion of the stripes. Our solution replicates the perceptual distortions and enabled us to design a nulling experiment to distinguish our 3D aperture solution from other candidate mechanisms (see Gori et al. (in this issue)). We suggest that our approach may generalize to other motion illusions visible in 2D displays. PMID- 21782388 TI - Effects of orthognathic surgery on oropharyngeal airway: a meta-analysis. AB - Oropharyngeal changes caused by orthognathic surgery have been a concern because the sleep quality of patients may be enhanced or worsened by these changes. The purpose of this meta-analysis was to identify, review and compare scientific literature about changes in airway in adult patients undergoing orthognathic surgery to correct anteroposterior osseous discrepancies. An electronic search of four databases was carried out up to July 2010, with supplemental hand searching of the references of the retrieved articles. Quality assessment of the included articles was carried out. Data were extracted and a meta-analysis was performed. Heterogeneity was assessed amongst the studies and results were presented in forest plots. 49 studies met the inclusion criteria. Only studies with moderate or high methodological soundness were included in the review. Moderate evidence was found to support a significant decrease in the oropharyngeal airway in mandibular setback surgery, a milder decrease in bimaxillary surgery to correct Class III and an increase in maxillomandibular advancement surgery. Evidence is lacking on airway volume changes after orthognathic surgery. PMID- 21782389 TI - Platelet rich plasma for the prevention of osteoradionecrosis. A double blinded randomized cross over controlled trial. AB - Osteoradionecrosis of the jaws is a complication of radiotherapy and controversy remains about the management of teeth in the field of radiotherapy. Platelet rich plasma has been advocated in multiple surgical sites, both bone and soft tissue, to promote healing and reduce complications. A randomized double blinded controlled trial was performed on patients receiving bilateral radiotherapy that affected the mandible who required pre treatment dental extractions. One side received platelet rich plasma and the other acted as a control. Twenty-two patients were recruited over 12 months and over a 5-year period following treatment three developed osteoradionecrosis (14%). Platelet rich plasma failed to show any benefit in the prevention of osteoradionecrosis. Nor was there any benefit in pain scores or mucosal healing on sides that were treated with platelet rich plasma. Platelet rich plasma fails to show a benefit in the prevention of osteoradionecrosis. The rate of osteoradionecrosis is high compared to other published series and the prophylactic removal of molar teeth should be questioned as a preventative measure. PMID- 21782390 TI - Associations between spontaneous movement abnormalities and psychotic-like experiences in the general population. AB - An accumulating body of literature supports the notion that psychotic-like experiences (PLEs) may occur as a continuous phenotype. However, researchers are still working to determine if these events accompany an underlying continuum of neurobiological vulnerability as well. Within this context, it is notable that spontaneous dyskinetic movements are linked to specific pathogenic factors underlying schizophrenia, but to date there has been little research directed towards determining whether these events are associated with PLEs. In this study, 119 individuals were assessed for PLEs and administered with a sensitive instrumental test of upper extremity dyskinesia. Present findings suggest a relationship between subtle dyskinesia and PLEs in the general population, and provide a new perspective of the psychosis continuum by indicating that basal ganglia pathology may also underlie PLEs at the non-clinical end of this spectrum. PMID- 21782391 TI - YKL-40 (chitinase 3-like-1) as a biomarker for psoriasis vulgaris and pustular psoriasis. PMID- 21782392 TI - Posaconazole for the treatment of mucormycosis. AB - Posaconazole (PCZ) is an orally administered, extended-spectrum triazole antifungal agent with activity against the Mucorales. This article describes the clinical and laboratory data supporting its use against this rare group of pathogens. To date, PCZ has been mostly used for salvage therapy and at present there is no strong published clinical evidence to support its role as a single agent in the treatment of mucormycosis. Further studies are required to explore its role as a single agent and in combination therapy for the management of these infections. PMID- 21782393 TI - Antimicrobial activity of cathelicidin peptides against Burkholderia pseudomallei, the causative agent of melioidosis. PMID- 21782394 TI - Intra-abdominal infections: model of antibiotic stewardship in an era with limited antimicrobial options. PMID- 21782395 TI - Aberrant visual circuitry associated with normal spatial match-to-sample accuracy in schizophrenia. AB - A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging (fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions. PMID- 21782396 TI - Technical aspects of fast magic-angle turning NMR for dilute spin-1/2 nuclei with broad spectra. AB - For obtaining sideband-free spectra of high-Z spin-1/2 nuclei with large (>1000 ppm) chemical-shift anisotropies and broad isotropic-shift dispersion, we recently identified Gan's modified five-pulse magic-angle turning (MAT) experiment as the best available broadband pulse sequence, and adapted it to fast magic-angle spinning. Here, we discuss technical aspects such as pulse timings that compensate for off-resonance effects and are suitable for large CSAs over a range of 1.8gammaB(1); methods to minimize the duration of z-periods by cyclic decrementation; shearing without digitization artifacts, by sharing between channels (points); and maximizing the sensitivity by echo-matched full-Gaussian filtering. The method is demonstrated on a model sample of mixed amino acids and its large bandwidth is highlighted by comparison with the multiple-pi-pulse PASS technique. Applications to various tellurides are shown; these include GeTe, Sb(2)Te(3) and Ag(0.53)Pb(18)Sb(1.2)Te(20), with spectra spanning up to 190 kHz, at 22 kHz MAS. We have also determined the (125)Te chemical shift anisotropies from the intensities of the spinning sidebands resolved by isotropic-shift separation. PMID- 21782397 TI - Reusable chromium-coated quartz crystal microbalance for immunosensing. AB - The application of oxidized chromium as a reusable platform for the development of immunosensors is presented. Chromium films were deposited on quartz crystal microbalances to study the affinity interaction between rabbit immunoglobulin G (IgG) and goat anti-rabbit IgG. A covalent approach, based on the silane chemistry, was followed for the grafting of either the rabbit IgG or the anti rabbit IgG on the silane-modified chromium surface. Next the differences between the deposition of rabbit IgG on immobilized anti-rabbit IgG and the deposition of anti-rabbit IgG on immobilized rabbit IgG were investigated. The chromium layer could be reused between experiments, after the proper removal of the organic layers with piranha etch, obtaining a high repeatability in the steps of the functionalization protocol. PMID- 21782398 TI - Mapping use of radiotherapy for patients with non-small cell lung cancer in the Netherlands between 1997 and 2008. AB - AIM: After the publication of several reports that the utilisation rate of radiotherapy for patients with non-small cell lung cancer (NSCLC) varies for both medical and non-medical reasons, the utilisation of radiotherapy was studied in four regions in the Netherlands. MATERIALS AND METHODS: Data from 1997-2008 were collected from the population-based cancer registries of four comprehensive cancer centres ('regions'), which represent about half of the Dutch population, resulting in 24 185 non-metastatic patients with NSCLC. Treatment had to be started or planned within 6 months of diagnosis. We evaluated the utilisation of radiotherapy according to age, gender and period for each region. RESULTS: The utilisation of radiotherapy alone decreased over time (from 35 to 19%), whereas the utilisation of radiotherapy in combination with chemotherapy increased (from 5 to 19%). The total utilisation rate remained rather stable at about 40%. The differences between the four regions remained in general no more than 15%. Elderly patients with stage I and II disease had increased odds of receiving radiotherapy (>=75 versus <50 years: odds ratio 2.6, 95% confidence interval 2.0 3.3, whereas this was the opposite for patients with stage III disease: odds ratio 0.5, 95% confidence interval 0.4-0.6). For 17-24% of all patients, especially the elderly, best supportive care was applied. CONCLUSIONS: In the Netherlands, with good accessibility to medical care and well-implemented national guidelines, variation between the four regions is limited for the treatment of non-metastatic NSCLC with radiotherapy. PMID- 21782399 TI - High-performance GPU-based rendering for real-time, rigid 2D/3D-image registration and motion prediction in radiation oncology. AB - A common problem in image-guided radiation therapy (IGRT) of lung cancer as well as other malignant diseases is the compensation of periodic and aperiodic motion during dose delivery. Modern systems for image-guided radiation oncology allow for the acquisition of cone-beam computed tomography data in the treatment room as well as the acquisition of planar radiographs during the treatment. A mid-term research goal is the compensation of tumor target volume motion by 2D/3D Registration. In 2D/3D registration, spatial information on organ location is derived by an iterative comparison of perspective volume renderings, so-called digitally rendered radiographs (DRR) from computed tomography volume data, and planar reference x-rays. Currently, this rendering process is very time consuming, and real-time registration, which should at least provide data on organ position in less than a second, has not come into existence. We present two GPU-based rendering algorithms which generate a DRR of 512*512 pixels size from a CT dataset of 53 MB size at a pace of almost 100 Hz. This rendering rate is feasible by applying a number of algorithmic simplifications which range from alternative volume-driven rendering approaches - namely so-called wobbled splatting - to sub-sampling of the DRR-image by means of specialized raycasting techniques. Furthermore, general purpose graphics processing unit (GPGPU) programming paradigms were consequently utilized. Rendering quality and performance as well as the influence on the quality and performance of the overall registration process were measured and analyzed in detail. The results show that both methods are competitive and pave the way for fast motion compensation by rigid and possibly even non-rigid 2D/3D registration and, beyond that, adaptive filtering of motion models in IGRT. PMID- 21782400 TI - Spatial resolution of proton tomography: Methods, initial phase space and object thickness. AB - PURPOSE: Proton radiography and tomography was investigated since the early 1970s because of its low radiation dose, high density resolution and ability to image directly proton stopping power. However, spatial resolution is still a limiting factor and as a consequence experimental methods and image reconstruction should be optimized to improve position resolution. METHODS: Spatial resolution of proton radiography and tomography is given by multiple Coloumb scattering (MCS) of the protons in the patient. In this paper we employ an improved MCS model to study the impact of various proton tomographic set-ups on the spatial resolution, such as different combinations of entrance and exit coordinate and angle measurements, respectively, initial particle energy and angular confusion of the incident proton field. RESULTS: It was found that best spatial resolution is obtained by measuring in addition to the entrance and exit coordinates also the entrance and exit angles. However, by applying partial backprojection and by using a perfect proton fan beam a sufficient spatial resolution can be achieved with less experimental complexity (measuring only exit angles). It was also shown that it is essential to use the most probable proton trajectory to improve spatial resolution. A simple straight line connection for image reconstruction results in a spatial resolution which is not clinically sufficient. The percentage deterioration of spatial resolution due to the angular confusion of the incident proton field is less than the phase space in mrad. A clinically realistic proton beam with 10 mrad angular confusion results in a less than 10% loss of spatial resolution. CONCLUSIONS: Clinically sufficient spatial resolution can be either achieved with a full measurement of entrance and exit coordinates and angles, but also by using a fan beam with small angular confusion and an exit angle measurement. It is necessary to use the most probable proton path for image reconstruction. A simple straight line connection is in general not sufficient. Increasing proton energy improves spatial resolution of an object of constant size. This should be considered in the design of proton therapy facilities. PMID- 21782401 TI - Vitamin E differentially affects short term exercise induced changes in oxidative stress, lipids, and inflammatory markers. AB - BACKGROUND AND AIM: Physical activity or exercise is a proven deterrent of cardiovascular diseases. The purpose of this study was to examine whether vitamin E supplementation interfere with the potential benefits of exercise. METHODS AND RESULTS: A total of 455 apparently healthy men and women were recruited, for a 2 month aerobic/cardiovascular exercise program. Subjects were randomly assigned for soft gel vitamin E or placebo (800 IU), and required to give blood at 0, 2, 4 and 8 weeks of exercise. Levels of lipid and markers of oxidative stress and inflammation were measured along with the VO2 and duration time spent on treadmill. Statistical analysis did not show significant changes in the levels of lipids and markers of oxidative stress and inflammation. Favorable trends among both of the randomization groups were observed in lipids, and some of the oxidative stress and inflammatory markers. This study also established several interesting correlations between VO2, and lipids on one hand and markers of oxidation and inflammation on the other hand. Reduction in LDL levels positively associated with increased levels of MCP-1 (P < 0.008) among placebo group, and also decreased hCRP levels strongly correlated with the increases in VO2 (P < 0.0004) among the placebo, and vitamin E subjects (P < 0.01). CONCLUSIONS: Exercise training induces oxidative stress might be instrumental in favorable lipid reduction and markers of oxidative stress and inflammation. However interestingly, vitamin E didn't demonstrate favorable effects on the level of oxidative stress and inflammation associated with exercise. PMID- 21782402 TI - Prevalence of low LDL-cholesterol levels and elevated high-sensitivity C-reactive protein levels in apparently healthy Korean adults. AB - BACKGROUND AND AIMS: The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality in patients with elevated C reactive protein (CRP) and low LDL-cholesterol (LDL-C) levels treated with statins. The aims of this study were to determine the proportion of "JUPITER eligible" Korean adults and to describe their characteristics. METHODS AND RESULTS: As many as 15,154 subjects with serum LDL-C levels <130 mg/dL were selected among 28,851 middle-aged participants (men >= 50 years, women >= 60 years) who participated in a routine health check-up program. Among the participants with LDL-C less than 130 mg/dL, only 15% had CRP levels >=2.0 mg/L (7.9% of original participants). Subjects were divided into four groups according to CRP levels (<0.5, >=0.5 - <1.0, >=1.0 - <2.0, and >=2.0 mg/L). Mean HDL-C and apolipoprotein A1 levels decreased significantly as the mean CRP values increased. The insulin and homeostasis model of insulin resistance was significantly different according to CRP quartile. The number of subjects with metabolic syndrome and its components increased significantly as the mean CRP values increased. CONCLUSION: In this Asian population, few individuals with low LDL-C levels had CRP levels >=2.0 mg/L. Elevated CRP levels were associated with components of atherogenic dyslipidemia and insulin resistance. Additional clinical trials should be designed and performed in different ethnic groups, as different CRP cut-off levels may be required in different ethnic groups. PMID- 21782403 TI - Plasma fatty acids profile and estimated elongase and desaturases activities in Tunisian patients with the metabolic syndrome. AB - This study aimed to determine plasma fatty acids pattern and to estimate desaturases activities in Tunisian subjects with metabolic syndrome (MetS). A total of 1975 adults were randomly selected from the Great Tunis region (Tunisia). MetS was defined according to the International Diabetes Federation criteria. Saturated and monounsaturated fatty acids levels and delta 9 desaturase activity were increased, but polyunsaturated fatty acids (PUFA) levels and delta 5 desaturase activity were decreased in patients with MetS. Using multivariate analysis, MetS was found inversely associated with PUFA; compared to first quartile, multi-adjusted odd ratios (95% confidence interval) of MetS were 0.80 (0.54-1.17), 0.47 (0.27-0.81) and 0.32 (0.15-0.68) for second, third and fourth quartiles of PUFA, respectively. Altered fatty acids pattern in MetS is likely related to both dietary and metabolic changes. PMID- 21782404 TI - Immune senescence. Editorial overview. PMID- 21782405 TI - Using the production possibility frontier to analyze operating room efficiency. PMID- 21782406 TI - Quercetin accumulates in nuclear structures and triggers specific gene expression in epithelial cells. AB - Quercetin is a flavonol modifying a number of cell processes in different cell lines. Here, we present evidence that nonconjugated quercetin enters cells possibly via organic anion transporter polypeptides and quickly accumulates in the nucleus where it concentrates at distinct foci. Furthermore, it induces major transcriptional events with a high number of transcripts being modified over time and about 2200 transcripts being continuously influenced by the agent. The latter transcripts are related to cell cycle and adhesion, xenobiotic metabolism, immune related factors and transcription. In addition, quercetin up-regulates the expression of estrogen receptors alpha and beta. The overall outcome on cell fate is reflected by an inhibition of cell proliferation, cell cycle arrest in the G1 phase and reduction of the cells' migratory potential due to actin cytoskeleton disorganization. Finally, we report that the flavonol modifies the transcription and/or activity of numerous transcription factors. In conclusion, our data support the idea that quercetin may actively accumulate in discrete cell structures and exert more than just antioxidant actions on epithelial cells by regulating mechanisms related to gene transcription. PMID- 21782407 TI - Marriage, mortgage, motherhood: what longitudinal studies can tell us about gender, drug 'careers' and the normalisation of adult 'recreational' drug use. AB - Through a consideration of quantitative and qualitative data obtained from young women aged 18-28 in the later years of the North West England Longitudinal Study, this paper explores how women's drug careers develop, progressing the authors' normalisation thesis of 'recreational' drug use from adolescence into adulthood. Longitudinal studies are here compared with repeated cross-sectional surveys more usually favoured and funded by governments. The authors argue that firstly, in relation to methodology, longitudinal studies provide a unique opportunity to elucidate how drug careers develop across the life course and to chart the various impacts of life events and transitions on these careers and vice versa. Secondly, through this exploration of gender differences in drug careers and life transitions, we develop an age and gender-sensitive understanding of how recreational drug use fits into women's adult lives. The paper concludes that the challenge for policy makers is how to address adult women's 'normalised' recreational drug use, in the face of a regime focused on educational provision aimed at adolescent prevention; public health information designed for teenagers; and treatment resources focused on predominantly male and non parenting problem drug users, and the links between addiction and acquisitive crime. PMID- 21782408 TI - Environmental friendly automated line for recovering the cabinet of waste refrigerator. AB - A large amount of hazardous trichloromonofluoromethane (CFC-11) is contained in the polyurethane (PUR) foam of refrigerator cabinet. How to recover the cabinet of waste refrigerator with environmental awareness has been the pressing problem in the treatment of waste refrigerator. The published literature of waste refrigerator cabinets recovering mainly focuses on policy making and conceptual design. Little information relates to the production line of waste refrigerator cabinet recovering and its detailed operation, which is the urgent needed literature. In this paper, an environmental friendly production line for recovering the cabinet of waste refrigerators was reported for helping enterprise or government to construct line to recover the obsolete refrigerators. It included closed shearing process, activated carbon fiber absorption (ACFA) process, air current separation, and magnetic/eddy current separation. The optimized operating parameters of every process were obtained from the experiments. Then, experiment of recovering 50 waste refrigerator cabinets by the production line was performed in factory. Mass balances of the recovered materials were carried out. The result shown the recovery rate of waste refrigerator cabinet could reach 97.6%. Finally, comparison between the production line and other recovery technologies was made. The results indicated that the proposed line provided environment-friendly recovery of waste refrigerator cabinets while achieving low cost of production. PMID- 21782409 TI - A membrane protein based biosensor: use of a phosphate--H+ symporter membrane protein (Pho84) in the sensing of phosphate ions. AB - A label free biosensor for direct detection of inorganic phosphate based on potential-step capacitance measurements has been developed. The high-affinity Pho84 plasma membrane phosphate/proton symporter of Saccharomyces cerevisiae was used as a sensing element. Heterologously expressed and purified Pho84 protein was immobilized on a self-assembled monolayer (SAM) on a capacitance electrode. Changes in capacitance were recorded upon exposure to phosphate compared to the control substance, phosphate analogue methylphosphonate. Hence, even without the explicit use of lipid membranes, the Pho84 membrane protein could retain its capacity of selective substrate binding, with a phosphate detection limit in the range of the apparent in vivo K(m). A linear increase in capacitance was monitored in the phosphate concentration range of 5-25 MUM. The analytical response of the capacitive biosensor is in agreement with that the transporter undergoes significant conformational changes upon exposure to inorganic phosphate, while exposure to the analogue only causes minor responses. PMID- 21782411 TI - TiO2 nanoparticle assisted mass spectrometry as biosensor of Staphylococcus aureus, key pathogen in nosocomial infections from air, skin surface and human nasal passage. AB - For the first time, we have demonstrated the use of mass spectrometry as a biosensor for detecting a clinically important bacterium: Staphylococcus aureus in air, nasal passage and skin samples using culture-free, rapid, direct analysis via TiO(2) nanoparticles (NPs) assisted MALDI-MS. When this bacterium is predominating, the nasal passage of an individual is observed to lead to wound infections especially when the individual has a surgery or some wounds. This study indicates that even at very low concentrations of an individual bacterium can be directly detected from a mixture of bacteria using the MALDI-MS analysis without the requirement of any culturing steps or any other sample pretreatment techniques. The current approach is extremely simple, rapid, straightforward and sensitive which could be widely applied for the detection of this deadly pathogen in clinical as well as environmental samples. PMID- 21782410 TI - Ultrasensitive electrochemical immunosensor employing glucose oxidase catalyzed deposition of gold nanoparticles for signal amplification. AB - This paper describes a novel enzymatic amplification strategy for ultrasensitive electrochemical immunosensing. This approach utilizes glucose oxidase for the enzymatic deposition of gold nanoparticles onto an indium tin oxide (ITO) electrode surface using a novel gold developer solution consisting of 20 mM of glucose, 20 mM of NaSCN, 0.5 M of p-benzoquinone (PBQ) and 1 mM of AuCl(4)(-) dissolved in 0.1 M of pH 7.5 phosphate buffer solution. The amount of gold deposited was quantified electrochemically by monitoring the reduction of gold oxide in an aqueous solution of 0.5 M of H(2)SO(4), which was correlated to the amount of antigens in the solution. The effectiveness of this strategy was demonstrated experimentally through the construction of an immunosensor for the detection of mouse IgG using a sandwich immunoassay in a linear dynamic range of 5 pg/ml to 50 ng/ml. A good mean apparent recovery in the range of 88-102% was obtained over the entire linear dynamic range of the sensor response in the serum samples. This suggested that the immunosensor would be useful for the testing of proteins in real clinical samples. PMID- 21782412 TI - A valuable visual colorimetric and electrochemical biosensor for porphyrin. AB - Porphyrin is able to specifically combine with phosphorus, thus a novel bifunctional sensing platform for determination of porphyrin by visual colorimetry and electrochemistry was demonstrated. A pretreated gold sheet (or electrode) with 2-mercatpoethanol (2-ME) was chemically modified by POCl(3) to obtain the surface phosphate active sites. The different stages of modified electrode were characterized by electrochemical impedance spectroscopy (EIS). The 1:1 cationic sitting-atop (SAT) complex P(V)-porphyrin was formed due to the high affinity of the modified gold sheet (or electrode) towards the porphyrin, resulting in electron transfer resistance increase of the electrode surface. Meanwhile, a dramatic color changing from burgundy to dark green of porphyrin solution was observed with the naked-eye within 3s. What's more, this was reflected by the notable change of the Soret band of porphyrin when using UV-vis. Two sensing systems provide different sensitivity for porphyrin analysis. With visual colorimetry, porphyrin can be detected at a level of 1.0*10(-6) M, whereas the detection limit of porphyrin is 3.0*10(-8) M using the EIS method. The practical application of the sensor to determination of pheophytin which was obtained from fresh spinach leaves has been accomplished. The results demonstrate the facility and effectivity of our introduced bifunctional biosensor for quantitative analysis of porphyrin. PMID- 21782413 TI - Magneto-controlled electrochemical immunosensor for direct detection of squamous cell carcinoma antigen by using serum as supporting electrolyte. AB - A new magneto-controlled microfluidic device for direct electrochemical determination of squamous cell carcinoma antigen (SCC-Ag) in serum was designed by using anti-SCC antibody (SCC-Ab)-functionalized magnetic mesoporous nanogold/thionine/NiCo(2)O(4) hybrid nanostructures as immunosensing probes (P(1) Ab) and horseradish peroxidase-SCC-Ab conjugates-labeled nanogold/graphene nanosheets as signal tags (P(2)-Ab). In the presence of the analyte SCC-Ag, the sandwich immunocomplex was formed between the immunosensing probes and the signal tags. With the aid of an external magnet, the formed immunocomplex was attached to the microfluidic device. The assay was implemented in newborn calf serum (NBCS) containing 2.5 mM H(2)O(2) based on the labeled peroxidase on the P(2)-Ab toward the catalytic reduction of H(2)O(2). Under optimal conditions, the increase in the current was proportional to the concentration of SCC-Ag from 2.5 pg/mL to 15 ng/mL. The detection limit (LOD) was 1.0 pg/mL SCC-Ag at 3s(B). The electrochemical immunoassay displayed an acceptable precision, selectivity and stability. Clinical serum specimens were assayed with the method, and the results were in acceptable agreement with those obtained from the referenced electrochemiluminescent method. Importantly, the method can be suitable for on line use in the mass production of miniaturized lab-on-a-chip devices and open a new opportunity for protein diagnostics and biosecurity. PMID- 21782414 TI - An electrochemical alkaline phosphatase biosensor fabricated with two DNA probes coupled with lambda exonuclease. AB - In this work we have developed a novel electrochemical biosensor for the detection of alkaline phosphatase (AP) by the use of two complementary DNA probes (DNA 1 and DNA 2) coupled with lambda exonuclease (lambda exo). Firstly, the 5' phosphoryl end of DNA 1 is dephosphorylated by AP. Then DNA 1 hybridizes with DNA 2, previously modified on a gold electrode surface. In this double-strand DNA, DNA 2 strand will be promptly cleaved by lambda exo with its phosphoryl at the 5' end. After the DNA 2 strand is completely digested, DNA 1 will be released from the double strands and then hybridizes with another DNA 2 strand on the electrode surface, thus the cycle of the release of DNA 1 and the digestion of DNA 2 continues. Since the DNA probes may absorb hexaammineruthenium(III) chloride, the electrochemical species, and the removal of the DNA 2 strand from the electrode surface will result in the decrease of the detected electrochemical signal, which is initially activated by AP, an electrochemical biosensor to assay the activity of AP is proposed in this work. This method may have a linear detection range from 1 to 20 unit/mL with a detection limit of 0.1 unit/mL, and the detection of the enzymatic activity in complex biological fluids can also be realized. PMID- 21782415 TI - Towards an integrated view of HCN channel role in epilepsy. AB - Epilepsy is the third most common brain disorder and affects millions of people. Epilepsy is characterized by the occurrence of spontaneous seizures, that is, bursts of synchronous firing of large populations of neurons. These are believed to result from abnormal regulation of neuronal excitability that favors hypersynchrony. Among the intrinsic conductances that govern neuronal excitability, the hyperpolarization-activated current (I(h)) plays complex and important roles in the fine-tuning of both cellular and network activity. Not surprisingly, dysregulation of I(h) and/or of its conducting ion-channels (HCN) has been strongly implicated in various experimental models of epilepsy, as well as in human epilepsy. Here we provide an overview of recent findings on the distinct physiological roles played by I(h) in specific contexts, and the cellular mechanisms that underlie these functions, including the subunit make-up of the channels. We further discuss current knowledge of dysregulation of I(h) and HCN channels in epilepsy in light of the multifaceted functions of I(h) in the brain. PMID- 21782416 TI - Nanobody stabilization of G protein-coupled receptor conformational states. AB - Remarkable progress has been made in the field of G protein-coupled receptor (GPCR) structural biology during the past four years. Several obstacles to generating diffraction quality crystals of GPCRs have been overcome by combining innovative methods ranging from protein engineering to lipid-based screens and microdiffraction technology. The initial GPCR structures represent energetically stable inactive-state conformations. However, GPCRs signal through different G protein isoforms or G protein-independent effectors upon ligand binding suggesting the existence of multiple ligand-specific active states. These active state conformations are unstable in the absence of specific cytosolic signaling partners representing new challenges for structural biology. Camelid single chain antibody fragments (nanobodies) show promise for stabilizing active GPCR conformations and as chaperones for crystallogenesis. PMID- 21782417 TI - The power of correlative microscopy: multi-modal, multi-scale, multi-dimensional. AB - Correlative microscopy is a sophisticated approach that combines the capabilities of typically separate, but powerful microscopy platforms: often including, but not limited, to conventional light, confocal and super-resolution microscopy, atomic force microscopy, transmission and scanning electron microscopy, magnetic resonance imaging and micro/nano CT (computed tomography). When targeting rare or specific events within large populations or tissues, correlative microscopy is increasingly being recognized as the method of choice. Furthermore, this multi modal assimilation of technologies provides complementary and often unique information, such as internal and external spatial, structural, biochemical and biophysical details from the same targeted sample. The development of a continuous stream of cutting-edge applications, probes, preparation methodologies, hardware and software developments will enable realization of the full potential of correlative microscopy. PMID- 21782418 TI - Health-related quality of life (HRQoL) after multimodal treatment for primarily non-resectable rectal cancer. Long-term results from a phase III study. AB - BACKGROUND: A randomised study in non-resectable rectal cancer showed that preoperative chemoradiotherapy (CRT) resulted in better local control and disease specific survival, but not overall survival than radiotherapy alone. The present paper presents long-term (>4 years) health-related quality of life (HRQoL) and a comparison between the results and reference values from the Norwegian general population. MATERIAL AND METHODS: A total of 207 patients with primarily non resectable rectal cancer were randomised to preoperative CRT (2Gyx25+5FU/leucovorin) or RT (2Gyx25) before surgery. HRQoL was assessed using EORTC QLQ-C30, completed at baseline and sent to all patients alive in Norway and Sweden (n=105) after a minimum of 4 years post treatment. A difference of >=5 points on the 0-100 scales was considered clinically significant. RESULTS: Seventy-six (72%) patients answered at follow-up. No statistically significant differences between the CRT and RT groups appeared at follow-up, although clinically significant differences in social functioning, dyspnoea and diarrhoea were found. Over time, a clinically significant reduction in physical functioning was found in both groups. Moreover, reduced social functioning and less diarrhoea in the CRT group and better role functioning and more diarrhoea in the RT group were found. Comparisons between the study group and age and gender matched reference values indicate impaired social functioning and more diarrhoea among the patients. CONCLUSION: There were no statistically significant differences in HRQoL between the randomisation groups. In general, despite having impaired social functioning and more diarrhoea, patients reported HRQoL comparable with the reference population several years after treatment. PMID- 21782419 TI - Improving cachectic symptoms and immune strength of tumour-bearing mice in chemotherapy by a combination of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang. AB - BACKGROUND: Cancer cachexia is characterised by the loss of body mass and directly compromises immune response and the quality of life of cancer patients. In the present study, we set out to investigate the role of Chinese herbs as anticancer medicines and/or chemotherapeutic adjuvants to increase therapeutic efficacy and/or ameliorate given side-effects in animal model. METHODS: Twelve kinds of herbs were chosen from the ingredients of major Chinese herbal medicines, and their effects on the antioxidant activity were investigated. To obtain the anticancer effects of 5-fluorouracil (5-FU) when consumed with minimal side-effects, we investigated the combination effect of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang that may enhance the anticancer activity of 5-FU on subcutaneous tumour growth in C57BL/6 mice challenged with Lewis lung carcinoma cells. RESULTS: Qing-Shu-Yi-Qi-Tang, a multiple-component herbal extract, was shown to have high anti-oxidation activity, while S. baicalensis (Chinese skullcap) was demonstrated to have high tumour-growth inhibition activity. Thus, S. baicalensis and Qing-Shu-Yi-Qi-Tang were evaluated for their combinaton effects on the cancer-induced cachectic murine upon receiving 5-FU chemotherapy. As a result, tumour masses and losses of carcass and/or gastrocnemius muscle were found to be significantly decreased. This combination otherwise increased both Th1/Th2 ratio and NK cytotoxicity. In the mice receiving with or without 5-FU, the serum levels of monocyte chemoattractant protein-1 (MCP-1) increased by all means but otherwise decreased when the herbal combination was administrated. Additionally, the expressions of nuclear factor-kappa B (NF-kappaB) and muscle RING finger protein-1 (MuRF-1) decreased in the gastrocnemius muscle when the herbal combination was applied. CONCLUSION: Our results revealed that the combination of S. baicalensis and Qing-Shu-Yi-Qi-Tang is able to ameliorate cachectic symptoms and positively stimulate anti-tumour immunity while undergoing chemotherapy in animal model. PMID- 21782420 TI - The effect of temperature and effluent recycle rate on hydrogen production by undefined bacterial granules. AB - Biohydrogen production in an anaerobic fluidized granular bed bioreactor was strongly dependent on temperature and effluent recycle rates. At 45 degrees C as the effluent recycle rate was increased from 1.3 to 3.5 L/min, the total H2 output for the bioreactor increased from 10.6 to 43.2 L/h. Volumetric H(2) productivity also increased from 2.1 to 8.7 L H2/L/h. At 70 degrees C as the effluent recycle was increased from 1.3 to 3.5 L/min, the total H2 output for the bioreactor increased from 13.8 to 73.8L/h. At 70 degrees C volumetric H(2) productivities increased from 2.8 to 14.8L H2/L/h as the effluent recycle rate was increased from 1.3 to 3.5 L/min. At 45 degrees C % H2 was 45% and reached 67% at 70 degrees C. Maximum hydrogen yields at 45 degrees C were 1.24 and 2.2 mol H2/mol glucose at 70 degrees C. PMID- 21782421 TI - Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans] as antimicrobial agents. AB - A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being connected via N-(CH(2))(n)-N linker. Synthesized compounds were evaluated for their antimicrobial activities in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Candida albicans) using Cup plate method. Bis spiro-indoles exhibited stronger antibacterial and antifungal efficiency than their corresponding mono spiro indoles. Compound 10e, the most active derivative was shown to inhibit the growth of all bacterial strains and two fungal strains (A. niger and C. albicans). PMID- 21782422 TI - Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer. AB - Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4 cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency. PMID- 21782423 TI - Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T type calcium channel (Cav3.2) inhibitors. AB - Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats. PMID- 21782424 TI - Synthesis and preliminary evaluation of a modified estradiol-core bearing a fused gamma-lactone as non-estrogenic inhibitor of 17beta-hydroxysteroid dehydrogenase type 1. AB - A non-estrogenic inhibitor of 17beta-hydroxysteroid dehydrogenase type 1 (17beta HSD1) was designed based on a modified 3-hydroxy-estra-1,3,5(10)-triene core having an additional five-member lactone ring and a benzamide group. The inhibitor was synthesized, fully characterized and tested for its ability to inhibit the enzyme activity. Estrogenicity was also investigated and tested on estrogen-dependent T-47D cell line. Interestingly, this steroid derivative showed inhibitory potency towards 17beta-HSD1 and did not present residual unwanted estrogenic activity. PMID- 21782425 TI - A novel binding assay identifies high affinity ligands to the rosiglitazone binding site of mitoNEET. AB - A novel outer mitochondrial membrane protein containing [2Fe-2S] clusters, mitoNEET was first identified through its binding to the anti-diabetic drug pioglitazone. Pioglitazone belongs to a family of drugs that are peroxisome proliferator-activated receptor (PPAR) gamma agonists, collectively known as glitazones. With the lack of pharmacological tools available to fully elucidate mitoNEET's function, we developed a binding assay to probe the glitazone binding site with the aim of developing selective and high affinity compounds. We used multiple thiazolidine-2,4-dione (TZD), 2-thioxothiazolidin-4-one (TTD), and 2 iminothiazolidin-4-one (ITD) compounds to establish several trends to enhance ligand development for the purpose of elucidating mitoNEET function. PMID- 21782426 TI - Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor. AB - The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability. PMID- 21782427 TI - Exploring Left-Hand-Side substitutions in the benzoxazinone series of 4-amino piperidine bacterial type IIa topoisomerase inhibitors. AB - An SAR survey at the C-6 benzoxazinone position of a novel scaffold which inhibits bacterial type IIa topoisomerase demonstrates that a range of small electron donating groups (EDG) and electron withdrawing groups (EWG) are tolerated for antibacterial activity. Cyano was identified as a preferred substituent that affords good antibacterial potency while minimizing hERG cardiac channel activity. PMID- 21782428 TI - Discovery of Lu AA33810: a highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder. AB - The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6 dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)] hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress. PMID- 21782430 TI - N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists. AB - Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K(i) 4 nM vs 1a 27 nM) and microsomal stability (human CL(int) 2.5 L/min vs 1a 35L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K(i) 9 nM, B/P 520/840 nM 10 mg/kg PO). PMID- 21782429 TI - Fragment library screening reveals remarkable similarities between the G protein coupled receptor histamine H4 and the ion channel serotonin 5-HT3A. AB - A fragment library was screened against the G protein-coupled histamine H(4) receptor (H(4)R) and the ligand-gated ion channel serotonin 5-HT(3A) (5-HT(3A)R). Interestingly, significant overlap was found between H(4)R and 5-HT(3A)R hit sets. The data indicates that dual active H(4)R and 5 HT(3A)R fragments have a higher complexity than the selective compounds which has important implications for chemical genomics approaches. The results of our fragment-based library screening study illustrate similarities in ligand recognition between H(4)R and 5 HT(3A)R and have important consequences for selectivity profiling in ongoing drug discovery efforts on H(4)R and 5-HT(3A)R. The affinity profiles of our fragment screening studies furthermore match the chemical properties of the H(4)R and 5 HT(3A)R binding sites and can be used to define molecular interaction fingerprints to guide the in silico prediction of protein-ligand interactions and structure. PMID- 21782431 TI - Monosubstituted gamma-lactam and conformationally constrained 1,3-diaminopropan-2 ol transition-state isostere inhibitors of beta-secretase (BACE). AB - The synthesis, evaluation, and structure-activity relationships of a class of gamma-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of gamma-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented. PMID- 21782432 TI - Identification of pyridazin-3-one derivatives as potent, selective histamine H3 receptor inverse agonists with robust wake activity. AB - H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model. PMID- 21782433 TI - Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors. AB - Inhibition of isoprenylcysteine carboxyl methyltransferase (Icmt) offers a promising strategy for K-Ras driven cancers. We describe the synthesis and inhibitory activity of substrate-based analogs derived from several novel scaffolds. Modifications of both the prenyl group and thioether of N-acetyl-S farnesyl-L-cysteine (AFC), a substrate for human Icmt (hIcmt), have resulted in low micromolar inhibitors of Icmt and have given insights into the nature of the prenyl binding site of hIcmt. PMID- 21782434 TI - Trehalose renders the dauer larva of Caenorhabditis elegans resistant to extreme desiccation. AB - Water is essential for life on Earth. In its absence, however, some organisms can interrupt their life cycle and temporarily enter an ametabolic state, known as anhydrobiosis [1]. It is assumed that sugars (in particular trehalose) are instrumental for survival under anhydrobiotic conditions [2]. However, the role of trehalose remained obscure because the corresponding evidence was purely correlative and based mostly on in vitro studies without any genetic manipulations of trehalose metabolism. In this study, we used C. elegans as a genetic model to investigate molecular mechanisms of anhydrobiosis. We show that the C. elegans dauer larva is a true anhydrobiote: under defined conditions it can survive even after losing 98% of its body water. This ability is correlated with a several fold increase in the amount of trehalose. Mutants unable to synthesize trehalose cannot survive even mild dehydration. Light and electron microscopy indicate that one of the major functions of trehalose is the preservation of membrane organization. Fourier-transform infrared spectroscopy of whole worms suggests that this is achieved by preserving homogeneous and compact packing of lipid acyl chains. By means of infrared spectroscopy, we can now distinguish a "dry, yet alive" larva from a "dry and dead" one. PMID- 21782435 TI - A maternal factor unique to ascidians silences the germline via binding to P-TEFb and RNAP II regulation. AB - Suppression of zygotic transcription in early embryonic germline cells is tightly linked to their separation from the somatic lineage. Many invertebrate embryos utilize localized maternal factors that are successively inherited by the germline cells for silencing the germline. Germline quiescence has also been associated with the underphosphorylation of Ser2 of the C-terminal domain (CTD Ser2) of RNA polymerase II [1-3]. Here, using the ascidian Halocynthia roretzi, we identified a first deuterostome example of a maternally localized factor, posterior end mark (PEM), which globally represses germline transcription. PEM knockdown resulted in ectopic transcription and ectopic phosphorylation of CTD Ser2 in the germline. Overexpression of PEM abolished all transcription and led to the underphosphorylation of CTD-Ser2 in the somatic cells. PEM protein was reiteratively detected in the nucleus of the germline cells and coimmunoprecipitated with CDK9, a component of posterior transcription elongation factor b (P-TEFb). These results suggest that nonhomologous proteins, PEM and Pgc of Drosophila [3-5] and PIE-1 of C. elegans [1, 6, 7], repress germline gene expression through analogous functions: by keeping CTD-Ser2 underphosphorylated through binding to the P-TEFb complex. The present study is an interesting example of evolutionary constraint on how a mechanism of germline silencing can evolve in diverse animals. PMID- 21782436 TI - The Circe principle explains how resource-rich land can waylay pollinators in fragmented landscapes. AB - Global declines in pollinators, associated with land-use change [1-6] and fragmentation [7-10], constitute a serious threat to crop production and biodiversity [11]. Models investigating impacts of habitat fragmentation on pollen flow have categorized landscapes simply in terms of habitat and nonhabitat. We show that pollen flow depends strongly on types of land use between habitat fragments. We used paternity analysis of seeds and a combination of circuit and general linear models to analyze pollen flow for the endangered tree Gomortega keule (Gomortegaceae) [12] in the fragmented Central Chile Biodiversity Hotspot [13]. Pollination probability was highest over pine plantation, moderate over low-intensity agriculture and native forest, and lowest over clearfells. Changing the proportions of the land uses over one kilometer altered pollination probability up to 7-fold. We explain our results by the novel "Circe principle." In contrast to models where land uses similar to native habitat promote pollinator movement, pollinators may actually be waylaid in resource-rich areas between habitat patches. Moreover, pollinators may move with higher probability between habitat patches separated by some resource-poor land uses. Pollination research in fragmented landscapes requires explicit recognition of the nature of the nonhabitat matrix, rather than applying simple binary landscape models. PMID- 21782437 TI - A new molecular logic for BMP-mediated dorsoventral patterning in the leech Helobdella. AB - Bone morphogenetic protein (BMP) signaling is broadly implicated in dorsoventral (DV) patterning of bilaterally symmetric animals [1-3], and its role in axial patterning apparently predates the birth of Bilateria [4-7]. In fly and vertebrate embryos, BMPs and their antagonists (primarily Sog/chordin) diffuse and interact to generate signaling gradients that pattern fields of cells [8-10]. Work in other species reveals diversity in essential facets of this ancient patterning process, however. Here, we report that BMP signaling patterns the DV axis of segmental ectoderm in the leech Helobdella, a clitellate annelid (superphylum Lophotrochozoa) featuring stereotyped developmental cell lineages, but the detailed mechanisms of DV patterning in Helobdella differ markedly from fly and vertebrates. In Helobdella, BMP2/4s are expressed broadly, rather than in dorsal territory, whereas a dorsally expressed BMP5-8 specifies dorsal fate by short-range signaling. A BMP antagonist, gremlin, is upregulated by BMP5-8 in dorsolateral, rather than ventral territory, and yet the BMP-antagonizing activity of gremlin is required for normal ventral cell fates. Gremlin promotes ventral fates without disrupting dorsal fates by selectively inhibiting BMP2/4s, not BMP5-8. Thus, DV patterning in the development of the leech revealed unexpected evolutionary plasticity of the conserved BMP patterning system, presumably reflecting its adaptation to different modes of embryogenesis. PMID- 21782440 TI - Epithelial organization, cell polarity and tumorigenesis. AB - Epithelial cells comprise the foundation for the majority of organs in the mammalian body, and are the source of approximately 90% of all human cancers. Characteristically, epithelial cells form intercellular adhesions, exhibit apical/basal polarity, and orient their mitotic spindles in the plane of the epithelial sheet. Defects in these attributes result in the tissue disorganization associated with cancer. Epithelia undergo self-renewal from stem cells, which might in some cases be the cell of origin for cancers. The PAR polarity proteins are master regulators of epithelial organization, and are closely linked to signaling pathways such as Hippo, which orchestrate proliferation and apoptosis to control organ size. 3D ex vivo culture systems can now faithfully recapitulate epithelial organ morphogenesis, providing a powerful approach to study both normal development and the initiating events in carcinogenesis. PMID- 21782441 TI - Gait functional assessment: Spatio-temporal analysis and classification of barefoot plantar pressure in a group of 11-12-year-old children. AB - Analysis of pedobarographical data requires geometric identification of specific anatomical areas extracted from recorded plantar pressures. This approach has led to ambiguity in measurements that may underlie the inconsistency of conclusions reported in pedobarographical studies. The goal of this study was to design a new analysis method less susceptible to the projection accuracy of anthropometric points and distance estimation, based on rarely used spatio-temporal indices. Six pedobarographic records per person (three per foot) from a group of 60 children aged 11-12 years were obtained and analyzed. The basis of the analysis was a mutual relationship between two spatio-temporal indices created by excursion of the peak pressure point and the center-of-pressure point on the dynamic pedobarogram. Classification of weight-shift patterns was elaborated and performed, and their frequencies of occurrence were assessed. This new method allows an assessment of body weight shift through the plantar pressure surface based on distribution analysis of spatio-temporal indices not affected by the shape of this surface. Analysis of the distribution of the created index confirmed the existence of typical ways of weight shifting through the plantar surface of the foot during gait, as well as large variability of the intrasubject occurrence. This method may serve as the basis for interpretation of foot functional features and may extend the clinical usefulness of pedobarography. PMID- 21782439 TI - Regulation of microtubule dynamics by TOG-domain proteins XMAP215/Dis1 and CLASP. AB - The molecular mechanisms by which microtubule-associated proteins (MAPs) regulate the dynamic properties of microtubules (MTs) are still poorly understood. We review recent advances in our understanding of two conserved families of MAPs, the XMAP215/Dis1 and CLASP family of proteins. In vivo and in vitro studies show that XMAP215 proteins act as microtubule polymerases at MT plus ends to accelerate MT assembly, and CLASP proteins promote MT rescue and suppress MT catastrophe events. These are structurally related proteins that use conserved TOG domains to recruit tubulin dimers to MTs. We discuss models for how these proteins might use these individual tubulin dimers to regulate dynamic behavior of MT plus ends. PMID- 21782438 TI - Adaptive introgression of anticoagulant rodent poison resistance by hybridization between old world mice. AB - Polymorphisms in the vitamin K 2,3-epoxide reductase subcomponent 1 (vkorc1) of house mice (Mus musculus domesticus) can cause resistance to anticoagulant rodenticides such as warfarin [1-3]. Here we show that resistant house mice can also originate from selection on vkorc1 polymorphisms acquired from the Algerian mouse (M. spretus) through introgressive hybridization. We report on a polymorphic introgressed genomic region in European M. m. domesticus that stems from M. spretus, spans >10 Mb on chromosome 7, and includes the molecular target of anticoagulants vkorc1 [1-4]. We show that in the laboratory, the homozygous complete vkorc1 allele of M. spretus confers resistance when introgressed into M. m. domesticus. Consistent with selection on the introgressed allele after the introduction of rodenticides in the 1950s, we found signatures of selection in patterns of variation in M. m. domesticus. Furthermore, we detected adaptive protein evolution of vkorc1 in M. spretus (Ka/Ks = 1.54-1.93) resulting in radical amino acid substitutions that apparently cause anticoagulant tolerance in M. spretus as a pleiotropic effect. Thus, positive selection produced an adaptive, divergent, and pleiotropic vkorc1 allele in the donor species, M. spretus, which crossed a species barrier and produced an adaptive polymorphic trait in the recipient species, M. m. domesticus. PMID- 21782442 TI - Familiarisation to body weight supported treadmill training for patients post stroke. AB - INTRODUCTION: Walking on a treadmill with body weight support (BWS) may require familiarisation. Patients post-stroke fatigue easily and the time needed to reach stable walking is important. However, even if body weight supported treadmill training (BWSTT) is commonly used in gait rehabilitation for patients post stroke, it is not known how much time that is needed before stable walking is reached in this population. The objective of this study therefore, was to investigate if patients post-stroke manage to stabilise walking patterns during a 5-min familiarisation-trial on the treadmill with BWS. METHOD: 35 patients post stroke walked on a treadmill at preferred speed and with 20 percent BWS during a 5-min familiarisation-period. A body-worn sensor assessed trunk acceleration. Intraclass correlation coefficient (ICC) was used for pairwise comparisons of successive 30s intervals during familiarisation, and one-way repeated-measures analysis of variance was used to investigate if there were linear trends between intervals. RESULTS: Mean ICCs across all variables stabilised above 0.90 after 3 min. Across intervals, walk ratio, cadence and step length obtained mean ICCs that were high, while interstride trunk regularity and trunk asymmetry obtained lower ICCs. However, except for mediolateral trunk acceleration, there was no linear trend after the first 3 min indicating that differences between intervals during the last 2 min were random. DISCUSSION AND CONCLUSION: This was the first study investigating familiarisation to BWSTT for patients post-stroke. Findings revealed that most of the familiarisation occurred within the first 3 min of walking, and therefore relatively stable walking could be achieved within a 5-min walking trial on the treadmill with BWS. PMID- 21782443 TI - Prolonged weight-shift and altered spinal coordination during sit-to-stand in practitioners of the Alexander Technique. AB - The Alexander Technique (AT) is used to improve postural and movement coordination and has been reported to be clinically beneficial, however its effect on movement coordination is not well-characterized. In this study we examined the sit-to-stand (STS) movement by comparing coordination (phasing, weight-shift and spinal movement) between AT teachers (n=15) and matched control subjects (n=14). We found AT teachers had a longer weight-shift (p<0.001) and shorter momentum transfer phase (p=0.01), than control subjects. AT teachers also increased vertical foot force monotonically, rather than unweighting the feet prior to seat-off, suggesting they generate less forward momentum with hip flexors. The prolonged weight-shift of AT teachers occurred over a greater range of trunk inclination, such that their weight shifted continuously onto the feet while bringing the body mass forward. Finally, AT teachers had greatly reduced spinal bending during STS (cervical, p<0.001; thoracic, p<0.001; lumbar, p<0.05). We hypothesize that the low hip joint stiffness and adaptive axial postural tone previously reported in AT teachers underlies this novel "continuous" STS strategy by facilitating eccentric contractions during weight-shift. PMID- 21782444 TI - Nuclear factor-kappaB and apoptosis in patients with intracerebral hemorrhage. AB - Studies using rat models have indicated that neuronal apoptosis is involved in the pathogenesis of intracerebral hemorrhage (ICH); however, the mechanism by which apoptosis occurs is unclear. In the present study, we aimed to quantify the number of nuclear factor-kappaB (NF-kappaB)-positive cells and apoptotic cells in specimens of middle temporal gyrus taken from 46 human subjects with hypertensive ICH. We also investigated the roles that intercellular adhesion molecule-1 (ICAM 1) and interleukin (IL)-1beta play in apoptosis following ICH. At about 24 hours after ICH, some neurons exhibited nuclear swelling and incomplete cellular structures were visible. The mean percentage of apoptotic cells was 39.28 +/- 21.83% at 49-72 hours after ICH. NF-kappaB immunoreactivity varied with time after ICH: the number of immunostained neurons increased during the 2-6 hours after ICH, and reached a maximum at 7-48 hours. The number of IL-1beta immunostained neurons reached a maximum at 2-6 hours after ICH. The number of ICAM-1-immunostained neurons increased during the 48 hours after ICH and reached a maximum at 49-72 hours. These observations indicate that apoptosis has a major role in pathological cell death after ICH and that activation of NF-kappaB is positively related to the progress of apoptosis. Additionally, activation of ICAM 1 and IL-1beta seem to be involved in apoptosis after ICH. PMID- 21782445 TI - An efficacy analysis of posterior fossa decompression techniques in the treatment of Chiari malformation with associated syringomyelia. AB - A retrospective study of the efficacy of posterior fossa decompression (PFD) was carried out in 132 patients with Chiari malformation (CM) with associated syringomyelia (SM). Of these 132 patients, 69 received extended PFD (large craniotomy group), and the other 63 patients received only local PFD (small craniotomy group). At the short-term postoperative evaluation (1-4 weeks) the extended PFD appeared to be more effective than the local PFD (p<0.05). However, there was no significant difference in long-term analysis (6 months-11 years) (p>0.05). In the large craniotomy group, there was no difference between the short-term and long-term efficacy (p>0.05). However, in the small craniotomy group, long-term efficacy clearly improved (p<0.05). Furthermore, patients who had undergone local PFD exhibited more obvious radiological improvement of SM (p<0.05) and fewer postoperative complications compared to patients undergoing extended PFD (p<0.05). Therefore, local PFD is preferable for the surgical treatment of CM with associated SM. PMID- 21782446 TI - Association between apolipoprotein E genotypes and Parkinson's disease. AB - Previous studies on the association between apolipoprotein E (APOE) alleles and Parkinson's disease (PD) have shown contradictory results. A recent study showed that APOE is involved in a molecular pathway of alpha-synuclein-induced neurodegeneration. We therefore conducted the first Thai study on APOE genotypes in patients with PD. We analysed the frequencies of APOE genotypes in our case control study of 155 patients with sporadic PD and 158 control participants. We identified a higher frequency of the APOE-epsilon2 allele among patients with PD than among controls (odds ratio=2.309, 95% confidence interval=1.111-4.799). Genetic association is a powerful tool for detecting disease susceptibility alleles, but there are many pitfalls to consider before claiming any association. The discrepancy among the results of the genetic association studies of APOE genotypes as a risk of susceptibility to PD emphasises that this association merits clarification by the study of a single large homogeneous population. PMID- 21782447 TI - Executive functions recover earlier than episodic memory after microsurgical transsphenoidal resection of pituitary tumors in adult patients--a longitudinal study. AB - Pituitary tumors may lead to cognitive dysfunction, and the most prevalent deficits are impaired memory and attention. To investigate whether memory and executive functions improve after surgical treatment we performed a prospective longitudinal study comprising 106 patients with pituitary tumors. Psychometric evaluation was performed with the d2-Letter Cancellation test, the Trail Making test, the Digit Span test and the Intelligence Structure test-Verbal Memory test at three timepoints: preoperatively, and at 3 months and 12 months after surgery. The preoperative and postoperative maximum suprasellar tumor extension and hormone status was assessed in all participants. The main finding was that concentration, working memory, and attentional speed improved significantly within the first 3 months after surgery (p<0.05), while improvement of episodic memory was not observed until 12 months after surgery (p<0.001). In the patients harbouring non-functioning adenomas, prolactinomas or other sellar lesions, the most important factor promoting improvement of neurocognitive function was the removal of the suprasellar tumor extension. PMID- 21782448 TI - Serum bilirubin concentrations and multiple sclerosis. AB - Bilirubin is the end product of heme catabolism by heme oxygenases. Although bilirubin has long been considered as a toxic waste product, it is now recognized as an endogenous antioxidant. It has been reported that bilirubin is an effective treatment in both acute and chronic experimental autoimmune encephalomyelitis (EAE) disease models. However, the relationship between bilirubin and multiple sclerosis (MS) has not been fully explored. The serum bilirubin concentrations were measured in 340 individuals comprising 88 healthy subjects, 133 patients with MS and 119 patients with cerebral infarction. Serum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) concentrations were significantly lower in patients with MS than in either patients with cerebral infarction or healthy controls (p<0.001). The correlation identified between bilirubin and MS was still highly significant when the effect of gender was eliminated. Among patients with MS, Tbil, Dbil and Ibil concentrations were lower in patients with MS with longer duration (>2 years), less disabling disease (Expanded Disability Status Scale score<3), and inactive MRI appearance, although the differences did not reach statistical significance. Our results suggest that there are reduced serum bilirubin concentrations in patients with MS. PMID- 21782449 TI - Surgical treatment and outcomes of metastatic breast cancer to the spine. AB - Metastatic vertebral body and spinal epidural lesions cause significant pain and neurological morbidity and negatively impact quality of life and survival. In instances of metastatic epidural spinal cord compression, treatment typically involves surgery and radiotherapy. The incidence of spinal metastases in breast cancer patients is high. In the light of recent improvements in survival among some patients with breast cancer, we reviewed the treatments and outcomes for patients with breast cancer who presented to our institution with metastatic epidural spinal cord compression. We identified all patients undergoing open surgery for the treatment of breast cancer metastases to the spine at our center from 1 January 2001 to 31 December 2009. We retrospectively reviewed records for the details of medical history, treatment, surgery, radiographic imaging, and follow-up. The Death Master File from the United States Social Security Administration was queried to identify the date of death where the medical record was incomplete. Outcomes were assessed by overall survival as well as preoperative and postoperative ambulatory status, bladder function, and the American Spinal Injury Association impairment classification system (ASIA). A total of 15 female patients were identified as having surgical intervention directly related to breast cancer metastasis to the spine. Most lesions (12/15) were located in the anterior vertebral column (vertebral body and/or pedicle). Two patients required re-operation, one for epidural fluid collection and one for infection. Roughly half of the patients (8/15) had well-controlled systemic disease at the time of surgery. Five patients had non-contiguous metastatic lesions elsewhere in the spine. Median survival following surgery was 1,025 days; control of systemic disease did not predict duration of postoperative survival. Seven patients had documented improvement in their ability to ambulate in the first 30 days following surgery. Bladder function was preserved in all. No patient deteriorated; and five patients had postoperative improvement of their ASIA impairment scale grade. We concluded that aggressive therapy, including surgery, is warranted for patients with symptomatic metastatic epidural spinal cord compression from breast cancer, including in the setting of advanced and progressive systemic disease. PMID- 21782450 TI - AMP-activated protein kinase: also regulated by ADP? AB - AMPK is a ubiquitous sensor of cellular energy status in eukaryotic cells. It is activated by stresses causing ATP depletion and, once activated, maintains energy homeostasis by phosphorylating targets that activate catabolism and inhibit energy-consuming processes. Evidence derived from non-mammalian orthologs suggests that its ancestral role was in the response to starvation for a carbon source. We review recent findings showing that AMPK is activated by ADP as well as AMP, and discuss the mechanism by which binding of these nucleotides prevent its dephosphorylation and inactivation. We also discuss the role of the carbohydrate-binding module on the beta subunit and the mechanisms by which it is activated by drugs and xenobiotics such as metformin and resveratrol. PMID- 21782451 TI - Change in body mass index during middle age affects risk of total knee arthoplasty due to osteoarthritis: a 19-year prospective study of 1003 women. AB - The evidence linking body mass index (BMI) to severe OA shows a strong association in the knee. There are limited data exploring the effect of BMI on the risk of joint arthroplasty in a healthy population with long periods of follow up. We compared the self-reported BMI at age 20, measured BMI at baseline, year 5 and year 10 with the year 19 risk of total knee arthroplasty (TKA) in a well-described, population based cohort of healthy women. A total of 733 women attended the 19th year visit, of whom 31 underwent TKA and 676 were used as a control group after 26 were removed for having hip arthoplasty. Using logistic regression, an increase in 1 unit of BMI at baseline was associated with a 10.5% increased risk of TKA (p=0.017) and at year 5 the increased risk is 8.6% (p=0.042). When adjusted for baseline age and smoking, baseline BMI was the only significant predictor of TKA at 10.0% with p=0.024. There was no significant association at 10 years or for change in BMI over time. In this prospective, population based study, BMI predicted the risk of TKA for OA. The risk was greatest at baseline when the patients were in middle age suggesting that this is the most important time to target weight reduction interventions. PMID- 21782452 TI - Knee joint preservation with combined neutralising high tibial osteotomy (HTO) and Matrix-induced Autologous Chondrocyte Implantation (MACI) in younger patients with medial knee osteoarthritis: a case series with prospective clinical and MRI follow-up over 5 years. AB - PURPOSE: There is no ideal treatment for younger patients with medial knee osteoarthritis (OA) and varus malalignment. We have investigated the first case series of combined neutralising high tibial osteotomy (HTO) and Matrix-induced Autologous Chondrocyte Implantation (MACI) with MRI. Treatment goals were clinical improvement and delay of arthroplasty. METHODS: Between 2002 and 2005 18 patients (Mean age 47 years) underwent surgery. Exclusion criteria were lateral compartment and advanced patellofemoral OA. The Knee Injury and Osteoarthritis Outcome Score (KOOS), six minute walk test (6MWT) and a validated MRI score were outcome measures. RESULTS: There were significant improvements (p<0.05) in all five KOOS domains. Four were significantly maintained to 5 years. The domain "symptoms" and results in the 6MWT dropped off at 5 years. MRI results were first significantly improved (24/12) but declined at 60 months. Good quality infill was found in 33% patients at the study endpoint (n=5/15). Histological investigation of one knee demonstrated full-thickness hyaline-like cartilage (20/12). After 2 early failures and one graft detachment graft fixation was changed (Smart nails instead of sutures in 14 cases). Graft hypertrophy requiring a chondroplasty occurred once. There were no other major complications. Specific minor complications included patellar tendinitis (n=8). CONCLUSIONS: This combined procedure provides a safe treatment option for younger patients with medial knee OA and varus alignment with significant clinical improvement at 5 years. However, overall graft survival and cartilage infill were poor. Larger studies are needed to statistically verify predictors for longer term cartilage repair in these patients. PMID- 21782453 TI - LuxR dependent quorum sensing inhibition by N,N'-disubstituted imidazolium salts. AB - Thirty N,N'-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagonists. Substitution on one of the imidazolium nitrogen atoms includes benzhydryl, fluorenyl or cyclopentyl substituent, and alkyl chains of various lengths on the second one. Most of these compounds displayed antagonist activity, with IC(50) reaching the micromolar range for the most active ones. The disubstituted imidazolium scaffold is thus shown to be a new pertinent pharmacophore in the field of AHL dependent QS inhibition. PMID- 21782454 TI - P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis. AB - Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15 membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the d phenylglycine epimers. PMID- 21782455 TI - Synthesis and evaluation of novel 2-butyl-4-chloro-1-methylimidazole embedded chalcones and pyrazoles as angiotensin converting enzyme (ACE) inhibitors. AB - A series of novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones and pyrazoles were synthesized and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. The condensation of 2 butyl-4-chloro-1-methylimidazole-5-carboxaldehyde with various aryl and heteroaryl methyl ketones in the presence of 10% aqueous NaOH in methanol proceeded efficiently to give the respective chalcones in very good yields. Further, the reaction of chalcones with hydrazine hydrate in acetic acid gave substituted pyrazole analogues. Screening all 36 new compounds using ACE inhibition assay, resulted chalcones with better ACE inhibitory activity compared to the respective pyrazole analogues. Among the chalcones 4a-r, three compounds, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(5-chlorothiophen-2-yl)prop 2-enone 4i, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2 yl)prop-2-enone 4l, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1 (dibenzo[b,d] thiophen-2-yl)prop-2-enone 4q were resulted as most active ACE inhibitors with IC(50) of 3.60 MUM, 2.24 MUM, and 2.68 MUM, respectively. PMID- 21782457 TI - Correlative microscopy: a powerful tool for exploring neurological cells and tissues. AB - Imaging tools for exploring the neurological samples have seen a rapid transformation over the last decade. Approaches that allow clear and specific delineation of targeted tissues, individual neurons, and their cell-cell connections as well as subcellular constituents have been especially valuable. Considering the significant complexity and extent to which the nervous system interacts with every organ system in the body, one non-trivial challenge has been how to identify and target specific structures and pathologies by microscopy. To this end, correlative methods enable one to view the same exact structure of interest utilizing the capabilities of typically separate, but powerful, microscopy platforms. As such, correlative microscopy is well-positioned to address the three critical problems of identification, scale, and resolution inherent to neurological systems. Furthermore, the application of multiple imaging platforms to the study of singular biological events enables more detailed investigations of structure-function relationships to be conducted, greatly facilitating our understanding of relevant phenomenon. This comprehensive review provides an overview of methods for correlative microscopy, including histochemistry, transgenic markers, immunocytochemistry, photo-oxidation as well as various probes and tracers. An emphasis is placed on correlative light and electron microscopic strategies used to facilitate relocation of neurological structures. Correlative microscopy is an invaluable tool for neurological research, and we fully anticipate developments in automation of the process, and the increasing availability of genomic and transgenic tools will facilitate the adoption of correlative microscopy as the method of choice for many imaging experiments. PMID- 21782456 TI - Oxadiazole derivatives containing 1,4-benzodioxan as potential immunosuppressive agents against RAW264.7 cells. AB - A series of oxadiazole derivatives containing 1,4-benzodioxan (4a-4s) have been first synthesized for their potential immunosuppressive activity. Among the compounds, compound 4i showed the most potent biological activity against RAW264.7 cells (inhibition=37.66+/-2.34% for NO overproduction and IC(50)=0.05MUM for iNOS). Docking simulation was performed to position compound 4i into the iNOS structure active site to determine the probable binding model. RT-PCR experiment results demonstrated that some of these compounds possessed good immunosuppressive activity against iNOS, especially for compound 4i. Therefore, compound 4i with potent inhibitory activity may be a potential agent. PMID- 21782458 TI - Structural basis of substrate methylation and inhibition of SMYD2. AB - Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class. PMID- 21782459 TI - Quantitative comparison between experimental and simulated gamma-ray spectra induced by 14 MeV tagged neutrons. AB - Fast neutron interrogation with the associated particle technique can be used to identify explosives in cargo containers (EURITRACK FP6 project) and unexploded ordnance on the seabed (UNCOSS FP7 project), by detecting gamma radiations induced by 14 MeV neutrons produced in the 2H(3H,alpha)n reaction. The origin of the gamma rays can be determined in 3D by the detection of the alpha particle, which provides the direction of the opposite neutron and its time-of-flight. Gamma spectroscopy provides the relative counts of carbon, nitrogen, and oxygen, which are converted to chemical fractions to differentiate explosives from other organic substances. To this aim, Monte Carlo calculations are used to take into account neutron moderation and gamma attenuation in cargo materials or seawater. This paper presents an experimental verification that C, N, and O counts are correctly reproduced by numerical simulation. A quantitative comparison is also reported for silicon, iron, lead, and aluminium. PMID- 21782460 TI - Assessing the performance and longevity of Nb, Pt, Ta, Ti, Zr, and ZrO2-sputtered Havar foils for the high-power production of reactive [18F]F by proton irradiation of [18O]H2O. AB - As water-soluble ionic contaminants, which arise following proton irradiation of [18O]H2O have been associated with decreased [18F]FDG yields, the minimization of these contaminants is an asset in improving the [18F]F reactivity. To this end, we have previously demonstrated that the use of Nb-sputtered Havar foils results in decreased radionuclidic and chemical impurities in proton irradiated [18O]H2O, improved [18F]FDG yields, and improved [18F]FDG yield consistency when compared with non-sputtered Havar. Resulting from the highly reactive chemical microenvironment within the target however, this niobium layer is observed to degrade over time. To find a material that displays increased longevity with regards to maintaining high [18F]F reactivity, this project extensively investigated and compared Havar foils sputtered with Nb, Pt, Ta, Ti, Zr and ZrO2. Of the materials investigated, the results of this study suggest that Ta sputtered Havar foil is the preferred choice. For similar integrated currents (~1,000,000 MUA min), when comparing the Ta-sputtered Havar with Nb-sputtered Havar we observed: (i) greater than an order of magnitude decrease in radionuclidic impurities, (ii) a 6.4 percent increase (p=0.0025) in the average TracerLab MX [18F]FDG yield, and (iii) an overall improvement in the FDG yield consistency. Excellent performance of the Ta-sputtered foil was maintained throughout its ~1,500,000 MUA min lifetime. PMID- 21782461 TI - Regulation of plant cytosolic aldolase functions by redox-modifications. AB - From the five genes which code for cytosolic fructose 1,6-bisphosphate aldolases in Arabidopsis thaliana L., the cDNA clone of cAld2 (At2g36460), was heterologously expressed in E. coli and incubated under various oxidizing and reducing conditions. Covalent binding of a GSH moiety to the enzyme was shown by incorporation of biotinylated GSH (BioGEE) and by immunodetection with monoclonal anti-GSH serum. Nitrosylation after incubation with GSNO or SNP was demonstrated using the biotin-switch assay. Mass-spectrometry analysis showed glutathionylation and/or nitrosylation at two different cysteine residues: GSH was found to be attached to C68 and C173, while the nitroso-group was incorporated only into C173. Non-reducing SDS-PAGE conducted with purified wild type and various Cys-mutant proteins revealed the presence of disulfide bridges in the oxidized enzyme, as described for rabbit muscle aldolase. Incubation of the purified enzyme with GSSG (up to 25 mM) led to partial and reversible inactivation of enzyme activity; NADPH, in the presence of the components of the cytosolic NADP-dependent thioredoxin system, could reactivate the aldolase as did DTT. Total and irreversible inactivation occurred with low concentrations (0.1 mM) of nitrosoglutathione (GSNO). Inactivation was prevented by co-incubation of cAld2 with fructose-1,6-bisphosphate (FBP). Nuclear localization of cAld2 and interaction with thioredoxins was shown by transient expression of fusion constructs with fluorescent proteins in isolated protoplasts. PMID- 21782462 TI - Is the electrolyte leakage assay an unequivocal test of membrane deterioration during leaf senescence? AB - The main symptoms of leaf senescence are the degradation of chlorophyll and proteins (which may be accompanied by ammonium accumulation), and an increase of electrolyte leakage (EL), which has been traditionally attributed to disruption of cell membranes. The aim of this study was to determine if ammonium efflux contributes to the increase EL in senescing barley leaves. During senescence of detached leaves the increase of EL correlated with ammonium leakage (r(2) = 0.82) and ammonium content in tissues (r(2) = 0.73), but not with K(1+) leakage (r(2) = 0.23). Although lower amounts of ammonium accumulated in senescing attached leaves, again changes in EL paralleled ammonium accumulation. EL increased early during senescence even though ion leakage was selective (leaves leaked proportionally more ammonium than K(1+)), and membranes appeared intact as judged from staining with the cell impermeant stain propidium iodide. Detached leaves maintained their capacity to regreen after 3 days of senescence-acceleration in darkness, i.e., membrane integrity was not severely compromised. During the early stages of senescence, EL increases due to ammonium accumulation (possibly resulting from protein degradation) even if there is no massive disruption of cell membranes. Therefore, increased EL in senescing leaves is not an unequivocal symptom of cell membrane damage. PMID- 21782463 TI - Considerations in HIV prevention for women affected by the criminal justice system. AB - Within the national dialogue of HIV prevention strategies, relatively little consideration is given to the millions of women and girls affected by the criminal justice system, either through their own incarceration or that of their partners. Statistics indicate that these women and girls are disproportionately infected or at risk for HIV and other sexually transmitted infections and much of this risk is directly related to the dynamics and circumstances that led to their incarceration or relationships with incarcerated men. As we look for the link between public health and correctional health within our National HIV/AIDS Strategy, it is imperative that the risks, obstacles, and opportunities facing women and girls affected by incarceration are brought into the discussion. Gender responsive HIV prevention policies and practices must be developed to address the unique risks and opportunities for these women and girls. This paper presents data on HIV risk and other health issues specific to this community of women and girls, discusses key factors for consideration when developing gender-responsive HIV strategies for these communities, and makes recommendations for inclusion in the National HIV/AIDS Strategy and other state and local HIV prevention efforts. PMID- 21782464 TI - Developing an effective HIV/AIDS response for women and girls in the U.S. Virgin Islands. AB - This article focuses on specific culturally and socially based gender issues that enhance HIV risk and complicate access to care and services for women and girls in the U.S. Virgin Islands (USVI). Literature review and interviews with clinicians providing HIV care in the USVI were used to examine causative factors for the high HIV prevalence rates among USVI women. Although the USVI population is almost evenly split between men (48%) and women (52%), females represent 46% of all USVI residents living with HIV and 33% of all people with AIDS. A primary barrier to adequate HIV/AIDS care for these women and girls is the insufficient number of clinicians available to provide that care. A primary barrier to adequate HIV prevention is the fact that, although the USVI are a territory of the United States, their cultural practices are those of the Caribbean. Thus, HIV programs developed on the U.S. mainland are often ineffective in USVI. A lack of consistent and accurate reporting to HIV/AIDS surveillance staff on the part of clinicians also hinders early trend detection efforts, as well as effective HIV management. Strategies to address HIV among USVI women and girls include: 1) increasing awareness of issues that impact them negatively and increase their vulnerability to HIV, 2) developing and funding delivery of effective, culturally appropriate HIV-related interventions, and 3) increasing the size and technical capacity of the USVI clinical workforce. Simultaneously updating current health care professionals on best practices for HIV screening, treatment, risk-reduction counseling and support could also substantially strengthen the USVI's response to HIV among women and girls. PMID- 21782465 TI - Multidisciplinary practical guidelines for gastrointestinal access for enteral nutrition and decompression from the Society of Interventional Radiology and American Gastroenterological Association (AGA) Institute, with endorsement by Canadian Interventional Radiological Association (CIRA) and Cardiovascular and Interventional Radiological Society of Europe (CIRSE). PMID- 21782467 TI - BODE index and quality of life in advanced chronic obstructive pulmonary disease before and after lung transplantation. AB - BACKGROUND: The BODE index (Body mass index, Obstruction, Dyspnea, Exercise), predicts the risk of death in patients with chronic obstructive pulmonary disease (COPD), and is used to identify candidates for lung transplantation. We hypothesized that a higher BODE index would be associated with worse health related quality of life (HRQL) in advanced COPD, and with larger improvements in HRQL after transplantation. METHODS: In this cohort study (n = 112), we administered the St. George's Respiratory Questionnaire (SGRQ), 36-Item Short Form (SF-36), Visual Analog Scale, Standard Gamble and EuroQol Group 5-Dimension (EQ-5D) index to otherwise healthy COPD patients with a FEV(1) <50% predicted. We compared mean HRQL values across BODE score groups, and tested for linear trends. In patients who received lung transplants during the study period, we compared SGRQ scores before and early (mean 4 months) after transplantation. RESULTS: BODE was directly associated with SGRQ and inversely related to all other HRQL measures (p < 0.05). Early post-transplant improvements in HRQL were also seen across the spectrum of BODE scores from 5 to 10. CONCLUSIONS: The BODE score is a significant predictor of HRQL in patients with severe COPD. We noted dramatic improvements in HRQL after transplantation, which appeared similar in magnitude for patients with pre-transplant BODE scores of 5 or 6 and 7 to 10, despite the difference in expected survival between these two groups. The association of the BODE score with HRQL further supports its use in identifying potential candidates for lung transplantation. PMID- 21782466 TI - Early statin use is associated with increased risk of infection after stroke. AB - BACKGROUND: Infection after stroke is common and likely detrimental. Given the potent immunomodulatory properties of statins, we hypothesized that early statin use might increase the risk of infection in the immediate post stroke period. METHODS: In a study cohort of 112 patients with ischemic stroke, we assessed the impact of early statin use on the risk of post stroke infection. RESULTS: After controlling for stroke severity and patient age, the odds ratio (OR) and 95% confidence interval (CI) for infection in the first 15 days after stroke among patients on a statin by day 3 after stroke was 7.21 (95% CI 1.40-37.98; P = .018). When controlling for univariate predictors of infection, the OR associated for infection associated with statin use actually increased, but was no longer significant (8.49 [95% CI 0.92-77.98]; P = .059). In addition, early statin use was associated with an increase in plasma interleukin-1 receptor antagonist (IL 1ra); IL-1ra was significantly higher in early statin users than in nonstatin users by day 7 after stroke. CONCLUSIONS: Our data suggest that early statin use appears to be associated with and increased risk of post stroke infection. This risk may, in part, be related to increases in plasma IL-1ra. If these findings are replicated in larger studies, they could have important implications for the timing of statin therapy after stroke. PMID- 21782468 TI - Sensitivity of different measures of the visibility of masked primes: influences of prime-response and prime-target relations. AB - Visual masking of primes lowers prime visibility but spares processing of primes as reflected in prime-target congruence and prime-response compatibility effects. However, the question is how to appropriately measure prime visibility. Here, we tested the influence of three procedural variables on prime visibility measures: prime-target similarity, prime-response similarity, and the variability of prime response mappings. Our results show that a low prime-target similarity is a favorable condition for a prime visibility measure because it increases the sensitivity of this measure in comparison to a high prime-target similarity. PMID- 21782469 TI - The myth of phenomenological overflow. AB - In this paper I examine the dispute between Hakwan Lau, Ned Block, and David Rosenthal over the extent to which empirical results can help us decide between first-order and higher-order theories of consciousness. What emerges from this is an overall argument to the best explanation against the first-order view of consciousness and the dispelling of the mythological notion of phenomenological overflow that comes with it. PMID- 21782470 TI - Accuracy of the biceps tendon sheath injection: ultrasound-guided or unguided injection? A randomized controlled trial. AB - BACKGROUND: Patients often localize pain in the anterior shoulder; however, this patient-localized pain does not necessarily correlate to the location of disease. Unguided shoulder injections are common in clinical practice. The accuracy of unguided biceps tendon sheath injections has not been studied. Patient management may be aided by the knowledge of injection accuracy. This study compared the accuracy of ultrasound-guided biceps tendon sheath injection with unguided injection. MATERIALS AND METHODS: The study comprised 30 patients (30 shoulders) with reported anterior shoulder pain who had a primary diagnosis of tenosynovitis or tendinitis of the biceps tendon, or both. Shoulders were randomly allocated into ultrasound-guided and unguided injection groups. Computed tomography (CT) imaging was performed immediately after a contrast agent was injected into the biceps tendon sheath. The locations of contrast seen on CT scan were classified into 3 types: only within the tendon sheath (type 1); inside the tendon, tendon sheath, and surrounding area (type 2); and only the area outside the tendon sheath (type 3). RESULTS: Ultrasound-guided injections resulted in 86.7% type 1 and 13.3% type 2 locations. Unguided injections resulted in 26.7% type 1, 40.0% type 2, and 33.3% type 3 locations. The difference for each location type was significant (P < .05). CONCLUSION: Injection into the tendon sheath of the long head of the biceps brachii can be more accurately performed using ultrasound guidance than by the blind method. PMID- 21782471 TI - A watertight construct in arthroscopic rotator cuff repair. AB - BACKGROUND: It is unknown which type of rotator cuff repair technique best isolates the healing zone interface from the synovial fluid environment. The purpose of this study was to determine the leakage area and pattern onto the rotator cuff footprint after 3 different rotator cuff repairs. MATERIALS AND METHODS: Six fresh frozen cadaveric glenohumeral joints in each of 3 groups were injected with gelatin to a pressure of 103 mm Hg (~2 psi) after 1 of 3 different rotator cuff repairs of a supraspinatus tear: (1) single-row repair (SR), (2) knotless transosseous equivalent repair (KTE), and (3) traditional transosseous equivalent repair (TTE), which uses medial tied knots. Specimens were cycled in external rotation and abduction and were cooled to allow the gelatin to solidify. The supraspinatus was dissected off the footprint and photographs were taken. Scion Image (Frederick, MD, USA) was used to quantify the area. RESULTS: The average area of leakage was 1.09 cm(2) for the SR and 1.15 cm(2) for the KTE. The TTE did not demonstrate any leakage. The pattern of leakage for the KTE was medial and central on the footprint, whereas the SR demonstrated leakage up to the tied knots. The difference in the area of leakage in the SR and KTE compared with the TTE was statistically significant. There was no difference in area of leakage between the SR and KTE. CONCLUSION: A transosseous equivalent repair technique best prevents leakage onto the rotator cuff footprint compared with single-row and knotless repairs. PMID- 21782473 TI - A 2-dimensional glenoid vault method for measuring glenoid version on computed tomography. AB - BACKGROUND: Accurate placement of the glenoid prosthesis in shoulder arthroplasty is critical; precise glenoid prosthesis alignment being a key element to avoid poor fixation and early loosening. The current recognized 2-dimensional (2-D) method for measuring glenoid version may be irrelevant to the above, as it does not take into account the complex and variable relationship of the scapular body in relation to the glenoid. On the contrary, a 3-dimensional (3-D) method, which focuses solely on the glenoid, is superior but not readily accessible. We have, therefore, developed a new 2-D method based solely on the glenoid vault which is readily accessible. MATERIALS AND METHODS: To determine normal version using our method, computer tomography (CT) scans of 107 normal shoulders were assessed as the control group. We then assessed 63 arthritic shoulders to establish any significant difference. Inter- and intraobserver reliability were assessed using 4 observers who independently reviewed 50 blinded CT images 3 weeks apart. For comparison, the currently recognized method, as described by Friedman et al, was also utilized in this study. RESULTS: Using our new method, the mean glenoid version in the control group was 19 +/- 3 degrees of retroversion; and in the arthritic group, 25 +/- 6 degrees of retroversion. Intra- and interobserver reliability were very high. CONCLUSION: Our new 2-D glenoid vault method is relevant, as it focuses solely on the glenoid vault, is precise with a low standard deviation, and is reliably reproducible as shown by the intra- and interobserver reliability data, all while remaining readily accessible. PMID- 21782472 TI - Reconstruction of the coronoid using an extended prosthesis: an in vitro biomechanical study. AB - BACKGROUND: When repair of comminuted coronoid fractures is not possible, prosthetic replacement may restore elbow stability. The purpose of this biomechanical study was to determine whether a coronoid implant with an extended tip would improve elbow stability compared with an anatomic prosthesis in the setting of collateral ligament insufficiency. MATERIALS AND METHODS: Passive elbow extension was performed in 7 cadaveric arms in the varus and valgus positions and active and passive extension in the horizontal position by use of an elbow motion simulator. Varus-valgus laxity of the ulna relative to the humerus was quantified with a tracking system with a native coronoid, a 40% coronoid deficiency, an anatomic prosthesis, and an extended prosthesis, with the collateral ligaments sectioned and repaired. RESULTS: Laxity significantly increased after a 40% coronoid deficiency with both repaired and sectioned collateral ligaments (P <= .01). With the ligaments repaired, there was no significant difference in laxity between the native coronoid, the anatomic implant, or the extended implant. Ligament sectioning alone produced severe instability, with a mean laxity of 42.75 degrees +/- 11.54 degrees (P < .01). With insufficient ligaments, the anatomic prosthesis produced no change in laxity compared with the native coronoid, whereas the extended implant significantly reduced laxity by 21.56 degrees +/- 17.70 degrees (P = .02). CONCLUSIONS: An anatomic coronoid implant with ligament repair restores stability to the coronoid deficient elbow to intact levels. In the setting of ligament insufficiency, an extended implant improves stability relative to an anatomic implant, but the elbow remains significantly less stable than an intact elbow. Studies are needed to evaluate the feasibility of these designs. PMID- 21782474 TI - Proximal humeral fracture fixation: locking plate construct +/- intramedullary fibular allograft. AB - BACKGROUND: Locking plate constructs for proximal humeral fractures can fail due to varus collapse, especially in osteoporotic bone with medial cortex comminution. Augmentation, using a fibular allograft as an intramedullary bone peg, may strengthen fixation preventing varus collapse. This study investigated the ability of the augmented locking plate construct to withstand repetitive varus stresses relative to the nonaugmented construct. MATERIALS AND METHODS: Proximal humeral fractures with medial comminution were simulated by performing wedge-shaped osteotomies at the surgical neck in cadaveric specimens. For each cadaver (n = 8), 1 humeral fracture was fixated with the locking plate construct alone and the other with the locking plate construct plus ipsilateral fibular autograft augmentation. The humeral head was immobilized and a repetitive, medially directed load was applied to the humeral shaft until construct collapse or until 25000 cycles were completed. RESULTS: No augmented construct collapsed. In comparison, 6 of 8 nonaugmented constructs collapsed (P < .05). Collapse in the 6 nonaugmented constructs occurred after an average +/-SD of 6604 +/- 1984 cycles. Screw penetration of the articular surface was found in only 1 of the nonaugmented constructs. CONCLUSION: Fibular allograft augmentation increased the ability of the locking plate to withstand repetitive varus loading. Clinically, this may assist proximal humeral fracture fixation in osteoporotic bone with medial cortex comminution. PMID- 21782475 TI - Intraoperative neurophysiological responses in epileptic patients submitted to hippocampal and thalamic deep brain stimulation. AB - PURPOSE: Deep brain stimulation (DBS) has been used in an increasing frequency for treatment of refractory epilepsy. Acute deep brain macrostimulation intraoperative findings were sparsely published in the literature. We report on our intraoperative macrostimulation findings during thalamic and hippocampal DBS implantation. METHODS: Eighteen patients were studied. All patients underwent routine pre-operative evaluation that included clinical history, neurological examination, interictal and ictal EEG, high resolution 1.5T MRI and neuropsychological testing. Six patients with temporal lobe epilepsy were submitted to hippocampal DBS (Hip-DBS); 6 patients with focal epilepsy were submitted to anterior thalamic nucleus DBS (AN-DBS) and 6 patients with generalized epilepsy were submitted to centro-median thalamic nucleus DBS (CM DBS). Age ranged from 9 to 40 years (11 males). All patients were submitted to bilateral quadripolar DBS electrode implantation in a single procedure, under general anesthesia, and intraoperative scalp EEG monitoring. Final electrode's position was checked postoperatively using volumetric CT scanning. Bipolar stimulation using the more proximal and distal electrodes was performed. Final standard stimulation parameters were 6Hz, 4V, 300MUs (low frequency range: LF) or 130Hz, 4V, 300MUs (high frequency range: HF). KEY FINDINGS: Bilateral recruiting response (RR) was obtained after unilateral stimulation in all patients submitted to AN and CM-DBS using LF stimulation. RR was widespread but prevailed over the fronto-temporal region bilaterally, and over the stimulated hemisphere. HF stimulation led to background slowing and a DC shift. The mean voltage for the appearance of RR was 4V (CM) and 3V (AN). CM and AN-DBS did not alter inter-ictal spiking frequency or morphology. RR obtained after LF Hip-DBS was restricted to the stimulated temporal lobe and no contralateral activation was noted. HF stimulation yielded no visually recognizable EEG modification. Mean intensity for initial appearance of RR was 3V. In 5 of the 6 patients submitted to Hip-DBS, an increase in inter-ictal spiking was noted unilaterally immediately after electrode insertion. Intraoperative LF stimulation did not modify temporal lobe spiking; on the other hand, HF was effective in abolishing inter-ictal spiking in 4 of the 6 patients studied. There was no immediate morbidity or mortality in this series. SIGNIFICANCE: Macrostimulation might be used to confirm that the hardware was working properly. There was no typical RR derived from each studied thalamic nuclei after LF stimulation. On the other hand, absence of such RRs was highly suggestive of hardware malfunction or inadequate targeting. Thalamic-DBS (Th-DBS) RR was always bilateral after unilateral stimulation, although they somehow prevailed over the stimulated hemisphere. Contrary to Th-DBS, Hip-DBS gave rise to localized RR over the ipsolateral temporal neocortex, and absence of this response might very likely be related to inadequate targeting or hardware failure. Increased spiking was seen over temporal neocortex during hippocampal electrode insertion; this might point to the more epileptogenic hippocampal region in each individual patient. We did not notice any intraoperative response difference among patients with temporal lobe epilepsy with or without MTS. The relationship between these intraoperative findings and seizure outcome is not yet clear and should be further evaluated. PMID- 21782476 TI - Progressive myoclonus epilepsy with nephropathy C1q due to SCARB2/LIMP-2 deficiency: clinical report of two siblings. AB - Action myoclonus-renal failure syndrome (AMRF) is considered a rare form of progressive myoclonus epilepsy (PME) associated with renal failure. A mutation on the gene encoding the lysosomal integral membrane protein type 2-LIMP-2 (SCARB2), the receptor responsible for targeting glucocerebrosidase to the lysosomes, was recently described, allowing a better understanding of its etiopathogenesis. We describe clinically two sisters with AMRF that resulted from a mutation in the SCARB2 gene. The renal involvement was due to nephropathy C1q. When substrate reduction therapy, to correct the possible glucocerebroside storage in the cells with glucocerebrosidase deficiency, was administered to one of the siblings, a significant improvement was observed. This report points out a rational for a therapeutical approach to this new lysossomopathy. PMID- 21782477 TI - Interictal magnetoencephalographic findings related with surgical outcomes in lesional and nonlesional neocortical epilepsy. AB - PURPOSE: To investigate whether interictal magnetoencephalography (MEG) concordant with other techniques can predict surgical outcome in patients with lesional and nonlesional refractory neocortical epilepsy (NE). METHODS: 23 Patients with lesional NE and 20 patients with nonlesional NE were studied. MEG was recorded for all patients with a 275 channel whole-head system. Synthetic aperture magnetometry (SAM) with excess kurtosis (g2) and conventional Equivalent Current Dipole (ECD) were used for MEG data analysis. 27 Patients underwent long term extraoperative intracranial video electroencephalography (iVEEG) monitoring. Surgical outcomes were assessed based on more than 1-year of post-surgical follow up using Engel classification system. RESULTS: As we expected, both favorable outcomes (Engel class I or II) and seizure freedom outcomes (Engel class IA) were higher for the concordance condition (MEG findings are concordant with MRI or iVEEG findings) versus the discordance condition. Also the seizure free rate was significantly higher (chi2=5.24, P<0.05) for the patients with lesional NE than for the patients with nonlesional NE. In 30% of the patients with nonlesional NE, the MEG findings proved to be valuable for intracranial electrode implantation. CONCLUSIONS: This study demonstrates that a favorable post-surgical outcome can be obtained in most patients with concordant MEG and MRI results even without extraoperative iVEEG monitoring, which indicates that the concordance among different modalities could indicate a likelihood of better postsurgical outcomes. However, extraoperative iVEEG monitoring remains prerequisite to the patients with discordant MEG and MRI findings. For nonlesional cases, our results showed that MEG could provide critical information in the placement of intracranial electrodes. PMID- 21782478 TI - Skin-resident murine dendritic cell subsets promote distinct and opposing antigen specific T helper cell responses. AB - Skin-resident dendritic cells (DCs) are well positioned to encounter cutaneous pathogens and are required for the initiation of adaptive immune responses. There are at least three subsets of skin DC- Langerhans cells (LC), Langerin(+) dermal DCs (dDCs), and classic dDCs. Whether these subsets have distinct or redundant function in vivo is poorly understood. Using a Candida albicans skin infection model, we have shown that direct presentation of antigen by LC is necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not for the generation of cytotoxic lymphocytes (CTLs). In contrast, Langerin(+) dDCs are required for the generation of antigen specific CTL and Th1 cells. Langerin(+) dDCs also inhibited the ability of LCs and classic DCs to promote Th17 cell responses. This work demonstrates that skin-resident DC subsets promote distinct and opposing antigen-specific responses. PMID- 21782479 TI - In vitro comparison of water displacement method and 3 Tesla MRI for MR-volumetry of the olfactory bulb: which sequence is appropriate? AB - RATIONALE AND OBJECTIVES: Magnetic resonance imaging olfactory bulb (OB) volumetry (OBV) is already used as a complementary prognostic tool to assess olfactory disorders. However, a reference standard in imaging for OBV has not been established. The aim of this in vitro study was to compare volumetric results of different magnetic resonance sequences for OBV at 3 T to genuine OB volumes measured by water displacement. MATERIALS AND METHODS: The volumes of 15 human cadaveric OBs were measured using the water displacement method in this institutional review board-approved prospective study. The magnetic resonance imaging protocol at 3 T included constructive interference in steady state (CISS), T2-weighted (T2w) three-dimensional (3D) sampling perfection with application-optimized contrasts using different flip-angle evolutions (SPACE), T2w two-dimensional (2D) turbo spin-echo (TSE), and T1-weighted (T1w) 3D fast low angle shot (FLASH) sequences. Two blinded observers independently performed two OB volumetric assessments per bulbus and sequence. Intraobserver and interobserver reliabilities were assessed by intraclass correlation coefficients. Bland-Altman plots were analyzed to evaluate systematic biases and concordance correlation coefficients to assess reproducibility. RESULTS: For both observers, intraclass correlation coefficient analysis yielded almost perfect results for intraobserver reliability (CISS, 0.94-0.98; T2w 3D SPACE, 0.93-0.98; T2w 2D TSE, 0.98-0.98; T1w 3D FLASH, 0.95-0.99). Interobserver reliability showed almost perfect agreement for all sequences (CISS, 0.98; T2w 3D SPACE, 0.89; T2w 2D TSE, 0.93; T1w 3D FLASH, 0.97). The CISS sequence yielded the highest mean concordance correlation coefficient (0.95) and the highest combination of precision (0.97) and accuracy (0.98) values. In comparison with the water displacement method, Bland-Altman analyses revealed the lowest systematic bias (-0.5%) for the CISS sequence, followed by T1w 3D FLASH (-1.3%), T2w 3D SPACE (-7.5%), and T2w 2D TSE (-10.9%) sequences. CONCLUSIONS: Compared to the water displacement method, the CISS sequence is suited best to validly and reliably measure OB volumes because of its highest values for accuracy and precision and lowest systematic bias. PMID- 21782480 TI - Imaging evidence for renomegaly in patients with POEMS syndrome. AB - RATIONALE AND OBJECTIVES: Organomegaly in POEMS syndrome generally refers to the liver, spleen, and lymph nodes. This study investigates whether there is a significant difference in kidney sizes in patients with POEMS compared to normal controls. MATERIALS AND METHODS: Calculated kidney volumes from 77 patients with POEMS syndrome who had undergone imaging by computed tomography or magnetic resonance imaging were compared to frequency-matched controls. For the POEMS patients and the controls, the volume of each kidney was obtained from a three dimensional segmentation algorithm. Univariate and multiple variable linear regression models were used to identify any differences in kidney size between normal and POEMS patients. RESULTS: There was a univariate statistically significant association between disease state and the difference in kidney volume; having POEMS was associated with 16.3 cm(3) greater kidney volume difference compared to control patients, P < .001. Using a multiple variable model and after adjusting for age, sex, and the smaller kidney size, there was a statistically significant association between disease state and the difference in kidney volume; having POEMS was associated with 16.8 cm(3) greater kidney volume compared to control patients, P < .001. There was not an independent statistically significant association between age, sex, or volume of the smaller kidney and the difference in kidney volume. CONCLUSION: This confirms what is known or suspected clinically, that organomegaly in POEMS includes renomegaly. PMID- 21782481 TI - Oncological outcome of docetaxel-based chemotherapy for Japanese men with metastatic castration-resistant prostate cancer. AB - OBJECTIVES: To retrospectively review the oncologic outcomes of docetaxel-based chemotherapy in Japanese men with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: This study included 257 consecutive Japanese patients with mCRPC who were treated with docetaxel-based chemotherapy between April 2007 and March 2010. The prognostic significance of several clinicopathologic factors in these patients was analyzed. RESULTS: In these 257 patients, the median age and serum value of prostate-specific antigen (PSA) prior to docetaxel-based chemotherapy were 72 years and 43.0 ng/ml, respectively. Of these patients, 64 (24.9%) and 193 (75.1%) received docetaxel as a weekly (30 mg/m(2)) and 3-weekly (70-75 mg/m(2)) regimen, respectively, and estramustine (EM) was administered in combination with docetaxel in 137 (53.3%). PSA decline was observed in 205 patients (79.8%), including 143 (55.6%) achieving PSA decline >= 50%. The median progression-free survival and overall survival (OS) were 4.3 and 25.4 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), PSA value, significant clinical pain, bone metastasis, prior treatment with EM, treatment cycle, and PSA response as significant predictors of OS, of which only PS, significant clinical pain, prior treatment with EM, treatment cycle, and PSA response appeared to be independently related to OS on multivariate analysis. Furthermore, there were significant differences in OS according to positive numbers of these 5 independent risk factors. CONCLUSIONS: Oncologic outcomes in Japanese mCRPC patients receiving docetaxel-based chemotherapy is generally favorable, and the risk stratification presented in this study may contribute to precisely predicting the prognosis of such patients. PMID- 21782482 TI - Do molecular biomarkers have prognostic value in primary T1G3 bladder cancer treated with bacillus Calmette-Guerin intravesical therapy? AB - OBJECTIVES: We examined whether altered protein expression for 7 potential biomarkers, including p53, pRb, PTEN, Ki-67, p27, FGFR3, and CD9, could predict tumor recurrence and progression in patients treated with bacillus Calmette Guerin (BCG) therapy for primary stage T1 grade 3 (T1G3) bladder cancer (BC). MATERIALS AND METHODS: The study included 61 patients with primary T1G3 BC who were treated with 6 weekly intravesical BCG instillations after clinically complete transurethral resection of bladder tumor between 1990 and 2007. All patients had proper muscle tissue in their specimen. Protein expression for 7 molecular biomarkers before BCG therapy was analyzed by immunohistochemistry based on tissue microarray methodology, and the percentage of positive cells was determined quantitatively in a blind fashion. Survival analysis was performed using Kaplan-Meier curves and Cox regression to determine the effect of each marker on recurrence-free survival (RFS) and progression-free survival (PFS) after BCG therapy. RESULTS: Overall 5-year RFS and PFS rates were 56.0% and 84.5%, respectively, with a median follow-up of 60.0 months (range 6-217). The altered expression for each marker were noted in 53.3% for p53, 73.3% for pRb, 63.8% for PTEN, 40.0% for Ki-67, 66.1% for p27, 37.3% for FGFR3, and 47.5% for CD9, respectively. No significant association was found between altered marker status and clinicopathologic characteristics. While increased p53 expression was associated with progression after BCG therapy (5-year PFS rates: 90.7% in p53 < 10% vs. 78.7% in p53 >= 10%, P = 0.0495), no single marker was associated with RFS and PFS after BCG therapy in univariate and multivariate Cox regression analysis. Similarly, in subgroup analysis according to tumor size, multiplicity, and morphology, no single marker was associated with RFS and PFS. No difference was noted in molecular marker status between BCG responders and nonresponders. CONCLUSIONS: Our findings indicate that immunohistochemical analysis for 7 potential molecular markers has no predictive value for recurrence and progression in primary T1G3 BC treated with BCG therapy. Large prospective studies are needed to validate the prognostic molecular markers in primary T1G3 BC. PMID- 21782483 TI - DynaCT in pre-treatment evaluation of aortic aneurysm before EVAR. AB - OBJECTIVE: DynaCT((r)) is a method for obtaining computed tomography (CT)-like images using a C-arm system. Our aim was to compare the accuracy of these images to multidetector CT (MDCT) images prior to endovascular aortic repair (EVAR). METHODS: A non-consecutive group of 20 elective patients were prospectively exposed to MDCT and one additional DynaCT before EVAR. Six arterial measurements and nine anatomical areas were chosen to: (1) visualise the peri-aortic soft tissue and assess the possibility to diagnose a potential haemorrhage from a ruptured aneurysm and (2) make the pre-treatment measurements before insertion of stent graft. Differences between modalities and readers were statistically compared using a linear mixed model. RESULTS: For maximum aortic diameter, a significant difference of 1.3 mm was found between techniques (p = 0.043). Visibility scores were significantly better for all areas in MDCT data. Pre treatment evaluation with DynaCT before EVAR was possible for all areas; evaluation of the iliac arteries were suboptimal due to a limited imaging volume size. Significant inter-reader differences were found for all anatomical areas. CONCLUSION: The result indicates that DynaCT gives sufficient information to determine the correct treatment and for selecting the proper stent graft before EVAR. A limited volume size reduces the evaluation of the iliac arteries. PMID- 21782484 TI - Lower limb arterio-venous fistula as a late complication of phlebectomy in a patient with Ehlers-Danlos type IV. AB - Ehlers-Danlos syndrome type IV (EDS type IV), the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture. The timing, frequency and course of these events are unpredictable. We report a 50-year-old patient with previous complications of EDS type IV who presented with recurrent varicose veins that subsequent imaging identified as an arteriovenous fistula (AVF) at the site of previous phlebectomy. Patients with EDS type IV present vascular surgeons manifold management problems. A pre-existing diagnosis of EDS type IV should alert the clinician to the risk of unusual presentations, both acutely and as complications subsequent to intervention. Once identified, appropriate investigation and follow-up of these patients by a vascular surgeon is mandated. PMID- 21782485 TI - Oral lichen planus and malignant transformation: a longitudinal cohort study. AB - OBJECTIVE: Oral lichen planus (OLP) is associated with risk for developing oral squamous cell carcinoma (OSCC). We performed a 7-year prospective study to assess the incidence of malignant transformation of OLP among adults. STUDY DESIGN: Three hundred twenty-seven OLP patients, 229 women (70.0%) and 98 men (30.0%), were observed during the follow-up period. RESULTS: During a mean follow-up of 81.7 months, 8 of 327 patients developed an OSCC in OLP areas (0.36%/y), yielding the high overall standardized incidence ratio of 17.7 (95% confidence interval [CI] 8.8-35.3). The standardized incidence ratio for OSCC was significantly higher in women [27.0 (95% CI 11.2-64.8)] than in men [11.2 (95% CI 3.6-34.9)]. Six OSCCs were well differentiated (75%) and 2 moderately differentiated (25%). Three subjects (37.5%) developed recurrences within 2 years (mean 16.1 +/- 3.5 months). Disease-free survival rate after 69.8 months was 97.3%. CONCLUSIONS: OLP was associated with a significant increase in the risk for OSCC. Close surveillance may help to reduce the morbidity of OSCC arising from OLP at 24 months. PMID- 21782486 TI - Presence and impact of the exercise-induced collapse associated DNM1 mutation in Labrador retrievers and other breeds. AB - The impact of the mutation causing dynamin 1 (DNM1)-associated exercise-induced collapse (d-EIC) was determined in a retrospective genetic survey. The frequency of DNM1 mutant allele carriers in Labrador retrievers from conformation show, field trial/hunt test, pet or service lines ranged from 17.9% to 38.0% and the frequency of homozygous mutant (EE genotype) individuals ranged from 1.8% to 13.6%; 83.6% of these EE Labradors were reported to have collapsed by 4 years of age. DNM1 mutation carriers and EE dogs with a collapse phenotype were also detected in Chesapeake Bay retrievers, Curly-coated retrievers, Boykin spaniels, Pembroke Welsh corgis and mixed breed dogs thought to be Labrador retriever crosses. The DNM1 mutation was not identified in Golden, Flat-coated, or Nova Scotia duck tolling retrievers, or 15 other non-retrieving breeds. Veterinarians and breeders should be aware that the DNM1 EE genotype is not completely penetrant and that d-EIC is a widespread health concern in several very popular breeds, as well as breeds whose genetic similarity to retrievers is not obvious. PMID- 21782487 TI - Plasma atrial natriuretic peptide concentrations in horses with heart disease: a pilot study. AB - Atrial natriuretic peptide (ANP) is a cardiovascular biomarker that might be useful in assessing the severity of cardiac disease in horses. Plasma ANP concentrations (Cp(ANP)) were compared between horses with heart disease but normal chamber size and function (Group A; n=6), horses with heart disease associated with left atrial (LA) enlargement, LA dysfunction, and/or left ventricular (LV) enlargement (Group B; n=5), and horses with no clinically apparent cardiovascular disease (Group C; n=13). The median (min-max) for Cp(ANP) was significantly higher in Group B (53.5 (36.0-70.7) pg/mL), compared to Group A (12.5 (6.3-19.8) pg/mL) and Group C (13.4 (7.2-34.0) pg/mL). Backwards stepwise multiple linear regression showed that Cp(ANP) in horses with heart disease was related to LA dimensions, but not to LV size, LA function, and LV function. The results indicated that Cp(ANP) in horses might be useful in detecting LA enlargement and that Cp(ANP) could be related to the severity of cardiac disease. Larger prospective studies are necessary to confirm these results. PMID- 21782488 TI - Quantitative phenomenological model of the BOLD contrast mechanism. AB - Different theoretical models of the BOLD contrast mechanism are used for many applications including BOLD quantification (qBOLD) and vessel size imaging, both in health and disease. Each model simplifies the system under consideration, making approximations about the structure of the blood vessel network and diffusion of water molecules through inhomogeneities in the magnetic field created by deoxyhemoglobin-containing blood vessels. In this study, Monte-Carlo methods are used to simulate the BOLD MR signal generated by diffusing water molecules in the presence of long, cylindrical blood vessels. Using these simulations we introduce a new, phenomenological model that is far more accurate over a range of blood oxygenation levels and blood vessel radii than existing models. This model could be used to extract physiological parameters of the blood vessel network from experimental data in BOLD-based experiments. We use our model to establish ranges of validity for the existing analytical models of Yablonskiy and Haacke, Kiselev and Posse, Sukstanskii and Yablonskiy (extended to the case of arbitrary time in the spin echo sequence) and Bauer et al. (extended to the case of randomly oriented cylinders). Although these models are shown to be accurate in the limits of diffusion under which they were derived, none of them is accurate for the whole physiological range of blood vessels radii and blood oxygenation levels. We also show the extent of systematic errors that are introduced due to the approximations of these models when used for BOLD signal quantification. PMID- 21782489 TI - Sonodegradation of 17alpha-ethynylestradiol in environmentally relevant matrices: laboratory-scale kinetic studies. AB - The sonochemical degradation of 17alpha-ethynylestradiol (EE2) in secondary treated effluents was investigated. Ultrasound irradiation was provided by a horn type sonicator operating at 80 kHz. The effect of various operating conditions such as estrogen concentration (25-160 MUg/L), power density (18-46 W/L), liquid bulk temperature (15-60 degrees C), gas sparging (air, oxygen, and helium), solution pH (3 and 7.8), as well as the addition of radical promoters (hydrogen peroxide) or catalysts (TiO2 and Fe2+) on degradation kinetics was evaluated. Changes in estrogen concentration were followed by high performance liquid chromatography and the yeast estrogen screening (YES) assay. EE2 degradation in the range 25-110 MUg/L follows first order kinetics in regard to its concentration, while lower order kinetics occur at higher concentrations. The reaction rate increases linearly with applied power and decreases exponentially with temperature at the conditions in question. Continuous sparging of air or oxygen has little effect on the kinetics relative to air-equilibrated conditions, while helium has a marginally positive effect. The inorganic and organic contents of the wastewater matrix appear to promote degradation at inherent conditions in comparison to experiments in ultrapure water. Nevertheless, the addition of H2O2 (8.6 and 86 mg/L), Fe2+ (2.5-25 mg/L) or TiO2 (50-2000 mg/L) has no or, in some cases, adverse effect on kinetics. PMID- 21782490 TI - Mutational screening of THAP1 in a German population with primary dystonia. PMID- 21782491 TI - Unintended consequences of regulating drinking water in rural Canadian communities: examples from Atlantic Canada. AB - Studies that explore social capital and political will [corrected] in the context of safe drinking water provision in [corrected] Canada are limited. This paper presents findings from a study that examines the capacity of rural Canadian communities to attain regulatory compliance for drinking water. Interviews were conducted with water operators and managers in ten rural communities across Atlantic Canada to identify the burden of compliance arising from the implementation of, and adherence to, drinking water regulations. This research identifies the operator as being particularly burdened by regulatory compliance, often resulting in negative consequences including job stress and a strained relationship with the community they serve. Findings indicate that while regulations are vital to ensuring safe drinking water, not all communities have the resources in place to rise to the challenge of compliance. As a result, some communities are being negatively impacted by these regulations, rather than benefit from their intended positive effect. PMID- 21782492 TI - Molecular aspects of defence priming. AB - Plants can be primed for more rapid and robust activation of defence to biotic or abiotic stress. Priming follows perception of molecular patterns of microbes or plants, recognition of pathogen-derived effectors or colonisation by beneficial microbes. However the process can also be induced by treatment with some natural or synthetic compounds and wounding. The primed mobilization of defence is often associated with development of immunity and stress tolerance. Although the phenomenon has been known for decades, the molecular basis of priming is poorly understood. Here, I summarize recent progress made in unravelling molecular aspects of defence priming that is the accumulation of dormant mitogen-activated protein kinases, chromatin modifications and alterations of primary metabolism. PMID- 21782493 TI - RNA-based regulation in the plant circadian clock. AB - The circadian clock is an endogenous, approximately 24-h timer that enables plants to anticipate daily changes in their environment and regulates a considerable fraction of the transcriptome. At the core of the circadian system is the oscillator, made up of interconnected feedback loops, involving transcriptional regulation of clock genes and post-translational modification of clock proteins. Recently, it has become clear that post-transcriptional events are also critical for shaping rhythmic mRNA and protein profiles. This review covers regulation at the RNA level of both the core clock and output genes in Arabidopsis (Arabidopsis thaliana), with comparisons with other model organisms. We discuss the role of splicing, mRNA decay and translational regulation as well as recent insights into rhythms of noncoding regulatory RNAs. PMID- 21782494 TI - Synthesis, spectroscopy, and characterization of some bis-nicotinamide metal(II) dihalide complexes. AB - We report synthesis of six new bis-nicotinamide metal(II) dihalide complexes [M(nia)(2)Cl(2); M = Mn, Co; nia:nicotinamide, M(nia)(2)Br(2); M = Mn, Hg; M(nia)(2)I(2); M = Cd, Cu], and their characterization by combining infrared spectroscopy with density functional theory (DFT) calculations. Infrared spectra indicate that ring-nitrogen is the active donor cite, and the atomic structure of the complexes is determined to be polymeric octahedral or distorted polymeric octahedral. Spin polarized electronic ground state is obtained for Mn, Co, and Cu halide complexes. The colors of the complexes also support the conclusion of octahedral coordination around the metal atoms, in agreement with DFT results. PMID- 21782495 TI - Raman spectroscopy of archaeological and ancient resins: problems with database construction for applications in conservation and historical provenancing. AB - The adoption of Raman spectroscopy as a screening technique for the presence of organic resins on diverse substrates is now being advocated for the first pass non-destructive examination of potential sites for limited sampling using other analytical techniques. The characterisation of ancient resins in art work and specimens recovered from archaeological excavations is critically dependent upon the analytical capability of Raman spectroscopy using different wavelengths of excitation from the visible to the near infrared and the interpretation of the data illustrates the advantages and limitations of the technique. Resin specimens from art works and artefacts span a period of about 7000 years of recorded history and the influence of factors such as the environmental degradation, burial deposition, reaction with associated substrates and mineral pigments on the observed Raman spectra have been assessed. The key molecular Raman spectral features that are definitive for the discrimination between contemporary resins are considered in respect of these factors and thereby illustrative of the difficulties posed for the creation of a Raman spectral database of ancient resins, in contrast with the extensive and definitive literature equivalents that are available for their mineral pigment and organic dye analogues. PMID- 21782496 TI - Investigation of the binding of Salvianolic acid B to human serum albumin and the effect of metal ions on the binding. AB - The studies on the interaction between HSA and drugs have been an interesting research field in life science, chemistry and clinical medicine. There are also many metal ions present in blood plasma, thus the research about the effect of metal ions on the interaction between drugs and plasma proteins is crucial. In this study, the interaction of Salvianolic acid B (Sal B) with human serum albumin (HSA) was investigated by the steady-state, synchronous fluorescence and circular dichroism (CD) spectroscopies. The results showed that Sal B had a strong ability to quench the intrinsic fluorescence of HSA through a static quenching mechanism. Binding parameters calculated showed that Sal B was bound to HSA with the binding affinities of 10(5) L mol(-1). The thermodynamic parameters studies revealed that the binding was characterized by positive enthalpy and positive entropy changes, and hydrophobic interactions were the predominant intermolecular forces to stabilize the complex. The specific binding distance r (2.93 nm) between donor (HSA) and acceptor (Sal B) was obtained according to Forster non-radiative resonance energy transfer theory. The synchronous fluorescence experiment revealed that Sal B cannot lead to the microenvironmental changes around the Tyr and Trp residues of HSA, and the binding site of Sal B on HSA is located in hydrophobic cavity of subdomain IIA. The CD spectroscopy indicated the secondary structure of HSA is not changed in the presence of Sal B. Furthermore, The effect of metal ions (e.g. Zn(2+), Cu(2+), Co(2+), Ni(2+), Fe(3+)) on the binding constant of Sal B-HSA complex was also discussed. PMID- 21782497 TI - Effect of inclusion complex on nitrous acid reaction with flavonoids. AB - The kinetic of the nitrous acid reactions with quercetin and catechin has been studied using spectrophotometric method in aqueous solution. The results show that these antioxidants participate in oxidation reactions with nitrous acid which is derived from protonation of nitrite ion in mild acidic conditions. Corresponding o-quinones as relatively stable products were detected by spectrophotometric techniques. pH dependence of the reactions has been examined and the rate constants of reactions were obtained by non-linear fitting of kinetic profiles. The effect of beta-cyclodextrin on the oxidation pathway was another object of this study. It is shown that beta-cyclodextrin has an inhibitory effect on the oxidation reaction. The rate constants of oxidation reactions for complexed forms and their stability constants were obtained based on changes in the reaction rates as a function of beta-cyclodextrin concentration. PMID- 21782498 TI - Conformational stability, the spectroscopic (FT-IR and UV), first order hyperpolarizability, NBO analysis, HOMO and LUMO analysis of 6,8 diphenylimidazo[1,2-alpha]pyrazine molecule by ab initio HF and density functional methods. AB - The conformational analysis of 6,8-diphenylimidazo[1,2-alpha]pyrazine molecule (abbreviated as 68DIP) was performed by using B3LYP/6-31G(d) level of theory to find the most stable form. Two staggered stable conformers were observed on the torsional potential energy surface. The equilibrium geometry, bonding features and vibrational frequencies of 68DIP have been investigated by using the DFT (B3LYP) and HF methods for the lowest energy conformer. The first order hyperpolarizability (beta(total)) of this molecular system and related properties (beta, MU, and Deltaalpha) are calculated using HF/6-311++G(d,p) and B3LYP/6-311++G(d,p) methods based on the finite-field approach. Stability of the molecule arising from hyperconjugative interactions, charge delocalization and C H?N intramolecular hydrogen-bond-like weak interaction has been analyzed using natural bond orbital (NBO) analysis by using B3LYP/6-311++G(d,p) method. The results show that electron density (ED) in the sigma* and pi* antibonding orbitals and second order delocalization energies E((2)) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. UV-vis spectrum of the compound was recorded and electronic properties, such as HOMO, LUMO energies, excitation energies and wavelength were performed by TD-DFT/B3LYP, CIS and TD-HF methods by using 6-311++G(d,p) basis set. Finally, the calculation results were applied to simulated infrared spectra of the title compound which show good agreement with observed spectra. PMID- 21782499 TI - EPR and optical absorption spectral studies on sphalerite mineral. AB - The mineral sphalerite (Zn,Fe)S has been characterized by a combination of X-ray diffraction, EPR and NIR spectroscopy. The optical absorption spectrum of mineral sphalerite is due to an iron impurity only, which is in a distorted octahedral environment. The g=2.2 is attributed to iron and g and A value observed in the spectrum 1.999 and 6.0 mT are assigned to Mn(II) impurity in the mineral. These results indicate that iron and Mn(II) impurity have entered the lattice by substitution. The EPR results confirm the presence of manganese in a distorted octahedral environment. It is evident from the chemical analysis that iron is present in higher concentrations. NIR results are due to the presence of water and sulphide fundamentals which also support the formula of the mineral. No sulphate in the sphalerite mineral was observed. PMID- 21782500 TI - Bivalent transition metal complexes of o-hydroxyacetophenone [N-(3-hydroxy-2 naphthoyl)] hydrazone: spectroscopic, antibacterial, antifungal activity and thermogravimetric studies. AB - Schiff base complexes of Cu(II), Ni(II) and Zn(II) with the o-hydroxyacetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone (H(2)o-HAHNH) containing N and O donor sites have been synthesized. Both ligand and its metal complexes were characterized by different physicochemical methods, elemental analysis, molar conductivity ((1)H NMR, (13)C NMR, IR, UV-visible, ESR, MS spectra) and also thermal analysis (TG and DTG) techniques. The discussion of the outcome data of the prepared complexes indicates that the ligand behave as a bidentate and/or tridentate ligand. The electronic spectra of the complexes as well as their magnetic moments suggest octahedral geometries for all isolated complexes. The room temperature solid state ESR spectrum of the Cu(II) complex shows d(x2-y2) as a ground state, suggesting tetragonally distorted octahedral geometry around Cu(II) centre. The molar conductance measurements proved that the complexes are non-electrolytes. The kinetic thermodynamic parameters such as: E(#), DeltaH(#), DeltaG(#), DeltaS(#) are calculated from the DTG curves, for the [Ni(H(O) HAHNH)(2)] and [Zn(H(2O)-HAHNH)(OAc)(2)].H(2)O complexes using the Coats-Redfern equation. Also, the antimicrobial properties of all compounds were studied using a wide spectrum of bacterial and fungal strains. The [Cu(Ho HAHNH)(OAc)(H(2)O)(2)] complex was the most active against all strains, including Aspergillus sp., Stemphylium sp. and Trichoderma sp. Fungi; E. coli and Clostridium sp. Bacteria. PMID- 21782501 TI - Determination of the sodium 2-mercaptoethanesulfonate based on surface-enhanced Raman scattering. AB - Based on the surface-enhanced Raman scattering (SERS) sodium 2 mercaptoethanesulfonate (mesna) was determined using unmodified gold colloid as the probe. The Raman scattering intensity was obviously enhanced in the presence of sodium chloride. The influence of experimental parameters, such as incubation time, sodium chloride concentration and pH value on SERS performance was examined. Under the optimum conditions, the SERS intensity is proportional to the concentration of mesna in the range of 9.0*10(-8) to 9.0*10(-7) mol/L and detection limit (S/N=3) is 1.16*10(-8) mol/L. The corresponding correlation coefficient of the linear equation is 0.996, which indicates that there is a good linear relationship between SERS intensity and mesna concentration. The experimental results indicate that the proposed method is a viable method for determination of mesna. The real samples were analyzed and the results obtained were satisfactory. PMID- 21782502 TI - The formation of a luminescent Mn(III,IV) intermediate of bis(2 pyridylmethyl)amine and acetone assistant its intramolecular C-H oxidation. AB - The dinuclear Mn(II) complexes of bis(2-pyridylmethyl)amine (dpa) reacted with H(2)O(2) producing a fluorescent dioxodimanganese(III,IV) intermediate [(dpa)Mn(2)Cl(2)(MU-O(2))(OHdpa)](3+), which was characterized by IR, UV, ESR, ES MS and fluorescence spectra. ES-MS data show that this intermediate could bind an acetone molecule forming dioxodimanganese(III,IV)-acetone adduct [(dpa)Mn(2)Cl(2)(MU-O)(CH(3)COCH(3))(OHdpa)](3+). The emission of dioxodimanganese(III,IV)-acetone at 378 nm was stronger than that of dioxodimanganese(III,IV) complex. Excess acetone molecules promoted the intramolecular C-H oxidation and the formation of one dimensional chain Mn(II) complex [(2-picolinic-acid)Mn(H(2)O)(2)Cl(O)](n) through possible intramolecular oxygen transfer reaction. PMID- 21782503 TI - Flexibility in interaction: sociotechnical design of an operating room scheduler. AB - PURPOSE: The purpose of this study was to learn about factors that influence the design and implementation of situated computing solutions that support hospital work. This includes social and technical aspects of the actual systems that will be implemented, as well as the appropriate design methodology for developing these systems. METHODS: Staff at a surgical department at a University hospital were engaged in a participatory design (PD) process to help solve a problem that was presented by the staff: scheduling of patients and surgery rooms, and creating awareness of the status of ongoing surgeries. The PD process was conceptually aided by a model that describes Medical Informatics Systems as comprising of three components, a service component, a technical component and a social component. The process included the use of ethnographic field work and iterative redesign of both technical and social components of the system after it had been implemented into day-to-day work practice. RESULTS: The PD process resulted in the creation of a system that was iteratively created over a period of about 2 years, and which then handed over to the IT department of the hospital and used by the surgical department for a period of about 1 additional year. The first version of the prototype that was implemented contained usability flaws that made the system difficult to use in time critical situations. As a result of observations and a redesign of the technical component and social component of the system a new version was possible to implement that managed to overcome this problem. A key feature of this second version of the system was that some responsibility for data entry validation was shifted from the technical component of the system to the social component of the system. This was done by allowing users to input poor data initially, while requiring them to fix this data later on. This solution breaks from "traditional" usability design but proved to be quite successful in this case. A challenge with the solution, however, was that the IT department could not understand the concept of systems being described as comprising of both social components and technical components, and thus they had difficulty in understanding the overall design of the system during the handover process. CONCLUSIONS: Situated computing can present a number of design challenges that may not be easy for designers and hospital workers to understand before a system has been implemented. Situated computing development may thus need to be aided by PD that includes both ethnographic observations and iterative redesign of the system after it has been implemented. Traditional data validation mechanisms may create poor system performance in cases where users are rushed to input data into the computer due to pressures created by other more critical work activities. In this case it may be better to rely on social mechanisms for correcting errors later on, rather than error catching mechanisms that reject incorrect data. It can be challenging, however, to maintain such systems over time, as IT-departments may lack skills and interest in social components. PMID- 21782504 TI - HTLV infection among foreign pregnant women living in Spain. AB - BACKGROUND: The overall seroprevalence of HTLV infection among pregnant women in Spain is below 0.02% and accordingly universal antenatal screening is not recommended. However, as the number of immigrants has significantly increased during the last decade, this population might warrant specific considerations. OBJECTIVE: To evaluate the seroprevalence of HTLV infection among immigrant pregnant women living in Spain. METHODS: From January 2009 to December 2010 a cross-sectional study was carried out in all foreign pregnant women attended at 14 Spanish clinics. All were tested for HTLV antibodies using a commercial enzyme immunoassay, being reactive samples confirmed by Western blot or PCR. RESULTS: A total of 3337 foreign pregnant women were examined. Their origin was as follows: Latin America 1579 (47%), North Africa 507 (16%), East Europe 606 (18%), Sub Saharan Africa 316 (9%), North America and West Europe 116 (3.5%) and Asia and Australia 163 (5%). A total of 7 samples were confirmed as HTLV positive, of which 6 were HTLV-1 and 1 HTLV-2. HTLV-1 infection was found in 5 women coming from Latin America and 1 from Morocco. The only woman with HTLV-2 came from Ghana. The overall HTLV seroprevalence was 0.2%, being 0.3% among Latin Americans and 0.2% among Africans. It was absent among women coming from other regions. CONCLUSIONS: The seroprevalence of HTLV infection among foreign pregnant women in Spain is 0.2%, being all cases found in immigrants from Latin America and Africa. Given the benefit of preventing vertical transmission, antenatal screening should be recommended in pregnant women coming from these regions. PMID- 21782505 TI - Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections. AB - Human herpesvirus 6 (HHV-6) is a ubiquitous virus inducing a life-long latent infection of its human host. Acute infections (AIs) have been recognized as the cause of severe diseases. These AIs correspond to primary infections (PIs), mainly occurring in young children, endogenous reactivations (ENRs), observed at any age, and putative exogenous reinfections (EXRs). The diagnosis of AIs is now essentially based on the quantification of viral load in bodily fluids and organs by means of real time PCR. However, this diagnosis is currently bothered by the lack of well established viral load thresholds for the different levels of virus replication, the concomitant infection with the two variants HHV-6A and HHV-6B, and the existence, albeit at low frequency, of chromosomal integration of viral DNA. An additional challenge is the difficulty to establish the causality relationship between AI and disease. Although many AIs are asymptomatic or poorly symptomatic with a spontaneous favourable outcome, some have been credited with serious clinical manifestations affecting central nervous system, liver, gastrointestinal tract, lungs, and bone marrow. The main favouring factor for such serious diseases is cellular immune deficiency. These severe diseases can be exemplified by encephalitis cases either associated with PI in young children or with ENR, especially in haematopoietic stem cell transplant recipients. The antiviral drugs ganciclovir, foscarnet and cidofovir have proven to be efficient against AIs and related diseases but the indications and conditions of their use are not yet formally approved. This emphasizes the need for controlled studies addressing both the clinical impact and therapy of HHV-6 AIs. PMID- 21782506 TI - Influence of artificial mediators on yeast-based fuel cell performance. AB - Soluble artificial mediators are often applied to enhance the electron transfer from living cells to an anode in microbial fuel cells. Recently, we have demonstrated that the Candida melibiosica 2491 yeast strain possesses electrogenic properties and can be used as a biocatalyst in yeast-based fuel cells even in the absence of artificial mediators. To enhance the generated electrical power, the potential application of several organic compounds as mediators in a C. melibiosica-based fuel cell was examined in this study. The choice of compounds was based upon observed cyclic voltammetry reversible electrochemical behavior at potentials appropriate for mediated electron transfer. Among the studied mediators, methylene blue, methyl orange, methyl red and neutral red significantly increased the current and power outputs in comparison with those obtained with a mediatorless yeast-based fuel cell. PMID- 21782507 TI - Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. AB - BACKGROUND: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. METHODS: Genomic DNA extracted from formalin fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17.5 months [95% CI 11.7-23.4] vs 8.5 months [7.1-10.8], hazard ratio [HR] 0.52 [0.32-0.84], p=0.0063; chemotherapy alone: 23.8 months [15.2-not reached] vs 10.0 months [8.7-11.0], HR 0.35 [0.21-0.59], p<0.0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11.4 months [8.6-13.6] vs 6.8 months [5.9-12.7], HR 0.80 [0.55-1.16], p=0.24; chemotherapy alone: 11.0 months [9.2-12.6] vs 9.3 months [7.6-11.9], HR 0.77 [0.54-1.10], p=0.16). INTERPRETATION: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. FUNDING: Merck KGaA. PMID- 21782508 TI - Are all KRAS mutations created equal? PMID- 21782510 TI - Height and cancer: consistent links, but mechanisms unclear. PMID- 21782509 TI - Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. AB - BACKGROUND: Epidemiological studies have shown that taller people are at increased risk of cancer, but it is unclear if height-associated risks vary by cancer site, or by other factors such as smoking and socioeconomic status. Our aim was to investigate these associations in a large UK prospective cohort with sufficient information on incident cancer to allow direct comparison of height associated risk across cancer sites and in relation to major potential confounding and modifying factors. METHODS: Information on height and other factors relevant for cancer was obtained in 1996-2001 for middle-aged women without previous cancer who were followed up for cancer incidence. We used Cox regression models to calculate adjusted relative risks (RRs) per 10 cm increase in measured height for total incident cancer and for 17 specific cancer sites, taking attained age as the underlying time variable. We also did a meta-analysis of published results from prospective studies of total cancer risk in relation to height. FINDINGS: 1 297 124 women included in our analysis were followed up for a total of 11.7 million person-years (median 9.4 years per woman, IQR 8.4-10.2), during which time 97 376 incident cancers occurred. The RR for total cancer was of 1.16 (95% CI 1.14-1.17; p<0.0001) for every 10 cm increase in height. Risk increased for 15 of the 17 cancer sites we assessed, and was statistically significant for ten sites: colon (RR per 10 cm increase in height 1.25, 95% CI 1.19-1.30), rectum (1.14, 1.07-1.22), malignant melanoma (1.32, 1.24-1.40), breast (1.17, 1.15-1.19), endometrium (1.19, 1.13-1.24), ovary (1.17, 1.11-1.23), kidney (1.29, 1.19-1.41), CNS (1.20, 1.12-1.29), non-Hodgkin lymphoma (1.21, 1.14 1.29), and leukaemia (1.26, 1.15-1.38). The increase in total cancer RR per 10 cm increase in height did not vary significantly by socioeconomic status or by ten other personal characteristics we assessed, but was significantly lower in current than in never smokers (p<0.0001). In current smokers, smoking-related cancers were not as strongly related to height as were other cancers (RR per 10 cm increase in height 1.05, 95% CI 1.01-1.09, and 1.17, 1.13-1.22, respectively; p=0.0004). In a meta-analysis of our study and ten other prospective studies, height-associated RRs for total cancer showed little variation across Europe, North America, Australasia, and Asia. INTERPRETATION: Cancer incidence increases with increasing adult height for most cancer sites. The relation between height and total cancer RR is similar in different populations. FUNDING: Cancer Research UK and the UK Medical Research Council. PMID- 21782511 TI - Neutrophil clearance: when the party is over, clean-up begins. AB - Maintenance of circulating, functional neutrophils and their robust recruitment to tissues in response to injury and/or microbial infection are crucial for host defense. Equally important, although less well understood, are the processes for removal of these short-lived cells. Here, we review recent findings of novel neutrophil characteristics that determine removal. These neutrophil-derived signals, in turn, can shape the responses of other cells and surrounding tissues and promote a return to homeostasis. If not removed, dying neutrophils disintegrate and release phlogistic cargo that can further contribute to ongoing inflammation, tissue destruction, or autoimmunity. PMID- 21782513 TI - Seven years of experience of preimplantation HLA typing: a clinical overview of 327 cycles. AB - Preimplantation human leukocyte antigen (HLA) typing allows the birth of healthy children who are potential donors of stem cells for their affected siblings. This technique can be used for acquired diseases such as leukaemia or can be used for single-gene disorders such as thalassaemia. This retrospective study presents clinical data obtained from 171 couples who had undergone 327 preimplantation HLA typing cycles: 262 cycles for HLA typing in combination with mutation analysis and 65 cycles for the sole purpose of HLA typing. Of the diagnosed embryos 17.6% were found to be HLA matched. Embryo transfer was performed in 212 cycles, 34.9% clinical pregnancy rate per transfer was achieved and 59 healthy and HLA compatible children were born. Twenty-one sick children have been cured through haemopoietic stem cell transplantation. The effect of maternal age and ovarian reserve on reproductive outcome was assessed retrospectively. The data demonstrated that, once a mutation-free and HLA-compatible embryo was found, clinical pregnancy rate did not differ statistically significantly despite the presence of some cycle-related limitations such as advanced maternal age and/or diminished ovarian reserve. Preimplantation HLA typing is an effective therapeutic tool for curing an affected sibling even for poor-prognosis patients. Preimplantation human leukocyte antigent (HLA) typing allows the birth of healthy children who are potential donors of stem cells for their affected siblings. This technique can be used for acquired diseases such as leukaemia or can be used for single-gene disorders such as thalassaemia. This study presents clinical data obtained from 171 couples who underwent 327 preimplantation HLA-typing cycles. Of these, 262 cycles were performed for HLA typing in combination with mutation analysis and 65 cycles were performed for the sole purpose of HLA typing. A total of 17.6% of the diagnosed embryos were found to be HLA matched. Embryo transfer was performed in 212 cycles. The clinical pregnancy rate per transfer was 34.9% and 59 healthy and HLA compatible children were born. Twenty-one sick children have been cured through haemopoietic stem cell transplantation. The effect of maternal age and ovarian reserve on reproductive outcome was assessed retrospectively. The data demonstrated that, once a mutation-free and HLA compatible embryo was found, clinical pregnancy rates did not differ statistically significantly by the presence of some cycle-related limitations such as advanced maternal age and/or diminished ovarian reserve. Preimplantation HLA typing is an effective therapeutic tool for curing an affected sibling even for poor-prognosis patients. PMID- 21782514 TI - Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial. AB - Sequential use of letrozole and human menopausal gonadotrophin (HMG) was compared with HMG only in poor ovarian responders undergoing IVF. Patients (n=53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either letrozole for 5days followed by HMG or HMG alone. The letrozole group had lower dosage of HMG (P<0.001), shorter duration of HMG (P<0.001) and fewer oocytes (P=0.001) when compared with controls. Live-birth rate was comparable with a lower miscarriage rate in the letrozole group (P=0.038). Serum FSH concentrations were comparable in both groups except on day 8, while oestradiol concentrations were all lower in the letrozole group from day 4 (all P<0.001). Follicular fluid concentrations of testosterone, androstenedione, FSH and anti-Mullerian hormone were higher in the letrozole group (P=0.009, P=0.001, P=0.046 and P=0.034, respectively). Compared with HMG alone, sequential use of letrozole and HMG in poor responders resulted in significantly lower total dosage and shorter duration of HMG, a comparable live birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment of follicular fluid. The management of poor ovarian responders or women with poor ovarian reserve in IVF is controversial. The use of letrozole has been studied; however, results are inconsistent. This randomized trial studied the sequential use of letrozole and gonadotrophin compared with gonadotrophin alone in poor responders undergoing IVF. The sequential use of letrozole and gonadotrophin led to a significantly lower dosage and shorter duration of gonadotrophin use, significantly fewer oocytes, comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment at a lower cost. PMID- 21782512 TI - T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. AB - T helper (Th)17 cells have been proposed to represent a new CD4(+) T cell lineage that is important for host defense against fungi and extracellular bacteria, and the development of autoimmune diseases. Precisely how these cells arise has been the subject of some debate, with apparent species-specific differences in mice and humans. Here, we describe evolving views of Th17 specification, highlighting the contribution of transforming growth factor-beta and the opposing roles of signal transducer and activator of transcription (STAT)3 and STAT5. Increasing evidence points to heterogeneity and inherent phenotypic instability in this subset. Ideally, better understanding of expression and action of key transcription factors and the epigenetic landscape of Th17 can help explain the flexibility and diversity of interleukin-17-producing cells. PMID- 21782515 TI - Computer-assisted embryo selection: a benefit in the evaluation of embryo quality? AB - Embryo selection is based on embryo developmental and morphological characteristics. Standard embryo evaluation has some disadvantages. New technology using multilevel images combined with a computer-assisted scoring system (CASS) has the potential to overcome these disadvantages. The aim of this study was to compare the value of a computer-assisted scoring system (CASS) versus a standard scoring system (SSS) in predicting implantation and live birth. This prospective study included 3185 embryos obtained during 502IVF/intracytoplasmic sperm injection cycles with single-embryo transfer on day 3. Embryos were evaluated with two scoring systems: SSS and CASS. Logistic regression analyses were performed using implantation and live birth as outcomes. According to multiple regression analysis, implantation was influenced by number and size of blastomeres on day 3 using CASS and by all embryo parameters on day 3 using SSS. Combined analysis of both scoring systems revealed that implantation was affected by number and size of blastomeres using CASS and by the degree of embryo fragmentation using SSS. Using live birth as outcome, only the number of blastomeres on day 3, evaluated by SSS and CASS, was predictive. Prediction of implantation and live birth may be superior using CASS when compared with SSS. Embryo selection is currently based on embryo developmental and morphological characteristics of an embryo using a standard scoring system. This evaluation system is limited by a number of disadvantages. New technology using multilevel images combined with a computer-assisted scoring system has the potential to overcome these disadvantages. The aim of this study was to compare the value of such computer-assisted scoring system versus a standard scoring system in predicting implantation and live birth rate. This study included 3185 embryos obtained during 502 IVF or intracytoplasmic sperm injection cycles with single embryo transfer on day 3. All the embryos were evaluated with two types of scoring systems: a standard scoring system and a computer-assisted scoring system. According to the statistical analysis, the implantation of an embryo was influenced by the number and size of blastomeres on day 3 when evaluated with the computer-assisted scoring system, and by all embryo parameters on day 3 using the standard scoring system. Combined analysis of both scoring systems revealed that implantation was affected by number and size of blastomeres using the computer assisted scoring system and by the degree of embryo fragmentation using the standard scoring system. Live birth was influenced by the number of blastomeres on day 3 evaluated by both scoring systems. Prediction of embryo implantation and live birth was superior using the computer-assisted scoring system. In conclusion, a computer-assisted scoring system may be superior to a standard scoring system in the prediction of implantation and live birth. PMID- 21782516 TI - Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development. AB - It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. PMID- 21782517 TI - Effect of pathogen inactivation on the storage lesion in red cells and platelet concentrates. AB - A primary function of blood transfusion services is to ensure the safety of the community's blood supply. Multilayer strategies of safety need to be incorporated into the processing of blood components in order to minimize untoward transfusion events related to infections or the blood storage lesion. While there have been considerable technical advances over the past few decades to advance blood component safety, there is a need for continued improvement. One significant problem area is transfusion transmitted bacterial infections. In infectious disease, blood borne bacteria are the major cause of morbidity in transfusion medicine. Proactive implementation of pathogen inactivation technologies, PIT can help to eliminate bacterial contamination of blood. This is accomplished by inactivation of various known and emerging bacterial pathogens, which have been identified through their nucleic acid sequences. The current PIT has additional positive impacts on transfusion safety by reducing adverse clinical events associated with viable residual leukocytes in the blood. Given the valuable benefits of pathogen inactivation, there is a practicable need to advance this technology. In order for a particular pathogen inactivation strategy to gain widespread acceptance, it must satisfy a number of important criteria. The technology shall be: (1) Effective to eliminate pathogens. (2) Uncomplicated and cost-effective to implement in the preparation of blood components. (3) Minimally toxic while maintaining the quality of blood storage products for transfusion purposes. (4) Safe. Currently, PIT is not suitable for all blood components. Future advances in PIT for whole blood and red cell components should expand the application of this technology across a broader range of blood products. Based on available laboratory and clinical data, current pathogen inactivation procedures appear to leave the cell components sufficiently viable to achieve an effective transfusion. Novel technologies continue to evolve for the inactivation of pathogens in the blood supply. We need to ensure these procedures do not worsen the storage lesion causing potential harm to patients. Quality research and development supporting multi-centre clinical trials are necessary. One purpose of such trials is to determine whether this new generation of procedures for processing blood yields bioequivalency regarding the quality of the products. Validated haematological assays should be utilized to test the extent of the blood storage lesion. Post-marketing surveillance involving active haemovigilance is necessary regarding possible adverse outcomes of transfusion. PMID- 21782518 TI - Efficacy of RTS,S malaria vaccine given with EPI vaccines. PMID- 21782520 TI - Implementation of processes of care to support transcatheter aortic valve replacement programs. AB - Transcatheter aortic valve replacement (TAVR) is increasingly accepted as a feasible and safe therapeutic alternative to open heart surgery in select patients. Procedural success and technological advances combined with favorable clinical outcomes and demonstrated prolonged survival are establishing TAVR as the standard of care in symptomatic patients who are at higher risk or not candidates for conventional surgery. The growing number of referrals and complexities of care of TAVR candidates warrants a program that ensures appropriate patient assessment and triage, establishes appropriate processes, and promotes continuity of care. To address these needs and prepare for the anticipated growth of transcatheter heart valve (THV) therapeutic options, the TAVR program at St. Paul's Hospital, Vancouver, Canada, implemented an electronic centralized and clinically managed referral and triage program, and a THV Nurse Coordinator position to support the program and patients, conduct a global functioning assessment, and provide clinical triage coordination, waitlist management, patient and family education and communication with clinicians. Interdisciplinary rounds assist in the selection of candidates, while a clinical data management system facilitates standardized documentation and quality assurance from referral to follow-up. The unique needs of TAVR patients and programs require the implementation of unique processes of care and tailored assessment. PMID- 21782519 TI - Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. AB - BACKGROUND: The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0.0012) against first malaria episodes and 59% (36-74; p=0.0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0.0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0.0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61.6% [95% CI 35.6 77.1], p<0.001; 0, 1, 7 month group, 63.8% [40.4-78.0], p<0.001, according-to protocol cohort). INTERPRETATION: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals. PMID- 21782521 TI - Effective nutrition education for Aboriginal Australians: lessons from a diabetes cooking course. AB - OBJECTIVES: To examine the experiences of Aboriginal Australians with or at risk of diabetes who attended urban community cooking courses in 2002-2007; and to develop recommendations for increasing the uptake and effectiveness of nutrition education in Aboriginal communities. METHODS: Descriptive qualitative approach using semistructured interviews with 23 Aboriginal course participants aged 19 72. Verbatim transcripts were coded using NVivo 7 software, and qualitative analysis was undertaken. RESULTS: Engagement and learning were increased by emphasizing the social aspects of the program, holding the course in a familiar Aboriginal community-controlled health setting and using small group learning with Aboriginal peers. Partnership with a vocational training institute provided teaching expertise, but there was conflict between vocational and health promotion objectives. CONCLUSIONS AND IMPLICATIONS: Nutrition programs for Aboriginal Australians should be social, flexible, and held in accessible, culturally appropriate settings and focus on healthful cooking techniques using simple, affordable ingredients. PMID- 21782522 TI - Foramen ovale electrodes in the evaluation of epilepsy surgery: conventional and unconventional uses. AB - Foramen ovale (FO) electrodes have been used in the evaluation of epilepsy surgery for more than 25 years. Their traditional application was in patients with mesial temporal lobe epilepsy. Due in part to advances in neuroimaging, their use has declined. We describe our cumulative experience with FO electrodes and use examples to illustrate a range of indications for FO recordings that extend beyond their conventional utility for mesial temporal lobe cases. We also summarize the pros and cons of FO electrodes implantation and attempt to reestablish their utility in presurgical evaluation. PMID- 21782523 TI - Neuropsychological characteristics of nonepileptic seizure semiological subgroups. AB - The present study sought to identify neuropsychological characteristics of patients with nonepileptic seizures (NESs) based on seizure semiological subgroups and to make comparisons among NES subgroups and with patients with temporal lobe epilepsy (TLE). A total of 173 patients with NESs and 180 patients with TLE were included in this study. Statistical comparisons were made between a NES four-subgroup model, a NES two-subgroup model, and patients with TLE on neurocognitive measures. A trend toward declining performance was noted across the subjective, catatonic, minor motor, and major motor subgroups, respectively. The nonmotor subgroup showed stronger performance on verbal intelligence, naming, verbal learning, and verbal memory compared with the TLE group. The motor subgroup generally performed equivalently to the patients with TLE. Results indicate that patients with more dramatic seizure semiology appear to have lower neurocognitive functioning at a level comparable to that of patients with TLE. Patients with NESs with the least dramatic semiology appear to have fewer neurocognitive abnormalities. PMID- 21782525 TI - Neural crest cell lineage restricts skeletal muscle progenitor cell differentiation through Neuregulin1-ErbB3 signaling. AB - Coordinating the balance between progenitor self-renewal and myogenic differentiation is required for a regulated expansion of the developing muscles. Previous observation that neural crest cells (NCCs) migrate throughout the somite regions, where trunk skeletal muscles first emerge, suggests a potential role for these cells in influencing early muscle formation. However, specific signaling interactions between NCCs and skeletal muscle cells remain unknown. Here we show that mice with specific NCC and peripheral nervous system defects display impaired survival of skeletal muscle and show skeletal muscle progenitor cell (MPC) depletion due to precocious commitment to differentiation. We show that reduced NCC-derived Neuregulin1 (Nrg1) in the somite region perturbs ErbB3 signaling in uncommitted MPCs. Using a combination of explant culture experiments and genetic ablation in the mouse, we demonstrate that Nrg1 signals provided by the NCC lineage play a critical role in sustainable myogenesis, by restraining MPCs from precocious differentiation. PMID- 21782526 TI - Genome-wide RNAi screens identify genes required for Ricin and PE intoxications. AB - Protein toxins such as Ricin and Pseudomonas exotoxin (PE) pose major public health challenges. Both toxins depend on host cell machinery for internalization, retrograde trafficking from endosomes to the ER, and translocation to cytosol. Although both toxins follow a similar intracellular route, it is unknown how much they rely on the same genes. Here we conducted two genome-wide RNAi screens identifying genes required for intoxication and demonstrating that requirements are strikingly different between PE and Ricin, with only 13% overlap. Yet factors required by both toxins are present from the endosomes to the ER, and, at the morphological level, the toxins colocalize in multiple structures. Interestingly, Ricin, but not PE, depends on Golgi complex integrity and colocalizes significantly with a medial Golgi marker. Our data are consistent with two intertwined pathways converging and diverging at multiple points and reveal the complexity of retrograde membrane trafficking in mammalian cells. PMID- 21782524 TI - Colorectal Chemoprevention Pilot Study (SWOG-9041), randomized and placebo controlled: the importance of multiple luminal lesions. AB - BACKGROUND: Colorectal cancer is common worldwide and chemoprevention has the potential of reducing the number of individuals who may suffer and perish from this disease. METHODS: A randomized placebo controlled pilot study in colorectal cancer patients was performed using calcium carbonate as the test agent in a multi-institutional oncology study group. RESULTS: Two hundred twenty volunteers were randomized in the study. The primary goals of compliance, accrual, and toxicity monitoring are presented. Presence of multiple adenomas at study entry and subsequent development of metachronous adenomas were recorded and found to be associated with synchronous adenomas. The secondary endpoint of recurrent adenomas indicated lower rates of new adenoma in the volunteers randomized to the calcium group. CONCLUSION: This pilot study indicates the feasibility of enrolling survivors of colorectal cancer as study volunteers in a colorectal neoplasm chemoprevention clinical trial and oral calcium continues to be a potentially effective drug in reducing colorectal adenomas. PMID- 21782527 TI - Increased estrogen receptor beta in adipose tissue is associated with increased intracellular and reduced circulating adiponectin protein levels in aged female rats. AB - BACKGROUND: Obesity and associated metabolic and cardiovascular disease risk are correlated with reduced circulating adiponectin (APN) levels. Metabolic and cardiovascular disease risk is also increased after menopause and may be linked to disturbances in estrogen receptor (ER) signaling in adipose. OBJECTIVE: We hypothesized that age-associated estrogen (E(2))-deficiency alters the ERalpha/beta ratio in adipose tissue and increases risk for metabolic disease via APN-ac activated mechanisms. METHODS: Visceral adipose was isolated from adult (6 months) and aged (24 months) female Fisher 344 rats (n = 5-6/group) with ovaries intact or removed by surgical ovariectomy (OVX) and subjected to western blotting. RESULTS: Notably, weight was greatest in aged OVX rats (P < 0.01) and associated with a 2-fold increase in ERbeta protein versus adult intact rats (P < 0.001). ER levels were increased in aged OVX versus adult OVX rats. Intra adipocyte APN was also increased in aged OVX rats versus all groups (P < 0.01), whereas circulating APN levels decreased in aged OVX versus adult OVX rats (P < 0.05). Endoplasmic reticulum protein of 44 kDa (Erp44) levels remained the same (P = 0.09). Adiponectin receptor-1 (AdipoR1) and peroxisome proliferator activated receptor-alpha (PPAR-alpha) were also unchanged. AdipoR2, PPAR-gamma, and phosphorylated adenosine monophosphate-dependant kinase (pAMPK) to total AMPK ratio all decreased with age (P < 0.05). CONCLUSIONS: Collectively, these data suggested that age-associated increases in ERbeta paired with decreased PPAR gamma levels might predispose E(2)-deficient postmenopausal women for increased adiposity and associated metabolic and cardiovascular disease risk. Reduced circulating APN and AdipoR2 levels might contribute to age and E(2)-deficiency linked disease progression. PMID- 21782528 TI - Modeling Alzheimer's disease progression using the disease system analysis approach. AB - A novel mechanistic model based on a disease system analysis paradigm was developed to explore the role of homeostatic mechanisms involved in Alzheimer's disease (AD) progression. We used longitudinal AD Assessment Scale-cognitive subscale (ADAS-cog) scores from 926 subjects with AD on stable acetylcholinesterase inhibitor therapy randomized to placebo treatment in two 54 week clinical trials. Alternative mechanistic models were evaluated by assuming that the rate of change of ADAS-cog over time was jointly regulated by a process characterizing the deterioration of ADAS-cog and by a process associated with a compensatory regulatory response. The model based on a time-varying deterioration rate of ADAS-cog performed better than the model based on a time-varying homeostatic control. The covariate analysis indicated that baseline Mini-Mental State Examination score, education, age, and apolipoprotein E4 genotype had a significant effect on the level and shape of the trajectories of the mean model predicted ADAS-cog change from baseline. PMID- 21782529 TI - Anxiety and depression in adolescents with CF and their caregivers. AB - BACKGROUND: To examine the prevalence of symptoms of anxiety and depression and the concordance of these symptoms in adolescents with Cystic Fibrosis (CF) and their caregivers, and to analyze their healthcare utilization for mental health problems. METHODS: 162 German adolescents with CF (aged 12-17 years) and their parental caregivers (88.3% mothers) completed screening measures for anxiety and depression and described their mental healthcare utilization. RESULTS: Compared to adolescent patients with CF, caregivers reported significantly more anxious and depressive symptoms. An association between adolescent and caregiver anxiety was found. Only a minority of affected patients and caregivers received any form of specialist treatment for their mental health problems. CONCLUSIONS: Screening for anxiety/depression and addressing mental health issues within the framework of a family perspective is recommended as an element of routine healthcare for adolescents with CF. PMID- 21782530 TI - Simultaneous determination of fifteen illegal dyes in animal feeds and poultry products by ultra-high performance liquid chromatography tandem mass spectrometry. AB - With the increasing presence of illegal dyes, such as sudan reds and malachite green, in animal feeds and food products during the last few years, there is an urgent need of accurate quantitative determination methods for these illicit compounds. Here we established an accurate method for the simultaneous determination of 15 illegal dyes in animal feeds, meat, eggs and other food products using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The samples were extracted with a simple procedure using acetonitrile and solid phase extraction cleaning up. The application of C(18) rapid column can achieve satisfactory separation of the 15 dyes within 16 min; and multiple reaction monitoring of positive ions ensure confirmative detection of these illegal dyes. With the developed method, a sample can be analyzed in less than 2h. Dyes spiked in feeds, poultry meat and eggs in the range of 0.1-5.0 mg kg(-1) were tested in terms of linearity, sensitivity, repeatability and recovery. Recoveries for the compounds ranged from 60 to 140%. Intra- and inter-day precisions (RSDs) were less than 15%. Limit of quantification ranged from 0.01 to 5.61 MUg kg(-1) for different dyes. The developed UHPLC-MS/MS method could be used as a qualitative and quantitative technique for the simultaneous determination of illegal dyes in animal feeds and poultry products. PMID- 21782531 TI - Simultaneous determination of cefdinir and cefixime in human plasma by RP-HPLC/UV detection method: Method development, optimization, validation, and its application to a pharmacokinetic study. AB - A novel isocratic reversed-phase high performance liquid chromatography/ultraviolet detection method for simultaneous determination of cefdinir and cefixime in human plasma was developed and validated after optimization of various chromatographic conditions and other experimental parameters. Sample preparation based on a simple extraction procedure consisting of deproteination and extraction with 3 parts of 6% trichloroacetic acid aqueous solution followed by volume make up with the aqueous component of the mobile phase obtained best recoveries of the two analytes. Samples were separated on a Supelco Discovery HS C(18) (150 mm * 4.6 mm, 5 MUm) analytical column protected by a Perkin Elmer C(18) (30 mm * 4.6 mm, 10 MUm) guard cartridge. The mobile phase, methanol/acetonitrile (50/50, v/v):0.05% trifluoroacetic acid (19:81, v/v), operated at 50 degrees C column oven temperature was pumped at a flow rate of 2.0 mL min(-1) and the column eluents were monitored at a wavelength of 285 nm. When Sample was injected into the Perkin Elmer high performance liquid chromatography system through Rheodyne manual (or auto-sampler) injector equipped with 20 MUL loop, separation was achieved within 4 min. The present method demonstrated acceptable values for selectivity, linearity within the expected concentration range (0.004-5.0 MUg mL(-1); r(2)>0.999 for both analytes), recovery (>95% for cefdinir and >96% for cefixime), precision (%RSD<2.0 for cefdinir and <2.2 for cefixime), sensitivity (limit of detection: 1 ng mL(-1) and lower limit of quantification: 4 ng mL(-1) for both analytes), stability of solutions, and robustness. The method was efficiently applied to a pharmacokinetic study in healthy volunteers. PMID- 21782532 TI - The theory of bio-energy transport in the protein molecules and its properties. AB - The bio-energy transport is a basic problem in life science and related to many biological processes. Therefore to establish the mechanism of bio-energy transport and its theory have an important significance. Based on different properties of structure of alpha-helical protein molecules some theories of bio energy transport along the molecular chains have been proposed and established, where the energy is released by hydrolysis of adenosine triphosphate (ATP). A brief survey of past researches on different models and theories of bio-energy, including Davydov's, Takeno's, Yomosa's, Brown et al.'s, Schweitzer's, Cruzeiro Hansson's, Forner's and Pang's models were first stated in this paper. Subsequently we studied and reviewed mainly and systematically the properties, thermal stability and lifetimes of the carriers (solitons) transporting the bio energy at physiological temperature 300 K in Pang's and Davydov's theories. From these investigations we know that the carrier (soliton) of bio-energy transport in the alpha-helical protein molecules in Pang's model has a higher binding energy, higher thermal stability and larger lifetime at 300 K relative to those of Davydov's model, in which the lifetime of the new soliton at 300 K is enough large and belongs to the order of 10(-10) s or tau/tau(0)>=700. Thus we can conclude that the soliton in Pang's model is exactly the carrier of the bio energy transport, Pang's theory is appropriate to alpha-helical protein molecules. PMID- 21782534 TI - Transanal endoscopic microsurgery after neoadjuvant therapy for rectal GIST. PMID- 21782535 TI - Lactic acidosis during Entecavir treatment in decompensated hepatitis B virus related cirrhosis. PMID- 21782533 TI - Chromatin and the DNA damage response: the cancer connection. AB - The integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management. PMID- 21782536 TI - An oestrogen receptor beta-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma cells over-express oestrogen receptor-beta, which displays anti-proliferative and pro-apoptotic effects. AIM: To evaluate the effects of a newly developed and highly selective oestrogen receptor-beta agonist (KB9520) on experimental intrahepatic cholangiocarcinoma. METHODS: In vitro, the effects of KB9520 on apoptosis and proliferation of HuH-28 cells, HuH-28 cells with selective oestrogen receptor-beta silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-alpha and oestrogen receptor-beta negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-alpha) were evaluated. In vivo, the effects of KB9520 on experimental intrahepatic cholangiocarcinoma, induced by thioacetamide administration were tested. RESULTS: In vitro, KB9520 induced apoptosis and inhibited proliferation of HuH-28 cells. KB9520 effects were absent in cells lacking oestrogen receptor-alpha and beta (HepG2) and in cells expressing only oestrogen receptor-alpha (HepER3); its pro apoptotic effect was impaired in cells where oestrogen receptor-beta expression was decreased by specific small interfering RNA. In vivo, KB9520 inhibited experimental intrahepatic cholangiocarcinoma development in thioacetamide-treated rats and promoted tumour regression in rats where tumour was already established. In treated animals, tumour areas showed reduced proliferation but increased apoptosis. CONCLUSIONS: KB9520 induced apoptosis in cholangiocarcinoma by selectively acting on oestrogen receptor-beta, suggesting that oestrogen receptor beta selective agonists may be a novel and effective therapeutic option for the medical treatment of intrahepatic cholangiocarcinoma. PMID- 21782537 TI - Ductal carcinoma in situ of the male breast presenting as adolescent unilateral gynaecomastia. AB - A 17 year old male patient was referred to the breast surgery service with a unilateral swelling of the left breast. Subsequent evaluation led to discharge with a diagnosis of adolescent gynaecomastia. Four years later the same patient was referred back to the breast surgery service and the referral was turned down without a consultation as the surgical treatment of gynaecomastia was not funded by the local Primary Care Trust (PCT). Three years following, this now 24 year old gentleman was referred to the Plastic surgery service at the Hospital Trust where he had been initially referred as a 17 year old. He underwent a nipple sparing mastectomy through a peri-areolar incision. The histology amounted to a diagnosis of ductal carcinoma in situ (DCIS). A literature review revealed the rarity of pure DCIS in the adolescent male. The variation in availability of treatments across the National Health Service in England has lead to a "postcode lottery" due to "rationing" decisions being made by individual Primary Care Trusts. "Action on Plastic Surgery", an NHS Modernisation Agency document, was designed as an aid to PCT's making funding decisions on Plastic Surgery patients in 2005. The case described in this report illustrates the difficulty in clinical diagnosis of a male breast lump. This persistent lesion was sampled on 2 separate occasions with fine needle aspiration, neither aspirate raising the possibility of DCIS. In conclusion this case describes a rare pre-malignant condition of the male breast. Complete histology of such a lump is the only conclusive investigation necessary and the limitations put upon the surgeon by the "rationing" of such treatment must be overcome on clinical grounds. PMID- 21782538 TI - Characteristics, complications and management of a large multiethnic cohort of younger adults with type 2 diabetes. AB - AIMS: To describe the characteristics and management of a cohort with type 2 diabetes (T2DM) <40 years. METHODS: Cross-sectional study of the last visit of 648 adults attending 2 specialist centres in the UK. Differences between the lowest (<=22) vs. highest quintile (>=33) of age of diagnosis were analysed. RESULTS: 57.9% were female; 45.5% Black or Minority Ethnic origin (91.9% of South Asian origin); median age at diagnosis was 28 years (24-31); diabetes duration of 4.0 years (1.9-7.0); BMI of 33.0 kg/m(2) (28.3-38.7). HbA1c of 8.2% (6.8-9.9) with HbA1c >7% in 70%. 71.8% had cholesterol >4 mmol/l, 54.9% triglycerides >1.7 mmol/l, 45% had hypertension, 19.8% retinopathy, 16.9% microalbuminuria. Insulin was used in 43.3%. 27.7% received antihypertensives and 31.5% a statin. Compared to the highest quintile of age of diagnosis, the lowest quintile had more often retinopathy (22.1% vs. 16.9%, p=0.021), was less on insulin (45.6% vs. 46.4%, p=0.039) and often managed with diet only (9.6% vs. 6.2%, p=0.005). CONCLUSIONS: These younger adults with T2DM often have inadequately treated risk factors. In particular, patients from the lowest quintile of age of diagnosis were less aggressively treated. There is a need for tailored strategies to manage this high risk group. PMID- 21782540 TI - Total hip arthroplasty dislocation rate following isolated cup revision using Hueter's direct anterior approach on a fracture table. AB - INTRODUCTION: Instability is a major complication after revision total hip arthroplasty. Studies in the literature have shown that the dislocation rate after primary arthroplasties by anterior approach on a fracture table is satisfactory, but the rate of instability following revision surgery is not known. HYPOTHESIS AND AIMS: We hypothesized that the Hueter direct anterior approach would result in a lower rate of postoperative dislocation following revision surgery. This hypothesis was tested in a series of isolated acetabular component replacements. PATIENTS AND METHODS: Seventy-three consecutive isolated acetabular component replacements were performed between January 2000 and December 2007. Twelve revisions using constrained liners or dual mobility cups were excluded, thus 61 revisions in 59 patients, mean age 65.8-year-old (range 27 86) were included. The indications for revision arthroplasty were: 51 (83.6%) cases of aseptic loosening, five (8.2%) non-integration of cementless cups, three (4.9%) cases of instability, one (1.6%) case of impingement with the psoas and one (1.6%) case of excessive (3cm) lengthening. Acetabular bone defects were moderate, with 12 stage I, 26 stage II, 19 stage III, and only four stage IV defects on the SOFCOT bone stock deficiency score. There was no acetabular reconstruction in 18 cases, while there were four isolated reconstruction cages and 39 cages with a graft. The replacement cup was cemented in 52 cases and cementless in nine. Inclination and anteversion were measured by the Pradhan method on standard X-rays. RESULTS: Results were evaluated after a mean follow-up of 2.4 years+/-1.7 years (1-7 years). Four dislocations were observed (6.6%) all anterior and early in the postoperative period (less than 2 months): three patients had a single episode of dislocation and one patient again underwent revision cup replacement by Hueter anterior approach for recurrent anterior dislocation. The only factor associated with a risk of dislocation was a high body mass index: 29.7+/-0.8 in the group with dislocation compared to 25.6+/-3.2 in the group without (P=0.008). A high number of prior interventions was also a significant risk factor (P=0.045). On the other hand, there was no difference in cup inclination or femoral offset between the group with dislocation and that without. DISCUSSION: Although the rate of dislocation is higher than after primary THA by anterior approach, it remains acceptable for revision THA and is similar to rates observed with other approaches. The literature does not clearly establish that one surgical approach is better than another in terms of instability. This study was limited by the absence of CT-scan measurements of component orientation both preoperatively to evaluate the femoral component which is preserved, as well as during follow-up to evaluate cup angle and compare the groups with and without dislocation. CONCLUSION: The Hueter direct anterior approach is a viable option for isolated cup revision, as long as femoral loosening has been excluded, and the orientation of the preserved femoral component is known. LEVEL OF EVIDENCE: Level IV; retrospective study. PMID- 21782539 TI - Exploring reasons for very poor glycaemic control in patients with Type 2 diabetes. AB - AIM: The aim was to determine prevalence and reasons for very poor glycaemic control (HbA1c>=10% [86 mmol/mol]) amongst people with Type 2 diabetes in an ethnically diverse urban population. METHODS: Databases of three primary health centres were searched for patients with Type 2 diabetes >=1 year, most recent HbA1c>=10% [86 mmol/mol]. Patients were invited to explore reasons for poor glycaemic control and develop an individualised management plan. Review of glycaemic control was undertaken at 6 months. RESULTS: Of a total population of 28,677, 1261 had Type 2 diabetes (4.4%). 143 (11.3%) had last recorded HbA1c>=10% [86 mmol/mol]; 128 were reviewed (46.9% South Asian). People with poorer control had longer duration of diabetes and more South Asian ethnicity. Reasons for poor glycaemic control were: THERAPY: lack of titration of tablets (7.8%) or insulin (12.5%), poor concordance with medication (14.0%), insulin refusal (11.7%), side effects (16.4%); Engagement: poor concordance with lifestyle (26.5%), lack of knowledge of diabetes (14.0%), infrequent attendance at clinic (16.4%); Psychosocial/mental health: denial that diabetes was a problem (7.0%), mental health problem (9.4%), social issues (10.9%); Occupation: refusal of insulin due to occupation (1.6%); difficulty in attending reviews (5.5%). At six month review, 54.5% of patients had improved HbA1c>=1%. CONCLUSIONS: Poor control affects 1 in 10 of our population. We have determined a number of factors which may explain most causes. Individualised management using care planning can significantly improve control. PMID- 21782541 TI - Education in the management of low back pain: literature review and recall of key recommendations for practice. AB - INTRODUCTION: Therapeutic patient education (TPE) is a continuous medical care process whose role in lower back pain (LBP) has yet to be well defined. OBJECTIVE: To evaluate the role and impact of TPE in the medical and surgical management of LBP. METHOD: A non-systematic literature review. RESULTS: Few formal TPE programmes have been rigorously evaluated in the context of LBP. In most cases, TPE tools have been combined with other interventional measures that vary according to the conceptual models used - thus limiting the extent to which the effect of TPE alone can be judged. Information that complies with the guidelines modifies knowledge and inappropriate beliefs. Whether formalized or not, TPE appears to modify (i) the physical disability and pain related to LBP and (ii) the patient's choice of therapy (e.g. surgery). The impact appears to be more marked in the (sub)acute phases. DISCUSSION: National and international guidelines suggest that TPE based on a biopsychosocial model has a positive impact on the patients' behaviour and treatment compliance. The cost/benefit ratio appears to be favourable. CONCLUSION: Therapeutic patient education appears to reduce the negative consequences of fear-avoidance behaviour and thus promotes treatment compliance in LBP patients, from the acute phase onwards. PMID- 21782542 TI - A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been investigated for its treatment efficacy for the negative symptoms of schizophrenia. Previous studies have targeted the dorsolateral prefrontal cortex (DLPFC), which is associated with the pathophysiology of this disorder. Several rTMS parameters have been explored in the treatment of negative symptoms and include stimulating the left and bilateral DLPFC at several different frequencies and number of sessions. Results of such studies have been inconsistent, while high-frequency rTMS has shown greatest promise. OBJECTIVE/HYPOTHESIS: The objective of this study was to evaluate the efficacy of bilateral high-frequency rTMS in the treatment of negative symptoms in schizophrenia. It was hypothesized rTMS would alleviate negative symptoms in schizophrenia. METHODS: Twenty-five patients were enrolled in this double-blind placebo-controlled randomized trial. Bilateral 20 Hz rTMS was MRI-targeted to the DLPFC at 90% RMT administered daily for 4 weeks for a total of 20 treatments. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative symptom scale (PANSS), and controlling for depression as measured with the Calgary Depression Scale (CDS) at baseline, 1, 2, 3, 4, and 2 weeks after the treatment course. RESULTS: No significant group or time differences were found on negative symptoms or depressive symptoms after rTMS. Bilateral high-frequency rTMS did not alleviate negative symptoms in patients with schizophrenia. CONCLUSIONS: These findings indicate that such symptoms are unresponsive to rTMS treatment or that more optimized parameters are needed to achieve improved therapeutic efficacy. PMID- 21782543 TI - Intraoperative microelectrode recording for the delineation of subthalamic nucleus topography in Parkinson's disease. AB - BACKGROUND: The subthalamic nucleus (STN) as an effective target for deep brain stimulation (DBS) in advanced Parkinson's disease is functionally divided into the dorsolateral sensorimotor and the ventromedial limbic and associative parts. To implant electrodes for DBS close to the sensorimotor region is considered crucial for optimal motor benefit and for avoidance of potential cognitive and behavioral side effects. OBJECTIVE: The aim of this study was to determine whether the functional segregation of the STN is associated with distinct and region-specific neuronal activity patterns and action potential properties obtained by intraoperative microelectrode recordings. METHODS: In 12 Parkinson's disease patients, stepwise intraoperative microelectrode recordings were performed using five concentrically configured electrodes starting 10 mm above the calculated target point until the dorsal border of the substantia nigra. RESULTS: Based on autocorrelogram analysis of a total of 329 single units, we found a higher occurrence of oscillatory (P < 0.01) and bursty (P = 0.058) spike pattern in the dorsal versus the ventral STN. In contrast the ventral region was characterized by irregular firing neurons (P < 0.01). There were no significant differences in firing frequency, coefficient of variance, asymmetry index as well as spike form, duration, and amplitude. CONCLUSIONS: Among all parameters analyzed in the study, spike pattern is the only convenient electrophysiologic parameter for the differentiation of STN subregions in patients with Parkinson's disease. The autocorrelogram-based analysis of spike activity seems to be of certain value for the delineation of the dorsolateral STN and might therefore facilitate the precise electrode implantation for DBS. PMID- 21782544 TI - Tremor-specific neuronal oscillation pattern in dorsal subthalamic nucleus of parkinsonian patients. AB - BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation effectively improves parkinsonian symptoms. It is hypothesized that distinct functional territories with different neurophysiologic activity within the STN relate to different symptoms. OBJECTIVE: The aim of the study was to identify distinctive characteristics of STN neuronal activity related to tremor by directly comparing tremor sides with no-tremor sides. In addition, we studied the spatial pattern of frequency distributions within the STN in more detail. METHODS: We analyzed intraoperative STN single/multiunit recordings from 33 tremor sides and 23 no tremor sides. STN tracks were normalized to a length of 1 and subdivided into eight successive layers. The power spectral density was split into six frequency bands: theta (3-8 Hz), alpha (9-12 Hz), lower beta (13-20 Hz), upper beta (21-30 Hz), lower gamma (31-59 Hz), and upper gamma (60-100 Hz). RESULTS: Tremor sides presented predominant theta frequency oscillations in the most dorsal layers of the STN, whereas in no-tremor sides beta frequencies predominated. Oscillatory activity was stronger in the dorsal STN than in the ventral, and this pattern was specific for frequencies in the theta, alpha, and beta bands, but not in the gamma bands. CONCLUSIONS: Our study supports the hypothesis that the presence of tremor is associated with a distinctive neuronal oscillations pattern. In particular, we demonstrate the specificity of the association of theta frequencies in the dorsal STN with tremor. Identification of symptom-specific characteristics of intraoperative microrecordings in the STN may lead to refinement of targeting for each patient, tailored to the specific clinical presentation. PMID- 21782545 TI - Effects of simultaneous bilateral tDCS of the human motor cortex. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a noninvasive technique that has been investigated as a therapeutic tool for different neurologic disorders. Neuronal excitability can be modified by application of DC in a polarity-specific manner: anodal tDCS increases excitability, while cathodal tDCS decreases excitability. Previous research has shown that simultaneous bilateral tDCS of the human motor cortex facilitates motor performance in the anodal stimulated hemisphere much more than when the same hemisphere is stimulated using unilateral anodal motor cortex tDCS. OBJECTIVE: The main purpose of this study was to determine whether simultaneous bilateral tDCS is able to increase cortical excitability in one hemisphere whereas decreasing cortical excitability in the contralateral hemisphere. To test our hypothesis, cortical excitability before and after bilateral motor cortex tDCS was evaluated. Moreover, the effects of bilateral tDCS were compared with those of unilateral motor cortex tDCS. METHODS: We evaluated cortical excitability in healthy volunteers before and after unilateral or bilateral tDCS using transcranial magnetic stimulation. RESULTS: We demonstrated that simultaneous application of anodal tDCS over the motor cortex and cathodal tDCS over the contralateral motor cortex induces an increase in cortical excitability on the anodal-stimulated side and a decrease in the cathodal stimulated side. We also used the electrode montage (motor cortex-contralateral orbit) method to compare the bilateral tDCS montage with unilateral tDCS montage. The simultaneous bilateral tDCS induced similar effects to the unilateral montage on the cathode-stimulated side. On the anodal tDCS side, the simultaneous bilateral tDCS seems to be a slightly less robust electrode arrangement compared with the placement of electrodes in the motor cortex-contralateral orbit montage. We also found that intersubject variability of the excitability changes that were induced by the anodal motor cortex tDCS using the bilateral montage was lower than that with the unilateral montage. CONCLUSIONS: This is the first study in which cortical excitability before and after bilateral motor cortex tDCS was extensively evaluated, and the effects of bilateral tDCS were compared with unilateral motor cortex tDCS. Simultaneous bilateral tDCS seems to be a useful tool to obtain increases in cortical excitability of one hemisphere whereas causing decreases of cortical excitability in the contralateral hemisphere (e.g.,to treat stroke). PMID- 21782546 TI - Detection of the facial expression of emotion and self-report measures in empathic situations are influenced by sensorimotor circuit inhibition by low frequency rTMS. AB - BACKGROUND: Empathic responses to facial cues are a main social competency. Both appraisal processes (facial emotion detection) and self-perceived empathy (empathic responsiveness) in response to emotional faces are thought to be related to empathic behavior, although no systematic analysis has been performed to assess their relationship. OBJECTIVES: The current research explored the contribution of the frontal sensorimotor system to facial detection and self reported empathic measures by using repetitive transcranial magnetic stimulation (rTMS) to produce a temporary disruption of this specific cortical site. METHODS: Eighteen subjects were asked to detect facial expression of emotions (anger, fear, happiness, and neutrality) and to evaluate their empathic responsiveness to these facial cues. A 5-second rTMS (1 Hz, inhibition paradigm) pulse was delivered before the stimulus onset. RESULTS: Error rates and response times (RTs) increased when brain activity was disrupted, specifically in response to anger and fear. Self-reported measures showed a concomitant decreased empathic response when the frontal sensorimotor system was deactivated. CONCLUSIONS: The ability to monitor emotional cues and the behavioral empathic responsiveness to emotional situations was shown to be partially compromised in the case of frontal activity disruption, highlighting the main role of the sensorimotor system for empathic social skills. PMID- 21782547 TI - Guidelines for precise and accurate computational models of tDCS. PMID- 21782548 TI - Pinworm and TNKS inhibitors, an eccentric duo to derail the oncogenic WNT pathway. AB - The WNT/beta-catenin pathway underlies many human cancers through mutations in the APC, beta-catenin, and Axin genes. Activation of WNT signalling can also occur due to the localization of glycogen synthase kinase 3beta(GSK3beta) to the multivesicular bodies, which prevents the degradation of beta-catenin. This leads to accumulation of beta-catenin within the cytoplasmic matrix and nucleus of cancer cells, which triggers the transactivation of genes involved in cell proliferation, including various oncogenes. Recent research into the mechanistic regulations of molecule homeostasis and identification of new small-targeted inhibitors has provided further insights into the WNT signalling pathway and its role in human cancers. Novel WNT inhibitors target unsuspected cellular enzymes, such as tankyrases, or casein kinase 1alpha/gamma, which controls the destruction of beta-catenin and GSK3beta. These could lead to the identification of new biomarkers and WNT-targeted inhibitors for the treatment of cancer. PMID- 21782549 TI - Accuracy of endoscopic ultrasound in staging and restaging patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. AB - BACKGROUND: To date, the role of endoscopic ultrasound (EUS) in restaging locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (NAT) have not been thoroughly investigated. AIM: To evaluate accuracy and clinical usefulness of EUS for both staging and restaging LARC. METHODS: According to EUS staging, patients with LARC were enrolled in the study. Those who underwent surgery directly represented a control group useful for evaluating the accuracy of EUS in staging LARC. In the study group, EUS was repeated seven weeks after NAT, before surgery. The results of EUS were compared with the corresponding pTN stages. RESULTS: From 2000 to 2006, 212 consecutive patients with RC underwent EUS staging. Among them EUS diagnosed 162 LARC (M/F = 93/69; mean age: 60 years [range 40-80]). The final study group included 85 patients with LARC. EUS restaging had an overall accuracy of 61% and 59% for T and N-stage, respectively. In the control group, the accuracy of EUS in staging LARC was 86% and 58% for T and N-stage, respectively. CONCLUSION: EUS accurately stages LARC and enables appropriate decision-making, with selection of those patients who need NAT. On the other hand, EUS restaging of LARC after NAT has low accuracy and should not be used in clinical practice. PMID- 21782550 TI - Woman with hypertension and seizure. Posterior reversible leukoencephalopathy syndrome in a postpartum eclamptic patient. PMID- 21782551 TI - Integrated vehicle-based safety systems: light vehicle field operational test, key findings report. PMID- 21782552 TI - Commentary: Emerging crash avoidance technology: what does it mean to my ED? PMID- 21782553 TI - Change of shift. Confetti. PMID- 21782554 TI - Shining light on pupillary response after paralysis and the role of case series in clinical research: answers to the March 2011 Journal Club questions. PMID- 21782555 TI - Infant with facial lesions. Cold panniculitis. PMID- 21782556 TI - Rocuronium versus succinylcholine: Cochrane synopsis reconsidered. PMID- 21782557 TI - The crisis in mental health care: a preliminary study of access to psychiatric care in Boston. PMID- 21782558 TI - Response to effect of deferasirox on iron absorption in a randomized, placebo controlled, crossover study in a human model of acute supratherapeutic iron ingestion. PMID- 21782560 TI - Natural and synthetic organic compounds in the environment-a symposium report. AB - In March 2000, an international two-day symposium was organized in Noordwijkerhout, The Netherlands, on 'Natural and synthetic organic compounds in the environment'. The emphasis of the symposium was on the following classes of compounds: polycyclic aromatic hydrocarbons, xeno-estrogens, phyto-estrogens, and veterinary drugs. Sources, environmental distribution, uptake, biotransformation and toxic effects from the molecular to the population level were discussed. Other important aspects were the development of biomarkers, analytical methods, bioassays, molecular modelling and other research tools. Finally, the implications of the findings for government policies were discussed. In this paper, a summary is given of the most important facts and views presented at the symposium. PMID- 21782561 TI - Potential transmission of the cytogenetic toxic effects of methotrexate in the male germline cells of Swiss mice. AB - On testing the cytogenetic toxic effects of methotrexate, a widely prescribed antineoplastic drug, in the male germline cells of Swiss mice, it was found highly clastogenic to the spermatogonial cells at 24-h post-treatment after a single intraperitoneal exposure. The occurrence of significant percentages of aberrant primary spermatocytes with atypical bivalents at week 4 post-treatment and a little higher percentages of sperm with abnormal morphology at week 8 post treatment indicated the potential transmission of the induced cytogenetic toxic effects of methotrexate from spermatogonia to sperm in the male germline cells of Swiss mice. PMID- 21782562 TI - Effect of fudosteine, a cysteine derivative, on blood flow of tracheal microvasculature increased by airway inflammation. AB - We examined the effect of fudosteine, a cysteine derivative, on blood flow of tracheal microvasculature increased by airway inflammation. Airway inflammation was elicited by sulfur dioxide (SO(2)) exposure for 2 weeks in rabbits. Each drug (500 mg/kg, p.o.) or 0.5% carboxymethylcellulose-Na (control group) was daily administered just before SO(2) exposure. After final SO(2) exposure was finished, blood flow of tracheal microvasculature was measured by blood perfusion monitor. Fudosteine or S-carboxymethylcysteine (S-CMC) significantly suppressed blood flow of tracheal microvasculature increased by SO(2) exposure. However, no effect of fudosteine was observed on the pharmacological microvascular response in trachea of SO(2)-exposed rabbits. On the other hand, fudosteine or S-CMC scavenged superoxide anion generated from rat neutrophils, and enzymatically generated from xanthine oxidase-acetaldehyde reaction. The results suggest that suppressive action in increased tracheal blood flow of fudosteine is due to anti-inflammatory activity, at least in part, via scavenging of superoxide anion. PMID- 21782563 TI - Tri-n-butyltin delays the cell death induced by hydrogen peroxide in rat thymocytes. AB - Tri-n-butyltin (TBT), one of environmental pollutants accumulated in mollusks, at nanomolar concentrations decreases cellular content of glutathione (GSH), suggesting that TBT increases cell vulnerability to oxidative stress because GSH has a role in catabolizing hydrogen peroxide (H(2)O(2)). In order to examine this possibility, the effect of tri-n-butyltin chloride (TBTCl) on rat thymocytes suffering from oxidative stress induced by H(2)O(2) was examined using a flow cytometer with four fluorescent probes; ethidium bromide, 2',7' dichlorofluorescin diacetate, 5-chloromethylfluorescein diacetate and annexin-V FITC. TBTCl at concentrations ranging from 100 nM to 1 MUM attenuated H(2)O(2) induced decrease in cell viability in a dose-dependent manner. It was unlikely that TBTCl reduced H(2)O(2)-induced oxidative stress because TBTCl failed to affect H(2)O(2)-induced oxidation of intracellular molecule (2',7' dichlorofluorescin) and H(2)O(2)-induced decrease in cellular content of GSH. Results suggest that TBTCl may inhibit the pathway of cell death induced by H(2)O(2) or that TBTCl may induce a protective substance against the oxidative stress produced by H(2)O(2). PMID- 21782564 TI - Effect of phthalate esters and alkylphenols on steroidogenesis in human adrenocortical H295R cells. AB - We investigated the inhibitory effects of phthalate esters and alkylphenols on steroidogenesis by human adrenocortical H259R cells, a model of human steroidogenic cells. Dicyclohexyl phthalate (DCHP) at a concentration of 30 MUM produced a significant decrease in the dibutyryl cAMP-stimulated cortisol secretion (76% reduction). 4-t-Pentylphenol (4-t-PP), 4-t-octylphenol (4-t-OP) and 4-nonylphenol (4-NP) also produced significant decreases in the dibutyryl cAMP-stimulated cortisol secretion by 58, 34 and 40%, respectively at 50 MUM. Reductions in cortisol secretion by these chemicals were dose-dependent. To elucidate the inhibitory effects of DCHP, 4-t-PP, 4-t-OP and 4-NP on cortisol secretion from H295R cells, the effects of these chemicals on various steroidogenic enzymes, such as C(20,22)-lyase (CYP11A), 3beta-hydroxysteroid dehydrogenase type II (3beta-HSDII), 17alpha-hyroxylase/C(17,20)-lyase (CYP17), 21-hydroxylase (CYP21B) and 11beta-hydroxylase (CYP11B1), were investigated. DCHP significantly inhibited CYP21B activity at 25 MUM. 4-t-OP strongly inhibited CYP11A activity at 12.5 and 25 MUM, and inhibited CYP17 and CYP21B at 25 MUM. Similarly, 4-NP inhibited CYP11A at 25 MUM and strongly inhibited CYP17 and CYP21B at 12.5 and 25 MUM. Neither DCHP nor any of the alkylphenols tested altered 3beta-HSDII activity. PMID- 21782565 TI - RH-3421 action and toxicokinetics in the trout: reduced brain involvement versus mammals. AB - The action and distribution of the insecticidal dihydropyrazole RH-3421 was examined in the trout and mouse. RH-3421 antagonized the depolarizing effect of the Na(+) channel activator veratridine and inhibited K(+)-stimulated uptake of (45)Ca(++) through voltage-sensitive calcium channels in trout brain synaptosomes. RH-3421 was a weaker inhibitor of these cellular targets in fish brain compared to mammalian brain. [(14)C]RH-3421 distributed rapidly following systemic administration to trout. Trunk kidney, muscle, liver and fat are important sites of accumulation, however, accumulation of [(14)C]RH-3421 in trout brain was low and polar metabolites were only found in bile. Mice administered an equivalent dose accumulated [(14)C]RH-3421 more efficiently into brain, and overall metabolism was more extensive. In trout, the brain is unlikely to be a major site of action of dihydropyrazoles. Our data indicate that perturbation of neuronal sites outside of brain cannot be excluded as contributing to the comparatively high acute toxicity of dihydropyrazoles in fish. PMID- 21782566 TI - Latex laboratory-gloves: an unexpected pitfall in amphibian toxicity assays with tadpoles. AB - This study examined the unexpected toxic effects of protective latex laboratory gloves on developing amphibians. Mortality after exposure to rinsing water from the outside of the gloves was observed in Xenopus laevis and Rana temporaria, with R. temporaria being more sensitive. This phenomenon was further confirmed using the microtiter-version of the Microtox-Assay, an in vitro assay for general toxicity. Latex gloves from the specific brand used in the experiment, in which the toxicity to tadpoles was observed for the first time, showed the highest toxicity of all materials and brands tested. Due to the high responsiveness of amphibian tadpoles to latex-glove contaminated rinsing water, special care is necessary when cleaning aquaria during toxicological experiments with amphibians as otherwise results may be biased. PMID- 21782567 TI - Dermal toxicity: effect of jet propellant-8 fuel exposure on the biophysical, macroscopic and microscopic properties of porcine skin. AB - The effect of jet propellant-8 (JP-8) fuel exposure on the biophysical, macroscopic and microscopic changes in vitro in porcine skin has been investigated. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the biophysical changes in stratum corneum (SC) lipid and protein. FTIR results showed that the treatment of the SC with JP-8 to increasing exposure time caused correspondingly greater percent decrease in the peak heights and areas under the absorbance curve of methylene and amide absorbances, suggesting greater loss of lipid and protein from SC layers. In vitro transepidermal water loss (TEWL) studies allowed an investigation into the macroscopic barrier properties of the skin. TEWL results were in consonance with that of FTIR. There was a significant increase (P<0.05) in TEWL through 8 and 24 h JP-8 exposed skin in comparison to the control. Light microscopy provided direct, corroborative, visual evidences of epidermal and dermal alterations. Epidermal swelling, dermal matrix granulation, mast cell granules, shortened collagen fibers were observed in the skin exposed with JP-8. Thus, it is concluded that JP-8 exposure causes appreciable biophysical and histological changes along with increased TEWL values in vitro in pig skin which may lead to skin irritation and dermal toxicity in vivo. PMID- 21782569 TI - Antioxidants: unlocking their potential. PMID- 21782568 TI - Antioxidants: biochemical facts and perspectives. PMID- 21782570 TI - The interplay of glutathione-related processes in antioxidant defense. AB - This review summarizes current knowledge on glutathione (GSH) associated cellular processes that play a central role in defense against oxidative stress. GSH itself is a critical factor in maintaining the cellular redox balance and has been demonstrated to be involved in regulation of cell signalling and repair pathways. Enhanced expression of various enzymes involved in GSH metabolism, including glutathione peroxidases, gamma-glutamyl cysteinyl synthetase (gamma GCS), glutathione S-transferases (GST) and membrane proteins belonging to the ATP binding cassette family, such as the multidrug resistance associated protein, have all been demonstrated to play a prominent role in cellular resistance towards oxidative stress. This review stresses the fact that aco ordinateinterplay between these systems is essential for efficient protection against oxidative stress. PMID- 21782571 TI - The biochemistry of selenium and the glutathione system. AB - In the context of defense against pro-oxidants, selenium and the glutathione (GSH) system play key functions. Major roles of GSH include direct interception of pro-oxidants, as well as a reduction of other antioxidants from their oxidized forms. Furthermore, GSH has ancillary functions, such as metabolism, cell signaling, and protein interactions, that can also mediate defense against oxidants. Protection by selenium in the mammalian cell is mediated by selenol aminoacids, either as selenocysteine or selenomethionine. The active site of the potent glutathione peroxidases (GPx) contains selenocysteine residues. Furthermore, other selenoproteins (e.g. selenoprotein P and thioredoxin reductase) also have been shown to possess antioxidant properties. Synthetic organoselenium compounds (e.g. ebselen) have also shown promise as pharmacologic antioxidants in in vivo models of tissue damage due to oxidative stress. The specific function of selenoproteins and organoselenium compounds in defense against peroxynitrite, by reduction of this potent oxidizing and nitrating species to nitrite, is also discussed. PMID- 21782572 TI - Should we recommend the therapeutical use of vitamin E in diabetic patients? AB - The therapeutic application of vitamin E was initially restricted to thrombocytopenic purpura and later extended to coronary artery diseases and peripheral vascular arteriosclerosis due to the potency of its effects. Several recent studies have pointed out that vitamin E supplementation is useful for reducing low-density lipoprotein oxidation and thus might be protective towards coronary heart disease. Such data has been confirmed in many in vitro data, while in vivo results of reports from epidemiological studies are much more controversial. More consistent is the evidence showing vitamin E to improve endothelial function especially in diabetic patients. Finally, chronic vitamin E has been demonstrated to improve the metabolic control in diabetic patients. Whether chronic vitamin E administration at pharmacological doses and for long time, is safe is still debated. A sure response to such a query will open the possibility for recommending vitamin E as a therapeutic agent in diabetic patients. PMID- 21782573 TI - The therapeutic use of lipoic acid in diabetes: a current perspective. AB - Lipoic acid and its reduced derivative, dihydrolipoic acid (DHLA) are highly promising antioxidant agents, which are potent attenuators of reactive species mediated damage in vitro and in animal studies. Lipoic acid is a universal antioxidant, effective in lipophilic and aqueous environments. In contrast to an equivalent endogenous agent, such as oxidised glutathione (GSSG), lipoic acid acts as an antioxidant in its oxidised form. Lipoic acid has been evaluated in diabetic polyneuropathy, a condition which is thought to result in part from oxidant damage caused by long-term hyperglycaemia. Diabetic patients are prone to incur enhanced cellular free radical formation and reduced antioxidant defence. Treatment with lipoic acid has improved nerve conduction velocity during studies in diabetic animals. Trials in diabetic patients have often observed some relief of neuropathic symptoms during treatment with lipoic acid, but consistent objective benefits have been difficult to establish. Lipoic acid is now used in Germany for the treatment of diabetic neuropathy and definitive evidence of efficacy should arise from postmarketing surveillance studies. It is possible that lipoic acid may be more effective as a long-term dietary supplement aimed at the prophylactic protection of diabetics from complications. PMID- 21782574 TI - Ascorbic acid in the 21st century - more than a simple antioxidant. AB - Ascorbic acid (AA) is an essential micronutrient for man, with many biological roles. It is a powerful antioxidant both directly via scavenging of reactive oxygen species and indirectly through regeneration of other antioxidant systems. Paradoxically, under certain conditions (low concentration in vitro, presence of metal ions) it can exert a pro-oxidant effect, increasing oxidative damage to lipids, DNA and protein. Herein, the effects of vitamin C both in vitro and in vivo are addressed in terms of modulation of oxidative DNA damage, gene expression and protein oxidation. The view of AA as a simple scavenger is outdated, where the arrival of new bioinformatic techniques, heralds a new dawning in our understanding of ascorbate as a potential direct or indirect modulator of gene expression. PMID- 21782575 TI - Antioxidants in critical care medicine. AB - Critically ill patients in the intensive care unit (ICU) present with a variety of different pathologies, and mortality is high despite extensive multi-organ supportive treatment. Reactive oxygen species (ROS) are believed to play a pivotal role in the pathophysiology of organ dysfunction in the ICU. In particular, the role of ROS as a final common pathway of cell damage has been increasingly emphasised in the adult respiratory distress syndrome (ARDS), in central nervous system traumatic and hypoxic states, and as a cause of ischaemic neurological deficits after subarachnoid haemorrhage. Measurement of total antioxidant status (TAS) has shown improved survival of patients with high TAS and poorer outcomes for those with lower values. Attempts to supplement endogenous antioxidant defences have not demonstrated clear benefits in randomised clinical trials, and the use of free radical scavenging agents have had similar mixed results. Considering the wide variation in the nature and severity of illness in the intensive care population, it is not surprising that clear evidence of the efficacy of antioxidant therapies in improving survival has not been clearly demonstrated. However, single component therapies for complex pathophysiological processes are rarely successful, and the role of antioxidants in the critically ill should be thought of as only part of a rational and logical therapeutic approach. PMID- 21782576 TI - Antioxidants and reactive oxygen species in human fertility. AB - The cellular components of the human reproductive system are as vulnerable as other cells to the potential detrimental effects of reactive oxygen species (ROS). Antioxidant protection is thus required, though not yet fully characterized, at sites of gametogenesis, fertilization and implantation. Spermatozoa are highly susceptible to oxidative damage due to the high content of polyunsaturated fatty acids within their plasma membrane and such damage may underlie certain aspects of male infertility. However, oral antioxidant therapy with, for example, Vitamin E or glutathione has to date only achieved limited success in treatment programmes. Infertility treatments involve in vitro manipulation of gametes and embryos, ranging from simple spermatozoa preparation techniques to several days culture, exposing cells to increased oxygen levels and potential oxidative stress compared with in vivo. A considerable body of data has demonstrated the benefits for animal embryo culture and human sperm preparation of antioxidant supplementation as well as the removal of sources of ROS such as leucocytes, although data supporting supplementation for human embryo culture are limited. However, the use of exogenous superoxide dismutase may improve embryo development to the blastocyst stage. Evidence is accumulating for a role for ROS in signalling events mediating both sperm capacitation and luteal function. Potential also exists for ROS (including nitric oxide) to fulfill as yet unidentified roles in modulation signalling, gene expression and/or apoptotic events during fertilization, embryo development and implantation. Increasing knowledge of the mechanisms whereby ROS and endogenous antioxidant systems influence reproductive processes can assist to optimise the application of exogenous antioxidants to fertility treatment. PMID- 21782577 TI - Peroxynitrite scavenging of flavonoids: structure activity relationship. AB - Peroxynitrite can oxidise and nitrosylate biomolecules and is associated with several diseases. The peroxynitrite scavenging of substituted phenols and several flavonoids was studied. The activity of phenol (poor scavenger) is positively influenced by electron donating substituents. A good correlation was found between the peroxynitrite scavenging activity of the substituted phenols and the Hammett sigma or the E(HOMO). Flavonols containing a catechol group (3'- and 4' OH) in ring B (rutin and monohydroxyethyl rutoside) or an AC-ring with three OH groups (3-, 5- and 7-OH) were potent scavengers. Evidence has been produced that in the AC-ring the 3-OH group was the reactive centre and that the reactivity of this group was positively influenced by electron donating groups at the 5 and/or 7 position (galangin, kaempferol, trihydroxyethyl quercetin). PMID- 21782578 TI - Monitoring diabetic antioxidant status: a role for in vitro methaemoglobin formation. AB - Diabetes leads to premature organ and system failure and considerably shortens lifespan. Careful control of glucose levels may not be enough to prevent the onset of complications in most diabetics. Compared with non-diabetics, diabetic tissues must not only resist a much greater long-term threat from hyperglycaemia mediated reactive species but also defend themselves with compromised antioxidant systems. Although antioxidant therapy is a logical step in the prevention of oxidant and carbonyl stresses in the face of intermittent hyperglycaemia, this approach is not yet universally accepted to be effective in preventing complications. Although there are many biochemical indices of oxidant stress, piecemeal elevations of individual markers may not necessarily reflect true diabetic cellular antioxidant status. A dynamic process such as in vitro methaemoglobin generation may provide an opportunity to compare the response of a diabetic erythrocyte with that of a non-diabetic before and after corrective antioxidant therapy. Due to compromised cellular antioxidant capacity, diabetic cells generate less methaemoglobin in the presence of aromatic amine hydroxylamines, 4-aminophenol and nitrite compared with non-diabetics. Agents such as dihydrolipoic acid have been shown to correct methaemoglobin formation mediated thiol deficits during in vitro studies. It is hoped that the progress of antioxidant supplementation studies in diabetics can be monitored with the aid of in vitro methaemoglobin generation using agents such as hydroxylamines, 4 aminophenol and nitrite. The most appropriate antioxidants and dosages can thus be recommended to diabetics worldwide to attenuate the development of complications. PMID- 21782579 TI - Redox control of caspases. AB - Caspases are critical mediators of apoptotic cell death. All members of the caspase family contain the sequence QACXG which contains the active site cysteine. The putative active site of caspase 3 contains a cysteine residue that is subject to redox control. Both thioredoxin and glutathione have been shown to be required for caspase-3 activity to induce apoptosis. The regulation of inducible caspase 3 activity by oxidation-reduction (redox) dependent mechanisms is reviewed. Up until a few years ago, reactive oxygen species (ROS) research mostly focussed on oxidative damage and ROS were thought to be a key trigger for cell death. This view has been refined, leading to the understanding that the biological function of ROS is determined by numerous variables such as concentration, chemical type and cellular localization. For example, ROS and reactive nitrogen species may intercept inducible cell death under certain circumstances via the redox regulation of inducible caspase activity and/or by depleting cellular energy stores. Likewise, death of unwanted diseased or degenerative cells may be facilitated by pharmacologically enhancing the thiol status of such cells using redox-active alpha-lipoic acid. PMID- 21782580 TI - Changes in fetal brain aromatase activity following in utero 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure in rats. AB - Aromatase catalyzes intraneuronal conversion of androgens to estrogens in the hypothalamus-preoptic area at a specific time during development. This local estrogen formation has a central role in sexual differentiation. To investigate the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on sexual differentiation, TCDD (800 and 1600 ng/kg) was orally administered to pregnant Holtzman rats on gestation day (GD) 15, and the change in brain aromatase activity of fetuses (GD20) and pups (postnatal day 2) was examined. Litter means of brain aromatase activity in the hypo-preoptic area of control fetuses were higher in males than in females (female/male ratio was 0.7). This ratio of aromatase activity increased in a TCDD-concentration dependent manner, reaching 1 at the higher dose. There was a similar change in aromatase activity in brains of pups (PND 2). These results suggest that in utero TCDD exposure induces demasculinization in male offspring by inhibiting the aromatase activity in the brain during central nervous system development. PMID- 21782581 TI - NAD-dependent malate dehydrogenase protects against oxidative damage in Escherichia coli K-12 through the action of oxaloacetate. AB - Reactive oxygen species including hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH) can be generated by ionizing radiation and has the potential to induce diseases. We provide the evidence that NAD-dependent malate dehydrogenase (MDH) is involved in the antioxidant role in preventing H(2)O(2) or gamma radiation-induced damage in Escherichia coli through the action of oxaloacetate. The E. colimdh mutant strain defective in MDH activity was more sensitive to H(2)O(2) or gamma-radiation than was the wild type strain, when challenged in the exponential growth phase. The mdh mutant cells pretreated with oxaloacetate (2.5 mM), a product of NAD-dependent MDH activity, prior to H(2)O(2) treatment or gamma-irradiation are resistant to H(2)O(2) or gamma-radiation-induced damage, so cell survivability is restored to similar levels with the wild type. The SOS induction of umu'-'lacZ fusion gene by H(2)O(2) is significantly repressed by pretreatment of oxaloacetate in a dose-dependent way. These results indicate that oxaloacetate effectively protects E. coli cells against damage caused by oxidative stress. Oxaloacetate strongly prevented the DNA strand breaks by OH in a metal-catalyzed oxidation (MCO) system that generated H(2)O(2) as a mediator. By contrast, the prevention of DNA damage by oxaloacetate in an gamma-irradiation system that directly generates OH from H(2)O in vitro was far less than that in an MCO system. Our results demonstrated that oxaloacetate, metabolite of NAD dependent MDH action, plays a role as an antioxidant, possibly by scavenging H(2)O(2). PMID- 21782582 TI - Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries. AB - The antidotal, anticonvulsant and neuroprotective effects of physostigmine (PhS) and procyclidine (PC), the combinational prophylactics for organophosphate poisoning, were evaluated. For the investigation of dose-response relationship in rats and guinea pigs, various doses (0-6 mg/kg) of PC in combination with a fixed dose (0.1 mg/kg) of PhS were pretreated subcutaneously 30 min prior to subcutaneous poisoning with soman. Procyclidine in combination with PhS exhibited remarkable synergistic effects in a dose-dependent manner, leading to 1.92-5.07 folds of protection ratio in rats and 3.00-4.70 folds in guinea pigs. On the other hand, a low effect (1.65 fold) was achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning, compared with a marked protection (5.50 fold) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg) in unpretreated rats. Noteworthy, the combinational prophylactics greatly potentiated the effect of atropine plus 2 pralidoxime to 6.13 or 12.27 folds and that of atropine plus HI-6 to 12.00 or 21.50 folds with 1.0 or 3.0 mg/kg of PC, respectively. A high dose (100 MUg/kg, 1.3*LD(50)) of soman induced severe epileptiform seizures in rats pretreated with HI-6 (125 mg/kg), resulting in brain injuries in discrete brain regions under histopathological examination in 24 h. Interestingly, such seizures and excitotoxic brain injuries were fully prevented by pretreatment with PhS (0.1 mg/kg) and PC (1 mg/kg). Taken together, it is proposed that the prophylactics composed of PhS and PC could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by soman poisoning. PMID- 21782583 TI - Mutagenic outcome of the urinary carcinogen 4-aminobiphenyl is increased in acidic pH. AB - One of the carcinogens from cigarette smoke, 4-aminobiphenyl, is excreted in urine as 4-N-hydroxyl aminobiphenyl metabolite conjugates that undergo pH mediated activation to nitreneum ions leading to bladder tumorigenesis via DNA adduct formation. We hypothesize that changing the pH of smokers' urine might impact the mutagenic outcome. 4-NOHABP was synthesized (~98% purity), structure confirmed by TLC and NMR; mutagenic activity, assessed by the Ames test, was measured after pre-incubation in buffer solutions or human urine at pH 4, 6, 7 and 8. An inverse correlation was observed between number of histidine revertant colonies and pH (r(2)=0.89), 4-NOHABP exhibiting significant mutagenicity at pH 4.0 (P<0.05). PMID- 21782584 TI - Estrogenic action of beta-HCH through activation of c-Neu in MCF-7 breast carcinoma cells. AB - beta-HCH is known to be a poor agonist for the estrogen receptor (ER), and yet it has been shown to act like an estrogen in stimulating foci formation in MCF-7 cells. We investigated the reason for such an action of beta-HCH, using a rat prolactin-luciferase reporter system transfected to MCF-7 cells. We found that the presence of c-Neu (erbB2), ER and ERE is needed for beta-HCH to act estrogenic at the transcription activation level in this cell line. We compared the action of beta-HCH to that of EGF which is known to act estrogenic without being an agonist for ER in this cell and found that their action patterns are quite similar, the only difference being that the former action is blocked by an antibody against c-Neu and the latter by both c-Neu and EGF receptor antibody. We concluded that beta-HCH's estrogenic action in this cell model is mediated through "ligand-independent activation of ER pathway". PMID- 21782585 TI - Dipyridamole reduces cholesterol and triglyceride levels in plasma and lipoproteins from young chicks fed a saturated fat-enriched diet. AB - We have studied the value of dipyridamole for the prevention of hypercholesterolemia caused by saturated fat. This study shows that supplementation of 10-20% coconut oil to the diet induced a significant hypercholesterolemia under postprandial conditions. Simultaneous administration of dipyridamole and 10% coconut oil for 2 weeks maintained plasma cholesterol and triglycerides at levels similar to control, counteracting the increase induced by coconut oil. Dipyridamole significantly reduced cholesterol levels in all the chick plasma lipoproteins that were increased by coconut oil administration. However, it should be emphasized that cholesterol and other chemical components were more drastically reduced by dipyridamole in intermediate- and very-low density lipoproteins than in other lipoprotein fractions. PMID- 21782586 TI - Imposex induction in laboratory reared juvenile Buccinum undatum by tributyltin (TBT). AB - Here we report a series of experiments on the development and occurrence of imposex in the common whelk, Buccinum undatum, under the influence of (chronic) exposure to butyltin compounds. The main objective of the experiments was to obtain more information about the effects of organotin compounds in the marine environment, which possibly relate to the reported decline of B. undatum in Dutch coastal waters. In these studies tributyltin (TBT) dose-dependently induced the development of male sexual organs in juvenile whelks. A TBT concentration >7 ng Sn/l induced imposex in juvenile whelks. Growth in TBT-exposed juvenile whelks was significantly reduced compared to the reference group at a nominal TBT dose >= 4 ng Sn/l in one of the exposure studies. After 5 years in the laboratory, egg laying was only observed in reference aquaria. Thus, TBT might impair whelk reproduction through growth reduction. The results showed a sensitivity towards imposex development in different life-stages. Juveniles were the most sensitive, adolescent females also responded, but adult females did not respond to TBT exposure, although they dose-dependently increased their organotin (OT) body burden when exposed. Environmental TBT during only the in ovo stage, did not result in an increased masculinisation compared to non-exposed developing whelks. Histological studies showed no sterilisation due to mechanical blockage of the (adult) female genital opening by sperm-duct tissue. Gonadal development in 2 year old juveniles was not observed. This implies that the differentiation of a penis and a vas deferens, which already occurred in the first few months after hatching, was not controlled by gonadal factors. No other sexual characteristics than those already visible with the eye were found. TBT inactivated CYP450 to its inactive form CYP420 in in vitro exposure studies with microsomal fractions of whelks. The studies have shown TBT to disrupt sexual development dose dependently in juvenile common whelks. TBT also dose dependently exerts an effect on enzymatic (CYP450) processes. Although no mechanical sterilisation was observed, reproduction might be impaired through growth reduction. PMID- 21782587 TI - Foci formation of MCF7 cells as an in vitro screening method for estrogenic chemicals. AB - Previously we reported a novel phenomenon that some organochlorine compounds mainly act through activation of c-Neu tyrosine kinase without being strong agonists for the estrogen receptor. In this study we tested the possibility of developing an assay system to identify estrogenic compounds acting through this c Neu-mediated mechanism. We describe herein an assay that utilizes foci formation of MCF7 cells as an endpoint, antibody 9G6 to neutralize the c-Neu-mediated pathway and 4-hydroxytamoxifen to block the ER. Aroclors 1242 and 1248, 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2'-dichlorobiphenyl (PCB), cis- and trans- permethrins, and chlorothalonil were found to render estrogenic effects through this c-Neu-mediated mechanism, while alpha and beta- endosulfans appeared to act through a pathway independent of the c-Neu-mediated one. Pentachloronitrobenzene was found to be capable of antagonizing the 17beta estradiol effect, which has never been reported previously. PMID- 21782588 TI - Effect of copper chloride on adrenocortical activities in adult and immature male rats. AB - Although copper is an important biological trace element required for normal metabolism, occupational exposure to copper in different industrial workers may result in abnormal rise in plasma copper level which can bring about adverse effects. Intraperitoneal injection of copper chloride at the dose of 2000 MUg/kg per day and higher doses for 26 days resulted in significant rise in adrenal weight, adrenal Delta(5)-3beta hydroxysteroid dehydrogenase (HSD) activity and serum corticosterone level in both adult and immature male rats, while 1000 MUg/kg per day dose for 26 days duration did not significantly alter the adrenocortical activities and adrenal weight in adult rats. On the contrary, the latter lower dose caused a significant decrease in adrenal Delta(5) 3beta HSD activity and serum corticosterone level in immature male rats. PMID- 21782589 TI - Cytotoxicity and apoptosis induction of sodium fluoride in human promyelocytic leukemia (HL-60) cells. AB - The role of sodium fluoride (NaF) in cytotoxicity and induction of apoptosis was investigated by treating human promyelocytic leukemia (HL-60) cells with varying concentrations of NaF, from 0 to 250 ppm for different periods (0-72 h). At lower concentrations (0-50 ppm), no significant cytotoxicity was observed in response to NaF treatment. However, at higher concentrations (100-250 ppm), NaF reduced cell viability, and decreased DNA and protein biosynthesis capability in cultured HL-60 cells. The growth inhibitory and antiproliferative effects of NaF appear to be attributable to its induction of apoptotic cell death, as NaF induced morphological changes, internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells. NaF treatment also gradually decreased the expression of the anti-apoptotic protein Bcl-2, and increased activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase. These results provides important information towards understanding the mechanism by which NaF mediates cytotoxicity and apoptosis. PMID- 21782590 TI - Neurotoxic effects of acute and subacute formaldehyde exposures in mice. AB - In this study, the effects of acute and subacute formaldehyde (FA) exposures on spontaneous locomotor activity (SLMA), wet dog shake (WDS) behavior and pentylenetetrazole (PTZ) induced seizures were evaluated in Balb/C mice. SLMA was concentration dependently reduced after acute FA exposures at 1.8, 3.2, 4.5, 6.4, 9.7, and 14.8 ppm. The incidence of WDS behavior was increased only after acute FA exposures at 1.8, 3.2 and 6.4-ppm. PTZ-injections caused more intensive seizures in mice acutely exposed to FA only at 1.8 ppm. Meanwhile, the incidence of PTZ induced seizures was significantly lower after acute FA exposure at 14.8 ppm. SLMA was also reduced after subacute FA exposure at 2.0 ppm for 3 weeks. The inhibitory effects were significant after 1-week exposure at this concentration, but a tolerance developed at the end of the second week. As the concentration increased to 3.2 ppm, SLMA has found to be reduced after 2-week exposure. There was no change either on the incidence of WDS or on the parameters of PTZ-induced seizures, due to the subacute exposures of FA at the respective concentrations. In conclusion, based upon these data, acute and subacute exposures of FA produce a significant behavioral depression on mice. The data also suggest that acute FA exposures at low concentrations (such as 1.8 ppm) may increase the excitability of central nervous system (CNS). PMID- 21782591 TI - Phototoxicity of benzo[a]pyrene by ultraviolet A irradiation: induction of apoptosis in Jurkat cells. AB - The toxicology of benzo[a]pyrene (BaP) has been mainly studied with regard to the carcinogenicity of its metabolites, but its phototoxicity is not well understood. Although some studies have indicated the lethal phototoxicity of BaP, there have been no reports regarding the pattern of cell death induced by this agent. In this study, we investigated the pattern and mechanism of cell death induced by coexposure to BaP plus ultraviolet A (UVA) in Jurkat cells. Coexposure to BaP plus UVA showed dose-dependent cytotoxicity. The pattern of cell death was apoptotic as determined by cell shrinkage, chromatin condensation, appearance of subdiploid apoptotic nuclei and translocation of phosphatidylserine to the outer membrane leaflet. Coexposure also strongly increased caspase-3/7 activity and slightly elevated those of caspase-8/6 and -9. The pan caspase inhibitor Z-VAD CH(2)-DCB partially inhibited the phototoxicity of BaP. Cytochrome c release was observed 6 h after coexposure, but not after 1 h. Furthermore, the phototoxicity was inhibited by NaN(3) (quencher of singlet oxygen), but not by mannitol (quencher of hydroxy radicals). Chromatin condensation and translocation of phosphatidylserine were also inhibited by NaN(3), suggesting that the induction of apoptosis by coexposure to BaP plus UVA was due to singlet oxygen production. PMID- 21782592 TI - Estimation of increased concentration of intracellular Cd(2+) by fluo-3 in rat thymocytes exposed to CdCl(2). AB - Cadmium, an environmental pollutant, has been reported to induce apoptosis in murine lymphocytes. To reveal the mechanism of cadmium-induced apoptosis, one of important questions is whether cadmium increases intracellular concentration of Ca(2+) ([Ca(2+)](i)), Cd(2+) ([Cd(2+)](i)) or both. It is difficult to detect the increase in [Ca(2+)](i) using Ca(2+)-chelator-based fluorescent Ca(2+) indicators in the presence of Cd(2+) because of their sensitivity to Cd(2+). Therefore, the study on membrane response such as Ca(2+)-dependent hyperpolarization gives a clue to reveal whether the [Ca(2+)](i) or [Cd(2+)](i) is increased. Cadmium at concentrations of 3 MUM or more dose-dependently augmented fluo-3 fluorescence in rat thymocytes, presumably suggesting an increased [Ca(2+)](i). However, the membranes were not hyperpolarized although the cells possess Ca(2+)-dependent K(+) channels. One may argue that cadmium inhibits Ca(2+)-dependent K(+) channels so that cadmium fails to hyperpolarize the membranes. It is unlikely because the [Ca(2+)](i) increased by A23187, a calcium ionophore, elicited the hyperpolarization in the presence of Cd(2+). Furthermore, the profile of cytotoxicity induced by cadmium, examined by ethidium bromide and annexin V-FITC, was different from that induced by A23187. Taken together, it is concluded that the application of cadmium increases the [Cd(2+)](i) rather than the [Ca(2+)](i) in rat thymocytes, resulting in the induction of cytotoxicity. PMID- 21782593 TI - A study on diurnal mRNA expression of CYP1A1, AHR, ARNT, and PER2 in rat pituitary and liver. AB - The ligand activated basic-helix-loop-helix (bHLH)-PAS transcription factor, the aryl hydrocarbon receptor (AHR) protein, heterodimerizes with its partner protein the aryl hydrocarbon receptor nuclear translocator (ARNT). The heterodimer activates transcription via xenobiotic responsive elements to regulate the transcription of a battery of biotransformation genes as well as genes involved in growth, differentiation, and cellular homeostasis. In this study we have investigated the diurnal expression of cytochrome P450 1A1, one of the genes in the AHR target gene battery, in rat pituitary and liver. The mRNA expression patterns of AHR, ARNT, and the periodic gene (PER2) were also analyzed. PER2 belongs to another group of bHLH-PAS transcription factor complexes, which are involved in the control of circadian rhythms. Diurnal variation of cytochrome P450 1A1 (CYP1A1) mRNA expression was observed in the anterior and posterior pituitary and in the liver. The accumulation of CYP1A1 mRNA occurred during different times of the day and exhibited an opposite expression in anterior and posterior pituitary, respectively. A daily upregulation of CYP1A1 and PER2 mRNAs that was in antiphase to the AHR and ARNT mRNAs was seen in the liver. The AHR/ARNT system is considered a defense system against toxic chemicals. The high inducibility of CYP1A1 in the pituitary, shown in an earlier study, as well as the tissue specific expression patterns shown here, suggest that AHR and CYP1A1 may play a physiological role in controlling neuroendocrine functions. PMID- 21782594 TI - The action of 2,4-Dichlorophenoxyacetic acid on the isolated heart of insect and amphibia. AB - The action of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) on the isolated heart of the frog (Rana ridibunda) and two insects, the honeybee (Apis mellifera macedonica) and the beetle (Tenebrio molitor), was investigated using basic electrophysiological methods. The results of this study showed that a concentration of 1 MUM 2,4-D was required to reduce the force and the frequency of the isolated heart of the honeybee to about 70% of the initial contraction in less than 20 min. To cause the same effects on the atria of the frog, 45 MUM 2,4 D was required and on the isolated heart of the beetle, over 1000 MUM of 2,4-D. The presence of an extensive system of gap junctions found in the honeybee is most probably the cause of the unusual sensitivity of its heart to 2,4-D, compared with the heart of the beetle, where no gap junctions were identified. PMID- 21782595 TI - Lead in hair and gasoline. PMID- 21782596 TI - [Not Available]. PMID- 21782597 TI - Interspecies sensitivity in the aquatic toxicity of aromatic amines. AB - It is known that Daphnia magna is highly sensitive to aniline. The objective of this study is twofold: (i) to find out if also other aromatic amines are more toxic to Daphnia; and (ii) to investigate if also other species are more sensitive to the effects of aromatic amines. Sensitivity histograms of anilines have been constructed based on literature data, taken from several publications, for acute toxicity to several species. The sensitivity distributions show that in particular water fleas are highly sensitive to some of the aromatic amines. Data for the acute and chronic excess toxicity of anilines and other 'polar narcotics' for D. magna has been analyzed. Anilines are significantly more toxic than other polar narcotic compounds. In addition, the acute to chronic ratios in D. magna are also higher for anilines than for other 'polar narcotics'. Finally, the effects of the position of the substituents on the excess toxicity to D. magna have been examined. Results show that excess toxicity is lower in case of ortho substituted aromatic amines. This may indicate a steric hindrance of the ortho substituent in the toxic process of anilines to daphnids. PMID- 21782598 TI - The role of calpains in apoptotic changes in isolated hepatocytes after attack by Natural Killer cells. AB - Previously, we showed that interleukin-2 activated Natural Killer cells (A-NK cells) in vitro rapidly induced apoptosis in freshly isolated rat hepatocytes (Blom et al., 1999. Hepatology 29 (3): 785-792) which was caused by a rapid decrease in the mitochondrial membrane potential and activation of caspases. In the present study we investigated the involvement of calpains in A-NK cell induced apoptosis in isolated hepatocytes. When NK cells and hepatocytes were incubated in the presence of a calpain inhibitor the number of apoptotic cells decreased from 46 to 36%. However, more hepatocytes became necrotic (48 vs. 30%) as compared to the uninhibited situation. Inhibition of the calpains alone could not prevent the induction of the nuclear and cytoskeletal disruptions occurring in the hepatocytes. Inhibition of both calpains and caspases increased the number of necrotic cells as compared to incubation with a single inhibitor. However, the damage to the cytoskeleton of the surviving cells was completely inhibited. We conclude that calpains play a role in induction of apoptosis by NK cells. However, their role is limited as compared to caspases. PMID- 21782599 TI - Threshold models for species sensitivity distributions applied to aquatic risk assessment for zinc. AB - Species sensitivity distributions (SSDs) are used in ecological risk assessment to derive maximum acceptable concentrations of toxicants in the environment from a limited set of ecotoxicity data obtained in the laboratory. Such distributions usually employ continuous bell-shaped functions such as the normal and the logistic distribution, which have the disadvantage that an arbitrary cut-off value must be chosen (usually the 5-percentile) to designate the concentration below which the fraction of species exposed above their no-effect level is considered acceptably small. In this paper the possibility is explored of introducing a true no-effect principle in the SSD framework by considering models with a finite lower threshold. Four of these distributions are elaborated, the uniform, triangular, exponential and Weibull distributions. The mathematical representations of these functions were re-parameterized allowing direct estimation of the threshold parameter by nonlinear regression. By way of example, a data set comprising chronic ecotoxicity of zinc to 21 different aquatic organisms was used. The exponential distribution did not describe the data well. The other distributions provided estimates for HC(0) (hazardous concentration for none of the species) between 1.66 and 7.83 MUg/l. The triangular distribution fitted best to the data and was consistent with previous models. Since threshold SSDs incorporate a true no-effect level they may be better communicable as a principle for environmental protection in comparison to the approach based on '95% protection'. PMID- 21782600 TI - Ecogenotoxicology: the evolving field. AB - The occurrence of chemical contaminants with DNA-damaging capacity in the environment represents a threat to human health as well as to the health of the ecosystem. This mini-review describes studies that were aimed to monitor at field conditions, the presence of such environmental toxicants and their DNA-damaging effects in aquatic and terrestrial species, as well as in birds. It is obvious that these studies, in particular are abundantly performed in fish and aquatic invertebrates, have brought forward new information on the levels and genotoxic effects of these compounds which complements data coming from monitoring the abiotic fractions of the ecosystem, thereby demonstrating that the ecogenotoxicological approach is fruitful. However, in order to assess the genotoxic impact on the health of the ecosystem, a second generation type of field studies is required focusing on adverse effects on biodiversity and on survival potency. For this, the application of DNA microarray-based technologies provides new opportunities. PMID- 21782601 TI - Kinetic parameters of OPT pesticide desulfuration by c-DNA expressed human CYPs. AB - The role of different cytochrome P450 isoforms (CYPs) in the desulfuration of four organophosphorothionate pesticides (OPTs), namely diazinon (DIA), azinphos methyl (AZ), chlorpyrifos (CPF) and parathion (PARA), at OPT levels representative of actual human exposure has been investigated. For this purpose c DNA expressed human CYPs and a method, based on acetylcholinesterase (AChE) inhibition, able to detect nM levels of oxon have been used. Our results indicate that the four tested OPTs at low concentration were mainly desulfurated by CYP2B6, 2C19 and 1A2, showing K(m) values in the range 0.8-5 MUM and the highest efficiency (intrinsic clearance (ICL)) values. CYP3A4 was generally endowed with high K(m) and resulted linear up to 25-100 MUM OPT, concentrations saturating the most efficient CYPs. The tentative extrapolation of the relative contribution of single CYPs, taking into account the average content of different isoforms in the human liver, indicate that CYP1A2 is the major responsible for oxon formation. Indeed this CYP catalyses the 50-90% of desulfuration reaction, depending on the OPT. As CYP3A4 activity is not completely saturated up to 100 MUM OPT, and due to the high hepatic content, its contribution to oxon formation may result relevant in poisoning episodes, when individuals are exposed at high doses of OPTs. PMID- 21782602 TI - ZnCl(2) prevents c-myc repression and apoptosis in serum-deprived Syrian hamster embryo cells. AB - In order to understand the c-myc implication in the apoptotic process better, we investigated the influence of ZnCl(2) on its expression in normal and transformed Syrian hamster embryo (SHE) cells in relation to apoptosis induced by serum withdrawal. Normal primary SHE cells exposed to a serum-free medium undergo rapid apoptosis characterised by a dramatic down-regulation of c-myc transcription. In these normal cells treated with ZnCl(2), c-myc expression is maintained in serum starved conditions while apoptosis is inhibited. The results shed light on the involvement of c-myc expression in the survival of normal cells in the absence of growth factors. The regulation of c-myc expression appears to be influenced by zinc treatment as an inhibitor of apoptosis, but mechanisms sustaining the level of c-myc transcription remain to be demonstrated. The hypothesis that maintenance of c-myc expression allows cells to escape apoptosis is in accordance with results in transformed SHE cells that underwent low apoptosis and poor down regulation of c-myc in serum-deprived conditions. PMID- 21782603 TI - Hapten-induced hypersensitivity reactions in the airways: atopic versus non atopic. AB - Hypersensitivity reactions induced by low molecular weight compounds are investigated extensively in the skin. However, these reactions can also occur in the lungs of previously sensitized individuals after local airway challenge. This hapten-induced pulmonary hypersensitivity reaction resembles features observed in asthmatic patients, such as bronchial hyperreactivity, accumulation of inflammatory cells, and airway edema. We review data that hapten-induced hypersensitivity reactions in mouse airways can be models for both atopic and non atopic asthma associated with low molecular weight compounds. PMID- 21782604 TI - Cyclopiazonic acid inhibits mutagenic action of aflatoxin B(1). AB - Cyclopiazonic acid and aflatoxin B(1) are mycotoxins which can both be produced by the same moulds. Men can be exposed to these mycotoxins directly via ingestion of plant-derived food, as well as, indirectly via consumption of animal products. Although it is well known that aflatoxin B(1) is mutagenic, contradictory results exist on the mutagenicity of cyclopiazonic acid. Using the Ames test cyclopiazonic acid was not found to be mutagenic either with or without metabolic activation by S9-mix of Arochlor treated rats. However, the mutagenicity of aflatoxin B(1) was inhibited in the presence of cyclopiazonic acid. Since cyclopiazonic acid inhibited the formation of certain metabolites of caffeine and testosterone, it was concluded that the reduction of the mutagenicity of aflatoxin B(1) in the presence of cyclopiazonic acid results from the inhibition of the bioactivation of aflatoxin B(1) by certain cytochrome P450 enzymes. PMID- 21782605 TI - The applicability of in vitro-derived data in hazard identification and characterisation of chemicals. AB - Toxicological hazard and risk assessments for chemicals presently are mainly based on highly standardised protocols for animal experimentation and exposure assessment. In this paper the possibilities are being discussed of developing systems in which the systemic (acute and chronic) toxicity of chemicals can be quantified, without the heavy reliance on animal experiments. On the basis of a chemical's structure, in vitro data on its toxicity, and biokinetic modelling a decision/flow scheme is presented. Key elements are the evaluation of chemical functionalities representing structural alerts for toxic actions, the construction of biokinetic models on the basis of non-animal data (e.g. tissue blood partition coefficients (PCs), in vitro biotransformation parameters), tests or batteries of tests for determining basal cytotoxicity and more specific tests for evaluating tissue- or organ toxicity. It is concluded that such a flow chart is a useful tool for different steps in the toxicological hazard and risk assessment, especially for those forms of toxicity for which validated in vitro and other non-animal tests have already been developed. PMID- 21782606 TI - From more to less than Haber's law. AB - We show how reformulating a first-order response theory with respect to both toxicant concentration and exposure time, in terms of relative instead of absolute increments, leads to a generalized version of Haber's law and to a combined sigmoid model for concentration and time response, derived on analytical rather than empirical grounds. More general presuppositions of Haber's law (without assuming sigmoid response) are briefly discussed. The relative intensities of time response and concentration response are measured by a single dimensionless parameter, characterizing each quadruple {toxicant, route, species, adverse effect}. Cross-species and cross-toxicant variability of this parameter is discussed and illustrated by new findings on algae and Daphniae exposed to selected inorganic and organic pollutants. PMID- 21782607 TI - Dose-related effects of the peroxisome proliferator methylclofenapate in rat liver. AB - Male Sprague-Dawley rats were fed diets containing 0 (control) and 2.5-750 ppm of the peroxisome proliferator methylclofenapate (MCP) for 1, 4 and 13 weeks. In other studies MCP has been shown to produce liver tumors at dietary levels of 50 and 250, but not 10 ppm. MCP treatment produced increases in relative liver weight and activities of peroxisomal and microsomal fatty acid oxidising enzymes at all time points at doses as low as 10 and 2.5 ppm, respectively. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2' deoxyuridine during study weeks 0-1, 3-4 and 12-13. Hepatocyte labelling index values were significantly increased by treatment with 10-750 ppm MCP for 1 week and 150-750 ppm MCP for 13 weeks. Treatment with 50-750 ppm MCP for 13 weeks increased hepatic peroxisome proliferator-activated receptor alpha and transforming growth factor-beta1 gene expression to 150-165 and 150-170% of control, respectively. These results demonstrate that while low doses of MCP produce sustained hepatomegaly and peroxisome proliferation in rat liver, higher doses are required to produce a sustained stimulation of replicative DNA synthesis. PMID- 21782608 TI - Conjugation of 4-nitrophenol and 4-hydroxylonazolac in V79-derived cells expressing individual forms of human sulphotransferases. AB - Sulpho conjugation of xenobiotics is catalysed by enzymes of the SULT superfamily. We have studied the conjugation of two model compounds, 4 nitrophenol and 4-hydroxylonazolac, in cultures of V79-derived cell lines that individually express human SULT1A1 (alloenzymes *1 and *V), 1A2 (alloenzymes *1 and *2), 1A3, 1B1, 1E1, 2A1 and rat SULT1E1. 4-Nitrophenol was sulphonated in all recombinant cell lines used but not in the control cell line (V79p). The relative activity in the various cell lines strongly depended on the substrate concentration used (1-1000 MUM). 4-Hydroxylonazolac was conjugated in the cell lines expressing the following enzymes, in this order, human SULT1E1>1A1 (*1>*V)>1A2 (*1>*2)>1A3. In all these cell lines, the rate of conjugation increased with the substrate concentration (1-100 MUM) without reaching a saturation level. The mass spectrometric and fluorometric analyses used are very sensitive. Preliminary experiments demonstrate that activities can readily be measured in microtitre-plate cultures. PMID- 21782609 TI - The toxicity of antioxidants and their metabolites. AB - Antioxidants are used on a very large scale to try to obtain and preserve optimal health. Nutraceuticals and food supplements frequently contain huge dosages of antioxidants. It is not generally recognised that high intake of antioxidants may also have adverse effects. Three antioxidants i.e. vitamin E, beta-carotene and lipoic acid are used to illustrate general considerations on the toxicity of antioxidants. Based on the examples the following recommendations for the evaluation of the toxicity of antioxidants are made: (i) classical safety factors should not be used. (ii) Knowledge on the mechanism of the efficacy and toxicity of antioxidants should be increased. (iii) Bio-kinetic/bio-efficacy modelling might be of help to optimise dosage. (iv) When antioxidant supplementation changes into therapy, a more accurate risk/benefit analyses is warranted. PMID- 21782610 TI - The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene. AB - A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the MU- and pi-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats. PMID- 21782611 TI - Absorption of a mutagenic metabolite released from protein-bound residues of furazolidone. AB - The use of nitrofurans as veterinary drugs has been banned in the EU since 1993 due to doubts on the safety of the protein-bound residues of these drugs in edible products. Following treatment of pigs with the veterinary drug furazolidone free 3-amino-2-oxazolidinone (AOZ), the side-chain of the drug, could be detected in the blood in concentrations up to 0.3 MUg/ml. The identity of the free AOZ was confirmed by LC/MS. This shows that the side-chain can be released from the parent drug, most likely under the acidic conditions in the stomach. Free AOZ was also detected in the blood of rats fed pig liver with protein-bound residues of furazolidone. Incubation of isolated pig hepatocytes with radiolabeled AOZ, resulted in the formation of protein-bound metabolites, to a similar extent as observed with furazolidone itself. Much lower levels were formed in the presence of dimethylsulfoxide or 4-chlorobenzenesulfonamide, most likely due to inhibition of the enzyme involved in the metabolic activation of AOZ. These compounds also prevented the inhibition by AOZ of monoamine-oxidase (MAO) activity in pig hepatocytes. These data strongly indicate that the protein bound metabolites of furazolidone in tissues of treated animals are derived following metabolic activation of furazolidone itself, but also of the free AOZ side-chain, following its release from the parent drug. In addition to the MAO inhibition and formation of protein-adducts, AOZ gave a dose-related positive respons in the Salmonella/microsome mutagenicity test especially in the presence of rat liver S9-mix, in tester strains TA 1535 and TA 100. Furthermore, a positive response was obtained in the chromosome aberration test with human lymphocytes and in the bone marrow micronucleus test with mice treated intraperitoneally with AOZ. It is concluded that ingestion of protein-bound residues of furazolidone results in the release and absorption of AOZ, a compound with potential mutagenic properties. This is the first report showing that protein-bound residues of veterinary drugs can be of toxicological significance. PMID- 21782612 TI - Aquatic toxicology: opportunities for enhancement through histopathology. AB - This paper briefly reviews the application of histopathology as aninstrument or endpoint in toxicity studies in fish. For long this has been applied rather occasionally in (regulatory) toxicology, and was mainly of interest in fundamental studies and limited carcinogenicity experiments. However, nowadays there are various incentives that ask for the application of pathology, such as field monitoring of pollution effects, the wish for optimal use and lower species of laboratory animals, the availability of modern histology techniques, and insight and interest in mechanistic data. This is timely illustrated by the current broad interest in endocrine disrupting pollutants-a threat mainly in the aquatic environment-where histopathological organ and tissue changes in intact sentinel fish species provide pivotal diagnostic and mechanistic features. PMID- 21782613 TI - Dietary n-6 and n-3 polyunsaturated fatty acids and colorectal carcinogenesis: results from cultured colon cells, animal models and human studies. AB - During the past few decades, many studies have been conducted to evaluate the effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colorectal carcinogenesis. This report provides a brief overview of the recent studies that have been performed in cultured colon cells, animal models as well as of the population-based and short-term biomarker studies with humans. No differential effect between n-6 and n-3 PUFAs has been observed in vitro. Results from animal models indicate that n-6 PUFAs have a tumor enhancing effect, predominantly during the post-initiation phase. n-3 PUFAs may protect against colorectal carcinogenesis during both the initiation and post-initiation phase. Population based human studies show little or no associations between n-6 or n-3 PUFA intake and colorectal cancer. Short-term biomarker studies in humans suggest though that fish oil (FO) supplementation with high amounts of n-3 PUFAs may protect against colorectal carcinogenesis and that n-6 PUFA supplementation may increase the risk. PMID- 21782614 TI - Cytotoxicity assays for mycotoxins produced by Fusarium strains: a review. AB - Mycotoxins are naturally occurring toxic secondary metabolites of fungi that may be present in food and feed. Several of these mycotoxins have been associated with human and animal diseases. Fusarium species, found worldwide in cereals and other food types for human and animal consumption, are the most important toxigenic fungi in northern temperate regions. The overall economical loss and the detrimental health effects in humans and animals of mycotoxin contamination are enormous and therefore, rapid screening methods will form an important tool in the protection of humans and animals as well as to minimize economical losses by early detection. An overview of methods for the determination of cytotoxicity and the application of such bioassays to screen solid fungal cultures, cereals, respectively, food/feedstuffs for the presence and toxic potential of Fusarium mycotoxins is presented. Various cell lines including different endpoints of toxicity using vertebrate cells and the predictive value of the in vitro assays are reviewed. Bioassays are compared with existing chemical analytical methods and the possibilities and limitations of such systems are discussed. The review is based on 149 references. PMID- 21782615 TI - The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. AB - Natural antioxidants like vitamin C, vitamin E, carotenoids, and polyphenols like flavonoids, are at present generally considered to be beneficial components from fruit and vegetables. The anti-oxidative properties of these compounds are often claimed to be responsible for various beneficial health effects of these food ingredients. Together these studies provide the basis for the present rapidly increasing interest for the use of natural antioxidants as functional food ingredients and/or as food supplements. However, at higher doses or under certain conditions antioxidant-type functional food ingredients may exert toxic pro oxidant activities. The present manuscript gives an overview of especially this pro-oxidative chemistry and toxicity of well-known natural antioxidants including vitamin C, vitamin E, carotenoids and flavonoids. PMID- 21782616 TI - Monolayers of IEC-18 cells as an in vitro model for screening the passive transcellular and paracellular transport across the intestinal barrier: comparison of active and passive transport with the human colon carcinoma Caco-2 cell line. AB - PURPOSE: previous studies have shown that the rat small intestinal cell line IEC 18 provides a size-selective barrier for paracellularly transported hydrophilic macromolecules. In order to determine the utility of IEC-18 cells as an in vitro model to screen the passive paracellular and transcellular components of the intestinal transport of nutrients and drugs, we have now examined the transport of GlySar (H(+)-coupled di/tripeptide carrier), O-methyl-d-glucose (glucose carrier), vincristine and rhodamine 123 (P-glycoprotein), and calcein and DNPSG (MRPs) and the bidirectional transport of paracellularly transported compounds. Transport of these compounds across the filter grown IEC-18 cells was compared with transport across the human colon carcinoma Caco-2 cells. RESULTS: in IEC-18 cells, transepithelial transport of GlySar and methylglucose was as fast as the transport of mannitol, which is transported passively via the paracellular route. Whereas in Caco-2 cells, mannitol transport was much slower than the transport of GlySar and methylglucose. In contrast to Caco-2 cells, no H(+)-coupled transport of GlySar could be measured in IEC-18 cells. P-Glycoprotein-mediated transport was characterised in Caco-2 cells by an enhanced transport of vincristine and rhodamine 123 in the basolateral to apical direction and by the inhibition of this transport by verapamil. In IEC-18 cells, permeability of vincristine and rhodamine 123 was similar in both directions and verapamil had no effect on the transport of these compounds. Both IEC-18 and Caco-2 cells efflux the organic anions calcein and DNPSG to the apical and basolateral compartments, and this efflux could be inhibited by probenecid. CONCLUSIONS: in conclusion, no carrier mediated transport of GlySar, methylglucose, vincristine and rhodamine 123 could be determined in IEC-18 cells in contrast to Caco-2 cells. However, both IEC-18 and Caco-2 cells showed MRP-mediated eflux system(s) in the apical and basolateral membrane. Monolayers of IEC-18 cells appear to be more suitable than monolayers of Caco-2 cells as an in vitro system to screen the passive component of the intestinal transport in a deconvoluted screening regimen, where passive transport is represented by the IEC-18 monolayer permeability and active transport is represented by monolayers of cells expressing the transport proteins heterologously. PMID- 21782617 TI - Induction of P-glycoprotein, glutathione-S-transferase and cytochrome P450 in rat liver by atrazine. AB - We studied the effects of intraperitoneally administered atrazine on two hepatic neoplastic markers, P-glycoprotein (P-gp), and glutathione-S-transferase (GST), and several phase I drug-metabolizing enzyme cytochrome P450 (CYP) subfamilies in hepatic microsomes and cytosol of Fischer rats. The P-gp content was increased after 24 h of atrazine administration at 50 mg/kg, and maximum P-gp induction was observed at 300 mg/kg for 3 days. GST-P was induced at a lower dose than P-gp, from 10 mg/kg, but no other form of GST, such as GST1A1, was induced by the same dose. Among the CYP families, CYP1A2 was highly and CYP2B was slightly induced by atrazine while the CYP3A content remained unchanged. The liver plasma membrane marker alkaline phosphatase (AP) was not induced by the same doses. The inductions of P-gp, GST-P and CYP1A2 observed may explain some of the reported tumor-promoting properties and toxicity of atrazine in vivo. PMID- 21782618 TI - Studies on the toxicity and efficacy of some ester analogues of dapsone in vitro using rat and human tissues. AB - The toxicity and efficacy of a series of 13 anti-tubercular sulphone esters has been evaluated using human and rat tissues. The toxicity studies involved comparison of the esters' ability to generate rat microsomally mediated NADPH dependent methaemoglobin with that of dapsone. All the compounds formed significantly less methaemoglobin in the 1 compartment studies compared with dapsone itself. The ethyl, propyl, 3-methyl-butyl cyclopentyl esters and the carboxy parent derivative all yielded less than 5% of the methaemoglobin generated by dapsone. The 3-nitro benzoic acid ethyl and propyl esters generated 30 and 25% of dapsone's methaemoglobin formation. A similar effect was seen in the 2 compartment system, except for the butyl ester, which yielded similar haemoglobin oxidation to dapsone. The low toxicity ethyl and propyl esters, were also low in toxicity using human liver microsomes, producing less than 30% of the dapsone mediated methaemoglobin. All the compounds except the benzoic acid parent were superior to dapsone in terms of suppression of human neutrophil respiratory burst using a lucigenin-based chemiluminescence assay. The most potent derivatives were the phenyl, propyl and 3-nitro benzoic acid ethyl esters, which were between two- and threefold more potent compared with dapsone in arresting the respiratory burst. Overall, the ethyl ester showed the best combination of low toxicity in the rat and human microsomal systems and its IC(50) was approximately 40% lower than that of dapsone in neutrophil respiratory burst inhibition. These compounds indicate some promise for future development in their superior anti-inflammatory capability and lower toxicity compared with the parent sulphone, dapsone. PMID- 21782619 TI - Cytochrome P450 (CYP1A) induction and DNA adducts in a rat hepatoma cell line (Fao), exposed to environmentally relevant concentrations of organic compounds, singly and in combinations. AB - Cytochrome P4501A (CYP1A) induction and DNA adduct formation were evaluated in the rat hepatoma cell line Fao, as biomarkers of exposure to organic compounds. Cells were exposed to environmentally relevant concentrations of benzo[a]pyrene (B[a]P) or 3,3',4,4'-tetrachlorobiphenyl (TCB), and to combinations of B[a]P and TCB. Both B[a]P and TCB induced CYP1A proteins in a concentration-dependent relationship, up to concentrations of 10 and 1 MUM, respectively, detected by Western blotting. DNA adducts, analyzed by (32)P-postlabeling, were found at the highest concentrations of B[a]P (1 and 10 MUM). No adducts were found in cells exposed to 0.1 MUM TCB alone. The cotreatment of TCB and B[a]P indicated an increase in DNA adduct formation, compared with B[a]P, but no further induction of CYP1A protein compared with TCB alone. This study suggests that Western blotting and (32)P-postlabeling might be suitable methods for detecting CYP1A protein induction and DNA adducts, respectively, after exposure to environmentally relevant concentrations of organic compounds. PMID- 21782620 TI - Identification of estrogenic activity of chlorinated bisphenol A using a GFP expression system. AB - A green fluorescent protein (GFP)-reporter vector regulated by an estrogen response element (ERE) was constructed and transfected into human breast carcinoma MCF7 cells. Stable transfectants were selected and their GFP fluorescence intensity was measured using a quantitative fluorescent imaging system. 17beta-estradiol (E(2)) and bisphenol A (BPA) induced a dose-dependent increase in GFP intensity in the cells, reaching maximum response at 5*10(-10) and 10(-5) M, respectively. Using this GFP expression system, we examined the estrogenicity of mono-, di-, tri-, and tetra-chlorinated BPAs, which were detected in wastewater from waste-paper recycling plants using sodium hypochlorite as a bleaching agent. 3-ClBPA and 3,3'-diClBPA showed similar estrogenicities, effective at lower concentrations than parent BPA. On the other hand, the maximum activities of BPA and 3,3',5-triClBPA, whose EC(50) were similar, were higher than other chlorinated BPAs. This is the first demonstration of the estrogenicity of chlorinated BPAs. Since polychlorinated BPAs were not easily biodegraded, chlorinated BPAs might be more severe endocrine disruptors than BPA. PMID- 21782622 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin: its effect on genes for mandible traits in mice. AB - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a powerful toxicant that exerts its effects through the aryl hydrocarbon receptor (AHR) governed by the Ahr locus that in mice is located on chromosome 12. We used single marker analyses of the offspring of female mice treated/not treated with TCDD to search for a gene (quantitative trait locus or QTL) on chromosome 12 near the site of the Ahr locus to test whether this locus appeared to affect mandible size, shape, and/or asymmetry especially in the treated mice. These mice were sampled from the F(2) generation of an original intercross of two strains (C57BL/6J and AKR/J) known to be divergent in their response to TCDD. A QTL affecting mandible shape was found on chromosome 12, but its effect on mice in the treated and control groups did not differ and it was concluded that this QTL probably was not the Ahr locus itself. We also probed a second chromosome (11) and found a QTL whose effects on asymmetry of mandible shape differed in the two environments. These results suggested that the entire genome in these mice should be scanned to search for additional QTLs that might be affected by TCDD to learn more about the potential effects of this powerful toxicant on these genes. PMID- 21782621 TI - Coexposure to benzo[a]pyrene plus ultraviolet A induces 8-oxo-7,8-dihydro-2' deoxyguanosine formation in human skin fibroblasts: preventive effects of anti oxidant agents. AB - The influence of environmental benzo[a]pyrene (BaP) contamination under ultraviolet A (UVA) on normal human skin fibroblasts was examined. Treatment of human skin fibroblasts with UVA in the presence of BaP induced cytotoxicity in a UVA- and BaP-dose-dependent manner, involving oxidative DNA damage (formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG)). Singlet oxygen quenchers significantly inhibited the formation of 8-oxo-dG, whereas hydroxyl radical and superoixide anion radical scavengers showed no effect. N-Acetyl-l-cysteine prevented the formation of 8-oxo-dG. These findings suggested the possibility of increased carcinogenesis in the skin via singlet oxygen produced by sunlight plus environmental BaP contamination and the efficiency of anti-oxidant agents for its prevention. PMID- 21782623 TI - Characterization of binding sites for diisopropyl phosphorofluoridate in spinal cord cytosol. AB - Gel filtration chromatography was performed on cytosol preparation of hen spinal cord to find molecular target(s) for organophosphorus-induced delayed neurotoxicity (OPIDN). Three binding peaks of [(3)H]diisopropyl phosphorofluoridate (DFP), an organophosphate that induces OPIDN, were separated from the cytosol preparation. The activities of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) that has been proposed as a screening method for OPIDN eluted in the fractions within these two DFP binding peaks. However, the other peak had none of the activities of AChE and NTE. Therefore, this DFP binding proteins in cytosol may be peculiar to the pathogenesis of OPIDN. PMID- 21782624 TI - Consequences and mechanisms of action of fish-borne toxicants: what we do not know and why. AB - We summarize and discuss issues that emerged from a workshop entitled 'Human and Animal Neurotoxicology-From Exposure to Great Lakes Pollutants' that was held as part of the May 2000 Annual Meeting of the International Association of Great Lakes Research in Cornwall, Ontario, Canada. The most apparent and distressing finding was the lack of communication that currently exists between scientists of different sub-disciplines-including in vitro and in vivo toxicologists, epidemiologists and risk assessors. Although all participants agreed that integrated, multi-disciplinary research is the only avenue that offers a realistic chance of identifying, characterizing and eventually preventing the adverse consequences of developmental exposure to neurological and reproductive toxicants, there was little consensus on how to achieve this goal. We leave to the readers of this Special Issue of Environmental Toxicology and Pharmacology the daunting task of implementing the greater degree of communication needed to begin to solve problems due to developmental exposure to environmental contaminants. PMID- 21782625 TI - Using biomarkers to characterise contaminant exposure among eaters of Great Lakes and St. Lawrence River fish. AB - Analyses of xenobiotics in human tissues are used to screen individuals whose habits or environments put them at high risk of overexposure, for the surveillance of exposure patterns over time and between places, and as part of research to identify the sources and pathways of exposure in a population. Both study goals and technical considerations should guide the choice of which xenobiotics to sample and in which tissues. Understanding the absorption and distribution of the specific compound to be measured is essential to the choice of when to sample and how to interpret results. Laboratory quality is of major concern. A particular issue in the statistical treatment of results are those near to the laboratory's detection limit. Theoretical concepts are discussed in the context of studies of xenobiotic exposure among eaters of Great Lakes and St. Lawrence River sport fish. PMID- 21782626 TI - Human developmental exposure to endocrine active compounds. AB - Quantification of exposure to environmental contaminants such as endocrine active chemicals (EACs) during critical periods of development, particularly in utero, remains largely unexplored. Therefore, we tested the hypothesis that EACs can be detected and quantified in second trimester human amniotic fluid. Amniotic fluid was obtained from women (n=175) undergoing routine amniocentesis between 14 and 21 weeks gestation. Samples were assayed by gas chromatography/mass spectrometry (GC/MS) for common organochlorine contaminants and dietary phytoestrogens. The DDT metabolite p,p'-DDE was found in approximately 25% of amniotic fluid samples (mean+/-S.D., 0.15+/-0.06 ng/ml) whereas the dietary phytoestrogens, genistein and or daidzein were found in 96.2% of samples tested (0.94+/-0.91 and 1.08+/ 0.91 ng/ml, respectively). Our results demonstrate that: (1) human amniotic fluid is a suitable biological medium to evaluate developmental exposure to EACs, and (2) fetuses are exposed to biologically active levels of EACs in mid pregnancy. PMID- 21782628 TI - Review of neurobehavioral deficits and river fish consumption from the Tapajos (Brazil) and St. Lawrence (Canada). AB - Our research group is carrying out studies on neurobehavioral changes associated with eating fish from the Upper St. Lawrence River (Quebec, Canada) and the Lower Tapajos River (Brazilian Amazon). Here, these studies are reviewed with respect to exposure, effects and intervention. Although mercury (Hg) levels in piscivorous fish are similar in both regions, in the Amazon, fish constitutes the dietary mainstay, while in Quebec, fish consumption is primarily occasional. Mercury exposure of Amazonian fish-eaters was considerably higher than Quebec (median blood total Hg: 28 and 1 MUg/l, respectively), but fish from the St. Lawrence contain multiple contaminants. For the Tapajos River, increasing hair Hg was associated with reduced motor and visual functions. Comparison of neurobehavioral performance of Quebec fish-eaters and non fish-eaters showed a consistent pattern of information processing slowing among the former; these deficits were not related to blood methyl Hg levels. Early changes associated with exposure can be used to trigger intervention. Since fish provide important essential nutrients, mitigation must balance the beneficial and harmful effects. In Canada, advisories from environmental and health agencies consider both these aspects. In the Amazon, we are currently involved in a participatory research whose goal is to reduce Hg absorption, while maintaining fish consumption. PMID- 21782627 TI - PCB congeners and pesticides and female fecundity, New York State Angler Prospective Pregnancy Study. AB - Consumption of PCB-contaminated sport fish from Lake Ontario has been reported to be associated with diminished female fecundity. To identify Polychlorinated biphenyl (PCB) congeners and other pesticides that might be associated with reduced fecundity, we followed 102 women aged 20-34 years attempting pregnancy who completed daily diaries for 12 at risk menstrual cycles. Fecundity referred to time-to-pregnancy (TTP) or the number of at risk menstrual cycles required for pregnancy. Blood specimens were obtained for 88 (86%) women and were analyzed using gas chromatography and electron capture for 66 PCB congeners and seven pesticides. Laboratory values were recovery, background and fat corrected prior to natural log transformation. Using stepwise discriminant analysis, congeners IUPAC #205 and #206 and hexaclorobenzene were significantly and positively associated with increasing TTP when women were categorized as becoming pregnant in the first or first three at risk menstrual cycles, respectively. Congeners #205 and #206 are reported to have (anti) estrogenic structural activity. PMID- 21782629 TI - Neurotoxic mechanisms of fish-borne methylmercury. AB - Methylmercury (MeHg) epidemics and studies in fish-eating populations have provided invaluable insights into the neurotoxic sequelae of MeHg exposure. MeHg is a ubiquitous environmental contaminant, and its accumulation in the food chain will continue to pose health risks given anthropogenic and natural contamination. This review briefly addresses recent epidemiological data associated with exposure to MeHg in fish-eating populations, identifies mechanisms of MeHg transport into the central nervous system (CNS), and discusses various theories on cellular processes afflicted by MeHg, which most certainly include astrocytic failure to maintain the composition of the extracellular fluid. PMID- 21782630 TI - Long-term consequences of developmental exposure to lead or polychlorinated biphenyls: Synaptic transmission and plasticity in the rodent CNS. AB - Exposure to lead (Pb) or polychlorinated biphenyls (PCBs) during early development has been associated with deficits in cognitive function in children (Pediatrics 87 (1991) 219; N. Engl. J. Med. 335 (1996) 783). These effects persist in the child long after exposure has ceased and body burdens have diminished. Despite intensive research, no consensus on the mechanisms of neurotoxicity of these chemicals has resulted. As the primary neurotoxic action of these agents is to impair cognitive ability, a number of laboratories have examined and reported on the detrimental the effects of Pb or PCBs on hippocampal synaptic transmission and long-term potentiation (LTP) in animals exposed during the perinatal period. Use-dependent synaptic plasticity, of which hippocampal LTP is the primary model system, is a fundamental property of neuronal function. In forebrain structures such as amygdala and hippocampus, LTP and related processes are purported to represent a physiological substrate for memory. During brain ontogeny, this type of plasticity guides the establishment and maintenance of synaptic connections in cortical structures based on sensory input. We postulate that the actions of PCBs and Pb in the developing nervous system perturb activity dependent plasticity and promote organizational changes in brain. Aberrant connectivity derived from perturbations in activity-dependent plasticity during development may manifest as impaired LTP and cognitive ability in the adult organism. PMID- 21782631 TI - Neurobehavioral toxicity of methylmercury and PCBs Effects-profiles and sensitive populations. AB - A large and growing body of literature is available on the neurotoxicity of methylmercury and PCBs as expressed in the behavior of both humans and laboratory animals. Methylmercury and PCBs will be compared with PCBs with attention directed at overlaps and distinctions in their profiles of neurotoxicity. It is possible with methylmercury and, to a lesser extent, with PCBs to characterize the sensory, motor, and cognitive consequences of exposure. Methylmercury is emerging as a life-span developmental neurotoxicant: adverse effects of exposure have been identified in development and during aging in human populations as well as in laboratory animals. Less is known about the PCBs on this count. While the mechanisms of neurotoxicity are not understood for either class of compounds, emerging clues are pointing to the possibility of overlap in some mechanisms of neurotoxicity. PMID- 21782632 TI - Biochemical alteration in freshwater fish Channa punctatus due to latices of Euphorbia royleana and Jatropha gossypifolia. AB - Exposure of fish over 96 h to 40 and 80% of LC(50) (24 h) of aqueous latex extracts of Euphorbia royleana and Jatropha gossypifolia of family Euphorbiaceae significantly altered the level of total protein, total free amino acids, nucleic acids, pyruvate, lactate, glycogen and as well as protease activity also in muscle, liver and gonadal tissue of the fish Channa punctatus. The alterations in all the biochemical parameters were significantly dose-dependent. Withdrawal study also shows that there is a partial recovery in the levels of glycogen, pyruvate, lactate and nucleic acids, but nearly complete recovery in total protein, total free amino acids level and protease activity in all the three tissues of the fish after the 7th day of the withdrawal of treatment, which supports the view that the plant product is safer in use as pesticides for control of common weed fishes in culture ponds. PMID- 21782633 TI - Inflammatory potential of the spores of Penicillium spinulosum isolated from indoor air of a moisture-damaged building in mouse lungs. AB - Excess moisture and microbial growth have been associated with adverse health effects, especially in the airways, of the inhabitants of moisture-damaged buildings. The spores of Penicillium spp. are commonly present in the indoor air, both in moisture-damaged and in reference buildings, though their numbers seem to be significantly higher in the damaged buildings. To assess the potential of Penicillium spinulosum to evoke harmful respiratory effects, mice were exposed via intratracheal instillation to a single dose of the spores of P. spinulosum, isolated from the indoor air of a moisture-damaged building (1*10(5), 1*10(6), 5*10(6), 1*10(7) or 5*10(7) spores). Inflammation and toxicity in lungs were evaluated 24 h later. The time-course of the effects was investigated with the dose of 5*10(6) spores for 28 days. The fungal spores caused mild transient inflammation. The spore exposure transiently increased proinflammatory cytokine (TNFalpha and IL-6) levels in bronchoalveolar lavage fluid (BALF) in a dose- and time-dependent manner. The highest concentrations of both cytokines were measured at 6 h after a single dosage. The spore exposure did not cause expression of inducible nitric oxide synthase in lavaged cells. Neutrophils were acutely recruited into airways, but the response leveled off in 3 days. Neither cytotoxicity nor major changes in vascular permeability (i.e. increases in albumin, total protein, lactate dehydrogenase or hemoglobin levels in BALF) were observed in the lungs. Considering the profile and magnitude of the changes and the dose of the spores, we conclude that P. spinulosum has a low potential to cause acute respiratory inflammation, nor does it cause direct cytotoxicity. PMID- 21782634 TI - Effects of an extract of oystercatcher (Haematopus ostralegus) eggs from the Zeehavenkanaal in The Netherlands, and of its major contaminant, hexachlorobenzene, on the chicken embryo. AB - Oystercatchers (Haematopus ostralegus) foraging on the canal 'Zeehavenkanaal' in the Netherlands have been shown to accumulate appreciable amounts of contaminants, especially hexachlorobenzene. The present study was performed to assess the embryotoxic effects of the present contaminants. To this end, a two step approach was followed. In step one, the toxic effects of hexachlorobenzene were studied in the chicken embryo bioassay, using concentrations realistic for the field situation. In step two, yolks of oystercatcher eggs were extracted and the embryotoxic potency of this extract was studied in the same bioassay, using doses of 1, 10 and 100% of the contaminant load in one average egg. The extract contained hexachlorobenzene and PCBs. However, presence of other compounds could not be excluded, since these were not analysed. Hexachlorobenzene induced a nonsignificant decrease in lymphocyte density in the bursa of Fabricius. The egg extract caused a 3.5 fold induction of EROD activity at the highest dose applied, and decreased lymphocyte density in the bursa of Fabricius. PMID- 21782635 TI - Chronic exposure to trichloroethylene affects neuronal plasticity in rat hippocampal slices. AB - Inhalational exposure to organic solvents is known to exert neurotoxic effects. Using the new multielectrode dish system (Panasonic) the effects of chronic exposure to trichloroethylene (TCE) on neuronal plasticity were assessed in different regions of the adult rat brain. Two groups of Long-Evans rats were exposed to 0 ppm or 500 ppm TCE, respectively, 6 h/day, 5 days/week for 6 months. Long-term potentiation (LTP) as well as paired-pulse potentiation/inhibition were assessed in slices from the visual cortex and the hippocampus. In addition, several behavioral tests were performed. Trichloroethanol concentrations were measured in blood and trichloroacetic acid concentrations were determined in urine. While TCE exposure impaired LTP as well as paired-pulse potentiation in hippocampal slices, no effects were seen in cortical slices. Our data demonstrate brain region specific functional changes following TCE exposure with the hippocampus being more vulnerable than the visual cortex. The behavioral measurements revealed no TCE related effects. PMID- 21782636 TI - Convergence of clinical toxicology and epidemiology in relation to health effects of chemicals. AB - An integrated approach of clinical toxicology and epidemiology is an essential ingredient in environmental health risk management through molecular epidemiology and environmental genomics. The last decade has also seen the emergence of several biochemical markers useful in chemical risk assessment and in epidemiological studies. An appraisal of the concepts involved, the approaches required, and the potential scope of this approach is attempted here. PMID- 21782637 TI - A transmission electron microscope investigation of the effect of lead acetate on the hepatopancreatic ceca of Gammarus pulex. AB - The freshwater Amphipod Gammarus pulex is a sensitive indicator organism for environmental contamination. In this study, effects of heavy metal lead acetate were investigated by using electron microscopy techniques. Control group was not expose to lead acetate but experimental group was for 96 h. The ultrastructural changes of hepatopancreatic ceca cells were studied in these two groups by electron microscopy techniques analysing cellular structure, structure of organelles and vacuolization. The number of cells based on the toxic effects of lead acetate was increased compared with the control group. The number and length of cell microvilli was decreased. Additionally degenerated mitocondria, dilation of golgi vesicules and cytoplasmic vacuolization were observed. The results of present study suggest that the exposure to the lead acetate may cause some ultrastructural changes on hepatopancreatic ceca of digestive system in Gammarus pulex. The significance of this change in terms of environmental toxicology needs to be further studied. PMID- 21782638 TI - Influence of dipyridamole on the fatty acid composition of the main lipid classes of chick serum. AB - We have studied the effects of dipyridamole treatment on the fatty acid composition of the main lipid classes of chick serum bearing in mind the relationship between platelet aggregation and eicosanoids production from arachidonic acid. In the free fatty acids, percentages of MUFA and n-6 PUFA fell. The effects of dipyridamole appeared to be less pronounced in triglyceride fraction, but more so in serum phospholipids and cholesterol esters. The percentage of arachidonic acid was significantly reduced by dipyridamole, as well as that of different n-3 PUFA present in phospholipid fraction. The percentage of linoleic acid in serum cholesterol esters was significantly lowered by dipyridamole, whereas that of arachidonic acid did not change significantly. Our results suggest that decreased arachidonic acid in the serum phospholipids and linoleic acid in all lipid classes may be of importance in order to dipyridamole participation in several pathologies characterized by an imbalance in the production of vasodilator and vasoconstrictor prostanoids. PMID- 21782639 TI - Botanical health products, positioning and requirements for effective and safe use. AB - Within the group of botanical products there is a large range of variation with regard to their properties. Some products are identical to foods while others come close to or are medicines. Botanical products are regulated differently within the different member states of the European Union (EU) and globally. They are regulated either as food or as medicinal products, and in the latter case often with simplified registration procedures. These differences are caused by differences in traditional use, in cultural and historical background, in scientific substantiation and in enforcement of current legislation. One may expect that in the future differences will remain, unless EU legislation is enacted with sufficient room for different approaches. The strengths and weaknesses of the different regulatory procedures have been reviewed and evaluated as well as the current methods for quality, efficacy and safety evaluation. Criteria to categorize botanical products have been defined, such that botanical products can be regulated under the current food and medicinal regulations. Furthermore, a decision tree has been developed as a tool to distinguish herbal medicinal products from botanical health products and vice versa, and to provide a stepwise framework for the assessment of safety and efficacy. PMID- 21782640 TI - Isoflavones protect against diesel engine exhaust injury in organotypic culture of lung tissue. AB - The wide range of potential health beneficial effects of isoflavones, including a chemoprentive action, have prompted us to study the potential benefits of genistein and daidzein in an experimental model of environmental pollution impact on lung tissue. A diesel engine placed was used to generate reproducible emissions including both gaseous and particulate matters that are commonly found in urban atmospheres. Isoflavones were added to culture medium of rat lung slices 2 h prior to their exposure to pollutants for 3 h. Intracellular ATP and GSH levels, TNFalpha production, nucleosome assay and TUNEL labeling were monitored. Isoflavones showed almost total in vitro protection against inflammatory and pro apoptotic responses in lung slices. Isoflavones 0.3 and 1 MUmol/l protected against exhaust induced GSH depletion. Isoflavones 0.3 MUmol/l appeared to exert the most beneficial effects. In conclusion, this study points out the potential interest of soy isoflavones consumption in polluted areas. Further studies should be undertaken to verify that similar effects could be obtained after in vivo administration of isoflavones. PMID- 21782641 TI - Metabolism of 1-fluoropyrene and pyrene in marine flatfish and terrestrial isopods. AB - Monofluorinated polycyclic aromatic hydrocarbons (F-PAHs) are useful reference compounds for a broad spectrum of PAH studies. The pyrene metabolite 1 hydroxypyrene is often used as a biomarker of PAH exposure. Two species, isopod (Porcellio scaber) and flatfish (Platichthys flesus), that produce 1 hydroxypyrene as the major intermediary metabolite and have distinct phase-II conjugates, were selected to investigate the cytochrome P450 catalyzed metabolism of 1-fluoropyrene. The fluorine atom blocks one of the four most favored carbon atoms, yielding different metabolite patterns and the results obtained in the selected species were compared with metabolite profiles obtained for unsubstituted pyrene. Charge densities in 1-fluoropyrene measured with (13)C-NMR were used to predict possible positions of hydroxylation, which were confirmed by (19)F-NMR. Additionally, the retention behaviour of conjugated 1-fluoropyrene metabolite isomers in reversed-phase liquid chromatography on a polymeric alkyl bonded phase was interpreted based on the slot model. Whereas three phase-I metabolites were found in isopod hepatopancreas, only two were observed in flatfish bile. Phase-II metabolism appeared unaffected by the fluorine substituent. It was concluded that the phase-I enzyme cytochrome P450 is non regioselective in the isopod: the activation is mostly influenced by the electron density distribution. In contrast, the enzymatic oxidation in the flounder is more selective. These differences will affect to what extent pyrene metabolite measurements can be used to assess the impact of PAHs to different species. PMID- 21782642 TI - Oxidative damage of sulfur dioxide inhalation on brains and livers of mice. AB - The effects of sulfur dioxide (SO(2)) on levels of thiobarbituric acid reactive substances (TBARS), levels of reduced glutathione(GSH) and the activities of Cu,Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were investigated in brains and livers of Kunming albino mice of both sexes. SO(2) at different concentrations (22, 56 and 112 mg/m(3)) was administered to animals of SO(2) groups in different exposure chambers for 6 h/day for 7 days, while control groups were exposed to filtered air in the same condition. Our results show that SO(2) caused lipid peroxidation and changes of antioxidative status in brains and livers of mice. Exposure to SO(2) at all concentrations tested caused significantly the increase of TRARS levels in brains and livers of mice. For the brains, activities of these antioxidant enzymes and levels of GSH were significantly unaltered by SO(2) at low concentrations, except significant increase of GSH levels in the brains of male mice; however, SO(2) at higher concentrations caused significantly decreases of GSH levels and activities of these antioxidant enzymes. For livers, SO(2) at all concentrations tested decreased significantly activities of SOD relative to control animals; SO(2) tended to decrease activities of GPx and CAT, but only the decreases of GPx and CAT activities caused by SO(2) exposures of higher concentrations (56 and 112 mg/m(3)) were statistically significant. SO(2) also tended to decrease levels of GSH, but only at 112 mg/m(3) caused significantly decrease of GSH levels in livers of both sexual mice. Unexpectedly, the decreases of activities of these antioxidative enzymes caused by SO(2) at different concentrations in brains and livers of mice did not follow a linear dose-response curves. In many respects, the decreased percentages of the activities of each antioxidative enzyme (SOD or GPx or CAT) caused by SO(2) at 22, 56 and 112 mg/m(3) in brains and livers of mice were similar. These results lead to conclusion that SO(2) exposure can caused oxidative damage to brains and livers of mice, and SO(2) is a toxin to brain and liver of mammals, not only to respiratory system. Further work is required to understand toxicological role of SO(2) on multiply or even all organs in human and animal. PMID- 21782643 TI - Role of vitamin C on lead acetate induced spermatogenesis in swiss mice. AB - In the present study significantly increased lipid peroxidation value (LPP) after a single intraperitioneal injection of lead acetate (LA) (100 mg/kg b.w.) indicated enormous generation of Reactive Oxygen Species (ROS). Lead-induced ROS has a direct inhibitory effect on the growth and differentiation of the spermatogonial cells showing a significant decline in sperm count. Chromosomal analysis of the primary spermatocytes at week 4 post-treatment in lead-treated mice revealed significantly higher no of aberrant cells including chromosomal deficiency, autosomal and XY-asynapsis plates compared to untreated control mice, Sperm morphology studies at week 1-4 and at week 8 post-treatment, indicated higher percentage of deformed sperm population compared to vehicle injected groups of mice. Supplementation of vitamin C (Vit C) at a dose of 10 mg/kg body weight to lead-treated mice groups, however, significantly reduced the LPP with a concomitant increase in sperm count, marked decrease in the no of aberrant cells and significant decline in the percentage of morphologically abnormal sperm population. Protective role of Vit C in combating lead-induced oxidative stress in mice testicular cells, has been discussed. PMID- 21782644 TI - The use of xenobiotic-mediated methaemoglobin formation to assess the effects of thyroid hormones on diabetic and non-diabetic human erythrocytic oxidant defence mechanisms in vitro. AB - Diabetes is associated with an abnormal incidence of hypothyroidism, which exacerbates hyperglycaemia, so further damaging already compromised erythrocytic defence mechanisms. Methaemoglobin formation is a useful measure of the health of these mechanisms, as it determines the resistance of diabetic erythrocytes to sustained oxidative stress. The effect of l-tri-iodothyronine (T(3)) was, therefore, studied on nitrite and monoacetyldapsone hydroxylamine (MADDS-NHOH) mediated methaemoglobin formation in diabetic and non-diabetic human erythrocytes. Diabetic erythrocytes showed less sensitivity compared with non diabetics to methaemoglobin formation mediated by both compounds. A 30 min pre incubation with T(3) at 3 and 30 nM did not affect nitrite-mediated methaemoglobin formation compared with control observations in both cell types. In diabetic erythrocytes incubated with T(3) at 30 nM, there were significant increases in MADDS-NHOH-mediated methaemoglobin formation compared with control in both diabetic and non-diabetic cells. Studies comparing blood isolated from diabetic patients stabilised on thyroxine (T(4); 50 MUG/day), T(4)-free diabetics and non-diabetics, showed that T(4) supplementation significantly increased MADDS NHOH-mediated methaemoglobin formation compared with T(4)-free diabetic cells so that for two time points, T(4)-treated diabetic erythrocytic methaemoglobin formation was indistinguishable from that of non-diabetics. These studies indicate that T(4) supplementation improves some erythrocytic oxidant defence mechanisms in a time dependent manner. PMID- 21782645 TI - Effect of pH on mutagenicity of urine from smokers and nonsmokers. AB - Cigarette smoking is a major risk factor for bladder cancer. Some chemicals from cigarette smoke e.g. aromatic amines, are metabolized in the liver and excreted in urine as either glucuronide or acetyl conjugates. These metabolites undergo pH mediated activation to reactive nitreneum ions that may lead to DNA adducts, initiating bladder tumorigenesis in some smokers. We hypothesize that changing the pH of smokers urine will impact the mutagenic outcome of these metabolites. Overnight samples were collected from smokers (n=11) and nonsmokers (n=11) and stored at -70 degrees C. Each urine sample was adjusted to neutral (7.0), basic (8.2) and acidic (5.5) pH. Mutagenic activity was assessed with the Ames test utilizing the Salmonella Typhimurium strain YG1024 microsuspension assay. Urine from smokers was significantly mutagenic compared with nonsmokers (P<0.001). In both the groups, there was no difference between urine adjusted at different pH (P>0.05). We conclude that changing the pH of smokers urine might not affect their subsequent risk for bladder cancer. PMID- 21782646 TI - Effects of A23187 and CaCl(2) on tri-n-butyltin-induced cell death in rat thymocytes. AB - As tri-n-butyltin (TBT), one of the environmental pollutants, is accumulated in wild animals, concern regarding the toxicity of TBT in both wildlife and human is increasing. TBT has been reported to increase intracellular Ca(2+) concentration in several types of cells. In order to examine how Ca(2+) is involved in TBT induced cell death, the effect of TBT on rat thymocytes has been compared with that of A23187, a calcium ionophore, under various concentrations of external Ca(2+) using a flow cytometer and fluorescent probes. Although both TBT and A23187 were toxic to cells under normal Ca(2+) condition, under external Ca(2+) free condition the cytotoxic action of TBT was potentiated without changing the threshold concentration while that of A23187 was completely abolished. A23187 attenuated the TBT-induced descent in cell viability under normal Ca(2+) concentration despite intracellular Ca(2+) concentration was increased. As external Ca(2+) concentration increased, the TBT-induced increase in number of dead cells gradually decreased whereas the number of cells in an early stage of apoptosis increased. Results suggest that Ca(2+) has contradictory actions on the process of TBT-induced cell death in rat thymocytes. PMID- 21782647 TI - Four-week inhalation toxicity, mutagenicity and immunotoxicity studies of Keum Yeon-Cho (NosmoQ), tobacco substitute composition, in mice. AB - Safety of Keum-Yeon-Cho (NosmoQ), a tobacco substitute composition, was evaluated in terms of acute- and 4 weeks repeated-inhalation toxicity, mutagenicity, and immunotoxicity using Balb/c mice. The air inside the inhalation chamber was collected and analyzed by GC-MS. In acute inhalation toxicity test, male and female mice were exposed to 40 Keum-Yeon-Cho cigarettes. The 50% lethal concentration (LC(50)) of NosmoQ was considered to be much higher than 40 cigarettes in both sexes. In 4-week repeated inhalation toxicity test, male and female mice were exposed for 6 h/day, 5 days/week for 4 weeks to 10 and 20 cigarettes per day, while control mice were exposed to filtered air. Our data indicated that no observed adverse effect level (NOAEL) of Keum-Yeon-Cho should be over 20 cigarettes per day. Results of Salmonella typhimurium reversion assay with/without histidine moiety, in vivo chromosomal aberration and in vivo micronucleus assays using mouse bone marrow cells revealed that Keum-Yeon-Cho has no mutagenicity. Evaluation of peripheral cellular immunity of mice treated with Keum-Yeon-Cho using in vitro lymphocyte proliferation assay showed no significant difference in mean stimulation index (SI) between mice exposed to Keum-Yeon-Cho and control mice. Mean CO concentrations and total particulate matter contents of 10 and 20 cigarettes were 21.1+/-1.23 and 40.7+/-1.21 ppm (mean+/-S.D., n=5), and 25.7+/-3.09 and 59.0+/-4.0 mg dry weight (mean+/-S.D., n=5), respectively. Although at negligible concentration (less than ppb level) several polycyclic aromatic hydrocarbons (PAHs) were also detected, these results indicate that NosmoQ has no toxic effect on mice. PMID- 21782648 TI - Effects of quercetin and quercetin-3-O-glycosides on oxidative damage in rat C6 glioma cells. AB - Flavonoids are reported to be powerful antioxidants in cell free systems. They naturally occur as glycosides rather than as aglycon. In this study the ability of the flavonoid quercetin and its glycosides, quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucoside and quercetin-3-O-(6"-O-acetyl)-glucoside, to protect in vitro rat C6 glioma cells from oxidative damage induced by cumene hydroperoxide was investigated. Cumene hydroperoxide induced cell death and lipid peroxidation. The cytotoxicity of cumene hydroperoxide could be prevented by the radical scavenger dimethyl thiourea and the ferric iron chelator deferoxamine, indicating that its cytotoxic activity is related to the generation of reactive oxygen radicals in the ferrous iron dependent Fenton reaction. Quercetin, in a concentration range of 10-100 MUM, but neither rutin nor the other two glycosides, were able to protect C6 cells from cytotoxicity and lipid peroxidation. Furthermore, cytoprotective concentrations of quercetin proved to be cytotoxic itself. These results call in question potential beneficial effects of dietary intake or therapeutic use of naturally occurring flavonoids. PMID- 21782649 TI - Fish bioaccumulation and biomarkers in environmental risk assessment: a review. AB - In this review, a wide array of bioaccumulation markers and biomarkers, used to demonstrate exposure to and effects of environmental contaminants, has been discussed in relation to their feasibility in environmental risk assessment (ERA). Fish bioaccumulation markers may be applied in order to elucidate the aquatic behavior of environmental contaminants, as bioconcentrators to identify certain substances with low water levels and to assess exposure of aquatic organisms. Since it is virtually impossible to predict the fate of xenobiotic substances with simple partitioning models, the complexity of bioaccumulation should be considered, including toxicokinetics, metabolism, biota-sediment accumulation factors (BSAFs), organ-specific bioaccumulation and bound residues. Since it remains hard to accurately predict bioaccumulation in fish, even with highly sophisticated models, analyses of tissue levels are required. The most promising fish bioaccumulation markers are body burdens of persistent organic pollutants, like PCBs and DDTs. Since PCDD and PCDF levels in fish tissues are very low as compared with the sediment levels, their value as bioaccumulation markers remains questionable. Easily biodegradable compounds, such as PAHs and chlorinated phenols, do not tend to accumulate in fish tissues in quantities that reflect the exposure. Semipermeable membrane devices (SPMDs) have been successfully used to mimic bioaccumulation of hydrophobic organic substances in aquatic organisms. In order to assess exposure to or effects of environmental pollutants on aquatic ecosystems, the following suite of fish biomarkers may be examined: biotransformation enzymes (phase I and II), oxidative stress parameters, biotransformation products, stress proteins, metallothioneins (MTs), MXR proteins, hematological parameters, immunological parameters, reproductive and endocrine parameters, genotoxic parameters, neuromuscular parameters, physiological, histological and morphological parameters. All fish biomarkers are evaluated for their potential use in ERA programs, based upon six criteria that have been proposed in the present paper. This evaluation demonstrates that phase I enzymes (e.g. hepatic EROD and CYP1A), biotransformation products (e.g. biliary PAH metabolites), reproductive parameters (e.g. plasma VTG) and genotoxic parameters (e.g. hepatic DNA adducts) are currently the most valuable fish biomarkers for ERA. The use of biomonitoring methods in the control strategies for chemical pollution has several advantages over chemical monitoring. Many of the biological measurements form the only way of integrating effects on a large number of individual and interactive processes in aquatic organisms. Moreover, biological and biochemical effects may link the bioavailability of the compounds of interest with their concentration at target organs and intrinsic toxicity. The limitations of biomonitoring, such as confounding factors that are not related to pollution, should be carefully considered when interpreting biomarker data. Based upon this overview there is little doubt that measurements of bioaccumulation and biomarker responses in fish from contaminated sites offer great promises for providing information that can contribute to environmental monitoring programs designed for various aspects of ERA. PMID- 21782650 TI - Metal ion-responsive transgenic Xenopus laevis as an environmental monitoring animal. AB - We generated germ line-transgenic Xenopus laevis that monitors environmental heavy metal ions. Sperm nuclei were transduced with cDNA of enhanced green fluorescent protein (EGFP) driven by murine metallothionein-1 gene promoters and were microinjected into unfertilized eggs. The eggs developed to sexually matured adults. The transgenic tadpoles at the premetamorphic stage were reared in water containing Zn(2+) and Cd(2+) separately at the concentrations of 0.38-1.52 and 0.09-0.44 MUM, respectively. These animals responded to Zn(2+) at as low as 0.38 MUM and Cd(2+) at as low as 0.44 MUM. The level of EGFP fluorescence emitted by tadpoles increased as the concentration increased up to 1.52 MUM and the exposure time prolonged up to 120 h. The fluorescent response was much more sensitive to Cd(2+) than to Zn(2+). We concluded that these transgenic tadpoles are useful as an animal indicator of environmental heavy metal ions. PMID- 21782651 TI - Ultrastructural alterations of the hepatopancreas in Porcellio scaber under stress. AB - Cellular ultrastructure varies in accordance with physiological processes, also reflecting responses to environmental stress factors. Ultrastructural changes of the hepatopancreatic cells in the terrestrial isopod Porcellio scaber exposed to sublethal concentrations of zinc or cadmium in their food were identified by transmission electron microscopy. The exclusive structural characteristic of the hepatopancreas of animals exposed to metal-dosed food was grain-like electrondense deposits (EDD) observed in the intercellular spaces and in vesicles of B cells. In addition, hepatopancreatic cells of metal-exposed animals displayed non-specific, stress-indicating alterations such as cellular disintegration, the reduction of energetic reserves (lipid droplets, glycogen), electron dense cytoplasm, ultrastructural alterations of granular endoplasmic reticulum (GER), the Golgi complex and mitochondria. PMID- 21782652 TI - Heavy metals in soil, vegetables and fruits in the endemic upper gastrointestinal cancer region of Turkey. AB - The environmental exposure to heavy metals is a well-known risk factor for cancer. We investigated levels of seven different heavy metals, (Co, Cd, Pb, Zn, Mn, Ni and Cu) in soil, fruit and vegetable samples of Van region in Eastern Turkey where upper gastrointestinal (GI) cancers are endemic. Heavy metal contents of the samples were determined by flame atomic absorption spectrometer. Four heavy metals (Cd, Pb, Cu and Co) were present in 2- to 50-fold higher concentrations whereas zinc levels were present in 40-fold lower concentrations in soil. The fruit and vegetable samples were found to contain 3.5- to 340-fold higher amounts of the six heavy metals (Co, Cd, Pb, Mn, Ni and Cu) tested. The volcanic soil, fruit and vegetable samples contain potentially carcinogenic heavy metals in such a high levels that these elements could be related to the high prevalence of upper GI cancer rates in Van region. PMID- 21782653 TI - A study on electrophysiological effects of subchronic cadmium treatment in rats. AB - Male Wistar rats were treated for 4, 8 and 12 weeks with 3.5, 7.0 or 14.0 mg/kg cadmium (in the form of cadmium chloride) by gavage. Changes induced in certain electrophysiological parameters-electrocorticogram frequency; latency and duration of cortical sensory evoked potentials; conduction velocity and relative and absolute refractory periods of a peripheral nerve-were analyzed. On the electrocorticogram, increased frequency was seen. Lengthened latency and duration of the cortical evoked potentials, as well as lowered conduction velocity and increased refractory periods in the peripheral nerve, were observed. These changes seemed to increase with the dose and the treatment time and were statistically significant mainly in the highest dose groups following 12 weeks of treatment. The results show that subchronic, low-level exposure by cadmium affects the rat's spontaneous and evoked bioelectric activity and point at the possible consequences in exposed humans. PMID- 21782654 TI - Age-related morphological impairments in the rat hippocampus following developmental lead exposure: an MRI, LM and EM study. AB - Lead is one of the most common neurotoxic metals present in our environment. Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Functional and morphological impairment of the rat brain has also been reported in the hippocampus (Hi) following developmental lead exposure. The present study was carried out to further investigate age-related morphological impairments in the rat Hi following developmental lead exposure with three methods: (1) magnetic resonance imaging (MRI); (2) light microscopy (LM); and (3) electron microscopy (EM) techniques. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking a 0.2% lead acetate solution. Age-related morphological alternations were investigated in the Hi of lead-exposed rats at various postnatal ages: postnatal day (PND) 17, 30 and 90. The MRI signal intensities (SIs) in the left, right, superior and inferior hippocampal regions of control and lead-exposed rats were analyzed. Compared with controls, the SIs of the four hippocampal regions of interest were significantly increased in lead-exposed rats at PND 17, 30 and 90. Moreover, the lead-induced impairment of the Hi showed an age-related decline and a specific topographical pattern. The impairment of inferior hippocampal regions was more severe than that of superior regions in lead-exposed rats at PND 17 and 30, while no significant difference of SIs was observed between left and right hippocampal regions in the three age groups, and between superior and inferior regions in the PND 90 lead exposed rats. The LM observations indicated that the morphological injury of hippocampal neurons in lead-exposed rats was also age-related. The EM observations revealed that the endoplasmic reticular, Golgi complex and mitochondria of hippocampal CA1 and dentate gyrus neurons in lead-exposed rats were damaged. These results demonstrate that lead-induced morphological impairments of the rat Hi follow a specific age- and site-related pattern. PMID- 21782655 TI - Fluoride causing abnormally elevated serum nitric oxide levels in chicks. AB - Serum fluoride, nitric oxide (NO), malondialdehyde (MDA) contents and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities were determined in chicks treated with graded doses of sodium fluoride. Compared with chicks in the control group, in the groups treated with fluoride, serum NO and MDA levels largely increased, and the activities of SOD, GSH-Px, and CAT decreased, most of which changed significantly (P<0.05). Serum fluoride levels significantly and positively correlated with serum NO, MDA levels, respectively (P<0.05), and significantly and negatively with serum SOD, GSH-Px, CAT activities, respectively (P<0.05). The results indicated fluoride was associated with the elevated NO levels and the decreased activities of antioxidant enzymes and the deposit of lipid peroxides (LPO). We suggest the mechanism of fluoride injuring soft tissues as follows: fluoride causes excessive production of NO, LPO and oxygen free radicals, which can damage seriously the structure and function of soft tissues. PMID- 21782656 TI - Triethyltin increases cytosolic Ca(2+) levels in human osteoblasts. AB - In human osteosarcoma MG63 cells, effect of triethyltin, an environmental toxicant, on intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured by using fura-2. Triethyltin (1-50 MUM) caused a rapid and sustained plateau rise of [Ca(2+)](i) in a concentration-dependent manner (EC(50)=10 MUM). Triethyltin induced [Ca(2+)](i) rise was prevented by 50% by removal of extracellular Ca(2+) but was not altered by voltage-gated Ca(2+) channel blockers. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum (ER) Ca(2+) ATPase, caused a monophasic [Ca(2+)](i) rise, after which the increasing effect of triethyltin on [Ca(2+)](i) was attenuated by 60%; also, pretreatment with triethyltin abolished thapsigargin-induced [Ca(2+)](i) increase. Depletion of mitochondrial Ca(2+) with carbonylcyanide m-chlorophenylhydrazone (CCCP; 2 MUM) did not affect triethyltin-induced Ca(2+) release. U73122, an inhibitor of phoispholipase C, abolished ATP (but not triethyltin)-induced [Ca(2+)](i) rise. A low concentration (1 MUM) of triethyltin failed to alter ATP and bradykinin induced [Ca(2+)](i) rises. These findings suggest that triethyltin rapidly increases [Ca(2+)](i) in osteoblasts by stimulating both extracellular Ca(2+) influx and intracellular Ca(2+) release via as yet unidentified mechanism(s). PMID- 21782657 TI - Developmental genetics and physiology of sex differentiation in vertabrates. AB - The involvement of the Y chromosome in sex determination was determined by the development and the application of techniques for karyotyping the mammalian chromosome in 1960s. There were many reports on the particular region of the Y chromosome, such as histocompatibility (H-Y) antigen, bandit krait minor satellite (Bkm) the zinc finger Y gene (ZFY) and the sex-determining region of the Y chromosome (SRY) which were believed to be the testis determining factors. However, converging experimental evidence have indicated that the sex determining region of the Y chromosome (sry) is the testis determining factor (TDF) in mammalian species since sex is determined genetically at the time of fertilization in these species. In non-mammalian vertebrates especially in fishes, amphibians and reptiles, genotypic sex can be overridden by the external application of steroid hormones and temperature. In this review paper, after reviewing the complex literature on the molecular and biochemical mechanisms of sex determination and differentiation in all vertebrates, the potential danger of environmentally induced sex determination will be focused on. PMID- 21782658 TI - In vitro and in vivo dose-dependent inhibition of methylmercury on glutamine synthetase in the brain of different species. AB - Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia and is associated with ischemic injury and neurological diseases. We investigated whether the in vitro and in vivo exposure to methylmercury (MeHg) produce changes in GS activity in the brain of different species. The brain in rats and mice was dissected into different regions for GS assay. MeHg levels in the brain tissues and blood of mice treated 2, 4 or 10 mg/kg MeHg were determined by a gas-chromatography/mass selective detector. In vitro exposure of MeHg (0.1 100 MUM) produced dose-dependent decreases of GS activity in rat brains with 50% inhibition occurred at 10-20 MUM. MeHg was a more potent GS inhibitor in vitro in the rat brain than other GS inhibitors (e.g., methionine sulfoximine, kainic acid). These effects were further confirmed using purified GS of sheep brains. In vivo GS activity was also inhibited in the hippocampus of mice given 4 or 10 mg/kg of MeHg. In mice concentration ratios of brain tissues to blood were 0.05 0.14 at 24 h post-dose. These data showed that MeHg produced significant changes in GS activity, indicating that GS is an effective biomarker for MeHg exposure. PMID- 21782659 TI - Role of lipophilic medium in the absorption of polycyclic aromatic compounds by biomembranes. AB - Polycyclic aromatic hydrocarbons (PAHs), before reaching DNA where they exert their activity, have to interact with the outer lipid layer of cell membranes and subsequently penetrate inside cells. Studying the interaction PAH-lipid membrane should be interesting in assessing the relevance of the medium in the absorption processes. A technique used to study such an interaction is differential scanning calorimetry (DSC) that detects the phase transition from an ordered to a disordered lipid structure, that can be affected by the presence of foreign molecules, when submitted to heating. Effects exerted by fluorene, fluoranthene and indeno(1,2,3-cd)pyrene on the thermotropic behavior of model membranes were here investigated. Aqueous dispersions of synthetic dimyristoylphosphatidylcholine (DMPC) were used as model membranes to study PAHs membrane interaction. All the examined PAHs, dispersed in liposomes during their preparation, affect, to a different extent, the DMPC liposome transitional phase temperature. A study carried out by leaving powdered PAHs in contact with DMPC vesicles, shows that all three PAHs are almost unable to migrate through the aqueous medium. Instead, when PAH loaded liposomes were left in contact with empty ones, it appears evident that fluorene is able to migrate from a loaded membrane to an empty one. Also fluoranthene, although to a minor extent relative to fluorene, is able to migrate through the lipid environment. Indeno(1,2,3 cd)pyrene is less able to migrate through liposomes. The obtained data seem to validate the employment of the DSC technique in studying the ability of bioactive and potentially mutagenic compounds not only to interact with biological membranes but also to be adsorbed into a cell when dispersed in a lipophilic medium. PMID- 21782660 TI - The use of computational QSAR analysis in the toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds. AB - A series of N(1)-benzylidene pyridine-2-carboxamidrazone anti-tuberculosis compounds has been evaluated for their cytotoxicity using human mononuclear leucocytes (MNL) as target cells. All eight compounds were significantly more toxic than dimethyl sulphoxide control and isoniazid (INH) with the exception of a 4-methoxy-3-(2-phenylethyloxy) derivative, which was not significantly different in toxicity compared with INH. The most toxic agent was an ethoxy derivative, followed by 3-nitro, 4-methoxy, dimethylpropyl, 4-methylbenzyloxy, 3 methoxy-4-(-2-phenylethyloxy) and 4-benzyloxy in rank order. In comparison with the effect of selected carboxamidrazone agents on cells alone, the presence of either N-acetyl cysteine (NAC) or glutathione caused a significant reduction in the toxicity of INH, as well as on the 4-benzyloxy derivative, although both increased the toxicity of a 4-N,N-dimethylamino-1-naphthylidene and a 2-t butylthio derivative. The derivatives from this and three previous studies were subjected to computational analysis in order to derive equations designed to establish quantitative structure activity relationships for these agents. Twenty five compounds were thus resolved into two groups (1 and 2), which on analysis yielded equations with r(2) values in the range 0.65-0.92. Group 1 shares a common mode of toxicity related to hydrophobicity, where cytotoxicity peaked at logP of 3.2, while Group 2 toxicity was strongly related to ionisation potential. The presence of thiols such as NAC and GSH both promoted and attenuated toxicity in selected compounds from Group 1, suggesting that secondary mechanisms of toxicity were operating. These studies will facilitate the design of future low toxicity high activity anti-tubercular carboxamidrazone agents. PMID- 21782661 TI - The effect of various substituents in ortho position of biphenyls on respiratory burst, intracellular calcium elevation in human granulocytes, and uptake of dopamine into rat brain synaptic vesicles and synaptosomes. AB - Polychlorinated biphenyls (PCBs) are a group of compounds, which have effects on the immune and nervous system. We have investigated the effects of seven diortho substituted biphenyls with different substituents on activation of respiratory burst and calcium elevation in human granulocytes, and inhibition of the uptake of dopamine into synaptic vesicles and synaptosomes isolated from rat brain. We have attempted to find the chemical and physical properties, which can contribute to the variation in biological effects. These properties include the absolute hardness, the molecular size, the hydrophobicity of the molecules, the retention time on a DB5-MS GC-column and the electronegativity of the substituents. In general the dichloro- and dibromobiphenyls were the most potent in all biological tests. The difluorosubstituted was less potent than the other two halide biphenyls presumably because of the smaller size of the substituent. Dimethylbiphenyl was active in all tests. Dihydroxy- and dimethanolbiphenyl were inactive in all tests, whereas dinitrobiphenyl was only active as a vesicular dopamine uptake inhibitor. Important physico-chemical parameters correlated to the effects were absolute hardness, molecular size and lipophilicity. Among the tested diortho-substituted biphenyls the most active were the chlorinated, brominated, and methylated. This indicates the significance of the molecular size in combination with the hydrophobicity for the studied toxic effects. PMID- 21782662 TI - Cell-metal interaction studied by cytotoxic and FT-IR spectroscopic methods. AB - The main purpose of this work is to investigate the possibility of utilizing both a classical biological method to test cytotoxicity and a physical measurement procedure as the FT-IR spectroscopy to study the interaction between cells lines and heavy metals. Jurkart, a lymphocyte cell line, was treated with cadmium chloride, cadmium oxide and the organic germanium compound named Ge-oxy-132. The utilized value of heavy metal concentration allows us to obtain significant results with both methods and with all metals. In fact by using lower values of concentration any effect is revealed after treatment with germanium. The results of the simultaneous measurements by both experimental procedures are here reported for the first time and show that, while the cytotoxic effects of the two cadmium compounds are confirmed, the organic germanium compound reveals a very different and interesting interaction with Jurkart cells. The behaviour of the Jurkart cells upon the uptake of cadmium or organic germanium is very different: while treatment with CdO and CdCl(2) determines proteins denaturation and lipids oxidation in cells until the death, these processes are not revealed after Ge-oxy 132 treatment. PMID- 21782663 TI - Evaluation of cell proliferation in ear and lymph node using BrdU immunohistochemistry for mouse ear swelling test. AB - The mouse ear swelling test (MEST) was developed as an alternative to guinea pig models for measuring the contact sensitization potential. However, the MEST relies on the quantitative measurement of ear swelling by micrometer as the means of determining the endpoint. The purpose of this study was to investigate the possibility of using cell proliferation in the ear and lymph node by bromodeoxyuridine (BrdU) immunohistochemistry as a reliable marker for MEST. Female Balb/c mice were treated by the topical application of various sensitizers, 2,4-dinitrochlorobenzene (DNCB), toluene diisocyanate (TDI) and alpha-hexylcinnamaldehyde (HCA) and an irritant, sodium lauryl sulfate (SLS) following the protocol of MEST. The proliferation of cells in the ear and auricular lymph node was analyzed by BrdU incorporations into cells. There were significant increases in the cell proliferations of the ear and auricular lymph node in mice treated with DNCB and TDI compared to the vehicle control. All allergens and the irritant were correctly identified by the MEST using BrdU immunohistochemistry of lymph node responses. The standard MEST assay showed positive results in the case of the strong sensitizers, DNCB and TDI. However, HCA and SLS were not correctly identified in the ear swelling assay. These results suggest that the measurement of cell proliferation in the auricular lymph node using BrdU immunohistochemistry could provide a reliable marker for MEST. PMID- 21782664 TI - A preliminary evaluation of a novel method to monitor a triple antioxidant combination (vitamins E, C and alpha-lipoic acid) in diabetic volunteers using in vitro methaemoglobin formation. AB - Eight otherwise healthy diabetic volunteers took a daily antioxidant supplement consisting of vitamin E (200 IU), vitamin C (250 mg) and alpha-lipoic acid (90 mg) for a period of 6 weeks. Diabetic dapsone hydroxylamine-mediated methaemoglobin formation and resistance to erythrocytic thiol depletion was compared with age and sex-matched non-diabetic subjects. At time zero, methaemoglobin formation in the non-diabetic subjects was greater at all four time points compared with that of the diabetic subjects. Resistance to glutathione depletion was initially greater in non-diabetic compared with diabetic samples. Half-way through the study (3 weeks), there were no differences between the two groups in methaemoglobin formation and thiol depletion in the diabetic samples was now lower than the non-diabetic samples at 10 and 20 min. At 6 weeks, diabetic erythrocytic thiol levels remained greater than those of non diabetics. HbA(1c) values were significantly reduced in the diabetic subjects at 6 weeks compared with time zero values. At 10 weeks, 4 weeks after the end of supplementation, the diabetic HbA1(c) values significantly increased to the point where they were not significantly different from the time zero values. Total antioxidant status measurement (TAS) indicated that diabetic plasma antioxidant capacity was significantly improved during antioxidant supplementation. Conversion of alpha-lipoic acid to dihydrolipoic acid (DHLA) in vivo led to potent interference in a standard fructosamine assay kit, negating its use in this study. This report suggests that triple antioxidant therapy in diabetic volunteers attenuates the in vitro experimental oxidative stress of methaemoglobin formation and reduces haemoglobin glycation in vivo. PMID- 21782665 TI - Percutaneous absorption, biophysical, and macroscopic barrier properties of porcine skin exposed to major components of JP-8 jet fuel. AB - JP-8 has been associated with toxicity in animal models and humans. There is a great potential for human exposure to JP-8. Quantitation of percutaneous absorption of JP-8 is necessary for assessment of health hazards involved in its occupational exposure. In this study, we selected three aliphatic (dodecane, tridecane, and tetradecane) and two aromatic (naphthalene and 2 methylnaphthalene) chemicals, which are major components of JP-8. We investigated the changes in skin lipid and protein biophysics, and macroscopic barrier perturbation from dermal exposure of the above five chemicals. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the biophysical changes in stratum corneum (SC) lipid and protein. FTIR results showed that all of the above five components of JP-8 significantly (P<0.05) extracted SC lipid and protein. Macroscopic barrier perturbation was determined by measuring the rate of transepidermal water loss (TEWL). All of the five JP-8 components studied, caused significant (P<0.05) increase in TEWL in comparison to control. We quantified the amount of chemicals absorbed assuming 0.25 m(2) body surface area exposed for 8 h. Our findings suggest that tridecane exhibits greater permeability through skin among aliphatic and naphthalene among aromatic JP-8 components. Amount of chemicals absorbed suggests that tridecane, naphthalene and its methyl derivatives should be monitored for their possible systemic toxicity. PMID- 21782666 TI - Alkylphenol concentrations in two rivers of Turkey. AB - Alkylphenol polyethoxylates (APEs) called environmental endocrine disruptors has been shown to accumulate in water around the world. In this study, the pollution level of alkylphenolic compounds was measured and quantified in water, sediment, and the tissues of fishes collected in two rivers, Sakarya and Degirmendere Rivers, Turkey. Butylphenol (BP) were detected in sediment samples at one sampling stations of both rivers with 1.68 and 3.15 MUg/g sediment, while nonylphenol (NP) were detected with the amount of 4.46 MUg/g sediment in one sampling station in Degirmendere river. Fish samples also showed the presence of alkylphenolic compounds in both rivers. The level of alkylphenol pollution in two rivers of Turkey was determined to be in the range of alkylphenol level reported in Europe but lower than that of in the USA. PMID- 21782667 TI - Influence of methyl parathion on reproductive parameters in male rats. AB - Exposure of human population to pesticides and industrial pollutants has considerably increased the risk of human health hazard. In the present study, therefore we have sought to investigate the toxic effects of Methyl Parathion on male reproductive system of rat. The tested dose was given orally to the rats for 30 days at the dose level of 30 mg/kg/day. Sex organs weight analysis, histochemical and histopathological changes and mating trials were the criteria used to evaluate the reproductive efficacy of the treated rats. The body weight of the animals did not show any significant change. However, Methyl Parathion caused significant decrease in the weight of testis, epididymis, seminal vesicle and ventral prostate with marked pathomorphological changes. Also, marked reduction in epididymial and testicular sperm counts in exposed males were noticed. Fertility test showed 80% -ve fertility in treated animals. A significant reduction in the sialic acid contents of testis, epididymis, seminal vesicle, ventral prostate and testicular glycogen were noticed, while the protein and cholesterol content were raised significantly. From the above-mentioned findings, it has been concluded that exposure to Methyl Parathion has deleterious effects on male reproductive system of rat. Therefore, application of such insecticide should be limited to a designed program. PMID- 21782668 TI - Effects of perinatal exposure to bisphenol A on the behavior of offspring in F344 rats. AB - The objective of this investigation is to evaluate whether perinatal maternal exposure to bisphenol A (BPA) at 4, 40, and 400 mg/kg per day affects the behavior of offspring in F344 rats. Perinatal BPA exposure inhibited the body weight increases of male and female offspring in a dose-dependent manner, which continued after weaning. Spontaneous activity analyses revealed that BPA elongated immobile time during the dark phase in female offspring. At 4 weeks of age, male offspring exposed to BPA at 40 and 400 mg/kg per day performed avoidance responses significantly higher in the shuttlebox avoidance test. At 8 weeks of age, however, male offspring only at 4 mg/kg per day showed significantly lower responses. In the open-field behavior test at 8 weeks of age, male offspring exposed to BPA only at 4 mg/kg per day showed a higher percent of grooming than the control male offspring. In conclusion, perinatal exposure to BPA caused the behavioral alterations in the offspring. PMID- 21782669 TI - Protective effects of N-acetylcysteine against carbon tetrachloride- and trichloroethylene-induced poisoning in rats. AB - This research investigates the protective effect of N-acetylcysteine (NAC) against carbon tetrachloride (CCl(4))- and trichloroethylene (TCE)-induced hepatotoxicity in rats. A single dose of 1.25 ml/kg of 20% CCl(4) in corn oil, administered orally, or 20% TCE, administered intraperitoneally, produced significantly elevated levels of serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) activities. Histopathological examinations showed massive centrilobular necrosis and fat accumulation in CCl(4) treated animals. In the curative test, especially in animals treated with higher dosages of NAC, there was significant reduction in SGPT and SGOT levels. Although there was no sign of abnormality in the livers of rats treated with TCE, NAC demonstrated its action against TCE-induced elevation of transaminases in the enzyme assays. Compared to the curative tests, the overall performance of NAC against toxin-induced toxicity in the preventive tests was poor. Even at the highest dosage applied, the effect was not as prominent as that achieved in the curative test. It is therefore concluded that NAC is effective for lowering chemical-induced elevated levels of SGPT and SGOT in the curative mode. PMID- 21782670 TI - The effects of zeta cypermethrin on the gills of common guppy Lebistes reticulatus. AB - Effects of lethal and sublethal concentrations 15, 20, 26 and 35 MUg/l of zeta cypermethrin on the gills of common guppies (L. reticulatus) were examined by light microscopy during 96 h exposure. The most common changes at all doses of zeta cypermethrin are the lifting of epithelial layer from gill lamellae and some necrosis. Besides the exudation, hyperplasia and the shortening of secondary lamellae were other histopathological effects. The 96 h LC(50) value for zeta cypermethrin to the L. reticulatus was determined 21.35 MUg/l. PMID- 21782671 TI - Effects of dihydrolipoic acid (DHLA), alpha-lipoic acid. N-acetyl cysteine and ascorbate on xenobiotic-mediated methaemoglobin formation in human erythrocytes in vitro. AB - alpha-Lipoic acid, dihydrolipoic acid (DHLA), N-acetyl cysteine and ascorbate were compared with methylene blue for their ability to attenuate and/or reduce methaemoglobin formation induced by sodium nitrite, 4-aminophenol and dapsone hydroxylamine in human erythrocytes. Neither alpha-lipoic acid, DHLA, N-acetyl cysteine nor ascorbate had any significant effects on methaemoglobin formed by nitrite, either from pre-treatment, simultaneous addition or post 30 min addition of the agents up to the 60 min time point, although N-acetyl cysteine did reduce methaemoglobin formation at 120 min (P<0.05). In all three treatment groups at 30, 60 and 120 min, there were no significant effects mediated by DHLA or N acetyl cysteine on 4-aminophenol (1 mM)-mediated haemoglobin oxidation. Ascorbate caused marked significant reductions in 4-aminophenol methaemoglobin in all treatment groups at 30-120 min except at 30 min in the simultaneous addition group (P<0.0001). Neither alpha-lipoic acid, nor N-acetyl cysteine showed any effects on hydroxylamine-mediated methaemoglobin formation at 30 and 60 in all treatment groups. In contrast, DHLA significantly reduced hydroxylamine-mediated methaemoglobin formation at all three time points after pre-incubation and simultaneous addition (P<0.001), while ascorbate was ineffective. Compared with methylene blue, which was effective in reducing methaemoglobin formation by all three toxins (P<0.01), ascorbate was only highly effective against 4-aminophenol mediated methaemoglobin, whilst the DHLA-mediated attenuation of dapsone hydroxylamine-mediated methaemoglobin formation indicates a possible clinical application in high-dose dapsone therapy. PMID- 21782672 TI - Intranasal effects in chemically sensitive volunteers: an experimental exposure study. AB - During inhalational exposure to irritants stimulation of the trigeminal nerve endings in the nasal mucosa or other biochemical mechanisms might initiate inflammatory processes. Increased sensitivity of this physiological system in response to chemical stimulation is postulated in subjects reporting chemical intolerance. In the present study 12 subjects reporting chemical sensitivity and 12 controls were exposed to different concentrations of the industrial solvents ethyl benzene and methyl ethyl ketone (MEK). Concentrations of various inflammatory biomarkers, namely eosinophil cationic protein (ECP), myeloperoxidase (MPO), interleukin 1beta (IL-lbeta), substance P (SP), and neurokinin A (NKA) were measured in nasal secretion after exposures. Before, during, and after the exposures subjects rated the severity of nasal irritations. The biomarker concentrations and reported irritations were not affected by the exposures. Regardless of substance and concentration sensitive subjects reported more nasal irritations. In conclusion, the investigated substances might possess weaker potency to elicit intranasal irritative effects than postulated. PMID- 21782673 TI - Increased synthesis of GFAP by TCDD in differentiation-disrupted SFME cells. AB - The effects of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) on gene expression and synthesis of glial fibrillary acidic protein (GFAP) in differentiation-disrupted serum-free mouse embryo (SFME) cells were examined. SFME cells were exposed to fetal calf serum (FCS) and dimethyl sulfoxide (DMSO) to induce differentiation and increase GFAP synthesis. Disruption of differentiation was caused by low level toluene, significantly inhibiting GFAP synthesis. TCDD at 0.01, 0.1 and 1 pg/ml in the presence of low-level toluene increased GFAP synthesis in the SFME cells, while expression of GFAP mRNA showed no significant change. The TCDD treated SFME cells detached from the culture substratum, indicating an apparent change in cell adhesion. These results suggest that low-level TCDD further disrupts differentiation of SFME cells in the presence of low-level toluene by upregulating GFAP synthesis and by altering the ability in cell adhesion and that GFAP synthesis is not disrupted at transcription but at translation. PMID- 21782674 TI - Temporal effects of mancozeb on testes, accessory reproductive organs and biochemical constituents in albino mice. AB - Mancozeb, a fungicide of ethylenebisdithiocarbamate group was orally administered at 800 mg/kg body weight to male Swiss albino mice for 5, 10, 20 and 30 days. Daily body weight of the mice were recorded. The mice were sacrificed by cervical dislocation after 24 h of terminal exposure of mancozeb. Testes weight decreased significantly in 20 and 30 days mancozeb treated mice. However, there was a significant decrease in the number of spermatogonia, diameter of spermatocytes and spermatids in 20 days and number of spermatids in 10 days mancozeb treated mice. Histologic studies of the testis of the mice treated with mancozeb for long duration revealed spermatogenesis inhibition reflected by significant decrease in the number of spermatogenic cells and sperms, when compared with that of controls. In the mice treated with mancozeb for 20 and 30 days showed significant decrease in the weight of the prostate gland. However weight of Cowper's glands decreased significantly in 30 days mancozeb treated mice. There was significant decrease in the kidney, spleen and liver weight, where as thyroid weight increased significantly in mice treated with mancozeb for 30 days. However, thymus weight increased significantly only in the mice treated with mancozeb for 10, 20 and 30 days. In mice treated with mancozeb for 20 days caused significant decrease in the level of protein and a significant increase in the level of total lipids in the testis. However, there was significant decrease in the level of glycogen in the kidney. In mice treated with mancozeb for 30 days caused significant decrease in the levels of protein and glycogen and significant increase in the level of total lipids in the testis and liver and a significant decrease in the protein, glycogen and total lipids in the kidney. These observed effects of mancozeb on testis and biochemical constituents may be due to hormonal imbalance in any of the stages in the hypothalamo-hypophysial-testicular axis. PMID- 21782675 TI - Thiamine protects against paraquat-induced damage: scavenging activity of reactive oxygen species. AB - To demonstrate the superoxide anion (O(2)(-)) scavenging activity of thiamine, we comparatively investigated the inhibition of cell growth reduction and repression of the oxidative stress-inducible gene expression (soxS, sodA, zwf and soi 19::lacZ) triggered by paraquat, intracellular O(2)(-) generator, using an Escherichia coli system. When thiamine (>1 MUM) was added to the culture, a decrease of growth rate caused by paraquat was significantly recovered. Paraquat treatment (1 MUM) to aerobically grown E. coli highly increased the expression of soxS and its regulons sodA and zwf, genes for manganese-containing superoxide dismutase (Mn-SOD) and glucose-6-phosphate dehydrogenase (G6PDH) to cope with the oxidative stress. However, the induction of Mn-SOD and G6PDH was suppressed by the thiamine supplement. The induction of the soi-19::lacZ gene, whose expression was dependent on paraquat, was also repressed by more than 10 MUM of the thiamine addition to the culture. To characterize the role of thiamine, which challenges the paraquat toxicity, an in vitro experiment of nitroblue tetrazolium (NBT) reduction was performed. The NBT reduction by O(2)(-) generated in the xanthine/hypoxanthine system was inhibited by the thiamine supplement in a dose dependent manner. Moreover, it competed with the 2-deoxy-d-ribose in absorbing the hydroxyl radical (OH) generated by gamma-irradiation (800 Gy) and thus inhibited the formation of malondialdehyde in vitro. In conclusion, this evidence suggests that thiamine may partly act as an antioxidant to scavenge O(2)(-) (or OH) directly and thus affect the cellular response to oxidative stress induced by reactive oxygen species. PMID- 21782676 TI - Aminoglutethimide-induced leucopenia in a mouse model: effects of metabolic and structural determinates. AB - A model of human leucopenia has been developed further in the female mouse. Following daily administration to female mice of 50 mg/kg of the aromatase inhibitor aminoglutethimide, significant falls in platelet and white cell counts occurred after 2 and 3 weeks. At week 4, drug dosage was stopped and the cell counts recovered at the end of that week, although on rechallenge at the beginning of week 5, both platelet and white cell counts fell rapidly. Administration to the mice of structural analogues of aminoglutethimide, such as WSP-3, glutethimide and 4-nitroglutethimide, showed no reductions in platelet and white cell counts. The haemotoxicity of aminoglutethimide over 21 days was unaffected by the presence of either the P-450 inhibitor SKF-525A or the hepatic P-450 inducer phenobarbitone. However, the co-administration of cimetidine abolished the haemotoxicity of aminoglutethimide in terms of platelet and white cell levels. In in vitro studies, both aminoglutethimide and WSP-3 were oxidised to cytotoxic species, although aminoglutethimide was significantly more cytotoxic than WSP-3. The NADPH-dependent covalent binding of (14)C aminoglutethimide to mouse microsomes in vitro was significantly reduced by the presence of cimetidine. The activation of the compound to reactive species in vitro, the inhibitory effects of cimetidine in vivo and in vitro, as well as the rapid fall in the in vivo white cell count on rechallenge with aminoglutethimide suggest that this model illustrates a form of leucopenia which may be related to hapten formation and subsequent immune-mediated platelet and white cell lysis. PMID- 21782677 TI - Effect of alkylphenols on adult male medaka: plasma vitellogenin goes up to the level of estrous female. AB - The effect that oral administration of four alkylphenols, (1) bisphenol A (BPA), (2) p-t-octylphenol (OP), (3) p-nonylphenol (NP) and (4) p-n-nonylphenol (n-NP), as well as 17alpha-ethynylestradiol (EE2) had on male medaka fish vitellogenin was investigated. The male medaka was fed diets containing different concentrations of these chemicals for 7 days, after which their plasma vitellogenin levels were measured. Vitellogenin levels up to ~10(7) ng/ml were found. This value is close to that of the normal estrous female medaka. The median effective concentration (EC(50)) values resulting from BPA, OP, NP and EE2 in the diet were calculated as 1600, 2600, 940 and 0.37 MUg/g diet, respectively. PMID- 21782678 TI - Thiophenes and furans derivatives: a new class of potential pharmacological agents. AB - A new class of potential pharmacological thiophenes and furans compounds has been prepared. The obtained thiophenes and furans derivatives were screened for anti inflammatory, antinociceptive and antioxidant activity in rats. In vitro hepatic ALA-D activity was also evaluated. Thiophene 2 exhibited higher anti-inflammatory effect than thiophenes 1 and 3. However, compound 1 demonstrated lower IC(50) for lipid peroxidation than 2 and 3 in liver and brain. Furan compounds 4-6 presented similar anti-inflammatory activity. The acetylenic furans 4 and 5 inhibited scarcely lipid peroxidation at low concentration as 10 MUM. Conversely, furan compound 6 was the most effective against lipid peroxidation in liver. Furans 4 and 5 inhibited lipid peroxidation, in brain, only in high concentrations. In contrast, furan 6 protected (90%) against lipid peroxidation at 10 MUM. Thiophene 1 was devoid of anti-inflammatory activity but was efficient in reducing acetic acid-induced constriction. Conversely, it analogue furan 4 presented anti inflammatory and antinociceptive activity. Thiophene and furan inhibited hepatic ALA-D only at high concentrations. All compounds displayed antioxidant activity however the anti-inflammatory activity is not related to antioxidant potential. PMID- 21782679 TI - Increase in number of annexin V-positive living cells of rat thymocytes by intracellular Pb(2+). AB - Lead is ubiquitous in our environment and lead poisoning is a major public health problem worldwide. In this study, to see if intracellular Pb(2+) induces the exposure of phosphatidylserine in rat thymocyte membranes, we have examined the effect of PbCl(2) on rat thymocytes treated with A23187 using a flow cytometer with appropriate fluorescent indicators under nominally-Ca(2+)-free condition. PbCl(2) at 1-30 MUM dose-dependently induced the exposure of phosphatidylserine on outer membranes, associated with increasing the concentration of intracellular Pb(2+). The potency of intracellular Pb(2+) to induce the apoptotic change in thymocyte membranes seems to be greater than those of intracellular Ca(2+) and Cd(2+). Results suggest that intracellular Pb(2+) triggers apoptosis of rat thymocytes. This action of Pb(2+) may be one of mechanisms for the lead-induced changes in immunity. PMID- 21782680 TI - Potential role of vitamins in chromium induced spermatogenesis in Swiss mice. AB - Chromium (Cr) (VI) compounds are known carcinogens and mutagens. The mechanism of carcinogenicity and mutagenicity caused by chromium(VI) compounds remained unclear for several years. However, in the recent past chromium-induced carcinogenicity and/or mutagenicity was known to happen due to the generation of reactive oxygen species (ROS). In the present context, chromic acid (CrO(3)), a potential Cr(VI) compound could be able to generate reactive oxygen radicals in the testes of Swiss mice as evidenced from significantly higher lipid peroxidation compared to untreated controls. The cytotoxic effects of the compound on the testes are depicted in terms of significantly reduced sperm count level accompanied with increased abnormal sperm population in treated mice. Supplementation of vitamins like Vitamin C and Vitamin E (Vit C and Vit E) to CrO(3) injected mice groups could partially prevent the incidence of abnormal sperm population and increased the sperm count. Of the two vitamins, taken for the study, Vit C happens to be more effective in ameliorating germ cells from degeneration and from mutation to abnormal sperm. Possible antioxidative role of both the vitamins have been studied for significant decrease in lipid peroxidation associated with marked elevation in sperm count level and significant decrease in the percentage of abnormal sperm formation in CrO(3) treated mice. PMID- 21782681 TI - Mechanisms for resin acid effects on membrane currents and GABA(A) receptors in mammalian CNS. AB - Resin acids from bleached wood pulp are toxic to fish. 12,14 Dichlorodehydroabietic acid (12,14-Cl(2)DHA) raises cytoplasmic Ca(2+) in synaptosomes and blocks neural GABA(A) receptors; however, the underlying mechanism remains unclear in these earlier rodent studies. 12,14-Cl(2)DHA (50MUM) almost completely blocked native GABA(A) currents (rat cortical cultures) but had no significant effect on picrotoxin-sensitive recombinant human receptors in oocytes (alpha1, beta2 and gamma2L: the most prevalent isoforms in mammalian brain). In oocytes, 12,14-Cl(2)DHA failed to produce a calcium-activated chloride current, in contrast to the calcium ionophore ionomycin (10MUM). However, in cultured cortical pyramidal cells, both ionomycin and 12,14-Cl(2)DHA produced chloride-selective currents of similar magnitude (presumably secondary to Ca(2+) release). 12,14-Cl(2)DHA was unable to stimulate phosphate labelling of [(3)H ] inositol in mouse synaptosomes, indicating that the study compound does not cause Ca(2+) release via an IP(3) mechanism. Calcium pump ATPase inhibition also seems unlikely since thapsigargin did not elevate free calcium in synaptosomes. 12,14 Cl(2)DHA clearly blocks GABA(A) currents indirectly: we infer that its toxicity may be secondary to the elevations in cytoplasmic Ca(2+) via an unidentified recognition site (or receptor) found in neuronal cells. PMID- 21782682 TI - Temporal effect of carbofuran on estrous cycle compensatory ovarian hypertrophy and follicles in hemiovariectomized albino mice. AB - Carbofuran, a systemic N-methyl carbamate pesticide was administered orally with an effective dose of 1.3mg/kg per day to hemiovariectomized (HOVX) mice for 5, 10, and 15 days. Sham-operated and HOVX control mice were administered a similar quantity of olive oil. The vaginal smear and body weight of the mice were recorded daily and mice were sacrificed on day 16. The results of the present study indicate that there is a significant decrease in the duration of the estrus with a concomitant significant increase in the duration of the diestrus with carbofuran treatment for 10 days. In the HOVX mice treated with carbofuran for 15 days there was a significant decrease in the length of the estrous cycle and the duration of the estrus and metestrus with a concomitant significant increase in the diestrus. There was a significant increase in the ovarian weight in HOVX control mice when compared to that of the sham operated control mice. HOVX mice treated with carbofuran for 10 and 15 days showed a significant decrease in the relative ovarian weight with a concomitant inhibition of compensatory ovarian hypertrophy in HOVX mice. There was also a significant decrease in the ovarian growth rate in relation to the contralateral ovary of the same animal. There was a significant decrease in the number of small and total number of healthy follicles with a concomitant significant increase in the number of medium, large and total number of atretic follicles in HOVX mice treated with carbofuran for 10 days. There was a significant decrease in the number of small, medium, large, and total number of healthy follicles with a concomitant significant increase in the number of medium, large, and total number of atretic follicles in HOVX mice treated with carbofuran for 15 days. The administration of carbofuran in the present study showed that there is no significant change in the body and organs weight such as uterus, kidney, adrenals, liver, spleen, thymus and thyroid in all the carbofuran-treated mice. The above findings such as disruption in the estrous cycle, inhibition of compensatory ovarian hypertrophy, and follicular toxicity may be due to a direct effect on the ovary or through the hypothalamo-hypophysial ovarian axis. PMID- 21782683 TI - Modulatory effects of caffeine on methotrexate-induced cytogenotoxicity in mouse bone marrow. AB - Caffeine (CAF), a widely used and extensively studied chemical, is known for the reports on its controversial and inconsistent genotoxic effects, potentiative and protective effects from the genotoxicity of chemical and physical mutagens, and its modulatory effects on the action of antineoplastic drugs. Methotrexate (MTX), an antifolate antimetabolite, is a widely prescribed antineoplastic drug with significant clastogenic effects. In the present study, in addition to the assessment of cytogenotoxicity of CAF 25, 50 or 100mg/kg in mouse bone marrow, their modulatory effects on the cytogenotoxicity of MTX 10mg/kg was assessed from the induced frequencies of aberrant metaphases, chromosomal aberrations (CAs) and percentages of dividing cells at 24h post-treatment and the induced frequency of micronuclei (MN) at 30h post-treatment. All the three doses of CAF induced higher percentages of aberrant metaphases, high frequency of CAs and MN and increased percentages of dividing cells, but the increase in the aberrant metaphases and CAs was statistically significant only with the highest dose of CAF. Thus, CAF was weakly clastogenic to mouse bone marrow cells. However, pre-treatment of each of the three doses of CAF reduced the frequency of MTX 10mg/kg-induced aberrant metaphases, CAs, MN and also the percentage of dividing cells, but significantly only by the two higher doses of CAF. Thus, the higher doses of CAF protected mouse bone marrow cells from the cytogenotoxicity of MTX. The possible mechanisms involved in bringing about the weak clastogenic action of CAF and its protection from the cytogenotoxic effects of MTX have been discussed, and bio-modulation of the effects of antineoplastic drugs has been highlighted. PMID- 21782684 TI - Toxic effect of two common Euphorbiales latices on the freshwater snail Lymnaea acuminata. AB - The aqueous and serially purified latex extracts of plants Euphorbia pulcherima and Euphorbia hirta (family Euphorbiaceae) have potent molluscicidal activity. Sub-lethal doses (40 and 80% of LC(50)) of aqueous and partially purified latex extracts of both the plants also significantly alter the levels of total protein, total free amino acid, nucleic acid (DNA and RNA) and the activity of enzyme protease and acid and alkaline phosphatase in nervous tissue of the snail Lymnaea acuminata in time and dose dependent manner. E. pulcherima and E. hirta are common medicinal plants of family Euphorbiaceae. E. pulcherima is useful for a variety of conditions, such as rheumatism, snakebite, asthma, obstipation, and skin-diseases. While, E. hirta is also used in cough, asthma, colic, dysentery, and genito urinary diseases. PMID- 21782685 TI - The toxicity of pyrethroid compounds in neural cell cultures studied with total ATP, mitochondrial enzyme activity and microscopic photographing. AB - Pyrethroids are important insecticides used largely because of their high activity as an insecticide and their low mammalian toxicity. Some studies have demonstrated that these products, especially compounds with an alpha-cyano group, show neurotoxic effects on the mammalian central nervous system (CNS). In this study, we investigate with different methods the cell toxic effects of commercial, chemically different pyrethroid compounds on neuronal cell line SH SY5Y. Natural pyrethrin and permethrin (both with no alpha-cyano group) and cypermethrin (with an alpha-cyano group), were studied. For toxicity determinations, SH-SY5Y neuroblastoma cells were exposed to pyrethroids at 0.1 100MUM concentrations for 1 day. The cell toxicity was evaluated by determining the total ATP with a luminescence method, the mitochondrial metabolic activity (WST-test) with a photometric method, and the morphological changes of the cell cultures with microscopic digital photographing at different dose levels of compounds. The results obtained with WST-1 method and with the measurement of total ATP were different. ATP measurement seemed to show cytotoxicity at lower concentrations than WST-1 method. There was induction of enzyme activities with WST-1 test with all pyrethroid compounds studied at low concentrations. With the ATP assay, exposure to 0.1-100MUM of natural pyrethrin, as well as of permethrin and cypermethrin showed dose-dependent cytotoxicity. The most toxic pyrethroid was cypermethrin followed by permethrin and natural pyrethrin. Our study confirms that the cell toxicity was dependent on the chemical structure of pyrethroids and pyrethroids without an alpha-cyano group show the weakest physiological effect. Microscopic photographs of exposed cell cultures correlated to the toxic effects revealed by the metabolic tests. PMID- 21782686 TI - Effects of 2-bromopropane on pregnant dams and embryo-fetal development in the ICR mouse. AB - 2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth's environment. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo fetal development after maternal exposure during the gestational days (GD) 6-17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 500, 1000, and 1500mg/kg per day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. Throughout the study period, no treatment-related deaths were found in the groups treated with 2-BP. Pregnant mice of the 1000 and 1500mg/kg groups showed treatment-related clinical signs such as rough fur and swelling, induration, crust formation, and ulceration in the injection sites which were dose dependent in incidence and severity. A decrease in fetal weight, an increase in fetal malformation, and an increase in fetal ossification delay were found at a dose level of 1500mg/kg per day in a dose-dependent manner. On the contrary, there were no adverse effects on body weight, body weight gain, gravid uterine weight, food consumption, gross finding at any dose tested. In addition, no treatment-related effects on the number of corpora lutea, implantations, resorptions, dead fetuses, live fetuses, and sex ratio of live fetuses were observed. These findings suggest that 2-BP was embryotoxic and teratogenic at a minimally maternally toxic dose (i.e., 1500mg/kg per day) in ICR mice. In the present experimental conditions, the no-observed-adverse-effect level of 2-BP is considered to be 500mg/kg per day for dams and 1000mg/kg per day for fetuses, respectively. PMID- 21782687 TI - Oxidation of protein in human low-density lipoprotein exposed to peroxyl radicals facilitates uptake by monocytes; protection by antioxidants in vitro. AB - Generation of neoepitopes on apolipoprotein B within oxidised low-density lipoprotein (LDL) is important in the unregulated uptake of LDL by monocytic scavenger receptors (CD36, SR-AI, LOX-1). Freshly isolated LDL was oxidised by peroxyl radicals generated from the thermal decomposition of an aqueous azo compound. We describe that formation of carbonyl groups on the protein component is early as protein oxidation was seen after 90min. This is associated with an increased propensity for LDL uptake by U937 monocytes. Three classes of antioxidants (quercetin, dehydroepiandrosterone (DHEA) and ascorbic acid) have been examined for their capacity to inhibit AAPH-induced protein oxidation, (protein carbonyls, Delta electrophoretic mobility and LDL uptake by U937 monocytes). CD36 expression was assessed by flow cytometry and was seen to be unaltered by oxidised LDL uptake. All three classes were effective antioxidants, quercetin (P<0.01), ascorbic acid (P<0.01), DHEA (P<0.05). As LDL protein is the control point for LDL metabolism, the degree of oxidation and protection by antioxidants is likely to be of great importance for (patho)-physiological uptake of LDL by monocytes. PMID- 21782688 TI - Short-term effects and teratogenicity of heptanol on embryos of Xenopus laevis. AB - This study examined teratogenic and short-term effects of heptanol on Xenopus embryos. Embryos were exposed for 5h to 2.5mM heptanol at different developmental stages. Teratogenic effects were found in embryos treated from cleavage to early neurula stages. Other heptanol concentrations, shorter exposure time, and the effect of temperature were also assayed. Short-term effects of hepatanol exposure were studied during cleavage and all treated blastulae showed cell separation with delaminated blastomeres inside the blastocel. Disruption of cell adhesion in addition to the uncoupling effect could account for heptanol teratogenicity. PMID- 21782689 TI - Mechanistic approaches for mixture risk assessments-present capabilities with simple mixtures and future directions. AB - Mechanistic studies with simple mixtures have provided insights into the nature of interactions among chemicals that lead to non-additive effects and have elucidated the exposure conditions under which interactions are likely to occur. This paper discusses studies on four mixtures: (1) 1,1-dichloroethylene and trichloroethylene, (2) carbon tetrachloride and Kepone, (3) hexane and methyl-n butylketone, and (4) coplanar and non-coplanar polychlorinated biphenyls. These mechanistic studies show that interactions should be described at the level of target tissue dose and are best categorized as either pharmacokinetic (PK) or pharmacodynamic (PD) interactions. In PK interactions the presence of a second chemical alters the kinetics such that a unit of administered dose no longer produces a unit of dose at the target tissue. In PD interactions, the presence of other compounds alters the PDs such that a unit tissue dose no longer produces a unit of response. Physiologically based pharmacokinetic (PBPK) models for mixtures have become important tools for predicting conditions under which interactions are likely to alter the assumption of additivity and have permitted calculation of interaction thresholds with more confidence. New cumulative risk assessment approaches have provided opportunities to classify compounds on the basis of similar chemistry-based modes of action (cholinesterase inhibitors) or similar physiological modes of action (diverse chemicals that alter a common biological outcome, such as defeminization of the developing nervous system). The latter examples present challenges for expanding our risk assessment paradigm to focus on the biology of responses more than on the kinetics of the xenobiotics. Some of the future advances in mixture research will depend on progress in systems biology, a discipline that integrates information across multiple level of biological organization producing PD models of normal function and assessing conditions under which exposures to chemicals lead to the perturbations sufficiently great to produce toxicity and disease. We describe briefly the elements of a systems biology approach for assessing the interactions between various PCB congeners. PMID- 21782690 TI - Evaluation of dose-response curve analysis in delineating shared or different molecular sites of action for osteolathyrogens. AB - Single-chemical and mixture concentration-response curves generated using a frog embryo model were examined for value in assessing whether chemicals exert toxic effects at the same or at different molecular sites of action. Toxicity tests were conducted on a series of osteolathyrogens, i.e. chemicals that inhibit cross linking of developing connective tissue fibers. Induction of osteolathyrism, which manifests as lesions in the notochord of exposed tadpoles, has several possible molecular sites of action, including agent-cofactor reactivity during the enzyme-mediated cross-linking process. UV-VIS spectrophotometry of osteolathyrogen-cofactor reactivity (i.e. in vitro analysis) was coupled with the 96-h frog embryo mixture toxicity assay (i.e. in vivo toxicity) to compare molecular sites of action for several osteolathyrogens with the combined osteolathyritic effects of the agents. Single-chemical concentration-response curves were used to calculate theoretical curves for the dose-addition model of combined effect. Slope and EC(50) values for both theoretical and experimental mixture curves were then generated to statistically examine the hypothesis that agents with shared sites of action have dose-response curve (DRC) slopes that are similar when given alone and in combination, and slope and EC(50) values that, when administered together, are consistent with those calculated for dose addition. For combinations of cofactor-binding agents (semicarbazide, thiosemicarbazide, aminoacetonitrile), slope values were generally similar with additivity quotients near 1.0 (1.0=dose-additive) and combined osteolathyritic effects that were consistent with dose-addition. None of these were true for combinations that included agents that did not show rapid cofactor binding (beta aminopropionitrile, methyleneaminoacetonitrile). The results suggest that DRC analysis could be a useful tool for delineating common or different molecular sites of toxic action and that the approaches used warrant further study for evaluating the mechanistic basis for combined effects of toxicants. PMID- 21782691 TI - Structure-mutagenicity modelling using counter propagation neural networks. AB - The set of 95 aromatic amines and their mutagenic potency was treated with counter propagation neural network, which enables analysis of self-organising maps (SOMs) and also the prediction of mutagenicity. Compounds were described with four classes of descriptors: topostructural (TS), topochemical (TC), geometrical, and quantum chemical (QC). The models were tested on their prediction ability with leave-one-out (LOO) cross-validation method. The squares of correlation coefficient lie between 0.65 and 0.75 and are comparable with models obtained by linear methods. In addition, we analysed self-organising maps and found clusters of structurally similar compounds. PMID- 21782692 TI - QSARs for chemical mutagens from structure: ridge regression fitting and diagnostics. AB - QSAR models have been developed for a diverse set of mutagens using computed molecular descriptors. Such models can be used in predicting mutagenicity from structure. All common methods-regression, neural nets, k-nearest neighbors-are 'linear smoothers'-weighted averages of the activities in the calibration data with weights dependent on the descriptors. While they have been studied extensively, a vital but overlooked area is 'case diagnostics', pointers to compounds that are poorly fitted, or are unusually influential in fitting the model. This is particularly true where the measured activity is binary-present or absent. We illustrate the use of numeric and graphic diagnostics, particularly that of the FF plot, with a data set with 508 compounds and 307 structural descriptors used to predict mutagenicity. PMID- 21782693 TI - Predicting blood:air partition coefficients using theoretical molecular descriptors. AB - Three regression methods, namely ridge regression (RR), partial least squares (PLS), and principal components regression (PCR), were used to develop models for the prediction of rat blood:air partition coefficient for increasingly diverse data sets. Initially, modeling was performed for a set of 13 chlorocarbons. To this set, 10 additional hydrophobic compounds were added, including aromatic and non-aromatic hydrocarbons. A set of 16 hydrophilic compounds was also modeled separately. Finally, all 39 compounds were combined into one data set for which comprehensive models were developed. A large set of diverse, theoretical molecular descriptors was calculated for use in the current study. The topostructural (TS), topochemical (TC), and geometrical or 3-dimensional (3D) indices were used hierarchically in model development. In addition, single-class models were developed using the TS, TC, and 3D descriptors. In most cases, RR outperformed PLS and PCR, and the models developed using TC indices were superior to those developed using other classes of descriptors. PMID- 21782694 TI - Application of physiologically-based pharmacokinetic modeling to investigate the toxicological interaction between chlorpyrifos and parathion in the rat. AB - Environmental exposure is usually due to the presence of multiple chemicals. In most cases, these chemicals interact with each other at both pharmacokinetic and pharmacodynamic toxicity mechanisms. In the absence of data, joint toxicity assessment of a mixture is based on default dose or response additivity. Although, the concept of additivity is mostly accepted at low dose levels, these levels need to be determined quantitatively to validate the use of additivity as an absence of any possible synergistic or antagonistic interactions at low environmental exposure levels. The doses at which interaction becomes significant define the interaction threshold. In most cases, estimation of these low-dose interaction thresholds experimentally is economically costly and challenging because of the need to use a large number of laboratory animals. Computational toxicology methods provide a feasible alternative to establish interaction thresholds. For example, a physiologically based pharmacokinetic (PBPK) model was developed to estimate an interaction threshold for the joint toxicity between chlorpyrifos and parathion in the rat. Initially, PBPK models were developed for each chemical to estimate the blood concentrations of their respective metabolite. The metabolite concentrations in blood out-put was then linked to acetylcholinesterase kinetics submodel. The resulting overall PBPK model described interactions between these pesticides at two levels in the organism: (a) the P450 enzymatic bioactivation site, and (b) acetylcholinesterase binding sites. Using the overall model, a response surface was constructed at various dose levels of each chemical to investigate the mechanism of interaction and to calculate interaction threshold doses. The overall model simulations indicated that additivity is obtained at oral dose levels below 0.08mg/kg of each chemical. At higher doses, antagonism by enzymatic competitive inhibition is the mode of interaction. PMID- 21782695 TI - Application of PBPK model for 2,4-D to estimates of risk in backpack applicators. AB - A PBPK model for 2,4-D was developed that involves flow-limited pH trapping modified to consider tissue binding, binding to plasma, and high-dose inhibition of urinary excretion. The PBPK model provides reasonable estimates of the kinetics of 2,4-D in rats as well as in humans, providing a common metric for expressing risk. The risk characterization for 2,4-D based on the PBPK model is consistent with that based on standard risk assessment methods, except that the apparent variability in the risk characterization is reduced. The model demonstrates that non-linear pharmacokinetics and inhibition of urinary excretion would not be expected in occupational exposures. This case study suggests that preliminary PBPK models could be developed for numerous pesticides based on commonly available data. If properly validated with well-designed worker exposure studies, such models may be useful in more complete assessments of risks to workers as well as members of the general public. PMID- 21782696 TI - PBPK modeling of the metabolic interactions of carbon tetrachloride and tetrachloroethylene in B6C3F1 mice. AB - Potential exists for widespread human exposure to low levels of carbon tetrachloride (CT) and tetrachloroethylene (TET). These halocarbons are metabolized by the cytochrome P450 system. CT is known to inhibit its own metabolism (suicide inhibition) and to cause liver injury by generation of metabolically derived free radicals. The objective of this research was to use develop a physiologically based pharmacokinetic (PBPK) model to forcast the metabolic interactions between orally administered CT and TET in male B6C3F1 mice. Trichloroacetic acid (TCA), a stable metabolite of TET, was used as a biomarker to assess inhibition of the cytochrome P450 system by CT. Metabolic constants utilized for CT were 1.0mg/kg/h for Vmaxc_CT and 0.3 for Km_CT (mg/l). Values for TET (based in TCA production), were 6.0mg/kg/h for Vmaxc_TET was 3.0mg/l for Km_TET. The rate of loss of metabolic capacity for CT (suicide inhibition) was describe as: Vmaxloss ( mg / h )=- Kd ( RAM * RAM ) , where Kd (h/kg) is a second-order rate constant, and RAM (mg/h) is the Michaelis-Menten description of the rate of metabolism of CT. For model simplicity, CT was assumed to damage the primary enzymes responsible for metabolism of CT (CYP2E1) and TET (CYP2B2) in an equal fashion. Thus, the calculated fractional loss of TET metabolic capacity was assumed to be equivalent to the calculated loss in metabolic capacity of CT. Use of a Kd value of 400h/kg successfully described serum TCA levels in mice dosed orally with 5-100mg/kg of CT. We report, for the first time, suicide inhibition at a very low dose of CT (1mg/kg). The PBPK model under-predicted the degree of metabolic inhibition in mice administered 1mg/kg of CT. This PBPK model is one of only a few physiological models available to predict the metabolic interactions of chemical mixtures involving suicide inhibition. The success of this PBPK model demonstrates that PBPK models are useful tools for examining the nature of metabolic interactions of chemical mixtures, including suicide inhibition. Further research is required to compare the inhibitory effects of inhaled CT vapors with CT administered by oral bolus dosing and determine the interaction threshold for CT-induced metabolic inhibition. PMID- 21782697 TI - PBPK modeling of complex hydrocarbon mixtures: gasoline. AB - Petroleum hydrocarbon mixtures such as gasoline, diesel fuel, aviation fuel, and asphalt liquids typically contain hundreds of compounds. These compounds include aliphatic and aromatic hydrocarbons within a specific molecular weight range and sometimes lesser amounts of additives, and often exhibit qualitatively similar pharmacokinetic (PK) and pharmacodynamic properties. However, there are some components that exhibit specific biological effects, such as methyl t-butyl ether and benzene in gasoline. One of the potential pharmacokinetic interactions of many components in such mixtures is inhibition of the metabolism of other components. Due to the complexity of the mixtures, a quantitative description of the pharmacokinetics of each component, particularly in the context of differing blends of these mixtures, has not been available. We describe here a physiologically-based pharmacokinetic (PBPK) modeling approach to describe the PKs of whole gasoline. The approach simplifies the problem by isolating specific components for which a description is desired and treating the remaining components as a single lumped chemical. In this manner, the effect of the non isolated components (i.e. inhibition) can be taken into account. The gasoline model was based on PK data for the single chemicals, for simple mixtures of the isolated chemicals, and for the isolated and lumped chemicals during gas uptake PK experiments in rats exposed to whole gasoline. While some sacrifice in model accuracy must be made when a chemical lumping approach is used, our lumped PK model still permitted a good representation of the PKs of five isolated chemicals (n-hexane, benzene, toluene, ethylbenzene, and o-xylene) during exposure to various levels of two different blends of gasoline. The approach may be applicable to other hydrocarbon mixtures when appropriate PK data are available for model development. PMID- 21782698 TI - Prediction of halocarbon toxicity from structure: a hierarchical QSAR approach. AB - Mathematical structural invariants and quantum theoretical descriptors have been used extensively in quantitative structure-activity relationships (QSARs) for the estimation of pharmaceutical activities, biological properties, physicochemical properties, and the toxicities of chemicals. Recently our research team has explored the relative importance of various levels of chemodescriptors, i.e. topostructural (TS), topochemical (TC), geometrical (3D), and quantum theoretical descriptors, in property estimation. This study examines the contribution of chemodescriptors ranging from topostructural to quantum theoretic calculations, up to the Gaussian STO-3G level, in predicting the results of six indicators of oxidative stress for a set of 20 halocarbons. Using quantum theoretical calculations in this study is of particular interest as molecular energetics is related to the likelihood of electron attachment and free radical formation, the mechanism of toxicity for these chemicals and should aid in modeling their potential for oxidative stress. PMID- 21782699 TI - Comparison of Caco-2, IEC-18 and HCEC cell lines as a model for intestinal absorption of genistein, daidzein and their glycosides. AB - Genistein and daidzein receive much attention because of their potential to prevent hormone-related cancer and cardiovascular diseases. Limited information is available on the pharmacokinetics of these compounds like, for instance, intestinal uptake by humans and systematic bioavailability. In this study the transport and metabolism of genistein, daidzein and their glycosides has been compared in various cellular models for intestinal absorption such as human colonic Caco-2, rat small intestinal IEC-18 and human immortalized colon HCEC cell lines. Genistein and daidzein were taken up by Caco-2, IEC-18 and HCEC cells and transported to almost same rate and extents. Glycosides were transported across IEC-18 and HCEC monolayers, but not across Caco-2 cells. In Caco-2 and IEC 18 cells, the glycosides were metabolized to their respective aglycones. Furthermore, it was shown that genistein and daidzein were glucuronidated and sulfated in Caco-2 cells, to glucuronidated forms in IEC-18 cells and to sulfated conjugates in HCEC cells. The results of this study compared with reported in vivo data indicate that Caco-2 cells are a valuable model for studying intestinal transport and metabolism of isoflavones. PMID- 21782700 TI - Effects of bis(2-ethylhexyl) phthalate and benzo[a]pyrene on the embryos of Japanese medaka (Oryzias latipes). AB - Effects of two widely found chemical pollutants, bis(2-ethylhexyl) phthalate (DEHP) and benzo[a]pyrene (BaP), on the embryos of Japanese medaka were investigated. The embryos were exposed to different concentrations (0.01, 0.1, 1, and 10MUg/l) of DEHP and BaP. The following were investigated: (1) hatching time and hatching rate in embryos, (2) mortality, sex ratio, body weight and gonadosomatic index (GSI) in adulthood. These two chemicals delayed the hatching time without dose-dependence, but these chemicals had no effect on hatching rate. Mortality was raised and body weight was reduced by DEHP and BaP-treatment; distortion of sex ratio appeared at the lowest concentration of DEHP tested. GSI was decreased because of the BaP-treatment. DEHP and BaP negatively affected Japanease medaka embryos, and the influences of the effects continued into adult stage. Moreover, the effects did not appear to be necessarily dose-dependent. PMID- 21782701 TI - Organic solvent-induced proximal tubular cell apoptosis via caspase-9 activation. AB - Long-term exposure to solvents is associated with apoptosis, which is implicated in the development and progression of tubulo-interstitial fibrosis and chronic renal failure. In our previous study, we demonstrated that toluene and p-xylene as the most commonly used organic solvents induced proximal tubular cells apoptosis. This study was conducted to assess the apoptotic pathway of toluene and p-xylene induced proximal tubular apoptosis. This was assessed by measuring the caspase-9 activity LLC-PK1 cells exposed to both compounds. A model of proximal tubular cell (LLC-PK1) cytotoxicity exposed to 1mM of either p-xylene or toluene was compared to untreated control for caspase-9 activity and Bax/Bcl-2 protein level. Furthermore, DNA fragmentation in the presence of caspase-9 inhibitor (Z-LEHD-FMK) in a dose-dependent manner was assessed. Both compounds induced caspase-9 activity, which was accompanied by up-regulation of Bax, whereas Bcl-2 level did not change. DNA fragmentation induced by both solvents was inhibited by caspase-9 inhibitor in dose-dependent manner. This data suggest that p-xylene or toluene induces nephrotoxicity via mitochondrial caspase-9 pathway. This mechanism involves up-regulation of the apoptotic protein, Bax. PMID- 21782702 TI - Dermal toxicity and microscopic alterations by JP-8 jet fuel components in vivo in rabbit. AB - In this study, we investigated the skin irritation, macroscopic and microscopic barrier alteration in vivo in rabbits from aliphatic and aromatic components of jet propellant-8 (JP-8) jet fuel. Macroscopic barrier properties were evaluated by measuring transepidermal water loss (TEWL), skin capacitance, and skin temperature; microscopic changes were observed by light microscopy. Draize visual scoring system was used to measure skin irritation. We found significant (P<0.05) increase in temperature at the site of all chemically saturated patches immediately after patch removal in comparison to the control site. Tridecane (TRI) produced a greater increase in temperature and capacitance at all time points than all the other components of JP-8. Both the aliphatic and aromatic components increased the TEWL at all time points. Tridecane produced greater increase in TEWL followed by naphthalene (NAP), 1-methylnaphthalene (1-MN), 2 metylnaphthalene (2-MN), tetradecane (TET), and dodecane (DOD). All of the above components of JP-8 caused moderate to severe erythema and edema, which were not resolved to the baseline even after 24h of patch removal. Light microscopy revealed an increase in epidermal thickness (ET), and decrease in length and thickness of collagen fibers' bundle by the above components of JP-8. These results suggest potential dermatotoxicity from the JP-8 components. PMID- 21782703 TI - Effect of polycyclic aromatic hydrocarbons on erythrocyte membranes by DSC and EPR. AB - Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) experiments were performed on human erythrocyte membranes and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) model systems in order to study the effect the polycyclic aromatic hydrocarbons on lipid structure and dynamics. Eight different compounds among others naphthalene and pyrene were compared, which occur in significant concentrations in dust collected from the air in large cities. Experiments using spin label technique showed that the compounds induced mobility changes in the lipid region in the environment of the fatty acid probe molecules incorporated into the membranes. The effects depended on the structure and concentration of the different compounds. Similarly to EPR observations, DSC measurements reported decrease of transition temperature in comparison to control DPPC vesicles. These results suggest that polycyclic aromatic hydrocarbons were able to modify the internal dynamics of erythrocyte membranes which might lead to damage of the biological functions. PMID- 21782704 TI - Differential effects of Co(2+) and Ni(2+) on protein metabolism in Scenedesmus obliquus and Nitzschia perminuta. AB - Growth, morphological changes, amino acid composition, total soluble protein, and protein electrophoretic pattern were monitored for Scenedesmus obliquus and Nitzschia perminuta grown in the presence of different concentrations of Co(2+) and Ni(2+). Lower concentrations of cobalt stimulated the dry mass production and total soluble protein content of the two algae, whereas higher concentrations were inhibitory. Generally, N. perminuta showed more tolerance to the phytotoxicity of the two metals than S. obliquus and more tolerance to nickel than cobalt. However, S. obliquus seems to be more tolerant to cobalt than nickel. Cobalt and nickel have induced an increase in cell volume, change and disorder in cell shape. The increase in cell volume was much observed in Ni(2+) treated cells. At the same time, the two metals did not induce any distinct morphological abnormalities in N. perminuta. Co(2+) has stimulated the biosynthesis of all free amino acids in S. obliquus, except aspartic acid and phenylalanine, whereas Ni(2+) caused 22% inhibition in the content of total free amino acids, except cystine and arginine. On the other hand, Co(2+) has reduced the content of free amino acids in N. perminuta, except cystine, methionine, valine, and lysine. On the other hand, Ni(2+) stimulated the biosynthesis of glycine, alanine and histidine and highly stimulated valine and sulphur containing amino acids (cystine and methionine) in N. perminuta. High cobalt concentration (4ppm) resulted in the disappearance of 28.7kDa protein, 3.5ppm Ni(2+) stimulated the appearance of 18 and 20kDa proteins in S. Obliquus, while 37kDa proteins disappeared from N. perminuta treated with high doses of Co(2+) and Ni(2+). PMID- 21782705 TI - Protective effect of polyurethane immobilized human butyrylcholinesterase against parathion inhalation in rat. AB - Organophosphates (OP) are used in large quantities around the world as agricultural insecticides. Exposure to these toxic chemicals is a serious global health problem. Human plasma butyrylcholinesterase is known to be a good scavenger of organophosphorus pesticides and chemical warfare agents. In this study, purified human plasma butyrylcholinesterase (HuBChE) from pooled outdated human plasma, was immobilized onto the polyurethane foam. The immobilized enzyme showed greater stability at and above room temperature (up to 55 degrees C), compared to the enzyme in solution. Scavenger properties of immobilized enzyme were tested in vitro with parathion and its active metabolite paraoxon. In, in vitro experiments polyurethane foam with immobilized active enzyme removed 40% of parathion and 50% of paraoxon inhibitory effect (based on cholinesterase inhibition). In, in vivo experiments groups of rats inhaled parathion through filters with immobilized active enzyme (Group I), immobilized inactivated enzyme (Group II), and control group (Group III) inhaled solvent only without any parathion or filter. In the Group II animals, activity of plasma and red blood cells cholinesterase was significantly decreased (30 and 28%, respectively) compared to Groups I and III animals. In other tissues such as brain, skeletal muscle and lung, activity of the acetylcholinesterase (AChE) in the Group II animals, was decreased significantly (29, 28, and 22%, respectively). There was no significant differences between Groups I and III animals enzyme activities. In conclusion, immobilized butyrylcholinesterase (BChE) may be useful in scavenging and detoxifying organophosphate compounds both for medical protection and decontamination procedures. PMID- 21782706 TI - Ozone exposure induces iNOS expression and tyrosine nitration in rat aorta. AB - The aim was to study whether ozone affects vascular endothelium by causing inducible nitric oxide synthase (iNOS) expression and tyrosine nitration. We also studied biomarkers of endothelial function. Male Wistar rats were exposed to ozone (0.25ppm, 4h/day) or filtered air (control, ozone <0.05ppm). After ozone exposure, blood samples were taken to measure 6-keto prostaglandin F1alpha (6 keto PGF1alpha), dehydro-thromboxane B(2) (DH-TxB(2)), endothelin-1 and NO(2)( )/NO(3)(-) (NO(x)(-)). iNOS and nitrotyrosine were detected in aorta by immunohistochemistry. Nitrotyrosine was also detected by immunoelectromicroscopy. Control aortae failed to show either iNOS or nitrotyrosine. Time-dependent positive iNOS and nitrotyrosine cells were observed in exposed animals. Except for NO(x)(-), endothelial markers decreased after 14 days of ozone exposure (P<0.05). After 28 days of ozone, 6-keto PGF1alpha remained low (P<0.05) while DH TxB(2) increased (P<0.05). It is concluded that ozone causes endothelial dysfunction manifested early with peroxynitrite formation and lately with changes in endothelial markers. PMID- 21782707 TI - Accumulation of ivermectin in the brain of sea bream, Sparus aurata after intraperitoneal administration. AB - Ivermectin, which is widely used in veterinary and human, has been considered safe due to its inability to penetrate into the central nervous system of higher vertebrates. This paper presents data on the ability of the drug to cross the blood-brain barrier of the marine teleost sea bream, Sparus aurata and accumulate in the brain. The concentration of the drug in the brain and the serum of the fish was assessed by the use of a direct competitive ELISA commercial kit. Our results showed a rapid uptake of the substance by the brain of the fish reaching a maximum concentration of 98.9ngg(-1) 8h post treatment. The trend of the absorption of the drug in brain followed that of the blood. Concentration of the drug in the brain remained high at each sampling point over the 24h duration of the experiment. In view of these findings, the need of study of the role of the blood-brain barrier and particularly the multidrug resistance mechanism in sea bream is outlined. PMID- 21782708 TI - Response of lympho-monocytes to phytohemagglutinin in urban workers. AB - The aim of this study is to evaluate whether traffic police exposed to urban pollutants could be at risk of changes on proliferative response of blood lympho monocytes to the mitogen phytohemagglutinin (PHA) compared to a control group. Traffic police were matched with controls by sex, age, length of service, drinking habits and smoking habits after excluding main confounding factors. So, 77 traffic police exposed to urban pollutants (43 men and 34 women) and 77 controls with indoor activity (43 men and 34 women) were included in the study. The proliferative response of blood lympho-monocytes to the mitogen PHA was significantly lower in male and female traffic police compared to controls (respectively, P=0.000 and 0.014). The possibility of an effect on immune system and therefore on the blood lympho-monocytes proliferative answer in traffic police exposed to urban pollutants, can be assumed. PMID- 21782709 TI - Nonylphenol induces thymocyte apoptosis through Fas/FasL pathway by mimicking estrogen in vivo. AB - Nonylphenol (NP) is the final biodegradation product of nonylphenol polyethoxylates, which are widely used surfactants in domestic and industrial products. Nonylphenol has been reported to have estrogenic activity and shown to have potential reproductive toxicity. However, its influence on immune system function remains unclear. In this study, we investigated the effects of nonylphenol on apoptosis and Fas/FasL gene expression in rat thymus. Nonylphenol were given orally by gavages at 125, 250, and 375mg/kg per day. Negative and positive controls were treated with the vehicle and E(2) 10ng/kg per day, respectively. Atrophy of thymus was determined by in situ morphological examination using hematoxylin and eosin staining. Apoptotic cells were identified by terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. A semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method was used to analyze Fas and FasL mRNA levels. The results showed that both nonylphenol and E(2) increased the rates of apoptotic death; reduced the expression of Fas; enhanced the expression of FasL. These findings demonstrated that nonylphenol with estrogen-like activity might affect the regulation of the immune function through thymocyte apoptosis. This apoptosis was mediated by altering the expression of Fas and FasL mRNA. PMID- 21782710 TI - Effects of tamoxifen, 17alpha-ethynylestradiol, flutamide, and methyltestosterone on plasma vitellogenin levels of male and female Japanese medaka (Oryzias latipes). AB - The effects of oral administration of tamoxifen, 17alpha-ethynylestradiol (EE2), flutamide, and methyltestosterone (MT), on plasma vitellogenin levels of male and female medaka were investigated. Medaka were fed diets containing different concentrations of these chemicals for 7 days, and these plasma vitellogenin levels were measured. Tamoxifen increased significantly the vitellogenin levels in male, but inhibited the normal vitellogenin induction in female in the high concentration groups. EE2 increased significantly vitellogenin levels in both sexes. Flutamide increased significantly the vitellogenin levels in female, but gave no effects on male. MT inhibited the normal vitellogenin induction in female, but increased slightly vitellogenin levels in male without a clear tendency. Administration of tamoxifen, EE2, flutamide, and MT showed the different pattern in vitellogenin levels in both sexes. PMID- 21782711 TI - Increased spontaneous motor activity in offspring after maternal cadmium exposure during lactation. AB - Lactating rats were exposed to 0, 5 or 25ppm cadmium as cadmium chloride in the drinking water. A battery of neurobehavioural tests was applied to the male offspring after weaning at 5 weeks until 4 months of age. The mean cadmium levels in exposed pup kidneys ranged from 0.006 to 0.030mg/kg wet weight at weaning, with the corresponding maternal kidney cadmium levels ranging from 4 to 13mg/kg wet weight. Significantly increased activity during the initial 20min of the spontaneous motor activity test was observed in the highest-dose group compared to the control group. The activity outcome was significantly positively correlated with cadmium levels in the pup kidneys. No cadmium-related changes in performance were observed in the Morris water maze, the E-shaped maze or the elevated plus-maze. The results indicate that neurobehavioural effects during development may be a more sensitive parameter for Cd toxicity than renal dysfunction. PMID- 21782712 TI - Cytotoxic effect of glycoprotein isolated from Solanum nigrum L. through the inhibition of hydroxyl radical-induced DNA-binding activities of NF-kappa B in HT 29 cells. AB - Solanum nigrum L. (SNL) has been traditionally used as an herbal plant for a long time. In the present study, SNL glycoprotein showed a dose-dependent radical scavenging activity on radicals, including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, hydroxyl radical (OH), and superoxide anion (O(2)(-)). When the HT-29 cells were treated with 60MUg/ml SNL glycoprotein, the cytotoxic effect was induced in a time-dependent manner. More specifically, it was more than 60% (P<0.01) after 4h, compared to the control. On the other hand, the cells treated with 100mU/ml glucose oxidase (GO) to generate the OH radical showed a cancer resistance up to 12h. Furthermore, the addition of GO to the SNL glycoprotein caused a strong cytotoxic effect, rather than a radical scavenging effect. Interestingly, when the cells were exposed to 100mU/ml GO for 4h, the DNA-binding activity of nuclear factor-kappa B (NF-kappaB) was increased 4.15-fold (P<0.01) compared to the control, whereas 40MUg/ml SNL glycoprotein completely blocked the DNA-binding activity of OH radical-induced NF-kappaB by electrophoretic mobility shift assays (EMSAs). Apoptosis, according to the apoptosis assay, increased as a result of treatment with 40MUg/ml SNL glycoprotein in a time-dependent manner, whereas they were weakly induced by GO in the cells. Consequently, the SNL glycoprotein may induce apoptosis through the inhibition of NF-kappaB activation, induced by oxidative stress in HT-29 cells. PMID- 21782713 TI - The methaemoglobin forming and GSH depleting effects of dapsone and monoacetyl dapsone hydroxylamines in human diabetic and non-diabetic erythrocytes in vitro. AB - The respective methaemoglobin forming and GSH depleting capabilities of monoacetyl dapsone hydroxylamine (MADDS-NHOH) and dapsone hydroxylamine (DDS NHOH) were compared in human diabetic and non-diabetic erythrocytes in vitro with a view to select the most potent agent for future oxidative stress and antioxidant evaluation studies. Administration of both metabolites to non diabetic erythrocytes over the 20min period of the study resulted in significantly more methaemoglobin formation at all four time points compared with the diabetic erythrocytes (P<0.0001). At all four time points, significantly more methaemoglobin was formed in response to MADDS-NHOH in non-diabetic cells compared with the effects of DDS-NHOH on diabetic erythrocytes (P<0.0001). At the 5 and 10min time points, significantly more methaemglobin was formed in non diabetic cells in the presence of MADDS-NHOH compared with DDS-NHOH (P<0.05). At the 5min time point only, significantly more methaemoglobin was formed in the presence of MADDS-NHOH in diabetic cells compared with that of DDS-NHOH (P<0.01). However, compared with diabetic control GSH levels, the presence of DDS-NHOH caused a significant depletion in GSH at 5, 10 and 20min time points in diabetic cells (P<0.001). In addition, the presence of DDS-NHOH caused a significant reduction in GSH levels in diabetic cells in comparison with those of non diabetics at the 5, 10 and 20min, (P<0.005). DDS-NHOH was also associated with a significant depletion of GSH levels in diabetic cells compared with those of non diabetic control erythrocytes (P<0.0001). The presence of MADDS-NHOH in diabetic erythrocytes led to a significant reduction in GSH levels at the 20min time point compared with those of non-diabetics (P<0.001), but there were no significant differences at the 5, 10 and 15min points. Due to its greater GSH-depleting action, DDS-NHOH will be selected for future use in the oxidative stress assessment in diabetic erythrocytes. PMID- 21782714 TI - Neonatal exposure to the brominated flame-retardant, 2,2',4,4',5 pentabromodiphenyl ether, decreases cholinergic nicotinic receptors in hippocampus and affects spontaneous behaviour in the adult mouse. AB - Polybrominated diphenyl ethers (PBDEs) are used as flame-retardants and have recently been shown to increase in the environment and in human milk. We have recently reported that neonatal exposure to 2,2',4,4',5-pentaBDE (PBDE 99) can induce persistent aberrations in spontaneous behaviour and also affect learning and memory functions in the adult animal. The present study indicates that the cholinergic system, in its developing stage, can be a target for PBDEs. Neonatal oral exposure of male NMRI mice, on postnatal day 10, to 2,2',4,4',5-pentaBDE (12mg/kg body weight) was shown to decrease the density of cholinergic nicotinic receptors in hippocampus, at an adult age. These findings show similarities to observations made from neonatal exposure to 2,2',4,4',5,5'-hexaBDE, PCBs and nicotine, compounds shown to affect cholinergic nicotinic receptors. The animals of the present study also showed disrupted spontaneous behaviour, and the highest dose that did not cause any significant behavioural disruption was 0.4mg 2,2',4,4',5-pentaBDE/kg b.w. PMID- 21782715 TI - The effects of low-esterified pectin on lead-induced thyroid injury in rats. AB - The main purpose of the study was to evaluate the effects of low-esterified pectin on lead-induced thyroid injury in rats. Animals were fed 100mg/kg of lead acetate through gavage for 3 weeks. After that, solution containing 50mg/kg of low-esterified pectin was administered through gavage for 2 weeks. At the end of experiment, the endpoints related to circulating thyroid hormone (serum thyroxine and triiodothyronine), thyroid gland histomorphology (thyroid follicle cross sectional area, epithelial height, follicle roundness or aspect ratio, and colloid/epithelial ratio), and thyroid gland weight were assessed. Administration of lead resulted in reduced blood hormone levels, decreased thyroid gland weight, and impaired alterations in histomorphology. At the end of experiment, thyroid gland weight and blood hormone level were increased because of additional administration of low-esterified pectin. Also, signs of improved thyroid histomorphology were registered. The results obtained indicate the beneficial effects of low-esterified pectin on lead-induced thyroid injury. PMID- 21782716 TI - Oxidative damage to lipids and proteins induced by aflatoxin B(1) in fish (Labeo rohita)-protective role of Amrita Bindu. AB - In the present study, fish (Labeo rohita) were treated with a single intraperitoneal administration of aflatoxin B(1) (AFB(1)) (100MUg/100gBW). The resultant oxidative damage to lipids (measured as conjugated diene and lipid peroxidation (LPO)) and proteins (protein carbonyl) in liver, kidney and brain at the end of 3rd and 6th day was assessed. Our results showed that AFB(1) induced a significant increase in conjugated diene formation and LPO not only in liver but also in kidney and brain. A parallel increase in protein carbonyl level was observed in these tissues. When 1:1 mixture of 20% solution of Amrita Bindu (a salt-spice-herbal mixture based on Indian system of medicine) was co-administered along with 100MUg AFB(1), the AFB(1) induced increase in conjugated diene, LPO and protein carbonylation were minimised to a greater extent. These results led to conclusion that (i) AFB(1) not only induces oxidative damage to the primary target organ-liver in L. rohita, but also in kidney and brain, (ii) co administration of Amrita Bindu confers protection to lipids and protein against the AFB(1) induced oxidative damage in all the three tissues. PMID- 21782717 TI - Effects of feeding status on biliary PAH metabolite and biliverdin concentrations in plaice (Pleuronectes platessa). AB - Relationships between feeding status and the biliary concentrations of biliverdin and metabolites of polycyclic aromatic hydrocarbons (PAH) have been investigated in plaice (Pleuronectes platessa) from the Firth of Clyde, Scotland. Plaice were caught at three times of the day, and kept, without feeding, in tanks for up to 24h. The mean concentrations of biliary PAH metabolites 2-OH naphthalene, 1-OH pyrene and 3-OH benzo-[a]-pyrene (3-OH B[a]P) were found to increase slightly over a 24h non-feeding period (only significant for 3-OH benzo-[a]-pyrene). This effect was not observed for mean biliary concentrations of 1-OH phenanthrene. During this period of starvation, bile volume, total amounts of all PAH metabolites in the gall bladder, and biliary biliverdin concentrations all significantly increased. No significant relationships (P>0.05) were found between indicators of feeding status and individual PAH metabolite concentrations, confusing the rationale for normalisation of data to account for differences in feeding status between fish. Normalisation of PAH metabolite concentrations to biliverdin concentrations did not consistently reduce the variance of the metabolite data for fish sampled after the same starvation period. However, the variation between mean metabolite concentrations of fish suffering different starvation periods was reduced by biliverdin normalisation for most of the metabolites measured. It is therefore recommended that biliary PAH metabolite data should be presented as raw concentrations, except in cases where there may be significant differences in feeding status between groups of fish. In such instances biliverdin normalised data should also be reported and observational guides such as bile volume and stomach contents may aid in the interpretation of data. PMID- 21782718 TI - Neutralization effects of interleukin-6 (IL-6) antibodies on sulfur mustard (HD) induced IL-6 secretion on human epidermal keratinocytes. AB - The proinflammatory cytokine human interleukin-6 (hIL-6) plays an important role in the early and late courses of inflammation, trauma, and wound healing caused by sulfur mustard (HD). Previously, we demonstrated that hIL-6 might be involved in the early event of structural changes of the signal transducer glycoprotein, which indirectly initiates the cascade of events, such as skin irritation and blister formation observed in the pathophysiology of HD injury. In this present work, we focus on the neutralization effect of IL-6 antibodies with regard to the modulation of hIL-6 secretion. Levels of secreted cytokine hIL-6 in normal human epidermal keratinocytes (NHEK) stimulated with HD (10(-4)M) and incubated for 24h at 37 degrees C were determined by enzyme immunoassay, protein immunocytologic assay and reverse-transcriptase-polymerase chain reaction (RT-PCR). The ratio of HD-treated NHEK to constitutive non-stimulated NHEK controls (S/C) on the induction of hIL-6 is reported. S/C was four-fold higher than non-stimulated NHEK controls as determined by ELISA. By using a more sensitive immunocytologic assay, Luminex(100)TM, the increment was verified. hIL-6 levels in NHEK stimulated with HD were 21+/-11ng/mL as measured by Luminex(100)TM. The messenger RNA expression of the cytokine (hIL-6) gene was analyzed semiquantitatively. RT-PCR demonstrated that HD induced an increase in the transcription of hIL-6 gene. Selective immunosuppression, using IL-6 neutralizing antibodies, led to a reduction of such expression of HD-induced transcription of hIL-6 in human keratinocytes. The neutralization by pre-incubating NHEK with monoclonal anti-IL6 antibodies decreased hIL-6 secretion by 76%+/-1.8 ((*)P<0.05). PMID- 21782719 TI - Evaluation of lymphocyte subpopulations in draining lymph node cells following allergen and irritant. AB - The murine local lymph node assay (LLNA) has been developed as an alternative to guinea pig models for the assessment of the contact sensitization potential. However, there is a need to develop a non-radioisotopic endpoint for the LLNA, because of the radioisotopic method's requiring the use of special facilities. In this study, we investigated to evaluate the lymphocyte subpopulations in the lymph node cells following allergen and irritant treatment. Female Balb/c mice were treated by the topical application on the dorsum of both ears with sensitizers, 2,4-dinitrochlorobenzene (DNCB), toluene diisocyanate (TDI), and alpha-hexylcinnamaldehyde (HCA), and an irritant, sodium lauryl sulfate (SLS), once daily for three consecutive days. The lymph node (LN) cells were harvested 72h after the final treatment. Phenotypic analysis of lymphocytes subsets was performed with a flow cytometry. The allergens DNCB, TDI, and HCA and an irritant, SLS increased cell number compared to the vehicle. Mice were treated with DNCB, HCA, and TDI showed a preferential increase in the percentage of B220+CD40+ cells compared with vehicle and irritant-treated mice. There was an increase in B220+CD86+ cells of mice treated with DNCB, TDI, and HCA, but no significant increases were observed in mice treated with SLS. Mice were treated with DNCB and TDI showed an increase in the percentage of B220+CD23+ cells compared with vehicle and irritant-treated mice. These results suggest that analysis of B cell activation marker, CD40 on B cells may be useful in differentiating allergen and irritant responses in the draining lymph nodes of chemically treated mice. PMID- 21782720 TI - Intestinal uptake of genistein and its glycoside in the rat using various isolated perfused gut segments. AB - Genistein receives much attention because of its potential to prevent hormone related cancer and cardiovascular diseases. Limited information is available on the pharmacokinetics of this compound like, for instance, their intestinal uptake by humans and systematic bioavailability. In this study, the fate of the absorption of genistein and its glycoside has been analysed in various isolated perfused gut segments of the rat. In all perfused gut segments the transport of genistein was higher compared to its glycoside. Furthermore, it appeared that the resorbate (i.e. serosal side) concentration of genistein was the highest in ileac segments, whereas the transport of genistein in the various other segments tested showed no difference between intestinal compartments. Less than 0.2% of genistin appeared in the resorbate fluid of all isolated gut segments. The main site of metabolism of genistein and its glycoside appears to be located in the jejunal compartment of the rat gut. About 38% of genistein and about 29% of genistin metabolised within 2h of perfusion. In the ileac and colonic intestinal segments, genistein metabolised for only 10%. For the first time, this study demonstrated that genistin could be metabolised by epithelial cells present in isolated colonic segments. However, the metabolites of genistin did not occur at the serosal side (the resorbate) of isolated colonic segments. We assume that there is no absorption of genistin and/or its metabolites in or through colonic tissue of the rat. PMID- 21782721 TI - The Salmonella mutagenicity of water and sediments from the Porsuk River in Turkey. AB - In this study, water and sediments from the Porsuk River were investigated for their potential mutagenicity in Salmonella typhimurium TA 98 and TA 100 strains by performing Ames test (plate incorporation assay) without metabolic activation. Different columns of XAD 4 and XAD 16 were used to fractionate the water samples. Positive results in XAD 4 extracts of water samples were obtained for TA 98 in two of these stations. Extracts of the sediment samples were assayed in five different doses of concentrations and mutagenic results were obtained for both of the two strains in different sampling sites. Total metal concentrations in the stream sediment samples were determined by atomic absorption spectrophotometry (AAS) in order to explain some of these mutagenic results. The presence of mutagens causing frameshift and base-pair substitution mutations in water and sediments of the Porsuk River was suggested by the results and this mutagenicity was discussed. PMID- 21782722 TI - Status of antioxidant defense system in chromium-induced Swiss mice tissues. AB - Based on epidemiological studies, chromium(VI) compounds are considered as more toxic and carcinogenic than chromium(III) compounds. The deleterious effects of chromium(VI) compounds are diversified affecting almost all the organ systems in a wide variety of animals. The present study, describes the cytotoxic effects of chromium trioxide, a well-known chromium(VI) compound in three tissues (liver, kidney, lungs) of male Swiss mice during post-treatment phase (5th-8th week after treatment). Lipid peroxidation, an index of oxidative stress, was determined as thiobarbituric acid-reactive substances (TBA-Rs) in mice tissues dosed with a single intraperitoneal injection of chromium trioxide (1mg/kg body weight). Tissue specific and statistically significant increases in TBA-Rs was observed in chromium-treated mice groups compared to controls in all the weeks of post treatment. Endogenous ascorbic acid (vit-C) content of tissues which happens to be one of the stable antioxidants, declined significantly due to chromium induction. Activity of antioxidative enzymes like superoxide dismutase (SOD), catalase (CT) and peroxidase (PD) was significantly inhibited among chromium injected mice groups compared to respective controls. Protective role of ascorbic acid and the antioxidative enzymes in chromium-induced cytotoxicity in mice is discussed. PMID- 21782723 TI - Inhibitory effects of ammonia and urea on gill carbonic anhydrase enzyme activity of rainbow trout (Oncorhynchus mykiss). AB - The effects of ammonia and urea on branchial carbonic anhydrase (CA) enzyme which plays a key role in ionoregulation, osmoregulation and acid-base balance of rainbow trout (Oncorhynchus mykiss) were investigated. CA activity of the control group for ammonia and urea was determined as 1285.7 +/- 67.9 and 1261.7 +/- 60.8EU/mg protein, respectively. The CA enzyme activities of the other groups were measured at 1, 2 and 3h after ammonia and urea applications. The corresponding activities of ammonia were 774.9 +/- 68.8, 732.1 +/- 48.6 and 768.1 +/- 59.5EU/mg protein, respectively and that of urea were 769.3 +/- 58.9, 638.2 +/- 47.7 and 1108.1 +/- 61.1EU/mg protein, respectively. The differences between the initial CA activities for the controls was not significantly (P > 0.01). The CA activities were significantly (P < 0.01) inhibited both in ammonia and urea group. However, the ammonia inhibited more than urea since there was significant differences between final values of gill CA activities. PMID- 21782724 TI - Comparison of cytopathological changes induced by mercury chloride exposure in renal cell lines (VERO and BGM). AB - The response to mercury chloride was assessed in two cell lines of renal origin, determining the range of toxic concentrations by Neutral Red assay after 24-h of exposure. Morphological changes in the Buffalo Green Monkey (BGM) and VERO cell lines after exposure to subcytotoxic doses (0.045 and 0.038mM, respectively) equivalent to EC10 (effective concentrations 10%) of mercury chloride were evaluated at the structural and ultrastructural level by optic, transmission and scanning microscopy. Using transmission electron microscopy, the most notable findings in treated cells were the presence of intracytoplasmic inclusion bodies and apoptotic bodies. Scanning microscopy pointed to a cell with a disrupted perinuclear region and a decreased number of surface microvilli. Similar alterations in both in vivo and in vitro experiments have been described by other authors. We conclude that BGM and VERO renal cell lines can be considered as useful tools for toxicological studies involving mercury chloride. PMID- 21782725 TI - Effects of glutathione, N-acetyl-cysteine, alpha-lipoic acid and dihydrolipoic acid on the cytotoxicity of a 2-pyridylcarboxamidrazone antimycobacterial agent in human mononuclear leucocytes in vitro. AB - A series of antioxidants was used to explore the cytotoxicity of one particularly toxic antimycobacterial 2-pyridylcarboxamidrazone anti-tuberculosis agent against human mononuclear leucocytes (MNL), in comparison with isoniazid (INH) to aid future compound design. INH caused a significant reduction of nearly 40% in cell recovery compared with control (P < 0.0001), although the co-incubation with either glutathione (GSH, 1mM) or (NAC, 1mM) showed abolition of INH toxicity. In contrast, the addition of GSH or NAC 1h after INH failed to protect the cells from INH toxicity (P < 0.0001). The 2-pyridyl-carboxamidrazone 'Compound 1' caused a 50% reduction in cell recovery compared with control (P < 0.001), although this was abolished by the presence of either GSH or NAC. A 1h post incubation with either NAC or GSH after Compound 1 addition failed to protect the cells from toxicity (P < 0.001). Co-administration of lipoic acid (LA) abolished Compound 1-mediated toxicity, although again, this effect did not occur after LA addition 1h post incubation with Compound 1 (P < 0.001). However, co administration of dihydrolipoic acid (DHLA) prevented Compound 1-mediated cell death when incubated with the compound and also after 1h of Compound 1 alone. Pre treatment with GSH, then removal of the antioxidant resulted in abolition of Compound 1 toxicity (vehicle control, 63.6 +/- 16.7 versus Compound 1 alone 26.1 +/- 13.6% versus GSH pre-treatment, 65.7 +/- 7.3%). In a cell-free incubation, NMR analysis revealed that GSH does not react with Compound 1, indicating that this agent is not likely to directly deplete membrane thiols. Compound 1's MNL toxicity is more likely to be linked with changes in cell membrane conformation, which may induce consequent thiol depletion that is reversible by exogenous thiols. PMID- 21782726 TI - Oxidative stress damage in the liver of fish and rats receiving an intraperitoneal injection of hexavalent chromium as evaluated by chemiluminescence. AB - The livers fractions of Oreochromis niloticus (Tilapia) and Wistar rats taken from treated animals to single intraperitoneal doses of hexavalent chromium (K(2)Cr(2)O(7)), were analyzed for tert butyl hydroperoxide-initiated chemiluminescence (CL), lipid peroxidation using thiobarbituric acid reactive substances (TBARS), enzymes superoxide dismutase (SOD) and catalase activities, and the quantification of cytochromes P450 and b5. The CL time course curve was significantly higher in O. niloticus treated with Cr(VI) at all times studied. The maximum CL was observed after 24h of exposure. The CL mean ratio treated/control was 4.6 and the initial velocity (V(0)) increased 7.4 times at 24h of intoxication. The TBARS levels however increased only 24h after intoxication. The CL time course curve was significantly higher in rats treated with Cr(VI) as early as 3h after intoxication. The maximum CL occurred 24h after exposure. The CL mean ratio treated/control was 2.1 and the V(0) increased 3.8 times at 24h of intoxication. On the contrary, was not observed any increase in TBARS in this study. Compared to the controls, in fish, SOD activity increased significantly only 24h after of exposure. In rats, there was a significant increase in SOD activity after 3 and 24h of intoxication. There was no catalase activity, nor cytochrome P450 and cytochrome b5 variation in both species studied. Through CL approach, it was possible to detect oxidative stress as early as 15min in fish and 3h in rats. Also a marked oxidative stress was revealed by the increased CL parameters that at 24h of intoxication was accompanied by arose SOD activity in liver of O. niloticus and Wistar rats and increased TBARS in O. niloticus. In addition, it was possible to show higher levels of oxidative stress in fish compared to the rat in spite of the dose to be four times smaller. Furthermore, CL provide a sensitive method for possible use to detect earlier biological impact in contaminated environments. PMID- 21782727 TI - Effects of Vitamin E pretreatment on subacute toxicity of mixture of Co, Pb, and Hg nitrate-induced nephrotoxicity in rats. AB - The aim of the study was to prove that Vitamin E has some beneficial effects on the kidneys of rats by protecting them from the toxicity of certain heavy metals. The protective effect of Vitamin E on Co, Pb, or Hg nitrate and a mixture of them induced nephrotoxicity was tested in a 3-months-old Norway strain (inberd) rat (Raltus norvigus) weighing 100-120g. A study was carried out, which comprised one control group and five experimental groups. In this experiment, nitrate salts of Co, Pb, or Hg were administered subcutaneously (s.c.) either alone (0.5mg/100g body weight) for 4 weeks or as a mixture (0.25mg/100g body weight); Vitamin E internal control (250IU/100g body weight) was administered by oral gavage for 4 weeks, Vitamin E pretreatment for 7 days was followed by concomitant administration of Co, Pb, and Hg, respectively and Vitamin E pretreatment for 7 days, followed by concomitant administration of mixture of three heavy metals for 4 weeks. Blood and kidney tissue samples were taken from the control and all the experimental groups for biochemical and histological study. Nephrotoxicity was characterized by histopathological as well as renal function data. The main pathological changes in the kidney after Co administration were shrunken and degeneration of renal tubule cells, disturbance in their position, size, shape, and staining affinity. Treatment with Hg caused desquamation, necrosis, atrophy, and loss of renal tubule cells and glomeruli. Lead intoxication had a profound effect on the structure and consequently on the function of the rat kidney. Most renal tubule cells were very dense, dehydrated with obscure cytoplasmic details. Most nuclei were shrunken and pyknotic. Also, most glomeruli revealed shrinkage and widening of capsular space. On the other hand, subacute exposure with the mixture of the three heavy metals showed marked destruction and distortion of the renal tubule cells. Marked fibrosis between the damaged tubules was also seen. On the other hand in the recovery groups, i.e., in groups II and III, the previously observed histopathological changes were still present with regression of their intensity. Four-week oral administration with Vitamin E (250IU/100g body weight) revealed no abnormal histological findings as compared with the normal kidney of the control animal, except for some Malpighian corpuscles which demonstrated wide capsular space, and spherical masses were seen within the glomeruli. After pretreatment with Vitamin E for 7 days, followed by treatment with (0.5mg/100g body weight ) Co, Pb, or Hg nitrate alone or with their mixture (0.25mg/100g body weight) for 4 weeks, an improvement in the histological changes were observed compared to those previously seen in groups II and III. The glomeruli showed minimal degenerated changes, the tubular arrangement and cytoplasmic basophilia more or less similar to the normal control. It was also found that the heavy metals were investigated both alone and in combination; the serum creatinine and blood urea level were significantly increased, and this elevation was diminished by Vitamin E pretreatment. According to the present results, it is concluded that combined exposure to a mixture of Vitamin E and examined heavy metals can minimize the histological alteration and diminish the serum creatinine and blood urea level. Also, it was found that the rank order of metal cytotoxicities was Hg > Co > Pb. PMID- 21782728 TI - Biomarkers of lead exposure in petrol station attendants and auto-mechanics in Abeokuta, Nigeria: effect of 2-week ascorbic acid supplementation. AB - In order to study the ameliorative effects of ascorbic acid in chronic lead poisoning, petrol station attendants and auto-mechanics in Abeokuta, Nigeria, who have been shown to be occupationally exposed to lead and university students (serving as control), were supplemented daily with 500mg ascorbic acid for 2 weeks. Blood and urine samples were collected from the subjects before and after ascorbic acid regimen and analysed for lead and biochemical effects associated with lead toxicity. The 2-week ascorbic acid supplementation resulted in a significant (P < 0.05) reduction in blood lead in the occupationally exposed subjects. The reduction in blood lead amounted to 57% in male petrol station attendants, 50% in female petrol station attendants and 44% in the auto mechanics. Urinary excretion of lead increased remarkably in the occupationally exposed subjects (P < 0.05). The biochemical effects associated with the toxic effects of lead also responded positively to the ascorbic acid regimen. Plasma and urine aminolevulinic acid (ALA) were reduced significantly (P < 0.05) by as much as 55% and 57% respectively. Plasma calcium also increased significantly (P < 0.05) in the subjects. Decreased levels of reduced glutathione (GSH) and hemoglobin observed in the occupationally exposed subjects were reversed by ascorbic acid. Glutathione-S-transferase (GST) and catalase (CAT) activities were not affected. Our findings indicate that ascorbic acid may be useful as an economical and convenient prophylactic agent for lead poisoning. PMID- 21782729 TI - Toxic effects of pulp and paper-mill effluents on male reproductive organs and some systemic parameters in rats. AB - The effect of pulp and paper-mill effluents on terrestrial animals was investigated using male albino rats as a test organism, under controlled laboratory conditions. Effluent consumption for 15 days caused a reduction in the relative weight of the testis (mg/100g body weight), compared to the control rats. The effects were not so pronounced in other regions of the male reproductive tract. Biochemical analysis revealed a drop in the activity of epididymal alpha-glucosidase in the effluent-treated animals. Although sperm collected from the cauda epididymis appeared morphologically normal, a decline in total sperm count and number of motile sperm was seen. The circulating level of testosterone in effluent-treated rats was slightly lower in some groups of rats given effluent treatment compared to controls. The level of progesterone and oestradiol, however, remained unaffected. Hematological and serological analyses suggest that effluents could produce anemia, liver and kidney dysfunction in rats. This inference stems from the altered blood cell counts, enhanced bilirubin and urea concentration in blood and high activity of serum GOT and GPT observed in effluent fed animals compared to controls. It is concluded that besides the general toxicity, the effluent affects the male reproductive system predominantly at the level of the testis. PMID- 21782731 TI - Study on pre-treatment of melatonin against radiation-induced oxidative stress in mice. AB - Antioxidants are part of the primary cellular defense against radiation-generated free radicals. Reports on low-level chronic administration of melatonin with its antiradiation influence are scanty. Although compelling logic suggests that melatonin may be effective for a variety of disorders, the mode and optimal dose of melatonin are still not clear. Most studies have used doses of supraphysiological blood levels. Present investigation reported that pre treatment with the lower concentration of melatonin (0.1mg/kg b.w./day) for 15 consecutive days affords potential protective effect against radiation-induced oxidative stress and mortality in mice. Radiation-induced augmentation in the levels of lipid peroxidation, glutathione disulphide (GSSG) and acid phosphatase was significantly ameliorated by melatonin pre-treatment. Radiation-induced depletion in the level of reduced glutathione (GSH), as well as glutathione peroxidase (GSH-Px) and alkaline phosphatase activities, was inhibited significantly by melatonin administration. Regression analysis of survival data yielded LD(50/30) as 7.16 and 11Gy for control (irradiation alone) and experimental (melatonin-treated irradiated) mice, respectively, and produced a dose reduction factor (DRF), 1.53. Radiation-induced deficit in the body and organ weight also got inhibited significantly in the melatonin pre-treated mice. The findings support property of melatonin as a free radical scavenger and singlet oxygen quencher and indicate the antioxidative properties of melatonin against the gamma radiation. PMID- 21782732 TI - Dioxin health risk to infants using simulated tissue concentrations. AB - Dioxin concentrations in infant and child were simulated using physiologically based pharmacokinetic (PBPK) models developed for these groups. The infant model was validated by comparing the simulated concentration with the measured concentration from the literature, and they showed good agreement. Simulations with our PBPK model showed temporal patterns in concentrations in various tissues. For risk assessment, estimated concentrations of 29 dioxins in the liver were summed up in a toxic equivalency (TEQ) basis to be compared with actual 2,3,7,8-TCDD concentrations in rat liver associated with toxicity. Maximum liver concentrations in breast-fed and formula-fed infants were 16.8pg TEQ/g and 3.5pg TEQ/g, respectively. The level in breast-fed infant liver was approximately 1/300 of the level associated with hepatocellular carcinoma and 1/5 of the level found in maternal rat liver associated with alterations in reproductive organs in the next generation. Based on our analysis, the present contamination level is not safe enough, but further dose-response data is required for a quantitative risk assessment. PMID- 21782730 TI - Effects of bis(2-ethylhexyl) phthalate, gamma-hexachlorocyclohexane, and 17beta estradiol on the fry stage of medaka (Oryzias latipes). AB - The effects of bis(2-ethylhexyl) phthalate (DEHP), gamma-hexachlorocyclohexane (gamma-HCH), and 17beta-estradiol (E2) on the fry stage of medaka were investigated. The medaka fry were exposed to different concentrations (0.01, 0.1, 1, and 10MUg/L) of these chemicals for 3 weeks after hatching. Then, mortality, body weight, sex ratio, and gonadosomatic index (GSI) of the matured fish (after 5 months) were measured. Mortality was increased significantly in the 10MUg/L E2 group. Distortion of sex ratio was found in 1 and 10MUg/L E2 groups. DEHP treated groups showed the GSI reduction only in male fish. All the gamma-HCH and parts of the E2 treated groups showed the GSI reduction in both sexes. Exposure of DEHP, gamma-HCH, and E2 during the fry stage affected normal maturation of medaka at the concentrations which had no impact on mortality or sex ratio. PMID- 21782733 TI - Molecular structural characteristics governing biocatalytic oxidation of PAHs with hemoglobin. AB - Based on some fundamental quantum chemical descriptors computed by PM3 hamiltonian, two quantitative structure-activity relationship (QSAR) models for biocatalytic oxidation specific activity of unmodified and chemically modified hemoglobin in the oxidation of different polycyclic aromatic hydrocarbons (PAHs) in 15% acetonitrile were developed, respectively, using partial least squares analysis (PLS). The cross-validated Q(cum)(2) values for the two optimal QSAR models are 0.785 and 0.747, respectively, indicating a good predictive ability for biocatalytic oxidation specific activity of PAHs. The main factors affecting specific activity of PAHs are most positive net atomic charges on a hydrogen atom (q(H)(+)), largest negative atomic charge on a carbon atom (q(C)(-)), dipole moment (MU), the energy of the highest occupied molecular orbital (E(HOMO)), and (E(LUMO) - E(HOMO))(2). The biocatalytic oxidation specific activity of PAHs with big q(C)(-) and (E(LUMO) - E(HOMO))(2) values tends to be slow. Increasing q(H)(+), MU, and E(HOMO) values of PAHs leads to increase of specific activity. PMID- 21782734 TI - Piscicidal and anti-acetylcholinesterase activity of Euphorbia royleana stem bark extracts against freshwater common predatory fish Channa punctatus. AB - The present paper deals with the piscicidal activity of different solvent extracts of Euphorbia royleana stem bark against freshwater predatory fish Channa punctatus, which is commonly present in shrimp and carp culture ponds. The rank of order of toxicity of different solvent extract was: diethyl ether (LC(50) (96h) 31.76mg DW/L) > chloroform (LC(50) (96h) 56.26mg DW/L) > methanol (LC(50) (96h) 56.80mg DW/L) > acetone (LC(50) (96h) 65.77mg DW/L). There was a significant (P < 0.05) negative correlation between LC values and exposure periods, thus increase in exposure time. The LC(50) values of diethyl ether extract of E. royleana stem bark decrease from 81.78mg DW/L (24h) to 31.76mg DW/L (96h). Similar trend were also observed in case of chloroform, methanol and acetone extracts. Exposure of sub-lethal doses (40% and 80% of LC(50)) of the diethyl ether extract for 24h or 96h caused significant inhibition in the activity of enzyme acetylcholinesterase (AChE) in liver and muscle tissue of fish C. punctatus. There was a significant recovery observed in the activity of enzyme acetylcholinesterase in both the tissues of fish after 7th day of the withdrawal of treatment. Thus, the diethyl ether extract of E. royleana stem bark can be used for control of unwanted predatory fish C. punctatus from fish culture ponds. Their toxicological action is due to their anti-acetylcholinesterase enzyme activity, reversibility in their action is advantageous factor for their use as environmentally safe piscicide in aquatic bodies. PMID- 21782735 TI - Seeking solutions to chemical mixtures challenges in public health. AB - The Agency for Toxic Substances and Disease Registry (ATSDR) identifies people near hazardous waste sites who are at potential health risk because of their exposure to environmental chemicals. Nearly, 2000 chemicals have been associated with such sites. Residents of U.S. communities are potentially exposed to hazardous substances through air, soil, drinking water, and food. The agency has determined that more than 73 million people live within a 4-mile radius of waste sites. More than 14 million Americans live within 1 mile of a National Priorities List site, of which 11% are 7 years of age or younger, 12% are 64 years of age or older, 24% are women of childbearing age, and 25% are minorities. The lack of adequate environmental sampling and information on human exposures often restricts ATSDR's evaluation and assessment activities. Assessing human exposure with its attendant health risks and outcomes is complex because many populations have a wide range of reported illnesses, and generally exposures are to mixtures of chemicals. This prompted ATSDR to consider mixtures issues more in depth and to establish a formal mixtures assessment and research program in 1994. In this paper, we present an overview of the agency activities, the genesis, legislative mandates, and pertinence of the mixtures program including applied research and the development of methods for evaluating the impact of multiple-chemical exposure. On the basis of 20-year experience of evaluating and researching environmental chemical mixtures at waste sites, ATSDR convened the International Conference on Chemical Mixtures (ICCM) in 2002. The conference was supported by several federal agencies and scientific organizations and attended by international and national experts. The conference addressed broad topics such as prevalence of exposures to chemical mixtures, importance of interactions at environmentally relevant levels, validity of assuming additivity (dose or response) as default for mixtures assessment, and promising avenues in the three broad areas, viz., research, assessment, and computational tools. PMID- 21782736 TI - Chemical mixture toxicology: from descriptive to mechanistic, and going on to in silico toxicology. AB - Because of the pioneering vision of certain leaders in the biomedical field, the last two decades witnessed rapid advances in the area of chemical mixture toxicology. Earlier studies utilized conventional toxicology protocol and methods, and they were mainly descriptive in nature. Two good examples might be the parallel series of studies conducted by the U.S. National Toxicology Program and TNO in The Netherlands, respectively. As a natural course of progression, more and more sophistication was incorporated into the toxicology studies of chemical mixtures. Thus, at least the following seven areas of scientific achievements in chemical mixture toxicology are evident in the literature: (a) the application of better and more robust statistical methods; (b) the exploration and incorporation of mechanistic bases for toxicological interactions; (c) the application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling; (d) the studies on more complex chemical mixtures; (e) the use of science-based risk assessment approaches; (f) the utilization of functional genomics; and (g) the application of technology. Examples are given for the discussion of each of these areas. Two important concepts emerged from these studies and they are: (1) dose-dependent toxicologic interactions; and (2) "interaction thresholds". Looking into the future, one of the most challenging areas in chemical mixture research is finding the answer to the question "when one tries to characterize the health effects of chemical mixtures, how does one deal with the infinite number of combination of chemicals, and other possible stressors?" Undoubtedly, there will be many answers from different groups of researchers. Our answer, however, is first to focus on the finite (biological processes) rather than the infinite (combinations of chemical mixtures and multiple stressors). The idea is that once we know a normal biological process(es), all stimuli and insults from external stressors are merely perturbations of the normal biological process(es). The next step is to "capture" the biological process(es) by integrating the recent advances in computational technology and modern biology. Here, the computer-assisted Reaction Network Modeling, linked with PBPK modeling, offers a ray of hope to dealing with the complex biological systems. PMID- 21782737 TI - Exposure of breast-fed children in the Czech Republic to PCDDs, PCDFs, and dioxin like PCBs. AB - Human milk samples from 81 mothers living in seven selected localities of the Czech Republic collected in 1999-2000 were analyzed for PCDDs, PCDFs, and dioxin like PCBs. Significant local differences in total WHO-TEQ values were observed (median ranges: 27.8-64.6pg/g fat) with the highest level in Uherske Hradiste, but the highest PCDD-TEQ value was in Prague. Seven congeners (2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 2,3,4,7,8-PeCDF, and PCBs 118, 126, 156, and 157) cover about 90 94% of the total TEQ level. The non- and mono-ortho PCBs account for approximately 50-70% of the total TEQ levels in individual groups. The calculated median daily intake of the total TEQ for breast-fed infants ranged from 271pg/kg b.w./day in Uherske Hradiste to 117pg/kg b.w./day in Liberec and exceeded by about two orders of magnitude a tolerable daily intake (TDI) of 1-4pg/kg b.w. recommended by the WHO. Our results confirmed significant local differences in the levels of dioxins and suggest that hot spot locations might exist within the country. PMID- 21782738 TI - Thyroid function in relation to burden of PCBs, p,p'-DDE, HCB, mirex and lead among Akwesasne Mohawk youth: a preliminary study. AB - The effects of endocrine disrupting environmental contaminants such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), p,p' dichlorophenyldichloroethylene (p,p'-DDE), mirex, and lead, are examined in a sample of youth of the Akwesasne Mohawk Nation who are 10-16.9 years of age (n=115). The Akwesasne community is located adjacent to hazardous waste sites where PCBs and other toxicants have contaminated the local ecology. This study examines the relationship between measures of thyroid function and endocrine disrupting environmental toxicants. Both with and without statistical adjustment for other toxicants, as well as age, sex and lipid levels, several indicators of PCB burden are significantly, negatively related to levels of free thyroxine and total thyroxine, and positively to thyrotropin. Lead level was positively related to triidothyronine. Future testing of non-linear relationships is warranted. Despite the linear associations with thyrotropin, free and total thyroxine, PCBs were not related to increased occurrence of these hormones outside the clinically normal range for the testing laboratory. PMID- 21782739 TI - Interactive toxicity of simple chemical mixtures of cadmium, mercury, methylmercury and trimethyltin: model-dependent responses. AB - Scientific and societal interest in the analysis of aggregate toxicity derives from the fact that people are seldom exposed to single chemicals, but rather to multiple agents from different sources and even to mixtures of agents from a single source. Many descriptive terms and mathematical, graphical, and statistical models have been used to evaluate the toxicity of simple mixtures. It is not very easy to distinguish clearly the intrinsic differences, distinctions and limitations of these models when applied to characterizing interactive toxicity. A series of experiments were performed to illustrate model-dependent consistencies and differences in interactive toxicity. Cultured murine renal cortical cells, target cells for metal toxicity, were treated with selected concentrations of one metal or binary mixtures of metals to give conditions of dose-additivity, response additivity, or with only one toxic member of the binary mixture. The cytotoxicity was determined at 24h by lactate dehydrogenase release. The data were analyzed graphically and mathematically by (a) Carter's statistical isobologram, (b) Barton's non-linear, and (c) Kodell and Pounds' linear models to characterize the interaction. These models were compared and contrasted for robustness, and consistency using these common data sets. The models gave generally consistent conclusions, but each model has limitations and strengths for assessing particular mixtures scenarios. This comparison illustrates the complexity of extrapolating conclusions between models, and difficulty of public health assessment from exposures to multiple chemicals in the environment. PMID- 21782740 TI - Analysis of functional effects of a mixture of five pesticides using a ray design. AB - The protection of human health from the adverse effects of cumulative environmental exposure to chemical mixtures is an important issue. Of particular interest is the detection and characterization of interaction among chemicals in complex mixtures. Response surface methodology, often supported by factorial designs, is the classical statistical experimental approach. Fixed-ratio ray designs, which may include the use of single chemical data in addition to data along mixture ray(s), have been proposed as an alternative approach. Such designs permit a reduction in the amount of experimental effort when the region of interest can be restricted to exposure-relevant mixing ratios. A 'single chemicals required' (SCR) approach and a 'single chemicals not required' (SCNR) approach are both described. The methods are illustrated with a five-chemical mixture of organophosphorus pesticides-acephate (ACE), diazinon (DIA), chlorpyrifos (CPF), malathion (MAL) and dimethoate (DIM). Their relative proportions in the mixture were based on the relative dietary human exposure estimates of each chemical as projected by the U.S. EPA Dietary Exposure Evaluation Model (DEEM). Use of the SCR and SCNR methods for binary endpoints are demonstrated using a dichotomized gait score as an indication of toxicity. For both methods, the overall hypothesis of additivity was rejected, indicating significant departure from additivity when the five pesticides were combined at the specified mixing ratio. By comparison of the predicted response under additivity to the modeled response of the experimental mixture data this departure from additivity was characterized as synergy (greater than additive toxicity). To examine the influence of malathion in the mixture, it was removed from the five-pesticide mixture (full ray) and the remaining four chemicals (reduced ray) were combined at the same relative proportions used in the full fixed-ratio ray There was not a significant departure from additivity along the ray with the four remaining pesticides omitting malathion. Thus, although malathion was not dose-responsive alone, it significantly interacted with the other pesticides. PMID- 21782741 TI - Toxicological evaluation of complex mixtures: fingerprinting and multivariate analysis. AB - The present paper describes a strategy for toxicological evaluation of complex mixtures based on chemical "fingerprinting" followed by pattern recognition (multivariate data analysis). The purpose is to correlate chemical fingerprints to measured toxicological endpoints, identify all major contributors to toxicity, and predict toxicity of additional mixtures. The strategy is illustrated with organic extracts of exhaust particles which are characterized by full scan gas chromatography-mass spectrometry (GC-MS). The complex GC-MS data are resolved into peaks and spectra for individual compounds using an automated curve resolution procedure. Projections to latent structures (PLS) is used for the regression modeling to correlate the GC-MS data to the measured responses; mutagenicity in the Ames Salmonella assay. The regression model identifies those peaks that co-vary with the observed mutagenicity. These peaks may be identified chemically from their spectra. Furthermore, the regression model can be used to predict mutagenicity from GC-MS chromatograms of additional samples. PMID- 21782742 TI - Toxicity assessment of complex mixtures remains a goal. AB - One of the initial steps in remediating contaminated environments is to assess the human and ecological health risk associated with exposure to contaminants in a specific medium. Presented here are the results of a five-year study investigating the toxicity of simple and complex mixtures. A series of model compounds and simple mixtures including polycyclic aromatic hydrocarbons (PAHs), pentachlorophenol (PCP), and halogenated aliphatic hydrocarbons (HAHs) were analyzed. Mixture toxicity was studied using microbial genotoxicity assays and cytotoxicity assays with renal and neural cells. The majority of binary mixtures described here induced additive responses. A limited number of samples were identified where binary mixtures induced inhibitory effects. For example, benzo(a)pyrene (BAP) alone induced 30% renal cell death, whereas an equimolar dose of chrysene and BAP only produced 1.6% cellular death. In none of the mixtures tested did the mixture toxicity results deviate from the predicted results by an order of magnitude. The results from testing binary mixtures in this study indicate that the results did not deviate significantly from additivity. Complex mixture results were more difficult to interpret. The toxicity of complex mixtures could not be accurately predicted based on chemical analysis. This could be due to chemical interactions or due to the presence of unidentified chemicals, such as alkyl PAHs or high molecular weight PAHs that are not included in the standard risk assessment procedure. Even though the results from these in vitro studies indicate that additive assumptions will generally be appropriate for binary mixtures similar to the ones tested here, the risk associated with complex mixtures remains a challenge to predict. Before the results of toxicity testing can be used to adjust risk assessment calculations, it is important to fully appreciate the chemical composition and to understand the mechanism of observed chemical interactions in animals chronically exposed to low doses of chemical mixtures. This research was supported by ATSDR Grant no. ATU684505 and NIEHS SBRP Grant no. P42 ES04917. PMID- 21782743 TI - Dose-dependent liver tissue repair in chloroform plus thioacetamide acute hepatotoxicity. AB - The objective of this study was to test whether a binary mixture (BM) of chloroform (CHCl(3)) and thioacetamide (TA) causes a dose-dependent liver injury and an opposing tissue repair. Liver injury was assessed by plasma alanine aminotransferase (ALT) and histopathology. Tissue repair was measured by [(3)H CH(3)]-thymidine ((3)H-T) incorporation into hepatonuclear DNA and PCNA over a time course of 0-72h. Male Sprague-Dawley (S-D) rats received six- and five-fold dose ranges of TA and CHCl(3), respectively. ALT levels and (3)H-T incorporation were in complete agreement with corresponding microscopic observations, and only ALT elevation and (3)H-T incorporation data are presented here. Liver injury observed after exposure to BM was no different than addition of injuries caused by individual compounds. Tissue repair was prompt and adequate, leading to recovery from injury and animal survival. Tissue repair is dose-dependent and plays central role in the hepatotoxic outcome. PMID- 21782744 TI - Liver regeneration: a critical toxicodynamic response in predictive toxicology. AB - The objective of the present review is to discuss the importance tissue repair in the mixture risk assessment. Studies have revealed the existence of two stages of toxicity: an inflictive stage (stage I) and progressive or regressive stage (stage II). While much is known about mechanisms by which injury is inflicted (stage I), very little is known about the mechanisms that lead to progression or regression of injury. A wide variety of additional experimental evidence suggests that tissue repair impacts decisively on the final toxic outcome and any modulation in this response has profound impact in the final outcome of toxicity. We designed the present research to investigate the importance of tissue repair in the final acute hepatotoxic outcome upon exposures to mixture of toxicants comprising thioacetamide (TA), allyl alcohol (AA), chloroform (CHCl(3)) and trichloroethylene (TCE). Dose response studies with individual compounds, binary mixtures (BM), ternary (TM) and quaternary mixtures (QM) have been conducted. Results of CHCl(3) + AA BM [Anand, S.S., Murthy, S.N., Vishal, V.S., Mumtaz, M.M., Mehendale, H.M., 2003. Tissue repair plays pivotal role in final outcome of supra-additive liver injury after chloroform and allyl alcohol binary mixture. Food Chem. Toxicol. 41, 1123] and CHCl(3) + AA + TA +TCE QM [Soni, M.G., Ramaiah, S.K., Mumtaz, M.M., Clewell, H., Mehendale, H.M., 1999. Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic forces in predictive toxicology. Regul. Phramcol. Toxicol. 19, 165], and two representative individual compounds (TA and AA) [Mangipudy, R.S., Chanda, S., Mehendale, H.M., 1995a. Tissue repair response as a function of dose in thioacetamide hepatotoxicity. Environ. Health Perspect. 103, 260; Soni, M.G., Ramaiah, S.K., Mumtaz, M.M., Clewell, H., Mehendale, H.M., 1999. Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic forces in predictive toxicology. Regul. Phramcol. Toxicol. 19, 165] are described in this review. In addition, modulation of tissue repair in the outcome of hepatotoxicity and its implications in the risk assessment have been discussed. Male Sprague-Dawley (S-D) rats (250-300g) received a single i.p. injection of individual toxicants as well as mixtures. Liver injury was assessed by plasma alanine amino transferase (ALT) and histopathology. Tissue regeneration response was measured by [(3)H]-thymidine ((3)H-T) incorporation into hepatocellular nuclear DNA and PCNA. Only ALT and (3)H-T data have been presented in this review for the sake of simplicity. Studies with individual hepatotoxicants showed a dose-related increase in injury as well as tissue repair up to a threshold dose. Beyond this threshold, tissue repair was inhibited, and liver injury progressed leading to mortality. Since the highest dose of individual compounds resulted in mortality, this dose was not employed for mixture studies. While CHCl(3) + AA BM caused supra-additive liver injury, QM caused additive liver injury. Due to the prompt and robust compensatory tissue repair, all the rats exposed to BM survived. With QM, the rats receiving the highest dose combination experienced some mortality consequent to the progression of liver injury attendant to suppressed tissue repair. These findings suggest that liver tissue repair, the opposing biological response that restores tissue lost to injury, may play a critical and determining role in the outcome of liver injury regardless of the number of toxicants in the mixture or the mechanism of initiation of injury. These data suggest that inclusion of this response in risk assessment might help in fine-tuning the prediction of toxic outcomes. PMID- 21782745 TI - Gene expression profiles in mammary gland of male rats treated with genistein and methoxychlor. AB - Humans and wildlife are frequently exposed to mixtures of natural and synthetic endocrine-active compounds. To understand the impact of dietary phytoestrogen on the susceptibility to synthetic chemicals in the environment, we studied the effects of a binary mixture consisting of the isoflavone genistein and the pesticide methoxychlor on the development of the mammary gland. Sprague-Dawley rats were exposed to genistein at 800ppm, methoxychlor at 800ppm, or their combination through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. At post-natal day (PND) 90, offspring rats were killed and their inguinal mammary glands collected for gene expression analysis utilizing the Clontech Atlas Rat 1.2 cDNA array, which contains probes for 1176 genes. Treatment with both genistein and methoxychlor altered gene expression profiles of the mammary glands in male rats, and the effects were more prominent in the combination treatment than the single-compound groups. Specific gene changes suggested that treatments affected the stromal and epithelial compartments of the mammary, involving genes controlling growth factor signaling, apoptosis, and tissue remodeling. This study demonstrates that dietary phytoestrogens in combination with a synthetic endocrine-active chemical can cause unique effects in endocrine-responsive tissues and highlights the importance of studying the effects of chemical combinations on the multiple biological processes underlying toxicological responses. PMID- 21782746 TI - A reaction network model for CYP2E1-mediated metabolism of toxicant mixtures. AB - In this paper, we describe a modeling approach to predict the interlinked pathways and kinetics resulting from CYP2E1-mediated metabolism of both pure species and chemical mixtures. This approach is based on the concept of chemical reaction networks, an idea that has formed the basis for simulation tools that have shown good predictive capabilities in the petroleum industry, but also an idea that has heretofore seen minimal application in the biomedical research arena. Although the initial target for developing this reaction network approach was cytochrome P450 2E1 (CYP2E1) and its over 200 substrates, this technology has been used for other families of CYP enzymes and their substrates in our laboratory. Utilizing this approach, we have produced a modular 'predictive metabolomics' simulation framework comprising interdependent software components that perform such tasks as testing of substrate binding feasibility, performing virtual chemistry, formulating reaction-rate equations, computing reaction kinetics and predicting time-dependent species concentrations. As an illustrative example, we outline the application of this framework to the prediction of the reaction networks resulting from the Phase I metabolism of two compounds of important toxicological interest. The potential of this modeling technology is immense in providing a computer simulation platform for complex-chemical mixtures and complex-biological systems. It is possible that this technology will play an important role in formulating a 'Virtual Human'. PMID- 21782747 TI - Effects of a desealant formulation, SR-51((r)) and its individual components on the oxidative functions of mitochondria. AB - The Royal Australian Air Force has reported that personnel involved in F-111 fuel tank maintenance were concerned that exposure to a range of chemicals during the period 1977-mid-1990s was the cause of health problems. Particular concern was directed at a desealant chemical mixture known as SR-51((r)). The current study, using in vitro submitochondrial assays, was designed to investigate the relative toxicities of the four components of SR-51((r)) (Aromatic 150 solvent (Aro150), dimethylacetamide (DMA), thiophenol (TP) and triethylphosphate (TEP)). Based on the EC(50) values, TP and Aro150 were the most toxic components and were markedly more toxic than TEP and DMA. PMID- 21782748 TI - Toxicology of chemical mixtures: a challenging quest along empirical sciences. AB - This paper describes the "quest" of our institute trying to assess the toxicology of chemical mixtures. In this overview, we will discuss some critical developments in hazard identification and risk assessment of chemical mixtures during these past 15 years. We will stand still at empirical and mechanistic modeling. "Empirical" means that only information on doses or concentrations and effects is available in addition to an often empirically selected quantitative dose-response relationship. Empirical models have played a dominant role in the last decade to identify health and safety characteristics of chemical mixtures. Many of these models are based on the work of pioneers in mixture toxicology who defined three basic types of action for combinations of chemicals: simple similar action, simple dissimilar action and interaction. Nowadays, empirical models are mainly based on response-surface analysis and make use of advanced statistical designs. However, possible interactions between components in a mixture can also be given in terms of mechanistic models. In terms of "mechanistic" (or biological) understanding, interactions between compounds may occur in the kinetic phase (processes of uptake, distribution, metabolism and excretion) or in the dynamic phase (effects of chemicals on the receptor, cellular target or organ). A biological phenomenon such as competitive agonism as described for mixtures of drugs (biotransformation enzymes) or sensory irritants (nerve receptors) can accurately predict the effect of any of these mixtures. Thus, far mechanistic and empirical analyses of interactions are usually unrelated. It is one of the future challenges for mixtures research to combine information from both approaches. Also, our current biology-based models have their limitations, since they cannot integrate every relevant biological mechanism. In this respect, mechanistic modeling of mixtures may benefit from the developments coming from the arena of molecular biology (toxicogenomics) which offers an in-depth analysis of several involved enzymatic pathways in parallel through the use of a systems biology approach. This was illustrated with mixtures of food additives known to affect the liver. Key to further maturation of mixture toxicology is collaboration of experimental toxicologists, biomathematicians, biologists, pharmacologists, model developers, molecular biologists and bioinformaticians to ensure parallel and coordinated research in this challenging area of toxicology. For this reason, the next sequel will be even more challenging and exciting to that first 15 years of empirical testing. PMID- 21782749 TI - EPA project-level research strategies for chemical mixtures: targeted research for meaningful results. AB - Project-level research strategies at the U.S. Environmental Protection Agency regarding chemical mixtures are impacted by administrative priorities, public interests, expert opinions, scientific advances, regulatory needs, and legislative actions, influencing the setting of priorities and goals. Perhaps, the most significant influence on conducting chemical mixtures research is the passage of laws requiring the EPA to investigate the potential toxicity of various mixtures, specifically the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, the Food Quality Protection Act of 1996, and the Safe Drinking Water Act Amendments of 1996. Scarce resources are allocated to broadly defined issues for consideration by teams of scientists, who design and implement specific projects. Because resources are limited, projects may have several goals, e.g., filling specific data gaps to support a regulation and, simultaneously, producing data to evaluate a risk assessment method. Research areas of emphasis are shaped by risk assessment needs, data gap uncertainties, and experimental design considerations. This paper discusses factors shaping EPA research strategies for chemical mixtures and presents an example of efficient research planning to investigate potential toxicity from exposure to drinking water disinfection by-products. PMID- 21782750 TI - Priorities for mixtures health effects research. AB - In order to better inform scientific decision making in the occupational environment, we need a better understanding of the toxicology of mixed exposures. In particular, we need an understanding of the dose-response relationship from the level of individual or population exposure down to the molecular level (and then back up again from the molecular level to the specific health-related response of the organism as a whole). Mixtures toxicology is proving to be different from single-chemical toxicology in several fundamental but barely recognized ways: Knowledge gained in mixtures research should be able to improve current risk assessment and mitigation or intervention methods. In NIOSH's National Occupational Research Agenda (NORA) three priority areas have been identified: PMID- 21782751 TI - Exposure to combinations of substances: a system for assessing health risks. AB - Combined exposures may be categorised as specified combinations or mixtures of substances, depending on composition and exposure scenario. The major characteristic of a specified combination is known composition and that of a mixture simultaneous exposure. A framework was developed as a guide for safety evaluation of combined exposures. This framework offers the possibility to evaluate mixtures as a single entity, or as a number of fractions or individual constituents. The evaluation of specified combinations will often focus on the individual components. To reduce the safety evaluation of complex exposures to manageable proportions, the "top n" and "pseudo top n" approaches were introduced, n representing the n most "risky" chemicals or groups of chemicals, respectively. To select the best method, the framework should always be walked through in its entirety, considering all options. The Mumtaz-Durkin weight-of evidence approach is included as a prioritization instrument for combined exposures. It is based on hazard indices supplemented with qualitative and quantitative weighting and interaction factors. PMID- 21782752 TI - Using the ATSDR Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures. AB - The Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures (Mixtures Guidance Manual) is intended to assist environmental health scientists and toxicologists in determining whether exposure to chemical mixtures at hazardous waste sites may affect public health. The Agency for Toxic Substances and Disease Registry (ATSDR) approach is a semi-quantitative screening process. Step-by-step procedures for assessing noncarcinogenic and carcinogenic effects are outlined in flow charts. Exposure data and toxicological information on the mixture of concern are the preferred basis for an assessment. If suitable whole mixture studies are not available, a components-based approach is undertaken. The hazard index (HI) method is used to screen for noncancer health hazards from potential additivity of the components. Cancer risks for the components are summed to screen for health hazards from potential additivity of carcinogenic effects. A weight-of-evidence (WOE) method is used to evaluate the potential impact of interactions on noncancer and cancer health effects. PMID- 21782753 TI - Interaction profile for lead, manganese, zinc, and copper. AB - This interaction profile discusses and evaluates the evidence for joint toxic action among lead, manganese, zinc, and copper. The interaction profile recommends how to incorporate concerns about possible interactions or additivity into public health assessments of hazardous waste sites where people might be exposed to mixtures of these chemicals. The profile recommends using endpoint specific hazard indexes and a hazard quotient to screen for potential health effects. The qualitative weight-of-evidence (WOE) approach is then used to predict the impact of interactions on the endpoint-specific hazard indexes and hazard quotient. PMID- 21782754 TI - Database for the toxicological evaluation of mixtures in occupational atmospheres. AB - Workers are regularly simultaneously exposed to multiple chemical substances. As in the ACGIH (American Conference of Governmental Industrial Hygienists) approach, the Quebec Regulation prescribes that when two or more hazardous substances are present in workplaces and have similar effects on the same organs of the human body, their effects should be considered additive, unless established otherwise. This project was undertaken to develop a user-friendly toxicological database aid in identification of possible interactive effects of mixtures present in the work environment. In the first phase of the project, standard general literature references were used to compile critical data, such as target organs, effects on the target organs, mechanisms of action, and toxicokinetic characteristics of each of the 668 chemical substances appearing in the regulation. Each substance was assigned to one or more of 32 classes of biological effects retained by a group of toxicologists. The resulting database allows the user to find if there is potential additivity among components of a mixture. PMID- 21782755 TI - PAHs and metals in the soils of inner-city and suburban New Orleans, Louisiana, USA. AB - Representative soil samples of an inner-city and suburban community (n = 19 each) are evaluated for 16 polycyclic aromatic hydrocarbons-PAHs (naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz(a)anthracene, chrysene, benzo[k]fluoranthene, benzo[j]fluoranthene, benzo(a)pyrene, indeno[1,2,3-cd]pyrene, dibenz[a,h]anthracene and benzo[g,h,i]perylene) and nine metals (Pb, Zn, Cd, Mn, Ni, Cu, Cr, Co and V). Surface (2.5cm deep) samples were air-dried and sieved (2mm USGS #10). Accelerated solvent extraction was used for PAH preparation prior to analysis with gas chromatography-mass spectrometry. Metals were extracted at a 5:1 ratio of 1mol nitric acid to soil, shaken at room temperature, centrifuged, filtered and analyzed by inductively coupled plasma-atomic emission spectrometry (ICP AES). Total PAHs (median 2927ngg(-1) versus 731ngg(-1)) and the total metals (median 1323MUgg(-1) versus 183MUgg(-1)) summarize differences (P < 0.0001) between the inner-city and suburb, respectively. A strong association exists between PAHs and metals for all 38 soil samples (correlation coefficient = 0.831, P < 0.00001). In terms of the specific sites of accumulation, both PAHs and metals show the same pattern: busy streets > foundations > residential streets > open areas. This study provides real-world data about various chemical mixtures which may be a factor of possible health disparities in sensitive populations, especially children, in different communities of New Orleans. PMID- 21782756 TI - Respiratory disease in relation to patient residence near to hazardous waste sites. AB - We have examined rates of hospitalization for respiratory diseases in relation to residences in zip codes with hazardous waste sites, as well as socio-economic status. Chronic bronchitis and chronic airway obstruction were elevated in persons who live in zip codes containing persistent organic pollutants (POPs) (PCBs and persistent pesticides) as compared to "clean" zip codes without hazardous waste sites or zip codes with hazardous waste sites containing other kinds of wastes, but the differences could be due to socio-economic status and behavioral risk factors since these are also important risk factors for respiratory diseases. Therefore, we investigated rates of hospitalization for individuals living in zip codes along the Hudson River, because here the average per capita income is higher than in the rest of the state, and there is less smoking, better diet and more exercise. We found a similar elevation of chronic bronchitis and chronic airway obstruction along the Hudson. These observations are consistent with the possibility that living near a POPs-contaminated site poses a risk of exposure and increased risk of chronic respiratory disease, probably secondary to suppression of the immune system. PMID- 21782757 TI - Persistent chemicals found in breast milk and their possible interactions. AB - Chlorinated dibenzo-p-dioxins (CDDs), hexachlorobenzene, dichlorodiphenyl dichloroethane (p,p'-DDE), methylmercury, and polychlorinated biphenyls (PCBs) were selected as an important subset of persistent chemicals detected in breast milk for the purpose of reviewing data on their joint toxic actions following oral exposure. Epidemiological studies of possible health hazards associated with exposure to biopersistent chemicals in breast milk identify mild neurodevelopmental deficits as a possible health hazard. However, the studies did not analyze all the components of the above defined mixture, and, therefore, they are not directly useful for the purposes of conducting exposure-based assessments of hazards associated with this mixture. For this purpose, component-based methodology such as binary weight-of-evidence, the hazard index (HI) and the target-organ toxicity dose (TTD) approaches are recommended. Weight-of-evidence evaluation of the limited animal studies' data on interactions among CDDs, hexachlorobenzene, p,p-DDE, methylmercury, and PCBs indicates that the data are inadequate to warrant a concern for deviations from the additivity assumption. Further, exposure-based health assessments are used, in conjunction with evaluation of community-specific health outcome data, consideration of community health concerns, and biomedical judgement, to assess the degree of public health hazard presented by mixtures of substances released into the environment. PMID- 21782758 TI - Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. AB - Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-based technologies as well as next-generation sequencing. Although currently diagnosis and classification of hepatocellular cancers still rely on histological examination of tumor sections, these technologies show great promise to advance the current knowledge of hepatocarcinogenesis, complement diagnostic classification in a setting of microarray-aided pathology, and rationalize the individual drug selection. This review aims to summarize recent progress of system biological approaches in hepatocarcinogenesis and outline potential areas for translational application in a clinical setting. Further, we give an update about known signaling pathways active in HCC, summarize the historical application of whole genomic approaches in liver cancer and indicate ongoing experimental research utilizing novel technologies in diagnosis and treatment of this deadly disease. This will also include the discussion and characterization of new molecular and cellular targets such as Cancer Stem Cells (CSCs). PMID- 21782759 TI - The liver X receptor in hepatic stellate cells: a novel antifibrogenic target? PMID- 21782760 TI - Herbal medicine hepatotoxicity revisited. PMID- 21782761 TI - Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma. AB - BACKGROUND & AIMS: The European Association for the Study of the Liver (EASL) criteria and, more recently, the modified Response Evaluation Criteria in Solid Tumors (mRECIST), have been widely adopted for evaluating responses to locoregional therapies for hepatocellular carcinoma (HCC). We wished to establish the optimum maximum number of target lesions that need to be measured in enhancement estimations. METHODS: From a prospective registry in our institution we identified 160 consecutive patients who had at least two measurable HCCs of nodular type exceeding 10mm in diameter, and who initially underwent transarterial chemoembolization (TACE). Intra-patient and inter-method agreement on confirmed response status were evaluated based on a maximum of one, two, or three target lesions selected among the measurable lesions according to size, versus all baseline lesions. RESULTS: Per patient analyses showed that the most consistent response distribution under both EASL and mRECIST was obtained using two or three targets versus all measurable lesions. These features were maintained even in analyses of subgroups stratified according to size, distribution, and number of tumors. The kappa values of comparisons between using a maximum of two or three targets versus using all the lesions were near 1.0, significantly higher than those obtained under both criteria using just the largest tumor. Similar conclusions were obtained when either two or three targets were measured. CONCLUSIONS: Our data indicate that evaluating the largest two lesions is generally the most useful procedure for measuring TACE responses under both EASL and mRECIST. PMID- 21782762 TI - Liver transplantation using Donation after Cardiac Death donors. AB - The success of solid organ transplantation has brought about burgeoning waiting lists with insufficient donation rates and substantial waiting list mortality. All countries have strived to expand donor numbers beyond the standard Donation after Brain Death (DBD). This has lead to the utilization of Donation after Cardiac Death (DCD) donors, also frequently referred to as Non-Heart Beating Donors (NHBD). Organs from these donors inevitably sustain warm ischaemic damage which varies in its extent and affects early graft function as well as graft survival. As a consequence, 'non-vital' organs such as renal transplants have increased rapidly from DCD donors but more 'vital' organ transplants such as the liver have lagged behind. However, an increasing proportion of liver transplants are now derived from DCD donors. This article covers this expansion, current results, pitfalls, and steps taken to minimize complications and to improve outcome, and future developments that are likely to occur. PMID- 21782763 TI - Peginterferon maintenance therapy in patients with advanced hepatitis C to prevent hepatocellular carcinoma: the plot thickens. PMID- 21782765 TI - Novel insights in the genetics of HCC recurrence and advances in transcriptomic data integration. PMID- 21782766 TI - The transcription factor Mxd4 controls the proliferation of the first blood precursors at the onset of hematopoietic development in vitro. AB - OBJECTIVE: The balance between proliferation and differentiation during hematopoietic development in the embryo is a complex process, the detailed molecular mechanisms of which remain to be fully characterized. The transcription factor Mxd4, a member of the Myc-Max-Mad network, was identified in a global gene expression profiling screen as being tightly regulated at the onset of hematopoietic lineage specification upon in vitro differentiation of mouse embryonic stem cells. Our study investigated the Mxd4 expression pattern at the onset of hematopoiesis and the biological relevance of its sharp and transient downregulation. MATERIALS AND METHODS: To study the expression pattern and role of Mxd4 at the onset of hematopoiesis, the in vitro differentiation of embryonic stem cells was used as a model system. Gain of function assays were performed using a doxycycline-inducible embryonic stem cell system. RESULTS: We show here that Mxd4 expression is transiently downregulated at an early stage of commitment to the hematopoietic lineage. Enforced expression of Mxd4 at this period of differentiation results in a defect in hematopoietic progenitor development, with impaired development of both primitive and definitive blood lineages. This effect is due to a severe decrease in cell proliferation, with an increased frequency of cells in the G(0)/G(1) phase of the cell cycle, alongside a reduced frequency of cells in the S phase. CONCLUSIONS: Together our results indicate that during embryonic hematopoietic differentiation Mxd4 is an important player in the regulation of blood progenitor proliferation, and suggest that downregulation of its expression might be required for a proliferative burst preceding lineage specification. PMID- 21782767 TI - Early expression of plasma CCL8 closely correlates with survival rate of acute graft-vs.-host disease in mice. AB - OBJECTIVE: To elucidate the significance of early expression of CC-chemokine ligand motif 8 (CCL8) in mice with graft-vs.-host disease (GVHD), we investigated its induction mechanisms and correlation with overall survival rate in GVHD mice. Plasma CCL8 increases on day 5 of allogeneic transplantation, when signs of GVHD are barely detectable. Increase of allogeneic splenocytes in grafts exacerbates GVHD and leads to upregulation of plasma CCL8 on day 5. Overall survival is the gold standard in determining the severity of acute GVHD in mice, but the absence of clinical and/or pathological manifestations in the early phase make it difficult to estimate vital outcomes at this stage of allogeneic marrow transplantation. MATERIALS AND METHODS: After lethal irradiation, BALB/c mice received bone marrow transplantation from C57BL/6 mice. Survival rate was monitored and clinical and pathological scores of GVHD were examined. Coculture of BALB/c-derived dendritic cells and C57BL/6-derived splenocytes was performed. CCL8 was measured by immunoassay. RESULTS: The plasma CCL8 level at day 5 of transplantation was closely correlated with survival rate and clinical/pathological scores on day 14. In vitro study revealed that the BALB/c derived dendritic cells expressed CCL8 upon stimulation of C57BL/6 CD4(+) T cells by cell interactions through major histocompatibility complex class II molecules. CONCLUSIONS: These investigations indicate that early and preclinical expression of CCL8 in plasma predicts overall survival of GVHD mice. Together with an involvement of allo-recognition in CCL8 expression, it suggests that CCL8 plays an important role in GVHD pathology. PMID- 21782768 TI - Anesthesiologist involvement in screening colonoscopy: temporal trends and cost implications in the medicare population. AB - BACKGROUND & AIMS: Colonoscopy is a recommended component of screening for colorectal cancer. We conducted a retrospective study of Medicare data to determine the frequency of anesthesiologist involvement and to identify patient and provider characteristics and cost implications associated with anesthesiologist involvement. METHODS: We used the linked Surveillance, Epidemiology, and End Results Medicare dataset to identify patients without cancer who received a screening colonoscopy examination from July 2001 through 2006 (n = 16,268). The outcome variable was anesthesiologist involvement, which was identified by searching Medicare claims. Logistic regression was used to explore the association between patient and provider characteristics and anesthesiologist involvement. Costs associated with the use of an anesthesiologist were derived based on a cost assessment by the Agency for Healthcare Research and Quality. RESULTS: Of the screening colonoscopies assessed, 17.2% involved an anesthesiologist. The screening colonoscopy rate more than doubled during the study period. The frequency of anesthesiologist involvement increased from 11.0% of screening colonoscopies in 2001 to 23.4% in 2006. Surgeons involved an anesthesiologist in 24.2% of colonoscopies, compared with 18.0% of gastroenterologists and 11.3% of primary care providers. The percentage of colonoscopies that involved an anesthesiologist varied among regions, ranging from 1.6% in San Francisco to 57.8% in New Jersey. Anesthesiologist involvement increased the cost by approximately 20% per screening colonoscopy. CONCLUSIONS: An increase in the involvement of anesthesiologists has significantly increased the cost of screening colonoscopies. Studies are needed to assess the effects of anesthesiologists on risks and benefits of colonoscopy, to determine the most safe and cost-effective approaches. PMID- 21782769 TI - Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. AB - BACKGROUND & AIMS: Symptom index (SI) and symptom association probability (SAP) are indexes used to analyze data collected from ambulatory pH and/or impedance monitoring and quantify the association between symptoms and reflux events. However, their characteristics are not well defined. We measured factors that affect SI and SAP values to determine their utility in assessing patients with refractory gastroesophageal reflux disease (GERD). METHODS: We conducted a cross sectional study of 254 patients with poor responses to proton pump inhibitor (PPI) therapy. Participants underwent esophagogastroduodenoscopy and wireless pH (n = 127) or impedance/pH monitoring when they were not receiving PPI therapy (n = 41) or impedance/pH monitoring while they received twice-daily PPI therapy (n = 86). SI and SAP values were calculated individually; ranges of values for each cell in the 2 * 2 contingency table were determined. Monte Carlo simulation was conducted to determine how varying reflux and symptom rates within the contingency table impacted the expected value and variability in SI and SAP. RESULTS: At best, only 33% of patients who were refractory to PPI therapy had positive SI or SAP scores for acid or nonacid reflux events. Abnormal SAP (>95%) and SI (>50%) scores required high rates of reflux. At reflux rates less than 10%, observed in 70% of the studied population, SI and SAP values were largely determined by chance occurrences, rather than the relationship between symptoms and reflux. The values for each index varied significantly day-to-day. CONCLUSIONS: SI or SAP indexes can be overinterpreted, unless patients with gastroesophageal reflux disease who are refractory to PPI therapy have high rates of reflux. PMID- 21782770 TI - Systematic review: Patterns of proton pump inhibitor use and adherence in gastroesophageal reflux disease. AB - BACKGROUND & AIMS: Variation in how proton pump inhibitors (PPIs) are taken likely influences their clinical effectiveness, and must be considered when estimating PPI failure rates. This review aimed to systematically investigate the literature on patterns of PPI use in patients with gastroesophageal reflux disease (GERD). METHODS: PubMed and Embase were searched (1989-May 2010) to identify observational studies providing information on patterns of PPI use in patients with GERD. RESULTS: Of 902 studies identified, 13 met prespecified selection criteria. Across 2 database studies, 53.8%-67.7% of patients with GERD had a medication possession ratio (MPR) of >0.80. Across 2 more database studies, the mean MPR for the study population was 0.68 to 0.84. Across 3 surveys, 70%-84% of patients reported daily PPI use. In 2 surveys, the presence and severity of reflux symptoms increased PPI adherence, as did Barrett's esophagus in another 2 studies. Across 3 surveys, 11%-22.2% of patients reported twice daily PPI use, and across 6 studies 11.0%-44.8% of patients took GERD medication in addition to a PPI. CONCLUSIONS: The results of this systematic review suggest that the majority of patients with GERD are relatively adherent to their PPI, although substantially different estimates were obtained using MPR data compared with surveys. Severe symptoms and the presence of Barrett's esophagus may increase PPI adherence, and other GERD medication is frequently taken in addition to a PPI. Limitations of studies in this area include inferring adherence from indirect MPR data, and recall bias associated with patient surveys. PMID- 21782771 TI - Mallory-Denk bodies are associated with outcomes and histologic features in patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Mallory-Denk bodies (MDBs) are inclusions found in hepatocytes of patients with chronic liver diseases. Their clinical significance and prognostic value are not understood. METHODS: We performed cross-sectional and longitudinal analyses of patients with chronic hepatitis C (CHC) enrolled in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial to identify clinical features associated with MDBs and changes in MDBs over time. Biopsy specimens were obtained at baseline and 1.5 and 3.5 years after patients were assigned to groups for the HALT-C trial; and patients were followed up to assess clinical and histologic outcomes. RESULTS: Of biopsy samples collected from 1050 patients, MDBs were present in 15%. They were associated with insulin resistance and laboratory and histologic markers of advanced liver disease (higher levels of periportal fibrosis, pericellular fibrosis, steatosis, and inflammation). After adjusting for disease severity (the ratio of aspartate aminotransferase to alanine aminotransferase, albumin, platelets, fibrosis, steatosis), the presence of MDBs was associated with histologic progression (odds ratio, 1.97; P = .04). Of the 844 patients from whom serial biopsy samples were collected, 61 (7.2%) developed MDBs (MDB gain) and 101 (12.0%) lost MDBs (MDB loss). The presence or absence of diabetes mellitus was associated with MDB gain (P = .006) or loss (P = .024), respectively. Development of MDBs was associated with decompensation (adjusted hazard ratio, 2.81; P < .001) and histologic signs of progression (adjusted odds ratio, 4.02; P = .004). CONCLUSIONS: The presence of MDBs in liver biopsy samples from patients with CHC is associated independently with fibrosis progression. Gain of MDBs over time is associated with decompensation and progression to cirrhosis; and occurs most frequently among diabetic patients. MDBs might be used as prognostic factors for patients with CHC. PMID- 21782772 TI - Increased perioperative mortality following bariatric surgery among patients with cirrhosis. AB - BACKGROUND & AIMS: The prevalence of nonalcoholic fatty liver disease and ensuing cirrhosis is expected to increase as a result of the obesity epidemic. These trends might increase the number of bariatric surgeries among patients with cirrhosis. We sought to assess the impact of cirrhosis on perioperative mortality after bariatric procedures. METHODS: Data on patients who underwent bariatric surgery in the United States between 1998 and 2007 were extracted from the Nationwide Inpatient Sample. In-hospital mortality and length of stay were compared for patients with no cirrhosis, compensated cirrhosis, and decompensated cirrhosis. RESULTS: Patients without cirrhosis had lower mortality rates than those with compensated and decompensated cirrhosis (0.3% vs 0.9% and 16.3%, respectively, P = .0002). After adjusting for covariates, the adjusted odds ratio of mortality among compensated and decompensated cirrhotic patients compared with noncirrhotic patients was 2.17 (95% confidence interval, 1.03-4.55) and 21.2 (95% confidence interval, 5.39-82.9), respectively. Mortality increased with volume of surgery among centers; those with more than 100 surgeries per year had the lowest mortality rates, compared with those with 50 to 100 surgeries per year and fewer than 50 surgeries per year (0.2% vs 0.4% and 0.7%, respectively; P < .0001). The average length of stay was longer for patients with decompensated and compensated cirrhosis, compared with patients without liver disease (6.7 and 4.4 d vs 3.2 d, respectively; P = .0001 and P = .03). CONCLUSIONS: Bariatric surgery in patients with cirrhosis should be performed while liver disease is well compensated. Patients with cirrhosis should undergo surgery at centers that perform large numbers of these procedures. PMID- 21782773 TI - Severity of esophageal injury predicts time to healing after radiofrequency catheter ablation for atrial fibrillation. AB - BACKGROUND: The delivery of radiofrequency (RF) energy to the posterior left atrium creates a risk of injury to the adjacent esophagus. Esophageal endoscopy (EGD) is used to screen patients at risk for esophageal thermal injury after RF ablation. OBJECTIVE: The purpose of this study was to analyze the macroscopic features of the severity of esophageal injuries induced by RF ablation to the left atrium as seen by EGD and evaluate the association of these descriptions with the time elapsed until complete healing. METHODS: This study analyzed 219 patients undergoing RF ablation for atrial fibrillation. Esophageal temperature probes were used during each ablation, and EGD was performed in cases with intraesophageal temperature >=39 degrees C. Repeat EGD was obtained at 10 days to evaluate for healing in all cases demonstrating esophageal injury. Serial endoscopies were repeated every 2 weeks until complete healing was documented. Lesions were classified according to severity as superficial or deep ulceration; size and shape were also noted. RESULTS: We found 37.4% of patients (82 of 219) with esophageal intraluminal temperatures >=39 degrees C. Of these, 22 patients (27%) were identified with esophageal injury, with 68% being superficial ulcerations and 32% deep. On repeat EGD at 10 days, only 29% of deep ulcerations were healed, as compared with 87% of the superficial injuries (P = .0136). No difference in healing was found when analyzed for size or shape. CONCLUSIONS: The macroscopic severity of esophageal lesions detected on endoscopy the day after RF ablation can predict the time to resolution, with severe, deep ulcerations requiring a longer time to heal. PMID- 21782774 TI - Rebuttal to EP testing predicts cardiac events in patients with Brugada syndrome. PMID- 21782775 TI - Concealed cardiomyopathies in competitive athletes with ventricular arrhythmias and an apparently normal heart: role of cardiac electroanatomical mapping and biopsy. AB - BACKGROUND: The diagnosis of subtle structural heart disease in competitive athletes with ventricular arrhythmias (VAs) and an apparently normal heart is challenging. Three-dimensional electroanatomic mapping (EAM) has been demonstrated to reliably identify low-voltage areas that correspond to different cardiomyopathic substrates. OBJECTIVE: The purpose of this study was to test whether EAM may help in the diagnosis of concealed cardiomyopathies in athletes with VAs and an apparently normal heart. METHODS: We studied 13 consecutive competitive athletes (12 males, age 30 +/- 13 years) who had documentation of VAs within the previous 6 months on 12-lead electrocardiogram (ECG), 24-hour Holter ECG, or ECG exercise testing and who were judged as having a structurally normal heart after a thorough noninvasive evaluation, including signal-averaged ECG, transthoracic echocardiogram, and cardiac magnetic resonance imaging. Depending on the presumed site of VA origin according to 12-lead ECG criteria, patients underwent right or left ventricular EAM and EAM-guided endomyocardial biopsy. RESULTS: Presenting arrhythmias included sustained ventricular tachycardia (n = 3), multiple episodes of nonsustained ventricular tachycardia (n = 7), and frequent ventricular ectopic beats (>1,000 during 24 hours; n = 3). Three patients had a history of syncope. Twelve (92%) patients had at least one low voltage region at EAM, which corresponded at EAM-guided endomyocardial biopsy to the histological diagnosis of active myocarditis in seven patients and of arrhythmogenic right ventricular cardiomyopathy in five. In one patient the histological evidence of contraction band necrosis allowed the unmasking of caffeine and ephedrine abuse. CONCLUSIONS: Electroanatomical substrate mapping may help diagnose concealed myocardial diseases in competitive athletes presenting with recent-onset VAs and an apparently normal heart. Further studies are warranted to assess the prognostic implications of such subtle myocardial abnormalities. PMID- 21782776 TI - Rebuttal to EP testing does not predict cardiac events in patients with Brugada syndrome. PMID- 21782777 TI - Left cardiac sympathetic denervation for the treatment of methadone-induced long QT syndrome. PMID- 21782778 TI - Investigations into an alternate approach to target mannose receptors on macrophages using 4-sulfated N-acetyl galactosamine more efficiently in comparison with mannose-decorated liposomes: an application in drug delivery. AB - In this study the potential of 2 different ligands, i.e., palmitoyl mannose (Man Lip) and 4-SO(4)GalNAc (Sulf-Lip) to target resident macrophages was investigated after surface decoration of Amphotericin B (AmB) loaded liposomes. In the case of Sulf-Lip, the 4-SO(4)GalNAc was adsorbed through electrostatic interaction on cationic liposomes, which was confirmed by change in zeta potential from +48.2 +/ 3.7 mV for Lip to +12.2 +/- 1.3 mV for Sulf-Lip. The mean particle size of Sulf Lip and Man-Lip was found to be 139.4 +/- 7.4 nm and 147.4 +/- 8.6 nm, respectively. Flow cytometric data reveal enhanced uptake of Sulf-Lip in both J774 and RAW cell lines in comparison with the uptake of Man-Lip. Intracellular localization studies indicate that the fluorescence intensity of Sulf-Lip was much higher in comparison with that of Man-Lip and Lip formulations. Sulf-Lip and Man-Lip showed significantly higher localization of AmB at all time points in comparison with Lip (P < 0.05) after intravenous (IV) administration. The studies provide evidence that 4-SO(4)GalNAc possesses a promising feature for targeting resident macrophages and its application in the conditions of leishmaniasis is in the offing. FROM THE CLINICAL EDITOR: This in vivo study compares two different ligands to deliver Amphotericin B l(AmB) loaded liposomes to resident macrophages. Targeted approaches showed significantly higher localization of AmB at all time points in comparison to non-targeted liposomes, and future applications in leishmaniasis are already under preparation. PMID- 21782779 TI - Antimicrobial and osteogenic properties of a hydrophilic-modified nanoscale hydroxyapatite coating on titanium. AB - Hydroxyapatite (HA)-coated titanium (Ti) is commonly used for implantable medical devices. This study examined in vitro osteoblast gene expression and antimicrobial activity against early and late colonizers of supra-gingival plaque on nanoscale HA-coated Ti prepared by discharge in a physiological buffered solution. The HA-coated Ti surface showed super-hydrophilicity, whereas the densely sintered HA and Ti surfaces alone showed lower hydrophilicity. The sintered HA and HA-coated Ti surfaces enhanced osteoblast phenotypes in comparison with the bare Ti surface. The HA-coated Ti enabled antimicrobial activity against early colonizers of supra-gingival plaques, namely Streptococcus mitis and Streptococcus gordonii. Such antimicrobial activity may be caused by the surface hydrophilicity, thereby leading to a repulsion force between the HA coated Ti surface and the bacterial cell membranes. On the contrary, the sintered HA sample was susceptible to infection of microorganisms. Thus, hydrophilic modified HA-coated Ti may have potential for use in implantable medical devices. From the Clinical Editor: This study establishes that Hydroxyapatite (HA)-coated titanium (Ti) surface of implanted devices may result in an optimal microenvironment to control and prevent infections and may have potential future clinical applications. PMID- 21782781 TI - Identification of novel KCNQ4 openers by a high-throughput fluorescence-based thallium flux assay. AB - To develop a real-time thallium flux assay for high-throughput screening (HTS) of human KCNQ4 (Kv7.4) potassium channel openers, we used CHO-K1 cells stably expressing human KCNQ4 channel protein and a thallium-sensitive dye based on the permeability of thallium through potassium channels. The electrophysiological and pharmacological properties of the cell line expressing the KCNQ4 protein were found to be in agreement with that reported elsewhere. The EC(50) values of the positive control compound (retigabine) determined by the thallium and (86)rubidium flux assays were comparable to and consistent with those documented in the literature. Signal-to-background (S/B) ratio and Z factor of the thallium influx assay system were assessed to be 8.82 and 0.63, respectively. In a large scale screening of 98,960 synthetic and natural compounds using the thallium influx assay, 76 compounds displayed consistent KCNQ4 activation, and of these 6 compounds demonstrated EC(50) values of less than 20 MUmol/L and 2 demonstrated EC(50) values of less than 1 MUmol/L. Taken together, the fluorescence-based thallium flux assay is a highly efficient, automatable, and robust tool to screen potential KCNQ4 openers. This approach may also be expanded to identify and evaluate potential modulators of other potassium channels. PMID- 21782780 TI - Annexin 1 released by necrotic human glioblastoma cells stimulates tumor cell growth through the formyl peptide receptor 1. AB - Highly malignant human gliomas overexpress the G-protein-coupled chemoattractant receptor formyl peptide receptor (FPR1), which promotes tumor progression when activated. Our previous studies demonstrated that necrotic glioblastoma cells release chemotactic agonist(s) that activate FPR1 on viable tumor cells. In the present study, we identified an FPR1 agonist released by necrotic human glioblastoma cells. Necrotic tumor cell supernatant (NecSup) contained Annexin 1 (Anx A1), a chemotatic polypeptide agonist for FPR1. Immunoabsorption of Anx A1 with a specific antibody markedly reduced the chemotactic activity of NecSup for tumor cells and diminished its capacity to promote tumor cell growth, invasion, and colony formation on soft agar. In addition, Anx A1 was present in tumor xenografts formed by human glioblastoma cells in nude mice. Anx A1 knockdown significantly reduced the tumorigenicity of glioblastoma cells in nude mice, but FPR1/Anx A1 double knockdown diminished tumor growth even further. The clinical relevance of Anx A1 in gliomas was supported by the observation that Anx A1 was more highly expressed in poorly differentiated human primary gliomas compared with lower grade tumors. Our study implicates Anx A1 as a major component in necrotic tumor cell-derived stimulants of the growth of glioblastoma via the activation of FPR1. PMID- 21782783 TI - Assessment of an ad hoc procedure for isolation and characterization of human albuminome. AB - The dynamic range of plasma protein abundance, ranging from milligrams to picograms per milliliter, makes characterization of this proteome nearly impossible with current analytical methods. Plasma preprocessing by high abundance protein depletion may concomitantly remove important diagnostic information. This article describes an original chromatographic procedure to isolate proteins bound to human serum albumin (HSA). Using HSA as an "affinity agent", we significantly improved the detection and identification of HSA ligands by two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS). Some of the characterized species were not previously reported in published blood databases. Albumin-binding proteins may be classified as belonging to several putative functional categories and span a wide variety of predicted physiological functions. PMID- 21782782 TI - Membrane inlet for mass spectrometric measurement of catalysis by enzymatic decarboxylases. AB - Membrane inlet mass spectrometry (MIMS) uses diffusion across a permeable membrane to detect in solution uncharged molecules of small molecular weight. We point out here the application of MIMS to determine catalytic properties of decarboxylases using as an example catalysis by oxalate decarboxylase (OxDC) from Bacillus subtilis. The decarboxylase activity generates carbon dioxide and formate from the nonoxidative reaction but is accompanied by a concomitant oxidase activity that consumes oxalate and oxygen and generates CO(2) and hydrogen peroxide. The application of MIMS in measuring catalysis by OxDC involves the real-time and continuous detection of oxygen and product CO(2) from the ion currents of their respective mass peaks. Steady-state catalytic constants for the decarboxylase activity obtained by measuring product CO(2) using MIMS are comparable to those acquired by the traditional endpoint assay based on the coupled reaction with formate dehydrogenase, and measuring consumption of O(2) using MIMS also estimates the oxidase activity. The use of isotope-labeled substrate ((13)C(2)-enriched oxalate) in MIMS provides a method to characterize the catalytic reaction in cell suspensions by detecting the mass peak for product (13)CO(2) (m/z 45), avoiding inaccuracies due to endogenous (12)CO(2). PMID- 21782784 TI - An in vitro coupled transcription/translation reporter system for hepatitis C virus RNA-dependent RNA polymerase. AB - Hepatitis C virus (HCV) NS5B, an RNA-dependent RNA polymerase (RdRp), is an attractive target for antiviral agents. The in vitro RNA synthesis system based on radioisotopic readout is commonly used for polymerase inhibitor screening; however, this system generates large amounts of radioactive waste and is not amenable to high-throughput applications. To overcome this limitation, we generated pFLuc-(-)UTRDeltaC-RLuc, a bicistronic reporter vector, which allows effective and sensitive distinction of RdRp activity by using a cell-free coupled transcription/translation system. This reporter construct comprises the firefly luciferase (FLuc) and the Renilla luciferase (RLuc) genes in reverse orientation flanked by the two negative strands of the HCV 5'- and 3'-untranslated regions in which FLuc and RLuc reporter proteins are regulated by bacteriophage T7 polymerase and NS5B polymerase, respectively. The increase in RLuc activity was proportional to the amount of active RdRp. This cell-free dual reporter system was further validated using specific RdRp inhibitors. Hence, linear dose-response curves between RLuc activity and specific inhibitors were obtained, as was faster drug screening through real-time measurement of chemiluminescence. Moreover, this reporter system is suitable for robust in vitro screening because of a statistically acceptable Z' factor value of 0.79 under the antiviral screening condition in the 96-well format. PMID- 21782785 TI - The Escherichia coli alkylation response protein AidB is a redox partner of flavodoxin and binds RNA and acyl carrier protein. AB - Microorganisms are exposed to a wide variety of exogenous and endogenous chemical agents that alkylate DNA. Escherichia coli cells exhibit an adaptive response that recognizes and repairs alkylated DNA lesions using Ada, AlkA, and AlkB enzymes. Another alkylation response protein, the DNA-binding flavoprotein AidB, was proposed to repair DNA or protect it from chemical alkylating agents, but direct evidence for its role is lacking. Here, AidB was shown to form tight complexes with both flavodoxin and acyl carrier protein. In addition, electron transfer between 1-electron and 2-electron reduced flavodoxin to oxidized AidB was observed, although with very small rate constants. AidB was found to bind to RNA, raising the prospect that the protein may have a role in protection of RNA from chemical alkylation. Finally, the reagent N-methyl-N'-nitro-N nitrosoguanidine was eliminated as a direct substrate of the enzyme. PMID- 21782786 TI - Different roles of the two components of human protein O-mannosyltransferase, POMT1 and POMT2. AB - Protein O-mannosyltransferase 1 (POMT1) and its homolog, POMT2, are responsible for the catalysis of the first step in O-mannosyl glycan synthesis. Mutations in their genes are associated with a type of congenital muscular dystrophy called Walker-Warburg syndrome. Arg(64), Glu(78) and Arg(138) in the N-terminus region of ScPmt1p, a POMT homolog in Saccharomyces cerevisiae, are important for transferase activity. Arg(138) is also essential for complex formation with ScPmt2p. Here we examined the effects of replacing the corresponding residues in human POMT1 and POMT2 with Ala on complex formation and enzymatic activity. The human POMT1 mutants lost almost all transferase activity while the POMT2 mutants retained enzymatic activity. Neither mutant lost its ability to form complexes with the native counter component. These results indicate that ScPmtps and human POMTs have different mechanisms of complex formation. They also suggest that human POMT1 and POMT2 have discrete functions since the effect of amino acid substitutions on enzymatic activity are different. PMID- 21782787 TI - Solution structure of a short-chain insecticidal toxin LaIT1 from the venom of scorpion Liocheles australasiae. AB - The solution structure of an insecticidal toxin LaIT1, a 36-residue peptide with a unique amino-acid sequence and two disulfide bonds, isolated from the venom of the scorpion Liocheles australasiae was determined by heteronuclear NMR spectroscopy. Structural similarity search showed that LaIT1 exhibits an inhibitory cystine knot (ICK)-like fold, which usually contains three or more disulfide bonds. Mutational analysis has revealed that two Arg residues of LaIT1, Arg(13) and Arg(15), play significant roles in insecticidal activity. PMID- 21782788 TI - Novel irreversible EGFR tyrosine kinase inhibitor 324674 sensitizes human colon carcinoma HT29 and SW480 cells to apoptosis by blocking the EGFR pathway. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is widely expressed in multiple solid tumors including colorectal cancer by promoting cancer cell growth and proliferation. Therefore, the inhibition of EGFR activity may establish a clinical strategy of cancer therapy. METHODS: In this study, using human colon adenocarcinoma HT29 and SW480 cells as research models, we compared the efficacy of four EGFR inhibitors in of EGFR-mediated pathways, including the novel irreversible inhibitor 324674, conventional reversible inhibitor AG1478, dual EGFR/HER2 inhibitor GW583340 and the pan-EGFR/ErbB2/ErbB4 inhibitor. Cell proliferation was assessed by MTT analysis, and apoptosis was evaluated by the Annexin-V binding assay. EGFR and its downstream signaling effectors were examined by western blotting analysis. RESULTS: Among the four inhibitors, the irreversible EGFR inhibitor 324674 was more potent at inhibiting HT29 and SW480 cell proliferation and was able to efficiently induce apoptosis at lower concentrations. Western blotting analysis revealed that AG1478, GW583340 and pan EGFR/ErbB2/ErbB4 inhibitors failed to suppress EGFR activation as well as the downstream mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR (AKT) pathways. In contrast, 324674 inhibited EGFR activation and the downstream AKT signaling pathway in a dose-dependent manner. CONCLUSION: Our studies indicated that the novel irreversible EGFR inhibitor 324674 may have a therapeutic application in colon cancer therapy. PMID- 21782789 TI - Palladin is a novel binding partner of ILKAP in eukaryotic cells. AB - Palladin was a novel binding partner of ILKAP in eukaryotic cells. Palladin's C terminal fragment including only its last three Ig domains (residues 710-1106) and the PP2C domain of ILKAP (residues 108-392) were necessary and sufficient for their interaction. The biological significance of the interaction between palladin and ILKAP was that palladin recruited the cytoplasmic ILKAP to initiate ILKAP-induced apoptosis. Our results suggested that palladin played a specific role in modulating the subcellular localization of the cytoplasmic ILKAP and promoting the ILKAP-induced apoptosis. PMID- 21782790 TI - Genetic-code evolution for protein synthesis with non-natural amino acids. AB - The genetic encoding of synthetic or "non-natural" amino acids promises to diversify the functions and structures of proteins. We applied rapid codon reassignment for creating Escherichia coli strains unable to terminate translation at the UAG "stop" triplet, but efficiently decoding it as various tyrosine and lysine derivatives. This complete change in the UAG meaning enabled protein synthesis with these non-natural molecules at multiple defined sites, in addition to the 20 canonical amino acids. UAG was also redefined in the E. coli BL21 strain, suitable for the large-scale production of recombinant proteins, and its cell extract served the cell-free synthesis of an epigenetic protein, histone H4, fully acetylated at four specific lysine sites. PMID- 21782791 TI - An ArsR-like transcriptional factor recognizes a conserved sequence motif and positively regulates the expression of phoP in mycobacteria. AB - Transcriptional regulation plays a critical role during the infection of Mycobacterium tuberculosis, the causative agent of tuberculosis. A two-component system, PhoPR, is clearly involved in the regulation of pathogenic virulence and persistence. However, the regulatory mechanism, as well as the regulator, of the phoPR operon remains uncharacterized in M. tuberculosis and its related species thus far. In the present study, we characterize an ArsR transcriptional factor, corresponding to Rv2034 and Ms6762 in M. tuberculosis and Mycobacterium smegmatis, respectively, as the first regulator of phoP in both mycobacterial species. The interaction between ArsR regulator and target promoters is conserved in these two mycobacterial species, and an inverted repeat sequence motif is successfully mapped out for the recognition of ArsR. Utilizing lacZ reporter genes and overexpression analysis, the ArsR regulator is shown to positively regulate the expression of phoP in M. smegmatis, different from most ArsR family regulators generally as a repressor. The current study establishes a direct link between the ArsR transcriptional factor and the regulation of phoP in mycobacteria. Our findings imply that ArsR may be involved in the pathogenesis of M. tuberculosis through its regulation of the phoPR operon. PMID- 21782792 TI - Mycobacterium tuberculosislpdC, Rv0462, induces dendritic cell maturation and Th1 polarization. AB - Mycobacterium tuberculosis, the etiological factor of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Activation of host immune responses for containment of mycobacterial infections involves participation of innate immune cells, such as dendritic cells (DCs). In this study, we demonstrated that the gene encoding lipoamide dehydrogenase C (lpdC) from M. tuberculosis, Rv0462, induce maturation and activation of DCs involved in the MAPKs signaling pathway. Moreover, Rv0462-treated DCs activated naive T cells, polarized CD4(+) and CD8(+) T cells to secrete IFN-gamma in syngeneic mixed lymphocyte reactions, which would be expected to contribute to Th1 polarization of the immune response. Our results suggest that Rv0462 can contribute to the innate and adaptive immune responses during tuberculosis infection, and thus modulate the clinical course of tuberculosis. PMID- 21782793 TI - Nuclear translocation of glutathione S-transferase pi is mediated by a non classical localization signal. AB - Glutathione S-transferase pi (GSTpi), a member of the GST family of multifunctional enzymes, is highly expressed in human placenta and involved in the protection of cellular components against electrophilic compounds or oxidative stress. We have recently found that GSTpi is expressed in the cytoplasm, mitochondria, and nucleus in some cancer cells, and that the nuclear expression of GSTpi appears to correlate with resistance to anti-cancer drugs. Although the mitochondrial targeting signal of GSTpi was previously identified in the amino-terminal region, the mechanism of nuclear translocation remains completely unknown. In this study, we find that the region of GSTpi195-208 is critical for nuclear translocation, which is mediated by a novel and non classical nuclear localization signal. In addition, using an in vitro transport assay, we demonstrate that the nuclear translocation of GSTpi depends on the cytosolic extract and ATP. Although further experiments are needed to understand in depth the precise mechanism of nuclear translocation of GSTpi, our results may help to establish more efficient anti-cancer therapy, especially with respect to resistance to anti-cancer drugs. PMID- 21782794 TI - Spleen tyrosine kinase suppresses osteoblastic differentiation through MAPK and PKCalpha. AB - Spleen tyrosine kinase (Syk) is a non-receptor protein kinase present in abundance in a wide range of hematopoietic cells. Syk reportedly plays a crucial role in immune signaling in B cells and cells bearing Fcgamma-activation receptors. The role of syk in osteoblastic differentiation has not been well elucidated. We report herein the role of syk in osteoblastic differentiation. We investigated the effects of two syk inhibitors on osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. Expression of syk was detected in these two cell lines. Two syk inhibitors stimulated mRNA expression of osteoblastic markers (ALP, Runx2, Osterix). Mineralization of extracellular matrix was also promoted by treatment with syk inhibitors. Knockdown of Syk caused increased mRNA expression of osteoblastic markers. In addition, syk inhibitor and knockdown of Syk suppressed phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase Calpha (PKCalpha). Our results indicate that syk might regulate osteoblastic differentiation through MAPK and PKCalpha. PMID- 21782795 TI - TGF-beta signals the formation of a unique NF1/Smad4-dependent transcription repressor-complex in human diploid fibroblasts. AB - We earlier reported the formation of a unique nuclear NF1/Smad complex in serum restricted fibroblasts that acts as an NF1-dependent repressor of the human adenine nucleotide translocase-2 gene (ANT2) [K. Luciakova, G. Kollarovic, P. Barath, B.D. Nelson, Growth-dependent repression of human adenine nucleotide translocator-2 (ANT2) transcription: evidence for the participation of Smad and Sp family proteins in the NF1-dependent repressor complex, Biochem. J. 412 (2008) 123-130]. In the present study, we show that TGF-beta, like serum-restriction: (a) induces the formation of NF1/Smad repressor complexes, (b) increases binding of the complexes to the repressor elements (Go elements) in the ANT2 promoter, and (c) inhibits ANT2 expression. Repression of ANT2 by TGF-beta is eliminated by mutating the NF1 binding sites in the Go repressor elements. All of the above responses to TGF-beta are prevented by inhibitors of TGF-beta RI and MAPK p38. These inhibitors also prevent NF1/Smad4 repressor complex formation and repression of ANT2 expression in serum-restricted cells, suggesting that similar signaling pathways are initiated by TGF-beta and serum-restriction. The present finding that NF1/Smad4 repressor complexes are formed through TGF-beta signaling pathways suggests a new, but much broader, role for these complexes in the initiation or maintenance of the growth-inhibited state. PMID- 21782796 TI - Differential expression of cellular microRNAs in HPV 11, -16, and -45 transfected cells. AB - Human papillomaviruses (HPVs) are highly prevalent giving rise to both benign and malignant lesions why they are classified as high- and low-risk viruses. In this study we selected one low-risk (HPV 11) and two high-risk (HPV 16 and -45) types for genomewide miRNA analysis to investigate possible common and distinct features in the expression profiles. For this purpose we developed a cell culture model system in HaCaT cells for expression of the viral genomes under standardized conditions. We identified 25 miRNAs which were differentially regulated in two or three HPV types where 13 miRNAs were in common for all three types. Among the miRNAs identified, miR-125a-5p, miR-129-3p, miR-363, and miR-145 are related to human cancers. Noteworthy, miR-145 is found upregulated in the miRNA profiles of both high-risk HPV types. For selected differentially expressed miRNAs in HPV 16 predicted miRNA target transcript involved in signal transduction, RNA splicing and tumor invasive growth were validated by qRT-PCR. In addition, our results imply that the early 3' untranslated region (3'UTR) of the three HPV genomes were not a target for miRNA regulation. PMID- 21782797 TI - SAP-like domain in nucleolar spindle associated protein mediates mitotic chromosome loading as well as interphase chromatin interaction. AB - Nucleolar spindle associated protein (NuSAP) is a microtubule-stabilizing protein that localizes to chromosome arms and chromosome-proximal microtubules during mitosis and to the nucleus, with enrichment in the nucleoli, during interphase. The critical function of NuSAP is underscored by the finding that its depletion in HeLa cells results in various mitotic defects. Moreover, NuSAP is found overexpressed in multiple cancers and its expression levels often correlate with the aggressiveness of cancer. Due to its localization on chromosome arms and combination of microtubule-stabilizing and DNA-binding properties, NuSAP takes a special place within the extensive group of spindle assembly factors. In this study, we identify a SAP-like domain that shows DNA binding in vitro with a preference for dsDNA. Deletion of the SAP-like domain abolishes chromosome arm binding of NuSAP during mitosis, but is not sufficient to abrogate its chromosome proximal localization after anaphase onset. Fluorescence recovery after photobleaching experiments revealed the highly dynamic nature of this NuSAP chromatin interaction during mitosis. In interphase cells, NuSAP also interacts with chromatin through its SAP-like domain, as evident from its enrichment on dense chromatin regions and intranuclear mobility, measured by fluorescence correlation spectroscopy. The obtained results are in agreement with a model where NuSAP dynamically stabilizes newly formed microtubules on mitotic chromosomes to enhance chromosome positioning without immobilizing these microtubules. Interphase NuSAP-chromatin interaction suggests additional functions for NuSAP, as recently identified for other nuclear spindle assembly factors with a role in gene expression or DNA damage response. PMID- 21782798 TI - Characterization of ADAM28 as a biomarker of bladder transitional cell carcinomas by urinary proteome analysis. AB - Human urine contains a large number of proteins and peptides (the urinary proteome). Global analysis of the human urinary proteome is important for understanding urinary tract diseases. Bladder cancer is the most common urological cancer with higher incidence rates in endemic areas of Blackfoot disease (BFD) in southern Taiwan. The aim of this study was to use the proteomic approach to establish urinary protein biomarkers of bladder cancer. ADAM28, identified by proteomic approaches and confirmed by Western blotting, showed significant differences compared with normal individuals, so it may be a biomarker of bladder cancer. PMID- 21782799 TI - In vitro and in vivo studies on antitumor effects of gossypol on human stomach adenocarcinoma (AGS) cell line and MNNG induced experimental gastric cancer. AB - The present study has evaluated the chemopreventive effects of gossypol on N methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and on human gastric adenocarcinoma (AGS) cell line. Gossypol, C(30)H(30)O(8), is a polyphenolic compound that has anti proliferative effect and induces apoptosis in various cancer cells. The aim of this work was to delineate in vivo and in vitro anti-initiating mechanisms of orally administered gossypol in target (stomach) tissues and in human gastric adenocarcinoma (AGS) cell line. In vitro results prove that gossypol has potent cytotoxic effect and inhibit the proliferation of adenocarcinoma (AGS) cell line. In vivo results prove gossypol to be successful in prolonging the survival of MNNG induced cancer bearing animals and in delaying the onset of tumor in animals administrated with gossypol and MNNG simultaneously. Examination of the target (stomach) tissues in sacrificed experimental animals shows that administration of gossypol significantly reduces the level of tumor marker enzyme (carcino embryonic antigen) and pepsin. The level of Nucleic acid contents (DNA and RNA) significantly reduces, and the membrane damage of glycoprotein subsides, in the target tissues of cancer bearing animals, with the administration of gossypol. These data suggest that gossypol may create a beneficial effect in patients with gastric cancer. PMID- 21782800 TI - A receptor-electromigration-based model for cellular electrotactic sensing and migration. AB - Directed cell migration in tissues mediates various physiological processes and is guided by complex cellular factors such as chemoattractant gradients and electric fields. Direct current (DC) electric fields can be generated in physiological settings and the electric field guided migration of various cell types (i.e., electrotaxis) has been demonstrated both in vitro and in vivo. Although several mechanisms have been proposed for electrotaxis, there are so far very few quantitative models. Furthermore, because chemoattractant gradients and electric fields co-exist in tissues, it is important to understand how chemotaxis and electrotaxis interact for mediating cell migration and trafficking. In this study, we developed a mathematical model to investigate the role of electromigration of cell surface chemoattractant receptors in mediating electrochemical sensing and migration of cells. Our results show that electromigration of chemoattractant receptors enables cell electrotactic sensing and migration in the presence of a uniform chemoattractant field. Furthermore, in the physiologically-relevant range of receptor electromigration rates, application of electric fields overcomes chemical guiding signals for directional sensing and migration of cells in co-existing competing electric fields and chemoattractant gradients. PMID- 21782801 TI - Degradation of the GAB1 adaptor by the ubiquitin-proteasome pathway hampers HGF/SF-MET signaling. AB - The GRB2 associated binder 1 (GAB1) is an essential docking/adaptor protein for transmitting intracellular signals of the MET tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). We found that in response to hours of HGF/SF treatment, the GAB1 protein level is degraded by a mechanism involving MET activity and the proteasomal machinery. We also showed that GAB1 is both multi- and poly-ubiquitinated in a CBL-dependent manner. A long term exposure to HGF/SF caused a more sustained down-regulation of GAB1 than of MET, associated with a loss of reactivation of the ERK MAP kinases to subsequent acute ligand treatment. These data demonstrate that GAB1 is ubiquitinated by CBL and degraded by the proteasome, and plays a role in negative-feedback regulation of HGF/SF-MET signaling. PMID- 21782802 TI - Erythropoietin, erythropoiesis and beyond. AB - Erythropoietin (EPO) is a glycoprotein that is mainly produced in the adult kidney, and it was initially highlighted for its action on the hematopoietic system. Moreover, EPO is also expressed in several non-hematopoietic tissues, where it plays a role in the protection from apoptosis and inflammation due to hypoxia, toxicity or injury. These protective effects are mainly known and studied in cardioprotection and neuroprotection but are also reported in retina degeneration, auditory injury and pancreatic-related diseases. The tissue protective effect of EPO is mainly mediated through the interaction with the heterodimeric receptor EPOR/betacR. Human recombinant EPO (HuREPO), which has been developed to treat anemia, is not adequate for tissue protection. The low affinity of the alternative receptor for EPO involves the injection of excessive concentration of erythropoiesis-stimulating agents (ESAs), implicating side effects due to the cross-talk with hematopoietic activity. For these reasons, EPO derivatives with less affinity for the EPO homodimeric receptor are under development. In this review, we provide an overview of the erythroid and non erythroid functions of EPO by detailing the molecular mechanisms activated by the binding of EPO to its receptors in different tissues. PMID- 21782804 TI - Low dose requirement for warfarin treatment in a patient with CYP2C9*3/*13 genotype. AB - BACKGROUND: Cytochrome P450 2C9 (CYP2C9) is the major isoform of the CYP2C subfamily, and is involved in the metabolism of many clinically important therapeutic agents. Here we describe a patient who was intolerant of warfarin treatment because of impaired drug metabolism related to the CYP2C9*3/*13 genotype and high warfarin sensitivity associated with the VKORC1 1173TT genotype. CASE: A 64-year-old Korean man had taken warfarin for treatment of an occluded left subclavian artery and atrial fibrillation. Although the warfarin doses prescribed were not high (14 mg/week) during the induction of anticoagulation, the prothrombin time (PT) was elevated to over 120 s after two weeks of warfarin therapy. For this patient, a very low dose of warfarin (4 mg/week) was required in order to achieve target INR values. CONCLUSIONS: To the best of our knowledge, this is the first report of a patient with CYP2C9*3/*13 and VKORC1 1173TT genotypes who had slower than normal warfarin metabolism, resulting in the need to administer an extremely low dose of warfarin in order to achieve the target INR value. Our report reinforces the relevance of pharmacogenetic testing to explain warfarin dose variability and to enable individualized dosage adjustments for improved warfarin treatment outcomes. PMID- 21782805 TI - Standardized detection of anti-ds DNA antibodies by indirect immunofluorescence - a new age for confirmatory tests in SLE diagnostics. PMID- 21782806 TI - Simulations of delta check rule performance to detect specimen mislabeling using historical laboratory data. AB - BACKGROUND: Despite their widespread use, the performance of delta check rules is rarely evaluated because errors are rare and lack a gold standard for detection. In this study we used a simulation-based approach to compare strategies for empirically defining criteria for univariate delta checks, and assessed the performance of these rules for detecting mislabeled specimens in 2 inpatient populations. METHODS: We performed simulations using historical laboratory test results by randomly sampling pairs of specimens successively drawn from the same patient or two different patients. We evaluated the performance of delta check rules using a variety of thresholds, including those currently in use in our laboratory. RESULT: Mean corpuscular volume had the highest positive predictive value for specimen mislabeling, and produced the fewest false positives. Conversely, rules using other laboratory tests had considerably poorer performance. Several of the "best guess" thresholds historically used in our laboratory, notably those for potassium and anion gap, were predicted to have extremely low yields. In addition, rule performance was not consistent between the two patient populations. CONCLUSIONS: The low yield of delta checks based on any single analyte should prompt careful evaluation of their practical utility. Furthermore, our results indicate that it may not be possible to generalize delta rules across institutions. PMID- 21782807 TI - Dyslipidemia in subclinical hypothyroidism in an Indian population. AB - OBJECTIVES: In view of inconsistent reports on the prevalence of dyslipidemia in subclinical hypothyroidism (SCH), we studied lipid abnormalities in Indian subjects with SCH. DESIGN AND METHODS: A cross sectional study of 5343 subjects divided in two groups, Group-1 (age<=18 years) and Group-2 (age>18 years) was undertaken. They were further subdivided on the basis of their thyroid functional status: Normal (Control); SCH with TSH<=10.0mIU/L (SCH-1); and SCH with TSH>10mIU/L (SCH-2). RESULTS: Prevalence of SCH was 14.7%. The only lipid abnormality in children and adolescents was low HDL in subjects with TSH>10mIU/L compared with controls. Serum total cholesterol (TC), and LDL cholesterol (LDL) were significantly higher in adults with TSH>10mIU/L compared to controls. There were no significant changes in lipid parameters in subjects with SCH having TSH<=10.0mIU/L, compared to controls. Serum TSH was positively and FT3 and FT4 were negatively correlated with TC and LDL. CONCLUSIONS: Atherogenic lipid abnormalities were observed in adult subjects with SCH-2 (TSH>10.0mIU/L), and not in subjects with SCH-1 who had TSH<=10.0mIU/L in Indian population. PMID- 21782808 TI - Hepatitis B virus large surface protein in serum as a candidate biomarker for evaluating hepatitis B virus infection. AB - AIM: To develop a sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of serum hepatitis B virus large surface protein (HBV-LP), and study the clinical value of HBV-LP. METHODS: Serum HBV-LP levels and a panel of other HBV markers were investigated in a large population of patients with chronic HBV. The clinical value of HBV-LP was evaluated by comparing the coincidence of detection of HBV markers and the change of serum HBV-LP level during antiviral therapy. RESULTS: The ELISA was found to be sensitive and specific for the detection of HBV-LP. Serum HBV-LP level was positively correlated with HBV DNA (r=0.743) in HBV patients. Among the five HBV markers tested, HBV-LP displayed the highest coincidence rate (94.7%) with HBV DNA. CONCLUSIONS: Serum HBV-LP was strongly correlated with HBV DNA. This ELISA therefore offers a promising approach for the diagnosis and treatment monitoring of HBV patients. PMID- 21782809 TI - Maternal Oct1/2 is required for Nodal and Vg1/Univin expression during dorsal ventral axis specification in the sea urchin embryo. AB - The TGFbeta family member Nodal is expressed early in the presumptive ventral ectoderm of the early sea urchin embryo and its activity is crucial for dorsal ventral (D/V) axis specification. Analysis of the nodal promoter identified a number of critical binding sites for transcription factors of different families including Sox, Oct, TCF and bZIP, but in most cases the specific factors that regulate nodal expression are not known. In this study, we report that the maternal factor Oct1/2 functions as a positive regulator of nodal and that its activity is essential for the initiation of nodal expression. Inhibition of Oct1/2 mRNA translation produced embryos with severe axial defects similar to those observed following inhibition of Nodal function. We show that perturbing Oct1/2 function specifically disrupted specification of the ventral and dorsal ectodermal regions and that these effects were caused by the failure of nodal to be expressed early in development. Furthermore, we identified the key gene vg1/univin, which is also necessary for nodal expression, as an additional factor that was completely dependent on Oct1/2 for its zygotic expression. These data demonstrate that the maternal Oct1/2 protein plays an early and essential role in D/V axis specification by initiating the expression of nodal and vg1/univin, two genes that act at the top of the D/V ectoderm gene regulatory network. PMID- 21782810 TI - Pabp binds to the osk 3'UTR and specifically contributes to osk mRNA stability and oocyte accumulation. AB - RNA localization is tightly coordinated with RNA stability and translation control. Bicaudal-D (Bic-D), Egalitarian (Egl), microtubules and their motors are part of a Drosophila transport machinery that localizes mRNAs to specific cellular regions during oogenesis and embryogenesis. We identified the Poly(A) binding protein (Pabp) as a protein that forms an RNA-dependent complex with Bic D in embryos and ovaries. pabp also interacts genetically with Bic-D and, similar to Bic-D, pabp is essential in the germline for oocyte growth and accumulation of osk mRNA in the oocyte. In the absence of pabp, reduced stability of osk mRNA and possibly also defects in osk mRNA transport prevent normal oocyte localization of osk mRNA. pabp also interacts genetically with osk and lack of one copy of pabp(+) causes osk to become haploinsufficient. Moreover, pointing to a poly(A) independent role, Pabp binds to A-rich sequences (ARS) in the osk 3'UTR and these turned out to be required in vivo for osk function during early oogenesis. This effect of pabp on osk mRNA is specific for this RNA and other tested mRNAs localizing to the oocyte are less and more indirectly affected by the lack of pabp. PMID- 21782803 TI - Mechanistic insights into nicotine withdrawal. AB - Smoking is responsible for over 400,000 premature deaths in the United States every year, making it the leading cause of preventable death. In addition, smoking-related illness leads to billions of dollars in healthcare expenditures and lost productivity annually. The public is increasingly aware that successfully abstaining from smoking at any age can add years to one's life and reduce many of the harmful effects of smoking. Although the majority of smokers desire to quit, only a small fraction of attempts to quit are actually successful. The symptoms associated with nicotine withdrawal are a primary deterrent to cessation and they need to be quelled to avoid early relapse. This review will focus on the neuroadaptations caused by chronic nicotine exposure and discuss how those changes lead to a withdrawal syndrome upon smoking cessation. Besides examining how nicotine usurps the endogenous reward system, we will discuss how the habenula is part of a circuit that plays a critical role in the aversive effects of high nicotine doses and nicotine withdrawal. We will also provide an updated summary of the role of various nicotinic receptor subtypes in the mechanisms of withdrawal. This growing knowledge provides mechanistic insights into current and future smoking cessation therapies. PMID- 21782811 TI - RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis. AB - Retinoic acid (atRA) signaling is essential for regulating embryonic development, and atRA levels must be tightly controlled in order to prevent congenital abnormalities and fetal death which can result from both excessive and insufficient atRA signaling. Cellular enzymes synthesize atRA from Vitamin A, which is obtained from dietary sources. Embryos express multiple enzymes that are biochemically capable of catalyzing the initial step of Vitamin A oxidation, but the precise contribution of these enzymes to embryonic atRA synthesis remains unknown. Using Rdh10(trex)-mutant embryos, dietary supplementation of retinaldehyde, and retinol dehydrogenase (RDH) activity assays, we demonstrate that RDH10 is the primary RDH responsible for the first step of embryonic Vitamin A oxidation. Moreover, we show that this initial step of atRA synthesis occurs predominantly in a membrane-bound cellular compartment, which prevents inhibition by the cytosolic cellular retinol-binding protein (RBP1). These studies reveal that widely expressed cytosolic enzymes with RDH activity play a very limited role in embryonic atRA synthesis under normal dietary conditions. This provides a breakthrough in understanding the precise cellular mechanisms that regulate Vitamin A metabolism and the synthesis of the essential embryonic regulatory molecule atRA. PMID- 21782812 TI - Toll-like receptor 4-mediated cAMP production up-regulates B-cell activating factor expression in Raw264.7 macrophages. AB - B-cell activating factor (BAFF) plays a role in the generation and the maintenance of mature B cells. Lipopolysaccharide (LPS) increased BAFF expression through the activation of toll-like receptor 4 (TLR4)-dependent signal transduction. Here, we investigated the mechanism of action on mouse BAFF (mBAFF) expression by cAMP production in Raw264.7 mouse macrophages. mBAFF expression was increased by the treatment with a cAMP analogue, dibutyryl-cAMP which is the activator of protein kinase A (PKA), cAMP effector protein. PKA activation was measured by the phosphorylation of cAMP-response element binding protein (CREB) on serine 133 (S133). cAMP production and CREB (S133) phosphorylation were augmented by LPS-stimulation. While mBAFF promoter activity was enhanced by the co-transfection with pS6-RSV-CREB, it was reduced by siRNA-CREB. PKA inhibitor, H 89, reduced CREB (S133) phosphorylation and mBAFF expression in control and LPS stimulated macrophages. Another principal cAMP effector protein is cAMP responsive guanine nucleotide exchange factor (Epac), a Rap GDP exchange factor. Epac was activated by the treatment with 8-(4-chloro-phenylthio)-2'-O methyladenosine-3',5'-cyclic monophosphate (CPT), Epac activator, as judged by the measurement of Rap1 activation. Basal level of mBAFF expression was increased by CPT treatment. LPS-stimulated mBAFF expression was also slightly enhanced by co-treatment with CPT. In addition, dibutyryl-cAMP and CPT enhanced mBAFF expression in bone marrow-derived macrophages (BMDM). With these data, it suggests that the activation of PKA and cAMP/Epac1/Rap1 pathways could be required for basal mBAFF expression, as well as being up-regulated in the TLR4 induced mBAFF expression. PMID- 21782813 TI - The in vivo anthelmintic efficacy of some Verbascum species growing in Turkey. AB - Verbascum L. (Scrophulariaceae) species are used for desiccating wounds and as a fish poison in Anatolia as well as for diarrhea and dysentery of animals in several countries. To further evaluate their activity, methanolic extracts obtained from 13 Verbascum species growing in Turkey, including V. chionophyllum Hub.-Mor., V. cilicicum Boiss., V. dudleyanum (Hub.-Mor.) Hub.-Mor., V. lasianthum Boiss., V. latisepalum Hub.-Mor., V. mucronatum Lam., V. olympicum Boiss., V. pterocalycinum var. mutense Hub.-Mor., V. pycnostachyum Boiss. & Heldr., V. salviifolium Boiss., V. splendidum Boiss., V. stachydifolium Boiss. & Heldr. and V. uschackense (Murb.) Hub.-Mor. were evaluated for their in vivo anthelmintic activity. The extracts from V. lasianthum, V. latisepalum, V. mucronatum and V. salviifolum showed the highest inhibitory rates against Aspiculuris tetraptera at 100mg/kg in mice. Additionally, extracts from V. dudleyanum and V. pterocalycinum var. mutense were found generally highly effective. The remaining species did not show any activity. Results of the present study support the utilization of these plant species employed in Turkish folk medicine. PMID- 21782814 TI - Hymenolepis diminuta: experimental studies on the antioxidant system with short and long term infection periods in the rats. AB - Many helminths cause long-lasting infections, living for several years in mammalian hosts reflecting a well balanced coexistence between host and parasite. There are many possible explanations as to how they can survive for lengthy periods. One possibility is their antioxidant systems, which can serve as defence mechanisms against host-generated oxygen radicals. Therefore, the aim of this experimental study was to examine the antioxidant system in Hymenolepisdiminuta during short (1.5 months young tapeworms) and long (1.5 years old tapeworms) term infection in the rat small intestine. The strobilae of H. diminuta tapeworms (14 young and three old) were divided into three pieces: the anterior part, containing the genital primordiae in the immature segments; the medial part, containing the early uterus in the mature, hermaphroditic proglottids and the terminal part with the mature gravid uterus in the gravid segments. Supernatants of these fragments were used for determination of markers of oxidative stress: concentration of thiobarbiturate reactive substances (TBARS) and of reduced glutathione (GSH), and the activity of antioxidant enzymes: superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidases (GSHPxs), glutathione transferase (GST) and glutathione reductase (GSHR). The results indicated changes in levels of oxidative stress markers and antioxidant enzyme activity in both the young and old forms of H. diminuta. Relatively high activity of SOD (particularly in the anterior part of young tapeworms) was observed, as was increased activity of total GSHPx and a relatively high concentration of GSH in all parts of the tapeworms. These are caused by exposure to increased amount of ROS, which are produced during the inflammatory state. Due to the high activity of antioxidant enzymes, the anterior section of young and old tapeworms is equipped with a very effective antioxidant system. Old organisms also effectively resist oxidative stress due to reduced levels of lipid peroxidation and the high activity of GST, all of which suggest good adaptation to the hostile environment in the host's intestine. PMID- 21782815 TI - Ligand entry pathways in the ligand binding domain of PPARgamma receptor. AB - To address the question of ligand entry process, we report targeted molecular dynamics simulations of the entry of the flexible ionic ligand GW0072 in the ligand binding domain of the nuclear receptor PPARgamma. Starting with the ligand outside the receptor the simulations led to a ligand docked inside the binding pocket resulting in a structure very close to the holo-form of the complex. The results showed that entry process is guided by hydrophobic interactions and that entry pathways are very similar to exit pathways. We suggest that TMD method may help in discriminating between ligands generated by in silico docking. PMID- 21782816 TI - Authorship: who should be included and how should it be determined? PMID- 21782818 TI - Stable expression and purification of a functional processed Fab' fragment from a single nascent polypeptide in CHO cells expressing the mCAT-1 retroviral receptor. AB - Monoclonal antibodies and derivative formats such as Fab' fragments are used in a broad range of therapeutic, diagnostic and research applications. New systems and methodologies that can improve the production of these proteins are consequently of much interest. Here we present a novel approach for the rapid production of processed Fab' fragments in a CHO cell line that has been engineered to express the mouse cationic amino acid transporter receptor 1 (mCAT-1). This facilitated the introduction of the target antibody gene through retroviral transfection, rapidly producing stable expression. Using this system, we designed a single retroviral vector construct for the expression of a target Fab' fragment as a single polypeptide with a furin cleavage site and a FMDV 2A self-cleaving peptide introduced to bridge the light and truncated heavy chain regions. The introduction of these cleavage motifs ensured equimolar expression and processing of the heavy and light domains as exemplified by the production of an active chimeric Fab' fragment against the Fas receptor, routinely expressed in 1-2mg/L yield in spinner-flask cell cultures. These results demonstrate that this method could have application in the facile production of bioactive Fab' fragments. PMID- 21782817 TI - Interaction of a Wolbachia WSP-like protein with a nuclear-encoded protein of Brugia malayi. AB - The Brugia malayi endosymbiont Wolbachia has recently been shown to be essential for its host's survival and development. However, relatively little is known about Wolbachia proteins that interact with the filarial host and which might be important in maintaining the obligate symbiotic relationship. The Wolbachia surface proteins (WSPs) are members of the outer membrane protein family and we hypothesise that they might be involved in the Wolbachia-Brugia symbiotic relationship. Notably, immunolocalisation studies of two WSP members, WSP-0432 and WSP-0284 in B. malayi female adult worms showed that the corresponding proteins are not only present on the surface of Wolbachia but also in the host tissues, with WSP-0284 more abundant in the cuticle, hypodermis and the nuclei within the embryos. These results confirmed that WSPs might be secreted by Wolbachia into the worm's tissue. Our present studies focus on the potential involvement of WSP-0284 in the symbiotic relationship of Wolbachia with its filarial host. We show that WSP-0284 binds specifically to B. malayi crude protein extracts. Furthermore, a fragment of the hypothetical B. malayi protein (Bm1_46455) was found to bind WSP-0284 by panning of a B. malayi cDNA library. The interaction of WSP-0284 and this protein was further confirmed by ELISA and pull-down assays. Localisation by immunoelectron microscopy within Wolbachia cells as well as in the worm's tissues, cuticle and nuclei within embryos established that both proteins are present in similar locations within the parasite and the bacteria. Identifying such specific interactions between B. malayi and Wolbachia proteins should lead to a better understanding of the molecular basis of the filarial nematode and Wolbachia symbiosis. PMID- 21782819 TI - Detection of cardiac myosin heavy chain-alpha-specific CD4 cells by using MHC class II/IA(k) tetramers in A/J mice. AB - A/J mice bearing the H-2 allele IA(k) are highly susceptible to autoimmune myocarditis induced with cardiac myosin heavy chain (Myhc)-alpha 334-352, whereas B10.A mice carrying a similar allele IA(k) are relatively resistant, suggesting that the generation of Myhc-alpha-reactive T cell repertoires is influenced by genetic background. To enumerate the precursor frequencies of Myhc-alpha-specific CD4 T cells, we sought to create IA(k) tetramers for Myhc-alpha 334-352. Tetramers were created using approaches that involve covalent tethering of individual peptide sequences or exogenous loading of peptides into empty IA(k) molecules by peptide-exchange reaction. Using ribonuclease 43-56 tetramers as controls, we demonstrated that by flow cytometry (FC), Myhc-alpha 334-352 tetramers specifically bind myosin-reactive T cells. CD4 cells isolated from A/J mice immunized with Myhc-alpha 334-352 were used to optimize conditions for tetramer staining, and neuraminidase treatment prior to tetramer staining permitted the detection of Myhc-alpha-specific cells ex vivo. The reagents are useful tools for monitoring the frequency of Myhc-alpha-reactive CD4 cells and to determine their pathogenic potential at a single cell level by FC. PMID- 21782821 TI - Screening of scFv-displaying phages recognizing distinct extracellular domains of EGF receptor by target-guided proximity labeling method. AB - We recently constructed the scFv-displaying phage library with extremely high repertoire and have successfully utilized for screening scFv antibodies against various proteins, polysaccharides and glyco-lipids. Here, we developed a new screening strategy to isolate scFv antibodies against cell surface EGF receptor (EGFR). For this, we applied two slightly different methods of "target-guided proximity labeling," such as Proximity selection (ProxiMol) method and a new sulfo-SBED labeling method with the aide of monoclonal anti-human EGFR antibody B4G7 as a guide molecule. ProxiMol method relies on the Biotin-labeling of scFv displaying phages that bound to the target in a vicinity of 100A from the guide molecule, whereas sulfo-SBED method transfers Biotin to scFv-displaying phages, which bound to the target in a distance of 20 A. After two rounds of panning on the EGFR-overexpressing A431 cells starting from approx. 1 * 1012 pfu, 47 each of Biotin-labeled scFv-displaying phages were recovered using Streptoavidin-coated magnetic beads, and among them total 11 scFv-phages were found to be definitely positive for binding to A431 cell surface by ELISA assay. Restriction mapping and sequencing analysis of these scFv-phage DNAs revealed that they encode 4 different scFv-nucleotide sequences in total. Immuno-fluorescent microscopy provided evidence that these 4 scFv antibodies bind specifically to EGFR on the A431 cells, showing slightly different staining patterns. Thus, "target-guided proximity labeling" methods were powerful for isolating scFv-displaying phages that recognize distinct extracellular domains of the target receptor. This novel screening strategy could be applicable to many other cell surface antigens and receptors. PMID- 21782820 TI - Dana-Farber repository for machine learning in immunology. AB - The immune system is characterized by high combinatorial complexity that necessitates the use of specialized computational tools for analysis of immunological data. Machine learning (ML) algorithms are used in combination with classical experimentation for the selection of vaccine targets and in computational simulations that reduce the number of necessary experiments. The development of ML algorithms requires standardized data sets, consistent measurement methods, and uniform scales. To bridge the gap between the immunology community and the ML community, we designed a repository for machine learning in immunology named Dana-Farber Repository for Machine Learning in Immunology (DFRMLI). This repository provides standardized data sets of HLA-binding peptides with all binding affinities mapped onto a common scale. It also provides a list of experimentally validated naturally processed T cell epitopes derived from tumor or virus antigens. The DFRMLI data were preprocessed and ensure consistency, comparability, detailed descriptions, and statistically meaningful sample sizes for peptides that bind to various HLA molecules. The repository is accessible at http://bio.dfci.harvard.edu/DFRMLI/. PMID- 21782822 TI - Phenotypic characterization and functional analysis of human tumor immune infiltration after mechanical and enzymatic disaggregation. AB - Multi-parametric flow cytometry analysis is a reliable method for phenotypic and functional characterization of tumor infiltrating immune cells (TIIC). The isolation of infiltrating leukocytes from solid tumors can be achieved through various methods which can be both enzymatic and mechanical; however, these methods may alter cell biology. The aim of this study was to compare the effects of three tissue disaggregation techniques on TIIC biology in breast, kidney and lung tumor specimens. We therefore compared two enzymatic treatments using either collagenase type IA alone or in combination with collagenase type IV and DNase I type II, and one mechanical system (MedimachineTM). We evaluated the impact of treatments on cell viability, surface marker integrity and proliferative capacity. We show that cell viability was not significantly altered by treatments. However, enzymatic treatments decreased cell proliferation; specifically collagenases and DNase provoked a significant decrease in detection of surface markers such as CD4, CD8, CD45RA and CD14, indicating that results of phenotypic studies employing these techniques could be affected. In conclusion, mechanical tissue disaggregation by MedimachineTM appears to be optimal to maintain phenotypic and functional TIIC features. PMID- 21782823 TI - EUVAC.NET collaborative study: evaluation and standardisation of serology for diagnosis of pertussis. AB - As part of the new EUVAC.NET contract with ECDC (Pertussis Work Area 4), a collaborative study was organised in July-December 2010. Two well-defined reference preparations with high and low IgG antibodies to pertussis toxin (PT), were sent to participants. The purposes of this study were to assess current laboratory performance of serological assays for pertussis; to compare in-house reference preparations that are currently used by participants for the serological assay; and to identify needs for standardisation of the serological assay. Reference Laboratories in Europe currently performing serological assays for the diagnosis of pertussis by measuring antibody to PT, were invited to participate in the study. A total of 17 laboratories/countries participated in this study. Results were reported from a total of 9 participants who used in house ELISA assays and 10 participants who used commercial kits. All participants using in-house ELISA with purified PT coating plates distinguished the 2 preparations and gave results that were comparable to the expected values. A total of 6 commercial kits included in the study showed different results. The kits coated with mixture antigens did not appear to be able to give results that were correlated to the WHO reference preparations. PMID- 21782824 TI - Planthopper "adaptation" to resistant rice varieties: changes in amino acid composition over time. AB - The brown planthopper, Nilaparvata lugens, shows considerable geographic and temporal variability in its response to varieties of cultivated rice. N. lugens has repeatedly "adapted" to resistant rice varieties; however, the physiological changes underlying planthopper adaptation are poorly understood. Endosymbionts within planthoppers, such as yeast-like endosymbionts (YLS) could play a role as they produce essential amino acids for planthoppers. We used a full factorial study to determine how natal rice variety, exposed rice variety, YLS presence, and the number of reared generations affected nymphal development, planthopper total nitrogen content, and planthopper hydrolyzed amino acid profiles. Nymphal development was strongly influenced by a four-way interaction between the exposed rice variety, natal rice variety, number of reared generations, and YLS presence. While symbiosis improved nymphal performance in the 8th generation, it appeared to be a drain on nymphs in the 11th generation, when the aposymbiotic nymphs actually showed higher performance than the symbiotic nymphs. This suggests that the symbiotic relationship may be acting beneficially in one generation while acting as a drain during another generation. Aposymbiotic planthoppers reared for 11 generations had a higher proportional concentration of rare amino acids than those reared for 8 generations, indicating that the planthopper itself appears to improve its ability to acquire rare amino acids. Therefore, the change in amino acid composition of planthoppers suggests an underlying change in protein expression or amino acid metabolism over time. PMID- 21782825 TI - Identification of the molecular origin and development of a panzootic caused by Beauveria bassiana in praying mantis populations in eastern China. AB - A panzootic in praying mantid species Tenodera sinensis and Statilia maculate, caused by Beauveria bassiana, occurred in north, southwest and southeast regions of Anhui Province, eastern China in Autumn, 2009. A 3-d principal component analysis (PCA) of 123 isolates from three sites revealed that the B. bassiana populations were heterogeneous with obvious dominance. Furthermore, the causal source of the panzootic in Anhui was shown to be polyphyletic. The populations were homogenized into homogenous subunits for investigation of genetic structure by inter-simple sequence repeat (ISSR) markers. Variance was greater than 70%, largely due to genetic differences within populations and subpopulations. Genetic distances and genetic differentiation were negatively associated with geographic distances and it was speculated that this was due to the effects of monsoons and topography. Mantid isolates were divided into five pathotypes based on a two-way cluster analysis of genetic distance. Pathotype I consisted of the predominant subpopulations of Huangcangyu and Chashui populations, with a genetic distance of 0.120 and gene flow up to 1.833. This pathotype caused a widespread epizootic in north and southwest Anhui, and Pathotype III caused enzootic at Site A in September and then epizootic in October, while the other three pathotypes caused enzootics at all three investigation sites. The widespread epizootics and isolated enzootics composed the polyphyletic panzootic in Anhui. A strong gene flow between isolates from the two mantid species was identified, resulting in negligible gene differentiation. This indicated a lack of host specificity in mantid isolates of B. bassiana. PMID- 21782826 TI - Combined growth factors enhanced angiogenic potential of cord blood-derived mononuclear cells transplanted to ischemic limbs. AB - Stem cell therapy has recently been limited by poor engraftment and the marginal influence of the administered cells. This study aimed to enhance the survival and angiogenic capacity of human umbilical cord blood (UCB)-derived mononuclear cells (MNCs) and to demonstrate their therapeutic effects on experimental ischemia. A specific culture medium containing five growth factors (Flt-3L, EGF, TPO, FGF and IGF-1) augmented cell proliferation, adhesion potential as well as stimulated MNCs to become progenitor-like cells. In addition, qRT-PCR demonstrated that MNCs cultured with these five growth factors (5f-MNCs) markedly up-regulated multiple angiogenic, arteriogenic and anti-apoptotic factors compared with uncultured MNCs. In an ischemic hindlimb model, the injection of 5f-MNCs prevented limb loss and augmented blood perfusion, capillary density, vascular maturation and angiogenic cytokines in the affected tissues. In addition, the 5f-MNCs exhibited an increased engraftment rate and an endothelial phenotype and stimulated angiogenic factors in ischemic hindlimbs as demonstrated by flow cytometric, immunohistochemical and qRT-PCR analyses. Taken together, these data suggest that 5f-MNCs could be used as a novel therapy for the treatment of ischemic cardiovascular disease due to their increased level of engraftment and angiogenic potential. PMID- 21782827 TI - Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology. AB - Compartmentation of signalling allows multiple stimuli to achieve diverse cellular responses with only a limited pool of second messengers. This spatial control of signalling is achieved, in part, by cellular structures which bring together elements of a particular cascade. One such structure is the caveola, a flask-shaped lipid raft. Caveolae are well-recognised as signalosomes, platforms for assembly of signalling complexes of receptors, effectors and their targets, which can facilitate efficient and specific cellular responses. Here we extend this simple model and present evidence to show how the protein and lipid profiles of caveolae, as well as their characteristic morphology, define their roles in creating local signalling domains in the cardiac myocyte. This article is part of a Special Issue entitled "Local Signaling in Myocytes." PMID- 21782829 TI - In vivo and in vitro analyses of toxic mutants of HET-s: FTIR antiparallel signature correlates with amyloid toxicity. AB - The folding and interactions of amyloid proteins are at the heart of the debate as to how these proteins may or may not become toxic to their host. Although little is known about this issue, the structure seems to be clearly involved with effects on molecular events. To understand how an amyloid may be toxic, we previously generated a yeast toxic amyloid (mutant 8) from the nontoxic HET s((218-289)) prion domain of Podospora anserina. Here, we performed a comprehensive structure-toxicity study by mutating individually each of the 10 mutations found in mutant 8. The study of the library of new mutants generated allowed us to establish a clear link between Fourier transform infrared antiparallel signature and amyloid toxicity. All of the mutants that form parallel beta-sheets are not toxic. Double mutations may be sufficient to shift a parallel structure to antiparallel amyloids, which are toxic to yeast. Our findings also suggest that the toxicity of antiparallel structured mutants may be linked to interaction with membranes. PMID- 21782828 TI - Conformation effects of base modification on the anticodon stem-loop of Bacillus subtilis tRNA(Tyr). AB - tRNA molecules contain 93 chemically unique nucleotide base modifications that expand the chemical and biophysical diversity of RNA and contribute to the overall fitness of the cell. Nucleotide modifications of tRNA confer fidelity and efficiency to translation and are important in tRNA-dependent RNA-mediated regulatory processes. The three-dimensional structure of the anticodon is crucial to tRNA-mRNA specificity, and the diverse modifications of nucleotide bases in the anticodon region modulate this specificity. We have determined the solution structures and thermodynamic properties of Bacillus subtilis tRNA(Tyr) anticodon arms containing the natural base modifications N(6)-dimethylallyl adenine (i(6)A(37)) and pseudouridine (psi(39)). UV melting and differential scanning calorimetry indicate that the modifications stabilize the stem and may enhance base stacking in the loop. The i(6)A(37) modification disrupts the hydrogen bond network of the unmodified anticodon loop including a C(32)-A(38)(+) base pair and an A(37)-U(33) base-base interaction. Although the i(6)A(37) modification increases the dynamic nature of the loop nucleotides, metal ion coordination reestablishes conformational homogeneity. Interestingly, the i(6)A(37) modification and Mg(2+) are sufficient to promote the U-turn fold of the anticodon loop of Escherichia coli tRNA(Phe), but these elements do not result in this signature feature of the anticodon loop in tRNA(Tyr). PMID- 21782830 TI - High-frequency electric field and radiation characteristics of cellular microtubule network. AB - Microtubules are important structures in the cytoskeleton, which organizes the cell. Since microtubules are electrically polar, certain microtubule normal vibration modes efficiently generate oscillating electric field. This oscillating field may be important for the intracellular organization and intercellular interaction. There are experiments which indicate electrodynamic activity of variety of cells in the frequency region from kHz to GHz, expecting the microtubules to be the source of this activity. In this paper, results from the calculation of intensity of electric field and of radiated electromagnetic power from the whole cellular microtubule network are presented. The subunits of microtubule (tubulin heterodimers) are approximated by elementary electric dipoles. Mechanical oscillation of microtubule is represented by the spatial function which modulates the dipole moment of subunits. The field around oscillating microtubules is calculated as a vector superposition of contributions from all modulated elementary electric dipoles which comprise the cellular microtubule network. The electromagnetic radiation and field characteristics of the whole cellular microtubule network have not been theoretically analyzed before. For the perspective experimental studies, the results indicate that macroscopic detection system (antenna) is not suitable for measurement of cellular electrodynamic activity in the radiofrequency region since the radiation rate from single cells is very low (lower than 10-20 W). Low noise nanoscopic detection methods with high spatial resolution which enable measurement in the cell vicinity are desirable in order to measure cellular electrodynamic activity reliably. PMID- 21782831 TI - How to asses, visualize and compare the anisotropy of linear structures reconstructed from optical sections--a study based on histopathological quantification of human brain microvessels. AB - Three-dimensional analyses of the spatial arrangement, spatial orientation and preferential directions of systems of fibers are frequent tasks in many scientific fields, including the textile industry, plant biology and tissue modeling. In biology, systems of oriented and branching lines are often used to represent the three-dimensional directionality and topology of microscopic blood vessels supplying various organs. In our study, we present a novel p(chi2) (chi square) method for evaluating the anisotropy of line systems that involves comparing the observed length densities of lines with the discrete uniform distribution of an isotropic line system with the chi2-test. Using this method in our open source software, we determined the rose of directions, preferential directions and level of anisotropy of linear systems representing the microscopic blood vessels in samples of various regions from human brains (cortex, subcortical gray matter and white matter). The novel method was compared with two other methods used for anisotropy quantification (ellipsoidal and fractional anisotropy). All three methods detected different levels of anisotropy of blood microvessels in human brain. The microvascular bed in the cortex was closer to an isotropic network, while the microvessels supplying the white matter appeared to be an anisotropic and direction-sensitive system. All three methods were able to determine the differences between various brain regions. The advantage of our p(chi2) method is its high correlation with the number of preferential directions of the line system. However, the software, named esofspy, is able to calculate all three of the measures of anisotropy compared and documented in this paper, thus making the methods freely available to the scientific community. PMID- 21782832 TI - Arsenicals affect base excision repair by several mechanisms. AB - Inorganic arsenic is a strong, widespread human carcinogen. How exactly inorganic arsenic exerts carcinogenicity in humans is as yet unclear, but it is thought to be closely related to its metabolism. At exposure-relevant concentrations arsenic is neither directly DNA reactive nor mutagenic. Thus, more likely epigenetic and indirect genotoxic effects, among others a modulation of the cellular DNA damage response and DNA repair, are important molecular mechanisms contributing to its carcinogenicity. In the present study, we investigated the impact of arsenic on several base excision repair (BER) key players in cultured human lung cells. For the first time gene expression, protein level and in case of human 8-oxoguanine DNA glycosylase 1 (hOGG1) protein function was examined in one study, comparing inorganic arsenite and its trivalent and pentavalent mono- and dimethylated metabolites, also taking into account their cellular bioavailability. Our data clearly show that arsenite and its metabolites can affect several cellular endpoints related to DNA repair. Thus, cellular OGG activity was most sensitively affected by dimethylarsinic acid (DMA(V)), DNA ligase IIIalpha (LIGIIIalpha) protein level by arsenite and X-ray cross complementing protein 1 (XRCC1 protein) content by monomethylarsonic acid (MMA(V)), with significant effects starting at >=3.2MUM cellular arsenic. With respect to MMA(V), to our knowledge these effects are the most sensitive endpoints, related to DNA damage response, that have been identified so far. In contrast to earlier nucleotide excision repair related studies, the trivalent methylated metabolites exerted strong effects on the investigated BER key players only at cytotoxic concentrations. In summary, our data point out that after mixed arsenic species exposure, a realistic scenario after oral inorganic arsenic intake in humans, DNA repair might be affected by different mechanisms and therefore very effectively, which might facilitate the carcinogenic process of inorganic arsenic. PMID- 21782833 TI - Pavlovian fear memory circuits and phenotype models of PTSD. AB - Pavlovian fear conditioning, also known as classical fear conditioning is an important model in the study of the neurobiology of normal and pathological fear. Progress in the neurobiology of Pavlovian fear also enhances our understanding of disorders such as posttraumatic stress disorder (PTSD) and with developing effective treatment strategies. Here we describe how Pavlovian fear conditioning is a key tool for understanding both the neurobiology of fear and the mechanisms underlying variations in fear memory strength observed across different phenotypes. First we discuss how Pavlovian fear models aspects of PTSD. Second, we describe the neural circuits of Pavlovian fear and the molecular mechanisms within these circuits that regulate fear memory. Finally, we show how fear memory strength is heritable; and describe genes which are specifically linked to both changes in Pavlovian fear behavior and to its underlying neural circuitry. These emerging data begin to define the essential genes, cells and circuits that contribute to normal and pathological fear. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21782835 TI - Somatosensory saccades reveal the timing of tactile spatial remapping. AB - Remapping tactile events from skin to external space is an essential process for human behaviour. It allows us to refer tactile sensations to their actual externally based location, by combining anatomically based somatosensory information with proprioceptive information about the current body posture. We examined the time course of tactile remapping by recording speeded saccadic responses to somatosensory stimuli delivered to the hands. We conducted two experiments in which arm posture varied (crossed or uncrossed), so that anatomical and external frames of reference were either put in spatial conflict or were aligned. The data showed that saccade onset latencies in the crossed hands conditions were slower than in the uncrossed hands condition, suggesting that, in the crossed hands condition, remapping had to be completed before a correct saccade could be executed. Saccades to tactile stimuli when the hands were crossed were sometimes initiated to the wrong direction and then corrected in-flight, resulting in a turn-around saccade. These turn-around saccades were more likely to occur in short-latency responses, compared to onset latencies of saccades that went straight to target. The latter suggests that participants were postponing their saccade until the time the tactile event was represented according to the current body posture. We propose that the difference between saccade onset latencies of crossed and uncrossed hand postures, and between the onset of a turn-around saccade and a straight saccade in the crossed hand posture, reveal the timing of tactile spatial remapping. PMID- 21782836 TI - Kindling of the lateral septum and the amygdala: effects on anxiety in rats. AB - Long-term kindling of limbic system structures may produce substantial changes in emotional behavior in rats. This study examined long-term changes in two kindled structures that have opposite effects on anxiety, the lateral septum and the central nucleus of the amygdala. The purpose of the experiment was to examine the specificity of the emotional effects of kindling by employing a double dissociation design. Animals were tested in two common animal models of anxiety, the water-lick conflict test and the elevated plus-maze. In the conflict test amygdala-kindled animals demonstrated a significant anxiolytic effect when compared with sham-kindled animals. This effect was potentiated by chlordiazepoxide. Septally-kindled animals exhibited a significant anticonflict effect when compared to sham-kindled animals in the first session. Septally kindled animals spent significantly more time on the open arms of the elevated plus-maze than did sham-kindled animals. Observed changes persisted 6weeks after the termination of 150 kindling sessions. The effects of long-term kindling were highly consistent with those of disruption rather than facilitation. PMID- 21782837 TI - Acquisition of steady-state operant behavior in long-living Ames Dwarf mice. AB - Ames dwarf mice have a Prop-1 mutation that has been identified with increased levels of IGF-I in the central nervous system, upregulation of neuroprotective systems, and increased lifespan. To elucidate the behavioral effects of the Prop 1 mutation, 8 Ames dwarf and 7 normal mice (all of whom were 8 months of age or younger) were compared on a differential-reinforcement-of-low-rate-of-responding schedule of reinforcement and a matching-to-sample task. On both tasks, nosepokes were reinforced with access to a saccharin solution. Comparisons were based on several measures of behavioral efficiency: pause durations, intertrial intervals, and numbers of responses. Ames dwarf mice were generally less efficient than normal mice. One possible cause of this outcome is that relatively young Ames dwarf mice show less cognitive development than age-matched normal mice. PMID- 21782834 TI - Stress modulation of drug self-administration: implications for addiction comorbidity with post-traumatic stress disorder. AB - Drug abuse and dependence present significant health burdens for our society, affecting roughly 10% of the population. Stress likely contributes to the development and persistence of drug use; for example, rates of substance dependence are elevated among individuals diagnosed with post-traumatic stress disorder (PTSD). Thus, understanding the interaction between stress and drug use, and associated neuroadaptations, is key for developing therapies to combat substance use disorders. For this purpose, many rodent models of the effects of stress exposure on substance use have been developed; the models can be classified according to three categories of stress exposure: developmental, adult nonsocial, and adult social. The present review addresses preclinical findings on the effect of each type of trauma on responses to and self-administration of drugs of abuse by focusing on a key exemplar for each category. In addition, the potential efficacy of targeting neuropeptide systems that have been implicated in stress responses and stress system neuroadaptation in order to treat comorbid PTSD and substance abuse will be discussed. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21782838 TI - Alternative markers for the long-term detection of oral testosterone misuse. AB - The screening of testosterone misuse in the doping control field is normally performed by the measurement of the ratio between the concentrations of testosterone and epitestosterone excreted as glucuronides (T/E). Despite the satisfactory results obtained with this approach, the measurement of T/E presents some limitations like the long-term detection of oral testosterone administration. Recently, several testosterone metabolites released after basic treatment of the urine have been reported (androsta-1,4-dien-3,17-dione, androsta 4,6-dien-3,17-dione, 17beta-hydroxy-androsta-4,6-dien-3-one and 15-androsten-3,17 dione). In the present work, the usefulness of these metabolites for the detection of oral testosterone misuse has been evaluated and compared with the conventional T/E measurement. For this purpose, 173 urine samples collected from healthy volunteers were analysed in order to obtain reference concentrations for the four metabolites released after alkaline treatment. On the other hand, urine samples collected from five volunteers before and after testosterone undecanoate administration were also analysed. Concentrations of androsta-4,6-dien-3,17-dione and 17beta-hydroxy-androsta-4,6-dien-3-one showed a similar behaviour as the T/E, allowing the detection of the misuse for several hours after administration. More promising results were obtained by quantifying androsta-1,4-dien-3,17-dione and 15-androsten-3,17-dione. The time in which the concentrations of these analytes could be differentiated from the basal level was between 3 and 6 times longer than the obtained with T/E, as a result, an improvement in the detection of testosterone abuse can be achieved. Moreover, several ratios between these compounds were evaluated. Some of them improved the detection of testosterone misuse when comparing with T/E. The best results were obtained with those ratios involving androsta-1,4-dien-3,17-dione. PMID- 21782839 TI - Priming of pop-out on multiple time scales during visual search. AB - When target-color repeats in pop-out visual search performance is faster than otherwise. While various characteristics of such priming of pop-out (PoP) are well known, relatively little is known about the temporal character of the memory traces underlying the effect. Recent findings on the perception of ambiguous stimuli show that the percept at any given moment is affected by perception over a long period, as well as by immediately preceding percepts. Intrigued by the existence of various parallels between this perceptual priming phenomenon and PoP, we here investigate whether similar multiplicity in timescales is seen for PoP. We contrasted long-term PoP build-up of a particular target color against shorter-term build-up for a different color. The priming effects from the two colors indeed reflect memory traces at different timescales: long-term priming build-up results in a more gradual decay than brief buildup, which is followed by faster decay. This is clearly demonstrated in Experiment 2 where sustained repetition of one target color is followed by a few repetitions of a second color. Following such a sequence, priming is initially stronger for the second target color, which was primed most recently; however, as more time passes longer term priming starts to dominate, resulting in better search performance for the first color later on. Our results suggest that priming effects in visual search contain both transient and more sustained components. Similarities between the time courses of attentional priming and perception of ambiguous stimuli are striking and suggest compelling avenues of further research into the relation between the two effects. PMID- 21782841 TI - Nicotine-induced plasma corticosterone is attenuated by social interactions in male and female adolescent rats. AB - Most smokers begin smoking during adolescence, a period during which social reward is highly influential. Initial exposure to nicotine can produce anxiogenic effects that may be influenced by social context. This study examined play behavior and plasma corticosterone following nicotine administration (0.6 mg/kg, s.c.) in both male and female adolescent (PND39) Sprague-Dawley rats in either isolate or social contexts. In blood samples collected immediately following the 15-min test session, nicotine increased plasma corticosterone relative to saline in both male and female isolate rats, but failed to do so in both males and females placed together in same-sex pairs. Nicotine also attenuated several indices of play behavior including nape attacks, pins and social contact. In isolate rats, nicotine selectively increased locomotor activity in females; however, when administered to social pairs, nicotine decreased locomotion in both sexes. These findings suggest that the presence of a social partner may decrease the initial negative, stress-activating effects of nicotine, perhaps leading to increased nicotine reward. PMID- 21782842 TI - Antidiabetic activity of levan polysaccharide in alloxan-induced diabetic rats. AB - This study aims to examine the effects of polysaccharide levan on oxidative stress and hyperglycemia in alloxan-induced diabetic rats. Levan, used in this study, was a microbial levan synthetisized by a non pathogenic bacteria recently isolated and identified as Bacillus licheniformis. Animals were allocated into four groups of six rats each: a control group (Control), diabetic group (Diab.), normal rats received levan (L) and diabetic rats fed with levan (DL). Treated diabetic rats were administrated with levan in drinking water through oral gavage for 60 days. The administration of polysaccharide levan in diabetic rats caused a significant increase in glycogen level by 52% and a decrease in glucose level in plasma by 52%. Similarly, the administration of polysaccharide levan in diabetic rats caused a decrease in the thiobarbituric acid-reactive substances (TBARS) by 31%, 41%, 39% and 25%, an increase in superoxide dismutase (SOD) by 40%, 50%, 44% and 34%, and in catalase (CAT) by 18%, 20%, 12% and 18% in liver, kidney, pancreas and heart, respectively. Furthermore, a significant decrease in hepatic and renal indices toxicity was observed, i.e. alkalines phosphatases (ALP), aspartate and lactate transaminases (AST and ALT) activities, total bilirubin, creatinine and urea levels by 19%, 31%, 32%, 36%, 37% and 23%, respectively. The results show that administration of polysaccharide levan can restore abnormal oxidative indice near normal levels. This study demonstrates, for the first time, that polysaccharide levan is efficient in inhibiting hyperglycemia and oxidative stress induced by diabetes and suggests that levan supplemented to diet may be helpful in preventing diabetic complications in adult rats. PMID- 21782840 TI - Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic beta cells. AB - Insulin secretion from pancreatic beta cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the beta cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP 1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating beta cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the beta cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2-mediated actions of GLP-1 to regulate ATP-sensitive K+ channels, voltage-dependent K+ channels, TRPM2 cation channels, intracellular Ca+ release channels, and Ca+-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM. PMID- 21782843 TI - Cationic lipid enhances assembly of bacterial cell division protein FtsZ: a possible role of bacterial membrane in FtsZ assembly dynamics. AB - The assembly of FtsZ plays an important role in bacterial cell division. Lipids in the bacterial cell membrane have been suggested to play a role in directing the site of FtsZ assembly. Using lipid monolayer and bilayer (liposome) systems, we directly examined the effects of cationic lipids on FtsZ assembly. We found that cationic lipids enhanced the assembly of FtsZ in association with an increase in the GTPase activity of FtsZ. The system consisting of lipid monolayer and bilayer (liposome) may mimic the bacterial membrane and therefore, the data might indicate the influence of bacterial membrane on the assembly of FtsZ protofilaments. PMID- 21782844 TI - Synthesis and characterization of pH-dependent glycol chitosan and dextran sulfate nanoparticles for effective brain cancer treatment. AB - A novel drug delivery system for the treatment of brain tumors was formulated by methotrexate (MTX)-loaded polymeric nanoparticles (NPs) based on Glycol chitosan (GCS) and Dextran sulfate (DS). The physicochemical properties of resulting particles were investigated, evidencing the contribution of these nanoparticles for brain targeting. In vitro release of MTX was also evaluated. The GCS-DS nanoparticles have been developed based on the modulation of ratio show promise as a system for controlled delivery of the drug to the brain. PMID- 21782845 TI - Stress and immune modulation in fish. AB - Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered. PMID- 21782846 TI - Brain regions with mirror properties: a meta-analysis of 125 human fMRI studies. AB - Mirror neurons in macaque area F5 fire when an animal performs an action, such as a mouth or limb movement, and also when the animal passively observes an identical or similar action performed by another individual. Brain-imaging studies in humans conducted over the last 20 years have repeatedly attempted to reveal analogous brain regions with mirror properties in humans, with broad and often speculative claims about their functional significance across a range of cognitive domains, from language to social cognition. Despite such concerted efforts, the likely neural substrates of these mirror regions have remained controversial, and indeed the very existence of a distinct subcategory of human neurons with mirroring properties has been questioned. Here we used activation likelihood estimation (ALE), to provide a quantitative index of the consistency of patterns of fMRI activity measured in human studies of action observation and action execution. From an initial sample of more than 300 published works, data from 125 papers met our strict inclusion and exclusion criteria. The analysis revealed 14 separate clusters in which activation has been consistently attributed to brain regions with mirror properties, encompassing 9 different Brodmann areas. These clusters were located in areas purported to show mirroring properties in the macaque, such as the inferior parietal lobule, inferior frontal gyrus and the adjacent ventral premotor cortex, but surprisingly also in regions such as the primary visual cortex, cerebellum and parts of the limbic system. Our findings suggest a core network of human brain regions that possess mirror properties associated with action observation and execution, with additional areas recruited during tasks that engage non-motor functions, such as auditory, somatosensory and affective components. PMID- 21782847 TI - Assessing nociceptive sensitivity in mouse models of inflammatory and neuropathic trigeminal pain. AB - Chronic orofacial pain encompasses a range of debilitating conditions, however in contrast to other body regions, few animal models are available to investigate mechanisms and treatments in the trigeminal area. Particularly, there is a lack of reliable models and testing methods in mice. We have behaviourally tested C57BL/6 mice subjected to unilateral chronic constriction injury (CCI) of the infraorbital nerve (IoN) or unilateral injections of Complete Freunds Adjuvant (CFA) into the vibrissal pad region with the aid of von Frey filaments and air puffs and the use of a newly designed restraining device. These models were validated by suppressing the pain responses with appropriate drugs. The IoN-CCI group showed significant hyperalgesia on the ipsilateral side in comparison to baseline values for up to 20 days post-CCI following von Frey and air-puff stimulation. Gabapentin (60mg/kg), but not saline, temporarily reversed the hyperalgesia. Animals that received a CFA injection showed hyperresponsivity to both von Frey and air-puff stimulation for up to 4 days post injection. These effects were transiently reversed with 3mg/kg i.p. morphine but not saline. Our study proposes a new restraining device for mice, and validates a behavioural testing procedure of several facial pain models in mice, allowing for reproducible and robust assessment of the effects of pain-related agents and treatments, or phenotyping of genetically modified animals. PMID- 21782848 TI - Structured multiplicity and confirmatory statistical analyses in pharmacodynamic studies using the quantitative electroencephalogram. AB - Pharmacodynamic (PD) clinical studies are characterised by a high degree of multiplicity. This multiplicity is the result of the design of these studies that typically investigate effects of a number of biomarkers at various doses and multiple time points. Measurements are taken at many or all points of a "hyper grid" that can be understood as the cross-product of a number of dimensions each of which has typically 3-30 discrete values. This exploratory design helps understanding the phenomena under investigation, but has made a confirmatory statistical analysis of these studies difficult, so that such an analysis is often missing in this type of studies. In this contribution we show that the cross-product structure of PD studies allows to combine several well-known techniques to address multiplicity in an effective way, so that a confirmatory analysis of these studies becomes feasible without unrealistic loss of power. We demonstrate the application of this technique in two studies that use the quantitative EEG (qEEG) as biomarker for drug activity at the GABA-A receptor. QEEG studies suffer particularly from the curse of multiplicity, since, in addition to the common dimensions like dose and time, the qEEG is measured at many locations over the scalp and in a number of frequency bands which inflate the multiplicity by a factor of about 250. PMID- 21782849 TI - The effects of motivation on response rate: a hidden semi-Markov model analysis of behavioral dynamics. AB - A central goal of neuroscience is to understand how neural dynamics bring about the dynamics of behavior. However, neural and behavioral measures are noisy, requiring averaging over trials and subjects. Unfortunately, averaging can obscure the very dynamics that we are interested in, masking abrupt changes and artificially creating gradual processes. We develop a hidden semi-Markov model for precisely characterizing dynamic processes and their alteration due to experimental manipulations. This method takes advantage of multiple trials and subjects without compromising the information available in individual events within a trial. We apply our model to studying the effects of motivation on response rates, analyzing data from hungry and sated rats trained to press a lever to obtain food rewards on a free-operant schedule. Our method can accurately account for punctate changes in the rate of responding and for sequential dependencies between responses. It is ideal for inferring the statistics of underlying response rates and the probability of switching from one response rate to another. Using the model, we show that hungry rats have more distinct behavioral states that are characterized by high rates of responding and they spend more time in these high-press-rate states. Moreover, hungry rats spend less time in, and have fewer distinct states that are characterized by a lack of responding (Waiting/Eating states). These results demonstrate the utility of our analysis method, and provide a precise quantification of the effects of motivation on response rates. PMID- 21782850 TI - Acute versus long-term effects of 6-hydroxydopamine on oxidative stress and dopamine depletion in the striatum of mice. AB - Oxidative stress is one of the mechanisms which may be important in the pathogenesis of Parkinson's disease. In the current study, the effects of 6 hydroxydopamine (6-OHDA) perfusion on hydroxyl radical formation in the mouse striatum were investigated using the in vivo salicylate trapping microdialysis technique. The latter uses salicylate as a trapping agent for hydroxyl radicals with formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), which is measured by HPLC. Two different approaches of the technique were validated in mice. First, perfusion of the trapping agent salicylate (1 mM) via the probe in combination with 6-OHDA (5 MUM) was used to screen for radical scavenging properties of compounds in mice. Alternatively, striatal administration of 6-OHDA in a concentration known to induce nigrostriatal denervation (1mM), without the trapping agent, allowed to maximally challenge the neuronal microenvironment and as such to investigate both its acute and long-term effects. In the first method, as expected, glutathione (GSH) (1.5 mM) prevented the 6-OHDA-induced increase in 2,3-DHBA levels. In the second method, GSH prevented the hydroxyl radical formation, while depletion of GSH with 2-cyclohexen-1-one (CHO) resulted in significantly higher 2,3-DHBA levels than when 6-OHDA was perfused alone. Three weeks after the local 6-OHDA perfusion, the total striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) content were reduced by 30%, compared to the intact striatum, accompanied by a reduction in striatal tyrosine hydroxylase (TH) immunoreactive (ir) nerve terminals. This suggests that the second method can be used to determine the acute as well as the long-term effects of 6-OHDA in the mouse striatum. PMID- 21782851 TI - Synergistic activity of baicalein with ribavirin against influenza A (H1N1) virus infections in cell culture and in mice. AB - Baicalein is a flavonoid derived from the root of Scutellaria baicalensis, a traditional Chinese medicine that has been used for hundreds of years; baicalein has also been demonstrated to have antiviral activity with low toxicity. The synergistic activity of baicalein with ribavirin against influenza virus infections in cell culture and in mice was investigated for the first time in our research. In vitro, maximal synergy at lower concentrations of baicalein (0.125 MUg/ml) and ribavirin (12.5 MUg/ml) was observed, and the reduced expression of the viral matrix protein (M) gene suggested that drug combinations caused greater inhibition than ribavirin alone, especially the combination of 0.5 MUg/ml baicalein and 5 MUg/ml ribavirin. In vivo, combinations of baicalein and ribavirin provided a higher survival rate and lower body weight loss. Moreover, fewer inflammatory responses in the lungs of mice infected with virus and treated with baicalein and ribavirin were observed; the mean scores were 1.0, 0.8, and 1.2 with the doses of ribavirin at 50 mg/kg/d combined with baicalein at 100 mg/kg/d, 200 mg/kg/d, and 400 mg/kg/d respectively, while the placebo group had a mean pathology score of 3.2. Thus, the data demonstrates that combinations of baicalein and ribavirin provide better protection against influenza infection than each compound used alone and could potentially be clinically useful. PMID- 21782852 TI - Antiviral Research, at its 30th anniversary, remembrances from its Editor-in Chief. PMID- 21782853 TI - Age increases anxiety and reactivity of the fear/anxiety circuit in Lewis rats. AB - A growing body of data indicates that changes in emotional behavior occur with age. Young Lewis rats are known to display hypofunction of the HPA axis. With age the reactivity of this axis is thought to increase with a concomitant rise in anxiety. In the current study, we investigate how and if the pattern of neuronal activation (measured as c-Fos protein expression) in Lewis rat brains changes with age and in response to novel environments differing in aversiveness. We found that distinct parts of the fear/anxiety circuit (i.e., the amygdalar complex, hippocampus and hypothalamus) undergo diverse age-related changes in response to behavioral challenges. While in the hypothalamus an increase in responsivity to mild stressors was observed with age, no such effect was present in the hippocampus. The amygdalar complex (especially the medial and cortical nuclei) on the other hand exhibited an age-dependent decrease in neuronal activation to mild stressors. This was accompanied by a marked increase in anxiety not correlated with a decline in locomotor activity. PMID- 21782854 TI - Different chronic ethanol exposure regimens in adolescent and adult male rats: effects on tolerance to ethanol-induced motor impairment. AB - Findings are mixed regarding the expression of tolerance after repeated ethanol exposure, perhaps in part due to dose/frequency variations in exposure regimens. The present study compared age-related differences in tolerance development following 10 days of 1g/kg twice daily, 2g/kg once daily, or intermittent 4g/kg ethanol exposure regimens. To measure expression of chronic tolerance and acute tolerance, ethanol-induced motor impairment was assessed on day 12, with functionally equivalent ethanol doses administered across age (2g/kg - adolescents; 1.5g/kg - adults). Subsequent challenge doses resulted in lower brain ethanol concentrations in both age groups as a function of the chronic ethanol regimens. Expected age-related differences emerged in acute tolerance expression in non-manipulated animals, with adolescents, but not adults showing acute tolerance. Regimens sufficient to induce alterations in ethanol metabolism did not result in chronic functional tolerance at either age, although chronic injections were sufficient to induce acute tolerance in adults. PMID- 21782855 TI - The enhanced host-cell permissiveness of human cytomegalovirus is mediated by the Ras signaling pathway. AB - Human cytomegalovirus utilizes cellular signal transduction pathways to activate viral or cellular transcription factors involved in the control of viral gene expression and DNA replication. In the present study, we demonstrate that Harvey ras-transformed cells show increased permissiveness to human cytomegalovirus when compared to their parental non-transformed cells. Both the progeny viral yield and the protein levels were elevated in the human cytomegalovirus-infected Harvey ras-transformed cells requiring active viral gene replication, as shown by the infection with UV-inactivated human cytomegalovirus. Inhibition of Ras or of key molecules of the Ras pathway, effectively suppressed viral infection in the Harvey-ras-transformed cells. On a cellular level, the human cytomegalovirus infected Harvey-ras-transformed cells formed larger cellular foci, which were significantly higher in number, compared to the uninfected cells and preferentially recruited human cytomegalovirus virions, thereby incriminating human cytomegalovirus infection for the increased transformation of these cells. Furthermore, proliferation assays revealed a higher rate for the human cytomegalovirus-infected Harvey-ras-transformed cells compared to mock-infected cells, whereas human cytomegalovirus infection had no considerable effect on the proliferation of the non-transformed cells. Higher susceptibility to apoptosis was also detected in the human cytomegalovirus-infected ras-transformed cells, which in combination with the higher progeny virus reveals a mode by which human cytomegalovirus achieves efficient spread of infection in the cells expressing the oncogenic Harvey-ras (12V) gene. Collectively, our data suggest that human cytomegalovirus employs the host-cell Ras signaling pathway to ensue viral expression and ultimately successful propagation. Transformed cells with an activated Ras signaling pathway are therefore particularly susceptible to human cytomegalovirus infection. PMID- 21782856 TI - Parcs/Gpn3 is required for the nuclear accumulation of RNA polymerase II. AB - Parcs/Gpn3 is a putative GTPase that is conserved in eukaryotic cells from yeast to humans, suggesting that it plays a fundamental, but still unknown, cellular function. Suppression of Parcs/Gpn3 expression by RNAi completely blocked cell proliferation in MCF-12A cells and other mammary epithelial cell lines. Unexpectedly, Parcs/Gpn3 knockdown had a more modest effect in the proliferation of the tumorigenic MDA-MB-231 and SK-BR3 cells. RNA polymerase II (RNAP II) co immunoprecipitated with Parcs/Gpn3. Parcs/Gpn3 depletion caused a reduction in overall RNA synthesis in MCF-12A cells but not in MDA-MB-231 cells, demonstrating a role for Parcs/Gpn3 in transcription, and pointing to a defect in RNA synthesis by RNAP II as the possible cause of halted proliferation. The absence of Parcs/Gpn3 in MCF-12A cells caused a dramatic change in the sub-cellular localization of Rpb1, the largest subunit of RNAP II. As expected, Rpb1 was present only in the nucleus of MCF-12A control cells, whereas in Parcs/Gpn3 depleted MCF-12A cells, Rpb1 was detected exclusively in the cytoplasm. This effect was specific, as histones remained nuclear independently of Parcs/Gpn3. Rpb1 protein levels were markedly increased in Parcs/Gpn3-depleted MCF-12A cells. Interestingly, Rpb1 distribution was only marginally affected after knocking-down Parcs/Gpn3 in MDA-MB-231 cells. In conclusion, we report here, for the first time, that Parcs/Gpn3 plays a critical role in the nuclear accumulation of RNAP II, and we propose that this function explains the relative importance of Parcs/Gpn3 in cell proliferation. Intriguingly, at least some tumorigenic mammary cells have evolved mechanisms that allow them to proliferate in a Parcs/Gpn3 independent manner. PMID- 21782858 TI - Assessing the roles of presynaptic ryanodine receptors and adenosine receptors in caffeine-induced enhancement of hippocampal mossy fiber transmission. AB - Caffeine robustly enhances transmitter release from the hippocampal mossy fiber terminals, although it remains uncertain whether calcium mobilization through presynaptic ryanodine receptors mediates this enhancement. In this study, we adopted a selective adenosine A1 blocker to assess relative contribution of A1 receptors and ryanodine receptors in caffeine-induced synaptic enhancement. Application of caffeine further enhanced transmission at the hippocampal mossy fiber synapse even after full blockade of adenosine A1 receptors. This result suggests that caffeine enhances mossy fiber synaptic transmission by two distinct presynaptic mechanisms, i.e., removal of A1 receptor-mediated tonic inhibition and ryanodine receptor-mediated calcium release from intracellular stores. PMID- 21782857 TI - PLTP regulates STAT3 and NFkappaB in differentiated THP1 cells and human monocyte derived macrophages. AB - Phospholipid transfer protein (PLTP) plays an important role in regulation of inflammation. Previously published studies have shown that PLTP binds, transfers and neutralizes bacterial lipopolysaccharides. In the current study we tested the hypothesis that PLTP can also regulate anti-inflammatory pathways in macrophages. Incubation of macrophage-like differentiated THP1 cells and human monocyte derived macrophages with wild-type PLTP in the presence or absence of tumor necrosis factor alpha (TNFalpha) or interferon gamma (IFNgamma) significantly increased nuclear levels of active signal transducer and activator of transcription 3, pSTAT3(Tyr705) (p<0.01). Similar results were obtained in the presence of a PLTP mutant without lipid transfer activity (PLTP(M159E)), suggesting that PLTP-mediated lipid transfer is not required for activation of the STAT3 pathway. Inhibition of ABCA1 by chemical inhibitor, glyburide, as well as ABCA1 RNA inhibition, reversed the observed PLTP-mediated activation of STAT3. In addition, PLTP reduced nuclear levels of active nuclear factor kappa-B (NFkappaB) p65 and secretion of pro-inflammatory cytokines in conditioned media of differentiated THP1 cells and human monocyte-derived macrophages. Our data suggest that PLTP has anti-inflammatory capabilities in macrophages. PMID- 21782859 TI - Deletion of cscR in Escherichia coli W improves growth and poly-3-hydroxybutyrate (PHB) production from sucrose in fed batch culture. AB - Sucrose has several advantages over glucose as a feedstock for bioprocesses, both environmentally and economically. However, most industrial Escherichia coli strains are unable to utilize sucrose. E. coli W can grow on sucrose but stops growing when sucrose concentrations become low. This is undesirable in fed-batch conditions where sugar levels are low between feeding pulses. Sucrose uptake rates were improved by removal of the cscR gene, which encodes a protein that represses expression of the sucrose utilization genes at low sucrose concentrations. Poly-3-hydroxybutyrate (PHB) was used as a model compound in order to assess the effect of improved sugar utilization on bio-production. In the cscR knockout strain, production from sucrose was improved by 50%; this strain also produced 30% more PHB than the wild-type using glucose. This result demonstrates the feasibility of utilizing sucrose as an industrial feedstock for E. coli-based bioprocesses in high cell density culture. PMID- 21782860 TI - The pathogenic and vaccine strains of equine infectious anemia virus differentially induce cytokine and chemokine expression and apoptosis in macrophages. AB - The attenuated equine infectious anemia virus (EIAV) vaccine was the first attenuated lentivirus vaccine to be used in a large-scale application and has been used to successfully control the spread of equine infectious anemia (EIA) in China. To better understand the potential role of cytokines in the pathogenesis of EIAV infection and resulting immune response, we used branched DNA technology to compare the mRNA expression levels of 12 cytokines and chemokines, including IL-1alpha, IL-1beta, IL-4, IL-10, TNF-alpha, IFN-gamma, IP-10, IL-8, MIP-1alpha, MIP-1beta, MCP-1, and MCP-2, in equine monocyte-derived macrophages (eMDMs) infected with the EIAV(DLV121) vaccine strain or the parental EIAV(DLV34) pathogenic strain. Infection with EIAV(DLV34) and EIAV(DLV121) both caused changes in the mRNA levels of various cytokines and chemokines in eMDMs. In the early stage of infection with EIAV(DLV34) (0-24h), the expression of the pro inflammatory cytokines TNF-alpha and IL-1beta were significantly up-regulated, while with EIAV(DLV121), expression of the anti-inflammatory cytokine IL-4 was markedly up-regulated. The effects on the expression of other cytokines and chemokines were similar between these two strains of virus. During the first 4 days after infection, the expression level of IL-4 in cells infected with the pathogenic strain were significantly higher than that in cells infected with the vaccine strain, but the expression of IL-1alpha and IL-1beta induced by the vaccine strain was significantly higher than that observed with the pathogenic strain. In addition, after 4 days of infection with the pathogenic strain, the expression levels of 5 chemokines, but not IP-10, were markedly increased in eMDMs. In contrast, the vaccine strain did not up-regulate these chemokines to this level. Contrary to our expectation, induced apoptosis in eMDMs infected with the vaccine strain was significantly higher than that infected with the pathogenic strain 4 days and 6 days after infection. Together, these results contribute to a greater understanding of the pathogenesis of EIAV and of the mechanisms by which the immune response is induced after EIAV infection. PMID- 21782861 TI - Hepatitis E viruses. Foreword. PMID- 21782862 TI - Genetic characterization and pathogenicity assessment of highly pathogenic H5N1 avian influenza viruses isolated from migratory wild birds in 2011, South Korea. AB - The continued spread of a highly pathogenic avian influenza (HPAI) H5N1 virus among wild birds and poultry has posed a potential threat to human public health. In the present study, we report the isolation of HPAI H5N1 viruses (A/Md/Korea/W401/11 and A/Md/Korea/W404/11) from fecal samples of migratory birds. Genetic and phlyogenetic analyses demonstrated that these viruses are genetically identical possessing gene segments from avian virus origin and showing highest sequence similarities (as high as 99.8%) to A/Ws/Hokkaido/4/11 and 2009-2010 Mongolian-like clade 2.3.2 isolates rather than previous Korean H5N1 viruses. Both viruses possess the polybasic motif (QRERRRK/R) in HA but other genes did not bear additional virulence markers. Pathogenicity of A/Md/Korea/W401/11 was assessed and compared with a 2006 clade 2.2 HPAI H5N1 migratory bird isolate (A/EM/Korea/W149/06) in chickens, ducks, mice and ferrets. Experimental infection in these hosts showed that both viruses have high pathogenic potential in chickens (2.3-3.0 LD(50)s) and mice (3.3-3.9 LD(50)s), but A/Md/Korea/W401/11 was less pathogenic in duck and ferret models. Despite recovery of both infection viruses in the upper respiratory tract, efficient ferret-to-ferret transmission was not observed. These data suggest that the 2011 Korean HPAI wild bird H5N1 virus could replicate in mammalian hosts without pre adaptation but could not sustain subsequent infection. This study highlights the role of migratory birds in the perpetuation and spread of HPAI H5N1 viruses in Far-East Asia. With the changing pathobiology caused by H5N1 viruses among wild and poultry birds, continued surveillance of influenza viruses among migratory bird species remains crucial for effective monitoring of high-pathogenicity or pandemic influenza viruses. PMID- 21782864 TI - Role of boronic acid moieties in poly(amido amine)s for gene delivery. AB - The effects of the presence of two different types of phenylboronic acids as side groups in disulfide-containing poly(amido amine)s (SS-PAA) were investigated in the application of these polymers as gene delivery vectors. To this purpose, a para-carboxyphenylboronic acid was grafted on a SS-PAA with pending aminobutyl side chains, resulting in p(DAB-4CPBA) and an ortho-aminomethylphenylboronic acid was incorporated through copolymerization, resulting in p(DAB-2AMPBA). Both polymers have 30% of phenylboronic acid side chains and 70% of residual aminobutyl side chains and were compared with the non-boronated benzoylated analogue p(DAB-Bz) of similar M(w). It was found that the presence of phenylboronic acid moieties improved polyplex formation with plasmid DNA since smaller and more monodisperse polyplexes were formed as compared to their non boronated counterparts. The transfection efficiency of polyplexes of p(DAB-4CPBA) was approximately similar to that of p(DAB-Bz) and commercial PEI (Exgen), both in the absence and the presence of serum, indicating that p(DAB-4CPBA) and p(DAB Bz) are potent gene delivery vectors. However, the polymers with phenylboronic acid functionalities showed increased cytotoxicity, which is stronger for the ortho-aminophenylboronic acid containing polyplexes of p(DAB-2AMPBA) than for the p(DAB-4CPBA) analog. The cytotoxic effect may be caused by increased membrane disruptive interaction as was indicated by the increased hemolytic activity observed for these polymers. PMID- 21782863 TI - HPMA-oligolysine copolymers for gene delivery: optimization of peptide length and polymer molecular weight. AB - Polycations are one of the most frequently used classes of materials for non viral gene transfer in vivo. Several studies have demonstrated a sensitive relationship between polymer structure and delivery activity. In this work, we used reverse addition-fragmentation chain transfer (RAFT) polymerization to build a panel of N-(2-hydroxypropyl)methacrylamide (HPMA)-oligolysine copolymers with varying peptide length and polymer molecular weight. The panel was screened for optimal DNA-binding, colloidal stability in salt, high transfection efficiency, and low cytotoxicity. Increasing polyplex stability in PBS correlated with increasing polymer molecular weight and decreasing peptide length. Copolymers containing K(5) and K(10) oligocations transfected cultured cells with significantly higher efficiencies than copolymers of K(15). Four HPMA-oligolysine copolymers were identified that met the desired criteria. Polyplexes formed with these copolymers demonstrated both salt stability and transfection efficiencies on-par with poly(ethylenimine) PEI in cultured cells. PMID- 21782865 TI - WITHDRAWN: Inorganic nanoparticles for cancer imaging and therapy. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jconrel.2011.07.005. The duplicate article has therefore been withdrawn. PMID- 21782866 TI - Drug-lactose binding aspects in adhesive mixtures: controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces. AB - For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations. PMID- 21782867 TI - Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling. AB - Embryonic stem cells (ESCs) are a useful source for various cell lineages. So far, however, progress toward reconstitution of mature liver morphology and function has been limited. We have shown that knockout mice deficient in adrenomedullin (AM), a multifunctional endogenous peptide, or its receptor activity modifying protein (RAMP2) die in utero due to poor vascular development and hemorrhage within the liver. In this study, using embryoid bodies (EBs) culture system, we successfully induced liver sinusoidal endothelial-like cells by modulation of AM-RAMP2. In an EB differentiation system, we found that co administration of AM and SB431542, an inhibitor of transforming growth factor beta (TGFbeta) receptor type 1, markedly enhanced differentiation of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)/stabilin-2-positive endothelial cells. These cells showed robust endocytosis of acetylated low-density lipoprotein (Ac-LDL) and upregulated expression of liver sinusoidal endothelial cells (LSECs)-specific markers, including factor 8 (F8), Fc-gamma receptor 2b (Fcgr2b), and mannose receptor C type 1 (Mrc1), and also possessed fenestrae-like structure, a key morphological feature of LSECs. In RAMP2-null liver, by contrast, LYVE-1 was downregulated in LSECs, and the sinusoidal structure was disrupted. Our findings highlight the importance of AM-RAMP2 signaling for development of LSECs. PMID- 21782869 TI - Lipopolysaccharide increases gastric and circulating NUCB2/nesfatin-1 concentrations in rats. AB - Bacterial lipopolysaccharide (LPS) is an established animal model to study the innate immune response to Gram-negative bacteria mimicking symptoms of infection including reduction of food intake. LPS decreases acyl ghrelin associated with decreased concentrations of circulating ghrelin-O-acyltransferase (GOAT) likely contributing to the anorexigenic effect. We also recently described the prominent expression of the novel anorexigenic hormone, nucleobindin2 (NUCB2)/nesfatin-1 in gastric X/A-like cells co-localized with ghrelin in different pools of vesicles. To investigate whether LPS would affect gastric and circulating NUCB2/nesfatin-1 concentration, ad libitum fed rats were equipped with an intravenous (iv) catheter. LPS was injected intraperitoneally (ip, 100MUg/kg) and blood was withdrawn before and at 2, 5, 7 and 24h post injection and processed for NUCB2/nesfatin-1 radioimmunoassay. Gastric corpus was collected to measure NUCB2 mRNA expression by RT-qPCR and NUCB2/nesfatin-1 protein concentration by Western blot. Injection of LPS increased plasma NUCB2/nesfatin-1 concentrations by 43%, 78% and 62% compared to vehicle at 2h, 5h and 7h post injection respectively (p<0.05) and returned to baseline at 24h. The plasma NUCB2/nesfatin-1 increase at 2h was associated with increased corpus NUCB2 mRNA expression (p<0.01), whereas NUCB2 mRNA was not detectable in white blood cells. Likewise, gastric NUCB2 protein concentration was increased by 62% after LPS compared to vehicle (p<0.01). These data show that gastric NUCB2 production and release are increased in response to LPS. These changes are opposite to those of ghrelin in response to LPS supporting a differential gastric regulation of NUCB2/nesfatin-1 and ghrelin expression derived from the same cell by immune challenge. PMID- 21782870 TI - Plantaricin A synthesized by Lactobacillus plantarum induces in vitro proliferation and migration of human keratinocytes and increases the expression of TGF-beta1, FGF7, VEGF-A and IL-8 genes. AB - This work showed the effect of pheromone plantaricin A (PlnA) on the proliferation and migration of the human keratinocytes NCTC 2544. PlnA was chemically synthesized and used as pure peptide or biologically synthesized during co-cultivation of Lactobacillus plantarum DC400 and Lactobacillus sanfranciscensis DPPMA174. The cell-free supernatant (CFS) was used as the crude preparation containing PlnA. The inductive effect of PlnA on the proliferation of NCTC 2544 cells was higher than that found for hyaluronic acid, a well known skin protective compound. As shown by scratch assay and image analyses, PlnA enhanced the migration of NCTC 2544 cells. Compared to the basal serum free medium (control), the highest inductive effect was found using 10MUg/ml of chemically synthesized PlnA. Similar results (P>0.05) were found for CFS. In agreement, the percentage of the starting scratch area was decreased after treatment (24h) with PlnA. The expression of transforming growth factor-beta1 (TGF-beta1), keratinocyte growth factor 7 (FGF7), vascular endothelial growth factor (VEGF-A), and interleukin-8 (IL-8) genes was affected by PlnA. Compared to control, TGF beta1 gene was under expressed in the first 4h of treatments and up-regulated after 8-24h. On the contrary, FGF7 gene was strongly up-regulated in the first 4h of treatments. Compared to control, VEGF-A and IL-8 genes were always up regulated during the 4-24h from scratching. Since capable of promoting the proliferation and migration of the human keratinocytes and of stimulating IL-8 cytokine, the use of PlnA for dermatological purposes should be considered. PMID- 21782868 TI - Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications. AB - Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, ghrelin-O acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, acute fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of ghrelin under these various stress conditions are still largely to be defined and may relate to stress associated autonomic changes. There is evidence that alterations of circulating ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of ghrelin signaling that may improve food intake and gastric motility alterations induced by stress. PMID- 21782871 TI - Sera from amyotrophic lateral sclerosis patients induce the non-canonical activation of NMDA receptors "in vitro". AB - Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the selective loss of both upper and lower motoneurons (MNs). The familial form of the illness is associated with mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD-1) enzyme, but it accounts for fewer than 10% of cases; the rest, more than 90%, correspond to the sporadic form of ALS. Although many proposals have been suggested over the years, the mechanisms underlying the characteristic selective killing of MN in ALS remain unknown. In this study we tested the effect of sera from sporadic ALS patients on NMDA receptors (NMDAR). We hypothesize that an endogenous seric factor is implicated in neuronal death in ALS, mediated by the modulation of NMDAR. Sera from ALS patients and from healthy subjects were pretreated to inactivate complement pathways and dialyzed to remove glutamate and glycine. IgGs from ALS patients and healthy subjects were obtained by affinity chromatography and dialyzed against phosphate-buffered saline. Human NMDAR were expressed in Xenopus laevis oocytes, and ionic currents were recorded using the two-electrode voltage clamp technique. Sera from sporadic ALS patients induced transient oscillatory currents in oocytes expressing NMDAR with a significantly higher total electrical charge than that induced by sera from healthy subjects. Sera from patients with other neuromuscular diseases did not exert this effect. The currents were inhibited by MK-801, a noncompetitive blocker of NMDAR. The PLC inhibitor, U-73122, and the IP(3) receptor antagonist, 2-APB, also inhibited the sera-induced currents. The oscillatory signal recorded was due to internal calcium mobilization. Isolated IgGs from ALS patients significantly affected the activity of oocytes injected with NMDAR, causing a 2 fold increase over the response recorded for IgGs from healthy subjects. Our data support the notion that ALS sera contain soluble factors that mobilize intracellular calcium, not opening directly the ionic conductance, but through the non-canonical activation of NMDAR. PMID- 21782872 TI - The COX-2 gene promoter polymorphism -765 delays CD4 T-cell reconstitution after lymphocyte depletion with antithymocyte globulins. AB - Polyclonal antithymocyte globulins (ATG) induce persistent changes in T lymphocyte subsets characterized by low CD4 T. The mechanisms remain partly unknown. Prostaglandin E(2) (PGE(2)) is involved in lymphocyte homeostasis. Whether PGE(2) may be involved in persistent CD4 T-cell lymphopenia after ATG is unknown. We examined the association between this polymorphism and CD4 T-cell count in 159 renal transplant recipients (RTR) who received ATG. Analysis of these patients identified 6 CC (3.8%), 32 GC (22.6%), and 117 GG (73.6%) genotypes. Patients with the GG genotype had significantly higher serum PGE(2) concentrations, leading us to compare C carriers with GG patients. Carriers of the C allele had lower CD4 T cell count 1 year (235 +/- 96 vs 323 +/- 227/mm(3); p = 0.022) and 2 years posttransplant (325 +/- 79 vs 422 +/- 231/mm(3); p = 0.024). In multivariate analysis, the C allele (p = 0.029) conferred an increased risk of posttransplant CD4 T-cell lymphocytopenia. Pretransplant T-cell receptor excision circle levels were lower in C carriers. COX-2 gene promoter polymorphism at position -765 (G -> C) is associated with persistent CD4 T-cell lymphopenia after ATG in RTR. This effect is likely to be mediated by the actions of PGE(2) on thymus function and viability. PMID- 21782873 TI - Hepatitis B vaccination coverage among high-risk adults 18-49 years, U.S., 2009. AB - BACKGROUND: Approximately 43,000 new hepatitis B virus (HBV) infections occurred in 2007. Although hepB vaccination has been recommended for adults at high-risk for incident HBV infection for many years, coverage remains low. METHODS: We used the 2009 National Health Interview Survey to assess self-reported HepB vaccine uptake (>= 1 dose), series completion (>= 3 dose), and independent predictors of vaccination among high-risk adults aged 18-49 years. High-risk adults were defined as those reporting male sex with men; injection drug use; hemophilia with receipt of clotting factors; sexually transmitted disease in prior five years; sex for money or drugs; HIV positive; sex with persons having any above risk factors; or who "felt they were at high risk for HIV". Persons with none of the aforementioned risk factors were considered non-high risk. Bivariate analysis was conducted to assess vaccination coverage. Independent predictors of vaccine uptake and series completion were determined using a logistic regression. RESULTS: Overall, 7.0% adults aged 18-49 years had high-risk behaviors. Unadjusted coverage with >= 1 dose was 50.5% among high-risk compared to 40.5% among non-high-risk adults (p-values <0.001) while series completion (>= 3 doses) was 41.8% and 34.2%, respectively (p-values <0.001). On multivariable analysis, >= 1 dose coverage, but not series completion, was higher (Risk Ratio 1.1, 95% CI=1.0-1.2, p-value=0.021) among high-risk compared to non-high risk adults. Other characteristics independently associated with a higher likelihood of HepB vaccination among persons 18-49 years included younger age groups, females, higher education, >= 2 physician contacts in the past year, ever tested for HIV, health care personnel, received influenza vaccination in the previous year, and ever received hepatitis A vaccination. Vaccine uptake with >= 1 dose increased by 5.1% (p=0.047) among high-risk adults between 2004 and 2009. CONCLUSIONS: A small increase in >= 1 dose HepB vaccination coverage among high-risk adults compared with non-high risk adults was documented for the first time in 2009. Higher coverage among persons 18-30 years may reflect aging of persons vaccinated when they were children and adolescents. To improve protection against hepatitis B among high-risk adults, healthcare providers should offer hepatitis B vaccination to persons at high risk and those who seek vaccination to protect themselves and facilitate timely completion of the three (3) dose HepB series. PMID- 21782874 TI - A randomized, double-blind, placebo-controlled, phase 1/2a study of the safety and immunogenicity of a live, attenuated human parainfluenza virus type 3 vaccine in healthy infants. AB - OBJECTIVE: To evaluate the safety, tolerability, immunogenicity, and viral shedding profiles of a recombinant, live, attenuated human parainfluenza virus type 3 (HPIV3) vaccine, rHPIV3cp45, in healthy HPIV3-seronegative infants 6 to <12 months of age. METHODS: In this double-blind, multicenter study, subjects were randomized 2:1 to receive a 10(5)TCID(50) dose of rHPIV3cp45 (n=20) or placebo (n=10) at enrollment and at 2 and 4 months after the first dose. Blood for evaluation of antibody to HPIV3 was collected at baseline and approximately 1 month after each dose. Solicited adverse events (SEs) and unsolicited adverse events (AEs) were collected on days 0-28 after each dose. Nasal wash samples for vaccine virus shedding were collected 3 times after each dose (7-10, 12-18, and 28-34 days post dose) and at unscheduled illness visits. Subjects were followed for 180 days after the last dose. RESULTS: Vaccine virus was shed by 85% of vaccine recipients after dose 1, by 1 subject after dose 2, and was not shed by any subject after dose 3. The highest titer of shed virus was detected on day 7 after dose 1. The attenuation phenotype and the genotype of the vaccine virus were stable in shed virus. Seroresponse (>= 4-fold rise in HPIV3 antibody from baseline) occurred in 61% of subjects after dose 1 and in 77% after dose 3. Either seroresponse or shedding occurred in 95% of vaccine subjects. Adverse events were similar in vaccine and placebo recipients. CONCLUSION: The safety, shedding, and immunogenicity profiles of rHPIV3cp45 in HPIV3-seronegative infants 6 to <12 months of age support further development of this vaccine. PMID- 21782875 TI - Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice. AB - The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required. PMID- 21782876 TI - Winter birth excess in schizophrenia and in non-schizophrenic psychosis: sex and birth-cohort differences. AB - OBJECTIVE: Despite the fact that association between winter birth excess and schizophrenia in the northern Hemisphere is well established, possible sex or birth-cohort differences in this winter birth excess remain unclear. We aimed to evaluate sex and birth-cohort differences in the seasonal birth distribution of patients with schizophrenia or non-schizophrenic psychosis. METHOD: The sample included 321 ICD-10 schizophrenia and 294 non-schizophrenic psychosis patients consecutively admitted into a psychiatric hospitalization unit in Granada, southern Spain, during a nine-year period (1998-2006). The distribution of births among the general population born over the same period as the patients was calculated. RESULTS: Among schizophrenia males (n=258), it was possible to demonstrate that the observed proportion of winter birth (December, January or February) was significantly higher than expected. Among schizophrenia females (n=63), although proportions were as in males and the effect size of the difference between observed and expected winter births was not lower than for men, only a statistical trend could be demonstrated. Among patients with non schizophrenic psychosis, the observed proportion of winter birth was significantly higher than expected in women, but not in men. The sex-adjusted proportion of winter birth among schizophrenia patients born in the 1940's (a time period characterized by poor economy and widespread food restrictions because of the Spanish post-civil-war period) was significantly higher than among those born later; a difference that does not occur among patients with a non schizophrenic psychosis. CONCLUSIONS: Among schizophrenia patients born in winter there appear to be slight sex-differences and strong birth-cohort differences, possibly due to epidemiological factors such as poverty or maternal nutritional deprivation. Epidemiological findings related to winter birth excess among patients with schizophrenia must be identified in longitudinal studies. PMID- 21782877 TI - 25-Methoxyhispidol A, a novel triterpenoid of Poncirus trifoliata, inhibits cell growth via the modulation of EGFR/c-Src signaling pathway in MDA-MB-231 human breast cancer cells. AB - The fruit of Poncirus trifoliata (Rutaceae) has been used a medicinal food and traditional medicine. Recently we reported the isolation of 25-methoxyhispidol A (25-MHA) as a novel triterpenoid from the immature fruit of P. trifoliata with the potential growth inhibition of cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells remain to be elucidated. In the present study, we investigated the anti-proliferative activity and mechanisms of actions mediated by 25-MHA in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. 25-MHA exhibited the growth inhibitory activity against MDA-MB-231 cells with the cell cycle arrest in the G0/G1 phase. The cell cycle arrest in the G0/G1 by 25-MHA was well correlated with the downregulation of cyclin D1, cyclin dependent kinase (CDK4), CDK2, cyclin A, phosphorylated retinoblastoma protein (pRb), and induction of cdk inhibitor p21(WAF1/Cip1) protein. 25-MHA also suppressed the activation of c-Src/epidermal growth factor receptor (EGFR)/Akt signaling, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that 25-MHA-mediated inhibitory activity of human breast cancer cell growth might be related with the cell cycle arrest and modulation of signal transduction pathways. PMID- 21782878 TI - A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats. AB - Rats received diets containing 0, 2000, 10,000, or 50,000 ppm advantame (N-[N-[3 (3-hydroxy-4-methoxyphenyl) propyl]-alpha-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) for 2 generations. F(0) animals (30/sex/group) were treated from 10 weeks before pairing. Males continued until week 16; females through gestation and lactation. Once weaned, F(1) animals (25/sex/group) continued receiving the same diet until F(2) pups were weaned. Mean advantame intakes from each of the diets were 164, 833, and 4410 mg/kg bw/day among F(0) males, and 204, 1036, and 5431 mg/kg bw/day among F(1) males. F(0) and F(1) females had comparable intakes up to lactation, when intakes increased (up to 8447 mg/kg bw/day from 50,000 ppm diet). No treatment-related effects on mortality, body weights, reproduction, litter observations, or postnatal offspring development were noted. Atypical coloration of the feces and cage liners seen with test diets was attributed to excretion of test material/metabolites in the feces and urine. Slightly higher food consumption was seen in F(0) and F(1) animals, especially males, receiving 50,000 ppm. However, these differences were considered to be a secondary response to the high levels of non-nutritive material in the diet. The no-observed-adverse-effect level for reproductive and developmental toxicity was considered to be 50,000 ppm, the highest dietary concentration tested. PMID- 21782879 TI - Luteolin attenuates the pulmonary inflammatory response involves abilities of antioxidation and inhibition of MAPK and NFkappaB pathways in mice with endotoxin induced acute lung injury. AB - Acute lung injury (ALI) in critically ill patients remains the leading cause of mortality and morbidity. Lipopolysaccharide (LPS) is a key mediator of lung injury. This study investigates the protective effects and mechanisms of luteolin in intratracheal instillation of LPS (100MUg)-induced ALI in mice. Pretreatment of mice with 70MUmol/kg luteolin significantly restores LPS-induced decrease in oxygen pressure and increase in carbon dioxide in arterial blood. The histopathological study established 70MUmol/kg luteolin pretreatment markedly attenuates lung histopathological changes, such as haemorrhaging, interstitial edema, and infiltration of polymorphonuclear neutrophils (PMNs) into the lung parenchyma and alveolar spaces. Sufficient evidence for luteolin (35 and 70MUmol/kg) suppresses activation and infiltration of PMNs is obtained in expression of surface marker CD11b and Ly6G on cells in bronchoalveolar lavage fluid (BALF) cells and myeloperoxidase activity in lung tissue. Furthermore, luteolin reduces the activity of catalase and superoxide dismutase, and the level of oxidative damage, and lipid peroxidation, in lung tissue. In addition, the secretion of TNF-alpha, KC, and ICAM-1 in the BALF after LPS challenge are also inhibited by luteolin. Moreover, luteolin reduced LPS-induced activation of MAPK and NFkappaB pathways. Therefore, luteolin is a potential protective antagonists for LPS-induced ALI in mice. PMID- 21782880 TI - Evidence for aconitine-induced inhibition of delayed rectifier K(+) current in Jurkat T-lymphocytes. AB - Aconitine (ACO) is a highly toxic diterpenoid alkaloid and known to exert the immunomodulatory action. However, whether it has any effects on ion currents in immune cells remains unknown. The effects of ACO and other related compounds on ion currents in Jurkat T-lymphocytes were investigated in this study. ACO suppressed the amplitude of delayed-rectifier K(+) current (I(K(DR))) in a time- and concentration-dependent manner. Margatoxin (100 nM), a specific blocker of K(V)1.3-encoded current, decreased the I(K(DR)) amplitude in these cells and the ACO-induced inhibition of I(K(DR)) was not reversed by 1-ethyl-2 benzimidazolinone (30 MUM) or nicotine (10 MUM). The IC(50) value for ACO mediated inhibition of I(K(DR)) was 5.6 MUM. ACO accelerated the inactivation of I(K(DR)) with no change in the activation rate of this current. Increasing the ACO concentration not only reduced the I(K(DR)) amplitude, but also accelerated the inactivation time course of the current. With the aid of minimal binding scheme, the inhibitory action of ACO on I(K(DR)) was estimated with a dissociation constant of 6.8 MUM. ACO also shifted the inactivation curve of I(K(DR)) to a hyperpolarized potential with no change in the slope factor. Cumulative inactivation for I(K(DR)) was enhanced in the presence of ACO. In Jurkat cells incubated with amiloride (30 MUM), the ACO-induced inhibition of I(K(DR)) remained unaltered. In RAW 264.7 murine macrophages, ACO did not modify the kinetics of I(K(DR)), although it suppressed I(K(DR)) amplitude. Taken together, these effects can significantly contribute to its action on functional activity of immune cells if similar results are found in vivo. PMID- 21782881 TI - Eye contact and arousal: the effects of stimulus duration. AB - The present study investigated the effect of stimulus duration on skin conductance responses (SCRs) evoked by different gaze directions of a live person. In two separate parts of the experiment, either two fixed stimulus durations (2s and 5s) or a participant-controlled stimulus duration was used. The results showed that the eye contact evoked enhanced SCRs compared to averted gaze or closed eyes conditions irrespective of the presentation time. Subjective evaluations of approach-avoidance-tendencies indicated that the direct gaze elicited either approach or avoidance, depending on the participant. Participants who had evaluated a direct gaze-condition as approachable were found to be more emotionally stabile than those who had evaluated the same condition as avoidable. In the self-timing condition, averted gaze was looked at longer than direct gaze. Our results suggest that direct gaze, also when encountered only briefly like in every-day social encounterings, increases autonomic sympathetic arousal. PMID- 21782882 TI - Polymorphisms in androgen signaling pathway predisposing to prostate cancer. AB - Prostate cancer is the most frequent male malignancy diagnosed in western countries and androgens are known to mediate key physiological processes in prostate tissue. Since endogenous androgens have long been considered to be risk factors for prostate cancer, genes involved in androgen biosynthesis and metabolism have been extensively studied. In this review, association of androgen pathway genes, their polymorphic sites and risk of prostate cancer in different ethnic backgrounds is addressed together with their use to predict susceptibility and clinical outcomes of prostate cancer patients. The effect of the polymorphisms seems vary in different patients, populations and ethnic backgrounds. To date it is evident that the association between androgen pathway gene polymorphisms and prostate cancer risk is complex and many of the results are characterized by irreproducibility, which can be attributed to a variety of biological, statistical and technical reasons. In the future, with increasing knowledge, developing technologies and new genomic biomarkers it likely becomes possible to better estimate the risk of prostate cancer, and distinguish indolent disease from aggressive based on molecular profiling, and the analysis of gene gene and gene-environment interactions. PMID- 21782883 TI - Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis. AB - The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body. PMID- 21782884 TI - Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review. AB - Cancer database analysis indicates that prostate cancer is one of the most seen cancers in men meanwhile composing the leading cause of morbidity and mortality among developed countries. Current available therapies are surgery, radiotherapy and androgene ablation for prostate carcinoma. The response rate is as high nearly 90% however, most of these recur or become refractory and androgene independent (AI). Therefore recent studies intensified on molecular factors playing role on development of prostate carcinoma and novel treatment strategies targetting these factors and their receptors. Insulin-like growth factor-I (IGF I) and its primary receptor insulin-like growth factor receptor-I (IGF-IR) are among these factors. Biologic functions and role in malign progression are primarily achieved via IGF-IR which is a type 2 tyrosine kinase receptor. IGF-IR plays an important role in mitogenesis, angiogenesis, transformation, apoptosis and cell motility. It also generates intensive proliferative signals leading to carcinogenesis in prostate tissue. So IGF-IR and its associated signalling system have provoked considerable interest over recent years as a novel therapeutic target in cancer. In this paper it is aimed to sum up the lately published literature searching the relation of IGF-IR and prostate cancer in terms of incidence, pathologic features, and prognosis. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH 717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, nordihydroguaiaretic acid Insm-18/NDGA). And the other end point is to yield an overview on the recent progress about usage of this receptor as a novel anticancer agent of targeted therapies in treatment of prostate carcinoma. PMID- 21782885 TI - Castration-induced changes in mouse epididymal white adipose tissue. AB - We analyzed the effects of castration on epididymal white adipose tissue (WAT) in C57BL/6J mice which were fed a regular or high-fat diet. Fourteen days following surgical castration profound effects on WAT tissue such as reductions in WAT wet weight and WAT/body weight ratio, induction of lipolysis and morphologic changes characterized by smaller adipocytes, and increased stromal cell compartment were documented in both dietary groups. Castrated animals had decreased serum leptin levels independent of diet but diet-dependent decreases in serum adiponectin and resistin. The castrated high-fat group had dramatically lower serum triglyceride levels. Immunohistochemical analysis revealed higher staining for smooth muscle actin, macrophage marker Mac-3, and Cxcl5 in the castrated than in the control mice in both dietary groups. We also detected increased fatty-acid synthase expression in the stromal compartment of WAT in the regular-diet group. Castration also reduces the expression of androgen receptor in WAT in the regular diet group. We conclude that castration reduces tissue mass and affects biologic function of WAT in mice. PMID- 21782886 TI - Intrinsic disorder in cell signaling and gene transcription. AB - Structural disorder, which enables unique modes of action often associated with molecular recognition and folding induced by a partner, is widespread in eukaryotic proteomes. Due to the ensuing advantages, such as specificity without strong binding, adaptability to multiple partners and subtle regulation by post translational modification, structural disorder is prevalent in proteins of signaling and regulatory functions, such as membrane receptors, scaffold proteins, cytoskeletal proteins, transcription factors and nuclear hormone receptors. In this review we survey the most important aspects of structural disorder, with major focus on features and advantages pertinent to signal transduction. Our major goal is to elucidate how the functional requirements of these protein classes concur with specific functional modes disorder enables. PMID- 21782887 TI - Circadian regulation of pineal gland rhythmicity. AB - The pineal gland is a neuroendocrine organ of the brain. Its main task is to synthesize and secrete melatonin, a nocturnal hormone with diverse physiological functions. This review will focus on the central and pineal mechanisms in generation of mammalian pineal rhythmicity including melatonin production. In particular, this review covers the following topics: (1) local control of serotonin and melatonin rhythms; (2) neurotransmitters involved in central control of melatonin; (3) plasticity of the neural circuit controlling melatonin production; (4) role of clock genes in melatonin formation; (5) phase control of pineal rhythmicity; (6) impact of light at night on pineal rhythms; and (7) physiological function of the pineal rhythmicity. PMID- 21782889 TI - A study of the catecholaminergic inputs to the dorsal premammillary nucleus. AB - The dorsal premammillary nucleus (PMd) is one of the most responsive hypothalamic sites during exposure to a predator or its odor, and to a context previously associated with a predatory threat; and lesions or pharmacological inactivation centered therein severely reduced the anti-predatory defensive responses. Previous studies have shown that beta adrenergic transmission in the PMd seems critical to the expression of fear responses to predatory threats. In the present study, we have investigated the putative sources of catecholaminergic inputs to the PMd. To this end, we have first described the general pattern of catecholaminergic innervation of the PMd by examining the distribution and morphology of the tyrosine hydroxylase (TH) immunoreactive fibers in the nucleus; and next, combining Fluoro Gold (FG) tracing experiments and TH immunostaining, we determined the putative sources of catecholaminergic inputs to the nucleus. Our results revealed that the PMd presents a moderately dense plexus of catecholaminergic fibers that seems to encompass the rostral pole and ventral border of the nucleus. Combining the results of the FG tract-tracing and TH immunostaining, we observed that the locus coeruleus was the sole brain site that contained double FG and TH immunostained cells. In summary, the evidence suggests that the locus coeruleus is seemingly a part of the circuit responding to predatory threats, and, as shown by the present results, is the sole source of catecholaminergic inputs to the PMd, providing noradrenergic inputs to the nucleus, which, by acting via beta adrenoceptor, seems to be critical for the expression of anti-predatory responses. PMID- 21782888 TI - Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network. PMID- 21782890 TI - Neonatal enucleation during a critical period reduces the precision of cortico cortical projections in visual cortex. AB - Previous studies have reported that intrahemispheric connections between area 17 (V1, striate cortex) and other cortical visual areas are not point-to-point, but instead have some degree of convergence and divergence. Many pathological conditions can interfere with the normal development of patterns of cortico cortical connections, but there is little information regarding whether or not early pathological insults can also induce permanent changes in the convergence and divergence of cortical connections. Obtaining this information is important because loss of precision in neural projections can contribute to functional deficits and behavioral impairment. In the present study we investigated whether retinal input is required for the development of normal values of convergence and divergence in the visual callosal pathway. We found that enucleation performed at birth induced significant increases in convergence and divergence compared to control animals. In contrast, values of convergence and divergence in rats enucleated at postnatal day 7 (P7) were similar to those in controls. Previous studies have shown that retinal input during the first postnatal week is required for the specification of the overall distribution and internal topography of visual callosal pathways. Our present results therefore extend these previous finding by showing that retinal input during the first postnatal week also specifies the precision of cortico-cortical projections. These findings raise the possibility that the precision of neural connections may be reduced in other pathological conditions that affect early development of neural connections. PMID- 21782891 TI - E-cadherin is required at GABAergic synapses in cultured cortical neurons. AB - Classical cadherins are cell adhesion molecules that are thought to contribute to the control of synapse formation, synaptic transmission, and synaptic plasticity. This is largely based on studies investigating the functions of N-cadherin at glutamatergic synapses, whereas other classical cadherins have hardly been examined at central synapses. We have now used a conditional knockout approach in cultured cortical neurons to address the role of E-cadherin mainly at inhibitory, GABAergic synapses. Cortical neurons were cultured from mouse fetuses carrying floxed E-cadherin alleles in homozygous configuration. E-cadherin knockout was induced in individual neurons by expression of an EGFP-Cre fusion protein. Immunocytochemical stainings for the vesicular GABA (VGAT) and glutamate (VGLUT1) transporters revealed a reduced density of dendritic GABAergic synapses in E cadherin knockout neurons, whereas glutamatergic synapses were unaffected. Electrophysiological recordings of miniature and action potential-evoked, GABA(A) receptor-mediated postsynaptic currents confirmed an impairment of GABAergic synapses at the functional level. In summary, our immunocytochemical and electrophysiological analysis of E-cadherin knockout neurons suggested that E cadherin signaling importantly contributes to the regulation of GABAergic synapses in cortical neurons. PMID- 21782892 TI - Simultaneous conditioning of "gaping" responses and taste avoidance in rats injected with LiCl and saccharin: examining the role of context and taste cues in the rodent model of anticipatory nausea. AB - This study examined whether rats can simultaneously learn to associate lithium chloride (LiCl)-induced nausea with both contextual and intravascular taste cues. During the conditioning phase (4 days, 72h apart), 32 male Long Evans rats were injected intraperitoneally with either isotonic saline (NaCl), lithium chloride (LiCl, 127mg/kg), saline plus 2% saccharin (NaCl+Saccharin), or lithium chloride plus 2% saccharin (LiCl+Saccharin) immediately prior to a 30min exposure to a novel context. 72h following the final conditioning day, each animal was re exposed to the context on a drug-free test day. The next day, animals received a 24h 2-bottle preference test with a choice between water and a palatable saccharin solution. Results showed that animals treated with LiCl during conditioning, with or without saccharin, displayed significantly higher levels of conditioned gaping responses, indicative of nausea, upon re-exposure to the context, relative to NaCl and NaCl+Saccharin controls. Animals administered LiCl+Saccharin during conditioning also displayed significant conditioned taste avoidance to the saccharin solution during the two bottle choice test. These results indicate that systemic administration (intraperitoneal) of a LiCl+Saccharin solution is effective in simultaneously conditioning toxin elicited nausea to both internal (taste) and external (context) cues. PMID- 21782893 TI - Effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval in mice using the elevated plus maze test. AB - Clozapine and olanzapine are antipsychotic drugs commonly used to treat schizophrenia and psychosis; however, few studies have investigated their effects on cognitive function using animal models. Thus, the effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval were investigated in naive mice using a modified elevated plus maze (mEPM) task. Olanzapine (0.15 and 0.30 mg/kg) and clozapine (0.5 and 1 mg/kg) were injected intraperitoneally (i.p.) into male Balb-c mice before training, immediately after training or before the second day of the trial. Our results showed that both olanzapine and clozapine disrupted the acquisition of spatial memory. In addition, clozapine impaired the consolidation of spatial memory, while olanzapine had no effect. Furthermore, olanzapine and clozapine significantly disrupted memory retrieval in naive mice. Thus, these results at least suggest that olanzapine can be a superior treatment for schizophrenia compared to clozapine. PMID- 21782894 TI - Macrophages play a key role in early blood brain barrier reformation after hypothermic brain injury. AB - The inflammatory response following traumatic injury to the central nervous system (CNS) includes the infiltration of large numbers of macrophages. This response has been implicated in both ongoing tissue damage as well as recovery following CNS injury. We investigated the role of invading macrophages on one important aspect of tissue repair in the brain, the reformation of the blood brain barrier (BBB). We used liposomal clodronate to deplete monocytes and tissue macrophages. This method led to a marked reduction in the accumulation of F4/80 expressing cells at sites of hypothermic brain injury in a murine model. The integrity of the blood brain barrier over time following injury was assessed by permeability of fluorescent labeled albumin. The reduction in macrophages at the injury site was accompanied by a delay in early reformation of the blood brain barrier. In control animals the permeability of the BBB to FITC-labeled albumin returned to normal levels by seven days post-injury. In macrophage-depleted mice leakage of albumin was still observed at seven days post-injury. These results suggest that macrophages play an important role in early post-traumatic reformation of the BBB. PMID- 21782896 TI - The binding and transport of alternative metals by transferrin. AB - BACKGROUND: The iron transport protein of the blood plasma, transferrin, is maintained only with about 30% of its capacity to bind Fe(3+) ions; this leaves the protein the potential ability to transport other metal ions from the bloodstream to the tissues. SCOPE OF REVIEW: This review examines the potential role of transferrin to bind and transport alternative metal ions with possible beneficial and deleterious effects. MAJOR CONCLUSIONS: Transferrin has been postulated to play a significant role in transporting Ti(4+), VO(2+) (V(4+)), Cr(3+), Ru(3+), and Bi(3+), all metal ions of potential therapeutic significance. Transferrin may possess a physiological role in the transport of manganese, as the trivalent ion. However, the protein may also play a role in carrying potentially toxic Al(3+) and actinide ions, including Pu(4+), to the tissues. Attempts to use transferrin in the selective removal of low concentrations of specific metal ions from aqueous mixed ions waste streams using a procedure called metalloprotein affinity metal chromatography are discussed. GENERAL SIGNIFICANCE: The binding of alternative metals to transferrins may have therapeutic and toxicological significance. This article is part of a Special Issue entitled Transferrins: Molecular Mechanisms of Iron Transport and Disorders. PMID- 21782895 TI - Thioredoxin glutathione reductase: its role in redox biology and potential as a target for drugs against neglected diseases. AB - BACKGROUND: There are two, largely autonomous antioxidant pathways in many organisms, one based on thioredoxin and one based on glutathione, with each pathway having a unique flavoprotein oxidoreductase to maintain them in a reduced state. A recently discovered protein, thioredoxin glutathione reductase (TGR) potentially connects these two pathways. In a large group of parasitic worms, responsible for hundreds of millions of infections in humans and animals, untold morbidity and significant mortality, TGR is the sole enzyme present to maintain redox balance. SCOPE OF REVIEW: In this review, the current understanding of the biochemical properties of TGR enzymes is compared to the related enzymes thioredoxin reductase and glutathione reductase. The role of the rare amino acid selenocysteine is discussed. An overview of the potential to target TGR for drug development against a range of parasitic worms and preliminary results to identify TGR inhibitors for schistosomiasis treatment is presented. MAJOR CONCLUSIONS: TGR has properties that are both unique and common to other flavoprotein oxidoreductases. TGR plays a fundamentally different and essential role in the redox biology of parasitic flatworms. Therefore, TGR is a promising target for drug development for schistosomiasis and other trematode and cestode infections. GENERAL SIGNIFICANCE: TGR may have differing functions in host organisms, but through analyses to understand its ability to reduce both glutathione and thioredoxin we can better understand the reaction mechanisms of an important class of enzymes. The unique properties of TGR in parasitic flatworms provide promising routes to develop new treatments for diseases. PMID- 21782897 TI - Different expression of tissue inhibitor of metalloproteinase family members in rat dorsal root ganglia and their changes after peripheral nerve injury. AB - Matrix metalloproteinase 9 (MMP9) and MMP2 are important in the development and maintenance of neuropathic pain behavior induced by peripheral nerve injury. The enzymatic activity of MMP9 and MMP2 is balanced specifically by tissue inhibitor of metalloproteinase 1 (TIMP1) and TIMP2, respectively. In present study, we measured the effect of peripheral nerve injury on the expression of TIMP1 and TIMP2 in adult dorsal root ganglia (DRG). A dramatic increase of TIMP1 mRNA and a decrease of TIMP2 in DRG after sciatic nerve transection (SNT) were displayed through a real-time PCR method. Furthermore, data showed by in situ hybridization that TIMP1 mRNA was only localized in DRG satellite cells under normal conditions. TIMP1 mRNA was increased in satellite cells, and induced within sensory neurons after SNT. Analysis of neuronal profiles showed that induced TIMP1 mRNA was mainly contained in small and medium DRG neurons. Further study displayed that induced TIMP1 mRNA was predominantly present in activating transcription factor 3 (ATF3)-positive injured DRG neurons. Comparatively, TIMP2 mRNA was mostly contained within sensory neurons and the overall amount decreased at the late stage after nerve injury. These data showed different change of TIMPs in DRG after peripheral nerve injury. PMID- 21782898 TI - Diazepam-induced neuronal plasticity attenuates locomotor responses to morphine and amphetamine challenges in mice. AB - A single administration of benzodiazepine-site ligands of the inhibitory GABA(A) receptors has been shown to lead to persistently potentiated AMPA receptor mediated responses in dopaminergic neurons of the ventral tegmental area (VTA). This plasticity has been suggested to be a common property of different kinds of addictive drugs. We now wanted to test if the plasticity induced by diazepam would also affect behaviors elicited by other drugs of abuse. Activity and plasticity of the VTA dopaminergic neurons are known to be essential for the initiation and/or sensitization of the psychomotor responses to morphine and amphetamine. The effect of diazepam pre-treatment (a single dose of 5 mg/kg) was studied 24-72 h later in behaving C57BL/6J mice on locomotor activity induced by acute and repeated administration of morphine (5 mg/kg) and amphetamine (2.5 mg/kg). The pre-treatment attenuated the locomotor-activating effect of morphine. On the other hand, it reduced the amphetamine-induced locomotor sensitization in male mice in N-methyl-d-aspartate (NMDA) receptor-dependent manner. The acute amphetamine effect was not affected. The results indicate that benzodiazepine induced neural plasticity transiently reduces the sensitivity to psychomotor stimulation by opioids and stimulants. PMID- 21782899 TI - Cyclophosphamide-induced disruption of umami taste functions and taste epithelium. AB - Clinical studies have reported taste dysfunctions developing in patients undergoing chemotherapy. This adverse side effect is a major concern for the doctors and patients because disrupted taste can reduce appetite, cause malnutrition, delay recovery, and affect quality of life. Cyclophosphamide (CYP) is a common atenoplastic drug used during chemotherapy and is thought to affect taste through learned tasted aversions. This study asked whether CYP also alters umami taste sensory functions and disrupts taste epithelium of mice. Behavioral tests focused on taste acuity, assessed by the ability of mice to discriminate between the taste qualities of two umami substances, monosodium glutamate (MSG) and inosine 5'-monophosphate (IMP), and taste sensitivity, assessed by detection thresholds of MSG and IMP, after an IP injection (75 mg/kg) of CYP. The behavioral results revealed a two-phase disturbance in taste acuity and loss of sensitivity, the first phase occurring within 2-4 days after injection and the second occurring 9-12 days after injection. The number of fungiform papillae (with and without pores) decreased immediately after injection and did not begin to recover until 12 days after injection. Circumvallate taste buds began to show disturbances by 8 days after injection and evidence of recovery beginning 12 days after injection. Von Ebner glands were smaller and secreted less saliva 4 days postinjection but not later. These findings suggest the initial behavioral deficits may be because of cytotoxic effects of the drug on taste sensory tissues, whereas the second phase may be because of a disturbance of the taste cell replacement cycle. PMID- 21782900 TI - Acute postnatal exposure to di(2-ethylhexyl) phthalate adversely impacts hippocampal development in the male rat. AB - The distribution of CA3 hippocampal axonal terminal fields undergo a period of widespread connectivity-based changes in the early postnatal stages of life. The purpose of the current study was to examine the effect of acute phthalate exposure during this period of hippocampal development (postnatal days 16-22 (p16 p22)) on morphological outcomes in male and female Long Evans rats. The reproductive toxicity of exposure to phthalates early in life has been well documented; however, much less is known about the effects of phthalates on brain development. The present research demonstrated that exposure to di(2-ethylhexyl) phthalate (DEHP; 10 mg/kg, i.p.) from p16 to p22 reduced axonal markers in the CA3 distal stratum oriens (SO) and reduced cell density of both immature and mature neurons in the dentate gyrus (DG) and CA3, respectively, in male rats. The same markers in the hippocampus of female rats were similar in saline and DEHP treated animals. These data suggest that DEHP has a negative impact on the development of the hippocampus in males but not females and recommend more extensive animal studies on phthalate exposure during the vulnerable post-natal developmental period when rapid structural and functional changes are taking place. PMID- 21782901 TI - Antecedent descriptions change brain reactivity to emotional stimuli: a functional magnetic resonance imaging study of an extrinsic and incidental reappraisal strategy. AB - In the present study we investigated whether individuals would take advantage of an extrinsic and incidental reappraisal strategy by giving them precedent descriptions to attenuate the emotional impact of unpleasant pictures. In fact, precedent descriptions have successfully promoted down-regulation of electrocortical activity and physiological responses to unpleasant pictures. However, the neuronal substrate underlying this effect remains unclear. Particularly, we investigated whether amygdala and insula responses, brain regions consistently implicated in emotional processing, would be modulated by this strategy. To achieve this, highly unpleasant pictures were shown in two contexts in which a prior description presented them as taken from movie scenes (fictitious) or real scenes. Results showed that the fictitious condition was characterized by down-regulation of amygdala and insula responses. Thus, the present study provides new evidence on reappraisal strategies to down-regulate emotional reactions and suggest that amygdala and insula responses to emotional stimuli are adaptive and highly flexible. PMID- 21782902 TI - In vivo detection of cortical abnormalities in BCNU-treated rats, model of cortical dysplasia, using manganese-enhanced magnetic resonance imaging. AB - The 1-3-bis-chloroethyl-nitrosurea (BCNU)-treated rats represent a good model of cortical dysplasia (CD), as proved by the presence of some histological alterations similar to those observed in human CD, including cortical thinning, laminar disorganization, and heterotopia. The cortical cytoarchitectonics of BCNU treated rats has been widely investigated by means of histological procedures, immunocytochemistry, and in situ hybridization techniques, implying the sacrifice of the animals. With the aim of identifying brain alterations in vivo to have the possibility of performing longitudinal studies, we used both conventional T(2) weighted magnetic resonance imaging (MRI) and manganese-enhanced MRI (MEMRI). Though the T(2)-weighted MRI showed the gross anatomical landmarks of BCNU treated rats, only following Mn(2+) administration T(1)-weighted MRI did reveal the brain cytoarchitectonics both of control and BCNU-treated rats. In particular, changes in MEMRI signal depicted the laminar architecture of control rats while BCNU-treated cortex showed no appreciable changes in MEMRI contrast, consistent with their abnormal cortical lamination. Furthermore, in the treated animals MEMRI revealed hyperintense signals corresponding to heterotopia, as shown by the comparison between MEMRI images and Thionin staining and calbindin immunocytochemistry from the same animals. The qualitative findings obtained with MEMRI were semi-quantitatively confirmed by image segmentation of grey matter. Overall, these data show that MEMRI can be used as a non-invasive technique to investigate cortical alterations in animal models of CD in vivo, giving the possibility to perform longitudinal studies, such as electrophysiological recordings or behavioural investigations. PMID- 21782903 TI - Local and retrograde gene transfer into primate neuronal pathways via adeno associated virus serotype 8 and 9. AB - Viral vector-mediated gene transfer has become increasingly valuable for primate brain research, in particular for application of genetic methods (e.g. optogenetics) to study neuronal circuit functions. Neuronal cell tropisms and infection patterns are viable options for obtaining viral vector-mediated transgene delivery that is selective for particular neuronal pathways. For example, several types of viral vectors can infect axon terminals (retrograde infections), which enables targeted transgene delivery to neurons that directly project to a particular viral injection region. Although recent studies in rodents have demonstrated that adeno-associated virus serotype 8 (AAV8) and 9 (AAV9) efficiently transduce neurons, the tropisms and infection patterns remain poorly understood in primate brains. Here, we constructed recombinant AAV8 or AAV9, which expressed an enhanced green fluorescent protein (EGFP) gene driven by a ubiquitous promoter (AAV8-EGFP and AAV9-EGFP, respectively), and stereotaxically injected it into several brain regions in marmosets and macaque monkeys. Immunohistochemical analyses revealed almost exclusive colocalization of EGFP fluorescence via AAV9-mediated gene transfer with a neuron-specific marker, indicating endogenous neuronal tropism of AAV9, which was consistent with our previous results utilizing AAV8. Injections of either AAV8-EGFP or AAV9-EGFP into the marmoset striatum resulted in EGFP expression in local striatal neurons as a result of local infection, as well as expression in dopaminergic neurons of the substantia nigra via retrograde transport along nigrostriatal axonal projections. Retrograde infections were also observed in the frontal cortex and thalamus, which are known to have direct projections to the striatum. These local and retrograde gene transfers were further demonstrated in the geniculocortical pathway of the marmoset visual system. These findings indicate promising capabilities of AAV8 and AAV9 to deliver molecular tools into a range of primate neural systems in pathway-specific manners through their neuronal tropisms and infection patterns. PMID- 21782904 TI - Heat shock protein 70 kDa over-expression and 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced nigrostriatal degeneration in mice. AB - Oxidative damage in the dopaminergic neurons of substantia nigra pars compacta (SNpc) plays an important role in the pathogenesis of Parkinson's disease (PD). Heat shock proteins 70 kDa (HSP70s) are a sub-family of molecular chaperones involved in not only protein folding and degradation but also antioxidant defense and anti-apoptotic pathways. Here, a transgenic mice over-expressing an inducible form of Hsp70 was used to determine whether HSP70 affects 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal degeneration, an experimental model of PD. The Hsp70 transgenic animals exhibited a high level of expression of HSP70 protein in ventral mesencephalon. Dopaminergic cell death in the SNpc was similar between wild-type and Hsp70 transgenic mice with either acute (40 mg/kg, single dose) or chronic (20 mg/kg, three times/week during 1 month) MPTP treatment. In addition, striatal dopamine loss was not different between wild-type and transgenic animals. Three months after the acute MPTP treatment, dopamine loss was partially recovered into a similar level between wild-type and transgenic groups. In conclusion, over-expression of Hsp70 does not suppress dopaminergic neuronal damage at either the somata or the axon terminals of dopaminergic neurons. Hsp70 over-expression does not help axon terminal regeneration either. These results indicate that HSP70 alone is not sufficient to reduce MPTP-induced dopaminergic neuronal damage. PMID- 21782905 TI - Penicillin induced epileptiform activity and EEG spectrum analysis of BDNF heterozygous mice: an in vivo electrophysiological study. AB - Brain-derived neurotrophic factor (BDNF) heterozygous mice (BDNF (+/-)) kindle slowly and have a higher seizure threshold. However, BDNF (+/-) mice exhibit reduced cortical inhibition and disrupted balance of excitation/inhibition synaptic transmission. We investigated penicillin-induced focal cortical epileptiform activity and electroencephalogram (EEG) spectral power of BDNF (+/-) mice, by using electrocorticogram (ECoG) recordings. BDNF (+/-) mice (n=10) and wild type littermates (n=9) were anesthetized with i.p. urethane (1.750g/kg). The recordings of ECoG were carried out by using a data acquisition system and 100IU penicillin was administered intracortically to induce epileptiform activity. The latencies for the onset of spikes and the amplitude of the spikes showed no differences. However the frequency of the spikes was significantly lower in BDNF (+/-) mice at 40th and 45th min following penicillin injection. Additionally, the EEG power for both BDNF (+/-) and wild type mice reduced after penicillin injection and enhanced during epileptiform activity. The spectral power analysis also revealed that the absolute Gamma power of BDNF (+/-) was significantly smaller than wild types. The results of the present study provide the first in vivo electrophysiological evidence that BDNF heterozygous mice exhibited suppressed epileptiform activity. Moreover, reduced levels of BDNF led to a reduction of absolute Gamma band power. PMID- 21782906 TI - A novel application of the fluorescent dye bis-ANS for labeling neurons in acute brain slices. AB - The cell-impermeant oligomer-(e.g. beta-amyloid-, or tubulin-) specific fluorescent dye, bis-ANS (4,4'-bis-1-anilinonaphtalene-8-sulfonate), was successfully used for labeling mechanically damaged but still viable neuron bodies, neurites and neurite cross sections in acute brain slices. Acute hippocampal brain slices of rats were co-stained with bis-ANS and the cell impermeant, DNA-specific dye propidium iodide (PI) and were then analyzed using fluorescence and confocal microscopes. Both the neuron bodies and the neurites were found to exhibit increased fluorescence intensities, suggesting that using this method they can be detected more easily. In addition, bis-ANS showed good region - but not cell specific co-localization with the neuron-specific fluorescent dye Dil (1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). These two dyes label different neuronal structures: Dil binds specifically to intact cell membranes while bis-ANS can enter cells with compromised cell membranes and then stain the microtubules in the cytoplasm. For a quick (10min) staining of acute brain slices with bis-ANS both HEPES and NaHCO(3) were needed in order to achieve high signal intensity. Labeling with bis ANS fluorescent dye is an easy method for imaging the neuronal structures on the surface of acute brain slices. PMID- 21782907 TI - Integration of molecular genetics and proteomics with cell metabolism: how to proceed; how not to proceed! AB - There now exists a resurgence of interest in the role of intermediary metabolism in medicine; especially in relation to medical disorders. Coupled with this is the contemporary focus on molecular biology, genetics and proteomics and their integration into studies of regulation and alterations in cellular metabolism in health and disease. This is a marriage that has vast potential for elucidation of the factors and conditions that are involved in cellular metabolic and functional changes, which heretofore could not be addressed by the earlier generations of biochemists who established the major pathways of intermediary metabolism. The achievement of this present potential requires the appropriate application and interpretation of genetic and proteomic studies relating to cell metabolism and cell function. This requires knowledge and understanding of the principles, relationships, and methodology, such as biochemistry and enzymology, which are involved in the elucidation of cellular regulatory enzymes and metabolic pathways. Unfortunately, many and possibly most contemporary molecular biologists are not adequately trained and knowledgeable in these areas of cell metabolism. This has resulted in much too common inappropriate application and misinformation from genetic/proteomic studies of cell metabolism and function. This presentation describes important relationships of cellular intermediary metabolism, and provides examples of the appropriate and inappropriate application of genetics and proteomics. It calls for the inclusion of biochemistry, enzymology, cell metabolism and cell physiology in the graduate and postgraduate training of molecular biology and other biomedical researchers. PMID- 21782908 TI - Enhancement of angiogenic effect of co-transfection human NGF and VEGF genes in rat bone marrow mesenchymal stem cells. AB - The current study explored the feasibility and efficacy of co-transfection of the human nerve growth factor (NGF) and vascular endothelial growth factor 165 (VEGF165) genes in rat bone marrow mesenchymal stem cells (BMSCs). The obtained hNGF and vascular endothelial growth factor (VEGF) cDNAs were cloned into the pEGFP-C1 expression vector to construct the recombinant vectors. Co-transfection in rat BMSCs was performed and the expressions of both genes were detected by RT PCR, Western blot, and enzyme-linked immunospecific assay. The biological activity of recombinant NGF and VEGF proteins was confirmed using the Chick Chorioallantoic Membrane (CAM) assay. NGF and VEGF genes could be expressed successfully in rat BMSCs. The recombinant NGF and VEGF from the rat BMSCs showed a more significant synergetic biological activity compared with single recombinant NGF or VEGF. These findings demonstrate that the co-transfection of hNGF+VEGF genes can enhance the angiogenic effect in vivo. PMID- 21782909 TI - The evolution of alternative splicing exons in vascular endothelial growth factor A. AB - The C-terminus alternative splicing in VEGFA (vascular endothelial growth factor A) is known for its impact on physiological and pathological angiogenesis. Based on our prediction and RT-PCR verification, we identified anti-angiogenic VEGFA165b isoforms in mouse and rabbit for the first time. We also found that the relative expression level of VEGFA165b isoform had been increasing from rodents to human, and exon8b may have experienced a minor-to-major form exon conversion, possibly correlated with its gain-of-function. It is suggested that introduction of alternative splicing exons (esp. exon6 and exon8b) made important contributions to the transcriptional diversity of VEGFA and played a crucial role in the evolution of its regulatory mechanism. PMID- 21782910 TI - Tissue slice model of human lung cancer to investigate telomerase inhibition by nanoparticle delivery of antisense 2'-O-methyl-RNA. AB - Nanoparticles delivery of oligonucleotides represents a potential approach for cancer treatment. However, most of the experiments were based on established cancer cell lines and may not reflect the original solid tumor in vivo. Both, tumor microenvironment and tumor cell biological properties in the tumor can influence the delivery efficiency of oligonucleotides. Therefore, it is important to understand the effect of nanoparticles delivery of oligonucleotides on tumor response in intact tissue architecture of individual tumors. We used freshly isolated human tumor tissue slices and primary lung cancer cells from non-small cell lung cancer patients to evaluate this nanocarrier system. Chitosan-coated poly(lactide-co-glycolide) (PLGA) nanoparticles were used to form oligonucleotide nanoparticle-complexes (nanoplexes) with antisense 2'-O-methyl-RNA (OMR) that can inhibit telomerase activity by binding to the RNA component of telomerase. OMR cellular uptake was strongly enhanced by nanoplexes mediated delivery in both, primary cells and tissue slices. More than 80% of primary cancer cells and 50% of cells in tissue slices showed OMR uptake. Telomerase activity was inhibited by approximately 45% in primary cancer cells and about 40% in tissue slices. Nanoplexes could penetrate into tumor tissue without influencing tissue architecture and the delivered OMR was able to inhibit telomerase activity with relatively low cytotoxicity. PMID- 21782911 TI - Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder. AB - Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 degrees C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution. PMID- 21782912 TI - Synthesis and biological evaluation of receptor-based tumor imaging agent: (99m)Tc-folate-glucaric acid. AB - The aim of the present study was to prepare (99m)Tc-folate-glucaric acid and investigate the radiopharmaceutical potential for tumors imaging that over express folate receptor. Folate-glucaric acid was synthesized and the synthesized folate conjugate was confirmed with (1)H NMR and LC-MS/MS methods. Folate glucaric acid was labeled with (99m)Tc, and its radiolabelling efficiency was found as 96 +/- 2.0%. Biodistribution study of (99m)Tc-folate-glucaric acid was carried out in vivo using two groups of female Albino Wistar rats: folate receptor (FR) saturated and unsaturated. Biodistribution study showed that (99m)Tc-folate-glucaric acid indicated high uptake in folate receptor rich tissues such as breast, ovary and uterus. Therefore, (99m)Tc-folate-glucaric acid shows good radiolabeling and biodistribution in FR organs, the radiolabeled conjugate is a reason potentially useful radiopharmaceutical for detection of FR positive tumors. PMID- 21782913 TI - Sustained release of 5-fluorouracil by incorporation into sodium carboxymethylcellulose sub-micron fibers. AB - This work introduces a novel route to the sodium carboxymethylcellulose sub micron fibers loaded with hydrophilic anticancer drug, 5-fluorouracil (5-Fu). The results show that 5-Fu is successfully incorporated into the biocompatible polymer, sodium carboxymethylcellulose (NaCMC)-based fibers with good stability, desired drug loading content and 100% entrapment efficiency. Furthermore, the drug release rate of the as-prepared drug-loaded fibers could be well controlled. The drug release behavior of the 5-Fu-loaded NaCMC fibers shows a diffusion mechanism, obeying Ritger-Peppas kinetics model. The drug release behavior of the as-prepared products demonstrates their promising application in drug delivery system. PMID- 21782915 TI - A segmentation method to obtain a complete geometry model of the hearing organ. AB - We present a method for obtaining a complete geometry model of the fluid chambers of cochlea (scalae) from tomography images. An accurate segmentation of cochlea is problematic due to the low contrast of the inner membranes of scalae. Our method of 3D segmentation is based on dynamic resampling of an original image stack to achieve a perpendicular cross-section of the scalae on all sections. Subsequently, perpendicular cross-section is being segmented using 2D active contours. The center of mass of the contour is extracted and used to predict further course of scalae centerline by Kalman filter. Cross-section contours are subsequently assembled to the total geometry model. This method has been applied to CT images, but we expect that it could be used for segmentation of strongly curved low-contrast tubular objects recorded with other tomography techniques. PMID- 21782914 TI - Apoptosis in acquired and genetic hearing impairment: the programmed death of the hair cell. AB - Apoptosis is an important physiological process. Normally, a healthy cell maintains a delicate balance between pro- and anti-apoptotic factors, allowing it to live and proliferate. It is thus not surprising that disturbance of this delicate balance may result in disease. It is a well known fact that apoptosis also contributes to several acquired forms of hearing impairment. Noise-induced hearing loss is the result of prolonged exposure to excessive noise, triggering apoptosis in terminally differentiated sensory hair cells. Moreover, hearing loss caused by the use of therapeutic drugs such as aminoglycoside antibiotics and cisplatin potentially may result in the activation of apoptosis in sensory hair cells leading to hearing loss due to the "ototoxicity" of the drugs. Finally, apoptosis is a key contributor to the development of presbycusis, age-related hearing loss. Recently, several mutations in apoptosis genes were identified as the cause of monogenic hearing impairment. These genes are TJP2, DFNA5 and MSRB3. This implies that apoptosis not only contributes to the pathology of acquired forms of hearing impairment, but also to genetic hearing impairment as well. We believe that these genes constitute a new functional class within the hearing loss field. Here, the contribution of apoptosis in the pathology of both acquired and genetic hearing impairment is reviewed. PMID- 21782916 TI - In vitro antitrypanosomal and antileishmanial activity of plants used in Benin in traditional medicine and bio-guided fractionation of the most active extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of the study was to evaluate the in vitro antitrypanosomal and antileishmanial activity of crude extracts of 10 plant species traditionally used in Benin to treat parasitic infections. MATERIALS AND METHODS: For each species, dichloromethane, methanol and aqueous extracts were tested. Their antitrypanosomal and antileishmanial activities were evaluated in vitro on Trypanosoma brucei brucei (strain 427) (Tbb) and on promastigotes of Leishmania mexicana mexicana (MHOM/BZ/84/BEL46) (Lmm). RESULTS: The best growth inhibition was observed with the dichloromethane extracts of aerial parts of Acanthospermum hispidum DC. (Asteraceae) (IC(50)=14.5 MUg/ml on Tbb and 11.1 MUg/ml on Lmm), twigs of Keetia leucantha (K. Krause) Bridson (syn. Plectronia leucantha Krause) (IC(50)=5.8 MUg/ml on Tbb), aerial parts of Byrsocarpus coccineus Schumach. & Thonn (syn. Rourea coccinea (Schumach. & Thonn.) Hook.f.) (IC(50)=14.7 MUg/ml on Tbb) and aerial parts of Carpolobia lutea G.Don. (IC(50)=18.3 MUg/ml on Tbb). All these extracts had a low cytotoxicity. It is not the case for the methanolic and water extracts of roots of Anchomanes difformis (Blume) Engl. (IC(50)=14.7 and 13.8 MUg/ml on Tbb) which were toxic at the same concentration range on WI38, human cells. A bio-guided fractionation of the most active extract of Keetia leucantha allowed to identify oleanolic acid and ursolic acid as responsible for the observed activities. CONCLUSION: Our study gives some justification for antiparasitic activity of some investigated plants. PMID- 21782917 TI - Neuroprotective effects of Buyang Huanwu decoction against hydrogen peroxide induced oxidative injury in Schwann cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu decoction (BYHWD) is a traditional Chinese medicine and can be used to promote peripheral nerve regeneration. However the regenerative mechanism of BYHWD remains unclear. The objective of this study was to investigate the protective mechanisms of BYHWD in Schwann cells damaged by hydrogen peroxide (H(2)O(2)). MATERIALS AND METHODS: Schwann cells which were derived from neonatal sciatic nerves of rats were used in subsequent experiments. Schwann cells were injured by various concentrations of H(2)O(2) (0.25, 0.5 and 1mM final concentration). BYHWD (600 MUg/ml final concentration) was added to the medium either simultaneously or 1h later after the addition of H(2)O(2). Subsequently, methyl thiazolyl tetrazolium (MTT) assay was performed. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were also examined after 12h. The expression of Caspase 3 and the concentration of intercellular Ca(2+) ([Ca(2+)]i) were also determined. RESULTS: Among three concentrations of H(2)O(2), 0.5mM H(2)O(2) induced Schwann cells swelled and neuritis disappeared after 12h. In the presence of BYHWD, MTT assay showed that more cells were viable in comparison with the H(2)O(2) injury group. Moreover, the addition of BYHWD has also increased the SOD activity with decreased in MDA level. Furthermore, the concentration of [Ca(2+)]i and expression of Caspase 3 were decreased with the addition of BYHWD in culture. CONCLUSIONS: Our results revealed that BYHWD protected Schwann cells from oxidative injury. The mechanism of BYHWD promoting neural regeneration possibly associated with its anti oxidative activity. PMID- 21782918 TI - Lemongrass and citral effect on cytokines production by murine macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cymbopogon citratus (DC) Stapf (Poaceae Gramineae), an herb commonly known as lemongrass (LG), is an important source of ethnomedicines as well as citral, the major constituent of Cymbopogon citratus, used in perfumery, cosmetic and pharmaceutical industries for controlling pathogens. Thus, the goal of this work was to analyze the effect of LG and citral on cytokines production (IL-1beta, IL-6 and IL-10) in vitro, as well as before or after LPS incubation. MATERIALS AND METHODS: Peritoneal macrophages from BALB/c mice were treated with LG or citral in different concentrations for 24h. The concentrations that inhibited cytokines production were tested before or after macrophages challenge with LPS, in order to evaluate a possible anti-inflammatory action. Supernatants of cell cultures were used for cytokines determination by ELISA. RESULTS: As to IL-1beta, only citral inhibited its release, exerting an efficient action before LPS challenge. LG and citral inhibited IL-6 release. Cymbopogon citratus showed inhibitory effects only after LPS challenge, whereas citral prevented efficiently LPS effects before and after LPS addition. Citral inhibited IL-10 production and although LG did not inhibit its production, the concentration of 100 MUg/well was tested in the LPS-challenge protocol, because it inhibited IL-6 production. LG inhibited LPS action after macrophages incubation with LPS, while citral counteracted LPS action when added before or after LPS incubation. CONCLUSION: LG exerted an anti-inflammatory action and citral may be involved in its inhibitory effects on cytokines production. We suggest that a possible mechanism involved in such results could be the inhibition of the transcription factor NF-kappaB. PMID- 21782919 TI - Proliferative effects of five traditional Nigerian medicinal plant extracts on human breast and bone cancer cell lines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plants Hunteria umbellata (HUL), Cola lepidota (CCL), Persea americana leaf (PAL), Root bark of Persea americana (RPA) and Plukenetia conophora (PCL) are used in Nigerian traditional medicine for the treatment of cancer and cancer related diseases. AIM OF THE STUDY: To scientifically evaluate the cell proliferative and apoptotic effects of the plants extracts using breast and osteocarcinoma cell lines, and also to identify the possible components via LC-MS to have a kind of chemical fingerprint. MATERIALS AND METHODS: The antiproliferative and apoptotic effects of methanolic extracts (10 MUg/ml) of the five medicinal plants were subjected to in vitro evaluation using four cancer cell lines (breast-MCF-7 and BT-20; Osteocarcinoma MG-63 and Saos-2) measured by flow cytometry. Non-tumorigenic controls MCF-12A and primary isolated osteoblasts (POB) were chosen to eliminate negative influence on healthy tissue. RESULTS: Of the five extracts RPA demonstrated a significant (P<0.05) anti-proliferative activity against estrogen receptor positive breast cancer cell lines (MCF-7). The proliferative phase was decreased by 18%, whereas, a significant increase in cell proliferation (about 27%) was observed for RPA at a concentration of 10 MUg/ml. PCL, CCL, HUL and PAL did not show marked inhibition of the proliferation of cell line MCF-7. CONCLUSION: These results give suggestive evidence that the plant extracts exhibit some correlation between the claimed ethnomedicinal uses and the cell proliferative activity. RPA extract includes chemical compounds with estrogen-like activity and validates its potential use as anticancer agent, particularly against breast carcinoma; provided important information potentially helpful in drug designing and discovery. Further studies will involve the isolation of anti tumour compounds in RPA by LC-MS and detailed mechanism of anticancer activities. PMID- 21782920 TI - Inhibition of glucose-induced vascular endothelial growth factor expression by Salvia miltiorrhiza hydrophilic extract in human microvascular endothelial cells: evidence for mitochondrial oxidative stress. AB - AIM OF STUDY: Diabetes mellitus is frequently combined with vascular diseases, which are associated with the expression of vascular endothelial growth factor (VEGF). An approach that can reverse the induction of VEGF by hyperglycemia may potentially benefit the outcome of diabetic patients. Therefore, in the present study, we investigated the effect of Salvia miltiorrhiza (S. miltiorrhiza) hydrophilic extract on the expression of VEGF induced by high concentration of glucose. MATERIALS AND METHODS: Vector of VEGF promoter luc was transiently transfected into HMEC-1 cells, and luciferase activity was measured to determine the promoter activity. In order to investigate the mechanism of Salvia miltiorrhiza hydrophilic extract, mitochondrial uncoupling protein 2(UCP2) was knockdown by using UCP2 siRNA. The expression of VEGF was obtained by using quantitative RT-PCR and dot blot. The level of reactive oxygen species (ROS) was expressed by the level of 2',7'-dichlorfluorescein. RESULTS: Exposure of HMEC-1 cells to 30 mM glucose resulted in a significant increase in the expression of VEGF mRNA (5.7 fold at 3mM glucose, P<0.005), and an increase of ROS formation (2.4 fold at 3mM glucose, P<0.005). These effects were completely antagonized by an inhibitor of electron transport chain complex II, thenoyltrifluoroacetone (TTFA) and an uncoupler of oxidative phosphorylation, carbonylcyanide-m chlorophenylhydrazone (CCCP). Addition of Salvia miltiorrhiza hydrophilic extract (10 MUg/ml) led to a significant decrease of VEGF mRNA and ROS formation in 30 mM glucose condition. Interestingly, knockdown of mitochondrial UCP-2 by UCP-2 siRNA abolished the reduction of VEGF expression and ROS formation by Salvia miltiorrhiza hydrophilic extract. CONCLUSIONS: These findings indicated that Salvia miltiorrhiza hydrophilic extract effectively reversed induction of VEGF expression by high glucose via ameliorating mitochondrial oxidative stress. Salvia miltiorrhiza hydrophilic extract can potentially be an effective antioxidant therapy for the treatment of diabetic chronic vascular complication. PMID- 21782921 TI - Ferulic acid promotes endothelial cells proliferation through up-regulating cyclin D1 and VEGF. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelicae Sinensis is a well known and commonly used traditional Chinese herbal medicine with many therapeutic effects such as neuroprotection, the promotion of hematopoiesis and the treatment of tumors. AIM OF THE STUDY: Ferulic acid (FA) is the main active component in Angelicae Sinensis. Previous research has demonstrated that Angelicae Sinensis is able to induce angiogenesis in vivo. This study investigated the effects of FA on the proliferation of a human umbilical vein endothelial cell line (ECV304) with regard to the modulation of endothelial cells, which is a key step of angiogenesis. MATERIALS AND METHODS: ECV304 cells were incubated with FA at different dosages (0.1 MUg/mL, 1 MUg/mL and 10 MUg/mL). A series of assays was used to detect the effects of FA on: (i) cell proliferation; (ii) DNA synthesis; (iii) cell-cycle distribution; and (iv) mRNA expression of cyclin D1 and vascular endothelial growth factor (VEGF). These were assessed using the Cell Counting Kit 8 (CCK-8), bromodeoxyuridine-enzyme-linked immunosorbent assay (BrdU-ELISA), flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS AND DISCUSSION: The results showed that FA at a range of concentrations from 0.1 MUg/mL to 10 MUg/mL could markedly improve cell proliferation and DNA synthesis in a dose-dependent manner. Flow cytometry showed a significant decrease in the percentage of cells in the G(0)/G(1) phase and a significant increase in the percentage of cells in the S phase. Furthermore, we found that FA enhanced cyclin D1 and VEGF mRNA expression in ECV304 cells. CONCLUSION: FA was able to promote ECV304 cells proliferation in vitro. This effect might be observed through the modulation of cyclin D1 and VEGF. PMID- 21782922 TI - Gastroprotective and safety effects of WIN-34B, a novel treatment for osteoarthritis, compared to NSAIDs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried flowers of Lonicera japonica, also known as Japanese honeysuckle, and the dried root of Anemarrhena asphodeloides, the component herbs of WIN-34B, are traditionally used in Eastern medicine to treat various inflammatory conditions including arthritis. OBJECTIVE: To study the acute and chronic toxicities of WIN-34B and to compare its effects on gastric mucosa with those of diclofenac, a widely used NSAID, and celecoxib, a selective COX-2 inhibitor. MATERIALS AND METHODS: To investigate acute toxicity, we orally administered a single dose of 5,000 mg/kg WIN-34B to rats. To investigate chronic toxicity, we orally administered 500, 1000 or 2,000 mg/kg WIN-34B to rats daily for 13 weeks. To assess its effects on gastric mucosa, rats received either a single dose or repeated doses of WIN-34B (400, 1000, or 2,000 mg/kg), diclofenac (10, 40, or 80 mg/kg), celecoxib (100 or 1,000 mg/kg), or vehicle, after which samples of gastric mucosa were assessed grossly and histologically. We also measured tissue activity of myeloperoxidase and synthesis of eicosanoids, including prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)). To further assess its effects, we administered WIN-34B to rats either intraperitoneally or orally, measured gastric injury scores using a rat model of diclofenac-induced gastric injury, and measured eicosanoid synthesis. RESULTS: WIN-34B showed no signs of acute or chronic toxicity in terms of general behavior, gross appearance of the internal organs, blood chemistry, or mortality. WIN-34B did not cause significant gastric mucosal damage after single or repeated doses. In contrast, diclofenac and celecoxib both caused gastric damage. In terms of eicosanoid synthesis, WIN-34B significantly suppressed LTB(4) synthesis while both diclofenac and celecoxib increased LTB(4) synthesis. WIN-34B slightly reduced PGE(2) production, while both diclofenac and celecoxib significantly reduced PGE(2) production. In a rat model of diclofenac-induced gastric injury, WIN-34B significantly suppressed LTB(4) synthesis and restored PGE(2) release. CONCLUSIONS: These results demonstrate that WIN-34B did not cause acute or chronic toxicity in male or female rats. In addition, WIN-34B did not cause significant gastric mucosal damage, instead appearing to protect the mucosa from diclofenac-induced gastric damage through the regulation of PGE(2) and LTB(4). PMID- 21782923 TI - Risk factors of gastrointestinal and hepatic adverse drug reactions in the treatment of rheumatoid arthritis with biomedical combination therapy and Chinese medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The exploration of risk factors on the gastrointestinal adverse drug reactions (GI ADRs) and hepatic ADRs in the treatment of rheumatoid arthritis (RA) with traditional Chinese medicien (CM) and convertional Western Medicien (WM) therapy will benifit the clincial drug administration. METHODS: A multi-center, randomized-clinical trial was conducted on RA patients in China. After 12 and 24 weeks of treatment, the efficacy and safety of WM therapy and CM therapy were evaluated. The Chi-square and logistic regression were conducted to analyze the correlations between the biological parameters, CM symptoms and the ADRs. RESULTS: 505 patients were recruited from 9 centers and randomly assigned into WM therapy group (n=251) or CM group (n=254). 397 of them completed the 24 week treatment (194 in WM and 203 in CM group). Total ADRs incidence and withdrawal rates were similar in two groups. For the patients treated with WM, logistic regression analysis showed that CRP level was negatively related to GI ADRs (p<0.05), dizziness was positively related to GI ADRs (p<0.05); and IgG level and chills were positively related to hepatic ADRs (p<0.01, p<0.05). In the patients treated with CM, no laboratory measurements were found related with GI ADRs and hepatic ADRs, lassitude and nocturia were risk factors for GI ADRs, cold extremities for hepatic ADRs, respectively (p<0.05). CONCLUSION: CRP in normal scale and dizziness were the risk factors for GI ADRs, higher IgG level and chills were the risk factors for hepatic ADRs in the RA patients treated with conventional WM therapy. Lassitude and nocturia were the risk factors for GI ADRs, and cold extremities were the risk factors for hepatic ADRs in the RA patients treated with CM therapy. PMID- 21782924 TI - Transcriptional repression of repeat-derived transcripts correlates with histone hypoacetylation at repetitive DNA elements in aged mice brain. AB - In order to better characterize epigenetic alterations at repetitive DNA elements with aging, DNA methylation and histone marks at various repeat classes were investigated. Repetitive DNA elements were hypermethylated in the brains of old mice. Histone hypoacetylation and altered histone trimethylation at repetitive sequences were detected in brain tissues during aging. The expression of repeat derived transcripts (RDTs) was then measured to explore any correlations with the observed epigenetic alterations. Large numbers of RDTs investigated were down regulated along with age. Bisulfite sequencing revealed that CpG dinucleotide methylation patterns at the repeats of the RDT promoter region were mostly well maintained during aging. ChIP assay showed that histones were deacetylated at the promoter region of RDTs in aged mice brain. The observations indicate that the transcriptional repression of RDTs appears to be related to histone hypoacetylation, but not to DNA hypermethylation at repeat DNA elements in the brains of aged mice. PMID- 21782925 TI - Ghrelin levels are reduced in Rett syndrome patients with eating difficulties. AB - Most patients with Rett syndrome (RTT) have both gastrointestinal problems and somatic growth failure, including microcephaly. Ghrelin is a peptide hormone involved in growth hormone secretion, interdigestive motility, and feeding behavior. Plasma ghrelin assays have previously been described for other neurodevelopmental disorders. To examine the pathophysiology of RTT, we measured plasma levels of ghrelin in patients with RTT. A case-control study examining plasma levels of ghrelin, serum growth hormone, and insulin-like growth factor-1 (IGF-1) was performed on 27 patients with RTT and 53 controls. Plasma levels of total (T)- and octanoyl (O)-ghrelin were significantly lower in patients with RTT than in controls. Plasma levels of T-ghrelin correlated significantly with serum IGF-1 levels and head circumference. Significantly lower levels of plasma T ghrelin and O-ghrelin were observed in RTT patients with eating difficulties, while lower levels of plasma T-ghrelin were observed in RTT patients with constipation, in comparison to patients without either of these symptoms. Alterations in plasma ghrelin levels may reflect various clinical symptoms and signs in RTT patients, including growth failure, acquired microcephalus, autonomic nerve dysfunction, and feeding difficulties. We describe the role of ghrelin in RTT and suggest this peptide as a novel biological marker in patients with RTT. PMID- 21782926 TI - Type IV(B) pili are required for invasion but not for adhesion of Salmonella enterica serovar Typhi into BHK epithelial cells in a cystic fibrosis transmembrane conductance regulator-independent manner. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) has been proposed as an epithelial cell receptor for the entry of Salmonella Typhi but not Salmonella Typhimurium. The bacterial ligand recognized by CFTR is thought to reside either in the S. Typhi lipopolysaccharide core region or in the type IV pili. Here, we assessed the ability of virulent strains of S. Typhi and S. Typhimurium to adhere to and invade BHK epithelial cells expressing either the wild-type CFTR protein or the ?F508 CFTR mutant. Both S. Typhi and S. Typhimurium invaded the epithelial cells in a CFTR-independent fashion. Furthermore and also in a CFTR-independent manner, a S. Typhi pilS mutant adhered normally to BHK cells but displayed a 50% reduction in invasion as compared to wild-type bacteria. Immunofluorescence microscopy revealed that bacteria and CFTR do not colocalize at the epithelial cell surface. Together, our results strongly argue against the established dogma that CFTR is a receptor for entry of Salmonella to epithelial cells. PMID- 21782927 TI - Dermal penetration of propylene glycols: measured absorption across human abdominal skin in vitro and comparison with a QSAR model. AB - The dermal penetration of undiluted monopropylene glycol (MPG) and dipropylene glycol (DPG) has been measured in vitro using human abdominal skin under conditions of infinite dose application, and the results compared with predictions from the SKINPERM QSAR model (ten Berge, 2009). The measured steady state penetration rates (Jss) for MPG and DPG were 97.6 and 39.3 MUg/cm2/h, respectively, and the permeability coefficients (Kp) were 9.48*10(-5) cm/h for MPG and 3.85*10(-5) cm/h for DPG. In comparison, the SKINPERM model slightly over predicted Jss and Kp for MPG and DPG by between 2.6- and 5.1-fold, respectively. The model predictions of 254 MUg/cm2/h and 24.6*10(-5) cm/h for MPG, and 202 MUg/cm2/h and 19.8*10(-5) cm/h for DPG were in fairly good agreement with the measured values. Further, the model predicted a Jss of 101 MUg/cm2/h and a Kp of 9.9*10(-5) cm/h for the homologue tripropylene glycol. Assuming that the measured Jss was the same under conditions of finite dose application (taken to be 10 MUL/ cm2) and was maintained over a 24-h period (both conservative assumptions), the relative dermal absorption of the applied dose was estimated to be 23% (0.96%/h) for MPG and 9% (0.39%/h) for DPG. However, the extrapolation for MPG may be further overestimated due to possible residence in the stratum corneum under infinite conditions of exposure that would not be applicable to a finite loading dose. PMID- 21782928 TI - Threshold of peroxynitrite cytotoxicity in bovine pulmonary artery endothelial and smooth muscle cells. AB - Peroxynitrite is widely reported as highly cytotoxic; yet recent evidence indicates that at certain concentrations, it can induce pulmonary cell hyper proliferation and tissue remodelling. This study aimed to establish the threshold concentration of peroxynitrite to induce functional impairment of bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC). PAEC or PASMC were exposed to solution of peroxynitrite or 3-morpholinosydnonimine (SIN 1). Twenty-four hour cell viability, DNA synthesis, and protein biochemistry were assessed by trypan blue dye exclusion, [3H] thymidine incorporation and western blot analysis, respectively. Threshold concentration of peroxynitrite to significantly impair viability of PAEC and PASMC was 2 MUM peroxynitrite. In PASMC and PAEC, low concentrations of peroxynitrite (2 nM-0.2 MUM) increased cell proliferation and did not activate p38 MAP kinase. The decrease in DNA synthesis and cell viability caused by 2 MUM peroxynitrite was associated with caspase-3 cleavage but not p38 activation. Also, 2-20 MUM peroxynitrite significantly activated poly ADP ribose polymerase and stress activated kinase JNK in PAEC. However, the higher concentration of 20 MUM peroxynitrite did cause a threefold increase in p38 activation. In conclusion, the threshold for the cytotoxic effects of peroxynitrite was 2 MUM; which caused apoptotic cell death independent of p38 MAP kinase activation in pulmonary artery cells. PMID- 21782929 TI - Luteolin protects osteoblastic MC3T3-E1 cells from antimycin A-induced cytotoxicity through the improved mitochondrial function and activation of PI3K/Akt/CREB. AB - Luteolin is a flavonoid found in many herbal extracts including celery, green pepper, parsley, perilla leaf and seeds, and chamomile. Antimycin A (AMA) is an inhibitor of the mitochondrial electron transport chain. In the present study, the protective effect of luteolin on AMA-induced cell damage was investigated in osteoblastic MC3T3-E1 cells. Luteolin significantly increased the viability of MC3T3-E1 cells in the presence of AMA and the effect of luteolin in increasing cell viability was completely prevented by the presence of LY294002, Akt inhibitor, or auranofin, suggesting that the effect of luteolin might be partly mediated from PI3K, Akt, and thioredoxin reductase. Pre-treatment with luteolin prior to AMA exposure significantly prevented mitochondrial membrane potential dissipation, ATP loss, inactivation of complex I and IV, ROS production, inactivation of thioredoxin reductase, intracellular calcium elevation, and cytochrome c release induced by AMA. Moreover, luteolin increased activities of PI3K (phosphoinositide 3-kinase) and Akt (protein kinase B), and CREB (cAMP response element-binding protein) phosphorylation inhibited by AMA treatment. Collectively, these results suggest that luteolin protects MC3T3-E1 cells from AMA-induced cell damage through the improved mitochondrial function and activation of PI3K/Akt/CREB. PMID- 21782931 TI - An assessment of genetic differences among ixodid ticks in a locus within the nuclear large subunit ribosomal RNA gene. AB - We examined the usefulness of the D3 domain and flanking core regions (=D3(+)) of the nuclear large subunit (LSU) ribosomal DNA as a genetic marker for species level identification and the inference of evolutionary relationships of ixodid ticks. Genetic variation was also examined in relation to the secondary structure of the LSU rDNA. The results revealed a lack of sequence difference in the D3(+) among species of Dermacentor and among some species of Ixodes, demonstrating that this gene region is not suitable as a species marker for all species of ixodid ticks. Of the 45 variable nucleotide positions in the sequence alignment of the D3(+), 23 did not alter the secondary structure of the LSU rDNA, because they occurred in unpaired positions, whereas 16 represented partial or full compensatory changes which maintained the secondary structure. Six deletions in the D3(+) sequence of all Ixodes species examined resulted in a shorter d4_1 helix compared with that of other tick species. The results of the phylogenetic analyses also showed that the D3(+) is of limited value in resolving evolutionary relationships among ixodid ticks. In addition, we also demonstrated that the D3(+) of ascomycete fungi could also be amplified along with, or instead of, the D3(+) of some tick species, depending upon the primers used in PCR. Nonetheless, the D3(+) of the fungal contaminants are readily distinguished from the D3(+) of ixodid ticks because of a shorter length and the absence of helix d4_1 in the secondary structure of the LSU rDNA. PMID- 21782932 TI - A half century of experimental neuroanatomical tracing. AB - Most of our current understanding of brain function and dysfunction has its firm base in what is so elegantly called the 'anatomical substrate', i.e. the anatomical, histological, and histochemical domains within the large knowledge envelope called 'neuroscience' that further includes physiological, pharmacological, neurochemical, behavioral, genetical and clinical domains. This review focuses mainly on the anatomical domain in neuroscience. To a large degree neuroanatomical tract-tracing methods have paved the way in this domain. Over the past few decades, a great number of neuroanatomical tracers have been added to the technical arsenal to fulfill almost any experimental demand. Despite this sophisticated arsenal, the decision which tracer is best suited for a given tracing experiment still represents a difficult choice. Although this review is obviously not intended to provide the last word in the tract-tracing field, we provide a survey of the available tracing methods including some of their roots. We further summarize our experience with neuroanatomical tracers, in an attempt to provide the novice user with some advice to help this person to select the most appropriate criteria to choose a tracer that best applies to a given experimental design. PMID- 21782933 TI - Stabilization of superoxide dismutase by acetyl-l-carnitine in human brain endothelium during alcohol exposure: novel protective approach. AB - Oxidative damage of the endothelium disrupts the integrity of the blood-brain barrier (BBB). We have shown before that alcohol exposure increases the levels of reactive oxygen species (ROS; superoxide and hydroxyl radical) and nitric oxide (NO) in brain endothelial cells by activating NADPH oxidase and inducible nitric oxide synthase. We hypothesize that impairment of antioxidant systems, such as a reduction in catalase and superoxide dismutase (SOD) activity, by ethanol exposure may elevate the levels of ROS/NO in endothelium, resulting in BBB damage. This study examines whether stabilization of antioxidant enzyme activity results in suppression of ROS levels by anti-inflammatory agents. To address this idea, we determined the effects of ethanol on the kinetic profile of SOD and catalase activity and ROS/NO generation in primary human brain endothelial cells (hBECs). We observed an enhanced production of ROS and NO levels due to the metabolism of ethanol in hBECs. Similar increases were found after exposure of hBECs to acetaldehyde, the major metabolite of ethanol. Ethanol simultaneously augmented ROS generation and the activity of antioxidative enzymes. SOD activity was increased for a much longer period of time than catalase activity. A decline in SOD activity and protein levels preceded elevation of oxidant levels. SOD stabilization by the antioxidant and mitochondria-protecting agent acetyl-L carnitine (ALC) and the anti-inflammatory agent rosiglitazone suppressed ROS levels, with a marginal increase in NO levels. Mitochondrial membrane protein damage and decreased membrane potential after ethanol exposure indicated mitochondrial injury. These changes were prevented by ALC. Our findings suggest the counteracting mechanisms of oxidants and antioxidants during alcohol-induced oxidative stress at the BBB. The presence of enzymatic stabilizers favors the ROS neutralizing antioxidant redox of the BBB, suggesting an underlying protective mechanism of NO for brain vascular tone and vasodilation. PMID- 21782935 TI - Lipid peroxidation and neurodegenerative disease. AB - Lipid peroxidation is a complex process involving the interaction of oxygen derived free radicals with polyunsaturated fatty acids, resulting in a variety of highly reactive electrophilic aldehydes. Since 1975, lipid peroxidation has been extensively studied in a variety of organisms. As neurodegenerative diseases became better understood, research establishing a link between this form of oxidative damage, neurodegeneration, and disease has provided a wealth of knowledge to the scientific community. With the advent of proteomics in 1995, the identification of biomarkers for neurodegenerative disorders became of paramount importance to better understand disease pathogenesis and develop potential therapeutic strategies. This review focuses on the relationship between lipid peroxidation and neurodegenerative diseases. It also demonstrates how findings in current research support the common themes of altered energy metabolism and mitochondrial dysfunction in neurodegenerative disorders. PMID- 21782934 TI - Transactivation of gene expression by NF-kappaB is dependent on thioredoxin reductase activity. AB - The redox-sensitive transcription factor NF-kappaB mediates the expression of genes involved in inflammation and cell survival. Thioredoxin reductase-1 (TR1) and its substrate thioredoxin-1 act together to reduce oxidized cysteine residues within the DNA-binding domain of NF-kappaB and promote maximal DNA-binding activity in vitro. It is not clear, however, if NF-kappaB is regulated via this mechanism within living cells. The purpose of this study was to determine the mechanism of NF-kappaB modulation by TR1 in cells stimulated with the inflammatory cytokine tumor necrosis factor-alpha (TNF). In both control cells and cells depleted of TR1 activity through chemical inhibition or siRNA knockdown, TNF stimulation resulted in degradation of the cytoplasmic NF-kappaB inhibitor IkappaB-alpha and translocation of NF-kappaB to the nucleus. Similarly, the DNA-binding activity and redox state of NF-kappaB were unaffected by TR1 depletion. In contrast, NF-kappaB-mediated gene expression was markedly inhibited in cells lacking TR1 activity, suggesting that the transactivation potential of NF-kappaB is sensitive to changes in TR1 activity. Consistent with this concept, phosphorylation of the transactivation domain of NF-kappaB was inhibited in the presence of curcumin. Surprisingly, another TR1 inhibitor, 1-chloro-2,4 dinitrobenzene, had no effect, and siRNA knockdown of TR1 actually increased phosphorylation at this site. These results demonstrate that TR1 activity controls the transactivation potential of NF-kappaB and that more than one mechanism may mediate this effect. PMID- 21782936 TI - Use of newly isolated phages for control of Pseudomonas aeruginosa PAO1 and ATCC 10145 biofilms. AB - Pseudomonas aeruginosa is a relevant opportunistic pathogen involved in nosocomial infections that frequently shows low antibiotic susceptibility. One of its virulence factors is associated with the ability to adhere to surfaces and form virulent biofilms. This work describes the isolation and characterization of lytic phages capable of infecting antibiotic-resistant P. aeruginosa strains. In addition, characterization of P. aeruginosa biofilms and the potential of newly isolated phages for planktonic and biofilm control was accessed. According to the results, the isolated phages showed different spectra of activity and efficiency of lysis. Four broad lytic phages were selected for infection of planktonic cells; however, despite their broad range of activity, two of the selected phages failed to efficiently control planktonic cultures. Therefore, only two phages (phiIBB-PAA2 and phiIBB-PAP21), highly capable of causing strong biomass reduction of planktonic cells, were tested against 24 h biofilms using a m.o.i. of 1. Both phages reduced approximately 1-2 log the biofilm population after 2 h of infection and reduction was further enhanced after 6 h of biofilm infection. However, biofilm cells of P. aeruginosa PAO1 acquired resistance to phiIBB-PAP21; consequently, an increase in the number of cells after 24 h of treatment was observed. Conversely, phage phiIB-PAA2 for P. aeruginosa ATCC10145 continued to destroy biofilm cells, even after 24 h of infection. In these biofilms, phages caused a 3 log reduction in the number of viable counts of biofilm cells. PMID- 21782937 TI - Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging. AB - Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2 associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease. PMID- 21782938 TI - Excellence in education and training advances competitiveness of the pharmaceutical industry in Europe. AB - This commentatory should be read in connection with the subsequent article about current trends in the evolvement of the pharmaceutical industries. It points to importance for the industries to have access to pharmaceutical sciences researchers educated and trained at the highest level through the newly established public-private system of courses in Europe supported by EU. PMID- 21782939 TI - Lactoferrin modified doxorubicin-loaded procationic liposomes for the treatment of gliomas. AB - In this study, a brain-targeted chemotherapeutical delivery system, doxorubicin loaded lactoferrin-modified procationic liposome (DOX-Lf-PCL) was developed, and its therapeutic effect for glioma was evaluated. The uptake profile of various DOX formulations in vitro by primary brain capillary endothelial cells (BCECs) and glioma cell C6 were studied by laser scanning confocal microscope and flow cytometry. An intracranial tumor model of rats was employed to evaluate the therapeutic effect of DOX-Lf-PCLs for glioma. Five groups of glioma-bearing rats (total n=50) were subjected to three cycles of 2.5mg/kg body weight of doxorubicin in different formulations or normal saline (N.S.) and analyzed for survival (median survival time, Kaplan-Meier). The results indicated that compared with the DOX solution or DOX-loaded conventional liposomes (DOX-Lips), DOX-PCLs and DOX-Lf-PCLs showed an improved performance in the uptake efficiency in BCECs and C6 cells. The DOX-Lf-PCLs can inhibit the growth of C6 more efficiently in vitro than other DOX formulations. The endocytosis involved in the DOX-Lf-PCLs uptake of C6 was mediated by both receptor- and absorption-mediated transcytosis. DOX-Lf-PCLs could significantly extend the survival time compared with the N.S. control and other DOX formulations. This study showed that the therapy with DOX-Lf-PCLs offers an effective therapeutic potential for gliomas. PMID- 21782940 TI - WITHDRAWN: Synthesis and Characterization of Anticancer Drug and Antibody conjugated Quantum Dots as A Novel Theranostic Probe for Pancreatic Cancer Detection and Therapy. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21782941 TI - Current trends in the pharmaceutical industry--a case study approach. AB - This commentary offers an overview of some current trends of the pharmaceutical industry drawing on examples taken from the analysis of four companies (Pfizer, Merck, Novo Nordisk, Crucell). The very brief analysis looks at diversification paths, pipeline management strategies, generic competition as well as corporate social responsibility policies. PMID- 21782942 TI - Retained topical delivery of 5-aminolevulinic acid using cationic ultradeformable liposomes for photodynamic therapy. AB - 5-Aminolevulinic acid (5-ALA), inducing photodynamic protoporphyrin (PpIX), is a hydrophilic molecule, resulting in leashing the capacity to cross tissue barriers like stratum corneum (SC) of skin. Here, we aimed to develop 5-ALA loaded ultradeformable liposomes (UDL) with different surface charges, and to investigate their physicochemical characteristics and capability for the skin penetration and retention of 5-ALA for topical photodynamic therapy (PDT). The effects of surface charges of UDL on in vitro permeation of 5-ALA and in vivo accumulation of 5-ALA-induced PpIX in viable skin were determined and then compared with conventional neutral liposomes (nLiposome). All UDL showed smaller particle size and better deformability than nLiposome. However, entrapment efficiency of 5-ALA was similar to each vesicle. Among vesicles, the cationic UDL (cUDL) demonstrated higher stability and permeability, and could deliver 5-ALA into deep skin tissue by topical application. Moreover, the 5-ALA loaded in cUDL was long retained, and induced more amount of PpIX in viable skin than those in other UDL and nLiposome. Considering that the conversion of 5-ALA into PpIX occurs preferentially in epidermis, these results suggested that topical delivery of 5-ALA loaded in cUDL could be an interesting proposal to optimize PDT related to 5-ALA. PMID- 21782943 TI - New steroidal lactones as 5alpha-reductase inhibitors and antagonists for the androgen receptor. AB - This study reports the synthesis of several new steroidal lactones: 5alpha,6beta dibromo-17a-oxa-D-homoandrostane-3beta-yl-3'-oxapentanoate (11), 5alpha,6beta dibromo-17a-oxa-D-homoandrostane-3beta-yl-propanoate (12), 5alpha,6beta-dibromo 17a-oxa-D-homoandrostane-3beta-yl-butanoate (13), 5alpha,6beta-dibromo-17a-oxa-D homoandrostane-3beta-yl-pentanoate (14), 5alpha,6beta-dibromo-17a-oxa-D homoandrostane-3beta-yl-hexanoate (15), 17a-oxa-D-homoandrost-5-en-17-one-3beta yl-3'-oxapentanoate (16), 17a-oxa-D-homoandrost-5-en-17-one-3beta-yl-propanoate (17), 17a-oxa-D-homoandrost-5-en-17-one-3beta-yl-butanoate (18), 17a-oxa-D homoandrost-5-en-17-one-3beta-yl-pentanoate (19) and 17a-oxa-D-homoandrost-5-en 17-one-3beta-yl-hexanoate (20) with a therapeutic potential as antiandrogens. The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of ten new steroidal derivatives on the weight of the prostate and seminal vesicle glands of gonadectomized hamsters treated with testosterone. For the in vitro studies, we determined the IC(50) values by measuring the concentration of the steroidal derivatives that inhibits 50% of the activity of the 5alpha-reductase enzyme present in human prostate and also its binding capacity to the androgen receptors (AR) obtained from rat's prostate cytosol. The results from these experiments indicated that compounds 11-20, significantly decreased the weight of the prostate and seminal vesicles as compared to testosterone treated animals; this reduction of the weight of these glands was comparable to that produced by Finasteride. On the other hand, compounds 11-20 inhibited the enzyme 5alpha reductase, with compounds 14-19 (IC(50) values of 4.2 +/- 0.95, 0.025 +/- 0.003, 1.2 +/- 0.45, 1.2 +/- 0.1, 0.028 +/- 0.003, and 0.069 +/- 0.005 nM, respectively) showing the highest inhibitory activity. The results from the in vitro experiments indicated that only 15-17 bind to the AR. PMID- 21782944 TI - Antibody-mediated allograft rejection: the emerging role of endothelial cell signalling and transcription factors. AB - The presence of antibodies against class I human leukocyte antigens (HLA) can cause the development of chronic allograft rejection. Although endothelial cell activation has been identified as a main effector, the mechanisms mediating this process are not fully understood. Exposure of endothelium to antibodies against HLA antigens induces cell activation which promotes rejection. This activation process can be divided into two phases: an early response in which intracellular signalling proteins and transcription factors are activated, and a later change in protein expression and cell function. In this review, antibody-mediated endothelial signalling and the role of transcription factors in organ transplantation will be described with a particular focus on their potential to mediate some of the graft-damaging effects of anti-HLA class I antibodies. PMID- 21782945 TI - Intimal fibrosis in human cardiac allograft vasculopathy. AB - Human Cardiac Allograft Vasculopathy (CAV) is one of the major complications for patients after heart transplantation. It is characterized by a concentric luminal narrowing due to (neo) intimal expansion in the coronary arteries of donor hearts after heart transplantation. In this process fibrosis plays an important role. Aim of this study is to analyze the factors and cells involved in this fibrotic process. Coronary arteries from five heart transplantation patients and three controls were obtained at autopsy. Quantitative real-time PCR was performed on mRNA obtained from various arterial layers isolated by laser micro dissection. Positive gene expression was confirmed by immunohistochemistry and/or in situ hybridisation. The strongest mRNA expression of fibrotic factors (predominantly pro-fibrotic) was found in the neo-intima. Especially, connective tissue growth factor expression was higher in the CAV vessels than in the controls. The lymphocyte activity of interferon gamma was only detected in CAV vessels. Furthermore as shown by in situ hybridisation, the lymphocytes producing interferon gamma also expressed transforming growth factor beta. Anti-fibrotic factors, such as bone morphogenic protein 4, were only expressed in CD3(-)/CD68( ) stromal cells. Macrophages present in the CAV and control vessels showed to be of the M2 type and did not produce any fibrotic factor(s). In conclusion, T-cells producing both interferon gamma and transforming growth factor beta, may play an important role in the fibrotic process in CAV vessels by upregulation of connective tissue growth factor production. PMID- 21782946 TI - Age and alpha-synuclein expression interact to reveal a dependence of dopaminergic axons on endogenous Akt/PKB signaling. AB - The mechanisms underlying the chronic neurodegeneration that occurs in Parkinson's disease (PD) are unknown. One emerging hypothesis is that neural systems deteriorate and eventually degenerate due to a primary failure of either extrinsic neurotrophic support or the intrinsic cellular pathways that mediate such support. One of the cellular pathways that have been often identified in mediating neurotrophic effects is that of PI3K/Akt signaling. In addition, recent observations have suggested a primary failure of PI3K/Akt signaling in animal models and in PD patients. Therefore, to explore the possible role of endogenous Akt signaling in maintaining the viability and functionality of substantia nigra (SN) dopamine neurons, one of the principal systems affected in PD, we have used an adeno-associated viral vector to transduce them with a dominant negative (DN) form of Akt, the pleckstrin homology (PH) domain alone (DN(PH)-Akt). In addition, we have examined the effect of DN(PH)-Akt in murine models of two risk factors for human PD: advanced age and increased expression of alpha-synuclein. We find that transduction of these neurons in normal adult mice has no effect on any aspect of their morphology at 4 or 7weeks. However, in both aged mice and in transgenic mice with increased expression of human alpha-synuclein we observe decreased phenotypic expression of the catecholamine synthetic enzyme tyrosine hydroxylase (TH) in dopaminergic axons and terminals in the striatum. In aged transgenic alpha-synuclein over-expressing mice this reduction was 2-fold as great. We conclude that the two principal risk factors for human PD, advanced age and increased expression of alpha-synuclein, reveal a dependence of dopaminergic neurons on endogenous Akt signaling for maintenance of axonal phenotype. PMID- 21782947 TI - Morin attenuates tau hyperphosphorylation by inhibiting GSK3beta. AB - Alzheimer's disease (AD) is the major form of age-related dementia and is characterized by progressive cognitive impairment, the accumulation of extracellular amyloid beta-peptide (Abeta), and intracellular hyperphosphorylated tau aggregates in affected brain regions. Tau hyperphosphorylation and accumulation in neurofibrillary tangles is strongly correlated with cognitive deficits, and is apparently a critical event in the dementia process because mutations in tau can cause a tangle-only form of dementia called frontotemporal lobe dementia. Among kinases that phosphorylate tau, glycogen synthase kinase 3beta (GSK3beta) is strongly implicated in AD pathogenesis. In the present study, we established an ELISA to screen for agents that inhibit GSK3beta activity and found that the flavonoid morin effectively inhibited GSK3beta activity and blocked GSK3beta-induced tau phosphorylation in vitro. In addition, morin attenuated Abeta-induced tau phosphorylation and protected human neuroblastoma cells against Abeta cytotoxicity. Furthermore, treatment of 3xTg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons. Morin is a novel inhibitor of GSK3beta that can reduce tau pathology in vivo and may have potential as a therapeutic agent in tauopathies. PMID- 21782949 TI - Neuronal protein trafficking: emerging consequences of endoplasmic reticulum dynamics. AB - The highly polarized morphology and complex geometry of neurons is determined to a great extent by the structural and functional organization of the secretory pathway. It is intuitive to propose that the spatial arrangement of secretory organelles and their dynamic behavior impinge on protein trafficking and neuronal function, but these phenomena and their consequences are not well delineated. Here we analyze the architecture and motility of the archetypal endoplasmic reticulum (ER), and their relationship to the microtubule cytoskeleton and post translational modifications of tubulin. We also review the dynamics of the ER in axons, dendrites and spines, and discuss the role of ER dynamics on protein mobility and trafficking in neurons. PMID- 21782948 TI - Sub-antimicrobial doxycycline for periodontitis reduces hemoglobin A1c in subjects with type 2 diabetes: a pilot study. AB - In vitro and animal studies suggest a possible role for the tetracycline class of drugs in the inhibition of non-enzymatic protein glycation. We conducted a 3 month, randomized placebo-controlled pilot clinical trial of conventional sub gingival debridement (periodontal therapy), combined with either a three month regimen of sub-antimicrobial-dose doxycycline (SDD), a two week regimen of antimicrobial-dose doxycycline (ADD), or placebo in 45 patients with long standing type 2 diabetes (mean duration 9 years) and untreated chronic periodontitis. Subjects were taking stable doses of oral hypoglycemic medications and/or insulin. Treatment response was assessed by measuring hemoglobin A1c (HbA1c), plasma glucose, and clinical periodontal disease measures. At one-month and three-month follow-up, clinical measures of periodontitis were decreased in all groups (data to be presented elsewhere). At three months, mean HbA1c levels in the SDD group were reduced 0.9% units from 7.2% units+/-2.2 (+/-SD), to 6.3% units+/-1.1, which represents a 12.5% improvement. In contrast, there was no significant change in HbA1c in the ADD (7.5%+/-2.0 to 7.8%+/-2.1) or placebo (8.5%+/-2.0 to 8.5%+/-2.6) groups. Mean HbA1c change from baseline was significantly greater in the SDD group compared with the ADD group (p=0.04) but not placebo (p=0.22). Moreover, a larger proportion of subjects in the SDD group experienced improvement (p<0.05) compared to the ADD or placebo groups. Mean plasma glucose levels were not significantly different between or within the groups. The results of this pilot study suggest that the treatment of periodontitis with sub-gingival debridement and 3-months of daily sub antimicrobial-dose doxycycline may decrease HbA1c in patients with type 2 diabetes taking normally prescribed hypoglycemic agents. PMID- 21782950 TI - Targeted endoradiotherapy using nucleotides. AB - Increased cellular proliferation is an integral part of the cancer phenotype. Hence, the sustained and continued demand on supply of DNA building blocks during the DNA replication presents a potential target for therapeutic intervention. For this propose, the alpha and Auger electron emitting nucleotides analogs are attractive for targeted endoradiotherapy, given that DNA of malignant cells is selectively addressed. This review summarizes development and preclinical and clinical studies of endoradiotherapeutic acting nucleoside analogs with a special focus on thymidine analogs. PMID- 21782951 TI - The expression analysis of inflammatory and antimicrobial genes in the goldfish (Carassius auratus L.) infected with Trypanosoma carassii. AB - We report results of a comprehensive analysis of inflammatory gene expression during the course of infection of Trypanosoma carassii in the goldfish. We observed significant increases in mRNA levels of genes encoding pro-inflammatory cytokines IFN-gamma, TNFalpha1 and TNFalpha2; IL-1beta-1 and IL-1beta-2; IL-12 p35 and IL-12-p40; CCL1; CXCL8, anti-inflammatory cytokines IL-10 and TGFbeta and iNOS A and iNOS B, using quantitative PCR. Expression levels and profiles of these cytokines and iNOS isoforms varied in the different tissues (kidney, spleen, liver) of goldfish during the course of T. carassii infection. The expression of majority of genes that encode pro- and anti-inflammatory cytokines were up-regulated during the acute phase of infection (days 7-21 post-infection). The mRNA levels of these cytokines returned to normal levels or were down regulated during the elimination phase of infection (days 28-56), with exception of IL-10 in the spleen and liver of infected fish. A parallel up-regulation of IFN-gamma and IL-10 mRNA levels were observed in all tissues of infected fish during the acute phase of the infection. The expression of iNOS genes (iNOS A and B) was significantly delayed (day 14 pi) in the kidney, liver and spleen of infected fish. These results provide insights into the interaction between T. carassii and goldfish, and suggest that Th1/Th2-like responses may be important for controlling T. carassii infection in the goldfish. PMID- 21782952 TI - Kalopanax pictus as feed additive controls bacterial and parasitic infections in kelp grouper, Epinephelus bruneus. AB - Feeding kelp grouper, Epinephelus bruneus (26.1 +/- 1.4), with 0%, 0.1%, 1.0%, and 2.0% Kalopanax pictus extract-supplementation diets, for 30 days reduced mortality on being challenged intraperitoneally 100 MUl with bacterium Vibrio alginolyticus (2.1 * 10(7) cfu ml(-1)) and ciliate parasite Philasterides dicentrarchi (2.3 * 10(7) ciliates ml(-1)). The red blood cells (RBC), white blood cells (WBC), haemoglobin, haematocrit, lymphocytes, and monocytes levels significantly increased in kelp grouper fed with all doses of K. pictus supplementation diets and challenged with bacterium and parasite when compared to control. However, the levels of mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), neutrophils, and thrombocytes did not significantly. The phagocytic activity, complement activity, and antiprotease activity did not significantly change in kelp grouper fed with 0.1% K. pictus-supplementation diets and challenged with bacterium and parasite. The respiratory activity, lysozyme activity, bactericidal activity, total protein level, and myeloperoxidase levels significantly increased in kelp grouper fed with all the doses of K. pictus-supplementation diet and challenged with bacterium and parasite. However, alpha2-macroglobulin level significantly increased with 1.0% diet, but not with 0.1% and 2.0% diets. Therefore this study suggests that 1.0% and 2.0% K. pictus-supplementation diets positively protected and enhanced the immune system in kelp grouper E. bruneus against V. alginolyticus and P. dicentrarchi infection. PMID- 21782953 TI - Hemoglobin of the bloody clam Tegillarca granosa (Tg-HbI) is involved in the immune response against bacterial infection. AB - Hemoglobins (Hb) are the major protein components of erythrocytes circulating in the red blood, but can serve additional functions besides the transport of oxygen. Here, the cDNA of the bloody clam (Tegillarca granosa) Hb dimer (designated Tg-HbI) was cloned and was found to be 748 bp in length, consisting of an open reading frame of 441 bp encoding a polypeptide of 147 amino acids. The deduced amino acid sequence of Tg-HbI shared 81.6% similarity with HbI from two species of the genus Scapharca and 46-51% similarity with the Hb proteins from other mollusks. The 3D structure of bloody clam Tg-HbI was predicted by the SWISS MODEL Protein Modelling Server and compared with that of Scapharca kagoshimensis. The mRNA transcript of Tg-HbI was detected in all of the clam cells/tissues examined, including haemocytes, the adductor muscle, foot, hepatopancreas, gill and mantle. The mRNA expression of Tg-HbI was significantly up-regulated after Vibrio parahaemolyticus, lipopolysaccharide and peptidoglycan challenge, indicating that Tg-HbI was involved in the immune defence responses against bacterial infection and exposure to bacterial pathogenic factors. As the first functional research on the Hb protein in bloody clam, our findings provide new insight into the innate immune defence mechanisms of T. granosa and other mollusks. PMID- 21782954 TI - Characterization of the gilthead seabream (Sparus aurata L.) transferrin gene: genomic structure, constitutive expression and SNP variation. AB - Transferrin (Tf) is a multi-function protein with a central role in iron metabolism, and it is this function that is associated with a role in the innate immune system response. The clear link between Tf and immune defense mechanism lead to propose Tf as a candidate gene for disease resistance. In this study, genomic and cDNA sequences of Tf gene in gilthead seabream (Sparus aurata L.) (SaTf gene), were identified and characterized. SaTf gene structure consists of a coding region of 2076 nucleotides divided into 17 exons and a no-coding region that includes 16 introns and spans 5495 nucleotides. The deduced Tf protein for gilthead seabream is composed of 691 amino acids and consists of an initial peptide and two lobes (N- and C-lobes). This gene structure is similar to that of previously described Tf genes in other fish species. RT-PCR analyses carried out in different tissues and two developmental stages showed tissue-and stage specific Tf expression in gilthead seabream. Finally, by sequencing the transferrin genomic sequences of 20 unrelated seabreams, 31 SNPs were identified. These data allowed the estimation of the frequency of nucleotide substitution in the SaTf gene as 1SNP per 253 bp. SNPs were detected in different regions of the genomic sequence but they were mainly localized in non-coding regions, specifically, SNP frequency in non-coding regions was fifteen-fold higher than within coding regions. PMID- 21782955 TI - An IRF-3 homolog that is up-regulated by DNA virus and poly I:C in turbot, Scophthalmus maximus. AB - In this study, we described the structure, mRNA tissue distribution and regulation of an IRF-3 gene from turbot, Scophthalmus maximus (SmIRF-3). The gene sequence of SmIRF-3 is 6077 bp long, composed of 11 exons and 10 introns similar to known IRF-3 genes of fish, and encodes a peptide of 466 amino acids. The deduced protein sequence shares the highest identity of 56.0-81.2% with fish IRF 3 and possesses a DNA-binding domain (DBD), an IRF association domain (IAD) and a serine-rich domain (SRD) known to be important for the functions of IRF-3 in vertebrates. Phylogenetic analysis grouped SmIRF-3 with other IRF3s of vertebrates. SmIRF-3 transcripts were detectable in limited tissue types of healthy fish, with higher expression observed in head, kidney, spleen and kidney,. The SmIRF-3 was transcriptionally up-regulated by turbot reddish body iridovirus (TRBIV) and polyinosinic:polycytidylic acid (poly I:C) in the head kidney, spleen and gills, with showing a two wave induced expression during a 7 day time course in all cases. The highest inducibility and the likely earliest increase of SmIRF-3 expression were observed in the spleen, and poly I:C was a stronger inducer. In addition, the maximal expression level of SmIRF-3 arose prior to that of the Mx in all the cases. PMID- 21782956 TI - Molecular cloning, characterization and expression analysis of receptor for activated C kinase 1 (RACK1) from pearl oyster (Pinctada martensii) challenged with bacteria and exposed to cadmium. AB - Receptor for activated C kinase 1 (RACK1) is involved in superoxide anion generation and play an important role in the immune response. In the study, we cloned the full-length sequence of pearl oyster, Pinctada martensii, RACK1 (designated as PmRACK1) by a combination of expression sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE). The full-length cDNA of PmRACK1 is 1176 bp in length, containing a 5' UTR of 83 bp, a 3' UTR of 139, and an open reading frame (ORF) of 954 bp encoding 317 amino acids. Analysis of protein domain features showed that the deduced polypeptide contain seven WD domains characteristic of RACK1 protein family. The tissue distribution of PmRACK1 in unchallenged pearl oysters and temporal expression pattern of PmRACK1 in pearl oysters challenged with bacteria and exposed to 0.1 ppm cadmium were analyzed by quantitative real-time PCR (qRT-PCR). The transcript was detected in all tissues tested, and the expression level was highest in hepatopancreas and lowest in adductor muscle. After challenge with bacteria, expression level of PmRACK1 in haemocytes was gradually decreased until 6 h post challenge, and then up-regulated over time. After exposure to cadmium, its expression level in gill decreased on 1 d post exposure, and then increased as time elapsed, and its expression level in hepatopancreas gradually decreased until 2 d post exposure, and then increased over time. These results suggested that PmRACK1 was involved in oxidative stress response caused by bacteria and cadmium and was a useful biomarker for cadmium exposure. The expression pattern of PmRACK1 in response to bacterial challenge also has a potential link with organism's immune response. PMID- 21782957 TI - Temporal dynamics of face selection mechanism in the context of similar and dissimilar faces: ERP evidence for biased competition within the ventral occipito temporal cortex using ICA. AB - This study was designed to investigate the spatio-temporal characteristic of face selection in the context of the Biased Competition (BC) model using electroencephalography (EEG). Pairs of similar (SIM) or dissimilar (DISS) faces were presented simultaneously. Subjects had to attend to one face (ATT) or ignore both faces (IGN). According to the BC account, simultaneously presented faces compete for representation. Spatial attention biases these competitive interactions towards neural processing of the attended face alone. A preceding functional magnetic resonance imaging (fMRI) study confirmed the validity of BC as selection principle in the occipital face area (OFA) and in the fusiform face area (FFA) (IGN SIM1000 MUg/ml and 4.4mm zone of inhibition) and Bacillus subtilis (MIC of 850 MUg/ml and 2.6mm zone of inhibition). Furthermore, DMBPO was found to be a potent inhibitor of opportunistic fungal pathogens too. It showed a maximum activity against Aspergillus niger with a MIC value of 1 MUg/ml and 28 mm zone of inhibition. CONCLUSION: The result of this study indicates that DMBPO possess antibiotic activity to selected bacterial and fungal pathogens and exhibited better activity against fungi than bacteria. PMID- 21782966 TI - Systemic features of immune recognition in the gut. AB - The immune system, to protect the body, must discriminate between the pathogenic and non-pathogenic microbes and respond to them in different ways. How the mucosal immune system manages to make this distinction is poorly understood. We suggest here that the distinction between pathogenic and non-pathogenic microbes is made by an integrated system rather than by single types of cells or single types of receptors; a systems biology approach is needed to understand immune recognition. PMID- 21782965 TI - Disruption of haemocyte function by exposure to cytochalasin b or nocodazole increases the susceptibility of Galleria mellonella larvae to infection. AB - Administration of non-toxic concentrations (10 MUM) of cytochalasin b and nocodazole to larvae of Galleria mellonella increased their susceptibility to infection by the yeast Candida albicans. These agents were found to inhibit the process of phagocytosis and to reduce the killing ability of haemocytes. In addition, both cytochalasin b and nocodazole reduced the release of antimicrobial peptides (e.g. apolipophorin 3) and enzymes (e.g. serine protease) from PMA stimulated haemocytes. Rhodamine coupled phalloidin staining revealed reduced F actin formation in haemocytes treated with nocodazole or cytochalasin b. By disrupting the formation of F-actin cytochalasin b and nocodazole have the ability to retard the function of haemocytes, in the same manner as they affect mammalian neutrophils, and thus increase the susceptibility of larvae to infection. The results presented here demonstrate that haemocytes are sensitive to inhibition by nocodazole and cytochalasin b, in a similar manner to neutrophils, thus highlighting another similarity between both cell types and so increasing the attractiveness of using insects as alternative models to the use of mammals for in vivo pathogen or drug screening. PMID- 21782964 TI - Vibrio parahaemolyticus cell biology and pathogenicity determinants. AB - Vibrio parahaemolyticus is a significant cause of gastroenteritis worldwide. Characterization of this pathogen has revealed a unique repertoire of virulence factors that allow for colonization of the human host and disease. The following describes the known pathogenicity determinants while establishing the need for continued research. PMID- 21782967 TI - Evolution of the physicochemical properties of marketed drugs: can history foretell the future? AB - A set of diverse bioactive molecules, relevant from a medicinal chemistry viewpoint, was assembled and used to navigate the physicochemical property space of new and old, or traditional drugs against a larger set of 12,000 diverse bioactive small molecules. Most drugs on the market only occupy a fraction of the property space of the bioactive molecules, whereas new molecular entities (NMEs) approved since 2002 are moving away from this traditional drug space. In this new territory, semi-empirical rules derived from knowledge accumulated from historic, older molecules are not necessarily valid and different liabilities become more prominent. PMID- 21782968 TI - Anglo-Saxon pharmacopoeia revisited: a potential treasure in drug discovery. AB - Three of the four major Anglo-Saxon collections reporting medicinal formulations in England from the 10th century, the Old English Herbarium, Bald's Leechbook and the Lacnunga, could contain leads and insights into new medicinal uses. Previous pharmacological studies of medicinal plants mentioned in Anglo-Saxon medical texts suggested that some were effective and led to the identification and isolation of natural compounds. For example, matricin from yarrow Achillea millefolium L., is a proprionic acid analogue that yields chamazulene carboxylic acid with cyclooxygenase-2 activity similar to that of ibuprofen. As we discuss here, multidisciplinary projects could further explore historical texts to discover additional plant metabolites with potential pharmacological applications. PMID- 21782969 TI - Recent advances in the administration of vaccines for infectious diseases: microneedles as painless delivery devices for mass vaccination. AB - Despite remarkable progress in the control of infectious diseases through vaccination, better delivery systems have been poorly explored. There is renewed interest in the discovery of novel vaccines and adjuvants owing to emerging and reemerging diseases and the burden and complexity of chronic infectious diseases. Conversely, the need for rapid local, regional, mucosal or parenteral bioavailability has led to advances in delivery systems and devices. Here, we present recent developments in the field of non-invasive cutaneous delivery of vaccines for infectious diseases. Transdermal delivery using microneedles could revolutionize the way prophylactic interventions for infectious diseases are carried out in the future. PMID- 21782970 TI - Mutation rates in scots pine (Pinus sylvestris L.) from the Chernobyl exclusion zone evaluated with amplified fragment-length polymorphisms (AFLPs) and microsatellite markers. AB - Ionizing radiation is a strong mutagenic factor and, accordingly, elevated mutation rates would be expected in plants exposed to high chronic or acute radiation after the Chernobyl accident in 1986. Somatic mutations were analyzed in pines (Pinus sylvestris L.) planted before and after the Chernobyl accident and in control material of the same origin planted in sites with natural radiation. Microsatellites (SSRs) and amplified fragment-length polymorphisms (AFLPs) were investigated. The mutation rates for microsatellites were estimated as 2.8 * 10(-4)-7.1 * 10(-4) per locus for different irradiated tree populations; no mutations were detected in the controls. In the case of AFLPs, the observed mutation rates were 3.74 * 10(-3) -3.99 * 10(-3) and 1.06 * 10(-3) per locus for contaminated and control areas, respectively. Thus a statistically highly significant three-fold increase in number of mutations was found by the use of AFLP markers, indicating that ionizing radiation causes strong DNA damage across the entire genome and that AFLPs may be the appropriate marker system for this kind of analysis. PMID- 21782971 TI - Secreted Opisthorchis viverrini glutathione S-transferase regulates cell proliferation through AKT and ERK pathways in cholangiocarcinoma. AB - Opisthorchis viverrini can develop mitogenic substances into the excretory/secretory product (ESP) that may play an important role in promoting the genesis of cholangiocarcinoma (CCA). In the present study, glutathione S transferase (GST) is identified as being secreted into Ov-ESP and acting as one of the parasitic mitogens. Its proliferative effect and possible mechanism were explored and its association with the tumor development is proposed. Ov-ESP was concentrated and purified by gel filtration chromatography. SDS-PAGE, 2-DE, and LC-MS/MS identified GST predominantly expressed in the proliferative ESP fraction. The recombinant OvGST (rOvGST) was produced by wheat germ cell-free expression and confirmed by an MTS assay to have a proliferative function on NIH 3T3 murine fibroblasts and MMNK1 non-tumorigenic human bile duct epithelial cells in a dose dependent manner with different optimal doses. The cell surface binding of rOvGST was confirmed in vitro and the activation of both pAKT and pERK was revealed as the mechanism of OvGST-mediated cell proliferation. With support from the observation of secreted OvGST on the biliary cells surrounding the parasites, it is suggested that OvGST can promote cell proliferation that consequently may accelerate the genesis of CCA. PMID- 21782972 TI - Cloning, expression, and characterization of a novel Opisthorchis viverrini calcium-binding EF-hand protein. AB - A novel 22.8 kDa of Opisthorchis viverrini (Ov) calcium-binding EF-hand protein (Ov CaBP) was identified and isolated from an immunoscreening of the adult stage Ov cDNA library by using a human cholangiocarcinoma (CCA) serum. This protein was related to other calcium-binding proteins and conserved among the trematodes. Ov CaBP shared 98% amino acid identity to 22.8 kDa of Clonorchis sinensis CaBP and both were classified as a new group of CaBP EF-hand protein by multiple sequence alignment and phylogenetic tree analysis. The open reading frame of Ov CaBP was 585 bp which encoded for 194 amino acids. The N-terminal part is composed of two calcium-binding EF-hand motifs whereas the C-terminal part contains a dynein light chain motif (DLC). In addition, transcription analysis by RT-PCR revealed that it was constitutively transcribed in all stages, including metacercariae, juvenile, and adult. Furthermore, recombinant Ov CaBP protein (rOv CaBP) was expressed as a soluble protein and antibody generated against this rOv CaBP protein was capable of detecting Ov CaBP in the Ov somatic extracts but not in Ov ES products. This anti-rOv CaBP serum was also used to localize Ov CaBP in Ov infected hamster's liver sections which the distribution of Ov CaBP was located in gut epithelium, miracidia in eggs and slightly in parenchyma. Moreover, rOv CaBP protein showed a calcium-binding property in non-denaturing gel mobility shift assay. PMID- 21782973 TI - YALI0E32769g (DGA1) and YALI0E16797g (LRO1) encode major triacylglycerol synthases of the oleaginous yeast Yarrowia lipolytica. AB - The oleaginous yeast Yarrowia lipolytica has an outstanding capacity to produce and store triacylglycerols resembling adipocytes of higher eukaryotes. Here, the identification of two genes YALI0E32769g (DGA1) and YALI0E16797g (LRO1) encoding major triacylglycerol synthases of Yarrowia lipolytica is reported. Heterologous expression of either DGA1 or LRO1 in a mutant of the budding yeast Saccharomyces cerevisiae defective in triacylglycerol synthesis restores the formation of this neutral lipid. Whereas Dga1p requires acyl-CoA as a substrate for acylation of diacylglycerol, Lro1p is an acyl-CoA independent triacylglycerol synthase using phospholipids as acyl-donor. Growth of Yarrowia lipolytica strains deleted of DGA1 and/or LRO1 on glucose containing medium significantly decreases triacylglycerol accumulation. Most interestingly, when oleic acid serves as the carbon source the ratio of triacylglycerol accumulation in mutants to wild-type is significantly increased in strains defective in DGA1 but not in lro1Delta. In vitro experiments revealed that under these conditions an additional acyl-CoA dependent triacylglycerol synthase contributes to triacylglycerol synthesis in the respective mutants. Taken together, evidence is provided that Yarrowia lipolytica contains at least four triacylglycerol synthases, namely Lro1p, Dga1p and two additional triacylglycerol synthases whereof one is acyl-CoA dependent and specifically induced upon growth on oleic acid. PMID- 21782974 TI - Glutathione peroxidase-deficient smooth muscle cells cause paracrine activation of normal smooth muscle cells via cyclophilin A. AB - BACKGROUND/AIMS: Reduced activity of the antioxidant glutathione peroxidase-1 (GPx1) correlates with increased risk of cardiovascular events in patients with coronary artery disease. However, it remains unclear whether this imbalance in antioxidant capacity directly contributes to activation of vascular cells. In response to oxidative stress, smooth muscle cells (SMCs) secrete the pro inflammatory immunomodulator cyclophilin A (CyPA). We hypothesized that reduction in vascular cell GPx1 activity causes secretion of CyPA and paracrine-mediated activation of NF-kappaB and proliferation of SMCs. METHODS/RESULTS: Using a murine model of GPx1 deficiency (GPx1(+/-)), we found elevated levels of hydrogen peroxide levels and increased secretion of CyPA in both arterial segments and cultured SMCs as compared to wild type (WT). Conditioned media from GPx1(+/-) SMCs caused increased NF-kappaB activation of quiescent WT SMCs, and this was inhibited by the antioxidant N-acetyl-l-cysteine or by cyclosporine A (CsA). In co-culture experiments, SMCs derived from GPx1(+/-) aorta caused increased proliferation of WT SMCs, which was also inhibited by CsA. CONCLUSIONS: Reduction in vascular cell GPx1 activity and the associated increase in oxidative stress cause CyPA-mediated paracrine activation of SMCs. These findings identify a novel mechanism by which an imbalance in antioxidant capacity may contribute to vascular disease. PMID- 21782976 TI - Power and sample size for cost-effectiveness analysis: fFN neonatal screening. AB - Randomised controlled trials (RCTs) which involve cost-effectiveness evaluations rarely use health economic input when undertaking sample size calculations for the trial design; however, in studies undertaken with cost-effectiveness as the primary outcome, sample size calculations should be directly related to the cost effectiveness result rather than to the effectiveness outcome alone. This paper reports on a case in which a clinical trial design sample size and power calculations were determined with regard to cost-effectiveness using the net monetary benefit (NMB) approach to demonstrate the feasibility of sample size calculation for cost-effectiveness in a real life setting. The proposed RCT of fetal fibronectin screening (fFN) for women with threatened pre-term labour is discussed, followed by the design of a preliminary model to inform the trial design calculation. The predictions from this pre-trial indicate potential cost savings, but with a marginal detrimental impact on the effectiveness endpoint, neonatal morbidity. The NMB approach for cost-effectiveness is discussed and used to calculate the required sample sizes for different powers. The sample size calculations are then recalculated using a non-inferiority margin, to ensure that the NMB sample size for the trial was also sufficient to demonstrate non inferiority for the effectiveness endpoint. Finally, a probabilistic analysis explored uncertainty in the model parameters and the impact on sample size. Considerations of economic assessments alongside clinical trials can and should be used to guide conventional trial design. This paper demonstrates the feasibility of such calculations, whilst simultaneously highlighting limitations and demonstrating the role for economic considerations to guide non-inferiority margins. PMID- 21782975 TI - Health is Power: an ecological, theory-based health intervention for women of color. AB - OBJECTIVE: Physical inactivity and poor dietary habits plague Americans as health challenges, with women of color most vulnerable to their detrimental effects. Individually focused interventions have not demonstrated lasting success, possibly due to the lack of focus on sustainable social and physical environment factors. This manuscript describes the rationale, design and methodology of Health Is Power (HIP), a transcultural, community based, randomized controlled trial that investigated the effectiveness of a group cohesion intervention to increase physical activity and improve dietary habits in African American and Hispanic or Latina women in Houston and Austin, Texas. METHODS: The intervention development was guided by group dynamics principles anchored within an ecologic model. RESULTS: Women participated in three health assessments and a six month face to face intervention that included evidence-based behavioral methods - integrated into strategies to promote group cohesion - framed to account for environmental factors contributing to health disparities. Women participated in team building activities, environmental mapping exercises, and supervised walks or taste tests. CONCLUSIONS: Neighborhood contextual and environmental measures are described to test ecologic factors that may contribute to behavioral maintenance. Theoretically guided interventions that account for multiple levels of influence in behavior initiation and maintenance stand to improve health outcomes in vulnerable populations. PMID- 21782977 TI - Screening of poultry-pig farms for methicillin-resistant Staphylococcus aureus: sampling methodology and within herd prevalence in broiler flocks and pigs. AB - Many reports described the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in different livestock animals from one-species farms. However, in no published reports the prevalence on mixed poultry-pig farms was mentioned, nor the possible relation in MRSA colonization between those two species on one farm, and the possible role of the farmer in the dissemination of MRSA between those two species. Furthermore, no data is available on the optimal sampling site to detect MRSA in broilers. Therefore this study aimed to determine the most suitable sample location in broiler chickens for MRSA and the within flock prevalence of MRSA in various broiler flocks and compared this with the MRSA prevalence in pigs, the colonization of the farmer and the contamination in the barn environment in three mixed poultry-pig farms. MRSA was most frequently isolated from the cloaca and nose shell and to a lesser extent from the skin beneath the wing and the pharynx. The relative sensitivity of the different anatomical sites was, 44.4% for the cloaca, 33.3% for the nose shell, 16.7% for the skin beneath the wing and 5.6% for the pharynx. Based upon these relative sensitivities combining cloaca and nose shell would increase the chance of MRSA detection. A rather low within flock prevalence of MRSA varying between 0% and 28% was detected in broilers, whereas in pigs on the same farms the within herd prevalence varied between 82% and 92%. No MRSA contamination in the direct barn environment of the broilers was found, this in contrast to the environment of the pigs, indicating a relationship between MRSA prevalence and contamination in the environment. Two farmers were continuously colonized, while the third one was only once. In conclusion, a major difference was seen in MRSA occurrence between broilers and pigs from the same farm. This may suggest that broilers are naturally less susceptible to MRSA ST398 colonization than pigs. Conversely, short production time in broilers, vacancy of the barn environment during one week and the higher frequency of disinfection might also explain the lower prevalence in broilers. The farmer may play an important role in the dissemination of MRSA from pigs to poultry, especially in mixed farms where pigs are highly colonized and may act as a reservoir for MRSA ST398 carriage in humans. PMID- 21782978 TI - Changes in mitochondrial reactive oxygen species synthesis during differentiation of skeletal muscle cells. AB - Myogenesis is accompanied by an intensive metabolic remodeling. We investigated the mitochondrial reactive oxygen species (ROS) generation at different levels of skeletal muscle differentiation: in C2C12 myoblasts, in C2C12 myotubes and in adult mouse skeletal muscle. Differentiation was accompanied by an increase in mitochondrial content and respiratory chain activity. The detected ROS production levels correlated with mitochondrial content, being the lowest in the myoblasts. Unlike the adult skeletal muscle, myoblast ROS production was significantly stimulated by the complex I inhibitor rotenone. Our results show that mitochondria are an important ROS source in skeletal muscle cells. The substantial changes in mitochondrial ROS synthesis during skeletal muscle differentiation can be explained by intensive bioenergetic remodeling. PMID- 21782979 TI - Rapamycin reduces oxidative stress in frataxin-deficient yeast cells. AB - Friedreich ataxia (FRDA) is a common form of ataxia caused by decreased expression of the mitochondrial protein frataxin. Oxidative damage of mitochondria is thought to play a key role in the pathogenesis of the disease. Therefore, a possible therapeutic strategy should be directed to an antioxidant protection against mitochondrial damage. Indeed, treatment of FRDA patients with the antioxidant idebenone has been shown to improve neurological functions. The yeast frataxin knock-out model of the disease shows mitochondrial iron accumulation, iron-sulfur cluster defects and high sensitivity to oxidative stress. By flow cytometry analysis we studied reactive oxygen species (ROS) production of yeast frataxin mutant cells treated with two antioxidants, N-acetyl L-cysteine and a mitochondrially-targeted analog of vitamin E, confirming that mitochondria are the main site of ROS production in this model. Furthermore we found a significant reduction of ROS production and a decrease in the mitochondrial mass in mutant cells treated with rapamycin, an inhibitor of TOR kinases, most likely due to autophagy of damaged mitochondria. PMID- 21782981 TI - Spinal respiratory motoneurons and interneurons. AB - Maintenance of life among higher vertebrates depends on permanent, rhythmic and coordinated activity of respiratory muscles. Fundamental to our understanding of breathing is an appreciation for the neural components involved in the generation, maintenance and modulation of respiratory rhythm. Multidisciplinary studies have revealed important perspectives about the spinal and supraspinal components contributing to breathing, but a complete understanding of respiratory pathways and their interconnectivity remains unknown. Definition of these pathways is essential for understanding how respiratory processes may be affected by injury or disease. The present review highlights our current understanding of the distribution of spinal motoneurons and interneurons involved in mammalian respiratory activity and how they are affected by injury or disease in the central nervous system. PMID- 21782980 TI - Role of MHC Class II genes in the pathogenesis of pemphigoid. AB - Pemphigoid (Pg) is an autoimmune subepidermal blistering disease that affects the elderly population. The phenotype can be Bullous Pemphigoid (BP), which primarily involves the skin, or Mucous Membrane Pemphigoid (MMP), which primarily involves mucus membranes. Ocular Cicatricial Pemphigoid (OCP) and Oral Pemphigoid (OP) are subsets of MMP. The known antigens in BP are Bullous Pemphigoid Antigen 1 (BPAG1, also known as BP230), Bullous Pemphigoid Antigen 2 (BPAG2, also known as BP180), and subunits of human integrins alpha6 and beta4. The Human Leukocyte Antigen (HLA) allele HLA-DQbeta1*0301 has been reported to be associated with enhanced susceptibility to all of these subsets. Sera of patients with the four subsets are characterized by the presence of anti-Basement Membrane Zone (anti-BMZ) antibodies. In this manuscript, we present a model in which relevant portions of the four different antigens involved in pemphigoid have potential sites that could be presented by an antigen presenting cell (APC) in conjunction with DQbeta1*0301 to a T cell receptor to initiate the process that results in anti BMZ antibody production. Thus, this model provides a hypothetical computer-based mechanism to explain how a single HLA allele can be associated with the production of antibodies to four different antigens that result in four different subsets of a disease with four different clinical profiles and prognoses. PMID- 21782982 TI - pH stability of the stromelysin-1 catalytic domain and its mechanism of interaction with a glyoxal inhibitor. AB - The stromelysin-1 catalytic domain(83-247) (SCD) is stable for at least 16 h at pHs 6.0-8.4. At pHs 5.0 and 9.0 there is exponential irreversible denaturation with half lives of 38 and 68 min respectively. At pHs 4.5 and 10.0 irreversible denaturation is biphasic. At 25 degrees C, C-terminal truncation of stromelysin-1 decreases the stability of the stromelysin-1 catalytic domain at pH values >8.4 and <6.0. We describe the conversion of the carboxylate group of (betaR)-beta [[[(1S)-1-[[[(1S)-2-Methoxy-1-phenylethyl]amino]carbonyl]-2,2 dimethylpropyl]amino]carbonyl]-2-methyl-[1,1'-biphenyl]-4-hexanoic acid (UK 370106-COOH) a potent inhibitor of the metalloprotease stromelysin-1 to a glyoxal group (UK-370106-CO(13)CHO). At pH 5.5-6.5 the glyoxal inhibitor is a potent inhibitor of stromelysin-1 (K(i)=~1MUM). The aldehyde carbon of the glyoxal inhibitor was enriched with carbon-13 and using carbon-13 NMR we show that the glyoxal aldehyde carbon is fully hydrated when it is in aqueous solutions (90.4ppm) and also when it is bound to SCD (~92.0ppm). We conclude that the hemiacetal hydroxyl groups of the glyoxal inhibitor are not ionised when the glyoxal inhibitor is bound to SCD. The free enzyme pK(a) values associated with inhibitor binding were 5.9 and 6.2. The formation and breakdown of the signal at ~92ppm due to the bound UK-370106-CO(13)CHO inhibitor depends on pK(a) values of 5.8 and 7.8 respectively. No strong hydrogen bonds are present in free SCD or in SCD-inhibitor complexes. We conclude that the inhibitor glyoxal group is not directly coordinated to the catalytic zinc atom of SCD. PMID- 21782983 TI - Structural characterization of recombinant human myoglobin isoforms by (1)H and (129)Xe NMR and molecular dynamics simulations. AB - Myoglobin (Mb), the main cytosolic oxygen storage/deliver protein, is also known to interact with different small ligands exerting other fundamental physiological roles. In Humans up to five different Mb isoforms are present. The two most expressed ones (>90%) differ only at the 54th position, K54 (Mb-I) and E54 (Mb II) respectively. High-altitude populations are characterized by a higher Mb concentration in skeletal muscle, totally attributable to Mb-II, as well as a higher efficiency of locomotion, leading to the hypothesis of a cause-effect relationship with the evolutionary response to the high-altitude hypoxic environment. In this work, a first structural characterization of the two more expressed human Mb isoforms has been carried out. In particular, a detailed (1)H and (129)Xe NMR study was aimed to characterize the structure of the hydrophobic cavities around the heme group. Experimental results have been compared to those from MD simulations, i.e. volume fluctuations and occurrence. Electronic structure of the heme ring ground state resulted to be comparable for the two investigated isoforms, despite the single point mutation at position 54. However, the use of (129)Xe as a probe revealed small but significant modifications in the structure of internal cavities. MD simulations supported NMR results indicating interesting structural/dynamical differences in the average volume and occurrence of the main cavities lining Mb prosthetic group. PMID- 21782985 TI - Xq12q13.1 microduplication encompassing the EFNB1 gene in a boy with congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) has an incidence of around 1/3000 births. Chromosomal anomalies constitute an important etiology for non-isolated CDH, and may participate to the identification of candidate genes for diaphragm development. We report on a microduplication identified by array-CGH (comparative genomic hybridization) including five contiguous genes (OPHN1, YIPF6, STARD8, EFNB1 and PJA1) and arising de novo in a male presenting a congenital diaphragmatic hernia (CDH). Our case is the second report of EFNB1 duplication associated with CDH in a male patient, supporting its implication sensitive to gene dosage in diaphragm development. PMID- 21782984 TI - The endosome-lysosome pathway and information generation in the immune system. AB - For a long time the lysosomal pathway was thought to be exclusively one for catabolism and recycling of material taken up by endocytosis from the external milieu or from the cytosol by autophagy. At least in the immune system it is clear now that endo/lysosomal proteolysis generates crucially important information, in particular peptides that bind class II MHC molecules to create ligands for survey by the diverse antigen receptors of the T lymphocyte system. This process of antigen processing and presentation is used to display not only foreign but also self peptides and therefore is important for 'self' tolerance as well as immunity to pathogens. Some cells, macrophages and particularly dendritic cells can load peptides on class I MHC molecules in the endosome system through the important, though still not fully characterised, pathway of cross presentation. Here I try to provide a brief review of how this area developed focussing to some extent our own contributions to understanding the class II MHC pathway. I also mention briefly recent work of others showing that proteolysis along this pathway turns out to regulate immune signalling events in the innate immune system such as the activation of some members of the Toll-like receptor family. Finally, our recent work on the endo/lysosome targeted protease inhibitor cystatin F, suggests that auto-regulation of protease activity in some immune cells occurs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21782986 TI - Saccharomyces cerevisiae in the stationary phase as a model organism- characterization at cellular and proteome level. AB - The yeast Saccharomyces cerevisiae has been used as a model organism to investigate responses to different environmental stressors. The importance of their conclusions has been expanded to human cells. The experiments were done with exponentially growing cells, which do not resemble human cells. Human and other eukaryotic cells spend the greater part of their lives in a quiescent state, known as G0 corresponding to the yeast stationary phase. Providing energy, which comes from mitochondrial respiration, is also common. Thus, in the present study S. cerevisiae was used in the stationary phase for characterization at the cellular and proteome levels. At the cellular level, optical density, cell viability, glycogen content, intracellular oxidation and cell energy metabolic activity were measured, while at the proteome level, protein profiles were analyzed using two-dimensional electrophoresis. The data obtained at both levels provide better insight into quiescence program state, which still remains poorly understood. At their base, optimal time period reflecting a stable metabolic and oxidative state of the yeast was determined. Consequently, this period is the appropriate to study changes in cell oxidant status and energy metabolic activity in response to different environmental stressors. PMID- 21782988 TI - Small animal bone healing models: standards, tips, and pitfalls results of a consensus meeting. AB - Small animal fracture models have gained increasing interest in fracture healing studies. To achieve standardized and defined study conditions, various variables must be carefully controlled when designing fracture healing experiments in mice or rats. The strain, age and sex of the animals may influence the process of fracture healing. Furthermore, the choice of the fracture fixation technique depends on the questions addressed, whereby intra- and extramedullary implants as well as open and closed surgical approaches may be considered. During the last few years, a variety of different, highly sophisticated implants for fracture fixation in small animals have been developed. Rigid fixation with locking plates or external fixators results in predominantly intramembranous healing in both mice and rats. Locking plates, external fixators, intramedullary screws, the locking nail and the pin-clip device allow different degrees of stability resulting in various amounts of endochondral and intramembranous healing. The use of common pins that do not provide rotational and axial stability during fracture stabilization should be discouraged in the future. Analyses should include at least biomechanical and histological evaluations, even if the focus of the study is directed towards the elucidation of molecular mechanisms of fracture healing using the largely available spectrum of antibodies and gene-targeted animals to study molecular mechanisms of fracture healing. This review discusses distinct requirements for the experimental setups as well as the advantages and pitfalls of the different fixation techniques in rats and mice. PMID- 21782990 TI - Health courts and other alternative medical liability solutions. PMID- 21782987 TI - Separation-of-function mutation in HPC2, a member of the HIR complex in S. cerevisiae, results in derepression of the histone genes but does not confer cryptic TATA phenotypes. AB - The HIR complex, which is comprised of the four proteins Hir1, Hir2, Hir3 and Hpc2, was first characterized as a repressor of three of the four histone gene loci in Saccharomyces cerevisiae. Using a bioinformatical approach, previous studies have identified a region of Hpc2 that is conserved in Schizosaccharomyces pombe and humans. Using a similar approach, we identified two additional domains, CDI and CDII, of the Hpc2 protein that are conserved among yeast species related to S. cerevisiae. We showed that the N terminal CDI domain (spanning amino acids 63-79) is dispensable for HIR complex assembly, but plays an essential role in the repression of the histone genes by recruiting the HIR complex to the HIR dependent histone gene loci. The second conserved domain, CDII (spanning amino acids 452-480), is required for the stability of the Hpc2 protein itself as well as for the assembly of the HIR complex. In addition, we report a novel separation of-function mutation within CDI of Hpc2, which causes derepression of the histone genes but does not confer other reported hir/hpc- phenotypes (such as Spt phenotypes, heterochromatin silencing defects and repression of cryptic promoters). This is the first direct demonstration that a separation-of-function mutation exists within the HIR complex. PMID- 21782991 TI - Does anyone care about what children eat? PMID- 21782992 TI - Nontraumatic bilateral bifid condyle and intermittent joint lock: a case report and literature review. PMID- 21782993 TI - Guiding surgical education. PMID- 21782994 TI - They don't make them like that anymore. PMID- 21782995 TI - Temporalis fascia in temporomandibular joint gap arthroplasty. PMID- 21782996 TI - The "missing" anterior loop. PMID- 21783000 TI - Hemostatic management in pediatric patients with type I von Willebrand disease undergoing oral surgery: case report and literature review. PMID- 21783001 TI - Safety of deep sedation in an urban oral and maxillofacial surgery training program. AB - PURPOSE: To study the safety of deep sedation in an urban-based oral maxillofacial surgery training program. MATERIALS AND METHODS: Charts of patients undergoing an intravenous sedation from January 2005 through December 2009 were reviewed. Data recorded included age, gender, type of procedures performed, and intravenous medications. Patients were divided in 2 groups depending on whether they received a general anesthetic agent (propofol or ketamine) or not. Anesthesia complications and failures were recorded and categorized. RESULTS: In total, 1,167 intravenous sedations were recorded. Eight patients developed adverse reactions, 3 of which required further evaluation in the emergency department. In addition, 7 intravenous sedations needed to be aborted because of patient agitation and combativeness. No deaths or long-term morbidities were reported. CONCLUSIONS: The safety of deep sedation in an urban-based oral maxillofacial training program is similar to office-based anesthesia. Sedations failures may be attributed to paradoxical benzodiazepine reactions. PMID- 21783002 TI - Gingival overgrowth in Pompe disease: a case report. AB - Pompe disease, or glycogen storage disease type 2, is a rare inheritable metabolic disease caused by a deficiency of the lysosomal enzyme acid alpha glucosidase. Patients with the classic infantile form of Pompe disease present with symptoms during the first 3 months after birth, and most will die within their first year. Recently, enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase became commercially available for Pompe disease. This is a case report of an 8-year-old girl with the infantile form of Pompe disease who is one of the longest survivors through ERT. The patient was tetraplegic when she started ERT. At age 3 years, she developed massive gingival overgrowth and could not close her mouth, prompting a reduction of the gingival overgrowth surgically. We expected that massive accumulation of glycogen would explain the gingival overgrowth. However, histopathology of the gingiva tissue showed marked glycogen accumulation in smooth muscle cells of the arteries, but the glycogen content in fibroblasts did not exceed that of control individuals. Further, there was an increase of immature collagen in the connective tissue, and signs of a mild chronic inflammation. We concluded that glycogen storage is not a direct causative factor of gingival overgrowth in our patient. Chronic inflammation, dryness of the gingiva, or even the minimal glycogen accumulation in the fibroblasts may have played a role. PMID- 21783003 TI - Mandibular fracture severity and patient health status are associated with postoperative inflammatory complications. AB - PURPOSE: To identify risk factors associated with postoperative inflammatory complications (POICs) after treatment of mandibular fractures. PATIENTS AND METHODS: The investigators designed a case-control study and enrolled a sample of patients treated for mandibular fractures at Massachusetts General Hospital between August 2004 and January 2010. Subjects who developed POICs after fracture management were categorized as cases. A POIC was defined as 1) recurrent swelling, fever, increased pain, or trismus; 2) wound dehiscence with purulent drainage; 3) exposed or infected hardware; 4) abscess formation; 5) radiographic evidence of osteomyelitis; and/or 6) presence of a fistula. Controls had no complications. For each case, 2 controls were selected. Predictor variables were categorized into the following sets: demographic, fracture-specific, and perioperative. Bivariate and multiple logistic regression analyses were used to identify factors associated with POICs. RESULTS: During the study interval, 575 subjects with mandible fractures were evaluated and treated. The study sample consisted of 44 cases and 88 controls. In the multiple regression model, an increasing Mandibular Injury Severity Score (odds ratio = 1.4; 95% confidence interval 1.2-1.6) and a positive medical history (odds ratio = 1.4; 95% confidence interval 1.03-1.8) were significantly (P < .05) associated with an increased risk for a POIC. CONCLUSION: Fracture severity assessed using the Mandibular Injury Severity Score and pre-existing medical problems were associated with increased risk for postoperative inflammatory complications following treatment of mandibular fractures. PMID- 21783004 TI - Predictors of velopharyngeal insufficiency after Le Fort I maxillary advancement in patients with cleft palate. AB - PURPOSE: Approximately 25% to 40% of patients with cleft lip/palate develop maxillary retrusion that requires Le Fort I osteotomy. Maxillary advancement brings the soft palate forward, and this may cause velopharyngeal insufficiency (VPI). The goal of this study was to identify predictors that place patients with repaired cleft palate at risk of developing VPI after Le Fort I advancement. MATERIALS AND METHODS: This was a retrospective study of nonsyndromic patients with cleft lip/palate who had a Le Fort I osteotomy between 2000 and 2008. Charts were reviewed and data were collected on patient characteristics, preoperative speech assessments, and nasopharyngoscopic reports. Pre- and postoperative cephalometric radiographs were used to measure maxillary advancement and to assess the structure of the velopharynx. Simple logistic regression analysis examined the association between each predictive variable and postoperative VPI, as indicated by need for pharyngeal flap. Predictors with P <= .10 were included in the multivariate regression model. In both the univariate and the multivariate analyses, P <= .05 was considered statistically significant. RESULTS: Univariate analysis showed a significant association between preoperative soft palatal length and need for a pharyngeal flap (P = .005). By multivariate analysis, both preoperative soft palatal length and postoperative pharyngeal depth were associated with need for pharyngeal flap (P = .003 and P = .030). CONCLUSION: This study shows that a short soft palate is associated with VPI after Le Fort I osteotomy. Assessment of palatal length and pharyngeal depth on cephalometric radiographs is helpful in predicting postoperative VPI and need for a pharyngeal flap in patients with cleft palate after maxillary advancement. PMID- 21783005 TI - Use of a simple mini-vacuum drain in small surgical wounds. PMID- 21783006 TI - Clinical update: psychosocial responses in breast cancer survivors. AB - OBJECTIVES: To present an update of the evidence on psychosocial responses and factors that contribute to psychosocial functioning and quality of life (QOL) in breast cancer survivors. DATA SOURCES: Research articles/abstracts and literature reviews. CONCLUSION: In the nearly 5 years since the original article, research has confirmed that the majority of breast cancer survivors demonstrate a pattern of recovery after treatment. Age, information, social support, degree of symptom distress, and unmet psychological needs remain key factors influencing psychosocial functioning and QOL outcomes. More knowledge has been disseminated about the experience of the transition to survivorship, women's perceived identity, and the potential benefits of survivorship plans to patient outcomes. IMPLICATIONS FOR NURSING PRACTICE: Assessment of psychological and social well being in the transition to survivorship is essential. Interventions should be targeted to meet informational needs, manage uncertainty, control symptoms, address cultural differences, and enhance social and emotional support. PMID- 21783007 TI - Introduction. Cancer symptom distress. PMID- 21783008 TI - Consumer empowerment in health care amid the internet and social media. AB - OBJECTIVES: Consumer empowerment in health and rapid change in health information and communication technologies have their roots in broader social trends. This article reviews the activities at the intersection of consumer empowerment and technology. DATA SOURCES: Technical reports, white papers, books, journal articles, and Web sites. CONCLUSION: Social trends are visible in the integration of information and communication technologies into health care, in both searching for and sharing information on the Internet, in the use of social media to create new types of interactions with family, providers, and peers, and in the e patient, who integrates these new roles and new technologies. IMPLICATIONS FOR NURSING PRACTICE: Changes in both patients and technology will impact oncology nursing practice as new, patient-centered, interactions emerge. PMID- 21783009 TI - A deliberate and rigorous approach to development of patient-centered technologies. AB - OBJECTIVES: Many technologies intended for patient use are never developed or evaluated with principles of user-centered design. In this review, we explore different approaches to assessing usability and acceptability, drawn from selected exemplar studies in the health sciences literature. DATA SOURCES: Peer reviewed research manuscripts were selected from Medline and other data sources accessible through pubmed.gov. We also present a framework for developing patient centered technologies that we recently employed. CONCLUSION: While there are studies using principles of user-centered design, many more do not report formative usability testing results and may only report post-hoc satisfaction surveys. Consequently, adoption by user groups may be limited. IMPLICATIONS FOR NURSING PRACTICE: We encourage nurses in practice to look for and examine usability testing results before considering implementation of any patient centered technology. PMID- 21783010 TI - Multi-media support for informed/shared decision-making before and after a cancer diagnosis. AB - OBJECTIVES: To define and distinguish informed decision-making (IDM) from shared decision-making (SDM) and review the evidence for technology-based interventions designed to facilitate informed decisions about cancer screening and treatment. DATA SOURCES: Peer-reviewed research articles from Medline and other data sources accessible through pubmed.gov. CONCLUSION: There is evidence that multi-media decision aids (DAs) or support systems can improve quality of decision-making in terms of enhancing knowledge relevant to decision-making, reducing decisional conflict, and customizing education and coaching of patients with cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurses have a key role to play in designing, deploying, monitoring, and evaluating multi-media DAs in oncology practice settings. DAs are an adjunct to interpersonal education, providing information to patients in both the clinical setting and in more familiar settings without the time constraints of clinical encounters. Nurses can adopt such DAs and support systems and work with patients to ensure that information has been comprehended, that values have been considered, and that patients play an active role in the decision-making process as they desire. PMID- 21783013 TI - Electronic health records and personal health records. AB - OBJECTIVES: To provide an overview of electronic personal health information technology. DATA SOURCES: Peer reviewed research studies, review articles, and web resources. CONCLUSION: As technology develops and electronic health records become more common, patients and clinicians are working toward a safer, more personal form of health care delivery. IMPLICATIONS FOR NURSING PRACTICE: Improving access and input to personal health information is still in its infancy, but with government funding, development of patient health records will continue to grow. Patients are the consumers of health care and are witness to the paradigm shift of access to health information and changes in information communication technology (ICT). For the oncology nurse, the transformation of health care and ICT will require nurses to educate patients and family members on available online resources for self management and health promotion. PMID- 21783012 TI - Technologies to support end-of-life care. AB - OBJECTIVES: To describe the current level of utilization of informatics systems in hospice and palliative care and to discuss two projects that highlight the role of informatics applications for hospice informal caregivers. DATA SOURCES: Published articles, Web resources, clinical practice, and ongoing research initiatives. CONCLUSION: There are currently few informatics interventions designed specifically for palliative and hospice care. Challenges such as interoperability, user acceptance, privacy, the digital divide, and allocation of resources all affect the diffusion of informatics tools in hospice. IMPLICATIONS FOR NURSING PRACTICE: Caregiver support through use of information technology is feasible and may enhance hospice care. PMID- 21783011 TI - Patient-reported symptoms and quality of life integrated into clinical cancer care. AB - OBJECTIVES: To provide an overview of research and practice related to patient reported symptom and quality-of-life assessment integrated into clinical care. DATA SOURCES: Literature retrieved through the PUBMED and CINAHL databases. CONCLUSION: Assessing and incorporating patient preferences, engaging the patient in self-report, and extending the interaction to the place and time favored by the patient are necessary to bring meaning to the term "patient-centered." There is beginning evidence that these approaches can make a difference, improving care quality. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses no longer need to be constrained by paper symptom checklists. Patient-reported symptom and quality-of life information can be electronically collected and simultaneously made available for home and clinical use through the utilization of Web-based programs. PMID- 21783014 TI - Online support of patients and survivors of cancer. AB - OBJECTIVES: To provide information on current use of a type of online support, Internet cancer support groups, by patients and survivors of cancer, and the factors that influence their usages. DATA SOURCES: The literature systematically searched and retrieved through the PUBMED, PsycInfo, and CINAHL databases. CONCLUSION: This literature review indicated five factors that influence the use of Internet cancer support groups (disease, background, cultural, need, and Internet use). IMPLICATIONS FOR NURSING PRACTICE: Health care providers need to give careful attention to multiple factors that may influence the use of online support. PMID- 21783016 TI - Resveratrol may be an effective prophylactic agent for ischemic stroke. PMID- 21783018 TI - Outcomes of assisted reproductive techniques for HIV-1-discordant couples using thawed washed sperm in Taiwan: comparison with control and testicular sperm extraction/microscopic epididymal sperm aspiration groups. AB - BACKGROUND/PURPOSE: An increasing number of human immunodeficiency virus-1 (HIV l)-discordant couples in Taiwan have been seeking fertility help. We conducted the first clinical trial in Taiwan of assisted reproductive technology (ART) using sperm washing and viral load measurement. METHODS: From 2005 to 2009, we performed 22 ART cycles on 14 HIV-1-discordant couples. The sperm washing involved density gradient centrifugation followed by swim-up method. HIV-1 RNA was checked by real-time reverse transcription-polymerase chain reaction with a sensitivity of 40 copies/mL. In addition, we enrolled two other groups of ART recipients using frozen sperm to compare the clinical outcomes. RESULTS: There were five pregnancies in the fresh cycles (23.8%) of HIV-1-discordant couples and the cumulative pregnancy per couple was 42.9% (6/14). The data were comparable with normal controls and testicular sperm extraction/microscopic epididymal sperm aspiration groups. The nine babies and the 14 women in this study showed no seroconversion. CONCLUSION: The preliminary data showed good ART results in HIV-1 discordant couples. Fertility services should not be withheld from individuals with HIV-1, although larger series are needed to reach conclusions about safety. PMID- 21783017 TI - Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. AB - Management of chronic pain, such as nerve-injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer, is a real clinical challenge. Major surgeries, such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery, also lead to chronic pain in 10 50% of individuals after acute postoperative pain, partly due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that, under all these conditions, the activated microglia not only exhibit increased expression of microglial markers CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin brain derived neurotrophic factor and the proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids. PMID- 21783019 TI - Trends in tuberculosis in Taiwan, 2002-2008. AB - BACKGROUND/PURPOSE: Tuberculosis (TB) remains an important infectious disease in Taiwan. To control TB effectively, the Taiwan Centers for Disease Control implemented the National Tuberculosis Program (NTP) in 2006, modeled on the World Health Organization global TB control program. The goal of the program was to reduce the number of TB cases by half within a decade. This study was designed to describe the epidemiology of TB in Taiwan, and to evaluate the preliminary effectiveness of the NTP. METHODS: We conducted a retrospective study of data from the National Tuberculosis Registry System collected between 2002 and 2008. Demographics, geographic distribution of disease, and change in rates of TB incidence and mortality were analyzed. RESULTS: From 2002 to 2008, new TB cases declined from 16,758 to 14,265, and incidence decreased from 75 per 100,000 population to 62 per 100,000 population. More than 50% of new cases occurred among elderly adults. Over the study period, TB mortality decreased from 5.7 per 100,000 population to 3.3 per 100,000 population, with over half of TB deaths occurring among patients aged >= 65 years. Since the NTP was implemented, from 2005 to 2008, TB incidence and mortality declined by 14% and 23%, respectively. CONCLUSION: TB-associated incidence and mortality decreased over the course of the study. Nevertheless, there continue to be high-incidence areas that show the opposite trend; these areas should strive to improve case management and consultation. In the most populous districts, rigorous surveillance is necessary to track incidence and mortality rate fluctuations. PMID- 21783020 TI - Prognostic evaluation of patients with multicentric papillary thyroid microcarcinoma. AB - BACKGROUND/PURPOSE: Patients with papillary thyroid microcarcinoma (PTMC) often have an excellent prognosis. We hypothesize that patients with multicentric PTMC are associated with good clinical outcome, although multicentricity in papillary thyroid carcinoma may be associated with poor prognosis. METHODS: Retrospective analysis of multicentric PTMC cases in one medical center enrolled from 1987 to 2008 was conducted. At the end of follow-up, patients were classified as "recurrence-free" or "recurrence or persistent disease". The tumor-node metastasis (TNM) staging system was used, and (T1, N0, M0) was regarded as "early clinical stage", whereas (T3-4, any N, any M) or (any T, N1, or M1) was regarded as "advanced clinical stage". RESULTS: There were 61 patients with a median age of 45 years. After a median follow-up period of 7.3 years (range: 2.1-22.1 years), the overall cause-specific survival rate was 98.36%. The patients with tumor diameters < 0.5 cm were all recurrence-free. Advanced clinical stage, especially distant metastasis, was highly associated with recurrence or persistent disease. CONCLUSION: Our results demonstrate excellent prognosis in multicentric PTMC patients. No patients with tumor diameter < 0.5 cm had recurrence or persistent disease. Tumor size is an important risk factor in patients with multicentric PTMC. PMID- 21783021 TI - Comparison of inspiratory muscle strength training effects between older subjects with and without chronic obstructive pulmonary disease. AB - BACKGROUND/PURPOSE: Inspiratory muscle strength training (IMST) has been traditionally recommended for patients with chronic obstructive pulmonary disease (COPD) to improve respiratory strength. Respiratory strength is reduced as age increases. However, few studies have focused on the effects of IMST on older adults without COPD. METHODS: Subjects were divided into training non-COPD (TNC, n = 24) and training COPD (TC, n = 12) according to their forced expiratory volume in 1 second (% predicted). Both groups received 6 weeks of IMST, with training at 75-80% of maximal inspiratory pressure using pressure threshold trainers. A second group of COPD subjects served as controls (CC, n = 24), which received no training. Dyspnea was measured using the basic dyspnea index. Health related quality of life was measured using the SF-36. The SF-36 subcategories, physical component summary and mental component summary were compared. A 6-minute walk test was performed to determine functional status. Two-way repeated measures analysis of variance was used to compare group effects and training effects of IMST. RESULTS: Maximal inspiratory pressure was increased in both training groups (TNC: 59.1 cmH(2)O pre-IMST to 82.5 cmH(2)O post-IMST; TC: 53.2 to 72.6), but not in the CC group. Therefore, the basic dyspnea index was improved in both training groups (TNC: 9.6 to 10.8; TC: 6.2 to 7.3). Functional status was improved in the TNC group (TNC: 392.1 m to 436.3 m), but not in the TC or CC groups. Quality of life was improved in the physical component summary in both training groups. CONCLUSION: IMST increases maximal inspiratory pressure, relieves dyspnea and improves health-related quality of life in older adults. IMST especially improves functional status in subjects without COPD. IMST benefits subjects with COPD and those without COPD. Therefore, IMST as a treatment tool is not confined to patients with COPD. PMID- 21783022 TI - Developmental profiles and temperament patterns in children with spastic cerebral palsy: relationships with subtypes and severity. AB - BACKGROUND/PURPOSE: Elucidating developmental profiles and temperament patterns in children with cerebral palsy (CP) could help clinicians elaborate more flexible strategies for treating these children. This study investigated the developmental profiles and temperament patterns in children with spastic CP (sCP) of different subtypes and severities. METHODS: One hundred and five children, aged 3-6 years, with sCP and 66 children with typical development (TD) were analyzed. Children with sCP were classified into spastic diplegia (SD; n = 60), and spastic quadriplegia (SQ; n = 45) groups. Motor severity was classified via the Gross Motor Function Classification System (GMFCS). Development quotients (DQs) of eight domains and temperament scores of nine dimensions were evaluated. RESULTS: The SQ group had lower DQs in all developmental functions than the SD group (p < 0.01). The DQ distributions of developmental profiles showed the same trend in SD and SQ groups, and both groups displayed lowest DQs in the gross motor domain. The SQ group was less adaptable and approachable than the TD group (p < 0.05), and both sCP groups had lower attention span and persistence and a higher threshold of responsiveness than the TD group (p < 0.05). Correlation analysis showed that GMFCS levels were highly related to all developmental functions (r < -0.54, p<0.01) and weakly related to some temperament dimensions in children with sCP. CONCLUSION: The subtype and severity of sCP were associated with developmental profiles in children with sCP Temperament patterns were different between SD and SQ groups, but only weakly related to motor deficit. These data could allow clinicians to anticipate the developmental profiles and temperament patterns and plan appropriate therapeutic strategies for children with sCP. PMID- 21783023 TI - Neuroimaging findings in a brain with Niemann-Pick type C disease. AB - Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI), magnetic resonance spectrography (MRS) and 18-fluoro-2 deoxyglucose positron emission tomography (PET) imaging results for a 22-year-old male NPC patient. The patient's two MRI studies (at age 19 years and 22 years) demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years) revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years) showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient. PMID- 21783024 TI - Establishment of electronic chart-based stroke registry system in a medical system in Taiwan. AB - To establish a prospective, real-time, self-sustainable stroke registry system, we incorporated a registry with an electronic chart to create an electronic chart based stroke registry system in November 2006. The International Classification of Diseases Ninth Revision code (430-437) was used to auto-enroll stroke patients admitted to neurology departments. Clinical information was written by doctors, nursing information was recorded by nurses, and basic patient information was entered by administrative departments. Numerical data and the date and time of any studies were auto-downloaded from the hospital computer. In total, 212 items were auto-downloaded, including basic patient information, laboratory blood test and examination results, and the date and time of imaging and special intervention. The stroke scales (121 items, National Institutes of Health Stroke Scale, Barthel index, and modified Rankin scale) were designed to be auto adjusted to reduce incompatibility. The 95 items with pull-down options were used to specify the contents. This registry system can be time-, labor- and money saving with secured data accuracy. PMID- 21783025 TI - Clinical significance of Mycobacterium avium complex isolates at a medical center in northern Taiwan. PMID- 21783026 TI - Electric fish. PMID- 21783027 TI - Desmosomes. PMID- 21783028 TI - Phagocytosis. PMID- 21783029 TI - Brief periods of monocular deprivation disrupt ocular balance in human adult visual cortex. PMID- 21783030 TI - Stomata: active portals for flourishing on land. AB - Two studies suggest early land plants could actively control stomata, facilitating gas exchange while limiting water loss, a critical adaption to life on land. PMID- 21783031 TI - Gene regulation: piecing together the puzzle of enhancer evolution. AB - The sequences of some gene regulatory elements diverge considerably, even between closely related species. A detailed analysis of the fast-evolving sparkling enhancer in Drosophila now identifies key compensatory mechanisms and 'grammar' elements that are critical for maintaining functional integrity. PMID- 21783032 TI - Speech perception: a language-trained chimpanzee weighs in. AB - A language-trained chimpanzee is able to interpret synthetic 'auditory caricatures' as speech. Important components of human speech perception thus rely upon general auditory mechanisms that predated the evolution of spoken language. PMID- 21783033 TI - Seed dispersal: same gene, different organs. AB - A single nucleotide change in a conserved promoter element is responsible for both human-selected retention of rice grains on pedicels and for naturally selected differences in dehiscence-associated fruit structures in mustards. PMID- 21783034 TI - Inflammation: cell recruitment versus local proliferation. AB - Inflammation leads to local accumulation of macrophages. A new study shows that macrophage accumulation in inflammatory reactions dominated by type 2 immune responses is a result of local cell proliferation as opposed to recruitment of monocytes from the blood. PMID- 21783035 TI - Mycorrhizal symbioses: how to be seen as a good fungus. AB - Plants continually encounter many microorganisms. Some are good, but many are bad. Two studies show how beneficial fungi tell the plant to let them in and how the fungus avoids setting off the plant's defense reaction. PMID- 21783036 TI - Cell biology: actin keeps endocytosis on a short leash. AB - High-resolution structural analysis of branched actin networks at the sites of clathrin-mediated endocytosis sheds light on the role of actin in endocytosis and mechanisms controlling actin assembly. PMID- 21783037 TI - Plant genomics: homoplasy heaven in a lycophyte genome. AB - The recent genomic sequencing of Selaginella, a member of the lycophyte lineage of vascular plants, opens up all kinds of new opportunities to examine the patterns of evolutionary innovation and the creation of the basic bauplan of plants. PMID- 21783038 TI - Cell division: aurora B illuminates a checkpoint pathway. AB - Separating mitotic error correction, chromosome biorientation and the spindle assembly checkpoint (SAC) is complicated by their interconnected relationships. New research finds that Aurora B kinase, which drives error correction and promotes biorientation, also directly regulates the SAC. PMID- 21783040 TI - Focusing on populations to improve the health of individual adolescents and young adults. PMID- 21783039 TI - Building distinct actin filament networks in a common cytoplasm. AB - Eukaryotic cells generate a diversity of actin filament networks in a common cytoplasm to optimally perform functions such as cell motility, cell adhesion, endocytosis and cytokinesis. Each of these networks maintains precise mechanical and dynamic properties by autonomously controlling the composition of its interacting proteins and spatial organization of its actin filaments. In this review, we discuss the chemical and physical mechanisms that target distinct sets of actin-binding proteins to distinct actin filament populations after nucleation, resulting in the assembly of actin filament networks that are optimized for specific functions. PMID- 21783041 TI - The viability of using alternative sites to increase rates of adolescent vaccination (or: "a rising tide floats all boats"). PMID- 21783042 TI - Suicidality and depression disparities between sexual minority and heterosexual youth: a meta-analytic review. AB - PURPOSE: To examine disparities between sexual minority youth (SMY) and heterosexual youth in rates of suicidality and depression symptoms. METHODS: Separate meta-analyses were conducted to examine suicidality and depression disparities. Studies were included if the average age of the participants was <18 years, and if suicidality or depression symptoms were compared across SMY and heterosexual youth. RESULTS: SMY reported significantly higher rates of suicidality (odds ratio [OR] = 2.92) and depression symptoms (standardized mean difference, d = .33) as compared with the heterosexual youth. Disparities increased with the increase in the severity of suicidality (ideation [OR = 1.96], intent/plans [OR = 2.20], suicide attempts [OR = 3.18], suicide attempts requiring medical attention [OR = 4.17]). Effects did not vary across gender, recruitment source, and sexual orientation definition. CONCLUSIONS: Disparities in suicidality and depression may be influenced by negative experiences including discrimination and victimization. Clinicians should assess sexual orientation, analyze psychosocial histories to identify associated risk factors, and promote prevention and intervention opportunities for SMY and their families. PMID- 21783043 TI - Health of adolescents and young adults: trends in achieving the 21 Critical National Health Objectives by 2010. AB - PURPOSE: The 21 Critical National Health Objectives (CNHOs) for Adolescents and Young Adults derived from Healthy People 2010 addressed the most significant threats to the health of individuals aged 10-24 years. This study assessed trends in the 21 CNHOs between 1991 and 2009, and from baseline years for which 2010 targets were established to 2009, and the extent to which targets were achieved. METHODS: For one CNHO (new HIV diagnoses), national data were not available. For CNHOs measured by census systems, the percentage of change in each health outcome was calculated between 1991 and 2009 and between baseline years and 2009. Any change >=5% was considered as an improvement or deterioration. For CNHOs measured by national probability-based surveillance surveys, multivariate logistic regression was conducted using Stata Version 10.0 (StataCorp, College Station, TX) to calculate odds ratios for each outcome from 1991, and from baseline years to 2009, controlling for gender, race/ethnicity, and age or school grade-level. To calculate the percentage of targets being achieved, the difference between baseline data and 2009 data was divided by that between baseline data and target. RESULTS: Adolescents and young adults achieved two targets (rode with a driver who had drunk alcohol, physical fighting), improved for 12 CNHOs, made mixed progress by sub-objective for two, showed no progress in four, and regressed in achieving two (Chlamydia infections; overweight). Progress varied by demographic variables. CONCLUSION: Although encouraging trends were seen in young people's health, the United States achieved only two CNHOs. Attention is needed to improve the health and reduce disparities among young people. PMID- 21783044 TI - Parents' acceptance of adolescent immunizations outside of the traditional medical home. AB - PURPOSE: Numerous barriers to vaccination exist for adolescents. Using the medical home as the sole source of adolescent vaccination has potential limitations. The objectives of the present study were to examine parents' acceptance of adolescent vaccination outside of the medical home and parents' preferred setting for adolescent vaccination. METHODS: A standardized, pilot tested telephone survey was administered to a stratified random sample (n = 1,998) of Colorado households between August 2007 and February 2008. Households with English-speaking parents and adolescent(s) aged 11-17 years were eligible. RESULTS: Survey response rate was 43%; there were no significant differences between respondents and nonrespondents for three known demographic variables. Although most parents (78%) preferred a doctor's office for adolescent vaccination, a majority were also definitively or probably accepting of vaccination in public health clinics (74%), school health clinics (70%), obstetrics and gynecology clinics (69%; asked for females only), and emergency departments (67%). Parents were less accepting of vaccination in family planning clinics (41%) and retail-based clinics (36%). Perceived convenience and adolescents' comfort in the setting were positively associated with vaccination acceptance in most settings; concern with keeping track of vaccines given outside of the medical home was negatively associated with acceptance. Parents in rural areas were more likely than parents in urban areas to identify a setting outside of the medical home as the preferred "best" setting for vaccination. CONCLUSIONS: Most parents assessed a doctors' office as the best setting for adolescent vaccination. However, vaccination in certain settings outside of the medical home seems to be acceptable to many parents. PMID- 21783045 TI - Objectified body consciousness and mental health in female adolescents: cross cultural evidence from Georgian and Swiss national samples. AB - PURPOSE: The current study tested both descriptive and explanatory similarities and differences in a latent objectified body consciousness (OBC) construct and its relationship to three mental health indicators among Georgian and Swiss adolescents. Few studies have been conducted on adolescents; similarly, most work has been completed on U.S. college-age women. METHODS: School-based questionnaire data were collected from a total of 18,239 adolescents in Georgia (n = 9,499) and Switzerland (n = 8,740), following the same protocol. Participants rated three measures of OBC (body shame, body surveillance, and appearance control beliefs) and three mental health indicators (depressive symptoms, somatic complaints, and suicidal ideation). Final study samples included 2,657 (mean age = 16.4 years) and 3,803 female youth (mean age = 17.8 years), respectively. Data analyses included mean level comparisons, confirmatory factor analysis, path analysis, and multigroup invariance tests. RESULTS: Findings provide support for a latent OBC construct across cultures, with partial evidence of cultural differences (one of two manifest indicators). By contrast, multigroup invariance tests provide consistent evidence of no differences in the relationships between the OBC latent construct and three mental health indicators between Georgian and Swiss samples. CONCLUSION: Despite mean level differences, findings support a latent OBC construct in both cultures, perhaps slightly more so among Swiss youth. The links between OBC and mental health indicators were also invariant across the two cultures, providing greater support for a global or universal (vs. "cultured") framework of adolescent development related to the constructs and relationships studied. PMID- 21783046 TI - The efficacy of the web-based childhood obesity prevention program in Chinese American adolescents (Web ABC study). AB - PURPOSE: To examine the feasibility and efficacy of a theory-driven and family based program delivered online to promote healthy lifestyles and weights in Chinese American adolescents. METHODS: A randomized controlled study of a web based intervention was developed and conducted in 54 Chinese American adolescents (ages, 12-15 years) and their families. Data on anthropometry, blood pressure, dietary intake, physical activity, and knowledge and self-efficacy regarding physical activity and nutrition were collected at baseline and 2, 6, and 8 months after the baseline assessment. Data were analyzed using linear mixed modeling. RESULTS: The intervention resulted in significant decreases in waist-to-hip ratio and diastolic blood pressure and increases in vegetable and fruit intake, level of physical activity, and knowledge about physical activity and nutrition. CONCLUSION: This web-based behavior program for Chinese American adolescents and their families seems feasible and effective in the short-term. Long-term effects remain to be determined. This type of program can be adapted for other minority ethnic groups who are at high-risk for overweight and obesity and have limited access to programs that promote healthy lifestyles. PMID- 21783047 TI - Reduced ratings of physical and relational aggression for youths with a strong cultural identity: evidence from the Naskapi people. AB - PURPOSE: Minority youth in general, and Aboriginal youth in particular, are at increased statistical risk for being perpetrators or victims of aggression. METHODS: We examined the potential protective aspect of cultural identity in relation to peer ratings of physical and relational aggression and factors typically associated with each among almost the entire cohort of Naskapi youths from Kawawachikamach, Quebec. RESULTS: Hierarchical multiple regressions revealed that a strong identity with their own Native culture predicted less perceived physical and social aggression by their peers. CONCLUSION: These findings are discussed in the context of the role of a positive affiliation with ancestral culture for the diminishment of adolescent aggression and for general adaptive development and well-being. PMID- 21783048 TI - Game on... girls: associations between co-playing video games and adolescent behavioral and family outcomes. AB - PURPOSE: Video game use has been associated with several behavioral and health outcomes for adolescents. The aim of the current study was to assess the relationship between parental co-play of video games and behavioral and family outcomes. METHOD: Participants consisted of 287 adolescents and their parents who completed a number of video game-, behavioral-, and family-related questionnaires as part of a wider study. Most constructs included child, mother, and father reports. RESULTS: At the bivariate level, time spent playing video games was associated with several negative outcomes, including heightened internalizing and aggressive behavior and lowered prosocial behavior. However, co-playing video games with parents was associated with decreased levels of internalizing and aggressive behaviors, and heightened prosocial behavior for girls only. Co playing video games was also marginally related to parent-child connectedness for girls, even after controlling for age-inappropriate games played with parents. CONCLUSIONS: This is the first study to show positive associations for co-playing video games between girls and their parents. PMID- 21783049 TI - The role of maternal early-life and later-life risk factors on offspring low birth weight: findings from a three-generational study. AB - PURPOSE: This study examined three research questions: (1) Is there an association between maternal early-life economic disadvantage and the birth weight of later-born offspring? (2) Is there an association between maternal abuse in childhood and the birth weight of later-born offspring? (3) To what extent are these early-life risks mediated through adolescent and adult substance use, mental and physical health status, and adult socioeconomic status (SES)? METHODS: Analyses used structural equation modeling to examine data from two longitudinal studies, which included three generations. The first generation (G1) and the second generation (G2) were enrolled in the Seattle Social Development Project (SSDP), and the third generation (G3) was enrolled in the SSDP Intergenerational Project. Data for the study (N = 136) focused on (G2) mothers enrolled in the SSDP and their children (G3). RESULTS: Analyses revealed that G2 low childhood SES predicted G3 offspring birth weight. Early childhood abuse among G2 respondents predicted G3 offspring birth weight through a mediated pathway including G2 adolescent substance use and G2 prenatal substance use. Birth weight was unrelated to maternal adult SES, depression, or obesity. CONCLUSIONS: To our knowledge, this is the first study to identify the effect of maternal early-life risks of low childhood SES and child maltreatment on later born offspring birth weight. These findings have far-reaching effects on the cumulative risk associated with early-life economic disadvantage and childhood maltreatment. Such findings encourage policies and interventions that enhance child health at birth by taking the mother's own early-life and development into account. PMID- 21783051 TI - Positive childhood experiences and positive adult functioning: prosocial continuity and the role of adolescent substance use. AB - PURPOSE: To examine positive childhood experiences as predictors of positive adult functioning, including civic involvement, productivity and responsibility, interpersonal connection, and physical exercise; and to examine adolescent substance use as a mediator of prosocial continuity. METHODS: A total of 429 rural participants were interviewed across seven waves from age 11 to 22 years. Structural equation models examined the relationship between positive childhood experiences and adult functioning, with adolescent substance use added to each model as a possible mediating mechanism. RESULTS: Positive childhood experiences predicted significantly better adult functioning for each model, even after accounting for adolescent substance use. Positive childhood experiences also consistently predicted significantly less adolescent substance use. In turn, adolescent substance use predicted significantly less civic involvement and less productivity and responsibility, but was not associated with interpersonal connection or physical exercise when accounting for childhood experiences. Results were largely consistent across gender and levels of family income. CONCLUSION: Findings show the enduring importance of positive childhood experiences in predicting positive functioning in early adulthood. Although adolescent substance use increased risk for poorer functioning in important domains of adult life, results suggest that positive experiences in late childhood continued to have a significant prosocial effect into young adulthood. The study also highlights the late elementary grades as a time when parents, teachers, and others can potentially have a large influence in proactively providing prosocial opportunities for children. PMID- 21783050 TI - Prime Time: 12-month sexual health outcomes of a clinic-based intervention to prevent pregnancy risk behaviors. AB - PURPOSE: Prime Time, a youth development intervention, aims to reduce pregnancy risk among adolescent girls seeking clinic service who are at high risk for pregnancy. This article examines sexual risk behaviors and hypothesized psychosocial mediators after 12 months of the Prime Time intervention. METHODS: This study was a randomized controlled trial with 253 girls aged 13-17 years meeting specified risk criteria. Intervention participants were involved in Prime Time programming plus usual clinic services for 18 months, control participants received usual clinic services. The intervention used a combination of case management and peer leadership programs. Participants in this interim outcomes study completed self-report surveys at baseline and 12 months after enrollment. Surveys assessed sexual risk behaviors and psychosocial factors targeted for change by Prime Time. RESULTS: At the 12-month interim, the intervention group reported more consistent use of condoms, hormonal contraception, and dual contraceptive methods with their most recent partner as compared with the control group. The intervention group also reported greater stress management skills with trends toward higher levels of prosocial connectedness at school and with family. No between-group differences were noted in psychosocial measures specific to sex and contraceptive use. CONCLUSION: Preventing early pregnancy among high-risk adolescents requires multifaceted, sustained approaches. An important research focus involves testing youth development interventions offered through clinic settings, where access to high-risk adolescents is plentiful and few efforts have emphasized a dual approach of building protective factors while addressing risk. Findings suggest that youth development interventions through clinic settings hold promise in reducing pregnancy risk among high-risk youth. PMID- 21783052 TI - Gender differences in the association between family conflict and adolescent substance use disorders. AB - PURPOSE: The objectives of this study were (1) to examine whether the association between childhood family conflict and the risk of substance use disorders (SUDs) in adolescence differs by gender, and (2) to determine whether anxious/depressive symptoms and conduct problems explain this association among adolescent males and females. METHODS: Data were obtained from 1,421 children aged 10-16 years at the time of enrollment in the Project on Human Development in Chicago Neighborhoods. We assessed gender differences in the association between childhood family conflict and adolescent SUDs by fitting a logistic regression model that included the interaction of gender and family conflict. We also investigated whether conduct problems and anxious/depressive symptoms explained the association between family conflict and SUDs differently for males and females through gender specific mediation analyses. RESULTS: The association between childhood family conflict and SUDs in adolescence differed by gender (p = .04). Family conflict was significantly associated with SUDs among females (OR: 1.61; CI: 1.20-2.15), but not among males (OR: 1.00; CI: .76-1.32). The elevated risk of SUDs among females exposed to family conflict was partly explained by girls' conduct problems, but not by anxious/depressive symptoms. CONCLUSIONS: Females living in families with elevated levels of conflict were more likely to engage in acting out behaviors, which was associated with the development of SUDs. Future epidemiologic research is needed to help determine when this exposure is most problematic with respect to subsequent mental health outcomes and the most crucial time to intervene. PMID- 21783054 TI - Relationship between life events and psychosomatic complaints during adolescence/youth: a structural equation model approach. AB - PURPOSE: To assess the contribution of life events (LEs) on psychosomatic complaints in adolescents/youths taking into account a set of socioeconomic variables. METHODS: We tested a conceptual model implemented with structural equation modeling on longitudinal data from a representative sample of adolescents/youths and parents. Psychosomatic complaints were measured by the Health Behaviour in School-aged Children scale and hypothesized to be affected by: (a) contextual factors at distal level: financial resources, home life and social support (KIDSCREEN), and parent baseline mental health (SF-12); (b) triggering factors: LEs (Coddington Life Events Scales, with two typologies: desirability and familiarity); (c) intermediate factors: same as distal level but measured at follow-up; (d) immediate cause: mental health at proximal level (Strengths and Difficulties Questionnaire at baseline and follow-up); and (e) gender. RESULTS: The structural model yielded a good fit (Comparative Fit Index = .95, Tucker-Lewis Index = .93, Root Mean Square Error = .04). Boys showed more psychosomatic complaints than girls (beta = .40, p < .05). Girls reported experiencing more LEs (p < .05). Only undesirable LEs showed a significant direct negative effect on psychosomatic complaints, which became nonsignificant when mediated by home life and mental health. Undesirable LEs had a remaining indirect effects on psychosomatic complaints (betaindirect = -.10, p < .05) via Home Life and Mental health, which were protective factors (beta = .41 and beta = -.15, p < .05). CONCLUSIONS: The experience of undesirable LEs increases the probability of psychosomatic complaints, but the final effect would be determined by previous levels of home life and mental health stability. PMID- 21783053 TI - A clinic-based motivational intervention improves condom use among subgroups of youth living with HIV. AB - PURPOSE: More than 50% of youth living with HIV (YLH) have unprotected sex. In previous studies, we reported effects of a motivational interviewing-based multirisk reduction intervention, "Healthy Choices" in improving motivation, depression, and viral load in YLH. In this study, we report the effect of the intervention on increasing condom use. METHODS: Six waves of longitudinal data (n = 142) across a period from baseline through 15 months postintervention were analyzed. The developmental trajectory modeling method was used for program effect evaluation. RESULTS: The three groups detected with distinct sexual risks were: Persistent low sexual risk (PLSR), delayed high sexual risk, and high and growing sexual risk with regard to levels and time trajectories of condom use throughout the trial. Receiving Healthy Choices increased the likelihood to be in the PLSR group (63% vs. 32%, p < .01) and reduced the likelihood to be in the delayed high sexual risk group (16% vs. 50%, p < .05). Receiving the intervention was also associated with progressive reductions in no-condom sex for PLSR youth (adjusted beta = -.325, p < .01) and high and growing sexual risk youth (adjusted beta = -.364, p < .01). CONCLUSION: The motivational interviewing-based program Healthy Choices, when delivered in clinic settings, can prevent unprotected sex in subgroups of YLH, although more intensive interventions may be needed to change risk trajectories among those at highest risk of transmitting the AIDS virus. Developmental trajectory analysis provides an alternative approach to evaluate program effects for study samples that contain distinct subgroups. PMID- 21783055 TI - Growing up with a chronic illness: social success, educational/vocational distress. AB - OBJECTIVES: We compared adult educational, vocational, and social outcomes among young adults with and without childhood-onset chronic illness in a nationally representative U.S. sample. METHODS: We used data from Wave IV (2008) of the National Longitudinal Study of Adolescent Health. We compared respondents who reported childhood-onset cancer, heart disease, diabetes, or epilepsy with young adults without these chronic illnesses in terms of marriage, having children, living with parents, romantic relationship quality, educational attainment, income, and employment. Multivariate models controlled for sociodemographic factors and adult-onset chronic illness. RESULTS: As compared with those without childhood chronic illness, respondents with childhood chronic illness had similar odds of marriage (odds ratios [OR] = .89, 95% CI: .65-1.24), having children (OR = .99, 95% CI: .70-1.42), and living with parents (OR = 1.49, 95% CI .94-2.33), and similar reports of romantic relationship quality. However, the chronic illness group had lower odds of graduating college (OR = .49, 95% CI: .31-.78) and being employed (OR = .56, 95% CI: .39-.80), and higher odds of receiving public assistance (OR = 2.13, 95% CI: 1.39-3.25), and lower mean income. CONCLUSIONS: Young adults growing up with chronic illness succeed socially, but are at increased risk of poorer educational and vocational outcomes. PMID- 21783056 TI - Disaster and youth violence: the experience of school-attending youth in New Orleans. AB - PURPOSE: Although disaster exposure has been linked with increased child aggression by previous reports, population-level trends are unknown. Pre- to post Katrina changes in violence-related behaviors among New Orleans high school youth (ages: 12-18 years) were assessed. METHODS: Data from the 2003 (pre-Katrina), 2005 (pre-Katrina), and 2007 (post-Katrina) New Orleans Youth Risk Behavior Survey (n = 5,267) were used. Crude comparisons across years of population characteristics and violence behavior prevalence were made with chi(2) analyses. Changes in violence-related behaviors over time were assessed with logistic regression models including indicators for survey years and controls for compositional changes. RESULTS: Age, gender, and race/ethnicity of school attending youth were stable across years. In models controlling for demographics, most behaviors were stable over time. Some changes were observed for all groups; dating violence and forced sex increased before the storm, whereas weapon carrying and missing school as a result of feeling unsafe decreased after the storm. Among African American adolescents only, being threatened at school increased before Katrina. CONCLUSIONS: Results do not support significant population-level increases in violent behavior post-Katrina among school attending youth in New Orleans. Factors that buffered New Orleans students from post-Katrina violence increases, such as population composition changes or increased supportive services, may explain these findings. PMID- 21783057 TI - The proportion of U.S. parents who talk with their adolescent children about dating abuse. AB - PURPOSE: To estimate the proportion of U.S. parents who talked about dating abuse (DA) with their adolescent children in the past year, and explore reasons among those who did not. METHODS: Five hundred parents of 11-18 year-old-children were assessed through a national online survey. RESULTS: Fifty-five percent of parents had discussed DA with their children in the past year. Mothers were more likely than fathers to discuss DA with both male and female children (59.0% vs. 50.2%, p < .05). Parents' age, income, and region of the United States were not related to having discussed DA. However, DA was substantially less likely to be discussed than school work, drugs, alcohol, family finances, the economy, money management, dating relationships in general, and sex. Parents who did not discuss DA reported that their children were not dating, that they were too young, that their children would learn about it through experience, that they would not know what to say, or that it was too embarrassing to discuss. CONCLUSIONS: Programs that equip parents to talk with children about DA are needed. PMID- 21783058 TI - Age group differences in healthcare access for people with disabilities: are young adults at increased risk? AB - PURPOSE: The purpose of this study was to quantify and describe the population of young adults with disability in Florida and to assess correlates of healthcare access in this population in contrast with adults belonging to middle and older age groups. METHODS: This study analyzed data of 36,704 respondents obtained from the 2007 Florida Behavioral Risk Factor Surveillance System. A test for homogeneity of the risk difference across the three age groups was conducted using inverse weighting to adjust for confounding and selection bias. RESULTS: The adjusted model for risk difference of not being able to see a doctor in the past 12 months because of cost was significantly heterogeneous across age groups (chi(2)(2df)F value = 12.40, p < .01). The risk difference between population of young adults with disability and their age peers decreased significantly across the groups. The risk difference was 15.5% for those aged 18-29, 11.9% for those aged 30-64, and 2.1% for those aged >=65. CONCLUSIONS: This article quantifies the differences in risk and access to health care between young adults with and without disability, using population-based data. It provides indirect evidence of the widely held belief that there is a problem in healthcare transition in the United States warranting continued investigation and intervention. PMID- 21783059 TI - Family and individual predictors of physical activity for older Mexican adolescents. AB - PURPOSE: Low levels of physical activity (PA) are associated with persistent obesity. Adolescent obesity is linked to adult morbidity and premature mortality. This study examined a model of perceived parental influence in Mexican older adolescents to uncover contemporaneous family and personal predictors of Mexican older adolescents' PA. METHOD: Participants 16- to 25-years-old (n = 3,908), Mexican college applicants, underwent a health screen and filled out questionnaires which included information on PA and potential correlates. A logistic regression model was used to ascertain family factors (socioeconomic status, conflict about PA, and perceived parental PA) and individual factors (age, sex, body mass index, depressive symptoms, enjoyment of PA, and sedentary behaviors) associated with adolescents' PA. RESULTS: Most participants reported being physically active (61.5%); less than half reported physically active parents (40.0%). Perceived parental PA (odds ratio [OR] = 8.67, p <= .0001), enjoyment of PA (OR = 2.11, p <= .0001), and conflicts about PA (OR = 1.16, p <= .0001) were important positive predictors of adolescents' PA. CONCLUSION: PA among Mexican older adolescents is influenced by parental PA. The role of conflicts about PA is likely to be influenced by culture and may indicate that older adolescents' PA is not completely accepted by parents. PMID- 21783061 TI - Metabolic myopathy a cause of rhabdomyolysis in adolescents. PMID- 21783062 TI - A rare tumour in a rare location: desmoplastic fibroma in a toe. AB - We report a case of desmoplastic fibroma occurring in the 2nd toe. This lesion most frequently occurs in the long bones or the mandible. This is only the second reported case of desmoplastic fibroma in a toe in the English language. The importance and process of establishing a differential diagnosis in such lesions is highlighted. The similarity between the clinical and histological findings of this tumour and other tumours, both benign and malignant, makes familiarity with the character of desmoplastic fibroma essential for proper treatment. PMID- 21783063 TI - Closed posterior subtalar dislocation without any associated fracture: a case report and review of the literature. AB - Pure posterior subtalar dislocation without any medial or lateral displacement of foot is extremely rare and hardly reported in the literature. Such an injury is more likely to be open and associated with fractures of the surrounding bones of the foot. Here we report a rare case of closed pure posterior subtalar dislocation without any associated fracture. We discuss in detail the mechanism of such an injury and highlight the importance of prompt closed reduction and early mobilization to ensure a satisfactory long term outcome. PMID- 21783064 TI - Hemiarthroplasty augmented with bone graft for the failed hallux metatarsophalangeal Silastic(r) implant. AB - Symptomatic failure of Silastic(r) implants at the hallux metatarsophalangeal joint can result in the challenging problem of instability which may be painful. There is often marked bone loss making reconstruction difficult. Arthrodesis sacrifices joint movement while excision arthroplasty shortens the ray and is less acceptable to active patients. We describe a case in which reconstruction was achieved by using a porous coated metatarsophalangeal hemiarthroplasty augmented with bone graft with good early results. This previously unreported technique may offer an additional surgical option for reconstruction, maintaining joint movement without compromising future arthrodesis or excision arthroplasty as salvage measures. Long term follow up is required to confirm the success of this technique. PMID- 21783065 TI - What is a revision of total ankle replacement? PMID- 21783066 TI - Comparative study of the Weil osteotomy with and without fixation. AB - BACKGROUND: Weil osteotomy is a technique widely used in patients with metatarsalgia which shortens the metatarsal and reduces the load under the metatarsal head. METHODS: The aim of this paper is to compare the results of the Weil osteotomy with and without any fixation system. We present a retrospective study of 92 patients (97 feet) who underwent treatment for metatarsalgia between 1999 and 2005. One hundred and six osteotomies were vixed using a screw amd no fixation was used in 92. The mean follow-up was 51.2 and 46.6 months respectively. RESULTS: All the patients were evaluated following the AOFAS LMIS scale, obtaining a mean score of 69.8 points (ranged 15-100) and 75.3 points (from 47 to 100) in each group (P=0.11). CONCLUSIONS: The results of fixed and unfixed Weil osteotomies were not significantly different. Our study could not find a significant relationship between metatarsal shortening and main complications (recurrent metatarsalgia, transfer metatarsalgia and stiffness of the metatarsophalangeal joint). PMID- 21783067 TI - Interpretation of the scarf osteotomy by 10 surgeons. AB - BACKGROUND: The study compared three-dimensional (3D) changes in geometry of the first metatarsal following scarf osteotomy performed on standardised Sawbone(r) models by consultant foot and ankle surgeons. The study considered the inter surgeon variances in interpretation and performance of the scarf osteotomy with respect to intra-surgeon variances. METHODS: The analysis used an accurate digitising system to measure and record points on the Sawbone(r) models in 3D space. Computer software performed vector analysis to calculate 3D rotations and translations of the first metatarsal head as well as the inter-metatarsal angle. Bone cut lengths and displacements were measured using a digital Vernier caliper. One surgeon performed the osteotomy 10 times to form an intra-surgeon control dataset, while 10 different surgeons each did one scarf osteotomy to form an inter-surgeon test dataset. RESULTS: Both surgical groups produced reductions in the 3D inter-metatarsal angle with non-significant differences between the groups (p>0.05). In contrast, the test group demonstrated highly significant (p=0.000) greater variance compared with the control dataset for all of the variables associated with surgical technique. In addition, there were highly significant (p=0.02 and 0.002) greater variances in the interpretation of the degree to which the metatarsal head should be translated medially (X) and inferiorly (Z). There was also a significant (p=0.001) increase in variances in the rotations about the dorsi/plantar-flexion (X) axis. The only significant differences (all p=0.000) attributable solely to differences in mean values were in proximal-distal (Y) translation, pronation (Y) rotation and medial (Z) rotation. The test group applied greater medial and plantar-flexion rotation of the metatarsal head than the control surgeon and significantly less (p=0.000) shortening of the first metatarsal than the control surgeon. CONCLUSIONS: The results of this geometric study demonstrate the versatility of the scarf osteotomy. As a result of the multi-planar nature of the osteotomy, there is a potential risk of producing unintended rotational mal-unions in all three planes. These rotational mal-unions may account for some of the poorer outcomes documented within the literature. PMID- 21783068 TI - The epidemiology of foot injuries in professional rugby union players. AB - BACKGROUND: Foot injuries represent a small but important proportion of injuries to professional rugby union players. There are no detailed epidemiological studies regarding these injuries. The aim of this study was to describe the epidemiology of foot injuries sustained by a cohort of professional rugby union players and identify areas that may be targeted for injury prevention in the future. METHODS: Medical personnel prospectively recorded injuries in professional Premiership rugby union players in England over four seasons. Injuries to the foot were identified and the time away from training and playing was reported. RESULTS: A total of 147 foot injuries were sustained resulting in 3542 days of absence in total. Acute events accounted for 73% of all foot injuries, with chronic, mostly overuse conditions, accounting for 25% (undiagnosed 2%). Chronic conditions led to proportionately more time away from training and playing (p=<0.001). Specifically, stress fractures in the foot accounted for 8% of the total foot injuries but 22% of the absence. Navicular stress fractures had the longest recovery time with the mean return to training and match play of 188 days. CONCLUSION: In collision sports such as rugby, some injuries may be inevitable but clinicians should always be seeking ways to minimise their occurrence and impact. This study revealed a high proportion of morbidity associated with chronic and overuse foot injuries in these professional athletes. With greater attention paid to risk factors, some of these injuries, and importantly, recurrent injuries may be avoided. PMID- 21783069 TI - Surgical technique for minimally invasive fibula fracture fixation. AB - This paper describes a minimally invasive percutaneous technique for reduction and fixation of distal fibula fractures using plate osteosynthesis. We believe this technique benefits patients with poor quality soft tissue envelopes. So far a total of 25 patients have undergone percutaneous fixation, 22 females and 3 males. At no stage yet has a minimally invasive procedure been abandoned intra operatively in favour of conversion to an open procedure. The mean age was 61.6 years (range 25-80 years). The mean time to surgery was 2.00 days (range 0-5) and mean time to discharge was 4.20 days (range 1-9). At a minimum of over 1 year's follow-up all fractures have healed, with no delayed unions or complications so far experienced. PMID- 21783070 TI - Does it matter how we measure metatarsal length? AB - INTRODUCTION: Variations in the relative lengths of the metatarsal bones have been implicated as a cause of forefoot pain. Osteotomies to balance the metatarsal lengths have been described as therapy. Although measurement of metatarsal length is required for these osteotomies, there is no gold standard method to measure it radiologically. We compared the three main radiological methods to measure the second metatarsal length described in the literature. MATERIALS AND METHODS: Standing dorsoplantar radiographs of 81 feet were measured using the methods described by Coughlin, Maestro and Hardy and Clapham. Bland and Altman's method was used to compare the above techniques for reproducibility and agreement between each method. RESULTS: The three methods produced markedly different results. Coughlin's and Maestro's methods showed a relative protrusion of the second metatarsal-relatively longer than the first metatarsal by an average of 4 & 3 mm respectively. Hardy and Clapham's method, however, showed a relative retraction of second metatarsal by an average of 1 mm. Both intra observer and inter-observer errors were smallest for the Coughlin method (the most reproducible) and largest for the Hardy/Clapham method. Significant lack of agreement was found when we compared the 3 techniques with bias for measuring the mean between methods ranging from 1mm to 5.5mm. CONCLUSIONS: Metatarsal lengths as measured by these three methods can be very variable. Thus their role in planning metatarsal osteotomies and establishing relationship of metatarsal protrusion with metatarsophalangeal joint instability and other similar conditions is questionable and require further studies. PMID- 21783071 TI - Triple arthrodesis of the foot after calcaneal fractures. Twelve patients treated using K wires stabilization. AB - The most frequent problem following intra-articular calcaneal fracture is pain from the subtalar joint. Subtalar arthrodesis is not considered to be an optimal solution because it can lead to degenerative changes in the ankle joint. The aim of this study was to evaluate patients with such fractures treated by triple arthrodesis. The treated group consisted of 12 patients (5 female, 7 male) with no bilateral fractures. The mean age at injury was 36 years (22-54). The patients had surgery 2 years on average after injury. In all cases the arthrodesis was stabilized with Kirschner wires. The follow-up ranged from 1 to 5 years (average 2.9 +/- 1.4). In 2 feet the calcaneal fracture was associated with a fracture of the talus. At clinical evaluation the Ankle-Hindfoot Scale (AOFAS) was applied. From the 100 point scale the question concerning movement in the subtalar joint was removed which made the scale range from 0 to 94 points. Postoperative scoring ranged from 19 to 92 points (mean 57.3 +/- 25.1). The patients also evaluated the result of treatment on a visual analogue scale from 0 to 10 points which gave a mean score of 7.7 +/- 2.2. Early results of the treatment of calcaneal fractures by triple arthrodesis show that this is valuable method for the prevention of significant foot pain. PMID- 21783072 TI - Repair of fresh open tear of Achilles tendon Tension regulation at the suture line. AB - BACKGROUND: Lack of the timely mechanical loading of the repaired tendon is detrimental for healing progress. The current knowledge knows the appropriate time for the mechanical loading, but need to find out a suitable tool for this purpose. Therefore we present a technique based on using of an absorbable reinforcement device for tension regulation at the suture line. METHODS: 24 patients with open tear of Achilles tendon were repaired surgically, the repair was reinforced using an absorbable suture and the outcomes were prospectively assessed at 24 months. RESULTS: No tendon lengthening or reruptures were reported; patients returned to pre-injury daily activates by fourth month. One patient reported 1cm atrophy of the calf, scar adhesion Grade 1 and ankle dorsiflexion decreased 5 degrees . CONCLUSION: Restoration of the continuity and actual length of repaired tendons support use of the absorbable reinforcement device for regulation of the mechanical environment at the suture line. PMID- 21783073 TI - Step activity monitoring to assess ambulation before and after total ankle arthroplasty. AB - BACKGROUND: The study objective was to compare walking activity before and after total ankle arthroplasty (TAA). METHODS: Nineteen patients who underwent TAA were prospectively reviewed with a dedicated ambulatory activity-monitoring device. Patients were tested 1 month prior to surgery, and at least 18 months post operative. Ambulatory parameters included number of steps at different cadences and time spent walking at different paces. The American Orthopaedic Foot and Ankle (AOFAS) hindfoot scale was assessed at similar intervals. RESULTS: Following TAA, there was significant improvement in the number of steps walked at normal cadence, while importantly the number of steps walked at low and medium cadence decreased. There was no significant difference between the time actually spent walking at any cadence after arthroplasty. The mean AOFAS hindfoot scale significantly improved. CONCLUSIONS: Following TAA, patients show an improved walking pace and AOFAS hindfoot scale, but no difference in the amount of time spent walking. PMID- 21783074 TI - Harmful cleats of football boots: a biomechanical evaluation. AB - BACKGROUND: Football players wear boots of varying cleat designs with some preferring the bladed cleats while others opting for the conventional studded cleats. The current study compares biomechanically the boots with differing cleat designs and their effect on feet, if any. METHODS: Twenty-nine healthy male volunteers were recruited from amateur football teams. They were asked to perform three trials each of two activities: a straight run and a run cutting at a 60 degrees angle wearing bladed and studded Adidas(r)-F series boots on artificial turf. Plantar pressure values were recorded using the Pedar(r)-X in-shoe pressure measuring device. Peak pressure and pressure-time integral were analysed over 11 clinically relevant areas under the foot. RESULTS: While the in-shoe pressure and pressure-time integral were higher under the medial half of the foot with studded boots, they were higher under the lateral half of the foot with the bladed design. CONCLUSIONS: The studded boots can be considered safer as the pressure distribution across the foot and the pattern of centre of pressure progression mimicked the normal motif, whereas the bladed boots could potentially be deemed relatively more harmful due to the unnatural increased loading under the lateral half of the foot, predisposing the foot to injuries. PMID- 21783075 TI - Quantitative ultrasound of lower leg and foot muscles: feasibility and reference values. AB - BACKGROUND: Ultrasound is a non-invasive method to quantitatively measure various muscle parameters. Purpose of this study was to assess the feasibility of ultrasound of lower leg and foot muscles and to obtain reference values for muscle thickness (MT) and echo intensity (EI). METHODS: Ultrasound measurements of leg and foot muscles were performed in 60 healthy adults. MT and EI were quantitatively determined for the abductor hallucis (AH), extensor digitorum brevis (EDB), extensor hallucis longus (EHL) and peroneus longus (PER) muscles. Influence of age, height, weight and sex was determined using a multiple linear regression analysis. RESULTS: All muscles except the AH could easily be visualized with ultrasound. EI tended to be increased above 60 years and MT was significantly higher in men compared to women, necessitating age- and sex dependent reference values. CONCLUSIONS: This study shows that muscle ultrasound is capable of visualizing lower leg and foot muscles and reference values for MT and EI can be obtained. Future research will focus on the use of these reference values to evaluate muscle abnormalities caused by neuromuscular disorders like hereditary motor and sensory neuropathy. PMID- 21783076 TI - Weil osteotomy: assessment of medium term results and predictive factors in recurrent metatarsalgia. AB - BACKGROUND: The angle of the Weil osteotomy is usually referenced relative to the floor irrespective of the plantar angulation of the metatarsal. This study aims to analyse the long term results following the Weil osteotomy and identify the cause of poor outcome. METHODS: This study presents a retrospective review of 61 patients (86 feet), with mean follow-up of 31 months. Each patient underwent clinical, pedobarographic and radiological examination. The radiographs obtained included 'Metatarsal Skyline Views' (MSV), to assess the plantar declination of the metatarsal heads following the osteotomy. The functional scoring was performed using AOFAS and Foot Function Index. RESULTS: Fifty-five patients (80 feet) showed good to excellent results clinically. Six patients had persistent metatarsalgia. All these 6 patients had callosities beneath metatarsal heads. Pedobarography showed peak pressures in the same distribution as callosities and the MSV showed increased plantar declination of the metatarsal heads. This correlation was found to be significant (p<0.05). CONCLUSION: The Weil osteotomy is a safe and effective treatment for metatarsalgia. An MSV radiograph is helpful to identify the plantar prominence of metatarsal which can be associated with poor clinical outcomes. PMID- 21783077 TI - A clinical classification system for rheumatoid forefoot deformity. AB - BACKGROUND AND PURPOSE: In the present study a classification system for the rheumatoid forefoot is reported with its intra- and interobserver reliability and clinical relevance. The classification is based on the sequence of anatomical changes resulting from the loss of integrity of the MTP joints, loss of motion and changes regarding the quality and position of the plantar soft tissues. It is hypothesized that with progression of the amount of deformity of the MTP joint(s), patients have more pain and functional loss. PATIENTS AND METHODS: In total 94 patients were included in the study following precise inclusion criteria. The forefeet of the patients were classified according to the introduced classification system by two observers in order to determine the intra and interobserver reliability. The relation of the suggested classification between pain, function scores, and plantar foot pressure measurements was examined. RESULTS AND CONCLUSION: According to the Cohen's kappa and the ICC, the intra- and inter-observer reliability were high. Despite the large variation between subjects in a certain grade, a clear trend was found between increase in classification and VAS for pain, FFI difficulty with activities, and plantar peak pressure under the metatarsals. The suggested classification is of clinical relevance and can be used to develop therapeutical algorithms and to test interventions. PMID- 21783078 TI - Normative data of the Visual Analogue Scale Foot and Ankle (VAS FA) for pathological conditions. AB - BACKGROUND: The purpose of this study was to analyze the Visual Analogue Scale Foot and Ankle (VAS FA) in patients to obtain normative data for pathological conditions. METHODS: The VAS FA was consecutively obtained in a foot and ankle outpatient clinic. The score results were categorized into different pathological foot and ankle conditions. RESULTS: 414 patients were evaluated. Overall scores and score categories of all pathology groups differed from non-pathological data (n=121). Within the different groups, no score differences occurred. Score standards were defined for these groups with sufficient statistical power (>.8): isolated Hallux valgus, Hallux valgus and claw toes, forefoot other pathology, midfoot other pathology, hindfoot pathology and ankle deformity. No standards were defined for other pathology groups. CONCLUSIONS: The obtained data is normative for different pathological conditions of the earlier validated VAS FA. The obtained data is normative for different pathological conditions of the earlier validated VAS FA. This data could serve as a basis for assessment patient scoring before, during and after treatment which has to then to be proved by ongoing research. PMID- 21783079 TI - Endosopic achilles tendon augmentation with a graft loop anatomic and radiologic study. AB - BACKGROUND: Mini-invasive techniques are commonly used for repair of tendon Achilles (TA) rupture. However, the use of these techniques is limited when graft augmentation is needed. METHOD: A radiological study was conducted on 18 normal ankles using multi-slice CT scan with soft tissue reconstruction to determine the endoscopic landmarks for Achilles tendon insertion. The surgical procedure was performed on six whole lower limb formaldehyde preserved specimens. Endoscopic assisted TA augmentation with a graft loop was done for all specimens. Postoperative assessment of the tunnel was done using multi-slice CT scan. RESULTS: Anatomic dissection showed that the sural nerve and neurovascular bundle were intact in all specimens. CONCLUSION: With the technique described a graft loop can be delivered endoscopically for Achilles tendon augmentation. The technique was found to be safe for the sural nerve and medial neurovascular structures. PMID- 21783080 TI - Split anterior tibial tendon transfer for varus equinus spastic foot deformity Initial clinical findings correlate with functional results: A series of 132 operated feet. AB - Spastic equinovarus foot deformity commonly occurs after stroke or head trauma. Management by split anterior tibial tendon transfer to the lateral border of the foot was chosen by the authors. The purpose of that work was to assess the reliability of this method to improve patient's functional autonomy and investigate the relationship between the initial clinical examination findings and the quality of the functional results. 84 feet, operated in 82 patients out of 130, of mean age 46 years, were reviewed at a mean follow-up of 65 months. Very few complications were observed. Toe deformities remain a commonly associated problem. 80 patients were able to walk barefoot, 74 reported an increase in their walking distance, and 73 could regularly wear normal shoes. There is a strong relationship (p<0.001) between the preservation of deep foot sensitivity and the level of functional autonomy. PMID- 21783081 TI - A novel pyrolytic carbon implant for hallux rigidus: a cadaveric study. AB - BACKGROUND: The aim of this cadaveric study was to assess the technical feasibility of inserting a novel interpositional pyrolytic carbon coated implant in the first MTP joint, determine the best surgical procedure for the implantation, and evaluate the dynamic behavior of the joint after surgery. METHODS: The marble implant was inserted in the first metatarsophalangeal joint of five pairs of cadaveric feet using two different surgical approaches, dorsal and medial, for each pair. The stability and mobility of the feet before and after implantation, as well as the relationship between the implant and the sesamoids, were assessed by static and dynamic fluoroscopy. RESULTS: After implantation, the stability was perfect in all positions and the mobility was conserved. There were no conflicts between the sesamoids and the implant during the movement of the first metatarsophalangeal joint. Both the dorsal and the medial surgical approaches led to similar findings. CONCLUSION: To our knowledge, this is the first anatomic evaluation of this type of implant. Whereas the results of the technique obtained on cadaveric feet were satisfactory, caution has to be applied to trying to apply this procedure to the living patient. PMID- 21783082 TI - An anatomical and radiological study of the fascia cruris and paratenon of the Achilles tendon. AB - BACKGROUND: The Achillon jig permits the placement of sutures deep to the fascia cruris and the paratenon through the substance of the ruptured tendon, permitting a safe minimally invasive repair. Our experience has suggested that these two layers may not be as clearly delineated as first thought or may merge at an, as yet, undefined level. METHODS: We performed an anatomical and radiological (US and MRI) study of the layers of tissue superficial to the Achilles tendon in cadaveric specimens. RESULTS: The mean distance for the confluence of the fascia cruris and paratenon from the postero-superior calcaneal tubercle (PSCT) was found to be 37.3mm (range 17-58mm). Ultrasound examination was found to be less distinct than MRI scanning. CONCLUSIONS: We recommend careful identification of the fascia cruris and paratenon and insertion of the central branches of the jig adjacent to the tendon substance when using this method for repair. PMID- 21783083 TI - The effect of collateral ligament release on ankle dorsiflexion: an anatomical study. AB - BACKGROUND: Ankle stiffness is a common complication after ankle fracture, reconstructive surgery or total ankle replacement, and the usual limitation is in dorsiflexion. There are few articles in the literature concerning this frequent problem, and furthermore they are not recent and tend to be controversial. The purpose of this anatomical study was to evaluate and quantify the effect of ankle collateral ligament release on dorsiflexion, specifically the amount of increase in ankle dorsiflexion following section of the two ligaments most often implicated in ankle stiffness: the deep posterior tibiotalar ligament (dPTTaL, or posterior deep deltoid) and the posterior talofibular ligament (PTaFL). METHODS: We dissected 18 adult fresh cadaveric ankle joints, and with an electronic goniometer combined with an electronic dynamometer measured their mobility in dorsiflexion before and after transection of each ligament separately, and the two ligaments combined. RESULTS: The results showed a significant difference between the two groups of ankles with section of the dPTTaL resulting in a greater increase in ankle dorsiflexion than section of the PTaFL (mean 7.45 degrees vs. 3.5 degrees , respectively; p<0.001). Combined section of both ligaments improved the gain in ankle dorsiflexion more than isolated section of each ligament, but was not statistically significant (p=0.88). CONCLUSION: If after gastrocnemius recession or Achilles tendon lengthening persistent restriction remains in ankle dorsiflexion, the results of our study demonstrate that the next step should be release of the dPTTaL. PMID- 21783084 TI - Morton's neuroma: clinical testing and imaging in 76 feet, compared to a control group. AB - BACKGROUND: Morton's neuroma is a mechanically induced degenerative neuropathy. METHODS: We compared clinical and MRI findings in 76 feet treated operatively for Morton's neuroma and 40 feet with different pathologies (controls). RESULTS: In the 'treatment group' web space tenderness (WST) was positive in 95%, foot squeeze (SQU) in 88%, plantar percussion (PLP) in 61%, and toe tip sensation deficit (TTSD) in 67%. MRI identified neuromata in 97%. Histological examination confirmed neuroma excision in 99%. Frequency of positive tests was significantly higher in the treatment group compared to controls. MRI revealed (asymptomatic) neuromata in 10/40 (25%) feet in the control group. TTSD was similarly positive in asymptomatic and symptomatic neuromata. TTSD in association with any other test being positive, was significantly more frequent in symptomatic neuromata. CONCLUSIONS: The diagnosis of Morton's neuroma, based on clinical and imaging findings, was accurate. Positive clinical testing was more frequent in the 'treatment' group compared to the 'control' group. PMID- 21783085 TI - Getting off on the wrong foot doctor-patient miscommunication: a risk for wrong site surgery. AB - BACKGROUND: Miscommunication between surgeon and patient can have far reaching consequences including the potential for wrong-site surgery (WSS). In the course of routine foot and ankle clinics, particular inconsistencies were noted between the terms used by surgeons and patients to label individual toes with the potential for miscommunication. METHODS: To investigate this phenomenon 100 consecutive patients were asked to label their own toes. The first fifty labelled their left foot, the subsequent fifty their right. RESULTS: Errors in communication were common with an average frequency of greater than one in 10. Miscommunication was most likely when patients used numbers to label their toes, accounting for 93% of all errors. CONCLUSIONS: As a result we recommend that healthcare professionals avoid the use of numbers to label toes when communicating with patients to help avoid miscommunication. PMID- 21783086 TI - Total ankle arthroplasty and tibialis posterior tendon transfer for ankle osteoarthritis and drop foot deformity. AB - Total ankle arthroplasty is an alternative to arthrodesis in selected patients with end-stage arthritis of the ankle. We report on the clinical features, radiographic findings, management and results in a 58-year-old man with associated ankle osteoarthritis and drop foot deformity. The patient was managed with a total ankle arthroplasty and tibialis posterior tendon transfer. Three years after the procedure, the patient was able to walk, had no pain, and had a stable joint with 5 degrees dorsiflexion and 20 degrees plantar flexion. PMID- 21783088 TI - Report of the 8th EFAS congress in Geneva. PMID- 21783087 TI - Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. PMID- 21783089 TI - Gastroenterology in a new era of accountability: part 2. Developing and implementing performance measures. PMID- 21783090 TI - The effects of diabetes share care program in southern Taiwan. PMID- 21783091 TI - Blockage of uterine-feeding vessels: a real choice to maintain the uterus? PMID- 21783092 TI - Metabolic outcome for diabetes shared care program outpatients in a veterans hospital of southern Taiwan. AB - BACKGROUND: To evaluate the metabolic outcomes of the Diabetes Shared Care Program (DSCP) for Type 2 diabetes after completion of 1 year and 3 years of intervention. METHODS: Total 162 Type 2 diabetes (average age 67.14 years with 62.35% men and 37.65% women) in 2004 were referred to the diabetes educator for DSCP. Parameters related to diabetes among these patients were inquired, and biochemical data were compared before and after the DSCP by using SPSS 12.0 software. RESULTS: These patients had 3.1% emergency utilization rate and 1.9% hospitalization utilization rate; significant improvement in diastolic blood pressure (DBP), body weight after one year; and significant improvement in systolic blood pressure, DBP, body weight, total cholesterol, high-density lipoproteins cholesterol (HDL-C) and low-density lipoproteins cholesterol (LDL-C) levels after three years. But only 4.84% and 8.87% met all the A1C, blood pressure, and LDL-C target values after the 1- and 3-year interventions, respectively. CONCLUSION: The A1C, blood pressure, and LDL-C achievement rate of DSCP in our hospital is low. DSCP is suggestive to patients with lower duration of diabetes, high baseline A1C, systolic blood pressure, DBP, LDL-C, and low baseline high-density lipoproteins cholesterol levels. Furthermore public health efforts are needed to control risk factors for vascular disease among diabetes. PMID- 21783093 TI - Augmentation cystoplasty and simultaneous ureteral reimplantation reduce high grade vesicoureteral reflux in children with neurogenic bladder. AB - BACKGROUND: To compare the incidence of residual high-grade vesicoureteral reflux (HVUR) (>=Grade III) in neurogenic bladder patients receiving augmentation cystoplasty alone or with simultaneous ureteral reimplantation. Furthermore, we also tried to find the risk factors of residual VUR and febrile urinary tract infection. METHODS: Between 1999 and 2009, urinary bladder augmentation was performed in 21 children with neurogenic bladder. Seventeen of these patients had VUR on preoperative voiding cystourethrography, of whom 11 patients (14 ureters) received augmentation alone (Group A) and 6 patients (8 ureters) received simultaneously ureteral reimplantation (Group B). Univariate logistic regression analysis and Fisher exact test were used for statistical analysis. RESULTS: Six patients (8 ureters) had residual HVURs in Group A, but none in Group B. The incidences of residual HVUR were 57.14% and 0%, respectively. Seven patients had febrile UTIs after operation, 6 of them had residual HVURs. In risk factor analysis, postoperative follow-up duration less than 12 months and lack of anti reflux operation were significant risk factors for residual HVUR; the residual HVUR was the significant risk factor for febrile urinary tract infection. CONCLUSION: Simultaneous ureteral reimplantation reduces postop HVUR significantly. We recommend augmentation and simultaneous ureteral reimplantation in children with HVUR and neurogenic bladder if technically feasible. PMID- 21783095 TI - Lactate peak on brain MRS in children with syndromic mitochondrial diseases. AB - BACKGROUND: Brain magnetic resonance spectroscopy (MRS) has been reported to be a valuable noninvasive tool in the diagnosis of some rare diseases. In this study, our aim was to assess lactate peak on single-voxel proton MRS in children with syndromic mitochondrial diseases (MDs). METHODS: From March 2004 to November 2010, 14 patients who were diagnosed with syndromic MDs underwent single-voxel proton MRS examination. The volume of interest was positioned on axial magnetic resonance imaging (MRI), and voxels were sampled using short (35 milliseconds), intermediate (144 milliseconds), or long (288 milliseconds) echo times for determination of lactate at 1.33 parts/million. RESULTS: Twelve of fourteen patients (85.7%) exhibited lactate peaks on the initial single-voxel proton MRS, and all of them showed abnormal MRI findings. The correlations of lactate level in blood and lactate peak on single-voxel proton MRS were inconsistent. Among the 12 patients, eight (66.7%) had corresponding elevated levels of blood lactate, and four (33.3%) had normal levels of blood lactate. Compared with a positive rate of 85.7% for patients with lactate peaks on the single-voxel proton MRS, the positive rates for diagnosing syndromic MDs by using electron microscopic examination of muscle biopsy, oral glucose lactate stimulation test, and blood lactate level were 100%, 91.7%, and 71.4%, respectively. CONCLUSION: Lactate acquisition on single-voxel proton MRS provides a noninvasive and complementary tool for the diagnosis of syndromic MDs, especially in children with abnormal signal changes on the brain MRI or a normal blood lactate level. PMID- 21783094 TI - Early experience of the pandemic influenza H1N1 2009 epidemic in Taiwan. AB - BACKGROUND: A novel influenza H1N1 began in March 2009, rapidly spread, and then became a pandemic outbreak. Diagnosis by polymerase chain reaction result was not always available because of a surge in workload and therefore clinical diagnosis became important. However, clinical differences between the patients infected by the novel H1N1 virus and those infected by the influenza-like non-novel H1N1 have not been reported. This study was conducted to compare the demographic background, clinical manifestations, and laboratory findings between novel H1N1 influenza infections and other non-novel H1N1 infections. METHODS: At an early stage of H1N1 spread, cases presenting with influenza-like symptom and travel or contact history were quarantined into infection disease-designated hospitals in Taiwan. Data on consecutive patients under investigation for infection with novel influenza A (H1N1) were collected between April 29 and June 19, 2009. The data set consisted of clinical manifestations, plain chest radiography, hematological results, and biochemical findings. Testing of nasopharyngeal swab samples by reverse transcription polymerase chain reaction was used to detect H1N1. RESULTS: Overall, 166 cases were collected. Among these individuals, there were 14 confirmed H1N1 cases. The clinical manifestations of the H1N1 cases included fever in 13 patients (92.9%), followed by cough, rhinorrhea, a sore throat, myalgia, headache, malaise, abdominal tenderness, and diarrhea. Leukopenia was present in nine patients (64.2%) and lymphocytopenia was present in five (35.7%). The duration of virus shedding was 7.0 +/- 1.8 days. When compared with the non H1N1 cases by multiple logistic regression analysis, cases infected by the novel H1N1 virus were more likely to be younger than 20 years [Odds ratio (OR) = 27.7, 95% confidence interval (CI) = 1.3-597.8, p = 0.034), have traveled from the US (OR = 14.5, 95% CI = 2.1-101.4, p = 0.007) or Thailand (OR = 56.7, 95% CI = 4.6 700.6, p = 0.002) and to have presented with myalgia (OR = 8.5, 95% CI = 1.4 52.0, p = 0.021) or leukopenia (OR = 17.4, 95% CI = 3.4-90.5, p = 0.001). CONCLUSION: When a patient presents with influenza-like acute febrile respiratory illness symptoms and is young in age, has a travel history involving an affected area, and is suffering from myalgia or leukopenia, physicians should be alerted to the possibility of novel H1N1 virus infection. PMID- 21783096 TI - The ocular biometric and corneal topographic characteristics of high anisometropic adults in Taiwan. AB - BACKGROUND: To investigate the difference of ocular biometric and corneal topographic characteristics between the two eyes in high anisometropes with difference of 4 D or more in spherical component. METHODS: Fifty-one young anisometropic men were collected. Detailed ocular examinations, including cycloplegic autorefraction, best-corrected visual acuity, intraocular pressure, A scan, and Orbscan topography were done and recorded. The comparisons between two eyes were performed and the correlations between different ocular parameters were evaluated. RESULTS: The mean axial length in the more myopic/less hyperopic eye was longer than that in the less myopic/more hyperopic eye [difference 1.8 mm, 95% confidence interval (CI) 1.6-2.0 mm, p < 0.001]. The mean thinnest corneal thickness in the more myopic/less hyperopic eye was an average of 4.0 MUm thicker than that in the other eye (95% CI 1.2-6.8 MUm, p = 0.007). The mean anterior chamber depth in the more myopic/less hyperopic eye was an average of 0.05 mm (95% CI 0.02-0.07 mm, p < 0.001) more than that in the other eye. The curvature and size of cornea were not significantly different. CONCLUSION: The anterior chamber depth is deeper, axial length is longer, and thinnest corneal thickness is thicker in the more myopic/less hyperopic eye of high-anisometropic patients. Anisometropic eyes provide the chance to understand the biometric changes of eyeball with different refractive statuses in the same person. Such information is helpful for us to calculate the intraocular lenses power in cataract surgery and to do the surgical planning for corneal refractive surgery in eyes of different refractive power. PMID- 21783097 TI - Comparison of a minimally invasive technique with open tension band wiring for displaced transverse patellar fractures. AB - BACKGROUND: Open reduction and internal fixation with tension band wire is the standard treatment for displaced transverse patellar fractures. Recently, some minimally invasive techniques have been proposed as possible alternative methods. This retrospective study compared a newly reported percutaneous osteosynthesis with conventional open method for the treatment of displaced transverse patellar fractures. METHODS: The minimally invasive technique was performed by percutaneous osteosynthesis with modified Carpenter's (POMC) technique, using figure-eight wiring through two-paired cannulated screws under the control of arthroscopy and fluoroscopy. The conventional open surgery was performed with open modified anterior tension band (OMATB) technique. Totally 60 displaced transverse fractures were included in our study. Twenty were treated with percutaneous technique and 40 with open method. Outcome assessment included analysis of radiographic images, range of motion, Lysholm scores, complications, and reoperations. RESULTS: Mean follow-up was 37.3 months. Comparison of POMC and OMATB groups showed statistically significant results as follows: shorter surgical time, 70.4 +/- 12.5 minutes for POMC group; greater degrees of flexion, 140.4 +/- 6.1 for POMC group; better total range of motion, 139.6 +/- 8.2 for POMC group; higher Lysholm scores, 93.6 +/- 3.1 for POMC group. Frequencies of total complications and reoperations were significantly lower in POMC group. CONCLUSION: POMC method was a reproducibly reliable method, offering better functional outcome, lower incidence of complications, and reoperations, as compared with standard OMATB group for transverse patellar fractures. Nevertheless, it is not recommended for severely comminuted fractures. PMID- 21783098 TI - Eosinophilic peritonitis: an unusual manifestation of tuberculous peritonitis in peritoneal dialysis patient. AB - Eosinophilic peritonitis is an uncommon clinical entity with diagnostic considerations separate from those of tuberculous peritonitis. We report a patient on continuous ambulatory peritoneal dialysis (CAPD) with eosinophilic peritonitis resulting from tuberculous peritonitis. Acid-fast stain and mycobacterial culture of peritoneal dialysis effluent were both negative result. In the peritoneal dialysis effluent and blood samples, Mycobacterium tuberculosis was detected by polymerase chain reaction analyses. The initiation of antituberculous therapy resulted in resolution of the eosionphilia in the dialysis effluent. After 14 days of antituberculous therapy, the polymerase chain reaction analyses of tuberculosis were negative for both the blood and peritoneal dialysis effluents. Evaluation of tuberculosis infection is necessary if the CAPD related peritonitis presents with an unusual and unexplained clinical course. Polymerase chain reaction can play an important role in the diagnosis of tuberculous peritonitis in patients undergoing CAPD. PMID- 21783099 TI - Extramammary Paget's disease of the scrotum. AB - Extramammary Paget's disease is an uncommon intra-epidermal malignant neoplasm that arises in area rich in apocrine glands. Common sites of occurrence include the vulva, perianal region, perineum, and scrotum. The lesion may be accompanied by an invasive adenocarcinoma or adenocarcinoma in situ of the apocrine glands. Generally, the prognosis is poor. Herein, we report two cases of extramammary Paget's disease, one involving the penoscrotal area with bilateral inguinal and pelvic lymph node metastases, the other involving the scrotal area without metastases. PMID- 21783100 TI - Upper airway obstruction caused by bilateral giant tonsilloliths. AB - Tonsilloliths are rare dystrophic calcifications caused by chronic inflammation of the tonsils. They are usually small and occur on one side. Herein, we report a case involving a 75-year-old man presenting odynophagia and progressive dyspnea for days who was found by computed tomography image to have bilateral giant tonsilloliths. Hyperdensity lesions were found over the tonsillar fossa on both sides. Tonsillectomy was performed leading to immediate relief of symptoms. A review of relevant literature revealed that most patients with tonsilloliths are asymptomatic and need only conservative treatment. Severe symptoms such as dyspnea are extremely rare. Although tonsillolith can be easily diagnosed by computed tomography, otolaryngologists should be careful to differentiate this entity. PMID- 21783101 TI - Do editors make a difference? PMID- 21783102 TI - Applications of knitted mesh fabrication techniques to scaffolds for tissue engineering and regenerative medicine. AB - Knitting is an ancient and yet, a fresh technique. It has a history of no less than 1,000 years. The development of tissue engineering and regenerative medicine provides a new role for knitting. Several meshes knitted from synthetic or biological materials have been designed and applied, either alone, to strengthen materials for the patching of soft tissues, or in combination with other kinds of biomaterials, such as collagen and fibroin, to repair or replace damaged tissues/organs. In the latter case, studies have demonstrated that knitted mesh scaffolds (KMSs) possess excellent mechanical properties and can promote more effective tissue repair, ligament/tendon/cartilage regeneration, pipe-like-organ reconstruction, etc. In the process of tissue regeneration induced by scaffolds, an important synergic relationship emerges between the three-dimensional microstructure and the mechanical properties of scaffolds. This paper presents a comprehensive overview of the status and future prospects of knitted meshes and its KMSs for tissue engineering and regenerative medicine. PMID- 21783104 TI - Effect of mineral-collagen interfacial behavior on the microdamage progression in bone using a probabilistic cohesive finite element model. AB - The interactions between mineral and collagen phases in the ultrastructural level play an important role in determining the mechanical properties of bone tissue. Three types of mineral-collagen interaction (i.e., ionic interactions, hydrogen/van der Waals bonds, and van der Waals/viscous shear in opening/sliding mode, respectively) have been simulated in this study, using cohesive zone modeling techniques. Considering the inhomogeneity of bone, a probabilistic failure analysis approach has been also employed to account for the effect of mineral-collagen interfacial behavior on microdamage accumulation in lamellar bone tissues. The results of this study suggested that different interfacial behaviors cause different types of microdamage accumulation. The ionic interactions between the mineral and collagen phases lead to the formation of linear microcracks, while the van der Waals/viscous shear interactions may facilitate the formation of diffuse damage. In the case of hydrogen/van der Waals bonds, a transitional behavior of microdamage accumulation in bone was observed. The findings of this study may help in understanding the mechanisms of mineral collagen interactions and its effects on the failure mechanism of bone. PMID- 21783103 TI - Axial creep loading and unloaded recovery of the human intervertebral disc and the effect of degeneration. AB - The intervertebral disc maintains a balance between externally applied loads and internal osmotic pressure. Fluid flow plays a key role in this process, causing fluctuations in disc hydration and height. The objectives of this study were to quantify and model the axial creep and recovery responses of nondegenerate and degenerate human lumbar discs. Two experiments were performed. First, a slow compressive ramp was applied to 2000 N, unloaded to allow recovery for up to 24 h, and re-applied. The linear-region stiffness and disc height were within 5% of the initial condition for recovery times greater than 8 h. In the second experiment, a 1000 N creep load was applied for four hours, unloaded recovery monitored for 24 h, and the creep load repeated. A viscoelastic model comprised of a "fast" and "slow" exponential response was used to describe the creep and recovery, where the fast response is associated with flow in the nucleus pulposus (NP) and endplate, while the slow response is associated with the annulus fibrosus (AF). The study demonstrated that recovery is 3-4X slower than loading. The fast response was correlated with degeneration, suggesting larger changes in the NP with degeneration compared to the AF. However, the fast response comprised only 10%-15% of the total equilibrium displacement, with the AF-dominated slow response comprising 40%-70%. Finally, the physiological loads and deformations and their associated long equilibrium times confirm that diurnal loading does not represent "equilibrium" in the disc, but that over time the disc is in steady state. PMID- 21783105 TI - Tribological characterization of a biocompatible thin film of UHMWPE on Ti6Al4V and the effects of PFPE as top lubricating layer. AB - Ultra-high molecular weight polyethylene (UHMWPE) thin film was coated onto Ti6Al4V alloy specimens using dip coating method. Tribological performance of this coating (thickness of 19.6 +/- 2.0 MUm) was evaluated using 4 mm diameter Si(3)N(4) ball counterface in a ball-on-disk tribometer. Tests were carried out for different normal loads (0.5, 1.0, 2.0 and 4.0 N) and rotational speeds of the disk (200 and 400 rpm). UHMWPE coating formed in this study exhibits high hydrophobicity with water contact angle of 135.5 +/- 3.3 degrees and meets the requirements of cytotoxicity test using the ISO 10993-5 elution method. This coating shows low coefficient of friction (0.15) and high wear durability (>96,000 cycles) for the tested conditions. PFPE overcoat on UHMWPE has further increased the wear durability of UHMWPE coating as evaluated at even higher rotational speed of 1000 rpm. PMID- 21783106 TI - Compressive mechanical properties of demineralized and deproteinized cancellous bone. AB - A method to completely demineralize and deproteinize bone was used to investigate the mechanical properties of either the mineral or protein phase in cancellous bone and compared to an untreated one. Compression tests on cancellous bovine femur and elk antler (Cervus elaphus canadensis) were performed on demineralized, deproteinized, and untreated samples in an air-dry condition. Results showed that the elastic modulus and compressive strength of the demineralized (protein only) and deproteinized (mineral only) samples were far lower than that of the untreated ones, indicating a strong synergetic effect between the two phases. Experimental data showed that the demineralized, deproteinized, and untreated samples can be modeled as cellular solids, with the strong dependence of mechanical properties on the relative density. Deformed samples were examined under SEM and different failure mechanisms were observed. Plastic buckling was observed in demineralized samples while brittle crushing was found in deproteinized ones. PMID- 21783107 TI - Loading velocity dependent permeability in agarose gel under compression. AB - A new approach for characterization of agarose gel permeability under compression at different loading velocities is proposed. Uniaxial compression tests on thin agarose gel specimens in a rigid porous confinement cell immersed in a water bath are undertaken. The equilibrium response of the gel, which is assumed to be achieved under extremely low-loading velocity (of the order of tens nanometers per second) is considered to be the response of the hydrated gel scaffold. The water exudation behavior from the agarose gel was extracted from the load displacement response under various loading velocities by subtracting the equilibrium response. It was found that the pressure on water in the gel is not a linear function of loading velocity or volume flow rate and therefore, the permeability of agarose gel was observed to vary with deformation and water flow velocity. In addition, it was inferred from the analysis that at low velocities and large strain levels the gel permeability dominates the compression behavior, and at higher velocities and small strain levels the viscosity of the hydrated matrix may contribute to the load. Finally, permeability variation in agarose gel at different loading velocities is attributed to the two states (free water and bound water) of water molecules in the gel. PMID- 21783108 TI - Fracture toughening mechanism of cortical bone: an experimental and numerical approach. AB - In this investigation, the crack propagation mechanisms contributing to the toughness of cortical bone were studied using a combination of experimental and numerical approaches. Compact tension (CT) specimens were prepared from bovine cortical bones to achieve crack propagation in the longitudinal and transverse directions. Stable crack extension experiments were conducted to distinguish the crack growth resistance curves, and virtual multidimensional internal bond (VMIB) modeling was adopted to simulate the fracture responses. Results from experiments indicated that cortical bone exhibited rising resistance curves (R-curves) for crack extension parallel and perpendicular to the bone axis; the transverse fracture toughness was significantly larger, indicating that the fracture properties of cortical bone are substantially anisotropic. Microscopic observations showed that the toughening mechanisms in the longitudinal and transverse directions were different. When the crack grew in the transverse direction, the crack deflected significantly, and crack bifurcations were found at the crack wake, while, in the longitudinal direction, the crack was straight and uncracked ligaments were observed. Numerical simulations also revealed that the fracture resistance in the transverse direction was greater than that in the longitudinal direction. PMID- 21783109 TI - On the role of oxygen vacancies, aliovalent ions and lattice strain in the in vivo wear behavior of alumina hip joints. AB - We have visualized at the nanometer scale the topological, chemical and mechanical characteristics of long-term in vivo exposed bearing surfaces of femoral heads made of monolithic alumina. Four self-mated alumina retrievals were studied, which were exposed in the human body for relatively long periods of time ranging between 7.7 and 10.7 yrs. Besides conventional morphological features, monitored by atomic force microscopy, the topographic distributions of point defects and lattice strain on the surface of the heads were systematically probed by collecting high spatially and spectrally resolved cathodoluminescence spectra from zones of different wear severity. Three types of optically active point defect site could be detected: (i) oxygen vacancies; (ii) substitutional (aliovalent) cations; and, (iii) interstitial aluminum cations. These luminescent sites represent the main defects progressively developed in the alumina lattice during exposure in human hip joints. A clear evolution toward (environmentally driven) off-stoichiometry was found with progressing wear. Moreover, the shallow electro-stimulated optical probe also detailed the presence of lattice strain fields (of both elastic and plastic nature) stored in the very neighborhood of the bearing surface. The present spectroscopic characterizations enable substantiating important tribochemical interactions between bearing surfaces and in vivo environment as pivotal parts of progressive events of wear degradation. PMID- 21783110 TI - Failure analysis of the fractured wires in sternal perichronal loops. AB - We report failure analysis of sternal wires in two cases in which a perichronal fixation technique was used to close the sternotomy. Various characteristics of the retrieved wires were compared to those of unused wires of the same grade and same manufacturer and with surgical wire specifications. In both cases, wire fracture was un-branched and transgranular and proceeded by a high cycle fatigue process, apparently in the absence of corrosion. However, stress anlysis indicates that the effective stress produced during strong coughing is lower than the yield strength. Our findings suggest that in order to reduce the risk for sternal dehiscence, the diameter of the wire used should be increased. PMID- 21783111 TI - Computer simulation of elastic constants of hydroxyapatite and fluorapatite. AB - Hydroxyapatite (HAP) and fluorapatite (FAP) are essential components of dental enamel and bone. In this paper, we report a computational study of the elastic properties of HAP and FAP using ab initio and force field techniques. We have obtained the HAP and FAP elastic stiffness constants in hexagonal symmetry by fitting the Hooke law for both the energy-strain and stress-strain relations. Our ab initio HAP stiffness constants differ from the results of previous calculations, but follow similar trends. The HAP and FAP stiffness constants calculated with the ab initio method are very similar, although FAP is slightly stiffer than HAP in the hexagonal plane, and more compliant along the hexagonal axis. The pseudo-single-crystal HAP experimental stiffness constants in current use are critically reviewed. Combining the data from the ab initio simulations with the experimental FAP stiffness constants, several alternative sets of HAP stiffness constants are proposed. The mismatch in properties between HAP and FAP is evidently too small to assume it to be directly responsible for dental enamel mechanical degradation with fluorosis disease. PMID- 21783112 TI - The effect of strain rate on fracture toughness of human cortical bone: a finite element study. AB - Evaluating the mechanical response of bone under high loading rates is crucial to understanding fractures in traumatic accidents or falls. In the current study, a computational approach based on cohesive finite element modeling was employed to evaluate the effect of strain rate on fracture toughness of human cortical bone. Two-dimensional compact tension specimen models were simulated to evaluate the change in initiation and propagation fracture toughness with increasing strain rate (range: 0.08-18 s(-1)). In addition, the effect of porosity in combination with strain rate was assessed using three-dimensional models of micro-computed tomography-based compact tension specimens. The simulation results showed that bone's resistance against the propagation of a crack decreased sharply with increase in strain rates up to 1 s(-1) and attained an almost constant value for strain rates larger than 1 s(-1). On the other hand, initiation fracture toughness exhibited a more gradual decrease throughout the strain rates. There was a significant positive correlation between the experimentally measured number of microcracks and the fracture toughness found in the simulations. Furthermore, the simulation results showed that the amount of porosity did not affect the way initiation fracture toughness decreased with increasing strain rates, whereas it exacerbated the same strain rate effect when propagation fracture toughness was considered. These results suggest that strain rates associated with falls lead to a dramatic reduction in bone's resistance against crack propagation. The compromised fracture resistance of bone at loads exceeding normal activities indicates a sharp reduction and/or absence of toughening mechanisms in bone during high strain conditions associated with traumatic fracture. PMID- 21783113 TI - Tradeoffs amongst fatigue, wear, and oxidation resistance of cross-linked ultra high molecular weight polyethylene. AB - This study evaluated the tradeoffs amongst fatigue crack propagation resistance, wear resistance, and oxidative stability in a wide variety of clinically-relevant cross-linked ultra-high molecular weight polyethylene. Highly cross-linked re melted materials showed good oxidation and wear performance, but diminished fatigue crack propagation resistance. Highly cross-linked annealed materials showed good wear and fatigue performance, but poor oxidation resistance. Moderately cross-linked re-melted materials showed good oxidation resistance, but moderate wear and fatigue resistance. Increasing radiation dose increased wear resistance but decreased fatigue crack propagation resistance. Annealing reduced fatigue resistance less than re-melting, but left materials susceptible to oxidation. This appears to occur because annealing below the melting temperature after cross-linking increased the volume fraction and size of lamellae, but failed to neutralize all free radicals. Alternately, re-melting after cross linking appeared to eliminate free radicals, but, restricted by the network of cross-links, the re-formed lamellae were fewer and smaller in size which resulted in poor fatigue crack propagation resistance. This is the first study to simultaneously evaluate fatigue crack propagation, wear, oxidation, and microstructure in a wide variety of clinically-relevant ultra-high. The tradeoff we have shown in fatigue, wear, and oxidation performance is critical to the material's long-term success in total joint replacements. PMID- 21783114 TI - Integrity and zeta potential of fluoridated hydroxyapatite nanothick coatings for biomedical applications. AB - Fluoridated hydroxyapatite (FHA) coatings exhibit great potential for applications on implants which require good bioactivity and high antibacterial activity. This work is a comparative study of chemical stability, adhesive strength and zeta potential of a nanothick (about 200 nm) FHA coating which is densely and uniformly deposited on a titanium substrate electrochemically. The chemical stability of the nanothick coatings was evaluated using a dissolution test in a simulated physiological solution. The dissolution tests indicate that the fluorine-containing calcium phosphate (CaP) coating with an appropriate heat treatment is chemically stable in a physiological environment, even more so than its HA counterpart. The adhesive strength of FHA coatings was evaluated by the critical load obtained from nanoscratching tests. The critical load which caused coating failure in scratching was determined by a method which correlated the scratching morphology with a sudden change in friction coefficient. The adhesive strength of a nanothick FHA coating was 147% larger than that of HA coating with the same thickness level. The fluorine addition does not have a significant effect on the characteristics of the negative zeta potential of apatite coatings. The solid integrity of this nanothick FHA coating makes it an excellent candidate for biomedical applications. PMID- 21783115 TI - Influence of occlusal geometry on ceramic crown fracture; role of cusp angle and fissure radius. AB - OBJECTIVES: To develop an approximate analytical model that identifies the influence of both cusp angle and notch radius on the failure load of all-ceramic premolar crowns. METHODS: The scatter of failure loads in a crown fracture resistance test was analyzed based on the stress intensity and stress concentration factors from mechanics models developed for simple compact tension to more sophisticated blunt V-notch specimens. Based on the same loading conditions and dimensions, the predicted loads were systematically compared with fracture loads of laboratory-tested crowns to identify the most relevant model. Finally, based upon these models a safe range of cusp angles and notch radii were identified for posterior all-ceramic crowns with various veneering materials' fracture toughness values as the selection criteria. RESULTS: The failure loads of the crowns were distributed in the range between the classical compact tension (lower bound) and blunt V-notch model (upper bound). Additionally, when considering the effect of different materials, the predicted trend of failure loads moves to higher loads well above typical occlusal forces when the fracture toughness of veneering porcelain is increased. The effects of notch radius on the failure load are still inconclusive due to the relatively complex shape of occlusal surfaces. Further studies on crowns with a range of material properties are required to substantiate the model. SIGNIFICANCE: Cusp angle is a key factor that controls the stress generated at the crown fissure. This study provides the rationale for evaluating such effects and clinical guidelines for occlusal design are proposed. PMID- 21783116 TI - Coupled experiment/finite element analysis on the mechanical response of porcine brain under high strain rates. AB - This paper presents a coupled experimental/modeling study of the mechanical response of porcine brain under high strain rate loading conditions. Essentially, the stress wave propagation through the brain tissue is quantified. A Split Hopkinson Pressure Bar (SPHB) apparatus, using a polycarbonate (viscoelastic) striker bar was employed for inducing compression waves for strain rates ranging from 50 to 750 s(-1). The experimental responses along with high speed video showed that the brain tissue's response was nonlinear and inelastic. Also, Finite Element Analysis (FEA) of the SHPB tests revealed that the tissue underwent a non uniform stress state during testing when glue is used to secure the specimen with the test fixture. This result renders erroneous the assumption of uniaxial loading. In this study, the uniaxial volume averaged stress-strain behavior was extracted from the FEA to help calibrate inelastic constitutive equations. PMID- 21783117 TI - The influence of the compounding process and testing conditions on the compressive mechanical properties of poly(D,L-lactide-co-glycolide)/alpha tricalcium phosphate nanocomposites. AB - The enhanced biological and degradation properties of bioresorbable polymer matrix nanocomposites intended for use in orthopaedic applications have been demonstrated recently. However, at the moment there are only limited reports addressing their mechanical properties under physiological conditions, which is of central importance to the successful design of these nanocomposites. Here, we show that at room temperature in dry conditions, the incorporation of alpha tricalcium phosphate nanoparticles into a matrix of poly(D,L-lactide-co glycolide) increases the compressive strength and modulus. The values at room temperature obtained for nanocomposites compounded by a modified solvent evaporation method via attrition milling in acetone were similar to those from samples compounded by twin screw extrusion. The values for nanocomposites tested at 37 degrees C in phosphate buffered saline solution were significantly lower than those tested at room temperature in dry conditions, and lower still after two weeks of degradation in PBS at 37 degrees C. These effects can be related to hydration, degradation and interface effects in the nanocomposites. PMID- 21783118 TI - Myocardial transversely isotropic material parameter estimation from in-silico measurements based on a reduced-order unscented Kalman filter. AB - Parameter estimation from non-invasive measurements is a crucial step in patient specific cardiac modeling. It also has the potential to provide significant assistance in the clinical diagnosis of cardiac diseases through the quantification of myocardial material heterogeneity. In this paper, we formulate a novel Reduced-order Unscented Kalman Filter (rUKF) applied to the left ventricular (LV) nonlinear mechanical model based on cubic-Hermite finite elements. Material parameters in the widely-employed transversely isotropic Guccione's constitutive law are successfully identified for both homogeneous and heterogeneous cases. We conclude that the four parameters in Guccione's law can be uniquely and correctly determined in-silico from noisy displacement measurements of material points located on the myocardial surfaces. The future application of this novel and effective approach to real clinical measurements is thus promising. PMID- 21783119 TI - Modeling shear behavior of the annulus fibrosus. AB - Modeling the mechanical properties of the annulus fibrosus has two distinct challenges: the complex loading state experienced in vivo and the anisotropic, nonlinear nature of the tissue. Previous efforts to model the annulus fibrosus have not considered shear data in the analysis, yet the shear response may be critical to understanding tissue behavior and damage. In this study, we compared four hyperelastic constitutive models fitted to uniaxial and biaxial tension, confined compression, and shear experiments from the literature. Models were either directly based on Spencer's formulation for a fiber-reinforced composite material with two equivalent fiber families or represented the annulus as two transversely isotropic materials. Each model was composed of additive strain energy terms that represent specific constituents of the annulus fibrosus (proteoglycan matrix, collagen fibers, and collagen crosslinks). Additionally, we investigated the effect of restricting the fibers such that they supported tensile loads only. Best fit coefficients for these models were calculated both including and excluding shear data from the regression. All of the models fit the data well when shear data was excluded from the regression; when shear data was included in the regression, two models that were based on Spencer's formulation performed better than the others. None of the models could consistently predict data that was not included in the regression. Restricting the fibers to support only tensile loads had only a modest effect on the fit of the models, but did alter which constituent carried the majority of the strain energy in shear deformations. Our study suggests that a single hyperelastic model may capture the anisotropic behavior of the annulus fibrosus for multiple loading cases, including shear. However, care must be taken when extrapolating these models to additional deformations outside of the training dataset. PMID- 21783120 TI - Hyper-frequency viscoelastic spectroscopy of biomaterials. AB - With the emergence of new biomaterials and elastography imaging techniques, there is a need for innovative instruments dedicated to viscoelasticity measurements. In this work, we introduce a novel hyper-frequency viscoelastic spectroscopy (HFVS) technique dedicated to characterize soft media subjected to mid-to-very high frequency stress ranges (or, equivalently, to probe short-to-very-short relaxation times). HFVS, which has been implemented in an analytical instrument performing non-contact measurements in less than 1 s between 10 and 1000 Hz, is a suitable tool to study viscoelasticity for bio-applications. In this context, HFVS has been compared to classical oscillatory rheometry on several classes of soft materials currently encountered in tissue repair, bioengineering and elastography imaging on a frequency range between 10 and 100 Hz. After having demonstrated the good correspondence between HFVS and rheometry, this study has been completed by exploring the sensitivity of HFVS to physicochemically induced variations of viscoelasticity. HFVS opens promising perspectives in the challenging field of biomaterial science and for viscoelasticity-based quality control of materials. PMID- 21783121 TI - Analysis of blood flow through a viscoelastic artery using the Cosserat continuum with the large-amplitude oscillatory shear deformation model. AB - In this investigation, semiempirical and numerical studies of blood flow in a viscoelastic artery were performed using the Cosserat continuum model. The large amplitude oscillatory shear deformation model was used to quantify the nonlinear viscoelastic response of blood flow. The finite difference method was used to solve the governing equations, and the particle swarm optimization algorithm was utilized to identify the non-Newtonian coefficients (k(upsilon) and gamma(upsilon)). The numerical results agreed well with previous experimental results. PMID- 21783122 TI - The role of heat treatment on microstructure and mechanical properties of Ti-13Zr 13Nb alloy for biomedical load bearing applications. AB - The suitability of heat treated Ti-13Zr-13Nb (TZN) alloy for biomedical load bearing applications has been investigated. Depending upon the heat treatment conditions, the microstructure of TZN alloy mainly consists of alpha, beta or alpha" martensite phases. In general, for all the deformation and solution treatment temperatures the variation of the hardness and tensile strength with cooling rate is similar. The elastic modulus of TZN alloy decreases with an increase in cooling rate from the solution treatment temperature. Relatively fine alpha+beta microstructure increases the hardness and tensile strength. The presence of martensite and/or retained beta in the microstructure decreases the hardness and elastic modulus and increases the ductility substantially whereas higher amount of alpha phase in the matrix increases the elastic modulus. Decomposition of martensite and retained beta into alpha phase during aging increases the hardness, elastic modulus and tensile strength and decreases the ductility. Among the samples studied, the aged TZN sample, which was deformed and solution treated at 800 degrees C followed by water quenching, is a promising candidate for the application as implant material. PMID- 21783123 TI - Mechanical properties and the laminate structure of Arapaima gigas scales. AB - The Arapaima gigas scales play an important role in protecting this large Amazon basin fish against predators such as the piranha. They have a laminate composite structure composed of an external mineralized layer and internal lamellae with thickness of 50-60 MUm each and composed of collagen fibers with ~1 MUm diameter. The alignment of collagen fibers is consistent in each individual layer but varies from layer to layer, forming a non-orthogonal plywood structure, known as Bouligand stacking. X-ray diffraction revealed that the external surface of the scale contains calcium-deficient hydroxyapatite. EDS results confirm that the percentage of calcium is higher in the external layer. The micro-indentation hardness of the external layer (550 MPa) is considerably higher than that of the internal layer (200 MPa), consistent with its higher degree of mineralization. Tensile testing of the scales carried out in the dry and wet conditions shows that the strength and stiffness are hydration dependent. As is the case of most biological materials, the elastic modulus of the scale is strain-rate dependent. The strain-rate dependence of the elastic modulus, as expressed by the Ramberg Osgood equation, is equal to 0.26, approximately ten times higher than that of bone. This is attributed to the higher fraction of collagen in the scales and to the high degree of hydration (30% H(2)O). Deproteinization of the scale reveals the structure of the mineral component consisting of an interconnected network of platelets with a thickness of ~50 nm and diameter of ~500 nm. PMID- 21783124 TI - Degradation of polysaccharide hydrogels seeded with bone marrow stromal cells. AB - In order to produce hydrogel cell culture substrates that are fit for the purpose, it is important that the mechanical properties are well understood not only at the point of cell seeding but throughout the culture period. In this study the change in the mechanical properties of three biopolymer hydrogels alginate, low methoxy pectin and gellan gum have been assessed in cell culture conditions. Samples of the gels were prepared encapsulating rat bone marrow stromal cells which were then cultured in osteogenic media. Acellular samples were also prepared and incubated in standard cell culture media. The rheological properties of the gels were measured over a culture period of 28 days and it was found that the gels degraded at very different rates. The degradation occurred most rapidly in the order alginate > Low methoxy pectin > gellan gum. The ability of each hydrogel to support differentiation of bone marrow stromal cells to osteoblasts was also verified by evidence of mineral deposits in all three of the materials. These results highlight that the mechanical properties of biopolymer hydrogels can vary greatly during in vitro culture, and provide the potential of selecting hydrogel cell culture substrates with mechanical properties that are tissue specific. PMID- 21783126 TI - Experimental verification of brain tissue incompressibility using digital image correlation. AB - For decades, incompressibility has been a major assumption in the mechanical study of brain tissue. This assumption is based on the hydrated nature of the biological tissues and the incompressibility of fluids. In this paper, an experimental validation of this assumption using digital image correlation is presented. Unconfined compression tests, relaxation tests and cyclic tests were performed on cylindrical samples of swine brains at loading rates suitable for neurosurgical applications. Digital image correlation was used to evaluate the evolution of the volume ratio throughout the tests. The preparation of the samples is described and it is demonstrated that it causes no statistically significant change of their mechanical properties. The results indicate that the brain tissue incompressibility assumption is verified. PMID- 21783125 TI - Active contraction of cardiac muscle: in vivo characterization of mechanical activation sequences in the beating heart. AB - Progressive alterations in cardiac wall strains are a classic hallmark of chronic heart failure. Accordingly, the objectives of this study are to establish a baseline characterization of cardiac strains throughout the cardiac cycle, to quantify temporal, regional, and transmural variations of active fiber contraction, and to identify pathways of mechanical activation in the healthy beating heart. To this end, we insert two sets of twelve radiopaque beads into the heart muscle of nine sheep; one in the anterior-basal and one in the lateral equatorial left ventricular wall. During three consecutive heartbeats, we record the bead coordinates via biplane videofluoroscopy. From the resulting four dimensional data sets, we calculate the temporally and transmurally varying Green Lagrange strains in the anterior and lateral wall. To quantify active contraction, we project the strains onto the local muscle fiber directions. We observe that mechanical activation is initiated at the endocardium slightly after end diastole and progresses transmurally outward, reaching the epicardium slightly before end systole. Accordingly, fibers near the outer wall are in contraction for approximately half of the cardiac cycle while fibers near the inner wall are in contraction almost throughout the entire cardiac cycle. In summary, cardiac wall strains display significant temporal, regional, and transmural variations. Quantifying wall strain profiles might be of particular clinical significance when characterizing stages of left ventricular remodeling, but also of engineering relevance when designing new biomaterials of similar structure and function. PMID- 21783127 TI - Mechanical testing and osteointegration of titanium implant with calcium phosphate bone cement and autograft alternatives. AB - The purpose of this study was to evaluate the osteointegration of a titanium (Ti) implant with the calcium phosphate cement (CPC) and autograft prostheses by pull out test and histological examination. Stems of sixty Ti cylinders were bilaterally inserted into femoral medullary canals in 30 rabbits at the 1st, 4th, 12th, 26th and 70th postoperative weeks. The bone autograft and CPC were filled into the pre-trimmed bone marrow cavity with a polymethyl methacrylate retarder in the distal end, and then a Ti cylinder was inserted into femurs. The CPC group was significantly (p<0.05) associated with a larger pull-out force at 4th (37%) and 12th (62%) weeks compared to the autograft group. The bone area and the bone to-implant contact ratios of the CPC groups were significantly higher than that of the autograft groups at early healing stage. The histological exams suggest that the CPC enhanced the earlier bone formation around the implant at a period not longer than 12 weeks postoperation. We conclude that CPC graft has the higher ability to facilitate the osteointegration and stabilize the Ti implant at a relatively early stage than the autograft in vivo. PMID- 21783128 TI - Engineering alginate for intervertebral disc repair. AB - Alginate is frequently studied as a scaffold for intervertebral disc (IVD) repair, since it closely mimics mechanical and cell-adhesive properties of the nucleus pulposus (NP) of the IVD. The aim of this study was to assess the relation between alginate concentration and scaffold stiffness and find preparation conditions where the viscoelastic behaviour mimics that of the NP. In addition, we measured the effect of variations in scaffold stiffness on the expression of extracellular matrix molecules specific to the NP (proteoglycans and collagen) by native NP cells. We prepared sample discs of different concentrations of alginate (1%-6%) by two different methods, diffusion and in situ gelation. The stiffness increased with increasing alginate concentration, while the loss tangent (dissipative behaviour) remained constant. The diffusion samples were ten-fold stiffer than samples prepared by in situ gelation. Sample discs prepared from 2% alginate by diffusion closely matched the stiffness and loss tangent of the NP. The stiffness of all samples declined upon prolonged incubation in medium, especially for samples prepared by diffusion. The biosynthetic phenotype of native cells isolated from NPs was preserved in alginate matrices up to 4 weeks of culturing. Gene expression levels of extracellular matrix components were insensitive to alginate concentration and corresponding matrix stiffness, likely due to the poor adhesiveness of the cells to alginate. In conclusion, alginate can mimic the viscoelastic properties of the NP and preserve the biosynthetic phenotype of NP cells but certain limitations like long-term stability still have to be addressed. PMID- 21783129 TI - Mechanical and biodegradable properties of porous titanium filled with poly-L lactic acid by modified in situ polymerization technique. AB - Porous titanium (pTi) can possess a low Young's modulus equal to that of human bone, depending on its porosity. However, the mechanical strength of pTi deteriorates greatly with increasing porosity. On the other hand, certain medical polymers exhibit biofunctionalities, which are not possessed intrinsically by metallic materials. Therefore, a biodegradable medical polymer, poly-L-lactic acid (PLLA), was used to fill in the pTi pores using a modified in-situ polymerization technique. The mechanical and biodegradable properties of pTi filled with PLLA (pTi/PLLA) as fabricated by this technique and the effects of the PLLA filling were evaluated in this study. The pTi pores are almost completely filled with PLLA by the developed process (i.e., technique). The tensile strength and tensile Young's modulus of pTi barely changes with the PLLA filling. However, the PLLA filling improves the compressive 0.2% proof stress of pTi having any porosity and increases the compressive Young's modulus of pTi having relatively high porosity. This difference between the tensile and compressive properties of pTi/PLLA is considered to be caused by the differing resistances of PLLA in the pores to tensile and compressive deformations. The PLLA filled into the pTi pores degrades during immersion in Hanks' solution at 310 K. The weight loss due to PLLA degradation increases with increasing immersion time. However, the rate of weight loss of pTi/PLLA during immersion decreases with increasing immersion time. Hydroxyapatite formation is observed on the surface of pTi/PLLA after immersion for >=8 weeks. The decrease in the weight loss rate may be caused by weight gain due to hydroxyapatite formation and/or the decrease in contact area with Hanks' solution caused by its formation on the surface of pTi/PLLA. PMID- 21783130 TI - Mechanical properties and thermal behaviour of PEGDMA hydrogels for potential bone regeneration application. AB - Poly(ethylene glycol) hydrogels are currently under investigation as possible scaffold materials for bone regeneration. The main purpose of this research was to analyse the mechanical properties and thermal behaviour of novel photopolymerised poly(ethylene glycol) dimethacrylate (PEGDMA) based hydrogels. The effect of varying macromolecular monomer concentration, molecular weight and water content on the properties of the resultant hydrogel was apparent. For example, rheological findings showed that storage modulus (G') of the hydrogels could be tailored to a range between approximately 14,000 and 70,000 Pa by manipulating both of the aforementioned criteria. Equally striking variations in mechanical performance were observed using uniaxial tensile testing where reduction in PEGDMA content in the hydrogels resulted in decrease in both tensile strength and Young's modulus values. Conversely, increases in the elongation at break values were observed as would be expected. Differential scanning calorimetry and dynamic mechanical thermal analysis showed that there was an increase in Tg with an increase in the molecular weight of PEGDMA. The relationship between the initial feed ratio, molecular weight of the macromolecular monomer and the subsequent mechanical properties of the hydrogels are further elucidated throughout this study. PMID- 21783131 TI - PVA hydrogel properties for biomedical application. AB - PVA has been proposed as a promising biomaterial suitable for tissue mimicking, vascular cell culturing and vascular implanting. In this research, a kind of transparent PVA hydrogel has been investigated in order to mimic the creatural soft tissue deformation during mini-invasive surgery with needle intervention, such as brachytherapy. Three kinds of samples with the same composition of 3 g PVA, 17 g de-ionized water, 80 g dimethyl-sulfoxide but different freeze/thaw cycles have been prepared. In order to investigate the structure and properties of polyvinyl alcohol hydrogel, micro-structure, mechanical property and deformation measurement have been conducted. As the SEM image comparison results show, with the increase of freeze/thaw cycles, PVA hydrogel revealed the similar micro-structure to porcine liver tissue. With uniaxial tensile strength test, the above composition with a five freeze/thaw cycle sample resulted in Young's modulus similar to that of porcine liver's property. Through the comparison of needle insertion deformation experiment and the clinical experiment during brachytherapy, results show that the PVA hydrogel had the same deformation property as prostate tissue. These transparent hydrogel phantom materials can be suitable soft tissue substitutes in needle intervention precision or pre operation planning studies, particularly in the cases of mimicking creatural tissue deformation and analysing video camera images. PMID- 21783133 TI - Effect of cyclic strain on the mechanical behavior of virgin ultra-high molecular weight polyethylene. AB - Ultra High Molecular Weight Polyethylene (UHMWPE) is a polymeric material employed in critical biomedical applications. Knowledge of its mechanical behavior is essential in order to obtain accurate prediction of stresses and deformations in real components, in particular when cyclic loading is considered. In the present research the effects of alternating and pulsating cyclic strain on the mechanical response of UHMWPE were studied by means of an experimental procedure based on tests carried out in strain control at different mean cyclic strain levels. During the tests the temperature increase due to hysteretic heating was controlled by means of a compressed air cooling apparatus specifically devised. By taking advantage of the possibility to control and stabilize temperature, cyclic steady-state mechanical response was investigated at room temperature and at 37 and 50 degrees C, comparing the effects of alternating and pulsating loading cycles. A transient thermal analysis using the finite element method (FEM) was also carried out to analyze temperature distribution within the specimen. UHMWPE exhibited cyclic softening as a result of a thermal contribution due to temperature increase and of a mechanical contribution related to the effects of applied load on the microstructure. The material exhibited different peak stress percent reductions for pulsating and alternating loading and during tensile and compressive loading phases. For pulsating tests significant cyclic mean stress relaxation was also observed. Based on the experimental procedure described the cyclic curve was determined as a function of temperature and fitted with a Ramberg-Osgood type constitutive equation, in which material parameters are temperature dependent. In this way the combined effects of temperature rises, such as those that might occur in biological environments or due to frictional heating, and mechanical loads could effectively be taken into account for constitutive modeling purposes of cyclic mechanical behavior of UHMWPE. PMID- 21783132 TI - Comparison of four methods to simulate swelling in poroelastic finite element models of intervertebral discs. AB - Osmotic phenomena influence the intervertebral disc biomechanics. Their simulation is challenging and can be undertaken at different levels of complexity. Four distinct approaches to simulate the osmotic behaviour of the intervertebral disc (a fixed boundary pore pressure model, a fixed osmotic pressure gradient model in the whole disc or only in the nucleus pulposus, and a swelling model with strain-dependent osmotic pressure) were analysed. Predictions were compared using a 3D poroelastic finite element model of a L4-L5 spinal unit under three different loading conditions: free swelling for 8 h and two daily loading cycles: (i) 200 N compression for 8 h followed by 500 N compression for 16 h; (ii) 500 N for 8 h followed by 1000 N for 16 h. Overall, all swelling models calculated comparable results, with differences decreasing under greater loads. Results predicted with the fixed boundary pore pressure and the fixed osmotic pressure in the whole disc models were nearly identical. The boundary pore pressure model, however, cannot simulate differential osmotic pressures in disc regions. The swelling model offered the best potential to provide more accurate results, conditional upon availability of reliable values for the required coefficients and material properties. Possible fields of application include mechanobiology investigations and crack opening and propagation. However, the other approaches are a good compromise between the ease of implementation and the reliability of results, especially when considering higher loads or when the focus is on global results such as spinal kinematics. PMID- 21783134 TI - The effect of cyclic hydrostatic pressure on the functional development of cartilaginous tissues engineered using bone marrow derived mesenchymal stem cells. AB - Mechanical signals can play a key role in regulating the chondrogenic differentiation of mesenchymal stem cells (MSCs). The objective of this study was to determine if the long-term application of cyclic hydrostatic pressure could be used to improve the functional properties of cartilaginous tissues engineered using bone marrow derived MSCs. MSCs were isolated from the femora of two porcine donors, expanded separately under identical conditions, and then suspended in cylindrical agarose hydrogels. Constructs from both donors were maintained in a chemically defined media supplemented with TGF-beta3 for 42 days. TGF-beta3 was removed from a subset of constructs from day 21 to 42. Loaded groups were subjected to 10 MPa of cyclic hydrostatic pressurisation at 1 Hz for one hour/day, five days/week. Loading consisted either of continuous hydrostatic pressure (CHP) initiated at day 0, or delayed hydrostatic pressure (DHP) initiated at day 21. Free swelling (FS) constructs were cultured in parallel as controls. Constructs were assessed at days 0, 21 and 42. MSCs isolated from both donors were morphologically similar, demonstrated comparable colony forming unit fibroblast (CFU-F) numbers, and accumulated near identical levels of collagen and GAG following 42 days of free swelling culture. Somewhat unexpectedly the two donors displayed a differential response to hydrostatic pressure. For one donor the application of CHP resulted in increased collagen and GAG accumulation by day 42, resulting in an increased dynamic modulus compared to FS controls. In contrast, CHP had no effect on matrix accumulation for the other donor. The application of DHP had no effect on either matrix accumulation or construct mechanical properties for both donors. Variability in the response to hydrostatic pressure was also observed for three further donors. In conclusion, this study demonstrates that the application of long-term hydrostatic pressure can be used to improve the functional properties of cartilaginous tissues engineered using bone marrow derived MSCs by enhancing collagen and GAG accumulation. The response to such loading however is donor dependent, which has implications for the clinical utilisation of such a stimulus when engineering cartilaginous grafts using autologous MSCs. PMID- 21783135 TI - Time-dependent evaluation of mechanical properties and in vitro cytocompatibility of experimental composite-based nerve guidance conduits. AB - The use of nerve guidance conduits to repair peripheral nerve discontinuities has attracted much attention from the biomaterials community, with many resorbable and non-resorbable materials in clinical use. However, a material with ideal biocompatibility, sufficient mechanical properties (to match that of the regenerating nerve) coupled with a suitable degradation rate, has yet to be realized. Recently, potential solutions (composite nerve guidance conduits) which support the emerging philosophy of allowing synthetic materials to establish key interactions with cells in ways that encourage self-repair (i.e. ionic mediators of repair such as those observed in hard tissue regeneration) have been proposed in the literature; such composites comprise specially designed bioactive phosphate-free glasses embedded in degradable polymeric matrices. Whilst much research has focussed on the optimization of such composites, there is no published literature on the performance of these experimental compositions under simulated physiological conditions. To address this key limitation, this paper explores the time-dependent variations in wet-state mechanical properties (tensile modulus and ultimate tensile strength) for NGC composites containing various compositions of PLGA (at 12.5, and 20 wt%), F127 (at 0, 2.5 and 5 wt%) and various loadings of Si-Na-Ca-Zn-Ce glass (at 0 and 20 wt%). It was observed that Young's modulus and ultimate tensile strength of these composites were in the range 5-203 MPa and 1-7 MPa respectively, indicating comparable mechanical performance to clinical materials. Furthermore, an analysis of the cytocompatibility of experimental compositions showed comparable (in some instances superior), compatibility when compared with the commercial product Neurolac((r)). Based on current synthetic devices and the demands of the indication, the CNGCs examined in this work offer appropriate mechanical properties and compatibility to warrant enhanced development. PMID- 21783136 TI - Characterization of PEEK biomaterials using the small punch test. AB - The small punch test is widely used to characterize the ductility and fracture resistance in metals and ceramics, when only a small volume of material is available. This study was conducted to investigate the suitability of the small punch test for characterizing polyetheretherketone (PEEK) polymeric biomaterials for changes in material grade, crystallinity, and molding process. The small punch test reproducibly characterized the mechanical behavior of PEEK and was able to distinguish differences induced by molding process alterations and annealing. Peak load was most sensitive to changes in crystallinity, grade, molding process, and increased with increasing crystallinity, but decreased with the addition of image contrast materials. The ultimate displacement was negatively correlated with crystallinity. Molding process conditions had the greatest influence on metrics of the small punch test, when compared with the effects of annealing and the addition of a radiopacifier. The results of this study validate the small punch test as a repeatable method for measuring the mechanical behavior of PEEK biomaterials. PMID- 21783137 TI - Effects of lactide monomer on the hydrolytic degradation of poly(lactide-co glycolide) 85L/15G. AB - The hydrolytic degradation of oriented poly(L-lactide-co-glycolide) 85 L/15 G (PLGA 85/15) sample materials with various amounts of lactide monomer was monitored in vitro at 37 degrees C. The materials were manufactured from medical grade PLGA 85/15 by a two-step melt extrusion-die drawing process. Results showed that the hydrolytic degradation rate depended highly on the lactide monomer content, which in turn influenced the retention of mechanical properties, mass loss, crystallinity, and dimensional stability. Even small quantities of lactide monomer (0.05-0.20 wt%) affected especially the retention of mechanical properties, which started to decline rapidly upon the inherent viscosity reaching 0.6-0.8 dl/g due to hydrolytic degradation. Based on our hydrolytic degradation data, we constructed a simplified mathematical model of degradation-related strength retention and recommend it as a functional quality control tool for melt processed biodegradable medical devices manufactured from poly(L-lactide-co glycolide) 85 L/15 G. PMID- 21783138 TI - Crack tip fracture toughness of base glasses for dental restoration glass ceramics using crack opening displacements. AB - The critical stress intensity factor, also known as the crack tip toughness K(tip), was determined for three base glasses, which are used in the manufacture of glass-ceramics. The glasses included the base glass for a lithium disilicate glass-ceramic, the base glass for a fluoroapatite glass-ceramic and the base glass for a leucite glass-ceramic. These glass-ceramic are extensively used in the form of biomaterials in restorative dental medicine. The crack tip toughness was established by using crack opening displacement profiles under experimental conditions. The crack was produced by Vickers indentation. The crack tip toughness parameters determined for the three glass-ceramics differed quite significantly. The crack tip parameters of the lithium disilicate base glass and the leucite base glass were higher than that of the fluoroapatite base glass. This last material showed glass-in-glass phase separation. The discussion of the results clearly shows that the droplet glass phase is softer than the glass matrix. Therefore, the authors conclude that a direct relationship exists between the chemical nature of the glasses and the crack tip parameter. PMID- 21783139 TI - A coupled electromechanical model for the excitation-dependent contraction of skeletal muscle. AB - This work deals with the development and implementation of an electromechanical skeletal muscle model. To this end, a recently published hyperelastic constitutive muscle model with transversely isotropic characteristics, see Ehret et al. (2011), has been weakly coupled with Ohm's law describing the electric current. In contrast to the traditional way of active muscle modelling, this model is rooted on a non-additive decomposition of the active and passive components. The performance of the proposed modelling approach is demonstrated by the use of three-dimensional illustrative boundary-value problems that include electromechanical analysis on tissue strips. Further, simulations on the biceps brachii muscle document the applicability of the model to realistic muscle geometries. PMID- 21783140 TI - Articular cartilage surface rupture during compression: investigating the effects of tissue hydration in relation to matrix health. AB - This study aimed at investigating articular cartilage rupture by investigating the response of healthy and degenerate cartilage through altering the osmotic swelling environment of surface-intact, cartilage-on-bone specimens. The osmotic environment in healthy and degenerate bovine cartilage was varied by soaking tissues in either distilled water or 1.5 M NaCl saline to render the tissues into a swollen or dehydrated state (respectively). Creep compression was applied using an 8 mm flat-ended polished indenter that contained a central pore of 450 MUm diameter, providing a consistent region for rupture to occur across all specimens. In the first set of experiments, surface rupture of healthy and degenerate specimens required similar levels of nominal compressive stress (8 MPa) when dehydrated than when swollen (7 MPa). In the second set of experiments, the time required for surface rupture to occur (for healthy and degenerate specimens) occurred over similar loading times (p>0.05). However, the time required for surface rupture for the swollen specimens occurred over a significantly longer time (approximately one order of magnitude) than that required for the dehydrated specimens (p<0.05). The compressive strains that were measured at rupture in the dehydrated degenerate specimens were significantly lower than those measured in the dehydrated healthy tissues (p<0.05). Rupture in dehydrated degenerate cartilage suggested a weakened articular surface, and it also suggested that dehydrated cartilage may undergo failure due to stress concentrations as it is unable to redistribute stress away from the site of loading. PMID- 21783141 TI - Incorporation of PLGA nanoparticles into porous chitosan-gelatin scaffolds: influence on the physical properties and cell behavior. AB - Bone regeneration can be accelerated by localized delivery of appropriate growth factors/biomolecules. Localized delivery can be achieved by a 2-level system: (i) incorporation of biomolecules within biodegradable particulate carriers (nanoparticles), and (ii) inclusion of such particulate carriers (nanoparticles) into suitable porous scaffolds. In this study, freeze-dried porous chitosan gelatin scaffolds (CH-G: 1:2 ratio by weight) were embedded with various amounts of poly(lactide-co-glycolide) (PLGA) nanoparticles, precisely 16.6%, 33.3% and 66.6% (respect to CH-G weight). Scaffolds loaded with PLGA nanoparticles were subjected to physico-mechanical and biological characterizations including morphological analysis, swelling and dissolution tests, mechanical compression tests and cell viability tests. Results showed that incorporation of PLGA nanoparticles into porous crosslinked CH-G scaffolds: (i) changed the micro architecture of the scaffolds in terms of mean pore diameter and pore size distribution, (ii) reduced the dissolution degree of the scaffolds, and (iii) increased the compressive modulus. On the other hand, the water uptake behavior of CH-G scaffolds containing PLGA nanoparticles significantly decreased. The incorporation of PLGA nanoparticles did not affect the biocompatibility of CH-G scaffolds. PMID- 21783142 TI - Comparison of the multiphasic model and the transport model for the swelling and deformation of polyelectrolyte hydrogels. AB - Polyelectrolyte hydrogel is a ternary mixture of water, polymer network and mobile ions. The present paper examined two popular models describing the swelling and deformation behaviors of polyelectrolyte hydrogels, i.e. the multiphasic model and the transport model. The water flow, the network deformation and the ionic diffusion are coupled in the multiphasic model, and the gradient of the fluid pressure is taken as the driving force for the network deformation. However, the water flow is neglected in the transport model with the ionic osmotic pressure taking the role of fluid pressure. Two simplified experiments, i.e. the free swelling of a hydrogel sphere in response to the concentration change of the external salt solution and the bending deformation of a hydrogel strip under an external electric field, are simulated by the two models. Simulation shows that the two models lead to the same predictions for the swelling equilibrium of the hydrogel sphere but different predictions for the swelling kinetics of the hydrogel sphere and the deformation of the hydrogel strip under the external electric field. These are due to the fact that the two models are equivalent in thermodynamic equilibrium situations, but in thermodynamic non-equilibrium situations, the transport model is no longer applicable as it neglects the water flow in the hydrogel and takes the ionic osmotic pressure as a mechanical parameter to play the role of swelling pressure. The present work will be helpful for understanding the hydrodynamics of polyelectrolyte hydrogels and the application of the two models. PMID- 21783143 TI - A study of the frictional properties of senofilcon-A contact lenses. AB - The frictional property of soft contact lenses could have a great impact on their clinical performance. However, to date, only a handful of studies have been conducted to understand the friction mechanism(s) of the soft contact lens. In the current paper, the friction of senofilcon-A contact lenses has been studied with a stainless steel ball as the counterface in a saline solution. The load applied was between 0.5 mN and 100 mN and the sliding velocity ranges from 0.01 cm/s to 0.5 cm/s. It was found that the friction force is proportional to normal load as described by Amonton's law and this unexpected behavior can be attributed to the fact that viscous flow contributes little to the overall friction and that solid-solid contact dominates the friction of senofilcon-A. It was also found that the coefficient of the friction increases with the velocity and the quantitative relationship between them can be explained reasonably well with a previously proposed "repulsion-adsorption" model. The impacts of material chemistry, water content, test media, applied load and the sliding velocity on the friction mechanism(s) are also discussed. PMID- 21783144 TI - Long-term stability of dentin matrix following treatment with various natural collagen cross-linkers. AB - OBJECTIVES: Collagen disorganization is one of the main degradation patterns found in unsuccessful adhesive restorations. The hypothesis of this study was that pretreatment using natural collagen cross-linking agents rich in proanthocyanidin (PA) would improve mechanical properties and stability over time of the dentin collagen and, thus, confer a more resistant and lasting substrate for adhesive restorations. METHODS: PA-based extracts, from grape seed (GSE), cocoa seed (CSE), cranberry (CRE), cinnamon (CNE) and acai berry (ACE) were applied over the demineralized dentin. The apparent elastic modulus (E) of the treated dentin collagen was analyzed over a 12 month period. Specimens were immersed in the respective solution and E values were obtained by a micro flexural test at baseline, 10, 30, 60, 120 and 240 min. Samples were stored in artificial saliva and re-tested after 3, 6 and 12 months. Data was analyzed using ANOVA and Tukey test. RESULTS: GSE and CSE extracts showed a time-dependent effect and were able to improve [240 min (MPa): GSE = 108.96 +/- 56.08;CSE = 59.21 +/- 24.87] and stabilize the E of the organic matrix [12 months (MPa): GSE = 40.91 +/- 19.69;CSE = 42.11 +/- 13.46]. CRE and CNE extracts were able to maintain the E of collagen matrices constant over 12 months [CRE = 11.17 +/- 7.22;CNE = 9,96 +/- 6.11;MPa]. ACE (2.64 +/- 1.22 MPa) and control groups immersed in neat distilled water (1.37 +/- 0.69 MPa) and ethanol-water (0.95 +/- 0.33 MPa) showed no effect over dentin organic matrix and enable their degradation and reduction of mechanical properties. SIGNIFICANCE: Some PA-based extracts were capable of improving and stabilizing collagen matrices through exogenous cross-links induction. PMID- 21783145 TI - Creep behavior of the intact and meniscectomy knee joints. AB - The mechanical functions of the menisci may be partially performed through the fluid pressurization in articular cartilages and menisci. This creep behavior has not been investigated in whole knee joint modeling. A three-dimensional finite element knee model was employed in the present study to explore the fluid-flow dependent creep behaviors of normal and meniscectomy knees. The model included distal femur, tibia, fibula, articular cartilages, menisci and four major ligaments. Articular cartilage or meniscus was modeled as a fluid-saturated solid matrix reinforced by a nonlinear orthotropic and site-specific collagen network. A 300 N compressive force, equal to half of body weight, was applied to the knee in full extension followed by creep. The results showed that the fluid pressurization played a substantial role in joint contact mechanics. Menisci bore more loading as creep developed, leading to decreased stresses in cartilages. The removal of menisci not only changed the stresses in the cartilages, which was in agreement with published studies, but also altered the distribution and the rate of dissipation of fluid pressure in the cartilages. The high fluid pressures in the femoral cartilage moved from anterior to more central regions of the condyles after total meniscectomy. For both intact and meniscectomy joints, the fluid pressure level remained considerably high for thousands of seconds during creep, which lasted even longer after meniscectomy. For the femoral cartilage, the maximum principal stress was generally in agreement with the fiber direction, which indicated the essential role of fibers in load support of the tissue. PMID- 21783146 TI - Stiffening by fiber reinforcement in soft materials: a hyperelastic theory at large strains and its application. AB - This work defines an incompressible, hyperelastic theory of anisotropic soft materials at finite strains, which is tested by application to the experimental response of fiber-reinforced rubber materials. The experimental characterization is performed using a uniaxial testing device with optical measures of the deformation, using two different reinforcing materials on a ground rubber matrix. In order to avoid non-physical responses of the underlying structural components of the material, the kinematics of the deformation are described using a novel deformation tensor, which ensures physical consistency at large strains. A constitutive relation for incompressible fiber-reinforced materials is presented, while issues of stability and ellipticity for the hyperelastic solution are considered to impose necessary restrictions on the constitutive parameters. The theoretical predictions of the proposed model are compared with the anisotropic experimental responses, showing high fitting accuracy in determining the mechanical parameters of the model. The constitutive theory is suitable to account for the anisotropic response at large compressive strains, opening perspectives for many applications in tissue engineering and biomechanics. PMID- 21783147 TI - Physico-mechanical properties of wound dressing material and its biomedical application. AB - A bioadhesive wound dressing material, based on gelatin, was prepared by solution casting, and its properties were evaluated. The tensile strength (TS) and percentage elongation at break (Eb) of the membranes were found to be 12.7 MPa and 40.4%, respectively. The buffer uptake and water uptake of the prepared membranes were found to be 298 and 312%, respectively, after 8 min. A scanning electron micrograph of the membrane revealed its uniform porosity, which is an essential criterion to be an ideal wound dressing. From microbial sensitivity analysis, it was found that the membrane had a significant resistance against infection. The wound-healing characteristics of the membrane were evaluated using a rat (Rattus norvegicus) model. Full-thickness wounds were created on the ventral side of the Rattus norvegicus and were dressed with the membrane; eco plast was used as a control. The wound healing and bioadhesion were monitored at 3-day intervals by real-time imaging. The results revealed that the prepared membrane was more effective in healing the wound than conventional wound dressing. PMID- 21783148 TI - High density polyethylene/graphite nano-composites for total hip joint replacements: processing and in vitro characterization. AB - The main objective of the present study is to investigate how the thermal, rheological, mechanical and cytotoxicity behavior of High Density Polyethylene (HDPE) can be changed by the addition of graphite nano particles (GNPs) at different contents. The HDPE/GNPs composites were prepared using melt blending in a co-rotating intermeshing twin screw extruder. The in vitro tests results showed that the original material (HDPE) and all HDPE/GNPs composites do not exhibit any cytotoxicity to the WISH cell line. The microscopic examination of the nano composite tensile-fractured surface found a good distribution of GNPs in the HDPE matrix. The Differential Scanning Calorimetry (DSC) results indicated that the crystallization percentage increased by adding GNPs to HDPE up to 4%. The XRD patterns of the HDPE/GNPs composites showed an increase in peak intensity compared to neat HDPE. This increase echoed the crystallinity results obtained from DSC. The rheological tests showed that the complex viscosity of the HDPE increased as the percentage of GNPs increased due to the restriction of the molecular mobility. The tensile test results showed that with increasing the GNPs content, Young's modulus and the yield strength of the HDPE/GNPs composite increased while the strain at fracture decreased. Finally, the preliminary results of the abrasion test indicated that the abrasion rate decreased by increasing the GNPs ratio up to 4% content. The prepared HDPE/GNPs composites appear to have fairly good comprehensive properties that make them a good candidate as a bearing material for the total joint replacement. PMID- 21783149 TI - Optimum gradient material for a functionally graded dental implant using metaheuristic algorithms. AB - Despite dental implantation being a great success, one of the key issues facing it is a mismatch of mechanical properties between engineered and native biomaterials, which makes osseointegration and bone remodeling problematical. Functionally graded material (FGM) has been proposed as a potential upgrade to some conventional implant materials such as titanium for selection in prosthetic dentistry. The idea of an FGM dental implant is that the property would vary in a certain pattern to match the biomechanical characteristics required at different regions in the hosting bone. However, matching the properties does not necessarily guarantee the best osseointegration and bone remodeling. Little existing research has been reported on developing an optimal design of an FGM dental implant for promoting long-term success. Based upon remodeling results, metaheuristic algorithms such as the genetic algorithms (GAs) and simulated annealing (SA) have been adopted to develop a multi-objective optimal design for FGM implantation design. The results are compared with those in literature. PMID- 21783150 TI - Microstructure and mechanical properties of open-cellular biomaterials prototypes for total knee replacement implants fabricated by electron beam melting. AB - Total knee replacement implants consisting of a Co-29Cr-6Mo alloy femoral component and a Ti-6Al-4V tibial component are the basis for the additive manufacturing of novel solid, mesh, and foam monoliths using electron beam melting (EBM). Ti-6Al-4V solid prototype microstructures were primarily alpha phase acicular platelets while the mesh and foam structures were characterized by alpha(')-martensite with some residual alpha. The Co-29Cr-6Mo containing 0.22% C formed columnar (directional) Cr(23)C(6) carbides spaced ~2 MUm in the build direction, while HIP-annealed Co-Cr alloy exhibited an intrinsic stacking fault microstructure. A log-log plot of relative stiffness versus relative density for Ti-6Al-4V and Co-29Cr-6Mo open-cellular mesh and foams resulted in a fitted line with a nearly ideal slope, n = 2.1. A stress shielding design graph constructed from these data permitted mesh and foam implant prototypes to be fabricated for compatible bone stiffness. PMID- 21783151 TI - Effects of osteoporosis and nutrition supplements on structures and nanomechanical properties of bone tissue. AB - In this study, the bone structures, nanomechanical properties and fracture behaviors in different groups of female C57BL/6 mice (control, sham operated, ovariectomized, casein supplemented, and fermented milk supplemented) were examined by micro-computed tomography, scanning and transmission electron microscopy, and nanoindentation. The control and sham operated mice showed dense bone structures with high cortical bone mineral densities of 544 mg/cm(3) (average) and high hardness of 0.9-1.1 GPa; resistance to bone fracture was conferred by microcracking, crack deflections and ligament bridging attributed to aligned collagen fibers and densely packed hydroxyapatite crystals. Bone mineral density, hardness and fracture resistance in ovariectomized mice markedly dropped due to loose bone structure with randomly distributed collagens and hydroxyapatites. The acidic casein supplemented mice with blood acidosis exhibited poor mineral absorption and loose bone structure, whereas the neutralized casein or fermented milk supplemented mice were resistant to osteoporosis and had high bone mechanical properties. PMID- 21783152 TI - Mechanical and corrosion resistance of a new nanostructured Ti-Zr-Ta-Nb alloy. AB - In this work, a multi-elementary Ti-10Zr-5Nb-5Ta alloy, with non-toxic alloying elements, was used to develop an accumulative roll bonding, ARB-type procedure in order to improve its structural and mechanical properties. The alloy was obtained by cold crucible semi-levitation melting technique and then was ARB deformed following a special route. After three ARB cycles, the total deformation degree per layer is about 86%; the calculated medium layer thickness is about 13 MUm. The ARB processed alloy has a low Young's modulus of 46 GPa, a value very close to the value of the natural cortical bone (about 20 GPa). Data concerning ultimate tensile strength obtained for ARB processed alloy is rather high, suitable to be used as a material for bone substitute. Hardness of the ARB processed alloy is higher than that of the as-cast alloy, ensuring a better behaviour as a implant material. The tensile curve for the as-cast alloy shows an elastoplastic behaviour with a quite linear elastic behaviour and the tensile curve for the ARB processed alloy is quite similar with a strain-hardening elastoplastic body. Corrosion behaviour of the studied alloy revealed the improvement of the main electrochemical parameters, as a result of the positive influence of ARB processing. Lower corrosion and ion release rates for the ARB processed alloy than for the as-cast alloy, due to the favourable effect of ARB thermo-mechanical processing were obtained. PMID- 21783153 TI - Impact of thermomechanical texture on the superelastic response of Nitinol implants. AB - The phenomenon of superelasticity in near-equiatomic NiTi, which originates from a first-order martensitic phase transition, is exploited in an increasing number of biomedical devices, most importantly endovascular stents. These stents are often manufactured from microtubing, which is shown to be highly textured crystallographically. Synchrotron X-ray microdiffraction provided microstructural, phase, and strain analysis from Nitinol tube sections that were deformed in situ along longitudinal, circumferential, and transverse orientations. We show that the large variation in the superelastic response of NiTi in these three tube directions is strongly influenced by the path that the martensitic transformation follows through the microstructure. Specifically, in severely worked NiTi, bands of [100] grains occur whose orientation deviates markedly from the surrounding matrix; these bands have an unusually large impact on the initiation and the propagation of martensite, and hence on the mechanical response. Understanding the impact of these local microstructural effects on global mechanical response, as shown here, leads to a much fuller understanding of the causes of deviation of the mechanical response from predictions and unforeseen fracture in NiTi biomedical devices. PMID- 21783154 TI - Multi-scale hierarchy of Chelydra serpentina: microstructure and mechanical properties of turtle shell. AB - Carapace, the protective shell of a freshwater snapping turtle, Chelydra serpentina, shields them from ferocious attacks of their predators while maintaining light-weight and agility for a swim. The microstructure and mechanical properties of the turtle shell are very appealing to materials scientists and engineers for bio-mimicking, to obtain a multi-functional surface. In this study, we have elucidated the complex microstructure of a dry Chelydra serpentina's shell which is very similar to a multi-layered composite structure. The microstructure of a turtle shell's carapace elicits a sandwich structure of waxy top surface with a harder sub-surface layer serving as a shielding structure, followed by a lamellar carbonaceous layer serving as shock absorber, and the inner porous matrix serves as a load-bearing scaffold while acting as reservoir of retaining water and nutrients. The mechanical properties (elastic modulus and hardness) of various layers obtained via nanoindentation corroborate well with the functionality of each layer. Elastic modulus ranged between 0.47 and 22.15 GPa whereas hardness varied between 53.7 and 522.2 MPa depending on the microstructure of the carapace layer. Consequently, the modulus of each layer was represented into object oriented finite element (OOF2) modeling towards extracting the overall effective modulus of elasticity (~4.75 GPa) of a turtle's carapace. Stress distribution of complex layered structure was elicited with an applied strain of 1% in order to understand the load sharing of various composite layers in the turtle's carapace. PMID- 21783155 TI - Compressive behaviour of bovine cancellous bone and bone analogous materials, microCT characterisation and FE analysis. AB - Compressive behaviour of bovine cancellous bone and three open-cell metallic foams (AlSi7Mg (30 ppi and 45 ppi); CuSn12Ni2 (30 ppi)) has been studied using mechanical testing, micro-focus computed tomography and finite element modelling. Whilst the morphological parameters of the foams and the bone appear to be similar, the mechanical properties vary significantly between the foams and the bone. Finite element models were built from the CT images of the samples and multi-linear constitutive relations were used for modelling of the bone and the foams. The global responses of the bone and foam samples were reasonably well captured by the FE models, whilst the percentage of yielded elements as a measure of damage evolution during compression seems to be indicative of the micro mechanical behaviour of the samples. The damage evolution and distribution patterns across the bone and the foams are broadly similar for the strain range studied, suggesting possible substitution of trabecular bones with appropriate foams for biomechanical studies. PMID- 21783156 TI - In vitro degradation, flexural, compressive and shear properties of fully bioresorbable composite rods. AB - Several studies have investigated self-reinforced polylactic acid (SR-PLA) and polyglycolic acid (SR-PGA) rods which could be used as intramedullary (IM) fixation devices to align and stabilise bone fractures. This study investigated totally bioresorbable composite rods manufactured via compression moulding at ~100 degrees C using phosphate glass fibres (of composition 50P(2)O(5)-40CaO 5Na(2)O-5Fe(2)O(3) in mol%) to reinforce PLA with an approximate fibre volume fraction (v(f)) of 30%. Different fibre architectures (random and unidirectional) were investigated and pure PLA rods were used as control samples. The degradation profiles and retention of mechanical properties were investigated and PBS was selected as the degradation medium. Unidirectional (P50 UD) composite rods had 50% higher initial flexural strength as compared to PLA and 60% higher in comparison to the random mat (P50 RM) composite rods. Similar initial profiles for flexural modulus were also seen comparing the P50 UD and P50 RM rods. Higher shear strength properties were seen for P50 UD in comparison to P50 RM and PLA rods. However, shear stiffness values decreased rapidly (after a week) whereas the PLA remained approximately constant. For the compressive strength studies, P50 RM and PLA rods remained approximately constant, whilst for the P50 UD rods a significantly higher initial value was obtained, which decreased rapidly after 3 days immersion in PBS. However, the mechanical properties decreased after immersion in PBS as a result of the plasticisation effect of water within the composite and degradation of the fibres. The fibres within the random and unidirectional composite rods (P50 RM and P50 UD) degraded leaving behind microtubes as seen from the SEM micrographs (after 28 days degradation) which in turn created a porous structure within the rods. This was the main reason attributed for the increase seen in mass loss and water uptake for the composite rods (~17% and ~16%, respectively). PMID- 21783157 TI - Respective roles of organic and mineral components of human cortical bone matrix in micromechanical behavior: an instrumented indentation study. AB - Bone is a multiscale composite material made of both a type I collagen matrix and a poorly crystalline apatite mineral phase. Due to remodeling activity, cortical bone is made of Bone Structural Units (BSUs) called osteons. Since osteon represents a fundamental level of structural hierarchy, it is important to investigate the relationship between mechanical behavior and tissue composition at this scale for a better understanding of the mechanisms of bone fragility. The aim of this study is to analyze the links between ultrastructural properties and the mechanical behavior of bone tissue at the scale of osteon. Iliac bone biopsies were taken from untreated postmenopausal osteoporotic women, embedded, sectioned and microradiographed to assess the degree of mineralization of bone (DMB). On each section, BSUs of known DMB were indented with relatively high load (~500 mN) to determine local elastic modulus (E), contact hardness (H(c)) and true hardness (H) of several bone lamellae. Crystallinity and collagen maturity were measured by Fourier Transform InfraRed Microspectroscopy (FTIRM) on the same BSUs. Inter-relationships between mechanical properties and ultrastructural components were analyzed using multiple regression analysis. This study showed that elastic deformation was only explained by DMB whereas plastic deformation was more correlated with collagen maturity. Contact hardness, reflecting both elastic and plastic behaviors, was correlated with both DMB and collagen maturity. No relationship was found between crystallinity and mechanical properties at the osteon level. PMID- 21783158 TI - Bioactive glass microspheres as osteopromotive inlays in macrotextured surfaces of Ti and CoCr alloy bone implants: trapezoidal surface grooves without inlay most efficient in resisting torsional forces. AB - We have tested the efficacy of porous bioactive glass (BG) inlays in enhancement of implant osseointegration. A total of 24 sheep underwent bilateral surgical implantation of three parallel implants on the anteromedial cortical surface of each tibia. The disc-shaped implants made of Ti6Al4V or cobalt chromium (CoCr) alloys had two parallel surface grooves (trapezoidal space with bottom widening) filled with sintered 100% bioactive glass microspheres or a selected mixture of bioactive and biocompatible glass microspheres. The surface of uncoated control implants was smooth, grit-blasted or had unfilled grooves. A subgroup of control smooth CoCr implants was coated with two or three BG layers. Implant incorporation with bone was evaluated using torque testing to failure, scanning electron microscopy and morphometry at 12 and 25 weeks. A total of 144 in vivo implants and 16 ex vivo cemented control implants were analyzed. Control Ti6Al4V implants with unfilled trapezoidal grooves showed highest torsional failure loads with excellent ingrowth of new bone and remodeling of ingrown bone into lamellar bone. Implants with BG inlays and microroughened control Ti6Al4V implants showed significantly lower torsional failure loads than control Ti6Al4V implants with unfilled grooves. In conclusion, BG inlays failed to enhance biological implant fixation. Macrotextured surface was more effective than grit-blasting in promotion of mechanical incorporation. PMID- 21783159 TI - Morphology based cohesive zone modeling of the cement-bone interface from postmortem retrievals. AB - In cemented total hip arthroplasty, the cement-bone interface can be considerably degenerated after less than one year in vivo service; this makes the interface much weaker relative to the direct post-operative situation. It is, however, still unknown how these degenerated interfaces behave under mixed-mode loading and how this is related to the interface morphology. In this study, we used a finite element (FE) approach to analyze the mixed-mode response of the cement bone interface taken from postmortem retrievals. We investigated whether it was feasible to generate a fully elastic and a failure cohesive model based on only morphological input parameters. Computed tomography-based FE-models of postmortem cement-bone interfaces were generated and the interface morphology was determined. The models were loaded until failure in multiple directions by allowing cracking of the bone and cement components and including periodic boundary conditions. The resulting stiffness was related to the interface morphology. A closed form mixed-mode cohesive model that included failure was determined and related to the interface morphology. The responses of the FE simulations compare satisfactorily with experimental observations, albeit the magnitude of the strength and stiffness are somewhat overestimated. Surprisingly, the FE-simulations predict no failure under shear loading and a considerable normal compression is generated which prevents dilation of the interface. The obtained mixed-mode stiffness response could subsequently be related to the interface morphology and subsequently be formulated into an elastic cohesive zone model. Finally, the acquired data could be used as an input for a cohesive model that also includes interface failure. PMID- 21783160 TI - Effect of aging on the transverse toughness of human cortical bone: evaluation by R-curves. AB - The age-related deterioration in the quality (e.g., strength and fracture resistance) and quantity (e.g., bone-mineral density) of human bone, together with increased life expectancy, is responsible for increasing incidence of bone fracture in the elderly. The present study describes ex vivo fracture experiments to quantitatively assess the effect of aging on the fracture toughness properties of human cortical bone specifically in the transverse (breaking) orientation. Because bone exhibits rising crack-growth resistance with crack extension, the aging-related transverse toughness is evaluated in terms of resistance-curve (R curve) behavior, measured for bone taken from a wide range of age groups (25-74 years). Using this approach, both the ex vivo crack-initiation and crack-growth toughness are determined and are found to deteriorate with age; however, the effect is far smaller than that reported for the longitudinal toughness of cortical bone. Whereas the longitudinal crack-growth toughness has been reported to be reduced by almost an order of magnitude for human cortical bone over this age range, the corresponding age-related decrease in transverse toughness is merely ~14%. Similar to that reported for X-ray irradiated bone, with aging cracks in the transverse direction are subjected to an increasing incidence of crack deflection, principally along the cement lines, but the deflections are smaller and result in a generally less tortuous crack path. PMID- 21783161 TI - Structure and mechanical properties of Saxidomus purpuratus biological shells. AB - The strength and fracture behavior of Saxidomus purpuratus shells were investigated and correlated with the structure. The shells show a crossed lamellar structure in the inner and middle layers and a fibrous/blocky and porous structure composed of nanoscaled particulates (~100 nm diameter) in the outer layer. It was found that the flexure strength and fracture mode are a function of lamellar organization and orientation. The crossed lamellar structure of this shell is composed of domains of parallel lamellae with approximate thickness of 200-600 nm. These domains have approximate lateral dimensions of 10-70 MUm with a minimum of two orientations of lamellae in the inner and middle layers. Neighboring domains are oriented at specific angles and thus the structure forms a crossed lamellar pattern. The microhardness across the thickness was lower in the outer layer because of the porosity and the absence of lamellae. The tensile (from flexure tests) and compressive strengths were analyzed by means of Weibull statistics. The mean tensile (flexure) strength at probability of 50%, 80-105 MPa, is on the same order as the compressive strength (~50-150 MPa) and the Weibull moduli vary from 3.0 to 7.6. These values are significantly lower than abalone nacre, in spite of having the same aragonite structure. The lower strength can be attributed to a smaller fraction of the organic interlayer. The fracture path in the specimens is dominated by the orientation of the domains and proceeds preferentially along lamella boundaries. It also correlates with the color changes in the cross section of the shell. The cracks tend to undergo a considerable change in orientation when the color changes abruptly. The distributions of strengths, cracking paths, and fracture surfaces indicate that the mechanical properties of the shell are anisotropic with a hierarchical nature. PMID- 21783162 TI - Static and dynamic moduli of posterior dental resin composites under compressive loading. AB - Dental resin composites are commonly used as restorative materials for dental treatment. To comprehend the static and dynamic moduli of dental resin composites, we investigated the mechanical behaviors of resin composites under static and dynamic loading conditions. Four commercially available resin composites for posterior restorations were evaluated. The percentages, by weight, of inorganic fillers of resin composites were examined by the ashing technique. The static compressive tests were undertaken with a constant loading speed of 1.0 mm/min using a computer-controlled INSTRON testing machine. The dynamic properties of composites were determined using the split Hopkinson pressure bar (SHPB) technique. When inorganic filler content was increased, a remarkable increase in the static modulus and dynamic modulus were observed. Furthermore, there was a strong relationship between the static modulus and dynamic modulus (r(2) = 0.947). The SHPB technique clearly demonstrated the dynamic properties of composites, and was a useful technique for determining the mechanical behavior of composites under dynamic compressive loading. PMID- 21783163 TI - The use of polyacrylamide gels for mechanical calibration of cartilage--a combined nanoindentation and unconfined compression study. AB - This study investigates polyacrylamide (PA) gel as a calibration material to measure the nanomechanical compressive modulus of cartilage using nanoindentation. Both nanoindentation and unconfined compression testing were performed on PA gel and porcine rib cartilage. The equilibrium moduli measured by the two methods were discernable. Nanoindentation has the advantage of distinguishing between spatially dependent constituent properties that affect tissue mechanical function in heterogeneous and hierarchically structured tissues such as cartilage. Both sets of measurements exhibited similar positive correlation with increasing gel crosslinker concentration. The compressive modulus measurements from compression in the PA gels ranged from 300 kPa-1.4 MPa, whereas those from nanoindentation ranged from 100 kPa-1.1 MPa. Using this data, a method for relating nanoindentation measurements to conventional mechanical property measurements is presented for porcine rib cartilage. It is shown that based on this relationship, the local tissue modulus as measured from nanoindentation (1.1-1.4 MPa) was able to predict the overall global modulus of the same sample of rib cartilage (2.2 MPa), as confirmed by experimental measurements from unconfined compression. This study supports the use of nanoindentation for the local characterization of cartilage tissues and may be applied to other soft tissues and constructs. PMID- 21783164 TI - Development of the novel ferrous-based stainless steel for biomedical applications, part I: high-temperature microstructure, mechanical properties and damping behavior. AB - This research investigated the high-temperature microstructure, mechanical properties, and damping behavior of Fe-9 Al-30 Mn-1C-5 Co (wt.%) alloy by means of electron microscopy, experimental model analysis, and hardness and tensile testing. Subsequent microstructural transformation occurred when the alloy under consideration was subjected to heat treatment in the temperature range of 1000 1150 degrees C: gamma -> (gamma+kappa). The kappa-phase carbides had an ordered L'1(2)-type structure with lattice parameter a = 0.385 nm. The maximum yield strength (sigma(y)), hardness, elongation, and damping coefficient of this alloy are 645 MPa, Hv 292, ~54%, and 178.5 * 10(-4), respectively. These features could be useful in further understanding the relationship between the biocompatibility and the wear and corrosion resistance of the alloy, so as to allow the development of a promising biomedical material. PMID- 21783165 TI - The effect of friction on indenter force and pile-up in numerical simulations of bone nanoindentation. AB - Nanoindentation is a useful technique for probing the mechanical properties of bone, and finite element (FE) modeling of the indentation allows inverse determination of elastoplastic constitutive properties. However, all but one FE study to date have assumed frictionless contact between indenter and bone. The aim of this study was to explore the effect of friction in simulations of bone nanoindentation. Two-dimensional axisymmetric FE simulations were performed using a spheroconical indenter of tip radius 0.6 MUm and angle 90 degrees . The coefficient of friction between indenter and bone was varied between 0.0 (frictionless) and 0.3. Isotropic linear elasticity was used in all simulations, with bone elastic modulus E = 13.56 GPa and Poisson's ratio of 0.3. Plasticity was incorporated using both Drucker-Prager and von Mises yield surfaces. Friction had a modest effect on the predicted force-indentation curve for both von Mises and Drucker-Prager plasticity, reducing maximum indenter displacement by 10% and 20% respectively as friction coefficient was increased from zero to 0.3 (at a maximum indenter force of 5 mN). However, friction has a much greater effect on predicted pile-up after indentation, reducing predicted pile-up from 0.27 to 0.11 MUm with a von Mises model, and from 0.09 to 0.02 MUm with Drucker-Prager plasticity. We conclude that it is potentially important to include friction in nanoindentation simulations of bone if pile-up is used to compare simulation results with experiment. PMID- 21783166 TI - Evaluating the effective shear modulus of the cytoplasm in cultured myoblasts subjected to compression using an inverse finite element method. AB - In the present study, we employ our recently developed confocal microscopy-based cell-specific finite element (FE) modeling method, which is suitable for large deformation analyses, to conduct inverse FE analyses aimed at determining the shear modulus of the cytoplasm of cultured skeletal myoblasts, G(cp), and its variation across a number of cells. We calibrate these cell-specific models against experimental data describing the force-deformation behavior of the same cell type, which were published by Peeters et al. (2005b) [J. Biomech.]. The G(cp) calculated for five different myoblasts were contained in the range of 0.8 2.4 kPa, with the median value being 1 kPa, the mean being 1.4 kPa, and the standard deviation being 0.7 kPa. The normalized sum of squared errors resulting from the fit between experimental and calculated force-deformation curves ranged between 0.12-0.73%, and Pearson correlations for all fits were greater than 0.99. Determining the mechanical properties of the cytoplasm through cell-specific FE will now allow calculation of cell stresses using cell-specific FE under various cell loading configurations, in support of experimental work in cellular mechanics. PMID- 21783167 TI - Glass ionomer layer thickness and its influence on zirconia failure. AB - OBJECTIVES: To investigate the influence of glass ionomer cement layers with various thickness and cement contamination on the fracture resistance of thin zirconia plates luted onto coplanar human molars. MATERIALS AND METHODS: Zirconia plates measuring 0.7 mm in thickness were luted onto 70 coplanarly trimmed human molars with glass ionomer cement. Cement layers measuring 100, 250, 1000, and 2000 MUm in thickness were produced. Contamination of the tooth surface was achieved by applying hand-piece oil, contamination of the cement by mixing glass ionomer with H(2)O(2) to produce voids and gas bubbles. RESULTS: Fracture resistance was independent from cement layer thickness (median ranging from 1220 to 1367 N). Oil contamination moderately reduced fracture resistance (1135 N). Fracture resistance was significantly affected by the presence of a considerable amount of voids or gas bubbles in the cement (877 N). CONCLUSIONS: The fracture resistance of thin zirconia plates was not affected by different cement layer thickness but by contamination of the tooth surface as well as by high cement porosity due to simulated handling errors. PMID- 21783168 TI - An investigation of the determinants of motor contagion in preschool children. AB - The influence of action perception on action execution has been demonstrated by studies of motor contagion in which the observation of an action interferes with the concurrent execution of a different action. The current study extends prior work on the extent of motor contagion in early childhood, a period of development when the effects of action observation on action execution may be particularly salient. During a classroom story reading, children (mean age 4.8 years) were familiarized with two different-colored bears, one of which was used as a seemingly animate hand puppet while the other bear remained lifeless and inanimate. Children then completed a task in which they were instructed to move a stylus on a graphics tablet in the presence of background videos of each bear making horizontal arm movements which had biological (human-moved) or non biological (machine-moved) origins. Motor contagion was assessed as the variability of stylus movements in the horizontal axis when children were instructed to produce vertical stylus movements. Significant levels of motor contagion were seen when children observed the previously animate bear in the non biological motion condition and when they observed the previously inanimate bear in the biological motion condition. For future studies of social perception, this finding points to the potential importance of examining mismatches between prior experience with (or knowledge about) a particular agent and the subsequent behavior of that agent in a different context. PMID- 21783169 TI - Dose-related effect of statins in venous thrombosis risk reduction. AB - BACKGROUND: Atherosclerosis and venous thromboembolism share similar pathophysiology based on common inflammatory mediators. The dose-related effect of statin therapy in venous thromboembolism remains controversial. This study investigated whether the use of antiplatelet therapy and statins decrease the occurrence of venous thromboembolism in patients with atherosclerosis. METHODS: We conducted a retrospective cohort study reviewing 1795 consecutive patients with atherosclerosis admitted to a teaching hospital between 2005 and 2010. Patients who had been treated with anticoagulation therapy were excluded. Patients who either used statins for <2 months or never used them were allocated to the nonuser group. RESULTS: The final analysis included 1100 patients. The overall incidence of venous thromboembolism was 9.7%. Among statin users, 6.3% (54/861) developed venous thromboembolism, compared with 22.2% (53/239) in the nonuser group (hazard ratio [HR] 0.24; P <.001). After controlling for confounding factors, statin use was still associated with a lower risk of developing venous thromboembolism (HR 0.29; P <.001). High-dose statin use (average 50.9 mg/day) (HR 0.25; P <.001) lowered the risk of venous thromboembolism compared with standard-dose statins (average 22.2 mg/day) (HR 0.38; P <.001). Dual antiplatelet therapy with aspirin and clopidogrel decreased occurrence of venous thromboembolism (HR 0.19; P <.001). Interestingly, combined statins and antiplatelet therapy further reduced the occurrence of venous thromboembolism (HR 0.16; P <.001). CONCLUSIONS: The use of statins and antiplatelet therapy is associated with a significant reduction in the occurrence of venous thromboembolism with a dose-related response of statins. PMID- 21783170 TI - Intravaginal microbial flora by the 16S rRNA gene sequencing. AB - OBJECTIVE: Conventional diagnosis of bacterial vaginosis contains some controversial points. To understand accurately the relationship between clinical stages and the microbiotas, the intravaginal microbial flora was analyzed by the clone library method. STUDY DESIGN: Vaginal fluid samples from 31 patients were examined. Lactobacillary grade, Nugent score, culture-based method, and clone library analysis using the 16SrRNA gene sequencing were performed and were compared with each other. RESULTS: Patients were categorized by Lactobacillary grade as I (normal) (n = 6), II (intermediate) (n = 11), and III (bacterial vaginosis) (n = 14). The clone library analysis detected 36 bacterial genera and 60 species from all 31 samples. A principal component analysis of the microbial proportions revealed a novel classification, which suggested the significance of the relative ratio of Lactobacillus iners, Atopobium vaginae and anaerobes in bacterial vaginosis. CONCLUSION: Clone library analysis in combination with the conventional method provides substantial information for diagnosis of bacterial vaginosis. PMID- 21783171 TI - Methicillin-resistant Staphylococcus aureus pelvic abscesses in a female after gynecologic pelvic surgery. AB - Pelvic abscesses occurring after gynecologic pelvic surgery are uncommon. We describe the case of a woman who, after undergoing such a procedure, was found to have pelvic abscesses infected with methicillin-resistant Staphyloccocus aureus. The purpose of this report is to raise awareness of a life-threatening complication of gynecologic pelvic surgery. PMID- 21783172 TI - Tooth injury increases expression of the cold sensitive TRP channel TRPA1 in trigeminal neurons. AB - OBJECTIVE: Transient receptor potential (TRP) channels, a family of structurally related proteins have been implicated in the sensation of pain and hyperalgesia caused by exogenous and endogenous agonists, as well as touch, pH, and temperature. The objective of this study was to determine the effects of tooth injury on the expression of the cold sensitive channel TRPA1, in the trigeminal ganglion, the primary source of sensory and nociceptive innervation of teeth. DESIGN: We analyzed TRPA1 expression in a rodent model of tooth injury, by Western blot analyses of proteins extracted from trigeminal ganglia. RESULTS: We found that TRPA1 was selectively increased in trigeminal ganglia innervating injured teeth when compared to TRPA1 expression in trigeminal ganglia innervating healthy teeth. CONCLUSIONS: Our results provide the first evidence of increased expression of a cold-sensitive TRP channel in trigeminal ganglia after pulp exposure, and are consistent with the possibility that increased expression and function of TRPA1 in trigeminal neurons contributes to hyperalgesia and allodynia following tooth injury. PMID- 21783173 TI - Relationship between maximal bite force and tooth wear in bruxist and non-bruxist individuals. AB - OBJECTIVE: (i) To compare individuals with self-reported bruxism and non-bruxist individuals in terms of maximal bite force (MBF) and temporomandibular joint (TMJ) primary assessment parameters and (ii) to examine the relationship between MBF and tooth wear in these subjects. MATERIALS AND METHODS: Twenty-nine bruxist subjects and 29 healthy controls were enrolled. MBF measurements were carried out by the use of bite force recorder. Tooth wear indices, maximal mouth opening, maximal lateral excursions and maximal protrusions were measured for every subject. RESULTS: MBF and tooth wear index scores were significantly higher in bruxists (p values <0.05) compared to non-bruxists. MBF and tooth wear index scores were found to be significantly correlated in the bruxist group (r=0.79, p=0.00). Less significant correlation was observed in the non-bruxist group (r=0.38, p=0.04). No differences in masticatory clinical examination parameters were identified between the groups. CONCLUSION: This study is the first to show that MBF can increase in bruxist individuals and that the increase in MBF are correlated with tooth wear in bruxist subjects. Further studies regarding the possible role of MBF in bruxism are to be done. PMID- 21783175 TI - Catechol-O-methyltransferase Val158Met polymorphism moderates anterior cingulate volume in posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with structural and functional compromise of the anterior cingulate cortex (ACC), which may in turn be associated with impairment of its ability to regulate the amygdala. The Val158Met polymorphism in the catechol-O-methyltransferase gene, which substantially influences dopamine inactivation in the frontal lobe in general and in ACC in particular, may moderate ACC integrity in PTSD. METHODS: We tested this hypothesis in a sample of Vietnam and Persian Gulf War veterans who experienced substantial military operational stress, including 51 who met criteria for PTSD and 48 matched controls who did not. RESULTS: Participants with PTSD were previously reported to have smaller ACC volumes than controls in this sample. A novel repeated-measures analysis of variance was conducted with PTSD diagnosis, Val158Met genotype, and their interaction predicting left and right ACC volume. Genotype was not directly related to ACC volume, but it did significantly interact with the PTSD diagnosis. The difference in ACC volume between the participants without PTSD and participants with PTSD was greater among individuals homozygous for the Val allele than among carriers of the Met allele. This finding was driven largely by the right ACC. Analyses of Caucasian-only, non Caucasian-only, and male-only subsamples indicated similar patterns. CONCLUSIONS: Our findings suggest Val158Met genotype moderates the effect of PTSD-related processes on right ACC volume. PMID- 21783174 TI - Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation. AB - BACKGROUND: The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive. METHODS: We completed functional magnetic resonance imaging targeting the amygdala with an emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years). RESULTS: Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to control subjects. Although both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than control subjects, which were associated with the reduced amygdala response. CONCLUSIONS: Although prior studies have emphasized a toxic gain-of-function effect of elevated messenger RNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior. PMID- 21783177 TI - Neural correlates of hypothalamic-pituitary-adrenal regulation of mothers with their infants. AB - BACKGROUND: Neural correlates of stress regulation via the hypothalamic-pituitary adrenal (HPA) axis have been identified, but little is known about how these apply to real-world interpersonal stress contexts such as mother-infant interaction. We extended stress regulation research by examining maternal neural activation to infant cry related to HPA regulation with their infants. METHODS: Twenty-two primiparous mothers listened to the cry sounds of their own 18-month old infant and an unfamiliar infant and a control sound during functional magnetic resonance imaging scanning. Salivary cortisol was collected at four timepoints in a separate session involving the Strange Situation stressor. Cortisol trajectories were modeled with hierarchical linear modeling, and trajectory terms were used to predict neural response to own infant cry. RESULTS: Mothers who showed less HPA reactivity-indexed by trajectory curvature rather than level-showed increased activation to the cry of their infant relative to control sound across limbic/paralimbic and prefrontal circuits. These included periaqueductal gray, right insula, and bilateral orbitofrontal cortex as well as anterior cingulate-medial prefrontal cortex. Activations overlapped to some extent with previous HPA regulation findings and converged more extensively with circuits identified in other maternal response paradigms. CONCLUSIONS: Maternal stress regulation involves both circuits found across stressor types (i.e., prefrontal) and areas unique to the mother-infant relationship (i.e., limbic/paralimbic). The shape of the HPA response trajectory of mothers was more important than the level of such response in defining stress-related neural correlates. Future research should consider dimensions of the stress context and of physiological trajectories to define stress-regulatory circuits. PMID- 21783178 TI - Site-specific genetic manipulation of amygdala corticotropin-releasing factor reveals its imperative role in mediating behavioral response to challenge. AB - BACKGROUND: Faulty regulation of the central extrahypothalamic corticotropin releasing factor (CRF) expression is associated with stress-related psychopathologies including anxiety disorders and depression. Extensive pharmacological literature describes the effects of CRF agonists or antagonists' administration on anxiety-like behavior. However, the relevance of the endogenous agonist, presumed to be CRF, has never been explicitly demonstrated. Several genetic models have been used to study the role of CRF in the physiological response to stress and in stress-related disorders. Nevertheless, developmental compensatory mechanisms and lack of spatial and temporal specificity limited the interpretations of these studies. METHODS: Two lentiviral-based systems were designed, generated, and used to knockdown (KD) or conditionally overexpress (OE) CRF in the central amygdala (CeA) of adult mice. Behavioral responses associated with the CeA, such as anxiety, depression and fear memory, and the plasma corticosterone levels were evaluated under both basal and stressful conditions. RESULTS: Changing the CeA-CRF levels mildly affected anxiety-like behaviors under basal conditions. However, following exposure to an acute stressor, CeA-CRF-KD strongly attenuated stress-induced anxiety-like behaviors, whereas a short-term CeA-CRF-overexpression enhanced the stress-induced effects on these behaviors. Interestingly, a significant increase in basal corticosterone levels in the CeA CRF-KD mice was observed, demonstrating the importance of endogenous CeA-CRF levels for basal, but not stress-induced, corticosterone levels. CONCLUSIONS: These results highlight the pivotal role of CeA CRF expression regulation in mediating adequate behavioral responses to stress and introduce these novel viral tools as a useful approach for dissecting the role of central CRF in mediating behavioral and neuroendocrine responses to stress. PMID- 21783176 TI - alpha(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. AB - BACKGROUND: Drug-associated cues can elicit stress-like responses in addicted individuals, indicating that cue- and stress-induced drug relapse may share some neural mechanisms. It is unknown whether alpha(2) adrenergic receptor agonists, which are known to attenuate stress-induced reinstatement of drug seeking in rats, also reduce cue-induced reinstatement. METHODS: Rats were tested for reinstatement of drug seeking following cocaine self-administration and extinction. We first evaluated the effects of clonidine, an agonist at alpha(2) and imidazoline-1 (I(1)) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific alpha(2) or I(1) agonists, postsynaptic adrenergic receptor (alpha(1) and beta) antagonists, and corticotropin-releasing factor receptor-1 antagonists. RESULTS: We found that clonidine, and the more selective alpha(2) agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I(1) receptor agonist moxonidine reduced cue-induced as well as cocaine-induced reinstatement. Clonidine or moxonidine effects on cue-induced reinstatement were reversed by the selective alpha(2) receptor antagonist RS-79948, indicating a role for alpha(2) receptors. Prazosin and propranolol, antagonists at the alpha(1) and beta receptor, respectively, reduced cue-induced reinstatement only when administered in combination. Finally, the corticotropin-releasing factor receptor-1 antagonist CP-154,526 reduced cue-induced reinstatement, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms. CONCLUSIONS: These results indicate that alpha(2) and I(1) receptor agonists are novel therapeutic options for prevention of cue induced cocaine relapse. Given that alpha(2) receptor stimulation is associated with sedation in humans, the I(1) agonist moxonidine seems to have substantial potential for treating addictive disorders. PMID- 21783179 TI - Do unexpected panic attacks occur spontaneously? AB - BACKGROUND: Spontaneous or unexpected panic attacks, per definition, occur "out of the blue," in the absence of cues or triggers. Accordingly, physiological arousal or instability should occur at the onset of, or during, the attack, but not preceding it. To test this hypothesis, we examined if points of significant autonomic changes preceded the onset of spontaneous panic attacks. METHODS: Forty three panic disorder patients underwent repeated 24-hour ambulatory monitoring. Thirteen natural panic attacks were recorded during 1960 hours of monitoring. Minute-by-minute epochs beginning 60 minutes before and continuing to 10 minutes after the onset of individual attacks were examined for respiration, heart rate, and skin conductance level. Measures were controlled for physical activity and vocalization and compared with time matched control periods within the same person. RESULTS: Significant patterns of instability across a number of autonomic and respiratory variables were detected as early as 47 minutes before panic onset. The final minutes before onset were dominated by respiratory changes, with significant decreases in tidal volume followed by abrupt carbon dioxide partial pressure increases. Panic attack onset was characterized by heart rate and tidal volume increases and a drop in carbon dioxide partial pressure. Symptom report was consistent with these changes. Skin conductance levels were generally elevated in the hour before, and during, the attacks. Changes in the matched control periods were largely absent. CONCLUSIONS: Significant autonomic irregularities preceded the onset of attacks that were reported as abrupt and unexpected. The findings invite reconsideration of the current diagnostic distinction between uncued and cued panic attacks. PMID- 21783180 TI - Propofol improved neurobehavioral outcome of cerebral ischemia-reperfusion rats by regulating Bcl-2 and Bax expression. AB - Propofol is an intravenous anesthetic with neuroprotective effects against cerebral ischemia-reperfusion (I/R) injury. Few studies regarding the neuroprotective and neurobehavioral effects of propofol have been conducted, and the underlying mechanisms are still unclear. Because I/R may result in neuronal apoptosis, the apoptosis regulatory genes B-cell leukemia-2 (Bcl-2) and Bcl-2 associated X protein (Bax) may be involved in the neuroprotective process. In this study, 120 Wistar rats were randomly divided into three groups (sham, I/R induced, and propofol-treated). Cerebral ischemia was induced by clamping the bilateral common carotid arteries for 10min. Propofol (1.0mg/kg/min) was administered intravenously for 1h before the induction of ischemia. Neuronal damage was evaluated by neurobehavioral scores and histological examination of the brain sections at the level of the dorsal hippocampus at 6h, 24h, 48h, 72h, 4days, 5days, 6days, and 7days after I/R. The apoptotic rate of hippocampal neurons was detected by flow cytometry. The expression of Bcl-2 and Bax was evaluated using immunohistochemical and Western blot methods. The results of this study showed that neurobehavioral scores were higher in propofol-treated rats compared with I/R-induced rats with no propofol treatment. Moreover, the hippocampal expression of Bcl-2 was significantly higher, while the expression of Bax was significantly lower in propofol-treated rats compared with I/R-induced rats at 24h after ischemia. Hence, this study suggests that the neuroprotective effects of propofol against neuronal apoptosis may be a consequence of the regulation of Bcl-2 and Bax. PMID- 21783182 TI - Bariatric surgery: a review of normal postoperative anatomy and complications. AB - The number of bariatric surgery procedures performed is increasing every year. Patients may be referred for radiological investigations to exclude complications not only in the early postoperative period but many months later. Radiologists who do not work in bariatric centres are therefore required to have an understanding of the complex normal anatomy and complications associated with bariatric surgery to interpret imaging studies correctly. The purpose of this article is to describe the surgical techniques and normal anatomy of the four bariatric operations performed today, review the most common problems encountered in this patient group, and to describe the imaging findings that allow the accurate diagnosis of complications. In particular, we focus on identification of the internal hernia, a grave complication of bariatric surgery often missed by radiologists. PMID- 21783181 TI - CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast-enhanced studies. AB - AIM: To describe the morphological and contrast-agent washout characteristics of adrenocortical carcinomas (ACCs) on computed tomography (CT). MATERIALS AND METHODS: Forty-one patients with histopathologically proven ACCs were retrospectively evaluated. The morphological characteristics of the ACCs were documented and compared with surgical and histopathological findings. The percentage of contrast agent enhancement washout (PEW) and relative PEW (RPEW) were calculated for 17 patients who had the combination of unenhanced, portal venous, and 15 min delayed phase images. RESULTS: Characteristic imaging findings of ACCs included large size (38 of 41 tumours were >6 cm), well-defined margin with a thin enhancing rim (25 patients), and central stellate area of low attenuation on contrast-enhanced CT images (21 patients). Tumour extension into the inferior vena cava (IVC) with associated thrombus was identified on CT in six (14.6%) patients. Of 17 tumours evaluated, 12 (71%) had a PEW value of <=60%, and 14 (82%) had an RPEW value of <=40%. CONCLUSION: Large size, a well-defined margin with a thin enhancing rim, central low attenuation, and a predilection for extension into the IVC are typical morphological characteristics of ACC on CT. The contrast-washout characteristics of ACCs, in concordance with their malignant nature, share those of non-adenomas rather than adenomas. PMID- 21783183 TI - An extended role for CT in the emergency diagnosis of malignant spinal cord compression. AB - AIM: To evaluate the usefulness of computed tomography (CT) for triaging between urgent transfer to a neurosurgical unit and delayed magnetic resonance imaging (MRI) in the local hospital. MATERIALS AND METHODS: Radiologists blinded to the MRI findings scored CT images from 1-5 using a novel grading system based on the degree of cord compression observed in 44 patients. Seventy separate levels were scored. The observers' CT scores were compared with the MRI findings. All scoring radiologists were specialist registrars at different stages of training. RESULTS: Agreement between CT and MRI scores for metastatic spinal cord compression (MSCC) were high with Cohen's weighted Kappa score 0.70 (p<0.001, 95% CI 0.65 to 0.75). CT has a sensitivity of 89% and specificity of 92% for MSCC. Half the false positive and false-negative results came from a single junior radiologist who would not normally report CT or MRI studies unsupervised. The best CT-MRI agreement was from the most senior trainee radiologist. CONCLUSIONS: Spinal findings on routine staging whole-body CT combined with clinical findings are sufficient to determine which patients with MSCC can safely wait for MRI the next working day at the local hospital and those who need emergency transfer to a neurosurgical unit for MRI and possible surgical decompression. PMID- 21783184 TI - Feasibility of quantitative analysis of regional left ventricular function in the post-infarct mouse by magnetic resonance imaging with retrospective gating. AB - We aimed testing feasibility of identification of regional left ventricular (LV) endocardial motion abnormalities in mice undergoing coronary ligation (MI), using cine magnetic resonance with retrospective gating and computation of regional fractional area change (RFAC), by comparison with histological "gold standard" evaluation. ROC analysis determined the optimal RFAC cut-off values for detecting regional ischemic injury. This approach was tested on 18 MI and 10 sham mice. Automated regional LV motion interpretation and bull's eye display allowed non invasive localization of the induced infarction. Possible applications to future studies assessing the effectiveness of pharmacological treatments or regenerative medicine are expected. PMID- 21783185 TI - Fuzzy-based framework for diagnosis of acid-base disorders. AB - The main objective of this research is to develop a fuzzy-based framework for diagnosis of different acid-base disorders. There are several acid-base disorders that cause many clinical complications and their proper diagnosis is the only way for their efficient treatment. The common disorders are metabolic acidosis, metabolic alkalosis, non-anion gap acidosis, anion-gap acidosis, acute respiratory alkalosis and chronic respiratory alkalosis. The proposed fuzzy-based framework was used to diagnose all of these disorders using four parameters directly measured in blood: hydrogen-ion concentration (pH), arterial blood carbon dioxide partial pressure (paCO2), sodium ions concentration (Na+) and chloride ions concentration (Cl-) along with 12 features extracted from the directly measured parameters. The validation results showed that the developed framework has an accuracy of 94%, an average sensitivity of 88% and a specificity of 93%. These results imply that the developed fuzzy-based framework is accurate and reliable one and can be used to help clinicians specially the non-expert ones to provide correct and rapid diagnosis of acid-base disorders. PMID- 21783186 TI - Sensitivity analysis of state-transition models: how to deal with a large number of inputs. AB - State-transition models are employed to project future prevalence rates of risk factors and diseases within populations. Sensitivity analysis should be performed to assess the reliability of the results but often the number of inputs of the model is so huge, and running the model is so time-consuming, that not all methods of sensitivity analysis are practically available. Screening methods detect which inputs have a major influence on the outputs. We briefly review the available screening methods, and discuss one in particular, Morris' OAT Design. We applied the method under different assumptions to a module of the RIVM Chronic Diseases Model, where we projected the rates of never smokers, former smokers and current smokers in time up to the year 2050, based on smoking rates, start, stop and quit rates from 2003 and information on selective mortality in smokers from the literature. Different assumptions with regard to the interval of the inputs used for screeing led to different conclusions, especially with regard to the importance of quit and relapse rates versus initial prevalence rates. This should not to be read as a lack of validity of the method, but it shows that any sensitivity method cannot be automated in a form that runs without expert guidance on the ranges. PMID- 21783187 TI - What am I thinking and who has the right to know? Contributions from a workshop on the wider societal implications of neuroimaging. PMID- 21783188 TI - Neuropsychology is nothing without control: a potential fallacy hidden in clinical studies. PMID- 21783189 TI - Neuroscience, neuroimaging and the law. PMID- 21783190 TI - Assessment of indoor environment in Paris child day care centers. AB - BACKGROUND: Children are sensitive to indoor environmental pollution. Up until now there has been a lack of data on air quality in child day care centers. OBJECTIVES: The aim of this study is to document the indoor environment quality of Paris child day care centers by repeated measurements, and to compare pollutant levels in child day care centers with levels in Paris dwellings. METHODS: We selected 28 child day care centers frequented by a random sample of babies who participated in the PARIS birth cohort environmental investigation, and visited the child day care centers for one week twice in one year. Biological contaminants assessed were fungi, endotoxin, dust mite allergens, and chemical pollutants: aldehydes, volatile organic compounds and nitrogen dioxide (NO2). Relative humidity, temperature, and carbon dioxide levels were measured simultaneously. A standardized questionnaire was used to gather information about the buildings and their inhabitants. RESULTS: Airborne endotoxin levels in child day care centers were higher than those found in Paris dwellings. Dust mite allergens in child day care centers were below the threshold level for sensitization in the majority of samples, and in common with dwelling samples. Penicillium and Cladosporium were the most commonly identified genera fungi. The child day care center indoor/outdoor ratio for most chemical pollutants was above unity except for NO2, the levels for NO2 being significantly higher than those measured in homes. CONCLUSION: Chemical and biological contamination in child day care centers appears to be low, apart from endotoxin and NO2. Failure to take child exposure in child day care centers into account could result in an overestimation of children's exposure to other pollutants. PMID- 21783191 TI - [Importance of the variable health care in the studies on community-acquired urinary tract infection]. PMID- 21783192 TI - Treading the tightrope between motherhood and an eating disorder: commentary on. PMID- 21783193 TI - Emerging role of high density lipoproteins as a player in the immune system. AB - High density lipoproteins (HDL) possess a number of physiological activities. The most studied and, perhaps, better understood is the ability of HDL to promote excess cholesterol efflux from peripheral tissues and transport to the liver for excretion, a mechanism believed to confer protection against atherosclerotic cardiovascular disease. The ability of HDL to modulate cholesterol bioavailability in the lipid rafts, membrane microdomains enriched in glycosphingolipids and cholesterol, is evolutionary conserved and affects the properties of cells involved in the innate and adaptive immune response, tuning inflammatory response and antigen presentation functions in macrophages as well as B and T cell activation. Also sphingosine-1 phosphate (S1P), a major active sphingolipid carried by HDL, is of relevance in the pathogenesis of several immuno-inflammatory disorders through the modulation of macrophage and lymphocyte functions. Furthermore, HDL influence the humoral innate immunity by modulating the activation of the complement system and the expression of pentraxin 3 (PTX3). Finally, in humans, HDL levels and functions are altered in several immune mediated disorders, such as rheumatoid arthritis, systemic lupus eritematosus, Crohn's disease and multiple sclerosis as well as during inflammatory responses. Altogether these observations suggest that the effects of HDL in immunity could be related, to either the ability of HDL to modulate cholesterol content in immune cell lipid rafts and to their role as reservoir for several biologically active substances that may impact the immune system. PMID- 21783194 TI - Importance of HDL functionality to cardiovascular risk. PMID- 21783195 TI - Construction of 3D human distal femoral surface models using a 3D statistical deformable model. AB - Construction of 3D geometric surface models of human knee joint is always a challenge in biomedical engineering. This study introduced an improved statistical shape model (SSM) method that only uses 2D images of a joint to predict the 3D joint surface model. The SSM was constructed using 40 distal femur models of human knees. In this paper, a series validation and parametric analysis suggested that more than 25 distal femur models are needed to construct the SSM; each distal femur should be described using at least 3000 nodes in space; and two 2D fluoroscopic images taken in 45 degrees directions should be used for the 3D surface shape prediction. Using this SSM method, ten independent distal femurs from 10 independent living subjects were predicted using their 2D plane fluoroscopic images. The predicted models were compared to their native 3D distal femur models constructed using their 3D MR images. The results demonstrated that using two fluoroscopic images of the knee, the overall difference between the predicted distal femur surface and the MR image-based surface was 0.16+/-1.16 mm. These data indicated that the SSM method could be a powerful method for construction of 3D surface geometries of the distal femur. PMID- 21783196 TI - A comparison of calibration methods for stereo fluoroscopic imaging systems. AB - Stereo (biplane) fluoroscopic imaging systems are considered the most accurate and precise systems to study joint kinematics in vivo. Calibration of a biplane fluoroscopy system consists of three steps: (1) correction for spatial image distortion; (2) calculation of the focus position; and (3) calculation of the relative position and orientation of the two fluoroscopy systems with respect to each other. In this study we compared 6 methods for calibrating a biplane fluoroscopy system including a new method using a novel nested-optimization technique. To quantify bias and precision, an electronic digital caliper instrumented with two tantalum markers on radiolucent posts was imaged in three configurations, and for each configuration placed in ten static poses distributed throughout the viewing volume. Bias and precision were calculated as the mean and standard deviation of the displacement of the markers measured between the three caliper configurations. The data demonstrated that it is essential to correct for image distortion when sub-millimeter accuracy is required. We recommend calibrating a stereo fluoroscopic imaging system using an accurately machined plate and a calibration cube, which improved accuracy 2-3 times compared to the other calibration methods. Once image distortion is properly corrected, the focus position should be determined using the Direct Linear Transformation (DLT) method for its increased speed and equivalent accuracy compared to the novel nested optimization method. The DLT method also automatically provides the 3D fluoroscopy configuration. Using the recommended calibration methodology, bias and precision of 0.09 and 0.05 mm or better can be expected for measuring inter marker distances. PMID- 21783197 TI - Multi-residue analysis of 80 environmental contaminants in honeys, honeybees and pollens by one extraction procedure followed by liquid and gas chromatography coupled with mass spectrometric detection. AB - One of the factors that may explain nowadays honeybees' colonies losses is the increasing presence of chemicals in the environment. The aim of this study is to obtain a global view of the presence of environmental contaminants in beehives and, develop a fast, cheap and sensitive tool to analyze environmental contaminants in apiarian matrices. A multi residue analysis was developed to quantify 80 environmental contaminants, pesticides and veterinary drugs, belonging to different chemical classes, in honeys, honeybees and pollens. It consists in a single extraction, based on a modified "QuEChERS method", followed by gas chromatography coupled with Time of Flight mass spectrometry (GC-ToF) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The "QuEChERS method" combines salting-out liquid-liquid extraction with acetonitrile and a dispersive-SPE clean up. It was adjusted to honey and especially to honeybee and pollen, by adding a small fraction of hexane in acetonitrile to eliminate lipids that interfere with mass spectrometry analysis. This method, combined with accurate and sensitive detection, allowed quantification and confirmation at levels as low as 10 ng/g, with recoveries between 60 and 120%. Application to more than 100 samples of each matrix was achieved for a global view of pesticide presence in the honeybee environment. Relatively high percentages of honeys, honeybees and pollens were found to be contaminated by pesticides used to combat varroa but also by fungicides like carbendazim and ubiquitous contaminants. PMID- 21783198 TI - MassUntangler: a novel alignment tool for label-free liquid chromatography-mass spectrometry proteomic data. AB - Liquid chromatography-mass spectrometry (LC-MS) has become an important analytical tool for quantitative proteomics and biomarker discovery. In the label free differential LC-MS approach computational methods are required for an accurate alignment of peaks extrapolated from the experimental raw data accounting for retention time and m/z signals intensity, which are strongly affected by sample matrix and instrumental performance. A novel procedure "MassUntangler" for pairwise alignment has been developed, relying on a pattern based matching algorithm integrated with filtering algorithms in a multi-step approach. The procedure has been optimized employing a two-step approach. Firstly, low-complexity LC-MS data derived from the enzymatic digestion of two standard proteins have been analyzed. Then, the algorithm's performance has been evaluated by comparing the results with other achieved using state-of-the-art alignment tools. In the second step, our algorithm has been used for the alignment of high-complexity LC-MS data consisting of peptides obtained by an Escherichia coli lysate available from a public repository previously used for the comparison of other alignment tools. MassUntangler gave excellent results in terms of precision scores (from 80% to 93%) and recall scores (from 68% to 89%), showing performances similar and even better than the previous developed tools. Considering the mass spectrometry sensitivity and accuracy, this approach allows the identification and quantification of peptides present in a biological sample at femtomole level with high confidence. The procedure's capability of aligning LC-MS data previously corrected for distortion in retention time has been studied through a hybrid approach, in which MassUntangler was interfaced with the OpenMS TOPP tool MapAligner. The hybrid aligner yielded better results, showing that an integration of different bioinformatic approaches for accurate label-free LC-MS data alignment should be used. PMID- 21783199 TI - Olfactory neuroblastoma in dogs and cats--a histological and immunohistochemical analysis. AB - Olfactory neuroblastoma (ONB) was identified in 13 dogs and nine cats. The tumours were subjected to microscopical examination and were graded using a human pathological grading system. In the canine and feline tumours there was more necrosis and higher mitotic activity (mitotic index and Ki67 labelling index) than reported in human ONB. Rosettes were a common feature of feline ONBs. A significant correlation was observed between the histological grade and the Ki67 labelling index. The histopathological diagnosis of ONB was confirmed immunohistochemically by demonstration of the neuronal marker neuron-specific enolase (NSE). Two other neuron-specific antibodies specific for microtubule associated protein-2 (MAP-2) and neuronal nuclei antigen (NeuN) were evaluated. MAP-2 expression proved to have higher specificity than labelling for NSE. NeuN expression was less sensitive and of limited practical value. PMID- 21783200 TI - Mycobacterium microti infection in two meerkats (Suricata suricatta). AB - Mycobacterium microti is a member of the Mycobacterium tuberculosis complex (MTC). M. microti is generally considered a pathogen of small rodents, although sporadic infections in a range of other mammals, including domestic animals and man, have been reported. While many human infections have been associated with immunosuppression, an increasing number of cases are being reported in immunocompetent patients. Two cases of M. microti infection in meerkats (Suricata suricatta) are reported. These are the first cases of mycobacterial disease to be described in meerkats outside Africa. PMID- 21783201 TI - Identification of six potential markers for the detection of circulating canine mammary tumour cells in the peripheral blood identified by microarray analysis. AB - The presence of circulating tumour cells (CTCs) in the peripheral blood is a prognostic factor for survival of human breast cancer patients. CTCs in the peripheral blood of dogs with mammary tumours have not been reported definitively. The present pilot study identifies mRNA markers for CTCs by comparing the transcriptome of canine mammary carcinoma cell lines CMM26 and CMM115 and peripheral blood leucocytes (PBLs). Genes with a 200-fold or higher mRNA expression in carcinoma cell lines were tested for specificity and sensitivity to detect CTCs using reverse transcriptase polymerase chain reaction (PCR). Six mRNA markers, AGR2, ATP8B1, CRYAB, F3 IRX3 and SLC1A1 were expressed in cell lines, but not PBL. All PCRs were able to detect one carcinoma cell admixed in 10(6) or more PBLs. The six mRNA markers may be suitable for detection of canine mammary CTCs and allow the analysis of their spatiotemporal distribution in dogs with mammary tumours. PMID- 21783202 TI - The pathology of experimental poxvirus infection in common marmosets (Callithrix jacchus): further characterization of a new primate model for orthopoxvirus infections. AB - Zoonotic orthopoxvirus (OPV) can induce severe disease in man and the virus has potential for use in bioterrorism. New vaccines and therapeutics against OPV infections must be tested in animal models. The aim of this study was to characterize the clinical course and pathology of a new OPV isolate, calpox virus, which is infectious in marmosets. Infection experiments were performed with 28 common marmosets (Callithrix jacchus) exposed to different challenge doses of calpox virus by the intravenous, oropharyngeal and intranasal (IN) routes. The median marmoset IN infectious dose corresponded to 8.3 * 10(2)plaque forming units of calpox virus. Infected animals developed reproducible clinical signs and died within 4-15 days post infection. Characteristic pox-like lesions developed in affected organs, particularly in the skin, mucous membranes, lymph nodes, liver and spleen. Calpox virus disease progression and pathological findings in the common marmoset appear to be consistent with lethal OPV infections in man and in other non-human primate (NHP) models. IN inoculation with low virus doses mimics the natural route of the human variola virus infection. Thus, the marmoset model of calpox virus infection can be considered to be relevant to investigation of the mechanisms of OPV pathogenesis and pathology and for the evaluation of new vaccines and antiviral therapies. PMID- 21783203 TI - Young children's haptic exploratory procedures. AB - Adults vary their haptic exploratory behavior reliably with variation both in the sensory input and in the task goals. Little is known about the development of these connections between perceptual goals and exploratory behaviors. A total of 36 children ages 3, 4, and 5 years and 20 adults completed a haptic intramodal match-to-sample task. Participants were instructed to feel the shape, texture, rigidity, or weight of a sample object and then were asked to find which of three test objects matched the sample on that specific property. Hand movements were examined to determine whether children produced the same exploratory procedures while gathering perceptual information about each property as adults who searched for the same kind of information. Children demonstrated that they had good haptic abilities in two ways: They matched the sample objects on the specified perceptual dimension at near ceiling levels, and they produced the same hand movement patterns to find the same properties as adults. PMID- 21783204 TI - Deficits in face perception in the amnestic form of mild cognitive impairment. AB - The fusiform gyrus is involved pathologically at an early stage of the amnestic form of mild cognitive impairment (aMCI), and is also known to be involved in the perceptual stage of face processing. We assessed face perception in patients with aMCI to determine if this cognitive skill was impaired. We compared 12 individuals (4 men) with aMCI and 12 age- and education-matched healthy controls on the ability to discriminate changes in the spatial configuration or color of the eyes or the mouth in faces. Patients with aMCI performed less quickly and accurately for all changes on trials with limited viewing duration. With unlimited duration, they could achieve normal perceptual accuracy for configural changes to the mouth, but remained impaired for changes to eye color or configuration. Patients with aMCI show deficits in face perception that are more pronounced for the highly salient ocular region, a pattern similar to that seen in acquired prosopagnosia. This form of perceptual impairment may be an early marker of additional cognitive deficits beyond memory in aMCI. PMID- 21783205 TI - Increased dopamine transporter density in Parkinson's disease patients with Social Anxiety Disorder. AB - Social Anxiety Disorder (SAD) is more common among PD patients than in the general population. This association may be explained by psychosocial mechanisms but it is also possible that neurobiological mechanism underlying PD can predispose to SAD. The aim of this study was to investigate a possible dopaminergic mechanism involved in PD patients with SAD, by correlating striatal dopamine transporter binding potential (DAT-BP) with intensity of social anxiety symptoms in PD patients using SPECT with TRODAT-1 as the radiopharmaceutical. Eleven PD patients with generalized SAD and 21 PD patients without SAD were included in this study; groups were matched for age, gender, disease duration and disease severity. SAD diagnosis was determined according to DSM IV criteria assessed with SCID-I and social anxiety symptom severity with the Brief Social Phobia Scale (BSPS). Demographic and clinical data were also collected. DAT-BP was significantly correlated to scores on BSPS for right putamen (r=0.37, p=0.04), left putamen (r=0.43, p=0.02) and left caudate (r=0.39, p=0.03). No significant correlation was found for the right caudate (r=0.23, p=0.21). This finding may reinforce the hypothesis that dopaminergic dysfunction might be implicated in the pathogenesis of social anxiety in PD. PMID- 21783207 TI - Tricuspid regurgitation as a result of Chiari network attachment. PMID- 21783206 TI - Simplified perfusion strategy for removing retroperitoneal tumors with extensive cavoatrial involvement. AB - OBJECTIVES: Our objective was to compare effectiveness and safety of a simplified approach for removing retroperitoneal tumors with extensive cavoatrial involvement using beating-heart cardiopulmonary bypass (CPB) versus hypothermic circulatory arrest (HCA). METHODS: From January 1984 to January 2009, 144 patients underwent radical nephrectomy and inferior vena caval tumor thrombectomy, 56 (39%) using CPB and 88 (61%) HCA. Compared with HCA patients, CPB patients were of similar age (62 +/- 10 vs 60 +/- 11 years, P = .4) and gender (39% vs 39% female, P > .9), with similar stroke history (3.6% vs 2.3%, P =.6), but had less pulmonary disease (18% vs 33%, P = .06) and lower preoperative creatinine concentration (1.3 +/- 0.72 vs 1.5 +/- 0.86 mg . dL(-1), P = .04). RESULTS: Complete tumor removal was achieved in all patients by both strategies. Compared with HCA procedures, CPB times were shorter (50 +/- 33 vs 94 +/- 40 minutes, P < .0001). CPB patients required fewer blood transfusions (36% no transfusion vs 17%, and 45% >=4 units vs 72%; P = .003) and had no statistical difference in morbidity, including reoperation for bleeding (3.8% vs 8.0%, P = .3), renal failure requiring dialysis (3.6% vs 10%, P = .14), respiratory insufficiency (21% vs 19%, P = .8), sepsis (5.4% vs 10%, P = .3), stroke (5.4% vs 1.1%, P = .13), and in-hospital mortality (7.1% vs 13%, P = .3). Ten-year survival (22% vs 22%, P > .9) and freedom from cancer recurrence (24% vs 28%, P = .8) were similar. CONCLUSIONS: Radical nephrectomy and removal of inferior vena caval tumor-thrombus can be simply, effectively, and safely performed with beating-heart CPB, avoiding the deleterious effects of HCA and providing clinical benefit without increasing morbidity or mortality. PMID- 21783208 TI - A fetal goat model of cardiopulmonary bypass with cardioplegic arrest and hemodynamic assessment. AB - OBJECTIVE: Increasing evidence shows that some cardiac defects may benefit from fetal interventions, including fetal cardiac surgery. We attempted to develop an in vivo animal model of fetal cardiopulmonary bypass with cardioplegic arrest. METHODS: Operations were performed on 14 pregnant goats. The extracorporeal circulation circuit consisted of a centrifugal pump, silicone tubings with an inner diameter of 6 mm, a roller pump, and a reservoir. The placenta was the sole oxygenator. Cardiopulmonary bypass was maintained at a mean flow rate of 344 +/- 68 mL/kg/min, including 30 minutes of cardiac arrest and 15 minutes of reperfusion. Mean arterial blood pressure and heart rate were monitored. Arterial blood samples were analyzed. The pulse index and resistance index of the fetal umbilical artery were monitored. RESULTS: Experiments were completed in 11 cases (79%), with the fetuses weighing 0.65 to 1.8 kg. Fetal mean arterial blood pressure and heart rate remained stable throughout the experiments. A decrease in partial pressure of oxygen with concomitant increase in carbon dioxide partial pressure was noted, but trends were relatively stable. Metabolic acidosis was recognized during and after cardiac bypass. The pulse index and resistance index of the umbilical artery increased significantly after 2 hours off bypass. CONCLUSIONS: We confirmed the technical feasibility of establishing an in vivo model of fetal cardiac bypass with cardioplegic arrest. This fetal goat model provides reproducible data and is suitable to study clinically relevant problems related to fetal cardiopulmonary bypass, myocardial protection, and hemodynamics. PMID- 21783209 TI - Less invasive surgical treatment for aortic arch aneurysms in high-risk patients: a comparative study of hybrid thoracic endovascular aortic repair and conventional total arch replacement. AB - OBJECTIVE: For aortic arch aneurysms, conventional total arch replacement has been the standard surgical option. In selected high-risk patients, we have attempted less invasive hybrid procedure involving supra-aortic bypass and endovascular stent-graft placement. We review the early and midterm outcomes to clarify the impact of the hybrid procedure. METHODS: Between October 2007 and December 2010, 27 patients were treated with the hybrid procedure. During the same period, 191 patients underwent elective conventional total arch replacement. On retrospective analysis, the hybrid procedure was feasible in 103 patients (hybrid feasible) and not feasible in 88 patients (hybrid impossible). Patients undergoing the hybrid procedure attained significantly higher additive (11.6 +/- 2.2 vs 9.5 +/- 2.4, 10.3 +/- 2.8, P < .001, P = .044) and logistic (31.1 +/- 14.1 vs 18.8 +/- 12.6, 23.7 +/- 16.0, P < .001, P = .047) European System for Cardiac Operative Risk Evaluation scores than hybrid-feasible and hybrid-impossible groups. RESULTS: Although the patients in the hybrid group had significantly higher risk, the early outcomes including mortality and morbidity were similar among the 3 groups, as were the 2-year survivals during the follow-up period: 85.9% for the hybrid group, 89.6% for the hybrid-feasible group, and 86.7% for the hybrid-impossible group (P = .510, .850, log-rank test). In the hybrid group, 2 patients required reintervention for type I endoleak. CONCLUSIONS: The early and midterm outcomes of the hybrid procedure for aortic arch aneurysms were satisfactory. This procedure has the potential to be an alternative for conventional total arch replacement for high-risk patients. PMID- 21783210 TI - How Hugh Hampton Young's treatment of President Woodrow Wilson's urinary retention and urosepsis affected the resolution of World War I. AB - PURPOSE: President Woodrow Wilson was never able to gain ratification of the Treaty of Versailles, the peace accord to end World War I. Before he could convince the American people of the importance of ratification, Wilson suffered a stroke followed by life threatening urinary sepsis due to urinary retention, and was treated by the father of modern urology, Hugh Hampton Young. The effects of these health problems are examined in the context of their implications on international affairs. MATERIALS AND METHODS: Biographical sources and primary documentation of Wilson's physicians were reviewed to determine the effect of Wilson's stroke on his voiding habits. Hugh Hampton Young's evaluation and decision making is examined in depth. RESULTS: In the fall of 1919 President Wilson was recovering from a stroke. Shortly after the stroke his preexisting voiding dysfunction progressed to urinary retention from which urinary sepsis developed. Hugh Hampton Young advised on Wilson's case and counseled patience over surgery. The President began voiding spontaneously and recovered from sepsis. The illness left him severely weakened and unable to mount an aggressive campaign to persuade the U.S. Senate of the importance of ratifying the Treaty of Versailles. His personal physician, Admiral Cary T. Grayson, stated that the President was mentally never the same after the sepsis. CONCLUSIONS: Wilson's voiding dysfunction contributed to his inability to win approval for the Treaty of Versailles and the League of Nations. As a result, the United States returned to a policy of isolationism and Europe plunged into 2 decades of upheaval, leading to World War II. PMID- 21783211 TI - Male rodent genital tract infection with Chlamydia muridarum: persistence in the prostate gland that triggers self-immune reactions in genetically susceptible hosts. AB - PURPOSE: We investigated Chlamydia trachomatis infection and its pathogenic consequences in the male rodent genital tract. MATERIALS AND METHODS: Male rats were inoculated in the meatal urethra with Chlamydia muridarum. We sought bacterial DNA at early and late times after inoculation in different parts of the male genital tract. Histological alterations and the immune response against prostate antigens were analyzed. RESULTS: Male rats showed ascending infection with wide dissemination of bacteria in the genital tract at an early time point after inoculation. At later stages bacteria persisted only in some parts of the genital tract and in the prostate gland. C. muridarum was also detected in semen in a high proportion of rats irrespective of an acute or chronic stage of infection. Histological alterations that accompanied C. muridarum were especially observed in the prostate and mainly composed of CD3+ cell infiltration. Positive humoral and cellular responses against prostate antigens were noted in a considerable number of infected rats. NOD mice, an autoimmune, prostatitis prone strain, showed a similar pattern with C. muridarum in the prostate of 100% of infected mice, which was again accompanied by mononuclear cell infiltration and antibodies against prostate antigens at early and late times after inoculation. CONCLUSIONS: Results reveal that C. muridarum infects the male rodent genitourinary tract with special persistence in the prostate gland, where it causes chronic inflammation that in turn may act as a trigger factor for self immune reactions in susceptible hosts. PMID- 21783212 TI - Numerical modeling with application to tracking marine debris. AB - This paper describes different numerical models of ocean circulation the output of which can be applied to study patterns and pathways of drifting marine debris. The paper focuses on model output that is readily available rather than on numerical models that could be configured and run locally. These include operational models from the US Navy (the Navy Layered Ocean Model (NLOM), Coastal Ocean Model (NCOM), and Hybrid Coordinate Ocean Model (HYCOM)), data assimilating reanalysis models (the Simple Ocean Data Assimilation (SODA), the Global Ocean Data Assimilation Experiment (GODAE) models), and the European Center for Medium Range Weather Forecasts (ECMWF) ocean reanalysis (Ocean Reanalysis System, ECMWF/ORA-S3). The paper describes the underlying physics in each model system, limitations, and where to obtain the model output. PMID- 21783213 TI - A thiocyanate-forming protein generates multiple products upon allylglucosinolate breakdown in Thlaspi arvense. AB - Glucosinolates, amino acid-derived thioglycosides found in plants of the Brassicales order, are one of the best studied classes of plant secondary metabolites. Together with myrosinases and supplementary proteins known as specifier proteins, they form the glucosinolate-myrosinase system that upon tissue damage gives rise to a number of biologically active glucosinolate breakdown products such as isothiocyanates, epithionitriles and organic thiocyanates involved in plant defense. While isothiocyanates are products of the spontaneous rearrangement of the glucosinolate aglycones released by myrosinase, the formation of epithionitriles and organic thiocyanates depends on both myrosinases and specifier proteins. Hydrolysis product profiles of many glucosinolate-containing plant species indicate the presence of specifier proteins, but only few have been identified and characterized biochemically. Here, we report on cDNA cloning, heterologous expression and characterization of TaTFP, a thiocyanate-forming protein (TFP) from Thlaspi arvense L. (Brassicaceae), that is expressed in all plant organs and can be purified in active form after heterologous expression in Escherichia coli. As a special feature, this protein promotes the formation of allylthiocyanate as well as the corresponding epithionitrile upon myrosinase-catalyzed hydrolysis of allylglucosinolate, the major glucosinolate of T. arvense. All other glucosinolates tested are converted to their simple nitriles when hydrolyzed in the presence of TaTFP. Despite its ability to promote allylthiocyanate formation, TaTFP has a higher amino acid sequence similarity to known epithiospecifier proteins (ESPs) than to Lepidium sativum TFP. However, unlike Arabidopsis thaliana ESP, its activity in vitro is not strictly dependent on Fe2+ addition to the assay mixtures. The availability of TaTFP in purified form enables future studies to be aimed at elucidating the structural bases of specifier protein specificities and mechanisms. Furthermore, identification of TaTFP shows that product specificities of specifier proteins can not be predicted based on amino acid sequence similarity and raises interesting questions about specifier protein evolution. PMID- 21783214 TI - [Bone substitutes: Classification and concerns]. AB - Autograft is considered as the "gold standard" for bone reconstruction. It provides osteoinductive factors, osteogenic cells, and appropriate osteoconductive scaffold. Donor site morbidity is the main limitation of autograft. Donor disease transmission limits the use of allograft. Synthetic bone substitutes still lack osteoinductive or osteogenic properties. Composite bone substitutes combining synthetic scaffold and biochemical substances initiating proliferation and cell differentiation, and possibly osteogenesis. Bone substitutes and grafts intended for clinical use are listed. PMID- 21783215 TI - Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis. AB - BACKGROUND: The purpose of this study was to assess acute lung injury when protection to the gut mucosal barrier offered by vagus nerve stimulation is eliminated by an abdominal vagotomy. METHODS: Male balb/c mice were subjected to 30% total body surface area steam burn with and without electrical stimulation to the right cervical vagus nerve. A cohort of animals were subjected to abdominal vagotomy. Lung histology, myeloperoxidase and ICAM-1 immune staining, myeloperoxidase enzymatic assay, and tissue KC levels were analyzed 24 hours after burn. Additionally, lung IkB-alpha, NF-kB immunoblots, and NF-kB-DNA binding measured by photon emission analysis using NF-kB-luc transgenic mice were performed. RESULTS: Six hours post burn, phosphorylation of both NF-kB p65 and IkB-alpha were observed. Increased photon emission signal was seen in the lungs of NF-kB-luc transgenic animals. Vagal nerve stimulation blunted NF-kB activation similar to sham animals whereas abdominal vagotomy eliminated the anti inflammatory effect. After burn, MPO positive cells and ICAM-1 expression in the lung endothelium was increased, and lung histology demonstrated significant injury at 24 hours. Vagal nerve stimulation markedly decreased neutrophil infiltration as demonstrated by MPO immune staining and enzyme activity. Vagal stimulation also markedly attenuated acute lung injury at 24 hours. The protective effects of vagal nerve stimulation were reversed by performing an abdominal vagotomy. CONCLUSION: Vagal nerve stimulation is an effective strategy to protect against acute lung injury following burn. Moreover, the protective effects of vagal nerve stimulation in the prevention of acute lung injury are eliminated by performing an abdominal vagotomy. These results establish the importance of the gut-lung axis after burn in the genesis of acute lung injury. PMID- 21783216 TI - Transfer status: a risk factor for mortality in patients with necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis (NF) is a rapidly progressive disease that requires urgent surgical debridement for survival. Interhospital transfer (IT) may be associated with delay to operation, which could increase mortality. We hypothesized that mortality would be higher in patients undergoing surgical debridement for necrotizing fasciitis after IT compared to Emergency Department (ED) admission. METHODS: We performed a retrospective cohort analysis from 2000 2006 using the Nationwide Inpatient Sample. Inclusion criteria were age >18 years, primary diagnosis of NF, and surgical therapy within 72 hours of admission. Logistic regression was used to assess the relationship between admission source, patient and hospital variables, and mortality. RESULTS: We identified 9,958 cases over the study period. Patients in the ED group were more likely to be nonwhite and of lower income when compared with patients in the IT group. Unadjusted mortality was higher in the IT group than ED group (15.5% vs 8.7%, P < .001). After adjusting for potential confounders, odds of mortality were still greater in the IT (OR 2.04, CI 95% 1.60-2.59, P < .001). CONCLUSION: Interhospital transfer is associated with increased risk of in-hospital mortality after surgical therapy for NF, a finding which persists after controlling for patient and hospital level variables. PMID- 21783217 TI - Agreement between patient survey and medical chart: Pitfalls in measurement strategies for hernia recurrence. AB - BACKGROUND: Little information is available on agreement between patient-reported outcomes and data collected from medical chart abstraction (MCA) for recurring events. Recurring conditions pose a risk of misclassification, especially when events occur relatively close together in time. We examined agreement, predictors of agreement, and relative accuracy of patient survey and MCA for assessment of outcomes of incisional hernia repair (IHR). METHODS: Surveys to assess hernia outcomes were mailed to 1,124 living patients who underwent >= 1 IHR during 1998 2002 at 16 Veteran's Affairs Medical Center study sites. Patients were asked if they developed a recurrence or an infection at their hernia site. Physician abstracted data from the medical chart were compared with patient response. Chi square tests were used to assess significance. RESULTS: Of 487 (43.3%) individuals responding to the survey, 33 (6.8%) with >1 re-repair during 1998 2002 and 98 (20.5%) with a repair before the 1998-2002 period were excluded from the analysis. Although recurrence rates derived from self-reported data and data abstracted from the medical chart were similar (29.3% and 26.1%, respectively), overall concordance was low. Only 49% (n = 54) of self-reported recurrences were confirmed by data abstracted from the medical chart. In addition, 16 (8.3%) recurrences abstracted from the medical chart were not reported by the patient. Factors associated with discordance were high reported pain intensity (P = .02), poorer general health (P = .03), and poorer perceived repair results (P < .0001). CONCLUSION: Multiple recurrences and subsequent operations across the study period complicate the interpretation of both patient response and data abstracted from the medical chart when referring to a hernia repair. Further study on how best to assess treatment outcomes for recurring conditions is warranted. PMID- 21783218 TI - Prognosis of patients undergoing hepatectomy for solitary hepatocellular carcinoma originating in the caudate lobe. AB - BACKGROUND: Operative and nonoperative treatment for hepatocellular carcinoma (HCC) originating in the caudate lobe is regarded as challenging because of its deep location in the liver and possibly worse prognosis than HCC in other sites in the liver. The objective of this study is to investigate the clinicopathologic factors and survival of patients who underwent hepatectomy for solitary HCC originating in the caudate lobe. METHODS: A retrospective review of 783 patients who underwent curative hepatectomy for solitary HCC between 1988 was performed. Clinicopathologic factors and survival rate of 46 (5.9%) patients with HCC originating in the caudate lobe were compared with those of 737 (94%) patients with HCC arising in other sites. RESULTS: The clinical backgrounds of patients with HCC in the caudate lobe and in other sites were comparable. Hepatectomy for HCC in the caudate lobe was associated with greater operative time and blood loss than for HCC in other sites of the liver. Pathologically, HCC in the caudate lobe was associated with less frequent intrahepatic metastasis, lesser operative margins, and more frequent tumor exposure than HCC in other sites. Overall and disease-free 5-year survival rates of the 46 patients with solitary HCC in the caudate lobe were 76% and 45%, respectively; no significant difference was observed in the overall or disease-free survival rates between the 2 groups (P = .07 and P = .77, respectively). Resection of HCC in the paracaval portion of the caudate lobe (n = 27) was associated with more frequent anatomic resection, greater operative time and blood loss, and a lesser operative margin than HCC in the Spiegel lobe or caudate process (n = 19). CONCLUSION: Resection for HCC in the caudate lobe, especially in the paracaval portion, remains technically demanding. The prognosis of patients with solitary HCC in the caudate lobe, however, was as good as that of patients with solitary HCC in other sites in the liver. PMID- 21783219 TI - Resveratrol supplementation abrogates pro-arteriogenic effects of intramyocardial vascular endothelial growth factor in a hypercholesterolemic swine model of chronic ischemia. AB - BACKGROUND: Clinical trials of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) have been disappointing, owing likely to endothelial dysfunction. We used a swine model of chronic ischemia and endothelial dysfunction to determine whether resveratrol coadministration would improve the angiogenic response to VEGF therapy. METHODS: Yorkshire swine fed a high cholesterol diet underwent left circumflex ameroid constrictor placement, and were given either no drug (high cholesterol control [HCC], n = 8), perivascular VEGF (2 MUg sustained release [high cholesterol VEGF-treated; HCV], n = 8), or VEGF plus oral resveratrol (10 mg/kg, [high cholesterol VEGF- and resveratrol treated; HCVR], n = 8). After 7 weeks, myocardial contractility, perfusion, and microvessel reactivity in the ischemic territory were assessed. Tissue was analyzed for vessel density, oxidative stress, and protein expression. RESULTS: Myocardial perfusion was significantly improved in the HCV group compared with the HCC group; resveratrol coadministration abrogated this improvement. There were no differences in regional myocardial contractility between groups. Endothelium-dependent microvessel relaxation was improved in the HCVR group, and endothelium-independent relaxation response was similar between groups. Arteriolar density was greatest in the HCV group, whereas capillary density was similar between groups. Expression of Akt and phospho-endothelial nitric oxide synthase were increased in the HCVR group. Total protein oxidative stress and myeloperoxidase expression were reduced in the HCVR group, but so was the oxidative-stress dependent phosphorylation of vascular endothelial cadherin (VE cadherin) and beta-catenin. CONCLUSION: Although resveratrol coadministration decreases oxidative stress and improves endothelial function, it abolishes improvements in myocardial perfusion and arteriolar density afforded by VEGF treatment alone. This effect is due likely to inhibition of the oxidative stress dependent phosphorylation of VE-cadherin, an essential step in the initiation of arteriogenesis. PMID- 21783220 TI - Ultrasound biomicroscopy in glaucoma. AB - Ultrasound biomicroscopy (UBM) is a high-resolution ultrasound technique that allows noninvasive in vivo imaging of structural details of the anterior ocular segment at near light microscopic resolution and provides detailed assessment of anterior segment structures, including those obscured by normal anatomic and pathologic relations. We summarize UBM applications in glaucoma. In some cases UBM elucidates the mechanism of elevated intraocular pressure by showing the relationship between the peripheral iris and the trabecular meshwork. It can be used to study the causes of secondary glaucoma, for example, the pigment dispersion syndrome, lens-induced glaucomas, ciliary block, cysts, and solid tumors of the anterior segment. It can also assess the effects of various interventions such as laser iridotomy, trabeculectomy, and non-penetrating drainage surgery. Precise quantitative evaluation of the anterior chamber angle structures can help in diagnosis and management of various pathologies related to glaucoma. PMID- 21783221 TI - Improving image quality of diagnostic ultrasound by using the safe use time model with the dynamic safety factor and the effect of the exposure time on the image quality. AB - Resolution and penetration are primary criteria for image quality of diagnostic ultrasound. In theory (and usually in practice), the maximum depth of imaging in a tissue increases as power (pressure) is increased. Alternatively, at a particular effective penetration, an increased power may be used to allow a higher ultrasound frequency for higher resolution and tissue contrast. Recently, Karagoz and Kartal proposed a safety parameter for thermal bioeffects of diagnostic ultrasound; that is, SUT (safe use time). The SUT model is constructed to determine how long one piece of tissue can be insonated safely according to a threshold exposure. Also, Karagoz and Kartal suggested that an increase in acoustic intensity beyond the current US Food and Drug Administration (FDA) limit of intensity can be theoretically possible by using SUT model while staying within the safe limit. The present study was motivated particularly by the goals of higher resolution and/or deeper penetration by using SUT model. The results presented here suggest that the safe use of higher exposure levels than currently allowed by the FDA may be possible for obtaining substantial improvements in penetration depth and/or resolution. Also, the study reveals that image quality can be functionally related to exposure time in addition to acoustic energy and frequency. PMID- 21783223 TI - Guided adaptive optimal decision making approach for uncertainty based watershed scale load reduction. AB - Previous optimization-based watershed decision making approaches suffer two major limitations. First of all, these approaches generally do not provide a systematic way to prioritize the implementation schemes with consideration of uncertainties in the watershed systems and the optimization models. Furthermore, with adaptive management, both the decision environment and the uncertainty space evolve (1) during the implementation processes and (2) as new data become available. No efficient method exists to guide optimal adaptive decision making, particularly at a watershed scale. This paper presents a guided adaptive optimal (GAO) decision making approach to overcome the limitations of the previous methods for more efficient and reliable decision making at the watershed scale. The GAO approach is built upon a modeling framework that explicitly addresses system optimality and uncertainty in a time variable manner, hence mimicking the real world decision environment where information availability and uncertainty evolve with time. The GAO approach consists of multiple components, including the risk explicit interval linear programming (REILP) modeling framework, the systematic method for prioritizing implementation schemes, and an iterative process for adapting the core optimization model for updated optimal solutions. The proposed approach was illustrated through a case study dealing with the uncertainty based optimal adaptive environmental management of the Lake Qionghai Watershed in China. The results demonstrated that the proposed GAO approach is able to (1) efficiently incorporate uncertainty into the formulation and solution of the optimization model, and (2) prioritize implementation schemes based on the risk and return tradeoff. As a result the GAO produces more reliable and efficient management outcomes than traditional non-adaptive optimization approaches. PMID- 21783222 TI - Waterborne infectivity of the Ranavirus frog virus 3 in Xenopus laevis. AB - Ranaviruses like frog virus 3 (FV3) are responsible for emerging infectious diseases spreading worldwide to fish, amphibian and reptilian species. We have developed, in Xenopus laevis, an experimental model to investigate viral transmission. We show that FV3 released in water by immunocompromised infected adults can infect adult and larval stages of Xenopus within 3h of exposure. Time course of virus load and viral transcription in different tissues suggests that early waterborne FV3 infection through the digestive tract leads to dissemination in the kidney. Finally, a fraction of adult macrophages becomes infected following exposure to waterborne FV3 as visualized by fluorescence microscopy using macrophage- and FV3-specific antibodies. Little cytopathicity and apoptosis were detected in infected macrophages, which is consistent with our proposition that macrophages are permissive to FV3. These data highlight the efficiency of FV3 infectivity by the water route and the ability of FV3 to adapt to its hosts. PMID- 21783224 TI - Apolipophorin III and transmission electron microscopy as toxicity indicators for harmaline and tea saponin in Spodoptera exigua (Noctuidae: Lepidoptera). AB - Apolipophorin III, traditionally known for lipid transport in insects is fairly established as toxicity indicator against harmaline and tea saponin during this study. Apolipophorin III expressed in the hemolymph and midgut tissues of 3rd, 4th, 5th larval instars and pupae of Spodoptera exigua. Apolipophorin III presence was further confirmed by achieving its partial cDNA (Genbank accession no. FJ606822) of 448bp. qRT PCR revealed that tea saponin resulted in significant reduction of gene expression in 3rd and 4th larval instars but increased in 5th instar as compared to control. Harmaline caused gradual increase of gene expression in 3rd, 4th and 5th instars after feeding on the treated diet. Fifth instar larvae synonymously resulted in the highest gene expressions against both the biochemicals. After the injection of harmaline and tea saponin abrupt increase in gene expression of 4th, 5th larval instar and pupae was observed as compared to control treatment. Transmission electron microscopy of midgut epithelium after being fed with harmaline and tea saponin depicted certain cytological changes. Harmaline treatment lead to cytoplasm vacuolization, mitochondrial disruption, spherocrystals with concentric layers, irregular nucleus and floating nuclei in cytoplasm. Tea saponin treatment resulted in denser cytoplasm, higher intracellular osmotic concentration and reduced complement of apical microvilli. Cells were found to have only a few mitochondria and glycogen deposits in comparison to control treatment. PMID- 21783225 TI - Polychlorinated naphthalenes (PCNs) in Irish foods: Occurrence and human dietary exposure. AB - The concentrations of selected polychlorinated naphthalene (PCN) congeners (PCNs 52, 53, 66/67, 68, 69, 71/72, 73, 74 and 75) were determined in 100 commonly consumed foods, in the first study on occurrence of these contaminants in the Republic of Ireland. Congener selection was based on current knowledge on PCN occurrence and toxicology, and the availability of reliable reference standards. The determinations were carried out using validated analytical methodology based on 13C10 labelled internal standardisation and measurement by HRGC-HRMS. The results showed PCN occurrence in the majority of studied foods--milk, fish, dairy and meat products, eggs, animal fat, shellfish, offal, vegetables, cereal products, etc. ranging from 0.09 ng kg(-1) whole weight for milk to 59.3 ng kg( 1) whole weight for fish, for the sum of the measured PCNs. The most frequently detected congeners were PCNs 66/67, PCN 52, and PCN 73. The highest concentrations were observed in fish, which generally showed congener profiles that reflect some commercial mixtures. The data compares well with other recently reported data for Western Europe. The dioxin-like toxicity (PCN TEQ) associated with these concentrations is lower than that reported for chlorinated dioxins or PCBs in food from Ireland. The dietary exposure of the Irish adult population to PCNs was calculated following a probabilistic approach, using the full dataset of occurrence and current consumption data. The estimates of dietary intakes at approximately 0.14 pg TEQ kg bw(-1) month(-1) for adults on an average diet, reflects the relatively lower occurrence levels. PMID- 21783226 TI - New 1.5 million-year-old Homo erectus maxilla from Sangiran (Central Java, Indonesia). AB - Sangiran (Solo Basin, Central Java, Indonesia) is the singular Homo erectus fossil locale for Early Pleistocene Southeast Asia. Sangiran is the source for more than 80 specimens in deposits with (40)Ar/(39)Ar ages of 1.51-0.9 Ma. In April 2001, we recovered a H. erectus left maxilla fragment (preserving P(3)- M(2)) from the Sangiran site of Bapang. The find spot lies at the base of the Bapang Formation type section in cemented gravelly sands traditionally called the Grenzbank Zone. Two meters above the find spot, pumice hornblende has produced an (40)Ar/(39)Ar age of 1.51 +/- 0.08 Ma. With the addition of Bpg 2001.04, Sangiran now has five H. erectus maxillae. We compare the new maxilla with homologs representing Sangiran H. erectus, Zhoukoudian H. erectus, Western H. erectus (pooled African and Georgian specimens), and Homo habilis. Greatest contrast is with the Zhoukoudian maxillae, which appear to exhibit a derived pattern of premolar-molar relationships compared to Western and Sangiran H. erectus. The dental patterns suggest distinct demic origins for the earlier H. erectus populations represented at Sangiran and the later population represented at Zhoukoudian. These two east Asian populations, separated by 5000 km and nearly 800 k.yr., may have had separate origins from different African/west Eurasian populations. PMID- 21783227 TI - Mercury regulation, fate, transport, transformation, and abatement within cement manufacturing facilities: review. AB - The USEPA's 2010 mercury rule, which would reduce emissions from non-hazardous waste burning cement manufacturing facilities by an estimated 94%, represents a substantial regulatory challenge for the industry. These regulations, based on the performance of facilities that benefit from low concentrations of mercury in their feedstock and fuel inputs (e.g., limestone concentration was less than 25 ppb at each facility), will require non-compliant facilities to develop innovative controls. Control development is difficult because each facility's emissions must be assessed and simple correlation to mercury concentrations in limestone or an assumption of 'typically observed' mercury concentrations in inputs are unsupported by available data. Furthermore, atmospheric emissions are highly variable due to an internal control mechanism that captures and loops mercury between the high-temperature kiln and low-temperature raw materials mill. Two models have been reported to predict emissions; however, they have not been benchmarked against data from the internal components that capture mercury and do not distinguish between mercury species, which have different sorption and desorption properties. Control strategies include technologies applied from other industries and technologies developed specifically for cement facilities. Reported technologies, listed from highest to lowest anticipated mercury removal, include purge of collected dust or raw meal, changes in feedstocks and fuels, wet scrubbing, cleaning of mercury enriched dust, dry sorbent injection, and dry and semi-dry scrubbing. The effectiveness of these technologies is limited by an inadequate understanding of sorption, desorption, and mercury species involved in internal loop mercury control. To comply with the mercury rule and to improve current mercury control technologies and practices, research is needed to advance fundamental knowledge regarding mercury species sorption and desorption dynamics on materials within cement facilities. PMID- 21783228 TI - Biomarker response in the earthworm Lumbricus terrestris exposed to chemical pollutants. AB - Earthworms are important organisms for the soil ecosystem. They are sensitive to toxic chemicals and represent useful bioindicator organisms for soil biomonitoring. Recently the use of biomarkers in earthworms has been increasingly investigated for soil monitoring and assessment purpose. The aim of the preset paper was to analyze the pollutant-induced response of a suite of cellular and biochemical biomarkers in the earthworm Lumbricus terrestris exposed to copper sulphate or methiocarb in OECD soil at the maximal concentrations recommended in agriculture. These responses were compared to lifecycle parameters such as survival, growth and reproduction. Granulocyte morphometric alteration, lysosomal membrane stability, metallothionein concentration, and acetylcholinesterase activity were considered. In either copper sulphate or methiocarb exposure conditions the mean percentage variation of the pollutant-induced molecular and cellular biomarkers was consistent with the whole organism end-point responses. In particular pollutant-induced granulocyte enlargement, detected in either copper sulphate or methiocarb exposed organisms, showed to be a potential general biomarker that may be directly linked to organism health. Compared to the other biological responses to pollutants, it showed high sensitivity to pollutant exposure suggesting its possible applications as a sensitive, simple, and quick general biomarker for monitoring and assessment applications. PMID- 21783229 TI - SIU Scholarship: Dr. Abdulwahab Akanbi Ajape. PMID- 21783230 TI - Two-port robot-assisted vs standard robot-assisted laparoscopic partial nephrectomy: a matched-pair comparison. AB - OBJECTIVE: To compare the outcomes between 2-port robot-assisted partial nephrectomy (2-portRALPN) and standard robot-assisted laparoscopic partial nephrectomy (sRALPN). METHODS: From May 2009 to February 2010, 35 2-portRALPN were done by a single surgeon in a university-based tertiary referral center. A cohort of 35 patients who underwent sRALPN from September 2006 to July 2009 was selected for retrospective comparison and matched for tumor complexity. All patients underwent partial nephrectomy (PN) using the daVinci surgical robotic platform (Intuitive Surgical, Sunnyvale, CA). In the 2-portRALPN, a homemade umbilical port and an infraumbilical assistant port were used, whereas standard laparoscopic port placement was used for sRALPN. The clinical, operative, pathologic, and follow-up information were collected. RESULTS: The operative time (187.5 vs 171.7 minutes, P=.110), warm ischemia time (29.5 vs 28.8 minutes, P=.209), blood loss (257 vs 242.5 mL, P=.967), complication rate (17.1 vs 11.4%, P=.495), and transfusion rate (8.6 vs 2.9%, P=.303) were comparable in both groups. The pain scores on the first postoperative day (4.5 vs 3.9, P=.236) and on the day of discharge (2.3 vs 1.9, P=.433), in-hospital morphine requirement (130.5 vs 122.2 mg, P=.115), and length of hospital stay (4.2 vs 4.2 days, P=.875) were likewise similar in both groups. CONCLUSION: This matched-pair study design comparing 2-portRALPN with sRALPN shows that the outcomes of both techniques are comparable. The 2-portRALPN technique is a viable option until a more advanced robotic platform specifically designed for laparoendoscopic single site surgery is developed and a pure robot-assisted laparoendoscopic single site surgery PN can be safely performed. PMID- 21783231 TI - Prostate-specific antigen/solvent interaction analysis: a preliminary evaluation of a new assay concept for detecting prostate cancer using urinary samples. AB - OBJECTIVE: To provide preliminary clinical performance evaluation of a novel prostate cancer (CaP) assay, prostate-specific antigen/solvent interaction analysis (PSA/SIA) that focused on changes to the structure of PSA. METHODS: Two hundred twenty-two men undergoing prostate biopsy for accepted clinical criteria at 3 sites (University Hospitals Case Medical Center in Cleveland, Cleveland Clinic, and Veterans Administration Boston Healthcare System) were enrolled in institutional review board-approved study. Before transrectal ultrasound-guided biopsy, patients received digital rectal examination with systematic prostate massage followed by collection of urine. The PSA/SIA assay determined the relative partitioning of heterogeneous PSA isoform populations in urine between 2 aqueous phases. A structural index, K, whose numerical value is defined as the ratio of the concentration of all PSA isoforms, was determined by total PSA enzyme-linked immunosorbent assay and used to set a diagnostic threshold for CaP. Performance was assessed using receiver operating characteristic (ROC) analysis with biopsy as the gold standard. RESULTS: Biopsies were pathologically classified as case (malignant, n=100) or control (benign, n=122). ROC performance demonstrated area under the curve=0.90 for PSA/SIA and 0.58 for serum total PSA. At a cutoff value of k=1.73, PSA/SIA displayed sensitivity=100%, specificity=80.3%, positive predictive value=80.6%, and negative predictive value=100%. No attempt was made in this preliminary study to further control patient population or selection criteria for biopsy, nor did we analytically investigate the type of structural differences in PSA that led to changes in k value. CONCLUSION: PSA/SIA provides ratiometric information independently of PSA concentration. In this preliminary study, analysis of the overall structurally heterogeneous PSA isoform population using the SIA assay showed promising results to be further evaluated in future studies. PMID- 21783233 TI - Radical prostatectomy for high-risk prostate cancer defined by preoperative criteria: oncologic follow-up in national multicenter study in 813 patients and assessment of easy-to-use prognostic substratification. AB - OBJECTIVE: To estimate the effect of predictive factors for oncologic outcomes after radical prostatectomy (RP) for high-risk prostate cancer (PCa). METHODS: A total of 813 patients underwent RP for high-risk PCa in a national retrospective multi-institutional study. High-risk PCa was defined as follows: prostate specific antigen (PSA) level>20 ng/mL, Gleason score 8-10, and/or clinical Stage T2c-T4 disease. The preoperative criteria of high-risk PCa were studied in a logistic regression model to assess the correlations with the pathologic findings in the RP specimens. The predictive factors isolated or combined in scores were assessed by Cox multivariate and Kaplan-Meier analyses in predicting PSA failure (recurrence-free survival [RFS]) and overall survival (OS). RESULTS: The median follow-up was 64 months. Organ-confined disease was reported in 36.5%. The 5-year RFS, metastasis-free survival, and OS rate was 74.1%, 96.1%, and 98.6%, respectively. Each preoperative criteria of high-risk PCa was an independent predictor of PSA failure. The PSA failure risk was increased by 1.5- and 2.8-fold in men with 2 and 3 criteria, respectively. The RFS, but not the OS, was significantly different according to the preoperative score (P<.001). The postoperative score was significantly predictive for RFS and OS (P<.001 and P<.035, respectively). The risk of PSA failure was significantly increased with an increasing postoperative score (2-4.6-fold). CONCLUSION: National data support evidence that RP can result in encouraging midterm oncologic outcomes for the management of high-risk PCa. At 5 years after surgery, 75% of patients remain disease free. Our easy-to-use risk stratification might help clinicians to better predict the clinical and PSA outcomes of high-risk patients after surgery. PMID- 21783235 TI - Methodologic considerations in trials assessing prevention of asthma exacerbation by vitamin D supplementation. PMID- 21783234 TI - Systemic exposure to fluticasone MDI delivered through antistatic chambers. PMID- 21783237 TI - Nasal allergen provocation test with multiple aeroallergens detects polysensitization in local allergic rhinitis. AB - BACKGROUND: Patients previously given a diagnosis of nonallergic rhinitis (NAR) might have a new form of local allergic rhinitis (LAR) with local production of specific IgE antibodies and a positive response to a nasal allergen provocation test (NAPT). OBJECTIVE: We evaluated an NAPT protocol using multiple aeroallergens (NAPT-M) for the detection of polysensitization to several aeroallergens in patients with LAR. METHODS: NAPT-Ms with 2 different panels of aeroallergens for patients with perennial and seasonal rhinitis were performed in 25 patients with LAR and 25 patients with NAR whose disease was diagnosed by means of NAPTs 1 year earlier. The response to nasal challenge was evaluated based on subjective (nasal-ocular symptoms) and objective (acoustic rhinometry) parameters. Nasal levels of tryptase and eosinophil cationic protein were determined by means of immunoassay at baseline, 15 minutes, and 1, 2, and 24 hours after challenge. RESULTS: NAPT-Ms showed 100% concordance with the gold standard of NAPTs with a single aeroallergen. No false-positive or false-negative responses were detected. The use of NAPT-Ms achieved 75% reduction in the total number of visits required for final diagnosis in the NAR group (from 168 to 42 visits) and a 55% reduction in the LAR group (from 144 to 65 visits) compared with NAPTs with a single aeroallergen. CONCLUSIONS: These results demonstrate that clinically relevant polysensitization to aeroallergens in patients with LAR occurred and that the NAPT-M is a useful, specific, sensitive, reproducible, and less time-consuming in vivo diagnostic test for the screening of patients with LAR. PMID- 21783238 TI - Influence of sire breed (Bos indicus versus Bos taurus) and interval from slaughter to oocyte aspiration on heat stress tolerance of in vitro-produced bovine embryos. AB - Based on in vitro experiments, Bos indicus embryos were more resistant to heat stress (HS) than Bos taurus embryos. To increase knowledge regarding differences between Bos indicus and Bos taurus in resistance to HS, the primary objective of this study was to determine if tolerance to HS is due to the breed, origin of the oocyte, sperm, or both. Additionally, the influence of the interval between ovary acquisition (in the abattoir) and oocyte aspiration in the laboratory, on early embryo development was ascertained. Oocytes were collected from Nelore and Holstein cows in an abattoir; 4.0 or 6.5 h later, oocytes were aspired in the laboratory, and then matured and fertilized using semen from Nelore (N), Gir (GIR), or Holstein (H) bulls. Ninety-six h post insemination (hpi), embryos with >= 16 cells were divided in two groups: control and HS. In the control group, embryos were cultured at 39 degrees C, whereas in the HS group, embryos were subjected to 41 degrees C for 12 h, and then returned to 39 degrees C. Rates of cleavage, and formation of morula and blastocysts were higher (P < 0.05) for oocytes aspirated at 4.0 versus 6.5 h after ovaries were acquired. Heat stress decreased rates of blastocyst formation for all breeds (N * N; H * H; and H * GIR) and in both time intervals (4.0 and 6.5 h). However, N * N had higher cleavage rate (P < 0.05) in both time intervals when compared with H * H and H * GIR. In addition, Nelore oocytes fertilized with Nelore semen (N * N) had higher blastocyst yields (P < 0.05) in the control and HS group, when compared with the other two breeds (H * H and H * GIR). We concluded that the breed of origin of the oocyte was more important than that of the sperm for development of thermotolerance, because bull breed did not influence embryo development after HS, and in vitro early embryonic development was impaired by increasing (from 4 to 6.5 h) the interval between ovary acquisition and oocyte aspiration. PMID- 21783239 TI - Sorption of water, ethanol or ethanol/water solutions by light-cured dental dimethacrylate resins. AB - OBJECTIVES: This work is concerned with the study of the sorption and desorption process of water, ethanol or ethanol/water solution 50% (v/v) or 75% (v/v) by the dental resins prepared by light curing of Bis-GMA, Bis-EMA, UDMA, TEGDMA or D3MA. METHODS: A thin resin disc is placed in a bath of time to obtain the sorption curve m(t)=f(t). Then the liquid is desorbed until a constant mass for the disc is reached and the desorption curve is recorded. These experimental curves help in the determination of the sorbed/desorbed liquid amount at equilibrium, the percentage of the extracted mass of unreacted monomer known as "solubility", and the sorption/desorption diffusion coefficient which expresses correspondingly the rate of the liquid sorption/desorption. RESULTS: The highest liquid uptake by dental resins was 13.3wt% ethanol for Bis-GMA-resin, 12.0wt% ethanol for UDMA resin, 10.10wt% ethanol/water solution for TEGDMA-resin, 7.34wt% ethanol for D(3)MA-resin and 6.61wt% ethanol for Bis-EMA-resin. The diffusion coefficient for all resins was higher in water than in ethanol/water solution or ethanol. Bis-GMA resin showed the highest diffusion coefficient (11.01 * 10-8cm2 s-1) followed by Bis-EMA-resin (7.43 * 10-8 cm2 s-1), UDMA-resin (6.88 * 10-8cm2 s-1), D(3)MA resin (6.22 * 10-8 cm2 s-1) and finally by TEGDMA-resin (1.52 *10-8 cm2 s-1). SIGNIFICANCE: All studied dental resins, except TEGDMA-resin, absorbed higher amount of pure ethanol than water or ethanol water solution. TEGDMA-resin absorbed higher amount of ethanol/water solution (50/50 or 75/25 (v/v)) than water or ethanol. For all studied dental resins the diffusion coefficient was higher in water than in ethanol/water solution or ethanol. PMID- 21783240 TI - Improving some selected properties of dental polyacid-modified composite resins. AB - OBJECTIVES: Polyacid-modified composite resins (compomers) are restorative dental materials that exhibit certain features of traditional dental composites and glass-ionomer cements. The aim of this paper was to develop experimental compomers with enhanced properties, based on adhesive monomers vinyl phosphonic acid and pyromellitic dianhydride glycerol dimethacrylate, and to compare their properties to those of commercially available products. METHODS: Factorial experimental design was employed to optimize both chemical and physical properties. Properties such as biaxial flexural strength (BFS), wear resistance (WR), water uptake (WU), and adhesion using shear bond strength (SBS) as well as fluoride release (FR) were evaluated and compared with those of commercial products. RESULTS: Results were subjected to one-way ANOVA (p<0.05); significant differences were observed in properties of materials such as WR, BFS and SBS but not in WU and FR compared to commercial products. Experimental materials exhibited significantly higher WR, BFS and SBS values than commercial materials. Properties of materials were affected by their respective storage media with time. SIGNIFICANCE: Based on the results of this study, higher amounts of vinyl phosphonic acid (VPA), pyromellitic dianhydride glycerol dimethacrylate (PMGDM) and reactive glasses render the material with enhanced fluoride release and adhesion with properties similar to glass-ionomers whereas their decrease gives properties similar to conventional dental composite resins with improved properties such as strength and wear resistance. PMID- 21783241 TI - Mother-daughter communication about sexual maturation, abstinence and unintended pregnancy: experiences from an informal settlement in Nairobi, Kenya. AB - Parental communication and support is associated with improved developmental, health and behavioral outcomes in adolescence. This study explores the quality of mother-daughter communication about sexual maturation, abstinence and unintended pregnancy in Korogocho, an informal settlement in Nairobi, Kenya. We use data from 14 focus group discussions (n = 124) and 25 interviews with girls aged 12 17, mothers of teenage girls, and key informant teachers. Many girls and women believed that mothers are the best source of information and support during puberty but only a minority described good experiences with communication in practice. Girls preferred communication to begin early and be repeated regularly. Mothers often combined themes of sexual maturation, abstinence and avoiding pregnancy in their messages. Communication was facilitated by mothers' availability, warmth and close parent-child relationships. Challenges included communication taboos, embarrassment, ambiguous message content, and parental lack of knowledge and uncertainty. Neighborhood poverty undermined some mothers' time and motivation for communicating. PMID- 21783242 TI - Allergic rhinitis. AB - Allergic rhinitis is a very common disorder that affects people of all ages, peaking in the teenage years. It is frequently ignored, underdiagnosed, misdiagnosed, and mistreated, which not only is detrimental to health but also has societal costs. Although allergic rhinitis is not a serious illness, it is clinically relevant because it underlies many complications, is a major risk factor for poor asthma control, and affects quality of life and productivity at work or school. Management of allergic rhinitis is best when directed by guidelines. A diagnostic trial of a pharmacotherapeutic agent could be started in people with clinically identified allergic rhinitis; however, to confirm the diagnosis, specific IgE reactivity needs to be recorded. Documented IgE reactivity has the added benefit of guiding implementation of environmental controls, which could substantially ameliorate symptoms of allergic rhinitis and might prevent development of asthma, especially in an occupational setting. Many classes of drug are available, effective, and safe. In meta-analyses, intranasal corticosteroids are superior to other treatments, have a good safety profile, and treat all symptoms of allergic rhinitis effectively. First-generation antihistamines are associated with sedation, psychomotor retardation, and reduced academic performance. Only immunotherapy with individually targeted allergens has the potential to alter the natural history of allergic rhinitis. Patients' education is a vital component of treatment. Even with the best pharmacotherapy, one in five affected individuals remains highly symptomatic, and further research is needed in this area. PMID- 21783243 TI - The performance of BMP-2 loaded TCP/HAP porous ceramics with a polyelectrolyte multilayer film coating. AB - Delivering rhBMP-2 (recombinant Bone Morphogenic Protein-2) at low but therapeutically efficient dose is one of the current challenges for bone tissue repair. In this context, Polyelectrolyte Multilayer films (PEM) represent an attractive rhBMP-2 carrier due to their ability to protect proteins from denaturation and to coat a wide variety of materials with complex geometry. Herein, we coated macroporous TCP/HAP granules with a biopolymeric PEM film to deliver rhBMP-2 in a "matrix-bound" manner. In vitro release kinetics indicated that the PEM-coated granules sequestered significant amounts of rhBMP-2. The degree of film cross-linking influenced the quantity of rhBMP-2 trapped within the films. Bare (uncoated) TCP/HAP scaffolds were also able to retain rhBMP-2. Bioactivity of rhBMP-2 in the PEM-coated granules was confirmed on two cell markers: luciferase expression on BMP-responsive-element/Luc C2C12 cells and alkaline phosphatase activity induction on C2C12 cells. Promisingly, rhBMP-2 adsorbed onto PEM-coated and on bare granules in a lesser extent, could be stored and remained bioactive over at least 3 weeks. In vivo, both uncoated and PEM coated TCP/HAP granules loaded with rhBMP-2 exhibited both osteoconductive and osteoinductive properties. This opens perspective for coating these bioactive PEM on other types of implantable materials, including metal alloy that do not exhibit any affinity for rhBMP-2. PMID- 21783244 TI - Biodegradable polymer - cisplatin(IV) conjugate as a pro-drug of cisplatin(II). AB - A Pt(IV) complex was covalently conjugated to a new biodegradable amphiphilic tri block copolymer, MPEG-b-PCL-b-PLL, which contains pendant amino groups, to form a polymeric pro-drug of cisplatin(II), MPEG-b-PCL-b-PLL/Pt(IV). The conjugate was assembled into nano-micelles. The Pt(IV) complex, the polymer carrier and the conjugate were characterized systematically. In vitro release experiments showed that drug release from the polymer-Pt(IV) micelles follows an acid responsive and oxidation-reduction sensitive kinetics. HPLC-ICP-MS analysis revealed that cisplatin(II) can be released from the conjugate under an acidic plus a reductive condition which is available inside a cancerous cell. In vitro MTT assay demonstrated that the polymer-Pt(IV) micelles display higher cytotoxicity against SKOV-3 tumor cells than both cisplatin(II) and Pt(IV) complex. This enhanced cytotoxicity is attributed to effective internalization of the micelles by the cells via endocytosis mechanism, which was observed by fluorescence imaging and by direct determination of the platinum uptake by the cells. This polymer-Pt(IV) conjugate is a promising polymeric pro-drug of cisplatin in micellar form. It can protect the Pt(IV) complex against blood clearance. It can enter cancerous cells via endocytosis mechanism and then cisplatin(II) can be released. Therefore, this polymeric pro-drug of cisplatin is expected to find clinical applications in the future. PMID- 21783245 TI - Inflamed leukocyte-mimetic nanoparticles for molecular imaging of inflammation. AB - Dysregulated host inflammatory response causes many diseases, including cardiovascular and neurodegenerative diseases, cancer, and sepsis. Sensitive detection of the site of inflammation will, therefore, produce a wide-ranging impact on disease diagnosis and treatment. We hypothesized that nanoprobes designed to mimic the molecular interactions occurring between inflamed leukocytes and endothelium may possess selectivity toward diverse host inflammatory responses. To incorporate inflammation-sensitive molecular interactions, super paramagnetic iron oxide nanoparticles were conjugated with integrin lymphocyte function-associated antigen (LFA)-1 I domain, engineered to mimic activated leukocytes in physiology. Whole body optical and magnetic resonance imaging in vivo revealed that leukocyte-mimetic nanoparticles localized preferentially to the vasculature within and in the invasive front of the tumor, as well as to the site of acute inflammation. This study explored in vivo detection of tumor-associated vasculature with systemically injected inflammation specific nanoparticles, presenting a possibility of tumor detection by inflamed tumor microenvironment. PMID- 21783246 TI - A combined cell therapy and in-situ tissue-engineering approach for myocardial repair. AB - Myocardial cell-replacement strategies are hampered by limited sources for human cardiomyocytes and by significant cell loss following transplantation. We tested the hypothesis that a combined delivery of cardiomyocytes with an in-situ polymerizable hydrogel into a post-MI rat heart will result in better functional outcomes than each intervention alone. A photopolymerizable, biodegradable, PEGylated-fibrinogen (PF) hydrogel matrix was used as the carrier for the cardiomyocytes [neonatal rat ventricular cardiomyocytes (NRVCMs) or human embryonic stem cell-derived cardiomyocytes (hESC-CMs)]. Infarcted rat hearts (LAD ligation) were randomized to injection of saline, NRVCMs, biopolymer, or combined biopolymer-cell delivery. Echocardiography revealed typical post-infarction remodeling after 30 days in the saline-injected control group [deterioration of fractional shortening (FS) by 31.0 +/- 3.6%]. Injection of NRVCMs or PF alone significantly (p < 0.01) altered this remodeling process (slightly increasing FS by 3.1 +/- 6.6% and 0.5 +/- 5.3% respectively). Co-injection of the NRVCMs with PF matrix resulted in a significant increase in the cell-graft area (by 144%) and in the highest improvements in FS (by 26.3 +/- 6.6%). Finally, feasibility studies were performed with the PF matrix and hESC-CMs. We conclude that an injectable in-situ forming hydrogel can act as a cardiomyocyte cell-carrier and add to the beneficial effects of the grafted cells in preventing unfavorable post infarction cardiac remodeling. PMID- 21783247 TI - Cograft of neural stem cells and schwann cells overexpressing TrkC and neurotrophin-3 respectively after rat spinal cord transection. AB - Effectively bridging the lesion gap is still an unmet demand for spinal cord repair. In the present study, we tested our hypothesis if cograft of Schwann cells (SCs) and neural stem cells (NSCs) with genetically enhanced expression of neurotrophin-3 (NT-3) and its high affinity receptor TrkC, respectively, could strengthen neural repair through increased NSC survival and neuronal differentiation at the epicenter after complete T10 spinal cord transection in adult rats. Transplantation of NT-3-SCs + TrkC-NSCs in Gelfoam (1 * 10(6)/implant/rat; n = 10) into the lesion gap immediately following injury results in significantly improved relay of the cortical motor evoked potential (CMEP) and cortical somatosensory evoked potential (CSEP) as well as ameliorated hindlimb deficits, relative to controls (treated with LacZ-SCs + LacZ-NSCs, NT-3 SCs + NSCs, NSCs alone, or lesion only; n = 10/group). Further analyses demonstrate that NT-3-SCs + TrkC-NSCs cografting augments levels of neuronal differentiation of NSCs, synaptogenesis (including inhibitory/type II-like synapses) and myelin formation of SCs, in addition to neuroprotection and outgrowth of serotonergic fibers in the lesioned spinal cord. Compared with controls, the treated spinal cords also show elevated expression of laminin, a pro-neurogenic factor, and decreased presence of chondroitin sulfate proteoglycans, major inhibitors of axonal growth and neuroplasticity. Together, our data suggests that coimplantation of neurologically compatible cells with compensatorily overexpressed therapeutic genes may constitute a valuable approach to study, and/or develop therapies for spinal cord injury (SCI). PMID- 21783248 TI - Three-dimensional arrayed amino aerogel biochips for molecular recognition of antigens. AB - The three-dimensional (3D) biochips prepared in this study are composed of a glass microscopy slide arrayed with amino aerogel dots. The amino aerogel was produced using the sol-gel process, with an ionic liquid as the template followed by a solvent extraction to remove the template and build a three-dimensional mesoporous structure. The FTIR spectrum verified that the major template was removed and the (29)Si solid-state NMR spectra recognized the cross-linkages in the SiO(2) network structure. SEM images measured the particles at around 100 nm. After grinding, the BET analysis confirmed that the nano-size amino aerogel powders had exhibited specific surface area of 188 m(2)/g, pore volume of 0.83 cm(3)/g, and average pore size of 16.2 nm. The as-prepared amino aerogel surface contained amino functional groups capable of performing a sandwich immunoassay. The primary antibody was immobilized on the internal surface of the arrayed amino aerogel to capture its affinity antigen. On the top of the captured antigen, the report antibody was read its labeling fluorescent dye. In comparison to the corresponding two-dimensional (2D) biochip, the 3D amino aerogel biochips were observed to amplify signal intensities more effectively due to their remarkable capturing capability. PMID- 21783249 TI - The impact of heparin intercalation at specific binding sites in telopeptide-free collagen type I fibrils. AB - Collagen-based biomaterials are currently used as cell culture scaffolds in tissue engineering approaches. These materials are being developed with increased functional complexity, such as the incorporation of glycosaminoglycans. Our study shows the impact of heparin intercalation at specific binding sites in telopeptide-free collagen fibrils in terms of their structure, mechanics, and cell response. We demonstrate that heparin binds specifically and in a competitive manner along the tropocollagen helix at places that are occupied in vivo by telopeptides in fibrillar collagen type I. On the basis of this finding, we elucidate the reason for the in vivo dogma that heparin does not intercalate in fibrillar collagens. We further reveal the direct relationship among structure, mechanics, and function in terms of the effect of incorporation of intercalated heparin on the fibrillar structure, fibrillar bending modulus and flexural rigidity and the dynamic response of adherent cells to collagen scaffolds. This tight relationship is considered particularly important when designing xenogeneic scaffolds based on natural collagen type I to trigger cell proliferation and differentiation. PMID- 21783250 TI - The effect of vascular endothelial growth factor (VEGF) presentation within fibrin matrices on endothelial cell branching. AB - Vascular endothelial growth factor (VEGF) has been extensively investigated to promote vascularization at damaged or diseased sites and in tissue implants. Here we are interested in determining if the manner in which VEGF is presented from a scaffold to endothelial cells influences the architecture of the blood vessels formed. We bound VEGF to nanoparticles and placed these nanoparticles inside fibrin hydrogels, which contained human umbilical vein endothelial cells (HUVECs) bound to cytodex beads. Fibroblast cells are plated on top of the fibrin gel to further mimic a physiologic environment. In addition, we used a chorioallantoic membrane (CAM) assay to determine the role of VEGF presentation on angiogenesis in vivo. We tested VEGF bound in high density and low density to study differences between growth factor presentation in heterogeneous nanodomains and homogenous distribution. VEGF covalently bound to nanoparticles at high density led to an increase in HUVEC tube branching, thickness, and total vessel network length compared to soluble VEGF. While VEGF bound electrostatically exhibited no significant difference with covalently bound VEGF in the tube formation assay, this method failed to promote host vessel infiltration into the fibrin implant on the CAM. Together our data suggest that the mode of VEGF presentation to endothelial cells influences the vessel architecture and vascularization of implants in vivo. PMID- 21783251 TI - Lineage restricted progenitors for the repopulation of decellularized heart. AB - The severe shortage of available donor hearts necessitates the development of other options for heart replacement. Recent results underline the promise of the decellularized organ approach in engineering a functional heart. However, little is known so far regarding the ability of decellularized heart ECM to differentiate embryonic stem cells or committed progenitor cells. In the present work, we compared the differentiation potential of human embryonic stem cells (hESCs) and human mesendodermal cells (hMECs) derived from hESCs, in decellularized hearts under static culture. Expression of various cardiac specific markers such as cTnT, Nkx-2.5, Myl2, Myl7, Myh6 and CD31 was elucidated by gene expression, immunostaining and flow cytometry. Both hMECs and hESCs upregulated expression of cardiac markers upon differentiation, but they exclusively expressed genes for myosin light chain (Myl2, Myl7) and myosin heavy chain (Myh6), respectively. To enhance the differentiation ability of the stem/progenitor cells in the acellular constructs, they were implanted subcutaneously in SCID mice. Immunostaining of the explants revealed the persistence of cardiac marker expressing cells, but which lacked beating function. Our results indicate that the intact extracellular matrix components and preserved mechanical properties of the decellularized heart had directed differentiation of the stem/progenitor cells into the cardiac lineage. PMID- 21783252 TI - Nucleolar proteins with altered expression in leukemic cell lines. AB - The function of the nucleolus is intimately connected to cell proliferation, division and growth. Many cancer cells have enlarged nucleoli, and several nucleolar proteins have been linked to tumorigenesis. In order to find proteins whose expression is altered in the nucleoli of leukemic cells, we carried out two dimensional difference gel electrophoresis (2-D DIGE) analyses. Prohibitin (PHB) and TAR-DNA-binding protein-43 (TDP-43) were strongly expressed in the nucleoli of the pre-B-ALL cell line MHH-CALL3. Our results demonstrate that leukemic cells have differences in their nucleolar protein composition, and suggest that it may be possible to exploit these differences in identification of leukemia subtypes. PMID- 21783253 TI - The relation between abuse and violent delinquency: the conversion of shame to blame in juvenile offenders. AB - OBJECTIVE: While the relationship between abusive parenting and violent delinquency has been well established, the cognitive and emotional processes by which this occurs remain relatively unidentified. The objective of this work is to apply a conceptual model linking abusive parenting to the conversion of shame into blaming others and therefore to violent delinquency. METHODS: A retrospective study of 112 adolescents (90 male; 22 female; ages 12-19 years; M=15.6; SD=1.4) who were incarcerated in a juvenile detention facility pending criminal charges, completed measures of exposure to abusive and nonabusive discipline, expressed and converted shame, and violent delinquency. RESULTS: Findings tend to confirm the conceptual model. Subjects who converted shame (i.e., low expressed shame, high blaming others) tended to have more exposure to abusive parenting and showed more violent delinquent behavior than their peers who showed expressed shame. Subjects who showed expressed shame (i.e., high expressed shame, low blaming others) showed less violent delinquency than those who showed converted shame. CONCLUSIONS: Abusive parenting impacts delinquency directly and indirectly through the effects of shame that is converted. Abusive parenting leads to the conversion of shame to blaming others, which in turn leads to violent delinquent behavior. PRACTICE IMPLICATIONS: For juvenile offenders, the conversion of shame into blaming others appears to contribute to pathological outcomes in relation to trauma. Translation of this work into clinical practice is recommended. PMID- 21783254 TI - Mechanisms of waterborne Cu toxicity to the pond snail Lymnaea stagnalis: physiology and Cu bioavailability. AB - We examined the mechanisms of toxicity of waterborne Cu to the freshwater pond snail Lymnaea stagnalis. The snail is one of the most sensitive species to acute Cu exposure (96 h LC(50), LC(20): 24.9, 18.0 MUgl(-1)); they are not protected by the water quality criteria of the US EPA. Tissue Na and Ca were also reduced by Cu in the acute exposure. In contrast, during 28 d chronic exposures to Cu in the presence of food, which resulted in higher DOC concentrations, there was no significant mortality but an inhibition of growth, which may reflect a re allocation of resources to detoxification. Cu detoxification was evidenced in chronic exposure by increases in metallothionein-like protein concentrations and Cu binding to metal-rich granules, decreases in thiobarbituric acid-reactive substances, and changes in the subcellular distribution in the soft tissues. Our results demonstrated that apart from external Cu bioavailability, compartmentalization of metals within the cells can alter toxicity of Cu to the snails. PMID- 21783255 TI - Embolization of carotid-cavernous fistula via direct percutaneous puncture of the inferior ophthalmic vein. AB - Carotid-cavernous fistulas (CCFs) are anomalous connections between the carotid circulation and the cavernous sinus, and may cause significant morbidity. Endovascular treatment of these lesions can be challenging if typical transvenous routes are inaccessible. We describe a case of a Barrow type D carotid-cavernous fistula in which transvenous embolization was attempted via the inferior petrosal sinus (IPS). No connection was found to the fistula, and the superior ophthalmic vein (SOV) was thrombosed. A novel direct percutaneous puncture of the IOV was performed with ultrasound guidance showing that this is a safe alternative route of CCF access and embolization when the IPS and SOV are inaccessible. PMID- 21783256 TI - Periocular port wine stain: the great ormond street hospital experience. AB - PURPOSE: To identify the sensitivity and specificity of risk factors for the development of glaucoma in patients with port wine stain (PWS). DESIGN: A retrospective case-control study involving a large cohort of patients with PWS. PARTICIPANTS: A total of 216 patients (total of 252 eyes) with unilateral or bilateral PWS seen in the eye department in Great Ormond Street Hospital, London, United Kingdom. METHODS: We studied the anatomic distribution of PWS and the incidence of choroidal hemangioma, episcleral hemangioma, iris heterochromia, and Sturge-Weber syndrome (SWS). We analyzed the sensitivity and specificity of these features as risk factors for glaucoma. MAIN OUTCOME MEASURES: Development of glaucoma. RESULTS: Mean age at presentation was 2.9 years (3 weeks to 18.8 years). Mean follow-up was 3.2 years (0-15 years). A total of 180 patients (83.3%) had unilateral lesion, and 36 patients (16.7%) had bilateral lesion. Thirty-one patients (14.3%) had isolated V1 lesion, 35 patients had V2 lesion only (16.2%), and 93 patients (43%) had both V1 and V2 involved. On the last visit, 46 eyes (18.3%) in 39 patients had glaucoma; their mean age was 3.25 years. Glaucoma was more common if PWS was bilateral (P=0.0001), both upper and lower lids were involved (P < 0.0001), and episcleral hemangioma (P < 0.0001), iris heterochromia (P=0.004), or choroidal hemangioma (P < 0.0001) was present. Twenty-four patients had SWS; this was significantly associated with upper lid PWS (P=0.001) and bilateral PWS (P=0.0003). Glaucoma was more common in patients with SWS compared with those without (66.7% vs. 18%, P=0.01). Combined upper and lower lid PWS, episcleral hemangioma, SWS, and iris heterochromia are sensitive prognosticators for the development of glaucoma. CONCLUSIONS: Iris heterochromia is associated with the development of early glaucoma in patients with PWS. Patients at high risk of glaucoma should be seen more often in clinic. Patients who do not have combined lid involvement or episcleral hemangioma have a lower risk and can therefore be seen less often in clinic. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21783257 TI - Is cerebellar volume related to bipolar disorder? AB - BACKGROUND: Recent data suggest that cerebellum influences emotion modulation in humans. The findings of cerebellar abnormalities in bipolar disorder (BD) are especially intriguing given the link between the cerebellum emotional and behavioral regulation. The purpose of this study was to evaluate cerebellar volume in patients with euthymic BD type I compared to controls. Moreover, we investigated the possible relationship between cerebellar volume and suicidal behavior. METHODS: Forty-patients with euthymic BD type I, 20 with and 20 without history of suicide attempt, and 22 healthy controls underwent an MRI scan. The participants were interviewed using the Structured Clinical Interview with the DSM-IV axis I (SCID-I), the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS) and the Barratt Impulsiveness Scale (BIS-11). RESULTS: Groups were age, gender and years of schooling-matched. The left cerebellum (p=0.02), right cerebellum (p=0.02) and vermis (p<0.01) were significantly smaller in the BD group; however, there were no volumetric differences between the BD subjects with and without suicidal attempt. There was no correlation between cerebellar measurements and clinical variables. LIMITATIONS: The main strength is that our sample consisted of patients with euthymic BD type I without any comorbidities, however, these results cannot establish causality as the cross sectional nature of the study. CONCLUSIONS: Our findings suggest that the reduction in cerebellar volumes observed in BD type I might be a trait-related characteristic of this disorder. Additional studies with larger samples and subtypes of this heterogeneous disorder are warranted to determine the possible specificity of this cerebellar finding. PMID- 21783258 TI - Association between bipolar I disorder and the L55M and Q192R polymorphisms of the paraoxonase 1 (PON1) gene. AB - BACKGROUND: The purpose of this work was to study the association between the PON1 L55M and Q192R polymorphisms and bipolar I disorder in Tunisian patients and to explore their relation to the sociodemographic, clinical and therapeutic characteristics of this disease. PATIENTS AND METHODS: Our study included 109 patients with bipolar I disorder and 110 controls aged 39.4+/-11.8 and 37.3+/-9.2 years, respectively. L55M and Q192R of the PON1 gene polymorphisms were determined by multiplex polymerase chain reaction. RESULTS: Significant difference was detected in the distribution of the genotype frequencies of L55M and Q192R polymorphisms (chi2=6.32, df=2, p=0.04; chi2=10.15, df=2, p=0.006 respectively) between patients and controls. We noted significant association between bipolar I disorder and QR and RR genotypes (OR 2.06, CI 95% 1.10-3.84, p=0.02; OR 1.72, CI 95% 1.07-2.75, p=0.02 respectively) and between this disease and LM and MM genotypes (OR 2.22, CI 95% 1.19-4.15, p=0.012; OR 3.04, CI 95% 1.60 5.77, p=0.01 respectively). There were no significant differences in gender, age at onset, illness episode and treatment among all genotypes. However, Q192R polymorphism was significantly associated with age and patients with RR genotype were the youngest. CONCLUSION: Bipolar I disorder was significantly associated with L55M and Q192R polymorphisms, suggesting that these polymorphisms may play a role for development of bipolar I disorder. There was no significant association between the clinical and therapeutic characteristics of this population and these polymorphisms. Further studies are required to clarify the implication of these polymorphisms in the pathophysiology of bipolar I disorder. PMID- 21783260 TI - Anxiety during the menopausal transition: a systematic review. AB - OBJECTIVE: There have been relatively few studies of the relationship between anxiety and menopause. Despite the paucity of clear evidence, some authors have suggested that the menopausal transition is a time of heightened risk for onset or exacerbation of anxiety symptoms. There is also controversy as to whether anxiety predates or is a consequence of hot flashes. The aim of this paper is to examine the evidence as to the relationship between menopause and anxiety, and between anxiety and hot flushes, one of the core symptoms of menopause. METHOD: A systematic review was undertaken based on literature published between 1960 and 2011, using the Medline, Web of Science and PsychINFO databases. The key terms 'anxiety', 'anxiety symptoms', 'anxiety disorder', 'menopause', 'menopausal transition', 'midlife', 'hot flushes or flashes' and 'vasomotor symptoms' were entered into the search. Studies were included if they reported original research using a clearly described measure of anxiety or investigated the relationship between anxiety and vasomotor symptoms. RESULTS: Nine studies reporting the relationship between menopause and anxiety, two studies reporting the prevalence of panic disorder, and eight studies investigating the relationship between anxiety and vasomotor symptoms were identified. Overall, anxiety symptom levels were low throughout the menopausal transition, but the studies were characterised by poor measurement of both menopausal status and anxiety symptoms and relied heavily on the use of brief, largely nonvalidated measures of anxiety symptoms, which are of unknown clinical significance. In the studies that also measured factors such as attitude to menopause, and dispositional optimism or changes in family life these emerged as important predictors of vasomotor symptom severity. CONCLUSIONS: None of the available studies provides solid data on the prevalence of anxiety disorders that meet diagnostic criteria, and the present state of knowledge does not be no justify the inclusion of "menopausal anxiety" as a reproductive-related disorder. With respect to the relationship between hot flashes and anxiety, studies need to ensure that somatic and psychological symptoms are not confounded by the use of unsuitable anxiety measures, and that psychological variables are given serious consideration. PMID- 21783259 TI - Prospective predictors of mood episodes in bipolar disorder. AB - BACKGROUND: : Bipolar disorder (BD) is associated with alterations in mood, personality, cognition and event-related potential (ERP) measures. The relationship between these multidimensional measures of state and subsequent course of the illness is not well understood. Therefore, this study aimed to prospectively identify factors that predicted the course of mood episodes. METHODS: : Sixty-five participants with BD were administered the auditory P300 oddball task, clinical assessment instruments and cognitive tests at baseline, and were subsequently administered the SCID interview once a month by telephone for 12 months. RESULTS: : Hierarchical regression analyses indicated that the Montgomery-Asberg Depression Rating Scale (MADRS) predicted the number of months spent in a depressed state (p<.001) and in a mixed state (p=.001), while both the MADRS (p<.001) and time to complete Trails A (p=.033) predicted total number of months in a mood episode (across all mood states). Among euthymic patients at entry, Cox regression analyses indicated that higher ratings on both the MADRS (p=.017) and Hypomanic Personality Scale (HPS; p<.001) were associated with both increased likelihood of a mood episode and less time until the onset of a mood episode. LIMITATIONS: : The sample size is relatively small, not all participants completed 12 months, and follow-up assessments were conducted via telephone. CONCLUSIONS: : Our results suggest that affective and cognitive measures, and personality factors, especially the MADRS and HPS, serve as important predictors of the course of mood episodes or relapse in BD patients. These prospective markers of acute mood states may be used to guide treatment decisions. PMID- 21783261 TI - Screening for depression in a sample of Egyptian secondary school female students. AB - BACKGROUND: Depression is common in female adolescents. Data on prevalence rates, socio-demographic correlates, and putative risk factors in Egyptian population are needed along with better screening tools to inform future research and service development. We aimed to estimate the point prevalence of depression in a representative sample of Egyptian female students; to detect the sensitivity and specificity of CDI as a screening tool, and to highlight some putative risk factors associated with depression. METHOD: Multistage random selection of 602 female students from public and private secondary schools in Eastern Cairo. All participants were subjected to screening using the Children Depression Inventory (CDI) and the Non-patient version of the Structured Clinical Interview for DSM-IV axis-I disorders. RESULTS: Depression was estimated to be 15.3% by CDI in comparison to 13.3% by SCID-I/NP. The sensitivity and specificity of CDI were 74.8% and 97.6% respectively. Regression Analysis pointed to a number of predictive factors as; academic underachievement, quarrelsome family atmosphere, socioeconomic status, negative life events and family history of psychiatric disorders. LIMITATIONS: The cross-sectional design, the lack of collateral information and access to records precluded inference of casualty. The lack of the rural comparator and samples from other governorates limits the generalisation of results. CONCLUSION: Depression was prevalent in a sample of Egyptian female secondary school students. It correlated with some psychosocial factors and can be effectively screened using CDI. Hence, there is a need for better screening, Psychoeducational programmes, and services for better identification, early intervention and targeting for those at risk. PMID- 21783262 TI - The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure I: Techniques. AB - Recurrent miscarriage affects approximately 1% of the population and in half of these cases no cause is found. Abnormally functioning immunocompetent cells, including natural killer (NK) cells, in the endometrium, are thought to be responsible for many such cases and treatment trials including oral prednisolone and intravenous immunoglobulins are now underway. Despite these encouraging developments, there is neither adequate standardization of counting uterine NK cells nor consensus as to what constitutes an abnormal level. To address this issue, immunohistochemistry was used to examine the presence and distribution of selected immune cells and macrophages in the endometrium from 222 women who had a routine endometrial biopsy for investigation of recurrent miscarriage or IVF failure, at various stages of the menstrual cycle, and accessioned prospectively over a 7-month period. Biopsies were examined by H+E and immunostained for CD8(+) T-cells, CD163(+) macrophages, CD56(+) NK cells, and CD57(+) cells. Cell numbers (expressed as immunopositive cells per mm(2)) were determined in the stroma of the functional layer of endometrium and the relative concentrations of some cell types (CD163(+) macrophages, CD56(+) NK cells) were expressed as a percentage of all stromal cells. Routine H+E sections revealed 12 patients with focal "endometritis" without plasma cells. CD8(+) T-cells showed focal perivascular aggregates in most instances, and non-random but scattered cells in all cases, with a twofold increase in the luteal phase. CD163(+) cells were distributed evenly throughout the superficial endometrial stroma and also present as single or clustered macrophages within the lumens of superficial glands, mostly in the luteal phase. CD56(+) NK cells showed "diffuse" but variable distribution throughout the functional layer and perivascular aggregates of various sizes in two thirds of cases. Raw cell counts were low and relatively stable in the proliferative phase, but increased somewhat during the first half of the secretory phase, while in the second half of secretory phase they increased six to tenfold. Percentage counts rose from approximately 5% of stromal cells in the early part of the secretory phase of the cycle to over 35% in premenstrual endometrium. CD57(+) cells were present in very low numbers in most cases. The study illustrates the complexity and variability of immune cell infiltration of endometrium. We stress the need for strict counting protocols and attention to histological criteria if any immunological perturbations potentially responsible for recurrent reproductive failure are to be identified. Reference ranges for individual cell types are only valid for individual "days" of a normalized menstrual cycle. PMID- 21783263 TI - Serum amyloid A is expressed in histologically normal tissues from horses and cattle. AB - mRNA expression of the acute phase protein serum amyloid A (SAA) in histologically normal tissues derived from horses (n=13) and cattle (n=4) was investigated by quantitative reverse-transcriptase real-time polymerase-chain reaction. As expected, high constitutive SAA mRNA expression was demonstrated in hepatic tissue in both species. In horses, moderate (>1% of the hepatic expression) SAA mRNA expression was detected in the lung, mammary gland, pancreas, synovial membrane, thymus, thyroid gland and uterus. Other equine tissues and organs sampled included adipose tissue, adrenal gland, aorta, brain, different gastro-intestinal tissues, heart, kidney, lymph node, ovary, testis, prostate, skeletal and cardiac muscle, skin and spleen; all showed low (<1% of the hepatic expression) SAA mRNA expression. In cattle, SAA mRNA was expressed in moderate levels in adipose tissue, colon, jejunum, mammary gland, skeletal muscle, synovial membrane, thymus, thyroid gland, and uterus; expression was low in the remainder of the samples (same tissue panel as horses). The results confirm the liver as the main site of SAA production. Even though there was some inter-species variation in tissues expressing SAA mRNA, several organs communicating with the external environment (lung, mammary gland, uterus, and certain parts of the gastro-intestinal tract) showed SAA mRNA expression, which supports the hypothesis that SAA might possess a role in the innate defence against invading pathogens. The results of the study thus warrant further studies into functions of hepatically and extrahepatically produced SAA isoforms. PMID- 21783264 TI - Erythrocyte aggregation as a cause of slow flow in patients of acute coronary syndromes. AB - BACKGROUND: There are multiple lines of evidence to suggest the role of erythrocyte aggregation (EA) in microcirculatory dysfunction during conditions of very slow flow. Such conditions might develop in the myocardium of patients with acute coronary syndromes (ACS). METHODS: EA as a function of shear stress was evaluated by using a cell flow properties analyzer (CFA) in a cohort of 91 ACS patients and in 36 patients with non specific chest pain or heart failure at the time of cardiac catheterization. RESULTS: The ACS group included 34 patients with acute myocardial infarction and 57 patients with unstable angina. In addition, we examined 36 patients who underwent angiography for non specific chest pain or heart failure. A significant (r=0.44, p<0.0005) correlation was found between the concentration of fibrinogen and the average aggregate size (AAS) only when using conditions of very slow flow and applying relatively low (0.15 dyn/cm(2)) shear stress in the ACS group. This correlation decreased and became insignificant when applying shear stress forces of 1 dyn/cm(2) and more. This correlation was nonsignificant for all the 5 shear stress forces (between 0.15 and 4 dyn/cm(2)) in the samples obtained from the non-ACS group. CONCLUSION: Erythrocytes that are suspended in autologous plasma obtained from patients with ACS tend to aggregate in conditions of very slow flow. These findings might be detrimental in terms of microcirculatory flow in ACS patients and might open new therapeutic options such as the use of low dose thrombolysis following PCI. PMID- 21783265 TI - Hypertrophic cardiomyopathy or storage cardiomyopathy? Role of genetics to predict outcome. PMID- 21783266 TI - Atrial cardiomyopathy--a not yet classified cardiomyopathy? PMID- 21783267 TI - Procollagen type III amino terminal peptide (PIIIP) is associated with left ventricular diastolic dysfunction in obstructive sleep apnoea. PMID- 21783268 TI - Rinderpest: the end of cattle plague. AB - This paper describes the demise of rinderpest, focussing on the 20th Century and especially the period of the Global Rinderpest Eradication Programme, before proceeding to describe the process of accreditation of rinderpest freedom which is now virtually complete. PMID- 21783270 TI - Influence of soluble copper on the electrokinetic properties and transport of copper oxychloride-based fungicide particles. AB - This article describes the influence of dissolved copper on the electrokinetic properties and transport of a copper oxychloride-based fungicide (COF) in porous media. The Zeta potential (zeta) of COF particles increases (viz. becomes less negative) with increasing concentration of Cu(2+) in the bulk solution. zeta decreases for COF when the electrolyte (NaNO(3)) concentration is raised from 1 to 10mM. This can be ascribed to ion correlation of Cu(2+) in the electrical double layer (EDL). COF transport tests in quartz sand columns showed the addition of Cu(2+) to the bulk solution to result in increased retention of the metal. Modelling particle deposition dynamics provided results consistent with kinetic attachment. Based on the effect of soluble Cu on colloid mobility, the transport of particulate and soluble forms of copper is coupled via the chemistry of pore water and colloid interactions. Mutual effects between cations and colloids should thus be considered when determining the environmental fate of particulate and soluble forms of copper in soil and groundwater (especially at copper-contaminated sites). PMID- 21783271 TI - A coupled THC model of the FEBEX in situ test with bentonite swelling and chemical and thermal osmosis. AB - The performance assessment of a geological repository for radioactive waste requires quantifying the geochemical evolution of the bentonite engineered barrier. This barrier will be exposed to coupled thermal (T), hydrodynamic (H), mechanical (M) and chemical (C) processes. This paper presents a coupled THC model of the FEBEX (Full-scale Engineered Barrier EXperiment) in situ test which accounts for bentonite swelling and chemical and thermal osmosis. Model results attest the relevance of thermal osmosis and bentonite swelling for the geochemical evolution of the bentonite barrier while chemical osmosis is found to be almost irrelevant. The model has been tested with data collected after the dismantling of heater 1 of the in situ test. The model reproduces reasonably well the measured temperature, relative humidity, water content and inferred geochemical data. However, it fails to mimic the solute concentrations at the heater-bentonite and bentonite-granite interfaces because the model does not account for the volume change of bentonite, the CO(2)(g) degassing and the transport of vapor from the bentonite into the granite. The inferred HCO(3)(-) and pH data cannot be explained solely by solute transport, calcite dissolution and protonation/deprotonation by surface complexation, suggesting that such data may be affected also by other reactions. PMID- 21783273 TI - Microfluidic tools for quantitative studies of eukaryotic chemotaxis. AB - Over the past decade, microfluidic techniques have been established as a versatile platform to perform live cell experiments under well-controlled conditions. To investigate the directional responses of cells, stable concentration profiles of chemotactic factors can be generated in microfluidic gradient mixers that provide a high degree of spatial control. However, the times for built-up and switching of gradient profiles are in general too slow to resolve the intracellular protein translocation events of directional sensing of eukaryotes. Here, we review an example of a conventional microfluidic gradient mixer as well as the novel flow photolysis technique that achieves an increased temporal resolution by combining the photo-activation of caged compounds with the advantages of microfluidic chambers. PMID- 21783272 TI - Mice expressing human CR1/CD35 have an enhanced humoral immune response to T dependent antigens but fail to correct the effect of premature human CR2 expression. AB - We have previously demonstrated that mice expressing human complement receptor type 2 (CR2/CD21) during the CD43(+)/CD25(-) late pro-B cell stage of B cell development have marked changes in their subsequent B cell ontogeny. Here, we show that the humoral immune response to the T cell dependent antigen, sheep red blood cells (SRBCs) can be moderately enhanced with the addition of human CR1 (driven by the lambda promoter/enhancer transgene) to endogenous mCR1/CR2 expression on the B cell surface but that hCR1 expression alone (on the mouse CR1/2 deficient background) has no effect on the humoral immune response or general B cell development. Furthermore, expression of hCR1 had no recuperative effect on the markedly altered B cell phenotype noted with premature expression of hCR2 (either in the presence or absence of endogenous mCR1/2). We conclude that hCR1 alone cannot replace the role of CR2 in mice and that the effects of premature hCR2 expression during BCR development are not significantly altered by the addition of hCR1 at that developmental stage or beyond; thus hCR2 signaling in the mouse remains dominant over subsequent input from either hCR1 or endogenous receptors. PMID- 21783275 TI - Direct detection of Clostridium difficile 027 in diarrhoeal stool samples. PMID- 21783274 TI - The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients. AB - BACKGROUND: There is a paucity of investigation on which to base the treatment of chronic urticaria after a patient fails maximum therapy with antihistamines. One prospective, open-label, uncontrolled study suggested that mycophenolate mofetil may be a successful second-line therapy. OBJECTIVE: We sought to evaluate the efficacy and safety of mycophenolate mofetil in 19 patients with autoimmune and chronic idiopathic urticaria. METHODS: In a retrospective chart review, records of patients with autoimmune and chronic idiopathic urticaria who were evaluated between 2001 and 2009 were analyzed. RESULTS: Improvement in urticaria was observed in 89% of patients, specifically 91% of patients with autoimmune urticaria and 88% with chronic idiopathic urticaria. Time to initial improvement ranged from 1 to 9 weeks. In 59% of these patients, complete control of urticaria was achieved, which included 70% of patients with autoimmune urticaria and 43% with chronic idiopathic urticaria. Mean time to complete control was 14 weeks, with a range of less than 1 to 31 weeks. The dose of mycophenolate mofetil at complete control ranged from 1000 to 6000 mg divided twice daily. Mycophenolate mofetil was tapered in 7 of these 10 patients after an average of 7 weeks. Six of the 7 patients tapered then discontinued mycophenolate mofetil with remissions lasting between 2 and 16 weeks up to when the chart review ended. Mycophenolate mofetil was well tolerated with no serious infections or laboratory abnormalities. Gastrointestinal symptoms were most common. LIMITATIONS: This was a retrospective chart analysis. The number of patients was relatively small. CONCLUSIONS: Mycophenolate mofetil is a useful and well-tolerated second-line therapy for patients with autoimmune and chronic idiopathic urticaria in whom antihistamines and other therapeutic agents have failed. PMID- 21783276 TI - Pandemic A/H1N1/2009 influenza in a paediatric haematology and oncology unit: successful management of a sudden outbreak. AB - Viral respiratory infections are potentially life-threatening among children treated for cancer. We report a nosocomial outbreak of six cases of pandemic influenza A/H1N1/2009 on a paediatric haematology and oncology ward. Three patients developed pneumonia and two of them sustained haemodynamic collapse. The source was probably a relative of the first infected patient. The outbreak was probably spread by cross-infection between patients during communal activities. A few days' delay in identifying the outbreak promoted spread of the influenza. Infection control measures included the use of oral oseltamivir treatment for all hospitalised patients, isolation of the infected patients, strict personal protective controls and a restriction on visitors. No new cases occurred after implementation of these containment measures. At the time when the outbreak was identified, all the patients were already isolated for other reasons. We conclude that A/H1N1/2009 influenza may spread rapidly and cause severe infection in paediatric cancer patients but can be efficiently contained. Identification of isolated or clustered cases should lead to the rapid implementation of appropriate infection control measures. PMID- 21783277 TI - Concerns about screening intensive care unit patients for methicillin-resistant Staphylococcus aureus. PMID- 21783278 TI - Infection control through the ages. AB - To appreciate the current advances in the field of health care epidemiology, it is important to understand the history of hospital infection control. Available historical sources were reviewed for 4 different historical time periods: medieval, early modern, progressive, and post-World War II. Hospital settings for the time periods are described, with particular emphasis on the conditions related to hospital infections. PMID- 21783279 TI - Health care-associated infections and visiting policy in an intensive care unit. AB - A frequent objection to the unrestricted visiting policy in intensive care units (ICUs) is the risk of acquired infections. In a mixed 8-bed ICU, an adopted shift from a restricted to a partially unrestricted visiting policy did not result in an increase in ICU-acquired infections. PMID- 21783281 TI - [Amoxicillin-induced cholestatic hepatitis]. AB - Drug-induced hepatotoxicity is a challenge in daily clinical practice. One of the most frequent causes is antibiotics. However, amoxicillin-induced liver injury is uncommon. We report the case of an 87-year-old man who developed cholestatic hepatitis after ingesting amoxicillin 500 mg/8 hours for dental disease. A review of the literature on this topic is provided. PMID- 21783280 TI - Testing the white matter retrogenesis hypothesis of cognitive aging. AB - The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimer's disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging. PMID- 21783282 TI - [Hepatic elastography. Position paper of the Catalan Society of Gastroenterology]. AB - This document provides a detailed description of the position of the Catalan Society of Gastroenterology on the accuracy and utility of elastography in the non-invasive diagnosis of liver fibrosis. The document was written by a group of experts in chronic liver diseases and liver transplantation and reflects the consensus reached on the methodology and indications of transient elastography. This document was reviewed and presented in an abbreviated form at the XX Congress of the Catalan Society of Gastroenterology and included on the website http://www.scdigestologia.org/index.php?link=docs_posicio. PMID- 21783283 TI - [Evaluation of the sentinel lymph node combining SPECT/CT with the planar image and its importance for the surgical act]. AB - The sentinel node biopsy procedure is based on the hypothesis of the existence of an orderly and predictable pattern of lymphatic drainage to a regional lymph node basin. This results in the consideration of all lymph nodes with direct drainage from the primary tumor as sentinel nodes. The sentinel node is not necessarily the hottest or the most nearby node, although this is often the case. Lymphoscintigraphy has been an essential component for preoperative sentinel node identification. With the new generation of multimodality gamma cameras, SPECT/CT has been incorporated into the sentinel node procedure. The resulting SPECT/CT fused images depict sentinel nodes in an anatomical landscape providing a helpful roadmap for surgeons. Therefore, it is necessary to define the role of SPECT/CT in relation to the classical planar lymphoscintigraphy for the identification of sentinel nodes. To understand the combined use of lymphoscintigraphy and SPECT/CT, the criteria for sentinel node identification on preoperative images must be specified. The authors, based on their experience in this field, present tentative criteria to identify lymph nodes as sentinel nodes both in planar and SPECT/CT images and classify them into different categories. The use of these scintigraphic categories to characterize radioactive lymph nodes is also helpful for surgical decision making. PMID- 21783284 TI - Synthesis and biological evaluation of some novel cyclic-imides as hypoglycaemic, anti-hyperlipidemic agents. AB - Certain new halogenated cyclic-imides related to N-substituted phthalimide moiety were synthesized. Spacers of one or two carbon atom distances were inserted to connect the N-terminus of the cyclic-imide nuclei to the used heteroaryl groups to evaluate the effect of such alteration on biological activity. The synthesized compounds were subjected to hypoglycaemic and anti-hyperlipidemic evaluation. Some of the tested compounds proved to be more potent than the reference drugs glibenclamide and clofibrate. Compound 5e remarkably reduced serum glucose level by 55%; while 5c, 5e, 7d and 8e reduced total serum cholesterol by 58, 56, 54 and 53%, respectively. Those new cyclic-imides could be considered as useful template for future development to obtain more potent hypoglycaemic and anti hyperlipidemic agents. PMID- 21783285 TI - Consent for orthognathic surgery: a UK perspective. AB - Obtaining consent to undertake orthognathic surgery is a legal requirement that starts at the initial visit when treatment is being considered and continues until the operation itself. The process includes discussion of the benefits, risks, and potential complications of the proposed procedure, and any alternative (including doing nothing), but there is no consensus about how much information should be disclosed. Guidance is provided on the basis of case law, which is itself evolving. The purpose of this study was to look at the current practice of obtaining consent for orthognathic surgery by oral and maxillofacial surgeons in the UK to act as a benchmark and potentially to stimulate further debate. We also review common and serious complications that might be included in the process. PMID- 21783286 TI - Sorption-desorption behavior of polybrominated diphenyl ethers in soils. AB - Polybrominated diphenyl ethers (PBDEs) are flame retardants that are commonly found in commercial and household products. These compounds are considered persistent organic pollutants. In this study, we used 4,4'-dibromodiphenyl ether (BDE-15) as a model compound to elucidate the sorption and desorption behavior of PBDEs in soils. The organic carbon-normalized sorption coefficient (K(OC)) of BDE 15 was more than three times higher for humin than for bulk soils. However, pronounced desorption hysteresis was obtained mainly for bulk soils. For humin, increasing concentration of sorbed BDE-15 resulted in decreased desorption. Our data illustrate that BDE-15 and probably other PBDEs exhibit high sorption affinity to soils. Moreover, sorption is irreversible and thus PBDEs can potentially accumulate in the topsoil layer. We also suggest that although humin is probably a major sorbent for PBDEs in soils, other humic materials are also responsible for their sequestration. PMID- 21783287 TI - Assessing the diurnal variability of pharmaceutical and personal care products in a full-scale activated sludge plant. AB - An intensive sampling campaign has been carried out in a municipal wastewater treatment plant (WWTP) to assess the dynamics of the influent pharmaceutical active compounds (PhAC) and musks. The mass loadings of these compounds in wastewater influents displayed contrasting diurnal variations depending on the compound. The musks and some groups of PhACs tended to follow a similar diurnal trend as compared to macropollutants, while the majority of PhACs followed either the opposite trend or no repeatable trend. The total musk loading to the WWTP was 0.74 +/- 0.25 g d(-1), whereas the total PhAC mass loading was 84.7 +/- 63.8 g d( 1). Unlike the PhACs, the musks displayed a high repeatability from one sampling day to the next. The range of PhAC loadings in the influent to WWTPs can vary several orders of magnitude from one day or week to the next, representing a challenge in obtaining data for steady-state modelling purposes. PMID- 21783288 TI - Species- and age-related variation in metal exposure and accumulation of two passerine bird species. AB - We measured the concentration of several elements (arsenic [As], calcium [Ca], cadmium [Cd], copper [Cu], nickel [Ni], lead [Pb], selenium [Se] and zinc [Zn]) in adult and nestling pied flycatchers (Ficedula hypoleuca) and great tits (Parus major) at different distances to a Cu-Ni smelter in 2009. Feces of nestlings generally failed to correspond with internal element concentrations but reflected the pollution exposure, indicating an increased stress by removal of excess metals. The uptake of Cu and Ni were regulated, but As, Cd, Pb and Se accumulated in liver tissue. Pied flycatchers had generally higher element concentrations than great tits. The higher accumulation of As and Pb in pied flycatcher livers was explained by a more efficient absorption, whereas the higher Cd concentration was primarily due to different intake of food items. Age-related differences occurred between the two species, though both Cd and Se accumulated with age. PMID- 21783290 TI - Living donor kidney transplantation in the United States--looking back, looking forward. AB - There is a desperate need for kidney donors. Twenty-five years ago, we urged more widespread acceptance of unrelated living donors for kidney transplantation. Since then, 2 of us have donated a kidney to an unrelated recipient. In our view, the major challenges for living donor transplantation today are to improve access to this extraordinary gift of life and ensure its safety. Our perspective is that altruism is the motivation for most living kidney donors and the decision to donate represents a shared responsibility among the donor, the donor's physician, and the team of professionals at the transplant center. Thus, sound knowledge of the benefits and risks to donors and recipients is required for informed decisions, and all parties share in the responsibility for the outcomes after living kidney donation. We encourage our colleagues and agencies within the US Department of Health and Human Services to accept the responsibility to do their utmost to provide access to this life-enhancing procedure and systematically evaluate the safety of kidney donation as it evolves to meet the needs of more of our patients. PMID- 21783291 TI - International differences in hemodialysis delivery and their influence on outcomes. AB - There are many variations in the delivery of hemodialysis. These variations include components of conventional dialysis, such as membrane type, dialysis dose, and session duration. In addition, alternative approaches to dialysis, such as hemodiafiltration, nocturnal hemodialysis, and short daily hemodialysis, also may be considered. For some of these practice variations, data exist to support one approach over another (eg, fistulas rather than grafts and catheters), but for many, no such data exist. Very few practice variations have been examined in randomized trials, and we are reliant predominantly on observational data. This review examines some practice variations in hemodialysis delivery, attempting to highlight which of these may be appropriate to consider when optimizing dialysis delivery in the clinic. PMID- 21783293 TI - Is there a role for a collagen conduit and anti-inflammatory agent in the management of partial peripheral nerve injuries? AB - PURPOSE: The purpose of this study was to investigate the effect of a collagen conduit and an anti-inflammatory agent in the treatment of acute partial sciatic nerve injuries in a rat chronic constrictive injury (CCI) model. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into 5 groups: group 1 (nerve damage with no treatment), group 2 (nerve damage and collagen tube), group 3 (nerve damage and collagen tube treated with anti-inflammatory agent), group 4 (sham surgery), and group 5 (naive rat). Each group consisted of 10 study animals. The nerve injury model used was the CCI model. Behavioral responses to thermal and mechanical stimuli were tested at 3, 7, and 14 days after surgery. Transverse sections of nerve tissue were harvested at day 14 and evaluated by standard error of mean (SEM). RESULTS: Tactile allodynia measurements showed initial increases in the threshold at day 3, followed by a significant decrease at day 7, and consistently remained lower than baseline by day 14. Heat allodynia measurements at day 3 showed a statistically significant decrease in threshold compared with the CCI group. However, at days 7 and 14, the threshold was not statistically different from the CCI group threshold. Groups with and without anti-inflammatory agents at day 7 showed a statistically significant decrease in threshold to both heat and tactile allodynia from day 3, indicating that groups with collagen and anti-inflammatory treatment had significant decreases in both heat and tactile allodynia. A similar relationship was observed at day 14. Transverse sections of nerve tissue evaluated by SEM of nerve tissue revealed a broad distribution of axons in group 1, with the greatest interaxonal distance in cross sections. Group 2 displayed less interaxonal distance compared with group 1, and group 3 had the least interaxonal distance. CONCLUSIONS: This study demonstrated a statistically significant decrease in pain secondary to the application of a collagen conduit and anti-inflammatory agent. Behavioral testing and SEM data also support the finding of a decrease in edema in the presence of a collagen conduit, with the greatest decrease being in the presence of both collagen conduit and anti-inflammatory agent. PMID- 21783292 TI - Joint association of hyperuricemia and reduced GFR on cardiovascular morbidity: a historical cohort study based on laboratory and claims data from a national insurance provider. AB - BACKGROUND: Hyperuricemia is common in patients with chronic kidney disease (CKD). We assessed the relationship of increased serum uric acid levels with cardiovascular risk across levels of kidney function. STUDY DESIGN: Historical cohort study. SETTING & PARTICIPANTS: Study data were drawn from administrative records of a national private health insurer (2003-2006). We included all adult beneficiaries with concurrently measured serum creatinine and serum uric acid. Patients with acute kidney failure or undergoing renal replacement therapy at baseline were excluded. PREDICTORS: Serum uric acid concentration and estimated glomerular filtration rate (eGFR). OUTCOMES & MEASUREMENTS: Cardiovascular diagnoses (myocardial infarction, subacute coronary heart disease, heart failure, cerebrovascular disease, or peripheral arterial disease) ascertained from billing claims. Cox proportional hazard models were used to test the association of predictors with cardiovascular morbidity. Models were adjusted for sociodemographic characteristics, selected comorbid conditions, and laboratory results. RESULTS: In 148,217 eligible patients, mean eGFR was 84 mL/min/1.73 m(2) and the prevalence of CKD stages 3-5 was 6.0%. Hyperuricemia (serum uric acid >7 mg/dL) was found in 15.6% of patients. The 40-month cumulative incidence of cardiovascular events (mean follow-up, 15.3 months) was 8.1%. Cardiovascular risk was associated independently with uric acid level, and this association was stronger in patients with lower eGFRs. LIMITATIONS: Observational design, lack of information for mortality and potential confounders, single creatinine and uric acid assessment. CONCLUSIONS: Serum uric acid concentration was an independent correlate of cardiovascular morbidity, and this association was stronger in patients with severely decreased eGFR. This investigation provides a rationale for further study of serum uric acid-lowering interventions on cardiovascular risk in the general population and patients with CKD. PMID- 21783289 TI - Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. AB - BACKGROUND: Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD are not well understood. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multiethnic CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTOR: Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex, and diabetic status. eGFR was treated as a continuous and a categorical variable compared with the reference value of >60 mL/min/1.73 m(2). MEASUREMENTS: CAC detected using computed tomography (CT) using either an Imatron C-300 electron beam computed tomography (CT) scanner or multidetector CT scanner. CAC was computed using Agatston score as a categorical variable. Analyses were performed using ordinal logistic regression. RESULTS: We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23 2.31) for eGFR of 50-59 mL/min/1.73 m(2) to 2.82 (95% CI, 2.06-3.85) for eGFR <30 mL/min/1.73 m(2). Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07-2.20) for eGFR <30 mL/min/1.73 m(2). LIMITATIONS: Use of eGFR rather than measured GFR. CONCLUSIONS: We showed a graded relationship between severity of CKD and CAC independent of traditional risk factors. These findings support recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing CKD treatment. PMID- 21783294 TI - Effect of open rhinoplasty on the smile line. AB - PURPOSE: Open rhinoplasty is an esthetic surgical technique that is becoming increasingly popular, and can affect the nose and upper lip compartments. The aim of this study was to evaluate the effect of open rhinoplasty on tooth show and the smile line. PATIENTS AND METHODS: The study participants were 61 patients with a mean age of 24.3 years (range, 17.2 to 39.6 years). The surgical procedure consisted of an esthetic open rhinoplasty without alar resection. Analysis of tooth show was limited to pre- and postoperative (at 12 months) tooth show measurements at rest and the maximum smile with a ruler (when participants held their heads naturally). Statistical analyses were performed with SPSS 13.0, and paired-sample t tests were used to compare tooth show means before and after the operation. RESULTS: Analysis of the rest position showed no statistically significant change in tooth show (P = .15), but analysis of participants' maximum smile data showed a statistically significant increase in tooth show after surgery (P < .05). In contrast, Pearson correlation analysis showed a positive relation between rhinoplasty and tooth show increases in maximum smile, especially in subjects with high smile lines. CONCLUSION: This study shows that the nasolabial compartment is a single unit and any change in 1 part may influence the other parts. Further studies should be conducted to investigate these interactions. PMID- 21783295 TI - Risk factors for hyperketonemia in cleft lip and palate infants during general anesthesia. AB - PURPOSE: The purpose of the present study was to investigate the risk factors for hyperketonemia with respect to patient age, the starting time of anesthesia (morning or afternoon), and the preoperative liquid intake when glucose was administered to infants before and during general anesthesia to avoid the hyperketonemia resulting from lipid catabolism. PATIENTS AND METHODS: The subjects were 147 healthy infants, including 55 infants 2 to 6 months old (cleft lip group) and 92 who were 10 to 24 months old (cleft palate [CP] group). For preoperative liquid intake, the infants were allowed to drink formula or breast milk for <= 5 hours before entering the operating room and 6.7% glucose solution for <= 2 hours before entering the operating room. As an intraoperative infusion, 195 mg/kg/hour of glucose was constantly administered. The levels of blood ketone bodies and glucose were measured at anesthesia induction and 2 hours after induction. Blood ketone body (beta-hydroxybutyrate) concentrations of >= 1.0 mmol/L were considered abnormally high. RESULTS: The ketone body concentrations were abnormally high in 34 infants and normal in 113 infants. Significant differences were present in relation to age (P = .001) and age group (CP group, P < .001), and starting time of anesthesia (afternoon cases, P = .003). However, no difference in preoperative liquid intake was seen between groups. Logistic regression analysis suggested age group (CP group) and starting time of anesthesia (afternoon cases) as factors associated with elevated blood ketone body concentrations. CONCLUSIONS: The risk factors for abnormally high ketone body concentrations were age group (CP group) and starting time of anesthesia (afternoon cases). PMID- 21783296 TI - How intensive should radiotherapy for head and neck cancer with synchronous distant metastases be? Review of cases. AB - PURPOSE: Given the differences in treatment objectives among oncologists and complexities of standards of therapy for advanced head and neck cancer (HNC), we sought to determine whether HNC patients with simultaneous distant metastases (M1) benefit from aggressive therapeutic intervention. MATERIALS AND METHODS: Among the 1,988 patients diagnosed with HNC during a 22-year period, 7 patients with synchronous M1 tumors were identified. Of these individuals, 4 were treated with a prolonged course of radiotherapy for HNC (group A) and 3 were not (group B). RESULTS: The median survival and 60-day mortality rate in group A were 14 months and 0%, respectively, whereas the corresponding observations for group B were 5.5 months and 50%. No difference in HNC stage or M1 extent was present between the 2 groups. The patients composing group A were older than those in group B. CONCLUSION: These data suggest that some benefit may be obtained by the application of a full course of irradiation for HNC with synchronous M1 disease. The practice of intensive radiotherapy for this particular complicated neoplastic condition needs to be reviewed, considering the health care reform and emphasis on cost-effectiveness in the near future. PMID- 21783297 TI - Pigmented villonodular synovitis of the temporomandibular joint: a radiologic diagnosis and case report. PMID- 21783298 TI - Pre-emptive analgesic effectiveness of meloxicam versus tramadol after mandibular third molar surgery: a pilot study. AB - PURPOSE: To compare the pre-emptive analgesic effectiveness of 15 mg of meloxicam and 50 mg of tramadol after mandibular third molar surgery. PATIENTS AND METHODS: This pilot study was a double-blind, randomized, parallel-group clinical trial. The patients were randomized into 2 treatment groups, each with 15 patients, by use of a series of random numbers: group A was administered 15 mg of meloxicam intramuscularly (IM) 50 minutes before the surgery and group B was given 50 mg of tramadol IM 50 minutes before the surgery. We evaluated pain intensity, analgesic consumption, swelling, and trismus. RESULTS: The group receiving 15 mg of meloxicam IM showed differences in pain intensity evaluated by the area under the curve of the visual analog scale and total analgesic consumption when compared with the group receiving 50 mg of tramadol IM. CONCLUSION: The patients receiving 15 mg of preoperative meloxicam had less pain intensity and total analgesic consumption than those receiving 50 mg of preoperative tramadol. PMID- 21783299 TI - Intraglandular tooth--rare case report of tooth in submandibular salivary gland duct. PMID- 21783300 TI - Primary oral mucosal melanoma: advocate a wait-and-see policy in the clinically N0 patient. AB - PURPOSE: Oral mucosal melanoma (OMM) is a rare disease associated with a very poor prognosis. Because well-established treatment protocols for OMM are in short supply, prognostic information regarding recent treatment modalities for this disease were sought. PATIENTS AND METHODS: A retrospective chart review was performed of 61 patients who were treated for OMM from 1998 through 2005. The clinical features and treatment modalities were identified and correlated with the outcomes. RESULTS: There were 41 male and 20 female patients (ratio, 2.1:1) with a mean age of 54.1 years. The mean follow-up was 31.9 months, and the overall 2-year and 5-year survival rates were 51.1% and 30.3%, respectively. According to the seventh edition of the American Joint Committee on Cancer staging system, there were 31 patients (50.8%) with stage III tumors. A more advanced stage and a tumor of at least 2 cm were associated with worse survival (P < .001 and P = .036, respectively). Elective lymph node dissection and biochemotherapy were not associated with a higher total survival rate (P = .53 and P = .76, respectively). CONCLUSIONS: OMM has a male predilection. The seventh edition of the American Joint Committee on Cancer stage and tumor size are effective prognostic parameters for patients with OMM. The American Joint Committee on Cancer staging system provides useful information for predicting the ultimate outcome and should be used as the primary staging system. Elective node dissection and adjuvant biochemotherapy offer no additional advantage in increasing the patient survival rate. A wait-and-see policy is advocated for patients with clinical stage N0 cancer. PMID- 21783301 TI - Problem-based learning in oral and maxillofacial surgery education: the Shanghai hybrid. AB - PURPOSE: A new hybrid course was designed for the practice of oral and maxillofacial surgery education, which included a problem-based learning (PBL) preclinical course and a 1-year clinical rotation under supervision. The aim of this study was to evaluate the effect of this hybrid course. MATERIALS AND METHODS: Eighty-seven students were included from 2006 to 2008. Of these students, 43 received PBL courses and 44 received traditional lecture-based courses. All the students took multiple-choice examinations before and after their clinical rotations. A self-assessment questionnaire was completed after completion of all preclinical courses. At the end of the 1-year clinical rotation, all students were asked to take the clinical skill test. We used t tests to assess the statistical significance of any changes in their scores. RESULTS: Students' scores on the multiple-choice examination showed significant improvement after taking both the PBL courses and the traditional lecture-based courses. The PBL group had better results regarding their overall scores than did the traditional group. The PBL group received higher scores in the "case analysis" and "operational skills" categories. The self-assessment showed that PBL students had more initiative to study in the library, a greater inclination toward teamwork, and more self-confidence before clinical practice. CONCLUSIONS: PBL courses combined with supervised clinical rotation were shown to improve students' operative skill, enhance their ability to perform case analysis, and improve their self-confidence. However, to determine the long-term effect after graduation, further series of testing should be performed in these students over the next few years. PMID- 21783302 TI - Pigmented squamous cell carcinoma of oral mucosa: clinicopathologic study of 3 cases. PMID- 21783303 TI - Limiting resident work hours: the case for the 80-hour work week. PMID- 21783304 TI - Sex and ear differences in spontaneous and click-evoked otoacoustic emissions in young adults. AB - Effects of sex and handedness on the production of spontaneous and click-evoked otoacoustic emissions (OAEs) were explored in a non-hearing impaired population (ages 17-25 years). A sex difference in OAEs, either produced spontaneously (spontaneous OAEs or SOAEs) or in response to auditory stimuli (click-evoked OAEs or CEOAEs) has been reported in infants and children, but healthy young adults seldom have been the target of study. In the current data, a robust sexual dimorphism was confirmed, with women producing more numerous and stronger SOAEs, and CEOAEs with greater response amplitude compared to men. A right-ear advantage was found for the number of SOAEs produced and, in women, for SOAE power. Although handedness did not moderate the ear asymmetry in production, exploratory analyses revealed that departures from strong right hand preference were associated in the present sample with reduced numbers or strengths of OAEs. The results are discussed with respect to differential exposure to androgens during prenatal development. PMID- 21783305 TI - [Importance of thorough removal of all affected tissues before grafting epidermolysis bullosa lesions: ten-year follow-up of one patient with multiple grafts]. AB - We present the case of a patient suffering from dominantly inherited dystrophic epidermolysis bullosa and followed over a period of ten years. Skin lesions of this patient have been treated with multiple thin skin grafts applied over Integra(r). The experience proved that, in order to have a perfect graft take, it was necessary to remove all the affected tissues, which includes an abnormally thickened dermis, and also a portion of the subcutaneous tissue. PMID- 21783306 TI - Anomalous origin of left brachiocephalic trunk from pulmonary trunk. PMID- 21783307 TI - [Toll-like receptor 2 R753Q polymorphisms are associated with an increased risk of infective endocarditis]. AB - The ability to respond to the ligands of toll-like receptors (TLR) could be affected by single nucleotide polymorphisms in TLR codifying genes. The influence of the polymorphisms TLR2 (R753Q, R677W), TLR4 (D299G, T399I) and CD14 (C-159T) was consecutively studied in 65 patients with infective endocarditis. The control group (n=66) consisted of healthy volunteers. All the polymorphisms were genotyped by means of restriction analysis after their amplification. An association between endocarditis and variants of TLR2 R753Q (P <.001) was observed, but no association with other polymorphisms was found. The TLR2 R753Q co-dominant (odds ratio=13.33), recessive (odds ratio=9.12) and dominant (odds ratio=3.65) genotypes showed a positive association with the infective endocarditis phenotype. The polymorphism TLR2 R753Q was associated with a greater susceptibility towards the development of infective endocarditis. Further studies are required to validate these results and identify other genetic risk factors. PMID- 21783308 TI - Prinzmetal angina in the migraine's aura resolving with headache. PMID- 21783309 TI - Intracardiac sterile pacemaker lead thrombosis. PMID- 21783310 TI - Impact of adjunctive cilostazol therapy versus high maintenance dose of clopidogrel in suboptimal responders with diabetes mellitus. PMID- 21783311 TI - Congenital aneurysm of the right atrial appendage in a newborn: a rare anomaly. PMID- 21783313 TI - Prognostic implications of asymmetric morphology in transcatheter aortic valve implantation: a case report. PMID- 21783314 TI - Outflow tract right ventricular pacing in patients with a persistent left superior vena cava. PMID- 21783315 TI - Out-of-hospital cardiac arrests in young adults in Melbourne, Australia-adding coronial data to a cardiac arrest registry. AB - AIM: We aim to describe the coronial findings of young adults where the out-of hospital cardiac arrest (OHCA) aetiology was 'presumed cardiac'. METHODS: Presumed cardiac aetiology OHCAs occurring in young adults aged 16-39 years were identified using the Victorian Ambulance Cardiac Arrest Registry (VACAR) and available coronial findings reviewed. RESULTS: We identified 841 young adult OHCAs where the Utstein aetiology was 'presumed cardiac'. Of these 740 died and 572 (77%) OHCAs were matched to coroner's findings. On review of the coroner's cause of death, 230 (40.2%) had a 'confirmed cardiac' aetiology, 221 (38.6%) were proven 'non-cardiac', 97 (17%) were inconclusive and 24 (4.2%) cases remained 'open'. 'Confirmed cardiac' causes of OHCA were ischemic heart disease (n=126, 55%), cardiomegaly (n=26, 11.3%), cardiomyopathy (n=25, 11%), congenital heart disease (n=15, 6.5%), cardiac tamponade due to dissecting thoracic aorta aneurysm (n=10, 4.3%), myocarditis (n=8, 3.5%), arrhythmia (n=7, 3%), others (n=13, 5.7%). 'Non-cardiac' causes of OHCA were epilepsy/sudden unexplained death in epilepsy (SUDEP) (n=56, 25%), pulmonary embolism (n=29, 13%), subarachnoid haemorrhage (n=17, 7.7%), other intracranial bleed (n=7, 3.2%), pneumonia (n=17, 7.7%), DKA (n=16, 7.2%), other complications of diabetes mellitus (n=8, 3.6%), complications of obesity (n=9, 4%), haemorrhage (n=12, 5.4%), sepsis (n=8, 3.6%), peritonitis (n=6, 2.7%), aspiration (n=6, 2.7%), renal failure (n=5, 2.3%), asthma (n=5, 2.3%), complications of anorexia (n=3) and alcohol abuse (n=2), thyrotoxicosis (n=2), meningitis (n=1) and others (n=12). Compared with coroner's diagnosed 'non cardiac' OHCAs, 'confirmed cardiac' were more likely to be witnessed (41% vs 23%, p<=0.01), receive bystander CPR (35% vs 20%, p<=0.001), have a shockable rhythm (27% vs 6.3%, p<0.001) and have EMS attempted resuscitation (62% vs 44%, p<0.001). DISCUSSION: Linking OHCA registries with coronial databases for aetiology of the arrest will improve the quality of the data and should be considered by all OHCA registries, particularly for young adult OHCA. PMID- 21783316 TI - Female pelvic congenital malformations. Part I: embryology, anatomy and surgical treatment. AB - This review covers the most important female congenital pelvic malformations. The first part focuses on the embryological development of the urogenital and anorectal apparatus, morphological features, and the diagnostic and surgical approach to abnormalities. Comprehension of the embryological development of the urogenital and anorectal apparatus is essential to understand the morphology of congenital pelvic abnormalities and their surgical treatment. Congenital pelvic malformations are characterized by specific common features; the severity of which often subverts the pelvic morphology completely and makes it difficult to comprehend before surgery. The development of imaging, mainly magnetic resonance imaging and ultrasound, in the investigation of pelvic floor disorders has recently become a fundamental tool for surgeons to achieve better understanding of the anatomy. Forty years ago, the primary aim of clinicians was to save the lives of such patients and to achieve anatomical normality. However, nowadays, functional reconstruction and recovery are essential parts of surgical management. Introduction of minimally invasive surgery has allowed the improvement of cosmetic results that is so important in paediatric or adolescent patients after reconstructive surgery. The option of sharing the complexity of pelvic congenital diseases by entrusting specific competencies to subspecialists (paediatric urologists, urogynaecologists, neurourologists, paediatric endocrinologists and neonatologists) has improved the quality of care for patients. However, at the same time, active interaction between various specialists remains fundamental. The exchange of knowledge and expertise, not only during the diagnostic-therapeutic process but also during follow-up, is crucial to obtain the best anatomical and functional results throughout the life of the patient. PMID- 21783317 TI - Effects of land clearing techniques and tillage systems on runoff and soil erosion in a tropical rain forest in Nigeria. AB - This work reports runoff and soil loss from each of 14 sub-watersheds in a secondary rain forest in south-western Nigeria. The impact of methods of land clearing and post-clearing management on runoff and soil erosion under the secondary forest is evaluated. These data were acquired eighteen years after the deforestation of primary vegetation during the ' West bank' project of the International Institute for Tropical Agriculture (IITA). These data are presented separately for each season; however, statistical analyses for replicates were not conducted due to differences in their past management. Soil erosion was affected by land clearing and tillage methods. The maximum soil erosion was observed on sub-watersheds that were mechanically cleared with tree-pusher/root-rake attachments and tilled conventionally. A high rate of erosion was observed even when graded-channel terraces were constructed to minimize soil erosion. In general there was much less soil erosion on manually cleared than on mechanically cleared sub-watersheds (2.5 t ha(-1) yr(-1) versus 13.8 t ha(-1) yr(-1)) and from the application of no-tillage methods than from conventionally plowed areas (6.5 t ha(-1) yr(-1) versus 12.1 t ha(-1) yr(-1)). The data indicate that tillage methods and appropriate management of soils and crops play an important role in soil and water conservation and in decreasing the rate of decline of soil quality. PMID- 21783318 TI - Gastrointestinal toxicity following radiotherapy for prostate cancer: a ring of fire. PMID- 21783319 TI - Metastatic potential of the small renal mass: why can't we agree? PMID- 21783320 TI - Highly efficient extraction of phenolic compounds by use of magnetic room temperature ionic liquids for environmental remediation. AB - A hydrophobic magnetic room temperature ionic liquid (MRTIL), trihexyltetradecylphosphonium tetrachloroferrate(III) ([3C(6)PC(14)][FeCl(4)]), was synthesized from trihexyltetradecylphosphonium chloride and FeCl(3) . 6H(2)O. This MRTIL was investigated as a possible separation agent for solvent extraction of phenolic compounds from aqueous solution. Due to its strong paramagnetism, [3C(6)PC(14)][FeCl(4)] responds to an external neodymium magnet, which was employed in the design of a novel magnetic extraction technique. The conditions for extraction, including extraction time, volume ratio between MRTIL and aqueous phase, pH of aqueous solution, and structures of phenolic compounds were investigated and optimized. The magnetic extraction of phenols achieved equilibrium in 20 min and the phenolic compounds were found to have higher distribution ratios under acidic conditions. In addition, it was observed that phenols containing a greater number of chlorine or nitro substituents exhibited higher distribution ratios. For example, the distribution ratio of phenol (D(Ph)) was 107. In contrast, 3,5-dichlorophenol distribution ratio (D(3,5-DCP)) had a much higher value of 6372 under identical extraction conditions. When compared with four selected traditional non-magnetic room temperature ionic liquids, our [3C(6)PC(14)][FeCl(4)] exhibited significantly higher extraction efficiency under the same experimental conditions used in this work. Pentachlorophenol, a major component in the contaminated soil sample obtained from a superfund site, was successfully extracted and removed by use of [3C(6)PC(14)][FeCl(4)] with high extraction efficiency. Pentachlorophenol concentration was dramatically reduced from 7.8 MUg mL(-1) to 0.2 MUg mL(-1) after the magnetic extraction by use of [3C(6)PC(14)][FeCl(4)]. PMID- 21783321 TI - Brominated and organophosphate flame retardants in selected consumer products on the Japanese market in 2008. AB - The concentrations of traditional brominated flame retardants (BFRs) and organophosphate flame retardants (OPFRs) in new consumer products, including electronic equipment, curtains, wallpaper, and building materials, on the Japanese market in 2008 were investigated. Although some components of the electronic equipment contained bromine at concentrations on the order of percent by weight, as indicated by X-ray fluorescence analysis, the bromine content could not be fully accounted for by the BFRs analyzed in this study, which included polybrominated diphenylethers, decabromodiphenyl ethane, tetrabromobisphenol A, polybromophenols, and hexabromocyclododecanes. These results suggest the use of alternative BFRs such as newly developed formulations derived from tribromophenol, tetrabromobisphenol A, or both. Among the 11 OPFRs analyzed, triphenylphosphate was present at the highest concentrations in all the products investigated, which suggests the use of condensed-type OPFRs as alternative flame retardants, because they contain triphenylphosphate as an impurity. Tripropylphosphate was not detected in any samples; and trimethylphosphate, tributyl tris(2-butoxyethyl)phosphate, and tris(1,3-dichloro-2-propyl)phosphate were detected in only some components and at low concentrations. Note that all the consumer products evaluated in this study also contained traditional BFRs in amounts that were inadequate to impart flame retardancy, which implies the incorporation of recycled plastic materials containing BFRs that are of global concern. PMID- 21783322 TI - Comparative electrochemical treatments of two chlorinated aliphatic hydrocarbons. Time course of the main reaction by-products. AB - Acidic aqueous solutions of the chlorinated aliphatic hydrocarbons 1,2 dichloroethane (DCA) and 1,1,2,2-tetrachloroethane (TCA) have been treated by the electro-Fenton (EF) process. Bulk electrolyses were performed at constant current using a BDD anode and an air diffusion cathode able to generate H(2)O(2) in situ, which reacts with added Fe(2+) to yield OH from Fenton's reaction. At 300 mA, almost total mineralization was achieved at 420 min for solutions containing 4mM of either DCA or TCA. Comparative treatments without Fe(2+) (anodic oxidation) or with a Pt anode led to a poorer mineralization. The better performance of the EF process with BDD is explained by the synergistic action of the oxidizing radicals, BDD(OH) at the anode surface and OH in the bulk, and the minimization of diffusional limitations. The decay of the initial pollutant accomplished with pseudo first-order kinetics. Chloroacetic and dichloroacetic acids were the major by-products during the degradation of DCA and TCA, respectively. Acetic, oxalic and formic acids were also identified. The proposed reaction pathways include oxidative and reductive (cathodic) dechlorination steps. Chlorine was released as Cl(-), being further oxidized to ClO(3)(-) and, mostly, to ClO(4)(-), due to the action of the largely generated BDD(OH) and OH. PMID- 21783323 TI - Comment on ''Acupuncture: does it alleviate pain and are there serious risks? A review of reviews" Ernst et al. [Pain 2011;152:755-764]. PMID- 21783324 TI - Measuring parent beliefs about child acceptance of pain: a preliminary validation of the Chronic Pain Acceptance Questionnaire, parent report. AB - Parent perceptions of and responses to pain have been identified as important factors in understanding pain-related disability among children and adolescents with chronic pain. The ability to accept chronic pain rather than focus on ways to avoid or control it has been linked to positive outcomes in chronic pain research. To examine parent beliefs about child acceptance of pain, the Chronic Pain Acceptance Questionnaire, parent report (CPAQ-P), was developed and administered to 195 parents of children with persistent pain evaluated in a multidisciplinary pain clinic. Analyses support the internal consistency of the CPAQ-P (alpha=.89) and 1-month stability estimates were acceptable for the total scale score (alpha=.72), and results suggest some responsivity to change. Exploratory factor analysis identified a 2-factor model with 4 items removed from the original 20-item measure. Confirmatory factor analysis strongly supported the modified version. For construct validity, parent beliefs about child acceptance were negatively correlated with parent pain catastrophizing and parent fear of pain. Greater acceptance was also negatively associated with protective parent responses to pain. These results support the CPAQ-P as a promising measure for assessing parent beliefs about child acceptance of pain and reinforce the importance of the social context and parental influence on child functioning. PMID- 21783325 TI - The temporal impact of chronic intermittent psychosocial stress on high-fat diet induced alterations in body weight. AB - BACKGROUND: Chronic stress and diet can independently or in concert influence the body's homeostasis over time. Thus, it is crucial to investigate the interplay of these parameters to gain insight into the evolution of stress-induced metabolic and eating disorders. METHODS: C57BL/6J mice were subjected to chronic psychosocial (mixed model of social defeat and overcrowding) stress in combination with either a high- or low-fat diet for three or six weeks. To determine the evolution of stress and dietary effects, changes in body weight, caloric intake and caloric efficiency were determined as well as circulating leptin, insulin, glucose and corticosterone levels and social avoidance behaviour. RESULTS: Exposure to stress for three weeks caused an increase in weight gain, in caloric intake and in caloric efficiency only in mice on a low fat diet. However, after six weeks, only stressed mice on a high-fat diet displayed a pronounced inhibition of body weight gain, accompanied by reduced caloric intake and caloric efficiency. Stress decreased circulating leptin levels in mice on a low-fat diet after three weeks and in mice on a high-fat diet after three and six weeks of exposure. Plasma levels of insulin and markers of insulin resistance were blunted in mice on high-fat diet following six weeks of stress exposure. Social avoidance following chronic stress was present in all mice after three and six weeks. CONCLUSIONS: This study describes the evolution of the chronic effects of social defeat/overcrowding stress in combination with exposure to high- or low-fat diet. Most importantly, we demonstrate that a six week chronic exposure to social defeat stress prevents the metabolic effects of high fat diet, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance as well as in plasma leptin and insulin levels. This study highlights the importance of considering the chronic aspects of both parameters and their time-dependent interplay. PMID- 21783326 TI - Using virtual reality to investigate complex and contextual cue reactivity in nicotine dependent problem drinkers. AB - Alcohol and cigarette smoking frequently co-occur among adults in the U.S., resulting in a myriad of deleterious health outcomes. Cue reactivity has been posited as one factor that precludes individuals from overcoming alcohol and nicotine dependency. While cue reactivity studies have focused on the impact of proximal cues on cue reactivity, much less is known about the unique impact of complex and contextual cues. This pilot study compares nicotine and alcohol cue reactivity among a sample of nicotine dependent, daily drinkers (N=21) across neutral, party, and office courtyard virtual reality (VR) contexts embedded with proximal smoking cues to: 1) explore and compare the effects of complex nicotine cues on alcohol cross-cue reactivity between nicotine/alcohol dependent drinkers and nicotine dependent/non-alcohol dependent daily drinkers, and 2) assess the effectiveness of VR for eliciting cue-induced nicotine craving responses using complex nicotine cues. Nicotine dependent/non-alcohol dependent drinkers had significantly lower craving for alcohol in the non-alcohol congruent office courtyard VR scene and there was no difference in the alcohol-congruent party scene when compared to the alcohol dependent group, suggesting that the non alcohol dependent daily drinking group was more likely to react to contextual cues. Consistent with prior cue reactivity studies, dependent smokers experienced significantly higher craving for nicotine in the VR smoking congruent contexts compared to the neutral contexts; however, nicotine/alcohol dependent participants did not return to baseline craving after exposure to smoking cues. These results suggest substantive differences in the ways that nicotine dependent, daily alcohol drinkers and nicotine/alcohol dependent drinkers experience craving, whether cross-cue or traditional. PMID- 21783327 TI - Medicine could be constructing human bodies in the future. AB - In the 21st century human life has been profoundly changed by developments in sanitation, medical interventions and public health measures. Practically every person born into a developed nation population has a chance to survive throughout entire reproductive life and well beyond. Human body has evolved in the past adaptations to hunting-gathering, and later, agricultural ways of life. In the new situation of practically non-existent premature mortality and technologically developed complex societies medical practice will devote less attention to "saving lives"--preventing premature deaths--and more to enhancing capacities of our biological organisms and providing for maintenance of the bodies beyond their biological limits established by evolution. The role of advances in nanotechnology, information technology, neuroscience and biotechnology is discussed in the context of mind and body enhancements. PMID- 21783328 TI - Changes in physico-chemical, microbiological, textural and sensory attributes during ripening of dry-cured foal salchichon. AB - The changes in the physico-chemical, microbiological, textural and sensory attributes of foal salchichon were followed during ripening. Foal salchichon samples were taken at 0 days (mix before stuffing), and after 7, 14, 21, 28, 35, 42 and 49 days of ripening. The final a(w) was 0.82, whereas pH values stayed around their initial values. TBAR'S values increased significantly (P<0.001) during processing, from 0.44 to 2.26 mg/kg of sausage. Ripening time also affected the lightness (L*), redness (a*) and yellowness (b*) (P<0.001). Hardness, gumminess and chewiness increased (P<0.001) from 0.96, 0.6 and 0.47 to 46.92 kg/cm(2), 21.34 kg/cm(2) and 15.14 kg, respectively during processing, whereas cohesiveness and springiness values decreased during ripening. Lactic acid bacteria increased slowly in number and a large increase of Micrococcaceae was noticed. Regarding sensorial characteristics, foal salchichon samples showed high values for intensity of flavour (7.22+/-0.44), hardness (7.33+/-0.71) and dryness (6.67+/-0.71) and low scores for acid taste (1.67+/-0.71) and saltiness (3.11+/-0.6). PMID- 21783329 TI - Cross-cultural adaptation and validation of the Korean version of the Michigan hand questionnaire. AB - PURPOSE: The Michigan hand questionnaire (MHQ) is increasingly being used and has been adapted cross-culturally in some Western and Asian countries, but the validation process for an Asian translation of MHQ has not been well described. In this study, we translated and adapted the original MHQ cross-culturally to produce a Korean version, and then assessed the validity and reliability of the Korean version of the MHQ. METHODS: A total of 176 patients with common hand disorders completed the Korean version of the MHQ and the Disabilities of the Arm, Shoulder, and Hand questionnaire. We included the pain score assessed by a visual analog scale during activity, range of motion, measurement of grip strength, and subjective assessment of the functional state by use of Cooney's scale in the validation process. RESULTS: There were no major linguistic or cultural problems during forward and backward translations of the MHQ, except for a minor change owing to cultural discrepancies in eating, such as the dominant hand using a spoon and chopsticks instead of both hands using a knife and fork. All subscales of the MHQ showed satisfactory internal consistency. The reproducibility test showed no significant difference. The construct validity revealed a moderate to strong correlation between every subscale of the Korean MHQ against DASH disabilities and symptoms. The aesthetic and satisfaction domains, unique domains of the MHQ, had little correlation with the objective measure of the pain visual analog scale, grip strength, motion and subjective functional state. CONCLUSIONS: The Korean version of MHQ showed satisfactory internal consistency, test-retest reliability, and validity and demonstrated a significant correlation with the patient-based upper extremity questionnaire and clinical assessment. We found the application and evaluation of the instrument to be feasible and understandable among patients in Korea. PMID- 21783330 TI - Antimicrobial susceptibilities and bacteriological characteristics of bovine Pseudomonas aeruginosa and Serratia marcescens isolates from mastitis. AB - The presence of metallo-beta-lactamase (MBL)-producing and multidrug-resistant Pseudomonas aeruginosa (MDRP) strains among bovine isolates of Gram-negative bacilli, and O-serotypes of bovine Serratia marcescens and P. aeruginosa isolates have been reported rarely. The aims of this study were to (1) elucidate antimicrobial susceptibilities and O-serotypes of P. aeruginosa and S. marcescens isolates from bovine mastitis and the presence of MBL-producers and MDRP strains among them and (2) evaluate their relationships to human isolates. We investigated the MICs of 24 antimicrobials and O-serotypes for 116 P. aeruginosa and 55 S. marcescens isolates in Japan, primarily in 2006. A total of 171 isolates exhibited high antimicrobial susceptibilities with the exception of a partial drug. P. aeruginosa isolates exhibited high susceptibilities of >= 95.7% to ciprofloxacin, imipenem, meropenem, piperacillin, ceftazidime, cefepime, cefoperazone/sulbactam, amikacin, tobramycin, and gentamicin; however, they exhibited a susceptibility of only 69.8% to aztreonam. They exhibited substantial resistances to ceftriaxone, enrofloxacin, cefotaxime, and moxalactam. S. marcescens isolates exhibited high susceptibilities of >= 90.9% to kanamycin, ceftiofur, sulfamethoxazole-trimethoprim, and the 15 aforementioned drugs, but exhibited resistance to minocycline. Neither MBL-producers nor MDRP strains were detected among the 171 strains. The dominant serotypes of P. aeruginosa isolates were OG, OA, OB, OI, OF, OE, and OK; those of S. marcescens isolates were O6 and O5. Every S. marcescens isolate was pigmented. These findings suggest that bovine P. aeruginosa and S. marcescens isolates differ from human isolates from both antibiogram and phenotypic perspectives, and could help to evaluate differences in bacteriological characteristics between bovine and human isolates. PMID- 21783331 TI - Tissue distribution of Red Spotted Grouper Nervous Necrosis Virus (RGNNV) genome in experimentally infected juvenile European seabass (Dicentrarchus labrax). AB - The distribution of viral genome in the tissues of juvenile European seabass (Dicentrarchus labrax) during the course of a Red Spotted Grouper Nervous Necrosis Virus (RGNNV) infection has not yet been described. The present study addresses this and indicates which target organs may be involved in viral replication. This information should enable more accurate detection of virus in asymptomatic carriers, and in turn help to control the spread of the disease. The aim of this study was to examine the pattern of expression of viral genomic segments RNA1 and RNA2, using two absolute real-time PCRs (RT-qPCR), over the course of a RGNNV infection after administering the virus by intramuscular injection. In situ hybridization was also used to locate the RNA2 viral segment in different organs throughout the infection. The experimental challenge provoked an acute form of viral nervous necrosis (VNN), with a resulting cumulative mortality of 37%. The RT-qPCRs designed allowed the detection of both genomic segments in all the organs tested (nervous and non-nervous tissues) at all sampling times examined. The highest viral RNA copy number was found in eyes, although viral replication appeared to begin in the brain. Viral replication was also recorded in pooled internal organs and in caudal fin. However, the increase in the viral RNA copy number in these organs did not result in an increased viral titre, which may indicate that a productive infection does not take place in non nervous tissues, possibly due to a failure in a viral post-replication step. PMID- 21783332 TI - The relation between farm specific factors and prevalence of Clostridium difficile in slaughter pigs. AB - Foodborne ingestion through pork products of Clostridium difficile has been suggested a possible route of transmission of C difficile from pigs to humans. To determine whether C. difficile bacteria are present in the intestines of slaughter pigs, rectum contents of 677 slaughter pigs from 52 farms were collected at the slaughterhouse. Data on farm specific factors were collected and the association of these factors with the presence of C. difficile in pig herds from 39 farms was assessed. The prevalence of C. difficile and the ribotypical diversity that were found in this study were much higher than previously reported in literature, with an overall C. difficile prevalence of 8.6% (58/677). Sixteen distinct C. difficile ribotypes were identified, predominantly type 078 (31.0%, 18/58). This type is also commonly found in humans with C. difficile infection (CDI). Both on individual pig level and on herd level, no significant difference between the prevalence of C. difficile in pigs derived from conventional or organic farming types was detected. Farm system, size, and presence of other animal species on the farm did not result in significant different prevalences of C. difficile. PMID- 21783333 TI - A functional study on L-type calcium channels in granulosa cells of small follicles in laying and forced molt hens. AB - To investigate Ca(2+) dynamics in earlier phases of follicular development we compared the resting [Ca(2+)](i) and tested the functional responses to agonist/antagonist of L-type voltage-operated calcium channels (VOCCs) in small follicles GCs from hens during oviposition (O-GCs) and forced molt (M-GCs), using the microspectrofluorimetric [Ca(2+)](i) imaging. O-GCs were obtained from prehierarchical follicles (F(6)-F(5)-F(4)<8mm). In basal and agonist/antagonist stimulated M-GCs we did not observe a change in the [Ca(2+)](i) under any of condition in all cells analyzed. Based on basal measurements we can distinguish three different patterns reflecting cells variability within O-GCs group: (a) 39% cells showed small oscillations and [Ca(2+)](i) was 108+/-11nM; (b) 36% cells displayed yet small oscillations and [Ca(2+)](i) was 167+/-14nM; (c) 25% were cells with repetitive irregular oscillations that peaked until 2 fold basal value and [Ca(2+)](i) very variable, was 248+/-41nM. In O-GCs L-type VOCCs stimuli displayed different effects on [Ca(2+)](i) for both treatment in three basal patterns. In our study we demonstrated: (1) at resting the [Ca(2+)](i) is low (111+/-5nM) in M-GCs and tend to increasing in prehierarchical O-GCs; (2) L-type Ca(2+) channels are functionally expressed in the major part of O-GCs whereas they are not activated nor inhibited in M-GCs and in a percentage of O-GCs; (3) there are three different cellular types in prehierarchical O-GCs that may be associated with increasing stages of follicular development, based on their Ca(2+) pathway. Therefore, the functional response of L-type Ca(2+) channels in cultured laying hen prehierarchical GCs may be correlated with the functional maturation phase of laying hens ovarian. We hypothesize that the L-type Ca(2+) dependent signaling could have a critical role in the regulatory mechanisms hormone mediated in hen ovarian cycle. PMID- 21783334 TI - A case of ADEM with atypical MRI findings of a centrally-located long spinal cord lesion. AB - The patient was a 14-year-old male diagnosed with acute disseminated encephalomyelitis (ADEM) with acute onset of multifocal central nervous system symptoms. He showed increased cerebrospinal fluid cell counts and high myelin basic protein levels, which responded well to steroid pulse therapy. Spinal MRI showed a centrally-located long spinal cord lesion (LCL) involving 17 vertebral bodies from C2 to T11 that later expanded into the white matter, and lesions on the ventral side of the medulla. The cause of LCL has been reported to be heterogeneous. In this case, LCL is considered to be associated with ADEM, an acute autoimmune response to myelin, and vascular inflammation of the gray matter of the spinal cord. PMID- 21783335 TI - Quantitative analysis of anti-inflammatory lignan derivatives in Ratanhiae radix and its tincture by HPLC-PDA and HPLC-MS. AB - Root preparations of Krameria lappacea (Dombey) Burdet et Simpson are traditionally used against oropharyngeal inflammation. Besides antimicrobial and astringent procyanidines, lignan derivatives, including ratanhiaphenol I, II, III and (+)-conocarpan, contribute to the activity of Ratanhiae radix, exerting a significant topical anti-inflammatory activity in vivo, and in vitro by inhibiting NF-kappaB and the formation of inflammatory prostaglandins and leukotrienes. Besides gravimetrical analysis of the ratanhiaphenols I, II and III, the content of these compounds in the herbal drug has never been determined. The developed HPLC method enables the quantification of twelve active lignan derivatives in the roots, and is also suitable for the determination of the constituents in Tinctura Ratanhiae. Separation was achieved on a phenyl-hexyl column material using a solvent gradient consisting of 0.02% aqueous TFA and a mixture of acetonitrile/methanol (75:25, v/v). Sensitivity, accuracy (recovery rates were between 95% and 105.6%), repeatability (RSD <= 4.6%), and precision (intra-day precision <= 4.8%; inter-day precision <= 3.4%) of the method were determined. HPLC-MS experiments in positive and negative electrospray ionization mode confirmed identity and peak purity of analytes. The analysis of several root and tincture samples revealed that (+)-conocarpan and ratanhiaphenol II dominated with contents of 0.49-0.71% and 0.51-0.53% in the roots and 0.66-0.68 mg/ml and 0.70-0.71 mg/ml in the commercial tinctures, respectively. PMID- 21783336 TI - Identification and characterization of stressed degradation products of prulifloxacin using LC-ESI-MS/Q-TOF, MSn experiments: development of a validated specific stability-indicating LC-MS method. AB - A rapid, specific and novel gradient LC-MS method has been developed and validated for the identification and characterization of stressed degradation products (DPs) of prulifloxacin (PF) using liquid chromatography combined with quadrupole time-of-flight electrospray ionization tandem mass spectrometry (LC/Q TOF-ESI-MS/MS). PF was subjected to hydrolytic (acidic, alkaline and neutral), oxidation, photolytic and thermal stress, as per ICH guidelines Q1A (R2). The drug showed extensive degradation in hydrolytic and oxidative, while it was stable to thermal and photolytic stress conditions. In total, 13 DPs were formed and the chromatographic separation of drug and its DPs was achieved on a C-18 column (4.6 * 250 mm, 5 MUm) using gradient elution method. All the DPs have been identified and characterized using MS(n) experiments and accurate mass measurements. The LC-MS method was validated with respect to specificity, linearity, accuracy, precision and robustness. PMID- 21783337 TI - Factors influencing early postoperative recovery after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can prolong survival in selected patients with peritoneal carcinomatosis (PC). However, there is little data on patients' recovery process after this complex treatment. This study aimed to describe the in-hospital postoperative recovery and factors related to the recovery of patients who undergo CRS and HIPEC. METHOD: A retrospective audit of the electronic health record (EHR) was undertaken for 76 PC patients (42 women, 34 men) treated primarily with CRS and HIPEC between 2005 and 2006 in Sweden. RESULTS: Oral intake, regaining bowel functions and mobilisation usually occurred between 7 and 11 days postoperatively. Patients experienced nausea for up to 13 days postoperatively. Forty-two patients were satisfied with their pain management, which usually took the form of epidural anaesthesia and which continued for about one week post-surgery. Sleep disturbance was observed in 51 patients and psychological problems in 49 patients during the first three postoperative weeks. Tumour burden, stoma formation, use of CPAP, primary diagnosis, and the length of stay in the ICU were factors related to an early recovery process. CONCLUSION: Drinking, eating, regaining bowel functions and mobilisation were re-established within 11 days of CRS and HIPEC. Tumour burden, stoma formation, use of CPAP, primary diagnosis and the length of stay in the ICU all had an impact on postoperative recovery, and should be discussed with the patients preoperatively and taken into consideration in designing an individualised patient care plan, in order to attain a more efficient recovery. PMID- 21783338 TI - Intramedullary rod and cement static spacer construct in chronically infected total knee arthroplasty. AB - Two-stage reimplantation, with interval antibiotic-impregnated cement spacer, is the preferred treatment of prosthetic knee joint infections. In medically compromised hosts with prior failed surgeries, the outcomes are poor. Articulating spacers in such patients render the knee unstable; static spacers have risks of dislocation and extensor mechanism injury. We examined 58 infected total knee arthroplasties with extensive bone and soft tissue loss, treated with resection arthroplasty and intramedullary tibiofemoral rod and antibiotic-laden cement spacer. Thirty-seven patients underwent delayed reimplantation. Most patients (83.8%) were free from recurrent infection at mean follow-up of 29.4 months. Reinfection occurred in 16.2%, which required debridement. Twenty-one patients with poor operative risks remained with the spacer for 11.4 months. All patients, during spacer phase, had brace-free ambulation with simulated tibiofemoral fusion, without bone loss or loss of limb length. PMID- 21783339 TI - Prospective mental imagery in patients with major depressive disorder or anxiety disorders. AB - Prospective negative cognitions are suggested to play an important role in maintaining anxiety disorders and major depressive disorder (MDD). However, little is known about positive prospective mental imagery. This study investigated differences in prospective mental imagery among 27 patients with anxiety disorders, 24 patients with MDD, and 32 control participants. Measures of both deliberately generated and intrusive imagery were completed. Results indicated that both patients with anxiety disorders and those with MDD provided poorer vividness ratings for deliberately generated prospective positive scenarios compared to the control group. Patients with anxiety disorders showed a greater ability to vividly generate imagery for prospective negative scenarios than both patients with MDD and control participants. Finally, both clinical groups reported greater levels of intrusive prospective imagery of personally relevant events as compared to the control group. The current findings underline the necessity to target prospective positive mental imagery in treating MDD and anxiety disorders. PMID- 21783341 TI - Editorial for the special issue ICANN-2010. PMID- 21783340 TI - PTSD symptoms, potentially traumatic event exposure, and binge drinking: a prospective study with a national sample of adolescents. AB - Research demonstrates substantial comorbidity between PTSD and alcohol use disorders. Evidence for functional relationships between PTSD and problematic alcohol use has not always been consistent, and there have been few investigations with adolescent samples. Further, research has not consistently controlled for cumulative potentially traumatic event (PTE) exposure when examining prospective relationships between PTSD and problematic alcohol use (i.e., binge drinking). This study examines the prospective relationships between PTSD symptoms, problematic alcohol use, and cumulative PTE exposure measured at three time points over approximately three years among a nationally representative sample of adolescents exposed to at least one PTE (n=2399 and age range=12-17 at Wave 1). Results from parallel process latent growth curve models demonstrated that increases in cumulative PTE exposure over time positively predicted increases in both PTSD symptoms and binge drinking, whereas increases in PTSD symptoms and increases in binge drinking were not related when controlling for the effect of cumulative PTE exposure. Further analyses suggested that these relationships are specific to assaultive PTEs and are not found with non-assaultive PTEs. Theoretical implications are discussed. PMID- 21783342 TI - Adaptive object recognition model using incremental feature representation and hierarchical classification. AB - This paper presents an adaptive object recognition model based on incremental feature representation and a hierarchical feature classifier that offers plasticity to accommodate additional input data and reduces the problem of forgetting previously learned information. The incremental feature representation method applies adaptive prototype generation with a cortex-like mechanism to conventional feature representation to enable an incremental reflection of various object characteristics, such as feature dimensions in the learning process. A feature classifier based on using a hierarchical generative model recognizes various objects with variant feature dimensions during the learning process. Experimental results show that the adaptive object recognition model successfully recognizes single and multiple-object classes with enhanced stability and flexibility. PMID- 21783344 TI - Diagnosis of epileptic syndrome after a new onset seizure and its correlation at long-term follow-up: longitudinal study of 131 patients from the emergency room. AB - This study aims to demonstrate the reliability of the diagnosis of epilepsy after a new onset seizure, supported by a detailed anamnesis and the complementary tests accessible at the emergency room (ER), such as CT-scan and video-EEG. It was a prospective study including 131 adult patients (55% males, medium age 52.42 (+/-21.5)[16-98] years-old, follow-up 25.22 (+/-13.69)[12-31] months). In half of cases we could not identify any predisposing factor. Within the first 72 h, patients were included into an epileptic syndrome according to the ILAE 1989 classification, if possible. Thereafter, they were followed-up in the outpatient clinic of the Epilepsy Unit, where seizure recurrence was recorded and further diagnostic examinations were performed. 94.1% of patients initially diagnosed of epilepsy were confirmed as epileptics, and up to 57% of patients could be classified into a particular syndrome from the ER. Conversely, 44.6% of patients with the initial diagnosis of isolated seizure and one third of patients with non epileptic seizures developed recurrence, switching their initial diagnosis to epilepsy. Both CT-scan and early EEG demonstrated its usefulness evaluating the risk of recurrence after a new onset seizure (Positive predictive value 78% and 88%, respectively). Epileptiform activity was a predictor of seizure recurrence (p<0.05), independently to the moment where the EEG was performed. According to our results, it is realistic to perform the diagnosis of epilepsy after a new onset seizure, although many patients still need further specific examinations, or seizure recurrence, to be diagnosed. PMID- 21783345 TI - Uptake and antileishmanial activity of meglumine antimoniate-containing liposomes in Leishmania (Leishmania) major-infected macrophages. AB - Leishmaniasis is a parasitic disease caused by the intramacrophage protozoa Leishmania spp. and may be fatal if left untreated. Although pentavalent antimonials are toxic and their mechanism of action is unclear, they remain the first-line drugs for treatment of leishmaniasis. An effective therapy could be achieved by delivering antileishmanial drugs to the site of infection. Compared with free drugs, antileishmanial agent-containing liposomes are more effective, less toxic and have fewer adverse side effects. The aim of this study was to develop novel meglumine antimoniate (MA)-containing liposome formulations and to analyse their antileishmanial activity and uptake by macrophages. Determination of the 50% inhibitory concentration (IC(50)) values showed that MA-containing liposomes were >=10-fold more effective than the free drug, with a 5-fold increase in selectivity index, higher activity and reduced macrophage toxicity. The concentration required to kill 100% of intracellular amastigotes was >=40 fold lower when MA was encapsulated in liposomes containing phosphatidylserine compared with the free drug. Fluorescence microscopy analysis revealed increased uptake of fluorescent liposomes in infected macrophages after short incubation times compared with non-infected macrophages. In conclusion, these data suggest that MA encapsulated in liposome formulations is more effective against Leishmania-infected macrophages than the non-liposomal drug. Development of liposome formulations is a valuable approach to the treatment of infectious diseases involving the mononuclear phagocyte system. PMID- 21783346 TI - In vivo degradation behavior of Ca-deficient hydroxyapatite coated Mg-Zn-Ca alloy for bone implant application. AB - In present paper, an in vivo study was carried out on uncoated and calcium deficient hydroxyapatite (Ca-def HA) coated Mg-Zn-Ca alloy to investigate the effect of Ca-def HA coating on the degradation behavior and bone response of magnesium substrate. Magnesium alloy rods were implanted into rabbit femora and evaluated during 24 weeks implantation. The characterization of both implants indicates that in vivo degradation of the Ca-def HA coating and magnesium substrate occurs almost simultaneously, and in vivo valid life of the coating is about 8 weeks, after that the degradation rate of the coated implants increases obviously. The main reasons for the Ca-def HA coating degradation can be attributed to its reaction with body fluid and the substitution of Mg(2+) ions in Ca-def HA. Histopathological examinations show that the Ca-def HA coating has good osteoconductivity and is in favor of the formation of more new bone on the surface of magnesium alloy. So the Ca-def HA coating could not only slow down in vivo degradation of magnesium alloy but also improve its bone response. PMID- 21783347 TI - Photochemically prepared polysulfone/poly(ethylene glycol) amphiphilic networks and their biomolecule adsorption properties. AB - Polysulfone/poly(ethylene glycol) amphiphilic networks were prepared via in situ photo-induced free radical crosslinking polymerization. First, the hydrophobic polysulfone diacrylate (PSU-DA) oligomer was synthesized by condensation polymerization and subsequent esterification processes. Then, the obtained oligomer was co-crosslinked with the hydrophilic poly(ethylene glycol) diacrylate (PEG-DA) or poly(ethylene glycol) methyl ether acrylate (PEG-MA) at different feed ratios. In the case of PEG-MA, the resulting network possessed dangling pendant hydrophilic chains on the crosslinked surface. The structure and the morphology of the membranes were characterized by attenuated total reflection infrared spectroscopy (ATR-IR) and scanning electron microscopy (SEM). The enhancement of surface hydrophilicity was investigated by water contact angle measurements. The biomolecule adsorption properties of these networks were also studied. The biomolecules easily adsorbed on the surface of the hydrophobic polysulfone networks whereas dangling hydrophilic chains on the surface prevented the adsorption of the biomolecules. PMID- 21783348 TI - Novel polyurethane ionomer nanoparticles displayed a good biosensor effection. AB - This study described the bioelectrochemistry property of hemoglobin (Hb) on biopolymer film of polyurethane ionomer nanoparticles (PUI-NPs) noncovalently functionalized with multiwall carbon nanotubes (MWCNTs). The polyurethane ionomer nanoparticles (PUI-NPs) were synthesized by emulsion polymerization, and could provide a good biocompatible microenvironment for Hb immobilization. The characteristic of (PUI-NPs)/MWCNTs and Hb/(PUI-NPs)/MWCNTs composite films were performed by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and circular dichroism (CD). Analytical results indicated that the immobilized Hb could maintain its native conformation in the (PUI-NPs)/MWCNTs hybrid film. Entrapped Hb in (PUI-NPs)/MWCNTs preserved its bioactivities and exhibited an excellent electrochemical behavior with a formal potential of -0.346 V in a pH 7.0 phosphate buffer. The formal potential of Hb varied linearly with the increase of pH in the range of 5.0-9.0 with a slope of 52.9 mV pH(-1), indicating that one proton participated in the electrochemical reaction process. Moreover, the resulting biosensor displays an electrocatalytic activity to hydrogen peroxide (H(2)O(2)). The linear range for the determination of H(2)O(2) was from 6.5*10( 7) to 8.0*10(-5)M with a detection limit of 2.4*10(-7)M and a Michaelis-Menten constant K(m)(app) value of 0.155 mM. Consequently, our investigation demonstrated that the proposed method opens a way to develop biosensors by using polymer with good biocompatible in its nanostructured information. PMID- 21783349 TI - The concepts, diagnosis and management of early imaging changes after therapy for glioblastomas. AB - Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with 'pseudoprogression' and 'pseudoresponse' are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies. PMID- 21783351 TI - A novel set-up to allow suctioning during direct endotracheal and fiberoptic intubation. PMID- 21783352 TI - Temperature probe used as a flexible stylet for unexpected difficult laryngoscopy in an infant. PMID- 21783353 TI - Prevalence of atopy, asthma and COPD in an urban and a rural area of an African country. AB - The objectives of this study were to determine the prevalence of asthma, atopy and COPD in Rwanda and to identify risk factors. The survey was conducted in Kigali, the Capital of Rwanda, and in Huye District, a rural area located in southern Rwanda. METHODS: A total of 2138 subjects were invited to participate in the study.1920 individuals (90%) answered to questionnaires on respiratory symptoms and performed spirometry, 1824 had acceptable spirograms and performed skin-prick test. In case of airflow obstruction (defined as pre-bronchodilator ratio FEV(1)/FVC < LLN) a post bronchodilator spirometry was performed. Reversibility was defined as an increase in FEV(1) of 200 ml and 12% above baseline FEV(1) after inhalation of 400 mcg of salbutamol. RESULTS: The mean age was 38.3 years; 48.1% of participants were males and 51.9% females. Airflow obstruction was found in 256 participants (14%); 163(8.9%) subjects were asthmatics and 82 (4.5%) had COPD. COPD was found in 9.6% of participants aged 45 years and above. 484 subjects had positive skin-prick tests (26.5%); house dust mite and grass pollen mix were the main allergens. Risk factors for asthma were allergy, female gender and living in Kigali. COPD was associated with cigarette smoking, age and male sex. CONCLUSION: this is the first study which shows the prevalence of atopy, asthma and COPD in Rwanda. Asthma and COPD were respectively diagnosed in 8.9% and 4.5% of participants. COPD was diagnosed in 9.6% of subjects aged >= 45 years.The prevalence of asthma was higher in urban compared to rural area. PMID- 21783354 TI - End-of-life flows of multiple cycle consumer products. AB - Explicit expressions for the end-of-life flows (EOL) of single and multiple cycle products (MCPs) are presented, including deterministic and stochastic EOL exit. The expressions are given in terms of the physical parameters (maximum lifetime, T, annual cycling frequency, f, number of cycles, N, and early discard or usage loss). EOL flows are also obtained for hi-tech products, which are rapidly renewed and thus may not attain steady state (e.g., electronic products, passenger cars). A ten-step recursive procedure for obtaining the dynamic EOL flow evolution is proposed. Applications of the EOL expressions and the ten-step procedure are given for electric household appliances, industrial machinery, tyres, vehicles and buildings, both for deterministic and stochastic EOL exit, (normal, Weibull and uniform exit distributions). The effect of the physical parameters and the stochastic characteristics on the EOL flow is investigated in the examples: it is shown that the EOL flow profile is determined primarily by the early discard dynamics; it also depends strongly on longevity and cycling frequency: higher lifetime or early discard/loss imply lower dynamic and steady state EOL flows. The stochastic exit shapes the overall EOL dynamic profile: Under symmetric EOL exit distribution, as the variance of the distribution increases (uniform to normal to deterministic) the initial EOL flow rise becomes steeper but the steady state or maximum EOL flow level is lower. The steepest EOL flow profile, featuring the highest steady state or maximum level, as well, corresponds to skew, earlier shifted EOL exit (e.g., Weibull). Since the EOL flow of returned products consists the sink of the reuse/remanufacturing cycle (sink to recycle) the results may be used in closed loop product lifecycle management operations for scheduling and sizing reverse manufacturing and for planning recycle logistics. Decoupling and quantification of both the full age EOL and of the early discard flows is useful, the latter being the target of enacted legislation aiming at increasing reuse. PMID- 21783355 TI - Site-specific sonoporation of human melanoma cells at the cellular level using high lateral-resolution ultrasonic micro-transducer arrays. AB - We developed a new instrumental method by which human melanoma cells (LU1205) are sonoporated via radiation pressures exerted by highly-confined ultrasonic waves produced by high lateral-resolution ultrasonic micro-transducer arrays (UMTAs). The method enables cellular-level site-specific sonoporation within the cell monolayer due to UMTAs and can be applicable in the delivery of drugs and gene products in cellular assays. In this method, cells are seeded on the biochip that employs UMTAs for high spatial resolution and specificity. UMTAs are driven by 30 MHz sinusoidal signals and the resulting radiation pressures induce sonoporation in the targeted cells. The sonoporation degree and the effective lateral resolution of UMTAs are determined by performing fluorescent microscopy and analysis of carboxylic-acid-derivatized CdSe/ZnS quantum dots passively transported into the cells. Models representing the transducer-generated ultrasound radiation pressure, the ultrasound-inflicted cell membrane wound, and the transmembrane transport through the wound are developed to determine the ultrasound-pressure-dependent wound size and enhanced cellular uptake of nanoparticles. Model-based calculations show that the effective wound size and cellular uptake of nanoparticles increase linearly with increasing ultrasound pressure (i.e., at applied radiation pressures of 0.21, 0.29, and 0.40 MPa, the ultrasound-induced initial effective wound radii are 150, 460, and 650 nm, respectively, and the post-sonoporation intracellular quantum-dot concentrations are 7.8, 22.8, and 29.9 nM, respectively) and the threshold pressure required to induce sonoporation in LU1205 cells is ~0.12 MPa. PMID- 21783356 TI - Fluorescence resonance energy transfer dye-labeled probe for fluorescence enhanced DNA detection: an effective strategy to greatly improve discrimination ability toward single-base mismatch. AB - In this article, we report on the first use of fluorescence resonance energy transfer (FRET) dye-labeled probe for fluorescence resonance enhanced DNA detection to greatly improve discrimination ability toward single-base mismatch using conjugation polymer poly(p-phenylenediamine) nanobelts (PNs) as a sensing platform. The suggested FRET dye-labeled probe contains a 5-carboxyfluorescein (FAM) group at 5' end of the oligomer as a donor and a 6-carboxy-X-rhodamine (ROX) attached to a modified cytosine (C) base as an acceptor, which were separated by three bases. The general concept used in this DNA assay is based on adsorption of the FRET dye-labeled single-stranded DNA (ssDNA) probe by PN, which is accompanied by substantial fluorescence quenching and disappearance of FRET. The subsequent specific hybridization with its target forms a double-stranded DNA (dsDNA), resulting in desorption of the hybridized duplex from PN surface accompanied by reoccurrence of FRET and fluorescence recovery. It suggests that the discrimination ability of this FRET probe based system toward single-base mismatch is about 5.2 times that of the system based on single dye-labeled probe based system. PMID- 21783357 TI - New opportunities for biocatalysis: driving the synthesis of chiral chemicals. AB - Various biocatalytic methods have been developed for the synthesis of chiral chemicals, which have made their synthesis more environmentally friendly and product-specific. New opportunities for biocatalysis, including new scientific developments in genomics and protein engineering technologies, novel process developments and the increased availability of useful enzymes, offer many possibilities for the manufacture of new chiral compounds and deliver greener and economically competitive processes. In this review, new opportunities for biocatalysis in the preparation of chiral molecules are outlined and highlighted. PMID- 21783358 TI - Modern insights into hepatic arterial infusion for liver metastases from colorectal cancer. AB - Hepatic arterial infusion (HAI) selectively achieves high drug exposure of liver metastases from colorectal cancer. Such pharmacologic advantage has doubled the response rate of liver metastases on fluoropyrimidines (FP) delivered as HAI rather than intravenously, in a meta-analysis of randomised clinical trials (RCT). However, the improvement in antitumour efficacy did not consistently translate into any significant survival advantage across all randomised studies. However, the results of this meta-analysis should be cautiously interpreted due to the heterogeneity of the studies, inadequate study designs, obsolete therapy and high rate of early treatment discontinuation due to HAI technical failures or hepato-biliary toxicity. Most studies actually were performed before year 2000 and did not integrate the considerable progresses accomplished in the management of CRC, such as multidrug regimens instead of single agent FP and secondary resection of metastases, a major contributing factor for prolonged survival. Furthermore, the systemic exposure of patients given HAI was low without concomitant IV therapy, facilitating extra-hepatic relapses. The role of HAI in liver metastases from CRC should, therefore, be revisited, using modern multidisciplinary therapeutic approaches and appropriate study designs. Recommendations for the design of future RCTs exploring HAI are provided. PMID- 21783359 TI - 2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-beta1 and activin A signalling. AB - Novel inhibitors of TGF-beta1 and activin A signalling based on a 2-aryl-4-(3 (pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-beta1. Synthetic compounds containing pyridin-3 yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-beta inhibitors. PMID- 21783360 TI - Novel and highly potent histamine H3 receptor ligands. Part 2: exploring the cyclohexylamine-based series. AB - Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation. PMID- 21783361 TI - Overcoming hERG activity in the discovery of a series of 4-azetidinyl-1-aryl cyclohexanes as CCR2 antagonists. AB - A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG. PMID- 21783363 TI - Synthesis and in vitro evaluation of derivatives of the beta1-adrenergic receptor antagonist HX-CH 44. AB - Isopropyl- and fluoroisopropyl-amino derivatives of the beta(1)-adrenergic receptor antagonist 2-[4-[3-(tert-butyl-amino)-2-hydroxypropoxy]phenyl]-3-methyl 6-methoxy-4(3H)-quinazolinone ((+/-)HX-CH 44) were synthesized, including a concise and efficient preparation of the core, 2-(4-hydroxyphenyl)-6-methoxy-3 methylquinazolin-4(3H)-one. In vitro binding assays showed that the fluorinated analog was selective towards beta(1)-adrenergic receptors over beta(2)-adrenergic and 5-HT(1A) receptors. An X-ray crystallographic characterization of the fluorinated analog is also reported. PMID- 21783362 TI - SAR analysis of innovative selective small molecule antagonists of sphingosine-1 phosphate 4 (S1P4) receptor. AB - Recent evidence suggests an innovative application of chemical modulators targeting the S1P(4) receptor as novel mechanism-based drugs for the treatment of influenza virus infection. Modulation of the S1P(4) receptor may also represent an alternative therapeutic approach for clinical conditions where reactive thrombocytosis is an undesired effect or increased megakaryopoiesis is required. With the exception of our recent research program disclosure, we are not aware of any selective S1P(4) antagonists reported in the literature to date. Herein, we describe complementary structure-activity relationships (SAR) of the high throughput screening (HTS)-derived hit 5-(2,5-dichlorophenyl)-N-(2,6 dimethylphenyl)furan-2-carboxamide and its 2,5-dimethylphenyl analog. Systematic structural modifications of the furan ring showed that both steric and electronic factors in this region have a significant impact on the potency. The furan moiety was successfully replaced with a thiophene or phenyl ring maintaining potency in the low nanomolar range and high selectivity against the other S1P receptor subtypes. By expanding the molecular diversity within the hit-derived class, our SAR study provides innovative small molecule potent and selective S1P(4) antagonists suitable for in vivo pharmacological validation of the target receptor. PMID- 21783364 TI - Synthesis and biological evaluation of substituted 4-arylthiazol-2-amino derivatives as potent growth inhibitors of replicating Mycobacterium tuberculosis H37Rv. AB - In search of potential therapeutics for tuberculosis, we describe herein synthesis and biological evaluation of some substituted 4-arylthiazol-2-amino derivatives as modified analogues of the antiprotozoal drug Nitazoxanide (NTZ), which has recently been reported as potent inhibitor of Mtb H(37)Rv (Mtb MIC=52.12 MUM) with an excellent ability to evade resistance. Among the synthesized derivatives, the two compounds 7a (MIC=15.28 MUM) and 7c (MIC=17.03 MUM) have exhibited about three times better Mtb growth inhibitory activity over NTZ and are free from any cytotoxicity (Vero CC(50) of 244 and 300 MUM respectively). These two compounds represent promising leads for further optimization. PMID- 21783365 TI - Photoresponsive 5'-cap for the reversible photoregulation of gene expression. AB - Photoresponsive 5'-caps that can be reversibly cis-trans isomerized by light irradiation were developed for the reversible photoregulation of gene expression. The 8-naphthylvinyl cap (8NV-cap) in the trans form completely inhibited translation of mRNA, whereas the cis form yielded protein with the same efficiency as mRNA capped with the normal-cap, a 26-fold higher efficiency than that of the trans form. The 8NV-capped mRNA could be switched between a translating state (ON state) and a non-translating state (OFF state) in a reversible fashion by alternately irradiating with monochromatic 410 nm or 310 nm light. PMID- 21783366 TI - Optimising the management of primary breast cancer in older women - a report of a multi-disciplinary study day. AB - PURPOSE: The objectives of the study day were to (i) develop an in-depth understanding around the biology and treatment options; (ii) explore the specific physical and psychosocial needs and consideration including patients perspective; and (iii) gain insight into the development of a dedicated, holistic and multi disciplinary clinic service and the importance of supporting research, for older women with primary breast cancer. DESIGN: The format included presentations (with lectures from external and local faculty, and short research papers from Nottingham) with a number of interactive discussions, and sharing of patients' experience. RESULTS: Four sessions were held covering (i) pathological features, (ii) role of radiotherapy and adjuvant chemotherapy, (iii) role of surgery, geriatric assessment and quality of life issues, and (iv) challenges in running research trials. CONCLUSIONS: A dedicated and joint team approach is required to improve clinical service and support research, in order to optimise the management of primary breast cancer in older women. PMID- 21783367 TI - Radiation-induced moyamoya disease after childhood astrocytoma. AB - Adjunctive radiation treatment of childhood intracranial neoplasms of grade II or higher creates a risk of subsequent vasculopathy. A 28-year-old male presented with a Glasgow Coma Scale 12 after acute collapse and hemiparesis with an intraparenchymal haematoma. Emergent craniotomy, histopathology and subsequent imaging confirmed the cause as radiation-induced moyamoya disease, subsequent to treatment for a grade 2 astrocytoma 24 years previously. He had been lost to follow-up after normal serial imaging performed up to 10 years after his initial diagnosis. Long term surveillance imaging may be of benefit in identifying treatable vascular anomalies. PMID- 21783368 TI - Marine diterpene glycosides. AB - Marine diterpene glycosides (MDGs) respresent a small but highly significant group of the much larger class of marine diterpenes. The three well-studied examples of MDGs are eleutherobins, pseudopterosins and fuscosides, all of which exhibit extremely promising biological activity. The eleutherobins are potent anti-mitotic agents, and the pseudopterosins and fuscosides are potent anti inflammatory agents. This review discusses the structures and biological activities of these compounds, as well as their biosynthesis and synthesis. PMID- 21783369 TI - Synthesis and topoisomerase I inhibitory activity of a novel diazaindeno[2,1 b]phenanthrene analogue of Lamellarin D. AB - A novel 5-oxa-6a,8-diazaindeno[2,1-b]phenanthren-7-one scaffold was designed and synthesized as an active analogue of the cytotoxic marine alkaloid Lamellarin D. The design was based on molecular modeling of the site of interaction of Lamellarin D with DNA-topoisomerase I cleavable complex, whereas the synthesis capitalized on a simple Friedel-Crafts cyclization of indole to a beta carbolinone nucleus. The product exhibited topoisomerase I poisoning activity and submicromolar cytotoxicity on human non-small cell lung cancer H460 cell line. PMID- 21783370 TI - Synthesis, biological evaluation, and molecular modeling of cinnamic acyl sulfonamide derivatives as novel antitubulin agents. AB - A series of novel cinnamic acyl sulfonamide derivatives (9a-16e) have been designed and synthesized and their biological activities were also evaluated as potential tubulin polymerization inhibitors. Among all the compounds, 10c showed the most potent growth inhibitory activity against B16-F10 cancer cell line in vitro, with an IC(50) value of 0.8MUg/mL. Docking simulation was performed to insert compound 10c into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 10c with potent inhibitory activity in tumor growth may be a potential anticancer agent. PMID- 21783372 TI - Thermal performance of batch boiling water targets for 18F production. AB - Batch boiling targets are commonly used in cyclotrons to produce Fluorine-18 by proton bombardment of Oxygen-18 enriched water. Computational models have been developed to predict the thermal performance of bottom-pressurized batch boiling production targets. The models have been validated with experimental test data from the Duke University Medical Cyclotron and the Wisconsin Medical Cyclotron. Good agreement has been observed between experimental measurements and model predictions of average target vapor fraction as a function of beam current and energy. PMID- 21783371 TI - Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides. AB - Inspired by the anti-human immunodeficiency virus (HIV) activity of analogues of beta-galactosylceramide (GalCer), a set of mono- and di-saccharide fatty acid esters were designed as GalCer mimetics and their binding to the V3 loop peptide of HIV-1 and anti-HIV activity evaluated. 1,1-linked Gal-Man and Glu-Man disaccharides with an ester on the Man subunit bound the V3 loop peptide and inhibited HIV infectivity in single round infection assays with the TZM-bl cell line. IC(50)'s were in the 50 MUM range with no toxicity to the cells at concentrations up to 200 MUM. These compounds appear to inhibit virus entry at early steps in viral infection since they were inactive if added post viral entry. Although these compounds were found to bind to the V3 loop peptide of gp120, it is not clear that this interaction is responsible for their anti-HIV activity because the relative binding affinity of closely related analogues did not correlate with their antiviral behavior. The low cytotoxicity of these 1,1 linked disaccharide fatty acid esters, combined with the easy accessibility to structurally diverse analogues make these molecules attractive leads for new topical anti-viral agents. PMID- 21783373 TI - Radon level and indoor gamma doses in dwellings of Trabzon, Turkey. AB - The seasonal variations of the indoor radon activity concentrations were determined in the 97 dwellings of Trabzon, Turkey. The annual average indoor radon activity concentration varied from 8 to 583 Bq/m3. The average winter/summer ratio of radon activity concentrations was 3.62. The gamma activity concentrations in the soil samples were determined as 41, 38, 443 and 25 Bq/kg for 226Ra, 232Th, 40K and 137Cs, respectively. The average gamma dose rate in air and the annual effective dose equivalent for outdoor occupancy were calculated as 63 nGy/h and 77 MUSv/y, respectively. PMID- 21783374 TI - Sutureless anastomoses: the main goal for a calcified aorta? PMID- 21783377 TI - Surviving critical illness. PMID- 21783378 TI - The incidence of falls in intensive care survivors. AB - BACKGROUND: Falling among adults in acute care is an important problem with falls rates in tertiary hospitals ranging from 2% to 5%. Factors that increase the risk of falling, such as advanced age, altered mental status, medications that act on the central nervous system and poor mobility, often characterise individuals who survive a prolonged intensive care unit (ICU) admission. PURPOSE: To measure the incidence of falls and describe the characteristics of fallers among intensive care survivors. METHODS: A comprehensive retrospective chart review was undertaken of 190 adults who were intubated and ventilated for >= 168 h and survived their acute care stay. Using a standardised form, several variables were extracted including falls during hospitalisation and risk factors such as age, severity of illness, and length of stay in intensive care and hospital. FINDINGS: Thirty-two (17%, 95% confidence interval 11.5-22.2%) patients fell at least once on the in-patient wards following their ICU stay. Compared with non-fallers, fallers were younger (53.2 +/- 17.9 vs. 44.1 +/- 18.3 years; p=0.009) and had a shorter duration of inotropic support in ICU (84 +/- 112 vs. 56 +/- 100 h; p=0.040). The majority of fallers were aged less than 65 years (84%). Both fallers and non-fallers had similar APACHE II scores (20 +/- 8 vs. 21 +/- 7; p=0.673), length of stay in intensive care (14.2 +/- 8.7 vs. 14.0 +/- 9.7 days; p=0.667) and hospital length of stay (43.9 +/- 33.1 vs. 41.0 +/- 38.8 days; p=0.533). CONCLUSION: Falling during hospitalisation is common in intensive care survivors. Compared with non-fallers, fallers were younger and required inotropes for a shorter duration. Those who survive a prolonged admission to an ICU may benefit from specific assessment of balance and falls risk by the multidisciplinary team. PMID- 21783379 TI - Her-2/neu gene amplification and over-expression in stomach and esophageal adenocarcinoma: from pathology to treatment. AB - Discovery of the over-expression of Her-2/neu or the amplification of its regulatory gene in stomach and esophageal cancer has resulted in targeted treatment directed at this protein. The fact itself and its consequences have been the topic of an abundance of studies and clinical trials. In the present report we review the current state of the art as regards diagnosis of the over expression and amplification of Her-2/neu, its inhibition as a new therapeutic concept, treatment toxicity, and the development of resistance to Her-2/neu as a limiting factor in stomach and esophageal adenocarcinoma. PMID- 21783380 TI - Estimating viral titres in solutions with low viral loads. AB - An important consideration in the manufacture of products derived from animal or human sources is the virus reduction capacity of the manufacturing process as estimated using validated bench-scale models of relevant manufacturing steps. In these studies, manufacturing process intermediates are spiked with virus and processed using the bench-scale model and the resulting viral titres of input and output samples are typically determined using cell-based infectivity assays. In these assays, the Spearman-Karber (SK) method is commonly used to estimate titres when there is one or more positive observation (i.e., the presence of any viral cytopathic effect). The SK method is most accurate when the proportion of positive observations ranges from <0.1 to >0.9 across dilutions but can be biased otherwise. Maximum likelihood (ML) based on a single-hit Poisson model is an alternative widely used estimation method. We compared SK with ML and found the methods to have similar properties except for situations in which the concentration of virus is low but measurable. In this case, the SK method produces upwardly biased estimates of titres. Based on our results, we recommend the use of either ML or SK at most virus concentrations; however, at low virus concentrations ML is preferred. PMID- 21783381 TI - Registration of similar biological products--Singapore's approach. AB - The expiration of patents on many biological medicinal products has prompted the development of these products as similar biological (biosimilar) products. The standard approach of demonstration of bioequivalence for chemical generic products is scientifically not applicable for biosimilar products. The biosimilar product approach, based on comparability (demonstration of similarity), should be adopted. In view of the impending submissions and to facilitate access of such products at a more affordable price in Singapore, the Health Sciences Authority (HSA) formalised the procedures and requirements for registration of biosimilar products in 2009. HSA has published the "Guideline on Registration of Similar Biological Products in Singapore" which describes the basic principles, submission procedure, and requirements pertaining to documentation, pharmacovigilance, and post-approval batch release for the registration of biosimilar products. This article provides a brief overview as well as key points on the registration of medicinal products and biosimilar products in Singapore. PMID- 21783382 TI - The first subsequent entry biologic authorized for market in Canada: the story of Omnitrope, a recombinant human growth hormone. AB - Omnitrope is the first Subsequent Entry Biologic (SEB)/Similar Biotherapeutic Product (SBP) filed with Health Canada, for purposes of marketing. Health Canada is the home organization of the Regulatory Authority in Canada. As the first SEB to be filed for actual review, it presented unique challenges. While the principles for the review and approval of a SEB were laid out in a "fact sheet" there remained still a guidance to be drafted. The review of the submissions proceeded in parallel with the development of the guideline. This article will provide the details of how the final decision was arrived at and how that decision validated the principles underlying the guidance document, in the absence of direct regulations specifically addressing SEBs in Canada. PMID- 21783383 TI - Permanent pacemaker implantation early and late after heart transplantation: clinical indication, risk factors and prognostic implications. AB - BACKGROUND: Permanent pacemaker implantation (PPM) early after cardiac transplantation has been shown not to predict a worse outcome. However, the requirement for pacing late after transplantation and its prognostic implications are not fully known. We describe the clinical indications, risk factors and long term outcome in patients who required pacing early and late after transplantation. METHODS: The transplant database, medical records and pacing database/records were reviewed for all patients undergoing de novo orthotopic cardiac transplantation (n = 389) at our institution between January 1995 and May 2006. RESULTS: A total of 48 patients (12.3%) received a pacemaker after transplantation. Of these patients, 30 were paced early, pre-hospital discharge (25 +/- 19 days post-transplantation), and 18 patients had late pacing (3.0 +/- 3.3 years post-transplantation). There were no differences in clinical characteristics, use of anti-arrhythmic drugs or length-of-stay post transplantation between early and late groups. Early indications for pacing were more often sino-atrial (SA) disease (24 of 30, 80%), whereas atrio-ventricular (AV) disease was more likely to occur later (p = 0.03). Risk factors for PPM included use of biatrial anastomosis (p = 0.001) and donor age (p = 0.002). Prior rejection was a univariate but not multivariate (p = 0.09) predictor of the need for PPM. Development of cardiac allograft vasculopathy was not predictive. There was no significant difference in mortality between late and early PPM patients or between late PPM patients and the non-paced patients who survived transplantation and initial stay. CONCLUSIONS: Patients who required PPM late after orthotopic cardiac transplantation had a prognosis comparable to those paced early and those who did not require PPM. The independent risk factors for PPM were biatrial anastomosis and increasing donor age. SA-nodal dysfunction as an indication for PPM was more prevalent early after transplantation, whereas atrioventricular (AV) disease more commonly presented late. The requirement for pacing late after transplantation was not associated with rejection or cardiac allograft vasculopathy. PMID- 21783384 TI - A three-dimensional analysis of humeral head retroversion. AB - INTRODUCTION: The anatomic neck of the humerus is used as a reference for the osteotomy in shoulder arthroplasty. Resection along the anterior portion of the cartilage/metaphyseal border is assumed to remove a cap of a sphere that can accurately be replaced with a spherical prosthetic implant oriented precisely to the original articular surface. The aim of this study was to determine the variability in retroversion of the cartilage/metaphyseal interface in the axial plane. METHODS: Surface topography data for 24 arms from deceased donors were collected by using a hand-held digitizer and a surface laser scanner. Data were combined into the same coordinate system and graphically presented. The humeral head was divided into 6 sections in the axial plane and the retroversion angle measured at each level with reference to the transepicondylar axis at the elbow. RESULTS: The mean retroversion of the humeral head at the midpoint between the superior and inferior margins was 18.6 degrees . The angle increased as the position of the measurement moved superiorly to 22.5 degrees . In contrast, the retroversion angle reduced as the position of measurement moved more inferiorly to 14.3 degrees . DISCUSSION: The results suggest that the cartilage/metaphyseal interface is not circular encompassing a spherical cap of a sphere. Furthermore, there appears to be a clockwise torsion of the cartilage/metaphyseal interface about the transverse axis from its medial to lateral aspect. CONCLUSION: The cartilage/metaphyseal interface shows a degree of variability that makes it an unreliable landmark to perform an osteotomy when the anterior aspect of the interface is used. PMID- 21783385 TI - Hemiarthroplasty versus nonoperative treatment of displaced 4-part proximal humeral fractures in elderly patients: a randomized controlled trial. AB - BACKGROUND: The aim of the study was to report the 2-year outcome after a displaced 4-part fracture of the proximal humerus in elderly patients randomized to treatment with a hemiarthroplasty (HA) or nonoperative treatment. PATIENTS AND METHODS: We included 55 patients, mean age 77 (range, 58-92) years, 86% being women. Follow-up examinations were done at 4, 12, and 24 months. The main outcome measures were health-related quality of life (HRQoL) according to the EQ-5D and the DASH and Constant scores. RESULTS: At the final 2-year follow-up the HRQoL was significantly better in the HA group compared to the nonoperative group, EQ 5D (index) score 0.81 compared to 0.65 (P = .02). The results for DASH and pain assessment were both in favor of the HA group, DASH score 30 versus 37 (P = .25) and pain according to VAS 15 versus 25 (P = .17). There were no significant differences regarding the Constant score or range of motion (ROM). Both groups achieved a mean flexion of approximately 90-95 degrees and a mean abduction of 85-90 degrees . The need for additional surgery was low: 3 patients in the HA group and 1 patient in the nonoperative group. CONCLUSION: The results of the study demonstrated a significant advantage in quality of life in favor of HA, as compared to nonoperative treatment in elderly patients with a displaced 4-part fracture of the proximal humerus. The main advantage of HA appeared to be less pain while there were no differences in ROM. PMID- 21783386 TI - Contrast-enhanced ultrasound characterization of the vascularity of the repaired rotator cuff tendon: short-term and intermediate-term follow-up. AB - BACKGROUND: The objectives of this study were to characterize and compare the vascularity of arthroscopically repaired rotator cuff tendons at short-term and intermediate-term follow-up. MATERIALS AND METHODS: Nineteen patients who underwent arthroscopic rotator cuff repair were prospectively monitored for an average of 21.2 months. Initial baseline, grayscale ultrasound images of the operated-on shoulder were obtained on all patients at 3 months and at a minimum of 10 months postoperatively. Perflutren-lipid microsphere contrast (DEFINITY, Lantheus Medical Imaging, North Billerica, MA, USA) was injected after baseline grayscale images and after exercise to obtain contrast-enhanced images of the repair. Three regions of interest--supraspinatus tendon, peribursal tissue, and bone anchor site--were evaluated before and after rotator cuff-specific exercises. RESULTS: The peribursal tissue demonstrated the greatest blood flow, followed by the bone anchor site and tendon, in pre-exercise and postexercise states. Significantly less blood flow was observed in all regions of interest before exercise (P < .05) and only at the bone anchor site after exercise (P < .001) at latest follow-up compared with the 3-month values. Intratendinous blood flow remained relatively low at both evaluation points after surgical repair. CONCLUSION: Preliminary findings suggest that the peribursal tissue and bone anchor site are the main conduits of blood flow for the rotator cuff tendon after arthroscopic repair, with the supraspinatus tendon being relatively avascular. Blood flow of the repaired rotator cuff tendon decreases with time. Furthermore, exercise significantly enhances blood flow to the repaired rotator cuff. PMID- 21783387 TI - A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry. AB - OBJECTIVE: Presurgical, window of opportunity trials have been proposed as a model to assess the activity of preventive and therapeutic interventions in a cost-effective manner in prostate cancer (CaP). The aim of the study was to explore karyometry as a method for monitoring the efficacy of intervention with preventive agents in patients with CaP. MATERIALS AND METHODS: The material used in this investigation was from the 2F study, i.e., an Italian prospective randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with CaP. Image analysis was performed in 16 cases treated with finasteride, 24 with flutamide, and 20 with placebo. For all these cases, CaP and normal looking secretory epithelium were present in the pretreatment biopsies as well as the post-treatment ex-vivo biopsies obtained from the radical prostatectomy specimens. RESULTS: To establish a direction of nuclear change from normal to malignancy, i.e., the so-called line of progression, a discriminant function was derived with the normal looking epithelium in the pretreatment biopsies as one endpoint, and the CaP in the pretreatment biopsies as the other. The discriminant function was then applied to the post-treatment groups. The increase in relative nuclear area was the dominant feature. In the placebo group, 15 out of 20 CaP (75%) cases had a higher discriminant function score at the end of study, with a significant increase of the mean score by 90%. The flutamide treated CaP cases had increased discriminant function scores in 19 out of 24 cases (79%) and an increase of the mean score by 43%; the 5 cases with lower scores involved only minor reductions. In contrast, the finasteride treated CaP cases had increased discriminant function scores for 8 out of 16 cases (50%), but the increase in the mean score was by only 8%. CONCLUSION: This exploratory study establishes that karyometric monitoring can track the results of subtle nuclear changes induced by preventive interventions in men with CaP, thus allowing assessment of agent activity in a cost-effective manner. PMID- 21783388 TI - Heterogeneity in surveillance after endovascular aneurysm repair in the UK. AB - OBJECTIVES: Surveillance after Endovascular Aneurysm Repair (EVAR) is considered mandatory, but the optimal regimen remains controversial. The aim of the present study was to report the nature of routine post-EVAR surveillance protocols in the UK, in order to identify the degree of variation in national practice and from the manufacturer's instructions for use (IFU). METHODS: A telephone survey was administered to 41 centres with 10 years' experience in EVAR to identify their standard surveillance protocol after EVAR. Data were collected regarding the number of surveillance CT or ultrasound performed up to 5 years postoperatively. RESULTS: 12/41 centres used CT as the primary mode of surveillance, 14/41 centres used USS as the primary mode of surveillance, and 15/41 centres used a combination of CT and USS. The mean +/- s.d. number of CT scans performed cumulatively up to 1 year and 5 years post surgery were 1.1 +/- 0.6 and 3.5 +/- 2.9 respectively. The mean +/- s.d. ultrasound scans performed at 1 year and 5 years post surgery were 0.5 +/- 0.9 and 4.7 +/- 3.6 respectively. CONCLUSIONS: Significant heterogeneity exists in surveillance after EVAR in the UK. Efforts should be made to establish consensus towards a national surveillance protocol. PMID- 21783389 TI - Increased oxidative metabolism is associated with erythroid precursor expansion in beta0-thalassaemia/Hb E disease. AB - Erythropoiesis in beta0-thalassaemia/Hb E patients, the most common variant form of beta-thalassaemia in Southeast Asia, is characterized by accelerated differentiation and over-expansion of erythroid precursor cells. The mechanism driving this accelerated expansion and differentiation remain unknown. To address this issue a proteomic analysis was undertaken to firstly identify proteins differentially expressed during erythroblast differentiation and a second analysis was undertaken to identify proteins differentially expressed between beta0-thalassaemia/Hb E erythroblasts and control erythroblasts. The majority of proteins identified as being differentially expressed between beta0 thalassaemia/Hb E and control erythroblasts were constituents of the glycolysis/TCA pathway and levels of oxidative stress correlated with the degree of erythroid expansion. A model was constructed linking these observations with previous studies showing increased phosphorylation of ERK1/2 in thalassemic erythroblasts which predicted the increased activation of PKA, PKB and PKC which Western analysis confirmed. Inhibition of PKA or PKC reduced beta0 thalassaemia/Hb E erythroblast differentiation and/or expansion. We propose that increased expansion and differentiation of beta0-thalassaemia/Hb E erythroblasts occur as a result of feedback loops acting through increased oxidative metabolism. PMID- 21783390 TI - Rapid, accurate detection of TMPRSS6 gene causative mutations with a high resolution melting assay. AB - Mutations of the TMPRSS6 gene are considered the major genetic factors for iron refractory iron deficiency anemia (IRIDA). Artificial clone libraries containing 17 known mutations of the TMPRSS6 gene were used to develop a high-resolution melting (HRM) assay for the detection of 17 TMPRSS6 gene mutations. The melting temperatures and melting curves were able to distinguish the different genotypes of the 17 TMPRSS6 gene mutations. We used replicate experiments to evaluate the reproducibility of the assay, and the coefficients of variation were in the range 0.0091% to 0.0873%. A total of 145 Chinese patients with IDA were screened with this assay and no TMPRSS6 gene causative mutation was found in any patient. The HRM assay was proved to be rapid, accurate and cost-effective method to identify the TMPRSS6 gene mutations and can be used in the clinical diagnosis of IRIDA. PMID- 21783391 TI - Primary cerebral arteritis in a young girl: an unusual cause of acute recurrent neurological deterioration. AB - BACKGROUND: Primary angiitis of the central nervous system (PACNS) is an idiopathic, usually recurrent vasculitis confined to the brain. PACNS has been reported rarely in children, although the disease is probably underdiagnosed. CLINICAL CASE: : We report the clinical history of a 3-year-old girl who presented subacute neurological deterioration characterised by headache, speech regression, and altered level of consciousness. Brain MRI revealed severe inflammatory lesions involving both grey and white matters. All blood and cerebrospinal fluid (CSF) tests for inflammatory or infectious processes were negative. Over the next 10 years, the patient relapsed eight times. Brain biopsy confirmed lesions suggestive of cerebral vasculitis. Based on histopathological features and due to the absence of systemic vasculitis, the patient was considered to have PACNS. She developed partial epilepsy, and clinical stabilisation was finally achieved via continuous oral corticosteroids and immunosuppressive agents. CONCLUSION: PACNS may be the cause of subacute and relapsing inflammatory encephalopathy in children after excluding other diagnoses, such as multiple sclerosis, sarcoidosis, recurrent acute disseminated encephalomyelitis (ADEM), and primary central nervous system lymphoma. Brain biopsy is necessary to confirm the diagnosis of PACNS and exclude diseases with similar symptoms. Neurological outcome remains poor. PMID- 21783392 TI - Morphometry and diffusion MR imaging years after childhood traumatic brain injury. AB - OBJECTIVE: Our goal was to detect possible unrecognized injury in cerebral white matter (WM) in adult survivors of traumatic brain injury (TBI) during childhood, who showed no detectable axonal injury or chronic contusion on late conventional MRI. MATERIAL AND METHODS: We used voxel-based morphometry (VBM) to detect subtle structural changes in brain morphology and diffusion-tensor imaging (DTI) to non invasively probe WM integrity. By means of VBM and DTI we examined a group of 12 adult patients who suffered from childhood closed head injury without axonal injury on late conventional MRI. RESULTS: Patients sustained complicated mild or moderate-to-severe TBI with a mean of 7 points based on the Glasgow Coma Scale. The mean time after trauma was 19 years (range 7-31 years). For VBM, group comparisons of segmented T1-weighted grey matter and WM images were performed, while for DTI we compared the fractional anisotropy and mean diffusivity (MD) between the groups. Patients presented with higher MD in the right cerebral white matter, bilaterally in the forceps major and in the body and splenium of the corpus callosum. These findings were supported by VBM, which showed reduced WM volume bilaterally, mainly along the callosal splenium. CONCLUSION: Our results indicate that persistent focal long-term volume reduction and underlying WM structural changes may occur after TBI during childhood and that their effects extend into adulthood. Normal late conventional MR findings after childhood TBI do not rule out non-apparent axonal injury. PMID- 21783393 TI - What could predict effectiveness of Botulinum Toxin to treat drooling: a search for evidence of discriminatory factors on the level of body functions or structures. AB - BACKGROUND: The treatment of drooling is important to families that experience the daily impact and research to elucidate clinical factors that play a role in the outcome of drooling treatment should be encouraged. AIM: To define clinical factors that influence therapy outcome of submandibular Botulinum Toxin (BoNT-A) injections for drooling. METHODS: Prospectively collected data of 128 children with cerebral palsy were evaluated; 80 spastic and 48 dyskinetic movement disorder, mostly Gross Motor Function Classification System III and higher; over 70% had an IQ <70. In addition, 23 fully ambulant children with exclusively intellectual disability were treated for drooling by ultrasound-guided injections of BoNT-A into the submandibular glands. Salivary flow rates and drooling quotients were measured at baseline and at 8 weeks after injection. Extensive information about the oral motor performance was gathered. Successful clinical response was defined as a 50% reduction of the baseline Drooling Quotient; 85 children were responsive to BoNT-A and 66 children unresponsive. RESULTS: Five nominated clinical factors that possibly could influence saliva reduction (head position, lip seal, voluntary control over the tongue, control of voluntary movement functions, and mental age) did not influence the responsiveness to BoNT A. INTERPRETATION: Other variables need to be considered to predict the outcome of BoNT-A treatment. This article describes the first attempt to reveal the contribution of body functions and structures to the outcome of BoNT-A submandibular injections. PMID- 21783394 TI - Systems wide analyses of lipids in the brainstem during inflammatory orofacial pain - evidence of increased phospholipase A(2) activity. AB - Recent studies suggest that CNS phospholipase A(2) (PLA(2) ) isoforms play a role in nociception, but until now, direct evidence of increased brain PLA(2) activity during allodynia or hyperalgesia is lacking. The present study was carried out, using lipidomics or systems wide analyses of lipids using tandem mass spectrometry, to elucidate possible changes in rat brain lipids after inflammatory pain induced by facial carrageenan injection. The caudal medulla oblongata showed decreases in phospholipids including phosphatidylethanolamine and phosphatidylinositol species, but increases in lysophospholipids, including lysophosphatidylethanolamine, lysophosphatidylinositol and lysophosphatidylserine, indicating increased PLA(2) activity and release of arachidonic acid after facial carrageenan injection. These changes likely occur in the spinal trigeminal nucleus which relays nociceptive input from the orofacial region. High levels of sPLA(2) -III, sPLA(2) -XIIA, cPLA(2) and iPLA(2) mRNA expression were detected in the medulla oblongata. Increase in sPLA(2) -III mRNA expression was found in the caudal medulla of carrageenan injected rats, although no difference in sPLA(2) -III protein expression was detected. The changes in lipids as determined by lipidomics were therefore consistent with an increase in PLA(2) enzyme activity, but no change in enzyme protein expression. Together, these findings indicate enhanced PLA(2) activity in the caudal medulla oblongata after inflammatory orofacial pain. PMID- 21783395 TI - Zeeman shift--a tool for assignment of 14N NQR lines of nonequivalent 14N atoms in powder samples. AB - The use of Zeeman perturbed 14N nuclear quadrupole resonance (NQR) to determine the nu+ and nu-14N lines in polycrystalline samples with several nonequivalent nitrogen atoms was investigated. The 14N NQR line shift due to a weak external Zeeman magnetic field was calculated, assuming isotropic distribution of EFG tensor directions. We calculated the broad line distribution of the nu+ and nu- line shifts and experimentally confirmed the calculated Zeeman field dependence of singularities (NQR peaks) in cyclotrimethylenetrinitramine (RDX) and aminotetrazole monohydrate (ATMH). The calculated and measured frequency shifts agreed well. The proposed measurement method enabled determination of which 14N NQR lines in ATMH belong to nu+ and which to nu- transitions. PMID- 21783396 TI - [Use, implementation and impact of the TEDDY network in Europe]. PMID- 21783397 TI - [Ethical and legal responsibility of the hospital pharmacist]. PMID- 21783398 TI - [Identification of simple safe practices in a primary care area]. AB - OBJECTIVES: To assess the safe practices (SP) prepared by the Health Risk Management Functional Unit (UFGRS), according to their complexity of introduction and the impact on patient safety, and to identify simple SP. MATERIAL AND METHODS: A number of important SP have been prepared by the UFGRS of Madrid Health Area 4 Primary Care (PC). They were subsequently assessed according to their complexity of introduction and their potential impact on patient safety, simple SP (SSP) for the prevention of adverse events, low complexity of introduction and impact on patient safety. Lastly, the barriers to their effective introduction were identified, and actions were designed to overcome these barriers. RESULTS: Of the 50 PS prepared, 42 have been applied in the whole Area. Seven Level 1 SP (which fulfil the ideal conditions) were identified as simple SP. The main barriers were due to lack of training, culture, leadership of the management teams and professionals of the centre and lack of knowledge of the SPs. CONCLUSIONS: A large number of SP has been prepared by the UFGRS, with simple SP being identified for PC. The majority of these have to do with the safe use of drugs and vaccines. PMID- 21783399 TI - [Pathogen inactivation technologies: a complex but necessary debate]. PMID- 21783400 TI - [Pathogen inactivation of platelets: organization consequences for platelet transfusion]. AB - In the past few years, pathogen reduction technologies for labile blood products have been part of the enhancement of global transfusion safety regarding residual risks of transmitting infectious pathogens. Having carried out a feasibility study for the implementation of pathogen inactivation of platelet concentrates by means of the amotosalen/HCl/UVA (InterceptTM) technology, and participated to a reinforced haemovigilance study, we took the opportunity to analyze the organization consequences for platelet concentrates inventory and distribution. This impact study first indicated that those novel needs forced the blood donation service, as well as the labile blood product preparation laboratory, to review and improve practices; secondly, it showed that the routine implementation has little (no major) consequence in the overall organization, independently of the economic consequences (not covered here). PMID- 21783401 TI - State of the art technologies in drug discovery 2011. PMID- 21783402 TI - Dominant genetic aberrations and coexistent EBV infection in HIV-related oral plasmablastic lymphomas. AB - We present common cytogenetic features in the largest cohort of plasmablastic lymphoma (PBL) of the oral cavity published to date. This cohort included 45 patients, 32 of whom had a known HIV status, of which 31 were HIV positive. Ninety eight per cent of all PBL cases were known to be EBV positive. In line with previous studies, we found that rearrangements of the MYC gene was the most common genetic abnormality seen in 60% of cases with the immunoglobulin heavy chain (IGH) locus as a partner in 51% of cases. Additional complex genetic aberrations were frequent, in particular, an increased copy number of the CCND1 gene was seen in 41% of cases with true amplification of CCND1 in 15% of cases. Aneuploidy was also observed for the BCL6 gene in 28% of cases. Interestingly, rearrangements of both IGH genes were detected in 16% of cases with t(14;18) and t(11;14) respectively involved in conjunction with a t(8;14) in two cases. These bi-allelic IGH rearrangements have not been described before in oral PBL. Our results reinforce the notion that EBV infection and MYC rearrangements are important events in the pathogenesis of oral PBL. The genetic diversity and complexity observed in these cases, underlines the importance to genetically characterise PBL patients at presentation as this may inform the choice of more effective treatment modalities. PMID- 21783403 TI - Intensity-modulated radiotherapy (IMRT)/Tomotherapy following neoadjuvant chemotherapy in stage IIB-IVA/B undifferentiated nasopharyngeal carcinomas (UCNT): a mono-institutional experience. AB - To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3-64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a-2b and T3-T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach. PMID- 21783404 TI - Bacteriophage-host interactions leading to genome internalization. AB - Bacteriophage infection is initiated by binding of the virion to a specific receptor located on the host surface. The genome is then released from the capsid and delivered to the host cytoplasm. Our knowledge of these early steps of infection has recently improved. The three-dimensional structure of numerous receptor binding proteins of tailed phages has been solved. Cryo-electron tomography has allowed characterization of the phage-host interactions in a cellular context and at nanometric resolution. The localization and motions of fluorescently labelled phages, receptors and viral DNA were monitored on individual bacteria. Altogether these approaches have revealed the intricacy of these early events and emphasize the link between infection and microbial architecture. PMID- 21783405 TI - The IRG protein-based resistance mechanism in mice and its relation to virulence in Toxoplasma gondii. AB - IRG proteins (immunity-related GTPases) provide an early defense mechanism in mice against the protozoal pathogen, Toxoplasma gondii. This is a particularly suitable time to provide a brief review of this host-pathogen interaction because the nature of the IRG resistance system, and to some extent its mode of action, have become known in the past few years. Likewise, forward genetic screens have recently drawn attention to a number of loci contributing to the differential virulence of T. gondii strains in mice. It is now clear that at least some important virulence mechanisms exert their action against components of the IRG resistance system. Thus these two mechanisms form the two poles of a dynamic host pathogen virulence-resistance relationship with interesting and accessible properties. PMID- 21783406 TI - Studies of the optical band positions and EPR g factors for Cu(H2O)6(2+) centers in Tutton salt crystals. AB - The optical band positions and EPR g factors g(i) (i = x, y, z) of Cu(H(2)O)(6)(2+) clusters in pure Tutton salts M(2)Cu(SO(4))(2).6H(2)O (M = NH(4), Rb) are calculated from the complete diagonalization (of energy matrix) method based on the cluster approach. In the calculation, the superposition model with the structural data is used to obtain the crystal-field parameters. The calculated results are in reasonable agreement with the experimental values, suggesting that the complete diagonalization method and superposition model are effective in the studies of optical and EPR data. The g factors g(i) of Cu(H(2)O)(6)(2+) clusters in Cu(2+)-doped isomorphous diamagnetic Tutton salts M(2)Zn(SO(4))(2).6H(2)O are also studied from the same method. It is found that the approximately tetragonally compressed Zn(H(2)O)(6)(2+) octahedra in the host crystals change to the approximately tetragonally elongated Cu(H(2)O)(6)(2+) octahedra in the impurity centers. The causes concerning the Jahn-Teller effect are discussed. It appears that in some cases the octahedral environment of an impurity M(I) in crystals differs from that of the replaced host ion, but is close to the one in the isomorphous pure crystals where M(I) is the host ion rather than the impurity ion. PMID- 21783407 TI - Synthesis, thermal and spectral characterization of nanosized Ni(x)Mg(1-x)Al2O4 powders as new ceramic pigments via combustion route using 3-methylpyrozole-5-one as fuel. AB - New Ni(x)Mg(1-x)Al(2)O(4) nanosized in different composition (0.1<=x<=0.8) powders have been synthesized successively for first time by using low temperature combustion reaction (LTCR) of corresponding metal chlorides, carbonates and nitrates as salts with 3-methylpyrozole-5-one (3MP5O) as fuel at 300 degrees C in open air furnace. Magnesium aluminate spinel (MgAl(2)O(4)) was used as crystalline host network for the synthesis of nickel-based nano ceramic pigments. The structure of prepared samples was characterized by using different techniques such as thermal analysis (TG-DTG/DTA), X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). UV/Visible and Diffuse reflectance spectroscopy (DRS) using CIE L*a*b* parameters methods have been used for color measurements. The obtained results reveal that Ni(x)Mg(1-x)Al(2)O(4) powder of samples is formed in the single crystalline and pure phase with average particle size of 6.35-33.11 nm in the temperature range 500-1200 degrees C. The density, particle size, shape and color are determined for all prepared samples with different calcination time and temperature. PMID- 21783408 TI - A logic programming approach to medical errors in imaging. AB - BACKGROUND: In 2000, the Institute of Medicine reported disturbing numbers on the scope it covers and the impact of medical error in the process of health delivery. Nevertheless, a solution to this problem may lie on the adoption of adverse event reporting and learning systems that can help to identify hazards and risks. It is crucial to apply models to identify the adverse events root causes, enhance the sharing of knowledge and experience. The efficiency of the efforts to improve patient safety has been frustratingly slow. Some of this insufficiency of progress may be assigned to the lack of systems that take into account the characteristic of the information about the real world. In our daily lives, we formulate most of our decisions normally based on incomplete, uncertain and even forbidden or contradictory information. One's knowledge is less based on exact facts and more on hypothesis, perceptions or indications. PURPOSE: From the data collected on our adverse event treatment and learning system on medical imaging, and through the use of Extended Logic Programming to knowledge representation and reasoning, and the exploitation of new methodologies for problem solving, namely those based on the perception of what is an agent and/or multi-agent systems, we intend to generate reports that identify the most relevant causes of error and define improvement strategies, concluding about the impact, place of occurrence, form or type of event recorded in the healthcare institutions. RESULTS AND CONCLUSIONS: The Eindhoven Classification Model was extended and adapted to the medical imaging field and used to classify adverse events root causes. Extended Logic Programming was used for knowledge representation with defective information, allowing for the modelling of the universe of discourse in terms of data and knowledge default. A systematization of the evolution of the body of knowledge about Quality of Information embedded in the Root Cause Analysis was accomplished. An adverse event reporting and learning system was developed based on the presented approach to medical errors in imaging. This system was deployed in two Portuguese healthcare institutions, with an appealing outcome. The system enabled to verify that the majority of occurrences were concentrated in a few events that could be avoided. The developed system allowed automatic knowledge extraction, enabling report generation with strategies for the improvement of quality-of-care. PMID- 21783409 TI - Effects of a computerized decision support system on pressure ulcers and malnutrition in nursing homes for the elderly. AB - BACKGROUND: Computerized decision support systems (CDSSs) have been shown to help health care professionals to avoid errors and improve clinical practice and efficiency in health care. Little is known about its influence on nursing practice and outcomes for residents in nursing homes. AIM: The aim of this study was to evaluate the effects on the risk for and prevalence of pressure ulcers (PUs) and malnutrition of implementing a CDSS to improve prevention and care of PUs and also to improve nutrition in the elderly in nursing homes. DESIGN SETTING AND PARTICIPANTS: The study used a quasi-experimental design with two intervention groups and one control group. A convenience sample of residents from 46 units in 15 nursing homes in rural areas in Norway was included. A total of 491 residents participated at baseline in 2007 and 480 residents at follow-up in 2009. METHODS: The intervention included educational sessions in prevention of PUs and malnutrition for registered nurses (RNs) and nursing aides (NAs) in the two intervention groups. In addition, one intervention group (intervention group 1) had a CDSS integrated into the electronic healthcare record (EHR) based on two research-based risk assessment instruments: the Risk Assessment Pressure Scale (RAPS) for PU risk screening and the Mini Nutritional Assessment (MNA((r))) scale for screening nutritional status. In each participating nursing home trained RNs and NAs examined all residents who consented to participate on the RAPS and the MNA((r)) scale. This examination included a skin assessment and details about PUs were collected. RESULTS: The proportion of malnourished residents decreased significantly in intervention group 1 between the two data collection periods (2007 and 2009). No other significant effects of the CDSS on resident outcomes based on the RAPS and MNA((r)) scores were found. CONCLUSION: CDSSs used by RNs and NAs in nursing homes are still largely unexplored. A CDSS can be incorporated into the EHR to increase the meaningful use of these computerized systems in nursing home care. The effects of CDSS on healthcare provider workflow, clinical decision making and communication about preventive measures in nursing home practice still need further exploration. Based on results from our study, recommendations would be to increase both sample size and the number of RNs and NAs who participate in CDSS education programs. PMID- 21783410 TI - Narrow antagonistic activity of antimicrobial peptide from Bacillus subtilis SCK 2 against Bacillus cereus. AB - Bacillus subtilis SCK-2, producing an antimicrobial peptide of this study, was isolated from Kyeopjang, the Korean traditional fermented-soybean paste. This strain showed a narrow antagonistic activity as it inhibited Bacillus cereus causing food poisoning in human. The antimicrobial peptide, tentatively named AMP IC-1, was purified, characterized, and compared to BSAP-254, another peptide which was previously recovered from traditionally fermented-soybean paste. AMP IC 1 was found to be more thermally stable than BSAP-254, retained inhibitory activity similar to that of BSAP-254 over wide range of pH values, and was also destroyed by proteolytic enzymes. Two compounds were detected by anti-BSAP-254 polyclonal antibody and showed to contain peptide moieties and aliphatic hydrocarbons by Fourier transform infrared analysis. AMP IC-1 had an identical R(f) value (0.69) on TLC plate and a molecular weight similar to that of BSAP-254 (AMP IC-1, m/z 3401; BSAP-254, m/z 3400 to 3473). AMP IC-1 was found to contain about 33 residues and 13 types of amino acids: Cys, Asp or Asn, Glu or Gln, Ser, Gly, Arg, Thr, Ala, Pro, Val, Ile, Leu, and Lys. Compared to BSAP-254, the molar ratios of Asp or Asn, Ser, Val, and Leu were different and only AMP IC-1 contained Arg, but not Trp. Both compounds showed non-hemolytic activity. A partial synergistic effect against B. cereus was observed in response to treatment when AMP IC-1 and BSAP-254 were administered in combination. Therefore, AMP IC-1 is a possible candidate as an antimicrobial agent to prevent food-borne infectious disease in human caused by B. cereus. PMID- 21783411 TI - Fc domain mediated self-association of an IgG1 monoclonal antibody under a low ionic strength condition. AB - Recently, we reported that IgG1 monoclonal antibody A (MAb A) underwent liquid liquid phase separation and separated into light and heavy phases under a low ionic strength condition. The liquid-liquid phase separation was induced due to self-association of MAb A in the heavy phase when the initial concentration of MAb A was between the two critical concentrations [Nishi et al., Pharm. Res., 27, 1348-1360 (2010)]. Here, we determined the interaction site of MAb A by using proteolytic Fab and Fc fragments of MAb A. The mean hydrodynamic diameter of the Fc fragment increased in a low ionic strength buffer, and furthermore the SPR measurement detected interactions of the Fc fragment with both whole MAb A and the Fc fragment, whereas the Fab fragment interacted with neither whole MAb A nor the Fc fragment. No binding was detected under an isotonic ionic strength condition. Zeta potential of MAb A was significant positive below pH 5.5 and negative above pH 6.5. Between pH 5.5 and 6.5 where the phase separation is significantly induced, MAb A had only a small positive or negative net charge. The isothermal titration calorimetry dilution method revealed that dissociation of MAb A accompanied endothermic heat changes, suggesting that intermolecular interactions among MAb A molecules were attributed to the enthalpically driven process. These results suggest that liquid-liquid phase separation of MAb A is mediated by a weak electrostatic intermolecular interaction among MAb A molecules mainly at Fc portions. PMID- 21783412 TI - New genera, species, and improved phylogeny of Glissomonadida (Cercozoa). AB - Glissomonadida is an important cercozoan order of predominantly biflagellate gliding bacterivores found largely in soil and freshwater. Their vast diversity is largely undescribed. We studied 23 mostly newly isolated strains by light microscopy and sequenced their 18S rDNA genes; nine represent new species. For two misidentified ATCC 'Heteromita triangularis' strains, we establish novel gliding genera and species: the sandonid Mollimonas lacrima, the only glissomonad forming anterior and posterior pseudopodia, and Dujardina stenomorpha, a strongly flattened member of the new family Dujardinidae. A new strain from Oxfordshire grassland soil is the first reliably identified isolate of the virtually uniflagellate, smooth-gliding glissomonad genus, AllantionSandon, 1924. Phylogenetic analysis and cytological features reveal Allantion to be a member of Allapsidae. Sandona limna and Bodomorpha prolixa from Lake Baikal and Sandona hexamutans from volcanic Costa Rican soil are described as new species. Fifteen glissomonad strains were from grassland beside Lake Baikal. We describe two as new species of Sandona (S. heptamutans and S. octamutans); the others included strains of Sandona and Allapsa species that have already been described; and three were new species of Sandona and Allapsa but these died before being described. We discuss the ecological and evolutionary significance of these new strains. PMID- 21783413 TI - A glance at Listeria and Salmonella cell invasion: different strategies to promote host actin polymerization. AB - The facultative intracellular bacterial pathogens Listeria monocytogenes and Salmonella enterica have evolved multiple strategies to invade a large panel of mammalian cells. These pathogens use the host cell actin system for invasion and became a paradigm for the study of host-pathogen interactions and bacterial adaptation to mammalian hosts. The key signaling component that these pathogens use to orchestrate actin remodeling is the Arp2/3 complex, which is related to polymerization of actin filaments. These bacterial pathogens are able to trigger distinct invasion mechanisms. On the one hand, L. monocytogenes invade a host cell in a way dependent on the specific interactions between bacterial and host cell proteins, which in turn activate the host cell actin polymerizing machinery that culminates with bacterial internalization. Also, Listeria escapes from the newly formed parasitophorous vacuole and moves among adjacent cells by triggering actin polymerization. On the other hand, Salmonella invades a host cell by delivering into the cytoplasm virulence factors which directly interact with host regulators of actin polymerization which leads to bacterial uptake. Moreover, Salmonella avoids vacuole lyses and modulates the early and late endosomal markers presented in the vacuole membrane. This mini-review focuses on the different pathways that L. monocytogenes and S. enterica activate to modulate the actin cytoskeleton in order to invade, to form the parasitophorous vacuole, and to migrate inside host cells. PMID- 21783414 TI - Outcomes sensitive to nursing service quality in ambulatory cancer chemotherapy: Systematic scoping review. AB - BACKGROUND: There is long standing interest in identifying patient outcomes that are sensitive to nursing care and an increasing number of systems that include outcomes in order to demonstrate or monitor the quality of nursing care. OBJECTIVE: We undertook scoping reviews of the literature in order to identify patient outcomes sensitive to the quality of nursing services in ambulatory cancer chemotherapy settings to guide the development of an outcomes-based quality measurement system. METHODS: A 2-stage scoping review to identify potential outcome areas which were subsequently assessed for their sensitivity to nursing was carried out. Data sources included the Cochrane Library, Medline, Embase, the British Nursing Index, Google and Google scholar. RESULTS: We identified a broad range of outcomes potentially sensitive to nursing. Individual trials support many nursing interventions but we found relatively little clear evidence of effect on outcomes derived from systematic reviews and no evidence associating characteristics of nursing services with outcomes. CONCLUSION: The purpose of identifying a set of outcomes as specifically nurse-sensitive for quality measurement is to give clear responsibility and create an expectation of strong clinical leadership by nurses in terms of monitoring and acting on results. It is important to select those outcomes that nurses have most impact upon. Patient experience, nausea, vomiting, mucositis and safe medication administration were outcome areas most likely to yield sensitive measures of nursing service quality in ambulatory cancer chemotherapy. PMID- 21783415 TI - Quality of life and barriers to symptom management in colon cancer. AB - PURPOSE OF THE RESEARCH: Pain and fatigue are recognized as critical symptoms that impact QOL for patients with colon cancer. Barriers to optimum pain and fatigue relief include patient-related beliefs and attitudes about the treatment of cancer-related symptoms. The overall objective of this paper was to describe quality of life (QOL) and barriers to pain and fatigue management in patients with colon cancer. METHODS AND SAMPLE: This longitudinal, descriptive study included was conducted in the ambulatory clinic of one NCI-designated comprehensive cancer center. A cohort of 56 patients with colon cancer and a pain and/or fatigue of >=4 (moderate to severe) was recruited. Subjects completed questionnaires to assess subjective ratings of overall QOL, fatigue, barriers to pain and fatigue, and pain and fatigue knowledge. KEY RESULTS: The majority of subjects (58%) reported having moderate to severe (4-6) fatigue at the time of accrual. Overall QOL score was moderate (M = 5.20, SD = 1.43), and the social well-being subscale had the lowest score (M = 4.57, SD = 1.82). Patient barriers to pain and fatigue existed in attitudes and beliefs regarding addiction, tolerance, and that fatigue is an inevitable part of cancer and its treatments. Patient knowledge of pain and fatigue was high (77%-88% correct), but lack of knowledge persisted in areas such as addiction to pain medications and utilizing physical activity to manage fatigue. CONCLUSIONS: Several patient-related attitudes and beliefs may hinder optimum relief of symptoms such as pain and fatigue. Social well-being may be a major determinant of overall QOL for patients with colon cancer. PMID- 21783416 TI - Anxiety, depression, traumatic stress and quality of life in colorectal cancer after different treatments: A study with Portuguese patients and their partners. AB - PURPOSE: This study examines the impact of different modes of treatment on depression, anxiety, traumatic stress and quality of life in colorectal cancer patients and their partners. METHODS: The sample was comprised of 114 oncology patients and 67 partners. All patients were diagnosed with colorectal cancer. Participants were recruited from an Oncology Hospital in the North of Portugal and had been submitted to three modes of treatment: surgery, surgery plus chemotherapy or surgery followed by radiotherapy. RESULTS: The results showed that patients who received only surgery, as treatment, had lower levels of depression, anxiety and traumatic stress symptoms when compared with patients who received surgery and chemotherapy or surgery plus radiotherapy. Partners of surgical patients presented lower levels of state anxiety and traumatic stress symptoms when compared with the other two groups. Patients with more depression had partners also more depressed. No relationship was found between anxiety and traumatic stress symptoms in patients and partners. Patients who received a diagnosis longer than 12 months had more traumatic stress, intrusion and hypervigilance. Patients with illness recurrence showed more traumatic symptoms. Anxiety and depression were the main predictors of patient's quality of life. Traumatic stress was a predictor of symptom distress - pain/bowel pattern. CONCLUSION: This study highlights the importance of providing psychological interventions for cancer patients and their partners. Chemotherapy patients and those diagnosed over a year, as well as their partners, are more at risk. PMID- 21783417 TI - Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. AB - BACKGROUND: Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. METHODS: We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up. FINDINGS: 83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]). INTERPRETATION: Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. FUNDING: F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality. PMID- 21783418 TI - Erlotinib, gefitinib, or chemotherapy for EGFR mutation-positive lung cancer? PMID- 21783419 TI - Understanding pharmacology in humans: Phase I and Phase II (data generation). AB - The discovery of novel drugs is a complex and highly regulated process organized around a critical moment, that is, when the novel compound is tested in humans. This process encompasses a series of clinical studies, identified as Phase I and Phase II, whose composite outcome should deliver the data needed for an informed decision about progressing or not the compound in full development (Phase III). Over the last 10 years the global delivery of novel treatments from the pharmaceutical industry has plunged to the level of the '70ies in spite of a 10 fold larger investment, the differential mostly due to failures in Phase III. There is the need to improve the decision making at the early clinical stage by using innovation and the high-profile achievements of basic science generated in academic and biomedical labs. A specific attention should be paid to applied biotechnologies, in particular nanotechnology and biomedical devices not only for drug deliver but also for biomarker detection. This path, also supported by regulatory agencies, is calling for an important change of perspective about how drug discovery is made, which we believe should start from the full implementation of the paradigm of Translational Medicine. PMID- 21783421 TI - From genome-wide association studies to etiology: probing autoimmunity genes by RNAi. AB - Autoimmunity cannot yet be prevented or cured, in large part due to our poor understanding of disease etiology. Remarkable advances in genomic technology have recently enabled the discovery of a large number of disease-associated gene variations by genome-wide association studies. The next step towards understanding autoimmune disorders entails the functional study of susceptibility genes within experimental disease models. RNA interference (RNAi) is a promising tool for such investigations. Several features of RNAi, including its specificity, versatility and reversible nature, allow experimental systems to be tailored to relevant gene variations. This review discusses how the experimental use of RNAi is invaluable in bridging the gap between the identification of susceptibility genes and the elucidation of their functional contribution to autoimmune disease. PMID- 21783423 TI - Advances in transfusion medicine in the first decade of the 21st century. PMID- 21783420 TI - Orchestrating house dust mite-associated allergy in the lung. AB - House dust mites (HDM; Dermatophagoides sp.) are one of the commonest aeroallergens worldwide and up to 85% of asthmatics are typically HDM allergic. Allergenicity is associated both with the mites themselves and with ligands derived from mite-associated bacterial and fungal products. Murine models of allergic airways disease for asthma research have recently switched from the use of surrogate allergen ovalbumin together with adjuvant to use of the HDM extract. This has accelerated understanding of how adaptive and innate immunity generate downstream pathology. We review the myriad ways in which HDM allergic responses are orchestrated. Understanding the molecular pathways that elicit HDM-associated pathology is likely to reveal novel targets for therapeutic intervention. PMID- 21783422 TI - TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. AB - Given the critical role for TDP-43 in diverse neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), there has been a recent surge in efforts to understand the normal functions of TDP-43 and the molecular basis of dysregulation that occurs in TDP-43 proteinopathies. Here, we highlight recent findings examining TDP-43 molecular functions with particular emphasis on stress-mediated regulation of TDP-43 localization, putative downstream TDP-43 target genes and RNAs, as well as TDP-43 interacting proteins, all of which represent viable points of therapeutic intervention for ALS, FTLD-TDP and related proteinopathies. Finally, we review current mouse models of TDP-43 and discuss their similarities and potential relevance to human TDP-43 proteinopathies including ALS and FTLD-TDP. PMID- 21783424 TI - Role of radiotherapy treatment of uterine sarcoma. AB - Uterine sarcomas are rare and, consequently, data supporting the use of adjuvant radiotherapy in uterine sarcomas consist of few randomised studies and multiple single-institution retrospective reports. It is becoming increasingly clear that each histologic subtype of uterine sarcoma is a distinct entity for which tailored treatment recommendations are needed. In this review, we analysed the effect of adjuvant radiotherapy for the main histologic subtypes of uterine sarcomas. When grouping all histologies, adjuvant radiotherapy has been shown in most studies to reduce local-regional failure without an overall survival advantage, as distant failure is the predominant pattern of relapse. Carcinosarcomas have the strongest indication for adjuvant radiotherapy, especially in early stage disease. Women with leiomyosarcomas and endometrial stromal sarcomas receiving adjuvant radiotherapy have improved local control compared with women undergoing surgery alone. As distant failure rates decrease with improvements in systemic therapies, there may be a broader indication for adjuvant radiotherapy. PMID- 21783426 TI - Prevention of seizure-induced sudden death in a chronic SUDEP model by semichronic administration of a selective serotonin reuptake inhibitor. AB - DBA/1 mice are a chronically susceptible model of sudden unexpected death in epilepsy (SUDEP) that exhibit chronic audiogenic generalized convulsive seizures (GCSs), leading to death from respiratory arrest (RA) if not resuscitated. Serotonin (5-HT) normally enhances respiration in response to elevated CO(2) levels, which occur during GCSs in humans. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, increase 5-HT availability. We examined whether fluoxetine can block GCS-induced sudden death in DBA/1 mice. Fluoxetine (15-70 mg/kg ip) was administered acutely with seizure induction at 30minutes or semichronically in five daily doses (20mg/kg/day) with induction after 5 days. Acute fluoxetine (45 or 70 mg/kg) significantly reduced the incidence of RA without blocking seizure susceptibility. Semichronic fluoxetine did not block seizures, but significantly reduced seizure-induced RA, which is consistent with effects of SSRIs on respiration in patients with epilepsy [Bateman LM, Li DS,LiN TC, Seyal M. Epilepsia 2010;51:2211-4]. These findings suggest that treatment with SSRIs should be evaluated for reducing the incidence of SUDEP in patients. PMID- 21783425 TI - Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years. AB - The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain. PMID- 21783427 TI - One-year postsurgical follow-up of 12 subjects with epilepsy and interictal psychosis. AB - We describe the 1-year follow-up after epilepsy surgery of 12 patients with chronic interictal psychosis and medically intractable epilepsy. The 12 cases described were part of a sample of 350 subjects who concluded a 1-year psychiatric follow-up from a total of 504 subjects operated on for medically intractable epilepsy between 2002 and 2009. Outcome was Engel class IA for five of these patients, IB for one, ID for one, IIB for one, IIIA for three, and IVA for one. Four patients had a worsening of psychotic symptoms at 6 months, but showed improvement after 1 year; two subjects had a worsening of psychotic symptoms at both 6 months and 1 year. Despite the severity of symptoms, compliance with preoperative assessment, surgical programs, and follow-up was satisfactory. PMID- 21783428 TI - The neuropathic components of chronic low back pain: a prospective multicenter study using the DN4 Questionnaire. AB - The present study investigated the neuropathic components of chronic low back pain (LBP) in patients with and without lower limb pain using the DN4 questionnaire and confirmed its psychometric properties. Patients (n = 132) from 11 French multidisciplinary pain or rheumatology centers were classified by a first investigator into 4 groups derived from the Quebec Task Force Classification of Spinal Disorders (QTFSD): group 1 (pain restricted to the lumbar area); group 2 (pain radiating proximally); group 3 (pain radiating below the knee without neurologic signs); and group 4 (pain radiating towards the foot in a dermatomal distribution, with neurological signs, corresponding to typical radiculopathy). A second investigator applied the DN4 questionnaire to the lower limb (groups 2 to 4) and lower back. A comparison of groups 1 and 4 confirmed the psychometric properties of DN4 (sensitivity 80%; specificity 92%, for a cutoff of 4/10, similar to other neuropathic conditions). In the lower limb, the proportion of patients with neuropathic pain (NP) was related to the distality of pain radiation (15, 39, and 80% in groups 2, 3 and 4, respectively; P < .0001). In the lower back, the proportion of patients with NP was higher for patients with typical radicular pain compared with the other groups (P = .006). Thus, typical radiculopathy has similar characteristics as other neuropathic conditions and is confirmed as the commonest neuropathic syndrome in LBP patients. The observation that neuropathic and nociceptive components of LBP vary in the back and lower limb probably accounts for the discrepancies of reported prevalence rates of NP in LBP. As this study was essentially based on a questionnaire, future studies combining standard clinical sensory testing, specific questionnaires, and more objective assessment of the sensory lesion are now required to further investigate the neuropathic component of chronic LBP. PERSPECTIVE: This study confirms the psychometric properties of the DN4 questionnaire to assess neuropathic pain in patients with low back pain. Neuropathic mechanisms largely contribute to pain in the lower limb as compared to the back, but neuropathic pain is not restricted to typical radiculopathy. This may have significant implications for the choice of treatment strategy in these patients. PMID- 21783429 TI - The homosexual and transgendered individual: deviant or part of the normal human continuum? PMID- 21783430 TI - Diagnosis and management of endometrial polyps: a critical review of the literature. AB - This review article summarizes the salient literature on the diagnosis and management of endometrial polyps. Electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE were searched with the MeSH terms including all subheadings and keywords endometrial polyps, abnormal uterine bleeding, polypectomy, polyp management, polyp and diagnosis, and polyp and malignancy. There is a paucity of level I evidence in the literature on the diagnosis and management of this common gynecologic disease. Noninvasive investigations such as transvaginal ultrasonography, with or without the use of 3 dimensional ultrasonography and contrast techniques remain the mainstay of first line investigation. Hysteroscopic resection is the most effective management for endometrial polyps and allows histologic assessment, whereas blind biopsy or curettage has low diagnostic accuracy and should not be performed. This article will review the cause, epidemiology, clinical presentation, diagnostic investigations, and management of endometrial polyps. PMID- 21783431 TI - An "intermediate curriculum" for advanced laparoscopic skills training with virtual reality simulation. AB - STUDY OBJECTIVE: To estimate face and construct validity for a novel curriculum designed for intermediately skilled laparoscopic surgeons on a virtual reality simulator. It consists of 5 exercises that focus on training precision and coordination between both hands. DESIGN: Prospective study (Canadian Task Force II-2). SETTING: Three university hospitals and 4 teaching hospitals in the Netherlands. SUBJECTS: Residents, consultants, and laparoscopic experts (n = 69) in the fields of general surgery, gynecology, and urology participated. Participants were divided into 4 groups on the basis of their level of laparoscopic experience: resident, years 1-3 (n = 15); resident, years 4-6 (n = 17); consultant (n = 19); and laparoscopic experts (n = 18). INTERVENTIONS: Participants completed 3 runs of 5 exercises. The first run was an introduction, and the second and third runs were used for analysis. The parameters time, path length, collisions, and displacement were compared between groups. Afterward the participants completed a questionnaire to evaluate their laparoscopic experience and identify issues concerning the simulator and exercises. MEASUREMENTS AND MAIN RESULTS: The expert group was significantly faster (p <.05) than other groups in 4 of 5 exercises. The parameter displacement demonstrated a significant difference between the expert group and other groups in 2 of the 4 exercises in which this parameter was relevant (p <.05). In the questionnaire (n = 68), training capacity of the curriculum was scored with a median of 4 points on a 5 point Likert scale. Of all participants, 92.6% indicated that this curriculum is suitable as an addition to a basic skills module within their residency program. CONCLUSION: Face and construct validity were estimated for an advanced virtual reality curriculum for intermediately skilled laparoscopic surgeons. The results indicate that the curriculum is suitable for training of residents and consultants and to assess and maintain their laparoscopic skills. PMID- 21783432 TI - Laparoscopic radical hysterectomy with pelvic lymphadenectomy in early invasive cervical cancer. AB - Laparoscopic radical hysterectomy is one surgical procedure currently performed to treat gynecologic cancer. The objective of this review was to update the current knowledge of laparoscopic radical hysterectomy in early invasive cervical cancer. Articles indexed in the MEDLINE database using the key words "Laparoscopic radical hysterectomy" and "Cancer of the cervix" were reviewed. Studies of laparoscopic radical hysterectomy for treatment of early cervical cancer with a minimum study population of 10 patients were selected. The laparoscopic approach was associated with less surgical morbidity (surgical bleeding) and with shorter length of hospital stay, although the duration of the operation may be longer. Laparoscopic radical hysterectomy with endoscopic pelvic lymphadenectomy, and paraaortic lymphadenectomy if needed, is a safe surgical option for treatment and staging of early invasive cervical cancer considering surgical risk, intraoperative bleeding, intraoperative and postoperative complications, and patient recovery. It is important to respect the learning curve. Surgical advances including new laparoscopic instrumentation and, in particular, use of robotics will contribute to reducing the duration of the operation and to facilitating learning and teaching of the procedure. PMID- 21783433 TI - A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice. AB - BACKGROUND: The identification by CFTR mRNA studies of a new deep-intronic splicing mutation, c.870-1113_1110delGAAT, in one patient of our series with mild CF symptoms and in three CF patients of an Italian study, led us to evaluate the mutation frequency and phenotype/genotype correlations. METHODS: 266 patients with CF and related disorders and having at least one undetected mutation, were tested at the gDNA level in three French reference laboratories. RESULTS: In total, the mutation was found in 13 unrelated patients (5% of those already carrying a mutation) plus 4 siblings, including one homozygote and 12 heterozygotes having a severe CF mutation. The sweat test was positive in 10/14 documented cases, the diagnosis was delayed after 20 years in 9/15 and pancreatic insufficiency was present in 5/16. CONCLUSION: c.870-1113_1110delGAAT should be considered as CF-causing with phenotype variability and overall delayed diagnosis. Its frequency highlights the potential of mRNA studies. PMID- 21783434 TI - Rapid UHPLC determination of polyphenols in aqueous infusions of Salvia officinalis L. (sage tea). AB - Sage tea, the aqueous infusion of dried sage leaves (Salvia officinalis L.), is used as a form of food as well as a form of traditional herbal medicine. Several in vivo and in vitro studies point to sage polyphenols as active principles that may inhibit lipid peroxidation and improve antioxidant defences. This study describes an UHPLC methodology with MS/MS and UV detection, which allows the separation, identification and quantification of the major phenolic constituents in sage tea within 34 min, and was used to characterize 16 commercial brands of sage tea.The quantitatively dominating compounds were either rosmarinic acid (12.2-296 mg/l) or luteolin-7-o-glucuronide (37.9-166 mg/l) [corrected].In general, considerable differences in polyphenolic composition between the brands were detected, leading to the demand for quality standardization and control, especially if these sage teas are to be used for therapeutic purposes. PMID- 21783435 TI - Chiral assay of omeprazole and metabolites and its application to a pharmacokinetics related to CYP2C19 genotypes. AB - Studies investigating the relationship between CYP2C19 genotype and the stereoselective metabolism of omeprazole have not been reported. In the present study, we developed a simple and sensitive analytical method based on column switching reversed phase high-performance liquid chromatography (HPLC) with UV detection to determine the concentrations of (R)- and (S)-omeprazole and of its principal metabolites, (R)- and (S)-5-hydroxyomeprazole, and the non-chiral, omeprazole sulfone, in human plasma. Sample preparation involved liquid-liquid extraction with diethyl ether:dichloromethane (60:40, v/v) followed by clean-up on a TSK BSA-ODS/S column (5 MUm, 10 mm * 4.6mm i.d.) using phosphate buffer:acetonitrile (97:3, v/v, pH 6.4). After column switching, separation was performed on a Shiseido CD-ph chiral column (5 MUm, 150 mm * 4.6mm i.d.) using phosphate buffer:methanol (45:55, v/v, pH 5.0) as mobile phase. The limit of quantitation (LOQ) was 5 ng/mL for all analytes with intra- and inter-day precisions (as coefficient of variation) of <9.5% and <9.6%, respectively for all analytes. The present method was successfully applied to a chiral pharmacokinetic study of omeprazole in human volunteers with different CYP2C19 genotypes. The results show that the formation of (R)-5-hydroxyomeprazole gives the best correlation with CYP2C19 genotype. PMID- 21783436 TI - A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen. AB - Accurate determinations of 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) in physiologic fluids are required for the diagnosis and therapeutic monitoring of acute porphyrias. Current colorimetric methods are insensitive and over estimate ALA and PBG due to poor specificity, while LC-MS/MS methods increase sensitivity, but have limited matrices. An LC-MS/MS method was developed to simultaneously determine ALA and PBG concentrations in fluids or tissues which were solid phase extracted, butanol derivatized, and quantitated by selective reaction monitoring using (13)C(5), (15)N-ALA and 2,4-(13)C(2)-PBG internal standards. ALA was separated from interfering compounds on a reverse phase C8 column. For ALA and PBG, the matrix effects (87.3-105%) and process efficiencies (77.6-97.8% and 37.2-41.6%, respectively) were acceptable in plasma and urine matrices. The assay was highly sensitive for ALA and PBG (LLOQ=0.05 MUM with 25 MUL urine or 100 MUL plasma), and required ~4 h from extraction to results. ALA and PBG accuracy ranged from 88.2 to 110% (n=10); intra- and inter-assay coefficients of variations were <10% for urine and plasma. In clinical applications, patients with mutation-confirmed acute porphyrias had normal to slightly increased urinary ALA and PBG levels when asymptomatic, and high levels during acute attacks, which decreased with hemin therapy. In AIP mice, baseline ALA and PBG levels in urine, plasma, and liver were increased after phenobarbital induction 28-/63-, 42-/266-, and 13-/316-fold, respectively. This LC-MS/MS method is rapid, specific, highly sensitive, accurate, and simultaneously measures ALA and PBG in urine, plasma, and tissues permitting porphyria clinical diagnoses, therapeutic monitoring, and research. PMID- 21783437 TI - Efficient and inexpensive method for purification of heparin binding proteins. AB - Heparin binding (HB) proteins mediate a wide range of important cellular processes, which makes this class of proteins biopharmaceutically important. Engineering HB proteins may bring many advantages, but it necessitates cost effective and efficient purification methodologies compared to currently available methods. One of the most important classes of HB proteins are fibroblast growth factors (FGFs) and their receptors (FGFRs). In this study, we report an efficient off-column purification of FGF-1 from soluble fractions and purification of the D2 domain of FGFR from insoluble inclusion bodies, using a weak Amberlite cation (IRC) exchanger. FGF-1 and the D2 domain have been expressed in Escherichia coli and purified to homogeneity using IRC resin. This approach is an alternative to conventional affinity column chromatography, which exhibits several disadvantages, including time-consuming experimental procedures for purification and regeneration and results in the expensive production of recombinant proteins. Results of the heparin binding chromatography and steady state fluorescence experiments show that the FGF-1 and the D2 are in a native conformation. The findings of this study will not only aid an in-depth investigation of this class of proteins but will also provide avenues for inexpensive and efficient purification of other important biological macromolecules. PMID- 21783438 TI - Quantitative analysis of NIM811, a cyclophilin inhibitor, in human dried blood spots using liquid chromatography-tandem mass spectrometry. AB - A high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the quantitative analysis of NIM811, a cyclophilin inhibitor, in human dried blood spot (DBS) samples, which were produced by spotting 20 MUl whole blood onto FTA cards. A 3mm disc was cut from the DBS samples and extracted using methanol, followed by liquid-liquid extraction with MTBE. The reconstituted extracts were chromatographed using a Halo C(18) column and gradient elution for MS/MS detection. The possible impact of hematocrit, blood sample volume and punching location on DBS sampling was investigated. The results showed that blood sample volume or punching location has no impact on assay performance, but the presence of a high hematocrit resulted in significantly increased analyte concentrations measured from the high QC samples. The current method was fully validated over the range of 10.0-5000 ng/ml with correlation coefficients (r(2)) for three validation batches equal to or better than 0.991. The accuracy and precision (CV) at the LLOQ were -0.7 to 6.0% bias of the nominal value (10.0 ng/ml) and 10.2-2.3%, respectively. For the balance of QC samples (20.0, 50.0, 750, 1500 and 3750 ng/ml), the precision (CV) ranged from 3.2 to 11.7% and from 5.6 to 10.2%, respectively, for the intra-day and inter-day evaluations. The accuracy ranged from -6.8 to 8.5% and -0.2% to 2.7% bias, respectively, for the intra-day and inter-day batches. NIM811 is stable in the DBS samples for at least 24h at room temperature and 4h at 60 degrees C. Interestingly, the long term stability (LTS) assessment showed that the stability of the analyte is better when the DBS samples were stored at a lower storage temperature (e.g. <= -60 degrees C) compared to storage at room temperature. This is probably due to the interaction of the additives and/or other materials (e.g. cellulose, etc) on the DBS card with NIM811, a cyclic peptide. The current methodology has been applied to determine the NIM811 levels in DBS samples prepared from a clinical study. PMID- 21783439 TI - Go with the flow: connecting energy demand, hydropower, and fish using constructal theory: comment on "The constructal law and the evolution of design in nature" by Adrian Bejan and Sylvie Lorente. PMID- 21783440 TI - Can a tailored approach be used for sedation in digestive endoscopy? PMID- 21783441 TI - Diabetes and gallstones. PMID- 21783442 TI - Performance and utility of transient elastography and noninvasive markers of liver fibrosis in primary biliary cirrhosis. AB - BACKGROUND: The performance of transient elastography in primary biliary cirrhosis has yet to be fully established. AIM: To assess: (1) the performance of transient elastography in identifying significant fibrosis in primary biliary cirrhosis by comparison with surrogate markers (AST platelet ratio index (APRI), FIB-4, Fibroindex, Forns, aspartate aminotransferase/alanine aminotransferase ratio); (2) the correlation between liver stiffness and Mayo score prognostic index. METHODS: One hundred and twenty patients with primary biliary cirrhosis were consecutively enrolled. The performance of each marker and of liver stiffness was compared with histological staging and METAVIR at time of liver biopsy. RESULTS: The area under receiver operating characteristic (ROC) of liver stiffness were 0.87, 0.88, 0.99 for histological stage >=II, >=III and =IV and 0.89, 0.92, 0.99 for METAVIR >=2, >=3 and =4. Transient elastography alone proved better able in identifying any grade of fibrosis or cirrhosis than noninvasive markers. Combining each surrogate marker with transient elastography did not improve the area under ROC. Transient elastography correlated positively with the Mayo score (P<0.001). Logistic regression analysis showed that transient elastography was associated with an advanced fibrosis (P<0.001). CONCLUSIONS: Transient elastography proved a simple, reliable and useful method for assessing liver fibrosis in primary biliary cirrhosis, whereas noninvasive surrogate markers proved unsatisfactory in predicting significant fibrosis. PMID- 21783443 TI - The effects of "thin ideal" media on women's body image concerns and eating related intentions: the beneficial role of an autonomous regulation of eating behaviors. AB - The present study examines the protective role of an autonomous regulation of eating behaviors (AREB) on the relationship between trait body dissatisfaction and women's body image concerns and eating-related intentions in response to "thin ideal" media. Undergraduate women (n=138) were randomly assigned to view a "thin ideal" video or a neutral video. As hypothesized, trait body dissatisfaction predicted more negative affect and size dissatisfaction following exposure to the "thin ideal" video among women who displayed less AREB. Conversely, trait body dissatisfaction predicted greater intentions to monitor food intake and limit unhealthy foods following exposure to the "thin ideal" video among women who displayed more AREB. PMID- 21783444 TI - Purse-string closure of large myelomeningoceles. PMID- 21783445 TI - Topographic anatomy of the nerve to masseter: an anatomical and clinical study. AB - BACKGROUND: The use of the motor nerve to masseter has proved to be a reliable and sensible solution in facial reanimation as a donor for free muscle transfer. In this paper we describe the topographic anatomy of the nerve to masseter and our original technique for its quick and safe harvesting. METHODS: This anatomical study is based on the dissection of the nerve to masseter in 17 embalmed cadaverous sites and is focused on the anatomical relations between the nerve and the surrounding structures. Also buccal and zygomatic branches of the facial nerve were dissected and assessed and the resulting data are compared. RESULTS: The nerve to masseter has a predictable track inside the muscle which can be identified topographically within a square area under the zygomatic arch. This area is different between males and females and its accuracy has been tested on six patients at the Canniesburn Unit. CONCLUSIONS: The nerve to masseter emerges in a very predictable point from the mandibular notch - immediately below the zygomatic arch - to run within the muscle belly. The approach here described allows safer and faster harvesting of the nerve to masseter with minimal dissection through the muscle. PMID- 21783446 TI - The contribution of a dermal substitute in the three-layers reconstruction of a nose tip avulsion. AB - Through and through defects of the nasal ala still remains debated challenge in plastic reconstructive surgery. We present a 36 y.o. woman who suffered by a through and through nose tip avulsion subsequently a dog bite. She refused the use of traditional auricular composite graft or the multiple stages midline forehead flap due to the secondary visible scars. We treated her with the combined use of mucoperichondrial septal flap, cartilage graft and dermal substitute Integra graft, followed by a secondary, full-thickness skin graft. We consider the Integra((r)) as a useful option for the treatment of a complex trauma of the nose with through and through tip and alar avulsion when, due to scar or consent problem, it's not possible the use of other techniques. PMID- 21783447 TI - Lateral thoracic perforator flap: additional perforator flap option from the lateral thoracic region. AB - BACKGROUND: Perforator flaps from the lateral thoracic region have not been as popular as other donor sites because of the misconception that the vascular anatomy in this region is less than predictable. However, the skin over the lateral thoracic region is vascularised by three rows of perforators of varied vascular dominance. Two perforator flaps from this region based on the middle and the posterior row of perforators from the thoracodorsal artery have been described. The lateral thoracic perforator flap based on the anterior row of perforators is another useful option. PATIENTS AND RESULTS: Nine patients underwent reconstructions using the lateral thoracic perforator flap for various defects in the head and neck region and lower limbs as a result of tumour extirpation, crush injury and chronic wound with osteomyelitis. All flaps were raised in the supine position. Three flaps were raised in a chimaeric fashion. The largest flap was 20*12 cm and the mean size was 106 cm2. All flaps survived without major complication. CONCLUSION: The lateral thoracic perforator flap is a reliable reconstructive option. It can be readily configured in terms of size, thickness and tissue composition. However, it is not the first-choice flap from this region because the resultant donor scar tends to extend visibly beyond the anterior axillary fold and the arterial and venous pedicles frequently have separate courses. The lateral thoracic region has become a versatile and universal donor site for free-style flap harvest with this additional flap option. PMID- 21783448 TI - The effect of preoperative radiotherapy on complication rate after microsurgical head and neck reconstruction. AB - BACKGROUND: The introduction of radiotherapy (XRT) has resulted in increased survival of patients diagnosed with head and neck malignancies. However, the potentially deleterious impact of radiotherapy on reconstructive efforts continues to be the subject of intense debate. The present study was designed to evaluate the effects of preoperative XRT on complication rates in patients undergoing microsurgical reconstruction of head and neck defects after oncosurgical resection. METHODS: A retrospective cohort study was conducted of all patients who underwent immediate microsurgical reconstruction of post ablative defects over a 3-year period. Study subjects were divided into two groups: (1) those who did not receive XRT and (2) those who received preoperative XRT. Clinical variables examined and analysed included age, gender, co-morbid conditions, tobacco history, the presence of recurrent disease and ischaemia time. Outcomes of interest included length of intensive care unit (ICU) and hospital stay and postoperative complications. Complications were further classified as flap-related as well as 'medical'. RESULTS: A total of 60 patients were included in this study (group 1: 26 patients; group 2: 34 patients). Results were similar between the study groups with the exception of a higher rate of flap related complications in patients undergoing XRT. Overall, 19 patients (31.7%) experienced flap-related complications, with 12% of the patients being in group 1 (N=3) versus 47% of patients being in group 2 (N=16) (p=0.003). CONCLUSIONS: Our data suggest that preoperative radiotherapy is associated with a significant increase in postoperative flap-related complications. However, these did not result in a prolonged hospital stay, reflecting the fact that the majority of flap-related complications can be managed on an outpatient basis. Although microsurgical reconstruction is frequently successful, patients with a history of XRT should be informed preoperatively about their increased risk of complications. PMID- 21783449 TI - Moving from research to large-scale change in child health care. AB - There is a large and persistent failure to achieve widespread dissemination of evidence-based practices in child health care. Too often studies demonstrating evidence for effective child health care practices are not brought to scale and across different settings and populations. This failure is not due to a lack of knowledge, but rather a failure to bring to bear proven methods in dissemination, diffusion, and implementation (DD&I) science that target the translation of evidence-based medicine to everyday practice. DD&I science offers a framework and a set of tools to identify innovations that are likely to be implemented, and provides methods to better understand the capabilities and preferences of individuals and organizations and the social networks within these organizations that help facilitate widespread adoption. Successful DD&I is dependent on making the intervention context sensitive without losing fidelity to the core components of the intervention. The achievement of these goals calls for new research methods such as pragmatic research trials that combine hypothesis testing with quality improvement, participatory research that engages the target community at the beginning of research design, and other quasi-experimental designs. With the advent of health care reform, it will be extremely important to ensure that the ensuing large demonstration projects that are designed to increase integrated care and better control costs can be rapidly brought to scale across different practices settings, and health plans and will be able to achieve effectiveness in diverse populations. PMID- 21783450 TI - Qualitative research methods for medical educators. AB - This paper provides a primer for qualitative research in medical education. Our aim is to equip readers with a basic understanding of qualitative research and prepare them to judge the goodness of fit between qualitative research and their own research questions. We provide an overview of the reasons for choosing a qualitative research approach and potential benefits of using these methods for systematic investigation. We discuss developing qualitative research questions, grounding research in a philosophical framework, and applying rigorous methods of data collection, sampling, and analysis. We also address methods to establish the trustworthiness of a qualitative study and introduce the reader to ethical concerns that warrant special attention when planning qualitative research. We conclude with a worksheet that readers may use for designing a qualitative study. Medical educators ask many questions that carefully designed qualitative research would address effectively. Careful attention to the design of qualitative studies will help to ensure credible answers that will illuminate many of the issues, challenges, and quandaries that arise while doing the work of medical education. PMID- 21783451 TI - Seize the day. PMID- 21783452 TI - Latino families' experiences with family-centered rounds at an academic children's hospital. AB - OBJECTIVE: To characterize Latino families' experiences with family-centered rounds at an academic children's hospital to identify areas for improvement. METHODS: Five focus groups of families of Latino children hospitalized on a general medical ward were conducted in Spanish by a single bilingual facilitator. Participants were recruited from a convenience sample of Spanish-speaking Latino family members present at the patients' bedside. Data were transcribed verbatim, content coded, and analyzed in Spanish for emergent themes. RESULTS: Twenty-eight Latino family members of 21 hospitalized children participated in the 5 focus groups. Most spoke only Spanish (75%), and Spanish was the preferred language of all focus group participants. Qualitative data analysis indicated that families reported positive experiences with rounds involving a Spanish-speaking provider. Thematic issues focused on family-physician communication problems, lack of family empowerment, family and provider participants for family-centered rounds, and cultural needs. Parents were dissatisfied with telephonic interpretation services and preferred a live interpreter in the absence of a fluent, bilingual physician. Many families did not feel empowered to request interpretation assistance or health information; parents often felt embarrassed as a result of their inability to understand the primary language (English) of the care providers. Some parents felt inhibited to express themselves in the presence of other family members. Addressing cultural needs (e.g., chaplain support) was appreciated by families. CONCLUSIONS: Spanish-speaking Latino families are not consistently receiving optimal family-centered rounds. Different strategies are needed to fully engage and empower Latino families. PMID- 21783453 TI - The relationship between epicardial fat volume and incident coronary artery calcium. AB - BACKGROUND: Epicardial fat volume (EFV) has been associated with prevalent but not incident coronary artery calcium. However, the relationship between EFV and development of incident coronary calcium (incCC) has not been reported. OBJECTIVE: We evaluated the relationship between epicardial fat volume and the development of coronary artery calcium over 3-5 years. METHODS: From 1248 subjects who underwent 2 serial noncontrast cardiac CT scans 3-5 years (median, 4 years) apart to measure coronary calcium score of 0 who subsequently developed incident coronary calcium (incCC(+)) were matched to 106 controls in whom coronary calcium score remained 0 (incCC(-)). EFV was calculated by determination of the pericardial contour, followed by identification of fat voxels with the use of validated software (QFAT). Baseline EFV and EFV indexed to body surface area (EFVi) and subsequent EFV and EFVi changes were compared between incCC(-) and incCC(+) populations. A significant EFV increase was defined as a >=10% and >=25% increase from the baseline value. RESULTS: Baseline EFVi was similar between the 2 groups [EFVi, 40.9 +/- 17.9 cm3 (median, 38.3 cm3) in incCC(-) vs 40.3 +/- 16.3 cm3 (median, 37.0 cm3) in incCC(+); P = 0.96]. On the follow-up CT, EFVi increased in 74.5% of incCC(-) and in 76.4% of incCC(+) (P = 0.75). EFVi changes between the 2 groups were similar [4.9 +/- 8.9 cm3 (median, 4.9 cm3) in incCC(-) vs 4.2 +/- 8.0 cm3) (median, 3.5 cm3) in incCC(+); P = 0.67]. On multivariate analysis, after adjusting for cardiovascular risk factors, incCC was not related to an increase in EFVi at a 10% or 25% level. CONCLUSIONS: In very low-risk subjects with a coronary calcium score of 0, baseline EFVi and change in EFVi after 3-5 years were not related to the development of incidental coronary artery calcium. PMID- 21783454 TI - Beneficial effects of caloric vestibular stimulation on denial of illness and manic delusions in schizoaffective disorder: a case report. AB - INTRODUCTION: Preliminary data suggests that caloric vestibular nerve stimulation (CVS) single session application of cold water to the left ear induces a clinically significant, short-lived beneficial effect on specific types of illness denial (i.e., anosognosia) and delusions (i.e., somatic type). METHODS: We recently studied the effect of left versus right ear ice water (4 degrees C) CVS on delusions and insight of illness in a patient with manic episode due to schizoaffective disorder. The patient was evaluated at baseline, immediately after the CVS, and then at 20 minutes, 60 minutes, and 24 hours. The method was first applied to one ear and 4 days later to the other. To assess whether the effect is specific to mania we employed the same procedure in two other patients with schizophrenia who also demonstrated delusions and impaired insight. RESULTS: All three patients showed a difference favoring left versus right ear CVS that was maintained for 20 minutes, and diminished over a 60 minute period. EEG analyses showed a numerically non-significant increase in bilateral frontal and central alpha EEG band activation (more pronounced in the right hemisphere) with left but not right ear CVS 5 minutes after the CVS, and that diminished after 20 minutes. DISCUSSION: The results suggest that left versus right CVS may have a short lived beneficial effect on manic delusions and insight of illness that seem to appear in other types of psychoses (i.e., schizophrenia). CONCLUSION: These preliminary results suggest that single session CVS may have short lived beneficial effects in mania and perhaps in other types of psychoses. Further research is mandatory. PMID- 21783455 TI - Deflated intragastric balloon-induced small bowel obstruction. AB - We describe the rare case of a 49-year-old man who had an air-filled intragastric balloon placed for weight control 11 months ago which had been lost of sight for follow-up and presented six months after the last radiologic control with acute small bowel obstruction. Computed tomography confirmed the migration of the deflated balloon in the small bowel. It was impacted in the ileum so an enterostomy-suture was performed for removal. Intragastric balloons are temporarily used to obtain weight reduction in the super-obese prior to bariatric surgery and in patients who are not fit for surgery. They were shown to be effective in restoring the metabolic syndrome as well. The use of fluid-filled balloons seems preferable for early migration diagnosis and management. If the intragastric balloon remains inside longer than recommended, it tends to deflate and is prone for migration and intestinal obstruction. Follow-up investigations (monthly X-rays) are mandatory for early migration diagnosis. PMID- 21783456 TI - Effects of dietary folate intake and folate binding protein-2 (Folbp2) on urinary speciation of sodium arsenate in mice. AB - Folate binding protein-2 (Folbp2(-/-)) knockout mice have been previously shown to be highly susceptible to the teratogenic effects of arsenic. Arsenic biotransformation is achieved primarily by biomethylation. Given the potential close relationship between folate biochemistry and arsenic biotransformation, the aims of our study were to: (1) test whether Folbp2(-/-) mice have altered arsenic biotransformation which would suggest a potential mechanism for their enhanced susceptibility; (2) examine whether dietary folate deficiency alters arsenic biotransformation. Folbp2(-/-) mice were found to have slightly lower plasma folate levels than wildtype mice. No genotype-specific effects were observed in arsenic speciation thereby negating altered biotransformation of arsenic as the mechanism of the enhanced teratogenicity seen in Folbp2(-/-) mice. Reduction in excretion of organic arsenicals was observed during folate deficiency, suggesting an important role for folic acid homeostasis in arsenic biotransformation. PMID- 21783457 TI - A mixture of environmental contaminants increases cAMP-dependent protein kinase in Spisula embryos. AB - Using the surf clam embryo, we investigated the effects of the combination of bromoform, chloroform, and tetrachloroethylene, three pollutants found in high concentrations in the municipal water supply in Brick, New Jersey. Exposure produced an increase in an isoform of the regulatory subunit (RII) of cAMP dependent protein kinase, demonstrated by confocal microscopy and western blotting. Embryos showed an increase in RII where the primordial gill and ciliated velar epithelium are innervated. This increase correlated with increased ciliary activity, indicating a corresponding rise in the catalytic subunit. Treatment resulted in decreased threonine phosphorylation of actin. There was no effect on neurotransmitters or receptors of the serotonergic-dopaminergic nervous system. These effects occurred only with the ternary mixture. No significant effect was seen with individual or paired components. This is the first report showing that bromoform, chloroform, and tetrachloroethylene act synergistically to alter a key regulator of neuronal development. PMID- 21783458 TI - Bisphenol A-induced downregulation of murine macrophage activities in vitro and ex vivo. AB - Bisphenol A (BPA) is known to have detrimental effects on the reproductive system, but the toxicity of BPA on immune responses has not been systematically investigated. We investigated the effects of BPA exposure on the activities of murine peritoneal macrophages through evaluation of BPA-induced alteration of nitric oxide (NO) production, tumor necrosis factor-alpha (TNF-alpha) synthesis, and expression of co-stimulatory molecules B7. Macrophages were examined ex vivo from mice orally treated with various doses of BPA for 5 consecutive days per week for 4 weeks followed by culture for 2 or 4 days in the presence of lipopolysaccharides (LPS). Macrophages from naive mice were also stimulated with LPS +/- BPA for 2 or 4 days. NO production was decreased with the in vitro exposure to 1, 10 and 100MUM BPA. NO production was lower in the BPA-exposed mice than the control mice with all doses. In vitro, BPA suppressed TNF-alpha secretion with significant reduction at 10 and 100MUM BPA. Similar findings were observed with the macrophages from the BPA-exposed mice. This study provides the substantial evidence on BPA-induced alteration in macrophage activity. PMID- 21783459 TI - Persistent immunotoxic effects of tributyltin in human natural killer cells can be reversed by interleukin 2. AB - Tributyltin (TBT) is a widespread environmental contaminant due to its use in marine antifouling paints and as an anti-microbial agent in other applications. There are measurable levels of TBT in some samples of human blood. Natural killer (NK) cells are lymphocytes capable of killing tumor and virally infected cells. Previously, we have shown that a 1h exposure to 300nM TBT caused a permanent decrease in the ability of human NK cells to bind to and destroy tumor target cells and in their expression of certain functionally relevant cell surface markers. The present study investigates the effect of the NK-stimulatory cytokine, interleukin (IL) 2 on TBT-induced decreases in NK cytotoxicity, binding function, and expression of CD16 and CD56. A 1h exposure to 300nM TBT followed by 24h in TBT-free media decreased cytotoxic function by 80%, and expression of CD16 by 16%. When 10ng/mL IL-2 was present during the 24h incubation there was no statistically significant decrease in cytotoxicity or expression of CD16. A 96h incubation in TBT-free media produced decreases in cytotoxicity (99%), binding function (65%), and expression of CD16 (48%) and CD56 (51%). IL-2 was able to reverse the TBT-induced decreases in each of these parameters seen after 96h. These results suggest that IL-2 restoration of NK ability to bind target cells correlates with its ability to restore CD16 and CD56 expression. Additionally, neither the loss of cytotoxic function (seen in the 24 or 48h periods following TBT exposure) nor its restoration by IL-2 can be substantially explained by the effects of TBT exposure on CD16 and CD56 expression or target binding. PMID- 21783460 TI - Aluminum-induced suppression of testosterone through nitric oxide production in male mice. AB - Excessive nitric oxide (NO) production in mice serum and testis due to aluminum (Al) exposure has been shown in previous studies. The aim of this study was to further investigate the role of NO on aluminum-suppressed testosterone level in male CD-1 mice. Each animal in six groups, was given intraperitoneal injections of either saline, aluminum chloride (AlCl(3)), l-N(6)-(1-iminoethyl) lysine (NO synthase inhibitor, l-NIL), or Al chloride along with l-NIL for a period of 12 days. These groups were denoted as C (control, saline), AL (35mg Al/kg/day, saline), NIL240 (total 240mg l-NIL/kg, saline), ALNIL240 (35mg Al/kg/day, total 240mg l-NIL/kg), ALNIL60 (35mg Al/kg/day, total 60mg l-NIL/kg), and NIL60 (total 60mg l-NIL/kg, saline). Results indicated that serum/testicular aluminum levels increased significantly in aluminum-treated animals compared to the controls, whereas the values observed from groups ALNIL240 than AL/ALNIL60 were markedly lower. Aluminum administration significantly increased NO production and decreased both testicular adenosine 3',5'-cyclic monophosphate (cAMP) and testosterone levels. A lower level of NO and higher concentrations of cAMP and testosterone observed in the ALNIL240 group indicated that the protective effect of NO synthase blockage was significant, although incomplete. In addition, aluminum induction significantly elevated the testicular cholesterol, but the values were lower in the ALNIL240 group than the AL or the ALNIL60 group. Finally, it was suggested that aluminum compounds exerted a significant adverse effects on the steroidogenesis and cAMP, which aided in the transport of cholesterol to the inner mitochondrial membrane. Furthermore, nitric oxide synthase blockage prevented aluminum-induced reproductive toxicity. PMID- 21783461 TI - Formation of estrogenic metabolites of benzo[a]pyrene and chrysene by cytochrome P450 activity and their combined and supra-maximal estrogenic activity. AB - Metabolism of polycyclic aromatic hydrocarbons (PAHs) has been studied intensively, and potential metabolites with estrogenic activity have been identified previously. However, little attention has been paid to the metabolic pathways in mammalians and to the combined effect of individual metabolites. Several hydroxylated metabolites of benzo[a]pyrene (BaP) and chrysene (CHN) were formed by rat liver microsomal cytochrome P450 (CYP) activity, some of which possess estrogenic activity. All mono- and several dihydroxylated metabolites of BaP and CHN were tested for ER affinity and estrogenic activity in a proliferation assay (E-screen) and in a reporter-gene assay (ER-CALUX). Twelve estrogenic metabolites were identified with EC50 values ranging from 40nM to 0.15mM. The combined effect of a mixture of seven PAH-metabolites was also studied in the ER binding assay. At concentrations that show little activity themselves, their joint action clearly exhibited significant estrogenic activity. BaP itself exhibited estrogenicity in the ER-CALUX assay due to bio-activation into estrogenic metabolites, probably via aryl hydrocarbon receptor (AhR) induced CYP activity. Furthermore, 2-hydroxy-CHN (2-OHCHN) induced supra-maximal (400%) estrogenic effects in the ER-CALUX assay. This effect was entirely ER-mediated, since the response was completely blocked with the ER-antagonist ICI182,780. We showed that 2-OHCHN increased ER-concentration, using ELISA techniques, which may explain the observed supra-maximal effects. Co-treatment with the AhR-antagonist 3',4'-dimethoxyflavone (DMF) enhanced ER-signaling, possibly via blockage of AhR ER inhibitory cross-talk. PMID- 21783462 TI - Identification of genes responsive to PFOS using gene expression profiling. AB - Perfluorooctane sulfonic acid (PFOS) is widely distributed in the environment including in the tissues of wildlife and humans, however, its mechanism of action remains unclear. Here, the Affymetrix rat genome U34A genechip was used to identify alterations in gene expression due to PFOS exposure. Rat hepatoma cells were treated with PFOS at 2-50mg/L (4-100MUM) for 96h. Sprague-Dawley rats were orally dosed with PFOS at 5mg/kg/day for 3 days or 3 weeks. Genes that were significantly (P <0.0025) induced were primarily genes for fatty acid metabolizing enzymes, cytochrome P450s, or genes involved in hormone regulation. Consistent expression profiles were obtained for replicate exposures, for short term and long-term in vivo exposures, and for acute and chronic exposures. One major pathway affected by PFOS was peroxisomal fatty acid beta-oxidation, which could be explained by the structural similarity between PFOS and endogenous fatty acids. PMID- 21783463 TI - PCB profiles in mouse skin biopsies and fat from an environmental mixture. AB - Fat, ear skin and trunk skin were collected from mice exposed to PCB-contaminated soil for PCB specific congener analysis. The soil had been retrieved from a Superfund site prior to remediation. Mice were exposed to either contaminated soil or control soil for 4 weeks. Skin samples were collected immediately after the 4-week exposure and again after 4-week recovery. Out of 141 PCB congeners measured, only 91 peaks representing 103 congeners were above quantification limits. Relative liver weights in PCB-exposed mice doubled indicating significant enzyme induction. Consistent with this observation, total PCB residues declined about 80% during the 4-week recovery. The PCB residue profiles in the ear skin (208mg/kg total) and trunk skin (129mg/kg) after 4-week exposure were identical and similar to those in body fat (370mg/kg) and in the contaminated soil. The results confirmed that both skin tissues are important reservoirs and can serve as useful biopsy media. PMID- 21783464 TI - Gonadal histology and characteristic histopathology associated with endocrine disruption in the adult fathead minnow (Pimephales promelas). AB - Examination of gonadal histopathology has been beneficial in understanding and assessing the effects of potential endocrine disrupting chemicals in fish and other organisms. The present study describes the normal gonadal histology of the fathead minnow (Pimephales promelas), a widely used test organism, reviews typical effects of endocrine disrupting chemicals with different modes/mechanisms of action on the histological structure of the ovaries and testes, and recommends methods for optimizing histopathological results. PMID- 21783465 TI - The impact of subchronic lead poisoning on the vascular effect of nitric oxide in rats. AB - Lead-induced arterial hypertension is suggested to have resulted mainly from a reduction in nitric oxide (NO) bioactivity in vessel walls. The aim of this study was to evaluate the impact of poisoning by lead in so-called hypertensive doses on the basal and stimulated released NO effect in the rat mesenteric bed. Male Buffalo rats were given lead in a dose of 50 or 100ppm in drinking water for three months. The isolated mesenteric bed preconstricted by norepinephrine (0.5MUg/ml) was used to determine the changes in vascular resistance induced by N omega-nitro-l-arginine injected in increasing doses from 1.0 to 200.0MUg or by acetylcholine administered in doses from 0.05 * 10(-10) to 5.0 * 10(-10)mol. These changes were measured as an increase or decrease in perfusion pressure in the constant flow system. In comparison with controls rats given 50ppm of lead, an increase in maximal response to N-omega-nitro-l-arginine (P < 0.01) and acetylcholine (P < 0.05) and a shift to the left of the dose-response curve for acetylcholine were demonstrated. Vascular responses in rats, who were given 100ppm of lead, were similar to those observed in the control group. It is concluded that lead induces NO-mediated changes of vascular tone and vascular reactivity only in the small range of doses known as hypertensive. PMID- 21783466 TI - Genotoxicity evaluation of metronidazole using the piscine micronucleus test by acridine orange fluorescent staining. AB - In this study, genotoxic potential of metronidazole, an antibiotic-antiparasitic agent widely used both clinical and veterinary areas, was evaluated using the piscine micronucleus test. Specimens of Oreochromis niloticus (Pisces: Cichlidae) were exposed to different concentrations (5, 10, 15mg/L) of metronidazole and 4mg/L cyclophosphamide (as positive control) for 24, 48 and 72h. A fluorescent staining technique with acridine orange (AO) was performed to improve the sensitivity of erythrocyte micronucleus assay with fish. AO selectively stains newly formed immature erythrocytes (PCEs) therefore allows to obtain more sensitive results by detection of the micronucleated PCEs differed than mature erythrocytes (NCEs) by their RNA-containing cytoplasm. The ratio of PCE/NCE in peripheral blood was also evaluated to assess cytotoxicity. As a result, it was observed that the frequencies of micronucleated PCEs increased both dose and time dependently while PCE/NCE ratios decreased. Our results revealed that metronidazole has cytotoxic and genotoxic effects on fish. The use of acridine orange staining technique also seems useful in assessment of short-term genotoxic effects of chemicals, when fish are used as experimental animal. PMID- 21783467 TI - Subchronic toxic effects of tributyltin (TBT) and inorganic lead (PbII) in rats. AB - This study evaluated the toxic effects of two doses of inorganic lead (PbII) and tributyltin (TBT), separately and together in different exposure times (30 and 60 days) in rats. After exposure, liver, kidney, brain and blood were sampled for histopathological, hematological and enzymatic analysis. The number of peritoneal cells and lipopolysaccharide (LPS)-induced neutrophil migration after exposure was also analyzed. The liver presented necrotic areas in all exposed individuals while hematological and enzymatic parameters showed no changes. TBT, but not PbII, reduced the number of resident peritoneal macrophages. The combination of both toxicants abolished TBT effects at lower doses and even increased the number of macrophages at higher doses. The neutrophil migration was increased by lead and lead associated with TBT. These results confirm the potential hepatotoxicity of these compounds and they may have antagonistic effects on the immune cells when administered alone. The combination of toxicants induced an increased inflammatory response suggesting that lead effects may prevail over TBT reduction on macrophage number. PMID- 21783468 TI - Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system. AB - Alkylphenol ethoxylates, widely used non-ionic surfactants, are biodegraded into alkylphenols such as nonylphenol (NP) and t-octylphenol (OP), short-chain ethoxylates such as NP-monoethoxylate (NP1EO) and NP-diethoxylate (NP2EO), and alkylphenoxy carboxylic acids such as 4-t-octylphenoxyacetic acid (OP1EC). Bisphenol S (BPS) is more heat-stable and photo-resistant than bisphenol A (BPA), and therefore replaces BPA. These chemicals could be chlorinated during wastewater treatment. We synthesized these compounds and their chlorinated derivatives to estimate their estrogenic activities using a GFP expression system. The EC(50) ranking of NP-related compounds was NP > ClNP > diClNP > NP1EO > ClNP1EO > NP2EO. The estrogenic activity of OP1EC was 10 times less potent than parent OP. Furthermore, BPS showed comparable estrogenic activity with BPA. The EC(50) ranking of BPS-related compounds was BPA >= BPS > triClBPS > diClBPS > ClBPS. Other tested BPS derivatives had no estrogenic activity. Chlorination of the tested chemicals did not enhance their estrogenic activity, in contrast to certain chlorinated BPAs. Thus, our results demonstrated that chlorinated derivatives of NP, OP, and BPS, even if artificially produced during wastewater processing, were less estrogenic than their parent chemicals, known as endocrine disruptors. PMID- 21783469 TI - Arsenic antagonism studies with monoisoamyl DMSA and zinc in male mice. AB - Administration of zinc either alone or in combination with monoisoamyl dimercaptosuccinic acid (DMSA) during and post-arsenic exposure was investigated in male mice. The animals were administered 2mgkg(-1) arsenic as sodium arsenite, intraperitoneally, once daily for 5 days either alone or in combination with 10mgkg(-1), zinc (as zinc acetate, orally), 50mgkg(-1) monoisoamyl dimercaptosuccinic acid (MiADMSA) given orally (p.o.), 2h after arsenic administration. Another group of arsenic treated animals was given both zinc (10mgkg(-1)) and MiADMSA (50mgkg(-1), p.o.). Animals were sacrificed 24h after the last dose. In another set of experimentation, arsenic pre-exposed mice (2mgkg(-1), i.p. for 5 days) were treated with saline, zinc, MiADMSA or zinc plus MiADMSA for next 3 days and sacrificed thereafter. Exposure to arsenic led to a significant inhibition of blood delta-aminolevulinic acid dehydratase (ALAD), depletion of glutathione (GSH) level and marginal elevations of zinc protoporphyrin (ZPP). Arsenic exposure caused a significant decrease in hepatic and renal GSH level and an increase in liver oxidized glutathione (GSSG) and liver and kidney thiobarbituric acid reactive substance (TBARS) levels. Concomitant administration of zinc with arsenic provided significant protection to blood ALAD activity while, GSH and ZPP levels remained unaltered. Co administration of MiADMSA with arsenic significantly prevented accumulation of arsenic in blood, liver and kidney while, zinc had no effect on tissue arsenic concentration. Combined administration of zinc and MiADMSA had no major additional beneficial effects over their individual effects. Interestingly, post arsenic exposure treatment with MiADMSA provided significant recovery in blood ALAD activity while, zinc supplementation alone had no effect. The best results however, were obtained when MiADMSA was administered along-with zinc. Most of the biochemical variables indicative of hepatic oxidative stress responded favorably to MiADMSA treatment while, zinc administration had no effect. Administration of MiADMSA significantly depleted arsenic concentration from the soft tissues while, combined zinc and MiADMSA had no additional beneficial effect over the individual effect of MiADMSA. The results thus lead us to conclude that in order to achieve best effects of chelation therapy, co-administration of zinc with chelator might be preferred. However, detailed experimental studies with variable doses and after chronic arsenic exposure are required. PMID- 21783470 TI - Pharmacokinetics of thiamine in female Baltic salmon (Salmo salar L.) broodfish. AB - A thiamine deficiency disease termed M74 syndrome affects the yolk-sac fry of wild and feral Baltic salmon. However, very little is known about the pharmacokinetics of thiamine in salmon. This study examined the pharmacokinetics of thiamine hydrochloride injected intraperitoneally into feral and farmed Baltic salmon females preparing for spawning. The total thiamine concentrations in the eggs and white muscle of feral females were only half of those in the farmed fish after injection. The relative inefficiency of the incorporation of thiamine into the eggs in feral Baltic salmon may be a predisposition factor for M74 syndrome. The relative bioavailability of intraperitoneally-injected thiamine hydrochloride was shown to be ca. 94% of that administered intra-aortically. A far lower intraperitoneal dose (ca. 20mgkg(-1) fish) than currently used was shown to elevate the total thiamine concentration in the eggs above the critical threshold of M74 syndrome. PMID- 21783471 TI - Comparison of gene expression methods to identify genes responsive to perfluorooctane sulfonic acid. AB - Genome-wide expression techniques are being increasingly used to assess the effects of environmental contaminants. Oligonucleotide or cDNA microarray methods make possible the screening of large numbers of known sequences for a given model species, while differential display analysis makes possible analysis of the expression of all the genes from any species. We report a comparison of two currently popular methods for genome-wide expression analysis in rat hepatoma cells treated with perfluorooctane sulfonic acid. The two analyses provided 'complimentary' information. Approximately 5% of the 8000 genes analyzed by the GeneChip array, were altered by a factor of three or greater. Differential display results were more difficult to interpret, since multiple gene products were present in most gel bands so a probabilistic approach was used to determine which pathways were affected. The mechanistic interpretation derived from these two methods was in agreement, both showing similar alterations in a specific set of genes. PMID- 21783472 TI - Protection against mercury-induced renal damage in Swiss albino mice by Ocimum sanctum. AB - Mercury is being widely used in the industry, medical, agriculture and other fields. However, mercury deposition affects the nervous, cardiovascular, pulmonary, gastrointestinal and renal systems, as well as the embryo. In most animals' species, including man, the kidney is one of the main sites of deposition of inorganic mercury and target organ for its toxicity. The present investigation reports protection against mercury-induced toxicity by Ocimum sanctum (a traditional sacred medicinal plant, family: Labiatae). Swiss albino mice were divided into four groups. (i) Control group-only vehicle (0.9% NaCl) was given (ii) HgCl(2)-treated group-5.0mg/kg b.w. HgCl(2) administered as i.p. (iii) Ocimum treated group-10mg/kg b.w. Ocimum leaves extract was administered orally. (iv) Combination group-Ocimum leaves extract was administered 10 days prior to mercuric chloride administration and continued upto 30 days after mercuric chloride administration (5.0mg/kg b.w.). The animals were autopsied on day 1, 3, 7, 15 and 30 after treatment. Activity of alkaline phosphatase (ALP), acid phosphatase (ACP), lactate dehydrogenase (LDH) and lipid peroxidation (LPO) were measured in kidney homogenates. The results indicated that there was a significant increase in LPO content, ACP activity and decrease in LDH and ALP activity after HgCl(2) treatment. The animals treated with Ocimum alone did not show any significant alterations in ACP and ALP activity. However, a significant increase in LDH activity and decrease in LPO level was observed. In combined treatment of Ocimum with HgCl(2), a significant decrease in LPO content and ACP and elevation in LDH and ALP activity was observed as compared to HgCl(2)-treated group. Ocimum extract is also effective in reducing the pathological alterations in the kidney. Thus, the results from the present study suggest that pre-and post treatment of Ocimum sanctum leaves extract can significantly protect the renal damage against mercuric chloride-induced toxicity. PMID- 21783473 TI - Motor impairment induced by oral exposure to methylmercury in adult mice. AB - The effects of oral exposure to methylmercury chloride (MeHg) on locomotor control and activity in adult mice were investigated in the present study. MeHg was diluted in drinking water (0, 20 and 40mg/L - as methylmercury chloride) and locomotion (spontaneous locomotor activity) and motor impairment tests (beam walking, footprint and clasping) were performed at 7, 14 and 21 days after the beginning of the treatment. MeHg exposure caused a significant decrease in spontaneous locomotor activity and this effect was dose- and time-dependent. Significant dose- and duration-dependent increases in beam walking latency were observed following chronic MeHg exposure. Furthermore, dose- and duration dependent locomotor deficits on footprint coordination were also observed. Taken together, these results show that MeHg-induced impairment on locomotor activity is not limited to exposures that take place during neural development. We discuss the possible relationship between our findings and the similar clinical signs observed in adult humans exposed to MeHg. PMID- 21783474 TI - Copper-induced oxidative stress in three-spined stickleback: relationship with hepatic metal levels. AB - The aim of this study was to characterise biomarker responses in three-spined sticklebacks exposed to copper. For this purpose, adult sticklebacks were exposed for 3 weeks to copper sulphate at 0, 25, 100 and 200MUgL(-1) as Cu. At days 4, 8, 12 and 21, several parameters were measured including liver, gonad and spleen somatic indexes, hepatic biomarkers (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), glutathione-S-transferase (GST) and 7-ethoxyresorufin-O-deethylase (EROD)) and hepatic copper and zinc concentrations. Copper induced a rapid and transient increase of antioxidant enzymes and a depletion of glutathione content during the first 8 days of exposure. Significant copper and zinc accumulation in fish liver were observed for the two higher exposure concentrations after 8 and 12 days, respectively. This study showed that copper induced an oxidative stress in fish liver before significant metal accumulation in the liver could be detected, suggesting the involvement of differential mechanisms in copper uptake and metabolism. Three spined stickleback appears to be a sensitive model to study oxidative stress induced by metals. PMID- 21783475 TI - Responses of the antioxidant defenses of the Goldfish Carassius auratus, exposed to 2,4-dichlorophenol. AB - Goldfish Carassius auratus were exposed to 0.1mg/l of 2,4-dichlorophenol (2,4 DCP), widely used as transportation power in China, for 2, 5, 10, 20 and 40 days, while one control group was designated for each exposure group. Antioxidant defenses consisting of contents of reduced glutathione (GSH) and glutathione disulfide (GSSG) and activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), selenium-dependent glutathione peroxidase (Se-GPx) and glutathione S-transferase (GST) in liver of freshwater fish were determined and the GSH-GSSG ratio and content of tGSH (total glutathione) were calculated. In the present study, the role of hepatic antioxidant defenses was evaluated and the possible poisoning mechanism of fish can be explained as an oxidative stress mechanism. In addition, hepatic SOD and GSH, especially tGSH, were sensitive to 2,4-DCP contamination and thus, can possibly be used in early assessment of 2,4 DCP-dominant polluted aquatic ecosystems. PMID- 21783476 TI - Effects of malathion subchronic exposure on rat skeletal muscle glucose metabolism. AB - Regarding the widespread use of organophosphorous pesticides (OP) especially malathion in environment and reported cases of muscle disturbances in human and animal, the present work was undertaken to explore effects of malathion subchronic exposure on rat leg skeletal muscle glucose metabolism by measuring key enzymes of glycogenolysis and glycolysis. Malathion was administered through food for 4 weeks at concentrations of 100, 200, and 400ppm to rats. Activities of enzymes including glycogen phosphorylase (GP), hexokinase (HK), and phosphofructokinase-1 (PFK) were measured in skeletal muscle homogenate of exposed rats. Levels of glucose and insulin were measured in blood. Four weeks administration of malathion at doses of 200 and 400ppm increased blood glucose concentrations to 44.4 and 60.6% of control, respectively. Malathion at doses of 200 and 400ppm increased blood insulin concentration to 36.6 and 143.2% of control, respectively. Malathion at doses of 100, 200, and 400ppm increased muscle PFK activity to 40.4, 53.5, and 83.1% of control, respectively. Malathion at doses of 400ppm increased skeletal muscle GP to 91.6% of control. Skeletal muscle HK was not influenced by malathion treatment. It is concluded that malathion influences muscle glycogenolysis and glycolysis as well as secretion of insulin from pancreas which all may explain diabetic potential of malathion. PMID- 21783477 TI - Evaluation of environmental waters using the comet assay in Tilapia rendalli. AB - Testing for environmental pollutants is an ever-growing concern. Various tests in organisms have been utilized for the detection and identification of toxic substances in the air, water and soil. In the present study, we utilized the comet assay in Tilapia rendalli to conduct an environmental assessment of Lake Igapo II, a lake located in the metropolitan area of Londrina, PR-Brazil. The results demonstrated that samples from Lake Igapo II had a significantly greater number of comets, mainly in classes 2 and 3. The results suggest a genotoxicity of the aquatic environment at Lake Igapo II and that the comet assay in T. rendalli provides adequate sensitivity to be utilized as a tool in the monitoring of water pollution and environmental risk assessment. PMID- 21783478 TI - Relative concentrations of organochlorines in adipose tissue and serum among reproductive age women. AB - Much of the available literature focusing on organochlorine exposure and human health effects has relied upon serum for quantifying exposure despite adipose tissue being the purported "gold standard". The accuracy of exposure status is dependent upon serum being a valid and reliable proxy for adipose tissue regardless of compound under study and served as the impetus for study. Serum and omentum fat concentrations for 62 polychlorinated biphenyls (PCBs) and 7 organochlorine pesticides (OCPs) were determined using gas chromatography with electron capture and compared to assess their relative abundance and correlation among 15 women aged 18-40 years undergoing laparoscopy. The relation between concentration in serum and fat was determined by linear regression. Of the 20 organochlorines (OCs) (29%) present in both serum and fat samples, moderate linear correlations (r > 0.6) were observed between lipid-adjusted serum and fat concentrations for PCBs #138, 153, 180, 188, 194, 206, and DDE. Forty-nine OCs were present in adipose samples but measured below the LOD in serum samples. Our findings underscore the potential for discrepant human health results associated with OC exposure on the basis of medium used for quantification purposes, especially for less ubiquitous compounds or when study samples include individuals with relatively low exposures. These data support earlier findings and argue for concerted methodological work aimed at developing standardized laboratory methods for epidemiologic studies. PMID- 21783479 TI - Exposure to pesticides increases levels of uPA and uPAR in pre-malignant human prostate cells. AB - Pesticides are associated with prostate carcinogenesis and mortality; however, their exact mechanisms of action are poorly defined. We have used a transformed but non-tumorigenic human prostate epithelial line to determine the effect of common herbicides and insecticides on expression of urokinase and its receptor, uPAR. The herbicide Roundup and insecticides Lorsban and Warrior induced uPA while Lorsban and Warrior also induced uPAR. Furthermore, a combination of Roundup + Lorsban or Roundup + Warrior produced greater increases in uPA and uPAR than when agents were used alone. Both active and "inactive" chemicals within these pesticides are important for the effects observed as the neat chemicals alone failed to induce uPA and were less potent inducers of uPAR. Thus, specific pesticide formulations, especially when combined, can increase uPA and uPAR expression in vitro in transformed prostate epithelial cells. PMID- 21783480 TI - Decreased membrane fluidity and hyperpolarization in aluminum-treated PC-12 cells correlates with increased production of cellular oxidants. AB - Effects of aluminum (Al) on membrane properties of excitable cells are not fully understood. Several reports have identified cellular membranes as sensitive targets for Al intoxication. In the present study, we tested the hypothesis that treatment with Al would alter membrane fluidity and potential and these changes would correlate with aberrant generation of cellular oxidants. The effects of in vitro Al exposure in resting rat pheochromocytoma (PC-12) cells, a model that exhibits neuron-like properties, were investigated. Treatment of PC-12 cells with Al (>0.01mM) resulted in a concentration-dependent decrease in membrane fluidity. Similar concentrations of Al increased the rate of extracellular acidification, measured by a cytosensor microphysiometer, indicating stimulation of proton extrusion from cells. This change in proton extrusion was accompanied by a rapid and concentration-dependent hyperpolarizion of the cell membrane as determined by decreased fluorescence of a potential-sensitive dye, bis-[1,3-dibutylbarbituric acid]trimethine oxonol [Dibac(4)(3)]. Al-induced perturbations of membrane properties correlated with an increased level of cellular oxidants, indicated by increasing dihydrorhodamine 123 oxidation. Results suggest that acute exposure to Al modifies membrane properties of neuron-like cells and therefore cellular membranes represent a plausible target for Al neurotoxicity. Alterations in membrane potential can have a dramatic impact on cellular communication especially in neurons and may be an important mechanism in Al neurotoxicity. PMID- 21783481 TI - T-Screen as a tool to identify thyroid hormone receptor active compounds. AB - The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumour cell line (GH3) in serum-free medium. It can be used to study interference of compounds with thyroid hormone at the cellular level, thus bridging the gap between limitations of assays using either isolated molecules (enzymes, transport proteins) or complex in vivo experiments with all the complex feedback mechanisms present. Compounds are tested both in the absence and presence of thyroid hormone (EC(50) concentration of T(3)) to test for both agonistic and antagonistic potency. Thyroid hormones (3,3'-5-triiodothyronine: T(3) and 3,3',5,5'-tetraiodothyroxine: T(4)) and compounds resembling the structure of thyroid hormones (3,3'-5-triiodothyroacetic acid: Triac; 3,3',5,5'-tetraiodothyroacetic acid: Tetrac) induced cell growth, with the rank order Triac > T(3) > Tetrac > T(4) (relative potency = 1.35 > 1 > 0.29 > 0.07), which is identical to published affinities of these compounds for nuclear thyroid hormone receptors. Exposure to 5,5'-diphenylhydantoin (DPH) in the presence of 0.25nM T(3) resulted in up to 60% decreased cell growth at 200MUM DPH. No effect of DPH on basal metabolic activity of GH3 cells was observed at this concentration. Fentinchloride (IC(50) = 21nM) decreased cell growth induced by 0.25nM T(3), whereas parallel exposure to these concentrations in the absence of T(3) did not alter basal metabolic activities of GH3 cells. Apolar sediment extracts from the Dommel (34%) and Terneuzen (14%) decreased cell growth in the presence of 0.25nM T(3), whereas the extract from Hoogeveen increased cell growth (26%) and the extract from North Sea Channel had no effect. The T-Screen proved to be a fast and functional assay for assessing thyroid hormone receptor active potencies of pure chemicals or environmental mixtures. PMID- 21783482 TI - Ebselen and diphenyl diselenide do not change the inhibitory effect of lead acetate on delta-aminolevulinate dehidratase. AB - It is known that lead is toxic to several species of animals, and growing data support the participation of oxidative in lead toxicity. Selenium compounds, like diphenyl diselenide and Ebselen have a thiol-peroxidase like and other antioxidant properties. In this work, we determine whether these non-thiol containing compounds with antioxidant properties could reverse the toxicity produced by Pb(2+). Lead acetate injection followed by injection with Ebselen or diphenyl diselenide did not change the levels of non-protein thiol groups (NPSH), whereas simultaneous treatment with lead plus Ebselen reduced NPSH levels in liver. Lead and Ebselen caused a marked reduction in TBARS level in kidney, whereas lead or selenium compounds did not change TBARS levels in brain or liver. Lead acetate inhibited, delta-aminolevulinate dehydratase (ALA-D) activity in blood, liver, kidney and brain. Selenium compounds did not change enzyme activity nor the inhibitory effect of lead acetate in kidney and liver. Ebselen reversed brain ALA-D inhibition caused by Pb(2+). Reactivation index for ALA-D by DTT was higher in lead-treated groups than control groups in all tissues. Lead acetate or selenium compounds did not demonstrate alteration on [(3)H]-glutamate uptake by synaptosomes, whereas lead acetate plus Ebselen showed an increase on [(3)H] glutamate uptake. The results of the present study indicate that ALA-D inhibition antecedes the overproduction of reactive oxygen species, which is becoming well documented in the literature. PMID- 21783483 TI - Methylmercury increases S100B content in rat cerebrospinal fluid. AB - S100B, a calcium binding protein physiologically produced and released by astrocytes, has been used as a peripheral marker of brain damage. Here, we investigated the effects of subcutaneous injections of methylmercury chloride (MeHg-5mg/kg), an environmental neurotoxicant, on S100B protein content in cerebrospinal fluid (CSF) of adult rats. In addition, the performance of animals in an open field (number of squares crossing and rearings) was also analyzed in order to obtain a possible link between alteration in S100B protein content in CSF and parameters related to neurological injury. MeHg treatment increased serum mercury and S100B protein levels in the CSF. A decrease in the numbers of crossings and rearings was observed in MeHg-treated animals when compared to control group, which suggests a possible neurological injury. The present data show, for the first time, increased S100B levels in CSF after exposure to a neurotoxic metal. Authors discuss the possibility of astrocytic involvement in MeHg-induced neurotoxicity. PMID- 21783484 TI - Ebselen and diphenyl diselenide change biochemical hepatic responses to overdosage with paracetamol. AB - The toxicity of paracetamol is largely related to its conversion to the reactive intermediate alkylating metabolite N-acetyl-para-benzo-quinoneimine (NAPQI). delta-Aminolevulinate dehydratase (delta-ALA-D) is a sulfhydril containing enzyme which is extremely sensitive to oxidizing and alkylating agents. In the present study, we examined whether acute treatment with paracetamol changes delta-ALA-D activity. The influence of two organochalcogenides with glutathione peroxidase like activity, diphenyl diselenide [(PhSe)(2)] and ebselen was also assessed as potential protecting agents against paracetamol toxicity. Paracetamol (1200mg/kg for three days 4h after the injection of DMSO, diphenyl diselenide (100MUmol/kg) or ebselen (100MUmol/kg) caused an inhibition of about 40% (P < 0.01) in hepatic delta-ALA-D. Ebselen restored enzyme activity to control values. Non-protein-SH and ascorbic acid were diminished to 50% of control value by paracetamol, independent of chalcogenides treatment (all P values <0.05). In view of the fact that paracetamol caused a massive reduction in non-protein-SH and ascorbic acid, we realize that the protective effect of ebselen on delta-ALA-D activity is mediated by its thiol peroxidase-like activity or by a direct interaction with NAPQI and other reactive species formed during paracetamol metabolism. PMID- 21783485 TI - Androgenic activity in surface water samples detected using the AR-LUX assay: indications for mixture effects. AB - This paper describes the screening of 22 extracts from 18 different aquatic environmental samples for androgenic activity, including indirect and interactive effects on androgen receptor (AR)-mediated signal transduction, using the AR-LUX bioassay. Four samples, originating from an industrial wastewater treatment plant (WTP) or the river Meuse, were shown to contain substantial androgenic activity. Moreover, the samples originating from the industrial WTP showed an enhancement of the maximal androgenic response relative to that elicited by the standard androgen methyltrienolone (R1881) in the AR-LUX assay. This indicates the involvement of cellular mechanisms other than receptor-ligand interaction influencing AR-regulated pathways. This also demonstrates the additional value of cell based assays featuring a more complete array of fully functional interacting pathways. Chemical analysis using GC-MS confirmed the presence of a number of androgens and also estrogens in these WTP samples. Subsequently, we showed that estrone and tributyltin hydride (TBT-H) enhance the response to androgens. This indicates that the presence of numerous compounds in addition to androgens in environmental mixtures might very well result in a more profound perturbation of the normal physiology of exposed organisms than estimated based on the androgen levels alone. Therefore, risk assessment of environmental samples should include an evaluation of the presence and the interactive effects of (ant)agonists of carefully selected relevant cellular receptors in order to provide a realistic estimate of the integrated ecotoxicological risk of the compounds present. PMID- 21783486 TI - Reduced thyroxine levels in mice perinatally exposed to polybrominated diphenyl ethers. AB - The aim of the study was to follow plasma thyroxine levels and hepatic enzyme activities in offspring after maternal gestational and lactational exposure to polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls. Mice were given 10 equimolar oral doses from gestational day (GD) 4 to postnatal day (PND) 17 of either Bromkal 70-5DE, 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) or Aroclor 1254 (total dose of 0.80mmol/kg, b.w.). Plasma thyroxine levels were reduced in offspring in the Aroclor and Bromkal groups on PND11 but had returned to control levels by PND37. No effects on thyroxine levels were seen in the dams. Hepatic activity of EROD was increased in all treated offspring groups and so was UDP-GT in Aroclor-exposed offspring on PND11 and PND18. This study shows that PBDEs and PCBs, probably after microsomal transformation, have endocrine disrupting properties in perinatally exposed juvenile mice, most pronounced at PND11. However, BDE-99 had no effect on thyroxine levels, suggesting that other components in Bromkal are responsible for the hypothyroxinemia. PMID- 21783487 TI - On the mechanisms involved in antinociception induced by diphenyl diselenide. AB - In this study, we described the local peripheral antinociceptive activity produced by diphenyl diselenide in the formalin test as compared to ebselen, an amply studied organoselenium compound. A second objective was to evaluate, the possible mechanisms underlying the antinociceptive effect caused by diphenyl diselenide. Administration of diphenyl diselenide or ebselen produced a significant antinociceptive local effect on the late phase (15-30min) of the formalin test. As well, diphenyl diselenide and ebselen injected in the contra lateral paw produced a significant decrease in licking time on the late phase (15 30min). The mechanisms underlying the analgesic action of diphenyl diselenide seem to be unlike the activation of opioid, dopaminergic D2, muscarinic cholinergic receptors or the interaction with alpha(1) and alpha(2) adrenoceptors. Furthermore, the effect of a 5-HT(3) receptor antagonist in abolishing the antinociception induced by diphenyl diselenide suggests the involvement of serotonergic pathways. PMID- 21783488 TI - AMP deaminase in vitro inhibition by xenobiotics A potential molecular method for risk assessment of synthetic nitro- and polycyclic musks, imidazolium ionic liquids and N-glucopyranosyl ammonium salts. AB - The usefulness of in vitro AMP deaminase inhibition was examined as a potential molecular method in risk assessment of xenobiotics. The enzyme participates in the principal purine nucleotide interconversion and degradation pathways, and its absence caused perturbations in the cellular ATP pool. The compounds selected were synthetic musks with a known negative environmental impact and the toxicologically unknown ionic liquids and N-glucopyranosyl ammonium bromides, which have recently attracted much interest from the chemical and related industries. All the compounds tested demonstrated a dose-dependent inhibition of AMP deaminase activity. IC(50) ranged from 0.3MUM for polycyclic musks to 500MUM for N-glucopyranosyl trimethylammonium bromide. Analysis of Dixon plots showed the inhibition type for all the compounds to be noncompetitive. The results support the choice of such an assay for the prospective risk assessment of these compounds. PMID- 21783489 TI - Comparison of the structure of key variants of microcystin to vasopressin. AB - Microcystins (MCs) are cyclic heptapeptide compounds [where X(2) (position 2) and Z(4) (position 4) are variable l-aminoacids] produced by cyanobacteria and responsible for severe liver damage in animals ingesting acute doses of the toxic compounds. Certain variants of microcystins are more toxic than others, the differences being commonly ascribed to the hydrophobic nature of the variant. Microcystin-LR (MCLR) [X = l-leucine (L); Z = l-arginine (R); R1 = R2 = CH(3)] is the most toxic of all the microcystins investigated to date. This study investigates the similarity of the structures of MCLR and selected MC variants to the liver specific hormone vasopressin. Structures were compiled in HyperChem((r)) (professional version 5.1). Initial comparisons of the MCLR and vasopressin indicated comparable volumes, surface areas and masses. Further studies using RMS overlays show that the microcystin derivative MCLR(Dha(7)) is comparably similar to vasopressin in terms of tertiary structure. PMID- 21783490 TI - Enhanced contractility of vascular smooth muscle after brief exposure to arsenate. AB - Epidemiological studies indicate that arsenic exposure induces hypertension. We hypothesized that arsenate exposure modulates the contractility of vascular smooth muscle through the stress response. Intraperitoneal injection of sodium arsenate (15mg/kg) 16h before increased not only the blood pressure of rats but also the pressor response to preganglionic nerve stimulation (2 and 16Hz) or to bolus injection of vasopressin or phenylephrine in pithed rats as compared with the control rats. Exposure of rat aortic rings to 4mM sodium arsenate for 60min enhanced the contractile responses to KCl or phenylephrine as well as the HSP 70 expression 8h later, but did not affect the relaxation responses to acetylcholine, histamine, or sodium nitroprusside. These results suggest that brief exposure to arsenate is associated with enhanced contractility of vascular smooth muscle through the stress response. PMID- 21783491 TI - Lindane stimulates neutrophils by selectively activating phospholipase C and phosphoinositide-kinase activity. AB - The organochlorine insecticide lindane is a known activator of neutrophil responses. In this work we delineated the biochemical pathways by which lindane stimulates neutrophil oxidant production. Plasma membrane GTPase activity was not stimulated by lindane, ruling out a role for lindane-induced activation of G proteins or G-protein coupled receptors, whereas inhibition of phospholipase C inhibited lindane-induced oxidant production. Together these data pointed to phospholipase C as the direct target of lindane activation. Type I phosphoinositide 3-kinase was not significantly activated by lindane and an inhibitor of phosphoinositide 3-kinases inhibited oxidant production by only 40%. Thus, Type I phosphoinositide 3-kinase played a minor role, if any, in lindane induced oxidant production. Lindane stimulated an increase in phosphatidylinositol phosphate suggesting a Type II or III phosphotidylinositol 3 kinase or phosphatidylinositol 4-kinase activity was also stimulated. PMID- 21783492 TI - Responsiveness of extracellular dopamine in the nucleus accumbens to systemic quinpirole and eticlopride is modulated by low-level lead exposure. AB - Environmental lead exposure has been linked to learning and memory impairments as well as psychosocial deficits in children. Although the precise mechanisms by which lead exerts these effects are not completely understood, experimental animal studies suggest the involvement of mesolimbic dopamine system. Here, we investigated the effects of post weaning, 90-day exposure to 50ppm lead on the responsiveness of extracellular dopamine in the nucleus accumbens core to quinpirole and eticlopride using in vivo microdialysis in anesthetized Long-Evans rats. Attenuation of dopamine release by 1mg/kg quinpirole was more pronounced in lead-exposed rats compared to control rats. In contrast, eticlopride did not significantly modulate extracellular dopamine in lead-exposed rats as it did in the control group. Taken together, these results provides further evidence that exposure to environmentally relevant levels of lead disrupts mesolimbic dopamine system function, at least in part, through perturbations of D(2) receptor systems. PMID- 21783493 TI - Inhalation of cadmium, lead or its mixture Effects on the bronchiolar structure and its relation with metal tissue concentrations. AB - The human population in the industrialized world is constantly exposed to chemical mixtures of pollutants such as metals; information about the consequences of the interactions of these compounds on health is scarce. The current study examines the effects of the inhalation of lead (Pb), cadmium (Cd) and Pb-Cd mixture in mice models analyzing the metal concentrations in lung, and the morphological modifications in the bronchiolar epithelium identified by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) after 4 weeks of inhalation. Our results showed that metal concentrations in lung were higher compared to controls; however, Pb concentrations drastically decrease with the mixture. This reduction was also observed in the inhalation chamber. These data correlate with the morphological alterations observed, which consisted of flattened and decreased number of nonciliated bronchiolar cells (NCBC), bald ciliated cells and bundles of NCBC. These modifications were mainly given by Cd, alone or in combination with Pb. The clusters formed by NCBC cells suggest cell proliferation which probably means that after metal inhalation, the cells enhance their proliferative capacity in order to repopulate the bronchiolar wall. PMID- 21783494 TI - Biological markers for metal toxicity. AB - Exposure assessment is often considered the weakest link in risk assessment. It is important for investigators to continue to utilize the full potential of biomarkers for chemicals whose exposure is of global concern. This review is concerned with the biomarkers of metal toxicity, as the overall exposure to metals encountered occupationally or in the environment would continue causing indirect, delayed effects therefore ecoepidemiology, using designed molecular probes and noninvasive diagnostics will be the leading component for future management of environmental health. An attempt is made here at appraising the need for the development of more biomarkers for use in environmental epidemiology and health risk assessment. PMID- 21783495 TI - Impact of fertilizer (urea) on oxygen consumption and feeding energetics in the fresh water fish Oreochromis mossambicus. AB - The effects of urea on survival, food utilization and oxygen consumption of the fresh water fish Oreochromis mossambicus were studied. The percentage survival of O. mossambicus when exposed to different concentrations of urea at 24, 48, 72 and 96h exposures was noted and it was found that 22,000 and 38,000mgL(-1) urea concentration were sublethal and lethal, respectively. The median lethal concentration, which killed 50% of the fishes during 96h exposure, was 28,000mgL( 1). Rearing the fish in increasing sublethal concentrations of urea, it was found that the feeding rate decreased from 34.341+/-7.067mgglivefish(-1)d(-1) (control) to 13.921+/-2.315mgglivefish(-1)d(-1) at the highest concentration of urea (22,000mgL(-1)). Growth rate was drastically reduced. The consumption of oxygen in O. mossambicus diminished from 0.962+/-0.208 to 0.645+/-0.118mgglivefish(-1)h( 1) when reared in the highest sublethal concentration of urea. PMID- 21783496 TI - Growth and heavy metals removal efficiency of Nostoc muscorum and Anabaena subcylindrica in sewage and industrial wastewater effluents. AB - The growth of Nostoc muscorum and Anabaena subcylindrica in sterilized sewage wastewater and N. muscorum in sterilized wastewater of El-Soda Company was higher than those grown in Allen synthetic medium. Whereas, the growth of A. subcylindrica in El-Soda Company sterilized wastewater and N. muscorum as well as A. subcylindrica grown in Verta Company sterilized wastewater was slightly lower than that grown in the standard synthetic medium. The contents of chlorophyll a, carotenoids and protein of N. muscorum and A. subcylindrica grown in sterilized sewage wastewater were higher than those grown in the standard medium. Similarly, N. muscorum and the bio-mixture of N. muscorum and A. subcylindrica grown in the sterilized wastewater of El-Soda Company showed high pigments and protein contents more than those reared in Allen medium. On the other hand, the bio mixture of N. muscorum and A. subcylindrica grown in the sterilized sewage wastewater, A. subcylindrica grown in El-Soda Company and Verta Company sterilized wastewater showed lower contents of pigments and protein compared to synthetic medium. Heavy metals, copper, cobalt, lead and manganese were removed by 12.5-81.8, 11.8-33.7, 26.4-100 and 32.7-100%, respectively, from wastewater by using cyanobacterial cultures. The metal sorption efficiency depended on the type of biosorbent, the physiological state of the cells, availability of heavy metal, concentration of heavy metal and chemical composition of wastewater. It was observed also that the single cultures in most cases was better than the mixed cultures in heavy metal removal, this may be due to the cyanobacterial competition for nutrients in mixed cultures. PMID- 21783497 TI - Decrease in brain serotonin level and short term memory loss in mice: a preliminary study. AB - Most of the information on the effects of benzene center around its hematotoxic and genotoxic effects. However, its effect on central neurotransmitters is inconclusive in terms of cognitive behavior of the host. The present results showed for the first time that chronic exposure to benzene, in drinking water, significantly inhibited serotonin (5-hydroxytryptamine (5-HT)) level in serotonergic neuron rich regions of the murine brain. This was paralleled with loss of short term memory, as evidenced by passive avoidance test, of the benzene treated animals. PMID- 21783498 TI - Acrylonitrile-induced toxicity and oxidative stress in isolated rat colonocytes. AB - Acrylonitrile (ACN), an environmental toxic pollutant, has been detected in drinking water, food products and occupational environment. The objective of the present work was to investigate the cytotoxic effects as well as the oxidative stress induced by ACN in cultured rat colonocytes. Colonocytes were exposed in vitro to different concentrations of ACN (0.1-2.0mM) for 60min. Also, colonocytes were incubated with ACN (1.0mM) for different time intervals extending to 180min. Cytotoxicity was determined by assessing cell viability and lactate dehydrogenase (LDH) release. Oxidative stress was assessed by determining reduced glutathione (GSH) level and lipid peroxidation as indicated by thiobarbituric acid reactive substances (TBARS) production. Exposure of colonocytes to ACN (1.0mM) for 60min caused nearly a 50% decrease in cell viability and induced a 2.5-fold increase of LDH leakage. In the same experiment, ACN caused a significant decrease in cellular GSH content as well as a significant enhancement of TBARS accumulation. These toxic responses to ACN were dependent on both concentration and duration of exposure to ACN. There was a good correlation between LDH release and TBARS formation (r(2)=0.97, p<0.05). Treatment of colonocytes with GSH, N-acetyl-l cysteine (NAC) or dithiothreitol (DDT) prior to exposure to ACN afforded different degrees of protection as indicated by significant decrease in the LDH leakage and TBARS formation as compared to ACN alone-treated cells. Also, pretreatment of colonocytes with the antioxidant enzyme superoxide dismutase (SOD) or catalase (CAT) significantly inhibited LDH leakage and TBARS production. Preincubation with dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger or desferroxiamine (DFO), an iron chelator, diminished ACN-induced LDH leakage and TBARS generation. Our results suggest that ACN has a potential cytotoxic effect in rat colonocytes; and thiol group-donors, antioxidant enzymes, hydroxyl radical scavengers and iron chelators can play an important role against ACN-induced colonotoxicity. PMID- 21783499 TI - The distribution patterns of trace elements in the blood and organs in a rabbit experimental model of copper pollution and study of haematology and biochemistry parameters. AB - In a rabbit model of five copper overfeeding, we investigated the distribution pattern of trace elements of copper [Cu], zinc [Zn], chromium [Cr], manganese [Mn], and selenium [Se] in blood serum, red cell, and whole blood and in the organs: brain, gallbladder, liver, intestines, heart, kidney, lung, and spleen. Furthermore, their haematology and biochemistry parameters as well as feed consumption and weight development were also performed in this study. Changes in trace element concentrations were determined by contrast and control group. Observably, the increased concentrations of Cr were observed in the heart; that of Cu, Zn, Cr, Mn in the liver; that of Cu, Cr, Mn in the intestines; that of Cu in the spleen; that of Cu in the blood serum; and that of Cu in the whole blood. But remarkably, the decreased concentrations of Mn were observed in heart; that of Zn and Se in the encephalon; that of Cr, Mn and Se in the spleen and that of Zn in the blood serum. In the gallbladder, the concentrations of Zn, Cr, Mn, and Se were also reduced. Excessive Cu was accumulated mainly in liver, intestines, and blood serum. In contrast group, only a few changes were detected in excretion of Mn, Zn, and Cr, but increased concentrations of Cu and Se compared with the control group. For the different biochemistry parameters measured, the contrast group showed changes, mainly owing to the altered activity of enzymes induced by trace element excess and imbalance. Increased concentrations of LDL were measured in contrast group, while a substantial decrease was seen in TG and VLDL as a result of excessive Cu. Regarding haematological parameters, increased concentrations of NEUT% and EO% were found in contrast group, but considerably decreased concentrations were detected in PLT, MONO%, BASO%, MONO#, BASO#, and P LCR, but a minor decrease was also seen in EO#. The present paper shows the effect of copper pollution in the animals and analyzes the interplay among trace elements in their bodies at length. It is significant for environment protection and toxicology study. PMID- 21783501 TI - Foreword. PMID- 21783500 TI - Novel screening test to assess the potential environmental toxicity of waste water samples. AB - Biological effects of waste water samples were investigated using the method for isometric contraction measurements that is widely employed in the medical field for studying the effects of various drugs on heart and smooth muscle preparations. Raw waste water samples from a municipal treatment plant were extracted with chloroform and diluted in dimethylsulfoxide. Some samples were also digested with NaOH or microwave. Our results show that the test is sensitive for the investigation of waste water samples. The liquid part of the samples exerted a more potent relaxing effect on terminal ilea than the solids. Alkaline (NaOH) or microwave treated samples showed similar effects as untreated samples. Therefore we conclude that the major part of the reactive agent might be located in the liquid phase. We also demonstrate with this study that the used method enables the screening of waste water samples and their effect on terminal ilea. This method might be a tool to assess the environmental relevance of complex environmental samples. PMID- 21783502 TI - Editorial. PMID- 21783503 TI - Diet-brain connections: role of neurotoxicants. AB - In certain cases, the consumption of food or beverages can lead to intoxication and disease. Such food-induced intoxications may be due to microbial toxins, to toxic substances naturally occurring in some foods, or to contaminants or residues of various kinds. Some of these agents have neurotoxic properties and may contribute to the etiology of certain psychiatric disorders or neurodegenerative diseases. This paper reviews a selected number of dietary neurotoxicants that naturally, or as a result of human interventions, find their way into food or beverages, and have been associated with neurotoxic outcomes in humans. Chosen examples include domoic acid, a phycotoxin associated with amnesic shellfish poisoning; beta-N-oxalylamine-l-alanine (l-BOAA), present in chickling peas and believed to be responsible for neurolathyrism; and two alcohols, methanol and ethanol, which can cause severe neurotoxic effects in adults and the developing fetus. PMID- 21783504 TI - Risk of human exposure to paralytic toxins of algal origin. AB - The most significant neurotoxins produced by harmful algal blooms (HABs) are paralytic shellfish toxins (PSTs) found in shellfish and freshwater. Human exposure to neurotoxins through the food consumption represents a severe hazard to human health and the exposure through contaminated water represents an added risk often difficult to recognize. Furthermore, there is an insufficient knowledge of toxicokinetics of these complex toxins produced by HABs. If human acute exposure occurs, the diagnosis of intoxication is typically based upon symptomatology and analysis of shellfish tissue by mouse bioassay, HPLC-FLD analysis and mouse neuroblastoma assay. However, the health risks due to chronic exposure should also be considered and its prevention could be reached with a better understanding of sub-lethal doses of these toxins. In this context, information required for development of a diagnostic protocol should include knowledge about toxicokinetics and toxicodynamics of these neurotoxins. We emphasise the importance of research on biomarkers to prevent, predict and diagnose acute and chronic human exposure to PST. PMID- 21783505 TI - Atypical parkinsonism on Guadeloupe, comparison with the parkinsonism-dementia complex of Guam, and environmental toxic hypotheses. AB - INTRODUCTION: : On Guadeloupe, atypical parkinsonism is abnormally frequent, and represents 75% of progressive parkinsonism while Parkinson's disease (PD) accounts for only 25%, which is an inversed percentage in comparison with Europe. Herbal tea made with Annonaceae leaves (containing benzyltetrahydroisoquinolines (Be-TIQ), tetrahydroprotoberberines (THPB) and acetogenins (potent mitochondrial complex I inhibitors) are commonly used on Guadeloupe. CLINICAL STUDY: : Of 265 patients studied on Guadeloupe, 66 (25%) had PD, and 199 (75%) had atypical parkinsonism. This latter group includes 58 patients (29%) with progressive supranuclear palsy (PSP), and 100 patients (50%) with unclassifiable parkinsonism (UP). This focus resembles the parkinsonism-dementia complex (PDC) described on Guam, where a very high prevalence of atypical parkinsonism has been reported since the second World War, including one-third of PSP. A preliminary case control study on Guadeloupe showed a significant higher consumption of fruits and herbal tea of Annonaceae in atypical parkinsonian cases (PSP and unclassifiable parkinsonism, UP), compared to hospital controls and to idiopathic PD. DISCUSSION: : The overrepresentation of atypical parkinsonism on Guadeloupe and Guam could be related to the consumption of plants containing (simultaneously) isoquinoline derivates which are toxic for dopaminergic neurons and inhibitors of the mitochondrial respiratory chain such as acetogenins. This hypothesis is in keeping with epidemiologic data and experimental studies showing neuronal loss after exposure to isoquinolines or acetogenins. PMID- 21783506 TI - Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration. AB - For nearly a century, manganese has been recognized as an essential nutrient for proper bone formation, lipid, amino acid and carbohydrate metabolism. While manganese deficiency is characterized by symptoms ranging from stunted growth and poor bone remodeling to ataxia, it is manganese toxicity that is far more devastating from a public health standpoint. Most cases of manganese toxicity are the result of occupational exposure to high levels of the metal, and are characterized by specific neurological symptoms referred to as manganism. While manganism shares many common features with Parkinson's disease, there are distinct differences between the two disorders suggesting that manganism might indirectly affect nigrostriatal dopaminergic function. Recent studies from our laboratory show that dietary iron deficiency is a risk factor for brain manganese accumulation and that the striatum is particularly vulnerable. This review briefly discusses manganese from nutritional and toxicological aspects. PMID- 21783507 TI - A secondary metabolite, 4,5-dibromopyrrole-2-carboxylic acid, from marine sponges of the genus Agelas alters cellular calcium signals. AB - A secondary metabolite from sponges of the genus Agelas, 4,5-dibromopyrrole-2 carboxylic acid, which is well known as feeding deterrent, was investigated for effects on the cellular calcium homeostasis in PC12 cells. 4,5-Dibromopyrrole-2 carboxylic acid did not change intracellular calcium levels if applied alone without cell depolarization. During depolarization of the cellular membrane using high potassium solution, a dose dependent reduction of intracellular calcium elevation was revealed utilizing Fura II as calcium indicator. Significant reduction was seen at concentrations higher than 30MUM in a series of experiments, but in single experiments a concentration of 300nM was still reversible effective. In the same concentration range, the onset of depolarization induced calcium elevations was significantly delayed by 4,5 dibromopyrrole-2-carboxylic acid. Dose dependent reduction and delay of depolarization evoked calcium elevations are probably due to a reduction of calcium entry via voltage operated calcium channels. One cellular mode of action of the feeding deterrent potential of 4,5-dibromopyrrole-2-carboxylic acid to fishes may be an interaction with the cellular calcium homeostasis of exposed cells. PMID- 21783508 TI - Can cholinesterase inhibitors affect neural development? AB - Accumulating evidence supports the view that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can influence the proliferation and differentiation of nerve cells. AChE in particular has been found to promote neurite outgrowth in a variety of model systems, possibly by serving as an adhesion molecule. Thus one might suspect that cholinesterase inhibitors would disturb neuronal development, with long-term implications for structure and function in the central and peripheral nervous systems. The actual picture is more complex because AChE's effects on neurite outgrowth may reflect protein-protein interactions that are not directly related to catalytic function but are nonetheless influenced by ligands with special structural features. The putative structural interactions have not yet been rigorously defined, but they are likely to involve enzyme regions at or near the peripheral anionic site. In addition to such effects, some organophosphorus anticholinesterases have been reported to act by still other mechanisms to depress macromolecule synthesis and cell survival in the developing brain. Taken together, this emerging information highlights the potential importance of anticholinesterase agents in developmental neurotoxicology. PMID- 21783509 TI - Pharmacology and toxicology of cholinesterase inhibitors: uses and misuses of a common mechanism of action. AB - Cholinesterase inhibitors have been used in the treatment of human diseases, the control of insect pests, and more notoriously as chemical warfare agents and weapons of terrorism. Most uses of cholinesterase inhibitors are based on a common mechanism of action initiated by inhibition of acetylcholinesterase (AChE). Extensive inhibition of this enzyme leads to accumulation of the neurotransmitter acetylcholine and enhanced stimulation of postsynaptic cholinergic receptors. This action is beneficial in cases where a reduction in cholinergic transmission contributes to clinical symptoms, e.g., low muscle tone in the autoimmune disorder myasthenia gravis due to loss of nicotinic receptors. Under normal conditions, however, extensive inhibition of AChE leads to excess synaptic acetylcholine levels, over-stimulation of cholinergic receptors, alteration of postsynaptic cell function and consequent signs of cholinergic toxicity. This biochemical cascade forms the basis for the use of anticholinesterase insecticides in pest control as well as for nerve agents in chemical warfare. Paradoxically, the short-acting cholinesterase inhibitor pyridostigmine, an important therapeutic agent in the treatment of myasthenia gravis, was used during the Persian Gulf War to prevent the long-term clinical consequences of possible organophosphate nerve agent exposure. As shown in the attacks in Matsumoto and Tokyo, these same nerve agents can be effectively used to inflict urban terror. Cholinesterase inhibitors thus share a common mechanism of pharmacological or toxicological action, ultimately modifying cholinergic signaling through disruption of acetylcholine degradation. While the use of cholinesterase inhibitors relies on their interaction with AChE, a variety of reports indicate that a number of cholinesterase inhibitors have additional sites of action that may have pharmacologic or toxicologic relevance. A variety of esterase and non-esterase enzymes, neurotransmitter receptors and elements of cell signaling pathways are targeted by some anticholinesterases. In some cases, these actions may occur at concentrations/dosages below those affecting cholinergic transmission. Studies of interactive toxicity of binary mixtures of common organophosphorus insecticides indicate that non-cholinesterase targets may be important in cumulative toxicity. Exposure to multiple anticholinesterases having selective effects on other macromolecules could confound the assumption of additivity in cumulative risk assessment. Knowledge of such selective additional targets may aid, however, in the optimization of strategies for poisoning therapy and in the further elucidation of mechanisms of toxicity for this class of compounds. PMID- 21783510 TI - Acute and chronic effects of sarin exposure from the Tokyo subway incident. AB - The Tokyo subway sarin attack was the second documented incident of nerve gas poisoning in Japan. The St. Luke's International Hospital received 640 patients on the day of the attack. Reduction in plasma cholinesterase (ChE) activity was generally associated with the severity of acute signs of toxicity. With time and treatment, the value rose quickly. To evaluate possible residual signs of symptoms 1 year after the attack, we sent questionnaires to the victims; of 303 respondents, 45% still had some symptoms including eye problems, easy fatigability, headache, and fear. Therefore, we conducted a study in collaboration with investigators at the Tokyo University Department of Public Health to evaluate possible long-term neuropsychological sequelae. The findings suggest the need to closely follow such patients for possible persistent functional changes. PMID- 21783511 TI - Novel protein targets for organophosphorus pesticides in rat brain. AB - We report preliminary results from a proteomic search for rat brain protein targets adducted by organophosphorous pesticides. Azamethaphos, chlorfenvinphos, diazinon, malathion and chlorpyrifos oxons (in rat brain homogenates) or pirimiphos-methyl (after systemic treatment) were tested at levels producing no more than 30% inhibition of brain acetylcholinesterase. Loss of reactivity with tritiated diisopropylflurophosphate was taken as proof of adduction by the test organophosphate. In addition to acetylcholinesterase other, previously unrecognised, adducted proteins were detected in total brain protein extracts at 30, 32, 41, 71 and 83kDa. Azamethiphos adducted all but the 30 and 32kDa bands, but chlorpyrifos only acetylcholinesterase. PMID- 21783512 TI - Developmental neurotoxicity of chlorpyrifos: targeting glial cells. AB - The pesticide chlorpyrifos (CPF) causes neurobehavioral damage, even at doses that do not elicit acute cholinergic toxicity. CPF disrupts the developing brain during glial proliferation and differentiation. Since glial cells play critical roles in brain development and function, we hypothesized that CPF neurotoxicity involves alteration of glial cell development. CPF effects in C6 glioma cells mirrored effects in the intact brain: inhibited DNA synthesis; interfered with adenylyl cyclase (AC) signaling; obstructed DNA binding to transcription factors involved in cell differentiation; and enhanced reactive oxygen species (ROS) formation. CPF was administered to prenatal and neonatal rats and examined for markers of astrocytes, oligodendrocytes, and neurons. Widespread effects were elicited by exposure during the peak period of gliogenesis. Males were preferentially targeted during postnatal exposures while females experienced delayed effects following gestational exposure, commensurate with behavioral outcomes. Alterations in glial cell development contribute to CPF neurotoxicity, extending vulnerability to myelination, synaptic plasticity, and architectural modeling, which continue into adolescence. PMID- 21783514 TI - Plasma acetylcholinesterase as a biomarker of triazophos neurotoxicity in young and adult rats. AB - The organophosphate pesticides exhibit their action by inhibiting acetylcholinesterase (AChE) enzyme in central and peripheral nervous system. They are known to affect the young animals to a greater extent, as their developing brain is more susceptible to their toxic effects. Besides inactivating acetylcholine at synaptic terminals AChE also plays an important role in neuronal growth and differentiation. A reduction in AChE activity in plasma has no known physiological function in causing brain or tissue damage, but if a good correlation between brain and plasma AChE inhibition exists, then circulating plasma AChE can be used as a reliable marker for detection of cholinesterase inhibitors. Therefore, the present investigation was designed to differentiate age and gender related neurotoxicity of an organophosphate pesticide-triazophos and to explore whether plasma AChE can serve as a biomarker of its neurotoxicity in young, i.e. post natal days 20 (PND 20) and adult rats i.e. post natal days 90 (PND 90) after single intraperitoneal administration in different doses. PMID- 21783513 TI - Life without acetylcholinesterase: the implications of cholinesterase inhibitor toxicity in AChE-knockout mice. AB - The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000*g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP. PMID- 21783515 TI - Acute effects of low doses of methyl parathion on human EEG. AB - Biological monitoring of workers exposed to organophosphates consists mainly of measuring serum or erythrocyte cholinesterase activity. However, animal experiments and a field study suggest that quantitative analysis of EEG may be more sensitive. In a parallel group design, 25 farmers were investigated, spraying methyl parathion or water for 50min. EEG was recorded before and after spraying. Serum and erythrocyte cholinesterase activity was compared with intraindividual pre-exposure values. Plasma methyl parathion concentrations ranged up to 12.1MUg/l, methyl paraoxon was not detectable. Based on plasma concentrations, two exposed subgroups were defined. In EEG recorded with closed eyes, alpha(1)-power increased insignificantly (Kruskal-Wallis test) in both subgroups. beta(1)-power was enhanced in both exposed subgroups, reaching significance (p<=0.05) at five of 17 electrodes. Spearman's rank correlation showed a significant association between methyl parathion plasma concentration and the median of beta(1)-band power of the 17 electrodes (rho=0.48, p=0.015). Cholinesterase activity did not decrease. On a group basis, EEG is possibly more sensitive than cholinesterase. EEG changes suggest brain cholinesterase inhibition following low exposure to methyl parathion. PMID- 21783516 TI - Homology of assessment of visual function in human and animal models. AB - To connect animal models with human neurobehavioral evaluations, it is necessary to understand the level of homology present between tests administered across species. This paper identifies four different levels of homology of assessment based on identity of measurement, function, and underlying neural substrate. These are discussed using detailed examples from toxicology of the visual system, with additional examples from tests of motor and cognitive function. This should provide a framework for considering both animal to human extrapolation and human to animal extrapolation, that is, how to import human experimental epidemiology findings into the lab for further work investigating mechanisms of toxicity. Designing neurobehavioral or sensory evaluations that permit easier extrapolation between human and animal models is necessary if we are to develop testing strategies that take advantage of mechanistic information at whole animal, in vitro, proteonomic, or genomic levels. PMID- 21783517 TI - Neuro-ophthalmologic manifestations of konzo. AB - Konzo is a permanent spastic paraparesis of acute onset attributed to the effect of cyanogenic compounds from insufficiently processed bitter cassava in combination with low protein intake. In all studies of konzo, ophthalmologic complaints have been presented but only recently systematic studies of the neuro ophthalmologic disturbances in konzo have been done. In this review, we see that about half the patients have an optic neuropathy with decreased visual acuity, alterations of the visual fields, atrophy of the temporal part of the retinal nerve fibre layer linked with temporal pallor of the optic disk. About half of the konzo patients also have abnormal visual evoked potentials, with both delayed latency and reduced amplitude. A small number of konzo patients have an ocular motor disturbance leading to a pendular nystagmus. The severity of the neuro ophthalmologic involvement is not parallel to the severity of the motor disturbance in konzo. This may suggest that two different pathogenic mechanisms are involved. PMID- 21783518 TI - Effects of long-term occupational solvent exposure on contrast sensitivity and performance in visual search. AB - Sensitive and easily applicable screening tests are greatly needed for the early detection of nervous system dysfunction in people working with neurotoxic substances. Previous studies have shown that long-term solvent exposure may cause deficits in visual perception. We, therefore, studied the effects of long-term occupational solvent exposure and chronic encephalopathy on performance in three vision tests novel in the present context. Two visual search tasks were used: the letter search test measured the speed of finding a letter in an array of numerals, and the pop-out search test required the observer to detect the presence or absence of a tilted line segment in an array of vertical line segments. With the letter contrast sensitivity test we measured the contrast threshold for the identification of band-pass filtered letters. Before testing, comprehensive eye examination was carried out to reveal any structural or functional abnormality and to ensure correct refraction. The patients had healthy eyes, 2 out of 14 had reduced contrast sensitivity (Vistech) and 5 out of 14 had deficits in colour vision (FM 100). In both visual search tasks, the patients were statistically highly significantly (p<0.001) slower than the age-matched control observers. Instead, in the contrast sensitivity test, the difference between the patient and the control group was small relative to normal variability although still statistically significant (p<0.05). The results suggest that visual search tests can be useful in evaluating and characterising the effects of long-term solvent exposure on visual perception. Because our patients' letter contrast sensitivity was only moderately deteriorated, it seems that the observed defect of visual search cannot be explained by deteriorated letter identification alone, although it can be a contributory factor. Rather, the finding suggests that the speed by which visual information is transmitted and/or processed in the central visual system has become considerably slower. PMID- 21783519 TI - Influence of chronic exposure to organic solvent mixtures on contrast sensitivity in silk-screen printers: matched-pair analysis. AB - The aim of the study was the determination of the influence of chronic occupational exposure to organic solvent mixtures on the contrast sensitivity (CS) of silk-screen printers. Contrast sensitivity was measured for 28 matched (age, sex) pairs of silk-screen printers and controls using the Vision Contrast Test System - VCTS 6500 chart. The duration of exposure to industrial neurotoxic substances was about 9 years. Contrast sensitivity impairments were recorded in 28.6% of the printers for both eyes at several spatial frequencies. Males and females differed in CS significantly, but no interaction between gender (male vs. female) and exposure (printers vs. controls) was found. PMID- 21783520 TI - Low-level styrene exposure and color vision in Swedish styrene workers. AB - Styrene exposure and color vision for 108 workers (21-65 years) was studied at Swedish reinforced plastic plants. Acute exposure was measured at work. Data on past exposures and personal background data were collected by questionnaire. Current exposure varied between 0.3 and 96mg/m(3). Cumulative past exposures varied from 18 to 4455mg years/m(3), and an index of lifetime weighted average exposure (LWAE) varied from 5 to 129mg/m(3). Color vision was tested using the Lanthony D15 desaturated panel binocularly without prior training in conditions with ample light (1400lx). Color vision was slightly correlated to LWAE (r=0.188, p=0.052). Workers were divided into two exposure groups according to LWAE. Analyses of variance revealed effects on the Vingrys' color vision confusion index (F=6.04; p=0.016) and total error (F=6.296; p=0.014). This study thus indicates that styrene exposure even at levels below the current Swedish OEL of 20mg/m(3) may affect color vision negatively. PMID- 21783521 TI - Visual impairment on dentists related to occupational mercury exposure. AB - A detailed assessment of visual function was obtained in subjects with low-level occupational mercury exposure by measuring hue saturation thresholds and contrast sensitivity functions for luminance and chromatic modulation. General practice dentists (n=15) were compared to age-matched healthy controls (n=13). Color discrimination estimated by the area of Mac Adam ellipses was impaired, showing diffuse discrimination loss. There was also reduction of contrast sensitivity for luminance and chromatic (red-green and blue-yellow) modulation, in all tested spatial frequencies. Low concentrations of urinary mercury (1.97+/-1.61MUg/g creatinine) were found in the dentists group. Color discrimination as well as contrast sensitivity function, assessed psychophysically, constitutes a sensitive indicator of subtle neurotoxic effect of elemental mercury exposure. PMID- 21783522 TI - Colour vision and contrast sensitivity losses of mercury intoxicated industry workers in Brazil. AB - We evaluated vision loss in workers from fluorescent lamp industries (n=39) who had retired due to intoxication with mercury vapour and had been away from the work situation for several years (mean=6.32 years). An age-matched control group was submitted to the same tests for comparison. The luminance contrast sensitivity (CSF) was measured psychophysically and with the sweep visual evoked potential (sVEP) method. Chromatic red-green and blue-yellow CSFs were measured psychophysically. Colour discrimination was assessed with the Farnsworth-Munsell 100-hue test, Lanthony D-15d test and Cambridge Colour Vision Test. Patient data showed significantly lower scores in all colour tests compared to controls (p<.001). The behavioural luminance CSF of the patients was lower than that of controls (p<.001 at all frequencies tested). This result was confirmed by the electrophysiologically measured sweep VEP luminance CSF except at the highest frequencies-a difference that might be related to stimulus differences in the two situations. Chromatic CSFs were also statistically significantly lower for the patients than for the controls, for both chromatic equiluminant stimuli: red green (p<.005) and blue-yellow (p<.04 for all frequencies, except 2 cycles per degree (cpd), the highest spatial frequency tested) spatial gratings. We conclude that exposure to elemental mercury vapour is associated with profound and lasting losses in achromatic and chromatic visual functions, affecting the magno-, parvo- and koniocellular visual pathways. PMID- 21783523 TI - Eye blinks as indicator for sensory irritation during constant and peak exposures to 2-ethylhexanol. AB - Two experiments were performed to re-evaluate the sensory irritating properties of 2-ethylhexanol in relation to dose and time and to examine the usability of electromyographic eye blink recordings as indicator of sensory irritation. Mean exposure levels of 1.5, 10 and 20ppm were realized in experimental models simulating either constant or variable 4h exposure. Each study was carried out with two subject samples, healthy young men with self-reported multiple chemical sensitivity (sMCS) and age matched controls. Although 2-ethylhexanol exposure was below the occupational threshold limit value of 50ppm, the study revealed strong dose-response relationships between airborne solvent concentrations and blink rates. During 40ppm peak exposures the blink rate increased threefold. In the course of 4h, exposure blink rates increased significantly showing no adaptation. Subjects with sMCS revealed, with one exception at start of exposure, no significantly higher blink rates than controls. The results indicate that the irritative potential of 2-ethylhexanol is higher than commonly expected. In both exposure scenarios with either constant or peak exposures, electromyographic eye blink recordings were an appropriate method for the examination of acute sensory irritations in time. PMID- 21783524 TI - Oxidative stress: a potential basis for potentiation of noise-induced hearing loss. AB - In the past two decades, researchers have determined that a broad range of environmental and occupational contaminants can interact with noise to enhance noise-induced hearing loss. This manuscript focuses upon the hypothesis that chemicals that promote oxidative stress might increase the risk of noise-induced hearing loss. Evidence is presented that confirms the role of oxidative stress in the production of hearing loss by both carbon monoxide and by acrylonitrile when noise is present at the time of chemical exposure. PMID- 21783525 TI - Exacerbation of noise-induced hearing loss by co-exposure to workplace chemicals. AB - BACKGROUND: : Numerous organic solvents applied in industry, like toluene, styrene, xylene and n-hexane have been demonstrated to impair hearing in animals. However, the effects of exposure to a given organic solvent and the interaction of noise and solvents on hearing in humans are still not fully recognized. STUDY DESIGN: : The study was aimed to assess the effects of occupational exposure to solvents alone or in combination with noise on hearing in 1117 employees of yacht, ship, plastic, shoe, and paint and lacquer industry. These persons were exposed either to the mixture of organic solvents with xylene as the main component, or predominantly to styrene, or to the mixture of n-hexane and toluene. Detailed questionnaire data and pure-tone audiometry were compared with data of the reference group that included white collar workers, exposed neither to solvents nor noise and metal factory workers exposed to noise only. In all statistics, the confounding factors were recognized as gender, age, exposure to noise, and other variables occurring at a different rate in study and reference group. RESULTS: : Odds ratio (OR) of hearing loss related with the particular exposure to chemicals was 2.4 (95%CI 1.59-3.74) in case of solvent mixture, 3.9 (95%CI 2.4-6.2) in case of styrene and 5.3 (95%CI 2.6-10.9) in case of n-hexane and toluene exposure. The odds of developing hearing loss substantially increased in the case of combined exposure to organic solvents and noise as compared to isolated exposure to each of these hazards. The highest OR (over 20-fold) was demonstrated in subgroups of subjects exposed simultaneously to noise and two ototoxic solvents (i.e. styrene and toluene or n-hexane and toluene). The mean hearing thresholds were significantly higher in the solvent-exposed groups than in the reference group. The differences in thresholds were observed at high frequencies in the solvent mixture- and n-hexane + toluene-exposed groups and at all frequencies in the styrene-exposed group. A positive linear relationship existed between exposure to solvents and hearing thresholds at high frequencies. CONCLUSIONS: : The results of the study provide the epidemiological evidence that exposure to organic solvents in humans is associated with an increased risk of hearing loss. The simultaneous exposure to organic solvents and noise seems to enhance the hearing deficit if compared with isolated exposures. PMID- 21783526 TI - Toxicokinetic parameters of toluene in the rat and guinea pig: a comparative study. AB - Toluene is the most widely used industrial solvent. It has been shown to cause cochlear disruptions in rats but markedly less ototoxic effects in guinea pigs. Susceptibility to the ototoxic properties of toluene is, therefore, species specific. In recent publications, an important difference in the solvent concentration in blood has been identified when rats and guinea pigs were exposed in strictly identical experimental conditions. Solvent concentrations in blood were greater in rats than in guinea pigs. The present studies were designed to compare blood affinity and toxicokinetic parameters of toluene in an attempt to understand the susceptibility differences in both species. The in vitro experiment, in which the headspace concentration of toluene was measured within a sealed vial containing blood, highlighted the greater toluene partition coefficient in rat than in guinea pig blood. The in vivo experiment showed that 10min after a single intravenous administration of 28MUL of toluene, the solvent concentration is approximately two-fold lower in guinea pig than in rat blood. Based on the toxicokinetic parameters of toluene and on the relative partition coefficient of toluene in blood, it seems plausible that guinea pigs are not susceptible to organic solvents because the solvent concentration in blood does not reach the concentration required to induce permanent damage. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper. PMID- 21783527 TI - Influence of age on noise- and styrene-induced hearing loss in the Long-Evans rat. AB - This paper reviews different investigations carried out with Long-Evans rats on the influence of age on the ototoxicity induced by styrene and on the vulnerability to noise. The first part of this article is focused on the differences in auditory susceptibility to noise (92 or 97dB octave band noise centered at 8kHz, 6 h/day, 5 days/week, 4 weeks) and styrene (700ppm, 6h/d, 5 d/w, 4 w) between young (three and half months) and old (24 months) Long-Evans rats. Auditory evoked potential measures revealed that the old rats tend to be more sensitive than young rats to higher noise levels (97dB), but equally vulnerable to moderate levels (92dB). By contrast, the aged rats were virtually insensitive to 700ppm styrene compared to the young animals. Two additional studies were performed controlling and examining the influence of body weight and post-natal age on the sensitivity to styrene. Rats of the same age (21 weeks) and but having different body weight (~310g versus ~410g) did not show any difference of sensitivity to 700ppm styrene, whereas 14-week-old rats with the same body weight as 21-week-old rats (~350g) revealed increased sensitivity to styrene. These results show that weight does not play a key role in the sensitivity to styrene, and suggest a long period of increased sensitivity to styrene during the first months of life. PMID- 21783528 TI - Extruding auditory hair cells in rats exposed to subchronic 3,3' iminodipropionitrile. AB - Hair cell loss by extrusion of nearly intact cells towards the endolimphatic cavity has been reported in the vestibular epithelia of rats subchronically exposed to 3,3'-iminodipropionitrile (IDPN). To investigate whether hair cell extrusion also occurs in the auditory system, adult male Long-Evans rats were exposed to IDPN through drinking water (0.2-0.4% for 4-14 weeks), and their organ of Corti were examined by light and scanning electron microscopy. IDPN exposure caused loss and protrusion of the outer hair cells. The surface appearance of the protruding outer hair cells was similar to that of extruding vestibular hair cells. However, the former showed cell shrinkage and irregularly shaped nucleus, by contrast to the almost normal ultrastructure shown by the latter. The results indicate that outer hair cells can suffer extrusion, but the final outcome of this process (complete extrusion versus apoptosis) remains to be determined. PMID- 21783529 TI - Intranasal trigeminal thresholds in healthy subjects. AB - The trigeminal chemosensory system responds to irritation of the nasal cavity. Despite its dominant role as a sentinel in protecting the respiratory tract from harmful substances and its involvement in the perception of odorous substances, it has received relatively little attention compared to the olfactory system. Aim of the present study was the comparison of two psychophysical techniques to assess intranasal trigeminal thresholds, namely (A) responses of subjects who focused on intranasal trigeminally mediated sensations, and (B) the ability of subjects to identify the side of the nose receiving unilaterally presented stimuli. Method A (0.81>r>0.56) was found to show a higher test-retest reliability than Method B (0.48>r>0.40). Method A revealed thresholds that were approximately 32 times lower than those measured with method B. With method A women were found to have lower thresholds than men; no such difference could be detected between older and younger subjects. In conclusion, if the objective is to assess the level at which trigeminal sensations are detected with the utmost objectivity and unconfounded by smell, the obvious choice is B. If one's purpose is to assess the level at which trigeminal sensations are detected and the quality perceived, in the context of an odor one might opt for Method A. Thus, preference of one method over the other may depend on the question being asked, provided a well-instructed/trained panel of subjects is used. PMID- 21783530 TI - Evaluating the human response to chemicals: odor, irritation and non-sensory factors. AB - Although airborne chemicals can directly elicit adverse reactions via stimulation of the olfactory and trigeminal nerves, such as sensory irritation of the mucous membranes of the eyes, nose and throat, an individual's subjective experience is often the result of a complex sequence of events involving those sensory, physiological signals and psychological processes involved in perception, memory and judgment. To evaluate the contribution of these processes, an information processing model of chemosensory perception is introduced. The model incorporates (1) the perception of odor and trigeminal irritation, and accompanying physiological and somatic changes that follow directly from the encounter with volatile organic compounds (VOCs) in the environment (bottom-up processing), and (2) any physiological/ somatic changes and subjective experiences of irritancy that are influenced by cognitive processes that have been primed by the perception of odor (top-down processing). The model is illustrated with data from our laboratory, and its utility in the context of setting occupational exposure limits is discussed. PMID- 21783531 TI - An integrative approach considering acute symptoms and intensity ratings of chemosensory sensations during experimental exposures. AB - Even at low concentrations airborne chemicals can excite olfactory and trigeminal receptors and inform the organism about the presence of airborne chemicals. Acutely, malodors or sensory irritations might trigger symptoms (e.g., bad air quality, eye irritations) and in the long-run functional impairment of chemoreception might occur. In humans, knowledge about short-term adaptational processes and effects of exposure peaks on these systems is limited. Therefore, two different experiments with human volunteers were conducted. In experiment A exposures (4h) with fluctuating concentrations of 2-ethylhexanol (1.5, 10, 20ppm C(TWA)) were investigated, experiment B used similar but constant vapor concentrations. Olfactory- and trigeminal-mediated symptoms and intensities of odor, eye, and nasal irritations were recorded. All measures showed a dose dependent response and peak exposure effects. In the course of the 4h exposures solely olfactory symptoms decreased. Nasal irritations remained nearly unchanged across the 4h, eye irritations slightly increased. Inter-individual differences related to the personality trait of self-reported chemical sensitivity had only minor effects on chemosensory symptoms in experiment B and no effect on intensity ratings in both experiments. Chemosensory effects seem to be amplified by exposure peaks and less adaptive than assumed. PMID- 21783532 TI - Applications of dosimetry modeling to assessment of neurotoxic risk. AB - Risk assessment procedures can be improved through better understanding and use of tissue dose information and linking tissue dose level to adverse outcomes. For volatile organic compounds, such as toluene and trichloroethylene (TCE), blood and brain concentrations can be estimated with physiologically based pharmacokinetic (PBPK) models. Acute changes in the function of the nervous system can be linked to the concentration of test compounds in the blood or brain at the time of neurological assessment. This set of information enables application to a number of risk assessment situations. For example, we have used this approach to recommend duration adjustments for acute exposure guideline levels (AEGLs) for TCE such that the exposure limits for each exposure duration yield identical tissue concentrations at the end of the exposure period. We have also used information on tissue concentration at the time of assessment to compare sensitivity across species, adjusting for species-specific pharmacokinetic differences. Finally this approach has enabled us to compare the relative sensitivity of different compounds on a tissue dose basis, leading to expression of acute solvent effects as ethanol-dose equivalents for purposes of estimating cost-benefit relationships of various environmental control options. PMID- 21783533 TI - Developing an exposure-dose-response model for the acute neurotoxicity of organic solvents: overview and progress on in vitro models and dosimetry. AB - We are developing an exposure-dose-response (EDR) model for volatile organic compounds (VOCs) to predict acute effects of VOCs on nervous system function from exposure data (concentration and duration of inhalation). This model contains both toxicokinetic and toxicodynamic components. One advantage of the EDR model will be its ability to relate in vitro effects of solvents on cellular ion channels (putative targets) to in vivo effects, using a combination of physiologically-based toxicokinetic (PBTK) modeling (to estimate VOC concentrations in the blood and brain) and in vitro studies to clarify the mode of action of the VOCs. Recent work in vitro has focused on quantifying the inhibitory effects of toluene, trichloroethylene (TCE) and perchloroethylene (PERC) on ion channel currents. All three VOCs inhibit current through voltage sensitive calcium channels (VSCCs) in pheochromocytoma cells; PERC blocked calcium currents and altered the current-voltage relationship at lower concentrations than did toluene or TCE. Recombinant nicotinic acetylcholine receptors (nAChRs), expressed in Xenopus oocytes, were also inhibited by PERC and toluene in a concentration-dependent manner. PERC inhibited alpha7 receptors more than alpha4beta2 receptors in recombinant human and rat nAChRs. However, human and rat alpha7 receptors were equally sensitive to PERC and TOL. These in vitro studies will be used to identify an appropriate neuronal receptor system to serve as an index of acute effects of VOCs in vivo. The PBTK model incorporates physiological input parameters derived from radiotelemetered heart rate data from rats performing operant tests of cognitive and motor functions. These studies should improve predictions of target organ concentrations of inhaled VOCs in subjects actively performing behavioral tests over a range of physical activity levels. PMID- 21783534 TI - Modeling developmental processes in animals: applications in neurodevelopmental toxicology. AB - Biologically based dose-response models can provide a framework for incorporating mechanistic information into our assessments of neurotoxicity considering both kinetic and dynamic processes. We have constructed models for normal midbrain and neocortex development and we have extended these models to evaluate the neurodevelopmental toxicity of ethanol and methyl mercury. Using such modeling approaches, we have been able to test hypothesized modes of action for these neurodevelopmental toxicants. Specifically, we have compared ethanol's effects on neocortical neurogenesis and exacerbation of apoptosis during the synaptogenesis period. We have used methylmercury as an example of how one can link toxicokinetic and toxicodynamic models and also as an example of how mechanistic data on gene expression can support model development. In summary, using examples from our research group, this paper illustrates the need for models that evaluate both qualitative and quantitative kinetic and dynamic factors in order to understand the potential impacts of neurodevelopmental toxicants. PMID- 21783535 TI - Behavioural effects and kinetics in brain in response to inhalation of constant or fluctuating toluene concentrations in the rat. AB - The toxicity of exposure by inhalation to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study the impact of the exposure scenario on the behavioural effects of the model solvent toluene in rats was investigated. Rats were exposed for 7.5h to either a constant concentration or fluctuating concentrations at total external dose levels of 20,000ppmh and 10,000ppmh. Different effects on measures of visual discrimination performance were observed in rats exposed to a constant or fluctuating concentrations, and when rats were tested immediately or sometime after the end of exposure to fluctuating concentrations. Motor activity was also differently affected by different exposure scenarios. Physiologically based toxicokinetic (PBTK) modelling was used to predict the toxicokinetics of toluene induced by these different exposure scenarios. The model was calibrated by measuring toluene concentrations in blood and brain during and after exposure. The results show that the acute effects of toluene on behaviour do not depend only on the concentration and duration of exposure, but primarily on the pattern of exposure. PMID- 21783536 TI - Changes of neurobehavioral and sensory functions due to toluene exposure below 50ppm? AB - Data of a follow up study with four examinations were summarized by odds ratio statistics in order to scrutinize the results of the earlier studies with cross sectional approaches. For a "high"- (n=106) and a "low"-exposed group (references, n=86) current toluene exposures of 26ppm versus 3ppm and lifetime weighted average exposures of 45ppm versus 9ppm were ascertained. As measures of sensory functions vibration thresholds, colour discrimination, and auditory thresholds were used. Measures of psychological performances were attention (symbol-digit substitution, switching attention, simple reaction), memory (digit span forward, delayed reproduction of pictures), and psychomotor functions (steadiness, line tracing, aiming, tapping, peg board). Additionally, the frequency of diseases and symptoms were ascertained. By odds ratio statistics including relevant cofactors no significant increase of "cases with impaired functions" among the high-exposed workers was found. Evidence for neurobehavioral effects due to long-term toluene exposure below 50ppm was not established. PMID- 21783537 TI - Neurobehavioral performance in workers exposed to toluene. AB - Toluene is widely used in adhesive, printing, painting and petroleum industries in many countries. This study was conducted to examine the effect of chronic exposure to toluene below 100ppm on neurobehavioral performance using a computerized neurobehavioral test battery that emphasizes simple instructions and practice prior to testing. The Behavioral Assessment and Research System (BARS) with Korean language instructions was administered to 54 workers from three different industries: oil refinery, gravure printing, and rubber boat manufacturing. The battery consisted of the following tests: Digit Span (DS), Simple Reaction Time (SRT), Selective Attention (SAT), Finger Tapping (FT), and Symbol Digit (SD). Urine was collected at the end-of-shift to analyze urinary hippuric acid to assess exposure level to toluene. Based on the previous air toluene level, workers were divided into three groups: Low (21 workers, less than 10ppm), Moderate (13 workers, 20-30ppm) and High (20 workers, 70-80ppm) exposure status. Analysis of Covariance (ANCOVA) adjusting for age, education and work duration as covariates, was performed to examine the relationship between the neurobehavioral performance and the exposure groups. Poorer performance of the High exposure group was found on FT-preferred (F=7.034, p=0.002) and SAT latency (F=11.710, p=0.000). Age showed a significant correlation with SD (r=0.417, p=0.002) and SAT number correct (r=-0.460, p=0.000). Years of education and work duration were not significantly correlated with any items. This study supports that toluene exposure below 100ppm is associated with neurobehavioral changes and that high-level toluene exposure could cause not only attention and concentration, but also motor performance deficits. PMID- 21783538 TI - A meta-analytical approach to neurobehavioural effects of occupational toluene exposure. AB - Twenty-two studies investigating neurobehavioural effects of toluene were reviewed. Repeatedly applied neuropsychological performance tests and appropriately documented results allowed to include 10 of the studies into a meta analysis based on effect sizes. Mean exposure level of the studies was 57ppm (range 20-117ppm) toluene. Five of the six analyses of neuropsychological tests obtained effect sizes suggesting a negative impact of toluene, but for none of the analyses a significant effect size was estimated at averaged exposure levels between 33 and 89ppm. The tests represented the psychological domains of attention and constructional performance. Additionally, the relation between exposure conditions (level of exposure, length of exposure), potential confounders (age, verbal intelligence), and effect sizes was analysed. Only pre exposure intellectual capacity showed a consistent relation to effect sizes. The study suggests that homogenisation of study groups with respect to intelligence, cultural background and practice trials is important when investigating low-level exposure. Efforts to homogenize studies should be completed by a thorough documentation of feasible influences. PMID- 21783539 TI - Impact of trait anxiety and social conformity on responses to experimental chemical challenge. AB - The study examined the impact of trait anxiety and social conformity on ratings and test performance during controlled solvent challenge. Healthy women (n=20) and men (n=18) were exposed to increasing levels of toluene and n-butyl acetate in a challenge chamber, during which they repeatedly rated smell intensity and annoyance, and completed neurobehavioral tests. Trait anxiety was measured by the Psychasthenia scale of the Karolinska Scales of Personality (KSP), and social conformity by the KSP Social Desirability scale. Among women, high Psychasthenia was related to higher increase in ratings of mucous membrane irritation, fatigue, and annoyance from other aspects of the environment than smell during challenges, and was related to a higher increase in reaction time variability. Among men, Psychasthenia was unrelated to annoyance ratings, and was inversely related to the increase in smell intensity ratings. Social desirability was unrelated to any rating or performance dimension for either gender. PMID- 21783540 TI - Acute exposure to 50ppm toluene does not increase sleepiness. AB - The Pupillographic Sleepiness Test (PST) is a new neurophysiological method to assess sleepiness. In an exposure study to a constant exposure level of 50ppm toluene on 20 healthy men, our aim was to find out, if increased sleepiness could be seen with PST. PST was performed before and after 4.5h of exposure. General complaints were assessed with the Swedish Performance Evaluation System (SPES) self-assessment questionnaire, once before and during exposure. Values obtained during exposure were related to pre-exposure values. Parametric cross-over analysis of logarithmic Pupillary Unrest Index (PUI) values did not show an effect of toluene exposure. In a nonparametric cross-over analysis of SPES-scores a significant increase of the scores of unpleasant smell and irritation to the throat, but not of tiredness was found. In conclusion, acute exposure to 50ppm toluene, corresponding to the German threshold limit value, did not increase sleepiness. PMID- 21783541 TI - Neurotoxicity of solvents in brain of glue abusers. AB - We reviewed the neuropathological changes in 12 forensic autopsies during a period of 6 months in cases with glue abuse suspicion, and observed specific macroscopic and microscopic changes in the brain with emphasis on the white matter substance. The information of this study was taken from the investigation documents, laboratory results, and neuropathological observations. The results were compared with the literature of neurotoxicology on solvents, especially with the examples caused by toluene and coincidences among them were described. The results showed changes related with solvents leukoencephalopathy: multifocal alterations, diminishment, loss and fragmentation of myeline density, conservation of neural filaments and neuropile vacuolization without inflammatory changes. A characterization of the cases was made and an average age of 28.8 was presented. In Colombia, the principal solvent legally used is toluene, but it is possible that other hydrocarbons are involved. PMID- 21783542 TI - Neurotoxicity of exposures to aluminium welding fumes in the truck trailer construction industry. AB - The aim of the study was to examine aluminium welders for central nervous changes due to the exposure to aluminium containing welding fumes. A group of 44 aluminium welders in the train body and truck trailer construction industry (mean age: 43 years) with an average of 11.4 years of occupational exposure to aluminium welding fumes and a control group of 37 production workers (mean age: 40 years) of the same plants participated in this longitudinal study. Medical and neuropsychological examinations were performed in 1999 and 2001. Performance was measured with computerised (EURO-NES, motor performance, simple reaction time) and non-computerised test systems (verbal intelligence, standard progressive matrices, trail making, block design) and symptoms with a modified version of the questionnaire Q16. Data was analysed by multivariate analysis of variance including age, education, and alcohol marker as covariates (MANCOVA). The pre /postshift average Al-urine concentrations of welders were in the range of 130 153MUg/l. Welders showed significantly poorer performance in symbol-digit substitution, block design, and to some extent in switching attention. However, motor performance and other measures did not differ between welders and controls. Summing up, the results give no clear hints on neurological changes in Al welders. PMID- 21783543 TI - Manganese exposure and age: neurobehavioral performance among alloy production workers. AB - Manganese (Mn) is associated with neurotoxic effects under certain conditions of exposure. A recent study on environmental Mn exposure showed an Mn*age interaction for several neurobehavioral functions. The objective of the present study was to examine the neurobehavioral test results in relation to age and Mn exposure, using an existing data set on 74 workers from an Mn alloy production plant and referents pair-matched for age (+/-3 years), educational level (+/-2 years), number of children, and smoking status. The pair differences between Mn exposed workers and referents increased significantly with age for scores on Delayed Word Recall, Trail Making B, Cancellation H, Nine-Hole Hand Steadiness Test, and Vibratometer. These results suggest that for certain neurobehavioral functions, and in particular for information processing, Mn-related deficits increase with age. This outcome could not be explained by higher cumulative Mn exposure. PMID- 21783544 TI - Neurobehavioral effects of occupational exposure to acrylonitrile in Chinese workers. AB - We examined neurobehavioral outcomes of Chinese workers exposed to acrylonitrile, a potentially neurotoxic substance. We used the WHO-recommended neurobehavioral core test battery to assess the neurobehavioral functions of all study subjects. We compared 81 workers in an acrylonitrile-monomer plant and 94 workers in an acrylic fibers plant with 174 workers with no workplace acrylonitrile exposure. Acrylonitrile workers reported increased tension, depression, anger, fatigue and confusion on the Profile of Mood States. Performances in the Simple Reaction Time, Digit Span, Benton Visual Retention and Pursuit Aiming II were also poorer among exposed workers compared to unexposed workers. Some of these poor performances in tests were also related to exposure duration. Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of neuropsychological impairment induced by exposure to acrylonitrile. Further studies are needed to characterize potential neurotoxicity from chronic and acute exposures to acrylonitrile. PMID- 21783545 TI - PCB-related neurodevelopmental deficit may be transient: follow-up of a cohort at 6 years of age. AB - Based on our own findings from a previous study we aimed to establish if cognitive deficit, shown to be induced by perinatal exposure to polychlorinated biphenyls (PCBs) at earlier ages, persists into school-age. Seventy-seven percent of a cohort last examined at 42 months of age using the Kaufman Assessment Battery for Children were reexamined with the same test at 72 months. At this point, and contrary to the results at 30 and 42 months no adverse PCB-effects were found. However, the positive effect of the home environment became even more pronounced. CONCLUSION: early PCB-exposure at current environmental background levels possibly induces transient delay in cognitive development rather than irreversible deficit. PMID- 21783546 TI - Neurobehavioural investigations in adolescents exposed to environmental pollutants. AB - Environmental exposures to industrial pollutants have been associated with lowered intelligence and behavioural problems. The Flemish Environmental and Health Study focussed on biomonitoring of exposure and associated health effects. This part of the study investigated neurobehavioural performance in adolescents in relation to lead (blood Pb), cadmium (urine Cd), polychlorinated biphenyls (PCB concentration of congeners 138, 153 and 180) and compounds with 'dioxin like' activity (measured by the CALUX-assay). One-hundred and twenty girls and 80 boys (mean age 17.4 years) were enrolled. The NES battery was used to assess simple reaction time, switching attention, digit span forward, hand-eye coordination and symbol-digit substitution (SDS). Multiple regression analysis was performed to study dose-effect relationships between the neurobehavioural outcome variables and the exposure parameters in boys and girls. Slowing of SDS with increasing logPbB and logCdU was seen in boys only (PbB 39-1549nmol/L, CdU 0.02-0.40nmol/mmol creatinine). No dose-effect relations were found with serum PCB concentrations or CALUX-TEQs. Only one of several tests showed a performance decrease related to given environmental exposures to heavy metals. Further studies are needed to clarify whether the pattern of results reflects gender effects or the different exposure characteristics of boys and girls in our study. PMID- 21783547 TI - Lymphocyte muscarinic receptors and platelet monoamine oxidase-B as biomarkers of CNS function: effects of age and gender in healthy humans. AB - Lymphocyte cholinergic muscarinic receptors (MRs) and platelet monoamine oxidase B (MAO-B) activity are considered surrogate markers of the same parameters in the central nervous system. Lymphocyte MR binding and platelet MAO-B activity were measured in a consistent number of healthy human adults and analysed according to gender and age. The mean value+/-S.D. of MR binding neither differed between males (12.2+/-10.0fmol/10(6)cells, range: 0.5-37.9, n=86) and females (10.7+/ 9.7fmol/10(6)cells, range: 0.5-39.7, n=69) nor among age groups. MAO-B activity was significantly higher in women (geometric mean: 11.3nmol/mgprotein/h, with 65% of values from 7.3 to 17.6; n=43), than in men (7.7nmol/mgprotein/h, with 65% of values from 4.5 to 13; n=95). Males aged 56-66 years displayed a higher, though not statistically significant, basal enzyme activity than younger subjects. Altogether these data indicate gender-related differences in MAO activity, but not in MR binding, and inter-individual differences in the basal values of both peripheral blood markers in healthy subjects. PMID- 21783548 TI - Intrathecal methotrexate neurotoxicity: clinical correlates and antidotal treatment. AB - The neurotoxicity of methotrexate (MTX) is more severe when administered intrathecally (IT) than by the oral and intravenous (IV) routes, and has been reported even with a single administration of therapeutic doses of 12 or 15mg. Prompt recognition and treatment are essential to improve the outcome after massive IT-MTX overdose. Treatment options include CSF drainage or CSF exchange, ventriculolumbar perfusion, IT corticosteroids to reduce CSF inflammation and IV leucovorin to reduce systemic toxicity. Toxicity resulting from IT injection of leucovorin is controversial. CSF drainage and exchange are particularly effective if performed soon after the overdose. In this paper we describe a protocol of treatment for severe cases of IT-MTX overdose in excess of 100mg. The mainstay of treatment is dilution and removal from CSF of excessive methotrexate alongside with specific antidotal therapy. PMID- 21783549 TI - Regulatory developmental neurotoxicology testing: data evaluation for risk assessment purposes. AB - The recent emphasis on children's health has led to new requirements in developmental neurotoxicity testing and evolving new approaches to children's risk assessment. As more regulatory DNT studies are being submitted and used for children's risk assessment, appropriate data interpretation of developmental neurotoxicity studies is an important step to improving the scientific basis for children's risk assessments. Preweaning motor activity testing is used to illustrate the types of issues important to appropriate data analysis and evaluation. The EPA guidelines require that motor activity be tested at PND 13, 17, 21 and 60. Total activity at each time point and activity levels at each intrasession interval must be reported. Consequently, one common method for analyzing this data is to evaluate total activity levels at each time point or activity level in each intrasession time interval as independent measurements. Review of the scientific literature indicates that data evaluation for motor activity during development should focus primarily on the overall inverted U shaped pattern of total activity over PND 13, 17 and 21 and secondarily on the development of intrasession response decrement. The interpretation of the data for risk assessment purposes needs to be guided by our understanding of the strengths and limitations of our knowledge of the biologic basis for these tests. PMID- 21783550 TI - In vitro and other alternative approaches to developmental neurotoxicity testing (DNT). AB - To address the growing need for scientifically valid and humane alternatives to developmental neurotoxicity testing (DNT), we propose that basic research scientists in developmental neurobiology be brought together with mechanistic toxicologists and policy analysts to develop the science and policy for DNT alternatives that are based on evolutionarily conserved mechanisms of neurodevelopment. In this article we briefly review in vitro and other alternative models and present our rationale for proposing that resources be focused on adapting alternative simple organism systems for DNT. We recognize that alternatives to DNT will not completely replace a DNT paradigm that involves in vivo testing in mammals. However, we believe that alternatives will be of great value in prioritizing chemicals and in identifying mechanisms of developmental neurotoxicity, which in turn will be useful in refining and reducing in vivo mammalian tests for exposures most likely to be hazardous to the developing human nervous system. PMID- 21783551 TI - Regulatory developmental neurotoxicity testing: a model study focussing on conventional neuropathology endpoints and other perspectives. AB - Our aim was to investigate a model of the morphologic approach proposed in guidelines for developmental neurotoxicity testing (DNT). Hereto, a limited DNT study [EPA Health Effects Test Guidelines OPPTS 870.6300, 1996a. Developmental Neurotoxicity Study "Public Draft", United States Environmental Protection Agency; Prevention, Pesticides and Toxic Substances (7101); EPA 712-C-96-239, June 1996. ] was carried out with different doses of methylazoxy methanol acetate (MAM), known to affect brain morphology and neuron numbers in the developing brain. After gross examination, the brains of F1-animals were further dissected along neuro-anatomical landmarks to ensure homology between tissues of different individuals. The (relative) weight of the brain (parts) was determined. One brain half (alternating left/right to avoid lateralization) was further used for microscopic slide reading and measurement of brain layer width (linear morphometry); the other was set aside for stereologic investigation in a later phase of the study. In the offspring, a clear reduction in brain size (gross macroscopy) and weight (MAM high- and top-dose groups) was observed on postnatal days (PN) 22 and 62, but this reduction was hard to pinpoint in the microscope as the changes primarily appeared quantitative in nature, rather than qualitative. Linear measurements of brain layer width appeared very sensitive and efficient. This first step of a project is presented and the perspectives of a further stereologic investigation are discussed. PMID- 21783552 TI - Developmental neurotoxicity of PHAHs: Endocrine-mediated and general behavioral endpoints in adult male rats. AB - During development, gonadal steroids exert effects on the nervous system which are long-lasting or organizational, in contrast to the transient activational actions in adulthood. Therefore, disturbance of neuroendocrine functions by developmental exposure to polyhalogenated aromatic hydrocarbons (PHAHs) is likely to affect sex-dependent behavior in adults. Our previous data revealed effects of maternal PCB exposure on sexual differentiation of the brain and subsequent sweet preference as sexually dimorphic behavior in adult offspring. Present research is focused on brominated flame retardants because of their wide-spread use and accumulation in human breast milk. Pregnant Long Evans rats were SC injected with PBDE 99 (2,2',4,4',5-PBDE) daily from gestational day 10 to 18. For comparison, an additional group was exposed to Aroclor 1254. Preliminary results indicate a dose-related increase in sweet preference in adult male offspring exposed to PBDE. Exposure also led to decreases in testosterone and estradiol serum levels. Additional decreases were detected in male anogenital distance. There were no changes of locomotor activity in the open field. On haloperidol-induced catalepsy, latencies were prolonged in all exposed males. In summary, PBDE induced endocrine effects and concomitant changes of sex-dependent behavior similar to PCBs. Outcome of general behavior suggests an involvement of dopaminergic processes in developmental PBDE exposure. PMID- 21783553 TI - Sex- and region-specific alterations of progesterone receptor mRNA levels and estrogen sensitivity in rat brain following developmental exposure to the estrogenic UV filter 4-methylbenzylidene camphor. AB - Recently, we reported on in vitro and in vivo estrogenic activity of UV filters and on developmental toxicity of 4-methylbenzylidene (4-MBC) camphor [Schlumpf, M., Cotton, B., Conscience, M., Haller, V., Steinmann, B., Lichtensteiger, W., 2001a. In vitro and in vivo estrogenicity of UV screens. Environ. Health Perspect. 109, 239; Schlumpf, M., Berger, L., Cotton, B., Conscience-Egli, M., Durrer, S., Fleischmann, I., Haller, V., Maerkel, K., Lichtensteiger, W., 2001b. Estrogen active UV screens. SOFW-J. 7, 10]. 4-MBC (7, 24, 47mg/(kgday)) was administered in chow to long Evans rats from 10 weeks before mating of the parent (F0) generation until adulthood of the F1 generation. Peripheral reproductive organs and central nervous system were studied in adult offspring. mRNA expression of progesterone receptor (PR), an estrogen-regulated gene, was investigated in medial preoptic area (MPO) and ventromedial hypothalamic nucleus (VMH) by real-time RT-PCR. We analyzed intact 12-week-old male and female offspring under steady state conditions and adult gonadectomized offspring 6h after a single s.c. injection of estradiol-17beta (E2) (10 or 50MUg/kg) in order to assess estrogen sensitivity. At steady state conditions we observed significantly higher PR mRNA expression in VMH of control females versus control males. 4-MBC exposed females exhibited a decrease in PR mRNA to levels of control males. The increase in PR mRNA in response to E2 was higher in VMH of males of both 4-MBC groups as compared to control males. PR mRNA levels were similar in MPO of control males and females. Developmental 4-MBC exposure increased PR mRNA levels in male MPO, but did not significantly change female levels. The acute response to the lower E2 dose was decreased in MPO of 4-MBC-exposed males, whereas females of the 7mg/kg dose group exhibited an increased reaction to 50MUg/kg of E2. Our data indicate that developmental exposure to endocrine active chemicals such as the UV filter 4-MBC can interfere with sexually dimorphic gene expression in brain in a sex- and region-specific manner. PMID- 21783554 TI - Prenatal cocaine exposure: effects on locomotor activity in rat offspring. AB - This study examines the developmental effects of prenatal exposure to cocaine in the rat, evaluated during the first month of life through open-field behavior. The offspring of Wistar dams that received 60mg/kg of cocaine, from gestational day 8 to 22, were examined in the open-field during the second, third and fourth weeks of postnatal life in three consecutive 15-min daily sessions, starting on postnatal day (PND) 14, (PND 14-16), PND 21 (PND 21-23) and PND 28 (PND 28-30). Results show that prenatal exposure to cocaine increased total activity and rearing behavior on PND 22 and PND 29. Also, on PND 14, cocaine-exposed animals reared significantly more than control rats. There were no significant differences in the frequency of center and peripheral ambulation, nor in the defecation rate. The present results evidence alterations in the emotional behavior of rats prenatally exposed to cocaine. The delayed onset of exploration in the open-field observed in cocaine-exposed animals suggests that they take more time to become habituated to a novel and open environment. PMID- 21783555 TI - Effect of acute administration of certain heavy metals and their combinations on the spontaneous and evoked cortical activity in rats. AB - The aim of this study was to see the effect of acutely administered inorganic lead, mercury, manganese, and their combinations, on the electrical activity in the somatosensory system of rats. Male Wistar rats were anaesthetised with urethane, the head was fixed in a stereotaxic frame and the left hemisphere was exposed. Weak electric shocks to the whiskers and the tail served as stimuli. Spontaneous and stimulus-evoked activity was recorded from the primary projection area of the whiskers and the tail. After an hour of control recording, one of the following was given to the rat i.p.: 1000mg/kg Pb(2+), 7mg/kg Hg(2+), 50mg/kg Mn(2+), 500mg/kg Pb(2+)+25mg/kg Mn(2+), or 500mg/kg Pb(2+)+3.5mg/kg Hg(2+). Lead caused a massive increase in the cortical response amplitude, starting immediately after administration and developing in the next 40-50min. Latency showed a minimal increase. The spontaneous activity was moderately shifted to lower frequencies. The effect of Hg(2+) on the response amplitude and on the ECoG was similar but stronger than that of Pb(2+). The effect of Mn(2+) on the evoked activity was marked but less strong than with Pb(2+). The ECoG shift was moderate. With Hg(2+) and Mn(2+), the response amplitude showed first a decrease than an increase. The effect of the Pb(2+)+Mn(2+) combination on the activities was not additive but the correlation between the alteration of the ECoG and the evoked potential was stronger than with any of the metals alone. With Pb(2+)+Hg(2+), the effect of Pb(2+) dominated on the evoked and that of Hg(2+) on the spontaneous activity. In the peripheral nerve, action potential amplitude and conduction velocity were decreased. These alterations of the spontaneous and stimulus-evoked cortical activity probably reflected a specific action of the heavy metals on the nervous activity. PMID- 21783556 TI - Behavioral and neurotoxic effects seen during and after subchronic exposure of rats to organic mercury. AB - Young adult male Wistar rats (24/group) were treated for 5 weeks with methyl mercury(II)chloride (corresponding to 0.5 and 2.0mgHg degrees /kg b.w., control: distilled water) by gavage, followed by a 19 weeks post-treatment period. Spontaneous motility, psychomotor performance and sensorimotor gating was repeatedly tested, electrophysiological recordings done, in the rats throughout the whole experiment. Decreased horizontal open field activity, reduced number of "noise positive" startle responses, as well as increase of startle response onset latency and peak time, and decrease of peak amplitude, was seen in the treated animals. Most changes disappeared in the post-treatment period. In the spontaneous cortical and hippocampal activity, altered distribution of the frequency bands was seen after 5 weeks of treatment but not at the end of the post-treatment period. Hippocampal population spikes in the treated animals were depressed and showed less potentiation, which effect was still present 19 weeks after finishing the treatment. The duration of the sensory cortical evoked potentials was shorter than in the controls. In the treated rats, tyrosine hydroxylase-immunoreactive boutons in the substantia nigra pars reticulata were shrunk; blood and brain Hg levels were significantly higher and decreased only slowly. Considering the continuous presence of low levels of mercurials in the human environment, effects of this kind may be supposed as the background of some human neurobehavioral abnormalities. PMID- 21783557 TI - Behavioral and neurotoxicological effects of subchronic manganese exposure in rats. AB - In male Wistar rats, behavioral and electrophysiological investigations, and blood and brain manganese level determinations, were performed; during 10 weeks treatment with low-dose manganese chloride and a 12 weeks post-treatment period. Three groups of 16 animals each received daily doses of 14.84 and 59.36mg/kg b.w. MnCl(2) (control: distilled water) via gavage. During treatment period, Mn accumulation was seen first in the blood, then in the brain samples of the high dose animals. Short- and long-term spatial memory performance of the treated animals decreased, spontaneous open field activity (OF) was reduced. The number of acoustic startle responses (ASR), and the pre-pulse inhibition (PPI) of these, diminished. In the cortical and hippocampal spontaneous activity, power spectrum was shifted to higher frequencies. The latency of the sensory evoked potentials increased, and their duration, decreased. By the end of the post-treatment period, Mn levels returned to the control in all samples. The impairment of long term spatial memory remained, as did the number of acoustic startle responses. Pre-pulse inhibition, however, returned to the pre-treatment levels. The changes of the open field activity disappeared but a residual effect could be revealed by administration of d-amphetamine. The electrophysiological effects were partially reversed. By applying a complex set of methods, it was possible to obtain new data for a better-based relationship between the known effects of Mn at neuronal level and the behavioral and electrophysiological outcomes of Mn exposure. PMID- 21783558 TI - Functional neurotoxic effects in rats elicited by 3-nitropropionic acid in acute and subacute administration. AB - Changes possibly induced by 3-NP in electrophysiological functional characteristics of the central nervous system are, in contrast to biochemical and morphological alterations, less well known. In this study, the usability of a standard neurophysiological investigation system to detect functional changes caused by 3-NP administration in rats was studied. In subacute treatment, 10 or 15mg/kg 3-NP was given i.p. on five consecutive days to groups of 10 rats and the effects were checked 4 weeks later. Acutely treated rats received 20mg/kg i.p. after several control records. For recording, the animals' left hemisphere was exposed in urethane anesthesia. Silver electrodes were placed on the cortical sensory foci and tungsten needles in the subcortical (caudatum, globus pallidus) recording sites. Spontaneous electrical activity, as well as somatosensory, visual and auditory evoked potentials, were recorded. Following subacute treatment, the slowest (theta) and fastest (beta2 and gamma) frequencies of the spontaneous activity were changed, differently in the cortical versus subcortical sites. In the sensory evoked potentials after subacute treatment, an increase of the latency was seen in all sensory areas. In the acutely treated animals, the amplitude of the somatosensory evoked potential decreased after giving 3-NP. With double stimuli, the relation of the two responses was treatment- and interval dependent. Understanding the mechanism of these effects may widen the knowledge base for using 3-NP in disease models. PMID- 21783559 TI - Photoprotective effect of sesamol on UVB-radiation induced oxidative stress in human blood lymphocytes in vitro. AB - Normal lymphocytes are highly sensitive to the damaging effect of radiation and undergo cell death. In the present study, the photoprotective effect of sesamol, a constituent of sesame oil, has been examined in the UVB-(280-320nm) irradiated human blood lymphocytes. Lymphocytes pretreated with increasing concentrations of sesamol (1, 5 and 10MUg/ml) for 30min, were irradiated and lipid peroxidation and antioxidant defense were examined. UVB-irradiated lymphocytes exhibited increased levels of lipid peroxidation and disturbances in antioxidant defense. Sesamol pretreatment resulted in significant reduction in lipid peroxidation marker, thiobarbituric acid reactive substances (TBARS). Further, antioxidants like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) increased, in a dose-dependent manner, in sesamol pretreated and UVB-irradiated lymphocytes. The maximum dose of sesamol (10MUg/ml) normalized the UVB induced lipid peroxidation, indicating the photoprotective effect of sesamol in irradiated lymphocytes. PMID- 21783560 TI - Evaluation of chronic cough in chemical chronic bronchitis patients. AB - BACKGROUND: : Coughing is one of the chronic respiratory symptoms of patients exposed to sulfur mustard (SM) used against Iranian combatants and civilians by Iraq during the Iran-Iraq war, between 1983 and 1989. This study carried out on SM exposed patients who referred to our clinic because of exacerbation of chronic cough. METHOD: : Fifty male SM injured patient in the age range of 21-79 years, all of them having chronic bronchitis and were suffering from chronic cough (>3 weeks) were evaluated. After history taking and performing physical examination our diagnostic evaluation included chest X-ray, pulmonary function test (PFT), para nasal computerized tomography, esophageal endoscopy and fiber optic bronchoscopy. RESULTS: : Apart from having chronic bronchitis as a constant disease in all patients, the other main causative factors behind chronic cough were bronchospasm, post-nasal drip syndrome (PNDS), and gastro esophageal reflux disease (GERD), which accounted for 66%, 46% and 44% of chronic cough of the patients, respectively. A single cause for chronic cough was found in 4 patients (8%), 2 causes in 17 patients (34%), 3 causes in 23 patients (46%) and 4 causes in 6 patients (12%). CONCLUSION: : Since a high majority of the patients had more than a single cause for chronic cough, multiplicity of causes of chronic cough in a patient is indicative for evaluation of possible exposure to chemical fumes, especially SM. Because of high prevalence of chronic bronchitis (100%) and bronchospasm (66%) among our study group we conclude that they should be considered at first, before assessment of other causes. PMID- 21783561 TI - Tributyltin chloride suppresses the P450cl7 transcription involved in testosterone production induced by gonadotropin stimulation in cultured pig Leydig cells. AB - We previously reported that organotin compounds, such as tributyltin chloride (TBT), dibutyltin dichloride and triphenyltin chloride, strongly suppressed the testosterone production level in isolated neonatal pig testicular Leydig cells at a concentration without cytotoxicity. In this report, the action mechanisms of suppressive effect of the testosterone production by TBT were investigated. TBT (0.1MUM) exposure to pig Leydig cells for 4h significantly decreased the intracellular cAMP level stimulated by human chorionic gonadotropin (hCG; 10IU/ml) and also the level stimulated by forskolin (25MUM). In the same way, TBT exposure for 6 and 24h significantly decreased the 17alpha-hydroxylase/17,20 lyase (P450cl7) mRNA level stimulated by hCG. However, TBT exposure did not affect the mRNA levels of other steroidogenic enzymes, such as cholesterol side chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase/Delta(4)-Delta(5) isomerase, 17beta-hydroxysteroid dehydrogenase, and steroidogenic acute regulatory protein, estimated by RT-PCR. These results suggest that TBT exposure inhibits the adenyl cyclase activity of Leydig cells, which in turn suppresses testosterone production due to a decrease in the P450cl7 transcription level induced by decreasing intracellular cAMP levels. PMID- 21783562 TI - Antagonism of a neonicotinoid insecticide imidacloprid at neuromuscular receptors. AB - We investigated interactions of the neonicotinoid insecticide imidacloprid with the nicotinic acetylcholine-regulated receptors (nAcChR) of embryonic frog muscle cells. The response of the muscle cells to acetylcholine, nicotine and imidacloprid was monitored as cell contractions. Acetylcholine was more potent than nicotine (EC(50)=5*10(-8)M versus 6*10(-7)M) in this physiological test system. Contractions induced by acetylcholine or nicotine were both blocked by alpha-bungarotoxin (IC(50)=9*10(-7)M). Imidacloprid itself did not cause cell contractions but at concentrations >=3.3*10(-6)M prevented or attenuated those induced by acetylcholine (5*10(-7)M and 5*10(-5)M) or nicotine (5*10(-6)M to 5*10(-3)M). The dose response relationship between acetylcholine or nicotine, imidacloprid and cell contractions suggests that imidacloprid is an antagonist at the nAcChR of the muscle cells in contrast to its established role as an agonist in its toxic action on insect neural receptors. In chicken embryos, imidacloprid caused arthrogryposis, presumably due to its interference with the embryonic neuromuscular nAcChR. A magnitude of imidacloprid dose that caused arthrogryposis indicates a negligible teratogenic potential of imidacloprid when applied for the insect pest control. PMID- 21783563 TI - Small concentrations of mercury enhances positive inotropic effects in the rat ventricular myocardium. AB - Small concentrations of mercury reduce the force development of the rat right myocardium and inhibit the sodium pump. This inhibition might increase the amount of activator Ca(2+) in the sarcoplasmic reticulum available upon activation. We further investigated whether this action could potentiate positive inotropic effects produced by Ca(2+) increment (0.62-1.25mM) and isoproterenol (20nM). Right ventricular strips contracting isometrically were treated with 0.1 and 1MUM HgCl(2). Results showed that after HgCl(2) treatment the magnitude of both inotropic interventions was increased. Considering that Hg(2+) amongst its effects induces hypertension and might be associated with cardiovascular diseases these potentiating effects might have hazardous consequences. PMID- 21783564 TI - Urginea sanguinea: medicinal wonder or death in disguise? AB - The Southern African plant, Urginea sanguinea Shinz (Hyacinthaceae) is well-known for its poisonous affects on livestock, but it is widely used as herbal medicines by traditional healers. It is most frequently used as a blood purifier, abortifacient, treatment for venereal diseases, abdominal pain, backache and hypertension. In this article we discuss the plant's morphology, distribution, medicinal values but also poisonous characteristics. Furthermore, we discuss the most important chemical components, with special reference to the significance and physiological action of the cardiac glycoside (CG), Transvaalin. Emphasis is placed on the physiological mechanism of CG toxicity involving the Na(+)/K(+) ATPase pump. This pump is of extreme importance, especially in conducting tissues such as nerve fibers, cardiac-, skeletal- and smooth muscles. Furthermore, we summarize the medicinal uses, the systems it influence as well the adverse effects in case of over dosage. PMID- 21783565 TI - Enhancement of sodium metabisulfite on sodium currents in acutely isolated rat hippocampal CA1 neurons. AB - The effect of sodium metabisulfite (SMB) on voltage-gated sodium channel currents (I(Na)) was examined in freshly isolated rat hippocampal CA1 neurons using whole cell patch-clamp technique under voltage-clamp conditions. SMB irreversibly enhanced I(Na) in a concentration-dependent manner, shifted the inactivation curve to more positive potential, without affecting the current activation curve. In addition, SMB increased the time to peak and the inactivation time constant of I(Na). Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) could all partly inhibit the effect of SMB on the sodium current. These results suggested that SMB have neuronal toxicity by increasing the excitability of neurons and its mechanism might involve the oxidative damage on ion channels. PMID- 21783566 TI - Assessing the estrogenicity of environmental chemicals with a stably transfected lactoferrin gene promoter reporter in HeLa cells. AB - Lactoferrin is an important marker protein of the estrogens. In mice, lactoferrin expression is stimulated in the uterus by ligand-bound estrogen receptors (ERs). With this study we aimed to evaluate the effect of different environmental estrogenic chemicals on the mouse lactoferrin gene expression in a cell-based assay. We constructed a reporter that contains the firefly luciferase gene under hormone-inducible control of a 1.1kbp fragment of the mouse lactoferrin gene promoter. In an attempt to study the promoter regulation in a chromatin context, we stably transfected the construct (pGL3-mLF-Luc) into HeLa cells, and a stable clone (HeLa-mLF-Luc) incorporating the construct was subsequently generated. Transient transfection of HeLa-mLF-Luc cells with ERalpha and ERbeta expression plasmids showed that both 17beta-estradiol (E2) and diethylstilbestrol (DES) at 10(-7)M significantly increased luciferase expression via ERalpha and ERbeta. Xenoestrogens such as bisphenol A, 4-octylphenol, 4-nonylphenol and the phytoestrogen genistein when used at increasing concentrations (10(-8) to 10( 5)M) revealed varying magnitudes of activation (1.96-8-fold). The environmental estrogens showed similar magnitudes of luciferase induction when acting through ERalpha and ERbeta-mediated pathways. Also, in the absence of ERs, the xenoestrogens could not induce luciferase expression thereby reflecting receptor dependency. Taken together, the results indicate a significant responsiveness of the stably transfected mouse lactoferrin promoter to endogenous estrogen and environmental estrogenic compounds through ERs. This cell-based transcription assay system may be useful in understanding the susceptibility of estrogen target gene expression by these chemicals at the chromatin level. PMID- 21783567 TI - Pulmonary toxicity induced by intratracheal instillation of Asian yellow dust (Kosa) in mice. AB - Asian yellow dust (Kosa) causes adverse respiratory health effects in humans. The objective of this study was to clarify the lung toxicity of Kosa. ICR mice (5 weeks of age) were administered intratracheally with Kosa samples-two samples from Maowusu desert and Shapotou desert, one sample consisted of Shapotou Kosa plus sulfate, and natural Asian dust (NAD) from the atmosphere of Beijing-at doses of 0.05, 0.10 or 0.20mg/mouse at four weekly intervals. The four Kosa samples tested had similar compositions of minerals and concentrations of elements. Instillation of dust particles caused bronchitis and alveolitis in treated mice. The magnitude of inflammation was much greater in NAD-treated mice than in the other particles tested. Increased neutrophils, lymphocytes or eosinophils in bronchoalveolar lavage fluids (BALF) of treated mice were dose dependent. The number of neutrophils in BALF at the 0.2mg level was parallel to the content of beta-glucan in each particle. The numbers of lymphocytes and eosinophils in BALF at the 0.2mg level were parallel to the concentration of SO(4)(2-) in each particle. Pro-inflammatory mediators-such as interleukin (IL) 12, tumor necrosis factor-(TNF)-alpha, keratinocyte chemoattractant (KC), monocyte chemotactic protein (MCP)-l and macrophage inflammatory protein-(MIP) lalpha in BALF-were greater in the treated mice. Specifically, NAD considerably increased pro-inflammatory mediators at a 0.2mg dose. The increased amounts of MlP-lalpha and TNF-alpha at 0.2mg dose corresponded to the amount of beta-glucan in each particle. The amounts of MCP-l or IL-12 corresponded to the concentration of sulfate (SO(4)(2-)) at a 0.2mg dose. These results suggest that inflammatory lung injury was mediated by beta-glucan or SO(4)(2-), which was adsorbed into the particles, via the expression of these pro-inflammatory mediators. The results also suggest that the variations in the magnitude of inflammation of the tested Kosa samples depend on the amounts of these toxic materials. PMID- 21783568 TI - Cytochrome P450 expression in rat gastric epithelium with intestinal metaplasia induced by high dietary NaCl levels. AB - Drug metabolizing enzymes like cytochrome P450 (CYP) play an important role in determining the susceptibility of organs or tissue to the toxic effects of drugs or other xenobiotics. There is some evidence indicating that individual isoforms of CYPs are over-expressed in different types of malignant tumors including that of oesophagus, pancreas, breast, lung, colon and stomach. Nevertheless, it is not clear if this change in expression is previous or after the appearance of malignancy. This is important in order to clarify the possible role of xenobiotics in the development of gastric cancer. On the other hand, it has been reported that a high salt ingestion leads to histological changes in rat stomach mucosa including enhanced cell proliferation, lipid peroxidation and intestinal metaplasia. The aim of this study is to explore the expression and activity of CYP families involved in the metabolism of carcinogens in normal rat stomach mucosa and intestinal metaplasia induced by high NaCl ingestion. Male Wistar rats were exposed to diets containing different NaCl concentrations (0.6% control group, 6%, 12%, 18% and 24%) for 12 weeks and histological changes as well as CYP modulation were monitored in gastric mucosa. Chronic gastritis, regenerative hyperplasia and focal metaplasia were noted in animals receiving the 12%, 18% and 24% NaCl diets. In the same groups, induction of CYP1A1 and CYP3A2 was produced, mainly in areas of metaplasia. The expression of xenobiotic metabolizing enzymes in the gastric mucosa might contribute to chemical activation in the stomach, metabolizing both exogenous and endogenous compounds implicated in the development of gastric cancer. PMID- 21783569 TI - Fenvalerate induced changes in the Ach and associated AchE activity in different tissues of fish Cirrhinus mrigala (Hamilton) under lethal and sub-lethal exposure period. AB - The disruption of acetylcholinesterase activity in freshwater fish Cirrhinus mrigala (Hamilton) is demonstrated in the present study using acetylcholine chloride as substrate. Fish, C. mrigala on exposure to lethal and sub-lethal concentration of synthetic pyrethroid insecticide, fenvalerate showed inhibition in the activity of the AchE suggesting decrease in the cholinergic transmission and consequent accumulation of Ach in the tissues, namely, gill, muscle, liver and brain. This might have lead to behavioural changes and create widespread disturbance in the normal physiology, ultimately causing the death of the fish. Residue analysis using gas-liquid chromatography technique (GLC) revealed that highest quantity of fenvalerate accumulated in gill followed by liver and muscle under lethal concentration, whereas in sub-lethal concentration muscle accumulated highest concentration followed by gill and liver. The results suggest that in biomonitoring programme, AchE can be a good diagnostic tool for fenvalerate toxicity. PMID- 21783570 TI - Role of blood transfusion in trichosanthin-induced anaphylaxis. AB - Trichosanthin (TCS) is a type 1 ribosome inactivating protein extracted from Chinese medicinal herb. It possesses various biological functions such as abortifacient, anti-tumor and anti-viral activities. Clinical trial of this compound against human immunodeficiency virus (HIV) had been conducted. However, its use is limited by its high immunogenicity that elicits hypersensitivity reaction. This may lead to fatal anaphylactic response. The study described an approach of using blood transfusion to reduce TCS induced anaphylaxis in rats using a cross-circulation model. A TCS-sensitized Sprague Dawley rat was connected to a normal rat via the femoral vessels in a cross-circulation circuit before antigenic challenge. The donor rat served as a blood exchange basin to lower the level of the blood-borne components responsible for the anaphylactic reaction in the sensitized rat. Our results showed that cross-circulation shortened the duration of circulatory hypotension and reduced mortality of TCS induced anaphylaxis. The control group not undergoing cross-circulation had a mortality of 50% at 2h post-TCS challenge and there was no mortality in the cross circulation group. This demonstrated that prior blood transfusion can be one of the alternatives to reduce anaphylactic response of TCS. PMID- 21783571 TI - Deltamethrin exposure affects host resistance to Plasmodium infection in mice. AB - Effects of exposure to deltamethrin on host resistance to malaria infection (Plasmodium berghei) were examined in Swiss albino male mice. Four doses of deltamethrin were initially tested with two non-lethal doses, 5 and 10mg/kg, selected for more detailed study. Survival times of infected mice did not change when they were exposed to the compound for 14 days before the infection. However, survival times were shortened when they were exposed to the compound, particularly at the high-dose, after and during the initial infection. Percent parasitemia of these animals also elevated faster than that of the control. Deltamethrin exposure also caused alteration of white blood cell populations. Specifically, total white blood cell and lymphocyte counts significantly decreased in the high-dose treated mice. Granulocyte counts were comparatively lower in both treated groups than that in the control. Red blood cells, hemoglobin, and hematocrit were not affected. The obtained results suggest that deltamethrin exhibits an immunosuppressive effect and negatively impacts host resistance to malaria infection. PMID- 21783572 TI - The roles of metallothionein on cadmium-induced testes damages in Sprague-Dawley rats. AB - The present study was to investigate whether metallothionein (MT) was involved in sensitivity of testis to cadmium (Cd) and protection of rats from Cd-induced testis damages. The rats were treated by intraperitoneal injection with 0.2, 0.4, and 0.8mg Cd/kg BW for 7 days. The atomic absorption spectrophotometry and cadmium hemoglobin affinity assay were applied to evaluate the contents of Cd and MT in testis and liver. The testis glutathione (GSH), malondialdehyde (MDA) and daily sperm production were measured. There were substantial increases of both Cd and MT in the liver after Cd exposure. The testis Cd and MT contents were lower than those in the corresponding liver in Cd-exposed rats. Low doses of Cd (0.2 and 0.4mg/kg BW) induced MT in testis, while a significant decline of MT was found in rats treated with 0.8mg Cd/kg BW. By a concomitant decrease of MT, there was an obvious increase of MDA and marked decreases of GSH, daily sperm production in rats treated with 0.8mg Cd/kg BW. These findings suggested MT was more difficult to be induced in the testis than in the liver by Cd, which might account for the high susceptibility of testis to Cd. MT, increased by a low dose of Cd, played an important role in protecting testis against Cd toxicity by sequestering and antioxidating. PMID- 21783573 TI - Oxidative stress in acute human poisoning with organophosphorus insecticides; a case control study. AB - Free radicals play an important role in toxicity of pesticides and environmental chemicals. Organophosphorus insecticides (OPIs) may induce oxidative stress leading to generation of free radicals and alteration in antioxidant system. To complete the previous surveys, this study was conducted to evaluate the existence of oxidative stress, balance between total antioxidant capacity and oxygen free radicals in patients with acute OPI exposure. In this case control study, a total of 22 acute OPI poisoning patients were included and blood samples were analyzed for lipid peroxidation, total antioxidant capacity, total thiol groups, and cholinesterase levels. The results showed significant lipid peroxidation accompanied with decreased levels of total antioxidant capacity, total thiols, and cholinesterase activity. A significant correlation existed between cholinesterase depression and reduced total antioxidant capacity. It is concluded that oxygen free radicals and their related interactions like lipid peroxidation are present in acute OPI poisoning. Use of antioxidants may be beneficial in treatment of OPIs acute poisoning which remains to be elucidated by further clinical trials. PMID- 21783574 TI - 2,5-Hexanedione induced reduction in protein content and mRNA expression of neurofilament in rat cerebral cortex. AB - Exposure chronically to n-hexane produces central-peripheral axonopathy mediated by 2,5-hexanedione (HD). Studies have shown neurofilament (NF) subunit proteins are decreased substantially in cerebral cortices, optic axons, spinal cords, and sciatic nerves from HD-exposed rats. To deeply investigate the alterations in NF contents in HD neuropathy, the relative levels of NF-L, NF-M, and NF-H in rat cerebral cortex were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. HD was administrated to Wistar rats by intraperitoneal injection at dosage of 200 or 400mg/kg. Rats were sacrificed after 6 weeks of treatment, and cerebral cortices were dissected, homogenized, and used for the determination of NF subunit proteins. The results, except for supernatant NF-L and NF-M that could not be assayed, showed HD intoxication resulted in significant decreases by 32-67% (P<0.01) in NF subunits in both of the pellet and supernatant fractions of cerebral cortex homogenate. As an initial investigation to determine how such changes in NF proteins might occur, the gene expression of NF-L, NF-M, and NF-H subunit mRNA was quantified using reverse transcription-polymerase chain reaction (RT-PCR). Statistical analysis revealed that HD exposure caused a significant reduction in the expression of NF-L and NF-H gene (P<0.05 or P<0.01), while the levels of NF-M mRNA kept unaffected (P>0.05). These suggest that the observed reduction in NF gene expression might be related to diminished levels of subunit proteins, while the actual contribution might be uncertain. The functional significance of the reduced protein contents and the regulation of gene expression remain to be determined. PMID- 21783575 TI - Oxidative stress-related and ATPase effects of etoxazole in different tissues of Oreochromisniloticus. AB - The aim of this study is to evaluate the effects of etoxazole, a new organofluorine acaricide-insecticide, on antioxidant enzyme activities, malondialdehyde content, and different adenosine triphosphatase (ATPase) activities in the gill, kidney and muscle tissues of freshwater fish, Oreochromisniloticus. Superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), Na(+), K(+)adenosine triphosphatase, Mg(2+)adenosine triphosphatase, Ca(2+)adenosine triphosphatase activities, and malondialdehyde (MDA) were measured spectrophotometrically in whole tissue homogenates of fish exposed to five different sublethal etoxazole concentrations (0.27, 0.54, 0.81, 1.08 and 1.35ppm) for 1, 7 and 15 days. Etoxazole did not cause oxidative stress. Increasing SOD activity in etoxazole-treated fish may be an important factor to restore susceptibility and to adapt to oxidative stress. Na(+), K(+)adenosine triphosphatase activities increase in gill and muscle tissues after etoxazole exposure while they reduce in kidney. Etoxazole treatment did not show significant alterations in Ca(2+) and Mg(2+)adenosine triphosphatase activities. These results suggest that etoxazole could not enhance the oxidative stress in O.niloticus. The effects of etoxazole were only observed at high concentrations and long treatment durations. Etoxazole may specifically have an effect on Na(+), K(+)adenosine triphosphatase activity, which could alter the ionic profiles of the cells in treated tissues. PMID- 21783576 TI - Antioxidant responses in Meretrix meretrix exposed to environmentally relevant doses of tributyltin. AB - The effects on reduced glutathione (GSH) levels, glutathione-S-transferases (GST) and glutathione peroxidase (GPx) activities of digestive gland in Meretrix meretrix exposed to tributyltin (TBT) at environmental levels (0.1, 1, 10ng/L as Sn), in experimental condition, were evaluated. The GST activities in 0.1ng/L groups were significantly elevated after exposure for 2 days, and were significantly inhibited after exposure to 10ng/L TBT for 8 and 20 days. The GPx activities were mainly induced by TBT exposure, except the GPx activities in 10ng/L groups were significantly inhibited after exposure for 2 days. The GSH content was significantly decreased with prolonged exposure. The GSH content, GST and GPx activities in all exposure groups, transferred to clean recovery tanks for 20 days, were recovered to the level corresponding to that of the control group. Taken together, our present studies indicate that exposure to TBT may induce strong production of reactive oxygen species in the clams. PMID- 21783577 TI - Protein carbonyls: novel biomarkers of exposure to oxidative stress-inducing pesticides in freshwater fish Channa punctata (Bloch). AB - It has been established in mammalian system including humans that direct damage to proteins or chemical modification of amino acids in proteins during oxidative stress can give rise to protein carbonyls. Protein carbonyl induction, as a biomarker of oxidative stress was used in laboratory studies to assess the toxic effects of pesticides in freshwater fish, Channa punctata (Bloch), exposed to deltamethrin, endosulfan and paraquat. Protein carbonyls were measured in gills, kidney and liver. Significant (P<0.05-0.001) increase in protein carbonyls was observed in response to single 48h exposure to various pesticides in all the tissues. The time kinetics study involving deltamethrin (0.75MUg/L) also showed a significant (P<0.05-0.001) induction of protein carbonyls in all the organs. The induction was significant (P<0.05-0.001) in all the durations of exposure (12h, 96h, 7 days, 14 days, 28 days). However, relatively pronounced induction was observed during shorter duration of exposure. The findings of the present investigation showed that deltamethrin had the maximum oxidative stress-inducing potential among the three pesticides used and gills are the most sensitive organs prone to oxidative damage. It is suggested that measurement of carbonyl groups may provide a convenient technique for detecting and quantifying oxidative modification of proteins during oxidative stress. The induction of protein carbonyl in fish was identified as a potentially useful biomarker of oxidative stress that warrants its application in the field investigations. PMID- 21783578 TI - Inhibition of collagen and DNA biosynthesis by a novel amidine analogue of chlorambucil is accompanied by deregulation of beta(1)-integrin and IGF-I receptor signaling in MDA-MB 231 cells. AB - A novel amidine analogue of chlorambucil N-(2-(4-(4-bis(2 chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2 furanecarboxamide hydrochloride (AB(1)), and the parent drug were compared for their effects on collagen and DNA synthesis in breast cancer MDA-MB 231 cells. IC(50) values for chlorambucil and its amidine analogue for collagen synthesis were found to be about 44 and 19MUM, respectively. Increased ability of AB(1) to suppress the protein synthesis, compared to chlorambucil, was found to be related to an inhibition of prolidase activity and expression. The phenomena were probably a result of disruption of beta(1)-integrin and the insulin-like growth factor-I (IGF-I) receptor mediated signaling caused by this compound. Expression of beta(1)-integrin receptor, as well as focal adhesion kinase pp125(FAK) (FAK), growth-factor receptor-bound protein 2 (GRB2), son of sevenless protein 1 (Sos1) and phosphorylated mitogen activated protein kinases (MAPK), extracellular-signal regulated kinase 1 (ERK(1)) and kinase 2 (ERK(2)) but not Src and Shc proteins was significantly decreased in cells incubated for 24h with 10MUM AB(1), compared to controls. Chlorambucil in the same conditions did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. In addition, AB(1) revealed a higher antiproliferative activity than chlorambucil, accompanied by a stronger down-regulation of IGF-I receptor expression. The results were confirmed by [(3)H]thymidine incorporation assay. Incubation of the cells with 10MUM AB(1) for 12 and 24h contributed to a decrease in DNA synthesis by about 33 and 46% of the control values, respectively, while in case of chlorambucil by about 23 and 29%, respectively. These data suggest that the amidine analogue of chlorambucil (AB(1)) disturbs MDA-MB 231 cell metabolism more potently than does the parent drug, chlorambucil. The mechanism of this phenomenon may be due to its stronger suppression of beta(1)-integrin and IGF-I receptor signaling. PMID- 21783579 TI - In vitro toxicity of antimicrobials on RTG-2 and RTL-W1 fish cell lines. AB - This study proposed a battery of endpoints based on in vitro fish cell lines. Two fish cell lines and four toxicity endpoints are considered. The tetracycline (TC), oxytetracycline (OTC), sulfachlorpyridazine (SCP), and septrin((r)) (ST) were selected as model antimicrobials and chlorpyrifos as positive control. EROD was induced by septrin((r)) (formulation containing sulfamethoxazole and trimethoprim) at concentrations higher than 20mg/L, but inhibited by tetracycline, oxytetracycline and chlorpyrifos. Dose dependent inhibition responses were observed for beta-galactosidase (beta-Gal) activity in cells exposed to septrin((r)), tetracycline or oxytetracycline. The EROD EC50s ranged between 2.29*10(-2)mg/L (chlorpyrifos) and 167.63mg/L (tetracycline). The beta Gal EC50s ranged between 22.1 (septrin((r))) and 84.59mg/L (tetracycline). Data suggest that in vitro testing using a battery of endpoints can be a cost effective solution for screening the toxicity of antimicrobials on fish. The absence of in vitro effects at concentrations well above those expected/measured in the environment may replace the need for conducting acute lethality tests on fish. PMID- 21783580 TI - The influence of aluminum exposure on male reproduction and offspring in mice. AB - The dominant lethal assay was utilized to assess the reproductive performance in male mice, possible genetic hazards, and persistent damage of aluminum (Al). Al chloride, AlCl(3), was administered subcutaneously to CD-1 adult male mice at dosages of 0, 7, or 13mg Al/kg body weight/day for 2 weeks of pre-mating periods. Females were not dosed at any time during this study. At the end of the exposure period, each male was caged with three virgin females each day. The mean mating frequencies of the Al-treated groups reduced consistently from week 4 to 6, and a dramatic reduction in male fertility was also observed. However, the mating frequency restored to near normal control levels as the experiment terminated. Results showed significantly higher numbers of post-implantation losses, foetal mortality, and induced petechial haemorrhage; also significant decreases in body weights of viable foetus throughout weeks 3-8 in the Al-treated groups. The weights of the reproductive organs of the Al-dosed animals decreased significantly as Al accumulation increased in the testes. The spermatogenetic impairment within the seminiferous tubules was also apparent. Nevertheless, these disturbances disappeared at the end of the experiments. In summary, the results demonstrated that Al exerted substantial hazards on male reproductive function and produced genetic toxicity. However, these effects were found to be reversible. PMID- 21783581 TI - Effect of noise stress on free radical scavenging enzymes in brain. AB - The levels of free radical scavenging enzymes in six discrete brain regions (cerebral cortex, cerebellum, midbrain, pons medulla, hippocampus and hypothalamus), after exposure to three different durations of noise stress (broadband white noise, 100dB, 4h/day, in acute: 1 day, sub acute: 15 days and chronic stress: 30 days) was studied in Wister strain male albino rats. Acute noise stress significantly increases the levels of superoxide dismutase (SOD: EC 1.15.1.1), catalase (EC 1.11.1.6), glutathione peroxidase (GPx: EC 1.11.1.9), oxidized glutathione (GSSG) and lipid peroxidation (LPO) and decreases the levels of reduced glutathione (GSH), GSH/GSSG ratio and protein thiols. The free radical scavenging enzymes levels, in sub acute and chronic noise stress also showed marked deviation in certain regions from the controls within the study duration. The results indicate that adaptation to noise stress does not occur immediately in all the brain regions. The noise induced alterations in free radicals may be assumed to serve as a linkage between the environmental noise and the manifestation of multifactorial diseases attributed to noise exposure. Moreover the quantification of the health effects of noise by the alterations in free radicals seems inappropriate in chronic noise stress. PMID- 21783582 TI - Acetylcholinesterase and neuropathy target esterase activity in female and male rats exposed to pesticide terbufos. AB - An organophosphate pesticide terbufos (S-t-butylthiomethyl-O,O-diethyl phosphorodithioate; TBF) has been extensively used as an insecticide. A sexual dimorphism in TBF toxicity was not reported and remains unclear. The objective of the work was to investigate the influence of TBF on sexual dimorphism after oral administration of TBF to rats by using acetylcholinesterase (AChE) and neuropathy target esterase (NTE) as endpoints. TBF was orally administered to Sprague-Dawley rats, where female rats were received 0, 0.1, 0.4 and 0.8mg/kg TBF for 2 days and male rats 0, 0.1, 0.5 and 1.0mg/kg TBF for 3 days for dose-dependent study. Age matched female and male rats also received equally 0.5mg/kg TBF for 2 days and sacrificed 0, 6, 12, 24 and 72h after the last dose for time-dependent study. In the dose-dependent study, mortality was 25% in 1.0mg/kg TBF group of male and 50% in 0.4 and 0.8mg/kg TBF groups of female rats, resulting in about two-fold higher in female than male. AChE was significantly decreased only in the frontal and entorhinal cortexes of female rats receiving 0.4 or 0.8mg/kg TBF. In the time dependent study, the maximal inhibition in the brain regions or plasma was two- or three-fold higher in female, which occurred 6 or 12h after the last dose. However, effects of TBF on alteration of NTE activity were minor, compared to AChE, indicating that AChE is more sensitive marker than NTE in TBF toxicity. These results also indicate that female was more vulnerable to AChE inhibition than male rats after exposure to TBF. PMID- 21783583 TI - Late effects of adriamycin single dose on fetal rat kidney-ultrastructural assessment. AB - The purpose of the study was ultrastructural evaluation of long-lasting activity of an antibiotic from anthracycline group-adriamycin (ADR), on fetal kidneys from rat females which 4 weeks before fertilization were given a single dose of adriamycin intraperitoneally. The results showed the damage of glomerular filtration barrier (fusion of podocytes' foot processes) and degenerative lesions in tubular epithelial cells (EC). Those changes were described in literature in the case of adriamycin induced nephrotic syndrome in adult rats. If those lesions are due to increased glomerular permeability for proteins or cytotoxic activity of adriamycin can be decided after further biochemical tests of fetal urine and blood. PMID- 21783584 TI - High nitrate intake impairs liver functions and morphology in rats; protective effects of alpha-tocopherol. AB - The aim of this study was to determine the effect of high dose nitrate ingested in drinking water, on liver enzymes and histopathology, liver weight/body weight (lw/bw) ratio, serum and liver malondialdehyde (MDA) levels and osmotic fragility in Sprague-Dawley rats. These parameters were compared on 40 rats divided into four groups; control animals (group A) drank filtered tap water containing maximum 10mg/L nitrate while treatment groups drank 200mg/L (group B), 400mg/L (group C) and alpha-tocopherol plus 400mg/L (group D) nitrate containing water ad libitum for 60 days. As a result, lw/bw ratio increased significantly (p<0.05) among rats that consumed water with 400mg/L nitrate. Osmotic fragility increased significantly in treatment groups (p<0.05 versus control). Liver but not serum MDA levels increased in group C (p<0.05 versus control). Group A showed normal hepatic lobular architecture and histology. After nitrate administration, there was hepatocellular degeneration with increased intercellular space of the liver cells in groups B and C. Liver MDA, osmotic fragility and liver histology have returned to nearly normal in group D. These findings show clearly that high nitrate ingestion can cause pathological changes in liver histology and functions. Moreover, alpha-tocopherol can prevent these effects, possibly through antioxidant properties. PMID- 21783585 TI - The antiemetic effect of a novel tropisetron patch in anticancer agents-induced kaolin pica model using rats. AB - The efficacy of a novel transdermal patch containing tropisetron, a 5 hydroxytryptamine 3 (5-HT(3)) receptor antagonist, against emesis induced by anticancer agents were evaluated, in comparison with the effect of traditional tropisetron injection, in rats. The antiemetic effects were assessed via the inhibitory activity on the anticancer agent-induced kaolin-consuming behavior, a pica model representing vomiting in emesis-resistant rodents. The tropisetron patch (10mg/patch, 3.5cm(2)) was attached on the shaved back area of rats. Eight h later, each anticancer agent, cisplatin (10mg/kg, i.v.), cyclophosphamide (200mg/kg, i.p.) or doxorubicin (8mg/kg, i.v.), was administered, and thereafter, daily kaolin consumption was measured for 3 days. In comparison, the effect of daily injection of tropisetron (2mg/kg, i.v.), given 10min, 24 and 48h after the anticancer agent administration, was also evaluated. Kaolin intake greatly increased to 21, 17 and 10 folds of control ingestion on the first day after administration with the anticancer agents, cisplatin, cyclophosphamide and doxorubicin, respectively, and then gradually decreased to near control level on day 3. Such anticancer agent-induced increases in the kaolin consumption were remarkably attenuated by the attachment of tropisetron patch, resulting in the reduction to half levels, which is comparable to the efficacy of daily tropisetron injection. In particular, the blood concentration of tropisetron following patch attachment reached a maximum level of 30-40ng/ml in 12h and exhibited a plateau until detachment of the patch, in contrast to a rapid elimination with a half-life of 2.21h after injection of the drug. Taken together, it is suggested that the novel tropisetron patch could be a promising regimen for the relief of emesis, based on the long-term antiemetic effects on the diverse anticancer agents and the convenience to use the transdermal delivery system for the cancer patients who have difficulty in taking drugs due to surgical operation or gastrointestinal dysfunction. PMID- 21783586 TI - Reduction in functional potency of the neurotoxin domoic acid in the presence of cadmium and zinc ions. AB - The tricarboxylic neurotoxin domoic acid (DA) binds trace metals such as iron and copper. In vitro brain slice recording (area CA1 of rat hippocampal slices) was used to assess changes in DA potency in the presence of cadmium and zinc. Cadmium or zinc alone had little or no effect on CA1 responses. DA alone produced hyperexcitability and, with prolonged administration, a robust suppression of CA1 responses. Coadministration of DA with either 2 or 4MUM Cd(2+) produced significant reductions in the potency of DA; less striking effects were seen in the presence of 4MUM Zn(2+). These findings suggest that interactions of Cd(2+) and Zn(2+) with DA result in the formation of trace metal-neurotoxin complexes which are either unavailable for binding to ionotropic glutamate receptors, or bind without producing full agonist activity. PMID- 21783587 TI - The toxic effects of pentachlorophenol on rat Sertoli cells in vitro. AB - Pentachlorophenol (PCP) is the most toxic contaminant of chlorophenols (CPs). Due to improper disposal, PCP has become an environmental pollutant and is now considered to be ubiquitous. Previous studies about the influences of PCP on reproductive function were mostly focused on experiments in vivo. The aim of our present study was to estimate the toxic effects of PCP on cultured Sertoli cells from Sprague-Dawley rats. The viability of Sertoli cells was detected and morphological examination was performed followed by flow cytometric assay to evaluate its toxic effects. The 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay showed that the toxic effects of PCP on cultured Sertoli cells were dose- and time-dependent. By flow cytometric assay, it was found that the number of dead Sertoli cells increased with the increase of exposed PCP levels. The results indicated that PCP had direct and dose-dependent cytotoxic effects on Sertoli cells in vitro. PMID- 21783588 TI - Disruption of normal embryonic angiogenesis by direct exposure of mainstream whole smoke solutions of commercial cigarettes. AB - Angiogenesis is activated in the female reproductive system during embryogenesis and embryo implantation. Smoking during pregnancy has been linked to interfere with normal process of angiogenesis resulting an increased incidence of ectopic pregnancy, spontaneous abortion, preterm delivery and sudden infant death syndrome. Chorioallantoic membrane (CAM) assay was used as an alternative in vivo approach to evaluate the toxicological effects of different mainstream whole smoke solutions (MSWSS) of commercial cigarettes on embryonic angiogenesis. Seventy 5-day-old CAMs, divided in seven groups were exposed to MSWSS with different nicotine concentration: 0.2mg (group B), 0.3mg (group C), 0.5mg (group D), 0.6mg (group E), 0.7mg (group F) and 1mg (group G). All smoke solutions caused varying levels of disruption on the normal process of angiogenesis and have shown to adversely affect the diameters of blood vessels, capillary plexus formation and organization of the fibrillar materials of CAMs. Abbot curve, angular spectrum and 3D surface roughness of CAMs were also measured for precise quantification of angiogenesis. Moderate to dramatic changes were observed in all treated groups with a very highly significant (P<0.001) disruption observed on CAMs of group G. No significant change was observed in different groups treated with pure nicotine. Current observations demonstrated that MSWSS of different commercial cigarettes have toxic effects on the process of angiogenesis and smoking during pregnancy may lead to an increased risk of spontaneous abortion and preterm delivery. PMID- 21783589 TI - The reported in vitro anti-estrogen pentachloronitrobenzene enhances the estrogenic activity of estradiol in vivo in the rat. AB - Pentachloronitrobenzene (PCNB) has been shown to inhibit foci-formation for MCF-7 cells in vitro (Zou, E., Hatakeyama, M., Matsumra, F., 2002. Foci-formation of MCF-7 cells as an in vitro screening method for estrogenic chemicals. Environ. Toxicol. Pharmacol. 11, 71) This effect was referred to as representing an anti estrogenic property of PCNB. However, we have found no evidence that PCNB acts as either an estrogen or an anti-estrogen, either in vitro or in vivo. The assays conducted were binding to human and rat estrogen receptors (ER), a hER yeast trans-activation assay, the immature rat uterotrophic assay and a pubertal female rat assay. Nonetheless, when PCNB was evaluated as a possible anti-estrogen against estradiol in the immature rat uterotrophic assay, it enhanced, rather than reduced the activity of estradiol. Absence of an effect by PCNB on the uterotrophic activity of diethylstilbestrol suggests that the effect with estradiol was related to alteration of its metabolism. However, PCNB was not hepatotoxic and failed to inhibit cytochrome P450 or estradiol sulphotransferase. Pentachlorophenol, a major metabolite of PCNB, was inactive as an estrogen and failed to enhance the uterotrophic activity of estradiol. PMID- 21783590 TI - Terephthalic acid occupational exposure and its effect on organ functions in fiber workers. AB - OBJECTIVES: : To investigate the exposure to terephthalic acid (TPA), and to evaluate it's effects on organ function including the potential risk factors for uroliths and bladder tumor to TPA. METHODS: : Exposure-response modeling was carried out in a cohort of 141 TPA exposure workers and three subgroups were classified according to their urine TPA concentration. The control group consisted of 77 workers with no exposure to TPA dust. The inhalatory exposure of the application workers was estimated from biological monitoring data. Urine and blood samples were collected from all workers before and after work shift to monitor variables of liver, kidney, and lung. Haematological variables and serum biochemistry were valued, pulmonary functions were tested, and ion changes in both serum and urine were measured. RESULTS: : Increased urinary excretion of TPA (0-5mmol/molCr after the shift) reflected occupational workers TPA exposure. We also observed the exposure-response relations for the intensity of TPA exposure and the urine variables. Increased serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) but within normal range is not increased. The slightly increased serum angiotensin-converting enzyme activity (SACE) was considered to be related to particulate of airborne TPA dust inhalation. No difference between referents and workers exposed to TPA was found for haematological variables. CONCLUSIONS: : No clinical organ dysfunctions were found in this investigation working with TPA. However, special precautions are still necessarily taken to avoid excessive or prolonged contact. PMID- 21783591 TI - Oxidative stress in radiology staff. AB - Excessive production of reactive oxygen species has been observed following acute and chronic exposure to radiation in animal models which can lead to several detrimental and irreversible outcomes in vital organs. Aim of this study was to determine the oxidative stress status in radiology unit workers which are exposed to persistent low-dose radiation. METHODS: : A group of 32 radiology unit employees along with 32 sex- and age-matched hospital workers, not exposed to low dose radiation were recruited from two separate hospitals for the study. Exposed subjects showed higher levels of lipid peroxidation (P=0.009), total antioxidant capacity (P=0.0006) and thiol groups (P=0.03). It is concluded that occupationally exposed individuals are oxidatively stressed and precautions such as antioxidant therapy seems reasonable. PMID- 21783592 TI - Chromosomal aberrations induced in mouse bone marrow cells by municipal landfill leachate. AB - The cytogenetic damage induced by municipal landfill leachate was studied using chromosomal aberration (CA) in mouse bone marrow assay. Results show that leachate samples collected in different seasons decreased the mitotic index (MI), and caused significant increases of CA frequencies in treatment concentration (Chemical oxygen demand (COD) measured by the method of potassium dichromate oxidation, COD(Cr))-dependent manners. Compared with the negative control, reductions of the MI of 54 and 38% were detected for the highest leachate concentration (COD(Cr) 320mg/L) in mouse bone marrow treated with both samples. The frequencies of CA increased significantly with increasing concentrations of sample 1 from COD(Cr) 40 to 320mg/L, and from 80 to 320mg/L after exposure to sample 2. In addition, a seasonal difference of MI and CA frequencies induced by leachate was observed. The results confirm that leachate is a genotoxic agent in mammalian cells, and imply that exposure to leachate in aquatic environment may pose a potential genotoxic risk to mammals and humans. The results suggest that the CA in mouse bone marrow bioassay is efficient in genotoxicity studies of leachate on mammals, and that there appears to be a correlation between the genotoxicity in mammal system and the chemical measurement (COD(Cr)) of leachate. The results also indicate that different discharge guidelines and environmental quality standards should be established for leachates discharged from landfills to aquatic environment in different seasons. PMID- 21783593 TI - Modulation of intracellular cytokines in draining lymph node cells following allergen and irritant. AB - The murine local lymph node assay (LLNA) has been developed as an alternative to guinea pig models for the assessment of the contact sensitization potential. However, there is a need to develop a non-radioisotopic endpoint for the LLNA because of the radioisotopic method's requiring the use of special facilities. In this study, we investigated to evaluate the populations of intracellular cytokine producing cells and to analyze the expression of mRNA levels in the lymph node (LN) cells following allergen and irritant. Female Balb/c mice were treated by the topical application on the dorsum of both ears with strong sensitizers, 2,4 dinitrochlorobenzene (DNCB) and toluene diisocyanate (TDI) and a strong irritant, sodium lauryl sulfate (SLS), once daily for 3 consecutive days. The lymph node cells were harvested 72h after the final treatment. The analysis of intracellular cytokine cell in LN cells was performed with a flow cytometry. Mice were treated with DNCB and TDI showed a preferential increase in the percentage of CD4+IL-2+ cells compared with vehicle and irritant-treated mice. There was an increase in CD4+IFN-g+ cells of mice treated with DNCB and TDI, but no significant increases were observed in mice treated with SLS. Mice were treated with DNCB and TDI showed an increase in the percentage of CD4+IL-4+ cells compared with vehicle and irritant-treated mice. There was an increase in the mRNA level for interleukin 4 (IL-4) in mice treated with DNCB and TDI, but no significant increases were observed in mice treated with SLS. These results suggest that the population of interferon-gamma (IFN-g+) and IL-4+ cells on CD4+ cells and the mRNA expression for IL-4 in lymphocytes could be selectively modulated in allergen-treated mice. PMID- 21783594 TI - In vivo microdialysis study of the relationship between lead-induced impairment of learning and neurotransmitter changes in the hippocampus. AB - Chronic exposure to lead during development is associated with cognitive dysfunction in children and animals and impairment of release of neurotransmitters in the brain. Some amino acid neurotransmitters in the CNS are critical for the induction of LTP, which is considered a potential mechanism of learning and memory. In this study, the extracellular levels of amino acids in the dentate gyrus (DG) of the hippocampus of early postnatal rats exposed to lead were measured by in vivo microdialysis, before and after 50 days of training. Samples of cerebrospinal fluid were analyzed by high-pressure liquid chromatography (HPLC) and fluorescence detection. Compared to pre-training, the concentration of glutamate in the post-training samples increased by 164.2 and 222.6% in the control and lead-exposure rats, respectively. After training, the extracellular concentration of GABA and glycine decreased by 49.4 and 44.3% in lead-exposed rats, respectively, whereas in the after-training samples of control rats, the concentration of GABA was unchanged and glycine decreased by 21.8%. The results of this study may suggest that concentrations of the neurotransmitters were changed during the learning process and lead impaired the neurotransmitter systems, especially glutamate and GABA systems. PMID- 21783595 TI - In vivo genotoxic evaluation of the furylethylene derivative 1-(5-bromofur-2-yl) 2-nitroethene in mouse bone marrow. AB - The genotoxic potential of the compound 1-(5-bromofur-2-yl)-2-nitroethene (2 betaNF) has been tested by using the in vivo mouse bone marrow micronucleus assay. Its ability to induce clastogenicity or aneugenicity, through the induction of micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow cells has been evaluated. Treatment groups of five CD-1 male mice were administered once intraperitoneally at the doses of 10, 20, and 30mg/kg, and their bone marrows were sampled at 24 and 48h after the administration, at the first sampling time animals administered with the three doses were used, and in the second sampling time, only animals administered with the highest dose were used. All animals treated with the highest dose of the test compound (30mg/kg) showed evident clinical symptoms of toxicity such as irritation, hunched posture, slight ataxia, dyspnoea, piloerection, and palpebral ptosis. However, no marked depression of bone marrow cell proliferation was observed, and no significant increases in the frequency of MNPCE were obtained in any of the concentrations tested at any sampling times. The positive control treated-animals were administered with cyclophosphamide at the dose of 40mg/mL. The compound caused a significant increase in the number of MNPCE in all treated animals, demonstrating the sensitivity of the mouse strain used. From the results obtained, it is concluded that the compound 2-betaNF is neither clastogenic nor aneugenic in the erythrocytes from the bone marrow of treated mice at the doses tested. PMID- 21783596 TI - Substantial inhibition of chromate induced DNA-protein crosslink formation in vivo by alpha-lipoic acid. AB - Cellular DNA-protein crosslink (DPCs) are the biologically active nucleoprotein complexes. Chromate compounds induce its formation. We have found that intraperitoneal-administration of alpha-lipoic acid (LA, a metabolic antioxidant) inhibited substantially the chromate induced DPCs formation in mouse peripheral blood lymphocytes (PBL). Change in LA administration schedule (i.e. pre-, co- or post-toxin) did not influence its effect. Results are of significance in two aspects viz. chemoprevention of chromate toxicity and exposure/effect estimation of chromate handling subjects. The antioxidant diet/therapy may mask the exposure/effect assessments and yield high frequency of false-negatives in study subjects. PMID- 21783597 TI - Effect of different schedules and efficacy of progesterone on implantation in dimethoate treated albino mice. AB - Dimethoate, an organophosphorus pesticide, was administered orally at a dose of 28mg/(kg body weight day) to nulliparous pregnant albino mice on day 3 only and for days 3, 5 and 7 to examine the possible mechanisms for the time dependent and efficacy of progesterone on implantation in dimethoate treated animals. Control mice received similar quantities of distilled water. Autopsy on day 8 revealed that the distilled water treated mice were pregnant and had a normal number of implantations and a normal duration of diestrus. Treatment with dimethoate on day 3 only and for days 3 pregnancy caused a partial inhibition of implantation wherein 6 and 4 out of 10 mice were pregnant with 68.04 and 83.69% pre implantation loss, respectively. However, treatment with 28mg/(kg body weight day) dimethoate for days 5 and 7 caused complete inhibition of implantation in all the mice with 100% pre-implantation loss and the uterus showed no implantations. There was a significant decrease in the body weight, ovaries and uterine weights in 28mg/(kg body weight day) dimethoate treatment for days 7 of pregnancy in mice as there was complete inhibition of implantations. These groups exhibited an increase in the estrus phase. However, there was no significant change in the weight of other organs in dimethoate treated mice. Inhibition of implantation by dimethoate may be due to imbalance in the estrogen:progesterone ratio, essential for implantation. Based on this hypothesis 4, 9 and 12mg/(kg body weight day) progesterone was administered subcutaneously along with 28mg/(kg body weight day) of dimethoate for days 7 of pregnancy to counteract the effect of dimethoate and to maintain the implantations. Mice treated with 4, 9 and 12mg/(kg body weight day) progesterone along with 28mg/(kg body weight day) dimethoate for days 7 of pregnancy was unable to maintain the implantation with the result there was a 100% pre-implantation loss. There was a significant decrease in the body weight with all the dimethoate and progesterone treated mice. However, uterine weight was significantly decreased with 12mg/(kg body weight day) progesterone along with dimethoate treated mice when compared to controls. PMID- 21783598 TI - Biochemical changes in dehydrogenase, hydroxylase and tyrosinase of a permethrin resistant strain of housefly larvae, Musca domestica L. AB - In the present study, a permethrin-resistant strain (ALHF) of housefly was used to understand some enzymic changes in normal biosynthetic pathways after insecticide selection. Aflatoxin B(1) (AFB(1)) as a natural substrate was used to verify the changes on the level of cytochrome P450-dependent monooxygenases and oxido-reductase activities in the ALHF strain compared to an insecticide susceptible strain, aabys. ALHF yielded three major biotransformation products: aflatoxin B(2a) (AFB(2a)), aflatoxin M(1) (AFM(1)), and aflatoxicol (AFL) by larvae. These principal products were also found in aabys. AFL production rate of ALHF larvae was 5-fold lower than that of aabys. Differences between ALHF larvae and aabys in AFM(1) production were found. ALHF did not differ significantly from aabys in AFB(2a) production. The levels of 17alpha- and beta-hydroxysteroid dehydrogenase (17alpha- and beta-HSD) were also determined to elucidate which type of dehydrogenase activities could be changed. The cytosolic fraction of ALHF larvae yielded about 2-fold higher 17alpha-estradiol than that of aabys larvae. In contrast, the microsomal fraction of ALHF larvae produced about 2-fold lower amount of 17alpha-estradiol than that of aabys larvae. The production rate of microsomal fraction of 17beta-estradiol ALHF larvae yielded 3-fold lower than that of aabys larvae. Inhibition studies on 17alpha-HSD and 17beta-HSD activities by pyrethroid insecticides showed that there was no inhibition by pyrethroids on the enzyme activity. Therefore, there seems to be no changes on the enzyme structures. Changes on enzyme expression may occur in ALHF larvae in relation to 17alpha- or beta-HSD. To assess biochemical changes of the cuticle formation phenylalanine 4-hydroxylase and tyrosinase activities were determined. The production rate of tyrosine from phenylalanine in ALHF was about 2-fold higher for larvae than that in aabys. l-(dihydroxylphenyl)alanine (DOPA) content was determined in larvae and ALHF possessed 1.6-fold larger amounts of DOPA than aabys. Tyrosinase activity of ALHF larval preparations showed 1.6-fold higher than aabys. In summary, many enzymic changes were found in ALHF strain compared to aabys strain and these changes may be resulted from the permethrin selection. PMID- 21783599 TI - Investigation of acute toxicity of (2,4-dichlorophenoxy)acetic acid (2,4-D) herbicide on larvae and adult Nile tilapia (Oreochromis niloticus L.). AB - A 48h LC(50) values of (2,4-dichlorophenoxy)acetic acid (2,4-D), a widely used agricultural herbicide, were determined on the larvae and adult Nile tilapia (Oreochromis niloticus L.). Each test was repeated three times. The data obtained were statistically evaluated by the use of the E.P.A computer program based on Finney's probit analysis method and a 48h LC(50) value for Nile tilapia (O. niloticus L.) larvae and adults were found to be 28.23mg/L and 86.90mg/L, respectively in a static bioassay test system. 95% lower and upper confidence limits for the LC(50) were 22.55-32.98 and 80.67-92.80mg/L, respectively. Water temperature was 24+/-1 degrees C. Behavioral changes of both tilapia life forms were examined for various herbicide concentrations. PMID- 21783600 TI - Screening estrogenic oxidized by-products by combining ER binding and ultrafiltration. AB - Ozonation and chlorination of 17beta-estradiol (E2), 17alpha-ethynylestradiol (EE2), bisphenol A (BPA), and nonylphenol (NP) were performed to evaluate the estrogenic activity of the by-products of these endocrine disrupting chemicals (EDCs). After 15min oxidation, samples were extracted using solid phase extraction (SPE) cartridges, and tested in vitro to measure the estrogenic activities of the oxidized products. MCF-7 cell proliferation assay showed that chlorinated BPA solution displayed slightly stronger estrogenicity than BPA, while chlorinated NP retained about one-tenth of its bioactivity. The estrogenic mono-, di-, tri-, and tetra-ClBPAs and di-ClNP were screened out from the corresponding chlorinated products by a combined application of estrogen receptor (ER) binding with ultrafiltration and identified by high performance liquid chromatography coupled with mass spectrometry (LC/MS). Ozonation of the above four estrogens and chlorination of E2 and EE2 significantly decreased their estrogenic activities under the applied conditions. PMID- 21783601 TI - Investigation of acute toxicity of cyfluthrin on tilapia fry (Oreochromis niloticus L. 1758). AB - Cyfluthrin, a synthetic pyrethroid pesticide contaminating aquatic ecosystems as a potential toxic pollutant, was investigated in the present study for acute toxicity. Tilapia fry (Oreochromis niloticus L. 1758) was selected for the bioassay experiments. The 48 and 72h LC(50) was determined for the tilapia fry. The experiments were repeated three times. The static test method of acute toxicity test was used. In addition, behavioral changes at each cyfluthrin concentration were determined for the individuals. Data obtained from the cyfluthrin acute toxicity tests were evaluated using the Probit Analysis Statistical Method. The 48 and 72h LC(50) value for tilapia fry were estimated as 25.82MUg/L (95% confidence limits: 20.92-43.26) and 21.07MUg/L (95% confidence limits: 16.21-30.39), respectively. PMID- 21783602 TI - Deranged spontaneous behaviour and decrease in cholinergic muscarinic receptors in hippocampus in the adult rat, after neonatal exposure to the brominated flame retardant, 2,2',4,4',5-pentabromodiphenyl ether (PBDE 99). AB - Polybrominated diphenyl ethers (PBDEs), which are used as flame-retardants, have recently been shown to be increasing in the environment and in human milk. We have recently reported that neonatal exposure to PBDEs, including 2,2',4,4',5 pentaBDE (PBDE 99), can induce persistent aberrations in spontaneous behaviour and also affect learning and memory functions and nicotinic cholinergic receptors in the adult mice. The present study indicates that spontaneous behaviour, along with the cholinergic system during its developing stage, can be targets for PBDEs in the rat as well. Neonatal oral exposure of male Sprague-Dawley rats, on postnatal day 10, to 0.8, 8.0, and 16mg PBDE 99/kg body weight, was shown to disrupt normal spontaneous behaviour in a dose-response related manner at 2 months of age. Also, the animals of the present study showed a decrease in density of muscarinic cholinergic receptors in hippocampus, at an adult age. These findings show similarities to observations made from neonatal exposure of mice to PBDE 99, 2,2',4,4',5,5'-hexaBDE (PBDE 153) and certain PCBs, compounds shown to affect both spontaneous behaviour and the cholinergic system. PMID- 21783603 TI - Modification of mercury-induced biochemical alterations in blood of Swiss albino mice by Spirulina fusiformis. AB - The present investigation has been undertaken to evaluate the role of Spirulina fusiformis in modifying the mercury-induced biochemical alterations in Swiss albino mice. Animals were divided into four groups: (i) control group - only vehicle (0.9% NaCl/olive oil) was given; (ii) HgCl(2) treated group - 5.0mg/kg b.w. HgCl(2) administered as i.p.; (iii) Spirulina treated group - 800mg/kg b.w. Spirulina extract was administered orally; (iv) combination group -S. fusiformis was administered 10 days before mercuric chloride administration and continued up to 30 days after mercuric chloride administration (5.0mg/kg b.w.). The animals were sacrificed on 1, 3, 7, 15 and 30 days and the activity of serum alkaline and acid phosphatase, serum iron level, serum calcium level, blood lipid peroxidation content and blood glutathione (GSH) level were measured. In the present investigation, mercury intoxication causes significant increase (P<0.001) in calcium level, acid phosphatase and lipid peroxidation content and significant decrease in iron level, alkaline phosphatase and glutathione level. Spirulina pre and post-treatment with mercury prevented or reduces mercury-induced alterations in terms of calcium level, iron level, acid and alkaline phosphatase activity in serum, and lipid peroxidation and GSH level in blood. Thus from the present investigation, it can be concluded that Spirulina pre- and post-treatment with HgCl(2) significantly modulate or modify mercury-induced biochemical alteration in blood of Swiss albino mice. PMID- 21783604 TI - Endothelial dysfunction after exposure to cobalt chloride enhanced vascular contractility. AB - Brief exposure to cobalt chloride augmented vascular contractility. We hypothesized that endothelial dysfunction plays a role in the augmentation of aortic contractility, after brief exposure to cobalt chloride. Rat aortic ring preparations were mounted in organ baths, exposed to cobalt chloride (0.3 300MUmol/L) for 30min, and then subjected to contractile agents or relaxants 1 and 5h after the end of exposure. Presence of cobalt chloride did not affect the contractile response to phenylephrine. Brief exposure to cobalt chloride, however, even at 5h after the end of exposure, not only augmented contractile responses to KCl or phenylephrine but also attenuated the relaxant response to acetylcholine. The mechanical denudation of endothelium or inhibition of endothelial nitric oxide synthase with 100MUmol/L N(omega)-nitro-l-arginine methyl ester abolished the augmentation of contractile responses. Pre-treatment with 150units/mL of superoxide dismutase also abrogated the augmented contractile responses. Brief exposure to cobalt chloride did not affect the contractile response to phorbol dibutyrate in the presence or absence of calcium, or the expression of HSP70. In conclusion, endothelial dysfunction plays an important role in the augmentation of aortic contractility, after brief exposure to cobalt chloride. PMID- 21783605 TI - Investigations into the cellular actions of the shellfish toxin gymnodimine and analogues. AB - The effects of the shellfish toxin gymnodimine and its analogues (gymnodimine acetate, gymnodimine methyl carbonate and gymnodamine) on cellular viability were tested using the Neuro2a neuroblastoma cell line. Concentrations of toxins up to 10MUM had variable effects on reducing cell number as determined using the MTT assay and no effects on the expression of a number of signal transduction proteins (c-Jun, ATF-2, ATF-3) which are sensitive to cellular stress. However, pre-exposure of Neuro2a cells to 10MUM concentrations of toxins for 24h greatly sensitized these cells to the apoptotic effects of another algal toxin, okadaic acid. These results suggest that gymnodimine and its analogues sensitize Neuro2a cells to cytotoxins and raise the possibility that algal blooms involving the production of both okadaic acid-type molecules and gymnodimine may generate greater cytotoxicity and pose a greater public health problem. Furthermore, our studies establish the Neuro2a cell line as a potentially high-throughput cellular system sensitive to the pharmacological effects of gymnodimine and analogues, and as a potential screen for algal-derived toxins. PMID- 21783606 TI - Evaluation of the toxicity and safety of the antioxidant beverage effective microorganisms-X (EM-X) in animal models. AB - The acute and chronic toxicity tests and the mutagenic test of the extracts from the fermentation of plants with effective microorganisms (EM-X) were performed in the mouse and the rat. In acute toxicity test, mice were orally treated three times per day with 20-fold of concentrated EM-X for 7 days. For chronic toxicity test, the rats were orally treated with original EM-X once a day for 90 days at the dosages of 180, 120 or 60ml/kg. At the levels tested EM-X did not lead to significant changes in food consumption, body weight, behaviors and stools. Hematological assays on red blood, white blood cell, hemoglobin, platelets, lymphocyte, granulocyte, middle cell and coagulation time and the biochemical assays on aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, total protein, albumin, glucose, total bilirubin, creatinine and total cholesterol did not show abnormal changes. The histological inspection of principal organs of the heart, liver, spleen, lung and kidney did not show significant pathological changes. The delaying toxic reactions were detected 2 weeks after administration of EM-X was stopped. The mutagenic test showed that EM-X did not cause mutagenesis and tests of micronucleus of bone marrow cell and sperm shape abnormality upon EM-X were negative. The maximal tolerance dose of EM-X was calculated to be 1800ml/kg BW in the mouse and rat. Thus, oral administration of EM-X does not present acute and chronic toxicity and mutagenic effects in the animals. PMID- 21783607 TI - Developmental toxicity evaluation of nerve growth factor for injection in Wistar rats. AB - Nerve growth factor (NGF) for injection is now used as an agent to cure peripheral nerve injury. To assess its potential embryo-lethal and teratogenic toxicity, five groups of pregnant Wistar rats received 0, 40, 200 and 1000U/kg NGF by muscle injection from gestational days (GD) 6 to 17. Maternal body weight was monitored at regular intervals throughout gestation. We selected 7mg/kg body weight cyclophosphamide (CPA) given to positive control group testing the Wistar rats of this study whether sensitive to teratogens or not. The dams were euthanized on GD 20, the day just before expected parturition. All fetuses were removed by cesarean section and examined for external, visceral and skeletal malformations under a dissecting microscope. There were no treatment-related maternal deaths. Our statistical findings were a reduction in maternal body weight and the occurrence of fetal body length shorten in 1000U/(kgday) dose group, which suggesting mild embryotoxicity of NGF. There were no major changes observed in other doses groups such as viable fetuses rate, resorption and dead fetuses rate, external, skeletal, visceral abnormality, fetal weight and length, tail length, indicating no evident maternal toxicity, embryotoxicity and teratogenicity resulted from NGF. Thus, it seems a favorable preclinical safety evaluation profile for NGF. PMID- 21783608 TI - Radioprotection by Podophyllum hexandrum in the liver of mice: A mechanistic approach. AB - To evaluate radiation protection offered by the extract of Podophyllum hexandrum, expression of various cytoprotective proteins was studied using liver of Swiss albino Strain 'A' male mouse by immunoblotting. Induction of heat-shock factor-1 (HSF-1), led to up-regulation of heat-shock protein-70 (HSP-70) upon P. hexandrum (200mg/kg b. wt.; i.p. 50% ethanolic extract) treatment 2h before irradiation (10Gy) as compared to sham-irradiated control. Translocation of free nuclear factor kappa B (NFkappaB) from cytoplasm to nucleus was found to be inhibited upon P. hexandrum treatment. An increase in Bcl-2, proliferating cell nuclear antigen (PCNA) along with a decrease in p53, caspase-3, apoptosis inducing factor (AIF) expression was observed in the mice treated with P. hexandrum. The present study indicated that P. hexandrum extract provides protection from radiation by modulation of expression of the proteins associated with apoptosis. PMID- 21783609 TI - Toxicological overview of cigarette smoking on angiogenesis. AB - Angiogenesis is the process of generating new capillary blood vessels. It occurs under tight regulation in the female reproductive system, during wound healing and during embryogenesis. Angiogenesis also plays an important role in the pregnancy-associated changes in the reproductive tract. Cigarette smoke inhibits processes that may hinder normal process of angiogenesis resulting in abnormal blood supply to tissues, decreased repair and remodeling. This report summarizes the evidences of the causal association between tobacco smoking and disruption of angiogenesis. Application of small amount of nicotine on day 5 old chorioallantoic membranes (CAMs) did not disrupt the process of angiogenesis, while application of mainstream smokes (MSS) solutions to CAMs caused varying levels of disruption on normal process of angiogenesis and adversely affect capillary plexus formation, diameters of secondary and tertiary vessels. We have also observed that at equivalent doses, sidestream smoke (SSS) can significantly be more potent than MSS and can alter the normal process of angiogenesis more drastically than MSS. It suggests that SSS either contains a toxicant(s) not present in MSS or that the toxicant(s) that produces these effects is present in higher concentration in SSS than in MSS. Therefore, it is undisputed that smoking can interfere the normal process of angiogenesis, which is a vital process to maintain pregnancy and development of fetus. Smoking during pregnancy is harmful to fetal development and is associated with an increased risk of miscarriage, perinatal death and sudden infant death syndrome. Smoking-cessation programs remain a crucial strategy for preventing poor birth outcomes and decreasing the social and financial costs of smoking during pregnancy. PMID- 21783610 TI - Lactate dehydrogenase isoenzyme patterns upon chronic exposure to cigarette smoke: Protective effect of bacoside A. AB - Despite a strong association between cigarette smoking and alarming increase in mortality rate from smoking-related diseases, around 35-40% of the world's population continues to smoke and many more are being exposed to environmental tobacco smoke. Since the role of free radicals and oxidative damage in the pathogenesis of smoking-related diseases has been suggested, bacoside A, a potent antioxidant was tested for its ability to protect against cigarette smoking induced toxicity in terms of lactate dehydrogenase (LDH) and its isoenzymes. Rats were exposed to cigarette smoke and simultaneously administered with bacoside A, for a period of 12 weeks. Total LDH activity was assayed in serum, lung, heart, brain, liver and kidney, and serum LDH isoforms were separated electrophoretically. Cigarette smoke exposure resulted in significant increase in serum LDH and its isoenzymes with a concomitant decrease in these organs. These alterations were prevented by administration of bacoside A. Excessive oxidants from cigarette smoke is known to cause peroxidation of membrane lipids leading to cellular damage, thereby resulting in the leakage of LDH into the circulation. Bacoside A could have rendered protection to the organs by stabilizing their cell membranes and prevented the release of LDH, probably through its free radical scavenging and anti-lipid peroxidative effect. PMID- 21783611 TI - Low dose mercury toxicity and human health. AB - Post Minamata incident there has been awareness about mercury toxicity even among the general public. Previous researches contributed a vast amount of data regarding acute mercury exposure, but gradually information about the low dose [Ninomiya, T., Ohmori, H., Hashimoto, K., Tsuruta, K., Ekino, S., 1995. Expansion of methylmercury poisoning outside minamata: an epidemiological study on chronic methylmercury poisoninig outside of Minamata. Environ. Res. 70 (1) 47-50; Lebel, J., Mergler, D., Lucotte, M., Amorim, M., Dolbec, J., Miranda, D., Arantes, G., Rheault, I., Pichet, P., 1996. Evidence of early nervous system dysfunction in Amazonian populations exposed to low-levels of methylmercury. Neurotoxicology 17 (1) 157-167] of mercury toxicity has been trickling in. With mercury contaminating rain-, ground- and sea-water no one is safe. Polluted water leads to mercury laced fish, meat and vegetable. In aquatic environments, inorganic mercury is microbiologically transformed into lipophilic organic compound 'methylmercury'. This transformation makes mercury more prone to biomagnification in food chains. Consequently, populations with traditionally high dietary intake of food originating from fresh or marine environment have highest dietary exposure to mercury. Extensive research done on locals across the globe have already established this, persons who routinely consume fish or a particular species of fish are at an increased risk of methylmercury poisoning. The easy access of the toxicant to man through multiple pathways air, water, food, cosmetic products and even vaccines increase the exposure. Foetus and children are more susceptible towards mercury toxicity. Mothers consuming diet containing mercury pass the toxicant to foetus and to infants through breast milk. Decreased performance in areas of motor function and memory has been reported among children exposed to presumably safe mercury levels. Similarly, disruption of attention, fine motor function and verbal memory was also found in adults on exposure to low mercury levels. It is an occupational hazard for dental staff, chloralkali factory workers and goldminers, etc. Mercury has been found to be a causative agent of various sorts of disorders, including neurological, nephrological, immunological, cardiac, motor, reproductive and even genetic. Recently heavy metal mediated toxicity has been linked to diseases like Alzeihemer's, Parkinson's, Autism, Lupus, Amyotrophic lateral sclerosis, etc. Besides this, it poses danger to wildlife. Therefore, it becomes imperative to spread the information regarding the threat of mercury exposure amongst the scientists and masses. PMID- 21783612 TI - Effect of tributyltin, benzo(a)pyrene and their mixture exposure on the sex hormone levels in gonads of cuvier (Sebastiscus marmoratus). AB - Tributyltin (TBT), an organometal used as an antifouling biocide, has been reported to induce masculinization of fish. Benzo(a)pyrene (BaP), a widespread carcinogenic polycyclic aromatic hydrocarbon, has been reported that its microsomal metabolites can produce an estrogenic response when tested in vitro. This study was therefore designed to examine the potential in vivo influence of TBT, BaP and their mixture on sex hormone levels in gonads of Sebastiscus marmoratus, which were given eight separate i.p. injections (a single injection every 7 days) of TBT (0.5, 1, 5 and 10mg/kg), BaP (0.5, 1, 5 and 10mg/kg), or both in combination (0.5, 1, 5 and 10mg/kg); control fish received olive oil vehicle only. Six days after the first (week 1), second (week 2), fourth (week 4) and eighth (week 8) injection, gonads samples were collected and analyzed for sex hormone levels. TBT treatment alone was found to be ineffective at week 1, but significantly elevated the testosterone level in testicle of the male fish at week 4 compared to the corresponding controls. TBT treatment significantly reduced the ovarian testosterone level of the female fish at week 2 in dose dependent manner. It was observed that TBT, BaP and their mixture significantly reduced the ovarian 17beta-estradiol level of the female fish at weeks 2 and 8 in dose-dependent manner, however, the ratios of testosterone to 17beta-estradiol in the ovary were elevated. This change of sex hormones levels would be one of the reasons to interpret the masculinization of fish by TBT. The present study demonstrates that BaP could influence in vivo ovarian sex hormone level of the female fish. The elevation of the ratios of testosterone to 17beta-estradiol in the female fish exposed to BaP implies that BaP would have an androgenic effect on the fish in vivo, which should be deserving of further study. The joint effect of TBT and BaP at 1:1 concentration ratio on the level of 17beta-estradiol in S. marmoratus was antagonism. TBT can antagonize bioactivation of BaP, and BaP can stimulate the Phase II metabolism of TBT and/or its biliary excretion, which were reported in previous studies, would be one of the causes that TBT and BaP had a antagonism on the level of ovarian 17beta-estradiol in the present study. PMID- 21783613 TI - Inter-element interactions in human hair. AB - The concentrations of 33 elements: Ca, Mg, Na, U, Cu, Zn, P, Fe, Mn, Cr, Se, B, Co, Mo, Si, V, Ni, Be, Hg, Cd, Al, Pb, As, Ba, Au, Pt, Ag, Sr, Sn, Ti, W, Sb and Zr in hair were determined by inductively coupled plasma-mass spectrometry (ICP MS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES). Hair samples (n=83) were collected between 1996 and 2003 from inhabitants of city of Wroclaw, located in Lower Silesia, south-west Poland (urbanized and industrialized region). Inter-element interactions were studied by evaluation of correlation coefficients between two elements, as well as by multiple regression analysis. The strongest relations found between the elements in the hair were as follows: Mg and Ca, Mn and Ca, Sr and Ca, Sr and Mg, U and Na, Ni and Zn, Mn and Sr, Cd and Ni, Sb and Pt. We obtained also the following essential linear multiple dependences (p<0.05): Al=f(U, P, Mn), As=f(Zn, Fe) (Zn is negatively correlated, beta<0), Cu=f(V), Fe=f(Mn, As), Mg=f(Ca), Ca=f(Mg, Ba), Ni=f(Zn, Cd), Sb=f(Pt, Sn, W) and Ti=f(Fe, Co). These relations can be useful in the explanation of relationships among the elements in man. PMID- 21783614 TI - Diazinon cytotoxicity and transfer in Caco-2 cells: Effect of long-term exposure to the pesticide. AB - The purpose of this work was to investigate the effect of prolonged exposure to diazinon (widely used organophosphorus pesticide) on the intestinal cell-line Caco-2. Cytotoxicity of the pesticide (50MUM-6mM) significantly decreased in long term exposed (20MUM, 2 months) cells, compared to untreated control cells. In long-term exposed cells, the resistance to diazinon cytotoxicity was reversed in the presence of PSC-833, a P-glycoprotein (P-gp) inhibitor, but not in the presence of MK 571, a Multidrug Resistance Protein (MRP) inhibitor. Cell exposure to 25MUM diazinon showed a secretory-directed transport of the molecule, which increased in long-term exposed cells. This efflux decreased significantly, for both long-term and non-exposed cells, in the presence of verapamil and PSC-833, but not MK 571. Furthermore, the total amount of P-gp increased in long-term exposed cells. These results suggest that ABC transporter P-gp is involved in the intestinal transfer of diazinon, and that repeated exposure to low doses of diazinon could strengthen the activity of ABC transporters in intestinal cells, thus increasing cell resistance to pesticide cytotoxicity. PMID- 21783615 TI - A case of contact urticaria due to adigraf, a PVC-made material. AB - Adigraf is a plastic material applied as thin sheets that may be incised and are used, also by children, to produce artistic drawing. The principal component of adigraf is polyvinyl chloride (PVC). Di-(2-ethylhexyl) adipate is added as a plasticizer. Herein we describe a case of a 14-year-old boy with facial angioedema and widespread urticaria, occurring 1h after contact with an adigraf sheet. Open patch-test with adigraf sheet showed swelling of the application site and widespread urticaria. To our knowledge, there are no similar reports of urticaria and angioedema from adigraf or similar PCV items. PMID- 21783616 TI - Evaluation of the role of Ace1 and Yap1 in cadmium absorption using the eukaryotic cell model Saccharomyces cerevisiae. AB - In a previous paper, we demonstrated that the cytoplasmic level of glutathione cadmium complex affects cadmium absorption by Saccharomyces cerevisiae, a usual eukaryotic cell model for studies of stress response. Furthermore, it was also observed that the absorption of this non-essential metal seems to be achieved by Zrt1, a zinc transporter of high affinity. Looking a little further into the control mechanism, we have verified that the deficiency in Ace1 impaired cadmium transport significantly. Ace1 is a transcription factor that activates the expression of CUP1, which encodes the S. cerevisiae metallothionein. On the other hand, the deficiency in the transcription factor Yap1 produced a two-fold increase in cadmium uptake. Cells lacking Yap1 showed low levels of glutathione, which could explain their higher capacity of absorbing cadmium. However, the mutant strain Ace1 deficient exhibited considerable amounts of glutathione. By using RT-PCR analysis, we observed that the lack of Yap1 activates the expression of both CUP1 and ZRT1, while the lack of Ace1 inhibited significantly the expression of these genes. Thus, metallothionein seems also to participate in the regulation of cadmium transport by controlling the expression of ZRT1. We propose that, at low levels of Cup1, the cytoplasmic concentration of essential metals, such as zinc, in free form (not complexated), increases, inhibiting ZRT1 expression. In contrast, at high levels of Cup1, the concentration of these metals falls, inducing ZRT1 expression and favoring cadmium absorption. These results confirm the involvement of zinc transport system with cadmium transport. PMID- 21783617 TI - Manganese accumulation in striatum of mice exposed to toxic doses is dependent upon a functional dopamine transporter. AB - The objective of this study was to determine the importance of the dopamine transporter (DAT) in manganese transport. Excessive manganese exposure is associated with a neurotoxicological disease known as manganism characterized by a specific accumulation of manganese in dopamine-rich brain regions. It has been hypothesized that the DAT mediates this specific transport, but its role in manganese neurotoxicity has not been directly examined. We examined brain tissues from manganese-exposed dopamine transporter knockout (DAT-KO) and wild-type (WT) mice. There was significantly less (p<0.05) manganese in the striatum of exposed DAT-KO mice compared to WT. However, the absence of a functioning DAT did not affect manganese accumulation in other brain regions examined. Furthermore, both iron and divalent metal transporter levels (two known modulators of brain manganese) were similar between DAT-KO and WT mice in all brain regions. These studies demonstrate that the DAT is involved in the facilitation of striatal manganese accumulation and that it may play a critical role in mediating manganese neurotoxicity. PMID- 21783618 TI - Dibutyltin exposure decreases granzyme B and perforin in human natural killer cells. AB - Natural killer (NK) cells are a subset of lymphocytes that are capable of killing tumor and virally-infected cells. Dibutyltin (DBT) is a catalyst in the production of PVC plastics and a breakdown product of tributyltin (TBT). DBT is a significant environmental contaminant. This study investigates the mechanism by which DBT exposure decreases the immune function of human NK cells. NK cells destroy their target cells by releasing cytotoxic proteins, perforin, and granzyme B. We examined the effect of DBT exposures on the levels of cytotoxic proteins and their mRNAs. Exposure of NK cells to DBT for 1h caused significant decreases in the mRNAs for granzyme B and perforin but not in protein levels. A 24h exposure to DBT decreased mRNAs as well as protein levels for both granzyme B and perforin. Exposure to DBT for 1h followed by either a 24 or 48h period in DBT free media, decreased levels of granzyme B and perforin. The results indicate that decreases in granzyme B and perforin levels in NK cells are consequences of DBT exposure. Additionally, DBT causes rapid decreases in mRNAs for perforin and granzyme B, suggesting decreases in transcription and/or increases in mRNA degradation. PMID- 21783619 TI - Reversal of aminolevulinic acid dehydratase (ALAD) inhibition and reduction of erythrocyte protoporphyrin levels by Vitamin C in occupational lead exposure in Abeokuta, Nigeria. AB - In order to investigate the toxic effects of lead during occupational exposure to this metal, the activity of aminolevulinic acid dehydratase (ALAD) and the concentrations of erythrocyte protoporphyrin (EPP) were determined in blood of various artisans in Abeokuta, Nigeria and these were related to blood lead levels. ALAD activity in the artisans was inhibited to varying extents. ALAD activity was inhibited to the tune of 77% in petrol station attendants while the lowest inhibition of 36% was obtained in the welders. EPP was also significantly increased in the artisans (p<0.001). The highest EPP level of 241.57+/ 89.27MUg/100ml of red blood cell was observed in upholsterers. A significant (p<0.001) negative correlation was observed between ALAD activity and blood lead levels on one hand (r=-0.631) and between ALAD activity and EPP on the other hand (r=-0.461). Administration of a daily dose of 500mg ascorbic acid for 2 weeks reversed the lead-induced inhibition of ALAD. Increased EPP levels observed in the artisans also responded positively to the ascorbic acid supplementation. A significant reduction (p<0.001) in blood lead was also observed in the artisans at the end of the 2-week ascorbic acid therapy. Our findings indicate that ascorbic acid may offer more advantages over the conventional agents for the treatment of lead poisoning, especially in cases where the subjects cannot be removed from the source of lead exposure. PMID- 21783620 TI - Activity of the enzymes of the antioxidative system in cadmium-treated Oxya chinensis (Orthoptera Acridoidae). AB - One purpose in this research was to determine the toxic effects of Cd on antioxidant enzymes of Oxya chinensis (Orthoptera: Acridoidae). Changes in the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and guaiacol peroxidase (GPx) were measured in O. chinensis insects injected with Cd(2+). Fifth-nymphs of O. chinensis insects were injected with Cd(2+) at different concentrations (0, 0.55*10(-4), 1.10*10(-4), 1.65*10(-4), 2.20*10(-4), and 2.75*10(-4)gg(-1)). An increase in SOD activity in O. chinensis was observed at 1.10*10(-4) to 2.75*10(-4)gg(-1) Cd(2+). The SOD activity was lower at 2.20*10(-4)and 2.75*10(-4)gg(-1) than that at 1.10*10(-4) and 1.65*10(-4)gg(-1). It appears that SOD had a positive protective effect at low Cd(2+) concentrations, and that this effect disappeared at high Cd(2+) concentrations. CAT activity was accelerated to varying degrees at 1.10*10(-4) to 2.75*10(-4)gg( 1) for males and at 1.10*10(-4), 2.20*10(-4), and 2.75*10(-4)gg(-1) for females. CAT showed a strong detoxification effect with all treatments. GPx activity decreased with increasing Cd(2+) concentration with all treatments for males and at 2.20*10(-4) and 2.65*10(-4)gg(-1) for females. We showed that GPx activity had a weak detoxification function with all treatments for males and at high Cd(2+) for females. Thus, CAT had a strong detoxification effect, whereas SOD had a medium and GPx had a weak detoxification effect. Among the three enzymes, CAT played an important role in the damaging mechanisms of reactive oxygen species in O. chinensis insects. Alterations of the antioxidant enzyme level under environmental stresses are suggested as indicators of biotic and abiotic stress. PMID- 21783621 TI - Attenuation of polychlorinated biphenyl induced uroporphyria by iron deprivation. AB - A toxic sequel to polyhalogenated aromatic hydrocarbon exposure in humans is the development of porphyria cutanea tarda. In a mouse model (experimental uroporphyria) utilizing an environmentally relevant polychlorinated biphenyl (PCB) mixture, we show that the toxicity can be markedly influenced by nutritional status. In mice made susceptible to uroporphyria through a targeted deletion of one allele of uroporphyrinogen decarboxylase (Uro-D+/-), an iron deficient diet prevented the development of the uroporphyria and the changes in associated parameters normally seen within three weeks following a single exposure to Aroclor 1254. Iron deprivation also completely prevented PCB-induced uroporphyria in mice wild-type at the Uro-D locus (Uro-D+/+), a model that requires delta-aminolevulinic acid administration for the development of uroporphyria. In Uro-D+/- mice consuming delta-aminolevulinic acid, PCB exposure produced a severe uroporphyria that was attenuated, not prevented, by iron deficiency. This attenuation moderated hepatic uroporphyrin and uroporphyrinogen decarboxylase inhibitor levels, but not the depression of cytosolic uroporphyrinogen decarboxylase activity. PMID- 21783622 TI - Genotoxicity testing of four food preservatives and their combinations in the Drosophila wing spot test. AB - In this study, four food preservatives (sodium nitrate, sodium nitrite, potassium nitrate and potassium nitrite) and there five combinations at a concentration of 25mM have been evaluated for genotoxicity in the somatic mutation and recombination test (SMART) of Drosophila melanogaster. Three-day-old larvae trans heterozygous including two linked recessive wing hair mutations (multiple wing hairs and flare) were fed at different concentrations of the test compounds (25, 50, 75 and 100mM) in standard Drosophila Instant Medium. Wings of the emerging adult flies were scored for the presence of spots of mutant cells, which can result from either somatic mutation or mitotic recombination. Also lethal doses of food preservatives used were determined in the experiments. A positive correlation was observed between total mutations and the number of wings having mutation. In addition, the observed mutations in each wing were classified according to the size and type of the mutation. For the evaluation of genotoxic effects, the frequencies of spots per wing in the treated series were compared to the control group, which is distilled water. Chemicals used were ranked as sodium nitrite, potassium nitrite, sodium nitrate and potassium nitrate according to their genotoxic and toxic effects. Moreover, the genotoxic and toxic effects produced by the combined treatments were considerably increased, especially when the four chemicals were mixed. The present study shows that correct administration of food preservatives/additives may have a significant effect on human health. PMID- 21783623 TI - Neurobehavioural evaluation and kinetics of inhalation of constant or fluctuating toluene concentrations in human volunteers. AB - The health risks of inhalation exposure to volatile organic solvents may not only depend on the total external dose, but also on the pattern of exposure. It has been suggested that exposure to regularly occurring peak concentrations may have a stronger impact on the brain than constant exposure at the same average level. Recent animal experimental studies conducted in our laboratory using relatively high concentrations of toluene have shown different effects on discrimination performance and motor activity during and after exposure, depending on the exposure scenario. Relevance of these findings for man was evaluated in a volunteer study in which 11 healthy men (age 20-49 years) were exposed by inhalation for 4h to either a constant concentration of 40ppm toluene or to three 30-min exposure peaks at 110ppm during this 4h period. Selected tests from the Neurobehavioural Evaluation System (NES) were performed repeatedly during and after exposure. Blood concentrations of toluene as well as urinary o-cresol excretion were measured at relevant time points. The results show that toluene concentration in blood increased during constant exposure and fluctuated during occupationally relevant peak exposures. Presumably, brain concentrations showed similar qualitative patterns. No clear changes were observed on neurobehavioural measures of motor performance, attention, perceptual coding and memory, or on measures of mood and affect. The exposure conditions do not seem to induce significant acute changes in central nervous system function similar to those observed at much higher concentrations in animals, although a statistical correlation was found between one motor performance test (Finger Tapping Test with alternating hands) and blood toluene concentrations. Urinary o-cresol excretion appeared to be significantly higher during the first 2h after exposure. PMID- 21783624 TI - Behavioral effects and ChE measures after acute and repeated administration of malathion in rats. AB - Organophosphorus compounds such as malathion are environmental contaminants that may evoke neurobehavioral responses including anxiety and depression. In this study, after a functional observational battery, rats were tested in an open field and temperature test to better define doses used in subsequent experiments. Then, we investigated the effects of acute and repeated treatment with malathion on elevated plus-maze and forced-swim test, which are validated animal models to observe for anxiety- and depressive-related behaviors, respectively. We found that both acute and repeated malathion administration induced anxiogenic and depressive-like responses at doses that affected neither locomotion nor systemic temperature. Biochemical assays demonstrated inhibition of cholinesterase activity by these effective doses. PMID- 21783625 TI - Exposure to polychlorinated naphthalenes affects GABA-metabolizing enzymes in rat brain. AB - There is substantial evidence that polychlorinated naphthalenes (PCNs) are widespread global environmental pollutants, which accumulate in biota. The aim of our study was to characterize the effect of prolonged PCNs exposure on gamma aminobutyric acid (GABA) metabolism in rat brain regions with a high amount of GABAergic neurons (cerebellum, brain stem and basal ganglia). PCNs mixture was administered intragastrically for 7, 14 and 21 days in a dose 10mg/kg of body weight daily, and next the activity of glutamate decarboxylase (GAD), GABA aminotransferase (GABA-T), succinic semialdehyde dehydrogenase (SDH) and succinate dehydrogenase (SSA-DH) was assayed. PCNs administration altered all examined activities in the selected brain areas, except GAD in basal ganglia. The results suggest the correlation between PCNs action and disturbance in GABA metabolism in rat brain. Moreover, the chronic PCNs intoxication increased SDH mediated activation of TCA cycle, and it may be a kind of protective mechanism developed in nervous tissue in response to administration of toxic compounds. PMID- 21783626 TI - Therapeutic effects of Moringa oleifera on arsenic-induced toxicity in rats. AB - Moringa oleifera Lamarack (English: Horseradish-tree, Drumstick-tree; Hindi: Saijan; Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil. Besides, the plant is reported to have various biological activities, including hypocholesterolemic agent, regulation of thyroid hormone status, anti-diabetic agent, gastric ulcers, anti-tumor agent and hypotensive agent, used for treating various diseases such as inflammation, cardiovascular and liver diseases. Therapeutic efficacy of oral administration of seed powder of M. oleifera (500mg/kg, orally, once daily) post arsenic exposure (100ppm in drinking water for 4 months) was investigated in rats. Animals exposed to arsenic(III) showed a significant inhibition of delta-aminolevulinic acid dehydratase (ALAD) activity, decrease in reduced glutathione (GSH) level and an increase in reactive oxygen species (ROS) in blood. On the other hand, a significant decrease in hepatic ALAD, and an increase in delta-aminolevulinic acid synthetase (ALAS) activity was noted after arsenic exposure. These changes were accompanied by an increase in thiobarbiturc acid reactive substances (TBARS) level in liver and kidney. Activities of liver, kidney and brain superoxide dismutase (SOD) and catalase also showed a decrease on arsenic exposure. Administration of M. oleifera seed powder post arsenic exposure, exhibited significant recovery in blood ALAD activity while, it restored blood GSH and ROS levels. Most of the other blood biochemical variables remained unchanged on M. oleifera supplementation. A significant protection in the altered ALAD and ALAS activities of liver and TBARS level in liver and kidney was however, observed after M. oleifera administration. Interestingly, there was a marginal but significant depletion of arsenic from blood, liver and kidneys. The results, thus lead us to conclude that post arsenic exposure administration with the seed powder of M. oleifera has significant role in protecting animals from arsenic induced oxidative stress and in the depletion of arsenic concentration. Further studies thus can be recommended for determining the effect of co-administrating seed powder of M. oleifera during chelation therapy with a thiol chelator. PMID- 21783627 TI - Comparative researches on effects of sodium dodecylbenzene sulfonate and sodium dodecyl sulfate upon Lateolabrax japonicus biomarker system. AB - Fish Lateolabrax japonicus were exposed to anion surfactant sodium dodecylbenzene sulfonate (SDBS) and sodium dodecyl sulfate (SDS) at 1mg/l, respectively, for 6, 12 and 18d, with one control group. Liver antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) and glutathione S-transferase (GST) were determined; brain acetylcholinesterase (AChE) and liver inducible nitric oxide synthase (iNOS) activities were also measured. The results of the study indicated that these parameters made different, sometimes, adverse responses to SDBS and SDS exposure, such as the activity of iNOS can be inhibited by SDBS and induced by SDS, the different physico-chemical characteristics of SDBS and SDS should be responsible for their effects on enzyme activities. PMID- 21783628 TI - Effect of Aerva lanata against hepatotoxicity of carbon tetrachloride in rats. AB - The partially purified petroleum ether extractable fraction of the whole plant Aerva lanata (PF) was evaluated for the protective effect against liver damage induced by carbon tetra chloride (CCl(4)) in Sprague Dawley rats. Rats were orally administered with PF (50 and 100mg/kg body weight) for 14 days before CCl(4) challenge and 100mg of PF alone for toxicity analysis without CCl(4) administration. The results showed that CCl(4) administration significantly damaged the liver as evident from histopathology and very high activity of serum and liver marker enzymes. It also reduced the antioxidant enzyme status of the animals. PF administration significantly reversed the histopathological changes and restored the elevated activities of liver marker enzymes and also enhanced the antioxidant enzyme activities. The extract also reduced hepatic lipid peroxidation and increased the serum total protein and albumin/globulin (A/G) ratio. Preliminary phytochemical analysis of PF showed the presence of alkaloids. These observations clearly indicate that PF contains antioxidant alkaloids capable of ameliorating the CCl(4)-induced hepatic injury by virtue of its antioxidant activity. PMID- 21783629 TI - Investigation of extracts from (Tunisian) Cyperus rotundus as antimutagens and radical scavengers. AB - This study evaluates mutagenic and antimutagenic effects of aqueous, total oligomers flavonoids (TOF), ethyl acetate and methanol extracts from aerial parts of Cyperus rotundus with the Salmonella typhimurium assay system. The different extracts showed no mutagenicity when tested with Salmonella typhimurium strains TA98, TA100, TA1535 and TA1538 either with or without the S9 mix. On the other hand, our results showed that all extracts have antimutagenic activity against Aflatoxin B1 (AFB1) in TA100 and TA98 assay system, and against sodium azide in TA100 and TA1535 assay system. TOF, ethyl acetate and methanol extracts exhibited the highest inhibition level of the Ames response induced by the indirect mutagen AFB1. Whereas, ethyl acetate and methanol extracts exhibited the highest level of protection towards the direct mutagen, sodium azide, induced response. In addition to antimutagenic activity, these extracts showed an important free radical scavenging activity towards the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical. TOF, ethyl acetate and methanol extracts showed IC(50) value of 15, 14 and 20MUg/ml, respectively. Taken together, our finding showed that C. rotundus exhibits significant antioxidant and antimutagenic activities. PMID- 21783630 TI - Differential organ expression patterns of thyroid hormone receptor isoform genes in p,p'-DDE-treated adult male common frog, Rana temporaria. AB - Using the European common frog, Rana temporaria, as a model, we have studied the organ-specific gene expression patterns of thyroid hormone receptor isoforms after exposure to an organochlorine (OC) compound, p,p'-DDE. Four groups of frogs were subcutaneously injected with p,p'-DDE at 0.01, 0.1, 1 and 10mg/kg body weight, respectively. In addition, one group, serving as the control group, was injected with pure corn oil. TH receptor isoforms (TRalpha and TRbeta) gene expressions were evaluated in the brain, kidney, testis and liver using real-time PCR with gene-specific primers. Our results show that p,p'-DDE doses induced slight elevations of TRalpha and TRbeta mRNA in the brain. In the testis, p,p' DDE induced an initial significant 3-fold increase of TRalpha mRNA at 0.01mg/kg and thereafter clear dose-dependent decreases of TRalpha mRNA levels were observed. For testicular TRbeta mRNA levels, p,p'-DDE induced a slight elevation at 0.01mg/kg and thereafter significant decreases in TRbeta mRNA levels were observed. p,p'-DDE induced significant 2-4-fold elevations of both TR isoforms in frog kidney. The strongest transcriptional effect of p,p'-DDE on TR isoforms was observed in the kidney. While TRalpha mRNA was not measurable in the liver, p,p' DDE induced an initial 1.7-fold increase at 0.01mg/kg of TRbeta mRNA and thereafter an apparent dose-dependent decrease was observed. The relative abundance of TRalpha and TRbeta gene expression in different organs are in the order: kidney>testis>brain>liver. While the induction TRalpha and TRbeta might result to hypersensitivity and subsequent gain of biological functions, the inhibition might result to loss of biological function. Given the high persistency in the environment and continued use in developing countries coupled with the tendency for global atmospheric transport, DDT and its metabolites such as p,p'-DDE will remain a focus of concern both for scientific and societal reasons. PMID- 21783631 TI - Role of diallyl tetrasulfide in ameliorating the cadmium induced biochemical changes in rats. AB - Cadmium (Cd) is an ubiquitous environmental and occupational toxic metal concerned with a variety of adverse effects. The present study was undertaken to evaluate the role of diallyl tetrasulfide (DTS), an organosulfur compound in alleviating the Cd induced biochemical changes in male Wistar rats. During the experiment, rats were injected with Cd (3mg/(kgday)) subcutaneously alone or with oral administration of DTS at different doses (10, 20 and 40mg/(kgday)) for 3 weeks. In Cd treated rats, the activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) were significantly increased in serum with elevated levels of bilirubin, urea and creatinine. The hemoglobin level and creatinine clearance were also significantly decreased in Cd treated rats. In addition, the levels of plasma lipid peroxidation markers: thiobarbituric acid reactive substances and lipid hydroperoxides were significantly increased while the levels of plasma reduced glutathione (GSH), Vitamins C and E were significantly decreased in Cd administered rats. Administration of DTS along with Cd significantly decreased the serum, liver and kidney markers towards near normal level in a dose dependent manner. DTS at a dose of 40mg/(kgday) was highly effective when compared to other doses (10 and 20mg/(kgday)). DTS also significantly reduced the accumulation of Cd in blood and tissues as well as decreased the level of lipid peroxidation markers with elevation of antioxidants in plasma. All these changes were accompanied by histological observations in liver. The obtained results demonstrated the beneficial effect of DTS in reducing the harmful effects of Cd. PMID- 21783632 TI - Acetylsalicylic acid prevents nickel-induced collagen biosynthesis in human fibroblasts. AB - Exposure to nickel compounds that occurs mainly via inhalation can have adverse effects on human health. One of them is pulmonary fibrosis that results from accumulation of collagen in lung tissues. The mechanism of this process as well as effective treatment of the disease is not known. To evaluate the effect of nickel on collagen biosynthesis human dermal fibroblasts were treated with various concentrations of nickel chloride(II) for 72h. The compound was found to stimulate collagen biosynthesis in dose-dependent manner. We considered prolidase as a potential target for nickel-dependent collagen biosynthesis regulation. Prolidase [E.C.3.4.13.9] is a cytosolic metalloproteinase, which specifically splits imidodipeptides with C-terminal proline that is recycled for collagen biosynthesis. However, it was found that 72h treatment of confluent cells with Ni(II) did not affect significantly prolidase activity. An addition of acetylsalicylic acid, known, non-specific inhibitor of prolidase to the cells treated with 100MUM NiCl(II), significantly reduced both collagen biosynthesis and prolidase activity. It suggests that acetylsalicylic acid prevents nickel induced increase in collagen biosynthesis through inhibition of prolidase activity in human fibroblasts. The results indicate that tissue fibrosis may be considered as a possible target for prolidase inhibitory therapy and acetylsalicylic acid may represent such an agent for potential application in tissue fibrosis prevention or early stages of tissue fibrosis. PMID- 21783633 TI - Effects of peritoneal aluminum overload on polyamines and nitric oxide contents of testes and epididymis in the mice. AB - Polyamines are involved in cellular growth, differentiation and regulation of oxidative stress. The present investigation was to determine the effect of aluminum (Al) toxicity on the nitric oxide products (NO(x)) and metabolism of polyamines in mouse testes and epididymis. Aluminum chloride, AlCl(3,) was administered intraperitoneally to CD-1 adult male mice at dosages of 0, 7 or 35mg Al/kg body weight/day for 14 days (C, LAL and HAL groups). Results obtained show that the weights of epididymis in HAL animals are significantly decreased due to Al administration. Al treatment significantly induced higher Al concentrations in serum, testis and epididymis tissue. In addition, the serum and testicular and epididymal NO(x) production in HAL and testicular NO(x) in LAH groups were increased remarkably compared to the control animals. On the contrary, the contents of putrescine and spermine in testis were significantly lower than the values of controls and LAL groups. The epididymal spermine levels of HAL animal also decreased significantly. It is suggested that the polyamine biosynthesis in the mouse testis and epididymis can be affected by Al, which is associated with the NO(x) production in the male reproductive toxicity. PMID- 21783634 TI - Glycoprotein isolated from Gardenia jasminoides Ellis has a scavenging activity against oxygen radicals and inhibits the oxygen radical-induced protein kinase C alpha and nuclear factor-kappa B in NIH/3T3 cells. AB - This study was earned out to investigate the antioxidative and anti-apoptotic effects of glycoprotein isolated from Gardenia jasminoides Ellis fruit (GJE glycoprotein), which has been used to heal hepatic and inflammatory diseases in folk medicine. GJE glycoprotein showed a single band with a molecular weight of 27kDa on the 15% sodium dodecyl sulfate polyacrylamide gel. It consists of a carbohydrate component (57.65%) and a protein component (42.35%). GJE glycoprotein has dose-dependent scavenging activities for DPPH, lipid peroxyl, superoxide anion and hydroxyl radicals in cell-free systems. We also evaluated the protective and anti-apoptotic activities of GJE glycoprotein on the glucose/glucose oxidase (G/GO)-induced or hypoxanthine/xanthine oxidase (HX/XO) induced cytotoxicity and apoptosis systems in NIH/3T3 cells, using 3-(4,5 diinettiylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT), DNA fragmentation and H33342/ethidium bromide staining assays, respectively. Results in this experiment showed that GJE glycoprotein has dose-dependent blocking activities against G/GO- or HX/XO-induced cytotoxicity and apoptosis. In addition, we investigated whether GJE glycoprotein blocks the activation of redox-sensitive signal mediators, protein kinase C alpha (PKCalpha) and nuclear factor-kappa B (NF-kappaB) in G/GO or HX/XO-induced apoptotic NIH/3T3 cells, using a Western blot analysis and an electrophoretic mobility shift assay (EMSA). We found that 100MUg/ml GJE glycoprotein has an inhibitory effect on PKCalpha translocation and the DNA binding activity of (NF-kappaB). Here, we speculate that GJE glycoprotein is a natural antioxidant and one of the modulators of apoptotic signal pathways in NIH/3T3 cells. PMID- 21783635 TI - A novel model of image acquisition and processing for holistic quantification of angiogenesis disrupted by application of mainstream and sidestream cigarette smoke solutions. AB - Angiogenesis is a vital process in the growth of new blood vessels from pre existing vasculature. Among several approaches being used for studies related to angiogenesis, chicken chorioallantoic membrane assay (CAM) is an excellent model system. However, its utility has been limited due to difficulty in quantifying putative angiogenic and anti-angiogenic response to an experimental compound in an objective and quantifiable manner. Herein, we report a novel approach of image acquisition and processing for better evaluation of neovascularization. The effects of mainstream cigarette smoke solutions (MSCSS) and sidestream cigarette smoke solutions (SSCSS) from different commercially available cigarettes on angiogenesis were quantified, using CAM assay. Different gross and nanometer scale topographies of CAMs were quantified, which are vital for 3D image scrutiny and can precisely enumerate angiogenesis. Pattern formation of blood vessels, diameter, area and 3D surface roughness of CAMs were substantially disrupted by application of cigarette-smoke extracts. An important point revealed in our study that SSCSS appeared to be significantly more toxic than MSCSS with respect to their effects on angiogenesis. This new imaging technique combined with other modalities, will provide a robust platform to optimize trial design and more patent studies in angiogenesis. PMID- 21783636 TI - Effect of environmental contaminants on male reproduction. AB - A substantial body of evidence has accumulated in recent years that consistently indicate various adverse effects of environmental contaminants on human health. Decreasing trend of male fertility in terms of sperm counts and sperm quality, along with other changes in male reproductive health, including congenital malformations and testicular cancer in humans, and similar problems in wildlife has been correlated to the exposure to environmental contaminants. Many environmental chemicals have been reported to cause these reproductive abnormalities by eliciting changes in endocrine control of reproduction; however the specific underlying mechanisms are poorly understood. The present review summarizes recent studies on environmental contaminants and associated possible mechanism leading to adverse effects on male reproduction. Numerous studies demonstrate the interaction of environmental toxicants with steroid receptors and thereby causing interference with developmental and functional aspects of testis, epididymis and accessory sex organs. Induction of reactive oxygen species (ROS) by environmental contaminants and associated oxidative stress also have role in defective sperm function and male infertility. PMID- 21783637 TI - Production and characterization of antimicrobial active substance from the cyanobacterium Nostoc muscorum. AB - In this investigation, the cyanobacterium Nostoc muscorum exhibited antagonistic activity against Gram-positive and Gram-negative bacteria and filamentous fungi. The results indicated that the active substance produced maximally after 12 days of incubation in shaken culture at 35 degrees C, at pH 8.0 in BG-11 medium. The increase in nitrate concentration of the medium led to an increase in the antimicrobial production. Chloroform was the best solvent for extracting the active material. The antagonistic material was purified using thin layer chromatography. The compound showed maximum absorption at 240nm. Infrared (IR) and nuclear magnetic resonance (NMR) indicated presence of gammaOH, gammaCH aromatic, gammaCH aliphatic, gammaCN, gammaCO, gammaCC and CO. Mass spectroscopy indicated that its molecular weight is 279. The results also indicated that the compound is phenolic compound. PMID- 21783638 TI - Cypermethrin alters Glial Fibrillary Acidic Protein levels in the rat brain. AB - Pyrethroids, widely used insecticides, are biologically active in neurons. Whether they act on the non-neuronal brain cells remains an open question. Thus, the aim of this study was to examine whether Cypermethrin intoxication affects astroglial cells in the rat brain. The levels of Glial Fibrillary Acidic Protein (GFAP) in different brain regions were measured by ELISA following oral treatment with 5 or 10% of LD(50) of Cypermethrin per day for 6 days. A significant decrease of GFAP was observed in different brain regions of treated animals. The cerebral cortex showed the most pronounced effect with GFAP levels reduced to 81% of the controls 2 days after treatment and 77% 21 days after treatment. Although we did not find profound changes in the morphology of astrocytes in Cypermethrin treated animals, the decrease in GFAP suggests that astrocytes were affected by low doses of pyrethroids. The possible consequences were discussed. PMID- 21783639 TI - Pentachlorophenol inhibits micronuclei induction by 2-acetylaminofluorene but not by thioacetamide. AB - Our study examined the capacity of pentachlorophenol (PCP) to inhibit the ability of 2-acetylaminofluorene (2-AAF) and thioacetamide (TAA) to induce micronuclei in mouse bone marrow cells in vivo. 2-AAF (5.6mg/kg) and TAA (60mg/kg) were administered intra-peritoneally (i.p.) to Mus musculus males (BALB/c), and the frequencies of polychromatic erythrocytes with micronuclei (PCE-MN) 24h after injection were analyzed. Treatment with 2-AAF or TAA resulted in high PCE-MN frequencies in comparison with untreated and negative controls (19.9 and 21.60/00, respectively, versus ~30/00). Pretreatment with a single PCP dose (44mg/kg) 24h prior to the 2-AAF administration virtually eliminated micronuclei formation by 2-AAF, although it had no inhibitory effect on TAA-induced micronuclei. Animals receiving cyclophosphamide (CP) served as positive control. Since PCP is known to inhibit arylsulfotransferase (AST) activity, which is involved in 2-AAF activation, this mechanism most likely produced the results with PCP and 2-AAF. Our results also are consistent with a different pathway involved in TAA induction of micronuclei, one that is not inhibited by PCP. PMID- 21783640 TI - Biochemical and physiological biomarkers in Prochilodus lineatus submitted to in situ tests in an urban stream in southern Brazil. AB - The aims of the present study were to verify the suitability of short-term in situ test with the neotropical fish Prochilodus lineatus and to evaluate from a set of biochemical and physiological biomarkers the ones which could work as sensitivity tools for the environmental quality assessment. In situ tests were carried out for 1 week in winter and summer, at three sites along an urban stream heavily contaminated by anthropogenic activities and at a reference site. The variables analyzed were: hemoglobin content (Hb), plasma concentrations of cortisol, glucose, total protein, Na(+) and Cl(-), plasma osmolarity, liver activities of glutathione-S-transferase (GST) and catalase and interrenal cells area. Results showed that glycemia, interrenal cell size and GST activity, which were significantly higher in fish caged in the urban stream, were best able to distinguish between the most disturbed sites and the reference and caged P. lineatus showed to be a promising tool for the assessment and monitoring of tropical aquatic ecosystems. PMID- 21783641 TI - Pharmacological activity in growth inhibition and apoptosis of cultured human leiomyomal cells of tropical plant Scutellaria barbata D. Don (Lamiaceae). AB - Scutellaria barbata D. Don (Lamiaceae) (SB), which is known in traditional Korean medicine, has been used as an anti-inflammatory and antitumor agent. Since uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium, we aimed to determine the growth inhibition and the induction of apoptotic cell death brought about by the herb SB in two different leiomyomal cells, named LM-1 and LM-2, and to clarify the mechanism of this apoptosis. Water soluble ingredients of SB, and the leiomyomal cell lines of LM-1 and LM-2, were used in vitro. Growth inhibition, induction of cell death, morphological features, the presence of DNA ladders, increases in Caspase 3-like activity, the effects of a Caspase 3 inhibitor on apoptotic cell death, and the release of Cytochrome C by SB were analyzed. SB inhibited the growth and decreased the viability of the leiomyomal cells. The viability of normal myomatrial smooth muscle cells (SMC) in the presence of low concentrations of SB was higher than those of leiomyomal cells. Apoptotic bodies and DNA ladders were observed to be induced in leiomyomal cells of LM-1 and LM-2 by SB. The synthetic tetrapeptide Caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibited the apoptotic cell death of leiomyomal cells induced by SB. The Caspase 3-like activity in leiomyomal cells LM-1 and LM-2 increased after the addition of SB. Cytochrome C was released from mitochondria into the cytosol 8h after the addition of SB, and reached a peak at 16h. The peak of Cytochrome C release was earlier than that of Caspase 3-like activity. We concluded that SB inhibited the growth of the leiomyomal cells and induced apoptosis. The apoptosis of leiomyomal cells induced by SB was associated with the release of Cytochrome C from the mitochondria, followed by an increase in Caspase 3-like activity. PMID- 21783642 TI - Antioxidant status in different regions of heroin addicts' brain. AB - Heroin is an illicit narcotic abused by millions of people worldwide. In the present work, we estimated peroxyl radical-trapping capacity (PRTC), oxidative stress markers - malondialdehyde and protein carbonyl groups, as well as antioxidant enzymes - superoxide dismutase and catalase, in different regions of brain. Studies conducted on nine brains from heroin abusers and eight from control subjects revealed a decrease in PRTC in each part of heroin intoxicated brains and an increase in lipid peroxidation in brain cortex, brain stem and white matter but not in hippocampus. Protein oxidation was increased in hippocampus and in brain stem, but it was unchanged in gray and white matters. Superoxide dismutase and catalase activities were unchanged in heroin addicts. We conclude that heroin intoxication changes the antioxidant status in human brain by increasing the amount of organic rather then inorganic peroxides. The most severe condition of oxidative stress occur in brain stem. PMID- 21783643 TI - Antisecretory and antiulcer effects of diphenyl diselenide. AB - The antisecretory and antiulcer effects of diphenyl diselenide were studied in vivo and in vitro. Diphenyl diselenide, administered intraperitoneally prevented the development of gastric lesions induced by ethanol and indomethacin. There was no difference in plasma uric acid concentrations in diphenyl diselenide-treated rats with gastric lesions induced by 70% ethanol. There were no changes in TBARS levels in diphenyl diselenide-treated rats with gastric lesions induced by indomethacin and ethanol. Diphenyl diselenide (5, 10 and 50mg/kg) inhibited gastric acid secretion in pylorus-ligated rats. In vitro results demonstrated that diphenyl diselenide inhibited lipid peroxidation induced by Fe(2+)/ascorbate/H(2)O(2) and reduced K(+)-dependent ATPase activity. The mechanisms by which pre-administered diselenide protects the damaged area in the gastric mucosa are not clear but it appears that the antiulcer activity of diphenyl diselenide is the result of antisecretory activity, via inhibition of gastric K(+)-ATPase activity. PMID- 21783644 TI - Combined and individual administration of diethyl phthalate and polychlorinated biphenyls and its toxicity in female Wistar rats. AB - Polychlorinated biphenyls (PCBs) are persistent environmental pollutants and known to act as xenoestrogens. PCBs and diethyl phthalate (DEP) are ubiquitous environmental pollutants because both are used as plasticizers and in various other industrial applications. Therefore, a study was undertaken to evaluate the interactive toxicity of DEP and PCBs in young female Wistar rats. Healthy young female albino rats of Wistar strain weighing 100g (7-8 weeks old) were randomly assigned to five groups of six each. Group I female rats were fed on normal diet and water ad libitum. Group II female rats were maintained on normal diet mixed with corn oil at 16.5mg/kg diet/day and 0.94mg/kg body weight/day as oil control. Groups III and IV female rats were given Clophen A60 and DEP dissolved in corn oil mixed with the diet at 50mg/(kgdietday), which is approximately equal to 2.85mg/(kgbodyweightday), individually to each group. Group V female rats received a mixture of DEP and Clophen A60, each dissolved in corn oil mixed with the diet at 50mg/(kgdietday), which is approximately equal to 2.85mg/(kgbodyweightday). Treatment was carried out for 150 days and after the completion of treatment, serum and liver enzymes and other biochemical parameters in the serum and liver were assessed. Liver weight to body weight ratio showed significant increase in Clophen A60 and Clophen A60+DEP treated rats. In the three treated groups, there was significant decrease in liver glutathione (GSH) and glutathione reductase (GR). Alanine amino transferase (ALT) was significantly increased in the liver of the three treated groups and in the serum of Clophen A60 and DEP alone treated groups and significant decrease only in the serum of Clophen A60+DEP treated rats. Significant increase in liver and serum lactate dehydrogenase (LDH) and acid phosphatase (ACP) activity was observed in the three treated groups. Alkaline phosphatase (ALP) activity was significantly increased only in the serum of the Clophen A60 and Clophen A60+DEP treated rats, whereas significant decrease in the serum and liver of DEP alone treated rats was observed. Aspartate aminotransferase (AST) activity and cholesterol levels were highly significant in the liver and serum of DEP treated rats. In addition, cholesterol level was significantly increased in the liver and serum of Clophen A60 treated rats and only in the liver of Clophen A60+DEP treated rats. Succinate dehydrogenase (SDH) activity was significantly increased in the liver of Clophen A60 and Clophen A60+DEP treated rats and highly significant increase in the serum of Clophen A60+DEP treated rats. There was significant increase in triglyceride levels in the liver and serum of Clophen A60 and Clophen A60+DEP treated rats, whereas significant increase in triglyceride levels in the serum of DEP alone treated rats was observed. Glycogen levels were significantly increased in the liver of Clophen A60+DEP treated rats, whereas serum glucose levels showed significant decrease, but in Clophen A60 alone treated rats showed significant increase in liver glycogen and serum glucose, whereas DEP alone treated rats showed significant increase in only serum glucose levels. Lipid peroxidation was increased in the liver of DEP treated rats, which was highly significant, compared to significant increase in Clophen A60 and Clophen A60+DEP treated rats. Histology of liver showed severe vacuolation, loss of hepatic architecture and granular deposits in the hepatocytes of DEP and Clophen A60+DEP treated rats, whereas in Clophen A60 alone treated rats, hepatocytes showed hyper pigmentation mild loss of hepatic architecture in centrilobular and periportal area. PMID- 21783645 TI - Distribution of organochlorine pollutants in ovine dental tissues and bone. AB - The distribution of selected lipophilic organochlorine pollutants, including two pairs of tetra- and hexa-chlorobiphenyl isomers (PCB-54, -80, -155, -169) and organochlorine pesticides [hexachlorobenzene (HCB) and 1,1-bis(4-chlorophenyl) 2,2-dichloroethene (4,4'-DDE)], in ovine dental pulp, dentine, enamel and mandibular bone was examined. Sheeps were given a single dose of individual organochlorine (1-4MUmol/kg) in olive oil by intramuscular injection and sacrificed 2 months later. Organochlorine residues were determined by gas chromatography. The highest levels of organochlorines were found in bone. The lipid adjusted levels varied significantly between tissues. Lower chlorinated, metabolically unstable, non-planar PCB-54 was enriched in enamel, while higher chlorinated, metabolically resistant, planar PCB-169 was preferentially retained in pulp. The ratio of planar to non-planar PCB homologues and pesticides (PCB 169/-155, PCB-80/-54, HCB/4,4'-DDE) decreased in the order pulp>dentine>enamel, suggesting that besides compound's lipophilicity and the tissue's lipid content, other physicochemical properties of organochlorines and tissue specific characteristics affect their distribution. PMID- 21783646 TI - Comparison of immunnological and genotoxicological parameters in automobile emission inspectors exposed to polycyclic aromatic hydrocarbons. AB - In this study, we investigated the immunotoxicities of polycyclic aromatic hydrocarbons in 54 automobile emission inspectors and in 84 control subjects, and evaluated associations between immunological and genotoxicological parameters. Specific surface antigens of peripheral lymphocytes, namely, CD3, CD4, CD8, CD19, and CD69 were subjected to measure immune status in automobile emission inspectors and control subjects. T-and B-cells showed no significant differences between automobile emission inspectors and control subjects (p=0.740 and 0.395). In addition, the ratio of T helper cells to T cytotoxic cells was not deferent (p=0.144). However, T-cell activation was found to be significantly higher in automobile emission inspectors (p=0.041), but not B-cell activation. The levels of two cytokines (IL-4 an INF-gamma) and four immunoglobulins (IgA, IgE, IgG, and IgM) were also determined in automobile emission inspectors and control subjects. All immunoglobulin types were lower in automobile emission inspectors, but this was significant only for IgG (0.047). In addition, the levels of two cytokines, IL-4 and INF-gamma, were also higher in automobile emission inspectors, though this was not significant. DNA damage in mononuclear and polynuclear lymphocytes and in the level of urinary metabolites, 1-OHP and 2-naphthol, were evaluated in automobile emission inspectors and in control subjects and significant differences were found between the two groups. Examinations of urinary metabolites, DNA damage, and immunological parameters, including leukocyte subpopulations, immunoglobulins, and cytokines, showed that the cytokines levels were associated with the levels of two urinary metabolites, 1-OHP and 2-naphthol. PMID- 21783647 TI - Human-based alternatives to animal experiments: is 'Replacement' credible? PMID- 21783648 TI - Progress in the development of in vitro human-based alternatives to animal models. PMID- 21783649 TI - The merits of in vitro versus in vivo modeling in investigation of the immune system. AB - Immunity is vital for determining self and for the recognition and swift eradication of foreign antigens without harming the host. Innate immunity developed in metazoan, multi-cellular organisms under overwhelming selection pressure of invasive microbes and, although imperfect, has performed admirably to enable the evolution of higher eukaryotes. Adaptive immunity developed within an existing innate immune system to more effectively eradicate foreign antigens, whether from pathogens, malignant cells, or microbial toxins, such that repeated stimulations with foreign antigens are more efficiently excluded. Investigation of the immune system requires both in vivo and in vitro experimentation, not only because of the inherent complexity of immunity and the required pertinence of using higher mammals to not falsely disrupt the immune system, but also to use isolates of the specific cellular and humoral components to determine function, signal transduction, and a possible role of these constituents without the complexity and redundancy of immunity in intact animals. The hypotheses of well designed in vitro experiments must also be tested in intact in vivo models to determine relevance and to discard artifactual findings secondary to the in vitro environment. The following review outlines the basic constituents and functions of both adaptive and innate immunity to demonstrate the importance of both in vivo and in vitro investigation of immunity in our attempt to define host defense and to decrease morbidity and mortality in humans. PMID- 21783650 TI - In vitro and animal models of drug-induced blood dyscrasias. AB - Drug-induced blood dyscrasias can be either acute and predictable or delayed and unpredictable (idiosyncratic). The predictable toxicity is relatively easy to reproduce with in vitro models, although they may not work for drugs that require bioactivation. It is very unlikely that idiosyncratic blood dyscrasias can be modeled in vitro, although some drugs (or their reactive metabolites) that cause idiosyncratic reaction are toxic to bone marrow cells in vitro. Although the mechanisms of idiosyncratic reactions are poorly understood, there is evidence that most are due to reactive metabolites and some are immune-mediated. Therefore screening drugs for their bioactivation by myeloperoxidase, the major oxidative enzyme in bone marrow, may provide some measure of the risk that a drug will cause blood dyscrasias. Several examples of drug-induced idiosyncratic agranulocytosis, aplastic anemia and thrombocytopenia are presented, but better in vivo models are clearly needed to gain a clearer understanding of these adverse reactions. PMID- 21783651 TI - The study of the pituitary gland using animals and alternatives: Can the latter completely replace the former? AB - In this review, the role experiments and procedures on animals and animal tissues in elucidating the understanding of the hypothalamus and pituitary gland are discussed. Such findings have led to direct application in the diagnosis and treatment of human endocrine disorders. In vitro methods for investigating the human pituitary gland have recently led to important new discoveries but even these 'alternative' techniques exploit animal research or procedures at least to some degree. Nevertheless, the need for use of animals has been significantly reduced by these novel methods. PMID- 21783652 TI - The use of erythrocytic and animal models in the study of protein phosphorylation. AB - Phosphorylation processes are common post-transductional mechanisms, by which it is possible to modulate a number of metabolic pathways. Proteins are highly sensitive to phosphorylation, which governs many protein-protein interactions. The enzymatic activity of some protein tyrosine-kinases is under tyrosine phosphorylation control, as well as several transmembrane anion-fluxes and cation exchanges. In addition, phosphorylation reactions are involved in intra and extra cellular 'cross-talk' processes. Early studies adopted laboratory animals to study these little known phosphorylation processes. The main difficulty encountered with these animal techniques was obtaining sufficient kinase or phosphatase activity suitable for studying the enzymatic process. Large amounts of biological material from organs, such as the liver and spleen were necessary to conduct such work with protein kinases. Subsequent studies revealed the ubiquity and complexity of phosphorylation processes and techniques evolved from early rat studies to the adaptation of more rewarding in vitro models. These involved human erythrocytes, which are a convenient source both for the enzymes, we investigated and for their substrates. This preliminary work facilitated the development of more advanced phosphorylative models that are based on cell lines. PMID- 21783653 TI - The value of alternative testing for neurotoxicity in the context of regulatory needs. AB - Detection and characterisation of chemical-induced toxic effects in the central and peripheral nervous system represent a major challenge for employing newly developed technologies in the field of neurotoxicology. Precise cellular predictive test batteries for chemical-induced neurotoxicity are increasingly important for regulatory decision making, but also the most efficient way to keep costs and time of testing within a reasonable margin. Current in vivo test methods are based on behavioural and sensory perturbations coupled with routine histopathological investigations. In spite of the empirical usefulness of these tests, they are not always sensitive enough and often, they do not provide information that facilitates a detailed understanding of potential mechanisms of toxicity, thus enabling predictions. In general, such in vivo tests are unsuitable for screening large number of agents. One way to meet the need for more powerful and comprehensive tests via an extended scientific basis is to study neurotoxicity in specific cell types of the brain and to derive generalised mechanisms of action of the toxicants from such series of experiments. Additionally, toxicokinetic models are to be developed in order to give a rough account for the whole absorption, distribution, metabolism, excretion (ADME) process including the blood-brain barrier (BBB). Therefore, an intensive search for the development of alternative methods using animal and human-based in vitro and in silico models for neurotoxic hazard assessment is appropriate. In particular, neurotoxicology represents one of the major challenges to the development of in vitro systems, as it has to account also for heterogeneous cell interactions of the brain which require new biochemical, biotechnological and electrophysiological profiling methods for reliable alternative ways with a high throughput. PMID- 21783654 TI - Predicting oral drug absorption and hepatobiliary clearance: Human intestinal and hepatic in vitro cell models. AB - Membrane transport proteins control the uptake and efflux of many drugs in tissues including the intestine, liver and kidneys and thus play important roles in drug absorption, distribution and excretion. With the development of high throughput screening in an industrial environment, the importance of having appropriate in vitro systems to study drug transporter function, regulation, and interactions are invaluable. Cell lines are efficient tools in screening individual transport processes. In this review, we focus on the processes involved in the absorption and hepatobiliary clearance of drugs and the potential of cell lines to model such process, paying particular attention to the use of Caco-2 and HepG2 cells. PMID- 21783655 TI - Utility of human/human-derived reagents in drug discovery and development: An industrial perspective. AB - The shift to combinatorial chemistry and parallel synthesis in drug discovery has resulted in large numbers of compounds entering the lead seeking and lead development phases of the process. To support this, higher throughput computational (in silico) and in vitro approaches have become the forefront of the drug metabolism and pharmacokinetic (DMPK) input into drug discovery. This has been accompanied by a shift in focus from animal-derived data to human based studies, reflecting the realisation that extrapolation from animals to human has its limitations. In silico approaches may be regarded as human derived tools for DMPK, since models (template/pharmacophore and protein homology modelling), for example, for the human CYP enzymes, are widely used for identifying qualitatively enzyme/substrate interactions. Quantitative assessment of drug metabolism using human hepatocytes or sub-cellular fractions provide a valuable tool both for the screening out of high metabolic lability and in estimations of human intrinsic clearance. In terms of drug absorption, the human colon adenocarcinoma cell line, Caco-2, offers a versatile human derived system for measuring drug permeability, despite over expression of the efflux transporter P-glycoprotein (P-gp). The importance of P-gp can then be further assessed in recombinant systems expressing the human P-gp, where substrate affinity and inhibition potency can be measured, important factors when considering transporter mediated drug-drug interactions. The primary cause of pharmacokinetic-based drug-drug interactions (DDIs) is through enzyme inhibition or induction, with the CYP enzymes being of major importance. Human liver microsomes and hepatocytes are invaluable tools in assessment of DDI vulnerability of new chemical entities, having the capacity to identify enzymes responsible for specific routes of metabolism, and hence areas of vulnerability for a DDI. In addition, human-based screening tools can be used to identify the perpetrator of a DDI through enzyme inhibition/induction. Large differences in the nature of enzymes induced and the extent of induction when comparing animals to man are known. Thus, in vitro models allowing assessment of induction potential in human tissue, establishes some relevance to the clinical situation. PMID- 21783656 TI - Can in vitro drug metabolism studies with human tissue replace in vivo animal studies? AB - Animals provide a physiologically relevant system for evaluation of drug metabolism, but marked inter-species differences limit extrapolation to humans. Liver microsomes are used extensively as an in vitro human drug metabolising system, and with appropriate selection of parameters, such as substrate and enzyme concentrations, may predict both routes and rate of metabolism. However, variable enzyme expression between donors and overlapping substrate specificity influence reproducibility, hence recombinant human CYP enzymes expressed in human, yeast or insect cells have been developed. For complex metabolic profiles involving sequential or competing pathways, isolated hepatocytes and liver slices are of value. Altered enzyme activity and restricted availability constrain their use. Cryopreservation or culture increase availability, but changes in enzyme activity remain a constraint. To date, human in vitro systems do not predict all aspects of drug metabolism, thus a combination of in vivo animal and in vitro human studies will be required for the foreseeable future. PMID- 21783657 TI - Structure and activity in assessing antioxidant activity in vitro and in vivo A critical appraisal illustrated with the flavonoids. AB - Structure-activity relationships are indispensable to identify the most optimal antioxidants. The advantages of in vitro over in vivo experiments for obtaining these relationships are, that the structure is better defined in vitro, since less metabolism takes place. It is also the case that the concentration, a parameter that is directly linked to activity, is more accurately controlled. Moreover, the reactions that occur in vivo, including feed-back mechanisms, are often too multi-faceted and diverse to be compensated for during the assessment of a single structure-activity relationship. Pitfalls of in vitro antioxidant research include: (i) by definition, antioxidants are not stable and substantial amounts of oxidation products are formed and (ii) during the scavenging of reactive species, reaction products of the antioxidants accumulate. Another problem is that the maintenance of a defined concentration of antioxidants is subject to processes such as oxidation and the formation of reaction products during the actual antioxidant reaction, as well as the compartmentalization of the antioxidant and the reactive species in the in vitro test system. So determinations of in vitro structure-activity relationships are subject to many competing variables and they should always be evaluated critically. PMID- 21783658 TI - In vitro studies-how good are they at replacing in vivo studies for measurement of skin absorption? AB - Measures of percutaneous penetration are required for risk assessment of exposure of man to chemicals. In vitro approaches and QSAR predictions can be used and reduce the use of in vivo animal experiments. The OECD Guidelines on in vitro dermal absorption studies were recently accepted but progress was hampered by a lack of direct in vitro/in vivo comparisons in humans or in rodents. Either flow through diffusion or static cell systems with full thickness, dermatomed skin or membranes can be used. In a study of the robustness of in vitro techniques, inter skin variability was greater than inter-laboratory or between cell variability. Recent studies with a number of chemicals have shown a reasonably good prediction but the difference between in vitro and in vivo results was greater for lipophilic molecules as lipophilic molecules which were retained in the stratum corneum. The experimental flux obtained in vitro using conditions that reflect the potential occupational exposure may be the most appropriate figure for risk assessment purposes. A database of in vitro and in vivo dermal penetration has been established. Dermal absorption data using infinite doses has been combined in a number of databases used for predictive QSAR modelling approaches to dermal absorption. However, absorption values derived from QSAR may over estimate the actual absorption from a finite dose. PMID- 21783659 TI - Ex vivo cancer chemoprevention research possibilities. AB - The concept of cancer prevention with naturally occurring or synthetic compounds is rapidly gaining momentum as a key field in cancer research. The availability of good models for the determination of the molecular mechanisms of these agents, which frequently have multiple sites of action within a cell, is key to the progression of the field. In this review, we concentrate on the emergence of several in vitro techniques that have significant advantages over more traditional monolayer cell culture, and/or in vivo models. In particular, we focus on the potential of 3D multicellular spheroid models as versatile intermediates between monolayer culture and tumours in situ. In these models, cell-cell interactions and cell-extracellular matrix interactions can closely mimic the environment to which tumour cells would be exposed in vivo, while maintaining the advantages of ease of manipulation of an in vitro system. The in vitro tube formation assay for the study of angiogenesis, the availability of human tissues for research, and the sophisticated technology surrounding DNA microarray and proteomics are also briefly discussed. PMID- 21783660 TI - A focus on the human lens in vitro. AB - The lens is a unique organ in that it is avascular and non-innervated, obtaining all nutrients from the aqueous and vitreous humours that bathe the lens. All lenses attempt to achieve the same goal, namely to maintain transparency and focus light on to the retina. However, the mechanisms by which these processes are maintained, or disrupted leading to a loss of transparency, are likely to differ in some cases between animals and humans. To allow comparison to take place, human in vitro models have been developed, ranging from whole organ culture to the generation of human lens cell lines. All have their merits and limitations, but as a whole, they permit extensive studies of lens cell behaviour and function to be carried out. Together, these in vitro methods allow the biological events of the lens to be further understood. Moreover, they could help identify the mechanisms that give rise to cataract and posterior capsule opacification, a problem that occurs following surgery, providing therapeutic targets for their prevention. PMID- 21783661 TI - Activity of rat UGT1A1 towards benzo[a]pyrene phenols and dihydrodiols. AB - Four UDP-glucuronosyltransferases from the rat UGT1A family were tested for activity towards benzo[a]pyrene phenols and dihydrodiols. UGT1A1 and UGT1A7 were found to be broadly active towards BaP metabolites. Antisera recognizing rat UGT1A1 and UGT1A7 were used to assess UGT levels in relation to UGT activity towards benzo[a]pyrene-7,8-dihydrodiol (BPD). The rank BPD UGT activities were liver=intestine?kidney, whereas UGT1A1 was highest in liver and UGT1A7 was highest in intestine. Phenobarbital, an inducer of hepatic UGT1A1, only slightly increased BPD UGT activity, whereas UGT1A7 inducers more potently increased the activity. Inhibition studies using the differential UGT1A1 inhibitor, bilirubin, suggest that UGT1A1 is not a major contributor to the constitutive BPD glucuronidating activity of control rat liver microsomes. These data suggest that multiple UGT1A enzymes contribute to glucuronidation of BPD and other BaP metabolites, and that their relative contributions depend on tissue- and environmental-specific factors. PMID- 21783662 TI - A possible mechanism of resistance to cadmium toxicity in male Long-Evans rats. AB - The susceptibility to cadmium (Cd)-induced toxicity in male Long-Evans (LE) rats was compared with that in male Fischer 344 (Fischer) and Wistar-Imamichi (WI) rats, which are sensitive and resistant, respectively, to Cd toxicity. All rats of the LE and WI strains survived for 7 days after the treatment with a toxic dose of Cd (6.5mg/kg b.w.). However, all rats of the Fischer strain died by the following day. The strong resistance to Cd toxicity in the LE strain was confirmed to be independent of metallothionein synthesis induced by Cd. The hepatic and renal Cd contents after its administration were significantly lower in the LE strain than in the Fischer strain. Furthermore, the hepatic and renal zinc (Zn) contents after its administration were significantly lower in the LE strain than in the Fischer strain. These limited data suggest that the strong resistance to Cd toxicity in male LE rats results from, at least in part, the lower accumulation of the metal in the liver and kidney, in a similar mechanism as the lower Zn accumulation. PMID- 21783663 TI - Influence of combined antioxidants against cadmium induced testicular damage. AB - Acute effects of cadmium (Cd) and combined antioxidants were evaluated in Sprague Dawley rat testes. The rats were subdivided into four groups. Cadmium chloride (2mg/kgday) injected intraperitoneally during 8 days. Vitamin C (250mg/kgday), vitamin E (250mg/kgday) and sodium selenate (0.25mg/kgday) were pretreated by gavage in both of control and cadmium injected rats. Testis lipid peroxidation and glutathione levels were determined by spectrophotometrically. In Cd treated rats, lipid peroxidation levels were increased and glutathione levels were decreased and combined antioxidants treatment was effective in preventing of lipid peroxidation and normalizing glutathione. In Cd treated animals, the degenerative changes were observed, but not observed in the administrated rats with Cd and antioxidants under the light microscope. Proliferating cell nuclear antigen, metallothionein and caspase-3 activities were evaluated by immunohistochemically. Proliferation activity was not seen in the spermatogonial cells of cadmium treated testis. Treatment with antioxidants in cadmium administrated testis leads to pronounced increase in proliferation activity. Cytoplasmic caspase-3 activity was determined in the spermatogenic cells but not spermatogonia in treatment of antioxidants with Cd. In control and treated with antioxidants animals, metallothionein expressions were localized in the cells of seminiferous tubules, although the expression only was observed in the interstitial cells of cadmium treated rats. Results demonstrated beneficial effects of combined vitamin C, vitamin E and selenium treatment in Cd toxicity. PMID- 21783664 TI - Effects of diazinon on acetylcholinesterase activity and lipid peroxidation in the brain of Oreochromis niloticus. AB - The aim of this study was to investigate the effects of organophosphorus (OP) pesticide diazinon on acetylcholinesterase (AChE: EC 3.1.1.7) activity and its relationship to lipid peroxidation (LPO) in the brain of a freshwater fish, Oreochromis niloticus. Malondialdehyde (MDA) content was used as biomarker for LPO. Fish were exposed to 1 and 2mg/L sublethal concentrations of diazinon for 1, 7, 15 and 30 days. In the entire experimental group, AChE activity in brain significantly decreased (up to 93% of control), whereas MDA content decreased after 1 day, and increased after 7 and 15 days of exposures. MDA was in similar level with the control group after diazinon exposure of 30 days. The findings of the present study show that diazinon inhibited AChE activity and it has LPO inducing potential in fish. The inhibition of AChE activity in the brain of O. niloticus correlated with increased MDA levels after 7 and 15 days diazinon exposures (r=-0.661, P<0.019; r=-0.652, P<0.022, respectively). PMID- 21783665 TI - Sublethal effects of commercial deltamethrin on the structure of the gill, liver and gut tissues of mosquitofish, Gambusia affinis: A microscopic study. AB - The histopathological effects of deltamethrin on the gill, liver and gut tissues of the mosquitofish, Gambusia affinis were determined by light microscopy. The fish were exposed to two sublethal concentrations of deltamethrin (0.25 0.50MUg/l) for periods of 10, 20 and 30 days. The most common gill changes at all doses of deltamethrin were desquamation and necrosis. Besides, epithelial hypertrophy, lifting of the lamellar epithelium, oedema, dilatation of the capillaries primary lamellae, aneurism, epithelial hyperplasia and fusion of the secondary lamellae were other histopathological effects. Hepatic lesions in the liver tissues of fish exposed to deltamethrin were characterized by hypertrophy of hepatocytes, significant increase of kupffer cells, circulatory disturbances, focal necrosis, fatty degeneration, nuclear pycnosis and narrowing of sinusoids. Infiltration of mononuclear leucocyte and eosinophils towards lamina propria, necrosis were detected in gut tissues of fish after exposure to deltamethrin. PMID- 21783666 TI - Modulation of methotrexate-induced cytogenotoxicity in mouse spermatogonia and its transmission in the male germline by caffeine. AB - Apart from its own controversial cytogenotoxic effects, caffeine (CAF), one of the most commonly consumed alkaloids worldwide, is found potentiative to and so also protective from the cytogenotoxic effects of numerous chemical and physical mutagens. It also has modulated the actions of several antineoplastic agents. Additionally, it has been tested as a chemopreventive of cancer and is reportedly associated inversely with different cancer risks. Therefore, in the present study, three different sub-lethal doses of CAF, 25, 50 and 100mg/kg, were tested in mouse to assess their cytogenotoxic effects on dividing spermatogonia at 24h post-treatment, and transmission of such effects in the male germline from the primary spermatocytes and sperm at week 4 and week 8 post-treatment, respectively. CAF was found to be weakly clastogenic to mouse spermatogonia and the effects were also found transmitted in the male germline. Interestingly, such induced effects were quantitatively related to the dose of CAF tested. On the other hand, methotrexate (MTX), an antifolate antimetabolite, is prescribed frequently for the treatment of various types of cancers. However, MTX is reportedly clastogenic. Modulation of the said three different pre-treated doses of CAF on MTX 10mg/kg-induced cytogenotoxic effects, tested in the same experimental protocol, indicated that CAF pre-treatment was decreasing the MTX induced clastogenicity in spermatogonia, and was lowering the concurrent transmission of such effects in the male germline of mice, significantly. Such decreases were related to the dose of CAF tested, i.e. higher the dose of CAF more was the decrease in the MTX-induced cytogenotoxic effects and in their transmission. The possible mechanisms that might have caused the manifestation of a weak clastogenic action of CAF on spermatogonia and in its transmission in the male germline, and the CAF modulation of MTX-induced cytogenotoxic effects in spermatogonia and in their transmission have been discussed. PMID- 21783667 TI - Chronic exposure to dioxin-like compounds and thyroid function among New York anglers. AB - Experimental studies suggest that dioxin-like compounds influence thyroid function, although human studies have presented equivocal results. Great Lakes sportfish consumers represent a population with greater potential for exposure to dioxin-like compounds than non-consumers. Thirty-eight licensed anglers participating in a dioxin exposure study, consumers and non-consumers, conducted as part of the New York Angler Cohort Study, donated blood and completed questionnaires regarding demographic, clinical, and sportfish consumption data. Sera were analyzed for polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), coplanar biphenyls (PCB), and PCB IUPAC #153, in addition to thyroid stimulating hormone (TSH), total and free thyroxine (T(4) and fT(4)), total triiodothyronine (T(3)), and lipids. An inverse linear association between serum fT(4) and the sum of dioxin-like congener concentrations (?DIOXs) in serum (B= 0.3, 95% CI=-0.5, -0.1) was identified adjusting for PCB #153 and serum lipids (R(2)=0.3, p=0.02, n=37). The results of this study are preliminary but suggest an inverse association between dioxin-like compounds and fT(4). PMID- 21783668 TI - Neurotoxic effect of maneb in rats as studied by neurochemical and immunohistochemical parameters. AB - Epidemiological investigations document that workers in agriculture, horticulture and people living near areas with frequent use of pesticides have increased risk of developing symptoms of Parkinson's disease. This study investigated the neurotoxic effect of the fungicide maneb by morphological, immunohistochemical and neurochemical methods applying young Sprague-Dawley male rat as the model. Intraperitoneal dosing (7.5, 15 or 30mg maneb/kg bodyweight/week for 12 weeks) demonstrated dose-related increased manganese concentration in corpus striatum. The striatal concentration of 5-hydroxytryptamine (5-HT) increased in a dose related manner, as did the 5-HT concentrations in the rest of the brain indicating early sign of neurotoxicity. Striatal acetylcholinesterase activity was not affected. The concentrations of noradrenaline, dopamine, neurotransmitter amino acids and the levels of the proteins alpha-synuclein and synaptophysin in corpus striatum and the rest of the brain were not changed. No histological parameter was affected when studied in corpus striatum and substantia nigra. PMID- 21783669 TI - Toluene toxicokinetics and metabolism parameters in the rat and guinea pig. AB - Cochlear disruptions induced by toluene were shown in the rat but not in the guinea pig. To better understand the differences between species, three investigations were carried out to study (1) the blood affinity and the pulmonary uptake of the solvent, (2) its clearance and (3) its urinary elimination in both species. The blood affinity of toluene was +44% higher in the rat than in the guinea pig (14.4MUg/g versus 10MUg/g). Similarly, the pulmonary uptake of toluene was approximately 46.5% more efficient in the rat than in the guinea pig (75.4MUg/g versus 40.3MUg/g) after 3h inhalation of 1500ppm toluene. Therefore, the physicochemical composition of the blood could explain the difference in the uptake performances between rats and guinea pigs. The clearance of the toluene showed that 10min after an intravenous administration of 400MUL of vehicle containing 28MUL (43mgkg(-1)) of toluene, the solvent concentration was approximately threefold higher in the rat than in the guinea pig blood. The last experiment was carried out to compare the concentrations of the urinary metabolites. The concentrations of o-cresol, hippuric and benzyl mercapturic acids measured in the urines were different before and after the toluene injection. These data give evidence for large differences of toluene uptake and metabolism between rat and guinea pig. Therefore, it seems reasonable to claim that guinea pigs cochleas are not susceptible to toluene as the blood burden of solvent does not reach the concentration required to induce permanent damages. PMID- 21783670 TI - Chemical change of chlorinated bisphenol A by ultraviolet irradiation and cytotoxicity of their products on Jurkat cells. AB - Chlorinated derivatives of bisphenol A (ClBPAs) have been detected in wastewater from waste paper recycling plants. BPA and ClBPAs are always exposed to ultraviolet (UV) radiation in the environment and consequently various photoproducts might be produced. Acute cytotoxicity of photoproducts of BPA and ClBPAs are not known. In this study, we investigated the cytotoxicity and chemical structure of photoproducts of BPA and ClBPAs (3-chlorobisphenol A (3 ClBPA), 3,3'-dichlorobisphenol A (3,3'-diClBPA) and 3,3',5-trichlorobisphenol A (3,3',5-triClBPA)) after UV irradiation (UVA, UVB and UVC). The toxicities of photoproducts on Jurkat cells were determined by Alamar Blue assay, and the chemical structures of the photoproducts were identified using GC/MS. The cytotoxicities of 3-ClBPA and 3,3'-diClBPA were higher than that of BPA and 3,3',5-triClBPA. In addition, the toxicities of ClBPAs were increased by the irradiation of UVB and UVC at 100J/cm(2) and decreased at 1000J/cm(2) in comparison with those at 100J/cm(2), indicating that their structures had changed. 3-Hydroxybisphenol A (3-OHBPA) was detected in the photoproducts of 3 ClBPA irradiated with UVB and UVC at 100J/cm(2), and 3-OHBPA and 3-chloro-3' hydroxybisphenol A (3-Cl-3'-OHBPA) were detected in those of 3,3'-diClBPA. However, these hydroxylated BPAs were not detected in the photoproducts exposed to 1000J/cm(2). The cytotoxicity of 3-OHBPA was the almost same as ClBPAs after UVB and UVC irradiation. These results indicate that the formation of hydroxylated BPAs might contribute to the increase in toxicity caused by UV irradiation. PMID- 21783671 TI - Impaired wound healing by exposure of different mainstream whole smoke solutions of commercial cigarettes. AB - Cigarette smoke has been shown to potentiate wound damage and delayed ulcer healing. The chicken dorsum excisional wound assay was used to elucidate the deleterious effects of different mainstream whole smoke solutions (MSWSS) on the fundamental processes of wound healing. Gross, histopathology, SEM and computer based 3D image probing techniques were utilized to quantify different toxic effects of MSWSS on wound healing. A total of 160 chicks, aged 1 week, divided in eight groups were exposed to MSWSS with different nicotine concentration; 0.2mg (group A), 0.3mg (group B), 0.5mg (group C), 0.6mg (group D), 0.7mg (group E) and 1mg (group F). A very highly significant reduction (P<0.001) in wound closure was observed among all MSWSS treated groups at day 8 post-wounding. Histological investigations revealed a significant impede outcome in the re-epithelialization of all MSWSS exposed wounds. Delayed dermal matrix regeneration and maturation of collagen bundles were observed among all MSWSS treated wounds. Similar results were achieved through SEM of treated wounds. Histological and image probing analysis unveiled the scanty neovascularization among MSWSS treated wounds. Abbot curve, angular spectrum and different other parameters of 3D surface topographies of wounds revealed a very highly significant reduction (P<0.001) in angiogenesis among all MSWSS treated groups. These annotations validate the damaging effects of MSWSS on the healing of wounds. PMID- 21783672 TI - Household disposal of pharmaceuticals and perception of risk to the environment. AB - The presence of pharmaceuticals in the aquatic environment has become a cause for increasing concern in recent years. A wide range of pharmaceuticals have been discovered in fresh and marine waters and it has recently been shown that even in small quantities these compounds have the potential to cause harm to aquatic life. Their main pathway into the environment is through household use, and the disposal of unused or expired pharmaceuticals as manufacture is well-regulated. This work aimed to investigate the link between risk perception and household disposal. A survey was carried out, and around 400 householders, predominantly from the South-East of England, were interviewed. Information on when and how they disposed of unfinished pharmaceuticals was gathered. These responses were cross referenced with data on personal information and attitudes in order to determine the factors affecting the methods of disposal that are chosen. Although a link between perception of risk and the choice of disposal methods was not proved, findings demonstrated that perceived environmental awareness had an impact on the method of disposal chosen. PMID- 21783673 TI - Impact of sidestream whole smoke solutions on the outcome of wound repair and related angiogenesis. AB - Wound angiogenesis is essential to support the regenerating tissue and any setback in angiogenesis may result in retarded wound repair. Cigarette smoking causes numerous adverse effects, some of which are associated with poor healing. The current experiment was carried out to elucidate the possible detrimental effects of sidestream whole smoke solutions (SSWSS) on wound healing and related angiogenesis, using a well-defined chicken dorsum excision wound assay. Gross, histopathologic, SEM and computer based 3D image-probing modalities were utilized to quantify different detrimental effects of SSWSS on the fundamental processes of wound healing. A total of 160 chicks, aged 1 week, divided in eight groups were topically exposed for 8 days to SSWSS with different nicotine concentrations. At day 6 and day 8 post-wounding, very highly significant reduction (P<0.001) in wound closure was observed among all SSWSS treated groups. Histological and SEM evaluation of SSWSS treated wounds unveiled deteriorated dermal matrix, delayed re-epithelialization and retarded neovascularization. Moreover, image-probing exploration of SSWSS treated wounds also divulge a very highly significant decrease (P<0.001) in angular spectrum, Sa, Sy and Sci, at day 6 post-wounding. Our study suggests that the cumulative effect of different components of SSWSS has a negative impact on wound healing and related angiogenesis. Furthermore, our study demonstrates the effects that can contribute to abnormal healing and may explain why people who are consistently exposed to sidestream smoke suffer from slow healing and excessive scarring of wounds, much like the smokers themselves. PMID- 21783674 TI - Impaired behaviour, learning and memory, in adult mice neonatally exposed to hexabromocyclododecane (HBCDD). AB - Brominated flame-retardants (BFRs) are a diverse group of global environmental pollutants. In the present study, we show that neonatal exposure to hexabromocyclododecane (HBCDD) can cause developmental behavioural defects that are similar to those recently reported for PBDEs and certain PCBs. Furthermore, HBCDD appears to be as potent as PBDEs in inducing developmental neurotoxic effects in mice. In this study, neonatal NMRI mouse pups were given either a single oral dose of 0.9mg HBCDD/kg body weight, 13.5mg HBCDD/kg body weight, or a 20% fat emulsion vehicle on postnatal day 10. At the age of 3 months, the mice were observed regarding spontaneous behaviour and concerning learning and memory capability. Mice exposed to 0.9mg HBCDD or to 13.5mg HBCDD/kg body weight showed a significantly altered spontaneous behaviour, manifested as a hyperactive condition and reduced habituation. Learning and memory, as observed in a Morris water maze, was also significantly affected in mice given the higher dose of HBCDD. PMID- 21783675 TI - Effects of tributyltin and 17beta-estradiol on immune and lysosomal systems of the Asian clam Corbicula fluminea (M.). AB - Freshwater clams Corbicula fluminea were experimentally exposed to a range of tributyltin (TBT) (50, 250 and 500ng Sn/L) and 17beta-estradiol (20, 200, 2000ng/L) for 30 days. After 15 and 30 days, phagocytosis activity of haemocytes and lysosomal structural changes in the digestive cells were assayed. 17beta Estradiol exerted a higher inhibition on phagocytosis than tributyltin. This would suggest the existence of estrogen receptors, influencing the immune function. The stereological parameters measured for lysosomal structural changes in animals exposed to tributyltin varied as observed in other studies. Tributyltin is then depurated as other contaminants via digestive cell lysosomal compartment. This experiment emphasized a possible approach on the influence of endocrine disrupting compounds on a hermaphroditic species for environmental surveys. PMID- 21783676 TI - Datura stramonium in asthma treatment and possible effects on prenatal development. AB - Southern Africa has a variety of medicinal plants, used as remedies; however, little information is available regarding the cytotoxic potential, particularly when used during pregnancy. One such plant is Datura stramonium (DS) (Solanaceae), used frequently as an anti-asmatic treatment. DS contains a variety of alkaloids including atropine and scopolamine that can cause anticholinergic poisoning if taken in large doses. Atropine and scopolamine act on the muscarinic receptors by blocking them (particularly the M(2) receptors) on airway smooth muscle and submucosal gland cells. However, this will cause a continuous release in acetylcholine (Ach). Ach also act on nicotinic receptors; however, it is known that "over exposure" of nicotinic receptors may cause desensitization. We suggest that exposure of the foetus to DS when a mother uses it for asthma, will cause a continuous release of Ach, resulting in the desensitizing of nicotinic receptors, this could ultimately result in permanent damage to the foetus. Therefore we conclude that this African herbal remedy should be used with caution during pregnancy. PMID- 21783677 TI - Ethanol inhibits delta-aminolevulinate dehydratase and glutathione peroxidase activities in mice liver: Protective effects of ebselen and N-acetylcysteine. AB - Changes in sulfhydryl status have been shown to be involved with the ethanol induced hepatotoxicity. In addition, evidence shows the importance of replenishing thiols in patients with alcoholic liver disease. This study was undertaken to examine the possible beneficial effects of the individual and simultaneous treatments with two antioxidant drugs (N-acetylcysteine and ebselen) against ethanol-induced changes in thiol status, as well as on the activities of delta-aminolevulinate dehydratase (delta-ALA-D) and glutathione peroxidase (GPx) in mice liver. Daily ethanol administrations (3g ethanol/kg, by gavage) decreased liver nonprotein thiols (NPSH) concentration after 30 days of treatment and N acetylcysteine (300mg/kg once a day, i.p.) or ebselen (5mg/kg once a day, subcutaneously) treatment restored this variable to control levels. However, additive beneficial effects concerning NPSH levels were not observed after the simultaneous administration with both drugs. While liver GPx and delta-ALA-D activities were inhibited by ethanol exposure and these inhibitions were significantly blunted by N-acetylcysteine or ebselen treatment, the simultaneous administration with both drugs did not show additive beneficial effects in relation to the enzymes' activities. NPSH levels were positively correlated with GPx and delta-ALA-D activities. The results presented herein show that ebselen and N-acetylcysteine alone are able to restore ethanol-induced thiols as well as the inhibition of hepatic enzymes whose catalytic functions depend on their thiol (delta-ALA-D) and selenol (GPx) groups. PMID- 21783678 TI - Activation of c-Jun N-terminal kinase by cadmium in mouse embryo neural cells in vitro. AB - Members of the c-Jun NH(2)-terminal kinase (JNK) signalling pathway have been found to be stimulated by a variety of stresses, including heavy metals, hyperthermia, and UV-irradiation. In the present study, we examined whether exposure of micromass cultures of mouse embryonic midbrain cells to a known teratogen, cadmium, leads to the phosphorylation and activation of JNK. Midbrain cells exposed to 0.5, 1, 2, or 4MUM cadmium chloride (CdCl(2)) showed a dose dependent decline in cell numbers, cell viability and differentiation after 5 days. In cells exposed to 4MUM CdCl(2) for up to 1h, the level of phosphorylated JNK increased by 15min and peaked at 30min exposure time, as determined by a phospho-specific anti-JNK antibody, while the total amount of JNK protein did not change. This phosphorylated JNK was active, as shown by a corresponding increase in the level of c-Jun phosphorylated on Ser63 in a kinase assay. These results demonstrate that CdCl(2) induces a rapid and transient activation of the JNK pathway in primary embryonic neuron cell cultures. PMID- 21783679 TI - Rhus verniciflua Stokes glycoprotein (36kDa) has protective activity on carbon tetrachloride-induced liver injury in mice. AB - This study was carried out to investigate the hepatoprotective effect of the glycoprotein isolated from Rhus verniciflua Stokes (RVS), which has traditionally been used for healing of inflammatory diseases. We evaluated the activities of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS), and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] activities in treatment with carbon tetrachloride (CCl(4)) in vivo. When mice were treated with CCl(4) in the absence of RVS glycoprotein, the activities of ALT, LDH, and TBARS were increased, while the antioxidant enzymes activities were decreased. However, when the mice were treated with CCl(4) in the presence of RVS glycoprotein, the activities of ALT, LDH, and TBARS were significantly reduced and SOD, CAT, and GPx activities were remarkably increased. In addition, RVS glycoprotein increased the nitric oxide (NO) production and decreased the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) activation in CCl(4)-treated mice. Collectively, these results pointed out that RVS glycoprotein can inhibit lipid peroxidation, enhance the activities of antioxidant enzymes, increase the NO production, and decrease the NF-kappaB and AP-1 activations. Therefore, we speculate that RVS glycoprotein protects from liver damage through its radical scavenging ability. PMID- 21783680 TI - Pro-oxidative versus antioxidative reactions between Trolox and Cr(VI): The role of H(2)O(2). AB - The effect of the Vitamin E model compound Trolox in reactions with Cr(VI) in the presence or absence of hydrogen peroxide was investigated. The aim of this study was to establish and discuss potential Trolox-mediated pro-oxidative reactions. The importance of the Trolox:Cr(VI) ratio in the Cr(VI) reduction process was determined from the EPR spectra and DNA cleavage reactions. In the absence of hydrogen peroxide, reduction of Cr(VI) occurred with concomitant oxidation of Trolox to the phenoxyl radical. In the presence of hydrogen peroxide, Cr(V), produced by the reduction of Cr(VI), reduced hydrogen peroxide to the hydroxyl radical. The latter was detected by spin-trapping the methyl radical following reaction with N-methyl sulfoxide. During Cr(VI) reduction with Trolox, DNA single or double-strand breaks due to Trolox radical formation were not observed. Relaxed DNA appeared only when H(2)O(2) was added to Trolox/Cr(VI) mixtures most probably due to hydroxyl radical formation during the redox cycling of Cr(V/IV) species. Fenton-like reactions do not play a significant role in the Trolox/Cr(VI) system in the absence of added H(2)O(2). PMID- 21783681 TI - Effects of water quality and fish size on toxicity of methiocarb, a carbamate pesticide, to rainbow trout. AB - The acute toxicity of methiocarb in juvenile rainbow trout (Oncorhynchus mykiss, 3.25+/-0.79g) was evaluated in glass aquaria under static conditions. Nominal concentrations of methiocarb in the toxicity test ranged from 1.25 to 7.50mgL( 1). The concentrations of methiocarb that killed 50% of the rainbow trout within 24-h (24-h LC(50)), 48-h LC(50), 72-h LC(50), and 96-h LC(50) were 5.43+/-0.19, 5.04+/-0.18, 4.95+/-0.19, and 4.82+/-0.21mgL(-1) (95% confidence limits), respectively. Mortality of fish increased with increasing water temperature. Increasing alkalinity from 19mgL(-1) as CaCO(3) to 40, 60, or 90mgL(-1) as CaCO(3) significantly decreased mortality of fish. Total hardness ranging from 50mgL(-1) as CaCO(3) to 147mgL(-1) as CaCO(3) did not affect mortality of fish exposed to methiocarb. Fish exposed to methiocarb had histological alterations such as lamellar edema, separation of epidermis from lamellae, and lamellar fusion. Methiocarb exposed fish had necrosis between molecular and granular layer of cerebellum where Purkinje cells present. Results indicate that alkalinity, temperature, and fish size affect methiocarb toxicity of rainbow trout. PMID- 21783682 TI - Glyphosate-induced antioxidant imbalance in HaCaT: The protective effect of Vitamins C and E. AB - Roundup 3 plus((r)), a glyphosate-based herbicide, is widely used in the ground, but its extensive use has posed a health risk in man. The aim of this study was firstly to investigate how glyphosate alone or included in Roundup 3 plus((r)) affected the antioxidant defense system and lipid peroxidation of human cutaneous cells, and secondly, to evaluate the ameliorating effects of antioxidants, as Vitamin C (VitC) and Vitamin E (VitE), against Roundup 3 plus((r))-induced epidermal antioxidant impairment. Our results showed that glyphosate alone or included in Roundup 3 plus((r)), induced significant changes in cellular antioxidant status as a glutathione depletion, enzymatic (catalase, glutathione peroxidase and superoxide dismutase) disorders, and increased lipid peroxidation. VitC or VitE supplementation increased superoxide dismutase, glutathione reductase and -peroxidase activities and reduced lipid peroxidation in Roundup 3 plus((r))-treated keratinocytes. These in vitro data indicated that VitC and VitE might have preventive effects against deleterious cutaneous cell damage caused by Roundup 3 plus((r)). PMID- 21783683 TI - The effects of different treatments on prolidase and antioxidant enzyme activities in patients with bronchial asthma. AB - The effects of two different treatment combinations of bronchial asthma on antioxidant defense systems and serum prolidase activity were investigated. The groups were organized as follows: the first group (control) consisted of healthy subjects. The second group (treatment 1) consisted of patients with bronchial asthma inhaling budesonide (2*400mcg/d, as puff)+formaterol (2*9mcg/d, as puff). In the third group (treatment 2) patients with bronchial asthma were treated with montelukast (1*10mg/d, as pill)+budesonide (2*400mcg/d, as puff)+formaterol (2*9mcg/d, as puff). The medical therapy of the patients in treatment 1 and treatment 2 lasted 12 weeks. Before and after treatment in all three groups blood samples were taken and the level of thiobarbituric acid-reactive substances (TBARS) and the activities of prolidase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-Rd) and catalase (CAT) were measured. Prolidase activity was found to be significantly higher in patients compared to control (p<0.05). Treatment 2 was successfully reduced the prolidase activity (p<0.05). Before treatments, SOD activity was significantly decreased whereas TBARS level and other antioxidant enzymes were increased in both treatment groups comparing with control (p<0.05). Both of different treatments given in treatment 1 and treatment 2 groups caused significant increase in SOD whereas decrease in TBARS, CAT, GSSG-Rd, GSH-Px (p<0.05). When compared the treatment groups after treatments, SOD activity was significantly higher in treatment 2 group than treatment 1 group (p<0.05). No significant difference was seen in other parameters. The balance between oxidant-antioxidant system is impaired in patients with asthma. PMID- 21783684 TI - Long QT and ST-T change associated with organophosphate exposure by aerial spray. AB - The relation between the electrocardiographic manifestation and the subjective symptoms accompanying organophosphate pesticide exposure caused by aerial spray was investigated. The study included 39 patients with a diagnosis of organophosphate poisoning, who visited A-clinic within 24h of exposure to aerial spray of organophosphate pesticide in Gumma Prefecture, from July 2001 to September 2001. Ages ranged from 3 to 82 years. Thirty-five patients were female. Three were diagnosed as severe, 11 moderate, and 25 mild, judged from the score of subjective symptoms. Electrocardiographic abnormalities were bradycardia (<50) 2; prolonged PQ interval 4; prolonged QTc interval (>430ms) 22; nonspecific ST-T change 35; supraventricular arrhythmia 13; and ventricular premature complex with R on T 1. Prolonged QTc interval developed in 2-3 severe cases, 4-11 moderate cases, and 16-25 mild cases. QT prolongation, ST-T change and arrhythmia were detected for some patients exposed to organophosphate by aerial spray. PMID- 21783685 TI - Effects of diazinon on pseudocholinesterase activity and haematological indices in rats: The protective role of Vitamin E. AB - Diazinon (DZN) is an organophosphate insecticide has been used in agriculture and domestic for several years. Vitamin E (200mg/kg, twice a week), diazinon (10mg/kg, per day) and Vitamin E (200mg/kg, twice a week)+diazinon (10mg/kg, per day) combination were given to rats orally via gavage for 7 weeks. Pseudocholinesterase in serum and haematological indices were investigated at the end of the 1st, 4th and 7th weeks comparatively with control group. At the end of 1st, 4th and 7th weeks, statistically significant decrease of pseudocholinesterase activity in serum were detected when diazinon- and Vitamin E+diazinon-treated groups compared to control group. When diazinon- and Vitamin E+diazinon-treated groups were compared to each other there were no significant changes. When diazinon-treated group was compared to control group, body weight decreased significantly at the end of the 4th and 7th weeks. It was observed that at the end of 1st, 4th and 7th weeks, there was a statistically significance in haematological indices except mean corpuscular hemoglobin (MCH) when diazinon treated group was compared to control group. At the end of 1st week increase of thrombocyte, at the end of the 4th week increase of hemoglobin and thrombocyte and at the end of the 7th week increase of red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular hemoglobin concentration (MCHC) and thrombocyte were observed statistically significant when Vitamin E+diazinon treated group was compared with diazinon treated group. According to the present study, we conclude that Vitamin E reduces diazinon toxicity, but it does not protect completely. PMID- 21783686 TI - The effect of age, sex, smoking habit and hair color on the composition of hair. AB - Hair samples (N=83) were collected between the years 1996 and 2003 from inhabitants of Wroclaw, a city located in Lower Silesia, south-western Poland (urbanized and industrialized region). The concentrations of 33 elements: Ca, Mg, Na, K, Cu, Zn, P, Fe, Mn, Cr, Se, B, Co, Mo, Si, V, Ni, Be, Hg, Cd, Al, Pb, As, Ba, Au, Pt, Ag, Sr, Sn, Ti, W, Sb and Zr in hair were determined by inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES) techniques. The effect of age, sex, smoking habits and hair color on the elemental composition of hair was investigated. Also, the obtained results were compared with literature data. It was found that the composition of hair varied with age, sex, hair color and smoking habits. This concerned the majority of elements except Ti, Se, Mn, Ni, Hg, Cd, As, Co (in the case of effect of age), Al, Cd, Co (sex), Cd, K, Ag, Ca, Co, Be (smoking habit), P, Fe, Al, Mn and Cr (hair color). Therefore, reference values for the level of the remaining elements should be normalized according to age, sex, smoking habit and hair color. This would make hair analysis more reliable. PMID- 21783687 TI - Protective effect of Aquilegia vulgaris L. on aflatoxin B(1)-induced hepatic damage in rats. AB - The aim of the study was to investigate the effect of ethanol and ethyl acetate extract obtained from Aquilegia vulgaris L. on microsomal lipid peroxidation, reduced glutathione level and antioxidant enzymes activity in the liver of rats intoxicated with aflatoxin B(1) (AFB(1)). Animals were pretreated with 12 daily p.o. doses of the extracts tested (100mg/kg body weight). Then AFB(1) was administered intraperitoneally at a single dose of 1.5mg/kg b.w. to evoke the liver damage. alpha-Tocopherol was used as a positive control. Reduced glutathione (GSH) was depleted in aflatoxin-treated rats by 80% in comparison with that in the controls. The extracts restored the GSH concentration up to the basal level. Microsomal lipid peroxidation stimulated by Fe(2+)/ascorbate (assessed by measuring TBARS) was enhanced in AFB(1)-treated rats by 28% as compared to that in the control group. The extracts caused a decrease in TBARS level by 40% and 27%. Only two antioxidant enzymes were affected by AFB(1) administration. The activity of catalase was reduced by 24% and the activity of glutathione-S-transferase (GST) was increased by 33%. The pretreatment with ethyl acetate and ethanol extract reduced the GST activity by 76% and 30%, respectively. No significant changes in the activity of other antioxidant enzymes were observed in rats treated with the extracts and AFB(1). It can be concluded that multiple pretreatment with the extracts obtained from A. vulgaris attenuated aflatoxin B(1)-induced hepatic damage as evidenced by inhibition of lipid peroxidation and preventing reduced glutathione depletion. PMID- 21783688 TI - Protection of gastric mucosal damage by Coriandrum sativum L. pretreatment in Wistar albino rats. AB - The effect of Coriander pretreatment on gastric mucosal injuries caused by NaCl, NaOH, ethanol, indomethacin and pylorus ligation accumulated gastric acid secretions was investigated in rats. Pretreatment at oral doses of 250 and 500mg/kg, body weight was found to provide a dose-dependent protection against the (i) ulcerogenic effects of different necrotizing agents; (ii) ethanol-induced histopathological lesions; (iii) pylorus ligated accumulation of gastric acid secretions and ethanol related decrease of Nonprotein Sulfhydryl groups (NP-SH). Results obtained on the study of gastric mucus and indomethacin-induced ulcers demonstrated that the gastro protective activity of Coriander might not be mediated by gastric mucus and/or endogenous stimulation of prostaglandins. The protective effect against ethanol-induced damage of the gastric tissue might be related to the free-radical scavenging property of different antioxidant constituents (linanool, flavonoids, coumarins, catechins, terpenes and polyphenolic compounds) present in Coriander. The inhibition of ulcers might be due to the formation of a protective layer of either one or more than one of these compounds by hydrophobic interactions. PMID- 21783689 TI - Effects of phenyl saligenin phosphate on phosphorylation of pig brain tubulin in vitro. AB - Phenyl saligenin phosphate (PSP) induces a characteristic neuropathy (OPIDN), the molecular basis of which has not been precisely defined. This study examined the in vitro effects of PSP on the phosphorylation of serine and threonine residues of proteins in porcine brain cytosol. Quantitative analysis of Western blots probed with antibodies recognizing phosphorylated serine residues demonstrated that 100MUM PSP induced a significant increase in the phosphorylation of serine residues of a 50kDa protein. This protein was identified as the alpha- and beta tubulin subunits by probing Western blots of extracts separated by two dimensional polyacrylamide gel electrophoresis with anti-phosphoserine and anti tubulin antibodies. By contrast, threonine phosphorylation of the 50kDa polypeptide and other proteins detected on Western blots probed with anti phosphothreonine antibodies, was not significantly affected by PSP. These data indicate that PSP is able to induce increased phosphorylation of tubulin in serine residues, consistent with a possible role for this phenomenon in OPIDN induction. PMID- 21783690 TI - Protein S-thiolation and depletion of intracellular glutathione in skin fibroblasts exposed to various sources of oxidative stress. AB - It is well established that oxidative stress plays a central role in the onset and progression of over a 100 different diseases. Recently, a growing body of evidence has shown that chemicals/agents as diverse as aromatic compounds, UV radiation and redox-active metals also generate oxy-radicals in vivo and lead to cellular oxidative stress. In this study we have used mouse skin fibroblasts to study the effects of oxidative stress caused by organic aromatic compounds (xylene), UV radiation and redox-active metals. Specifically, we tested the effect of these treatments on intracellular GSH levels, as well as on protein S thiolation. We show that acute exposure of these diverse set of conditions cause dramatic depletion of the intracellular GSH pool in mouse skin fibroblast cells. We also found evidence of synergistic effects of combined exposure to different sources of oxidative stress. Furthermore, we also found that these treatments also caused significant S-thiolation (protein mixed-disulfide formation) of a 70kDa cytosolic protein. PMID- 21783691 TI - Isolation and structural elucidation of two secondary metabolites from the filamentous fungus Penicillium ochrochloron with antimicrobial activity. AB - In this investigation, the extracts of filamentous fungi exhibited inhibitory effect on the growth of Gram positive and Gram negative bacteria, as well as against the yeast Candida albicans. Penicillium ochrochloron has been proven as the most active fungus against all tested microorganisms. Further bio-guided chemical analysis of P. ochrochloron afforded two components with antimicrobial activity identified as (-) 2, 3, 4-trihydroxybutanamide and (-) erythritol. PMID- 21783692 TI - Subacute toxicity of celecoxib on thyroid and testis of rats: Hormonal and histopathological changes. AB - Celecoxib is an effective agent in the treatment of signs and symptoms of inflammation, rheumatoid arthritis and osteoarthritis. The purpose of this study is to assess the effects of two different doses of celecoxib on some hormones and endocrine glands of male rats. In this study, the doses of 10 and 50mg/kg/day of celecoxib were given to male rats orally for 28 days. At the end of the study, serum total triiodothyronine (T(3)), total thyroxine (T(4)), thyroid stimulating hormone (TSH), testosterone and luteinizing hormone (LH) levels of rats were analyzed by radioimmunoassay technique using RIA kits. Thyroid and testis tissues of male rats were examined histopathologically. While there was no a change in serum T(3), T(4) and LH levels of celecoxib-treated rats, there were differences in serum TSH and testosterone levels of rats treated with 50mg/kg/day celecoxib for 28 days compared with those of control rats. In histopathological examinations, celecoxib-related changes were found in thyroid glands of the rats. PMID- 21783693 TI - Induction of oxidative stress by lindane in epididymis of adult male rats. AB - Lindane, an organochlorine pesticide, has been reported to induce reproductive abnormalities in male rats. The mechanism of action of lindane on male reproductive system remains unclear. In the present study we have sought to investigate the effect of lindane on antioxidant parameters and sialic acid levels of caput, corpus and cauda epididymis of adult male rats. Lindane (1, 5, and 50mg/kg per day) was administered orally to adult male rats for 45 days. The animals were killed using anaesthic ether on the day following the last treatment. The body weight of the animals did not show significant change. However, the weights of caput, corpus and cauda epididymis decreased in lindane treated animals. Administration of lindane caused decrease in epididymal sperm count and motility. Sialic acid levels in the epididymis decreased significantly at 5 and 50mg/kg dosage of lindane treatment. Significant decline in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase along with increase in hydrogen peroxide generation and lipid peroxidation were observed in lindane treated animals. In conclusion, lindane induces oxidative stress by decreasing the activities of antioxidant enzymes and sialic acid levels in the epididymis thereby causing impaired sperm function. PMID- 21783694 TI - Cultivated microalgae and the carotenoid fucoxanthin from Odontella aurita as potent anti-proliferative agents in bronchopulmonary and epithelial cell lines. AB - The antiproliferative activities of several extracts from cultivated microalgae in France have been studied against bronchopulmonary and epithelial cell lines, respectively (A549, NSCLC-N6 and SRA 01/04). The algal extracts, of Diatomae (Odontella aurita, Chaetoseros sp.), as well as of Haptophyceae: Isochrisys aff. galbana, appeared as the most active among all the assayed species, expressing a broad spectrum of in vitro antiproliferative activity of well-differentiated pathologic cells such as NSCLC-N6 by terminal differentiation. Bio-guided fractionation of the above referred extracts, led us to the isolation, of the carotenoid fucoxanthin. Fucoxanthin has been structurally determined, through modern spectral means and has been studied separately for its activities. PMID- 21783695 TI - Xenoestrogens modulate genotoxic (UVB)-induced cellular responses in estrogen receptors positive human breast cancer cells. AB - Human populations and wildlife are exposed to mixtures of both anthropogenic and natural chemicals. Some of these compounds are known to interact principally with the endocrine function, whereas others act mainly on genomic DNA. Given this evidence, we wanted to address the question of whether concomitant exposure of such chemicals was able to interact at the cellular level. We have previously shown that 17beta-Estradiol (E(2)) modulates the DNA repair capacity of cells. In this work, we wanted to examine if other xenoestrogens (i.e. industrial compounds, pesticides or pharmaceuticals) were able to interact with the UVB induced cellular response as E(2) does. Here, we show that xenoestrogens modulate the capacity of cells to repair their DNA damage according to the type of compounds. For example, the oral contraceptive 17alpha-Ethinylestradiol down regulated the repair of UVB-induced DNA damage whereas the UV filter Eusolex 6007 up-regulated this pathway. The notion that xenoestrogens could interact with a genotoxic stress is reinforced by the modulation of the estrogens-dependent luciferase reporter gene expression when cells are UVB-irradiated. Finally, these observations suggested the potential role of xenoestrogens in carcinogenesis by their capacity to modulate cells responses to genotoxic stress. PMID- 21783696 TI - Cytotoxic and radioprotective effects of Podophyllum hexandrum. AB - Podophyllum hexandrum, a herb thriving in Himalayas has already been reported to exhibit antitumor and radioprotective properties. Present study was undertaken to unravel the possible mechanism responsible for the cytotoxic and radioprotective properties of REC-2001, a fraction isolated from the rhizome of P. hexandrum using murine peritoneal macrophages and plasmid DNA as model systems. Cell death, levels of intracellular reactive oxygen species (ROS) and apoptosis were studied employing trypan blue exclusion assay, dichlorofluorescein diacetate and DNA fragmentation assay, respectively. Superoxide anions, hydroxyl radicals and DNA damage were estimated following nitroblue tetrazolium, 2-deoxyribose degradation and plasmid DNA relaxation assays, respectively. Pre-irradiation administration of REC-2001 to peritoneal macrophages in the concentration range of 25-200MUg/ml significantly reduced radiation induced ROS generation, DNA damage, apoptosis and cell killing in comparison to radiation control group indicating radioprotective potential. Studies with plasmid DNA indicated the ability of REC-2001 to inhibit 20Gy induced single and double strand breaks further supporting the antioxidative potential. However, REC-2001 in a dose-dependent fashion induced cell death, ROS and DNA fragmentation indicating the cytotoxic nature. REC-2001, in presence of 100MUM copper sulfate, generated significant amount of hydroxyl radicals and superoxide anions indicating ability to act as a pro-oxidant in presence of metal ions. The superoxide anion generation was found to be sensitive to metal chelators like EDTA and deferoxamine mesylate (DFR). These results suggest that the ability of REC-2001 to act as a pro-oxidant in presence of metal ions and antioxidant in presence of free radicals might be responsible for cytotoxic and radioprotective properties. PMID- 21783697 TI - Microcalorimetric investigation of the toxic action of Cr(VI) on the metabolism of Tetrahymena thermophila BF(5) during growth. AB - Tetrahymena thermophila BF(5) produce heat by metabolism and movement. Using a TAM air isothermal microcalorimeter, the power-time curves of the metabolism of T. thermophila BF(5) during growth were obtained and the action on them by the addition of Cr(VI) were studied. The morphological change with Cr(VI) coexisted and biomass change during the process of T. thermophila BF(5) growth were studied by light microscope. Chromium has been regarded as an essential trace element for life. However, hexavalent chromium is a known carcinogen, mutagen, cytotoxicant and strong oxidizing agent. Cr(VI) of different concentration have different effects on T. thermophila BF(5) growth with the phenomenon of low dose stimulation (0-3*10(-5)molL(-1)) and high dose inhibition (3*10(-5) to 2.4*10( 4)molL(-1)). The relationship between the growth rate constant (k) and c is a typical U-shaped curve, which is a characteristic of hormesis. T. thermophila BF(5) cannot grow at all when the concentration of Cr(VI) is up to 2.4*10( 4)molL(-1). The microscopic observations agree well with the results obtained by means of microcalorimetry. And T. thermophila BF(5) had obviously morphological changes by the addition of Cr(VI). PMID- 21783698 TI - Evaluation of latent hemoptysis in Sulfur Mustard injured patients. AB - INTRODUCTION: Hemoptysis is one of the mustard exposed patients' symptoms. Data from one study on survivors of Sulfur Mustard attacks during World War I had revealed an increased rate of lung cancer among them. Aim of this study was to determine lung HRCT and fluorescence bronchoscopy findings in mustard exposed patients with hemoptysis. MATERIALS AND METHODS: In this cross-sectional study we evaluated 98 patients with protracted hemoptysis in association with history of single exposure to SM. For this mean we used different lung cancer screening tools including HRCT, bronchoscopy (WLB and fluorescence) and pathology (bronchial lavage cytology and biopsy). RESULTS: Mean time of exposure to SM among cases was 15.5+/-4.3 (mean+/-S.D.) years ago. Mean age of studied patients was 48.3+/-8.2 years. No finding had been found supporting the malignancy in any of cases via imaging and pathological evaluations. Cytological investigation of bronchial lavage for TB (staining and culture) and/or malignancy in all cases was negative. Pathology findings of specimens were: 9% normal, 83% chronic inflammation and 8% squamous metaplasia. CONCLUSION: Though our findings are in accordance to other studies which are conducted by other Iranian researchers so far, we cannot overlook the risk of lung cancer among SM patients in future. In conclusion, hemoptysis per se in acutely exposed SM patients could not be considered as a valuable evidence of lung malignancy and it is more likely due to other pathologies of respiratory system in SM patients and close monitoring of these patients for early detection of any kind of malignancy is suggested. PMID- 21783699 TI - Plasma IL-2, NK, IFN-gamma, and C3 in male workers exposed to traffic pollutants. AB - The aim of the study is to evaluate if the occupational exposure to urban stressors could cause alterations in interleukin-2 (IL-2), NK, interferon-gamma (IFN-gamma) and C3 plasma levels in male traffic police officers compared to controls. After excluding the principal confounding factors, 108 traffic police officers were matched with 108 controls by age, working life, habitual consumption of alcohol and spirits. IL-2 mean levels were significantly higher in traffic police officers compared to controls (p=0.04). The distribution of IL-2 values in traffic police officers and in controls was significant (p=0.01). The distribution of NK value percentage in traffic police officers and in controls was significant (p=0.000). IFN-gamma and C3 mean levels were not significant in traffic police officers compared to controls. Our results suggest that the occupational chronic exposure to low doses of urban stressors could affect NK and IL-2 plasma concentrations in traffic police officers of male sex. PMID- 21783700 TI - Induction of mitochondria-mediated apoptosis by methanol fraction of Ulmus davidiana Planch (Ulmaceae) in U87 glioblastoma cells. AB - Mitochondria play a pivotal role in apoptosis of mammalian cells by releasing apoptogenic proteins such as cytochrome c into the cytoplasm. Mitochondrial membrane permeability during apoptosis is regulated directly by the Bcl-2 family of proteins. In glioma cells, there are no specific features of apoptosis compared with apoptosis in other cell types. Ulmus davidiana Planch (Ulmaceae) is a deciduous tree, which is widely distributed in Korea. The barks of the stem and the root of the plant have been used in oriental traditional medicine for the treatment of oedema, mastitis, gastric cancer, and inflammation. Our results demonstrate that the methanol fraction of the stem bark extracts of Ulmus davidiana Planch induce mitochondria-mediated apoptosis in U87 glioblastoma cells. The methanol fraction exhibited a comparatively higher cytotoxic activity (IC(50)=7.5+/-0.7MUg/ml) in a dose-dependent manner than chloroform, and hexane fractions. The results show the typical ladder profile of oligonucleosomal fragments characteristics of apoptosis and the secreted cytosolic cytochrome c level was increased by treatment of methanol fraction of UD. Moreover, the expressional changes of the Bcl-2 family protein occurred within 30min after treatment with methanol fraction. All results indicate that the methanol fraction of U. davidiana Planch (the barks of the stem) is capable of inducing apoptosis in U87 glioblastoma cells. PMID- 21783701 TI - Comparative toxicity studies in birds using nimesulide and diclofenac sodium. AB - Nimesulide, a sulfonanilide derivative, was compared with diclofenac sodium for toxicity in poultry. In this study, Vanaraja and PB1 birds of 6 weeks old (either sex) were mixed and equally divided into 5 groups of 10 birds each. The birds were inoculated with nimesulide, @ 5 and 2mg; vehicle @ 0.5ml; and diclofenac sodium @ 5mg on kg bwt basis. One group served as untreated control. All the groups were observed for a period of 28days. Forty percent mortality was observed within 12 days in diclofenac-treated group. While birds inoculated with nimesulide remained normal. No significant differences in the weight gain, haematology, total protein contents in the nimesulide and diclofenac groups (survived birds) were observed when compared with the control group of birds. Serum creatinine, cholesterol, alkaline phosphatase, and aspartate aminotransferase levels were significantly (P<0.05) high in diclofenac-treated group compared to nimesulide (P>0.05) and control groups. Nimesulide-treated groups did not show any histopathological lesions, where as diclofenac-treated birds showed histopathological lesions in liver and kidney. PMID- 21783702 TI - Protective effect of NADP-isocitrate dehydrogenase on the paraquat-mediated oxidative inactivation of aconitase in heart mitochondria. AB - Protective role of NADP-isocitrate dehydrogenase in the oxidative inactivation of mitochondrial enzymes was analyzed. Administration of paraquat to the rat inactivated liver mitochondrial enzymes: the aconitase activity decreased to one quarter, and citrate synthase and fumarase to half, whereas cytosolic enzymes were not affected. Activities of heart mitochondrial and cytosolic enzymes were not at all changed in the rat treated with paraquat, but paraquat directly inactivated aconitase in the heart mitochondria isolated from the non-treated rats. The paraquat-dependent inactivation of aconitase was prevented by activating NADP-isocitrate dehydrogenase in the presence of oxidized glutathione. NADP-isocitrate dehydrogenase could regenerate glutathione in isolated heart mitochondria, indicating that paraquat-mediated inactivation depends on the glutathione-regenerating activity by enhanced NADPH supply. Lower NADP-isocitrate dehydrogenase activity in liver mitochondria cannot regenerate reduced glutathione for scavenging reactive oxygen species, resulting in the paraquat induced oxidative inactivation of mitochondrial enzymes. However, higher activity of NADP-isocitrate dehydrogenase participates in the regeneration of reduced glutathione causing stabilization of enzymes in heart mitochondria. PMID- 21783703 TI - Effect of N-glucuronidation on urinary bladder genotoxicity of 4-aminobiphenyl in male and female mice. AB - Urinary bladder cancer is the fourth most commonly diagnosed malignancy in men and the tenth most commonly diagnosed malignancy in women in the US. Arylamines have long been associated with bladder cancer and several studies documented that men exposed to arylamines (cigarette smokers, hairdressers, and workers of dye and textile industries) have several times increased risk compared to women. N glucuronidation is an important phase II conjugation reaction that delivers the active metabolites of arylamines from the liver to the urinary bladder. In the current study, we found that male mice are more active in 4-ABP N-glucuronidation than female mice and this difference was statistically significant. In the in vivo experiments, male and female mice (strain C57BL/6) were treated with 4-ABP after modulating their 4-ABP N-glucuronidation using the plant steroid, hecogenin. The distribution of 4-ABP adducts in liver and bladder was then determined. In animals treated with 4-ABP only, males had statistically significant higher levels of DNA adducts in the bladder (p-value 0.0004) while females had statistically significant higher levels in the liver (p value<0.0001). Hecogenin co-treatment increased levels of DNA adducts in the liver in both males and females but this increase was statistically significant only in males (p-value 0.0024). There was a slight decrease in levels of DNA adducts in the bladder in both males and females co-treated with hecogenin, but this decrease was statistically insignificant. Using two-way ANOVA, we found that gender and hecogenin treatment both had a statistically significant effect on liver DNA adduct levels, whereas only gender had statistically significant effect on bladder adduct levels where males have about 2.2-fold higher DNA adducts than females. The current data suggests that N-glucuronidation of 4-ABP may have an important impact on the organ distribution of DNA damage. The fact that there was only a slight decrease in bladder adduct levels compared to the significant increase in the liver in groups co-treated with hecogenin indicates that besides N-glucuronidation, conjugation and metabolic activation by other enzymes may also contribute to the transport of the proximate metabolites of 4-ABP to the bladder. PMID- 21783704 TI - Methylglyoxal-bis(guanylhydrazone), a polyamine analogue, sensitized gamma radiation-induced cell death in HL-60 leukemia cells Sensitizing effect of MGBG on gamma-radiation-induced cell death. AB - Methylglyoxal-bis(guanylhydrazone) (MGBG), a polyamine analogue, has been known to inhibit the biosynthesis of polyamines, which are important in cell proliferation. We showed that MGBG treatment significantly affected gamma radiation-induced cell cycle transition (G(1)/G(0)->S->G(2)/M) and thus gamma radiation-induced cell death. As determined by micronuclei and comet assay, we showed that it sensitized the cytotoxic effect induced by gamma-radiation. One of the reasons is that polyamine depletion by MGBG treatment did not effectively protect against the chemical (OH) or physical damage to DNA caused by gamma radiation. Through in vitro experiment, we confirmed that DNA strand breaks induced by gamma-radiation was prevented more effectively in the presence of polyamines (spermine and spermidine) than in the absence of polyamines. MGBG also blocks the cell cycle transition caused by gamma-radiation (G(2) arrest), which helps protect cells by allowing time for DNA repair before entry into mitosis or apoptosis, via the down regulation of cyclin D1, which mediates the transition from G(1) to S phase of cell cycle, and ataxia telangiectasia mutated, which is involved in the DNA sensing, repair and cell cycle check point. Therefore, the abrogation of G(2) arrest sensitizes cells to the effect of gamma-radiation. As a result, gamma-radiation-induced cell death increased by about 2.5-3.0-fold in cells treated with MGBG. However, exogenous spermidine supplement partially relieved this gamma-radiation-induced cytotoxicity and cell death. These findings suggest a potentially therapeutic strategy for increasing the cytotoxic efficacy of gamma-radiation. PMID- 21783705 TI - Effects of subchronic malathion exposure on the pharmacokinetic disposition of pefloxacin. AB - Malathion is one of the most extensively used organophosphorus pesticides applied in agriculture, mosquito eradication and in the control of animal ectoparasites and human body lice. The widespread use of malathion has raised concern over its potential to cause untoward health effects in humans, animals and birds. Malathion inhibits cytochrome P450 monooxygenases and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The present study was undertaken to evaluate the impact of subchronic exposure of malathion on the pharmacokinetic disposition of pefloxacin. Chickens were given either normal diet or malathion through food at a concentration of 1000ppm for 28 days. Subsequently, pefloxacin was administered either intravenously or orally (control) to birds fed normal diet and orally to malathion-exposed chickens at a dosage of 10mgkg(-1) body weight. Blood samples were drawn from the brachial vein at predetermined time intervals after drug administration. Plasma was separated and analyzed for pefloxacin by reverse-phase high performance liquid chromatography. The plasma concentration-time data were analyzed by non compartmental techniques. Following intravenous administration of pefloxacin, elimination half-life (t(1/2beta)), area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were 8.2+/-0.7h, 66+/-9MUghml(-1) and 10.5+/-1.1h, respectively, and when the drug was administered orally, the respective values of pharmacokinetic parameters were 8.2+/-0.4h, 31+/-3.1MUghml( 1) and 11.7+/-0.6h. Malathion exposure significantly increased maximum plasma drug concentration, t(1/2beta), AUC and MRT of pefloxacin to 54, 22, 117 and 37% of control, respectively. These findings provide evidence that subchronic malathion exposure markedly influences the elimination kinetics of pefloxacin which may be due to malathion-mediated inhibition of metabolism of pefloxacin. PMID- 21783706 TI - Immunohistochemical analysis for cell regulatory proteins in bladder carcinogenesis induced by N-methyl-N-nitrosourea-terephthalic acid. AB - To explore the cell cycle regulatory mechanism in bladder carcinogenesis promoted by terephthalic acid calculi (TPA-calculi), male Wistar rats were initiated with N-methyl-N-nitrosourea (MNU) (20mg/kg b.w. i.p.) twice a week for 4 weeks, and then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO(3)) or 1% TPA for the next 22 weeks. Major regulatory proteins in G1 cell cycle checkpoint including p16(INK4a), cyclin-dependent kinase 4 (Cdk4), cyclin D(1), retinoblastoma protein (pRb) were determined during various stages of urinary bladder carcinogenesis by using immunohistochemistry. In MNU-5% TPA treated group, the incidences of overexpression of Cdk4, cyclin D(1) and pRb in papilloma were significantly higher than these in simple hyperplasia (p=0.023, p<0.001 and 0.001, respectively) and in PN hyperplasia (p=0.042, 0.012 and 0.002, respectively). The incidence of absent expression of p16(INK4a) in papilloma was much higher than that in simple hyperplasia (p=0.004) and in PN hyperplasia (p=0.02). Our results clearly reveal that the deregulation of p16(INK4a)-cyclin D(1)/Cdk4-pRb pathway is associated with bladder carcinogenesis promoted by TPA calculi. PMID- 21783707 TI - Effects of polychlorinated biphenyls, hexachlorocyclohexanes, and mercury on human neutrophil apoptosis, actin cytoskelton, and oxidative state. AB - Apoptosis, or programmed cell death, has been proposed as a biomarker for environmental contaminant effects. In this work, we test the hypothesis that in vitro assays of apoptosis are sensitive indicators of immunological effects of polychlorinated biphenyls, hexachlorocyclohexanes, and mercury on human neutrophils. Apoptosis, necrosis, and viability as well as the related indicators F-actin levels, and active thiol state were measured in purified human neutrophils after treatment with contaminants. Effective concentrations observed were 0.3MUM (60MUg/L) mercury, 750MUg/L Aroclor 1254, and 50MUM (14,500MUg/L) hexachlorocylcohexanes. Concentrations of contaminants that induced apoptosis also decreased cellular F-actin levels. Active thiols were altered by mercury, but not organochlorines. Comparison of these data with levels of contaminants reported to be threats to human health indicate neutrophil apoptosis is a sensitive indicator of mercury toxicity. PMID- 21783708 TI - Comparison of the effect of Aminopielik D pesticide and its active components on human erythrocytes. AB - In the present work, the effect of Aminopielik D [417.5g/l of dimethylamino salts of 2,4-dichlorophenoxyacetic acid (2,4-D) and 32.5g/l of 3,6-dichloro-2 metoxybenzoic acid (Dicamba)] and its active components (used separately and in mixture) on human erythrocytes was examined. The parameters studied were: lipid peroxidation, metHb formation and catalase activity. Aminopielik D used at doses of 100-1000ppm was found to increase lipid peroxidation, decrease of catalase activity and oxidation of haemoglobin. 2,4-D and Dicamba are present in Aminopielik D in the dimethylamino form; their sodium salts in solution (separately and as a mixture) did not cause such strong effects. A synergistic action of 2,4-D and Dicamba was excluded as the individual compounds caused the same effects as their mixture. Aminopielik D provoked slightly higher changes in the lipid peroxidation and catalase activity than its active components alone and in mixture, which was probably a result of the properties of the additives and interaction of tested systems with the dimethylamino group. PMID- 21783709 TI - Thimerosal induces oxidative stress in HeLa S epithelial cells. AB - Thimerosal is one of the most widely used preservatives and is found in a variety of biological products, including vaccines, contact lens cleaning solutions, and cosmetics. It has been reported to have harmful effects on epithelial tissues, such as causing conjunctivitis or contact dermatitis. However, the molecular mechanism of its toxicity has not been characterized using epithelial tissues. In the present study, we report that reactive oxygen species play a key role in thimerosal-induced cytotoxicity in HeLa S epithelial cells. Thimerosal significantly reduced HeLa S cell viability and it was associated with a decrease in intracellular glutathione levels. Flow cytometric cell cycle analysis showed a marked increase in the hypodiploidic cell population, indicating apoptosis of thimerosal-treated cells. The apoptotic cell death of epithelial cells was confirmed by observing a significant increase of caspase-3 activity in the cytosolic fraction of the treated cells. Thimerosal also induced a concentration dependent increase of genomic DNA fragmentation, a biochemical hallmark of apoptosis. Hoechst 33342 nuclear staining demonstrated apoptotic-fragmented multinuclei in thimerosal-treated cells. All the thimerosal-mediated toxic responses observed in the present study were almost completely suppressed by pretreating cells with N-acetyl-l-cysteine, a radical scavenger. Taken together, these results suggest for the first time that epithelial cytotoxicity of thimerosal is mediated by oxidative stress. PMID- 21783710 TI - Gill and kidney histopathology in the freshwater fish Cyprinus carpio after acute exposure to deltamethrin. AB - The histopathological effects of deltamethrin on the gill and kidney tissues of the common carp, Cyprinus carpio were determined by light microscopy. The fish were exposed to 0.029mgl(-1) (50% of 96h LC(50)) and 0.041mgl(-1) (70% of 96h LC(50)) solutions of deltamethrin for short-term (96h). The most common gill changes at all doses of deltamethrin were desquamation and necrosis. Besides, aneurism in secondary lamellae, lifting of the lamellar epithelium, oedema, epithelial hyperplasia and fusion of the secondary lamellae were reported. Lesions in the kidney tissues of fish exposed to deltamethrin were characterized by degeneration in the epithelial cells of renal tubule, pycnotic nuclei in the hematopoietic tissue, dilation of glomerular capillaries, degeneration of glomerulus, intracytoplasmatic vacuoles in epithelial cells of renal tubules with hypertrophied cells and narrowing of the tubular lumen. PMID- 21783711 TI - Effects and mechanisms of Clematis mandshurica Maxim. as a dual inhibitor of proinflammatory cytokines on adjuvant arthritis in rats. AB - Effect and mechanism of Clematis mandshurica Maxim. water extract (CMA), a dual inhibitor of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on rat adjuvant arthritis (AA) were investigated. Complete Freund's adjuvant (CFA) was used to induce AA in rats. The extents of inflammation and treatment response were evaluated with regard to lymphocyte proliferation. Serial evaluation was carried out on days 1, 7, 14, 21 and 28 after creation of inflammation. The lymphocyte proliferation study revealed cellular immunosuppression during the early phase of the disease. Administration of CMA on the same day or 5 days prior to inflammatory insult into the joint significantly reduced the inflammation as compared to the untreated animals in a dose dependent manner. The administration of CMA (2, 5 and 10mg/kg, subcutaneously (s.c.)) inhibited the inflammatory response and restored the weight of body and immune organs of AA rats. Synoviocytes proliferation of AA rats significantly increased, and the levels of TNF-alpha and IL-1 in supernatants of synoviocytes in AA rats were also elevated compared with the nonimmunized rats group. The administration of CMA (2, 5 and 10mg/kg, s.c.) reduced the above changes significantly. In contrast to TNF-alpha and IL-1, IL-10 production and the level of its mRNA of synoviocytes in AA rats were apparently decreased. CMA (2, 5 and 10mg/kg, s.c.) markedly increased IL-10 in synoviocytes at protein and transcription level. The results indicated that CMA had a beneficial effect on rats AA due to modulating inflammatory cytokines production of synoviocytes, which played a crucial role in pathogenesis of this disease. PMID- 21783712 TI - Tri-n-butyltin-induced blockade of store-operated calcium influx in rat thymocytes. AB - Tri-n-butyltin (TBT), one of environmental pollutants, disturbs intracellular Ca(2+) homeostasis by increasing intracellular Ca(2+) concentration ([Ca(2+)]i). Effect of TBT on oscillatory change in [Ca(2+)]i (Ca(2+) oscillation) of rat thymocytes was examined using a laser microscope with fluo-3-AM in order to further elucidate the TBT toxicity related to intracellular Ca(2+). The Ca(2+) oscillation was completely attenuated by 300nM TBT. Since store-operated Ca(2+) channels are involved in the generation of Ca(2+) oscillation, the action of TBT on an increase in [Ca(2+)]i by Ca(2+) influx through store-operated Ca(2+) channels was examined. The increase in [Ca(2+)]i by the store-operated Ca(2+) influx was not affected by 3nM TBT. However, TBT at 10nM or more significantly reduced the increase in [Ca(2+)]i. It is likely that TBT attenuates the Ca(2+) oscillation by reducing the Ca(2+) influx through store-operated Ca(2+) channels. PMID- 21783713 TI - Combined effects of coenzyme Q(10) and Vitamin E in cadmium induced alterations of antioxidant defense system in the rat heart. AB - Our study investigated the possible protective effects of coenzyme Q(10) (CoQ(10)) and Vitamin E (Vit E) alone or in combination against cadmium (Cd) induced alterations of antioxidant defense system in the rat heart. Male Wistar rats were injected with a single dose of CdCl(2) (0.4mg Cd/kg BW i.p.), CoQ(10) (20mg CoQ(10)/kg BW i.m.) and Vit E (20IU Vit E/kg BW i.m.), alone or in combination. Acute intoxication of rats with Cd were followed by significantly increased activity of antioxidant defense enzymes (CuZn SOD, GSH-Px, GST and GR), while the activity of Mn SOD was decreased in the heart. The treatment with Cd significantly decreased Vit C and Vit E concentrations. Treatment with CoQ(10) and Vit E reversed Cd-induced alterations of antioxidant defense system. The obtained results support the assumption that CoQ(10) and Vit E functions cooperatively with endogenous antioxidants and diminished toxic effects of Cd in rat heart. PMID- 21783714 TI - Methylmercury accumulation, histopathology effects, and cholinesterase activity alterations in medaka (Oryzias latipes) following sublethal exposure to methylmercury chloride. AB - A series of specific toxicological effects including bioaccumulation of the pollutant, histological changes and influences on cholinesterase (ChE) activities were examined in the adult Japanese medaka after the exposure to graded sublethal concentrations (40, 20, 10, 5, 2.5ngHg/mL) of methylmercury chloride (MMC). Methylmercury (MeHg) contents in the exposed medaka tissues ranged from 0.03 to 64.4MUgHg/g (wet weight, w.w.). High concentrations of MeHg were accumulated in the liver and brain, while the concentrations in muscle and fat were relatively low. A dose-dependent and exposure time-dependent increase of MeHg contents in tissues was observed. Histopathological changes, such as oedema, vacuolization, pyknotic nucleus, telangiectasis, and degenerative sperm, can clearly be observed in the slices from the liver, gill, and male gonad of the exposed medaka. Inhibition of ChE activity was common in the exposed fish's brain, liver, gill, and muscle. The serious intoxication of MMC to medaka was definitely demonstrated herein. PMID- 21783715 TI - Modification of vulnerability to dodecylbenzenesulfonate, an anionic surfactant, by calcium in rat thymocytes. AB - We have previously reported that cremophor EL, a nonionic surfactant, at clinical concentrations significantly decreases the cell viability of rat thymocytes with phosphatidylserine-exposed (PS-exposed) membranes under in vitro condition. It is reminiscent of a possibility that sodium dodecylbenzenesulfonate (DCBS), an anionic surfactant world-widely used for detergents, also affects the cells in the similar manner. To test the possibility, the effect of DCBS on rat thymocytes has been examined using a flow cytometer with fluorescent probes. Exposure of PS on outer surface of cell membranes was induced by A23187, a calcium ionophore to increase intracellular Ca(2+) concentration ([Ca(2+)](i)). DCBS at 1MUg/mL (2.87MUM) significantly decreased the viability of cells with PS-exposed membranes, but not with intact membranes. DCBS also significantly decreased the viability of cells exposed to H(2)O(2), an oxidative stress increasing the [Ca(2+)](i). On the other hand, the decrease in extracellular Ca(2+) concentration ([Ca(2+)](e)) increased the cell vulnerability to DCBS and vice versa. Intact membrane lipid bilayer and extracellular Ca(2+) are required to maintain membrane integrity. Therefore, the change of membrane property by manipulation of [Ca(2+)](i) and [Ca(2+)](e) is one of causes for the augmentation of DCBS cytotoxicity. PMID- 21783716 TI - Acute toxic effects of dioctyltin on immune system of rats. AB - In the present study, dioctyltin chloride (DOTC: 100mg/kg, BW) was orally administered to immature (30-day-old) male rats, and the acute toxic effects were studied. Di- and monooctyltin (its metabolite) accumulations were mainly detected in the liver, and peaked 48h later. A similar pattern was also found in the kidney, but the levels were low or trace amounts. Significantly low thymus and spleen weights were detected in DOTC-treated animals. Increased apoptotic cell numbers in the thymus and spleen were observed in DOTC-treated animals also. Although the expression of 97 genes involved in apoptosis was studied in the thymus, at least 24h after treatment, we could not detect clearly different expressions between DOTC- and vehicle-treated animals. The present results suggest that DOTC was selectively immunotoxic. One of the mechanisms for its immunotoxicity would be via its stimulation of immune cell apoptosis. PMID- 21783717 TI - The toxicity of hexanedione isomers in neural and astrocytic cell lines. AB - The metabolite 2,5-hexanedione (HD) is the cause of neurotoxicity linked with chronic n-hexane exposure. Acute exposure to high levels of 2,5-HD, have also shown toxic effects in neuronal cells and non-neuronal cells. Isomers of 2,5-HD, 2,3- and 3,4-HD, added to foodstuffs, are reported to be non-toxic. The acute cytotoxic effects of 2,5-, 2,3- and 3,4-HD were evaluated in neural (NT2.N, SK-N SH), astrocytic (CCF-STTG1) and non-neural (NT2.D1) cell lines. All the cell lines were highly resistant to 2,5-HD (34-426mM) at 4-h exposure, although sensitivity was greatest with NT2.D1, then SK-N-SH, NT2.N and finally the CCF STTG1 line. At 24-h exposure, cell vulnerability increased 5-10-fold. The NT2.D1 cells were again the most sensitive, followed by NT2.N, SK-N-SH and then the CCF STTG1 cells. 2,3- and 3,4-HD (8-84mM), were significantly more toxic towards all four cell lines compared with 2,5-HD, after 4-h exposure. After 24-h exposure there was a 12-fold increase in inhibition of MTT turnover in the SK-N-SH cells and a 4-fold increase in the CCF-STTG1 cells, compared with 2,5-HD exposure. 2,3- and 3,4-HD, were significantly less toxic to the NT2.N cells than the SK-N-SH cells after 24-h exposure to the compounds, demonstrating a differing toxin vulnerability between these neural and neuroblastoma cell lines. This study indicates that these non-neuronal and neuronal cells are acutely resistant to 2,5 HD cytotoxicity, whilst the previously unreported sensitivity of all four cell lines to the 2,3- and 3,4- isomers of HD to has been shown to be significantly greater than that of 2,5-HD. PMID- 21783718 TI - Percutaneous malathion absorption by anuran skin in flow-through diffusion cells. AB - There is increased concern about the sublethal effects of organophosphorous (OP) compounds on human and animal health, including the potential role of OP compounds in the global decline of amphibian populations. Malathion is one of the most widely used OP pesticides with numerous agricultural and therapeutic applications, and exposure to environmentally applied malathion can lead to adverse systemic effects in anurans. Cutaneous absorption is considered a potentially important route of environmental exposure to OP compounds for amphibians, especially in aquatic environments. One in vitro system commonly used to determine the absorption kinetics of xenobiotics across the skin is the two compartment Teflon flow-through diffusion cell system. To establish cutaneous absorption kinetics of malathion, six full thickness skin samples taken from both the dorsal and ventral surfaces of each of three bullfrogs (Rana catesbeiana) and three marine toads (Bufo marinus) were placed into two-compartment Teflon flow through diffusion cells perfused with modified amphibian Ringer's solution. A 26MUg/cm(2) dose of malathion-2,3-(14)C diluted in 100% ethanol was applied to each sample (0.44-0.45MUCi). Perfusate was collected at intervals over a 6h period and analyzed for (14)C in a scintillation counter. At the end of 6h, surface swabs, tape strips, biopsy punches of the dosed area of skin, and peripheral samples were oxidized and analyzed for residue effects. Malathion absorption was greater across the ventral skin compared to dorsal skin in both bullfrogs and marine toads. PMID- 21783719 TI - Percutaneous malathion absorption in the harvested perfused anuran pelvic limb. AB - The objective of this study was to establish an accurate in vitro model for cutaneous absorption in anurans. The harvested perfused anuran pelvic limb (HPAPL) model maintains the anatomic and physiologic integrity of the skin from the pelvic limb, including the intact capillary network. Radiolabeled malathion was applied to the skin of the dorsal thigh, and perfusate was collected over a 6h period. Residues from the skin surface, stratum externum, and dosed area beneath the stratum externum were analyzed. Kinetic parameters were calculated from these data. Absorption was significantly less for the HPAPL than previously reported for Teflon flow-through diffusion cells. However, partitioning effects were comparable. The HPAPL is an appropriate in vitro model for examining cutaneous absorption kinetics in the bullfrog. PMID- 21783720 TI - Pesticides and their binary combinations as P-glycoprotein inhibitors in NIH 3T3/MDR1 cells. AB - The purpose of the present study was to assess do selected pesticides as well as their binary combinations act as inhibitors of P-glycoprotein (P-gp) activity of NIH 3T3 mouse fibroblasts stably transfected with human MDR1 gene (NIH 3T3/MDR1). As a result of P-gp inhibition, the increase of intracellular accumulation of a model P-gp substrate fluorescent calcein acetoxymethyl ester was measured. Pesticide and verapamil individual dose-response data were scaled and expressed as percent of maximum effect. Results showed that out of 14 pure pesticides tested, endosulfan, phosalone and propiconazole were nearly as potent as model inhibitor verapamil (EC(50)=1.5MUM), while diazinon showed a lower potency of inhibiting P-gp transport activity (EC(50)=58.4MUM). Concentrations of pesticides that produced the same inhibiting effect (isoboles) were combined binary. Results calculated using the isobole method revealed that diazinon caused synergistic effect in inhibiting P-gp transport activity in all combinations. PMID- 21783721 TI - Oxidative damage of dust storm fine particles instillation on lungs, hearts and livers of rats. AB - The purpose of this study was to investigate the effects of dust storm fine particles (PM(2.5)) on oxidative damage in lungs, hearts and livers of rats. Wistar rats were randomly divided into treated groups using PM(2.5) at different concentration (1.5, 7.5, 37.5mg/kg) and control groups using saline. After a single intratracheal instillation 24h, rats were sacrificed and activities of Cu,Zn-superoxide dismutase (SOD), levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were investigated in these three organs of rats. Results show that dust storm PM(2.5) and normal weather PM(2.5) from both Baotou city and Wuwei city caused a dose-dependent decrease of SOD activities and GSH contents in lungs and livers, and a dose-dependent increase of TBARS levels in lungs, hearts and livers of rats as compared to their respective controls. Though the effects induced by normal weather PM(2.5) slightly heavier than dust storm PM(2.5) in both Baotou city and Wuwei city on each examined index, no significant difference was found. Furthermore, no significant difference was observed between the effects induced by dust storm PM(2.5) from Baotou city and that from Wuwei city, or between the effects induced by normal weather PM(2.5) from Baotou city and that from Wuwei city. These results lead to conclusions that both dust storm PM(2.5) and normal weather PM(2.5) could lead to oxidative damage of different disagrees in lungs, hearts and livers, suggesting that the dust storm PM(2.5) whose airborne mass concentrations were much higher should be more harmful. Its toxic effects might be attributed to oxidative damage mediated by pro oxidant/antioxidant imbalance or excess free radicals. Further work is required to understand the toxicological role of dust storm PM(2.5) on multiple or even all organs in mammals. PMID- 21783722 TI - Effects of tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) on the activation of ERK1/2 MAP kinases and the proliferation of human mammary epithelial cells. AB - Cigarette smoking is a risk factor in the developing of various cancers including breast tumors. There are more than 60 chemical carcinogens in the cigarette smoke; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being one of the strongest tobacco-specific carcinogens. In this study, we demonstrated that NNK rapidly activated ERK1 and ERK2 MAP kinases and stimulated proliferation in human normal mammary epithelial cells. MEK1/2 specific inhibitor UO126 completely blocked NNK-induced ERK1/2 activation and cell proliferation, whereas nicotinic receptor nAchR antagonist mecamylamine partially and the selective alpha(7)-nAchR antagonist alpha-bungarotoxin essentially inhibited the NNK-induced ERK1/2 activation and cell proliferation. Surprisingly, receptor tyrosine kinase inhibitor genistein, the selective beta(1)-adrenergic antagonist atenolol, and the selective beta(2)-adrenergic antagonist ICI118.551 had a strong inhibitory effect on ERK1/2 activation and cell proliferation induced by NNK. These results suggest that there are at least two different routes in activating ERK1/2 by NNK. One is through nicotinic receptor alpha(7)-nAchR to MEK1/2; the other is from beta(1)/beta(2)-adrenergic transactivation of tyrosine kinase containing receptor(s) to MEK1/2. In human cancer mammary epithelial cell lines, we found that ERK MAPK signaling pathway was deregulated: (1) ERK1/2 was constitutively activated at various levels; (2) ERK1/2 was further significantly activated in response to NNK induction; (3) UO126 partially or totally failed to inhibit ERK1/2 activation induced by NNK; (4) The expression levels of ERK1/2 in the cancer cell lines were much higher than those in the normal mammary epithelial cells. The tobacco-specific carcinogen NNK showed a strong proliferative effect on human normal and cancer mammary epithelial cells; the proliferation multitudes of these cells are well correlated with the activation levels of ERK1/2 MAP kinases. PMID- 21783723 TI - Evaluation of micronucleus induction of sand dust storm fine particles (PM(2.5)) in human blood lymphocytes. AB - Sand dust storms are common phenomena in the arid and semi-arid regions. Previous studies have demonstrated that the airborne air fine particulate matter (PM(2.5), particulates with an aerodynamic diameter <=2.5MUm) and its extracts can induce human genetic damage of lymphocytes such as micronucleus formation, chromosomal aberration and so on. However, little is known about the health risks associated with sand dust storm PM(2.5) and its extracts. The aim of the present study is to investigate the micronucleus induction of sand dust storm PM(2.5) (include its organic and inorganic extract) from two different towns on human lymphocytes. The samples of normal PM(2.5) and sand dust storm PM(2.5) were collected in Wuwei (Gansu Province) and Baotou (Inner Mongolia), China. The cytochalasin-B cytokinesis-block test was employed and the cells were treated with 0, 33, 100, 300MUgml(-1) sand dust storm PM(2.5) or normal ambient air PM(2.5) suspension (physiological saline as solvent control), or inorganic extract (0, 75, 150, 300MUgml(-1), physiological saline as solvent control) or organic extract (0, 20, 40, 80MUgml(-1), DMSO as solvent control) at the beginning of the cell culture. Both sand dust storm and normal PM(2.5) and their extract treatment cultures revealed an increase in the frequency of micronucleus. With the increase of treatment concentrations the frequency of micronucleus increased and the nuclear division index (NDI) values declined in a dose-response manner (P<0.01). In the same concentrates, the frequency of micronucleus of normal ambient air PM(2.5) and its extract were significant higher than those of sand dust storm PM(2.5) (P<0.01) except the treatment of Wuwei sample at higher doses, the treatment of inorganic extract of PM(2.5) at the highest dose (300MUgml(-1)) and the treatment of organic extract of PM(2.5) at the higher dose (40 and 80MUgml(-1)) either in Baotou or in Wuwei (P>0.05). The toxicity of sand dust storm PM(2.5) and its extract at high dose is very potent. The frequency of micronucleus of normal PM(2.5) (include its organic extract) from Baotou were higher than those of Wuwei especially in low and middle dose (P<0.05), but the treatment results of sand dust storm PM(2.5) (include its all extract) was not significantly different between the towns (P>0.05). PMID- 21783724 TI - Prevention of cadmium induced lipid peroxidation, depletion of some antioxidative enzymes and glutathione by a series of novel organoselenocyanates. AB - A series of organoselenocyanate compounds 4a-d were synthesized utilizing 1,8 naphthalic anhydride as the building unit. To evaluate the preventive potential of the Se compounds against Cd induced hepatic lipid peroxidation and oxidative stress, female Swiss Albino mice were exposed to Cd (as CdCl(2)) during 20 days at a dose of 1 or 2mg/kg bw given ip and the selenium compounds were given at the dose of 3mg/kg bw orally in a pretreatment and concomitant treatment schedule. Hepatic lipid peroxidation level was increased significantly by Cd, whereas the glutathione-S-transferase (GST), superoxide dismutase(SOD), reduced glutathione(GSH) and catalase(CAT) levels were decreased. The selenium compounds effectively decreased the hepatic lipid peroxidation level of the animals treated with Cd. The compounds were also effective in restoring the GST, SOD, and GSH as well as CAT level towards normal. Cadmium induced enhanced Serum alanine aminotransferase (ALT) and aspertate aminotransferase (AST) level were also decreased by the selenium compounds. The study evidences the preventive effects of organoselenocyanates 4a-d (Scheme 1) against Cd induced lipid peroxidation and oxidative stress, 4d showing the highest activity. PMID- 21783725 TI - Free radicals and antioxidant status in rat liver after dietary exposure of environmental mercury. AB - Potential health effect of dietary exposure to environmental mercury was examined in this study. Dietary exposure significantly increased content of reduced glutathione (GSH) and activity of glutathione peroxidase (GSH-Px) in rat liver at 7 or 20 days (P<0.05; P<0.01), but parameters droped to normal levels after 90 days of exposure. The early increases of the two antioxidants were partly associated with the co-accumulated selenium. However, activity of superoxide dismutase (SOD) was observed significantly decreased after 30 and 90 days of exposure (P<0.05, P<0.05). Changes of antioxidants were paralleled by the induction and aggravation of free radicals in rat liver at 30 and 90 days (P<0.01, P<0.01), increased nitric oxide (NO) content at 90 days (P<0.01). The excess availability of free radicals and the decreased levels of antioxidants resulted in a significant increase of malonyldialdehyde (MDA) after 90 days of exposure, indicating the aggravation of hepatic oxidative status. A number of biomarkers were required to monitor and minimize the health risk for the local population. PMID- 21783726 TI - A broad-spectrum organophosphate pesticide O,O-dimethyl O-4-nitrophenyl phosphorothioate (methyl parathion) adversely affects the structure and function of male accessory reproductive organs in the rat. AB - Methyl parathion (MP) is an organophosphate pesticide used in agriculture, but also illegally used to spray homes and businesses to control insects. The present study was designed to investigate adverse effects of MP on accessory reproductive organs. Male Wistar rats aged 13-14 weeks were treated and sacrificed as follows. Experiment 1: 0.0 (water vehicle), 1.75, 3.5 or 7mg/kg (i.p.) for 5 days and sacrificed on day 14; experiment 2: 0.0, 0.5 or 1mg/kg (i.p.) for 12 days and sacrificed on day 130; experiment 3: 0.0, 0.5 or 1mg/kg (i.p.) for 12 days and sacrificed on day 77; experiment 4: 0.0, 0.75 or 1.5mg/kg (i.p.) for 25 days and sacrificed on day 17 and experiment 5: 0.0 or 3.5mg/kg (p.o.) for 25 days and sacrificed on day 17, after the last exposure. The accessory reproductive organs were removed, weighed and processed for histopathological analysis. Structural qualitative changes such as epithelial cell morphology and luminal observations were carried out for each organ in all experiments. Epididymis of one side was homogenized and biochemical estimations of acid phosphatase (ACP), cholesterol, total protein, uric acid, and Vitamin C were conducted by calorimetric methods in experiments 4 and 5. In experiment 1 the organ weights did not change; in experiment 2, the epididymal weight increased (P<0.001); in experiment 3, the weights of ductus deferens decreased at 1mg/kg and that of seminal vesicle decreased at both dose-levels (P<0.001). In experiments 4 and 5, weights of epididymis and prostate decreased, whereas in experiment 5, weights of ductus deferens and seminal vesicle increased (P<0.05-0.001). The sperm density was normal in control, moderately decreased in experiment 1 at 3.5 and 7mg/kg; in experiment 2 at 1mg/kg, and in experiment 5 at 3.5mg/kg, and severely decreased in experiment 3 at 1mg/kg and in experiment 4 at both dose-levels. The epithelial necrosis and nuclear pyknosis were seen in experiments 1, 3, 4 and 5, whereas nuclear degeneration was seen in experiment 1 and 4 and germ cells in the lumina of epididymis were seen in experiment 4. The nuclear pyknosis in the ductus deferens was seen in all experiments, except at 1.75mg/kg in experiment 1 and at 0.5mg/kg in experiment 3. Brush border disruption in the ductus deferens was seen in experiments 1 and 4; sperms were seen in the lumen in experiment 1 at 7mg/kg, and in experiments 4 and 5. The vacuoles in the epithelium were seen in experiments 1 and 4 and immature germ cells were seen in the lumen in experiment 4. The ACP and Vitamin C levels decreased in experiment 4 at both dose-levels, and in experiment 5 all biochemical parameters tested found decreased (P<0.01 0.001). The present results indicate that MP affects the structure and function of accessory reproductive organs in the rat. PMID- 21783727 TI - Effect of particle emissions from biofuel combustion on surface activity of model and therapeutic pulmonary surfactants. AB - This study was designed to determine the effects of particle emissions from biofuel combustion in household cooking devices, commonly used in rural India, on surface activity of model lung surfactants using Langmuir monolayers. The effect of wood and dried particles from combustion of cowdung on the surface activity of model lung surfactant dipalmitoylphosphatidylcholine (DPPC), DPPC:PG (phosphatidyl glycerol) 7:3 and the therapeutic surfactant, Exosurf, were evaluated. Dried particles from combustion of cowdung in 50wt.% mixture with DPPC elevated the gamma(min) to 15.08+/-1.28mN/m and 50wt.% particles from combustion of wood increased minimum surface tension gamma(min) to 13.46+/-1.70mN/m from a zero value for DPPC alone. A graded response of inhibitory potential for all three surfactants with increasing doses was found for each type of particles. An increase in the minimum surface tension achieved by surfactants in the presence of biofuel particles implies surfactant dysfunction, a greater tendency of alveolar collapse in vivo on exposure to biofuel emissions and can lead to respiratory distress. PMID- 21783728 TI - Sulfur amino acid deprivation in cadmium chloride toxicity in hepatoma cells. AB - The aim of this study was to investigate the effect of individual sulfur amino acid deprivation in cadmium chloride toxicity. HTC cells were deprived of cystine and/or methionine for 12h and then exposed to CdCl(2) for 12h. HepG2 cells were deprived of cystine for 3 and 5h and exposed to CdCl(2) for 3h. In addition HepG2 cells were deprived of methionine for 12h and then exposed to CdCl(2) for 5 and 12h. Our results indicate that only cystine depletion increased cadmium toxicity in HTC cells but not in HepG2 cells as indicated by the neutral red assay. This effect was due to glutathione depletion as indicated by measurement of intracellular glutathione in HTC cells following deprivation of cystine. Methionine depletion had only a slight effect on the viability of HepG2 cells. PMID- 21783729 TI - Is heart rate in fish a sensitive indicator to evaluate acute effects of beta blockers in surface water? AB - We have investigated if propranolol, a non-selective beta-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48h exposure to a very high concentration of propranolol (70.9MUg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naive fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets. PMID- 21783730 TI - Effects of perfluorooctane sulfonate on mallard and northern bobwhite quail exposed chronically via the diet. AB - Adult mallard ducks and northern bobwhite quail were exposed to 0, 10, 50, or 150mg perfluorooctane sulfonate (PFOS)/kg in the diet for up to 21 weeks. Adult health, body and liver weight, feed consumption, gross morphology and histology of body organs, and reproduction were examined. Due to mortality, birds exposed to 50 or 150mg PFOS/kg feed were terminated by Week 7. In quail, the lowest observable adverse effect level (LOAEL) was 10mg PFOS/kg feed based on decreased survivorship of 14-day-old quail offspring. For adult female quail fed 10mg/kg feed, there was a slight but statistically significantly PFOS-related increase in liver weight when compared to controls. When liver weight was normalized to body weight, the statistically significant differences were still observed indicating that PFOS affected liver size. However, no other pathological effects were observed livers of quail from this treatment group which suggests that this enlargement may have been an adaptive response. For adult mallards, no treatment related effects on feed consumption, body or liver weight, growth, or reproductive performance were observed. There was a slightly greater incidence of small testes (length) in adult male mallards and quail exposed to 10mg PFOS/kg, feed when compared to controls. However, spermatogenesis was not affected and there was no effect on the rates of egg fertilization. Due to transfer to eggs, concentrations of PFOS measured in the liver and blood at study termination were greater in male birds than female birds. PMID- 21783731 TI - Aquatic toxicity and abiotic thiol reactivity of aliphatic isothiocyanates: Effects of alkyl-size and -shape. AB - Aquatic toxicity data in the TETRATOX assay and reactivity data in an abiotic thiol assay were collected for a series of aliphatic isothiocyanates. These compounds can act as Michael-type acceptors with N-hydro-C-mercapto-addition to cellular thiols as a molecular mechanism of action. Comparison of both toxicity and reactivity among the analogues revealed that derivatives with a branch hydrocarbon moiety, especially branched in the beta-position were less toxic and less reactive. In contrast, the di-isothiocyanate and the allyl and propargyl derivatives are more toxic than their 1-alkyl homologues. The toxicity and reactivity differences are consistent but except for the tert-butyl-derivative not remarkable. The differences are due to variations in steric hindrance at the reaction center. For the mono-isothiocyanates compounds toxicity (IGC(50)) is linearly related to thiol reactivity (EC(50)): log(1/IGC(50))=1.33(log(1/EC(50))) 0.41; n=23, s=0.24, r(2)=0.911, q(2)=0.907, F=215. PMID- 21783732 TI - Effect of a series of triorganotins on the immune function of human natural killer cells. AB - Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. They are able to destroy tumor and virally infected cells. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. Organotins (OTs) have been shown to interfere with the tumor-destroying function of human NK cells. The purpose of the current study was to explore the relationship of a series of triorganotins, that differ in structure by only a single organic group, for their capacity to block NK tumor cell destroying (lytic) function. Here we examine the series: trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT). NK cells were exposed to TMT, DMPT, MDPT or TPT for 1, 24, 48h, or 6d. A 1h exposure to TMT, at concentrations as high as 20MUM, had no effect on lytic function. However, concentrations as low as 2.5MUM were able to decrease NK tumor destroying function after 6d. A 1h exposure to DMPT had no effect on lytic function, however, after 6d there was an 80-90% decrease in lytic function at 1MUM. Exposure to MDPT (as low as 2.5MUM) decreased NK function at 1h, after 6d there was as much as a 90% decrease at concentrations as low as 100nM MDPT. TPT decreased lytic function in a manner similar to MDPT, however, it was more effective at 1h than MDPT. The effect of the triorganotins on the ability of NK cells to bind to targets was studied, to determine if this contributed to the loss of lytic function. The relative immunotoxic potential of this series of compounds is TPT~MDPT>DMPT>TMT. PMID- 21783733 TI - beta-Glucan protects against chronic nicotine-induced oxidative damage in rat kidney and bladder. AB - In this study, we investigated the protective effect of beta-glucan against nicotine induced oxidative damage in urinary bladder and kidney tissues. Wistar albino rats were injected i.p. with nicotine hydrogen bitartarate (0.6mg/kg daily for 21 days) or saline. beta-Glucan (50mg/kg, p.o.) was administered alone or with nicotine injections for 21 days. After decapitation, the urinary bladder and kidney tissues were taken for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Tissue samples were also examined histologically. In serum samples MDA, GSH, BUN, creatinine, TNF alpha levels and LDH activity were analyzed. Chronic nicotine administration caused a significant decrease in GSH levels and increases in MDA levels and MPO activity in kidney and bladder tissues, suggesting oxidative organ damage, which was also histologically verified. Furthermore, beta-glucan restored the reduced GSH levels, while it significantly decreased MDA levels and MPO activity. Renal function tests, LDH and TNF-alpha levels, which were increased significantly due to nicotine administration, were decreased with beta-glucan treatment. The present data suggest that beta-glucan supplementation effectively counteracts the chronic nicotine toxicity and attenuates oxidative damage of bladder and kidney tissues possibly by its antioxidant effects. PMID- 21783734 TI - The effects of temperature and metal exposures on the profiles of metallothionein like proteins in Oreochromis niloticus. AB - Freshwater fish Oreochromis niloticus were exposed individually to 1mg/L concentrations of cadmium and zinc for 14 days at 20, 25 and 30 degrees C. Heat treated (80 degrees C) liver tissue homogenates were run on a column packed with Sephadex G-75 to obtain eluats for determination of metallothionein-like proteins, sulfhydryl groups and metal concentrations. Elution profiles of the liver showed that there were three heat-resistant protein peaks detected at 254 and 280nm in all samples. Approximate molecular weights of proteins obtained from the first, second and third peaks were 70,000, 43,000 and 6500Da, respectively. Metallothionein-like proteins (6500) of control fish contained sulfhydryl groups and zinc, but not cadmium. Concentrations of zinc and cadmium in MT-like proteins increased in metal exposed fish and these increases were temperature dependent. However, zinc concentration in control fish decreased in relation to temperature increase. Data indicated that temperature plays significant role on metals bound on metallothioneins. This suggests that season of sampling should be taken into account when natural monitoring studies are carried out with metallothioneins. PMID- 21783735 TI - In vitro metabolism and interactions of the fungicide metalaxyl in human liver preparations. AB - In order to provide additional information for risk assessment of the fungicide metalaxyl, the main objectives were (1) to elucidate the interactions of metalaxyl with different human liver cytochrome P450 enzymes, (2) to tentitatively identify and (semi)quantify metabolites in vitro and (3) to identify human CYP enzymes responsible for metabolism. The mean inhibitory concentrations (IC(50)) for 7-pentoxyresorufin-O-dealkylation (CYP2B) and bupropion hydroxylation (2B6) were 48.9 and 41.7MUM, respectively. The biotransformation reactions were hydroxylation, (di)demethylation and lactone formation. In human liver microsomes predominant metabolites were two hydroxymetalaxyl derivatives or atropisomers of one of the derivatives. On the basis of previous rat studies these could be N-(2-hydroxymethyl-6-methylphenyl)-N (methoxyacetyl)alanine methyl ester and/or N-(2,6-dimethyl-5-hydroxyphenyl)-N (methoxyacetyl)alanine methyl ester. The amounts of didemethylmetalaxyl N-(2,6 dimethylphenyl)-N-(hydroxyacetyl)alanine and lactone 4-(2,6-dimethylphenyl)-3 methylmorpholine-2,5-dione were higher in homogenates than microsomes. The carcinogenic 2,6-dimethylaniline was not detected. Among the nine major human CYPs, CYP3A4 was the only one responsible for metalaxyl hydroxylation, while CYP2B6 was the major isoform responsible for (di)demethylation and lactone formation. PMID- 21783736 TI - Evaluation of oxidative stress responses and neurotoxicity potential of diazinon in different tissues of Cyprinus carpio. AB - Toxicity of organophosphorus insecticides is mainly due to the inhibition of acetylcholinesterase, but, oxidative stress may be involved in the toxicity of this pesticides. Therefore, it was investigated whether diazinon, a commonly used organophosphate, may induce oxidative stress and cholinesterase inhibition in different tissues of Cyprinus carpio. Sublethal concentrations of diazinon (0.0036, 0.018 and 0.036ppb) were administired to C. carpio L. for 5, 15 and 30 days. The study was made by measuring biochemical stress responses of C. carpio L. spectrophotometrically taking into account acetylcholinesterase (AChE), Na(+)K(+)-adenosine triphosphatase (Na(+)K(+)-ATPase) and other antioxidant enzyme activities, as well as malondialdehyde and protein contents in gill, muscle and kidney tissues of the fish. Results of the study suggest that AChE (in gill and muscle tissues) and Na(+)K(+)-ATPase (in muscle and kidney tissues) activities decreased; that antioxidant enzymes, in particular superoxide dismutase (SOD), increased in gill, kidney and muscle tissues. We also observed the existence of a protective function of antioxidant enzymes against lipid peroxidation in muscle tissue. The changes in MDA content varied between increases and decreases in kidney tissue. In gill tissue, however, lipid peroxidation could not be prevented despite induction of SOD and glutathione peroxidase activities. We could see that the protein content decreased only in gill tissue as diazinon dosage was gradually increased until the 15th day of the experiment. During the period between 15th and the 30th days, the protein level in the fish was observed to have reached to that of the control group. This change in protein level can be attributed to adjustment of the fish to its new environmental conditions. Considering most of the parameters in tissues, it can be stated that diazinon exerted its effect at low concentration and during a long period of time, and its toxicity increased dose dependently. This study reveals that C. carpio developed tissue-specific adaptive response to neutralize the oxidative stress following pesticide exposure depending on different antioxidant levels in tissues and that SOD can be used as a biomarker in determining diazinon toxicity due to its early response at even low concentration levels. PMID- 21783737 TI - Screening of antimutagenicity via antioxidant activity in different extracts from the leaves of Acacia salicina from the center of Tunisia. AB - The effect of extracts obtained from Acacia salicina on genotoxicity and SOS response induced by Benzo(a)pyrene (B[a]P) as well as nifuroxazide was investigated in a bacterial assay system, i.e., the SOS chromotest with Escherichia coli PQ37. Preparations obtained from the leaves of A. salicina exhibited no genotoxicity either with or without the external S9 activation mixture. However, all extracts significantly decreased the genotoxicity induced by (B[a]P) and nifuroxazide. Ethyl acetate, methanol and TOF extracts exhibited the highest inhibition level of the SOS response induced by the direct mutagen nifuroxazide. Whereas, aqueous, ethyl acetate and methanol extracts displayed the greatest level of protection towards the indirect mutagen, (B[a]P), induced response. In addition to their antigenotoxic activity, TOF, aqueous, methanol and chloroform extracts showed an important free radical scavenging activity towards the 1,1-diphenyl 2-picrylhydrazyl (DPPH) free radical. These extracts showed IC(50) value of 36, 73, 65, and 87MUg/ml respectively. Taken together, our finding showed that A. salicina exhibits significant antioxidant and antigenotoxic activities. PMID- 21783738 TI - Interactive effects of methyl tertiary-butyl ether (MTBE) and tertiary-amyl methyl ether (TAME), ethanol and some drugs: Triglyceridemia, liver toxicity and induction of CYP (2E1, 2B1) and phase II enzymes in female Wistar rats. AB - The abilities of the gasoline additives methyl tert-butyl ether (MTBE) and tert amyl methyl ether (TAME) to cause liver damage following oral administration, dosed alone or in combination with model hepatotoxins, were investigated in the rat. Inducibility of liver drug-metabolizing enzyme activities was also studied. Exposure to these ethers (10-20mmol/kg) for 3 days resulted in hepatomegaly (13 30%) and induction of cytochrome P450 (CYP) activity towards N nitrosodimethylamine (NDMAD), 7-pentoxyresorufin (PROD), and 7-ethoxyresorufin (EROD). Immunoinhibition assays with monoclonal antibodies showed that the ethers were equipotent as inducers of CYP2E1 activity (2-fold increase) but not of CYP2B1, which was elevated up to 260-fold in TAME-treated rats but only by 20 fold in MTBE rats. A slight or no modifying effect was observed on the NADPH:quinone oxidoreductase (NQO1), glutathione S-transferase (GST), and UDP glucuronosyltransferase (UGT) activities. Alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) were elevated in blood plasma after administration of the ethers. No dramatic enhancement of liver damage could be detected by plasma enzyme analysis (ALT, AST, alkaline phosphatase, gamma glutamyltransferase) following ether administration (13.5mmol/kg) to rats pretreated with mildly hepatotoxic dosages of ethanol, pyrazole, phenobarbital, acetaminophen (paracetamol), or 13-cis-retinoic acid (13-cis-RA or isotretinoin). Plasma triglycerides increased in TAME-treated rats (1.7-fold) and in all 13-cis RA-treated groups (2.1-2.8-fold). The findings that MTBE and TAME exhibited a clear but differential inducing effect on two ether-metabolizing CYP forms (2E1 and 2B1) with no marked effect on phase II activities may reflect the importance of these pathways in vivo. The observation that only TAME by itself induced hypertriglyceridemia while acetaminophen- and 13-cis-RA-induced hypertriglyceridemia were aggravated by both ethers, points to differences in their effects on lipid metabolism. TAME was clearly a more potent CNS depressant than MTBE. There was no marked potentiation of drug/chemical-induced acute liver damage either by MTBE or TAME. PMID- 21783739 TI - Multigenerational study of the hepatic effects exerted by the consumption of nonylphenol- and 4-octylphenol-contaminated drinking water in Sprague-Dawley rats. AB - Our multigenerational study evaluates the hepatic effects of the xenoestrogens nonylphenol (NP), and 4-octylphenol (4OP) on male and female rats when they are exposed uninterruptedly, from conception to adult age, to tap water containing 25ppm of NP or 4OP. Our results showed that these compounds did not induce any change in liver/body weight ratio (relative liver weight, RLW). In the morphological analysis we did not find evident signs of cytotoxicity. The most relevant findings were the presence of both an increase in the apoptotic index and in the percentage of binuclear hepatocytes in livers from exposed animals. Additionally, our study revealed the presence of hepatocellular glycogenosis (mainly in 4OP-exposed rats): the type of glycogen accumulated was in aggregates (gamma-glycogen), a non-functional form of glycogen. This study demonstrates that, at levels close to those described in the environment, NP and 4OP are capable of inducing a number of hepatic effects, potentially related with adaptive, and/or metabolic alterations of liver tissue. PMID- 21783740 TI - Effects of Mandrax and Cannabis on the cellular function of chick embryonic neurons. AB - Cannabis and Mandrax abuse is unique to South Africa; and most research has focused on the socio-economic impact rather than the adverse effects on the developing brain. Therefore, the aim of this study is to determine the effects of Mandrax and Cannabis alone and in combination on the developing brain by using primary and suspension cultures of the chick embryo brain. Exposure of primary chick embryo neuronal (CEN) cultures to the carrier ethanol, Mandrax and Cannabis, for 24h resulted in a significant dose dependent decrease in cell number for Mandarx alone. Increasing concentrations of Cannabis in combination with Mandrax inhibited the toxic effect of Mandrax. In CEN suspensions, Mandrax alone induced a significant time-concentration dependent decrease in esterase activity following 1 and 4h exposure. In combination with Cannabis, a significant increase in esterase activity was observed after 4h exposure. In conclusion Mandrax is toxic to CEN cells in vitro while Cannabis seemed to have a protective effect; however, this study does not investigate the abuse of these drugs in the form commonly abused, namely inhaled smoke. PMID- 21783741 TI - Genotoxic activity and induction of biotransformation enzymes in two human cell lines after treatment by Erika fuel extract. AB - On 12 December 1999, the tanker Erika broke in two parts at about 60km from the Brittany French coasts (Point of Penmarc'h, Sud Finistere, France). About 10,000tonnes of heavy oil fuel were released in the sea. DNA adduct have been detected in fish liver and mussels digestive gland exposed to the Erika oil spill. In order to investigate the mechanism by which Erika fuel extract exhibits genotoxic effects the induction of DNA adducts by an Erika fuel extract have been analysed on two cell lines, human epithelial bronchial cells (WI) and human hepatoma cells. DNA adducts, reflected by a diagonal radioactive zone and individual adducts are detected only in hepatoma cells indicating biotransformation via CYP 1A2 and CYP 1B1. In addition, Erika fuel extract induces some metabolizing enzymes such CYP 1A2, COX2 and 5-LOX, the two later are involved in cancer processes. Formation of leucotrienes B4 (LTB(4)), a mediator playing a role in inflammation, is induced in epithelial bronchial cells. Since inhalation is one of the ways of contamination for human, the above results are important for human health and prevention. PMID- 21783742 TI - Quantitative changes in the testicular structure in mice exposed to low doses of cadmium. AB - The purpose of this study was to quantify the consequences of a long-term exposure to low doses of cadmium on the testicular structure. Sexually mature male mice were orally exposed to cadmium (0.015g/1 of CdCl2 in drinking water) for 1, 3, 6 and 12 months and then sacrificed; cadmium withdrawal was also considered in two groups raised with cadmium for 3 and 6 months, and without cadmium for 3 and 6 months before sacrifice, respectively. Morphometrical and stereological estimations were applied to quantify the structural constituents of the testes. The morphological parameters (testicular mass and size) were significantly decreased at 6 and 12 months of cadmium exposure. Interstitium was the testicular constituent most sensitive to cadmium so that significant decreases in the volume fractions of interstitium and Leydig cells were recorded as from 3 months of cadmium exposure. Cadmium-exposed seminipherous tubules showed increased diameters and lumens together with decreased tubular densities and epithelial percentages. PMID- 21783743 TI - Anti-inflammatory effect of Ulmus davidiana Planch (Ulmaceae) on collagen-induced inflammation in rats. AB - Ulmus davidiana Planch (Ulmaceae) extract (UD) has long been known to have anti inflammatory and anticancer activities. UD has been also known to have protective effects on damaged tissue, inflammation and bone among other functions. Effects of UD on inflammatory and immune responses and its mechanisms in collagen-induced inflammation (CII) rat were studied. Hind paw volumes of rats were measured by volume meter; lymphocyte proliferation, interleukin (IL)-1, IL-2, tumor necrosis factor (TNF)-alpha level was determined by 3-(4,5-2dimethylthiazal-2yl)2,5 diphenyltetrazoliumbromide assay. Antibodies to collagen type II (BC-II) were determined by enzyme-linked immunosorbent assay. There was a marked secondary inflammatory response in CII model, which accompanied with the decrease of body weight and the weight of immune organs simultaneously. The administration of UD (20, 80, 150mg/kg, intragastrically*10 days) inhibited the inflammatory response and restored body weight and the weight of immune organs of CII rats. Lymphocyte proliferation and IL-2 production of CII rats increases, together with IL-1 and TNF-alpha in peritoneal macrophages and synoviocytes. The administration of UD (20, 80, 150mg/kg, 10 days) reduced above changes significantly. UD had no effect on the concentration of antibodies to BC-II. From the results, it was concluded that UD possesses anti-inflammatory and immunoregulatory activities and has a therapeutic effect on CII rats. PMID- 21783744 TI - Infrasound-induced changes on sexual behavior in male rats and some underlying mechanisms. AB - To investigate some bioeffects of infrasound on copulation as well as underlying mechanisms, we inspected the changes of sexual behavior, serum testosterone concentration and mRNA expression levels of steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) in testes of rats exposed to infrasound of 8Hz at 90 or 130dB for 1, 7, 14 and 21 days (2h/day), respectively. Rats exposed to 90dB exhibited significant decrement in sexual behavior, serum testosterone levels and mRNA expression levels of StAR and P450scc at the time point of 1 day but not at the rest time points, and no significantly change of SF-1 mRNA expression was observed over the period of 21 days in spite of mild fluctuation. Rats exposed to 130dB exhibited significant decrement in all aspects above, which became more profound with prolonged exposure. Our conclusion is that adverse bioeffects of infrasound on reproduction depend on some exposure parameters, the mechanism of which could involve in the decreased expression of some key enzymes or regulator for testosterone biosynthesis. PMID- 21783745 TI - Expression and activity of arsenic methyltransferase Cyt19 in rat tissues. AB - Arsenic has been reportedly metabolized by the repetitive reduction and methylation, and is excreted mainly in urine as methylated arsenicals such as monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)). Although it has been demonstrated that the methylation of arsenic is catalyzed by arsenic methyltransferase, Cyt19, very little is known about the characteristics of this enzyme. We investigated mRNA and protein levels of Cyt19 and the enzyme activity of Cyt19 in rat tissues by Northern and Western blottings and high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC ICP MS). Both mRNA and protein levels of the liver were higher than those of other tissues. An intermediate expression of Cyt19 mRNA was observed in the heart and testis. Methylated arsenicals were found to be produced by the liver cytosol using the current HPLC-ICP MS method. PMID- 21783746 TI - Estrogenic activity of the chlorinated derivatives of estrogens and flavonoids using a GFP expression system. AB - Estrogenic chemicals are widely reported to be present in the environment. Their chlorinated derivatives are considered to be produced through the chlorination process in water purification and sewage treatment plants. In this study, several chlorinated derivatives of estrogens and flavonoids, including phytoestrogens, were synthesized by the reaction with hypochlorous acid, and their estrogenic activities were investigated using a devised GFP expression system in human breast carcinoma MCF7 cells. The chlorinated derivatives were less estrogenic than the parent compounds. The EC(50) ranking of estrogen-related compounds was 17beta-estradiol (E2)>4-ClE2>estrone (E1)>4-ClE1>10-Cl-1,4-estradiene-3,17-dione (10-Cl-3,17-dione)>2-ClE2>2-ClE1. 2,4-diClE2, 2,4-diClE1, and 2,4,16,16-tetraClE1 showed lower or no estrogenic activity. Genistein and daidzein are well known as phytoestrogens. 6,8-diCl-genistein, 3',8-diCl-daidzein, (+)-6,8-diCl-naringenin, and 6,8-diCl-apigenin showed lower estrogenic activity than their parent compounds. 3',5',8-triCl-daidzein exhibited no estrogenic activity. No activity was detected in chrysin, (+)-catechin, and their chlorinated derivatives. Similar results were obtained in a cell proliferation assay using MCF7 cells. PMID- 21783747 TI - Cobalt release from glazed earthenware: Observations in a case of lead poisoning. AB - In a case of lead poisoning caused by a Greek jug, high levels of whole blood cobalt were also recorded. Cobalt was probably released from the underglaze dye by juice stored in the jug. The element was rapidly eliminated from the circulation and no signs of cardiotoxicity were observed in the patient. This case illustrates a possibly novel route of alimentary cobalt exposure. PMID- 21783748 TI - Nitrate and nitrite concentrations in rabbit saliva Comparison with rat saliva. AB - The purpose of this work was to investigate the interest of rabbits for studying pharmacology and toxicology of dietary nitrate. Twenty-one females were given 1, 300 and 600mg/l nitrate in drinking water for 11 weeks. Saliva and blood were analysed for nitrate/nitrite. There is a linear relationship between the amounts of nitrate ingested and amount of nitrate in saliva, contrary to what is observed in rats. However, salivary nitrite concentrations remain low, and nitrate reductase activity in the oral cavity of the rabbit seems very weak. PMID- 21783749 TI - Chlorinated pesticide concentration in semen of fertile and infertile men and correlation with sperm quality. AB - In recent years controversy has evolved regarding the role of environmental pollutants especially chlorinated pesticides and heavy metals on male infertility. Previous data generated on the correlation of chlorinated pesticides with human semen are scarce and controversial. The objective is to explore the possibility of correlation if any between the chlorinated pesticides and sperm count and motility. Semen analysis were performed in 50 samples collected each from fertile and infertile men and pesticides estimation for dichlorodiphenyltrichloroethane (DDT) and its metabolites dichloro-2,2-bis(p chlorophenyl) ethylene (DDE); 1,1,1-trichloro-2,2-bis(p-chlorophenyl ethane) (pp'DDT); 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (pp'DDD), 1,1,1-trichloro-2 (o-chlorophenyl)-2-(p-chlorophenyl)ethane (op'DDT), aldrin, hexachlorocyclohexane (HCH) isomers alpha (alpha), beta (beta), gamma (gamma), delta (delta) were done by gas liquid chromatography. The higher concentrations of pesticide, viz. alpha , beta-, gamma-, delta-HCH, DDT and its metabolites (pp'DDE and pp'DDD) were detected in semen samples of infertile males. The data showed significant association between beta-HCH, gamma-HCH, pp'DDE, pp'DDD with semen quality parameters. PMID- 21783750 TI - Polychlorinated biphenyls disrupt the actin cytoskeleton in hippocampal neurons. AB - It is well known that developmental exposure to polychlorinated biphenyls (PCBs) could cause learning and memory deficits, but the underlying mechanisms are not clear. Actin cytoskeleton is directly involved in synaptic plasticity which is considered critical to learning and memory formation by LIM kinase 1 (LIMK 1)/cofilin pathway. To determine whether PCBs could alter actin cytoskeleton, we exposed the cultured hippocampal neurons to PCBs mixture Aroclor 1254 (A 1254). By biochemical measurement, fluorimetric assay and fluorescence microscopy, we found that A 1254 elicited a loss of filamentous actin, which preceded cytotoxicity. Western blots showed that a concentration-dependent decrease in the phosphorylation of cofilin and a decrease in LIMK-1 were induced by A 1254. We concluded that PCBs induced actin depolymerization in hippocampal neurons, probably by inhibiting the LIMK-1/cofilin signaling pathway. The above findings offer new perspectives for the understanding of PCBs-induced learning and memory deficits. PMID- 21783751 TI - Prevention of collagen-induced arthritis in mice by Cervus korean TEMMINCK var. mantchuricus Swinhoe. AB - The effect of water extract of deer antler (DAA) prepared from the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong) on collagen-induced mouse rheumatoid arthritis (RA) model was studied. Identification of common DAA capable of affording protection or modulating the onset and severity of arthritis may have important human health implications. DAA has been shown to possess anti inflammatory and anti-carcinogenic properties in experimental animals. In this study, we determined the effect of DAA-injection on collagen-induced arthritis in mice. In three independent experiments, mice given DAA in water exhibited significantly reduced incidence of arthritis (30-45%) as compared with mice not given DAA in water (86-98%). The arthritis index also was significantly lower in DAA-injected animals. Western blot analysis showed a marked reduction in the expression of inflammatory mediators such as cyclooxygenase 2, IFN-gamma, and tumor necrosis factor alpha in arthritic joints of DAA-injected mice. The neutral endopeptidase activity was approximately six-fold higher in arthritic joints of non-DAA-injected mice in comparison to non-arthritic joints of unimmunized mice, whereas it was only two-fold higher in the arthritic joints of DAA-injected mice. Additionally, total IgG and type II collagen-specific IgG levels were lower in serum and arthritic joints of DAA-injected mice. Taken together our studies suggest that DAA may be useful in the prevention of onset and severity of arthritis. PMID- 21783752 TI - Immunomodulatory activity of Ulmus davidiana Planch (Ulmaceae) water and ethanolic extracts on bone cells: Stimulation of proliferation, alkaline phosphatase activity and type I collagen synthesis. AB - Ulmus davidiana Planch (Ulmaceae) (UD) frequently appears as the main ingredient in prescriptions for bone injuries, however, the action mechanism is unclear. In the present study, (i) the effect of the aqueous extract of UD on bone cells was investigated in vitro and (ii) the immunomodulatory activity of UD was investigated with regard to cellular and humoral immunity. The osteoprecursor cells (OPC) were incubated in the medium with different concentrations of the UD and the cell proliferation was studied. When the concentration of UD was <100MUg/ml, the proliferation of OPC was enhanced. However, the proliferation of OPC was inhibited by UD with the concentrations >180MUg/ml. Under most treatments, the cells presented low expression for cyclooxygenase-2 (Cox-2) protein. On the other hand, oral administration of the ethanolic and water extracts of UD, at the doses of 20, 50, 100 and 200mg/kg in mice, dose dependently potentiated the delayed-type hypersensitivity reaction induced both by sheep red blood cells (SRBC) and oxazolone. It significantly enhanced the production of circulating antibody titers in mice in response to SRBC. UD had no any effect on macrophage phagocytosis. Chronic administration of UD significantly ameliorated the total white blood cell counts and also restored the myelosuppressive effects induced by cyclophosphamide. From the results, it was concluded that UD directly stimulates the proliferation, alkaline phosphatase activity, protein secretion and particularly type I collagen synthesis of OPC in a dose-dependent manner, and that UD possesses immunomodulatory activity. PMID- 21783753 TI - Composition, antimicrobial activity and cytotoxicity of essential oils from Aristolochia mollissima. AB - The compositions of the essential oils from the rhizome and the aerial part of Aristolochia mollissima were analysed by GC-MS, 68 constituents (88.2% of the total oil) and 74 constituents (89.4% of the total oil) were identified, respectively. 2,2,7,7-Tetramethyltricyclo[6.2.1.0(1,6)]undec-4-en-3-one was the most abundant constituent among all in the ratios of 15.9% and 13.5% from the rhizome and the aerial part of A. mollissima, respectively. Among other main compounds, (E)-beta-santalol acetate (10.3%) and camphene (6.7%) were detected in the rhizome oil, spathulenol (6.8%) was detected in the oil from the aerial par of A. mollissima. The antimicrobial activity of the essential oils from the rhizome and the aerial part of A. mollissima was evaluated against 20 microorganisms using disc diffusion and broth microdilution methods. The gram positive bacteria were more sensitive to both oils than gram-negative bacteria and yeasts. The rhizome oil showed the strongest bactericidal activity against Staphylococcus saprophyticus, whereas the oil from the aerial part of A. mollissima exerted the strongest bactericidal activity against methicillin resistant and methicillin-senstive Staphylococcus aureus. The in vitro cytotoxicity of both oils on six human cancer cell lines were also examined. The cytotoxicity of the rhizome oil on four cancer cell lines (ACHN, Bel-7402, Hep G2 and HeLa) was significantly stronger than that of the oil from the aerial part of A. mollissima. PMID- 21783754 TI - BjMT2, a metallothionein type-2 from Brassica juncea, may effectively remove excess lead from erythrocytes and kidneys of rats. AB - The remedial effects of a plant metallothionein type-2 were observed from lead (Pb) injured rats. BjMT2 from Brassica juncea was expressed in Escherichia coli and purified by affinity chromatography, a purified BjMT2 protein was obtained which strongly reacted with the thiol reagent MBB (monobromobimane). The profiles of erythrocytes, renal tubules and glomerulus of kidney of rats suffered pathological changes from excess Pb were evidently improved by supplying the BjMT2. Quantitative analysis showed that the content of Pb and the amount of leukocytes in blood were significantly declined after supplying BjMT2 to rats. The results indicated that the BjMT2 may have the potential function to decrease Pb toxicification in rate organs and tissues. PMID- 21783755 TI - Flame retardant tetrabromobisphenol A induced hepatic changes in ICR male mice. AB - Tetrabromobisphenol A (TBBPA) is widely used throughout the world as flame retardant for electronic equipment or building materials, and is detected in air at the dismantling plant, sewage sludge, sediment or human serum samples. In the present study, we examined the effects of TBBPA on the liver when administered to mice for 14 consecutive days. Groups of 7 (control group) or 8 (treated group) Crlj:CD1 (ICR) male mice were given 0 (control), 350, 700 or 1400mg/kg body weight/day TBBPA (99.1% pure) in olive oil for 14 days. The serum concentration of total-cholesterol in high-dose (1400mg/kg BW) group was higher than those of the control group. Absolute and relative liver weights were dose-dependently increased, and were significantly increased in high-dose (1400mg/kg BW) group. The histological findings showed that the slight enlargement of the hepatocytes, inflammatory cell infiltrations and focal necrosis of hepatocytes were more marked in liver of treated groups (from 350mg/kg BW) than in control group. The present data suggest the possibility of inducing hepatic lesion by TBBPA dosing. PMID- 21783756 TI - Morphological changes in the kidney of a fish living in an urban stream. AB - This study reports the incidence of histological alterations in the posterior kidney and morphometric changes in the interrenal tissue of the Neotropical fish Astyanax altiparanae collected from an urban stream impaired by anthropogenic activities and from a clean site (reference). The histological alterations observed in fish kidney from the disturbed stream were in complete contrast to those from the reference site, in respect of the type, severity and number of lesions observed. Tissue lesions found in fish from the urban stream were more severe and in some cases irreparable. The morphometric analysis of interrenal cells showed that fish from the urban stream exhibited increased cellular and nuclear areas and nuclear diameter, indicating hyperactivity of the interrenal cells, which is a sign of long-term stimulation of the hypothalamus-pituitary interrenal axis. The high incidence of histological alterations in the kidney of A. altiparanae is an evidence of the poor environmental quality of this urban stream, while interrenal cells hypertrophy indicates that these fish are chronically exposed to stressors in their environment. Although the specific causative factors for the observed alterations are unknown this study demonstrates the application of kidney histopathology as a general quality indicator of the aquatic environment. PMID- 21783757 TI - Zinc supplementation ameliorates static magnetic field-induced oxidative stress in rat tissues. AB - The present study was undertaken to find out the effect of zinc supplementation on the antioxidant enzymatic system, lipid peroxidation and DNA oxidation in liver and kidney of static magnetic field (SMF) exposed rats. The exposure of rats to SMF (128mT, 1h/day during 30 consecutive days) decreased the activities of glutathione peroxidase (GPx), catalase (CAT) and the superoxide dismutase (SOD) in liver and kidney. By contrast, sub-chronic exposure to SMF increased the malondialdehyde (MDA) concentration in liver and kidney. Our results revealed an increase of the 8-oxo-7,8-dihydro-2'-desoxyguanosine (8-oxodGuo) in kidney of SMF exposed rats. However, this biomarker of DNA oxidation remained unchanged in liver. Zinc supplementation (ZnCl(2), 40mg/l, per os) in SMF-exposed rats restored the activities of GPx, CAT and SOD in liver to those of control group. However, only CAT activity was restored in kidney. Moreover, zinc administration was able to bring down the elevated levels of MDA in the liver but not in the kidney. Interestingly, zinc supplementation attenuated DNA oxidation induced by SMF in kidney to the control level. Our investigations suggested that zinc supplementation minimizes oxidative damage induced by SMF in rat tissues. PMID- 21783758 TI - Oxidative stress after acute and sub-chronic malathion intoxication in Wistar rats. AB - Malathion is an insecticide of the group of organophosphate pesticides (OPs), which shows strong insecticidal effects. However, it possesses mutagenic and carcinogenic properties and shows organ-specific toxicity in relation to the heart, kidney and other vertebrate organs. The exact mechanism of the genotoxic effects of malathion is not yet known. Free radical damage is an important direct or indirect factor in several pathological and toxicological processes, including malathion poisoning. The aim of the present study was the evaluation of oxidative damage in different tissues of Wistar rats, administered intra peritoneally at doses of 25, 50, 100 and 150mgmalathion/kg, after acute and sub-chronic malathion exposure. Oxidative stress evaluation was based on lipid peroxidation by levels of thiobarbituric acid reactive substances (TBARS), protein oxidation by levels of carbonyl groups, and also on the activities of superoxide dismutase and catalase, two antioxidant enzymes that detoxity superoxide radical (O(2)(-)) and hydrogen peroxide, respectively. The results showed that the most sensitive targets of oxidative damage were kidney, lung and diaphragm after acute treatment, and liver, quadriceps and serum after sub-chronic treatment. Also, in general, increased lipid peroxidation measured as TBARS levels seems to be a better biomarker of oxidative stress compared to the contents of protein carbonyls after acute and sub-chronic malathion treatments. The present findings reinforce the concept that oxidative stress and particularly lipoperoxidation, are involved in OPs toxicity. PMID- 21783759 TI - Subchronic exposure to a mixture of groundwater-contaminating metals through drinking water induces oxidative stress in male rats. AB - The current study examines the oxidative stress-inducing potential of a mixture of metals, representative of groundwater contamination in different areas of India. Male albino rats were exposed to the mixture through drinking water for 90 days at 0, 1, 10 and 100 times the mode concentrations of the metals in contaminated waters and at concentrations equal to their WHO maximum permissible limit (MPL) in drinking water. The endpoints evaluated were lipid peroxidation (LPO), GSH content and activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in heart, liver, kidney and brain. MPL and 1* levels did not induce any alterations. The mixture at 10* and 100* doses increased LPO and decreased GSH level and activities of the antioxidases in kidney, liver and brain, but no alterations were observed in heart. An inverse correlation between LPO and GSH or antioxidaes and a positive correlation between GSH and glutathione peroxidase or glutathione reductase were found in the affected organs. The findings suggest that the mixture induces oxidative stress and decreases antioxidant status in 10* and 100* the mode concentrations of the metals in drinking water. PMID- 21783760 TI - Induction of caspase-3 activated DNase mediated apoptosis by hexane fraction of Tinospora cordifolia in EAT cells. AB - Tinospora cordifolia (Guduchi) has been used for centuries for treating various ailments including cancer in Ayurvedic system of medicine. In this study, we report the mechanism of cell death exhibited by the hexane extract fraction of T. cordifolia (TcHf) against Ehrlich ascites tumor (EAT) in mice. Treatment of EAT bearing animals with TcHf resulted in growth inhibition and induction of apoptosis in a dose-dependent manner. TcHf induced the formation of apoptotic bodies, nuclear condensation, typical DNA ladder, activation of caspase-3, decreased cell number and ascites volume. We examined TcHf for its effect on proliferation and cell cycle progression in EAT cells. The results showed that TcHf inhibited the proliferation of EAT cells by blocking cell cycle progression in the G1 phase. In Western blot analysis, apoptosis in the EAT cells was associated with the constitutive expression of caspase activated DNase (CAD) in both nucleus and cytoplasm after TcHf treatment. Further more the expression of pro-apoptotic gene, Bax, was increased and the expression of anti-apoptotic gene, Bcl-2, was decreased in a time dependent manner by TcHf treatment. All results indicate that the hexane fraction of T. cordifolia is capable of inducing apoptosis in EAT cells in vivo. PMID- 21783761 TI - Evaluation of caspase-dependent apoptosis during methyl parathion-induced endometrial damage in rats: Ameliorating effect of Vitamins E and C. AB - The role of reactive oxygen species (ROS) in various diseases of the female reproductive tract has been shown, and oxidative stress is an important component of the mechanism of toxicity of OPIs. Methyl parathion (MPT) is one of the most widely used organophosphate insecticides (OPIs) in agriculture. The aim of the study was to elucidate the effect of subchronic MPT exposure on lipid peroxidation and serum activities of cholinesterase (ChE), and the protective effects of combination of antioxidant Vitamins E and C in rats. Additionally, histopathological and immunohistochemical changes in endometrium were aimed to be examined. Three groups of rats were used in the experiment. The first group was treated with 5mg/kg MPT; the second group was treated with 5mg/kg body weight MPT plus Vitamin E and Vitamin C (MPT+Vit); and the third group was given only corn oil (control). MPT and MPT+Vit groups were given MPT by gavage 5 days a week for 4 weeks at a dose level of 4mg/(kgday) by using corn oil as the vechicle. Vitamins E and C were injected at doses of 50mg/kg i.m. and 20mg/kg body weight i.p. Histopathological and immunohistochemical examinations for caspase-3 and caspase-9 were accomplished in the endometrium. The level of malondialdehyde (MDA) increased significantly in the MPT group compared with the control group (p<0.05). MDA significantly decreased in the MPT+Vit group compared with the MPT group (p<0.05). Administration of Vitamins E and C along with MPT significantly reduced the histopathological changes and the extent of apoptosis. In conclusion, subchronic MPT administration caused endometrial damage and that treatment with a combination of Vitamins E and C reduced endometrial damage caused by MPT. PMID- 21783762 TI - Cytogenetic analysis in lymphocytes from workers occupationally exposed to low levels of ionizing radiation. AB - The aim of the present study was to perform a cytogenetic analysis in peripheral lymphocytes of 36 individuals occupationally exposed to low levels of ionizing radiation, and compare the results with 36 controls, using the chromosomal aberrations test (CA), sensitivity to bleomycin and cytokinesis-blocked micronucleus assay (MN). The frequencies of CA/100 cells observed for the exposed workers were not significantly higher than in controls (P>0.05). The mean break/cell (b/c) for the controls and exposed workers was 0.59+/-0.39 and 0.57+/ 0.29, respectively (P>0.01). The MN frequencies were significantly increased (P<0.01) in exposed workers (6.13+/-3.18) in comparison with controls (5.11+/ 3.85). The mean MN was also statistically higher in the non-smoker exposed when compared with non-smoker controls, 5.80+/-3.09 and 5.15+/-4.08, respectively (P<0.01). The cytogenetic analysis of MN proved to be the most sensitive biological marker to assess the cellular response to low levels of irradiation. PMID- 21783763 TI - Glycoprotein isolated from Ulmus davidiana Nakai modulates inflammatory related factors in mouse colonic tissues. AB - This study was carried out to investigate the anti-inflammatory effects of a 116kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN glycoprotein) in dextran sodium sulfate (DSS)-treated mice. In DSS-treated mouse, the results showed that pretreatment with UDN glycoprotein [40mg/kg body weight (BW)] normalized the augment of disease activity index (DAI) level and shortening of the large intestine. In addition, UDN glycoprotein inhibited myeloperoxidase (MPO) activation, thiobarbituric acid reactive substances (TBARS) formation, nitric oxide (NO) production and lactate dehydrogenase (LDH) release, whereas increased the activity of anti-oxidant enzymes [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], accompanying the inhibition of pro-inflammatory-related signal mediators [colonic nuclear factor-kappa B (NF kappaB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)] in DSS-stimulated mice colitis. These results speculate that UDN glycoprotein may be useful for prevention of inflammatory disease and colorectal carcinogenesis. PMID- 21783764 TI - Histopathological changes in the livers and kidneys of fish in Sariyar Reservoir, Turkey. AB - In this study, a total of 180 fish specimens (wels: Silurus glanis-60; common carp: Cyprinus carpio-60; bleak: Alburnus escherichii-60) of ages between one and two were caught at three different stations in Sariyar Reservoir. The histological changes in the livers and kidneys of three different species of fish were detected microscopically and evaluated with quantitative analyses. Also, organochlorine pesticide residues (OCP) have also been determined in the water and sediment samples and in the adipose tissues of fish caught in these stations. Results show that the reservoir was polluted by different kinds of OCP compounds and these chemicals have accumulated in the fish tissues. As a result of these analyses, histopathological changes were observed in the livers and kidneys of fish specimens, such as mononuclear cell infiltration, congestion and nuclear picnosis. Also intra-cytoplasmic cholestasis in their livers and tubular degenerations in the kidneys were observed. The incidences of the histopathological changes in wels and carps were found to be higher than bleak. Furthermore, histopathological changes in fish samples caught from Usakbuku were much more than the samples caught from other stations (Sariyar and Nallihan Bird Paradise Stations). In this study the possible reasons of histopathological changes were evaluated with respect to different fish species and localities and also the findings were evaluated in relation to OCP contamination. PMID- 21783765 TI - Alterations in rabbit aorta induced by types I and II pyrethroids. AB - Since pyrethroids are involved in reactive oxygen species production and no investigations have yet been performed on smooth muscle cell integrity, we studied the influence of permethrin- and cypermethrin-treatment on rabbit aorta using confocal laser scanning fluorescence microscopy, which allows cell viability to be assessed within the wall of living rabbit aorta. The data obtained show that the pyrethroid-treatment (10-100MUM) impairs the smooth muscle cell viability. A double-labeling protocol allowed us to distinguish cytotoxic effects of permethrin- and cypermethrin-treatment in aortic rings. In conclusion, permethrin seems to induce more oxidative stress on the aorta wall than that cypermethrin does. PMID- 21783766 TI - Comparative toxicity studies of NSAIDs in birds: A criticism of Reddy et al. PMID- 21783767 TI - DNA damage induced by coexposure to PAHs and light. AB - Polycyclic aromatic hydrocarbons (PAHs) are widely distributed in the environment as pollutants in air, water and soil, and some are carcinogenic, being associated with various types of cancer. A majority of the research concerning the biological effects of PAHs has focused on the metabolic activation and DNA adducts leading to mutation and transformation. Although the role of the PAHs as photosensitizers has received much less attention, investigators have shown that PAHs excited by sunlight induced significant cytotoxicity and several kinds of DNA damage. Some PAHs were recently proved to be photomutagenic. In this review, we discuss the influence of PAHs in combination with sunlight focusing on the phototoxicity and cellular DNA damage produced. PMID- 21783768 TI - Fluconazole induces teratogenic effects in the tunicate Phallusia mammillata. AB - Fluconazole (FLUCO) is an azole derivative used to treat fungal and yeast infections. Embryotoxicity tests on the ascidian Phallusia mammillata were performed to evaluate the effects of this drug. FLUCO proved to have strong consequences on P. mammillata development. Incidence of malformations and of lethality increased in a dose dependent way. Probit analysis showed that FLUCO had a high TI value (Teratogenic Index, LC(50)/TC(50)), thus this substance could be classified as a teratogenic compound for ascidians. Larvae exposed to FLUCO showed a typical phenotype characterized by malformations restricted to the trunk region: the trunk appeared round in shape with flat palps, the sensory vesicle cavity was absent or reduced and the anterior central nervous system failed to correctly differentiate. These anomalies resulted similar to those induced by retinoic acid (RA) treatment. Thus, it could be hypothesized that FLUCO and RA may act with a similar pathogenic mechanism in ascidian larvae, as it has been proposed for mammals. PMID- 21783769 TI - Di(2-ethylhexyl)phthalate leached from medical PVC devices serves as a substrate and inhibitor for the P-glycoprotein. AB - A di(2-ethylhexyl)phthalate (DEHP) was accidentally extracted from plastics in the process of purification of chemosensitizers reversing P-glycoprotein (Pgp) mediated multidrug resistance (MDR). The purpose of this study was to investigate the Pgp-reversal activities of phthalates, which are endocrine-disrupting chemicals, by utilizing the Pgp-overexpressing leukemic cell line AML-2/D100. The phthalates includes DEHP, diethyl phthalate (DEP) and dibutyl phthalate (DBP). Of the tested phthalates, DEHP showed the highest Pgp-reversal activity and DEP the most potent drug-accumulating activity. On the other hand, they did not show any chemosensitizing activity against multidrug resistance associated protein mediated MDR. The complete inhibition of Pgp by verapamil increased the cytotoxicity of DEHP, but neither DEP nor DBP had this effect, suggesting that DEHP alone may be a possible substrate for the Pgp. DEHP showed higher hydrophobicity than the other phthalates when determined by reverse phase-HPLC. In addition, DEHP, but not the others increased the ATPase activity in a concentration-dependent manner. This is the first report that phthalates can reverse Pgp-mediated MDR by increasing drug accumulation, as well as serving as substrates for the Pgp. It is thought that the hydrophobic characteristics of phthalates could play an important role in Pgp-inhibitory activity. Therefore, pharmaco- and toxicokinetic interactions between phthalates leached from medical PVC devices and substrates for the Pgp should be kept in mind. PMID- 21783770 TI - Evaluation of the acute toxicity of perfluorinated carboxylic acids using eukaryotic cell lines, bacteria and enzymatic assays. AB - The acute biological activity of a homologous series of perfluorinated carboxylic acids - perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) - was studied. To analyze the potential risk of the perfluorinated acids to humans and the environment, different in vitro toxicity test systems were employed. The cytotoxicity of the chemicals towards two different types of mammalian cell lines and one marine bacteria was investigated. The viability of cells from the promyelocytic leukemia rat cell line (IPC-81) and the rat glioma cell line (C6) was assayed calorimetrically with WST-1 reagent. The evaluation was combined with the Vibrio fischeri acute bioluminescence inhibition assay. The biological activity of the compounds was also determined at the molecular level with acetylcholinesterase and glutathione reductase inhibition assays. This is the first report of the effects of perfluorinated acids on the activity of purified enzymes. The results show these compounds have a very low acute biological activity. The observed effective concentrations lie in the millimole range, which is well above probable intracellular concentrations. A relationship was found between the toxicity of the perfluorinated carboxylic acids and the perfluorocarbon chain length: in every test system applied, the longer the perfluorocarbon chain, the more toxic was the acid. The lowest effective concentrations were thus recorded for perfluorononanoic and perfluorodecanoic acids. PMID- 21783771 TI - Effects of deltamethrin on rainbow trout (Oncorhynchus mykiss). AB - The aim of this study was to assess the effect of deltamethrin on rainbow trout (Oncorhynchus mykiss). Control and experimental group of fish were exposed to Decis EW 50 pesticide preparation (active substance 50g/l of deltamethrin). The acute semistatical toxicity test lasting 96h was performed on rainbow trout juveniles. The 96hLC(50) value of Decis EW 50 was 0.02mg/l. Examination of haematological and biochemical profile and histological tissue examination was performed on 1-2-year-old rainbow trout after 96h of exposure to Decis EW 50 in a concentration of 0.02mg/l. The experimental group showed significantly lower values (p<0.05) of plasma glucose, alanine aminotransferase, cholinesterase and significantly higher (p<0.05) values of erythrocyte count, haemoglobin content, haematocrit and plasma total protein, albumins, ammonia, aspartate aminotransferase, creatinekinase and calcium compared to the control group. The deltamethrin-based Decis EW 50 pesticide preparation was classified among substances strongly toxic for fish. PMID- 21783772 TI - Thyroid hormone receptor isoform selectivity of thyroid hormone disrupting compounds quantified with an in vitro reporter gene assay. AB - Some compounds, including brominated diphenyl ethers (BDEs), can interfere with thyroid hormone (TH) receptor (TR)-mediated TH-signalling. In this study, the TR isoform selectivity of some TH disrupting compounds was investigated with TRalpha/beta specific reporter gene assays. For this purpose, the effects of compounds on 3,3',5-triiodothyronine (T(3))-induced TRalpha- or TRbeta-activation were tested in green monkey kidney fibroblast (CV-1) cells transiently transfected with Xenopus TRs and a luciferase reporter gene. The T(3)-like BDE-OH and diiodobiphenyl (DIB) increased T(3)-induced TRalpha-activation, but not T(3) induced TRbeta-activation. BDE28 (100nM) did not act via TRalpha, but almost tripled T(3)-induced TRbeta-activation relative to T(3) at its EC(50). BDE206 (100nM) was antagonistic on both TRs with a maximum repression -54% relative to T(3) at its EC(50). Contrary to previous results obtained with the T-screen, HBCD was inactive. The present study illustrates the importance of testing potential TH disrupting compounds in model systems that enable independent characterization of effects on both T(3)-induced TRs. PMID- 21783773 TI - Chronic exposure to sub-lethal concentration of a glyphosate-based herbicide alters hormone profiles and affects reproduction of female Jundia (Rhamdia quelen). AB - This work was carried out to verify the effect of a glyphosate-based herbicide on Jundia hormones (cortisol, 17beta-estradiol and testosterone), oocyte and swim-up fry production. Earthen ponds containing Jundia females were contaminated with glyphosate (3.6mg/L); blood samples were collected from eight females from each treatment immediately before, or at 1, 10, 20, 30 and 40 days following contamination. A typical post-stress rise in cortisol levels was observed at the 20th and 40th days following exposure to glyphosate. At the 40th day, 17beta estradiol was decreased in the exposed females. A similar number of oocytes were stripped out from females from both groups; however, a lower number of viable swim-up fry were obtained from the herbicide exposed females, which also had a higher liver-somatic index (LSI). The results indicate that the presence of glyphosate in water was deleterious to Rhamdia quelen reproduction, altering steroid profiles and egg viability. PMID- 21783774 TI - Efficacy of catalpol as protectant against oxidative stress and mitochondrial dysfunction on rotenone-induced toxicity in mice brain. AB - Rotenone, a specific inhibitor of mitochondrial complex I, reproduces many features of Parkinson's disease. The aim of the study was carried out to investigate how rotenone affected the mitochondrial function and antioxidant/oxidant parameters of mouse striatum, and secondly, to evaluate the ameliorating effects of catalpol against rotenone-induced damage. Our results showed that rotenone induced significant changes in mitochondrial function such as complex I activity and mitochondrial membrane potential decreased, and enhanced antioxidant status as glutathione depletion, enzymatic (glutathione peroxidase and superoxide dismutase) disorders, and increased lipid peroxidation. Catalpol increased complex I, superoxide dismutase and glutathione peroxidase activities, reduced lipid peroxidation and loss of mitochondrial membrane potential in rotenone-treated mice. These in vivo data indicated that catalpol might have protection against deleterious mouse damage caused by rotenone. PMID- 21783775 TI - Chronic toxicity of diethyl phthalate-A three generation lactational and gestational exposure study on male Wistar rats. AB - Diethyl phthalate (DEP) is widely used in the perfume industry as a vehicle for fragrances and in personal care products making human exposure of DEP significant to adults as well as neonatals, as confirmed by levels recorded in blood as well as breast milk samples of human populations in some parts of the world. Therefore, a study was undertaken to understand the toxic effect of DEP over three generations in male Wistar rats. Healthy male and female albino rats of Wistar strain weighing 75-100g (6-7 weeks old) were randomly assigned to two groups of six each. Group I (Control) male and female rats were fed on normal diet and water ad libitum. Group II (DEP) male and female rats were given DEP dissolved in corn oil mixed with the diet at 50mg/kg of the diet/day. Hundred days after the treatment, females were mated with males for 10 days. Exposure to DEP was continued throughout mating, gestation until termination at weaning, which was 150 days of total treatment period of the parental generation. The F1 and F2 generation pups were then segregated on the basis of their sex and six male and female pups of both generations were allowed to grow till they were 75 100g in weight. The treatment was then carried out similar to the parental generation but with reduced dose of 25mg/kg of the diet/day for F1 generation and 10mg/kg of the diet/day for F2 generation. Hundred days after the treatment, females were mated with males for 10 days. Exposure to DEP was continued throughout mating, gestation (21 days) until termination at weaning (21 days), which was 150 days of total treatment period of the F1 and F2 generation. Liver and serum ALT, AST and triglycerides were significantly increased over the three generations, which was much more significant in the F2 generation DEP treated group. The serum cholesterol and liver glutathione and glutathione reductase showed a significant decrease over the three generations, which was much more significant in the F2 generation DEP treated group as compared to the parental and F1 generation DEP treated rats. Histology of the liver showed remarkably enhanced fatty degeneration in the F2 generation DEP treated rats as compared to parental and F1 generation DEP treated rats. Vacuolations were much more significant in the F1 generation DEP treated rats as compared to the controls and F2 generation DEP treated rats. It can be concluded from this study, that continuous exposure through food, gestation and lactation over three generation's inspite of dose reduction of DEP leads to an enhanced toxic effect in the latter generations. PMID- 21783776 TI - Effect of Semecarpus anacardium Linn. nut extract on mammary and hepatic expression of xenobiotic enzymes in DMBA-induced mammary carcinoma. AB - Breast cancer is the major cause of cancer death in women worldwide. Environmental risk factors particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH) are likely to account for a much higher mortality. Xenobiotic metabolising enzymes in breast tissue are potentially important determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. The well known carcinogen 7,12-dimethylbenz(a)anthrazene of PAH family was given (25mg/ml) orally by gastric intubation to induce mammary carcinoma in Sprague-Dawley rats. Increased level of cytochromes (P(450), B(5)), EROD, PROD activities, Phase I biotransformation enzymes (NADPH-cytochrome (P(450)) reductase, NADPH-cytochrome (b(5)) reductase, epoxide hydrolase) and expression of CYP1A1, CYP1A2 and CYP1B1 in liver and breast tissue microsome were documented in DMBA treated group. Phase II enzyme activities (glutathione-S-transferase, gluthatione peroxidase, gluatathione reductase, UDP-glucuronyl transferease) were decreased markedly in cancerous rats. The nut extract of Semecarpus anacardium was administered orally (200mg/kg body wt/day) to the mammary carcinoma rats for 14 days. Drug treatment restored back the altered Phase I and II biotransformation enzymes thus achieving complete detoxification of the carcinogen. These findings suggest that S. anacardium can effectively modulate the catabolism of xenobiotics in rats. PMID- 21783777 TI - Cell passage-associated transient high oxygenation causes a transient decrease in cellular glutathione and affects T cell responses to apoptotic and mitogenic stimuli. AB - Routine cell line maintenance involves removal of waste products and replenishment of nutrients via replacement of cell culture media. Here, we report that routine maintenance of three discrete cell lines (HSB-CCRF-2 and Jurkat T cells, and phaeo-chromocytoma PC12 cells) decreases the principal cellular antioxidant, glutathione, by up to 42% in HSB-CCRF-2 cells between 60 and 120min after media replenishment. However, cellular glutathione levels returned to baseline within 5h after passage. The decrease in glutathione was associated with modulation of the response of Jurkat T cells to apoptotic and mitogenic signals. Methotrexate-induced apoptosis over 16h, measured as accumulation of apoptotic nucleoids, was decreased from 22 to 17% if cells were exposed to cytotoxic agent 30min after passage compared with cells exposed to MTX in the absence of passage. In contrast, interleukin-2 (IL-2) production over 24h in response to the toxin phytohaemagglutinin (PHA), was increased by 34% if cells were challenged 2h after passage compared with PHA treatment in the absence of passage. This research highlights the presence of a window of time after cell passage of non-adherent cells that may lead to over- or under-estimation of subsequent cell responses to toxins, which is dependent on cellular antioxidant capacity or redox state. PMID- 21783778 TI - In vitro effects of oxygen on physico-chemical properties of horse erythrocyte membrane. AB - Whether direct exposure to different concentrations (0%, 13%, 100%) of oxygen may affect horse erythrocyte membrane fluidity (EMF) and fatty acid (FA) composition was studied during 1 (T60) and 2h (T120) exposure. EMF was investigated at the head group level and hydrophobic core thanks to phosphorus nucleus 31 ((31)P) nuclear magnetic resonance ((31)P NMR) and electronic paramagnetic resonance (EPR) using two spin probes: 5-nitroxydestearic acid and 16-doxylstearic acid. Lipid structure of the membranes was studied by gas liquid chromatography. 4 Hydroxy-2E-nonenal was also analyzed as a marker of lipid peroxidation. It increased at T120 13% and 100% oxygen whereas there were no significant changes in membrane dynamic or structure. Correlation was demonstrated between EMF and partial pressure of oxygen in the blood ( [Formula: see text] ). In vitro high rate of oxygenation was efficient to induce lipid peroxidation but did not change membrane dynamics. This may be due to a low free radical production in vitro or to the high red blood cells antioxidant properties. PMID- 21783779 TI - Exposure of birds to cholinesterase-inhibiting pesticides following a forest application for tick control. AB - A mixture of malathion (4%), carbaryl (2%) and cypermethrin (4%) was applied as dry powder to forest and grasslands at a rate of 5kg/ha for tick control in 1500ha of a deer hunting estate in the south of Spain. The effect on plasma cholinesterase (ChE) of house sparrow and nightingale, and brain ChE of red legged partridge was studied. Plasma ChE was lower after the treatment in passerine birds, but brain AChE was not affected in partridges. The body condition of house sparrows was significantly lower after the treatment. PMID- 21783780 TI - Cadmium neurotoxicity. AB - The Cd has been recognized as one of the most toxic environmental and industrial pollutants due to its ability to induce disturbances in several organs and tissues following either acute or chronic exposure. This review accounts for the recent evidence on its mechanisms to induce neurotoxicity, the role of the blood brain barrier, oxidative stress, interference with calcium, and zinc-dependent processes and apoptosis induction as well as the modulatory effect of metallothionein. Discussion about cadmium neurotoxicity is centered on mechanisms of induction of cellular disfunctions. Future investigations must address those neuronal mechanisms in detail in order to understand cadmium-induced neurotoxicity. PMID- 21783781 TI - Effect of subacute methyl parathion administration on the pharmacokinetics and pharmacodynamics of nifedipine in rats. AB - Families living in agricultural areas may submitted to repeated exposure of methyl parathion (MP) that has been widely used as an agricultural insecticide. MP inhibits cytochrome P450 enzymes and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The aim of the present study is to investigate the possibility that the increased pharmacokinetic and pharmacodynamic effects of nifedipine is due to the inhibition of the metabolism after repeated administration of low doses of MP in rats. Male rats received commercial formulation of diluted MP (1/100 LD(50) or 1/25 LD(50), n=6) or tap water (control, n=5) via gastric gavage (0.5ml) for 14 days. On the 15th day, the carotid artery and jugular vein were cannulated for measurement of cardiovascular parameters and blood sampling, respectively. Nifedipine was administered 3mg/kg via the cannula inserted in the duodenum of the rat. Subacute MP administration did not change pharmacokinetic AUC((0-240)), C(max), t(max), t(1/2)) and pharmacodynamic (mean arterial pressures and heart rates) parameters of nifedipine. These findings provide evidence that repeated exposure of low doses of commercial MP did not affect the elimination of nifedipine which might be due to the lack of inhibition of CYP3A in rats. PMID- 21783782 TI - Developmental changes of the activity of monoamine oxidase in pre- and postnatally lead exposed rats. AB - The effects of prenatal and postnatal lead exposure on monoamine oxidase (MAO) activity were investigated in rat brain. MAO activity was examined in 2, 4, 6, and 8 weeks old rat to investigate the effects of lead in the different stages of rat brain development. Prenatal lead exposure was achieved by providing mother rats with drinking water containing either low (0.05%) or high (0.2%) concentration of lead acetate from gestation to birth. Postnatal lead treatment was performed through drinking water to mothers and pups from birth to the day of experiment. MAO activity was gradually increased with the development in all the brain regions examined, i.e. telencephalon, diencephalons, midbrain, pons/medulla, and cerebellum. Lead exposure increased MAO activity in most of the brain regions especially at early developmental stages (2 weeks of age) and the toxicity was gradually decreased with the development of rats. High concentration of lead showed greater effects on MAO activity compared to low concentration. Postnatal lead exposure showed stronger effects on MAO activity compared to prenatal lead exposure demonstrating the importance of preventing lead exposure to lactating mother. The increased MAO activity by lead intoxication may contribute to the neurobehavioral changes such as cognitive and attention deficit as well as hyperactivity, which is commonly observed both in lead intoxication and perturbed monoaminergic neurotransmission. PMID- 21783783 TI - Compositions and oxidative damage of condensate, particulate and semivolatile organic compounds from gasoline exhausts. AB - The effects of extracts of condensate, particulate and semivolatile organic compounds from absolute gasoline exhausts on DNA single strand break, levels of malondialdehyde (MDA), carbonyl protein and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were investigated in lungs and brains of adult Sprague-Dawley rats of both sexes. In addition, the non-conventional components of the extracts and concentrations of 13 polycyclic aromatic hydrocarbon (PAHs) in gasoline exhaust were measured by GS/MS. Extract of gasoline exhaust at different doses (5.6, 16.7 and 50.0L/kg) were given to administered animals by intratracheal instillation once a week for 4 weeks, while blank control and solvent groups were given with physiological saline and dimethyl sulfoxide (DMSO). Our results showed that gasoline exhaust increased DNA single strand break, promoted lipid peroxidation and oxidative protein damage and decreased activities of SOD in lungs and brains. While, it decreased the activities of GPx in lungs but not in brains. The present data suggested that gasoline exhaust exposure could cause oxidative damage to lung and brain of rats. That was to say that gasoline is a toxin to brain of mammals, not only to lung. PMID- 21783784 TI - Cysteine turnover in human cell lines is influenced by glyphosate. AB - Pesticides are widely spread in the environment and there is a lack of knowledge concerning the impact of these substances on the human cell. In the present study the effect of low doses of the pesticides bentazon, metalaxyl and glyphosate on the cellular metabolism of glutathione and cysteine was examined in HeLa and hepatoma cell cultures. No effect was observed when the cells were exposed to bentazon or metalaxyl. However, significant changes in the intra- and extracellular concentration of cysteine, a precursor for glutathione synthesis, were detected when glyphosate was added to the medium. This finding was observed in the presence of micromolar concentration range of glyphosate, and is relevant when compared to concentrations observed in monitoring programmes. PMID- 21783785 TI - Tamoxifen effects on the early life stages and reproduction of Japanese medaka (Oryzias latipes). AB - Tamoxifen is widely used in the treatment of breast cancer and can enter the aquatic environment in municipal wastewater. To evaluate potential effects on embryonic development of Japanese medaka, fertilized eggs were exposed to tamoxifen at 1-625MUg/l for 14 days. Adverse effects on hatchability and time to hatching only occurred at 125 and 625MUg/l. Reproductive effects were assessed by exposing adults for 21 days to the same dose range. At all concentrations tested, tamoxifen significantly increased plasma vitellogenin levels in males in a dose dependent manner. Fecundity and fertility were detrimentally affected at 625MUg/l. Additionally, F1 eggs were removed from tamoxifen-contaminated water to evaluate transgenerational effects. Hatchability was affected at 625MUg/l but no morphological deformities were observed. A significant dose-dependent increase in the proportion of genotypic males occurred at all concentrations greater than 5MUg/l. PMID- 21783786 TI - The immunosuppressive effects of 10mg/kg cyclophosphamide in Wistar rats. AB - The purpose of this study is to identify the immunosuppressive effects of cyclophosphamide (a known immunosuppressant) in male Wistar rats which were administered orally for 30 days repeatedly, and to find a proper dose of cyclophosphamide at which the immunosuppressive effects is identified. The dose of cyclophosphamide is 2, 5, 10mg/kg bw, respectively. The results showed that 10mg/kg cyclophosphamide treatment induced decreases in body weight, body weight gain, relative weight of spleen and thymus, antibody plaque-forming cells, delayed-type hypersensitivity reaction, natural killer cell activity, lipopolysaccharide-induced B-cell proliferation, and Concanavalin A-induced T cell proliferation. The histopathology observation on spleen and thymus revealed as decreased cellularity. But, no significant clinical symptoms of toxicities and stress were observed and no rats died. These results indicated that the immunosuppressive effects of 10mg/kg cyclophosphamide dosed for 30 days orally were identified in male Wistar rats. Based on the results, it is considered that the dose of 10mg/kg of cyclophosphamide orally for 30 days in male Wistar rats could be used as the dose of positive control group for chemicals immunotoxicity assessment tests. This study also proved that the testing procedures and the experimental techniques established in our laboratory for immunotoxicity tests in male Wistar rats are reliable and feasible. PMID- 21783787 TI - Facile and sensitive spectrophotometric determination of vanadium in various samples. AB - Novel reactions were developed for facile, sensitive and selective rapid spectrophotometric determination of trace amounts of vanadium(V) in various samples. The methods were based on the interactions of 3-methyl-2 benzothiazolinone hydrazone hydrochloride (MBTH) with N-(1 naphthyl)ethylenediamine dihydrochloride (NEDA) in the presence of vanadium to give blue colored derivative or on oxidation of dopamine hydrochloride (DPH) by vanadium in acidic medium and coupling with MBTH to yield pink color derivative. The blue color derivative having an absorbance maximum at 595nm was stable for 9 days and the pink color derivative with lambda(max) 526nm for 5 days. Beer's law is obeyed for vanadium in the concentration range 0.05-6.0MUgml(-1) (blue color derivative) and 0.06-7.0MUgml(-1) (pink color derivative), respectively. The optimum reaction conditions and other important analytical parameters were established. Interference due to various non-target ions was also investigated. The proposed methods were applied to the analysis of vanadium(V) in environmental, biological, pharmaceutical and steel samples. The performance of proposed method was evaluated in terms of Student's t-test and variance ratio F test that indicates the significance of proposed method over reported method. PMID- 21783788 TI - Cadmium-induced apoptosis in human normal liver L-02 cells by acting on mitochondria and regulating Ca(2+) signals. AB - Cadmium is a well-known toxic compound for the liver. It has been demonstrated to induce hepatotoxicity partly via apoptosis, but no uniform mechanism of apoptosis has so far been proposed. This study was first to determine whether cadmium induced apoptosis in L-02 cells, second to observe the mechanism of cadmium induced apoptosis. Studies of morphology, DNA fragmentation and apoptotic rate demonstrated that 60MUM cadmium induced apoptosis with strong effects on cell viability. A concomitant time-dependent decrease of Bcl-2 and mitochondrial transmembrane potential (DeltaPsi(m)) was observed. Subsequently, increase of caspase-3 activity and release of mitochondrial AIF were detected. However, cell pretreatment with a broad-specificity caspase inhibitor (Z-Asp) did not abolish apoptosis. These data demonstrated that the apoptotic events involved a mitochondria-mediated apoptotic pathway but not necessarily caspase-dependent signaling. On the other hand, intracellular free Ca(2+) concentration ([Ca(2+)](i)) of cadmium-exposed cells had significant increases and the Bapta AM, a well-known calcium chelator, pretreatment partially blocked cadmium-induced apoptosis, indicating that the elevation of [Ca(2+)](i) may play an important role in the apoptosis. Together, these results support the notion that cadmium induced hepatotoxicity is comparable to effects in L-02 by inducing apoptotic pathways on the basis of acting on mitochondria and regulating Ca(2+) signals. PMID- 21783789 TI - Selenium toxicokinetics after oral and intravenous administration in buffalo calves. AB - The blood levels, toxicokinetics and urinary excretion of selenium were investigated in healthy male buffalo calves after single oral and intravenous administration of selenourea at the dose rate of 0.75mg/kg (providing 0.48mg/kg selenium). The concentration of selenium in blood and urine was estimated spectrophotometrically. Following administration of the drug, the blood selenium disposition patterns exhibited two distinct peaks. The toxicokinetic parameters of selenium were determined by employing non-compartmental analysis. The values of AUC, t(1/2elm), Cl(B) and Vd(SS) were 18.46MUgml(-1)h, 10.33h, 20.04mlkg(-1)h( 1)and 0.3lkg(-1), respectively, after oral administration and 23.97MUgml(-1)h, 7.12h, 20.53mlkg(-1)h(-1) and 0.2lkg(-1), respectively, following intravenous injection of selenourea. The value of MRT was higher after oral dosing. The bioavailability of selenium, following oral administration of selenourea was 77%. Approximately, 22% of the total intravenous dose and 5.9% of total oral dose of selenium was excreted in urine within 24h of administration of selenourea. The data on blood Se levels may be of help in diagnosing the impeding selenium toxicosis and thus preventing mortality due to selenium toxicity. PMID- 21783790 TI - Production of M2000 (beta-d-mannuronic acid) and its therapeutic effect on experimental nephritis. AB - The present research introduces the method of Production of M2000 (beta-d mannuronic acid) and its therapeutic effect on experimental model of nephritis. M2000 was produced using enzymatic and chemical procedure on prepared alginate from Pseudomonas fluorescens. The experimental glomerulonephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of bovine serum albumin (BSA). M2000 solution (30mg/kg) was administered intraperitoneally at regular 48-h intervals for 4 weeks. Onset of treatment was day 56. Urinary protein was measured weekly and serum anti-BSA antibody was assessed by ELISA method at different intervals. Animals were killed on day 84 and blood samples and kidney specimens were obtained. Serum (creatinine, BUN, cholesterol, and triglyceride) and urine (protein, urea, and creatinine) determinants were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. The fibrosarcoma cell line was used for assaying tolerability and matrix metalloproteinase type 2 (MMP-2) activity. MMP-2 activity was assessed using zymography. Our data showed that M2000 therapy could significantly reduce the urinary protein excretion in treated rats versus non-treated controls. Anti-BSA antibody titer was lower in treated rats than in controls at the 12th experimental week. PMN infiltration and glomerular immune complex deposition was less intense in treated rats than in controls. Cytotoxicity analysis of M2000 showed a much higher tolerability compared with other tested drugs (diclofenac, piroxicam and dexamethasone). The inhibitory effect of M2000 in MMP-2 activity was significantly greater than that of dexsamethasone and of piroxicam at a concentration of 200MUg/ml. Moreover, the toxicological study revealed that M2000 had no influence on serum (BUN, creatinine, triglyceride and cholesterol) determinants, urinary protein excretion and glomerular histology in healthy group receiving drug. CONCLUSIONS: In this research, for the first time we introduced the procedure of production of M2000 (beta-d-mannuronic acid) and our data suggest that treatment with M2000, as a novel anti-inflammatory drug can reduce proteinuria, diminish antibody production and suppress the progression of disease in experimental model of glomerulonephritis. PMID- 21783791 TI - Verapamil abolished the enhancement of protein phosphorylation of brainstem mitochondria and synaptosomes from the hens dosed with tri-o-cresyl phosphate. AB - To explore the changes of the endogenous phosphorylation of brainstem mitochondrial and synaptosomal proteins in adult hens dosed with tri-o-cresyl phosphate (TOCP) following the development of organophosphate-induced delayed neurotoxicity (OPIDN). Verapamil (7mg/(kgday), i.m.) was given for 4 days. A dose of TOCP (750mg/kg, p.o.) was administrated in second day after verapamil. Phosphorylation of the proteins from brainstem mitochondria and synaptosomes was assayed in vitro by using [gamma-(32)P]ATP as phosphate donor. Radiolabeled proteins were separated by SDS-PAGE and visualized by autoradiography. The results showed that TOCP administration enhanced the phosphorylation of the cell organelle proteins (mitochondria: 60, 55, 45, and 20kDa; synaptosomes: 65, 60, and 20kDa), while verapamil abolished the enhancement induced by TOCP. Additionally, the reaction for the phosphorylation is catalyzed by the calcium/calmodulin protein kinase. Therefore, TOCP can enhance the phosphorylation of the brainstem mitochondrial and synaptosomal proteins from the hens with OPIDN; however, protection from the enhancement of the phosphorylation should be involved in the mechanisms of the amelioration of TOCP-induced delayed neurotoxicity by verapamil. PMID- 21783792 TI - The association of exposure to cadmium through cigarette smoke with pregnancy induced hypertension in a selenium deficient population. AB - Oxidative stress has been postulated as major contributor to endothelial dysfunction and pregnancy-induced hypertension. We have examined the association of exposure to cadmium through cigarette smoke with hypertension disorders during pregnancy in the selenium deficient population. Markers of lipid peroxidation and antioxidative defense were measured and correlated with cadmium blood concentration in normotensive and hypertensive pregnant smokers and nonsmokers. We have observed significantly higher blood Cd in hypertensive smokers and significant differences in all other parameters. Se concentrations were lower in smokers, both in normotensive and hypertensive group as well as values of nonenzymatic (Zn, Cu, and glutathione) and enzymatic (superoxide dismutase, glutathione peroxidase, and glutathione reductase) parameters of antioxidative defense. Results of the study indicate that exposure to cadmium through cigarette smoke in pregnant women, living in Se deficient areas is associated with significantly higher cadmium concentrations and lower levels of enzymatic and nonenzymatic antioxidants and that it can be considered as a risk factor for pregnancy-induced hypertension. Selenium supplementation should be considered for recommendation in such condition. PMID- 21783793 TI - Resveratrol (trans-3,4',5-trihydroxystilbene) decreases lipid peroxidation level and protects antioxidant capacity in sera and erythrocytes of old female Wistar rats induced by the kidney carcinogen potassium bromate. AB - Resveratrol is a natural polyphenolic compound and it is found in number of edible plants, especially grapes and peanuts, has been shown to have anti inflammatory, anti-oxidant, anti-tumor and anti-platelet activities. The aim of the study was to examine the effects of resveratrol on the level of malondialdehyde (MDA), homocysteine, cholesterol, GSH, GSSG and lipophylic vitamins in serum and erythrocytes of old female Wistar rats induced by the kidney carcinogen potassium bromate (KBrO(3)). In the study, total 30-old female Wistar rats were used, and the rats were randomly divided into three groups. The first group was used as a control, the second group KBrO(3) group, and third group R+KBrO(3). Rats in KBrO(3) and R+KBrO(3) groups were injected intraperitoneally a single dose KBrO(3) (80mg/kg) in physiologic saline buffer. After 2days, those in R+KBrO(3) group were intraperitoneally injected with resveratrol (33mg/kg) four times per week, and physiological saline was injected to control group rats. All the analysis was performed fully automatic with high performance liquid chromatography equipment. The results indicate that serum cholesterol level in the R+KBrO(3) group was higher than the control group (p<0.05), and level of the cholesterol in erythrocytes membranes was lower in the same group (p<0.01). The MDA level in serum and erythrocytes of the R+KBrO(3) were lower than the control and KBrO(3) groups (p<0.01). However, the MDA level in erythrocytes of the KBrO(3) group was high compared to the control group (p<0.05). Homocysteine and delta-tocopherol levels in serum of the R+KBrO(3) group were lower than the control group (p<0.05, p<0.001). alpha-Tocopherol level in serum and erythrocytes of the KBrO(3) group was lower than the control group (p<0.05), whereas its level was not found to differ between the control and R+KBrO(3) groups. GSH and GSSG levels in the KBrO(3) group of erythrocytes were higher than control group (p<0.05, p<0.01), however the ratio GSH/GSSG in the same group was lower than control group. In conclusion, our results confirm that the lipid peroxidation formation in serum and erythrocytes of old female Wistar rats by induced the KBrO(3) is prevented by the resveratrol. It was observed that the antioxidant capacity of erythrocytes was protected by resveratrol. PMID- 21783794 TI - Protective effect of caffeic acid phenethyl ester (CAPE) on fluoride-induced oxidative stress and apoptosis in rat endometrium. AB - High fluoride intake may affect biological systems by increasing free radicals, which may enhance lipid peroxidation levels of the tissues, thus leading to oxidative damage. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygen species mediated oxidative stress in ischemia-reperfusion and toxic injuries. Several studies suggest that supplementation with anti-oxidant can influence fluoride induced tissue damage. The aims of this study was to investigate the possible role of malondialdehyde (MDA) levels and activity of superoxide dismutase (SOD) and catalase (CAT), in the pathogenesis of fluoride-induced endometrial damage and to demonstrate the effect of CAPE, the potent antioxidant, in decreasing the toxicity. Twenty-four adult female rats were randomly divided into three experimental groups, as follows: control group, fluoride-treated group (F), and fluoride plus CAPE treated group (F+CAPE). Fluoride was given orally as 30mg/L NaF solution in spring water daily for 45 days. CAPE was co-administered intraperitoneally (i.p.) with a dose of 10MUM/(kgday) for 46 days. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the terminal deoxynucleotidyl transferase (TdT)-mediated d UTP-biotin nick and labeling (TUNEL) method. The activities of antioxidant enzymes such as SOD and CAT as well as the concentration of MDA, as an indicator of lipid peroxidation, were measured to evaluate oxidative stress in homogenates of the endometrium. Fluoride administration increased MDA levels (p<0.05), decreased SOD (p<0.05) and CAT (p<0.05) activities. CAPE co-administration with fluoride treatments caused significantly decreased MDA levels (p<0.05), increased SOD (p<0.05) and CAT (p<0.05) activities in endometrial tissue when compared with F alone. Diffuse apoptosis in glandular epithelium and stromal cells was found by TUNEL method in endometrial tissues of rats treated with fluoride. The severity of these lesions was reduced by administration of CAPE. In conclusion, our study demonstrated that MDA may play an important role in the pathogenesis of fluoride-induced oxidative endometrial damage. CAPE may have protective aspects in this process by its antioxidant and anti-inflammatory effect. PMID- 21783795 TI - Small doses of mercury increase arterial pressure reactivity to phenylephrine in rats. AB - Mercury reduces cardiac contractility and arterial pressure at micromolar concentrations. We investigated the actions of 680ng/kg HgCl(2) on arterial pressure, heart rate (HR) and on the pressor reactivity to phenylephrine (PHE) in rats before and 1h after HgCl(2) administration and after hexametonium, verapamil and tempol treatments. HgCl(2) increased baseline systolic (SAP) and diastolic pressure (DAP) and HR, sensitivity (pD(2)) and maximal response (E(max)) to PHE pressor reactivity. Hexametonium and verapamil reduced baseline pressures and HR that increased after HgCl(2) treatment. Hexametonium did not change pD(2) or E(max) to PHE but verapamil reduced them. These parameters increased after HgCl(2) administration. Tempol did not alter baseline pressures, HR or PHE reactivity before and after HgCl(2). Results suggest that HgCl(2) increases SAP, DAP, HR and PHE reactivity; autonomic reflexes reduces HgCl(2) action; baseline pressure level do not interfere on HgCl(2) pressor effects but free radicals seems to be involved. PMID- 21783796 TI - Modulatory effects of curcumin on gamma-radiation-induced cellular damage in primary culture of isolated rat hepatocytes. AB - Ionizing radiation is known to induce oxidative stress through generation of reactive oxygen species (ROS) resulting in imbalance of the pro-oxidant and antioxidant in the cells, which is suggested to culminate in cell death. The present work was aimed to evaluate the radioprotective effect of curcumin, a yellow pigment of turmeric on gamma-radiation-induced toxicity in primary cultures of isolated rat hepatocytes. Hepatocytes were isolated from the liver of rats by collagenase perfusion. The cellular changes were estimated using lipid peroxidative indices like thiobarbituric acid reactive substances (TBARS), the antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH), ceruloplasmin, vitamins A, E and C and uric acid. The comet assay is a sensitive and rapid technique for quantifying and analyzing DNA damage in individual cells was exposed under gamma-radiation. The increase in the severity of DNA damage was observed with the increase dose (1, 2 and 4Gy) of gamma-radiation in cultured hepatocytes. TBARS were increased significantly, whereas the levels of GSH, vitamins C, E and A, ceruloplasmin, uric acid and antioxidant enzymes were significantly decreased in gamma irradiated hepatocytes. The maximum damage to hepatocytes was observed at 4Gy irradiation. On pretreatment with curcumin (1, 5 and 10MUg/ml) showed a significant decrease in the levels of TBARS and DNA damage. The antioxidant enzymes were increased significantly along with the levels of GSH, vitamins A, E and C, uric acid and ceruloplamin. The maximum protection of hepatocytes was observed at 10MUg/ml of curcumin pretreatment. Thus, pretreatment with curcumin helps in protecting the hepatocytes against gamma-radiation-induced cellular damage and can be developed as an effective radioprotector during radiotherapy in near future. PMID- 21783797 TI - Examination of lung toxicity, oxidant/antioxidant status and effect of erdosteine in rats kept in coal mine ambience. AB - Occupational exposure to coal dust causes pneumoconiosis and other diseases. Reactive oxygen species (ROS) have been implicated in the pathogenesis of coal dust-induced lung toxicity. In this experimental study, we investigated the oxidant/antioxidant status, nitric oxide (NO) and hydroxyproline (HP) levels in lungs and blood of rats exposed to coal dust in mine ambience. In addition, we also investigated the attenuating effects of erdosteine. At the end of the experiment processes, tissue levels of HP, malondialdehyde (MDA) and NO, as well as the activities of superoxide dismutase, glutathione peroxidase, catalase, xanthine oxidase (XO), myeloperoxidase (MPO) and proinflammatory cytokines (IL-6 and TNF-alpha) were evaluated in the lung tissues, plasma samples or erythrocytes of rats. Exposure to coal dust resulted in a significant increase in the oxidant parameters (MDA, NO levels, and XO activity) and HP levels, as compared to the controls. A decrease in activities of antioxidant enzymes, and an increase in MPO activity were found in the study group, compared to the controls. Increased NO levels of lung were found in the study groups, that were significantly reduced by erdosteine. Our studies provide evidence that supports the hypothesis for ROS mediated coal workers' pneumoconiosis. Erdosteine may be beneficial in the coal dust-induced lung toxicity via antioxidant and free radical scavenger properties. PMID- 21783798 TI - Development of a yeast-based assay to determine the (anti)androgenic contaminants from pulp and paper mill effluents in India. AB - We have constructed an efficient and reliable yeast-based detection system to evaluate the androgenic activity of endocrine disruptors from pulp and paper mill effluents (PPME). This system consists of human androgen receptor and androgen response elements driven beta-galactosidase genes transformed in yeast, Saccharomyces cerevisiae. The transcriptional activation by known androgens, correlated with androgenic activities as measured by other assay systems. This assay system when applied to evaluate anti-androgenic activities, the known anti androgens effectively inhibited reporter gene induction by testosterone. The specificity of the assay was tested by incubating the transformed cells with supraphysiological concentrations of non-androgenic steroids and none of them gave a significant response. The extracted PPME from five different mills demonstrated strong androgenic activities (about five- to eight-folds over control). These results suggest that PPME are rich in androgenic chemicals and the employed detection system could be applicable to primary screening for effectors on androgen receptor functions. PMID- 21783799 TI - Different effects of Pb(2+) and Cu(2+) on immune and antioxidant enzyme activities in the mantle of Pinctada fucata. AB - The aim of this study was to investigate the natural role of the mantle in pearl oyster, Pinctada fucata. The mantle is believed to be the tissue responsible for shell and pearl formation. However, our current study on lead and copper accumulation in tissues of the oyster showed that the secondary tissue for lead accumulation was not the digestive gland but the mantle. In view of high lead concentrations in the mantle, its general metabolic condition (including immune and antioxidant defense systems) as affected by the two metals was studied. The results indicated that activities of antioxidant enzymes (superoxide dismutase, SOD; Se-dependent glutathione peroxidase, Se-GPx) were altered by lead and copper in the similar way. However, the immune enzyme activities (acid phosphatase, AcPase; phenoloxidase, PO) were perturbed differently by two metals. Therefore, the mantle of P. fucata was predicted to participate in immune processes and accumulation or detoxification of lead besides shell formation. Our observations described here may also provide important clues to further understanding of the biomarker responses of bivalves. PMID- 21783800 TI - Proteomic investigation of 1,6-dimethoxyhexane testicular toxicity. AB - The aliphatic ether 1,6-dimethoxyhexane (DMH) was previously identified as a testicular toxicant. Testis protein extracts from control and DMH-treated rats were subjected to two-dimensional gel electrophoresis for comparison of protein expression profiles. MALDI-ToF peptide mass fingerprinting of differentially expressed proteins resulted in the conclusive identification of heat shock related 70kDa protein 2 (HSP70.2), 60kDa heat shock protein, mitochondrial precursor (HSP60) and protein disulfide isomerase A3 precursor (ERp60). The potential involvement of these proteins in chemically induced perturbation of spermatogenesis and their utility as biomarkers of testicular toxicity are discussed in light of the knowledge currently available from the literature. PMID- 21783801 TI - Biliary excretion and cerebrospinal fluid partition of perfluorooctanoate and perfluorooctane sulfonate in humans. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are detected in the environment and, more specifically, in wildlife and humans. The large variation in the reported biological half-lives for PFOA and PFOS has remained unexplored. In this study, we aimed to evaluate their partition from serum to bile and cerebrospinal fluid (CSF) in humans. Four pairs of serum and bile, and 7 pairs of serum and CSF were donated by patients. In considering biliary excretion, the median concentrations of PFOA and PFOS in serum samples were 3.8 and 23.2ng/mL, respectively, whereas those in bile samples were 1.0 and 27.9ng/mL, respectively. The median ratio of PFOS concentrations (bile/serum: 0.60) was significantly higher than that for PFOA, 0.21 (p<0.01). Biliary excretion rates for PFOA and PFOS in the present study subjects were estimated as 1.06 and 2.98mL/kg/day, respectively, which is significantly higher than serum clearances via urine in humans and might represent a major excretion route. Biliary reabsorption rates of PFOA and PFOS were estimated to be 0.89 and 0.97, respectively. In considering partition into the cerebrospinal fluid, the median concentrations of PFOA and PFOS in serum samples were 2.6 and 18.4ng/mL, respectively, whereas those in CSF samples were 0.06 and 0.10ng/mL, respectively. The median ratio of PFOS concentrations (CSF/serum: 9.1 (*10(-3))) was comparable to that of PFOA, 17.6 (*10(-3)), suggesting that PFOA and PFOS cannot pass through the blood-brain barrier freely. In conclusion, the biliary excretion of these compounds was comparable in both rats and humans and the long half-lives in humans might be attributable to low levels of excretion in urine and high biliary reabsorption rates. PMID- 21783802 TI - Protective effects of green tea polyphenols against subacute hepatotoxicity induced by microcystin-LR in mice. AB - Green tea polyphenols (GTP) have been shown to possess anti-oxidative, anti mutagenic and anti-carcinogenic activities. The present study aimed to evaluate the chemopreventive efficacy of GTP against subacute hepatotoxicity induced by microcystin-LR (MC-LR) in mice and also elucidates the underlying mechanisms. In this study, healthy Kunming male mice (24-26gbw) were randomly assigned to five groups. Group I was fed on normal diet and water ad libitum as control. Group II was maintained on normal diet and received MC-LR intraperitoneal injection (10MUg/kg/day) from day 6 till sacrifice. Mice in groups III, IV and V were daily pre-treated with GTP through intragastric administration at doses of 50, 100 and 200mg/kg/day from day 0 prior to MC-LR intoxication, consecutively 18 days. The results showed MC-LR alone led to oxidative stress and to damage antioxidant defense system, as evidenced by elevation of serum and liver lipid peroxidation. Additionally, hepatocellular apoptosis and injury were significantly observed. GTP pre-treatment caused a significant elevation in serum antioxidant enzymes GSH and SOD activities as well as a decrease in hepatic lipid peroxidation MDA level and serum ALT, AST, ALP activities. GTP pre-treatment obviously inhibited hepatocellular apoptosis and up-regulated Bcl-2 protein expression. The damages in liver were less severe in GTP pre-treated mice in correlation with the biochemical parameters. In summary, this study confirmed that repeated exposure to MC-LR could induce hepatotoxicity. Our study demonstrated that GTP can reduce MC-LR-induced oxidant stress and prevent biochemical parameters and pathological changes caused by MC-LR in a dose-dependent manner. The results indicated that tea polyphenols have a potential to be developed as a preventive agent against MC LR-induced toxicity and the mechanism involved in the protection could be due to their antioxidant activities. PMID- 21783803 TI - Effects of butyltin compounds on follicular steroidogenesis in the bullfrog(Rana catesbeiana). AB - The effects of butyltin compounds on follicular steroidogenesis in amphibians were examined using ovarian follicles of Rana catesbeiana. Isolated follicles were cultured for 18h in the presence and absence of frog pituitary homogenate (FPH) or various steroid precursors, and the steroid levels in the follicles or culture media were measured by radioimmunoassay (RIA). Among the butyltin compounds, tributyltin (TBT) strongly inhibited the FPH-induced synthesis of pregnenolone (P(5)), progesterone (P(4)) and testosterone (T). It also inhibited the conversion of P(5)-P(4) and T to estradiol-17beta(E(2)) and it partially suppressed the conversion of androstenedione (AD) to T, but not P(4) to 17alpha hydroxyprogesterone (17alpha-OHP(4)). A high concentration of dibutyltin (DBT) also inhibited steroidogenesis by the follicles while monobutyltin (MBT) and tetrabutylin (TeBT) had no effect. These results suggest that the initial step of steroidogenesis (P(5) synthesis) and enzymes such as 3beta-HSD, 17beta-HSD and aromatase are inhibited by TBT or DBT. However, 17alpha-hydroxylase was not suppressed by TBT or the other butyltin compounds. PMID- 21783804 TI - Vitellogenic responses of 17beta-estradiol and bisphenol A in male Chinese loach (Misgurnus anguillicaudatus). AB - In this study, male Chinese loaches were exposed to 17beta-estradiol (E2), bisphenol A (BPA) and their mixtures, respectively, for 42 days using a semi static exposure system. Plasma vitellogenin (Vtg) in male Chinese loaches was used as the determining endpoint. The results demonstrated that male Chinese loaches were sensitive to E2, and the vitellogenic responses showed time- and dose-dependent increase. Similarly, BPA induced the estrogenic effects in male Chinese loaches, and the vitellogenic response increased in a time- and dose dependent manner. The synthesis of Vtg was initiated by the exposure to higher level of BPA (500MUg/L) within 7 days, and a relative long-term exposure to lower concentrations of BPA (10-100MUg/L) also led to the production of Vtg. The estrogenic effect of the binary mixture of E2 and BPA also showed a time- and dose-dependent response, which was more potent than that of individual compounds, and Vtg contents in the binary mixture group were higher than the summation of Vtg contents in the single-compound groups at the same concentration. PMID- 21783805 TI - Effect of curcumin on chromium-induced oxidative damage in male reproductive system. AB - Hexavalent chromium, an environmental contaminant, undergoes redox cycling with generation of free radicals inside the biological system. Curcumin, the yellow bioactive component of turmeric has established its antioxidant activities. The present study evaluates possible ameliorating effects of curcumin on potassium dichromate (K(2)Cr(2)O(7)) (hexavalent chromium) induced reproductive toxicity in adult male Sprague-Dawley rats. Three experimental groups, each consisting of eight rats, were treated with 0.4mg K(2)Cr(2)O(7)/kg bw/day, 0.4mg K(2)Cr(2)O(7)/kg bw/day+20mg curcumin/kg bw on every alternate day and 20mg curcumin/kg bw on every alternate day, respectively, for 26 days. Altered testicular histology, reduced sperm count, low testosterone level, decreased accessory sex organs weight, enhanced lipid peroxidation along with reduced SOD and catalase activities were observed following K(2)Cr(2)O(7) exposure while curcumin supplementation along with K(2)Cr(2)O(7) exposure had shown to prevent the altered parameters. The results thus suggest that curcumin may have a protective role against chromium(VI) induced oxidative damage in male reproductive system. PMID- 21783806 TI - Protective effect of U-74389G on paraquat induced pneumotoxicity in rats. AB - Paraquat is a very toxic herbicide and a dangerous pollutant of the environment. It forms reactive oxygen species and increases the lipid peroxidation in the pulmonary cells. Our aim in this study was to estimate the protective effects of the lazaroid U-74389G possessing antilipidperoxidation activity and membrane stabilizing effect. The experiment was carried out with 96 male Wistar rats. Paraquat dichloride was administered orally at 80mg/kg. The lazaroid U-74389G was injected intraperitoneally twice - 2h before receiving the paraquat with 10mg/kg and four hours later with 5mg/kg. Isolated application of paraquat increased enzyme activities of lactate dehydrogenase (LDH) and acid phosphatase (AcP) and the total protein content in bronchoalveolar lavage fluid (BALF). In the same experimental group the number of polymorphonuclear cells (PMNs) in BALF is elevated significantly on days 1 and 3. The combined treatment with paraquat and U-74389G did not increase the total protein content and the number of PMNs and it elevated the enzyme activities of LDH and AcP significantly less than the alone application of paraquat. It is concluded that the lazaroid U-74389G reduces the pneumotoxic effects of paraquat, estimated by sensitive cytologic and biochemical markers in BALF. The protective effect of U-74389G is well-expressed until day 3 after the treatment. PMID- 21783807 TI - Formaldehyde exposure induces airway inflammation by increasing eosinophil infiltrations through the regulation of reactive oxygen species production. AB - Formaldehyde (FA) is a well-known cytotoxic irritant to the airways, but the mechanism of airway inflammation due to FA has not been clarified. In the present study, C57BL/6 mice were exposed to two concentrations (5 and 10ppm) of FA for 6h/day, 5days/week, for 2 weeks. The FA-exposed mice had much higher number of CCR3(+) eosinophils than control mice, and showed upregulated gene expression of CC-chemokine receptor-3 (CCR3), eotaxin and intercellular adhesion molecules-1 (ICAM-1) as well as an increased expression of proinflammatory and Th2 cytokines, such as interleukin (IL)-1beta, IL-4 and IL-5. In addition, FA exposure revealed a considerable increase in the serum levels of IgG1, IgG3, IgA and IgE compared to controls. Histopathological analysis of the lung tissues demonstrated eosinophils and mononuclear cell infiltration of the alveolar cell walls and alveolar spaces. Gene expression of thioredoxin (TRX), redox-regulating antioxidant proteins, was markedly suppressed in FA-exposed mice, and thereby intracellular ROS levels were increased along with increased FA concentration. These results were consistent with an increase in the number of CCR3-expressing eosinophils, and indicate that FA-induced ROS was generated from eosinophils recruited to the inflammatory sites of the airways. PMID- 21783808 TI - Erythrocyte acetylcholinesterase activity as a surrogate indicator of lead induced neurotoxicity in occupational lead exposure in Abeokuta, Nigeria. AB - Dose-effect and dose-response relationships in occupational neurotoxicology are rarely studied by means of biochemical methods. In order to investigate the potential neurotoxic effects of lead during occupational exposure to this metal, the activity of erythrocyte acetylcholinesterase (AcChE), as well as blood pressure and pulse, were determined in various artisans in Abeokuta, Nigeria, who have been shown to be occupationally exposed to lead, and these were related to blood lead levels. AcChE activity in the artisans was inhibited to varying extents. While AcChE activity was inhibited to the tune of 39% in the male petrol station attendants, the inhibition amounted to 32% in female petrol station attendants. In other artisans, AcChE inhibition ranged from 31% in the welders to 38% in painters. The lowest inhibition of 15% was obtained in the panel beaters. Correlations, as calculated by Pearson's method, revealed a significant (p<0.001) inverse linear relationship between AcChE activity and blood lead levels (r= 0.40; y=-120.38x+13935.59; p<0.001). Blood pressure and pulse were not significantly different between control and lead-exposed subjects. Our findings suggest that erythrocyte AcChE activity could be used as a biomarker of lead induced neurotoxicity in occupationally exposed subjects. PMID- 21783809 TI - Growth-promoting effect of environmental endocrine disruptors on human neuroblastoma SK-N-SH cells. AB - Bisphenol A (BPA), a monomer component of polycarbonate plastics and epoxy resins, is widely used in many consumer products. Zearalenone (ZEA), a non steroidal estrogenic mycotoxin, is present in high concentrations in dairy products and cereals. Numerous researches describe a possible correlation between environmental endocrine disruptors and human tumors, but only a few papers concerned solid tumors in childhood. We investigated the effects of BPA and ZEA on the proliferation in the human neuroblastoma SK-N-SH cell line. Cell counting kit-8 and flow cytometric analysis were used to determine whether BPA and ZEA promote cell proliferation. The results indicated that BPA and ZEA-mediated increase in cell proliferation is significant (p<0.05). To explore the possible underlying mechanism, additive effect of the estrogen receptor antagonist ICI182780 or insulin-like growth factor I (IGF-I) was observed. ICI182780 could inhibit these proliferative effects of BPA and ZEA. However, no synergistic or additive growth-promoting effect was noted when IGF-1 was added. These results suggested that BPA and ZEA can promote the proliferation of SK-N-SH cells, and the estrogen receptor pathway may be involved in this effect. PMID- 21783810 TI - Short-term in vivo exposure to the water contaminant triclosan: Evidence for disruption of thyroxine. AB - Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. The structural similarity of triclosan to thyroid hormones and recent studies demonstrating activation of the human pregnane X receptor (PXR) and inhibition of diiodothyronine (T(2)) sulfotransferases, have raised concerns about adverse effects on thyroid homeostasis. The current research tested the hypothesis that triclosan alters circulating concentrations of thyroxine. The hypothesis was tested using a 4-day oral triclosan exposure (0 1000mg/kg/day) in weanling female Long-Evans rats, followed by measurement of circulating levels of serum total thyroxine (T(4)). Dose-dependent decreases in total T(4) were observed. The benchmark dose (BMD) and lower bound on the BMD (BMDL) for the effects on T(4) were 69.7 and 35.6mg/kg/day, respectively. These data demonstrate that triclosan disrupts thyroid hormone homeostasis in rats. PMID- 21783811 TI - Vasorelaxation by Samhwangsasim-tang, an herb medicine, is associated with decreased phosphorylation of the myosin phosphatase target subunit. AB - Samhwangsasim-tang (SST) is a widely used herbal medicine with vasodilatory actions in oriental countries. We hypothesized that SST modulates vascular contractility by decreasing phosphorylation of the myosin phosphatase target subunit. Rat aortic ring preparations were mounted in organ baths and subjected to contractions or relaxations. Phosphorylation of 20kDa myosin light chains (MLC(20)) and MYPT1, a target subunit of myosin phosphate 1, were examined with immunoblots. SST relaxed aortic ring preparations precontracted with phenylephrine whether endothelium was intact or denuded. Treatment of aortic rings with N(omega)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of endothelial nitric oxide synthase or methylene blue, an inhibitor of guanylyl cyclase, did not affect the relaxing action of SST. Furthermore, SST inhibited vascular contractions induced by NaF or phenylephrine, but not by phorbol dibutyrate. SST also decreased vascular tension precontracted by 8.0mmol/L NaF or 1.0MUmol/L phenylephrine, but not by 1.0MUmol/L phorbol dibutyrate. In vascular strips, SST decreased the phosphorylation level of both MLC(20) and MYPT1 induced by 8.0mmol/L NaF. In conclusion, SST inhibited vascular contraction by decreasing phosphorylation of the myosin phosphatase target subunit. PMID- 21783812 TI - Metabolism, tissue distribution, and pharmacokinetics of N-methyl-N-2,4,6 tetranitroaniline (tetryl). AB - Tetryl (N-methyl-N,2,4,6-tetranitroaniline) is a booster explosive that was used in the production of detonators and blasting caps. It is an environmental contaminant that is found in detectable levels in areas associated with its production, use, storage, and disposal. Preliminary microsomal assays showed that one major metabolite was formed under anaerobic and aerobic conditions with both NADH and NADPH as cofactors. Metabolite formation was not inhibited by carbon monoxide but did not form in the absence of cofactor or with heat-killed microsomes. The major metabolite was identified as N-methyl-2,4,6-trinitroaniline (NMPA) by IR spectroscopy, (1)H and (14)C NMR, and chemical ionization/MS. Kinetic parameters of NMPA formation in the microsomal fraction were determined using Lineweaver-Burke plots. A V(max) of 448nmoles/(minmg) of protein and K(m) of 1.25mM was determined when NAD+ was the cofactor. When NADP+ was the cofactor, a V(max) of 139nmoles/(minmg) of protein and a K(m) of 1.4mM was determined. In the microsomal fraction, inhibition studies revealed that NMPA formation was slightly inhibited (10%) by 2'-AMP (2mM) when NADP+, but not NAD+, was used as a cofactor. This suggests that NMPA formation is partially dependent on cytochrome P450 reductase. NMPA formation was also inhibited by dicumarol (2mM) when NADP+ (14%) and NAD+ (84%) (14%) were cofactors, suggesting that NAD(P)H: quinone oxidoreductase catalyzes NMPA formation in the microsomes. A nonspecific flavoprotein inhibitor, DPI, inhibited NMPA formation (91%) using NADP+ as a cofactor, but not NAD+. Other inhibitors, miconazole (cytochrome-P450), methimazole (flavin monooxygenase), and propylthiouracil (NADH: b5 reductase), did not prevent NMPA formation in the microsomal fraction. PMID- 21783813 TI - Acute intoxication of deltamethrin in monosex Nile tilapia, Oreochromis niloticus with special reference to the clinical, biochemical and haematological effects. AB - Deltamethrin, a synthetic pyrethroid pesticide, potential toxic pollutant and significant direct risk to the aquatic ecosystems, was investigated in the present study for its toxic impact on adult monosex Nile tilapia on the basis of acute static bioassay test, and comparison of clinical, biochemical and haemato logical examinations with deltamethrin-free control group. The 96hLC(50) value of deltamethrin for monosex tilapia was 14.6MUg/L. The abnormal behavioral responses and toxic symptoms were described. Fish exposed to the higher deltamethrin concentration (15MUg/L) for 96h showed significantly higher lymphocytes, total leucocytic and erythrocytic counts, haemoglobin percentage and packed cell volume content and significantly lower neutrophils compared to the control group. Deltamethrin caused adverse effects in the form of hypoproteinemia, hypoalbuminemia, hypercholesterolemia, hypoglycemia and significant increase of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities. The results provide evidence that deltamethrin pollution may have adverse impacts and was highly toxic to monosex tilapia. PMID- 21783814 TI - Inhibitory effect of Uncaria sinensis on human aortic smooth muscle cell migration is based on matrix metalloproteinase-9 inhibitory activity. AB - Medicinal extracts of Cho-Deung-san and Uncaria sinensis Havil. (UR) have previously been shown to have inhibitory effects on migration of vascular smooth muscle cells (VSMC) and matrix metalloproteinase (MMP)-2/9 production, which play key roles in the development of atherosclerosis. In this study, we have more extensively investigated the inhibitory effect of UR on MMP-9 activity and TNF alpha induced human aortic smooth muscle cells (HASMC) migration. The result from gelatin zymography showed that UR inhibited MMP-9 activity in a dose-dependent manner (IC(50)=55MUg/ml). In addition, UR strongly inhibited the migration of HASMC induced by TNF-alpha treatment (IC(50)=125MUg/ml), although it has very low cytotoxic effect on HASMC (IC(50)>500MUg/ml). These results suggest that UR is a potential anti-atherosclerotic agent through inhibition of MMP-9 activity and VSMC migration. PMID- 21783815 TI - The phenotypic and behavioral defects can be transferred from zinc-exposed nematodes to their progeny. AB - In despite of the essential functions of zinc as trace element for humans, toxic effects will be pronounced while organisms are exposed to high levels of zinc. However, whether the multiple biological toxicities caused by zinc exposure could be transferred to progeny is still largely unknown. In the present study, we explored the model organism, Caenorhabditis elegans, to analyze the multiple toxicities from zinc exposure and their possibly transferable properties. Our results indicate that the zinc exposure could result in multiple biological defects by affecting the endpoints of life span, development, reproduction, locomotion behavior and chemotaxis plasticity. Zinc exposure could specially cause the appearance of uncoordinated (UNC) animals. In addition, Zn exposure could result in the stress responses in most of the tissues in exposed nematodes. Moreover, these phenotypic and behavioral toxicities could be transferred from zinc-exposed nematodes to their progeny. The fold changes of hsp16-2-gfp expression in embryos of progeny animals suggest that the zinc toxicity might be deposited in eggs of nematodes. We summarized these defects into two groups according to their transferable properties. Therefore, our data suggest that zinc exposure can result in multiple toxicities and these multiple biological defects can be largely transferred to progeny in C. elegans. PMID- 21783816 TI - Cadmium-induced apoptosis of hepatocytes is not associated with death receptor related caspase-dependent pathways in the rat. AB - Cadmium (Cd) is a heavy metal of considerable environmental and occupational concern. The liver is the major target organ of Cd toxicity that follows from repeated exposure to Cd. The aim of this study was to investigate the mechanism of cell death of Cd-induced hepatotoxicity in a rat model. Eighteen adult male Sprague-Dawley (SD) rats were injected daily with a dose of Cd acetate (30MUM/kg body weight, subcutaneously). After 1, 2 and 7 days rats were euthanized and blood and liver tissues were sampled for analysis. Biochemical analyses of the level of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were undertaken. Histopathological and Western blot analyses for liver cellular damage and cell death were also performed. The results for the Cd treated group of animals were compared to those from 12 control rats. The serum AST/ALT levels increased significantly 24h after CD exposure. From the Western blot analyses, activation of Bid, independent of caspase-8 was seen and Bax induced the release of cytochrome c into the cytosol from mitochondria in a dose dependent manner. The level of Bcl-2 was decreased. Eventually, caspase-9 and caspase-3 were activated, and poly(ADP-ribose) polymerase (PARP) was cleaved in a dose-dependent manner. A histopathological analysis and DNA fragmentation test showed apoptotic cell death of the hepatocytes increased over time. These results suggest that Cd-induced liver cell apoptosis in the rat, over a period of 7 days, may not be related to the death-receptor pathway. Moreover, apoptosis is dose dependent and associated with the decrement of Bcl-2. PMID- 21783817 TI - Comparative study on the acute pulmonary toxicity induced by 3 and 20nm TiO(2) primary particles in mice. AB - The acute pulmonary toxicity induced by 3-nm TiO(2) primary particles was preliminary investigated after they were intratracheally instilled at doses of 0.4, 4 and 40mg/kg into lungs of mice. The biochemical parameters in bronchoalveolar lavage fluid (BALF) and pathological examination were used as endpoints to assess their pulmonary toxicity at 3-day postexposure. As such, the pulmonary toxicity assessment of 20-nm TiO(2) primary particles was performed using the same method. It was found that the 3-nm TiO(2) primary particles induced no pulmonary toxicity at dose of 0.4mg/kg, moderate toxicity at 4mg/kg and lung overload at 40mg/kg, and this kind of particles did not produce more pulmonary toxicity than the 20-nm ones at any instilled doses. As regards physicochemical characteristics of the two TiO(2) particles, their pH values in medium, other than particle size, surface area and aggregation, may play important role in affecting their pulmonary toxicity. PMID- 21783818 TI - Exposure and recovery response of isomers of HCH, metabolites of DDT and estradiol-17beta in the female catfish, Heteropneustes fossilis. AB - Effects of 40 days of exposure and 20 days of recovery response at sublethal concentration of technical grades of gamma isomer of hexachlorocyclohexane (gamma HCH, 0.025ppm, 99.8%) and dichlorodiphenyltrichloroethane (DDT, 5.0ppm) in tissue (liver, brain and ovary) bioconcentrations, gonadosomatic index (GSI) and plasma levels of estradiol-17beta (E2) have been estimated during prespawning phase in the catfish Heteropneustes fossilis (Bloch). The results indicated that the tissue bioconcentrations of both HCHs (HCH isomers) and DDTs (metabolites of DDT) in liver, brain and ovary were in preferential order (liver>brain>ovary). The GSI and plasma levels of E2 were declined in response to exposure of gamma-HCH and DDT. On withdrawal of exposure of pesticide there was recovery of HCHs in exposed fish for all tissues studied, whereas DDTs exposed fish showed recovery only in liver. Recovery of E2 production was also recorded in gamma-HCH exposed fish whereas very little recorded in DDT exposed fish. It is suggested that HCHs and DDTs have preferential order (liver>brain>ovary) of their tissue bioconcentrations and HCH/DDT-withdrawal-dependent recovery during studied phase. PMID- 21783819 TI - Phosphorylation of Stats at Ser727 in renal proximal tubular epithelial cells exposed to cadmium. AB - The effects of cadmium exposure on serine phosphorylation of signal transducers and activators of transcription (Stats) and an upstream kinase were examined in renal proximal tubular cells. In porcine LLC-PK1 cells treated with cadmium, Stat1 and Stat3 proteins were phosphorylated at Ser727 without changing total Stat protein levels. While phosphorylated forms of the members of mitogen activated protein kinases (MAPKs) increased in response to cadmium exposure, treatment with a p38 inhibitor, SB203580 reduced Ser727 phosphorylation of Stat1 and Stat3 markedly in LLC-PK1 cells. The expression of human matrix metalloproteinase-3 (MMP-3), a Stats-inducible gene, was found to be up-regulated in human HK-2 cells exposed to cadmium, and suppressed by preincubation with SB203580. These results suggest that cadmium might induce the phosphorylation of Stat1 and Stat3 at Ser727 via the p38 pathway at least in part, and modulate gene expression in these proximal tubular cells. PMID- 21783820 TI - Validating the domestic fowl as a model to investigate the pathophysiology of diclofenac in Gyps vultures. AB - Diclofenac has recently been identified as a cause of the widespread vulture decline on the Indian subcontinent. Although the clinical signs and pathology have been described, the pathophysiology of toxicity remains unexplained. In the following study we attempt to validate the domestic fowl as a model, to allow for the further characterisation of diclofenac's mechanism of toxicity. In a lethal dose study, diclofenac was shown to have an approximate intramuscular LD(50) of 9.8mg/kg in 18-week old layers. Signs of toxicity in the affected birds were severe depression that persisted from 24h post-dosing to death with corresponding increased plasma uric acid concentrations. Post-mortem examinations showed signs of gout with deposits of urates (tophi) in the kidneys, liver, heart and spleen. The pharmacokinetics after both the intramuscular and oral route showed that diclofenac had a short half-life of elimination of approximately 1h, a volume of distribution of 0.09-0.24l/kg and relative oral bioavailability of 50% compared to intramuscular administration. With the similarity in the clinical signs, necropsy findings, histopatological lesions and clinical pathological changes, the fowl may be used in further studies to characterise the mechanism of toxicity of diclofenac. However, due to the large difference in susceptibility of the fowl, it is not a suitable model to simulate the dose-response relationship of the vulture to the other non-steroidal anti-inflammatory drugs. PMID- 21783821 TI - Variations in bioconcentration of human pharmaceuticals from sewage effluents into fish blood plasma. AB - The "Fish Plasma Model" has been proposed for prioritizing pharmaceuticals for in depth environmental risk assessment efforts. The model compares estimated drug concentrations in fish plasma with human therapeutic plasma concentrations in order to assess the risk for a pharmacological interaction in the fish. In this study the equation used to estimate bioconcentration from water to fish blood plasma was field-tested by exposing rainbow trout in situ to sewage effluents from three treatment plants. Measured plasma levels of diclofenac, naproxen, ketoprofen and gemfibrozil were similar or lower than those modelled, which is acceptable for an early tier. However, measured levels of ibuprofen were >200 times higher than modelled for the largest plant (Gryaab Goteborg). Comparing measured fish plasma concentrations to the human therapeutic concentrations ranked the relative risks from the pharmaceuticals. Diclofenac and gemfibrozil, followed by ibuprofen, presented the highest risk for target interactions, whereas naproxen and ketoprofen presented little risk. Remarkably, measured bioconcentration factors varied considerably between sites. This variation could not be attributed to differences in water concentrations, temperatures, pH or exposure times, thereby suggesting that chemical characteristics of effluents and/or recipient waters strongly affected the uptake/bioconcentration of the pharmaceuticals. PMID- 21783822 TI - Immunoassays for avian butyrylcholinesterase: Implications for ecotoxicological testing and clinical biomonitoring. AB - Limitations of using the cholinesterases as biomarkers for assessing organophosphate (OP) pesticides impact on avian wildlife are a matter of concern for both toxicologists and environmentalists. One limitation appears to be the assumption of proportionality between enzyme activity and enzyme protein content. However, this proportionality does not hold during exposure to OP pesticides which can cause changes in both factors. Therefore, RIA and ELISA were developed to investigate the relationship between BChE enzyme mass and activity during exposure to OP pesticides in birds. The sensitivity of RIA was 0.60ng protein/ml and of the competitive ELISA was 0.15ng protein/ml. A third enzyme-antigen immunoassay (EAIA) for measuring BChE catalytic activity was also developed to increase the specificity of cholinesterase assays by immunoprecipitation. Results also showed that although exposure of birds to malathion produced 47% (+/-6%) decrease in serum BChE activity, this inhibition was associated with a statistically significant (p<0.0001) increase in immunoreactive concentration of BChE in all exposed birds. The increased BChE concentration observed in the present study while its activity continued to be inhibited will diminish the apparent overall inhibition of the enzyme. Hence, the degree of exposure to OP pesticides will be underestimated if enzyme activity is the only biomarker used. There is now a case for measuring the "actual" specific activities of serum esterases as a rational diagnostic tool. This approach requires the simultaneous measurement of enzyme mass and enzyme activity. PMID- 21783823 TI - Histopathology of lambda-cyhalothrin on tissues (gill, kidney, liver and intestine) of Cirrhinus mrigala. AB - The histopathology of lambda-cyhalothrin, a synthetic pyrethroid pesticide, on the gill, liver, intestine and kidney tissues in fish, mrigal (Cirrhinus mrigala), which is one of Indian major carp species were determined by light microscopy. The fish were experimentally exposed to sub-lethal concentrations (0.3ppb and 0.6ppb) of lambda-cyhalothrin for 10 days. Tissues were normal in the control group. Epithelial hyperplasia, aneurism, epithelial necrosis, desquamation, epithelial lifting, oedema, shortening of secondary lamellae and lamellar fusion were observed in gill tissues exposed to lambda-cyhalothrin. Necrosis of tubular epithelium, cloudy swelling of epithelial cells of renal tubules, narrowing of the tubular lumen, contraction of the glomerulus and expansion of space inside the Bowman's capsule were observed in the kidney tissues of fish after exposure. Hepatic lesions in fish exposed to lambda cyhalothrin were characterized by hypertrophy of hepatocytes, cloudy degeneration, congestion, karyolysis, karyohexis, dilatation of sinusoids and focal necrosis. The intestinal lesions included infiltration of eosinophils into the lamina propria and atrophy of epithelial cells. The present study proves its toxic potential in terms of the damages induced by lambda-cyhalothrin in organ level. In natural condition lambda-cyhalothrin will be less than the present study, but continuous usage of the pesticide might lead to the concentration that was used in the experimental condition. PMID- 21783824 TI - Diesel exhaust particles suppress expression of sex steroid hormone receptors in TM3 mouse Leydig cells. AB - Murine Leydig TM3 cells, derived from mouse testis, were exposed to diesel exhaust particles (DEP) and DEP components for 24h. mRNA expression of estrogen receptor (ER) alpha and CYP1A1 were then measured by real-time PCR. Exposure to DEP (10MUg/ml) reduced ERalpha mRNA expression by approximately 50% and increased P450 1A1 mRNA expression by approximately fivefold. Cycloheximide (CHX), an inhibitor of protein synthesis, abolished the DEP-induced effects on ERalpha mRNA expression. Thus, protein synthesis mediated the DEP-induced reduction of ERalpha mRNA expression. PMID- 21783825 TI - Tissue-specific induction of the carcinogen-inducible cytochrome P450 isoforms in the gastrointestinal tract. AB - Gastrointestinal tissues are directly exposed to dietary xenobiotics. In spite of this, modulation of cytochrome P450 (CYP) enzymes in the gastrointestinal tract is not well established. CYP induction could facilitate transformation of chemical agents to potentially toxic or carcinogenic metabolites. This might also determine drug efficacy, burden of foreign chemicals on tissues or bioavailability of certain therapeutic agents. In order to assess the induction of the CYP subfamilies 1A1/2, 2B1/2, 2E1 and 3A2 in the gastrointestinal tract, male Wistar rats were treated with phenobarbital/beta-naphthoflavone (PB/NF), cyclohexanol/albendazole (CH/ABZ) or toluene (TL). Microsomal fractions were prepared from tissue samples of the esophagus, the stomach, the duodenum, the colon and the liver. Western blot and enzymatic activity analyses revealed an increase in the expression and activity of CYP1A1/2 and CYP3A2 isoenzymes in the esophageal, duodenal and colonic microsomes from animals treated with PB/NF. CYP1A1/2 and CYP3A2 were induced in hepatic and duodenum microsomes by treatment with CH/ABZ. Our results demonstrate differential induction of CYP along the gastrointestinal tract by known CYP hepatic inducers, being the treatment with PB/NF the best induction system of the CYPs. PMID- 21783826 TI - Reflection of hydrocarbon pollution on hepatic EROD activity in the black goby (Gobius niger). AB - Hepatic ethoxyresorufin-O-deethylase (EROD) activity was measured in black gobies (Gobius niger) collected from seven sampling sites along the Slovenian coast during spawning and non-spawning periods. Sediments from the same sites were tested for their toxicity and for total polycyclic aromatic hydrocarbon (PAH) content. EROD activity was significantly higher during the non-spawning period in winter than during the spawning period in spring and generally correlated well with increased total PAH content in sediments and with sediment toxicity. An 11 fold increase of EROD activity was induced 48h after injecting 10MUgg(-1) weight of benzo(a)pyrene into black gobies. On the basis of these results and of its ecological characteristics, the black goby is proposed as a suitable candidate for future biomonitoring programmes. PMID- 21783827 TI - Structural properties of estrogen receptor ligand obtained by study of hydroxylated phthalate ester derivatives. AB - Phthalate esters (PEs), a group of plasticizers, are suspected to be endocrine disrupting chemicals. Here, PE derivatives were used as probes for elucidating the structural properties of estrogen receptor (ER) ligands. A comprehensive study was performed using more than 40 PE derivatives including ring-/alkyl hydroxylated and nonsymmetrical diesters possessing independently altered alkyls of C1-C8. Estrogenic activity of these derivatives is determined with three assays for ER-binding, coactivator-recruiting and transactivation. Phenolic hydroxylation increased activity, while hydroxylation of the ester alkyl group had no distinct effect on ER binding or transcription coactivator recruitment. Ring-hydroxylated PE derivatives harboring different ester alkyls revealed that the length of both alkyls independently affects transactivation of ER. These comprehensive data would be useful for the better understanding of structure activity relationship of endocrine-disrupting chemicals. PMID- 21783828 TI - Effects of lipopolysaccharide and chelator on mercury content in the cerebrum of thimerosal-administered mice. AB - Thimerosal is one of the best-known preservative agents for vaccines in the world but a relationship between its use and autism has long been suspected so that its effects on the brain need more detailed research. We here examined the influence of lipopolysaccharide injury to the blood-brain barrier on the penetration of mercury from thimerosal into mouse cerebrums, as well as the effect of chelator of heavy metals on cerebrum mercury content. Mercury can be expected to be detected in the cerebrum of normal mice, because the metal is present in standard mouse chow. When 60MUg/kg of thimerosal was subcutaneously injected into the mouse, the mercury content in the cerebrum was significantly higher 48h after the thimerosal injection with a maximum peak after 72h. In addition, mercury content in the cerebrum was still higher on day 7 than in the control group. When lipopolysaccharide was pre-injected into mice to induce damage on blood-brain barrier, the mercury content in the cerebrum was significantly higher at 24 and 72h after the injection of 12MUg/kg of thimerosal compared to the control group, this dose alone does not cause any increase. The mercury content in the cerebrums of mice was decreased to the control group level on day 7 when a chelator, dimercaprol, was administered once a day from days 3 to 6 after a 60MUg/kg, s.c. injection. In addition, d-penicillamine as a chelator decreased the mercury contents in the cerebrum after the high dose administration. In conclusion, a physiological dose of thimerosal did not increase the content of mercury in the cerebrum, but levels were increased when damage to the blood-brain barrier occurred in mice injected with thimerosal. In addition, a chelator of heavy metals may be useful to remove mercury from the cerebrum. PMID- 21783829 TI - Mini-review of studies on the carcinogenicity of deoxynivalenol. AB - The purpose of this article is to make a summary of the information regarding the researches on the carcinogenicity of DON and to discuss implications on future researches. Publications of experiments were collected through databases, experts, previous reviews, citation tracking. To guarantee the quality of the studies included in this review, we set up different criteria for different kinds of studies. As a result, all three gene mutation assays had negative results; all four chromosome aberration tests had positive results, even one of which had a dose-response effect; six from ten DNA damage/repair tests had positive results and tow of those six ones had dose-response effects; one mammalian cell malignant transformation assay showed positive result; two from three medium-term and long term carcinogenicity studies had negative results; all six epidemiologic studies had positive results. In conclusion, DON cannot be classified as carcinogen according to these tests and studies because the results from the short-term in vitro studies were quite contradictory, and the results from the medium-term and long-term in vivo studies and from the epidemiological studies in humane beings were invalid due to their poor methodology quality. It is necessary to make more and better researches on the carcinogenicity of DON considering its chronic and low level of exposure to the human beings. PMID- 21783830 TI - Zizyphus jujuba and Origanum majorana extracts protect against hydroquinone induced clastogenicity. AB - Hydroquinone (HQ) is a myelotoxin that is found in many foods and formed through the metabolism of benzene. HQ is genotoxic in several in vitro and in vivo test systems, inducing micronuclei (MN), sister-chromatid exchange (SCE), and chromosomal aberrations. The aim of the current study was to explore the protective effect of Zizyphus jujuba and Origanum majorana extracts against HQ induced genotoxicity in male mice. Five groups of mice included the control group, HQ-treated group, and the groups treated with the extracts alone or in combination with HQ. The results indicated that treatment with HQ resulted in significant clastogenetic effects and histological changes typical to those reported in the literature. Both extracts exhibited a protection against HQ induced cytogenesis and histological changes. Moreover, Z. jujuba extract was effective than O. majorana extract. It could be concluded that both extracts are useful especially for people who are occupationally exposed to benzene or its metabolites. PMID- 21783831 TI - Contributors to estrogenic activity in wastewater from a large wastewater treatment plant in Beijing, China. AB - Wastewater at various stages of treatment was sampled from a large wastewater treatment plant (WWTP) in Beijing, China. A fractionation method was conducted to identify the dominant contributors to estrogenic activity of those samples using silica gel column chromatography combined with a recombinant yeast bioassay for detecting estrogenic activity and gas chromatography-mass spectrometry (GC/MS) for quantifying estrogenic substances. Total estradiol equivalents (EEQ) found in the influent and effluent of the WWTP were 15.7+/-2.0 and 10.4+/-0.4ng/L, indicating the low removal efficiency of the WWTP. The endocrine disrupting chemicals (EDCs) most frequently detected in the wastewater by GC/MS included phthalate esters, PAHs and phenolic compounds, while the natural and synthetic estrogens such as estradiol (E2), estrone (E1), and ethinylestradiol (EE2) were not detected. The concentrations of nonylphenol (NP), octylphenol (OP) and bisphenol A (BPA) were 13.4, 1.4 and 89.0MUg/L in the influent and 0.41, 0.11 and 0.32MUg/L in the effluent, respectively. Based on the concentrations and estradiol equivalency factors (EEF) of NP, OP and BPA, 60% of the total estrogenic activity in GBD-WWTP influent could be explained by the calculated EEQ, showing that BPA, OP and NP were mainly responsible for estrogenic activity in the influent. However, their contributions to estrogenic activity in the effluent were only 3%, indicating that some unknown estrogenic components were still present in the wastewater. PMID- 21783832 TI - Hepatic and extrahepatic expression of glutathione S-transferase isozymes in mice and its modulation by naturally occurring phenolic acids. AB - A simple plant phenolic acid, protocatechuic acid and a polyphenol, tannic acid are potential chemopreventive agents which inhibited the chemically induced carcinogenesis in many experimental models. We previously demonstrated that those compounds modulate the activity of xenobiotic detoxifying enzymes, including GST in mouse liver, kidney and epidermis. Intraperitoneal (i.p.) treatment with protocatechuic acid in the dose of 80mg/kg for three consecutive days increased the GST activity in liver and kidney. In case of tannic acid the same effect was observed in kidney after i.p. administration of the single dose of 80mg/kg. Topical application of phenolic acids resulted in enhancement of epidermal GST activity. The focus of this study was to further investigate the effects of these phenolic acids on the protein levels of GST isozymes in the same tissues using the treatment protocols used in our previous studies. The results confirmed the expression of GST alfa, mu, pi and theta in mouse liver, kidney and epidermis. Treatment with protocatechuic acid resulted in an increase of the expression of GST class mu in liver, but did not affect this isoform in skin and kidney. This compound inhibited the level of kidney GST pi by 35%. Tannic acid decreased the expression of GST mu, alpha and theta in liver. Application of the equimolar doses of both phenolic acids on mouse skin resulted in reduced level of the GST alpha protein. The results of our study indicate that, although moderate, the effect of protocatechuic acid and tannic acid on GST subunits in mice may play certain role in biological activity of these compounds. Of special importance could be the increased expression of GST mu in liver which is involved in detoxification of many carcinogens including polycyclic aromatic hydrocarbons. PMID- 21783833 TI - Responses of metallothionein and reduced glutathione in a freshwater fish Oreochromis niloticus following metal exposures. AB - In this study, levels of reduced glutathione (GSH) and metallothionein (MT) which are known to be biomarker of metal exposures were measured in a freshwater fish Oreochromis niloticus following exposure to 0, 5, 10 and 20MUM concentrations of Cu, Zn, Cd and Pb for 14 days. Metals and GSH were measured in the liver, gill, intestine, muscle and blood, and MT in the liver. Copper accumulation occurred only in the gill, while Zn accumulation occurred only in the muscle. Lead accumulated in the liver and gill, whereas Cd accumulated in all the tissues. Metal exposures did not alter GSH levels in the blood, muscle and gill, but its levels increased in the liver following Cd, Zn and Cu exposures. MT levels in the liver increased only in Cd-exposed fish. The results showed that there was no significant change in tissue GSH levels following metal exposures, except in the liver. The levels of liver GSH increased significantly by all the metals, except lead. Data indicated that only the liver may be suitable indicator tissue to determine the response of GSH and MTs to metal exposure in environmental monitoring studies. PMID- 21783834 TI - Maturation arrest of neutrophils-a possible reason for the leucopenia in sodium selenite induced sub-chronic selenosis in cow calves. AB - The effect of long-term administration of sodium selenite on leucocyte indices of peripheral blood of calves was determined. Nine calves, 9-12 months old, with an average body weight of 104kg were divided into three groups. Calves of groups 2 and 3 were administered with sodium selenite at 0.1 and 0.25mg/kg body weight for 98 consecutive days. The clinical signs characteristic of selenosis viz. alopecia, cracking of hooves, intradigital lesions and discoloration of hard palate, started appearing from 45 to 60 days onwards with high dose, whereas only subtle indications of toxicosis were observed in the low-dose group. The prolonged administration of sodium selenite produced a progressive and dose dependent decline in the circulating leucocyte count with concomitant decline in the circulating neutrophil count. There was a high negative correlation (0.94) between blood selenium levels and neutrophils. Granulocyte/agranulocyte ratio was also significantly reduced in the treated animals. Evaluation of bone marrow smears revealed a decline in the myeloid to erythroid ratio. In addition, there was also maturation arrest of neutrophils at promyelocyte or myelocyte level as shown by differential granulocyte count in the bone marrow. The results indicated that host's immune response may be adversely affected. PMID- 21783835 TI - Protective effect of hawthorn extract against genotoxicity induced by cyclophosphamide in mouse bone marrow cells. AB - The preventive effect of hawthorn (Crataegus microphylla) fruit extract was investigated in mouse bone marrow cells against genotoxicity induced by cyclophosphamide. Mice were orally (gavages) pretreated with solutions of hawthorn extract which was prepared at five different doses (25, 50, 100, 200 and 400mg/kg b.w.) for seven consecutive days. Mice were injected intraperitoneally on the seventh day with cyclophosphamide (50mg/kg b.w.) and killed after 24h for the evaluation of micronucleated polychromatic erythrocytes (MnPCEs) and the ratio of PCE/(PCE+NCE) (polychromatic erythrocyte/polychromatic erythrocyte+normochromatic erythrocyte). All of five doses of extract significantly reduced MnPCEs induced by cyclophosphamide (P<0.0001). Hawthorn extract at dose 100mg/kg b.w. reduced MnPCEs 2.5 time and also completely normalized PCE/(PCE+NCE) ratio. Hawthorn extract exhibited concentration dependent antioxidant activity on 1,1-diphenyl-2-picryl hydrazyl free radical. Hawthorn contains high amounts of phenolic compounds; the HPLC analysis showed that it contained chlorogenic acid, epicatechin and hyperoside. It is obvious that hawthorn, particularly flavonoids constituents with antioxidative activity, reduced the oxidative stress and genotoxicity induced by cyclophosphamide in mouse bone marrow cells. PMID- 21783836 TI - The effect of sub-acute and sub-chronic exposure of rats to the glyphosate-based herbicide Roundup. AB - Roundup is a glyphosate-based herbicide that includes 78.5% glyphosate and surfactant at lower toxic concentrations. Glyphosate is an organophosphorated non selective agrochemical widely used in many countries including Turkey and acts after the sprout in a systemic way. The objective of this study was to analyze toxic effects of the herbicide Roundup in rat liver. Animals were treated with 56mg/kg (p.o.) and 560mg/kg (p.o.) of Roundup (78% glyphosate+surfactant) each day, during 5 and 13 weeks. Hepatotoxicity was monitored by quantitative analysis of the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities and measured amount of serum lipoprotein (LDL, HDL), total cholesterol and creatinine were used as the biochemical markers of liver damages. Besides the biochemical analysis, we also investigated liver tissues histopathologically. Sub-chronic treatment, starting from the low and high doses of Roundup, it was observed that there were mild effects on activity of ALT, AST and LDH enzymes indicating the hepatic toxicity induced by Roundup. It was found that the mild effects were different on the enzymes in male and female rats of treatment groups. Also it was found some difference in serum lipoprotein (LDL, HDL) and t-cholesterol. There was no difference creatinine value between control and treatment groups but it was observed that degenerative formation such as mononuclear cell infiltration and congestion of the liver tissues of treatment groups. PMID- 21783837 TI - In vitro and in vivo genotoxicity assessment of Cr(VI) using comet assay in earthworm coelomocytes. AB - Hexavalent chromium is the major terrestrial pollutant released from electroplating industries, tanneries, thermal power plants and sewage. Cr(VI) is reported genotoxicant in vertebrates. Sub-lethal level of Cr(VI) can cause DNA damage. Earthworms are ecologically important soil invertebrates, used for ecotoxicological studies. In present study coelomocytes of Dichogaster curgensis were used for assessing Cr(VI) genotoxicity using single cell gel electrophoresis [(SCGE) i.e. comet assay] following in vitro and in vivo exposures. Cr(VI) produces reactive oxygen species (ROS) in the cellular system, which can be a major cause of DNA damage. Dose dependent DNA damage was observed during in vitro exposure, while in vivo exposure showed increasing DNA damage till 30ppm in terms of arbitrary units and unexpected decrease in arbitrary units at 70 and 100ppm of Cr(VI). It is speculated that the decrease in arbitrary units at higher concentrations might be due to lower DNA mobility, caused by formation of different types of cross-links. PMID- 21783838 TI - A new assay system for evaluation of developmental immunotoxicity of chemical compounds using respiratory syncytial virus infection to offspring mice. AB - We evaluated the effect of 6-propyl-2-thiouracil (PTU), an anti-thyroid agent, on developmental immunity using respiratory syncytial virus (RSV) infection to offspring mice as a new risk assessment for brominated flame retardants (BFRs), because some BFRs are suspected of affecting the thyroid system. Pregnant mice were exposed to PTU in drinking water from gestation day 10 to weaning on postnatal day 21. Their offspring mice were infected intranasally with RSV. Exposure of 100ppm PTU significantly increased virus titers in the lungs of RSV infected offspring compared with the control, and the 10ppm also elevated levels of interferon-gamma, a marker of pneumonia, in the bronchoalveolar lavage fluids of offspring. Histopathological analysis revealed that PTU-exposure exacerbated pneumonia in RSV-infected offspring. Thus, exacerbation of RSV infection suggested PTU-exposure of dams elicited developmental immune disorder in the offspring. The murine RSV infection model may be useful to evaluate the developmental immunotoxicity of BFRs. PMID- 21783839 TI - Screening of estrogenic and antiestrogenic activities from medicinal plants. AB - The medicinal plant extracts commercially used in Asia were screened for their estrogenic and antiestrogenic activities in a recombinant yeast system featuring both a human estrogen receptor (ER) expression plasmid and a reporter plasmid. Pueraria lobata (flower) had the highest estrogenic relative potency (RP, 7.75*10(-3); RP of 17beta-estradiol=1), followed by Amomum xanthioides (1.25*10( 3)). Next potent were a group consisting of Glycyrrhiza uralensis, Zingiber officinale, Rheum undulatum, Curcuma aromatica, Eriobotrya japonica, Sophora flavescens, Anemarrhena asphodeloides, Polygonum multiflorum, and Pueraria lobata (root) (ranging from 9.5*10(-4) to 1.0*10(-4)). Least potent were Prunus persica, Lycoppus lucidus, and Adenophora stricta (ranging from 9.0*10(-5) to 8.0*10(-5)). The extracts exerting antiestrogenic effects, Cinnamomum cassia and Prunus persica, had relative potencies of 1.14*10(-3) and 7.4*10(-4), respectively (RP of tamoxifen=1). The solvent fractions from selected estrogenic or antiestrogenic herbs had higher estrogenic relative potencies, with their RP ranging from 9.3*10(-1) to 2.7*10(-4) and from 8.2*10(-1) to 9.1*10(-3), respectively. These results support previous reports on the efficacy of Oriental medicinal plants used or not used as phytoestrogens for hormone replacement therapy. PMID- 21783840 TI - The teratogenic effects of polychlorinated naphthalenes (PCNs) on early development of the zebrafish (Danio rerio). AB - The present study examines the effects of PCN congeners (PCN50 and PCN66) on zebrafish embryos. The embryos were exposed to different concentrations (20, 30 and 50MUg/l) of the respective congeners by dissolving 0.08% acetone. The following endpoints were investigated (mortality, hatching rate, abnormalities and heart rate). No effect on survival was recorded for 20MUg/l PCN congeners. On the other hand, embryos exposed to 30 and 50MUg/l PCNs showed a significant reduction in survival rate. No developmental defects occurred with any of the congeners at the 20MUg/l concentration. However, starting with 30MUg/l, weak to very pronounced abnormalities (Lordosis, Kyphosis, disrupted axial body, tail defect, reduced heartbeat, and abnormal hatching) were observed depending on the congener and the concentration used. PCN66 has been shown to be more embryotoxic congener than PCN50. This demonstration of zebrafish responsiveness to PCNs early life stage toxicity coupled with the considerable information on developmental biology and genetics of zebrafish provides a foundation for future investigations into the mechanism of PCNs developmental toxicity. PMID- 21783841 TI - Formaldehyde adduct to human serum albumin with reference to aspartame intake. AB - A preliminary study was performed to evaluate the role of formaldehyde (F) deriving from aspartame intake in the production of the adduct F-human serum albumin (F-HSA) by mean of a sera-epidemiological investigation. A blood-donors population (68 subjects) was analysed for the presence of anti-F-HSA IgG by an indirect competitive immunoenzymatic assay (displacement assay). Only the 41% of the subjects were aspartame consumer and with a low daily intake (0.96mg/(kgday)). A 50% sera-prevalence of IgG anti-F-HSA was observed in the population, but no association between this biomarker and aspartame intake was pointed out. A significant association was found between the IgG anti-F-HSA presence and exogenous F exposure sources (cigarette active smoke and occupational exposure). Considering the low number of the investigated subjects and the low doses of aspartame consumption, the results of this preliminary study seems to suggest that aspartame low intake does not influence the formation of F adducts. PMID- 21783842 TI - Lindane toxicity on early life stages of gilthead seabream (Sparus aurata) with a note on its histopathological manifestations. AB - Eggs/embryos and larvae were exposed to nominal concentrations ranging from 0.1 to 10mg/L lindane. High percentage of mortality was observed in larvae exposed to 1mg/L (76.38%) and in embryos exposed to 10mg/L (81.98%) of lindane at 24h exposure. The acute toxicity expressed as LC(50) 48-h was 0.122mg/L for embryos and 0.318mg/L for larvae. Larvae alterations included weak swimming, incapacity to respond to external stimuli, uncoordinated movements, trembling, myoskeletal defects, opaque skin and exophthalmia. Mucous epithelium of the digestive tissue showed a severe alteration with hypertrophy and desquamation of mucous cells. A high cellular disorganization in the renal and hepatic tissue is observed. Results obtained showed the sensitivity of Sparus aurata early life stages to lindane and the presence of sublethal effects like histopathological alterations; therefore, the relevance of pesticides substances control in the aquatic environment. PMID- 21783843 TI - Neurobehavioral assessment of rats exposed to low doses of PCB126 and methyl mercury during development. AB - Epidemiological and laboratory studies have suggested that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or synergistic effects on CNS function. Aim of this study was to characterize the effects of exposure to low levels of MeHg (0.5mg/kgday in drinking water) and PCB126 (100ng/kgday in food), alone and in combination, on neurobehavioral development in Wistar rats. Dams were treated from gestational day 7 to post-natal day (PND) 21. Animals were tested for developmental landmarks and reflexes (PND1-21), attention deficits (PND40), locomotor activity (PND30, 110), spatial learning (PND75), coordination and balance (PND90), object discrimination (PND80), anxiety (PND100), and conditioned learning (PND110). Parameters related to pregnancy, sex ratio at birth, and physical development (at weaning) did not differ among groups, though PCB126 decreased number of pups at birth. A slight delay in negative geotaxis was found in female rats in all treatment groups. No significant effects were seen in attention, coordination and balance, object discrimination, and spatial and conditioned learning. Increased motor activity was present in PCB126-treated male and in MeHg+PCB-treated female rats in the elevated plus maze test, and in PCB126-treated male rats in the open field test (PND110). The results do not support the hypothesis that co-exposure to MeHg and PCB126 results in additive or synergistic effects. This finding is in agreement with more recent in vitro and in vivo studies. PMID- 21783844 TI - Protective activity of 30kDa phytoglycoprotein from glucose/glucose oxidase induced cell death in primary cultured mouse thymocytes. AB - Dioscorea batatas Decne (DBD) has been traditionally used as herbal agent in folk medicine. DBD glycoprotein with a molecular weight of 30kDa consists of carbohydrate (83.75%) and protein (16.25%), and has a strong anti-oxidative activity. To understand the protection from thymocytes death, we evaluated the activity changes of pro-apoptotic factors [cytochrome c, caspase 3, poly(ADP ribose) polymerase (PARP), AP-1, NF-kappaB and nitric oxide (NO)] by DBD glycoprotein from glucose/glucose oxidase (G/GO)-induced cell death in primary cultured mouse thymocytes. In the activity of the apoptotic related proteins [cytochrome c, caspase 3 and PARP], the results showed that DBD glycoprotein (200MUg/ml) has an inhibitory effect on cytochrome c release into cytosol, caspase 3 activation and PARP cleavage in thymocytes. In the transcription factors (AP-1 and NF-kappaB) activity and NO production, the activities of NF kappaB and NO production significantly decreased after DBD glycoprotein (200MUg/ml) treatment for 4h in G/GO-induced thymocytes, compared with the control. Therefore, we speculate that DBD glycoprotein is one of the natural compounds for the protection of thymocytes that can produce cytokines. PMID- 21783845 TI - Proteomic evaluation of adults of Rhyzopertha dominica resistant to phosphine. AB - A proteomic study using a PH(3)-susceptible (RD2) and -resistant strain (CRD343) of Rhyzopertha dominica was undertaken to validate the relation between change of proteins and PH(3) resistance. Protein expression levels were compared using PD Quest program after two-dimensional polyacrylamide gel-electrophoresis. Comparing the intensity of proteins, 15 proteins decreased and 6 proteins were newly expressed in CRD343. After MALDI-TOF and LC-MS/MS analyses, the decreased proteins were identified as arginine kinases, dihydrolipoamide dehydrogenase, Hsp60, reverse transcriptase, glyceraldehydes-3-phosphate dehydrogenase, triosephosphate isomerase and hypothetical proteins. Dihydrolipoamide dehydrogenase is involved in the Krebs cycle and glyceraldehydes-3-phosphate dehydrogenase and triosephosphate isomerase are involved in the glycolysis pathway. Among up-regulated proteins, sodium channel, glutamate racemase, enolase and vitellogenin were identified. Taken together, PH(3) affected glycolysis as well as Krebs cycle and the induction of enolase might recover this dysfunction. PMID- 21783846 TI - Preface. PMID- 21783847 TI - Dioxin/furan formation and release in the cement industry. AB - Cement kilns firing hazardous waste are explicitly mentioned in the Stockholm Convention as an "industrial source having the potential for comparatively high formation and release of these chemicals to the environment". The substitution of fossil fuels with alternative waste derived fuels is a well-developed practice in a number of countries. In the European cement industry about 6 million tonnes are used which corresponds to a thermal substitution rate of 17%. The current study evaluates around 2200 dioxin/furan stack emission measurements collected from various sources. It is demonstrated that most cement kilns can meet an emission level of 0.1ngTEQ/Nm(3) if primary measures, i.e. process-integrated measures, are applied. Reducing the temperature to a level lower than 200 degrees C at the inlet of the air pollution control device is the key factor which has shown to limit dioxin formation and emissions at all types of cement kilns, independent of waste feeding. PMID- 21783848 TI - Application of validated method for determination of selected polychlorinated biphenyls in human adipose tissue samples. AB - The validation method has been employed to determine PCBs in human female adipose tissue and in different tissue samples (brain, kidney, liver and adipose tissue) collected from five donors from the Wielkopolska region, Poland. The contents of 15 PCB congeners have been determined in the tissues (brain, kidney, liver and adipose tissue) of 5 donors aged 18-78. The highest PCB concentrations have been found in the adipose tissue, in which the total of 15 congeners occur in the amount 78-591ng/g tissue, and in the liver tissue in the amount 16-94ng/g tissue. In 16 samples of adipose tissue taken from women aged 25-36, 4 PCB congeners (PCB 105, 138, 150 and 180) have been determined. The mean content of the total of these congeners has been 41ng/g tissue. This result is lower than the concentration of analogous PCB in the tissues collected from women from the other European countries, which well correlates with the low content of PCB in the food produced in Poland. PMID- 21783849 TI - Contamination of Russian Baltic fish by polychlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like biphenyls. AB - Nineteen species of fish products caught and produced in the Russian economic zone of the Baltic region in 2002-2005 were analyzed for polychlorinated dibenzo p-dioxins (PCDDs), dibenzofurans (PCDFs) and dioxin-like biphenyls (WHO-PCBs). Freshwater fish had significantly lower PCDD/PCDFs levels than most saltwater fish, except cod's fillet for which TEQ was comparable. In some cases pollutant levels of sea fish tissues essentially exceeded current regulatory values. Concentration of WHO(PCDD/F)-TEQ ranged from 0.06 to 0.57pg/g f.w. for freshwater fish, and from 0.16 to 17.83pg/g f.w. for sea fish. The special concern is caused by the high concentration of dioxin-like PCBs, whose contribution to the WHO TEQ(PCDD/F,PCB) considerably exceeded that of PCDDs and PCDFs. Concentration of WHO(PCB)-TEQ ranged from 2.56 to 124.40pg/g f.w. Profiles of PCDD/Fs congeners in fish were rather similar: in our opinion, the most probable sources of pollution were chlorine bleaching and outflow of PCBs. There is no real reason to assume that fish contamination was affected by the fungicide Ky-5 or similar chlorophenols mixtures. Relative contributions of each dioxin-like PCBs congener to total TEQ in fish tissue are presented in Fig. 2. Profiles of dioxin-like PCBs in general are close to Aroclor 1254, though in some cases there are essential differences. PMID- 21783850 TI - Dechlorination of PCB in the presence of plant nitrate reductase. AB - The dechlorination of PCB, specifically the noncoplanar congener PCB 153, has been observed in the presence of a crude nitrate reductase extract from Medicago sativa leaves. These observations were further confirmed using a commercially available and pure nitrate reductase from Zea mays. The presence of nitrate reductase increased PCB 153 dechlorination. Then, the addition of molybdenum, the enzyme's cofactor, enhanced dechlorination of the environmental contaminant. The ability of plant nitrate reductase to dechlorinate PCB is a new observation. PMID- 21783851 TI - Thermochemical properties and relative stability of polychlorinated biphenyls. AB - The values of thermochemical quantities (enthalpy and Gibbs energy of formation, entropy and molar heat capacity) in the ideal gas state and dihedral angles for all 209 polychlorinated biphenyls were obtained by the Benson contribution method and ab initio calculations. The di-, tri- and tetra-ortho-chlorinated biphenyls are related with properties of WHO non-ortho- and mono-ortho-biphenyls in connection with their potential human toxicities. PMID- 21783852 TI - PCB, PCDD and PCDF congener profiles in two types of Aroclor 1254. AB - Monsanto produced two distinct variants of Aroclor 1254. The late-production variant resulted from a change in Monsanto's manufacturing process in the early 1970s. Previous literature had reported that the late-production variant was produced from 1974 to 1976, but subsequent work has identified a sample known to be obtained in 1972. In this paper, we present congener-specific PCB and PCDD/F data for this 1972 late-production sample, and a brief historical record of late production Aroclor 1254. PMID- 21783853 TI - The Belgian PCB/dioxin crisis-8 years later An overview. AB - In January 1999, 50kg polychlorinated biphenyls (PCBs) contaminated with 1g dioxins were accidentally added to a stock of recycled fat used for the production of 500tonnes animal feed in Belgium. Although signs of poultry poisoning were noticed by February 1999, the extent of the contamination was publicly announced only in May 1999, when it appeared that more than 2500 poultry and pig farms could have been involved. This has resulted in a major food crisis, known worldwide as the "Belgian PCB/dioxin crisis". The crisis was resolved by the implementation of a large food monitoring program for the seven PCB markers (PCBs 28, 52, 101, 118, 138, 153 and 180). When PCB concentrations exceeded the tolerance levels of 100, 200 or 1000ng/g fat for milk, meat or animal feed, respectively, the 17 toxic polychlorinated dibenzodioxins and furans (PCDD/Fs) congeners were also determined. By December 1999, more than 55,000 PCB and 500 dioxin analyses were already done by Belgian and international laboratories. The highest concentrations of PCBs and dioxins and the highest percentage of affected animals were found in poultry. Several important consequences of the food crisis were: (1) the introduction in 1999 of norms for PCBs in feedstuffs and food in Belgium followed by the introduction in 2002 of European harmonized norms for PCDD/Fs in animal feed and food of animal origin; (2) the systematic national monitoring of food of animal origin; and (3) the creation of the Federal Agency for Food Safety in Belgium. The human health risk following this major incident was assessed with contradictory results. It was suggested that, since only a limited proportion of the food chain was contaminated, it is unlikely that adverse effects were inflicted in the Belgian population. However, another assessment suggests that neurotoxic and behavioural effects in neonates, together with an increase in the number of cancers, may be observed. PMID- 21783854 TI - Assessment of the Serbian population exposure to polychlorinated biphenyls by crops. AB - Data on occurrence of six marker polychlorinated biphenyls (PCBs) in 35 composite samples of some crop products (wholegrain wheat flour, edible sunflower oil and white sugar) and by-products of food processing industry (bran, dried sugar beet pulp and molasses) were collected and combined with food consumption data to assess the dietary intake of these persistent food contaminants by the Serbian adult population. The average daily intake of sum of PCBs was assessed to be 172.2ng using a mean weight of 60kg for the general population in Serbia. The wheat-based products contributed largely (141.0ngday(-1)) to the estimated value, due to fact that these products are notably consumed in Serbia, while the contribution of edible oil (19.8ngday(-1)) and sugar (11.4ngday(-1)) were not pronounced. The estimated daily intakes were compared with the maximum permissible risk (MPR) level of 600ngday(-1) established by the Dutch National Institute for Public Health and the Environment. The additional source seemed to be found in the market basket that included meat products, fish, dairy products and eggs. PMID- 21783855 TI - PCB pollution of early milk in the Province of Vojvodina. AB - Seven EPA PCB congeners (28, 52, 101, 118, 138, 153, and 180) were determined in samples of early human milk collected from 18 mothers in Novi Sad, using GC-ECD (HP 5890) supplied with a Quadra fused silica column 5% Ph for PCBs. The sum of seven PCB congeners was 3.26+/-3.90 (X-+/-S.D.), median 1.25, range 0.4-14.31 and the range of individual congeners was for: 28: 0.04-0.37; 52: 0.04-0.44, 101: 0.04-1.21; 118: 0.05-0.62; 138: 0.13-4.61; 153: 0.13-4.81; 180: 0.10-3.07, ng/g wet. No correlation was found between maternal age and seven PCB congeners. In two primiparous mothers below 30 years, the sum of seven PCB congeners was three to fourfold, and in one multiparous twofold higher than the average for the group. Unchanged level of assumed total PCBs in early human milk in 2003, compared with measured total PCBs in 1993, suggest the continuous inlet of these chemicals into the environment. PMID- 21783856 TI - Dietary PCB intake in Belgium. AB - A food market-basket, representative for the general Belgian population, containing various meat, fish and dairy food products, was analysed for its polychlorinated biphenyl (PCB) content. Additionally, fast food samples were also investigated. Based on the measured PCB levels (sum of 23 congeners), an average daily dietary intake estimate of PCBs was calculated. Of all foods analysed, fish had the highest average sum of PCB levels (7.1ng/g ww), with a high variation between the investigated species, followed by dairy products and eggs (3.2ng/g ww), fast food (1.9ng/g ww) and meat products (0.62ng/g ww). One fresh salmon filet had the highest total concentration of PCBs (36ng/g ww or 200ng/g lw), whereas levels in steak and chicken breast were the lowest of all foods analysed. PCB intake calculations were based on the average daily food consumption in Belgium and were estimated between 404 and 535ng/day of total PCBs (lower and upper bound). This value is in accordance with what was previously reported for diets from geographical distinct areas. Although it is only a minor constituent of the Belgian diet, fish is the major contributor to the total daily PCB intake (around 50%) due to the high PCB levels in this type of food. Meat products account for around 20% of the total dietary intake of PCBs, while dairy products and eggs contribute to a lesser degree (less than 20%). PMID- 21783857 TI - Exposure to polychlorinated biphenyls and hearing impairment in children. AB - The objective of this cross-sectional epidemiological study was to assess if long term exposure to polychlorinated biphenyls (PCBs) is associated with hearing impairment. Four hundred and thirty-three children aged 8-9 years residing in an area polluted by PCBs in Eastern Slovakia were examined otoscopically, tympanometrically and by pure tone audiometry. PCB levels in their serum were determined by gas chromatography. Transient otoacoustic emissions (TEOAE) were measured in a subgroup of 161 children. The mean of the sum of PCB concentrations in serum was 528.2ng/g serum lipids (median 321ng/g serum lipids). Serum PCB concentrations were associated with an increase of hearing threshold at low frequencies and a negative correlation between serum PCBs and the amplitude of TEOAE response was observed in the uppermost tertile of children grouped with regard to serum PCBs, not related to thyroid hormone levels. It was concluded that long-term environmental exposure to PCBs is associated with subclinical but diagnosable hearing deficits. PMID- 21783858 TI - Dental caries in Faroese children exposed to polychlorinated biphenyls. AB - The effects of exposure to polychlorinated biphenyls (PCBs) on dental caries of first permanent molars in children in the Faroe Islands, where the population is exposed to PCBs in their traditional diet, were evaluated. This study was part of a cohort study aimed at determining developmental risks resulting from the consumption of contaminated seafood. One hundred and fourteen children from a birth cohort of 182 mother-child pairs, aged 9-10 years, were examined. Caries scoring was performed according to WHO criteria; cavitated and noncavitated lesions were included. Exposure assessment was based on the PCB concentrations in maternal milk samples. Data from the project data set provided information on various confounding factors. Mean maternal milk PCB concentration was 2205 (range 70-11,150)ng/g lipids. The number of carious surfaces of first permanent molars correlated with milk PCB concentration (r=0.26, p=0.01). In multivariate linear regression analysis, PCB exposure was significantly related to caries susceptibility. The findings support an association between children's PCB exposure and caries prevalence. PMID- 21783859 TI - Impact of nutrition on PCB toxicity. AB - Studies are evolving which suggest that nutritional intervention can modify pathologies of diseases associated with environmental toxic insults. The diet is a major route of exposure to environmental toxins, such as persistent organic pollutants and heavy metals. Many persistent organics, such as polychlorinated biphenyls (PCBs), bioaccumulate in our bodies and "bioremediation" is extremely difficult. Furthermore, many environmental toxins induce signaling pathways that are oxidative stress-sensitive and similar or the same as the ones associated with the etiology and early pathology of many chronic diseases. There is now increasing evidence that exposure to PCBs can contribute to the development of inflammatory diseases such as atherosclerosis. Activation, chronic inflammation, and dysfunction of the vascular endothelium are critical events in the initiation and acceleration of atherosclerotic lesion formation. Our studies indicate that an increase in cellular oxidative stress and an imbalance in antioxidant status are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. We also have evidence that the plasma membrane microdomains called caveolae play an important role in endothelial activation and toxicity mediated by coplanar PCBs. Caveolae are particularly abundant in endothelial cells and play a major role in endothelial trafficking and the regulation of signaling pathways associated with the pathology of vascular diseases. There is a great need to further explore this nutritional paradigm in environmental toxicology and to improve our understanding of the relationship between nutrition and lifestyle, exposure to environmental toxins and disease. Our studies suggest that certain dietary fats can increase the risk of environmental insult induced by PCBs, while other dietary factors may provide protection. Nutrition may provide the most sensible means to develop primary intervention and prevention strategies of diseases associated with many environmental toxic insults. PMID- 21783860 TI - CYP1A1 and MT1K are congener specific biomarker genes for liver diseases induced by PCBs. AB - We have identified two most significant biomarker genes, CYP1A1 (69.81 up regulation) and MT1K (14.66 up-regulation), showing highest overexpression at p value <0.005. These were selected out of several hundred genes induced in vitro, using PCB exposed human liver (HepG2) cells. Over expression of the CYP1A1 (cytochrome P450) gene was specific to PCB-77 and MT1K (Metallothionein) to PCB 153. Affymetrix oligonucleotide microarrays (mRNA) were used to screen the entire genome of human liver cells in a time-dependent exposure and were further validated by quantitative real-time RT-PCR. PMID- 21783861 TI - In vivo and in vitro effects of PCB126 and PCB153 on rat testicular androgenesis. AB - In this study we compared the effects of PCB126 and PCB153 on adult rat testicular androgenesis and the status of antioxidant enzymes in the interstitial cell compartment 96h after local intratesticular application. Obtained results indicated PCB126-induced inhibition of conversion of progesterone (P) and Delta(4)-androstenedione (A(4)) to testosterone (T), and stimulation of conversion of P to T induced by PCB153, while combined application had no effect. Activities of antioxidant enzymes were unchanged, except of decreased activity of SOD in PCB126-treated group. In parallel experiments, adult purified Leydig cells challenged with PCB congeners were incubated for 2h in the presence of corresponding steroid substrates. Results demonstrated that in the presence of subsaturating substrate concentrations PCB126 induced inhibition of conversion of P and A(4) to T at nM to MUM doses, while PCB153 caused stimulation at nM concentrations. Further studies should indicate possible mechanism(s) of modulation of androgenesis by tested PCB congeners. PMID- 21783862 TI - Effects of estradiol, PCB3, and their hydroxylated metabolites on proliferation, cell cycle, and apoptosis of human breast cancer cells. AB - Certain estradiol metabolites and industrial pollutants, like polychlorinated biphenyls, may play a more important role in enhancing breast cancer risk than 17beta-estradiol. The aim of this study was to compare the effects of 17beta estradiol (E2) with that of the air pollutant 4-chlorobiphenyl (PCB3) and four of their hydroxylated metabolites on cell cycle, proliferation, and apoptosis in MCF 7 human breast cancer cells at concentrations of 0.1-10nM (E2, 2-OH-E2, and 4-OH E2) and 0.3-300nM (PCB3, 4-OH-PCB3, and 3, 4-diOH-PCB3) and 24-260h of exposure. E2 increased cell proliferation and cells in S-phase at all time points. 2-OH-E2 and 4-OH-E2 had no effect on the cell cycle, but a stimulatory action on cell proliferation from 72 to 260h of exposure to 4-OH-E2 and at 260h to 2-OH-E2 was seen. E2 and its metabolites had no effect on apoptosis. PCB3 and 4-OH-PCB3 showed no effect on proliferation, apoptosis or cell cycle distribution at any concentration and time point. Longer time exposures to 3,4-di-OH-PCB at 300nM caused a decrease of cells and an increase in G2/M and apoptotic cells. These results confirm the proliferative effect of E2 and its metabolite 4-OH-E2 in estrogen receptor positive breast cancer cells, but show no mitogenic activity for PCB3 and 4-OH-PCB3. However, the cell cycle and apoptosis effects of 3,4-diOH PCB3 need further analysis. PMID- 21783863 TI - DNA damage associated with PCBs in the whole blood cells of Inuit. AB - Lower chlorinated PCBs can damage DNA directly or via free radical mechanisms. In order to assess the DNA-damaging potential of PCBs in humans, blood samples were collected from Inuit population from Salluit, Northern Canada. Their diet comprises blubber from sea mammals and fatty fish, which accumulate non biodegradable PCBs at varying levels. The 103 samples thus collected were categorized into low-, medium- and high-PCB exposure groups. A comprehensive (32)P-postlabeling adductomics technology, which allows measure differences in DNA adduct profiles of polar and lipophilic adducts between control and exposure groups, was applied to these samples to assess the effect of PCB on DNA damage. The adduct patterns obtained were qualitatively similar to other human tissues studied previously. A range of highly polar to lipophilic subgroups of adducts were detected. The known oxidative lesion, 8-oxodG was predominant. While some individual adducts appear to accumulate with increasing PCB levels, a definitive association could not be made. A possible confounder effect of selenium is discussed. PMID- 21783864 TI - Chemical exposures at hazardous waste sites: Experiences from the United States and Poland. AB - The U.S. Agency for Toxic Substances and Disease Registry (ATSDR) and the Polish Nofer Institute of Occupational Health collaborate on issues related to hazardous chemical exposure at or near hazardous waste sites. This paper outlines the scope of hazardous chemical exposure in the United States and in Poland and identifies priority chemicals and chemical mixtures. Special attention is paid to exposures to metals and to evaluation of the health risks associated with those exposures. Studies in the United States indicate that exposure to hazardous waste site chemicals may be associated with an increased risk of adverse developmental - specifically cardiovascular and neurodevelopmental - effects. PMID- 21783865 TI - Protective effect of carnosine against cisplatin-induced nephrotoxicity in mice. AB - The nephroprotective effect of the natural antioxidant carnosine was evaluated in mice with cisplatin-induced acute renal damage, in which generation of reactive oxygen species plays a major role. Nephrotoxicity was induced by a single i.p. injection of cisplatin (20mg/kg). Carnosine was administered for six consecutive days in a dose of 10mg/kg/day, i.p., starting 3 days before cisplatin injection. The results revealed that carnosine treatment significantly reduced blood urea nitrogen and serum creatinine levels elevated by cisplatin administration. Also, carnosine significantly attenuated cisplatin-induced increase in malondialdehyde and decrease in reduced glutathione, and catalase and superoxide dismutase activities in renal cortical homogenates. Additionally, histopathological examination and scoring showed that carnosine markedly ameliorated cisplatin induced renal tubular necrosis. In conclusion, carnosine can be considered a feasible candidate to protect against nephrotoxicity commonly encountered with cisplatin treatment. PMID- 21783866 TI - Genotoxic effect of Catha edulis (khat) crude extract after sub-chronic administration in rats. AB - The aim of this study was to evaluate the genotoxic effects of a crude extract of khat (Catha edulis, Forsk) leaves in rats. Two groups were fed khat crude extract, 1000 and 2000mg/kg body weight, for 90 days and were compared with a control group. The alkaline (pH>13) version of comet assay was used in this study. However, no previous published work has been undertaken and showed the effect of khat on DNA migration in the comet assay. To compare the comet assay results with another genetic endpoint, blood samples were analyzed for chromosomal aberrations. These results showed no DNA damage detected using comet assay in both the khat treated groups, while the results of chromosomal aberrations assay showed a significant increase (P<0.05) in the 2000mg/kg body weight treated group compared to the control group. PMID- 21783867 TI - Effects of dietary methylmercury on zebrafish skeletal muscle fibres. AB - Mercury and more specifically methylmercury have been reported as hazardous environmental pollutants able to accumulate along the aquatic food chain with severe risk for animal and human health. Adult male zebrafish (Danio rerio) were distributed in two groups: a control group (fed with uncontaminated food) and a MeHg-contaminated group (fed with food containing 13.5MUgHgg(-1) (dry wt)). Five fish per condition were removed after 7, 21 and 63 days. Bioaccumulation of mercury was determined and muscle samples from control and exposed groups were fixed for histological and ultrastructural studies. In contaminated muscles were observed a decrease of the inter-bundle surface, mitochondria with variable shapes, sizes and cristae disorganization, also decreasing the surface area and inter-bundle surfaces. Indeed, damage in the endoplasmic reticulum cisternae was observed. For statistical evaluation the damages in mitochondria was quantified by image. According to the current results, methylmercury affects the structure of fibre cells of D. rerio after trophic and low dose exposure. PMID- 21783868 TI - Aconitum and Delphinium alkaloids "Drug-likeness" descriptors related to toxic mode of action. AB - Large series of Aconitum and Delphinium alkaloids have been investigated by means of QSAR analysis. Descriptors related to "drug-likeness" of molecules were selected to discriminate between "drugs" and "non-drugs" amongst diterpenoid alkaloids of interest. A usefulness of such approach has been assessed and it proved to give reliable results on whether a particular diterpenoid alkaloid is likely to be either poison or drug. A number of QSAR models with "drug-likeness" descriptors have also been obtained and discussed in terms of their relativity to the mode of toxic action exhibited by the alkaloids. The QSAR models were obtained with r value in the range 0.69-0.94. The q(2) (cross validation of r(2)) values also confirm the statistical significance of our models. PMID- 21783869 TI - Amelioratory effect of Andrographis paniculata Nees on liver, kidney, heart, lung and spleen during nicotine induced oxidative stress. AB - The ameliorative properties of bioactive compound andrographolide (ANDRO), aqueous extract of Andrographis paniculata (AE-AP) and vitamin E (vit.E) were tested against nicotine induced liver, kidney, heart, lung and spleen toxicity. A group of male Wistar rats were intraperitoneally administered vehicle, nicotine (1mg/kg body weight/day), nicotine+ANDRO (250mg/kg body weight/day), nicotine+AE AP (250mg/kg body weight/day) and nicotine+vit.E (50mg/kg body weight/day) for the period of 7 days. The significantly increased levels of lipid peroxidation, protein oxidation and the decreased antioxidant enzyme status were noted in nicotine treated group as compared to vehicle treated group. ANDRO, AE-AP and vit.E significantly reduced the lipid peroxidation, protein oxidation and increased the antioxidant enzyme status. This indicates A. paniculata and vit.E may act as putative protective agent against nicotine induced tissue injury and may pave a new path to develop suitable drug therapy. PMID- 21783870 TI - Daphnia intoxicated by nerve agent tabun can be treated using human antidotes. AB - Application of human antidotes against nerve agent intoxications to microcrustacean Daphnia magna (Crustacea, Cladocera) intoxicated by a nerve agent tabun (O-ethyl-N,N-dimethylphosphoramidocyanidate) and their efficacy was investigated. It was found that antidotes can be successfully applied to intoxicated daphnids. Three different treatment regimens were tested: the combination of atropine and acetylcholinesterase reactivator (trimedoxime was chosen), atropine only and trimedoxime alone, too. The most efficient was the combination of atropine and trimedoxime followed by treatment with atropine only. The proportion of recovered animals increased with time not only in treated groups but also in the control as well. This can be explained by a spontaneous reactivation of tabun-inhibited cholinesterase in daphnids probably indicating a difference between mammalian and crustacean cholinesterases. PMID- 21783871 TI - Carbofuran in water: Subchronic toxicity to rats. AB - Carbofuran toxicity on rats was studied during subchronic exposure. Female and male rats were administered carbofuran in drinking water in concentrations of 25, 100 and 400ppm for a period of 90 days. Clinical symptoms, water consumption, body weight gain, organ weight, pathological and histopathological changes in the liver and kidneys were observed and biochemical and haematological examinations were carried out. The results obtained show that carbofuran administered to rats caused a significant decrease in water consumption as well as in brain, serum and erythrocyte cholinesterase activities. Statistically significant increases in relation to the control were found in the serum enzyme activities. The haematological data showed that carbofuran had no significant effect on Hb concentration and total RBC, but total WBC showed a significant statistical decrease. The histopathological changes in liver and kidneys were observed. However, cell regeneration in the liver and kidneys was found in all test groups. PMID- 21783872 TI - Pesticide bioaccumulation and plasma sex steroids in fishes during breeding phase from north India. AB - The investigation was done to monitor the total hexachlorocyclohexane (?HCH) and total dichlorodiphenyltrichloroethane (?DDT), aldrin, endosulfan and chlorpyrifos in liver, brain and ovary, gonadosomatic index (GSI) and plasma levels of testosterone (T) and estradiol-17beta (E2) during breeding season of captured catfishes and carps from the unpolluted ponds of Gujartal, Jaunpur (reference site) and polluted rivers Gomti, Jaunpur and Ganga, Varanasi. Results have indicated that catfishes have higher bioaccumulation of pesticides than the carps, which was beyond the permissible limits for ?HCH whereas ?DDT only by catfishes of polluted rivers. The GSI and plasma levels of T and E2 were lowered in the fishes captured from the polluted rivers. In conclusion, the fishes from river Gomti and Ganga showed a high degree of contamination and disrupted reproductive axis when compared to those from the reference site reflecting the degree of pesticide pollution present in those water bodies. PMID- 21783873 TI - Microcalorimetric investigation of the toxic action of ammonium ferric(III) sulfate on the metabolic activity of pure microbes. AB - A series of calorimetric experiments were performed to investigate toxic action of ammonium ferric sulfate (AFS) on Bacillus subtilis, Pseudomonas putida and Candida humicola. The power-time curves of micro-organism metabolism were obtained, and the action of them by addition of AFS was studied. C. humicola, B. subtilis and P. putida were inhibited completely when the concentrations were up to 320.0, 160.0 and 160.0MUgmL(-1), respectively. The relationships between growth rate constant (k) and doses of AFS were approximately linear for three microbes, P. putida for 10.0-160.0MUgmL(-1) (R=-0.9746), B. subtilis for 0 160.0MUgmL(-1) (R=-0.9868) and C. humicola for 10.0-320.0MUgmL(-1) (R=-0.9955). The total heat dissipated per milliliter (Q(T)) for three microbes remained balance approximately during the lower doses, P. putida and B. subtilis less than the dose of 20.0MUgmL(-1), 0.56+/-0.01 and 0.26+/-0.01JmL(-1), respectively, C. humicola less than the dose of 40.0MUgmL(-1), 0.58+/-0.03JmL(-1). The biomass and OD(600) of three micro-organisms growth in the absence of AFS also were obtained. The power-time curve of C. humicola growth coincided with its turbidity curve. It elucidates that microcalorimetric method agreed with the routine microbiology method. PMID- 21783874 TI - Induction of in vitro EROD activity and in vivo caffeine metabolism in two species of New Zealand birds. AB - In birds, induction of cytochrome P4501A (CYP1A) is usually assessed as liver microsomal ethoxyresorufin O-deethylase (EROD) activity, but in mammals, it can be determined by a caffeine metabolism blood test. We investigated both of these measures in two species of New Zealand birds. Administration of a model CYP1A inducer, beta-naphthoflavone (BNF) (80mg/kg i.p. twice 2 days apart), to paradise shelducks (Tadorna variegata; herbivore) and southern black-backed gulls (Larus dominicanus; omnivore) (n=5 or 6) caused marked increases in EROD activity (80- and 20-fold, respectively). In both species, BNF treatment also caused significant increases (>8-fold) in caffeine metabolism determined prior to sacrifice as the serum concentration ratio of the major metabolite, paraxanthine, to caffeine, after caffeine administration (1mg/kg i.p.). The results suggest in vivo caffeine metabolism is a potentially useful non-destructive biomarker of CYP1A induction in wild birds. PMID- 21783875 TI - Behavioural and gill histopathological effects of acute exposure to sodium chloride in moneda (Metynnis orinocensis). AB - To evaluate the toxicity of sodium chloride (NaCl), juveniles and adult Metynnis orinocensis were exposed for 96h to 0, 5, 10, 15, 20 or 40gL(-1) of salt. Food intake, behaviour, opercular frequency (OF), mortality, body weight and gill microscopic alterations were evaluated. Behavioural changes were observed in fish exposed to concentrations higher than 10gL(-1). Juveniles and adults showed a progressive decrease in the OF and body weight. Food intake decreased in concentrations below 15gL(-1). Juveniles and adults exposed to 15, 20 or 40gL(-1) had 100% mortality. Lamellar congestion, hyperplasia and fusion were the common microscopic alterations at higher concentrations. The gill congestion severity increased with salt concentration. The LC(50) for juveniles and adults were 10.5gL(-1) and 10.8gL(-1), respectively. These results suggest that salt concentrations lower than 5gL(-1) are safe for preventive and therapeutic practices in Metynnis orinocensis; whereas prolonged exposure higher than 10gL( 1) is deleterious in this species. PMID- 21783876 TI - Vehicle effects on in vitro transdermal absorption of sevoflurane in the bullfrog, Rana catesbeiana. AB - The experimental objectives were to identify a vehicle which produces a homogenous formulation when combined with the anesthetic solution sevoflurane and understand the dermal absorption of sevoflurane in silastic membranes and amphibian skin in vitro utilizing a flow-through diffusion system. Seven vehicles were evaluated in varying ratios with 5 formulations resulting in the desired homogenous consistency for practical application. Sevoflurane diffusion across silastic membranes was influenced by pluronic/lecithin organogel (PLO), pluronic F 127 20% gel, and sterile lube. Flux and permeability across silastic membranes were significantly greater in sterile lube than in the other formulations. While no significant vehicle effects were observed in bullfrog skin, the flux-time profiles suggest that sevoflurane diffusion in bullfrog skin may be positively influenced by PLO. Future in vivo studies are required to assess sevoflurane retention after removal of these formulations to more accurately control the plane of anesthesia in amphibians. PMID- 21783877 TI - Effects of perinatal combined exposure to 1,1-dichloro-2,2-bis(p chlorophenyl)ethylene (p,p'-DDE) and tributyltin (TBT) on rat female reproductive system. AB - 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is the most prevalent metabolite of DDT used as a pesticide before and tributyltin (TBT) compounds are used primarily as antifouling agents on vessels, ships, and aqua culture facilities, as they exert biocidal actions. Currently, p,p'-DDE and TBT are ubiquitously distributed in the environment and bio-accumulated in marine products, especially fish or shellfish. Thus, oral p,p'-DDE and TBT intake through marine products is demonstrated to be rather high in Japan. Consequently, the fetus and neonate will be exposed to p,p'-DDE and TBT via mother. Therefore, effects of perinatal combined exposure to p,p'-DDE and TBT on the female reproductive system after maturation have been investigated in rat female offspring of dams ingesting 125ppm p,p'-DDE (approximately 10mg/kg) and 25ppm TBT (approximately 2mg/kg) during the perinatal period from gestation to lactation. In the present study, no deleterious reproductive outcomes were recognized in p,p'-DDE and/or TBT-treated dams. In contrast, growth retardation had developed in rat female offspring following perinatal exposure to TBT and sustained even after cessation of exposures. Further, reduced ovarian weights with elevated serum follicle-stimulating hormone (FSH) concentrations were observed in the reproductive system of matured female offspring following perinatal exposure to TBT. At present, biological relevance of these alterations remains unknown, but there is a possibility that these alterations lead to reproductive malfunctions in matured female offspring. PMID- 21783878 TI - Environmental exposure to PBDEs and thyroid function among New York anglers. AB - Experimental studies suggest that polybrominated diphenyl ethers (PBDEs) can influence thyroid function, although the few human studies reported provide little support for this premise. Great Lakes sportfish anglers represent a population with potentially elevated dietary exposure to PBDEs due to the lipophilic nature of these compounds. Thirty-six licensed anglers who participated in the New York State Angler Cohort Study donated blood and completed questionnaires regarding demographic, clinical and sportfish consumption information. Archived blood specimens were analyzed for thyroid stimulating hormone, total and free thyroxine, total triiodothyronine, total serum lipids and nine PBDE congeners. PBDE congener profiles were dominated by BDE-47 (median=7.9ng/g lipids), BDE-153, and BDE-99 (medians=1.8ng/g lipids). No significant associations were observed between congeners, or their sum (SigmaPBDEs), and thyroid function. However, the possibility of a positive association between SigmaPBDEs and fT(4), detectable with an approximate ninefold increase in sample size, suggests that additional studies are needed. PMID- 21783879 TI - Chemical-induced alteration of hemoglobin expression in the 4th instar larvae of Chironomus tentans Mg. (Diptera: Chironomidae). AB - In this study, a preliminary characterization of the multiplicity of Chironomus hemoglobin (Hb) was conducted on the larvae of Chironomus tentans Mg. (Diptera: Chironomidae) by the molecular mass and isoelectric point. In order to identify Chironomus Hb as potential biomarker of environmental contamination, alteration of individual Hb by exposure to environmental chemicals, namely, nonylphenol, benzo[a]pyrene, chloropyriphos and cadmium chloride, were evaluated. To validate the ecotoxicological relevance of Chironomus Hb as a potential biomarker, ecotoxicity test using growth rate as toxic endpoint was also conducted. This study revealed a striking heterogeneity in C. tentans Hb; 10 Hb isoforms were observed in the larvae of 4th instar C. tentans by their molecular mass and by their isoelectric point. Chemical-induced alteration of individual Hb expression suggests that C. tentans Hb can be a target molecule for chemical exposure. Overall results suggest that the expression pattern of Hb proteins may potentially contribute to the development of a biomarker for ecotoxicity monitoring in C. tentans. PMID- 21783880 TI - Alternative electron acceptors: Proposed mechanism of paraquat mitochondrial toxicity. AB - Paraquat (PQ) is a relatively safe and effective herbicide used all over the world. PQ is very toxic to all living organisms; and many cases of acute poisoning and death have been reported over the past decade. The main suggested potential mechanism for PQ toxicity is the production of superoxide radicals from the metabolism of the PQ by microsomal enzyme systems, and by inducing mitochondrial toxicity. Mitochondria are considered to be a major source of reactive oxygen species in cells and according to this hypothesis, PQ, through suitable oxidation and reduction processes, is able to participate in the redox system in mitochondria. The potential ability of PQ to accept electrons from complex (I, II, III, IV) leads to rapid reaction with molecular oxygen to yield superoxide anion which can lead to the formation of more toxic reactive oxygen species, e.g., hydroxyl radical, often taken as the main toxicant. Lipid peroxidation due to PQ has been implicated in a number of deleterious effects such as increased membrane rigidity, osmotic fragility, decreased mitochondrial components, reduced mitochondrial survival and lipid fluidity. The biological effect of reactive oxygen species (ROS) is controlled by a wide spectrum of enzymatic and non-enzymatic defense mechanisms such as superoxide dismutas (SOD), catalase (CAT) and glutathione. According to this hypothesis, the chemical cascades lead to the reduction of PQ, which reacts quite rapidly with molecular oxygen to yield superoxide anion. The generation of free radicals and lipid peroxidation are the main factors that lead to mitochondrial damage. PMID- 21783881 TI - Gene expression profiles in liver of zebrafish treated with microcystin-LR. AB - Microcystin-LR (MC-LR) is the most frequently studied cyclic heptatoxin produced by cyanobacteria, which has tremendous negative impacts on fish, while its molecular mechanism behind remained unclear at present. Here, Affymetrix Zebrafish GeneChip was used to identify alterations in gene expression of zebrafish (Danio rerio) after MC-LR exposure. Among the 14,900 transcripts in the microarray, 273 genes were differentially expressed, in which 243 genes were elevated and 30 were decreased. According to GOstat analysis, MC-LR mainly influenced the cell cycle and mitogen-activated protein kinases (MAPK) signaling pathways. In addition, many immune-related genes were also influenced. These data suggest that MC-LR could promote tumorigenesis and cause immunotoxicity in fish. PMID- 21783882 TI - Neuroprotective effects of chlorogenic acid against apoptosis of PC12 cells induced by methylmercury. AB - Chlorogenic acid (CGA) widely exists in edible and medicinal plants. We aimed to evaluate the effect of CGA on the protection from apoptosis by methylmercury (MeHg) in PC12 cells. Cell viability was evaluated by MTT assay. Apoptosis was assayed by flow cytometry detection. Caspase-3 activity was measured by confocal microscopy. Intracellular GSH levels were determined by bicinchoninic acid protein assay. Intracellular reactive oxygen species (ROS) was assessed by means of chloromethyl-dihydrodichlorofluorescein diacetate. Glutathione peroxidase (GPx) activity was determined by UV. In order to elucidate the action of CGA, the protective effects of CGA were compared to Vit.E. CGA was effective at protecting PC12 cells against MeHg-induced damage in dose-dependent manner. CGA not only suppressed the generation of ROS, the decrease of activity in GPx and the decrease of GSH, but also attenuated caspase-3 activation in PC12 cells by MeHg. CGA eventually protected PC12 cells against MeHg-induced apoptosis. The results highlighted that CGA may exert neuroprotective effects through its antioxidant actions. PMID- 21783883 TI - Evaluation of nicotinic receptors agonists and antagonists against paraoxon exposed PC12 cells. AB - Chronic and acute exposure to organophosphate pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. In an attempt to elucidate the mechanism by which paraoxon affects the nicotinic receptors gene expression, the effects of exposure of PC12 cells to 100MUM concentrations of paraoxon for 48h in the presence and the absence of nicotinic acetylcholine receptors (nAChRs) agonists and antagonists were characterized. Paraoxon at 100MUM significantly inhibited AChE activity. On the mRNA level, the alpha(4) and beta(2) subunits of nAChR mRNA were significantly decreased in the cells exposed to paraoxon. On the protein level, alpha(4) and beta(2) subunits of nAChR protein were also significantly reduced. Mecamylamine (10MUM), dihydro-beta-erythroidine (DHbetaE) (5MUM) and nicotine (10MUM) efficiently prevented the decrease of alpha(4) and beta(2) nAChR mRNA and protein in PC12 cells, but carbamaylcholine a weak agonist of nAChR was not efficient. These observations suggest that alpha(4)beta(2) nAChRs are involved in paraoxon related toxicity and nicotinic receptors antagonists could play some protective role against organophosphate related damages. PMID- 21783884 TI - Debilitating stresses do not increase blood-brain barrier permeability: Lack of the involvement of corticosteroids. AB - The involvement of corticosteroids in stress-induced change in blood-brain barrier (BBB) permeability was investigated. Mice were adrenalectomized and administered with pyridostigmine bromide (PB) or Evan's blue, markers of BBB penetration, followed by 18-h cold-restraint stress (CRS). Rats were administered with mifepristone, a corticosteroid receptor blocker, and the markers, followed by 4-h water immersion-restraint stress (WIRS). Separately, soman was administered to induce seizures-mediated BBB opening. CRS did not induce PB and Evan's blue penetration, which were not affected by adrenalectomy. Also, the markers were not detected in the brain of rats subjected to WIRS, regardless of the treatment of mifepristone. In comparison, 1-h epileptic seizures increased the penetration of Evan's blue by 875%. The results suggest that in contrast to seizure-related BBB opening, profound stresses do not practically increase the BBB permeability, and that corticosteroids are not involved in the stress-induced BBB penetration of charged chemicals and albumin-dye complex. PMID- 21783885 TI - Can 17-beta estradiol induce vitellogenin-like proteins in the clam Tapes philippinarum? AB - Estrogenic potency of 17-beta estradiol (E2) was evaluated for the first time in both sexually undifferentiated (during resting phase, at the very early stage of gametogenesis) and differentiated (in pre-spawning phase) clams (Tapes philippinarum), following waterborne exposure for 7 and 14 days to various E2 concentrations (0, 0+acetone, 5, 25, 50, 100 and 1000ng/L). Vitellogenin (Vg) like protein levels were evaluated in both haemolymph and digestive glands by the alkali-labile phosphate (ALP) assay. In the resting phase of clams, exposure for 7 days to all E2 concentrations tested resulted in significant increases in ALP in haemolymph with respect to controls. Conversely, no statistically significant differences were observed in digestive gland from E2-exposed bivalves, compared with controls. After 14-days exposure, ALP significantly increased in haemolymph from 1000ng E2/L-exposed clams and in digestive gland from 5ng E2/L-exposed animals. Interestingly, in the pre-spawning phase of clams, significant decreases in ALP levels were recorded in haemolymph from females exposed for 7 days, whereas no differences were observed in males. No significant variations were observed in ALP content in digestive gland from both females and males. ALP levels in haemolymph were shown to increase significantly in females exposed for 14 days to 50ng E2/L, and in males exposed to 100ng E2/L. Exposure for 14 days to all the E2 concentrations tested resulted in significant increases of ALP levels in the digestive gland of females. Conversely, variations in ALP content of male digestive glands were not significant. Results obtained appeared controversial and somewhat difficult to explain. Indeed, no univocal response by clams was observed after 7 and 14 days exposure to E2. Further studies need to elucidate the role of E2 in promoting Vg induction in clams. PMID- 21783886 TI - In vivo changes in antioxidant system and protective role of selenium in chlorpyrifos-induced subchronic toxicity in bubalus bubalis. AB - Chlorpyrifos, an organophosphate, is one of the widely used insecticides for control of pests in various agricultural and animal husbandry operations. The objective of the present investigation was to assess the effect of subchronic exposure of chlorpyrifos on the antioxidant status of buffalo calves and to perceive the role of selenium in cases of chlorpyrifos toxicity. Chlorpyrifos at a dose rate of 0.05mg/kg per day for 20 consecutive weeks, significantly elevated the enzymic activity of glutathione peroxidase (GPx) (54.8%), glutathione reductase (GR) (79.4%), glutathione-S-transferase (GST) (34.2%), glucose-6 phosphate dehydrogenase (G6PD) (33.2%), superoxide dismutase (SOD) (19.3%) and catalase (CAT) (63.8%). The altered antioxidant status was well evident from the depleting glutathione levels and a two-fold rise in the extent of lipid peroxidation. Supplementation of selenium in the form of sodium selenite @ 0.05mg/kg per day for 20 weeks in chlorpyrifos intoxicated calves had a marked beneficial effect on the overall antioxidant potential of the animals as evident by no significant alteration in the extent of lipid peroxidation, levels of blood glutathione and activities of various antioxidant enzymes viz. GST, GR, SOD, CAT and G6PD. There was only a significant increase in the activity of GPx to the tune of 27.4%. Therefore, on the basis of the present investigation it can be suggested that oxidative stress is one of the main mechanism involved in chlorpyrifos toxicity and supplementation with sodium selenite in such cases can have significant beneficial and therapeutic effects. PMID- 21783887 TI - Protective effects of ligustrazine on cisplatin-induced oxidative stress, apoptosis and nephrotoxicity in rats. AB - Cisplatin is an effective agent against various solid tumors. However, its nephrotoxicity been reported to be a dose-limiting factor for treating various types of tumors. The aim of this study was to determine the protective effects of ligustrazine on cisplatin-induced nephrotoxicity through tissue oxidant/antioxidant parameters, light microscopic evaluation, and tubular apoptosis in rats. Ligustrazine was administered in doses of 50 and 100mg/kg/day intraperitoneally (i.p.), for 7 consecutive days, starting 2 days before a single intraveneous dose of cisplatin (8mg/kg). Results revealed that treatment with cisplatin alone caused significant changes in the levels of urinary protein, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine, blood urea nitrogen, and kidneys histopathological damages. All the aforementioned changes were effectively attenuated by ligustrazine. In addition, cisplatin caused increases in the levels of malondialdehyde, nitric oxide, nitric oxide synthase and decreases in the levels of reduced glutathione, glutathione-S-transferase, superoxide dismutase. These changes were restored to near normal levels by ligustrazine at 100mg/kg. In conclusion, ligustrazine has dose dependent protective effects against cisplatin-induced renal tubular toxicity. PMID- 21783888 TI - Disposition kinetics and urinary excretion of levofloxacin on concomitant administration with meloxicam in cross-bred calves. AB - The disposition kinetics and urinary excretion study of levofloxacin was conducted in 5 male cross-bred calves following its single intravenous administration (4mgkg(-1)) concurrently with meloxicam (0.5mgkg(-1)). Levofloxacin was estimated by microbiological assay. The drug levels above MIC(90) in plasma, were detected up to 10h. Disposition kinetic parameters were calculated by two-compartment open model. Rapid distribution of levofloxacin was evidenced by a small distribution half-life (0.13+/-0.01h) and high K(12)/K(21) ratio (2.21+/-0.15). High ratio of AUC/MIC (90.2+/-3.41) indicated good antibacterial activity of levofloxacin. The AUC, Vd(area), elimination half-life, MRT and total body clearance were 9.02+/-0.34MUgml(-1)h, 1.38+/-0.05lkg(-)1, 2.16+/-0.08h, 2.58+/-0.11h and 0.45+/-0.02lkg(-1)h(-1), respectively. About 38.4% of the administered dose of levofloxacin was excreted in urine within 24h. A suitable intravenous dosage regimen for levofloxacin would be 1.8mgkg(-1) repeated at 8h intervals when prescribed with meloxicam in calves. PMID- 21783889 TI - Propolis induces cell cycle arrest and apoptosis in human leukemic U937 cells through Bcl-2/Bax regulation. AB - We investigated mechanism(s) where propolis induces apoptosis in human leukemic U937 cells. Propolis inhibited the proliferation of U937 cells in a dose dependent manner by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Western blot analysis showed that propolis increases the expression of p21 and p27 proteins, and decreases the levels of cyclin B1, cyclin A, Cdk2 and Cdc2, thereby contributing to cell cycle arrest. DAPI staining assay revealed typical morphology features of apoptotic cells. Propolis-induced apoptosis was also confirmed by assays with annexin V-FITC, PI-labeling and DNA fragmentation assay. The increase in apoptosis level induced by propolis was associated with down-regulation of Bcl-2 and activation of caspase-3, but not with Bax. These results suggests that propolis-induced apoptosis is related to the selective activation of caspase-3 and induction of Bcl-2/Bax regulation. PMID- 21783890 TI - Food flavor cinnamaldehyde-induced biochemical and histological changes in the kidney of male albino wistar rat. AB - Rats were given food flavor cinnamaldehyde (CNMA) orally by gavage at the dose of 2.14, 6.96, 22.62 and 73.5mg/kg body weight/day for 10, 30 and 90 days. Only the group of rats treated with CNMA at the dose 73.5mg/kg body weight/day for 90 days showed histological changes in the kidney followed by increased activities of renal, serum and urinary enzymes. CNMA-induced glucosuria in these rats was accompanied by marked proteinuria and creatinuria. Increased serum blood urea nitrogen and serum creatinine and decreased serum protein and glucose levels were observed in these rats. Thus, CNMA at the dose of 73.5mg/kg body weight/day for 90 days exert its effect on kidney of male albino wistar rat and its effect is time and dose dependent. PMID- 21783891 TI - Effect of long-term geomagnetic field deprivation on the concentration of some elements in the hair of laboratory rats. AB - The aim of the study was to determine the effect of long-term geomagnetic field (GMF) deprivation on the concentration of selected elements in the hair of laboratory rats. A total of 32 Wistar laboratory rats were divided into four equal groups (males and females) kept under hypomagnetic conditions (GMF vertical component below 20nT) and two control groups (males and females) kept free of field disturbances (GMF vertical component approx. 38000nT). At the beginning and at 7 months of the experiment, hair was taken from the dorsal part of all rats and analysed using atomic emission spectrometry for the concentration of selected magnetic elements (Fe, Ni, Co, Cr, Mn and Cu). Long-term GMF deprivation was found to affect the concentration of Fe, Mn, Cu and Cr, but had no significant effect on the concentration of Co or Ni in the hair of the analysed rats. PMID- 21783892 TI - Polysaccharides isolated from Ganoderma lucidum occurring in Southern parts of India, protects radiation induced damages both in vitro and in vivo. AB - The in vivo and in vitro radioprotective property of the polysaccharides isolated from Ganoderma lucidum were determined by survival studies, induction of micronucleus in reticulocytes of mice, strand breaks in plasmid pBR322 DNA and inhibition of lipid peroxidation (TBARS assay). Polysaccharides were administered as a single dose after whole body exposure to 10Gy (60)Co gamma-radiation to Swiss albino mice. At a dose of 500MUg/kg body wt, the polysaccharides were most effective in protecting animals from radiation induced loss of lethality. Administration of 500MUg/kg body wt to animal exposed to 10Gy gamma radiation resulted in more than 60% survival on the 30th day compared to the dose of 300mg/kg/body wt administration of amifostine, a clinically used radioprotective drug. The induction of micronuclei was reduced by the administration of polysaccharides. The decrease in micronuclei induction was dose dependent. Thus following 4Gy exposure the micronuclei in polychromatic erythrocytes (MNCE) was reduced from 28.16+/-3.049 to 16.0243+/-2.074 and 6.30+/-2.422 by polysaccharides at doses of 250MUg/kg body wt and 500MUg/kg body wt, respectively, and to 10.4+/ 2.581 by amifostine at a dose of 300mg/kg body wt. The results indicate the significant protective effect of Ganoderma polysaccharides against radiation induced damages. The findings thus suggest the potential use of Ganoderma polysaccharides as novel radioprotective agent. PMID- 21783893 TI - Effects of catalpalactone on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells. AB - The effects of catalpalactone on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Catalpalactone at 5-30MUM decreased intracellular dopamine content with the IC(50) value of 22.1MUM. Catalpalactone at 5-20MUM, but not 30MUM, did not alter cell viability. Catalpalactone at 20MUM inhibited tyrosine hydroxylase (TH) and aromatic-l-amino acid decarboxylase (AADC) activities. Catalpalactone also decreased cyclic AMP levels and inhibited TH phosphorylation. In addition, catalpalactone at 20MUM reduced the increases in dopamine levels induced by L-DOPA (20-50MUM). Catalpalactone (5-30MUM) associated with L-DOPA (50-100MUM) enhanced L-DOPA-induced cytotoxicity at 48h, which was prevented by N-acetyl-l-cysteine. These results suggest that catalpalactone inhibited dopamine biosynthesis by reducing TH and AADC activities and enhanced L DOPA-induced cytotoxiciy in PC12 cells. PMID- 21783894 TI - Anti-inflammatory activity of four solvent fractions of ethanol extract of Mentha spicata L. investigated on acute and chronic inflammation induced rats. AB - Anti-inflammatory effects of four solvent fractions of ethanol extract of Mentha spicata were evaluated in acute and chronic inflammation induced in Wistar albino rats. Lipid peroxidation (LPO) and some antioxidants produced during chronic inflammation were quantitated. Hexane (320mg/kg of body weight in 25% DMSO), chloroform (320mg/kg body weight in 25% DMSO), ethyl acetate (160mg/kg body weight in 25% DMSO), aqueous (320mg/kg of body weight in ddH(2)O) fractions, two negative control groups (25% DMSO and ddH(2)O) and two anti-inflammatory drugs (Diclofenac: 25mg/kg of body weight; Indomethacin: 10mg/kg of body weight both in ddH(2)O) were administered by oral intubations to the eight groups of rats consisting six animals, each. In acute study, 1% carrageenan was injected subcutaneously in the sub-plantar region of the right hind paw after 1h of administration of test doses. The increased paw edema was measured at 0.5, 1, 2, 4, 8, 16 and 24h intervals. In the chronic study, the oral administration was carried out for seven consecutive days. On eighth day, four sterile cotton pellets (50mg each) were implanted subcutaneously in the dorsal region of the rats. On the sixteenth day, the rats were sacrificed and the cotton pellets with granulomatous tissue were dissected out and weighed (fresh and dry). Both in chronic and acute inflammation, ethyl acetate (EAF) and aqueous fraction (AF) were effective. EAF is comparable with the positive standards in chronic inflammation. The results indicate that EAF's anti-inflammatory activity is largely due to its ability to modulate in vivo antioxidants. PMID- 21783895 TI - Damage to lung epithelial cells and lining fluid antioxidant defense by humic acid. AB - Humic acid causes diseases including lung emphysema and fibrosis. Emerging evidence indicates that oxidative stress is involved in humic acid-induced effects. In the present study, we investigated generation of hydroxyl radicals from humic acid, as well as the effects of humic acid to lung epithelial cells and artificial alveolar lining fluid antioxidant mixture. The involvement of iron in humic acid-induced effects was also determined. We found that humic acid (concentration and time dependently) reduced the cell survival, increased caspase 3 activity, depleted GSH and raised lipid peroxidation in epithelial cells. Humic acid reduced antioxidant levels in the lining fluid antioxidant mix, which could be prevented by adding metal ion chelators. These findings suggest that humic acid causes oxidative stress in lung cells and alveolar lining fluid, which is most likely triggered by hydroxyl radicals produced directly from humic acid. Iron is probably involved in humic acid toxicity. PMID- 21783896 TI - Glutathione-dependent interaction of heavy metal compounds with multidrug resistance proteins MRP1 and MRP2. AB - The interactions of three heavy metal-containing compounds, cisplatin (CDDP), arsenic trioxide (As(2)O(3)), and mercury dichloride (HgCl(2)), with the multidrug resistance transporters MRP1 and MRP2 and the involvement of glutathione (GSH)-related processes herein were investigated. In Madin-Darby canine kidney cells stably expressing MRP1 or MRP2, viability, GSH content, calcein efflux and polarized GSH efflux were measured as a function of exposure to CDDP, As(2)O(3) and HgCl(2). In isolated Sf9-MRP1 and Sf9-MRP2 membrane vesicles, the interaction with MRP-associated ATPase activity was measured. In the latter model system adduct formation with GSH is not an issue. The data show that (1) CDDP interacts with both MRP1 and MRP2, and GSH appears to play no major role in this process, (2) As(2)O(3) interacts with MRP1 and MRP2 in which process GSH seems to be essential, and (3) HgCl(2) interacts with MRP1 and MRP2, either alone and/or as a metal-GSH complex. PMID- 21783897 TI - Suppression of zinc-induced p53 phosphorylation and p21 expression by wortmannin in A549 human pulmonary epithelial cells. AB - In A549 cells treated with zinc sulfate (ZnSO(4)), the levels of p53 phosphorylated at Ser15 and total p53 protein increased. Treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K)-related kinases, suppressed ZnSO(4)-induced phosphorylation and accumulation of p53 protein. Expression of cyclin-dependent kinase inhibitor p21, one of the genes regulated by p53, was up-regulated following exposure to ZnSO(4), and suppressed by preincubation with wortmannin. These results suggest that zinc might induce the phosphorylation of p53 at Ser15 through wortmannin-sensitive pathway(s) at least in part, and result in the transactivation of the p21 gene in this human pulmonary epithelial cell line. PMID- 21783898 TI - Chemical warfare agents. AB - Chemical warfare agents (CWA's) are defined as any chemical substance whose toxic properties are utilised to kill, injure or incapacitate an enemy in warfare and associated military operations. Chemical agents have been used in war since times immemorial, but their use reached a peak during World War I. During World War II only the Germans used them in the infamous gas chambers. Since then these have been intermittently used both in war and acts of terrorisms. Many countries have stockpiles of these agents. There has been a legislative effort worldwide to ban the use of CWA's under the chemical weapons convention which came into force in 1997. However the manufacture of these agents cannot be completely prohibited as some of them have potential industrial uses. Moreover despite the remedial measures taken so far and worldwide condemnation, the ease of manufacturing these agents and effectiveness during combat or small scale terrorist operations still make them a powerful weapon to reckon with. These agents are classified according to mechanism of toxicity in humans into blister agents, nerve agents, asphyxiants, choking agents and incapacitating/behavior altering agents. Some of these agents can be as devastating as a nuclear bomb. In addition to immediate injuries caused by chemical agents, some of them are associated with long term morbidities and psychological problems. In this review we will discuss briefly about the historical background, properties, manufacture techniques and industrial uses, mechanism of toxicity, clinical features of exposure and pharmacological management of casualties caused by chemical agents. PMID- 21783899 TI - Manganese-induced single strand breaks of mitochondrial DNA in vitro and in vivo. AB - The aim of this study was to examine the single strand breaks (SSB) of mitochondrial DNA (mtDNA) induced by MnCl(2) in vitro and in vivo and discuss the possible underlying mechanism. In in vitro study the formation of mtDNA SSB and reactive oxygen species (ROS) in isolated hepatic mitochondria treated with MnCl(2) (0-1.0mmolL(-1)) was observed. In in vivo study the SSB of brain and liver mtDNA was examined, meanwhile the level of glutathione (GSH) and malondialdehyde (MDA) and activity of antioxidant enzymes were examined after 3 month intraperitoneal administration of MnCl(2) daily (0, 5, 10 and 20mg/kg/d) in Sprague-Dawley rats. The in vitro results indicated that MnCl(2) increased the formation of mtDNA SSB and ROS in **a dose-dependent manner in vitro. MnCl(2) exposure in vivo increased in mtDNA SSB in rat brain and liver and decreased in level of GSH in rat hepatic mitochondria and brain homogenates in a dose dependent manner. The level of MDA and the activities of SOD and GPx were not significantly changed in both hepatic mitochondria and brain homogenates of rats. These results indicated that Mn treatment increased in mtDNA SSB in vitro and in vivo, mediated probably via Mn-induced oxidative stress. PMID- 21783900 TI - Mechanism based QSAR studies of N-phenylbenzamides as antimicrobial agents. AB - N-Phenyl benzamides are potent antibacterial agents. They are active against both Gram-positive and Gram-negative bacteria. The Gram-positive bacteria have strong and thick cell wall while the Gram-negative bacterial have thin and permeable cell wall. The DFT based QSAR reveals that molecular weight and total energy significantly contribute to activity against both kinds of target. The electrophilicity index involved in QSAR models derived with anti-Gram-positive activity indicates the dominance of electrostatic interaction. The molar refractivity and logP is involved in QSAR model derived with anti-Gram-negative activity shows steric and hydrophobic interaction. The CoMFA and CoMSIA results also indicate that anti-Gram-positive bacterial activity is a function of electrostatic field effect but the anti-Gram-negative activity depends on hydrophobicity and steric field effect. The CoMFA and CoMSIA contour maps give an indication, the electropositive group around benzene "X" and an electronegative group around carbonyl oxygen is desirable for better anti-Gram-positive bacterial activity. A hydrophobic group around meta position of ring "X" with bulky group at ortho position and a small group at para position are desirable for better activity against Gram-negative target. The findings are reasonable and the mechanism might be different due to difference in composition of cell wall. The cell wall of Gram-positive target does not allow the permeability and only external electrostatic interaction is possible while the cell wall of Gram negative target allows the permeability of molecules inside the cell for possible hydrophobic and steric bulk interaction. PMID- 21783901 TI - Acute toxicity impacts of hexavalent chromium on behavior and histopathology of gill, kidney and liver of the freshwater fish, Channa punctatus (Bloch). AB - Alteration in behavioral patterns and histopathology of gill, kidney and liver were studied in Channa punctatus, after acute exposure to hexavalent chromium. The 96h LC(50) of chromium salt, potassium dichromate was determined to be 41.75mg/L. The exposed fish displayed erratic swimming and became lethargic. The changes in gills were characterized by epithelial hyperplasia, lamellar fusion, oedema, epithelial lifting, epithelial necrosis and desquamation, aneurism as well as curling of secondary lamellae. Hypertrophy of epithelial cells of renal tubules with reduced lumens, atrophy of the renal tubules, glomeruli contraction in the Bowman's capsules and necrosis of haematopoietic tissues were observed in the trunk kidney of exposed fish. The interrenal cells of the head kidney exhibited distinct hypertrophy and vacuolization. The liver hepatocytes showed cytoplasmic vacuolization with the lateral nuclei arrangement. Hepatocytes atrophy and increase in sinusoidal space were also observed. The result showed that acute chromium toxicity severely affects the vital organs and normal behavior which may be deleterious for fish populations. PMID- 21783902 TI - Antioxidant, cytotoxic and genotoxic evaluation of alcoholic extract of Polyalthia cerasoides (Roxb.) Bedd. AB - Antioxidative potential of alcohol extract of Polyalthia cerasoides was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical, superoxide anion scavenging, and reducing power assays were performed. The extract showed significant reactive oxygen species (ROS) scavenging activity in all in vitro antioxidant assays and contained high level of total phenolic content. For in vivo genotoxic evaluation, Swiss albino mice were treated with alcohol extract at the concentration of 40mg/kg body weight. Frequency of aberration was compared with control. Both the sets did not showed genotoxic effect. Further the extract was subjected to cytotoxic study using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphynyl tetrazolium bromide (MTT) assay, the extract confirmed to show moderate cytotoxicity against L929 cell line. PMID- 21783903 TI - Temperature effect on chemical-induced carcinogenesis in hamster cheek pouch. AB - 7,12-Dimethylbenz[a]anthracene (DMBA), a potent chemical carcinogen, was used to induce oral cancer on hamster buccal pouch, under two temperature regimes (22+/-2 and 28+/-2 degrees C) for 25 weeks of observation. The animal group under high temperature showed rapid tumour incidence and weight loss. It also exhibited biochemical changes such as reduced lipid peroxidation in the oral tumour tissue, accompanied by significant increase in the levels of reduced glutathione, glutathione peroxidase and glutathione-s-transferase. Therefore, we propose that elevated temperature is a cofactor, accelerating the process of DMBA-induced carcinogenesis in hamster cheek pouch. PMID- 21783904 TI - Simultaneous application of t-test and fold change criteria to identify acetaminophen and carbon tetrachloride affected genes in mice liver. AB - t-Test and fold change criteria were employed simultaneously following acute exposure to acetaminophen and carbon tetrachloride to provide high statistical confidence in the identification of affected genes in mice livers. Furthermore, gene expression data was also investigated with either t-test or fold change criteria alone. Gene expression studies were also accompanied by liver histological and serum biochemical studies for toxicity evaluation. We identified a large number of affected genes using both filtering criteria (p<0.01 and twofold) simultaneously following both the hepatotoxicants. In some cases gene expression studies provided the earliest evidence of tissue response in the absence of traditional markers at histological and biochemical level. We conclude that simultaneous application of t-test and fold change criteria helps to identify important genes with greater statistical confidence than the use of either of them alone, however, this approach results in the reduction of identified probes. Thus, data analysis at different statistical stringencies is needed to know exact outcome of any toxicological event. PMID- 21783905 TI - Genotoxicity evaluation of low doses of clodinafop-propargyl to the silkworm Bombyx mori using alkaline single-cell gel electrophoresis. AB - In the present study, DNA damage caused by clodinafop-propargyl was evaluated in silkworm, Bombyx mori, by the alkaline single-cell gel electrophoresis (SCGE). The second, fourth and fifth instar larvae of silkworm were exposed to clodinafop propargyl by oral feeding with mulberry leaves treated using the different concentration of 30, 60, 120, 240, 480mgL(-1), respectively. The results showed that comet percentage, the head DNA percentage, tail DNA percentage, tail length, tail moment and olive moment of the five tested groups were significantly different from the controlled group (P<0.01). A statistically significant (olive tail moment, P<0.01) dose-dependent increase in DNA damage was observed in silkworm. In addition, the significant dose-dependent reduce in percentage of cocooning and pupating was found in the second instar larvae of silkworm exposed to clodinafop-propargyl. To our knowledge, this was the first report describing the genotoxicity assessment of pesticide using silkworm by the alkaline SCGE. PMID- 21783906 TI - Prioritizing veterinary pharmaceuticals for aquatic environment in Korea. AB - Pharmaceutical residues may have serious impacts on nontarget biological organisms in aquatic ecosystems, and have therefore precipitated numerous investigations worldwide. Many pharmaceutical compounds available on the market need to be prioritized based on their potential ecological and human health risks in order to develop sound management decisions. We prioritized veterinary pharmaceuticals in Korea by their usage, potential to enter the environment, and toxicological hazard. Twenty compounds were identified in the top priority class, most of which were antibiotics. Among these compounds, 8 were identified as deserving more immediate attention: amoxicillin, enramycin, fenbendazole, florfenicol, ivermectin, oxytetracycline, tylosin, and virginiamycin. A limitation of this study is that we initially screened veterinary pharmaceuticals by sales tonnage for veterinary use only. However, this is the first attempt to prioritize veterinary pharmaceuticals in Korea, and it provides important concepts for developing environmental risk management plans for such contaminants in aquatic systems. PMID- 21783907 TI - Toxic effects of enrofloxacin on growth rate and catalase activity in Eisenia fetida. AB - Enrofloxacin (EFLX) has been proven effective against both gram-negative and gram positive microorganisms and used widely in animal husbandry. It may enter the soil environment with the excreta of treated animals. The aim of this study is to determine the toxicity of EFLX on the whole earthworms as well as its different tissues. Earthworms of Eisenia fetida were exposed to EFLX at 0, 500, 1000, 3000, and 5000mg/kg concentrations; samples were taken at days 2, 7, and 14 of exposure for determination of catalase (CAT) activity and growth rate. The growth rate showed little differences in all treatment groups. CAT activity was shown to be changeable at different tissues, exposure time, and EFLX concentrations. The intestinal tissues were more sensitive to EFLX than the body wall muscle tissues and whole earthworms. The investigation of CAT activity, especially in the intestinal tissues, can provide important information in terms of toxic effects of soil contamination. PMID- 21783908 TI - Selected markers of cardiovascular disease in a population exposed to arsenic from drinking water. AB - This study examined prevalence and serum levels of selected markers of cardiovascular disease in 34 subjects from a Croatian rural population exposed to high levels of arsenic (As) from drinking water (611.89+/-10.06MUg/l). The prevalences of overweight and obese subjects in the population were 32% and 35%. Half the subjects had hypertension, 29% had increased fasting serum glucose level and two were diabetic. Median total cholesterol (5.82mmol/l) and triglycerides (2.15mmol/l) were above the desirable margins. The median C-reactive protein level (1.20mg/l) was slightly higher than previously reported for healthy subjects. Serum Hsp70 level was significantly higher in nonsmokers. Total urinary As levels were positively correlated with age-adjusted serum levels of cobalamin. Near significance were also serum total bilirubin, antibodies to Hsp60 and folate. Tentative investigation of risk factors among subjects classified by tumor necrosis factor-alpha -308G/A and interleukin-6-174G/C gene polymorphisms was also performed. Collectively, the results are in agreement with the hypothesis of As-induced and/or compounded cardiovascular disease. PMID- 21783909 TI - Antiproliferative and immunostimulatory protein fraction from edible mushrooms. AB - Fruit bodies and mycelia of various higher Basidiomycetes were studied in search of biological effector molecules. In this study, we evaluated the antiproliferative and immunomodulatory properties of a protein fraction designated as Cibacron blue affinity eluted protein (CBAEP) isolated from five different species of edible mushrooms (Termitomyces clypeatus, Pleurotus florida, Calocybe indica, Astraeus hygrometricus, and Volvariella volvacea). This protein fraction (10-100MUg/ml) mediated antiproliferative activity on several tumor cell lines through the induction of apoptosis. Also the isolated protein fraction from all five mushrooms had a stimulatory effect on splenocytes, thymocytes and bone marrow cells. Further it enhanced mouse natural killer (NK) cell cytotoxicity and stimulated macrophages to produce nitric oxide (NO). The highest immunostimulatory activity was determined in the CBAEP from T. clypeatus and the highest antiproliferative activity from C. indica. PMID- 21783910 TI - Toxic effects of chlorpyrifos on antioxidant enzymes and target enzyme acetylcholinesterase interaction in mosquito fish, Gambusia affinis. AB - The recovery effect of chlorpyrifos (CPF) on antioxidant enzymes, locomotor behaviour and the target enzyme acetylcholinesterase (AChE) interaction were studied after exposure to 297MUgL(-1) (LC(50) for 96h) in mosquito fish, Gambusia affinis. Activities of the antioxidant enzymes-superoxide dismutase, catalase, glutathione reductase in viscera, and AChE in brain were inhibited at 96h of exposure. However, induction in lipid peroxidation was observed. The antioxidant levels were restored to near control by 16-18 days. Similarly, swimming speed and AChE were also recovered but comparatively needs longer period. In vitro AChE study indicated that CPF alters the apparent K(m) values, resulting in a competitive type of inhibition and the inhibitory constant K(i) was found to be 4.57*10(-4)M. The results showed that the organophosphate CPF besides its inhibitory effect on target enzyme AChE also inhibits antioxidant enzymes, which can be used as biomarkers in the pesticide-contaminated aquatic streams. PMID- 21783911 TI - Histopathological effects of 4-tert-octylphenol treatment through the pregnancy period, on the pituitary, adrenal, pancreas, thyroid and parathyroid glands of offspring rats at adulthood. AB - The present study was carried out to investigate the effects of 4-tert octylphenol (OP) exposure at fetal period on adrenal, pituitary, thyroid+parathyroid and pancreas tissues of male and female offsprings. Pregnant rats were treated with OP (100 or 250mg/(kgday)) in vehicle (corn oil) or vehicle alone daily from day 1 to 20 of pregnancy. After birth, young rats were allowed to growth until adulthood. While there were no differences in data of organ weight between control and treatment groups, in contrast, a decrease of relative organ weights of thyroid+parathyroid and adrenal in high dose treatment group in male rats, otherwise an increase of final body weights was found in 250mg/(kgday) treatment group in all rats. Also, a lot of histopathological findings were observed in investigated tissues. The results of this study suggest that, the octylphenol which was applied in fetal period causes negative effects on the adrenal, pituitary gland, thyroid+parathyroid and pancreas in rats. PMID- 21783912 TI - Effect of ivermectin on male fertility and its interaction with P-glycoprotein inhibitor (verapamil) in rats. AB - Administration of permeability-glycoprotein (Pgp) inhibitors can modify the pharmacological properties or induce toxic effects of Pgp substrates. The effects of administration of ivermectin (anthelmentic drug, Pgp substrate), either alone or simultaneously with verapamil (Pgp inhibitor) on male fertility were studied by determining mounting behavior, epididymal spermatozoal analysis, weight and histopathological examination of male reproductive organs and cytogenetic evaluation of meiotic chromosome. The results revealed that administration of ivermectin once weekly for 8 weeks induced slight fertility disturbances. While, pre-treatment with verapamil disturbed male fertility through altering different sperm parameters and histological structure of reproductive organs. Cytogenetic study revealed partial effect of ivermectin on meiosis. Meanwhile, the combined treatment of ivermectin and verapamil induced stronger effects on germ cells, increased frequency of meiotic structural chromosomal aberrations and increased X Y chromosomal dissociation, raising the attention to the genetic quality of mature sperm. We concluded that ivermectin has slight effects on male fertility, but when taken with verapamil induced adverse effects on meiosis and fertility. PMID- 21783913 TI - Exercise intolerance and chronotropic impairment-The long-term cardiovascular sequelae of mustard gas exposure: A paired-comparative study. AB - BACKGROUND: Although there are some data regarding the pulmonary manifestations of mustard gas exposure, little is known about its cardiovascular sequelae. METHODS: The spirometric and exercise tolerance test results of two groups of patients with chronic bronchitis one with (group A) and one without (group B) previous exposure to mustard gas and a group of veterans with no bronchitis (group C) were compared. RESULTS: The exercise capacity was similar in groups "A" and "B" patients. Both groups, showed a remarkable impairment of exercise capacity (p<0.001) compared to the group "C" individuals. Although the mean resting heart rate was significantly higher in group "A" patients than group "B" individuals (p=0.01), their mean peak exercise heart rate was significantly lower (p=0.01). Both groups, however, achieved a significant lower peak exercise heart rates, compared to the group "C" subjects (p<0.001). CONCLUSION: Mustard gas exposure can limit the exercise capacity and abolish the normally expected chronotropic response to exercise. PMID- 21783914 TI - Risk assessment of human antibiotics in Korean aquatic environment. AB - In Korea, antibiotic usage has received a lot of attention from the public due to the increasing number of bacteria resistant to the currently used antibiotics. In this study based on FDA regulation and EU draft guideline, the most concerned antibiotics regarding their environmental risk in Korea were assessed and the refined predicted environmental concentration in surface water (PEC(surface water)) was obtained by applying a GIS-based KORea ECOlogical Risk assessment (KOREOCORisk) model. Thirteen antibiotics, which expected introductory concentration (EIC) greater than the trigger value (1.0MUg/L), were chosen to assess ecological risk and the PEC/PNEC ratio exceeded 1.0 for amoxicillin, erythromycin and roxithromycin. The results in this study using conservative assumptions did not represent that there is a risk for acute toxic effects in the environment based on today's use of pharmaceuticals in Korea. However, the results do not exclude the potential for chronic environmental effects. PMID- 21783915 TI - Low dose 4-MBC effect on neuroendocrine regulation of reproductive axis in adult male rats. AB - 4-Methylbenzylidene camphor (4-MBC) is an ultraviolet absorbent. The objective of this paper was to evaluate the effect of 4-MBC low-dose exposure on the neuroendocrine reproductive regulation in male rats. Wistar male adult rats were injected sc. with 4-MBC during 5 days with a dose of 2 and 10mg/kg or during 2 days with a dose of 2 and 20mg/kg. In all rats serum prolactin, LH and FSH concentration were assayed. The hypothalamus of rats injected during 2 days were also dissected to study GnRH release. Rats that received 2 and 10mg/kg of 4-MBC during 5 days showed a decrease in the LH and FSH serum concentration. In rats injected during 2 days, serum LH decreased with 2 and 20mg/kg and FSH decreased with 2mg/kg of 4-MBC. In vitro hypothalamic GnRH release also decreased in these animals. These results show that low doses of 4-MBC inhibit the reproductive axis in adult male rats. PMID- 21783916 TI - Oxidative stress induced by lambda-cyhalothrin (LTC) in rat erythrocytes and brain: Attenuation by vitamin C. AB - The objective of this study was to investigate the propensity of lambda cyhalothrin (LTC) to induce oxidative stress in blood and brain of male Wistar rats and its possible attenuation by vitamin C. Rats were randomly divided into four groups: group I served as control rats. group II was treated daily with 200mgvit C/(kgbw) administered by intraperitoneal way. Rats of group III have received orally 668ppm LTC. Animals of group IV were treated with LTC and vitamin C. A decrease of some hematologic parameters (RBC, Hb, Ht: p<0.01) and a significant increase of MDA levels (p<0.05) in erythrocytes and brain were observed in LTC group compared to controls. Antioxidant enzyme activities in both tissues were modified in LTC group compared to controls. Administration of vitamin C ameliorated these parameters. Our results indicated the potential effects of LTC to induce oxidative damage in tissues and the ability of vitamin C to attenuate LTC-induced oxidative damage. PMID- 21783917 TI - In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. AB - Manganese (Mn) is an essential trace element for human nutrition but also a toxicant when humans are exposed to high concentration. Occupational exposures to excess levels of Mn are known to cause manganism in humans. Mn is known to induce mitochondrial dysfunction in excessive dose, however the mechanisms underlying its action are not elucidated clearly. To determine the possible role of energy metabolism and oxidative stress in Mn-induced mitochondria injury, isolated mitochondria were exposed to different concentrations of MnCl(2) (5, 50, 500, 1000MUmol/L), aconitase and mitochondrial complex I activities, MDA and GSH contents, MMP were investigated. In addition, effects of NAC (500MUmol/L) were studied at 500MUmol/L MnCl(2). Dose-dependent inhibition of aconitase and mitochondrial complex I activities, increase of MDA content, decrease of GSH content and MMP were observed. Further investigation indicated NAC pre-treatment significantly reversed toxic effect of MnCl(2). The results indicated that manganese could dose-dependently induce the decline of energy metabolism and cause oxidative damage of mitochondria isolated from rat brain, and this change could be prevented by pre-treating with NAC. PMID- 21783918 TI - Effects of Ligustrum delavayanum Hariot. on cholesterol levels and arrhythmogenesis induced by myocardial ischaemia-reperfusion injury in diabetic hypercholesterolaemic rats. AB - The present study was conducted to determine the effects of Ligustrum delavayanum Hariot. (Oleaceae) on cholesterol levels and the outcome of myocardial reperfusion injury in diabetic-hypercholesterolaemic rats. Per orally daily administration of a Ligustrum infusion (1000mg/kg, calculated on the dry plant material) to the rats with induced diabetes and hypercholesterolaemia significantly reduced the liver total cholesterol content. Similarly, increased severity of reperfusion arrhythmias in the double-diseased rats was diminished upon Ligustrum-treatment. These results suggest a potential use of Ligustrum in the prevention/therapy of risk factors and coronary heart disease itself. PMID- 21783919 TI - Evaluation of DNA damage in jewellery workers occupationally exposed to nitric oxide. AB - Nitric oxide is a metastable radical, reacts with oxygen to produce toxic nitrogen oxides (N(2)O(3), ONOO(-)) which damage DNA. Occupational exposure to nitric oxide leads to increased frequency of chromosomal aberrations in humans. In the present study the DNA damage among the jewellery workers occupationally exposed to nitric oxide was analyzed using buccal cell comet assay. The result of this study shows increased levels of DNA damage among jewellery workers. The habit of cigarette smoking among the jewellery workers has a synergistic effect on inducing DNA damage. PMID- 21783920 TI - Bioactivities of Piper aduncum L. and Piper obliquum Ruiz & Pavon (Piperaceae) essential oils from Eastern Ecuador. AB - Essential oils from aerial parts of Piper aduncum (Matico) and Piper obliquum (Anis del Oriente) of ecuadorian origin were analyzed by GC-FID, GC-MS, (13)C NMR and their biological and pharmacological activities were assessed. Chemical composition proved to be unusually different from previous reports for safrole rich P. obliquum (45.8%), while P. aduncum main constituent was dillapiol (45.9%). No genotoxic activity was found in the Ames/Salmonella typhimurium (TA98 and TA100) assay, either with or without S9 activation. Mutagen-protective properties, evaluated using sodium azide, 2-nitrofluorene and 2-aminoanthracene as mutagens/promutagens, was observed against promutagen 2-aminoanthracene, likely in consequence of microsomial deactivation. Antimicrobial assays have been performed on Gram+/Gram- bacteria, dermatophyte and phytopathogenic fungi and best results were provided by P. aduncum against fungal strains with complete inhibition at 500MUg/ml. Preliminary analgesic and antithrombotic activities evidenced the absence of the former in hot plate and edema assays and a limited antiplatelet action against three different agonists (ADP, AA and U46619). Both oils have a very limited antioxidant capacity. PMID- 21783921 TI - Removal of radioisotopes in solution and bactericidal/bacteriostatic sterilising power in activated carbon and metal silver filters. AB - Activated carbon filters play an important role in water filtration and purification from contaminants of different origin. Their limit consists in bacterial proliferation, which may occur only during prolonged periods of non-use and in their ability to remove radioactive contaminants present in waste water from Industry or Nuclear Medicine departments. In this work we tested a commercially available activated carbon filter for water purification enriched with silver plated parts incubating in static condition at room temperature different micro organisms (Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis, Staphylococcus aureus, Aspergillum niger), up to 78 days. The microbial growth was in general more inhibited in the presence of metal silver into the activated carbon in respect to filters with the activated carbon alone: >4log inhibition of bacterial proliferation after 78 days of incubation the presence of silver vs. 2log without silver. When the filters were incubated empty of carbon, the sterilizing power of silver was confirmed further. The activated carbon filters proved also their ability in removing from water the principal radioisotopes used for residues liquid medical and research purposes ((131)I, (99m)Tc, (201)Tl, (67)Ga). These results contribute useful data for the use of the silver-enriched carbon filters in water filtration both for daily use at home, and professional use in a Nuclear Medicine laboratory. PMID- 21783922 TI - Bacopa monnieri modulates antioxidant responses in brain and kidney of diabetic rats. AB - Role of oxidative stress has been reported in various diabetic complications including neuropathy, nephropathy and cardiopathy. This study was undertaken to evaluate the protective effect of Bacopa monnieri, a medicinal plant, on tissue antioxidant defense system and lipid peroxidative status in streptozotocin induced diabetic rats. Extract of B. monnieri was administered orally, once a day for 15 days (at doses 50, 125 and 250mg/(kgbw)) to diabetic rats. Activity of antioxidant enzymes (SOD, Catalase, and GPx), levels of GSH and lipid peroxidation were estimated in kidney, cerebrum, cerebellum and midbrain of diabetic rats and compared to reference drug, Glibenclamide. Administration of plant extract to diabetic rats showed significant reversal of disturbed antioxidant status and peroxidative damage. Significant increase in SOD, CAT, GPx activity and levels of GSH was observed in extract treated diabetic rats. The present study indicates that extract of B. monnieri modulates antioxidant activity, and enhances the defense against ROS generated damage in diabetic rats. PMID- 21783923 TI - Placental lead-induced oxidative stress and preterm delivery. AB - It has been reported that impaired oxidant/antioxidant status is involved in a variety of pregnancy complications. To elucidate the possible free radical mediated mechanism of preterm delivery due to lead exposure by determining the placental lead level and oxidant/antioxidant status in women with the preterm and full-term deliveries. Twenty-nine women with preterm deliveries (gestational age 28-37 weeks) and 31 women with full-term deliveries (gestational age >37 weeks) attending a local hospital of Lucknow, India were recruited. Placental lead level, thiobarbituric acid reactive species (TBARS) level, as an end product of lipid peroxidation, antioxidant molecule glutathione (GSH) level, and activity of antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) were measured in the placental tissue. In the group with preterm delivery, significantly higher placental lead levels were recorded than in those of full term (0.39MUg/g vs. 0.27MUg/g; p<0.05). TBARS was significantly higher while GSH was significantly lower in the placenta of women with the preterm deliveries as compared to the full-term deliveries (p<0.05 for each). Activity of antioxidant enzymes; SOD, CAT, GPx, and GR were significantly higher in the placenta of women having preterm deliveries than those of the full-term (p<0.05 for each). Furthermore, placental lead has significant positive correlations with TBARS (r=0.34, p<0.05), SOD (r=0.30, p<0.05) and CAT (r=0.41, p<0.05), and negative correlation with GSH (r=-0.31, p<0.05). There may be a number of plausible reasons for increased oxidative stress in preterm delivery. However, results of this pilot study suggest that lead-induced oxidative stress may be one of the underlying mechanism(s) of preterm delivery and emphasizes the importance of evaluating the impact of persistent environmental pollutants on adverse pregnancy outcome. PMID- 21783924 TI - In vitro toxicology assessment of cadmium bioavailability on primary porcine oviductal epithelial cells. AB - This study assessed the in vitro effects of cadmium ion (Cd(2+)) and cadmium fulvic acid complexes (Cd(2+)-FA) on porcine oviductal epithelial cells (POEC) using transmission electron microscopy (TEM). Fresh POEC were cultured for 24h and then exposed for 3h in the tested solutions. Absorbed cadmium was analyzed by graphite furnace atomic absorption spectrophotometer (AAS). Dissociation and exchange rate constants were determined using the competing ligand, Chelex-100 and predicted cadmium species were calculated using the MINTEQA2 program. The results showed that the dissociation rate constant of Cd(2+)-FA was equal to 1.023*10(-3)s(-1) which was slower than the exchange rate at 2.062*10(-3)s(-1). Nevertheless, the absorbed concentrations of Cd(2+) and Cd(2+)-FA of POEC were similar and were 47+/-6.25MUgL(-1) and 54+/-3.61MUgL(-1), respectively. Although both levels of absorptions were not significantly different (t-test p=0.168 at alpha 0.01), their morphological effects as examined by TEM were substantially different with the effects being most marked with Cd(2+)>Cd(2+)-FA>FA. Aggregations around nuclei and nuclear membranes were observed with FA treatment whilst Cd(2+)-FA treatment produced more cytoplasmic damage. Cd(2+) treatment caused nuclear deformities. In conclusion, FA appears to penetrate the cells but was less likely to enter the nucleus. It also reduced the toxicity of Cd(2+) as the nuclei from the Cd(2+)-FA treatment appeared normal. Nevertheless, some Cd(2+) could still enter the nucleus. This might be because there was still 67.8% Cd(2+) left unbound from the Cd(2+)-FA treatment as calculated from the MINTEQA2 program compared to 99.1% Cd(2+) with Cd(2+) treatment, thus underlining the inherent toxicity of soluble cadmium ion. PMID- 21783925 TI - Mutual synergistic toxicity between environmental toxicants: A study of mercury chloride and 4-nonylphenol. AB - Mercury chloride (HgCl(2)) and 4-nonylphenol (NP) are widespread environmental and industrial pollutants that are known to have toxic effects as well as endocrine disrupting activities. Although the individual effects of HgCl(2) and NP in liver have been relatively well recognized, little is known about the interaction of NP and HgCl(2) during the induction of their toxicity. In the current study, we investigated the synergism between HgCl(2) and NP using HepG2 cells. Surprisingly, the concurrent treatment of HepG2 with HgCl(2) and NP induced a significant cytotoxicity at concentrations where neither of them have any cytotoxic effect when treated alone. The cytotoxicity of NP is enhanced in the presence of HgCl(2) (a shift from 74.9 to 47.4MUM in LC(50)) and vice versa (a shift from 94.9 to 66.3MUM in LC(50)). Estrogen receptor antagonists such as ICI 182,780 did not protect HepG2 cells from these cytotoxic insults. Whereas the intracellular level of reduced form glutathione (GSH) was considerably decreased upon the co-treatment with NP and HgCl(2). Furthermore, the synergistic cytotoxicity was significantly inhibited by 20-mM N-acetylcysteine (NAC). These results indicate that the mutual synergistic cytotoxicity of HgCl(2) and NP on HepG2 cell is not associated with estrogen receptor signaling but mediated by reactive oxygen species (ROS) generation. In our real life, we are continuously and often simultaneously exposed to many different kinds of environmental pollutants. The present study suggests a mechanism of potential synergistic adverse effects of these toxic pollutants. PMID- 21783926 TI - Cyhalothrin increased c-fos immunoreactivity at the paraventricular nucleus of the hypothalamus in rats, and suppressed macrophage activity in an adrenal dependent fashion. AB - Synthetic type II pyrethroid insecticides, such as cyhalothrin at certain dosage levels, simultaneously induce stress-like symptoms and innate immunosuppressive effects in laboratory animals. The present study was designed to further analyze the stress-like effects induced by cyhalotrin and also investigate the role of Hypothalamus-Hypophysis-Adrenal (HHA) axis and Sympathetic Nervous Systems (SNS) and their effects on macrophage activity of rats. Results showed that cyhalothrin treatment (3.0mg/kg/day, for 7 days) increased corticosterone serum levels and c fos immunoreactivity at the paraventricular nucleus of the hypothalamus (PVN) but induced no changes in c-fos expression at the basolateral amygdala (BLA). Both areas were related to HHA axis and SNS activations by stress. Further analysis showed that adrenalectomy partially abrogated the suppression effects of cyhalothrin on macrophage activity and that 6-OHDA-induced peripheral symphatectyomy had no effects on this innate immune cell activity. The present observed data support and reinforce the notion that cyhalotrin at this treatment schedule induces stress-like symptoms and suggest that other factors, beyond indirect neuroadaptative responses, are necessary for the suppression effects of insecticide on innate immune response. PMID- 21783927 TI - In vitro protective effects of pyrroloquinoline quinone on methylmercury-induced neurotoxicity. AB - Methylmercury (MeHg), as a well-known neurotoxicant, has been implicated to induce massive neurodegeneration. Pyrroloquinoline quinone (PQQ) is a novel redox cofactor and also exists in various plants and animal tissues. In vivo as well as in vitro experimental studies have shown that PQQ functions as an essential nutrient or antioxidant. In this study, we demonstrated the protective effects of PQQ on MeHg-induced neurotoxicity in PC12 cells. The results showed that after pretreatment of PC12 cells with PQQ prior to MeHg exposure, the MeHg-induced cytotoxicity was significantly attenuated, and then DNA fragmentation was correspondingly reduced. PQQ prevented the disruption of mitochondrial membrane potential, up-regulated the level of Bcl-2, and consequently inhibited the activation of caspase-3. Moreover, PQQ also decreased the production of ROS and maintained the GSH levels in PC12 cells exposed to MeHg. Thus, these data indicate that PQQ can protect neurons against MeHg-induced apoptosis and oxidative stress via ameliorating the mitochondrial dysfunction. Data from this study provide a new useful strategy for the treatment of neuronal toxicity induced by mercury toxins. PMID- 21783928 TI - Effect of tobacco compounds on gene expression profiles in human epithelial cells. AB - This study was carried out to investigate the effects of the tobacco compounds (TC), nicotine, B(a)P, and 2-naphthylamine, on gene expression profiles in a human epithelial cells (A549). We treated A549 with the TC and analyzed gene expression using microarray and real-time PCR (RTP). Gene expression varied according to the TC used. By microarray, we found that apoptosis-related genes such as apoptosis-associated tyrosine kinase, interleukin 10 receptor beta, caspase 1 and DNA fragmentation factor beta subunit (40kDa) were down-regulated in TC-treated A549 cells. RTP showed significant increases in the expression of Ahr, Arnt, CYP1A1, and CYP1B1 in TC-treated A549 cells. From these results, we suggest that tobacco compounds can influence apoptosis, inflammation, immunity, and the cell cycle in A549 cells. Also, our study demonstrates that a microarray based genomic survey is a suitable high-throughput approach for the evaluation of gene expression and for the characterization of TC-induced toxicity. PMID- 21783929 TI - Taurine enhances the metabolism and detoxification of ethanol and prevents hepatic fibrosis in rats treated with iron and alcohol. AB - The study examines the effects of taurine on the metabolism and detoxification of ethanol in liver fibrosis induced by simultaneous administration of iron carbonyl (0.5%, w/w) and ethanol (6g/(kgday)). Ethanol and iron administration caused liver damage and fibrosis as evidenced by liver histology and biochemical profile in plasma. Over accumulation of iron and a loss in taurine in hepatic tissue was observed in fibrotic animals. The activities of alcohol dehydrogenase and aldehyde dehydrogenase were significantly reduced in these rats compared to control. Adaptive induction of activities of Cytochrome P4502E1 (CYP2E1) and aniline hydroxylase accompanied by the reduction in glutathione-S-transferase, DT diaphorase and glyoxalases I and II was observed. Taurine administration (2% in drinking water) ameliorated the effects of ethanol and iron. Hepatic damage and fibrosis were reduced in taurine-supplemented rats. Thus taurine has the potential for the treatment of alcoholic liver fibrosis. PMID- 21783930 TI - Altered p53 response and enhanced transgenerational transmission of carcinogenic risk upon exposure of mice to betel nut. AB - Alteration of p53 protein level, and possible mutation of the p53 gene during carcinogenesis in mice exposed chronically (P) and transgenerationally to 2mg/ml aqueous extract of betel nut (AEBN) in drinking water, were studied. Exons 5 and 7 of the p53 gene were not mutated under both chronic and transgenerational exposure, but, p53 protein response was altered. In P mice, p53 protein was initially upregulated in comparison to age-matched controls, reaching 2.5 folds in the liver after 6 weeks of exposure. Subsequently, p53 protein declined to control level after 16 weeks, with concomitant preneoplastic nodulation of the liver. After 24 weeks, p53 protein was below control level, and preneoplastic nodules were well-developed. The level of p53 protein in transgenerationally exposed mice remained invariant in comparison to age-matched controls. Liver nodulation was significantly advanced, developing in F1 mice after 8 weeks, F2 mice after 6 weeks and F3 mice after 4 weeks of exposure. Anomalies not observed in P mice, developed in transgenerationally exposed mice, albeit, non significantly. Thus, AEBN exposure enhanced transgeneration transmission of carcinogenic risk. PMID- 21783931 TI - The effect of in vivo co-exposure to estrone and AhR-ligands on estrogenic effect to vitellogenin production and EROD activity. AB - We evaluated the effect of combination chemical exposure on estrogenic activity, in vivo using Japanese medaka (Oryzias latipes) during co-exposure to estrone (E1) and beta-naphthoflavone (betaNF) or alpha-naphthoflavone (alphaNF). We used E1 because which is one of the major estrogenic substances in the environment, and betaNF or alphaNF are both AhR-ligands and usually used as a model substance of common environmental pollutants such as PAHs from physiological response standpoint. The results of present study demonstrate that both betaNF and alphaNF inhibit the E1-induced production of plasma VTG in a concentration-dependent manner. These results indicate that estrogenic activity is suppressed by AhR ligands in aquatic environment. At the same time, significant increase of EROD was observed in groups of betaNF co-exposed with E1, conversely no significant alteration of EROD was observed in groups of alphaNF co-exposed with E1. Therefore, we conclude that the inhibition of VTG synthesis effect was not directly related to EROD. PMID- 21783932 TI - In vitro metabolism of norbormide in rat, mouse and guinea pig liver preparations. AB - Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and LC/MS identification revealed that NRB undergoes metabolism primarily to hydroxylated form that was tentatively identified in both rat and non-rat species with NADPH as the preferred cofactor. However, the metabolic profile and the rate are different between species. Gender differences are also reported in the metabolic rate in rats and we postulate that this may be responsible for different toxic sensitivities seen between sexes. Using this knowledge, we aim to develop pharmacological tool(s) for use in designing a new class of drugs that can be targeted in a tissue-selective manner. Further in vivo pharmacokinetic with receptor affinity studies are warranted. PMID- 21783933 TI - Saw palmetto extract induces nuclear heterogeneity in mice. AB - Saw palmetto (SW), a phytotherapeutic compound used in the treatment of prostate disease, was examined for potential nuclear effects. SW extract was incorporated into a complete casein-based semisynthetic rodent chow at 0%, 0.1% and 1% SW. SW was fed to mice for 6 weeks, after which the mice received a single i/p injection of either the known genotoxic agent methyl methanesulfonate (MMS) in saline or just saline. Forty-eight hours after injection, blood and bone marrow were collected for flow cytometric analysis. A significant effect of MMS was observed in both male and female mice with respect to: an increase in nuclear heterogeneity in bone marrow cells as measured by the coefficient of variation of the G1 peak in a flow histogram (6.32 versus 4.8 in male mice, 7.0 versus 4.9 in female mice) and an increase in the number of micronucleated blood cells (3.4% versus 0.56% male mice, 3.1% versus 0.6 in female mice) indicating a positive genotoxic response. SW also appears to increase the heterogeneity of bone marrow nuclei in a dose dependent manner (0-5.1%, 0.1-5.5% and 1-5.7% in male mice, 0 5.7%, 0.1-6.0% and 1-6.2% in female mice) without a concomitant increase in blood cell micronuclei. These results indicate that SW is not genotoxic with respect to physical DNA damage and that the changes observed in the bone marrow are due to chromatin conformation modifications in the nuclei of in vivo treated mouse cells. PMID- 21783934 TI - Induction of GADD153 expression by tributyltin in SH-SY5Y human neuroblastoma cells. AB - The effects of tributyltin (TBT) exposure on the expression of growth arrest- and DNA damage-inducible gene 153 (GADD153), also called C/EBP homologous protein (CHOP), were examined in SH-SY5Y human neuroblastoma cells. In response to TBT exposure, the levels of both GADD153 mRNA and GADD153 protein increased significantly. This effect was preceded by phosphorylation of c-Jun NH(2) terminal kinase (JNK). Treatment with the JNK inhibitor, SP600125, markedly suppressed TBT-induced GADD153 expression. TBT may induce the expression of GADD153, a gene highly responsive to endoplasmic reticulum (ER) stress, in a manner at least partially dependent upon the JNK pathway in SH-SY5Y cells. PMID- 21783935 TI - Environmental risk and toxicology of human and veterinary waste pharmaceutical exposure to wild aquatic host-parasite relationships. AB - Pollution of the aquatic environment by human and veterinary waste pharmaceuticals is an increasing area of concern but little is known about their ecotoxicological effects on wildlife. In particular the interactions between pharmaceuticals and natural stressors of aquatic communities remains to be elucidated. A common natural stressor of freshwater and marine organisms are protozoan and metazoan parasites, which can have significant effects on host physiology and population structure, especially under the influence of many traditional kinds of toxic pollutants. However, little is known about the effects of waste pharmaceuticals to host-parasite dynamics. In order to assess the risk waste pharmaceuticals pose to aquatic wildlife it has been suggested the use of toxicological data derived from mammals during the product development of pharmaceuticals may be useful for predicting toxic effects. An additional similar source of information is the extensive clinical studies undertaken with numerous classes of drugs against parasites of human and veterinary importance. These studies may form the basis of preliminary risk assessments to aquatic populations and their interactions with parasitic diseases in pharmaceutical-exposed habitats. The present article reviews the effects of the most common classes of pharmaceutical medicines to host-parasite relationships and assesses the risk they may pose to wild aquatic organisms. In addition the effects of pharmaceutical mixtures, the importance of sewage treatment, and the risk of developing resistant strains of parasites are also assessed. PMID- 21783936 TI - Aluminum accumulation induced testicular oxidative stress and altered selenium metabolism in mice. AB - Present work was carried out to investigate how testicular selenium (Se) metabolisms respond to oxidative stress induced by aluminum (Al). Mice were intraperitoneally exposed to 0, 7, or 35mg Al/kg/d for 14 days (CNL, LAL and HAL groups). Al administration significantly increased Al, reactive oxygen radical and malondialdehyde (MDA) levels, as well as decreased glutathione peroxidase (GPx) and glutathione reductase (GR) activities in serum and testes. The serum concentrations of Se were remarkably lower at LAL and HAL groups compared to the controls, whereas the testicular Se levels significantly reduced only in the HAL group. In addition, RT-PCR analysis revealed an increased testicular selenoprotein P (SelP) expression by Al treatment. Western blot analysis showed increased levels of SelP protein expression in the LAL group, but the expression levels were significantly reduced in HAL group. It was suggested that altered metabolism of Se, further stimulated testicular SelP transcription that may compensate for the loss of SelP protein resulted from Al-induced oxidative damage. PMID- 21783937 TI - Effects of prometryne on apoptosis and necrosis in thymus, lymph node and spleen in mice. AB - Prometryne is a methylthio-s-triazine herbicide. Significant traces are documented in environment, mainly waters, soil and plants used for nutrition. The aim of this study was to estimate prometryne immunotoxic properties through induction of apoptotic and/or necrotic changes in thymocytes, splenocytes and lymph node cells after repeated subchronical exposure. Three different doses of prometryne (185, 375, 555mgkg(-1)) were applied per os every 48h, over 28 days. Flow cytometry assay (annexinV-FITC and PI) was conducted to record apoptotic and necrotic damage. In the spleen significant changes in the percentage of apoptotic cells were not detected between treated and control groups respectively. In thymus and lymph node, within the lowest dose group (185mgkg(-)1), an increase in percentage of early apoptosis without any significant increase in necrosis was detected. Medium (375mgkg(-1)) as well as high dose triggered increase in late apoptosis in lymph node while in thymus; late apoptosis was increased only in animals exposed to the highest dose (555mgkg(-1)). The highest applied dose, in thymus and lymph node respectively, caused a general decrease in percentage of vital cells in favour of marked increase of percentages of all types of dying cells (apoptotic, late apoptotic/early necrotic and necrotic). Prometryne caused disbalance in major organs of immune system, markedly lymph nodes and thymus, by induction of early apoptotic changes in dose/time specific manner. PMID- 21783938 TI - Antigenotoxic and antioxidant activities of Pituranthos chloranthus essential oils. AB - The SOS-chromotest in Escherichia coli is a widely used bacterial genotoxicity assay to test potential carcinogens. The aim of this work is to evaluate the genotoxic and antigenotoxic activities of essential oils obtained from aerial parts of Pituranthos chloranthus. The tested essential oils were not genotoxic towards both E. coli PQ37 and PQ35 strains. These essential oils reduced significantly Nifuroxazide and H(2)O(2)-induced genotoxicity. Essential oils showed a protective effect against damages induced by radicals, obtained from the photolysis of H(2)O(2), on DNA plasmid through free radical scavenging mechanisms. The scavenging capacity of these essential oils was also estimated by evaluating the inhibition of ABTS(+.) radical. PMID- 21783939 TI - Oxidative stress response after prolonged exposure of domestic rabbit to a lower dosage of extracted microcystins. AB - Oxidative stress response after prolonged exposure to a low dose of microcystins (MCs) was studied in liver, kidney and brain of domestic rabbits. Rabbits were treated with extracted MCs (mainly MC-LR and MC-RR) at a dose of 2 MC-LReq. MUg/kg body weight or saline solution every 24h for 7 or 14 days. During the exposure of MCs, increase of lipid peroxidation (LPO) levels were detected in all the organs studied, while antioxidant enzymes responded differently among different organs. The enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) in liver decreased in the MCs treated animals. In brain, there were obvious changes in glutathione peroxidase (GPx) and GR, while only CAT was obviously influenced in kidney. Therefore, daily exposure at a lower dosage of MCs, which mimicked a natural route of MCs, could also induce obvious oxidative stress in diverse organs of domestic rabbits. The oxidative stress induced by MCs in brain was as serious as in liver and kidney, suggesting that brain may also be a target of MCs in mammals. And it seems that animals may have more time to metabolize the toxins or to form an adaptive response to reduce the adverse effects when exposed to the low dose of MCs. PMID- 21783940 TI - Nicotine withdrawal alleviates acetic acid-induced gastric injury in rats. AB - Epidemiological and experimental studies have demonstrated that cigarette smoking intensifies gastric ulceration. Although nicotine can act as an anxiolytic and antidepressant, its withdrawal may also lead to increased anxiety and depression. In order to associate the toxic actions of nicotine on gastric mucosa with alterations of anxiety level and to evaluate the impact of nicotine withdrawal on the anxiety level and the severity of ulcer, an acetic acid-induced ulcer model was used. Male Sprague-Dawley rats were given either tap water or nicotine bitartarate (50MUg/ml in drinking water) for 15 days, while another group of rats had 5 days of withdrawal following 10 days of nicotine treatment. Ulcer was induced by acetic acid on the 15th day of the treatments, and the rats were followed for 3 days until they were decapitated and the gastric tissues were obtained. Using the hole-board test, basal anxiety levels measured on the first day of the treatments were compared with the measurements made at the early and late phases of ulcer induction. Chronic administration of nicotine did not have a potentiating effect on acetic acid-induced gastric ulcer, since the gastric injury, as assessed by both macroscopic and microscopic evaluation and increased gastric myeloperoxidase activity indicating neutrophil recruitment, was not exaggerated or attenuated by nicotine intake. On the other hand, nicotine withdrawal attenuated gastric mucosal injury, despite an increased level of anxiety. Smoking cessation, which triggers the onset of depressive symptoms with nicotine withdrawal, still has a worthwhile positive effect on the gastric mucosa. PMID- 21783941 TI - Development of atropine sulphate nasal drops and its pharmacokinetic and safety evaluation in healthy human volunteers. AB - INTRODUCTION: The increased use of organophosphate (OP) insecticides and the ever increasing possibility of terror groups using nerve agents underscore the need to develop effective and safe antidotes against OP poisoning. While intramuscular administration of nerve gas antidotes like atropine sulphate has certain lacunae, intravenous route is neither practical nor feasible in the field conditions for mass casualties. The objective was to develop a novel atropine sulphate nasal drop formulation, evaluate and characterize it using scintigraphy and to carry out safety-efficacy study in human volunteers with a view to obtain early pharmacological effects in comparison to the existing options, particularly the conventional intramuscular route. METHODS: Permeability studies were done using atropine sulphate solution containing variable amount of chitosan. Radiometric method was developed for scintigraphy studies while standard spectroscopy was used for the quantification of atropine sulphate in fluids. Concentration of atropine sulphate in nasal drops to produce therapeutic concentration in blood was calculated. Six volunteers (age range 18-53 years) were administered the formulation delivering 6mg of atropine sulphate each. Bioavailability and atropinization were noted serially. RESULTS: Based on the results of in vitro, human scintigraphy and analytical data, 1% atropine sulphate-0.5% chitosan was chosen as the final nasal formulation. Human bioavailability curve was created which showed that the therapeutic concentration of the drug in blood was reached within 5min with nasal drops suggesting that drug delivery through the nasal route is significantly better than the intramuscular route. Unpaired t-test between the means of baseline value of heart rate and that of each time interval showed that increase in heart rate of all the volunteers became significant at 15min (P<0.01) and extremely significant at 30min (P<0.001). Correlation was evident from 5min (c>0.7). Pupil diameter showed maximal increase at 30min (P<0.01). CONCLUSIONS: This novel product, 1% atropine sulphate-0.5% chitosan nasal drops might be a safe and efficacious emergency treatment of organophosphorous poisoning with several advantages over the present management, including early atropinization and capability of mass treatment in least amount of time. PMID- 21783942 TI - Proteomic changes in response to acute cadmium toxicity in gill tissue of Paralichthys olivaceus. AB - In the present study, we developed a two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique for examining the response of the proteome from gill tissue of Paralichthys olivaceus (POGT) to acute cadmium (AC) toxicity. Approximately 700 protein spots were detected from the gill sample when applying a 600MUg protein 2D-PAGE gel in the pH range 5.0-8.0, and approximately 400 of these were identified by peptide mass fingerprinting (PMF) and database search. Compared to a control sample, significant changes were visualized in 18 protein spots exposed to seawater cadmium acute toxicity at 10.0ppm for 24h. Among these spots, two were up-regulated, one was down-regulated, seven showed low expression, and eight showed high expression. The collected spots were further identified by PMF and database search. Ten of the 18 proteins identified on the 2D-PAGE gel, including heat shock protein 70 and calcium-binding protein, demonstrated a synchronous response to AC, and we suggest that the variable levels and trends of these spots on the gel might be utilized as biomarker profiles to investigate cadmium contamination levels in seawater and to evaluate the degree of risk of human fatalities. The experimental results emphasize that the application of multiple biomarkers has an advantage over single biomarkers for monitoring levels of heavy metal contamination in seawater. PMID- 21783943 TI - A comparative study on oxidative stress induced by LPS and rotenone in homogenates of rat brain regions. AB - Lipopolysaccharide (LPS) and rotenone induced oxidative stress was investigated in homogenates of rat brain regions - striatum, mid brain, frontal cortex and hippocampus. LPS at concentration 1, 25 and 50MUg and rotenone 1, 2 and 4mM was incubated with the brain homogenates and caused decrease in reduced glutathione (GSH) and rise in malondialdehyde (MDA) in different brain regions but in a varied manner. Anti-oxidants melatonin and nimesulide (0.75, 1.5 and 3mM) were incubated concurrently with LPS (50MUg) and rotenone (4mM) in the homogenates. Melatonin as well as nimesulide (3mM) suppressed the LPS and rotenone induced increase in MDA but their effect on GSH differed. Lack of uniform response by different brain areas to LPS, rotenone and antioxidants indicate that sensitivity to oxidative stress may differ among the brain areas; this variability in sensitivity may be of significance in relation to free radicals induced selective neuronal degeneration. PMID- 21783944 TI - Screening of herbal medicines for recovery of acetaminophen-induced nephrotoxicity. AB - This study was conducted to quantitatively evaluate the recovery effects of herbal medicines on acetaminophen-induced nephrotoxicity. In the present study, the recovery effects of 251 herb medicines on HEK 293 cells that had been damaged by acetaminophen were evaluated using an MTS assay. HEK 293 cells were cultured in 96-well plates and then pretreated with or without 20MUM acetaminophen (IC(50) value: 17.5+/-1.9) for 1h. Next, different herbal medicines were added to the wells, after which the cells were reincubated at 37 degrees C for 24h. After the first round of screening, the candidate herbal medicines were selected based on a recovery rate of greater than 20% and their efficacy were then determined by dose response kinetic analysis. Among these extracts, 8 herbal medicines (Ledebouriella divaricata, Sparganium simplex, Panax ginseng, Aster tataricus, Citrus aurantium, Sanguisorba officianlis, Arisaema consanguineum, and Polygonum aviculare) had a strong recovery effect on acetaminophen-induced damage in HEK 293 cells. Dose response non-linear regression analysis demonstrated that P. aviculare showed the best recovery rate (98%), and that its EC(50) (0.1ng/mL) was the smallest among the screened candidate herbal medicines. Additional studies of these herbal medicines should be conducted to determine if they possess novel therapeutic agents for the prevention or treatment of renal disorders. PMID- 21783945 TI - In vitro mutagenicity of Acid Violet 7 and its degradation products by Pseudomonas putida mt-2: Correlation with chemical structures. AB - Acid Violet 7 (AV7), a very important commercial azo dye used in the textile, food, paper and cosmetic industries, was degraded by Pseudomonas putida mt-2 at a concentration up to 200mg/l. HPLC analysis of the biodegradation media revealed the presence of either 4'-aminoacetanilide (4'-AA) or 5-acetamido-2-amino-1 hydroxy-3,6-naphthalene disulfonic acid (5-ANDS) deriving from AV7 azoreduction which attests the expression of an azoreductase by this bacterium. These amines were identified only in media of static incubation, which is consistent with their biotransformation under shaken incubation (aerobic conditions). Pure azo dye, pure azoreduction products and total lyophilized biodegradation extracts were assayed for their mutagenic properties using Ames test. Mutagenicity of AV7 even with or without the S9 metabolizing system increased significantly after static biodegradation and totally disappeared after shaken incubation. In addition, mutagenicity of pure azo reduction products of AV7 was assessed and compared with that of the parent unsubstituted amines. 4'-AA exhibited a strong mutagenicity which was imputed to the presence of the acetoxy (COCH(3)) substituent on the aromatic amine; however, the presence of sulphonic groups in 5 ANDS limited its mutagenicity. PMID- 21783946 TI - Subchronic toxicity and toxicokinetics of MCC-555, a novel thiazolidinedione, after 270-day repeated oral administration in dogs. AB - MCC-555, a treatment candidate for type 2 diabetes, is a novel thiazolidinedione which has comparatively high anti-diabetic efficacy. The present study was conducted to evaluate its toxicity and toxicokinetics in beagle dogs by oral administration at doses of 0, 6.67, 20 or 40mg/kg/day for 270 days. A 30-day recovery period was included at the end of the study to evaluate the reversibility of the toxic effects. During the treatment and recovery periods, the effects of the test agent on mortality, body weight, food consumption, hematology, serum biochemistry, urinalysis, electrocardiogram (ECG), organ weights, bone marrow and histopathology were examined. There were no treatment related mortalities. Vomiting was observed in dogs receiving 40mg/kg/day during administration, but the dogs recovered within 1h after oral administration. Significant increases in total bilirubin and alkaline phosphatase were observed in dogs receiving the 40mg/kg/day dose during the treatment period, but the levels returned toward normal during the 30-day recovery period. Mild hydropic or fatty degeneration in the liver and inflammatory cell infiltration in the hepatic lobule or portal area was also observed sporadically without a dose-dependent relationship at the end of treatment and recovery periods. The most apparent toxicity in dogs was in the digestive system. However, these toxic effects of MCC 555 were transient and reversible. The accumulation of MCC-555 after 270-day oral administration was not notable at the toxic dose of 40mg/kg/day and the no observed-adverse-effect level (NOAEL) was 20mg/kg/day. No differences in toxicokinetics of MCC-555 were observed between male and female dogs and no significant accumulation of MCC-555 was observed in tissues after 270 days of repeated treatments. MCC-555 distribution into different organs showed a higher penetration in the liver, kidneys and testes, followed by the ovaries and uterus. Metabolites and the metabolic style of MCC-555 are to be approved. PMID- 21783947 TI - Glycoprotein isolated from Cudrania tricuspidata Bureau inhibits iNO and COX-2 expression through modulation of NF-kappaB in LPS-stimulated RAW 264.7cells. AB - Glycoprotein of Cudrania tricuspidata Bureau (CTB glycoprotein) was isolated from CTB fruits which have been used to heal various disorders of the injury and lung as an herbal agent in Korea since long time ago. The CTB glycoprotein was identified to have a molecular weight of 75kDa and consists of carbohydrate (72.5%) and protein moiety (27.5%). To know inhibitory ability of CTB glycoprotein for inflammation mediated by reactive oxygen radicals, firstly we tested about anti-oxidative activity (DPPH, superoxide anion, and hydroxyl radicals) in cell-free system, and then evaluated changes of inflammation-related signals [intracellular reactive oxygen species (iROS), nitric oxide (NO), nuclear factor-kappa B (NF-kappaB), COX-2, and iNOS] in the LPS (1MUg/ml)-treated RAW 264.7cells. The results in this study showed that CTB glycoprotein (100MUg/ml) has a strong scavenging activity against DPPH, superoxide anion, and hydroxyl radicals without any pro-oxidant activity in vitro. In the inflammation-related signals, expression of iROS, NO, NF-kappaB, COX-2, and iNOS were inhibited by treatment with CTB glycoprotein (50MUg/ml) in the presence of LPS (1MUg/ml). Taken together, our data obtained from these experiments indicated that CTB glycoprotein suppresses expression of the inflammatory-related proteins (iNOS and COX-2) through regulation of NF-kappaB. Thus, we speculate that CTB glycoprotein may have therapeutic potential for inflammation-associated disorders. PMID- 21783948 TI - Morphological and functional disorders of the immature rat uterus after postnatal exposure to benz[a]anthracene and benzo[k]fluoranthene. AB - We investigated the effects of postnatal exposure to benz[a]anthracene (B[a]A) and benzo[k]fluoranthene (B[k]F) on the development of the rat uterus. Neonates were injected on each postnatal days 1-14 with B[a]A (0.1, 1.0 or 10.0mg/kg), B[k]F (0.1, 1.0 or 5.0mg/kg), ethynylestradiol (EE; 1.0MUg/kg) or a vehicle. The rats were killed on day 23. All doses of B[a]A and B[k]F induced a reduction of the uterine weight, a reduction of the estrogen receptor alpha expression in the luminal epithelium, glandular epithelium and stromal cells. Moreover, the uterotrophic response to EE (3-day administration of 1.0MUg/kg on postnatal days 20-22) in rats exposed to B[a]A, B[k]F and EE was lower than in controls. The study showed that postnatal exposure to B[a]A and B[k]F resultes in morphological and functional disorders of the immature rat uterus. PMID- 21783949 TI - Nephrotoxicity of CCA-treated wood: A comparative study with As(2)O(5) and CrO(3) on mice. AB - The purpose of this work was to assess the acute toxicity on male mice to a chromated copper arsenate (CCA) solution, a widespread wood preservative used in building industry until 2002. Animals were subcutaneously injected with CCA (7.2mg/kg arsenic and 10.2mg/kg chromium per body weight), CrO(3) (10.2mg/kg), As(2)O(5) (7.2mg/kg) and NaCl (0.9%) per se, during 48h and 96h, for histopathology, histochemistry, chromium and arsenic analysis. The results showed some histopathological changes within renal tubules lumen of CCA exposed animals (during 48h, and 96h), and CrO(3) (for the period of 96h). Furthermore, the renal levels of arsenic and chromium in treated animals were statistically more evident than controls. Although, the same contents of pentavalent arsenic and hexavalent chromium were injected into treated animals with CCA and with the prepared solutions of As(2)O(5) and CrO(3), a different distribution of the pattern of these compounds was observed in kidneys. PMID- 21783950 TI - Ardipusilloside I induces apoptosis in human glioblastoma cells through a caspase 8-independent FasL/Fas-signaling pathway. AB - Ardipusilloside I, a triterpenoid saponin isolated from Ardisia pusilla A. DC, suppresses the growth of a variety of cancer cells, and has certain immunomodulative properties. Herein, we investigated its effect on glioblastoma cell line U87MG cells and primary cultured human glioblastoma cells, and examined the underlying mechanism of action. Ardipusilloside I substantially decreased the number of viable cells of both cell lines in a time- and concentration-dependent manner, with a similar IC(50) of 4.05MUM. Microscopy revealed apoptotic characteristics, including chromatin condensation and cell nucleus fragmentation, demonstrating that ardipusilloside I-induced apoptosis. Ardipusilloside I exposure also gradually increased the sub-G1 fraction (the apoptotic cell population) and an S phase-arrest of both glioblastoma cells. Furthermore, ardipusilloside I increased the expression of Fas and its ligand (FasL), and enhanced the activation of caspase-8 and caspase-3. Additionally, we observed a significant decreased apoptosis after the trigger effection of FasL was abolished by the neutralization antibody anti-FasL antibody and an unchanged apoptosis level when the activation of caspase-8 was interrupted by specific inhibitor z IETD-fmk, which suggested that a casepase-8 independent FasL/Fas-signaling mediated death receptor pathway is involved. These data suggested that ardipusilloside I could be developed as a chemotherapeutic agent for the management of gliomas. PMID- 21783951 TI - Structural modifications into diphenyl diselenide molecule do not cause toxicity in mice. AB - The aim of the present study was to evaluate toxicological parameters of following compounds: 1a (4,4'-dichloro-diphenyl diselenide [(ClPhSe)(2)]), 1b (3,3'-ditrifluoromethyl-diphenyl diselenide [(F(3)CPhSe)(2)]) and 1c (4,4' dimethoxyl-diphenyl diselenide [(CH(3)OPhSe)(2)]). Calculated lethal dose (LD(50)) values for mice exposed, by oral route, to a single application of compounds 1a, 1b or 1c were estimated to be >381, 278 and >372mg/kg, respectively. Compounds 1a and 1b significantly reduced body weight gain as well as food and water intake in mice. delta-Aminolevulinate dehydratase (delta-ALA-D) and catalase activities were inhibited in mice which received the highest dose of compounds 1a or 1b. Exposure to compounds 1a, 1b and 1c did not modify lipid peroxidation, vitamin C levels, cerebral Na(+)/K(+)-ATPase activity and the biochemical parameters evaluated. The important point for medicinal chemistry is that the structural modifications are not introducing toxicity for the compounds in mice. PMID- 21783952 TI - Therapeutic potential of hemin in acetaminophen nephrotoxicity in rats. AB - The therapeutic potential of hemin, the heme oxygenase-1 inducer, was investigated against renal damage induced by acute acetaminophen overdose in rats. Nephrotoxicity was induced by a single oral dose of acetaminophen (2.5g/kg). Hemin was given as a single s.c. injection (40MUmol/kg), 1h following acetaminophen administration. Hemin treatment restored blood urea nitrogen and serum creatinine levels that were elevated by acetaminophen. Hemin also compensated deficits in the antioxidant defense mechanisms (reduced glutathione, and catalase and superoxide dismutase activities), and suppressed lipid peroxidation in renal tissue resulted from acetaminophen administration. Hemin attenuated the acetaminophen-induced elevations in renal tumor necrosis factor alpha and nitric oxide levels, and caspase-3 activity. Additionally, hemin ameliorated acetaminophen-induced renal damage observed by light microscopic examination. The therapeutic effect afforded by hemin was abolished by prior administration of zinc protoporphyrin-IX, the heme oxygenase-1 inhibitor. It was concluded that hemin represents a potential therapeutic option to protect renal tissue from the detrimental effects of acute acetaminophen overdose. PMID- 21783953 TI - The toxic activities of Arisaema erubescens and Nerium indicum mixed with Streptomycete against snails. AB - The comparative molluscicidal activities of Arisaema erubescens tuber extracts and Nerium indicum leaf extracts mixed with Streptomycete violacerruber dilution (SD) against the snail Oncomlania hupensis and the responses of the isozymes, esterase (EST) and superoxide dismutase (SOD) to the A. erubescens extracts and the mixtures were investigated. The molluscicidal activity of A. erubescens water extracts mixed with S. violacerruber dilution was 4-5 times higher than a single A. erubescens or S. violacerruber dilution after 24-h exposure, and is also higher than that of N. indicum leaf water extracts mixed with S. violacerruber dilution. At the end of exposure to the N-butanol extracts of A. erubescens tubers (NEAT), the EST activity in snail liver decreased and some enzyme bands (EST 1 and EST 3 in exposure to NEAT) disappeared but the activities of SOD 1 increased. The effect was more obvious in mixture treatment than in single NEAT or SD treatment. The results indicated that molluscicidal activities of plant and microorganism could be more effective than single plant. The decline of the detoxic ability in snail liver cells could be the reason of the snail dying. PMID- 21783954 TI - Involvement of Sertoli cells in spermatogenic failure induced by carbendazim. AB - The aim of this study is to determine whether Sertoli cells are involved in spermatogenic failure induced by carbendazim, a benzimidazole fungicide that is widely used in agriculture. Total 40 rats were treated with carbendazim by oral gavage at dosages of 0, 20, 100 and 200mg/kg for 60 days. The testis weight, sperm counts, sperm motility and Sertoli cell morphology and secretions including vimentin, ABP, inhibin B, SCFs and SCFm in testis were examined. In 100 and 200mg/kg groups, the testis weight, the sperm counts and motility and SCFm levels were significantly decreased, the sloughing of germ cells and ABP levels were increased, and the vimentin filaments and Sertoli cell morphology were altered. Inhibin B and SCFs levels were unchanged. The results suggested that alterations of Sertoli cell morphology and function were involved in spermatogenic failure induced by carbendazim. PMID- 21783955 TI - 17beta-estradiol decreases methylmercury-induced neurotoxicity in male mice. AB - There is increasing evidence that health effects of toxic metals, including methylmercury (MeHg), differ in prevalence or are manifested differently in men and women. The present study was aimed at investigating the potential differential susceptibility of male and female Swiss mice against MeHg-induced neurotoxicity, which was evaluated by biochemical (cerebellar oxidative stress related parameters) and behavioral (locomotor activity and motor performance) variables. We also aimed to evaluate the potential protective effects of 17beta estradiol against such toxicity in MeHg-exposed male animals. MeHg exposure (40mg/L, diluted in tap water, during 2 weeks) decreased locomotor activity and motor performance in both male and female animals, but such phenomena were higher in males. 17beta-estradiol co-treatment (10MUg/animal, in alternate days) prevented MeHg-induced locomotor deficits in males. MeHg exposure caused a significant increase (60%) in cerebellar lipid peroxidation in male mice, but did not in females. In close agreement, MeHg exposure decreased (43%) cerebellar glutathione peroxidase activity in males, but did not in females. These events were prevented by 17beta-estradiol administration. Cerebellar GR activity was increased (25%) in MeHg-exposed males and such event was partially prevented by 17beta-estradiol administration. These results indicate that the low susceptibility of female mice to the neurotoxicity elicited by MeHg is linked to neuroprotective effects of sex steroids, which appear to modulate the activities of glutathione-related enzymes. Our experimental observation corroborates previous epidemiological studies showing the greater developmental effects in male than in female humans exposed to MeHg. PMID- 21783956 TI - Conformational analysis of the effects of methylmercury on nerve growth factor and brain derived neurotrophic factor. AB - Methylmercury is a neurotoxicant that is detrimental to the development and physiology of the nervous system. One possible mechanism for methylmercury's toxicity stems from its ability to interfere with the signaling of the neurotrophins nerve growth factor and brain derived neurotrophic factor. In this study, we examine the effect of methylmercury to determine if it interferes with neurotrophin conformation in a manner similar to Hg(2+), or if it occurs via an alternate mechanism. Our findings indicate that although MeHg inhibits neurotrophin signaling, its toxic effects are not mediated via an induced conformational change, as seen with other metal ions, including Hg(2+). PMID- 21783957 TI - Reduced production of anti-inflammatory soluble HLA-G molecules in styrene exposed workers. AB - HLA-G antigens are non-classical HLA-class I anti-inflammatory molecules. Since styrene exposure has been suggested to induce immune alteration, we analyzed plasma levels and "in vitro" peripheral blood mononuclear cell (PBMC) production of soluble HLA-G (sHLA-G) and interleukin-10 (IL-10) molecules after lipopolysaccharide (LPS) stimulation, in styrene exposed workers and healthy subjects. Exposed workers showed reduced plasma levels of sHLA-G and IL-10 in comparison to healthy controls. Similarly, lower levels of sHLA-G and IL-10 molecules were observed in PBMC culture supernatants after LPS activation. These data propose styrene exposure as a mediator of impaired sHLA-G production. PMID- 21783958 TI - Motor alterations induced by chronic lead exposure. AB - Lead (Pb) as other environmental neurotoxicants substances has the capability to interfere with many biochemical events present in cells throughout the body and it can produce a wide spectrum of alterations in many organs and systems. Among that alterations induced by Pb exposure in adults and children those involving motor system dysfunction represent a common public health problem. The review summarizes the sources of lead exposures in both occupational and residential environments and motor deficits induced by chronic Pb exposure taking in account the last literature in the field. We wish to focus on the current state of knowledge concerning the long-lasting neurological effects of Pb in motor functions and to correlate the neurological deficits induced by Pb exposure in animal models with those reported in humans. The great interest in whether exposure to Pb can cause long-term, progressive declines in central nervous system (CNS) function have revealed that Pb exposure is involved in chronic CNS diseases such Parkinson's and poor motor coordination in children. PMID- 21783959 TI - The neurotoxic effects of heavy metal exposure on GABAergic nervous system in nematode Caenorhabditis elegans. AB - The number of cell body or synapse made by Caenorhabditis elegans GABAergic neurons is constant during development. The neurotoxic effects of metal (Pb, Hg, Cu, Cd, Cr, and Mn) exposure on GABAergic motor neurons were investigated in C. elegans. Exposure to examined metals could not alter the position of GABA neurons, whereas exposure to high concentrations (75MUM and 200MUM) of metals caused noticeable axonal degeneration and neuronal loss in nerve cords, suggesting neurodegeneration will be induced by metal exposure to different degrees. In addition, exposure to Pb, Hg, Cu, and Cd at the low concentration (2.5MUM) could also induce obviously neuronal loss. Moreover, exposure to high concentrations (75MUM and/or 200MUM) of most of examined metals significantly reduced the relative size and fluorescent intensities of AVL, RMEs, and RIS neurons. Therefore, the neurodegeneration and abnormal structures may be formed in GABAergic motor neurons after metal exposure, and the endpoint of neuronal loss will be useful for the neurotoxicity assessment from trace metal exposure. PMID- 21783960 TI - Paraquat and temperature affect nonspecific immune response of Colossoma macropomum. AB - This study evaluated the effect of paraquat (PQ) and temperature on hematological parameters and nonspecific immune system of fish Colossoma macropomum (Cachama). Juveniles were used for all experiments. Fish were exposed to three temperatures (18, 28, 35 degrees C) and 10mg/L PQ during 21 days (PQ LC(50) 96h was of 48.05mg/L). Hematological (Hb, Ht, VCM, HCM and CHCM and RBC) and immunological parameters (WBC, differential count of white cells, phagocytes, and bacterial killing by phagocytes) were analyzed for 7, 14 and 21 days. Fishes PQ exposed at 18 degrees C decreased Hb, MCH and MCHC; we observed sickle erythrocytes in control group at 18 degrees C, and in PQ-exposed groups at 18 and 35 degrees C. Immunological parameters were not affected by temperature. Neutrophils decreased significantly in all PQ-exposed groups. Bacterial killing by phagocytes decreased in 18 and 35 degrees C PQ-groups; a synergistic interaction was shown between PQ and temperature on WBC and lymphocytes. These results indicate that PQ affected neutrophils counts independently of temperature exposure; the temperature exerted a synergistic effect on PQ toxicity in lymphocyte counts and phagocytic response and besides nonspecific immune response, PQ and temperature affects hematological parameters such as Hb, MCH, MCHC and erythrocytes morphology. PMID- 21783961 TI - Effects of tetrabrominated diphenyl ether and hexabromocyclododecanes in single and complex exposure to hepatoma HepG2 cells. AB - This study was designed to determine cytotoxic effects of PBDE-47 and HBCDs individually or with a mixture of both compounds exposure to Hep G2 cells. The results showed PBDE-47 and HBCDs induced increase of nitric oxide synthase (NOS) activity, release of NO, dissipation of mitochondria membrane potential and cell apoptosis. Exposure to HBCDs induced ROS formation. Moreover, preincubation with PTIO (NO scavanger) and N-acetylcysteine (ROS scavanger) partially reversed cytotoxic effects of these compounds. The possible mechanism is that PBDE-47 and HBCDs could boost generation of NO and/or ROS, impact mitochondria, and result in start-ups of apoptosis program. Cells exposed to mixture of both compounds and each of them showed non-apoptotic rate significant difference, but the combination of them caused more adverse effects on cells. These results suggest that PBDE-47 and HBCDs in single and complex exposure have the cytotoxic activity of anti-proliferation and induction of apoptosis in tumor cells in vitro. PMID- 21783962 TI - Effects of perfluorooctane sulfonate on ion channels and glutamate-activated current in cultured rat hippocampal neurons. AB - Concern on an emerging persistent contaminant, perfluorooctane sulfonate (PFOS), is increasingly growing. Although the fate, transport, distribution and bioaccumulation of PFOS have been documented, its toxicological effects especially neurotoxicity remain largely unknown. In this study, the effects of PFOS on ion channels including potassium and sodium channels and exogenous glutamate-activated current in cultured rat hippocampal neurons were examined, based on whole-cell patch-clamp recording. PFOS markedly increased two subtypes of potassium currents, including transient outward current and delayed rectifier current, at doses over 10MUM. PFOS did not affect the amplitude of sodium current at all administrated doses (1, 10 or 100MUM) but clearly shifted the activation current-voltage curve toward negatively potential. Further, PFOS significantly altered the glutamate-activated current at all doses. Taken together these findings indicated that PFOS disturbs the neuronal physiological processes, which revealed the damage of this pollutant to nerve system and will be helpful for further exploration to its underlying mechanism. PMID- 21783963 TI - Effects of subchronic cadmium poisoning on DNA methylation in hens. AB - Cadmium is a persistent pollutant that poses a threat to most biological organisms including birds. Although toxicity of cadmium is mainly linked to cancer, the mechanism of its carcinogenic activity remains poorly understood. Since DNA methylation is linked to cancer, we have examined the effect of cadmium on DNA methylation and DNMTs mRNA expression in hen liver and kidney. Sixty 50 day-old hyline-white hens were randomly allocated into 3 equal groups; a control group fed a basal diet, a low-dose group fed the basal diet spiked with 140mg/kg CdCl(2), and a high-dose group fed the basal diet spiked with 210mg/kg CdCl(2). After 60 days, liver and kidney samples were analysed for cadmium by FAAS, DNA methylation level by HPLC and DNMTs mRNA levels by semi-quantitative RT-PCR. The DNA methylation levels and the expressions of DNMT1 and DNMT3a mRNA in liver and kidney were significantly elevated by the cadmium treatment but there was no change in the expression of DNMT3b mRNA in the two tissues. The fact that cadmium increases DNA methylation and the expressions of DNMT1 and DNMT3a mRNA in liver and kidney suggests DNA methylation may be involved in the carcinogenic action of cadmium. PMID- 21783964 TI - Plasma biochemical responses of the planktivorous filter-feeding silver carp (Hypophthalmichthys molitrix) and bighead carp (Aristichthys nobilis) to prolonged toxic cyanobacterial blooms in natural waters. AB - The planktivorous filter-feeding silver carp (Hypophthalmichthys molitrix) and bighead carp (Aristichthys nobilis) are the attractive candidates for bio-control of plankton communities to eliminate odorous populations of cyanobacteria. However, few studies focused on the health of such fishes in natural water body with vigorous toxic blooms. Blood parameters are useful and sensitive for diagnosis of diseases and monitoring of the physiological status of fish exposed to toxicants. To evaluate the impact of toxic cyanobacterial blooms on the planktivorous fish, 12 serum chemistry variables were investigated in silver carp and bighead carp for 9 months, in a large net cage in Meiliang Bay, a hypereutrophic region of Lake Taihu. The results confirmed adverse effects of cyanobacterial blooms on two phytoplanktivorous fish, which mainly characterized with potential toxicogenomic effects and metabolism disorders in liver, and kidney dysfunction. In addition, cholestasis was intensively implied by distinct elevation of all four related biomarkers (ALP, GGT, DBIL, TBIL) in bighead carp. The combination of LDH, AST activities and DBIL, URIC contents for silver carp, and the combination of ALT, ALP activities and TBIL, DBIL, URIC concentrations for bighead carps were found to most strongly indicate toxic effects from cyanobacterial blooms in such fishes by a multivariate discriminant analysis. PMID- 21783965 TI - Evaluation of reproductive toxicity in rats caused by organic extracts of Jialing River water of Chongqing, China. AB - OECD 421 screening test protocol was used to evaluate the reproductive toxicity of organic extracts of river water. These extracts, at doses of 0, 2, 16, or 80 equivalent L/kgbody weight(bw), were administered to rats daily by oral gavage. Vacuole degeneration of seminiferous epithelium was observed in the dosed groups. The caudal sperm counts/epididymis weight and the percentages of sperm with abnormal heads were increased in the group dosed with 80L/kgbw/day compared to the control group. Exposure of rats to organic extracts at the high dose resulted in a decrease in testosterone levels. The serum level of follicle-stimulating hormone increased in the groups dosed with 16 or 80L/kgbw/day compared to the control group. The number of apoptotic spermatid increased in the dosed groups. The results suggest that the extracts cause pathological damage to testicular tissue and disruption of spermatogenesis. PMID- 21783966 TI - Phosphorylated-ERK 1/2 and neuronal degeneration induced by rotenone in the hippocampus neurons. AB - Rotenone, a mitochondrial complex-I inhibitor, has been verified to cause dopaminergic neurons degeneration in vivo and in vitro, and the substantia nigra pars compacta (SNc) and the striatum are the main target organs of rotenone in the rat brain. However, whether rotenone could cause damage to other regions in the brain has been unclear till now. To address this question, the rotenone induced neurotoxicity in the hippocampal neurons was investigated in the present study. Rotenone (4mg/kg) was given to the male Sprague-Dawley rats per day for up to 4 weeks by using the osmotic minipumps. Results showed that neurodegeneration was formed and phosphorylated ERK1/2 (p-ERK1/2) was induced in the hippocampus of rats following rotenone treatment. In additionally, Ras, PKA and PKC were also activated and free [Ca(2+)](i) was increased in the cytoplasm of the hippocampus neurons. To determine how ERK cascade was activated, studies in the primary cultured hippocampus neurons were carried out in a further. Cell viability was reduced, and also apoptosis was induced in vitro following rotenone administration. Expressions of p-ERK1/2 were also enhanced evidently in the cultured neurons treated by rotenone. Free [Ca(2+)](i) was also increased in the cultured neurons induced by rotenone. However, this influx might not take main effect in ERK1/2 phosphorylation. In conclusion, Ras-Raf-1-MEK-ERK1/2 classic signal pathway, not by PKA/PKC alternative pathway may be the mainly contributor to the ERK1/2 phosphorylation. And also, Ras protein is the dominant activator in the ERK phosphorylation induced by rotenone. PMID- 21783967 TI - Toxicological evaluation of the effects of 2-stroke auto-rickshaw smoke solutions on wound healing. AB - Vehicle exhaust from traffic is a widespread air pollutant. The use of 3-wheel auto-rickshaws powered by a 2-stroke engine is widespread in south Asia; exhaust from these vehicles may cause different types of toxicities resulting in different pathologies. The aim of this study was to explore the association between exposure to 2-stroke auto-rickshaw smoke solution (2SARSS) and wound healing. The in vivo model of wound healing was customized to evaluate different stages of wound healing: dermal matrix regeneration, re-epithelialization, and neovascularization. A total of 72 adult mice were divided into 8 groups and exposed to 2SARSS for 12 days. A highly significant reduction (p<0.001) in wound closure was observed among all 2SARSS-treated groups at day 8 post-wounding. Histological examination revealed a significant delay in the outcome of re epithelialization, dermal matrix regeneration, and maturation of collagen bundles among all 2SARSS-exposed wounds. Delayed activation of neovascularization was seen in the 2SARSS-treated groups at day 12 post-wounding. The Abbot curve, angular spectrum, and several other 3D surface parameters of reverse wound topographies revealed a highly significant reduction (p<0.001) in angiogenesis. These results demonstrate that application of 2SARSS causes a substantial delay in the progression of angiogenesis, resulting in delayed onset of wound healing. These observations validate the damaging effects of 2SARSS on wound healing. Thus, people who are directly or indirectly exposed to this toxic exhaust are expected to have delayed wound healing, which could result in chronic wounds. PMID- 21783968 TI - Reduction of cyclophosphamide-induced DNA damage and apoptosis effects of ginsenoside Rb(1) on mouse bone marrow cells and peripheral blood leukocytes. AB - The present study investigated the protective effects of ginsenoside Rb(1) (GRb(1)) against genotoxicity induced by cyclophosphamide (CP). Single cell gel electrophoresis, flow cytometry assay with annexin V-FITC/propidine iodide (PI) and acridine orange (AO)/ethidium bromide (EB) staining assay were employed to measure DNA damage and cell apoptosis, respectively. The activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GPx) and the malondialdehyde (MDA) content were also investigated by a number of colormetric methods. The results showed that the CP produced significant DNA damage and cell apoptosis in mouse bone marrow cells or peripheral blood leukocytes, markedly inhibited the activities of T-SOD and GPx, and markedly increased the MDA content. GRb(1) significantly inhibited DNA damages and cell apoptosis in mouse bone marrow cells or peripheral blood leukocytes induced by CP and antagonized the reduction of CP-induced T-SOD and GPx activities, and inhibited the increase in MDA content induced by CP. The anti-tumor study of GRb(1) showed that GRb(1) did not affect the anti-tumor activities of CP. In conclusion, GRb(1) had significant protective effects against DNA damage and apoptosis induced by CP. PMID- 21783969 TI - Developmental anomalies induced by a non-selective COX inhibitor (ibuprofen) in zebrafish (Danio rerio). AB - Effects of ibuprofen (a non-selective COX inhibitor) on the embryonic development, hatching success, larval growth, behavioral pattern and survival competence were studied in Danio rerio. Embryos at 2/4 celled stage were exposed to graded doses (0, 1, 5, 10, 50 and 100MUg/L distilled water) of ibuprofen in triplicate sets (n=30). The experiment was repeated thrice. The results indicate that developing embryos tolerated lower (1 and 5MUg/L) doses of the drug readily but, exposure to higher doses (>10MUg/L) caused retarded development, decreased hatching rate and growth, cardiac anomalies, spinal curvature, pectoral fin malformation and behavioral alterations resulting in greater mortality of experimental embryos. This study suggests that, ibuprofen which is marketed as over-the-counter (OTC) drug is embryotoxic at least at higher (>10MUg/L) dose level to zebrafish embryos. PMID- 21783971 TI - Prevention of cadmium-induced toxicity in liver-derived cells by the combination preparation Hepeel((r)). AB - Cadmium is a heavy metal of considerable environmental concern that causes liver damage. This study examined the possible prevention of cadmium toxicity in human HepG2 cells and primary rat hepatocytes by Hepeel((r)), a combined preparation of tinctures from seven different plants. Hepeel((r)) prevented cadmium chloride (CdCl(2))-induced cell death in both HepG2 cells and hepatocytes, and also reduced the loss of glutathione, lipid peroxidation, nuclear fragmentation, caspase activation and release of mitochondrial cytochrome C. To compare their relative efficacy, the seven constituent plant tinctures of Hepeel((r)) were also separately tested. The tinctures China and Nux moschata, which exert solely anti oxidative effects, failed to reduce cytotoxicity, and only protected against loss of glutathione and lipid peroxidation. In contrast, the tinctures Carduus marianus and Chelidonium, demonstrated anti-apoptotic effects, and protected HepG2 cells and primary hepatocytes against CdCl(2)-induced cell death. These results demonstrate how the effectiveness of Hepeel((r)) is determined by the synergistic features of its constituent tinctures. Furthermore, we conclude that cadmium toxicity in the liver is mainly due to stimulation of the intrinsic apoptotic pathway, but may be intensified by increased oxidative stress. PMID- 21783970 TI - Stimulatory effect of components of rose flowers on catalytic activity and mRNA expression of superoxide dismutase and catalase in erythrocytes. AB - In the present study, two antioxidant components (polysaccharopeptide complex P(1 a) and condensed tannin P(1-b)) from rose (Rosa rugosa) flowers were each incubated with mouse erythrocytes to investigate their effect on erythrocyte superoxide dismutase (SOD), and catalase (CAT) activities. It was found that the activities of Cu, Zn-SOD and CAT were markedly increased after incubation for 3h with rose flower fractions at the concentration of 500MUg/ml. Similar changes were also observed in the erythrocyte gene expression of SOD and CAT. These results show that P(1-a) and P(1-b) are effective antioxidants that increase the activity and the gene expression of SOD and CAT in mouse erythrocytes. PMID- 21783972 TI - Impact of the UV-B filter 4-(Methylbenzylidene)-camphor (4-MBC) during prenatal development in the neuroendocrine regulation of gonadal axis in male and female adult rats. AB - 4-(Methylbenzylidene)-camphor (4-MBC), a UV-B ray filter, is an endocrine disruptors (ED). Our goal was to study the effect of 4-MBC on the neuroendocrine parameters that regulate reproduction in adult female and male rats that received this disrupter during prenatal development. The 4-MBC was administered (sc) to female rats (FO) since pregnancy onset, in doses of 100mg/kg every other day. The litters (F1) were sacrificed at 70 days to determine gonadotrophin serum levels and also GnRH and the amino acids glutamate, aspartate and GABA release from the hypothalamus. The male litter rats (F1) present at adult age a decrease in serum LH and FSH concentration and so also GnRH, excitatory amino acids and GABA hypothalamic secretion. The female litters (F1) rats present at adult age an increase in serum LH and FSH concentration, whereas hypothalamic GnRH release was not modified. In these animals a significant increase of hypothalamic aspartate release as well as GABA secretion decrease were observed. Glutamate secretion was not modified. All these changes were accompanied by an advance (3 days) on the vaginal opening in 4-MBC rats group. In conclusion, prenatal administration of 4 MBC disrupts the gonadal axis in a sexual dimorphic mode that could be connected with the physiological sexual differences in the development of gonadotrophin secretion hypothalamic control mechanisms. PMID- 21783973 TI - A QSAR/QSTR study on the human health impact of the rocket fuel 1,1-dimethyl hydrazine and its transformation products Multicriteria hazard ranking based on partial order methodologies. AB - The possible impact of the rocket fuel 1,1-dimethyl hydrazine (heptyl) (1) and its transformation products on human health has been studied using (Quantitative) Structure Activity/Toxicity ((Q)SAR/(Q)STR) modelling, including both ADME models and models for acute toxicity, organ specific adverse haematological effects, the cardiovascular and gastrointestinal systems, the kidneys, the liver and the lungs, as well as a model predicting the biological activity of the compounds. It was predicted that all compounds studied are readily bioavailable through oral intake and that significant amounts of the compounds will be freely available in the systemic circulation. In general, the compounds are not predicted to be acutely toxic apart from hydrogen cyanide, whereas several compounds are predicted to cause adverse organ specific human health effects. Further, several compounds are predicted to exhibit high probabilities for potential carcinogenicity, mutagenicity, teratogenicity and/or embryotoxicity. The compounds were ranked based on their predicted human health impact using partial order ranking methodologies that highlight which compounds on a cumulative basis should receive the major attention, i.e., N-nitroso dimethyl amine, 1,1,4,4 tetramethyl tetrazene, trimethyl, trimethyl hydrazine, acetaldehyde dimethyl hydrazone, 1, 1-formyl 2,2-dimethyl hydrazine and formaldehyde dimethyl hydrazone, respectively. PMID- 21783974 TI - Phthalate metabolites in urine of CF patients are associated with use of enteric coated pancreatic enzymes. AB - In metabolomic studies using liquid chromatography mass spectrometry of urine from children with cystic fibrosis (CF), high levels of metabolites of low molecular weight phthalates were found. Phthalate metabolite excretion was explained by therapy with enteric-coated pancreatic enzyme replacements. Phthalate metabolite identity was confirmed by tandem mass spectrometry. Pancreatic insufficient CF children taking Cotazym ECS((r)), which is formulated with diethyl phthalate (DEP), had urinary metabolites of DEP. Children taking Creon((r)), which has dibutyl phthalate (DBP), excreted DBP metabolites. The estimated concentrations of free MEP were 2-3 orders of magnitude higher than reported from environmental phthalate exposure. Enteric-coated pancreatic enzymes can expose individuals with CF to incessant, high oral intakes of phthalates. Although adverse effects have neither been shown to be present nor absent, we raise the need to consider that individuals requiring life-long therapy with some current pancreatic enzyme replacements chronically ingest high amounts of phthalates. PMID- 21783975 TI - About coffee, cappuccino and connective tissue growth factor-Or how to protect your liver!? AB - Several epidemiological studies suggest that coffee drinking is inversely correlated with the risk of development of liver fibrosis. However, a causal, mechanistic explanation has long been pending. New results indicate that the methylxanthine caffeine, major component of coffee and the most widely consumed pharmacologically active substance in the world, might be responsible for this phenomenon as it, and even more potently its derived primary metabolite paraxanthine, inhibits transforming growth factor (TGF)-beta-dependent and independent synthesis of connective tissue growth factor (CTGF/CCN2) in liver parenchymal cells in vitro and in vivo. CTGF plays a crucial role in the fibrotic remodeling of various organs which has therefore frequently been proposed as therapeutic target in the management of fibrotic disorders. This article summarizes the clinical-epidemiological observations as well as the pathophysiological background of the antifibrotic effects of coffee consumption and provides suggestions for the therapeutic use of caffeine and its derived metabolic methylxanthines as potentially powerful drugs in patients with chronic fibrogenic liver disease by their inhibitory effect on (hepatocellular) CTGF synthesis. PMID- 21783976 TI - Chemopreventive potential of piperine in 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in Swiss albino mice. AB - The chemopreventive potential of orally administered piperine was studied in Swiss albino mice against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis. The mechanistic pathway for the chemopreventive potential of piperine was evaluated by analysing the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants during DMBA-induced skin carcinogenesis. Skin squamous cell carcinoma was induced in the shaved back of mice, by painting with DMBA (25MUg in 0.1ml acetone/mouse) two times weekly for 8 weeks. We observed severe hyperplasia, dysplasia, and well differentiated squamous cell carcinoma in the 8th, 10th and 15th week of experimental period respectively in mice treated with DMBA alone. Marked alterations in the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants were observed in tumor bearing mice. Oral administration of piperine (50mgkg(-1) body weight) by gastric gavage significantly prevented the formation of skin tumors during DMBA-induced mouse skin carcinogenesis. Also, piperine administration brought back the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants to near normal range in DMBA treated mice. The present study thus demonstrates that piperine has significant suppressing effect on cell proliferation during DMBA-induced mouse skin carcinogenesis. The chemopreventive potential of piperine is probably due to its modulating effect on the status of lipid peroxidation, antioxidants and detoxification agents during DMBA-induced skin carcinogenesis. PMID- 21783977 TI - Effects of tributyltin on epididymal function and sperm maturation in mice. AB - The effects of tributyltin (TBT) on sperm parameters and epididymal function were investigated following oral doses of 0.5, 5 and 50MUg/kg every 3 days for 45 days to male KM mouse. The TBT-treated groups showed a significant decrease in sperm counts and a significant increase in sperm abnormality both in a dose-dependent manner. The expression of matrilysin (MMP7) transcript in epididymis of mice exposed to TBT was significantly decreased in 5 and 50MUg/kg group. There was a dose-dependent decline trend in the acid phosphatase activity, which somewhat relates with the TBT-induced increase in sperm abnormality. Acrosin and lactate dehydrogenase-X isoenzyme (LDH-X) activities from the cauda epididymal spermatozoa showed a dose-dependent decrease in the TBT groups. The result indicates a suppression of essential sperm maturational processes that precede the penetration of the oocyte by the sperm, such as capacitation and acrosome reaction. These results suggest that TBT could cause a spermatotoxic effects, the decline of sperm count and quality caused by TBT suggests that this chemical could impair fertility in animals. PMID- 21783978 TI - Genetic polymorphism of glutathione S-transferase M1 and T1 in Delhi population of Northern India. AB - Glutathione S-transferases (GSTs), protect cells from reactive chemical intermediates and oxidative stress. Among different classes of GSTs, GSTM1 (Mu) and GSTT1 (theta) are found to be genetically deleted. Present study was intended to genotype homozygous null distribution of GSTM1 and GSTT1 in healthy individuals of Delhi, located in Northern India. Out of 309 healthy individuals included in this study, we have found genetic deletion in 21% and 27.4%, GSTM1 and GSTT1 genes, respectively. A small proportion (0.7%) population showed deletion of both the genes. The prevalence of the GSTM1(*)0/0 and GSTT1(*)0/0 genotypes varied within India compared to communities in Chinese, Japanese, Korean and Caucasian. PMID- 21783979 TI - Protective effect of hopeahainol A, a novel acetylcholinesterase inhibitor, on hydrogen peroxide-induced injury in PC12 cells. AB - In this study, we evaluated the effects of hopeahainol A, a novel acetylcholinesterase inhibitor (AChEI) from Hopea hainanensis, on H(2)O(2) induced cytotoxicity in PC12 cells and the possible mechanism. Exposure of PC12 cells to 200MUM H(2)O(2) caused cell apoptosis, reduction in cell viability and antioxidant enzyme activities, increment in malondialdehyde (MDA) level, and leakage of lactate dehydrogenase (LDH). Pretreatment of the cells with hopeahainol A at 0.1-10MUM before H(2)O(2) exposure significantly attenuated those changes in a dose-dependent manner. Moreover, hopeahainol A could mitigate intracellular accumulation of reactive oxygen species (ROS) and Ca(2+), the loss of mitochondrial membrane potential (MMP), and the increase of caspase-3, -8 and 9 activities induced by H(2)O(2). These results show that hopeahainol A protects PC12 cells from H(2)O(2) injury by modulating endogenous antioxidant enzymes, scavenging ROS and prevention of apoptosis. There was potential for hopeahainol A to be used in treating Alzheimer's disease (AD) that involved acetylcholinesterase, free radical, oxidative damage and cell apoptosis. PMID- 21783980 TI - Genotoxicity of glyphosate assessed by the comet assay and cytogenetic tests. AB - It was evaluated the genotoxicity of glyphosate which up to now has heterogeneous results. The comet assay was performed in Hep-2 cells. The level of DNA damage in the control group (5.42+/-1.83 arbitrary units) for tail moment (TM) measurements has shown a significant increase (p<0.01) with glyphosate at a range concentration from 3.00 to 7.50mM. In the chromosome aberrations (CA) test in human lymphocytes the herbicide (0.20-6.00mM) showed no significant effects in comparison with the control group. In vivo, the micronucleus test (MNT) was evaluated in mice at three doses rendering statistical significant increases at 400mg/kg (13.0+/-3.08 micronucleated erythrocytes/1000 cells, p<0.01). In the present study glyphosate was genotoxic in the comet assay in Hep-2 cells and in the MNT test at 400mg/kg in mice. Thiobarbituric acid reactive substances (TBARs) levels, superoxide dismutase (SOD) and catalase (CAT) activities were quantified in their organs. The results showed an increase in these enzyme activities. PMID- 21783981 TI - Anti-angiogenic activities associated with exposure of environmental smoke solutions from 2-stroke auto-rickshaw. AB - Angiogenesis, the formation of new blood vessels, is vital for embryonic development and disruption of this process can be a powerful mechanism of abortion. Over the last few decades there has been increasing global concern regarding the public health impact attributed to environmental smoke pollution. However, no study has yet examined the relation between exhaust from 2-stroke auto-rickshaws and angiogenesis. The current experiment was carried out to elucidate the possible detrimental effects of 2-stroke auto-rickshaw smoke solutions (2SARSS) on physiological angiogenesis, using a well-defined chicken chorioallantoic membrane (CAM) assay. Gross computer based 3D image probing and histopathologic modalities were utilized to quantify different detrimental effects of 2SARSS on the fundamental processes of angiogenesis. Macroscopic investigations of 2SARSS treated CAMs revealed severe disruption in the orientation and normal branching pattern of the blood vessels with profound disorganization. Application of 2SARSS caused substantial decrease in the total vascular area of CAM (p<0.001) diameters of the primary, secondary (p<0.01) and tertiary blood vessels (p<0.001) as well as capillary plexuses formation (p<0.001). Evaluation of different 3D parameters of 2SARSS treated CAMs unveiled diminished surface roughness, angular distribution, and height of the Abbott curves. Moreover, histological evaluations of 2SARSS treated CAMs also revealed disruption of the normal architecture of the blood vessel with marked thinning of ectodermal layer and mesodermal extracellular matrix. The anti-angiogenic effects of 2SARSS clearly demonstrate its toxicity to those travelling and/or living in the vicinity of these vehicles and these populations may suffer from several angiogenesis related pathologies. PMID- 21783982 TI - Immunomodulatory role of piperine in cadmium induced thymic atrophy and splenomegaly in mice. AB - Cadmium being a potent immunotoxicant, affects both humoral and cell mediated immunity. In rodents, it is primarily characterized by marked thymic atrophy and splenomegaly. Cadmium induces apoptosis in mice and suppresses the immune functions. Piperine, major alkaloid of Piper longum Linn. and Piper nigrum Linn. with a long history of medicinal value, has shown anti-apoptotic activity in vitro. Thus, to delineate its role in vivo, piperine (2.5mg/kg/day, oral, 7 days) treated Balb/C mice were administered Cd as CdCl(2) (1.8mg/kg, i.p., once, 4th day). The various biochemical indexes of cell damage such as cytotoxicity (MTT assay), oxidative stress (glutathione, reactive oxygen species), apoptosis (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) along with lymphocyte phenotyping, cell proliferative response and cytokine secretion (IL-2 and IFNgamma) were assessed in thymic and splenic single cell suspensions. Lowering of body weight gain and cellularity and a loss in cell viability seen in Cd group, were abrogated by piperine treatment. Similarly, oxidative stress and apoptotic markers altered by Cd were also modulated by this alkaloid. In addition, a pronounced inhibition of cell proliferative response, alterations in T- and B-cell phenotypes, cytokine release and morphological changes were restored to normalcy. The present in vivo data corroborating with our previous in vitro findings, provide confirmatory evidence of the immuno-protective efficacy of piperine. PMID- 21783983 TI - Cadmium-induced alterations of gene expression in human cells. AB - We have reported the changes in gene expression in human HeLa cells exposed to a low concentration (5MUM) of Cd. In the present study, cells exposed to a higher concentration of Cd were analyzed using a DNA microarray with 9182 human cDNA probes, in an attempt to obtain a comprehensive view on the biological effects of Cd. After a 6h exposure to 50MUM Cd, 48 genes were up-regulated 2.5-fold or greater and 14 genes were down-regulated to 40% or less. Marked up-regulation of genes coding for metallothioneins, anti-oxidant proteins, and heat shock proteins was observed. Cd appeared to repress cell proliferation by modulating genes involved in multiple pathways. Cd also affected a number of genes related to apoptosis. Interestingly, it appeared that a series of genes were regulated to accelerate the intrinsic pathway of apoptosis, while others were directed to suppress the extrinsic pathway. Of these, rapid and transient induction of the TR3 gene was noted as a possible key process in Cd-induced apoptosis. Effects on several genes that may reflect mechanistic backgrounds of Cd toxicity were also observed. The present study disclosed a complex pleiotypic response of human cells to Cd, which was composed of a variety of changes in gene expression directed to defense, growth arrest, recovery from damage, apoptosis and so on. PMID- 21783984 TI - Tributyltin-induced Ca(2+) mobilization via L-type voltage-dependent Ca(2+) channels in PC12 cells. AB - The effects of tributyltin (TBT) on cytosolic Ca(2+) concentration ([Ca(2+)](c)) and cell viability were investigated in nerve growth factor-differentiated PC12 cells. TBT concentration dependently increased [Ca(2+)](c) with an EC(50) value of 0.07MUM. This effect was markedly reduced by removal of the extracellular Ca(2+) or membrane depolarization with a high K(+) medium, but unaffected by thapsigargin causing depletion of intracellular Ca(2+) stores. The L-type voltage dependent Ca(2+) channel (VDCC) blocker nicardipine blocked the effect of TBT, but the N-type VDCC blocker omega-conotoxin did not. TBT decreased the number of viable cells with an EC(50) value of 0.09MUM. The TBT-induced cell death was prevented by nicardipine or by chelating the cytosolic Ca(2+) with BAPTA-AM, but not by omega-conotoxin. The results show that TBT causes an increase in [Ca(2+)](c) via activating L-type VDCCs, and support the idea that the organotin induced cell death arises through Ca(2+) mobilization via L-type VDCCs. PMID- 21783985 TI - Ethanolic Hwaeumjeon induces mitochondrial dependent apoptosis partly via PI3K/AKT/HSP27/ERK pathways and inhibits PSA and AR in LNCaP cells. AB - Hwaeumjeon is a classical prescription that has been traditionally used for treatment of urogenital diseases with no scientific evidences until now. Thus, the present study was performed to evaluate antitumor mechanism of ethanolic Hwaeumjeon (EHEJ). 2-Dimensional electrophoresis (2-DE) proteomic analysis, cell culture study, and Western blotting on apoptosis and prostate-specific antigen (PSA) related proteins were carried out in LNCaP prostate cancer cells. Eight spots with significant increased or decreased expression revealed by 2-DE based comparative proteomic analysis were identified as an increased protein ENC-1AS, four decreased proteins such as RAB34, SFRS1, heat shock 27, and proteasome activator, and three novel proteins such as Rho GDP dissociation inhibitor alpha, cytoplasmic antiproteinase, and EIF3EIP protein in EHEJ-treated LNCaP cells. In addition, EHEJ selectively inhibited the growth of LNCaP prostate cancer cells compared to normal human umbilical vein endothelial cells. Furthermore, EHEJ inhibited PSA and androgen receptor (AR) expression in androgen sensitive LNCaP prostate cancer cells at nontoxic concentrations. Also, EHEJ increased sub-G1 apoptotic portion, activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) and increased the ratio of Bax to Bcl-2. Interestingly, EHEJ also attenuated phosphatidylinositol-3 kinase (PI3K) expression and suppressed the phosphorylation of survival gene AKT, ERK, and HSP27 in LNCaP cells. Consistently, PI3K and ERK inhibitors potentiated EHEJ-induced cytotoxicity and overexpression of Bcl-2 attenuated EHEJ-mediated apoptosis in LNCaP cells. These findings suggest that EHEJ induces mitochondrial dependent apoptosis partly via PI3K/AKT/HSP27/ERK pathways and inhibits PSA and AR in LNCaP cells as a prostate cancer chemopreventive candidate. PMID- 21783986 TI - Genotoxicity and ecotoxicity assays using the freshwater crustacean Daphnia magna and the larva of the aquatic midge Chironomus riparius to screen the ecological risks of nanoparticle exposure. AB - Genotoxic and ecotoxic assessments of widely used nanoparticles, cerium dioxide (CeO(2)), silicon dioxide (SiO(2)) and titanium dioxide (TiO(2)), were conducted on two aquatic sentinel species, the freshwater crustacean Daphnia magna and the larva of the aquatic midge Chironomus riparius. CeO(2) may have genotoxic effects on D. magna and C. riparius, given that the DNA strand breaks increased in both species when exposed to this nanoparticle; whereas, neither exposure to SiO(2) nor TiO(2) had a genotoxic effect on either species. A statistically significant correlation was observed between DNA damage and mortality in the CeO(2)-exposed C. riparius, which suggests that CeO(2)-induced DNA damage might provoke higher level consequences. SiO(2) did not seem to affect the DNA integrity; whereas, the mortality of both the SiO(2)-exposed D. magna and C. riparius increased. The TiO(2) nanoparticle did not lead to significant alterations in geno- or ecotoxic parameters of both species. Overall, these results suggest that CeO(2) nanoparticles may be genotoxic toward aquatic organisms, which may contribute to the knowledge relating to the aquatic toxicity of the most widely used nanomaterials on aquatic ecosystems, for which little data are available. PMID- 21783987 TI - Correlation between urinary nicotine, cotinine and self-reported smoking status among educated young adults. AB - The objective of this study was to correlate, differentiate and validate the self reported smoking status of educated young adults with urinary biomarkers (i.e. nicotine and cotinine). Freshmen students were recruited on voluntary basis. They filled-up self-administered questionnaire and their urine samples were collected for analysis. The urinary nicotine (UN) and cotinine (UC) were measured by gas chromatograph-mass spectrometry. Smokers, non-smokers and ex-smokers were found to be both significantly correlated and different in their UN and UC levels. UC level of 25ng/ml was the optimal cut-off to differentiate smokers from non smokers. Using this cut-off value, the prevalence of smoking among the students was found to be higher (15.4%) than the self-reported data (14.3%). UC is useful in validating individual recent smoking history and the cut-off could serve as a marker for assessing the clinical impact of smoking and environmental tobacco smoke (ETS) exposure on human health. PMID- 21783988 TI - Reactive oxygen species production and Bax/Bcl-2 regulation in honokiol-induced apoptosis in human hepatocellular carcinoma SMMC-7721 cells. AB - We investigated possible mechanism(s) where honokiol induces apoptosis in human hepatocellular carcinoma SMMC-7721 cells. MTT assay showed that honokiol has strong inhibition on SMMC-7721 cells in a dose-dependent manner. SMMC-7721 cells after honokiol treatment display morphological characteristics such as cell shrinkage, detachment from the culture plate, formation of apoptotic bodies, change to a round shape, and marked nuclear condensation and fragmentation after 32258 staining. Cell apoptosis was measured by Annexin-V/PI staining and alternatively, by the subG0/G1 percentage of the cell cycle analysis followed by FACS. An obvious loss of DeltaPsi(m) and a quick burst of ROS was detected when honokiol reached 4MUg/ml, which was coincident with the high apoptosis percentage in our previous research. Up-regulation of Bax and down-regulation of Bcl-2 were observed, suggesting that honokiol-induced apoptosis was associated with reactive oxygen species (ROS) production and an increase of Bax/Bcl-2 ratios. PMID- 21783989 TI - Exposure to metals induces morphological and functional alteration of AFD neurons in nematode Caenorhabditis elegans. AB - Previous studies have revealed that metal exposure will cause severe deficits in perception behaviors. Here we investigated the effects of metal (Hg, Cu, Ag, and Cr) exposure on thermotaxis to cultivation temperature in Caenorhabditis elegans. Our data suggest that exposure to higher concentrations of examined metals induced severe deficits in thermotaxis, and a significant reduction in thermotaxis could be even observed in nematodes exposed to 2.5MUM of Hg. Moreover, exposure to higher concentrations of examined metals and 2.5MUM of Hg induced significant decreases in relative intensities and relative sizes of fluorescent puncta of cell bodies in AFD thermosensory neurons. In addition, exposure to higher concentrations of examined metals resulted in a significant reduction in relative intensities and relative lengths of sensory endings in AFD neurons. Furthermore, the relative transcript levels of ttx-1, which functions in specifying the fate of AFD neuron, were significantly decreased in nematodes exposed to 2.5MUM of Hg, and 50 and 100MUM of examined metals. Thus, metal exposure at high concentrations will induce the severe deficits in thermotaxis to cultivation temperature possibly by altering the morphology or development of AFD neuron and damaging the molecular basis for function of AFD neuron in nematodes. PMID- 21783990 TI - Does selenium modify neurobehavioural impacts of developmental methylmercury exposure in mice? AB - There is controversy as to whether low-level chronic exposure to methylmercury (MeHg) through maternal fish consumption may cause subtle effects in the developing child, owing in part to the potential ameliorating effects of beneficial seafood nutrients. The aim of the present investigation was to assess the ameliorating potential of selenium (Se; as the naturally occurring methionine complex) on the neurobehavioural toxicity of foodborne MeHg (as the naturally occurring cysteinate) in prenatally exposed mice. Pups from dams exposed to a diet containing 3mg/kg of MeHg fed throughout gestation showed delayed fur development and impaired performance in a motor function assessment. These effects were not apparent in pups born to dams concurrently exposed to Se (at 1.3mg/kg). These results, using natural dietary forms of the elements administered through the relevant exposure pathway, suggest only minor impacts of MeHgCys on neurobehaviour, and possible amelioration of these effects by Se. PMID- 21783991 TI - Evaluation of chemopreventive activity of glutamine by the comet and the micronucleus assay in mice's peripheral blood. AB - This research has evaluated the effects of enteral supplementation of glutamine in clastogens and genotoxic damages caused by the acute administration of cisplatin. For this, it was utilized Swiss mice distributed in eight experimental groups: control, cisplatin, glutamine, in three different doses and the combination of these with cisplatin. The results show that the glutamine was present in neither genotoxic nor mutagenic activity. When in association with glutamine and cisplatin, in simultaneous treatment, it was verified the frequency decreased of micronuclei and comets. The damage reduction percentages to the micronucleus ranged from 95.4 to 91.8% after 24h of administration of these compounds and 76.7 to 56.8% after 48h. In the same time the damage reduction percentages to the comet test ranged from 117.0 to 115.0%. The results suggest that glutamine is capable of preventing genotoxic and mutagenic damage according to the experimental design proposed. PMID- 21783992 TI - Toxicity evaluation in nematode Caenorhabditis elegans after chronic metal exposure. AB - In this study, specific developmental stage for adults from day 1 to day 10 was selected to evaluate the chronic metal toxicity, because the population of dead nematodes and the accumulation of intestinal autofluorescence increased sharply after day 10. Chronic exposure to Cr, Pb, Cu, and Hg caused a significant elevation in fractions of dead animals after day 4, and resulted in a significant induction of hsp-16.2::gfp expression at all assayed metal concentrations. Moreover, chronic exposure to Ag, Cr, Pb, Cu, Hg, and Cd would induce a more severe stress response than exposure to Zn and Mn in intestine, and chronic exposure to Pb, Hg, Cr, Zn, and Mn would induce a more severe stress response than exposure to Ag, Cu and Cd in head neurons. Therefore, in determining the usefulness of animals in metal toxicity assessment, this study established a method using nematodes in testing the chronic metal toxicity. PMID- 21783993 TI - Histopathological changes in the reproductive system (ovaries and testes) of Oreochromis mossambicus following exposure to DDT. AB - This study assesses the effects of 1,1-bis (4-chlorophenyl)-2,2,2-trichloroethane (DDT) on the reproduction and gonadal histology of adult Mozambique tipalia (Oreochromis mossambicus). The fish were allowed to breed, following exposure to 2 and 5MUg/l of waterborne technical-grade DDT for 40 days. Fertilized eggs were artificially incubated. In the 5MUg/l exposure, posthatch survival was significantly lower, and prevalence of larval skeletal deformities significantly higher, compared to the control (p<0.05). Incomplete axial development was the common gross deformity in posthatch larvae, caused by failure to develop chondroblasts posterior to the buccopharyngeal cavity. There were no significant differences in the gonadosomatic index of exposed and non-exposed male and female adults. The exposure caused increased oocyte atresia in the ovaries and disorganization of seminiferous lobules in the testes of adults. DDT exposure reduced survival and increased deformities in larvae, at levels that did not cause severe histopathological changes to parental gonads. PMID- 21783994 TI - Oral co-administration of alpha-lipoic acid, quercetin and captopril prevents gallium arsenide toxicity in rats. AB - Gallium arsenide (GaAs), an inter-metallic semiconductor, known to exhibit superior optical and electronic properties compared to silicon, promotes its use in semiconductor industries. Extensive use of GaAs will inevitably lead to an increase in the exposure of workers manufacturing these products. Antioxidants are exogenous or endogenous compounds acting in several ways, including scavenging reactive oxygen species (ROS) or their precursors, inhibiting ROS formation, and binding metal ions needed for the catalysis of ROS generation. In the present study we investigated the protective efficacy of alpha-lipoic acid, quercetin and captopril individually against gallium arsenide exposure. Co administration of alpha-lipoic acid with GaAs was most effective in reducing GaAs induced inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity, liver, kidney and brain reduced glutathione (GSH) level and elevation of oxidized glutathione (GSSG). Captopril, on the other hand was effective in reducing thiobarbituric acid reactive substance (TBARS) levels, while quercetin reduced ROS in liver and kidney. The results suggest comparatively better preventive efficacy of concomitant alpha-lipoic acid administration during Gallium arsenide exposure compared to quercetin and captopril in preventing GaAs induced oxidative stress. PMID- 21783995 TI - In vivo metabolism of norbormide in rats and mice. AB - Norbormide's species-selective lethality displays 150-fold and 40-fold more sensitivity to rats than mice and guinea pigs, respectively. Our previous study revealed marked inter-species differences in rate and route of metabolism in liver preparations from different species, with hydroxylation the major route. To examine whether rapid metabolic clearance or species-dependent formation of a toxic metabolite play a role in the marked species-sensitivity, we initiated in vivo metabolic studies in rats and mice. After oral dosing, norbormide was detected in mouse but not rat blood. In contrast, liver analysis revealed that norbormide concentration was significantly higher in rat compared with mouse, and that it underwent extensive metabolism tentatively identified via hydroxylation in rat, whilst none was detected in mouse. Although an unidentified metabolite (M3) was detected in rat blood after oral dosing, no metabolites were detected 1min after intravenous dosing, which proved lethal at 0.5mg/kg. Taken together, the data indicate that the toxicity resides with the parent compound, rather species-dependent formation of a potent metabolite and that species sensitivity may be controlled at the pharmacodynamic level. PMID- 21783996 TI - Effects of acidosis and Fe (II) on lipid peroxidation in phospholipid extract: Comparative effect of diphenyl diselenide and ebselen. AB - The influence of acidosis on lipid peroxidation in phospholipids extract from egg yolk was studied. In addition, we have also tested the effect of pH on the anti oxidant properties of diphenyl diselenide and ebselen. Acidosis increased rate of lipid peroxidation both in the absence and presence of Fe (II). Diphenyl diselenide significantly protected TBARS production at all studied pH values while ebselen offered only a small statistically non-significant protection. However, changing the pH of the reaction medium did not alter the anti-oxidant activity of the tested compounds. This study provides in vitro evidence for acidosis-induced oxidative stress in phospholipids extract and anti-oxidant action of diphenyl diselenide. PMID- 21783997 TI - Disruption of gap junctional intercellular communication by antibiotic gentamicin is associated with aberrant localization of occludin, N-cadherin, connexin 43, and vimentin in SerW3 Sertoli cells in vitro. AB - Spermatogenesis is a very complex process by which male germ cells differentiate into mature spermatozoa. The sophisticated communication network that controls spermatogenesis can be derailed so that dysfunction of one cell type propagates to all types as a cascade. This accounts for the particular vulnerability of the testis to environmental factors such as drugs and xenobiotics. Sertoli cells play an important role in protecting developing germ cells by forming a physiological barrier, limiting exposure to potentially toxic substrates, or conversely, facilitating uptake of xenobiotics within the testis. In this study, cells from the rat Sertoli line (SerW3) were incubated for 3, 6 and 9 subsequent days in serum free DMEM (SFDM) composed of DMEM supplemented with three different concentrations of antibiotic gentamicin (10, 30, and 100 MUg). The effect of the three different concentrations of this antibiotic was determined on Sertoli cell cell interaction through impaired expression of their constitutive tight junction proteins as early targets for different toxicants in vitro by immunochemistry analysis. The Sertoli SerW3 cell line illustrated the cytotoxicity of GS, as the intercellular junction proteins such as occludin, N-cadherin, connexin 43, and vimentin were delocalized from the membrane to the cytoplasmic compartment during exposure to the antibiotic. This study underlines the potential deleterious effects of the routine use of antibiotics during continuous cell culture. PMID- 21783998 TI - A case-only study of interactions between metabolic enzyme polymorphisms and industrial pollution in childhood acute leukemia. AB - Cancer risk is modulated by gene-environment interactions between toxic exposure and genetic variation in carcinogen metabolism. Our objective was to assess interactions between exposure to industrial pollutants and polymorphisms affecting cytochrome P450s (CYP1A1 and CYP2E1) and glutathione S-transferases (GSTP1 and GSTT) in childhood acute leukemia (AL). A case-only design was conducted in 123 Chinese children with sporadic AL. Industrial plants in the vicinity were recorded and, if present, their size and proximity to the usual place of residence of AL children was evaluated. Unconditional logistic regression analysis was performed across the AL study group adjusting for age, gender, parental education, occupation and smoking, indoor and outdoor pesticide use, presence of television sets, refrigerators, microwave ovens and furniture material in children's rooms, and electric transformers, power lines, and telecommunication transmitters within 500 m. This analysis revealed an interaction between the GSTT null allele and industrial plants within 500 m of the residences of childhood AL patients (interaction odds ratio, COR=2.96, 95% CI: 1.09-8.01). Furthermore, the COR for the interaction between GSTT null and industrial plants within 50 m was 5.99 (95% CI: 1.41-25.45). Our results suggest an association between proximity to industrial plants and the GSTT null allele in patients with childhood AL. PMID- 21783999 TI - Acute toxicity assessment of perfluorinated carboxylic acids towards the Baltic microalgae. AB - The presence of high-energy carbon-fluorine bonds in perfluoro compounds lends them great stability and causes them to be environmentally persistent. Relatively little is known about the acute toxicity of perfluorinated carboxylic acids (PFCAs) to ecotoxicological markers such as aquatic plants and animals. This study tested the toxicity of these compounds to the green alga Chlorella vulgaris, the diatom Skeletonema marinoi and the blue-green alga Geitlerinema amphibium, which are species representative of the algal flora of the Baltic Sea. The EC(50) values obtained range from 0.28 mM to 12.84 mM. A distinct relationship between hydrophobicity and toxicity is demonstrated. For every extra perfluoromethylene group in the alkyl chain, the toxicity increases twofold. LogEC(50) values are very well correlated linearly with both the number of carbon atoms in the perfluoroalkyl chain and the partition coefficients. The results also indicate that there are clear differences between the responses of particular taxonomic groups of algae: blue-green algae and diatoms are far more sensitive to PFCAs than green algae, probably because of differences in cell wall structure. PMID- 21784000 TI - Cognitive impairment in an adult Mexican population non-occupationally exposed to manganese. AB - We examined the association between non-occupational exposure to Mn and cognitive functions. The study was carried out in a mining district located in Hidalgo State, Mexico, with 288 adults. Air and blood Mn concentrations were determined, and neuropsychological tests were administered to explore cognitive functions and depression. Blood Mn mean was 9.5 +/- 4.14 MUg/L. A total of 73% of the study group were in contact with air Mn levels that surpassed the EPA recommended guideline level for non-occupational environments (0.05 MUg/m(3)). Air Mn concentration was associated as a risk factor for attention impairment (OR=1.75, 95% CI: 1.01-3.06). Blood Mn levels were not associated to any of the measured outcomes. The main finding of this study is the presence of attention impairments associated to high levels of air Mn exposure. These results confirm previous studies, in which cognitive impairment is reported for exposed population. PMID- 21784001 TI - Physiological modeling and derivation of the rat to human toxicokinetic uncertainty factor for the carbamate pesticide aldicarb. AB - Aldicarb (ALD, 2-methyl-2-(methylthio)-propionalaldehyde O-(methyl-carbamoyl) oxime, Temik) is widely used as an insecticide, nematocide and acaricide and it is oxidized to aldicarb sulfoxide (ALX) and aldicarb sulfone (ALU). Neither a toxicokinetic model nor an estimate of the target tissue dose of ALD and its metabolites in exposed organisms is available. The objective of this study was: (i) to develop a physiologically based toxicokinetic (PBTK) model for ALD in the rat and humans, and (ii) to determine the interspecies toxicokinetic uncertainty factor (UF(AH-TK)) of ALD. The model consists of a series of mass balance differential equations that describe the time course behavior of ALD in blood, liver, kidney, lungs, brain, fat, and rest of the body compartments. The physiological parameters of the model (blood flow rates, cardiac output, and tissue volumes) were obtained from the literature, while the maximum velocity (mg/kg/min) and the Michaelis constant (mg/l) for ALD oxidation in rats and humans were determined by in vitro AH-TK microsomal assays. The estimation of the tissue:blood partition coefficient was accomplished within the PBTK model by representing the tissues as a composite of neutral lipids, phospholipids and water, and providing the vegetable oil:water partition coefficient as input parameter. The validity of the rat PBTK model was assessed by comparing the model simulations of ALX time course blood concentrations and the inhibition patterns of acetylcholinesterase (AChE) in erythrocytes and plasma obtained by administering rats ALD (0.1 and 0.4 mg/kg, iv). The human PBTK model was validated by comparing the simulations of AChE inhibition patterns in blood with human experimental data obtained from oral administrations of ALD. The UF(AH-TK) for ALD was determined by dividing the areas under the blood and brain concentration vs time curve (AUCCV, AUCCBR) for ALD and ALX in the rat and in human exposed to the same dose. The results indicate that with respect to parent chemical, equivalent applied doses in rats and humans result in a 9.5-fold difference in the AUC(CV) and AUC(AH-TK) respectively, in the two species, and 17 fold difference in the AUC(CV) and AUC(CBR) with respect to the metabolite. In other words, in order to have toxicokinetic equivalence in rats and humans, the former species must be exposed to a dose that is 9.5 and 17 times higher than the human with respect to the parent chemical and the metabolite respectively. Overall, the present study demonstrates the applicability of PBTK models in the quantitative evaluation of UH(AH-TK), and shows that their current default values are inaccurate, at least with respect to ALD, which has potential negative implications in the alleged protection of risk estimates derived from them. PMID- 21784002 TI - Antioxidant potential of sesamol and its role on radiation-induced DNA damage in whole-body irradiated Swiss albino mice. AB - Sesamol (SM) is a dietary phytochemical present in the processed sesame oil. In this present study we have evaluated the antioxidant potential of SM and its role in the protection of radiation-induced DNA damage in gamma-irradiated mice. The antioxidant properties of SM were evaluated by using different in vitro antioxidant assays. SM shows scavenging effect against hydroxyl (OH), superoxide anion (O(2)(-)), nitric oxide, 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid radical cation (ABTS(+)) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Our results demonstrate that SM exhibits strong antioxidant property in all the in vitro assays. When mice were exposed to 7 Gy gamma-radiations there was an increase in % tail DNA, tail length, tail moment and Olive tail moment in blood lymphocytes. SM (100mg/kg b.wt) pretreatment significantly decreased the % tail DNA, tail length, tail moment and Olive tail moment in irradiated mice lymphocytes. These results suggest that SM protects gamma-radiation-induced DNA damage in mice lymphocytes, which may be attributed to its antioxidant property. PMID- 21784003 TI - Cypermethrin-induced histopathological and biochemical changes in Nile tilapia (Oreochromis niloticus), and the protective and recuperative effect of ascorbic acid. AB - The objective of this study was to investigate the effects of ascorbic acid on the toxicity of cypermethrin's on histopathological lesions in tissues and protein, glycogen levels in Oreochromis niloticus. Nile tilapia was exposed to 0.22 and 0.44 MUg/l cypermethrin+control diet, 0.22 and 0.44 MUg/l cypermethrin+ascorbic acid supplemented diet for 20 days. The fish were allowed recuperation period of 15 days in pesticide-free water and fed with ascorbic acid suplementation diet. In light microscopic investigation, histopathological lesions were observed in the gill, liver and kidney. The severity of lesions accreted depending on increased pesticide concentration and control diet. Some of the lesions were reversible or at least were less pronounced after recuperation period. Protein levels decreased in some groups after treatment period according to control groups (p<0.05). The highest depletions in liver, muscle and gill protein levels were found in 0.44 MUg/l cypermethrin+ascorbic acid supplemented diet group (62.23%), in 0.22 MUg/l cypermethrin+control diet group (53.12%) and in 0.44 MUg/l cypermethrin+control diet group (61.87%) after 10 days, respectively. These levels increased at the end of the recuperation period. The highest depletion in liver glycogen levels was found in 0.22 MUg/l cypermethrin+control diet group (50.50%) after 10 days (p<0.05). At the end of recuperation period, there was no difference between the groups (except 0.22 MUg/l cypermethrin+ascorbic acid supplemented diet group) and controls. The decrease of muscle glycogen, except 0.22 MUg/l cypermethrin+ascorbic acid supplemented diet group, was recorded at the end of 10 and 20 days. In the recuperation period, an increase was observed at all groups. These results revealed that the histopathology, protein and glycogen can work as good indicators of stress of a toxicant on fish. Ascorbic acid serves fish as an antitoxic agent against pesticide toxicity. PMID- 21784004 TI - Screening of herbal medicines for the recovery of cisplatin-induced nephrotoxicity. AB - The goal of this study was to quantitatively determine the recovery effects of herbal medicines (HM) on the cisplatin-induced nephrotoxicity. In the present study, the recovery effects of 239 HM on HEK 293 cells that had been damaged by cisplatin were evaluated by a mitochondrial activity MTS assay. After the first round of screening, candidate HM were selected based on a recovery rate of greater than 20%. The efficacy of the selected herbs was then determined by dose response kinetic analysis. Of the extracts evaluated, 7 HM (Paeonia suffruticosa (PS), Curcuma longa (CL), Centipeda minima (CM), Loranthus parasiticus (LP), Pulsatilla dahurica (PD), Sinapis alba (SA), and Scutellaria barbata (SB)) had a strong recovery effect on cisplatin-induced damage in HEK 293 cells. An LDH assay showed that LP, CM, SB, CL, SA, and PS had the best recovery effect, whereas a comet assay indicated that PS, SB, SA, PD, and CL had the best recovery effect. Taken together, these results suggest that SB, CL, PS, and SA are the best candidate HM for the recovery of cisplatin-induced nephrotoxicity. Therefore, additional studies should be conducted to determine if these HM possess novel therapeutic agents that can be used for the prevention or treatment of renal disorders. PMID- 21784005 TI - Effects of simultaneous repeated exposure at high levels of arsenic and malathion on hepatic drug-biotransforming enzymes in broiler chickens. AB - Groundwater contamination with arsenic is a major global health concern. The organophosphorus insecticide malathion has gained significance as an environmental pollutant due to its widespread use in agriculture, grain storage, ectoparasite control and public health management. The deleterious effects produced by arsenic or malathion alone are documented, but very little is known about the consequences of their coexposure. The aim of the current study was to examine the effects of repeated simultaneous exposure to arsenic and malathion on drug-biotransforming enzymes in the liver of broiler chickens. One-month-old broiler chickens were exposed daily to arsenic (50 ppm)-supplemented drinking water, malathion (500 ppm)-mixed diet or in a similar fashion coexposed to these agents for 28 days. At the term, changes in body weight, organ weights, and levels of hepatic cytochrome P450 (CYP), cytochrome b(5), microsomal and cytosolic proteins; aminopyrine N-demethylase (ANDM), aniline P-hydroxylase (APH), glutathione S-transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) were assessed. Arsenic, malathion or their coexposure decreased the body weight gain and liver weight. Brain weight (relative) was increased with arsenic or malathion, but not with the coexposure. Treatment with arsenic decreased the CYP and cytochrome b(5) contents by 39 and 36%, than with malathion by 54 and 22% and the coexposure by 45 and 28%, respectively. The ANDM activity was decreased with arsenic (44%), malathion (23%) and the coexposure (32%). Arsenic (23%) and the coexposure (37%), but not malathion (14%), reduced the APH activity. The activities of hepatic microsomal and cytosolic GST were increased with all the three treatments [Arsenic (microsomal: 88% cytosolic: 113%), malathion (microsomal: 137%, cytosolic: 94%) and coexposure (microsomal: 140%, cytosolic: 148%)]. These treatments did not significantly affect the hepatic UGT activity, but reduced the hepatic microsomal (arsenic: 28%, malathion: 34% and coexposure: 43%) and cytosolic (17-19%) protein contents. The effects of coexposure on the activities of various phase I and phase II drug-biotransforming enzymes were almost similar to that of arsenic or malathion. This study provides evidence that repeated coexposure to arsenic and malathion may influence the extent of drug metabolism in chickens. PMID- 21784006 TI - Comparative study on pesticide mixture of organophosphorus and pyrethroid in commercial formulation. AB - The marketing of mixtures of organophosphate and pyrethroid insecticides has become very common in developing countries and has resulted in an increase in the prevalence of toxicity. The present study aimed to evaluate the toxic effects of a commercial preparation of the pesticide mixture durasin, which contains 60% diazinon and 0.5% deltamethrin, compared with the individual commercial pesticides of diazinon 30% and deltamethrin 5%. Forty male albino rats weighing 160 +/- 20 g were divided into; DA (diazinon 20mg/Kg b.w.), DA (deltamethrin 2mg/Kg b.w.), M (durasin 20mg/Kg b.w.) and control (C); cholinesterase (ChE), malonaldehyde (MDA), glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), total cholesterol (TC), triglyceride (TG) and non specific esterase's isoenzymes in rat's blood were determined following 7 and 14 days of treatment. The weekly- recorded biochemical results were used as criteria for estimating the joint effects of the tested pesticide mixture. Antioxidant defense mechanisms and lipid peroxidation in rat plasma displayed the same responses with intensities which were related to the different treatments. Biochemical analysis showed that (DA) or (DM) individually cause alteration in lipid metabolism and non-specific esterase, while mixture treatment (M) induced antagonistic effects toward all the tested parameters except total reduced glutathione level, which was synergistic at the 2nd week. In conclusion the commercial mixture (M) under study has potentially greater toxic impact than the components alone in the rat. PMID- 21784007 TI - Lungs: remote inflammatory target of systemic cadmium administration in rats. AB - Pulmonary inflammation is a biological response to cadmium entering the body via the respiratory route. Systemic administration of this metal revealed the lungs as a significant site of its disposition. In this study, the presence of basic indicators of lung inflammation (leukocyte infiltration and activity of cells recovered from lungs by enzyme digestion) was analyzed in the rat model of acute systemic cadmium intoxication. Intraperitoneal administration of both cadmium doses (0.5mg/kg and 1.0mg/kg) resulted in increased numbers of neutrophils. Signs of spontaneous activation of lung cells including the capacity of reduction of nitroblue tetrazolium (NBT), increase in myeloperoxidase (MPO) intracellular content and increase in interleukin-6 (IL-6) production were noted at both cadmium doses. Increased lung cell responsiveness to stimulation in vitro was noted at the higher cadmium dose. The presence of pulmonary inflammatory parameters in rats administered intraperitoneally with cadmium revealed the lungs as remote inflammatory targets of this metal. PMID- 21784008 TI - Effects of cadmium on osteoblasts and osteoclasts in vitro. AB - Cadmium (Cd) may have direct effects on bone metabolism and the mechanism is not fully understood. To investigate the effects of Cd on bone metabolism, effects of Cd on osteoblasts and osteoclasts in vitro were observed at cellular and molecular levels. Osteoblasts were cultured by sequential enzyme digestion from Sprague-Dawley rats calvarial bone and osteoclasts were isolated from long bones of new-born male and female Sprague-Dawley rats, and then cells were exposed to different concentrations of Cd (0-2.0 MU mol/L for osteoblasts; 0.03 MUmol/L for osteoclasts). As for osteoblasts, cell viability, alkaline phosphatase (ALP) activity, and mineralization were determined. Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANKL) were studied via reverse transcription polymerase chain reaction (RT-PCR). For osteoclasts, after exposure to Cd (0.03 MUmol/L) for 72 h and 120 h, number of osteoclasts and pits formation was observed. Cd inhibited the viability, ALP activity, mineralization and up regulated RANKL mRNA expression in osteoblasts. But Cd had no obvious effect on OPG mRNA expression. For osteoclasts, cadmium (0.03 MUmol/L) could increase the numbers of osteoclasts (p<0.05) and enhance pits formation (p<0.05). These results suggested that Cd could inhibit bone formation at high concentrations and enhance bone resorption at low level. OPG/RANKL may constitute an important pathway of Cd effects on bone. PMID- 21784009 TI - The use of biochemical responses to assess ecotoxicological effects of Pharmaceutical and Personal Care Products (PPCPs) after injection in the mussel Elliptio complanata. AB - A biomarker approach was undertaken using the mussel Elliptio complanata to assess the ecotoxicological effects after injection of a range concentration (0 10mM) of three different PPCPs: carbamazepine, caffeine, methotrexate; and an effluent extract (C8) from St. Lawrence wastewaters treatment plant (Montreal, Canada). A battery of biomarkers, involving oxidative stress and genotoxicity responses: glutation-S-transferase (GST), ethoxyresorufin O-deethylase (EROD), dibenzylflourescein dealkylase (DBF), xanthine oxidoreductase (XOR) activities, lipid peroxidation (LPO) and DNA damage were determined in gonad and digestive gland tissues after 48 h of injection. Results showed an induction of the oxidative metabolism with increasing pharmaceutical concentration in those mussels injected with the PPCPs and the effluent extract. Phase I detoxification enzymes were significantly induced (p<0.05), concretely DBF activity was significantly induced after caffeine, carbamazipine and C8 injection; and EROD activity after C8 and methotrexate injection. Oxidative stress induction only lead to lipid peroxidation (p<0.05) in organisms injected with carbamazepine and caffeine and DNA damage in organisms injected with methotrexate (p<0.05). EROD and DBF enzymatic activities have been found to be suitable biomarkers to determine bioavailability of pharmaceuticals. LPO and DNA damage to determine possible associated adverse effects. Nevertheless, their validation in realistic exposure scenarios and under exposure conditions should be performed in future research. PMID- 21784010 TI - Effects of infrasound on hippocampus-dependent learning and memory in rats and some underlying mechanisms. AB - To investigate the effect of infrasound on the hippocampus-dependent spatial learning and memory as well as its underlying mechanisms, we measured the changes of cognitive abilities, brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signal transduction pathway and neurogenesis in the hippocampus of rats. The results showed that rats exposed to infrasound of 16 Hz at 130 dB for 14 days exhibited longer escape latency from day 2 and shortened time staying in the quadrant P in Morris water maze (MWM). It was found that mRNA and protein expression levels of hippocampal BDNF and TrkB were significantly decreased in real-time PCR and Western blot, and the number of BrdU-labeled cells in hippocampus was also reduced when compared to control. These results provided novel evidences that the infrasound of a certain exposure parameter can impair hippocampus-dependent learning and memory, in which the downregulation of the neuronal plasticity-related BDNF-TrkB signal pathway and less neurogenesis in hippocampus might be involved. PMID- 21784011 TI - Geranylgeranylacetone protects rat and striatum neurons against heat injury via induction of Hsp70. AB - GGA (geranylgeranylacetone) may induce Hsp70 synthesis, thus contributing to the protective effects of GGA in several disease states. This study evaluated the protective effects of GGA against heat injury to rat and striatum neurons in terms of mechanisms. Rats were exposed to 41.5 degrees C for 35 min to induce heatstroke; the protective effects of GGA were then evaluated by change in rectal temperature (Tre) during heat exposure and survival time after heatstroke. Primary cultured striatum neurons were incubated with GGA for 24h, and then heat treated at 43 degrees C for a further 1h. The viability, membrane surface ultrastructure and Hsp70 expression of striatum neurons were all observed. Furthermore, the effects of quercetin an inhibitor of Hsp70 synthesis were also investigated. Compared to the heatstroke group, GGA delayed Tre in reaching 42.1 degrees C (P<0.05) and prolonged the survival time after heatstroke (P<0.01). The LDH releasing percentage decreased in GGA groups (P<0.05, P<0.01) compared to the heat-treatment group and increased in quercetin groups (P<0.05) compared to GGA group. Results from AFM showed that GGA protected membrane surface ultrastructure against heat injury. In addition, results from Western blot showed that GGA induced Hsp70 expression of neurons both in normal and heat-treatment conditions (P<0.01, P<0.05) and quercetin inhibited GGA-induced Hsp70 expression (P<0.05). Therefore, GGA had protective effects against heat injury in striatum neurons and rat heatstroke. Quercetin inhibited GGA-induced Hsp70 expression and prevented GGA-protective effects, which indicated that this protection was dependent on the Hsp70 synthesis. PMID- 21784012 TI - Decreased learning ability and low hippocampus glutamate in offspring rats exposed to fluoride and lead. AB - Fluoride (F) and lead (Pb) are two common environmental pollutants which are linked to the lowered intelligence, especially for children. Glutamate, a major excitatory neurotransmitter in the central nervous system, plays an important role in the process of learning and memory. However, the impact of F and Pb alone or in combination on glutamate metabolism in brain is little known. The present study was conducted to assess the glutamate level and the activities of glutamate metabolism related enzymes including asparate aminotransferase (AST), alanine aminotransferase (ALT) and glutamic acid decarboxylase (GAD) in the hippocampus, as well as learning abilities of offspring rat pups at postnatal week 6, 8, 10 and 12 exposed to F and/or Pb. During lactation, the pups ingested F and/or Pb via the maternal milk, whose mothers were exposed to sodium fluoride (150 mg/L in drinking water) and/or lead acetate (300 mg/L in drinking water) from the day of delivery. After weaning at postnatal day 21, the pups were exposed to the same treatments as their mother. Results showed that the learning abilities and hippocampus glutamate levels were significantly decreased by F and Pb individually and the combined interaction of F and Pb. The activities of AST and ALT in treatment groups were significantly inhibited, while the activities of GAD were increased, especially in rats exposed to both F and Pb together. These findings suggested that alteration of hippocampus glutamate by F and/or Pb may in part reduce learning ability in rats. PMID- 21784013 TI - Up-regulation of RAGE and S100A6 in rats exposed to cigarette smoke. AB - Cigarette smoke has been widely investigated in terms of epidemiology and pathological endpoints in relation to human lung diseases and animal study. In this study we exposed Wistar rats to cigarette smoke at concentrations of 20% and 60% to explore potential molecular mechanisms at the protein level. Exposures were conducted twice a day, 5 days a week for 43 weeks. As a major metabolite of nicotine in cigarette, cotinine level in rat urine was determined by HPLC-MS. A dose-dependent analysis indicated that cotinine may be used as an exposure marker of cigarette smoke. Expression of receptor for advanced glycation endproducts (RAGE), an immunoglobulin super family that triggers the intracellular signal cascade reaction leading to inflammation and its ligand S100A6 (calgranulin) in bronchial epithelial cells and lung tissues of rats, were found to be positive correlated with cotinine levels, indicating that RAGE and S100A6 may be attributable to inflammation and oxidative damage caused by cigarette smoke. PMID- 21784014 TI - Lectins but not antifungal proteins exhibit anti-nematode activity. AB - A variety of lectins and antifungal proteins were tested for toxicity against the plant parasitic nematodes Ditylenchus dipsaci and Heterodera glycines. It was found that lectins from the mushrooms Xylaria hypoxylon, Agrocybe cylindracea and Tricholoma mongolicum (TML-1) were the most potent against D. dipsaci, with EC(50) being 4.7, 9, and 20mg/ml, respectively. Lectins from Pseudostellaria heterophylla, samta tomato, and the mushrooms T. mongolicum (TML-2), Ganoderma lucidum, and Boletus edulis, and antifungal proteins from Ginkgo biloba toward D. dipsaci and pumpkin Cucurbita moschata had much lower anti-nematode potencies and could be considered as inactive for practical purposes. All lectins except that from P.heterophylle were potent against H.glycines. PMID- 21784015 TI - Multi-level ecotoxicity assay on the aquatic midge, Chironomus tentans (Diptera, Chironomidae) exposed to octachlorostyrene. AB - Octachlorostyrene (OCS) is a ubiquitously distributed compound, of which, ecotoxicological property is little known. To investigate the ecotoxicity of OCS, short- and long-term experiments were conducted under controlled laboratory conditions, using the aquatic midge, Chironomus tentans, as a biological model system. Ecophysiological responses using organism/population level endpoints, such as growth, reproduction and development, were investigated. Moreover, oxidative stress-related parameters and the expression of heat shock protein and hemoglobin gene were also investigated as potential biomarkers for OCS exposure. Significant disturbance in male/female adult ratio and on oviposition by chronic exposure to OCS suggests that this compound may have serious consequences on Chironomus population by affecting reproduction. To elucidate the mechanism of these speculated phenomena, direct experimental demonstrations on the relationships between observed ecotoxicological response and upstream-induced molecular/biochemical events may be needed. PMID- 21784016 TI - Studying the impact of S9 on cyto-genotoxicity of cigarette smoke in human peripheral blood lymphocytes in vitro. AB - In present study, human lymphocytes were exposed to cigarette smoke condensates (CSCs) at the doses of 25, 50, 75, 100 and 125 MUg ml(-1) with and without S9, and the cyto-genotoxic effects were detected with CCK-8, cell apoptosis and micronucleus assays. DNA repair kinetics was observed with comet assay. Our results indicated that the cell viability decreased with CSCs doses, the percentages of apoptosis cell and the frequencies of micronuclei increased with CSCs doses, and DNA damage of human lymphocytes induced by CSCs could be basically repaired within 240 min. However, the cytotoxicity induced by CSCs +S9 was significantly lower than that induced by CSCs -S9 in CCK-8 and cell apoptosis assays, and the DNA repair speed in +S9 group was quicker than that in -S9 group. In conclusion, S9 may affect not only the cyto-genotoxicity of CSCs but also the repair process of DNA damage induced by CSCs in lymphocytes. PMID- 21784017 TI - Antioxidant effect of alkynylselenoalcohol compounds on liver and brain of rats in vitro. AB - Alkynylselenoalcohol compounds were screened for in vitro antioxidant activity. Alkynylselenoalcohols (2a-2d) were tested against lipid and protein oxidation induced by sodium nitroprusside (SNP) in rat brain and liver. The influence of molecular structural modifications of alkynylselenoalcohols in their antioxidant activity was investigated. The 1,1'-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and the interaction of alkynylselenoalcohols with iron were carried out. The results revealed that the antioxidant activity depends on their chemical structures. Compounds 2e (without hydroxyl group) and 3a (with a tellurium atom) presented better antioxidant profiles than 2b (with a hydroxyl group and selenium atom) against lipid and protein oxidation. Compound 1a (with a butyl group) did not modify the effect of compound 2a (with a phenyl group) on lipid oxidation. Compounds 2e and 3a showed DPPH radical-scavenging activity. Compounds 2b, 2c and 3a inhibited isocitrate-mediated oxidation of Fe(2+). Alkynylselenoalcohols demonstrated antioxidant effects and the modifications in the molecular structure of compound 2b improved its antioxidant potency. PMID- 21784018 TI - Evaluation of the toxic and genotoxic potential of landfill leachates using bioassays. AB - Landfill leachates are liquid effluents with elevated concentrations of chemical compounds that can cause serious environmental pollution. In the south of the state of Santa Catarina, Brazil, a sanitary landfill was installed that employs a system of anaerobic/facultative lagoons for the treatment of its leachate. The present work examined the toxic and genotoxic potential of untreated and treated landfill leachates using bioassays. The chemical, toxic, genotoxic and mutagenic properties of the untreated leachate and the treated leachate were determined. Examination of the chemical properties showed a marked decrease in parameters after treatment, as well as in toxicity towards all the organisms tested. The results of the comet assay demonstrated that both leachates showed genotoxicity in all of the organisms tested, indicating the persistence of genotoxic substances even after treatment. A significant decrease in micronucleated cells was detected in Geophagus brasiliensis exposed to the treated leachate compared to untreated. PMID- 21784019 TI - Induction profile of HSP70-cognate genes by environmental pollutants in Chironomidae. AB - Several species of invertebrates have been studied to examine the toxicological effects of chemicals that include insecticides and heavy metals. We characterized heat-shock protein (hsp) genes from the ubiquitous midge, Chironomidae. More than 70 fold induction of hsp70 expression was detected by quantitative PCR after 37 degrees C treatment in the midge. Expression of hsp70 was induced not only by heat but also by exposure to insecticides and heavy metals such as cadmium and copper. Expression time courses for hsp70 were highly specific to each chemical. When midges were exposed to sub-lethal level of a pyrethroid insecticide, ethofenprox, hsp70 expression was increased over 20 fold with a transient peak at 1.5h. Heavy metal exposure led to delayed hsp70 up regulation of 7 fold at 6-7h. Expression of another hsp70-cognate gene (hsc70) was also characterized. Using these genes we propose a novel system for biomonitoring of heavy metals and other pollutants. PMID- 21784020 TI - Oxidative stress, protein carbonylation and heat shock proteins in the black tiger shrimp, Penaeus monodon, following exposure to endosulfan and deltamethrin. AB - The impact of commonly used pesticides, endosulfan and deltamethrin, on the molecular stress level in black tiger shrimp Penaeus monodon, was assessed using classical oxidative stress biomarkers, protein carbonylation profiles, and levels of heat shock proteins. Results showed that 4 days exposure to 0.1 MUg L(-1) deltamethrin significantly (p<0.05) increased lipid peroxidation (LPO) level in gills (64.3 +/- 3.2 compared to 34.2 +/- 5.3 nmol MDA equiv.g(-1) tissue at day 0). However, no pesticide treatment had significant effect on the activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). Carbonylated protein profiles were determined on gills following 2,4-dinitrophenylhydrazine derivatization and 2D-PAGE along with Western blotting. Immunoblotting with dinitrophenol-specific antibody revealed 17 protein spots carbonylated in response to 4 days exposure to 0.1 MUg L(-1) deltamethrin while 24 protein spots specifically oxidized at day 0 were no longer detected after deltamethrin treatment. On the other hand, endosulfan exposure at 0.1 and 1 MUg L(-1) induced up to 2.1-fold increase of HSP90 level in muscle. This approach is providing new insights into the molecular impacts of deltamethrin and endosulfan on an economically important crustacean. While deltamethrin has shown a pro-oxidant effect in gills, endosulfan exposure rather induced proteotoxic effects in muscles. This argues that LPO level, protein carbonylation specificities, and HSP90 levels may be potential discriminating biomarkers to assess the chemical stress level in farm shrimp. PMID- 21784021 TI - Calculating the retention of volatile organic compounds in the lung on the basis of their physicochemical properties. AB - In the workplace, deliberate or accidental exposure to volatile organic compounds (VOCs) may occur by ingestion, but more usually through inhalation or dermal contact. The basic model of occupational exposure assumes repeated inhalation exposure during long periods of time, such as 8-h daily, 40-h per working week. Evaluation of the systemic health effects of industrial chemicals can be based on biological levels or internal doses absorbed in dermal or inhalation exposures. The lungs are the primary route of absorption in exposure to gases, vapors, and aerosols. In inhalation exposure, the dose absorbed can be calculated using the following equation: [formula in text] where C, concentration in the air; T, duration of exposure; V, lung ventilation; R, lung retention expressed as % of intake. As lung retention of VOCs has been studied on human volunteers in costly and time-consuming chamber-type experiments, available data are limited. To calculate dosage for the purpose of risk assessment, the default value of 100% is used. As the lung retention of VOCs in lungs can vary from less than 20 to more than 90%, a possibility of predicting the retention values on the basis of blood/air partition coefficients (K(B)) has been investigated. Lung retention data for 36 compounds were obtained from the existing scientific literature. These values derive from human volunteer studies lasting at least 2h. The K(B) values were either the already published experimental data or were calculated based on their physicochemical properties using a published solvation equation. The compounds under study were divided arbitrarily into two groups: water soluble (>10 g/l) and slightly soluble in water (<10 g/l) compounds. For water soluble compounds, the correlation between K(B) and lung retention was high (r=0.75 and 0.73 respectively); this referred both to K(B) values obtained experimentally or calculated in this report. For the compounds slightly soluble in water, the respective values amounted to 0.79 and 0.82. The obtained results indicate that VOC retention in the lung can be calculated solely on the basis of the partition coefficient K(B). As the descriptors used in the solvation equation can be predicted from chemical structure, this finding indicates that it is possible to assess lung retention for any chemical structure of VOC. The model described in the present report can be a practical alternative to the necessity costly and long-lasting chamber-type experiments which are also questionable on ethical grounds. PMID- 21784022 TI - Modulation of carcinogen metabolizing enzymes by chromanone A; a new chromone derivative from algicolous marine fungus Penicillium sp. AB - A marine fungal isolate, Penicillium sp. fungus isolated from seaweed, Ulva sp., led to the isolation of a new chromone derivatives, 2-(hydroxymethyl)-8-methoxy-3 methyl-4H-chromen-4-one (chromanone A). The structure was determined by interpretation of their spectroscopic data (1D and 2D NMR, MS, UV and IR). At the nitiation stage of carcinogenesis, carcinogens is activated by cytochrome P-450 1A (CYP1A) and detoxified by glutathione S-transferases (GST), quinine reductase (QR), and epoxide hydrolase (mEH). We tested the modulatory effect of chromanone A on these carcinogen metabolizing enzymes. The results indicated that chromanone A (4MUg/ml) is a promising inhibitor of CYP1A activity up to 60% of the stimulated-CYP1A in murine hepatoma cells (Hepa1c1c7), and it significantly induced GST but not total thiols at low concentrations. Chromanone A had no influence on QR activity, while it resulted in a significant dose-dependant enhancement mEH activity in Hepa1c1c7 cells (P<0.05-0.01). Additionally, chromanone A possessed a potent specific radical scavenging activity against hydroxyl radicals more than peroxyl radicals that may be responsible for the inhibitory effect of chromanone A on the induced-DNA damage in cells. In conclusion, this study proved that chromanone A may act as an active tumor anti initiating via modulation of carcinogen metabolizing enzymes and protection from DNA damage. PMID- 21784023 TI - Pollution dilemma in Asian population: CNG and wound healing. AB - Automobile exhaust constituents contribute significantly to air pollution in urban areas and compressed natural gas (CNG) is considered one of the most promising fuel alternatives for the future. CNG-powered four-stroke engine auto rickshaws are ubiquitous in South Asian cities as taxi and for commercial transportation. Automotive exhaust contains several toxins, which are overwhelmingly toxic to the processes of wound healing. By utilizing the in vivo mouse model of wound healing, this report analyzes the effects of CNG-powered four-stroke auto-rickshaws smoke solution (4SARSS) on different events of wound healing; dermal matrix regeneration, re-epithelialization and neovascularization. A total of 72 adult mice, divided in eight groups were exposed to 4SARSS for 12 days. A highly significant reduction (P<0.001) in wound closure was observed among all 4SARSS treated groups, at each time point of the experiment. An immature development in both the neoepidermis and the neodermis was observed among all 4SARSS treated wounds with defective re-epithelialization, dermal matrix regeneration and maturation of collagen bundles. Abbott curve, angular spectrum, 3D surface topographies, and histological investigations of wounds explicated highly significant activation (P<0.001) of delayed-neovascularization among 4SARSS treated wounds. All these annotations advocate excessive toxicity of emission from CNG-powered auto-rickshaws to the process of wound healing and people occupationally exposed to this toxic emissions may suffer varying degree of delayed wound healing. PMID- 21784024 TI - Suppressive effects on the biosynthesis of inflammatory mediators by Aralia elata extract fractions in macrophage cells. AB - The aim of this study is to elucidate the anti-inflammatory effects of Aralia elata extract fractions (AEEFs). A. elata-ethyl acetate fraction (AEEF) had the strongest antioxidant activity. A. elata-chloroform fraction (AECF) and A. elata butanol fraction (AEBF) inhibited potently LPS-induced nitrite production from RAW 264.7 macrophage cells. The inhibition of nitric oxide (NO) production by AEEFs was partially due to chemical scavenge of NO and the suppression of inducible NOS (iNOS) transcription level in LPS-induced macrophage cells. In addition, AEEFs inhibited significantly the biosynthesis of Prostaglandin E(2) (PGE(2)), and cyclooxygenase-2, which regulates the synthesis of PGE(2), was attenuated partially by the treatment of AEEFs in LPS-induced macrophage cells. Also, A. elata-methanolic extract (AEME) suppressed remarkably IL-1beta and IL-6 level to the basal (more than 99% inhibition) in concentration-dependant manners. Its anti-inflammatory actions might be related with inhibition of NF-kappaB activation in LPS-stimulated macrophage cells. It is concluded that AEEFs may be useful as a functional food material and an alternative medicine for the relief and retardation of immunological inflammatory responses. PMID- 21784025 TI - Protective effects of Eucommia ulmoides Oliv. bark and leaf on amyloid beta induced cytotoxicity. AB - The objectives of this study were to investigate the protective effects of Eucommia ulmoides Oliv. (EUO) bark and leaf against cytotoxicity induced by amyloid-beta peptide (Abeta) and to explore their active components. The PC-12 cells injury mediated by Abeta(25-35) was employed to assess the neuroprotective effects of EUO bark, EUO leaf and various compounds. Intracellular Ca(2+) determination, MTT reduction assay, lactate dehydrogenase leakage evaluation and HO33258/PI staining were used to quantitatively or qualitatively evaluate cell viability and injury. The organic solvents partition and the macroporous resin separation were also applied to tracing the active constituents of EUO bark. Moreover, the effects of 8 compounds (3 iridoid glucoside, 3 phenylpripanoids and 2 flavonoids) were tested to identify the active compounds of EUO leaf. The results demonstrated that the water extracts of EUO barks and leaves, geniposidic acid and chlorogenic acid could efficiently protect PC-12 cells against the cytotoxicity of Abeta(25-35). This research suggests that EUO may represent a potential treatment strategy for Alzheimer's disease. Meanwhile, geniposidic acid and chlorogenic acid are the major active constituents of EUO barks and leaves, respectively. PMID- 21784026 TI - Resveratrol ameliorates carbon tetrachloride-induced acute liver injury in mice. AB - Present investigation aimed to evaluate the hepatoprotective potential of resveratrol (30mg/kg, po) in mice following two different routes (po and sc) of exposure to carbon tetrachloride (CCl(4), 1.0ml/kg). Administration of CCl(4) caused significant increase in the release of transaminases, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, creatinine kinase, total bilirubin, urea and uric acid in serum. Significantly enhanced hepatic lipid peroxidation and oxidized glutathione with marked depletion in reduced glutathione were observed after CCl(4) intoxication. It was also found that CCl(4) administration caused severe alterations in liver histology. Hepatic injury was more severe in those animals who received CCl(4) by oral route than those who exposed to CCl(4) subcutaneously. Resveratrol treatment was able to mitigate hepatic damage induced by acute intoxication of CCl(4) and showed pronounced curative effect against lipid peroxidation and deviated serum enzymatic variables as well as maintained glutathione status toward control. Treatment of resveratrol lessened CCl(4) induced damage in liver. The results of the present study suggest that resveratrol has potential to exert curative effects against liver injury. PMID- 21784027 TI - Intracellular glutathione plays important roles in pyrrolizidine alkaloids induced growth inhibition on hepatocytes. AB - Pyrrolizidine alkaloids (PAs) are well-known natural hepatotoxins distributed widely in thousands of plants in the world. Adonifoline (Adon), senecionine (Sene) and monocrotaline (Mono) are retronecine-type PAs, and the present study is designed to observe the effects of intracellular glutathione on toxicity of these three PAs in human normal liver L-02 cells. The ratio of cellular reduced glutathione (GSH) and oxidized glutathione (GSSG) was assayed after L-02 cells were incubated with these three PAs for various times. Results showed that Adon, Sene and Mono all significantly decreased the ratio of GSH/GSSG in L-02 cells in the time- and concentration-dependent manner. The results of 3-(4,5 dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and trypan blue staining assay showed that these three PAs all significantly decreased cell viability in L-02 cells when pretreated with 10MUM BSO (L-Buthionine-S-R Sulfoximine) for 24h to deplete intracellular GSH. Further results showed that anti-oxidant compounds such as NAC (N-Acetyl-Cysteine) and GSH could rescue the cytotoxicity caused by these three PAs with BSO pretreatment. Taken together, those results suggest that intracellular GSH plays important roles in regulating the cytotoxicity induced by PAs. PMID- 21784028 TI - Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure. AB - The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. PMID- 21784029 TI - The inducibility of human cytochrome P450 1A by environmental-relevant xenobiotics in the human hepatoma derived cell line HepG2. AB - Overexpression of the CYP1 family, independent of gender, is focal to the evaluation of the risk of human cancer. We have analysed the ability of 17 anthropogenic environmental xenobiotics widely used in Europe within households and agriculture to induce the human cytochrome P450 1A (CYP1A) in the human hepatoma derived cell line HepG2. The xenobiotics were potent to concomitantly induce both CYP1A mRNA and CYP1A activity in a dose-response relationship. Exceptions were shown by the organophosphate insecticide chlorpyrifos and the imidazole fungicide prochloraz in high concentrations which were capable of both inhibiting the basal or abolishing the initially induced CYP1A activity, respectively. A CYP1A induction has been shown for the first time by the aromatic xenobiotics irgasan, permethrin and azoxystrobin, the nonaromatic tributyltinoxide and for humans by the piperonylbutoxide. The xenobiotics additionally differed by their induced CYP1A isoenzyme pattern. A pronounced CYP1A1 and CYP1A2 mRNA induction was given by the phenyl urea herbicide diuron and benzodiazole insecticide piperonylbutoxide, respectively. In conclusion, out of the environmental xenobiotics, we described new members of human CYP1A inducers which extend chemical structures of biotransformation activators. PMID- 21784030 TI - Oxidative stress responses of rats exposed to Roundup and its active ingredient glyphosate. AB - Glyphosate is the active ingredient and polyoxyethyleneamine, the major component, is the surfactant present in the herbicide Roundup formulation. The objective of this study was to analyze potential cytotoxicity of the Roundup and its fundamental substance (glyphosate). Albino male rats were intraperitoneally treated with sub-lethal concentration of Roundup (269.9mg/kg) or glyphosate (134.95mg/kg) each 2 days, during 2 weeks. Hepatotoxicity was monitored by quantitative analysis of the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities, total protein, albumin, triglyceride and cholesterol. Creatinine and urea were used as the biochemical markers of kidney damages. The second aim of this study to investigate how glyphosate alone or included in herbicide Roundup affected hepatic reduced glutathione (GSH) and lipid peroxidation (LPO) levels of animals as an index of antioxidant status and oxidative stress, respectively, as well as the serum nitric oxide (NO) and alpha tumour necrosis factor (TNF-alpha) were measured. Treatment of animals with Roundup induced the leakage of hepatic intracellular enzymes, ALT, AST and ALP suggesting irreversible damage in hepatocytes starting from the first week. It was found that the effects were different on the enzymes in Roundup and glyphosate-treated groups. Significant time-dependent depletion of GSH levels and induction of oxidative stress in liver by the elevated levels of LPO, further confirmed the potential of Roundup to induce oxidative stress in hepatic tissue. However, glyphosate caused significant increases in NO levels more than Roundup after 2 weeks of treatment. Both treatments increased the level of TNF-alpha by the same manner. The results suggest that excessive antioxidant disruptor and oxidative stress is induced with Roundup than glyphosate. PMID- 21784031 TI - Detection of trace anthracene in soil samples with real-time fluorescence quantitative immuno-PCR using a molecular beacon probe. AB - We developed a highly sensitive and robust real-time fluorescence quantitative immuno-PCR (RTFQ-IPCR) method which uses molecular beacon (MB) probe to detect trace anthracene in the environment. This method was performed on serial dilutions of known anthracene concentrations equivalent to 10-fold dilutions of 10fg/mL to 100pg/mL. We obtained a linear relationship between 10fg/mL and 100pg/mL, with y=0.684x+13.221. A correlation coefficient of 0.994 was also identified, with a detection limit of 4.5fg/mL. After investigating the presence of anthracene in soil samples via RTFQ-IPCR, the obtained concentrations were confirmed by ELISA to be correct and believable, with the recovery ratio ranging from 82% to 112.5%. Based on its sensitivity and reproducibility, MB-based RTFQ IPCR was found to be acceptable for use in on-site field tests to provide rapid, quantitative, and reliable test results for making environmental decisions. PMID- 21784032 TI - Frequency of common CYP1B1 polymorphic variations in Delhi population of Northern India. AB - Cytochrome P4501B1 (CYP1B1) is an extrahepatic enzyme, important in the activation of procarcinogens. It is expressed in steroidegenic tissues and is active in the metabolism of estradiol. CYP1B1 polymorphisms have been shown to be associated with cancer susceptibility related to environmental toxins and hormone exposure. CYP1B1 is also involved in the metabolism of some clinically relevant anticancer drugs. Polymorphisms in the gene have also been associated in primary open-angle glaucoma (POAG). Their genotypes may also display ethnicity dependent population frequencies. Present study was aimed to determine the frequency of five known CYP1B1 polymorphisms in Delhi population. Frequency of CYP1B1 polymorphisms, CYP1B1*2, CYP1B1*3, CYP1B1*4 and CYP1B1*7 were found to be 39, 48.8, 47.3 and 17.07% respectively in normal, healthy individuals. Arg48Gly and Ala119Ser were found to be completely linked with each other. Analysis of CYP1B1 polymorphisms might help in predicting the risk of cancer as well as susceptibility to POAG. Our results emphasize the need for more such studies in "high risk populations". PMID- 21784033 TI - Risk factors for bango abuse in upper Egypt. AB - Cannabis is the most commonly abused drug in the world. In Egypt, the Anti Narcotic General Administration, showed that the narcotics problem costs the Egyptian economy approximately 800 million dollars annually. The present study was designed to determine the risk factors that lead to bango abuse among secondary school students and drivers in Assiut province. Urine samples were taken from 1000 volunteers after filling questionnaires and the risk factors were determined. Ethical consideration and informed consent was taken on. In drivers, the study found that bango abuse was concentrated in age group (21 to <31 years) and in those driving microbus, van and half van. In students, abuse concentrated in male students by 100%, and in those with high daily fund. The abused students tend to be more aggressive. Also, tend to be lazy to share in school activities. Abused students present in large family (8-11 persons) and families with troubles between parents (81% in divorced parents). In conclusion, bango abuse leads to deterioration of the academic achievement, and may be associated with antisocial and violent behavior. PMID- 21784034 TI - Reversal of propoxur-induced impairment of step-down passive avoidance, transfer latency and oxidative stress by piracetam and ascorbic acid in rats. AB - Propoxur, a carbamate pesticide has been shown to adversely affect memory and induce oxidative stress. The present study was designed to correlate the effect of propoxur, piracetam (a nootropic drug) and ascorbic acid (an antioxidant) on oxidative stress and cognitive function. Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on elevated plus maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and non-protein thiol (NP-SH) levels. A significant reduction in SDL and prolongation of TL was found for the propoxur-treated group at weeks 6 and 7 as compared with control (p<0.001). One week treatment by piracetam (400mg/kg/d, i.p.) or ascorbic acid (120mg/kg/d, i.p.) antagonized the effect of propoxur on SDL as well as TL. Both piracetam and ascorbic acid attenuated the propoxur-induced increase in brain MDA levels and decrease in brain NP-SH levels. Results of the present study show that ascorbic acid and piracetam have the potential to reverse cognitive dysfunction and oxidative stress induced by propoxur in the brain. PMID- 21784035 TI - A cadmium toxicity assay using stress responsive Caenorhabditis elegans mutant strains. AB - To test the applicability of Caenorhabditis elegans mutant for toxicity screening, the sensitivity of cadmium (Cd) in C. elegans was investigated on 14 mutant strains using median lethal concentration (LC50) tests, with further analysis on growth and reproduction conducted on five selected strains. The 24h LC50 of Cd observed on the wildtype and mutant strains of C. elegans was in the order of age-1(hx546)>mtl-2(gk125)>sod-3(gk235)>daf-21(p673)>cyp35a2(gk317)>skn 1(or13)>daf-12(rh62rh157)>hsp-16.2(gk249)>daf-18(e1375)>ctl 2(ok1137)>wildtype(N2)>sod-1(or13)>daf-16(mu86)>cep-1(gk138)>cdr-2(ok1996). Compared to the wildtype response, a decreased reproduction potential was observed in mtl-2(gk125), sod-3(gk235), cdr-2(ok1996) and cep-1(gk138) strains. To gain a mechanistic understanding of different sensitivities of the mutant strains, a time-course gene expression analysis was also performed on the five genes. A dramatic increase in the expression of the mtl-2 gene due to Cd exposure confirmed the importance of this gene in C. elegans Cd toxicity. An increased expression of the sod-3 gene at the longer exposure time period (48h) suggests that oxidative stress may not be a direct toxic mechanism, but may rather be a consequence of Cd toxicity. Even though, LC50 values for the age-1(hx546) mutant strain were the highest among the tested strains, the response on the reproduction potential in age-1(hx546) mutant was unchanged compared to the wildtype, and the age-1 gene expression remained unaltered on exposure to Cd, which may be interpreted as the maintenance of age-1 expression level is needed for the exertion of Cd toxicity; however, the role of the age-1 gene in Cd toxicity may not be via a reproduction-related pathway. The overall results suggest that the C. elegans mutant assay seems to be a promising tool for the study of toxic mechanisms, as well as for toxicity screening in ecotoxicological research. PMID- 21784036 TI - Sublethal effects of pesticide mixtures on selected biomarkers of Carassius auratus. AB - In the present study, the in vivo effects of commercial propoxur alone and in combination with isoprocarb and chlorpyrifos on acetylcholinesterase and glutathione S-transferases activities in goldfish (Carassius auratus) were investigated. Brain and muscle AChE activity was significantly inhibited (88% and 85% at most, respectively) by propoxur after 5 d of exposure at concentrations between 141 and 2263MUg/L, bell-shaped concentration-response curves were obtained. In most cases, time dependence was apparent. Under insecticide mixture exposure (binary mixture propoxur/isoprocarb and ternary mixture propoxur/isoprocarb/chlorpyrifos), the inhibition of AChE activity was significant in all cases and linear concentration-response relationships were observed. Propoxur (alone and in combination) significantly inhibited gill GST activity, and both mixtures also induced significant inhibition of liver GST activity. However, concentration and time dependence were not apparent. AChE is likely to be more informative than GST and seems to be a good biomarker to diagnose exposure to anticholinesterase pesticides in wild populations of this species. PMID- 21784037 TI - The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population. AB - We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2mg of nicotine gum chewing for 30min. The urinary excretion of cotinine was normally distributed over a 2h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01-0.21, and 0.52 94.99MUg/2h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject). A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3-4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5+/-218.2ng/2h) than that of non smokers (40.5+/-78.4ng/2h). Among the smokers (n=16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n=14) than in PMs (n=0). PMID- 21784038 TI - AZT dilates rat cardiac intercalated discs, and the effect is prevented by vitamin C. AB - We investigated whether chronic zidovudine (AZT) administration in rats could impair cardiac function by affecting intercellular junctions and whether vitamin C could prevent these possible effects. Rats were treated for 8 months with AZT, vitamin C, and AZT plus vitamin C. Cardiac fractional shortening (FS) was assessed by echocardiographic examination, intercellular junctions morphology was detected by electron microscopy (EM) and immunocytochemistry (ICC). AZT-treated rats showed a reduced FS that was not prevented by vitamin C. EM revealed that AZT treatment did not affect coronary endothelial intercellular junctions whereas it caused an enlargement of fascia adherens of the intercalated discs that was prevented by vitamin C. AZT treatment did not induce either alterations of gap junctions morphology or distribution of connexin-43, the major protein expressed in the gap junctions. We conclude that AZT treatment may be potentially deleterious to the heart by inducing a ROS-mediated damage of cardiac intercalated discs. PMID- 21784039 TI - Protective effect of Bojungbangdocktang on cisplatin-induced cytotoxicity and apoptosis in MCF-10A breast endothelial cells. AB - Although cisplatin has been extensively used as a cancer chemotherapeutic agent for the treatment of various human cancers, it causes significant side effects such as nephrotoxicity and hepatotoxicity due to lethal bystander damage to normal cells. Thus, in the current study, we investigated the Oriental herbal medicine Bojungbangdocktang (BJBDT), as we reported previously its anti angiogenic activity at nontoxic concentrations that could prevent cisplatin induced toxicity and apoptosis in human normal breast epithelial cell MCF-10A, but not in MCF-7 and MDA MB-231 breast cancer cells. BJBDT protected cisplatin induced cytotoxicity in MCF-10A cells and potentiated cytotoxicity and MMP loss in MCF-7 cells. Also, 4',6-diamidino-2-phenylindole (DAPI) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay revealed that BJBDT reduced cisplatin-induced apoptotic bodies in MCF-10A cells compared with cisplatin-treated control. Consistently, BJBDT attenuated the apoptotic portion sub-G1 DNA contents as well as blocked the activation of caspase-3 and -9 and poly(ADP-ribose)polymerase (PARP) cleavage in cisplatin treated MCF-10A cells. Taken together, our findings suggest that BJBDT can protect cisplatin-induced cytotoxicity and apoptosis in normal MCF-10A breast cells as a cancer chemopreventive agent. PMID- 21784040 TI - Metallothioneins and heat shock proteins 70 in marine mussels as sensors of environmental pollution in Northern Adriatic Sea. AB - In an attempt to assess the intensity of environmental pollution in industrial zones of Kvarnerian Bay in Northern Adriatic Sea and the reactivity of Mytilus galloprovincialis to these changes, in this study we estimated the concentration of heavy metals at four locations in both sea-sediment and in the mussels. Further we tried to correlate these changes with seasonal variations in environmental temperature, pH and salinity, as well as with the expression of metallothioneins (MTs) and heat shock proteins (HSPs) in the digestive tract of the mussels. Sampling in vivo was performed monthly, during the year 2008, while under the laboratory conditions the reactivity of acclimated mussels were tested to increasing concentrations of CdCl(2) and to thermal stress. The data have shown that the induction of MTs and HSP isoforms of the 70-kDa size class were highly affected by model agents treatment including contamination of sea-sediment by Pb, Hg and Cd, implying that these stress proteins might be power biomarkers of marine pollution. PMID- 21784041 TI - Assessment of the mutagenic effect of 1,1-dimethyl hydrazine. AB - The mutagenic effect of the rocket fuel 1,1-dimethyl hydrazine has been studied experimentally and compared to the well-recognized mutagene N-nitroso dimethylamine. The manifestation of the effect for both compounds was disclosed through a significant increase in the chromosome aberration frequency in the bone marrow cells of intoxicated rats. The levels of chromosome aberrations induced by 1,1-dimetyl hydrazine were studied following both single (1h) and repeated doses (daily for 10 consecutive days) by inhalation (205-1028mg/m(3)) and gavage (5.4 26.8mg/kg) administration, respectively. For comparison N-nitroso dimethylamine were administered by inhalation (2h/daily for 10 consecutive days) and by gavage in concentrations of 2.4-48mg/m(3) and 1-30mg/kg, respectively. A clear dependence of concentration as well of time was disclosed. The BenchMark Dose approach was employed to derive guideline doses for the two compounds, the implications towards human health being discussed. PMID- 21784042 TI - The genome-wide expression profile of Paeonia suffruticosa-treated cisplatin stimulated HEK 293 cells. AB - The root cortex of Paeonia suffruticosa Andrews (PS) is a crude Chinese drug used in many traditional prescriptions. This study was conducted to evaluate the recovery mechanisms induced by PS in HEK 293 cells treated with cisplatin. Previous studies revealed that 1MUg/ml PS treatment showed greater than 20% recovery of 14MUM cisplatin-induced 50% loss of cell proliferation (IC(50)) determined by mitochondrial activity MTS assay in HEK 293 cells (Sohn et al., 2009). In the present study, the effects of PS on gene expression profiles in stimulated HEK 293 cells were evaluated by oligonucleotide microarray and real time RT-PCR. The results of the microarray analysis and real-time RT-PCR revealed that DNA repair- and cell proliferation-related genes were up-regulated in PS treated HEK 293 cells. The mechanism responsible for the effects of PS on HEK 293 cells is closely associated with the regulation of DNA repair and cell proliferation. Thus, PS possesses novel therapeutic potential that could be used for the prevention or treatment of cisplatin-induced nephrotoxicity. PMID- 21784043 TI - Pre-treatment with mild metal exposure suppresses the neurotoxicity on locomotion behavior induced by the subsequent severe metal exposure in Caenorhabditis elegans. AB - Adaptive response to neurotoxicity on locomotion behavior by severe metal exposure was investigated in Caenorhabditis elegans. Exposure to 2.5MUM of metals induced a moderate but significant reduction of locomotion behavior and induction of hsp-16.2::gfp expression. After pre-exposure to 2.5MUM of metals, the reduced locomotion behavior induced by subsequent 50 and 100MUM of metal exposure were significantly prevented, and the induction of hsp-16.2::gfp expression caused by subsequent 50 and 100MUM of metal exposure were significantly suppressed. In contrast, after pre-exposure to 50MUM examined metals, the reduced locomotion behavior induced by subsequent 50 and 100MUM metal exposure were further decreased, and the noticeable induction of hsp-16.2::gfp expression caused by subsequent severe metal exposure were further enhanced. Therefore, pre-treatment with mild metal exposure can activate the adaptive response to neurotoxicity on locomotion behavior induced by subsequent severe metal exposure in nematodes. PMID- 21784044 TI - Antioxidant defense system in rats simultaneously intoxicated with agrochemicals. AB - The effect of dimethoate, zineb and glyphosate administered alone or in combination on liver, kidney, brain and plasma antioxidant defense system was investigated. Lipid peroxidation, and RNS production were increased in all tissues studied, especially in those groups that received a combination of drugs. Intoxicated rats exhibited lower antioxidant ability, higher oxidized protein and glutathione levels in plasma with a decreased concentration of alpha-tocopherol in brain and liver, between 30% and 60% of control. Superoxide dismutase was decreased in liver and brain. Glutathione reductase was inhibited in liver while glutathione peroxidase and transferase were unaffected. Plasma lactate dehydrogenase and gamma-glutamyl transpeptidase activities were both increased. The associations of drugs produce more damage than individual administration being the effects observed strongly dependent on the kind of tissue analyzed. In conclusion, the present paper evidenced both the role of the oxidative stress as a mechanism of action of some pesticides and the potential additive effects of a simultaneous exposure to more than one compound. In addition, results suggest a potential contribution of pesticide mixtures to the aetiology of some neurodegenerative diseases. PMID- 21784045 TI - Cost-effectiveness analysis of a quantitative immunochemical test for colorectal cancer screening. AB - BACKGROUND & AIMS: Two European randomized trials (N = 30,000) compared guaiac fecal occult blood testing with quantitative fecal immunochemical testing (FIT) and showed better attendance rates and test characteristics for FIT. We aimed to identify the most cost-effective FIT cutoff level for referral to colonoscopy based on data from these trials and allowing for differences in screening ages. METHODS: We used the validated MIcrosimulation SCreening ANalysis (MISCAN)-Colon microsimulation model to estimate costs and effects of different screening strategies for FIT cutoff levels of 50, 75, 100, 150, and 200 ng/mL hemoglobin. For each cutoff level, screening strategies were assessed with various age ranges and screening intervals. We assumed sufficient colonoscopy capacity for all strategies. RESULTS: At all cost levels, FIT screening was most effective with the 50 ng/mL cutoff level. The incremental cost-effectiveness ratio of biennial screening between ages 55 and 75 years using FIT at 50 ng/mL, for example, was 3900 euro per life year gained. Annual screening had an incremental cost effectiveness ratio of 14,900 euro per life year gained, in combination with a wider age range (between ages 45 and 80 years). In the sensitivity analysis, 50 ng/mL remained the preferred cutoff level. CONCLUSIONS: FIT screening is more cost-effective at a cutoff level of 50 ng/mL than at higher cutoff levels. This supports the recommendation to use FIT at a cutoff level of 50 ng/mL, which is considerably lower than the values used in current practice. PMID- 21784046 TI - Improved responses to pegylated interferon alfa-2b and ribavirin by individualizing treatment for 24-72 weeks. AB - BACKGROUND & AIMS: Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS: We treated 398 treatment-naive patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS: Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P < .0001 for noninferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P < .0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS: Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders. PMID- 21784047 TI - Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. AB - BACKGROUND & AIMS: Patients with recurrent bleeding from gastrointestinal vascular malformations are a challenge to treat. We investigated the long-term efficacy and safety of thalidomide for refractory bleeding from gastrointestinal vascular malformations in an open-label, randomized study. METHODS: Eligible patients were randomly assigned to groups that were given either 100 mg thalidomide (n = 28) or 400 mg iron (n = 27, controls), daily for 4 months; patients were followed for at least 1 year (mean, 39 months). Bleeding was defined by a positive result from an immunoassay fecal occult blood test. The primary end point was the effective response rate, defined as the proportion of patients in whom bleeding episodes had decreased by >= 50% in the first year of the follow-up period. The secondary end points included the rates of cessation of bleeding, blood transfusion, overall hospitalization, and hospitalization for bleeding. We also quantified yearly bleeding episodes, bleeding duration, levels of hemoglobin, and yearly requirements for transfusions of red cells, numbers of hospitalizations for bleeding, and hospital stays. Plasma levels of vascular endothelial growth factor were measured in the group given thalidomide. RESULTS: Rates of response in the thalidomide and control groups were 71.4% and 3.7%, respectively (P < .001). All secondary end points differed significantly different between groups; thalidomide was more effective. No severe adverse effects were observed, although minor side effects were common among patients in the thalidomide group. Levels of vascular endothelial growth factor were significantly reduced by thalidomide (P < .001). CONCLUSIONS: Thalidomide is an effective and relatively safe treatment for patients with refractory bleeding from gastrointestinal vascular malformations. Mechanisms of thalidomide activity might involve vascular endothelial growth factor. PMID- 21784048 TI - Ultrasound elasticity imaging for detecting intestinal fibrosis and inflammation in rats and humans with Crohn's disease. AB - BACKGROUND: Intestinal fibrosis causes many complications of Crohn's disease (CD). Available biomarkers and imaging modalities lack sufficient accuracy to distinguish intestinal inflammation from fibrosis. Transcutaneous ultrasound elasticity imaging (UEI) is a promising, noninvasive approach for measuring tissue mechanical properties. We hypothesized that UEI could differentiate inflammatory from fibrotic bowel wall changes in both animal models of colitis and humans with CD. METHODS: Female Lewis rats underwent weekly trinitrobenzene sulfonic acid enemas yielding models of acute inflammatory colitis (n = 5) and chronic intestinal fibrosis (n = 6). UEI scanning used a novel speckle-tracking algorithm to estimate tissue strain. Resected bowel segments were evaluated for evidence of inflammation and fibrosis. Seven consecutive patients with stenotic CD were studied with UEI and their resected stenotic and normal bowel segments were evaluated by ex vivo elastometry and histopathology. RESULTS: Transcutaneous UEI normalized strain was able to differentiate acutely inflamed (-2.07) versus chronic fibrotic (-1.10) colon in rat models of inflammatory bowel disease (IBD; P = .037). Transcutaneous UEI normalized strain also differentiated stenotic ( 0.87) versus adjacent normal small bowel (-1.99) in human CD (P = .0008), and this measurement also correlated well with ex vivo elastometry (r = -0.81). CONCLUSIONS: UEI can differentiate inflammatory from fibrotic intestine in rat models of IBD and can differentiate between fibrotic and unaffected intestine in a pilot study in humans with CD. UEI represents a novel technology with potential to become a new objective measure of progression of intestinal fibrosis. Prospective clinical studies in CD are needed. PMID- 21784049 TI - Mentorship in academic medicine. PMID- 21784050 TI - Adding to the toolbox: receptor tyrosine kinases as potential targets in the treatment of hepatitis C. PMID- 21784051 TI - Comparison of the heart and breathing rate of acutely ill medical patients recorded by nursing staff with those measured over 5 min by a piezoelectric belt and ECG monitor at the time of admission to hospital. AB - BACKGROUND: Heart and breathing rates are predictors of disease severity and of a poor outcome. However, few reports have compared their machine measurements with traditional manual methods. SETTING: A small rural Irish hospital. METHODS: The heart and breathing rates of 377 acutely ill medical patients (mean age 68.3 SD 16.8 years) recorded by nursing staff at the time of admission to hospital was compared with those measured over 5 min by a piezoelectric belt and ECG monitor (the BT16 acquisition system). RESULTS: The mean breathing rate measured by the nursing staff (20.9 SD 4.8 breaths per min) and that measured by the BT16 piezoelectric belt (19.9 SD 4.5 breaths per min) were significantly different (p 0.004), as were the nurse and BT16 measured heart rates (85.4 SD 21.3 vs. 81.2 SD 18.7, p 0.004), and the correlation coefficient between the two methods of breathing and heart rate measurement were low. Nurse measured breathing rate measurements were clustered around rates of 18, 20 and 22 breaths per min. Unlike those obtained by nurses, BT16 measured heart and breathing rates were shown by logistic regression to be independent predictors of in-hospital mortality. CONCLUSION: There is a poor correlation between breathing and heart rates measured by traditional methods and those obtained by the BT16 device. BT16 derived breathing and heart rates, but not those measured manually, were independent predictors of in-hospital mortality. PMID- 21784052 TI - miR-10a overexpression is associated with NPM1 mutations and MDM4 downregulation in intermediate-risk acute myeloid leukemia. AB - OBJECTIVE: The study investigated differential microRNA (miRNA) expression patterns in acute myeloid leukemia (AML) patients with intermediate-risk (IR) characteristics. After characterization and validation of miR-10a, which was specifically upregulated in nucleophosmin 1 (NPM1) mutant AML samples, functional consequences of miR-10a overexpression were further delineated in vitro. MATERIALS AND METHODS: Microarray analysis of miRNAs in bone marrow samples from AML (IR) patients with NPM1 mutations and healthy donors was performed to detect differential expression patterns. After validation of miRNA expression specific for NPM1 mutation in AML patients by quantitative reverse transcription polymerase chain reaction, a functional target gene search was conducted using complementary DNA microarray data from samples transfected with miR-10a. Potential target gene validation was done using transient transfection of K562 cells followed by Western blotting and luciferase reporter assay. RESULTS: In comparison with wild-type samples, NPM1 mutant AML samples were shown to markedly overexpress miR-10a. Subsequent in vitro miR-10a overexpression induced differential gene expression as determined by microarray analysis. Here the murine double minute 4 (MDM4) gene turned out as a candidate gene for miR-10a. Validation of MDM4 in leukemic cells revealed a robust negative relationship between miR-10a overexpression and MDM4 downregulation. Furthermore, we determined an inverse association between miR-10a and MDM4 expression in AML (IR) samples with respect to their NPM1 mutational status. CONCLUSIONS: miR-10a expression is highly characteristic for AML (IR) patients with NPM1 mutations and may influence its biological properties in AML by interfering with the p53 machinery partly regulated by MDM4. PMID- 21784053 TI - Global challenges of changing epidemiological patterns of malaria. AB - In the absence of secular climatic changes, the global challenges of changing epidemiological patterns of malaria have to be induced by man, i.e. by a disturbance of the equilibrium between man, vector and the parasite in an environment conducive to the natural transmission of the pathogen. There are many ways of attempting such a disturbance, from the use of personal protection to the use of diagnostic and remedial antiplasmodial treatment, up to the application of vector control measures for the elimination of breeding places, larviciding and the use of intradomestic insecticides. This will be done by looking at the parasites responsible for the specific infection, and considering the various arthropod hosts and the human hosts, before the comprehensive treatment of the environmental features. This will be followed by a section on the quantitative epidemiology. The various tools of intervention and their relative efficacy precede the section on common denominators of previously malarious countries having achieved and maintained malaria-free status. Similarly, the reasons for failing the declared goal of eliminating malaria sets the new scene for the global challenges ahead of us in the endeavour of future attempts at eliminating malaria. PMID- 21784054 TI - Simultaneous measurement of plasma vitamin D(3) metabolites, including 4beta,25 dihydroxyvitamin D(3), using liquid chromatography-tandem mass spectrometry. AB - Simultaneous and accurate measurement of circulating vitamin D metabolites is critical to studies of the metabolic regulation of vitamin D and its impact on health and disease. To that end, we have developed a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that permits the quantification of major circulating vitamin D(3) metabolites in human plasma. Plasma samples were subjected to a protein precipitation, liquid-liquid extraction, and Diels-Alder derivatization procedure prior to LC-MS/MS analysis. Importantly, in all human plasma samples tested, we identified a significant dihydroxyvitamin D(3) peak that could potentially interfere with the determination of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] concentrations. This interfering metabolite has been identified as 4beta,25 dihydroxyvitamin D(3) [4beta,25(OH)(2)D(3)] and was found at concentrations comparable to 1alpha,25(OH)(2)D(3). Quantification of 1alpha,25(OH)(2)D(3) in plasma required complete chromatographic separation of 1alpha,25(OH)(2)D(3) from 4beta,25(OH)(2)D(3). An assay incorporating this feature was used to simultaneously determine the plasma concentrations of 25OHD(3), 24R,25(OH)(2)D(3), 1alpha,25(OH)(2)D(3), and 4beta,25(OH)(2)D(3) in healthy individuals. The LC-MS/MS method developed and described here could result in considerable improvement in quantifying 1alpha,25(OH)(2)D(3) as well as monitoring the newly identified circulating metabolite, 4beta,25(OH)(2)D(3). PMID- 21784055 TI - CD38/ADP-ribosyl cyclase in the rat sublingual gland: subcellular localization under resting and saliva-secreting conditions. AB - CD38 is a 42-45 kDa transmembrane glycoprotein that exhibits ADP-ribosyl cyclase enzyme activity. In the rat, we have previously reported strong ADP-ribosyl cyclase activity in the sublingual salivary gland (Masuda W. and Noguchi T. Biochem. Biophys. Res. Commun. (2000) 270, 469-472). Here, we have examined the specific localization of CD38/ADP-ribosyl cyclase activity in this gland and whether that localization changes upon saliva-secretary stimulation. Under resting conditions, CD38/ADP-ribosyl cyclase activity in the post-nuclear fraction of SLG homogenates was separated into two major peaks by sucrose density gradient centrifugation. The first peak included the plasma membrane proteins Na+/K+ ATPase and aquaporin 5, while the second peak included mucous secretory protein mucin and vesicle-associated membrane protein 2. When rats were subjected to the muscarinic agonist pilocarpine, the CD38/ADP-ribosyl cyclase activity disappeared from the second peak, as did mucin and vesicle-associated membrane protein 2. Pre-treatment of rats with the muscarinic antagonist atropine before pilocarpine administration, or adrenergic stimulation with isoproterenol, the sucrose density gradient separation profiles were same as that seen under resting condition. Using an immunofluorescent strategy, we observed the preferential localization of CD38 in the basolateral plasma membrane and intracellular granule like membrane in sublingual acinar cells under resting conditions. PMID- 21784056 TI - Vitamin D deficiency diminishes the severity and delays onset of experimental autoimmune encephalomyelitis. AB - Multiple sclerosis incidence is clearly inversely related to sun exposure. This observation led to the idea that vitamin D might be responsible for this relationship. Providing super-physiologic doses of the hormonal form of vitamin D, 1alpha,25-dihydroxyvitamin D3, suppresses an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE) but causes unwanted hypercalcemia. Further, dietary calcium is needed for this activity of 1alpha,25-dihydroxyvitamin D3. B10PL mice were maintained on a vitamin D deficient diet for two generations to produce frank vitamin D deficiency. These animals showed delayed onset and reduced severity of EAE compared to control animals on the same diet and given vitamin D3 or provided a vitamin D-containing chow diet. Thus, vitamin D deficiency interferes with the development of this autoimmune disease rather than increasing susceptibility. PMID- 21784057 TI - EGCG disaggregates amyloid-like fibrils formed by Plasmodium falciparum merozoite surface protein 2. AB - Merozoite surface protein 2 (MSP2), one of the most abundant proteins on the surface of Plasmodium falciparum merozoites, is a promising malaria vaccine candidate. MSP2 is intrinsically unstructured and forms amyloid-like fibrils in solution. As this propensity of MSP2 to form fibrils in solution has the potential to impede its development as a vaccine candidate, finding an inhibitor that inhibits fibrillogenesis may enhance vaccine development. We have shown previously that EGCG inhibits the formation of MSP2 fibrils. Here we show that EGCG can alter the beta-sheet-like structure of the fibril and disaggregate pre formed fibrils of MSP2 into soluble oligomers. The fibril remodelling effects of EGCG and other flavonoids were characterised using Thioflavin T fluorescence assays, electron microscopy and other biophysical methods. PMID- 21784058 TI - Guanine-induced inhibition of renal Na(+)-ATPase activity: evidence for the involvement of the Gi protein-coupled receptor. AB - There is some evidence to show a possible role of guanosine in the modulation of cellular function, in particular, in the neuronal system. However, nothing is known about the role of guanine in renal function. The aim of the present work was to investigate the role of guanine on modulation of Na+-ATPase activity in isolated basolateral membrane (BLM) of the renal cortex. Guanine inhibited the enzyme activity in a dose-dependent manner with maximal effect (56%) obtained at 10-6 M. This effect was reversed by DPCPX (8-cyclopentyl-1,3-dipropylxanthine), an antagonist of A1 receptors, but it was not changed by 10-8 M DMPX (3,7 dimethyl-1-propargylxanthine) or 10-8 M MRS (2,3-diethyl-4,5-dipropyl-6 phenylpyridine-3-thiocarboxylate-5-carboxylate), antagonists of A2 and A3 receptors, respectively. Furthermore, it was observed that guanine increased [gamma-35S]GTP-specific binding with the maximal effect observed at 10-6 M and this effect was abolished by 10-6 M GDPbetaS. The inhibitory effect of 10-6 M guanine on Na+-ATPase activity was reversed by 10-6 M GDPbetaS, 10-6 M forskolin, 10-6 M pertussis toxin and 10-8 M cholera toxin. These results indicate that guanine binds to a DPCPX-sensitive receptor promoting the activation of Gi protein and leading to a decrease in cAMP level and, consequently, inhibition of BLM Na+-ATPase activity. PMID- 21784059 TI - Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1gamma in human cells. AB - The cohesin loading factor NIPBL is required for cohesin to associate with chromosomes and plays a role in DNA double-strand break (DSB) repair. Although the NIPBL homolog Scc2 is recruited to an enzymatically generated DSB and promotes cohesin-dependent DSB repair in yeast, the mechanism of the recruitment remains poorly understood. Here we show that the human NIPBL is recruited to the sites of DNA damage generated by micro-irradiation as well as to the sites of DSBs induced by homing endonuclease, I-PpoI. The recruitment of NIPBL was impaired by RNAi-mediated knockdown of MDC1 or RNF168, both of which also accumulate at DSBs. We also show that the recruitment of NIPBL to the sites of DNA damage is mediated by its C-terminal region containing HEAT repeats and Heterochromatin protein 1 (HP1) interacting motif. Furthermore, NIPBL accumulation at damaged sites was also compromised by HP1gamma depletion. Taken together, our study reveals that human NIPBL is a novel protein recruited to DSB sites, and the recruitment is controlled by MDC1, RNF168 and HP1gamma. PMID- 21784060 TI - The NADPH oxidase cytosolic component p67phox is constitutively phosphorylated in human neutrophils: Regulation by a protein tyrosine kinase, MEK1/2 and phosphatases 1/2A. AB - Neutrophils play a key role in host defense and inflammation through the production of superoxide anion and other reactive oxygen species (ROS) by the enzyme complex NADPH oxidase. The cytosolic NADPH oxidase component, p67phox, has been shown to be phosphorylated in human neutrophils but the pathways involved in this process are largely unknown. In this study, we show that p67phox is constitutively phosphorylated in resting human neutrophils and that neutrophil stimulation with PMA further enhanced this phosphorylation. Inhibition of the constitutively active serine/threonine phosphatases type 1 and type 2A (PP1/2A) by calyculin A resulted in the enhancement of p67phox phosphorylation. Constitutive and calyculin A-induced phosphorylation of p67phox was completely inhibited by the protein tyrosine kinase inhibitor genistein and partially inhibited by the MEK1/2 inhibitor PD98059, but was unaffected by GF109203X, wortmannin and SB203580, inhibitors of PKC, PI3K and p38MAP kinase, respectively. Two-dimensional phosphopeptide mapping revealed that constitutive and calyculin A induced p67phox phosphorylation occurred on the same major sites. Interestingly, calyculin A enhanced formyl-Met-Leu-Phe (fMLP)-induced superoxide production, while genistein inhibited this process. Taken together, these results suggest that (i) p67phox undergoes a continual cycle of phosphorylation/dephosphorylation in resting cells; (ii) p67phox phosphorylation is controlled by MEK1/2 and an upstream tyrosine kinase; (iii) PP1/2A directly or indirectly antagonize this process. Thus, these pathways could play a role in regulating ROS production by human neutrophils at inflammatory sites. PMID- 21784061 TI - Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263. AB - YM155, a small-molecule survivin suppressant, exhibits anti-tumor activities in vitro, in vivo and in clinical trials. However, the mechanism of YM155 action remains unclear. In this study, YM155 was administered to a panel of cell lines and the effects of YM155 on Bcl-2 family members were analyzed. Our results show that YM155 strikingly downregulates Mcl-1 in a broad spectrum of cancer cell lines and that the Mcl-1 modulation occurs at the transcriptional level, independently of survivin modulation or caspase activity. Furthermore, analysis of the contribution of Mcl-1 or survivin downregulation to YM155-induced cell death in vitro showed that knockdown of Mcl-1 sensitizes cells to YM155-induced cytotoxicity. Finally, our data demonstrate that downregulation of Mcl-1 by YM155 synergistically lowers the threshold of Bcl-2 family member inhibitor ABT-263 induced cell death. Our findings reveal a novel mechanism by which survivin independent Mcl-1 suppression plays a critical role in YM155-mediated anti-tumor activities. YM155 treatment in combination with ABT-263 thus affords a new strategy for cancer treatment. PMID- 21784062 TI - Characterization of cationic liposomes. Influence of the bilayer composition on the kinetics of the liposome breakdown. AB - The cationic large unilamellar mixed liposomes from 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) and didodecyldimethylammonium bromide (DDAB) or dioctadecyldimethylammonium bromide (DODAB) were prepared. The influence of the addition of Triton X-100 (TX-100) or octaethylene glycol mono-n-dodecylether (C(12)E(8)) on the membrane integrity was investigated turbidimetrically. The stability of the liposomal systems was estimated by monitoring fluorimetrically at 25 degrees C the rate of spontaneous and surfactant-induced release of entrapped 5(6)-carboxyfluorescein (CF). In order to evaluate the interaction of the cationic DODAB guest with the host POPC membrane, the main phase transition temperatures (T(m)) were determined by electron paramagnetic resonance spectroscopy (EPR). All the results obtained show that the presence of DODAB and DDAB stabilizes the POPC liposomes. The extent of stabilization depends on the concentration and nature of the cationic guest. PMID- 21784063 TI - The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in cervical cancer. AB - OBJECTIVE: The aim of this study was to compare the metabolism of cervical cancer cells and normal cervical cells by measurement of ADH isoenzymes and ALDH activities. METHODS: The study material consisted of 40 cancerous cervical tissues. Class III, IV of ADH and total ADH activity was measured by the photometric method and class I, II ADH and ALDH activity by the fluorometric method with class-specific fluorogenic substrates. RESULTS: The activity of the class I ADH isoenzyme and the total ADH were significantly higher in cervical cancer as compared to healthy tissues. Class I of ADH and total ADH activity are significantly higher in every stage of cancer as compared to the control. There are no significant differences between planoepitheliale and adenocarcinoma. CONCLUSION: The increased activity of total ADH in cervical cancer may be the cause of some metabolic disorders in cancer cells, which may intensify carcinogenesis in this organ. PMID- 21784064 TI - Standardising biochemical assessment of bone turnover in osteoporosis. PMID- 21784065 TI - Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development. AB - Hox genes play a crucial role during embryonic patterning and organogenesis. Of the 39 Hox genes, Hoxa1 is the first to be expressed during embryogenesis and the only anterior Hox gene linked to a human syndrome. Hoxa1 is necessary for the proper development of the brainstem, inner ear and heart in humans and mice; however, almost nothing is known about the molecular downstream targets through which it exerts its function. To gain insight into the transcriptional network regulated by this protein, we performed microarray analysis on tissue microdissected from the prospective rhombomere 3-5 region of Hoxa1 null and wild type embryos. Due to the very early and transient expression of this gene, dissections were performed on early somite stage embryos during an eight-hour time window of development. Our array yielded a list of around 300 genes differentially expressed between the two samples. Many of the identified genes play a role in a specific developmental or cellular process. Some of the validated targets regulate early neural crest induction and specification. Interestingly, three of these genes, Zic1, Hnf1b and Foxd3, were down-regulated in the posterior hindbrain, where cardiac neural crest cells arise, which pattern the outflow tract of the heart. Other targets are necessary for early inner ear development, e.g. Pax8 and Fgfr3 or are expressed in specific hindbrain neurons regulating respiration, e.g. Lhx5. These findings allow us to propose a model where Hoxa1 acts in a genetic cascade upstream of genes controlling specific aspects of embryonic development, thereby providing insight into possible mechanisms underlying the human HoxA1-syndrome. PMID- 21784068 TI - Role of aquaporins in cell migration and edema formation in human brain tumors. AB - The aquaporins (AQPs) are a family of transmembrane water channel proteins widely distributed and play a major role in transcellular and transepithelial water movement. Moreover, recent evidence indicates that AQPs may be involved in cell migration, angiogenesis, and tumor growth. This review article summarizes literature data concerning the involvement of AQP-1 and -4 in human brain tumor growth and edema formation and suggests a potential therapeutic approach by antagonizing their biological activity. PMID- 21784067 TI - The transcription factor HLH-2/E/Daughterless regulates anchor cell invasion across basement membrane in C. elegans. AB - Cell invasion through basement membrane is a specialized cellular behavior critical for many developmental processes and leukocyte trafficking. Invasive cellular behavior is also inappropriately co-opted during cancer progression. Acquisition of an invasive phenotype is accompanied by changes in gene expression that are thought to coordinate the steps of invasion. The transcription factors responsible for these changes in gene expression, however, are largely unknown. C. elegans anchor cell (AC) invasion is a genetically tractable in vivo model of invasion through basement membrane. AC invasion requires the conserved transcription factor FOS-1A, but other transcription factors are thought to act in parallel to FOS-1A to control invasion. Here we identify the transcription factor HLH-2, the C. elegans ortholog of Drosophila Daughterless and vertebrate E proteins, as a regulator of AC invasion. Reduction of HLH-2 function by RNAi or with a hypomorphic allele causes defects in AC invasion. Genetic analysis indicates that HLH-2 has functions outside of the FOS-1A pathway. Using expression analysis, we identify three genes that are transcriptionally regulated by HLH-2: the protocadherin cdh-3, and two genes encoding secreted extracellular matrix proteins, mig-6/papilin and him-4/hemicentin. Further, we show that reduction of HLH-2 function causes defects in polarization of F-actin to the invasive cell membrane, a process required for the AC to generate protrusions that breach the basement membrane. This work identifies HLH-2 as a regulator of the invasive phenotype in the AC, adding to our understanding of the transcriptional networks that control cell invasion. PMID- 21784066 TI - Posttranslational arginylation as a global biological regulator. AB - Posttranslational modifications constitute a major field of emerging biological significance as mounting evidence demonstrates their key role in multiple physiological processes. Following in the footsteps of protein phosphorylation studies, new modifications are being shown to regulate protein properties and functions in vivo. Among such modifications, an important role belongs to protein arginylation - posttranslational tRNA-mediated addition of arginine, to proteins by arginyltransferase, ATE1. Recent studies show that arginylation is essential for embryogenesis in many organisms and that it regulates such important processes as heart development, angiogenesis, and tissue morphogenesis in mammals. This review summarizes the key data in the protein arginylation field since its original discovery to date. PMID- 21784069 TI - CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury. AB - Traumatic injury to the spinal cord triggers a systemic inflammatory response syndrome (SIRS), in which inflammatory cells from the circulation invade organs such as the liver, lung and kidney, leading to damage of these organs. Our previous study (Gris, et al, Exp. Neurol, 2008) demonstrated that spinal cord injury (SCI) activates circulating neutrophils that then invade the lung and kidney from 2 to 24 h after injury, increasing myeloperoxidase activity, cyclooxygenase-2 and matrix metalloproteinase-9 expression and lipid peroxidation in these organs. The present study was designed to ascertain whether a treatment that limits the influx of leukocytes into the injured spinal cord would also be effective in reducing the SIRS after SCI. This treatment is intravenous delivery of a monoclonal antibody (mAb) against the CD11d subunit of the CD11d/CD18 integrin expressed by neutrophils and monocytes. We delivered the anti-CD11d mAb at 2 h post moderate clip compression SCI at the 4th or 12th thoracic segments and assessed inflammation, oxidative activity and cellular damage within the lung, kidney and liver at 12 h post-injury. In some analyses we compared high and low thoracic injuries to evaluate the importance of injury level on the intensity of the SIRS. After T4 injury, treatment with the anti-integrin mAb reduced the presence of neutrophils and macrophages in the lung, with associated decreases in expression of NF-kappaB and oxidative enzymes and in the concentration of free radicals in this organ. The treatment also reduced lipid peroxidation, protein nitration and cell death in the lung. The anti-CD11d treatment also reduced the inflammatory cells within the kidney after T4 injury, as well as the free radical concentration and amount of lipid peroxidation. In the liver, the mAb treatment reduced the influx of neutrophils but most of the other measures examined were unaffected by SCI. The inflammatory responses within the lung and kidney were often greater after T4 than T12 injury. Clinical studies show that SIRS, with its associated organ failure, contributes significantly to the morbidity and mortality of SCI patients. This anti-integrin treatment may block the onset of SIRS after SCI. PMID- 21784070 TI - Schistosoma mansoni: molecular characterization of Alkaline Phosphatase and expression patterns across life cycle stages. AB - Here we describe the cloning and characterization of the Schistosoma mansoni Alkaline Phosphatase (SmAP), previously identified in the tegument of adult worms. SmAP encodes a complete sequence composed of 536 amino acids containing an N-terminal signal peptide, five N-glycosylation sites, and a GPI anchor signal, similar to that described for mammalian orthologs. Real-time RT-PCR and Western blot experiments suggest a rapid translation as soon as cercariae are transformed into schistosomula. Immunolocalization analysis shows that the protein is widely distributed in the worm tissues, with increased concentration in the vitelline glands of female parasites. Furthermore, the surface localization of this enzyme was quantitatively supported by its enzymatic activity in live ex vivo or cultured parasites throughout the life cycle stages. The fact that cercariae accumulate large amounts of SmAP mRNA, which rapidly translates into protein upon schistosomula transformation, indicates it may have an important role in host invasion. PMID- 21784071 TI - Turnover of ATP synthase subunits in F1-depleted HeLa and yeast cells. AB - Mitochondrial translation of the Saccharomyces cerevisiae Atp6p subunit of F(1) F(0) ATP synthase is regulated by the F(1) ATPase. Here we show normal expression of Atp6p in HeLa cells depleted of the F(1) beta subunit. Instead of being translationally down-regulated, HeLa cells lacking F(1) degrade Atp6p, thereby preventing proton leakage across the inner membrane. Mammalian mitochondria also differ in the way they minimize the harmful effect of unassembled F(1) alpha subunit. While yeast mutants lacking beta subunit have stable aggregated F(1) alpha subunit in the mitochondrial matrix, the human alpha subunit is completely degraded in cells deficient in F(1) beta subunit. These results are discussed in light of the different properties of the proteins and environments in which yeast and human mitochondria exist. PMID- 21784072 TI - Antiviral effects of human microRNAs and conservation of their target sites. AB - MicroRNAs are small non-coding RNAs that modulate gene expression at post transcriptional level, playing a crucial role in cell differentiation and development. Recently, some reports have shown that a limited number of mammalian microRNAs also display antiviral effects. This article summarizes the data in the field paying a special attention to the conservation of the microRNA target sequences in the viral populations. This issue is relevant both for the evaluation of the biological significance of the antiviral effects and for the development of microRNA-based strategies for antiviral intervention. PMID- 21784073 TI - Adipokine ganglioside GM2 activator protein stimulates insulin secretion. AB - Recently, we identified ganglioside GM2 activator protein (GM2AP) as a novel adipokine, and revealed that treatment of cultured cells with GM2AP impairs insulin signal transduction. The aim of this study was to examine the impact of GM2AP on glucose metabolism in vivo. Injection of recombinant GM2AP in mice significantly lowered blood glucose levels in glucose tolerance tests. Administration of GM2AP to mice for 10 days increased serum insulin levels, whereas the contents of glucose, leptin and FFA were significantly decreased. Stimulation of calcium influx and insulin secretion by GM2AP was observed in hamster insulinoma HIT-T15 cells. Blockage of GM2AP function by specific antibodies inhibited GM2AP-induced insulin secretion. These results provide novel insights into the physiological functions of GM2AP in obesity. PMID- 21784074 TI - A non-coding transcript of nephronectin promotes osteoblast differentiation by modulating microRNA functions. AB - We investigated the roles of the non-coding transcripts and found that expression of a fragment containing the 3'-untranslated region (3'-UTR) of nephronectin in osteoblast progenitor cells MC3T3-E1 promoted cell differentiation dramatically. We hypothesized that the ectopically expressed 3'-UTR binds microRNAs and modulates their functions. beta-Catenin and GSK3beta were up-regulated in the 3' UTR-transfected cells, contributing to the increased cell differentiation, through reduction of EGFR and ERK phosphorylation. Activator of GSK3beta promoted differentiation, while inhibitor of GSK3beta blocked differentiation. Our results indicate that the non-coding transcripts are important in regulating cell activities and may have potential application for modulating endogenous microRNA functions. PMID- 21784075 TI - Pigment-dispersing activities and cortisol-releasing activities of melanocortins and their receptors in xanthophores and head kidneys of the goldfish Carassius auratus. AB - The five subtypes of melanocortin receptors (MCRs) mediate the functions of alpha melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). In fish, these hormones are involved in pigment dispersion and cortisol release, respectively. alpha-MSH-related peptides exhibit ACTH-like activity in certain fishes. We recently found that multiple Mcr transcripts are expressed in some cell types in the barfin flounder, which is related to regulation of alpha MSH activities. Similar results were also observed for the cortisol-releasing activity of alpha-MSH-related peptides in the head kidney. The present study was undertaken to assess relationship between the expression of multiply expressed Mcrs and alpha-MSH activities using goldfish. We also determined if alpha-MSH related peptides exhibit ACTH-like activity in goldfish. The transcripts of Mc1r, but not those of other subtypes, were observed in xanthophores. alpha-MSH, which has an acetyl group at the N-terminus, was found to disperse pigment in a dose dependent manner in xanthophores. This potency was found to be slightly greater than that of desacetyl-alpha-MSH. These results support our findings that MCR has a higher affinity for alpha-MSH when single Mcr subtype is expressed. On the other hand, transcripts of Mc2r, but not those of other subtypes, were observed in the head kidney. ACTH(1-24)-stimulated cortisol release was observed in a dose dependent manner, while alpha-MSH-related peptides showed no activity. It therefore appears that MC2R also acts as an ACTH-specific receptor in goldfish and that association of alpha-MSH-related peptides upon release of cortisol is uncommon in fishes. PMID- 21784076 TI - Aggressive interactions differentially modulate local and systemic levels of corticosterone and DHEA in a wild songbird. AB - During the nonbreeding season, when gonadal androgen synthesis is basal, recent evidence suggests that neurosteroids regulate the aggression of male song sparrows. In particular, dehydroepiandrosterone (DHEA) is rapidly converted in the brain to androgens in response to aggressive interactions. In other species, aggressive encounters increase systemic glucocorticoid levels. However, the relationship between aggression and local steroid levels is not well understood. Here, during the breeding and nonbreeding seasons, we tested the effects of a simulated territorial intrusion (STI) on DHEA and corticosterone levels in the brachial and jugular plasma. Jugular plasma is enriched with neurosteroids and provides an indirect index of brain steroid levels. Further, during the nonbreeding season, we directly measured steroid levels in the brain and peripheral tissues. Both breeding and nonbreeding males displayed robust aggressive responses to STI. During the breeding season, STI increased brachial and jugular corticosterone levels and jugular DHEA levels. During the nonbreeding season, STI did not affect plasma corticosterone levels, but increased jugular DHEA levels. During the nonbreeding season, STI did not affect brain levels of corticosterone or DHEA. However, STI did increase corticosterone and DHEA concentrations in the liver and corticosterone concentrations in the pectoral muscle. These data suggest that 1) aggressive social interactions affect neurosteroid levels in both seasons and 2) local steroid synthesis in peripheral tissues may mobilize energy reserves to fuel aggression in the nonbreeding season. Local steroid synthesis in brain, liver or muscle may serve to avoid the costs of systemic increases in corticosterone and testosterone. PMID- 21784077 TI - Schistosoma mansoni population structure and persistence after praziquantel treatment in two villages of Bahia, Brazil. AB - Praziquantel has been used to treat schistosome infections since 1979 and currently is the only chemotherapeutic agent in production for this purpose, raising concerns about the potential for the emergence of drug resistance. In practice, 10-20% of infected patients will continue to excrete eggs after treatment. It is not understood to what degree this represents selection of a resistant population or incomplete elimination due to the presence of immature worms at the time of treatment. We used a population genetics approach to test whether or not persistent Schistosomamansoni parasites were drawn from the same population as susceptible parasites. In this study, stool samples were collected from 96% of individuals in two small Brazilian communities (populations 482 and 367) and examined for S.mansoni eggs. The combined prevalence of S.mansoni infections in the villages was 41%. Total egg DNA was extracted from each sample and was genotyped at 15 microsatellite markers. Day-to-day variation of the infrapopulation from an individual human host was low (median differentiation using Jost's D=0.010), so that a single stool was representative of the genotypes present in stool eggs, at least in the short term. Average pairwise analysis of D among all pre-treatment infrapopulations suggested moderate differentiation (mean D=0.082 and 0.122 for the two villages), whereas the pre-treatment component population differentiation between the two communities was 0.047. The differentiation of the component population remaining after treatment from the fully susceptible component population was low (mean D=0.007 and 0.020 for the two villages), suggesting that the persistent parasites were not selected by praziquantel treatment. We will continue to follow these communities for evidence of selection or changes in population structure. PMID- 21784078 TI - Intracellular detection of differential APOBEC3G, TRIM5alpha, and LEDGF/p75 protein expression in peripheral blood by flow cytometry. AB - Expression studies on specific host proteins predominantly use quantitative PCR and western blotting assays. In this study, we optimized a flow cytometry-based assay to study intracellular expression levels of three important host proteins involved in HIV-1 replication: apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G), tripartite motif 5alpha (TRIM5alpha), and lens epithelium-derived growth factor (LEDGF/p75). An indirect intracellular staining (ICS) method was optimized using antibodies designed for other applications like enzyme-linked immunosorbent assay (ELISA), confocal imaging, and western blotting. The median fluorescence intensity (MFI) value--a measure for the protein expression level--increased upon higher antibody concentration and longer incubation time, and was reduced following preincubation with recombinant proteins. Staining of stably transfected or knock-down cell lines supported the method's specificity. Moreover, confocal microscopy analysis of peripheral blood mononuclear cells (PBMC), when stained according to the ICS method, confirmed the localization of APOBEC3G and TRIM5alpha in the cytoplasm, and of LEDGF/p75 in the nucleus. Also, stimulation with mitogen, interferon-alpha, or interferon-beta resulted in detectable, albeit weak, increases in intracellular expression of APOBEC3G and TRIM5alpha. After optimization, the method was applied to healthy control and HIV-1 infected subjects. For all subjects studied, the memory subset of CD4+ T cells showed significantly higher expression levels of APOBEC3G, TRIM5alpha, and LEDGF/p75, while the CD16+ subset of monocytes was characterized by higher expression levels of LEDGF/p75. In addition, we observed that therapy naive HIV-1 patients tended to have lower expression levels of APOBEC3G and TRIM5alpha than HIV-1 negative controls. In summary, our data provide proof-of principle for the detection of specific host factors at the level of a single cell, which may prove useful for our further understanding of their role in virus host interactions. PMID- 21784080 TI - Cardamonin suppresses nitric oxide production via blocking the IFN-gamma/STAT pathway in endotoxin-challenged peritoneal macrophages of ICR mice. AB - AIMS: Overproduction of nitric oxide (NO) from inducible NO synthase (iNOS) plays many pivotal roles in various inflammatory diseases. In this study, we examined the effects of 6 flavonoids on lipopolysaccharide (LPS)-induced NO generation in macrophage (Mphi), and addressed molecular mechanisms of cardamonin. MAIN METHODS: Suppressive effects on NO generation in vitro were assayed in LPS stimulated macrophages (Mphi). In vivo anti-inflammatory activity was evaluated with LPS-challenged ICR mice. Mechanistic analyses were done by ELISA, Western blot, RT-PCR, etc. KEY FINDINGS: Cardamonin, a chalcone, exhibited pronounced suppressive activity, while pinocembrin, a counterpart flavanone, was much less active. Administration of cardamonin (0.02-2 mg/kg body weight) significantly decreased NOx concentrations in the sera from LPS-challenged ICR mice. This efficacy was superior to that of curcumin, a well-known anti-inflammatory agent present in turmeric. Cardamonin down-regulated iNOS mRNA expression and suppressed activation of STAT-1, but not nuclear factor kappaB, both of which are transcription factors for the iNOS gene in peritoneal Mphi of ICR mice. Interferon (IFN)-gamma was identified as the major cytokine which mediates LPS induced STAT-1 activation and resultant iNOS expression. Intriguingly, cardamonin suppressed the activation of not only STAT-1 but also STATs-2, 3 and 4. The involvement of the JAK/STATs pathway in NO generation was suggested because its specific inhibitor, AG490, decreased NO generation. SIGNIFICANCE: Cardamonin was identified to be a unique phytochemical that targets the production of IFN- and thereby suppresses the STAT pathway for mitigating inflammation. PMID- 21784081 TI - Astrocyte activation but not neuronal impairment occurs in the hippocampus of mice after 2 weeks of d-galactose exposure. AB - AIMS: The objective of this study is to prove that activation of astrocytes precedes neuron cell death in the neurodegenerative process induced by d galactose (d-gal) exposure. MAIN METHODS: Male adult mice were given intraperitoneal injection of d-gal (200 mg/kg per day) for 2 weeks. The whole brain homogenate and hippocampal sections were then prepared for biochemical analyses, immunohistochemistry and electron microscopy, respectively. KEY FINDINGS: There were no statistically significant differences in brain oxidative and antioxidative parameters between d-gal-treated mice and saline controls. There was also lack of morphological impairment in hippocampal neuronal soma, dendrites and synapses in the model mice. In contrast, hippocampal astrocytes were dramatically activated, and perisynaptic processes of astrocytes were swelling as revealed by ultrastructural analysis. Moreover, d-gal-treated group showed increases in immunostaining levels of glutamate transporter-1 and aquaporin-4 in the hippocampus, which might increase uptake of glutamate from the synaptic cleft into astrocytes. SIGNIFICANCE: These results reveal that astrocytes undergo structural and biochemical changes while no impairment of neuronal elements occurs after 2 weeks of d-gal exposure. Thus, targeting astrocytes may be a promising strategy for the treatment of neurodegenerative diseases at the early stages. PMID- 21784079 TI - Protein S-glutathiolation: redox-sensitive regulation of protein function. AB - Reversible protein S-glutathiolation has emerged as an important mechanism of post-translational modification. Under basal conditions several proteins remain adducted to glutathione, and physiological glutathiolation of proteins has been shown to regulate protein function. Enzymes that promote glutathiolation (e.g., glutathione-S-transferase-P) or those that remove glutathione from proteins (e.g., glutaredoxin) have been identified. Modification by glutathione has been shown to affect protein catalysis, ligand binding, oligomerization and protein protein interactions. Conditions associated with oxidative or nitrosative stress, such as ischemia-reperfusion, hypertension and tachycardia increase protein glutathiolation via changes in the glutathione redox status (GSH/GSSG) or through the formation of sulfenic acid (SOH) or nitrosated (SNO) cysteine intermediates. These "activated" thiols promote reversible S-glutathiolation of key proteins involved in cell signaling, energy production, ion transport, and cell death. Hence, S-glutathiolation is ideally suited for integrating and mounting fine tuned responses to changes in the redox state. S-glutathiolation also provides a temporary glutathione "cap" to protect protein thiols from irreversible oxidation and it could be an important mechanism of protein "encryption" to maintain proteins in a functionally silent state until they are needed during conditions of stress. Current evidence suggests that the glutathiolation-deglutathiolation cycle integrates and interacts with other post-translational mechanisms to regulate signal transduction, metabolism, inflammation, and apoptosis. This article is part of a Special Section entitled "Post-translational Modification." PMID- 21784082 TI - Effect of delay in a Lotka-Volterra type predator-prey model with a transmissible disease in the predator species. AB - We consider a system of delay differential equations modeling the predator-prey ecoepidemic dynamics with a transmissible disease in the predator population. The time lag in the delay terms represents the predator gestation period. We analyze essential mathematical features of the proposed model such as local and global stability and in addition study the bifurcations arising in some selected situations. Threshold values for a few parameters determining the feasibility and stability conditions of some equilibria are discovered and similarly a threshold is identified for the disease to die out. The parameter thresholds under which the system admits a Hopf bifurcation are investigated both in the presence of zero and non-zero time lag. Numerical simulations support our theoretical analysis. PMID- 21784083 TI - In vivo visualization of the origination of skin graft vasculature in a wild type/GFP crossover model. AB - INTRODUCTION: Skin substitutes are increasingly produced in tissue engineering, but still the understanding of the physiological skin revascularization process is lacking. To study in vivo conditions we recently introduced a mouse model, in which we already characterized the angiogenic changes within the wound bed and the skin graft. The aim of this study was to identify the origination of the vasculature during skin graft revascularization in vivo and to track vessel development over time. METHODS: We created a crossover wild-type/GFP skin transplantation model, in which each animal carried the graft from the other strain. The preparation of the modified dorsal skin fold chamber including cross over skin grafting was performed in male C57BL/6J wild-type mice (n=5) and C57BL/6-Tg(ACTB-EGFP)1O sb/J mice (n=5). Intravital microscopy in 12 areas of wild-type and GFP skin grafts was performed daily over a time period of 10 days. RESULTS: Graft reperfusion started after 48-72 h. After reperfusion GFP-positive structures from the wound bed were visible in the graft capillaries with the highest density in the center of the graft. Overall, we observed a replacement of existing graft capillaries with vessels from the wound bed in 68% of the vessels. Of note, vessel replacement occurred in almost 100% of graft vessels in the periphery. Additionally, vessels within the graft showed a temporary angiogenic response between days 3-8, which originated predominantly from the autochthonous graft vasculature, but also contained already grown-in vessels from the wound bed. CONCLUSIONS: These in vivo data indicate an early in-growth of angiogenic bed vessels into the existing vascular channels of the graft and subsequent centripetal replacement. Additionally we observed a temporary angiogenic response of the autochthonous capillaries of the skin graft with contribution from bed vessels. These findings further support the theory that sprouting angiogenesis from the wound bed in combination with the replacement of existing graft vessels are the key factors in skin graft taking. Thus, manufacturing of skin substitutes should be aimed at providing pre-formed vascular channels within the construct to improve vascularization. PMID- 21784084 TI - Distance between laser head and skin does not influence skin blood flow values recorded by laser speckle imaging. AB - BACKGROUND: Laser Speckle contrast imaging (LSCI) allows non-contact, real-time recording of cutaneous blood flow (CBF). Different distances from laser-head to skin (distances(L-S)) can be chosen by the operator to perform these recordings. We aimed to evaluate the impact of different Distances(L-S) on the analysis of rest blood flow and post-occlusive reactive hyperemia (PORH). METHODS: Four distances(L-S) (10, 15, 20, and 30 cm) were evaluated in a random order in 11 healthy subjects. We analyzed the concordance between each recording at each distance(L-S). We compared CBF results (absolute values and cutaneous vascular conductance (CBF divided by mean arterial pressure)) obtained for each distance(L S). The intra-subject coefficients of variation due to distances(L-S) (intra-CV, in%) were also studied. RESULTS: The mean "r" (standard deviation) cross correlation coefficient was 0.99 (0.00) between each CBF trace issued from different distance(L-S). Both kinds of CBF results, at rest and for PORH peak, show non-significant differences when the distance(L-S) is modified. The intra-CV varies from 5.9% to 8.6% at rest and from 5.6% to 9.1% for the PORH peak. CONCLUSION: Distance(L-S) neither influences SBFR at rest, nor at peak post occlusive hyperemia in the 10-30 cm interval using LSCI. PMID- 21784085 TI - Repeated exposure of human fibroblasts to ionizing radiation reveals an adaptive response that is not mediated by interleukin-6 or TGF-beta. AB - Exposing cells to a low dose can protect them against a subsequent higher exposure. This phenomenon is known as adaptive response and is frequently observed in a variety of cells. Even though similarities are suspected with other non-targeted effects, such as bystander effects, the exact mechanism behind adaptive response is not fully clarified. In this study human primary fibroblasts were tested for their response to ionizing radiation (IR) after administrating a low priming dose (0.1-0.5Gy). Both the abundance of gammaH2AX as a marker for double-stranded breaks and the levels of cytokines, secreted in the medium, were monitored in time. Upon challenge, IR-primed cells showed modified gammaH2AX spot size distributions and altered repair kinetics, consistent with an adaptive response. In addition, 24h after priming with IR, four cytokines were significantly upregulated in the medium - GM-CSF (1.33*); IL6 (4.24*); IL8 (1.33*); TGF-beta (1.46*). In order to mimick the protective effect of IR priming, we primed the cells with either IL6 or TGF-beta. This did not elicit an altered gammaH2AX response as observed in IR-primed cells, indicating that the adaptive response in these primary fibroblasts is regulated in an IL-6 and TGF beta independent manner. PMID- 21784086 TI - RNA silencing: Mechanism, biology and responses to environmental stress. AB - Much early work on environmental stress, including ionizing radiation and environmental toxins, emphasised their action on DNA and subsequent mutagenesis in long term effects including germ cell mutagenesis, carcinogenesis and trans generational effect. However, recent studies are increasingly pointing a complementary role of epigenetic effects in these processes. While a substantial part of the literature focuses on DNA methylation, there is increasing recognition of the role of non-coding RNAs, including small-, micro-, and pi RNAs, as well as transposable elements. These play key roles in carcinogenesis, and in germ cell changes including trans-generational effects. PMID- 21784087 TI - Reduction of 8-oxodGTP in the nucleotide pool by hMTH1 leads to reduction in mutations in the human lymphoblastoid cell line TK6 exposed to UVA. AB - UVA has been suggested to play an important role in UV-induced mutagenesis. The mechanisms by which UVA induces mutations are still a matter of debate. Our aim was to investigate the protective capacity of hMTH1, a nucleotide pool sanitization enzyme with 8-oxodGTPase activity. Human B lymphoblastoid cells were stably transfected with shRNA directed against hMTH1. Clonogenic survival, mutations, intracellular and extracellular levels of 8-oxodG (8-oxo-7, 8-dihydro 2'-deoxyguanosine) and dG in the nucleotide pool of UVA-irradiated transfected and non-transfected cells were investigated. Mutations were determined in the thymidine kinase locus. Intracellular 8-oxodG and dG were measured using a modified ELISA and HPLC, respectively, after extraction of the nucleotide pool and conversion of nucleotides to their corresponding nucleosides. 8-oxodG in the medium was measured using ELISA. UVA-induced mutations were significantly higher while the survival was slightly lower in transfected compared to non-transfected cells. The increased mutation rate in transfected cells at increased exposure correlated with enhanced levels of 8-oxodG in the nucleotide pool, and a somewhat reduced level of 8-oxodG in the medium. The results indicate that the nucleotide pool is a significant target for UVA-induced mutations and implicates that hMTH1 plays an important role in protecting cells from UVA-induced oxidative stress. PMID- 21784088 TI - Inactivation of PTEN is responsible for the survival of Hep G2 cells in response to etoposide-induced damage. AB - The chemo-resistance character of human hepatocellular carcinoma cells is well known but the anomalies associated with such resistance character are not completely understood. In this study, etoposide-induced signaling events in human hepatocellular carcinoma cell line, Hep G2 has been compared with Chang Liver cells, a normal human liver cell line. Hep G2 cells are resistant to etoposide when compared with Chang Liver cells. Etoposide-induced gammaH2AX foci in Hep G2 cells are persisted for a longer time without affecting cell cycle, indicating that Hep G2 cells are able to maintain its growth with damaged DNA. Further, Akt signaling pathway is deregulated in Hep G2 cells. The upstream negative regulator of Akt, PTEN remains inactive, as it is hyperphosphorylated in Hep G2 cells. Inhibition of PI-3K pathway by wortmannin partially reverses the etoposide resistance character of Hep G2 cells. Either Hep G2 or Chang Liver cells when transfected with plasmid carrying active Akt (myr-Akt) become resistance towards etoposide compared to the cells transfected with empty vectors or kinase defective Akt. Transient transfection of wild type PTEN in Hep G2 cells does not change its response towards etoposide whereas Chang Liver cells become sensitive after transfection with same plasmid. These results suggest that inactivation of PTEN, which renders activation of Akt, may contribute largely for the etoposide resistance character of Hep G2 cells. PMID- 21784089 TI - Non-targeted radiation effects-an epigenetic connection. AB - Ionizing radiation (IR) is a pivotal diagnostic and treatment modality, yet it is also a potent genotoxic agent that causes genome instability and carcinogenesis. While modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. IR-induced genome instability has been well-documented in directly exposed cells and organisms. It has also been observed in distant 'bystander' cells. Enigmatically, increased instability is even observed in progeny of pre-conceptually exposed animals, including humans. The mechanisms by which it arises remain obscure and, recently, they have been proposed to be epigenetic in nature. Three major epigenetic phenomena include DNA methylation, histone modifications and small RNA-mediated silencing. This review focuses on the role of DNA methylation and small RNAs in directly exposed and bystander tissues and in IR-induced transgenerational effects. Here, we present evidence that IR-mediated effects are maintained by epigenetic mechanisms. PMID- 21784090 TI - Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain. AB - Dichlorvos is a synthetic insecticide that belongs to the family of chemically related organophosphate (OP) pesticides. It can be released into the environment as a major degradation product of other OPs, such as trichlorfon, naled, and metrifonate. Dichlorvos exerts its toxic effects in humans and animals by inhibiting neural acetylcholinesterase. Chronic low-level exposure to dichlorvos has been shown to result in inhibition of the mitochondrial complex I and cytochrome oxidase in rat brain, resulting in generation of reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt c) from mitochondria to cytosol resulting in apoptotic cell death. MitoQ is an antioxidant, selectively targeted to mitochondria and protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in dichlorvos induced neurodegeneration, then MitoQ should ameliorate neuronal apoptosis. Administration of MitoQ (100 MUmol/kg body wt/day) reduced dichlorvos (6 mg/kg body wt/day) induced oxidative stress (decreased ROS production, increased MnSOD activity and glutathione levels) with decreased lipid peroxidation, protein and DNA oxidation. In addition, MitoQ also suppressed DNA fragmentation, cyt c release and caspase-3 activity in dichlorvos treated rats compared to the control group. Further electron microscopic studies revealed that MitoQ attenuates dichlorvos induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that MitoQ may be beneficial against OP (dichlorvos) induced neurodegeneration. PMID- 21784091 TI - Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database. AB - The present study was performed to develop a robust gene-based prediction model for early assessment of potential hepatocarcinogenicity of chemicals in rats by using our toxicogenomics database, TG-GATEs (Genomics-Assisted Toxicity Evaluation System developed by the Toxicogenomics Project in Japan). The positive training set consisted of high- or middle-dose groups that received 6 different non-genotoxic hepatocarcinogens during a 28-day period. The negative training set consisted of high- or middle-dose groups of 54 non-carcinogens. Support vector machine combined with wrapper-type gene selection algorithms was used for modeling. Consequently, our best classifier yielded prediction accuracies for hepatocarcinogenicity of 99% sensitivity and 97% specificity in the training data set, and false positive prediction was almost completely eliminated. Pathway analysis of feature genes revealed that the mitogen-activated protein kinase p38- and phosphatidylinositol-3-kinase-centered interactome and the v-myc myelocytomatosis viral oncogene homolog-centered interactome were the 2 most significant networks. The usefulness and robustness of our predictor were further confirmed in an independent validation data set obtained from the public database. Interestingly, similar positive predictions were obtained in several genotoxic hepatocarcinogens as well as non-genotoxic hepatocarcinogens. These results indicate that the expression profiles of our newly selected candidate biomarker genes might be common characteristics in the early stage of carcinogenesis for both genotoxic and non-genotoxic carcinogens in the rat liver. Our toxicogenomic model might be useful for the prospective screening of hepatocarcinogenicity of compounds and prioritization of compounds for carcinogenicity testing. PMID- 21784092 TI - Classic toxins. PMID- 21784093 TI - The role of search difficulty in intertrial feature priming. AB - Previous research has shown that intertrial repetition of target and distractors task-relevant properties speeds visual search performance, an effect known as priming of pop-out (PoP). Recent accounts suggest that such priming results, at least in part, from a mechanism that speeds post-selectional, response-related processes, the marker of which is an interaction between repetition of the target and distractor features and repetition of the response from the previous trial. However, this response-based component of inter-trial priming has been elusive, and it remains unclear what its boundary conditions might be. In addition, what information is represented in the episodic memory traces that underlie the response-based component has not yet been characterized. Here, we show that the response-based component of feature priming reflects an episodic memory retrieval mechanism that is not mandatory or automatic but may be described as a heuristic that subjects sometimes use, in particular when the overall difficulty of the search task is high. In addition, we show that the conjunction of the target and distractor features forms the context that is reactivated during episodic retrieval. Finally, we show that target-distractor discriminability is an important modulator of the selection-based component. The findings are discussed within the framework of the dual-stage model of inter-trial priming (Lamy, Yashar, & Ruderman, 2010). PMID- 21784095 TI - The where, what and when of gaze allocation in the lab and the natural environment. AB - How do people distribute their visual attention in the natural environment? We and our colleagues have usually addressed this question by showing pictures, photographs or videos of natural scenes under controlled conditions and recording participants' eye movements as they view them. In the present study, we investigated whether people distribute their gaze in the same way when they are immersed and moving in the world compared to when they view video clips taken from the perspective of a walker. Participants wore a mobile eye tracker while walking to buy a coffee, a trip that required a short walk outdoors through the university campus. They subsequently watched first-person videos of the walk in the lab. Our results focused on where people directed their eyes and their head, what objects were gazed at and when attention-grabbing items were selected. Eye movements were more centralised in the real world, and locations around the horizon were selected with head movements. Other pedestrians, the path, and objects in the distance were looked at often in both the lab and the real world. However, there were some subtle differences in how and when these items were selected. For example, pedestrians close to the walker were fixated more often when viewed on video than in the real world. These results provide a crucial test of the relationship between real behaviour and eye movements measured in the lab. PMID- 21784094 TI - Age-related changes in matching novel objects across viewpoints. AB - Object recognition is an important visual process. We are not only required to recognize objects across a variety of lighting conditions and variations in size, but also across changes in viewpoint. It has been shown that reaction times in object matching increase as a function of increasing angular disparity between two views of the same object, and it is thought that this is related to the time it takes to mentally rotate an object. Recent studies have shown that object rotations for familiar objects affect older subjects differently than younger subjects. To investigate the general normalization effects for recognizing objects across different viewpoints regardless of visual experience with an object, in the current study we used novel 3D stimuli. Older and younger subjects matched objects across a variety of viewpoints along both in-depth and picture plane rotations. Response times (RTs) for in-depth rotations were generally slower than for picture plane rotations and older subjects, overall, responded slower than younger subjects. However, a male RT advantage was only found for objects that differed by large, in-depth rotations. Compared to younger subjects, older subjects were not only slower but also less accurate at matching objects across both rotation axes. The age effect was primarily due to older male subjects performing worse than younger male subjects, whereas there was no significant age difference for female subjects. In addition, older males performed even worse than older females, which argues against a general male advantage in mental rotations tasks. PMID- 21784096 TI - Intervention effects of exercise self-regulation on physical exercise and eating fruits and vegetables: a longitudinal study in orthopedic and cardiac rehabilitation. AB - OBJECTIVE: The primary objective of this study was to unveil the mechanisms by which an exercise self-regulation intervention affects physical exercise in a rehabilitation context. The second aim was to investigate whether the intervention led to changes in fruit and vegetable intake that was not targeted in the intervention. Finally, it was tested whether changes in exercise habit strength may explain such a transfer effect. METHOD: A quasi-experimental design was conducted in Germany between 2009 and 2011 with 725 rehabilitation patients. Patients received either a self-regulation intervention or an online questionnaire. Six weeks after discharge, self-reported changes in exercise and dietary behaviors, exercise habit strength, and cognitions were measured. QUANTITATIVE RESULTS: The exercise self-regulation intervention led to a higher increment in exercise behavior, exercise habit strength, and fruit and vegetable intake than the control condition. Changes in physical exercise were mediated by changes in action control (slope=0.04; 99% CI=0.01 to 0.06) and satisfaction (slope=0.05; 99% CI:=0.02 to 0.08), but not in action planning. Changes in fruit and vegetable intake were mediated by changes in exercise habit strength (slope=0.05; 99% CI=0.01 to 0.08). CONCLUSION: Interventions could be optimized if they aim at fostering exercise habits. This in turn may also facilitate transfer effects from one health behavior to the other. PMID- 21784097 TI - Construction of a recombinant eukaryotic expression plasmid containing human PDLIM2 gene and its biological activity. AB - In order to obtain a full-length expression plasmid for human PDLIM2 gene, fragment amplification was used to clone its full-length coding sequence (CDS) region. The amplified PCR product was then digested and inserted into the pMD 18 T vector and subcloned into the pIRES2-EGFP plasmid to form the pIRES2-EGFP PDLIM2 eukaryotic expression vector. After it was transfected to the bladder cancer cell line, BIU-87, the biological activities of high expression were verified by RT-PCR and Western blotting. Meanwhile the mRNA and protein expressions of p65 were detected. Finally we analyzed the effect of overexpressed PDLIM2 on BIU-87 cell proliferation. In conclusion, a recombinant eukaryotic expression vector pIRES2-EGFP-PDLIM2 containing the complete CDS region of PDLIM2 was successfully constructed. PDLIM2 negatively regulated p65 expression and inhibited BIU-87 cell proliferation. We laid the foundations for further research into the function of the PDLIM2 gene in bladder cancer. PMID- 21784099 TI - Multidrug resistant tuberculous meningitis in the United States, 1993-2005. PMID- 21784100 TI - Serum activity of indoleamine 2,3-dioxygenase predicts prognosis of community acquired pneumonia. AB - OBJECTIVES: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. By depleting Trp, IDO plays a critical role in inducing immune suppression and tolerance. The aim of present study was to investigate serum IDO activity, determined by Kyn-to-Trp ratio (Kyn/Trp ratio), in community-acquired pneumonia (CAP) and to examine its clinical significance. METHODS: This study subjects consisted of 129 consecutive patients with CAP and 64 healthy controls. The concentrations of Kyn and Trp were measured simultaneously by liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: The CAP patients had significantly higher Kyn concentrations and significant lower Trp concentrations than the controls (p < 0.0001 and p < 0.0001, respectively). Accordingly, IDO activity was significantly higher (2.4-fold) in the patients than in the controls (p < 0.0001). IDO activity correlated well with PSI (Pneumonia Severity Index) and CURB65 (p = 0.0005 and p < 0.0001, respectively). Moreover, the IDO activity and Kyn concentration were significantly higher in the nonsurvivors and were found to predict mortality in multivariate analysis. CONCLUSIONS: IDO activity was increased in CAP, and this activity was associated with the severity and outcome of this disease. These results suggest that IDO activity can predict prognosis of CAP. PMID- 21784098 TI - Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: clinical significance. AB - Galantamine, a drug used to treat Alzheimer's disease, protects guinea pigs against the acute toxicity and lethality of organophosphorus (OP) compounds, including soman. Here, we tested the hypothesis that a single exposure of guinea pigs to 1xLD50 soman triggers cognitive impairments that can be counteracted by galantamine. Thus, animals were injected intramuscularly with saline (0.5 ml/kg) or galantamine (8 mg/kg) and 30 min later injected subcutaneously with soman (26.3 MUg/kg) or saline. Cognitive performance was analyzed in the Morris water maze (MWM) four days or three months after the soman challenge. Fifty percent of the saline-injected animals that were challenged with soman survived with mild-to moderate signs of acute toxicity that subsided within a few hours. These animals showed no learning impairment and no memory retention deficit, when training in the MWM started four days post-soman challenge. In contrast, animals presented significant learning impairment when testing started three months post-challenge. Though the magnitude of the impairment correlated with the severity of the acute toxicity, animals that presented no or only mild signs of toxicity were also learning impaired. All guinea pigs that were treated with galantamine survived the soman challenge with no signs of acute toxicity and learned the MWM task as control animals, regardless of when testing began. Galantamine also prevented memory extinction in both saline- and soman-challenged animals. In conclusion, learning impairment develops months after a single exposure to 1xLD50 soman, and galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by this OP poison. PMID- 21784101 TI - Muscular timing and inter-muscular coordination in healthy females while walking. AB - The dynamic interplay between muscles surrounding the knee joint, the central nervous system and external factors require a control strategy to generate and stabilise the preferred gait pattern. The electromyographic (EMG) signal is a common measure reflecting the neuromuscular control strategies during dynamic tasks. Neuromuscular control mechanisms, found in processed EMG signals, showed a precise pacing with a pacing rhythm and a tight control of muscle activity in running and maximally contracted muscles. The purpose of this study was to provide an insight how muscles get activated during walking. The EMG power, extracted by the wavelet transform (92-395Hz), over a time period encompassing 250ms before and 250ms after heel strike was analysed. The study showed that the wavelet-based analysis of EMG signals was sufficiently sensitive to detect a synchronisation of the activation of thigh muscles while walking. The results within each single subject and within the group consisting of 10 healthy females showed that, although there was a lot of jitter in the locations of the intensity peaks, the muscle activation is controlled, on average, by a neuromuscular activity paced at about 40ms, however with variable amplitudes. Albeit the jitter of the signal, the results resolved the temporal dependency of intensity peaks within muscles surrounding the knee and provided an insight into neural control of locomotion. The methodology to assess the stabilising muscle activation pattern may provide a way to discriminate subjects with normal gait pattern form those with a deteriorated neuromuscular control strategy. PMID- 21784102 TI - Activin A stimulates mouse macrophages to express APRIL via the Smad3 and ERK/CREB pathways. AB - A proliferation-inducing ligand (APRIL) is primarily expressed by macrophages and dendritic cells, and stimulates B cell proliferation, differentiation, survival, and Ig production. In the present study, we investigated the role and signaling mechanisms of activin A in APRIL expression by mouse macrophages. Activin A markedly enhanced APRIL expression in mouse macrophages at both the transcriptional and protein levels. Overexpression of dominant-negative (DN) Smad3 and SB431542 abrogated activin-induced APRIL transcription. Furthermore, activin A induced Smad3 phosphorylation. These results indicate that activin A enhances APRIL expression through both activin receptor-like kinase 4 (ALK4) and Smad3. In a subsequent analysis of activin A signaling, it was found that PD98059, an extracellular signal-related kinase (ERK) inhibitor, eliminated activin A-induced APRIL expression. On the other hand, overexpression of cAMP responsive element-binding protein (CREB), a molecule downstream of ERK, augmented activin A-induced APRIL expression, and this effect could be abolished by PD98059. This finding that activin A induces ERK and CREB phosphorylation suggests that ERK and CREB act as intermediates in APRIL expression. Taken together, these results demonstrate that activin A can enhance APRIL expression through two different pathways, Smad3 and ERK/CREB. PMID- 21784103 TI - Highly efficient large-scale lentiviral vector concentration by tandem tangential flow filtration. AB - Large-scale lentiviral vector (LV) concentration can be inefficient and time consuming, often involving multiple rounds of filtration and centrifugation. This report describes a simpler method using two tangential flow filtration (TFF) steps to concentrate liter-scale volumes of LV supernatant, achieving in excess of 2000-fold concentration in less than 3h with very high recovery (>97%). Large volumes of LV supernatant can be produced easily through the use of multi-layer flasks, each having 1720 cm(2) surface area and producing ~560 mL of supernatant per flask. Combining the use of such flasks and TFF greatly simplifies large scale production of LV. As a demonstration, the method is used to produce a very high titer LV (>10(10)TU/mL) and transduce primary human CD34+ hematopoietic stem/progenitor cells at high final vector concentrations with no overt toxicity. A complex LV (STEMCCA) for induced pluripotent stem cell (iPSC) generation is also concentrated from low initial titer and used to transduce and reprogram primary human fibroblasts with no overt toxicity. Additionally, a generalized and simple multiplexed real-time PCR assay is described for lentiviral vector titer and copy number determination. PMID- 21784104 TI - Dopamine D2-like receptor agonists induce penile erection in male rats: differential role of D2, D3 and D4 receptors in the paraventricular nucleus of the hypothalamus. AB - Pramipexole, a dopamine D3/D2 receptor agonist, induces penile erection when administered subcutaneously (s.c.) or into the paraventricular nucleus of the hypothalamus of male rats, like apomorphine, a mixed D1/D2 receptor agonist, and PD 168,077, a D4 receptor agonist. A U-inverted dose-response curve was found with pramipexole and apomorphine, but not with PD 168,077 (0.025-0.5mg/kg s.c.). Pramipexole effect was abolished by L-741,626, a D2 receptor antagonist (2.5 and 5mg/kg s.c.) and raclopride, a D2/D3 receptor antagonist (0.025 and 0.1mg/kg s.c.), but not by SB277011A (2.5 and 10mg/kg s.c.) or FAUC 365 (1 and 2mg/kg s.c.), two D3 receptor antagonists, or L-745,870 (1 and 5mg/kg i.p.), a D4 receptor antagonist. Similar results were found with apomorphine (0.08mg/kg s.c.), although its effect was also partially reduced by L-745,870. In contrast, PD 168,077 effect was abolished by L-745,870, but not L-741,626, SB277011A, FAUC 365 or raclopride. Similar results were found when dopamine agonists (5 200ng/rat) and antagonists (1-5MUg/rat) were injected into the paraventricular nucleus. However, no U-inverted dose-response curve was found with any of the three dopamine agonists injected into this nucleus. As pramipexole- and apomorphine-induced penile erection was reduced mainly by D2, but not D3 or D4 antagonists, D2 receptors are those that mediate the pro-erectile effect of these dopamine agonists. Although the selective stimulation of paraventricular D4 receptors induces penile erection, D4 receptors seem to play only a modest role in the pro-erectile effect of the above dopamine agonists. PMID- 21784105 TI - Beta2-containing neuronal nicotinic receptors as major actors in the flexible choice between conflicting motivations. AB - Beside a critical role in nicotine addiction, the role of nicotinic receptors in cognitive or emotional processes remains difficult to elucidate, mostly because of a lack of specificity of compounds and because they up or down regulate easily. Using knockout mice may be one key to elucidate the role of nicotinic receptors stimulated by their endogenous ligand acetylcholine. We and others have previously explored the behaviour of mice knockout for the beta2-subunit containing nicotinic receptor - beta2*nAChRs - beta2(-/-) mice. These mice exhibit a particular kind of hyperactive locomotion, with profound deficits in cognitive and social interaction tasks, only when they have to show flexible choices. We wonder here whether the latter is due to a lack of motor control - i.e. motor impulsivity, a lack of estimation of reward value - i.e. cognitive impulsivity, and/or a lack of appropriate ranking or choice between different motivations. We designed behavioural tasks allowing the study of these distinct processes in mice. Our current results highlight the important role of beta2*nAChRs in flexible behaviours in conflicting situations, such as social contact, spatial exploration and food consumption. They also show that the cognitive deficits exhibited by beta2(-/-) mice cannot be explained by impaired inhibitory behaviours. Although social cognition is considerably enriched in humans as compared to rodents, we provide here novel data for the neurobiology of flexible social behaviours that could ultimately be useful for humans. Indeed, the ability to show flexible behaviours and to display adapted social interactions is profoundly impaired in a myriad of psychiatric disorders. PMID- 21784107 TI - Comparative effects of alcohol and thiamine deficiency on the developing central nervous system. AB - The present study addresses the still unresolved issue of the character of alcohol-thiamine metabolic interferences in the developing central nervous system (CNS). Investigations compare developmental neurotoxicity evoked by three patterns of maternal thiamine deficiency (pre, peri and postnatal), with two patterns of maternal chronic alcohol intake (alcohol alone and alcohol+thiamine cotreatment), on seven neurodevelopmental abilities in the offspring. The three patterns of thiamine deficiency, pair-compared with controls, highlight four sequences of development: (1) embryonic-perinatal sequence; (2) perinatal postnatal sequence; (3) "ontogeny in ontogeny out" sequence; (4) "off and on" developing sequence. The results suggest a temporally- and regionally emergence of structures and centers underlying functional maturation during CNS ontogenesis. Furthermore, both developmental thiamine deficiencies and ethanol exposure produce two waves of neurofunctional alterations, peaking at P15 (postnatal day 15) and P25, respectively. The first peak of vulnerability is a prenatal event; it may interfere with the periods of intense cellular proliferation and migration. The second peak represents both perinatal and postnatal events; it may interfere with the periods of cellular differentiation, synaptogenesis, axonogenesis and myelinogenesis. Alcohol+thiamine cotreatment fails to reduce the first peak, but neutralizes essentially the second peak. The results suggest that alcohol interferes with thiamine during cellular differentiation and membrane developmental processes mainly. Indeed, among the three conditions of thiamine-deficient diet, only perinatal thiamine deficiency exhibits a closer relationship with developmental alcohol exposure. Together, these observations suggest that the critical period for alcohol-thiamine antagonism occurs perinatally and affects primarily cellular differentiation. PMID- 21784108 TI - Slower gastric emptying in high-fat diet induced obese rats is associated with attenuated plasma ghrelin and elevated plasma leptin and cholecystokinin concentrations. AB - Gastrointestinal (GI) motility and gut hormones have been considered to be involved in the development and maintenance of obesity. Our aim was to assess the relationships between gastric emptying (GE), GI transit and gut hormones and leptin concentrations in diet-induced obese rat model. Male 6-week-old Sprague Dawley rats were fed with a high-fat (HF) diet for 8weeks to generate diet induced obesity (DIO) and diet resistant (DR) rats. GE, GI transit and plasma ghrelin, cholecystokinin (CCK), PYY and leptin concentrations were determined in DIO, DR and control (CON) rats. The DIO rats had slower GE, higher plasma leptin and CCK concentrations, and lower plasma ghrelin concentration compared with CON and DR rats. GE was correlated with plasma ghrelin (r=0.402, P=0.028), CCK (r= 0.518, P=0.003) and leptin concentration (r=-0.514, P=0.004). The slower GE, which can be considered as an adaptive response aimed at HF diet induced obesity, may be mediated by changes of plasma ghrelin, CCK and leptin concentrations. PMID- 21784106 TI - Age differences in spatial working memory contributions to visuomotor adaptation and transfer. AB - Throughout our life span we encounter challenges that require us to adapt to the demands of our changing environment; this entails learning new skills. Two primary components of motor skill learning are motor acquisition, the initial process of learning the skill, and motor transfer, when learning a new skill is benefitted by the overlap with a previously learned one. Older adults typically exhibit declines in motor acquisition compared to young adults, but remarkably, do not demonstrate deficits in motor transfer [10]. Our recent work demonstrates that a failure to engage spatial working memory (SWM) is associated with skill learning deficits in older adults [16]. Here, we investigate the role that SWM plays in both motor learning and transfer in young and older adults. Both age groups exhibited performance savings, or positive transfer, at transfer of learning for some performance variables. Measures of spatial working memory performance and reaction time correlated with both motor learning and transfer for young adults. Young adults recruited overlapping brain regions in prefrontal, premotor, parietal and occipital cortex for performance of a SWM and a visuomotor adaptation task, most notably during motor learning, replicating our prior findings [12]. Neural overlap between the SWM task and visuomotor adaptation for the older adults was limited to parietal cortex, with minimal changes from motor learning to transfer. Combined, these results suggest that age differences in engagement of cognitive strategies have a differential impact on motor learning and transfer. PMID- 21784109 TI - From chronic kidney disease to transplantation: the roles of obestatin. AB - BACKGROUND: Kidney transplantation is the therapy of choice in most cases of end stage renal disease. The purpose of the present study was to evaluate serum obestatin levels in kidney transplant recipients (Tx), compare levels in patients with renal failure (CKD) with those in healthy subjects (HS), and to assess the role of this hormone in energetic metabolism. PATIENTS AND METHODS: A total of 95 subjects were studied: 40 were Tx; 35 had CKD and 20 were HS. Inclusion criteria were age>18years and good allograft function. Patients with an inflammatory disease or a diagnosis of cancer were excluded from the study. RESULTS: Obestatin levels in Tx patients were significantly lower than in HS (3.5 [3-4.8] versus 11 [8.56-28.60] ng/mL; p<0.0001) and patients with CKD (3.5 [3-4.8] versus 4.7 [3, 5 6, 1] ng/mL; p=0.008). At univariate analysis, a direct correlation was found between obestatin and calcemia (p: 0.0001; r: 0.51), phosphoremia (p: 0.0005; r: 0, 46), calcium-phosphate product (p<0.0001; r:0.53), and parathormone (p: 0.01; r: 0.32), whereas significant inverse correlations were evidenced for BMI (p<0.0001; r: -0.52). At multivariate analysis, significance was maintained for the correlation between obestatin and phosphoremia (beta=0.47; p=0.008), for the calcium-phosphate product (beta=0.55; p=0.0005) and for BMI (beta=-0.53; p=0.01). CONCLUSION: Obestatin, present in lower levels in Tx patients than in CKD patients and HS, plays a role in energy metabolism, affecting BMI and the metabolism of calcium-phosphorus. PMID- 21784110 TI - Induction of the intrinsic apoptosis pathway in insulin-secreting cells is dependent on oxidative damage of mitochondria but independent of caspase-12 activation. AB - Pro-inflammatory cytokine-mediated beta cell apoptosis is activated through multiple signaling pathways involving mitochondria and endoplasmic reticulum. Activation of organelle-specific caspases has been implicated in the progression and execution of cell death. This study was therefore performed to elucidate the effects of pro-inflammatory cytokines on a possible cross-talk between the compartment-specific caspases 9 and 12 and their differential contribution to beta cell apoptosis. Moreover, the occurrence of ROS-mediated mitochondrial damage in response to beta cell toxic cytokines has been quantified. ER-specific caspase-12 was strongly activated in response to pro-inflammatory cytokines; however, its inhibition did not abolish cytokine-induced mitochondrial caspase-9 activation and loss of cell viability. In addition, there was a significant induction of oxidative mitochondrial DNA damage and elevated cardiolipin peroxidation in insulin-producing RINm5F cells and rat islet cells. Overexpression of the H(2)O(2) detoxifying enzyme catalase effectively reduced the observed cytokine-induced oxidative damage of mitochondrial structures. Taken together, the results strongly indicate that mitochondrial caspase-9 is not a downstream substrate of ER-specific caspase-12 and that pro-inflammatory cytokines cause apoptotic beta cell death through activation of caspase-9 primarily by hydroxyl radical-mediated mitochondrial damage. PMID- 21784111 TI - Two types of tyrosine hydroxylase-immunoreactive neurons in the zebrafish retina. AB - The purpose of the present study is to identify the dopaminergic amacrine (DA) cells in the inner nuclear layer (INL) of zebrafish retina through immunocytochemistry and quantitative analysis. Two types of tyrosine hydroxylase immunoreactive (TH-IR) cells appeared on the basis of dendritic morphology and stratification patterns in the inner plexiform layer (IPL). The first (DA1) was bistratified, with branching planes in both s1 and s5 of the IPL. The second (DA2) was diffuse, with dendritic processes branched throughout the IPL. DA1 and DA2 cells corresponded morphologically to A(on)(-s1/s5) and A(diffuse)(-1) (Connaughton et al., 2004). The average number of total TH-IR cells was 1088+/ 79cells per retina (n=5), and the mean density was 250+/-27cells/mm(2). Their density was highest in the mid central region of ventrotemporal retina and lowest in the periphery of dorsonasal retina. Quantitatively, 45.71% of the TH-IR cells were DA1 cells, while 54.29% were DA2 cells. No TH-IR cells expressed calbindin D28K, calretinin or parvalbumin, markers for the various INL cells present in several animals. Therefore the TH-IR cells in zebrafish are limited to very specific subpopulations of the amacrine cells. PMID- 21784112 TI - Interplay of salicylaldehyde, lysine, and M2+ ions on alpha-synuclein aggregation: cancellation of aggregation effects and determination of salicylaldehyde neurotoxicity. AB - In this study, alpha-synuclein was treated in vitro with salicylaldehyde (SA), lysine (lys) and M(n+) (Cu(2+) or Zn(2+)) in various ratios. SA induced aggregation of alpha-syn in the ratio of 1:500 (alpha-syn:SA) after incubation (pH 7.4, PBS buffer, 16-24h). Free lys can thus scavenge SA, inhibiting the aggregation of alpha-syn up to ~63% (alpha-syn:SA:lys=1:1000:5000). When Cu(2+) and Zn(2+) are added to SA and alpha-syn, protein aggregation is induced. In the case of Zn(2+), the aggregation of alpha-syn increased to 74% (ratio=1:1000:50). Fluorescence studies support the production of protein-bound Zn(2+) salicylaldimine species. For Cu(2+), aggregation of alpha-syn was shown (138%). Thus, possible protective or inducing effects of lys, Cu(2+) and Zn(2+) may exist with alpha-syn. alpha-Syn, SA and Cu(2+) can undergo complexation (fluorescence, CD and MALDI data). Cellular toxicity of SA (700MUM), Zn(2+) (700MUM) and Cu(2+) (700MUM) on SH-SY5Y (1*10(5) cells) showed 9.8%, 38.0% and 14.4% compared to control values. Combinations showed more severe toxicities: 71.9% and 93.1% for SA (70MUM)+Cu(2+) (700MUM) and SA (70MUM)+Zn(2+) (700MUM), respectively, suggesting complexation itself may be toxic. PMID- 21784113 TI - Covalently stabilized trimethyl chitosan-hyaluronic acid nanoparticles for nasal and intradermal vaccination. AB - The physical stability of polyelectrolyte nanocomplexes composed of trimethyl chitosan (TMC) and hyaluronic acid (HA) is limited in physiological conditions. This may minimize the favorable adjuvant effects associated with particulate systems for nasal and intradermal immunization. Therefore, covalently stabilized nanoparticles loaded with ovalbumin (OVA) were prepared with thiolated TMC and thiolated HA via ionic gelation followed by spontaneous disulfide formation after incubation at pH 7.4 and 37 degrees C. Also, maleimide PEG was coupled to the remaining thiol-moieties on the particles to shield their surface charge. OVA loaded TMC/HA nanoparticles had a size of around 250-350nm, a positive zeta potential and OVA loading efficiencies up to 60%. Reacting the thiolated particles with maleimide PEG resulted in a slight reduction of zeta potential (from +7 to +4mV) and a minor increase in particle size. Stabilized TMC-S-S-HA particles (PEGylated or not) showed superior stability in saline solutions compared to non-stabilized particles (composed of nonthiolated polymers) but readily disintegrated upon incubation in a saline buffer containing 10mM dithiothreitol. In both the nasal and intradermal immunization study, OVA loaded stabilized TMC-S-S-HA particles demonstrated superior immunogenicity compared to non-stabilized particles (indicated by higher IgG titers). Intranasal, PEGylation completely abolished the beneficial effects of stabilization and it induced no enhanced immune responses against OVA after intradermal administration. In conclusion, stabilization of the TMC/HA particulate system greatly enhances the immunogenicity of OVA in nasal and intradermal vaccination. PMID- 21784114 TI - Feeding infants and young children. From guidelines to practice. AB - Following a workshop on infant feeding held at the Rowett Institute of Nutrition and Health, University of Aberdeen on March 17, 2010 experts were invited to exchange ideas and to review evidence on both pre and post natal dietary environments in shaping children's eating habits. A central theme during the workshop was the idea of "sensitive periods" during infancy for learning about foods and a particular focus was developed around acceptance and intake of fruits and vegetables. Presentations covered the guidelines provided by various governments on how to feed infants during weaning; the importance of the in utero experience; the impact of varying the sensory experience at weaning; the effect of parenting styles and practices on children's eating habits; the use of visual experience in promoting intake of vegetables; and reports from mothers regarding their decisions about weaning and the introduction of vegetables. This collection of papers seeks to review guidance from governments on feeding infants and to consider current evidence on parental feeding practices with the aim of enhancing insight into best practice in establishing healthy eating in children. PMID- 21784115 TI - Prostaglandin E2 produced by microsomal prostaglandin E synthase-1 regulates the onset and the maintenance of wakefulness. AB - This study examined the effect of prostaglandin E(2) (PGE(2)) produced by microsomal prostaglandin E synthase-1 (mPGES-1) on circadian rhythm. Using wild type mice (WT) and mPGES-1 knockout mice (mPGES-1(-/-)), I recorded and automatically analyzed the natural behavior of mice in home cages for 24h and measured brain levels of PGE(2). The switch to wakefulness was not smooth, and sleepiness and the total duration of sleep were significantly longer in the mPGES 1(-/-) mice. Moreover, the basal concentration of PGE(2) was significantly lower in the mPGES-1(-/-) mice. These findings suggest that PGE(2) produced by mPGES-1 regulates the onset of wakefulness and the maintenance of circadian rhythm. PMID- 21784116 TI - Evaluation of the genetic diversity of domain II of Plasmodium vivax Apical Membrane Antigen 1 (PvAMA-1) and the ensuing strain-specific immune responses in patients from Sri Lanka. AB - Antigenic polymorphism displayed by malaria parasites is a skewed schema to escape the host immune system. The prevailing genetic diversity at domain II of the Plasmodium vivax Apical Membrane Antigen-1 (Pvama-1DII) was characterized in 64 single clone P. vivax isolates from Sri Lanka, where unstable malaria prevails with low intensity. In Sri Lanka, the Pvama-1DII gene showed meager meiotic recombination with the enclosure of single nucleotide polymorphisms (SNPs). Eleven amino acid (a.a.) variant positions defined 21 a.a. haplotypes with 9 unique to the island, where the predominant haplotype, H1, was identical to the reference Salvador I strain. A further 376 globally dispersed isolates defined 38 a.a. haplotypes (H22-H59), with 4 and 26 haplotypes exclusive to India and Thailand, respectively. The phylogenetic tree revealed no clustering, where most isolates had a very recent common origin. The polymorphism detected in PvAMA-1DII B and T cell epitopes evidenced an immune evasion mechanism exploited by the parasite. Majority of Sri Lankan patients developed antibody responses to both conformational and linear B cell epitopes. The ensuing strain-specific immunity due to extensive antigenic polymorphism was evaluated by aligning a.a. sequences of PvAMA-1DII with the homologous total (IgM+IgG) antibody responses assayed by in-house established indirect ELISAs against 7 PvAMA-1DII overlapping synthetic peptides, P01-P07. While the antibody responses to P01-P03, P06, P07 harbouring P. vivax clinical isolates with polymorphic a.a. haplotype to Sal I was clearly strain-transcending (cross-reactive), individuals with isolates identical to the Sal I strain observed varying antibody prevalence against the seven PvAMA-1DII Sal-I synthetic peptides, with the highest prevalence detected against P04. Synthetic peptide P04, spanning a.a. positions 302-324 of the PvAMA-1DII of the Sal I strain that included the epitope recognized by the invasion inhibitory 4G2 monoclonal antibody of PfAMA-1, was highly conserved in all 440 local and global P. vivax isolates examined. A functional role for this region is reinforced by the highly immunogenic nature of P04, and could point towards a presumably "protective" anti-P04 antibody response that elicited an isotype switch from IgM to IgG, with increasing exposure to malaria exclusively in endemic residents. Thus the conserved and seemingly "protective" nature of the domain II loop of PvAMA-1 makes it a putative contender to be included in a cocktail vaccine against P. vivax asexual erythrocytic stages in Sri Lanka. PMID- 21784117 TI - A computerized pneumococcal vaccination reminder system in the adult emergency department. AB - BACKGROUND: Pneumococcal vaccination is an effective strategy to prevent invasive pneumococcal disease in the elderly. Emergency department (ED) visits present an underutilized opportunity to increase vaccination rates; however, designing a sustainable vaccination program in an ED is challenging. We examined whether an information technology supported approach would provide a feasible and sustainable method to increase vaccination rates in an adult ED. METHODS: During a 1-year period we prospectively evaluated a team-oriented, workflow-embedded reminder system that integrated four different information systems. The computerized triage application screened all patients 65 years and older for pneumococcal vaccine eligibility with information from the electronic patient record. For eligible patients the computerized provider order entry system reminded clinicians to place a vaccination order, which was passed to the order tracking application. Documentation of vaccine administration was then added to the longitudinal electronic patient record. The primary outcome was the vaccine administration rate in the ED. Multivariate logistic regression analysis was used to estimate the odds ratios and their 95% confidence intervals, representing the overall relative risks of ED workload related variables associated with vaccination rate. RESULTS: Among 3371 patients 65 years old and older screened at triage 1309 (38.8%) were up-to-date with pneumococcal vaccination and 2062 (61.2%) were eligible for vaccination. Of the eligible patients, 621 (30.1%) consented to receive the vaccination during their ED visit. Physicians received prompts for 428 (68.9%) patients. When prompted, physicians declined to order the vaccine in 192 (30.9%) patients, while 222 (10.8%) of eligible patients actually received the vaccine. The computerized reminder system increased vaccination rate from a baseline of 38.8% to 45.4%. Vaccination during the ED visit was associated younger age (OR: 0.972, CI: 0.953-0.991), Caucasian race (OR: 0.329, CI: 0.241 0.448), and longer ED boarding times (OR: 1.039, CI: 1.013-1.065). CONCLUSION: The integrated informatics solution seems to be a feasible and sustainable model to increase vaccination rates in a challenging ED environment. PMID- 21784118 TI - Subchronic toxicity evaluation of aloesin. AB - Aloesin, an aromatic chromone present in various Aloe species, shows potential beneficial effects on indices related to pre-diabetic states, including metabolic syndrome. Aloesin may have utility as a functional food ingredient. As part of a program to assess its safety, aloesin was administered by oral gavage at doses of 250, 500, and 1000 mg/kg body weight/day to groups of 10 male and 10 female Sprague-Dawley rats for 90 days. Treatment was not associated with mortality and appeared to be well tolerated. There were no toxicologically or statistically significant changes in body weight gain or in feed and water consumption. A few statistically significant changes in serum biochemistry and hematology parameters were noted, but all were mild in nature, were confined to one sex, and/or did not show dose-response relationships. Urinalysis revealed dose-dependent increases in urinary ketones. This result was due to the presence of aloesin, which possesses ketone functionalities, in the urine and not due to a systemic effect. There was no effect of treatment on organ weights or on the results of the histopathological examinations. The no-observed-adverse-effect level was considered to be 1000 mg/kg body weight/day, the highest dose tested. The results support potential use of aloesin as a functional food ingredient. PMID- 21784119 TI - Endogenous allergen upregulation: transgenic vs. traditionally bred crops. AB - The safety assessment for transgenic food crops currently includes an evaluation of the endogenous allergy potential (via serum IgE screening) when the non transgenic counterpart is a commonly allergenic food. The value of this analysis in the safety assessment of transgenic crops, especially with reference to recent requests to quantify individual allergen concentrations in raw commodities, is examined. We conclude that the likelihood of upregulating an endogenous allergen due to transgenesis is no greater than from traditional breeding which has a history of safety and is largely unregulated. The potential consequences of upregulating an endogenous allergen are also unclear. PMID- 21784120 TI - Phenolic composition and biological activities of Juniperus drupacea Labill. berries from Turkey. AB - The present study was designed to define the phenolic profile and the biological potential of berries methanol extract of Juniperus drupacea Labill. from Turkey. The total phenolic content (Folin-Ciocalteau assay) was 48.06+/-0.99mgGAE/g extract. The HPLC-DAD-ESI-MS analysis allowed the determination of the complete phenolic profile of J. drupacea berries. Phenolic acids represented more than 60% of the total phenolics, and tyrosol was the major one (1324+/-0.64MUg/g extract); within the flavonoids amentoflavone was detected as the main constituent (927+/ 0.35MUg/g extract). The extract exhibited good antioxidant properties, as determined by different in vitro models: DPPH test (IC(50) 0.38+/-0.02mg/mL), reducing power (12.63+/-0.14ASE/mL), Fe(2+) chelating ability (IC(50) 2.26+/ 0.06mg/mL), and TBA test (IC(50) 2.47+/-1.13MUg/mL). Cytotoxicity against Artemia salina was highlighted (LC(50) 489.47+/-27.8MUg/mL), and a significant decrease (p?0.05; p?0.01) in HepG2 cells viability was observed at the higher concentrations (5-10MUg/mL). The extract displayed good antibacterial activity towards Gram-positive bacteria and in particular Staphylococcus aureus was the most susceptible strain (MIC 78.12MUg/mL). PMID- 21784121 TI - Antimutagenic effect of Phellinus rimosus (Berk) Pilat against chemical induced mutations of histidine dependent Salmonella typhimurium strains. AB - Mutations are one of the important factors contributing to oncogenesis. Somatic mutations have been detected in oncogenes and tumor suppressor genes in various types of cancers. In vitro antimutagenic activity of ethyl acetate extract of macro fungus, Phellinus rimosus was evaluated by Ames' mutagenicity assay. The effect was evaluated against the direct acting mutagens (sodium azide, N-methyl N'-nitro-N-nitrosoguanidine, doxorubicin and 4-nitro-o-phenylenediamine) and mutagen needing activation (2-acetyl aminofluorine, and benzo[a]pyrene). The extract was significantly (p<0.05) and dose dependently effective against direct acting mutagens and mutagen needing activation. Among the antimutagenic activity against directly acting mutagens, effect was found to be highest against doxorubicin-induced mutation. The antimutagenic effect of the extract against indirect acting mutagen in the presence of mammalian metabolic activation system was also found to be significant (p<0.01). The background bacterial growth and number of revertant colonies in the extract alone treated plate with or with out metabolic activator was almost same as that of spontaneous revertants. This indicated the non-toxic nature of the extract. The effect was partially ascribed to the antioxidant activity. The results of the study suggest the possible antitumor mechanisms of P. rimosus. PMID- 21784122 TI - Heparin affects the interaction of kininogen on endothelial cells. AB - In the plasma kallikrein-kinin system, it has been shown that when plasma prekallikrein (PK) and high molecular weight kininogen (HK) assemble on endothelial cells, plasma kallikrein (huPK) becomes available to cleave HK, releasing bradykinin, a potent mediator of the inflammatory response. Because the formation of soluble glycosaminoglycans occurs concomitantly during the inflammatory processes, the effect of these polysaccharides on the interaction of HK on the cell surface or extracellular matrix (ECM) of two endothelial cell lines (ECV304 and RAEC) was investigated. In the presence of Zn(+2), HK binding to the surface or ECM of RAEC was abolished by heparin; reduced by heparan sulfate, keratan sulfate, chondroitin 4-sulfate or dermatan sulfate; and not affected by chondroitin 6-sulfate. By contrast, only heparin reduced HK binding to the ECV304 cell surface or ECM. Using heparin-correlated molecules such as low molecular weight dextran sulfate, low molecular weight heparin and N-desulfated heparin, we suggest that these effects were mainly dependent on the charge density and on the N-sulfated glucosamine present in heparin. Surprisingly, PK binding to cell- or ECM-bound-HK and PK activation was not modified by heparin. However, the hydrolysis of HK by huPK, releasing BK in the fluid phase, was augmented by this glycosaminoglycan in the presence of Zn(2+). Thus, a functional dichotomy exists in which soluble glycosaminoglycans may possibly either increase or decrease the formation of BK. In conclusion, glycosaminoglycans that accumulated in inflammatory fluids or used as a therapeutic drug (e.g., heparin) could act as pro- or anti-inflammatory mediators depending on different factors within the cell environment. PMID- 21784123 TI - Characterization of the betagamma-crystallin domains of betagamma-CAT, a non-lens betagamma-crystallin and trefoil factor complex, from the skin of the toad Bombina maxima. AB - betagamma-CAT is a naturally existing 72-kDa complex of a non-lens betagamma crystallin (alpha-subunit, CAT-alpha) and a trefoil factor (beta-subunit, CAT beta) that contains a non-covalently linked form of alphabeta(2) and was isolated from the skin secretions of the toad Bombina maxima. The N-terminal region of CAT alpha (CAT-alphaN, residues 1-170) contains two betagamma-crystallin domains while the C-terminal region (CAT-alphaC) has sequence homology to the membrane insertion domain of the Clostridium perfringens epsilon toxin. To examine the biochemical characteristics of the betagamma-crystallin domains of betagamma-CAT, CAT-alphaN, CAT-alphaC and CAT-beta were expressed in Escherichia coli. Co immunoprecipitation of the naturally assembled betagamma-CAT confirmed that the CAT-alpha and CAT-beta complex always exists. Furthermore, recombinant CAT-beta bound recombinant CAT-alphaN. Ca(2+)-binding motifs were identified in CAT alphaN, and recombinant CAT-alphaN was able to bind the calcium probe terbium. However, the conformation of CAT-alphaN was not significantly altered upon Ca(2+) binding. betagamma-CAT possesses strong hemolytic activity toward human erythrocytes, and treatment of erythrocytes with betagamma-CAT resulted in a rapid Ca(2+) influx, eventually leading to hemolysis. However, in the absence of extracellular Ca(2+), no significant hemolysis was detected, even though the binding and oligomerization of betagamma-CAT in the erythrocyte membrane was observed. Our data demonstrate the binding of CAT-beta (a trefoil factor) to CAT alphaN (betagamma-crystallin domains) and provide a basis for the formation of a betagamma-crystallin and trefoil factor complex in vivo. Furthermore, the betagamma-crystallin domains of betagamma-CAT are able to bind Ca(2+), and betagamma-CAT-induced hemolysis is Ca(2+) dependent. PMID- 21784124 TI - Binary function of mRNA. AB - Since the discovery of messenger RNA (mRNA) over half a century ago, the assumption has always been that the only function of mRNA is to make a protein. However, recent studies of prokaryotic and eukaryotic organisms unexpectedly show that some mRNAs may be functionally binary and have additional structural functions that are unrelated to their translation product. These findings imply that some of the phenotypic features of cells and organisms can also be binary, that is, they depend both on the function of a protein and the independent structural function of its mRNA. In this review, we will discuss this concept within the framework of multifunctional RNA molecules and the RNA World Hypothesis. PMID- 21784125 TI - Automating the search of molecular motor templates by evolutionary methods. AB - Biological molecular motors are nanoscale devices capable of transforming chemical energy into mechanical work, which are being researched in many scientific disciplines. From a computational point of view, the characteristics and dynamics of these motors are studied at multiple time scales, ranging from very detailed and complex molecular dynamics simulations spanning a few microseconds, to extremely simple and coarse-grained theoretical models of their working cycles. However, this research is performed only in the (relatively few) instances known from molecular biology. In this work, results from elastic network analysis and behaviour-finding methods are applied to explore a subset of the configuration space of template molecular structures that are able to transform chemical energy into directed movement, for a fixed instance of working cycle. While using methods based on elastic networks limits the scope of our results, it enables the implementation of computationally lightweight methods, in a way that evolutionary search techniques can be applied to discover novel molecular motor templates. The results show that molecular motion can be attained from a variety of structural configurations, when a functional working cycle is provided. Additionally, these methods enable a new computational way to test hypotheses about molecular motors. PMID- 21784126 TI - Interactions of the mineralocorticoid receptor--within and without. AB - The mineralocortoid receptor (MR) regulates salt homeostasis in the kidneys and plays a range of other roles in the heart, vasculature, brain and adipose tissue. It interacts with both mineralocorticoids and glucocorticoids to mediate transcription of target genes. The ability of the MR to exert tissue- and ligand specific effects relies on its interactions with a range of binding partners, including the chaperone proteins, coregulators, other transcription factors, DNA and modifying proteins. Interactions within the domains of the MR also modulate the overall transcriptional complex. This review will discuss the current understanding of interactions involving the MR and highlight their relevance to ligand- or tissue-specificity as well as their suitability as therapeutic targets. PMID- 21784127 TI - Aldosterone, mineralocorticoid receptor, and heart failure. AB - Several large clinical studies have demonstrated the important benefit of mineralocorticoid receptor (MR) antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. Aldosterone adjusts the hydro-mineral balance in the body, and thus participates decisively to the control of blood pressure. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical and experimental studies indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels. These deleterious effects include cardiac and renal fibrosis, inflammation and vascular remodeling. It is important to underscore that these effects are due to elevated MR activation that is inadequate for the body salt requirements. Aldosterone is generally considered as the main ligand of MR. However, this is a matter of debate especially in heart. Complexity arises from the glucocorticoids with circulating concentrations much higher than those of aldosterone, and the fact that the MR has a high affinity for 11beta-hydroxyglucocorticoids. Nevertheless, the beneficial effects of MR inhibition in patients with heart failure emphasize the importance of this receptor in cardiovascular tissue. Diverse experimental models and strains of transgenic mice have allowed to dissect the effects of aldosterone and the MR in the heart. Taken together experimental and clinical data clearly highlight the deleterious cardiovascular effects of MR stimulation. PMID- 21784128 TI - Circadian nature of immune function. AB - The primary physiological role of the circadian system is to synchronize and coordinate organ systems, particularly in response to dynamics in the environment. The immune system is under direct circadian control by systemic cues and molecular clocks within immune cells. The master circadian pacemaker called the suprachiasmatic nucleus (SCN) conveys timing information to the immune system through endocrine and autonomic pathways. These signals promote phase coherence of peripheral clocks in the immune system, and also govern daily variations in immune function. The coordination of immune response may compose an anticipatory state for optimal immune response. Interactions between circadian and immune systems are bidirectional, in that immune factors can modulate phasing of circadian clocks. Circadian disruption, such as environmental desynchronization and/or anomalous molecular clock functions, may lead to lack of system coordination, and particular vulnerabilities to infection and disease may develop. PMID- 21784129 TI - Tumor necrosis factor-alpha activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor alpha. AB - The pro-inflammatory cytokine TNF-alpha and the female hormone estrogen have been implicated in the pathophysiology of two common gynecological diseases, endometriosis and endometrial adenocarcinoma. Here we describe a novel capacity of TNF-alpha to activate ER signaling in endometrial epithelial cells. TNF-alpha induced luciferase expression in the absence and presence of estradiol and also augmented expression of the estrogen-regulated genes c-fos, GREB1, and progesterone receptor. Furthermore, TNF-alpha mediated ER transcriptional activity is dependent on the Extracellular Regulated Kinase (ERK) 1/2 pathway. Co treatment with a pure ER antagonist resulted in an inhibition of this TNF-alpha induced ERE luciferase activity and gene expression, demonstrating that this cytokine signals through ERs. Additional investigations confirmed that TNF-alpha acts specifically via ERalpha. Taken together, these data provide a rationale for the potential use of inhibitors of TNF-alpha and estrogen production/activity in combination for the treatment of endometrial pathologies. PMID- 21784130 TI - Mitochondrial signals drive insulin secretion in the pancreatic beta-cell. AB - beta-Cell nutrient sensing depends on mitochondrial function. Oxidation of nutrient-derived metabolites in the mitochondria leads to plasma membrane depolarization, Ca(2+) influx and insulin granule exocytosis. Subsequent mitochondrial Ca(2+) uptake further accelerates metabolism and oxidative phosphorylation. Nutrient activation also increases the mitochondrial matrix pH. This alkalinization is required to maintain elevated insulin secretion during prolonged nutrient stimulation. Together the mitochondrial Ca(2+) rise and matrix alkalinization assure optimal ATP synthesis necessary for efficient activation of the triggering pathway of insulin secretion. The sustained, amplifying pathway of insulin release also depends on mitochondrial Ca(2+) signals, which likely influence the generation of glucose-derived metabolites serving as coupling factors. Therefore, mitochondria are both recipients and generators of signals essential for metabolism-secretion coupling. Activation of these signaling pathways would be an attractive target for the improvement of beta-cell function and the treatment of type 2 diabetes. PMID- 21784131 TI - Androgen receptor-mediated gene repression. AB - Androgens have an essential role in inducing the genetic program for masculinization during development. Androgens mediate their effect through the androgen receptor (AR), a ligand-controlled transcription factor and regulator of rapid signaling. Inactivated AR results in complete feminization. Androgens are also essential in later life for reproduction, behavior, muscle development, breast, and prostate growth. In general, androgens inhibit breast and promote prostate growth. In the latter context the AR is a major drug target. On the one hand, many insights have been obtained how the AR mediates gene activation on a molecular level. Gene activation is mediated by a battery of factors including coactivators, chromatin remodeling complex proteins and transcription factors which either directly or indirectly interact with the AR at DNA binding sites. On the other hand, there are important AR target genes that are repressed by androgen-bound AR. However, the underlying molecular mechanisms are poorly understood although genes repressed by AR are key factors involved in cell proliferation and invasion. Here, we summarize molecular mechanisms of AR mediated gene repression, thereby differentiating between direct and indirect DNA/chromatin recruitment and between genomic and non-genomic effects. PMID- 21784132 TI - Antagonism of cannabinoid 1 receptors reverses the anxiety-like behavior induced by central injections of corticotropin-releasing factor and cocaine withdrawal. AB - The endocannabinoid (eCB) system is an important regulator of the stress response and mediates several stress-related behaviors, including anxiety. Despite anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), few data exist that address functional interactions between these systems. Accordingly, we examined the effects of the CB1 receptor antagonist, AM251, on behavioral anxiety induced by (1) exogenous CRF, and (2) withdrawal from chronic cocaine exposure (mediated by CRF). After behavioral testing, we collected blood and assessed plasma corticosterone levels. In Experiment 1, male Long-Evans rats were pretreated with AM251 (0, 10, 100, or 200 MUg, i.c.v.), followed by CRF (0 or 0.5 MUg, i.c.v.), before testing for anxiety-like behavior in the elevated plus maze (EPM). In Experiment 2, rats were exposed to cocaine (20 mg/kg, i.p.) or saline for 14 consecutive days. Forty eight hours following cocaine exposure, rats were pretreated with AM251 (0, 10, or 100 MUg, i.c.v.) and tested in the EPM. AM251 produced an anxiogenic response at the highest dose, but reversed the behavioral anxiety induced by CRF and withdrawal from chronic cocaine in a dose-dependent manner. AM251 also increased plasma corticosterone levels, but did so irrespective of CRF treatment or cocaine preexposure. Our findings suggest that the anxiogenic effects of CRF and cocaine withdrawal are mediated, at least in part, by CB1 receptor transmission, and provide evidence in support of eCB-CRF interactions that are independent of the hypothalamic-pituitary-adrenal axis. PMID- 21784134 TI - Nerve growth factor augments neuronal responsiveness to noradrenaline in cultured dorsal root ganglion neurons of rats. AB - Increasing evidence indicates that both the nerve growth factor (NGF) and adrenergic systems play a very important role in the development of nociception. However, there is little information concerning the functional interactions between these two systems in the dorsal root ganglion (DRG). The present study tested the hypothesis that NGF could affect neuronal responsiveness to noradrenaline (NA) on the nociceptive DRG neurons, thus enhancing the nociceptive signals. To investigate this issue, spontaneous action potentials were recorded in cultured DRG neurons using current-clamp recording. When NGF (50 ng/ml, 24 h) was administered in the neuronal cultures, the neuronal firing response to NA (10 MUM) was augmented in TrkA-positive neurons (3.02+/-0.28 Hz with NGF treatment vs. 1.36+/-0.14 Hz in control, P<0.05), indicating that chronic NGF treatment significantly enhanced the neuronal response to NA. Pretreatment of neurons with either the alpha-adrenergic receptor (AR) antagonist phentolamine (100 MUM) or alpha1-AR antagonist prazosin (50 MUM) significantly inhibited the enhanced firings of DRG neurons induced by NA. In addition, treatment of neuronal cultures with NGF (50 ng/ml, 24 h) induced a two-fold increase in alpha1b-AR expression, as detected with real-time reverse transcription PCR (RT-PCR) and Western blots, but had no effect on alpha2-AR expression. These observations indicate that NGF augmented neuronal responsiveness to NA in DRG neurons via increasing alpha1b-AR expression, and this could contribute to the development of pain sensitization. PMID- 21784133 TI - Serotonergic inputs to FoxP2 neurons of the pre-locus coeruleus and parabrachial nuclei that project to the ventral tegmental area. AB - The present study demonstrates that serotonin (5-hydroxytryptamine, 5-HT) containing axons project to two sets of neurons in the dorsolateral pons that have been implicated in salt appetite regulation. These two neuronal groups are the pre-locus coeruleus (pre-LC) and a region in the parabrachial nucleus termed the external lateral-inner subdivision (PBel-inner). Neurons in both regions constitutively express the transcription factor Forkhead protein2 (FoxP2), and become c-Fos activated after prolonged sodium depletion. They send extensive projections to the midbrain and forebrain, including a strong projection to the ventral tegmental area (VTA)-a reward processing site. The retrograde neuronal tracer cholera toxin beta-subunit (CTb) was injected into the VTA region; this was done to label the cell bodies of the pre-LC and PBel-inner neurons. After 1 week, the rats were killed and their brainstems processed by a triple-color immunofluorescence procedure. The purpose was to determine whether the CTb labeled pre-LC and PBel-inner neurons, which also had FoxP2 immunoreactive nuclei, received close contacts from 5-HT axons. Neurons with these properties were found in both sites. Since the origin of this 5-HT input was unknown, a second set of experiments was carried out in which CTb was injected into the pre LC or lateral PB. One week later, the rats were perfused and the brainstems from these animals were analyzed for the presence of neurons that co-contained CTb and tryptophan hydroxylase (synthetic enzyme for 5-HT) immunoreactivity. Co-labeled neurons were found mainly in the area postrema and to a lesser degree, in the dorsal raphe nucleus. We propose that the 5-HT inputs to the pre-LC and PBel inner may modulate the salt appetite-related functions that influence the reward system. PMID- 21784135 TI - H2S releasing aspirin protects amyloid beta induced cell toxicity in BV-2 microglial cells. AB - beta-Amyloid (Abeta) plaques are characteristic hallmarks of Alzheimer's disease. In the present study, we examined the neuroprotective effects of S-aspirin, a hydrogen sulfide (H(2)S)-releasing aspirin, on Abeta-induced cell toxicity. 3 [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay showed that S-aspirin, but not aspirin, significantly increased cell viability in BV-2 microglial cells, indicating that S-aspirin may protect cells against injury via releasing H(2)S. S-aspirin at 2.5-10 MUM significantly increased cell viability and decreased lactate dehydrogenase release in Abeta-treated BV-2 microglial cells. Western blotting analysis showed that S-aspirin suppressed the protein expression levels of cyclooxygenase-2 and growth arrest DNA damage (GADD). These data suggest that S-aspirin may protect microglial cells by inhibition of Abeta induced inflammation and cell cycle re-entry. To study whether S-aspirin can protect mitochondria function, mitochondria membrane potential was measured with molecular probe JC-1. It was found that S-aspirin protected mitochondria from Abeta-induced loss of mitochondrial member potential. (DeltaPsim). In addition, S aspirin also prevented Abeta-induced activation of p38-mitogen activated protein kinase (MAPK). In conclusion, our results suggest that S-aspirin may protect microglial injury via inhibition of inflammation, prevention of mitochondria function, and stimulation of cell growth via stimulating p38-MAPK pathway. Our study may suggest that S-aspirin may have potential therapeutic value for the treatment of Alzheimer's disease. PMID- 21784136 TI - Distinct expression of Tim-3 during different stages of rat experimental autoimmune neuritis. AB - Experimental autoimmune neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Tim-3 had been identified as a Th1-specific marker negatively regulating autoimmunity or inflammatory diseases. Here we have studied by immunohistochemistry the spatiotemporal accumulation of Tim-3(+) cells in sciatic nerves of EAN rats, particularly focusing on its association with alternatively activated macrophages. Our results showed that time course of Tim-3(+) cell accumulation correlated positively with disease progression of EAN; but distinct major cellular resources of Tim-3 were observed at different disease stages of EAN: during the early phase of EAN, the main cellular resource were T cells, but at the peak and during recovery phase of EAN, Tim-3 was mostly expressed on CD68(+) macrophages or CD163(+) cells. Further investigation suggested that accumulation of CD163(+) cells, particularly their relative abundances to activated macrophages at different time points, were in accordance with the recovery from EAN. Therefore, Tim3(+) cells might include a distinct macrophage population, which may be involved in anti-inflammatory effect and recovery from EAN. PMID- 21784137 TI - Hypoglycemic effects and constituents of the barks of Cyclocarya paliurus and their inhibiting activities to glucosidase and glycogen phosphorylase. AB - The various fractions of the barks of Cyclocarya paliurus were systematically tested for hypoglycemic effects in alloxan-induced diabetic rats. The results showed that the chloroform fraction of the 75% EtOH extract of the barks of this plant exhibited significant blood sugar reducing activity, most of which were significantly higher than that of positive-drug metformin hydrochloride. A new compound, together with nine known compounds, was isolated from the most active fraction. The structure elucidation was based on spectroscopic methods, including two-dimensional NMR experiments (1H-1H COSY, HMQC, and HMBC). All of the isolates were evaluated for their alpha-glycosidase and glycogen phosphorylase inhibitory activities. PMID- 21784138 TI - Basal transcription of the human TBX3 gene, a key developmental regulator which is overexpressed in several cancers, requires functional NF-Y and Sp1 sites. AB - TBX3 is a member of the T-box family of genes that encode developmentally important transcription factors. Mutations resulting in decreased levels of functional TBX3 lead to Ulnar-Mammary Syndrome and increased levels of TBX3 have been linked to several cancers. To understand the mechanisms regulating TBX3 expression we have previously cloned the 5'-flanking region of the human TBX3 gene and here we describe cis-elements required for its basal transcription. Using site-directed mutagenesis, luciferase reporter assays and in vitro and in vivo DNA binding experiments we identify a Sp1 element and two CCAAT boxes to be essential for basal TBX3 promoter activity. Our results are consistent with reports that these sites are necessary for efficient basal transcription in genes which lack TATA boxes or an Initiator which we show to be the case for TBX3. PMID- 21784139 TI - Molecular cloning and expression of a cucumber (Cucumis sativus L.) heme oxygenase-1 gene, CsHO1, which is involved in adventitious root formation. AB - Our previous work showed that in cucumber (Cucumis sativus), auxin rapidly induces heme oxygenase (HO) activity and the product of HO action, carbon monoxide (CO), then triggers the signal transduction events leading to adventitious root formation. In this study, the cucumber HO-1 gene (named as CsHO1) was isolated and sequenced. It contains four exons and three introns and encodes a polypeptide of 291 amino acids. Further results show that CsHO1 shares a high homology with plant HO-1 proteins and codes a 33.3 kDa protein with a 65 amino transit peptide, predicting a mature protein of 26.1 kDa. The mature CsHO1 was expressed in Escherichia coli to produce a fusion protein, which exhibits HO activity. The CsHO1:GFP fusion protein was localized in the chloroplast. Related biochemical analyses of mature CsHO1, including Vmax, Km, Topt and pHopt, were also investigated. CsHO1 mRNA was found in germinating seeds, roots, stem, and especially in leaf tissues. Several well-known adventitious root inducers, including auxin, ABA, hemin, nitric oxide donor sodium nitroprusside (SNP), CaCl(2), and sodium hydrosulfide (NaHS), differentially up-regulate CsHO1 transcripts and corresponding protein levels. These results suggest that CsHO1 may be involved in cucumber adventitious rooting. PMID- 21784140 TI - Gene expression of biomarkers of nephrotoxicity in F344 rats co-exposed to melamine and cyanuric acid for seven days. AB - A number of studies have demonstrated that co-exposure to low levels of melamine and cyanuric acid elicits renal toxicity due to the formation of melamine cyanurate crystals in the kidney nephrons. In this work, we investigated if co exposure of rats to these compounds leads to alterations in the expression of the genes encoding kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), clusterin, osteopontin, and neutrophil gelatinase-associated lipocalin/lipocalin 2 (NGAL), which have been proposed as urinary biomarkers for nephrotoxicity. Six-week-old male and female F344 rats were fed ad libitum a diet fortified with 0 (control), 7, 23, 69, 229, or 694 ppm melamine and cyanuric acid (co-exposure groups), 1388 ppm melamine, or 1388 ppm cyanuric acid for seven days. Histopathology and clinical chemistry examination indicated marked toxicity only in the animals exposed to the two highest combined doses of melamine and cyanuric acid. Consistent with these observations, quantitative real-time polymerase chain reaction analysis of kidney tissue indicated increased expression of all genes analyzed relative to the control in both male and female rats fed daily with 229 or 694 ppm melamine and cyanuric acid. Exposure to lower levels of both compounds or to the individual compounds did not induce gene expression changes. These data indicate that quantifying the expression levels of the selected biomarker genes constitutes a useful endpoint to assess the combined toxicity of melamine and cyanuric acid in both male and female rats. PMID- 21784141 TI - European Paediatric Formulation Initiative's (EuPFI) 2nd conference commentary- Formulating better medicines for children. PMID- 21784142 TI - Evaluation of gastrointestinal motility directly from human pharmacokinetic data. AB - Since the 1980s, a considerable body of research has been dedicated to the development of in silico models for the prediction of human pharmacokinetic data based on absorption in a series of discreet intestinal compartments. While some of these models have been successfully used to predict future pharmacokinetic results or to explain previous results, evidence for compartmental absorption in individual pharmacokinetic data has not been published. This article presents in vivo evidence for compartmental drug absorption along with an empirical method for determining gastrointestinal (GI) tract location during absorption, using individual time-absorption rate profiles. Comparisons are shown between the absorption rate profiles and corresponding gamma scintigraphy images, to demonstrate the reliability of the GI position assignments and a hypothesis is proposed to explain the appearance of peaks and troughs in absorption rate profiles. Absorption rate analysis is shown to be a reliable and low cost tool for interpretation of unexpected pharmacokinetic data. Pharmaceutical scientists should find it useful for understanding the in vivo performance of drug products and it is hoped this will result in fewer delays and lower costs during drug development programs. PMID- 21784143 TI - Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bu-yang Huan-wu decoction (BHD) is a famous traditional Chinese medicine formula that has been used clinically in Asia to treat stroke-induced disability for centuries, but the underlying neuroprotective mechanisms are not fully understood. AIM OF THE STUDY: In this study, we aim to investigate the mechanisms of action using an integrative neurofunctional and broad genomics approach. MATERIALS AND METHODS: Male ICR mice were subjected to an acute ischemic stroke by inducing a middle cerebral ischemic/reperfusion (CI/R) injury. To examine whether BHD could extend the lifespan of mice with a stroke, we used oral administration of BHD (0.5 and 1.0g/kg) twice daily starting from 2h after ischemia and compared this with vehicle control treatments, recombinant tissue-type plasminogen activator (rt-PA, 10mg/kg, i.v.), and MK-801 (0.2mg/kg, i.p.). An integrative neurofunctional and genomic approach was performed to elucidate the underlying molecular mechanisms of BHD. RESULTS: More than 80% of the mice died within 2 days after stroke induction in the vehicle control treatment group. However, the survival rates and life-spans of mice treated with BHD, rt-PA and MK-801 were significantly enhanced as compared to the vehicle-treated CI/R group in all three cases. Mice treated with BHD (1.0g/kg) showed the greatest protective effect across all groups. BHD successfully restored brain function, ameliorated the cerebral infarction, and significantly improved the neurological deficits of the mice with a stroke. BHD also reduced inflammation, oxidative stress, and apoptosis, as well as improved neurogenesis. The molecular impacts of BHD were assessed by genome-wide transcriptome analysis using brains from the CI/R mice. The results showed a total of 377 ischemia induced probe-sets that were significantly influenced by BHD including 93 probe sets that were commonly more abundant in BHD-treated and sham mice, and another 284 ischemia-induced probe sets that were suppressed by BHD. Mining the functional modules and genetic networks of these 377 genes revealed a significant upregulation of neuroprotective genes associated with neurogenesis (6 genes) and nervous system development (9 genes), and a significant down-regulation of destructive genes associated with the induction of inflammation (14 genes), apoptosis (15 genes), angiogenesis (11 genes) and blood coagulation (7 genes) by BHD. CONCLUSIONS: Our results suggested that BHD is able to protect mice against stroke and extend lifespan primarily through a significant down-regulation of genes involved in inflammation, apoptosis, angiogenesis and blood coagulation, as well as an up-regulation of genes mediating neurogenesis and nervous system development. The changes in expression after treatment with BHD are beneficial after ischemic stroke. PMID- 21784144 TI - Rational design and optimization of downstream processes of virus particles for biopharmaceutical applications: current advances. AB - The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. PMID- 21784146 TI - Aerobic fitness is associated with lower proportions of senescent blood T-cells in man. AB - Senescent T-cells accumulate with age, lowering the naive T-cell repertoire and increasing host infection risk. As this response is likely to be influenced by certain lifestyle factors, we examined the association between aerobic fitness (VO(2max)) and the age-related accumulation of senescent T-cells. Blood lymphocytes from 102 healthy males (18-61 yr) were analyzed for KLRG1, CD57, CD28, CD45RA, CD45RO surface expression on CD4+ and CD8+ T-cells by 4-color flow cytometry. Advancing age (yr) was positively associated with the proportion (%) of senescent (KLRG1+/CD57+; KLRG1+/CD28-) CD4+ (B=1.00; 1.02) and CD8+ (B=0.429; 1.02) T-cells and inversely associated with naive (KLRG1-/CD28+) CD4+ (B=-1.000) and CD8+ (B=-0.993) T-cells. VO(2max) was inversely associated with senescent CD4+ (B=-0.97) and CD8+ (B=-0.240). Strikingly, age was no longer associated with the proportions of senescent or naive T-cells after adjusting for VO(2max), while the association between VO(2max) and these T-cell subsets withstood adjustment for age, BMI and percentage body fat. Ranking participants by age-adjusted VO(2max) revealed that the highest tertile had 17% more naive CD8+ T-cells and 57% and 37% less senescent CD4+ and CD8+ T-cells, respectively, compared to the lowest tertile. VO(2max) was not associated with latent cytomegalovirus (CMV), Epstein-Barr virus (EBV) or herpes simplex virus-1 (HSV-1) infection, indicating that the moderating associations of VO(2max) were not confounded by persistent viral infections. This is the first study to show that aerobic fitness is associated with a lower age-related accumulation of senescent T-cells, highlighting the beneficial effects of maintaining a physically active lifestyle on the aging immune system. PMID- 21784145 TI - Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. AB - Observational studies have linked lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and higher omega-6 (n-6) PUFAs with inflammation and depression, but randomized controlled trial (RCT) data have been mixed. To determine whether n-3 decreases proinflammatory cytokine production and depressive and anxiety symptoms in healthy young adults, this parallel group, placebo-controlled, double-blind 12 week RCT compared n-3 supplementation with placebo. The participants, 68 medical students, provided serial blood samples during lower-stress periods as well as on days before an exam. The students received either n-3 (2.5 g/d, 2085 mg eicosapentaenoic acid and 348 mg docosahexanoic acid) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Compared to controls, those students who received n-3 showed a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms, without significant change in depressive symptoms. Individuals differ in absorption and metabolism of n-3 PUFA supplements, as well as in adherence; accordingly, planned secondary analyses that used the plasma n 6:n-3 ratio in place of treatment group showed that decreasing n-6:n-3 ratios led to lower anxiety and reductions in stimulated IL-6 and tumor necrosis factor alpha (TNF-alpha) production, as well as marginal differences in serum TNF-alpha. These data suggest that n-3 supplementation can reduce inflammation and anxiety even among healthy young adults. The reduction in anxiety symptoms associated with n-3 supplementation provides the first evidence that n-3 may have potential anxiolytic benefits for individuals without an anxiety disorder diagnosis. ClinicalTrials.gov identifier: NCT00519779. PMID- 21784147 TI - The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein. AB - The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25MUg/ml) decreased nitric oxide ((*)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10MUg/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (O(2)(*-)) production. Gene expression for arginase-1, nuclear factor kappaB (NF-kappaB), interleukin-8, and tissue factor (TF) increased within 4h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24h. Therefore, in addition to modulating (*)NO bioavailability by stimulating O(2)(*-) production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, MUg/ml) before (not after) SAA treatment ameliorated the Ca(2+) influx and O(2)(*-) production; decreased TF, NF-kappaB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (*)NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium. PMID- 21784148 TI - Reduced expression of MAPK/ERK genes in perinatal arsenic-exposed offspring induced by glucocorticoid receptor deficits. AB - Changes within the glucocorticoid receptor (GR) cellular signaling pathway were evaluated in adolescent mice exposed to 50 ppb arsenic during gestation. Previously, we reported increased basal plasma corticosterone levels, decreased hippocampal GR levels and deficits in learning and memory performance in perinatal arsenic-exposed mice. The biosynthesis of members of the mitogen activated protein kinase (MAPK) signaling pathway, known to be involved in learning and memory, is modulated by the binding of GR to glucocorticoid response elements (GREs) in the gene promoters. Two genes of the MAPK pathway, Ras and Raf, contain GREs which are activated upon binding of GRs. We evaluated the activity of GRs at Ras and Raf promoters using chromatin immunoprecipitation and real-time PCR and report decreased binding of the GR at these promoters. An ELISA based GR binding assay was used to explore whether this decreased binding was restricted to in vivo promoters and revealed no differences in binding of native GR to synthetic GREs. The decreased in vivo GR binding coincides with significantly decreased mRNA levels and slight reductions of protein of both H Ras and Raf-1 in perinatally arsenic-exposed mice. Nuclear activated extracellular-signal regulated kinase (ERK), a downstream target of Ras and Raf, whose transcriptional targets also play an important role in learning and memory, was decreased in the hippocampus of arsenic-exposed animals when compared to controls. GR-mediated transcriptional deficits in the MAPK/ERK pathway could be an underlying cause of previously reported learning deficits and provide the link to arsenic-induced deficiencies in cognitive development. PMID- 21784150 TI - Interaction of an amphiphilic squalenoyl prodrug of gemcitabine with cellular membranes. AB - We have designed an amphiphilic prodrug of the anticancer agent gemcitabine (dFdC), by covalent coupling to squalene. This bioconjugate, which self-assembled into nanoparticles (NPs) in water, was previously found to display an impressive anticancer activity both in vitro and in vivo. The present study aims to investigate the impact of SQdFdC nanoparticles on cellular membranes. MTT assays showed that, in the nanomolar range, squalenoyl gemcitabine (SQdFdC) was slightly less active than dFdC on a panel of human cancer cell lines, in vitro. However, above 10 MUmol L(-1) SQdFdC was considerably more cytotoxic than dFdC. Contrarily to its parent drug, SQdFdC also induced cell lysis in a few hours, as evidenced by LDH release assays. Erythrocytes were used as an experimental model insensitive to the antimetabolic activity of dFdC to further investigate the putative membrane-related cytotoxic activity of SQdFdC. The bioconjugate also induced hemolysis in a time- and dose-dependent fashion, unlike squalene or dFdC, which clearly proved that SQdFdC could permeabilize cellular membranes. Structural X-ray diffraction and calorimetry studies were conducted in order to elucidate the mechanism accounting for these observations. They confirmed that SQdFdC could be transferred from NPs to phospholipid bilayers and that the insertion of the prodrug within model membranes resulted in the formation of nonlamellar structures, which are known to promote membrane leakage. As a whole, our results suggested that due to its amphiphilic nature, the cell uptake of SQdFdC resulted in its insertion into cellular membranes, which could lead to the formation of nonlamellar structures and to membrane permeation. Whether this mechanism could be the source of toxicity in vivo, however, remains to be established, since preclinical studies have clearly proven that squalenoyl gemcitabine displayed a good toxicity profile. PMID- 21784151 TI - Comparison of tissue distribution of a PEGylated Radix Ophiopogonis polysaccharide in mice with normal and ischemic myocardium. AB - PEGylation was found to be a promising approach to improve the anti-myocardial ischemic activity of Radix Ophiopogonis polysaccharide (ROP) by prolonging its retention in plasma. To fully evaluate the effectiveness and safety of this strategy, the tissue distribution of PEGylated ROP was investigated in this study. A long-circulating and bioactive PEGylated ROP with 1.04 mol 20-kDa mPEG per mol ROP ((1.04)P(20k)-R) was prepared by a moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG. Its tissue distribution in mice with normal and ischemic myocardium was studied and compared with ROP. The results show that the descending order of tissue distribution of (1.04)P(20k) R ranked by AUC was kidney, lung, heart, liver, and brain in normal mice and kidney ~ lung ~ heart, liver and brain in mice with myocardial ischemia. With the exception of the heart, myocardial ischemia did not cause obvious changes in the distribution of (1.04)P(20k)-R in the other tissues studied. Owing to the enhanced permeability and retention effect caused by ischemia, the AUC of (1.04)P(20k)-R in ischemic hearts was approximately 1.6-fold greater than in normal hearts. Compared with ROP in rats, the distribution tendency of (1.04)P(20k)-R in mouse kidney, brain, and lung was reduced by approximately 42, 1.6, and 1.3 times, respectively, whereas it was increased by approximately 1.3 fold in the liver. The results of this study are highly instructive for the further pharmaceutical development of PEGylated ROP. PMID- 21784149 TI - Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets. AB - Amyloid-beta (Abeta) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-beta peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Abeta peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures. Our experiments revealed that both aorta and platelets contained Abeta peptides, predominately Abeta40. The source of the Abeta pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Abeta42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques. Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Abeta peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls. PMID- 21784152 TI - Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation. AB - Although antibody induction has gained in popularity, two agents are rarely combined. We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody/combination: alemtuzumab(C1H), Thymoglobulin(rATG), daclizumab(Dac), rATG+C1H, and rATG+Dac. CD4+ T-cells were suppressed by C1H and rATG+C1H, as well as by rATG and rATG+Dac but to a lesser extent. The effect lasted for 3 years at around 40% of baseline values. CD8+ T-cells showed a similar trend but had a more rapid recovery to baseline. CD19+ B-cells were effectively suppressed for 2 months by C1H and rATG+C1H, and abruptly returned to baseline afterwards; suppression by rATG(7 doses) was modest but lasted longer. A higher proportion of CD56+CD16+ Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type. Low CD25+ T-cells by 5-dose Dac returned to baseline around 6 months, whereas rATG+C1H and rATG+Dac showed persistent effect. CD4+CD25hi T-cells were suppressed by both rATG+C1H and rATG+Dac, but the initial proportion of CD4+CD25hi T-cells among CD4+ T-cells and CD4+CD25hi/CD4+CD25lo ratio were significantly higher in rATG+C1H. Overall, with extensive and persistent lymphocyte suppression by a simple administration of agents, single-dose rATG+C1H induction can be an alternative in renal transplantation. PMID- 21784153 TI - Evidence that erythrocyte DARC-positive phenotype can affect the GVHD occurrence after HLA-identical sibling HSCT. AB - Chemokine receptors are very important players in the pathogenesis of GVHD. The aim of this study is to test the hypothesis that the lack of expression of the DARC receptor on erythrocytes can affect the GVHD incidence. A total of 105 recipients and their 105 respective sibling donors of HSCs were enrolled in this study. All patients were evaluated for acute and chronic GVHD. The DARC genotyping assay was performed using the SSP-PCR method. The case-control analyses showed that the donor DARC 146G allele and T(-46)G(146) haplotype, coding for the FY2 version of DARC, are very significant in the GVHD paradigm because they are associated with the incidence of acute effects of this outcome in recipients (p=0.007, chi2=7.200). It seems that this version of DARC receptor is a powerful facilitator of chemokine transcytosis and subsequently leukocyte migration into GVHD target organs. PMID- 21784154 TI - Characterization of a PLP-overexpressing transgenic rat, a model for the connatal form of Pelizaeus-Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) most frequently results from duplication of the Plp1 gene with a correlation between disease severity and increasing copy number of the gene. Animal models of PMD, in particular those overexpressing the Plp1 gene, have been sought in attempts to provide systems in which potential therapies can be tested. Here we describe a rat model of the severe connatal form of PMD and provide a detailed characterization of its pathology and molecular biology, prior to testing therapeutic approaches. We determined the exact copy number of Plp1, and the resulting effects on RNA and protein expression. Distinct differences in myelin and disparate distributions of myelin protein markers in comparison to wild-type controls were observed. Altered expression of Plp1 also caused an increase in the apoptotic cell death of oligodendrocytes. These results provide the platform from which to test the effectiveness of in vivo therapies. PMID- 21784155 TI - Impairment of cognitive performance after reelin knockdown in the medial prefrontal cortex of pubertal or adult rats. AB - The glycoprotein reelin is important for embryonic neuronal migration. During adulthood reelin possibly acts as a modulator of synaptic plasticity. Several studies link reduced levels of reelin messenger RNA and protein to the pathophysiology of certain neuropsychiatric disorders. However, little is known about reelin's role for behavioral and cognitive functions in vivo. Therefore, the effect of a reelin knockdown in the medial prefrontal cortex (mPFC) of Wistar rats was examined in behavioral tasks related to neuropsychiatric disorders, such as schizophrenia. Rats treated with reelin antisense phosphothioate oligonucleotides in the mPFC during puberty or adulthood were tested for prepulse inhibition (PPI) of the acoustic startle reflex, spatial working memory, object recognition, and locomotor activity. Reelin quantification in the mPFC was assessed by Western blotting. Local reelin knockdown during puberty or adulthood induced (1) a PPI deficit as well as (2) an impairment of spatial working memory and object recognition following pubertal injections. Western blot analyses showed a distinct and highly selective reelin knockdown in the rats' mPFC. These results indicate that mPFC reelin signaling plays an important role in behavioral tasks with relevance to e.g. schizophrenia. Understanding reelin's function as a neurotrophic modulator of the extracellular matrix may help to achieve new insights into the etiology of certain neuropsychiatric diseases and foster prospective treatment strategies. PMID- 21784157 TI - Persistence of excitatory shaft synapses adjacent to newly emerged dendritic protrusions. AB - In the early postnatal hippocampus, the first synapses to appear on excitatory pyramidal neurons are formed directly on dendritic shafts. Very few dendritic spines are present at this time. By adulthood, however, the overwhelming majority of synapses are located at the tips of dendritic spines. Several models have been proposed to account for the transition from mostly shaft to mostly spinous synapses but none has been demonstrated conclusively. To investigate the cellular mechanism underlying the shaft-to-spinous synapse transition, we designed live imaging experiments to directly observe the dynamics of shaft and spinous synapses on developing dendrites. Immunofluorescent synaptic labeling of GFP filled neurons showed that the shaft-to-spinous synapse transition in dissociated culture mirrors that in vivo. Along with electron microscopy, the fluorescent labeling also showed that veritable shaft synapses are abundant in dissociated culture and that shaft synapses are frequently adjacent to spines or other dendritic protrusions, a configuration previously observed in vivo by others. We used live long-term time lapse confocal microscopy of GFP-filled dendrites and VAMP2-DsRed-labeled boutons to record the fate of shaft synapses and associated dendritic protrusions and boutons with images taken hourly for up to 31 continuous hours. Inspection of the time lapse imaging series revealed that shaft synapses can persist adjacent to either existing or newly grown dendritic protrusions. Alternatively, a shaft synapse bouton can redistribute to contact an adjacent dendritic protrusion. However, we never observed shaft synapses transforming themselves into spines or any type of dendritic protrusions. We conclude that repeated iterations of dendritic protrusion or spine outgrowth adjacent to shaft synapses is very likely to be a critical component of the shaft to-spinous synapse transition during CNS development. PMID- 21784158 TI - Three dimensional morphology of rabies virus studied by cryo-electron tomography. AB - The rabies virus (RABV) continues to be a worldwide health problem. RABV contains a single-stranded RNA genome that associates with the nucleoprotein N. The resulting ribonucleoprotein complex is surrounded by matrix protein M, lipid bilayer and glycoprotein G. RABV was reported to organize in bullet-like virions, but the role of each viral component in adopting this morphology is unclear. We present here a cryo-electron tomography study of RABV showing additional morphologies consisting in bullet-like virions containing a tubular, lipidic appendage having G-protein at its apex. In addition, there was evidence for an important fraction of pleomorphic particles. These pleomorphic forms differed in the amount of membrane-associated M-, M/N-protein providing interesting insight into its role in viral morphogenesis. In the absence of membrane-associated M-, M/N-protein viral morphology was almost spherical. Other images, showing straight membrane portions, correlate with the M-protein recruitment at the membrane independently of the presence of the G-protein. The viral membrane was found to contain a negative net charge indicating that M-, M/N-protein-membrane charge attraction drives this interaction. PMID- 21784156 TI - Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder. AB - Alterations of multiple G protein-mediated signaling pathways are detected in schizophrenia. G protein-coupled receptor kinases (GRKs) and arrestins terminate signaling by G protein-coupled receptors exerting a powerful influence on receptor functions. Modifications of arrestin and/or GRKs expression may contribute to schizophrenia pathology. Cortical expression of arrestins and GRKs was measured postmortem in control and subjects with schizophrenia or schizoaffective disorder. Additionally, arrestin/GRK expression was determined in elderly patients with schizophrenia and age-matched control. Patients with schizophrenia, but not schizoaffective disorder, displayed a reduced concentration of arrestin and GRK mRNAs and GRK3 protein. Arrestins and GRK significantly decreased with age. In elderly patients, GRK6 was reduced, with other GRKs and arrestins unchanged. A reduced cortical concentration of GRKs in schizophrenia (resembling that in aging) may result in altered G protein dependent signaling, thus contributing to prefrontal deficits in schizophrenia. The data suggest distinct molecular mechanisms underlying schizophrenia and schizoaffective disorder. PMID- 21784159 TI - Defining terminally differentiating B cell populations in rainbow trout immune tissues using the transcription factor XbpI. AB - The nature of antibody-secreting cells in the rainbow trout is poorly defined. Here we describe a flow cytometric approach to help differentiate between four major trout B cell subsets present during terminal B cell differentiation: resting B cells, activated B cells, plasmablasts, and plasma cells. To aid in the identification of B cell subsets, the LPS-inducible transcription factor XbpI-S was used as a marker. An antibody specific to the stable form of inducible transcription factor X-box protein I (XbpI) was generated, which detects XbpI-S protein expression for species within the Oncorhyncus genus, including rainbow trout. Combinatorial expression patterns, or B cell signatures, were established using antibodies to XbpI-S, Pax5, and IgM in combination with a proliferation marker. We show that XbpI-S induction in trout splenic B cells increases throughout a 10-day in vitro LPS-induction period and that increased XbpI-S expression correlates with increased HCmu expression in the cell. PBLs displayed a lower level of XbpI-S induction during this incubation period, compared to spleen. We conclude that trout B cells follow a highly conserved B cell activation pathway, albeit slower than what has been observed in mammalian species. The use of XbpI-S as an activation marker for trout humoral immune activation promises to be useful for future in vivo studies, and can be applied to a broad range of teleost species. PMID- 21784160 TI - Effects of dietary beta-1,3-glucan, chitosan or raffinose on the growth, innate immunity and resistance of koi (Cyprinus carpio koi). AB - This study was performed to determine the efficacy of three immunomodulators viz., beta-1,3 glucan, chitosan and raffinose on the innate immune response of koi, Cyprinus carpio koi. Kois were divided into 4 groups and each group was fed with diets supplemented with or without immunostimulant for 56 days. Total leukocyte counts (WBC), the non-specific humoral (lysozyme, alternative complement pathway and superoxide dismutase) and cellular (phagocytic capacity and respiratory burst activity) responses were determined and compared with controls (no supplement) after 7, 14, 21 and 56 days of feeding. The results of 8 weeks feeding trial showed that beta-1,3 glucan supplementation significantly enhanced koi growth, whereas other immunostimulants did not. Variation in the levels of responses was evident among different supplements. Compared with chitosan or raffinose, beta-1,3 glucan could maintain the immunity of kois at a higher level during the experimental period. However, continuously applying beta 1,3 glucan, chitosan or raffinose into the diet caused immunity fatigue in koi. No significant change in alternative complement pathway (ACP) activity was observed for any of the three supplements over the four different periods. After feeding for 14 days, the total leukocyte count (WBC), respiratory burst activity and superoxide dismutase (SOD) activity of the kois fed with chitosan or raffinose continuously remained relatively unchanged, subsequently decreased on the 56th day, but SOD did not. Meanwhile, lysozyme activity was no longer significantly higher on the 7th day, and for phagocytic capacity on the 14th day. After 56 days, these three immunostimulants groups also exhibited a decrease in the cumulative symptom rates compared to the controls when challenged with Aeromonas veronii. These results indicated that dietary intake containing immunostimulants could enhance the immune responses of koi and improve its resistance to infection by A.veronii. Especially supplementation with beta-1,3 glucan to the kois for 56 days showed considerable improvement in the growth, survival and immune response of the kois. PMID- 21784161 TI - A semi-automatic method to determine electrode positions and labels from gel artifacts in EEG/fMRI-studies. AB - The analysis of simultaneous EEG and fMRI data is generally based on the extraction of regressors of interest from the EEG, which are correlated to the fMRI data in a general linear model setting. In more advanced approaches, the spatial information of EEG is also exploited by assuming underlying dipole models. In this study, we present a semi automatic and efficient method to determine electrode positions from electrode gel artifacts, facilitating the integration of EEG and fMRI in future EEG/fMRI data models. In order to visualize all electrode artifacts simultaneously in a single view, a surface rendering of the structural MRI is made using a skin triangular mesh model as reference surface, which is expanded to a "pancake view". Then the electrodes are determined with a simple mouse click for each electrode. Using the geometry of the skin surface and its transformation to the pancake view, the 3D coordinates of the electrodes are reconstructed in the MRI coordinate frame. The electrode labels are attached to the electrode positions by fitting a template grid of the electrode cap in which the labels are known. The correspondence problem between template and sample electrodes is solved by minimizing a cost function over rotations, shifts and scalings of the template grid. The crucial step here is to use the solution of the so-called "Hungarian algorithm" as a cost function, which makes it possible to identify the electrode artifacts in arbitrary order. The template electrode grid has to be constructed only once for each cap configuration. In our implementation of this method, the whole procedure can be performed within 15 min including import of MRI, surface reconstruction and transformation, electrode identification and fitting to template. The method is robust in the sense that an electrode template created for one subject can be used without identification errors for another subject for whom the same EEG cap was used. Furthermore, the method appears to be robust against spurious or missing artifacts. We therefore consider the proposed method as a useful and reliable tool within the larger toolbox required for the analysis of co registered EEG/fMRI data. PMID- 21784162 TI - Fast and tissue-optimized mapping of magnetic susceptibility and T2* with multi echo and multi-shot spirals. AB - Gradient-echo MRI of resonance-frequency shift and T2* values exhibit unique tissue contrast and offer relevant physiological information. However, acquiring 3D-phase images and T2* maps with the standard spoiled gradient echo (SPGR) sequence is lengthy for routine imaging at high-spatial resolution and whole brain coverage. In addition, with the standard SPGR sequence, optimal signal-to noise ratio (SNR) cannot be achieved for every tissue type given their distributed resonance frequency and T2* value. To address these two issues, a SNR optimized multi-echo sequence with a stack-of-spiral acquisition is proposed and implemented for achieving fast and simultaneous acquisition of image phase and T2* maps. The analytical behavior of the phase SNR is derived as a function of resonance frequency, T2* and echo time. This relationship is utilized to achieve tissue optimized SNR by combining phase images with different echo times. Simulations and in vivo experiments were designed to verify the theoretical predictions. Using the multi-echo spiral acquisition, whole-brain coverage with 1 mm isotropic resolution can be achieved within 2.5 min, shortening the scan time by a factor of 8. The resulting multi-echo phase map shows similar SNR to that of the standard SPGR. The acquisition can be further accelerated with non-Cartesian parallel imaging. The technique can be readily extended to other multi-shot readout trajectories besides spiral. It may provide a practical acquisition strategy for high resolution and simultaneous 3D mapping of magnetic susceptibility and T2*. PMID- 21784164 TI - Sustained gamma band synchronization in early visual areas reflects the level of selective attention. AB - Cortical gamma band synchronization is associated with attention. Accordingly, directing attention to certain visual stimuli modulates gamma band activity in visual cortical areas. However, gradual effects of attention and behavior on gamma band activity in early visual areas have not yet been reported. In the present study, the degree of selective visual attention was gradually varied in a cued bimodal reaction time paradigm using audio-visual stimuli. Brain activity was recorded with magnetoencephalography (MEG) and analyzed with respect to time, frequency, and location of strongest response. Reaction times to visual and auditory stimuli reflected three presumed graded levels of visual attention (high, medium, and low). MEG data showed sustained gamma band synchronization in all three conditions in early visual areas (V1 and V2), while the intensity of gamma band synchronization increased with the level of visual attention (from low to high). Differences between conditions were seen for up to 1600 ms. The current results show that in early visual areas the level of gamma band synchronization is related to the level of attention directed to a visual stimulus. These gradual and long-lasting effects highlight the key role of gamma band synchronization in early visual areas for selective attention. PMID- 21784165 TI - Functions of the mitotic B-type cyclins CLB1, CLB2, and CLB3 at mitotic exit antagonized by the CDC14 phosphatase. AB - In the budding yeast Saccharomyces cerevisiae, cell cycle progression and cytokinesis at mitotic exit are proposed to be linked by CDC14 phosphatase antagonizing the function of mitotic B-type cyclin (CLBs). We have isolated a temperature-sensitive mutant, cdc14(A280V), with a mutation in the conserved phosphatase domain. Prolonged arrest in the cdc14(A280V) mutant partially uncoupled cell cycle progression from the completion of cytokinesis as measured by bud re-emergence, in the form of elongated apical projections, and DNA re replication. In contrast to previous mitotic exit mutants, cdc14(A280V) mutants displayed a strong bias for the first apical projection to form in the mother cell body. Using cdc14(A280V) mutant phenotypes, the functions of the B-type cyclins at mitotic exit were investigated. The preference in mother-daughter apical projection formation was observed to be independent of any individual CLB function. However, cdc14(A280V)clb1Delta cells displayed a pronounced increase in apical projections, while cdc14(A280V)clb3Delta cells were observed to form round cellular chains. While cdc14(A280V) cells arrested at mitotic exit, both cdc14(A280V)clb1Delta and cdc14(A280V)clb3Delta cells completed cytokinesis, but failed cell separation. cdc14(A280V)clb2Delta cells displayed a defect in actin ring assembly. These observations differentiate the functions of CLB1, CLB2, and CLB3 at mitotic exit, and are consistent with the hypothesis that CLB activities are antagonized by the CDC14 phosphatase in order to couple cell cycle progression with cytokinesis at mitotic exit. PMID- 21784163 TI - Longitudinal regression analysis of spatial-temporal growth patterns of geometrical diffusion measures in early postnatal brain development with diffusion tensor imaging. AB - Although diffusion tensor imaging (DTI) has provided substantial insights into early brain development, most DTI studies based on fractional anisotropy (FA) and mean diffusivity (MD) may not capitalize on the information derived from the three principal diffusivities (e.g. eigenvalues). In this study, we explored the spatial and temporal evolution of white matter structures during early brain development using two geometrical diffusion measures, namely, linear (Cl) and planar (Cp) diffusion anisotropies, from 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects. The growth trajectories were estimated with generalized estimating equations (GEE) using linear fitting with logarithm of age (days). The presence of the white matter structures in Cl and Cp was observed in neonates, suggesting that both the cylindrical and fanning or crossing structures in various white matter regions may already have been formed at birth. Moreover, we found that both Cl and Cp evolved in a temporally nonlinear and spatially inhomogeneous manner. The growth velocities of Cl in central white matter were significantly higher when compared to peripheral, or more laterally located, white matter: central growth velocity Cl=0.0465+/ 0.0273/log(days), versus peripheral growth velocity Cl=0.0198+/-0.0127/log(days), p<10-6. In contrast, the growth velocities of Cp in central white matter were significantly lower than that in peripheral white matter: central growth velocity Cp=0.0014+/-0.0058/log(days), versus peripheral growth velocity Cp=0.0289+/ 0.0101/log(days), p<10-6. Depending on the underlying white matter site which is analyzed, our findings suggest that ongoing physiologic and microstructural changes in the developing brain may exert different effects on the temporal evolution of these two geometrical diffusion measures. Thus, future studies utilizing DTI with correlative histological analysis in the study of early brain development are warranted. PMID- 21784166 TI - Auxotrophic mutant of Staphylococcus aureus interferes with nasal colonization by the wild type. AB - Staphylococcus aureus nasal carriage is a risk factor for infection in humans, particularly in the hospital setting. Bacterial interference was used as an alternative strategy for the prevention of upper respiratory, urogenital and gastrointestinal tract infections. This study was designed to assess if the administration of a live-attenuated aroA mutant of S. aureus is useful as a potential approach to prevent transient staphylococcal nasal carriage by virulent strains. We constructed an aroA mutant of S. aureus Newman strain by homologous recombination. The auxotrophic NK41 mutant was attenuated as determined by the increase of the LD(50) after intraperitoneal challenge. In mice, previous nasal colonization with the NK41 mutant significantly reduced the number of CFU of S. aureus (HU-71 and Hde288) clinical isolates and the parental Newman strain. The NK41 mutant was unable to induce a pro-inflammatory response and to damage the invaded human respiratory epithelial cells. Moreover, the cells previously or simultaneously infected with the NK41 mutant were invaded by virulent strains in a significantly lower degree than those of the control group. In conclusion, the attenuated NK41 mutant interfered with the colonization and establishment of pathogenic strains of S. aureus, which produce severe infections. PMID- 21784167 TI - Burkholderia pseudomallei-induced cell fusion in U937 macrophages can be inhibited by monoclonal antibodies against host cell surface molecules. AB - Burkholderia pseudomallei induces the formation of multinucleated giant cells in cell monolayers. After infection of human macrophage-like U937 cells with B. pseudomallei, addition of monoclonal antibodies against integrin-associated protein (CD47), E-selectin (CD62E), a fusion regulatory protein (CD98), and E cadherin (CD324) suppressed multinucleated giant cells in a concentration dependent manner while monoclonal antibodies against other surface molecules did not inhibit fusion despite binding to the cell surface. Flow cytometric analysis showed increased expression of CD47 and CD98, but not CD62E and CD324, upon B. pseudomallei infection. Our data suggest the involvement of specific cellular factors in the process of B. pseudomallei-induced fusion. PMID- 21784169 TI - Basal damage and oxidative DNA damage in children with chronic kidney disease measured by use of the comet assay. AB - One consequence of chronic kidney disease (CKD) is an elevated risk for cancer. There is sufficient evidence to conclude that there is an increased incidence of at least some cancers in kidney-dialysis patients. Cancer risk after kidney transplantation has mainly been attributed to immunosuppressive therapy. There are no data evaluating DNA damage in children with CKD, in dialysis patients, or following kidney transplantation. In this study, the comet assay and the enzyme modified comet assay - with the use of endonuclease III (Endo III) and formamidopyrimidine glycosylase (FPG) enzymes - were conducted to investigate the basal damage and the oxidative DNA damage as a result of treatment in peripheral blood lymphocytes of children. Children at various stages of treatment for kidney disease, including pre-dialysis patients (PreD) (n=17), regular hemodialysis patients (HD) (n=15), and those that received kidney transplants (Tx) (n=17), comprised the study group. They were compared with age- and gender-matched healthy children (n=20) as a control group. Our results show that the %DNA intensity, a measure of basal damage, was significantly increased in children with CKD (mean +/- SD) (5.22 +/- 1.57) and also in each of the PreD, HD, and Tx groups [(4.92 +/- 1.23), (4.91 +/- 1.35), and (5.79 +/- 1.94), respectively, vs the healthy children (2.74 +/- 2.91) (p<0.001). Significant increases in oxidative DNA damage were only found in the FPG-sensitive sites for the PreD and Tx groups, compared with control and HD groups (p<0.05), suggesting that basal DNA damage was more evident for the PreD, HD, and Tx groups. The findings of the present study indicate a critical need for further research on genomic damage with different endpoints and also for preventive measures and improvements in treatment of pediatric patients, in order to improve their life expectancy. PMID- 21784168 TI - The challenge of developing robust drugs to overcome resistance. AB - Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust drugs and the selection of resilient targets can lead to successful strategies for combating resistance. PMID- 21784170 TI - Induction of TK mutations in human lymphoblastoid TK6 cells by the rat carcinogen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). AB - 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a chlorine disinfection by-product in drinking water, is carcinogenic in rats and genotoxic in mammalian cells in vitro. In the current study, the mechanism of genotoxicity of MX in human lymphoblastoid TK6 cells was investigated by use of the Comet assay, the micronucleus test, and the thymidine kinase (TK) gene-mutation assay. MX induced a concentration-dependent increase in micronuclei and TK mutations. The lowest effective concentrations in the MN test and the TK gene-mutation assay were 37.5MUM and 25MUM, respectively. In the Comet assay, a slight although not statistically significant increase was observed in the level of DNA damage induced by MX in the concentration range of 25-62.5MUM. Molecular analysis of the TK mutants revealed that MX induced primarily point mutations or other small intragenic mutations (61%), while most of the remaining TK mutants (32%) were large deletions at the TK locus, leading to the hemizygous-type loss-of heterozygosity (LOH) mutations. These findings show that aside from inducing point mutations, MX also generates LOH at the TK locus in human cells and may thus cause the inactivation of tumour-suppressor genes by LOH. PMID- 21784171 TI - A novel carbohydrate antigen expression during development of Opisthorchis viverrini- associated cholangiocarcinoma in golden hamster: a potential marker for early diagnosis. AB - Poor prognosis of cholangiocarcinoma (CCA) is primarily due to delayed diagnosis because of the lack of appropriate tumor marker(s) to detect cancer development at an early stage. We have recently established a S121 monoclonal antibody (mAb) which recognizes an unidentified glycan epitope on MUC5AC, designated as CCA associated carbohydrate antigen (CCA-CA). This antigen is expressed in human CCA cells but not in normal biliary epithelia. Detection of CCA-CA effectively distinguished CCA patients' sera from normal control sera with high specificity and sensitivity. In the present study, we examined a time profile of the expression of CCA-CA by immunohistochemical methods in the liver tissues of Opisthorchis viverrini (Ov)-associated CCA in a hamster model. Hamsters were divided into four groups; non-treated, Ov infected, NDMA (N-nitrosodimethamine) treated and Ov+NDMA treated groups, and animals from each group were euthanized at 1, 3 and 6 months post-treatment. CCA-CA was not detected in normal biliary cells of non-treated hamsters throughout the course of experiment. CCA-CA became detectable in the cytoplasm and apical surface of biliary cells of the NDMA and Ov+NDMA groups at early stage (1 month) of tumor development and increased with tumor progression. In contrast, CCA-CA was detected as nuclear staining at the 1 month post Ov infection and declined thereafter. These results suggest the possibility of CCA-CA as an early marker for CCA. PMID- 21784172 TI - Infection dynamics of hepatitis E virus in naturally infected pigs in a Chinese farrow-to-finish farm. AB - To analyze the changes that occur in pigs during hepatitis E virus (HEV) infection, 256 serial serum samples were obtained from 32 pigs from one pig farm at ages 0 (cord blood), 15, 30, 60, 75, 90, 120, and 150 days. All HEV markers were assayed in these samples and showed that total anti-HEV antibodies and IgG formed two peaks. The first peak occurred at 0-60 days and the second after 75 days. No markers of infection, such as HEV RNA, antigen and anti-HEV IgM, were detectable during the first peak. Most newborn piglets (< 24 h of age) were negative for total anti-HEV and IgG. However, colostrum from all of the sows had evidence of these antibodies. Thus, the anti-HEV in the first peak was assumed to be acquired from maternal milk. Some infectious markers were positive at the beginning of second peak. PCR products were cloned and sequenced and the results indicated those sequences belonged to HEV genotype 4. The antibody present during the second peak may be induced by natural infection with HEV. In conclusion, pigs are susceptible to HEV infection and may remain infectious after the first peak of anti-HEV antibody. PMID- 21784173 TI - A first insight on the population structure of Mycobacterium tuberculosis complex as studied by spoligotyping and MIRU-VNTRs in Bogota, Colombia. AB - With an incidence of 25.6/100,000 in 2008, tuberculosis (TB) remains an important public health problem in Colombia. In this study, a total of 152 Mycobacterium tuberculosis complex strains isolated in Bogota, Colombia between years 1995 and 2007 were genotyped by spoligotyping and 12-loci MIRU-VNTRs. The various spoligotyping-based genotypic lineages in our sample were: Latin American & Mediterranean (LAM) n=75, 49.34%; Haarlem, n=38, 25.0%; ill-defined T group, n=21, 13.82%; S family, n=5, 3.29%; X clade, n=2, 1.32%; Beijing, n=1, 0.65%, while strains with unknown signatures (n=10) represented 6.58% of isolates. Using spoligotyping as a first molecular marker and MIRU-VNTRs as second marker, we obtained 102 single patterns and 14 clustered patterns (n=52 strains from 49 patients, 2-8 strains per cluster). The MIRU-VNTRs patterns corresponded to 50 MITs for 109 strains and 43 orphan patterns. The most frequent patterns were MIT190 (n=12), MIT45 (n=10), and MIT25 (n=9). The Hunter & Gaston discriminatory index (HGDI) of both methodologies used together showed a value of 0.992. In our setting, the HGDI of five loci subset (MIRU10, 16, 23, 26 and 40) contributed most to the discriminatory power of 12-loci format used (HGDI=0.977). The lineage distribution of M. tuberculosis showed that more than 3/4 of strains in Bogota are commonly found in Latin America, Caribbean, and Europe. This observation might reflect the shared post-Columbus history of Colombia and its Latin-American neighbors as well as strains brought in by 20th century immigrants from Europe. We also demonstrate the usefulness of MIRU-VNTR to detect suspected links among patients and polyclonal infections. PMID- 21784174 TI - Allergic rhinitis: an update on disease, present treatments and future prospects. AB - Allergic rhinitis (AR) is an inflammation of nasal mucosa mediated by IgE associated processes occurring independently, or concurrently with asthma. AR is characterized by sensitization-formation and expression of antigen specific IgE, followed by inflammation in two phases. The early phase response involves cross linking of IgE molecules leading to degranulation of mast cells and release of preformed mediators such as histamine and tryptase, or newly synthesized mediators such as prostaglandins and leukotrienes. The late phase response is predominated by the presence of eosinophils, lymphocytes, cytokines, and adhesion molecules. Newer insights reveal that the whole phenomenon of immunological inflammation is intricately knit with neural pathways, which strongly influence the process. Furthermore, AR can impact psychological health and vice versa. Classical pharmacotherapy of AR includes use of oral or topical antihistamines, oral antileukotrienes, topical corticosteroids, mast cell stabilizers, decongestants, and an anticholinergic agent. Among immunomodulatory treatments, immunotherapy is gaining widespread use, while antibody treatment is restricted mainly to resistant cases. Several small molecules with improved safety profile, or targeting novel mechanisms are in the clinical research. Newer antihistamines and corticosteroids with improved safety profile and antagonists of the prostaglandin D(2) (CRTH2) receptors are likely to be available for clinical use in the near future. Lack of properly validated animal models and complexities associated with clinical evaluation are some of the challenges facing the researchers in AR. Comprehensive understanding of immunological and neurological processes in AR would facilitate the future quest for more effective and safer management of this disease. PMID- 21784175 TI - Multifunctional alginate microspheres for biosensing, drug delivery and magnetic resonance imaging. AB - This research aims to develop and investigate a multifunctional implantable system capable of biosensing, drug delivery and magnetic resonance imaging (MRI) for continuous monitoring, controlled anti-inflammatory drug delivery and imaging, respectively. A glucose biosensor, diclofenac sodium (Diclo) and magnetic nanoparticles (MNP) were used as the biosensor component, anti inflammatory agent and MRI contrast agent, respectively. MNP were synthesized by the co-precipitation technique and loaded with the sensor and drug components into alginate microspheres using a commercial droplet generator. The multifunctional system was then characterized using optical microscopy, scanning electron microscopy, transmission electron microscopy, X-ray diffraction, vibrating sample magnetometry (VSM) and MRI. The MNP were found to be in the size range of 5-15 nm. The final system, comprising the biosensor, drug and MNP loaded inside alginate microspheres, was found to be in the size range of 10-60 MUm. Biosensing studies indicated an excellent glucose response curve, with a regression coefficient of 0.974 (0-10mM of glucose, response time: 4 min). In vitro Diclo release shows that MNP loading in alginate microspheres increases the burst release percentage by 11-12% in both 60 and 10 MUm particles. However, the duration of release for 85% drug release decreases with MNP loading by 7 and 6 days for 39 the 60 and 10 MUm particles, respectively. Super-paramagnetism was confirmed by VSM, with 2.09 and 1.368 emu g(-1), respectively, for the 60 and 10 MUm particles, with no hysteresis. MRI showed significant contrast for both sizes. The particles showed an excellent biocompatibility (>80%) for all combinations of formulations. The system shows a great potential for biosensing with concurrent drug delivery and visualization for biomedical applications. PMID- 21784176 TI - The role of hydroxyapatite in citric acid-based nanocomposites: surface characteristics, degradation, and osteogenicity in vitro. AB - The incorporation of nanoscale hydroxyapatite (HA) into biodegradable polymers can potentially mimic the native structure of bone and influence the mechanical properties and the extent of bioactivity. In this study nanocomposites of poly(1,8-octanediol-co-citrate) (POC) containing 40, 50, and 60 wt.% HA (POC-HA) were fabricated and characterized. Nanocomposite hydrophilicity and the degradation properties in vitro were evaluated via contact angle measurements, scanning electron microscopy (SEM), and mass loss measurements. Human mesenchymal stem cells (hMSC) were cultured on POC-HA nanocomposites in both growth and osteogenic media. Cell proliferation, alkaline phosphatase activity, and osteocalcin were measured. The equilibrium water in air contact angles confirmed all of the nanocomposites to be hydrophilic (23.4 +/- 8.1 degrees , 27 +/- 9.1 degrees , and 27.7 +/- 3.5 degrees for 40, 50, and 60 wt.% HA, respectively). Over a period of 26 weeks the degradation rate increased with decreasing HA content and pore formation was evident for POC-HA containing 40 wt.% HA, whereas POC with 50 and 60 wt.% HA lacked pores (mass loss at 26 weeks for 40, 50, and 60 wt.% HA, 27.4 +/- 1.6%, 17.7 +/- 1.6%, and 6.3 +/- 2.6%, respectively). hMSC adhered and proliferated well on all composites, confirming biocompatibility for at least 21 days. An increase in adhesion and proliferation was found with increasing HA nanoparticle content (ng DNA at day 21 for 40, 50, and 60 wt.% HA, 130.4 +/- 49.4, 184.4 +/- 86.4, 314.1 +/- 92.3). Alkaline phosphatase activity and osteocalcin concentration correlated with HA content (alkaline phosphate activity in expansion medium and osteogenic medium for 40, 50, and 60 wt.% HA, 256.1 +/- 71.8%, 304.0 +/- 128.7%, and 500.2 +/- 89.9%, and 358.4 +/- 124.1%, 653.7 +/- 216.5%, and 814.4 +/- 68.8%, respectively; osteocalcin concentration in expansion medium and osteogenic medium for 40, 50, and 60 wt.% HA, 236.9 +/- 7.8%, 253.0 +/- 7.5%, and 285.2 +/- 11.4%, and 265.8 +/- 15.0%, 288.3 +/- 17.9%, and 717.3 +/- 38.7%, respectively). This study provides insight into how the HA nanoparticle content can modulate the cell compatibility and physical properties of POC-HA nanocomposites. PMID- 21784177 TI - Quantitative determination of the composition of multi-shell calcium phosphate oligonucleotide nanoparticles and their application for the activation of dendritic cells. AB - Biodegradable calcium phosphate nanoparticles as carriers for the immunoactive toll-like receptor ligands CpG and polyinosinic-polycytidylic acid for the activation of dendritic cells (DC) combined with the viral antigen hemagglutinin (HA) were prepared. A purification method based on ultracentrifugation and ultrasonication was developed to separate the nanoparticles from dissolved biomolecules. The number of biomolecules, i.e., oligonucleotides and peptide, incorporated into the nanoparticles was quantitatively determined by UV spectroscopy, using fluorescent derivatives of the biomolecules. The immunostimulatory effects of purified calcium phosphate nanoparticles on DC were studied, i.e., cytokine production and activation of the cells in terms of the upregulation of surface molecules. Purified calcium phosphate nanoparticles, i.e., without dissolved biomolecules, are capable of inducing adaptive immunity by activation of DC. Immunostimulatory effects of purified calcium phosphate nanoparticles on DC were demonstrated by increased expression of co-stimulatory molecules and MHC II and by cytokine secretion. In addition, DC treated with purified functionalized calcium phosphate nanoparticles induced an antigen specific T-cell response in vitro. PMID- 21784178 TI - Systematic strontium substitution in hydroxyapatite coatings on titanium via micro-arc treatment and their osteoblast/osteoclast responses. AB - This study attempts to enhance the osseointegration of titanium implants by adopting a micro-arc treatment (MAT) capable of replacing calcium (Ca) with different percentages of strontium (Sr) in order to fabricate strontium containing hydroxyapatite (Sr-HAp) coatings. Sr, regarded as a significant therapy promoting bone mass and bone strength, has a dual mechanism, enhancing osteoblast differentiation and inhibiting osteoclast differentiation. This study also investigates how Sr content affects the microstructure of and osteoblast/osteoclast growth on the coatings. Experimental results indicate that an increase in the Sr content in the electrolyte bath results in a greater degree of Sr substitution at Ca sites within the HAp phase, facilitating the formation of Sr-HAp coatings with Sr fully solid soluble in the HAp phase. Irrespective of the Sr content, most coatings are similar in porous morphology and pore size. Additionally, the Sr-HAp coating shows higher osteoblast compatibility than raw titanium metal and the HAp coating. Moreover, cell adhesion and proliferation after 48 h was greater than that after 4 h, indicating that Sr can stimulate osteoblast adhesion and proliferation. Further, Sr significantly inhibits osteoclast differentiation when the Sr-HAp coatings exceed 38.9 at.% Sr. PMID- 21784179 TI - Amorphous calcium phosphate offers improved crack resistance: a design feature from nature? AB - Amorphous calcium phosphate (ACP) is found in biological organisms and coated implants, used in calcium phosphate cements, and has been recently confirmed as a precursor in mineralized tissue; however, nothing is known about crack initiation in ACP or its fracture toughness. The objective of this study was to determine the crack resistance of ACP to help understand its role in biological organisms and assist in the design of calcium-phosphate-based implants. ACP was manufactured by quenching droplets to form a bulk sample and individual splats. Testing of Berkovich and cube-corner indenter types revealed that the Berkovich indenter was more suitable, providing ease of crack detection. Nanoindentation was performed on polished ACP and hydroxyapatite (HAp), and cracks were identified with scanning electron microscopy. Additional nanoindentation was done on splats to assess the suitability for testing microarrays used in high throughput discovery of new bioceramics. ACP required about three times more force to initiate a crack compared to sintered HAp, but about nine times more than a single crystal. Crack initiation resistance decreased with increasing grain size. The fracture toughness of ACP was comparable to a single crystal, but higher for nanograined HAp. The crack initiation load can be potentially used for evaluating microsized samples. ACP prevents crack formation, but requires the presence of nanograins to provide a greater toughness. The implications of the higher crack initiation load in ACP are discussed for biological organisms and thermally processed biomaterials such as thermally sprayed and sintered HAp. PMID- 21784180 TI - Effects of phase constitution on magnetic susceptibility and mechanical properties of Zr-rich Zr-Mo alloys. AB - The effects of the microstructures and phases of Zr-rich Mo alloys on their magnetic susceptibilities and mechanical properties were investigated in order to develop a Zr alloy with low magnetic susceptibility for use in magnetic resonance imaging (MRI). The magnetic susceptibility was measured with a magnetic susceptibility balance, while mechanical properties were evaluated by a tensile test. The microstructure was evaluated with an X-ray diffractometer, an optical microscope, and a transmission electron microscope. Evaluation of the microstructures revealed that the alpha' phase was the dominant form at less than 2% Mo content in the as-cast alloy. The omega phase was formed in as-cast Zr-3Mo but disappeared with aging at 973 K. Magnetic susceptibility was reflected in the phase constitution: the susceptibility showed a local minimum at Zr-(0.5-1)Mo with mostly alpha' phase and a minimum at Zr-3Mo with mostly beta and omega phases. The magnetic susceptibility of as-cast Zr-3Mo increased at 973 K due to disappearance of the omega phase. However, the susceptibility was still as low as that of as-cast Zr-1Mo. The ultimate tensile strength of alpha'-based Zr-Mo alloys was tailored from 674 to 970 MPa, and the corresponding elongation varied from 11.1% to 2.9%. Because Zr-Mo alloys containing omega phase were found, through tensile tests, to be brittle this phase should be avoided, irrespective of the low magnetic susceptibility, in order to maintain mechanical reliability. Elongation of the Zr-3Mo alloy was dramatically improved when the phase constitution was changed to alpha and beta phases by aging at 973 K for 86.4 ks. The magnetic susceptibilities of the alpha'-based Zr-Mo alloys are one-third those of Ti-6Al-4V and Ti-6Al-7Nb, and thus these Zr alloys are useful for medical devices under MRI. PMID- 21784182 TI - Various preparation methods of highly porous hydroxyapatite/polymer nanoscale biocomposites for bone regeneration. AB - Tissue engineering utilizes expertise in the fields of materials science, biology, chemistry, transplantation medicine, and engineering to design materials that can temporarily serve in a structural and/or functional capacity during regeneration of a defect. Hydroxyapatite (HAp) scaffolds are among the most extensively studied materials for this application. However, HAp has been reported to be too weak to treat such defects and, therefore, has been limited to non-load-bearing applications. To capitalize the advantages of HAp and at the same time overcome the drawbacks nanocrystalline HAp (nHAp) is combined with various types of bioactive polymers to generate highly porous biocomposite materials that are used for osteoconduction in the field of orthopedic surgery. In this study we have reviewed nanosized HAp-based highly porous composite materials used for bone tissue engineering, introduced various fabrication methods to prepare nHAp/polymer composite scaffolds, and characterized these scaffolds on the basis of their biodegradability and biocompatibility through in vitro and in vivo tests. Finally, we provide a summary and our own perspectives on this active area of research. PMID- 21784183 TI - An injectable bone substitute composed of beta-tricalcium phosphate granules, methylcellulose and hyaluronic acid inhibits connective tissue influx into its implantation bed in vivo. AB - In this study, the in vivo tissue reaction to a new triphasic and injectable paste-like bone-substitute material composed of beta-tricalcium phosphate (beta TCP), methylcellulose and hyaluronic acid was analyzed. Using a subcutaneous implantation model, the interaction of these materials and the peri-implant tissue reaction were tested in Wistar rats for up to 60 days by means of established histological methods, including histomorphometrical analysis. The study focused on tissue integration, classification of the cellular inflammatory response and the degradation of the material. Groups composed of animals injected only with beta-TCP granules, sham-operated animals and animals injected with saline were used as controls. After implantation, the triphasic bone-substitute material was present as a bulk-like structure with an inner and outer core. Over a period of 60 days, the material underwent continuous degradation from the periphery towards the core. The implantation bed of the beta-TCP granule control group was invaded by phagocytes and formed a poorly vascularized connective tissue soon after implantation. This inflammatory response continued throughout the study period and filled the implantation bed. Significantly, the combination of the three biocompatible materials into one injectable paste-like bone substitute material enabled modification of the tissue reaction to the implant and resulted in a longer in vivo lifetime than that of beta-TCP granules alone. In addition, this combination increased the vascularization of the implantation bed, which is essential for successful tissue regeneration. PMID- 21784181 TI - Biomaterial implants mediate autologous stem cell recruitment in mice. AB - Autologous stem cells, recognized as the best cells for stem cell therapy, are associated with difficult extraction procedures which often lead to more traumas for the patients and time-consuming laboratory work, which delays their subsequent application. To combat such challenges, it was recently uncovered that, shortly after biomaterial implantation, following the recruitment of inflammatory cells, substantial numbers of mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC) were recruited to the implantation sites. These multipotent MSC could be differentiated into various lineages in vitro. Inflammatory signals may be responsible for the gathering of stem cells, since there is a good relationship between biomaterial-mediated inflammatory responses and stem cell accumulation in vivo. In addition, the treatment with the anti inflammatory drug dexamethasone substantially reduced the recruitment of both MSC and HSC. The results from this work support that such strategies could be further developed towards localized recruitment and differentiation of progenitor cells. This may permit the future development of autologous stem cell therapies without the need for tedious cell isolation, culture and transplantation. PMID- 21784184 TI - Neural network models for biological waste-gas treatment systems. AB - This paper outlines the procedure for developing artificial neural network (ANN) based models for three bioreactor configurations used for waste-gas treatment. The three bioreactor configurations chosen for this modelling work were: biofilter (BF), continuous stirred tank bioreactor (CSTB) and monolith bioreactor (MB). Using styrene as the model pollutant, this paper also serves as a general database of information pertaining to the bioreactor operation and important factors affecting gas-phase styrene removal in these biological systems. Biological waste-gas treatment systems are considered to be both advantageous and economically effective in treating a stream of polluted air containing low to moderate concentrations of the target contaminant, over a rather wide range of gas-flow rates. The bioreactors were inoculated with the fungus Sporothrix variecibatus, and their performances were evaluated at different empty bed residence times (EBRT), and at different inlet styrene concentrations (C(i)). The experimental data from these bioreactors were modelled to predict the bioreactors performance in terms of their removal efficiency (RE, %), by adequate training and testing of a three-layered back propagation neural network (input layer hidden layer-output layer). Two models (BIOF1 and BIOF2) were developed for the BF with different combinations of easily measurable BF parameters as the inputs, that is concentration (gm(-3)), unit flow (h(-1)) and pressure drop (cm of H(2)O). The model developed for the CSTB used two inputs (concentration and unit flow), while the model for the MB had three inputs (concentration, G/L (gas/liquid) ratio, and pressure drop). Sensitivity analysis in the form of absolute average sensitivity (AAS) was performed for all the developed ANN models to ascertain the importance of the different input parameters, and to assess their direct effect on the bioreactors performance. The performance of the models was estimated by the regression coefficient values (R(2)) for the test data set. The results obtained from this modelling work can be useful for obtaining important relationships between different bioreactor parameters and for estimating their safe operating regimes. PMID- 21784185 TI - Strategies for the identification of arginine ADP-ribosylation sites. AB - Mono-ADP-ribosylation of arginine is a protein modification in eukaryotic cells regulating protein activity and thereby influencing signal transduction and metabolism. Due to the complexity of the modification and the fragmentation pattern in MS/MS CID experiments, the identification of ADP-ribosylation sites in complex mixtures is difficult. Here we describe a two-step strategy, in the first step enriching and identifying potentially ADP-ribosylated proteins and in the second step identifying the sites of modification by a combination of LC/MS-, LC/MS(E) (MS at elevated fragmentation energy)- and LC/MS/MS experiments. Using this technique we could identify two ADP-ribosylation sites in TNFalpha digested with trypsin, protease V8 and both proteases and thereby demonstrate the specific ADP-ribosylation of TNFalpha. In complex samples the detection of ADP-ribosylated peptides requires further enrichment of the modified peptides. We tested various materials routinely used for the isolation of phosphopeptides. IMAC as well as TiO(2) chromatography were successfully applied for the selective enrichment of ADP-ribosylated model peptides. PMID- 21784187 TI - In vivo dynamic bone growth modulation is less detrimental but as effective as static growth modulation. AB - Longitudinal bone growth, which occurs in growth plates, has important implications in pediatric orthopedics. Mechanical loads are essential to normal bone growth, but excessive loads can lead to progressive deformities. In order to compare the effects of in vivo static and dynamic loading on bone growth rate and growth plate histomorphometry, a finely controlled, normalized and equivalent compression was applied for a period of two weeks on the seventh caudal vertebra (Cd7) of rats during their pubertal growth spurt. The load was sustained (0.2MPa, 0.0Hz) in the static group and sinusoidally oscillating (0.2MPa+/-30%, 0.1Hz) in the dynamic group. Control and sham (operated but no load applied) groups were also studied. Cd7 growth rate was statistically reduced by 19% (p<0.001) for both static and dynamic groups when compared to the sham group. Loading effects on growth plate histomorphometry were greater in the static than dynamic groups with significant reductions (p<0.001) observed for growth plate thickness, proliferative chondrocyte number per column and hypertrophic chondrocyte height in the static group when compared to the sham group. Significant differences (p<0.01) were also found between static and dynamic groups for growth plate thickness and proliferative chondrocyte number per column while the difference nearly reached significance (p=0.014) for hypertrophic chondrocyte height. This in vivo study shows that static and dynamic loading are equally effective in modulating bone growth of rat caudal vertebrae. However, dynamic loading causes less detrimental effects on growth plate histomorphometry compared to static loading. This knowledge is greatly relevant for the improvement and/or development of new minimally invasive approaches, which are based on the local modulation of bone growth, to correct several progressive musculoskeletal deformities. PMID- 21784188 TI - alpha-Actinin-3 deficiency is associated with reduced bone mass in human and mouse. AB - Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. alpha-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the alpha-actinin-3 protein in approximately 20% of Eurasians. Absence of alpha-actinin-3 does not cause any disease phenotypes in muscle because of compensation by alpha-actinin 2. However, alpha-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for alpha-actinin-3 in bone. alpha-Actinin-3 but not alpha-actinin-2 is expressed in osteoblasts. The Actn3(-/-) mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14%) and trabecular number (-61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3(-/-) mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study. PMID- 21784189 TI - Performance of the MRI-based virtual bone biopsy in the distal radius: serial reproducibility and reliability of structural and mechanical parameters in women representative of osteoporosis study populations. AB - Serial reproducibility and reliability critically determine sensitivity to detect changes in response to intervention and provide a basis for sample size estimates. Here, we evaluated the performance of the MRI-based virtual bone biopsy in terms of 26 structural and mechanical parameters in the distal radius of 20 women in the age range of 50 to 75 years (mean=62.0 years, S.D.=8.1 years), representative of typical study populations in drug intervention trials and fracture studies. Subjects were examined three times at average intervals of 20.2 days (S.D.=14.5 days) by MRI at 1.5 T field strength at a voxel size of 137*137*410 MUm(3). Methods involved prospective and retrospective 3D image registration and auto-focus motion correction. Analyses were performed from a central 5*5*5 mm(3) cuboid subvolume and trabecular volume consisting of a 13 mm axial slab encompassing the entire medullary cavity. Whole-volume axial stiffness and sub-regional Young's and shear moduli were computed by finite-element analysis. Whole-volume-derived aggregate mean coefficient of variation of all structural parameters was 4.4% (range 1.8% to 7.7%) and 4.0% for axial stiffness; corresponding data in the subvolume were 6.5% (range 1.6% to 13.0%) for structural, and 5.5% (range 4.6% to 6.5%) for mechanical parameters. Aggregate ICC was 0.976 (range 0.947 to 0.986) and 0.992 for whole-volume-derived structural parameters and axial stiffness, and 0.946 (range 0.752 to 0.991) and 0.974 (range 0.965 to 0.978) for subvolume-derived structural and mechanical parameters, respectively. The strongest predictors of whole-volume axial stiffness were BV/TV, junction density, skeleton density and Tb.N (R(2) 0.79 0.87). The same parameters were also highly predictive of sub-regional axial modulus (R(2) 0.88-0.91). The data suggest that the method is suited for longitudinal assessment of the response to therapy. The underlying technology is portable and should be compatible with all general-purpose MRI scanners, which is appealing considering the very large installed base of this modality. PMID- 21784191 TI - Race/ethnicity and age-related macular degeneration. PMID- 21784190 TI - A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures--a randomized, active comparator, double-blind study. AB - BACKGROUND: Eldecalcitol is an analog of 1,25-dihydroxyvitamin D(3) that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456. METHODS AND RESULTS: This 3 year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75 MUg eldecalcitol versus 1.0 MUg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92 years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25 hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (<50 nmol/L) were supplemented with 400 IU/day vitamin D(3). Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36 months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56-0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11-0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups. CONCLUSIONS: Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol. PMID- 21784192 TI - The parameters to establish a new corneal dystrophy. PMID- 21784194 TI - Reduction of anterior chamber contamination rate after cataract surgery by intraoperative surface irrigation with 0.25% povidone-iodine. PMID- 21784195 TI - The concentration of povidone-iodine for preoperative disinfection: relation to endophthalmitis incidence. PMID- 21784197 TI - Postoperative risk factors influencing corneal graft survival in the Singapore corneal transplant study. PMID- 21784198 TI - Descemet stripping automated endothelial keratoplasty in failed penetrating keratoplasty patients. PMID- 21784201 TI - Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age related macular degeneration. PMID- 21784203 TI - Intravitreal injection of autologous plasmin enzyme for macular edema associated with branch retinal vein occlusion. PMID- 21784205 TI - Ocular treatment of diabetic macular edema in Canada: where are we going? PMID- 21784206 TI - Practice patterns of Canadian vitreoretinal specialists in diabetic macular edema treatment. AB - OBJECTIVE: To establish the practice patterns of Canadian vitreoretinal (VR) specialists in the treatment of diabetic macular edema (DME). DESIGN: A survey was mailed, faxed, e-mailed, and published online for access by all Canadian VR specialists. PARTICIPANTS: All VR specialists identified from the Canadian Ophthalmology Society directory and the Canadian Retina and Vitreous Society directory. METHODS: A 19-item survey investigating treatment of DME was mailed to all VR specialists. A reminder fax and e-mail was sent with the survey attached. In all correspondence, physicians were given information regarding an available online version of the survey. The survey data was descriptively analyzed with the Statistical Package for the Social Sciences. RESULTS: With clinically significant macular edema (CSME) that is either away from the foveal avascular zone (FAZ) or diffuse, the most common first-line treatment option was macular photocoagulation 48 (78.8%) and 33 (54.1%), respectively. For microaneurysms within the FAZ, 33 (54.1%) of respondents chose intravitreal antivascular endothelial growth factor agents as their first-line treatment. In all, 51 respondents (83.6%) felt that vitrectomy played a role in the management of treatment-resistant CSME. Before utilizing intravitreal triamcinolone acetonide (IVT) injections, 34 (55.7%) of respondents did use a topical steroid trial to look for raised intraocular pressure whereas 16 (26.2%) of respondents did not use IVT injections at all. CONCLUSIONS: This survey provides valuable practical information on how DME is currently being treated in Canada and may serve as a baseline to assess how these patterns evolve over time. PMID- 21784207 TI - Visual function analysis in acute posterior vitreous detachment. AB - OBJECTIVE: To determine whether the visual function of patients with posterior vitreous detachment (PVD)changes between the initial visit and a 6-week follow-up visit, and to compare their visual function with that of patients with macular degeneration, cataract, glaucoma, low vision, cytomegalovirus (CMV) retinitis, or diabetic retinopathy and a reference population. DESIGN: Prospective cohort study. PARTICIPANTS: All patients presenting to the Hotel Dieu Hospital Emergency Eye Clinic between September 2008 and June 2009 who were diagnosed with acute PVD were offered enrollment in the study. METHODS: Patients were administered the National Eye Institute Visual Function Questionnaire NEI VFQ-25 at two points in time. The composite scores from the initial and the 6-week visits were compared. The scores were also compared with established normative data and 6 ophthalmologic diagnoses. RESULTS: The NEI VFQ-25 composite score for patients with acute PVD (n = 84) at baseline was 93.26 +/- 5.59 (mean +/- SD). After 6 weeks and a second ocular examination, there was no statistical difference in the composite score of 93.47 +/- 6.20 (mean +/- SD). (1-sided paired t-test, t = 0.57; P = 0.28). CONCLUSIONS: The visual function of patients with acute PVD remains stable over the first 6 weeks after diagnosis. It is significantly higher than that of patients with 6 other ophthalmologic conditions but comparable to that of a normal population. PMID- 21784208 TI - Pars plana vitrectomy versus combined pars plana vitrectomy and scleral buckle for primary repair of rhegmatogenous retinal detachment. AB - OBJECTIVE: To compare pars plana vitrectomy (PPV) with PPV and scleral buckle (PPV/SB) for repair of rhegmatogenous retinal detachment (RRD). DESIGN: A retrospective chart review. PARTICIPANTS: Patients who underwent PPV or PPV/SB for RRD repair at a single institution. METHODS: A retrospective chart review of patients in two different treatment groups and analysis of the anatomic and functional results. RESULTS: Single-surgery anatomic success was achieved in 31 of 37 (83.8%) phakic eyes that underwent PPV and in 66 of 68 (97.1%) phakic eyes that underwent PPV/SB (p = 0.0216). Among pseudophakic eyes, 42 of 48 (87.5%) in the PPV group and 62 of 66 (93.9%) in the PPV/SB group achieved single-surgery reattachment (p = 0.3175). Visual acuity improvement was marginally greater in the PPV group among phakic (p = 0.4898) and pseudophakic (p = 0.2465) eyes. CONCLUSIONS: PPV/SB may be associated with a decreased risk for retinal redetachment when compared to PPV for repair of phakic RRD. In pseudophakic eyes, the anatomic success rate between the two techniques appears to be similar. PMID- 21784209 TI - Effects of corneal thickness and axial length on intraocular pressure and ocular pulse amplitude before and after cataract surgery. AB - OBJECTIVE: To investigate the relationship between the biophysical properties of the cornea and eye on the intraocular pressure (IOP) and ocular pulse amplitude (OPA) before and after cataract surgery. DESIGN: Intervention study. PARTICIPANTS: The left eyes of 311 patients. METHODS: The left eyes of 338 patients undergoing cataract surgery without other eye pathology were studied. IOP and OPA were recorded by dynamic contour tonometry (DCT) 1 week before and 14 weeks after cataract surgery. The axial length, corneal curvature, central corneal thickness, anterior chamber depth, and anterior chamber angle were measured 1 week before cataract surgery. Multiple regression analyses of these factors to the preoperative OPA were performed. The difference between the pre- and postoperative IOP and OPA were investigated by paired t tests. RESULTS: Three hundred and eleven of 338 eyes were analyzed. The preoperative OPA was negatively correlated with axial length (beta = -0.24, p < 0.0001) and positively correlated with the preoperative IOP (beta = 0.13, p < 0.0001). The average OPA was significantly decreased after cataract surgery (p < 0.0001). The mean change in postoperative OPA was -0.45 +/- 0.63 mm Hg (95% CI -0.52 to -0.38 mm Hg). CONCLUSIONS: The preoperative OPA was negatively correlated with axial length as reported. A significant decrease in OPA was observed after the cataract surgery. PMID- 21784210 TI - Follow-up of angle closure glaucoma suspects after laser iridotomy in Caucasians with normal intraocular pressure at diagnosis. AB - OBJECTIVE: To study the long-term outcome of Caucasian eyes with iridotrabecular trabecular apposition or peripheral anterior synechiae (PAS) and fellow eyes with narrow angles only, in eyes with intraocular pressure (IOP) <22 mm Hg at diagnosis and treated with laser peripheral iridotomy (LPI). DESIGN: Cohort study. PARTICIPANTS: Two hundred and fifty-seven Caucasian phakic patients (469 eyes) with a minimum follow-up of 2 years that had both an undilated and dilated gonioscopy after LPI. METHODS: In this retrospective cohort study, we included phakic patients with a minimum follow-up of 2 years that had both an undilated and dilated gonioscopy after LPI. Excluded were patients with pseudoexfoliation, intraocular surgery, prior acute angle-closure glaucoma or antiglaucoma medication, suspicious glaucoma disk, secondary angle closure, or iridoplasty. We censored patients after any kind of intraocular surgery. Main outcome measures where the date of IOP elevation and beginning of antiglaucoma medication. RESULTS: Four hundred and sixty-nine eyes were included. Mean follow-up was 8.5 +/- 5.53 years. No apposition/PAS was observed in 84.0% of the eyes after LPI. At 10 years, 38.7% of the eyes had increased IOP and 17.3% required medication. No difference in outcomes was observed between argon and neodymium-YAG LPI or between the eyes with and without apposition/PAS before LPI. Younger patients and those with no apposition/PAS after LPI had a better prognosis (p < 0.01). CONCLUSIONS: Many angle closure glaucoma suspects developed increased IOP and required medical treatment after LPI. PMID- 21784211 TI - Screening for glaucoma with Moorfields regression analysis and glaucoma probability score in confocal scanning laser ophthalmoscopy. AB - OBJECTIVE: To compare the validity of Moorfields regression analysis (MRA) and glaucoma probability score (GPS) of the confocal scanning laser ophthalmoscopy (Heidelberg retina tomograph 3; HRT3) in detecting glaucomatous optic nerve damage in a screening population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Subjects at high risk for development of open-angle glaucoma (OAG). METHODS: All subjects underwent confocal scanning ophthalmoscopy (Heidelberg retina tomograph; HRTII) testing, visual fields testing with frequency-doubling technology perimetry (FDT), and a standard ophthalmologic examination. All HRTII images were reprocessed with HRT3. Based on an ophthalmologic examination and FDT results, eyes were classified into 4 categories: normal, possible glaucoma, probable glaucoma, and definitive glaucoma. Main outcome measures included sensitivity and specificity of HRTII/MRA, HRT3/MRA, HRT3/GPS, and combination HRT3/MRA/GPS. RESULTS: The left eyes of 221 of 291 subjects were included; 4 (1.8%) eyes were classified as definitively having glaucoma. Depending on the reference standard diagnosis as well as on the borderline test-positive definition of the HRTII-3, sensitivity and specificity varied between 36.4% and 100%. For HRTII/MRA, 88.2% to 96.5%, 54.5% to 100%, and 74.5% to 93.6%; for HRT3/MRA, 61.9% to 100% and 64.3% to 85.2%; for HRT3/GPS, 85.7% to 100%; and for combination HRT3/MRA/GPS, 73.4% to 78.2%. CONCLUSIONS: In this pilot study, the MRA of the HRT3 appears to be more sensitive but less specific than the MRA in the HRTII version. The GPS, although somewhat less specific than MRA (and some discs are nonclassifiable by this technique), had greater sensitivity and as a screening method may have the additional advantage of being contour-line independent. PMID- 21784212 TI - Combining rim area to disc area asymmetry ratio and Moorfields regression analysis of confocal scanning laser ophthalmoscopy for glaucoma screening. AB - OBJECTIVE: To determine the utility of combining rim area to disc area asymmetry ratio (RADAAR) and Moorfields regression analysis (MRA) to detect primary open angle glaucoma (POAG) using confocal scanning laser ophthalmoscopy (CSLO) (Heidelberg retina tomograph 3 (HRT3)) in high-risk populations. DESIGN: Cross sectional study. PARTICIPANTS: Subjects with high risk for developing POAG. METHODS: Subjects underwent HRT, frequency doubling technology perimetry (FDT), and complete ophthalmic examination. Based on an ophthalmologic examination and FDT results of the worse eye, subjects were classified into 4 categories: normal, possible glaucoma, probable glaucoma, and definite glaucoma. Main outcome measures included sensitivities (Se), specificities (Sp), positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (PLR, NLR) of the MRA, RADAAR, and combined MRA- RADAAR tests. RESULTS: Of 375 subjects, 11 were classified as having definite glaucoma. Depending on the reference standard, range results for Se, Sp, PPV, NPV, PLR, and NLR were, respectively, 57.7% to 100%; 55.1% to 85.4%; 6.3% to 39%; 92.6% to 100%; 1.97 to 4.9; 0 to 0.49 for MRA; 11.5% to 27.3%; 98.1% to 98.8%; 30% to 60%; 87.4% to 97.8%; 9.29 to 14.1; and 0.74 to 0.89 for RADAAR; and 57.7% to 90.9%; 81.3% to 85.1%; 12.8% to 38.5%; 92.6% to 99.7%; 3.87 to 4.85; 0.11 to 0.50 for combination MRA-RADAAR. DISCUSSION: When using HRT in populations at high risk for glaucoma, RADAAR had a higher specificity than MRA in identifying glaucoma. When patients were classified as borderline on MRA, combining RADAAR values decreased the number of false-positives as well, and may be recommended when high specificity is required. PMID- 21784213 TI - Social phobia and other psychiatric problems in children with strabismus. AB - OBJECTIVE: To investigate the rate of social phobia, anxiety, depression, and other psychiatric problems in children with strabismus. DESIGN: Prospective, cross-sectional, case-control study. PARTICIPANTS: Forty-two children with strabismus and 47 control subjects 8-13 years of age were enrolled in this study. METHODS: After the ophthalmologist's examination, all cases were assessed by a psychiatrist based on the structured interview technique of Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version (Kiddie-SADS-PL). The Screen for Child Anxiety Related Emotional Disorders (SCARED) was administered to each subject to evaluate social phobia. All participants completed the Children's Depression Inventory (CDI). RESULTS: Age as well as sex and income were comparable between the strabismus patients and control groups. Social phobia was diagnosed in 8 (19.04%) of the 42 strabismic children and in 1 (2.12%) of the control subjects. The CDI and SCARED (total score, social phobia, separation anxiety) scores of strabismus patients were significantly higher than the control group (p = 0.001, p = 0.004, p = 0.0001, p = 0.05, respectively). CONCLUSIONS: A relationship between strabismus in children and social phobia, depression, and anxiety on a symptom basis was underlined by our data. PMID- 21784214 TI - [Local and global stereopsis in children with microstrabismus]. AB - INTRODUCTION: It is generally accepted that stereopsis is present in patients with microstrabismus, although it is reduced. This concept relies primarily on the evaluation of local stereopsis, which contains visible monocular cues. However, microstrabismic patients seem to present much more impairment in identifying the global form in random dot stereograms (global stereopsis). The present study aims to verify the hypothesis that local stereopsis is superior to global stereopsis in children with microstrabismus. METHOD: In this retrospective study, a sample of 26 children (6 to 14 years of age) with microstrabismus was selected at the Clinique Universitaire de la Vision of the University of Montreal. Their local (visible contours) and global (random dot stereograms) stereoscopic thresholds were obtained using the Randot Stereotest((r)). RESULTS: Normal, or slightly inferior to normal, local stereoscopic threshold were found in nineteen microstrabismic children (19/26, 73%), some of them presenting up to 20 seconds of arc. A complete lack of local stereopsis was observed in 7 (27%) children. However, none of the children tested were able to perceive global stereopsis with the exception of one child. CONCLUSION: Local stereoscopic vision is present, although altered, in microstrabismic children but global stereoscopic vision is generally absent. PMID- 21784215 TI - Effects of pictograms in educating 3 distinct low-literacy populations on the use of postoperative cataract medication. AB - OBJECTIVE: To examine the effectiveness of pictograms in educating low-literacy patients in order to improve adherence to postoperative cataract regimens. DESIGN: Multicenter, single-blinded, randomized controlled trial. PARTICIPANTS: A group of 225 patients from across India, all below a 10th-grade education level, were divided into 3 groups of 75 patients. METHODS: Each group was educated differently regarding medication use and frequency of dose. The control group was given verbal instruction only. Experimental group 1 (EG1) was taught using the pictograms in the clinic. Experimental group 2 (EG2) was taught in the same way as EG1 but was given the pictograms to take home. Each group was given three 10 point oral exams: on the operative day (Test 1); on postoperative day 7 (Test 2); and on day 28 (Test 3). During the patients' final visit, medication bottles were measured to ascertain use. RESULTS: Test 1 showed no significant difference in mean scores among groups. For Test 2, EG1 and EG2 scored similarly but significantly better than Control (control group, 5.77; EG1, 7.33; EG2, 7.62 ; p < 0.001). For Test 3, EG2 scored significantly better than Control and EG1 (control group, 4.37; EG1, 5.44; EG2, 7.17; p < 0.001). The only parameter significant for a higher test score was the participants' educational level. Higher test scores were significantly associated (p < 0.001) with greater medication consumption. CONCLUSIONS: Taking the pictograms home proved to be the most effective way to educate patients who had low literacy levels, and it increased adherence to regimens by 28 days or more. Education through pictograms strictly in the clinic was sufficient for short regimens (<= 7 days). PMID- 21784216 TI - Immediately sequential bilateral cataract surgery versus delayed sequential bilateral cataract surgery: potential hospital cost savings (Vol. 45[6]). PMID- 21784218 TI - From iPhone to eyePhone: a technique for photodocumentation. PMID- 21784219 TI - Melkersson-Rosenthal syndrome presenting with isolated bilateral eyelid swelling: a clinicopathologic correlation. PMID- 21784220 TI - Report of 3 histopathologically documented cases of syringocystadenoma papilliferum involving the eyelid. PMID- 21784221 TI - The Peters anomaly following antenatal exposure to methotrexate and hydroxychloroquine. PMID- 21784222 TI - Iatrogenic globe penetration in a case of infraorbital nerve block. PMID- 21784223 TI - Canaliculitis involving Mycobacterium fortuitum after dacryocystorhinostomy with silicone stenting. PMID- 21784224 TI - The application of baculoviruses in human and veterinary medicine: an overview. Preface. PMID- 21784225 TI - Requirements for baculoviruses for clinical gene therapy applications. AB - Baculoviruses have proven capacity for the production of recombinant proteins including virus-like particles and as viral vectors. Recent progress in preclinical studies suggest that baculoviruses have potential as new vectors for gene therapy but so far no clinical trials have been performed. To date, no specific guidelines for the use of baculoviruses as human gene therapy vectors exist but researchers can utilize existing guidelines made for other biological products. Because of the long history of research on baculoviruses, a lot of knowledge has been obtained that forms a good basis for the gene therapy development process. This article gives an overview of the current status of the application of baculovirus vectors in gene therapy and summarizes some of the challenges to overcome before the first clinical trials with baculoviruses can be accomplished. PMID- 21784226 TI - An initiative to manufacture and characterize baculovirus reference material. AB - This letter to the editor brings to the attention of researchers an initiative to develop a baculovirus reference material repository. To be successful this initiative needs the support of a broad panel of researchers working with baculovirus vectors for recombinant protein production and gene delivery for either therapy or vaccination. First there is a need to reach a consensus on the nature of the reference material, the production protocols and the baculovirus characterization methods. It will also be important to define repository and distribution procedures so that the reference material is available to any researcher for calibrating experimental data and to compare experiments performed in the various laboratories. As more and more baculovirus-based products are licensed or in the final stages of development, the development of a repository of baculovirus reference material is timely. This letter describes the requirements for the reference material and for the project as a whole to be successful and calls for a partnership that would involve academic, industrial laboratories and governmental organizations to support this international initiative. PMID- 21784227 TI - Arbovirus vaccines; opportunities for the baculovirus-insect cell expression system. AB - The baculovirus-insect cell expression system is a well-established technology for the production of heterologous viral (glyco)proteins in cultured cells, applicable for basic scientific research as well as for the development and production of vaccines and diagnostics. Arboviruses form an emerging group of medically important viral pathogens that are transmitted to humans and animals via arthropod vectors, mostly mosquitoes, ticks or midges. Few arboviral vaccines are currently available, but there is a growing need for safe and effective vaccines against some highly pathogenic arboviruses such as Chikungunya, dengue, West Nile, Rift Valley fever and Bluetongue viruses. This comprehensive review discusses the biology and current state of the art in vaccine development for arboviruses belonging to the families Togaviridae, Flaviviridae, Bunyaviridae and Reoviridae and the potential of the baculovirus-insect cell expression system for vaccine antigen production The members of three of these four arbovirus families have enveloped virions and display immunodominant glycoproteins with a complex structure at their surface. Baculovirus expression of viral antigens often leads to correctly folded and processed (glyco)proteins able to induce protective immunity in animal models and humans. As arboviruses occupy a unique position in the virosphere in that they also actively replicate in arthropod cells, the baculovirus-insect cell expression system is well suited to produce arboviral proteins with correct folding and post-translational processing. The opportunities for recombinant baculoviruses to aid in the development of safe and effective subunit and virus-like particle vaccines against arboviral diseases are discussed. PMID- 21784228 TI - Opportunities and challenges for the baculovirus expression system. AB - In this review background information on the baculovirus-insect cell expression system and its applications for producing protein subunits and virus-like particles for vaccine and other purposes is provided. This review will illustrate the principle structure of baculovirus vectors commonly used for heterologous gene expression in insect cells and describe adaptations that have been made over the last 10 years to improve the system in terms of quality of the protein produced and stability of the baculovirus genome. These improvements include enhanced trafficking, folding and glycosylation of the recombinant protein as well as preventing intracellular degradation. Challenges and progress in stabilizing the baculovirus genome in order not to lose the transgene cassette will also be discussed. Recent developments such as how to make multiple alterations in the baculovirus genome without accumulating marker genes are included. PMID- 21784229 TI - A fast track influenza virus vaccine produced in insect cells. AB - The viral surface protein hemagglutinin (HA) has been recognized as a key antigen in the host response to influenza virus in both natural infection and vaccination because neutralizing antibodies directed against HA can mitigate or prevent infection. The baculovirus-insect cell system can be used for the production of recombinant HA molecules and is suitable for influenza vaccine production where annual adjustment of the vaccine is required. This expression system is generally considered safe with minimal potential for growth of human pathogens. Extensive characterization of this novel cell substrate has been performed, none of which has revealed the presence of adventitious agents. Multiple clinical studies have demonstrated that the vaccine is safe, well-tolerated and immunogenic. The baculovirus-insect cell system could, therefore, be used for the expedited production of a safe and efficacious influenza vaccine. As a result, this technology should provide a fast track worldwide solution for newly emerging influenza strains or pandemic preparedness within a few years. PMID- 21784230 TI - Large-scale production and purification of VLP-based vaccines. AB - Virus-like particles (VLPs) hold tremendous potential as vaccine candidates. These innovative biopharmaceuticals present the remarkable advantages of closely mimicking the three-dimensional nature of an actual virus while lacking the virus genome packaged inside its capsid. As a result, an equally efficient but safer prophylaxis is anticipated as compared to inactivated or live attenuated viral vaccines. With the advent of successful cases of approved VLP-based vaccines, pharmaceutical companies are indeed redirecting their resources to the development of such products. This paper reviews the current choices and trends of large-scale production and purification of VLP-based vaccines generated through the baculovirus expression vector system using insect cells. PMID- 21784231 TI - Baculovirus as vectors for human cells and applications in organ transplantation. AB - The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is able to transduce a wide range of mammalian cells and shows preferential uptake in some, particularly liver and kidney cells. This suggests that the virus may be useful for delivery of protective genes for ameliorating the effects of ischaemia reperfusion injury (IRI) in solid organs during transplantation procedures. In this chapter we discuss the advantages of the baculovirus over other virus vectors for gene delivery in organ transplantation and describe some of the protective genes which may be used to ameliorate the effects of IRI. We then describe a method for concentrating baculovirus for use in an ex vivo transduction model. Data are also provided for the effects of virus transduction in vitro on the innate and adaptive immune response. We conclude with a discussion on the future considerations for using baculovirus for delivery and expression of protective genes in organ transplantation. PMID- 21784232 TI - Baculoviruses as gene therapy vectors for human prostate cancer. AB - Prostate cancer is the most commonly diagnosed cancer in ageing men in the western world. While the primary cancers can be treated with androgen ablation, radiotherapy and surgery, recurrent castration resistant cancers have an extremely poor prognosis, hence promoting research that could lead to a better treatment. Targeted therapeutic gene therapy may provide an attractive option for these patients. By exploiting the natural ability of viruses to target and transfer their genes into cancer cells, either naturally or after genetic manipulation, new generations of biological control can be developed. In this review we present the advantages and practicalities of using baculovirus as a vector for prostate cancer gene therapy and provide evidence for the potential of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) as a safer alternative vehicle for targeting cancer cells. Strategies to target baculovirus binding specifically to prostate cell surfaces are also presented. The large insertion capacity of baculoviruses also permits restricted, prostate specific gene expression of therapeutic genes by cloning extended human transcriptional control sequences into the baculovirus genome. PMID- 21784233 TI - How to avoid complement attack in baculovirus-mediated gene delivery. AB - Serum inactivation of baculovirus vectors is a significant barrier to the development of these highly efficient vectors for therapeutic gene delivery. In this review we will describe the efforts taken to avoid complement attack by passive or active measures. Evidently good targets for baculovirus-mediated gene delivery include immunoprivileged tissues, such as eye, brain and testis. Similarly baculovirus vectors have also proven their efficacy in an ex vivo setting for tissue engineering. Active measures to inhibit complement include the use of pharmacological inhibitors of complement as well as surface engineering of the baculoviral vectors through the use of synthetic polymers, pseudotyping or display of complement inhibitors. Lessons learned from these studies will significantly increase the possibility of using baculovirus vectors for therapeutic applications. PMID- 21784234 TI - Latest developments in the large-scale production of adeno-associated virus vectors in insect cells toward the treatment of neuromuscular diseases. AB - Adeno-associated viral (AAV) vectors are gene vectors of choice for the development of gene therapy treatments for many rare diseases affecting various tissues including retina, central nervous system, liver, and muscle. The AAV based gene therapy approach became conceivable only after the development of easily scalable production systems including the Sf9 cell/baculovirus expression system. Since the establishment of the production of AAV in the Sf9/baculovirus system by the group of Rob Kotin, this new production system has largely been developed for optimizing the large scale production of different serotypes of AAV for preclinical and clinical purposes. Today this manufacturing system allows for the production of purified vector genome (vg) quantities of up to 2 * 10(15) for AAV1 using a 50L reactor and the scale up to larger reactor volumes is paralleled by a corresponding increase in the vector yield. This review presents the principles and achievements of the Sf9/baculovirus system for the production of AAV in comparison to other expression systems based on mammalian cells. In addition, new developments and improvements, which have not yet been implemented at a large scale, and perspectives for further optimization of this production system will be discussed. All of these achievements as well as further process intensifications are urgently needed for the production of clinical doses for the treatment of neuromuscular diseases for which estimated doses of up to 10(14)vg/kg body mass are required. PMID- 21784235 TI - Quality control and analytical methods for baculovirus-based products. AB - Recombinant baculoviruses (rBac) are used for many different applications, ranging from bio-insecticides to the production of heterologous proteins, high throughput screening of gene functions, drug delivery, in vitro assembly studies, design of antiviral drugs, bio-weapons, building blocks for electronics, biosensors and chemistry, and recently as a delivery system in gene therapy. Independent of the application, the quality, quantity and purity of rBac-based products are pre-requisites demanded by regulatory authorities for product licensing. To guarantee maximization utility, it is necessary to delineate optimized production schemes either using trial-and-error experimental setups ("brute force" approach) or rational design of experiments by aid of in silico mathematical models (Systems Biology approach). For that, one must define all of the main steps in the overall process, identify the main bioengineering issues affecting each individual step and implement, if required, accurate analytical methods for product characterization. In this review, current challenges for quality control (QC) technologies for up- and down-stream processing of rBac based products are addressed. In addition, a collection of QC methods for monitoring/control of the production of rBac derived products are presented as well as innovative technologies for faster process optimization and more detailed product characterization. PMID- 21784236 TI - [The supplements of the journal Radiologia]. PMID- 21784237 TI - [Solution to case 31. Peliosis hepatis]. PMID- 21784238 TI - [Solution to case 32. Leiomyoma of the pyriform sinus diagnosed by imaging techniques]. PMID- 21784239 TI - 50th anniversary special issue of Vision Research--volume 2. PMID- 21784240 TI - Glioma development: where did it all go wrong? AB - Investigating the family tree of a tumor to identify its cellular origins is a daunting task. Liu et al. (2011) now use an elegant lineage tracing technique (MADM) to visualize glioma from its earliest stages. They show that mutations originally induced in neural stem cells lie dormant and only trigger malignant transformation following differentiation into oligodendrocyte precursor cells. PMID- 21784241 TI - Tethered genes get checked during replication. AB - Although events associated with replication stress have long formed the cornerstone of checkpoint activation, questions remain about how cells maintain the integrity of replicating genomes. Now, Bermejo et al. (2011) identify a mechanism directly linking checkpoint function to the relief of topological tension at nuclear pore tethered genes. PMID- 21784242 TI - Nuclear pore structure: warming up the core. AB - Structural determination of the nuclear pore complex has been limited by the complexity and size of this cellular megalith. By taking advantage of exceptionally stable nucleoporins from the thermophilic fungus Chaetomium thermophilum, Amlacher et al. (2011) provide new insight into a core element of the nuclear pore scaffold. PMID- 21784243 TI - Genetics of sleep and sleep disorders. AB - Sleep remains one of the least understood phenomena in biology--even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ~14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. PMID- 21784244 TI - SSB functions as a sliding platform that migrates on DNA via reptation. AB - SSB proteins bind to and control the accessibility of single-stranded DNA (ssDNA), likely facilitated by their ability to diffuse on ssDNA. Using a hybrid single-molecule method combining fluorescence and force, we probed how proteins with large binding site sizes can migrate rapidly on DNA and how protein-protein interactions and tension may modulate the motion. We observed force-induced progressive unraveling of ssDNA from the SSB surface between 1 and 6 pN, followed by SSB dissociation at ~10 pN, and obtained experimental evidence of a reptation mechanism for protein movement along DNA wherein a protein slides via DNA bulge formation and propagation. SSB diffusion persists even when bound with RecO and at forces under which the fully wrapped state is perturbed, suggesting that even in crowded cellular conditions SSB can act as a sliding platform to recruit and carry its interacting proteins for use in DNA replication, recombination and repair. PMID- 21784245 TI - The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores. AB - Transcription hinders replication fork progression and stability, and the Mec1/ATR checkpoint protects fork integrity. Examining checkpoint-dependent mechanisms controlling fork stability, we find that fork reversal and dormant origin firing due to checkpoint defects are rescued in checkpoint mutants lacking THO, TREX-2, or inner-basket nucleoporins. Gene gating tethers transcribed genes to the nuclear periphery and is counteracted by checkpoint kinases through phosphorylation of nucleoporins such as Mlp1. Checkpoint mutants fail to detach transcribed genes from nuclear pores, thus generating topological impediments for incoming forks. Releasing this topological complexity by introducing a double strand break between a fork and a transcribed unit prevents fork collapse. Mlp1 mutants mimicking constitutive checkpoint-dependent phosphorylation also alleviate checkpoint defects. We propose that the checkpoint assists fork progression and stability at transcribed genes by phosphorylating key nucleoporins and counteracting gene gating, thus neutralizing the topological tension generated at nuclear pore gated genes. PMID- 21784246 TI - FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. AB - FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention. PMID- 21784247 TI - The inside-out mechanism of Dicers from budding yeasts. AB - The Dicer ribonuclease III (RNase III) enzymes process long double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that direct RNA interference. Here, we describe the structure and activity of a catalytically active fragment of Kluyveromyces polysporus Dcr1, which represents the noncanonical Dicers found in budding yeasts. The crystal structure revealed a homodimer resembling that of bacterial RNase III but extended by a unique N-terminal domain, and it identified additional catalytic residues conserved throughout eukaryotic RNase III enzymes. Biochemical analyses showed that Dcr1 dimers bind cooperatively along the dsRNA substrate such that the distance between consecutive active sites determines the length of the siRNA products. Thus, unlike canonical Dicers, which successively remove siRNA duplexes from the dsRNA termini, budding-yeast Dicers initiate processing in the interior and work outward. The distinct mechanism of budding yeast Dicers establishes a paradigm for natural molecular rulers and imparts substrate preferences with ramifications for biological function. PMID- 21784248 TI - Insight into structure and assembly of the nuclear pore complex by utilizing the genome of a eukaryotic thermophile. AB - Despite decades of research, the structure and assembly of the nuclear pore complex (NPC), which is composed of ~30 nucleoporins (Nups), remain elusive. Here, we report the genome of the thermophilic fungus Chaetomium thermophilum (ct) and identify the complete repertoire of Nups therein. The thermophilic proteins show improved properties for structural and biochemical studies compared to their mesophilic counterparts, and purified ctNups enabled the reconstitution of the inner pore ring module that spans the width of the NPC from the anchoring membrane to the central transport channel. This module is composed of two large Nups, Nup192 and Nup170, which are flexibly bridged by short linear motifs made up of linker Nups, Nic96 and Nup53. This assembly illustrates how Nup interactions can generate structural plasticity within the NPC scaffold. Our findings therefore demonstrate the utility of the genome of a thermophilic eukaryote for studying complex molecular machines. PMID- 21784249 TI - SNARE proteins are required for macroautophagy. AB - Macroautophagy mediates the degradation of long-lived proteins and organelles via the de novo formation of double-membrane autophagosomes that sequester cytoplasm and deliver it to the vacuole/lysosome; however, relatively little is known about autophagosome biogenesis. Atg8, a phosphatidylethanolamine-conjugated protein, was previously proposed to function in autophagosome membrane expansion, based on the observation that it mediates liposome tethering and hemifusion in vitro. We show here that with physiological concentrations of phosphatidylethanolamine, Atg8 does not act as a fusogen. Rather, we provide evidence for the involvement of exocytic Q/t-SNAREs in autophagosome formation, acting in the recruitment of key autophagy components to the site of autophagosome formation, and in regulating the organization of Atg9 into tubulovesicular clusters. Additionally, we found that the endosomal Q/t-SNARE Tlg2 and the R/v-SNAREs Sec22 and Ykt6 interact with Sso1-Sec9, and are required for normal Atg9 transport. Thus, multiple SNARE-mediated fusion events are likely to be involved in autophagosome biogenesis. PMID- 21784251 TI - SnapShot: hair follicle stem cells. PMID- 21784250 TI - Autophagosome precursor maturation requires homotypic fusion. AB - Autophagy is a catabolic process in which lysosomes degrade intracytoplasmic contents transported in double-membraned autophagosomes. Autophagosomes are formed by the elongation and fusion of phagophores, which can be derived from preautophagosomal structures coming from the plasma membrane and other sites like the endoplasmic reticulum and mitochondria. The mechanisms by which preautophagosomal structures elongate their membranes and mature toward fully formed autophagosomes still remain unknown. Here, we show that the maturation of the early Atg16L1 precursors requires homotypic fusion, which is essential for subsequent autophagosome formation. Atg16L1 precursor homotypic fusion depends on the SNARE protein VAMP7 together with partner SNAREs. Atg16L1 precursor homotypic fusion is a critical event in the early phases of autophagy that couples membrane acquisition and autophagosome biogenesis, as this step regulates the size of the vesicles, which in turn appears to influence their subsequent maturation into LC3 positive autophagosomes. PMID- 21784252 TI - Animals in research: "can they suffer?". PMID- 21784253 TI - The long road to improvement of human rights in China. PMID- 21784254 TI - Oral health care in the USA. PMID- 21784255 TI - Richard Moxon: a virtuoso of vaccinology. PMID- 21784256 TI - Greek academic psychiatry and neurology before the firing squad? PMID- 21784257 TI - Helicobacter pylori eradication. PMID- 21784258 TI - Male circumcision for prevention of oncogenic HPV infection. PMID- 21784259 TI - Helicobacter pylori eradication. PMID- 21784261 TI - Human papillomavirus vaccination in Africa. PMID- 21784264 TI - Blocking out the real diagnosis. PMID- 21784265 TI - Brazilian health-service organisation: problems at a glance. PMID- 21784266 TI - Post-disaster mental health care in Japan. PMID- 21784267 TI - Post-disaster mental health care in Japan. PMID- 21784268 TI - Life, health, and community in a tsunami-affected town. PMID- 21784269 TI - Crimean-Congo haemorrhagic fever in India. PMID- 21784271 TI - Disease-specific kidney imaging: introduction. PMID- 21784272 TI - Imaging approaches to patients with polycystic kidney disease. AB - Imaging is an important approach to diagnosis, monitoring, and predicting outcomes for patients with autosomal-dominant polycystic kidney disease. This article reviews three common clinical imaging techniques, ultrasonography, computed tomography, magnetic resonance imaging, and their role in the management of autosomal-dominant polycystic kidney disease. Ultrasonographic criteria for diagnosis in children and adults are reviewed. Total kidney volume, as measured by magnetic resonance imaging, is suggested as an important potential marker to determine disease progression and overall prognosis. Renal blood flow and a novel approach to interpreting noncystic renal parenchyma by computed tomography images are other innovative imaging approaches described. PMID- 21784273 TI - Imaging techniques for the patient with renal cell carcinoma. AB - The imaging of renal cell carcinoma continues to evolve from radiographic tomography to state-of-the-art three-dimensional imagery using computed tomography (CT) or magnetic resonance imaging (MRI). This article reviews the current techniques of imaging the patient with renal cell carcinoma. Careful and accurate imaging of these patients allows for the appropriate diagnosis, treatment planning, and follow-up care. At each point in the care of these patients, imaging plays an important role. In particular, the diagnosis and staging of renal cell carcinoma can be accomplished with CT and MRI, with each modality having strengths and weaknesses that are contrasted. Intraoperative ultrasound is used during laparoscopic or conventional partial nephrectomies, whereas ultrasound, CT, and MRI can be used for guiding ablative technologies. Imaging also plays an important role in the follow-up care of these patients. The particular follow-up care is dependent on the stage and grade of the lesion and the treatment modality used. In summary, this article reviews the current imaging approaches for the diagnosis, staging, treatment, and follow-up care of patients with renal cell carcinoma. PMID- 21784274 TI - Imaging evaluation in the patient with renal stone disease. AB - Numerous imaging modalities are available for the evaluation of patients with renal stone disease. The study of choice is dependent on the clinical scenario and the indication for imaging. Additional factors such as patient age and pregnancy status will influence the radiographic study that is chosen. Currently available technologies for the evaluation of urolithiasis include plain abdominal radiography, ultrasound, intravenous pyelogram, computed tomography, and magnetic resonance imaging. This article reviews the indications, advantages, and disadvantages of each study in the evaluation of patients with known or suspected stone disease. PMID- 21784275 TI - Imaging evaluation of kidney transplant recipients. AB - Renal transplantation is nowadays accepted as the treatment of choice for patients with end-stage renal disease. However, despite progress in immunosuppression and surgical techniques, various complications still can occur. Complications vary from vascular disorders and urologic diseases to parenchymal and immunologically related complications. The clinician evaluating the recipient with graft dysfunction has the option of choosing among a variety of imaging modalities including ultrasonography, nuclear medicine, computed tomography, and magnetic resonance imaging to start or continue the diagnostic work-up. In this article, we discuss the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality. PMID- 21784276 TI - Imaging for renovascular disease. AB - Renal artery stenosis is frequently considered in the diagnosis of severe hypertension and renal insufficiency, but the benefits of screening and the choice of imaging modalities is controversial. Sonography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and conventional angiography are all used and each has advantages and disadvantages. However, performance and interpretation of each requires significant experience and expertise. Since there are no clear data or consensus on the choice of imaging modalities, this should be based on the level of expertise that is available. PMID- 21784277 TI - Imaging techniques in the management of chronic kidney disease: current developments and future perspectives. AB - The measurement of both renal function and structure is critical in clinical nephrology to detect, stage, and monitor chronic kidney disease (CKD). Current imaging modalities especially ultrasound (US), computed tomography, and magnetic resonance imaging (MRI) provide adequate information on structural changes but little on functional impairment in CKD. Although not yet considered first-line procedures for evaluating patients with renal disease, new US and MR imaging techniques may permit the assessment of renal function in the near future. Combined with established imaging techniques, contrast-enhanced US, dynamic contrast-enhanced MRI, blood oxygen level dependency MRI, or diffusion-weighted imaging may provide rapid, accurate, simultaneous, and noninvasive imaging of the structure of kidneys, macrovascular and microvascular renal perfusion, oxygenation, and glomerular filtration rate. Recent developments in molecular imaging indicate that pathophysiological pathways of renal diseases such as apoptosis, coagulation, fibrosis, and ischemia will be visualized at the tissue level. These major advances in imaging and developments in hardware and software could enable comprehensive imaging of renal structure and function in four dimensions (three dimensions plus time), and imaging is expected to play an increasing role in the management of CKD. PMID- 21784278 TI - Positron emission tomography (PET) assessment of renal perfusion. AB - Positron emission tomography (PET) is a radionuclide imaging technique that allows noninvasive mapping of radiopharmaceutical concentrations in three dimensional space. PET methods have been described for imaging and quantification of renal perfusion using cyclotron-produced (15)O-water and (13)N-ammonia, as well as using generator-produced (82)RbCl and (62)Cu-ETS. Although the majority of clinical PET facilities will lack the in-house biomedical cyclotron needed for (15)O and (13)N production, the generator-produced tracers are available to virtually any clinical site with a PET camera. Studies with these radiopharmaceuticals have largely focused on methodologic issues, and agent validation for renal blood flow measurements. However, the resulting PET methods for quantification of renal perfusion do appear suitable for application to both research and clinical problems in renal pathophysiology. PMID- 21784280 TI - Gadolinium-induced nephrogenic systemic fibrosis. AB - Nephrogenic systemic fibrosis is a new disease whose incidence has peaked and receded over the past decade. It occurs in the presence of significant renal impairment, either acute or chronic (MDRD creatinine clearance of <30 mL/min/1.73 m(2)), and is associated with the administration of gadolinium-based contrast (GBC). Since 2006, the incidence of this disease has decreased markedly in patients with renal impairment, mainly owing to protocols that have not administered GBC to patients with creatinine clearances of less than 30 mL/min/1.73 m(2), and in some cases with the use of less toxic and lower doses of GBC. The purpose of this article is to review the current status of GBC use for imaging in patients with kidney disease. PMID- 21784279 TI - Contrast-induced acute kidney injury: short- and long-term implications. AB - The intravascular administration of iodine-based contrast media remains a common cause of acute kidney injury and a leading cause of iatrogenic renal disease. Past research has elucidated the principal risk factors for contrast-induced acute kidney injury (CIAKI) and helped to establish the efficacy of various interventions for the prevention of this condition. The importance of preventing CIAKI has been underscored by a growing number of studies showing strong associations of CIAKI with serious adverse short- and long-term outcomes. However, it remains unclear whether these associations are causal. This is important because considerable health care resources are used to prevent CIAKI. If CIAKI is a marker, but not a mediator, of serious adverse downstream outcomes, more judicious and selective use of preventive care may be appropriate. Moreover, with an increasing number of studies reporting the underuse of coronary angiography in patients with acute coronary syndrome and underlying chronic kidney disease, presumably in part because of a fear of CIAKI, a clear understanding of whether this condition directly results in adverse downstream outcomes is essential. Careful inspection of past studies that investigated the association of CIAKI with adverse short- and long-term events sheds light on their strengths and weaknesses and provides insight into how future research may be better able to characterize the short- and long-term implications of this iatrogenic condition. PMID- 21784281 TI - Competency-based training to create the 21st century mental health workforce: strides, stumbles, and solutions. AB - In response to sustained concerns about the capability of the mental health workforce, federal groups have urged educators to adopt a competency-based system for training students in core mental health skills. A particular emphasis is training students to work in integrated systems, intervene with evidence-based practice, and employ culturally relevant therapies. Creating such a program, particularly one delivered online, requires structures that engage students in their own learning and tools for tracking competencies. We report on our competency-based graduate psychiatric mental health nursing program and the unique methods used to track student skill development and clinical reasoning. PMID- 21784282 TI - Development of the patient-centered recovery resource system for veterans on long term mental health medications. AB - The aim of this qualitative descriptive study was to develop, with and for Veterans on long-term mental health medication regimens, a resource to promote self-management behavior. Focus groups were conducted with 19 outpatient Veterans who were self-administering their medications. Five themes emerged that informed the structure and content of the Recovery Resource System. Additional focus groups with 15 outpatient Veterans were conducted to evaluate the Recovery Resource System. Veterans assessed it to be flexible, dynamic, adaptable, and user-friendly. The goal of this patient-driven, patient-centered Recovery Resource System is to improve health outcomes and quality of life among those with chronic mental disorders. PMID- 21784283 TI - Graduate psychiatric nurse's training on firearm injury prevention. AB - Psychiatric nurses should be uniquely positioned for helping to prevent firearm suicides and homicides among the mentally ill. This study assessed the prevalence of firearm injury prevention training in graduate psychiatric nursing training programs through a three-wave mail survey of program directors. Most (87%) of the directors reported that they had not seriously thought about providing firearm injury prevention training. Almost half (48%) reported they did not routinely screen patients for firearm ownership. In addition, most (66%) thought that the American Psychiatric Nurses Association (APNA) should provide curriculum guidelines regarding firearm injury prevention training. Leadership is needed by the APNA to help reduce firearm violence in the mentally ill. PMID- 21784284 TI - Psychophenomenology of the postpsychotic adjustment process. AB - A clinical phenomenological study with nine adults with schizophrenia explored the postpsychotic adjustment stage of recovery from a psychotic episode to map a psychological recovery trajectory. Participants (ages 21-37 years) were actively involved in an early psychosis outpatient treatment program. Psychophenomenological analysis of interview data resulted in 458 descriptive expressions reflecting four structural elements. Cognitive dissonance involved achieving pharmacological efficacy and cognitive efforts to "sort out" the experience. Insight was distinguished by mastery of autonomous performance of reality checks. Cognitive constancy was marked by resuming interpersonal relationships and age-appropriate activities. Ordinariness involved consistent engagement in daily activities reflective of prepsychosis functioning. PMID- 21784285 TI - Mediating role of illness representation among social support, therapeutic alliance, experience of medication side effects, and medication adherence in persons with schizophrenia. AB - The purpose of this cross-sectional research study was to examine factors affecting medication adherence in Thai individuals with schizophrenia. The Common Sense Model of Illness Representation was used to guide the study. Two hundred twenty-five subjects met the inclusion criteria and were interviewed. Variables of interest focused on experience of medication side effects, therapeutic alliance, social support, illness representation, and behavior change with medication adherence. Results indicated that therapeutic alliance and the experience of medication side effects enhanced illness representation, which in turn led to an intention to change adherence behavior. Social support did not alter illness representation or adherence behavior. Because illness representation positively influenced patients' intention to change adherence behavior, mental health nurses should promote patients' perception about their illness to enhance medication adherence. PMID- 21784286 TI - The Wellness Planner: empowerment, quality of life, and continuity of care in mental illness. AB - Coordination of mental health services has often been a challenge from the user's point of view. Resulting gaps in care can lead to increased use of crisis services, more frequent hospitalization, and impaired quality of life. This study examined an innovative approach to building an individual's self-care capacities by testing the use of a wellness intervention: an adaptation of a client-held medical record/crisis plan in booklet form. Fifty individuals using community mental health services were recruited. Using a pretest-posttest design, participants completed measures of empowerment, continuity of care, quality of life, and satisfaction with services at the start of and again following 3 months of using the booklet. The booklet, referred to as the Wellness Planner, included components that have been empirically demonstrated as effective, such as crisis planning, goal setting, and resource planning. For the 42 individuals who completed the study, statistically significant increases were seen in empowerment, continuity of care, and satisfaction with services after 3 months of using the Wellness Planner. Qualitative data further demonstrated positive acceptance of the booklet by the users. Findings of the study suggest that the use of such a booklet could not only have a positive impact on the recovery of individuals but could also have utility within the mental health system. Since the completion of this study, the Winnipeg Regional Health Authority has adopted the booklet for use within all its adult mental health programs. Future research will focus on the impact of the booklet on system-wide indicators such as service utilization and readmission rates. PMID- 21784287 TI - Stigma and trust among mental health service users. AB - This article investigates whether and how the stigma experiences of mental health service users relate to trust in the professionals caring for them, and how both stigma and trust relate to service user satisfaction. The study uses survey data gathered from mental health service users (N = 650 service users from 36 organizations) and applies multilevel regression analyses. The results show that service users with more stigma experiences report less trust and are, partially for that reason, less satisfied with the services. Furthermore, service users with more severe symptoms and those with a psychotic disorder seem the most vulnerable ones for the processes occurring. PMID- 21784288 TI - Psychiatric mental health nursing's psychotherapy role: are we letting it slip away? PMID- 21784289 TI - In this issue/abstract thinking: in pursuit of causal mechanisms for psychiatric disorders. PMID- 21784290 TI - Gaps in quality measures for child mental health care: an opportunity for a collaborative agenda. PMID- 21784291 TI - Preventing youth suicide: time to ask how. PMID- 21784292 TI - Nonsuicidal self-injury: a clear marker for suicide risk. PMID- 21784293 TI - Coming closer to describing the variable onset patterns in autism. PMID- 21784294 TI - Trichotillomania: awareness and advances. PMID- 21784295 TI - Pharmacologic treatments for pediatric bipolar disorder: a review and meta analysis. AB - OBJECTIVE: A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention deficit/hyperactivity disorder was undertaken. METHOD: A systematic search was conducted through PubMed from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania. RESULTS: There have been 46 open-label (n = 29) and randomized (n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years. CONCLUSIONS: A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention deficit/hyperactivity disorder. PMID- 21784296 TI - Behavior therapy for pediatric trichotillomania: a randomized controlled trial. AB - OBJECTIVE: To examine the efficacy and durability of a behavioral therapy (BT) protocol for pediatric TTM compared with a minimal attention control (MAC) condition. It was hypothesized that the BT condition would be superior to MAC at the end of acute treatment, and would also demonstrate durability of gains through the maintenance treatment phase. METHOD: A randomized controlled trial in which 24 youths were assigned to either a pilot-tested BT protocol, consisting of eight weekly sessions, or to MAC, consisting of three sessions and five telephone calls over 8 weeks. Independent evaluators assessed outcome at pretreatment (week 0) and post-treatment (week 8) for BT and MAC, and again at week 16 for BT patients only. The primary outcome measure was the National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). RESULTS: For the BT condition, the week 8 mean NIMH-TSS score was significantly lower than that of the MAC condition. The BT condition's mean week 8 score was also significantly lower than their own mean week 0 score, whereas no such reductions were observed for the MAC condition. Upon completion of acute treatment at week 8, the BT group's gains were maintained through an 8-week maintenance treatment phase. CONCLUSIONS: BT produced a superior outcome compared with a condition that controlled for participation in a pediatric TTM research study, nonspecific therapist contact effects, repeated assessments, and the passage of time. Maintenance of gains after acute BT provides preliminary support for the durability of treatment gains. CLINICAL TRIAL REGISTRATION INFORMATION: Cognitive Behavioral Treatment of Pediatric Trichotillomania; http://www.clinicaltrials.gov; R21 MH 61457. PMID- 21784297 TI - Suicide attempts and nonsuicidal self-injury in the treatment of resistant depression in adolescents: findings from the TORDIA study. AB - OBJECTIVE: To evaluate the clinical and prognostic significance of suicide attempts (SAs) and nonsuicidal self-injury (NSSI) in adolescents with treatment resistant depression. METHOD: Depressed adolescents who did not improve with an adequate SSRI trial (N = 334) were randomized to a medication switch (SSRI or venlafaxine), with or without cognitive-behavioral therapy. NSSI and SAs were assessed at baseline and throughout the 24-week treatment period. RESULTS: Of the youths, 47.4% reported a history of self-injurious behavior at baseline: 23.9% NSSI alone, 14% NSSI+SAs, and 9.5% SAs alone. The 24-week incidence rates of SAs and NSSI were 7% and 11%, respectively; these rates were highest among youths with NSSI+SAs at baseline. NSSI history predicted both incident SAs (hazard ratio [HR]= 5.28, 95% confidence interval [CI] = 1.80-15.47, z = 3.04, p = .002) and incident NSSI (HR = 7.31, z = 4.19, 95% CI = 2.88-18.54, p < .001) through week 24, and was a stronger predictor of future attempts than a history of SAs (HR = 1.92, 95% CI = 0.81-4.52, z = 2.29, p = .13). In the most parsimonious model predicting time to incident SAs, baseline NSSI history and hopelessness were significant predictors, adjusting for treatment effects. Parallel analyses predicting time to incident NSSI through week 24 identified baseline NSSI history and physical and/or sexual abuse history as significant predictors. CONCLUSIONS: NSSI is a common problem among youths with treatment-resistant depression and is a significant predictor of future SAs and NSSI, underscoring the critical need for strategies that target the prevention of both NSSI and suicidal behavior. CLINICAL TRIAL REGISTRATION INFORMATION: Treatment of SSRI-Resistant Depression in Adolescents (TORDIA). URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00018902. PMID- 21784298 TI - Deconstructing pediatric depression trials: an analysis of the effects of expectancy and therapeutic contact. AB - OBJECTIVE: This study investigated how study type, mean patient age, and amount of contact with research staff affected response rates to medication and placebo in acute antidepressant trials for pediatric depression. METHOD: Data were extracted from nine open, four active comparator, and 18 placebo-controlled studies of antidepressants for children and adolescents with depressive disorders. A multilevel meta-analysis examined how study characteristics affected response rates to antidepressants and placebo. RESULTS: The primary finding was a main effect of study type across patient age and contact amount, such that the odds of medication response were greater in open versus placebo-controlled studies (odds ratio 1.87, 95% confidence interval 1.17-2.99, p = .012) and comparator studies (odds ratio 2.01, 95% confidence interval 1.16-3.48, p = .015) but were not significantly different between comparator and placebo-controlled studies. No significant main effects of patient age or amount of contact with research staff were found for analyses of response rates to medication and placebo. Response to placebo in placebo-controlled trials did significantly increase with the amount of therapeutic contact in older patients (age by contact; odds ratio 1.08, 95% confidence interval 1.01-1.15, p = .038). CONCLUSIONS: Although patient expectancy strongly influences response rates to medication and placebo in depressed adults, it appears to be less important in the treatment of children and adolescents with depression. Attempts to limit placebo response and improve the efficiency of antidepressant trials for pediatric depression should focus on other causes of placebo response apart from expectancy. PMID- 21784299 TI - Onset patterns in autism: correspondence between home video and parent report. AB - OBJECTIVE: The onset of autism is usually conceptualized as occurring in one of two patterns, early onset or regressive. This study examined the number and shape of trajectories of symptom onset evident in coded home movies of children with autism and examined their correspondence with parent report of onset. METHOD: Four social-communicative behaviors were coded from the home video of children with autism (n = 52) or typical development (n = 23). All home videos from 6 through 24 months of age were coded (3199 segments). Latent class modeling was used to characterize trajectories and determine the optimal number needed to describe the coded home video. These trajectories were then compared with parent reports of onset patterns, as defined by the Autism Diagnostic Interview-Revised. RESULTS: A three-trajectory model best fit the data from the participants with autism. One trajectory displayed low levels of social-communication across time. A second trajectory displayed high levels of social-communication early in life, followed by a significant decrease over time. A third trajectory displayed initial levels of behavior that were similar to the typically developing group but little progress in social-communication with age. There was poor correspondence between home video-based trajectories and parent report of onset. CONCLUSIONS: More than two onset categories may be needed to describe the ways in which symptoms emerge in children with autism. There is low agreement between parent report and home video, suggesting that methods for improving parent report of early development must be developed. PMID- 21784300 TI - Genome-wide association study of the child behavior checklist dysregulation profile. AB - OBJECTIVE: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. RESULTS: CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N = 128) and the MGH (N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p < 5E-05: TMEM132D, LRRC7, SEMA3A, ALK, and STIP1. CONCLUSIONS: We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP. PMID- 21784301 TI - Shared genetic influences on negative emotionality and major depression/conduct disorder comorbidity. AB - OBJECTIVE: To investigate whether genetic contributions to major depressive disorder and conduct disorder comorbidity are shared with genetic influences on negative emotionality. METHOD: Primary caregivers of 2,022 same- and opposite-sex twin pairs 6 to 18 years of age comprised a population-based sample. Participants were randomly selected across five regions in Tennessee, with stratification by age and geographic location. Face-to-face structured interviews were conducted with the primary caregiver of a representative sample of twins. RESULTS: After accounting for genetic influences on negative emotionality, genetic influences on major depressive disorder/conduct disorder comorbidity were nonsignficant, but only in male twins. Specifically, 19% of the variance in the two disorders was accounted for by genetic factors shared with negative emotionality in male twins. Although the full hypothesis could not be tested in female twins, 10% to 11% of the variance in the two disorders was also accounted for by genetic factors shared with negative emotionality. Common shared environmental and nonshared environmental influences were found for major depressive disorder/conduct disorder comorbidity in male and female twins. CONCLUSIONS: Negative emotionality represents an important dispositional trait that may explain genetic influences on major depressive disorder/conduct disorder comorbidity, at least for boys. Models of major depressive disorder/conduct disorder comorbidity must simultaneously measure common and specific genetic and environmental factors for a full understanding of this phenomenon. Gender differences require specific research attention in dispositional factors and developmental progression. PMID- 21784304 TI - HIV, HCV, and HBV co-infections in a rural area of Shanxi province with a history of commercial blood donation. AB - BACKGROUND: Unhygienic blood collection in the early 1990s led to blood-borne infections in Central China. This study aimed to estimate human immunodeficiency virus (HIV) co-infection with hepatitis C and B viruses (HCV and HBV) and their risk factors in a rural area of Shanxi Province with a history of commercial blood donation. METHODS: A cross-sectional study was conducted in 2004. All adult residents in the target area were invited to participate in the study. Face-to face interviews were completed and blood specimens were tested for HIV, HCV, and HBV surface antigen (HBsAg). RESULTS: Prevalence rates of HIV, HCV, and HBsAg were 1.3% (40/3 062), 12.7% (389/3 062), and 3.5% (103/2982), respectively. Of the 40 HIV-positive specimens, 85% were HCV positive and 2.5% were HBsAg positive. The history of commercial blood donation was positively associated with HIV, HCV, and HIV/HCV co-infections, but was negatively associated with HBsAg seropositivity. Migration for employment in the last 5 years was positively related to HIV, HBsAg, and HIV/HCV co-infections. Univariate logistic analysis showed that illegal drug use, number of sex partners, extramarital sex behavior, commercial sex behavior, and condom use rate were not related to anti-HIV, anti HCV, HBsAg seropositivity or their co-infections. CONCLUSION: The history of commercial blood donation was the main risk factor for HIV, HCV, and HIV/HCV co infections in this former commercial blood donation area. HIV and HCV prevention and treatment interventions are important in this area. PMID- 21784302 TI - Abnormal amygdalar activation and connectivity in adolescents with attention deficit/hyperactivity disorder. AB - OBJECTIVE: Emotional reactivity is one of the most disabling symptoms associated with attention-deficit/hyperactivity disorder (ADHD). We aimed to identify neural substrates associated with emotional reactivity and to assess the effects of stimulants on those substrates. METHOD: We used functional magnetic resonance imaging (fMRI) to assess neural activity in adolescents with (n = 15) and without (n = 15) ADHD while they performed a task involving the subliminal presentation of fearful faces. Using dynamic causal modeling, we also examined the effective connectivity of two regions associated with emotional reactivity, i.e., the amygdala and the lateral prefrontal cortex (LPFC). The participants with ADHD underwent scanning both on and off stimulant medication in a counterbalanced fashion. RESULTS: During the task, we found that activity in the right amygdala was greater in adolescents with ADHD than in control subjects. In addition, in adolescents with ADHD, greater connectivity was detected between the amygdala and LPFC. Stimulants had a normalizing effect on both the activity in the right amygdala and the connectivity between the amygdala and LPFC. CONCLUSIONS: Our findings demonstrate that in adolescents with ADHD, a neural substrate of fear processing is atypical, as is the connectivity between the amygdala and LPFC. These findings suggest possible neural substrates for the emotional reactivity that is often present in youths with ADHD, and provide putative neural targets for the development of novel therapeutic interventions for this condition. PMID- 21784305 TI - Characterization of hand, foot, and mouth disease in China between 2008 and 2009. AB - OBJECTIVE: To investigate the epidemiological and clinical features of hand, foot and mouth disease (HFMD) since several outbreaks of HFMD caused by enteroviruses were documented in China between 2007 and 2008. METHODS: HFMD cases reported to the National Infectious Disease Information Management System database between May 2008 and April 2009 were assessed. Clinical features in some of the severe and fatal cases were analyzed the etiology of the outbreaks was investigated. RESULTS: 89.1% of reported HFMD cases were found in children<5 year-old with an age-specific incidence rate of 834.1/100 000 in the first year as the notifiable disease in China from May 2008 to April 2009. The incidence, mortality and percentage of severe cases were studied for three regions of China and found to be highest in the central region. The incidence of severe cases and mortality in rural population were significantly higher than those in urban population. Among the laboratory confirmed EV17 positive cases there were 52.6% mild, 83.5% severe, and 96.1% fatal cases. More myoclonic jerks were found in the severe case group than in group that died. Tachypnea, lip purpling, pink foaming and low limb temperature occurred more frequently in the fatal cases than in the severe cases. CONCLUSION: The epidemic of HFMD in China was characterized predominantly by EV71 infections, had relatively high mortality rates especially in the central region, and was most prevalent in young, rural populations. PMID- 21784306 TI - Effect of occupational manganese exposure on uric Acid levels in human urine. AB - OBJECTIVE: To investigate the effect of long-term and low-level occupational Mn exposure on the level of uric acid (UA) in human urine. METHODS: In this study, 65 volunteers were recruited, who were working on welding and foundry work in an plant in Gansu province, China. Additionally, 29 control samples were collected from individuals who did not have any history of excessive Mn exposure. An improved high performance liquid chromatography system equipped with a diode array detector (HPLC-DAD) method was developed to determine the UA level in human urine. A Spectra AA 220 Atomic Absorption Spectrophotometer (AAS) was used to measure the Mn level in the urine. RESULTS: The analytical method was validated for concentrations ranging from 3.82-45.84 MUg/mL with acceptable accuracy, precision, and recovery. Overall, the UA levels of Mn exposure samples were significantly lower than that of control samples (P<0.05). CONCLUSION: The practical method developed here is suitable for both routine monitoring of UA level in human urine and metabolism research. Long-term and low-level occupational Mn exposure may lead to a lower UA level in urine, and UA might be an indicator of the early stage of manganism. PMID- 21784307 TI - Factors associated with generic and disease-specific quality of life in epilepsy. AB - OBJECTIVE: To investigate the association between quality of life (QOL) and sociodemographic factors, clinical seizure factors, depression and anxiety in patients suffering from epilepsy. METHODS: We examined 141 consecutive patients with epilepsy (mean age 25.8+/-9.6, 61.7% male). All patients completed the Self Rating Depression Scale, Self-Rating Anxiety Scale, WHOQOL-BREF and QOLIE 31(Chinese version). Multiple linear regression analyses were applied to investigate factors impact on QOL. RESULTS: The results revealed that scores on two domains of the WHOQOL-BREF (i.e., physical and psychological domains, P<0.05) were significantly lower in the epilepsy group compared with the control group. Multiple regression analyses showed that anxiety, depression and course explained approximately 40% of the variance in patients' QOL. Anxiety was consistently the strongest predictor of lower scores on almost all QOL domains. In addition, the severity of depressive symptoms was significantly associated with lower scores across many QOL domains. CONCLUSION: Our findings suggest that QOLIE scores might be substantially affected by the presence and severity of anxiety symptoms and, to a lesser degree, of depressive symptoms and prolonged course of illness. In contrast, clinical seizure variables had a weaker association with QOL. Healthcare professionals should be aware of the significance of patients' emotional state and of the role it plays in their QOL. PMID- 21784308 TI - The relationships between erythrocyte membrane n-6 to n-3 polyunsaturated fatty acids ratio and blood lipids and C-reactive protein in Chinese adults: an observational study. AB - OBJECTIVE: To investigate the relationships between erythrocyte membrane n-6:n-3 PUFAs ratio and blood lipids and high sensitivity C-reactive protein (hs-CRP). METHODS: The observational study consisted of a population-based cross-sectional study of 456 Chinese and a subsequent 1-year follow-up study of 171 subjects with the fasting plasma total cholesterol of 5.13-8.00 mmol/L. RESULTS: In the cross sectional analysis, plasma low-density lipoprotein cholesterol (LDL-c) had a significant and negative association with the erythrocyte membrane n-6:n-3 PUFAs ratio (P for trend=0.019) after adjusting for sex, age and total PUFA percentage. In the follow-up study, 171 subjects were categorized into quartiles by the changes of n-6:n-3 ratio in erythrocyte membrane (Delta=month 12-month 0). In the top quartile whose ratios of n-6:n-3 increased by an average of 1.25 during the follow-up, the LDL-c-lowering extent was 3.3 times of that in the lowest quartile whose ratios of n-6:n-3 decreased by an average of 1.13 (-1.07 mmol/L v.s. -0.32 mmol/L). The hsCRP decreased by 0.11 mg/dL in the lowest quartile while increasing by 0.10 mg/dL in the top quartile (P for difference=0.052). CONCLUSION: Our results suggested that the balance between n-6 and n-3 fatty acids may optimize the cardiovascular benefits from dietary PUFAs. PMID- 21784309 TI - Change of BMD after weaning or resumption of menstruation in Chinese women with different FokI VDR-genotypes: a randomized, placebo-controlled, calcium supplementation trial. AB - OBJECTIVE: To investigate the effect of calcium supplementation on bone mineral density (BMD) in Chinese women with different FokI vitamin D receptor (VDR) genotypes (FF, Ff, and ff) after weaning or resumption of menstruation during lactation. METHODS: A total of 40 subjects with the same FokI VDR genotype were randomly divided into two groups: one received calcium tablet (600 mg once daily as CaCO(3)) and the other placebo tablet once daily for 1 year. At baseline, BMD was measured by dual-energy X-ray absorptiometry at lumbar spine (L2-L4) and at left hip whereas serum PICP, serum OC, and urinary CTX, serum 25(OH)VitD(3), and serum estradiol were measured at weaning and 1 year thereafter. RESULTS: After the intervention, BMD at lumbar spine and at left hip increased significantly in all these women with a trend among different FokI VDR genotypes such as FF > Ff > ff (P<0.05, <0.01, and <0.001, respectively). BMD at lumbar spine in women with FF VDR genotype increased much more rapidly than in those with ff VDR genotype (P<0.05). Compared with the control group women with the FF genotype regained more BMD after calcium supplementation (P<0.05). CONCLUSION: Daily calcium 600 mg supplementation has beneficial effect on the bone health of women with FF VDR genotype. PMID- 21784310 TI - Differences in heart stroke volume between Han and Korean-Chinese nationalities and correlative factors. AB - OBJECTIVE: To compare the differences in stroke volume (SV) and stroke volume index (SI) between Han and Korean-Chinese and to investigate the correlated risk factors. METHODS: A total of 1 647 Han and 876 Korean-Chinese aged 10-80 years were investigated. SV, SI, cardiac output, cardiac output index, heart rate (HR), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI), and blood pressure were measured. RESULTS: SV/SI values in Korean-Chinese were lower than those in the Han of the same sex and age. Covariance analysis showed that, apart from the effect of sex, age and body mass index (BMI), the differences in SV and SI between the two cohorts were still significant (P<0.001). Multiple regression analysis revealed that the SV difference between the two ethnicities was affected (in descending order from a strong to weak correlation) by SVR, SVRI, HR, diastolic blood pressure, mean arterial pressure, BMI, and systolic blood pressure, while the SI difference was affected by SVR, SVRI, HR, mean arterial pressure, diastolic and systolic blood pressure, and BMI. CONCLUSION: The Fact that SV and SI in Korean-Chinese are lower than those in Han is related with higher SVR, HR and blood pressure in the Korean-Chinese. PMID- 21784311 TI - Kinetics of ozonation of typical sulfonamides in water. AB - OBJECTIVE: To investigate the kinetic rate constants ozone and hydroxyl radicals towards two groups of antimicrobials -sulfadiazine (SD) and sulfamethoxazole (SMX). METHODS: The solute consumption method was used to detect the rate constants of ozone alone with sulfadiazine and sulfamethoxazole, and tertiary butanol was selected as a scavenging agent and pH was adjusted to 2.5 by adding orthophosphate buffers (OB); and the competition kinetics studying methodwith nitrobenzene as a reference was applied to measure the rate constants of hydroxyl radicals towards sulfadiazine and sulfamethoxazole, and pH was adjusted to 7.0 by adding OB. RESULTS: The rate constants of SD and SMX with ozone alone were 261 mol(-1) . dm(3) . s(-1) and 303 mol(-1) . dm3 . s(-1) by calculating in low reaction system. The rate constants of hydroxyl radicals with SD and SMX were 2.2*1010 mol(-1) . dm(3) . s(-1) and 2.7*1010 mol(-1) . dm(3) . s(-1), respectively. Moreover, the rate constants of hydroxyl radicals with SMX were found to have increased from 3.6*109 mol(-1) . dm(3) . s(-1) to 2.8*1010 mol(-1) . dm(3) . s(-1) with pH value rising from 5.0 to 7.8. CONCLUSION: SMX and SD are both refractory to ozone oxidation alone, and are liable to be degraded by hydroxyl radicals, and the rate constants of SMX with the hydroxyl radical slightly increases with pH rise. PMID- 21784312 TI - Kinetic models of dichloroethylene biodegradation by two strains of aerobic bacteria. AB - OBJECTIVE: In this study, we examined the biodegradation of Dichloroethylene (DCE) by two strains of aerobic bacteria. METHODS: Using batch experiments, we measured the biodegradation rates of DCE and the residual concentrations of DCE for each bacterial strain. The varying trends in biodegradation rates with different initial concentrations of DCE were fitted to kinetic models. RESULTS: The biodegradation kinetics of DCE by the strain DT-X, which uses toluene as co metabolic substrate, fitted the Monod model (corresponding parameters: v(max)=0.0075 h(-1), K(s)=2.12 mg/L). The biodegradation kinetics of DCE by the strain DT-M, which uses 1,1-Dichloroethylene as single substrate, fitted the Haldane model (parameters: v(max) =0.0046 h(-1), K(s)=4.25 mg/L, K(i)=8.47 mg/L). CONCLUSION: The substrate removal rate constant of 1,1-Dichloroethylene of the co metabolic strain DT-X was much higher than that of strain DT-M. The substrate removal rates obtained from both bacterial strains in this study were higher than those reported in similar studies. PMID- 21784313 TI - Interaction between XRCC1 polymorphisms and intake of long-term stored rice in the risk of esophageal squamous cell carcinoma: a case-control study. AB - OBJECTIVE: This study aimed to explore the roles of three common single nucleotide polymorphisms in the X-ray repair cross-complementing group-1 gene (XRCC1) and of life style factors and their possible interactions in the risk of esophageal squamous cell carcinoma (ESCC) in China. METHODS: A population-based case-control study of 432 cases and 915 controls was conducted in Yangzhong County, Jiangsu Province, China. Subjects were interviewed by trained interviewers using a structured questionnaire that included questions on demographics and life style. XRCC1 genotypes were analyzed using a polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) assay. Unconditional logistic regression analysis was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations of ESCC with XRCC1 polymorphisms and lifestyle-related factors. RESULTS: Both the drinking of river water and alcohol intake history were significantly associated [SW1]with an increased risk of ESCC among men with aORs of 4.20 (95% CI: 2.90-6.07) and 2.03 (95% CI: 1.43-2.89), respectively. For women, the corresponding odds ratios were 8.37 (95% CI: 5.09-13.75) for river water drinking and 12.78 (95% CI: 2.69-60.69) for long-term stored rice intake. After the XRCC1 G28152A polymorphism was adjusted for potential confounders, subjects with GA and AA genotypes had an increased risk for ESCC (aOR: 1.21, 95% CI: 0.93-1.56), compared with subjects with a GG genotype, and a positive multiplicative interaction between intake of long-term stored rice and the XRCC1 G28152A polymorphism was observed (P=0.009). CONCLUSIONS: Our findings suggest that both lifestyle-related factors, including drinking river water, long-term stored rice and alcohol intake, and the XRCC1 G28152A polymorphism were possible risk factors for ESCC, and that the XRCC1 G28152A polymorphism modified the effect of long-term stored rice intake on the risk of ESCC among Chinese people. PMID- 21784314 TI - Epidemiological survey and analysis on an outbreak of gastroenteritis due to water contamination. AB - OBJECTIVE: To document the investigation and control of an outbreak of gastroenteritis in City G, South China, and provide a reference for preventing future outbreaks. METHODS: An ambispective cohort study was designed. Attack rate (AR) and relative risks (RR) were calculated to identify the causes of gastroenteritis. Investigations using questionnaires included personal interviews with patients and doctors, reviews of medical records, laboratory examinations of fecal specimens and continuous hygiene monitoring of water samples from the waterworks. RESULTS: Overall, 427/71534 (AR=5.97%) cases were identified between October 31 and November 12 2010. Geographic distribution was highly localized, with 80% of cases occurring in the areas supplied by waterworks-A. Consumption of water provided solely by waterworks-A was found to be associated with illness (RR=8.20, 95 CI%:6.12-10.99) compared with that from waterworks-B. Microbiological analyses confirmed the presence of Norovirus in six of eight fecal samples from symptomatic patients, two water samples from waterworks-A and two sewage samples. After taking effective measures, the hygienic indices of waterworks-A met health criteria again on November 9 and no cases were reported 3 days later. CONCLUSION: The outbreak reported here was caused by drinking tap water contaminated with sewage at the source. Early identification of possible contamination sources and awareness of changes that might negatively impact water quality are important preventive measures to protect public health. PMID- 21784315 TI - The covalent binding of genistein to the non-prosthetic-heme-moiety of bovine lactoperoxidase leads to enzymatic inactivation. AB - OBJECTIVE: Genistein, a major soy isoflavone metabolite (SIF), inactivates oxidation activity of bovine lactoperoxidase (LPO). Modification of the heme moiety of LPO by nitrogen-containing compounds has been shown to inactivate LPO. In contrast, SIF mediated inactivation of LPO does not involve a heme modification and the mechanism of SIF inhibition is poorly understood. METHODS: After inactivation of LPO by genistein in the presence of H(2)O(2), trypsin digested LPO peptide fragments were collected and analyzed by MALDI-TOF-MS to characterize the chemical binding of genistein(s) to LPO. RESULTS: The heme moiety of LPO was not modified by genistein. A covalent binding study showed that (3)H-genistein bound to LPO with a ratio of ~12 to 1. After HPLC analysis and peak collection, trypsin-digested peptide fragments were analyzed by MALDI-TOF MS. The 3H-genistein co-eluted peptide fragments (RT=24 min) were putatively identified as 199IVGYLDEEGVLDQNR214 with two bound genistein molecules or a genistein dimer (2 259 Da), 486TPDNIDIWIGGNAEPMVER504 with two bound genistein molecules or a genistein dimer (2 663 Da), and 161ARWLPAEYEDGLALPFGWTQR182 with three bound genistein molecules or a genistein trimer (3 060 Da). The fragment with a mass of 1 792 Da (RT=36 min) was identified as 132CDENSPYR139 with three genistein molecules or a genistein trimer. CONCLUSIONS: The results suggest that LPO was inactivated by irreversible covalent binding of genistein or genistein polymers to particular peptide fragments constituting regions of the outward domain. No genistein interaction with the prosthetic heme moiety of LPO was observed. PMID- 21784316 TI - A sensitive and specific IgM-ELISA for the serological diagnosis of human leptospirosis using a rLipL32/1-LipL21-OmpL1/2 fusion protein. AB - OBJECTIVE: To construct a lipL32/1-lipL21-OmpL1/2 fusion gene and its prokaryotic expression system, and to establish an enzyme-linked immunosorbent assay (ELISA) using the rLipL32/1-LipL21-OmpL1/2 fusion antigen of Leptospira interrogans for sensitive and specific detection of IgM in the serum of patients with leptospirosis. METHODS: lipL32/1-lipL21-OmpL1/2 fusion genes were constructed using a primer-linking PCR. The target recombinant protein antigens, rLipL32/1, rLipL21, rOmpL1/2 and rLipL32/1-LipL21-OmpL1/2, were expressed and the purified antigens were then immobilized to the surface of microplate wells for ELISA-based detection of IgM in the sera of leptospirosis patients. RESULTS: Of 493 acute leptospirosis patients, 95.7% and 97.8% were positive by rLipL32/1-LipL21- OmpL1/2-IgM-ELISA using different serum dilutions, which was higher than the rLipL32/1-IgM-ELISA (93.1% and 90.3%), rLipL21-IgM-ELISA (90.3% and 87.0%), and rOmpL1-IgM-ELISA (85.6% and 81.1%) (P<0.01). All IgM-ELISAs tested negative against 56 non-leptospirosis patients with typhoid fever, hemorrhagic fever or dengue fever. CONCLUSION: Trigeminal fusion antigen increases ELISA sensitivity and the rLipL32/1-LipL21-OmpL1/2- IgM-ELISA is a sensitive and specific serological diagnostic method for clinical leptospirosis. PMID- 21784317 TI - Detection of CYP2E1, a genetic biomarker of susceptibility to benzene metabolism toxicity in immortal human lymphocytes derived from the Han Chinese Population. AB - OBJECTIVE: Cytochrome P450 2E1 (CYP2E1) is an important metabolizing enzyme involved in oxidative stress responses to benzene, a chemical associated with bone marrow toxicity and leukemia. We aimed to identify the CYP2E1 genetic biomarkers of susceptibility to benzene toxicity in support of environmental and occupational exposure prevention, and to test whether a model using immortal human lymphocytes might be an efficient tool for detecting genetic biomarkers. METHODS: Immortalized human lymphocyte cell lines with independent genotypes on four CYP2E1 SNP sites were induced with 0.01% phenol, a metabolite of benzene. CYP2E1 gene function was evaluated by mRNA expression and enzyme activity. DNA damage was measured by Single-Cell Gel Electrophoresis (SCGE). RESULTS: Among the four SNPs, cells with rs2070673TT and rs2030920CC showed higher levels of CYP2E1 transcription and enzymatic activity than the other genotypes in the same SNP site. Cells with higher gene expression genotypes also showed higher comet rates compared with lower gene expression genotypes. CONCLUSION: These results suggest that CYP2E1 rs2070673 and rs2030920 might be the genetic biomarkers of susceptibility to benzene toxicity and that the immortalized human lymphocytes model might be an efficient tool for the detection of genetic biomarkers of susceptibility to chemicals. PMID- 21784318 TI - Genetic relationship between Francisella tularensis strains from China and from other countries. AB - OBJECTIVE: To study the types of subspecies of Francisella tularensis from China and to investigate the genetic relationships between F. tularensis strains from China and from other countries. METHODS: Ten strains of F. tularensis isolated from China were amplified by using typing primers C1/C4 and RD1. On the basis of the lengths of the polymerase chain reaction (PCR) products, it was concluded that these strains of F. tularensis belonged to the same subspecies. At the same time, the fopA, tul4, and 16S rRNA genes of the 10 strains were amplified, and a three-gene based phylogenetic analysis was performed using the Molecular Evolutionary Genetics Analysis software version 4.0. RESULTS: The 10 strains of F. tularensis from China were all identified as belonging to subspecies holarctica (type B). We found no direct relationship between the genotypes of F. tularensis subsp. holarctica and the geographical area from where they were isolated. CONCLUSION: The F. tularensis strains isolated from North China mainly belong to subspecies holarctica (type B). The strains of F. tularensis subsp. holarctica from China may have evolved earlier than those from Europe and North America. PMID- 21784319 TI - The identification of the Cryptosporidium ubiquitum in pre-weaned Ovines from Aba Tibetan and Qiang autonomous prefecture in China. AB - OBJECTIVE: Cryptosporidium spp. are prevalent globally and sheep are an important zoonotic reservoir. Little data regarding the rates of Cryptosporidium infections in ovines in China are available. This study assessed the prevalence of Cryptosporidium spp. in pre-weaned ovines from Aba Tibetan and Qiang Autonomous Prefecture in the Sichuan province of China. METHODS: A total of 213 fecal samples were collected from pre-weaned ovines and were examined microscopically (following modified acid fast staining). In addition, 18S rRNA genetic sequences were amplified from fecal samples by nested PCR and phylogenetically analyzed. RESULTS: The prevalence of Cryptosporidium in the collected samples was at 14.6% (31/213) and four isolates identified by PCR belonged to the Cryptosporidium cervine genotype (Cryptosporidium ubiquitum) demonstrating that this species was the primary sheep species found in sheep in China. CONCLUSION: The present study suggested that the high incidence of Cryptosporidium in sheep poses a significant public health threat and that surveillance practices must be established to prevent zoonotic disease of humans. PMID- 21784320 TI - Updating systematic reviews--when and how? PMID- 21784322 TI - The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study. AB - INTRODUCTION: In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education. PATIENTS AND METHODS: Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI). RESULTS: AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations. CONCLUSION: AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment. PMID- 21784323 TI - How cognitive assessment through clinical neurophysiology may help optimize chronic alcoholism treatment. AB - Alcohol dependence constitutes a serious worldwide public health problem. The last few decades have seen many pharmacological studies devoted to the improvement of alcoholism treatment. Although psychosocial treatments (e.g. individual or group therapy) have historically been the mainstay of alcoholism treatment, a successful approach for alcohol dependence consists in associating pharmacologic medications with therapy, as 40-70% of patients following only psychosocial therapy typically resume alcohol use within a year of post detoxification treatment. Nowadays, two main pharmacological options, naltrexone and acomprosate, both approved by the US Food and Drug Administration, are available and seemingly improve on the results yielded by standard techniques employed in the management of alcoholism. However, insufficient data exist to confirm the superiority of one drug over the other, and research is ongoing to determine what type of alcohol-dependent individual benefits the most from using either medication. Available data on the application of both drugs clearly suggest different practical applications. Thus, a fundamental question remains as to how we can identify which alcoholic patients are likely to benefit from the use of naltrexone, acamprosate or both, and which are not. The aim of the present manuscript is to suggest the use of cognitive event-related potentials as an interesting way to identify subgroups of alcoholic patients displaying specific clinical symptoms and cognitive disturbances. We propose that this may help clinicians improve their treatment of alcoholic patients by focusing therapy on individual cognitive disturbances, and by adapting the pharmaceutical approach to the specific needs of the patient. PMID- 21784324 TI - [The strategy of Revista de Calidad Asistencial]. PMID- 21784325 TI - Molecules and nanoparticles in extreme homeopathic dilutions: is Avogadro's Constant a dogma? PMID- 21784326 TI - Homeopathic ear drops as an adjunct to standard therapy in children with acute otitis media. AB - OBJECTIVE: To assess the effectiveness of a homeopathic ear drop for treatment of otalgia in children with acute otitis media (AOM). METHODS: Children with AOM were enrolled in the study at the time of diagnosis and randomized to receive either standard therapy alone or standard therapy plus a homeopathic ear drop solution that was to be used on as needed basis for up to 5 days. Parents of children in both treatment groups rated the severity of 5 AOM symptoms twice daily for 5 days in a symptom diary. A symptom score was computed for each assessment with lower scores denoting less severe symptoms. Parents of children randomized to receive ear drops also recorded information regarding symptoms being treated and response to treatment. RESULTS: A total of 119 eligible children were enrolled in the study; symptom diaries were received from 94 (79%). Symptom scores tended to be lower in the group of children receiving ear drops than in those receiving standard therapy alone; these differences were significant at the second and third assessments (P = 0.04 and P = 0.003, respectively). In addition, the rate of symptom improvement was faster in children in the ear drop group compared with children in standard therapy alone group (P = 0.002). The most common reason for administration of ear drops was ear pain, recorded for 93 doses; improvement was noted after 78.4% of doses for this indication. There were no significant side effects related to use of the ear drops. CONCLUSIONS: This study suggests that homeopathic ear drops were moderately effective in treating otalgia in children with AOM and may be most effective in the early period after a diagnosis of AOM. Pediatricians and other primary health care providers should consider homeopathic ear drops a useful adjunct to standard therapy. PMID- 21784327 TI - Homeopathic Plumbum metallicum for lead poisoning: a randomized clinical trial. AB - INTRODUCTION: Poisoning due to lead and its compounds has short and long-term effects primarily on the nervous, hematopoietic, gastrointestinal, cardiovascular, musculoskeletal, renal and reproductive systems. It can manifest in acute or chronic symptoms. Measuring serum concentration is the primary method for diagnosing and monitoring exposed workers. Presently, elevated lead levels are treated by drugs whose effectiveness is contested on various fronts. Experimental studies suggest that homeopathic preparations may be in controlling blood lead levels in laboratory animals, creating the need for controlled studies to evaluate the effectiveness and safety of these preparations in humans. OBJECTIVE: To evaluate the effectiveness of the homeopathic preparation Plumbum metallicum in reducing the blood lead level of workers exposed to this metal. DESIGN: Double-blind randomized trial. SETTING: Workers' clinic in the Ajax battery plant, which employs 900 workers with varying degrees of lead exposure in Bauru, Sao Paulo State, Brazil. SUBJECTS: 131 workers exposed to lead. INTERVENTION: Plumbum metallicum 15 cH or placebo, orally for 35 days. RESULTS: The percentage of workers who demonstrated a reduction in lead counts by a percentage greater than or equal to 25% following treatment was the same for both groups: 20.3% in the homeopathic groups versus 21% in the control group [Relative Risk (RR) = 0.95, confidential interval (CI) 95%: 0.47-1.92)]. Analysis by intention-to-treat also did not show any difference between the groups: 18.2% in the treated group versus 20% in the placebo group (RR = 0.91, CI 95%: 0.45-1.84). CONCLUSION: The homeopathic preparation Plumbum metallicum had no effect, in this study, in terms of reducing serum lead in workers exposed to lead. PMID- 21784328 TI - The feasibility of a pragmatic randomised controlled trial to compare usual care with usual care plus individualised homeopathy, in children requiring secondary care for asthma. AB - OBJECTIVE: To test the feasibility of a pragmatic trial design with economic evaluation and nested qualitative study, comparing usual care (UC) with UC plus individualised homeopathy, in children requiring secondary care for asthma. This included recruitment and retention, acceptability of outcome measures patients' and health professionals' views and experiences and a power calculation for a definitive trial. METHODS: In a pragmatic parallel group randomised controlled trial (RCT) design, children on step 2 or above of the British Thoracic Society Asthma Guidelines (BTG) were randomly allocated to UC or UC plus a five visit package of homeopathic care (HC). Outcome measures included the Juniper Asthma Control Questionnaire, Quality of Life Questionnaire and a resource use questionnaire. Qualitative interviews were used to gain families' and health professionals' views and experiences. RESULTS: 226 children were identified from hospital clinics and related patient databases. 67 showed an interest in participating, 39 children were randomised, 18 to HC and 21 to UC. Evidence in favour of adjunctive homeopathic treatment was lacking. Economic evaluation suggests that the cost of additional consultations was not offset by the reduced cost of homeopathic remedies and the lower use of primary care by children in the homeopathic group. Qualitative data gave insights into the differing perspectives of families and health care professionals within the research process. CONCLUSIONS: A future study using this design is not feasible, further investigation of a potential role for homeopathy in asthma management might be better conducted in primary care with children with less severe asthma. PMID- 21784329 TI - Modulation of arthritis in rats by Toxicodendron pubescens and its homeopathic dilutions. AB - BACKGROUND: Toxicodendron pubescens P. Mill (Anacardiaceae) known in homeopathy as Rhus toxicodendron (Rhus tox) is used as an anti-inflammatory medicine in homeopathic practice. In this study, Rhus tox in its crude form and homeopathic dilutions (3cH, 6cH, 30cH, 200cH) was evaluated for effects on Complete Freund's Adjuvant (CFA) induced arthritis in rats. METHOD: We assessed the severity of arthritis through observations including inflammatory lesions, body and organ weight and hematological parameters including C-reactive protein (CRP). Blinded radiological analysis of the affected joints and pain intensity determination was also carried out. RESULTS: Rhus tox protected rats from CFA-induced inflammatory lesions, body weight changes and hematological alterations. Rhus tox protected against radiological joint alterations due to arthritis. Arthritic pain scores were also favorably affected by Rhus tox. All the dilutions of Rhus tox including crude form showed anti-arthritic activity. The maximum protective effect was evident in the crude form at 10mg/kg/day, by mouth. CONCLUSION: This study supports claims in the homeopathic literature on the role of Rhus tox and its ultra dilutions in the treatment of arthritis and associated pain. Further study is needed to explain this anti-arthritic effect of Rhus tox. PMID- 21784330 TI - Anti-asthmatic and anti-anaphylactic activities of Blatta orientalis mother tincture. AB - OBJECTIVES: To study the anti-asthmatic and anti-anaphylactic activities of Blatta orientalis mother tincture (B. orientalis MT), a homeopathic medicine, in experimental animal models. METHODS: The anti-asthmatic activity of B. orientalis MT was studied in the bronchial hyperactivity models, acetylcholine and histamine induced bronchospasm, in guinea pigs. Anti-anaphylactic activity was tested by active and passive anaphylaxis models in rats, anti-eosinophilic activity was tested by milk-induced eosinophilia in mice. RESULTS: Significant protection against acetylcholine and histamine aerosol-induced bronchospasm in B. orientalis MT treated guinea pigs was seen. In active and passive anaphylaxis albino rat models significant reduction in mesenteric mast cells degranulation, serum IgE level and eosinophil cell count was observed in the B. orientalis MT treated rat group when compared with the sensitized control rat group. CONCLUSION: These results reveal broad activity of B. orientalis MT. It may have nonselective anti asthmatic activity. The anti-anaphylactic activity of B. orientalis MT may be due to mast cell stabilization, suppression of IgE and eosinophil cell count. PMID- 21784331 TI - The frequency of dietary references in homeopathic consultations. AB - A retrospective quantitative study on dietary references found in medical records of 2753 patients attending consultations from 10/1/1994 to 5/31/2007 was conducted. The symptoms found in the rubrics relating to food and drink aggravation and amelioration, aversion and craving of homeopathic repertories reflect diets at different places and times and do not correspond fully, to contemporary gastronomy. Desires for sweet and spicy foods were statistically more frequent, revealing the prevailing taste for such food among the studied population. Food cravings should be carefully analyzed before considering them as indications for choosing homeopathic therapy, they are less significant than aversions, aggravations and ameliorations. PMID- 21784332 TI - Rebound acid hypersecretion after withdrawal of gastric acid suppressing drugs: new evidence of similitude. AB - BACKGROUND: Homeopathy is based on the principle of similitude (similia similibus curentur) using medicines that cause effects similar to the symptoms of disease in order to stimulate the reaction of the organism. Such vital, homeostatic or paradoxical reaction of the organism is closely related to rebound effect of drugs. METHOD: Review of the literature concerning the rebound effects of drugs used to suppress gastric acidity, particularly proton pump inhibitors (PPIs). RESULTS: The mechanism of action of these effects is discussed. Rebound in terms of clinical symptoms and physiological effects occur in about 40% of people taking PPIs, their timing depends on the half-life of the drug and the adaptation period of the physiological mechanisms involved. The wide use of PPIs may be linked to the rising incidence of carcinoid tumours. CONCLUSIONS: These findings support Hahnemann's concept of secondary action of drugs. We are developing a homeopathic materia medica and repertory of modern drugs on the basis of reported rebound effects. PMID- 21784333 TI - Homeopathy in the treatment of tubercular lymphadenitis (TBLN)--an Indian experience. AB - Tuberculosis (TB) has been known since antiquity. In spite of effective antibiotic treatment, it is still a major worldwide public health problem. Endogenous factors are important in the development of active disease. Homeopathic medicines have the potential for immune-modulation and hence to influence endogenous factors in disease. In India, patients with tubercular lymphadenitis (TBLN) often consult homeopaths but such cases are seldom documented. The objective of the present study is to document such experience. A retrospective exploratory study of 25 positively diagnosed cases of TBLN has lead to the development of a homeopathic regime consisting of a patient specific constitutional medicine, one disease specific biotherapy (Tuberculinum) and Silicea 6x as supportive medicine. Homeopathy can be used as a complement to conventional anti tubercular treatment (ATT) with beneficial results. Further validation in controlled trials with immunological markers is required. PMID- 21784334 TI - Blisters and homeopathy: case reports and differential diagnosis. AB - Blisters are skin lesions characterized by accumulation of fluid between the layers of the skin. Their severity varies from the common blisters caused by friction to severe autoimmune and congenital bullous disorders, some of them currently without treatment in conventional medicine or requiring drugs with potentially severe side-effects. This article reports cases of blistering diseases successfully treated with homeopathic medicines, which represent an alternative for the treatment of such disorders. PMID- 21784335 TI - Comparison of effectiveness of frequently and infrequently used homeopathic medicines. AB - RATIONALE: Patients treated with homeopathy may respond to infrequently used or even 'new' medicines. But does the introduction of an unlimited number of (new) medicines improve homeopathy? Do new medicines solve old problems? METHODS: 1. Consensus meetings to evaluate best cases. 2. Patient outcome study in 10 Dutch practices. RESULTS: Good cases are scarce for many medicines, random variance is an important source of uncertainty. 50 Medicines are responsible for 72% of all successful prescriptions. There is no difference in effectiveness of frequently and less frequently used medicines. Confirmation bias is found for a few well known symptom-medicine combinations. CONCLUSION: 'New' and infrequently medicines are as effective as 'old' frequently used medicines. Improving the use of frequently used medicines is more effective in improving results than seldom used medicines. Large numbers are required and old mistakes should be avoided developing new medicines. A research agenda for improving the use of homeopathic medicines is imperative. PMID- 21784336 TI - A discussion: the future role of homeopathy in the National Health Service (NHS). AB - Homeopathy has been provided by the National Health Service in the UK for over 60 years, funded largely by taxpayer's money. However, in recent years, its provision has come under much criticism questioning its true value. Taking a neutral stance, arguments both for and against the provision of homeopathy on the NHS is presented. It includes issues such as the evidence and safety profile of homeopathy, but also takes into account costs and benefits of homeopathy in a wider perspective. Overall, the provision of homeopathy is justified as long as there is a need within the population, occupying a complementary role alongside conventional medicine. PMID- 21784337 TI - An analogy between effects of ultra-low doses of biologically active substances on biological objects and properties of spin supercurrents in superfluid 3He-B. AB - The effects of ultra-low doses (ULDs) of biologically active substances (BASs) (with concentrations of 10(-13)M or lower) on biological objects (BOs), such as cells, organisms, etc., and the properties of spin supercurrents in superfluid (3)He-B are discussed. It is shown that the effects of ULDs of BASs on biologic objects can be specified by the same set of physical characteristics and described by the same mathematical relations as those used for the specification and description of the properties of spin supercurrents between spin structures in superfluid (3)He-B. This is based on the up-to-date physical concepts: 1) the physical vacuum has the properties of superfluid (3)He-B; 2) all quantum entities (hence, the BAS and the BO, which consist of such entities) produce spin structures in the physical vacuum. The photon being a quantum entity, the features of the effects of low-intensity electromagnetic radiation on BOs can be explained using the same approach. PMID- 21784338 TI - Nanoparticles and membrane anisotropy. PMID- 21784339 TI - Homeopathy for the panic attacks following the L'Aquila earthquake. PMID- 21784340 TI - Homeopathy in severe sepsis. PMID- 21784342 TI - Volumetric and visual rating of magnetic resonance imaging scans in the diagnosis of amnestic mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: In the diagnosis of Alzheimer's disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non-Alzheimer's causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage. METHODS: Elderly subjects (n = 224) were diagnosed with either no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or AD. Hippocampal and hemispheric gray matter volumes were measured on structural MRI scans, and a new visual rating system was used to score the severity of medial temporal atrophy (VRS-MTA) of the hippocampus (HPC), entorhinal cortex, and perirhinal cortex on a coronal image intersecting the mammillary bodies. RESULTS: Although both VRS-MTA scores and HPC volumes distinguished between subjects with NCI, aMCI, and AD, subjects with aMCI and NCI could be better distinguished using right VRS-MTA scores, in comparison with right HPC volumes. VRS-MTA scores were more highly correlated with episodic memory and Clinical Dementia Rating scores. A combination of left sided VRS-MTA scores and left sided hippocampal volume was the most predictive measure of diagnostic classification. CONCLUSION: VRS-MTA is a clinically convenient method or distinguishing aMCI or AD from NCI. As compared with volumetric measures, it provides better discriminatory power and correlates more strongly with memory and functional scores. PMID- 21784343 TI - AMPA workshop on challenges faced by investigators conducting Alzheimer's disease clinical trials. AB - The recruitment and retention of patients are among the greatest challenges currently being faced by researchers who conduct Alzheimer's disease (AD) clinical trials. To discuss these challenges and other major issues associated with clinical research in AD, an international workshop was organized by the Association Monegasque pour la recherche sur la Maladie d'Alzheimer at Monte Carlo, Monaco, in February 2010, with the participation of leading research experts in the field of Alzheimer's. Key topics discussed were as follows: (1) the selection, recruitment, and retention of clinical trial subjects; (2) international co-operation among researchers; and (3) patient rights and informed consent for participants in clinical trials. This article highlights some of the challenges faced by investigators when conducting clinical trials in AD, and it also offers some recommendations aimed at overcoming these challenges. PMID- 21784344 TI - Genetic association of complement receptor 1 polymorphism rs3818361 in Alzheimer's disease. AB - Complement receptor 1 gene polymorphism rs3818361 was recently shown to increase the risk of Alzheimer's disease (AD). We performed an independent replication study of this genetic variant in 2,470 individuals from Spain. By applying an allelic model, we observed a trend toward an association between this marker and late-onset AD susceptibility in our case-control study (odds ratio = 1.114, 95% confidence interval: 0.958-1.296, P = .16). Meta-analysis of available studies (n = 31,771 individuals), including previous studies and public genome-wide association study resources (Alzheimer's Disease Neuroimaging Initiative, Translational Genomics Research Institute, and Multi-site Collaborative Study for Genotype-Phenotype Associations in Alzheimer's Disease), strongly supports the effect of rs3818361 (odds ratio = 1.180, 95% confidence interval: 1.113-1.252, P < 2.99E-8) and suggests the existence of between-study heterogeneity (P < .05). We concluded that the complement receptor 1 gene may contribute to AD risk, although its effect size could be smaller than previously estimated. PMID- 21784345 TI - In silico modeling systems: learning about the prevalence and dynamics of dementia through virtual experimentation. AB - BACKGROUND: Virtual experimentation using computer modeling creates opportunities for researchers who want to better understand disease processes, foresee effects of future demographics, and evaluate combinations of interventions when applied to larger target groups. METHODS: We created a computer model of dementia prevalence consisting of six population groups representing diagnosed and undiagnosed dementia at mild, moderate, and severe levels. Dynamic transitions between these groups corresponded to the gradual progression of disease. The seventh group represented the general population without dementia aged >60 years from which new dementia cases emerged. Through a series of virtual experiments we estimated future changes in the severity-specific prevalence of dementia in Australia. RESULTS: The projected total prevalence of dementia in Australia for year 2040 changed from 742,000 to 986,000 (+33%) and to 433,000 (-42%) when the incidence rate was altered by +/-50%. Increasing the transition time between mild and moderate dementia from 5 to 7 years and between moderate to severe from 7 to 9 years increased the prevalence of mild dementia by 23% and decreased the prevalence of severe dementia by 24%. CONCLUSIONS: As computer modeling becomes more accepted, in silico experiments are being routinely performed to update demographic projections. Despite its simplicity, the framework of this model integrates a large pool of knowledge and consists of components which are dynamically interconnected. The computational logic underpins series of assumptions and binds them together with demographic data. PMID- 21784346 TI - Building an integrated neurodegenerative disease database at an academic health center. AB - BACKGROUND: It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. These comparative studies rely on powerful database tools to quickly generate data sets that match diverse and complementary criteria set by them. METHODS: In this article, we present a novel integrated neurodegenerative disease (INDD) database, which was developed at the University of Pennsylvania (Penn) with the help of a consortium of Penn investigators. Because the work of these investigators are based on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, it allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used the Microsoft SQL server as a platform, with built-in "backwards" functionality to provide Access as a frontend client to interface with the database. We used PHP Hypertext Preprocessor to create the "frontend" web interface and then used a master lookup table to integrate individual neurodegenerative disease databases. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database. RESULTS: Using the INDD database, we compared the results of a biomarker study with those using an alternative approach by querying individual databases separately. CONCLUSIONS: We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies on several neurodegenerative diseases. PMID- 21784347 TI - Output of the working group on magnetic resonance imaging abnormalities and treatment with amyloid-modifying agents. PMID- 21784350 TI - Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease study cohorts from phase 3 trials of semagacestat and solanezumab. AB - BACKGROUND: Cerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood-brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD). METHODS: Fluid-attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double-blind, placebo-controlled, phase 3 trials in patients with mild-to-moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a gamma-secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding alzhEimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti-Abeta monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol-specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point. RESULTS: Four cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra-axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy-related inflammation or Abeta-related angiitis. The final VE case demonstrated localized sulcal fluid-attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status. CONCLUSIONS: VE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2,762 associated with AD. Additional cohorts should be evaluated to support these findings. PMID- 21784348 TI - Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. AB - Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-beta burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research. PMID- 21784352 TI - Serum homocysteine and dementia: meta-analysis of eight cohort studies including 8669 participants. AB - BACKGROUND: Prospective cohort studies have not been consistent in showing an association between serum homocysteine and dementia. OBJECTIVE: To conduct a meta analysis of cohort studies that examined the relationship between serum homocysteine and dementia, and to estimate the change in risk of dementia for a unit change in serum homocysteine. METHODS: The data from eight cohort studies (involving 8,669 participants; range of mean ages, 47-81 years; median duration of study, 5 years) of serum homocysteine on the incidence of dementia were combined and the odds ratio of dementia per 5 MUmol/L increase in serum homocysteine was determined. RESULTS: There was a statistically significant association between serum homocysteine and the incidence of dementia: the odds ratio for a 5 MUmol/L increase in serum homocysteine was 1.35 (95% confidence interval, 1.02-1.79) or 1.50 (1.13-2.00) adjusted for regression dilution bias. The odds ratio for a 3 MUmol/L decrease in serum homocysteine (the average reduction expected using folic acid and B12) was 0.78 (0.66-0.93). CONCLUSION: The meta-analysis of epidemiological cohort studies shows a positive association between serum homocysteine and dementia. Although the results do not provide evidence of cause and effect, they do provide an estimate of the expected effect if the relationship were causal; an approximate 20% reduction in risk of dementia from treatment with folic acid and B12. PMID- 21784349 TI - The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. AB - BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid beta (Abeta)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. METHODS: The program is open for laboratories using commercially available kits for Abeta, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. RESULTS: Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Abeta-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Abeta triplex (AbetaN-42, AbetaN-40, and AbetaN-38) or T tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. CONCLUSIONS: Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers. PMID- 21784353 TI - Diabetes and cognitive decline in elderly African Americans: a 15-year follow-up study. AB - BACKGROUND: Diabetes mellitus is associated with an increased risk for cognitive impairment and vascular factors seem to play a role in this relationship. In a sample involving elderly African Americans, we tested the hypothesis that diabetes accelerates cognitive decline and explored possible mediating mechanisms within a follow-up period of 15 years. METHODS: A total of 1,702 subjects, of whom 441 had diabetes, were given the community screening interview for dementia to measure cognitive functioning at six different time points spread over a 15 year follow-up period. Mixed effects models with repeated measures were used to examine the association of diabetes and vascular risk factors with cognitive scores over time. RESULTS: African American subjects with diabetes reported having a significant accelerated cognitive decline as compared with those without diabetes (P = .046), when controlling for basic demographics and baseline comorbid conditions (heart disease, hypertension, stroke, and depression). Adjusting for incident heart disease, and especially stroke, weakened this association (P = .098), thereby indicating a mediating effect of stroke on the association between diabetes and cognitive decline. However, when incident stroke was incorporated into the model, the effect for participants with diabetes increased greatly (P = .007). CONCLUSIONS: Diabetes, mediated by cerebrovascular pathology, accelerates cognitive decline within a follow-up period of 15 years in a sample comprising African Americans. PMID- 21784351 TI - Extended results of the Alzheimer's disease anti-inflammatory prevention trial. AB - BACKGROUND: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. METHODS: We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Abeta(1-42.) RESULTS: Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. CONCLUSIONS: These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies. PMID- 21784354 TI - The effect of TOMM40 poly-T length on gray matter volume and cognition in middle aged persons with APOE epsilon3/epsilon3 genotype. AB - OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE epsilon4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism. METHODS: Among healthy APOE epsilon3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging. RESULTS: The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD. CONCLUSIONS: These findings among APOE epsilon3/epsilon3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD related cognitive and brain changes. PMID- 21784355 TI - Costs of care in a mild-to-moderate Alzheimer clinical trial sample: key resources and their determinants. AB - BACKGROUND: Costs of care are frequently included as secondary endpoint in Alzheimer clinical trials because payers demand evidence of the budgetary effects of novel therapies. Future clinical trial protocols can be optimized on the basis of the currently available data, including what are the key resources and how are they correlated to disease severity measures. METHODS: Primary patient-level data from two 18 months clinical trials of a putative disease modifier in mild-to moderate Alzheimer's disease (n = 2,744) were analyzed to identify key components of costs of care and their determinants in a clinical trial setting. Costs of care were assessed with the resource utilization in dementia Lite (RUD) instrument, which includes patient accommodation, informal care, community care, and hospitalizations. The contribution of each component to total costs of care and their correlation with one another and key disease severity measures (Alzheimer's Disease Assessment Scale--Cognitive Subscale, Mini-Mental State Examination, Clinical Dementia Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory, and Neuropsychiatric Inventory Questionnaire) was explored. RESULTS: Informal care constituted 82% to 86% of the total costs of care over the 18-months trial and community care services and patient accommodation contributed 6% to 8% each. Informal care was positively correlated with hospitalizations but negatively to patient accommodation, indicating that these services are supplements. Informal care also had the strongest pair-wise correlation with key disease severity measures, suggesting a higher chance of identifying a treatment effect on this component. ADL-ability (Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory) was the strongest predictor of costs of care of all disease severity measures. CONCLUSIONS: Informal care is the most important component of costs of care in a mild-to-moderate Alzheimer clinical trial sample, and it is primarily driven by the ADL-ability of the patient. Investigators should focus on the assessment of this economic endpoint because a significant treatment effect on this resource is likely to also affect total costs of care. PMID- 21784357 TI - How golden is the gold standard of neuropathology in dementia? AB - Current Alzheimer's disease (AD) criteria state that a definite diagnosis can only be made by postmortem examination. The neuropathological confirmation is often referred to as the "gold standard." In this article, we review what constitutes a gold standard and how the neuropathological examination of AD lives up to that standard. We conclude that there is no evidence for this notion because results between different laboratories differ to an important extent, especially when the clinical picture is in doubt, for example, when the dementia is mild. As an alternative, we propose to abandon thinking in standards and value neuropathology as any other biomarker, and to strive to use and integrate multiple sources of information to make the diagnosis of AD in all its complexity. PMID- 21784358 TI - Stem cell therapy for chronic heart failure: lessons from a 15-year experience. AB - Although cell therapy has entered the clinical arena since 2000, its benefits are still controversial. This is partly due to a shift of the whole paradigm from the mere provision of new cells intended to replenish the pool of dead cardiomyocytes to the exploitation of the cell's paracrine effects to activate host-associated cytoprotective signalling pathways, particularly those involved in angiogenesis, prevention of apoptosis and possibly recruitment of endogenous cells capable to mature into functional cardiomyocytes. This review will discuss how these two basic mechanisms (direct donor cell-derived myocardial regeneration versus paracrine signalling) underlie the rational selection of cells in light of the target clinical indication, with a particular focus on chronic heart failure, and will emphasize the importance of optimizing cell delivery and survival to fully exploit the potential benefits of this novel approach to acute and chronic heart diseases. PMID- 21784356 TI - Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease. AB - BACKGROUND: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. METHODS AND RESULTS: The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. CONCLUSIONS: Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers. PMID- 21784359 TI - Towards a reconciling model about the initial peopling of America. AB - The last two decades have seen numerous debates in the field of the initial settlement of America and noteworthy was the disagreement between physical and molecular anthropologists. Recently, it has been pointed out that this discordance could partly originate from the description methods and classification labels used in craniometry, which did not account fairly for the within-sample and within-group variance. From there, a federative model for the initial peopling of America has been designed which could now explain the biological variability found at both the craniofacial and genetic level. This is a major step in the study of the initial settlement of America, which deserved to be highlighted. The present paper recalls the two conflicting models that prevailed for the last 20 years of anthropological studies in America before browsing the newly accepted hypothesis about the origin of the first Amerindians as seen by its authors. Lastly, the article evokes some areas of investigations, which could furnish significant fallouts about the dynamics of the peopling of Americas in the future. PMID- 21784360 TI - Hyperbolic symmetry breaking and its role in the establishment of the body plan of vertebrates. AB - This Note presents experimental evidence that a hyperbolic tissue flow plays an important role in the establishment of the organization plan of vertebrates. We have followed the development of chicken embryos from the gastrula stage up to the moment when the body plan is recognizable. We have found that establishment of this plan occurs in the presence of a uniform tissue flow which at all stages presents a hyperbolic pattern. The flow is bidirectional in the antero-posterior direction, with a fixed point (stagnation point of the flow) which is a point of zero speed in all directions, in the reference frame of the egg. This stagnation point of the flow is located at the level of the presumptive yolk stalk of the chicken (analogous to the mammal navel). On either sides (left and right) of the body, the flow is also bidirectional. The antero-posterior bidirectionality and the left-right bidirectionality result in splitting of the embryo into four domains with vortex-like flow, with partial mirror symmetry between the left/right halves and top/bottom ones. The center of symmetry is the stagnation point. The broken symmetry of the flow is up-scaled in the adult animal. Areas with straightforward tissue movement are the ones where axial structures develop. The lateral domains with vortex-like flow colocalize with the future limb plates. PMID- 21784361 TI - [An ultrastructural study of oogenesis in the planarian Schmidtea mediterranea (Platyhelminthe, Paludicola)]. AB - The ovary of the freshwater planarian Schmidtea mediterranea has been studied for the first time using both light and electron microscopy methods. The ultrastructure of the ovary revealed two types of cells: accessory cells and germinal cells at various stages of differentiation, distributed along a maturation axis. Initially, oogonia underwent cytoplasm growth due to the development of organelles, such as endoplasmic reticulum, Golgi complex, and mitochondria, which are all involved in the production of cytoplasmic inclusions or yolk globules. It is shown that the chromatoid body and fibrogranular aggregates may participate in the synthesis of vitelline inclusions. When completely mature, the oocytes have become larger, due to the accumulation of nutritive inclusions, which are round in shape and have a paracrystalline structure. These inclusions are interpreted as being yolk globules and may represent a kind of nutritive material for the developing embryo. These ultrastructural features of the ovary agree with the available phylogenetic tree, based on morphological and karyological characters that considers Schmidtea group as a genus and not a subgenus. The presence of sperm between the oocytes suggests that fertilization may occur within the ovary, representing an uncommon condition within the Triclads, in which fertilization usually takes places outside of the ovaries. PMID- 21784362 TI - Ion uptake and structural modifications induced by nitrogen source in tomato (Solanum lycopersicum Mill. Cv. Ibiza F1). AB - Interactions between NO(3)(-) and NO(2)(-) were studied at the level of root uptake, ion translocation (NO(3)(-), NO(2)(-), K(+)), ion xylem exudates composition and inorganic cation contents (K(+), Ca(2+), Mg(2+)) using tomato seedling (Solanum lycopersicum Mill cv. Ibiza F1). Nitrite was supplied in the medium as KNO(2) (0, 0.25, 2.5, 5 and 10 mM). Plants cultivated on the same doses of KNO(3) served as control. The experimental system allowed direct measurements of net NO(3)(-) and NO(2)(-) uptake. Our results showed that NO(3)(-) uptake and translocation were stimulated by external supply of K(+), while they were hardly decreased by NO(2)(-) supply. Contents of K(+) and Mg(2+) were negatively affected in all tomato tissues by increasing nitrite concentration in the medium. Highest dose of NO(2)(-) decreased Ca(2+) accumulation in shoots and conversely increased that in the roots. Histological study at the stem level revealed that nitrite (10 mM) induced a restriction of the tissue territories as well as less developed regions and some conductor tissues disorganization in this organ structure. The overall results suggest that nitrite exposure delayed growth and injured cell structure and overall nutrient uptake. PMID- 21784363 TI - The role of the parenchyma sheath and PCD during the development of oil cavities in Pterodon pubescens (Leguminosae-Papilionoideae). AB - Pterodon pubescens cavities are constituted by lumen and uniseriated epithelium surrounded by multiseriate parenchyma sheath. We studied the development of secretory cavities, including the role of parenchyma sheath, using light and transmission electron microscopy. A Tunel assay was performed to verify whether programmed cell death (PCD) occurs during the process. The lumen is formed by schizogeny and lysigeny occur in later developmental stages of the secretory cavities. Ultrastructurally, epithelial cells in later developmental stages become dark and with sinuous walls; the protoplast becomes retracted and the cytoplasm shows low organelle definition. Degenerated cells are released toward the lumen. Our results showed that PCD occurs during later developmental stages of cavities and plays a critical role in functioning of these glands. New cells originated from the parenchyma sheath differentiate into secretory cells and replace those degenerated ones. This fact associated to PCD guarantees epithelium renovation during the secretory cycle and the maintenance of secretory activity of cavities. PMID- 21784364 TI - DNA barcoding of African fruit bats (Mammalia, Pteropodidae). The mitochondrial genome does not provide a reliable discrimination between Epomophorus gambianus and Micropteropus pusillus. AB - Sequences of the mitochondrial cytochrome c oxidase subunit I (COI) gene have been shown to be useful for species identification in various groups of animals. However, the DNA barcoding approach has never been tested on African fruit bats of the family Pteropodidae (Mammalia, Chiroptera). In this study, the COI gene was sequenced from 120 bats collected in the Central African Republic and belonging to either Epomophorus gambianus or Micropteropus pusillus, two species easily diagnosed on the basis of morphological characters, such as body size, skull shape and palatal ridges. Two additional molecular markers were used for comparisons: the complete mitochondrial cytochrome b gene and the intron 7 of the nuclear beta-fibrinogen (FGB) gene. Our results reveal an unexpected discordance between mitochondrial and nuclear genes. The nuclear FGB signal agrees with our morphological identifications, as the three alleles detected for E. gambianus are divergent from the fourteen alleles found for M. pusillus. By contrast, this taxonomic distinction is not recovered with the analyses of mitochondrial genes, which support rather a polyphyletic pattern for both species. The conflict between molecular markers is explained by multiple mtDNA introgression events from M. pusillus into E. gambianus or, alternatively, by incomplete lineage sorting of mtDNA haplotypes associated with positive selection on FGB alleles of M. pusillus. Our work shows the failure of DNA barcoding to discriminate between two morphologically distinct fruit bat species and highlights the importance of using both mitochondrial and nuclear markers for taxonomic identification. PMID- 21784365 TI - A new genus and new species of Philippine stick insects (Insecta: Phasmatodea) and phylogenetic considerations. AB - Based on characters of both sexes, a new genus and species of the basal euphasmatodean lineage Aschiphasmatidae is described and figured from the Philippines. Dallaiphasma eximius gen. et sp. n. displays interesting features for the group, including: a cone-shaped vertex, which is notably raised above the pronotum; the tibial area apicalis represented by a depressed membranous posterior lateral region, and a strongly sclerotized central apical region; the euplantulae consisting of smooth-type attachment pads; the pretarsal claws pectination reduced to minute denticulations; and the well-differentiated boundary between the metanotum and the first abdominal tergum. The phylogenetic information content of the new findings is discussed. Furthermore, as a result of this study, the Aschiphasmatidae are newly recorded from Mindoro island, and now include five genera and six species of the Philippines. PMID- 21784366 TI - Arbuscular mycorrhizas enhance nutrient uptake in different wheat genotypes at high salinity levels under field and greenhouse conditions. AB - Since most experiments regarding the symbiosis between arbuscular mycorrhizal (AM) fungi and their host plants under salinity stress have been performed only under greenhouse conditions, this research work was also conducted under field conditions. The effects of three AM species including Glomus mosseae, G. etunicatum and G. intraradices on the nutrient uptake of different wheat cultivars (including Roshan, Kavir and Tabasi) under field and greenhouse (including Chamran and Line 9) conditions were determined. At field harvest, the concentrations of N, Ca, Mg, Fe, Cu, and Mn, and at greenhouse harvest, plant growth, root colonization and concentrations of different nutrients including N, K, P, Ca, Mg, Mn, Cu, Fe, Zn, Na and Cl were determined. The effects of wheat cultivars on the concentrations of N, Ca, and Mn, and of all nutrients were significant at field and greenhouse conditions, respectively. In both experiments, AM fungi significantly enhanced the concentrations of all nutrients including N, K, P, Ca, Mg, Mn, Cu, Fe, Zn, Na and Cl. The synergistic and enhancing effects of co-inoculation of AM species on plant growth and the inhibiting effect of AM species on Na(+) rather than on Cl(-) uptake under salinity are also among the important findings of this research work. PMID- 21784367 TI - Initial behavior in colony fragments of an introduced population of the invasive ant Wasmannia auropunctata. AB - We investigated in the laboratory the initial behavior of propagules of the invasive ant Wasmannia auropunctata in Cameroon where it has been introduced. Both workers and queens at first feigned death (thanatosis), and then the workers slowly moved around the experimental arena; the queens did the same about 10seconds later. Each queen antennated selected workers that then aggregated together by grasping the hind leg of another ant with their mandibles. When encountering the queen again, the lead worker climbed up the queen's hind leg and onto her back, followed by some other individuals. The remaining workers followed the queen to a location in the experimental arena. When brood was present, the workers transferred it to this location. Orphaned workers did not aggregate, but gathered the brood together and took care of it. By permitting propagules to survive, these behaviors likely contribute to the success of W. auropunctata as an invader. PMID- 21784368 TI - From the editor. PMID- 21784369 TI - Assessment and management of vascular disease risk in patients with chronic kidney disease. PMID- 21784370 TI - Can conclusions that seem discordant be concordant after all? PMID- 21784371 TI - Reliability of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B measurement. AB - There is little understanding of the reliability of laboratory measurements among clinicians. Low-density lipoprotein cholesterol (LDL-C) measurement is the cornerstone of cardiovascular risk assessment and prevention, but it is fraught with error. Therefore, we have reviewed issues related to accuracy and precision for the measurement of LDL-C and the related markers non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B. Despite the widespread belief that LDL-C is standardized and reproducible, available data suggest that results can vary significantly as the result of methods from different manufacturers. Similar problems with direct HDL-C assays raise concerns about the reliability of non-HDL C measurement. The root cause of method-specific bias relates to the ambiguity in the definition of both LDL and HDL, and the heterogeneity of LDL and HDL particle size and composition. Apolipoprotein B appears to provide a more reliable alternative, but assays for it have not been as rigorously tested as direct LDL-C and HDL-C assays. PMID- 21784372 TI - Persisting thrombin activity in elderly patients with atrial fibrillation on oral anticoagulation is decreased by anti-inflammatory therapy with intensive cholesterol-lowering treatment. AB - BACKGROUND: It has been demonstrated that the occurrence of ischemic stroke is more prevalent in AF patients, when increased levels of inflammatory markers are present. OBJECTIVE: The aim of this study was to evaluate the effect of intensive cholesterol lowering therapy on inflammatory markers and evidence of thrombotic in elderly AF patients treated with OAC. METHODS: 34 elderly patients (69-85 yrs) were randomized to double blind treatment with atorvastatin 40 mg plus ezetimibe 10 mg (n = 17) or double placebo (n = 17) for one year. All were anticoagulated with warfarin (target INR 2.5-3.5). Every 3 months inflammatory markers and parameters for evaluation of haemostatic and fibrinolytic activity were measured. RESULTS: Anti-inflammatory effects in the treatment arm were reflected by a significant decrease from baseline in hs-CRP, FGF, G-CSF, GM-CSF, IL-1ra, IL-9, IL-13, IL-17 and interferon-gamma (P < .05). There was no significant decrease in the control group. Endogenous thrombin potential was still present and active but decreased during treatment (P = .0005) compared to the placebo group. After 12 months treatment, a significant correlation was found between changes in endogenous thrombin potential and hs-CRP, interferon-gamma and G-CSF, respectively. No hemorrhagic complications occurred. CONCLUSION: Intensive cholesterol lowering significantly reduced inflammation and was accompanied by reduced thrombin generation. Larger clinical studies should determine which inflammatory markers are most specific and sensitive for estimating the inflammatory burden in these patients and at which corresponding thrombin activity level it is beneficial and safe to add intensive cholesterol lowering therapy even if normal cholesterol levels are present. PMID- 21784373 TI - Extended-release niacin/laropiprant lowers serum phosphorus concentrations in patients with type 2 diabetes. AB - BACKGROUND: Niacin compounds lower serum phosphorus concentrations in patients with end-stage renal disease. METHODOLOGY: We evaluated the impact of extended release niacin, given in fixed-dose combination with laropiprant, a specific inhibitor of prostaglandin-mediated, niacin-induced flushing, versus placebo, on serum phosphorus concentrations measured serially (at weeks 0, 4, 8, 12, 18, 24, 30, and 36) during a 36-week randomized, controlled trial. All subjects had a confirmed diagnosis of type 2 diabetes (n = 446 niacin/laropiprant; n = 339 placebo). Estimated glomerular filtration rate ranged from 36 to 184 mL/min/1.73 m(2), with n = 111 (14.1%) having a value <60 mL/min/1.73 m(2). Subjects received one tablet daily of extended-release niacin/laropiprant (1g niacin/ 20 mg laropiprant) for the first 4 weeks, and 2 tablets once daily, thereafter, or matched placebo. Niacin lowered serum phosphorus concentrations by 0.36 mg/dL (95% CI: -0.40, -0.31; P < .001), relative to placebo, from baseline values of 3.57 and 3.56 mg/dL in the niacin and placebo groups, respectively. Subgroup analyses revealed no evidence for phosphorus-lowering effect modification by these baseline variables: glomerular filtration rate <60 (n = 111;14.1%) vs >=60 mL/min/m(2) (n = 674; 85.9%); phosphorus <=3.5 mg/dL (n = 392; 49.9%) vs >3.5 mg/dL (n = 393; 50.1%); or prior statin use (n = 618; 78.7%) vs nonuse (n = 167; 21.3%). CONCLUSIONS AND IMPLICATIONS: These data confirm that niacin's phosphorus lowering effects-which may have therapeutic implications for the management of hyperphosphatemia and possible prevention of cardiorenal outcomes in renal disease-extend across a broad spectrum of renal function in type 2 diabetics without stage 4 or 5 chronic kidney disease (a glomerular filtration rate >=30 mL/min/1.73 m(2)). PMID- 21784374 TI - Serum fatty acids, antioxidants, and treatment response in hepatitis C infection: greater polyunsaturated fatty acid and antioxidant levels in hepatitis C responders. AB - BACKGROUND: Patients suffering from chronic hepatitis C (CHC) may exhibit impaired liver functions such as disturbances of fatty acid storage, synthesis and degradation. OBJECTIVE: Possible associations between serum fatty acid (SFA) profiles, antioxidant status and treatment response were investigated in a trans sectional study of untreated and treated CHC patients in comparison to a healthy control group. METHODS: SFA composition and antioxidant status were examined in female patients with CHC: 9 were naive to Interferon-alpha and ribavirin treatment (IFR), 21 sustained treatment responders, 21 were nonresponders, and 21 were healthy control group members. Additionally, in all CHC patients gammaglutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. RESULTS: Responders and healthy control group members had significantly higher antioxidant (P < .001), eicosapentaenoic (P < .001) and arachidonic acid (P < .004) levels, but lower stearic acid (P < .001) concentrations than non-responders and untreated patients. ALT was higher in untreated CHC patients than in treated ones (P < .028). GGT and AST did not differ significantly between patient groups, however GGT levels were associated with serum Gamma-Linolenic-Acid concentration (P = .009). CONCLUSION: SFA profiles and antioxidant status in female CHC patients differ markedly from those of healthy controls, a phenomenon which is possibly related with their effect of HCV replication. PMID- 21784375 TI - The relationship between body mass index and the variation in plasma levels of triglycerides after short-term red wine consumption. AB - BACKGROUND: Alcoholic beverages may have protective cardiovascular effects but are known to increase the plasma levels of triglycerides (TG). Both TG and the ratio of TG to high-density lipoprotein cholesterol (TG/HDL-cholesterol) are associated with increased cardiovascular risk. OBJECTIVES: To determine the predictive factors for variations in plasma levels of TG and the TG/HDL cholesterol ratio in patients after they had consumed red wine for 14 days. METHODS: Forty-two subjects (64% men, 46 +/- 9 years, baseline body mass index [BMI] 25.13 +/- 2.76 kg/m(2)) were given red wine (12% or 12.2% alc/vol, 250 mL/day with meals). Plasma concentration of lipids and glucose were measured before and after red wine consumption. Blood was collected after 12 hours of fast and alcohol abstention. RESULTS: Red wine increased plasma levels of TG from 105 +/- 42 mg/dL to 120 +/- 56 mg/dL (P = .001) and the TG/HDL-cholesterol ratio from 2.16 +/- 1.10 to 2.50 +/- 1.66 (P = .014). In a multivariate linear regression model that included age, baseline BMI, blood pressure, lipids, and glucose, only BMI was independently predictive of the variation in plasma TG after red wine (beta coefficient 0.592, P < .001). BMI also predicted the variation in TG/HDL cholesterol ratio (beta coefficient 0.505, P = .001, adjusted model). When individuals were divided into three categories, according to their BMI, the average percentage variation in TG after red wine was -4%, 17%, and 33% in the lower (19.60-24.45 kg/m(2)), intermediate, and greater (26.30-30.44 kg/m(2)) tertiles, respectively (P = .001). CONCLUSIONS: Individuals with higher BMI, although nonobese, might be at greater risk for elevation in plasma TG levels and the TG/HDL-cholesterol ratio after short-term red wine consumption. PMID- 21784376 TI - Clinical and laboratory phenotype of patients experiencing statin intolerance attributable to myalgia. AB - BACKGROUND: Muscle pain without elevation of serum creatine phosphokinase (CPK) (myalgia) is the most common medication-related adverse effect of statin therapy; it occurs in up to 10% of patients who are prescribed statin therapy. Although much is known regarding risk factors for overt myositis, very few studies have provided information on this common form of statin intolerance. METHODS: We defined a detailed clinical and laboratory phenotype of a cohort of patients referred to the lipid clinic of a governmental health maintenance organization for statin intolerance attributable to muscle pain without CPK elevation (myalgia) and characterized their response to alternative lipid-lowering therapy. Baseline and follow-up data were analyzed for 104 patients with statin intolerance attributable to myalgia and 211 statin-tolerant control patients identified from the referral population. RESULTS: Among patients with myalgia, more were white and had hypertension. The prevalence of known risk factors for overt myositis, including renal disease, type 2 diabetes mellitus, thyroid disease, and electrolyte abnormalities, did not differ between statin intolerant and statin tolerant patients. Although individual cases were identified in which the addition of interacting medications was temporally associated with development of statin intolerance, overall use of interacting medications was not more frequent among statin-intolerant patients. The majority of patients were intolerant of two or more statins; however, in more than one-half the cases, successful rechallenge with an alternative statin was accomplished. Despite this and extensive use of nonstatin lipid medications after lipid clinic referral, control of plasma lipoproteins remained significantly worse in statin-intolerant patients. CONCLUSIONS: Statin intolerance attributable to myalgia is a significant barrier to effective treatment of hyperlipidemia. Conventional clinical risk factors for myositis do not appear to predictive of statin associated myalgia. These findings underscore the need to better define the pathophysiology of statin-induced myalgia and develop methodologies to guide treatment of statin-intolerant patients. PMID- 21784377 TI - Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. AB - BACKGROUND: Many patients who could benefit from hydroxymethylglutaryl coenzyme-A reductase inhibitors (statins) are unable to take statins because of myalgias while taking previous statin therapy. OBJECTIVE: The primary objective was to assess the efficacy and tolerability of once-weekly rosuvastatin in patients with documented myalgias on statins who were not currently taking a statin and not at low-density lipoprotein (LDL) goal. METHODS: In this randomized, double-blind, placebo-controlled crossover study we enrolled a total of 17 Clement J. Zablocki Veterans Affairs (VA) primary care patients with a diagnosis of hyperlipidemia and a history of myalgias on statin therapy who were not currently on a statin and not at LDL goal. Two 8-week treatment phases consisted of rosuvastatin 5 mg once-weekly or matching placebo, with a dose titration to 10 mg once-weekly if not at LDL goal at week 4. The primary efficacy outcome was the difference in the mean percentage change in LDL from baseline between rosuvastatin and placebo. RESULTS: A significant difference in the mean percentage change in LDL from baseline for rosuvastatin vs. placebo was identified (12.2% reduction vs. 0.4% reduction, respectively; P = .002). Two of the 17 patients (11.8%) in the placebo treatment phase and three of the 15 patients (20%) in the rosuvastatin treatment phase experienced myalgias requiring cessation of therapy. In addition, three patients (20%) were able to attain LDL goal on rosuvastatin compared with zero patients (0%) on placebo. CONCLUSION: Once-weekly low-dose rosuvastatin is an effective and well-tolerated lipid-lowering therapy option for patients not at LDL goal and previously unable to tolerate statins because of a history of myalgias. PMID- 21784378 TI - Concordance between plasma apolipoprotein B levels and cholesterol indices among patients receiving statins and nonstatin treatment: Post-hoc analyses from the U.K. InPractice study. AB - BACKGROUND: Apolipoprotein B (ApoB) is a superior predictor of low-density lipoprotein (LDL) particle number and cardiovascular disease (CVD) risk compared with LDL-cholesterol (LDL-C) levels. Current evidence has shown a degree of discordance between LDL-C with ApoB levels among patients not receiving lipid lowering therapy. The extent of this discordance among patients receiving LDL lowering therapies however is less clear. METHODS: We performed a post hoc analysis of the InPractice data looking at the concordance between LDL-C, non high density lipoprotein-cholesterol (nonHDL-C) and total cholesterol with ApoB values. The study involved 786 high-risk CVD patients from 34 primary care centers initially treated with simvastatin (S) 40 mg at baseline subsequently randomized to adding ezetimibe 10 mg to S 40 mg (E/S40) or changed to atorvastatin (A) 40 mg or to rosuvastatin (R) 5-10 mg for 6 weeks. RESULTS: At 6 weeks after treatment, the association between LDL-C and ApoB values for the different treatment regimes were similar; Pearson's correlation coefficients between LDL-C and ApoB were 0.84 (E/S40), 0.82 (A), and 0.83 (R). Overall, ApoB appeared to have a slightly greater correlation with nonHDL-C than with LDL-C across all treatment groups, for baseline and posttreatment values. The analysis of quintile frequencies showed a similar pattern; the proportion of patients who had values that fell in the same quintile post treatment for ApoB and LDL-C levels were 52.2% (E/S40), 44.5% (A), and 49.4% (R). Concordance between ApoB and nonHDL-C was 60.6% (E/S40), 62.4% (A), and 61.8% (R). Kappa analysis confirmed fair agreement between LDL-C and ApoB levels for all treatment groups; 0.59 (E/S40), 0.54 (A), and 0.56(R). CONCLUSION: We showed that the association between ApoB and LDL-C is similar across different lipid-lowering treatment regimes, which suggests that the use of different lipid-lowering agent confers similar ability to predict ApoB levels. When determining CVD risk at an individual patient level, limitation exists when using LDL-C or nonHDL-C per se as risk markers. In the absence of ApoB measurement, we believe that information from both LDL-C and nonHDL-C should be used together to improve the estimation of residual CVD risk among patients who are already receiving lipid lowering therapy. PMID- 21784379 TI - Multiple lipoprotein and electrolyte laboratory artifacts caused by lipoprotein X in obstructive biliary cholestasis secondary to pancreatic cancer. AB - Lipoprotein X (Lp-X) is an abnormal lipoprotein which may form in patients with intra- and extra-hepatic cholestasis. The presence of very high levels of Lp-X has been shown to be a rare cause of pseudohyponatremia. We present a patient with severe obstructive cholestasis secondary to pancreatic cancer leading to very high Lp-X concentrations resulting in pseudohyponatremia, pseudohypokalemia, pseudohypochloremia and interference with the selective micellary solubilization direct low density lipoprotein cholesterol assay. These spurious laboratory anomalies impeded the initial clinical management of the patient including the attempted correction of the electrolyte abnormalities. After relief of obstruction following biliary stent placement, the patient's lipid levels normalized. Clinicians must be wary of laboratory artifacts and remember to correlate the laboratory values with the clinical presentation of the patient. Assays employing direct ion-selective electrodes such as those in blood gas analyzers are not subject to the interference of high concentrations of lipids or proteins, and maybe useful in situations where such interference is suspected. Furthermore the Vertical Auto Profile (VAP(r)) ultracentrifugation assay may be useful to detect lipoprotein X and low density lipoprotein cholesterol levels when the selective micellary solubilization technique fails to detect or quantify these lipid moieties. PMID- 21784380 TI - Fatal cardiac atherosclerosis in a child 10 years after liver transplantation: a case report and a review. AB - We hereby review liver transplantation for homozygous familial hypercholesterolemia and report the case of a 14-year-old girl presenting with severe bilateral coronary ostial stenosis and tight supra-valvular aortic narrowing 10 years after liver transplantation. Despite normalization of the lipids after liver transplantation, the patient showed evidence of severe cardiac atherosclerosis 10 years later and died of apparent sepsis. PMID- 21784381 TI - The inversion effect reveals species differences in face processing. AB - Face recognition is a complex skill that requires the integration of facial features across the whole face, e.g., holistic processing. It is unclear whether, and to what extent, other species process faces in a manner that is similar to humans. Previous studies on the inversion effect, a marker of holistic processing, in nonhuman primates have revealed mixed results in part because many studies have failed to include alternative image categories necessary to understand whether the effects are truly face-specific. The present study re examined the inversion effect in rhesus monkeys and chimpanzees using comparable testing methods and a variety of high quality stimuli including faces and nonfaces. The data support an inversion effect in chimpanzees only for conspecifics' faces (expert category), suggesting face-specific holistic processing similar to humans. Rhesus monkeys showed inversion effects for conspecifics, but also for heterospecifics' faces (chimpanzees), and nonfaces images (houses), supporting important species differences in this simple test of holistic face processing. PMID- 21784382 TI - Severe coronary tortuosity or myocardial bridging in patients with chest pain, normal coronary arteries, and reversible myocardial perfusion defects. AB - We reviewed patients with normal or near-normal coronary angiograms enrolled in the SPAM contrast stress echocardiographic diagnostic study in which 400 patients with chest pain syndrome of suspected cardiac origin with a clinical indication to coronary angiography were enrolled. Patients underwent dipyridamole contrast stress echocardiography (cSE) with sequential analysis of wall motion, myocardial perfusion, and Doppler coronary flow reserve before elective coronary angiography. Ninety-six patients with normal or near-normal epicardial coronary arteries were screened for the presence of 2 prespecified findings: severely tortuous coronary arteries and myocardial bridging. Patients were divided in 2 groups based on the presence (false-positive results, n = 37) or absence (true negative results, n = 59) of reversible myocardial perfusion defects during cSE and compared for history and clinical and angiographic characteristics. Prevalence of severely tortuous coronary arteries (35% vs 5%, p <0.001) or myocardial bridging (13% vs 2%, p <0.05) was 7 times higher in patients who demonstrated reversible perfusion defects at cSE compared to those without reversible perfusion defects. No significant differences were found between the 2 groups for the main demographic variables and risk factors. Patients in the false positive group more frequently had a history of effort angina (p <0.001) and ST segment depression at treadmill electrocardiography (p <0.001). In conclusion, we hypothesize that patients with a positive myocardial perfusion finding at cSE but without obstructive epicardial coronary artery disease have a decreased myocardial blood flow reserve, which may be caused by a spectrum of causes other than obstructive coronary artery disease, among which severely tortuous coronary arteries/myocardial bridging may play a significant role. PMID- 21784383 TI - Progression from concentric left ventricular hypertrophy and normal ejection fraction to left ventricular dysfunction. AB - Concentric left ventricular (LV) hypertrophy develops in response to a chronically increased LV afterload and is associated with increased cardiovascular events. Although the progression to systolic and diastolic heart failure is a known consequence of LV hypertrophy, few data are available on the frequency of deterioration to systolic dysfunction in patients with LV hypertrophy who originally had a normal LV ejection fraction. We evaluated the baseline and follow-up characteristics in 1,024 patients with concentric LV hypertrophy and a normal ejection fraction who had paired echocardiograms that were separated by >=1 year. Systolic dysfunction occurred in 134 patients (13%) after a mean follow-up of 33 +/- 24 months. The most common associated variable was interval myocardial infarction, which occurred in 43% of patients. Other risk factors for developing LV systolic dysfunction included QRS prolongation (>120 ms) and elevated follow-up arterial impedance defined as a value >4.0 mm Hg/ml/m(2). Patients with either a prolonged QRS interval or an elevated follow up arterial impedance had twice the likelihood of developing LV systolic dysfunction, and, if both factors were present, there was a greater than fourfold increased risk of developing systolic dysfunction. Blood pressure measurements alone did not adequately reflect an elevated arterial impedance. In conclusion, 13% of patients with a normal ejection fraction and concentric LV hypertrophy progress to systolic dysfunction during approximately 3 years of follow-up. The risk factors for loss of function were interval myocardial infarction, prolonged QRS, and chronically elevated arterial impedance. PMID- 21784384 TI - Cardiovascular medications and risk of cancer. AB - Cardiovascular disease and cancer are 2 of the leading causes of death globally. Certain cardiovascular medications have been linked to an increased risk for cancer. Although individual reviews of specific classes of cardiovascular medications have been published previously, a more complete review of several classes has not been performed. The aim of this review is to evaluate the associations of various cardiovascular agents with the risk for developing cancer and provide guidance for clinicians. A comprehensive search of published research was conducted using MEDLINE from 1994 to 2011. Three trials demonstrated an increased risk for cancer using angiotensin II receptor blockers. Additionally, risk for cancer was shown in a number of trials that included the use of angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors. Five trials suggested that diuretics increased the risk for specific cancers, especially in women and those who had been using diuretics for >4 years. Statins and ezetimibe, in contrast, did not show this increased risk. Prasugrel was shown to be associated with an increased risk for cancer in 1 study. It appears that the use of certain cardiovascular medications is associated with an increased risk for cancer. In conclusion, clinicians need to balance the risks and benefits of the use of these agents and provide the appropriate therapy on an individual basis. PMID- 21784385 TI - Comparison between direct volumetric and speckle tracking methodologies for left ventricular and left atrial chamber quantification by three-dimensional echocardiography. AB - In an era of rapidly expanding and evolving 3-dimensional echocardiographic (3DE) technology, 1 of the issues facing the 3DE quantification of chamber volumes and function is that different software vendors use different methodologies and algorithms. The aim of this study was to evaluate the comparability and reproducibility of 3DE direct volumetric and speckle-tracking methods for left ventricular (LV) and left atrial (LA) chamber quantification. A total of 120 subjects (mean age 53 +/- 17 years, 65% men), including 88 unselected patients and 32 healthy volunteers, underwent 3DE acquisitions and analysis using direct volumetric and speckle-tracking methods successively. Measurements of LV and LA volumes and LV function were compared between the 2 3DE methods. Additionally, intraobserver and interobserver reproducibility was assessed in 40 randomly selected patients. Measurements of LV end-diastolic volume, end-systolic volume, and ejection fraction by 3DE direct volumetric and 3DE speckle-tracking methods were comparable, with good correlations (r = 0.98, r = 0.98, and r = 0.87, respectively), small biases, and narrow limits of agreement (-1 +/- 8 ml, -1 +/- 8 ml, and 0 +/- 6%, respectively). For measurements of LA end-systolic volume and end-diastolic volume, similar correlations (r = 0.96 for both), small biases, and narrow limits of agreement (-2 +/- 6 and -1 +/- 5 ml, respectively) were found between the 2 methods. Intraobserver and interobserver reproducibility for LV and LA quantification were comparable for the 2 methods. In conclusion, 3DE direct volumetric and speckle-tracking methods give comparable and reproducible quantification of LV and LA volumes and function, making interchangeable application a viable option in daily clinical practice. PMID- 21784386 TI - Usefulness of physical fitness and the metabolic syndrome to predict vascular disease risk in older Chinese (from the Guangzhou Biobank Cohort Study Cardiovascular Disease Subcohort [GBCS-CVD]). AB - Physical fitness can independently lower the risk of cardiovascular disease (CVD). We explored the independent and combined associations of physical fitness, measured using the seated at rest heart rate (RHR), and the metabolic syndrome (MS), with CVD risk, as described by an elevated pulse wave velocity (PWV) in older Chinese. Data from 1,996 participants were drawn from the Guangzhou Biobank Cohort Study-Cardiovascular Disease Subcohort. Analysis of variance and logistic regression analysis were used to establish the independent and combined associations of the RHR and the MS with PWV. The RHR was independently associated with an elevated PWV (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.22 to 2.18), as was the MS (OR 2.36, 95% CI 1.76 to 3.17). The participants with a high RHR, but without the MS, had an adjusted OR of 1.63 (95% CI 1.15 to 2.30) for the presence of the CVD proxy. Those with a low RHR and the MS had an adjusted OR of 2.35 (95% CI 1.66 to 3.33). The risk of an elevated PWV increased almost fourfold with both a high RHR and a diagnosis of the MS (OR 3.87, 95% CI 2.39 to 6.28, p = 0.52 for interaction). In conclusion, physical fitness, measured using the RHR, and the MS are independently associated with an elevated PWV, a surrogate marker for CVD. The strength of this association was further increased in the presence of both. These findings confirm the beneficial effects of physical fitness on attenuating the risk of CVD among older Chinese. PMID- 21784387 TI - Recovery from hospital-acquired anemia after acute myocardial infarction and effect on outcomes. AB - New-onset, hospital-acquired anemia (HAA) during acute myocardial infarction (AMI) is independently associated with poor outcomes. The patterns of recovery from HAA after AMI and their association with mortality and health status are unknown. In the prospective 24-center Translational Research Investigating Underlying disparities in acute myocardial infarction Patients' Health Status (TRIUMPH) registry, we identified 530 patients with AMI and HAA (defined as normal hemoglobin at admission with the development of anemia by discharge) who had a repeat, protocol-driven hemoglobin measurement at 1 month after discharge. The 1-month measures were used to define persistent (persistent anemia) and transient (anemia resolved) HAA. The patients' health status was assessed at 1, 6, and 12 months after AMI using the Short-Form 12 Physical Component Summary, and the health status of patients with persistent and transient HAA was compared using multivariate repeated measures regression analysis. Mortality was compared using the log-rank test and proportional hazards regression analysis. Overall, 165 patients (31%) developed persistent HAA. The adjusted mean Short-Form 12 Physical Component Summary scores at the follow-up visit were significantly lower in those with persistent HAA than in those with transient HAA (-2.0 points, 95% confidence interval -3.6 to -0.3; p = 0.02). During a median follow-up of 36 months, the crude mortality (13% vs 5%, p = 0.002) and multivariate-adjusted mortality (hazard ratio 2.08, 95% confidence interval 1.02 to 4.21, p = 0.04) was greater in patients with persistent HAA. In conclusion, HAA persists 1 month after discharge in nearly 1 of 3 patients and is associated with worse health status and greater mortality. Additional investigation is needed to understand whether HAA prevention, recognition, and treatment, particularly among those with persistent HAA, will improve outcomes. PMID- 21784388 TI - Outcomes of coronary arterial perforations during percutaneous coronary intervention with bivalirudin anticoagulation. AB - Coronary perforation (CP) is a rare but catastrophic event that may be influenced by the procedural anticoagulation regimen. This study compared the consequences of CP in patients who underwent anticoagulation with bivalirudin (BIV; a nonreversible direct thrombin inhibitor with a shorter 1/2-life than heparin) to those in patients who underwent anticoagulation with heparin (HEP) at time of CP. Patients with CP were identified from 33,613 procedures available in our institutional angioplasty registry. The outcome of this group was compared based on anticoagulation regimen (BIV vs HEP). The primary end point for this analysis was the composite of in-hospital death, cardiac tamponade, or emergency cardiac surgery. Overall a cohort of 69 patients (0.2%) with CP was identified. BIV was the intraprocedural anticoagulant in 41 patients, whereas HEP was used in 28. Baseline characteristics were comparable between groups except for a higher frequency of systemic hypertension and hypercholesterolemia in the BIV group. Procedural characteristics were also similar including lesion complexity and perforation severity. Nearly 1/2 of CPs in each group was managed with prolonged balloon inflation alone. Protamine was used in 46% of HEP-treated patients. Covered stents tended to be used more frequently in the BIV group (p = 0.061). The primary composite end point was similar between groups (odds ratio 1.42, 95% confidence interval 0.47 to 4.29, p = 0.53). However, there was a lower rate of cardiac surgery requirement in BIV-treated patients (p = 0.037). In conclusion, our study suggests that choice of procedural anticoagulant agent does not influence outcome when CP occurs. Therefore, use of BIV should not be discouraged in patients undergoing high-risk intervention for perforations. PMID- 21784389 TI - Relation of growth-differentiation factor 15 to left ventricular remodeling in ST segment elevation myocardial infarction. AB - The development of left ventricular remodeling (LVR) after myocardial infarction is associated with a high risk of heart failure and death. LVR is difficult to predict, and limited information is available on the association of cardiac biomarkers and LVR. Growth-differentiation factor-15 (GDF-15) is induced during heart failure development and, in animals models, might influence the different processes involved in cardiac remodeling. The aim of the present investigation was to assess the association between the serum levels of GDF-15 within the first 24 hours of ST-segment elevation myocardial infarction and the development of subsequent LVR at 12 months of follow-up. This prospective study included 97 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Echocardiography was performed in all patients within the first 96 hours of admission and at 12 months of follow-up. LVR was defined as a >20% increase in the left ventricular end-diastolic volume at 12 months of follow-up compared to baseline. Blood samples for the determination of GDF-15 and brain natriuretic peptide were obtained within the first 24 hours after symptom onset. According to the pre-established criteria, 21 patients (22%) had LVR. Patients with LVR had greater levels of GDF-15 at study entry (median 3,439 pg/ml, interquartile range 2,391 to 6,168 vs median 1998 pg/ml, interquartile range 1,204 to 3,067, respectively; p <0.001). Multivariate analysis showed that GDF-15 (odds ratio 10.1, 95% confidence interval 2.5 to 40.1, p <0.001) and treatment with angiotensin-converting enzyme inhibitors (odds ratio 3.9, 95% confidence interval 1.2 to 12.3, p <0.01) were independents predictors of LVR. Receiving operating characteristics analysis showed an area under the curve of 0.77 for GDF-15 (95% confidence interval 0.67 to 0.84, p <0.001). In conclusion, the results of the present study have identified GDF-15 as an independent marker of LVR in patients with ST-segment elevation myocardial infarction. PMID- 21784390 TI - Sex differences in neointimal hyperplasia following endeavor zotarolimus-eluting stent implantation. AB - Inconsistent results in outcomes have been observed between the genders after drug-eluting stent implantation. The aim of this study was to investigate gender differences in neointimal proliferation for the Endeavor zotarolimus-eluting stent (ZES) and the Driver bare-metal stent (BMS). A total of 476 (n = 391 ZES, n = 85 BMS) patients whose volumetric intravascular ultrasound analyses were available at 8-month follow-up were studied. At 8 months, neointimal obstruction and maximum cross-sectional narrowing (CSN) were significantly lower in women than in men receiving ZES (neointimal obstruction 15.5 +/- 9.5% vs 18.2 +/- 10.9%, p = 0.025; maximum CSN 30.3 +/- 13.2% vs 34.8 +/- 15.0%, p = 0.007). Conversely, these parameters tended to be higher in women than in men receiving BMS (neointimal obstruction 36.3 +/- 15.9% vs 27.5 +/- 17.2%, p = 0.053; maximum CSN 54.3 +/- 18.6% vs 45.6 +/- 18.3%, p = 0.080). There was a significant interaction between stent type and gender regarding neointimal obstruction (p = 0.001) and maximum CSN (p = 0.003). Multivariate linear regression analysis revealed that female gender was independently associated with lower neointimal obstruction (p = 0.027) and maximum CSN (p = 0.004) for ZES but not for BMS. Compared to BMS, ZES were independently associated with a reduced risk for binary restenosis in both genders (odds ratio for women 0.003, p = 0.001; odds ratio for men 0.191, p <0.001), but the magnitude of this risk reduction with ZES was significantly greater in women than men (p = 0.015). In conclusion, female gender is independently associated with decreased neointimal hyperplasia in patients treated with ZES. The magnitude of risk reduction for binary restenosis with ZES is significantly greater in women than in men. PMID- 21784391 TI - Comparison of the heart function adaptation in trained and sedentary men after 50 and before 35 years of age. AB - The effects of aging and of sustained athletic activity on the heart in men aged >50 years are unknown. The aim of this study was to assess the adaptation of the heart in athletic and sedentary men aged <35 and >=50 years. Echocardiograms recorded at rest and during submaximal exercise were analyzed in 59 athletic seniors (S(ATH) group) and 16 sedentary seniors (S(SED) group) (age >=50 years) and in 18 athletic youth (Y(ATH) group) and 27 sedentary youth (Y(SED) group) (age <35 years). All subjects were healthy. The reproducibility of measurements was examined, and the echocardiographic characteristics were compared among the study groups. No differences were found in baseline characteristics between the Y(ATH) and Y(SED) groups and between the S(ATH) and S(SED) groups, except for their exercise routines, consisting of >8 hours of bicycling per week in the athletic groups. Left ventricular mass was greater in the Y(ATH) than in the S(ATH) group (p <0.01) and greater in the S(ATH) than in the S(SED) group (p <0.001). Likewise, left ventricular volumes were greater in the athletic than in the sedentary groups (p <0.05), although they were smaller in the seniors than in youth (p <0.01). Left ventricular stroke volume was greater in the athletic than in the sedentary groups (p <0.001); global longitudinal strain during exercise was -20.0 +/- 2.4% in the S(ATH) group and -22.1 +/- 2.1% in the Y(ATH) group, compared to -19.2 +/- 3.4% in the S(SED) group and -20.2 +/- 2.4% in the Y(SED) group (p <0.05, athletic vs sedentary). The e' velocities recorded at the septal and lateral mitral annulus were higher at rest and during exercise (p <0.01) in the youth than in the senior groups. In conclusion, systolic and diastolic myocardial adaptation to regular exercise was significantly more prominent in young than in senior volunteers. PMID- 21784392 TI - Safety of dental extractions during uninterrupted single or dual antiplatelet treatment. AB - Optimal dental management in patients on long-term antiplatelet treatment is not clearly defined. Antiplatelet discontinuation increases the risk of thrombotic complications, whereas uninterrupted antiplatelet therapy, which is the currently recommended approach, is assumed to increase the bleeding hazard after dental procedures. We sought to prospectively compare the risk of immediate and late postextraction bleeding in patients receiving uninterrupted single or dual antiplatelet therapy. We recruited 643 consecutive patients referred for dental extractions. In total 111 (17.3%) were on clinically indicated antiplatelet therapy: aspirin (n = 42), clopidogrel (n = 36), and aspirin and clopidogrel (n = 33). Controls (n = 532, 82.7%) were not on antiplatelet treatment. Immediate and late bleeding complications were recorded. Compared to controls the risk of prolonged immediate bleeding was higher in patients on dual antiplatelet therapy (relative risk [RR] 177.3, 95% confidence interval [CI] 43.5 to 722, p <0.001) but not in patients on aspirin alone (RR = 6.3, 95% CI 0.6 to 68.4, p = 0.2) or clopidogrel alone (RR = 7.4, 95% CI 0.7 to 79.5, p = 0.18); however, all immediate bleeding complications in all treatment groups were successfully managed with local hemostatic measures. No patient developed any late hemorrhage. In conclusion, dental extractions may be safely performed in patients receiving single or dual antiplatelet therapy when appropriate local hemostatic measures are taken, thus averting thrombotic risk of temporary antiplatelet discontinuation. PMID- 21784393 TI - Comparison of severity of aortic regurgitation by cardiovascular magnetic resonance versus transthoracic echocardiography. AB - Transthoracic echocardiography is the current standard for assessing aortic regurgitation (AR). AR severity can also be evaluated by flow measurement in the ascending aorta using cardiac magnetic resonance (CMR); however, the optimal site for flow measurement and the regurgitant fraction (RF) severity grading criteria that best compares with the transthoracic echocardiographic assessment of AR are not clear. The present study aimed to determine the optimal site and RF grading criteria for AR severity using phase-contrast flow measurements and CMR. A prospective observational study was performed of 107 consecutive patients who were undergoing CMR of the thoracic aorta. Using CMR, the AR severity and aortic dimensions were measured at 3 levels in the aorta (the sinotubular junction, mid ascending aorta, and distal ascending aorta). The results were compared to the transthoracic echocardiographic grade of AR severity using multiple qualitative and quantitative criteria (grade 0, none; I+, mild; II+, mild to moderate; III+, moderate to severe; and IV+, severe). The mean RF values were significantly greater at the sinotubular junction than at the distal ascending aorta (13 +/- 13.3% vs 9.4 +/- 12.6%, respectively; p <0.001). The RF values that best defined AR severity using phase-contrast CMR were as follows: grade 0 to I+, <8%; grade II+, 8% to 19%; grade III+, 20 to 29%; and grade IV+, 30%) at the sinotubular or mid-ascending aorta. In conclusion, the quantitative RF values of AR severity using phase-contrast flow are best assessed in the proximal ascending aorta and differ from recognized quantitative echocardiographic criteria. PMID- 21784394 TI - Prognostic value of renal dysfunction for the prediction of outcome versus results of computed tomographic coronary angiography. AB - Chronic kidney disease (CKD) is associated with cardiovascular (CV) events caused by advanced atherosclerosis. Computed tomographic coronary angiography (CTA) can accurately diagnose coronary artery disease (CAD) and predict CV outcomes. The aim of the present study was to evaluate whether moderate CKD provides prognostic information for CV events in patients undergoing CTA. In total 885 patients with suspected CAD underwent CTA and were stratified to moderate CKD (85 patients) or no CKD (770 patients) based on a cut-off estimated glomerular filtration rate of 60 ml/min/1.73 m(2). After 896 days of follow-up, 42 patients developed CV events. Annualized CV event rates were 1.2% in patients with no CKD and no CAD, 2.5% in patients with moderate CKD alone, 2.5% in patients with obstructive CAD alone, and 3.7% in those with moderate CKD and obstructive CAD. Multivariate models demonstrated that moderate CKD (hazard ratio 2.39, confidence interval 1.09 to 5.21, p = 0.03) and obstructive CAD (hazard ratio 2.76, confidence interval 1.40 to 5.44, p <0.01) were independent predictors of CV events. Importantly, moderate CKD provided incremental prognostic information in addition to clinical characteristics and obstructive CAD (chi-square 49.4, p = 0.04). In conclusion, moderate CKD was associated with CV events and provided incremental prognostic information. PMID- 21784395 TI - Frequency of stroke and embolism in left ventricular hypertrabeculation/noncompaction. AB - Left ventricular hypertrabeculation/noncompaction (LVHT/NC) is associated with stroke or embolism (S/E). The aim of this retrospective study was to assess the rate, risk factors, and cause of S/E in patients with LVHT/NC. The medical records of patients with LVHT/NC were retrospectively screened for S/E. For stroke classification, the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria were applied, and for peripheral embolism, angiographic findings were used. Baseline clinical, echocardiographic, and electrocardiographic data were compared between patients with and without S/E. In 22 of 144 patients (15%), stroke (n = 21) or peripheral embolism (n = 1) had occurred. The cause of S/E was cardioembolic (n = 14), atherosclerotic (n = 5), or undetermined (n = 3). S/E occurred before (n = 14) and after (n = 8) the diagnosis of LVHT/NC. Only mean age (60 vs 53 years, p <0.05) and the prevalence of hypertension (32% vs 59%, p <0.05) were higher in patients with S/E than in those without S/E. Among patients with cardioembolic S/E, 13 of 14 had either atrial fibrillation (AF) or systolic dysfunction, and AF as well as systolic dysfunction were found in 4 of 14 patients. In conclusion, S/E in patients with LVHT/NC is not always cardioembolic but may also have an atherosclerotic cause. In the absence of AF or left ventricular systolic dysfunction, cardioembolic S/E is rare in patients with LVHT/NC. These findings suggest that patients with LVHT/NC with systolic dysfunction or AF should receive oral anticoagulation as primary prophylaxis against S/E. PMID- 21784396 TI - Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. AB - OBJECTIVE: Glial fibrillary acidic protein (GFAP) is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole-body cooling. STUDY DESIGN: We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole-body cooling to gestational age-matched controls without neurological injury and neonates with HIE by brain abnormalities on magnetic resonance imaging (MRI). RESULTS: Neonates with HIE had increased GFAP levels compared with controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared with neonates with HIE and normal imaging. CONCLUSION: Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers such as GFAP could help triage neonates with HIE to treatment, measure treatment efficacy, and provide prognostic information. PMID- 21784397 TI - Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome. AB - OBJECTIVE: The objective of the study was to investigate whether resistance to annexin A5 anticoagulant activity (AnxA5) occurs in women with histories for obstetric complications of antiphospholipid syndrome (Obs-APS) and whether this correlates with antibody recognition of domain 1 of beta2-glycoprotein. STUDY DESIGN: One hundred thirty-six women with antiphospholipid antibodies, including 70 with histories for Obs-APS and 30 controls, were investigated. RESULTS: Women with Obs-APS showed resistance to AnxA5 activity (median, 216%; range, 130-282% vs controls; median, 247%; range, 217-283%; P < .0001) and elevated levels of anti-domain I immunoglobulin (Ig) G (optical density: median, 0.056; range, 0.021 0.489 vs median, 0.042; range, 0.020-0.323; P = .002). Those in the lowest tertile of AnxA5 anticoagulant ratios had an odds ratio for Obs-APS of 58.0 (95% confidence interval, 3.3-1021.5). There was an inverse correlation between levels of annexin A5 anticoagulant activity and anti-domain I IgG. CONCLUSION: Resistance to AnxA5 anticoagulant activity is associated with antibody recognition of domain I of beta2-glycoprotein I and identifies a subset of women with histories for Obs-APS. PMID- 21784398 TI - Methadone and perinatal outcomes: another perspective. PMID- 21784400 TI - Prediction of safe and successful vaginal twin birth. AB - OBJECTIVE: The objective of the study was to establish predictors of vaginal twin birth and evaluate perinatal morbidity according to mode of delivery. STUDY DESIGN: One thousand twenty-eight twin pregnancies were prospectively recruited. For this prespecified secondary analysis, obstetric characteristics and a composite of adverse perinatal outcome were compared according to the success or failure of a trial of labor and further compared with those undergoing elective cesarean delivery. Perinatal outcomes were adjusted for chorionicity and gestational age using a linear model for continuous data and logistic regression for binary data. RESULTS: Nine hundred seventy-one twin pregnancies met the criteria for inclusion. A trial of labor was considered for 441 (45%) and was successful in 338 of 441 (77%). The cesarean delivery rate for the second twin was 4% (14 of 351). Multiparity and spontaneous conception predicted vaginal birth. No statistically significant differences in perinatal morbidity were observed. CONCLUSION: A high prospect of successful and safe vaginal delivery can be achieved with trial of twin labor. PMID- 21784401 TI - Implications of early staples removal at cesarean delivery. PMID- 21784402 TI - Preterm premature rupture of membranes >= 32 weeks' gestation: impact of revised practice guidelines. AB - OBJECTIVE: The purpose of this study was to determine the perinatal impact of the 2007 American College of Obstetricians and Gynecologists Practice Bulletin on preterm premature membrane rupture. STUDY DESIGN: Perinatal outcomes were compared in women who had experienced preterm membrane rupture in the 3 years before the 2007 Practice Bulletin to similar women who experienced preterm premature rupture of membranes in the 3 years after the issue and implementation of the guideline. RESULTS: After adjustment for gestational age at membrane rupture and steroids, composite severe morbidity (death, respiratory distress syndrome, assisted ventilation for >= 6 hours, sepsis, pneumonia, grade 3 or 4 intraventricular hemorrhage, or necrotizing enterocolitis) was similar by group. Infants in the "after" group experienced less pneumonia and sepsis, similar respiratory morbidity, but more labor inductions and postpartum hemorrhage. CONCLUSION: The new guideline significantly decreases severe neonatal infections but is associated with more frequent labor induction and postpartum hemorrhage. PMID- 21784403 TI - Exclusive breastfeeding, maternal HIV disease, and the risk of clinical breast pathology in HIV-infected, breastfeeding women. AB - OBJECTIVE: The objective of the study was to examine the relationship between breastfeeding patterns, markers of maternal human immunodeficiency virus (HIV) disease, and woman's breast pathology. STUDY DESIGN: Secondary data analysis from a randomized breastfeeding trial including 947 HIV-infected women (n = 5982 visits) from breastfeeding initiation until 6 months postpartum; 1 month after breastfeeding cessation; or loss to follow-up or death. Generalized estimating equations assessed the effects of breastfeeding pattern and maternal HIV status on breast pathology. RESULTS: One hundred ninety women (20.1%) had a breast problem; 86 (9.1%) had mastitis; and 31 (3.3%) had abscess. After confounder adjustment, nonexclusively breastfeeding women had an increased risk of breast problems (odds ratio, 1.98; 95% confidence interval, 1.33-2.95) and mastitis (odds ratio, 2.87, 95% confidence interval, 1.69-4.88) compared with exclusive breastfeeders. Women with a CD4 count less than 200 cells/MUL tended to have an increased risk of abscess. CONCLUSION: Nonexclusive breastfeeding significantly increased the risk of breast pathology. Exclusive breastfeeding is not only optimal for infant health but it also benefits mothers by reducing breast problems. PMID- 21784404 TI - Despite 2009 guidelines, few women report being counseled correctly about weight gain during pregnancy. AB - OBJECTIVE: The purpose of this study was to determine the information that pregnant women report receiving when being counseled about weight gain and the risks of inappropriate gain. STUDY DESIGN: With the use of a self-administered questionnaire at prenatal clinics in Hamilton, Ontario, Canada, a cross-sectional survey was conducted of women who had had at least 1 prenatal visit, who could read English, and who had a live singleton gestation. RESULTS: Three hundred ten women completed the survey, which was a 93.6% response rate. Although 28.5% (95% confidence interval, 23.5-33.6%) reported that their health care provider had made a recommendation about how much weight they should gain, only 12.0% (95% confidence interval, 8-16.1%) of the women reported having achieved the recommended weight gain in accordance with the 2009 guidelines. One quarter of the women reported being told that there were risks with inappropriate gain. CONCLUSION: Despite the recent 2009 publication of the gestational weight gain guidelines, only 12% of women reported being counseled correctly, which suggests an urgent need for improved patient education. PMID- 21784405 TI - Effects of leptin on lipopolysaccharide-induced myometrial apoptosis in an in vitro human model of chorioamnionitis. AB - OBJECTIVE: This study was aimed at assessing the role of leptin on human myometrium, by studying its receptor expression in pregnant myometrium and the interaction of leptin with inflammation-induced apoptosis. STUDY DESIGN: Myometrial samples were obtained from women with uncomplicated pregnancies who underwent cesarean delivery at term before labor onset. The effect of leptin on apoptosis was assessed by the incubation of myometrial strips with leptin (10( 10) to 10(-8) mol/L; 48 hours) before lipopolysaccharide treatment (10 MUg/mL; 48 hours). RESULTS: Long and short leptin receptor isoforms were expressed in myometrial cells of pregnant women. Leptin prevented lipopolysaccharide-induced apoptosis, in a concentration-dependent manner, by down-regulating cleaved caspase-3 and BCL2-associated X protein and up-regulating BCL2 expression. This effect was mediated specifically through leptin receptor stimulation, followed by ERK1/2 signaling pathway activation. CONCLUSION: These results suggest a new potential pathway that is involved in delivery disorders of obese women and propose a role for the leptin-induced inhibition of myometrial apoptosis in the development of such disorders. PMID- 21784406 TI - Appendectomy in pregnancy: evaluation of the risks of a negative appendectomy. AB - BACKGROUND: In pregnant women, a high negative appendectomy (NA) rate often is reported; however, the outcome of pregnancy after a NA is not well studied. METHODS: Among 1,696 consecutive patients (728 men and 968 women) who underwent an appendectomy at our institution (1996-2005), 87 pregnant women were identified. Postoperative surgical and obstetric outcomes were analyzed based on the final pathologic report of the appendix (normal appendix, inflamed, or perforated). RESULTS: The NA rate was significantly higher in pregnant women compared with nonpregnant women (36% vs 14%; P < .05). The fetal demise rate was similar between the NA group and the inflamed group (3% vs 2%; P = NS), and highest (14%) in the perforated group, although this difference did not reach statistical significance (P = .3). Wound infections were most frequent in the perforated group (P < .05). CONCLUSIONS: NA during pregnancy is not free of risk to the fetus. We recommend careful assessment to avoid unnecessary exploration when appendicitis is suspected in pregnant women. PMID- 21784407 TI - Carotid stenosis: change of treatment plan based on repeat duplex ultrasonography. AB - BACKGROUND: This study was conducted to evaluate the change in the treatment plan observed when clinical decisions are made based on initial carotid duplex ultrasonography (DU) performed at an outside center before surgical consultation versus those made based on DU performed in a dedicated vascular laboratory. METHODS: A prospective study of patients who underwent initial DU at an outside facility and repeat DU in a dedicated vascular laboratory for evaluation of carotid stenosis was performed. Initial DU was compared with repeat DU to evaluate clinical impact. RESULTS: Ninety-six consecutive patients were evaluated. Disagreement between initial DU and repeat DU was observed in 27.1% of patients. This disagreement led to a change of treatment plan in 23 of 146 (15.8%) carotid arteries studied. CONCLUSIONS: Reliance on 1 DU in clinical practice, when performed outside a dedicated vascular laboratory, may lead to both unnecessary surgery and missed opportunities for surgery to prevent stroke. PMID- 21784408 TI - Accessory spleen in the greater omentum. AB - Although accessory spleen is a frequently encountered entity, accessory spleen in the greater omentum is rare. A 22-year-old woman presented with dull pain in the left upper abdomen. Cross-sectional imaging studies with 3-dimensional reconstruction suggested the presence of a huge tumor in the greater omentum that was associated with the spleen. At laparotomy, the diagnosis of accessory spleen was made. This accessory spleen was unusual in its size and location. Awareness of this entity and familiarity with typical imaging findings is mandatory for preoperative diagnosis. The importance of recognition and appropriate confirmatory diagnosis of an accessory spleen is discussed. PMID- 21784409 TI - Pulmonary leiomyosarcoma metastatic to the thyroid gland: case report and review of the literature. AB - BACKGROUND: Leiomyosarcoma metastatic to the thyroid is extremely rare. Especially, metastasis of pulmonary leiomyosarcoma to the thyroid is extremely rare-only one such case has been previously reported. CASE PRESENTATION: A 55 year-old woman presented with a chief complaint of a cough of 1.5 months duration. Chest radiography (PA view) and chest computed tomography revealed 1cm sized subpleural nodule in left apical lung and a 8.3*4cm sized, lobulated mass in anterior segment of left upper lobe of the lung. We decided on left upper lobectomy and excision by video-assisted thoracoscopic surgery (VATS). They were leiomyosarcomas. During follow-up chest computed tomography at 23 months after first surgery, we noticed that a nodule on the left lobe of the thyroid gland had increased in size over 3 months. The patient underwent total thyroidectomy and central lymph node dissection. Immunohistochemical staining showed that tumor cells were positive for smooth muscle actin, focal positive for desmin and positive for vimentin, but negative for CD34 and S-100 protein. C-kit staining showed focal, weak positivity. The Ki-67 proliferation index was around 30-40%. CONCLUSIONS: Our case represents the first report of pulmonary leiomyosarcoma metastatic to the thyroid, although extrapulmonary leiomyosarcomas metastatic to the thyroid is encountered infrequently. PMID- 21784410 TI - The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation. AB - BACKGROUND: Approximately 5% to 15% of patients develop protein-losing enteropathy (PLE) after the Fontan operation. Oral controlled release (CR) budesonide has been used as a treatment strategy, but its use in the older Fontan population has not been described. METHODS: Seven patients with refractory PLE after the Fontan operation were started on oral CR-budesonide at 9 mg. After 3 to 9 months, the dose was weaned to 3 mg. Response to treatment was assessed by clinical evaluation, serum albumin levels, and fecal alpha-1 antitrypsin clearance when available. RESULTS: Median age at last evaluation was 20 years (range, 16 to 32 years). Six patients had increases in serum albumin levels but only 4 patients had symptomatic improvement. Systemic side effects included: cushingoid features (5), adrenal insufficiency (4), and new-onset type 2 diabetes mellitus (2). One patient had improvement in cushingoid features after weaning CR budesonide to 3 mg. Older patients (ages 27 to 32 years) had the worst side effect profiles and were the most refractory to treatment. These patients had sonographic evidence of hepatic cirrhosis but normal serum liver function tests. Two deaths occurred: 1 from sepsis 1 month after CR-budesonide initiation and 1 from respiratory arrest 5 months after CR-budesonide discontinuation. CONCLUSIONS: CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well. PMID- 21784411 TI - Urease activity as a risk factor for caries development in children during a three-year study period: a survival analysis approach. AB - Recent cross-sectional studies suggest that reduced ability to generate alkali via the urease pathway in dental plaque may be an important caries risk factor, but it has not been assessed prospectively. OBJECTIVE: To evaluate the effect of plaque and saliva urease activity on the risk for developing new caries over a three-year period in children. METHODS: A panel of 80 children, three to six years of age at recruitment, was followed prospectively for three years. Plaque urease activity, saliva urease activity and dental caries were measured every six months. Survival analysis methodology was used to evaluate the effect of urease on caries development during the study period adjusted for gender, age, baseline caries levels, sugar consumption, amount of plaque, and mutans streptococci levels. RESULTS: The risk for developing new caries increased in a dose responsive manner with increasing levels of urease activity in saliva (adjusted HR(Q4 vs. Q1): 4.98; 95% CI: 1.33, 18.69) and with decreasing urease activity in plaque (adjusted HR(Q4 vs. Q1): 0.29; 95% CI: 0.11, 0.76). Multiple measurements of urease activity were conducted to overcome the variability of urease activity in this study. Baseline caries and mutans streptococci in saliva were also important predictors of caries risk. CONCLUSIONS: Increased urease activity in saliva can be an indicator of increased caries risk in children, whilst increased urease activity in plaque may be associated with reduced caries risk. The reproducibility of urease measurements must be improved before these findings can be further tested and clinically applied. PMID- 21784412 TI - Cognitive-behavioral therapy for geriatric compulsive hoarding. AB - This investigation examined response to a manualized cognitive-behavioral therapy (CBT) protocol for compulsive hoarding (Steketee & Frost, 2007) in a sample of 12 adults over age 65. All participants were cognitively intact, not engaging in any other psychotherapy, and had compulsive hoarding as their primary problem. All received 26 sessions of individual CBT over the course of 17 weeks. The primary outcome measures were the Savings Inventory-Revised and UCLA Hoarding Severity Scale, which were administered at baseline, mid-treatment, post-treatment, and 6 month follow-up. Other outcomes included Clinical Global Impression (CGI) scores, depression, anxiety, disability, and clutter image ratings. Results demonstrated statistically significant changes on hoarding severity and depression. However, only three of the twelve participants were classified as treatment responders at post-treatment, and their gains were not maintained at 6-month follow-up. CGI, anxiety, disability, and clutter ratings were unchanged at post-treatment and follow-up. No participants dropped out, but homework compliance was variable and correlated with decreases in hoarding severity. Findings suggest that older adults with compulsive hoarding may require an enhanced or alternative treatment. PMID- 21784413 TI - Competitive Memory Training for treating depression and rumination in depressed older adults: a randomized controlled trial. AB - Although rumination is an important mediator of depressive symptoms, there is insufficient proof that an intervention that specifically targets rumination ameliorates the clinical condition of, depressed patients. This study investigates whether a time-limited cognitive behavioral intervention (Competitive Memory Training, or COMET for depressive rumination) is an effective treatment for depression and rumination. This intervention was tested in older adult depressed outpatients. A total of 93 patients (aged >= 65 years with major depression and suffering from rumination) were treated in small groups according to the COMET protocol in addition to their regular treatment. Patients were randomized to two treatment conditions: 7 weeks of COMET + treatment-as-usual (TAU) versus TAU only. COMET + TAU showed a significant improvement in depression and rumination compared with TAU alone. This study shows that the transdiagnostic COMET protocol for depressive rumination might also be successful in treating depression and rumination in older adults. PMID- 21784414 TI - Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. AB - BACKGROUND: Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals. METHODS: The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake. RESULTS: A repeated-measures analysis showed significant age-by group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures. CONCLUSIONS: Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia. PMID- 21784415 TI - Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system. AB - Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of a superfamily of detoxification enzymes found in various tissues that participate in the oxidation of both aliphatic and aromatic aldehydes. In the brain, ALDH1A1 participates in the metabolism of catecholamines including dopamine (DA) and norepinephrine, but is uniquely expressed in a subset of dopaminergic (DAergic) neurons in the ventral mesencephalon where it converts 3,4-dihydroxyphenylacetaldehyde, a potentially toxic aldehyde, to 3,4-dihydroxyphenylacetic acid, a non toxic metabolite. Therefore, loss of ALDH1A1 expression could be predicted to alter DA metabolism and potentially increase neurotoxicity in ventral mesencephalic DA neurons. Recent reports of reduced levels of expression of both Aldh1a1 mRNA and protein in the substantia nigra (SN) of Parkinson's disease patients suggest possible involvement of ALDH1A1 in this progressive neurodegenerative disease. The present study used an Aldh1a1 null mouse to assess the influence of ALDH1A1 on the function and maintenance of the DAergic system. Results indicate that the absence of Aldh1a1 did not negatively affect growth and development of SN DA neurons nor alter protein expression levels of tyrosine hydroxylase, the DA transporter or vesicular monoamine transporter 2. However, absence of Aldh1a1 significantly increased basal extracellular DA levels, decreased KCl and amphetamine stimulated DA release and decreased DA re-uptake and resulted in more tyrosine hydroxylase expressing neurons in the SN than in wildtype animals. These data suggest that in young adult animals with deletion of the Aldh1a1 gene there is altered DA metabolism and dysfunction of the DA transporter and DA release mechanisms. PMID- 21784417 TI - Preparation and evaluation of lactose-modified monoliths for the adsorption and decontamination of plant toxins and lectins. AB - A series of sugar-modified porous silica monoliths with different sugar ligands (beta-lactoside, beta-N-acetyllactosaminide, beta-d-galactoside, beta-d-N acetylgalactosaminide and beta-d-glucoside) and linkers were prepared and evaluated using plant toxins and lectins including ricin and a Ricinus communis agglutinin (RCA(120)). Among these sugar monoliths, a lactose monolith carrying a triethylene glycol spacer adsorbed ricin and RCA(120) with the highest efficiency. The monolith showed no binding with albumin, globulin, and lectins from Jack beans, Osage orange, Amur maackia and wheat germ. All these data support the utility of the lactose-modified monolith as a tool for adsorption and decontamination of plant toxins. PMID- 21784418 TI - Interactions between metal ions and carbohydrates. Syntheses and spectroscopic studies of several lanthanide nitrate-D-galactitol complexes. AB - Two complexes of neutral D-galactitol (C(6)H(14)O(6), G) with terbium nitrate, TbGN(I) and TbGN(II), and one complex with samarium nitrate SmGN were synthesized and characterized. From IR, FIR, THz and luminescence spectra the possible coordinations were suggested, and the single-crystal X-ray diffraction results confirm the spectroscopic conclusions. In TbGN(I) (Tb(NO(3))(3).C(6)H(14)O(6).3H(2)O), the Tb(3+) is 9-coordinated with three water molecules and six OH groups from two D-galactitol molecules. Nitrate ions do not coordinate to metal ions, which is different from other reported lanthanide nitrate-D-galactitol complexes. In TbGN(II) and SmGN (Ln(NO(3))(3).C(6)H(14)O(6)), Ln(3+) is 10-coordinated with six OH groups from two D-galactitol molecules and four oxygen from two bidentate nitrate ions, and one nitrate ion is hydrogen bonded. No water exists in the structures. D Galactitol molecules provide their 1-, 2- and 3-hydroxyl groups to coordinate with one metal ion and their 4-, 5- and 6-hydroxyl groups to coordinate with another metal ion in the three structures. There is still a new topological structure that can be observed for lanthanide-d-galactitol complexes, which indicates that the coordinations between hydroxyl groups and metal ions are complicated. PMID- 21784416 TI - CSF xanthine, homovanillic acid, and their ratio as biomarkers of Parkinson's disease. AB - Diminished nigrostriatal dopaminergic neurotransmission is a biochemical hallmark of Parkinson's disease. Despite this, a reliable trait biomarker of sporadic Parkinson's disease has not emerged from measurements of cerebrospinal fluid dopamine metabolites. Previous studies have highlighted strong neurochemical relationships between dopamine and various purine compounds. In this study, we analyzed cerebrospinal fluid concentrations of homovanillic acid (the major catabolite of dopamine) and the purine compound xanthine for a comparison of 217 unmedicated Parkinson's disease subjects and 26 healthy controls. These compounds were highly correlated for both the Parkinson's disease subjects (r=0.68) and for controls (r=0.73; both groups, p<0.001). While neither homovanillic acid nor xanthine concentrations differentiated Parkinson's disease from controls, their ratio did. For controls, the mean [xanthine]/[homovanillic acid] quotient was 13.1+/-5.5 as compared to the Parkinson's disease value of 17.4+/-6.7 at an initial lumbar CSF collection (p=0.0017), and 19.7+/-8.7 (p<0.001) at a second CSF collection up to 24 months later. The [xanthine]/[homovanillic acid] ratio in the Parkinson's disease subjects differed as a function of disease severity, as measured by the sum of Unified Parkinson's Disease Rating Scale Activities of Daily Living and Motor Exam ratings. The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease. PMID- 21784419 TI - Solvent-induced anomeric diastereoselectivity switching using a single glycosyl donor. AB - Highly diastereoselective glycosylation reactions have been developed; however, not all glycosylation reactions are diastereoselective and these reactions have probably not been reported. For some fucosylation reactions, unusually low or abnormally opposite selectivities have been demonstrated. In the present study, the fucosylation reaction of long-chain hydrocarbon alcohols, ethyl 9 hydroxynonanoate and decanol using a series of the 2-O-benzyl-protected fucopyranosyl donors were investigated. The resulting products demonstrated the solvent-induced diastereoselectivity switching using diethyl ether (Et(2)O) or dichloromethane (CH(2)Cl(2)). Practical alpha-selectivities were observed using ether solvents. In contrast, practical beta-selectivities were observed using CH(2)Cl(2). The anomeric diastereoselectivity switching was similarly observed in the alcohol galactosylation reaction. The larger spin-lattice relaxation time constant (T(1)) actually indicated that molecular motion of ethyl 9 hydroxynonanoate was more vigorous in Et(2)O than in CH(2)Cl(2), suggesting its dissociation in Et(2)O and association in CH(2)Cl(2). The bulkiness of the associated alcohols is most likely responsible for the observed diastereoselectivity. PMID- 21784420 TI - A facile synthesis of sugar-pyrazole derivatives. AB - A facile synthesis of sugar-pyrazole derivatives has been accomplished by condensation of sugar-chalcone with hydrazine hydrate under neutral conditions resulting in yields of 70-85%. The products are characterized by FTIR and NMR spectroscopy and by elemental analysis. The beta-anomeric forms for these derivatives were assigned by NMR spectroscopy. PMID- 21784421 TI - Tumour seeding following percutaneous needle biopsy: the real story! AB - The demand for percutaneous needle biopsy is greater than ever before and with the majority of procedures requiring imaging guidance, radiologists have an increasingly important role in the diagnostic work-up of patients with suspected malignancy. All invasive procedures incur potential risks; therefore, clinicians should be aware of the most frequently encountered complications and have a realistic idea of their likelihood. Tumour seeding, whereby malignant cells are deposited along the tract of a biopsy needle, can have disastrous consequences particularly in patients who are organ transplant candidates or in those who would otherwise expect good long-term survival. Fortunately, tumour seeding is a rare occurrence, yet the issue invariably receives a high profile and is often regarded as a major contraindication to certain biopsy procedures. Although its existence is in no doubt, realistic insight into its likelihood across the spectrum of biopsy procedures and multiple anatomical sites is required to permit accurate patient counselling and risk stratification. This review provides a comprehensive overview of tumour seeding and examines the likelihood of this much feared complication across the range of commonly performed diagnostic biopsy procedures. Conclusions have been derived from an extensive analysis of the published literature, and a number of key recommendations should assist practitioners in their everyday practice. PMID- 21784422 TI - The self in action effects: selective attenuation of self-generated sounds. AB - The immediate experience of self-agency, that is, the experience of generating and controlling our actions, is thought to be a key aspect of selfhood. It has been suggested that this experience is intimately linked to internal motor signals associated with the ongoing actions. These signals should lead to an attenuation of the sensory consequences of one's own actions and thereby allow classifying them as self-generated. The discovery of shared representations of actions between self and other, however, challenges this idea and suggests similar attenuation of one's own and other's sensory action effects. Here, we tested these assumptions by comparing sensory attenuation of self-generated and observed sensory effects. More specifically, we compared the loudness perception of sounds that were either self-generated, generated by another person or a computer. In two experiments, we found a reduced perception of loudness intensity specifically related to self-generation. Furthermore, the perception of sounds generated by another person and a computer did not differ from each other. These findings indicate that one's own agentive influence upon the outside world has a special perceptual quality which distinguishes it from any sort of external influence, including human and non-human sources. This suggests that a real sense of self-agency is not a socially shared but rather a unique and private experience. PMID- 21784423 TI - Altitudinal distribution patterns of the native and alien woody flora in Kashmir Himalaya, India. AB - BACKGROUND: Many studies have shown that alien species richness pattern follows that of native species richness patterns along environmental gradients, without taking the specific composition of the two groups into account. OBJECTIVES: To compare species richness patterns of native and alien woody plants along an altitudinal gradient in Kashmir Himalaya, India, and to analyse the specific composition, e.g. proportion of life forms. METHODS: Analysis of secondary data from published floristic inventories. The gradient (500-4800m asl) was split into 100m bands and presence/absence data for each species were obtained, for each band. RESULTS: Species richness of both native and alien species followed a hump shaped distribution. Alien species richness dropped faster above 2000masl than the native did. The ratio of trees to shrubs decreased monotonically along the gradient in native species, but showed a peak at c. 2500masl in alien species. Alien species flowered in average earlier than native species. CONCLUSIONS: The change of species richness of native and alien species along altitude is similar, but the proportion of life forms is not. Most likely both climatic and socio economic factors affect alien species richness and its specific composition in the Kashmir Himalaya. PMID- 21784424 TI - Arterial stiffness is associated with minimally elevated high-sensitivity cardiac, troponin T levels in a community-dwelling population. AB - OBJECTIVES: Arterial stiffness predicts an increased risk of future cardiovascular events, possibly via myocardial damage. Minimally elevated levels of plasma cardiac troponin T (TnT), a marker of cardiomyocyte injury, can be detected by the high-sensitivity TnT (hsTnT) assay. The current study investigated the relationship between plasma hsTnT levels and alterations in arterial stiffness in a community-based population. METHODS: We related levels of plasma hsTnT to measures of arterial stiffness (carotid-femoral pulse wave velocity [PWV], office pulse pressure [PP] and carotid-radial PWV) in 1479 participants (mean age, 62.3 years; 619 men, 860 women) from a community-based population in Beijing, China. RESULTS: In multiple logistic regression models, carotid-femoral PWV (OR: 1.84; 95% CI: 1.06-3.17; P=0.028) and office PP (OR: 2.02; 95% CI: 1.31-3.11; P=0.002) were associated with a higher likelihood of detectable hsTnT. In addition, carotid-femoral PWV (OR: 2.34; 95% CI: 1.03-5.30; P=0.042) and office PP (OR: 2.30; 95% CI: 1.13-4.66; P=0.022) were significantly related to elevated hsTnT levels. A subsequent subgroup analysis found that, in subjects aged 60 years and older, the associations between carotid-femoral PWV and office PP and hsTnT levels were strengthened. The associations between hsTnT with any of the arterial stiffness measures were not present in the younger subgroup (<60 years old). CONCLUSIONS: Carotid-femoral PWV and office PP are associated with minimally elevated hsTnT levels in the elderly, indicating a relationship between central artery stiffness and subclinical myocardial damage. PMID- 21784425 TI - Comments on "Assessment of amputee socket-stump-residual bone kinematics during strenuous activities using Dynamic Roentgen Stereogrammetric Analysis" (Volume 43, Issue 5, 2010). PMID- 21784426 TI - Estimation of low back moments from video analysis: a validation study. AB - This study aimed to develop, compare and validate two versions of a video analysis method for assessment of low back moments during occupational lifting tasks since for epidemiological studies and ergonomic practice relatively cheap and easily applicable methods to assess low back loads are needed. Ten healthy subjects participated in a protocol comprising 12 lifting conditions. Low back moments were assessed using two variants of a video analysis method and a lab based reference method. Repeated measures ANOVAs showed no overall differences in peak moments between the two versions of the video analysis method and the reference method. However, two conditions showed a minor overestimation of one of the video analysis method moments. Standard deviations were considerable suggesting that errors in the video analysis were random. Furthermore, there was a small underestimation of dynamic components and overestimation of the static components of the moments. Intraclass correlations coefficients for peak moments showed high correspondence (>0.85) of the video analyses with the reference method. It is concluded that, when a sufficient number of measurements can be taken, the video analysis method for assessment of low back loads during lifting tasks provides valid estimates of low back moments in ergonomic practice and epidemiological studies for lifts up to a moderate level of asymmetry. PMID- 21784427 TI - Influence of surfactant amphiphilicity on the phase behavior of IL-based microemulsions. AB - In this work, we report on the phase behavior of 1-ethyl-3-methyl-imidazolium ethylsulfate ([emim][etSO(4)])/limonene/polyethylene glycol tert-octylphenyl ether (Triton X-114 or TX-114) microemulsions as a function of ionic liquid (IL) content and temperature. Phase diagrams, conductivity measurements, and small angle X-ray scattering (SAXS) experiments will be presented. A hydrophilic IL, instead of water is used with the goal to enlarge the temperature range on which stable microemulsions can be formed. Indeed, the system shows remarkably large temperature stability, in particular down to -35 degrees C. We will emphasize on a comparison with a recently published work about microemulsions composed of [emim][etSO(4)], limonene, and Triton X-100 that to some extent are stable at temperatures well below the freezing point of water. The key parameter responsible for the difference in phase behavior, microstructure, and temperature stability is the average repeating number of ethylene oxide units in the surfactant head group, which is smaller for Triton X-114 compared to Triton X 100. Among the fundamental interest, how the amphiphilicity of the surfactant influences the phase diagram and phase behavior of IL-based microemulsions, the exchange of Triton X-100 by Triton X-114 results in one main advantage: along the experimental path the temperature where phase segregation occurs is significantly lowered leading to single phase microemulsions that exist at temperatures beneath 0 degrees C. PMID- 21784428 TI - Spontaneous periodic pulsation of contact line in oil/water system--frequency control with divalent cations and applied voltage. AB - Periodic oscillatory change of hydrophilicity (or hydrophobicity) of a glass surface was studied. A glass capillary was immersed normally at an oil/water interface. The water phase contained the cationic surfactant trimethyloctadecylammoniumchloride, and the oil phase contained bis(2ethylhexyl) phosphate. Adsorption of the surfactant molecules and their desorption via anionic chemicals dissolved in the oil generated a gradual wetting by the water, followed by a rapid wetting by oil. The three phase contact line exhibited a pulse-like motion that continued, at least for a few minutes. The frequency depended on the cation species dissolved in water and the applied voltage across the oil/water interface. Four kinds of cations, Mg(2+), Ca(2+), Sr(2+) and Ba(2+) were used. While the frequency order was Ba(2+)>Sr(2+)>Mg(2+), the Ca(2+) containing interface did not show any motion irrespective of the applied voltage. There was a threshold voltage and concentration of anionic chemical that was necessary for the onset of this motion. The pulsation mechanism and its ion selectivity are also discussed. This interfacial motion was a typical nonlinear oscillation with an ion-selective nature. In this regard, this interfacial motion had biomimetic characteristics. PMID- 21784429 TI - Diffusion-controlled evaporation of sodium dodecyl sulfate solution drops placed on a hydrophobic substrate. AB - In this work, the effect of SDS anionic surfactant on the diffusion-controlled evaporation rate of aqueous solution drops placed on TEFLON-FEP substrate was investigated with 11 different SDS concentrations. Drop evaporation was monitored in a closed chamber having a constant RH of 54-57% by a video camera. The initial contact angle, theta(i) decreased from 104+/-2 degrees down to 68+/-1 degrees due to the adsorption of SDS both at the water-air and the solid-water interfaces. The adsorption of SDS on the solid surface was found to be 76% of that of its adsorption at the water-air interface by applying Lucassen-Reynders approach. An equation was developed for the comparison of the evaporation rates of drops having different theta(i) on the same substrate. It was found that the addition of SDS did not alter the drop evaporation rate considerably for the first 1200 s for all the SDS concentrations. The main difference was found to be the change of the mode of drop evaporation by varying the SDS concentration. The constant theta mode was operative up to 80 mM SDS concentration, whereas constant contact area mode was operative after 200 mM SDS concentrations due to rapid drop pining on the substrate. PMID- 21784430 TI - Elaboration of nano-structured grafted polymeric surface. AB - The surface grafting of multi-polymeric materials can be achieved by grafting as components such as polymers poly(N-isopropylacrylamide) and/or surfactant molecules (hexatrimethylammonium bromide, polyoxyethylene sorbitan monolaurate). The chosen grafting techniques, i.e. plasma activation followed by coating, allow a large spectrum of functional groups that can be inserted on the surface controlling the surface properties like adhesion, wettability and biocompatibility. The grafted polypropylene surfaces were characterized by contact angle analyses, XPS and AFM analyses. The influence of He plasma activation, of the coating parameters such as concentrations of the various reactive agents are discussed in terms of hydrophilic character, chemical composition and morphologic surface heterogeneity. The plasma pre-activation was shown inevitable for a permanent polymeric grafting. PNIPAM was grafted alone or with a mixture of the surfactant molecules. Depending on the individual proportion of each component, the grafted surfaces are shown homogeneous or composed of small domains of one component leading to a nano-structuration of the grafted surface. PMID- 21784431 TI - Biomimetic gelatin-octacalcium phosphate core-shell microspheres. AB - Calcium phosphate/polymeric microparticles synthesized through a biomimetic approach are regarded with increasing interest for their various potential applications, including tissue engineering and regenerative medicine. Herein we report the synthesis and characterization of gelatin/octacalcium phosphate core/shell microspheres. Deposition of the calcium phosphate shell on the polymeric microspheres was obtained through bio-inspired mineralization on the surface of functionalized gelatin microparticles. Gelatin microspheres stabilized by alginate dialdehyde were prepared using an inverse microemulsion. Functionalization was achieved by enriching the microspheres composition with calcium ions or, alternatively, with alendronate, a bisphosphonate widely employed for the treatment of bone diseases. Functionalization and synthesis of the inorganic phase in the microemulsion environment were key factors for the achievement of a complete coating of the microspheres with calcium phosphate. The inorganic shell is constituted of small crystals of octacalcium phosphate, which control gelatin and alendronate release. PMID- 21784432 TI - Heart rate adjustment of PR interval in middle-aged and older adults. AB - Prolonged PR interval has been associated with adverse cardiac events. Consequently, the scientific community and regulatory agencies have become concerned about PR interval prolongation induced by cardioactive agents. We evaluated PR dependence on heart rate (HR) in 5757 men and women aged 40 years and older from the US third National Health and Nutrition Survey with the objective to determine if rate adjustment for the PR interval is warranted as is the case with QT interval. Electrocardiograms were computer-processed in a central electrocardiogram laboratory. There was a statistically significant negative correlation between PR and HR (r = -0.15; P < .001); notably weaker than that between QT and HR (r = -0.76; P < .001). Evaluation of subgroups stratified by sex, race, and age revealed a significant interaction between PR and HR with age (P = .006). A subsequent search for optimal rate-adjusted PR (PRa) formula that eliminates PR dependence on HR within each age group produced the formula: PRa = PR + 0.26 (HR - 70) for age group younger than 60 years and PRa = PR + 0.42 (HR - 70) for age group 60 years or older. The application of this formula in the study population effectively made the PR interval rate-invariant (residual slope of regression, -0.0054; 95% confidence interval, -0.064 to 0.053; P = .86). Based on the distribution of PRa, the 98th percentile limit of 220 milliseconds would be a reasonable overall threshold for defining first-degree AV block, with the 95th percentile limit of 205 as a threshold for borderline PR prolongation. In conclusion, the association between PR and HR is age- and rate-dependent and a separate rate-adjustment formula is needed for adults in younger and older age groups. The prognostic significance of the rate-adjusted PR needs to be investigated. PMID- 21784433 TI - Event memory and suggestibility in abused and neglected children: trauma-related psychopathology and cognitive functioning. AB - This study examined event memory and suggestibility in 3- to 16-year-olds involved in forensic investigations of child maltreatment. A total of 322 children were interviewed about a play activity with an unfamiliar adult. Comprehensive measures of individual differences in trauma-related psychopathology and cognitive functioning were administered. Sexually and/or physically abused children obtained higher dissociation scores than neglected children, and sexually abused children were more likely to obtain a diagnosis of posttraumatic stress disorder than physically abused children, neglected children, and children with no substantiated abuse histories. Overall, older children and children with better cognitive functioning produced more correct information and fewer memory errors. Abuse status per se did not significantly predict children's memory or suggestibility whether considered alone or in interaction with age. However, among highly dissociative children, more trauma symptoms were associated with greater inaccuracy, whereas trauma symptoms were not associated with increased error for children who were lower in dissociative tendencies. Implications of the findings for understanding eyewitness memory in maltreated children are discussed. PMID- 21784434 TI - Clinical status and cardiovascular risk profile of adults with a history of juvenile dermatomyositis. AB - OBJECTIVE: A pilot study of adults who had onset of juvenile dermatomyositis (JDM) in childhood, before current therapeutic approaches, to characterize JDM symptoms and subclinical cardiovascular disease. STUDY DESIGN: Eight adults who had JDM assessed for disease activity and 8 healthy adults (cardiovascular disease controls) were tested for carotid intima media thickness and brachial arterial reactivity. Adults who had JDM and 16 age-, sex-, and body mass index matched healthy metabolic controls were evaluated for body composition, blood pressure, fasting glucose, lipids, insulin resistance, leptin, adiponectin, proinflammatory oxidized high-density lipoprotein (HDL), and nail-fold capillary end row loops. RESULTS: Adults with a history of JDM, median age 38 years (24-44 years) enrolled a median 29 years (9-38 years) after disease onset, had elevated disease activity scores, skin (7/8), muscle (4/8), and creatine phosphokinase (2/8). Compared with cardiovascular disease controls, adults who had JDM were younger, had lower body mass index and HDL cholesterol (P = .002), and increased intima media thickness (P = .015) and their brachial arterial reactivity suggested impairment of endothelial cell function. Compared with metabolic controls, adults who had JDM had higher systolic and diastolic blood pressure, P = .048, P = .002, respectively; lower adiponectin (P = .03); less upper arm fat (P = .008); HDL associated with end row loops loss (r = -0.838, P = .009); and increased proinflammatory oxidized HDL (P = .0037). CONCLUSION: Adults who had JDM, 29 years after disease onset, had progressive disease and increased cardiovascular risk factors. PMID- 21784435 TI - Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. AB - OBJECTIVE: To investigate the outcomes after prolonged empirical antibiotic administration to premature infants in the first week of life, and concluding subsequent late onset sepsis (LOS), necrotizing enterocolitis (NEC), and death. STUDY DESIGN: Study infants were <= 32 weeks gestational age and <= 1500 g birth weight who survived free of sepsis and NEC for 7 days. Multivariable logistic regression was conducted to determine independent relationships between prolonged initial empirical antibiotic therapy (>= 5 days) and study outcomes that control for birth weight, gestational age, race, prolonged premature rupture of membranes, days on high-frequency ventilation in 7 days, and the amount of breast milk received in the first 14 days of life. RESULTS: Of the 365 premature infants who survived 7 days free of sepsis or NEC, 36% received prolonged initial empirical antibiotics, which was independently associated with subsequent outcomes: LOS (OR, 2.45 [95% CI, 1.28-4.67]) and the combination of LOS, NEC, or death (OR, 2.66 [95% CI, 1.12-6.3]). CONCLUSIONS: Prolonged administration of empirical antibiotics to premature infants with sterile cultures in the first week of life is associated with subsequent severe outcomes. Judicious restriction of antibiotic use should be investigated as a strategy to reduce severe outcomes for premature infants. PMID- 21784438 TI - Potential risks of hemolysis after short-term administration of analgesics in children with glucose-6-phosphate dehydrogenase deficiency. AB - OBJECTIVE: To evaluate the risk of hemolysis in children with glucose-6-phosphate dehydrogenase (G6PD) deficiency after short-term administration of analgesics, such as paracetamol, ibuprofen, tramadol, sufentanil, and parecoxib. STUDY DESIGN: This was a prospective study of children with G6PD deficiency who were treated with analgesics for 3 days after undergoing surgery. Hemoglobin (Hb) concentration, reticulocyte count, unconjugated bilirubin level, lactate dehydrogenase level, and the presence of Heinz bodies on blood smear microscopy were assessed at baseline and after analgesic treatment. Telephone interviews and clinical reviews were provided during a 7-day study period. The primary outcome was evidence of hemolysis. Statistical analyses were done using the paired Student t test or Wilcoxon signed-rank test as appropriate. RESULTS: Ten male infants (mean age, 4.3 +/- 1.3 years) completed the study. The mean decrease in (Hb) concentration was -0.2 g/dL (P, not significant). The mean reticulocyte count increased by 0.1% (95% CI, 0.08%-0.2%; P = .001). However, the change in reticulocyte count was not correlated with the changes in Hb concentration or other laboratory results and was not accompanied by the clinical signs and symptoms of hemolysis. CONCLUSION: Short-term administration of paracetamol, ibuprofen, tramadol, sufentanil, and parecoxib in therapeutic dosages did not increase the risk of hemolysis in children with G6PD deficiency. PMID- 21784437 TI - An evaluation of a clinical approach to staging tobacco addiction. AB - OBJECTIVES: To determine whether adolescents' symptom reports are consistent with the developmental sequence of tobacco addiction and whether the sequential appearance of these symptoms signifies increasing addiction. STUDY DESIGN: An anonymous survey was administered to 349 tobacco users in grades 9 through 12 in Florida. The combinations of withdrawal symptoms reported were examined to determine whether they were consistent with the developmental sequence described by case reports (wanting, then craving, then needing). Dependence was measured by several validated measures, including the Hooked on Nicotine Checklist, the Autonomy Over Tobacco Scale, and the modified Fagerstrom Tolerance Questionnaire. RESULTS: The combinations of withdrawal symptoms reported by 99.4% of subjects were consistent with case reports stating that wanting, craving, and needing develop in that sequence. Across the stages, from wanting to needing, higher stages were associated with significant increases in the strength of addiction as measured by the Hooked on Nicotine Checklist, the Autonomy Over Tobacco Scale, the modified Fagerstrom Tolerance Questionnaire, and all other measures. CONCLUSIONS: Our data confirmed that withdrawal symptoms develop in an orderly sequence, as proposed, and indicate that each progressive step along the sequence of wanting, craving, and needing represents a substantial increase in tobacco addiction. This provides the foundation for a clinical approach to staging the progression of tobacco addiction. PMID- 21784436 TI - Factors affecting growth in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial. AB - OBJECTIVES: To describe growth patterns in infants with single ventricle physiology and determine factors influencing growth. STUDY DESIGN: Data from 230 subjects enrolled in the Pediatric Heart Network Infant Single Ventricle Enalapril Trial were used to assess factors influencing change in weight-for-age z-score (z) from study enrollment (0.7 +/- 0.4 months) to pre-superior cavopulmonary connection (SCPC; 5.1 +/- 1.8 months, period 1) and pre-SCPC to final study visit (14.1 +/- 0.9 months, period 2). Predictor variables included patient characteristics, feeding regimen, clinical center, and medical factors during neonatal (period 1) and SCPC hospitalizations (period 2). Univariate regression analysis was performed, followed by backward stepwise regression and bootstrapping reliability to inform a final multivariable model. RESULTS: Weights were available for 197 of 230 subjects for period 1 and 173 of 197 subjects for period 2. For period 1, greater gestational age, younger age at study enrollment, tube feeding at neonatal hospitalization discharge, and clinical center were associated with a greater negative z (poorer growth) in multivariable modeling (adjusted R(2) = 0.39, P < .001). For period 2, younger age at SCPC and greater daily caloric intake were associated with greater positive z (better growth; R(2) = 0.10, P = .002). CONCLUSIONS: Aggressive nutritional support and earlier SCPC are modifiable factors associated with a favorable change in weight-for-age z score. PMID- 21784439 TI - Transfusion-related necrotizing enterocolitis. PMID- 21784440 TI - Variability in the characteristics and quality of care for injured youth treated at trauma centers. AB - OBJECTIVE: To survey US level I trauma centers to assess the characteristics of child and adolescent psychosocial service delivery. STUDY DESIGN: Trauma program staff at US level I trauma centers were asked to complete a survey on the characteristics and quality of service delivery for youth. The presence of pediatric services and screening of injured youth for alcohol use problems and posttraumatic stress disorder symptoms were assessed. RESULTS: A total of 150 of 202 trauma centers (74%) responded to the survey. Substantial variability was observed in trauma center age cutoff points for pediatric and adolescent patients. Although most sites endorsed having specialized pediatric, intensive care unit, and surgical services, marked differences were found in the reported percentage of youth receiving psychosocial services. Although most sites screened injured youth for alcohol use problems, variability was observed in the actual percentage of children and adolescents screened. Only 20% of sites endorsed specialized posttraumatic stress disorder services. CONCLUSIONS: Our investigation observed marked variability across trauma centers in the delivery of child and adolescent services. Future research could develop high-quality pediatric psychosocial services to inform trauma center standards nationwide. PMID- 21784441 TI - Racial/ethnic and sex differences in the ability of metabolic syndrome criteria to predict elevations in fasting insulin levels in adolescents. AB - OBJECTIVE: To evaluate racial/ethnic and sex differences in the relationship between metabolic syndrome (MetS) diagnosis and fasting insulin in adolescents. STUDY DESIGN: We analyzed data from the National Health and Nutrition Evaluation Survey 1999-2008 for 3693 non-Hispanic-white, non-Hispanic-black, and Hispanic adolescents (12 to 19 years of age). We used linear regression to evaluate differences in fasting insulin levels between those with and without an adolescent adaptation of ATPIII-MetS in a sex- and race/ethnicity-specific basis. RESULTS: Females had higher insulin levels than males, and non-Hispanic blacks and Hispanics had higher levels than non-Hispanic whites. Adolescents with MetS had higher insulin levels than those without MetS. The difference in insulin levels between those with and without MetS was greater in non-Hispanic blacks than in non-Hispanic whites (P < .05) but not Hispanics (P = .10). The sensitivity of MetS in detecting elevated insulin levels was lower in non Hispanic blacks and females than in other ethnicities and males, respectively. Correlations between insulin and individual MetS components were similar among ethnicities. CONCLUSION: MetS diagnosis performed more poorly in predicting elevated insulin levels in non-Hispanic blacks and in females. These data support the hypothesis that non-Hispanic blacks do not meet current criteria for MetS until they have reached a more advanced degree of insulin resistance. PMID- 21784442 TI - Furosemide for packed red cell transfusion in preterm infants: a randomized controlled trial. AB - OBJECTIVE: To assess the effect of furosemide administered with packed red blood cell transfusion on cardiopulmonary variables of hemodynamically stable, electively transfused preterm infants beyond the first week of life. STUDY DESIGN: A randomized, stratified, double-blind, placebo-controlled trial of intravenous furosemide (1 mg/kg) versus placebo (normal saline) just before "top up" packed red blood cell transfusion (20 mL/kg over 4 hours) in a tertiary neonatal intensive care unit. RESULTS: The primary outcome was a change in fraction of inspired oxygen (FiO(2)) during the 24 hours posttransfusion compared with the 6-hour pretransfusion period. Secondary outcomes were functional echocardiographic and clinical/biochemical variables. Of 51 consecutive preterm infants with mean (+/- SD) birth weights of 900 g (+/- 28); enrollment weights of 1342 g (+/- 432); birth gestation of 27 weeks (+/- 1); and postmenstrual age of 32 weeks (+/- 4), 40 completed the study. Pretransfusion variables were comparable between the furosemide (n = 21) and placebo (n = 19) groups. There was a small but significant increase (P < .05) in posttransfusion FiO(2) in placebo (relative increase of 7%, equivalent to an absolute increase from 0.27 to 0.29) compared with the furosemide group. Other variables were similar. No infant received open-label furosemide. CONCLUSIONS: Routine furosemide in electively transfused preterm infants confers minimal clinical benefits. Prevention of a clinically insignificant FiO(2) rise needs to be balanced against potential adverse effects. PMID- 21784444 TI - Traumatic brain injury: is the pituitary out of harm's way? PMID- 21784445 TI - Infant behavioral assessment and intervention program in very low birth weight infants improves independency in mobility at preschool age. AB - OBJECTIVE: To evaluate the effects of the Infant Behavioral Assessment and Intervention Program((c)) (IBAIP) in very low birth weight infants on sensory processing and daily activities at preschool age. STUDY DESIGN: Follow-up of children included in a randomized controlled trial. Eighty-six infants were enrolled in post-discharge IBAIP until 6 months corrected age, and 90 infants received standard care. At 3.5 years of age, the Sensory Profile-Dutch version (SP-NL) and Pediatric Evaluation of Disability Inventory-Dutch version (PEDI-NL) were administered. For comparison, parents of 41 term-born children also completed the SP-NL. RESULTS: Seventy-six children (88%) in the IBAIP group and 75 children (83%) children in the control group were examined at 44 months corrected age. After adjustment for pre-randomization differences in perinatal characteristics, the IBAIP group outperformed the control group significantly on SP-NL domains of oral sensory processing and sensory processing related to endurance/tone and PEDI-NL domains of mobility. The control group only scored significantly lower than the term group on the SP-NL domain endurance/tone. The very low birth weight groups performed significantly below the PEDI-NL's norm. CONCLUSION: In line with the positive developmental effects of the IBAIP until 24 months corrected age, independency in mobility in daily activities was improved at 3.5 years. PMID- 21784447 TI - Benefits of supplemented preterm formulas on insulin sensitivity and body composition after discharge from the neonatal intensive care unit. AB - OBJECTIVE: To evaluate body composition and fasting insulin level in preterm infants receiving preterm formulas (higher protein plus docosahexaenoic acid) for longer periods compared with a recent historical cohort receiving these formulas for shorter periods. STUDY DESIGN: A total of 95 infants fed preterm formula for 6 months or longer (postdischarge formula group) and 87 infants fed preterm formula only during their hospital stay (hospital formula group) were included in this arm of the study. RESULTS: Bone mineral density, content, and lean mass were not different at 1 year and 2 years. However, in the postdischarge formula group, total fat mass (%) was lower by the second year (19.3% +/- 5.3% vs 21.7% +/- 4.2%; P < .01), trunk fat was lower by the first year (14.7% +/- 5.0% vs 16.9% +/ 4.9%; P < .005) and at the second year (14.1% +/- 5.7% vs 17.2% +/- 4.7%; P < .001), and fasting insulin was lower by the first year (13.2% +/- 7.1% vs 17.2% +/- 13.6% mIU/L; P = .06) and at the second year (13.6% +/- 6.1% vs 26.4% +/- 14.2%; P < .001). CONCLUSION: Preterm infants fed formulas enriched with docosahexaenoic acid may have a better subsequent metabolic profile. PMID- 21784446 TI - Urine biomarkers predict acute kidney injury and mortality in very low birth weight infants. AB - OBJECTIVES: To test the hypothesis that noninvasive urinary biomarkers may improve early identification, differentiate causes, and predict outcomes of acute kidney injury (AKI) in very low birth weight subjects. STUDY DESIGN: We performed 2 nested case-control studies to compare the ability of 6 urine biomarkers to predict AKI (rise in serum creatinine of at least 0.3 mg/dL) and mortality (death before 36 weeks postmenstrual age). RESULTS: Compared to subjects without AKI (n = 21), those with AKI (n = 9) had higher maximum neutrophil gelatinase-associated lipocalin (OR = 1.2 [1.0, 1.6]; P < .01; receiver operator characteristics [ROC] area under the curve [AUC] = .80) and higher maximum osteopontin (OR = 3.2 [1.5, 9.9]; P < .01; ROC AUC = 0.83). Compared with survivors (n = 100), nonsurvivors (n = 23) had higher maximum kidney injury molecule 1 (OR = 1.1 [1.0, 1.2]; P < .02; ROC AUC = 0.64) and higher maximum osteopontin (OR = 1.8 (1.2, 2.7); P < .001; AUC of ROC = 0.78). The combination of biomarkers improved predictability for both AKI and mortality. Controlling for gestational age and birth weight did not affect results considerably. CONCLUSIONS: Urinary biomarkers can predict AKI and mortality in very low birth weight infants independent of gestational age and birth weight. PMID- 21784448 TI - Chronic leg ulceration as the presenting feature of diffuse systemic sclerosis in childhood. PMID- 21784449 TI - School absenteeism as a perpetuating factor of functional somatic symptoms in adolescents: the TRAILS study. AB - OBJECTIVE: To examine whether school absenteeism is a perpetuating factor of functional somatic symptoms and whether this holds true for bullied adolescents. STUDY DESIGN: This study is part of the longitudinal population-based study Tracking Adolescents' Individual Lives Survey. Data from assessment wave 2 (n = 2149; 51.0% girls; mean age = 13.65, SD = 0.53) and assessment wave 3 (n = 1816; 53.3% girls; mean age = 16.25, SD = 0.72) were used. Peer victimization was assessed by peer nominations, school absenteeism by both parent and teacher reports, and functional somatic symptoms with the Youth Self-Report. RESULTS: With structural equation modeling, school absenteeism at the second wave, adjusted for functional somatic symptoms at the second wave, was revealed to predict functional somatic symptoms at the third wave in the entire cohort (beta = 0.12; 95% CI, 0.02-0.22), but not in the subgroup of bullied adolescents (beta = -0.13; 95% CI, -0.62--0.26). However, the difference between bullied and unbullied adolescents did not reach significance. CONCLUSION: This study provides evidence that school absenteeism is a perpetuating factor of functional somatic symptoms in adolescents. A clinical intervention study is necessary to examine whether preventing school absenteeism truly helps to reduce functional somatic symptoms in adolescents. PMID- 21784450 TI - Transition to adult care: systematic assessment of adolescents with chronic illnesses and their medical teams. AB - OBJECTIVE: To examine the process of transition from pediatric to adult health care services from the perspectives of young adults with chronic disease and both pediatric and adult health care providers. STUDY DESIGN: A qualitative approach using focus-group interviews was performed to investigate transition experiences. Novel games were also used to generate data. Content and narrative analyses of interview transcripts were performed. RESULTS: We conducted 6 focus groups with 10 young adults who had chronic disease and with 24 health care providers. Content analysis yielded 3 content domains: (1) transition experiences in the context of relationships among patients, parents, and health care providers; (2) differences between pediatric and adult-oriented medicine and how these differences inhibit or facilitate transition; and (3) identification of transition services that should be provided to young patients who have chronic disease. CONCLUSION: This study demonstrates the need for gradual transfer of disease management from parent to child and the need for better communication between adult and pediatric services during the transition process. Pediatric medicine and adult medicine represent different subcultures; acknowledging these differences may improve cooperation during transition from pediatric to adult providers. Young-adult patients with chronic disease embrace the use of technology for specific interventions to improve the transition experience. PMID- 21784451 TI - Vitamin D deficiency, adiposity, and cardiometabolic risk in urban schoolchildren. AB - OBJECTIVE: To determine the relationship between serum vitamin D levels and cardiometabolic risk factors independent of adiposity in urban schoolchildren. STUDY DESIGN: We assessed the relationships among serum 25-hydroxyvitamin D [25(OH)D], adiposity measured by body mass index (BMI) z-score (BMIz), and 6 cardiometabolic risk factors (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, interleukin-6, and C-reactive protein [CRP]) in a cross-sectional sample of 263 racially and ethnically diverse schoolchildren from the Boston area during late winter. Multivariate regression analyses adjusting for sociodemographic characteristics and BMIz examined associations of 25(OH)D and cardiometabolic risk factors. RESULTS: Overall, 74.6% of the children were vitamin D deficient [25(OH)D <50 nmol/L; mean, 41.8 +/- 13.7 nmol/L]; 45% were overweight or obese (20% and 25%, respectively; BMIz = 0.75 +/- 1.1). The 25(OH)D level was not associated with BMIz, but was positively associated with the cardiometabolic risk factor CRP (beta = 0.03; P < .05). BMIz was associated with elevated triglycerides (beta = 0.13), CRP (beta = 0.58), and interleukin-6 (beta= 0.14) and low high-density lipoprotein cholesterol (beta = -0.09; all P < .01). CONCLUSIONS: Vitamin D deficiency is highly prevalent during the late winter months in urban schoolchildren living in the northeastern United States. This widespread deficiency may contribute to the lack of associations between 25(OH)D and both BMIz and cardiometabolic risk factors. The association between 25(OH)D and CRP warrants further study. PMID- 21784452 TI - Six children with pyruvate kinase deficiency from one small town: molecular characterization of the PK-LR gene. AB - We identified the pyruvate kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with pyruvate kinase deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have pyruvate kinase deficiency did not, because they were heterozygous. PMID- 21784453 TI - Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. AB - OBJECTIVES: To investigate mutation spectrums and their correlations to phenotypes in Noonan syndrome (NS) and NS-related disorders that share functional alterations of the Ras-mitogen-activated protein kinase pathway. STUDY DESIGN: Clinical characteristics and genotypes of 10 previously known and 2 candidate genes, SPRY1-4 and SPRED1, were investigated in 59 patients with NS, 17 with cardiofaciocutaneous syndrome, 5 with Costello syndrome, and 2 with LEOPARD syndrome. RESULTS: PTPN11 (39.0%), SOS1 (20.3%), RAF1 (6.8%), KRAS (5.1%), and BRAF (1.7%) mutations were identified in NS; BRAF (41.2%), SHOC2 (23.5%), and MEK1 (5.9%) mutations in cardiofaciocutaneous syndrome; and HRAS and PTPN11 mutations in Costello syndrome and LEOPARD syndrome, respectively. No additional mutations were identified in 28.9% of NS and 35.3% of cardiofaciocutaneous syndrome. Functional characterizations of 2 RAF1 novel variants, p.P261T and p.S259T, and one SOS1 variant, p.K170E, showed enhanced activity of Ras-mitogen activated protein kinase pathway. Normal stature was frequent in SOS1 mutations, hypertrophic cardiomyopathy in RAF1, and developmental delay in RAF1, BRAF, or SHOC2 mutations. CONCLUSIONS: By identifying genotype-phenotype correlations, our study highlights the role of molecular genetic testing in the process of differential diagnosis of NS and NS-related disorders. Pathophysiologies that underlie these correlations are needed to be investigated in terms of their effects on Ras-mitogen-activated protein kinase pathway. PMID- 21784454 TI - Cardiac disease in methylmalonic acidemia. AB - Methylmalonic acidemia (MMA) is a heterogeneous disorder, with onset from infancy to adulthood and varying degrees of organ involvement and severity. Cardiac disease is a known lethal complication of other organic acidemias, but has not been associated with MMA. We identified 3 patients with MMA and cardiac disease. PMID- 21784455 TI - Examining the health and drug exposures among Canadian children residing in drug producing homes. AB - OBJECTIVE: To examine the health and well-being of children residing in residences where drug production is occurring. STUDY DESIGN: Starting in January 2006, children identified by police and the Children's Aids Society in the York region of Ontario, Canada, were referred to the Motherisk Program at the Hospital for Sick Children for pediatric assessment of their general health and well being, with specific focus on illicit-drug exposure. We used a standard protocol to collect all available medical and environmental history, conducted physical and neurologic examinations, and collected hair for analysis of illicit drugs. RESULTS: In total, 75 children, at the mean age of 6.5 years, were referred to us after being removed from homes where marijuana was grown (80%) or other operations linked to drug production were occurring (20%). Overall, rates of health issues in this cohort fell below reference values for Canadian children. Of the hair tests, 32% were positive for illicit substances. In the majority there were no clinical symptoms related to these drugs. CONCLUSION: The majority of children removed from drug-producing homes were healthy and drug free. Comprehensive evaluations should be performed on a case-by-case basis in order to determine what is ultimately in the best interest of the child. PMID- 21784456 TI - Cysteamine toxicity in patients with cystinosis. AB - OBJECTIVE: To report new adverse effects of cysteamine. STUDY DESIGN: Detailed clinical information was obtained from the patients' physicians. RESULTS: New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. CONCLUSION: Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated. PMID- 21784457 TI - Direct health care costs of children and adolescents with Down syndrome. AB - OBJECTIVE: To assess the direct annual health care costs for children and adolescents with Down syndrome in Western Australia and to explore the variation in health care use including respite, according to age and disease profile. STUDY DESIGN: Population-based data were derived from a cross-sectional questionnaire that was distributed to all families who had a child with Down syndrome as old as 25 years of age in Western Australia. RESULTS: Seventy-three percent of families (363/500) responded to the survey. Mean annual cost was $4209 Australian dollars ($4287 US dollars) for direct health care including hospital, medical, pharmaceutical, respite and therapy, with a median cost of $1701. Overall, costs decreased with age. The decline in costs was a result of decreasing use of hospital, medical, and therapy costs with age. Conversely, respite increased with age and also with dependency. Health care costs were greater in all age groups with increasing dependency and for an earlier or current diagnosis of congenital heart disease. Annual health care costs did not vary with parental income, including cost of respite. CONCLUSIONS: Direct health care costs for children with Down syndrome decrease with age to approximate population costs, although costs of respite show an increasing trend. PMID- 21784458 TI - Hypertriglyceridemia as a possible predictor of early neurological deterioration in acute lacunar stroke. AB - BACKGROUND: Early neurological deterioration (END) is not uncommon in lacunar stroke and may lead to poor outcome. Several predictors for END have been previously reported, however, well-designed, MRI-based studies are rare in lacunar stroke. We prospectively enrolled consecutive patients with acute lacunar infarct (<= 48 h) confirmed by MRI to investigate possible predictors for END. METHODS: Demographic data, vascular risk factors, laboratory findings, and neurological status were obtained. END was defined as an increment of the National Institutes of Health Stroke Scale (NIHSS), >= 1 in motor power, or >= 2 in any scores during the first week. RESULTS: A total of 131 patients were recruited and 17 (13%) developed END after admission. Univariate analysis revealed that diabetes, systolic blood pressure, triglyceride (TG), total cholesterol, low density lipoprotein-cholesterol, and homocysteine were associated with END. After multiple logistic regression analysis, the highest quartile of TG level (>145 mg/dL) remained independent [adjusted odds ratio (OR) = 11.46, 95% confidence interval (CI) = 1.07-122.87, P = 0.044]. CONCLUSION: Hypertriglycedemia may be a possible predictor for END in acute lacunar stroke. Thrombogenecity and microcirculatory disturbance augmented by hypertriglyceridemia may be suggested as potential mechanisms. Further studies are warranted to confirm these results. Pathophysiological and therapeutic considerations remain to be determined. PMID- 21784459 TI - Toll-like receptor responses of normal human urothelial cells to bacterial flagellin and lipopolysaccharide. AB - PURPOSE: We determined toll-like receptor expression in normal human urothelium and functional responses in normal human urothelial cell cultures to bacterial lipopolysaccharide via toll-like receptor-4 and to flagellin via toll-like receptor-5. MATERIALS AND METHODS: Toll-like receptor protein expression was examined immunohistochemically. Toll-like receptor transcript expression was determined in freshly isolated urothelium, and in proliferating and differentiated normal human urothelial cultured cells. Lipopolysaccharide binding was assessed by flow cytometry. Functional responses of proliferating and differentiated normal human urothelial cells to lipopolysaccharide and flagellin were determined by interleukin-6 and 8 secretion, and transcription factor activation. Polymyxin B and siRNA were used to confirm the specificity of toll like receptor-4 and 5 responses, respectively. Western blot detection of phosphorylated IkappaB was used to confirm toll-like receptor-4 results. RESULTS: Human urothelium expressed transcripts for toll-like receptor-4 and 5. Although bladder cancer derived T24 cells responded to lipopolysaccharide, there was no lipopolysaccharide binding to normal human urothelial cells and no functional response of proliferative or differentiated normal human urothelial cells even in the presence of exogenous CD14 and MD-2 accessory proteins. In contrast, flagellin evoked a toll-like receptor-5 mediated response in proliferating but not in differentiated normal human urothelial cells, which was abrogated by toll like receptor-5 specific siRNA. CONCLUSIONS: Results suggest that human urothelium may mediate a host response to uropathogenic Escherichia coli through the detection of flagellin. The absent constitutive toll-like receptor-4 response may reflect an adaptation of urothelium toward sustaining barrier function and limiting inflammation to soluble bacterial products. PMID- 21784460 TI - Fibromuscular dysplasia and renal transplantation. PMID- 21784461 TI - Stimulation of soluble guanylate cyclase improves renal recovery after relief of unilateral ureteral obstruction. AB - PURPOSE: The antifibrotic effects of soluble guanylate cyclase stimulation and cyclic guanosine monophosphate production have been observed in cases of anti thy1-induced renal disease. We analyzed the action of the specific soluble guanylate cyclase stimulator BAY 41-8543 on the renal recovery phase in rats with unilateral ureteral obstruction after obstruction was relieved. MATERIALS AND METHODS: Sprague-Dawley(r) rats underwent reversible unilateral ureteral obstruction for 5 days, after which obstruction was relieved. Rats were randomly assigned to unilateral ureteral obstruction and unilateral ureteral obstruction plus BAY 41-8543 (10 mg/kg body weight daily). Seven days after relief of obstruction we determined treatment effects on renal atrophy, apoptosis, fibrosis and nitric oxide/cyclic guanosine monophosphate signaling. RESULTS: Untreated obstructed rats showed mildly increased systolic blood pressure, marked tubular atrophy and apoptosis, tubulointerstitial macrophage infiltration and fibrosis. Plasma cyclic guanosine monophosphate levels were unaltered in untreated rats with obstruction while renal soluble guanylate cyclase mRNA expression was increased. BAY 41-8543 administration significantly increased plasma cyclic guanosine monophosphate, which was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis and renal macrophage infiltration. Also, soluble guanylate cyclase stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, alpha-smooth muscle actin expression, collagen IV deposition and transforming growth factor-beta1 mRNA expression. CONCLUSIONS: Soluble guanylate cyclase stimulation by BAY 41-8543 increases cyclic guanosine monophosphate production and subsequently enhances renal recovery after unilateral ureteral obstruction relief through an array of pathways. This finding suggests that soluble guanylate cyclase stimulation may serve as a novel treatment approach to restore or preserve renal structure and function in cases of obstructive kidney disease. PMID- 21784462 TI - The mechanoreceptor TRPV4 is localized in adherence junctions of the human bladder urothelium: a morphological study. AB - PURPOSE: TRPV4 (transient receptor potential vanilloid 4 channel) is a nonselective cation channel involved in different sensory functions that was recently implicated in bladder mechanosensation. We investigated the cellular site of TRPV4 in bladder urothelium and explored a molecular connection between TRPV4 and urothelial adherence junctions. MATERIALS AND METHODS: We obtained healthy tissues sections from cystectomy in humans due to cancer in 3 and noncancerous conditions in 2. Besides human biopsies tissues from 7 normal and 7 TRPV4-/-mice, and the urothelial cell line RT4 were also used. Experiments were done with polyclonal antibody against TRPV4 (against the N-terminus of rat TRPV4). A molecular connection between TRPV4 and different adherence junction components was investigated using immunofluorescence, Western blot and immunoprecipitation. RESULTS: Results revealed TRPV4 on urothelial cell membranes near adherence junctions. Results were comparable in the urothelial cell line, human bladders and mouse bladders. Subsequent immunoprecipitation experiments established a molecular connection of TRPV4 to alpha-catenin, an integral part of the adherence junction that catenates E-cadherin to the actin-microfilament network. CONCLUSIONS: Results provide evidence for the location of TRPV4 in human bladder urothelium. TRPV4 is molecularly connected to adherence junctions on the urothelial cell membrane. TRPV4 coupling to a rigid intracellular and intercellular structural network would agree with the hypothesis that TRPV4 can be activated by bladder stretch. PMID- 21784463 TI - Oxalate impairs aminophospholipid translocase activity in renal epithelial cells via oxidative stress: implications for calcium oxalate urolithiasis. AB - PURPOSE: We evaluated the possible involvement of phospholipid transporters and reactive oxygen species in the oxalate induced redistribution of renal epithelial cell phosphatidylserine. MATERIALS AND METHODS: Madin-Darby canine kidney cells were labeled with the fluorescent phospholipid NBD-PS in the inner or outer leaflet of the plasma membrane and then exposed to oxalate in the presence or absence of antioxidant. This probe was tracked using a fluorescent quenching assay to assess the bidirectional transmembrane movement of phosphatidylserine. Surface expressed phosphatidylserine was detected by annexin V binding assay. The cell permeable fluorogenic probe DCFH-DA was used to measure the intracellular reactive oxygen species level. RESULTS: Oxalate produced a time and concentration dependent increase in phosphatidylserine, which may have resulted from impaired aminophospholipid translocase mediated, inward directed phosphatidylserine transport and from enhanced phosphatidylserine outward transport. Adding the antioxidant N-acetyl-L-cysteine significantly attenuated phosphatidylserine externalization by effectively rescuing aminophospholipid translocase activity. CONCLUSIONS: To our knowledge our findings are the first to show that oxalate induced increased reactive oxygen species generation impairs aminophospholipid translocase activity and decreased aminophospholipid translocase activity has a role in hyperoxaluria promoted calcium oxalate urolithiasis by facilitating phosphatidylserine redistribution in renal epithelial cells. PMID- 21784464 TI - Complete primary repair of bladder exstrophy: a single institution referral experience. AB - PURPOSE: The reasons for referral and treatment strategies in patients who underwent complete primary repair of bladder exstrophy elsewhere in the newborn period were evaluated. MATERIALS AND METHODS: An institutionally approved database identified patients who underwent complete primary repair of exstrophy and were subsequently referred for continued care. RESULTS: A total of 10 females and 55 males were referred for treatment between 1996 and 2010. Six females and 23 males were referred for complications following initial complete primary repair of exstrophy. Female complications included dehiscence (3 patients), prolapse (2) and stricture (1). Male complications included dehiscence (10 patients), prolapse (9), pubic separation (1) and stricture (3). Nine males had posterior urethral loss and 13 had major penile soft tissue injuries. Grade V vesicoureteral reflux and severe hydronephrosis were seen in the 4 patients with urethral strictures. Patients with dehiscence or prolapse underwent successful reclosure with osteotomy. Cases with posterior urethral loss or strictures were repaired with grafts. Four females and 32 males were referred for incontinence. Nine of these patients had poor bladder capacity, of whom 5 underwent bladder augmentation with continent stoma and 4 are awaiting further bladder growth. A total of 27 patients underwent bladder neck repair, with 15 (56%) subsequently continent, 5 (19%) daytime continent with nocturnal incontinence and 7 (26%) continuously incontinent. At initial closure osteotomy had been performed in all patients who were continent following bladder neck reconstruction and in 4 of 5 who were daytime continent. CONCLUSIONS: Complications of complete primary repair of bladder exstrophy can result in undesired upper urinary tract changes and penile soft tissue loss. Surgical reconstruction of such complications and acceptable continence are attainable in select cases. PMID- 21784465 TI - Micropapillary urothelial carcinoma of the urinary tract. PMID- 21784468 TI - miRNA profiling for clear cell renal cell carcinoma: biomarker discovery and identification of potential controls and consequences of miRNA dysregulation. AB - PURPOSE: Renal cell carcinoma is the most common neoplasm of the adult kidney. Currently to our knowledge there are no biomarkers for diagnostic, prognostic or predictive applications for renal cell carcinoma. miRNAs are nonprotein coding RNAs that negatively regulate gene expression and are potential biomarkers for cancer. MATERIALS AND METHODS: We analyzed 70 matched pairs of clear cell renal cell carcinoma and normal kidney tissues from the same patients by microarray analysis and validated our results by quantitative real-time polymerase chain reaction. We also performed extensive bioinformatic analysis to explore the role and regulation of miRNAs in clear cell renal cell carcinoma. RESULTS: We identified 166 miRNAs that were significantly dysregulated in clear cell renal cell carcinoma, including miR-122, miR-155 and miR-210, which had the highest over expression, and miR-200c, miR-335 and miR-218, which were most down regulated. Analysis of previously reported miRNAs dysregulated in RCC showed overall agreement in the direction of dysregulation. Extensive target prediction analysis revealed that many miRNAs were predicted to target genes involved in renal cell carcinoma pathogenesis. In renal cell carcinoma miRNA dysregulation can be attributed in part to chromosomal aberrations, co-regulation of miRNA clusters and co-expression with host genes. We also performed a preliminary analysis showing that miR-155 expression correlated with clear cell renal cell carcinoma size. This finding must be validated in a larger independent cohort. CONCLUSIONS: Analysis showed that miRNAs are dysregulated in clear cell renal cell carcinoma and may contribute to kidney cancer pathogenesis by targeting more than 1 key molecule. We identified mechanisms that may contribute to miRNA dysregulation in clear cell renal cell carcinoma. Dysregulated miRNAs represent potential biomarkers for kidney cancer. PMID- 21784469 TI - Face, content and construct validity of a novel robotic surgery simulator. AB - PURPOSE: We evaluated the face, content and construct validity of the novel da Vinci(r) Skills SimulatorTM using the da Vinci SiTM Surgeon Console as the surgeon interface. MATERIALS AND METHODS: We evaluated a novel robotic surgical simulator for robotic surgery using the da Vinci Si Surgeon Console and MimicTM virtual reality. Subjects were categorized as novice-no surgical training, intermediate-surgical training with fewer than 100 robotic cases or expert-100 or more primary surgeon robotic cases. Each participant completed 10 virtual reality exercises with 3 repetitions and a questionnaire with a 1 to 10 visual analog scale to assess simulator realism (face validity) and training usefulness (content validity). The simulator recorded performance based on specific metrics. The performance of experts, intermediates and novices was compared (construct validity) using the Kruskal-Wallis test. RESULTS: We studied 16 novices, 32 intermediates with a median surgical experience of 6 years (range 1 to 37) and a median of 0 robotic cases (range 0 to 50), and 15 experts with a median of 315 robotic cases (range 100 to 800). Participants rated the virtual reality and console experience as very realistic (median visual analog scale score 8/10) while expert surgeons rated the simulator as a very useful training tool for residents (10/10) and fellows (9/10). Experts outperformed intermediates and novices in almost all metrics (median overall score 88.3% vs 75.6% and 62.1%, respectively, between group p<0.001). CONCLUSIONS: We confirmed the face, content and construct validity of a novel robotic skill simulator that uses the da Vinci Si Surgeon Console. Although it is currently limited to basic skill training, this device is likely to influence robotic surgical training across specialties. PMID- 21784470 TI - Editorial comment. PMID- 21784471 TI - Editorial comment. PMID- 21784472 TI - Involvement of purinergic neurotransmission in ketamine induced bladder dysfunction. AB - PURPOSE: Long-term ketamine abuse in humans causes significant lower urinary tract symptoms. However, the etiology of ketamine associated cystitis is still not clear. We created a mouse model of ketamine induced lower urinary tract dysfunction to explore the pathogenesis of this condition. MATERIALS AND METHODS: Female C57BL/6 mice randomly distributed into control and ketamine groups received daily intraperitoneal injection of saline and ketamine (100 mg/kg), respectively. Cystometry was done in each group at 4, 8 and 16 weeks. After sacrifice the bladders were harvested for isometric muscle tension recording and immunohistochemical examination. RESULTS: After 8 weeks of treatment body weight growth was significantly decreased in ketamine treated mice. Cystometry revealed a significantly decreased intercontraction interval (mean+/-SEM 237+/-9 vs 360+/ 20 seconds, p<0.001) and decreased bladder capacity (0.1+/-0.004 vs 0.13+/-0.006 ml, p<0.001) in ketamine vs saline injected mice. Increased adenosine triphosphate evoked detrusor contraction developed in the ketamine group. Immunohistochemical examination revealed increased P2X1 receptor expression in ketamine treated mouse bladders while M2 and M3 receptor expression was unchanged. CONCLUSIONS: At 8 weeks mice treated with ketamine showed increased voiding frequency and decreased bladder capacity, the same symptoms that develop in human ketamine abusers. Enhanced noncholinergic contractions and P2X1 receptor expression in the ketamine bladder indicate that dysregulation of purinergic neurotransmission may underlie detrusor overactivity in cases of ketamine induced bladder dysfunction. PMID- 21784473 TI - Editorial comment. PMID- 21784474 TI - Editorial comment. PMID- 21784476 TI - Editorial comment. PMID- 21784477 TI - Trends in hospitalization for pediatric pyelonephritis: a population based study of California from 1985 to 2006. AB - PURPOSE: We examined trends in pediatric hospitalization for pyelonephritis from 1985 to 2006 and identified factors associated with admission. MATERIALS AND METHODS: We performed a population based analysis of hospital discharges using the Office of Statewide Health Planning and Development database to evaluate trends in California regarding pediatric hospitalizations for pyelonephritis from 1985 to 2006. Multivariable logistic regression was performed to identify factors associated with admission for pyelonephritis. RESULTS: A total of 46,300 children were hospitalized for pyelonephritis in California from 1985 to 2006. The overall rate of hospitalization for pyelonephritis increased by greater than 80%, from 17 per 100,000 children in the California population in 1985 to 31 per 100,000 in 2005. This change was primarily due to the nearly ninefold increase in pyelonephritis hospitalizations observed in children younger than 1 year, from 28 per 100,000 in 1985 to 238 per 100,000 in 2005. Among children younger than 1 year males without private insurance and of nonwhite race had increased odds of hospitalization, while females with private insurance and of Asian race had increased odds of hospitalization, compared with nonprivate insurance and white race, respectively. CONCLUSIONS: A significant increase in hospital admissions for pyelonephritis, primarily in children younger than 1 year, occurred in California between 1985 and 2006. Further studies are needed to establish the cause of this striking increase and to determine why certain pediatric populations are at increased risk for hospitalization. PMID- 21784479 TI - Re: Percutaneous renal cryoablation: local control at mean 26 months of followup. T. D. Atwell, M. R. Callstrom, M. A. Farrell, G. D. Schmit, D. A. Woodrum, B. C. Leibovich, G. K. Chow, D. E. Patterson, M. L. Blute and J. W. Charboneau. J Urol 2010;184: 1291-1295. PMID- 21784480 TI - Unilateral multicystic dysplastic kidney with progressive infundibular stenosis in the contralateral kidney: experience at 1 center and review of literature. AB - PURPOSE: We analyzed the association between unilateral multicystic dysplastic kidney and subsequent contralateral infundibular stenosis, which can result in progressive calyceal dilatation, and has been linked to global hyperfiltration injury and renal impairment. MATERIALS AND METHODS: During the last 10 years 200 children presented with unilateral multicystic dysplastic kidney. Of these children 5 subsequently exhibited contralateral infundibular stenosis. We reviewed the published data on multicystic dysplastic kidney as well as infundibular stenosis to examine this association further. RESULTS: Three patients underwent open surgical exploration since rapid progression with associated parenchymal thinning was detected. Literature review failed to identify any discussion of infundibular stenosis in studies focusing on long-term followup of children with a unilateral multicystic dysplastic kidney. Several case reports and case series discuss this condition in association with other collecting system anomalies. However, these anomalies are hypothesized to be part of a disease spectrum resulting from aberrant formation of the collecting system. Bilateral involvement has been reported in fewer than 10 cases. CONCLUSIONS: Our cases represent a part of the spectrum of pyelocalyceal dysgenesis that can have bilateral involvement of varying degrees. Of particular concern was the delayed presentation in some of our patients and the progressive nature of the lesions. Although exceedingly rare, we wish to highlight the association of multicystic dysplastic kidney and progressive infundibular stenosis of the contralateral kidney and renal impairment. PMID- 21784481 TI - Factors influencing quality of life in children with urinary incontinence. AB - PURPOSE: We evaluated quality of life in children with urinary incontinence using a disease specific tool (Pediatric Incontinence Questionnaire) and determined factors that decrease quality of life in affected children. MATERIALS AND METHODS: The Pediatric Incontinence Questionnaire was self-administered by children 6 to16 years old with urinary incontinence while attending outpatient clinics at a tertiary pediatric hospital in Australia between October 2009 and May 2010. A weighted summative quality of life score with a range of 1.75 to 7 (7 being lowest quality of life) was generated, and patient characteristics (age, gender, ethnicity, symptom severity) were evaluated as potential predictors. RESULTS: Of 146 children invited to participate 138 consented (response rate 95%). About half of the participants (77) were boys, and mean patient age was 10 years. Girls had a lower quality of life than boys (mean score 3.60 vs 3.31, 95% CI 0.10-0.57, p=0.04), and nonwhite children had a lower quality of life than white children (3.97 vs 3.35, 95% CI 0.23-0.99, p<0.01). Older age (r=0.21, p=0.01) but not increasing symptom severity (r=0.15, p=0.09) or underlying chronic disease (difference 0.12, p=0.91) was correlated to decreased quality of life. Multivariate regression analysis demonstrated that older age, nonwhite ethnicity and female gender were independent predictors of decreased quality of life. CONCLUSIONS: Older age, female gender and nonwhite ethnicity are associated with a lower disease specific quality of life in children with urinary incontinence. Clinicians need to be aware of the differential effect of urinary incontinence in children of different ages and ethnic backgrounds. PMID- 21784482 TI - Factors affecting complication rates of ureteroscopic lithotripsy in children: results of multi-institutional retrospective analysis by Pediatric Stone Disease Study Group of Turkish Pediatric Urology Society. AB - PURPOSE: We evaluated factors affecting complication rates of ureteroscopy for pediatric ureteral calculi. MATERIALS AND METHODS: We retrospectively evaluated 642 children who underwent ureteroscopy at 16 Turkish centers between 2000 and 2010. Semirigid ureteroscopy was used with various calibers to treat 670 ureteral units in 660 sessions. Complications were evaluated according to the Satava and Clavien classification systems. Univariate and multivariate analyses were done to determine predictive factors affecting complication rates. RESULTS: A total of 367 females and 265 males were studied. Mean+/-SD patient age was 90.2+/-51.4 months (range 4 to 204). Mean+/-SD stone size, operative time and postoperative hospital stay were 8.9+/-4.7 mm, 45.8+/-23.8 minutes and 1.8+/-2.8 days, respectively. At a mean+/-SD followup of 13.3+/-17.6 months 92.8% of patients were stone-free and efficacy quotient was 90.3%. Complications, which occurred in 8.4% of patients (54 of 642), were intraoperative in 25 (Satava grade I to II in 22), early postoperative in 25 (Clavien grade I to II in 23) and late postoperative in 4 (all grade III). While operative time, age, institutional experience, orifice dilation, stenting and stone burden were statistically significant on univariate analysis, multivariate analysis revealed that operative time was the only statistically significant parameter affecting the complication rate. CONCLUSIONS: Semirigid ureteroscopy is effective, with a 90% stone-free rate and efficacy quotient. Most complications are low grade and self-limiting. Our results confirm that prolonged operative time is an independent predictor of complications, and should be considered when choosing and performing the treatment modality. PMID- 21784483 TI - Ultrastructural investigation of crystal deposits in Npt2a knockout mice: are they similar to human Randall's plaques? AB - PURPOSE: Idiopathic Ca oxalate stones may develop with attachment to renal interstitial Ca phosphate deposits (Randall's plaques). Sodium phosphate cotransporter (Npt2a) null mice have hypercalciuria and hyperphosphaturia, and produce tubular and interstitial Ca phosphate deposits. To determine whether this mouse is suitable for Randall's plaque investigations we chronologically studied Ca phosphate deposit sites, structure and composition. MATERIALS AND METHODS: The kidneys of Npt2a null mice 2 days to 1 year old were examined by light, scanning and transmission electron microscopy. Electron diffraction and energy dispersive x-ray microanalyses were done to determine mineral composition. RESULTS: Poorly crystalline, biological apatite deposits were seen in collecting duct lumina. Deposits consisted of aggregates approximately 5 MUm in diameter appearing as microspheres of concentrically organized needle or plate-like, matrix rich crystals. Epithelium/crystal interfaces were filled with membrane bound vesicles. Some tubules were completely occluded by crystals and occasionally lost the epithelium while crystals moved into the interstitium. CONCLUSIONS: Ca phosphate crystals formed in the tubular lumina and were organized as microspheres. The aggregation of Ca phosphate crystals produced nuclei, which grew by adding crystals at the periphery. They eventually became large enough to occlude the tubular lumina and obliterate the tubular epithelium, leading to the relocation of microliths into the interstitium. The pathogenesis of interstitial deposits in Npt2a null mice appears different from that proposed for Randall's plaques. Since Npt2a null mice purge the renal crystal deposits, these mice may serve as a model in which to investigate the elimination of crystal deposits in children and adults with nephrocalcinosis. PMID- 21784484 TI - Changes in bladder wall blood oxygen saturation in the overactive obstructed bladder. AB - PURPOSE: Several studies suggest that hypoxia of the bladder wall contributes to bladder dysfunction but the exact relation between bladder function and blood oxygen saturation, a surrogate marker for hypoxia, is not known. We determined bladder wall blood oxygen saturation in vivo in an animal model of bladder outlet obstruction to establish the exact relation between blood oxygen saturation and bladder function. MATERIALS AND METHODS: In 8 sham operated and 8 urethrally obstructed guinea pigs we measured blood oxygen saturation of the bladder wall by differential path length spectroscopy before surgery and 8 weeks postoperatively. Urodynamic investigations performed during the whole 8-week period provided data on bladder function. RESULTS: Before surgery and 8 weeks after sham surgery blood oxygen saturation in the bladder wall was between 88% and 95% during filling. It decreased during voiding and returned to greater than 90% within 30 seconds. Eight weeks after obstruction saturation was significantly lower than in the sham operated group during filling and voiding. The decrease was positively related to bladder pressure during filling and voiding, and was more pronounced when overactivity was present. Local bladder contractions occurred without a measurable increase in bladder pressure but were associated with a decrease in saturation. CONCLUSIONS: A normal bladder maintains a high oxygen saturation level during filling. Bladder obstruction compromises this ability, especially when it involves overactivity. Local bladder contractions without a measurable increase in bladder pressure were associated with a decrease in blood saturation. PMID- 21784485 TI - B7-H3 over expression in prostate cancer promotes tumor cell progression. AB - PURPOSE: We compared B7-H3 expression in benign prostatic hyperplasia and prostate cancer tissue specimens, and determined the effects of low B7-H3 expression on the PC-3 human prostate cancer cell line using RNA interference. MATERIALS AND METHODS: B7-H3 expression in prostate specimens was determined by enzyme-linked immunosorbent assay. A PC-3 cell line with low B7-H3 expression was established by RNA interference to investigate the effect of B7-H3 on cell proliferation, adhesion, migration and invasion in vitro. RESULTS: B7-H3 in tissue samples was significantly higher in the prostate cancer group than in the benign prostatic hyperplasia group (mean+/-SEM 174.73+/-56.80 vs 82.69+/-46.19 ng/gm, p<0.001). B7-H3 expression down-regulated by small interfering RNA decreased cell adhesion to PC-3 fibronectin more than 30%, and migration and MatrigelTM invasion up to 50%. No apparent impact was observed on cell proliferation. CONCLUSIONS: B7-H3 is aberrantly expressed in prostate cancer. In addition to modulating tumor immunity, B7-H3 may have a novel role in regulating PC-3 cell progression. PMID- 21784486 TI - Comparison of ultrasound and magnetic resonance urography for evaluation of contralateral kidney in patients with multicystic dysplastic kidney disease. AB - PURPOSE: The contralateral kidney is abnormal in up to 25% of patients with multicystic dysplastic kidney. Traditionally, anatomical and functional evaluation of the contralateral kidney has been performed with ultrasound and dimercapto-succinic acid renal scintigraphy, as indicated. Recently magnetic resonance urography has been used to evaluate renal anatomy and function in other urological abnormalities. We compared the results of magnetic resonance urography and ultrasound for evaluating the contralateral kidney in patients with multicystic dysplastic kidney and we describe the range of findings detected. MATERIALS AND METHODS: Patients with multicystic dysplastic kidney who underwent magnetic resonance urography were identified. Anatomical findings on magnetic resonance urography were analyzed and compared to those on renal ultrasound. Additional functional information derived from magnetic resonance urography was also recorded. RESULTS: We retrospectively identified 58 patients with a unilateral multicystic dysplastic kidney who had undergone magnetic resonance urography, of whom 54 also underwent ultrasound. Of the patients 19 (32.8%) had a contralateral abnormality. A discrepancy between magnetic resonance urography and ultrasound was seen in 9 patients (16.7%). Of these patients only 1 had a completely normal contralateral kidney by ultrasound on retrospective review. The incidence and range of parenchymal abnormalities was wider than previously reported. CONCLUSIONS: Contralateral abnormalities in children with multicystic dysplastic kidney are common and more definitively evaluated with magnetic resonance urography vs ultrasound. Renal ultrasound remains the most appropriate modality for the initial evaluation of children with multicystic dysplastic kidney, and magnetic resonance urography is recommended when a functional study is required either to confirm the diagnosis of multicystic dysplastic kidney or to evaluate suspected abnormalities of the contralateral kidney. PMID- 21784489 TI - Re: Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer. N. Lawrentschuk, A. Finelli, T. H. Van der Kwast, P. Ryan, D. M. Bolton, N. E. Fleshner, J. Trachtenberg, L. Klotz, M. Robinette and H. Woo. J Urol 2011;185: 862-868. PMID- 21784490 TI - Re: A critical analysis of the tumor volume threshold for clinically insignificant prostate cancer using a data set of a randomized screening trial. T. Wolters, M. J. Roobol, P. J. van Leeuwen, R. C. van den Bergh, R. F. Hoedemaeker, G. J. van Leenders, F. H. Schroder and T. H. van der Kwast. J Urol 2011;185: 121-125. PMID- 21784491 TI - Re: Urology resident publication output and its relationship to future academic achievement. G. Yang, U. B. Zaid, B. A. Erickson, S. D. Blaschko, P. R. Carroll and B. N. Breyer. J Urol 2011;185: 642-646. PMID- 21784492 TI - Re: Surgical outcomes of mini laparoscopic herniorrhaphy in infants. C. D. Lin, Y. C. Tsai, S. J. Chang and S. S. Yang. J Urol 2011;185: 1071-1076. PMID- 21784494 TI - Occurrence and accumulation features of polycyclic aromatic hydrocarbons and synthetic musk compounds in finless porpoises (Neophocaena phocaenoides) from Korean coastal waters. AB - Reports of the occurrence and accumulation patterns of polycyclic aromatic hydrocarbons (PAHs) and synthetic musk compounds (SMCs) in marine mammals are scarce. In this study, the concentrations and accumulation profiles of PAHs and SMCs were determined in blubber from finless porpoises in Korean coastal waters. Total concentrations of PAHs and SMCs ranged from 6.0 to 432 (mean: 160) ng/g lipid weight and from 17 to 144 (mean: 52) ng/g lipid weight, respectively. Residue levels of PAHs were lower than those reported from other studies, while residue levels of SMCs were relatively higher than those reported in other studies. Naphthalene was the most abundant PAH and HHCB was the dominant SMC observed in finless porpoises. The concentrations of PAHs and SMCs were not correlated with each other, but were significantly correlated within the same chemical groups. No correlations were found between body size and residue levels of PAHs and SMCs. PMID- 21784495 TI - Globally engaged nursing education: an academic program framework. AB - OBJECTIVE: This paper presents a model for designing, providing, and evaluating global experiential education, both local and internationally. METHODS: A literature review was conducted to identify studies and models of global nursing education experiences in the scientific indexed literature and the gray literature on the Internet published by professional associations. RESULTS: Key elements of the model developed include institutional and program mission and goals, global health core content, program characteristics, student characteristics, reflection, and perspective transformation. These factors combine to address the range of interweaving factors that need to be considered in providing well-designed global health offerings. CONCLUSIONS: The framework is offered for use in developing global experiences and in conducting studies to advance our understanding of what and how students learn and are transformed from participation in global education. PMID- 21784496 TI - Alkyl phenols and saponins from the roots of Labisia pumila (Kacip Fatimah). AB - Recently, there is a remarkable boom in the sales of Labisia pumila (Kacip Fatimah) in the Malaysian market, as an extract of the plant is used to gain energy and libido as well as to treat many other ailments. A chemical analysis of its roots was undertaken and three metabolites, demethylbelamcandaquinone B (1), fatimahol (2), and dexyloprimulanin (3) together with 21 known compounds including epoxyoleanane glycosides, alkenated phenolics, cerebroside, glycerogalactolipids, and lipids were isolated and identified. Structure elucidation was achieved by spectroscopic and chemical studies. The MeOH extract of KF and compounds 12 and 13 exhibited moderate in vitro antibacterial activity. PMID- 21784497 TI - [Emergency radiology: what clinicians expect from radiologists]. AB - We review the relations between the radiology department and the clinicians that attend emergency patients, complementing our opinions with a survey conducted in the emergency departments of hospitals in the autonomous region of Madrid. A dedicated emergency radiology section is present in 63.2% of hospitals. Radiologists are readily available to consult in the emergency department in 100%. Radiologists are involved in the initial workup in 61% of hospitals, in follow-up in 22.3%, and in both the initial workup and follow-up in 16.7%. At least one common protocol is shared by radiologists and emergency clinicians in 73.7% of hospitals. Radiologists participate in deciding which imaging tests to perform in 78.9% of hospitals. Radiologists provide a written report of the examination in 83.3% of cases. Continual assessment of the relations between the emergency department and the radiology department will enable us to understand their dynamics and to know what aspects can be improved. PMID- 21784498 TI - Diseases of periocular hair. AB - Diseases of the periocular hair range from localized disease to systemic processes and may present challenging diagnostic questions. We present a comprehensive clinical guide to the evaluation and diagnosis of these disorders. Deficiencies in growth, excess production, changes in pigmentation, aberrant position, or abnormalities in form may affect this region's hair. These range from benign to sight-, and even life-, threatening pathologies. PMID- 21784499 TI - Resonant-type Smooth Impact Drive Mechanism (SIDM) actuator using a bolt-clamped Langevin transducer. AB - The Smooth Impact Drive Mechanism (SIDM) is a linear piezoelectric actuator that has seen practically applied to camera lens modules. Although previous SIDM actuators are easily miniaturized and enable accurate positioning, these actuators cannot actuate at high speed and cannot provide powerful driving because they are driven at an off-resonant frequency using a soft-type PZT. In the present study, we propose a resonant-type SIDM using a bolt-clamped Langevin transducer (BLT) with a hard-type PZT. The resonant-type SIDM overcomes the above mentioned problems and high-power operation becomes possible with a very simple structure. As a result, we confirmed the operation of resonant-type SIDM by designing a bolt-clamped Langevin transducer. The properties of no-load maximum speed was 0.28m/s at driving voltages of 80V(p-p) for 44.9kHz and 48V(p-p) for 22.45kHz with a pre-load of 3.1N. PMID- 21784500 TI - Bacteriophage P22 capsid size determination: roles for the coat protein telokin like domain and the scaffolding protein amino-terminus. AB - Assembly of icosahedral capsids of proper size and symmetry is not understood. Residue F170 in bacteriophage P22 coat protein is critical for conformational switching during assembly. Substitutions at this site cause assembly of tubes of hexamerically arranged coat protein. Intragenic suppressors of the ts phenotype of F170A and F170K coat protein mutants were isolated. Suppressors were repeatedly found in the coat protein telokin-like domain at position 285, which caused coat protein to assemble into petite procapsids and capsids. Petite capsid assembly strongly correlated to the side chain volume of the substituted amino acid. We hypothesize that larger side chains at position 285 torque the telokin like domain, changing flexibility of the subunit and intercapsomer contacts. Thus, a single amino acid substitution in coat protein is sufficient to change capsid size. In addition, the products of assembly of the variant coat proteins were affected by the size of the internal scaffolding protein. PMID- 21784502 TI - Advanced oxidation of alkylphenol ethoxylates in aqueous systems. AB - Alkylphenols and alkylphenol ethoxylates are ubiquitous wastewater contaminants. In this study the oxidation of nonylphenol ethoxylates (NPEO) and octylphenol ethoxylates (OPEO) by oxidant systems generating hydroxide radicals was evaluated. The reaction of each oxidant with a technical mixture of NPEO (TergitolTM) and OPEO (Triton X-100TM) in ultrapure laboratory water and four aqueous environmental matrices was carried out in order to develop an understanding of reaction kinetics. The oxidation of APEOs was evaluated by hydroxyl radical generated by (1) hydrogen peroxide in the presence of ultraviolet light, (2) Fenton's reagent, and (3) a photo-Fenton's process. The second order kinetic rate constant for both NPEO and OPEO with hydroxyl radical was calculated to be 1.1*1010 M-1 s-1. The efficacy of the AOPs within an aqueous environmental matrix was dependent on the rate of formation of hydroxyl radical and the scavenging capacity of the matrix. A model based on the hydroxyl radical formation, scavenging capacity and the kinetic rate constant of target APEO was developed from the existing literature and applied to predict the concentration of APEOs in solution during advanced oxidation in different aqueous environmental matrices. PMID- 21784501 TI - Sites and roles of phosphorylation of the human cytomegalovirus DNA polymerase subunit UL44. AB - The human cytomegalovirus DNA polymerase subunit UL44 is a phosphoprotein, but its sites and roles of phosphorylation have not been investigated. We compared sites of phosphorylation of UL44 in vitro by the viral protein kinase UL97 and cyclin-dependent kinase 1 with those in infected cells. Transient treatment of infected cells with a UL97 inhibitor greatly reduced labeling of two minor UL44 phosphopeptides. Viruses containing alanine substitutions of most UL44 residues that are phosphorylated in infected cells exhibited at most modest effects on viral DNA synthesis and yield. However, substitution of highly phosphorylated sites adjacent to the nuclear localization signal abolished viral replication. The results taken together are consistent with UL44 being phosphorylated directly by UL97 during infection, and a crucial role for phosphorylation-mediated nuclear localization of UL44 for viral replication, but lend little support to the widely held hypothesis that UL97-mediated phosphorylation of UL44 is crucial for viral DNA synthesis. PMID- 21784503 TI - Dissolution behavior of selenium from coal fly ash particles for the development of an acid-washing process. AB - Coal fly ash emitted from coal-fired electric power stations generally contains environmentally regulated trace elements. In particular, boron, arsenic, and selenium have been recognized as troublesome trace elements because elutions from the fly ash contain them. In order to design an effective removal process for these trace elements, we have developed and investigated an acid-washing process. The dissolution behavior of selenium from coal fly ash particles was focused on for the improvement of the process, and was found to greatly depend on the pH of the acid solutions. The species of selenium in solutions with a pH of around 0-1 was determined to be H2SeO3. The dissolved H2SeO3 transformed into HSeO3- and adsorbed onto the surface of the ash particles in solution upon elevation of the pH. The re-elution of the absorbed HSeO3- as SeO3(2-) at a pH of 10 was also confirmed, and will cause the elution of the excess selenium from the acid-washed ash. PMID- 21784504 TI - Dental microwear texture analysis of hominins recovered by the Olduvai Landscape Paleoanthropology Project, 1995-2007. AB - Dental microwear analysis has proven to be a valuable tool for the reconstruction of aspects of diet in early hominins. That said, sample sizes for some groups are small, decreasing our confidence that results are representative of a given taxon and making it difficult to assess within-species variation. Here we present microwear texture data for several new specimens of Homo habilis and Paranthropus boisei from Olduvai Gorge, bringing sample sizes for these species in line with those published for most other early hominins. These data are added to those published to date, and microwear textures of the enlarged sample of H. habilis (n = 10) and P. boisei (n = 9) are compared with one another and with those of other early hominins. New results confirm that P. boisei does not have microwear patterns expected of a hard-object specialist. Further, the separate texture complexity analyses of early Homo species suggest that Homo erectus ate a broader range of foods, at least in terms of hardness, than did H. habilis, P. boisei, or the "gracile" australopiths studied. Finally, differences in scale of maximum complexity and perhaps textural fill volume between H. habilis and H. erectus are noted, suggesting further possible differences between these species in diet. PMID- 21784505 TI - Hair can be a good biomarker of occupational exposure to mercury vapor: simulated experiments and field data analysis. AB - Generally, urine mercury (U-Hg) is widely used for assessment of inorganic mercury (I-Hg) exposure in humans. The reliability of scalp hair as an indicator of mercury vapor exposure is contentious. However, significant correlations were found between hair total mercury (T-Hg) and U-Hg and between hair I-Hg and total gaseous mercury (TGM) in ambient air in our previous studies. Simulated experiments were designed to assess the contribution of direct absorption/adsorption of mercury vapor in the hair. Results indicated that the increases of hair T-Hg concentrations were less than 1 MUg/g, which was negligible compared with hair T-Hg concentrations in occupationally exposed workers. The beta-mercaptoethanol washing can remove 30% of mercury (Hg) in the exposed hair samples. The inhaled Hg constituted the major fraction (97.4%) of I Hg exposure for the artisanal Hg mining workers. From the simulated experiments and field data analysis, we can conclude that hair I-Hg can be a useful tool for monitoring occupational exposure to Hg vapor. PMID- 21784506 TI - Snails as indicators of pesticide drift, deposit, transfer and effects in the vineyard. AB - This paper presents a field-study of real pesticide application conditions in a vineyard. The objective was to measure the exposure, the transfer and the effects of pesticides on a non-target soil invertebrate, the land snail Helix aspersa. There was no drift of the herbicides (glyphosate and glufosinate) whereas the fungicides (cymoxanil, folpet, tebuconazole and pyraclostrobin) were detected up to 20 m from the treated area. For folpet and particularly tebuconazole, spray deposits on soil (corresponding to losses for the intended target i.e. the vine leaves) were high (41.1% and 88.8% loss of applied dose, respectively). For herbicides, the target was the soil and losses (percentage of compounds which did not reach the soil) were of 22% for glufosinate and 52% for glyphosate. In the study plot, glyphosate was transferred to and accumulated in snail tissues (4 mg kg(-1) dry weight, dw), as was its metabolite AMPA (8 mg kg(-1) dw) which could be in relation with the reduced growth observed in snails. No effects on snail survival or growth were found after exposure to the other organic compounds or to copper and sulphur-fungicides, although transfer of tebuconazole, pyraclostrobin and copper occurred. This study brings original field data on the fate of pesticides in a vineyard agro-ecosystem under real conditions of application and shows that transfer and effects of pesticides to a non-target organism occurred. PMID- 21784507 TI - Exon-skipping therapy for Duchenne muscular dystrophy. PMID- 21784509 TI - G-quadruplex DNAzyme based molecular catalytic beacon for label-free colorimetric logic gates. AB - Efficient and economic DNA nanomaterials that can work as logic components are necessary for the development of DNA computers with high speed and outstanding data storage capacity. A new molecular catalytic beacon (MCB) and a series of label-free colorimetric logic gates based on the formation and dissociation of G quadruplex DNAzyme were established in this work. These logic gates (NOT, NOR, IMPLICATION, AND, OR and INHIBIT) were realized by the interaction between the special designed oligonucleotide hairpins and the short input single strand complementary DNA. We were able to recognize the logic output signals effortlessly by our naked eyes. It is a simple, economic and safe approach for the design of complex multiple input DNA logic molecular device. PMID- 21784508 TI - Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. AB - BACKGROUND: We report clinical safety and biochemical efficacy from a dose ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. METHOD: We undertook an open-label, phase 2, dose-escalation study (0.5, 1.0, 2.0, 4.0, 10.0, and 20.0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. FINDINGS: 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0.0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8.9% (95% CI 7.1-10.6) to 16.4% (10.8-22.0) of normal control after treatment (p=0.0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0.9% to 17%, and from 0% to 7.7% of normal muscle, respectively. The dystrophin-associated proteins alpha-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. INTERPRETATION: The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. FUNDING: UK Medical Research Council; AVI BioPharma. PMID- 21784510 TI - The use of a gold nanoparticle-based adjuvant to improve the therapeutic efficacy of hNgR-Fc protein immunization in spinal cord-injured rats. AB - As a common receptor for three myelin associated inhibitors, Nogo-66 receptor (NgR) mediates their inhibitory activities on neurite outgrowth in the adult mammalian central nervous system (CNS). Therapeutic vaccination protocol targeting NgR emulsified with Freund's adjuvant (FA) has been used in spinal cord injury (SCI) models. However, the vaccine emulsified with FA may induce some side effects, which are not suitable for further clinical application. As an adjuvant, gold nanoparticles (GNPs) could stimulate a stronger immune response without producing detectable toxicity and physiological damage than FA. There is, however, uncertainty regarding the efficacy of axon regeneration and neuroprotection in vaccines with GNPs as an adjuvant. In this investigation, a recombinant protein vaccine targeting NgR, human NgR-Fc (hNgR-Fc) fusion protein conjugated with 15 nm GNPs was prepared and its effects on axonal regeneration and functional recovery in spinal cord-injured rats were investigated. The results showed that adult rats immunized with the protein vaccine produced higher titers of anti-NgR antibody than that with FA, and the antisera promoted neurite outgrowth in presence of MAG in vitro. In a spinal cord dorsal hemisection model, vaccine immunized with GNPs promoted axonal regeneration more effectively than FA, resulted in significant protection from neuronal loss, and improved functional recovery. Thus, as an adjuvant, 15 nm GNPs can effectively boost the immunogenicity of hNgR-Fc protein vaccine, and promote the repair of spinal cord injured rats. The utilization of GNPs, for clinical considerations, may be a more beneficial supplement than FA to the promising therapeutic vaccination strategy for promoting SCI repair. PMID- 21784511 TI - Gadolinium-labeled peptide dendrimers with controlled structures as potential magnetic resonance imaging contrast agents. AB - Gadolinium (Gd(3+)) based dendrimers with precise and tunable nanoscopic sizes are excellent candidates as magnetic resonance imaging (MRI) contrast agents. Control of agents' sensitivity, biosafety and functionality is key to the successful applications. We report the synthesis of Gd(III)-based peptide dendrimers possessing highly controlled and precise structures, and their potential applications as MRI contrast agents. These agents have no obvious cytotoxicity as verified by in vitro studies. One of the dendrimer formulations with mPEG modification showed a 9-fold increase in T(1) relaxivity to 39.2 Gd(III) mM(-1) s(-1) comparing to Gd-DTPA. In vivo studies have shown that the mPEGylated Gd(III)-based dendrimer provided much higher signal intensity enhancement (SI) in mouse kidney, especially at 60 min post-injection, with 54.8% relatively enhanced SI. The accumulations of mPEGylated dendrimer in mouse liver and kidney were confirmed through measurement of gadolinium by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Meanwhile, mPEGylated dendrimer showed much higher Gd(III) concentration in blood with 38 MUg Gd(III)/g blood at 1 h post-injection comparing to other dendrimer formulations. These findings provide an attractive alternative strategy to the design of multifunctional gadolinium-based dendrimers with controlled structures, and open up possibilities of using the Gd(III)-based peptide dendrimers as MRI probes. PMID- 21784512 TI - Multi-core vesicle nanoparticles based on vesicle fusion for delivery of chemotherapic drugs. AB - The Pluronic nanoparticles (NPs) composed of Pluronic (F-68) and liquid polyethylene glycol (PEG, molecular wt: 400) containing docetaxel (DTX) were stabilized with the vesicle fusion. When DTX-loaded Pluronic NPs were mixed with vesicles in the aqueous medium, DTX-loaded Pluronic NPs were incorporated into vesicles to form multi-core vesicle NPs. The morphology and size distribution of multi-core vesicle NPs were observed using FE-SEM, cryo-TEM and a particle size analyzer. To apply multi-core vesicle NPs as a delivery system for DTX, a model anti-cancer drug, the release pattern of DTX was observed and the tumor growth was monitored by injecting the DTX-loaded multi-core vesicle NPs into the tail veins of tumor-bearing mice. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor targeting capability of multi-core vesicle NPs using a non-invasive live animal imaging technology. PMID- 21784513 TI - Using acellular porcine limbal stroma for rabbit limbal stem cell microenvironment reconstruction. AB - To investigate the feasibility of using acellular porcine limbal stroma for limbal stem cell microenvironment reconstruction. Limbal reconstruction was performed in rabbit partial limbal defect models. Rabbits were randomly divided into four groups: acellular porcine limbal stroma, de-epithelized rabbit limbal autograft stroma, de-epithelized porcine limbal stroma and acellular porcine corneal stroma transplantation groups. In both the acellular porcine limbal stroma and de-epithelized rabbit limbal autograft stroma groups, cornea transparency and epithelium integrity were sustained and graft rejection was not observed. The basal epithelial cells of the grafts showed the K3+/P63+/Ki67+ phenotype at postoperative month 1, but it returned to K3-/P63+/Ki67+(phenotype characteristic of limbal epithelium) by postoperative months 3 and 6. In the de epithelized porcine limbal stroma group, acute and serious immune rejection occurred by postoperative days 8-10. The basal epithelial cells of the grafts showed the K3+/P63+/Ki67+ phenotype at postoperative month 1. In the acellular porcine corneal stroma group, there were some new vessel invasion into the peripheral cornea and mild corneal opacity. The basal epithelial cells of the grafts showed the K3+/P63+/Ki67+ phenotype at postoperative months 1, 3, and 6. In conclusion, acellular porcine limbal stroma possessed very low immunogenicity, retained a good original limbal ECM microenvironment, and thus the reconstructed rabbit limbal microenvironment maintained limbal epithelial stem cell stemness and proliferation. PMID- 21784514 TI - Multifunctional quantum-dot-based siRNA delivery for HPV18 E6 gene silence and intracellular imaging. AB - The functional quantum dots (QDs) were specifically designed to overcome barriers in siRNA delivery such as siRNA protection, cellular penetration, endosomal release, carrier unpacking, intracellular transport and gene silencing. In this paper, two l-arginine-functional-modified CdSe/ZnSe QDs were synthesized as siRNA carriers to silence HPV18 E6 gene in HeLa cells. Using such constructs, these QDs showed significantly low cellular cytotoxicity and good siRNA protection. Flow cytometric and confocal microscopic analyses confirmed that the QDs delivered siRNA into HeLa cells efficiently. Importantly, superior gene silencing efficiency was achieved as evaluated by Reverse Transcription-PCR (RT-PCR) and Western blotting and HeLa cells growth was inhibited in xCELLigence installation analysis and MTT assay when treated with QD-siRNA complexes. Interestingly, the QDs coated with beta-CD-l-Arg showed optimized property compared with those coated with l-Arg. Furthermore, these QDs complexes could also be used as nanocrystal probing agents, allowing real-time tracking and localization of QDs during delivery and transfection. The properties and capabilities of these QDs showed that amino acid-modified QDs could be used as useful siRNA carriers to effectively silence a target gene as well as fluorescence probes to analyze intracellular imaging in vivo. PMID- 21784515 TI - Injectable in situ crosslinkable RGD-modified alginate matrix for endothelial cells delivery. AB - Cell-based therapies offer an attractive approach for revascularization and regeneration of tissues. However, and despite the pressing clinical needs for effective revascularization strategies, the successful immobilization of viable vascular cells within 3D matrices has been difficult to achieve. In this paper the in vitro potential of a natural, injectable RGD-alginate hydrogel as an in situ forming matrix to deliver endothelial cells was evaluated. Several techniques were employed to investigate how these microenvironments could influence the behavior of vascular cells, namely their ability to promote the outward migration of viable, proliferative cells, retaining the ability to form a 3D arrangement. Cells within RGD-grafted alginate hydrogel were able to proliferate and maintained 80% of viability for at least 48 h post immobilization. Additionally, entrapped cells created a 3D organization into cellular networks and, when put in contact with matrigel, cells migrated out of the RGD-matrix. Overall, the obtained results support the idea that the RGD peptides conjugated to alginate provide a 3D environment for endothelial cells adhesion, survival, migration and organization. PMID- 21784516 TI - The role of cell surface markers and enamel matrix derivatives on human periodontal ligament mesenchymal progenitor responses in vitro. AB - Periodontitis is a chronic-, infectious-disease of the human periodontium that is characterized by the loss of supporting tissues surrounding the tooth such as the periodontal ligament (PDL), cementum and alveolar bone. Regeneration of the periodontium is dependent on the participation of mesenchymal stem/stromal cells (MSC) resident in the PDL. Enamel matrix derivative (EMD), an extract from immature porcine enamel rich in amelogenin protein but that also contain bone morphogenetic protein (BMP), is used to treat periodontal defects. The effects of EMD on MSC cells of the PDL are not well characterized. In this in vitro study, we identify PDL progenitor cells from multiple individuals and demonstrate that EMD stimulates them. We show that the effect of EMD on cell proliferation and migration is mediated through the amelogenin it contains, while the differentiation of these progenitor cells to cell types of mineralized tissue is mainly due to BMP signaling. PMID- 21784517 TI - Nanostructuring PEG-fibrinogen hydrogels to control cellular morphogenesis. AB - The nanostructuring of hydrogel scaffolds used in tissue engineering aims to provide an ability to control cellular morphogenesis through defined cell-matrix interactions. Toward this objective, we developed a method that alters the molecular network structure of biosynthetic hydrogel scaffolds made from crosslinked poly(ethylene glycol)-fibrinogen conjugates (PEG-fibrinogen, PF). The modifications were based on Pluronic((r)) F127 micelles that were formed in the hydrogel precursor solution and that altered the hydrogel network assembly during photopolymerization crosslinking. Two variations of the cell-encapsulating hydrogels (high and low crosslinking density) were prepared with three concentrations of Pluronic((r)) F127 (3%, 7%, 10% w/v). Quantitative morphometrics were used to characterize fibroblast shape parameters (both transient and stable) in all hydrogels, and rheological characterizations were used to measure the elastic (storage) component of the complex shear modulus of these hydrogels. The morphometric data was then correlated to both the nanostructure and modulus of the hydrogels for day 1 and day 4 in culture. These correlations revealed that structural features imparted by the Pluronic((r)) F127 micelles were able to reverse the normally strong correlations found between indicators of cell spreading and the hydrogel's mechanical properties. Therefore, the data supports the conclusion that nanostructural features in the encapsulating hydrogel culture environment can facilitate better cell spreading in a dense hydrogel milieu, simply by introducing imperfections into the network structure. This research also provides further prospective regarding biocompatible approaches toward making structural modifications to hydrogel scaffolds for the purpose of 3-D cell culture and tissue engineering. PMID- 21784518 TI - Robotics in reproductive surgery: strengths and limitations. AB - Minimally invasive surgical techniques are becoming increasingly common in gynecologic surgery. However, traditional laparoscopy can be challenging. A robotic surgical system gives several advantages over traditional laparoscopy and has been incorporated into reproductive gynecological surgeries. The objective of this article is to review recent publications on robotically-assisted laparoscopy for reproductive surgery. Recent clinical research supports robotic surgery as resulting in less post-operative pain, shorter hospital stays, faster return to normal activities, and decreased blood loss. Reproductive outcomes appear similar to alternative approaches. Drawbacks of robotic surgery include longer operating room times, the need for specialized training, and increased cost. Larger prospective studies comparing robotic approaches with laparoscopy and conventional open surgery have been initiated and information regarding long-term outcomes after robotic surgery will be important in determining the ultimate utility of these procedures. PMID- 21784519 TI - Benefit and risk of application of European tissue management regulation in ART. AB - The application of the European Tissues and Cells Directive requires that a high standard of quality and safety be applied to all tissue establishments, including that of assisted reproductive centres. In the countries where the Directive has been implemented, changes in the ART clinic and laboratory procedures have been made. However, many requirements stipulated in the Directive are already in place in some European countries and are mandatory by the country specific laws, while some other requirements have been recently implemented. In this article the benefits and the potential risks of the Directive implementation on the efficacy, safety and cost of all the different assisted reproductive technologies performed, including cryopreservation techniques and storage policies have been widely analysed. The feasibility of the implementation of some of the specific requirements when considering the delicate issues of reproductive cells in contrast to other cells or tissues covered by the Directive has been evaluated. PMID- 21784521 TI - Inhibition of K562 leukemia angiogenesis and growth by selective Na+/H+ exchanger inhibitor cariporide through down-regulation of pro-angiogenesis factor VEGF. AB - To investigate the effect of inhibition of Na(+)/H(+) exchanger isoform1 (NHE1) on K562 leukemia-driven angiogenesis, the selective NHE1 inhibitor cariporide was used. Cariporide treatment of K562 resulted in a decrease in pHi and down regulation of VEGF secretion. The proliferation, migration and in vitro tube formation of human umbilical vein endothelial cells was decreased in cariporide treated K562 condition medium (CM) while VEGF supplement could partially restore the inhibitory effect. Subcutaneous injection of nude mice with cariporide inhibited K562 tumor growth with a reduction of the density of microvessels compared to the control group. PMID- 21784520 TI - S100A1 and calmodulin regulation of ryanodine receptor in striated muscle. AB - The release of Ca2+ ions from the sarcoplasmic reticulum through ryanodine receptor calcium release channels represents the critical step linking electrical excitation to muscular contraction in the heart and skeletal muscle (excitation contraction coupling). Two small Ca2+ binding proteins, S100A1 and calmodulin, have been demonstrated to bind and regulate ryanodine receptor in vitro. This review focuses on recent work that has revealed new information about the endogenous roles of S100A1 and calmodulin in regulating skeletal muscle excitation-contraction coupling. S100A1 and calmodulin bind to an overlapping domain on the ryanodine receptor type 1 to tune the Ca2+ release process, and thereby regulate skeletal muscle function. We also discuss past, current and future work surrounding the regulation of ryanodine receptors by calmodulin and S100A1 in both cardiac and skeletal muscle, and the implications for excitation contraction coupling. PMID- 21784522 TI - Genetic analysis of TP53 in childhood myelodysplastic syndrome and juvenile myelomonocytic leukemia. AB - Among 9 children with myelodysplastic syndrome (MDS) and 18 children with juvenile myelomonocytic leukemia, one MDS patient with der(5;17)(p10;q10) exhibited deletion of the TP53 gene in one allele and mutation (410 T>A) in the other allele in myeloid and erythroid cells. Since the mutation was not detected in peripheral blood leukocytes 9 months before the diagnosis, biallelic somatic inactivation of the TP53 gene might play an important role in the occurrence of MDS. His poor outcome might be associated with resistance to chemotherapy/radiation of a minor clone with both TP53 gene alteration and MLL duplication that already existed at onset. PMID- 21784523 TI - Marine microbial community response to inorganic and organic sediment amendments in laboratory mesocosms. AB - Sediment amendments provide promising strategies of enhancing sequestration of heavy metals and degradation of organic contaminants. The impacts of sediment amendments for metal and organic remediation including apatite, organoclay (and apatite and organoclay in geotextile mats), acetate, and chitin on environmental microbial communities in overlying water and sediment profiles are reported here. These experiments were performed concurrent with an ecotoxicity evaluation (data submitted in companion paper) and X-ray absorption spectroscopy of zinc speciation post apatite amendments. X-ray absorption spectra showed that a modest modification of zinc speciation occurred in amended treatments. Significant changes in both bacterial cell densities and populations were observed in response to amendments of apatite+organoclay, chitin, and acetate. The enriched bacteria and breakdown of these amendments were likely attributed to water quality degradation (e.g. ammonia and dissolved oxygen). Molecular fingerprints of bacterial communities by denaturant gradient gel electrophoresis (DGGE) showed that distinct bacterial populations occurred in overlying waters from different amendments: apatite+organoclay led to the dominance of Gammaproteobacteria, acetate enriched Alphaproteobacteria, and chitin treatment led to a dominance of Bacteroidetes and Alphaproteobacteria. In amended sediments, Firmicutes, Bacteroidetes, and Deltaproteobacteria (Desulfovibrio) were commonly found with chitin and apatite+chitin treatments. Finally, sulfate-reducing bacteria (e.g. Desulfovibrio) and metal-reducing bacteria were also recovered with most probable number (MPN) analyses in treatments with acetate, chitin, and apatite+chitin. These geochemically important bacteria were stimulated by amendments and may play critical functional roles in the metal and organic contaminant remediation process for future investigations of contaminated sediments. PMID- 21784524 TI - A semi-fluid gellan gum medium improves nematode toxicity testing. AB - This study examined an alternative test medium for nematodes that use gellan gum as the gelling agent instead of agar. The semi-fluid consistency of the gel-like component nematode growth gellan gum (CNGG) supports three-dimensional distribution of the nematodes and food bacteria, but still allows free movement of the former. Moreover, flexible preparation of the medium and easy recovery of the test organisms are possible. Here, the effects of the nematicides ivermectin (pharmaceutical) and aldicarb (pesticide) and of the metal cadmium on the growth and reproduction of the free-living nematodes Caenorhabditis elegans and Panagrolaimus cf. thienemanni were studied in CNGG media. Results were compared to those obtained with the standard liquid test media in order to evaluate the applicability of CNGG for nematode toxicity testing. The sensitivity of P. cf. thienemanni to all three substances was found to be higher than that of C. elegans, but both nematodes showed the highest sensitivity to ivermectin exposure. This raises concerns about the risk posed by the pharmaceutical to non target nematodes. In contrast to ivermectin bioassays carried out in CNGG medium, those conducted in liquid medium resulted in wide-ranging variability between and within replicates. Thus, CNGG seems to be particularly valuable for testing hydrophobic substances with a high sorption affinity as it favors their sorption to food bacteria and minimizes contact with the surfaces of the test vessels. However, the medium was less suitable for deriving toxicity thresholds for cadmium and may likewise not be an appropriate choice for testing other metals. The medium introduced herein was shown to be appropriate for sublethal nematode toxicity testing and likely provides a convenient environment for testing other nematode species. Besides improved testing of hydrophobic substances, CNGG also offers advantages for long-term studies, such as full life-cycle experiments, in which fresh medium is regularly needed. Moreover it may be beneficial for testing other poorly soluble or insoluble substances, such as nanoparticles. PMID- 21784525 TI - Can the Flutter Valve improve respiratory mechanics and sputum production in mechanically ventilated patients? A randomized crossover trial. AB - OBJECTIVE: The Flutter Valve (Varioraw SARL, Scandipharm Inc, Birmingham, AL) has proven efficacy in hypersecretive spontaneously ventilated patients. This study was designed to evaluate whether an airway clearance protocol using the Flutter Valve can affect the therapeutic and physiologic outcomes in mechanically ventilated patients with pulmonary infection. METHODS: In a randomized crossover study, sputum production, respiratory mechanics, hemodynamics, and gas exchange were evaluated from 20 mechanically ventilated patients submitted to 2 interventions. FLUTTER intervention consisted of connecting the Flutter Valve to the exhalation port of the mechanical ventilator. Control intervention (CTRL) was normal ventilation in pressure controlled mode. RESULTS: Compared with CTRL, FLUTTER improved sputum production (P < .001), respiratory system static compliance (P = .02), peak expiratory flow (P = .048), expiratory flow at 75% of tidal volume (P = .005), and arterial PO(2)-to-inspired oxygen concentration ratio (P < .001). Respiratory resistance, heart rate, and mean arterial pressure remained unaltered during the interventions (P > .05). CONCLUSION: The Flutter Valve improves lung secretion removal, mucus production, respiratory mechanics, and arterial oxygenation in mechanically ventilated patients with respiratory infection, without causing clinically relevant hemodynamic repercussions. PMID- 21784526 TI - Cardiorenal syndrome. AB - The combination of decompensated heart failure and kidney failure is frequently referred to as the "cardiorenal syndrome." The cause and pathophysiology of this entity are complex and poorly understood, and treatment options are limited. This report describes 2 patients who were hospitalized for decompensated heart failure and developed diuretic resistance with rapidly worsening renal function. Understanding the underlying causes helped break the cardiorenal syndrome in the first patient but only had a transient beneficial effect in the second patient. PMID- 21784527 TI - The experiences of patients with pulmonary arterial hypertension receiving continuous intravenous infusion of epoprostenol (Flolan) and their support persons. AB - OBJECTIVE: Little is known about the day-to-day experiences of patients and their support persons during the course of epoprostenol treatment for pulmonary arterial hypertension (PAH). The study objective was to describe the experiences of patients and their support persons adjusting to PAH and continuous intravenous epoprostenol. METHODS: A qualitative descriptive design with semistructured interviews was conducted jointly with the patient and his/her support person. Seven patients and their support persons (spouse, child, friend) were included. RESULTS: Patients demonstrated personal growth and resilience as they adapted to PAH. Four patient themes emerged: initial shock, figuring it out, giving life, and ongoing struggles. Themes specific to the support person included "their life is in my hands," pressure to perform, and continuation of my role. CONCLUSION: Nurses may assist these patients and support persons by teaching technical skills, problem-solving and troubleshooting strategies, mobilizing social support, and providing opportunities to reflect on lifestyle changes and long term adjustment to PAH. PMID- 21784528 TI - Underrepresentation of minorities in clinical trials: a current problem with escalating future implications. PMID- 21784529 TI - Short-term lower leg growth in 5- to 11-year-old asthmatic children using beclomethasone dipropionate inhalers with chlorofluorocarbon or hydrofluoroalkane propellants: a 9-week, open-label, randomized, crossover, noninferiority study. AB - BACKGROUND: Beclomethasone dipropionate-hydrofluoroalkane (BDP-HFA) is a non chlorofluorocarbon (CFC)-propelled metered dose inhaler. Data is needed to support the registration of BDP-HFA in pediatric populations for countries in the European Union. OBJECTIVE: The aim of the study was to assess short-term lower leg growth in children with asthma during treatment with BDP-HFA 100 MUg BID compared with BDP-CFC 200 MUg BID. METHODS: Children with asthma were included in this open-label, randomized, crossover study with 2-week run-in, active treatment, and washout periods. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hour urine was collected for assessment of free cortisol. Interventions were inhaled BDP-HFA 100 MUg BID with AeroChamber Plus spacer and BDP-CFC 200 MUg BID with Volumatic spacer. RESULTS: In 63 patients with asthma aged 5 to 11 years, BDP-HFA 100 MUg BID was noninferior to BDP-CFC 200 MUg BID, as the lower margin of CI (-0.03 to 0.10 mm/wk) of the estimated difference (0.03 mm/wk) was greater than the prespecified lower limit for noninferiority of -0.12 mm/wk. Mean (SD) lower leg growth rate during run-in, BDP-HFA 100 MUg BID, and BDP-CFC 200 MUg BID was 0.36 (0.17), 0.27 (0.21), and 0.23 (0.18) mm/wk, respectively (BDP-HFA estimate of difference, -0.09 [95% CI, 0.16 to -0.03 mm/wk; P < 0.01]; BDP-CFC estimate of difference, -0.13 [95% CI, 0.19 to -0.06 mm/wk; P < 0.001]). No statistically significant differences were seen in urinary free cortisol assessments. Eight and 6 mild to moderate adverse events in 10 children were reported during treatment with BDP-HFA and BDP-CFC, respectively. One event in each group was judged to be probably related to the study medication; no others were judged to be related. CONCLUSIONS: No statistically significant differences were found in lower leg growth between BDP HFA 100 MUg BID with AeroChamber Plus spacer and BDP-CFC 200 MUg BID with Volumatic spacer during 2-week treatment. Evidence of differences in systemic activity between the treatments was not found. EudraCT registration: 2007-007455 14. PMID- 21784530 TI - Generation of a comprehensive panel of crustacean allergens from the North Sea Shrimp Crangon crangon. AB - BACKGROUND: Published data on crustacean allergens are incomplete. The identification of tropomyosin (TM), arginine kinase (AK), sarcoplasmic Ca-binding protein (SCP) and myosin light chain (MLC) as shrimp allergens are all important contributions but additional allergens are required for the development of a complete set of reagents for component resolved diagnosis and the exploration of novel vaccination strategies. METHODS: The North Sea shrimp (Crangon crangon), which is frequently consumed in Europe, served as a model organism in this study. TM and AK were directly cloned from mRNA based on sequence homology and produced as recombinant proteins. Additional IgE-reactive proteins were isolated by preparative SDS-PAGE and identified by mass spectrometry and corresponding cDNAs were cloned and expressed in E. coli. The relevance of the 6 cloned crustacean allergens was confirmed with sera of 31 shrimp-allergic subjects, 12 of which had a positive double-blind, placebo-controlled food challenge (DBPCFC) to shrimp and 19 a convincing history of food allergy to shrimp, including 5 cases of anaphylaxis. Quantitative IgE measurements were performed by ImmunoCAP. RESULTS: Six recombinant crustacean proteins: TM, AK, SCP, a novel MLC, troponin C (TnC), and triosephosphate isomerase (TIM) bound IgE in ImmunoCAP analysis. Specific IgE to at least one of these single shrimp allergens was detected in 90% of the study population, thus the in vitro diagnostic sensitivity was comparable to that of shrimp extract (97%). In 75% of the subjects, the combined technical sensitivity was similar to or greater with single shrimp allergens than with natural shrimp extract. CONCLUSIONS: We identified six IgE-binding proteins from C. crangon, three of which have not before been described as allergens in crustaceans. This extensive panel of shrimp allergens forms a valuable asset for future efforts towards the identification of clinically relevant biomarkers and as a basis to approach patient-tailored immunotherapeutic strategies. PMID- 21784531 TI - Lifetime suicidal ideation and attempt are common among HIV+ individuals. AB - BACKGROUND: Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART). METHOD: Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204). RESULTS: Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non attempters. LIMITATIONS: Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt. CONCLUSIONS: High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggest that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era. PMID- 21784533 TI - The influence of personality factors on paroxetine response time in patients with major depression. AB - BACKGROUND: Determining the factors that predict antidepressant response and offering suitable treatments to people who suffer from major depressive disorder (MDD) is important. We investigated the personality factors that influence paroxetine treatment response by dividing antidepressant responders into two groups. METHODS: We treated 93 patients with MDD using 40 mg/day of paroxetine for six weeks. We used the Cloninger's Temperament and Character Inventory (TCI) to evaluate each participant's personality before the treatment. Of the 93 patients, 75 completed the protocol. The Montgomery Asberg Depression Rating Scale (MADRS) was used to evaluate depressive symptoms before the treatment and at one-, two-, four-, and six-week intervals. We divided the patients into four groups: later responders (LRs), early responders (ERs), nonresponders (NRs), and dropouts (DOs). RESULTS: Compared with 91 normal control participants, patients with MDD had less novelty seeking and self-directedness and greater harm avoidance. ERs showed less harm avoidance and more self-directedness than the other groups. LRs' TCI scores did not differ from the other groups. CONCLUSIONS: These results suggest that ERs' personality characteristics are different from those of other patients with MDD and that evaluating patients' personality using the TCI at baseline may predict their antidepressant response. LIMITATIONS: Our sample of patients with MDD was small. Some of the patients with severe MDD had difficulty completing the TCI. PMID- 21784534 TI - Do facets of self-reported impulsivity predict decision-making under ambiguity and risk? Evidence from a community sample. AB - We investigated the links among decision-making assessed by the Iowa Gambling Task (IGT) and the Game of Dice Task (GDT), and the four facets of impulsivity (urgency, lack of premeditation, lack of perseverance, and sensation seeking, UPPS) proposed by Whiteside and Lynam (2001) in a sample of 107 healthy volunteers. Hierarchical regressions controlling for age and gender indicated that sensation seeking and urgency were linked to disadvantageous decisions on the GDT while no association was found between IGT performance and the UPPS. Sensation seeking and urgency facets of impulsivity are related in healthy individuals, to decision-making processes where potential consequences of different options and their subsequent probabilities rely on explicit information. In healthy controls, there is little overlap between decision-making influenced by both implicit and explicit information and impulsivity as measured by the UPPS. These findings add evidence to the notion that self-reported trait impulsivity is associated with the decision making process. Decisions made under risk seemed to be differentially associated with specific facets of impulsivity. PMID- 21784532 TI - Estimating risk for suicide attempt: are we asking the right questions? Passive suicidal ideation as a marker for suicidal behavior. AB - BACKGROUND: Desire for death is not generally considered a harbinger of more severe suicidal behavior and is not routinely included in suicide research and assessment interviews. We aimed to compare desire for death and suicidal ideation as clinical markers for suicide attempts. METHODS: Using data from two nationally representative surveys (n=42,862 and n=43,093 respectively), we examined whether desire for death predicts suicide attempts. We compared the odds ratio (OR) and "Number Needed to be Exposed for one additional person to be Harmed" [NNEH] for lifetime suicide attempts among those with desire for death but no suicidal ideation; those with suicidal ideation but no desire for death, and those with both desire for death and suicidal ideation, compared to those with neither desire for death nor suicidal ideation. RESULTS: The risk for lifetime suicide attempt was similar among those with lifetime desire for death with no suicidal ideation and those with lifetime suicidal ideation with no desire for death. Respondents with both lifetime desire for death and suicidal ideation had the highest risk for lifetime suicide attempts. LIMITATIONS: Cross-sectional design and self-reported suicidal ideation/attempts are viewed as limitations of this study. CONCLUSIONS: Querying individuals on desire for death has the same value as assessing suicidal ideation to examine risk for suicide attempt. A combination of desire for death and suicidal ideation is the best predictor for suicide attempts. This is of high clinical relevance since we suggest that desire for death should be included as a potential clinical marker of suicidality in clinical assessments. PMID- 21784535 TI - Low serum 25-hydroxyvitamin D levels are associated with depression in an adult Norwegian population. AB - Observational and intervention studies have suggested an association between low levels of 25-hydroxyvitamin D (25(OH)D) and depressive symptoms in several subgroups of disease and age. This study tests the hypothesis in a general population. Our data are based on 10,086 persons who participated in the sixth Tromso study carried out in 2007-2008. Depressive symptoms were evaluated using the Hopkins Symptoms Check List 10 (SCL-10) based on answers from a questionnaire. Results were adjusted for known confounders such as age, gender, body-mass index, physical exercise, alcohol, education, marital status, kidney function and chronic disease. Results are presented for smokers (N=1966) and non smokers (N=8120) separately as our immunoassay seems to overestimate 25(OH)D levels for smokers. Low serum 25(OH)D levels were found to be a significant predictor of depressive symptoms in both smokers and non-smokers. The association seemed to be stronger in women. The odds ratios for depression in the highest 25(OH)D quartile were 0.59 (0.39-0.89) in smokers and 0.74 (0.58-0.95) in non smokers compared with the lowest quartile. However, no conclusions with regard to causality can be drawn due to the cross-sectional design of the study. PMID- 21784536 TI - Transplantation of CD6-depleted peripheral blood stem cells after DLA haploidentical bone marrow transplantation contributes to engraftment and tolerance in a preclinical model of stem cell transplantation. AB - Human leukocyte antigen (HLA)-haploidentical stem cell transplantation is an opportunity for nearly all patients lacking an HLA matched stem cell donor. However, graft rejection and graft-versus-host disease (GvHD) as well as infectious complications still result in high treatment-related mortality. Here, we used the dog as a preclinical model for the study of tolerance induction with the aim to optimize and to improve a clinical protocol of haploidentical stem cell transplantation. For this purpose CD6-depleted peripheral blood stem cells (PBSCs) were transfused 6d after transplantation of unmodified bone marrow from dog leukocyte antigen (DLA)-haploidentical littermate donors in order to induce immune tolerance. Besides hematopoietic stem cells CD6-depleted PBSC contain, NK cells and a minority of suppressive CD8-positive cells that may suppress activated T lymphocytes. Recipients were conditioned with, cyclophosphamide and antithymocyte globulin (ATG) preceded by a transfusion of donor buffy coat and either 1, 2 or 3 * 3.3 Gy total body irradiation (TBI). Postgrafting immunosuppression was limited to 30 d of cyclosporine and methotrexate. The additional administration of CD6-depleted PBSCs after unmodified marrow could not prevent GvHD, but it may improve engraftment and chimerism after conditioning with 2 * 3.3 Gy TBI. Reasons for incomplete suppression and possible improvements for clinical applications are discussed. PMID- 21784537 TI - Postoperative massive tongue edema in craniosynostotic children. AB - OBJECTIVE: Although rarely encountered in the clinical setting, massive tongue edema is a known phenomenon that can occur in craniosynostotic children in the postoperative period. In 1998, Kunhert described an encounter with an adolescent patient with Crouzon syndrome who required craniectomy for complications associated with Chairi malformation [1]. Following her procedure she had rapid tongue edema which was felt to be secondary to obstruction of the venous drainage of the tongue. Despite extensive workup and unsuccessful medical attempts to reduce the swelling, she was extubated with rapid resolution of the tongue edema [1]. METHODS AND RESULTS: In our facility, two children with underlying craniofacial diagnoses underwent elective surgical procedures. During their postoperative course, they encountered postoperative massive tongue swelling which ultimately required tracheotomy to relieve the compression and upper airway obstruction. CONCLUSION: We describe the clinical manifestations, treatment, and postoperative outcomes identified in these two cases. PMID- 21784538 TI - Genetic mutations and functions of PINK1. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in PINK1 (PARK6) are the second most frequent cause of autosomal recessive, young-onset PD, after parkin (PARK2). PINK1 (a kinase with an N terminal mitochondrial targeting sequence) provides protection against mitochondrial dysfunction and regulates mitochondrial morphology via fission/fusion machinery. PINK1 also acts upstream of parkin (a cytosolic E3 ubiquitin ligase) in a common pathway. Recent studies have described PINK1/parkin function in the maintenance of mitochondrial quality via autophagy (mitophagy). PINK1/parkin-mediated mitophagy provides new insights into the etiology of PD and could be a suitable target for new treatment of PD. In this review, we discuss the molecular genetics and functions of PINK1, which could be key factors in novel rational therapy for sporadic PD as well as PINK1-linked PD. PMID- 21784539 TI - Age-related changes of Nrf2 and phosphorylated GSK-3beta in a mouse model of accelerated aging (SAMP8). AB - SAMP8 mice show spontaneously accelerated aging and a short life span with systemic accumulation of oxidative stress. Nrf2 translocates into the nucleus upon oxidative stress and induces the expression of detoxifying and antioxidant enzymes. Recently, several studies reported that Nrf2 is associated with aging and various diseases. In the present study, we investigated the levels of Nrf2 nuclear translocation and phosphorylation of Akt and GSK-3beta in livers of SAMP8 and normal aging SAMR1 mice. The protein level of Nrf2 in the nucleus of the liver was significantly decreased in SAMP8 at 10 months old compared with that in age-matched SAMR1. The protein level of Keap1, which anchors Nrf2 in the cytoplasm, did not differ between SAMP8 and SAMR1. In addition, the mRNA expression of Nrf2 in the liver of SAMP8 was significantly lower than that of SAMR1. Moreover, mRNA levels of detoxification and antioxidant enzymes, GSTa1 and NQO1, were significantly decreased in SAMP8 compared with SAMR1. These results indicate that a higher level of oxidative stress in SAMP8 might be caused by a lower level of Nrf2. Furthermore, the phosphorylation of Akt and GSK-3beta was significantly decreased in the liver of SAMP8 at 10 months old. Recent studies have suggested that the Akt/GSK-3beta signaling pathway is involved in the nuclear translocation of Nrf2. Therefore, it is suggested that the reduction of the translocation of Nrf2 into the nucleus might be induced by a decrease of GSK 3beta phosphorylation, resulting in an increase of oxidative stress in SAMP8 mice. PMID- 21784540 TI - Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. AB - The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators. PMID- 21784541 TI - Pathophysiology of contrast-induced nephropathy. AB - Contrast media induce various factors that may increase vasoconstriction and decrease vasodilatation in the renal medulla, leading to hypoxia and acute tubular necrosis known as contrast-induced nephropathy (CIN) that tends to occur in diabetics and patients with preexisting renal insufficiency. Contrast media inhibit mitochondrial enzyme activities and subsequently increase adenosine through hydrolysis of ATP. Both catabolism of adenosine and medullary hypoxia generate reactive oxygen species (ROS) that scavenge nitric oxide (NO). Released along with endothelin and prostaglandin from endothelial cells exposed to contrast media, adenosine activates the A1 receptor that mainly constricts afferent arteriole at the glomerulus but not the medullary vasculature. Adenosine also activates the A2 receptor that increases NO production, leading to medullary vasodilatation which is induced by activation of endothelin-B receptor and G protein coupled E-prostanoid receptor 2, and 4 of prostaglandin PGE2 respectively as well. Conversely medullary vasoconstriction is mediated by activating endothelin-A receptor and G-protein coupled E-prostanoid receptor 1, and 3 of prostaglandin PGE2 respectively. The osmotic load of contrast media increases interstitial pressure and sodium transport and thus oxygen consumption. Risking hypoxia, increased medullary oxygen consumption may also result from stimulating Na(+)-K(+)-ATPase activity by endothelin-A receptor. N-acetylcysteine (NAC) scavenges ROS and therefore preserves NO that not only dilates medullary vasculature but also reduces sodium reabsorption and oxygen consumption, tipping the balance against medullary vasoconstriction, hypoxia, and thus CIN. While prostacyclin and its analog, iloprost, prevent CIN by inducing medullary vasodilatation, atrial natriuretic peptide (ANP) may do so by inhibiting renin secretion. PMID- 21784542 TI - Effects of hepatitis C virus on cardiovascular risk in infected patients: a comparative study. AB - The role of hepatitis C virus (HCV) in the pathogenesis of atherosclerosis and cardiovascular events is unclear. The aim of this study was to evaluate the direct effect of HCV on cardiovascular risk and correlate it with pro and anti inflammatory cytokines in patients with HCV. HCV monoinfected patients, genotype 1, naive, non-obese (BMI<30) and non-diabetics were included and compared to controls (blood donors). Patients with prior diagnosis of cardiovascular diseases, hypertension, chronic renal failure, cancer and chronic use of lipid lowering drugs or immunosuppressants were excluded. Age, BMI, systolic blood pressure (SBP) and diastolic (DBP), fasting glucose and lipid levels were determined. Serum cytokines (IL-6, IL-10 and TNF-alpha) and Framingham score were also evaluated. 62 HCV patients, 34 (54.8%) were males and none of them was smoking. The Framingham scores (median and 25th and 75th percentiles) were 12% (6.5-14%), showing an intermediate cardiovascular risk in patients with HCV. There was significant direct correlation between Framingham and total cholesterol (p=0.043) and DBP (p=0.007). HDL-C (p=0.002) was inversely correlated with the Framingham score. HCV patients had higher levels of proinflammatory cytokines (IL 6 and TNF-alpha) compared to controls (p<0.0001) and the relation of proinflammatory/anti-inflammatory TNF-alpha/IL10 and IL-6/IL10 were higher in HCV patients (p<0.01). The Framingham score was directly correlated to IL-6 and TNF alpha, but differences were not statistically significant. Patients with HCV monoinfected, nonobese, naive and non diabetic have an intermediate cardiovascular risk, as measured by the Framingham score and high levels of proinflammatory cytokines (IL-6 and TNF). PMID- 21784543 TI - Coronary perforation during conventional time domain optical coherence tomography. PMID- 21784544 TI - Development and validation of a nomogram for prediction of survival and local control in laryngeal carcinoma patients treated with radiotherapy alone: a cohort study based on 994 patients. AB - INTRODUCTION: To advise laryngeal carcinoma patients on the most appropriate form of treatment, a tool to predict survival and local control is needed. MATERIALS AND METHODS: We performed a population-based cohort study on 994 laryngeal carcinoma patients, treated with RT from 1977 until 2008. Two nomograms were developed and validated. Performance of the models is expressed as the Area Under the Curve (AUC). RESULTS: Unfavorable prognostic factors for overall survival were low hemoglobin level, male sex, high T-status, nodal involvement, older age, lower EQD(2T) (total radiation dose corrected for fraction dose and overall treatment time), and non-glottic tumor. All factors except tumor location were prognostic for local control. The AUCs were 0.73 for overall survival and 0.67 for local control. External validation of the survival model yielded AUCs of 0.68, 0.74, 0.76 and 0.71 for the Leuven (n=109), the VU Amsterdam (n=178), the Manchester (n=403) and the NKI cohort (n=205), respectively, while the validation procedure for the local control model resulted in AUCs of 0.70, 0.71, 0.72 and 0.62. The resulting nomograms were made available on the website www.predictcancer.org. CONCLUSIONS: For patients with a laryngeal carcinoma treated with RT alone, we have developed visual, easy-to-use nomograms for the prediction of overall survival and primary local control. These models have been successfully validated in four external centers. PMID- 21784545 TI - Optimization and evaluation of a modified enrichment procedure combined with immunomagnetic separation for detection of E. coli O157:H7 from artificially contaminated alfalfa sprouts. AB - Escherichia coli O157:H7 has been linked to foodborne disease outbreaks with alfalfa sprouts. Detection of the organism in sprouts by standard cultural methods can be difficult due to the high background microflora. The objective of this study was to develop and optimize an enrichment protocol with and without post-enrichment immunomagnetic separation (IMS) for the rapid detection by real time PCR (RTiPCR) and cultural recovery of E. coli O157:H7 from artificially contaminated alfalfa sprouts. Initially we found that the FDA BAM procedure, enriching samples in modified buffered peptone water with pyruvate and at 37 degrees C for 5h, followed by the addition of acriflavin, cefsulodin and vancomycin (mBPWp+ACV) and static incubation at 42 degrees C gave poor results for both PCR detection and isolation for alfalfa sprouts artificially contaminated at 0.2cfu/g. The addition of post-enrichment IMS improved detection but not isolation. This procedure was modified and optimized by changing to mBPWp with cefsulodin and vancomycin at 42 degrees C and shaking for 24h with and without IMS prior to PCR detection and cultural isolation. Using the resulting protocol we were able to detect E. coli O157:H7 in 100% of samples of alfalfa sprouts contaminated at 0.2cfu/g. This was validated for five strains of E. coli O157:H7. Isolation was 84% without added post-enrichment IMS and 100% with IMS. The optimized procedure was effective for detection and isolation of E. coli O157:H7 from this difficult food matrix. PMID- 21784546 TI - The quorum sensing luxS gene is induced in Lactobacillus acidophilus NCFM in response to Listeria monocytogenes. AB - The luxS gene involved in quorum sensing has been shown to control different behaviour of probiotic lactobacilli. In this study we investigated if luxS in Lactobacillus acidophilus NCFM was up-regulated in response to Listeria monocytogenes EGD-e. The two bacterial strains were grown in mono- and co-culture and the growth of both bacteria and the transcriptional level of luxS in L. acidophilus cells were monitored. Contrary to L. acidophilus, the growth of L. monocytogenes was significantly affected by co-cultivation. Transcriptional analysis showed that the expression of luxS increased during exponential growth in L. acidophilus cells with the highest level in the late-exponential growth phase, decreasing in the stationary phase. Following co-cultivation with L. monocytogenes, the transcriptional level of luxS increased significantly in mid exponential growing cells of L. acidophilus after incubation with viable L. monocytogenes cells and by addition of cell-free culture supernatant of L. monocytogenes, whereas incubation with heat killed cells of L. monocytogenes had no effect on the transcriptional level. This could indicate that the up regulation of luxS is due to a response to a secreted compound produced by L. monocytogenes cells. PMID- 21784547 TI - A model of cerebral cortex formation during fetal development using reaction diffusion-convection equations with Turing space parameters. AB - The cerebral cortex is a gray lamina formed by bodies of neurons covering the cerebral hemispheres, varying in thickness from 1.25 mm in the occipital lobe to 4mm in the anterior lobe. The brain's surface is about 30 times greater that of the skull because of its many folds; such folds form the gyri, sulci and fissures and mark out areas having specific functions, divided into five lobes. Convolution formation may vary between individuals and is an important feature of brain formation; such patterns can be mathematically represented as Turing patterns. This article describes how a phenomenological model was developed by describing the formation pattern for the gyri occurring in the cerebral cortex by reaction diffusion equations with Turing space parameters. Numerical examples for simplified geometries of a brain were solved to study pattern formation. The finite element method was used for the numerical solution, in conjunction with the Newton-Raphson method. The numerical examples showed that the model can represent cerebral cortex fold formation and reproduce pathologies related to gyri formation, such as polymicrogyria and lissencephaly. PMID- 21784548 TI - The evolution of human parental care and recruitment of juvenile help. AB - Provisioning of juveniles is a defining characteristic of human life history. Human children are also unusual in cooperating with their siblings, mothers and other adults in the exchange of resources and labor. This article highlights this distinctly human and twofold nature of juvenility within the context of life history evolution and cooperative breeding. Juveniles benefit from continued investment and from helping to support their siblings during a life stage when they cannot contribute to their own reproduction. Rather than juvenile dependence signifying a costly extension of parental care, juvenile provisioning and help are suggested to develop in tandem with the broader pattern of food sharing and division of labor that characterizes human subsistence and sociality. PMID- 21784549 TI - CO2-dependent meticillin-resistant Staphylococcus aureus: implications for screening. PMID- 21784550 TI - First report of community-acquired meticillin-resistant Staphylococcus aureus from a Slovenian hospital. PMID- 21784551 TI - Safety-engineered needle devices: evaluation prior to introduction is essential. PMID- 21784552 TI - Medical management of incomplete miscarriage. PMID- 21784553 TI - Balloon dilation of the pediatric airway: potential for disaster. AB - OBJECTIVE: The aim of this study was to report on a serious adverse event during balloon dilation of pediatric subglottic stenosis. METHOD: This study is a case report on safety and risk. RESULTS: Airway balloon dilation risk and consideration of serious complications were re-evaluated. CONCLUSIONS: Airway balloon dilation carries the risk of acute and complete airway obstruction by the development and persistence of subglottic edema. The surgeon has to be aware of the risk and be ready to intervene. Guidelines and precautions outlined for use of balloons should be carefully observed. PMID- 21784554 TI - Superior semicircular canal dehiscence: a possible pathway for intracranial spread of infection. AB - Otogenic brain abscesses account for 31.4% of all cerebral abscesses: bone erosion due to coalescent otomastoiditis or cholesteatomas, osteothrombophlebitis, and hematogenous spreading are the most frequent pathways of infection. We briefly reported and discussed the first case of otogenic brain abscess due to infectious labyrinthitis that (likely) spread intracranially through a dehiscence of the superior semicircular canal. PMID- 21784555 TI - High endemic levels of multidrug-resistant Acinetobacter baumannii among hospitals in southern Brazil. AB - BACKGROUND: Most published data on multidrug-resistant Acinetobacter baumanii (MDR Ab) are derived from outbreaks. We report incidence trends on health care acquired infections due to MDR Ab over a 12-month period in the city of Porto Alegre in southern Brazil. METHODS: Clinical and epidemiologic data were obtained from the local health care information system of the municipal health department. Polymerase chain reaction was used to detect the presence of the genes bla(OXA-23 like), bla(OXA-24-like), bla(OXA-51), and bla(OXA-58), and repetitive sequence based polymerase chain reaction and pulsed-field gel electrophoresis were performed for molecular typing. RESULTS: The highest rate of infection (9.0/1,000 inpatient-days) was identified in a trauma hospital. The gene bla(OXA-23-like) was identified in 99.0% of MDR Ab isolates. Eight main clonal groups were identified by molecular typing, and 3 of these were found in all hospitals. CONCLUSION: The presence of 3 clones in all hospitals demonstrates the ability of MDR Ab to spread among hospitals. Moreover, the occurrence of one particular clone (clone 4) throughout the study period suggests its increased ability to cause outbreaks and to remain in the environment. The monitoring of epidemic strains by molecular methods is of paramount importance to prevent or reduce the spread of MDR Ab. PMID- 21784556 TI - Department of Health and Human Services releases new immersive simulation experience to improve infection control knowledge and practices among health care workers and students. AB - In this article, we review a newly developed evidence-based immersive simulation experience for use with health care personnel and students. The article provides information necessary for infection control professionals to understand the development process of the training. Evidence supporting the use of such training is provided, and opportunities to integrate this training into the health care setting and classroom are discussed. PMID- 21784557 TI - Health care worker opinions on use of isolation precautions in long-term care facilities. AB - To address controversies surrounding contact isolation precautions in skilled nursing facilities (SNF), we surveyed 356 nurses and nurses' aides from 7 SNFs on their opinions regarding benefits and harms of contact isolation precautions. Whereas a majority of health care workers believed that contact isolation reduces transmission of antibiotic-resistant organisms, they were also concerned about potentially harmful consequences to the SNF residents including depression and isolation. PMID- 21784558 TI - Mycobacterium fortuitum misidentified as Corynebacterium jeikeium in catheter related bloodstream infection. PMID- 21784559 TI - Bloodstream infections with OXA-23-producing Acinetobacter baumannii isolates in a university-affiliated hospital in Brazil: epidemiology and clinical outcomes. PMID- 21784560 TI - Local factors affecting cost/benefit of methicillin-resistant Staphylococcus aureus screening, a study from a low-income country. PMID- 21784562 TI - 99mTc-MDP uptake in thyroid nodule: contribution of SPECT-CT and ultrasonography. PMID- 21784561 TI - [Classification of mental disorders in the Intensive Care Unit]. AB - PURPOSE: To determine the incidence and characteristics of mental disorders (MD) in the Intensive Care Unit (ICU), and to define a classification system adapted to the ICU environment. DESIGN: A retrospective, descriptive analysis. SETTING: Intensive Care Unit, Arnau de Vilanova Hospital in Lerida (Spain). PATIENTS: All patients with MD admitted during 5-year period (January, 1 2004 to December 31, 2008). MAIN VARIABLES: General variables included clinical-demographic data, diagnostic variables, procedures, severity score, length of stay and mortality. Specific variables included psychiatric history, screening for substance abuse, psychiatric assessment, monitoring and transfer to a psychiatric center. Classification of the MD was as follows: 1) acute substance intoxication (SI); 2) suicide attempts (SA); and 3) MD associated with the main diagnosis (AMD). RESULTS: A total of 146 patients had MD (7.8%); they were predominantly male (74%) and were younger than the general ICU population (43.9 vs. 55.3 years, p<0.001). The ICU stays of the patients with MDs were shorter (4 days vs. 7 days, p<0.001), and there was less hospital mortality (17.1 vs. 25%, p<0.05). They also showed a higher incidence of pneumonia (19.9 vs. 13.8%, p<0.05), but no differences in the level of severity were observed. The SI group (24.7%) contained the highest number of young people; the SA group (36.3%) showed a predominance of women; and the AMD (39%) group had the longest stays and the highest mortality. Psychiatric consultation was carried out mainly in the SA group (62.3%). CONCLUSIONS: MD is a relatively common problem in the ICU. Collaboration with the Psychiatry Department seldom occurs, but must be encouraged to develop fully integrated management of critical patients with MD. PMID- 21784563 TI - Synthesis, crystal structures, and biological evaluation of manganese(II) and nickel(II) complexes of 4-cyclohexyl-1-(1-(pyrazin-2 yl)ethylidene)thiosemicarbazide. AB - 4-Cyclohexyl-1-(1-(pyrazin-2-yl)ethylidene)thiosemicarbazide (HL) and its transition metal complexes formulated as [Mn(L)(2)] (1) and [Ni(L)(2)] (2) have been prepared in 55-75% yield and characterized by elemental analysis, IR, MS, NMR and single-crystal X-ray diffraction studies. Biological activities of the synthesized compounds have been evaluated against selected Gram positive bacteria Bacillus subtilis, Gram negative bacteria Pseudomonas aeruginosa and the K562 leukemia cell line, respectively. The cytotoxicity data suggest that these compounds may be endowed with important biological properties, especially the nickel complex 2 with MIC = 31.2 MUg/mL and IC(50) = 0.53 MUM, respectively. Effect of the free ligand and its two complexes on Mitochondria membrane potential (MMP) and PI-associated fluorescence intensity as well as their effect on cell apoptosis in K562 leukemia cell line was also studied. The tested compounds may exert their cytotoxicity activity via induced loss of MMP. PMID- 21784564 TI - Revision of deposition and weathering parameters for the ingestion dose module (ECOSYS) of the ARGOS and RODOS decision support systems. AB - The ECOSYS model is the ingestion dose model integrated in the ARGOS and RODOS decision support systems for nuclear emergency management. The parameters used in this model have however not been updated in recent years, where the level of knowledge on various environmental processes has increased considerably. A Nordic work group has carried out a series of evaluations of the general validity of current ECOSYS default parameters. This paper specifically discusses the parameter revisions required with respect to the modelling of deposition and natural weathering of contaminants on agricultural crops, to enable the trustworthy prognostic modelling that is essential to ensure justification and optimisation of countermeasure strategies. New modelling approaches are outlined, since it was found that current ECOSYS approaches for deposition and natural weathering could lead to large prognostic errors. PMID- 21784565 TI - Identifying genes and gene networks involved in chromium metabolism and detoxification in Crambe abyssinica. AB - Chromium pollution is a serious environmental problem with few cost-effective remediation strategies available. Crambe abyssinica (a member of Brassicaseae), a non-food, fast growing high biomass crop, is an ideal candidate for phytoremediation of heavy metals contaminated soils. The present study used a PCR Select Suppression Subtraction Hybridization approach in C. abyssinica to isolate differentially expressed genes in response to Cr exposure. A total of 72 differentially expressed subtracted cDNAs were sequenced and found to represent 43 genes. The subtracted cDNAs suggest that Cr stress significantly affects pathways related to stress/defense, ion transporters, sulfur assimilation, cell signaling, protein degradation, photosynthesis and cell metabolism. The regulation of these genes in response to Cr exposure was further confirmed by semi-quantitative RT-PCR. Characterization of these differentially expressed genes may enable the engineering of non-food, high-biomass plants, including C. abyssinica, for phytoremediation of Cr-contaminated soils and sediments. PMID- 21784566 TI - Wastewater treatment plants and landfills emit volatile methyl siloxanes (VMSs) to the atmosphere: investigations using a new passive air sampler. AB - Volatile methyl siloxanes (VMSs) are a class of chemicals with an increasing range of applications and widespread distribution in the environment. Passive air samplers (PAS) comprising sorbent-impregnated polyurethane-foam (SIP) disks were first calibrated and then deployed around two wastewater treatment plants (WWTPs) and at two landfill sites to investigate inputs of VMSs to air. SIP-derived air concentrations for SigmaVMSs (ng/m(3)) at background sites on the perimeter of the WWTP were 479 +/- 82.3 and comparable to results for the upwind samples at the landfills (333 +/- 194). Order of magnitude higher concentrations of SigmaVMSs (ng/m(3)) were found for on-site samples at the WWTPs (3980 +/- 2620) and landfills (4670 +/- 3360). Yearly emissions (kg/yr) to air were estimated and ranged from 60-2100 and 80-250, respectively, for the cyclic VMSs. These findings demonstrate and quantify for the first time, waste sector emissions of VMSs to the atmosphere. PMID- 21784567 TI - Dynamics of social health insurance development: examining the determinants of Chinese basic health insurance coverage with panel data. AB - Social health insurance (SHI) is gaining popularity in many developing countries, but there are few systematic empirical studies on the dynamics of SHI development. This study investigates the determinants of coverage of the Basic Healthcare Insurance for Urban Employees (BHI) in China. Using a panel database ranging from 1999 to 2007, the study finds that: (1) economic development plays a valuable role in BHI development; (2) strong financial capacity and administrative capacity in the government contributes to BHI progress; (3) higher trade union density is closely related to more rapid BHI expansion; and (4) taxation agencies are better at collecting SHI premiums. These findings provide evidence-based lessons for new and ongoing SHI programs. In addition, this article aims to make a more general contribution to the study of social policy development by expanding the scope of current theories on social policy development. PMID- 21784568 TI - Fixation of Le Fort I osteotomies with poly-DL-lactic acid mesh and ultrasonic welding--a new technique. AB - PURPOSE: This report describes a technique for use of resorbable mesh (Resorb-X) and an ultrasonic sonotrode unit (SonicWeld Rx) to bond a pin (SonicPin Rx) to the mesh and underlying bone for Le Fort I osteotomy fixation, precluding the need to tap, shortening the time needed for fixation, and eliminating many disadvantages of titanium. In total, 659 cases have been performed from October 2005 through December 2010. This study examined the first 103 consecutive Le Fort osteotomies performed with this resorbable system and thus those with the longest follow-up. MATERIALS AND METHODS: One hundred three consecutive patients who had completed growth and presurgical orthodontics were operated on using the Resorb-X plating system and SonicWeld Rx. Intraoperative adverse events were monitored and a minimum 12-month postoperative follow-up for complications was completed. RESULTS: One patient (0.9%) had maxillary mobility at initial postoperative evaluation that resolved without malocclusion. Two patients (1.9%) exhibited signs of residual soreness and swelling in the maxilla, attributed to sterile abscess formation. At last follow-up, all patients demonstrated a clinically stable maxilla with correction of their malocclusion. CONCLUSION: Use of ultrasonic-aided pins in fixation of resorbable mesh plates, in Le Fort I osteotomies, is a viable technique and superior resorbable plating system because it is easy to use, results in adequate fixation strength, and shortens time of application by eliminating the need for tapping. In addition, this resorbable system eliminates many disadvantages associated with using all-titanium fixation. PMID- 21784569 TI - Iatrogenic anterior papillary muscle rupture. PMID- 21784570 TI - [Prognostic impact of interventional approach in non-ST segment elevation acute coronary syndrome in very elderly patients]. AB - INTRODUCTION AND OBJECTIVES: In moderate or high risk non-ST segment elevation acute coronary syndrome, clinical practice guidelines recommend a coronary angiography with intent to revascularize. However, evidence to support this recommendation in very elderly patients is poor. METHODS: All patients over 85 years old admitted to our hospital between 2004 and 2009 with a diagnosis of non ST segment elevation acute coronary syndrome were retrospectively included. Using a propensity score, patients undergoing the interventional approach and those undergoing conservative management were matched and compared for survival and survival without ischemic events. RESULTS: We included 228 consecutive patients with a mean age of 88 years (range: 85 to 101). Those in the interventional approach group (n=100) were younger, with a higher proportion of males and less comorbidity, less cognitive impairment and lower troponin I levels compared with patients in the conservative management group (n=128). We matched 63 patients from the interventional approach group and 63 from the conservative management group using propensity score. In the matched patients, the interventional approach group exhibited better survival (log rank 4.24; P=.039) and better survival free of ischemic events (log rank 8.63; P=.003) at the 3-year follow-up. In the whole population, adjusted for propensity score quintiles, the interventional approach group had lower mortality (hazard ratio 0.52; 95% confidence interval: 0.32-0.85) and a better survival free of ischemic events (hazard ratio 0.48; 95% confidence interval: 0.32-0.74). CONCLUSIONS: Nearly all the very elderly patients admitted with non-ST segment elevation acute coronary syndrome were of moderate or high risk. In these patients, the interventional approach was associated with overall better survival and better survival free of ischemic events. PMID- 21784571 TI - [Minimum salvaged myocardium after rescue percutaneous coronary intervention: quantification by cardiac magnetic resonance]. AB - INTRODUCTION AND OBJECTIVES: When fibrinolysis fails in patients with ST elevation myocardial infarction, they are referred for a rescue percutaneous coronary intervention (PCI). However, there is still no evidence of how much myocardium potentially at risk we can actually salvage after rescue PCI. METHODS: Fifty consecutive patients. Cardiac magnetic resonance was performed within 6 days. Myocardial necrosis was defined by the extent of abnormal late enhancement, myocardium at risk by extent of edema, and the amount of salvaged myocardium by the difference between myocardium at risk and myocardial necrosis. Finally, myocardial salvage index (MSI) resulted from the fraction (area-at-risk minus infarct-size)/area-at-risk. RESULTS: The mean time elapsed between pain onset and fibrinolitic agent administration was 176 +/- 113 min; time lysis-rescue=PCI 209 +/- 122 min; time pain onset-PCI = 390 +/- 152 min. The area at risk was 37% +/- 13% and infarct size 34.5% +/- 13%. Salvaged myocardium was 3% +/- 4% and MSI 9 +/- 8. Salvaged myocardium and MSI were similar between patients with the artery open on arrival at the catheterization lab (Thrombolysis in Myocardial Infarction [TIMI] 3) and those with TIMI flow <= 2 (3.3% +/- 3.6% and 8.2 +/- 6.9 in TIMI 0 2 vs 3.0% +/- 3.7% and 10.8 +/- 10.9 in TIMI 3; P=.80 and 0.31, respectively). No significant difference was observed between patients who went through rescue PCI within a shorter time and those with longer delay times. CONCLUSIONS: The myocardial salvage after rescue PCI quantified by cardiac magnetic resonance is very small. The long delay times between pain onset and the opening of the infarct-related artery with PCI are most probably the reason for such a minimal effect of rescue PCI. PMID- 21784572 TI - Cardiac cyst hydatid: a multimodality approach. PMID- 21784573 TI - Nutritional evaluation of fruit and vegetable waste as feedstuff for diets of lactating Holstein cows. AB - Organic waste from markets represents about 10-20% of the total waste of a city. A large proportion comes from the overproduction of fruit and vegetables, turning them into potential pollutant. The nutritional value found for fruit and vegetable waste (FV) from a marketplace, in a previous work, showed that this product might be considered as a potential alternative for animal feeding. This study evaluated the use of FV as feedstuff for diets of lactating Holstein cows with an emphasis on milk yield and quality. FV was included in 0, 6, 8, 12, and 18% of the concentrate. A 4 x 4 Latin squares model was used to analyze data (4 animal groups, 4 periods of evaluation, and 4 treatments). No statistical differences in milk yield per kilogram of eaten concentrate or concentrate intake were recorded between groups fed FV and the control group. There was a significant effect of the treatment on cis-9,trans-11 CLA and alpha-linolenic acid content in milk. These results showed that FV can be used as a dietary ingredient for high-yield lactating cows without detriment in the milk yield and with improvement in the milk quality. FV could be included at proportions of between 6% and 18% in the concentrate, as long as the animal's dietary requirements are covered. The main impact of these results is the alternative generated for the improvement of the environment. PMID- 21784575 TI - Effect of 4-aminoantipyrine on oxidative stress induced by glutathione depletion in single human erythrocytes using a microfluidic device together with fluorescence imaging. AB - The effects of 4-aminoantipyrine (AAP) on oxidative stress induced by glutathione (GSH) depletion in single human erythrocytes were investigated using microfluidic technique and fluorescence imaging. Most cell-based toxicity evaluations on GSH are performed with bulk experiments based on analysis of cell populations. This work established a single-cell toxicity evaluation method to statistically analyze the GSH amount in single erythrocytes incubated with AAP in different concentrations. The experimental conditions of cell flow rate and cell concentration were optimized. The GSH contents in erythrocytes decreased with increasing dose of AAP. At low concentration, AAP had a little effect on GSH; while at high concentration, AAP led to GSH depletion reaching a maximum of 14.53%. The depletion of GSH leads to a significant shift to a more oxidizing intracellular environment. This study provides basic data for presenting the effect of AAP on GSH in erythrocytes and is helpful for understanding its toxicity during the blood transportation process. In addition, it will also complement studies on the environmental risk assessment of AAP pollution. PMID- 21784574 TI - Early primary tumor size reduction is an independent predictor of improved overall survival in metastatic renal cell carcinoma patients treated with sunitinib. AB - BACKGROUND: In metastatic renal cell carcinoma (mRCC) patients treated with targeted agents and their primary tumor (PT) in situ, early PT decrease in size correlates with improved overall PT response, but the effect on overall survival (OS) is unknown. OBJECTIVE: To evaluate whether early PT size reduction is associated with improved OS in patients with mRCC undergoing treatment with sunitinib. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between January 2004 and December 2009 without prior systemic treatment who received sunitinib with their PT in situ. MEASUREMENTS: Two independent reviewers measured the diameter of the PT and metastatic disease at baseline and subsequent scans to assess response. Early minor response was defined as >=10% decrease within 60 d of treatment initiation. Univariate and multivariate analyses were used to calculate a hazard ratio (HR) corresponding to the risk of death based on clinical and pathologic factors as well as PT response. RESULTS AND LIMITATIONS: We identified 75 consecutive patients with a median follow-up of 15 mo. All patients were intermediate or poor risk by common risk stratification systems. Median initial PT diameter was 9.7cm. Median maximum PT size reduction was -10.2% overall and -36.4% in patients who had early minor PT response. Median OS for patients without minor PT response, with minor PT response after 60 d, and with early minor PT response was 10.3, 16.5, and 30.2 mo, respectively. On multivariate analysis, early minor response was an independent predictor of improved OS (HR: 0.26; p=0.031). Other significant predictors included venous thrombus, multiple bone metastases, lactate dehydrogenase above the upper limit of normal, symptoms at presentation, and more than two metastatic sites. CONCLUSIONS: Early minor PT response is associated with improved OS. Future studies should evaluate this prognostic factor to identify patients with prolonged OS. PMID- 21784576 TI - Kinetic and safety parameters analysis for 1,1,-di-(tert-butylperoxy)-3,3,5 trimethylcyclohexane in isothermal and non-isothermal conditions. AB - Over the past 30 years, the field of thermal analysis of organic peroxides has become an important issue in chemical engineering departments, safety departments, and in companies working with polymerization, petrifaction process, and so on. The contributions of thermal analysis to the evaluation and prediction of the runaway reactions have been important for decreasing or preventing a hazard, such as fire or explosion accident. This study was carried out using differential scanning calorimetry (DSC) to evaluate the kinetic and safety parameters in isothermal and non-isothermal conditions, for instance, temperature of no return (T(NR)), self accelerating decomposition temperature (SADT), time to maximum rate (TMR), activation energy (E(a)), frequency factor (A), reaction order (n), and reaction heat (DeltaH), in terms of the hazardous material of 1,1, di-(tert-butylperoxy)-3,3,5-trimethylcyclohexane (TMCH) 88 mass%. On the basis of this study, we demonstrated that TMCH 88 mass% must be well controlled in the manufacturing process due to the unstable structure of O-O, which releases a great quantity of heat, higher than 1300 J/g under decomposition. Results of this study could contribute to the relevant plants adopting TMCH 88mass% in a process, in order to prevent a fire or explosion accident from happening. PMID- 21784577 TI - Direct photolysis of polycyclic aromatic hydrocarbons in drinking water sources. AB - The widely used low pressure lamps were tested in terms of their efficiency to degrade polycyclic aromatic hydrocarbons listed as priority pollutants by the European Water Framework Directive and the U.S. Environmental Protection Agency, in water matrices with very different compositions (laboratory grade water, groundwater, and surface water). Using a UV fluence of 1500 mJ/cm(2), anthracene and benzo(a)pyrene were efficiently degraded, with much higher percent removals obtained when present in groundwater (83-93%) compared to surface water (36-48%). The removal percentages obtained for fluoranthene were lower and ranged from 13 to 54% in the different water matrices tested. Several parameters that influence the direct photolysis of polycyclic aromatic hydrocarbons were determined and their photolysis by-products were identified by mass spectrometry. The formation of photolysis by-products was found to be highly dependent on the source waters tested. PMID- 21784578 TI - Solidification/stabilization of fly and bottom ash from medical waste incineration facility. AB - In the present work, the stabilization/solidification of fly and bottom ash generated from incinerated hospital waste was studied. The objectives of the solidification/stabilization treatment were therefore to reduce the leachability of the heavy metals present in these materials so as to permit their disposal in a sanitary landfill requiring only a lower degree of environmental protection. Another objective of the applied treatment was to increase the mechanical characteristics of the bottom ash using different amounts of Ordinary Portland Cement (OPC) as a binder. The solidified matrix showed that the cement is able to immobilize the heavy metals found in fly and bottom ash. The TCLP leachates of the untreated fly ash contain high concentrations of Zn (13.2 mg/l) and Pb (5.21 mg/l), and lesser amounts of Cr, Fe, Ni, Cu, Cd and Ba. Cement-based solidification exhibited a compressive strength of 0.55-16.12 MPa. The strength decreased as the percentage of cement loading was reduced; the compressive strength was 2.52-12.7 MPa for 60% cement mixed with 40% fly ash and 6.62-16.12 MPa for a mixture of 60% cement and 40% bottom ash. The compressive strength reduced to 0.55-1.30 MPa when 30% cement was mixed with 70% fly ash, and to 0.90 7.95 MPa when 30% cement was mixed with 70% bottom ash, respectively. PMID- 21784579 TI - Recovery of platinum, tin and indium from spent catalysts in chloride medium using strong basic anion exchange resins. AB - This work describes a route for platinum recovery from spent commercial Pt and PtSnIn/Al(2)O(3) catalysts using strong basic mesoporous and macroporous anion exchange resins (Cl(-) form). The catalysts were leached with aqua regia (75 degrees C, 20-25 min). Platinum adsorption was influenced by the presence of other metals which form chlorocomplexes (tin, indium) and also base metals (aluminum). However, it was possible to overcome this fact by a sequential desorption procedure. Aluminum was selectively removed from the resins by elution with 3 mol L(-1) HCl. Platinum was desorbed passing 1 mol L(-1) Na(2)S(2)O(3) (pH 9). Tin was removed by elution with 0.1 mol L(-1) ascorbic acid. Indium was removed using 0.1 mol L(-1) EDTA as eluent. Desorption efficiency exceeded 99% for all metals. Metals were recovered in high yields (>98 wt%). PMID- 21784580 TI - Surface engineered magnetic nanoparticles for removal of toxic metal ions and bacterial pathogens. AB - Surface engineered magnetic nanoparticles (Fe(3)O(4)) were synthesized by facile soft-chemical approaches. XRD and TEM analyses reveal the formation of single phase Fe(3)O(4) inverse spinel nanostructures. The functionalization of Fe(3)O(4) nanoparticles with carboxyl (succinic acid), amine (ethylenediamine) and thiol (2,3-dimercaptosuccinic acid) were evident from FTIR spectra, elemental analysis and zeta-potential measurements. From TEM micrographs, it has been observed that nanoparticles of average sizes about 10 and 6 nm are formed in carboxyl and thiol functionalized Fe(3)O(4), respectively. However, each amine functionalized Fe(3)O(4) is of size ~40 nm comprising numerous nanoparticles of average diameter 6 nm. These nanoparticles show superparamagnetic behavior at room temperature with strong field dependent magnetic responsivity. We have explored the efficiency of these nanoparticles for removal of toxic metal ions (Cr(3+), Co(2+), Ni(2+), Cu(2+), Cd(2+), Pb(2+) and As(3+)) and bacterial pathogens (Escherichia coli) from water. Depending upon the surface functionality (COOH, NH(2) or SH), magnetic nanoadsorbents capture metal ions either by forming chelate complexes or ion exchange process or electrostatic interaction. It has been observed that the capture efficiency of bacteria is strongly dependent on the concentration of nanoadsorbents and their inoculation time. Furthermore, these nanoadsorbents can be used as highly efficient separable and reusable materials for removal of toxic metal ions. PMID- 21784581 TI - Enhancing foam drainage using foam fractionation column with spiral internal for separation of sodium dodecyl sulfate. AB - A new type of foam fractionation column with spiral internal had been designed for enhancing the foam drainage and thus for the removal of minute hazardous materials. The column without spiral internal was served as the comparison column, and an anionic surfactant sodium dodecyl sulfate (SDS) was used as the foaming solution. Effects of liquid loading volume, initial SDS concentration and superficial gas velocity on enrichment ratio and recovery percentage of SDS were investigated. The experimental results showed that the spiral column successfully enhanced the enrichment ratio of SDS by reducing countercurrent resistance between the rising bubbles and the entrained liquid of reflux. Enrichment ratio of SDS obtained by using the spiral column was 15.7, which was 2.5 times of that obtained by using the comparison column under the suitable operating conditions of liquid loading volume 0.4 L, initial SDS concentration 0.2g/L and superficial gas velocity 1.7 mm/s. PMID- 21784582 TI - Analysis of concentration fluctuations in gas dispersion around high-rise building for different incident wind directions. AB - This article presents experimental results that illustrate the unsteady characteristics of gas dispersion around a complex-shaped high-rise building for different incident wind directions. A series of wind tunnel experiments were conducted using a 1:30 scale model that represented the real structures under study. The objective of this paper is to study the behaviour of concentration fluctuations through transient analysis. Tracer gas was continuously released from a point source located at different positions, and a time series of fluctuating concentrations were recorded at a large number of points using fast flame ionization detectors. The experimental data were analysed to provide a comprehensive data set including variances and associated statistical quantities. Both the unsteady characteristics of the system and their potential practical impact are presented and discussed. Under crowd living conditions, the air pollutant exhausted from one household could probably re-enter into the neighbouring households, traveling with ambient airflow. Such pollutant dispersion process is defined as air cross-contamination in this study. The results indicate that the wind-induced cross-contamination around the studied type of high-rise building should not be overlooked, and the fluctuating concentrations should be paid attention to particularly during the evaluation of a potential contamination risk. This study can help deepen our understanding of the mechanisms of air cross-contamination, and will be useful for implementing optimization strategies to improve the built environments in metropolitan cities such as Hong Kong. PMID- 21784583 TI - Destabilization of emulsions by natural minerals. AB - This study developed a novel method to destabilize emulsions and recycle oils, particularly for emulsified wastewater treatment. Natural minerals were used as demulsifying agents, two kinds of emulsions collected from medical and steel industry were treated. The addition of natural minerals, including artificial zeolite, natural zeolite, diatomite, bentonite and natural soil, could effectively destabilize both emulsions at pH 1 and 60 degrees C. Over 90% of chemical oxygen demand (COD) can be removed after treatment. Medical emulsion can be even destabilized by artificial zeolite at ambient temperature. The mechanism for emulsion destabilization by minerals was suggested as the decreased electrostatic repulsion at low pH, the enhanced gathering of oil microdroplets at elevated temperature, and the further decreased surface potential by the addition of minerals. Both flocculation and coalescence were enhanced by the addition of minerals at low pH and elevated temperature. PMID- 21784584 TI - Effect of sunflower cake supplementation on meat quality of indigenous goat genotypes of South Africa. AB - The effect of four castrated goat genotypes and sunflower cake supplementation on goat meat quality was determined. Supplemented Boer (BOR) and Xhosa-Boer cross (XBC) goats had significantly higher (P<0.05) SLW and CDM than non-supplemented groups. The Xhosa lop-eared (XLE) and Nguni (NGN) goats had higher pH24 (P<0.05) than BOR and XBC goats. For each genotype, the sunflower cake supplemented and non-supplemented goats had similar a* values, except for the XLE goats. In the XLE goats, the a* values were lower in the sunflower cake supplemented goats. Sunflower cake supplemented BOR goats had higher L*values than their non supplemented counterparts (P<0.05). The sunflower cake supplemented BOR and NGN goats also had higher b* values as compared to their non-supplemented counterparts. In comparison with the Boer goat, the XLE and NGN goats had lower CDM, L* and WBF values but generally had higher CL and a* values. Sunflower cake supplementation improved meat quality attributes of the goats. PMID- 21784585 TI - Single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiation therapy in the treatment of intermediate-risk prostate cancer - long term results. AB - PURPOSE: We present the long-term results of a cohort of patients with intermediate-risk prostate cancer (PC) treated with single-fraction high-dose rate brachytherapy (HDRB) combined with hypofractionated external beam radiation therapy (HypoRT). METHODS AND MATERIALS: Patients were treated exclusively with HDRB and HypoRT. HDRB delivered a dose of 10 Gy to the prostate surface and HypoRT consisted of 50 Gy delivered in 20 daily fractions. The first 121 consecutive patients with a minimum of 2 years posttreatment follow-up were assessed for toxicity and disease control. RESULTS: The median follow-up was 65.2 months. No acute Grade III or higher toxicity was seen. Late Grade II gastrointestinal toxicity was seen in 9 patients (7.4%) and Grade III in 2 (1.6%). Late Grade III genitourinary toxicity was seen in 2 patients (1.6%). After a 24-month follow-up, a rebiopsy was offered to the first 58 consecutively treated patients, and 44 patients agreed with the procedure. Negative biopsies were found in 40 patients (91%). The 5-year biochemical relapse-free survival rate was 90.7% (95% CI, 84.5-96.9%), with 13 patients presenting biochemical failure. Among them, 9 were diagnosed with distant metastasis. Prostate cancer specific and overall survival rates at 5 years were 100% and 98.8% (95% CI, 96.4 100%), respectively. CONCLUSION: The combination of HDRB and HypoRT is well tolerated, with acceptable toxicity rates. Furthermore, results from rebiopsies revealed an encouraging rate of local control. These results confirm that the use of conformal RT techniques, adapted to specific biological tumor characteristics, have the potential to improve the therapeutic ratio in intermediate-risk PC patients. PMID- 21784586 TI - Leukogram abnormalities in gnotobiotic pigs infected with porcine circovirus type 2. AB - Porcine circovirus type 2 (PCV2) is a single-stranded circular DNA virus that is the causative agent of porcine circovirus associated disease (PCVAD), a disease complex affecting swine around the world. Although this virus is believed to negatively affect the host's immune system, the mechanism by which PCV2 induces disease is not completely understood. This report describes a series of PCV2 experiments using the gnotobiotic pig model in which a relationship was demonstrated between abnormal leukograms and development of clinical disease in PCV2-infected pigs. When compared to control pigs the leukogram was characterized by a decrease in lymphocytes within 14 days post inoculation (dpi) followed by an increase in neutrophils 7-14 days later. No significant changes in the circulating monocyte, basophil, and eosinophil cell populations were detected. The combination of an absolute neutrophilia and lymphopenia produced a neutrophil/lymphocyte ratio that was predictive of clinical disease and was inversely correlated with the presence of neutralizing antibodies. Based on previous reports, the lymphopenia may be attributed to a direct cytolytic effect of the virus and could negatively affect the pig's immune response. The role of the neutrophilia in the pathogenesis of PCVAD in gnotobiotic pigs is unknown. PMID- 21784587 TI - Disaster-related prenatal maternal stress influences birth outcomes: project Ice Storm. AB - BACKGROUND: Previous research suggests that prenatal maternal stress (PNMS) impacts birth outcomes, but many human studies cannot distinguish between the effects of different types of stressors or examine effects of exposure timing on outcomes. OBJECTIVES: Our goal was to determine how timing and severity of exposure during pregnancy to objective and subjective stress due to a natural disaster influenced gestation length and fetal growth patterns. METHODS: We assessed objective and subjective PNMS levels among 172 women exposed to an ice storm during or shortly before pregnancy. We analyzed associations between PNMS levels and outcomes (gestation length, birth weight, birth length, head circumference, and growth ratios), controlling for other variables such as age, obstetric complications, socioeconomic status, and trait anxiety. RESULTS: Gestation lengths and predicted birth weights were shorter among participants exposed to the ice storm during early to mid pregnancy, compared to 3rd trimester and pre-pregnancy exposure. Birth lengths were shorter in the sample compared to population references, and predicted values were shorter among participants with a "discrepancy" between their objective and subjective PNMS levels. High objective PNMS levels predicted smaller head circumferences in early pregnancy, but we also observed patterns in predicted values of head circumference to birth length ratios suggesting the sparing of brain development relative to birth length among boys in early pregnancy. These sparing effects decreased in later pregnancy. CONCLUSIONS: Exposure to stressful events during pregnancy influences birth outcomes independently of other factors. Exposure timing, newborn sex, and the type of stressor influence the effects observed. PMID- 21784588 TI - Neonatal morbidity in twin-twin transfusion syndrome. AB - Twin-twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies associated with high perinatal mortality and morbidity rates. Management in TTTS is a major challenge for obstetricians and neonatologists. Twins which are often born prematurely and may suffer from typical conditions associated with prematurity. In addition, surviving twins with TTTS are at increased risk for other complications including neurological, cardiovascular, renal and hematologic morbidity. Rare complications such as hypoxic-ischemic lesions to limbs or intestines and amniotic band syndrome have also been reported in TTTS survivors. This review focuses on the neonatal and pediatric mortality and morbidity in TTTS survivors, with special emphasis on the long-term neurodevelopmental outcome. PMID- 21784589 TI - Effects of centrifugation through three different discontinuous Percoll gradients on boar sperm function. AB - In this study, different combinations of 2-step, discontinuous gradient centrifugation were used, consisting of three different combinations of isotonic Percoll (45/60, 60/75 and 45/90%) that allowed us to select different sperm subpopulations from fertile and normozoospermic boars. Our objective in this study is to evaluate the effects of centrifugation through three different discontinuous Percoll gradients on sperm function parameters (motility, viability, morphology, acrosome status, chromatin condensation, DNA fragmentation, ROS generation, tyrosine phosphorylation and intracellular calcium concentration) and the sperm penetrating capacity in an IVF system. All the Percoll treatments evaluated increased the percentage of spermatozoa with normal morphology, the proportion of un-damaged DNA, normal chromatin condensation, motion parameters measured by CASA and the percentage of capacitated spermatozoa with tyrosine phosphorylated proteins compared to control group. Finally, the in vitro oocyte penetrating capacity of boar spermatozoa was significantly affected by Percoll centrifugation. All the Percoll treatments increased the penetration rates and mean number of sperm per penetrated oocyte. Despite the efficiency of all three of the sperm treatments tested in selecting spermatozoa with improved sperm parameters and capacity to penetrate oocytes in vitro, the optimum performance of this system was demonstrated after preselecting spermatozoa by centrifugation on a discontinuous 45/90 Percoll gradient. The P45/90 treatment leads to obtain a higher percentage of spermatozoa which develop properly the capacitation process as it was shown measuring tyrosine phosphorylation and intracellular calcium concentration. PMID- 21784590 TI - A case of acute encephalopathy with hemophagocytic lymphohistiocytosis and clonal T-cell expansion. AB - We report on a 9-year-old boy who presented with acute encephalopathy and hemophagocytic lymphohistiocytosis (HLH). The patient was referred to our hospital because of fever, seizures, and decreased consciousness. He showed moderately elevated levels of proinflammatory cytokines in the cerebrospinal fluid and plasma, and clonal expansion of highly activated CD8+ T cells in the peripheral blood. These CD8+ T cells were found to be larger cells that stained positive for T-cell receptor Vbeta13.6, and decreased shortly after steroid therapy. Our findings suggest that his acute encephalopathy was likely a clinical manifestation of HLH, and that immunophenotypic analysis may be helpful for early recognition of HLH in such rare encephalopathy. PMID- 21784591 TI - [Property of data and fertility decline]. PMID- 21784592 TI - Reduction of radiation exposure and improvement of image quality with BMI-adapted prospective cardiac computed tomography and iterative reconstruction. AB - PURPOSE: To assess the impact of body mass index (BMI)-adapted protocols and iterative reconstruction algorithms (iDose) on patient radiation exposure and image quality in patients undergoing prospective ECG-triggered 256-slice coronary computed tomography angiography (CCTA). METHODS: Image quality and radiation exposure were systematically analyzed in 100 patients. 60 Patients underwent prospective ECG-triggered CCTA using a non-tailored protocol and served as a 'control' group (Group 1: 120 kV, 200 mAs). 40 Consecutive patients with suspected coronary artery disease (CAD) underwent prospective CCTA, using BMI adapted tube voltage and standard (Group 2: 100/120 kV, 100-200 mAs) versus reduced tube current (Group 3: 100/120 kV, 75-150 mAs). Iterative reconstructions were provided with different iDose levels and were compared to filtered back projection (FBP) reconstructions. Image quality was assessed in consensus of 2 experienced observers and using a 5-grade scale (1=best to 5=worse), and signal- and contrast-to-noise ratios (SNR and CNR) were quantified. RESULTS: CCTA was performed without adverse events in all patients (n=100, heart rate of 47-87 bpm and BMI of 19-38 kg/m2). Patients examined using the non-tailored protocol in Group 1 had the highest radiation exposure (3.2+/-0.4 mSv), followed by Group 2 (1.7+/-0.7 mSv) and Group 3 (1.2+/-0.6 mSv) (radiation savings of 47% and 63%, respectively, p<0.001). Iterative reconstructions provided increased SNR and CNR, particularly when higher iDose level 5 was applied with Multi-Frequency reconstruction (iDose5 MFR) (14.1+/-4.6 versus 21.2+/-7.3 for SNR and 12.0+/-4.2 versus 18.1+/-6.6 for CNR, for FBP versus iDose5 MFR, respectively, p<0.001). The combination of BMI adaptation with iterative reconstruction reduced radiation exposure and simultaneously improved image quality (subjective image quality of 1.4+/-0.4 versus 1.9+/-0.5 for Group 2 reconstructed using iDose5 MFR versus Group 1 reconstructed using FBP, p<0.05). CONCLUSIONS: Prospective ECG-triggered 256-slice CCTA allows for visualization of the coronary artery tree with high image quality within a wide range of heart rates and BMIs. The combination of BMI adapted protocols with iterative reconstruction algorithms can reduce radiation exposure for the patients and simultaneously improve image quality. PMID- 21784593 TI - Technical and clinical outcome of transjugular intrahepatic portosystemic stent shunt: bare metal stents (BMS) versus viatorr stent-grafts (VSG). AB - PURPOSE: To compare retrospectively angiographical and clinical results in patients undergoing transjugular intrahepatic portosystemic stent-shunt (TIPS) using BMS or VSG. MATERIALS AND METHODS: From February 2001 to January 2010, 245 patients underwent TIPS. From those, 174 patients matched the inclusion criteria with elective procedures and institutional follow-up. Group (I) consisted of 116 patients (mean age, 57.0+/-11.1 years) with BMS. Group (II) consisted of 58 patients with VSG (mean age, 53.5+/-16.1 years). Angiographic and clinical controls were scheduled at 3, 6 and 12 months, followed by clinical controls every 6 months. Primary study goals included hemodynamic success, shunt patency as well as time to and number of revisions. Secondary study goals included clinical success. RESULTS: Hemodynamic success was 92.2% in I and 91.4% in II (n.s.). Primary patency was significantly higher in II compared to I (53.8% after 440.4+/-474.5 days versus 45.8% after 340.1+/-413.8 days; p<0.05). The first TIPS revision was performed significantly later in II compared to I (288.3+/-334.7 days versus 180.1+/-307.0 days; p<0.05). In the first angiographic control, a portosystemic pressure gradient >=15 mmHg was present in 73.9% in I and in 39.4% in II (p<0.05). Clinical success was 73.7-86.2% after 466.3+/-670.1 days in I and 85.7-90.5% after 617.5+/-642.7 days in II (n.s.). Hepatic encephalopathy was 37.5% in I and 36.5% in II (n.s.). CONCLUSION: VSG increased primary shunt patency as well as decreased time to and number of TIPS revisions. There was a trend of higher clinical success in VSG without increased hepatic encephalopathy. PMID- 21784594 TI - Effects of bile salts on propranolol distribution into liposomes studied by capillary electrophoresis. AB - The objective of this study was to study the effect of four different bile salts, cholate (C), deoxycholate (DC), taurocholate (TC), monoketocholate (MKC), on the membrane binding of a cationic model drug, propranolol, using capillary electrophoresis. The apparent distribution coefficient of propranolol in a buffer/liposome system, in the absence and presence of various concentrations of the bile salts, was measured using capillary electrophoresis frontal analysis. At bile salt concentrations which did not disrupt the liposomes, the bile salts increased the apparent distribution coefficient of propranolol in a concentration dependent manner, to various extents (DC>C>TC>MKC). The mechanisms for these increases were inferred from studies of ion pairing between bile salts and propranolol using mobility shift affinity capillary electrophoresis and from zeta potential measurements. The bile salts ion-paired with propranolol to different extents as indicated by the estimated complexation constants (K range: 30-58 M( 1)). This was found to have a minor effect on the membrane distribution of propranolol only. The major effect is proposed to be due to the insertion of bile salt into the liposomal membranes leading to a more negatively charged membrane surface thereby providing stronger electrostatic interactions with the positively charged propranolol. PMID- 21784595 TI - Application of automated serial blood sampling and dried blood spot technique with liquid chromatography-tandem mass spectrometry for pharmacokinetic studies in mice. AB - The goal of this work was to obtain full pharmacokinetic profiles from individual mice with the use of an automated blood sampling system and dried blood spot (DBS) technique. AMG 517, a potent and selective vanilloid receptor (VR1) antagonist, was dosed to mice (n=3) intravenously and blood samples were collected using the automated blood sampling system with the "no blood waste" method. The collected blood samples were a mixture of 25 MUL blood and 50 MUL of heparinized saline solution. Two 15 MUL aliquots were manually spotted onto a DBS card and dried at room temperature for at least 2h before being stored in zip bags with desiccant. The remaining samples (45 MUL) were stored at -70 degrees C until analysis. Both the DBS and the whole blood samples (diluted with saline (1:2, v/v)) were extracted and analyzed by liquid chromatography-tandem mass spectrometry. The overall extraction recovery of the analyte from the dried blood spots was determined to be about 90%. The pharmacokinetic parameters calculated using the whole blood or the DBS concentration data were comparable, and were obtained from only 3 mice, whereas conventional sampling and analysis would have required up to 27 mice to achieve the same result. The analyte was shown to be stable in the diluted whole blood (blood:saline 1:2) at room temperature for at least 4h and in the DBS for at least 34 days when stored at room temperature. These results indicated that the automated blood sampling system and DBS collection are promising techniques to obtain full pharmacokinetic profiles from individual mice and reduce the use of animals. PMID- 21784596 TI - Clinical utility of a combination of lipoarabinomannan, 38-kDa, and 16-kDa antigens as a diagnosis tool for tuberculosis. AB - The aim of this study was to evaluate the diagnostic value of tests detecting antibodies against lipoarabinomannan (LAM), 38-kDa, and 16-kDa antigens for Mycobacterium tuberculosis (MTB). Sera from 160 tuberculosis (TB) patients and 150 non-TB healthy controls were subjected to simultaneous detection of antibodies against LAM, 38-kDa, and 16-kDa antigens using protein chips. The diagnostic value of the 3 TB antigens, alone or combined, was evaluated. Results showed that LAM and 38-kDa antigens had the highest positive rates in the TB patients. Tests showing any single positive antibody, 2 positive antibodies, and 3 positive antibodies had a sensitivity of 93.1%, 51.3%, and 15.6%, and a specificity of 81.3%, 96.6%, and 99.3%, respectively. The positive predictive value of tests showing any 2 positive antibodies and 3 positive antibodies was 94.2% and 96.1%, respectively. Combined detection of a selected panel of TB antibodies can improve the positive rates for TB diagnosis and can serve as an important aid to the diagnosis of TB especially extrapulmonary TB. PMID- 21784597 TI - Antiviral resistance surveillance for influenza A virus in Brazil: investigation on 2009 pandemic influenza A (H1N1) resistance to oseltamivir. PMID- 21784599 TI - Physician assistants training on firearm injury prevention. AB - OBJECTIVE: The purpose of this study was to assess physician assistant training programs incorporation of firearm injury prevention training in their curricula. Also, content of such programs as well as perceived benefits and barriers of providing such training were explored. METHODS: A three-wave postal mailing of a 24-item questionnaire was sent to the population (n=145) of physician assistant program directors. RESULTS: The majority (77%) of directors responded. The majority (81.3%) reported they had not seriously thought about providing such training (pre-contemplation). The three most important barriers to providing firearm injury prevention training were: lack of time, lack of faculty expertise on the topic, and lack of standardized teaching materials. Those programs that offered training averaged one-half hour. Yet, 77.7% thought that firearm injuries were a very large or large problem to the health and wellbeing of the U.S. population. CONCLUSION: There is a paucity of professional training for physician assistants regarding firearm injury prevention. It appears unlikely that physician assistants are playing a role in helping to reduce one of the leading causes of death in the U.S., firearm trauma. The American Academy of Physician Assistants needs to take the lead in improving training in this area for physician assistants. PRACTICE IMPLICATIONS: Physician Assistant training program directors should consider offering firearm injury prevention training to help reduce patient suicides and homicides. PMID- 21784598 TI - Oncology healthcare providers' implementation of the 5A's model of brief intervention for smoking cessation: patients' perceptions. AB - OBJECTIVE: Health care providers (HCPs) can play an important role in promoting smoking cessation and preventing relapse. Public Health Service guidelines recommend the "5A's" model of brief intervention. The goal of the current study was to examine cancer patients' perceptions of 5A's model implementation by their oncology HCPs. METHODS: This study included 81 thoracic and 87 head and neck cancer patients at a large NCI-designated comprehensive cancer center. Patients completed questionnaires assessing perceptions of their oncology HCPs' implementation of the 5A's model of brief intervention. RESULTS: Results indicate partial implementation of the 5A's model. The majority of patients reported that their providers had asked about smoking and advised them to quit, however; only half reported that their interest in quitting had been assessed, and few reported assistance in quitting or follow-up. Delivery of the 5A's was greater among patients who requested cessation advice from their HCPs. CONCLUSION: The current findings suggest a need to increase adherence to the 5A's in the oncology setting. PRACTICAL IMPLICATIONS: Efforts to increase smoking cessation treatment provision by HCPs may improve the rate of cessation among cancer patients, and ultimately translate into better long-term cancer treatment outcomes. PMID- 21784600 TI - How do lay people assess the quality of physicians' communicative responses to patients' emotional cues and concerns? An international multicentre study based on videotaped medical consultations. AB - OBJECTIVE: to establish which kind of physician communicative responses to patient cues and concerns are appreciated by lay people. METHODS: A balanced sample (259 people) was recruited in public places to participate in a full day observation of four videotaped standardized medical consultations. In a two-step procedure participants gave their individual quality ratings of the whole consultations and then of a set of four fragments from each consultation. They contained a patient negative emotional expression and the subsequent physician response, according to the VR-CoDES. RESULTS: Higher quality ratings were given to physician responses which provided space to the patient to talk and to the explicit expressions of empathy. The explicit responses were favored above non explicit responses. Participants' global evaluation of the whole consultation affected their quality assessments of the fragments (halo-effect). In a multivariate model, lay people's background characteristics appeared to be relevant: to be female, of lower educational level and living in Belgium or Italy predicted higher ratings. CONCLUSIONS: Providing space to patients is appreciated by all participants, combined with the need for tailor made communication. PRACTICE IMPLICATIONS: To teach physicians listening skills and how to show empathy with distressed patients should be a core element in medical education. PMID- 21784601 TI - A double aortic arch mimicking a right aortic arch with an aberrant subclavian artery. AB - A 4-month-old boy was referred for persistent respiratory symptoms despite having undergone division of the ligamentum arteriosus for the diagnosis of a right aortic arch with an aberrant left subclavian artery. A computed tomography scan demonstrated symmetric arch vessels around the trachea at the thoracic inlet, with the left common carotid artery being tethered posteriorly, more suggestive of a double aortic arch with an atretic left arch between the left common carotid and subclavian arteries. This diagnosis was confirmed intraoperatively, and division of the atretic portion released the bronchial obstruction. This case highlights the importance of careful evaluation of the vascular anatomy. PMID- 21784602 TI - Successful percutaneous thrombectomy of an infected vena-caval thrombus due to a toothpick. AB - We report a case of a 25-year-old Caucasian female with a septic thrombosis in the inferior vena cava (IVC) which contained a toothpick. She was admitted with fever and abdominal pain for 2 weeks. Computed tomography scan showed thrombus with air density in the suprarenal IVC. However, there was no evidence of duodenocaval fistula. Because of the patient's reluctance for surgery, endovascular therapy was tried. A partially-deployed nitinol stent was used as a filter, and aspiration thrombectomy was performed. Unexpectedly, a toothpick was retrieved within the stent. Anticoagulants and antibiotics were administered. A follow-up computed tomography after 2 months showed total resolution of the residual thrombus. PMID- 21784603 TI - Influence of peripheral arterial disease and supervised walking on heart rate variability. AB - OBJECTIVE: To examine the influence of peripheral arterial disease (PAD) on heart rate variability (HRV) in patients, and to examine the influence of an intense long-term (12 months) exercise program on HRV in PAD patients. METHODS: This study involved ambulatory patients attending a local hospital and university center. Participants were twenty-five patients with diagnosed PAD and intermittent claudication and 24 healthy, age-matched adults. Interventions involved random allocation of PAD patients to 12 months of conservative medical treatment (Conservative) or medical treatment with supervised treadmill walking (Exercise). The main outcome measures were time- and frequency-domain, nonlinear HRV measures during supine rest, and maximal walking capacity prior to and following the intervention. RESULTS: Despite significantly worse walking capacity (285 +/- 190 m vs 941 +/- 336 m; P < .05), PAD patients exhibited similar resting HRV to healthy adults. At the 12-month follow-up, Exercise patients exhibited a significantly greater improvement in walking capacity (183% +/- 185% vs 57% +/- 135%; P = .03) with similar small nonsignificant changes in HRV compared with Conservative patients. CONCLUSIONS: The current study demonstrated that PAD patients exhibited similar resting HRV to healthy adults with 12 months of intense supervised walking producing similar HRV changes to that of conservative medical treatment. The greater walking capacity of healthy adults and PAD patients following supervised exercise does not appear to be associated with enhanced HRV. PMID- 21784604 TI - The application of infrared thermography in evaluation of patients at high risk for lower extremity peripheral arterial disease. AB - OBJECTIVE: We investigated the usefulness of infrared thermography in evaluating patients at high risk for lower extremity peripheral arterial disease (PAD), including severity, functional capacity, and quality of life. METHODS: A total of 51 patients (23 males; age 70 +/- 9.8 years) were recruited. They completed three PAD-associated questionnaires, including walking impairment, vascular quality of life, and 7-day physical activity recall questionnaires before a 6-minute walking test (6MWT). Ankle-brachial index (ABI) and segmental pressure were analyzed for PAD diagnosis and stenotic level assessment. The cutaneous temperature at shin and sole were recorded by infrared thermography before and after the walk test. Detailed demographic information and medication list were obtained. RESULTS: Twenty-eight subjects had abnormal ABI (ABI <1), while PAD was diagnosed in 20. No subjects had non-compressible artery (ABI >1.3). Demographic profiles and clinical parameters in PAD and non-PAD patients were similar, except for age, smoking history, and hyperlipidemia. PAD patients walked shorter distances (356 +/- 102 m vs 218 +/- 92 m; P < .001). Claudication occurred in 14 patients, while seven failed in completing the 6MWT. The rest temperatures were similar in PAD and non-PAD patients. However, the post-exercise temperature dropped in the lower extremities with arterial stenosis, but was maintained or elevated slightly in the extremities with patent arteries (temperature changes at sole in PAD vs non PAD patients: -1.25 vs -0.15 degrees C; P < .001). The exercise-induced temperature changes at the sole were not only positively correlated with the 6MWD (Spearman correlation coefficient = 0.31, P = .03), but was also correlated with ABI (Spearman correlation coefficient = 0.48, P < .001) and 7-day physical activity recall scores (Spearman correlation coefficient = 0.30, P = .033). CONCLUSION: By detecting cutaneous temperature changes in the lower extremities, infrared thermography offers another non-invasive, contrast-free option in PAD evaluation and functional assessment. PMID- 21784605 TI - Emergency procedures on the descending thoracic aorta in the endovascular era. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR), initially developed for the treatment of degenerative aneurysms of the descending thoracic aorta, has been applied to the entire spectrum of descending thoracic aortic pathology in both the elective and emergent settings. This single center study evaluates the effectiveness of TEVAR for the treatment of acute surgical emergencies involving the descending thoracic aorta, including traumatic aortic disruption (TAD), ruptured descending thoracic aneurysm (RDTA), and acute complicated Type B dissection (cTBD). METHODS: A retrospective review of the medical records of all patients undergoing emergent TEVAR at the University of Mississippi Medical Center between August 2007 and November 2010 was undertaken. Patients were studied for 30-day survival, complications, type of device used for the repair, and technical aspects of the procedure. RESULTS: A total of 44 patients (59% male) with an average age of 49 years (range, 16-87 years) underwent emergent TEVAR during the study period. The technical success rate was 100%, with no patient requiring emergent open surgery for conditions involving the descending thoracic aorta at our institution during the study period. The majority (73%) of the repairs were accomplished using commercially available thoracic stent grafts. Abdominal endograft proximal extension cuffs were used in 12 (38%) of the 32 patients undergoing repair of TAD. Twenty-one patients (48%) required coverage of the left subclavian artery, two (10%) of whom subsequently required subclavian artery revascularization. Procedure-related complications included two strokes, one spinal cord ischemia, one unintentional coverage of the left carotid artery, one episode of acute renal failure, and three access site injuries. One patient undergoing repair of TAD had collapse of the stent graft in the early postoperative period. He was successfully treated by placement of an additional stent graft. Seven patients (16%) died within 30 days of surgery. Three of the deaths occurred in patients who had successfully undergone repair of a TAD and died of associated injuries. CONCLUSIONS: Emergent TEVAR has become the treatment of choice for acute surgical emergencies involving the descending thoracic aorta. Short-term morbidity and mortality compare favorably with historic results for emergent open surgical procedures on the descending thoracic aorta. Survival is highest in patients undergoing repair of TAD. Using current endograft technology, nearly all emergent conditions of the descending thoracic aorta can be successfully treated with TEVAR. PMID- 21784606 TI - Use of endostaples to secure migrated endografts and proximal cuffs after failed endovascular abdominal aortic aneurysm repair. AB - Distal migration of aortic abdominal endografts may lead to endoleaks and must be overcome. Revision surgery has been related to substantial morbidity and mortality. In this case report, a new endovascular technique has been described to secure migrated primary endografts and proximal extender cuffs during revision surgery after failed endovascular aneurysm repair with the use of endostaples. At 6-month follow-up, no complications were noticed in both treated patients. PMID- 21784607 TI - Placement of a branched stent graft into the false lumen of a chronic type B aortic dissection. AB - The treatment of chronic type B aortic dissections remains challenging and controversial. Currently most centers advocate open or endovascular intervention for patients with evidence of malperfusion, rupture or impending rupture, continued pain, or aneurysm formation. Regardless of the type of intervention, the incidence of complications or death remains high, even when undertaken in an elective setting. The standard endovascular treatment usually involves placement of a stent graft into the true lumen of the dissection in an effort to exclude the false lumen. This case report describes the placement of a branched stent graft into the false lumen of a patient with chronic type B dissection to encourage exclusion and thrombosis of the true lumen whilst maintaining flow to all visceral vessels. PMID- 21784608 TI - The survival gap between middle-aged and elderly colon cancer patients. Time trends in treatment and survival. AB - AIMS: For several types of cancer, including colon cancer, the survival gap between middle-aged patients and elderly patients widened between 1988 and 1999 in Europe. The aim of our study was to describe treatments and compare survival rates over time (1991-2005) between middle-aged (<65 years), aged (65-74 years) and elderly (>= 75 years) colon cancer patients in the mid-western part of the Netherlands to assess whether this survival gap further increased. METHODS: All 8926 patients with invasive colon cancer diagnosed between 1991 and 2005 were selected from the Comprehensive Cancer Centre West. Relative survival was calculated. Relative Excess Risks of death (RER) were estimated using a multivariable generalized linear model with a Poisson distribution. RESULTS: There were no significant changes in the treatment for stage I and II colon. Patients with stage III and IV more often received chemotherapy over time (from 9.6% to 54.3% and from 7.5% to 44.2% for all ages, respectively), while less stage IV patients were operated on (from 73.1% to 55.2%). Relative 5-year survival increased significantly for middle-aged patients (RER = 0.97, 95%CI = 0.95-0.98, p < 0.001), borderline significantly (RER = 0.98, 95%CI = 0.97-0.99, p = 0.05) for elderly patients and not significantly for aged patients (RER = 0.99, 95%CI = 0.97-1.00, p = 0.08) after adjustment for sex, age, grade, stage, and treatment. CONCLUSIONS: The survival gap earlier found by the EUROCARE is confirmed for the mid-western part of the Netherlands, even after adjustment for age, sex, grade, stage and treatment. However, present study does not show an increase in the survival gap between middle-aged and elderly patients. PMID- 21784611 TI - The current management of aortic, common iliac, and external iliac artery disease: basic data underlying clinical decision making. AB - The management of aortoiliac occlusive disease is a rapidly evolving field in vascular medicine and surgery. There are multiple approaches that must be considered, ranging from medical management to endovascular and open surgical procedures. The introduction of percutaneous endovascular techniques has significantly changed the landscape of the field forever. We will compare and contrast different treatment strategies and critically review the available literature to allow for evidence-based clinical decisions to be made about the surgical and endovascular management of aortoiliac occlusive disease. PMID- 21784609 TI - [Non-communicable chronic diseases, a global public health priority recognized by the United Nations]. PMID- 21784612 TI - A Kinect-based system for physical rehabilitation: a pilot study for young adults with motor disabilities. AB - This study assessed the possibility of rehabilitating two young adults with motor impairments using a Kinect-based system in a public school setting. This study was carried out according to an ABAB sequence in which A represented the baseline and B represented intervention phases. Data showed that the two participants significantly increased their motivation for physical rehabilitation, thus improving exercise performance during the intervention phases. Practical and developmental implications of the findings are discussed. PMID- 21784613 TI - A new motion illusion based on competition between two kinds of motion processing units: the accordion grating. AB - Parametric psychophysical investigations are reported for two related illusory effects that occur when viewing an elementary square-wave grating while making "back and forth" head movements along the projection line. Observers report a non rigid distortion of the pattern, including: (i) an expansion in a direction perpendicular to the stripes, and (ii) a perceived curvature of the stripes. We investigated these two phenomena independently. The first depends on the classical physiological aperture problem that confronts early cells in the vision system. Interactions between ambiguous and unambiguous motion signals, generated at line interiors and line ends, respectively, can explain why the perceived expansion occurs only in directions perpendicular to the stripes. A simple model is presented and successfully tested by a nulling psychophysical experiment with four subjects. The experiment varies key stimulus attributes that generate ambiguous and unambiguous motion signals. Regarding the illusory curvature, a differential geometry model of the optics of our display, which identifies a non classical three-dimensional (3D) aperture problem, is proposed (Yazdanbakhsh & Gori, 2011). We tested that model by implementing its closed form prediction of distortion to design displays for a second psychophysical experiment that also uses a nulling technique. Results from four subjects allow the quantification of the degree of perceived curvature as a function of speed, distance and stimulus type (blurred vs. unblurred grating) and are compatible with the predictions of the model. PMID- 21784615 TI - Does calculus-related chronic sialadenitis represent a risk state for adenoid cystic carcinoma? PMID- 21784614 TI - Hypolipidimic and antioxidant activities of virgin olive oil and its fractions in 2,4-diclorophenoxyacetic acid-treated rats. AB - OBJECTIVE: We examined the effects of extra virgin olive oil (EVOO) and its hydrophilic and lipophilic fractions on serum lipids, oxidative stress, and morphologic and functional liver damages induced by 2,4-diclorophenoxyacetic acid (2,4-D). METHODS: Male Wistar rats were divided randomly into eight groups: control; 2,4-D at a dose of 5 mg/kg of body weight (2,4-D); 2,4-D plus EVOO (2,4 D/EVOO); 2,4-D plus the hydrophilic fraction (2,4-D/OOHF); 2,4-D plus the lipophilic fraction (2,4-D/OOLF); only EVOO (EVOO); only the hydrophilic fraction (OOHF); and only the lipophilic fraction (OOLF). These components were administered daily by gavage for 4 wk. RESULTS: A hepatic architecture aberration, increased activities of aspartate and alanine aminotransferase enzymes, total and low-density lipoprotein cholesterol, and malondialdehyde (MDA) level, and a decreased antioxidant defense system were observed in the 2,4-D group. The administration of EVOO restored the damage caused by 2,4-D by a significant decrease of plasma total and low-density lipoprotein levels and a moderate increase of high-density lipoprotein cholesterol. The 2,4-D/OOHF group exhibited a pronounced enhancement of the antioxidant defense system by an increase of superoxide dismutase, catalase, and glutathione peroxidase levels and a decrease of plasma and liver MDA levels. However, less improvement in the liver histoarchitecture and antioxidant status was observed in rats supplemented with OOLF diet, despite its richness in alpha-tocopherol. CONCLUSION: Extra virgin olive oil may be a potential functional food source of antioxidants than can decrease the frequency of cardiovascular diseases and liver damage. PMID- 21784616 TI - A study of word finding difficulties in Spanish speakers with temporal lobe epilepsy. AB - It is well established that naming deficits can be found in temporal lobe epilepsy (TLE). The aim of this study was to determine in Spanish speakers with pharmacoresistant TLE the characteristics of subjective naming difficulties and to examine performance in a definition task and a picture task in left TLE and right TLE. We observed that almost one-third of patients report frequent and severe word finding problems during spontaneous speech. In naming tests, our patients exhibited delayed times for finding words. Even if the target word was identified and semantically activated, there was difficulty with lexical access, which improved when a phonetic cue was given. Left TLE patients derived a lower benefit from phonetic cues in accessing words, even when the word is known and recognized semantically. These findings were not related to any demographic or clinical characteristics analyzed. The fact that the only weakly lateralized variable has been a lexical access facilitation measurement could support a lexical access hypothesis for naming deficits in TLE. PMID- 21784617 TI - A critical appraisal on the utility of long-term video-EEG monitoring in older adults. AB - BACKGROUND: World-over, the majority of patients undergoing video-EEG monitoring (VEM) are in their second or third decades. Although elderly represent the fastest growing segment of population with epilepsy, only few of them undergo VEM. We critically evaluated the utility of VEM in the diagnosis and long-term management of older adults with paroxysmal behavioral events. METHODS: 148 consecutive patients aged 45 and above, who underwent long-term (>=8 h) inpatient VEM from 1996 to 2009 formed the study cohort. Utilizing a structured proforma, we gathered their demographic, clinical, electrophysiological and long-term outcome data. VEM was considered as "useful" when it changed the diagnosis and/or management; it was "corroborative" when it helped the treating physician to confirm the diagnosis and "not useful" when it neither helped to improve the diagnosis nor the management. RESULTS: The mean age was 51.3 (SD 6.4) years; mean duration of VEM was 69.3 h. Out of 117 patients with a diagnosis of epileptic seizures referred for presurgical evaluation or classification, VEM was "useful" or "corroborative" in 111 patients (94.8%; p=0.0001). It was also "useful" or "corroborative" in 29 out of 31 patients (93.5%) referred with a suspicion of associated or pure psychogenic non-epileptic seizures (p=0.0001). None developed any complications during monitoring. At a mean follow-up of 37.7 months there was significant reduction in AED usage in patients with epilepsy (p=0.0001) and epilepsy with associated PNES (p=0.001). At a mean follow-up of 34.2 months, all patients with pure PNES were event-free and medication-free at last follow-up (p=0.002). Twenty-three patients (19.6%) underwent surgery, all except one remaining seizure-free at a mean follow-up of 39.2 months. CONCLUSIONS: VEM is a safe and cost-effective investigation strategy in older-adults. It aided in improving the diagnosis, offered better treatment including surgery and helped in excluding non-epileptic paroxysmal events in majority. PMID- 21784618 TI - Ultra high-risk state for psychosis and non-transition: a systematic review. AB - BACKGROUND: Most effort in ultra high-risk (UHR) research has been directed at defining the clinical and neurobiological characteristics of those UHR subjects who go on to develop psychosis. The characteristics and outcome of the remaining UHR subjects have remained relatively unexplored. METHOD: We performed a systematic review of clinical UHR studies to investigate whether information was available on the characteristics and outcome of UHR subjects who did not convert to psychosis. RESULTS: Of 2462 potentially relevant papers, 31 met inclusion criteria, i.e. 20 naturalistic and 11 intervention studies. On average 76% (range 46-92.6%) of the UHR patients made no transition to psychosis during follow-up (range 6 to 40 months). Nearly half of the studies provided no characteristics of those UHR subjects who did not develop psychosis. Six studies reported remission rates from initial UHR status (range 15.4% to 54.3%). Linear regression showed that more recent studies reported significantly lower transition rates as compared to earlier publications. An older mean age at baseline was associated with significant lower transition rates in publications with follow-ups exceeding 1 year. CONCLUSIONS: Our review illustrates that the long-term outcome of UHR subjects that do not develop psychosis is to date under-investigated. The studies reporting remission rates suggest that UHR criteria capture a non-negligible proportion of subjects that do not convert to psychosis. PMID- 21784619 TI - Reduced amygdala and hippocampal volumes in patients with methamphetamine psychosis. AB - The similarity between psychotic symptoms in patients with schizophrenia such as hallucinations and delusions and those caused by administration of methamphetamine has been accepted. While the etiology of schizophrenia remains unclear, methamphetamine induced psychosis, which is obviously occurred by methamphetamine administration, had been widely considered as a human pharmaceutical model of exogenous psychosis. Although volume reductions in medial temporal lobe structure in patients with schizophrenia have repeatedly been reported, those in patients with methamphetamine psychosis have not yet been clarified. Magnetic resonance images (MRI) were obtained from 20 patients with methamphetamine psychosis and 20 age, sex, parental socio-economic background, and IQ matched healthy controls. A reliable manual tracing methodology was employed to measure the gray matter volume of the amygdala and the hippocampus from MRIs. Significant gray matter volume reductions of both the amygdala and hippocampus were found bilaterally in the subjects with methamphetamine psychosis compared with the controls. The degree of volume reduction was significantly greater in the amygdala than in hippocampus. While the total gray, white matter and intracranial volumes were also significantly smaller-than-normal in the patients; the regional gray matter volume reductions in these medial temporal structures remained statistically significant even after these global brain volumes being controlled. The prominent volume reduction in amygdala rather than that in hippocampus could be relatively specific characteristics of methamphetamine psychosis, since previous studies have shown significant volume reductions less frequently in amygdala than in hippocampus of the other psychosis such as schizophrenia. PMID- 21784620 TI - A novel point mutation at donor splice-site in intron 18 of ATP2A2 gene resulting in the insertion of 27 nucleotides into the mature mRNA in a Chinese patient with severe Darier's disease. PMID- 21784621 TI - Aripiprazole augmentation strategy in clomipramine-resistant depressive patients: an open preliminary study. AB - Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 +/- 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved. PMID- 21784622 TI - Metabolic syndrome and atrial fibrillation in patients with essential hypertension. AB - BACKGROUND AND AIM: Metabolic syndrome (MS) has been recently associated with an increased risk for the development of atrial fibrillation (AF) in the general population. Whether this relation is also apparent in patients with arterial hypertension remains to be clarified. In the present study we sought to investigate the independent association of the MS with the AF in a large cohort of hypertensive patients. MATERIAL AND METHODS: The study comprised 15,075 consecutive, non-diabetic patients with essential hypertension (age range: 40-95 years, 51.1% males). All subjects underwent a complete clinical and lipidemic profile assessment as well as a standard 12-lead ECG at drug free baseline. MS was diagnosed by using five different definitions, including the National Cholesterol Education Program Third Adult Treatment Panel (ATPIII) and the GISSI Score. RESULTS: The prevalence of the MS varied from 31.7% to 47.8% according to the each time definition used. In multiple logistic regression analysis, MS was associated with the presence of AF (odds ratio from 1.61 to 1.99, p < 0.001 for all), independenty of the definition used. All ATPIII MS components were found to be independently associated with an increased incidence of AF. The prevalence of AF increased progressively with the severity of the metabolic syndrome as assessed by the number of the metabolic syndrome components (p < 0.001). CONCLUSION: In non-diabetic patients with essential hypertension, the MS is directly and independently related to the AF prevalence. PMID- 21784623 TI - Anticonvulsant, antidepressant-like activity of Abelmoschus manihot ethanol extract and its potential active components in vivo. AB - Depression is the most common psychiatric comorbidity in patients with epilepsy. Searching for antiepileptic (anticonvulsant) and antidepressant-like medicines from natural products is very important for the treatment of this disease. The flower of Abelmoschus manihot (Linn.) Medicus has been reported to have neuroprotective effect against cerebral ischemia injury. In order to further explore the activity of Abelmoschus manihot on the central nervous system, the anticonvulsant and antidepressant-like effects of Abelmoschus manihot ethanol extract (AMEE) as well as its potential active components in vivo was investigated in the present study. It was found that AMEE could protect mice against PTZ-induced clonic convulsions and mortality. AMEE could also decrease immobility time in the FST in mice. Furthermore, the potential active components of AMEE in rat brain were identified by ultra performance liquid chromatography mass spectrometer (UPLC-MS). Five parent components including isoquercitrin, hyperoside, hibifolin, quercetin-3'-O-glucoside, quercetin and three metabolites were detected in rat brain after administration of AMEE. In conclusion, eight flavonoids were identified in rat brain after administration of AMEE; meanwhile, these flavonoids might represent the potential bioactive components of AMEE and contribute to its anticonvulsant and antidepressant-like activity in vivo. PMID- 21784624 TI - Baseline severity but not gender modulates quantified Crataegus extract effects in early heart failure--a pooled analysis of clinical trials. AB - OBJECTIVE: The efficacy of quantified Crataegus extract in chronic heart failure (CHF) has been assessed in numerous clinical studies. The present pooled analysis evaluates the impact of baseline severity and gender on objective and patient reported endpoints and associations between both types of outcomes in patients with early CHF. METHODS: Available data from 687 individual patients treated with quantified Crataegus extract or placebo in ten studies were pooled. Treatment effects on physiologic outcome parameters and on symptoms were analysed for their association with baseline severity and gender. Changes in symptom scores were investigated with respect to their relation to physiologic outcome parameters. Results were compared with observations in a 3-year cohort study. RESULTS: Physiologic outcome parameters maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50 W ergometric exercise improved more in active treatment than in placebo patients. Magnitude of improvement was independent from baseline for LVEF but increased for MWL and PHRPI with baseline severity. Improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms. A weak association between improvements in MWL, PRHP, and symptoms could be demonstrated. Gender differences in treatment effects could be explained by baseline differences. Results of the pooled analysis are in agreement with observations in the cohort study. CONCLUSIONS: Crataegus extract treatment effects on physiologic outcomes and typical symptoms were modulated by baseline severity. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart failure. PMID- 21784625 TI - Dietary n-3 polyunsaturated fatty acid deprivation together with early maternal separation increases anxiety and vulnerability to stress in adult rats. AB - Low concentrations of n-3 polyunsaturated fatty acid (PUFA) and chronic stress are implicated in susceptibility to mood disorders. We have investigated the combined effects of chronic n-3 PUFA dietary deficiency and early maternal separation (MS) stress on the reactivity to stressful situations of rats as adults. Pups fed a control or an n-3 PUFA deficient diet were daily separated for two weeks before weaning They were all tested at 3 month-old to determine their anxiety, and their ability to learn two aversive tasks differing in the control they could exert on the situation: auditory fear conditioning and brightness avoidance discrimination. Neither the n-3 PUFA-deficient diet nor MS alone significantly affected behavior. But n-3 PUFA-deficient rats that had been separated were more anxious and fearful in inescapable situations, while their ability to cope with an aversive avoidance task remained unaffected. These results support the notion that PUFA-unbalanced diet, together with stress, may be a determinant risk factor in emotional disorders. PMID- 21784626 TI - Compressive strength and resistance to chloride ion penetration and carbonation of recycled aggregate concrete with varying amount of fly ash and fine recycled aggregate. AB - Construction and demolition waste has been dramatically increased in the last decade, and social and environmental concerns on the recycling have consequently been increased. Recent technology has greatly improved the recycling process for waste concrete. This study investigates the fundamental characteristics of concrete using recycled concrete aggregate (RCA) for its application to structural concrete members. The specimens used 100% coarse RCA, various replacement levels of natural aggregate with fine RCA, and several levels of fly ash addition. Compressive strength of mortar and concrete which used RCA gradually decreased as the amount of the recycled materials increased. Regardless of curing conditions and fly ash addition, the 28 days strength of the recycled aggregate concrete was greater than the design strength, 40 MPa, with a complete replacement of coarse aggregate and a replacement level of natural fine aggregate by fine RCA up to 60%. The recycled aggregate concrete achieved sufficient resistance to the chloride ion penetration. The measured carbonation depth did not indicate a clear relationship to the fine RCA replacement ratio but the recycled aggregate concrete could also attain adequate carbonation resistance. Based on the results from the experimental investigations, it is believed that the recycled aggregate concrete can be successfully applied to structural concrete members. PMID- 21784627 TI - Ultra-fine Pt nanoparticles supported on ionic liquid polymer-functionalized ordered mesoporous carbons for nonenzymatic hydrogen peroxide detection. AB - Poly(ionic liquid) (PIL) coated ordered mesoporous carbons (OMCs) were prepared by in situ polymerization of 3-ethyl-1-vinylimidazolium tetrafluoroborate ([VEIM]BF(4)) monomer on OMCs matrix. PIL on the surface of OMCs can provide sufficient binding sites to anchor the precursors of metal ion. PIL/OMCs were employed as support material for the deposition and formation of ultra-fine Pt nanoparticles, via the self-assembly between the negative Pt precursor and positively charged functional groups of PIL-functionalized OMCs. The combination of the unique properties of each component endows Pt/PIL/OMCs as a good electrode material. Compared with the Pt/OMCs nanocomposite, the Pt/PIL/OMCs modified electrode displays high electrocatalytic activity towards hydrogen peroxide (H(2)O(2)) and gives linear range from 1.0 * 10(-7) to 3.2 * 10(-3) M (R=0.999). The Pt/PIL/OMCs responds very rapidly to the changes in the level of H(2)O(2), producing steady-state signals within 4-5s. A high sensitivity of 24.43 MUA mM( 1) and low detection limit of 0.08 MUM was obtained at Pt/PIL/OMCs modified electrode towards the reduction of H(2)O(2). The improved activity makes Pt/PIL/OMCs nanocomposite promising for being developed as an attractive robust and new electrode material for electrochemical sensors and biosensors design. PMID- 21784628 TI - Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. AB - BACKGROUND: Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are approved as treatment of non-small-cell lung cancer (NSCLC). Despite an initially impressive response to EGFR-TKIs, patients with an activating EGFR mutation invariably relapse. For these patients few treatment options are available after additional progression during or after chemotherapy. The aim of this study is to examine the effect of retreatment with an EGFR-TKI after a drug holiday. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 14 patients with stage IV NSCLC who progressed after long-term disease control with EGFR-TKI, who were subsequently treated with standard chemotherapy and at renewed progression retreated with EGFR-TKI. RESULTS: Fourteen patients (five male, nine female, median age 55 years (39-70 years) received retreatment with erlotinib. The median interval from the discontinuation of EGFR-TKI to the 2nd episode was 9.5 months (3-36 months). Before starting retreatment 36% (n=5) had a T790M mutation. Retreatment resulted in 36% (n=5) partial response, 50% stable disease (n=7) and 14% progressive disease (n=2). Among patients with a T790M mutation this number was two, one and two, respectively. Seven patients are still on therapy without signs of progression. Median follow up is 9 months (1.5-16+months) and median PFS is 6.5 months (1 16+months). CONCLUSION: Our findings suggest that retreatment with erlotinib is an option for patients with NSCLC who initially benefited from previous EGFR-TKI treatment and progressed after standard cytotoxic chemotherapy. PMID- 21784629 TI - Two-stage pretreatment of rice straw using aqueous ammonia and dilute acid. AB - Liberation of fermentable sugars from recalcitrant lignocellulosic biomass is one of the key challenges in production of cellulosic ethanol. Here we developed a two-stage pretreatment process using aqueous ammonia and dilute sulfuric acid in a percolation mode to improve production of fermentable sugars from rice straw. Aqueous NH3 was used in the first stage which removed lignin selectively but left most of cellulose (97%) and hemicellulose (77%). Dilute acid was applied in the second stage which removed most of hemicellulose, partially disrupted the crystalline structure of cellulose, and thus enhanced enzymatic digestibility of cellulose in the solids remaining. Under the optimal pretreatment conditions, the enzymatic hydrolysis yields of the two-stage treated samples were 96.9% and 90.8% with enzyme loadings of 60 and 15FPU/g of glucan, respectively. The overall sugar conversions of cellulose and hemicellulose into glucose and xylose by enzymatic and acid hydrolysis reached 89.0% and 71.7%, respectively. PMID- 21784630 TI - An investigation of biooxidation ability of Acidithiobacillus ferrooxidans using NMR relaxation measurement. AB - NMR relaxation measurements can provide a simple means for understanding biological activity of cells in solution with known composition. It has the advantage that it is an in situ, non-intrusive technique, and the acquisition is fast. The iron oxidation ability of Acidithiobacillus ferrooxidans was investigated using NMR relaxation measurements. The transversal relaxation is characterized by a time constant, T2, which is sensitive to the chemical environment. Fe3+ ion has more significant T2 shortening than Fe2+ ion. In the presence of A. ferrooxidans in solutions containing Fe2+ ion, T2 shortening was found with increasing time as the bacteria oxidize Fe2+ to Fe3+ ions. In the optimal growth medium, the bacteria concentration increased 80 times and high iron oxidation rate was found. In 10 mM K2SO4 medium, however, bacteria concentration remained almost unchanged and the iron oxidation rate was significantly lower. PMID- 21784631 TI - Bioactive components from the heartwood of Pterocarpus santalinus. AB - One new phenanthrenedione, pterolinus K (1), and one new chalcone, pterolinus L (2) were isolated from the heartwood extract of Pterocarpus santalinus. The structures were elucidated by spectroscopic methods. Both 1 and 2 showed inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC(50) value of 4.24 and 0.95 MUM, and compound 1 also inhibited superoxide anion generation with IC(50) value of 0.99 MUM. In addition, compound 1 showed selective cytotoxicity against HepG2 with IC(50) value of 10.86 MUM, while compound 2 showed a moderate cytotoxicity against KB with IC(50) values of 17.18 MUM. PMID- 21784633 TI - Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus. AB - The highly constitutively active G-protein coupled receptor US28 of human cytomegalovirus (HCMV) is an interesting pharmacological target because of its implication on viral dissemination, cardiovascular diseases and tumorigenesis. We found that dihydroisoquinolinone and tetrahydroisoquinoline scaffolds may be promising lead structures for novel US28 allosteric inverse agonists. These scaffolds were rapidly synthesized by radical carboamination reactions followed by non-radical transformations. Our novel US28 allosteric modulators provide valuable scaffolds for further ligand optimization and may be helpful chemical tools to investigate molecular mechanisms of US28 constitutive signaling and its role in pathogenesis. PMID- 21784632 TI - New inhibitors of colony spreading in Bacillus subtilis and Bacillus anthracis. AB - We have recently characterized sliding motility in Bacillus subtilis strains that lack functional flagella, and here describe the discovery of inhibitors of colony spreading in these strains as well as the aflagellate pathogen, Bacillus anthracis. Aflagellate B. subtilis strains were used to screen for new types of antibacterials that might inhibit colony spreading on semi-solid media. From a diverse set of organic structures, p-nitrophenylglycerol (NPG), an agent used primarily in clinical laboratories to control Proteus swarming, was found to inhibit colony spreading. The four stereoisomers of NPG were synthesized and tested, and only the 1R,2S-(1R-anti) and 1R,2R-(1R-syn) NPG isomers had significant activity in a quantitative colony-spreading assay. Twenty-six NPG analogs and related structures were synthesized and tested to identify more active inhibitors. p-Methylsulfonylphenylglycerol (p-SPG), but not its ortho or meta analogs, was found to be the most effective of these compounds, and synthesis and testing of all four p-SPG stereoisomers showed that the 1R-anti isomer was the most active with an average IC(50) of 16 MUM (3-5 MUg mL(-1)). For B. anthracis, the colony-spreading IC(50) values for 1R-anti-SPG and 1R-anti-NPG are 12 MUM (2-4 MUg mL(-1)) and >150 MUM, respectively. For both Bacillus species tested, 1R-anti-SPG inhibits colony spreading of surface cultures on agar plates, but is not bacteriostatic or bacteriocidal in liquid cultures. Work is in progress to find the cellular target(s) of the NPG/SPG class of compounds, since this could lead to an understanding of the mechanism(s) of colony spreading as well as design and development of more potent inhibitors for the control of B. anthracis surface cultures. PMID- 21784634 TI - Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents. AB - An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 * 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors. PMID- 21784635 TI - Coordination conjugates of therapeutic proteins with drug carriers: a new approach for versatile advanced drug delivery. AB - We present here a general system for the coordination attachment of therapeutic proteins to a drug delivery system and its application in combined therapy. Proof of concept is demonstrated by the synthesis and testing of the targeted drug delivery system for cytostatics, which is based on a combination of the drug carrier Zn-porphyrin-cyclodextrin conjugates and their supramolecular coordination complexes with immunoglobulins. This system can be as readily used for a variety of therapeutic and targeting proteins including PAs, MAs, lectins, and HSA. Moreover, it allows combined photodynamic therapy, cell targeted chemotherapy and immunotherapy. When tested in a mouse model with human C32 carcinoma, the therapeutic superiority of the coordination assembly nanosystem was shown in comparison with the efficacy of building blocks used for the construction of the system. PMID- 21784636 TI - Combination of steroids and ischial weight-bearing knee ankle foot orthoses in Duchenne's muscular dystrophy prolongs ambulation past 20 years of age--a case report. AB - Patients with Duchenne muscular dystrophy (DMD) lose ambulation by age 12. Long term steroids have lengthened ambulation by 2-5 years. Ischial weight-bearing knee ankle foot orthoses prolong ambulation for 2-3 years. We report the outcome of the ambulatory status of a patient with DMD treated with daily steroid therapy and orthoses. This male patient was diagnosed with DMD at age of 2. He has been treated with daily steroids since age 7 years. He lost the ability to arise from the floor and walk up steps at age 14 and lost ambulation by age 16. He was fitted with orthoses at age 16 following surgical correction of his lower extremity contractures and regained independent ambulation. At age 20, he was able to stand independently in his orthoses and take steps with moderate support. We conclude that a combination of daily steroids and orthoses prolongs ambulation beyond that of the natural history DMD. PMID- 21784637 TI - Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis. AB - PURPOSE: To perform a meta-analysis in order to quantify the actual cumulative randomized evidence for the benefit and toxicity of trastuzumab combined with neoadjuvant chemotherapy in HER2-positive breast cancer. METHODS: Potentially eligible trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. The endpoints that we assessed were pathologic complete response (pCR) rate, breast-conserving surgery (BCS) rate and toxicity. RESULTS: Five trials were identified with 515 eligible patients. The probability to achieve pCR was higher for the trastuzumab plus chemotherapy arm (RR 1.85, 95% CI: 1.39-2.46; p-value < 0.001). No significant difference in terms of breast-conserving surgery between the two treatment arms was observed (OR: 0.98, 95% CI: 0.80-1.19, p-value = 0.82). Regarding toxicity, the addition of trastuzumab did not increase the incidence of neutropenia, neutropenic fever, and cardiac adverse events. CONCLUSION: The addition of trastuzumab in HER2-positive breast cancer in the neoadjuvant setting improves the probability of achieving higher pCR with no additional toxicity. Based on the available evidence, the use of trastuzumab combined with neoadjuvant chemothetherapy in patients with HER2 positive breast cancer seems to offer substantial benefit in terms of pCR. PMID- 21784639 TI - The factors which influence nurses when weaning patients from mechanical ventilation: findings from a qualitative study. AB - The aim of the study was to describe the factors that influence critical care nurses when deciding to wean patients from mechanical ventilation. The study adopted a qualitative methodology, using semi-structured interviews and a vignette. An invited sample of critical care nurses (n=24) from one Irish intensive care unit was employed. Each nurse was interviewed once and a vignette was used to structure the interview questioning. The findings were analysed using thematic content analysis. Six major themes influencing nurses' decision to wean emerged, as follows: physiological influences; clinical reassessment and decision making; the nurse's experience, confidence and education; the patient's medical history and current ventilation; the intensive care working environment; and use of protocols. The findings highlight the complex nature of weaning patients from mechanical ventilation and the major role of the nurse in this process. PMID- 21784638 TI - Plithotaxis and emergent dynamics in collective cellular migration. AB - For a monolayer sheet to migrate cohesively, it has long been suspected that each constituent cell must exert physical forces not only upon its extracellular matrix but also upon neighboring cells. The first comprehensive maps of these distinct force components reveal an unexpected physical picture. Rather than showing smooth and systematic variation within the monolayer, the distribution of physical forces is dominated by heterogeneity, both in space and in time, which emerges spontaneously, propagates over great distances, and cooperates over the span of many cell bodies. To explain the severe ruggedness of this force landscape and its role in collective cell guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad range of epithelial and endothelial cell sheets, collective cell migration is governed instead by a newly discovered emergent mechanism of innately collective cell guidance - plithotaxis. PMID- 21784640 TI - Staphylococcal biofilm disassembly. AB - Staphylococcus aureus and Staphylococcus epidermidis are a frequent cause of biofilm-associated infections that are a tremendous burden on our healthcare system. Staphylococcal biofilms exhibit extraordinary resistance to antimicrobial killing, limiting the efficacy of antibiotic therapy, and surgical intervention is often required to remove infected tissues or implanted devices. Recent work has provided new insight into the molecular basis of biofilm development in these opportunistic pathogens. Extracellular bacterial products, environmental conditions, and polymicrobial interactions have all been shown to influence profoundly the ability of these bacteria to colonize and disperse from clinically relevant surfaces. We review new developments in staphylococcal biofilm disassembly and set them in the context of potential strategies to control biofilm infections. PMID- 21784641 TI - Experimental human pneumococcal carriage models for vaccine research. AB - Pneumococcal conjugate vaccines have had unprecedented success in controlling vaccine-type invasive pneumococcal disease. As serotype replacement and the complexity of designing vaccines to multiple capsular polysaccharides ultimately pose a threat to these vaccines, the development of alternative protein vaccines is important. Protein vaccines offer the promise of extended serotype coverage, reduced cost, and improved protection against otitis media and pneumococcal pneumonia. As placebo-controlled trials are not currently ethically justifiable, human pneumococcal challenge models using prevention of carriage as a test endpoint offer an attractive link between preclinical studies and clinical efficacy trials. Experimental human pneumococcal carriage studies offer a means of describing mechanisms of protection against carriage and a clinical tool to choose between vaccine candidates. PMID- 21784642 TI - Non-operative management of an extensive anteriorly located epidural abscess. AB - Spinal epidural abscess is a rare, but potentially devastating, infection. The atypical involvement of more than five spinal levels (termed "extensive") is very uncommon. In this report we discuss the successful non-operative treatment of a 71-year-old male with an anteriorly located holocord abscess and review the pertinent literature. PMID- 21784643 TI - A prospective series of patients with hyperglycaemia-associated movement disorders. AB - Hyperglycaemia-associated movement disorders (MD) usually appear in older patients with diabetes and are related to acute peaks in blood glucose levels. This study aimed to describe the clinical features of a prospective series of patients with movement disorders associated with hyperglycaemia. We present a series of seven women and three men diagnosed with hyperglycaemia-associated MD who were followed for at least 1 year. Clinical evolution, treatment and neuroimaging findings are presented. Mean (+/- standard deviation [SD]) of the age at onset was 67.7 +/- 11.7 years and mean (+/- SD) fasting glucose was 359.7 +/- 162.5mg/dL. Putaminal hyperintensity on T1-weighted MRI was present in almost all instances. Two patients had pontine lesions compatible with osmotic myelinolysis. At follow-up, eight patients had a complete remission. We conclude that the clinical profile of patients in our series is similar to those reported in the literature. No clinical or metabolic features were found to be correlated with remission. Similarities with osmotic myelinolysis syndromes are discussed as an alternative aetiological hypothesis. PMID- 21784644 TI - Expression of N-myc downstream regulated gene 1 (NDRG1) in central neurocytoma. AB - N-myc downstream regulated gene 1 (NDRG1), also known as Cap43, Drg-1, and rit42, is expressed in various normal tissues and cancers, in which it is often associated with a favorable prognosis. It also plays a critical role in central nervous system development, with NDRG1 deficiency resulting in neural defects in mice. Central neurocytoma (CN) is a relatively rare tumor of the neurocytes in the brain, which occurs mainly in young adults. In the present study, we found that tissue samples from four patients with CN had both nuclear and cytoplasmic/membranous expression of NDRG1 protein in highly differentiated CN tumor cells. NDRG1 was also expressed in intratumoral microvessels. Immunohistochemical study of serial sections from the same patients revealed a marked association between the expression pattern of NDRG1 and that of neuron specific enolase, a tumor differentiation marker. The data presented in this study suggest that NDRG1 could be considered a potential differentiation marker for CN. PMID- 21784645 TI - Risk factors associated with haemodynamic depression during and after carotid artery stenting. AB - We aimed to investigate the risk factors for haemodynamic depression (HD) during and after carotid artery stenting (CAS). A total of 251 patients with CAS, enrolled between June 2004 and December 2008, were divided into two groups according to periprocedure observations: (i) a group with HD (systolic blood pressure<90 mm Hg and heart beat rate<50/ beats per minute); and (ii) a group without (non-HD). The risk factors for HD were analysed by univariate analysis and a logistic regression model. The univariate analysis of variance showed that the following factors were significantly associated with HD in patients with CAS: severe calcified plaque, stenosis greater than 70%, distance from the carotid bifurcation to the maximum stenotic lesion of <10mm, balloon dilation lasting more than 5 s with a pressure of more than 8 atmospheres (atm), multiple balloon dilations, balloon length, balloon diameter, and bilateral stenting. The results of the logistic regression model analysis showed that the following were independent risk factors for HD during and after CAS: the degree of stenosis, severe calcified plaque, bilateral stenting and a balloon dilation pressure of >8 atm. We concluded that patients with stenosis>70%, severe calcified plaque, bilateral stenting and a balloon dilation pressure>8 atm may be more likely to develop HD during and after CAS. PMID- 21784646 TI - Retrieval analysis of modular total knee replacements: factors influencing backside surface damage. AB - Retrieved knee implants were examined to investigate the influence of patient and implant related factors on backside damage. Fifty-two implants of three different models were examined that all had cemented tibial trays without screw holes. A semi-quantitative grading system supplied backside damage scores (BDS) for each polyethylene (PE) tibial insert. Evidence was obtained to support the use of a constraining partial-peripheral locking mechanism and polished tibial tray surface (particularly for male patients) to reduce backside damage. Overall, male patients in the present study were associated with higher body mass and higher BDS compared with female patients. Furthermore, PE inserts sterilized by gamma-in air had higher BDS than PE inserts sterilized in inert environments (gas-plasma or ethylene-oxide). Also, the proximal surfaces of tibial trays that had been grit-blasted showed embedded particles that may have increased backside damage. While none of these overall findings was unexpected, the present study provided detailed supporting analysis based on data from clinical retrievals, which may further support the use of a polished tibial tray combined with partial peripheral locking mechanism to reduce BDS. PMID- 21784647 TI - Ion mobility mass spectrometry enables the efficient detection and identification of halogenated natural products from cyanobacteria with minimal sample preparation. AB - Direct observation of halogenated natural products produced by different strains of marine cyanobacteria was accomplished by electrospray ionization and matrix assisted laser desorption ionization and gas phase separation via ion mobility mass spectrometry of extracts as well as intact organisms. PMID- 21784648 TI - Isolation of the beta-galactosphingolipid coniferoside using a tumor cell proteome reverse affinity protocol. AB - New approaches are vital to the development of marine natural products (MNP) as therapeutic leads. One of the more time consuming aspects of MNP research arises in the connection between structure and function. Here, we describe an isolation protocol that adapts tumor cell proteomes as a vehicle for MNP isolation therein uniting structural and functional analysis. Application of this method to extracts of the sponge Agelas conifera led to the isolation of a unique poly hydroxybutyrated beta-galactosphingolipid, coniferoside. PMID- 21784649 TI - Boron neutron capture in prostate cancer cells. AB - A modified enhanced thermal neutron beam (METNB) assembly at Fermilab was used to irradiate borylphenylalanine (BPA) treated human prostate cancer cells, DU 145. Acceptable cellular uptake levels of BPA and no BPA cytotoxicity were observed. In the absence of BPA, the relative biological effectiveness (RBE) of the METNB was determined to be 2.3-4.8 times greater than gamma rays. An additional 1.2 or 1.4 fold relative enhancement from boron neutron capture (RE(BNC)) was observed for METNB irradiated DU 145 cells treated with 4.9 or 12mM BPA, respectively. The additional cell killing of the BPA loaded DU 145 cells by the METNB at Fermilab is evidence for a BNC enhanced cell killing. PMID- 21784650 TI - Transformation of a vascularised iliac crest or scapula bone to a pedicled osteomuscular transplant for reconstruction of distant defects in the head and neck region: a new method of transforming two island flaps to one longer island flap. AB - OBJECTIVE: Bone defects in the maxillofacial region after ablative surgery require reconstructive surgery, usually using microvascular free flaps. This paper presents a new method of reconstructing extensive defects in patients not suitable for microvascular surgery using prefabrication of a vascularised osteomuscular flap from the scapula or iliac crest bone. METHODS: Three patients who were treated with this new technique are presented. Two patients (one mandibular defect and one defect in the maxillary region) received prefabricated osteomuscular flaps from the iliac crest bone using the latissimus dorsi muscle as a pedicle. One patient also presenting a mandibular defect after tumour surgery received a scapula transplant for reconstruction of the defect using the pectoralis major muscle as pedicle. RESULTS: In all three cases vital bone could be transplanted. The pedicle was strainless in all three cases. Minor bone loss could be seen initially only in one case. The results are stable now and one patient received dental implants for later prosthetic treatment. CONCLUSION: The presented two-step surgery provides an excellent method for reconstruction of bony defects in the maxillofacial region in patients where microvascular surgery is not possible due to reduced state of health or lack of recipient vessels. PMID- 21784651 TI - Reviewing non clinical data for a granulocyte colony stimulatory factor product: experience in Brazil. AB - Non clinical studies are one of the requirements for the Brazilian National Regulatory Authority, ANVISA, for licensing a similar biotherapeutic product. During the WHO/KFDA workshop on implementing WHO guidelines on evaluating similar biotherapeutic products (SBP) in Seoul, Republic of Korea, the Brazilian experience with the non clinical studies of a Granulocyte Colony Stimulatory Factor (G-CSF), filgrastim, was presented. The applicant presented a reduced non clinical data package, but the key studies with relevant species were conducted and the non-clinical studies were considered sufficient for approval. Using the comparability exercise, these studies were taken together with the appropriate quality and clinical packages presented. PMID- 21784652 TI - Biosimilars and non-innovator biotherapeutics in India: an overview of the current situation. AB - Globally, a large number of blockbuster biotherapeutic molecules are going off patent in the next few years. For emerging economies, like India, it is imperative to be able to provide safe and cost effective drugs for its huge, non insured and poor population. India has a robust pharmaceutical industry including the biopharmaceutical sector which is actively engaged in the production and marketing of 'non-innovator' or 'copy' biotherapeutic products These products are approved through an abbreviated route which relies on limited safety and efficacy data enabling the local companies to keep the production costs low and pass on the price benefit to the patient and make the product affordable to the masses. Some of the available products may not be truly 'similar' and may be of suspect quality. The WHO [1] and the European Medicines Agency (EMA) [2] have published guidelines for the development and marketing of biosimilar products. These products, as stated in both guidelines undergo extensive head-to-head comparability testing with the reference biotherapeutic product (RBP) to show their similarity to the RBP in terms of quality, efficacy and safety. Regulators and administrators of different countries need to strike a balance in cost-to benefit versus risks that are perceived for these products, keeping in mind global regulatory issues. PMID- 21784653 TI - Regulatory guideline for biosimilar products in Korea. AB - The regulatory framework of biosimilar products in Korea is a 3-tiered system: 1) Pharmaceutical Affairs Act; 2) Notification of the regulation on review and authorization of biological products; 3) Guideline on evaluation of biosimilar products. A biosimilar product is regulated under the same regulation as biological products. The difference from new biological product is that biosimilar product requires full comparability data with reference product. Based on these data, some of the non-clinical and clinical data could be abbreviated. As Korean guideline for biosimilar products was developed along with that of the WHO's, most of the recommendations were based on similar principle except the clinical evaluation to demonstrate similarity. No biosimilar products are licensed yet, however, 4 IND products have been approved for phase I or III clinical trials. The addressed issues during review were as follows: acceptability of reference products manufactured in different sites, determination of acceptable criteria for differences and selection of analytical tests for the comparability exercise to detect potential differences in quality attributes, relevant species for non-clinical study, and duration of toxicity study, etc. These and other future issues will be dealt with scientific advancement, experiences of collaborating work with WHO or other NRAs, which will be reflected in the guidelines on regulations of biosimilar products in Korea. PMID- 21784654 TI - A biosimilar industry view on the implementation of the WHO guidelines on evaluating similar biotherapeutic products. AB - The WHO guidelines on evaluating biosimilar products represent an important step forward in the global harmonization of biosimilar(1) products regulation, and provide clear guidance for regulatory bodies and industry. They confirm the key principles of biosimilarity, namely stand alone manufacturing process development and demonstrated comparability, which are described in many existing regional guidelines for biosimilars. Based on the premise that companies which have developed capabilities for the production of safe and efficacious recombinant biopharmaceuticals also have the foundation and tools available to make safe and efficacious biosimilars, the guidelines provide industry with clear direction on how to actually do so. Finally, when applying the WHO guidelines, it should be considered that the experience gained by industry and regulators when evaluating manufacturing process changes of originator products can be leveraged and directly applied to the development and approval of biosimilar products. PMID- 21784655 TI - Regulatory guidelines for biosimilars in Malaysia. AB - The biosimilars sector continues to attract huge interest and controversy. Biosimilars are new biopharmaceuticals that are "similar" but not identical to the innovator product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which implies that the products cannot be exactly duplicated. Minuscule differences in the product's structure and manufacturing process can result in different clinical outcome. This raises concerns over the safety, efficacy and even pharmacovigilance of biosimilars. Thus, biosimilars are unique - they are not a true chemical generic and are regulated via a distinct regulatory framework. This report discusses the features of Malaysian regulatory oversight of biosimilars and experience acquired in the evaluation of some products from various countries. Ensuring regulatory position adequately reflects scientific advancement, expertise/resources is key. The regulatory situation is an evolving process. Various guidance documents are being prepared with the aim of developing a uniform global framework towards assuring the dual goal of lower costs and patient safety while expediting the availability of important biosimilar products. PMID- 21784656 TI - Association between birthweight and cognitive function in middle age: the atherosclerosis risk in communities study. AB - PURPOSE: We aimed to examine the relationship of birthweight to cognitive performance in middle aged participants of the Atherosclerosis Risk in Communities Study (ARIC). METHODS: Cognitive function, assessed by means of three neuropsychological tests-the Delayed Word Recall Test (DWR), the Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised (DSS/WAIS-R), and the Word Fluency (WF) Test, was evaluated in relation to birthweight, as recalled through standardized interviews, by the use of data from the second and fourth follow-up visits of the Atherosclerosis Risk in Communities study cohort (1990 1992 and 1996-1998, respectively). Overall, 6785 participants satisfied the inclusion criteria and were included in the analysis. RESULTS: After adjusting for adult sociodemographic factors, childhood socioeconomic environment and parental risk factors, and adult anthropometric, health status-related. and behavioral variables, we observed linear trends for the relationship of birthweight to WF scores, although the trend was statistically significant only for those reporting exact birthweights (p for trend = .004). For the other cognitive test results, results were either null or inconsistent with the a priori hypotheses. CONCLUSIONS: Except for WF in those reporting exact birthweights, our study does not support the notion that birthweight influences cognitive function in adults. PMID- 21784658 TI - Dose-response relation between physical activity and cognitive function: guangzhou biobank cohort study. AB - PURPOSE: To examine, via cross-sectional analysis, the dose-response association between physical activity and cognitive function in Chinese subjects. METHODS: A total of 27,651 participants aged 50 to 85 years were recruited from 2003 to 2008. Information on potential confounders, including demographic and anthropometric characteristics, socioeconomic position, lifestyle, and disease history, was collected by standardized interview and procedures. Cognitive function was assessed by the delayed 10-word recall test (DWRT). RESULTS: When the International Physical Activity Questionnaire was used, we found that most of the participants were classified as physically active (53.1%), with 42.4% moderately active and 4.5% physically inactive. Significant dose-response relations across quintiles of metabolic equivalent value (METs) with DWRT score in participants with or without good self-rated health were found (all p for trend <.001). In participants with poor self-rated heath, compared with the first quintile of METs, those in the fifth quintile (highest METs) had a significantly reduced risk for mild cognitive impairment by 28% (adjusted odds ratio, 0.72; 95% confidence interval, 0.58-0.89, p < .01; p for trend = .006). After additional adjustment for depression, we found that the association between physical activity and DWRT score remained significant. CONCLUSIONS: A significant dose response relationship between physical activity and cognitive function was found, and the association was more pronounced in participants with poor self-rated health. PMID- 21784657 TI - White blood cell count, C-reactive protein, and incident heart failure in the Atherosclerosis Risk in Communities (ARIC) Study. AB - PURPOSE: To test the hypothesis that inflammation measured by white blood cell count (WBC) and C-reactive protein (CRP) is associated positively with incident heart failure (HF). METHODS: Using the Atherosclerosis Risk in Communities (ARIC) Study, we conducted separate Cox proportional hazards regression analyses for WBC (measured 1987-1989) and CRP (measured 1996-1998) in relation to subsequent heart failure occurrence. A total of 14,485 and 9,978 individuals were included in the WBC and CRP analyses, respectively. RESULTS: There were 1647 participants that developed HF during follow-up after WBC assessment and 613 developed HF after CRP assessment. After adjustment for demographic variables and traditional HF risk factors, the hazard ratio (95% confidence interval) for incident HF across quintiles of WBC was 1.0, 1.10 (0.9-1.34), 1.27 (1.05-1.53), 1.44 (1.19-1.74), and 1.62 (1.34-1.96), p trend < .001; hazard ratio across quintiles of CRP was 1.0, 1.03 (0.68-1.55), 0.99 (0.66-1.51), 1.40 (0.94-2.09), and 1.70 (1.14-2.53), p trend .002. Granulocytes appeared to drive the relation between WBCs and heart failure (hazard ratios across quintiles: 1.0, 0.93 [0.76-1.15], 1.26 [1.04-1.53], 1.67 [1.39-2.01], and 2.19 [1.83-2.61], p trend < .0001), whereas lymphocytes or monocytes were not related. CONCLUSIONS: Greater levels of WBC (especially granulocytes) and CRP are associated with increased risk of heart failure in middle-aged adults, independent of traditional risk factors. PMID- 21784659 TI - Sexual risk behaviors among African-American and Hispanic women in five counties in the Southeastern United States: 2008-2009. AB - PURPOSE: We examined sexual risk behaviors and unrecognized HIV infection among heterosexually active African-American and Hispanic women. METHODS: Women not previously diagnosed with HIV infection were recruited in rural counties in North Carolina (African American) and Alabama (African American), and an urban county in southern Florida (Hispanic) using multiple methods. They completed a computer administered questionnaire and were tested for HIV infection. RESULTS: Between October 2008 and September 2009, 1,527 women (1,013 African American and 514 Hispanic) enrolled in the study. Median age was 35 years (range, 18-59), 33% were married or living as married, 50% had an annual household income of $12,000 or less, and 56% were employed full or part time. Two women (0.13%) tested positive for HIV. In the past 12 months, 19% had been diagnosed with a sexually transmitted infection (other than HIV), 87% engaged in unprotected vaginal intercourse (UVI), and 26% engaged in unprotected anal intercourse (UAI). In multivariate analysis, UAI was significantly (p < .05) more likely among those who reported ever being pregnant, binge drinking in the past 30 days, ever exchanging sex for things needed or wanted, engaging in UVI, or being of Hispanic ethnicity. UAI was also more likely to occur with partners with whom women had a current or past relationship as opposed to casual partners. CONCLUSION: A high percentage of our sample of heterosexually active women of color had recently engaged in sexual risk behaviors, particularly UAI. More research is needed to elucidate the interpersonal dynamics that may promote this high-risk behavior. Educational messages that explicitly address the risks of heterosexual anal intercourse need to be developed for heterosexually active women and their male partners. PMID- 21784660 TI - Comparison of single versus multiple spontaneous extra- and/or intracranial arterial dissection. AB - BACKGROUND: Anecdotal data suggest that approximately 20% of patients with a spontaneous extra- and/or intracranial arterial dissection have multiple arterial involvement. Limited data exist regarding the clinical and angiographic characteristics of patients with multiple arterial dissections. We compared the clinical and angiographic features of patients with spontaneous multiple extra- and/or intracranial arterial dissections with those who have a single arterial dissection. METHODS: A retrospective chart review of the consecutive ischemic stroke database over a 7-year period, maintained at 2 institutions, was conducted to identify patients with spontaneous extra- and/or intracranial arterial dissection. The patients' clinical characteristics and angiographic features (including the artery affected, presence of pseudoaneurysm, fibromuscular dysplasia, and degree of stenosis) were analyzed. RESULTS: A total of 76 patients were admitted with spontaneous extra- and/or intracranial arterial dissection; 46 dissections were confirmed with 4-vessel cerebral angiography. Multiple arterial dissections were found in a total of 10 (22%) patients. Involvement of multiple arteries was more prevalent in the young, when compared to a single spontaneous arterial dissection (7 [70%] in patients <45 years of age v 11 [31%]; P = .03). Patients with multiple arterial dissections had a higher proportion of pseudoaneurysms (9 [90%] v 11 [31%]; P = .001), a higher prevalence of underlying fibromuscular dysplasia (3 [30%] v 3 [8%]; P = .11), and were more likely to involve the posterior circulation (P < .0001). CONCLUSIONS: The presence of multiple, simultaneous spontaneous extra- and/or intracranial arterial dissections must be considered when a single spontaneous arterial dissection is identified. PMID- 21784662 TI - Magnetic resonance imaging investigation of secondary degeneration of the mesencephalic substantia nigra after cerebral infarction. AB - Secondary degeneration of the mesencephalic substantia nigra after cerebral infarction is widely known to occur in animal experiments, but has yet to be sufficiently investigated in human cerebral infarction. This study investigated the background and features of patients exhibiting secondary degeneration of the mesencephalic substantia nigra. The subjects comprised 43 patients admitted to our hospital for cerebral infarction between April 2007 and October 2010 showing secondary degeneration of the mesencephalic substantia nigra on cranial magnetic resonance imaging (MRI). We investigated clinical disease type, location of vascular occlusion, lesion site, and time from onset of symptoms to lesion identification by MRI. The clinical disease type was cardiogenic embolism in 29 patients (67%), atheromatous embolism (artery to artery) in 8 patients (19%), embolism (origin unknown) in 2 patients (5%), infarction after coil embolization for internal carotid aneurysm in 1 patient (2%), arterial dissection in 2 patients (5%), and vasculitis due to Takayasu disease in 1 patient (2%). Magnetic resonance angiography (MRA) identified the occluded vessel as the internal carotid artery in 19 patients (44%), the middle cerebral artery (M1) in 20 patients (47%), and the middle cerebral artery (M2) in 3 patients (7%); MRA was not performed in 1 patient (2%). The cerebral infarctions were striatal in 7 patients (16%) and striatal and cortical in 36 patients (84%). Hyperintense regions in the mesencephalic substantia nigra were observed in all patients after 7-28 days (mean, 13.3 days) on diffusion-weighted imaging or fluid-attenuated inversion recovery and T2-weighted MRI. Most patients with secondary degeneration of the substantia nigra demonstrated clinical disease comprising vascular occlusion of the internal carotid artery or the neighborhood of the middle cerebral artery, which was envisaged to cause a sudden drop in brain circulation across a wide area. Striatal infarctions were observed in all patients. Secondary degeneration of the substantia nigra appeared at 1-4 weeks after onset and disappeared after several months. PMID- 21784663 TI - Angiographically visible and invisible arteriovenous malformation in the same patient. AB - A pathologically confirmed angiographically visible and invisible arteriovenous malformation in the same patient is described. The potential clinical significance of these observations is detailed and discussed. PMID- 21784661 TI - Sleep apnea treatment after stroke (SATS) trial: is it feasible? AB - Sleep apnea affects more than half of patients with acute ischemic stroke and is associated with poor stroke outcome. This pilot study assessed the feasibility of a randomized, sham-controlled continuous positive airway pressure (CPAP) trial in subjects with acute ischemic stroke. Subjects identified with sleep apnea based on an apnea-hypopnea index>=5 on overnight polysomnography or portable respiratory monitoring within 7 days of onset of stroke symptoms were randomized to receive active or sham CPAP for a 3-month period. Objective usage was ascertained by compliance data cards. Subjects, treating physicians, and outcome assessors were masked to intervention allocation. Among 87 subjects who provided consent, 74 were able to complete sleep apnea screening, 54 (73%) of whom had sleep apnea. Thirty-two subjects agreed to randomization. Of the 15 subjects who commenced active titration, 11 (73%) took the device home, and 8 (53%) completed the 3-month follow-up. Of the 17 subjects who commenced sham titration, 11 (65%) took the sham device home and completed the 3-month follow-up. The median cumulative usage hours over the 90 days were similar in the active group (53 hours; interquartile range, 22-173 hours) and the sham group (74 hours; interquartile range, 17-94 hours), and blinding to subject condition was successfully maintained. This first-ever randomized, sham-controlled trial of CPAP in patients with recent stroke and sleep apnea demonstrates that sham treatment can be an effective placebo. PMID- 21784664 TI - The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome. AB - BACKGROUND: Long-term survival after lung transplantation is hindered by the development of bronchiolitis obliterans syndrome (BOS), and recent evidence suggests that dysregulated epithelial repair may underlie its development. Because matrix metalloproteinase (MMP) -2 and MMP-9 secretion is integral to repair, we hypothesized that airway epithelial cells from patients with BOS would over-express these matrix-degrading enzymes. METHODS: Cells obtained from bronchial and bronchiolar brushings from patients with and without BOS (without acute rejection or infection) were analyzed via quantitative polymerase chain reaction and immunocytochemistry for MMP-2, and MMP-9 gene and protein expression. The expression of tissue inhibitor of metalloproteinase (TIMP)2 and TIMP1 was also assessed. MMP activity in bronchoalveolar lavage was determined via gelatin zymography. RESULTS: MMP-2 and MMP-9 production was significantly higher in bronchoalveolar lavage (3.85- and 11.59-fold, p < 0.001) and airway epithelium (MMP-2 bronchial: 6.33-fold, bronchiolar: 3.57-fold, both p < 0.001; MMP-9 bronchial: 32.55-fold, p < 0.001; bronchiolar: 8.60-fold, p = 0.01) in patients with BOS, but expression in patients without BOS was not different from healthy controls. TIMP expression was similar in patients with and without BOS. Immunostaining confirmed that the airway epithelium was a direct source of MMP-2 and MMP-9 expression in patients with BOS. CONCLUSION: In patients with BOS, the airway epithelium over-expresses MMPs, even in the absence of acute rejection or infection. Dysregulated epithelial repair may be a key feature of BOS. PMID- 21784666 TI - Concomitant endoscopic radiofrequency ablation and laparoscopic reflux operative results in more effective and efficient treatment of Barrett esophagus. AB - BACKGROUND: Barrett esophagus (BE) caused by gastroesophageal reflux disease can lead to esophageal cancer. The success of endoscopic treatments with BE eradication depends on esophageal anatomy and post-treatment acid exposure. STUDY DESIGN: Between January 2008 and December 2009, 10 patients were selected for combination treatment of BE using laparoscopic anti-reflux surgery and endoscopic radiofrequency ablation. Retrospective review of preoperative, procedural, and postoperative data was performed. RESULTS: Seven study patients had a pathologic diagnosis of nondysplastic BE and 3 patients had a diagnosis of low-grade dysplasia. Average length of BE lesions was 6.4 +/- 4.8 cm. Procedure time averaged 154.4 +/- 46.4 minutes. At the time of surgery, the mean number of ablations performed was 4.39 +/- 1.99. Six patients were noted to have major hiatal hernias requiring reduction. Five patients (80%) had 100% resolution of their BE at their first postoperative endoscopy. The remaining 3 patients had a >=50% resolution and underwent subsequent endoscopic ablation. Symptomatic results revealed that 4 patients had substantial dysphagia to solids and other symptoms were minimal. Two patients were noted to have complications related to the ablative treatments. One stricture and 1 perforation were observed. CONCLUSIONS: Endoscopic radiofrequency ablation of BE at the time of laparoscopic fundoplication is feasible and can effectively treat BE lesions. A single combined treatment can result in fewer overall procedures performed to obtain BE eradication. PMID- 21784667 TI - Logistic versus hierarchical modeling: an analysis of a statewide inpatient sample. AB - BACKGROUND: Although logistic regression is traditionally used to calculate hospital standardized mortality ratio (HSMR), it ignores the hierarchical structure of the data that can exist within a given database. Hierarchical models allow examination of the effect of data clustering on outcomes. STUDY DESIGN: Traditional logistic regression and random intercepts fixed slopes hierarchical models were fitted to a dataset of patients hospitalized between 2005 and 2007 in Massachusetts. We compared the observed to expected (O/E) in-hospital death ratios between the 2 modeling techniques, a restricted HSMR using only those diagnosis models that converged in both methods and a full hybrid HSMR using a combination of the hierarchical diagnosis models when they converge, plus the remaining diagnoses using standard logistic regression models. RESULTS: We restricted the analysis to the 36 diagnoses accounting for 80% of in-hospital deaths nationally, based on 1,043,813 admissions (59 hospitals). A failure of the hierarchical models to converge in 15 of 36 diagnosis groups hindered full HSMR comparisons. A restricted HSMR, derived from a dataset based on the 21 diagnosis groups that converged (552,933 admissions) showed very high correlation (Pearson r = 0.99). Both traditional logistic regression and hierarchical model identified 12 statistical outliers in common, 7 with high O/E values and 5 with low O/E values. In addition, the multilevel analysis identified 5 additional unique high outliers and 1 additional unique low outlier, and the conventional model identified 2 additional unique low outliers. CONCLUSIONS: Similar results were obtained from the 2 modeling techniques in terms of O/E ratios. However, because a hierarchical model is associated with convergence problems, traditional logistic regression remains our recommended procedure for computing HSMRs. PMID- 21784668 TI - Surgical treatment of chronic groin and testicular pain after laparoscopic and open preperitoneal inguinal hernia repair. AB - BACKGROUND: Standard triple neurectomy does not address inguinodynia secondary to neuropathy of the genitofemoral nerve and the preperitoneal segment of its genital branch seen after inguinal hernia repair performed laparoscopically or in open preperitoneal fashion. STUDY DESIGN: Standard triple neurectomy was extended to include the genitofemoral nerve. Sixteen patients with chronic groin pain after laparoscopic and open preperitoneal inguinal hernia repair underwent operative triple neurectomy, with resection of the main trunk of the genitofemoral nerve in the retroperitoneum over the psoas muscle. All patients had previously undergone unsuccessful extensive nonsurgical pain management. RESULTS: Fourteen of 16 patients had significant improvement of their pain, as evidenced by a decrease in subjectively reported postoperative pain levels as compared with their preoperative baseline, a decrease or complete elimination of daily narcotic dependence, and return to baseline activities of daily living and work. One of the nonresponder patients underwent a previous open prostatectomy, and exposure of the genitofemoral nerve was not possible due to scarring from the prostatectomy. The other nonresponder patient continues to experience subjective pain equivalent to preoperative levels due to the sensation of firmness and incisional pain that arose in the setting of a postoperative wound infection. He does, however, report that his pain is of different character and quality from his preneurectomy pain and is primarily centered around the incision. His follow up has not been long enough to determine if his symptoms will improve as his incision and scar remodel. CONCLUSIONS: Extension of the standard triple neurectomy to include the genitofemoral nerve for treatment of inguinodynia after open and laparoscopic preperitoneal mesh repair is a safe and effective procedure. PMID- 21784669 TI - Gray-scale contrast-enhanced ultrasonography for quantitative evaluation of the blood perfusion of the sciatic nerves with crush injury. AB - RATIONALE AND OBJECTIVES: Blood perfusion of peripheral nerves plays an important role in regeneration after nerve injury. Functional recovery after a peripheral nerve injury depends not only on the survival of the affected neurons but also on the recovered blood perfusion. Previous studies have shown that it is possible to quantitatively assess blood perfusion of tissue using contrast-enhanced ultrasound (CEUS). The aim of this study was to evaluate the usefulness of CEUS for the quantitative evaluation of blood perfusion of the sciatic nerves with crush injury. MATERIALS AND METHODS: Crush injuries were created in the left sciatic nerve of 30 New Zealand white rabbits. CEUS of the bilateral sciatic nerves was performed in six experimental rabbits at 3 days, 1 week, 2 weeks, 4 weeks, and 8 weeks after injury. Pulse-inversion harmonic imaging was used for real-time CEUS. The other six rabbits were used as a control group. Serial laser Doppler measurements of blood flow and quantitative histologic evaluation were performed parallel to CEUS on all animals. RESULTS: Quantitative analysis of CEUS showed that the perfusion index of the crushed sciatic nerves was increased at 3 days after injury, with a peak at 1 week after injury (P = .000). The area under the curve for the crushed sites was increased at 3 days after injury, with a peak at 2 weeks after injury (P = .000). The mean transit time and maximum intensity of the crushed site of the left sciatic nerves were not significantly changed during the 2 months after injury (P = .335 and P = .157 respectively). The perfusion indices measured by CEUS correlated well with those measured by laser Doppler (r = 0.791, P = .000). Marked Wallerian degeneration was found at the crushed site of sciatic nerves at 3 days after injury. The percentage of degenerated myelinated axons was increased during the first 2 weeks after injury and then decreased during the following period. Regenerated axons with small diameter and thin myelin sheaths were found at 2 weeks after injury and during the following period. CONCLUSIONS: CEUS may provide a new imaging method to quantitatively analyze blood perfusion of injured peripheral nerves. PMID- 21784670 TI - Parkinson's disease: interhemispheric textural differences in MR images. AB - RATIONALE AND OBJECTIVES: Early-stage diagnosis of Parkinson's disease (PD) is essential in making decisions related to treatment and prognosis. However, there is no specific diagnostic test for the diagnosis of PD. The aim of this study was to evaluate the role of texture analysis (TA) of magnetic resonance images in detecting subtle changes between the hemispheres in various brain structures in patients with early symptoms of parkinsonism. In addition, functional TA parameters for detecting textural changes are presented. MATERIALS AND METHODS: Fifty-one patients with symptoms of PD and 20 healthy controls were imaged using a 3-T magnetic resonance device. Co-occurrence matrix-based TA was applied to detect changes in textures between the hemispheres in the following clinically interesting areas: dentate nucleus, basilar pons, substantia nigra, globus pallidus, thalamus, putamen, caudate nucleus, corona radiata, and centrum semiovale. The TA results were statistically evaluated using the Mann-Whitney U test. RESULTS: The results showed interhemispheric textural differences among the patients, especially in the area of basilar pons and midbrain. Concentrating on this clinically interesting area, the four most discriminant parameters were defined: co-occurrence matrix correlation, contrast, difference variance, and sum variance. With these parameters, differences were also detected in the dentate nucleus, globus pallidus, and corona radiata. CONCLUSIONS: On the basis of this study, interhemispheric differences in the magnetic resonance images of patients with PD can be identified by the means of co-occurrence matrix-based TA. The detected areas correlate with the current pathophysiologic and neuroanatomic knowledge of PD. PMID- 21784671 TI - Association of single nucleotide polymorphisms in promoter of matrix metalloproteinase-2, 8 genes with bladder cancer risk in Northern India. AB - OBJECTIVE: Matrix metalloproteinases (MMPs) are expressed in melanocytes and their overexpression has been linked to tumor development, progression, and metastasis. At the genetic level, following functional promoter polymorphisms are known to modify the gene transcription: -1306 C > T, -735 C > T in MMP2, and 799 C > T in MMP8 gene. Hence we hypothesize that functional polymorphisms in the 2 MMP SNPs in promoter region may modulate the risk for bladder cancer (BC) progression in North Indian population. MATERIALS AND METHODS: Genotyping for these polymorphisms were done in a group of 200 BC and 200 age matched, similar ethnicity unrelated healthy controls using PCR-based methods. Two-sided chi(2), Cox-regression was utilized to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known BC confounders such as age and gender. Survival analysis was done using the Kaplan-Meier method and differences in survival were assessed using the log rank test. RESULTS: Individuals with MMP2 (-1306) TT genotype as well as T allele were at higher risk of BC (P, 0.042; OR, 2.85; P, 0.001; OR, 1.76). This effect was even more apparent in case of CT+TT (P < 0.001; OR, 2.61). In MMP2 (735), CT+TT demonstrated significant risk (P, 0.034; OR, 1.66). In MMP8 (799), reduced risk was observed with TT genotype (P, 0.006; OR, 0.27). Haplotype analysis showed that individuals with haplotype 735C-1306T and 735T-1306C were at 1.9- and 1.5-fold higher risk. MMP2 -1306CC in combination with MMP8 799CT genotype showed protective effect. The genotype CT and CT+TT of MMP2 1306C > T were associated with high risk of recurrence in BCG treated patients (HR, 4.32; P, 0.006 and HR, 2.06; P, 0.047) thus showing reduced recurrence free survival (CT+TT/CC = 34/45 months; log rank P, 0.039). CONCLUSION: Our data suggested that variant allele of MMP2 1306C > T was associated with high risk of tumor recurrence and reduced recurrence free survival in superficial BC patients. PMID- 21784673 TI - The risk of bladder cancer in patients diagnosed with other primary neoplasms: analysis of the SEER database. AB - OBJECTIVE: We evaluated patients with history of previous malignancy to determine risk of an ensuing bladder cancer. MATERIALS AND METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results 9 registry database from 1973 to 1999 (SEER) was reviewed for patients with initial primary cancers in oral cavity and pharynx, colon and rectum, respiratory system, breast, prostate, testis, or penis. This group of patients was then examined to identify subsequent separate primary malignancies in the bladder. Comparison was made to the incidence of bladder cancer in the general population to determine a standardized incidence ratio (SIR). Additional analysis was performed based on age at diagnosis, stage, gender, race, and use of external beam radiation for treatment of initial cancer. RESULTS: A total of 7,289 (0.5%) of patients had a bladder cancer following their initial malignancy. Patients with prostate cancer had the largest increase in risk of bladder cancer with a SIR of 8.24, and all initial cancer groups had an elevated risk of bladder cancer relative to the general population. External beam radiation and non-White gender were associated with an increased risk of bladder cancer. Older age at diagnosis of the initial cancer correlated with a lower risk of subsequent bladder cancer. CONCLUSIONS: This study suggests an increased risk of bladder cancer following a separate initial cancer. Lower threshold for working up those patients for bladder cancer may be warranted. PMID- 21784672 TI - Eastern Cooperative Oncology Group Phase II Trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer. AB - PURPOSE: Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer. PATIENTS AND METHODS: Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT) <12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status. RESULTS: Forty-nine patients were enrolled (14 ineligible), resulting in 35 patients for analysis. No PSA response was observed; best response was stable disease (n = 28, 80.0%). Pretreatment average slope was 0.19 log (PSA)/month (PSADT = 3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT = 5.44 months) using linear mixed effects models (P = 0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (P = 0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (P = 0.09). CONCLUSION: Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated. PMID- 21784674 TI - Composite bone graft for treatment of osseous defects after surgical removal of impacted third and second molars: case report and review of the literature. AB - The aim of this case report was to evaluate the clinical and radiographic measurements of mandibular first molar bone support after mandibular third and second molar extraction and immediate augmentation of the extraction site with a combined autogenous bone graft with Bio-Oss materials. A pyramidal full-thickness mucoperiosteal flap with 1 distal releasing incision was used for removal of impacted third and second molars. During the procedure, autogenous bone graft was collected with a bone trap and then combined with Bio-Oss materials. The osseous defects distal to first molar and extraction site was filled with the composite bone graft and covered with Bio-Gide membrane. After 1 year, there was a successful defect regression and gain of bone and clinical attachment level. Moreover, there was a reduction of probing pocket depth and gingival inflammation. From the results of this study, it can be concluded that grafting of osseous defects and extraction site with autogenous bone graft combined with Bio-Oss materials will predictably result in a decreased risk of developing a periodontal defect on the distal aspect of mandibular first molar. PMID- 21784675 TI - Silver solder "tattoo," a novel form of oral pigmentation identified with the use of field emission scanning electron microscopy and electron dispersive spectrography. AB - OBJECTIVE: The aim of this study was to investigate the use of field emission scanning electron microscopy and electron dispersive spectrography (SEM-EDS) to identify silver solder "tattoo." STUDY DESIGN: SEM-EDS was used to analyze material present in the connective tissue of a patient who presented with bilateral pigmentation of the mandibular lingual gingiva adjacent to the first molars. No dental restorations were present. RESULTS: SEM-EDS analysis identified silver, with no evidence of tin, copper, or mercury. The patient was wearing an orthodontic appliance where brackets had been soldered to the archwire with silver solder. It is hypothesed that the solder underwent electrolytic corrosion with subsequent regrouping of silver ions in the submucosa leading to blue-gray discoloration. CONCLUSION: Spectrography proved to be a powerful diagnostic tool in identifying the metal within the oral mucosa. Attention is drawn to this newly described lesion, which should be included as a differential diagnosis for pigmented oral mucosal lesions. PMID- 21784676 TI - Normal sleep patterns in infants and children: a systematic review of observational studies. AB - This is a systematic review of the scientific literature with regard to normal sleep patterns in infants and children (0-12 years). The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Mean and variability data for sleep duration, number of night wakings, sleep latency, longest sleep period overnight, and number of daytime naps were extracted from questionnaire or diary data from 34 eligible studies. Meta-analysis was conducted within age-bands and categories. In addition, fractional polynomial regression models were used to estimate best-fit equations for the sleep variables in relation to age. Reference values (means) and ranges (+/-1.96 SD) for sleep duration (hours) were: infant, 12.8 (9.7-15.9); toddler/preschool, 11.9 (9.9-13.8); and child, 9.2 (7.6-10.8). The best-fit (R(2)=0.89) equation for hours over the 0-12 year age range was 10.49 5.56*[(age/10)^0.5-0.71]. Meta-regression showed predominantly Asian countries had significantly shorter sleep (1h less over the 0-12 year range) compared to studies from Caucasian/non-Asian countries. Night waking data provided 4 age bands up to 2 years ranging from 0 to 3.4 wakes per night for infants (0-2 months), to 0-2.5 per night (1-2 year-olds). Sleep latency data were sparse but estimated to be stable across 0-6 years. Because the main data analysis combined data from different countries and cultures, the reference values should be considered as global norms. PMID- 21784677 TI - Fatigue-proofing: a new approach to reducing fatigue-related risk using the principles of error management. AB - In this review we introduce the idea of a novel group of strategies for further reducing fatigue-related risk in the workplace. In contrast to the risk-reduction achieved by reducing the likelihood an individual will be working while fatigued (e.g., by restricting hours of work), fatigue-proofing strategies are adaptive and protective risk-reduction behaviours that improve the resilience of a system of work. That is, they increase the likelihood that a fatigue-related error will be detected and not translate into accident or injury, thus reducing vulnerability to fatigue-related error. The first part of the review outlines the theoretical underpinnings of this approach and gives a series of ethnographically derived examples of informal fatigue-proofing strategies used in a variety of industries. A preliminary conceptual and methodological framework for the systematic identification, development and evaluation of fatigue-proofing strategies is then presented for integration into the wider organisational safety system. The review clearly identifies fatigue-proofing as a potentially valuable strategy to significantly lower fatigue-related risk independent of changes to working hours. This is of particular relevance to organisations where fatigue is difficult to manage using reductions in working hours due to operational circumstances, or the paradoxical consequences for overall safety associated with reduced working hours. PMID- 21784679 TI - Long-term facial artery catheter implantation for serial arterial blood sampling and invasive arterial blood pressure measurement in horses. AB - The purpose of this investigation was to evaluate surgical catheter implantation in the facial artery of horses and the long-term maintenance of such arteries using heparin and ascorbic acid as filling solution. Nine horses were implanted with a polyurethane catheter. The catheters were flushed with a heparin/ascorbic acid solution every 8h and remained patent for 25 days. Arterial blood samples were collected twice a day, and one exercise test that included serial blood samples and arterial pressure recordings was performed on a treadmill. Polyurethane catheters surgically implanted in the facial artery can be kept patent by filling with a heparin/ascorbic acid solution and provide convenient invasive arterial access in horses which is suitable for use for serial blood sampling and blood pressure recordings, even during exercise on treadmill. PMID- 21784678 TI - Longitudinal associations between sleep duration and subsequent weight gain: a systematic review. AB - OBJECTIVE: To systematically examine the relationship between sleep duration and subsequent weight gain in observational longitudinal human studies. METHODS: Systematic review of twenty longitudinal studies published from 2004-October 31, 2010. RESULTS: While adult studies (n = 13) reported inconsistent results on the relationship between sleep duration and subsequent weight gain, studies with children (n = 7) more consistently reported a positive relationship between short sleep duration and weight gain. CONCLUSION: While shorter sleep duration consistently predicts subsequent weight gain in children, the relationship is not clear in adults. We discuss possible limitations of the current studies: 1) the diminishing association between short sleep duration on weight gain over time after transition to short sleep, 2) lack of inclusion of appropriate confounding, mediating, and moderating variables (i.e., sleep complaints and sedentary behavior), and 3) measurement issues. PMID- 21784680 TI - Management of chronic pain among older patients: inside primary care in the US. AB - Under-treatment of pain is a worldwide problem. We examine how often pain was addressed and the factors that influence how much time was spent on treating pain. We analyzed 385 videotapes of routine office visits in several primary care practices in the Southwest and Midwest regions of the United States. We coded the visit contents and the time spent on pain and other topics. Logistic regression and survival analyses examined the effects of time constraint, physician's supportiveness, patient's health, and demographic concordance. We found that discussion of pain occurred in 48% of visits. A median of 2.3 min was spent on addressing pain. The level of pain, physician's supportiveness, and gender concordance were significantly associated with the odds of having a pain discussion. Time constraints and racial concordance significantly influenced the length of discussion. We conclude that despite repeated calls for addressing under-treatment for pain, only a limited amount of time is used to address pain among elderly patients. This phenomenon could contribute to the under-treatment of pain. PMID- 21784681 TI - Avoiding eddy-current problems in ultra-low-field MRI with self-shielded polarizing coils. AB - In ultra-low-field magnetic resonance imaging (ULF MRI), superconductive sensors are used to detect MRI signals typically in fields on the order of 10-100 MUT. Despite the highly sensitive detectors, it is necessary to prepolarize the sample in a stronger magnetic field on the order of 10-100 mT, which has to be switched off rapidly in a few milliseconds before signal acquisition. In addition, external magnetic interference is commonly reduced by situating the ULF-MRI system inside a magnetically shielded room (MSR). With typical dipolar polarizing coil designs, the stray field induces strong eddy currents in the conductive layers of the MSR. These eddy currents cause significant secondary magnetic fields that may distort the spin dynamics of the sample, exceed the dynamic range of the sensors, and prevent simultaneous magnetoencephalography and MRI acquisitions. In this paper, we describe a method to design self-shielded polarizing coils for ULF MRI. The experimental results show that with a simple self-shielded polarizing coil, the magnetic fields caused by the eddy currents are largely reduced. With the presented shielding technique, ULF-MRI devices can utilize stronger and spatially broader polarizing fields than achievable with unshielded polarizing coils. PMID- 21784682 TI - Repetitive cross-polarization contacts via equilibration-re-equilibration of the proton bath: Sensitivity enhancement for NMR of membrane proteins reconstituted in magnetically aligned bicelles. AB - Thermodynamic limit of magnetization corresponding to the intact proton bath usually cannot be transferred in a single cross-polarization contact. This is mainly due to the finite ratio between the number densities of the high- and low gamma nuclei, quantum-mechanical bounds on spin dynamics, and Hartmann-Hahn mismatches due to rf field inhomogeneity. Moreover, for fully hydrated membrane proteins refolded in magnetically oriented bicelles, short spin-lock relaxation times (T1rho) and rf heating can further decrease cross polarization efficiency. Here we show that multiple equilibrations-re-equilibrations of the high- and low spin reservoirs during the preparation period yield an over twofold gain in the magnetization transfer as compared to a single-contact cross polarization (CP), and up to 45% enhancement as compared to the mismatch-optimized CP-MOIST scheme for bicelle-reconstituted membrane proteins. This enhancement is achieved by employing the differences between the spin-lattice relaxation times for the high- and low-gamma spins. The new technique is applicable to systems with short T1rho's, and speeds up acquisition of the multidimensional solid-state NMR spectra of oriented membrane proteins for their subsequent structural and dynamic studies. PMID- 21784684 TI - Treatment and outcome of four cats with apocrine gland carcinoma of the anal sac and review of the literature. AB - Anal sac adenocarcinoma is uncommon in cats. We report the outcome of multi modality therapy in two cats (surgery, definitive radiotherapy and systemic chemotherapy) and surgery alone in two cats. All received surgical excision of the primary tumour followed by radiotherapy and carboplatin chemotherapy in two cases. Both cats that underwent multimodal therapy developed distant metastatic disease and one developed recurrence of the primary tumour. One cat that underwent surgery alone with incomplete margins also developed rapid recurrence. Overall survival times were 89, 161 and 169 days. One cat that had complete surgical excision is still alive without recurrence 425 days postoperatively. Whilst the role of radiation in the local control of this disease is yet to be defined, clearly a more effective systemic therapy is required before such aggressive local treatment can be routinely recommended. PMID- 21784683 TI - Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. AB - Late infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in the gene encoding tripeptidyl-peptidase 1 (TPP1). LINCL patients accumulate lysosomal storage materials in the CNS accompanied by neurodegeneration, blindness, and functional decline. Dachshunds homozygous for a null mutation in the TPP1 gene recapitulate many symptoms of the human disease. The objectives of this study were to determine whether intrathecal (IT) TPP1 treatment attenuates storage accumulation and functional decline in TPP1-/- Dachshunds and to characterize the CNS distribution of TPP1 activity. TPP1 was administered to one TPP1-/- and one homozygous wild-type (WT) dog. An additional TPP1-/- and WT dog received vehicle. Four IT administrations of 32 mg TPP1 formulated in 2.3 mL of artificial cerebrospinal fluid (aCSF) or vehicle were administered monthly via the cerebellomedullary cistern from four to seven months of age. Functional decline was assessed by physical and neurological examinations, electrophysiology, and T-maze performance. Neural tissues were collected 48 h after the fourth administration and analyzed for TPP1 activity and autofluorescent storage material. TPP1 was distributed at greater than WT levels in many areas of the CNS of the TPP1-/- dog administered TPP1. The amount of autofluorescent storage was decreased in this dog relative to the vehicle-treated affected control. No improvement in overall function was observed in this dog compared to the vehicle-treated TPP1-/- littermate control. These results demonstrate for the first time in a large animal model of LINCL widespread delivery of biochemically active TPP1 to the brain after IT administration along with a decrease in lysosomal storage material. Further studies with this model will be necessary to optimize the dosing route and regimen to attenuate functional decline. PMID- 21784685 TI - QA of dynamic MLC based on EPID portal dosimetry. AB - PURPOSE: Dynamic delivery of intensity modulated beams (dIMRT) requires not only accurate verification of leaf positioning but also a control on the speed of motion. The latter is a parameter that has a major impact on the dose delivered to the patient. Time consumed in quality assurance (QA) procedures is an issue of relevance in any radiotherapy department. Electronic portal imaging dosimetry (EPID) can be very efficient for routine tests. The purpose of this work is to investigate the ability of our EPID for detecting small errors in leaf positioning, and to present our daily QA procedures for dIMRT based on EPID. METHODS AND MATERIALS: A Varian 2100 CD Clinac equipped with an 80 leaf Millennium MLC and with amorphous silicon based EPID (aS500, Varian) is used. The daily QA program consists in performing: Stability check of the EPID signal, Garden fence test, Sweeping slit test, and Leaf speed test. RESULTS AND DISCUSSION: The EPID system exhibits good long term reproducibility. The mean portal dose at the centre of a 10 * 10 cm(2) static field was 1.002 +/- 0.004 (range 1.013-0.995) for the period evaluated of 47 weeks. Garden fence test shows that leaf position errors of up to 0.2 mm can be detected. With the Sweeping slit test we are able to detect small deviations on the gap width and errors of individual leaves of 0.5 and 0.2 mm. With the Leaf speed test problems due to motor fatigue or friction between leaves can be detected. CONCLUSIONS: This set of tests takes no longer than 5 min in the linac treatment room. With EPID dosimetry, a consistent daily QA program can be applied, giving complete information about positioning/speed MLC. PMID- 21784686 TI - Five-year experience of quality control for a 3D LSO-based whole-body PET scanner: results and considerations. AB - PET scanners require routine monitoring and quality control (QC) to ensure proper scanner performance. QC helps to ensure that PET equipment performs as specified by the manufacturer and that there have not been significant changes in the system response since acceptance. In this work we describe the maintenance history and we report on the results obtained from the PET system QC testing program over 5 years at two centers, both utilizing a Siemens Biograph 16 HiRez PET/CT system. QC testing programs were based on international standards and included the manufacturer's daily QC, monthly uniformity and sensitivity, quarterly cross-calibration and annual resolution and image quality. For the Winnipeg and Novara sites, two and one PET detector blocks have been replaced, respectively. Neither system has had other significant PET system related hardware replacements. The manufacturer's suggested daily QC was sensitive to detecting problems in the function of PET detector elements. The same test was not sensitive for detecting long term drifts in the systems: the Novara system observed a significant deterioration over five years of testing in the sensitivity which exhibited a decrease of 16% as compared to its initial value measured at system installation. The measure of the energy spectrum, showed that the 511 keV photopeak had shifted to a position of 468 keV. This shift was corrected by having service personnel perform a complete system calibration and detector block setup. We recommend including tests of system energy response and of sensitivity as part of a QC program since they can provide useful information on the actual performance of the scanner. A modification of the daily QC test by the manufacturer is suggested to monitor the long term stability of the system. Image quality and spatial resolution tests have proven to be of limited value for monitoring the system over time. PMID- 21784687 TI - Antiviral drug-associated potential vaccine-escape hepatitis B virus mutants in Turkish patients with chronic hepatitis B. AB - BACKGROUND: The hepatitis B virus (HBV) polymerase (pol) gene completely overlaps with the envelope (S) gene. Mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in the overlapping hepatitis B surface antigen (HBsAg). Recent studies have conferred a new acronym to these HBV pol/S gene overlap mutants: ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The present study aimed to assess the prevalence and pattern of ADAPVEMs in Turkish patients with chronic hepatitis B (CHB). METHODS: The investigation was conducted between March 2007 and July 2010 and involved a total of 442 patients. These patients were in the following phases of HBV infection: immune tolerant (n=50), immune reactive (n=37), inactive carrier (n=90), HBeAg-negative CHB (n=217), and HBsAg-negative (n=12), or were hemodialysis patients (n=36). One hundred eighty-six patients were receiving nucleos(t)ide analogue (NUC) therapy and 256 patients had treatment-naive CHB. RESULTS: Seven types of ADAPVEM were detected in the total CHB patients: rtM204V/sI195M, rtM204I/sW196S, rtM204I/sW196L, rtV173L/sE164D, rtA181T/sW172*, rtA181T/sW172L, and rtA181V/sL173F. The ADAPVEMs were associated with lamivudine, telbivudine, and adefovir. The prevalence of ADAPVEMs in all CHB patients was found to be 10% (46/442). The difference in the prevalence of ADAPVEMs across the different CHB clinical phases was not significant (Pearson Chi-square, p=0.112). The prevalence of ADAPVEMs was 24% (44/186) in those undergoing NUC therapy and 0.7% (2/256) in the treatment-naive group; this difference was significant (Pearson Chi-square, p=0.00). CONCLUSIONS: We determined the prevalence and pattern of ADAPVEMs in Turkish patients in the different phases of CHB. Preferred drugs in Turkey, such as lamivudine, have the potential to cause the emergence of ADAPVEMs, with the possibility that these will spread to both individuals immunized with the hepatitis B vaccine and nonimmunized individuals. ADAPVEMs should be monitored in infected and treated patients and their public health risks assessed. PMID- 21784688 TI - Nanocrystalline CoSn2-carbon composite electrode prepared by using sonochemistry. AB - A sonochemical method has been used to prepare negative electrode materials containing intermetallic nanoparticles and polyacrylonitrile (PAN). The ultrasound irradiation is applied to achieve small particle size. After annealing at 490 degrees C under Ar-flow, the polymer PAN is partially carbonized and the metallic nanoparticles are surrounded by a carbonaceous matrix. The main metallic phase is CoSn(2). The carbonaceous coating and the surface oxides have been explored by using XPS. The resulting CoSn(2)-carbonaceous phase electrode (CoSn(2)@C) shows improved electrochemical behavior (ca. 450 mAh/g after 50 cycles) in comparison with previous reports on pure crystalline CoSn(2). The reaction between CoSn(2)@C and Li has been studied by using XRD and (119)Sn Mossbauer spectroscopy. The formation of large grains of crystalline Li(x)Sn phases after the first discharge is discarded. The small particle size which is achieved by using ultrasonication and the carbonaceous matrix contribute to maintain the Co-Sn interactions during the electrochemical cycling. The aggregation of the nanosized metallic particles upon electrochemical cycling can be suppressed by the carbonaceous matrix (pyrolytic PAN). PMID- 21784689 TI - Continuous and pulsed ultrasound-assisted extractions of antioxidants from pomegranate peel. AB - There is a great demand for developing efficient extraction methods in order to reduce extraction time and increase the yield and activity of functional antioxidants. The yields, activities, and extraction kinetics of antioxidants from the dry peel of pomegranate marc were studied using ultrasound-assisted extraction in continuous and pulsed modes and the results were compared with conventional extraction (CE) at a temperature of 25+/-2 degrees C and water/peel ratio of 50/1, w/w. The studied factors were intensity level and treatment time for continuous ultrasound-assisted extraction (CUAE), and intensity level, number of pulse repetition, and pulse duration and interval for pulsed ultrasound assisted extraction (PUAE). The results showed that all factors significantly affected the antioxidant yield, but only treatment time had a significant effect on the antioxidant activity. Compared to CE, PUAE at an intensity level of 59.2 W/cm(2), and a pulse duration of 5s and a resting interval of 5s increased the antioxidant yield by 22% and reduced the extraction time by 87%. Similarly, CUAE at the same intensity level increased the antioxidant yield by 24% and reduced the extraction time by 90%. Since PUAE had 50% energy saving compared to CUAE, we recommend using PUAE for the extraction with antioxidant yield of 14.5% and DPPH scavenging activity of 5.8 g/g. A second-order kinetic model was successfully developed for describing the mechanism of ultrasound-assisted extractions under PUAE and CUAE. This research clearly demonstrated the superiority of PUAE for producing antioxidants from peel of pomegranate marc. PMID- 21784690 TI - Ultrasound-enhanced extraction of lignin from bamboo (Neosinocalamus affinis): characterization of the ethanol-soluble fractions. AB - Bamboo was submitted to ultrasound-assisted extraction in aqueous ethanol to evaluate the effect of ultrasonic irradiation on the dissolution of lignin. In this case, the dewaxed bamboo culms were subjected to ball milling for 48 h, and then were suspended in 95% ethanol followed by ultrasonic irradiations for varied times at 20 degrees C to obtain ethanol-soluble fractions. The structural and thermal properties of the ethanol-soluble fractions were comparatively investigated by chemical analysis including alkaline nitrobenzene oxidation, bound carbohydrate determination, FT-IR spectra, HSQC spectra, TG, and DTA. The results showed that the yields of the ethanol-soluble fractions were between 4.29% and 4.76% for the fractions prepared with ultrasonic irradiation time ranging from 5 to 55 min, as compared to 4.02% for the fraction prepared without ultrasonic irradiation. It was found that the lignin content of the fraction increased with the increase of the ultrasonic irradiation time. There was a slight increase of the molecular weight of the lignin with the increase of the ultrasonic irradiation time. Alkaline nitrobenzene oxidation coupled with HSQC analysis indicated that the lignin in the fractions was mainly composed of GSH type units as well as minor amounts of ferulic acids. In addition, the fraction prepared with ultrasonic irradiation exhibited a slightly higher thermal stability as compared to the fraction prepared without ultrasonic irradiation. PMID- 21784691 TI - Bioreactor cultivation and remodelling simulation for cartilage replacement material. AB - For the development of articular cartilage replacement material, it is essential to study the dependence between mechanical stimulation and cell activity in cellular specimens. Bioreactor cultivation is widely used for this purpose, however, it is hardly possible to obtain a quantitative relationship between collagen type II production and applied loading history. For this reason, a bioreactor system is developed, measuring applied forces and number of loading cycles by means of a load cell and a forked light barrier, respectively. Parallel to the experimental study, a numerical model by means of the finite element method is proposed to simulate the evolution of material properties during cyclic stimulation. In this way, a numerical model can be developed for arbitrary deformation cases. PMID- 21784692 TI - Correlation between the Movement Disorders Society Unified Parkinson's Disease rating scale (MDS-UPDRS) and the Unified Parkinson's Disease rating scale (UPDRS) during L-dopa acute challenge. AB - While Movement Disorders Society Unified Parkinson's Disease rating scale (MDS UPDRS) validation has been exhaustive; performance evaluation to detect acute changes arising after administration of a single dose of L-dopa has yet to be explored. To determine the correlation between UPDRS and MDS-UPDRS during the acute challenge with Ldopa and the MDS-UPDRS equivalent to 30% cutoff score of UPDRS for defining responsiveness, 64 patients were assessed. Consecutive assessments were performed immediately before and after administration of a single dose of L-dopa/carbidopa 250/25 mg using the motor section of the UPDRS and the MDS-UPDRS. Good diagnostic accuracy, consistent with published findings of high correlation between scales was observed. Area under the curve (AUC) was 0.99 (CI = 0.97-1.00, P < 0.001) and maximum Youden index (Y = 0.905) corresponded to a cutoff of 24.5%. In conclusion we have found an excellent correlation between UPDRS and MDS-UPDRS and that the 30% of variation in UPDRS score used for predicting sustained long term L-dopa response was equivalent to 24% in MDS-UPDRS. PMID- 21784694 TI - Social capital, health and life satisfaction in 50 countries. AB - We explored links between social capital and self-rated health and life satisfaction in a diverse sample of rich and developing countries. A four-factor measure of social capital was developed using data on 69,725 adults in 50 countries that were collected in the World Values Survey. Multilevel analyses showed links between country social capital and health and life satisfaction. However, cross-level interactions indicated that the benefits of social capital were greater in women than men, in older adults and in more trusting, affiliated individuals. Social inequalities in the contributions of social capital to population health are worthy of further study. PMID- 21784693 TI - A multilevel analysis of the association between social networks and support on leisure time physical activity: evidence from 40 disadvantaged areas in London. AB - There has been extensive conceptual and empirical work on the associations between social relations and health in recent years. However, the specific pathways through which social interactions impact on health have not been fully elucidated. The aim of this paper is to estimate associations between Leisure Time Physical Activity (LTPA) and social networks and support. Using data from a cross-sectional household survey in 40 disadvantaged lower super-output areas in London, we applied a multilevel model to investigate psychosocial and environmental determinants of physical activity in these populations. Our findings present a strong case for the influence of individual-level social networks on the level of LTPA, although the associations between the types of social support and LTPA were insignificant. We also found that crime rate was an important area-level correlates of LTPA. PMID- 21784695 TI - The RCT means nothing to me! AB - Research is a cornerstone of evidence based practice with the randomised controlled trial (RCT) regarded as the 'gold standard' for evaluating the effectiveness of interventions. However, it is not uncommon for RCT's to arrive at conflicting conclusions. This conflict might be explained by the quality of the different studies and their inherent risk of bias. Despite this, discussion and debate around methodological issues is limited in physiotherapy specific journals. It is important that clinicians are aware of the inherent risk of bias within studies and what this means for their practice. Hence, this paper presents a clinically focused methodological discussion with the intention of offering a platform upon which readers can develop their understanding of meaningful critical appraisal and hence gain confidence when reading and appraising published RCT's. PMID- 21784696 TI - Do inertial sensors represent a viable method to reliably measure cervical spine range of motion? AB - A rise in neck pain cases has initiated an exponential interest in the assessment and treatment of cervical spine range of motion (CROM). Experimental limitations, however, have been reported as therapists strive to collect continuous, dynamic data to aid prognosis. This technical report seeks to explore the viability of using inertial sensors to reliably assess CROM. In recognition of the need for secure skin-sensor attachment, four combinations of sensor pairings were established and investigated based upon four clinically identifiable surface landmarks. Twelve participants were recruited and asked to perform three specific movement cycles in each plane (i.e. flexion-extension; rotation; lateral bending). The reliability of the peak CROM, and the movement pattern, recorded in each of the three movement cycles was statistically analysed using the intra class correlation coefficient (ICC) and coefficient of multiple correlations (CMC). It was determined that the most reliable positions of the orientation sensors, with one adhered to the forehead and the other representing T4, enables data to be recorded with a reliability that is comparable to other CROM measuring techniques. Subsequently, it is concluded that inertial sensors represent a viable method to assess CROM. PMID- 21784697 TI - Xerostomia in children and adolescents after stem cell transplantation conditioned with total body irradiation or busulfan. AB - To study salivary secretion rates and symptoms of xerostomia in children and adolescents conditioned with either radiation therapy or with chemotherapy only in the setting of hematopoietic stem cell transplantation (HSCT). Thirty patients conditioned with 10 Gy single dose TBI (sTBI) and cyclophosphamide (Cy) 60 mg/kg for two days and 35 conditioned busulfan (Bu) and Cy as part of the preparative regimen were included in the study. All patients were treated before 13 years of age, and had survived 2-16 years after HSCT. All patients were interviewed according to a standard questionnaire on symptoms of xerostomia and the unstimulated and stimulated whole salivary secretion rate was determined. The stimulated salivary secretion rates were 0.8+/-0.5 ml/min in sTBI/Cy group compared to 1.1+/-0.6 ml/min in the Bu/Cy group (p=0.01). Dysfunction of either unstimulated or stimulated salivary secretion rates were found in 18/30 (60%) in sTBI/Cy group and 9/35 (26%) in Bu/Cy group (p<0.01). There were no differences regarding the number of xerostomia related symptoms in children conditioned with either sTBI/Cy or Bu/Cy. Both unstimulated and stimulated salivary secretion rates were inversely correlated to the total number of complaints of xerostomia. This study shows that children exhibit xerostomia after HSCT irrespective of conditioning with busulfan or sTBI. It is of importance that salivary function is evaluated and that both salivary function as well as the subjective feeling of mouth dryness is evaluated. PMID- 21784698 TI - Molecular mechanism of Aspergillus fumigatus adherence to host constituents. AB - Inhaled conidia of Aspergillus fumigatus rapidly adhere to pulmonary epithelial cells and other host constituents. Identifying molecular mechanisms underlying A. fumigatus adherence has therefore been the focus of a number of studies aimed at identifying novel therapeutic targets. Early studies of A. fumigatus adherence to host constituents focused on fungal proteins, including RodA and AspF2. None of these proteins however has been found to play a role in virulence in experimental animal models. Recent advances have suggested an important role for fungal carbohydrate components of the cell wall and extracellular matrix in adherence, including sialic acid and mannose residues, and the newly described polysaccharide galactosaminogalactan. Despite these advances, the host cell receptors that are bound by these ligands remain unknown. PMID- 21784699 TI - Determination of DNA based on localized surface plasmon resonance light scattering using unmodified gold bipyramids. AB - The DNA was determined based on resonance light scattering (RLS) spectrometry and the localized surface plasmon resonance. The gold bipyramids were used as the probes and synthesized by a seed-mediated method. Cetyltrimethylammonium bromide was used as stabilizing agent. DNA can be bound to the gold bipyramids due to electrostatic interaction and aggregates, which results in a strong enhancement of the RLS intensity. Under the optimal conditions, the intensity of RLS is directly proportional to the concentration of DNA in the range from 0.1 to 2.0 MUg mL(-1). PMID- 21784700 TI - Vibrational spectroscopic studies and Natural Bond Orbital analysis of 4,6 dichloro-2-(methylthio)pyrimidine based on density functional theory. AB - The FT-IR and FT-Raman spectra of 4,6-dichloro-2-(methylthio)pyrimidine (DMP) have been recorded and analyzed. The optimized geometry, intramolecular hydrogen bonding, and harmonic vibrational wave numbers of DMP have been investigated with the help of B3LYP density functional theory (DFT) method supplemented with 6 31G** basis set. The infrared and Raman spectra were predicted theoretically from the calculated intensities. Natural Bond Orbital (NBO) analysis of DMP has been performed to indicate the presence of intramolecular C-H?Cl hydrogen bonding. The formation of Lewis and non-Lewis orbitals and second-order perturbation energies of DMP have also been reported. PMID- 21784701 TI - National questionnaire study on clinical ICT systems proofs: physicians suffer from poor usability. AB - OBJECTIVE: In the health informatics field, usability studies typically focus on evaluating a single information system and involve a rather small group of end users. However, little is known about the usability of clinical information and communication technology (ICT) environment in which healthcare professionals work daily. This paper aims at contributing to usability research and user-oriented development of healthcare technologies with three objectives: inform researchers and practitioners about the current state of usability of clinical ICT systems, increase the understanding of usability aspects specific for clinical context, and encourage a more holistic approach on studying usability issues in health informatics field. METHODS: A national web questionnaire study was conducted in Finland in spring 2010 with 3929 physicians actively working in patient care. For the purposes of the study, we described three dimensions of clinical ICT system usability that reflect the physicians' viewpoint on system usage: (1) compatibility between clinical ICT systems and physicians' tasks, (2) ICT support for information exchange, communication and collaboration in clinical work, and (3) interoperability and reliability. The dimensions derive from the definitions of usability and clinical context of use analysis, and reflect the ability of ICT systems to have a positive impact on patient care by supporting physicians in achieving their goals with a pleasant user experience. The research data incorporated 32 statements with a five-point Likert-scale on physicians' experiences on usability of their currently used ICT systems and a summative question about school grade given to electronic health record (EHR) systems. RESULTS: Physicians' estimates of their EHR systems were very critical. With the rating scale from 4 or fail to 10 or excellent, the average of the grades varied from 6.1 to 8.4 dependent on the kind of facility the physician is working. Questionnaire results indicated several usability problems and deficiencies which considerably hindered the efficiency of clinical ICT use and physician's routine work. Systems lacked the appropriate features to support typical clinical tasks, such as decision making, prevention of medical errors, and review of a patient's treatment chart. The systems also required physicians to perform fixed sequences of steps and tasks, and poorly supported the documentation and retrieval of patient data. The findings on ICT support for collaboration showed mainly negative results, aside from collaboration between co-located physicians. In addition, the study results pointed out physicians suffering from system failures and a lack of integration between the systems. CONCLUSIONS: The described study and related results are unique in several ways. A national usability study with nearly 4000 respondents had not been conducted in other countries in which healthcare technologies are widely adopted. The questionnaire study provided a generalized picture about the usability problems, however, it should be noted that there were significant differences between legacy systems in use. Previously, researchers had not approached contextual aspects of usability the context of clinical work, where numerous systems are in use. The described usability dimensions and the presented study results can be considered as the first step towards conceptualizing ICT usability in the unique setting of clinical work. PMID- 21784702 TI - qEEG may increase the reliability of diagnostic and prognostic procedures in cerebral arterial gas embolism. PMID- 21784703 TI - Vorticella Linnaeus, 1767 (Ciliophora, Oligohymenophora, Peritrichia) is a grade not a clade: redefinition of Vorticella and the families Vorticellidae and Astylozoidae using molecular characters derived from the gene coding for small subunit ribosomal RNA. AB - Recent phylogenetic analyses of the peritrich genus Vorticella have suggested that it might be paraphyletic, with one Vorticella species - Vorticella microstoma grouping with the swimming peritrichs Astylozoon and Opisthonecta in a distant clade. These results were based on very limited taxon sampling and thus could not be accepted as conclusive evidence for revising the generic classification. We tested paraphyly of the genus Vorticella by making a new analysis with a broad range of samples from three continents that yielded 52 new sequences of the gene coding for small subunit rRNA. Our results, together with the available sequences in Genbank, form a comprehensive set of data for the genus Vorticella. Analyses of these data showed that Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta form a well-supported, monophyletic clade, that is distinct from and basal to the family Vorticellidae containing other species of Vorticella. Paraphyly of the genus Vorticella and family Vorticellidae was strongly confirmed by these results. Furthermore, the two clades of Vorticella identified by the SSU rRNA gene are so genetically diverse whereas the genetic distances within the one containing Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta were so slight, which marked it as a separate family that must be defined by molecular characters in the absence of unifying morphological and morphogenetic characters. An emended characterization and status of the genus Vorticella, the families Vorticellidae and Astylozoidae are presented and discussed. PMID- 21784704 TI - Yersinia pestis autoagglutination factor is a component of the type six secretion system. AB - Autoagglutination (AA) is a protective phenotypic trait facilitating survival of bacteria in hostile environments and in the host during infection. Autoagglutination factors (AFs) that possess self-associating ability are currently characterized in many Gram-negative bacteria, but Yersinia pestis AFs are still a matter of debate. Previously, we have shown that AF of Hms(-) strain Y. pestis EV76 is a complex of the 17,485-kDa protein and a low-molecular-weight component with siderophore activity. Here, we identified the protein moiety of AF and examined its role in AA of Hms(+) and Hms(-)Y. pestis strains. Using MALDI TOF MS of trypsin-hydrolyzed AF, we unambiguously identified the protein as YPO0502, which belongs to a family of Hcp-proteins forming pilus-like structures of the type six secretion system (T6SS). To address the role of YPO0502 in AA, we cloned ypo0502 in E. coli, overexpressed it in Y. pestis and constructed its knock-out mutant in Y. pestis. However, all these approaches failed: YPO0502 was not secreted in E. coli, formed inclusion bodies when overexpressed in Y. pestis, and could probably be compensated by other Hcp-like proteins in Y. pestis. In contrast, downregulation of ypo0502 expression by its antisense RNA supported the contribution of YPO0502 in AA of Hms(+) and Hms(-)Y. pestis strains. The results of the present study indicate that the Hcp-like component of T6SS encoded by ypo502 is involved in Y. pestis AA and suggest that at least one (ypo0499-0516) of the 6 T6SS clusters of Y. pestis is involved in bacterial interaction. PMID- 21784706 TI - Editorial. PMID- 21784705 TI - Taxane-induced nail changes: Predictors and efficacy of the use of frozen gloves and socks in the prevention of nail toxicity. AB - PURPOSE: The primary endpoint of this study was to determine predictors of taxane related nail toxicity. The secondary endpoint was to evaluate the efficacy of the use of frozen gloves and socks in the prevention of taxane-related nail toxicity. METHODS: This descriptive, interventional, cross-sectional study was conducted with 200 patients. The patients were assigned to the frozen gloves/socks intervention group or control group. Frozen gloves/socks were applied only in hourly taxane-based treatments. The Patients Record Forms of the clinic were used in data collection. Nail changes were graded using the NCI Common Toxicity Criteria for each patient and treatment. Logistic regression analysis was performed to predict the factors that affect nail changes. RESULTS: The majority of the patients enrolled in the study were women diagnosed with breast cancer. The two groups were statistically similar for the cancer diagnosis, type and number of taxane cycles administered. Grade 1 nail toxicity was found in 34%, grade 2 in 11%, and grade 3 in 5.5% patients. Taxane-related nail toxicity was higher in patients who were female, had a history of diabetes, received capecitabine in conjunction with docetaxel and had breast or gynecological cancer diagnosis. Nail changes increased with an increase in the number of taxane cycles administered, BMI and severity of treatment-related neuropathy. CONCLUSIONS: The multivariate analysis demonstrated that BMI, breast or ovarian cancer diagnosis and the number of taxane cycles administered were the independent factors for this toxicity. No statistically significant difference in nail toxicity incidence and time to occurrence of nail changes was found between the intervention and the control groups. PMID- 21784707 TI - Tigecycline: benefits and risks. PMID- 21784708 TI - Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. AB - BACKGROUND: Multidrug resistance among bacteria increases the need for new antimicrobial drugs with high potency and stability. Tigecycline is one candidate drug, and a previous meta-analysis of only published randomised controlled trials suggested that it might as effective as comparator treatments; we did a meta analysis to include new and unpublished trials to assess its efficacy for the treatment of adult patients with serious bacterial infection. METHODS: We searched PubMed, Cochrane Central Register, and Embase up to March 30, 2011, to identify published studies, and we searched clinical trial registries to identify completed unpublished studies, the results of which were obtained through the manufacturer. Eligible studies were randomised trials assessing the clinical efficacy, safety, and eradication efficiency of tigecycline versus other antimicrobial agents for any bacterial infection. The primary outcome was treatment success in patients who received at least one dose of the study drug, had clinical evidence of disease, and had complete follow-up (the clinically assessable population). Meta-analysis was done with random-effects models because of heterogeneity across the trials. FINDINGS: 14 randomised trials, comprising about 7400 patients, were included. Treatment success was lower with tigecycline than with control antibiotic agents, but the difference was not significant (odds ratio 0.87, 95% CI 0.74-1.02). Adverse events were more frequent in the tigecycline group than in the control groups (1.45, 1.11-1.88), with significantly more vomiting and nausea. All-cause mortality was higher in the tigecycline group than in the comparator groups, but the difference was not significant (1.28, 0.97-1.69). Eradication efficiency did not differ between tigecycline and control regimens, but the sample size for these comparisons was small. INTERPRETATION: Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections. Our findings show that assessment with unpublished studies is needed to make appropriate decisions about new agents. FUNDING: None. PMID- 21784710 TI - Local area network inhibition: a model of a potentially important paraepileptic pathomechanism in neuropsychiatric disorders. AB - Electroencephalographic abnormalities in the absence of any other major laboratory or imaging findings are a frequently encountered phenomenon in many psychiatric disorders. In some cases, clear-cut interictal epileptiform EEG abnormalities in patients with classic primary psychiatric disorders lead to referrals to epilepsy departments for diagnostic evaluation. Although video/EEG telemetry in these cases generally proves that there is no direct temporal link between the EEG pathologies and psychiatric symptoms, and therefore the psychiatric syndrome cannot be regarded as epilepsy, the relevance of the EEG abnormalities remains open to discussion. In this article we put forward the model of a paraepileptic pathomechanism, which might explain the pathogenetic role of such EEG pathologies, at least in subgroups of such patients. We propose that ictal or nonictal epileptic neurophysiological activity can lead to local area neuronal network inhibition (LANI). In this model clinical symptoms are related not to the excitatory epileptiform abnormalities themselves, but to the extent, site, and dynamics of the resulting local neuronal network inhibition. The LANI hypothesis is capable of explaining the complex relationship between EEG abnormalities and clinical symptoms in different neuropsychiatric syndromes and can be verified and falsified in empirical research. PMID- 21784709 TI - Nonconvulsive seizures in patients presenting with altered mental status: an evidence-based review. AB - Definitive diagnosis of nonconvulsive seizures (NCS) can be made only by electroencephalography, and delay in diagnosis can increase morbidity, resource utilization, and length of hospitalization. We performed an evidence-based literature review to estimate the prevalence of NCS in patients with altered mental status (AMS) of unknown cause. PUBMED, EMBASE, the Cochrane Library, and other resources were searched for studies that included AMS and seizure as topics. The resulting 276 articles were screened for predetermined inclusion and exclusion criteria, leaving 5 studies enrolling 478 patients for review. The prevalence of NCS in patients with AMS ranged from 8 to 30% (overall prevalence of 21.5%, 95% CI: 18-25%), suggesting that the prevalence of NCS is sufficiently high to consider routine use of urgent electroencephalography in such patients. However, methodological weaknesses limit the generalizability of the results. A large, prospective study enrolling and screening for NCS in all patients who present with acute AMS is needed. PMID- 21784711 TI - Combat-related L3 fracture treated with L2-L4 posterior spinal fusion complicated by multidrug-resistant acinetobacter infection. PMID- 21784712 TI - Mitochondrial gene expression in the human annulus: in vivo data from annulus cells and selectively harvested senescent annulus cells. AB - BACKGROUND CONTEXT: Mitochondrial dysfunction is recognized during cell senescence and apoptosis, two important components of human disc aging/degeneration. We hypothesize that mitochondrial dysfunction is present in the degenerating and senescent annulus cells. The objective of the present study was to analyze gene expression profiles related to mitochondrial function in vivo. PURPOSE: This study had two objectives in the analysis of gene expression patterns related to mitochondria in the human annulus: First, to assess human annulus cells in a genome-wide microarray analysis approach to evaluate mitochondrial gene expression in annulus tissue from degenerated compared with healthier discs. Second, to use laser capture microdissection (LCM) to selectively isolate senescent versus nonsenescent annulus cells to evaluate their mitochondrial gene expression patterns. STUDY DESIGN: Following approval by our Human Subjects Institutional Review Board, annulus cells from 20 human lumbar discs were analyzed for gene groups related to mitochondrial function; a subset was also analyzed, which focused on senescent versus nonsenescent annulus cells in a study of annulus cells from 10 lumbar discs. PATIENT SAMPLE: Human annulus tissue was used in molecular studies following institutional review board approval. OUTCOME MEASURES: Gene expression levels identified with microarray analyses were statistically evaluated using GeneSifter Web-based software (VizX Labs, Seattle, WA, USA). METHODS: Human annulus specimens were assessed for gene expression related to mitochondrial function. Approaches used whole annulus tissue and senescent or nonsenescent annulus cells selectively harvested using LCM. Microarray data were analyzed using gene ontology searches and GeneSifter Web-based software. RESULTS: Analysis of annulus cells compared mitochondrial gene expression patterns in annulus cells from more degenerated discs with patterns in annulus cells derived from healthier discs. Important findings included significant upregulation of p53 and several proapoptotic genes (including apoptosis-inducing factor, mitochondrion-associated 1, BCL2-like 11 [an apoptosis facilitator]; caspase 7 apoptosis-related cysteine peptidase; proteasome 26S subunit nonadenosine triphosphatase 10, programmed cell death 6, and reticulon 3). Methionine sulfoxide reductase (Msr), a repair enzyme that reduces methionine sulfoxide residues in proteins damaged by oxidation, was also significantly upregulated (2.02-fold increase). The gene "membrane-associated ring finger (C3HC4) 5" was significantly upregulated and relevant because it is believed to play a role in preventing cell senescence acting to regulate mitochondrial quality control. Nitric oxide synthase 3 (endothelial nitric oxide synthase [eNOS]) showed a 5.9-fold downregulation in more degenerated versus healthier annulus cells. In LCM-harvested senescent cells, Msr was significantly downregulated in senescent versus nonsenescent cells, a finding previously recognized in other types of senescent cells. CONCLUSIONS: Novel data showed that significant gene expression patterns are present in the human annulus related to mitochondrial dysfunction; changes were identified in important genes involving apoptosis, eNOS and Msr expressions, and solute carrier genes. Because current research efforts are focusing on bioactive compounds for mitochondria, we suggest that future biologic cell-based therapies for annulus degeneration should also consider mitochondrial-focused therapies. PMID- 21784713 TI - Prospective evaluation of quality of life in total versus supracervical laparoscopic hysterectomy. AB - STUDY OBJECTIVE: To evaluate and compare recovery times and quality of life (QOL) in patients undergoing a total laparoscopic hysterectomy (TLH) and laparoscopic supracervical hysterectomy (LSH). DESIGN: Patients underwent either a TLH or LSH. After surgery, patients maintained a daily log documenting pain, nausea, use of pain medications, and return to daily activities. They also completed a QOL questionnaire (SF-36) before and after surgery. DESIGN CLASSIFICATION: Prospective cohort study (Canadian Task Force Classification II-1). SETTING: University teaching hospital. PATIENTS: A total of 122 women undergoing laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: A total of 122 women underwent TLH (n = 71) or LSH (n = 51) for benign indications from February 2008 to January 2010. There was a significantly higher postoperative improvement of QOL scores in the LSH group in 6 of 10 questionnaire categories and summary scores, including physical functioning (p =.03), role physical (p =.002), and bodily pain (p =.03). There were no significant differences in use of pain medications, level of pain, level of nausea, or return to normal activities. CONCLUSION: LSH appears to provide greater improvement in short-term postoperative QOL compared with TLH. No significant differences were found in postoperative pain or return to daily activities. PMID- 21784714 TI - Introduction to the special issue on comparative physiology of the autonomic nervous system. PMID- 21784715 TI - Electrochemical determination of a hemorheologic drug, pentoxifylline at a multi walled carbon nanotube paste electrode. AB - The electrochemical oxidation of a hemorheologic drug, pentoxifylline was investigated at a multi-walled carbon nanotubes-paraffin oil paste electrode using cyclic and differential pulse voltammetry. The oxidation process was irreversible over the pH range studied and exhibited an adsorption-controlled behavior. All experimental parameters have been optimized. Under the optimum conditions, the oxidation peak current was linearly proportional to the concentration of pentoxifylline in the range of 3.0 * 10(-5) to 2.0 * 10(-4)M with a detection limit of 1.69 * 10(-7)M by differential pulse voltammetry with 180s accumulation. The proposed method was successfully applied to pentoxifylline determination in pharmaceutical and urine samples. Satisfactory recoveries of the analyte from the real samples and a good agreement between the concentration ranges studied and the real ranges encountered in the urine samples, when treated with the drug make the developed method applicable in clinical analysis. This method can also be employed in quality control and routine determination of drugs in pharmaceutical formulations. PMID- 21784716 TI - Redox behavior of biofilm on glassy carbon electrode. AB - Marine and freshwater biofilm usually shift the open circuit potential (OCP) of stainless steel towards the electropositive direction by +450 mV vs SCE. The nature of oxide film and bacterial metabolism were also correlated with ennoblement process by various investigators. Glassy carbon electrode (GCE) was used in the present study and a shifting of potential in the positive side (+450 mV) was noticed. It indicates that biofilm contributes to the ennoblement process without any n/p-type semiconducting oxide film. The nature of the cathodic curve for the biofilm covered GCE is compared with the previous literature on the electrochemical behavior of stainless steel. The present study explains the oxidation and reduction peaks of biofilm covered GCE by cyclic voltammetry. Electrochemical impedance result reveals the diffusion process within the manganese biofilm. The present study confirms the previous investigations that the manganese biofilm rules the electrochemical behavior of materials and suggests that oxide film is not necessary to assist the ennoblement process. PMID- 21784717 TI - Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis. AB - BACKGROUND: 1,25-Dihydroxycholecalciferol (1,25(OH)(2)D(3)) has been shown to mitigate epithelial inflammatory responses after antigen exposure. Patients with cystic fibrosis (CF) are at particular risk for vitamin D deficiency. This may contribute to the exaggerated inflammatory response to pulmonary infection in CF. METHODS: CF respiratory epithelial cell lines were exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) and Pseudomonas conditioned medium (PCM) in the presence or absence of 1,25(OH)(2)D(3) or a range of vitamin D receptor (VDR) agonists. Levels of IL-6 and IL-8 were measured in cell supernatants, and cellular total and phosphorylated IkappaBalpha were determined. Levels of human cathelicidin antimicrobial peptide (hCAP18) mRNA and protein were measured in cells after treatment with 1,25(OH)(2)D(3). RESULTS: Pretreatment with 1,25(OH)(2)D(3) was associated with significant reductions in IL-6 and IL-8 protein secretion after antigen exposure, a finding reproduced with a range of low calcaemic VDR agonists. 1,25(OH)(2)D(3) treatment led to a decrease in IkappaBalpha phosphorylation and increased total cellular IkappaBalpha. Treatment with 1,25(OH)(2)D(3) was associated with an increase in hCAP18/LL-37 mRNA and protein levels. CONCLUSIONS: Both 1,25(OH)(2)D(3) and other VDR agonists significantly reduce the pro-inflammatory response to antigen challenge in CF airway epithelial cells. VDR agonists have significant therapeutic potential in CF. PMID- 21784718 TI - A photogrammetric study of the effects of alveolar bone graft on nose symmetry among unilateral cleft patients. AB - Alveolar bone graft is considered conducive to tooth eruption and maxilla stability in unilateral cleft patients, but its contribution to nasal symmetry is still under discussion. To explore the detailed effects of alveolar bone graft on nasal symmetry and its role in rhinoplasty, 90 mixed-dentition complete unilateral cleft lip and palate patients were studied and categorised according to the operation they underwent during the mixed dentition period (bone graft, secondary rhinoplasty or bone graft and rhinoplasty combined). Standardised frontal and submental oblique photographs were taken before and after surgery, and objective measurements for the evaluation of nasal symmetry were devised. Measurement reliability was examined with the intraclass correlation coefficient. Intra- and inter-group comparisons were performed to explore the effect of bone graft on nasal symmetry and its role in rhinoplasty. The intraclass correlation coefficient values were >0.84. Preoperative inter-group analysis yielded satisfactory comparability. Among the bone-graft-only patients, seven of 10 measurements demonstrated significant differences, five indicated enhanced symmetry and two indicated compromised symmetry. For the rhinoplasty-only patients, all measurements revealed significant improvement. Compared with the patients who underwent rhinoplasty only, those who underwent combined bone graft and rhinoplasty were superior in nasal-base elevation only. The photogrammetric strategy appeared reliable for evaluation of nasal symmetry. Most of the effects imposed by alveolar bone graft on nasal symmetry were localised to the alar base and would be camouflaged by rhinoplasty. Considering the limited benefit in symmetry and the potential risk of more complications, overextended dissection during mixed dentition bone graft may be unnecessary. PMID- 21784719 TI - Lipoblastomatosis appearing as an unusual symmetric upper lip deformity. AB - We report an unusual case of a bilateral, symmetric upper lip deformity. The submucosal tissue of the resected redundant portion of the lip was occupied by a mass that was diagnosed histopathologically as lipoblastomatosis. Differential diagnoses of lesions with symmetric upper lip deformity and current controversy regarding the surgical treatment are discussed here. PMID- 21784720 TI - Clinical experience with a reverse-flow anterolateral thigh perforator flap for the reconstruction of soft-tissue defects of the knee and proximal lower leg. AB - BACKGROUND: Soft-tissue defects in the knee region are usually complex and require adequate reconstruction with flaps. The aim of this article is to present the authors' experience using the reverse-flow anterolateral thigh perforator flap for the reconstruction of a variety of soft-tissue defects around the knee including the upper third of the leg. METHODS: A total of 17 reverse-flow anterolateral thigh perforator flaps were used for reconstruction of soft-tissue defects around the knee and the upper third of the leg between December 2006 and December 2010. The ages of patients ranged from 26 to 82 years (mean, 64.3). Defect sizes ranged from 6*8 to 10*14 cm. The application of the reverse-flow anterolateral thigh perforator flaps in relation to the variable arterial anatomy was described. RESULTS: The dimensions of the largest flap used for reconstruction were 10*16 cm. The perforators were musculocutaneous in 14 patients and septocutaneous in three patients. The maximal pedicle length was 28 cm. All of the flaps survived. Only two flaps developed partial skin necrosis at the distal end. Good aesthetic and functional results with adequate range of motion were achieved in all cases. CONCLUSION: Despite a variable vascular anatomy that can be challenging for the surgeon, reverse-flow anterolateral thigh perforator flap is a safe and reliable method for reconstruction of the defects around the knee and even the upper third of the leg. PMID- 21784721 TI - Outcome of pregnancy in patients with autoimmune hepatitis/primary biliary cirrhosis overlap syndrome: a report of two cases. PMID- 21784722 TI - Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. AB - OBJECTIVES: Past studies have reported conflicting rates of venous thrombotic events (VTEs) in rheumatoid arthritis (RA). The current study aimed to compare (1) the rates of VTEs in patients with RA treated with anti-tumour necrosis factor (anti-TNF) therapy versus those treated with non-biological disease modifying antirheumatic drugs (nbDMARDs) alone and (2) the rates between each individual anti-TNF agent and nbDMARDs. METHODS: Using data from the British Society for Rheumatology Biologics Register, a national prospective observational cohort study of biological safety in patients with RA, the authors compared the incidence of VTEs between 11 881 anti-TNF- and 3673 nbDMARD-treated patients. Analysis was limited to the first VTE per person. HRs were calculated using Cox modelling. Adjustment was made for potential confounders including surgery performed during follow-up. RESULTS: A total of 196 first VTEs were reported (151 anti-TNF, 45 nbDMARD). Overall there was no difference in the rates of VTEs between anti-TNF- and nbDMARD-treated patients (adjusted HR 0.8 (95% CI 0.5 to 1.5)). The risk was similar across all anti-TNF agents. Rates of postoperative VTEs did not significantly differ between groups. CONCLUSIONS: These data suggest that anti-TNF therapy is not associated with an increased risk of VTEs in RA patients. PMID- 21784723 TI - Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies. AB - Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed. PMID- 21784724 TI - Examination of intra and interrater reliability with a new ultrasonographic reference atlas for scoring of synovitis in patients with rheumatoid arthritis. AB - OBJECTIVE: Synovitis in patients with rheumatoid arthritis (RA) may be scored semiquantitatively (0-3) for B-mode (BM) and power Doppler (PD) ultrasonography. The objective was to assess the reliability of BM and PD examinations with a novel ultrasonographic atlas as reference. METHODS: Representative ultrasound images (including scores 0-3) of BM and PD from 24 different joints were collected to develop an ultrasonographic atlas. Ten RA patients were assessed twice by five rheumatologists performing BM and PD scoring (0-3) of 16 joints bilaterally (metacarpophalangeal 1-5, wrist (radiocarpal, intercarpal, radioulnar), elbow, knee, talocrural and metatarsophalangeal 1-5), with the novel ultrasonographic atlas as a reference. RESULTS: The median (range) percentages of exact agreements for BM/PD assessments were 73.1 (70.3-80.6)/83.7 (76.7-87.6) and for close agreement 98.1 (96.2-99.7)/98.0 (96.8-98.4) with weighted kappa values of median (range) 0.77 (0.70-0.83) for BM and 0.83 (0.73-0.86) for PD. The intrarater intraclass correlation coefficients (ICC) for BM/PD scores were 0.95 (0.93-0.99)/0.97 (0.95-0.99) and interrater ICC were 0.95 (0.86-0.99)/0.97 (0.94 1.00). Scoring of 32 joints was completed in median 15 min (range 12-20). CONCLUSION: With the use of an ultrasonographic atlas as reference high intra and interrater reliability was found for BM and PD scoring. This novel atlas may be a useful resource in clinical practice and research. PMID- 21784725 TI - Lack of activation of renal functional reserve predicts the risk of significant renal involvement in systemic sclerosis. AB - OBJECTIVE: To evaluate if defective activation of renal functional reserve (RFR) in systemic sclerosis (SSc) without clinical signs of renal involvement predicts the risk of developing clinically relevant renal damage. METHODS: Twenty-eight normotensive SSc patients with normal renal function and no urinary abnormalities were submitted to an intravenous amino acid load to activate RFR. Nineteen patients (six with diffuse cutaneous SSc (dcSSc)) had an RFR activation defect, while nine (two with dcSSc) showed normal RFR. All patients were followed up for 5 years, with periodic evaluation of renal function, urinary protein excretion and systemic blood pressure (BP). RESULTS: At admission, patients with normal RFR had lower BP than those with abnormal RFR; no age, disease duration or creatinine clearance (CCr) differences were found. Five years later, patients with abnormal RFR showed, with respect to basal values, a significantly higher CCr reduction than patients with normal RFR (mean percent decrease 15.4 +/- 9.5 vs 2.6 +/- 3.8, p<0.001). Among patients with abnormal RFR, 13 (68.4%) showed a CCr reduction of >= 2 ml/min/year, with a final CCr of <= 70 ml/min in eight cases; two patients developed microalbuminuria and 10 grade 1 or 2 systemic hypertension. Significant CCr reduction rates were found in eight patients with high BP and in five patients who remained normotensive. No patient with normal RFR had proteinuria or high BP during follow-up. CONCLUSIONS: Lack of RFR activation is an early sign of renal involvement in SSc, and is a harbinger of an increased risk of developing renal insufficiency and systemic hypertension. PMID- 21784726 TI - Increased mortality in ankylosing spondylitis is related to disease activity. AB - BACKGROUND: The onset of disease in ankylosing spondylitis (AS) is generally earlier than in other joint diseases, exposing patients to a prolonged burden of disease. Whether this is associated with excess mortality is still uncertain. Radiation therapy for AS has previously been shown to increase mortality. The present study investigated standardised mortality ratios, causes of death and survival predictors in a large regional cohort of patients with AS. METHOD: A total of 677 patients with AS followed at our hospital since 1977 were matched by gender, age and postal area to three controls from the general population and standardised mortality rates (SMRs) were calculated. Cause of death was established using patients' hospital records. In a subset of 360 patients, clinical and demographic data collected during an earlier research visit (1998 2000) were used in a prospective multivariate analysis of predictors for mortality in AS. RESULTS: The crude mortality among patients with AS in this study was 14.5% (98 patients); SMR was only significantly increased among male patients compared with female patients (1.63 vs 1.38, p<0.001). Circulatory disease was the most frequent cause of death (40.0%), followed by malignant (26.8%) and infectious (23.2%) diseases. Factors independently associated with reduced survival were diagnostic delay (OR 1.05), increasing levels of C-reactive protein (OR 2.68), work disability (OR 3.65) and not using any non-steroidal anti inflammatory drugs (OR 4.35). CONCLUSIONS: Mortality is increased in patients with AS and circulatory disease is the most frequent cause of death. Parameters reflecting the duration and intensity of inflammation are associated with reduced survival. These results indicate that, to improve long-term survival in AS, there is a need for early detection and anti-inflammatory treatment as well as a vigilant approach for cardiovascular risk factors. PMID- 21784728 TI - Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population. AB - BACKGROUND: The genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations. OBJECTIVE: To investigate these associations in the Han Chinese population. METHODS: Haplotypes from the HapMap database Chinese population were used to select tag-single nucleotide polymorphisms (SNPs) (r(2)=0.8) across 19 distinct RA genomic regions. A two phase case-control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving p<0.2 in the first phase being genotyped in phase II (n=464 cases, n=822 controls). Association statistics were calculated using permutation tests both unadjusted and adjusted for the number of markers studied. RESULTS: Robust association was detected for MMEL1 and CTLA4, and modest association was identified for another six loci: PADI4, STAT4, PRDM1, CDK6, TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6 * 10(-5) unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4, significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3 * 10(-5) unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed. CONCLUSION: This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis. PMID- 21784727 TI - Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres. AB - OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study. PMID- 21784729 TI - Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO FORWARD trial. AB - OBJECTIVE: To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX). METHODS: Patients (n=444) were randomly assigned to placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX, or golimumab 100 mg plus MTX (subcutaneous injections every 4 weeks). A subset of 240 patients participated in an MRI substudy. MRIs (1.5T+contrast enhancement) of the dominant wrist and metacarpophalangeal (MCP) joints were obtained at baseline and weeks 12 and 24. Images were scored by two independent, blinded readers for synovitis (0-9 wrist only (n=240), 0-21 wrist+MCP (n=223)), bone oedema (osteitis) (0-69) and bone erosions (0-230) using the OMERACT Rheumatoid Arthritis MRI Scoring system. RESULTS: Significant improvements in synovitis and bone oedema (osteitis) were observed in the combined golimumab plus MTX groups versus placebo plus MTX at week 12 (-1.77 vs -0.15, p<0.001 wrist+MCP and -2.00 vs 0.19, p=0.003, respectively) and week 24 (-1.91 vs -0.38, p<0.001 wrist+MCP and -1.74 vs 0.71, p=0.004, respectively). Fewer than 10% of patients had a substantial degree of erosive progression (most showed no progression) across all treatment groups (including the control group), precluding adequate evaluation of golimumab's effect on bone erosions. CONCLUSION: Golimumab plus MTX significantly improved MRI-detected synovitis and osteitis (prognosticators of future structural damage) versus placebo plus MTX at weeks 12 and 24. The effect of golimumab on bone erosions could not be determined by semi-quantitative scoring in these RA patients with minimal progression of bone erosions. PMID- 21784731 TI - Patient doses in paediatric CT: feasibility of setting diagnostic reference levels. AB - Despite the fact that doses to paediatric patients from computed tomography (CT) examinations are of special concern, only few data or studies for setting of paediatric diagnostic reference levels (DRLs) have been published. In this study, doses to children were estimated from chest and head CT, in order to study the feasibility of DRLs for these examinations. It is shown that for the DRLs, patient dose data from different CT scanners should be collected in age or weight groups, possibly for different indications. For practical reasons, the DRLs for paediatric chest CT should be given as a continuous DRL curve as a function of patient weight. For paediatric head CT, DRLs for a few age groups could be given. The users of the DRLs should be aware of the calibration phantom applied in the console calibration for different paediatric scanning protocols. The feasibility of DRLs should be re-evaluated every 2-3 y. PMID- 21784730 TI - Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. AB - OBJECTIVES: To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological disease-modifying antirheumatic drug (nbDMARD)-treated patients. RESULTS: 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. CONCLUSIONS: Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life threatening complication. PMID- 21784732 TI - Twin pregnancies with a 'vanished' embryo: a higher risk multiple gestation group? AB - BACKGROUND: Prior studies have documented increased risks to the offspring of IVF singletons that result from a vanished twin pregnancy. We aim to investigate the effect on perinatal outcomes of having an early vanished triplet in IVF twins. METHODS: This is a retrospective cohort study of twins from a large academic IVF practice. Multivariate analysis was performed to examine the perinatal risks- including small for gestational age (SGA), low-birthweight (LBW), preterm delivery and early preterm delivery--in twins that resulted from an early vanished triplet compared with twins without a vanished embryo. RESULTS: Of 829 IVF twin deliveries, 59 were a result of vanished triplet pregnancies (7.1%). There was no significant increase in SGA, LBW or delivery <37 weeks in the vanished triplets compared with other twins; however, the risk of early preterm birth (<32 weeks) was significantly higher (OR 3.09, 95% CI 1.63-5.87) and the length of gestation of these pregnancies was on average 1.5 weeks shorter (P < 0.01). In addition, the unadjusted mean birthweight was lower by nearly 200 g in the vanished triplet pregnancies (P < 0.01). CONCLUSIONS: IVF twin pregnancies with a vanished triplet are at an increased risk for early preterm birth compared with other twin pregnancies. These pregnancies should be recognized at higher risk for early preterm birth and considered for increased obstetrical monitoring. A significant limitation of this study is that the cause for preterm birth was unknown. PMID- 21784733 TI - Impact of CCN3 (NOV) glycosylation on migration/invasion properties and cell growth of the choriocarcinoma cell line Jeg3. AB - BACKGROUND: Recently we have shown that the matricellular CCN3 protein expressed in invasive extravillous trophoblast cells (EVTs) is decreased in early-onset pre eclampsia and is regulated by oxygen tension. Pathogenesis of pre-eclampsia relies on a shallow invasion of EVTs into the spiral arteries, which leads to hypoxia accompanied by uteroplacental insufficiency. Here we investigated the function of glycosylated and non-glycosylated CCN3 protein on cell growth as well as migration and invasion properties of the malignant trophoblast cell line Jeg3 which is a widely used model for the invasive trophoblast. METHODS AND RESULTS: Stable transfection of Jeg3 choriocarcinoma cells with full length CCN3 resulted in high expression of secreted glycosylated and cellular non-glycosylated CCN3. These cells revealed significantly reduced growth in cell numbers combined with a significantly increased migratory and invasive capacity. Matrix metalloprotease (MMP)-2 and MMP-9 activities were enhanced dependent on CCN3 expression, which could be confirmed by CCN3 knockdown studies. Using recombinant glycosylated and non-glycosylated CCN3, we revealed that CCN3 decreased growth in Jeg3 cell numbers independent of its glycosylation status, whereas only non-glycosylated CCN3 was able to enhance migration and invasion properties. CONCLUSIONS: The present results suggest that CCN3 protein regulates the decrease in Jeg3 cell numbers independent of its glycosylation status, whereas migratory and invasive properties are influenced only by non-glycosylated CCN3. An impaired balance in the expression of glycosylated and non-glycosylated CCN3 could contribute to the shallow invasion of EVTs observed in pre-eclampsia. PMID- 21784735 TI - Recurrent pre-clinical pregnancy loss is unlikely to be a 'cause' of unexplained infertility. AB - BACKGROUND: A proportion of women with 'unexplained' infertility may present with subfertility because their pregnancies fail before they are clinically recognized. In order to test whether pre-clinical early pregnancy losses (EPL) occur more frequently in women with unexplained infertility, serial urinary hCG concentrations were measured to compare EPL per cycle rates following spontaneous conception in patients with unexplained infertility versus healthy volunteers. METHODS: Sixty patients under 39 years of age with unexplained infertility and 60 healthy controls, who were trying to conceive spontaneously, participated in this study. All participants were asked to collect daily urine samples from cycle day 14 until menstruation for three consecutive cycles or until a positive pregnancy test was obtained. Urinary hCG and creatinine levels were measured by immunoassay. Implantation was detected when urinary hCG levels rose above reference levels constructed from samples obtained from 12 women not attempting to conceive. EPL rates were determined by a linear mixed model using logarithmically transformed hCG/creatinine data. RESULTS: In the 133 cycles of 60 women with unexplained infertility, just one implantation was detected, which became an ongoing pregnancy. In contrast, in 103 such cycles in 46 control patients, 30 implantations were detected (24 clinical pregnancies, 6 cases of EPL). The odds ratio for EPL/cycle in the unexplained versus control group was 0 (95% confidence interval: 0-0.795, P = 0.026). CONCLUSIONS: Our data do not support the hypothesis that recurrent EPL may present as unexplained infertility. Post-implantation failure is therefore unlikely to contribute significantly to the presentation of subfertility. PMID- 21784734 TI - Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double blind Phase III trial. AB - BACKGROUND: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E(2)V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology. METHODS: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E(2)V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90 day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. RESULTS: The intention-to-treat population comprised 231 women. The E(2)V/DNG response rate was much higher than with placebo (P < 0.0001). The mean reduction in MBL volume in E(2)V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E(2)V/DNG (95% confidence interval 490, 255 ml; P < 0.0001). Significant improvements in iron metabolism parameters were observed with E(2)V/DNG but not placebo. Overall, 14 women (9.7%) treated with E(2)V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E(2)V/DNG and placebo groups (each n = 2). CONCLUSIONS: E(2)V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E(2)V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801. PMID- 21784736 TI - Polycystic ovarian morphology in adolescents with regular menstrual cycles is associated with elevated anti-Mullerian hormone. AB - BACKGROUND: The significance of polycystic ovarian morphology (PCOM) during adolescence is not clear. The aim of this study was to determine the relationship between PCOM and anti-Mullerian hormone (AMH), inhibin B, testosterone and insulin levels in healthy girls during the second decade of life. We also determined whether AMH could be used as a surrogate marker of PCOM during adolescence. METHODS: Seventy-four non-obese adolescents (age range: 13.5-19.75 years old) with regular menstrual cycles participated in this study. Transabdominal ultrasound and blood samples were obtained during the follicular phase. RESULTS: PCOM was present in 33.8% of the subjects. Girls with PCOM had higher AMH levels than girls without PCOM (72.5 +/- 6.1 versus 33.4 +/- 2.6 pmol/l; P < 0.0001) and lower FSH levels (5.4 +/- 0.3 versus 6.2 +/- 0.2 mUI/ml; P < 0.036). Similar levels of inhibin B, androgens and LH were observed in girls with and without PCOM. PCOM prevalence and AMH levels were not associated with age (P = 0.745 and 0.2, respectively) or BMI-SDS (P = 0.951 and 0.096, respectively). AMH levels positively correlated with the of 2-5 mm follicle number. AMH levels >= 60.15 pmol/l had a sensitivity and specificity of 64.0 and 89.8%, respectively, to diagnose PCOM (area under the curve = 0.873). CONCLUSIONS: These data confirm that PCOM in healthy non-hyperandrogenic girls with regular menstrual cycles is prevalent and is not associated with hyperandrogenism. The elevated AMH and lower FSH levels observed in healthy girls with regular menses and PCOM suggest that this ovarian pattern is secondary to a larger number of 2-5 mm follicles. An elevated AMH level is suggestive of the presence of PCOM during adolescence. PMID- 21784737 TI - Analysis of global gene expression following mouse blastocyst cryopreservation. AB - BACKGROUND: The aim of this study was to examine the effect of the cryopreservation procedure (slow freezing or vitrification) and cryoprotectants (1,2-propanediol or dimethylsulphoxide) on mouse blastocyst gene expression. METHODS: Cultured mouse blastocysts were cryopreserved with different protocols. Following thawing/warming, total RNA from re-expanded blastocysts was isolated, amplified and then analyzed using mouse whole-genome microarrays. RESULTS: Compared with non-cryopresevered control blastocysts, gene expression was only significantly altered by slow freezing. Slow freezing affected the expression of 115 genes (P < 0.05). Of these, 100 genes exhibited down-regulation and 15 genes were up-regulated. Gene ontology revealed that the majority of these genes are involved in protein metabolism, transcription, cell organization, signal transduction, intracellular transport, macromolecule biosynthesis and development. Neither of the vitrification treatment groups showed statistically different gene expression from the non-cryopreserved control embryos. Hierarchical cluster analysis, did however, reveal that vitrification using 1,2 propanediol could result in a gene expression profile closest to that of non cryopreserved blastocysts. CONCLUSIONS: Investigating the effects of cryopreservation on cellular biology, such as gene expression, is fundamental to improving techniques and protocols. This study demonstrates that of the cryopreservation regimens employed, slow freezing induced the most changes in gene expression compared with controls. PMID- 21784738 TI - GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study. AB - BACKGROUND: It is now well established that a GnRH agonist (GnRHa) ovulation trigger completely prevents ovarian hyperstimulation syndrome. However, early studies, using conventional luteal support, showed inferior clinical results following a GnRHa trigger compared with a conventional hCG trigger in normal responder IVF patients. We here present a novel approach for luteal support after a GnRHa trigger. METHODS Normal responder patients who failed at least one previous IVF attempt, during which a conventional hCG trigger was used, were consecutively enrolled in the study. A GnRH antagonist-based ovarian stimulation protocol was used in combination with a GnRHa trigger (Triptorelin 0.2 mg). The luteal phase was supported with a total of two boluses of 1500 IU hCG: on the day of oocyte retrieval and 4 days later. Neither progesterone nor estradiol was administered for luteal support. RESULTS: The mean age was 33.8 years. The mean (+/- SD) numbers of oocytes and fertilized oocytes were 6.7 (+/- 2.5) and 3.6 (+/ 1.7), respectively. All 15 patients had embryo transfers and 11 patients conceived. On the day of pregnancy test (14 days after retrieval), the mean serum E(2) and progesterone levels were 6607 (+/- 3789) and 182 (+/- 50) nmol/l, respectively. Of the pregnancies, seven are ongoing, while four ended as miscarriages. CONCLUSIONS: These preliminary results suggest that two boluses of 1500 IU hCG revert the luteolysis after a GnRHa trigger in the normo-responder patient. Importantly, no additional luteal support is needed. The novel concept combines the potential advantages of a physiological dual trigger (LH and FSH) with a simple, patient friendly, luteal support. PMID- 21784739 TI - Outpatient costs in patients with atrial fibrillation are underestimated. PMID- 21784741 TI - Pulmonary vein anatomy and long-term outcome after multi-electrode pulmonary vein isolation with phased radiofrequency energy for paroxysmal atrial fibrillation. AB - AIMS: We evaluated the effect of pulmonary vein (PV) anatomical characteristics on PV isolation (PVI) and long-term efficacy of ablation with phased radiofrequency (RF) energy and pulmonary vein ablation catheter (PVAC) multi electrode catheter. METHODS AND RESULTS: Before the procedure, PV anatomy was visualized by magnetic resonance imaging (MRI). Consecutive patients with paroxysmal atrial fibrillation were treated with the PVAC with successful acute isolation. Follow-up was performed at 3, 6, and 12 months with electrocardiogram and 7-day Holter recording at 6 and/or 12 months. Symptomatic patients received additional event recording. In 110 patients a pre-procedure cardiac MRI was performed. Ninety-seven (88%) had a separate left superior PV and separate left inferior PV, all patients had a separate right superior PV and separate right inferior PV. Fourteen (13%) had a left PV with common trunk and 27 (25%) had a separate right middle PV (RMPV). After a follow-up of 1 year, 57 of 110 (52%) patients were free of AF without anti-arrhythmic drug. No specific anatomical variable that was related to long-term failure could be found. There was a trend for patients with larger veins (>24 mm) or separate RMPV to have a lower efficacy. The number of applications per vein or procedure did not influence long term outcome. CONCLUSIONS: In patients who have undergone PVI with phased RF energy and PVAC multi-electrode ablation, long-term efficacy is not significantly affected by PV anatomy or number of applications, although a trend for reduced efficacy is seen for PV with diameter >24 mm, and presence of RMPV. PMID- 21784740 TI - Rationale and current perspective for early rhythm control therapy in atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia and an important source for mortality and morbidity on a population level. Despite the clear association between AF and death, stroke, and other cardiovascular events, there is no evidence that rhythm control treatment improves outcome in AF patients. The poor outcome of rhythm control relates to the severity of the atrial substrate for AF not only due to the underlying atrial remodelling process but also due to the poor efficacy and adverse events of the currently available ion-channel antiarrhythmic drugs and ablation techniques. Data suggest, however, an association between sinus rhythm maintenance and improved survival. Hypothetically, sinus rhythm may also lead to a lower risk of stroke and heart failure. The presence of AF, thus, seems one of the modifiable factors associated with death and cardiovascular morbidity in AF patients. Patients with a short history of AF and the underlying heart disease have not been studied before. It is fair to assume that abolishment of AF in these patients is more successful and possibly also safer, which could translate into a prognostic benefit of early rhythm control therapy. Several trials are now investigating whether aggressive early rhythm control therapy can reduce cardiovascular morbidity and mortality and increase maintenance of sinus rhythm. In the present paper we describe the background of these studies and provide some information on their design. PMID- 21784742 TI - Implantable cardioverter-defibrillators in France: practices and regional variability. AB - AIMS: The rates of cardiac defibrillator implantation (ICD) in Europe and within countries are heterogeneous. We examined the characteristics of ICD recipients and device implantation rates in France, with the goal of identifying patterns and regional differences in medical practices. METHODS AND RESULTS: We compiled the information available on devices and patients from a manufacturer's database for the years 2008 and 2009 and the Stidefix national registry from January 2008 to April 2010 and reported the descriptive statistics and comparisons of implantation practices among regions. We analysed data from 10 766 patients enrolled in Stidefix (mean age=63 +/- 13 years; 83% men) after implantation of single-chamber (24%), dual-chamber (33%), or triple-chamber (43%) ICD. Implantation was for primary prevention in 63% of patients. Between 2008 and 2009, the national implant rate increased from 126 to 147 per million inhabitants, with regional variations related to the number of cardiologists and of implant centres. Patients were significantly older and more likely to undergo implantation for primary prevention or for cardiac resynchronization therapy (CRT) in higher-volume regions. In Ile de France (Paris and its suburbs), patients tended to be younger, as in low-implantation regions, but with a high rate of CRT implants, as in high-implantation regions. A comparison of the Stidefix data with the manufacturer's database revealed that only 57% of all ICD implanted in 2009 were reported to Stidefix. CONCLUSION: Despite an increasing rate of ICD implantation in France, important regional disparities persist, with a median position occupied by Ile de France. PMID- 21784743 TI - How many electrical cardioversions should be applied for repetitive recurrences of atrial arrhythmias following ablation of persistent atrial fibrillation? AB - AIMS: We aimed to determine how many electrical cardioversions (ECs) should be applied to treat repetitive persistent recurrences of atrial fibrillation (AF) following ablation of persistent AF within the early post-procedural period. METHODS AND RESULTS: A total of 40 patients with >1 episode of recurrent AF in the form of persistent atrial arrhythmias within 3 months following the ablation were recruited from 108 patients who underwent ablation for persistent or long standing persistent AF. Electrical cardioversions were applied up to six times, if necessary, to restore sinus rhythm at clinical visits at 2-week intervals until 3 months after the ablation. Fourteen (35%) ablation failures defined as recurrences of AF identified from the 3rd month after the ablation procedure were finally diagnosed during the follow-up period (14 +/- 4 month). The patients with an ablation failure more frequently required ECs than those without (3.7 +/- 0.3 vs. 1.2 +/- 0.2 times; P < 0.0001). A receiver-operating characteristic curve identified a number of ECs of >=3 as the optimal cut-off value for predicting an ablation failure (area under the curve 0.91; sensitivity, 86%, and specificity, 96%; P = 0.0007). In the multivariate logistic regression analysis, a number of ECs of >=3 was the only independent predictor of an ablation failure (odds ratio, 11.32; 95% confidence interval, 3.83-58.22; P = 0.0019). CONCLUSION: It was difficult to maintain sinus rhythm in patients with persistent AF who required several ECs for recurrences of AF within the early post-ablation period. PMID- 21784744 TI - Dynamic ventricular overdrive stimulation in atrial fibrillation: effects on ventricular rate irregularity, ventricular pacing, and fusion beats. AB - AIMS: In pacemaker patients with preserved atrio-ventricular (AV) conduction, atrial fibrillation (AF) can lead to symptomatic ventricular rate irregularity and loss of ventricular stimulation. We tested if dynamic ventricular overdrive (DVO) as a potentially pacemaker-integrated algorithm could improve both aspects. METHODS AND RESULTS: Different settings of DVO and ventricular-ventricular inhibited-pacing (VVI) with different base rates were tested in two consecutive phases during electrophysiological studies for standard indications. Mean heart rate (HR), HR irregularity and percentage of ventricular pacing were evaluated. A fusion index (FI) indicative of the proportion of fusion beats was calculated for each stimulation protocol. Dynamic ventricular overdrive from the right ventricular apex was acutely applied in 38 patients (11 females, mean age 62.1 +/ 11.5 years) with sustained AF and preserved AV conduction. Dynamic ventricular overdrive at LOW/MEDIUM setting increased the amount of ventricular pacing compared with VVI pacing at 60, 70, and 80 beats per minute (bpm; to 81/85% from 11, 25, and 47%, respectively; P < 0.05). It also resulted in a maximum decrease in interval differences (to 48 +/- 18 ms from 149 +/- 28, 117 +/- 38, and 95 +/- 46 ms, respectively; P < 0.05) and fusion (to 0.13 from 0.41, 0.42, and 0.36, respectively; P < 0.05) compared with VVI pacing at 60, 70, and 80 bpm. However, the application of DVO resulted in a significant increase in HR compared with intrinsic rhythm and VVI pacing at 80 bpm (to 97 bpm from 89 and 94 bpm, respectively; P < 0.05). CONCLUSION: Dynamic ventricular overdrive decreases HR irregularity and increases ventricular pacing rate compared with VVI pacing at fixed elevated base rates and spontaneous rhythm. Fusion index might help to refine information on pacing percentages provided by device counters. PMID- 21784745 TI - Defining potential to benefit from implantable cardioverter defibrillator therapy: the role of biomarkers. AB - AIMS: Implantable cardioverter defibrillator (ICD) therapy improves survival in patients at high sudden cardiac death (SCD) risk. However, some patient groups fulfilling indications for ICD therapy may not gain significant benefit: patients whose absolute risk of SCD is low and patients whose risk of death even with an ICD is high. The value of biomarkers in identifying patients' potential for survival benefit from ICD therapy is unknown. We performed a pilot study to investigate this. METHODS AND RESULTS: Five established cardiovascular biomarkers were measured in patients with ICDs on the background of left ventricular dysfunction: N-terminal pro-brain natriuretic peptide [NT-proBNP], soluble ST2 [sST2], growth differentiation factor-15, C-reactive protein, and interleukin-6. The endpoints were all-cause mortality and survival with appropriate ICD therapy. One hundred and fifty-six patients were enrolled (age 69 years [Q1-Q3 62-77], 85% male, 76% ischaemic aetiology). During a follow-up of 15 +/- 3 months, 12 patients died and 43 survived with appropriate ICD therapy. In a Cox proportional hazards model, the strongest predictors of death were Log sST2 (P< 0.001), serum creatinine (P< 0.001), and Log NT-proBNP (P= 0.002). The strongest predictor of survival with appropriate ICD therapy was Log NT-proBNP (P= 0.01). CONCLUSION: The biomarkers NT-proBNP and sST2 are promising biomarkers for identifying patients with little potential to gain significant survival benefit from ICD therapy. However, their incremental benefit, in addition to currently available clinical risk prediction models, remains unclear. These results demand a confirmatory prospective cohort study, designed and powered to derive and validate prediction algorithms incorporating these markers. PMID- 21784746 TI - Rationale and design for programming implantable cardioverter-defibrillators in patients with primary prevention indication to prolong time to first shock (PROVIDE) study. AB - AIMS: Shock therapy delivery by implantable cardioverter-defibrillators (ICD) can be painful and may have negative psychological consequences. Reducing shock burden for patients with ICDs and cardiac resynchronization therapy defibrillators (CRT-Ds) may have beneficial consequences. This may be achieved by avoiding inappropriate shocks for supraventricular tachycardia (SVT) and by limiting appropriate shocks to only those that are necessary to convert ventricular arrhythmias. METHODS AND RESULTS: The programming implantable cardioverter-defibrillators in patients with primary prevention indication to prolong time to first shock study (PROVIDE) is a prospective, randomized, multicentre study that will test the hypothesis that a combination of pre selected ventricular tachyarrhythmia detection, anti-tachycardia pacing, and SVT discriminator parameters will prolong the time to first shock without increasing arrhythmic syncope in patients receiving ICDs for primary prevention. Patients receiving St Jude Medical ICDs and CRT-Ds for primary prevention will be randomized 1:1 to one of two arrhythmia detection and therapy approaches. The study will enroll and follow 1600 patients for at least 1 year or until 226 first shocks have been documented in the total study population. The primary endpoint of the study is the mean time to first shock and the safety endpoint is the rate of arrhythmic syncope. CONCLUSION: The PROVIDE trial is a randomized controlled study, designed to assess if a pre-selected combination of programming parameters can reduce shock burden among patients receiving ICDs/CRT-Ds for primary prevention. PMID- 21784747 TI - Right ventricular pacing improves haemodynamics in right ventricular failure from pressure overload: an open observational proof-of-principle study in patients with chronic thromboembolic pulmonary hypertension. AB - AIMS: Right ventricular (RV) failure in patients with chronic thromboembolic pulmonary hypertension (CTEPH), and other types of pulmonary arterial hypertension is associated with right-to-left ventricle (LV) delay in peak myocardial shortening and, consequently, the onset of diastolic relaxation. We aimed to establish whether RV pacing may resynchronize the onsets of RV and LV diastolic relaxation, and improve haemodynamics. METHODS AND RESULTS: Fourteen CTEPH patients (mean age 63.7 +/- 12.0 years, 10 women) with large (>=60 ms) RV to-LV delay in the onset of diastolic relaxation (DIVD, diastolic interventricular delay) were studied. Temporary RV pacing was performed by atrioventricular (A-V) sequential pacing with incremental shortening of A-V delay to advance RV activation. Effects were assessed using tissue Doppler echocardiography and LV pressure-conductance catheter measurements in a subset of patients. Compared with right atrial pacing, RV pacing at optimal A-V delay (average 140 +/- 22 ms, range 120-180 ms) resulted in significant DIVD reduction (59 +/- 19 to 3 +/- 22 ms, P < 0.001), and increase in LV stroke volume as measured by LV outflow tract velocity-time integral (14.9 +/- 2.8 to 16.9 +/- 3.0 cm, P < 0.001), along with enhanced global RV contractility and LV diastolic filling. CONCLUSION: Right-to-left ventricle resynchronization of the onset of diastolic relaxation results in stroke volume increase in CTEPH patients. Whether RV pacing may be a novel therapeutic target in RV failure following chronic pressure overload remains to be investigated. PMID- 21784748 TI - Complications of atrial fibrillation ablation: when prevention is better than cure. AB - As atrial fibrillation ablation is becoming increasingly popular in many cardiac electrophysiological laboratories around the world, preventing, avoiding, or treating procedure-related complications is of utmost importance. In our review of the literature regarding this issue, we addressed in detail all the potential collateral and undesired effects associated to this intervention. PMID- 21784749 TI - Prevalence of the type 1 Brugada electrocardiogram in Caucasian patients with suspected coronary spasm. AB - AIMS: Sporadic cases have reported the coexistence of coronary spasm and Brugada syndrome. However, the prevalence of the Brugada phenotype in coronary spasm is unknown, particularly in non-Japanese populations. In this study, we sought to examine the prevalence of the type 1 Brugada electrocardiogram (ECG) in a large European patient population undergoing intracoronary provocation testing for suspected coronary spasm. METHODS AND RESULTS: We retrospectively evaluated ECG data for the presence of type 1, 2, and 3 Brugada ECGs from 955 consecutive German patients without obstructive coronary artery disease undergoing intracoronary acetylcholine (ACH) provocation (ACH-test). Eight hundred and twenty-seven patients (age 63 +/- 12 years; 42% male) with complete ECG data were eligible for further analysis. The ACH-test revealed coronary spasm in 325 patients (39.3%). A Brugada ECG of any type was found in six patients (0.7%) at baseline and eight patients (0.9%) at any time. There was no difference in the prevalence of coronary spasm in patients with (37.5%) and without (39.3%) Brugada type ECGs. The type 1 Brugada ECG was not seen at baseline, but two type 1 Brugada ECGs were observed during ACH-administration into the right coronary artery (RCA; 0.2%), one with simultaneous RCA spasm and one without. Ajmaline provocation testing reproduced the type-1 Brugada ECG in the patient without coronary spasm but she had no other features of the Brugada syndrome. CONCLUSIONS: This study reports a low prevalence of the type 1 Brugada ECG in the largest known European collection of intracoronary ACH provocation. In these patients, we found no evidence for the coexistence of Brugada syndrome and coronary spasm. This is in contrast to available Japanese data. PMID- 21784751 TI - Changes in patient measures as predictors of therapists' ratings of treatment collaboration and change in eating disorder subgroups. AB - This study examined how implicit and explicit changes following integrative inpatient treatment of adolescents with eating disorder (ED) may predict the posttreatment ratings of psychodynamic therapists of their patients' openness to therapeutic processes and their change (Therapist Evaluation Inventory). The relative contribution of inpatients' ego functions was compared with that of their mental distress and ED symptoms in two subgroups: restricting type anorexia (AN-R) and binging/purging type EDs (B/P). Data indicated that the implicit personality variable of elevated ability to modulate affects was the best predictor of therapist-rated global outcome among patients with B/P symptoms, whereas in patients with AN-R, evolving openness to implicit negative affects and a reduction in reported distress were best predictors. In patients with AN-R, attenuated affect control was also significantly correlated with therapist posttreatment ratings. These data point that in addition to addressing behavioral/symptomatic aspects, personality variables should be addressed in the psychological treatment of EDs. PMID- 21784750 TI - The reproducibility of the early detection of alcohol consumption test using split samples analyzed in different laboratories. AB - AIMS: This study analyzes the reproducibility of the Early Detection of Alcohol Consumption (EDAC) test by sending blood samples obtained from nine volunteers to four different laboratories. It also describes the reproducibility of the EDAC over time by analyzing the results of testing one subject whose blood sample was sent to seven different laboratories over a 10-year period. METHODS: The EDAC is a method of interpreting routine laboratory profiles to identify either binge drinking or heavy drinking; the components of the routine panel were chosen based on a best fit predictions model published previously. RESULTS: Overall, the results of the cross-sectional analysis showed that the coefficients of variations (CVs) of the routine tests in the panel were mostly below 16%. Only three analytes (total bilirubin, aspartate aminotransferase and monocytes) showed CVs between 20 and 38%. The differences in the EDAC predictions for these volunteers ranged from 0 to 24%. In the long-term analysis, the variation of the EDAC prediction ranged from 0 to 21% probability of heavy drinking for one subject over time. Thus, mild variations of the EDAC are to be expected when the blood samples are analyzed in different laboratories. However, based on this study, these variations in the prediction of heavy drinking should not exceed >24% when using the EDAC test. CONCLUSION: This study supports the standard practice established for similar contemporary alcohol biomarkers stipulating that indications of heavy drinking become evident only when subjects experience changes of >30% in the probability of heavy drinking over time. PMID- 21784752 TI - Both self-report and interview-based measures of psychopathy predict attention abnormalities in criminal offenders. AB - Historically, psychopathy has been viewed as a clinical syndrome with a unitary etiology, assessed via clinical interview. However, factor analytic studies suggest that psychopathy may also be understood as a combination of two subfactors consisting of (a) interpersonal-affective and (b) lifestyle-antisocial traits. Furthermore, evidence supports the use of self-report measures to assess psychopathy and these subfactors. This investigation employed a Stroop-like task to determine the relationship of the two psychopathy factors, as assessed by both interview-based and self-report measures, to attention-related abnormalities in psychopathy. For both instruments, the factors interacted to predict performance (i.e., interference), though the unique main effects were nonsignificant. The results suggest that the anomalous selective attention of psychopathic offenders is specific to individuals with high scores on both factors. Moreover, these results have important implications for the two-factor model of psychopathy and provide preliminary support for the functional similarity of self-report and interview-based measures of psychopathy. PMID- 21784753 TI - A revised interpersonal circumplex inventory of children's social goals. AB - Motivational factors such as social goals are important features of developing social adjustment, and thus researchers studying social adjustment need psychometrically sound measures of social goals. A valid measure of social goals for English-speaking youth is lacking. Such a measure would increase understanding of children's social adjustment and allow for testing developmental models of social goals and interpersonal functioning. The authors' aim was to revise the Interpersonal Goals Inventory for Children (IGI-C) for an English speaking sample and examine its validity. The revised IGI-C (IGI-CR) fit a circumplex model and performed as expected with most external criterion variables examined. In addition, some differences were observed across males and females, offering insights into gender differences in social goals. Results support the IGI-CR as a sound measure. PMID- 21784754 TI - Unrelieved pain and suffering in patients with advanced cancer. AB - Even with specialist-level palliative care, cancer pain can be difficult to treat especially when the pain is complicated by profound suffering. It is paramount to consider not only the patients' biochemical factors but also their psychosocial and spiritual/existential influences. A multidimensional approach with knowledge of the risk factors for poor pain control is important to prevent, detect, and manage risk factors for intractable pain, including psychosocial distress, addictive behavior, and delirium in patients with terminal cancer. We present 3 cases of patients with advanced cancer with intractable bone pain whose hospital courses were complicated by severe psychosocial distress and delirium. We also propose an algorithm of multidimensional approach to unrelieved pain and suffering in patients with advanced cancer. PMID- 21784755 TI - Production of 2-hydroxyglutarate by isocitrate dehydrogenase 1-mutated gliomas: an evolutionary alternative to the Warburg shift? PMID- 21784756 TI - Treatment of high-grade glioma in children and adolescents. AB - Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRalpha and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG. PMID- 21784757 TI - Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. AB - OBJECTIVES: To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double blind, placebo-controlled, parallel group study. METHODS: Patients being treated with oral prednisolone at doses equivalent to 10-20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study. RESULTS: Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p = 0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted. CONCLUSIONS: This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT00309088. Name of the trial registry: FK506 Phase 3 STUDY: A STUDY for Steroid Non-Resistant MG Patients. PMID- 21784758 TI - Association of a genetic variant of BTN2A1 with metabolic syndrome in East Asian populations. AB - BACKGROUND: The authors previously showed that the C->T polymorphism (rs6929846) of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with myocardial infarction in Japanese individuals. Given that metabolic syndrome (MetS) is an important risk factor for myocardial infarction, the association of the rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to MetS. AIM: The aim of the present study was to examine the relation of the rs6929846 of BTN2A1 to MetS in East Asian populations. METHODS: The study population comprised 5210 Japanese or Korean individuals (3982 individuals with MetS, 1228 controls) from three independent subject panels. Japanese subject panels A and B comprised 1322 individuals with MetS and 654 controls, and 1909 individuals with MetS and 170 controls, respectively, whereas the Korean population samples comprised 751 individuals with MetS and 404 controls. RESULTS: Comparison of genotype distributions using the chi(2) test revealed that the genotype distributions and allele frequencies of rs6929846 were significantly (p<0.05) associated with MetS in Japanese subject panels A (T allele frequency: MetS, 0.091; controls, 0.054; p=6.1*10(-5)) and B (T allele frequency: MetS, 0.091; controls, 0.039; p=0013) but not in the Korean population samples (T allele frequency: MetS, 0.102; controls, 0.125; p=0.0997). Multivariable logistic regression analysis with adjustment for covariates revealed that the rs6929846 of BTN2A1 was significantly (p<0.017) associated with MetS in Japanese subject panel A (p=0.0055, OR 1.97) and in all individuals (p=0.0038, OR 1.38), with the T allele representing a risk factor for this condition. CONCLUSION: BTN2A1 may be a susceptible gene for MetS in Japanese individuals. PMID- 21784759 TI - Alcohol use of older adults: drinking alcohol for medicinal purposes. PMID- 21784760 TI - Joint geriatric and psychiatric wards: a review of the literature. AB - Joint geriatric/psychiatric wards are a potential solution to improving care of older patients with both psychiatric and medical illnesses in acute hospitals. A literature search using Medline, PsycINFO, Embase and CINAHL between 1980 and 2010 was carried out for information about joint wards for older people. Thirteen relevant papers were identified. These wards share common characteristics and there is evidence that they may reduce length of stay and be cost-effective, but there are no high-quality randomised controlled trials. Further research is needed, particularly regarding cost-effectiveness. PMID- 21784762 TI - Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression. AB - AIMS: The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit(+) cells. METHODS AND RESULTS: Acidic preconditioning was achieved by exposing BM ckit(+) cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca(2+)]i mobilization and on nitric oxide (NO), as determined by [Ca(2+)]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit(+) cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. CONCLUSION: Acidic preconditioning represents a novel strategy to enhance BM ckit(+) cell therapeutic potential via NO-dependent increase in CXCR4 expression. PMID- 21784763 TI - Admission proinsulin is associated with mortality in patients with admission hyperglycemia during acute coronary syndrome: results from a pilot observational study. AB - BACKGROUND: Acute hyperglycemia (AHG) is associated with mortality in patients with acute coronary syndrome (ACS). The extent to which hyperproinsulinemia contributes to worse clinical outcomes for this specific patient population is unknown. METHODS: We included 308 consecutive ACS patients who underwent coronary angioplasty in this pilot observational study. Patients were separated into 3 groups: patients with proven diabetes mellitus (DM group) (n =55), nondiabetic patients with a normal glucose concentration at admission (NAG group) (n =175), and nondiabetic patients with AHG at presentation (AHG group) (n =78). Blood samples for glucose, insulin, and proinsulin measurements were obtained at admission. The primary end point of the study was all-cause mortality, which was assessed at a mean follow-up of 19 months (interquartile range, 12-28 months). RESULTS: Patients in the AHG and DM groups had significantly (P =0.048) higher all-cause mortality compared with the NAG group. A univariate Cox regression analysis revealed that the proinsulin concentration was significantly associated with all-cause mortality for all study participants (hazard ratio, 1.013; 95% CI, 1.002-1.024; P =0.023). AHG patients with increased proinsulin concentrations showed a mortality rate similar to that of DM patients but had a significantly higher mortality rate than patients with AHG and a low proinsulin concentration (chi2 =7.57; P =0.006) and patients with NAG (with or without increased proinsulin) [chi2 =7.66 (P =0.006) and 13.98 (P < 0.001), respectively]. A multivariate regression analysis revealed that the concentrations of glucose and proinsulin at admission were significant (P =0.002) predictors of all-cause mortality. CONCLUSIONS: An increased proinsulin concentration may be a marker for mortality in ACS patients with hyperglycemia at admission and without known diabetes. Further studies are needed to evaluate the role of metabolic parameters such as proinsulin. PMID- 21784764 TI - Quality error rates in point-of-care testing. AB - BACKGROUND: Although a theoretical consideration suggests that point-of-care testing (POCT) might be uniquely vulnerable to error, little information is available on the quality error rate associated with POCT. Such information would help inform risk/benefit analyses when one considers the introduction of POCT. METHODS: This study included 1 nonacute and 2 acute hospital sites. The 2 acute sites each had a 24-h central laboratory service. POCT was used for a range of tests, including blood gas/electrolytes, urine pregnancy testing, hemoglobin A(1c) (Hb A(1c)), blood glucose, blood ketones, screening for drugs of abuse, and urine dipstick testing. An established Quality Query reporting system was in place to log and investigate all quality errors associated with POCT. We reviewed reports logged over a 14-month period. RESULTS: Over the reporting period, 225 Quality Query reports were logged against a total of 407 704 POCT tests. Almost two-thirds of reports were logged by clinical users, and the remainder by laboratory staff. The quality error rate ranged from 0% for blood ketone testing to 0.65% for Hb A(1c) testing. Two-thirds of quality errors occurred in the analytical phase of the testing process. These errors were all assessed as having no or minimal adverse impact on patient outcomes; however, the potential adverse impact was graded higher. CONCLUSIONS: The quality error rate for POCT is variable and may be considerably higher than that reported previously for central laboratory testing. PMID- 21784765 TI - Passing the paternite test. PMID- 21784766 TI - Early dynamic change in high-sensitivity cardiac troponin T in the investigation of acute myocardial infarction. AB - BACKGROUND: The definition of acute myocardial infarction (AMI) requires a rise and/or fall in troponin with 1 or more results >=99th percentile of the reference range. How much troponin must change has not been specified. We ascertained whether dynamic changes (delta) in high-sensitivity troponin T (hs-TnT) improved diagnostic and prognostic test performance in the emergency department. METHODS: We recruited 939 patients with symptoms suggestive of acute coronary syndrome (without ST elevation). hs-cTnT was measured at 0 h and 2 h after presentation. End-points were admission diagnosis of AMI and 1-year adverse events (composite of death, AMI, revascularization). RESULTS: Diagnostic specificity of 0-2-h hs cTnT for AMI (incurred by 200 patients) improved from 79.8% (78.8%-80.5%) by using the 99th percentile alone to 94.2% (92.9%-95.4%) when we also included a delta >=20%, but diagnostic sensitivity decreased from 94.5% (90.7%-96.9%) to 49.5% (44.6%-53.9%). With the inclusion of those patients with a delta >=20% when 0-2-h hs-cTnT was <99th percentile, in addition to any with concentrations >=99th percentile, diagnostic sensitivity increased to 97.5% (94.4%-98.9%). hs-cTnT >=99th percentile predicted adverse events (incurred by 111 patients), adjusted hazard ratio 1.9 (1.2-2.8), whereas a delta >=20% did not, hazard ratio 1.1 (0.7 1.7). CONCLUSIONS: Diagnostic specificity of hs-cTnT improved with the use of a delta >=20% in those patients with concentrations >=99th percentile, but at a cost of a large reduction in sensitivity. Diagnostic sensitivity improved with the use of a delta >=20% in patients with 0-2-h concentrations <99th percentile. Both approaches may be required for optimum rule-in and rule-out strategies, respectively. The delta criteria seem to be less useful for medium-term risk stratification. PMID- 21784768 TI - Point-of-care testing quality: some positives but also some negatives. PMID- 21784767 TI - Prognostic utility of secretory phospholipase A(2) in patients with stable coronary artery disease. AB - BACKGROUND: Secretory phospholipase A(2) (sPLA(2)) may contribute to atherogenesis. To date, few prospective studies have examined the utility of sPLA(2) for risk stratification in coronary artery disease (CAD). METHODS: We measured plasma sPLA(2) activity at baseline in 3708 subjects in the PEACE randomized trial of trandolapril vs placebo in stable CAD. Median follow-up was 4.8 years. We used Cox regression to adjust for demographics, clinical risk factors, apolipoprotein B, apolipoprotein A1, and medications. RESULTS: After multivariable adjustment, sPLA(2) was associated with an increased risk of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio Q4:Q1 1.55, 95% CI 1.13-2.14) and cardiovascular death or heart failure (1.91, 1.20-3.03). In further multivariable assessment, increased activity levels of sPLA(2) were associated with the risk of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio 1.47, 95% CI 1.06-2.04), independent of lipoprotein-associated phospholipase A(2) mass and C-reactive protein, and modestly improved the area under the curve (AUC) beyond established clinical risk factors (AUC 0.668-0.675, P = 0.01). sPLA(2), N-terminal pro-B-type natriuretic peptide, and high-sensitivity cardiac troponin T all were independently associated with cardiovascular death or heart failure, and each improved risk discrimination (P = 0.02, P < 0.001, P < 0.001, respectively). CONCLUSIONS: sPLA(2) activity provides independent prognostic information beyond established risk markers in patients with stable CAD. These data are encouraging for studies designed to evaluate the role of sPLA(2) as a therapeutic target. PMID- 21784769 TI - Circulating tumor cells in breast cancer: detection systems, molecular characterization, and future challenges. AB - BACKGROUND: Circulating tumor cell (CTC) analysis is a promising new diagnostic field for estimating the risk for metastatic relapse and metastatic progression in patients with cancer. CONTENT: Different analytical systems for CTC isolation and detection have been developed as immunocytochemical and molecular assays, most including separation steps by size or biological characteristics, such as expression of epithelial- or cancer-specific markers. Recent technical advancements in CTC detection and characterization include methods based on multiplex reverse-transcription quantitative PCR and approaches based on imaging and microfilter and microchip devices. New areas of research are directed toward developing novel assays for CTC molecular characterization. QC is an important issue for CTC analysis, and standardization of micrometastatic cell detection and characterization methodologies is important for the incorporation of CTCs into prospective clinical trials to test their clinical utility. The molecular characterization of CTCs can provide important information on the molecular and biological nature of these cells, such as the status of hormone receptors and epidermal and other growth factor receptor family members, and indications of stem-cell characteristics. This information is important for the identification of therapeutic targets and resistance mechanisms in CTCs as well as for the stratification of patients and real-time monitoring of systemic therapies. SUMMARY: CTC analysis can be used as a liquid biopsy approach for prognostic and predictive purposes in breast and other cancers. In this review we focus on state of-the-art technology platforms for CTC isolation, imaging, and detection; QC of CTC analysis; and ongoing challenges for the molecular characterization of CTCs. PMID- 21784770 TI - Longitudinal associations of socioeconomic position in childhood and adulthood with decline in lung function over 20 years: results from a population-based cohort of British men. AB - BACKGROUND: Associations of socioeconomic position with lung function are reported mostly from cross-sectional studies. The aim of this study was to investigate the associations between socioeconomic position both in adulthood and childhood with changes in lung function over a 20-year period. METHODS: A socioeconomically representative cohort of 7735 British men aged 40-59 years was followed-up from 1978-1980 to 1998-2000. Lung function (height-standardised forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)) was assessed at both time points in 4252 survivors. Adult socioeconomic position was derived from longest-held occupation in middle age and childhood socioeconomic position from father's longest-held occupation. RESULTS: Both FEV(1) and FVC declined over time; the decline increased progressively from social class I (highest) to V (lowest); p for trend <= 0.0001. The mean difference in decline comparing manual versus non-manual groups was -0.13 litres (95% CI -0.16 to 0.10) for FEV(1) and -0.09 litres (95% CI -0.13 to -0.05) for FVC. These differences remained after adjustment for age, cigarette smoking, body mass index, physical activity and history of bronchitis. Similar differences in lung function decline were observed comparing manual with non-manual childhood social classes, although the differences were reduced by adjustment for adult social class and risk factors. Men in manual social classes in both childhood and adulthood had the greatest decline in lung function compared to those in non manual groups in childhood and adulthood. CONCLUSIONS: Socioeconomic position across the life course could have a significant impact on decline in lung function in later life. The role of environmental factors associated with socioeconomic position merits further exploration. PMID- 21784772 TI - The skeleton: no bones about it. PMID- 21784771 TI - L-arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge. AB - In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of beta-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 beta-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0 1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1beta, tumour necrosis factor alpha and interferon gamma). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L arginine at 1.15 mmol/l attenuated the loss of beta-cell viability observed in the presence of proinflammatory cytokines. L-arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate beta-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of beta-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for beta-cells during inflammatory challenge. PMID- 21784773 TI - Drug-induced changes in cortical inhibition in medication overuse headache. AB - BACKGROUND: We investigated whether chronic headache related to medication overuse (MOH) is associated with changes in brain mechanisms regulating inhibitory cortical responses compared with healthy volunteers and episodic migraineurs recorded between attacks, and whether these changes differ according to the drug overused. SUBJECTS AND METHODS: We studied 40 MOH patients whose symptoms were related to triptans alone, non-steroidal anti-inflammatory drugs (NSAIDs) or both medications combined, 12 migraineurs and 13 healthy volunteers. We used high-intensity transcranial magnetic stimulation over the primary motor cortex to assess the silent period from contracted perioral muscles. RESULTS: In MOH patients the cortical silent period differed according to the type of headache medication overused: in patients overusing triptans alone it was shorter than in healthy volunteers (44.7 +/- 14.2 vs. 108.1 +/- 30.1 ms), but similar to that reported in migraineurs (59.9 +/- 30.4 ms), whereas in patients overusing NSAIDs alone or triptans and NSAIDs combined duration of silent period was within normal limits (80.6 +/- 46.4 and 103.8 +/- 47.2 ms). CONCLUSIONS: Compared with episodic migraineurs, MOH patients overusing triptans have no significant change in cortical inhibition, whereas those overusing NSAIDs have an increase in cortical inhibitory mechanisms. We attribute these changes to medication-induced neural adaptation promoted by changes in central serotonin neurotransmission. PMID- 21784774 TI - Trigger factors for familial hemiplegic migraine. AB - OBJECTIVE: The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample. METHODS: 127 FHM patients were sent a questionnaire listing 16 trigger factors. Distinction was made between attacks of hemiplegic migraine (HM) and migraine with aura (MA) or without aura (MO) within each patient. RESULTS: The response rate was 59% (75/127) of whom 57 (76%) had current HM attacks. Sixty-three per cent (47/75) reported at least one factor triggering HM, and 36% (27/75) reported at least one factor that often or always caused HM. Twenty per cent (15/75) reported only HM, whereas FHM in combinations with MA and MO were reported by 80% (60/75). Stress (with attacks either following or during the stress), bright light, intense emotional influences and sleeping too much or too little were the trigger factors mentioned by most. CONCLUSION: Many FHM patients report trigger factors and one-third reported at least one trigger factor often or always triggering FHM. The typical triggers are the same as for MA. Patients should be educated to avoid these factors. The role of trigger factors in the onset of new or first attacks of FHM remains unknown. PMID- 21784775 TI - Do children really recover better? Neurobehavioural plasticity after early brain insult. AB - Plasticity is an intrinsic property of the central nervous system, reflecting its capacity to respond in a dynamic manner to the environment and experience via modification of neural circuitry. In the context of healthy development, plasticity is considered beneficial, facilitating adaptive change in response to environmental stimuli and enrichment, with research documenting establishment of new neural connections and modification to the mapping between neural activity and behaviour. Less is known about the impact of this plasticity in the context of the young, injured brain. This review seeks to explore plasticity processes in the context of early brain insult, taking into account historical perspectives and building on recent advances in knowledge regarding ongoing development and recovery following early brain insult, with a major emphasis on neurobehavioural domains. We were particularly interested to explore the way in which plasticity processes respond to early brain insult, the implications for functional recovery and how this literature contributes to the debate between localization of brain function and neural network models. To this end we have provided an overview of normal brain development, followed by a description of the biological mechanisms associated with the most common childhood brain insults, in order to explore an evidence base for considering the competing theoretical perspectives of early plasticity and early vulnerability. We then detail these theories and the way in which they contribute to our understanding of the consequences of early brain insult. Finally, we examine evidence that considers key factors (e.g. insult severity, age at insult, environment) that may act, either independently or synergistically, to influence recovery processes and ultimate outcome. We conclude that neither plasticity nor vulnerability theories are able to explain the range of functional outcomes from early brain insult. Rather, they represent extremes along a 'recovery continuum'. Where a child's outcome falls along this continuum depends on injury factors (severity, nature, age) and environmental influences (family, sociodemographic factors, interventions). PMID- 21784776 TI - Maternal coping during early motherhood among first-time Chinese mothers. AB - This qualitative study explored the coping strategies used by first-time Hong Kong Chinese mothers in adjusting to the demands of early motherhood. A purposive sample of 26 first-time Chinese mothers who had participated in a childbirth psycho-education program was interviewed in-depth at six weeks postpartum in respect to their coping strategies. Two main categories emerged: making personalized and achievable decisions and seeking emotional and spiritual solace. Implications for health professionals are discussed, including the need to support individual women's personal resources and foster social networks to optimize maternal and infant health. PMID- 21784777 TI - Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus. AB - Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C->T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects. PMID- 21784778 TI - Rituximab induces a rapid and sustained remission in Colombian patients with severe and refractory systemic lupus erythematosus. AB - Despite aggressive treatment for systemic lupus erythematosus (SLE) with high dose glucocorticoids and immunosuppressive agents, a significant proportion of patients persist with activity or relapse. Although the results from randomized studies showed no beneficial effects of rituximab (RTX) in SLE, this treatment has proven promising results in open label trials including patients with severe and refractory disease. We report a prospective cohort of 42 Colombian patients with severe and refractory SLE treated with RTX after failure response to glucocorticoids and, at least, another immunosuppressive drug. We observed a reduction in steroid requirement [47.4 mg/day at 24 months (p < 0.001)]. Since the first three-month follow-up, 28% and 36% of the patients fulfilled criteria of complete or partial remission according to proteinuria, and 12.5% and 33% according to creatinine clearance, respectively. These response criteria remained at 12 months. Both neuropsychiatric and hematological sub-groups had a favorable clinical response. The median reinfusion-free survival time was 44 months (95% confidence interval: 10.1-50.1) and 80% of the patients did not require RTX reinfusion. Eleven adverse events were reported in 28 subjects. Most of these occurred during the first three-month follow-up, time during which patients were exposed to high-dose glucocorticoids. PMID- 21784779 TI - Antiphospholipid syndrome and relapsing polychondritis: an unusual association. PMID- 21784780 TI - Autoimmune encephalitis: a case series and comprehensive review of the literature. AB - Encephalitic syndromes are a common medical emergency. The importance of early diagnosis and appropriate treatment is paramount. If initial investigations for infectious agents prove negative, other diagnoses must be considered promptly. Autoimmune encephalitides are being increasingly recognized as important (and potentially reversible) non-infectious causes of an encephalitic syndrome. We describe four patients with autoimmune encephalitis--3 auto-antibody positive, 1 auto-antibody negative--treated during the last 18 months. A comprehensive review of the literature in this expanding area will be of interest to the infectious diseases, general medical and neurology community. PMID- 21784781 TI - Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI). AB - OBJECTIVES: Aztreonam for inhalation solution (AZLI) is an inhaled antibiotic for patients with cystic fibrosis (CF) and Pseudomonas aeruginosa airway infection. The risk of selecting for P. aeruginosa isolates with reduced susceptibility to antibiotics is inherent to their use, but is of particular concern following repeated exposure and when complete eradication of lung pathogens is difficult to obtain. We investigated whether repeated treatment courses of AZLI led to decreases in P. aeruginosa susceptibility to aztreonam or other antibiotics. METHODS: Serial sputum specimens were collected and processed for isolation and quantification of all P. aeruginosa isolates in a Phase 3 open-label, 18 month study (NCT00128492) including 274 CF patients receiving up to nine courses of AZLI twice daily (AZLI2) or thrice daily (AZLI3) (28 days on/28 days off). P. aeruginosa antibiotic susceptibility testing was conducted. RESULTS: No changes were observed in the aztreonam MIC(50) for all P. aeruginosa isolates collected from AZLI3 patients, while intermittent increases were observed in the aztreonam MIC(90). Approximately 70% of the P. aeruginosa isolates with the highest aztreonam MIC from each patient receiving AZLI3 remained unchanged or decreased relative to that patient's equivalent isolate at baseline; 30% experienced an increase in MIC. Few decreases in P. aeruginosa susceptibility to other antibiotics were observed in AZLI3 patients, while increases in P. aeruginosa susceptibility to tobramycin were observed. CONCLUSIONS: Few decreases in aztreonam susceptibility were reported in patients receiving AZLI3. Increases in tobramycin susceptibility were observed, suggesting that novel treatment paradigms may be able to prolong antibiotic susceptibility in CF patients. PMID- 21784782 TI - Do general practitioners' consultation rates influence their prescribing patterns of antibiotics for acute respiratory tract infections? AB - OBJECTIVES: To examine general practitioners' (GPs') antibiotic prescribing patterns for acute respiratory tract infections (ARTIs) as compared with national guidelines. We also wanted to explore possible predictors of antibiotic prescription patterns. METHODS: Observational study based on prescription data from 440 Norwegian GPs in December 2004 through to November 2005. Outcome measures were the type and frequency of antibiotic prescriptions for various ARTI diagnoses, with patients' and GPs' characteristics as explanatory variables. RESULTS: In the study period, the 440 GPs treated a total of 142 900 ARTI episodes. In 33.5% [95% confidence interval (CI): 31.9%-35.1%] of these episodes an antibiotic was issued, of which penicillin V (pcV) accounted for 41.2% (95% CI: 37.4%-44.9%). GPs with a high number of total annual encounters had higher antibiotic prescription rates for ARTIs and used more non-pcV antibiotics compared with GPs with fewer annual patient encounters. GPs in the highest quintile with respect to the total annual encounter rate had 1.6 times the odds of prescribing antibiotics compared with GPs in the lowest quintile. Correspondingly, the odds of choosing a non-pcV antibiotic were 2.8 times higher in the top quintile of GPs compared with GPs in the bottom quintile with respect to antibiotic prescription rates. CONCLUSIONS: ARTIs are frequently treated with antibiotics and often with broader spectrum agents than pcV, which is the recommended first-line antibiotic in the Norwegian guidelines. GPs with a high practice activity are, in general, more liberal with respect to the prescription of antibiotics for ARTIs, and the higher the antibiotic prescription rate, the larger the share of non-pcV agents. PMID- 21784783 TI - Putting public confidence first: doctors, precautionary suspension, and the General Medical Council. PMID- 21784784 TI - Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism. AB - GPR39, a constitutively active 7TM receptor important for glucose-induced insulin secretion and maturation of pancreatic beta-cell function, is up-regulated in adipose tissue on abstinence from food and chemically induced diabetes. In the present study, we investigated the effect of GPR39 deficiency on body weight and adipocyte metabolism. GPR39-deficient mice were subjected to a high-fat diet and body composition, glucose tolerance, insulin secretion, food intake, and energy expenditure were evaluated. The cell biology of adipocyte metabolism was studied on both mRNA and protein levels. A significant increase in body weight corresponding to a 2-fold selective increase in fat mass was observed in GPR39 deficient mice fed a high-fat diet as compared with wild-type littermate controls fed the same diet. The GPR39-deficient animals had similar food intake but displayed almost eliminated diet-induced thermogenesis, measured by the oxygen consumption rate (Vo(2)) on change from normal to high-fat diet. Analysis of the adipose tissue for lipolytic enzymes demonstrated decreased level of phosphorylated hormone-sensitive lipase (HSL) and a decreased level of adipose triglyceride lipase (ATGL) by 35 and 60%, respectively, after food withdrawal in the GPR39-deficient mice. Extracellular signal-regulated kinases (ERK1/2), a signaling pathway known to be important for lipolysis, was decreased by 56% in the GPR39-deficient mice. GPR39 deficiency is associated with increased fat accumulation on a high-fat diet, conceivably due to decreased energy expenditure and adipocyte lipolytic activity. PMID- 21784785 TI - Characterization of novel glycolipid antigens with an alpha-galactose epitope in lactobacilli detected with rabbit anti-Lactobacillus antisera and occurrence of antibodies against them in human sera. AB - Anti-Lactobacillus johnsonii (LJ) antisera generated by immunization of rabbits with LJ reacted with glyceroglycolipids in LJ, i.e. dihexaosyl diacylglycerol (DH DG), trihexaosyl DG (TH-DG) and tetrahexaosyl DG (TetH-DG), whose reactivities with antisera increased proportionally with longer carbohydrate chains of glycolipids. Structural analyses of glycolipids from LJ revealed that DH-DG was Galalpha1-2Glcalpha1-3'DG, and TH-DG and TetH-DG were novel derivatives of it with alpha-Gal at the non-reducing terminal, i.e. Galalpha1-6Galalpha1-2Glcalpha1 3'DG and Galalpha1-6Galalpha1-6Galalpha1-2Glcalpha1-3'DG, respectively. DH-DG was commonly present in several lactobacilli examined, but TetH-DG was restricted to LJ, L. intestinalis and L. reuteri, while the TH-DGs from L. casei were Glc1 6Galalpha1-2Glcalpha1-3'DG and an esterified derivative of it, Glc1-6Galalpha1 2Glc(6-fatty acid)alpha1-3'DG, as reported in the literature. Anti-LJ antisera reacted with TH-DG and esterified TH-DG from L. casei to lesser extents, but not at all with gentibiosyl DG from Staphylococcus epidermidis or kojibiosyl DG from Streptococcus salivalis or sphingoglycolipids containing alpha-Gal residues. The major molecular species of glycolipids obtained from lactobacilli were 11 octadecenoic and 11,12-methylene-octadecanoic acids-containing ones. Also, human IgM antibodies against TH-DG and TetH-DG from LJ were detected in human sera, with various antibody titres, indicating that an immune reaction to symbiotic lactobacilli occurs against their glycolipid antigens, TH-DG and TetH-DG. PMID- 21784786 TI - Arabidopsis RPT2a encoding the 26S proteasome subunit is required for various aspects of root meristem maintenance, and regulates gametogenesis redundantly with its homolog, RPT2b. AB - The 26S proteasome plays fundamental roles in the degradation of short-lived regulatory proteins, thereby controlling diverse cellular processes. In Arabidopsis, the essential RPT2 subunit is encoded by two highly homologous genes: RPT2a and RPT2b. Currently, only RPT2a has been reported to regulate various developmental processes, including the maintenance of the root apical meristem (RAM), although the roles of RPT2a in the RAM are still obscure. Here, we analyzed the cell type-specific requirement for RPT2a. When RPT2a was expressed locally in the rpt2a mutant, pleiotropic defects in the RAM, such as cell death and distorted cellular organization, were rescued differently, suggesting that RPT2a regulates various specific activities, which converge to maintain the RAM. On the other hand, the homologous RPT2b was also expressed in meristems, and the expression of RPT2b protein under the control of the RPT2a promoter complemented the rpt2a RAM defects, although the rpt2b mutant showed no obvious defect in all developmental aspects we examined. These results show that RPT2b might work in the RAM, but is dispensable for RAM maintenance in the presence of RPT2a. In contrast, the rpt2a rpt2b double mutant was lethal in male and female gametophytes, suggesting that RPT2a and RPT2b are redundantly required for gametogenesis. Furthermore, we showed that similar meristematic and gametophytic defects were caused by mutations in other subunit genes, RPT5a and RPT5b, suggesting that proper activity of the proteasome, not an RPT2-specific function, is required. Taken together, our results suggest that RPT2a and RPT2b contribute differently to the proteasome activity required for each developmental context. PMID- 21784787 TI - Ghrelin reduces hypertonic saline intake in a variety of natriorexigenic conditions. AB - Ghrelin is a gut peptide that has been studied extensively for its role in food intake and energy balance. More recent studies show that ghrelin reduces water intake in rats and some non-mammalian species. Despite the importance of the regulation of NaCl intake in body fluid homeostasis, the effects of ghrelin on saline intake have not been investigated. Accordingly, we tested the effect of ghrelin on water and 1.8% NaCl intake in two-bottle test conditions with the following five stimuli that increase hypertonic saline intake: central angiotensin II administration; 24 h fluid deprivation; water deprivation followed by partial rehydration; dietary sodium deficiency; and polyethylene glycol administration combined with dietary sodium deficiency. We found that ghrelin attenuated saline intake stimulated by angiotensin II, by water deprivation followed by partial rehydration and by dietary sodium deficiency. We did not detect an effect of ghrelin on saline intake after 24 h fluid deprivation without partial rehydration or after the combination of polyethylene glycol and dietary sodium deficiency. The finding that ghrelin reduced hypertonic saline intake in some, but not all, natriorexigenic conditions mirrors the previously published findings that in one-bottle tests of drinking, ghrelin reduces water intake in only some conditions. The results provide evidence for a new role for ghrelin in the regulation of body fluid homeostasis. PMID- 21784789 TI - How can we tell if frogs jump further? PMID- 21784788 TI - Brachial artery vasodilatation during prolonged lower limb exercise: role of shear rate. AB - We recently observed a marked increase in brachial artery (BA) diameter during prolonged leg cycling exercise. The purpose of the present study was to test the hypothesis that this increase in BA diameter during lower limb exercise is shear stress mediated. Accordingly, we determined whether recapitulation of cycling induced BA shear rate with forearm heating, a known stimulus evoking shear induced conduit artery dilatation, would elicit comparable profiles and magnitudes of BA vasodilatation to those observed during cycling. In 12 healthy men, BA diameter and blood velocity were measured simultaneously using Doppler ultrasonography at baseline and every 5 min during 60 min of either steady-state semi-recumbent leg cycling (120 W) or forearm heating. At the onset of cycling, the BA diameter was reduced (-3.9 +/- 1.2% at 5 min; P < 0.05), but it subsequently increased throughout the remainder of the exercise bout (+15.1 +/- 1.6% at 60 min; P < 0.05). The increase in BA diameter during exercise was accompanied by an approximately 2.5-fold rise in BA mean shear rate (P < 0.05). Similar increases in BA mean shear with forearm heating elicited an equivalent magnitude of BA vasodilatation to that observed during cycling (P > 0.05). Herein, we found that in the absence of exercise the extent of the BA vasodilator response was reproduced when the BA was exposed to comparable magnitudes of shear rate via forearm heating. These results are consistent with the hypothesis that shear stress plays a key role in signalling brachial artery vasodilatation during dynamic leg exercise. PMID- 21784790 TI - The uraemic milieu, the ubiquitin-proteasome pathway and the endothelial cell: a pathway to dysfunction. PMID- 21784791 TI - Retraction: Exercise-induced metallothionein expression in human skeletal muscle fibres. PMID- 21784792 TI - GenSSI: a software toolbox for structural identifiability analysis of biological models. AB - SUMMARY: Mathematical modeling has a key role in systems biology. Model building is often regarded as an iterative loop involving several tasks, among which the estimation of unknown parameters of the model from a certain set of experimental data is of central importance. This problem of parameter estimation has many possible pitfalls, and modelers should be very careful to avoid them. Many of such difficulties arise from a fundamental (yet often overlooked) property: the so-called structural (or a priori) identifiability, which considers the uniqueness of the estimated parameters. Obviously, the structural identifiability of any tentative model should be checked at the beginning of the model building loop. However, checking this property for arbitrary non-linear dynamic models is not an easy task. Here we present a software toolbox, GenSSI (Generating Series for testing Structural Identifiability), which enables non-expert users to carry out such analysis. The toolbox runs under the popular MATLAB environment and is accompanied by detailed documentation and relevant examples. AVAILABILITY: The GenSSI toolbox and the related documentation are available at http://www.iim.csic.es/%7Egenssi. CONTACT: ebalsa@iim.csic.es. PMID- 21784793 TI - Structural analysis of the hot spots in the binding between H1N1 HA and the 2D1 antibody: do mutations of H1N1 from 1918 to 2009 affect much on this binding? AB - MOTIVATION: Worldwide and substantial mortality caused by the 2009 H1N1 influenza A has stimulated a new surge of research on H1N1 viruses. An epitope conservation has been learned in the HA1 protein that allows antibodies to cross-neutralize both 1918 and 2009 H1N1. However, few works have thoroughly studied the binding hot spots in those two antigen-antibody interfaces which are responsible for the antibody cross-neutralization. RESULTS: We apply predictive methods to identify binding hot spots at the epitope sites of the HA1 proteins and at the paratope sites of the 2D1 antibody. We find that the six mutations at the HA1's epitope from 1918 to 2009 should not harm its binding to 2D1. Instead, the change of binding free energy on the whole exhibits an increased tendency after these mutations, making the binding stronger. This is consistent with the observation that the 1918 H1N1 neutralizing antibody can cross-react with 2009 H1N1. We identified three distinguished hot spot residues, including Lys(166), common between the two epitopes. These common hot spots again can explain why 2D1 cross reacted. We believe that these hot spot residues are mutation candidates which may help H1N1 viruses to evade the immune system. We also identified eight residues at the paratope site of 2D1, five from its heavy chain and three from its light chain, that are predicted to be energetically important in the HA1 recognition. The identification of these hot spot residues and their structural analysis are potentially useful to fight against H1N1 viruses. CONTACT: jinyan.li@uts.edu.au AVAILABILITY: Z-score is available at http://155.69.2.25/liuqian/indexz.py SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21784794 TI - Identifying disease-associated SNP clusters via contiguous outlier detection. AB - MOTIVATION: Although genome-wide association studies (GWAS) have identified many disease-susceptibility single-nucleotide polymorphisms (SNPs), these findings can only explain a small portion of genetic contributions to complex diseases, which is known as the missing heritability. A possible explanation is that genetic variants with small effects have not been detected. The chance is < 8 that a causal SNP will be directly genotyped. The effects of its neighboring SNPs may be too weak to be detected due to the effect decay caused by imperfect linkage disequilibrium. Moreover, it is still challenging to detect a causal SNP with a small effect even if it has been directly genotyped. RESULTS: In order to increase the statistical power when detecting disease-associated SNPs with relatively small effects, we propose a method using neighborhood information. Since the disease-associated SNPs account for only a small fraction of the entire SNP set, we formulate this problem as Contiguous Outlier DEtection (CODE), which is a discrete optimization problem. In our formulation, we cast the disease associated SNPs as outliers and further impose a spatial continuity constraint for outlier detection. We show that this optimization can be solved exactly using graph cuts. We also employ the stability selection strategy to control the false positive results caused by imperfect parameter tuning. We demonstrate its advantage in simulations and real experiments. In particular, the newly identified SNP clusters are replicable in two independent datasets. AVAILABILITY: The software is available at: http://bioinformatics.ust.hk/CODE.zip. CONTACT: eeyu@ust.hk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21784795 TI - Estimating classification probabilities in high-dimensional diagnostic studies. AB - MOTIVATION: Classification algorithms for high-dimensional biological data like gene expression profiles or metabolomic fingerprints are typically evaluated by the number of misclassifications across a test dataset. However, to judge the classification of a single case in the context of clinical diagnosis, we need to assess the uncertainties associated with that individual case rather than the average accuracy across many cases. Reliability of individual classifications can be expressed in terms of class probabilities. While classification algorithms are a well-developed area of research, the estimation of class probabilities is considerably less progressed in biology, with only a few classification algorithms that provide estimated class probabilities. RESULTS: We compared several probability estimators in the context of classification of metabolomics profiles. Evaluation criteria included sparseness biases, calibration of the estimator, the variance of the estimator and its performance in identifying highly reliable classifications. We observed that several of them display artifacts that compromise their use in practice. Classification probabilities based on a combination of local cross-validation error rates and monotone regression prove superior in metabolomic profiling. AVAILABILITY: The source code written in R is freely available at http://compdiag.uni regensburg.de/software/probEstimation.shtml. CONTACT: inka.appel@klinik.uni regensburg.de. PMID- 21784796 TI - phyloMeta: a program for phylogenetic comparative analyses with meta-analysis. AB - SUMMARY: phyloMeta is an easy to use console program for integrating phylogenetic information into meta-analysis. It is designed to help ecologists, evolutionary biologists and conservation biologists analyze effect size data extracted from published studies in a comparative phylogenetic context. This software estimates phylogenetic versions of all the traditional meta-analytical statistics used for: pooling effect sizes with weighted regressions; evaluating the homogeneity of these effect sizes; performing moderator tests akin to ANOVA style analyses; and analyzing data with fixed- and random-effects models. phyloMeta is developed in C/C++ and can be used via command line in MS Windows environments. AVAILABILITY: phyloMeta can be obtained freely as an executable on the web at http://lajeunesse.myweb.usf.edu/publications CONTACT: lajeunesse@usf.edu. PMID- 21784797 TI - Further consultation on proposals for a badger cull in England. PMID- 21784798 TI - Young scientist recognised for feline gene therapy research. PMID- 21784799 TI - Business index suggests improved trading conditions for practices. PMID- 21784800 TI - Hopes rise for continued controls on E multilocularis. PMID- 21784801 TI - Rise in scientific procedures on animals. PMID- 21784802 TI - Work begins on charity's cancer centre. PMID- 21784803 TI - UFAW medal marks outstanding contributions to animal welfare science. PMID- 21784805 TI - Veterinary union links up with Unite. PMID- 21784806 TI - From London to Dorset: honing students' farm animal skills. PMID- 21784807 TI - Changes to pet travel rules: rabies, ticks and tapeworms. PMID- 21784808 TI - Antibiotic use in farm animal practice. PMID- 21784809 TI - Climate change as a scapegoat for veterinary public health problems. PMID- 21784810 TI - Overcoming difficulties with cascade labelling. PMID- 21784811 TI - Excess vitamin A intake during pregnancy as a possible cause of congenital cleft palate in puppies and kittens. PMID- 21784812 TI - Benzimidazole resistance in Nematodirus battus. PMID- 21784813 TI - New genotype of avian bornavirus in wild geese and trumpeter swans in Canada. PMID- 21784814 TI - Systematic shifts in cystatin C between 2006 and 2010. AB - BACKGROUND AND OBJECTIVES: Cystatin C is used increasingly as a biomarker of renal function; however, cystatin C assays are not standardized. Our objective was to compare cystatin C results within the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study over time and in repeated measures to evaluate for assay drift. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum samples were obtained at baseline (visit 1 [V1], 2000 to 2002) and follow-up (visit 2 [V2], 2003 to 2005; visit 3 [V3], 2006 to 2008) and were assayed in 2006 (V1), 2007 to 2008 (V2), and 2010 (V3) in the same laboratory. RESULTS: Mean cystatin C levels measured using the Dade-Behring assay decreased over time in subjects, with measures at all three visits (V1: 0.80 +/- 0.19 [0.42 to 3.41], V2: 0.75 +/- 0.22 [0.39 to 3.77], and V3: 0.69 +/- 0.22 [0.39 to 3.79]). Cystatin C values were lower in V1 and V2 samples remeasured in 2010 (mean differences -0.13 +/- 0.04 and -0.08 +/- 0.04, P < 0.0001 for both). Correlations for original and re-run values were strong for V1 (r = 0.99) and V2 (r = 0.99). Deming regression equations and Bland-Altman plots suggest a systematic shift in the values over time. CONCLUSIONS: Systematic shifts in cystatin C levels, which can be corrected by regression adjustment, occurred in our laboratory in samples measured in 2006 and 2007 to 2008 as compared with 2010. Assay standardization and measurement reliability for cystatin C must be addressed. PMID- 21784815 TI - Insights from the Chronic Kidney Disease in Children (CKiD) study. AB - Over the last 5 years, the Chronic Kidney Disease in Children (CKiD) prospective cohort study has enrolled close to 600 children ages 1 to 16 years with mild to moderate chronic kidney disease (CKD). The main purpose of this interim report is to review the initial cross-sectional data and conclusions derived from the clinical studies conducted within CKiD in the context of findings from other pediatric CKD and end-stage renal disease (ESRD) registry and cohort studies. In particular, special emphasis was placed on studying four aspects of chronic kidney disease in children, including the identification of risk factors related to disease progression, the impact of CKD on neurocognition and quality of life (QoL), the cardiovascular morbidity associated with CKD, and identifying the causes and effects of growth failure in the context of mild to moderate kidney failure. PMID- 21784817 TI - Change in kidney function over time and risk for adverse outcomes: is an increasing estimated GFR harmful? PMID- 21784816 TI - Long-term viral negativity after interferon for chronic hepatitis C virus infection in hemodialysis. AB - BACKGROUND AND OBJECTIVES: Interferon (IFN) and pegylated-IFN treatment of hepatitis C virus (HCV) infection in hemodialysis patients result in sustained virological response (SVR) rates of 45% and 37%, respectively. Although most nonhemodialysis patients who achieve SVR remain persistently viral negative, the durability of SVR in hemodialysis patients is unknown. We analyzed the rate of long-term virological negativity in hemodialysis patients who achieved SVR after IFN or pegylated-IFN through analysis of patient-level data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: After performing a systematic literature review for IFN-based treatment of hemodialysis patients with chronic HCV infection, we extracted patient-level data on patients who achieved SVR. We performed life table analysis to estimate long-term virological negativity rates after SVR in patients who continued on hemodialysis or subsequently underwent kidney transplantation. RESULTS: Long-term HCV RNA outcomes following SVR were available for 121 hemodialysis patients (20 studies) and 45 patients who subsequently underwent transplantation (11 studies). The probability of remaining HCV RNA negative was 86% (95% confidence interval, 77% to 96%) for patients followed on hemodialysis 48 months after SVR and 95% (95% confidence interval, 89% to 100%) for kidney recipients followed 48 months after transplant. CONCLUSIONS: Viral negativity from IFN-based HCV treatment in hemodialysis patient appears durable during extended follow-up, including after kidney transplantation. The certainty of the viral negativity estimate is limited by the small number with follow-up beyond 48 months or longer. Transplantation does not confer an increased risk of relapse. Future research should investigate whether IFN-based treatment improves clinical outcomes for hemodialysis patients. PMID- 21784818 TI - Vision-threatening retinal abnormalities in chronic kidney disease stages 3 to 5. AB - BACKGROUND AND OBJECTIVES: Retinal abnormalities are common in inherited and acquired renal disease. This study determined the prevalence of retinal abnormalities in chronic kidney disease (CKD) stages 3 to 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred fifty patients with CKD stages 3 to 5 and 150 age- and gender-matched hospital patients with CKD stages 1 to 2 underwent bilateral retinal photography. These images were reviewed for incidental abnormalities, microvascular (Wong and Mitchell classification) and diabetic retinopathy (Airlie House criteria), and macular degeneration (Seddon classification). RESULTS: Three (2%) patients with CKD stages 3 to 5 had retinal features characteristic of inherited renal disease (atrophy in Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes [MELAS] syndrome; and 2 with drusen in dense deposit disease). Fifty-nine (39%) patients had moderate severe microvascular retinopathy (hemorrhages, exudates, etc.) compared with 19 (13%) with CKD stages 1 to 2. Forty-one (28%) had moderate-severe diabetic retinopathy (microaneurysms, exudates, etc.) compared with 16 (11%) with CKD stages 1 to 2. Ten (7%) had severe macular degeneration (geographic atrophy, hemorrhage, exudates, membranes) compared with one (1%) with CKD stages 1 to 2. Renal failure was an independent risk factor for microvascular retinopathy, diabetic retinopathy, and macular degeneration. Eleven (7.3%) patients with renal failure and one (0.7%) with CKD stages 1 to 2 had previously unrecognized vision threatening retinal abnormalities that required immediate ophthalmologic attention. CONCLUSIONS: Retinal abnormalities are common in CKD stages 3 to 5, and are more severe and more likely to threaten vision than in hospital patients with CKD stages 1 to 2. PMID- 21784820 TI - Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Hyperphosphatemia and subclinical endotoxemia are important sources of inflammation in HD. Proinflammatory cytokines are strong correlates of soluble CD14 (sCD14) concentrations, an independent predictor of mortality in this population. We evaluated the effects of calcium acetate and sevelamer hydrochloride on serum inflammatory profile, endotoxin concentrations, and sCD14 levels in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective, randomized, open-label, parallel design trial. Fifty-nine stable HD patients, 30 receiving sevelamer, and 29 receiving calcium acetate were evaluated. Serum levels of inflammatory parameters (high-sensitivity C-reactive protein [hs-CRP], TNF-alpha, interleukin (IL)-1, -6, -10, and -18), as well as endotoxin and sCD14 concentrations, were measured at baseline and after 3 months of therapy. RESULTS: Serum IL-6 increased in patients receiving calcium acetate, whereas hs-CRP and IL-6 significantly decreased in subjects treated with sevelamer, with IL-10 experiencing a trend to increase (P = 0.052). Serum endotoxin and sCD14 levels did not change after treatment with calcium acetate. However, these parameters decreased by 22.6% and 15.2%, respectively (P < 0.01), in patients receiving sevelamer. Multiple regression analysis showed that variation in serum endotoxin concentrations was the strongest factor associated with IL-6 change, whereas the only variables independently associated with changes in sCD14 levels were the variations in serum IL-6 and endotoxin concentrations. CONCLUSIONS: Administration of the noncalcium phosphate binder sevelamer to maintenance HD patients is associated with a significant decrease in hs-CRP, IL-6, serum endotoxin levels and sCD14 concentrations. PMID- 21784819 TI - Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. AB - BACKGROUND AND OBJECTIVES: We assessed the activation of the oxidative stress pathway in patients with IgA nephropathy (IgAN), while evaluating the classic marker of the disease (galactose-deficient serum IgA1). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sera from 292 patients and 69 healthy controls from Italy and the United States were assayed for advanced oxidation protein products (AOPPs), free sulfhydryl groups on albumin (SH-Alb), and IgA1 with galactose deficient hinge-region O-glycans (Gd-IgA1). Gd-IgA1 was detected by binding to Helix aspersa agglutinin (HAA) and expressed as total Gd-IgA1 or as degree of galactose deficiency relative to a standard Gd-IgA1 myeloma protein (%HAA). RESULTS: Sera from IgAN patients showed higher levels of Gd-IgA1, %HAA, and AOPPs, but lower levels of SH-Alb in comparison to that from healthy controls. Serum levels of AOPPs significantly correlated with serum Gd-IgA1 and %HAA. The relationship between these biomarkers and clinical features at sampling and during follow-up was assessed in 62 patients with long-term follow-up. AOPPs and %HAA correlated with proteinuria at sampling and independently associated with subsequent proteinuria. Levels of AOPPs correlated with rate of decline in renal function after sampling. The combination of a high level of AOPPs and a high level of %HAA associated with decline in estimated GFR. CONCLUSIONS: Serum levels of aberrantly glycosylated IgA1 are elevated and oxidative stress pathways are activated in patients with IgAN; the intensity of the stress correlated with expression and progression of the disease. We speculate that oxidative stress may modulate the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN. PMID- 21784821 TI - Survival trends of US dialysis patients with heart failure: 1995 to 2005. AB - BACKGROUND AND OBJECTIVES: Congestive heart failure (CHF) is a major risk factor for death in end-stage kidney disease; however, data on prevalence and survival trends are limited. The objective of this study was to determine the prevalence and mortality effect of CHF in successive incident dialysis cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a population-based cohort of incident US dialysis patients (n = 926,298) from 1995 to 2005. Age- and gender specific prevalence of CHF was determined by incident year, whereas temporal trends in mortality were compared using multivariable Cox regression. RESULTS: The prevalence of CHF was significantly higher in women than men and in older than younger patients, but it did not change over time in men (range 28% to 33%) or women (range 33% to 36%). From 1995 to 2005, incident death rates decreased for younger men (<=70 years) and increased for older men (>70 years). For women, the pattern was similar but less impressive. During this period, the adjusted mortality risks (relative risk [RR]) from CHF decreased in men (from RR = 1.06 95% Confidence intervals (CI) 1.02-1.11 in 1995 to 0.91 95% CI 0.87-0.96 in 2005) and women (from RR = 1.06 95% CI 1.01-1.10 in 1995 to 0.90 95% CI 0.85-0.95 in 2005 compared with referent year 2000; RR = 1.00). The reduction in mortality over time was greater for younger than older patients (20% to 30% versus 5% to 10% decrease per decade). CONCLUSIONS: Although CHF remains a common condition at dialysis initiation, mortality risks in US patients have declined from 1995 to 2005. PMID- 21784822 TI - Role of the calcium-sensing receptor in reducing the risk for calcium stones. AB - The tight control of blood Ca2+ levels within a narrow range is essential for the performance of vital physiologic functions. Muscle contraction, neuronal excitation, and intracellular signaling processes acquisitively require Ca2+. It is the concerted action of intestine, bone, and kidney that controls the Ca2+ balance through the regulation of intestinal absorption, bone (de)mineralization, and renal excretion of Ca2+, respectively. Along the nephron, fine-tuning of blood Ca2+ levels takes place by Ca2+ reabsorption. The calciotropic hormones regulate Ca2+ transport processes, leading to whole-body Ca2+ homeostasis and, importantly, preserving a constant Ca2+ concentration in the blood. Defects in renal Ca2+ handling can lead to hypercalciuria, consecutive kidney stone formation, and obstructive nephropathy. Here we give an overview of the key players involved in normal Ca2+ management and describe the in-depth investigations on a renal hypercalciuric model of disease, the Trpv5 knockout mouse, which naturally displays molecular adaptations that prevent Ca2+ precipitation in the kidney. PMID- 21784823 TI - Chronic kidney disease stage progression in liver transplant recipients. AB - BACKGROUND AND OBJECTIVES: There is little information on chronic kidney disease (CKD) stage progression rates and outcomes in liver transplant recipients. Identifying modifiable risk factors may help prevent CKD progression in liver transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective review of 1151 adult, deceased-donor, single-organ primary liver transplants between July 1984 and December 2007 and analyzed kidney outcomes and risk factors for CKD stage progression. Seven hundred twenty-nine patients had an available estimated GFR at 1 year posttransplant to establish a baseline stage. The primary end point was the CKD progression from one stage to a higher stage (lower GFR). RESULTS: Kaplan-Meier estimates of patient survival were 91%, 74%, and 64% at 5, 10, and 15 years, respectively. Estimates of liver allograft survival were 89%, 71%, and 60% at the same time points. At 1 year, 7%, 34%, 56%, 3%, and 1% of patients were in CKD stages 1, 2, 3, 4, and 5. The incidence of stage progression was 28%, 40%, and 53% at 3, 5, and 10 years. The incidence of ESRD was 2.6%, 7.5%, and 18% at 5, 10, and 20 years. Multivariable Cox regression analyses demonstrated that CKD stage at 1 year, pretransplant diabetes and urinary tract infections/hypercholesterolemia in the first year proved to be independent risk factors for stage progression (hazard ratio 1.9, 0.28, 1.39, and 1.46, respectively, P < 0.05). CONCLUSIONS: Future studies will determine whether treatment of risk factors in the first posttransplant year prevent CKD progression in liver transplant recipients. PMID- 21784824 TI - Kidney function reference values in US adolescents: National Health And Nutrition Examination Survey 1999-2008. AB - BACKGROUND AND OBJECTIVES: Few data are available on kidney function in normal US adolescents. This study characterizes the distribution of kidney function measures and associated factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum creatinine, cystatin C, and urinary albumin-to-creatinine ratios were measured in US adolescents (aged 12 to 17 years; n = 5575) in the cross-sectional National Health and Nutrition Examination Survey 1999-2008. The reference population was defined as healthy adolescents with BP <120/80 mmHg and a Z-score for weight-to-height <=1.645, without self-reported diabetes or hypertension, not using prescription medications in the preceding 30 days, not pregnant or currently menstruating. RESULTS: were analyzed by age, gender, race, ethnicity, body mass index, and BP; estimated GFR (eGFR) was calculated using the original and revised Schwartz formulas. Results Mean values for eGFR(Schwartz original formula), serum creatinine, and serum cystatin C were 147 ml/min/1.73 m(2), 0.71 mg/dl, 0.82 mg/L, respectively. The median urinary albumin-to-creatinine ratio was 6.8 mg/g creatinine. In the reference population (n = 2881), eGFR differed significantly using the two Schwartz formulas; values were higher using the original formula (median values 143 versus 96 ml/min/1.73 m(2)). Serum creatinine level (0.7 versus 0.72 mg/dl), but not cystatin C level (0.82 versus 0.82 mg/L), was lower in the reference population than in a nonreference population of adolescents. CONCLUSIONS: These findings provide important demographic information and highlight the need for confirmatory testing of the revised Schwartz formula by comparison to measured GFR in healthy US adolescents. PMID- 21784825 TI - Chronic kidney disease in kidney stone formers. AB - Recent population studies have found symptomatic kidney stone formers to be at increased risk for chronic kidney disease (CKD). Although kidney stones are not commonly identified as the primary cause of ESRD, they still may be important contributing factors. Paradoxically, CKD can be protective against forming kidney stones because of the substantial reduction in urine calcium excretion. Among stone formers, those with rare hereditary diseases (cystinuria, primary hyperoxaluria, Dent disease, and 2,8 dihydroxyadenine stones), recurrent urinary tract infections, struvite stones, hypertension, and diabetes seem to be at highest risk for CKD. The primary mechanism for CKD from kidney stones is usually attributed to an obstructive uropathy or pyelonephritis, but crystal plugs at the ducts of Bellini and parenchymal injury from shockwave lithotripsy may also contribute. The historical shift to less invasive surgical management of kidney stones has likely had a beneficial impact on the risk for CKD. Among potential kidney donors, past symptomatic kidney stones but not radiographic stones found on computed tomography scans were associated with albuminuria. Kidney stones detected by ultrasound screening have also been associated with CKD in the general population. Further studies that better classify CKD, better characterize stone formers, more thoroughly address potential confounding by comorbidities, and have active instead of passive follow-up to avoid detection bias are needed. PMID- 21784826 TI - Incompatible live-donor kidney transplantation in the United States: results of a national survey. AB - BACKGROUND AND OBJECTIVES: Use of incompatible kidney transplantation (IKT) is growing as a response to the organ shortage and the increase in sensitization among candidates. However, recent regulatory mandates possibly threaten IKT, and the potential effect of these mandates cannot be estimated because dissemination of this modality remains unknown. The goal of this study was to better understand practice patterns of IKT in the United States. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Directors from all 187 unique active adult kidney transplant programs were queried about transplantation across the following antibody barriers: positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); positive cytotoxic crossmatch (PCC); and ABO incompatible (ABOi). RESULTS: Responses from 125 centers represented 84% of the live-donor transplant volume in the United States. Barriers of PLNF, PFNC, PCC, and ABOi are being crossed in 70%, 51%, 18%, and 24%, respectively, of transplant centers that responded. Desensitization was performed in 58% of PLNF, 76% of PFNC, 100% of PCC, and 80% of ABOi using plasmapheresis and low-dose intravenous Ig (IVIg) in 71% to 83% and high-dose IVIg in 29% to 46%. CONCLUSIONS: A higher proportion of centers perform IKT than might be inferred from the literature. The rapid dissemination of these protocols despite adequate evidence of a clear advantage of IKT transplants argues for the creation of a national registry and randomized studies. PMID- 21784827 TI - GFR estimation in children: questions and answers (and questions). PMID- 21784828 TI - The microvasculature in chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Individuals with chronic kidney disease (CKD) stages 3 to 5 have an increased risk of cardiac and other vascular disease. Here we examined the association of CKD 3 to 5 with small vessel caliber. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a cross-sectional observational study of 126 patients with CKD stages 3 to 5 (estimated GFR [eGFR] <60 ml/min per 1.73 m(2)) and 126 age- and gender-matched hospital patients with CKD 1 or 2. Retinal vessel diameters were measured from digital fundus images by a trained grader using a computer-assisted method and summarized as the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE). RESULTS: Patients with CKD 3 to 5 had a smaller mean CRAE and CRVE than hospital controls (139.4 +/- 17.8 MUm versus 148.5 +/- 16.0 MUm, P < 0.001; and 205.0 +/- 30.7 MUm versus 217.4 +/- 25.8 MUm, respectively; P = 0.001). CRAE and CRVE decreased progressively with each stage of renal failure CKD1-2 to 5 (P for trend = 0.08 and 0.04, respectively). CKD and hypertension were independent determinants of arteriolar narrowing after adjusting for age, gender, diabetes, dyslipidemia, and smoking history. Patients with CKD 5 and diabetes had a larger mean CRAE and CRVE than nondiabetics (141.4 +/- 14.9 MUm versus 132.9 +/- 14.2 MUm; 211.1 +/- 34.4 MUm versus 194.8 +/- 23.8 MUm). CONCLUSIONS: The microvasculature is narrowed in patients with reduced eGFR. PMID- 21784829 TI - Association of hemoglobin and survival in peritoneal dialysis patients. AB - BACKGROUND AND OBJECTIVES: Interventional trials and some observational studies show target hemoglobin >13 g/dl to be associated with higher mortality in erythropoiesis-stimulating agent-treated (ESA-treated) hemodialysis patients; data for peritoneal dialysis (PD) patients are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested our hypothesis that higher and lower achieved hemoglobin levels are associated with increased mortality in 9269 ESA treated PD patients from all DaVita dialysis clinics during the time period July 2001 through June 2006 followed through June 2007 using a time-dependent analysis. RESULTS: Lower hemoglobin was associated with significantly higher all cause mortality in ESA-treated PD patients: with hemoglobin of 11.0 to <12.0 g/dl as reference, the time-dependent adjusted death hazard ratios for hemoglobin levels of 10.0 to <11.0, 9.0 to <10.0, and <=9.0 g/dl were 1.12 (1.00 to 1.24), 1.30 (1.12 to 1.50), and 1.38 (1.14 to 1.67), respectively. The time-dependent adjusted hazard ratios for cardiovascular death with hemoglobin levels of 10.0 to <11.0, 9.0 to <10.0, and <=9.0 g/dl were 1.11 (0.93 to 1.32), 1.37 (1.09 to 1.72), and 1.12 (0.79 to 1.57), respectively. The same trend for association of lower hemoglobin level with higher mortality was seen in African-American and non African American men and women. In contrast, there was no association between higher achieved hemoglobin and all-cause or cardiovascular mortality in ESA treated PD patients. CONCLUSIONS: Lower, but not higher, achieved hemoglobin is associated with higher mortality in ESA-treated PD patients. Randomized controlled trials are needed to examine the target hemoglobin level with lowest mortality in PD patients. PMID- 21784830 TI - Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? AB - BACKGROUND AND OBJECTIVES: Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. RESULTS: All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (kappa four of six, lambda two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal lambdaLC deposits were observed on a follow-up kidney biopsy after 4 years. CONCLUSIONS: GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein. PMID- 21784831 TI - Flow-mediated vasodilation in end-stage renal disease. AB - BACKGROUND AND OBJECTIVES: An intact endothelium is essential for adaptations between arterial vasomotor tone and shear stress (SS), i.e., flow-mediated vasodilation (FMD). Endothelial dysfunction occurs in hypertension, cardiac insufficiency, diabetes, atherosclerosis, and in end-stage renal disease (ESRD) patients, whose renal failure is associated with many of those cardiovascular diseases (CVD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a progressive hand-warming protocol and repeated measures ANOVA, we analyzed SS mediated increase of brachial artery diameter (DeltaBA) in 22 healthy controls, 18 CVD-negative ESRD patients (ESRD-CVD(-)), and 17 CVD-positive ESRD patients (ESRD-CVD(+)) to analyze the role of uremia versus CVD on FMD. RESULTS: Hand warming increased SS (P < 0.001) and DeltaBA (P < 0.001). Negative interactions were observed between DeltaBA and ESRD (P < 0.001), and between DeltaBA and CVD(+) (P < 0.02), but there was no interaction between ESRD and CVD(+) (P = 0.69). For low and mild SS increases, ESRD-CVD(-) patients were characterized by similar DeltaBA as controls, but it was lower than controls at higher SS (P < 0.01). In ESRD-CVD(+) patients, brachial artery diameter did not respond to mild and moderate SS increases, and showed "paradoxical" vasoconstriction at higher SS (P < 0.05). In ESRD, a positive and independent interaction was observed between DeltaBA and 25(OH) vitamin D(3) insufficiency (<=15 MUg/L; P < 0.02). CONCLUSIONS: These observations indicate that, independently of each other, ESRD and CVD(+) history are associated with endothelial dysfunction. They also suggest the importance of considering the relationships between SS and endothelial function in different clinical conditions. PMID- 21784833 TI - Cardiovascular evaluation before renal transplantation: to cath or not to cath? PMID- 21784832 TI - Chronic kidney disease awareness among individuals with clinical markers of kidney dysfunction. AB - BACKGROUND AND OBJECTIVES: Awareness of chronic kidney disease (CKD) among providers and patients is low. Whether clinical cues prompt recognition of CKD is unknown. We examined whether markers of kidney disease that should trigger CKD recognition among providers are associated with higher individual CKD awareness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: CKD awareness was assessed in 1852 adults with an estimated GFR <60 ml/min per 1.73 m(2) using 1999 to 2008 National Health and Nutrition Examination Survey data. CKD awareness was a "yes" answer to "Have you ever been told you have weak or failing kidneys?" Participants were grouped by distribution of the following abnormal markers of CKD: hyperkalemia, acidosis, hyperphosphatemia, elevated blood urea nitrogen, anemia, albuminuria, and uncontrolled hypertension. Odds of CKD awareness associated with each abnormal marker and groupings of markers were estimated by multivariable logistic regression. RESULTS: Among individuals with kidney disease, only those with albuminuria had greater odds of CKD awareness (adjusted odds ratio, 4.0, P < 0.01) than those without. Odds of CKD awareness increased with each additional manifested clinical marker of CKD (adjusted odds ratio, 1.3, P = 0.05). Nonetheless, 90% of individuals with two to four markers of CKD and 84% of individuals with >=5 markers of CKD were unaware of their disease. CONCLUSIONS: Although individuals who manifest many markers of kidney dysfunction are more likely to be aware of their CKD, their CKD awareness remains low. A better understanding of mechanisms of awareness is required to facilitate earlier detection of CKD and implement therapy to minimize associated complications. PMID- 21784834 TI - Nephrolithiasis--new directions in 2011. PMID- 21784836 TI - Measured GFR as "gold standard"--all that glitters is not gold? PMID- 21784835 TI - Racial and ethnic differences in mortality among individuals with chronic kidney disease: results from the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is prevalent in minority populations and racial/ethnic differences in survival are incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Secondary analysis of Kidney Early Evaluation Program participants from 2000 through 2008 with CKD, not on dialysis, and without previous kidney transplant was performed. Self-reported race/ethnicity was categorized into five groups: non-Hispanic white, African American, Asian, American Indian/Alaska Native, and Hispanic. CKD was defined as a urinary albumin to creatinine ratio of >=30 mg/g among participants with an estimated GFR (eGFR) >=60 ml/min per 1.73 m(2) or an eGFR of <60 ml/min per 1.73 m(2). The outcome was all-cause mortality. Covariates used were age, sex, obesity, diabetes, hypertension, albuminuria, baseline eGFR, heart attack, stroke, smoking, family history, education, health insurance, geographic region, and year screened. RESULTS: 19,205 participants had prevalent CKD; 55% (n = 10,560) were White, 27% (n = 5237) were African American, 9% (n = 1638) were Hispanic, 5% (n = 951) were Asian, and 4% (n = 813) were American Indian/Alaska Native. There were 1043 deaths (5.4%). African Americans had a similar risk of death compared with Whites (adjusted Hazard Ratio (AHR) 1.07, 95% CI 0.90 to 1.27). Hispanics (AHR 0.66, 95% CI 0.50 to 0.94) and Asians (AHR 0.63, 95% CI 0.41 to 0.97) had a lower mortality risk compared with Whites. In contrast, American Indians/Alaska Natives had a higher risk of death compared with Whites (AHR 1.41, 95% CI 1.08 to 1.84). CONCLUSIONS: Significant differences in mortality among some minority groups were found among persons with CKD detected by community-based screening. PMID- 21784837 TI - Should living kidney donor candidates with impaired fasting glucose donate? AB - As the kidney transplant waiting list grows, the willingness of transplant centers to accept complex donors increases. Guidelines for the evaluation of living kidney donors exist but do not provide clear guidance when evaluating the complex donor. Although few transplant centers will approve donor candidates with impaired glucose tolerance and most, if not all, will deny candidates with diabetes, many will approve candidates with impaired fasting glucose (IFG). Furthermore, the demographic of living donors has changed in the past 10 years to increasingly include more nonwhite and Hispanic individuals who are at greater risk for future diabetes and hypertension. IFG may be more of a concern in potential donors whose nonwhite and Hispanic ethnicity already places them at greater risk. We review the definition of diabetes, diabetes prediction tools, and transplant guidelines for donor screening and exclusion as it pertains to impaired glucose metabolism, and additional ethnic and nonethnic factors to consider. We offer an algorithm to aid in evaluation of potential living donors with IFG in which ethnicity, age, and features of the metabolic syndrome play a role in the decision making. PMID- 21784838 TI - A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. AB - BACKGROUND AND OBJECTIVES: Endothelial dysfunction is an early manifestation of vascular injury and contributes to the development of atherosclerotic cardiovascular disease. Recent studies have implicated hyperuricemia as a risk factor for cardiovascular disease. We hypothesized that lowering uric acid in subjects with asymptomatic hyperuricemia with allopurinol might improve endothelial dysfunction, BP, estimated GFR (eGFR), and inflammatory markers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Subjects with asymptomatic hyperuricemia and no history of gout and 30 normouricemic control subjects were enrolled in this 4-month randomized prospective study. Thirty hyperuricemic patients received 300 mg/d allopurinol and were compared with 37 hyperuricemic patients and 30 normouricemic subjects in matched control groups. Flow-mediated dilation (FMD), eGFR, ambulatory BP monitoring, spot urine protein-creatine ratio, and highly sensitive C-reactive protein were measured at baseline and at 4 months. RESULTS: Age, gender, lipid profile, eGFR, hemoglobin, glucose, and level of proteinuria were similar in hyperuricemic subjects and controls at baseline. As expected, hyperuricemic patients had higher levels of highly sensitive C reactive protein and lower FMD compared with normouricemic patients. Allopurinol treatment resulted in a decrease in serum uric acid, a decrease in systolic BP, an increase in FMD, and an increase in eGFR compared with baseline. No significant difference was observed in the control hyperuricemic and normouricemic groups. In a multiple regression analysis, FMD levels were independently related to uric acid both before (beta = -0.55) and after (beta = 0.40) treatment. CONCLUSIONS: Treatment of hyperuricemia with allopurinol improves endothelial dysfunction and eGFR in subjects with asymptomatic hyperuricemia. PMID- 21784839 TI - Effects of antiproteinuric intervention on elevated connective tissue growth factor (CTGF/CCN-2) plasma and urine levels in nondiabetic nephropathy. AB - BACKGROUND AND OBJECTIVES: Connective tissue growth factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra- and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 +/- 62 versus 93 +/- 52 mmol Na(+)/d). RESULTS: CTGF was elevated in plasma (464 [387 to 556] pmol/L) and urine (205 [135 to 311] pmol/24 h) of patients compared with healthy controls (n = 21; 96 [86 to 108] pmol/L and 73 [55 to 98] pmol/24 h). Urinary CTGF was lowered by antiproteinuric intervention, in proportion to the reduction of proteinuria, with normalization during triple therapy (CTGF 99 [67 to 146] in CKD versus 73 [55 to 98] pmol/24 h in controls). In contrast, plasma CTGF was not affected. CONCLUSIONS: Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD. PMID- 21784840 TI - Zebrafish mll gene is essential for hematopoiesis. AB - Studies implicate an important role for the mixed lineage leukemia (Mll) gene in hematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated hematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, particularly hematopoiesis. Mll depletion caused severe defects in hematopoiesis as indicated by a lack of blood flow and mature blood cells as well as a significant reduction in expression of hematopoietic progenitor and mature blood cell markers. Furthermore, mll depletion prevented the differentiation of hematopoietic progenitors. In addition, we identified the N-terminal mini-peptide of Mll that acted as a dominant negative form to disrupt normal function of mll during embryogenesis. As expected, mll knockdown altered the expression of a subset of Hox genes. However, overexpression of these down-regulated Hox genes only partially rescued the blood deficiency, suggesting that mll may target additional genes to regulate hematopoiesis. In the mll morphants, microarray analysis revealed a dramatic up-regulation of gadd45alphaa. Multiple assays indicate that mll inhibited gadd45alphaa expression and that overexpression of gadd45alphaa mRNA led to a phenotype similar to the one seen in the mll morphants. Taken together, these findings demonstrate that zebrafish mll plays essential roles in hematopoiesis and that gadd45alphaa may serve as a potential downstream target for mediating the function of mll in hematopoiesis. PMID- 21784842 TI - Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease. AB - CEL-maturity onset diabetes of the young (MODY), diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frameshift mutations in the acinar cell carboxyl ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered and intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably overexpressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion, and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physicochemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short and long range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues. PMID- 21784841 TI - Molecular determinants of ciliary membrane localization of Trypanosoma cruzi flagellar calcium-binding protein. AB - The flagellar calcium-binding protein (FCaBP) of Trypanosoma cruzi is localized to the flagellar membrane in all life cycle stages of the parasite. Myristoylation and palmitoylation of the N terminus of FCaBP are necessary for flagellar membrane targeting. Not all dually acylated proteins in T. cruzi are flagellar, however. Other determinants of FCaBP therefore likely contribute to flagellar specificity. We generated T. cruzi transfectants expressing the N terminal 24 or 12 amino acids of FCaBP fused to GFP. Analysis of these mutants revealed that although amino acids 1-12 are sufficient for dual acylation and membrane binding, amino acids 13-24 are required for flagellar specificity and lipid raft association. Mutagenesis of several conserved lysine residues in the latter peptide demonstrated that these residues are essential for flagellar targeting and lipid raft association. Finally, FCaBP was expressed in the protozoan Leishmania amazonensis, which lacks FCaBP. The flagellar localization and membrane association of FCaBP in L. amazonensis suggest that the mechanisms for flagellar targeting, including a specific palmitoyl acyltransferase, are conserved in this organism. PMID- 21784843 TI - Hepatic nuclear factor 1alpha (HNF1alpha) dysfunction down-regulates X-box binding protein 1 (XBP1) and sensitizes beta-cells to endoplasmic reticulum stress. AB - Correct endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic beta-cell, and ER stress is often a contributory factor to beta-cell death in type 2 diabetes. We have used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1alpha, a transcription factor vital for correct beta-cell development and function, to show that HNF1alpha is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1alpha expression sensitizes the beta-cell to ER stress by directly down-regulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1alpha alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the beta-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1alpha-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursodeoxycholate. Rat insulin 2 promoter-DN HNF1alpha mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo. PMID- 21784844 TI - Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. AB - Autophagy has been recently demonstrated to control cell and tissue homeostasis, including the functions of various metabolic tissues. However, it remains unclear whether autophagy is critical for the central nervous system and particularly the hypothalamus for exerting metabolic regulation. Using autophagy-related protein 7 (Atg7) as an autophagic marker, this work showed that autophagy was highly active in the mediobasal hypothalamus of normal mice. In contrast, chronic development of dietary obesity was associated with autophagic decline in the mediobasal hypothalamus. To investigate the potential role of autophagy in the hypothalamic control of metabolic physiology, a mouse model was developed with autophagic inhibition in the mediobasal hypothalamus using site-specific delivery of lentiviral shRNA against Atg7. This model revealed that hypothalamic inhibition of autophagy increased energy intake and reduced energy expenditure. These metabolic changes were sufficient to increase body weight gain under normal chow feeding and exacerbate the progression of obesity and whole-body insulin resistance under high-fat diet feeding. To explore the underlying mechanism, this study found that defective hypothalamic autophagy led to hypothalamic inflammation, including the activation of proinflammatory IkappaB kinase beta pathway. Using brain-specific IkappaB kinase beta knockout mice, it was found that the effects of defective hypothalamic autophagy in promoting obesity were reversed by IkappaB kinase beta inhibition in the brain. In conclusion, hypothalamic autophagy is crucial for the central control of feeding, energy, and body weight balance. Conversely, decline of hypothalamic autophagy under conditions of chronic caloric excess promotes hypothalamic inflammation and thus impairs hypothalamic control of energy balance, leading to accelerated development of obesity and comorbidities. PMID- 21784845 TI - Microarray and proteomic analysis of breast cancer cell and osteoblast co cultures: role of osteoblast matrix metalloproteinase (MMP)-13 in bone metastasis. AB - Dynamic reciprocal interactions between a tumor and its microenvironment impact both the establishment and progression of metastases. These interactions are mediated, in part, through proteolytic sculpting of the microenvironment, particularly by the matrix metalloproteinases, with both tumors and stroma contributing to the proteolytic milieu. Because bone is one of the predominant sites of breast cancer metastases, we used a co-culture system in which a subpopulation of the highly invasive human breast cancer cell line MDA-MB-231, with increased propensity to metastasize to bone, was overlaid onto a monolayer of differentiated osteoblast MC3T3-E1 cells in a mineralized osteoid matrix. CLIP CHIP(r) microarrays identified changes in the complete protease and inhibitor expression profile of the breast cancer and osteoblast cells that were induced upon co-culture. A large increase in osteoblast-derived MMP-13 mRNA and protein was observed. Affymetrix analysis and validation showed induction of MMP-13 was initiated by soluble factors produced by the breast tumor cells, including oncostatin M and the acute response apolipoprotein SAA3. Significant changes in the osteoblast secretomes upon addition of MMP-13 were identified by degradomics from which six novel MMP-13 substrates with the potential to functionally impact breast cancer metastasis to bone were identified and validated. These included inactivation of the chemokines CCL2 and CCL7, activation of platelet-derived growth factor-C, and cleavage of SAA3, osteoprotegerin, CutA, and antithrombin III. Hence, the influence of breast cancer metastases on the bone microenvironment that is executed via the induction of osteoblast MMP-13 with the potential to enhance metastases growth by generating a microenvironmental amplifying feedback loop is revealed. PMID- 21784846 TI - Forced expression of heat shock protein 27 (Hsp27) reverses P-glycoprotein (ABCB1)-mediated drug efflux and MDR1 gene expression in Adriamycin-resistant human breast cancer cells. AB - Mutant p53 accumulation has been shown to induce the multidrug resistance gene (MDR1) and ATP binding cassette (ABC)-based drug efflux in human breast cancer cells. In the present work, we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, including Hsp27, which is normally known to augment proteasomal p53 degradation, are inhibited in Adriamycin (doxorubicin)-resistant MCF-7 cells (MCF-7/adr). Such an endogenous inhibition of HSF-1 and Hsp27 in turn results in p53 mutation with gain of function in its transcriptional activity and accumulation in MCF-7/adr. Also, lack of HSF-1 enhances nuclear factor kappaB (NF kappaB) DNA binding activity together with mutant p53 and induces MDR1 gene and P glycoprotein (P-gp, ABCB1), resulting in a multidrug-resistant phenotype. Ectopic expression of Hsp27, however, significantly depleted both mutant p53 and NF kappaB (p65), reversed the drug resistance by inhibiting MDR1/P-gp expression in MCF-7/adr cells, and induced cell death by increased G(2)/M population and apoptosis. We conclude from these results that HSF-1 inhibition and depletion of Hsp27 is a trigger, at least in part, for the accumulation of transcriptionally active mutant p53, which can either directly or NF-kappaB-dependently induce an MDR1/P-gp phenotype in MCF-7 cells. Upon Hsp27 overexpression, this pathway is abrogated, and the acquired multidrug resistance is significantly abolished so that MCF-7/adr cells are sensitized to Dox. Thus, clinical alteration in Hsp27 or NF-kappaB level will be a potential approach to circumvent drug resistance in breast cancer. PMID- 21784847 TI - HNK-1 glycan functions as a tumor suppressor for astrocytic tumor. AB - Astrocytic tumor is the most prevalent primary brain tumor. However, the role of cell surface carbohydrates in astrocytic tumor invasion is not known. In a previous study, we showed that polysialic acid facilitates astrocytic tumor invasion and thereby tumor progression. Here, we examined the role of HNK-1 glycan in astrocytic tumor invasion. A Kaplan-Meier analysis of 45 patients revealed that higher HNK-1 expression levels were positively associated with increased survival of patients. To determine the role of HNK-1 glycan, we transfected C6 glioma cells, which lack HNK-1 glycan expression, with beta1,3 glucuronyltransferase-P cDNA, generating HNK-1-positive cells. When these cells were injected into the mouse brain, the resultant tumors were 60% smaller than tumors emerging from injection of the mock-transfected HNK-1-negative C6 cells. HNK-1-positive C6 cells also grew more slowly than mock-transfected C6 cells in anchorage-dependent and anchorage-independent assays. C6-HNK-1 cells migrated well after treatment of anti-beta1 integrin antibody, whereas the same treatment inhibited cell migration of mock-transfected C6 cells. Similarly, alpha dystroglycan containing HNK-1 glycan is different from those containing the laminin-binding glycans, supporting the above conclusion that C6-HNK-1 cells migrate independently from beta1-integrin-mediated signaling. Moreover, HNK-1 positive cells exhibited attenuated activation of ERK 1/2 compared with mock transfected C6 cells, whereas focal adhesion kinase activation was equivalent in both cell types. Overall, these results indicate that HNK-1 glycan functions as a tumor suppressor. PMID- 21784848 TI - Classical and neonatal Marfan syndrome mutations in fibrillin-1 cause differential protease susceptibilities and protein function. AB - Mutations in fibrillin-1 give rise to Marfan syndrome (MFS) characterized by vascular, skeletal, and ocular abnormalities. Fibrillins form the backbone of extracellular matrix microfibrils in tissues including blood vessels, bone, and skin. They are crucial for regulating elastic fiber biogenesis and growth factor bioavailability. To compare the molecular consequences of mutations causing the severe neonatal MFS with mutations causing the milder classical MFS, we introduced representative point mutations from each group in a recombinant human fibrillin-1 fragment. Structural effects were analyzed by circular dichroism spectroscopy and analytical gel filtration chromatography. Proteolytic susceptibility was probed with non-physiological and physiological proteases, including plasmin, thrombin, matrix metalloproteinases, and cathepsins. All mutant proteins showed a similar gross secondary structure and no differences in heat stability as compared with the wild-type protein. Proteins harboring neonatal mutations were typically more susceptible to proteolytic cleavage compared with those with classical mutations and the wild-type protein. Proteolytic neo-cleavage sites were found both in close proximity and distant to the mutations, indicating small but significant structural changes exposing cryptic cleavage sites. We also report for the first time that cathepsin K and V cleave non-mutated fibrillin-1 at several domain boundaries. Compared with the classical mutations and the wild type, the group of neonatal mutations more severely affected the ability of fibrillin-1 to interact with heparin/heparan sulfate, which plays a role in microfibril assembly. These results suggest differential molecular pathogenetic concepts for neonatal and classical MFS including enhanced proteolytic susceptibility for physiologically relevant enzymes and loss of function for heparin binding. PMID- 21784849 TI - Activation of liver X receptor (LXR) inhibits receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation in an LXRbeta dependent mechanism. AB - Bone destruction is the major pathological process in many bone metabolic diseases and is a result of increased osteoclast formation and bone resorption. The liver X receptors (alpha,beta), important regulators of cholesterol metabolism and inflammatory signaling, have recently been observed to play a role in both physiological and pathological bone turnover. However, the relationship between liver X receptors (LXR) and osteoclast differentiation/formation remains unknown. Here, we report that the LXR ligand GW3965 is able to clearly and potently inhibit the formation of mature osteoclasts from receptor activator of nuclear factor kappaB ligand (RANKL)-stimulated human and murine osteoclast precursors. This results in a significant inhibition of bone resorption. We observed that GW3965 significantly inhibited expression of the osteoclast markers tartrate-resistant acid phosphatase, cathepsin K, osteoclast-associated receptor (OSCAR), and calcitonin receptor, appearing to act in an NFATc1/p38/microphthalmia-associated transcription factor (MITF)-dependent mechanism, independently of receptor activator of nuclear factor kappaB or c-Fos and not directly involving the NFkappaB pathways. GW3965 was less effective in RAW264.7 monocyte/macrophage cells, which are more committed into the osteoclast lineage. Also, GW3965 seemed to act differently depending on the source of the progenitor cells as it had no effect on calvarial osteoclasts, compared with marrow or blood-derived monocytes. As these effects were abolished in osteoclast precursors derived from LXRbeta(-/-) mice, we suggest that GW3965 acts via an LXRbeta-dependent mechanism. Taken together, our results suggest that the LXR can act as an important inhibitor of RANKL-mediated osteoclast differentiation. PMID- 21784850 TI - Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A interacting protein 1-like (FILIP-1L). AB - Heat shock factor Hsf1 is involved in the regulation of a variety of cellular processes including heat shock response, development and differentiation, aging, and tumorigenesis. Hsf1 transcriptional activity is tightly controlled through phosphorylation, sumoylation, and acetylation, and through association with a number of regulatory proteins. However, regulation of Hsf1 protein stability or turnover remains unknown. We have identified a novel Hsf1-interacting protein, FILIP-1L, that was found to bind to Hsf1 through yeast two-hybrid screening. FILIP-1L encodes multiple isoforms spanning from 711 to 1135 amino acid residues. FILIP-1L contains four coiled-coil and two N-terminal leucine zipper domains. Ectopic expression of FILIP-1L reduces the expression of the Hsf1 protein because FILIP-1L promotes Hsf1 ubiquitination and degradation through the ubiquitin proteasome system, leading to a reduction in Hsf1-mediated transcription. FILIP 1L, Hsf1, and the ubiquitin-binding domain of HhR23A, a receptor that transports polyubiquitinated proteins to the 19 S proteasome subunit targeting them for degradation, are found in a complex. This indicates that FILIP-1L is a potential adaptor that is involved in the Hsf1 degradation pathway. Taken together, our results indicate that FILIP-1L interacts with Hsf1, controlling its stability and thus modulating the heat shock response. These data indicate a novel function for FILIP-1L and a pathway for Hsf1 degradation through the ubiquitin-proteasome system. PMID- 21784851 TI - Eukaryotic translation initiation factor 4E binding protein 1 (4EBP-1) function is suppressed by Src and protein phosphatase 2A (PP2A) on extracellular matrix. AB - Human lung fibroblasts utilize integrins to attach and proliferate on type I collagen. beta1 integrin is the major integrin subunit for this attachment. Integrins coordinate cellular responses to cell-cell and cell-extracellular matrix interactions that regulate a variety of biological processes. Although beta1 integrin-mediated signaling pathways in lung fibroblasts have been studied, a detailed molecular mechanism regulating translational control of gene expression by 4EBP-1 is not understood. 4EBP-1 inhibits cap-dependent translation by binding to the eIF4E translation initiation factor. We found that when lung fibroblasts attach to collagen via beta1 integrin, high Src activity suppresses 4EBP-1 expression via PP2A, and the decrease of 4EBP-1 is due to protein degradation. The inhibition of Src activity dramatically increases PP2A and 4EBP 1 expression. Furthermore ectopic expression of PP2A, or PP2A silencing using PP2A siRNA confirmed that 4EBP-1 is regulated by PP2A. In addition, we found that 4EBP-1 inhibition by fibroblast attachment to collagen increases cap-dependent translation. Our study showed that when lung fibroblasts are attached to collagen matrix, the beta1 integrin/Src/PP2A-mediated 4EBP-1 regulatory pathway is activated. We suggest that beta1 integrin-mediated signaling pathway may be a crucial event in regulating fibroblast translational control machinery on collagen matrix. PMID- 21784852 TI - A novel role for Bruton's tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells. AB - The limited success of dendritic cell (DC)-based immunotherapy in multiple myeloma is partly due to hepatocyte growth factor (HGF)-induced DC dysfunction. From a therapeutic standpoint, it is important to understand the molecular events involved in inhibition of DC activation/maturation by HGF. Because Bruton's tyrosine kinase (Btk) negatively regulates maturation and immunostimulatory function of DCs, a role for Btk in HGF-induced inhibition of both murine and human DCs was investigated. We demonstrate that Btk is a novel proximal component of HGF-induced c-MET (HGF receptor) signaling. Following HGF treatment, Btk binds to c-MET and becomes activated. Btk activation in turn blocks the NF-kappaB pathway and subsequent DC activation via the c-Src-PI3K-AKT-mammalian target of rapamycin (mTOR) pathway. Notably, Btk activation is necessary for HGF-induced association of c-Src and PI3K with c-MET. Furthermore, we provide the first evidence that HGF inhibits DC activation by inducing autocrine interleukin (IL) 10 secretion, which requires activation of Btk. Blocking activation of Btk and its downstream the c-Src-PI3K-AKT-mTOR pathway prevents HGF-induced IL-10 secretion by DCs. In addition, neutralization of IL-10 secretion from DCs impaired the inhibitory effect of HGF on DCs. Thus, our study identifies a novel role for Btk in HGF-induced DC inhibition. PMID- 21784853 TI - Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET. AB - Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling. PMID- 21784854 TI - Interaction of human, rat, and mouse immunoglobulin A (IgA) with Staphylococcal superantigen-like 7 (SSL7) decoy protein and leukocyte IgA receptor. AB - Host survival depends on an effective immune system and pathogen survival on the effectiveness of immune evasion mechanisms. Staphylococcus aureus utilizes a number of molecules to modulate host immunity, including the SSL family of which SSL7 binds IgA and inhibits Fcalpha receptor I (FcalphaRI)-mediated function. Other Gram-positive bacterial pathogens produce IgA binding proteins, which, similar to SSL7, also bind the Fc at the CH2/CH3 interface (the junction between constant domains 2 and 3 of the heavy chain). The opposing activities of the host FcalphaRI-IgA receptor ligand pair and the pathogen decoy proteins select for host and pathogen variants, which exert stronger protection or evasion, respectively. Curiously, mouse but not rat IgA contains a putative N-linked glycosylation site in the center of this host receptor and pathogen-binding site. Here, we demonstrate that this site is glycosylated and that the effect of amino acid changes and glycosylation of the CH2/CH3 interface inhibits interaction with the pathogen IgA binding protein SSL7, while maintaining binding of pIgR, essential to the biosynthesis and transport of SIgA. PMID- 21784855 TI - Na/K-ATPase mimetic pNaKtide peptide inhibits the growth of human cancer cells. AB - Cells contain a large pool of nonpumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of alpha1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/K-ATPase to regulate Src-related signaling processes. A supplement of pNaKtide, a peptide derived from alpha1 Na/K-ATPase, reduces the activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics. PMID- 21784856 TI - Epithelial sodium channel regulation by cell surface-associated serum- and glucocorticoid-regulated kinase 1. AB - Serum- and glucocorticoid-regulated kinase 1 (sgk1) participates in diverse biological processes, including cell growth, apoptosis, and sodium homeostasis. In the cortical collecting duct of the kidney, sgk1 regulates sodium transport by stimulating the epithelial sodium channel (ENaC). Control of subcellular localization of sgk1 may be an important mechanism for modulating specificity of sgk1 function; however, which subcellular locations are required for sgk1 regulated ENaC activity in collecting duct cells has yet to be established. Using cell surface biotinylation studies, we detected endogenous sgk1 at the apical cell membrane of aldosterone-stimulated mpkCCD(c14) collecting duct cells. The association of sgk1 with the cell membrane was enhanced when ENaC was co transfected with sgk1 in kidney cells, suggesting that ENaC brings sgk1 to the cell surface. Furthermore, association of endogenous sgk1 with the apical cell membrane of mpkCCD(c14) cells could be modulated by treatments that increase or decrease ENaC expression at the apical membrane; forskolin increased the association of sgk1 with the apical surface, whereas methyl-beta-cyclodextrin decreased the association of sgk1 with the apical surface. Single channel recordings of excised inside-out patches from the apical membrane of aldosterone stimulated A6 collecting duct cells revealed that the open probability of ENaC was sensitive to the sgk1 inhibitor GSK650394, indicating that endogenous sgk1 is functionally active at the apical cell membrane. We propose that the association of sgk1 with the apical cell membrane, where it interacts with ENaC, is a novel means by which sgk1 specifically enhances ENaC activity in aldosterone-stimulated collecting duct cells. PMID- 21784857 TI - Environmental and biofilm-dependent changes in a Bacillus cereus secondary cell wall polysaccharide. AB - Bacterial species from the Bacillus genus, including Bacillus cereus and Bacillus anthracis, synthesize secondary cell wall polymers (SCWP) covalently associated to the peptidoglycan through a phospho-diester linkage. Although such components were observed in a wide panel of B. cereus and B. anthracis strains, the effect of culture conditions or of bacterial growth state on their synthesis has never been addressed. Herein we show that B. cereus ATCC 14579 can synthesize not only one, as previously reported, but two structurally unrelated secondary cell wall polymers (SCWP) polysaccharides. The first of these SCWP, ->4)[GlcNAc(beta1 3)]GlcNAc(beta1-6)[Glc(beta1-3)][ManNAc(alpha1-4)]GalNAc(alpha1-4)ManNAc(beta1->, although presenting an original sequence, fits to the already described the canonical sequence motif of SCWP. In contrast, the second polysaccharide was made up by a totally original sequence, ->6)Gal(alpha1-2)(2-R-hydroxyglutar-5 ylamido)Fuc2NAc4N(alpha1-6)GlcNAc(beta1->, which no equivalent has ever been identified in the Bacillus genus. In addition, we established that the syntheses of these two polysaccharides were differently regulated. The first one is constantly expressed at the surface of the bacteria, whereas the expression of the second is tightly regulated by culture conditions and growth states, planktonic, or biofilm. PMID- 21784858 TI - Adiponectin ameliorates doxorubicin-induced cardiotoxicity through Akt protein dependent mechanism. AB - Accumulating evidence shows that obesity is associated with doxorubicin cardiac toxicity in the heart, but the molecular mechanisms that contribute to this pathological response are not understood. Adiponectin is an adipose-derived, cardioprotective factor that is down-regulated in obesity. Here, we investigated the effect of adiponectin on doxorubicin (DOX)-induced cardiotoxicity and assessed the mechanisms of this effect. A single dose of DOX was intraperitoneally injected into the abdomen of adiponectin knock-out (APN-KO) and wild-type (WT) mice. APN-KO mice had increased mortality and exacerbated contractile dysfunction of left ventricle compared with WT mice. APN-KO mice also showed increased apoptotic activity and diminished Akt signaling in the failing myocardium. Systemic delivery of adenoviral vector expressing adiponectin improved left ventricle dysfunction and myocardial apoptosis following DOX injection in WT and APN-KO mice but not in Akt1 heterozygous KO mice. In cultured rat neonatal cardiomyocytes, adiponectin stimulated Akt phosphorylation and inhibited DOX-stimulated apoptosis. Treatment with sphingosine kinase-1 inhibitor or sphingosine 1-phosphate receptor antagonist diminished adiponectin-induced Akt phosphorylation and reversed the inhibitory effects of adiponectin on myocyte apoptosis. Pretreatment with anti-calreticulin antibody reduced the binding of adiponectin to cardiac myocytes and blocked the adiponectin-stimulated increase in Akt activation and survival in cardiomyocytes. Interference of the LRP1/calreticulin co-receptor system by siRNA or blocking antibodies diminished the stimulatory actions of adiponectin on Akt activation and myocyte survival. These data show that adiponectin protects against DOX-induced cardiotoxicity by its ability to promote Akt signaling. PMID- 21784859 TI - Redox regulates mammalian target of rapamycin complex 1 (mTORC1) activity by modulating the TSC1/TSC2-Rheb GTPase pathway. AB - Mammalian target of rapamycin (mTOR) is a kinase that plays a key role in a wide array of cellular processes and exists in two distinct functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although mTORC2 is primarily activated by growth factors, mTORC1 is regulated by numerous extracellular and intracellular signals such as nutrients, growth factors, and cellular redox. Previous study has shown that cysteine oxidants sufficiently activate mTORC1 activity under amino acid-depleted conditions and that a reducing agent effectively suppresses amino acid-induced mTORC1 activity, thereby raising the possibility that redox-sensitive mechanisms underlie amino acid-dependent mTORC1 regulation. However, the molecular mechanism by which redox regulates mTORC1 activity is not well understood. In this study, we show that the redox-sensitive regulation of mTORC1 occurs via Rheb but not the Rag small GTPase. Enhancing cellular redox potential with cysteine oxidants significantly increases Rheb GTP levels. Importantly, modulation of the cellular redox potential with a cysteine oxidant or reducing agent failed to alter mTORC1 activity in TSC1(-/-) or TSC2(-/ ) mouse embryonic fibroblast cells. Furthermore, a cysteine oxidant has little effect on mTOR localization but sufficiently activates mTORC1 activity in both p18(-/-) and control mouse embryonic fibroblast cells, suggesting that the redox sensitive regulation of mTORC1 occurs independent of the Ragulator.Rag complex. Taken together, our results suggest that the TSC complex plays an important role in redox-sensitive mTORC1 regulation and argues for the activation of mTORC1 in places other than the lysosome upon inhibition of the TSC complex. PMID- 21784860 TI - A20-binding inhibitor of nuclear factor-kappaB (NF-kappaB)-2 (ABIN-2) is an activator of inhibitor of NF-kappaB (IkappaB) kinase alpha (IKKalpha)-mediated NF kappaB transcriptional activity. AB - NF-kappaB transcription factors are pivotal players in controlling inflammatory and immune responses, as well as cell proliferation and apoptosis. Aberrant regulation of NF-kappaB and the signaling pathways that regulate its activity have been involved in various pathologies, particularly cancers, as well as inflammatory and autoimmune diseases. NF-kappaB activation is tightly regulated by the IkappaB kinase (IKK) complex, which is composed of two catalytic subunits IKKalpha and IKKbeta, and a regulatory subunit IKKgamma/NEMO. Although IKKalpha and IKKbeta share structural similarities, IKKalpha has been shown to have distinct biological functions. However, the molecular mechanisms that modulate IKKalpha activity have not yet been fully elucidated. To understand better the regulation of IKKalpha activity, we purified IKKalpha-associated proteins and identified ABIN-2. Here, we demonstrate that IKKalpha and IKKbeta both interact with ABIN-2 and impair its constitutive degradation by the proteasome. Nonetheless, ABIN-2 enhances IKKalpha- but not IKKbeta-mediated NF-kappaB activation by specifically inducing IKKalpha autophosphorylation and kinase activity. Furthermore, we found that ABIN-2 serine 146 is critical for the ABIN-2 dependent IKKalpha transcriptional up-regulation of specific NF-kappaB target genes. These results imply that ABIN-2 acts as a positive regulator of NF-kappaB dependent transcription by activating IKKalpha. PMID- 21784861 TI - Sumoylation-promoted enterovirus 71 3C degradation correlates with a reduction in viral replication and cell apoptosis. AB - Enterovirus 71 (EV71), a member of the Picornaviridae family, may cause serious clinical manifestations associated with the central nervous system. Enterovirus 3C protease is required for virus replication and can trigger host cell apoptosis via cleaving viral polyprotein precursor and cellular proteins, respectively. Although the role of the 3C protease in processing viral and cellular proteins has been established, very little is known about the modulation of EV71 3C function by host cellular factors. Here, we show that sumoylation promotes EV71 3C protein ubiquitination for degradation, correlating with a decrease of EV71 in virus replication and cell apoptosis. SUMO E2-conjugating enzyme Ubc9 was identified as an EV71 3C-interacting protein. Further studies revealed that EV71 3C can be SUMO (small ubiquitin-like modifier)-modified at residue Lys-52. Sumoylation down-regulated 3C protease activity in vitro and also 3C protein stability in cells, in agreement with data suggesting 3C K52R protein induced greater substrate cleavage and apoptosis in cells. More importantly, the recombinant EV71 3C K52R virus infection conferred more apoptotic phenotype and increased virus levels in culture cells, which also correlated with a mouse model showing increased levels of viral VP1 protein in intestine and neuron loss in the spinal cord with EV71 3C K52R recombinant viral infection. Finally, we show that EV71 3C amino acid residues 45-52 involved in Ubc9 interaction determined the extent of 3C sumoylation and protein stability. Our results uncover a previously undescribed cellular regulatory event against EV71 virus replication and host cell apoptosis by sumoylation at 3C protease. PMID- 21784862 TI - Roles of the four DNA polymerases of the crenarchaeon Sulfolobus solfataricus and accessory proteins in DNA replication. AB - The hyperthermophilic crenarchaeon Sulfolobus solfataricus P2 encodes three B family DNA polymerase genes, B1 (Dpo1), B2 (Dpo2), and B3 (Dpo3), and one Y family DNA polymerase gene, Dpo4, which are related to eukaryotic counterparts. Both mRNAs and proteins of all four DNA polymerases were constitutively expressed in all growth phases. Dpo2 and Dpo3 possessed very low DNA polymerase and 3' to 5' exonuclease activities in vitro. Steady-state kinetic efficiencies (k(cat)/K(m)) for correct nucleotide insertion by Dpo2 and Dpo3 were several orders of magnitude less than Dpo1 and Dpo4. Both the accessory proteins proliferating cell nuclear antigen and the clamp loader replication factor C facilitated DNA synthesis with Dpo3, as with Dpo1 and Dpo4, but very weakly with Dpo2. DNA synthesis by Dpo2 and Dpo3 was remarkably decreased by single-stranded binding protein, in contrast to Dpo1 and Dpo4. DNA synthesis in the presence of proliferating cell nuclear antigen, replication factor C, and single-stranded binding protein was most processive with Dpo1, whereas DNA lesion bypass was most effective with Dpo4. Both Dpo2 and Dpo3, but not Dpo1, bypassed hypoxanthine and 8-oxoguanine. Dpo2 and Dpo3 bypassed uracil and cis-syn cyclobutane thymine dimer, respectively. High concentrations of Dpo2 or Dpo3 did not attenuate DNA synthesis by Dpo1 or Dpo4. We conclude that Dpo2 and Dpo3 are much less functional and more thermolabile than Dpo1 and Dpo4 in vitro but have bypass activities across hypoxanthine, 8-oxoguanine, and either uracil or cis-syn cyclobutane thymine dimer, suggesting their catalytically limited roles in translesion DNA synthesis past deaminated, oxidized base lesions and/or UV induced damage. PMID- 21784863 TI - Multiligand specificity of pathogen-associated molecular pattern-binding site in peptidoglycan recognition protein. AB - The peptidoglycan recognition protein PGRP-S is an innate immunity molecule that specifically interacts with microbial peptidoglycans and other pathogen associated molecular patterns. We report here two structures of the unique tetrameric camel PGRP-S (CPGRP-S) complexed with (i) muramyl dipeptide (MDP) at 2.5 A resolution and (ii) GlcNAc and beta-maltose at 1.7A resolution. The binding studies carried out using surface plasmon resonance indicated that CPGRP-S binds to MDP with a dissociation constant of 10(-7) M, whereas the binding affinities for GlcNAc and beta-maltose separately are in the range of 10(-4) M to 10(-5) M, whereas the dissociation constant for the mixture of GlcNAc and maltose was estimated to be 10(-6) M. The data from bacterial suspension culture experiments showed a significant inhibition of the growth of Staphylococcus aureus cells when CPGRP-S was added to culture medium. The ELISA experiment showed that the amount of MDP-induced production of TNF-alpha and IL-6 decreased considerably after the introduction of CPGRP-S. The crystal structure determinations of (i) a binary complex with MDP and (ii) a ternary complex with GlcNAc and beta-maltose revealed that MDP, GlcNAc, and beta-maltose bound to CPGRP-S in the ligand binding cleft, which is situated at the interface of molecules C and D of the homotetramer formed by four protein molecules A, B, C, and D. In the binary complex, the muramyl moiety of MDP is observed at the C-D interface, whereas the peptide chain protrudes into the center of tetramer. In the ternary complex, GlcNAc and beta maltose occupy distinct non-overlapping positions belonging to different subsites. PMID- 21784864 TI - LytN, a murein hydrolase in the cross-wall compartment of Staphylococcus aureus, is involved in proper bacterial growth and envelope assembly. AB - Cell cycle progression for the spherical microbe Staphylococcus aureus requires the coordinated synthesis and remodeling of peptidoglycan. The majority of these rearrangements takes place at the mid-cell, in a compartment designated the cross wall. Secreted polypeptides endowed with a YSIRK-G/S signal peptide are directly delivered to the cross-wall compartment. One such YSIRK-containing protein is the murein hydrolase LytN. lytN mutations precipitate structural damage to the cross wall and interfere with staphylococcal growth. Overexpression of lytN also affects growth and triggers rupture of the cross-wall. The lytN phenotype can be reversed by the controlled expression of lytN but not by adding purified LytN to staphylococcal cultures. LytN harbors LysM and CHAP domains, the latter of which functions as both an N-acetylmuramoyl-L-alanine amidase and D-alanyl-glycine endopeptidase. Thus, LytN secretion into the cross-wall promotes peptidoglycan separation and completion of the staphylococcal cell cycle. PMID- 21784865 TI - Small angle neutron scattering reveals pH-dependent conformational changes in Trichoderma reesei cellobiohydrolase I: implications for enzymatic activity. AB - Cellobiohydrolase I (Cel7A) of the fungus Trichoderma reesei (now classified as an anamorph of Hypocrea jecorina) hydrolyzes crystalline cellulose to soluble sugars, making it of key interest for producing fermentable sugars from biomass for biofuel production. The activity of the enzyme is pH-dependent, with its highest activity occurring at pH 4-5. To probe the response of the solution structure of Cel7A to changes in pH, we measured small angle neutron scattering of it in a series of solutions having pH values of 7.0, 6.0, 5.3, and 4.2. As the pH decreases from 7.0 to 5.3, the enzyme structure remains well defined, possessing a spatial differentiation between the cellulose binding domain and the catalytic core that only changes subtly. At pH 4.2, the solution conformation of the enzyme changes to a structure that is intermediate between a properly folded enzyme and a denatured, unfolded state, yet the secondary structure of the enzyme is essentially unaltered. The results indicate that at the pH of optimal activity, the catalytic core of the enzyme adopts a structure in which the compact packing typical of a fully folded polypeptide chain is disrupted and suggest that the increased range of structures afforded by this disordered state plays an important role in the increased activity of Cel7A through conformational selection. PMID- 21784866 TI - Does N-terminal processing of Mcl-1 occur at mitochondrial outer membrane or matrix? PMID- 21784868 TI - The intron of tRNA-TrpCCA is dispensable for growth and translation of Saccharomyces cerevisiae. AB - A part of eukaryotic tRNA genes harbor an intron at one nucleotide 3' to the anticodon, so that removal of the intron is an essential processing step for tRNA maturation. While some tRNA introns have important roles in modification of certain nucleotides, essentiality of the tRNA intron in eukaryotes has not been tested extensively. This is partly because most of the eukaryotic genomes have multiple genes encoding an isoacceptor tRNA. Here, we examined whether the intron of tRNA-Trp(CCA) genes, six copies of which are scattered on the genome of yeast, Saccharomyces cerevisiae, is essential for growth or translation of the yeast in vivo. We devised a procedure to remove all of the tRNA introns from the yeast genome iteratively with marker cassettes containing both positive and negative markers. Using this procedure, we removed all the introns from the six tRNA Trp(CCA) genes, and found that the intronless strain grew normally and expressed tRNA-Trp(CCA) in an amount similar to that of the wild-type genes. Neither incorporation of (35)S-labeled amino acids into a TCA-insoluble fraction nor the major protein pattern on SDS-PAGE/2D gel were affected by complete removal of the intron, while expression levels of some proteins were marginally affected. Therefore, the tRNA-Trp(CCA) intron is dispensable for growth and bulk translation of the yeast. This raises the possibility that some mechanism other than selective pressure from translational efficiency maintains the tRNA intron on the yeast genome. PMID- 21784869 TI - Structural basis for the dual U4 and U4atac snRNA-binding specificity of spliceosomal protein hPrp31. AB - Human proteins 15.5K and hPrp31 are components of the major spliceosomal U4 snRNP and of the minor spliceosomal U4atac snRNP. The two proteins bind to related 5' stem loops (5'SLs) of the U4 and U4atac snRNAs in a strictly sequential fashion. The primary binding 15.5K protein binds at K-turns that exhibit identical sequences in the two snRNAs. However, RNA sequences contacted by the secondary binding hPrp31 differ in U4 and U4atac snRNAs, and the mechanism by which hPrp31 achieves its dual specificity is presently unknown. We show by crystal structure analysis that the capping pentaloops of the U4 and U4atac 5'SLs adopt different structures in the ternary hPrp31-15.5K-snRNA complexes. In U4atac snRNA, a noncanonical base pair forms across the pentaloop, based on which the RNA establishes more intimate interactions with hPrp31 compared with U4 snRNA. Stacking of hPrp31-His270 on the noncanonical base pair at the base of the U4atac pentaloop recapitulates intramolecular stabilizing principles known from the UUCG and GNRA families of RNA tetraloops. Rational mutagenesis corroborated the importance of the noncanonical base pair and the U4atac-specific hPrp31-RNA interactions for complex stability. The more extensive hPrp31-U4atac snRNA interactions are in line with a higher stability of the U4atac compared with the U4-based ternary complex seen in gel-shift assays, which may explain how U4atac snRNA can compete with the more abundant U4 snRNA for the same protein partners in vivo. PMID- 21784870 TI - The perception of 2D orientation is categorically biased. AB - Three experimental paradigms were used to investigate the perception of orientation relative to internal categorical standards of vertical and horizontal. In Experiment 1, magnitude estimation of orientation (in degrees) relative to vertical and horizontal replicated a previously reported spatial orientation bias also measured using verbal report: Orientations appear farther from horizontal than they are, whether numeric judgments are made relative to vertical or to horizontal. Analyses of verbal response patterns, however, suggested that verbal reports underestimate the true spatial bias. A non-verbal orientation bisection task (Experiment 2) confirmed that spatial errors are not due to numeric coding and are larger than the 6 degrees error replicated using verbal methods. A spatial error of 8.6 degrees was found in the bisection task, such that an orientation of about 36.4 degrees from horizontal appears equidistant from vertical and horizontal. Finally, using a categorization ("ABX") paradigm in Experiment 3, it was found that there is less memory confusability for orientations near horizontal than for orientations near vertical. Thus, three different types of measures, two of them non-verbal, provide converging evidence that the coding of orientation relative to the internal standards of horizontal and vertical is asymmetrically biased and that horizontal appears to be the privileged axis. PMID- 21784871 TI - Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model. AB - The tumor microenvironment (TME) mediates immunosuppression resulting in tumor cell escape from immune surveillance and cancer vaccine failure. Immunosuppression is mediated by the STAT-3 transcription factor, which potentiates signaling in tumor and immune cells. Because immunosuppression continues to be a major inhibitor of cancer vaccine efficacy, we examined in this study whether therapeutically targeted delivery of a synthetic STAT-3 inhibitor to the TME, combined with an HER-2 DNA vaccine can improve immune surveillance against HER-2(+) breast cancer and prevent its recurrence. To this end, we developed a novel ligand-targeted nanoparticle (NP) encapsulating a CDDO-Im payload capable of specific delivery to the TME, which showed an effective therapeutic inhibition of STAT-3 activation in primary tumors. Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells. These changes correlated with delayed growth of orthotopic 4TO7 breast tumors and, when combined with an HER-2 DNA vaccine, prevented HER-2(+) primary tumor recurrence in immunocompetent mice. Furthermore, antitumor T-cell responses were enhanced in splenocytes isolated from mice treated with this combination therapy. Together, these data show effective protection from cancer recurrence through improved immune surveillance against a tumor-specific antigen. PMID- 21784872 TI - Bcl-2 family genetic profiling reveals microenvironment-specific determinants of chemotherapeutic response. AB - The Bcl-2 family encompasses a diverse set of apoptotic regulators that are dynamically activated in response to various cell-intrinsic and -extrinsic stimuli. An extensive variety of cell culture experiments have identified effects of growth factors, cytokines, and drugs on Bcl-2 family functions, but in vivo studies have tended to focus on the role of one or two particular members in development and organ homeostasis. Thus, the ability of physiologically relevant contexts to modulate canonical dependencies that are likely to be more complex has yet to be investigated systematically. In this study, we report findings derived from a pool-based shRNA assay that systematically and comprehensively interrogated the functional dependence of leukemia and lymphoma cells upon various Bcl-2 family members across many diverse in vitro and in vivo settings. This approach permitted us to report the first in vivo loss of function screen for modifiers of the response to a front-line chemotherapeutic agent. Notably, our results reveal an unexpected role for the extrinsic death pathway as a tissue specific modifier of therapeutic response. In particular, our findings show that particular tissue sites of tumor dissemination play critical roles in demarcating the nature and extent of cancer cell vulnerabilities and mechanisms of chemoresistance. PMID- 21784873 TI - Genome-scale phylogenetic function annotation of large and diverse protein families. AB - The Statistical Inference of Function Through Evolutionary Relationships (SIFTER) framework uses a statistical graphical model that applies phylogenetic principles to automate precise protein function prediction. Here we present a revised approach (SIFTER version 2.0) that enables annotations on a genomic scale. SIFTER 2.0 produces equivalently precise predictions compared to the earlier version on a carefully studied family and on a collection of 100 protein families. We have added an approximation method to SIFTER 2.0 and show a 500-fold improvement in speed with minimal impact on prediction results in the functionally diverse sulfotransferase protein family. On the Nudix protein family, previously inaccessible to the SIFTER framework because of the 66 possible molecular functions, SIFTER achieved 47.4% accuracy on experimental data (where BLAST achieved 34.0%). Finally, we used SIFTER to annotate all of the Schizosaccharomyces pombe proteins with experimental functional characterizations, based on annotations from proteins in 46 fungal genomes. SIFTER precisely predicted molecular function for 45.5% of the characterized proteins in this genome, as compared with four current function prediction methods that precisely predicted function for 62.6%, 30.6%, 6.0%, and 5.7% of these proteins. We use both precision-recall curves and ROC analyses to compare these genome-scale predictions across the different methods and to assess performance on different types of applications. SIFTER 2.0 is capable of predicting protein molecular function for large and functionally diverse protein families using an approximate statistical model, enabling phylogenetics-based protein function prediction for genome-wide analyses. The code for SIFTER and protein family data are available at http://sifter.berkeley.edu. PMID- 21784874 TI - Coevolution of retroelements and tandem zinc finger genes. AB - Vertebrate genomes encode large and highly variable numbers of tandem C2H2 zinc finger (tandem ZF) transcription factor proteins. In mammals, most tandem ZF genes also encode a KRAB domain (KZNF proteins). Very little is known about what forces have driven the number and diversity of tandem ZF genes. Recent studies suggest that one role of KZNF proteins is to bind and repress transcription of exogenous retroviruses and their endogenous counterpart LTR retroelements. We report a striking correlation across vertebrate genomes between the number of LTR retroelements and the number of host tandem ZF genes. This correlation is specific to LTR retroelements and ZF genes and was not explained by covariation in other genomic features. We further show that recently active LTR retroelements are correlated with recent tandem ZF gene duplicates across vertebrates. On branches of the primate phylogeny, we find that the appearance of new families of endogenous retroviruses is strongly predictive of the appearance of new duplicate KZNF genes. We hypothesize that retroviral and LTR retroelement burden drives evolution of host tandem ZF genes. This hypothesis is consistent with previously described molecular evolutionary patterns in duplicate ZF genes throughout vertebrates. To further explore these patterns, we investigated 34 duplicate human KZNF gene pairs, all of which underwent an early burst of divergence in the major nucleotide contact residues of their ZF domains, followed by purifying selection in both duplicates. Our results support a host-pathogen model for tandem ZF gene evolution, in which new LTR retroelement challenges drive duplication and divergence of host tandem ZF genes. PMID- 21784875 TI - Large-scale methylation domains mark a functional subset of neuronally expressed genes. AB - DNA methylation is essential for embryonic and neuronal differentiation, but the function of most genomic DNA methylation marks is poorly understood. Generally the human genome is highly methylated (>70%) except for CpG islands and gene promoters. However, it was recently shown that the IMR90 human fetal lung fibroblast cells have large regions of the genome with partially methylated domains (PMDs, <70% average methylation), in contrast to the rest of the genome which is in highly methylated domains (HMDs, >70% average methylation). Using bisulfite conversion followed by high-throughput sequencing (MethylC-seq), we discovered that human SH-SY5Y neuronal cells also contain PMDs. We developed a novel hidden Markov model (HMM) to computationally map the genomic locations of PMDs in both cell types and found that autosomal PMDs can be >9 Mb in length and cover 41% of the IMR90 genome and 19% of the SH-SY5Y genome. Genomic regions marked by cell line specific PMDs contain genes that are expressed in a tissue specific manner, with PMDs being a mark of repressed transcription. Genes contained within N-HMDs (neuronal HMDs, defined as a PMD in IMR90 but HMD in SH SY5Y) were significantly enriched for calcium signaling, synaptic transmission, and neuron differentiation functions. Autism candidate genes were enriched within PMDs and the largest PMD observed in SH-SY5Y cells marked a 10 Mb cluster of cadherin genes with strong genetic association to autism. Our results suggest that these large-scale methylation domain maps could be relevant to interpreting and directing future investigations into the elusive etiology of autism. PMID- 21784876 TI - Reconstructive surgery for chronic lymphedema: a viable option, but. AB - The aim of the paper is to assess the efficacy of reconstructive lymphatic surgery in the treatment of chronic lymphedema via retrospective analysis. Lymphovenous anastomotic surgery (LVAS) or free lymph node transplant surgery (FLTS) was performed on 32 patients who failed to respond to complex decongestive therapy (CDT) alone for a minimum of a one-year period. In LVAS, three patients with good compliance among 19 were able to maintain initial improvement through the four-year follow-up period. All three had secondary lymphedema in clinical stage II. In FLTS, among 13 patients, three compliant patients with the secondary lymphedema in clinical stage II kept initial improvement through the four-year follow-up. In conclusion, reconstructive lymphatic surgery (LVAS and FLTS) appears to be more effective in secondary lymphedema versus primary lymphedema when performed in the early stages. Patient compliance to maintain CDT postoperatively remains the most critical factor in maintaining durable long-term results. FLTS seems to have an additional risk involved to the donor lymph node harvest and a limited role compared to LVAS. Further extended study on FLTS is required to demonstrate its efficacy compared with LVAS. PMID- 21784877 TI - Mesenchymal stem cell-based tissue engineering of small-diameter blood vessels. AB - The aim of the study was to construct small-diameter vascular grafts using canine mesenchymal stem cells (cMSCs) and a pulsatile flow bioreactor. cMSCs were isolated from canine bone marrow and expanded ex vivo. cMSCs were then seeded onto the luminal surface of decellularized arterial matrices, which were further cultured in a pulsatile flow bioreactor for four days. Immunohistochemical staining and scanning electron microscopy was performed to characterize the tissue-engineered blood vessels. cMSCs were successfully seeded onto the luminal surface of porcine decellularized matrices. After four-day culture in the pulsatile flow bioreactor, the cells were highly elongated and oriented to the flow direction. Immunohistochemistry demonstrated that the cells cultured under pulsatile flow expressed Von Willebrand factor, an endothelial cell marker. In conclusion, cMSCs seeded onto decellularized arterial matrices could differentiate into endothelial lineage after culturing in a pulsatile flow bioreactor, which provides a novel approach for tissue engineering of small diameter blood vessels. PMID- 21784878 TI - Why we need open simulation to train surgeons in an era of work-hour restrictions. AB - Surgical training in the USA and Europe has undergone radical changes with respect to working patterns, culture and limitation on working hours in recent years. Many surgeons who trained prior to the Accreditation Council for Graduate Medical Education (ACGME) duty-hour restrictions have expressed concern that surgeons currently exiting from training may not have had the same operative experience as in the pre-ACGME era. These concerns are particularly relevant in vascular surgery with the prevalence of endovascular therapies reducing the exposure of trainees to more traditional open vascular operations. Simulation has been used in many non-medical fields for technical skill acquisition prior to real-life performance and in recent years has been identified as a useful tool in surgical training. This article highlights the growing need for open vascular simulation as exposure to complex open vascular operations diminishes. The culture of, 'see one, do one, teach one' is fast becoming replaced by 'do many on a simulator, attain competency then perform under supervision in the operating room'. This will only be successfully achieved by the widespread incorporation of open vascular simulation into current vascular training programs if work hours remain limited and endovascular modalities continue to replace traditional open operations. PMID- 21784879 TI - Gram-negative groin sepsis treated with covered stents and systemic antibiotics. AB - Prosthetic graft infections are hazardous conditions. Those due to Gram-negative bacteria are particularly serious. When Gram-negative microorganisms are present, entire graft excision is recommended, with revascularization if needed, preferably with autogenous tissues or with prosthetic grafts via non-infected planes if autogenous options are not available. We herein report the case of a diabetic man with critical limb ischemia, who after lower-extremity revascularization with a prosthetic graft, developed an early graft infection due to Gram-negative and fungal organisms, and who was successfully treated with a covered stent placed across grossly infected tissues. A discussion on the pertinent literature is also offered. PMID- 21784880 TI - Recommendations for examining and interpreting funnel plot asymmetry in meta analyses of randomised controlled trials. PMID- 21784881 TI - Dementia with cardiac problems. PMID- 21784882 TI - 40 Million children have no access to the most basic healthcare services. PMID- 21784883 TI - US institute list eight services for women that all insurers should provide. PMID- 21784885 TI - Nurse is arrested over deaths at Stepping Hill hospital. PMID- 21784887 TI - Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension. AB - We examined a novel therapeutic approach for hypertension, a small-molecule direct inhibitor of smooth muscle myosin, CK-2018448 (CK-448), which is an N,N' alkylurea (U.S. Patent Publication 2009-0275537 A1) in conscious dogs with renal hypertension and compared its efficacy with that of a calcium channel blocker, amlodipine. Dogs were instrumented with a miniature left ventricular pressure gauge, an aortic pressure catheter, and ultrasonic flow probes in the ascending aorta and renal and iliac arteries for measurement of cardiac output and regional blood flow. In the hypertensive state, mean arterial pressure increased from 101 +/- 3.8 to 142 +/- 1.9 mm Hg. At the doses selected, CK-448 and amlodipine increased cardiac output similarly (30 +/- 11% versus 33 +/- 6.4%) and similarly reduced mean arterial pressure (-22 +/- 3.6% versus -16 +/- 3.4%) and total peripheral resistance (-36 +/- 5.9% versus -37 +/- 5.8%). CK-448 had the greatest vasodilator effect in the renal bed, where renal blood flow increased by 46 +/- 9.0%, versus 11 +/- 3.4% for amlodipine (p < 0.01). CK-488 produced significantly less vasodilation in the limb, where iliac blood flow did not change; in contrast, it rose by 48 +/- 12% with amlodipine (p < 0.01). The minimal effects on limb blood flow could limit the development of peripheral edema, an adverse side effect of Ca(2+) channel blockers. In addition, in a rodent model of hypertension, oral administration of a smooth muscle myosin inhibitor resulted in a sustained antihypertensive effect. Thus, the smooth muscle myosin inhibitor's preferential effect on renal blood flow makes this drug mechanism particularly appealing, because many patients with hypertension have renal insufficiency, and patients with heart failure could benefit from afterload reduction coupled with enhanced renal blood flow. PMID- 21784888 TI - Copper deficiency exacerbates bile duct ligation-induced liver injury and fibrosis in rats. AB - Copper levels are elevated in a variety of liver fibrosis conditions. Lowering copper to a certain level protects against fibrosis. However, whether severe copper deficiency is protective against liver fibrosis is not known. The purpose of the present study is to evaluate this question by inducing severe copper deficiency using the copper chelator, tetrathiomolybdate (TM), in a bile duct ligation (BDL) rat model. Male Sprague-Dawley rats were divided into four groups: sham, sham plus TM, BDL, and BDL plus TM. TM was given in a daily dose of 10 mg/kg by body weight by means of intragastric gavage, beginning 5 days after BDL. All animals were killed 2 weeks after surgery. Severe copper deficiency was induced by TM overdose in either sham or BDL rats, as shown by decreased plasma ceruloplasmin activity. Liver injury and fibrosis were exacerbated in BDL rats with TM treatment, as illustrated by robustly increased plasma aspartate aminotransferase and hepatic collagen accumulation. Iron stores, as measured by plasma ferritin, were significantly increased in copper-deficient BDL rats. Moreover, hepatic heme oxygenase-1 expression was markedly down-regulated by copper deficiency in BDL rats. In addition, hepatic gene expression involving mitochondrial biogenesis and beta-oxidation was significantly up-regulated in BDL rats, and this increase was abolished by copper deficiency. In summary, severe copper deficiency exacerbates BDL-induced liver injury and liver fibrosis, probably caused by increased iron overload and decreased antioxidant defenses and mitochondrial dysfunction. PMID- 21784889 TI - Anatomically selective serotonergic type 1A and serotonergic type 2A therapies for Parkinson's disease: an approach to reducing dyskinesia without exacerbating parkinsonism? AB - L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT(1A)) receptor agonists and serotonergic type 2A (5-HT(2A)) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair l-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT(1A) and 5-HT(2A) receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT(1A)- and 5-HT(2A)-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT(1A) and 5-HT(2A) receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively. PMID- 21784890 TI - GP who saw Baby P can practise again after two and a half years. PMID- 21784891 TI - Selection bias explains apparent differential mortality between dialysis modalities. AB - The relative risk of death for patients treated with peritoneal dialysis compared with those treated with hemodialysis appears to change with duration of dialysis therapy. Patients who start dialysis urgently are at high risk for mortality and are treated almost exclusively with hemodialysis, introducing bias to such mortality comparisons. To better isolate the association between dialysis treatment modality and patient mortality, we examined the relative risk for mortality for peritoneal dialysis compared with hemodialysis among individuals who received >=4 months of predialysis care and who started dialysis electively as outpatients. From a total of 32,285 individuals who received dialysis in Ontario, Canada during a nearly 8-year period, 6,573 patients met criteria for elective, outpatient initiation. We detected no difference in survival between peritoneal dialysis and hemodialysis after adjusting for relevant baseline characteristics. The relative risk of death did not change with duration of dialysis therapy in our primary analysis, but it did change with time when we defined our patient population using the more inclusive criteria typical of previous studies. These results suggest that peritoneal dialysis and hemodialysis associate with similar survival among incident dialysis patients who initiate dialysis electively, as outpatients, after at least 4 months of predialysis care. Selection bias, rather than an effect of the treatment itself, likely explains the previously described change in the relative risk of death over time between hemodialysis and peritoneal dialysis. PMID- 21784892 TI - Circulating anti-PLA2R autoantibodies to monitor immunological activity in membranous nephropathy. PMID- 21784893 TI - Identification of the nephropathy-susceptibility locus HIVAN4. AB - HIVAN1, HIVAN2, and HIVAN3 are nephropathy-susceptibility loci previously identified in the HIV-1 transgenic mouse, a model of collapsing glomerulopathy. The HIVAN1 and HIVAN2 loci modulate expression of Nphs2, which encodes podocin and several other podocyte-expressed genes. To identify additional loci predisposing to nephropathy, we performed a genome-wide scan in 165 backcross mice generated between the nephropathy-sensitive HIV-1-transgenic FVB/NJ (TgFVB) strain and the resistant Balb/cJ (BALB) strain. We identified a major susceptibility locus (HIVAN4) on chromosome 6 G3-F3, with BALB alleles conferring a twofold reduction in severity (peak LOD score = 4.0). Similar to HIVAN1 and HIVAN2, HIVAN4 modulated expression of Nphs2, indicating a common pathway underlying these loci. We independently confirmed the HIVAN4 locus in a sister TgFVB colony that experienced a dramatic loss of nephropathy subsequent to a breeding bottleneck. In this low-penetrance line, 3% of the genome was admixed with BALB alleles, suggesting a remote contamination event. The admixture localized to discrete segments on chromosome 2 and at the HIVAN4 locus. HIVAN4 candidate genes include killer lectin-like receptor genes as well as A2m and Ptpro, whose gene products are enriched in the glomerulus and interact with HIV-1 proteins. In summary, these data identify HIVAN4 as a major quantitative trait locus for nephropathy and a transregulator of Nphs2. Furthermore, similar selective breeding strategies may help identify further susceptibility loci. PMID- 21784894 TI - GFR normalized to total body water allows comparisons across genders and body sizes. AB - The normalization of GFR to a standardized body-surface area of 1.73 m(2) impedes comparison of GFR across individuals of different genders, heights, or weights. Ideally, GFR should be normalized to a parameter that best explains variation in GFR. Here, we measured true GFR by iohexol clearance in a representative sample of 1627 individuals from the general population who did not have diabetes, cardiovascular disease, or kidney disease. We also estimated total body water (TBW), extracellular fluid volume, lean body mass, liver volume, metabolic rate, and body-surface area. We compared two methods of normalizing GFR to these physiologic variables: (1) the conventional method of scaling GFR to each physiologic variable by simple division and (2) a method based on regression of the GFR on each variable. TBW explained a higher proportion of the variation in GFR than the other physiologic variables. GFR adjusted for TBW by the regression method exhibited less dependence on gender, height, and weight compared with the other physiologic variables. Thus, adjusting GFR for TBW by the regression method allows direct comparisons between individuals of different genders, weights, and heights. We propose that regression-based normalization of GFR to a standardized TBW of 40 L should replace the current practice of normalizing GFR to 1.73 m(2) of body-surface area. PMID- 21784895 TI - Colonic contribution to uremic solutes. AB - Microbes in the colon produce compounds, normally excreted by the kidneys, which are potential uremic toxins. Although p-cresol sulfate and indoxyl sulfate are well studied examples, few other compounds are known. Here, we compared plasma from hemodialysis patients with and without colons to identify and further characterize colon-derived uremic solutes. HPLC confirmed the colonic origin of p cresol sulfate and indoxyl sulfate, but levels of hippurate, methylamine, and dimethylamine were not significantly lower in patients without colons. High resolution mass spectrometry detected more than 1000 features in predialysis plasma samples. Hierarchical clustering based on these features clearly separated dialysis patients with and without colons. Compared with patients with colons, we identified more than 30 individual features in patients without colons that were either absent or present in lower concentration. Almost all of these features were more prominent in plasma from dialysis patients than normal subjects, suggesting that they represented uremic solutes. We used a panel of indole and phenyl standards to identify five colon-derived uremic solutes: alpha phenylacetyl-l-glutamine, 5-hydroxyindole, indoxyl glucuronide, p-cresol sulfate, and indoxyl sulfate. However, compounds with accurate mass values matching most of the colon-derived solutes could not be found in standard metabolomic databases. These results suggest that colonic microbes may produce an important portion of uremic solutes, most of which remain unidentified. PMID- 21784896 TI - Discriminants of prevalent fractures in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have higher rates of fracture than the general population. Increased bone remodeling, leading to microarchitectural deterioration and increased fragility, may accompany declining kidney function, but there are no reliable methods to identify patients at increased risk for fracture. In this cross-sectional study of 82 patients with predialysis CKD, high resolution imaging revealed that the 23 patients with current fractures had significantly lower areal density at the femoral neck; total, cortical, and trabecular volumetric bone density; cortical area and thickness; and trabecular thickness. Compared with levels in the lowest tertile, higher levels of osteocalcin, procollagen type-1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b were associated with higher odds of fracture, even after adjustment for femoral neck T-score. Discrimination of fracture prevalence was best with a femoral neck T-score of -2.0 or less and a value in the upper two tertiles for osteocalcin, procollagen type-1 N-terminal propeptide, or tartrate resistant acid phosphatase 5b; these values corresponded to the upper half of the normal premenopausal reference range. In summary, these cross-sectional data suggest that measurement of bone turnover markers may increase the diagnostic accuracy of densitometry to identify patients with CKD at high risk for fracture. PMID- 21784898 TI - Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. AB - Autoantibodies to the M-type phospholipase A(2) receptor (PLA(2)R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA(2)R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA(2)R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti PLA(2)R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA(2)R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA(2)R. In summary, measuring anti-PLA(2)R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy. PMID- 21784897 TI - IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1alpha. AB - Increased expression of Induced-by-High-Glucose 1 (IHG-1) associates with tubulointerstitial fibrosis in diabetic nephropathy. IHG-1 amplifies TGF-beta1 signaling, but the functions of this highly-conserved protein are not well understood. IHG-1 contains a putative mitochondrial-localization domain, and here we report that IHG-1 is specifically localized to mitochondria. IHG-1 overexpression increased mitochondrial mass and stabilized peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Conversely, inhibition of IHG-1 expression decreased mitochondrial mass, downregulated mitochondrial proteins, and PGC-1alpha-regulated transcription factors, including nuclear respiratory factor 1 and mitochondrial transcription factor A (TFAM), and reduced activity of the TFAM promoter. In the unilateral ureteral obstruction model, we observed higher PGC-1alpha protein expression and IHG-1 levels with fibrosis. In a gene-expression database, we noted that renal biopsies of human diabetic nephropathy demonstrated higher expression of genes encoding key mitochondrial proteins, including cytochrome c and manganese superoxide dismutase, compared with control biopsies. In summary, these data suggest that IHG-1 increases mitochondrial biogenesis by promoting PGC-1alpha dependent processes, potentially contributing to the pathogenesis of renal fibrosis. PMID- 21784899 TI - Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. AB - Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis. Using wild-type (WT), TLR4-knockout, and bone marrow chimeric mice, we found that endotoxin is readily filtered and internalized by S1 proximal tubules through local TLR4 receptors and through fluid-phase endocytosis. Only receptor-mediated interactions between endotoxin and S1 caused oxidative stress in neighboring S2 tubules. Despite significant endotoxin uptake, S1 segments showed no oxidative stress, possibly as a result of the upregulation of cytoprotective heme oxygenase-1 and sirtuin-1 (SIRT1). Conversely, S2 segments did not upregulate SIRT1 and exhibited severe structural and functional peroxisomal damage. Taken together, these data suggest that the S1 segment acts as a sensor of filtered endotoxin, which it takes up. Although this may limit the amount of endotoxin in the systemic circulation and the kidney, it results in severe secondary damage to the neighboring S2 segments. PMID- 21784900 TI - Calcium mediates glomerular filtration through calcineurin and mTORC2/Akt signaling. AB - Alterations to the structure of the glomerular filtration barrier lead to effacement of podocyte foot processes, leakage of albumin, and the development of proteinuria. To better understand the signaling pathways involved in the response of the glomerular filtration barrier to injury, we studied freshly isolated rat glomeruli, which allows for the monitoring and pharmacologic manipulation of early signaling events. Administration of protamine sulfate rapidly damaged the isolated glomeruli, resulting in foot process effacement and albumin leakage. Inhibition of calcium channels and chelation of extracellular calcium reduced protamine sulfate-induced damage, suggesting that calcium signaling plays a critical role in the initial stages of glomerular injury. Calcineurin inhibitors (FK506 and cyclosporine A) and the cathepsin L inhibitor E64 all inhibited protamine sulfate-mediated barrier changes, which suggests that calcium signaling acts, in part, through calcineurin- and cathepsin L-dependent cleavage of synaptopodin, a regulator of actin dynamics. The mTOR inhibitor rapamycin also protected glomeruli, demonstrating that calcium signaling has additional calcineurin-independent components. Furthermore, activation of Akt through mTOR had a direct role on glomerular barrier integrity, and activation of calcium channels mediated this process, likely independent of phosphoinositide 3-kinase. Taken together, these results demonstrate the importance of calcium and related signaling pathways in the structure and function of the glomerular filtration barrier. PMID- 21784901 TI - Allelic variants of complement genes associated with dense deposit disease. AB - The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies. PMID- 21784902 TI - TGF-beta/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. AB - TGF-beta/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific genes. In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy. In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction. In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-beta(1) induced downregulation of miR-29 by binding to the promoter of miR-29. Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-beta/Smad3-mediated fibrosis. In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-beta(1)-induced expression of collagens I and III by renal tubular cells. Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis. In conclusion, miR-29 is a downstream inhibitor of TGF-beta/Smad3 mediated fibrosis and may have therapeutic potential for diseases involving fibrosis. PMID- 21784903 TI - Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. AB - Pheochromocytomas and paragangliomas are neuroendocrine tumors that occur in the context of inherited cancer syndromes in ~30% of cases and are linked to germline mutations in the VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127 genes. Although genome-wide expression studies have revealed some of the mechanisms likely to be involved in pheochromocytoma/paraganglioma tumorigenesis, the complete molecular distinction of all subtypes of hereditary tumors has not been solved and the genetic events involved in the generation of sporadic tumors are unknown. With these purposes in mind, we investigated 202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, using expression profiling, BAC array comparative genomic hybridization and somatic mutation screening. Gene expression signatures defined the hereditary tumors according to their genotype and notably, led to a complete subseparation between SDHx- and VHL-related tumors. In tumor tissues, the systematic characterization of somatic genetic events associated with germline mutations in tumor suppressor genes revealed loss of heterozygosity (LOH) in a majority of cases, but also detected point mutations and copy-neutral LOH. Finally, guided by transcriptome classifications and LOH profiles, somatic mutations in VHL or RET genes were identified in 14% of sporadic pheochromocytomas/paragangliomas. Overall, we found a germline or somatic genetic alteration in 45.5% (92/202) of the tumors in this large series of pheochromocytomas/paragangliomas. Regarding mutated genes, specific molecular pathways involved in tumorigenesis mechanisms are identified. Altogether, these new findings suggest that somatic mutation analysis is likely to yield important clues for personalizing molecular targeted therapies. PMID- 21784905 TI - Unexpected stress-reducing effect of PhaP, a poly(3-hydroxybutyrate) granule associated protein, in Escherichia coli. AB - Phasins (PhaP) are proteins normally associated with granules of poly(3 hydroxybutyrate) (PHB), a biodegradable polymer accumulated by many bacteria as a reserve molecule. These proteins enhance growth and polymer production in natural and recombinant PHB producers. It has been shown that the production of PHB causes stress in recombinant Escherichia coli, revealed by an increase in the concentrations of several heat stress proteins. In this work, quantitative reverse transcription (qRT)-PCR analysis was used to study the effect of PHB accumulation, and that of PhaP from Azotobacter sp. strain FA8, on the expression of stress-related genes in PHB-producing E. coli. While PHB accumulation was found to increase the transcription of dnaK and ibpA, the expression of these genes and of groES, groEL, rpoH, dps, and yfiD was reduced, when PhaP was coexpressed, to levels even lower than those detected in the non-PHB-accumulating control. These results demonstrated the protective role of PhaP in PHB synthesizing E. coli and linked the effects of the protein to the expression of stress-related genes, especially ibpA. The effect of PhaP was also analyzed in non-PHB-synthesizing strains, showing that expression of this heterologous protein has an unexpected protective effect in E. coli, under both normal and stress conditions, resulting in increased growth and higher resistance to both heat shock and superoxide stress by paraquat. In addition, PhaP expression was shown to reduce RpoH protein levels during heat shock, probably by reducing or titrating the levels of misfolded proteins. PMID- 21784906 TI - D1/D2 domain of large-subunit ribosomal DNA for differentiation of Orpinomyces spp. AB - This study presents the suitability of D1/D2 domain of large-subunit (LSU) ribosomal DNA (rDNA) for differentiation of Orpinomyces joyonii and Orpinomyces intercalaris based on PCR-restriction fragment length polymorphism (RFLP). A variation of G/T in O. intercalaris created an additional restriction site for AluI, which was used as an RFLP marker. The results demonstrate adequate heterogeneity in the LSU rDNA for species-level differentiation. PMID- 21784904 TI - Novel [NiFe]- and [FeFe]-hydrogenase gene transcripts indicative of active facultative aerobes and obligate anaerobes in earthworm gut contents. AB - The concomitant occurrence of molecular hydrogen (H(2)) and organic acids along the alimentary canal of the earthworm is indicative of ongoing fermentation during gut passage. Fermentative H(2) production is catalyzed by [FeFe] hydrogenases and group 4 [NiFe]-hydrogenases in obligate anaerobes (e.g., Clostridiales) and facultative aerobes (e.g., Enterobacteriaceae), respectively, functional groups that might respond differently to contrasting redox conditions. Thus, the objectives of this study were to assess the redox potentials of the alimentary canal of Lumbricus terrestris and analyze the hydrogenase transcript diversities of H(2) producers in glucose-supplemented gut content microcosms. Although redox potentials in the core of the alimentary canal were variable on an individual worm basis, average redox potentials were similar. The lowest redox potentials occurred in the foregut and midgut regions, averaging 40 and 110 mV, respectively. Correlation plots between hydrogenase amino acid sequences and 16S rRNA gene sequences indicated that closely related hydrogenases belonged to closely related taxa, whereas distantly related hydrogenases did not necessarily belong to distantly related taxa. Of 178 [FeFe]-hydrogenase gene transcripts, 177 clustered in 12 Clostridiales-affiliated operational taxonomic units, the majority of which were indicative of heretofore unknown hydrogenases. Of 86 group 4 [NiFe]-hydrogenase gene transcripts, 79% and 21% were affiliated with organisms in the Enterobacteriaceae and Aeromonadaceae, respectively. The collective results (i) suggest that fermenters must cope with variable and moderately oxidative redox conditions along the alimentary canal, (ii) demonstrate that heretofore undetected hydrogenases are present in the earthworm gut, and (iii) corroborate previous findings implicating Clostridiaceae and Enterobacteriaceae as active fermentative taxa in earthworm gut content. PMID- 21784907 TI - Diversity and plasticity of the intracellular plant pathogen and insect symbiont "Candidatus Liberibacter asiaticus" as revealed by hypervariable prophage genes with intragenic tandem repeats. AB - "Candidatus Liberibacter asiaticus" is a psyllid-transmitted, phloem-limited alphaproteobacterium and the most prevalent species of "Ca. Liberibacter" associated with a devastating worldwide citrus disease known as huanglongbing (HLB). Two related and hypervariable genes (hyv(I) and hyv(II)) were identified in the prophage regions of the Psy62 "Ca. Liberibacter asiaticus" genome. Sequence analyses of the hyv(I) and hyv(II) genes in 35 "Ca. Liberibacter asiaticus" DNA isolates collected globally revealed that the hyv(I) gene contains up to 12 nearly identical tandem repeats (NITRs, 132 bp) and 4 partial repeats, while hyv(II) contains up to 2 NITRs and 4 partial repeats and shares homology with hyv(I). Frequent deletions or insertions of these repeats within the hyv(I) and hyv(II) genes were observed, none of which disrupted the open reading frames. Sequence conservation within the individual repeats but an extensive variation in repeat numbers, rearrangement, and the sequences flanking the repeat region indicate the diversity and plasticity of "Ca. Liberibacter asiaticus" bacterial populations in the world. These differences were found not only in samples of distinct geographical origins but also in samples from a single origin and even from a single "Ca. Liberibacter asiaticus"-infected sample. This is the first evidence of different "Ca. Liberibacter asiaticus" populations coexisting in a single HLB-affected sample. The Florida "Ca. Liberibacter asiaticus" isolates contain both hyv(I) and hyv(II), while all other global "Ca. Liberibacter asiaticus" isolates contain either one or the other. Interclade assignments of the putative Hyv(I) and Hyv(II) proteins from Florida isolates with other global isolates in phylogenetic trees imply multiple "Ca. Liberibacter asiaticus" populations in the world and a multisource introduction of the "Ca. Liberibacter asiaticus" bacterium into Florida. PMID- 21784908 TI - Defining components of the chromosomal origin of replication of the hyperthermophilic archaeon Pyrococcus furiosus needed for construction of a stable replicating shuttle vector. AB - We report the construction of a series of replicating shuttle vectors that consist of a low-copy-number cloning vector for Escherichia coli and functional components of the origin of replication (oriC) of the chromosome of the hyperthermophilic archaeon Pyrococcus furiosus. In the process of identifying the minimum replication origin sequence required for autonomous plasmid replication in P. furiosus, we discovered that several features of the origin predicted by bioinformatic analysis and in vitro binding studies were not essential for stable autonomous plasmid replication. A minimum region required to promote plasmid DNA replication was identified, and plasmids based on this sequence readily transformed P. furiosus. The plasmids replicated autonomously and existed in a single copy. In contrast to shuttle vectors based on a plasmid from the closely related hyperthermophile Pyrococcus abyssi for use in P. furiosus, plasmids based on the P. furiosus chromosomal origin were structurally unchanged after transformation and were stable without selection for more than 100 generations. PMID- 21784909 TI - Persistent, toxin-antitoxin system-independent, tetracycline resistance-encoding plasmid from a dairy Enterococcus faecium isolate. AB - A tetracycline-resistant (Tet(r)) dairy Enterococcus faecium isolate designated M7M2 was found to carry both tet(M) and tet(L) genes on a 19.6-kb plasmid. After consecutive transfer in the absence of tetracycline, the resistance-encoding plasmid persisted in 99% of the progenies. DNA sequence analysis revealed that the 19.6-kb plasmid contained 28 open reading frames (ORFs), including a tet(M) tet(L)-mob gene cluster, as well as a 10.6-kb backbone highly homologous (99.9%) to the reported plasmid pRE25, but without an identified toxin-antitoxin (TA) plasmid stabilization system. The derived backbone plasmid without the Tet(r) determinants exhibited a 100% retention rate in the presence of acridine orange, suggesting the presence of a TA-independent plasmid stabilization mechanism, with its impact on the persistence of a broad spectrum of resistance-encoding traits still to be elucidated. The tet(M)-tet(L) gene cluster from M7M2 was functional and transmissible and led to acquired resistance in Enterococcus faecalis OG1RF by electroporation and in Streptococcus mutans UA159 by natural transformation. Southern hybridization showed that both the tet(M) and tet(L) genes were integrated into the chromosome of S. mutans UA159, while the whole plasmid was transferred to and retained in E. faecalis OG1RF. Quantitative real-time reverse transcription-PCR (RT-PCR) indicated tetracycline-induced transcription of both the tet(M) and tet(L) genes of pM7M2. The results indicated that multiple mechanisms might have contributed to the persistence of antibiotic resistance encoding genes and that the plasmids pM7M2, pIP816, and pRE25 are likely correlated evolutionarily. PMID- 21784910 TI - Effective antibiotic resistance mitigation during cheese fermentation. AB - Controlling antibiotic-resistant (ART) bacteria in cheese fermentation is important for food safety and public health. A plant-maintained culture was found to be a potential source for ART bacterial contamination in cheese fermentation. Antibiotics had a detectable effect on the ART population from contamination in the finished product. The decrease in the prevalence of antibiotic resistance (AR) in retail cheese samples from 2010 compared to data from 2006 suggested the effectiveness of targeted AR mitigation in related products. PMID- 21784911 TI - Genetic exchange in an arbuscular mycorrhizal fungus results in increased rice growth and altered mycorrhiza-specific gene transcription. AB - Arbuscular mycorrhizal fungi (AMF) are obligate symbionts with most terrestrial plants. They improve plant nutrition, particularly phosphate acquisition, and thus are able to improve plant growth. In exchange, the fungi obtain photosynthetically fixed carbon. AMF are coenocytic, meaning that many nuclei coexist in a common cytoplasm. Genetic exchange recently has been demonstrated in the AMF Glomus intraradices, allowing nuclei of different Glomus intraradices strains to mix. Such genetic exchange was shown previously to have negative effects on plant growth and to alter fungal colonization. However, no attempt was made to detect whether genetic exchange in AMF can alter plant gene expression and if this effect was time dependent. Here, we show that genetic exchange in AMF also can be beneficial for rice growth, and that symbiosis-specific gene transcription is altered by genetic exchange. Moreover, our results show that genetic exchange can change the dynamics of the colonization of the fungus in the plant. Our results demonstrate that the simple manipulation of the genetics of AMF can have important consequences for their symbiotic effects on plants such as rice, which is considered the most important crop in the world. Exploiting natural AMF genetic variation by generating novel AMF genotypes through genetic exchange is a potentially useful tool in the development of AMF inocula that are more beneficial for crop growth. PMID- 21784913 TI - Spoilage-related activity of Carnobacterium maltaromaticum strains in air-stored and vacuum-packed meat. AB - One hundred three isolates of Carnobacterium spp. from raw meat were analyzed by random amplification of polymorphic DNA (RAPD) and PCR and were identified by 16S rRNA gene sequencing. Forty-five strains of Carnobacterium maltaromaticum were characterized for their growth capabilities at different temperatures, NaCl concentrations, and pH values and for in vitro lipolytic and proteolytic activities. Moreover, their spoilage potential in meat was investigated by analyzing the release of volatile organic compounds (VOCs) in meat stored in air or vacuum packs. Almost all the strains were able to grow at 4, 10, and 20 degrees C, at pH values of 6 to 9, and in the presence of 2.5% NaCl. The release of VOCs by each strain in beef stored at 4 degrees C in air and vacuum packs was evaluated by headspace solid-phase microextraction (HS-SPME)-gas chromatography mass spectrometry (GC-MS) analysis. All the meat samples inoculated and stored in air showed higher numbers of VOCs than the vacuum-packed meat samples. Acetoin, 1 octen-3-ol, and butanoic acid were the compounds most frequently found under both storage conditions. The contaminated meat samples were evaluated by a sensory panel; the results indicated that for all sensory odors, no effect of strain was significant (P > 0.05). The storage conditions significantly affected (P < 0.05) the perception of dairy, spoiled-meat, and mozzarella cheese odors, which were more intense in meat stored in air than in vacuum packs but were never very intense. In conclusion, different strains of C. maltaromaticum can grow efficiently in meat stored at low temperatures both in air and in vacuum packs, producing volatile molecules with low sensory impacts, with a negligible contribution to meat spoilage overall. PMID- 21784912 TI - Biodiversity and biogeography of rhizobia associated with soybean plants grown in the North China Plain. AB - As the putative center of origin for soybean and the second largest region of soybean production in China, the North China Plain covers temperate and subtropical regions with diverse soil characteristics. However, the soybean rhizobia in this plain have not been sufficiently studied. To investigate the biodiversity and biogeography of soybean rhizobia in this plain, a total of 309 isolates of symbiotic bacteria from the soybean nodules collected from 16 sampling sites were studied by molecular characterization. These isolates were classified into 10 genospecies belonging to the genera Sinorhizobium and Bradyrhizobium, including four novel groups, with S. fredii (68.28%) as the dominant group. The phylogeny of symbiotic genes nodC and nifH defined four lineages among the isolates associated with Sinorhizobium fredii, Bradyrhizobium elkanii, B. japonicum, and B. yuanmingense, demonstrating the different origins of symbiotic genes and their coevolution with the chromosome. The possible lateral transfer of symbiotic genes was detected in several cases. The association between soil factors (available N, P, and K and pH) and the distribution of genospecies suggest clear biogeographic patterns: Sinorhizobium spp. were superdominant in sampling sites with alkaline-saline soils, while Bradyrhizobium spp. were more abundant in neutral soils. This study clarified the biodiversity and biogeography of soybean rhizobia in the North China Plain. PMID- 21784914 TI - Comparative 13C metabolic flux analysis of pyruvate dehydrogenase complex deficient, L-valine-producing Corynebacterium glutamicum. AB - L-Valine can be formed successfully using C. glutamicum strains missing an active pyruvate dehydrogenase enzyme complex (PDHC). Wild-type C. glutamicum and four PDHC-deficient strains were compared by (13)C metabolic flux analysis, especially focusing on the split ratio between glycolysis and the pentose phosphate pathway (PPP). Compared to the wild type, showing a carbon flux of 69% +/- 14% through the PPP, a strong increase in the PPP flux was observed in PDHC-deficient strains with a maximum of 113% +/- 22%. The shift in the split ratio can be explained by an increased demand of NADPH for l-valine formation. In accordance, the introduction of the Escherichia coli transhydrogenase PntAB, catalyzing the reversible conversion of NADH to NADPH, into an L-valine-producing C. glutamicum strain caused the PPP flux to decrease to 57% +/- 6%, which is below the wild type split ratio. Hence, transhydrogenase activity offers an alternative perspective for sufficient NADPH supply, which is relevant for most amino acid production systems. Moreover, as demonstrated for L-valine, this bypass leads to a significant increase of product yield due to a concurrent reduction in carbon dioxide formation via the PPP. PMID- 21784915 TI - Temporal variation and host association in the Campylobacter population in a longitudinal ruminant farm study. AB - Campylobacter jejuni and C. coli were quantified and typed, using multilocus sequence typing (MLST), from fecal samples collected from a mixed cattle and sheep farm during summer. Cattle had a significantly higher prevalence than sheep (21.9% [74/338] and 14.0% [30/214], respectively), but both decreased over time. There were no differences in the average Campylobacter concentrations shed by cattle (600 CFU g(-1)) and sheep (820 CFU g(-1)), although sheep did show a significant temporal reduction in the number of Campylobacter organisms shed in their feces. A total of 21 different sequence types (STs) (97.7% C. jejuni, 2.3% C. coli) were isolated from cattle, and 9 different STs were isolated from sheep (40.6% C. jejuni, 59.4% C. coli). The Campylobacter population in cattle was relatively stable, and the frequencies of genotypes isolated showed little temporal variation. However, the composition of subtypes isolated from sheep did show significant temporal differences. The cattle and sheep consistently showed significant differences in their carriage of Campylobacter species, STs, and CCs despite the fact that both were exposed to the same farming environment. This work has highlighted the patterns of a Campylobacter population on a ruminant farm by identifying the existence of both temporal and between-host variations. PMID- 21784916 TI - Isolation of generalized transducing bacteriophages for uropathogenic strains of Escherichia coli. AB - The traditional genetic procedure for random or site-specific mutagenesis in Escherichia coli K-12 involves mutagenesis, isolation of mutants, and transduction of the mutation into a clean genetic background. The transduction step reduces the likelihood of complications due to secondary mutations. Though well established, this protocol is not tenable for many pathogenic E. coli strains, such as uropathogenic strain CFT073, because it is resistant to known K 12 transducing bacteriophages, such as P1. CFT073 mutants generated via a technique such as lambda Red mutagenesis may contain unknown secondary mutations. Here we describe the isolation and characterization of transducing bacteriophages for CFT073. Seventy-seven phage isolates were acquired from effluent water samples collected from a wastewater treatment plant in Madison, WI. The phages were differentiated by a host sensitivity-typing scheme with a panel of E. coli strains from the ECOR collection and clinical uropathogenic isolates. We found 49 unique phage isolates. These were then examined for their ability to transduce antibiotic resistance gene insertions at multiple loci between different mutant strains of CFT073. We identified 4 different phages capable of CFT073 generalized transduction. These phages also plaque on the model uropathogenic E. coli strains 536, UTI89, and NU14. The highest-efficiency transducing phage, PhiEB49, was further characterized by DNA sequence analysis, revealing a double-stranded genome 47,180 bp in length and showing similarity to other sequenced phages. When combined with a technique like lambda Red mutagenesis, the newly characterized transducing phages provide a significant development in the genetic tools available for the study of uropathogenic E. coli. PMID- 21784917 TI - Role of alcohols in growth, lipid composition, and membrane fluidity of yeasts, bacteria, and archaea. AB - Increased membrane fluidity, which causes cofactor leakage and loss of membrane potential, has long been documented as a cause for decreased cell growth during exposure to ethanol, butanol, and other alcohols. Reinforcement of the membrane with more complex lipid components is thus thought to be beneficial for the generation of more tolerant organisms. In this study, organisms with more complex membranes, namely, archaea, did not maintain high growth rates upon exposure to alcohols, indicating that more complex lipids do not necessarily fortify the membrane against the fluidizing effects of alcohols. In the presence of alcohols, shifts in lipid composition to more saturated and unbranched lipids were observed in most of the organisms tested, including archaea, yeasts, and bacteria. However, these shifts did not always result in a decrease in membrane fluidity or in greater tolerance of the organism to alcohol exposure. In general, organisms tolerating the highest concentrations of alcohols maintained membrane fluidity after alcohol exposure, whereas organisms that increased membrane rigidity were less tolerant. Altered lipid composition was a common response to alcohol exposure, with the most tolerant organisms maintaining a modestly fluid membrane. Our results demonstrate that increased membrane fluidity is not the sole cause of growth inhibition and that alcohols may also denature proteins within the membrane and cytosol, adversely affecting metabolism and decreasing cell growth. PMID- 21784918 TI - Dissimilar properties of two recombinant Lactobacillus acidophilus strains displaying Salmonella FliC with different anchoring motifs. AB - Display of heterologous antigens on the cell surface is considered a useful technique for vaccine delivery by recombinant lactobacilli. In this study, two recombinant Lactobacillus acidophilus derivatives displaying Salmonella flagellin (FliC) were constructed using different anchor motifs. In one instance, the FliC protein was fused to the C-terminal region of a cell envelope proteinase (PrtP) and was bound to the cell wall by electrostatic bonds. In the other case, the same antigen was conjugated to the anchor region of mucus binding protein (Mub) and was covalently associated with the cell wall by an LPXTG motif. These two recombinant L. acidophilus cell surface displays resulted in dissimilar maturation and cytokine production by human myeloid dendritic cells. The surface associated antigen was highly sensitive to simulated gastric and small intestinal juices. By supplementation with bicarbonate buffer and soybean trypsin inhibitor, the cell surface antigen was protected from proteolytic enzymes during gastric challenge in vitro. The protective reagents also increased the viability of the L. acidophilus cells upon challenge with simulated digestive juices. These results demonstrate the importance of protecting cells and their surface associated antigens during oral immunization. PMID- 21784919 TI - Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. AB - Gastrointestinal disturbance is frequently reported for individuals with autism. We used quantitative real-time PCR analysis to quantify fecal bacteria that could influence gastrointestinal health in children with and without autism. Lower relative abundances of Bifidobacteria species and the mucolytic bacterium Akkermansia muciniphila were found in children with autism, the latter suggesting mucus barrier changes. PMID- 21784920 TI - Detection of Coxiella burnetii in complex matrices by using multiplex quantitative PCR during a major Q fever outbreak in The Netherlands. AB - Q fever, caused by Coxiella burnetii, is a zoonosis with a worldwide distribution. A large rural area in the southeast of the Netherlands was heavily affected by Q fever between 2007 and 2009. This initiated the development of a robust and internally controlled multiplex quantitative PCR (qPCR) assay for the detection of C. burnetii DNA in veterinary and environmental matrices on suspected Q fever-affected farms. The qPCR detects three C. burnetii targets (icd, com1, and IS1111) and one Bacillus thuringiensis internal control target (cry1b). Bacillus thuringiensis spores were added to samples to control both DNA extraction and PCR amplification. The performance of the qPCR assay was investigated and showed a high efficiency; a limit of detection of 13.0, 10.6, and 10.4 copies per reaction for the targets icd, com1, and IS1111, respectively; and no cross-reactivity with the nontarget organisms tested. Screening for C. burnetii DNA on 29 suspected Q fever-affected farms during the Q fever epidemic in 2008 showed that swabs from dust-accumulating surfaces contained higher levels of C. burnetii DNA than vaginal swabs from goats or sheep. PCR inhibition by coextracted substances was observed in some environmental samples, and 10- or 100 fold dilutions of samples were sufficient to obtain interpretable signals for both the C. burnetii targets and the internal control. The inclusion of an internal control target and three C. burnetii targets in one multiplex qPCR assay showed that complex veterinary and environmental matrices can be screened reliably for the presence of C. burnetii DNA during an outbreak. PMID- 21784922 TI - Intra-amygdala ZIP injections impair the memory of learned active avoidance responses and attenuate conditioned taste-aversion acquisition in rats. AB - We have investigated the effect of protein kinase Mzeta (PKMzeta) inhibition in the basolateral amygdala (BLA) upon the retention of a nonspatial learned active avoidance response and conditioned taste-aversion (CTA) acquisition in rats. ZIP (10 nmol/MUL) injected into the BLA 24 h after training impaired retention of a learned avoidance-jumping response assessed 7 d later when compared with control groups injected with scrambled-ZIP. Nevertheless, a retraining session applied 24 h later indicated no differences between the groups. Additionally, a similar ZIP injection into the BLA during the conditioned stimulus-unconditioned stimulus (CS US) interval attenuated CTA acquisition. These findings support the BLA PKMzeta role in various forms of memory. PMID- 21784921 TI - Characterization of two distinct glycosyl hydrolase family 78 alpha-L rhamnosidases from Pediococcus acidilactici. AB - alpha-L-Rhamnosidases play an important role in the hydrolysis of glycosylated aroma compounds (especially terpenes) from wine. Although several authors have demonstrated the enological importance of fungal rhamnosidases, the information on bacterial enzymes in this context is still limited. In order to fill this important gap, two putative rhamnosidase genes (ram and ram2) from Pediococcus acidilactici DSM 20284 were heterologously expressed, and the respective gene products were characterized. In combination with a bacterial beta-glucosidase, both enzymes released the monoterpenes linalool and cis-linalool oxide from a muscat wine extract under ideal conditions. Additionally, Ram could release significant amounts of geraniol and citronellol/nerol. Nevertheless, the potential enological value of these enzymes is limited by the strong negative effects of acidity and ethanol on the activities of Ram and Ram2. Therefore, a direct application in winemaking seems unlikely. Although both enzymes are members of the same glycosyl hydrolase family (GH 78), our results clearly suggest the distinct functionalities of Ram and Ram2, probably representing two subclasses within GH 78: Ram could efficiently hydrolyze only the synthetic substrate p-nitrophenyl-alpha-L-rhamnopyranoside (V(max) = 243 U mg(-1)). In contrast, Ram2 displayed considerable specificity toward hesperidin (V(max) = 34 U mg(-1)) and, especially, rutinose (V(max) = 1,200 U mg(-1)), a disaccharide composed of glucose and rhamnose. Both enzymes were unable to hydrolyze the flavanone glycoside naringin. Interestingly, both enzymes displayed indications of positive substrate cooperativity. This study presents detailed kinetic data on two novel rhamnosidases, which could be relevant for the further study of bacterial glycosidases. PMID- 21784923 TI - Pole age affects cell size and the timing of cell division in Methylobacterium extorquens AM1. AB - A number of recent experiments at the single-cell level have shown that genetically identical bacteria that live in homogeneous environments often show a substantial degree of phenotypic variation between cells. Often, this variation is attributed to stochastic aspects of biology-the fact that many biological processes involve small numbers of molecules and are thus inherently variable. However, not all variation between cells needs to be stochastic in nature; one deterministic process that could be important for cell variability in some bacterial species is the age of the cell poles. Working with the alphaproteobacterium Methylobacterium extorquens, we monitored individuals in clonally growing populations over several divisions and determined the pole age, cell size, and interdivision intervals of individual cells. We observed the high levels of variation in cell size and the timing of cell division that have been reported before. A substantial fraction of this variation could be explained by each cell's pole age and the pole age of its mother: cell size increased with increasing pole age, and the interval between cell divisions decreased. A theoretical model predicted that populations governed by such processes will quickly reach a stable distribution of different age and size classes. These results show that the pole age distribution in bacterial populations can contribute substantially to cellular individuality. In addition, they raise questions about functional differences between cells of different ages and the coupling of cell division to cell size. PMID- 21784924 TI - Identification and characterization of a re-citrate synthase in Dehalococcoides strain CBDB1. AB - The genome annotations of all sequenced Dehalococcoides strains lack a citrate synthase, although physiological experiments have indicated that such an activity should be encoded. We here report that a Re face-specific citrate synthase is synthesized by Dehalococcoides strain CBDB1 and that this function is encoded by the gene cbdbA1708 (NCBI accession number CAI83711), previously annotated as encoding homocitrate synthase. Gene cbdbA1708 was heterologously expressed in Escherichia coli, and the recombinant enzyme was purified. The enzyme catalyzed the condensation of oxaloacetate and acetyl coenzyme A (acetyl-CoA) to citrate. The protein did not have homocitrate synthase activity and was inhibited by citrate, and Mn2+ was needed for full activity. The stereospecificity of the heterologously expressed citrate synthase was determined by electrospray ionization liquid chromatography-mass spectrometry (ESI LC/MS). Citrate was synthesized from [2-(13)C]acetyl-CoA and oxaloacetate by the Dehalococcoides recombinant citrate synthase and then converted to acetate and malate by commercial citrate lyase plus malate dehydrogenase. The formation of unlabeled acetate and 13C-labeled malate proved the Re face-specific activity of the enzyme. Shotgun proteome analyses of cell extracts of strain CBDB1 demonstrated that cbdbA1708 is expressed in strain CBDB1. PMID- 21784925 TI - Characterization of Escherichia coli UmuC active-site loops identifies variants that confer UV hypersensitivity. AB - DNA is constantly exposed to chemical and environmental mutagens, causing lesions that can stall replication. In order to deal with DNA damage and other stresses, Escherichia coli utilizes the SOS response, which regulates the expression of at least 57 genes, including umuDC. The gene products of umuDC, UmuC and the cleaved form of UmuD, UmuD', form the specialized E. coli Y-family DNA polymerase UmuD'2C, or polymerase V (Pol V). Y-family DNA polymerases are characterized by their specialized ability to copy damaged DNA in a process known as translesion synthesis (TLS) and by their low fidelity on undamaged DNA templates. Y-family polymerases exhibit various specificities for different types of DNA damage. Pol V carries out TLS to bypass abasic sites and thymine-thymine dimers resulting from UV radiation. Using alanine-scanning mutagenesis, we probed the roles of two active-site loops composed of residues 31 to 38 and 50 to 54 in Pol V activity by assaying the function of single-alanine variants in UV-induced mutagenesis and for their ability to confer resistance to UV radiation. We find that mutations of the N-terminal residues of loop 1, N32, N33, and D34, confer hypersensitivity to UV radiation and to 4-nitroquinoline-N-oxide and significantly reduce Pol V dependent UV-induced mutagenesis. Furthermore, mutating residues 32, 33, or 34 diminishes Pol V-dependent inhibition of recombination, suggesting that these mutations may disrupt an interaction of UmuC with RecA, which could also contribute to the UV hypersensitivity of cells expressing these variants. PMID- 21784926 TI - Proteolytic cleavage inactivates the Staphylococcus aureus lipoteichoic acid synthase. AB - Lipoteichoic acid (LTA) is a crucial cell envelope component in Gram-positive bacteria. In Staphylococcus aureus, the polyglycerolphosphate LTA molecule is synthesized by LtaS, a membrane-embedded enzyme with five N-terminal transmembrane helices (5TM domain) that are connected via a linker region to the C-terminal extracellular enzymatic domain (eLtaS). The LtaS enzyme is processed during bacterial growth, and the eLtaS domain is released from the bacterial membrane. Here we provide experimental evidence that the proteolytic cleavage following residues 215Ala-Leu-Ala217 is performed by the essential S. aureus signal peptidase SpsB, as depletion of spsB results in reduced LtaS processing. In addition, the introduction of a proline residue at the +1 position with respect to the cleavage site, a substitution known to inhibit signal peptidase dependent cleavage, abolished LtaS processing at this site. It was further shown that the 5TM domain is crucial for enzyme function. The observation that the construction of hybrid proteins between two functional LtaS-type enzymes resulted in the production of proteins unable to synthesize LTA suggests that specific interactions between the 5TM and eLtaS domains are required for function. No enzyme activity was detected upon expression of the 5TM and eLtaS domains as separate fragments, indicating that the two domains cannot assemble postsynthesis to form a functional enzyme. Taken together, our data suggest that only the full length LtaS enzyme is active in the LTA synthesis pathway and that the proteolytic cleavage step is used as a mechanism to irreversibly inactivate the enzyme. PMID- 21784927 TI - Spatial distribution and diffusive motion of RNA polymerase in live Escherichia coli. AB - By labeling the beta' subunit of RNA polymerase (RNAP), we used fluorescence microscopy to study the spatial distribution and diffusive motion of RNAP in live Escherichia coli cells for the first time. With a 40-ms time resolution, the spatial distribution exhibits two or three narrow peaks of 300- to 600-nm full width at half-maximum that maintain their positions within 60 nm over 1 s. The intensity in these features is 20 to 30% of the total. Fluorescence recovery after photobleaching (FRAP) measures the diffusive motion of RNAP on the 1-MUm length scale. Averaged over many cells, 53%+/-19% of the RNAP molecules were mobile on the 3-s timescale, with a mean apparent diffusion constant of 0.22+/-0.16 MUm2-s(-1). The remaining 47% were immobile even on the 30-s timescale. We interpret the immobile fraction as arising from RNAP specifically bound to DNA, either actively transcribing or not. The diffusive motion of the mobile fraction (fmobile) probably involves both one-dimensional sliding during nonspecific binding to DNA and three-dimensional hopping between DNA strands. There is significant cell-to-cell heterogeneity in both DRNAP and fmobile. PMID- 21784928 TI - SpoIIE is necessary for asymmetric division, sporulation, and expression of sigmaF, sigmaE, and sigmaG but does not control solvent production in Clostridium acetobutylicum ATCC 824. AB - In order to better characterize the initial stages of sporulation past Spo0A activation and the associated solventogenesis in the important industrial and model organism Clostridium acetobutylicum, the spoIIE gene was successfully disrupted and its expression was silenced. By silencing spoIIE, sporulation was blocked prior to asymmetric division, and no mature spores or any distinguishable morphogenetic changes developed. Upon plasmid-based complementation of spoIIE, sporulation was restored, although the number of spores formed was below that of the plasmid control strain. To investigate the impact of silencing spoIIE on the regulation of sporulation, transcript levels of sigF, sigE, and sigG were examined by semiquantitative reverse transcription-PCR, and the corresponding sigmaF, sigmaE, and sigmaG protein levels were determined by Western analysis. Expression of sigF was significantly reduced in the inactivation strain, and this resulted in very low sigmaF protein levels. Expression of sigE was barely detected, and no sigG transcript was detected at all; consequently, no sigmaE or sigmaG proteins were detected. These data suggest an autostimulatory role for sigmaF in C. acetobutylicum, in contrast to the model organism for endospore formation, Bacillus subtilis, and confirm that high-level expression of sigmaF is required for expression of sigmaE and sigmaG. Unlike the sigmaF and sigmaE inactivation strains, the SpoIIE inactivation strain did not exhibit inoculum dependent solvent formation and produced good levels of solvents from both exponential- and stationary-phase inocula. Thus, we concluded that SpoIIE does not control solvent formation. PMID- 21784929 TI - Osmotically controlled synthesis of the compatible solute proline is critical for cellular defense of Bacillus subtilis against high osmolarity. AB - Bacillus subtilis is known to accumulate large amounts of the compatible solute proline via de novo synthesis as a stress protectant when it faces high-salinity environments. We elucidated the genetic determinants required for the osmoadaptive proline production from the precursor glutamate. This proline biosynthesis route relies on the proJ-encoded gamma-glutamyl kinase, the proA encoded gamma-glutamyl phosphate reductase, and the proH-encoded Delta1-pyrroline 5-caboxylate reductase. Disruption of the proHJ operon abolished osmoadaptive proline production and strongly impaired the ability of B. subtilis to cope with high-osmolarity growth conditions. Disruption of the proA gene also abolished osmoadaptive proline biosynthesis but caused, in contrast to the disruption of proHJ, proline auxotrophy. Northern blot analysis demonstrated that the transcription of the proHJ operon is osmotically inducible, whereas that of the proBA operon is not. Reporter gene fusion studies showed that proHJ expression is rapidly induced upon an osmotic upshift. Increased expression is maintained as long as the osmotic stimulus persists and is sensitively linked to the prevalent osmolarity of the growth medium. Primer extension analysis revealed the osmotically controlled proHJ promoter, a promoter that resembles typical SigA type promoters of B. subtilis. Deletion analysis of the proHJ promoter region identified a 126-bp DNA segment carrying all sequences required in cis for osmoregulated transcription. Our data disclose the presence of ProA-interlinked anabolic and osmoadaptive proline biosynthetic routes in B. subtilis and demonstrate that the synthesis of the compatible solute proline is a central facet of the cellular defense to high-osmolarity surroundings for this soil bacterium. PMID- 21784930 TI - The RpiR-like repressor IolR regulates inositol catabolism in Sinorhizobium meliloti. AB - Sinorhizobium meliloti, the nitrogen-fixing symbiont of alfalfa, has the ability to catabolize myo-, scyllo-, and D-chiro-inositol. Functional inositol catabolism (iol) genes are required for growth on these inositol isomers, and they play a role during plant-bacterium interactions. The inositol catabolism genes comprise the chromosomally encoded iolA (mmsA) and the iolY(smc01163)RCDEB genes, as well as the idhA gene located on the pSymB plasmid. Reverse transcriptase assays showed that the iolYRCDEB genes are transcribed as one operon. The iol genes were weakly expressed without induction, but their expression was strongly induced by myo-inositol. The putative transcriptional regulator of the iol genes, IolR, belongs to the RpiR-like repressor family. Electrophoretic mobility shift assays demonstrated that IolR recognized a conserved palindromic sequence (5'-GGAA-N6 TTCC-3') in the upstream regions of the idhA, iolY, iolR, and iolC genes. Complementation assays found IolR to be required for the repression of its own gene and for the downregulation of the idhA-encoded myo-inositol dehydrogenase activity in the presence and absence of inositol. Further expression studies indicated that the late pathway intermediate 2-keto-5-deoxy-D-gluconic acid 6 phosphate (KDGP) functions as the true inducer of the iol genes. The iolA (mmsA) gene encoding methylmalonate semialdehyde dehydrogenase was not regulated by IolR. The S. meliloti iolA (mmsA) gene product seems to be involved in more than only the inositol catabolic pathway, since it was also found to be essential for valine catabolism, supporting its more recent annotation as mmsA. PMID- 21784932 TI - Localization of the Clostridium difficile cysteine protease Cwp84 and insights into its maturation process. AB - Clostridium difficile is a nosocomial pathogen involved in antibiotic-associated diarrhea. C. difficile expresses a cysteine protease, Cwp84, which has been shown to degrade some proteins of the extracellular matrix and play a role in the maturation of the precursor of the S-layer proteins. We sought to analyze the localization and the maturation process of this protease. Two identifiable forms of the protease were found to be associated in the bacteria: a form of ~80 kDa and a cleaved one of 47 kDa, identified as the mature protease. They were found mainly in the bacterial cell surface fractions and weakly in the extracellular fraction. The 80-kDa protein was noncovalently associated with the S-layer proteins, while the 47-kDa form was found to be tightly associated with the underlying cell wall. Our data supported that the anchoring of the Cwp84 47-kDa form is presumably due to a reassociation of the secreted protein. Moreover, we showed that the complete maturation of the recombinant protein Cwp84(30-803) is a sequential process beginning at the C-terminal end, followed by one or more cleavages at the N-terminal end. The processing sites of recombinant Cwp84 are likely to be residues Ser-92 and Lys-518. No proteolytic activity was detected with the mature recombinant protease Cwp84(92-518) (47 kDa). In contrast, a fragment including the propeptide (Cwp84(30-518)) displayed proteolytic activity on azocasein and fibronectin. These results showed that Cwp84 is processed essentially at the bacterial cell surface and that its different forms may display different proteolytic activities. PMID- 21784931 TI - Two new complete genome sequences offer insight into host and tissue specificity of plant pathogenic Xanthomonas spp. AB - Xanthomonas is a large genus of bacteria that collectively cause disease on more than 300 plant species. The broad host range of the genus contrasts with stringent host and tissue specificity for individual species and pathovars. Whole genome sequences of Xanthomonas campestris pv. raphani strain 756C and X. oryzae pv. oryzicola strain BLS256, pathogens that infect the mesophyll tissue of the leading models for plant biology, Arabidopsis thaliana and rice, respectively, were determined and provided insight into the genetic determinants of host and tissue specificity. Comparisons were made with genomes of closely related strains that infect the vascular tissue of the same hosts and across a larger collection of complete Xanthomonas genomes. The results suggest a model in which complex sets of adaptations at the level of gene content account for host specificity and subtler adaptations at the level of amino acid or noncoding regulatory nucleotide sequence determine tissue specificity. PMID- 21784933 TI - Transcriptional hierarchy of Aeromonas hydrophila polar-flagellum genes. AB - Aeromonas hydrophila polar-flagellum class I gene transcription is sigma70 dependent, which is consistent with the fact that the A. hydrophila polar flagellum is constitutively expressed. In contrast to other bacteria with dual flagellar systems such as Vibrio parahaemolyticus, the A. hydrophila LafK protein does not compensate for the lack of the polar-flagellum regulator FlrA (V. parahaemolyticus FlaK homologue). This is consistent with the fact that the A. hydrophila FlrA mutation abolishes polar-flagellum formation in liquid and on solid surfaces but does not affect inducible lateral-flagellum formation. The results highlight that the polar- and lateral-flagellum interconnections and control networks are specific and that there are differences between the dual flagellar systems in A. hydrophila and V. parahaemolyticus. Furthermore, our results indicate that the A. hydrophila polar-flagellum transcriptional hierarchy (also in class II, III, and IV genes) shares some similarities with but has many important differences from the transcriptional hierarchies of Vibrio cholerae and Pseudomonas aeruginosa. The A. hydrophila flhF and flhG genes are essential for the assembly of a functional polar flagellum because in-frame mutants fail to swim in liquid medium and lack the polar flagellum. In Vibrio and Pseudomonas flhG disruption increases the number of polar flagella per cell, and Pseudomonas flhF disruption gives an aberrant placement of flagellum. Here, we propose the gene transcriptional hierarchy for the A. hydrophila polar flagellum. PMID- 21784934 TI - Pseudomonas aeruginosa tssC1 links type VI secretion and biofilm-specific antibiotic resistance. AB - Biofilm-specific antibiotic resistance is influenced by multiple factors. We demonstrated that Pseudomonas aeruginosa tssC1, a gene implicated in type VI secretion (T6S), is important for resistance of biofilms to a subset of antibiotics. We showed that tssC1 expression is induced in biofilms and confirmed that tssC1 is required for T6S. PMID- 21784935 TI - The fimbrial usher FimD follows the SurA-BamB pathway for its assembly in the outer membrane of Escherichia coli. AB - Fimbrial ushers are the largest beta-barrel outer membrane proteins (OMPs) known to date, which function in the polymerization of fimbriae and their translocation to the bacterial surface. Folding and assembly of these complex OMPs are not characterized. Here, we investigate the role of periplasmic chaperones (SurA, Skp, DegP, and FkpA) and individual components of the beta-barrel assembly machinery (BAM) complex (BamA, BamB, BamC, and BamE) in the folding of the Escherichia coli FimD usher. The FimD level is dramatically reduced (~30-fold) in a surA null mutant, but a strong cell envelope stress is constitutively activated with upregulation of DegP (~10-fold). To demonstrate a direct role of SurA, FimD folding was analyzed in a conditional surA mutant in which SurA expression was controlled. In this strain, FimD is depleted from bacteria in parallel to SurA without significant upregulation of DegP. Interestingly, the dependency on SurA is higher for FimD than for other OMPs. We also demonstrate that a functional BAM complex is needed for folding of FimD. In addition, FimD levels were strongly reduced (~5-fold) in a mutant lacking the accessory lipoprotein BamB. The critical role of BamB for FimD folding was confirmed by complementation and BamB depletion experiments. Similar to SurA dependency, FimD showed a stronger dependency on BamB than OMPs. On the other hand, folding of FimD was only marginally affected in bamC and bamE mutants. Collectively, our results indicate that FimD usher follows the SurA-BamB pathway for its assembly. The preferential use of this pathway for the folding of OMPs with large beta-barrels is discussed. PMID- 21784936 TI - Characterization of an N-acetylmuramic acid/N-acetylglucosamine kinase of Clostridium acetobutylicum. AB - We report here the cloning and characterization of a cytoplasmic kinase of Clostridium acetobutylicum, named MurK (for murein sugar kinase). The enzyme has a unique specificity for both amino sugars of the bacterial cell wall, N acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc), which are phosphorylated at the 6-hydroxyl group. Kinetic analyses revealed Km values of 190 and 127 MUM for MurNAc and GlcNAc, respectively, and a kcat value (65.0 s( 1)) that was 1.5-fold higher for the latter substrate. Neither the non-N acetylated forms of the cell wall sugars, i.e., glucosamine and/or muramic acid, nor epimeric hexoses or 1,6-anhydro-MurNAc were substrates for the enzyme. MurK displays low overall amino acid sequence identity (24%) with human GlcNAc kinase and is the first characterized bacterial representative of the BcrAD/BadFG-like ATPase family. We propose a role of MurK in the recovery of muropeptides during cell wall rescue in C. acetobutylicum. The kinase was applied for high-sensitive detection of the amino sugars in cell wall preparations by radioactive phosphorylation. PMID- 21784937 TI - Mutations in Flavobacterium johnsoniae sprE result in defects in gliding motility and protein secretion. AB - Cells of the gliding bacterium Flavobacterium johnsoniae move rapidly over surfaces. Transposon mutagenesis was used to identify sprE, which is involved in gliding. Mutations in sprE resulted in the formation of nonspreading colonies on agar. sprE mutant cells in wet mounts were almost completely deficient in attachment to and movement on glass, but a small percentage of cells exhibited slight movements, indicating that the motility machinery was not completely disrupted. SprE is a predicted lipoprotein with a tetratricopeptide repeat domain. SprE is similar in sequence to Porphyromonas gingivalis PorW, which is required for secretion of gingipain protease virulence factors. Disruption of F. johnsoniae sprE resulted in decreased extracellular chitinase activity and decreased secretion of the cell surface motility protein SprB. Reduced secretion of cell surface components of the gliding machinery, such as SprB, may account for the defects in gliding. Orthologs of sprE are found in many gliding and nongliding members of the phylum Bacteroidetes, suggesting that similar protein secretion systems are common among members of this large and diverse group of bacteria. PMID- 21784938 TI - Characterization of a glucosamine/glucosaminide N-acetyltransferase of Clostridium acetobutylicum. AB - Many bacteria, in particular Gram-positive bacteria, contain high proportions of non-N-acetylated amino sugars, i.e., glucosamine (GlcN) and/or muramic acid, in the peptidoglycan of their cell wall, thereby acquiring resistance to lysozyme. However, muramidases with specificity for non-N-acetylated peptidoglycan have been characterized as part of autolytic systems such as of Clostridium acetobutylicum. We aim to elucidate the recovery pathway for non-N-acetylated peptidoglycan fragments and present here the identification and characterization of an acetyltransferase of novel specificity from C. acetobutylicum, named GlmA (for glucosamine/glucosaminide N-acetyltransferase). The enzyme catalyzes the specific transfer of an acetyl group from acetyl coenzyme A to the primary amino group of GlcN, thereby generating N-acetylglucosamine. GlmA is also able to N acetylate GlcN residues at the nonreducing end of glycosides such as (partially) non-N-acetylated peptidoglycan fragments and beta-1,4-glycosidically linked chitosan oligomers. Km values of 114, 64, and 39 MUM were determined for GlcN, (GlcN)2, and (GlcN)3, respectively, and a 3- to 4-fold higher catalytic efficiency was determined for the di- and trisaccharides. GlmA is the first cloned and biochemically characterized glucosamine/glucosaminide N acetyltransferase and a member of the large GCN5-related N-acetyltransferases (GNAT) superfamily of acetyltransferases. We suggest that GlmA is required for the recovery of non-N-acetylated muropeptides during cell wall rescue in C. acetobutylicum. PMID- 21784939 TI - Putative role of cellulosomal protease inhibitors in Clostridium cellulovorans based on gene expression and measurement of activities. AB - This study is the first to demonstrate the activity of putative cellulosomal protease/peptidase inhibitors (named cyspins) of Clostridium cellulovorans, using the Saccharomyces cerevisiae display system. Cyspins exhibited inhibitory activities against several representative plant proteases. This suggests that these inhibitors protect their microbe and cellulosome from external attack by plant proteases. PMID- 21784940 TI - Quantifying aggregation dynamics during Myxococcus xanthus development. AB - Under starvation conditions, a swarm of Myxococcus xanthus cells will undergo development, a multicellular process culminating in the formation of many aggregates called fruiting bodies, each of which contains up to 100,000 spores. The mechanics of symmetry breaking and the self-organization of cells into fruiting bodies is an active area of research. Here we use microcinematography and automated image processing to quantify several transient features of developmental dynamics. An analysis of experimental data indicates that aggregation reaches its steady state in a highly nonmonotonic fashion. The number of aggregates rapidly peaks at a value 2- to 3-fold higher than the final value and then decreases before reaching a steady state. The time dependence of aggregate size is also nonmonotonic, but to a lesser extent: average aggregate size increases from the onset of aggregation to between 10 and 15 h and then gradually decreases thereafter. During this process, the distribution of aggregates transitions from a nearly random state early in development to a more ordered state later in development. A comparison of experimental results to a mathematical model based on the traffic jam hypothesis indicates that the model fails to reproduce these dynamic features of aggregation, even though it accurately describes its final outcome. The dynamic features of M. xanthus aggregation uncovered in this study impose severe constraints on its underlying mechanisms. PMID- 21784941 TI - Regulation of the virulence determinant OspC by bbd18 on linear plasmid lp17 of Borrelia burgdorferi. AB - Persistent infection of a mammalian host by Borrelia burgdorferi, the spirochete that causes Lyme disease, requires specific downregulation of an immunogenic outer surface protein, OspC. Although OspC is an essential virulence factor needed by the spirochete to establish infection in the mammal, it represents a potent target for the host acquired immune response, and constitutive expression of OspC results in spirochete clearance. In this study, we demonstrate that a factor encoded on a linear plasmid of B. burgdorferi, lp17, can negatively regulate ospC transcription from the endogenous gene on the circular plasmid cp26 and from an ospC promoter-lacZ fusion on a shuttle vector. Furthermore, we have identified bbd18 as the gene on lp17 that is responsible for this effect. These data identify a novel component of ospC regulation and provide the basis for determining the molecular mechanisms of ospC repression in vivo. PMID- 21784942 TI - Complete genome and proteome of Acholeplasma laidlawii. AB - We present the complete genome sequence and proteogenomic map for Acholeplasma laidlawii PG-8A (class Mollicutes, order Acholeplasmatales, family Acholeplasmataceae). The genome of A. laidlawii is represented by a single 1,496,992-bp circular chromosome with an average G+C content of 31 mol%. This is the longest genome among the Mollicutes with a known nucleotide sequence. It contains genes of polymerase type I, SOS response, and signal transduction systems, as well as RNA regulatory elements, riboswitches, and T boxes. This demonstrates a significant capability for the regulation of gene expression and mutagenic response to stress. Acholeplasma laidlawii and phytoplasmas are the only Mollicutes known to use the universal genetic code, in which UGA is a stop codon. Within the Mollicutes group, only the sterol-nonrequiring Acholeplasma has the capacity to synthesize saturated fatty acids de novo. Proteomic data were used in the primary annotation of the genome, validating expression of many predicted proteins. We also detected posttranslational modifications of A. laidlawii proteins: phosphorylation and acylation. Seventy-four candidate phosphorylated proteins were found: 16 candidates are proteins unique to A. laidlawii, and 11 of them are surface-anchored or integral membrane proteins, which implies the presence of active signaling pathways. Among 20 acylated proteins, 14 contained palmitic chains, and six contained stearic chains. No residue of linoleic or oleic acid was observed. Acylated proteins were components of mainly sugar and inorganic ion transport systems and were surface-anchored proteins with unknown functions. PMID- 21784943 TI - Quorum sensing contributes to natural transformation of Vibrio cholerae in a species-specific manner. AB - Although it is a human pathogen, Vibrio cholerae is a regular member of aquatic habitats, such as coastal regions and estuaries. Within these environments, V. cholerae often takes advantage of the abundance of zooplankton and their chitinous molts as a nutritious surface on which the bacteria can form biofilms. Chitin also induces the developmental program of natural competence for transformation in several species of the genus Vibrio. In this study, we show that V. cholerae does not distinguish between species-specific and non-species specific DNA at the level of DNA uptake. This is in contrast to what has been shown for other Gram-negative bacteria, such as Neisseria gonorrhoeae and Haemophilus influenzae. However, species specificity with respect to natural transformation still occurs in V. cholerae. This is based on a positive correlation between quorum sensing and natural transformation. Using mutant strain analysis, cross-feeding experiments, and synthetic cholera autoinducer-1 (CAI-1), we provide strong evidence that the species-specific signaling molecule CAI-1 plays a major role in natural competence for transformation. We suggest that CAI-1 can be considered a competence pheromone. PMID- 21784944 TI - TroA of Streptococcus suis is required for manganese acquisition and full virulence. AB - Streptococcus suis causes infections in pigs and occasionally in humans, resulting in manifestations as meningitis, sepsis, arthritis, and septic shock. For survival within the host, S. suis requires numerous nutrients including trace metals. Little is known about the specific proteins involved in metal scavenging in S. suis. In this study we evaluated the role of the putative high-affinity metal binding lipoprotein TroA in metal acquisition and virulence. A mutant strain deficient in the expression of TroA (DeltatroA mutant) was constructed. Growth of the DeltatroA mutant in Todd-Hewitt broth was similar to wild-type growth; however, growth of the DeltatroA mutant in cation-deprived Todd-Hewitt broth and in porcine serum was strongly reduced compared to growth of wild-type bacteria. Supplementing the medium with extra manganese but not with magnesium, zinc, copper, nickel, or iron restored growth to wild-type levels, indicating that TroA is specifically required for growth in environments low in manganese. The DeltatroA mutant also showed increased susceptibility to H2O2, suggesting that TroA is involved in counteracting oxidative stress. Furthermore, the expression of the troA gene was subject to environmental regulation at the transcript level. In a murine S. suis infection model, the DeltatroA mutant displayed a nonvirulent phenotype. These data indicate that S. suis TroA is involved in manganese acquisition and is required for full virulence in mice. PMID- 21784945 TI - Provirus induction in hyperthermophilic archaea: characterization of Aeropyrum pernix spindle-shaped virus 1 and Aeropyrum pernix ovoid virus 1. AB - By in silico analysis, we have identified two putative proviruses in the genome of the hyperthermophilic archaeon Aeropyrum pernix, and under special conditions of A. pernix growth, we were able to induce their replication. Both viruses were isolated and characterized. Negatively stained virions of one virus appeared as pleomorphic spindle-shaped particles, 180 to 210 nm by 40 to 55 nm, with tails of heterogeneous lengths in the range of 0 to 300 nm. This virus was named Aeropyrum pernix spindle-shaped virus 1 (APSV1). Negatively stained virions of the other virus appeared as slightly irregular oval particles with one pointed end, while in cryo-electron micrographs, the virions had a regular oval shape and uniform size (70 by 55 nm). The virus was named Aeropyrum pernix ovoid virus 1 (APOV1). Both viruses have circular, double-stranded DNA genomes of 38,049 bp for APSV1 and 13,769 bp for APOV1. Similarities to proteins of other archaeal viruses were limited to the integrase and Dna1-like protein. We propose to classify APOV1 into the family Guttaviridae. PMID- 21784946 TI - Role of leucine zipper motifs in association of the Escherichia coli cell division proteins FtsL and FtsB. AB - FtsL and FtsB are two inner-membrane proteins that are essential constituents of the cell division apparatus of Escherichia coli. In this study, we demonstrate that the leucine zipper-like (LZ) motifs, located in the periplasmic domain of FtsL and FtsB, are required for an optimal interaction between these two essential proteins. PMID- 21784947 TI - Characterization of the Fur regulon in Pseudomonas syringae pv. tomato DC3000. AB - The plant pathogen Pseudomonas syringae pv. tomato DC3000 (DC3000) is found in a wide variety of environments and must monitor and respond to various environmental signals such as the availability of iron, an essential element for bacterial growth. An important regulator of iron homeostasis is Fur (ferric uptake regulator), and here we present the first study of the Fur regulon in DC3000. Using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 312 chromosomal regions were highly enriched by coimmunoprecipitation with a C-terminally tagged Fur protein. Integration of these data with previous microarray and global transcriptome analyses allowed us to expand the putative DC3000 Fur regulon to include genes both repressed and activated in the presence of bioavailable iron. Using nonradioactive DNase I footprinting, we confirmed Fur binding in 41 regions, including upstream of 11 iron-repressed genes and the iron-activated genes encoding two bacterioferritins (PSPTO_0653 and PSPTO_4160), a ParA protein (PSPTO_0855), and a two-component system (TCS) (PSPTO_3382 to PSPTO_3380). PMID- 21784948 TI - A molecular basis for tungstate selectivity in prokaryotic ABC transport systems. AB - The essential trace compounds tungstate and molybdate are taken up by cells via ABC transporters. Despite their similar ionic radii and chemical properties, the WtpA protein selectively binds tungstate in the presence of molybdate. Using site directed mutagenesis of conserved binding pocket residues, we established a molecular basis for tungstate selectivity. PMID- 21784949 TI - Rice MADS6 interacts with the floral homeotic genes SUPERWOMAN1, MADS3, MADS58, MADS13, and DROOPING LEAF in specifying floral organ identities and meristem fate. AB - AGAMOUS-LIKE6 (AGL6) genes play essential roles in flower development, but whether and how they work with floral organ identity genes remain less understood. Here, we describe interactions of the rice (Oryza sativa) AGL6 gene MADS6 with other rice floral homeotic genes in flower development. Genetic analyses revealed that MADS6 specifies the identity of the three inner whorls and floral meristem determinacy redundantly with SUPERWOMAN1/MADS16 (B-gene) or MADS3 (C-gene). MADS6 was shown to define carpel/ovule development and floral determinacy by interacting with MADS13 (D-gene) and control the palea and floral meristem identities together with the YABBY gene DROOPING LEAF. Expression analyses revealed that the transcript levels of six B-, C-, and E-class genes were reduced in mads6-1 at the early flower developmental stage, suggesting that MADS6 is a key regulator of early flower development. Moreover, MADS6 can directly bind to a putative regulatory motif on MADS58 (C-gene), and mads6-1 mads58 displayed phenotypes similar to that of mads6-1. These results suggest that MADS6 is a key player in specifying flower development via interacting with other floral homeotic genes in rice, thus providing new insights into the mechanism by which flower development is controlled. PMID- 21784950 TI - Perturbation of Arabidopsis amino acid metabolism causes incompatibility with the adapted biotrophic pathogen Hyaloperonospora arabidopsidis. AB - Reliance of biotrophic pathogens on living plant tissues to propagate implies strong interdependence between host metabolism and nutrient uptake by the pathogen. However, factors determining host suitability and establishment of infection are largely unknown. We describe a loss-of-inhibition allele of ASPARTATE KINASE2 and a loss-of-function allele of DIHYDRODIPICOLINATE SYNTHASE2 identified in a screen for Arabidopsis thaliana mutants with increased resistance to the obligate biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa). Through different molecular mechanisms, these mutations perturb amino acid homeostasis leading to overaccumulation of the Asp-derived amino acids Met, Thr, and Ile. Although detrimental for the plant, the mutations do not cause defense activation, and both mutants retain full susceptibility to the adapted obligate biotrophic fungus Golovinomyces orontii (Go). Chemical treatments mimicking the mutants' metabolic state identified Thr as the amino acid suppressing Hpa but not Go colonization. We conclude that perturbations in amino acid homeostasis render the mutant plants unsuitable as an infection substrate for Hpa. This may be explained by deployment of the same amino acid biosynthetic pathways by oomycetes and plants. Our data show that the plant host metabolic state can, in specific ways, influence the ability of adapted biotrophic strains to cause disease. PMID- 21784951 TI - The promise of a cancer-free world: where are we? The presidential address from the 35th annual meeting of the American Society of Preventive Oncology (ASPO). PMID- 21784952 TI - Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case control study. AB - BACKGROUND: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. METHODS: The 25-hydroxy vitamin D [25(OH)D]-prostate cancer relation was examined in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (+/-1 year) and fasting blood collection date (+/-30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. RESULTS: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95-1.74), 1.34 (1.00-1.80), 1.26 (0.93-1.72), and 1.56 (1.15-2.12), with P(trend) = 0.01. Analyses based on prespecified clinical categories and season-adjusted values yielded similar results. These findings seemed stronger for aggressive disease [OR (95% CI) for fifth quintile of serum 25(OH)D [1.70 (1.05-2.76), P(trend) = 0.02], among men with greater physical activity [1.85 (1.26-2.72), P(trend) = 0.002], higher concentrations of serum total cholesterol [2.09 (1.36-3.21), P(trend) = 0.003] or alpha-tocopherol [2.00 (1.30-3.07), P(trend) = 0.01] and higher intakes of total calcium [1.82 (1.20-2.76), P(trend) = 0.01] or vitamin D [1.69 (1.04-2.75), P(trend) = 0.08], or among those who had received the trial alpha-tocopherol supplements [1.74 (1.15-2.64), P(trend) = 0.006]. CONCLUSION: Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer. IMPACT: Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels. PMID- 21784953 TI - Association of census tract-level socioeconomic status with disparities in prostate cancer-specific survival. AB - BACKGROUND: Social determinants of prostate cancer survival and their relation to racial/ethnic disparities thereof are poorly understood. We analyzed whether census tract-level socioeconomic status (SES) at diagnosis is a prognostic factor in men with prostate cancer and helps explain racial/ethnic disparities in survival. METHODS: We used a retrospective cohort of 833 African American and white, non-Hispanic men diagnosed with prostate cancer at four Chicago area medical centers between 1986 and 1990. Tract-level concentrated disadvantage (CD), a multidimensional area-based measure of SES, was calculated for each case, using the 1990 U.S. census data. Its association with prostate cancer-specific survival was measured by using Cox proportional hazard models adjusted for case and tumor characteristics, treatment, and health care system [private sector vs. Veterans Health Administration (VA)]. RESULTS: Tract-level CD associated with an increased risk of death from prostate cancer (highest vs. lowest quartile, HR = 2.37, P < 0.0001). However, the association was observed in the private sector and not in the VA (per 1 SD increase, HR = 1.33, P < 0.0001 and HR = 0.93, P = 0.46, respectively). The multivariate HR for African Americans before and after accounting for tract-level CD was 1.30 (P = 0.0036) and 0.96 (P = 0.82), respectively. CONCLUSIONS: Census tract-level SES is a social determinant of prostate-specific mortality and helps account for racial/ethnic disparities in survival. An equal-access health care system may moderate this association. IMPACT: This study identifies a potential pathway for minimizing disparities in prostate cancer control. The findings need confirmation in a population-based study. PMID- 21784954 TI - Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. AB - BACKGROUND: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. METHODS: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. RESULTS: There was increased CIN and clonal heterogeneity in ER-negative compared with ER positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER positive breast cancer was observed, using three independent measures of CIN. CONCLUSIONS: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup. IMPACT: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. PMID- 21784955 TI - Circulating soluble CD30 and future risk of lymphoma; evidence from two prospective studies in the general population. AB - BACKGROUND: Elevated circulating soluble CD30 (sCD30) has been previously associated with AIDS-related non-Hodgkin lymphoma (NHL) risk. This finding was recently extended to the general population where elevated levels of sCD30 were reported in prediagnostic serum among subjects that developed NHL later in life. METHODS: We carried out a replication study within the Italian European Prospective Investigation into Cancer and Nutrition cohort. Plasma sCD30 concentration was measured by ELISA in prospectively collected blood of 35 B-cell lymphoma cases and 36 matched controls. RESULTS: We observed significantly increased relative risks for lymphoma with increasing sCD30 levels [OR (95% CI) for second and third tertiles vs. first tertile: 5.5 (1.5-20.2), 4.0 (1.1-13.9), respectively]. In addition, spline analyses showed that the dose-response curve of sCD30 and lymphoma risk was monotonic and quite similar to the risks reported in the previous study. CONCLUSION: This replication study adds to the evidence that sCD30 is related to future lymphoma risk in a concentration-dependent manner in the general population. IMPACT: The results of this study strengthen the observation that chronic sustained B-cell activation plays an important role in lymphomagenesis. PMID- 21784956 TI - Cancer disparities: unmet challenges in the elimination of disparities. AB - BACKGROUND: The first 20 years of publication of Cancer Epidemiology, Biomarkers & Prevention occurred during a period of increased attention to health disparities and advances in knowledge about their determinants. Yet, despite clear documentation of disparities and advanced understanding of determinants, we have made little headway in reducing disparities at the population level. Multilevel models, such as one produced by the Centers for Population Health and Health Disparities (CPHHD), hold promise for understanding the complex determinants of cancer disparities and their interactions as well as translating scientific discoveries into solutions. The CPHHD model maps across a range of scientific disciplines, from the biological to the social, each with its own disciplinary language and methods. The ability to work effectively across disciplinary boundaries is essential to framing comprehensive solutions. METHODS: After briefly characterizing the current state of knowledge about health disparities, we outline three major challenges faced by disparities researchers and practitioners and offer suggestions for addressing these challenges. RESULTS: These challenges are how to consider race and ethnicity in disparities research, how best to translate discoveries into public health solutions to cancer disparities, and how to create a research environment that supports the successful execution of multilevel research. CONCLUSIONS: Attention to all three of the challenges outlined above is urgently needed to advance our efforts to eliminate cancer disparities. IMPACT: Addressing the challenges outlined above will help to eliminate disparities in the future. PMID- 21784957 TI - The business of research: budgets, personnel, planning, and pitfalls--a report from the American Society of Preventive Oncology's Junior Members Interest Group. PMID- 21784959 TI - High visfatin expression in breast cancer tissue is associated with poor survival. AB - BACKGROUND: Adipocytokines, adipocyte-secreted hormones, play a critical role in breast cancer development. The expression of visfatin, a newly discovered adipocytokine, in breast cancer tissues was determined and correlated with patient clinicopathologic variables. METHODS: Visfatin expression in breast cancer tissues was analyzed by immunohistochemistry. Visfatin expression was correlated with clinicopathologic variables as well as recurrence rates, using the chi(2) test. The prognostic value of visfatin for disease-free and overall survival was evaluated by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. RESULTS: High visfatin expression in breast cancer tissues was significantly correlated with tumor size, estrogen receptor (ER) negativity, and progesterone receptor (PR) negativity. Hormone therapy, but not radiotherapy or chemotherapy, decreased the recurrence rate in patients with high visfatin expression. Whereas high visfatin expression alone was associated with poor disease-free and overall survival, worse disease-free and overall survival was observed when high visfatin expression was combined with ER- and PR-negative status. Cox regression analysis also revealed that visfatin is an independent predictor of disease-free and overall survival. CONCLUSION: High visfatin expression in breast cancer tissue is associated with more malignant cancer behavior as well as poor patient survival. IMPACT: Visfatin is an independent prognosis predictor for breast cancer. PMID- 21784958 TI - Mitochondrial DNA copy number and risk of gastric cancer: a report from the Shanghai Women's Health Study. AB - BACKGROUND: Mitochondrial DNA (mtDNA) is an approximately 16,000-bp circular double-stranded DNA molecule that is a prime target of oxidative damage. Several somatic mutations in mtDNA have been observed in gastric tumors, suggesting an involvement in gastric cancer risk and progression. mtDNA copy number in leukocyte DNA has also been linked to several other cancers, although the temporal relationship between mtDNA and cancer has not been adequately explored. METHODS: Using a nested case-control study design, we examined the association between mtDNA copy number in 162 gastric cancer cases and 299 matched controls within the Shanghai Women's Health Study, a large population-based prospective cohort. Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay in peripheral leukocytes. RESULTS: mtDNA copy number levels were comparable among cases and controls, with a median of 1.04 [interquartile range (IQR), 0.87-1.25] and 1.06 (IQR, 0.88-1.29), respectively. Overall, mtDNA was not associated with gastric cancer risk. However, the association differed when stratified by the time between sample collection and cancer diagnosis. An association between low levels of mtDNA copy number (5 %) were C(18:1)omega7c (63.5 %), summed feature 2 (C(14:0) 3-OH and/or iso-C(16:1) I, 10.8 %) and C(16:0) (9.9 %). The major polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and an unknown aminolipid. The genomic DNA G+C content was 69.6 mol% and Q-10 was the major respiratory quinone. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain SB22(T) was most closely related to Skermanella aerolata 5416T-32(T) (97.3 %), Skermanella parooensis ACM 2042(T) (95.8 %) and Skermanella xinjiangensis 10-1 101(T) (92.9 %). The DNA-DNA hybridization value between strain SB22(T) and S. aerolata KACC 11604(T) ( = 5416T-32(T)) was 43.3 %. On the basis of phenotypic, chemotaxonomic and phylogenetic characteristics of strain SB22(T) and related species, it is considered that the isolate represents a novel species of the genus Skermanella, for which the name Skermanella stibiiresistens sp. nov. is proposed. The type strain is SB22(T) ( = CGMCC 1.10751(T) = KCTC 23364(T)). An emended description of the genus Skermanella is provided. PMID- 21784961 TI - Cryobacterium flavum sp. nov. and Cryobacterium luteum sp. nov., isolated from glacier ice. AB - Gram-positive, rod-shaped bacteria, strains Hh8(T), Hh15(T) and Hh40-2, were isolated from the No. 1 glacier in Xinjiang, north-west China. Colonies of strain Hh8(T) were orange-yellow, convex and round on PYG plates. Strain Hh8(T) grew at 0-19 degrees C and pH 5.5-10.5. Colonies of strain Hh15(T), which was able to grow at 0-20 degrees C and pH 5.5-12, were lemon yellow, convex and round on PYG plates. Phylogenetic analysis based on 16S rRNA gene sequences showed that these three strains were related to members of the genus Cryobacterium. The major cellular fatty acids of the novel strains were anteiso-C(15:0), iso-C(16:0), iso C(15:0) and anteiso-C(15:1) A. On the basis of phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness data, two novel species, Cryobacterium flavum sp. nov. (type strain Hh8(T) = CGMCC 1.11215(T) = NBRC 107879(T)) and Cryobacterium luteum sp. nov. (type strain Hh15(T) = CGMCC 1.11210(T) = NBRC 107880(T)), are proposed. PMID- 21784962 TI - Mycobacterium koreense sp. nov., a slowly growing non-chromogenic species closely related to Mycobacterium triviale. AB - A novel slow-growing, non-chromogenic mycobacterium (strain 01-305(T)) was isolated from a patient with pulmonary dysfunction. Growth characteristics, acid fastness and the results of 16S rRNA gene sequencing supported the placement of this strain within the genus Mycobacterium. Phenotypically, strain 01-305(T) was generally similar to Mycobacterium triviale ATCC 23292(T), but some unique biochemical characteristics were observed. The 16S rRNA gene sequence of strain 01-305(T) was similar to those of M. triviale ATCC 23290 (GenBank accession no. AY734996, 99.9 % similarity) and M. triviale ATCC 23291 (AY734995, 99.9 %); however, it differed substantially from that of M. triviale ATCC 23292(T) (X88924, 98.2 %). Phylogenetic analysis based on 16S rRNA gene sequences placed strain 01-305(T) in the slow-growing Mycobacterium group close to M. triviale ATCC 23290 and M. triviale ATCC 23291, but not M. triviale ATCC 23292(T). Unique mycolic acid profiles and phylogenetic analysis based on two different chronometer molecules, and the hsp65 and rpoB genes, strongly supported the taxonomic status of this strain as representing a distinct species. These data support the conclusion that strain 01-305(T) represents a novel mycobacterial species, for which the name Mycobacterium koreense sp. nov. is proposed. The type strain is 01-305(T) ( = DSM 45576(T) = KCTC 19819(T)). PMID- 21784963 TI - Paenibacillus sediminis sp. nov., a xylanolytic bacterium isolated from a tidal flat. AB - A Gram-positive, rod-shaped, xylanolytic, spore-forming bacterium, strain GTH 3(T), was isolated from a tidal flat adjacent to Ganghwa Island, Republic of Korea, and was characterized to determine its taxonomic position. On the basis of 16S rRNA gene sequence similarity, strain GTH-3(T) was shown to belong to the family Paenibacillaceae, being most closely related to the type strains of Paenibacillus ginsengisoli (94.9 %), Paenibacillus anaericanus (94.8 %), Paenibacillus urinalis (94.4 %), Paenibacillus cookii (94.2 %), Paenibacillus alvei (94.1 %) and Paenibacillus chibensis (94.0 %). The G+C content of the genomic DNA of strain GTH-3(T) was 45.9+/-0.2 mol% (mean+/-sd). The major menaquinone was MK-7. The major fatty acids were anteiso-C(15:0) and iso-C(16:0). The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Phenotypic and chemotaxonomic data supported the affiliation of strain GTH-3(T) to the genus Paenibacillus. The results of physiological and biochemical tests allowed strain GTH-3(T) to be distinguished genotypically and phenotypically from recognized species of the genus Paenibacillus. Strain GTH-3(T) is therefore considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus sediminis sp. nov. is proposed. The type strain is GTH-3(T) ( = DSM 23491(T) = LMG 25635(T)). PMID- 21784965 TI - A peroxygenase pathway involved in the biosynthesis of epoxy fatty acids in oat. AB - While oat (Avena sativa) has long been known to produce epoxy fatty acids in seeds, synthesized by a peroxygenase pathway, the gene encoding the peroxygenase remains to be determined. Here we report identification of a peroxygenase cDNA AsPXG1 from developing seeds of oat. AsPXG1 is a small protein with 249 amino acids in length and contains conserved heme-binding residues and a calcium binding motif. When expressed in Pichia pastoris and Escherichia coli, AsPXG1 catalyzes the strictly hydroperoxide-dependent epoxidation of unsaturated fatty acids. It prefers hydroperoxy-trienoic acids over hydroperoxy-dienoic acids as oxygen donors to oxidize a wide range of unsaturated fatty acids with cis double bonds. Oleic acid is the most preferred substrate. The acyl carrier substrate specificity assay showed phospholipid and acyl-CoA were not effective substrate forms for AsPXG1 and it could only use free fatty acid or fatty acid methyl esters as substrates. A second gene, AsLOX2, cloned from oat codes for a 9 lipoxygenase catalyzing the synthesis of 9-hydroperoxy-dienoic and 9-hydroperoxy trienoic acids, respectively, when linoleic (18:2-9c,12c) and linolenic (18:3 9c,12c,15c) acids were used as substrates. The peroxygenase pathway was reconstituted in vitro using a mixture of AsPXG1 and AsLOX2 extracts from E. coli. Incubation of methyl oleate and linoleic acid or linolenic acid with the enzyme mixture produced methyl 9,10-epoxy stearate. Incubation of linoleic acid alone with a mixture of AsPXG1 and AsLOX2 produced two major epoxy fatty acids, 9,10-epoxy-12-cis-octadecenoic acid and 12,13-epoxy-9-cis-octadecenoic acid, and a minor epoxy fatty acid, probably 12,13-epoxy-9-hydroxy-10-transoctadecenoic acid. AsPXG1 predominately catalyzes intermolecular peroxygenation. PMID- 21784966 TI - S-nitrosoglutathione supplementation to ovalbumin-sensitized and -challenged mice ameliorates methacholine-induced bronchoconstriction. AB - S-nitrosoglutathione (GSNO) is an endogenous bronchodilator present in micromolar concentrations in airway lining fluid. Airway GSNO levels decrease in severe respiratory failure and asthma, which is attributable to increased metabolism by GSNO reductase (GSNOR). Indeed, we have found that GSNOR expression and activity correlate inversely with lung S-nitrosothiol (SNO) content and airway hyperresponsiveness (AHR) to methacholine (MCh) challenge in humans with asthmatic phenotypes (Que LG, Yang Z, Stamler JS, Lugogo NL, Kraft M. Am J Respir Crit Care Med 180: 226-231, 2009). Accordingly, we hypothesized that local aerosol delivery of GSNO could ameliorate AHR and inflammation in the ovalbumin sensitized and -challenged (OVA) mouse model of allergic asthma. Anesthetized, paralyzed, and tracheotomized 6-wk-old male control and OVA C57BL/6 mice were administered a single 15-s treatment of 0-100 mM GSNO. Five minutes later, airway resistance to MCh was measured and SNOs were quantified in bronchoalveolar lavage (BAL). Duration of protection was evaluated following nose-only exposure to 10 mM GSNO for 10 min followed by measurements of airway resistance, inflammatory cells, and cytokines and chemokines at up to 4 h later. Acute delivery of GSNO aerosol protected OVA mice from MCh-induced AHR, with no benefit seen above 20 mM GSNO. The antibronchoconstrictive effects of GSNO aerosol delivered via nose cone were sustained for at least 4 h. However, administration of GSNO did not alter total BAL cell counts or cell differentials and had modest effects on cytokine and chemokine levels. In conclusion, in the OVA mouse model of allergic asthma, aerosolized GSNO has rapid and sustained antibronchoconstrictive effects but does not substantially alter airway inflammation. PMID- 21784967 TI - Evidence for early fibrosis and increased airway resistance in bone marrow transplant recipient mice deficient in MMP12. AB - Idiopathic pneumonia syndrome (IPS) is a significant cause of morbidity and mortality post-bone marrow transplantation (BMT) in humans. In our established murine IPS model in which lethally conditioned recipients are given allogeneic bone marrow and splenocytes, recruitment of host monocytes occurs early post-BMT, followed by donor T cells concomitant with development of severe lung dysfunction. Because matrix metalloproteinase 12 (MMP12) is important for macrophage infiltration and injury in other mouse models of lung disease such as emphysema, lethally conditioned MMP12(-/-) mice were used as allogeneic recipients to determine whether MMP12 plays a similar role in potentiating lung injury in IPS. Surprisingly, MMP12(-/-) mice developed IPS and exhibited an accelerated allogeneic T cell-dependent decrease in compliance compared with wild type (WT) recipients. MMP12(-/-), but not WT, mice also had allogeneic T cell dependent elevated lung resistance post-BMT. Recruitment of monocytes and T cells into the lungs was not altered on day 7 post-BMT, but the lungs of MMP12(-/-) recipients had increased collagen deposition, a feature normally not seen in our IPS model. MMP12(-/-) mice had a compensatory increase in MMP2 in the lungs post BMT, as well as increased beta6-integrin compared with WT recipients, and only in the presence of allogeneic T cells. Levels of total transforming growth factor (TGF)-beta1 protein in the lungs were elevated compared with WT recipients, consistent with the profibrotic function of beta6-integrin as an activator of TGF beta. These data indicate that host-derived MMP12 may be important in limiting development of IPS by allowing proper remodeling of extracellular matrix and effective repair of BMT-related injury. PMID- 21784968 TI - Surfactant protein A is defective in abrogating inflammation in asthma. AB - Surfactant protein A (SP-A) regulates a variety of immune cell functions. We determined the ability of SP-A derived from normal and asthmatic subjects to modulate the inflammatory response elicited by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. Fourteen asthmatic and 10 normal control subjects underwent bronchoscopy with airway brushing and bronchoalveolar lavage (BAL). Total SP-A was extracted from BAL. The ratio of SP-A1 to total SP-A (SP-A1/SP-A) and the binding of total SP-A to M. pneumoniae membranes were determined. Airway epithelial cells from subjects were exposed to either normal or asthmatic SP-A before exposure to M. pneumoniae. IL-8 protein and MUC5AC mRNA were measured. Total BAL SP-A concentration did not differ between groups, but the percentage SP A1 was significantly increased in BAL of asthmatic compared with normal subjects. SP-A1/SP-A significantly correlated with maximum binding of total SP-A to M. pneumoniae, but only in asthma. SP-A derived from asthmatic subjects did not significantly attenuate IL-8 and MUC5AC in the setting of M. pneumoniae infection compared with SP-A derived from normal subjects. We conclude that SP-A derived from asthmatic subjects does not abrogate inflammation effectively, and this dysfunction may be modulated by SP-A1/SP-A. PMID- 21784969 TI - NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues. AB - Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IkappaBalpha degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-alpha-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-alpha was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity. PMID- 21784970 TI - Thyroid transcription factor-1 (TTF-1) gene: identification of ZBP-89, Sp1, and TTF-1 sites in the promoter and regulation by TNF-alpha in lung epithelial cells. AB - Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) is a homeodomain-containing transcription factor essential for the morphogenesis and differentiation of the lung. In the lung, TTF-1 controls the expression of surfactant proteins that are essential for lung stability and lung host defense. In this study, we identified functionally important transcription factor binding sites in the TTF-1 proximal promoter and studied tumor necrosis factor-alpha (TNF-alpha) regulation of TTF-1 expression. TNF-alpha, a proinflammatory cytokine, has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) and inhibits surfactant protein levels. Deletion analysis of TTF-1 5'-flanking DNA indicated that the TTF-1 proximal promoter retained high-level activity. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and mutational analysis experiments identified functional ZBP-89, Sp1, Sp3, and TTF-1 sites in the TTF-1 proximal promoter. TNF-alpha inhibited TTF-1 protein levels in H441 and primary alveolar type II cells. TNF-alpha inhibited TTF-1 gene transcription and promoter activity, indicating that transcriptional mechanisms play important roles in the inhibition of TTF-1 levels. TNF-alpha inhibited TTF-1 but not Sp1 or hepatocyte nuclear factor-3 DNA binding to TTF-1 promoter. Transactivation experiments in A549 cells indicated that TNF-alpha inhibited TTF-1 promoter activation by exogenous Sp1 and TTF-1 without altering their levels, suggesting inhibition of transcriptional activities of these proteins. TNF-alpha inhibition of TTF-1 expression was associated with increased threonine, but not serine, phosphorylation of Sp1. Because TTF-1 serves as a positive regulator for surfactant protein gene expression, TNF-alpha inhibition of TTF-1 expression could have important implications for the reduction of surfactant protein levels in diseases such as ARDS. PMID- 21784972 TI - Long-distance regulation of fetal V(delta) gene segment TRDV4 by the Tcrd enhancer. AB - Murine Tcra and Tcrd gene segments are organized into a single genetic locus (Tcra/Tcrd locus) that undergoes V(D)J recombination in CD4(-)CD8(-) double negative (DN) thymocytes to assemble Tcrd genes and in CD4(+)CD8(+) double positive thymocytes to assemble Tcra genes. Recombination events are regulated by two developmental stage-specific enhancers, E(delta) and E(alpha). Effects of E(alpha) on Trca/Tcrd locus chromatin have been well documented, but effects of E(delta) have not. In this regard, E(alpha) acts over long distances to activate many V(alpha) and J(alpha) segments for recombination in double-positive thymocytes. However, in DN thymocytes, it is unclear whether E(delta) functions over long distances to regulate V(delta) gene segments or functions only locally to regulate D(delta) and J(delta) gene segments. In this study, we analyzed germline transcription, histone modifications, and recombination on wild-type and E(delta)-deficient alleles in adult and fetal thymocytes. We found that E(delta) functions as a local enhancer whose influence is limited to no more than ~10 kb in either direction (including D(delta), J(delta), and TRDV5 gene segments) in adult DN thymocytes. However, we identified a unique long-distance role for E(delta) promoting accessibility and recombination of fetal V(delta) gene segment TRDV4, over a distance of 55 kb, in fetal thymocytes. TRDV4 recombination is specifically repressed in adult thymocytes. We found that this repression is enforced by a developmentally regulated loss of histone acetylation. Constitutively high levels of a suppressive modification, histone H3 lysine 9 dimethylation, may contribute to repression as well. PMID- 21784971 TI - Reduced functional integration and segregation of distributed neural systems underlying social and emotional information processing in autism spectrum disorders. AB - A growing body of evidence suggests that autism spectrum disorders (ASDs) are related to altered communication between brain regions. Here, we present findings showing that ASD is characterized by a pattern of reduced functional integration as well as reduced segregation of large-scale brain networks. Twenty-three children with ASD and 25 typically developing matched controls underwent functional magnetic resonance imaging while passively viewing emotional face expressions. We examined whole-brain functional connectivity of two brain structures previously implicated in emotional face processing in autism: the amygdala bilaterally and the right pars opercularis of the inferior frontal gyrus (rIFGpo). In the ASD group, we observed reduced functional integration (i.e., less long-range connectivity) between amygdala and secondary visual areas, as well as reduced segregation between amygdala and dorsolateral prefrontal cortex. For the rIFGpo seed, we observed reduced functional integration with parietal cortex and increased integration with right frontal cortex as well as right nucleus accumbens. Finally, we observed reduced segregation between rIFGpo and the ventromedial prefrontal cortex. We propose that a systems-level approach whereby the integration and segregation of large-scale brain networks in ASD is examined in relation to typical development-may provide a more detailed characterization of the neural basis of ASD. PMID- 21784973 TI - Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. AB - We previously reported that extracellular histones are major mediators of death in sepsis. Infusion of extracellular histones leads to increased cytokine levels. Histones activate TLR2 and TLR4 in a process that is enhanced by binding to DNA. Activation of TLR4 is responsible for the histone-dependent increase in cytokine levels. To study the impact of histone release on pathology we used two models: a Con A-triggered activation of T cells to mimic sterile inflammation, and acetaminophen to model drug-induced tissue toxicity. Histones were released in both models and anti-histone Abs were protective. TLR2- or TLR4-null mice were also protected. These studies imply that histone release contributes to death in inflammatory injury and in chemical-induced cellular injury, both of which are mediated in part through the TLRs. PMID- 21784974 TI - Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. AB - The chorioamnionitis associated with preterm delivery is often polymicrobial with ureaplasma being the most common isolate. To evaluate interactions between the different proinflammatory mediators, we hypothesized that ureaplasma exposure would increase fetal responsiveness to LPS. Fetal sheep were given intra-amniotic (IA) injections of media (control) or Ureaplasma parvum serovar 3 either 7 or 70 d before preterm delivery. Another group received an IA injection of Escherichia coli LPS 2 d prior to delivery. To test for interactions, IA U. parvum-exposed animals were challenged with IA LPS and delivered 2 d later. All animals were delivered at 124 +/- 1-d gestation (term = 150 d). Compared with the 2-d LPS exposure group, the U. parvum 70 d + LPS group had 1) decreased lung pro- and anti-inflammatory cytokine expression and 2) fewer CD3(+) T lymphocytes, CCL2(+), myeloperoxidase(+), and PU.1(+) cells in the lung. Interestingly, exposure to U. parvum for 7 d did not change responses to a subsequent IA LPS challenge, and exposure to IA U. parvum alone induced mild lung inflammation. Exposure to U. parvum increased pulmonary TGF-beta1 expression but did not change mRNA expression of either the receptor TLR4 or some of the downstream mediators in the lung. Monocytes from fetal blood and lung isolated from U. parvum 70 d + LPS but not U. parvum 7 d + LPS animals had decreased in vitro responsiveness to LPS. These results are consistent with the novel finding of downregulation of LPS responses by chronic but not acute fetal exposures to U. parvum. The findings increase our understanding of how chorioamnionitis-exposed preterm infants may respond to lung injury and postnatal nosocomial infections. PMID- 21784976 TI - Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL 1beta production in human macrophages. AB - Mycobacterium tuberculosis is a virulent intracellular pathogen that survives in macrophages even in the presence of an intact adaptive immune response. Type I IFNs have been shown to exacerbate tuberculosis in mice and to be associated with disease progression in infected humans. Nevertheless, the mechanisms by which type I IFNs regulate the host response to M. tuberculosis infection are poorly understood. In this study, we show that M. tuberculosis induces an IFN-related gene expression signature in infected primary human macrophages, which is dependent on host type I IFN signaling as well as the mycobacterial virulence factor, region of difference-1. We further demonstrate that type I IFNs selectively limit the production of IL-1beta, a critical mediator of immunity to M. tuberculosis. This regulation occurs at the level of IL1B mRNA expression, rather than caspase-1 activation or autocrine IL-1 amplification and appears to be preferentially used by virulent mycobacteria since avirulent M. bovis bacillus Calmette-Guerin (BCG) fails to trigger significant expression of type I IFNs or release of mature IL-1beta protein. The latter property is associated with decreased caspase-1-dependent IL-1beta maturation in the BCG-infected macrophages. Interestingly, human monocytes in contrast to macrophages produce comparable levels of IL-1beta in response to either M. tuberculosis or BCG. Taken together, these findings demonstrate that virulent and avirulent mycobacteria employ distinct pathways for regulating IL-1beta production in human macrophages and reveal that in the case of M. tuberculosis infection the induction of type I IFNs is a major mechanism used for this purpose. PMID- 21784975 TI - Cytokine-induced alterations of alpha7 nicotinic receptor in colonic CD4 T cells mediate dichotomous response to nicotine in murine models of Th1/Th17- versus Th2 mediated colitis. AB - Ulcerative colitis (UC) and Crohn's disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and trinitrobenzene sulfonic acid (TNBS)-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with an increased percentage of colonic regulatory T cells and a reduction of Th17 cells. TCR stimulation of naive CD4(+)CD62L(+) T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL 17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of regulatory T cells. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory alpha7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4) and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and they underscore the potential for nicotinergic drugs in regulating colonic inflammation. PMID- 21784977 TI - Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation. AB - Zinc finger protein tristetraprolin (TTP) modulates macrophage inflammatory activity by destabilizing cytokine mRNAs. In this study, through a screen of TTP bound mRNAs in activated human macrophages, we have identified CCL3 mRNA as the most abundantly bound TTP target mRNA and have characterized this interaction via conserved AU-rich elements. Compared to the wild-type cells, TTP(-/-) macrophages produced higher levels of LPS-induced CCL3. In addition, the plasma level of CCL3 in TTP(-/-) mice was markedly higher than that in wild-type mice. To determine the in vivo significance of TTP-regulated CCL3, we generated CCL3(-/-)TTP(-/-) double-knockout mice. Along with decreased proinflammatory cytokines in their paw joints, there were significant functional and histologic improvements in the inflammatory arthritis of TTP(-/-) mice when CCL3 was absent, although cachexia, reflecting systemic inflammation, was notably unaffected. Furthermore, the marked exacerbation of aortic plaque formation caused by TTP deficiency in the APOE(-/-) mouse model of atherosclerosis was also rescued by disrupting CCL3. Taken together, our data indicate that the interaction between TTP and CCL3 mRNA plays an important role in modulating localized inflammatory processes in tissues that are dissociated from the systemic manifestations of chronic inflammation. PMID- 21784978 TI - Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. AB - Mutations in presenilins (PS) account for most early-onset familial Alzheimer's disease (FAD). Accumulating evidence suggests that disrupted Ca(2+) signaling may play a proximal role in FAD specifically, and Alzheimer's disease (AD) more generally, but its links to the pathogenesis of AD are obscure. Here we demonstrate that expression of FAD mutant PS constitutively activates the transcription factor cAMP response element binding protein (CREB) and CREB target gene expression in cultured neuronal cells and AD mouse models. Constitutive CREB activation was associated with and dependent on constitutive activation of Ca(2+)/CaM kinase kinase beta and CaM kinase IV (CaMKIV). Depletion of endoplasmic reticulum Ca(2+) stores or plasma membrane phosphatidylinositol bisphosphate and pharmacologic inhibition or knockdown of the expression of the inositol trisphosphate receptor (InsP(3)R) Ca(2+) release channel each abolished FAD PS-associated constitutive CaMKIV and CREB phosphorylation. CREB and CaMKIV phosphorylation and CREB target gene expression, including nitric oxide synthase and c-fos, were enhanced in brains of M146V-KI and 3xTg-AD mice expressing FAD mutant PS1 knocked into the mouse locus. FAD mutant PS-expressing cells demonstrated enhanced cell death and sensitivity to Abeta toxicity, which were normalized by interfering with the InsP(3)R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated InsP(3)R Ca(2+) signaling in FAD PS-expressing cells may represent a signaling pathway involved in the pathogenesis of AD. PMID- 21784979 TI - VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. AB - Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF(flox/flox) alleles were combined to create TetON-HIF-1:VEGF(Delta) mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF 1 induction failed to produce neovascularization in TetON-HIF-1:VEGF(Delta) mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF(Delta) mice. Impaired TetON-HIF-1:VEGF(Delta) neovascularization could be partially rescued by 12-O tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF. PMID- 21784980 TI - Regulation of cyclic and linear electron flow in higher plants. AB - Cyclic electron flow is increasingly recognized as being essential in plant growth, generating a pH gradient across thylakoid membrane (DeltapH) that contributes to ATP synthesis and triggers the protective process of nonphotochemical quenching (NPQ) under stress conditions. Here, we report experiments demonstrating the importance of that DeltapH in protecting plants from stress and relating to the regulation of cyclic relative to linear flow. In leaves infiltrated with low concentrations of nigericin, which dissipates the DeltapH without significantly affecting the potential gradient, thereby maintaining ATP synthesis, the extent of NPQ was markedly lower, reflecting the lower DeltapH. At the same time, the photosystem (PS) I primary donor P700 was largely reduced in the light, in contrast to control conditions where increasing light progressively oxidized P700, due to down-regulation of the cytochrome bf complex. Illumination of nigericin-infiltrated leaves resulted in photoinhibition of PSII but also, more markedly, of PSI. Plants lacking ferredoxin (Fd) NADP oxidoreductase (FNR) or the polypeptide proton gradient regulation 5 (PGR5) also show reduction of P700 in the light and increased sensitivity to PSI photoinhibition, demonstrating that the regulation of the cytochrome bf complex (cyt bf) is essential for protection of PSI from light stress. The formation of a DeltapH is concluded to be essential to that regulation, with cyclic electron flow playing a vital, previously poorly appreciated role in this protective process. Examination of cyclic electron flow in plants with a reduced content of FNR shows that these antisense plants are less able to maintain a steady rate of this pathway. This reduction is suggested to reflect a change in the distribution of FNR from cyclic to linear flow, likely reflecting the formation or disassembly of FNR-cytochrome bf complex. PMID- 21784981 TI - Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery. AB - Analogous to an assembly line, we employed a modular design for the high throughput study of 1,536 structurally distinct nanoparticles with cationic cores and variable shells. This enabled elucidation of complexation, internalization, and delivery trends that could only be learned through evaluation of a large library. Using robotic automation, epoxide-functionalized block polymers were combinatorially cross-linked with a diverse library of amines, followed by measurement of molecular weight, diameter, RNA complexation, cellular internalization, and in vitro siRNA and pDNA delivery. Analysis revealed structure-function relationships and beneficial design guidelines, including a higher reactive block weight fraction, stoichiometric equivalence between epoxides and amines, and thin hydrophilic shells. Cross-linkers optimally possessed tertiary dimethylamine or piperazine groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications. PMID- 21784982 TI - Self-recognition mechanism of MamA, a magnetosome-associated TPR-containing protein, promotes complex assembly. AB - The magnetosome, a biomineralizing organelle within magnetotactic bacteria, allows their navigation along geomagnetic fields. Magnetosomes are membrane-bound compartments containing magnetic nanoparticles and organized into a chain within the cell, the assembly and biomineralization of magnetosomes are controlled by magnetosome-associated proteins. Here, we describe the crystal structures of the magnetosome-associated protein, MamA, from Magnetospirillum magneticum AMB-1 and Magnetospirillum gryphiswaldense MSR-1. MamA folds as a sequential tetra-trico peptide repeat (TPR) protein with a unique hook-like shape. Analysis of the MamA structures indicates two distinct domains that can undergo conformational changes. Furthermore, structural analysis of seven crystal forms verified that the core of MamA is not affected by crystallization conditions and identified three protein-protein interaction sites, namely a concave site, a convex site, and a putative TPR repeat. Additionally, relying on transmission electron microscopy and size exclusion chromatography, we show that highly stable complexes form upon MamA homooligomerization. Disruption of the MamA putative TPR motif or N-terminal domain led to protein mislocalization in vivo and prevented MamA oligomerization in vitro. We, therefore, propose that MamA self-assembles through its putative TPR motif and its concave site to create a large homooligomeric scaffold which can interact with other magnetosome-associated proteins via the MamA convex site. We discuss the structural basis for TPR homooligomerization that allows the proper function of a prokaryotic organelle. PMID- 21784983 TI - Tapping natural reservoirs of homing endonucleases for targeted gene modification. AB - Homing endonucleases mobilize their own genes by generating double-strand breaks at individual target sites within potential host DNA. Because of their high specificity, these proteins are used for "genome editing" in higher eukaryotes. However, alteration of homing endonuclease specificity is quite challenging. Here we describe the identification and phylogenetic analysis of over 200 naturally occurring LAGLIDADG homing endonucleases (LHEs). Biochemical and structural characterization of endonucleases from one clade within the phylogenetic tree demonstrates strong conservation of protein structure contrasted against highly diverged DNA target sites and indicates that a significant fraction of these proteins are sufficiently stable and active to serve as engineering scaffolds. This information was exploited to create a targeting enzyme to disrupt the endogenous monoamine oxidase B gene in human cells. The ubiquitous presence and diversity of LHEs described in this study may facilitate the creation of many tailored nucleases for genome editing. PMID- 21784984 TI - Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins. AB - ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [N(G)-monomethyl-L-arginine (L-NMMA)] and cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P = 0.22-0.99). In protocol 2 (n = 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 +/- 24%; high = 706 +/- 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (DeltaFVC = -31 +/- 11%)- and high-dose ATP (DeltaFVC -25 +/- 11%; P = 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans. PMID- 21784985 TI - Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice. AB - Physiological functions of arterial smooth muscle cell ATP-sensitive K(+) (K(ATP)) channels, which are composed of inwardly rectifying K(+) channel 6.1 and sulfonylurea receptor (SUR)-2 subunits, during metabolic inhibition are unresolved. In the present study, we used a genetic model to investigate the physiological functions of SUR2-containing K(ATP) channels in mediating vasodilation to hypoxia, oxygen and glucose deprivation (OGD) or metabolic inhibition, and functional recovery following these insults. Data indicate that SUR2B is the only SUR isoform expressed in murine cerebral artery smooth muscle cells. Pressurized SUR2 wild-type (SUR2(wt)) and SUR2 null (SUR2(nl)) mouse cerebral arteries developed similar levels of myogenic tone and dilated similarly to hypoxia (<10 mmHg Po(2)). In contrast, vasodilation induced by pinacidil, a K(ATP) channel opener, was ~71% smaller in SUR2(nl) arteries. Human cerebral arteries also expressed SUR2B, developed myogenic tone, and dilated in response to hypoxia and pinacidil. OGD, oligomycin B (a mitochondrial ATP synthase blocker), and CCCP (a mitochondrial uncoupler) all induced vasodilations that were ~39-61% smaller in SUR2(nl) than in SUR2(wt) arteries. The restoration of oxygen and glucose following OGD or removal of oligomycin B and CCCP resulted in partial recovery of tone in both SUR2(wt) and SUR2(nl) cerebral arteries. However, SUR(nl) arteries regained ~60-82% more tone than did SUR2(wt) arteries. These data indicate that SUR2-containing K(ATP) channels are functional molecular targets for OGD, but not hypoxic, vasodilation in cerebral arteries. In addition, OGD activation of SUR2-containing K(ATP) channels may contribute to postischemic loss of myogenic tone. PMID- 21784986 TI - Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts. AB - Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (r = 0.51), relative to DYSS, were positively correlated (P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing (P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure. PMID- 21784988 TI - The impact of baseline artery diameter on flow-mediated vasodilation: a comparison of brachial and radial artery responses to matched levels of shear stress. AB - An inverse relationship between baseline artery diameter (BAD) and flow-mediated vasodilation (FMD) has been identified using reactive hyperemia (RH) to create a shear stress (SS) stimulus in human conduit arteries. However, RH creates a SS stimulus that is inversely related to BAD. The purpose of this study was to compare FMD in response to matched levels of SS in two differently sized upper limb arteries [brachial (BA) and radial (RA) artery]. With the use of exercise, three distinct, shear rate (SR) stimuli were created (SR = blood velocity/vessel diameter; estimate of SS) in the RA and BA. Artery diameter and mean blood velocity were assessed with echo and Doppler ultrasound in 15 healthy male subjects (19-25 yr). Data are means +/- SE. Subjects performed 6 min of adductor pollicis and handgrip exercise to increase SR in the RA and BA, respectively. Exercise intensity was modulated to achieve uniformity in SR between arteries. The three distinct SR levels were as follows: steady-state exercise 39.8 +/- 0.6, 57.3 +/- 0.7, and 72.4 +/- 1.2 s(-1) (P < 0.001). %FMD and AbsFMD (mm) at the end of exercise were greater in the RA vs. the BA at each shear level [at the highest level: RA = 15.7 +/- 1.5%, BA = 5.4 +/- 0.8% (P < 0.001)]. The mean slope of the within-subject SR-%FMD regression line was greater in the RA (RA = 0.33 +/- 0.04, BA = 0.13 +/- 0.02, P < 0.001), and a strong within-subjects relationship between %FMD and SR was observed in both arteries (RA: r(2) = 0.92 +/- 0.02; BA: r(2) = 0.90 +/- 0.03). Within the RA, there was a significant relationship between baseline diameter and %FMD; however, this relationship was not present in the BA (RA: r(2) = 0.76, P < 0.001; BA: r(2) = 0.03, P = 0.541). These findings suggest that the response to SS is not uniform across differently sized vessels, which is in agreement with previous studies. PMID- 21784987 TI - Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin related peptides. AB - Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man. PMID- 21784989 TI - Reactivity of the aorta and mesenteric resistance arteries from the obese spontaneously hypertensive rat: effects of glitazones. AB - The obese spontaneously hypertensive rat (SHROB) is a model of metabolic syndrome in which, to our knowledge, vascular function has never been studied. The actions of insulin sensitizers (glitazones) on vascular function have not been analyzed either. Our purpose was to characterize microvascular and macrovascular responses of the SHROB and to study the effects of glitazones on these responses. The reactivity of mesenteric resistance arteries (MRAs) and the aorta from SHROBs and control rats to cumulative concentrations of phenylephrine, ACh, and sodium nitroprusside (SNP) was myographically analyzed. Some animals were orally treated with rosiglitazone (3 mg.kg(-1).day(-1), 3 wk), and myography was performed. Phenylephrine, ACh, and SNP dose-response curves were impaired to different extents in arteries of SHROBs. Incubation with N-nitro-L-arginine methyl ester caused little effects on phenylephrine and ACh curves in MRAs but enhanced phenylephrine contractions and abolished ACh-induced relaxations of aortae. Incubation with indomethacin reduced phenylephrine reactivity and improved ACh induced relaxations of all vessels studied. NS-398 and tempol increased relaxations to ACh of MRAs. Incubation with pioglitazone or rosiglitazone (both 10(-5) M) or oral treatment with rosiglitazone improved, to different extents, ACh and SNP curves in all vessels. Glitazone incubation diminished aortic ACh sensitivity. The release of thromboxane A(2) and PGI(2) metabolites (thromboxane B(2) and 6-keto-PGF(1alpha)) was analyzed. ACh increased the MRA release of thromboxane B(2) from SHROBs but not control rats, and the former was prevented by rosiglitazone coincubation. In contrast, in aortae, ACh failed to alter the release of metabolites, and rosiglitazone treatment increased that of 6-keto PGF(1alpha). Thus, SHROBs displayed microvascular and macrovascular dysfunction. MRAs, but not aortae, of SHROBs revealed an impaired endothelial nitric oxide pathway, whereas both, but especially MRAs, displayed an impaired cyclooxygenase pathway. Glitazones elicited beneficial effects on macrovascular and, especially, microvascular function of SHROBs. PMID- 21784991 TI - Effects of mechanical limitation of apical rotation on left ventricular relaxation and end-diastolic pressure. AB - Left ventricular (LV) twist is thought to play an important role in cardiac function. However, how twist affects systolic or diastolic function is not understood in detail. We acquired apical and basal short-axis images of dogs undergoing open-chest procedures (n = 15) using a GE Vivid 7 at baseline and during the use of an apical suction device (Starfish) to limit apical rotation. We measured LV pressure and stroke volume using a micromanometer-tipped catheter and an ultrasonic flow probe, respectively. Peak radial strain, peak rotation, peak twist, peak systolic twisting rate (TR), peak untwisting rate during isovolumic relaxation period (UR(IVR)), and peak early diastolic untwisting rate after mitral valve opening (UR(E)) were determined using speckle tracking echocardiography. Immobilizing the apex with gentle suction significantly decreased apical rotation (-50 +/- 27%) and slightly increased basal rotation, resulting in a significant decrease in twist. The time constant of LV relaxation (tau) was prolonged, and LV end-diastolic pressure increased. TR and UR(IVR) decreased. LV systolic pressure, peak positive and negative first derivative of LV pressure (+/-dP/dt), stroke volume, radial strain, and UR(E) were not changed. The correlation between tau and UR(IVR) (r = 0.63, P = 0.0006) was stronger than that between peak +dP/dt and TR (r = 0.46, P = 0.01). Diastolic function was impaired with reduced apical rotation and UR(IVR) when the apex of the heart was immobilized using an apical suction device. PMID- 21784990 TI - Desmin-related cardiomyopathy: an unfolding story. AB - The intermediate filament protein desmin is an integral component of the cardiomyocyte and serves to maintain the overall structure and cytoskeletal organization within striated muscle cells. Desmin-related myopathy can be caused by mutations in desmin or associated proteins, which leads to intracellular accumulation of misfolded protein and production of soluble pre-amyloid oligomers, which leads to weakened skeletal and cardiac muscle. In this review, we examine the cellular phenotypes in relevant animal models of desmin-related cardiomyopathy. These models display characteristic sarcoplasmic protein aggregates. Aberrant protein aggregation leads to mitochondrial dysfunction, abnormal metabolism, and altered cardiomyocyte structure. These deficits to cardiomyocyte function may stem from impaired cellular proteolytic mechanisms. The data obtained from these models allow a more complete picture of the pathology in desmin-related cardiomyopathy to be described. Moreover, these studies highlight the importance of desmin in maintaining cardiomyocyte structure and illustrate how disrupting this network can be deleterious to the heart. We emphasize the similarities observed between desmin-related cardiomyopathy and other protein conformational disorders and speculate that therapies to treat this disease may be broadly applicable to diverse protein aggregation-based disorders. PMID- 21784992 TI - PwHAP5, a CCAAT-binding transcription factor, interacts with PwFKBP12 and plays a role in pollen tube growth orientation in Picea wilsonii. AB - The HAP complex occurs in many eukaryotic organisms and is involved in multiple physiological processes. Here it was found that in Picea wilsonii, HAP5 (PwHAP5), a putative CCAAT-binding transcription factor gene, is involved in pollen tube development and control of tube orientation. Quantitative real-time reverse transcription-PCR showed that PwHAP5 transcripts were expressed strongly in germinating pollen and could be induced by Ca(2+). Overexpression of PwHAP5 in pollen altered pollen tube orientation, whereas the tube with PwHAP5RNAi showed normal growth without diminishing pollen tube growth. Furthermore, PwFKBP12, which encodes an FK506-binding protein (FKBP) was screened and a bimolecular fluorescence complementation assay performed to confirm the interaction of PwHAP5 and PwFKBP12 in vivo. Transient expression of PwFKBP12 in pollen showed normal pollen tube growth, whereas the tube with PwFKBP12RNAi bent. The phenotype of overexpression of HAP5 on pollen tube was restored by FKBP12. Altogether, our study supported the role of HAP5 in pollen tube development and orientation regulation and identified FKBP12 as a novel partner to interact with HAP5 involved in the process. PMID- 21784993 TI - Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. AB - OBJECTIVES: To determine if interventions during the pre-hemolytic uremic syndrome (HUS) diarrhea phase are associated with maintenance of urine output during HUS. DESIGN: Prospective observational cohort study. SETTINGS: Eleven pediatric hospitals in the United States and Scotland. PARTICIPANTS: Children younger than 18 years with diarrhea-associated HUS (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction), thrombocytopenia (platelet count <150 * 103/mm3), and impaired renal function (serum creatinine concentration > upper limit of reference range for age). INTERVENTIONS: Intravenous fluid was given within the first 4 days of the onset of diarrhea. OUTCOME MEASURE: Presence or absence of oligoanuria (urine output <= 0.5 mL/kg/h for >1 day). RESULTS: The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those who received no intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = .02) and sodium (r = -0.27; P = .05) in the first 4 days of illness than those without oligoanuria. In multivariable analysis, the most significant covariate was volume infused, but volume and sodium strongly covaried. CONCLUSIONS: Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS. PMID- 21784994 TI - Detection, evaluation and minimization of nonenzymatic deamidation in proteomic sample preparation. AB - Identification of deamidated sites in proteins is commonly used for assignment of N-glycosylation sites. It is also important for assessing the role of deamidation in vivo. However, nonenzymatic deamidation occurs easily in peptides under conditions commonly used in treatment with trypsin and PNGase F. The impact on proteomic sample preparation has not yet been evaluated systematically. In addition, the (13)C peaks of amidated peptides can be misassigned as monoisotopic peaks of the corresponding deamidated ones in database searches. The 19.34 mDa mass difference between them is proposed as a means for eliminating the resulting false positive identifications in large-scale proteomic analysis. We evaluated five groups of proteomic data, obtained mainly through an electrostatic repulsion hydrophilic interaction chromatography (ERLIC)-reverse phase (RP) chromatography sequence, and ascertained that nonenzymatic asparagine deamidation occurred to some extent on 4-9% of the peptides, resulting in the false positive identification of many N-glycosylation sites. A comprehensive investigation indicated that the chief causative factors were the mildly alkaline pH and prolonged incubations at 37 degrees C during proteomic sample preparation. An improved protocol is proposed featuring tryptic digestion at pH 6 and deglycosylation at pH 5, resulting in a significant decrease in nonenzymatic deamidation while conserving adequate digestion efficiency. The number of identified deamidation sites was improved significantly by increasing the sample loading amount in liquid chromatography-tandem MS. This permitted the identification of a significant number of glutamine deamidation sites, which featured sequence motifs largely different from those for asparagine deamidation: -Q-V-, -Q-L- and -Q-G- and, to a lesser extent, -Q-A- and -Q-E-. PMID- 21784998 TI - Cell wall chitosan is necessary for virulence in the opportunistic pathogen Cryptococcus neoformans. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis. Its cell wall is composed of glucans, proteins, chitin, and chitosan. Multiple genetic approaches have defined a chitosan-deficient syndrome that includes slow growth and decreased cell integrity. Here we demonstrate chitosan is necessary for virulence and persistence in the mammalian host. PMID- 21784999 TI - Anterior cruciate ligament graft failure: a comparison of graft type based on age and Tegner activity level. AB - BACKGROUND: When reviewing anterior cruciate ligament instability, age, gender, activity level, associated injury, and type of graft should all be considered. HYPOTHESIS: The authors hypothesized that patients under 25 years of age will have higher failure rates with anterior cruciate ligament reconstruction than those older than 25 years, and that in the patients younger than 25 years, bone patellar tendon-bone autograft will have the lowest failure rate. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: With use of a computerized relational database, all patients having primary anterior cruciate ligament reconstruction at 1 institution between January 2000 and July 2007 with allograft, bone-patellar tendon-bone, and hamstring grafts were evaluated. RESULTS: A significant association was found between age group and graft failure (P = .012). Patients 25 years and younger had a significantly higher failure rate (16.5%) than patients older than 25 years (8.3%). Pairwise comparisons indicated that both allograft (29.2%) and semitendinosus/gracilis (25.0%) grafts resulted in significantly higher failure rates than bone-patellar tendon-bone grafts (11.8%) in the age group of patients 25 years and younger. CONCLUSION: Autograft hamstrings and allografts had a significantly higher failure rate in the age group of patients 25 years and younger compared with the bone-patellar tendon bone autograft. These data suggest that bone-patellar tendon-bone autografts may be a better graft source for young, active individuals. PMID- 21785000 TI - Is the anterior tibial artery safe during ankle arthroscopy?: anatomic analysis of the anterior tibial artery at the ankle joint by magnetic resonance imaging. AB - BACKGROUND: Pseudoaneurysm of the anterior tibial artery (ATA) after ankle arthroscopy is an uncommon complication but can cause unexpected consequences. However, its contributing factor is not fully understood. HYPOTHESIS: Anatomic factors, such as ATA variations and the distance between the ATA and joint capsule, may contribute to the occurrence of pseudoaneurysm. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The magnetic resonance images and medical records of 358 ankle cases were analyzed. According to locations of the ATA in relation to the peroneus tertius (PT) and the extensor digitorum longus (EDL) tendon on axial magnetic resonance imaging, patients were classified as type 1 (safe type), type 2 (increased risk type), or type 3 (high-risk type). In addition, distances between the anterior joint capsule and the ATA were measured to evaluate the thickness of the anterior fat pad, which contains the ATA and anterior compartment tendons. RESULTS: In 336 cases (93.8%), the ATA was located medial to the EDL (type 1, safe). In 7 cases (2.0%), the ATA was located lateral to the EDL and PT tendon (type 2, increased risk); and in 15 cases (4.2%), the branching artery was observed lateral to the EDL and PT tendon and the ATA was in the normal position (type 3, high risk). The mean distance between the anterior joint capsule and the ATA was 2.3 +/- 1.1 mm. CONCLUSION: In 22 (6.2%) of the 358 cases, the ATA and its branches were located near the anterolateral ankle portal, which introduces the risk of vascular damage during arthroscopic surgery. Furthermore, the mean distance between the ATA and the joint capsule was only 2.3 +/- 1.1 mm, and thus the ATA is very close to the anterior working space of the ankle joint. Careful preoperative evaluation and an intra-articular procedure may reduce the risk of vascular complications attributable to ankle arthroscopy. PMID- 21785001 TI - Functional and structural outcomes of single-row versus double-row versus combined double-row and suture-bridge repair for rotator cuff tears. AB - BACKGROUND: Although previous biomechanical research has demonstrated the superiority of the suture-bridge rotator cuff repair over double-row repair from a mechanical point of view, no articles have described the structural and functional outcomes of this type of procedure. HYPOTHESIS: The structural and functional outcomes after arthroscopic rotator cuff repair may be different between the single-row, double-row, and combined double-row and suture-bridge (compression double-row) techniques. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: There were 206 shoulders in 201 patients with full thickness rotator cuff tears that underwent arthroscopic rotator cuff repair. Eleven patients were lost to follow-up. Sixty-five shoulders were repaired using the single-row, 23 shoulders using the double-row, and 107 shoulders using the compression double-row techniques. Clinical outcomes were evaluated at an average of 38.5 months (range, 24-74 months) after rotator cuff repair. Postoperative cuff integrity was determined using Sugaya's classification of magnetic resonance imaging (MRI). RESULTS: The retear rates after arthroscopic rotator cuff repair were 10.8%, 26.1%, and 4.7%, respectively, for the single-row, double-row, and compression double-row techniques. In the subcategory of large and massive rotator cuff tears, the retear rate in the compression double-row group (3 of 40 shoulders, 7.5%) was significantly less than those in the single-row group (5 of 8 shoulders, 62.5%, P < .001) and the double-row group (5 of 12 shoulders, 41.7%, P < .01). Postoperative clinical outcomes in patients with a retear were significantly lower than those in patients without a retear for all 3 techniques. CONCLUSION: The additional suture bridges decreased the retear rate for large and massive tears. The combination of the double-row and suture-bridge techniques, which had the lowest rate of postoperative retear, is an effective option for arthroscopic repair of the rotator cuff tendons because the postoperative functional outcome in patients with a retear is inferior to that without retear. PMID- 21785002 TI - Therapeutic ultrasound affects IGF-1 splice variant expression in human skeletal muscle. AB - BACKGROUND: Animal models of skeletal muscle damage and repair demonstrate that therapeutic ultrasound (TUS) enhances muscle force recovery after damage, increases satellite cell proliferation, and decreases insulin-like growth factor (IGF)-1 splice variant (mechano growth factor) gene expression. However, these effects have not been verified in humans. PURPOSE: This study was undertaken to examine the 3 known splice variants of the IGF-1 gene in human skeletal muscle after damage and TUS treatment. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen healthy men (18-29 years of age), physically active, were randomized to either a control (CON) or experimental group (EXP). The EXP group underwent 200 lengthening contractions (muscle damage) of the quadriceps of both legs, 48 hours before TUS. Both groups received TUS, delivered for 10 minutes on a standardized area of the vastus lateralis of only 1 leg (1.0 MHz, 1.5 W/cm(2)). Bilateral muscle biopsy samples were taken from all participants, 6 hours after TUS. Total RNA was extracted, and quantitative real-time polymerase chain reaction conducted for each IGF-1 splice variant. RESULTS: Muscle damage was confirmed by a decrease in the isometric peak torque and increase in creatine kinase activity levels 48 hours after damage (P < .01). After muscle damage, gene expression of total IGF-1 and 2 IGF-1 splice variants increased. Therapeutic ultrasound induced significant increase in IGF-1Eb gene expression in undamaged muscle (1.4 +/- 0.2-fold, P < 0.01). In damaged skeletal muscle, no significant change in gene expression attributable to TUS was determined. CONCLUSION: Insulin like growth factor-1 splice variants are differentially regulated in human skeletal muscle in response to exercise-induced muscle damage and TUS treatment. A single treatment of TUS in damaged muscle induces no change in the gene expression of the 3 IGF-1 splice variants in humans. In contrast, in undamaged skeletal muscle, TUS significantly increased IGF-1Eb splice variant gene expression. CLINICAL RELEVANCE: These findings suggest that TUS may have additional therapeutic uses beyond its current common practice but may not be effective for muscle injury treatment in a young, healthy population. PMID- 21785003 TI - Dentoskeletal changes in adult Class II division 1 Herbst treatment--how much is left after the retention period? AB - The aim of this study was to assess dentoskeletal changes following Herbst Multibracket treatment in adult Class II division 1 patients. The subject material comprised 15 adult Class II division 1 subjects exhibiting a Class II molar relationship more than or equal to 0.5 cusps bilaterally or more than or equal to 1.0 cusps unilaterally and an overjet more than or equal to 6.0 mm. The average treatment time was 9 months (Herbst phase) plus 13.9 months (Multibracket phase). Lateral headfilms from before treatment (T1), after Herbst-Multibracket treatment (T2), and after at least 24 months of retention (T3) were analysed using the 'sagittal-occlusal analysis' (Pancherz, 1982) as well as standard cephalometric variables. During the treatment period (T2-T1), molar relationship, overjet (-6.2 mm), and overbite (-2.1 mm) were successfully corrected. The Class II jaw base relationship improved (ANB -0.8 degrees and Wits -1.1 mm) and the hard as well as soft tissue profile straightened (NApg +1.5 degrees, NsNoPgs +1.2 degrees, and NsSnPgs +1.5 degrees). During the retention period of on average 35.5 months (T3-T2), the amount of occlusal relapse (T3-T2) was small (less than or equal to 1.0 mm). The jaw base relationship (ANB +0.3 degrees and Wits +0.7 mm) and the profile convexities (NApg -0.3 degrees, NsNoPgs -0.6 degrees, and NsSnPgs +0.6 degrees) deteriorated slightly. Following the retention period, only minimal amounts of skeletal changes contributing to Class II correction in adult Herbst-Multibracket treatment were retained. Thus, adult Herbst-Multibracket treatment results in mainly dental changes, which however, showed good stability. PMID- 21785004 TI - The aging self in a cultural context: the relation of conceptions of aging to identity processes and self-esteem in the United States and the Netherlands. AB - OBJECTIVES: To study the aging self, that is, conceptions of one's own aging process, in relation to identity processes and self-esteem in the United States and the Netherlands. As the liberal American system has a stronger emphasis on individual responsibility and youthfulness than the social-democratic Dutch system, we expect that youthful and positive perceptions of one's own aging process are more important in the United States than in the Netherlands. METHODS: Three hundred and nineteen American and 235 Dutch persons between 40 and 85 years participated in the study. A single question on age identity and the Personal Experience of Aging Scale measured aspects of the aging self. The Identity and Experiences Scale measured identity processes and Rosenberg's scale measured self esteem. RESULTS: A youthful age identity and more positive personal experiences of aging were related to identity processes and self-esteem. These conceptions of one's own aging process also mediate the relation between identity processes and self-esteem. This mediating effect is stronger in the United States than in the Netherlands. DISCUSSION: As expected, the self-enhancing function of youthful and positive aging perceptions is stronger in the liberal American system than in the social-democratic Dutch welfare system. The aging self should therefore be studied in its cultural context. PMID- 21785005 TI - Enterovirus coinfection during an outbreak of hand, foot, and mouth disease in Shandong, China. PMID- 21785006 TI - Regulation of metabolism by hypoxia-inducible factor 1. AB - The maintenance of oxygen homeostasis is critical for survival, and the master regulator of this process in metazoan species is hypoxia-inducible factor 1 (HIF 1), which controls both O(2) delivery and utilization. Under conditions of reduced O(2) availability, HIF-1 activates the transcription of genes, whose protein products mediate a switch from oxidative to glycolytic metabolism. HIF-1 is activated in cancer cells as a result of intratumoral hypoxia and/or genetic alterations. In cancer cells, metabolism is reprogrammed to favor glycolysis even under aerobic conditions. Pyruvate kinase M2 (PKM2) has been implicated in cancer growth and metabolism, although the mechanism by which it exerts these effects is unclear. Recent studies indicate that PKM2 interacts with HIF-1alpha physically and functionally to stimulate the binding of HIF-1 at target genes, the recruitment of coactivators, histone acetylation, and gene transcription. Interaction with HIF-1alpha is facilitated by hydroxylation of PKM2 at proline 403 and -408 by PHD3. Knockdown of PHD3 decreases glucose transporter 1, lactate dehydrogenase A, and pyruvate dehydrogenase kinase 1 expression; decreases glucose uptake and lactate production; and increases O(2) consumption. The effect of PKM2/PHD3 is not limited to genes encoding metabolic enzymes because VEGF is similarly regulated. These results provide a mechanism by which PKM2 promotes metabolic reprogramming and suggest that it plays a broader role in cancer progression than has previously been appreciated. PMID- 21785008 TI - Moral hazard. PMID- 21785007 TI - Surviving starvation: essential role of the ghrelin-growth hormone axis. AB - After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation. PMID- 21785009 TI - Expert reflection--easier said than done. PMID- 21785010 TI - Relative Affordability of Health Insurance Premiums under CHIP Expansion Programs and the ACA. AB - Affordability is integral to the success of health care reforms aimed at ensuring universal access to health insurance coverage, and affordability determinations have major policy and practical consequences. This article describes factors that influenced the determination of affordability benchmarks and premium-contribution requirements for Children's Health Insurance Program (CHIP) expansions in three states that sought to universalize access to coverage for youth. It also compares subsidy levels developed in these states to the premium subsidy schedule under the Affordable Care Act (ACA) for health insurance plans purchased through an exchange. We find sizeable variability in premium-contribution requirements for children's coverage as a percentage of family income across the three states and in the progressivity and regressivity of the premium-contribution schedules developed. These findings underscore the ambiguity and subjectivity of affordability standards. Further, our analyses suggest that while the ACA increases the affordability of family coverage for families with incomes below 400 percent of the federal poverty level, the evolution of CHIP over the next five to ten years will continue to have significant implications for low-income families. PMID- 21785011 TI - We all want it, but we don't know what it is: toward a standard of affordability for health insurance premiums. AB - The 2010 Patient Protection and Affordable Care Act (P.L. 111-148), or ACA, requires that U.S. citizens either purchase health insurance or pay a fine. To offset the financial burden for lower-income households, it also provides subsidies to ensure that health insurance premiums are affordable. However, relatively little work has been done on how such affordability standards should be set. The existing literature on affordability is not grounded in social norms and has methodological and theoretical flaws. To address these issues, we developed a series of hypothetical vignettes in which individual and household sociodemographic characteristics were varied. We then convened a panel of eighteen experts with extensive experience in affordability standards to evaluate the extent to which each vignette character could afford to pay for one of two health insurance plans. The panel varied with respect to political ideology and discipline. We find that there was considerable disagreement about how affordability is defined. There was also disagreement about what might be included in an affordability standard, with substantive debate surrounding whether savings, debt, education, or single parenthood is relevant. There was also substantial variation in experts' assessed affordability scores. Nevertheless, median expert affordability assessments were not far from those of ACA. PMID- 21785012 TI - Perspective--the need for public deliberation: giving the public a voice on affordable health insurance. PMID- 21785013 TI - What if gut hormones aren't really hormones: DPP-4 inhibition and local action of GLP-1 in the gastrointestinal tract. PMID- 21785014 TI - Selective glucocorticoid receptor modulators: future of glucocorticoid immunosuppressive therapy? PMID- 21785015 TI - HCV protease inhibitors bring new options for patients. PMID- 21785016 TI - Kidney transplant drug approved. PMID- 21785017 TI - House legislation proposes early warning system for drug shortages. PMID- 21785018 TI - Hospitals take paperless plunge. PMID- 21785020 TI - Severe hypermagnesemia after enteral administration of Epsom salts. PMID- 21785021 TI - Detectable serum tobramycin concentrations in a patient with renal dysfunction receiving tobramycin by inhalation. PMID- 21785022 TI - Rhabdomyolysis and phentermine: coincidence, not causation. PMID- 21785023 TI - Alternative pharmacy practice model. PMID- 21785026 TI - Including indications when writing prescriptions. PMID- 21785027 TI - Pharmacist-run zoledronic acid clinic. PMID- 21785028 TI - Watershed events in health-system pharmacy practice. PMID- 21785029 TI - A step forward in bar coding? PMID- 21785030 TI - Denosumab for treatment of postmenopausal osteoporosis. AB - PURPOSE: The pharmacologic properties, clinical efficacy, and safety profile of the injectable agent denosumab for the treatment of postmenopausal women with osteoporosis are reviewed. SUMMARY: Denosumab, a human monoclonal antibody that targets a key protein mediator of bone resorption, was approved by the Food and Drug Administration in June 2010 for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, including "patients who have failed or are intolerant to other available osteoporosis therapy." Available in a 60-mg prefilled syringe, denosumab should be administered subcutaneously by a health care professional at six-month intervals. In Phase III clinical efficacy trials involving nearly 10,000 postmenopausal women, the use of denosumab was associated with a number of significant benefits: reduced bone resorption, increased bone mass, and reduced rates of vertebral, nonvertebral, and hip fractures. Results of two comparison studies indicated that denosumab therapy increased bone mineral density (BMD) at various skeletal sites to a significantly greater extent than alendronate therapy. In the largest clinical trial of the drug to date, adverse effects occurring significantly more often with denosumab versus placebo included eczema-related effects and cellulitis; long-term safety evaluations are ongoing. CONCLUSION: Denosumab has been shown to decrease bone resorption; increase BMD at all skeletal sites measured; and significantly reduce rates of vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Denosumab appears to have a favorable risk:benefit profile and provides a new treatment option for many patients in this population. PMID- 21785031 TI - Use of pure opioid antagonists for management of opioid-induced pruritus. AB - PURPOSE: Published reports on placebo-controlled clinical trials and other studies investigating the use of pure opioid antagonists for the prevention and treatment of opioid-induced pruritus (OIP) were evaluated. SUMMARY: OIP is a common adverse effect of therapeutic use of opioid medications that can have a major impact on patients' comfort, quality of life, and willingness to continue opioid therapy. A literature search identified more than a dozen published reports on the use of pure opioid antagonists (naloxone, naltrexone, methylnaltrexone) for the management of OIP in pediatric and adult patients. Of the studies included in this review, most investigated the effects of naloxone administered by various parenteral routes for the prevention of OIP. Some of those studies indicated a significant reduction in the frequency or severity of pruritus with use of naloxone (a low-dose, continuous i.v. infusion of naloxone appeared to be the most effective treatment). A significant diminution of analgesia requiring increased cumulative doses of morphine was also observed in some studies. A number of studies evaluating the use of orally administered naltrexone for the management of OIP yielded generally less favorable results. Evidence from one small study suggested a potential role for orally administered methylnaltrexone in the prevention of OIP. CONCLUSION: Based on the existing data, a low-dose, continuous i.v. infusion of naloxone has the largest body of evidence supporting its use for prevention of OIP in adult and pediatric patients. PMID- 21785032 TI - Paralytic ileus associated with use of diltiazem. AB - PURPOSE: A case of paralytic ileus in a patient receiving oral diltiazem therapy for atrial fibrillation is reported. SUMMARY: A 64-year-old man with a history of multiple serious comorbidities, poly-pharmacy, and a recent hospital stay for acute cardiac problems was readmitted to the hospital for gastrointestinal (GI) bleeding. On day 2 of the readmission, he suffered a myocardial infarction complicated by atrial fibrillation with a rapid ventricular response. After initial treatment with oral metoprolol for ventricular rate control was discontinued (due to ineffective rate control and patient complaints of respiratory symptoms), oral diltiazem hydrochloride therapy (30 mg every six hours) was initiated on day 7; the dose was adjusted to a maximum of 120 mg every six hours on day 10. On day 12, the patient complained of nausea, abdominal pain and tenderness, and infrequent bowel movements; imaging studies on day 13 indicated paralytic ileus. Pursuant to a surgical consultation, a nasogastric tube was inserted and nothing was given by mouth except medications. After initial improvement of the GI symptoms, the feeding tube was removed; however, the symptoms worsened over the next two to three days, requiring reinsertion of the tube on day 16. On day 18, after other potential causes of ileus were ruled out, diltiazem therapy was withdrawn. The man experienced rapid symptomatic improvement, with no further GI symptoms, and was discharged four days later. CONCLUSION: A 64-year-old man receiving high-dose diltiazem to treat atrial fibrillation developed paralytic ileus, which quickly resolved after the medication was discontinued. PMID- 21785033 TI - Impact of health disparities on staff workload in pharmacist-managed anticoagulation clinics. AB - PURPOSE: Pharmacists' provision of services unrelated to anticoagulant therapy at an anticoagulation clinic in an area of prevalent health disparities (health status differences between minority and nonminority populations) was evaluated. SUMMARY: A prospective cohort study was conducted to compare the frequency and types of additional services (i.e., services unrelated to anticoagulation) provided by pharmacists during an eight-week period at an urban clinic serving a primarily minority and socioeconomically disadvantaged patient population (clinic A) and a suburban clinic serving a primarily nonminority and affluent population (clinic B). Over the study period, additional services were provided during 42% of all patient visits (n = 444) at clinic A and 8% of all visits (n = 443) at clinic B. The most commonly provided additional services involved nonanticoagulation-related medical problems, which were addressed during about 9% of visits at clinic A and 3% of visits at clinic B; other additional services included setting up appointments, arranging transportation, and providing refills of nonanticoagulant medications. Missed appointments, early or late arrivals, and walk-in appointments were much more common at clinic A. The average daily pharmacist-staffing requirement was 3.8 hours higher at clinic A; over the entire study period, clinic A required a total of about 60 more staffed hours than clinic B. CONCLUSION: Pharmacists practicing in an anticoagulation clinic serving an area of prevalent health disparities frequently spent a substantial amount of time addressing medical problems and administrative tasks unrelated to anticoagulation therapy. PMID- 21785034 TI - Characteristics of postgraduate year 1 pharmacy residency programs at academic medical centers. AB - PURPOSE: The training components and other characteristics of postgraduate year 1 (PGY1) pharmacy residency programs at a sample of academic medical centers were evaluated. SUMMARY: A questionnaire was sent via e-mail to the directors of 98 PGY1 residency programs at academic medical centers in the University HealthSystem Consortium (UHC) to elicit benchmarking data on issues such as recruitment, learning experiences, resident staffing requirements, resident research projects and professional presentations, opportunities for resident participation in teaching activities, and requirements for faculty service as preceptors; 72 program directors responded to the survey. The residency programs represented in the survey reported an average of approximately 14 applicants for each available position in 2010 and an average of about five candidate interviews per available position. The survey results indicated wide variation in the learning experiences offered by PGY1 programs (the most commonly reported rotations were in administration, critical care, internal medicine, ambulatory care, and drug information), with a high degree of individualization of elective rotations. Almost all programs had a mandatory staffing component, typically requiring 4-10 hours of service weekly. CONCLUSION: Results of this survey indicate that there is a large amount of variation in the components of PGY1 pharmacy residency programs among UHC academic medical centers. The majority of respondents reported no change in the number of residency positions offered within the past two years, but they reported an increase in the number of applications from 2009 to 2010. PMID- 21785035 TI - Accepting accountability for the medication-use system. PMID- 21785036 TI - Addressing challenges in bar-code scanning of large-volume infusion bags. AB - PURPOSE: A hospital pharmacy's efforts to identify and address challenges with bedside scanning of bar codes on large-volume parenteral (LVP) infusion bags are described. SUMMARY: Bar-code-assisted medication administration (BCMA) has been shown to reduce medication errors and improve patient safety. After the pilot implementation of a BCMA system and point-of-care scanning procedures at a medical center's intensive care unit, it was noted that nurses' attempted bedside scans of certain LVP bags for product identification purposes often were not successful. An investigation and root-cause analysis, including observation of nurses' scanning technique by a multidisciplinary team, determined that the scanning failures stemmed from the placement of two bar-code imprints-one with the product identification code and another, larger imprint with the expiration date and lot number-adjacently on the LVP bags. The nursing staff was educated on a modified scanning technique, which resulted in significantly improved success rates in the scanning of the most commonly used LVP bags. Representatives of the LVP bag manufacturer met with hospital staff to discuss the problem and corrective measures. As part of a subsequent infusion bag redesign, the manufacturer discontinued the use of the bar-code imprint implicated in the scanning failures. CONCLUSION: Failures in scanning LVP bags were traced to problematic placement of bar-code imprints on the bags. Interdisciplinary collaboration, consultation with the bag manufacturer, and education of the nursing and pharmacy staff resulted in a reduction in scanning failures and the manufacturer's removal of one of the bar codes from its LVP bags. PMID- 21785037 TI - Relationship between kinetics of albumin-bound bilirubin and water-soluble urea in extracorporeal blood purification. AB - BACKGROUND: The purpose of the study was to examine the relationship between urea and conjugated bilirubin kinetics during extracorporeal liver support (ELS) therapy and to determine the dose of therapy for urea and conjugated bilirubin as markers for water-soluble and protein-bound solutes, respectively. METHODS: Kinetics of urea and bilirubin were described by standard two-compartment models with central clearance, constant intercompartment clearance, constant generation rate and constant volume. While the concentration of urea was assumed as equilibrated between compartments at the beginning of ELS therapy, the concentration of conjugated bilirubin between compartments was assumed to follow the partition of albumin between plasma and interstitial spaces. Treatment dose was calculated as removed solute mass and fractional solute removal. RESULTS: Seven patients were studied during 15 treatments lasting at least 6 h. Bilirubin distribution volume of 14.8 +/- 5.4 L was not different from urea extracellular water volume of 15.0 +/- 2.8 L. The correspondence between models was used to predict the mass of bilirubin removed based on extracellular volume obtained from urea kinetics, average data from bilirubin kinetics, as well as selected treatment and patient information. The prediction of bilirubin mass removed based on this reduced information was not different from the mass of solute removed based on complete bilirubin kinetic analysis. CONCLUSIONS: The correspondence between kinetics of urea and conjugated bilirubin can be used to identify the bilirubin distribution volume from urea kinetic analysis. This information is then useful to estimate and predict the solute removal of conjugated bilirubin in ELS. PMID- 21785038 TI - mTOR inhibition and erythropoiesis: microcytosis or anaemia? AB - BACKGROUND: Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro. METHODS: Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL). RESULTS: SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 +/- 1.8 versus 57 +/- 1.7 fL; P = 0.0156; Red blood count 7.4 +/- 0.3 * 10(9)/L versus 8.6 +/- 0.5 * 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 +/- 11.4 versus with SRL: 27.5 +/- 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies. CONCLUSION: mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells. PMID- 21785039 TI - Hepcidin: another culprit for complications in patients with chronic kidney disease? AB - Hepcidin has been established as a central regulator of iron metabolism. In most patients with chronic kidney disease (CKD), serum hepcidin levels are relatively high, favoring iron sequestration in several cell types and organs and thereby leading to iron-related complications. In the absence of overt inflammation, serum hepcidin has been found to be most closely associated with serum ferritin in healthy subjects and in CKD patients. Intestinal iron absorption is tightly regulated by both iron stores and hepcidin. The expression of the mammalian iron exporter, ferroportin (FPN), limits the growth of intracellular bacteria by depleting cytosolic iron. An upregulation of hepcidin could diminish FPN and favor bacterial growth. Of note, in patients with hyperferritinemia impaired hepcidin expression caused by a mutation in the hemochromatosis gene associates with an attenuation of atherosclerosis. Thus, hepcidin might accelerate atherosclerosis by preventing iron exit from macrophages or other cells in the arterial wall. High hepcidin levels have also been found to be linked to good erythropoiesis-stimulating agents (ESAs) response, in conjunction with the strong hepcidin-ferritin correlation. Finally, hepcidin may also play a significant role by itself in the pathogenesis of CKD complications associated with disturbed iron metabolism, i.e. unrelated to ESA hyporesponsiveness, such as bacterial infections and atherosclerosis. PMID- 21785040 TI - Very early steroid withdrawal or complete avoidance for kidney transplant recipients: a systematic review. AB - BACKGROUND: The safety and efficacy of early steroid withdrawal or avoidance in patients receiving a kidney transplant (KT) are controversial. METHODS: We performed a systematic review and a meta-analysis of the randomized controlled studies about steroid avoidance or withdrawal after a few days in patients receiving a KT and treated with antibody induction and cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) (nine available studies and 1934 participants). RESULTS: Death and graft loss (including or excluding death with function) were similar in steroid avoidance and control patients, with no differences between CsA and Tac studies. After steroid avoidance, acute rejection was more frequent than conventional steroid use in CsA trials [risk ratios (RR) 1.59, 95% confidence intervals (95% CI) 1.01-2.49] but not when Tac was used (RR 1.06, 95% CI 0.79-1.42). Steroid avoidance was associated with less frequent new onset diabetes mellitus, but this decrease was only evident with CsA (RR 0.54, 95% CI 0.30-0.98), whereas this difference was not significant analysing Tac studies (RR 0.75, 95% CI 0.32-1.77). Despite this trend, the corresponding interaction tests were not statistically significant (P = 0.140 and P = 0.535, for acute rejection and new-onset diabetes mellitus, respectively). Serum creatinine, creatinine clearance, mean blood pressure, serum cholesterol and serum triglycerides were similar in both groups. CONCLUSIONS: Steroid avoidance or early withdrawal within the first 2 weeks is safe in KT recipients receiving induction with anti-interleukin-2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and MMF. However, the real benefits remain unclear. PMID- 21785041 TI - Gender differences in the association between HDL cholesterol and the progression of diabetic kidney disease in type 2 diabetic patients. AB - BACKGROUND: The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD. METHODS: Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (+/- SD) age of 63 +/- 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted. RESULTS: During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint. CONCLUSIONS: Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women. PMID- 21785042 TI - Premise that fructose causes microvascular disease is flawed. PMID- 21785043 TI - Impact of endoscopic surgical techniques on efficiency in pituitary surgery. AB - OBJECTIVE: To assess the impact of the introduction of endoscopic surgical techniques into a neurosurgical practice for pituitary surgery on operative efficiency. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Patients undergoing transsphenoidal pituitary surgery over a 4-year period were identified. The approach over this period evolved from classic transseptal surgery to exclusively endoscopic techniques. Patients were classified as having transseptal surgery, endoscopic approach with microsurgical resection, aborted endoscopic resection with subsequent microsurgery, and exclusive endoscopic techniques. Patient and surgeon demographics, operative times, total operating room times, and room setup time were examined. Univariate analysis and multivariate regression modeling were used to assess outcome measures. RESULTS: One hundred seven patients were identified. The use of the endoscope for either sphenoid exposure alone (n = 41) or for the entire procedure (n = 35) resulted in a significant reduction in operative and room times compared to transseptal approaches (n = 25). Exclusively endoscopic techniques resulted in a significant reduction in operative and room times independent of all other clinical and surgical parameters (P < .001). Progressive use of endoscopic techniques resulted in statistically significant progressive reduction in setup time (P = .001), operative time (P = .04), and total room time (P = .03) over the study period. CONCLUSION: The transition from transseptal transsphenoidal pituitary surgery to endoscopic techniques implies a learning process for both neurosurgeon and otolaryngologist. Despite this, a noteworthy reduction in operative times, operating room times, and room setup times is observed. The impact of endoscopic techniques on efficiency in pituitary surgery is discussed. PMID- 21785044 TI - Hypervascular liver lesions on MRI. PMID- 21785045 TI - Imaging of acute pancreatitis. PMID- 21785046 TI - Automatic MDCT injectors: hygiene and efficiency of disposable, prefilled, and multidosing roller pump systems in clinical routine. AB - OBJECTIVE: This study evaluated three different injection systems with regard to microbiological contamination, time efficiency, and user handling during a clinical routine. SUBJECTS AND METHODS: A total of 825 patients were included. A double-syringe contrast injector with disposable syringes (system A; n = 150) and one that used prefilled syringes (system B; n = 150) were microbiologically analyzed during single use of the syringes in one patient. Moreover, the contamination of a roller pump injector capable of multidosing several patients from a contrast agent container, without the need for prior filling, was determined after being used for an entire day (system C; n = 35 injections/day for 15 days). The hygienic background was guaranteed by taking imprints of the surfaces of devices and the palms of the hands of members of CT staff before the clinical investigation. The time required for assembly of the injection systems and for filling or refilling of each injector system was measured. The handling of the three systems also was subjectively ranked by the technicians. RESULTS: Injection systems A, B, and C remained microbiologically sterile and free of contamination throughout their use in clinical routine. The mean (+/- SD) time for injection system assembly and installation of syringes and filling did not differ significantly between injection systems A and B (system A, 2.5 +/- 1.1 minutes; system B, 1.9 +/- 1.3 minutes; p = 0.12), whereas the time for assembly of system C was significantly shorter (0.9 +/- 0.6 minutes; p < 0.05 vs system A; p < 0.05 vs system B). In the subjective ranking of injector handling, systems B and C were preferred. CONCLUSION: Double-syringe injectors used with disposable or prefilled contrast agent syringes, as well as roller pump injectors, ensure hygienic conditions in clinical routine. However, time efficiency and handling are aspects that favor prefilled and roller pump systems. PMID- 21785047 TI - Blast and ballistic trajectories in combat casualties: a preliminary analysis using a cartesian positioning system with MDCT. AB - OBJECTIVE: The purpose of this study is to determine the agreement with which radiologists identify wound paths in vivo on MDCT and calculate missile trajectories on the basis of Cartesian coordinates using a Cartesian positioning system (CPS). MATERIALS AND METHODS: Three radiologists retrospectively identified 25 trajectories on MDCT in 19 casualties who sustained penetrating trauma in Iraq. Trajectories were described qualitatively in terms of directional path descriptors and quantitatively as trajectory vectors. Directional descriptors, trajectory angles, and angles between trajectories were calculated based on Cartesian coordinates of entrance and terminus or exit recorded in x, y image and table space (z) using a Trajectory Calculator created using spreadsheet software. The consistency of qualitative descriptor determinations was assessed in terms of frequency of observer agreement and multirater kappa statistics. Consistency of trajectory vectors was evaluated in terms of distribution of magnitude of the angles between vectors and the differences between their paraaxial and parasagittal angles. RESULTS: In 68% of trajectories, the observers' visual assessment of qualitative descriptors was congruent. Calculated descriptors agreed across observers in 60% of the trajectories. Estimated kappa also showed good agreement (0.65-0.79, p < 0.001); 70% of calculated paraaxial and parasagittal angles were within 20 degrees across observers, and 61.3% of angles between trajectory vectors were within 20 degrees across observers. CONCLUSION: Results show agreement of visually assessed and calculated qualitative descriptors and trajectory angles among observers. The Trajectory Calculator describes trajectories qualitatively similar to radiologists' visual assessment, showing the potential feasibility of automated trajectory analysis. PMID- 21785048 TI - Radiologic aspects of immune-related tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy. AB - OBJECTIVE: The objective of this article is to illustrate examples of radiologic immune-related response criteria and toxicity in patients with advanced melanoma treated with the immunotherapeutic agent ipilimumab. CONCLUSION: Novel immune related tumor response criteria should be applied to patients undergoing therapy with ipilimumab for advanced melanoma. Ipilimumab also produces a spectrum of immune-related adverse effects that can be recognized radiologically. PMID- 21785049 TI - Positron emission mammography: correlation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status and 18F-FDG. AB - OBJECTIVE: The study objective was to assess the correlation between (18)F-FDG uptake values on positron emission mammography (PEM), expressed as maximum uptake value and lesion-to-background ratio, and receptor status (i.e., estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), tumor histology, and tumor grade. We also evaluated for the correlation between maximum uptake value on PEM and maximum uptake value on a whole-body PET/CT. MATERIALS AND METHODS: We retrospectively reviewed our database for patients with newly diagnosed breast cancer who were referred for PEM between June 2007 and September 2009. A subset of patients also underwent a whole-body PET/CT scan. The original pathology reports were reviewed to establish the histologic type, grade, and receptor status. RESULTS: The study involved 98 patients with 100 lesions. ER-negative tumors and PR-negative tumors had significantly higher mean lesion-to-background ratio than did their respective receptor-positive tumors (p = 0.02). Triple-negative tumors (i.e., ER-negative, PR-negative, and HER2-negative tumors) had statistically higher mean lesion-to background ratio than did ER-positive PR-positive HER2-negative tumors (p = 0.04). Infiltrating ductal carcinomas had significantly higher PEM FDG uptake values than did infiltrating lobular carcinomas (p = 0.02-0.04). Breast tumors with higher histologic grade also had significantly higher PEM FDG uptake values than did those with lower grade (p = 0.03 and p < 0.001). A moderately high correlation (0.76-0.79) was seen between whole-body PET/CT and PEM uptake values. CONCLUSION: This study shows a correlation between PEM FDG uptake values and the prognostic factors that have been shown to predict breast cancer survival. PMID- 21785050 TI - Value of PET/CT in the management of liver metastases, part 1. AB - OBJECTIVE: Metastasis is the most common (95%) of liver lesions. Early diagnosis and staging are the keys to treatment planning and prognosis. There is a consistent benefit to the use of PET/CT for detecting hepatic, local, and distant metastases from a variety of primary malignancies, which can contribute to staging and ultimately helps to establish the best course of treatment and to determine prognosis. CONCLUSION: For colorectal cancer, FDG PET and FDG PET/CT are particularly effective for identification of additional hepatic and extrahepatic metastases, frequently upstaging the tumor stage and affecting management. In addition, PET/CT is very useful in local ablative and systemic therapy assessment and surveillance for liver metastases. PMID- 21785051 TI - Value of PET/CT in the management of primary hepatobiliary tumors, part 2. AB - OBJECTIVE: Primary hepatobiliary malignancies consist of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder cancer. Benign hepatic lesions include hepatic cysts, hemagiomas, adenomas, and focal nodular hyperplasias. The utility of PET/CT in imaging primary hepatobiliary lesions varies according to the type and location of the lesion. CONCLUSION: There is a consistent benefit to the use of PET/CT for detection and staging, and it ultimately helps to establish the best course of treatment and to determine prognosis. In addition, PET/CT is very useful in local ablative and systemic therapy assessment and surveillance for hepatobiliary malignancies. PMID- 21785052 TI - CT findings of pulmonary nocardiosis. AB - OBJECTIVE: Nocardiosis is an opportunistic infection that primarily affects the lungs. Most infected patients have deficits in cell-mediated immunity such as those with AIDS, transplant recipients, and those receiving corticosteroid therapy. We review the various CT appearances of pulmonary nocardiosis and discuss the differential diagnosis. CONCLUSION: Common CT findings include lung consolidation and nodules and masses. Cavitation may occur. Chest wall involvement develops in a small number of patients. PMID- 21785053 TI - Image quality of low-energy pulmonary CT angiography: comparison with standard CT. AB - OBJECTIVE: The purpose of this article is to prospectively compare visualization of central and peripheral pulmonary arteries on simultaneously acquired low energy and standard pulmonary CT angiography. SUBJECTS AND METHODS: Thirty-three consecutive patients (20 women and 13 men; mean age, 55.6 years; range, 21-92 years) with suspected pulmonary embolism (PE) were scanned (140 kVp; 250-300 mA) on a single-source dual-layer dual-energy MDCT scanner. Attenuation and image noise were measured at the main and segmental pulmonary arteries. Signal-to-noise ratios were calculated. Two blinded experienced radiologists assessed segmental and subsegmental artery visibility in consensus, using slab maximum-intensity projection (MIP) reconstructions. Nonparametric sign test and kappa statistic were used for statistical analysis. RESULTS: PE was detected in three patients (9.1%); two segmental vessel and subsegmental emboli were seen in the low-energy images only. Higher attenuation was noted in low-energy versus standard images for all arteries evaluated, with a mean (+/- SD) increase of 66.6 +/- 4.4 HU (p < 0.0001). Low-energy images improved visualization of segmental and subsegmental arteries from 97.0% to 99.2% and from 88.0% to 93.9%, respectively. A larger number of subsegmental vessels was seen on low-energy MIP reconstructions in 69.7% (95% CI, 36.5-71.89%) of studies compared with 9.1% on the standard images. Visualization of subsegmental vessels was superior in 55.5% of cases using low energy imaging. The mean image noise increased by 9.7 +/- 0.6 HU (p < 0.0001). The mean signal-to-noise ratio showed no significant difference in the low-energy (8.2) versus standard (8.1) CT images (p = 0.7759). CONCLUSION: Improved visualization of central and peripheral arteries can be obtained with low-energy pulmonary CT angiography, without a substantial decrease in image quality. PMID- 21785054 TI - T2* measurements of 3-T MRI with ultrashort TEs: capabilities of pulmonary function assessment and clinical stage classification in smokers. AB - OBJECTIVE: The purpose of this study was to determine the usefulness of MRI with ultrashort TEs on a 3-T system and of thin-section MDCT for pulmonary function assessment and clinical stage classification of chronic obstructive pulmonary disease (COPD) in smokers. SUBJECTS AND METHODS: Forty smokers (24 men and 16 women; mean age +/- SD, 68.0 +/- 9.3 years) underwent MRI with ultrashort TEs and thin-section MDCT. Pulmonary function testing was also performed to determine the following: the ratio of forced expiratory volume in 1 second to forced vital capacity (percentage predicted) (FEV(1/)FVC%), percentage predicted forced expiratory volume in 1 second (%FEV(1)), and percentage predicted diffusing capacity of lung for carbon monoxide corrected for alveolar volume (%DLCO/V(A)). All subjects were classified into one of four groups as follows: smokers without COPD, with mild COPD, with moderate COPD, and with severe or very severe COPD. T2(*) maps were expressed using proprietary software. Regional T2(*) values were determined by region of interest measurements and were averaged to determine a mean T2(*) value for each subject. CT-based functional lung volume and the ratio of the wall area to the total airway area were also determined. All indexes were statistically correlated with pulmonary function parameters. Then, all indexes were compared among all groups by means of Tukey's honest significance test. RESULTS: All indexes had significant correlation with FEV(1)/FVC%, %FEV(1), and % DLCO/V(A) (p < 0.05). All indexes except WA% of smokers without COPD and smokers with mild COPD differed significantly from those of smokers with moderate COPD and smokers with severe or very severe COPD (p < 0.05). Moreover, the mean T2(*) value of the moderate COPD group was significantly different from that of the severe or very severe COPD group (p < 0.05). CONCLUSION: MRI with ultrashort TEs is potentially as useful as quantitatively assessed MDCT for pulmonary function loss assessment and clinical stage classification of COPD in smokers. PMID- 21785055 TI - Spectrum of medication-induced complications in the abdomen: role of cross sectional imaging. AB - OBJECTIVE: This article provides a comprehensive review of the role of MDCT and MRI in the diagnosis of drug-induced complications in the abdomen and pelvis in adults. A systematic organ-based review of these complications is presented, including but not limited to hepatic changes after chemotherapy, renal complications such as tumor lysis syndrome and lithium nephropathy, gastrointestinal manifestations, various opportunistic infections and secondary neoplasms, mycotic aortic aneurysm from intravesical bacille Calmette-Guerin, complications of anticoagulant therapy, and oral contraceptives. CONCLUSION: Advancements in imaging have led to recognition of radiologic features of previously unsuspected diseases. Occasionally, imaging may also identify effects of treatments instituted for these diseases. Consequently, imaging plays a critical role in the accurate diagnosis of a broad spectrum of drug-induced complications in the abdomen, both in emergent and nonemergent settings. Knowledge of the natural history, clinical manifestations, and salient imaging features of these entities is crucial to facilitate accurate clinical diagnosis in a timely fashion. PMID- 21785056 TI - Benign biliary strictures: a current comprehensive clinical and imaging review. AB - OBJECTIVE: There is a wide spectrum of nonneoplastic causes of biliary stricture that can pose a significant challenge to clinicians and radiologists. Imaging plays a key role in differentiating benign from malignant strictures, defining the extent, and directing the biopsy. We describe the salient clinical and imaging manifestations of benign biliary strictures that will help radiologists to accurately diagnose these entities. CONCLUSION: Accurate diagnosis and management are based on correlating imaging findings with epidemiologic, clinical, and laboratory data. Cross-sectional imaging modalities permit precise localization of the site and length of the segment involved, thereby serving as a road map to surgery, and permit exclusion of underlying malignancy. PMID- 21785057 TI - Comparison of sagittal T2-weighted BLADE and fast spin-echo MRI of the female pelvis for motion artifact and lesion detection. AB - OBJECTIVE: The objective of this study was to evaluate the effectiveness of BLADE (proprietary name for periodically rotated overlapping parallel lines with enhanced reconstruction [PROPELLER] in MR systems from Siemens Healthcare) MRI compared with conventional T2-weighted fast spin-echo (FSE) MRI for reducing artifacts and improving image quality when imaging the female pelvis. MATERIALS AND METHODS: Sagittal T2-weighted BLADE and FSE examinations of the pelvis of 26 women were performed on a 1.5-T scanner. Three radiologists assessed the images for the presence of artifacts, level of anatomic detail, and overall image quality using a modified Likert scale. Scores for each radiologist and each imaging sequence were analyzed with a linear mixed model, adjusting for correlation within radiologist and within patient. A quantitative comparison was conducted to investigate signal uniformity. RESULTS: The BLADE sequence was superior for evaluation of the junctional zone (p = 0.0019), delineation of ovarian borders and depiction of follicles (p < 0.0001), and detection of fibroids (p = 0.022). Overall image quality was improved with BLADE, with fewer respiratory motion artifacts. The BLADE sequence introduced "radial" artifact that was absent from the FSE images, but this artifact did not affect image quality. Quantitative analysis revealed mean coefficients of variation for BLADE and FSE in the uterus of 21.6% and 22.5%, respectively (p = 0.36). The mean coefficients of variation were 4.6% and 6.1% in fat (p = 0.0007), indicating less variation with BLADE. The mean acquisition times for the BLADE and FSE sequences were 4 minutes 31 seconds and 3 minutes 46 seconds, respectively. CONCLUSION: Imaging of uterine junctional zone anatomy, ovaries, and fibroids was improved and artifacts were reduced with BLADE compared with FSE. Radial artifact introduced by the BLADE sequence and slightly longer imaging times needed for the BLADE sequence were offset by improved image quality. PMID- 21785058 TI - Utilization of lower extremity arterial disease diagnostic and revascularization procedures in Medicare beneficiaries 2000-2007. AB - OBJECTIVE: The recent escalation in lower extremity revascularization procedures suggests a concomitant increase in peripheral arterial disease (PAD) screening. We hypothesized that self-referring physicians would show the greatest growth in noninvasive physiologic testing for PAD and similar trends for revascularization procedures. We compared utilization rates for self-referring specialties (vascular surgery, interventional radiology, and cardiology) with the utilization rate for a referral-based specialty (diagnostic radiology), assuming the latter to be "basal"--that is, responsive only to changes in demographics and medical knowledge. MATERIALS AND METHODS: We analyzed 100% procedure-specific claims for services provided to Medicare Part B beneficiaries during 6 years over an 8-year span (2000-2007). We extracted all Current Procedural Terminology codes for lower extremity vascular noninvasive physiologic studies, peripheral arterial stent placement, and transluminal angioplasty. Utilization volumes were adjusted per 100,000 beneficiaries. Compound annual growth rates were calculated. RESULTS: Utilization of both noninvasive physiologic and revascularization services increased steadily over the study period. Growth rates of diagnostic services provided by interventional radiologists (7%) and vascular surgeons (8%) were slightly higher than the basal rate (7%), with cardiologists (14%) at the top of the list. For revascularization procedures, vascular surgery showed the greatest growth (28%), a rate more than twice that of cardiology (13%); radiology experienced a decrease in volumes (-2%). CONCLUSION: Self-referring specialists are screening large volumes of Medicare beneficiaries for lower extremity PAD at an accelerated rate compared with testing done by those who do not self-refer. Similar trends exist for endovascular interventions. PMID- 21785059 TI - Feasibility of dose reduction using needle-structured image plates versus powder structured plates for computed radiography of the knee. AB - OBJECTIVE: A newly developed computed radiography (CR) detector that uses a storage phosphor plate made of needle-shaped crystals provides improved dose efficiency. The aim of our study was to compare the image quality of standard dose CR and dose-reduced CR achieved using needle technology for knee imaging in a clinical setting. MATERIALS AND METHODS: We compared standard CR images obtained using a powder-structured image plate (PIP) (ADC Compact Plus) with images obtained using the new needle-structured image plate (NIP) (DX-S). In 30 consecutive patients with knee pain willing to participate in this study, anteroposterior knee radiographs were acquired with both systems at a standard dose. In addition, NIP images were obtained with approximately 75% and 50% of the standard dose (corresponding incident doses: 300, 235, and 154 MUGy, respectively). Images were evaluated in a blinded, side-by-side comparison. Six radiologists determined whether there was an appreciable difference in image quality at five anatomic landmarks in regions with high and low differences of attenuation. They also assessed the delineation of selected abnormalities and ranked them using a 10-point scale. The rating scores were tested for statistical differences using an analysis of variance with repeated measures. RESULTS: The mean overall rating scores for the evaluation of anatomic landmarks were 6.97 for NIP images obtained at full dose, 6.48 for NIP images obtained at about 75% dose, 5.47 for NIP images obtained at half dose, and 6.01 for PIP images. There was a significant difference in favor of the CR system with an NIP at the same dose level (p < 0.05). The NIP images obtained at a dose of about 75% were also ranked significantly better than the PIP images with regard to the depiction of both anatomic landmarks and abnormalities. The readers ranked half-dose NIP images inferior to the PIP images with regard to abnormalities and anatomic landmarks in areas with high attenuation, whereas in areas with low attenuation, the image quality was regarded as equivalent to the standard technique. CONCLUSION: NIP technology allows a dose reduction of approximately 25% compared with PIP while still providing higher image quality. Even at the half-dose level, there was no relevant loss of image quality with regard to the delineation of anatomic landmarks in areas with low attenuation in anteroposterior knee images. The higher dose efficiency of the needle-detector CR technology compared with conventional CR can be used either for dose reduction or for improved image quality. PMID- 21785060 TI - Positive predictive value and interobserver variability of preoperative staging sonography for thyroid carcinoma. AB - OBJECTIVE: The purpose of this article is to evaluate the positive predictive value (PPV) and interobserver variability of preoperative staging sonography for thyroid carcinoma. SUBJECTS AND METHODS: Eighty-five patients (median age, 45 years) were included. The T and N staging were classified according to TNM classification. Extrathyroidal extension was defined as contact with the capsule greater than 25% of the perimeter of a malignant lesion or loss of the capsule line. The sonography criteria for lymph node metastases were absence of echogenic fatty hilum, round shape, hyperechogenicity, microcalcifications, cystic change, and peripheral vascularity. The PPV and interobserver variability of two radiologists were calculated. RESULTS: The mean size of 85 malignancies was 8.6 mm, with 17 that were larger than 10 mm and 68 that were 10 mm or smaller. PPV ranges of sonography by two radiologists were 65-100% for T staging, 44.4-45.5% for multifocality, 71.4-81.8% for bilaterality, 28.6-80% for N1a staging, and 40 100% for N1b staging. In all malignancies, the kappa values were 0.5319 for T staging, 0.7741 for multifocality, 0.8604 for bilaterality, and 0.6793 for N staging. In 17 malignancies larger than 10 mm, the corresponding kappa values were lower (kappa = 0.4516, 0.5952, 0.8211, and 0.6364, respectively). In 68 malignancies 10 mm or smaller, the corresponding kappa values showed slight improvements, except for T staging (kappa = 0.5016, 0.8413, 0.8721, and 0.6821, respectively). CONCLUSION: The T staging, bilaterality, and N1b staging of preoperative staging sonography showed high PPV. Agreements for T and N staging, multifocality, and bilaterality were moderate, substantial, substantial, and excellent, respectively. PMID- 21785061 TI - Locoregional control of metastatic well-differentiated thyroid cancer by ultrasound-guided radiofrequency ablation. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of ultrasound-guided radiofrequency ablation (RFA) in the control of metastatic well differentiated thyroid carcinoma in patients for whom surgery is not feasible. MATERIALS AND METHODS: Between December 2004 and June 2008, 12 metastatic differentiated thyroid carcinomas (mean diameter, 13.8 mm; range, 4-28 mm) in 10 patients (six women, four men; mean age, 44.8 years) were treated with RFA. The inclusion criteria for RFA were fewer than three metastatic tumors confirmed with ultrasound-guided fine-needle aspiration biopsy, no metastatic tumor beyond the neck at RFA, and infeasibility of surgery. A radiofrequency generator and 18 gauge internally cooled electrodes with a 7-cm shaft length and 0.5- and 1-cm active tips were used depending on the size of the targeted tumors. Ten of the 12 metastatic tumors (83%) were treated in a single session of RFA, and the other two required two sessions. The ablation time ranged from 60 to 900 seconds. RESULTS: After treatment, the mean largest diameter decreased significantly from 13.8 +/- 7.0 mm to 3.3 +/- 3.9 mm (p = 0.002), as did mean volume, from 55.5 +/- 50.3 mm(3) to 5.7 +/- 9.3 mm(3) (p = 0.002). At the last follow-up evaluation, the serum thyroglobulin concentration had decreased in 7 of 10 patients. One patient had dysphonia immediately after RFA of a left surgical bed. CONCLUSION: Although surgery is the standard treatment of locally metastatic thyroid cancer, RFA is effective for locoregional control of metastatic well-differentiated thyroid carcinoma in patients for whom surgery is infeasible. PMID- 21785062 TI - C-arm CT for assessing initial failure of iodized oil accumulation in chemoembolization of hepatocellular carcinoma. AB - OBJECTIVE: The purpose of our study was to assess the feasibility of using C-arm CT to detect incomplete accumulation of iodized oil in hepatocellular carcinoma immediately after transarterial chemoembolization (TACE). MATERIALS AND METHODS: This retrospective study included 80 hepatocellular carcinoma lesions in 55 patients (41 men and 14 women; mean age, 69.2 years; mean tumor size, 18.1 mm [range, 5-55 mm]) who underwent TACE with a flat-detector C-arm angiographic system. C-arm CT images were acquired at the end of each session, and unenhanced MDCT images were obtained 7 days later. Two independent observers scored both sets of images, using a predefined detection scale for incomplete iodized oil accumulation. The accuracy for predicting residual lesions was compared using the area under the receiver-operating characteristic curve (A(z)). Contrast-enhanced CT findings obtained 1 month after TACE served as reference standards. RESULTS: Viable lesions were observed in 18 of the 80 study lesions by contrast-enhanced CT. The accuracy of the C-arm CT (A(z) = 0.816) was not significantly different (p = 0.449) from that of the MDCT (A(z) = 0.841). Sensitivity, specificity, and positive and negative predictive values for C-arm CT (80.5%, 74.2%, 47.5%, and 92.9%, respectively) and MDCT (86.1%, 75.0%, 50.0%, and 94.9%, respectively) did not differ significantly. CONCLUSION: C-arm CT is nearly equivalent to MDCT for detecting incomplete iodized oil accumulation after TACE, suggesting that the immediate assessment of iodized oil accumulation with C-arm CT without the need to perform follow-up unenhanced MDCT is likely feasible. PMID- 21785063 TI - Moxifloxacin prophylaxis for chemoembolization or embolization in patients with previous biliary interventions: a pilot study. AB - OBJECTIVE: Abscess formation is a common serious adverse event after intraarterial therapy for hepatic malignancy in patients with colonized bile ducts. The combination of antibiotic prophylaxis and bowel preparation has been used to prevent hepatic abscess. We describe our outcomes with moxifloxacin prophylaxis alone without bowel preparation. CONCLUSION: Ten patients underwent 25 procedures and were followed for a median of 250 days. No abscesses developed. Our results suggest moxifloxacin alone may suffice for prophylaxis. PMID- 21785064 TI - Preliminary clinical experience at 3 T with a 3D T2-weighted sequence compared with multiplanar 2D for evaluation of the female pelvis. AB - OBJECTIVE: The purpose of this article is to compare 3D T2-weighted sampling perfection with application-optimized contrast with different flip-angle evolutions (SPACE) with three-plane 2D turbo-spin echo (TSE) sequences for female pelvic imaging at 3 T. MATERIALS AND METHODS: Twenty women were imaged with 2D TSE and 3D SPACE sequences. Three radiologists independently assessed image quality, diagnostic quality, and artifacts; measured normal anatomic structures; evaluated pathologic abnormalities; and recorded interpretation time. Readers subsequently performed a side-by-side comparison, and their preferences were graded according to overall interpretation, sharpness of lesion edges, motion and other artifacts, uterine and cervical zonal anatomy distinction, identification of adnexal pathologic abnormalities, and distinction between fat and fluid. Quantitative comparison of relative signal intensity and relative tissue contrast was performed. RESULTS: The mean acquisition time of 3D SPACE was significantly shorter than that of 2D TSE (6 minutes 35 seconds vs 8 minutes 50 seconds; p < 0.005). Intrareader agreement between interpretations of 2D and 3D sequences was excellent. There were no significant differences among readers in detecting artifacts, normal structures, and pathologic abnormalities or in determining endometrial thickness, image quality, or interpretation time (p > 0.05). Except for distinctions between fat and fluid, the average reader score indicated a slight preference for the 3D sequence. Three-dimensional multiplanar reconstructions were helpful but not considered essential. Relative agreement between readers was moderate (r >= 0.4) to strong (r >= 0.7). The relative signal intensity was higher for fat and bladder fluid on the 3D sequence than on the 2D sequence (p = 0.014 and p = 0.018, respectively). Relative tissue contrast was higher for the 3D sequence (p < 0.05), with no significant difference in bladder or fat contrast (p = 0.31) but a trend toward more superior contrast on the 2D sequence. CONCLUSION: At 3 T, 3D SPACE has similar image quality and diagnostic quality with shorter scan time when compared with 2D TSE but with reduced contrast between fat and fluid. PMID- 21785065 TI - Microcalcifications around a collagen-based breast biopsy marker: complication of biopsy with a percutaneous marking system. AB - OBJECTIVE: The purpose of this article is to present the cases of four women who underwent percutaneous breast biopsy with deployment of a titanium metallic marker embedded in a bioresorbable collagen plug. Routine follow-up mammography after benign pathologic results were obtained revealed new fine microcalcifications at the biopsy sites, requiring repeat biopsy. Pathologic examination confirmed the presence of microcalcifications associated with an acidophilic foreign material. CONCLUSION: Awareness that development of microcalcifications can complicate biopsy performed with collagen-based markers is important for correct mammographic interpretation and management. PMID- 21785066 TI - Standard of care for nonradiologist interpretations. PMID- 21785067 TI - Informed consent for contrast media and gadolinium injections. PMID- 21785068 TI - Diagnosis of soft-tissue masses. PMID- 21785069 TI - Treatment of calcific tendinitis of the rotator cuff by ultrasound-guided single needle lavage technique. PMID- 21785070 TI - Patient selection and study indications for shoulder ultrasound. PMID- 21785071 TI - Contrast-enhanced ultrasound for characterizing lymph nodes with focal cortical thickening in patients with cutaneous melanoma. PMID- 21785072 TI - Fat-fluid intravessical level: a new sign of bladder rupture. PMID- 21785073 TI - FDG PET/CT in patients with HIV. AB - OBJECTIVE: This article will discuss the (18)F-FDG normal variant uptake and the role of FDG PET/CT in malignancies in HIV-infected patients, CNS manifestations of HIV, assessing fever of unknown origin in HIV patients, assessing response to highly active antiretroviral therapy and assessing complications. CONCLUSION: FDG PET/CT is a valuable imaging study in the management of HIV-infected patients. PMID- 21785074 TI - Molecular imaging in pulmonary diseases. AB - OBJECTIVE: In this article, we consider a multitude of the latest techniques used for evaluating benign and malignant pulmonary diseases. Our review will include mostly clinically pertinent studies, but we have also included breakthrough basic science research that has potentially significant clinical implications. CONCLUSION: Molecular imaging enables noninvasive visualization and measurement of the dynamic molecular processes within living organisms. Early recognition of molecular and cellular malfunctions can help optimize diagnostic and therapeutic strategies. PMID- 21785075 TI - Multimodality molecular imaging of apoptosis in oncology. AB - OBJECTIVE: The purposes of this review are to describe the signaling pathways of and the cellular changes that occur with apoptosis and other forms of cell death, summarize tracers and modalities used for imaging of apoptosis, delineate the relation between apoptosis and inhibition of protein translation, and describe spectroscopic technologies that entail high-frequency ultrasound and infrared and midinfrared light in characterizing the intracellular events of apoptosis. CONCLUSION: Apoptosis is a highly orchestrated set of biochemical and morphologic cellular events. These events present many potential targets for the imaging of apoptosis in vivo. Imaging of apoptosis can facilitate early assessment of anticancer treatment before tumor shrinkage, which may increase the effectiveness of delivery of chemotherapy and radiation therapy and speed drug development. PMID- 21785076 TI - Molecular theranostics: a primer for the imaging professional. AB - OBJECTIVE: A theranostic system integrates some form of diagnostic testing to determine the presence of a molecular target for which a specific drug is intended. Molecular imaging serves this diagnostic function and provides powerful means for noninvasively detecting disease. We briefly review the paradigms rooted in nuclear medicine and highlight recent advances in this field. We also explore how nanometer-sized complexes, called nanomedicines, present an excellent theranostic platform applicable to both drug discovery and clinical use. CONCLUSION: For imagers, molecular theranostics represents a powerful emerging platform that intimately couples targeted therapeatic entities with noninvasive imaging that yields information on the presence of defined molecular targets before, during, and after cognate therapy. PMID- 21785077 TI - Key variables for interpreting 99mTc-mercaptoacetyltriglycine diuretic scans: development and validation of a predictive model. AB - OBJECTIVE: The purpose of this study was to facilitate interpretation of (99m)Tc mercaptoacetyltriglycine (MAG3) diuretic scans by identifying key interpretative variables and developing a predictive model for computer-assisted diagnosis. MATERIALS AND METHODS: Ninety-seven studies were randomly selected from an archived database of MAG3 baseline and furosemide acquisitions and scan interpretations (obstruction, equivocal finding, or no obstruction) derived from a consensus of three experts. Sixty-one studies (120 kidneys) were randomly chosen to build a predictive model for diagnosing or excluding obstruction. The other 36 studies (71 kidneys) composed the validation group. The probability of normal drainage (no obstruction) at the baseline acquisition and the probability of no obstruction, equivocal finding, or obstruction after furosemide administration were determined by logistic regression analysis and proportional odds modeling of MAG3 renographic data. RESULTS: The single most important baseline variable for excluding obstruction was the ratio of postvoid counts to maximum counts. Renal counts in the last minute of furosemide acquisition divided by the maximum baseline acquisition renal counts and time to half-maximum counts after furosemide administration in a pelvic region of interest were the critical variables for determining obstruction. The area under the receiver operating characteristic curve (AUC) for predicting normal drainage in the validation sample was 0.93 (standard error, 0.02); sensitivity, 85%; specificity, 93%. The AUC for the diagnosis of obstruction after furosemide administration was 0.84 (standard error, 0.06); sensitivity, 82%; specificity, 83%. CONCLUSION: A predictive system has been developed that provides a promising computer-assisted diagnosis approach to the interpretation of MAG3 diuretic renal scans; this system has also identified the key variables required for scan interpretation. PMID- 21785078 TI - Radiofrequency ablation of medically inoperable stage IA non-small cell lung cancer: are early posttreatment PET findings predictive of treatment outcome? AB - OBJECTIVE: The purpose of this study was to evaluate initial experience with (18)F-FDG PET/CT after pulmonary radiofrequency ablation of stage IA non-small cell lung cancer to determine whether treatment success or residual disease can be predicted with early postablation PET. SUBJECTS AND METHODS: Thirty patients with medically inoperable stage IA non-small cell lung cancer (12 men, 18 women; median age, 76 years; range, 60-87 years) underwent outpatient CT-guided radiofrequency ablation over a 33-month period. Mean tumor size was 2.0 cm (range, 1.3-2.9 cm). PET/CT was performed within 60 days before radiofrequency ablation (RFA), within 4 days after RFA, and 6 months after RFA. Metabolic response was categorized as complete response or partial or no response at early post-RFA PET/CT and complete response, partial response, or progressive metabolic disease at 6-month post-RFA PET/CT and was compared with the 1-year clinical event rate (death, disease progression at contrast-enhanced CT, or repeat ablation). RESULTS: Early PET/CT images, obtained within 4 days of RFA, were evaluable for 26 patients (23 at 6 months). Patients with a complete metabolic response at early PET/CT had a 1-year event rate of 43%, whereas those with partial or no response or disease progression had a 1-year event rate of 67% (p = 0.27). Patients with a complete metabolic response at 6-month PET/CT had a 1-year event rate of 0%. Those with a partial response and those with disease progression had an overall event rate of 75% (p = 0.001). CONCLUSION: Early post RFA PET/CT is not necessary and 6-month post-RFA PET/CT findings correlate better with clinical outcome at 1 year. PMID- 21785079 TI - Clinical significance of incidental finding of focal activity in the breast at 18F-FDG PET/CT. AB - OBJECTIVE: The purpose of this study was to determine the clinical significance of the incidental finding of hypermetabolic foci in the breast at (18)F-FDG PET/CT in patients with malignant disease other than breast cancer or during a screening examination. MATERIALS AND METHODS: The files of 13,897 women who underwent FDG PET/CT from November 2004 to October 2009 were retrospectively reviewed. Forty-eight patients with incidental breast uptake had undergone either tissue confirmation or clinical follow-up with additional sonographic imaging. The following four variables were evaluated: age, maximum standard uptake value (SUV(max)) of breast uptake at FDG PET, findings in the CT portion of PET/CT, and sonographic findings. Malignancy rates were calculated for each variable. RESULTS: Malignancy was diagnosed in 18 (37.5%) patients and a benign condition in 30 (62.5%) patients. Statistically significant differences in malignancy rate were found between the groups with SUV(max) less than 2 (24.2%) and the group with SUV(max) of 2 or greater (66.7%) and between the group with lesions in a BI RADS ultrasound category lower than 4 (10.7%) and the group with lesions in category 4 or higher (75.0%) (p < 0.05). There was no significant difference in malignancy rates between the groups younger than 45 years (11.1%) and 45 years and older (53.3%) or between the group with lesions in a BI-RADS category lower than 4 (30.2%) and that with lesions in category 4 or higher (100%) on the CT portion of PET/CT. CONCLUSION: Incidental hypermetabolic foci in the breast may represent malignancy in as many as 37.5% of cases. The SUV(max) and sonographic findings can be useful for differentiating benign from malignant lesions. PMID- 21785080 TI - Extranodal lymphoma from head to toe: part 1, the head and spine. AB - OBJECTIVE: Lymphoma can affect virtually every tissue in the body, producing a variety of imaging appearances. In this article, the extranodal manifestations of lymphoma in the head and spine are illustrated and the imaging features that aid in diagnosis are reviewed. CONCLUSION: Knowledge of the imaging appearances of extranodal lymphoma can aid in the differential diagnosis of mass lesions encountered in tissues throughout the body on different imaging modalities. PMID- 21785081 TI - Extranodal lymphoma from head to toe: part 2, the trunk and extremities. AB - OBJECTIVE: Lymphoma can affect virtually every tissue in the body, producing a variety of imaging appearances. In this article, the extranodal manifestations of this disease in the trunk and extremities are illustrated and the imaging features that aid in the diagnosis are reviewed. CONCLUSION: Knowledge of the imaging appearances of extranodal lymphoma can aid the differential diagnosis of mass lesions encountered in tissues throughout the body on different imaging modalities. PMID- 21785082 TI - Breast surface radiation dose during coronary CT angiography: reduction by breast displacement and lead shielding. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate the effect of cranial breast displacement and lead shielding on in vivo breast surface radiation dose in women undergoing coronary CT angiography. SUBJECTS AND METHODS: Fifty-four women (mean age, 59.2 +/- 9.8 years) prospectively underwent coronary 64-MDCT angiography for evaluation of chest pain. The patients were randomly assigned to a control group (n = 16), breast displacement group (n = 22), or breast displacement plus lead shielding group (n = 16). Thermoluminescent dosimeters (TLDs) were placed superficially on each breast quadrant and the areolar region of both breasts. Breast surface radiation doses, the degree of breast displacement, and coronary image quality were compared between groups. A phantom dose study was conducted to compare breast doses with z-axis positioning on the chest wall. RESULTS: A total of 1620 TLD dose measurements were recorded. Compared with control values, the mean breast surface dose was reduced 23% in the breast displacement group (24.3 vs 18.6 mGy, p = 0.015) and 36% in the displacement plus lead shielding group (24.3 vs 15.6 mGy, p = 0.0001). Surface dose reductions were greatest in the upper outer (displacement alone, 66%; displacement plus shielding, 63%), upper inner (65%, 58%), and areolar quadrants (44%, 53%). The smallest surface dose reductions were recorded for A-cup breasts: 7% for the displacement group and 3% for the displacement plus lead group (p = 0.741). Larger reductions in surface dose were recorded for B-cup (25% and 56%, p = 0.273), C-cup (38% and 60%, p = 0.001), and D-cup (31% and 25%, p = 0.095) sizes. Most of the patients (79%) had either good (< 50% of breast above scan range) or excellent (< 75% of breast above the scan range) breast displacement. No significant difference in coronary image quality was detected between groups. The phantom dose study showed that surface TLD measurements were underestimates of absorbed tissue dose by a mean of 9% and that a strong negative correlation exists between the amount of cranial displacement and breast dose. CONCLUSION: Use of breast displacement during coronary CTA substantially reduces the radiation dose to the breast surface. PMID- 21785083 TI - Use of 2D sensitivity encoding for slow-infusion contrast-enhanced isotropic 3-T whole-heart coronary MR angiography. AB - OBJECTIVE: The purpose of this study was to improve the blood-pool signal-to noise ratio (SNR) and blood-myocardium contrast-to-noise ratio (CNR) of slow infusion 3-T whole-heart coronary MR angiography (MRA). SUBJECTS AND METHODS: In 2D sensitivity encoding (SENSE), the number of acquired k-space lines is reduced, allowing less radiofrequency excitation per cardiac cycle and a longer TR. The former can be exploited for signal enhancement with a higher radiofrequency excitation angle, and the latter leads to noise reduction due to lower data sampling bandwidth. Both effects contribute to SNR gain in coronary MRA when spatial and temporal resolution and acquisition time remain identical. Numeric simulation was performed to select the optimal 2D SENSE pulse sequence parameters and predict the SNR gain. Eleven patients underwent conventional unenhanced and the proposed 2D SENSE contrast-enhanced coronary MRA acquisition. Blood-pool SNR, blood-myocardium CNR, visible vessel length, vessel sharpness, and number of side branches were evaluated. RESULTS: Consistent with the numeric simulation, using 2D SENSE in contrast-enhanced coronary MRA resulted in significant improvement in aortic blood-pool SNR (unenhanced vs contrast-enhanced, 37.5 +/- 14.7 vs 121.3 +/ 44.0; p < 0.05) and CNR (14.4 +/- 6.9 vs 101.5 +/- 40.8; p < 0.05) in the patient sample. A longer length of left anterior descending coronary artery was visualized, but vessel sharpness, coronary artery coverage, and image quality score were not improved with the proposed approach. CONCLUSION: In combination with contrast administration, 2D SENSE was found effective in improving SNR and CNR in 3-T whole-heart coronary MRA. Further investigation of cardiac motion compensation is necessary to exploit the SNR and CNR advantages and to achieve submillimeter spatial resolution. PMID- 21785084 TI - Comparative evaluation of the modified CT severity index and CT severity index in assessing severity of acute pancreatitis. AB - OBJECTIVE: The purpose of this study was to compare the modified CT severity index (MCTSI) with the CT severity index (CTSI) regarding assessment of severity parameters in acute pancreatitis (AP). Both CT indexes were also compared with the Acute Physiology, Age, and Chronic Health Evaluation (APACHE II) index. MATERIALS AND METHODS: Of 397 consecutive cases of AP, 196 (49%) patients underwent contrast-enhanced CT (n = 175) or MRI (n = 21) within 1 week of onset of symptoms. Two radiologists independently scored both CT indexes. Severity parameters included mortality, organ failure, pancreatic infection, admission to and length of ICU stay, length of hospital stay, need for intervention, and clinical severity of pancreatitis. Discrimination analysis and kappa statistics were performed. RESULTS: Although for both CT indexes a significant relationship was observed between the score and each severity parameter (p < 0.0001), no significant differences were seen between the CT indexes. Compared with the APACHE II index, both CT indexes more accurately correlated with the need for intervention (CTSI, p = 0.006; MCTSI, p = 0.01) and pancreatic infection (CTSI, p = 0.04; MCTSI, p = 0.06) and more accurately diagnosed clinically severe disease (area under the curve, 0.87; 95% CI, 0.82-0.92). Interobserver agreement was excellent for both indexes: for CTSI, 0.85 (95% CI, 0.80-0.90) and for MCTSI, 0.90 (95% CI, 0.85-0.95). CONCLUSION: No significant differences were noted between the CTSI and the MCTSI in evaluating the severity of AP. Compared with APACHE II, both CT indexes more accurately diagnose clinically severe disease and better correlate with the need for intervention and pancreatic infection. PMID- 21785085 TI - Angiotensin-converting enzyme inhibitor-induced small-bowel angioedema: clinical and imaging findings in 20 patients. AB - OBJECTIVE: The purpose of this article is to retrospectively review the radiologic and clinical findings in patients with angiotensin-converting enzyme inhibitor (ACEI)-induced small-bowel angioedema, with an emphasis on CT findings. MATERIALS AND METHODS: Imaging findings, with an emphasis on CT, and clinical characteristics of 20 patients (23 presentations) presenting to two institutions' emergency departments from 1996 through 2010 with ACEI-induced small-bowel angioedema were retrospectively reviewed by two abdominal radiologists who were aware of the diagnosis. Examinations were reviewed in consensus to determine common radiographic findings. RESULTS: Patient age range was 23-83 years (mean, 56 years). Sixteen of the 20 patients were women, and 15 of 20 were obese. All had acute onset of severe abdominal pain. The date of the initial episode prompting CT evaluation ranged from 2 days to 10 years after the start of ACEI therapy (average, 3.3 years). All patients underwent abdominal CT examinations while symptomatic; five patients also underwent a small-bowel series. Three patients underwent urgent surgery for presumed small-bowel ischemia. All patients had resolution of symptoms within 4 days of hospitalization. CT findings included ascites in all patients, small-bowel wall thickening (mean, 1.3 cm), mild dilatation (mean, 2.9 cm), and straightening. There was no small-bowel obstruction. CONCLUSION: ACEI-induced small-bowel angioedema should be included in the differential diagnosis when patients receiving ACEI therapy present with abdominal complaints and the following combination of findings on CT examination: ascites, small-bowel wall thickening, dilatation without obstruction, and straightening. PMID- 21785086 TI - Gadoxetate disodium-enhanced hepatobiliary phase MRI of hepatocellular carcinoma: correlation with histological characteristics. AB - OBJECTIVE: The purpose of this study was to assess whether gadoxetate disodium enhanced hepatobiliary phase MRI could predict the histologic factors of hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Fifty-three HCCs histopathologically proved by surgery in 51 patients were evaluated retrospectively. All patients underwent gadoxetate disodium-enhanced MRI before surgical resection. The differences in contrast enhancement ratio of the lesions and differences in contrast-to-noise ratio (CNR) among the histologic grades of HCC were compared by using the Kruskal-Wallis test. The Spearman method was used to determine the correlations among contrast enhancement ratio, CNR, cell density ratio, and positivity for anti-hepatocyte antibody, keratin 7, and keratin 19. RESULTS: Of 53 HCCs, 50 showed low signal intensity on hepatobiliary phase images, whereas three HCCs were hyperintense on hepatobiliary phase images compared with surrounding hepatic parenchyma. Although well-differentiated HCCs tended to show higher contrast enhancement, there was no statistical significance between contrast enhancement ratio of the tumors and histologic grade (p = 0.414). No significant difference was observed between CNR and histologic grade (p = 0.965). The contrast enhancement ratios of the tumors were significantly lower in the keratin 19-positive group than in the keratin 19-negative group (p = 0.015). There was no significant correlation among contrast enhancement ratio, anti-hepatocyte antibody positivity, cell density ratio, and keratin 7 positivity (p > 0.05). CONCLUSION: The contrast enhancement ratio and CNR of HCCs were not correlated with histologic grades. The contrast enhancement ratio was significantly lower in keratin 19-positive HCCs. PMID- 21785087 TI - Locally recurrent prostate cancer after high-dose-rate brachytherapy: the value of diffusion-weighted imaging, dynamic contrast-enhanced MRI, and T2-weighted imaging in localizing tumors. AB - OBJECTIVE: The purpose of this article is to retrospectively evaluate the utility of prostate MRI for detecting locally recurrent prostate cancer after high-dose rate (HDR) brachytherapy. MATERIALS AND METHODS: Sixteen men with biochemical failure after HDR brachytherapy for prostate cancer underwent prostate MRI, including T2-weighted imaging, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI), using a 1.5-T MRI unit before 12-core-specimen biopsy. Two radiologists in consensus assessed the presence of tumor on each sequence within eight regions of the prostate (six from the peripheral zone [PZ] and two from the transition zone [TZ]) on the basis of biopsy. RESULTS: Biopsy revealed locally recurrent prostate cancer in 22 (17 in PZ and five in TZ) of 128 regions (17.2%). The sensitivity, specificity, and accuracy of each MRI method in the detection of recurrent tumor were 27%, 99%, and 87%, respectively, for T2 weighted imaging; 50%, 98%, and 90%, respectively, for DCE-MRI; and 68%, 95%, and 91%, respectively, for DWI. The sensitivity of DWI in detecting recurrent tumor was significantly higher than that of T2-weighted imaging (p = 0.004). Multiparametric MRI achieved the highest sensitivity (77%) but with slightly decreased specificity (92%). CONCLUSION: These results indicate that a multiparametric MRI protocol that includes DWI provides a sensitive method to detect local recurrence after HDR brachytherapy. PMID- 21785088 TI - Characterization of adrenal lesions with 1.5-T MRI: preliminary observations on comparison of three in-phase and out-of-phase gradient-echo techniques. AB - OBJECTIVE: The purpose of this study was to use previously described quantitative evaluation methods to compare the performance of 3D gradient-recalled echo (GRE) and magnetization-prepared (MP) GRE in-phase and out-of phase sequences with standard 2D GRE technique in the characterization of adrenal lesions. MATERIALS AND METHODS: The study sample consisted of 44 consecutively registered patients (22 men, 22 women; mean age, 59.1 +/- 11.6 years) with 50 adrenal lesions who underwent standard abdominal MRI that included in-phase and out-of-phase 2D GRE (n = 41), 3D GRE (n = 35), MP GRE (n = 36), or a combination of these techniques. The adrenal signal intensity (SI) index and adrenal-to-spleen, adrenal-to-liver, and adrenal-to-muscle SI ratios of each lesion were calculated and compared for the three techniques by independent samples Student t test. The area under the receiver operating characteristic (ROC) curve (AUC) for each evaluation method was determined, and comparisons of independent ROC curves were performed for all sequences. RESULTS: For all sequences, the mean adrenal SI index and SI ratios of adenomas and nonadenomas differed significantly (p < 0.001). For the 3D GRE and MP GRE techniques, adrenal SI index and modified adrenal-to-spleen ratio, respectively, had the larger AUCs, but the difference was not statistically significant. Different thresholds for the three techniques were recommended for discriminating adenoma from nonadenoma. CONCLUSION: The results of characterization of adrenal lesions with MP GRE and 3D GRE in-phase and out-of phase MRI techniques are comparable to those obtained with the reference standard 2D GRE technique. Different thresholds should be selected according to the in phase and out-of-phase techniques used and for the various evaluation methods. PMID- 21785089 TI - Evaluation of upper urinary tract tumors with portal venous phase MDCT: a case control study. AB - OBJECTIVE: The purpose of this article is to assess the detection and negative prediction rate of upper urinary tract tumors in nonopacified urinary tracts on portal venous phase MDCT. MATERIALS AND METHODS: This retrospective case-control study included 20 patients with upper urinary tract tumors and 40 age- and sex matched control subjects. All studies were assessed independently by two reviewers. Reviewers determined whether each of four segments of the upper urinary tract could be fully visualized and whether tumor was present or absent. For each tumor, reviewers characterized its morphologic features (i.e., infiltrative or polypoid mass, urothelial thickening, and associated hydroureter or hydronephrosis). RESULTS: The detection rate of the proximal two upper urinary tract segments was significantly higher than that for the distal segments (p < 0.001). For each upper urinary tract, the sensitivity, specificity, and negative predictive value of portal venous phase MDCT for detecting tumors were 95%, 97%, and 100%, respectively. The positive predictive value for an estimated population prevalence of 0.0005-0.004 was 0.6-4.8%. The morphologic features significant for the presence of tumor were urothelial thickening and the presence of a discrete polypoid mass. Interobserver agreement for all features was good or very good, except for moderate agreement on urothelial thickening involving the ureter (kappa = 0.60). CONCLUSION: The detection rate of upper urinary tract tumors on nonopacified portal venous phase is high. Furthermore, in the absence of morphologic features suggestive of urothelial malignancy, a normal-appearing ureter may be reassuring. PMID- 21785091 TI - Image noise and liver lesion detection with MDCT: a phantom study. AB - OBJECTIVE: The purpose of this study was to determine the upper limit of noise for detection of small low-contrast lesions in a liver phantom. MATERIALS AND METHODS: A CT liver phantom containing 21 low-contrast, low-attenuation, circular simulated lesions ranging in size from 2.4 to 10 mm was scanned 23 times at different tube current ranges (varying noise index) on a 64-MDCT scanner with automatic tube current modulation. The attenuation of the simulated lesions was 20 HU less than that of the liver-equivalent background. Three radiologists independently reviewed the resultant CT images, which contained either a low contrast lesion or no lesion and scored certainty of lesion detection using a 4 point Likert scale. Overall performance was evaluated by sensitivity analysis with receiver operator curve and area under the curve (A(z)) computation for ranges of noise index. RESULTS: The reviewers achieved 100% sensitivity with a noise index of 15 or less for lesions measuring 6.3-10.0 mm (A(z) = 0.96). Increasing noise index to the 17-21 range resulted in a minor decrease in sensitivity and overall performance (sensitivity, 92.3%; A(z) = 0.93). A further increase in noise index to the 23-27 range resulted in a moderate decrease in sensitivity (sensitivity, 81.4%; A(z) = 0.77). Beyond the noise index 23-27 range, sensitivity dropped markedly from 81.4% to 39%. Agreement between the three readers in assessing the image sets was moderate. CONCLUSION: For detection of small low-contrast lesions in the liver phantom model used in this study, the upper limit of noise index may be in the 15-21 range for sensitivity greater than 90%. PMID- 21785090 TI - Detection of renal dysfunction by point-of-care creatinine testing in patients undergoing peripheral MR angiography. AB - OBJECTIVE: The objective of our study was to analyze the effectiveness of prestudy questionnaires in identifying at-risk patients and estimate the prevalence of chronic kidney disease (CKD), nephrogenic systemic fibrosis risk factors, and other comorbidities in patients scheduled to undergo lower extremity MR angiography (MRA) studies using gadolinium-based contrast agents. MATERIALS AND METHODS: Patent demographics, comorbidities, contrast type, and point-of-care (POC) serum creatinine values were recorded from the medical records of consecutive patients undergoing lower extremity MRA examinations in a single year. Patients were divided into groups by CKD stage (non-CKD, stage III, stage IV, or stage V) on the basis of estimated glomerular filtration rate values determined from POC creatinine results. Patient awareness of a history of CKD was noted if patients admitted to any form of CKD on prestudy questionnaires. RESULTS: Of 199 patients, 72 patients (36.2%) had stage III CKD, six patients (3.0%) had stage IV CKD, and seven patients (3.5%) had stage V CKD. Comorbidities including smoking status, transplant status, and presence of diabetes, hypertension, and coronary artery disease-as well as administered contrast type and dosage showed significant differences among the CKD groups (p < 0.05). Only five stage III patients (7%) were aware of any history of renal dysfunction, whereas three stage IV patients (50%) and seven stage V patients (100%) admitted any history of renal dysfunction via questionnaires. CONCLUSION: Compared with POC creatinine testing, a prestudy questionnaire used alone is ineffective in identifying all patients with histories of CKD who are scheduled to undergo gadolinium-based peripheral MRA studies. PMID- 21785092 TI - MRI of the knee ligaments and menisci: comparison of isotropic-resolution 3D and conventional 2D fast spin-echo sequences at 3 T. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of sampling perfection with application-optimized contrasts using different flip angle evolutions (SPACE) 3D fast spin-echo acquisition relative to conventional 2D fast spin-echo acquisition in the 3-T MRI evaluation of the menisci and ligaments of the knee. MATERIALS AND METHODS: Images from all MRI knee examinations performed with a single 3-T system from September 2008 to January 2009 were reviewed. Seventy-one examinations of patients who subsequently underwent knee arthroscopy and an additional 29 examinations of patients who did not undergo surgery were selected for a total of 100 examinations. All imaging was performed with multiplanar conventional 2D and SPACE 3D fast spin-echo acquisitions. Six musculoskeletal radiologists independently reviewed the images. Area under the receiver operating characteristic (ROC) curve was calculated for the menisci and anterior cruciate ligament with arthroscopy as the reference standard. Disagreement between the two acquisitions was calculated for the posterior cruciate ligament and medial and lateral collateral ligaments. The Wilcoxon signed rank test was used to compare each reader's confidence scores for the two techniques. RESULTS: For the medial meniscus, the average area under the ROC curve was statistically significantly larger (p = 0.01) with the conventional 2D (0.931) than with the SPACE 3D (0.893) technique. Average confidence in diagnosing medial meniscal tears also was statistically significantly greater with the 2D than with the 3D technique (p = 0.001). No statistically significant differences were found for the lateral meniscus or anterior cruciate ligament. The rate of discordance between findings with the 2D and 3D techniques was low for the posterior cruciate ligament and medial and lateral collateral ligaments (range, 4.2-5.7%). CONCLUSION: In evaluation of menisci with 3-T MRI, readers performed better with conventional 2D acquisition than with SPACE 3D acquisition. In evaluation of ligaments, the readers had similar performance with the two acquisition methods. PMID- 21785093 TI - New vertebral compression fractures after prophylactic vertebroplasty in osteoporotic patients. AB - OBJECTIVE: Previous studies have shown the possible efficacy of prophylactic cement injection for nonfractured vertebrae during percutaneous vertebroplasty for compression fractures. The purpose of this study was to investigate risk factors for subsequent fractures after prophylactic percutaneous vertebroplasty. MATERIALS AND METHODS: This retrospective study included 116 patients with osteoporotic compression fractures who underwent prophylactic percutaneous vertebroplasty. The patients were monitored with physical examinations and radiographs at 1 day and at 3 and 12 months after percutaneous vertebroplasty, and if back pain recurred. We analyzed the following multiple covariates to determine whether they were associated with recurrence: age, sex, steroid use, and the preoperative number of unhealed or chronic compression fractures. RESULTS: Subsequent fractures in any vertebra occurred within 3 months after the procedure at 26 vertebrae in 21 patients (18.1%), and 36 occurred in 28 patients (24.1%) within 12 months. The occurrence of subsequent fractures within 12 months depended on the preoperative number of unhealed vertebrae: the occurrence rate was 16.9% (11/65) for one vertebra, 27.0% (10/37) for two vertebrae, and 50.0% (7/14) for three or more vertebrae. The incidence of subsequent fractures was significantly higher in patients with three or more fractures than in those with one fracture (p < 0.05). There were no statistically significant differences for the other factors. CONCLUSION: Patients with three or more fractures tended to have subsequent fractures, despite undergoing prophylactic percutaneous vertebroplasty. However, there was no increased risk of subsequent fractures related to prophylactic percutaneous vertebroplasty. PMID- 21785094 TI - Revisiting CT-guided percutaneous core needle biopsy of musculoskeletal lesions: contributors to biopsy success. AB - OBJECTIVE: The purpose of this article is to investigate potential technical, imaging, and histopathologic contributors to the success of CT biopsy. MATERIALS AND METHODS: Four hundred forty-four consecutive CT biopsies of musculoskeletal lesions performed from 2005 to 2008 were retrospectively classified as diagnostic or nondiagnostic and as accurate or inaccurate. A biopsy was considered as diagnostic if it provided a definitive pathologic diagnosis or was clinically useful; as accurate if it was concordant with the ultimate diagnosis with respect to identification of malignancy, grade, and histopathologic features; and as successful if it was both diagnostic and accurate. Biopsy success rate, diagnostic yield, and accuracy were assessed according to lesion location, use of sedation, biopsy equipment type, bone lesion matrix type, and lesion histologic type (i.e., bone or soft-tissue origin, malignant or benign neoplasm, and low-or intermediate-to-high-grade neoplasm). RESULTS: Of 444 biopsies, 71% were diagnostic, 86% were accurate, and 70% were successful. Biopsy success and diagnostic yield were greater in bone lesions, malignant neoplasms, and intermediate-to-high-grade neoplasms compared with soft-tissue lesions (p < 0.01), benign neoplasms (p < 0.0001), and low-grade neoplasms (p < 0.0001). Success and diagnostic yield were not significantly associated with technical or imaging factors. Biopsy accuracy was not associated with any of the tested variables. Of the 128 nondiagnostic biopsy results, 53% were accurate with respect to subsequent surgical pathologic findings. Most of these biopsy results were of benign soft-tissue lesions. CONCLUSION: CT biopsy of musculoskeletal lesions is accurate and effective. It may be limited in the evaluation of benign and low-grade soft-tissue neoplasms. PMID- 21785095 TI - Screening cervical spine CT in a level I trauma center: overutilization? AB - OBJECTIVE: The objective of our study was to analyze the use of screening cervical spine CT performed after trauma and establish the opportunity of potentially avoidable studies when evidence-based clinical criteria are applied before imaging. MATERIALS AND METHODS: All cervical spine CT examinations performed in the emergency department of a level 1 trauma center between January and December 2008 on adult patients with trauma were analyzed; 1589 studies were evaluated. Radiology reports and clinical data were reviewed for the presence of fracture or ligamentous injury and for the mode of injury. We also looked for documentation of clinical criteria used to perform the CT study. In particular, we looked for mention of posterior midline cervical tenderness, focal neurologic deficit, level of alertness, evidence of intoxication, and clinically apparent distracting injury. These five criteria were established by the National Emergency X-Radiography Utilization Study (NEXUS) to identify patients with a low probability of cervical spine injury who consequently needed no cervical spine imaging. RESULTS: Of the 1589 studies reviewed, 41 (2.6%) were positive for an acute cervical spine injury and 1524 (95.9%) were negative. The remaining 24 studies (1.5%) were indeterminate on the initial CT examination but subsequent imaging and clinical follow-up failed to show acute injury. Of the 1524 examinations with no acute injury, 364 (23.9%) had no documentation of any of the five NEXUS low-risk criteria. CONCLUSION: The strict application of the NEXUS low risk criteria could potentially reduce the number of screening cervical spine CT examinations in the setting of trauma in more than 20% of cases, thereby avoiding a significant amount of unnecessary radiation and significant cost. PMID- 21785096 TI - The relative effect of vendor variability in CT perfusion results: a method comparison study. AB - OBJECTIVE: There are known interoperator, intraoperator, and intervendor software differences that can influence the reproducibility of quantitative CT perfusion values. The purpose of this study was to determine the relative impact of operator and software differences in CT perfusion variability. MATERIALS AND METHODS: CT perfusion imaging data were selected for 11 patients evaluated for suspected ischemic stroke. Three radiologists each independently postprocessed the source data twice, using four different vendor software applications. Results for cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) were recorded for the lentiform nuclei in both hemispheres. Repeated variables multivariate analysis of variance was used to assess differences in the means of CBV, CBF, and MTT. Bland-Altman analysis was used to assess agreement between pairs of vendors, readers, and read times. RESULTS: Choice of vendor software, but not interoperator or intraoperator disagreement, was associated with significant variability (p < 0.001) in CBV, CBF, and MTT. The mean difference in CT perfusion values was greater for pairs of vendors than for pairs of operators. CONCLUSION: Different vendor software applications do not generate quantitative perfusion results equivalently. Intervendor difference is, by far, the largest cause of variability in perfusion results relative to interoperator and intraoperator difference. Caution should be exercised when interpreting quantitative CT perfusion results because these values may vary considerably depending on the postprocessing software. PMID- 21785097 TI - Pause and pulse: ten steps that help manage radiation dose during pediatric fluoroscopy. AB - OBJECTIVE: The Image Gently Campaign of The Alliance for Radiation Safety in Pediatric Imaging seeks to increase awareness of opportunities to lower radiation dose in the imaging of children. Pause and Pulse is the most recent phase of the campaign, addressing methods of dose optimization in pediatric fluoroscopy. CONCLUSION: This article discusses 10 steps that can be taken for fluoroscopic dose optimization in pediatric diagnostic fluoroscopy. PMID- 21785098 TI - Feasibility of using single-slice MDCT to evaluate visceral abdominal fat in an urban pediatric population. AB - OBJECTIVE: Obesity is a growing clinical problem, especially among children of low socioeconomic status. Increased visceral abdominal fat is implicated in the metabolic syndrome and its health consequences. The purpose of this study is to validate measurement of a single MDCT slice as a predictor of total visceral abdominal fat and to correlate over a wide range of body mass indexes (BMIs). MATERIALS AND METHODS: A two-phase retrospective analysis was performed. For validation, MDCTs of 21 consecutive healthy children (8-14 years old) were reviewed. In these cases, visceral abdominal fat and subcutaneous abdominal fat area were calculated using a body fat analysis function from single 0.625-mm MDCT slices at the umbilicus and were compared with total visceral abdominal fat area as measured from T11 to the coccyx. Subsequently, visceral abdominal fat area was obtained from single slices at the umbilicus from abdominal MDCT scans of 146 consecutive healthy children (age range, 6-14 years; 80 boys and 66 girls; 77 Hispanic, 41 African American, 15 white, and 13 multiracial or other race) for whom BMI was available. Associations between visceral abdominal fat area and sex, race, and BMI were determined. Effective radiation dose for a 1.25-mm axial MDCT slice was calculated using a mathematic model that uses derived scaling factors for pediatric patients. RESULTS: Visceral abdominal fat area obtained from a 0.625-mm slice at the umbilicus was highly correlated with total visceral abdominal fat area (r = 0.96; p < 0.0001). Visceral abdominal fat area from single slices at the umbilicus was significantly correlated with BMI (r = 0.72; p < 0.0001). Umbilical visceral abdominal fat area was significantly lower in African American children compared with others (median, 14 vs 22 cm(2); p = 0.02) and was not associated with sex. In our population, the effective radiation dose from the smallest obtainable slice was 0.015-0.019 mSv/37-54 kg of patient weight. CONCLUSION: Visceral abdominal fat area calculated from a single abdominal MDCT slice obtained in children is highly correlated with total visceral abdominal fat and with BMI and involves limited radiation exposure. PMID- 21785099 TI - Radiofrequency ablation combined with chemoembolization: treatment of recurrent hepatocellular carcinomas after hepatectomy. AB - OBJECTIVE: The purpose of this study is to evaluate the treatment effect and prognostic factors of radiofrequency ablation (RFA) combined with chemoembolization for patients with recurrent hepatocellular carcinomas (HCCs) after hepatectomy. MATERIALS AND METHODS: Fifty-five consecutive patients who received combination therapy as a curative treatment of recurrent HCCs after hepatectomy were included in this retrospective study. The mean maximum tumor diameter was 2.2 cm (range, 1.0-4.8 cm). Under CT fluoroscopic guidance, RFA was performed 1-2 weeks after chemoembolization. Technique effectiveness rates, complications, local tumor progression rates, survival rates, and prognostic factors were evaluated. RESULTS: Tumor enhancement disappeared on contrast enhanced CT images in all patients after 72 RFA sessions (technique effectiveness rate, 100%). Pneumothorax requiring chest drainage was the only major complication that developed in one RFA session (1%). Four of 55 patients (7%) showed local tumor progression. New tumors emerged in the untreated liver in 27 patients (49%) during the mean follow-up of 35 months (range, 1-82 months). The 5 year overall and recurrence-free survival rates after combination therapy were 74% (95% CI, 54-87%) and 28% (95% CI, 14-45%), respectively. The presence of a single tumor at initial hepatectomy and a low alpha-fetoprotein level (<= 100 ng/mL) at recurrence were significantly favorable independent factors affecting overall and recurrence-free survival. CONCLUSION: For treatment of recurrent HCCs after hepatectomy, RFA combined with chemoembolization is a useful therapeutic option. This study identified prognostic factors that will help to stratify patients with recurrent HCCs after hepatectomy. PMID- 21785100 TI - Transarterial prostatic embolization: initial experience in a canine model. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate pathologic responses to transarterial prostatic embolization and its technical safety in a canine model. MATERIALS AND METHODS: Ten adult male beagle dogs were surgically castrated and given hormonal therapy for 4 months to induce prostatic hyperplasia. After three months of hormonal therapy, the dogs were randomly assigned to a transarterial prostatic embolization group (n = 7) or a control group (n = 3). Dogs in the transarterial prostatic embolization group were subjected to embolization with microspheres 300-500 MUm in diameter. Four months after the study was begun, all dogs were sacrificed for pathologic study. Transrectal ultrasound and MRI were performed to evaluate pathologic responses. The data on prostate size acquired with transrectal ultrasound were processed for statistical analysis by paired Student t test. RESULTS: The canine prostatic hyperplasia model was successfully established in 10 dogs. The increase in mean prostate size being as great as 572% after 3 months of hormonal therapy. An intraprostatic cavity was detected 1 month after transarterial prostatic embolization in all seven dogs. Four dogs had significant shrinkage of the prostate, and the other three had an increase in prostate size. Imaging examinations and necropsy revealed a huge cavity occupying almost the entire prostate in the three dogs with increased prostate size. No complications associated with transarterial prostatic embolization were encountered. CONCLUSION: Transarterial prostatic embolization is a safe procedure that can induce prostatic infarction and ablate the prostate. The findings suggest the procedure has potential clinical applications in the care of patients with benign prostatic hyperplasia. PMID- 21785101 TI - Modified percutaneous transhepatic variceal embolization with 2 octylcyanoacrylate for bleeding gastric varices: long-term follow-up outcomes. AB - OBJECTIVE: The objective of our study was to evaluate the long-term efficacy and safety of a modified percutaneous transhepatic variceal embolization procedure with 2-octylcyanoacrylate (2-OCA) in the treatment of gastric variceal bleeding. MATERIALS AND METHODS: From January 2003 to December 2008, 71 patients with a history of gastric variceal bleeding underwent modified percutaneous transhepatic variceal embolization with 2-OCA in our hospital: 12 patients with acute gastric variceal bleeding underwent emergency obliteration and the remaining 59 patients with recent variceal bleeding underwent modified percutaneous transhepatic variceal embolization as a secondary prophylaxis. The initial hemostasis rate, rebleeding rate, survival rate, and complications were evaluated. RESULTS: Complete obliteration--that is, all the gastric varices and their feeding veins were obliterated--was achieved after the percutaneous transhepatic variceal embolization procedure in 67 patients (94.4%). Acute variceal bleeding was arrested after the procedure in all 12 patients (100%). The mean follow-up period was 24.2 +/- 12.4 (SD) months (range, 6-62 months). During the follow-up period, the cumulative probability of remaining free of gastric variceal rebleeding in patients with complete obliteration was 100%, 88.2%, and 88.2% at 1, 3, and 5 years after the procedure, respectively. Follow-up CT revealed that the modified percutaneous transhepatic variceal embolization procedure with 2-OCA can achieve long-lasting obliteration in the entire varices and in all the feeding veins. The cumulative survival rates at 1, 3, and 5 years after the procedure were 96.9%, 68.9%, and 53.7%. No severe complications occurred after the procedure. CONCLUSION: The modified percutaneous transhepatic variceal embolization with 2 OCA is considered to be an effective and safe method for the extensive and permanent obliteration of both gastric varices and their feeding veins. PMID- 21785102 TI - Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients' immediate response to radiofrequency ablation and cryoablation. AB - OBJECTIVE: The purpose of this article was to compare periprocedural analgesic requirements and hospital length of stay for treatment of patients with painful metastatic tumors involving bone using either percutaneous radiofrequency ablation (RFA) or cryoablation. MATERIALS AND METHODS: A retrospective review was conducted of patients who underwent either imaging-guided cryoablation or imaging guided RFA for painful metastatic tumors involving bone. The total analgesic usage for 24 hours after the procedure was expressed as a standard morphine equivalent dose. Analgesic usage at admission served as a baseline for comparison. Total hospital stay was used as an additional measurement of procedure-related morbidity. RESULTS: Fifty-eight patients underwent either cryoablation (n = 36) or RFA (n = 22) for painful metastatic tumors involving bone. Twenty-two primary tumors were treated. The most common treatment site was the pelvis (n = 31). There was no significant difference between the two groups with regard to tumor histologic type (p = 0.52) and location (p = 0.72). The median tumor diameter was 4.4 cm for the cryoablation group and 5.0 cm for the RFA group (p = 0.63). Pretreatment pain scores, measured on a scale of 0 to 10, were not significantly different between the two groups: 6.5 for cryoablation and 6.0 for RFA (p = 0.78). Analgesic use in the 24 hours immediately after the procedure decreased significantly by 24 morphine-equivalent doses after cryoablation, whereas it increased by a median of 22 morphine-equivalent doses after RFA (p = 0.03). Total hospital length of stay for patients undergoing cryoablation was a median of 2.5 days less than that for patients receiving RFA (p = 0.003). CONCLUSION: The use of cryoablation compared with RFA is associated with a greater reduction in analgesic dose and shorter hospital stays after the procedure in the perioperative time frame. PMID- 21785103 TI - Army doctor. PMID- 21785104 TI - Hip fractures and other problematic radiologic terminology. PMID- 21785105 TI - Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study. AB - AIMS: Atrial fibrillation (AF) is linked to cardiomyocyte apoptosis, leading to atrial remodelling and reduction in electrical conduction velocity. We hypothesized that genetic suppression of an apoptotic key enzyme, caspase 3, would prevent the development of persistent AF by reducing apoptosis which may serve as an arrhythmogenic substrate. METHODS AND RESULTS: Atrial fibrillation was induced in domestic pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Cas3 gene therapy to inactivate caspase 3 or green fluorescent protein (Ad-GFP) as a control. Adenoviruses were applied using a hybrid technique employing right and left atrial virus injection followed by epicardial electroporation to increase expression of plasmid DNA. In pigs treated with Ad-siRNA-Cas3, the onset of AF was suppressed or significantly delayed compared with controls (10.3 +/- 1.2 days vs. 6.0 +/- 1.6 days; P= 0.04). Electrical mapping revealed prolonged atrial conduction in the control group that was prevented by Ad-siRNA-Cas3 gene therapy. On the molecular level, Ad-siRNA-Cas3 application resulted in down-regulation of caspase 3 expression and suppression of apoptotic activity. CONCLUSION: Knockdown of caspase 3 by atrial Ad-siRNA-Cas3 gene transfer suppresses or delays the onset of persistent AF by reduction in apoptosis and prevention of intra-atrial conduction delay in a porcine model. These results highlight the significance of apoptosis in the pathophysiology of AF and demonstrate short-term efficacy of gene therapy for suppression of AF. PMID- 21785106 TI - Long-term prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. AB - AIMS: An association has been described between death from arrhythmia and early repolarization, an electrocardiogram pattern characterized by elevation of the QRS-ST junction (J-point). Little is known about this relationship in non-white populations. This study examines the relationship between J-point elevation (JPE) and sudden cardiac death (SCD) and whether this relationship differs by race or sex. METHODS AND RESULTS: A total of 15 141 middle-aged subjects from the prospective, population-based Atherosclerosis Risk in Communities (ARIC) study were included in this analysis. The primary endpoint was physician-adjudicated SCD occurring from baseline (1987-1989) through December 2002, secondary endpoints were fatal and non-fatal coronary events and all-cause mortality occurring through December 2007. J-point elevation was defined as J-point amplitude >= 0.1 mV. Pre-specified subgroup analyses by sex and race were conducted. J-point elevation in any lead was present in 1866 subjects (12.3%). After adjustment for demographic, clinical, lifestyle, and laboratory variables, JPE was not significantly related to SCD in the overall sample [adjusted hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.87-1.75]. However, significant interactions were present between race and JPE (P = 0.006) and between sex and JPE (P = 0.020). J-point elevation was significantly predictive of SCD in whites (adjusted HR, 2.03; 95% CI, 1.28-3.21) and in females (adjusted HR, 2.54; 95% CI, 1.34-4.82). CONCLUSION: Our results suggest that JPE is associated with an increased risk of SCD in whites and in females, but not in blacks or males. Further studies are needed to clarify which subgroups of individuals with JPE are at increased risk for adverse cardiac events. PMID- 21785107 TI - Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial. AB - AIM: To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. METHODS AND RESULTS: Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (<=40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr >=0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m2). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. CONCLUSION: The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated. PMID- 21785108 TI - Influence of left ventricular geometry and function on aortic annular dimensions as assessed with multi-detector row computed tomography: implications for transcatheter aortic valve implantation. AB - AIMS: Evaluate changes in aortic annular dimensions in relation to severe aortic stenosis (AS) and left ventricular (LV) dysfunction. METHODS AND RESULTS: Mean aortic annular diameters and geometries were compared between 90 severe AS patients and 111 controls by multi-detector row computed tomography (MDCT). All severe AS patients were also dichotomized into two groups based on the presence of preserved (>= 50%) or impaired (<50%) LV ejection fraction (EF). The influence of LV geometry and function on changes in aortic annular dimensions was examined. Patients with severe AS had similar aortic annular dimensions and geometries compared with controls even after correcting for baseline differences in age and body surface area (BSA). However, severe AS patients with LV dysfunction (LVEF <50%) had significantly larger mean aortic annular diameter (26.4 +/- 1.9 vs. 24.5 +/- 2.1 mm, P < 0.001) compared with patients with preserved LVEF. The presence of LV dysfunction, male gender, and larger BSA were independent determinants of a larger aortic annulus on MDCT. CONCLUSION: In severe AS patients, the presence of LV dysfunction, not the presence of severe AS, was an independent determinant of a larger aortic annular diameter. PMID- 21785109 TI - Worsening kidney function in decompensated heart failure: treat the heart, don't mind the kidney. PMID- 21785110 TI - Deficiency of type 1 cannabinoid receptors worsens acute heart failure induced by pressure overload in mice. AB - AIMS: We investigated the influence of type one cannabinoid receptor (CB1) deficiency on acute heart failure (AHF) and the underlying mechanism. Acute heart failure syndrome is an important clinical problem because of its high morbidity and mortality rates. Activation of CB1 induces vascular dilation and reinforces the properties of morphine, long-standing therapies for AHF syndrome, but the effect of endogenous CB1 activation on AHF is largely unknown. METHODS AND RESULTS: Acute heart failure mouse model characterized by hypertension and pulmonary oedema was created by using transverse aortic constriction (TAC). Mortality, echocardiography, haemodynamic, morphology, and circulatory catecholamine levels in response to TAC were evaluated in CB1 knockout (KO) and wild-type mice. Type one cannabinoid receptor KO mice had a much higher mortality rate at 1 week after TAC attributable to AHF (65 vs. 11%, P< 0.001). One hour after TAC, CB1 KO mice had significant larger lung weight to body weight ratio (LW/BW, 14.53 + 1.09 mg/g in KO vs. 10.42 + 0.36 mg/g in WT, P < 0.01) and higher plasma epinephrine levels (9720 + 1226 pg/mL vs. 6378 + 832 pg/mL, P < 0.05). Pharmacological activation of CB1 reduced LW/BW in wild-type mice. Administration of epinephrine to wild-type TAC mice significantly increased left ventricular end diastolic pressure and LW/BW, while CB1 agonists reduced the LW/BW and the plasma levels of catecholamine and increased myocardial activity of AMP-activated protein kinase. CONCLUSION: Endogenous activation of CB1 in mice has cardiac protection in AHF, which is attributable to the inhibition of excessive sympathetic activation. PMID- 21785111 TI - Silent myocardial ischaemia and long-term coronary artery disease outcomes in apparently healthy people from families with early-onset ischaemic heart disease. AB - AIMS: A family history of premature coronary artery disease (CAD) in an apparently healthy individual conveys an increased risk of future CAD. The extent to which inducible myocardial ischaemia exists and is associated with long-term incident CAD in apparently healthy siblings of early-onset CAD patients is unknown. METHODS AND RESULTS: Asymptomatic siblings (n = 1287, aged 30-59 years) of patients with onset of CAD <60 years of age underwent risk factor screening and maximal graded treadmill testing with nuclear perfusion imaging, and were followed for incident CAD events for up to 25 years. Incident CAD occurred in 15.2% of siblings (68% acute coronary syndromes); mean time to first CAD event was 8.2 +/- 5.2 years. Inducible ischaemia was highly prevalent in male siblings (26.9%), and was independently associated with incident CAD. Male siblings >= 40 years of age who were low or intermediate risk by traditional risk assessment, had a prevalence of inducible ischaemia and a 10-year risk of incident CAD that were near or >= 20%. In female siblings >= 40 years of age, the presence of inducible ischaemia was also independently associated with incident CAD, but the prevalence of inducible ischaemia was markedly lower, as was the risk of incident CAD. CONCLUSION: Inducible ischaemia is highly prevalent in male siblings, suggesting a previously unknown long quiescent period before the occurrence of a clinical event. While inducible ischaemia is associated with a worse prognosis, male siblings with negative tests still bear a high risk of incident disease, such that we propose that in male siblings over 40 years of age, aggressive primary prevention interventions be instituted without nuclear testing. For women, the prevalence of ischaemia was so low as to not warrant screening, but the incidence of CAD was high enough to at least warrant lifestyle interventions. PMID- 21785112 TI - The mechanism of neogambogic acid-induced apoptosis in human MCF-7 cells. AB - Neogambogic acid (NGA), an active ingredient in garcinia, can inhibit the growth of some solid tumors and result in an anticancer effect. We hypothesize that NGA may be responsible for the inhibition of proliferation of human breast cancer cell line MCF-7 cells. To investigate its anticancer mechanism in vitro, MCF-7 cells were treated with various concentrations of NGA. Results of MTT (methyl thiazolyl tetrazolum) assay showed that treatment with NGA significantly reduced the proliferation of MCF-7 cells in a dose-dependent manner. NGA could increase the expression of the apoptosis-related proteins FasL, caspase-3, caspase-8, caspase-9, and Bax and decrease the expression of anti-apoptotic protein Bcl-2 accompanied by the mitochondrial transmembrane damage. The antiproliferative effect of NGA on MCF-7 cells is due to the G(0)/G(1) arrest, increased apoptosis and activation of Fas/FasL and cytochrome C pathway. These results provide an important insight into the cellular and molecular mechanisms through which NGA impairs the proliferation of breast cancer cells. PMID- 21785114 TI - Potentiation of arsenic trioxide-induced apoptosis by 8-bromo-7-methoxychrysin in human leukemia cells involves depletion of intracellular reduced glutathione. AB - The novel chrysin analog 8-bromo-7-methoxychrysin (BrMC) has been reported to induce apoptosis of various cancer cell lines. Arsenic trioxide (ATO) treatment induces clinical remission in acute promyelocytic leukemia patients. The combination of ATO with other agents has been shown to improve therapeutic effectiveness in vitro and in vivo. In this report, the mechanism of apoptosis induced by treatment with ATO alone or in combination with BrMC was studied in U937, HL-60, and Jurkat cells. Our results demonstrated that BrMC cooperated with ATO to induce apoptosis in human leukemia cells. This co-treatment caused mitochondrial transmembrane potential dissipation and stimulated the mitochondrial apoptotic pathway, as evidenced by cytochrome c release, down regulation of X-linked inhibitor of apoptosis (XIAP) and Bcl-XL, and up regulation of Bax. BrMC alone or in combination with ATO, decreased Akt phosphorylation as well as intracellular reduced glutathione (GSH) content. The thiol antioxidant N-acetylcysteine and exogenous GSH restored GSH content and attenuated apoptosis induced by co-treatment with ATO plus BrMC. In contrast, the non-thiol antioxidant butylated hydroxyanisole and mannitol failed to do so. These findings suggest that GSH depletion explains at least in part the potentiation of ATO-induced apoptosis by BrMC. PMID- 21785113 TI - Spatial regulation of the mTORC1 system in amino acids sensing pathway. AB - The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that regulates numerous cellular processes including cell growth, proliferation, cell cycle, and autophagy. mTOR forms two different multi-protein complexes referred to as mTOR complex 1 (mTORC1) and mTORC2, and each complex exerts distinct functions exclusively. mTORC1 activity is sensitive to the selective inhibitor rapamycin, whereas mTORC2 is resistant. mTORC1 is regulated by many intra- and extra-cellular cues such as growth factors, nutrients, and energy-sensing signals, while mTORC2 senses ribosome maturation and growth factor signaling. This review focuses on current understandings by which mTORC1 pathway senses cellular nutrient availability for its activation. PMID- 21785115 TI - Effectiveness of workplace interventions in Europe promoting healthy eating: a systematic review. AB - BACKGROUND: The worksite is a promising setting for health promotion. This review summarizes the evidence of effect of intervention studies in European countries promoting a healthy diet solely and in combination with increasing physical activity at the workplace. METHODS: A systematic review of published literature was carried out. Inclusion criteria were: studies conducted in European countries; papers published from 1 January 1990 to 1 October 2010; worksite-based interventions promoting a healthy diet solely or in combination with physical activity; primary prevention; measurement of anthropometrical or behavioural change and adults (>=18 years old). Levels of evidence for intervention effectiveness on behavioural determinants, nutrition and physical activity behaviours and body composition and the quality of the included interventions were assessed. RESULTS: Seventeen studies solely focusing on promotion of a healthy diet were identified. Eight were educational, one used worksite environmental change strategies, and eight used a combination of both (multi component). None of the interventions were rated as 'strong'; seven met the criteria for 'moderate' quality. The reviewed studies show moderately evidence for effects on diet. Thirteen studies focusing both on nutrition and physical activity (nine educational and four multi-component studies) were identified. Ten were rated as having 'weak' and three as having 'moderate' methodological quality, providing inconclusive evidence for effects. CONCLUSION: Limited to moderate evidence was found for positive effects of nutrition interventions implemented at the workplace. Effects of workplace health promotion interventions may be improved if stronger adherence to established quality criteria for such interventions is realized. PMID- 21785116 TI - Revision of the European Data Protection Directive: opportunity or threat for public health monitoring? PMID- 21785117 TI - Convergent grey and white matter evidence of orbitofrontal cortex changes related to disinhibition in behavioural variant frontotemporal dementia. AB - Disinhibition is a common behavioural symptom in frontotemporal dementia but its neural correlates are still debated. In the current study, we investigated the grey and white matter neural correlates of disinhibition in a sample of behavioural variant frontotemporal dementia (n = 14) and patients with Alzheimer's disease (n = 15). We employed an objective (Hayling Test of inhibitory functioning) and subjective/carer-based (Neuropsychiatric Inventory) measure of disinhibition to reveal convergent evidence of disinhibitory behaviour. Mean and overlap-based statistical analyses were conducted to investigate profiles of performance in patients with behavioural variant frontotemporal dementia, Alzheimer's disease and controls. Hayling Test and Neuropsychiatric Inventory scores were entered as covariates in a grey matter voxel-based morphometry, as well as in a white matter diffusion tensor imaging analysis to determine the underlying grey and white matter correlates. Patients with behavioural variant frontotemporal dementia showed more disinhibition on both behavioural measures in comparison to patients with Alzheimer's disease and controls. Voxel-based morphometry results revealed that atrophy in orbitofrontal/subgenual, medial prefrontal cortex and anterior temporal lobe areas covaried with total errors score of the Hayling Test. Similarly, the Neuropsychiatric Inventory disinhibition frequency score correlated with atrophy in orbitofrontal cortex and temporal pole brain regions. The orbitofrontal atrophy related to the objective (Hayling Test) and subjective (Neuropsychiatric Inventory) measures of disinhibition was partially overlapping. Diffusion tensor imaging analysis revealed that white matter integrity fractional anisotropy values of the white matter tracts connecting the identified grey matter regions, namely uncinate fasciculus, forceps minor and genu of the corpus callosum, correlated well with the total error score of the Hayling Test. Our results show that a network of orbitofrontal, anterior temporal and mesial frontal brain regions and their connecting white matter tracts are involved in inhibitory functioning. Further, we find convergent evidence for objective and subjective disinhibition measures that the orbitofrontal/subgenual brain region is critical for adapting and maintaining normal behaviour. PMID- 21785118 TI - Drug interaction of levothyroxine with infant colic drops. AB - Infacol (Forest Laboratories UK, Kent, UK) is a widely available over-the-counter preparation used to relieve colic symptoms in neonates and infants. The active ingredient is simeticone. No drug interactions with simeticone are documented in the current summary of product characteristics. The authors report the case of an infant with confirmed congenital hypothyroidism on levothyroxine who experienced a possible drug interaction with simeticone. Despite adequate levothyroxine dosage, thyroid stimulating hormone (TSH) was high, suggesting undertreatment. Questioning revealed the child was taking Infacol drops before feeds while on levothyroxine. The colic drops were immediately discontinued and TSH promptly normalised with a reduction in thyroxine requirement to an age appropriate dosage. Drug interaction of thyroxine with simeticone has not been reported previously and is not listed in the British National Formulary for Children. Clinicians and parents need to be aware of this interaction to avoid unnecessary undertreatment and prevent potential long-term neurological sequelae. PMID- 21785120 TI - Thimerosal exposure in early life and neuropsychological outcomes 7-10 years later. AB - OBJECTIVE: The authors used a public use data set to investigate associations between the receipt of thimerosal-containing vaccines and immune globulins early in life and neuropsychological outcomes assessed at 7-10 years. METHODS: The data were originally created by evaluating 1,047 children ages 7-10 years and their biological mothers. This study developed seven latent neuropsychological factors and regressed them on a comprehensive set of covariates and thimerosal exposure variables. RESULTS: The authors found no statistically significant associations between thimerosal exposure from vaccines early in life and six of the seven latent constructs. There was a small, but statistically significant association between early thimerosal exposure and the presence of tics in boys. CONCLUSIONS: This finding should be interpreted with caution due to limitations in the measurement of tics and the limited biological plausibility regarding a causal relationship. PMID- 21785119 TI - Ciprofloxacin safety in paediatrics: a systematic review. AB - OBJECTIVE: To determine the safety of ciprofloxacin in paediatric patients in relation to arthropathy, any other adverse events (AEs) and drug interactions. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL, CENTRAL and bibliographies of relevant articles was carried out for all published articles, regardless of design, that involved the use of ciprofloxacin in any paediatric age group <= 17 years. Only articles that reported on safety were included. RESULTS: 105 articles met the inclusion criteria and involved 16 184 paediatric patients. There were 1065 reported AEs (risk 7%, 95% CI 3.2% to 14.0%). The most frequent AEs were musculoskeletal AEs, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. There were six drug interactions (with aminophylline (4) and methotrexate (2)). The only drug related death occurred in a neonate who had an anaphylactic reaction. 258 musculoskeletal events occurred in 232 paediatric patients (risk 1.6%, 95% CI 0.9% to 2.6%). Arthralgia accounted for 50% of these. The age of occurrence of arthropathy ranged from 7 months to 17 years (median 10 years). All cases of arthropathy resolved or improved with management. One prospective controlled study estimated the risk of arthropathy as 9.3 (OR 95% CI 1.2 to 195). Pooled safety data of controlled trials in this review estimated the risk of arthropathy as 1.57 (OR 95% CI 1.26 to 1.97). CONCLUSION: Musculoskeletal AEs occur due to ciprofloxacin use. However, these musculoskeletal events are reversible with management. It is recommended that further prospective controlled studies should be carried out to evaluate the safety of ciprofloxacin, with particular focus on the risk of arthropathy. PMID- 21785121 TI - Improved diagnosis of post-operative myocardial infarction by contrast echocardiography after coronary artery bypass graft surgery. AB - OBJECTIVE: Contrast echocardiography is a more accurate means of assessment of left ventricular (LV) regional motion compared with non-enhanced echocardiography. Despite new tests, the diagnosis of post-operative myocardial infarction (MI) remains difficult. The aim of this study was to determine whether contrast echocardiography can facilitate this diagnosis. METHODS: We performed standard and contrast echocardiography in 79 consecutive patients before and up to 10 days after they underwent isolated coronary artery bypass graft (CABG) surgery. RESULTS: The post-operative intra- and interobserver reproducibility of echocardiographic measurements of the LV ejection fraction and wall motion score was significantly higher with than without contrast enhancement. The proportion of non-visualized LV myocardial segments was significantly greater with non enhanced (6.6%) than with contrast (0.3%) echocardiography (P< 0.0001). The mean peak serum cardiac troponin (cTnI) concentration was significantly higher in the group of patients with new wall motion abnormalities detected with contrast enhanced echocardiography. A correlation was found (r = -0.43, P< 0.01) between peak cTnI and changes in wall motion score only when a contrast agent was used. CONCLUSION: Contrast echocardiography facilitated the detection of new LV wall motion abnormalities after CABG. This observation, added to other markers, might facilitate the diagnosis of post-operative MI. PMID- 21785122 TI - Triple-orifice congenital stenotic mitral valve: a unique finding characterized by multimodality echocardiography. PMID- 21785123 TI - Active infective prosthetic endocarditis after percutaneous edge-to-edge mitral valve repair. PMID- 21785124 TI - Cohort profile: the Quebec adipose and lifestyle investigation in youth cohort. PMID- 21785125 TI - Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations. AB - BACKGROUND: Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia. AIMS: To study variation of serum hepcidin concentration in a normal population. RESULTS: Hepcidin showed age and sex dependent variations that correlated with ferritin but not with serum iron and transferrin saturation. The size of the study population was underpowered to find genome wide significant associations with hepcidin concentrations but it allowed to show that association with serum iron, transferrin saturation and erythrocyte traits of common DNA variants in HFE (rs1800562) and TMPRSS6 (rs855791) genes is not exclusively dependent on hepcidin values. When multiple interactions between environmental factors, the iron parameters and hepcidin were taken into account, the HFE variant, and to lesser extent the TMPRSS6 variant, were associated with ferritin and with hepcidin normalised to ferritin (the hepcidin/ferritin ratio). CONCLUSIONS: The results suggest a mutual control of serum hepcidin and ferritin concentrations, a mechanism relevant to the pathophysiology of HFE haemochromatosis, and demonstrate that the HFE rs1800562 C282Y variant exerts a direct pleiotropic effect on the iron parameters, in part independent of hepcidin. PMID- 21785126 TI - Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. AB - BACKGROUND: Combined Malonic and Methylmalonic Aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterised by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). Nearly all reported cases are caused by malonyl-CoA decarboxylase (MCD) deficiency. Most patients have metabolic acidosis, developmental delay, seizures and cardiomyopathy. CMAMMA was also described in symptomatic patients with normal MCD activity, suggesting heterogeneity in this disorder. METHODS AND RESULTS: We identified two probands with a non-classical CMAMMA variant through the Quebec newborn urine screening program. While they share the biochemical phenotype of elevated MA and MMA, the MMA excretion was higher than MA, the clinical courses were benign, MYLCD gene sequencing was normal and MCD activity, measured in one proband, was normal. Using exome sequencing in the single consanguineous proband, we identified a homozygous missense allele in the ACSF3 gene, encoding an Acyl-CoA Synthetase (ACS) with unknown substrate and function. The second proband was homozygous for a different ACSF3 missense allele. Both substitutions were in conserved residues and were identified in less than 0.5% of their respective ethnic control populations. CONCLUSION: These results suggest that ACSF3 is a candidate gene for non-classical CMAMMA observed in our patients and document the value of exome sequencing of a limited number of patients for the identification of novel disease genes. PMID- 21785127 TI - Fitness to fly testing in term and ex-preterm babies without bronchopulmonary dysplasia. AB - BACKGROUND: During air flight, cabin pressurisation produces an effective fraction of inspired oxygen (FiO(2)) of 0.15. This can cause hypoxia in predisposed individuals, including infants with bronchopulmonary dysplasia (BPD), but the effect on ex-preterm babies without BPD was uncertain. The consequences of feeding a baby during the hypoxia challenge were also unknown. METHODS: Ex preterm (without BPD) and term infants had fitness to fly tests (including a period of feeding) at 3 or 6 months corrected gestational age (CGA) in a body plethysmograph with an FiO(2) of 0.15 for 20 min. A 'failed' test was defined as oxygen saturation (SpO(2)) <90% for at least 2 min. RESULTS: 41 term and 30 ex preterm babies (mean gestational age 39.8 and 33.1 weeks, respectively) exhibited a significant median drop in SpO(2) (median -6%, p<0.0001); there was no difference between term versus ex-preterm babies, or 3 versus 6 months. Two term (5%) and two ex-preterm (7%) babies failed the challenge. The SpO(2) dropped further during feeding (median -4% in term and -2% in ex-preterm, p<0.0001), with transient desaturation (up to 30 s) <90% seen in 8/36 (22%) term and 9/28 (32%) ex-preterm infants; the ex-preterm babies desaturated more quickly (median 1 vs 3 min, p=0.002). CONCLUSIONS: Ex-preterm babies without BPD and who are at least 3 months CGA do not appear to be a particularly at-risk group for air travel, and routine preflight testing is not indicated. Feeding babies in an FiO(2) of 0.15 leads to a further fall in SpO(2), which is significant but transient. PMID- 21785128 TI - Improvement of the crystallizability and expression of an RNA crystallization chaperone. AB - Crystallizing RNA has been an imperative and challenging task in the world of RNA research. Assistive methods such as chaperone-assisted RNA crystallography (CARC), employing monoclonal antibody fragments (Fabs) as crystallization chaperones have enabled us to obtain RNA crystal structures by forming crystal contacts and providing initial phasing information. Despite the early successes, the crystallization of large RNA-Fab complex remains a challenge in practice. The possible reason for this difficulty is that the Fab scaffold has not been optimized for crystallization in complex with RNA. Here, we have used the surface entropy reduction (SER) technique for the optimization of DeltaC209 P4-P6/Fab2 model system. Protruding lysine and glutamate residues were mutated to a set of alanines or serines to construct Fab2SMA or Fab2SMS. Expression with the shake flask approach was optimized to allow large scale production for crystallization. Crystal screening shows that significantly higher crystal-forming ratio was observed for the mutant complexes. As the chosen SER residues are far away from the CDR regions of the Fab, the same set of mutations can now be directly applied to other Fabs binding to a variety of ribozymes and riboswitches to improve the crystallizability of Fab-RNA complex. PMID- 21785129 TI - Characterization of Oncidium 'Gower Ramsey' transcriptomes using 454 GS-FLX pyrosequencing and their application to the identification of genes associated with flowering time. AB - Oncidium 'Gower Ramsey' is a valuable and successful commercial orchid for the floriculture industry in Taiwan. However, no genome reference for entire sequences of the transcribed genes currently exists for Oncidium orchids, to facilitate the development of molecular biological studies and the breeding of these orchids. In this study, we generated Oncidium cDNA libraries for six different organs: leaves, pseudobulbs, young inflorescences, inflorescences, flower buds and mature flowers. We utilized 454-pyrosequencing technology to perform high-throughput deep sequencing of the Oncidium transcriptome, yielding >0.9 million reads with an average length of 328 bp, for a total of 301 million bases. De novo assembly of the sequences yielded 50,908 contig sequences with an average length of 493 bp from 796,463 reads and 120,219 singletons. The assembled sequences were annotated using BLAST, and a total of 12,757 and 13,931 unigene transcripts from the Arabidopsis and rice genomes were matched by TBLASTX, respectively. A Gene Ontology (GO) analysis of the annotated Oncidium contigs revealed that the majority of sequenced genes were associated with 'unknown molecular function', 'cellular process' and 'intracellular components'. Furthermore, a complete flowering-associated expressed sequence that included most of the genes in the photoperiod pathway and the 15 CONSTANS-LIKE (COL) homologs with the conserved CCT domain was obtained in this collection. These data revealed that the Oncidium expressed sequence tag (EST) database generated in this study has sufficient coverage to be used as a tool to investigate the flowering pathway and various other biological pathways in orchids. An OncidiumOrchidGenomeBase (OOGB) website has been constructed and is publicly available online (http://predictor.nchu.edu.tw/oogb/). PMID- 21785130 TI - Structure of the chloroplast NADH dehydrogenase-like complex: nomenclature for nuclear-encoded subunits. AB - The chloroplast NADH dehydrogenase-like complex (NDH) was first discovered based on its similarity to complex I in respiratory electron transport, and is involved in electron transport from photoproduced stromal reductants such as NADPH and ferredoxin to the intersystem plastoqunone pool. However, a recent study suggested that it is a ferredoxin-dependent plastoquinone reductase rather than an NAD(P)H dehydrogenase. Furthermore, recent advances in subunit analysis of NDH have revealed the presence of a novel hydrophilic subcomplex on the stromal side of the thylakoid membrane, as well as an unexpected lumenal subcomplex. This review discusses these new studies on the structure of NDH, and proposes a unified nomenclature for newly discovered NDH subunits. PMID- 21785131 TI - CAM-CM: a signal deconvolution tool for in vivo dynamic contrast-enhanced imaging of complex tissues. AB - SUMMARY: In vivo dynamic contrast-enhanced imaging tools provide non-invasive methods for analyzing various functional changes associated with disease initiation, progression and responses to therapy. The quantitative application of these tools has been hindered by its inability to accurately resolve and characterize targeted tissues due to spatially mixed tissue heterogeneity. Convex Analysis of Mixtures - Compartment Modeling (CAM-CM) signal deconvolution tool has been developed to automatically identify pure-volume pixels located at the corners of the clustered pixel time series scatter simplex and subsequently estimate tissue-specific pharmacokinetic parameters. CAM-CM can dissect complex tissues into regions with differential tracer kinetics at pixel-wise resolution and provide a systems biology tool for defining imaging signatures predictive of phenotypes. AVAILABILITY: The MATLAB source code can be downloaded at the authors' website www.cbil.ece.vt.edu/software.htm CONTACT: yuewang@vt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21785132 TI - STEME: efficient EM to find motifs in large data sets. AB - MEME and many other popular motif finders use the expectation-maximization (EM) algorithm to optimize their parameters. Unfortunately, the running time of EM is linear in the length of the input sequences. This can prohibit its application to data sets of the size commonly generated by high-throughput biological techniques. A suffix tree is a data structure that can efficiently index a set of sequences. We describe an algorithm, Suffix Tree EM for Motif Elicitation (STEME), that approximates EM using suffix trees. To the best of our knowledge, this is the first application of suffix trees to EM. We provide an analysis of the expected running time of the algorithm and demonstrate that STEME runs an order of magnitude more quickly than the implementation of EM used by MEME. We give theoretical bounds for the quality of the approximation and show that, in practice, the approximation has a negligible effect on the outcome. We provide an open source implementation of the algorithm that we hope will be used to speed up existing and future motif search algorithms. PMID- 21785134 TI - Conformational change of single-stranded RNAs induced by liposome binding. AB - The interaction between single-stranded RNAs and liposomes was studied using UV, Fourier Transform Infrared spectroscopy (FTIR) and Circular Dichroism spectroscopy (CD). The effect of the surface characteristics of liposomes, which were composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and modified with cholesterol (Ch) or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), on the liposome-RNA interaction was investigated. The fluorescence of 6 (p-toluidino)naphthalene-2-sulfonate (TNS) embedded in the liposome surface (epsilon = 30-40) was decreased in the presence of tRNA, suggesting that single stranded tRNA could bind onto the liposome. The dehydration of -PO2--, guanine (G) and cytosine (C) of tRNA molecules in the presence of liposomes suggested both an electrostatic interaction (phosphate backbone of tRNA and trimethylammonium group of POPC, DOTAP) and a hydrophobic interaction (guanine or cytosine of tRNA and aliphatic tail of lipid). The tRNA conformation on the liposome was determined by CD spectroscopy. POPC/Ch (70/30) maintained tRNA conformation without any denaturation, while POPC/DOTAP(70/30) drastically denatured it. The mRNA translation was evaluated in an Escherichia coli cell-free translation system. POPC/Ch(70/30) enhanced expression of green fluorescent protein (GFP) (116%) while POPC/DOTAP(70/30) inhibited (37%), suggesting that the conformation of RNAs was closely related to the translation efficiency. Therefore, single-stranded RNAs could bind to liposomal membranes through electrostatic and hydrophobic attraction, after which conformational changes were induced depending on the liposome characteristics. PMID- 21785133 TI - Tup1 stabilizes promoter nucleosome positioning and occupancy at transcriptionally plastic genes. AB - Despite technical advances, the future of chromatin mapping studies requires an ability to draw accurate comparisons between different chromatin states to enhance our understanding of genome biology. In this study, we used matched chromatin preparations to enable specific and accurate comparisons of Saccharomyces cerevisiae chromatin structures in the presence and absence of the co-repressor protein Tup1. Analysis of wild-type and tup1 Delta chromatin data sets revealed unique organizational themes relating to the function of Tup1. Regulatory regions bound by Tup1 assumed a distinct chromatin architecture composed of a wide nucleosome-depleted region, low occupancy/poorly positioned promoter nucleosomes, a larger number and wider distribution of transcription factor-binding sites and downstream genes with enhanced transcription plasticity. Regions of Tup1-dependent chromatin structure were defined for the first time across the entire yeast genome and are shown to strongly overlap with activity of the chromatin remodeler Isw2. Additionally, Tup1-dependent chromatin structures are shown to relate to distinct biological processes and transcriptional states of regulated genes, including Tup1 stabilization of Minus 1 and Minus 2 promoter nucleosomes at actively repressed genes. Together these results help to enhance our mechanistic understanding of Tup1 regulation of chromatin structure and gene expression. PMID- 21785135 TI - Evolutionary genome engineering using a restriction-modification system. AB - Modification of complex microbial cellular processes is often necessary to obtain organisms with particularly favorable characteristics, but such experiments can take many generations to achieve. In the present article, we accelerated the experimental evolution of Escherichia coli populations under selection for improved growth using one of the restriction-modification systems, which have shaped bacterial genomes. This resulted in faster evolutionary changes in both the genome and bacterial growth. Transcriptome/genome analysis at various stages enabled prompt identification of sequential genome rearrangements and dynamic gene-expression changes associated with growth improvement. The changes were related to cell-to-cell communication, the cell death program, as well as mass production and energy consumption. These observed changes imply that improvements in microorganism population growth can be achieved by inactivating the cellular mechanisms regulating fraction of active cells in a population. Some of the mutations were shown to have additive effects on growth. These results open the way for the application of evolutionary genome engineering to generate organisms with desirable properties. PMID- 21785136 TI - Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function. AB - We collected a massive and heterogeneous dataset of 20 255 gene expression profiles (GEPs) from a variety of human samples and experimental conditions, as well as 8895 GEPs from mouse samples. We developed a mutual information (MI) reverse-engineering approach to quantify the extent to which the mRNA levels of two genes are related to each other across the dataset. The resulting networks consist of 4 817 629 connections among 20 255 transcripts in human and 14 461 095 connections among 45 101 transcripts in mouse, with a inter-species conservation of 12%. The inferred connections were compared against known interactions to assess their biological significance. We experimentally validated a subset of not previously described protein-protein interactions. We discovered co-expressed modules within the networks, consisting of genes strongly connected to each other, which carry out specific biological functions, and tend to be in physical proximity at the chromatin level in the nucleus. We show that the network can be used to predict the biological function and subcellular localization of a protein, and to elucidate the function of a disease gene. We experimentally verified that granulin precursor (GRN) gene, whose mutations cause frontotemporal lobar degeneration, is involved in lysosome function. We have developed an online tool to explore the human and mouse gene networks. PMID- 21785137 TI - Targeted bisulfite sequencing by solution hybrid selection and massively parallel sequencing. AB - We applied a solution hybrid selection approach to the enrichment of CpG islands (CGIs) and promoter sequences from the human genome for targeted high-throughput bisulfite sequencing. A single lane of Illumina sequences allowed accurate and quantitative analysis of ~1 million CpGs in more than 21,408 CGIs and more than 15,946 transcriptional regulatory regions. Of the CpGs analyzed, 77-84% fell on or near capture probe sequences; 69-75% fell within CGIs. More than 85% of capture probes successfully yielded quantitative DNA methylation information of targeted regions. Differentially methylated regions (DMRs) were identified in the 5'-end regulatory regions, as well as the intra- and intergenic regions, particularly in the X-chromosome among the three breast cancer cell lines analyzed. We chose 46 candidate loci (762 CpGs) for confirmation with PCR-based bisulfite sequencing and demonstrated excellent correlation between two data sets. Targeted bisulfite sequencing of three DNA methyltransferase (DNMT) knockout cell lines and the wild-type HCT116 colon cancer cell line revealed a significant decrease in CpG methylation for the DNMT1 knockout and DNMT1, 3B double knockout cell lines, but not in DNMT3B knockout cell line. We demonstrated the targeted bisulfite sequencing approach to be a powerful method to uncover novel aberrant methylation in the cancer epigenome. Since all targets were captured and sequenced as a pool through a series of single-tube reactions, this method can be easily scaled up to deal with a large number of samples. PMID- 21785138 TI - hnRNP Q mediates a phase-dependent translation-coupled mRNA decay of mouse Period3. AB - Daily mRNA oscillations of circadian clock genes largely depend on transcriptional regulation. However, several lines of evidence highlight the critical role of post-transcriptional regulation in the oscillations of circadian mRNA oscillations. Clearly, variations in the mRNA decay rate lead to changes in the cycling profiles. However, the mechanisms controlling the mRNA stability of clock genes are not fully understood. Here we demonstrate that the turnover rate of mouse Period3 (mPer3) mRNA is dramatically changed in a circadian phase dependent manner. Furthermore, the circadian regulation of mPer3 mRNA stability requires the cooperative function of 5'- and 3'-untranslated regions (UTRs). Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) binds to both 5'- and 3'-UTR and triggers enhancement of translation and acceleration of mRNA decay. We propose the phase-dependent translation coupled mRNA decay mediated by hnRNP Q as a new regulatory mechanism of the rhythmically regulated decay of mPer3 mRNA. PMID- 21785139 TI - Enhancers regulate progression of development in mammalian cells. AB - During development and differentiation of an organism, accurate gene regulation is central for cells to maintain and balance their differentiation processes. Transcriptional interactions between cis-acting DNA elements such as promoters and enhancers are the basis for precise and balanced transcriptional regulation. We identified modules of combinations of binding sites in proximal and distal regulatory regions upstream of all transcription start sites (TSSs) in silico and applied these modules to gene expression time-series of mouse embryonic development and differentiation of human stem cells. In addition to tissue specific regulation controlled by combinations of transcription factors (TFs) binding at promoters, we observed that in particular the combination of TFs binding at promoters together with TFs binding at the respective enhancers regulate highly specifically temporal progression during development: whereas 40% of TFs were specific for time intervals, 79% of TF pairs and even 97% of promoter enhancer modules showed specificity for single time intervals of the human stem cells. Predominantly SP1 and E2F contributed to temporal specificity at promoters and the forkhead (FOX) family of TFs at enhancer regions. Altogether, we characterized three classes of TFs: with binding sites being enriched at the TSS (like SP1), depleted at the TSS (like FOX), and rather uniformly distributed. PMID- 21785140 TI - Yeast two-hybrid junk sequences contain selected linear motifs. AB - Yeast two-hybrid (Y2H) screenings result in identification of many out-of-frame (OOF) clones that code for short (2-100 amino acids) peptides with no sequence homology to known proteins. We hypothesize that these peptides can reveal common short linear motifs (SLiMs) responsible for their selection. We present a new protocol to address this issue, using an existing SLIM detector (TEIRESIAS) as a base method, and applying filters derived from a mathematical model of SLiM selection in OOF clones. The model allows for initial analysis of likely presence of SLiM(s) in a collection of OOF sequences, assisting investigators with the decision of whether to invest resources in further analysis. If SLiM presence is detected, it estimates the length and number of amino acid residues involved in binding specificity and the amount of noise in the Y2H screen. We demonstrate that our model can double the prediction sensitivity of TEIRESIAS and improve its specificity from 0 to 1.0 on simulated data and apply the model to seven sets of experimentally derived OOF clones. Finally, we experimentally validate one SLiM found by our method, demonstrating its utility. PMID- 21785141 TI - Two RNA-binding sites in plant fibrillarin provide interactions with various RNA substrates. AB - Fibrillarin, one of the major proteins of the nucleolus, plays several essential roles in ribosome biogenesis including pre-rRNA processing and 2'-O-ribose methylation of rRNA and snRNAs. Recently, it has been shown that fibrillarin plays a role in virus infections and is associated with viral RNPs. Here, we demonstrate the ability of recombinant fibrillarin 2 from Arabidopsis thaliana (AtFib2) to interact with RNAs of different lengths and types including rRNA, snoRNA, snRNA, siRNA and viral RNAs in vitro. Our data also indicate that AtFib2 possesses two RNA-binding sites in the central (138-179 amino acids) and C terminal (225-281 amino acids) parts of the protein, respectively. The conserved GCVYAVEF octamer does not bind RNA directly as suggested earlier, but may assist with the proper folding of the central RNA-binding site. PMID- 21785142 TI - Ensembl BioMarts: a hub for data retrieval across taxonomic space. AB - For a number of years the BioMart data warehousing system has proven to be a valuable resource for scientists seeking a fast and versatile means of accessing the growing volume of genomic data provided by the Ensembl project. The launch of the Ensembl Genomes project in 2009 complemented the Ensembl project by utilizing the same visualization, interactive and programming tools to provide users with a means for accessing genome data from a further five domains: protists, bacteria, metazoa, plants and fungi. The Ensembl and Ensembl Genomes BioMarts provide a point of access to the high-quality gene annotation, variation data, functional and regulatory annotation and evolutionary relationships from genomes spanning the taxonomic space. This article aims to give a comprehensive overview of the Ensembl and Ensembl Genomes BioMarts as well as some useful examples and a description of current data content and future objectives. Database URLs: http://www.ensembl.org/biomart/martview/; http://metazoa.ensembl.org/biomart/martview/; http://plants.ensembl.org/biomart/martview/; http://protists.ensembl.org/biomart/martview/; http://fungi.ensembl.org/biomart/martview/; http://bacteria.ensembl.org/biomart/martview/. PMID- 21785143 TI - The InterPro BioMart: federated query and web service access to the InterPro Resource. AB - The InterPro BioMart provides users with query-optimized access to predictions of family classification, protein domains and functional sites, based on a broad spectrum of integrated computational models ('signatures') that are generated by the InterPro member databases: Gene3D, HAMAP, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY and TIGRFAMs. These predictions are provided for all protein sequences from both the UniProt Knowledge Base and the UniParc protein sequence archive. The InterPro BioMart is supplementary to the primary InterPro web interface (http://www.ebi.ac.uk/interpro), providing a web service and the ability to build complex, custom queries that can efficiently return thousands of rows of data in a variety of formats. This article describes the information available from the InterPro BioMart and illustrates its utility with examples of how to build queries that return useful biological information. Database URL: http://www.ebi.ac.uk/interpro/biomart/martview. PMID- 21785144 TI - The use of whole-body CT for trauma patients: survey of UK emergency departments. AB - INTRODUCTION: Whole-body computed tomography (WBCT) is advocated for use in some trauma patients presenting to the emergency department (ED). It is unclear how widespread the use of WBCT is in the UK and the best way to select patients for WBCT remains controversial. The aim of this study was to investigate the current use and nature of WBCT policies in ED in the UK. METHODS: A postal questionnaire was devised and distributed to lead doctors of 245 ED in the UK in May 2010. Two further rounds of questionnaires were sent out in June and July to non responders. RESULTS: 184/245 hospitals responded (75.1%). 41/184 (22.3%) ED had a WBCT policy. 43 (23.4%) further ED indicated that they used WBCT in certain cases, without a formal policy. Hospitals with a WBCT policy saw significantly more trauma cases than those that did not. Most hospitals with a WBCT policy used multiple criteria to decide which patients received WBCT, although there were variations in the timing of CT and in who could request it. Out-of-hours CT scans were less likely to be reported by a consultant radiologist, and reporting times were longer. DISCUSSION: The use of WBCT in the UK is variable, although centres that see more trauma seem more likely to have a WBCT policy. The results do raise concerns about how effectively WBCT can be delivered, especially out of hours, but nationwide plans to reorganise trauma care may potentially affect how and at which ED WBCT is offered in the future. PMID- 21785145 TI - Trauma systems: the potential impact of a trauma divert policy on a regional ambulance service. AB - INTRODUCTION: Recent initiatives in the Care of the Trauma patient in the UK have led to the establishment of Major Trauma Centres (MTCs), supporting a Trauma Network. It is envisaged that any person suffering from major trauma will be taken directly to one of these centres, with an expectant increase in survivability and decrease in morbidity. This will have an impact on the Ambulance Service in terms of journey times, and the MTCs in terms of bed days. Whilst these are not 'new' patients to the NHS, they may require a redistribution of funds. Most of the modelling into the effects of this has been carried out in London, which may not be applicable to more rural areas. We therefore determined to gain data on how a similar policy would affect trauma services in our rural region. METHOD: A retrospective study of all trauma patients conveyed by a regional ambulance service. The London Trauma Divert Criteria were applied to the patient report forms, and the number of patients who may have transported directly (or by secondary transfer) to MTCs identified. RESULTS: We found that between 28 and 58 additional patients a month would be transferred. CONCLUSION: As this is more than 1 patient a day, there may be considerable strain on the MTCs and Ambulance Services. We believe service commissioners in rural areas need to consider the funding and organisational arrangements for major trauma in light of this. PMID- 21785146 TI - Future research in emergency medicine: explanation or pragmatism? Large or small? Simple or complex? PMID- 21785147 TI - Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. AB - OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2 year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy. PMID- 21785148 TI - A misleading chest plain radiograph acquired after the return of spontaneous circulation. PMID- 21785149 TI - A functional 'three-joint limb'. PMID- 21785150 TI - Criteria for cancelling helicopter emergency medical services (HEMS) dispatches. AB - INTRODUCTION: In The Netherlands there is no consensus about criteria for cancelling helicopter emergency medical services (HEMS) dispatches. This study assessed the ability of the primary HEMS dispatch criteria to identify major trauma patients. The predictive power of other early prehospital parameters was evaluated to design a safe triage model for HEMS dispatch cancellations. METHODS: All trauma-related dispatches of HEMS during a period of 6 months were included. Data concerning prehospital information and inhospital treatment were collected. Patients were divided into two groups (major and minor trauma) according to the following criteria: injury severity score 16 or greater, emergency intervention, intensive care unit admission, or inhospital death. Logistic regression analysis was used to design a prediction model for the early identification of major trauma patients. RESULTS: In total, 420 trauma-related dispatches were evaluated, of which 155 concerned major trauma patients. HEMS was more often cancelled for minor trauma patients than for major trauma patients (57.7% vs 20.6%). Overall, HEMS dispatch criteria had a sensitivity of 87.7% and a specificity of 45.3% for identifying major trauma patients. Significant differences were found for vital sign abnormalities, anatomical components and several parameters of the mechanism of injury. A triage model designed for cancelling HEMS correctly identified major trauma patients (sensitivity 99.4%). CONCLUSION: The accuracy of the current HEMS dispatch criteria is relatively low, resulting in high cancellation rates and low predictability for major trauma. The new HEMS cancellation triage model identified all major trauma patients with an acceptable overtriage and will probably reduce unjustified HEMS dispatches. PMID- 21785151 TI - Trauma patients with the 'triad of death'. AB - INTRODUCTION: Injured patients presenting with hypothermia, acidosis and coagulopathy have been identified at high risk of death. This study aimed to describe the presentation, management and outcome of major trauma patients presenting with the 'triad of death' and identify ways to improve survival. METHODS: A retrospective, explicit chart review was undertaken on patients presenting to a level I adult major trauma centre with the 'triad of death'. These patients presented directly from the scene, were coagulopathic (international normalised ratio (INR) >1.5), hypothermic (temperature <35 degrees C) and acidotic (pH <7.2) on arrival. RESULTS: There were 90 patients over an 8 year period, with an overall mortality of 47.8%. No significant differences were observed among demographics and injury severity scores between survivors and non survivors. Extremes of systolic blood pressure and heart rate, a high activated partial thromboplastin time activated partial thromboplastin time, low fibrinogen counts, pH, bicarbonate, base excess and haemoglobin were present among survivors. There were no survivors in our cohort with an initial INR greater than 3.2. Survivors received significantly lower volumes of packed red blood cells. CONCLUSIONS: There has been little change in mortality over time in this subgroup of major trauma patients. While the presence of the triad alone does not determine futility, there were no survivors over 8 years with extreme coagulopathy with concurrent hypothermia and acidosis. PMID- 21785152 TI - Radiological misinterpretations by emergency physicians in discharged minor trauma patients. AB - INTRODUCTION: Unerring radiological interpretation is essential in discharged minor trauma patients without follow-up visits based on the rapid decision of emergency physicians (EPs). Misinterpretation may raise issues concerning patient care, reimbursement and lawsuits. The authors investigated the discrepancies and associated factors in radiological interpretation for discharged trauma patients between EPs and radiologists. METHODS: The authors included trauma patients who visited the emergency department, from 1 August 2009 to 31 July 2010, and searched for cases showing discrepancy using the 'modified quality assurance model for radiological interpretation'. The overall/clinically significant discrepancy (CSD)/clinically insignificant discrepancy (CinSD) rates were calculated. The authors also looked at the relationship between discrepancies and several factors including age and time of visit. RESULTS: 10,243 cases were related to minor trauma, in which the radiological images were interpreted as normal by EPs. The overall discrepancy, the CSD and CinSD rates were 0.77% (n=79), 0.47% (n=48) and 0.3% (n=31), respectively. No discrepancy was shown to be related to the day or time of visit. The discrepancy rate turned out to be relatively higher with increasing age, and for injuries of the extremities. No associated factors were found between the CSD and CinSD groups. CONCLUSIONS: Despite a relatively low CSD rate, careful interpretation is recommended considering age and body areas imaged. A modified model would be needed as a supportive tool for training and improving the quality of care. A further development of the modified system for efficient use of resources will be needed to focus on quality improvement and education in each hospital. PMID- 21785153 TI - Update on patient safety. PMID- 21785154 TI - Residual corneal stroma in big-bubble deep anterior lamellar keratoplasty: a histological study in eye-bank corneas. AB - AIM: To determine if residual corneal stroma remains on the recipient posterior lamella in big-bubble deep anterior lamellar keratoplasty (DALK). METHODS: Pneumodissection using the big-bubble technique was carried out on eye-bank corneas mounted on an artificial anterior chamber. Samples that had a successful big-bubble formation were sent for histological evaluation to determine if any residual stroma remained on the Descemet membrane (DM). RESULTS: Big-bubble formation was achieved in 32 donor corneas. Two distinct types of big-bubble were seen: the bubble had either a white margin (30 corneas) or a clear margin (two corneas). The posterior lamellae of all the white margin corneas showed residual stroma on DM with a mean central thickness of 7.0 MUm (range 2.6-17.4 MUm). The clear margin corneas showed no residual stroma on DM. CONCLUSION: It should no longer be assumed that big-bubble DALK, where the bubble has a white margin, routinely bares DM. True baring of DM may only occur with the less commonly seen clear margin bubble. PMID- 21785155 TI - Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients. AB - AIM: To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. METHODS: 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. RESULTS: Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). CONCLUSIONS: MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes. PMID- 21785156 TI - Effect of an action plan with ongoing support by a case manager on exacerbation related outcome in patients with COPD: a multicentre randomised controlled trial. AB - BACKGROUND: An individualised action plan (AP) is a potentially effective method of helping patients with chronic obstructive pulmonary disease (COPD) to recognise and anticipate early exacerbation symptoms. This multicentre randomised controlled trial evaluates the hypothesis that individualised APs reduce exacerbation recovery time. METHODS: Two hundred and thirty-three patients with COPD (age 65+/-10 years, forced expiratory volume in 1 s 56+/-21% predicted) were randomised to receive either an individualised AP (n=111) or care as usual (n=122). The AP provides individualised treatment prescriptions (pharmaceutical and non-pharmaceutical) related to a colour-coded symptom status to enhance an adequate response to periods of symptom deterioration (reinforced at 1 and 4 months). Exacerbation onset was defined using the Anthonisen symptom diary card algorithm. Every 3 days the Clinical COPD Questionnaire (CCQ) was assessed to evaluate the longitudinal course of health status. The primary outcome was health status recovery in the event of an exacerbation. RESULTS: During the 6-month follow-up period there was no difference in exacerbation rates and healthcare utilisation between the two groups. Cox-adjusted survival analysis including frailty showed enhanced health status recovery (HR 1.58; 95% CI 0.96 to 2.60) and reduced length of the exacerbation (HR 1.30; 95% CI 0.92 to 1.84). The mean difference in symptom recovery time was -3.68 days (95% CI -7.32 to -0.04). Mixed model repeated measure analysis showed that an AP decreased the impact of exacerbations on health status both in the prodromal and early post-onset periods. Between-group differences in CCQ scores were above the minimal clinically relevant difference of 0.4 points (3.0+/-0.7 vs. 3.4+/-0.9; p<=0.01). CONCLUSION: This study shows that an individualised AP, including ongoing support by a case manager, decreases the impact of exacerbations on health status and tends to accelerate recovery. APs can be considered a key component of self management programmes in patients with COPD. PMID- 21785157 TI - Systemic upregulation of neutrophil alpha-defensins and serine proteases in neutrophilic asthma. AB - BACKGROUND: The well-characterised airway inflammatory phenotypes of asthma include eosinophilic, neutrophilic, mixed eosinophilic/neutrophilic and paucigranulocytic asthma, identified based on the proportion of sputum granulocytes. Systemic inflammation is now recognised as an important part of some airway diseases, but the involvement of systemic inflammation in the pathogenesis of airway inflammatory phenotypes of asthma remains unknown. METHODS: Induced sputum samples and peripheral blood were collected from participants with asthma (n=36). Airway inflammatory cell counts were performed from induced sputum and inflammatory phenotype assigned based on the airway eosinophil and neutrophil cut-offs of 3% and 61%, respectively. RNA was extracted from whole blood and gene expression profiles were generated (Illumina Humanref-8 V3) and analysed using GeneSpring GX11. RESULTS: There were six genes classified as differentially expressed between the four asthma phenotypes, including the alpha-defensins (DEFA) 1, 1B, 3 and 4 and neutrophil proteases cathepsin G (CTSG) and elastase (ELA2). Systemic expression of DEFA1,1B,3,4,CTSG and ELA2 was significantly higher in the neutrophilic asthma (NA) phenotype. Microarray results of the alpha-defensins and neutrophil proteases were successfully validated using real-time PCR. Plasma elastase was significantly increased in people with neutrophilic airway inflammation. CONCLUSION: There is systemic upregulation of alpha-defensin and neutrophil protease expression in NA, which may represent proinflammatory effects on the bone marrow and the release of immature neutrophils into the circulation. This demonstrates a systemic inflammatory component in NA that further differentiates this from other asthma phenotypes and indicates different mechanisms in NA. PMID- 21785158 TI - Inequalities in outcomes for non-small cell lung cancer: the influence of clinical characteristics and features of the local lung cancer service. AB - BACKGROUND: The treatment given to patients with lung cancer and survival vary between and within countries. The National Lung Cancer Audit (NLCA) linked to Hospital Episode Statistics was used to quantify the extent to which these outcomes are influenced by patient features and/or hospital facilities and performance indicators. METHODS: All patients with a histological diagnosis of non-small cell lung cancer (NSCLC) were included. Logistic regression was used to quantify the independent influence of features of both patients and hospitals on the likelihood of having surgery and Cox regression was used for survival analyses. RESULTS: There were 34,513 patients with NSCLC in our dataset. After adjusting for age, sex, performance status, stage and Charlson Index of comorbidity, patients with NSCLC first seen in thoracic surgical centres (27% of the cohort) were 51% more likely to have surgery than those seen in non-surgical centres (adjusted OR 1.51, 95% CI 1.16 to 1.97). Resection rates varied from 13% to 17% between non-surgical and thoracic surgical centres. Surgery was the most powerful determinant of overall survival (adjusted HR 0.41, 95% CI 0.39 to 0.44). CONCLUSION: A minority of patients with NSCLC first seen in a thoracic surgical centre are more likely to have surgery and to benefit from the survival advantage this confers. This finding suggests that there is an opportunity to improve the outcome for patients with lung cancer in England by optimising access to thoracic surgeons in non-surgical centres. PMID- 21785159 TI - Intervention in acute cerebral ischaemic stroke: a review of the role of pharmacological therapies and intra-arterial mechanical thrombectomy devices. AB - Acute ischaemic stroke (AIS) is the leading cause of death and disability in developed nations. In the past decade pharmacologic and endovascular therapy has been approved for use in treatment of patients presenting with AIS. The time window from symptom onset to be eligible for treatment is narrow, allowing for only a small proportion of these patients to be treated. Currently the established method of treatment is intravenous thrombolytic therapy for patients without contraindication, presenting within the time window of 4.5 h from the onset of symptoms. The improvement in patient outcome with this therapy is poor. This has led to exploration of intra-arterial mechanical thrombectomy devices to both increase the time window and also attempt to improve patient outcome with and without intravenous thrombolytic therapy. Several studies have shown a high rate of vessel recanalisation with endovascular techniques; however, their efficacy and translation to improved patient outcome is not yet established. Advanced imaging techniques may help select patients who would predictably benefit from endovascular intervention. In the light of existing controversies, this review discusses the current evidence for intravenous and intra-arterial thrombolytics, intra-arterial mechanical thrombectomy devices, and intracranial stent placement for treatment of AIS. PMID- 21785160 TI - Fear of a female planet: how John Harris came to endorse eugenic social engineering. AB - In this paper, I respond to criticisms by John Harris, contained in a commentary on my article "Harris, harmed states, and sexed bodies", which appeared in the Journal of Medical Ethics, volume 37, number 5. I argue that Harris's response to my criticisms exposes the strong eugenic tendencies in his own thought, when he suggests that the reproductive obligations of parents should be determined with reference to a claim about what would enhance 'society' or 'the species'. PMID- 21785161 TI - Understanding the Villain: DMBA-induced preantral ovotoxicity involves selective follicular destruction and primordial follicle activation through PI3K/Akt and mTOR signaling. AB - 7,12-Dimethylbenz-[a]anthracene (DMBA) is an environmental carcinogen which has a potent ovotoxic affect on rat and mouse ovaries, causing complete follicular depletion resulting in premature ovarian failure. Although the overall effects of DMBA on ovarian folliculogenesis are well known, little is known about the exact molecular mechanisms behind its ovotoxicity. In this study, we characterized the mechanisms behind DMBA-induced ovotoxicity in immature follicles. Microarray analysis of neonatal mouse ovaries exposed to DMBA in vitro revealed a multilayered mechanism of DMBA-induced neonatal ovotoxicity involving a distinct cohort of genes and ovarian signaling pathways primarily associated with follicular atresia, tumorigenesis, and follicular growth. Histomorphological and immunohistological analysis supported the microarray data, showing evidence of primordial follicle activation and preantral follicle atresia both in vitro and in vivo. Further immunohistological analysis identified increased Akt1 phosphorylation, mTOR activation, and decreased FOXO3a expression in DMBA-treated primordial oocytes. Our results reveal a novel mechanism of DMBA-induced preantral ovotoxicity involving selective immature follicle destruction and primordial follicle activation involving downstream members of the PI3K/Akt and mTOR signaling pathways. PMID- 21785162 TI - Calreticulin binds to gentamicin and reduces drug-induced ototoxicity. AB - Aminoglycosides like gentamicin are among the most commonly used antibiotics in clinical practice and are essential for treating life-threatening tuberculosis and Gram-negative bacterial infections. However, aminoglycosides are also nephrotoxic and ototoxic. Although a number of mechanisms have been proposed, it is still unclear how aminoglycosides induce cell death in auditory sensory epithelia and subsequent deafness. Aminoglycosides bind to various intracellular molecules, such as RNA and phosphoinositides. We hypothesized that aminoglycosides, based on their tissue-specific susceptibility, also bind to intracellular proteins that play a role in drug-induced ototoxicity. By conjugating an aminoglycoside, gentamicin, to agarose beads and conducting a gentamicin-agarose pull-down assay, we have isolated gentamicin-binding proteins (GBPs) from immortalized cells of mouse organ of Corti, HEI-OC1. Mass spectrometry identified calreticulin (CRT) as a GBP. Immunofluorescence revealed that CRT expression is concentrated in strial marginal cells and hair cell stereocilia, primary locations of drug uptake and cytotoxicity in the cochlea. In HEI-OC1 cells treated with gentamicin, reduction of CRT expression using small interfering RNA (siRNA) reduced intracellular drug levels. CRT-deficient mouse embryonic fibroblast (MEF) cells as well as CRT siRNA-transfected wild-type MEFs also had reduced cell viability after gentamicin treatment. A pull-down assay using deletion mutants of CRT determined that the carboxyl C-domain of CRT binds to gentamicin. HeLa cells transfected with CRT C-domain deletion mutant construct were more susceptible to gentamicin-induced cytotoxicity compared with cells transfected with full-length CRT or other deletion mutants. Therefore, we conclude that CRT binding to gentamicin is protective against gentamicin-induced cytotoxicity. PMID- 21785163 TI - Kinetics of ethylene and ethylene oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and of human livers. AB - Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST). Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ET-exposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of V(max) [nmol/(min.mg protein)] and of the apparent Michaelis constant (K(m) [mmol/l ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, V(max) values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly. By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as V(max)/K(m) [MUl/(min.mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO. PMID- 21785164 TI - Chronic administration of 2-acetylaminofluorene alters the cellular iron metabolism in rat liver. AB - Dysregulated intracellular iron homeostasis has been found not only in rodent and human hepatocellular carcinomas but also in several preneoplastic pathological states associated with hepatocarcinogenesis; however, the precise underlying mechanisms of metabolic iron disturbances in preneoplastic liver and the role of these disturbances remain unexplored. In the present study, using an in vivo model of rat hepatocarcinogenesis induced by 2-acetylaminofluorene, we found extensive alterations in cellular iron metabolism at preneoplastic stages of liver carcinogenesis. These were characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in foci of initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of intracellular iron homeostasis. Gene expression analysis revealed that the decreased intracellular levels of iron in preneoplastic foci might be attributed to increased iron export from the cells, driven by upregulation of ferroportin (Fpn1), the only known non-heme iron exporter. Likewise, increased Fpn1 gene expression was found in vitro in TRL1215 rat liver cells with an acquired malignant phenotype, suggesting that upregulation of Fpn1 might be a specific feature of neoplastically transformed cells. Other changes observed in vivo included the downregulation of hepcidin (Hamp) gene, a key regulator of Fpn1, and this was accompanied by decreased levels of CCAAT/enhancer binding proteins alpha and beta, especially at the Hamp promoter. In conclusion, our results demonstrate the significance of altered intracellular iron metabolism in the progression of liver carcinogenesis and suggest that correction of these alterations could possibly affect liver cancer development. PMID- 21785165 TI - Checking semiparametric transformation models with censored data. AB - Semiparametric transformation models provide a very general framework for studying the effects of (possibly time-dependent) covariates on survival time and recurrent event times. Assessing the adequacy of these models is an important task because model misspecification affects the validity of inference and the accuracy of prediction. In this paper, we introduce appropriate time-dependent residuals for these models and consider the cumulative sums of the residuals. Under the assumed model, the cumulative sum processes converge weakly to zero mean Gaussian processes whose distributions can be approximated through Monte Carlo simulation. These results enable one to assess, both graphically and numerically, how unusual the observed residual patterns are in reference to their null distributions. The residual patterns can also be used to determine the nature of model misspecification. Extensive simulation studies demonstrate that the proposed methods perform well in practical situations. Three medical studies are provided for illustrations. PMID- 21785166 TI - Proteomic profiling of S-acylated macrophage proteins identifies a role for palmitoylation in mitochondrial targeting of phospholipid scramblase 3. AB - S-Palmitoylation, the reversible post-translational acylation of specific cysteine residues with the fatty acid palmitate, promotes the membrane tethering and subcellular localization of proteins in several biological pathways. Although inhibiting palmitoylation holds promise as a means for manipulating protein targeting, advances in the field have been hampered by limited understanding of palmitoylation enzymology and consensus motifs. In order to define the complement of S-acylated proteins in the macrophage, we treated RAW 264.7 macrophage membranes with hydroxylamine to cleave acyl thioesters, followed by biotinylation of newly exposed sulfhydryls and streptavidin-agarose affinity chromatography. Among proteins identified by LC-MS/MS, S-acylation status was established by spectral counting to assess enrichment under hydroxylamine versus mock treatment conditions. Of 1183 proteins identified in four independent experiments, 80 proteins were significant for S-acylation at false discovery rate = 0.05, and 101 significant at false discovery rate = 0.10. Candidate S-acylproteins were identified from several functional categories, including membrane trafficking, signaling, transporters, and receptors. Among these were 29 proteins previously biochemically confirmed as palmitoylated, 45 previously reported as putative S acylproteins in proteomic screens, 24 not previously associated with palmitoylation, and three presumed false-positives. Nearly half of the candidates were previously identified by us in macrophage detergent-resistant membranes, suggesting that palmitoylation promotes lipid raft-localization of proteins in the macrophage. Among the candidate novel S-acylproteins was phospholipid scramblase 3 (Plscr3), a protein that regulates apoptosis through remodeling the mitochondrial membrane. Palmitoylation of Plscr3 was confirmed through (3)H palmitate labeling. Moreover, site-directed mutagenesis of a cluster of five cysteines (Cys159-161-163-164-166) abolished palmitoylation, caused Plscr3 mislocalization from mitochondrion to nucleus, and reduced macrophage apoptosis in response to etoposide, together suggesting a role for palmitoylation at this site for mitochondrial targeting and pro-apoptotic function of Plscr3. Taken together, we propose that manipulation of protein palmitoylation carries great potential for intervention in macrophage biology via reprogramming of protein localization. PMID- 21785168 TI - Redefining diabetes: is it really necessary? PMID- 21785167 TI - Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity. AB - alpha-Phenyl-N-tert-butylnitrone (PBN), a free radical spin trap, has been shown previously to protect retinas against light-induced neurodegeneration, but the mechanism of protection is not known. Here we report that PBN-mediated retinal protection probably occurs by slowing down the rate of rhodopsin regeneration by inhibiting RPE65 activity. PBN (50 mg/kg) protected albino Sprague-Dawley rat retinas when injected 0.5-12 h before exposure to damaging light at 2,700 lux intensity for 6 h but had no effect when administered after the exposure. PBN injection significantly inhibited in vivo recovery of rod photoresponses and the rate of recovery of functional rhodopsin photopigment. Assays for visual cycle enzyme activities indicated that PBN inhibited one of the key enzymes of the visual cycle, RPE65, with an IC(50) = 0.1 mm. The inhibition type for RPE65 was found to be uncompetitive with K(i) = 53 MUm. PBN had no effect on the activity of other visual cycle enzymes, lecithin retinol acyltransferase and retinol dehydrogenases. Interestingly, a more soluble form of PBN, N-tert-butyl-alpha-(2 sulfophenyl) nitrone, which has similar free radical trapping activity, did not protect the retina or inhibit RPE65 activity, providing some insight into the mechanism of PBN specificity and action. Slowing down the visual cycle is considered a treatment strategy for retinal diseases, such as Stargardt disease and dry age-related macular degeneration, in which toxic byproducts of the visual cycle accumulate in retinal cells. Thus, PBN inhibition of RPE65 catalytic action may provide therapeutic benefit for such retinal diseases. PMID- 21785169 TI - Association between levels of circulating soluble CD40 ligand on admission and in hospital events among acute coronary syndrome patients. AB - AIM: to investigate the association between on admission circulating sCD40L level and in-hospital events among patients admitted with acute coronary syndrome. METHODS: a short prognostic study which recruited consecutively patients with acute coronary syndrome (ACS) admitted in Intensive Coronary Care Unit (ICCU). INCLUSION CRITERIA: between 35-70 years old, onset of chest pain 24 hours and approved informed consent. Patients with acute infection, renal failure, heart failure, liver cirrhosis, chronic inflammation, venous thromboemboli, malignancies and pregnancy were excluded. Blood samples of sCD40L was withdrawn on admission and measured with ELISA. Follow-up was conducted during intensive hospitalization. In-hospital events were re-infarction, acute heart failure, cardiogenic shock and mortality. RESULTS: of 77 study patients, 64 (83%) were male with mean age 55 years old. In-hospital events occurred in 33 (43%) patients, namely mortality 6 (18%), acute heart failure 25 (75%) and cardiogenic shock 2 (6%). The level of circulating sCD40L was significantly higher in patients with in-hospital events compared with those without in-hospital events (8559.6 pg/ml vs. 7393.8 pg/ml respectively, p value <0.05). Using ROC curve, we determined cut-off point 7107.0 pg/ml. On multivariate analysis, high sCD40L (7107.0 pg/ml) had a trend to increase the risk of in-hospital events, although statistically not significant (adjusted OR 1.66, 95% CI : 0.56-4.87; p value 0.36). CONCLUSION: on admission circulating sCD40L level was higher in patients with in-hospital events. Nonetheless, high sCD40L level did not significantly associate with increasing risk to develop in-hospital events among ACS. PMID- 21785170 TI - Adjustment of cut-off values in ELISA for detection of Helicobacter pylori infection. AB - AIM: to detect Helicobacter pylori infection in Indonesian patients. METHODS: serum samples were collected from patients referred for upper endoscopy. Gastric biopsies were taken for polymerase chain reaction (PCR) examination. The gold standard for diagnosing H. pylori infection was 294 bp amplication target of PCR examination with primer ureC. The serum samples were tested for H. pylori antibodies using Biohit Anti-H. pylori ELISA according to the manufacturer instructions. By using analysis of receiver operating characteristic (ROC), an optimal cut-off point of serum IgG H.pylori and area under curve (AUC) ROC were determined. The accuracy of test was calculated according to a new cut-off value. Significance level was determined by p value <0.05. RESULTS: a total of 81 patients were recruited, 31 (41.9%) subjects were H. pylori-positive. We found a new optimal cut-off point on serum IgG H.pylori at 15,2 IU/mL with AUC ROC of 0.84. By using the new cut-off value, we conclude that the Biohit Anti-H. pylori ELISA has a good sensitivity and specificity, i.e. 94.1% (95% CI 59.9 - 89.6) and 97.9% (95% CI 92.3 - 100.0) respectively. CONCLUSION: by adjusting new cut-off values for Indonesian patients, we are able to improve the performance of Biohit Anti-H. pylori ELISA. This study illustrates the importance of local validation. PMID- 21785171 TI - AADMA as a marker of endothelial dysfunction in prediabetic women. AB - AIM: to determine the correlation between glycohemoglobin (HbA1c) with level of asymmetric dimethylarginine (ADMA) in serum, between HbA1c and value of brachial artey flow-mediated dilatation (FMD) by ultrasound study, and between ADMA serum and FMD in prediabetes women. METHODS: the study was done in prediabetes women aged between 30-55 years of age in Cipto Mangunkusumo Hospital Jakarta (RSCM). Prediabetes was based on PERKENI criteria. Subject with fasting blood glucose less than 126 mg/dL and 2-hours blood glucose less than 200 mg/dL met the criteria. Laboratory test of HbA1c and ADMA plasma were performed. To asses brachial FMD, the left brachial artery diameter was measured both at rest and during reactive hyperemia. Increased flow was induced by inflation of pneumatic tourniquet around the forearm to a pressure of 50 mm Hg upper systolic pressure for 5 minutes, followed by release. Measurements of arterial diameter were performed at end diastole at rest and 60 seconds after cuff release. The vessel diameter in scans after reactive hyperemia was expressed as the percentage relative to resting scan (100%). All ultrasound scans were analyzed by a single reader. RESULTS: from 41 prediabetes subjects could be found correlation between ADMA serum with 2-hours post prandial blood glucose (p 0,003 and r 0,457) and HbA1c (p <0,001 and r 0,720). We also found correlation between FMD value with 2 hours post prandial blood glucose (p 0,01 and r -0.487) and HbA1c (p <0,001 and r -0.763). Besides that, there was correlation between ADMA serum with FMD value (p <0,001 and r -0,617). From multivariate analysis, we could determine that HbA1c is the influential factor of ADMA serum and FMD. CONCLUSION: in prediabetes women there was correlation between HbA1c with ADMA, between HbA1c with FMD and between ADMA serum with FMD. PMID- 21785172 TI - Prevalence of diabetes among suburban population of Ternate--a small remote island in the eastern part of Indonesia. AB - AIM: to study the prevalence of diabetes in a sub-urban population of one of the less developed provinces in eastern part of Indonesia and its associated risk factors. METHODS: a cross-sectional survey was conducted in 2008 in adult population of TernateCityof North Moluccas Province, Indonesia, aged 20 years or more. Subjects were interviewed regarding diabetes risk factors by a standard questionnaire.Anthropometric (height, weight, waist and hip circumference) and blood pressure measurements were also taken. Diagnosis of diabetes was established by measuring overnight fasting capillary blood glucose with a glucose meter. Venous blood was also drawn for blood lipid profiling. RESULTS: 495 subjects consisted of 187 (37.8%) men and 308 (62.2%) women aged 20 to 84 years (mean age 47.30+/-12.78)were enrolled. Prevalence of diabetes (fasting blood glucose >126 mg/dL) was 19.6%. Four independent risk factors were identified, i.e. age at 45 years or older (OR=4.1, 95% CI = 2.4-7.1), having a positive family history (OR=2.4, 95% CI=1.5-4.0), a body mass index more than 23 kg/m2 (OR=1.8, 95% CI=1.02-3.3) and triglycerides levels more than 200 mg/dL (OR=2.6, 95% CI=1.2-5.6). CONCLUSION: the prevalence of diabetes in Ternate City, a sub urban population in the eastern part of Indonesia is high. Having a family history of diabetes and being older are major risk factors of developing the disease. Metabolic factors are identified as the potential modifiable risk factors requiring intervention in the future. PMID- 21785173 TI - The association between infection burden in Iranian patients with acute myocardial infarction and unstable angina. AB - AIM: to evaluate the association of ischemic heart disease (IHD) with the number of pathogens (infection burden) among individuals with infection. METHODS: a total of 120 patients with IHD as the acute myocardial infarction (AMI; n=60) or unstable angina (UA; n=60) group and 60 healthy subjects with sex- and age matched as control group were enrolled in this study. Serum samples of all participants were tested for the presence of antibodies to Helicobacter pylori (H. pylori), cytomegalovirus (CMV), type-1 herpes simplex virus (HSV-1) and type- 2 HSV (HSV-2) by using ELISA. RESULTS: Regarding the association of the infection burden with IHD, the prevalence ratios and 95% confidence intervals (CI) were 3.18 (CI: 1.50-6.72; P<0.001) for 3 seropositivities and 3.83 (CI: 0.84-17.43; P<0.05) for 4 seropositivities. The rate of subjects with high infection burden (3 seropositivities) was significantly higher in IHD group as compared to control group (53.4% vs 21.6%; P<0.01). Moreover, the mean number of seropositivities was also significantly higher in patients with IHD in comparison to control group (2.47 vs 1.68; P<0.01). The seroprevalence of anti-H. pylori antibodies in AMI and UA groups was significantly higher compared to control group (P<0.0001). The seroprevalence of anti-CMV antibodies in AMI and UA group was also significantly higher than those observed in control group (P<0.01). Moreover, the seroprevalence of anti-HSV-1 antibodies was significantly higher in AMI and UA groups in comparison to control group (P<0.001). The seroprevalence of anti-HSV-2 antibodies was similarly expressed in patients and healthy control group. CONCLUSION: the infection burden was significantly higher in patients with IHD, which represent that the parameter should also be considered as an independent risk factor for development of IHD. The seroprevalence of H. pylori, CMV and HSV 1 were also higher in patients with IHD. PMID- 21785174 TI - Safety and feasibility of combined granulocyte colony stimulating factor and erythropoetin based-stem cell therapy using intracoronary infusion of peripheral blood stem cells in patients with recent anterior myocardial infarction: one-year follow-up of a phase 1 study. AB - AIM: to assess the safety and feasibility of combined granulocyte colony stimulating factor (G-CSF) and erythropoietin (EPO) based intracoronary peripheral blood stem cells (PBSCs) therapy in patients with recent myocardial infarction (RMI) who had successful reperfusion therapy with drug-eluting stent. METHODS: a total of 18 patients diagnosed with anterior ST-segment elevation AMI who had successful percutaneous coronary intervention (PCI) with drug-eluting stent implantation within 15 days after onset of symptom were enrolled. PBSCs were harvested and injected into the infarct-related artery after 5 consecutive days of G-CSF administration. Recombinant human erythropoietin was administered at the time of intracoronary PBSCs injection. RESULTS: there were no procedural and periprocedural complications, such as ventricular arrhythmia, visible thrombus formation, distal embolization, injury of the coronary artery associated with the cell infusion catheterization procedure or elevation of CK-MB of more than two-times. After PBSCs injection, all patients had grade III myocardial blush grade. At follow-up of 21.1+/-5.5 months (range 12 to 30 months) there was no death, no re-infarction, no target lesion revascularization nor re hospitalization for heart failure. Paired cardiac MRI demonstrated no change in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) at 3 months, but they increased significantly at one year. Despite this, left ventricular ejection fraction (LVEF), wall motion score index (WMSI) and perfusion score index (PSI) improved at 3 months and remained stable at one year. The percentage of late gadolinium enhancement to LV mass (%LGE) were continuously improved until one year. There was no correlation between the level of CD34+, CD 45+, other cell subtypes as well as total number of PBSCs injected to the changes of LVEDV, LVESV, LVEF, WMSI, PSI, and %LGE (p >0.05). CONCLUSION: combined G-CSF and EPO based- intracoronary infusion of PBSCs in patients RAMI is safe and feasible. PMID- 21785175 TI - Diagnosis and management of acromegaly: giant invasive adenoma. AB - Acromegaly is a rare disorder caused by excessive growth hormone. Majority of acromegaly are due to pituitary adenoma. It is estimated that 5% of pituitary adenoma become invasive and may grow to gigantic sizes (>4 cm in diameter). We would like to describe a man with giant invasive adenoma. We describe the case of 52-year-old man with acromegaly. The patient was presented to medical care because of hemichorea. He also had visual field defect, uncontrolled diabetes, and dyslipidemia. Hormonal profile showed increment of GH 2-hour after a standard 75-g oral glucose load and of high IGF-1 level with low level of FSH and LH. The next was performed by pituitary imaging. Magnetic resonance imaging showed a macroadenoma with diameter 2.3x3.5x6.6 cm3 that fills the sella tursica, and enlarges into suprasella, genu of corpus collosum, and invades third ventricle. This report describes a rare case of acromegalic patient with giant invasive adenoma. This could be a demonstrative case and lesson for diagnosis and manage acromegalic patient. PMID- 21785176 TI - Dengue virus infection: predictors for severe dengue. AB - Dengue virus (DENV) infection is a mosquito born disease that is endemic in all WHO regions, except European region, and may present a broad range of severity. It may appear as an asymptomatic condition, dengue fever (DF), or life threatening forms, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), or the currently defined severe dengue. Currently there are means to diagnose DENV infection, but there is no accurate means to early predict the progress into severe manifestations. Therefore, this article addresses the factors that might be used to predict the progress into severe dengue. Predictors for severe dengue are the previously established warning signs, and coexisting conditions, as is recommended by the WHO, in addition to Caucasian race, and people with AB blood group. In the future, viral load assessment, viral serotype testing, NS1, cytokine, elastase, hyaluronan, soluble thrombomodulin, and NO level, and circulating endothelial cell detection test are promising to be studied and developed as early predictors of severe dengue. PMID- 21785177 TI - The difficulty of medical management of Cushing disease. PMID- 21785178 TI - The role of omega-3 fatty acids contained in olive oil on chronic inflammation. AB - Nowadays, people have been eating lots of unhealthy dietary excesses, that make them have chronic inflammatory diseases or known as chronic diseases. Countless millions of people worldwide can not help eating selectively massive quantities of unhealthy foods, until they become sick, often mortality. The omega-6 fatty acids account for the majority of PUFA (Poly Unsaturated Fatty Acids) in the food supply. They are the pre-dominant PUFA in all diets, especially the western diets, which produce pro-inflammatory metabolic products. The persistent antigenic or cytotoxic effects will lead to chronic inflammation. Olive tree is native to the Mediterranean basin and parts of Asia Minor. Its compression extracted oil from the fruit has a wide range of therapeutic and culinary applications. It had been used as aphrodisiacs, emollients, laxatives, nutritives, sedatives, and tonics. In the later part of the 20th century, several studies had revealed that the olives in the Mediteranian diet is linked to a reduced incidence of degenerative diseases. It is one of phytomedicine which has omega-3 fatty acid as its constituent, may inhibit inflammation composing chronic inflammatory process in many chronic diseases, such as coronary artery disease, rheumatoid arthritis, hypertension, and even cancer. PMID- 21785179 TI - Strategy of insulin intensification after basal failure for type 2 diabetes in the outpatient setting. AB - Type 2 diabetes has become a worldwide pandemic and the problem continues to grow. As the disease progresses, the majority of patients will require insulin therapy within 6 years of diagnosis. During the therapy, evaluation and intensification of the current treatment is required in order to achieve the good glycaemic state. In patients who are taking basal insulin or premix OD but failing to achieve the recommended glycaemic targets of HbA1c <6.5%-7%, one option is to intensify to a modern premixed insulin BID or TID. Its formulations have both basal and short or rapid-acting insulin capabilities, enabling them to cover both fasting and postprandial blood glucose levels. Other strategy is known as basal-plus method, basal plus 1 and then basal plus 2. This strategy is used by adding OD short-acting or rapid-acting insulin (analog) before having largest portion meal or before meal when blood glucose before the next meal is high. It is very important for clinicians to have the capability of choosing the right regimen based on individual's need and applying the right strategy to intensify the insulin therapy for their patients. PMID- 21785180 TI - Electronic structure, Born effective charges and spontaneous polarization in magnetoelectric gallium ferrite. AB - We present a theoretical study of the structure-property correlation in gallium ferrite, based on first-principles calculations followed by a subsequent comparison with experiments. The local spin density approximation (LSDA + U) of the density functional theory has been used to calculate the ground state structure, electronic band structure, density of states and Born effective charges. The calculations reveal that the ground state structure is orthorhombic Pc 2(1)n having A-type antiferromagnetic spin configuration, with lattice parameters matching well with those obtained experimentally. Plots of the partial density of states of constituent ions exhibit noticeable hybridization of Fe 3d, Ga 4s, Ga 4p and O 2p states. However, the calculated charge density and electron localization function show a largely ionic character of the Ga/Fe-O bonds which is also supported by a lack of any significant anomaly in the calculated Born effective charges with respect to the corresponding nominal ionic charges. The calculations show a spontaneous polarization of ~ 59 uC cm( - 2) along the b-axis which is largely due to asymmetrically placed Ga1, Fe1, O1, O2 and O6 ions. PMID- 21785181 TI - Effects of temperature on transition energies of GaAsSbN/GaAs single quantum wells. AB - The energy transitions of GaAsSbN/GaAs strained-layer single quantum wells (QWs), grown by molecular-beam epitaxy, are studied in detail, using photoluminescence (PL) and photoreflectance (PR) spectroscopies. The optical transitions energy observed in the PL and PR spectra of GaAsSbN/GaAs QWs show a strong decrease with a small increase in the N composition. These effects are explained through the interaction between the conduction band and a narrow resonant band formed by nitrogen states in the GaAsSbN alloy. The temperature dependence of ground-state energy of strained-layer QWs is analyzed using the Bose-Einstein relation in the temperature range from 9 to 295 K. The parameters that describe the temperature variations of the ground-state energies are evaluated and discussed. PMID- 21785182 TI - Novel hexagonal polytypes of silver: growth, characterization and first principles calculations. AB - We report a study of the relative effects of dimensional and kinetic constraints on the stabilization of metastable, polytypic forms of metallic silver. We show that the hexagonal 4H polytype (hitherto observed only in size-constrained systems) can be produced in the form of bulk thin films by suitably slowing down the growth kinetics. Further, using extremely slow growth conditions, we have been successful in depositing a novel, two-dimensional, metastable polytype (2H) of silver, which is highly reactive (easily oxidized) and has a density 23% lower than normal silver. First-principles calculations based on density functional theory confirm that the 4H structure is relatively stable. However, local stability analysis via a determination of the phonon dispersion of the 2H structure reveals that it is only marginally stable with an energy surface that is rather flat or weakly varying with respect to many of the modes. This makes a large contribution to the configurational entropy and is probably the reason for the metastability of the observed 2H polytype with an unusually large lattice constant along the c-direction. PMID- 21785183 TI - Monte Carlo simulations for describing the ferroelectric-relaxor crossover in BaTiO3-based solid solutions. AB - The properties induced by the M(4+) addition (M = Zr, Sn, Hf) in BaM(x)Ti(1 x)O(3) solid solutions have been described on the basis of a 2D Ising-like network and Monte Carlo calculations, in which BaMO(3) randomly distributed unit cells were considered as being non-ferroelectric. The polarization versus temperature dependences when increasing the M(4+) concentration (x) showed a continuous reduction of the remanent polarization and of the critical temperature corresponding to the ferroelectric-paraelectric transition and a modification from a first-order to a second-order phase transition with a broad temperature range for which the transition takes place, as commonly reported for relaxors. The model also describes the system's tendency to reduce the polar clusters' average size while increasing their stability in time at higher temperatures above the Curie range, when a ferroelectric-relaxor crossover is induced by increasing the substitution (x). The equilibrium micropolar states during the polarization reversal process while describing the P(E) loops were comparatively monitored for the ferroelectric (x = 0) and relaxor (x = 0.3) states. Polarization reversal in relaxor compositions proceeds by the growth of several nucleated domains (the 'labyrinthine domain pattern') instead of the large scale domain formation typical for the ferroelectric state. The spatial and temporal evolution of the polar clusters in BaM(x)Ti(1-x)O(3) solid solutions at various x has also been described by the correlation length and correlation time. As expected for the ferroelectric-relaxor crossover characterized by a progressive increasing degree of disorder, local fluctuations cause a reducing correlation time when the substitution degree increases, at a given temperature. The correlation time around the Curie temperature increases, reflecting the increasing stability in time of some polar nanoregions in relaxors in comparison with ferroelectrics, which was experimentally proved in various types of relaxors. PMID- 21785184 TI - Photoluminescence from exciton-polarons in GaGdN/AlGaN multiquantum wells. AB - Exciton-polaron formation in GaGdN/AlGaN multiquantum wells was inferred from the lower energy of the photoluminescence peak observed for the GaGdN quantum wells (QWs) compared with GaN QWs. The rather low value of the excitonic transition energy is attributed to exciton-polarons bound to the Gd ions. Exciton-polarons are most likely to occur due to the lattice distortion around the substituted Gd ions in addition to the exchange interaction between Gd(3+) magnetic ions and the strongly confined charge carrier spins in GaGdN QWs. The mechanism of exciton polaron formation is discussed. The magnetic behavior is briefly presented. PMID- 21785185 TI - Determination of the magnetic ground state in the martensite phase of Ni-Mn-Z (Z = In, Sn and Sb) off-stoichiometric Heusler alloys by nonlinear AC susceptibility. AB - DC and AC magnetic measurements were carried out to clarify the difference in the magnetic ground state depending on the kinds of Z element used in the martensite phase in Ni-Mn-Z (Z = In, Sn and Sb) off-stoichiometric Heusler alloys. Magnetic field cooling effects were observed in the DC thermomagnetization curves in the low temperature regions, and a frequency dependence on AC susceptibility was also observed in both real and imaginary parts of the susceptibility. Negative divergence was clearly observed in nonlinear AC susceptibility only for the Ni(50)Mn(40)Sb(10) alloy, suggesting that the magnetic feature of its ground state is the spin-glass state. The magnetic ground state of the martensite phase in these alloys would relate to the magnetic configuration of the Mn atoms in the ferromagnetic austenite phase. PMID- 21785186 TI - Optimized effective potential model for the double perovskites Sr2 - xYxVMoO6 and Sr2 - xYxVTcO6. AB - In an attempt to explore half-metallic properties of the double perovskites Sr(2 x)Y(x)VMoO(6) and Sr(2 - x)Y(x)VTcO(6), we construct an effective low-energy model, which describes the behavior of the t(2g) states of these compounds. All parameters of such a model are derived rigorously on the basis of first principles electronic structure calculations. In order to solve this model, we employ the optimized effective potential method and treat the correlation interactions in the random phase approximation. Although correlation interactions considerably reduce the intraatomic exchange splitting in comparison with the Hartree-Fock approach, this splitting still substantially exceeds the typical values obtained in the local-spin-density approximation (LSDA), which alters many predictions based on the LSDA. Our main results are summarized as follows. (i) All ferromagnetic states are expected to be half-metallic. However, their energies are generally higher than those of the ferrimagnetic ordering between V and Mo/Tc sites (except Sr(2)VMoO(6)). (ii) All ferrimagnetic states are metallic (except fully insulating Y(2)VTcO(6)) and no half-metallic antiferromagnetism has been found. (iii) Moreover, many of the ferrimagnetic structures appear to be unstable with respect to the spin-spiral alignment. Thus, the true magnetic ground state of these systems is expected to be more complex. In addition, we discuss several methodological issues related to nonuniqueness of the effective potential for the half-metallic and magnetic insulating states. PMID- 21785187 TI - Atomic and electronic structure of ultrathin fluoride barrier layers at the oxide/Si interface. AB - A SrF(2) ultrathin barrier layer on Si(001) is used to form a sharp interface and block reactivity and intermixing between the semiconductor and a Yb(2)O(3) overlayer. Yb(2)O(3)/Si(001) and Yb(2)O(3)/SrF(2)/Si(001) interfaces grown in ultra high vacuum by molecular beam epitaxy are studied by photoemission and x ray absorption fine structure. Without the fluoride interlayer, Yb(2)O(3)/Si(001) presents an interface reacted region formed by SiO(x) and/or silicate compounds, which is about 9 A thick and increases up to 14-15 A after annealing at 500-700 degrees C. A uniform single layer of SrF(2) molecules blocks intermixing and reduces the oxidized Si region to 2.4 A after deposition and to 3.5 A after annealing at 500 degrees C. In both cases we estimate a conduction band offset and a valence band offset of ~ 1.7 eV and 2.4 eV between the oxide and Si, respectively. X-ray absorption fine structure measurements at the Yb L(III) edge suggest that the Yb oxide films exhibit a significant degree of static disorder with and without the fluoride barrier. Sr K edge measurements indicate that the ultrathin fluoride films are reacted, with the formation of bonds between Si and Sr; the Sr-Sr and Sr-F interatomic distances in the ultrathin fluoride barrier film are relaxed to the bulk value. PMID- 21785188 TI - Fulvic acid inhibits aggregation and promotes disassembly of tau fibrils associated with Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-beta) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products. PMID- 21785190 TI - High-tech orthodontics. PMID- 21785189 TI - Lack of Association Between COMT Polymorphisms and Apathy in Alzheimer's Disease. AB - We tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD). We analyzed a cohort of 105 Caucasian individuals with AD (age = 79.3 +/- 7.03 years; MMSE = 20.2 +/- 4.4) according to the presence of apathy, as defined either by the Neuropsychiatric Inventory or the Apathy Inventory. Polymorphisms in seventeen SNPs in COMT were examined. A replication cohort consisting of 176 Caucasian AD subjects in the ADNI database was also analyzed. None of the candidate gene SNPs were significantly associated with the presence of apathy in either cohort. We did not find any SNPs in COMT that were consistently associated with apathy in individuals with AD. PMID- 21785191 TI - Efficient tooth movement with new technologies for customized treatment. PMID- 21785192 TI - The digital-titanium Herbst. PMID- 21785193 TI - En-masse retraction using skeletal anchorage in the tuberosity and retromolar region. PMID- 21785194 TI - Wire jigs for stabilizing lingual retainers. PMID- 21785195 TI - Late expression of Class III malocclusion. PMID- 21785196 TI - A power arm for canine retraction with miniscrew anchorage. PMID- 21785197 TI - Non-surgical correction of skeletal open bite: A goal-oriented approach evaluated by CBCT. PMID- 21785198 TI - Orthodontic closure of a midline diastema with an infrabony defect. PMID- 21785199 TI - Quick conversion of an expander to a transpalatal arch. PMID- 21785200 TI - The OrthoCAD iOC intraoral scanner: A six-month user report. PMID- 21785201 TI - Anatomical guidelines for miniscrew insertion: Vestibular interradicular sites. PMID- 21785202 TI - Unilateral application of the Carriere Distalizer. PMID- 21785203 TI - Analog meets digital. PMID- 21785204 TI - Efficient tooth movement with early full-size archwires. PMID- 21785205 TI - A three-dimensional setup model with dental roots. PMID- 21785206 TI - Importance of the occlusal plane in virtual treatment planning. PMID- 21785207 TI - Mandibular molar protraction with the Twin Force Bite Corrector in a Class II patient. PMID- 21785208 TI - Closure of a minor midline diastema using Essix trays. PMID- 21785209 TI - An in-office wire-bending robot for lingual orthodontics. PMID- 21785210 TI - Quantity, not quality, of antibody response decreased in the elderly. AB - The burden of disease during seasonal influenza epidemics is felt most keenly among the very young and the elderly. Although vaccination effectively protects children and young adults against infection, it has limited efficacy in elderly individuals. This has been linked to a reduced ability to induce a robust serum antibody response. In this issue of the JCI, Sasaki et al. identify some of the cellular and molecular deficits that underlie the reduced serum antibody response induced by influenza vaccination in elderly individuals. Importantly, they show that it is the quantity of the response, and not its quality, that needs to be improved if we are to enhance the success of influenza vaccination in this vulnerable population. PMID- 21785211 TI - Oxidized CaMKII: a "heart stopper" for the sinus node? AB - Each normal heart beat is triggered by an electrical impulse emitted from a group of specialized cardiomyocytes that together form the sinoatrial node (SAN). In this issue of the JCI, Swaminathan and colleagues demonstrate a new molecular mechanism that can disrupt the normal beating of the heart: angiotensin II - typically found in increased levels in heart failure and hypertension - oxidizes and activates Ca2+/calmodulin-dependent kinase II via NADPH oxidase activation, causing SAN cell death. The loss of SAN cells produces an electrical imbalance termed the "source-sink mismatch," which may contribute to the SAN dysfunction that affects millions of people later in life and complicates a number of heart diseases. PMID- 21785212 TI - Shock and awe: unleashing the heat shock response to treat Huntington disease. AB - The heat shock response (HSR) is a highly conserved protective mechanism that enables cells to withstand diverse environmental stressors that disrupt protein homeostasis (proteostasis) and promote protein misfolding. It has been suggested that small-molecule drugs that elicit the HSR by activating the transcription factor heat shock factor 1 might help mitigate protein misfolding and aggregation in several devastating neurodegenerative disorders, including Huntington disease (HD). In this issue of the JCI, Labbadia et al. use a brain-penetrant Hsp90 inhibitor, HSP990, to induce the HSR in mouse models of HD. Unexpectedly, they observed that HSP990 confers only transient amelioration of a subset of HD related phenotypes, because alterations in chromatin architecture impair the HSR upon disease progression. These findings suggest that synergistic combination therapies that simultaneously unleash the HSR and prevent its impairment are likely to be needed to restore proteostasis in HD. PMID- 21785213 TI - Of SMN in mice and men: a therapeutic opportunity. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that predominantly affects motor neurons, resulting in progressive muscular atrophy and weakness. SMA arises due to insufficient survival motor neuron (SMN) protein levels as a result of homozygous disruption of the SMN1 gene. SMN upregulation is a promising and potent treatment strategy for this currently incurable condition. In this issue of the JCI, two independent research groups report novel observations in mouse models of severe SMA that provide hope that this approach will afford meaningful benefit to individuals with SMA. PMID- 21785214 TI - Was Feuerbach right: are we what we eat? AB - Food and stress are powerful modulators of the body-mind connection, which is imbalanced in obese individuals. Why do we choose chocolate over an apple when overworked and stressed, and why does comfort food make us feel better? Two independent studies in the JCI, one in this issue, home in on the role of stress on gut hormones and food choices and, conversely, on the effect of the intestinal system on modulation of brain activity by sadness. These studies broaden our understanding of the ties between food and mood and underscore promising targets for obesity treatments. PMID- 21785215 TI - Oxidized CaMKII causes cardiac sinus node dysfunction in mice. AB - Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47-/- mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients. PMID- 21785216 TI - Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that is characterized by the loss of motor neurons, resulting in progressive muscle atrophy. It is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. A potential treatment strategy for SMA is to upregulate levels of SMN protein. Several agents that activate STAT5 in human and mouse cell lines enhance SMN expression from the SMN2 gene and can compensate, at least in part, for the loss of production of a functional protein from SMN1. Here, we have shown that prolactin (PRL) increases SMN levels via activation of the STAT5 pathway. PRL increased SMN mRNA and protein levels in cultured human and mouse neuronal cells. Administration of STAT5-specific siRNA blocked the effects of PRL, indicating that the PRL-induced transcriptional upregulation of the SMN-encoding gene was mediated by activation of STAT5. Furthermore, systemic administration of PRL to WT mice induced SMN expression in the brain and spinal cord. Critically, PRL treatment increased SMN levels, improved motor function, and enhanced survival in a mouse model of severe SMA. Our results confirm earlier work suggesting STAT5 pathway activators as potential therapeutic compounds for the treatment of SMA and identify PRL as one such promising agent. PMID- 21785217 TI - Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. AB - Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated. PMID- 21785218 TI - Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. AB - During seasonal influenza epidemics, disease burden is shouldered predominantly by the very young and the elderly. Elderly individuals are particularly affected, in part because vaccine efficacy wanes with age. This has been linked to a reduced ability to induce a robust serum antibody response. Here, we show that this is due to reduced quantities of vaccine-specific antibodies, rather than a lack of antibody avidity or affinity. We measured levels of vaccine-specific plasmablasts by ELISPOT 1 week after immunization of young and elderly adults with inactivated seasonal influenza vaccine. Plasmablast-derived polyclonal antibodies (PPAbs) were generated from bulk-cultured B cells, while recombinant monoclonal antibodies (re-mAbs) were produced from single plasmablasts. The frequency of vaccine-specific plasmablasts and the concentration of PPAbs were lower in the elderly than in young adults, whereas the yields of secreted IgG per plasmablast were not different. Differences were not detected in the overall vaccine-specific avidity or affinity of PPAbs and re-mAbs between the 2 age groups. In contrast, reactivity of the antibodies induced by the inactivated seasonal influenza vaccine toward the 2009 pandemic H1N1 virus, which was not present in the vaccine, was higher in the elderly than in the young. These results indicate that the inferior antibody response to influenza vaccination in the elderly is primarily due to reduced quantities of vaccine-specific antibodies. They also suggest that exposure history affects the cross-reactivity of vaccination-induced antibodies. PMID- 21785219 TI - Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment. PMID- 21785220 TI - Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans. AB - Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression. PMID- 21785221 TI - Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. AB - Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies - cytoplasmic inclusions containing alpha-synuclein protein aggregates - in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[18F]-dopamine (18F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18F-DA was followed by assessment of arterial plasma levels of the 18F-DA metabolite 18F-dihydroxyphenylacetic acid (18F-DOPAC). The ratio of myocardial 18F-DA to arterial 18F-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple system atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular 18F-DA uptake and accelerated 18F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18F-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention. PMID- 21785222 TI - Tumor necrosis factor-alpha converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha, which is released as a soluble form by ectodomain shedding of TNF-alpha converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-alpha expression in liver, and increased adipocyte size, macrophage infiltration and TNF-alpha and monocyte chemoattractant protein 1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders. PMID- 21785223 TI - Diabetes and old age could affect long-term patency of paramalleolar distal bypass for peripheral arterial disease in Japanese patients. AB - BACKGROUND: The results of paramalleolar distal bypass for critical limb ischemia in patients with peripheral arterial disease were reviewed to determine the factors affecting the long-term patency of this procedure in Japanese subjects. METHODS AND RESULTS: A total of 65 legs from 60 consecutive Japanese patients with critical limb ischemia who underwent distal bypass to the ankle were retrospectively reviewed. Postoperative graft patency, morbidity and mortality were analyzed. All patients were monitored during a mean follow-up period of 2.2 +/- 1.7 years (median, 1.7 years). The accumulated primary and secondary patency rates were both 81.0% at 1 year and 78.7% at 3 and 5 years. The amputation-free rates and survival rates at 1 year, and 3 and 5 years were 94.5% and 82.6%, 82.6% and 88.1%, and 76.7% and 69.7%, respectively. The Cox proportional hazard model was used to determine factors contributing to long-term results. Age (odds ratio, 1.1; P<0.05) and diabetes (odds ratio, 18.0; P<0.05) were found to be the significant determinant factors of graft occlusion. No variables were found to be significant determinant factors of amputation-free or survival rates. CONCLUSIONS: Distal bypass to the paramalleolar tibial artery is an effective strategy for peripheral arterial disease with reasonable long-term reliability. Diabetes and old age were found to be the possible determinant factors of graft failure in Japanese patients. PMID- 21785224 TI - Current state of symptomatic aortic valve stenosis in the Japanese elderly. AB - BACKGROUND: There have been few reports regarding treatment selection and prognosis of symptomatic aortic valve stenosis (AS) in the elderly in Japan. METHODS AND RESULTS: Sixty-one patients hospitalized between January 2000 and December 2007 for symptomatic severe AS were investigated. The average observation period was 27 months. Thirty-seven patients (61%) were diagnosed with AS for the first time on hospitalization. Thirty-six patients had onset of symptoms within 1 month before admission. Thirty-six patients received aortic valve replacement (group S) and 25 received medical therapy (group M). The patients in group M were older than those in group S (84.1 +/- 5.3 years vs. 74.2 +/- 4.6 years, P<0.001). Maximum flow velocity measured by echocardiography was lower in group M (4.5 +/- 0.3 m/s vs. 4.9 +/- 0.5 m/s, P<0 .01), but there was no difference in valve area between the 2 groups (0.62 +/- 0.19 cm2 vs. 0.57 +/- 0.15 cm2, P=0.12). One-year mortality rate derived from the Kaplan-Meier curve was higher in group M than group S (53.1% vs. 6.4%, respectively). On multivariate analysis, the only independent favorable prognostic factor was aortic valve replacement (HR: 0.02, 95%CI: 0.01-0.15, P<0.01). CONCLUSIONS: Medical therapy is often selected for treatment of symptomatic AS in the elderly, but the prognosis is very poor. Symptomatic severe aortic stenosis should be treated surgically, or with transcatheter aortic valve implantation in cases with high surgical risk. PMID- 21785225 TI - Elevated cystatin C levels predict the incidence of vasospastic angina. AB - BACKGROUND: Cystatin C, a marker for early stage chronic kidney disease, has been shown to be involved in cardiovascular disease. The relationship between serum cystatin C levels and coronary vasospastic angina (VSA), however, remains to be elucidated. The aim of the present study was to investigate whether elevated cystatin C levels predict the incidence of VSA. METHODS AND RESULTS: One hundred and ten patients were referred to hospital due to suspected VSA. VSA was evoked in 59 patients by a vasospasm provocation test with administration of acetylcholine into the coronary arteries. The patients with VSA had lower levels of high-density lipoprotein cholesterol and a higher history of cigarette smoking, higher levels of triglyceride, high-sensitivity C-reactive protein, and higher cystatin C levels compared with those without VSA. There were no differences in serum creatinine or estimated glomerular filtration rate between patients with and without VSA. Multivariate logistic regression indicated that history of smoking (odds ratio, 2.956 P<0.05) and cystatin C levels (odds ratio, 2.285; P<0.01) were independently associated with the incidence of VSA. CONCLUSIONS: Elevated cystatin C levels were associated with higher incidence of VSA, suggesting that mild renal dysfunction may be implicated in the pathogenesis of coronary artery spasm. PMID- 21785226 TI - Dynamics of reactive oxygen metabolites and biological antioxidant potential in the acute stage of Kawasaki disease. AB - BACKGROUND: The dynamics of oxidation/reduction control system activities using reactive oxygen metabolites (ROM) and biological antioxidant potential (BAP) in acute stage patients was evaulated to understand the mechanism of vascular injury and remodeling in Kawasaki disease (KD). METHODS AND RESULTS: ROM, BAP, high sensitivity C-reactive protein (hs-CRP), interleukin-1,2,6, and tumour necrosis factor-alpha in 19 KD patients were measured. ROM decreased in good correlation only with hs-CRP (P<0.05) at 2 weeks after intravenous immunoglobulin (IVIG). Patients were further classified as responding well (Group A) or responding poorly (Group B) to IVIG. Both treatment groups had significantly higher ROM values than the control group (P<0.01). ROM decreased in Group A both immediately and 2 weeks after the IVIG treatment (P<0.05), but it did not decrease in Group B until 2 weeks post-treatment (P<0.01). BAP levels were unremarkable in Group A, but were significantly lower in Group B than in both other groups (P<0.05). BAP increased in Group A 2 weeks after IVIG treatment (P<0.01), but remained low in Group B (P<0.01). CONCLUSIONS: Acute stage KD patients suffer from obvious hyperoxidant stress, and improved in response to IVIG treatment in most patients. Blood BAP level might be a useful index for predicting responsiveness to IVIG the treatment. PMID- 21785227 TI - The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion. AB - Insulin secretion from pancreatic beta-cells is the only efficient means to decrease blood glucose concentrations. Glucose is the principal stimulator of insulin secretion with the ATP-sensitive K+ channel-voltage-gated Ca2+ channel mediated pathway being the primary one involved in glucose-stimulated insulin secretion. Recently, several reports demonstrated that some transient receptor potential (TRP) channels are expressed in pancreatic beta-cells and contribute to pancreatic beta-cell functions. Interestingly, six of them (TRPM2, TRPM4, TRPM5, TRPV1, TRPV2 and TRPV4) are thermosensitive TRP channels. Thermosensitive TRP channels in pancreatic beta-cells can function as multimodal receptors and cause Ca2+ influx and membrane depolarization at physiological body temperature. TRPM channels (TRPM2, TRPM4 and TRPM5) control insulin secretion levels by sensing intracellular Ca2+ increase, NAD metabolites, or hormone receptor activation. TRPV2 is involved not only in insulin secretion but also cell proliferation, and is regulated by the autocrine effects of insulin. TRPV1 expressed in sensory neurons is involved in beta-cell stress and islet inflammation by controlling neuropeptide release levels. It is thus clear that thermosensitive TRP channels play important roles in pancreatic beta-cell functions, and future analyses of TRP channel function will lead to better understanding of the complicated mechanisms involved in insulin secretion and diabetes pathogenesis. PMID- 21785228 TI - Total coronary artery plaque burden measured by cardiac computed tomography is associated with metabolic syndrome. AB - AIM: Increased coronary plaque burden, which could be involved in the pathogenesis of atherothrombotic events, is difficult to evaluate in the three major coronary arteries. The purpose of this study was to quantify coronary plaque volume using 64-slice computed tomography (CT). METHODS: We measured coronary plaque volume with our new protocol in 23 consecutive patients (48% men; 66 +/- 11 years old) who underwent cardiac CT for suspicion of coronary artery disease and had noncalcified plaques. We counted the total pixel volume of noncalcified plaques in the three major coronary arteries. RESULTS: The coronary plaque volume was 1.29 +/- 0.56 cm(3) in the right coronary artery, 1.29 +/- 0.42cm(3) in the left main coronary artery and left anterior descending artery, and 0.88 +/- 0.32 cm(3) in the left circumflex artery. The total coronary plaque burden (TCPB) was 3.45 +/- 1.02 cm(3)/patient and had a positive correlation with waist circumference (r =0.44, p < 0.05) and insulin resistance (r = 0.46, p < 0.05). TCPB was significantly greater in men (3.89 +/- 1.07 cm(3) vs. 3.06 +/- 0.82 cm(3) in women, p < 0.05), patients with diabetes or impaired glucose tolerance (3.77 +/- 0.94 cm(3) vs. 2.86 +/- 0.92 cm(3) in non-diabetics, p < 0.05), and patients with metabolic syndrome (3.91 +/- 0.95 cm(3) vs. 3.03 +/- 0.91 cm(3) in patients without metabolic syndrome, p < 0.05). CONCLUSIONS: Cardiac CT can provide a noninvasive assessment of TCPB, which was significantly associated with metabolic syndrome and its components. Measuring TCPB by CT could be an important strategy for identifying high-risk patients with suspected coronary artery disease. PMID- 21785229 TI - Accurate description of the cell survival and biological effect at low and high doses and LET's. AB - To accurately describe the radiation response over a wide dose and ionization density range Binomial and Poisson statistics have been combined with the recently developed potentially Repairable-Conditionally-Repairable (RCR) damage response model and the combination is shown to have several advantages for the accurate description of the cell survival at both low and very high doses and LET's, especially when compared with the classical Linear and Linear Quadratic cell survival models. Interestingly, the potentially and conditionally repairable damage types of the RCR model may also be linked to the two major radiation damage repair pathways of eukaryotic cells namely Non Homologous End Joining (NHEJ) and Homologous Recombination (HR) respectively. In addition it describes the damage interaction of low and high LET damage in different dose fractions more accurately than any other model (cf. (6) and Fig. 7d). This is of considerable importance when describing the response of tumors and normal tissues during pencil beam scanning with light ion beams where low and high LET dose fractions from the plateau and Bragg peak can interact synergistically when being delivered quasi simultaneously. In conclusion, considering the unique biological properties of light ion beams such as their increased effect on hypoxic tumors, their microdosimetric energy deposition heterogeneity and their pencil beam energy deposition kernels the largest clinical advantages are obtained with medium LET beams (? 20-50 eV/nm). This applies even for radiation resistant tumors, at least when the goal is to maximize tumor cure with minimal adverse reactions in normal tissues. PMID- 21785230 TI - Differences in sensitivity to DNA-damaging Agents between XRCC4- and Artemis deficient human cells. AB - Non-homologous end-joining (NHEJ) is the predominant pathway for the repair of DNA double-strand breaks (DSBs) in human cells. XRCC4 is indispensable to NHEJ and functions together with DNA ligase IV in the rejoining of broken DNA ends. Artemis is a nuclease required for trimming of some, but not all, types of broken DNA ends prior to rejoining by the DNA ligase IV/XRCC4 complex. To better understand the roles of these factors, we generated XRCC4- and Artemis-deficient cells from the human colon adenocarcinoma cell line HCT116 by gene targeting and examined their cellular responses to several DNA-damaging agents including X rays. As anticipated, kinetic analyses of gamma-H2AX foci and chromosomal aberrations after ionizing radiation (IR) demonstrated a serious incompetence of DSB repair in the XRCC4-deficient cells, and relatively moderate impairment in the Artemis-deficient cells. The XRCC4-deficient cells were highly sensitive to etoposide and 5-fluoro-2'-deoxyuridine as well as IR, and moderately sensitive to camptothecin, methyl methanesulfonate, cisplatin, mitomycin C, aphidicolin and hydroxyurea, compared to the parental HCT116 cells. The Artemis-deficient cells were not as sensitive as the XRCC4-deficient cells, except to cisplatin and mitomycin C. By contrast, the Artemis-deficient cells were significantly more resistant to hydroxyurea than the parental cells. These observations suggest that Artemis also functions in some DNA damage response pathways other than NHEJ in human cells. PMID- 21785231 TI - Detection of novel human MiRNAs responding to X-ray irradiation. AB - Up to now, more than 1048 human miRNAs have been identified. However, the recognition of new human miRNAs is becoming more and more difficult. Based on the hypothesis that the expression of some miRNAs can be induced by ionizing radiation, total RNAs of HeLa cells were isolated 1 h after exposure to 2 Gy of X rays, and total small RNAs were enriched and sequenced by PAGE and Solexa technology, respectively. As a result, 421 kinds of known miRNAs and 337 kinds of unknown sequences were identified, among which 10 novel miRNAs were characterized by bioinformatic approach and verified by qRT-PCR. Finally, putative targets of these miRNAs were predicted by TargetScan software and compared with known proteins down-regulated by radiation. It was confirmed that some of the targets of these novel miRNAs were radiation-related proteins. These results imply that these 10 novel miRNAs are radiation-related miRNAs. This study reveals a new way to find novel miRNAs. PMID- 21785232 TI - Visualization of heavy ion tracks by labeling 3'-OH termini of induced DNA strand breaks. AB - African green monkey kidney cells, CV-1, were irradiated with Carbon ions (LET: 735 keV/um Argon ions (LET: 3,000 keV/um) to visualize ion tracks through the cell nucleus by labeling the 3'-OH termini result of DNA strand breaks. The 3'-OH termini of DNA were labeled with BrdU-triphosphate catalyzed by TdT. This method of TUNEL (TdT-mediated dUTP Nick End labeling) is based on the specific binding of TdT to 3'-OH termini of DNA. Subsequent immuno-fluorescent staining with the primary monoclonal antibody against BrdU, followed by a secondary antibody of Alexa Fluor 488, was performed to visualize the BrdU labeled DNA termini. Images of the cell nuclei were acquired by confocal laser microscopy. When cell monolayers were irradiated perpendicularly with argon ions, induced DSBs in cell nuclei were identifiable as fluorescent spots. In another irradiation setup, when cells were irradiated at a small angle with incident argon ions, DNA strand breaks were detected as fluorescent stripes across the cell nucleus. These results demonstrate the induction of 3'-OH termini at sites of DNA strand breaks along Argon ion tracks. PMID- 21785233 TI - Photosynthetic capacity of Arabidopsis plants at the reproductive stage tolerates gamma irradiation. AB - The developmental stage has an influence on the overall responses of plants under biotic or abiotic stress conditions. However, there is a lack of data about the effects of ionizing radiation in plants at different developmental stages. We examined radiation sensitivity of Arabidopsis plants in terms of photosynthetic ability and oxidative stress resistance at two distinct vegetative and reproductive stages, which correspond to 23 and 43 d after seeding (DAS), respectively. When plants were exposed to gamma rays at a dose rate 50 Gy h(-1) for 4 h, they were characterized as various common or differential cellular responses depending on the developmental stage. Radial expansion of leaves, inhibition of non-photochemical quenching, and production of *O(2)(-) and H(2)O(2) under methyl viologen-induced photooxidative stress were commonly more conspicuous in the irradiated leaves of both plants than in the respective control. In contrast, the 23 and 43-DAS plants were explicitly discriminated in growth, chloroplast number & ultrastructure, photosynthetic pigment content & activity, and protein damage after gamma irradiation. Natural leaf senescence was thereby enhanced in the irradiated leaves of the 23-DAS plants, while it was reversely alleviated in those of the 43-DAS ones. These results suggest that photosynthetic machineries of Arabidopsis plants at the reproductive stage can be relatively tolerant to gamma rays of 200 Gy. PMID- 21785234 TI - 8-Aminoadenosine enhances radiation-induced cell death in human lung carcinoma A549 cells. AB - The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH(2)-Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH(2)-Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH(2) Ado. 8-NH(2)-Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and 9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8 NH(2)-Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and XIAP was observed. These results indicate that 8-NH(2)-Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors. PMID- 21785235 TI - RhG-CSF improves radiation-induced myelosuppression and survival in the canine exposed to fission neutron irradiation. AB - Fission-neutron radiation damage is hard to treat due to its critical injuries to hematopoietic and gastrointestinal systems, and so far few data are available on the therapeutic measures for neutron-radiation syndrome. This study was designed to test the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in dogs which had received 2.3 Gy mixed fission-neutron-gamma irradiation with a high ratio of neutrons (~90%). Following irradiation, rhG-CSF treatment induced 100% survival versus 60% in controls. Only two of five rhG-CSF treated dogs experienced leukopenia (white blood cells [WBC] count < 1.0 * 10(9)/L) and neutropenia (neutrophil [ANC] count < 0.5 * 10(9)/L), whereas all irradiated controls displayed a profound period of leukopenia and neutropenia. Furthermore, administration of rhG-CSF significantly delayed the onset of leukopenia and reduced the duration of leucopenia as compared with controls. In addition, individual dogs in the rhG-CSF-treated group exhibited evident differences in rhG-CSF responsiveness after neutron-irradiation. Finally, histopathological evaluation of the surviving dogs revealed that the incidence and severity of bone marrow, thymus and spleen damage decreased in rhG-CSF treated dogs as compared with surviving controls. Thus, these results demonstrated that rhG-CSF administration enhanced recovery of myelopoiesis and survival after neutron-irradiation. PMID- 21785236 TI - High LET radiation enhances nocodazole Induced cell death in HeLa cells through mitotic catastrophe and apoptosis. AB - To understand how human tumor cells respond to the combined treatment with nocodazole and high LET radiation, alterations in cell cycle, mitotic disturbances and cell death were investigated in the present study. Human cervix carcinoma HeLa cells were exposed to nocodazole for 18 h immediately followed by high LET iron ion irradiation and displayed a sequence of events leading to DNA damages, mitotic aberrations, interphase restitution and endocycle as well as cell death. A prolonged mitotic arrest more than 10 h was observed following nocodazole exposure, no matter the irradiation was present or not. The occurrence of mitotic slippage following the mitotic arrest was only drug-dependent and the irradiation did not accelerate it. The amount of polyploidy cells was increased following mitotic slippage. No detectable G(2) or G(1) arrest was observed in cells upon the combined treatment and the cells reentered the cell cycle still harboring unrepaired cellular damages. This premature entry caused an increase of multipolar mitotic spindles and amplification of centrosomes, which gave rise to lagging chromosomal material, failure of cytokinesis and polyploidization. These mitotic disturbances and their outcomes confirmed the incidence of mitotic catastrophe and delayed apoptotic features displayed by TUNEL method after the combined treatment. These results suggest that the addition of high-LET iron ion irradiation to nocodazole enhanced mitotic catastrophe and delayed apoptosis in HeLa cells. These might be important cell death mechanisms involved in tumor cells in response to the treatment of antimitotic drug combined with high LET radiation. PMID- 21785237 TI - High-dose-rate interstitial brachytherapy with computed tomography-based treatment planning for patients with locally advanced uterine cervical carcinoma. AB - The aims of this study were to carry out a dose volume analysis of high-dose-rate interstitial brachytherapy with computed tomography-based treatment planning and to investigate the treatment outcome of patients with locally advanced bulky and/or irregularly shaped uterine cervical carcinoma. Between July 2003 and December 2007, 15 patients were treated with external beam radiation therapy and high-dose-rate interstitial brachytherapy with or without intracavitary brachytherapy. Seven patients were treated with interstitial brachytherapy alone, and 8 were treated with combined use of intracavitary and interstitial brachytherapy. A comparison of the volume and dose parameters with intracavitary and interstitial brachytherapy in patients who received both treatments showed that the median D90 of the high-risk clinical target volume per fraction was 4.4 Gy with intracavitary brachytherapy and 5.6 Gy with interstitial brachytherapy, and the median V100 was 66% with intracavitary brachytherapy and 85% with interstitial brachytherapy. The median D2cc of the bladder with intracavitary and interstitial brachytherapy per fraction was 5.5 Gy and 4.7 Gy, respectively, and the median D2cc of the rectum with intracavitary and interstitial brachytherapy was 5.9 Gy and 4.1 Gy, respectively. The median follow-up time was 37 months, and the overall and progression-free survival rates for all patients at 3 years were 78% and 51%, respectively. The actuarial 2-year and 3-year locoregional control rates were 80% and 71%, respectively. Dose distribution was improved with image based interstitial brachytherapy, and satisfactory local control was achieved for patients with locally advanced uterine cervical carcinoma in which intracavitary brachytherapy may result in a suboptimal dose distribution. PMID- 21785238 TI - Prokinetic effect of the 5-HT4R agonist mosapride on canine gastric motility. AB - We assessed prokinetic action of gastroprokinetic agent, mosapride in dogs. Open label cross-over study. Six healthy beagles were administered single oral mosapride at doses of 0.5, 0.75, 1, and 2 mg/kg 30 min prior to feeding, followed by 1-week interval. The motility index (MI) of gastric contraction was ultrasonographically evaluated by change rate of antral area and contraction number. Significant increases in MI were observed at doses of 0.75 mg/kg (mean +/ SEM, 11.11 +/- 0.19), 1 mg/kg (11.65 +/- 0.34), and 2 mg/kg (12.04 +/- 0.34), compared with that of the control (9.37 +/- 0.51). Mosapride administration (2.0 mg/kg, BID) for 1 week had no adverse effects on blood tests or health of the animals. In conclusion, 0.75 to 2 mg/kg of mosapride produces gastric prokinetic actions without adverse effects. PMID- 21785239 TI - Relationship between bacterial translocation and isolation of enteric bacteria from extraintestinal organs in slaughtered pigs. AB - Enteric bacteria, especially Escherichia coli, have been isolated from porcine livers affected with ascariasis. We hypothesized that reason for this bacterial isolation was due to bacterial translocation (BT). In order to clarify the association between ascariasis and isolation of Enterobacteriaceae in the livers,12 pigs with ascariasis (ascariasis group), 12 pigs without ascariasis (non-ascariasis A group) were used. Jejunum, ileum, cecum, colon, livers, mesenteric lymph nodes (MLN), and portal blood were obtained from these pigs. Furthermore, in order to confirm the presence of BT in pigs, the samples mentioned above as well as spleens were obtained from 11 pigs without ascariasis (non-ascariasis B group) and 6 specific pathogen free (SPF) pigs without ascariasis (non-ascariasis SPF group). In the first experiment, the gram-negative bacteria were isolated from livers (66.7%), MLN (91.7%), and portal blood (55.6%) regardless the presence of ascariasis. In the second experiment, isolation rates of gram-negative and -positive bacteria were 52.9 and 66.7% for livers, 52.9 and 80% for MLN, 11.8 and 26.7% for spleens, and 40 and 20% for portal blood of the pigs examined, respectively. E. coli and Staphylococcus were the predominant isolates from these pigs. A large number of antigens immunodetected by E. coli polyclonal antibody were found in the damaged cecal mucosa. These findings present evidence that BT is generally observed in slaughtered pigs regardless the presence of ascariasis. This has challenged our notion that extraintestinal organs of pigs are usually maintained as sterile. PMID- 21785241 TI - Radiculopathy caused by osteoporotic vertebral fractures in the lumbar spine. AB - The clinical features of radiculopathy caused by osteoporotic vertebral fractures (OVFs) in the lumbar spine were investigated in 66 patients treated for pain caused by OVFs from January 2006 to December 2009. Ten of the patients complained of persistent radiculopathy. The cause of radiculopathy was initially diagnosed as lumbar canal stenosis (LCS) in seven patients, lumbar foraminal stenosis (LFS) in two, and both in one. One patient with LFS had reduced pain with conservative treatment, and the other nine needed surgical treatments. LCS was treated with posterior decompression, and LFS complicated with LCS at the same spinal level was treated with posterior lumbar interbody fusion (PLIF). Vertebroplasty was performed for one patient with LFS to attain indirect nerve root decompression achieved as a result of vertebral reconstruction and stabilization. Four of the patients treated with posterior decompression for LCS suffered from residual radiculopathy postoperatively, which was caused by LFS at the same level or the level below the treated level. Two patients underwent second operative procedure (PLIF) for recurrent radiculopathy. The Japanese Orthopedic Association and Visual Analogue Scale scores of the pain improved after operations, but the scores of the patients treated without spinal fusion gradually worsened during the follow-up period, whereas the scores of the patients treated with PLIF remained stable at various levels. Seven of the ten patients developed LFS following OVF, suggesting that radiculopathy following OVF involves LFS with high frequency. PMID- 21785240 TI - Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity using brain perfusion single-photon emission computed tomography in patients with major cerebral artery steno-occlusive diseases. AB - Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity using brain perfusion single-photon emission computed tomography (SPECT) were prospectively investigated in 100 patients with major cerebral artery, atherosclerotic, and steno-occlusive diseases. All patients underwent two SPECT studies (with and without acetazolamide challenge) at an interval of 2 or 3 days, received a questionnaire immediately after each SPECT study, and returned the answered questionnaire within 7 days after the study. None of the 100 patients studied experienced any symptoms during the SPECT study without acetazolamide challenge. Sixty-three patients (63%) developed symptoms during the SPECT study with acetazolamide challenge, such as headache, nausea, dizziness, tinnitus, numbness of the extremities, motor weakness of the extremities, and general malaise 1-3 hours (mean 1.6 hours) after administration of acetazolamide, and these symptoms lasted for 0.5-72 hours (mean 7.9 hours). Multivariate statistical analysis revealed that younger age (95% confidence interval [CI] 0.896-0.980, p = 0.0047) and female sex (95% CI 1.178-16.129, p = 0.0274) were significantly associated with development of symptoms with acetazolamide challenge. The incidences of the development of symptoms with acetazolamide challenge were 91% (21/23) and 41% (12/29) in subgroups of women <70 years and men >=70 years, respectively. Patients should be informed of such adverse effects of intravenous acetazolamide administration prior to the acetazolamide challenge test for evaluation of cerebrovascular reactivity. PMID- 21785242 TI - Usefulness of intraoperative computed tomography in surgery for low-grade gliomas: a comparative study between two series without and with intraoperative computed tomography. AB - We have routinely used an intraoperative CT (i-CT) system in over 800 neurosurgical procedures since 1997. To investigate the utility of i-CT in low grade glioma (LGG) surgery, we investigated whether i-CT improved the extent of tumor resection and prognosis in 46 patients with histologically confirmed LGG consisting of 27 patients with World Health Organization grade II astrocytoma, 12 with oligodendroglioma, and 7 with oligoastrocytoma. The patients were divided into two groups, 23 who underwent tumor resection without i-CT (non i-CT group) and 23 who underwent surgery using i-CT (i-CT group). We investigated the extent of tumor resection, pre- and postoperative Karnofsky performance status scores, and overall survival in each group. The extent of tumor resection was biopsy 26.1%, partial resection 60.9%, subtotal resection 13.0%, and gross total resection 0% in the non i-CT group, and 4.4%, 21.7%, 34.8%, and 39.1%, respectively, in the i-CT group. The i-CT group showed significantly longer overall survival than the non i-CT group among patients with astrocytoma (p < 0.05) and oligodendroglioma or oligoastrocytoma (p < 0.005). Prolonged survival was related to the extent of resection. There were no significant differences between pre- and postoperative Karnofsky performance status scores between the groups. Surgical resection using i-CT may improve the outcomes of patients with LGG. Additional resection or emergency treatment can be quickly performed as the surgical results are confirmed intraoperatively or immediately after the operation using i-CT. PMID- 21785243 TI - Chronological changes in astrocytes induced by chronic electrical sensorimotor cortex stimulation in rats. AB - Motor cortex stimulation (MCS) is a treatment option for various disorders such as medically refractory pain, poststroke hemiplegia, and movement disorders. However, the exact mechanisms underlying its effects remain unknown. In this study, the effects of long-term chronic MCS were investigated by observing changes in astrocytes. A quadripolar stimulation electrode was implanted on the dura over the sensorimotor cortex of adult rats, and the cortex was continuously stimulated for 3 hours, 1 week, 4 weeks, and 8 weeks. Immunohistochemical staining of microglia (ionized calcium-binding adaptor molecule 1 [Iba1] staining) and astrocytes (glial fibrillary acidic protein [GFAP] staining), and neuronal degeneration histochemistry (Fluoro-Jade B staining) were carried out to investigate the morphological changes following long-term chronic MCS. Iba1 staining and Fluoro-Jade B staining showed no evidence of Iba1-positive microglial changes or neurodegeneration. Following continuous MCS, GFAP-positive astrocytes were enlarged and their number increased in the cortex and the thalamus of the stimulated hemisphere. These findings indicate that chronic electrical stimulation can continuously activate astrocytes and result in morphological and quantitative changes. These changes may be involved in the mechanisms underlying the neuroplasticity effect induced by MCS. PMID- 21785244 TI - Ischemic stroke due to dissection of the middle cerebral artery treated by superficial temporal artery-middle cerebral artery anastomosis--case report. AB - A 62-year-old man presented with dissection of the right middle cerebral artery (MCA) manifesting as mild headache, right hemiparesis, and slurred speech. Magnetic resonance (MR) imaging and MR angiography revealed fresh infarction in the right basal ganglia, and severe stenosis and dilatation of the right MCA. Digital subtraction angiography approximately 24 hours after admission revealed a linear contrast defect indicating an intimal flap of the M(1) segment. The diagnosis was dissection of the MCA. His neurological deficits improved gradually. Although he was neurologically stable, diffusion-weighted MR imaging revealed enlarging infarct size over the right MCA territory, and the right M(1) segment had progressive stenosis. Superficial temporal artery (STA)-MCA anastomosis was performed on the 26th day. Follow-up angiography showed good patency of the STA-MCA anastomosis, repair of the dissection of the M(1) segment, and improvement of the flow in the MCA. The patient was discharged from our hospital with no neurological deficits. Although the dissection in this case was spontaneously repaired, STA-MCA anastomosis was useful to get through a critical time. If the stenosis shows further progression or the infarction size enlarges, STA-MCA anastomosis may be effective. PMID- 21785245 TI - Carotid-cavernous fistula caused by rupture of persistent primitive trigeminal artery trunk aneurysm--case report. AB - A 60-year-old female presented with a carotid-cavernous fistula (CCF) manifesting as left abducens nerve palsy. Left internal carotid digital subtraction angiography showed a persistent primitive trigeminal artery (PPTA) near the CCF. Super-selective angiography showed direct shunt flow between the PPTA trunk aneurysm and the left cavernous sinus. The aneurysm was successfully occluded with detachable coils. The CCF disappeared and the PPTA was preserved. The abducens nerve paralysis had disappeared 6 months later. CCF caused by a PPTA trunk aneurysm is extremely rare. We speculate that the PPTA trunk aneurysm formed and then ruptured due to hemodynamic stress caused by hypoplasia of the basilar artery. PMID- 21785246 TI - Intraoperative magnetic resonance imaging in the successful surgical treatment of an arteriovenous malformation--case report. AB - A 44-year-old female presented with left occipital arteriovenous malformation (AVM) manifesting as sudden onset of severe headache. Magnetic resonance (MR) imaging and conventional angiography showed the left occipital AVM with hemorrhage. Intraoperative MR imaging (iMR imaging) and intraoperative time resolved imaging of contrast-kinetics (iTRICKS) at 1.5 T revealed complete removal of the nidus of the AVM without conventional catheter angiography. Conventional catheter angiography is commonly used in preoperative and intraoperative examination of AVMs, and for documentation of the surgical outcome, but less-invasive techniques are desirable for both preoperative screening and intraoperative examination. iMR imaging with iTRICKS is less invasive and safer than conventional angiography for both brain tumor surgery and AVM surgery. PMID- 21785247 TI - Neuroendoscope-assisted removal of an organized chronic subdural hematoma in a patient on bevacizumab therapy--case report. AB - A 78-year-old Japanese man with a history of colon cancer was referred to our department of neurosurgery for the management of asymptomatic left chronic subdural hematoma (CSDH). He was receiving bevacizumab therapy for colon cancer, and the size of the CSDH increased or decreased depending on bevacizumab administration. Simple drainage was performed because of the risk of a critical increase in the size of CSDH during bevacizumab therapy, but since the CSDH was organized and firm, the drainage was insufficient. Therefore, neuroendoscope assisted craniotomy was performed, and the organized CSDH was almost completely removed. The present case indicates the possible involvement of bevacizumab in the occurrence of CSDH and the efficacy of the neuroendoscopic approach in the surgical treatment of organized CSDH. PMID- 21785248 TI - Spontaneous intracranial hypotension presenting without orthostatic headache complicated by acute subdural hematoma after drainage for chronic subdural hematoma--case report. AB - A 28-year-old man presented with a case of spontaneous intracranial hypotension (SIH) manifesting as a bilateral chronic subdural hematoma (CSDH) without orthostatic headache. He developed life-threatening acute SDH as a complication of CSDH drainage. Neurosurgeons should be aware that SIH patients do not always present with orthostatic headache. Brain magnetic resonance imaging with gadolinium may be recommended for young adults with non-traumatic CSDH before drainage to exclude SIH, even if they do not present with orthostatic headache. PMID- 21785249 TI - Angiocentric glioma and surrounding cortical dysplasia manifesting as intractable frontal lobe epilepsy--case report. AB - A 26-year-old man presented with a case of angiocentric glioma manifesting as medically refractory epilepsy. Magnetic resonance imaging revealed a hyperintense lesion in the right superior frontal gyrus on T(2)-weighted imaging, with cortical hyperintense rim on T(1)-weighted images and minimum contrast enhancement. Video-electroencephalography (EEG) monitoring characterized his seizures as originating from the right frontal lobe. Long-term EEG recording from implanted subdural electrodes disclosed epileptic activities extending beyond the margin of the radiological lesion. Extended cortical resection of the superior frontal gyrus including the tumor and the surrounding epileptic cortices was performed. Postoperatively, he became seizure-free with antiepileptic medication during a 12-month follow-up period. Histological examination of the surgical specimen showed the characteristic findings of angiocentric glioma. Associated cortical dyslamination consistent with cortical dysplasia was found in the surrounding cortex. Angiocentric glioma is a slow-growing or stable tumor frequently presenting with intractable epilepsy. Surgical treatment would be aimed primarily at control of epilepsy. Complete lesionectomy usually results in postoperative seizure freedom, but the present case shows evidence for associated cortical dysplasia with this tumor entity. Careful pre-surgical evaluation for epilepsy is necessary to achieve better seizure outcome. PMID- 21785250 TI - Primary central nervous system mucosa-associated lymphoid tissue lymphoma--case report. AB - A 55-year-old woman presented with an extremely rare primary central nervous system mucosa-associated lymphoid tissue (MALT) lymphoma manifesting as seizure and was subsequently diagnosed with dural MALT lymphoma in the cranium. Magnetic resonance imaging revealed a left frontal dural mass with peritumoral edema. Histological examination of the dural mass confirmed MALT lymphoma and revealed infiltration of small cells with irregular nuclear borders and expression of a B cell marker (CD20) but absence of CD5, CD10, CD23, and cyclinD1. Reactive T-cell infiltration was also seen. Subsequently, local irradiation (40 Gy/20 fractions) was performed. Magnetic resonance imaging showed complete remission just after irradiation was completed. There was no evidence of systemic MALT lymphoma. There has been no recurrence for 3 years without additional therapy. PMID- 21785251 TI - Surgical strategy for intracranial endodermal cyst--case report. AB - Two cases of endodermal cyst of the posterior fossa are reported. A 12-year-old girl presented with severe headache and vomiting caused by increased intracranial pressure. Computed tomography and magnetic resonance (MR) imaging showed a cystic mass occupying the ambient and quadrigeminal cisterns. A 65-year-old woman presented with dizziness, and MR imaging revealed a cystic mass in the posterior fossa. The two patients underwent surgery for decompression and resection of the cyst. Surgical specimens of the cyst walls consisted of a single layer of ciliated columnar epithelium. The diagnoses were endodermal cyst. The optimal surgical goal is total resection of the cyst wall, but the cyst wall sometimes tightly adheres to the adjacent nerves, vessels, and vital structures. The cyst must communicate adequately with the surrounding cerebrospinal fluid space, and a newly closed cyst space must be avoided, by the widest possible resection of the cyst wall. PMID- 21785252 TI - Surgical treatment of a calcified Rathke's cleft cyst with endoscopic extended transsphenoidal surgery--case report. AB - A 34-year-old male presented with a rare case of Rathke's cleft cyst (RCC) with calcification manifesting as persistent high fever and impaired consciousness. Physical findings revealed panhypopituitarism and bitemporal hemianopsia. Computed tomography showed mass lesions with marked calcification within the sella turcica and the suprasellar region. Magnetic resonance imaging showed solid and cystic components compressing the optic nerve. The preoperative diagnosis was craniopharyngioma. Initial endonasal transsphenoidal surgery (TSS) was performed with a surgical microscope, but the mass was extremely hard, so only partial removal was possible. Second endonasal extended TSS was performed with a neuroendoscope. The solid components were totally removed, but calcifications adhering to the optic nerve could not be removed completely. The histological diagnosis was RCC with marked granulation reaction. RCC with calcification is rare and difficult to differentiate from craniopharyngioma on neuroimages. Extremely thick calcification of the sella turcica enclosing granulation tissue and the cyst similar to armor, here called "armor-like calcification," is a characteristic imaging finding of RCC with calcification. The most important aspect is choosing a surgical approach to carefully and effectively relieve pressure upon the optic nerve. Endonasal extended TSS with an endoscope was effective in the present case. PMID- 21785253 TI - Spinal angiolipoma--case report. AB - A 69-year-old male presented with a rare spinal angiolipoma manifesting as history of back pain, and numbness in both lower limbs, which progressed over a period of 5 years. Total T10-T12 laminectomy was performed and the tumor was removed en bloc. The symptoms gradually improved postoperatively. Spinal angiolipoma is an uncommon benign extradural tumor of spine, which accounts for 0.14-1.2% of all spinal tumors and is a rare cause of spinal cord compression. Recognition of this entity is crucial as a benign and curable cause of paraplegia and back pain. PMID- 21785254 TI - Freehand technique for putaminal hemorrhage--technical note. AB - We designed a new endoscopic surgical procedure for putaminal hemorrhage (freehand technique) and evaluated its effectiveness and safety in patients with putaminal hemorrhage. Computed tomography (CT) data sets from 40 healthy patients were used. The CT data were transformed into three-dimensional images using AZE VirtualPlace(TM) Plus. The nasion and external auditory foramen were the intraoperative reference points. The median point from medial of the globus pallidus to the insula was the target point. The location of the burr hole point was 80-125 mm above and 27.5 mm lateral to the nasion, and the direction was parallel to the midline and a line drawn from the burr hole to the ipsilateral external auditory foramen. This point was used for 15 patients with putaminal hemorrhage. In all cases, only one puncture was required, and there were no complications. The median surgical time was 91.7 minutes, and the median hematoma removal rate was 95.9%. No recurrent bleeding or operative complications occurred. The freehand technique is a simple and safe technique for patients with putaminal hemorrhage. We believe that this technique of endoscopic hematoma evacuation may provide a less-invasive method for treating patients with putaminal hemorrhage. PMID- 21785255 TI - The discoveries of uranium 237 and symmetric fission - from the archival papers of Nishina and Kimura. AB - Shortly before the Second World War time, Nishina reported on a series of prominent nuclear physical and radiochemical studies in collaboration with Kimura. They artificially produced (231)Th, a member of the natural actinium series of nuclides, by bombarding thorium with fast neutrons. This resulted in the discovery of (237)U, a new isotope of uranium, by bombarding uranium with fast neutrons, and confirmed that (237)U disintegrates into element 93 with a mass number of 237. They also identified the isotopes of several middle-weighted elements produced by the symmetric fission of uranium. In this review article, the highlights of their work are briefly summarized along with some explanatory commentaries. PMID- 21785256 TI - Transport of silicon from roots to panicles in plants. AB - Silicon (Si) is the most abundant minerals in soil and exerts beneficial effects on plant growth by alleviating various stresses. The transport of Si from soil to the panicles is mediated by different transporters. Lsi1, belonging to a NIP group of the aquaporin family, is responsible for the uptake of Si from soil into the root cells in both dicots and monocots although its expression patterns and cellular localization differ with plant species. The subsequent transport of Si out of the root cells towards the stele is medicated by an active efflux transporter, Lsi2. Lsi1 and Lsi2 are polarly localized at the distal and proximal sides, respectively, of both exodermis and endodermis in rice root. Silicon in the xylem sap is presented in the form of monosilicic acid and is unloaded by Lsi6, a homolog of Lsi1 in rice. Lsi6 is also involved in the inter-vascular transfer of Si at the node, which is necessary for preferential Si distribution to the panicles. PMID- 21785257 TI - The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy. AB - In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease. PMID- 21785258 TI - Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels - "ABC method". AB - The current status of screening for gastric cancer-risk (gastritis A, B, C, D) method using combined assay for serum anti-Helicobacter pylori (Hp) IgG antibody and serum pepsinogen (PG) levels, "ABC method", was reviewed and the latest results of our ongoing trial are reported. It was performed using the following strategy: Subjects were classified into 1 of 4 risk groups based on the results of the two serologic tests, anti-Hp IgG antibody titers and the PG I and II levels: Group A [Hp(-)PG(-)], infection-free subjects; Group B [Hp(+)PG(-)], chronic atrophic gastritis (CAG) free or mild; Group C [Hp(+)PG(+)], CAG; Group D [Hp(-)PG(+)]), severe CAG with extensive intestinal metaplasia. Continuous endoscopic follow-up examinations are required to detect early stages of gastric cancer. Asymptomatic Group A, which accounts for 50-80% of all the subjects may be excluded from the secondary endoscopic examination, from the viewpoint of efficiency. Hp-infected subjects should be administered eradication treatment aimed at the prevention of gastric cancer. PMID- 21785259 TI - Increased numbers of oligodendrocyte lineage cells in the optic nerves of cerebroside sulfotransferase knockout mice. AB - Sulfatide is a myelin glycolipid that functions in the formation of paranodal axo glial junctions in vivo and in the regulation of oligodendrocyte differentiation in vitro. Cerebroside sulfotransferase (CST) catalyzes the production of two sulfated glycolipids, sulfatide and proligodendroblast antigen, in oligodendrocyte lineage cells. Recent studies have demonstrated significant increases in oligodendrocytes from the myelination stage through adulthood in brain and spinal cord under CST-deficient conditions. However, whether these result from excess migration or in situ proliferation during development is undetermined. In the present study, CST-deficient optic nerves were used to examine migration and proliferation of oligodendrocyte precursor cells (OPCs) under sulfated glycolipid-deficient conditions. In adults, more NG2-positive OPCs and fully differentiated cells were observed. In developing optic nerves, the number of cells at the leading edge of migration was similar in CST-deficient and wild-type mice. However, BrdU(+) proliferating OPCs were more abundant in CST deficient mice. These results suggest that sulfated glycolipids may be involved in proliferation of OPCs in vivo. PMID- 21785260 TI - Combination of two fat saturation pulses improves detectability of glucose signals in carbon-13 MR spectroscopy. AB - In order to improve the fat suppression performance of in vivo (13)C-MRS operating at 3.0 Tesla, a phantom model study was conducted using a combination of two fat suppression techniques; a set of pulses for frequency (chemical shift) selective suppression (CHESS), and spatial saturation (SAT). By optimizing the slab thickness for SAT and the irradiation bandwidth for CHESS, the signals of the -(13)CH(3) peak at 49 ppm and the -(13)CH(2)- peak at 26 ppm simulating fat components were suppressed to 5% and 19%, respectively. Combination of these two fat suppression pulses achieved a 53% increase of the height ratio of the glucose C1beta peak compared with the sum of all other peaks, indicating better sensitivity for glucose signal detection. This method will be applicable for in vivo (13)C-MRS by additional adjustment with the in vivo relaxation times of the metabolites. PMID- 21785261 TI - The role of centrosomal casein kinase 1 delta in neurite outgrowth and beyond. PMID- 21785262 TI - Delineating oncogene/tumor suppressor interactions in human mammary epithelial cells. PMID- 21785263 TI - TFEB regulates autophagy: an integrated coordination of cellular degradation and recycling processes. AB - Autophagy is a fundamental catabolic process that plays a central role in health and disease. An efficient autophagic process relies on the cooperation of two distinct types of organelles: the autophagosome and the lysosome. We have identified a gene network that regulates the biogenesis and function of both organelles. Our findings reveal an important role of transcription in the regulation of starvation-induced autophagy, and link lysosomal biogenesis to autophagy. PMID- 21785264 TI - Tissue-based immune monitoring I: tumor core needle biopsies allow in-depth interrogation of the tumor microenvironment. AB - We sought to assess the feasibility and reproducibility of performing tissue based immune characterization of the tumor microenvironment using CT-compatible needle biopsy material. Three independent biopsies were obtained intraoperatively from one metastatic epithelial ovarian cancer lesion of 7 consecutive patients undergoing surgical cytoreduction using a 16-gauge core biopsy needle. Core specimens were snap-frozen and subjected to immunohistochemistry (IHC) against human CD3, CD4, CD8, and FoxP3. A portion of the cores was used to isolate RNA for 1) real-time quantitative (q)PCR for CD3, CD4, CD8, FoxP3, IL-10 and TGF beta, 2) multiplexed PCR-based T cell receptor (TCR) CDR3 Vbeta region spectratyping, and 3) gene expression profiling. Pearson's correlations were examined for immunohistochemistry and PCR gene expression, as well as for gene expression array data obtained from different tumor biopsies. Needle biopsy yielded sufficient tissue for all assays in all patients. IHC was highly reproducible and informative. Significant correlations were seen between the frequency of CD3+, CD8+ and FoxP3+ T cells by IHC with CD3epsilon, CD8A, and FoxP3 gene expression, respectively, by qPCR (r=0.61, 0.86, and 0.89; all p< 0.05). CDR3 spectratyping was feasible and highly reproducible in each tumor, and indicated a restricted repertoire for specific TCR Vbeta chains in tumor infiltrating T cells. Microarray gene expression revealed strong correlation between different biopsies collected from the same tumor. Our results demonstrate a feasible and reproducible method of immune monitoring using CT-compatible needle biopsies from tumor tissue, thereby paving the way for sophisticated translational studies during tumor biological therapy. PMID- 21785266 TI - Double duty for Exo1 during meiotic recombination. PMID- 21785265 TI - Tumor-selective, adenoviral-mediated GFP genetic labeling of human cancer in the live mouse reports future recurrence after resection. AB - We have previously developed a telomerase-specific replicating adenovirus expressing GFP (OBP-401), which can selectively label tumors in vivo with GFP. Intraperitoneal (i.p.) injection of OBP-401 specifically labeled peritoneal tumors with GFP, enabling fluorescence visualization of the disseminated disease and real-time fluorescence surgical navigation. However, the technical problems with removing all cancer cells still remain, even with fluorescence-guided surgery. In this study, we report imaging of tumor recurrence after fluorescence guided surgery of tumors labeled in vivo with the telomerase-dependent, GFP containing adenovirus OBP-401.. Recurrent tumor nodules brightly expressed GFP, indicating that initial OBP-401-GFP labeling of peritoneal disease was genetically stable, such that proliferating residual cancer cells still express GFP. In situ tumor labeling with a genetic reporter has important advantages over antibody and other non-genetic labeling of tumors, since residual disease remains labeled during recurrence and can be further resected under fluorescence guidance. PMID- 21785267 TI - Tubby-tagged balancers for the Drosophila X and second chromosomes. AB - We generated FM7a and CyO balancer chromosomes bearing a Tubby1 (Tb1) dominant transgene. Flies heterozygous for these FM7a and CyO derivatives exhibit a phenotype undistinguishable from that elicited by the Tb1 mutation associated with the TM6B balancer. We tested two of these Tb-bearing balancers (FM7-TbA and CyO-TbA) for more than 30 generations and found that the Tb1 transgene they carry is stable. Thus, these new Tb-tagged balancers are particularly useful for balancing lethal mutations and distinguish homozygous mutant larvae from their heterozygous siblings. PMID- 21785269 TI - Mimicking synaptic effects of addictive drugs with selective dopamine neuron stimulation. AB - The synaptic changes induced by initial drug exposure leave a trace on neural systems that can eventually manifest in compulsive drug-seeking behavior. A single injection of cocaine has been shown to induce a change in the AMPA receptor (AMPAR) subunit composition at glutamatergic synapses onto ventral tegmental area (VTA) dopamine (DA) neurons. This change is long-lasting (up to months following self-administration) and represents an important functional change at the synaptic level following cocaine use. We recently published findings that cocaine's action at the DA transporter (DAT) is necessary for the induction of AMPAR redistribution and that this can also be mimicked by selective DA neuron stimulation. The stimulation effect is dependent on D1 receptors within the VTA. Furthermore other addictive drugs, although they act through distinct mechanisms, also induce this synaptic change. Here we discuss literature that expands on these observations in an attempt to further clarify the synaptic changes following early drug use. PMID- 21785268 TI - Fourier transform coupled tryptophan scanning mutagenesis identifies a bending point on the lipid-exposed deltaM3 transmembrane domain of the Torpedo californica nicotinic acetylcholine receptor. AB - The nicotinic acetylcholine receptor (nAChR) is a member of a family of ligand gated ion channels that mediate diverse physiological functions, including fast synaptic transmission along the peripheral and central nervous systems. Several studies have made significant advances toward determining the structure and dynamics of the lipid-exposed domains of the nAChR. However, a high-resolution atomic structure of the nAChR still remains elusive. In this study, we extended the Fourier transform coupled tryptophan scanning mutagenesis (FT-TrpScanM) approach to gain insight into the secondary structure of the deltaM3 transmembrane domain of the Torpedo californica nAChR, to monitor conformational changes experienced by this domain during channel gating, and to identify which lipid-exposed positions are linked to the regulation of ion channel kinetics. The perturbations produced by periodic tryptophan substitutions along the deltaM3 transmembrane domain were characterized by two-electrode voltage clamp and (125)I labeled alpha-bungarotoxin binding assays. The periodicity profiles and Fourier transform spectra of this domain revealed similar helical structures for the closed- and open-channel states. However, changes in the oscillation patterns observed between positions Val-299 and Val-304 during transition between the closed- and open-channel states can be explained by the structural effects caused by the presence of a bending point introduced by a Thr-Gly motif at positions 300 301. The changes in periodicity and localization of residues between the closed and open-channel states could indicate a structural transition between helix types in this segment of the domain. Overall, the data further demonstrate a functional link between the lipid-exposed transmembrane domain and the nAChR gating machinery. PMID- 21785270 TI - Prediction of proapoptotic anticancer therapeutic response in vivo based on cell death visualization and TRAIL death ligand-receptor interaction. AB - Tumor growth is often associated with insufficient apoptosis. The Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) and its proapoptotic receptors death receptor 4 (DR4) and DR5 agonistic monoclonal antibodies are being developed as targeted therapeutics because they kill cancer cells while sparing normal cells. A challenge to targeted therapeutics is the selection of patients who are most likely to benefit from targeted drugs because of the heterogeneity of cancer. Molecular imaging may be useful in targeted drug development by assessing the target expression and drug-target interaction, and for predicting therapeutic response. We hypothesized that the cell surface expression level of DR4/5 may predict the proapoptotic targeted therapeutic response if the signaling pathway downstream is intact. The goal of this proof-of concept study was to develop a molecular imaging strategy to predict proapoptotic anti-cancer therapy response at an early stage of treatment. TRAIL and the DR5 agonistic monoclonal antibody HGS-ETR2 (Lexatumumab, TRM-2) were labeled with a near-infrared dye and these were used to image the TRAIL receptors on cultured TRAIL sensitive and TRAIL resistant human tumor cells as well as tumor xenografts. Imaging of cells and tumor-bearing animals was conducted with near infrared fluorescence imagers and apoptosis in cells was assessed by western blots of PARP-cleavage and flow cytometry of sub-G1 content. Apoptosis in tumors was evaluated by imaging near-infrared dye-labeled Annexin V and tumor tissue activated caspase-3 staining. Both in vitro and in vivo studies showed that imaging of death inducing ligand-receptor interaction was consistent with the apoptosis readout. Thus TRAIL sensitive tumors that express TRAIL receptors underwent cell death following treatment whereas tumors lacking TRAIL receptor expression were shown to be TRAIL resistant. In vivo molecular imaging of TRAIL receptor expression correlated with response to TRAIL therapy and an apoptotic response in vivo. PMID- 21785271 TI - Clinical significance of Myb protein and downstream target genes in salivary adenoid cystic carcinoma. AB - Adenoid cystic carcinoma (ACC), the second most frequent malignancy of the major and minor salivary glands, comprise of approximately 15-23% of all carcinomas at these locations. ACC is uniquely formed of dual epithelial and myoepithelial cells that give rise to different phenotypic patterns. We hypothesize that the dual myoepithelial/ epithelial composition of ACCs underlie their biological heterogeneity and may impact on their therapeutic management. A recurrent reciprocal translocation of t(6;9)(q22-23; p23-24) resulting in fusion gene partners comprising MYB gene the transcription factor NFIB has been reported in ACC of breast, salivary, lachrymal and ceruminal glands. In fusion positive and a subset of fusion negative ACCs, high expression of the transcript Myb was found. However, the role of Myb protein expression and the potential effect on the downstream targets have not been investigated. To investigate the biological and prognostic significance of use of elevated levels of Myb and its downstream target genes (c-kit, cox-2, bcl-2), we analyzed, by immunohistochemistry, the protein expression of these genes in 156 ACCs. We have found that 55% of ACCs have increased Myb expression mainly confined to myoepithelial cells. We validated Myb expression on a large cohort of ACCs (156 patients). Although no significant effects of the individual Myb and downstream targets c-kit, bcl-2 and cox-2 on survival was noticed, the combinations survival curve for Myb+/c kit+/cox-2+ showed better survival than combination Myb-/c-kit+/cox-2+. Myb may serve as a new target for the management of this disease, and future therapeutic trials of these tumors may be better based on biomarker stratification and the cellular composition of these tumors. PMID- 21785272 TI - Effects of IL-17A on the occurrence of lung adenocarcinoma. AB - The relationship between IL-17A and cancer, whether beneficial or antagonistic, continues to be a controversial issue. In this study, effects of IL-17A on lung adenocarcinoma were investigated using lung cancer cell lines, 95D and 95C. In the presence or absence of IL-17A, cell proliferation and VEGF secretion were detected. Effects of IL-17A on capillary networks and process of angiogenesis were also evaluated. In vivo, the level of IL-17A was assayed in the serum of lung adenocarcinoma patients. At the same time, slices of adenocarcinoma tissue were analyzed for expression of IL-17A, its receptor (IL-17RA), VEGF, CD4(+)-IL 17A+ cells and CD8(+)-IL-17A+ cells by immunohistochemistry and immunofluorescence assays. IL-17A did not have effect on the proliferation of 95D or 95C cells, however, the elevated expression of VEGF in supernatant of 95D or 95C cells was found to be IL-17A concentration-dependent. Supernatants from 95D or 95C cells treated with IL-17A could obviously facilitate angiogenesis, compared with IL-17A absence group (P < 0.01). Higher levels of IL-17A were detected in serum of patients with lung adenocarcinoma than healthy controls (P < 0.001). Higher positive expressions of IL-17A, IL-17RA and VEGF were confirmed in lung adenocarcinoma lesion tissues compared to pericancerous normal tissues (P < 0.001). Tnc17 cells, as well as Th17 cells were found in adenocarcinoma tissue, indicating a potential role of these cells in disease. In summary, IL-17A might affect lung adenocarcinoma by promoting angiogenesis, while the role of Tnc17 cells or Th17 cells remains to be elucidated. PMID- 21785273 TI - Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility. AB - The Snail family of zinc finger transcription factors plays an important role in epithelial to mesenchymal transition (EMT) in a variety of tissues and systems. Slug (SNAI2) expression has been shown to directly contribute to a subset of events required for EMT in events such as re-epithelialization during wound healing and neural crest cell migration. In addition, slug expression was shown to correlate with disease recurrence in head and neck squamous cell carcinoma (HNSCC) patients. Based on this association we chose to specifically examine the effects of exogenous slug expression in HNSCC cells and specifically assess adhesive junction assembly and the motility characteristics in these cells. Slug expression led to changes in adherens junction and desmosome assembly characterized by a classical cadherin switch and loss of desmosome assembly. Additionally, we performed gene expression profiling to identify novel slug dependent gene expression changes in a HNSCC cell line. In addition to genes known to be altered during EMT, we identified a novel set of Slug responsive genes that will provide a better understanding of slug overexpression during EMT and HNSCC progression. PMID- 21785274 TI - Dissecting cell adhesion architecture using advanced imaging techniques. AB - Cell adhesion to extracellular matrix proteins or to other cells is essential for the control of embryonic development, tissue integrity, immune function and wound healing. Adhesions are tightly spatially regulated structures containing over a hundred different proteins that co-ordinate both dynamics and signalling events at these sites. Extensive biochemical and morphological analysis of adhesion types over the past three decades has greatly improved understanding of individual protein contributions to adhesion signalling and, in some cases, dynamics. However, it is becoming increasingly clear that these diverse macromolecular complexes contain a variety of protein sub-networks, as well as distinct sub-domains that likely play important roles in regulating adhesion behaviour. Until recently, resolving these structures, which are often less than a micron in size, was hampered by the limitations of conventional light microscopy. However recent advances in optical techniques and imaging methods have revealed exciting insight into the intricate control of adhesion structure and assembly. Here we provide an overview of the recent data arising from such studies of cell:matrix and cell:cell contact and an overview of the imaging strategies that have been applied to study the intricacies and hierarchy of proteins within adhesions. PMID- 21785275 TI - Should I stay or should I go? Shedding of RPTPs in cancer cells switches signals from stabilizing cell-cell adhesion to driving cell migration. AB - Dissolution of cell-cell adhesive contacts and increased cell-extracellular matrix adhesion are hallmarks of the migratory and invasive phenotype of cancer cells. These changes are facilitated by growth factor binding to receptor protein tyrosine kinases (RTKs). In normal cells, cell-cell adhesion molecules (CAMs), including some receptor protein tyrosine phosphatases (RPTPs), antagonize RTK signaling by promoting adhesion over migration. In cancer, RTK signaling is constitutive due to mutated or amplified RTKs, which leads to growth factor independence, or autonomy. An alternative route for a tumor cell to achieve autonomy is to inactivate cell-cell CAMs such as RPTPs. RPTPs directly mediate cell adhesion and regulate both cadherin-dependent adhesion and signaling. In addition, RPTPs antagonize RTK signaling by dephosphorylating molecules activated following ligand binding. Both RPTPs and cadherins are downregulated in tumor cells by cleavage at the cell surface. This results in shedding of the extracellular, adhesive segment and displacement of the intracellular segment, altering its subcellular localization and access to substrates or binding partners. In this commentary we discuss the signals that are altered following RPTP and cadherin cleavage to promote cell migration. Tumor cells both step on the gas (RTKs) and disconnect the brakes (RPTPs and cadherins) during their invasive and metastatic journey. PMID- 21785276 TI - The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease. AB - The amyloid-beta (Abeta) peptide is the derivative of amyloid precursor protein (APP) generated through sequential proteolytic processing by beta- and gamma secretases. Excessive accumulation of Abeta, the main constituent of amyloid plaques, has been implicated in the etiology of Alzheimer's disease (AD). It was found recently that the impairments of neurogenesis in brain were associated with the pathogenesis of AD. Furthermore recent findings implicated that APP could function to influence proliferation of neural progenitor cells (NPC) and might regulate transcriptional activity of various genes. Studies demonstrated that influence of neurogenesis by APP is conferred differently via its two separate domains, soluble secreted APPs (sAPPs, mainly sAPPalpha) and APP intracellular domain (AICD). The sAPPalpha was shown to be neuroprotective and important to neurogenesis, whereas AICD was found to negatively modulate neurogenesis. Furthermore, it was demonstrated recently that microRNA could function to regulate APP expression, APP processing, Abeta accumulation and subsequently influence neurotoxicity and neurogenesis related to APP, which was implicated to AD pathogenesis, especially for sporadic AD. Based on data accumulated, secretase balances were proposed. These secretase balances could influence the downstream balance related to regulation of neurogenesis by AICD and sAPPalpha as well as balance related to influence of neuron viability by Abeta and sAPPalpha. Disruption of these secretase balances could be culprits to AD onset. PMID- 21785278 TI - Bacterial expression and characterization of a novel human anti-IgE scFv fragment. AB - Antibodies highly specific to human immunoglobulin (Ig) E are capable of selectively blocking the IgE interaction or eliminating IgE-producing cells, thus providing valuable agents for diagnostics and treatment of various allergic illness. An example is omalizumab, a humanized monoclonal anti-IgE antibody that is approved for the treatment of patients with moderate-to-severe allergic diseases in the United States, European Union and other countries. Here, we describe the generation and characterization of a novel human anti-IgE as a single-chain antibody fragment (scFv). The bacterially-synthesized scFv showed high affinity (86 nM) and specificity to the Fc region of human IgE. To our knowledge, this is the first report of the production of a human anti-IgE scFv in E. coli. Its further development as a potential candidate for medical applications is discussed. PMID- 21785277 TI - Rap1GAP impairs cell-matrix adhesion in the absence of effects on cell-cell adhesion. AB - The significance of the widespread downregulation of Rap1GAP in human tumors is unknown. In previous studies we demonstrated that silencing Rap1GAP expression in human colon cancer cells resulted in sustained increases in Rap activity, enhanced spreading on collagen and the weakening of cell-cell contacts. The latter finding was unexpected based on the role of Rap1 in strengthening cell cell adhesion and reports that Rap1GAP impairs cell-cell adhesion. We now show that Rap1GAP is a more effective inhibitor of cell-matrix compared to cell-cell adhesion. Overexpression of Rap1GAP in human colon cancer cells impaired Rap2 activity and the ability of cells to spread and migrate on collagen IV. Under the same conditions, Rap1GAP had no effect on cell-cell adhesion. Overexpression of Rap1GAP did not enhance the dissociation of cell aggregates nor did it impair the accumulation of beta-catenin and E-cadherin at cell-cell contacts. To further explore the role of Rap1GAP in the regulation of cell-cell adhesion, Rap1GAP was overexpressed in non-transformed thyroid epithelial cells. Although the formation of cell-cell contacts required Rap1, overexpression of Rap1GAP did not impair cell-cell adhesion. These data indicate that transient, modest expression of Rap1GAP is compatible with cell-cell adhesion and that the role of Rap1GAP in the regulation of cell-cell adhesion may be more complex than is currently appreciated. PMID- 21785279 TI - Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies. AB - Therapeutic antibodies have captured substantial attention due to the relatively high rate at which these products reach marketing approval, and the subsequent commercial success they frequently achieve. In the 2000s, a total of 20 antibodies (18 full-length IgG and 2 Fab) were approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). In the 2010s to date, an additional 3 antibodies (denosumab, belimumab, ipilimumab) have been approved and one antibody-drug conjugate (brentuximab vedotin) is undergoing regulatory review and may be approved in the US by August 30, 2011. However, a less heralded group of antibody-based therapeutics comprising proteins or peptides fused with an Fc is following the success of classical antibodies. PMID- 21785282 TI - Use of basophil activation test in the investigation of adverse effects to vaccines. AB - Diagnosis of adverse effects caused by vaccines mainly includes investigative approaches based on skin tests, histamine, tryptase and serum IgE levels which should allow to diagnose an IgE-mediated allergy reaction, most caused by additive components. Incidence of vaccine-related allergy and anaphylaxis due to vaccination are very poorly represented among population, based on the latest epidemiological and safety reports. Notwithstanding, routinely allergy diagnostic tools show many pitfalls and contradictory results when used to highlight an allergy onset or a clinical manifestation recalling an hypersensitivity reaction. Furthermore, adjuvants in vaccines may trigger innate cells response by toll-like receptors, thus eliciting a possible non-IgE mediated allergy phenomenon or causing B-cell activation and autoimmunity. A cellular test, such as a basophil activation test, or more widely a flow cytometry analysis of immune cells, might add new insights to the comprehension of allergy due to vaccination , thus ameliorating the diagnostic endowment in the hand of physicians. PMID- 21785281 TI - Next-generation outer membrane vesicle vaccines against Neisseria meningitidis based on nontoxic LPS mutants. AB - Outer membrane vesicles (OMVs) have been used extensively as experimental vaccines against Neisseria meningitidis. Classical meningococcal OMV vaccines contain wildtype lipopolysaccharide (LPS) with a hexa-acylated lipid A moiety, which is a very potent activator of the TLR4 receptor. While this may make the LPS an effective "internal" adjuvant, it also contributes to vaccine reactogenicity. Reduction of endotoxic activity has therefore been essential for the application of meningococcal OMV vaccines in humans. Classical OMV vaccines have a reduced LPS content as a result of detergent extraction, mostly with deoxycholate. An alternative method is the use of meningococcal strains with genetically detoxified LPS, in particular where mutation in the lpxL1 gene has resulted in penta-acylated lipid A with strongly attenuated endotoxic activity. This allows the use of native OMVs without any need for LPS removal by detergent extraction, making it a much easier to produce and more versatile vaccine platform. Several groups have now started the development of native OMV vaccines based on non-toxic LPS mutants, and this Commentary provides an overview of the various approaches and results thus far. PMID- 21785280 TI - Tissue-based immune monitoring II: multiple tumor sites reveal immunologic homogeneity in serous ovarian carcinoma. AB - The presence of tumor-infiltrating lymphocytes (TILs) in epithelial ovarian cancer indicates a host antitumor response and is associated with improved survival. We wished to determine the extent to which TIL density differs from site to site within a given patient. We initially studied multiple paired metastases from serous ovarian carcinoma obtained at the time of primary debulking. The expression of genes in specific immune-related pathways was profiled on a pilot set of five patients. We then used immunohistochemistry and quantitative PCR to estimate the density of CD3+, CD8+, and FoxP3+ TILs in these same tumors. To extend the findings to a larger cohort, we semiquantitatively measured intraepithelial and stromal TILs in a tissue microarray (TMA) containing both primary tumors and metastases from 50 patients. In the pilot group, genes related to antimicrobial signaling and TGF-beta signaling showed between-site heterogeneity, whereas cytokines and antigen presentation transcripts were more homogeneous in any given patient. IHC and qPCR for T cell markers were concordant. In the TMA cohort, 2-way ANOVA showed that TIL heterogeneity between sites was present in some but not all patients. The stroma of extra-ovarian metastases showed significantly greater TIL infiltration than ovarian sites. A simulation showed that at clinically meaningful levels of precision, up to 3% of patients will be misclassified for intraepithelial TILs by a single biopsy. In conclusion, between-site heterogeneity exists in some patients with metastatic serous ovarian cancer. The predictive value of biopsies should be considered in clinical trial design. PMID- 21785283 TI - Indirect effects by meningococcal vaccines: herd protection versus herd immunity. AB - The term "herd immunity" for the indirect effect of meningococcal conjugate vaccines is inaccurate. A more appropriate term is "herd protection," because this term correctly describes the public effects imparted by vaccination campaigns against the meningococcus. PMID- 21785284 TI - Hospitalization in Spain associated with malignant neoplasias of the vulva and vagina (1997-2008). AB - An important percentage of vulvar and vaginal cancers may be attributed to infections by the human papillomavirus. Although the incidence of invasive vulvar and vaginal cancers is low, it has remained stable over the past years. Hospital discharges related to malignant neoplasias and in situ carcinomas of the vulva and vagina from 1997 to 2008 were selected from the Minimum Data Set of the Ministry of Health in Spain. 17,883 hospital admissions related to vulvar and vaginal malignant neoplasias and 2,185 admissions related to in situ carcinomas of the vulva and vagina were gathered, with a hospitalization rate of 7,054 and 0.862 discharges per 100,000 women/year, respectively. The mean age of patients was 57 (SD:18) years, and the mean length of hospital stay was 8 (SD:10) days. There was a statistically significant increase in the hospitalization rate for malignant neoplasias and in situ carcinomas with increasing patient age. This increase was significant for all locations. Overall, there was a case fatality rate of 9.34% for vulvar and vaginal malignant neoplasias and 0.46% for in situ carcinomas of an external genital organ. Mortality and case fatality rates increased significantly throughout the length of the study. 92% of all deaths occurred in those older than 55 years of age. Mortality and case fatality rates also increased significantly with age. The hospitalization rate follows a north south pattern. These data of the pre-anti-HPV vaccine era may be useful to develop cost-effectiveness models and strategies and evaluate the impact of HPV vaccination in Spain. PMID- 21785285 TI - Factors associated with increased vaccination in 2009 H1N1 school-located influenza vaccination programs. AB - In the United States, school-located influenza vaccination (SLIV) programs have increased significantly in recent years. In June 2010, the Office of Inspector General issued a report regarding 38 elementary school H1N1 SLIV programs conducted in 6 localities in November/December 2009. By locality, there was a mean of 14 to 46 first doses of vaccine administered per 100 students. The locality that conducted programs in early November had a higher uptake rate than localities with later programs (46 vs 21 per 100 students; p < 0.01). Among localities with programs in mid- to late-November, the locality with programs after school hours had a lower uptake rate than the two localities with programs during school hours (16 vs. 28, p = 0.05 and 16 vs. 30, p < 0.01, respectively). These data suggest that future SLIV programs may achieve higher uptake rates if conducted during school hours with advance parental consent and when parental demand is highest. PMID- 21785286 TI - Multidetector computed tomography detection of absent right superior vena cava and persistent left superior vena cava in an adult. AB - We report a rare case of the absence of the right superior vena cava and a persistent left superior vena cava in a 46-year-old man. This congenital venous anomaly was incidentally found on low-dose chest computed tomography and was clearly demonstrated by 3-dimensional volume-rendering image of multidetector computed tomography. Prior to computed tomography scanning, the scan range, optimal contrast enhancement, and reconstruction methods should be carefully planned to obtain the best diagnostic image of the venous anomalies using multidetector computed tomography. PMID- 21785287 TI - Sequential versus volumetric computed tomography in the follow-up of chronic bronchopulmonary diseases: comparison of diagnostic information and radiation dose in 63 adults. AB - PURPOSE: To compare diagnostic information and radiation dose between volumetric and sequential scanning in the follow-up of chronic and diffuse bronchopulmonary diseases. MATERIALS AND METHODS: Sixty-three consecutive patients, aged 50 years or younger, referred for the follow-up of diffuse infiltrative lung disease (group 1; n=38) or cystic fibrosis (group 2; n=25), underwent a noncontrast high resolution volumetric computed tomography (CT) examination with individually adapted selection of kilovoltage and 4-dimensional tube current modulation. From each acquisition, 2 sets of lung images were generated, namely the contiguous thin-collimated lung images, further referred to as the volumetric examination and considered as the reference standard, and thin-collimated lung images, spaced 10 mm apart, further referred to as the sequential examination. Several weeks apart, 2 radiologists interpreted by consensus the volumetric and sequential examinations to assess the presence and extent of lung parenchyma and airways abnormalities. The dose-length-product (DLP) value of each volumetric examination was available at the acquisition workstation; the DLP value of the corresponding sequential examination was retrospectively calculated. RESULTS: In group 1, the kappa values between sequential and volumetric CT examinations ranged between 0.87 and 1 for the detection of individual CT features and between 0.83 and 1 for the regional distribution of the CT features. In group 2, the values of the intraclass correlation coefficients (r) for individual criteria of the scoring system ranged between 0.87 and 1, except for the extent of mucus plugging (r: 0.67); the r value for the patients' Bhalla score was 0.99. The mean DLP of sequential examinations was significantly lower than that of the volumetric examinations (16.1 mGy.cm vs. 77.7 mGy.cm; P<0.0001), enabling a 79.4% dose reduction. CONCLUSION: The magnitude of dose reduction without loss of diagnostic information achievable with sequential scanning suggests reconsidering this scanning mode in the follow-up of chronic diffuse bronchopulmonary diseases in adults 50 years of age and younger. PMID- 21785288 TI - Pulmonary nocardiosis: computed tomography features at diagnosis. AB - PURPOSE: To review the computed tomography (CT) imaging features of pulmonary nocardiosis (PN) at the time of initial presentation. MATERIALS AND METHODS: All patients from 1991 to 2008 with PN were identified (n=105). Patients without CT scan available at initial presentation were excluded (n=52). For the remaining 53 patients, standardized radiographic features were recorded. The patients were grouped by predisposing condition. Analysis includes descriptive summary statistics as well as associations among radiographic findings, associated findings, and host characteristics. Parametric and nonparametric statistical methods were used. RESULTS: Median age of the patients was 52 years (range, 6 to 82 y). Some form of immunosuppression was present in 83% of the cases. Preexisting structural abnormalities of the lung were uncommon (bronchiectasis, 7; chronic obstructive pulmonary disease, 3). Twenty (38%) patients had interstitial opacities. Airspace disease was seen in 34 (64%) cases. Thirty (57%) cases revealed discrete nodules, 25 patients had 1 to 6 nodules (mean, 2), and 5 patients had fewer than 6 nodules, with the mean size of the largest nodule being 1.67 cm. Masses were seen in 11 patients (21%), 9 of whom had concomitant nodules. Cavitary lesions, including nodules, masses, or airspace disease, occurred in 40% of the cohort. Mediastinal lymphadenopathy was present in 8 (15%) patients. Fifteen patients (28%) had pleural effusions; the effusions were unilateral in 10 patients. Analysis of radiographic associations with patient groups found discrete nodules to be more often associated with immunosuppression compared with the nonimmunosuppressed group (66% vs. 11%; P=0.0067). CONCLUSION: The CT presentation of PN is heterogeneous. Airspace disease appeared most frequently (in 64% of the cases), and nodules were present in 57% of the cases. Nocardiosis should be considered in the differential diagnosis of immunosuppressed patients with new nodules or masses. PMID- 21785289 TI - The epidemiology of alcohol use disorders and subthreshold dependence in a middle aged and elderly community sample. AB - OBJECTIVE: To estimate 1-year prevalence and correlates of alcohol abuse, dependence, and subthreshold dependence (diagnostic orphans) among middle-aged and elderly persons in the United States. DESIGN: 2005-2007 National Surveys on Drug Use and Health. METHOD: Sample included 10,015 respondents aged 50-64 years and 6,289 respondents older than 65 years. Data were analyzed by bivariate and multinomial regression analyses. MEASUREMENTS: Sociodemographic variables; alcohol use; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition abuse and dependence; major depression; nicotine dependence; illicit drug use; and nonmedical use of prescription drugs. RESULTS: Fifty-one percent of the sample used alcohol during the past year (56% in the 50-64 age group and 43% in the older than 65 age group). Overall, 11% (dependence 1.9%, abuse 2.3%, and subthreshold dependence 7.0%) of adults aged 50-64 and about 6.7% (dependence 0.6%, abuse 0.9%, and subthreshold dependence 5.2%) of those older than 65 reported alcohol abuse, dependence or dependence symptoms. Among past-year alcohol users, 20% (dependence 3.4%, abuse 4.0%, and subthreshold dependence 12.5%) of adults aged 50-64 and 15.4% (dependence 1.3%, abuse 2.1%, and subthreshold dependence 12.0%) of those older than 65 endorsed alcohol abuse or dependence symptoms. "Tolerance" (48%) and "time spent using" (37%) were the two symptoms most frequently endorsed by the subthreshold group. Compared with alcohol users without alcohol abuse or dependence symptoms, blacks or Hispanics and those who had nicotine dependence or used nonmedical prescription drugs had increased odds of subthreshold dependence. Diagnostic orphans also were more likely to engage in binge drinking than the asymptomatic group. CONCLUSIONS: Diagnostic orphans among middle-aged and elderly community adults show an elevated rate for binge drinking and nonmedical use of prescription drugs that require attention from healthcare providers. PMID- 21785290 TI - Trends in substance abuse treatment 1998-2008: increasing older adult first-time admissions for illicit drugs. AB - OBJECTIVES: To see whether the percentage of older adults entering substance abuse treatment for their first time was increasing and whether there were changes in the use patterns leading to the treatment episode, particularly an increase in illicit drugs. SETTING: The Treatment Episode Data Sets publicly available from the Substance Abuse Mental Health Services Administration from 1998 to 2008. PARTICIPANTS: Young adults age 30-54 years as a comparison group (N = 3,547,733) and those age 55 years or older (N = 258,542) with a first-time admission for a publicly funded substance abuse treatment. MEASUREMENTS: Demographic and substance use history variables at admission. RESULT: The proportion of older adults going for substance abuse treatment for the first time is increasing relative to younger adults. The pattern of drug use is also changing, with an increasing illicit drug involvement (cocaine and heroin) in older adult admissions. CONCLUSIONS: We know little of these long-time users, their current medical state, cognitive abilities, and psychiatric symptoms after such a long exposure time. Previous studies on heroin and cocaine exposure focused on individuals identified much earlier in life, and the aging long-term users might represent a relatively large but unknown population. PMID- 21785291 TI - Incidence and predictors of advance care planning among persons with cognitive impairment. AB - OBJECTIVE: Persons with mild cognitive impairment (MCI) and Alzheimer disease (AD) are at heightened risk for future decisional incapacity. We sought to characterize advance care planning (ACP) rates over time in individuals who had no advance directives (living will or durable power of attorney) in place when they initially presented for a cognitive evaluation. DESIGN: Retrospective analysis of data that had been prospectively collected. SETTING: Alzheimer's Disease Research Center memory disorders clinic. PARTICIPANTS: Persons (N = 127) with a diagnosis of MCI or early AD (n = 72) or moderate to severe AD (n = 55) and no advance directives upon initial presentation for a cognitive evaluation. MEASUREMENTS: Extraction of responses to items pertaining to ACP assessed during annual semistructured interviews. RESULTS: By 5 years of follow-up, 39% of the sample had initiated ACP, with little difference by baseline diagnosis. Younger subjects (younger than 65 years) were significantly more likely to initiate advance directives (43%) than older subjects (37%). This age effect was more pronounced in men than in women as well as in married subjects, those with a family history of dementia, those with no depressive disorder, and subjects with moderate to severe AD (versus those with MCI or early AD) at baseline. CONCLUSION: Only a minority of subjects initiated ACP. The findings suggest the need for interventions aimed at enhancing ACP completion rates, particularly among older adults with cognitive impairment, since these individuals may have a time-limited opportunity to plan for future medical, financial, and other major life decisions. PMID- 21785292 TI - Physiological correlates of skating performance in women's and men's ice hockey. AB - The purpose of the current investigation was to identify relationships between physiological off-ice tests and on-ice performance in female and male ice hockey players on a comparable competitive level. Eleven women, 24 +/- 3.0 years, and 10 male ice hockey players, 23 +/- 2.4 years, were tested for background variables: height, body weight (BW), ice hockey history, and lean body mass (LBM) and peak torque (PT) of the thigh muscles, VO2peak and aerobic performance (Onset of Blood Lactate Accumulation [OBLA], respiratory exchange ratio [RER1]) during an incremental bicycle ergometer test. Four different on-ice tests were used to measure ice skating performance. For women, skating time was positively correlated (p < 0.05) to BW and negatively correlated to LBM%, PT/BW, OBLA, RER 1, and VO2peak (ml O2.kg(-1) BW(-1).min(-1)) in the Speed test. Acceleration test was positively correlated to BW and negatively correlated to OBLA and RER 1. For men, correlation analysis revealed only 1 significant correlation where skating time was positively correlated to VO2peak (L O2.min(-1)) in the Acceleration test. The male group had significantly higher physiological test values in all variables (absolute and relative to BW) but not in relation to LBM. Selected off ice tests predict skating performance for women but not for men. The group of women was significantly smaller and had a lower physiological performance than the group of men and were slower in the on-ice performance tests. However, gender differences in off-ice variables were reduced or disappeared when values were related to LBM, indicating a similar capacity of producing strength and aerobic power in female and male hockey players. Skating performance in female hockey players may be improved by increasing thigh muscle strength, oxygen uptake, and relative muscle mass. PMID- 21785298 TI - Finite element modeling of kinematic and load transmission alterations due to cervical intervertebral disc replacement. AB - STUDY DESIGN: A parametric finite element investigation of the cervical spine. OBJECTIVE: To determine what effect, if any, cervical disc replacement has on kinematics, facet contact parameters, and anterior column loading. SUMMARY OF BACKGROUND DATA: Anterior cervical discectomy and fusion has been a standard treatment for certain spinal degenerative disorders, but evidence suggests that fusion contributes to adjacent-segment degeneration. Motion-sparing disc replacement implants are believed to reduce adjacent-segment degeneration by preserving kinematics at the treated level. Such implants have been shown to maintain the mobility of the intact spine, but the effects on load transfer between the anterior and posterior elements remain poorly understood. METHODS: To investigate the effects of disc replacement on load transfer in the lower cervical spine, a finite element model was generated using cadaver-based computed tomography imagery. Mesh resolution was varied to establish model convergence, and cadaveric testing was undertaken to validate model predictions. The validated model was altered to include disc replacement prosthesis at the C4/C5 level. The effect of disc-replacement on range of motion, anteroposterior load distribution, contact forces in the facets, as well as the distribution of contact pressure on the facets were examined. Three sizes of implants were examined. RESULTS: Model predictions indicate that the properly sized implant retains the mobility, load sharing, and contact force magnitude and distribution of the intact case. Mobility, load sharing, nuclear pressures, and contact pressures at the adjacent motion segments were not strongly affected by the presence of the properly sized implant, indicating that disc replacement may not be a significant cause of postoperative adjacent-level degeneration. Implant size affected certain mechanical parameters, such as anteroposterior load sharing, and did not affect compliance or range of motion. CONCLUSION: The results of this work support the continued use of motion sparing implants in the lower cervical spine. Load sharing data indicate that implant size may be an important factor that merits further study; although, the deleterious effects of improper size selection may be less significant than those of fusion. PMID- 21785293 TI - Hormonal and inflammatory responses to different types of sprint interval training. AB - We evaluated the effect of different types of sprint interval sessions on the balance between anabolic and catabolic hormones and circulating inflammatory cytokines. Twelve healthy elite junior handball players (17-25 years) participated in the study. Exercise consisted of increasing distance (100 m, 200 m, 300 m, 400 m) and decreasing distance (400 m, 300 m, 200 m, 100 m) sprint interval runs on a treadmill (at random order), at a constant work rate of 80% of the personal maximal speed (calculated from the maximal speed of a 100 m run). The total rest period between the runs in the different interval sessions were similar. Blood samples were collected before, after each run, and after 1-hour recovery. Both types of sprint interval trainings led to a significant (p < 0.05) increase in lactate and the anabolic factors growth hormone, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and testosterone levels. Both types of sprint interval sessions led to a significant (p < 0.05) increase in the circulating pro- and anti-inflammatory mediators IL-1, IL-6, and IL1ra. IL-6 remained elevated in both sessions after 1-hour recovery. Area under the curve was significantly greater (p < 0.05) for lactate and growth hormone (GH) in the decreasing distance session. In contrast, rate of perceived exertion was higher in the increasing distance session, but this difference was not statistically significant (p = 0.07). Changes in anabolic-catabolic hormones and inflammatory mediators can be used to gauge the training intensity of anaerobic-type exercise. Changes in the GH-IGF-I axis and testosterone level suggest exercise-related anabolic adaptations. Increases in inflammatory mediators may indicate their important role in muscle tissue repair after anaerobic exercise. The decreasing distance interval was associated with a greater metabolic (lactate) and anabolic (GH) response but not with a higher rate of perceived exertion. Coaches and athletes should be aware of these differences, and as a result, of a need for specific recovery adaptations after different interval training protocols. PMID- 21785299 TI - Preoperative evaluation of the cervical spondylotic myelopathy with flexion extension magnetic resonance imaging: about a prospective study of fifty patients. AB - STUDY DESIGN: The authors evaluated preoperative modifications of the cervical spinal canal in flexion and extension in 50 patients with cervical spondylotic myelopathy (CSM) and looked for impingement of the spinal cord not diagnosed in the neutral position. OBJECTIVE: To evaluate the usefulness of preoperative flexion-extension magnetic resonance imaging (MRI) for patients with CSM. SUMMARY OF BACKGROUND DATA: Dynamic factors contribute to CSM. Although the clinical manifestations and spinal or spinal cord morphology in patients with myelopathy have been reported, to our knowledge, there are no studies that include the cervical spinal cord length, sagittal diameter, and available space in patients with CSM in flexion, extension, and the neutral position. METHODS: Dynamic MRI changes in canal stenosis during flexion-extension were evaluated in 50 patients with CSM in the supine position. The authors determined length of the cervical cord (LCC, C1-C7), cervical cord sagittal diameter (CCSD, C3-T1), cervical cord available space (CCAS, C3-T1), intramedullary high-intensity signal (IHIS) changes, number of stenosis, and severity of cord impingement in flexion, extension, and the neutral positions. RESULTS: On both the anterior and posterior edges of the cord, mean LCC in flexion was longer than in extension or the neutral position and longer in the neutral position than in extension (P < 0.05). In all three positions, the average length of the anterior edge of the cervical cord was longer than the posterior edge (P < 0.05). The mean value of CCSD at each level in extension was greater than in flexion or the neutral position (P < 0.05). In the neutral position, CCSDs were greater than in flexion from C4 to C7 (P < 0.05), but this difference failed to reach significance at levels C3 and T1. In the neutral position, CCAS was greater than in either extension or flexion (P < 0.05), and CCAS was greater in flexion than in extension (P < 0.05) at all levels except C6, at which CCAS was greater in flexion than in either extension or the neutral position (P < 0.05). MRI demonstrated functional cord impingement (grade 3 of Muhle) in 6 of the 50 (12%) patients in flexion, in 17 patients (34%) in the neutral position, and in 37 patients (74%) in extension. IHIS was observed in flexion in 20 patients (40%), in the neutral position in 13 patients (26%), and in extension in 7 patients (14%). CONCLUSION: Cervical spondylotic myelopathy results from the synergistic action of static and dynamic factors, the latter of which play an important role. In some patients, IHIS on T2 images is only visible with the neck in flexion. That might explain why IHIS is first detected after surgery in some patients in whom MRI was obtained before surgery only in the neutral position. Dynamic MRI is useful to determine more accurately the number of levels where the spinal cord is compromised, and to better evaluate narrowing of the canal and IHIS. New information provided by flexion-extension MRI might change our strategy for CSM management. PMID- 21785300 TI - Administration of sodium ibandronate in the treatment of complicated giant cell tumor of the spine. AB - STUDY DESIGN: Case study. OBJECTIVE: To present three complicated cases of giant cell tumor of the spine treated with sodium ibandronate. SUMMARY OF BACKGROUND DATA: Spinal giant cell tumors are a rare clinical entity with a high recurrence rate after operation. Furthermore, complete resection of such lesions remains a challenging surgical problem. Up to this point, no effective adjuvant therapy has been reported for primary or recurrent spinal giant cell tumors. METHODS: One patient with a recurrent giant cell tumor of the seventh thoracic vertebra, one patient with a fifth lumbar vertebral giant cell tumor, and one patient with recurrent giant cell tumor of the sacrum were treated with sodium ibandronate either postoperatively or upon recurrence of the tumor. RESULTS: The first patient with recurrent thoracic giant cell tumor recovered both clinically and radiologically after treatment with sodium ibandronate without reoperation at 6 years follow-up. The second patient also recovered with no recurrence of the tumor at 4-years follow-up. In the third case, although not fully recovered, the recurrent sacral tumor was under control after treatment with sodium ibandronate at 2-years follow-up. CONCLUSION: These case studies demonstrate the potential promise of using sodium ibandronate in the treatment of primary and recurrent giant cell tumors of the spine. Furthermore, clinical evaluation should be performed in future studies. PMID- 21785301 TI - Percutaneous endoscopic lumbar discectomy via contralateral approach: a technical case report. AB - STUDY DESIGN: Technical case report. OBJECTIVE: The authors report a new percutaneous endoscopic lumbar discectomy (PELD) technique for the treatment of lumbar disc herniation via a contralateral approach. SUMMARY OF BACKGROUND DATA: When there are highly down-migrated lumbar disc herniation along just medial to pedicle and narrow ipsilateral intervertebral foramen, the conventional PELD is not easily accessible via ipsilateral transforaminal route. METHODS: Five patients manifested gluteal and leg pain because of a soft disc herniation at the L4-L5 level. Transforaminal PELD via a contralateral approach was performed to remove the herniated fragment, achieving complete decompression of the nerve root. RESULTS: The symptom was relieved and the patient was discharged the next day. CONCLUSION: When a conventional transforaminal PELD is difficult because of some anatomical reasons, PELD via a contralateral route could be a good alternative option in selected cases. PMID- 21785303 TI - Dysphagia after anterior cervical spine surgery: a prospective study using the swallowing-quality of life questionnaire and analysis of patient comorbidities. AB - STUDY DESIGN: Prospective study of 29 patients who underwent anterior cervical (AC) or posterior lumbar (PL) spinal surgery. A validated measure of dysphagia, the Swallowing-Quality of Life (SWAL-QOL) survey, was used to assess the degree of postoperative dysphagia. OBJECTIVE: To determine the degree of dysphagia preoperatively and postoperatively in patients undergoing AC surgery compared with a control group that underwent PL surgery. SUMMARY OF BACKGROUND DATA: Dysphagia is a well-known complication of AC spine surgery and has been shown to persist for up to 24 months or longer. METHODS: A total of 18 AC patients and a control group of 11 PL patients were prospectively enrolled in this study and were assessed preoperatively and at 3 weeks and 1.5 years postoperatively using a 14-item questionnaire from the SWAL-QOL survey to determine degree of dysphagia. Other patient factors and anesthesia records were examined to evaluate their relationship to dysphagia. RESULTS: There were no significant differences between the AC and PL groups with respect to age, sex, body mass index, or length of surgery. The SWAL-QOL scores at 3 weeks were significantly lower for the AC group than for the PL group (76 vs. 96; P = 0.001), but there were no differences between the groups preoperatively or at final follow-up. Smokers, patients with chronic obstructive pulmonary disease, and women had lower SWAL-QOL scores at one or more time point. CONCLUSION: Patients undergoing AC surgery had a significant increase in the degree of dysphagia 3 weeks after surgery compared with patients undergoing PL surgery. By final follow-up, swallowing in the AC group recovered to a level similar to preoperative and comparable to that in patients undergoing lumbar surgery at 1.5 years. Smoking, chronic obstructive pulmonary disease, and female sex are possible factors in the development of postoperative dysphagia. PMID- 21785304 TI - Teaching medical students about disability: the use of standardized patients. AB - Standardized patients (SPs), now a mainstay of the undergraduate medical education experience, are beginning to play larger roles in helping students build competencies to better serve patients who have disabilities, in educating students about the lived experiences of persons with disabilities, and in testing students' understanding of disability-related issues. In this article, the authors discuss several U.S. training programs that involve SPs who have disabilities or SPs who do not have disabilities but who portray patients who do. The authors review the goals of each program (e.g., to provide students with opportunities to gain experience with patients with disabilities), describe their commonalities (enhancing students' interview skills) and differences (some programs are educational; some are evaluative), and summarize the evaluative data of each. The authors also explore the benefits and challenges of working with SPs with disabilities and of working with SPs without disabilities. Finally, they consider the practical issues (e.g., recruiting SPs) of developing and implementing such programs. PMID- 21785305 TI - Perspective: global medicine: opportunities and challenges for academic health science systems. AB - Globalization is having a growing impact on health and health care, presenting challenges as well as opportunities for the U.S. health care industry in general and for academic health science systems (AHSSs) in particular. The authors believe that AHSSs must develop long-term strategies that address their future role in global medicine. AHSSs should meet global challenges through planning, engagement, and innovation that combine traditional academic activities with entrepreneurial approaches to health care delivery, research, and education, including international public-private partnerships. The opportunities for U.S. based AHSSs to be global health care leaders and establish partnerships that improve health locally and globally more than offset the potential financial, organizational, politico-legal, and reputational risks that exist in the global health care arena. By examining recent international activities of leading AHSSs, the authors review the risks and the critical factors for success and discuss external policy shifts in workforce development and accreditation that would further support the growth of global medicine. PMID- 21785306 TI - The physician as health advocate: translating the quest for social responsibility into medical education and practice. AB - There is a growing demand for educating future physicians to be socially responsible. It is not clear, however, how social responsibility is understood and acted on in medical education and practice, particularly within the context of a growing desire to improve health care through an equitable and sustainable delivery system. The authors conduct a concept analysis, exploring the practical philosophical understanding of social responsibility and its implications for medical education and practice. The aim is to inform curricular development, professional practice, and further research on social responsibility. The particular ways in which social responsibility is interpreted can either enhance or establish limits on how it will appear across the continuum of medical education and practice. A physician's place in society is closely tied to a moral sense of responsibility related to the agreed-on professional characteristics of physicianhood in society, the capacity to carry out that role, and the circumstances under which such professionals are called to account for failing to act appropriately according to that role. The requirement for social responsibility is a moral commitment and duty developed over centuries within societies that advanced the notion of a "profession" and the attendant social contract with society. A curriculum focused on developing social responsibility in future physicians will require pedagogical approaches that are innovative, collaborative, participatory, and transformative. PMID- 21785307 TI - Resource allocation in academic health centers: creating common metrics. AB - Optimizing resource allocation is essential for effective academic health center (AHC) management, yet guidelines and principles for doing so in the research and educational arenas remain limited. To address this issue, the authors analyzed responses to the 2007-2008 Association of Academic Health Centers census using ratio analysis. The concept was to normalize data from an individual institution to that same institution, by creating a ratio of two separate values from the institution (e.g., total faculty FTEs/total FTEs). The ratios were then compared across institutions. Generally, this strategy minimizes the effect of institution size on the responses, size being the predominant limitation of using absolute values for developing meaningful metrics. In so doing, ratio analysis provides a range of responses that can be displayed in graphical form to determine the range and distribution of values. The data can then be readily scrutinized to determine where any given institution falls within the distribution. Staffing ratios and operating ratios from up to 54 institutions are reported. For ratios including faculty numbers in the numerator or denominator, the range of values is wide and minimally discriminatory, reflecting heterogeneity across institutions in faculty definitions. Values for financial ratios, in particular total payroll expense/total operating expense, are more tightly clustered, reflecting in part the use of units with a uniform definition (i.e., dollars), and emphasizing the utility of such ratios in decision guidelines. The authors describe how to apply these insights to develop metrics for resource allocation in the research and educational arenas. PMID- 21785308 TI - The CARE model of social accountability: promoting cultural change. AB - On the 10th anniversary of Health Canada and the Association of Faculties of Medicine of Canada's publication in 2001 of Social Accountability: A Vision for Canadian Medical Schools, the authors review the progress at one Canadian medical school, the College of Medicine at the University of Saskatchewan, in developing a culture of social accountability. They review the changes that have made the medical school more socially accountable and the steps taken to make those changes possible. In response to calls for socially accountable medical schools, the College of Medicine created a Social Accountability Committee to oversee the integration of these principles into the college. The committee developed the CARE model (Clinical activity, Advocacy, Research, Education and training) as a guiding tool for social accountability initiatives toward priority health concerns and as a means of evaluation. Diverse faculty and student committees have emerged as a result and have had far-reaching impacts on the college and communities: from changes in curricula and admissions to community programming and international educational experiences. Although a systematic assessment of the CARE model is needed, early evidence shows that the most significant effects can be found in the cultural shift in the college, most notably among students. The CARE model may serve as an important example for other educational institutions in the development of health practitioners and research that is responsive to the needs of their communities. PMID- 21785309 TI - Tensions in informed self-assessment: how the desire for feedback and reticence to collect and use it can conflict. AB - PURPOSE: Informed self-assessment describes the set of processes through which individuals use external and internal data to generate an appraisal of their own abilities. The purpose of this project was to explore the tensions described by learners and professionals when informing their self-assessments of clinical performance. METHOD: This 2008 qualitative study was guided by principles of grounded theory. Eight programs in five countries across undergraduate, postgraduate, and continuing medical education were purposively sampled. Seventeen focus groups were held (134 participants). Detailed analyses were conducted iteratively to understand themes and relationships. RESULTS: Participants experienced multiple tensions in informed self-assessment. Three categories of tensions emerged: within people (e.g., wanting feedback, yet fearing disconfirming feedback), between people (e.g., providing genuine feedback yet wanting to preserve relationships), and in the learning/practice environment (e.g., engaging in authentic self-assessment activities versus "playing the evaluation game"). Tensions were ongoing, contextual, and dynamic; they prevailed across participant groups, infusing all components of informed self-assessment. They also were present in varied contexts and at all levels of learners and practicing physicians. CONCLUSIONS: Multiple tensions, requiring ongoing negotiation and renegotiation, are inherent in informed self-assessment. Tensions are both intraindividual and interindividual and they are culturally situated, reflecting both professional and institutional influences. Social learning theories (social cognitive theory) and sociocultural theories of learning (situated learning and communities of practice) may inform our understanding and interpretation of the study findings. The findings suggest that educational interventions should be directed at individual, collective, and institutional cultural levels. Implications for practice are presented. PMID- 21785310 TI - Use of simulation-based education to improve outcomes of central venous catheterization: a systematic review and meta-analysis. AB - PURPOSE: Central venous catheterization (CVC) is increasingly taught by simulation. The authors reviewed the literature on the effects of simulation training in CVC on learner and clinical outcomes. METHOD: The authors searched computerized databases (1950 to May 2010), reference lists, and considered studies with a control group (without simulation education intervention). Two independent assessors reviewed the retrieved citations. Independent data abstraction was performed on study design, study quality score, learner characteristics, sample size, components of interventional curriculum, outcomes assessed, and method of assessment. Learner outcomes included performance measures on simulators, knowledge, and confidence. Patient outcomes included number of needle passes, arterial puncture, pneumothorax, and catheter-related infections. RESULTS: Twenty studies were identified. Simulation-based education was associated with significant improvements in learner outcomes: performance on simulators (standardized mean difference [SMD] 0.60 [95% CI 0.45 to 0.76]), knowledge (SMD 0.60 [95% CI 0.35 to 0.84]), and confidence (SMD 0.41 [95% CI 0.30 to 0.53] for studies with single-group pretest and posttest design; SMD 0.52 (95% CI 0.23 to 0.81) for studies with nonrandomized, two-group design). Furthermore, simulation-based education was associated with improved patient outcomes, including fewer needle passes (SMD -0.58 [95% CI -0.95 to -0.20]), and pneumothorax (relative risk 0.62 [95% CI 0.40 to 0.97]), for studies with nonrandomized, two-group design. However, simulation-based training was not associated with a significant reduction in risk of either arterial puncture or catheter-related infections. CONCLUSIONS: Despite some limitations in the literature reviewed, evidence suggests that simulation-based education for CVC provides benefits in learner and select clinical outcomes. PMID- 21785311 TI - Analysis of cash flow in academic medical centers in the United States. AB - PURPOSE: To examine cash flow margins in academic medical centers (AMCs; i.e., teaching hospitals) in an effort both to determine any significant differences in a set of operational and financial factors known to influence cash flow for high- and low-cash-flow AMCs and to discuss how these findings affect AMC operations. METHOD: The authors sampled the Medicare cost report data of 103 AMCs for fiscal years 2005, 2006, and 2007, and then they applied the t test to test for significant mean differences between the two cash flow groups across operational and financial variables (e.g., case mix, operating margin). RESULTS: Compared with low-cash-flow AMCs, high-cash-flow AMCs were larger-bed-size facilities, treated cases of greater complexity, generated higher net patient revenue per adjusted discharge, served a significantly lower percentage of Medicaid patients, had significantly higher average operating profit margins and cash flow margin ratios, possessed a higher number of days of cash on hand, and collected their receivables more quickly. CONCLUSIONS: Study findings imply that high-cash-flow AMCs were earning higher cash flow returns than low-cash-flow AMCs, which may be because high-cash-flow AMCs generate higher patient revenues while serving fewer lower-paying Medicaid patients. PMID- 21785312 TI - The influence of causal explanations and diagnostic labeling on medical students' views of schizophrenia. AB - PURPOSE: Negative attitudes toward mental illness among medical professionals can influence the quality of medical care they provide. The authors examined the impact of causal explanations and diagnostic labeling on medical students' views of schizophrenia. METHOD: Medical students in their fifth and sixth years at the Second University of Naples (Italy) who attended lectures from April through June 2010 completed a self-report questionnaire regarding their beliefs about the mental disorder described (but not named) in a case vignette depicting a person who meets the International Classification of Diseases-10 criteria for schizophrenia. RESULTS: Of the 232 students invited, 194 (84%) completed the questionnaire. Students most frequently cited heredity as the cause (81%), followed by stress (69%), psychological traumas (45%), and misuse of street drugs (44%). Most students (82%) labeled the case "schizophrenia"; a minority (24%) believed that persons with the case vignette disorder could be well again. Both labeling the case as "schizophrenia" and naming heredity as the cause were independently associated with pessimism about the possibility of recovery and with the perception that "others" keep their distance from persons with this diagnosis. Heredity was more frequently cited by respondents who labeled the case schizophrenia and was significantly associated with students' perception that people with this diagnosis are unpredictable. CONCLUSIONS: These findings confirm that, in a sample of medical students, biogenetic causal explanations and diagnostic labeling have negative effects on beliefs about schizophrenia. They highlight the need to educate medical students about recovery from and stigma related to schizophrenia. PMID- 21785313 TI - Desired educational outcomes of disability-related training for the generalist physician: knowledge, attitudes, and skills. AB - The problems adults with disabilities face obtaining quality primary care services are persistent and undermine national efforts to improve the health status of this group. Efforts to address this issue by providing disability related training to physicians are hampered by limited information about what generalist physicians need to know to care for patients with disabilities. The authors consider the desired outcomes of disability-related training for generalists by exploring the contributions of the domains of knowledge, attitudes, and skills to patient-directed behavior and summarizing the empirical data.Because disability reflects a complex interplay among individual, interpersonal, institutional, community, and societal factors, generalist physicians can promote and protect the health of adults with disabilities by interventions at multiple levels. Thus, the authors use the social-ecological framework, an approach to health promotion that recognizes the complex relationships between individuals and their environments, to delineate the recommended knowledge, attitudes, and skills in the context of primary care. The importance of role models who demonstrate the three domains, the interactions among them, and issues in evaluation are also discussed. This clear delineation of the recommended educational outcomes of disability-related training in terms of knowledge, attitudes, and skills will support efforts to better prepare generalist physicians-in training and in practice-to care for adults with disabilities and to evaluate these training strategies. PMID- 21785314 TI - Tracking development of clinical reasoning ability across five medical schools using a progress test. AB - PURPOSE: Little is known about the acquisition of clinical reasoning skills in medical school, the development of clinical reasoning over the medical curriculum as a whole, and the impact of various curricular methodologies on these skills. This study investigated (1) whether there are differences in clinical reasoning skills between learners at different years of medical school, and (2) whether there are differences in performance between students at schools with various curricular methodologies. METHOD: Students (n = 2,394) who had completed zero to three years of medical school at five U.S. medical schools participated in a cross-sectional study in 2008. Students took the same diagnostic pattern recognition (DPR) and clinical data interpretation (CDI) tests. Percent correct scores were used to determine performance differences. Data from all schools and students at all levels were aggregated for further analysis. RESULTS: Student performance increased substantially as a result of each year of training. Gains in DPR and CDI performance during the third year of medical school were not as great as in previous years across the five schools. CDI performance and performance gains were lower than DPR performance and gains. Performance gains attributable to training at each of the participating medical schools were more similar than different. CONCLUSIONS: Years of training accounted for most of the variation in DPR and CDI performance. As a rule, students at higher training levels performed better on both tests, though the expected larger gains during the third year of medical school did not materialize. PMID- 21785315 TI - Promoting the transition to independent scientist: a national career development program. AB - The loss of new investigators from academic science places the future of biomedical science at risk. Failure to obtain independent funding contributes significantly to attrition from the academic career path. In this article, the authors describe the Advanced Research Institute (ARI) in Geriatric Mental Health, a national program based at Weill Cornell Medical College of Cornell University that matches new investigators with mentors to help them make a successful transition to independence. The program is multidisciplinary, and its faculty and participants (the latter known as "scholars") span the spectrum of translation, interventions, and services research. ARI helps scholars overcome three barriers to independence through the development of grant-preparation and time-management skills and consultation with statistical and other experts. The authors analyze the record of federal grant funding among the first four cohorts of ARI scholars (2004-2007, n = 42). As of January 2010, 45.2% of these scholars had achieved R01 funding and 69.1% had obtained National Institutes of Health grants (not including career development or small grants). The 24 scholars who had National Institute of Mental Health (NIMH) mentored career development (mentored K) awards were 2.36 times (P = .048) more likely than the other 380 recipients of NIMH mentored K awards during the same period (2001-2005) to achieve R01 funding. Based on objective outcomes, ARI offers an effective model for stemming attrition of new investigators from the academic career path that is generalizable to other fields and promotes innovative, translational science. PMID- 21785316 TI - A model for integration of formal knowledge and clinical experience: the advanced doctoring course at Mayo Medical School. AB - Early clinical experiences that are integrated with basic/clinical science content are considered beneficial to medical students, but little has been published concerning how to accomplish this. In this article, the authors describe the yearlong Advanced Doctoring course, a multidisciplinary clinical skills course for second-year students that was implemented at Mayo Medical School in 2006-2007. Of 197 course hours, 163 (83%) are integrated with the basic/clinical science curriculum, which is organized into six blocks (e.g., circulation, oxygen). During most blocks, all second-year students (approximately 50) participate in integrated clinical, surgical, diagnostic, and simulation experiences related to the basic/clinical science block's content. In the circulation block, for example, students complete workups on inpatients with chest pain, examine inpatients and outpatients with heart murmurs, review pediatric presentations of shock, observe valve replacement in the operating room, observe an echocardiogram, and participate in a simulation (i.e., Harvey heart sounds). Student feedback on course evaluation forms is highly positive. Further, on the 2009 Association of American Medical Colleges Graduation Questionnaire, graduating Mayo medical students were twice as likely as U.S. medical students nationally to strongly agree that the basic science content was sufficiently integrated and had sufficient illustrations of clinical relevance. The authors propose that the Advanced Doctoring course may be a useful model for other institutions contemplating curricular reform that targets better integration of formal knowledge and clinical experiences. PMID- 21785317 TI - How much is too much reading for medical students? Assigned reading and reading rates at one medical school. AB - PURPOSE: To determine how medical students' reading rates affect their ability to complete assigned reading. METHOD: The authors calculated the total amount of reading assigned during 71 weeks in 12 modules of the preclinical basic science curriculum at Mercer University School of Medicine for the 2009-2010 academic year. In September 2010, they surveyed the 351 enrolled students, asking them to estimate their reading rates, number of hours spent reading each day, and the amount of the assigned reading they had completed. The authors used the data collected to estimate time required to complete the reading assignments over a range of reading rates and compared these rates with previously published reading rates. RESULTS: Faculty assigned 29,239 pages of reading across the modules. The 104 respondents (30% response rate) reported they could read an average of 6 hours per day. The authors calculated that 17% of the students read no faster than 150 words per minute (WPM), whereas another 66% did not exceed 100 WPM. If students reserved the last week of each module for review prior to an examination, they would need to read 496 pages per week, which would require 28 to 41 hours per week at these rates, to complete the assigned reading only once. CONCLUSIONS: Medical students require significant time to complete assigned reading just once at the reading rates required to comprehend the cognitively challenging material. Before assigning reading, faculty should consider the amount that could reasonably be accomplished by their students. PMID- 21785318 TI - Association of osteonecrosis and osteoporosis in HIV-1-infected patients. AB - BACKGROUND: We questioned whether heightened impairment of regenerative capacity of osteoblasts might account for the excess of osteonecrosis and osteoporosis seen in HIV-infected patients. Were that the case, patients with osteonecrosis would have more osteoporosis than the patients without osteonecrosis. METHODS: Eleven thousand, five hundred and six patients with HIV infection were studied for the presence of osteonecrosis and osteoporosis and for confounding factors. RESULTS: Depending upon whether dual-energy X-ray absorptiometry (DEXA) was before or after the diagnosis of osteonecrosis, osteoporosis was between 6.3 and 18 times more frequent in those with than in those without osteonecrosis. Those who received DEXA were similar to those who did not in median CD4 level at the time of DEXA or at a comparable time after their first recorded CD4 cell count in our system; in nadir CD4 level; and in use and amount of corticosteroids. Those with osteonecrosis and osteoporosis did not use more corticosteroids than those with osteoporosis without osteonecrosis. Alcohol abuse had not been diagnosed more often before the occurrence of osteonecrosis than in those without osteonecrosis. Tenofovir was not more used by those with than by those without osteoporosis. CONCLUSION: Osteonecrosis and osteoporosis in HIV-infected patients were concurrent more often than expected. PMID- 21785319 TI - Temporal changes in risk factors associated with HIV seroconversion among injection drug users in eastern central Canada. AB - OBJECTIVES: To investigate temporal trends in HIV incidence rates and to assess changes over time in associated risk factors. METHODS: Since 1995, the SurvUDI network has conducted surveillance among IDUs recruited in harm reduction programmes in eastern central Canada. Among the 11,731 participants, 2903 repeaters were initially HIV-negative. HIV incidence was calculated and compared for two time periods (1995-2002 vs. 2003-2009). Multivariate Cox proportional hazard models with time-dependent covariates were used to assess risk factors associated with HIV seroconversion. Interactions between covariates and time periods were examined. RESULTS: The overall HIV incidence rate was 2.7 per 100 person-years [95% confidence interval (CI) 2.4-3.1]. It significantly decreased from 3.1 per 100 person-years in 1995-2002 to 2.2 person-years in 2003-2009. Sex, needle borrowing, and cocaine as most often injected drug were independent and stable determinants of HIV seroconversion. Age, daily injection, sex work and being recruited in an urban area showed significant interactions with time. Being aged 25 years and older, injecting daily and being recruited in an urban area predicted HIV incidence in 1995-2002 but were no longer risk factors in 2003 2009. HIV incidence increased significantly among younger IDUs and sex work emerged as a new determinant of HIV incidence in 2003-2009. CONCLUSION: HIV incidence has decreased over time but remains high among IDUs in eastern central Canada. Associations between risk factors and HIV incidence have changed. Further research is needed to better understand HIV transmission among younger IDUs and IDU sex workers. PMID- 21785320 TI - Impact of cotrimoxazole prophylaxis on the health of breast-fed, HIV-exposed, HIV negative infants in a resource-limited setting. AB - WHO guidelines recommend cotrimoxazole prophylaxis (CTXP) in all HIV-exposed negative infants who are still breastfeeding. This is based on the evidence of efficacy in HIV-infected infants, but there is no evidence of benefit in HIV negative, breast-fed infants. We assessed the impact of CTXP on diarrhoeal and respiratory morbidity in breast-fed, HIV-exposed negative infants in a community programme. CTXP for more than 60 days showed no consistent evidence of benefit for incidence of lower respiratory tract infection [incidence rate ratio (IRR) 0.71, 95% confidence interval (CI) 0.39-1.26; P = 0.241] but an increased incidence of diarrhoea (IRR = 1.38, 95% CI 0.98-1.94; P = 0.065). The guidelines should be reconsidered by conducting a randomized control trial. PMID- 21785322 TI - Can cost studies improve the performance of donor-financed HIV treatment? PMID- 21785321 TI - Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. AB - BACKGROUND: Physiologic and behavioral changes during pregnancy may alter HIV-1 susceptibility and infectiousness. Prospective studies exploring pregnancy and HIV-1 acquisition risk in women have found inconsistent results. No study has explored the effect of pregnancy on HIV-1 transmission risk from HIV-1-infected women to male partners. METHODS: In a prospective study of African HIV-1 serodiscordant couples, we evaluated the relationship between pregnancy and the risk of HIV-1 acquisition among women and HIV-1 transmission from women to men. RESULTS: Three thousand three hundred and twenty-one HIV-1-serodiscordant couples were enrolled, 1085 (32.7%) with HIV-1 susceptible female partners and 2236 (67.3%) with susceptible male partners. HIV-1 incidence in women was 7.35 versus 3.01 per 100 person-years during pregnant and nonpregnant periods [hazard ratio 2.34, 95% confidence interval (CI) 1.33-4.09]. This effect was attenuated and not statistically significant after adjusting for sexual behavior and other confounding factors (adjusted hazard ratio 1.71, 95% CI 0.93-3.12). HIV-1 incidence in male partners of infected women was 3.46 versus 1.58 per 100 person years when their partners were pregnant versus not pregnant (hazard ratio 2.31, 95% CI 1.22-4.39). This effect was not attenuated in adjusted analysis (adjusted hazard ratio 2.47, 95% CI 1.26-4.85). CONCLUSION: HIV-1 risk increased two-fold during pregnancy. Elevated risk of HIV-1 acquisition in pregnant women appeared in part to be explained by behavioral and other factors. This is the first study to show that pregnancy increased the risk of female-to-male HIV-1 transmission, which may reflect biological changes of pregnancy that could increase HIV-1 infectiousness. PMID- 21785324 TI - Dermatofibrosarcoma protuberans treated with wide local excision and followed at a cancer hospital: prognostic significance of clinicopathologic variables. AB - Dermatofibrosarcoma protuberans (DFSP) is a relatively rare low-grade sarcoma. Local control can usually be achieved by wide local excision, but some patients still develop recurrences. The aim of this study was to investigate the correlation between clinicopathologic factors and recurrence-free survival (RFS)/overall survival (OS) in a large series of DFSP patients from a single institution. The study group included sections and medical records of 122 patients (63 women and 59 men, median age of 43) with primary DFSP from UT-MD Anderson Cancer Center between 1976 and 2005. Fibrosarcomatous change was detected in 24 (20.9%) patients. Thirty-eight of 120 patients (31.7%) recurred with a median RFS of 10.2 years. The 5-year RFS rate was 64.2%. Based on univariate analyses, fibrosarcomatous change, mitotic count, metastasis at time of diagnosis, and acral location were significantly associated with shorter RFS. On multivariate analysis, acral location and fibrosarcomatous change remained significant for shorter RFS. Five-year OS was 95.5% (95% confidence interval: 75.42%-99.3%). On univariate analysis, mitotic count per square millimeter, presence of necrosis, and metastasis at time of diagnosis were significantly associated with lower OS. On multivariate analysis, only presence of metastasis remained significantly associated with shorter OS. DFSP-FS variant and acral site are associated with shorter recurrence-free interval after wide local excision. Therefore, patients with tumors on acral sites or those with a fibrosarcomatous component may benefit from aggressive therapies other than wide local excision. The only factor that remains significantly associated with decreased OS is detection of metastasis. PMID- 21785323 TI - The development of an expert system to predict virological response to HIV therapy as part of an online treatment support tool. AB - OBJECTIVE: The optimum selection and sequencing of combination antiretroviral therapy to maintain viral suppression can be challenging. The HIV Resistance Response Database Initiative has pioneered the development of computational models that predict the virological response to drug combinations. Here we describe the development and testing of random forest models to power an online treatment selection tool. METHODS: Five thousand, seven hundred and fifty-two treatment change episodes were selected to train a committee of 10 models to predict the probability of virological response to a new regimen. The input variables were antiretroviral treatment history, baseline CD4 cell count, viral load and genotype, drugs in the new regimen, time from treatment change to follow up and follow-up viral load values. The models were assessed during cross validation and with an independent set of 50 treatment change episodes by plotting receiver-operator characteristic curves and their performance compared with genotypic sensitivity scores from rules-based genotype interpretation systems. RESULTS: The models achieved an area under the curve during cross validation of 0.77-0.87 (mean = 0.82), accuracy of 72-81% (mean = 77%), sensitivity of 62-80% (mean = 67%) and specificity of 75-89% (mean = 81%). When tested with the 50 test cases, the area under the curve was 0.70-0.88, accuracy 64-82%, sensitivity 62-80% and specificity 68-95%. The genotypic sensitivity scores achieved an area under the curve of 0.51-0.52, overall accuracy of 54-56%, sensitivity of 43-64% and specificity of 41-73%. CONCLUSION: The models achieved a consistent, high level of accuracy in predicting treatment responses, which was markedly superior to that of genotypic sensitivity scores. The models are being used to power an experimental system now available via the Internet. PMID- 21785325 TI - Clear cells of Toker in the developing anogenital region of male and female fetuses. AB - The clear cells of Toker are a mysterious population of intra-epidermal glandular cells. They were originally described in nipples, but were recently observed in the vulva as well. It was hypothesized that intra-epidermal embryonic remnants or underlying glands were a potential source. The embryological aspects were investigated by studying specimens of the anogenital region of 18 male and 15 female fetuses between 12 and 39 weeks gestation. The search for Toker cells was enhanced by cytokeratin (CK) 7 immunohistochemistry. The investigation showed that Toker cell elements are a normal, though highly variable constituent of the developing anogenital region. The study revealed the following: (1) single intra epidermal glandular vesicles near follicular anlages in interlabial sulcuses of female fetuses of 15 and 16.5 weeks gestation; (2) CK7+ solitary cells, clusters, and vesicles which were related to developing intra-epidermal follicular canal tracks and tended to disperse inside the epidermis in fetuses of approximately 18 weeks gestation; (3) dispersed CK7+ cells in fetuses of 19-23 weeks gestation; (4) characteristic CK7+ Toker cell proliferations in fetuses more than 23 weeks gestation. These observations indicate that in the anogenital region, primordial follicular cells programmed to participate in the formation of apocrine and mammary-like glands, become displaced into the epidermis where they disperse, and proliferate into Toker cell populations. However, the proximity of Toker cells to CK7+ cells in excretory ducts of late fetal apocrine and mammary-like glands suggested a possible additional source. Consequences for Toker cells of the breast and primary Paget disease are discussed. PMID- 21785326 TI - Progression from atypical/dysplastic intraepidermal proliferations and carcinoma in situ to invasive tumors: a pathway based on current knowledge. AB - Oncology research efforts in recent years have begun to elucidate the role of the peritumoral stroma in the development of dysplasia and subsequent invasive malignancy. In the skin, the stroma surrounding keratinocytic and melanocytic tumors reacts to the dysplastic epidermis in a similar fashion to the wound healing response. Once epidermal genetic mutations and aberrant molecular signaling have occurred, the stroma responds through a 3-phase process extracellular matrix degradation is produced by matrix metalloproteinases; angiogenesis is induced by vascular endothelial growth factor and mast cell mediators; and the inflammatory response is elicited by cytokines and cyclin D1 overexpression balanced by the immunosuppression of mast cell mediators such as tumor necrosis factor alpha, histamine, and transforming growth factor beta. By reacting like injured dermis, the actions of various stromal mediators directly allow for, and even encourage, the progression of in situ atypia/dysplasia to invasive malignancy. The intent of this article is to review the multistep biological and chemical stromal processes, which are involved in the progression of atypical/dysplastic intraepidermal proliferations to invasive malignancy. PMID- 21785327 TI - Subcutaneous thrombotic vasculopathy syndrome: an ominous condition reminiscent of calciphylaxis: calciphylaxis sine calcifications? AB - Ischemic skin necrosis can be a cause of severe morbidity and mortality. It can be due to a number of systemic conditions such as (1) thrombotic vasculopathy syndromes, (2) calciphylaxis, (3) septic or cholesterol emboli, and (4) cutaneous vasculitis. We present 3 patients with a clinicopathological syndrome consisting of ischemic skin necrosis associated with histological pattern of subcutaneous thrombotic vasculopathy-extensive microvascular thrombosis confined to small vessels and capillaries of the subcutaneous tissue. All 3 patients were obese and had severe pre-existing medical conditions. Skin biopsies showed intravascular thrombosis involving small arterioles and capillaries of the subcutaneous tissue. Distribution of vascular involvement by thrombotic process was similar to that observed in calciphylaxis, but calcifications were not observed. Two patients died within 3 months of diagnosis. One patient died 2 years after the presentation. Review of 15 biopsies of calciphylaxis revealed areas of subcutaneous thrombotic vasculopathy in 11 cases (73%). Our study shows that subcutaneous thrombotic vasculopathy syndrome is a potentially lethal condition showing overlapping features between thrombotic vasculopathy syndromes and calciphylaxis. Clinicopathological analysis suggests that it may be a rare variant of calciphylaxis sine calcifications or an early prodromal stage of calciphylaxis. This conclusion is in keeping with increasing appreciation of importance of thrombosis and vascular injury in calciphylaxis. PMID- 21785328 TI - Immunohistochemical differences between normal and chronically inflamed conjunctiva: diagnostic features. AB - PURPOSE: There is widespread misinterpretation of normal conjunctival fibrinogen. In differentiating between normal conjunctiva and cicatrizing conjunctivitis, including ocular cicatricial pemphigoid, atopic keratoconjunctivitis, and lichen planus, it is important to properly evaluate and characterize the histologic appearance of the structures seen and not base a diagnosis on just the presence or absence of certain features. One feature of conjunctival histology prone to misinterpretation and misdiagnosis is the presence of subepithelial fibrinogen, particularly when the diagnosis of lichen planus is being considered. Although the presence of subepithelial fibrinogen in oral mucous membranes and in skin can be indicative of lichen planus, such is not the case for conjunctiva. An erroneous diagnosis of lichen planus based on the presence of conjunctival subepithelial fibrinogen can initiate prolonged treatment with topical steroids leading to avoidable, blinding, complication, and further, delay therapy for the real cause of the conjunctivitis. We conducted a cross sectional, controlled, blinded and prospective Institutional Review Board-approved study on the occurrence and pattern of fibrinogen at the epithelial basement membrane zone (BMZ) of normal and inflamed conjunctiva. METHODS: Bulbar conjunctiva was obtained from 10 cases of undiagnosed chronic conjunctivitis of at least 6 months duration and 8 patients with normal conjunctiva. Immunofluorescent staining with antifibrinogen antibodies, periodic acid-schiff stain (PAS), and Giemsa staining were performed. RESULTS: BMZ fibrinogen was found in all cases. This layer was linear, smooth, and continuous in normal conjunctiva and 7 cases of chronic conjunctivitis. It was fragmented and lumpy in 1 case of ocular cicatricial pemphigoid (OCP) and showed spikes and spurs in 2 cases of lichen planus. CONCLUSIONS: BMZ fibrinogen is a normal component of the conjunctiva and its morphological features rather than its mere presence should be assessed as a diagnostic tool. PMID- 21785329 TI - Microarray comparative genomic hybridization detection of copy number changes in desmoplastic melanoma and malignant peripheral nerve sheath tumor. AB - Desmoplastic melanoma (DM) and malignant peripheral nerve sheath tumor (MPNST) can appear morphologically and immunophenotypically similar. We attempted to determine whether microarray comparative genomic hybridization could detect copy number differences between them to aid in the diagnosis. S-100 immunohistochemistry was performed on 5 cases of DM and 9 cases of MPNST using formalin-fixed paraffin-embedded specimens. Genomic DNA was extracted from microdissected cells. Whole genome amplification was performed on 5 of 5 DMs and 6 of 9 MPNST cases. A multiplex polymerase chain reaction assay was used to determine the quality of the DNA samples, which were run on the Spectral Chip 2600 bacterial artificial chromosome array platform. DM showed gains involving chromosomes 1p, 2p, 9q, 13q, 14q, and 20q and losses involving chromosomes 5p, 11p, 12q, 15q, and 18q. Several cancer-associated genes were involved, including gain of BCL2L1, ARTN, AMPK, NRAS, and CCNA1 and loss of IGF2, CDKN1C, PAX6, WT1, TRAF6, MAPK8IP1, and IMP3. MPNST had gains involving chromosomes 1p, 2q, and 19p and loss of chromosome 21q. Gains of MUM1, APC2, MAP2K2, JMJD2B, SP110, PTMA, GPI, and CDKN2D were detected. DM and MPNST have chromosomal alterations detected by array comparative genomic hybridization that might be useful in distinguishing these 2 tumors, although further studies with a larger sample size will be needed to test this. PMID- 21785330 TI - Cutaneous apocrine mixed tumor with intravascular tumor deposits: a diagnostic pitfall. AB - Apocrine mixed tumor of the skin is a benign adnexal neoplasm usually posing no diagnostic problem for a histopathologist. The purpose of our investigation is to present a small series of 4 benign cutaneous apocrine mixed tumors of the skin that contained small foci of intravascular tumor deposits, a feature not previously described, to the best of our knowledge. The 4 lesions were identified retrospectively after a review of 312 apocrine mixed tumors and 51 eccrine mixed tumors in the collective files of the authors. In all cases, this feature was originally overlooked. The patients were 3 men and 1 woman, ranging in age at diagnosis from 29 to 66 years. Locations included nose (2), forehead (1), and the fifth toe (1). Histopathologically, all 4 neoplasms demonstrated typical features of a benign apocrine mixed tumor; 2 cases were classified as hyaline cell-rich tumors. In all cases, there were either blood or lymphatic vessels containing small intraluminal collections of neoplastic cells, which had the appearances of hyaline cells and immunohistochemically expressed cytokeratins and were partly immunoreactive for S-100 protein and calponin, thus indicating the myoepithelial phenotype. The intravascular location of the neoplastic cells was confirmed by CD31 staining. The nature of the vessels (lymphatics vs. blood vessels) was supported by staining for alpha smooth muscle actin, which stained pericytes in blood vessels. Lymphatic vessels were also stained for D2-40. No eccrine mixed tumor manifested intravascular tumor deposits. Follow-up of the patients revealed no recurrences or metastasis (range: 2-21 years). It is concluded that occurrence of intravascular involvement in benign apocrine mixed tumor of the skin is rare (approximately 1%-2%). This feature is discrete and is easy to overlook. At present, its significance is not completely clear. Until proved otherwise in future, we suggest to consider intravascular deposits in cutaneous apocrine mixed tumors as an innocuous phenomenon. PMID- 21785331 TI - Histopathologic features of exanthematous drug eruptions of the macular and papular type. AB - Although exanthematous drug eruptions of the macular and papular type are common and often cause diagnostic problems, histopathologic features are not precisely defined in the literature. We present the first prospective histopathologic study of maculopapular drug eruption in 48 patients in whom the diagnosis had been made on the basis of clinical examination, history of a known offending drug, and follow-up. Because more than 1 biopsy was taken in 11 patients, 60 biopsy specimens could be examined. The most consistent epidermal features were mild spongiosis mainly of the lower layers (97% of biopsies), some hyperplasia (72%), a few lymphocytes (82%), and neutrophils (32%). The dermoepidermal junction revealed discrete vacuolization (97%), scattered lymphocytes (75%), and rare necrotic keratinocytes (32%). All cases showed a dermal perivascular inflammatory infiltrate that was superficial only in 72% of biopsies and superficial and deep in 28% of biopsies. An interstitial infiltrate in the papillary dermis could be found in 93%, more often patchy than lichenoid. In general, the perivascular infiltrate was mild and composed of lymphocytes (100%), eosinophils (60%), and neutrophils (50%). In the papillary dermis, neutrophils often outnumbered the eosinophils. Another feature were the clusters of neutrophils (38%) and eosinophils (20%) in the lumina of dilated, otherwise normal, blood vessels. Rashes induced by anticonvulsants and anxiolytics were characterized by predominance of neutrophils and largish lymphocytes. Edema of the papillary dermis was encountered frequently (85%), whereas wiry collagen bundles were an exceptional finding. In conclusion, our study defined a constellation of histopathologic findings highly suggestive of the diagnosis of exanthematous drug eruption of the macular and papular type. PMID- 21785332 TI - A reliable method for treatment of nonhealing ulcers in the hindfoot and midfoot region in diabetic patients: reconstruction with abductor digiti minimi muscle flap. AB - The foot has a unique anatomic composition and a perfect architecture, which is necessary for mobilization. However, this complex structure is also responsible for healing problems in foot reconstruction. After 25 years of experience in diabetic foot surgery practice, we observed that some hindfoot ulcers are like an iceberg in that they have much more involvement in the plantar fat pad than the skin, and the lateral midfoot region is a common site for ulcer formation. Also the fifth tarsometatarsal joint region is a prominent anatomic structure vulnerable to repetitive trauma and ulcer formation that may easily spread to other parts of the foot. These ulcers should be reconstructed with well vascularized tissues such as muscle flaps after debridement. Between 2003 and 2010, 17 diabetic patients with foot ulcers, involving bone and joint, were reconstructed with abductor digiti minimi muscle flap. When it is needed, the flap is covered with a small split-thickness skin graft. In all cases, complete healing was achieved. The muscle flap functioned well as a versatile and shock absorbent coverage without recurrence of the ulcer during a mean follow-up period of around 2 years. Diabetic foot ulcers should be evaluated and treated individually depending on their location and affected tissue composition. The most appropriate reconstructive option should be selected for each lesion. The abductor digiti minimi muscle flap is extremely useful for the reconstruction of small- to moderate-sized defects that have exposed bone, joint, or tendons in the hindfoot and lateral plantar midfoot. PMID- 21785333 TI - The forked liposuction cannula: a novel approach to the correction of cicatricial contracture deformities in breast reconstruction. AB - Cicatricial contracture deformities in breast reconstruction can result from delayed wound healing, fat necrosis, or chest wall radiation. Secondary revision can be difficult as these contour deformities compromise the final result. The authors describe correction of these scar deformities with a forked liposuction cannula in 38 breast reconstructions (32 patients). Mean follow-up time was 6 months, and no complications resulted from the use of the forked cannula. In 33 reconstructions (86.8%), autologous fat grafting was performed simultaneously. Multiple revisions were required in 8 reconstructions (23.7%). Three patients had a residual contracture after treatment; all 3 had a history of radiation therapy. This early experience demonstrates that use of a forked liposuction cannula for cicatricial breast deformities is both easy and safe. This technique can be a useful adjunct, especially in patients undergoing autologous fat grafting; however, residual contracture may be observed in patients with a history of radiation therapy. PMID- 21785334 TI - The suitability of end-to-side microvascular anastomosis in free flap transfer for limb reconstruction. AB - BACKGROUND: End-to-end (ETE) microvascular anastomosis used in free flap transfer for limb reconstruction often requires the sacrifice of a major artery, which may aggravate distal circulation of the limb. The purpose of this study is to investigate the relationship between the type of microvascular anastomosis and the survival of free flaps, and to highlight the end-to-side (ETS) anastomotic technique when facing vascular anatomic variations. METHODS: Between 1999 and 2008, a retrospective review was conducted by a single microsurgeon on 203 patients who underwent free flap reconstruction for limb reconstruction. We examined the clinical course of 209 arterial and 308 venous anastomoses. ETS anastomoses were performed for 99 vessels, whereas ETE anastomoses for 418 vessels. The distribution and outcome of ETS and ETE anastomoses were compared. RESULTS: One arterial thrombosis (1.15%, 1/87) was recorded in ETS anastomosis group, whereas none (0%, 0/122) was recorded in ETE anastomosis group (P = 0.419). Four venous thromboses (1.35%, 4/296) were found in ETE group, whereas none was found in ETS group (0%, 0/12). There was no statistically significant difference between the 2 anastomotic techniques. Six cases with double pedicles needed ETS anastomosis for 2 arterial and 2 venous reconstructions. Flap survival rate in ETS arterial group was 98.8%, whereas in ETE arterial group, it was 100%. CONCLUSIONS: ETS microvascular anastomosis has an equivalent flap survival rate as compared with ETE microvascular anastomosis. ETS anastomosis should be considered first when facing vessel size discrepancy and for preserving the major arteries of limbs. PMID- 21785335 TI - Polyacrylamide hydrogel injection for augmentation mammaplasty: loss of ability for breastfeeding. AB - Polyacrylamide hydrogel (PAAG) has been widely used for injection augmentation mammaplasty in Russia, China, and Iran for more than 2 decades. In recent years, it has been advocated as a safe permanent filler for soft-tissue augmentation. However, the complications associated with PAAG injection in soft-tissue augmentation have not been extensively investigated. Augmentation mammaplasty through PAAG injection is associated with some complications. The incidence of infection during breastfeeding was reported to be higher than 50%. Herein, we report 58 cases of infection in breastfeeding women receiving PAAG injection, including 50 with unilateral injection (36 on the right, 14 on the left) and 8 bilateral injection. They experienced large breast autoinflation and some severe symptoms, such as local and systemic fever, breast swelling, nipple bulging, tenderness, and pain, which lead to surgical removal of galactocele or intraprosthetic collection of sterile pus resulting in deformity. Operation and comprehensive measures including removal of the injected material, clearing residual cavity, and pharmacotherapy were carried out to control infection and inflammation for 1 to 2 weeks. In the following 12 months, no relapse or recurrence of residual cavity was noted. Therefore, we do not recommend PAAG injection for augmentation mammaplasty, especially in women intending to breastfeed. Patients undergoing PAAG injection for augmentation mammaplasty should avoid breastfeeding. PAAG injection will cause serious consequences resulting in tissue atrophy and breast resection if inappropriately handled. PMID- 21785336 TI - The doctor and the warlord: a fictional tale of moral ambiguity. PMID- 21785337 TI - In the eyes of the beholder! PMID- 21785338 TI - Inflammatory myofibroblastic tumor within intrahepatic inferior vena cava. PMID- 21785339 TI - Sevoflurane reduces leukocyte and platelet adhesion after ischemia-reperfusion by protecting the endothelial glycocalyx. AB - BACKGROUND: Adhesion of polymorphonuclear neutrophils and platelets to the vessel wall contributes to generating ischemia-reperfusion injury. Endothelial adhesion molecules are harbored within the glycocalyx, which covers every healthy vascular endothelium but is deteriorated by ischemia-reperfusion. Pretreating the heart with volatile anesthetics reduces myocardial infarct size and protects against ischemia-reperfusion injury. The authors analyzed a possible protective effect of sevoflurane on the glycocalyx and implications for postischemic cell adhesion. METHODS: Isolated guinea pig hearts were perfused with crystalloid buffer and subjected to 20 min of global warm ischemia and 10 min of reperfusion. An intracoronary bolus of 3 x 10(6) polymorphonuclear neutrophilic leukocytes or 1 x 10(9) platelets of human origin was applied after reperfusion, either with or without pretreating with 0.5 or 1 minimal alveolar concentration sevoflurane. The number of sequestered cells was calculated from the difference between coronary input and output. Coronary effluent was collected throughout reperfusion to measure shedding of the glycocalyx. RESULTS: Ischemia-reperfusion induced a significant increase in median (interquartile range) adhesion versus control nonischemic hearts of both leukocytes (38.9 (36.3-42.9) vs. 14.5 (13.1-16.0)%) and platelets (25.0 (22.5-27.1) vs. 9.4 (8.4-10.7)%). Shedding was evidenced by eightfold increases in washout of syndecan-1 and heparan sulfate versus basal. Sevoflurane reduced cell adhesion to near basal at 1 minimal alveolar concentration (leukocytes: 21.2% (19.2-23.9%), platelets: 11.5% (10.4-12.0%). Shedding measurements and electron microscopy demonstrated that sevoflurane treated hearts retained much of their 200 nm-thick glycocalyx. CONCLUSIONS: Sevoflurane reduces glycocalyx shedding in the postischemic coronary bed, maintaining the natural cover for endothelial adhesion molecules and, thus, reducing cell adhesion. This may explain beneficial outcomes linked to clinical use of volatile anesthetics after ischemia-reperfusion. PMID- 21785340 TI - The prognostic significance of micrometastases: clinical implications. PMID- 21785341 TI - Transthoracic versus transhiatal esophagectomy for the treatment of esophagogastric cancer: a meta-analysis. AB - OBJECTIVE: To study the differences in short and long-term outcomes of transthoracic and transhiatal esophagectomy for cancer. BACKGROUND: Studies have compared transthoracic with transhiatal esophagectomy with varying results. Previous systematic reviews (1999, 2001) do not include the latest randomized controlled trials. METHODS: Systematic review of English-language studies comparing transthoracic with transhiatal esophagectomy up to January 31, 2010. Meta-analysis was used to summate the study outcomes. Methodological and surgical quality of included studies was assessed. RESULTS: Fifty-two studies, comprising 5905 patients (3389 transthoracic and 2516 transhiatal) were included in the analysis. No study met all minimum surgical quality standards. Transthoracic operations took longer and were associated with a significantly longer length of stay. There was no difference in blood loss. The transthoracic group had significantly more respiratory complications, wound infections, and early postoperative mortality, whereas anastomotic leak, anastomotic stricture, and recurrent laryngeal nerve palsy rate was significantly higher in the transhiatal group. Lymph node retrieval was reported in 4 studies and was significantly greater in the transthoracic group by on average 8 lymph nodes. Analysis of 5 year survival showed no significant difference between the groups and was subject to significant heterogeneity. CONCLUSIONS: This meta-analysis of studies comparing transthoracic with transhiatal esophagectomy for cancer demonstrates no difference in 5-year survival, however lymphadenectomy and reported surgical quality was suboptimal in both groups and the transthoracic group had significantly more advanced cancer. The finding of equivalent survival should therefore be viewed with caution. PMID- 21785342 TI - Ectomorphic body habitus, microcephaly, developmental delay with characteristic facial phenotype: a new entity? PMID- 21785343 TI - Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype. PMID- 21785344 TI - Phantom limb pain in young cancer-related amputees: recent experience at St Jude children's research hospital. AB - OBJECTIVES: This study in children and young adults having cancer-related amputation aimed to examine the incidence of phantom limb pain (PLP) in the first year after amputation and also the proportion of patients who had preamputation pain. METHODS: A retrospective review of medical records was undertaken. The proportion of patients with PLP was reported. Fisher exact test was used to examine the association between PLP and the presence of preamputation pain and between PLP and age (<= 18 y vs. >18 y). RESULTS: Twenty-six amputations were performed on 25 patients. During the year after amputation, 76% of patients had experienced PLP at some time. After 1 year, though, only 10% still had PLP. Preamputation pain was present in 64% of patients. Although both of our patients with PLP at 1 year were young adults (older than or equal to 18 y) and both had preamputation pain, we found no statistically significant associations between age or the presence of preamputation pain with PLP. DISCUSSION: PLP after cancer related amputation in children and young adults seems to be common but generally short lived in most patients. PMID- 21785345 TI - Effects of exercise of different intensities on the angiogenesis, infarct healing, and function of the left ventricle in postmyocardial infarction rats. AB - BACKGROUND: Lifestyle interventions, including physical exercise, are feasible options for the prevention and treatment of cardiovascular diseases. In this study, the effects of exercise of different intensities on the infarct region, function, and angiogenesis of the left ventricle (LV) in postmyocardial infarction (MI) rats were investigated and the levels of vascular endothelial growth factor (VEGF) proteins in the LV and plasma were examined. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly assigned to six groups. The exercise-trained rats observed a daily 60-min treadmill routine 5 days/weeks for 6 weeks. Different treadmill speeds were used in the high-intensity exercise (HIE), moderate-intensity exercise (MIE), and low-intensity exercise (LIE) groups, whereas the untrained rats remained sedentary (Sed). At 6 weeks, all rats underwent either an acute MI operation or a sham (Sh) MI operation 24 h after their last treadmill exercise or the corresponding Sed protocol. They were then killed 7 days after recovery. Echocardiographic and hemodynamic measurements were taken at the end of the experimental protocol. The infarct regions were analyzed using Masson's trichrome staining, whereas intramyocardial microvessels were detected using Factor VIII-related antigen staining. The cardiac VEGF protein levels were determined by western blotting analysis, and plasma VEGF concentrations were examined by enzyme-linked immunosorbent assay. RESULTS: Compared with the corresponding parameters in the Sed-Sh group, LV function did not significantly ameliorate and microvessel density did not increase in the MIE Sh group. Compared with the Sed-MI group, the MIE-MI and HIE-MI groups had significantly reduced LV infarct size, improved hemodynamic parameters, and increased fractional shortening, scar thickness, and microvessel density, these parameters did not significantly change in the LIE-MI group. In addition, the MIE MI and HIE-MI rats had significant differences in hemodynamic parameters and microvessel density. Compared with those of the Sed-MI group, the heart and plasma of the exercise-trained rats in the MIE-MI and HIE-MI groups displayed higher levels of VEGF protein, but the difference between the MIE-MI and HIE-MI groups was not significant. CONCLUSIONS: Moderate-intensity running before acute MI improved LV function, reduced scar size, and increased scar thickness and microvessel density in post-MI rats. Exercise at a higher intensity could have further small effects. LIE may be beneficial, but it would not be sufficient to improve MI. Moderate-intensity and high-intensity running upregulated the expression of VEGF protein and increased microvessels, which may have partly improved cardiac function after MI in this study. PMID- 21785347 TI - Diagnosis of drug-induced skin reactions: a future role for computer-aided systems? AB - PURPOSE OF REVIEW: The diagnosis of drug-induced hypersensitivity reactions is a common clinical challenge and the skin is considered a signal organ for a large percentage of these reactions. In order to assure clinical improvement of the patient, nondermatologists in primary or intensive care settings attending to patients receiving several drugs are often confronted with the need for an immediate decision which drug to stop and which drug to continue. As reliable allergological tests are missing for most drugs and are not available for immediate interventions, computer-aided diagnostic systems might be of assistance. RECENT FINDINGS: This review highlights the evolution of automated diagnostic aides in dermatology, emphasizes prerequisites for the development of appropriate computational algorithms and discusses the specific requirements and chances for the development of computer-aided diagnostic systems as a supportive approach in the diagnosis of culprit drugs for putative drug-induced hypersensitivity reactions. SUMMARY: As complex computational algorithms have to be created integrating both image and data analysis, the development of a computer-aided system for supporting nondermatologists in the diagnosis of drug related hypersensitivity reactions is an ambitious task but might represent an achievable goal for the medium-term future. PMID- 21785348 TI - Epidemiology of allergic conjunctivitis. AB - PURPOSE OF REVIEW: To describe currently available epidemiological data on the prevalence of allergic conjunctivitis. Allergic conjunctivitis is often underdiagnosed and consequently undertreated except when it is severe and the chief complaint of a consultation in a specialty clinic. Use of healthcare resources and reduced quality of life of affected individuals justify studies on the prevalence of allergic conjunctivitis. RECENT FINDINGS: The association of allergic nasal and ocular symptoms (rhinoconjunctivitis) is common. Most children with allergic conjunctivitis have allergic rhinitis. Older population studies estimate a prevalence of 15-20% of allergic conjunctivitis, but more recent studies implicate rates as high as 40%. Ocular symptoms are common and contribute to the burden of allergic rhinitis and lower quality of life. Ocular allergies rank a very close second and at times may overcome the primary complaints of nasal congestion in rhinoconjunctivitis patients. SUMMARY: Little focus has been set on the impact of allergic conjunctivitis as comorbidity to asthma and rhinitis in atopic patients. Conjunctivitis symptoms are at least as severe as rhinitis symptoms in patients with 'hay fever' and some have even generated the term of conjunctivorhinitis stressing the ocular symptoms. Prevalence studies should be specifically addressed to ocular allergy symptoms. PMID- 21785349 TI - Radionuclide cardiac stress testing. AB - PURPOSE OF REVIEW: To briefly review the field of radionuclide stress imaging, including recent technologic advances and clinical applications. RECENT FINDINGS: ECG gating and attenuation correction help increase specificity and accuracy of myocardial single-photon emission computed tomography (SPECT) imaging. Furthermore, advances in camera hardware and software enable more rapid image acquisition and/or radiation dose reduction. Position emission tomography (PET) and hybrid imaging with computer tomography (CT) are emerging technologies which provide improved image resolution and complementary anatomical data. Nuclear cardiology also demonstrates a wide variety of prognostic applications for a diverse group of patient subgroups. More judicious use of SPECT technology using application of the recently updated appropriateness criteria is encouraged. SUMMARY: Radionuclide stress imaging provides essential clinical information and has clear impact on patient assessment and management. PMID- 21785350 TI - Prolonged sitting: is it a distinct coronary heart disease risk factor? AB - PURPOSE OF REVIEW: Prolonged sitting (sedentary behavior) has deleterious cardiovascular and metabolic correlates; however, little is known about the associations of too much sitting with all-cause and cardiovascular mortality risk. In addition to the adverse effects of total sitting time, the manner in which it is accumulated has also been postulated to be important for cardiovascular health. RECENT FINDINGS: We describe recent evidence from several research papers published in the last 12-18 months, showing deleterious relationships of sedentary behavior with mortality outcomes. We also explore emerging findings on breaking up sedentary time and its potential beneficial impact on cardiovascular health. SUMMARY: Consistent independent associations have been observed between sitting time/sedentary behaviors and elevated all cause and cardiovascular disease mortality risk. Generally, these associations have persisted following adjustment for physical activity. Furthermore, total sedentary time (measured objectively via accelerometer) is detrimentally associated with several cardiovascular risk factors, whereas breaking up sedentary time (independent of total sedentary time and moderate-to-vigorous intensity activity) is beneficially associated. This evidence provides further support to the importance of avoiding prolonged, uninterrupted periods of sitting time for cardiovascular health. However, further evidence from intervention trials is required to establish the causal pathways. PMID- 21785346 TI - Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. AB - OBJECTIVE: It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality. DESIGN: Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative vs. liberal fluid management and of management guided by a central venous vs. pulmonary artery catheter. SETTING: Acute Respiratory Distress Syndrome Network hospitals. PATIENTS: One thousand patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The incidence of acute kidney injury, defined as an absolute rise in creatinine of >=0.3 mg/dL or a relative change of >50% over 48 hrs, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of acute kidney injury before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57% vs. 51%, p = .04). After adjustment for fluid balance, the incidence of acute kidney injury was greater in those managed with the liberal fluid protocol (66% vs. 58%, p = .007). Patients who met acute kidney injury criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet acute kidney injury criteria both before and after adjustment for fluid balance (31% vs. 12%, p < .001) and those who had acute kidney injury before but not after adjustment for fluid balance (31% vs. 11%, p = .005). The mortality of those patients meeting acute kidney injury criteria after but not before adjustment for fluid balance was similar to patients with acute kidney injury both before and after adjustment for fluid balance (31% vs. 38%, p = .18). CONCLUSIONS: Fluid management influences serum creatinine and therefore the diagnosis of acute kidney injury using creatinine-based definitions. Patients with "unrecognized" acute kidney injury that is identified after adjusting for positive fluid balance have higher mortality rates, and patients who have acute kidney injury before but not after adjusting for fluid balance have lower mortality rates. Future studies of acute kidney injury should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis. PMID- 21785352 TI - Evolving techniques in colonoscopy. AB - PURPOSE OF REVIEW: This review summarizes recent clinical studies of colonoscopy technique and new technologies. RECENT FINDINGS: Water immersion reduces pain and sedation doses in unsedated and lightly sedated colonoscopy. Cap-fitted colonoscopy makes insertion faster and improves detection of lesions behind folds, but the latter effect is operator-dependent. A single controlled trial showed improved detection with the Third Eye Retroscope, but the two arms of the study were not controlled for withdrawal time. Chromoendoscopy increases detection of diminutive adenomas, but adds time to the colonoscopy procedure. Electronic chromoendoscopy methods (narrow band imaging, Fujinon Intelligent ChromoEndoscopy, i-scan, and autofluorescence) have been either unsuccessful in improving detection or require more study. However, these methods and several other methods (chromoendoscopy with magnification, confocal laser microscopy, and endocytoscopy) allow accurate real time determination of polyp histology. SUMMARY: Water immersion is a clear advance in unsedated colonoscopy. Cap-fitted colonoscopy is a promising method for both practical and effective visualization of the proximal sides of haustral folds. Electronic chromoendoscopy has been largely ineffective at improving polyp detection, but is effective (as are confocal laser microscopy and endocytoscopy) for diagnosis of polyp histology. PMID- 21785351 TI - Iron and intestinal immunity. AB - PURPOSE OF REVIEW: Recent advances in the study of iron metabolism have led to a better understanding of the molecular basis for the interactions between iron and the inflammatory response. We will review this new information in the context of the gastrointestinal tract. RECENT FINDINGS: The effects of iron on microbial enteropathogens are well known. Recent work has demonstrated that iron also has potentially important effects on the intestinal microbiota. On the host side, hepcidin, a key regulator of mammalian iron metabolism, has emerged as an important mediator of the cross-talk between iron homeostasis and inflammation. Hepcidin-dependent changes in iron flux can influence the expression of inflammatory cytokines, and conversely, inflammatory cytokines can induce hepcidin expression and alter iron homeostasis. Hepcidin levels have been found to be elevated in some studies of inflammatory bowel disease, while manipulating hepcidin expression in animal models of this condition has beneficial effects on both inflammation and dysregulated iron metabolism. SUMMARY: The information on iron metabolism that has become available in recent years has shed new light on the pathogenesis of inflammatory diseases of the gastrointestinal tract, and is also starting to suggest new approaches to treating such diseases. PMID- 21785354 TI - Change. PMID- 21785353 TI - Auditory mechanics of the tectorial membrane and the cochlear spiral. AB - PURPOSE OF REVIEW: This review is timely and relevant because new experimental and theoretical findings suggest that cochlear mechanics from the nanoscale to the macroscale are affected by the mechanical properties of the tectorial membrane and the cochlea's spiral shape. RECENT FINDINGS: Main tectorial membrane themes addressed in this review are composition and morphology, nanoscale mechanical interactions with the outer hair cell bundle, macroscale longitudinal coupling, fluid interaction with inner hair cell bundles, and macroscale dynamics and waves. Main cochlear spiral themes are macroscale, low-frequency energy focusing and microscale organ of Corti shear gain. SUMMARY: Recent experimental and theoretical findings reveal exquisite sensitivity of cochlear mechanical performance to tectorial membrane structural organization, mechanics, and its positioning with respect to hair bundles. The cochlear spiral geometry is a major determinant of low-frequency hearing. These findings suggest a number of important research directions. PMID- 21785355 TI - Adjuvant therapy with bone-targeted agents. AB - PURPOSE OF REVIEW: The use of bone-targeting agents in the adjuvant setting has focused on two main areas: prevention of chemotherapy-induced bone loss (CTIBL) and the potential antitumour effects in preventing development of metastasis. Here, we review recent advances within these two areas. RECENT FINDINGS: Trials of oral and intravenous bisphosphonates for prevention of CTIBL in breast cancer have informed both UK and European guidelines on management. A large randomized trial of denosumab, an antibody to RANK ligand, in prostate cancer has demonstrated prevention of bone loss and a reduction in fractures. The data supporting the use of bone-targeted agents in prevention of metastasis are less consistent, with variable findings from the randomized controlled trials in both breast and prostate cancer reported to date. However, the emerging evidence suggests that modification of the bone microenvironment does influence the clinical course of both early breast cancer and castrate-resistant prostate cancer, particularly in clinical settings in which bone metabolism is no longer primarily regulated by reproductive hormones. SUMMARY: The role of bisphosphonates in CTIBL in breast cancer is now defined, but in other malignancies more evidence is needed prior to recommendation as standard treatment. In the role of preventing metastasis, results of ongoing studies are awaited to help clarify populations of patients who will derive benefit. Alternative therapies including the RANKL inhibitor denosumab may provide an alternative adjuvant treatment strategy. Combination therapy with adjuvant bone targeted agents is yet to be investigated. PMID- 21785356 TI - Postoperative delirium. Part 1: pathophysiology and risk factors. AB - Delirium presents clinically with differing subtypes ranging from hyperactive to hypoactive. The clinical presentation is not clearly linked to specific pathophysiological mechanisms. Nevertheless, there seem to be different mechanisms that lead to delirium; for example the mechanisms leading to alcohol withdrawal delirium are different from those responsible for postoperative delirium. In many forms of delirium, the brain's reaction to a peripheral inflammatory process is considered to be a pathophysiological key element and the aged brain seems to react more markedly to a peripheral inflammatory stimulus than a younger brain. The effects of inflammatory mediators on the brain include changes in neurotransmission and apoptosis. On a neurotransmitter level, impaired cholinergic transmission and disturbances of the intricate interactions between dopamine, serotonin and acetylcholine seem to play an important role in the development of delirium. The risk factors for delirium are categorised as predisposing or precipitating factors. In the presence of many predisposing factors, even trivial precipitating factors may trigger delirium, whereas in patients without or with only a few predisposing factors, a major precipitating insult is necessary to trigger delirium. Well documented predisposing factors are age, medical comorbidities, cognitive, functional, visual and hearing impairment and institutional residence. Important precipitating factors apart from surgery are admission to an ICU, anticholinergic drugs, alcohol or drug withdrawal, infections, iatrogenic complications, metabolic derangements and pain. Scores to predict the risk of delirium based on four or five risk factors have been validated in surgical patients. PMID- 21785357 TI - Patient safety in anaesthesia: assessment of status quo in the Berlin-Brandenburg area, Germany. PMID- 21785358 TI - The role of pneumonia scores in the emergency room in patients infected by 2009 H1N1 infection. AB - Despite the severity of pneumonia in patients with pandemic influenza A infection (H1N1), no validated risk scores associated with H1N1 pneumonia were tested. In this prospective observational study, we analyzed data of consecutive patients in our emergency room, hospitalized because of pneumonia between July and August 2009 in a public hospital in Brazil. The following pneumonia scoring systems were applied: the SMART-COP rule; the Pneumonia Severity Index; and the CURB-65 rule. Of 105 patients with pneumonia, 53 had H1N1 infection. Among them, only 9.5% that had a low risk according to SMART-COP were admitted to ICU, compared with 36.8% of those with the Pneumonia Severity Index score of 1-2 and 49% of those with CURB-65 score of 0-1. The SMART-COP had an accuracy of 83% to predict ICU admission. The SMART-COP rule presented the best performance to indicate ICU admission in patients with H1N1 pneumonia. PMID- 21785359 TI - How many training modalities are needed to obtain procedural confidence in intraosseous access? A questionnaire study. AB - Participants in advanced resuscitation courses are often expected to learn to perform intraosseous access (IO). But how many learning modalities are needed to achieve procedural confidence in IO? We distributed an online questionnaire to members of emergency medicine, paediatric and anaesthesiology societies in Scandinavia. The responders without real-life experience with IO (n=322) were classified as 'not confident' or 'confident' in IO. Of total responders 22.8% without training felt confident. Confidence increased to 74.8% after one training modality, 87.9% after two modalities, 98.7% after three modalities and 100% after four modalities (P<0.0001). Of total responders 89.5% who had 'workshop or similar training with hands-on experience' as sole teaching method was confident. Confidence in IO increases with the number of learning modalities. 'Workshop or similar training with hands-on experience' as single training modality seemed as effective as the combination of two modalities. PMID- 21785360 TI - To share or not to share: a randomized trial of consent for data sharing in genome research. AB - PURPOSE: Despite growing concerns toward maintaining participants' privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. Our purpose was to assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing. METHODS: A single-blinded, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas, between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n = 110; binary, n = 103; and tiered, n = 110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation. RESULTS: Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns. CONCLUSION: Our findings indicate that most participants are willing to publicly release their genomic data; however, a significant portion prefers restricted release. These results suggest discordance between existing data sharing policies and participants' judgments and desires. PMID- 21785361 TI - A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. AB - PURPOSE: Although Lynch syndrome is characterized by marked genetic heterogeneity, some specific mutations are observed at high frequency in well defined populations or ethnic groups due to founder effects. METHODS: Genomic breakpoint identification, haplotype analysis, and mutation age determination were performed in 14 unrelated patients and 95 family members presenting the same MLH1 exonic rearrangement, among a series of 84 Lynch syndrome families with germline mutations in MLH1, MSH2, or MSH6. RESULTS: All 14 probands harbored an identical deletion, comprising exons 17-19 of the MLH1 gene and exons 26-29 of the LRRFIP2 gene, corresponding to the MLH1 mutation c.1896 + 280_oLRRFIP2:c.1750 678del. This mutation represents 17% of all deleterious mismatch repair mutations in our series. Haplotype analysis showed a conserved region of approximately 1 Mb, and the mutation age was estimated to be 283 +/- 78 years. All 14 families are originated from the Porto district countryside. CONCLUSION: We have identified a novel MLH1 exonic rearrangement that is a common founder mutation in Lynch syndrome families, indicating that screening for this rearrangement as a first step may be cost-effective during genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the Porto district. PMID- 21785362 TI - Biomechanical anchorage evaluation of mini-implants treated with sandblasting and acid etching in orthodontics. AB - PURPOSE: The purpose of this study was to assess the stability of sandblasted and acid-etched miniscrew implants based on orthodontic mechanics for space closure after tooth extraction. MATERIALS AND METHODS: Twenty-four orthodontic mini implants were placed in 13 patients, for a skeletal anchorage purpose, all prepared by the manufacturer (3M Unitek-IMTEC Ortho USA) with sandblasting and acid treatment. Anchorage measurements were made on occlusal radiographs, on a monthly basis in a 6-month period. RESULTS: All the mini-implants were effective for the clinical trial; but 65% of the mini-implants, after been loaded, showed up to 1 degree, or less, of displacement, while 35% showed >=2 degrees shift. The mandible mini-implants resulted in a smaller amount of displacement than the ones located in the maxilla. The ones located at the anterior maxilla displaced less than the posterior. The best results were obtained with the 8-mm mini-implants, followed by the 6-mm and 10-mm mini-implants. CONCLUSIONS: Modifying the mini implant surface with sandblasting and acid treatment offers good bone anchoring for orthodontic purposes. PMID- 21785363 TI - Structure fires, smoke production, and smoke alarms. AB - Smoke inhalation injury causes severe morbidity and death. In the United States, the majority of fatalities from fire and burns occur because of inhalation of smoke. Medical treatment is only supportive; there is no known antidote to the damaging effects of smoke toxicants on pulmonary tissue. Without question, minimization of the morbidity and mortality that are caused by smoke inhalation is best accomplished by prevention of the injury. Effective prevention programs depend on a thorough and detailed understanding of the mechanism of damage caused by smoke, as well as of the available options for efficacious prevention. This summary presents details of smoke production from structure fires, the effects of smoke on physiology, and the devices currently in use to prevent damage and death from smoke. PMID- 21785364 TI - The results of a national survey regarding nutritional care of obese burn patients. AB - Little is known about the nutritional needs of obese burn patients. Given the impact of obesity on the morbidity and mortality of these patients, a uniform understanding of perceptions and practices is needed. To elucidate current practices of clinicians working with the obese burn population, the authors constructed a multidisciplinary survey designed to collect this information from practitioners in United States burn centers. An electronic approach was implemented to allow for ease of distribution and completion. A portable document format (pdf) letter was e-mailed to the members of the American Burn Association and then mailed separately to additional registered dietitians identified as working in burn centers. This letter contained a link to a 29-question survey on the SurveyMonkey.com server. Questions took the form of multiple choice and free text entry. Responses were received from physicians, mid-level practitioners, registered dietitians, and nurses. Seventy-five percent of respondents defined obesity as body mass index >30. The Harris-Benedict equation was identified as the most frequently used equation to calculate the caloric needs of burn patients (32%). Fifty-eight percent indicated that they alter their calculations for the obese patient by using adjusted body weight. Calculations for estimated protein needs varied among centers. The majority did not use hypocaloric formulas for obese patients (79%). Enteral nutrition was initiated within the first 24 hours for both obese and nonobese patients at most centers. Sixty-three percent suspend enteral nutrition during operative procedures for all patients. Oral feeding of obese patients was the most preferred route, with total parenteral nutrition being the least preferred. Longer length of stay, poor wound healing, poor graft take, and prolonged intubation were outcomes perceived to occur more in the obese burn population. In the absence of supporting research, clinicians are making adjustments to the nutritional care of obese burn patients. This indicates the need for further research to determine consistent best practices. PMID- 21785365 TI - CD4+CD25+Foxp3+ regulatory T cells suppress cardiac fibrosis in the hypertensive heart. AB - BACKGROUND: CD4+CD25+Foxp3+ regulatory T cells (Tregs) are potent inhibitors of inflammation and autoimmune diseases. Because inflammation has been associated with development of cardiac fibrosis in experimental hypertension, here we investigated whether adoptively transferred Tregs would inhibit development of cardiac fibrosis initiated by elevating blood pressure. METHODS: Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Immediately after the operation mice received either vehicle or purified, cultured Tregs (1.5 * 106). Fourteen days later we assessed effects on developing left ventricular fibrosis, blood pressure, inflammation, myofibroblasts and the transforming growth factor-beta1 (TGF-beta1) system. RESULTS: Fourteen days after aortic constriction, marked left-ventricular fibrosis was apparent and this was greatly reduced in mice receiving adoptively transferred Tregs. This reduction in fibrosis was associated with attenuated inflammatory cell numbers, reduced interstitial myofibroblast numbers and attenuated activity of the TGF-beta1 system, indicated by reductions in the expression of TGF-beta1 and its receptors activin-like kinase-5 and type II TGF-beta receptor. Adoptively transferred Tregs did not affect blood pressure and exerted only a small effect on left-ventricular hypertrophy. CONCLUSIONS: These data indicate that Tregs attenuate cardiac fibrosis associated with hypertensive heart disease by suppressing inflammation. PMID- 21785366 TI - The cost-effectiveness of interventions designed to reduce sodium intake. AB - BACKGROUND: To guide resource allocation, policy makers need evidence of the cost effectiveness of interventions. We summarized such evidence on selected interventions to reduce sodium intake that would be intended as population-wide approaches to control hypertension. METHODS: We conducted a comprehensive literature review of journal articles published in English from January 2000 to May 2010 by searching the databases of PubMed, EMBASE, MEDLINE, and EconLit. We selected original research articles for abstracting the evidence on cost effectiveness of interventions, cost savings and the costs of intervention implementation. RESULTS: From the 53 references obtained from the literature search, we identified 11 original research articles that provided relevant information on the medical cost savings, implementation costs, or cost effectiveness of interventions to reduce sodium intake. The interventions were low in cost, e. g., one study showed that the cost ranged from US$ 0.03 to 0.32 per person per year for awareness campaign through mass media outlets and government regulations on food products in low and middle-income countries. Population-wide interventions for salt reduction are very cost-effective such as only ARS$ 151 per disability-adjusted life-year (DALY) saved in Argentina, whereas statin therapy to lower high cholesterol was $ 70,994 per DALY saved. Another study showed that sodium reduction could save US$ 18 billion in annual US healthcare costs by reducing sodium intake to 2300 mg/day. CONCLUSION: The literature provided economic evidence that was in favor of population-wide interventions designed to reduce sodium intake. Reducing the intake of sodium through such initiatives might be one of the best buys in public health. However, the small body of literature and hypothetical scenarios in most studies might limit policy implications of the findings. PMID- 21785367 TI - Lung transplantation for end-stage silicosis. AB - OBJECTIVE: To evaluate whether lung transplantation conferred acceptable survival compared with conventional treatment for end-stage silicosis. METHODS: We retrospectively analyzed data for five consecutive patients with silicosis between September 2002 and December 2010, four underwent single lung transplantation and one bilateral lung transplantation. RESULTS: There was no perioperative mortality. Extracorporeal membrane oxygenation was required in four patients, three underwent single lung transplantation and one received bilateral lung transplantation, three of them were successfully weaned. One developed primary graft dysfunction 2 days after transplant and died of multiple organ failure on postoperative day 8. The remaining four patients were discharged from hospital. During follow-up, one recipient died of severe infection 7 months after transplant. All remaining patients returned to work and had a good quality of life after 5, 3 and 2 years, respectively. CONCLUSIONS: Lung transplantation offers effective therapy for patients with end-stage silicosis. PMID- 21785368 TI - A web-based approach to address cardiovascular risks in managers: results of a randomized trial. AB - OBJECTIVES: To examine whether a Web-based health and leadership development program--designed specifically for managers--was associated with changes in self reported and biometric indicators of cardiovascular disease within the context of a randomized control trial. METHODS: A total of 145 managers from 8 organizations participated in a 6-month Internet-based program or a control condition. They completed pre- and posttest assessments that included both self-reported attitudes (on diet, exercise, and mental health) and biometric measures (eg, body weight, waist circumference). RESULTS: The intervention was associated with improvements in dietary attitudes, dietary self-efficacy, and exercise, and reductions in distress symptoms. Women in the program reduced their waist circumference significantly more than controls. CONCLUSIONS: The program showed promise for reducing cardiovascular disease risk factors. Similar results across diverse organizations suggest the program may be useful across industry types. PMID- 21785369 TI - Employee self-rated productivity and objective organizational production levels: effects of worksite health interventions involving reduced work hours and physical exercise. AB - OBJECTIVE: To investigate how worksite health interventions involving a 2.5-hour reduction of weekly working hours with (PE) or without (RWH) mandatory physical exercise affects productivity. METHODS: Six workplaces in dental health care were matched and randomized to three conditions (PE, RWH and referents). Employees' (N = 177) self-rated productivity and the workplaces' production levels (number of patients) were examined longitudinally. RESULTS: Number of treated patients increased in all conditions during the intervention year. While RWH showed the largest increase in this measure, PE showed significant increases in self-rated productivity, that is, increased quantity of work and work-ability and decreased sickness absence. CONCLUSIONS: A reduction in work hours may be used for health promotion activities with sustained or improved production levels, suggesting an increased productivity since the same, or higher, production level can be achieved with lesser resources. PMID- 21785370 TI - Sleep problems, depression, substance use, social bonding, and quality of life in professional firefighters. AB - OBJECTIVE: Little attention has been given to factors contributing to firefighters' psychosomatic well-being. The purpose of this descriptive study was to examine such contributing factors in a sample of professional firefighters. METHODS: Measures assessing sleep, depression, substance use, social bonding, and quality of life were examined in 112 firefighters. RESULTS: Overall, many firefighters reported sleep deprivation (59%), binge drinking behavior (58%), poor mental well-being (21%), current nicotine use (20%), hazardous drinking behavior (14%), depression (11%), poor physical well-being (8%), caffeine overuse (5%), or poor social bonding (4%). CONCLUSIONS: Small-to-medium correlations were identified between sleep deprivation, depression, physical/mental well-being, and drinking behaviors. High-risk behaviors that impact psychosomatic well-being are prevalent in professional firefighters, which require environmental and individual-based health promotion interventions. The inter-correlation relationships between such behaviors, therefore, need to be explored in further details. PMID- 21785371 TI - Sleep duration and biomarkers of metabolic function among police officers. AB - OBJECTIVE: To investigate associations between sleep duration and biomarkers of metabolic function among police officers. METHODS: Metabolic markers were measured using standardized methods and sleep duration was assessed from questionnaire data. Mean levels of leptin and adiponectin were assessed across five levels of sleep duration using ANCOVA and linear regression models. RESULTS: Police officers (n = 443) who reported an average of less than 5 hours and at least 8 hours of sleep had higher levels of leptin compared to those who reported an average of 5 to 7 hours of sleep. These associations were stronger and statistically significant among women, officers with BMI of 24.9 kg/m or less and smaller abdominal height (< 20 cm), and officers who primarily worked on the day shift. CONCLUSION: Short and long sleep duration were associated with higher leptin levels and may have implications for obesity-related conditions. PMID- 21785372 TI - Serum estradiol levels are not associated with urinary incontinence in midlife women transitioning through menopause. AB - OBJECTIVE: We evaluated the relationship between annually measured serum endogenous estradiol and the development or worsening of stress and urge incontinence symptoms during a period of 8 years in women transitioning through menopause. METHODS: This is a longitudinal analysis of women with incontinence in the Study of Women's Health Across the Nation, a multicenter, multiracial/ethnic prospective cohort study of community-dwelling women transitioning through menopause. At baseline and at each of the eight annual visits, the Study of Women's Health Across the Nation elicited the frequency and type of incontinence using a self-administered questionnaire and drew a blood sample on days 2 to 5 of the menstrual cycle. All endocrine assays were performed using a double-antibody chemiluminescent immunoassay. We analyzed the data using discrete Cox survival models and generalized estimating equations with time-dependent covariates. RESULTS: Estradiol levels drawn at either the annual visit concurrent with or previous to the first report of incontinence were not associated with the development of any (hazard ratio, 0.99; 95% CI, 0.99-1.01), stress, or urge incontinence in previously continent women. Similarly, estradiol levels were not associated with the worsening of any (odds ratio, 1.00; 95% CI, 0.99-1.01), stress, or urge incontinence in incontinent women. The change in estradiol levels from one year to the next was also not associated with the development (hazard ratio, 0.98; 95% CI, 0.97-1.00) or worsening (odds ratio, 1.03; 95% CI, 0.99 1.05) of incontinence. CONCLUSIONS: We found that annually measured values and year-to-year changes in endogenous estradiol levels had no effect on the development or worsening of incontinence in women transitioning through menopause. PMID- 21785373 TI - Sleep problems after short-term hormone therapy suspension: secondary analysis of a randomized trial. AB - OBJECTIVE: Because hormone therapy use benefits sleep, sleep problems may occur after suspension. We tested the effects of short-term hormone therapy suspension on sleep problems. METHODS: A total of 1,704 women aged 45 to 80 years at Group Health were randomized to suspend hormone therapy for 1 or 2 months or to continue using hormone therapy. This study included 1,405 women willing to suspend hormone therapy use who returned both baseline and follow-up questionnaires, administered within approximately 3 months of randomization. We used generalized linear models to examine the relationships between hormone therapy suspension and nine individual items from a modified General Sleep Disturbance Scale (number of days experienced in the past week) and an overall sleep quality index at follow-up. We tested whether age, hormone therapy type, or duration of use modified these relationships. RESULTS: Suspension of hormone therapy for 1 or 2 months was associated with greater frequency of sleep problems for the overall sleep quality index and most individual sleep items. For example, the incident rate ratios for waking too early (95% CI) were 1.23 (1.10-1.38) for the women in the 1-month suspension group and 1.30 (1.17-1.45) for the 2-month suspension group, compared with women who continued the use of hormone therapy. Age and type of and duration of hormone therapy use did not modify these relationships. CONCLUSIONS: Short-term hormone therapy suspension was related to moderately greater frequency of sleep problems. Alternative forms of sleep management may benefit women who choose to discontinue hormone therapy use. PMID- 21785374 TI - Can the increase in breast cancer observed in the estrogen plus progestin arm of the Women's Health Initiative trial be explained by progesterone receptor membrane component 1? PMID- 21785375 TI - Bone health medications: research questions versus clinical choices. PMID- 21785376 TI - Relationship between inhibin-alpha gene polymorphisms and premature ovarian failure in Korean women. AB - OBJECTIVE: The aim of this study was to determine the relationship between inhibin-alpha (INHalpha) gene polymorphisms and the prevalence of premature ovarian failure (POF) in Korean women. METHODS: The INHalpha -124A/G, -16C/T, 679G/A, and 769G/A polymorphisms were analyzed in 52 women with POF and 55 normal healthy women using polymerase chain reaction-restriction enzyme fragment length polymorphism analysis. RESULTS: The 679G/A and 769G/A polymorphisms were not observed. The frequencies of the C allele of the INHalpha -16C/T polymorphism and the G allele of the INHalpha -124A/G polymorphism were significantly lower in the women with POF than in the normal control women. The frequencies of the CG haplotype allele of these INHalpha -16C/T and -124A/G gene polymorphisms were also significantly lower in the women with POF than in the control women. CONCLUSIONS: The INHalpha -16C/T and -124A/G polymorphisms are genetic factors associated with the prevalence of POF in Korean women. PMID- 21785377 TI - Topical diclofenac gel for the management of periocular actinic keratosis. AB - PURPOSE: We sought to evaluate the efficacy of topical 3% diclofenac gel in the management of periocular actinic keratosis. METHODS: Four consecutive patients with periocular actinic keratosis who were treated with topical 3% diclofenac gel twice daily for up to 4 months were included in the study. Patients were reviewed at 1 and 2 months and then as clinically required up to 13 months after treatment. RESULTS: All 4 patients had biopsy-proven actinic keratosis. Three of the 4 patients tolerated the therapy well. In 1 patient, an adverse reaction developed, with erythema, crusting, and scaling after 2 months of therapy, which resolved within a month of discontinuing topical diclofenac. In all the patients, a visible decrease in lesion severity was seen after 1 month, and complete resolution, within 4 months. Recurrences occurred in 2 patients at 4 months and 7 months after treatment. These were successfully managed, in one patient, by excision, and in the other, with further 3% diclofenac gel followed by cryotherapy. CONCLUSION: The use of 3% diclofenac gel in extraocular sites has been widely described in the dermatology literature. However, no published reports exist of its use in ophthalmology. It may be a useful therapeutic option when used alone in patients with localized disease or to reduce the size of larger, more-diffuse lesions before excision or cryotherapy, leading to improved cosmesis. Furthermore, it may also be useful in patients prone to actinic keratoses, such as organ-transplant recipients, to reduce the need for multiple excision procedures or uncomfortable ablative techniques. PMID- 21785378 TI - The effect of orbital decompression surgery on lid retraction in thyroid eye disease. AB - PURPOSE: To determine the effect of orbital decompression surgery on lid retraction as a function of proptosis reduction in the setting of thyroid eye disease. METHODS: Retrospective interventional case series of all consecutive medial and lateral orbital decompressions performed by the authors for thyroid eye disease from 1999 to 2008. Primary outcome measures included postoperative proptosis and lid retraction. RESULTS: One hundred sixty-five eyes of 89 patients were included. The average amount of proptosis reduction at final follow up (average 30 months) was 4.6 mm. The average improvement in upper lid retraction was 0.9 mm, and the average improvement in lower lid retraction was 0.8 mm. There was a statistically significant correlation (0.12, p = 0.005) between the amount of proptosis reduction and lower lid elevation. No such correlation (-0.010, p = 0.90) was seen for upper lid position. In cases where inferior rectus recession was performed subsequent to decompression surgery (n = 20), the effect of proptosis reduction on lower lid position was negated (correlation -0.01, p = 0.980). CONCLUSION: A statistically significant correlation exists between the amount of proptosis reduction from orbital decompression surgery and improvement in lower lid retraction. No such correlation exists between proptosis reduction and upper lid retraction. Inferior rectus recession negates the positive effect of orbital decompression on lower lid position. PMID- 21785379 TI - Confirmation of and differentiation among primary vascular lesions using ultrasonography. AB - PURPOSE: To demonstrate the utility of orbital ultrasound in the evaluation and management of suspected orbital vascular lesions. METHODS: Clinical case series of 15 patients with suspected orbital vascular lesions seen in the Neuro ophthalmology clinic of the Wilmer Eye Institute. The techniques of standardized echography (combined use of a contact B-scan and standardized A-scan) were performed by an experienced echographer, and data obtained were compared with other available imaging modalities to determine appropriate management. Patients were monitored for improvement, stability, or worsening of symptoms and signs. RESULTS: Based on echographic data obtained, 6 patients underwent surgery, 9 were observed over a follow-up period of 0-14 (mean 3.3) years. All patients demonstrated improvement or remained stable, and no complications developed from misdiagnosis during subsequent follow-up. CONCLUSIONS: Orbital ultrasound provides reliable imaging parameters and can be used as the primary imaging modality when evaluating suspected orbital vascular lesions. PMID- 21785380 TI - An anatomical study of the positional relationship between the ethmoidal foramina and the frontoethmoidal suture. AB - PURPOSE: To examine the positional relationship between the ethmoidal foramina and the frontoethmoidal suture. METHODS: Eighty-four orbits of 42 Japanese cadavers (24 male and 18 female cadavers; average age at death, 81.0 years; range, 61-101 years), fixed in 10% buffered formalin, were used for investigation. The most anterior or posterior ethmoidal foramen was defined as the anterior or posterior ethmoidal foramen, respectively. All the intermediate foramina were determined as the accessory foramina. The vertical distances from the frontoethmoidal suture to the anterior, posterior, and accessory ethmoidal foramina were examined. RESULTS: Seventeen anterior ethmoidal foramina (20.2%) were situated above the frontoethmoidal suture (mean distance, 1.8 mm), and 2 posterior ethmoidal foramina (2.3%) were situated at 1.0 mm and 1.5 mm above the suture. Although accessory ethmoidal foramina were detected in 32 orbits (38.1%), one accessory foramen (middle ethmoidal foramen) was identified in 30 orbits, and 2 foramina (additional deep-middle ethmoidal foramina), in 2 orbits. One middle ethmoidal foramen (3.1%) and 1 deep-middle ethmoidal foramen (50.0%) were located at 1.5 mm above the suture. In total, 2 of the 34 accessory ethmoidal foramina (5.9%) exhibited the extrasutural location. CONCLUSIONS: Several ethmoidal foramina were situated above the frontoethmoidal suture. The anterior ethmoidal foramen most frequently showed the situation, followed by the accessory and posterior foramina, in order. Our findings help predict the anatomical variations in the location of the ethmoidal foramina in relation to the frontoethmoidal suture, thereby enhancing safety for medial orbital wall surgery. PMID- 21785381 TI - The assessment of orbital apical temperature change with local cool compress application. AB - PURPOSE: To examine the change in orbital apical temperature over time, with a local ice/water admixture compress placed over the eyelid. METHODS: A six-month old, 220-pound Landrace/Hampshire/Duroc mixed breed pig was intubated and maintained under anesthesia with a steady average body temperature. An incision in the lateral third of the right lower eyelid along the inferior orbital rim was made, and a digital thermometer was inserted and guided toward the orbital apex by fluoroscopic imaging of the orbit. After the baseline apical temperature was measured, an ice/water admixture compress was placed on the right eyelid, and serial temperatures were taken every 5 minutes for 20 minutes. A final measurement was taken at 45 minutes after the ice/water admixture compress placement. RESULTS: At an average core body temperature of 38.9 degrees C, the baseline apical temperature was 37.2 degrees C. After placement of a 0 degrees C ice/water admixture, there was an exponential decrease in apical temperature, reaching a plateau after a period of 20 minutes, with a decrease of 1.4 degrees C from baseline. The same apical temperature noted 20 minutes after placement of the cool compress was measured 45 minutes after ice/water compress placement. CONCLUSIONS: There was only a limited decrease in apical temperature by placing a local 0 degrees C ice/water admixture over the eyelid. This information is useful in determining whether local hypothermia may be a potential alternative for traumatic optic neuropathy. PMID- 21785382 TI - A comparison of argon laser and radiofrequency in trichiasis treatment. AB - PURPOSE: The aim of this study was to find concrete clinical evidence for determination of the best method of treatment for trichiasis and the location that responds best to treatment with radiofrequency and argon laser. METHODS: This study was performed in 2007 and 2008 on 100 patients, involving a total of 1,181 lashes in contact with the globe. Patients were randomly assigned to 2 groups of treatment: the radiofrequency group (group 1; 2 watts, 2- to 3-mm depth, cut-coagulating mode) and the argon laser group (group 2; spot size 50 MUm, 760 mW, 930-nm wavelengths, continuous). After complete ophthalmic examination and photography, the eyelid was divided into 3 segments (medial, central, and lateral) and treated. The patients were examined 3 months later in terms of response to treatment, pain, and complications. RESULTS: The mean age of the patients was 57.1 +/- 24, ranging from 14 to 98 years. Of the 100 patients included, 56% were women and 44% were men. The results revealed the successful treatment of 472 (82.4%) lashes in the radiofrequency group and 383 (62.9%) in the argon laser group. Responses were significant in the central regions of the upper and lower lids (p = 0.001). Similarly, notching was observed in 4 cases, 3 of which (75%) belonged to the radiofrequency group. However, this trend was not statistically significant. CONCLUSION: The radiofrequency method was found to be superior in comparison to argon laser in the central regions of both upper and lower eyelids. PMID- 21785383 TI - Differentially expressed microRNAs in pancreatic cancer stem cells. AB - OBJECTIVE: The objective of this study was to analyze and identify pancreatic cancer stem cell-specific microRNAs (miRNAs) and messenger RNAs (mRNAs) to investigate their correlations to cancer stem cell biology. METHODS: We used sphere cultivation methods to enrich the stem cell population and analyzed overall miRNA and mRNA expressions using microarray analysis. RESULTS: Differentially expressed miRNAs including miR-99a, miR-100, miR-125b, miR-192, and miR-429 were detected in pancreatic cancer stem cells. Furthermore, examining both profiles, we obtained 210 miRNAs and 258 stem cell-associated mRNAs that were differentially expressed in the pancreatic cancer stem cells. These miRNAs and mRNAs were further investigated using cross-correlation analysis, which yielded 6 groups of miRNAs and 3 groups of mRNAs. The number of miRNA clusters and mRNA clusters showed high correlation based on microarray result. CONCLUSIONS: Differentially expressed miRNAs in pancreatic cancer stem cells provide insights into possible linkages between clusters of miRNAs and clusters of stem cell-associated mRNAs in cancer stem cells and have broad implications in our understanding of cancer stem cells and cancer stem cell-targeted cancer therapy. PMID- 21785384 TI - Lipid profile changes and importance of low serum alpha-lipoprotein fraction (high-density lipoprotein) in cases with acute pancreatitis. AB - OBJECTIVES: Acute pancreatitis (AP) is a common systemic inflammatory disorder of the pancreas. The data related to the lipid changes in patients with AP were insufficient. In this study, we aimed to investigate the relation between high density lipoprotein (HDL) and the other lipid parameters and the severity of the disease in AP cases. METHODS: Seventy-five cases admitted to the Gastroenterohepatology Clinic with diagnosis of AP were included in the study. Ranson scores and Glasgow scores were used for prognosis. Lipid parameters were evaluated for the first 24 hours and after clinic and laboratory remission. RESULTS: The causes of the disease among patients included in the study were as follows: 44 biliary origin (58.7%), 14 alcohol dependent (18.7%), 10 idiopathic (13.3%), 6 hyperlipidemic (8%), and 1 endoscopic retrograde cholangiopancreatography dependent (1.3%). Triglyceride (TG) levels of the patients included in the study measured in the first 2 days were significantly higher than TG levels measured after clinic and laboratory remission (P = 0.013). High-density lipoprotein was significantly lower in alcoholic and hypertriglyceridemic AP cases. There was a statistical correlation between HDL and Ranson (P = 0.023). CONCLUSION: The low levels of HDL in AP cases during acute attack are associated with severity of the disease. PMID- 21785385 TI - Robotic extended pancreatectomy with vascular resection for locally advanced pancreatic tumors. AB - OBJECTIVES: Limited involvement of the major peripancreatic vessels is no longer considered a contraindication for resection in cases of locally advanced pancreatic cancer. Extended open pancreatectomies associated with vascular resection are performed in experienced centers with mortality and morbidity rates comparable to standard pancreatic resection. We evaluate the safety, feasibility, and outcomes of robotic extended pancreatectomy with vascular resection. METHODS: We reviewed data of 5 patients with a median age of 60 years (range, 52-74 years) who underwent robotic surgery for pancreatic tumors with vascular involvement between May 2007 and March 2010 at our institution. The types of resection included 2 left-sided splenopancreatectomy with celiac axis resection, 1 left sided splenopancreatectomy with portal vein resection, and 2 pancreaticoduodenectomy with portal vein resection. RESULTS: No conversions occurred. The overall mean operating time was 392 +/- 66 minutes (range, 310-460 min). The overall mean blood loss was 200 +/- 61 mL (range, 150-300 mL) with no transfusions. No mortalities occurred. At a median follow-up of 6 months (range, 3-20 months), 4 patients were alive and disease free. CONCLUSIONS: This early series by a single surgeon supports the feasibility and safety of robotic pancreatectomy with vascular resection for selected patients with locally advanced pancreatic tumor. PMID- 21785386 TI - The association of quality-of-life measures with malignancy and survival in patients with pancreatic pathology. AB - OBJECTIVES: This study assessed whether pretreatment quality-of-life (QoL) scores could predict the presence of pancreatic malignancy and survival. METHODS: Patients with pancreatic lesions completed the SF-36, containing 8 domains: physical functioning, role-physical, role-emotional, bodily pain, vitality, mental health, social functioning, and general health. Data obtained included age, sex, resectability, additional antineoplastic therapy, stage, pathology, and survival. Patients were categorized by pathology (benign vs malignant), stage (local, regional, or distant), resectability (resected vs not), survival (<1 vs >1 year), and their pretreatment QoL scores. RESULTS: Of the 323 patients assessed, 210 had malignancies. In 6 of the 8 domains, patients with malignancies had lower median QoL scores compared with patients with benign lesions. Of the patients with malignancies, patients surviving at 1 year or less had lower pretreatment scores in all domains. Stage, resection, adjuvant therapy, and vitality score were independent predictors of survival. CONCLUSIONS: Patients with pancreatic malignancies had lower QoL scores than patients with benign pancreatic disease. Patients with malignancies surviving at 1 year or less had lower scores, even after controlling for stage. This suggests that pretreatment QoL scores are associated with pancreatic malignancy and survival. PMID- 21785387 TI - Effects of zinc deuteroporphyrin bis glycol on newborn mice after heme loading. AB - Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 MUmol/kg body weight (BW). At a dose of 15 MUmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease. PMID- 21785388 TI - The effect of simulation on clinical performance: a junior nursing student clinical comparison study. AB - INTRODUCTION: Patient simulation has been used to augment the traditional clinical model, but its value is unclear. The aim of this study was to evaluate the effects of a theory-driven pediatric simulation curriculum on nursing students' clinical performance. METHODS: The convenience sample included 116 junior nursing students enrolled in a pediatric course. Using a staggered timing model, students attended simulation instead of clinical for 2 weeks (25%) of an 8 week semester. The students spent the same amount of time in simulation as in clinical (12 hours per week). Student clinical performance was assessed using a Likert-style tool at 2-week intervals by the clinical faculty. Scores of students who attended simulation in the first 2 weeks were compared with students who had not yet attended simulation. Data were analyzed using repeated measure analysis with the mixed model, and covariate effects were considered. A Compound Symmetry covariance model was used to control the correlation between weeks within each subject. Statistical significance was determined at the 5% level. RESULTS: Faculty rated students with patient simulation experience higher than those who had not yet attended simulation (mean +/- standard error: 1.74 +/- 0.75, P = 0.02). On item-level analysis, therapeutic skills were positively impacted by simulation (P = 0.02). CONCLUSIONS: Time in simulation enhanced clinical performance, as simulation students achieved higher scores more quickly than those without simulation and maintained high performance levels. These findings suggest patient simulation is a valuable addition to augment the apprenticeship model. PMID- 21785389 TI - Thyroid storm precipitated by stress in an undiagnosed hyperthyroid patient: a simulated medical crisis. PMID- 21785390 TI - Advanced cancer of the extremities treated by cryosurgery. AB - AIM: Cryosurgery with liquid nitrogen (LN) is a safe and effective method to treat skin cancer. With the correct protocol, its efficacy is extended to advanced and inoperable tumors. The aim of this study was to report the author's experience in the treatment of advanced squamous-cell carcinomas of the extremities. METHODS: Forty-eight patients (31 women and 17 men; mean age of 79 years) with 50 advanced squamous-cell carcinomas (SCC) of the extremities were treated with open and thick LN spray--two freeze-thaw cycles--reaching a temperature around -50 oC inside the tumor, but not less than -20 oC in the tumor limits and the underlying structures. Temperature monitoring was made by thermocouples. All cases in this series were treated by the author. RESULTS: The overall cure rate was 88%, with follow-up between 1 and 8 years (mean of 2.64 years). CONCLUSION: This cryosurgical method is an effective treatment for advanced cancers of the extremities, yielding a high cure rate and, in many cases, preventing amputation. PMID- 21785392 TI - Cosmetic procedures in skin of color. AB - An increasing proportion of patients undergoing aesthetic procedures are individuals with skin of color (Fitzpatrick skin types IV-VI). Racial or ethnic differences exist in perceptions of beauty, the prevalence of specific cosmetic concerns, as well as optimal approaches to treatment. Most important, is the need to avoid treatment-associated pigmentary alterations and keloid scarring, of which there is a greater risk in patients with skin of color. Here we review leading esthetic concerns in the darker skinned patient and discuss approaches to treatment. PMID- 21785391 TI - Optimal suturing techniques for superior results: hints from a plastic surgeon and a dermatologic surgeon. AB - Suturing the skin together has been a part of medicine for hundreds of years. Over the centuries, the materials used and techniques utilized have evolved. Presently, there are more than 100 materials that are used for suturing and the needles to place these materials are even more varied. Methods of placing sutures in the skin also vary and run the gamut from simple, running sutures to intricate mattress sutures. Each material and method has its place. This review will present a brief overview of the materials and methods used for suturing. PMID- 21785394 TI - Superficial acral fibromyxoma: a clinicopathological and immunohistochemical analysis of 12 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. AB - AIM: Superficial acral fibromyxoma (SAFM) is a rare soft tissue tumor, recently delineated and documentated as a separate entity. We report 12 cases of SAFM observed in our department from June 2004 to June 2010 and highlight pathological features and differential diagnosis. METHODS: Radiographic examination of the affected digit was performed in all patients. All the tumors were surgically excised under local anesthesia. Follow-up was made every 6-8 months for a maximum period of five years. RESULTS: The patients consisted of 8 men and 4 women, age range 28-76 years (mean 51), presenting with a solitary mass or nodule located in the toes and fingers. Histologically the lesions were well circumscribed dermal nodules composed of stellate and spindle cells, arranged in a myxoid matrix. Very low grade atypia and a few mitotic figures were found in only one case. Neoplastic cells showed immunoreactivity for CD34 (12 patients). In contrast focally positive or negative staining was shown for the epithelial membrane antigen (EMA) and CD 99. Actin, S100 protein, HMB45 and cytokeratin were negative. In three cases marked hyperkeratosis and acanthosis of the epidermis was present. Pathological analysis confirmed the diagnosis of superficial acral fibromyxoma. No recurrences were observed even in a long term, 2-5 year follow up. CONCLUSION: Complete surgical excision of the tumors and a careful follow-up is suggested, despite the benign course previously reported. PMID- 21785393 TI - Adverse reactions during biological drug therapy in psoriasis:clinical series and a review of the literature. AB - AIM: Psoriasis is a chronic, inflammatory skin disorder, histologically characterized by epidermal hyperplasia, anomalous keratinocyte differentiation, angiogenesis, and by inflammatory cell infiltrate. Psoriasis has a significant impact on quality of life and is often associated with serious psychological effects. The use of biological agents is expanding worldwide as alternative treatment for chronic inflammatory diseases including psoriasis. The European Medicines Agency (EMEA) approved the use of Efalizumab, Etanercept, Infliximab and Adalimumab in the treatment of psoriasis on the basis of the positive findings obtained from well-designed clinical trials. The ongoing monitoring of tolerability and possible side-effects of these drugs has, however, recently lead to the EMEA suspending Efalizumab on the grounds that the possible risks of its use outweighed the benefits. METHODS: Fifty-four patients treated with the two classes of biological drug (Efalizumab and anti-TNF-alpha) were studied. The choice of biological drug therapy was conditioned by the extent and seriousness of the disease and by the presence of concomitant pathologies. RESULTS: Nineteen patients presented adverse reactions, of which 9 necessitated interruption in treatment (6 Efalizumab and 3 anti-TNF-alpha). CONCLUSION: This work reports the adverse reactions to these biological therapies found in our patients along with a review of the literature concerning adverse reactions in psoriasis treatment. From our experience and basing ourselves on the literature reporting studies conducted in large centres, we feel that it is indispensable to continue monitoring any reactions during biological drug treatment. In this way, there is more likelihood of preventing, where possible, or better managing any reactions linked to the use of these drugs. PMID- 21785395 TI - Assessing the reliability of the Modified Wash Test. AB - AIM: The aim of this paper was to find a simple method to evaluate reliably diagnosis and severity of androgenetic alopecia (AGA) and telogen effluvium (TE). METHODS: We adopted the modified wash test (MWT), which accomplishes such task through assessing the number of shed hair and the vellus percentage. To evaluate its reliability, 25 subjects were submitted to MWT once a week for 4 consecutive weeks according to the procedure published elsewhere. The data were analysed by the intraclass correlation coefficient and ROC curves. RESULTS: The subjects were diagnosed as having TE (7 subjects), AGA (6 subjects), AGA+TE (4 subjects) and normal subjects (8 patients). An almost perfect reliability was found in AGA group for both total hair and vellus hair percentage, and in normal and TE groups for vellus hair count. Good reliability were found in all other cases, but in the total hair count in normal subjects in which it was only moderate. The areas under the ROC curve showed a sensitivity and specificity ranging from 50% to 100%. CONCLUSION: MWT can be employed with confidence in the office. It is simple, non-invasive and non-expensive and helps to distinguish TE from AGA, to identify cases of association TE+AGA, to assess the severity of the three conditions and, in TE+AGA association, to select which one is the most important and should be treated first. Possible biases and drawbacks are discussed. PMID- 21785396 TI - The separate daily application of tacalcitol 4 ug/g ointment and budesonide 0.25 mg/g cream is more effective than the single daily application of a two compound ointment containing calcipotriol 50 ug/g and betamethasone dipropionate 0.5 mg/g. AB - AIM: This pilot randomized intra-patient side to side trial was designed to assess the antipsoriatic efficacy, safety and tolerability of once daily versus the separate application of a vitamin D3 analogue and a powerful corticosteroid. METHODS: Twenty patients with plaque type psoriasis were enrolled. Two similar symmetrical lesions were randomized to be treated with an application of an ointment containing calcipotriol 50 ug/g plus betamethasone dipropionate 0.5 mg/g once daily or the application of budesonide 0.25 mg/g cream in the morning and tacalcitol 4 ug/g ointment in the evening. RESULTS: Eighteen patients completed the study. Both treatments proved to be effective but budesonide cream and tacalcitol ointment gave a faster improvement of lesions and itching relief at t1 and were better tolerated. CONCLUSION: The separate daily regimen may represent a suitable treatment option for patients who need a faster improvement and a better moisturizing activity. Further studies which compare the efficacy and safety of these regimens need to be developed. PMID- 21785397 TI - Further discussion on dermatological radiotherapy. AB - Dermatological radiotherapy has used for decades in the treatment of skin diseases with very good results. The Florentine school has always played a fundamental role in the development of this technique, this is where a phototherapy institute, which was going, in the future, to be 1st one in Italy to perform contact radiotherapy regularly, started. As time went by and with the development to new therapeutical modalities, the roentgentherapy met with a decreasing consent. So far, it is still proposed as an effective therapeutically modality in dermatological oncology, if even in selected cases. Basal cell carcinomas can reach big dimensions mainly for recurrence or because the tumor was overlooked for a long time. We bring to attention the case of a 65-year-old man presenting an ulcerated, sharp-bordered, infiltrating and bleeding lesion, occupying most of the left wing of the nose, with a diameter of about 3 cm. The man hadn't received any previous treatment. The lesion was subjected to a biopsy and the istopathological analysis diagnosed an ulcus rodens. The man refused the complete surgical removal, and was thus treated with roentgentherapy, with satisfying results and without any complications in the irradiated area. The patient didn't show any relapse after one year of follow-up. Radiotherapy can still be considered as an effective therapeutical alternative both for lesion requiring a surgical approach and for those developing in patients that couldn't be subjected to any other therapies. PMID- 21785398 TI - An unusual variant of Ramsay Hunt syndrome. PMID- 21785399 TI - A case of eczematous and vesicular dermatitis during anti-TNFalpha therapy for rheumatoid arthritis. PMID- 21785400 TI - Pseudoepitheliomatous hyperplasia arising from hypertrophic lichen planus mimicking squamous cell carcinoma. PMID- 21785401 TI - Superimposed linear psoriasis: low effectiveness of biologic therapy. PMID- 21785402 TI - Importance of laser treatment in vascular malformations in the child. PMID- 21785403 TI - Can optimal target FiO2 be used to determine open lung strategy in premature infants with respiratory distress syndrome? PMID- 21785404 TI - Adherence to recommendations for fall prevention significantly affects the risk of falling after hip fracture: post-hoc analyses of a quasi-randomized controlled trial. AB - BACKGROUND: Few studies focused on fall prevention in hip-fracture survivors. AIM: To investigate the role of adherence to targeted recommendations on both home environment and behaviors in affecting the hazard of falling after a fall related hip fracture. DESIGN: Post-hoc analysis of a quasi-randomized controlled trial. SETTING: Post-acute rehabilitation hospital. POPULATION: Ninety-five of 119 women living in the community with a fall-related fracture of the hip. METHODS: We assessed home hazard of falling and suggested targeted modifications of home environment and behaviors in activities of daily living to prevent falls during inpatient rehabilitation. Falls were recorded at a six-month follow-up during a pre-planned home visit. RESULTS: Nineteen of the 95 women sustained at least one fall during the six-month follow-up. Women with > 2 uncorrected risk factors had a significantly higher risk of falling than those with 0-2 risk factors; the odds ratio adjusted for four confounders was 4.58 (95%CI 1.472 4.250; P=0.009). Adherence to recommendations for fall prevention was negatively associated with fall risk. The adjusted odds ratio for a ten percent increase in adherence rate was 0.749 (95%CI 0.594-0.945; P=0.015). CONCLUSION: Uncorrected environmental and behavioral risk factors and poor adherence to targeted recommendations for fall prevention significantly predicted the risk of falling in community-dwelling women who sustained a fall-related hip fracture. CLINICAL REHABILITATION IMPACT: Fall-risk assessment should be performed during inpatient rehabilitation following a fall-related hip fracture. Improving adherence to targeted recommendations emerges as a major goal to prevent falls in hip-fracture survivors. PMID- 21785405 TI - Unusual consecutive sacral stress fractures in a female distant runner: a case report. AB - Sacral stress fractures are rare overuse injuries predominantly perceived in female long-distance runners. Our case report describes left-sided sacral wing stress fracture followed by contralateral sacral wing fracture after return to running. A 21-year-old female amateur long-distance runner presented with nonspecific low back and left buttock pain. Plain radiograph at presentation was unremarkable. Magnetic resonance imaging (MRI) revealed extensive bone marrow oedema in the cranial part of the left sacral wing and oblique fracture line. After six weeks of moderate training and two months of tailored running program she felt sharp pain in her right buttock during landing on her right leg. MRI confirmed contralateral sacral wing stress fracture. Additional two-month program to correct lumbar hyperlordotic posture with relaxation techniques and stretching of quadratus lumborum, psoas, multifidus and rectus femoris muscles was carried out. Strengthening of the abovementioned muscles was also done together with abdominal wall muscles and gluteals to stabilize the lumbar spine. She regained full level of training six months after the second fracture. Two years after the second stress fracture of the sacral wing she is free of pain, running about 60 to 70 km per week. Despite rapid rehabilitation program after first sacral stress fracture, contralateral stress fracture occurred. After a few months of additional conditional training and strengthening of lumbar, abdominal and pelvic muscles she regains her long-distance running including four marathons without obstacles. From this case we can assume that following proper rehabilitation program with correction of hyperlordotic posture sacral stress fractures can be avoided. PMID- 21785406 TI - [Food intolerance: reliability and characteristics of different diagnostic alternative tests]. AB - The expression "food intolerance" dates back to the ancient Greece and can be generally defined as a sum of unpleasant symptoms of varying etiology that can onset in some patients after the ingestion of various food products. Adverse reactions to food can be divided into toxic and non-toxic. The last ones are classified as immunologically mediated, called "allergies", and non immunologically mediated, commonly defined as "intolerances". The gut wall is directly involved in these adverse reactions to some foods, since it plays a key role in food absorption and in the regulation of the immunitary system. In this paper we discuss food intolerances and allergies, evaluating the available diagnostic methods and their scientific reliability and focusing on IgG analysis based immunoenzymatic test which is the most relevant test for intolerance diagnosis. PMID- 21785407 TI - Lentiviral-mediated knockdown during ex vivo erythropoiesis of human hematopoietic stem cells. AB - Erythropoiesis is a commonly used model system to study cell differentiation. During erythropoiesis, pluripotent adult human hematopoietic stem cells (HSCs) differentiate into oligopotent progenitors, committed precursors and mature red blood cells. This process is regulated for a large part at the level of gene expression, whereby specific transcription factors activate lineage-specific genes while concomitantly repressing genes that are specific to other cell types. Studies on transcription factors regulating erythropoiesis are often performed using human and murine cell lines that represent, to some extent, erythroid cells at given stages of differentiation. However transformed cell lines can only partially mimic erythroid cells and most importantly they do not allow one to comprehensibly study the dynamic changes that occur as cells progress through many stages towards their final erythroid fate. Therefore, a current challenge remains the development of a protocol to obtain relatively homogenous populations of primary HSCs and erythroid cells at various stages of differentiation in quantities that are sufficient to perform genomics and proteomics experiments. Here we describe an ex vivo cell culture protocol to induce erythroid differentiation from human hematopoietic stem/progenitor cells that have been isolated from either cord blood, bone marrow, or adult peripheral blood mobilized with G-CSF (leukapheresis). This culture system, initially developed by the Douay laboratory, uses cytokines and co-culture on mesenchymal cells to mimic the bone marrow microenvironment. Using this ex vivo differentiation protocol, we observe a strong amplification of erythroid progenitors, an induction of differentiation exclusively towards the erythroid lineage and a complete maturation to the stage of enucleated red blood cells. Thus, this system provides an opportunity to study the molecular mechanism of transcriptional regulation as hematopoietic stem cells progress along the erythroid lineage. Studying erythropoiesis at the transcriptional level also requires the ability to over-express or knockdown specific factors in primary erythroid cells. For this purpose, we use a lentivirus-mediated gene delivery system that allows for the efficient infection of both dividing and non-dividing cells. Here we show that we are able to efficiently knockdown the transcription factor TAL1 in primary human erythroid cells. In addition, GFP expression demonstrates an efficiency of lentiviral infection close to 90%. Thus, our protocol provides a highly useful system for characterization of the regulatory network of transcription factors that control erythropoiesis. PMID- 21785408 TI - Autophagy and innate immunity ally against bacterial invasion. PMID- 21785409 TI - Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. AB - TorsinA is a membrane-associated enzyme in the endoplasmic reticulum (ER) lumen that is mutated in DYT1 dystonia. How it remains in the ER has been unclear. We report that a hydrophobic N-terminal domain (NTD) directs static retention of torsinA within the ER by excluding it from ER exit sites, as has been previously reported for short transmembrane domains (TMDs). We show that despite the NTD's physicochemical similarity to TMDs, it does not traverse the membrane, defining torsinA as a lumenal monotopic membrane protein and requiring a new paradigm to explain retention. ER retention and membrane association are perturbed by a subset of nonconservative mutations to the NTD, suggesting that a helical structure with defined orientation in the membrane is required. TorsinA preferentially enriches in ER sheets, as might be expected for a lumenal monotopic membrane protein. We propose that the principle of membrane-based protein sorting extends to monotopic membrane proteins, and identify other proteins including the monotopic lumenal enzyme cyclooxygenase 1 (prostaglandin H synthase 1) that share this mechanism of retention with torsinA. PMID- 21785410 TI - Targeting of Nbp1 to the inner nuclear membrane is essential for spindle pole body duplication. AB - Spindle pole bodies (SPBs), like nuclear pore complexes, are embedded in the nuclear envelope (NE) at sites of fusion of the inner and outer nuclear membranes. A network of interacting proteins is required to insert a cytoplasmic SPB precursor into the NE. A central player of this network is Nbp1 that interacts with the conserved integral membrane protein Ndc1. Here, we establish that Nbp1 is a monotopic membrane protein that is essential for SPB insertion at the inner face of the NE. In vitro and in vivo studies identified an N-terminal amphipathic alpha-helix of Nbp1 as a membrane-binding element, with crucial functions in SPB duplication. The karyopherin Kap123 binds to a nuclear localization sequence next to this amphipathic alpha-helix and prevents unspecific tethering of Nbp1 to membranes. After transport into the nucleus, Nbp1 binds to the inner nuclear membrane. These data define the targeting pathway of a SPB component and suggest that the amphipathic alpha-helix of Nbp1 is important for SPB insertion into the NE from within the nucleus. PMID- 21785411 TI - The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. AB - Interferon-gamma (IFN-gamma) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-gamma and regulate IFN-gamma production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guerin (BCG) downregulated miR-29 expression in IFN-gamma-producing natural killer cells, CD4(+) T cells and CD8(+) T cells. Moreover, miR-29 suppressed IFN-gamma production by directly targeting IFN-gamma mRNA. We developed mice with transgenic expression of a 'sponge' target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-gamma and lower L. monocytogenes burdens in L. monocytogenes-infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (T(H)1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-gamma. PMID- 21785412 TI - A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion. AB - The crystal structure of complexin bound to a prefusion SNAREpin mimetic shows that the accessory helix extends away from the SNAREpin in an 'open' conformation, binding another SNAREpin and inhibiting its assembly, to clamp fusion. In contrast, the accessory helix in the postfusion complex parallels the SNARE complex in a 'closed' conformation. Here we use targeted mutations, FRET spectroscopy and a functional assay that reconstitutes Ca(2+)-triggered exocytosis to show that the conformational switch from open to closed in complexin is needed for synaptotagmin-Ca(2+) to trigger fusion. Triggering fusion requires the zippering of three crucial aspartate residues in the switch region (residues 64-68) of v-SNARE. Conformational switching in complexin is integral to clamp release and is probably triggered when its accessory helix is released from its trans-binding to the neighboring SNAREpin, allowing the v-SNARE to complete zippering and open a fusion pore. PMID- 21785413 TI - Complexin activates and clamps SNAREpins by a common mechanism involving an intermediate energetic state. AB - The core mechanism of intracellular vesicle fusion consists of SNAREpin zippering between vesicular and target membranes. Recent studies indicate that the same SNARE-binding protein, complexin (CPX), can act either as a facilitator or as an inhibitor of membrane fusion, constituting a controversial dilemma. Here we take energetic measurements with the surface force apparatus that reveal that CPX acts sequentially on assembling SNAREpins, first facilitating zippering by nearly doubling the distance at which v- and t-SNAREs can engage and then clamping them into a half-zippered fusion-incompetent state. Specifically, we find that the central helix of CPX allows SNAREs to form this intermediate energetic state at 9 15 nm but not when the bilayers are closer than 9 nm. Stabilizing the activated clamped state at separations of less than 9 nm requires the accessory helix of CPX, which prevents membrane-proximal assembly of SNAREpins. PMID- 21785415 TI - Epitaxial growth of three-dimensionally architectured optoelectronic devices. AB - Optoelectronic devices have long benefited from structuring in multiple dimensions on microscopic length scales. However, preserving crystal epitaxy, a general necessity for good optoelectronic properties, while imparting a complex three-dimensional structure remains a significant challenge. Three-dimensional (3D) photonic crystals are one class of materials where epitaxy of 3D structures would enable new functionalities. Many 3D photonic crystal devices have been proposed, including zero-threshold lasers, low-loss waveguides, high-efficiency light-emitting diodes (LEDs) and solar cells, but have generally not been realized because of material limitations. Exciting concepts in metamaterials, including negative refraction and cloaking, could be made practical using 3D structures that incorporate electrically pumped gain elements to balance the inherent optical loss of such devices. Here we demonstrate the 3D-template directed epitaxy of group III-V materials, which enables formation of 3D structured optoelectronic devices. We illustrate the power of this technique by fabricating an electrically driven 3D photonic crystal LED. PMID- 21785414 TI - Complexin cross-links prefusion SNAREs into a zigzag array. AB - Complexin prevents SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. To understand the mechanism for this inhibition, we determined the structure of complexin bound to a mimetic of a prefusion SNAREpin lacking the portion of the v-SNARE that zippers last to trigger fusion. The 'central helix' of complexin is anchored to one SNARE complex, while its 'accessory helix' extends away at ~45 degrees and bridges to a second complex, occupying the vacant v-SNARE binding site to inhibit fusion. We expected the accessory helix to compete with the v-SNARE for t-SNARE binding but found instead that the interaction occurs intermolecularly. Thus, complexin organizes the SNAREs into a zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion. PMID- 21785416 TI - Bifurcation-based acoustic switching and rectification. AB - Switches and rectification devices are fundamental components used for controlling the flow of energy in numerous applications. Thermal and acoustic rectifiers have been proposed for use in biomedical ultrasound applications, thermal computers, energy- saving and -harvesting materials, and direction dependent insulating materials. In all these systems the transition between transmission states is smooth with increasing signal amplitudes. This limits their effectiveness as switching and logic devices, and reduces their sensitivity to external conditions as sensors. Here we overcome these limitations by demonstrating a new mechanism for tunable rectification that uses bifurcations and chaos. This mechanism has a sharp transition between states, which can lead to phononic switching and sensing. We present an experimental demonstration of this mechanism, applied in a mechanical energy rectifier operating at variable sonic frequencies. The rectifier is a granular crystal, composed of a statically compressed one-dimensional array of particles in contact, containing a light mass defect near a boundary. As a result of the defect, vibrations at selected frequencies cause bifurcations and a subsequent jump to quasiperiodic and chaotic states with broadband frequency content. We use this combination of frequency filtering and asymmetrically excited bifurcations to obtain rectification ratios greater than 10(4). We envisage this mechanism to enable the design of advanced photonic, thermal and acoustic materials and devices. PMID- 21785417 TI - Nucleation mechanism for the direct graphite-to-diamond phase transition. AB - Graphite and diamond have comparable free energies, yet forming diamond from graphite in the absence of a catalyst requires pressures that are significantly higher than those at equilibrium coexistence. At lower temperatures, the formation of the metastable hexagonal polymorph of diamond is favoured instead of the more stable cubic diamond. These phenomena cannot be explained by the concerted mechanism suggested in previous theoretical studies. Using an ab initio quality neural-network potential, we carried out a large-scale study of the graphite-to-diamond transition assuming that it occurs through nucleation. The nucleation mechanism accounts for the observed phenomenology and reveals its microscopic origins. We demonstrate that the large lattice distortions that accompany the formation of diamond nuclei inhibit the phase transition at low pressure, and direct it towards the hexagonal diamond phase at higher pressure. The proposed nucleation mechanism should improve our understanding of structural transformations in a wide range of carbon-based materials. PMID- 21785418 TI - Seebeck effect in magnetic tunnel junctions. AB - Creating temperature gradients in magnetic nanostructures has resulted in a new research direction, that is, the combination of magneto- and thermoelectric effects. Here, we demonstrate the observation of one important effect of this class: the magneto-Seebeck effect. It is observed when a magnetic configuration changes the charge-based Seebeck coefficient. In particular, the Seebeck coefficient changes during the transition from a parallel to an antiparallel magnetic configuration in a tunnel junction. In this respect, it is the analogue to the tunnelling magnetoresistance. The Seebeck coefficients in parallel and antiparallel configurations are of the order of the voltages known from the charge-Seebeck effect. The size and sign of the effect can be controlled by the composition of the electrodes' atomic layers adjacent to the barrier and the temperature. The geometric centre of the electronic density of states relative to the Fermi level determines the size of the Seebeck effect. Experimentally, we realized 8.8% magneto-Seebeck effect, which results from a voltage change of about -8.7 MUV K-1 from the antiparallel to the parallel direction close to the predicted value of -12.1 MUV K-1. In contrast to the spin-Seebeck effect, it can be measured as a voltage change directly without conversion of a spin current. PMID- 21785419 TI - Sediments of soft spheres arranged by effective density. AB - Colloidal sedimentation has been studied for decades from both thermodynamic and dynamic perspectives. In the present work, binary mixtures of colloidal spheres are observed to separate spontaneously into two distinct layers on sedimentation. Both layers have a high volume fraction and contain distinct compositions of particles. Although predicting these compositions using settling dynamics is challenging, here we show that the compositions are readily predicted thermodynamically by minimizing the gravitational energy of the system. As the random packing fraction of a mixture of spheres exceeds that of monodisperse spheres of either type, the mixture produces a denser suspension that forms the bottom phase. Experimentally, the use of charged particles and low-ionic-strength solutions provides interparticle repulsions that keep the packed particles mobile, avoiding a glassy state that would prevent particles from reaching their equilibrium configuration. We extend this work beyond binary systems, showing similar separated layers for a five-component mixture of particles. PMID- 21785420 TI - N-WASP regulates the epithelial junctional actin cytoskeleton through a non canonical post-nucleation pathway. AB - N-WASP is a major cytoskeletal regulator that stimulates Arp2/3-mediated actin nucleation. Here, we identify a nucleation-independent pathway by which N-WASP regulates the cytoskeleton and junctional integrity at the epithelial zonula adherens. N-WASP is a junctional protein whose depletion decreased junctional F actin content and organization. However, N-WASP (also known as WASL) RNAi did not affect junctional actin nucleation, dominantly mediated by Arp2/3. Furthermore, the junctional effect of N-WASP RNAi was rescued by an N-WASP mutant that cannot directly activate Arp2/3. Instead, N-WASP stabilized newly formed actin filaments and facilitated their incorporation into apical rings at the zonula adherens. A major physiological effect of N-WASP at the zonula adherens thus occurs through a non-canonical pathway that is distinct from its capacity to activate Arp2/3. Indeed, the junctional impact of N-WASP was mediated by the WIP-family protein, WIRE, which binds to the N-WASP WH1 domain. We conclude that N-WASP-WIRE serves as an integrator that couples actin nucleation with the subsequent steps of filament stabilization and organization necessary for zonula adherens integrity. PMID- 21785421 TI - Lpd depletion reveals that SRF specifies radial versus tangential migration of pyramidal neurons. AB - During corticogenesis, pyramidal neurons (~80% of cortical neurons) arise from the ventricular zone, pass through a multipolar stage to become bipolar and attach to radial glia, and then migrate to their proper position within the cortex. As pyramidal neurons migrate radially, they remain attached to their glial substrate as they pass through the subventricular and intermediate zones, regions rich in tangentially migrating interneurons and axon fibre tracts. We examined the role of lamellipodin (Lpd), a homologue of a key regulator of neuronal migration and polarization in Caenorhabditis elegans, in corticogenesis. Lpd depletion caused bipolar pyramidal neurons to adopt a tangential, rather than radial-glial, migration mode without affecting cell fate. Mechanistically, Lpd depletion reduced the activity of SRF, a transcription factor regulated by changes in the ratio of polymerized to unpolymerized actin. Therefore, Lpd depletion exposes a role for SRF in directing pyramidal neurons to select a radial migration pathway along glia rather than a tangential migration mode. PMID- 21785422 TI - esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. AB - Signalling by the cytokine LIF and its downstream transcription factor, STAT3, prevents differentiation of pluripotent embryonic stem cells (ESCs). This contrasts with most cell types where STAT3 signalling induces differentiation. We find that STAT3 binding across the pluripotent genome is dependent on Brg1, the ATPase subunit of a specialized chromatin remodelling complex (esBAF) found in ESCs. Brg1 is required to establish chromatin accessibility at STAT3 binding targets, preparing these sites to respond to LIF signalling. Brg1 deletion leads to rapid polycomb (PcG) binding and H3K27me3-mediated silencing of many Brg1 activated targets genome wide, including the target genes of the LIF signalling pathway. Hence, one crucial role of Brg1 in ESCs involves its ability to potentiate LIF signalling by opposing PcG. Contrary to expectations, Brg1 also facilitates PcG function at classical PcG targets, including all four Hox loci, reinforcing their repression in ESCs. Therefore, esBAF does not simply antagonize PcG. Rather, the two chromatin regulators act both antagonistically and synergistically with the common goal of supporting pluripotency. PMID- 21785423 TI - Cytoskeletal polarity mediates localized induction of the heart progenitor lineage. AB - Cells must make appropriate fate decisions within a complex and dynamic environment. In vitro studies indicate that the cytoskeleton acts as an integrative platform for this environmental input. External signals regulate cytoskeletal dynamics and the cytoskeleton reciprocally modulates signal transduction. However, in vivo studies linking cytoskeleton/signalling interactions to embryonic cell fate specification remain limited. Here we show that the cytoskeleton modulates heart progenitor cell fate. Our studies focus on differential induction of heart fate in the basal chordate Ciona intestinalis. We have found that differential induction does not simply reflect differential exposure to the inductive signal. Instead, pre-cardiac cells employ polarized, invasive protrusions to localize their response to an ungraded signal. Through targeted manipulation of the cytoskeletal regulator CDC42, we are able to depolarize protrusive activity and generate uniform heart progenitor fate specification. Furthermore, we are able to restore differential induction by repolarizing protrusive activity. These findings illustrate how bi-directional interactions between intercellular signalling and the cytoskeleton can influence embryonic development. In particular, these studies highlight the potential for dynamic cytoskeletal changes to refine cell fate specification in response to crude signal gradients. PMID- 21785424 TI - Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly. AB - Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1-50 kb) including insertions, deletions, inversions and their precise breakpoints, and in contrast to other methods, can resolve complex rearrangements. In total, we identified 277,243 SVs ranging in length from 1-23 kb. Validation using computational and experimental methods suggests that we achieve overall <6% false positive rate and <10% false-negative rate in genomic regions that can be assembled, which outperforms other methods. Analysis of the SVs in the genomes of 106 individuals sequenced as part of the 1000 Genomes Project suggests that SVs account for a greater fraction of the diversity between individuals than do single-nucleotide polymorphisms (SNPs). These findings demonstrate that whole genome de novo assembly is a feasible approach to deriving more comprehensive maps of genetic variation. PMID- 21785425 TI - Contributions of counter-charge in a potassium channel voltage-sensor domain. AB - Voltage-sensor domains couple membrane potential to conformational changes in voltage-gated ion channels and phosphatases. Highly coevolved acidic and aromatic side chains assist the transfer of cationic side chains across the transmembrane electric field during voltage sensing. We investigated the functional contribution of negative electrostatic potentials from these residues to channel gating and voltage sensing with unnatural amino acid mutagenesis, electrophysiology, voltage-clamp fluorometry and ab initio calculations. The data show that neutralization of two conserved acidic side chains in transmembrane segments S2 and S3, namely Glu293 and Asp316 in Shaker potassium channels, has little functional effect on conductance-voltage relationships, although Glu293 appears to catalyze S4 movement. Our results suggest that neither Glu293 nor Asp316 engages in electrostatic state-dependent charge-charge interactions with S4, likely because they occupy, and possibly help create, a water-filled vestibule. PMID- 21785427 TI - The second Phytophthora mating hormone defines interspecies biosynthetic crosstalk. AB - The heterothallic species of the agricultural pest Phytophthora use mating hormones alpha1 and alpha2 to regulate their sexual reproduction. Here we describe the absolute stereostructure of the second mating hormone alpha2 as defined by spectroscopic analysis and total synthesis. We have uncovered not only the interspecies universality of alpha hormones but also the pathway by which alpha2 is biosynthesized from phytol by A2-mating type strains and metabolized to alpha1 by A1 strains. PMID- 21785426 TI - CODA-RET reveals functional selectivity as a result of GPCR heteromerization. AB - Here we present a new method that combines protein complementation with resonance energy transfer to study conformational changes in response to activation of a defined G protein-coupled receptor heteromer, and we apply the approach to the putative dopamine D1-D2 receptor heteromer. Remarkably, the potency of the D2 dopamine receptor (D2R) agonist R-(-)-10,11-dihydroxy-N-n-propylnoraporphine (NPA) to change the Galpha(i) conformation via the D2R protomer in the D1-D2 heteromer was enhanced ten-fold relative to its potency in the D2R homomer. In contrast, the potencies of the D2R agonists dopamine and quinpirole were the same in the homomer and heteromer. Thus, we have uncovered a molecular mechanism for functional selectivity in which a drug acts differently at a G protein-coupled receptor (GPCR) protomer depending on the identity of the second protomer participating in the formation of the signaling unit--opening the door to enhancing pharmacological specificity by targeting differences between homomeric and heteromeric signaling. PMID- 21785428 TI - Electrically tuned spin-orbit interaction in an InAs self-assembled quantum dot. AB - Electrical control over electron spin is a prerequisite for spintronics spin based quantum information processing. In particular, control over the interaction between the orbital motion and the spin state of electrons would be valuable, because this interaction influences spin relaxation and dephasing. Electric fields have been used to tune the strength of the spin-orbit interaction in two dimensional electron gases, but not, so far, in quantum dots. Here, we demonstrate that electrical gating can be used to vary the energy of the spin orbit interaction in the range 50-150 ueV while maintaining the electron occupation of a single self-assembled InAs quantum dot. We determine the spin orbit interaction energy by observing the splitting of Kondo effect features at high magnetic fields. PMID- 21785429 TI - Deconfinement leads to changes in the nanoscale plasticity of silicon. AB - Silicon crystals have an important role in the electronics industry, and silicon nanoparticles have applications in areas such as nanoelectromechanical systems, photonics and biotechnology. However, the elastic-plastic transition observed in silicon is not fully understood; in particular, it is not known if the plasticity of silicon is determined by dislocations or by transformations between phases. Here, based on compression experiments and molecular dynamics simulations, we show that the mechanical properties of bulk silicon and silicon nanoparticles are significantly different. We find that bulk silicon exists in a state of relative constraint, with its plasticity dominated by phase transformations, whereas silicon nanoparticles are less constrained and display dislocation-driven plasticity. This transition, which we call deconfinement, can also explain the absence of phase transformations in deformed silicon nanowedges. Furthermore, the phenomenon is in agreement with effects observed in shape-memory alloy nanopillars, and provides insight into the origin of incipient plasticity. PMID- 21785430 TI - Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. AB - Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions. PMID- 21785431 TI - Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. AB - Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs. PMID- 21785432 TI - HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated alpha-tubulin abundance and induced severe axonal transport deficits. An increase of alpha-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of alpha-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies. PMID- 21785433 TI - Foxp3+ follicular regulatory T cells control the germinal center response. AB - Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response. PMID- 21785434 TI - Brain cannabinoid CB2 receptors modulate cocaine's actions in mice. AB - The presence and function of cannabinoid CB(2) receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB(1) receptor knockout (CB(1)(-/-), also known as Cnr1(-/-)) mice, but not in CB(2)(-/-) (Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB(1)(-/-) mice, but not in CB(2)(-/-) mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB(2) receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism. PMID- 21785435 TI - Acute destruction of the synaptic ribbon reveals a role for the ribbon in vesicle priming. AB - In vision, balance and hearing, sensory receptor cells translate sensory stimuli into electrical signals whose amplitude is graded with stimulus intensity. The output synapses of these sensory neurons must provide fast signaling to follow rapidly changing stimuli while also transmitting graded information covering a wide range of stimulus intensity and must be able to sustain this signaling for long time periods. To meet these demands, specialized machinery for transmitter release, the synaptic ribbon, has evolved at the synaptic outputs of these neurons. We found that acute disruption of synaptic ribbons by photodamage to the ribbon markedly reduced both sustained and transient components of neurotransmitter release in mouse bipolar cells and salamander cones without affecting the ultrastructure of the ribbon or its ability to localize synaptic vesicles to the active zone. Our results indicate that ribbons mediate both slow and fast signaling at sensory synapses and support an additional role for the synaptic ribbon in priming vesicles for exocytosis at active zones. PMID- 21785436 TI - Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. AB - The thalamic reticular nucleus (TRN) is hypothesized to regulate neocortical rhythms and behavioral states. Using optogenetics and multi-electrode recording in behaving mice, we found that brief selective drive of TRN switched the thalamocortical firing mode from tonic to bursting and generated state-dependent neocortical spindles. These findings provide causal support for the involvement of the TRN in state regulation in vivo and introduce a new model for addressing the role of this structure in behavior. PMID- 21785437 TI - Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching. AB - Mitochondrial uncoupling protein 2 (UCP2) is an integral membrane protein in the mitochondrial anion carrier protein family, the members of which facilitate the transport of small molecules across the mitochondrial inner membrane. When the mitochondrial respiratory complex pumps protons from the mitochondrial matrix to the intermembrane space, it builds up an electrochemical potential. A fraction of this electrochemical potential is dissipated as heat, in a process involving leakage of protons back to the matrix. This leakage, or 'uncoupling' of the proton electrochemical potential, is mediated primarily by uncoupling proteins. However, the mechanism of UCP-mediated proton translocation across the lipid bilayer is unknown. Here we describe a solution-NMR method for structural characterization of UCP2. The method, which overcomes some of the challenges associated with membrane-protein structure determination, combines orientation restraints derived from NMR residual dipolar couplings (RDCs) and semiquantitative distance restraints from paramagnetic relaxation enhancement (PRE) measurements. The local and secondary structures of the protein were determined by piecing together molecular fragments from the Protein Data Bank that best fit experimental RDCs from samples weakly aligned in a DNA nanotube liquid crystal. The RDCs also determine the relative orientation of the secondary structural segments, and the PRE restraints provide their spatial arrangement in the tertiary fold. UCP2 closely resembles the bovine ADP/ATP carrier (the only carrier protein of known structure), but the relative orientations of the helical segments are different, resulting in a wider opening on the matrix side of the inner membrane. Moreover, the nitroxide-labelled GDP binds inside the channel and seems to be closer to transmembrane helices 1-4. We believe that this biophysical approach can be applied to other membrane proteins and, in particular, to other mitochondrial carriers, not only for structure determination but also to characterize various conformational states of these proteins linked to substrate transport. PMID- 21785438 TI - A Polycomb-based switch underlying quantitative epigenetic memory. AB - The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between them. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming. PMID- 21785440 TI - The role of varicocele sclerotherapy in men with severe oligo-astheno teratozoospermia. AB - The aim of this study was to verify the role of antegrade scrotal sclerotherapy for the treatment of varicoceles in infertile men with severe oligo-astheno teratozoospermia (OAT). The 59 patients with severe OAT in this study underwent antegrade scrotal sclerotherapy for the treatment of varicoceles. The outcome was assessed in terms of improvement in semen parameters and spontaneous conception rate. Semen parameters and reproductive hormones were evaluated before antegrade sclerotherapy (AS) and 6 months after AS. After an average follow-up time of 34.8+/-3.2 months, significant improvement was noted in the mean sperm concentration, motility and morphology in 36 patients (61%). Spontaneous pregnancy occurred in nine couples (15%). Six months after treatment, inhibin B levels were significantly higher (P<0.04), whereas follicle-stimulating hormone (FSH) levels were significantly lower (P<0.001) than before treatment. Antegrade internal spermatic vein sclerotherapy can significantly improve seminal parameters and hormonal parameters in men with severe OAT and may even result in spontaneous pregnancy in couples who would otherwise be candidates for intracytoplasmic sperm injection (ICSI). PMID- 21785441 TI - Potential for targeted therapy in prostate cancers with ERG abnormalities. PMID- 21785442 TI - Pathological findings following radical prostatectomy in patients who are candidates for active surveillance: impact of varying PSA levels. AB - Active surveillance is an acceptable treatment option in men with a low-risk prostate cancer. In the present study, we have retrospectively reviewed the outcomes of 509 men who fit the criteria for active surveillance but selected radical prostatectomy. Then, the impact of varying prostate-specific antigen (PSA) levels on the risk of upstaging and upgrading in these patients was assessed. Pathological characteristics of patients who fulfilled the inclusion criteria under three active surveillance criteria--those of the University of California-San Francisco, the National Cancer Institute and the European Association of Urology--were examined. The proportion of men who were deemed candidates for active surveillance but were subsequently upstaged or upgraded was determined. Of 509 patients, 186 (36.5%), 132 (25.9%) and 88 (17.3%) men fulfilled the active surveillance criteria, respectively. Upgrading (Gleason scores 7-10) ranged from 32.8% to 38.6%, while upstaging (>=pT3) ranged from 10.2% to 12.5%, depending on the three active surveillance criteria. After a median follow-up of 24 months, three patients developed a biochemical recurrence. When the impact of varying PSA levels was examined using a test for trend analysis in the context of PSA for each protocol, rates of upstaging were lower in men with PSA <4 ng ml(-1). However, there was no impact of varying PSA levels on upgrading. In conclusion, commonly used active surveillance protocols carry the risks of upgrading and upstaging. More reliable and accurate markers are needed to better stratify the risks of men who are appropriate candidates for active surveillance. PMID- 21785443 TI - The X and Y chromosome in meiosis: how and why they keep silent. PMID- 21785444 TI - Androgen deprivation therapy through bilateral orchiectomy: increased metabolic risks. AB - Prostate cancer is one of the most common malignancies in men. Previous research has determined that androgen deprivation therapy (ADT) may be accompanied by an unfavourable metabolic profile. In this prospective study, 133 men were recruited, including 46 prostate cancer patients who had undergone bilateral orchiectomy and been on flutamide (the ADT group), 37 men with prostate cancer who had undergone radical prostatectomy (the non-ADT group) and 50 normal control subjects (the control group). All subjects were followed for at least 12 months. From baseline to 3 months, men in the ADT group had increased levels of fasting serum insulin and low-density lipoprotein compared to the other two groups (P<0.05). No obvious changes were found in the other parameters (P>0.05). After 12 months, men in the ADT group had increased levels of waist circumference, fasting serum insulin and glucose, total cholesterol, high-density lipoprotein and low-density lipoprotein compared to the other two groups (P<0.05). Additionally, the morbidity rate of metabolic syndrome in the ADT group was higher (P<0.05) compared to the other two groups. ADT through surgical castration for men with prostate cancer may be associated with unfavourable metabolic changes. The benefits of the therapy should be balanced prudently against these risks. PMID- 21785439 TI - Using the Acropora digitifera genome to understand coral responses to environmental change. AB - Despite the enormous ecological and economic importance of coral reefs, the keystone organisms in their establishment, the scleractinian corals, increasingly face a range of anthropogenic challenges including ocean acidification and seawater temperature rise. To understand better the molecular mechanisms underlying coral biology, here we decoded the approximately 420-megabase genome of Acropora digitifera using next-generation sequencing technology. This genome contains approximately 23,700 gene models. Molecular phylogenetics indicate that the coral and the sea anemone Nematostella vectensis diverged approximately 500 million years ago, considerably earlier than the time over which modern corals are represented in the fossil record (~240 million years ago). Despite the long evolutionary history of the endosymbiosis, no evidence was found for horizontal transfer of genes from symbiont to host. However, unlike several other corals, Acropora seems to lack an enzyme essential for cysteine biosynthesis, implying dependency of this coral on its symbionts for this amino acid. Corals inhabit environments where they are frequently exposed to high levels of solar radiation, and analysis of the Acropora genome data indicates that the coral host can independently carry out de novo synthesis of mycosporine-like amino acids, which are potent ultraviolet-protective compounds. In addition, the coral innate immunity repertoire is notably more complex than that of the sea anemone, indicating that some of these genes may have roles in symbiosis or coloniality. A number of genes with putative roles in calcification were identified, and several of these are restricted to corals. The coral genome provides a platform for understanding the molecular basis of symbiosis and responses to environmental changes. PMID- 21785445 TI - Effect of tamsulosin on ejaculatory function in BPH/LUTS. AB - This study was undertaken to determine the impact on ejaculatory function of tamsulosin (0.2 mg) given once daily (OD) for 12 weeks and to identify risk factors for ejaculatory dysfunction in patients undergoing this treatment. Males with an International Prostatic Symptom Score (IPSS) >=8 were enrolled in this study. All participants completed questionnaires, including the IPSS and the Male Sexual Health Questionnaire (MSHQ), and serum prostate-specific antigen, transrectal ultrasound and uroflowmetry with post-void residual were measured. After initiating 0.2 mg OD tamsulosin, patients were re-evaluated on the fourth and twelfth weeks of medication. The chi-squared test, the independent t-test and one-way ANOVA were used to compare means. Binary logistic regression analysis was used to calculate the odds ratio for all risk factors. A total of 177 men constituted the study cohort. No significant difference was observed between baseline and follow-up for the erectile function, ejaculatory function, satisfaction, sexual activity and desire domains (EFD, EjFD, SDA and ADD) or for erectile or ejaculatory bother mean scores. After 12 weeks, the overall incidence of ejaculatory dysfunction (EjD) was 13.4%. Incidences of the seven different types of EjD (decreased frequency, delay, dryness, decreased strength/force, decreased volume, decreased pleasure and pain at ejaculation) were 2.4%, 3.1%, 3.9%, 3.9%, 6.3%, 7.1% and 3.1%, respectively. Baseline EjFD scores were higher for IPSS responders than for non-responders (26.09 vs. 24.06, P=0.03). An EjFD score reduction was more frequent in IPSS responders. The incidence of EjD was small, but not negligible and was more frequent in patients with less lower urinary tract symptoms, a smaller prostate, higher baseline MSHQ totals and higher EjFD scores. PMID- 21785446 TI - Long-term results of the surgical treatment of Peyronie's disease with plaque incision and grafting. PMID- 21785447 TI - In vitro and in vivo percutaneous absorption of seleno-L-methionine, an antioxidant agent, and other selenium species. AB - AIM: To investigate the in vitro and in vivo percutaneous absorption of seleno-L methionine (Se-L-M), an ultraviolet (UV)-protecting agent, from aqueous solutions. METHODS: Aqueous solutions of Se-L-M were prepared in pH 4, 8, and 10.8 buffers. The pH 8 buffer contained 30% glycerol, propylene glycol (PG) and polyethylene glycol (PEG) 400. The in vitro skin permeation of Se-L-M via porcine skin and nude mouse skin was measured and compared using Franz diffusion cells. The in vivo skin tolerance study was performed, which examined transepidermal water loss (TEWL), skin pH and erythema. RESULTS: In the excised porcine skin, the flux was 0.1, 11.4 and 8.2 MUg.cm(-2).h(-1) for the pH 4, 8, and 10.8 buffers, respectively. A linear correlation between the flux and skin deposition was determined. According to permeation across skin with different treatments (stripping, delipidation, and ethanol treatments), it was determined that the intracellular route comprised the predominant pathway for Se-L-M permeation from pH 8 buffer. Aqueous solutions of seleno-DL-methionine (Se-DL-M), selenium sulfide and selenium-containing quantum dot nanoparticles were also used as donor systems. The DL form showed a lower flux (7.0 vs 11.4 MUg.cm(-2).h(-1)) and skin uptake (23.4 vs 47.3 MUg/g) as compared to the L form, indicating stereoselective permeation of this compound. There was no or only negligible permeation of selenium sulfide and quantum dots into and across the skin. With in vivo topical application for 4 and 8 h, the skin deposition of Se-L-M was about 7 MUg/g, and values were comparable to each other. The topical application of Se-L-M for up to 5 d did not caused apparent skin irritation. However, slight inflammation of the dermis was noted according to the histopathological examination. CONCLUSION: Se-L M was readily absorbed by the skin in both the in vitro and in vivo experiments. The established profiles of Se-L-M skin absorption will be helpful in developing topical products of this compound. PMID- 21785449 TI - Bacterial volatiles give the game away. PMID- 21785448 TI - Efficient induction of a Her2-specific anti-tumor response by dendritic cells pulsed with a Hsp70L1-Her2(341-456) fusion protein. AB - Heat shock proteins (HSPs) have been shown to interact with antigen-presenting cells (APCs), especially dendritic cells (DCs). HSPs act as potent adjuvants, inducing a Th1 response, as well as antigen-specific CD8(+) cytotoxic T lymphocytes (CTL) via cross-presentation. Our previous work has demonstrated that Hsp70-like protein 1 (Hsp70L1), a new member of the Hsp70 subfamily, can act as a powerful Th1 adjuvant in a DC-based vaccine. Here we report the efficient induction of tumor antigen-specific T cell immune response by DCs pulsed with recombinant fusion protein of Hsp70L1 and Her2(341-456), the latter of which is a fragment of Her2/neu (Her2) containing E75 (a HLA-A2 restricted CTL epitope). The fusion protein Hsp70L1-Her2(341-456) promotes the maturation of DCs and activates them to produce cytokines, such as IL-12 and TNF-alpha, and chemokines, such as MIP-1alpha, MIP-1beta and RANTES. Taken together, these results indicate that the adjuvant activity of Hsp70L1 is maintained in the fusion protein. Her2-specific HLA-A2.1-restricted CD8(+) CTLs can be generated efficiently either from the Peripheral blood lymphocytes (PBL) of healthy donors or from the splenocytes of immunized HLA-A2.1/K(b) transgenic mice by in vitro stimulation or immunization with DCs pulsed with the Hsp70L1-Her2(341-456) fusion protein. This results in more potent target cell killing in an antigen-specific and HLA-A2.1-restricted manner. Adoptive transfer of splenocytes from transgenic mice immunized with Hsp70L1-Her2(341-456)-pulsed DCs can markedly inhibit tumor growth and prolong the survival of nude mice with Her2(+)/HLA-A2.1(+) human carcinomas. These results suggest that Hsp70L1-Her2(341-456)-pulsed DCs could be a new therapeutic vaccine for patients with Her2(+) cancer. PMID- 21785452 TI - B cells: the B boyz of sepsis. PMID- 21785453 TI - Innate immunity: SHP regulates TLR signalling. PMID- 21785454 TI - T cells: a metabolic sHIFt to turn 17. PMID- 21785457 TI - Heat shock proteins are no DAMPs, rather 'DAMPERs'. PMID- 21785459 TI - DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. AB - DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in cooperation with Ras. Increased DJ-1 expression is associated with tumorigenesis in many cancers, whereas the loss of DJ-1 function is linked to an autosomal recessive form of Parkinson's disease (PD). It has been reported that DJ-1 protects cells from TRAIL (tumor necrosis factor-related apoptosis inducing ligand)-induced apoptosis. However, the mechanism by which DJ-1 is involved is still largely unknown. Here we show that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated pro caspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, binds to FADD to inhibit the formation of the death-inducing signaling complex (DISC). DJ-1 competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby repressing the recruitment and activation of pro-caspase-8 to the active form of caspase-8. Thus, our study suggests that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation. PMID- 21785456 TI - Neutrophils in the activation and regulation of innate and adaptive immunity. AB - Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer. PMID- 21785460 TI - A refined molecular taxonomy of breast cancer. AB - The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ER+ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ER+/PR+/AR+, one was ER-/PR-/AR+ and one was triple negative (AR-/ER-/PR-). ERBB2-amplified tumors were split between the ER-/PR-/AR+ subgroup and the highly proliferative ER+ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapse-free survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent well-defined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer. PMID- 21785461 TI - HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation. AB - Malignant glioma is the most common brain tumor with 16,000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc and nuclear factor-kappaB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis. PMID- 21785462 TI - Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway. AB - The Hippo signaling network is proving to be an essential regulator within the cell, participating in multiple cellular phenotypes including cell proliferation, apoptosis, cell migration and organ size control. Much of this pathway is conserved from flies to mammals; however, how the upstream components, namely Expanded, affect downstream processes in mammalian systems has remained elusive. Only recently has human Expanded (hEx), also known as FRMD6 or Willin, been identified. However, its functional significance with respect to its putative tumor suppressor function and activation of the Hippo pathway has not been studied. In this study, we show for the first time that hEx possesses several tumor suppressor properties. First, hEx dramatically inhibits cell proliferation in two human cancer cell lines, MDA-MB-231 and MDA-MB-436 cells, and sensitizes these cells to the chemotherapeutic drug Taxol. Furthermore, downregulation of hEx in the immortalized MCF10A breast cell line leads to enhanced proliferation and resistance to Taxol treatment. As evidence for its tumor suppressor function, overexpression of hEx inhibits colony formation, soft agar colony growth in vitro and in vivo tumor growth in nude mice. Although Drosophila expanded (ex) can activate the Hippo pathway, surprisingly no significant alterations were discovered in the phosphorylation status of any of the Hippo pathway components, including downstream tumor suppressor LATS1, upon overexpression of hEx. In addition, knockdown of both LATS1 and LATS2 in hEx-overexpressing cells was unable to rescue the hEx phenotype, suggesting that hEx functions independently of the Hippo pathway in this cell line. Alternatively, we propose a mechanism through which hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. This is the first study to functionally characterize hEx and show that hEx acts in a distinct manner compared with Drosophila expanded. PMID- 21785463 TI - JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. AB - JAK2(V617F) is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured CD34(+) cells from MPN patients, we demonstrate that expression of JAK2(V617F) affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2(V617F) cells. Altogether, these data indicate that the JAK2(V617F) mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2(V617F) MPN and might have a role in disease progression. PMID- 21785464 TI - Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death. AB - Increased activity of SRC family kinases promotes tumor invasion and metastasis, and overexpression of the mitotic regulator Aurora kinase A (AURKA) drives tumor aneuploidy and chromosomal instability. These functions nominate SRC and AURKA as valuable therapeutic targets for cancer, and inhibitors for SRC and Aurora kinases are now being used in the clinic. In this study, we demonstrate potent synergy between multiple inhibitors of Aurora and SRC kinases in ovarian and colorectal cancer cell lines, but not in normal ovarian epithelial cell lines. Combination of Aurora and SRC inhibitors selectively killed cells that have undergone a preceding aberrant mitosis, and was associated with a postmitotic reattachment defect, and selective removal of aneuploid cell populations. Combined inhibition of Aurora kinase and SRC potentiated dasatinib-dependent loss of activated (Y(416)-phosphorylated) SRC. SRC and AURKA share a common interaction partner, NEDD9, which serves as a scaffolding protein with activities in cell attachment and mitotic control, suggesting SRC and AURKA might interact directly. In vitro, we observed physical interaction and mutual cross phosphorylation between SRC and AURKA that enhanced SRC kinase activity. Together, these findings suggest that combination of SRC and Aurora-targeting inhibitors in the clinic may be a productive strategy. PMID- 21785465 TI - Hipk2 cooperates with p53 to suppress gamma-ray radiation-induced mouse thymic lymphoma. AB - A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/- and p53-/- mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30% of radiation-induced tumors from both p53+/- and p53-/- mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by gamma-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene. PMID- 21785466 TI - New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization. AB - Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo[3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclin dependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a well-established adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy. PMID- 21785468 TI - Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics. AB - Treatment or prophylaxis of invasive fungal infection in recipients of haemopoietic SCT (HSCT) may require management of coexistent malnutrition, organ dysfunction and GVHD, all of which create added potential for inter- and intra patient variations in drug metabolism as well as drug interactions. Polymorphism is common in genes encoding pathway components of antifungal drug metabolism such as enzymes (cytochrome P450 (CYP450), glutathione S-transferase, N acetyltransferase and uridine 5'-diphospho-glucuronosyltransferase), uptake transporters (organic cationic transporter, novel organic cationic transporter, organic anion transporter protein (OATP), organic anion transport (OAT), and peptide tranporter) and efflux transporters (breast cancer resistance protein, bile sale export pump (BSEP), multidrug and toxin extrusion type transporter, multidrug resistance protein (MRP), OAT, permeability glycoprotein (P-gp), and urate transporter). Specific polymorphisms may be generalised throughout a population or largely confined to ethnic groups. CYP450 enzymes, especially 2C9 and 2C19, exhibit extensive polymorphism and are central to the metabolism of azole antifungals and their interactions with other drugs including calcineurin inhibitors, cytotoxics and benzodiazepines. Polymorphism may ultimately affect drug efficacy: CYP2C19 variation leads to a fivefold variation in voriconazole levels between individuals. Anticipated routine provision of pharmacogenomic data in the future for new drugs, together with accumulating knowledge about established agents, challenge physicians to assimilate and apply that information to drug prescribing. Increasing availability of pharmacogenomic data may strengthen demand for rapid turn-around therapeutic drug monitoring of antifungal agents in HSCT recipients. PMID- 21785469 TI - Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis. AB - Systemic amyloid light-chain (AL) amyloidosis is a protein conformation disorder caused by clonal plasma cell dyscrasias. Symptoms result from fibrillar extracellular deposits in various tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis is poor and depends mostly on the severity of cardiac involvement. The treatment is derived from the therapy of multiple myeloma with the main goal being to reach a complete hematological remission (CR). High-dose melphalan (HDM) and autologous hematopoietic cell transplantation can induce CR rates in about 40%. The main concern was the high transplant-related mortality of up to 40% due to organ dysfunction, which could be reduced to <12% by careful patient selection in experienced centers. However, >50% of patients in CR survive longer than 10 years, suggesting that HDM has the potential to change the natural course of the disease. As there is evidence that 'graft-versus-plasma-cell-dyscrasia' effects are active in AL amyloidosis, allogeneic hematopoietic cell transplantation might be an option for younger patients with preserved organ functions who have relapsed after HDM. PMID- 21785467 TI - MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. AB - MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL. PMID- 21785470 TI - Disseminated Geosmithia argillacea infection in a patient with gastrointestinal GvHD. PMID- 21785471 TI - T-cell-depleted hematopoietic SCT from unrelated donors for the treatment of congenital amegakaryocytic thrombocytopenia. PMID- 21785472 TI - Lack of efficacy of rituximab in refractory sclerodermatous chronic GVHD. PMID- 21785473 TI - Oral cryotherapy can significantly reduce oral mucositis but not acute GVHD incidence in Flu/Mel conditioning allo-SCT. PMID- 21785475 TI - A prospective evaluation of bleeding risk of interventional techniques in chronic pain. AB - BACKGROUND: The role of antithrombotic therapy is well known for primary and secondary prevention of cardiovascular disease to decrease the incidence of acute cerebral and cardiovascular events. Data shows that the risk of coronary thrombosis after antiplatelet drug withdrawal is much higher than that of surgical bleeding if the antiplatelet drug therapy were continued. However, it has been a common practice to discontinue antiplatelet therapy prior to performing interventional techniques, which may potentially increase the risk of acute cerebral and cardiovascular events. STUDY DESIGN: A prospective study of 3,179 patients undergoing interventional techniques with 12,000 encounters and 18,472 procedures from May 2008 to December 2009. STUDY SETTING: An interventional pain management practice, a specialty referral center, a private practice setting in the United States. OBJECTIVE: To assess the rates of adverse events in patients undergoing interventional techniques on antithrombotic therapy with cessation or without cessation and compare them to a group of patients without antithrombotic therapy. METHODS: Measurable outcomes employed were intravascular entry of the needle, bruising, local bleeding, profuse bleeding, local hematoma, oozing, and postoperative soreness.The prospective evaluation was performed utilizing the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement which was developed with recommendations to improve the quality of reporting observational studies. RESULTS: The results of this study illustrated that in one-quarter (3,087) of patient encounters utilizing interventional pain management techniques, antithrombotic therapy was included. Among these, for approximately 55%, or 1,711 encounters, antithrombotic therapy was continued during the interventional techniques, whereas, for 45%, or 1376 encounters, antithrombotic therapy was discontinued. Overall, these results illustrate that while intravascular penetration and oozing were higher in patients with continued antithrombotic therapy, bruising and local bleeding were higher in patients with discontinued antithrombotic therapy without any difference either statistical or clinical in any of the other aspects, either intraoperative, post procedure in the recovery room, or postoperative period. LIMITATIONS: Limitations include the nonrandomized observational nature of the study and that antiplatelet therapy was limited to aspirin and clopidogrel (Plavix). CONCLUSION: No significant prevalence of adverse events was observed in those who continued with or ceased antithrombotic therapy. PMID- 21785476 TI - Alternative approach for lumbar transforaminal epidural steroid injections. AB - The traditional superoanterior approach for transforaminal epidural steroid injection (TFESI) carries a risk of complication by obstructing arterial flow to the anterior portion of the spinal cord by puncturing the spinal radicular artery that passes through the superoanterior foraminal zone or "safe triangle" zone, which does not describe vascular safety, but rather describes neural safety. Consequently, multiple disasters have been described in recent years with transforaminal epidural injections. They are utilized extensively even though their effectiveness has been debated. Here we describe a dorsal technique through transforaminal epidural injections to place the tip of the needle immediately dorsal to the dorsal root ganglion. Multiple different techniques have been discussed and described in recent years, the majority of them to avoid the radicular artery injection. The primary goal of this paper is to describe another posterior approach to place the tip of spinal needle directly toward the posterior epidural space to avoid puncturing the spinal radicular artery and minimize nerve root penetrations while delivering medication into the epidural space through the foramen. PMID- 21785477 TI - Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. AB - BACKGROUND: Various methods exist for trialing patients for intrathecal drug delivery. Currently no standards exist regarding "best practices" for trialing techniques. OBJECTIVES: The specific aim of the current study is to report results of patients trialed using a low-dose intrathecal morphine technique in the treatment of chronic noncancer pain. SETTING: academic pain medicine practice STUDY DESIGN: Retrospective Review METHOD: Visual analog pain scores (VAS) were obtained at the initial visit, after a 6 week opioid-free interval prior to trial, at intrathecal doses of 25, 50, 100, 200 and 400 MUg of intrathecal morphine during the trial, at one month post-implant, and current VAS. Additionally, intrathecal opioid doses at implant and current state are reported. RESULTS: VAS scores at the initial visit and after 6 weeks of opioid cessation were identical. There was a significant improvement in VAS after the trial, which was sustained over the course of therapy. Additionally, the use of the protocol described in this article suggests that the dose-response relationship following opioid cessation is in the 50-400 MUg/d range for intrathecal morphine and that tolerance may be reversed during the 6 week opioid-free period. LIMITATIONS: Small trialing study CONCLUSIONS: Opioid taper and a 6 week opioid-free period may 1) improve long-term analgesia versus a combination of oral/ intrathecal drug delivery system therapy 2) it may be possible to maintain analgesia at microgram doses and 3) opioid tolerance may be reversible in 6 weeks. Further it appears that a dose response relationship for effective analgesia may be less than 400 MUg of intrathecal morphine. PMID- 21785478 TI - Lumbar retrodiscal versus post-ganglionic transforaminal epidural steroid injection for the treatment of lumbar intervertebral disc herniations. AB - BACKGROUND: Lumbar transforaminal epidural steroid injections (TFESIs) are procedures often utilized in the treatment of radicular pain. TFESIs with a preganglionic approach have been reported to be more effective than TFESIs performed using a classic approach. However, it is unknown whether TFESIs using a retrodiscal approach are as effective as other approaches. OBJECTIVE: To investigate the effect of an epidural steroid injection (ESI) on radicular pain, we conducted a randomized, controlled trial comparing a retrodiscal approach with a classic approach to treat lumbar disc herniation. DESIGN: A case control study. METHODS: Forty patients were randomized to receive lumbar TFESIs with either a retrodiscal approach (n=20) or with a classic approach (n=20). Measurements were taken before as well as 4 and 8 weeks after treatment using a visual analog scale (VAS) score, Patient Satisfaction Index (PSI) and the Roland 5-point pain score. RESULTS: In the retrodiscal group, there was a statistically significant improvement in the VAS score after injection compared to baseline. In the classic group, there was a statistically significant improvement in the VAS score after injection compared to baseline. There was no statistically significant difference in the VAS score, PSI, or the Roland 5-point pain score between those treated with a retrodiscal approache and those treated with a classic approach. LIMITATIONS: Secondary outcomes were not measured and the study did not include a mid- or long-term follow-up period. CONCLUSION: In this study, TFESIs performed using a retrodiscal or classic approach had similar effects on radicular pain. The classic and the retrodiscal transforaminal steroid injection resulted in equivalent pain relief. PMID- 21785479 TI - The dosages of corticosteroid in transforaminal epidural steroid injections for lumbar radicular pain due to a herniated disc. AB - BACKGROUND: Intervertebral disc herniations are the most common cause of lumbosacral radiculopathy, and transforaminal epidural steroid injection (TFESI) is an important tool in treating lumbosacral radiculopathy. But the ideal dose of corticosteroid in the epidural management of lumbosacral radiculopathy has yet to be determined. OBJECTIVE: The aim of this study was to determine the effective dose of steroids in TFESI for pain reduction in patients with lumbosacral radiculopathy. STUDY DESIGN: A randomized, double blind, controlled trial. SETTING: An interventional pain management practice center. METHODS: A total of 160 participants received 2 epidural injections of either 5 mg, 10 mg, 20 mg, or 40 mg of triamcinolone in one week intervals via TFESI. The degree of participant satisfaction and verbal numerical rating scale (VNRS) were assessed at pretreatment, one week, and 2 weeks after the first TFESI. RESULTS: The number of participants experiencing pain relief was significantly less than in other groups in the 5 mg triamcinolone group at one week after the first TFESI. There were no significant differences among the groups at one week after the second TFESI. VNRS decreased in the other groups except the triamcinolone 5 mg group at one week after the first TFESI. VNRS decreased in all groups at one week after the second TFESI. LIMITATIONS: The limitations include lack of placebo control group and lack of long-term follow-up. CONCLUSIONS: We recommend a minimal effective dose of corticosteroid (triamcinolone 10 mg) in TFESI for patients with lumbosacral radiculopathy. PMID- 21785480 TI - Retrospective review of the efficacy and safety of repeated pulsed and continuous radiofrequency lesioning of the dorsal root ganglion/segmental nerve for lumbar radicular pain. AB - BACKGROUND: Chronic lumbosacral radicular pain is a common source of radiating leg pain seen in pain management patients. These patients are frequently managed conservatively with multiple modalities including medications, physical therapy, and epidural steroid injections. Radiofrequency has been used to treat chronic radicular pain for over 30 years; however, there is a paucity of literature about the safety and efficacy of repeat radiofrequency lesioning. OBJECTIVES: To determine the safety, success rate, and duration of pain relief of repeat pulsed radiofrequency (PRF) and continuous radiofrequency (CRF) lesioning of the dorsal root ganglion (DRG)/ sacral segmental nerves (SN) in patients with chronic lumbosacral radicular pain. STUDY DESIGN: Retrospective chart review SETTING: Outpatient multidisciplinary pain center METHODS: Medical record review of patients who were treated with pulsed and continuous radiofrequency lesioning of the lumbar dorsal root ganglia and segmental nerves and who reported initial success were evaluated for recurrence of pain and repeat radiofrequency treatment. Responses to subsequent treatments were compared to initial treatments for success rates, average duration of relief, and adverse neurologic side effects. LIMITATIONS: Retrospective chart review without a control group. RESULTS: Twenty-six women and 24 men were identified who received 50% pain relief or better after PRF and CRF of the lumbar DRG/ sacral SN for lumbosacral radicular pain. The mean age was 62 years (range, 25-86). The mean duration of relief for the 40 patients who had 2 treatments was 4.7 months (range 0-24; Se [standard error] 0.74). Twenty-eight patients had 3 treatments with an average duration of relief of 4.5 months (range 0-19 months; Se 0.74). Twenty patients had 4 treatments with a mean duration of relief of 4.4 months (range 0.5-18; Se 0.95) and 18 patients who had 5 or more treatments received an average duration of relief of 4.3 months (range 0.5-18; Se 1.03). The average duration of relief and success frequency remained constant after each subsequent radiofrequency treatment. Of the 50 total patients, there was only 1 reported complication, specifically, transient thigh numbness which resolved after one week. CONCLUSIONS: Repeated pulsed and continuous radiofrequency ablation of the lumbar dorsal root ganglion/segmental nerve shows promise to be a safe and effective long-term palliative management for lumbosacral radicular pain in some patients. PMID- 21785481 TI - Dural sac cross-sectional area does not correlate with efficacy of percutaneous adhesiolysis in single level lumbar spinal stenosis. AB - BACKGROUND: Spinal stenosis is a narrowing of the spinal canal, which causes mechanical compression of spinal nerve roots. The compression of these nerve roots can cause low back pain and/or leg pain, as well as neurogenic claudication. Lumbar epidural steroid injections have commonly been used in patients with lumbar spinal stenosis (LSS). In cases that are refractory to epidural steroid injections, percutaneous epidural adhesiolysis has been used. OBJECTIVE: The aim of our study is to determine the relationship between the severity of spinal stenosis and the participants' response to adhesiolysis, and to evaluate the mid-term effectiveness of adhesiolysis. STUDY DESIGN: A prospective observational study. METHODS: Sixty-six patients with degenerative LSS were enrolled in this prospective study. All participants underwent lumbar spine magnetic resonance imaging (MRI). The cross-sectional area of the dural sac was measured on the transverse angled sections through the central part of the disc on conventional MR images. All percutaneous adhesiolyses were performed in the operating room. One hour following the procedure, 6 mL of 8% sodium chloride solution was infused during 30 minutes in the recovery room while the patient underwent monitoring. Outcome measures were obtained using the 5-point patient satisfaction scale at 2 weeks and 6 months post-treatment. To evaluate outcome predictors, we divided the participants into 2 groups according to their response to treatment. LIMITATIONS: Secondary outcomes were not measured and the study did not include a long-term follow-up period. RESULTS: Improvement (including reports of slightly improved, much improved, and no pain) was observed in 49 participants (74.2%) at 2 weeks and 45 participants (66.7%) at 6 months after the procedure. The dural sac cross-sectional area (DSCSA) did not differ between participants who reported improvement and those who did not. There was no statistically significant correlation between pain relief and DSCSA, age, or participant sex. CONCLUSION: Percutaneous adhesiolysis was shown to be effective for the treatment of LSS, with mid-term result, without affecting DSCSA. PMID- 21785482 TI - Retrospective review of physician opioid prescribing practices in patients with aberrant behaviors. AB - In the past few decades, opioid use for the treatment of chronic noncancer pain has slowly gained acceptance. With this increase in prescription opioid use, there has also been an increase in prescription opioid abuse. To help detect aberrant drug related behaviors, clinicians have utilized urine drug screens to determine patient noncompliance in outpatient pain clinics. The primary objective is to determine how the use of urine drug testing (UDT) affects health care outcomes. The secondary outcome is to evaluate these findings as it relates to pharmacoeconomics and aberrant behaviors in an outpatient clinical setting. In this study we will determine if UDT influences prescribing practices among physicians. Patients at an academic center's chronic pain outpatient clinic were categorized as having urine screens that were "normal" (expected findings based on their prescribed drugs) or abnormal. Abnormal findings were those with either 1) the absence of a prescribed opioid, 2) the presence of an additional nonprescribed controlled substance, 3) detection of an illicit substance, or 4) an adulterated urine sample. We examined the incidence of such aberrant behaviors as well as concomitant pain diagnoses, psychiatric comorbidities, and the ultimate effect upon the prescribing patterns of the physicians in this clinic. Results of the study showed that the patients exhibiting aberrant drug behaviors have similar pain and psychiatric diagnoses as other chronic pain patients. The most common aberrancy detected was an abnormal urine drug screen, often with the presence of illegal substances. However, in the great majority of aberrancies detected, providers chose to continue prescribing opioids. We speculate on the reasons for this, and discuss the role of the urine drug screen in influencing prescriber behaviors. PMID- 21785483 TI - Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability. AB - BACKGROUND: Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. OBJECTIVES: Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed. METHODS: The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUCinfinity]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). RESULTS: Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (p < 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MS-sNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed. LIMITATIONS: Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers. CONCLUSIONS: When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MS-sNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed. PMID- 21785484 TI - The Independent Payment Advisory Board. AB - The Independent Payment Advisory Board (IPAB) is a vastly powerful component of the president's health care reform law, with authority to issue recommendations to reduce the growth in Medicare spending, providing recommendations to be considered by Congress and implemented by the administration on a fast track basis. Ever since its inception, IPAB has been one of the most controversial issues of the Patient Protection and Affordable Care Act (ACA), even though the powers of IPAB are restricted and multiple sectors of health care have been protected in the law. IPAB works by recommending policies to Congress to help Medicare provide better care at a lower cost, which would include ideas on coordinating care, getting rid of waste in the system, providing incentives for best practices, and prioritizing primary care. Congress then has the power to accept or reject these recommendations. However, Congress faces extreme limitations, either to enact policies that achieve equivalent savings, or let the Secretary of Health and Human Services (HHS) follow IPAB's recommendations. IPAB has strong supporters and opponents, leading to arguments in favor of or against to the extreme of introducing legislation to repeal IPAB. The origins of IPAB are found in the ideology of the National Institute for Health and Clinical Excellence (NICE) and the impetus of exploring health care costs, even though IPAB's authority seems to be limited to Medicare only. The structure and operation of IPAB differs from Medicare and has been called the Medicare Payment Advisory Commission (MedPAC) on steroids. The board membership consists of 15 full-time members appointed by the president and confirmed by the Senate with options for recess appointments. The IPAB statute sets target growth rates for Medicare spending. The applicable percent for maximum savings appears to be 0.5% for year 2015, 1% for 2016, 1.25% for 2017, and 1.5% for 2018 and later. The IPAB Medicare proposal process involves mandatory recommendations and advisory recommendations with multiple reporting requirements. However, although IPAB has been described as having limited authority, some believe that it has unlimited authority due to the lack of judicial review and the requirement of two-thirds of the Congress to override any recommendations by IPAB. PMID- 21785485 TI - Pharmacology of opioids in the treatment of chronic pain syndromes. AB - The perpetual pursuit of pain elimination has been constant throughout human history and pervades human cultures. In some ways it is as old as medicine itself. Cultures throughout history have practiced the art of pain management through remedies such as oral ingestion of herbs or techniques believed to have special properties. In fact, even Hippocrates wrote about the practice of trepanation, the cutting of holes in the body to release pain. Current therapies for management of pain include the pervasive utilization of opioids, which have an extensive history, spanning centuries. There is general agreement about the appropriateness of opioids for the treatment of acute and cancer pain, but the long-term use of these drugs for treatment of chronic non-malignant pain remains controversial. The pros and cons regarding these issues are beyond the scope of this review. Instead, the purpose of this review will be directed towards the pharmacology of commonly prescribed opioids in the treatment of various chronic pain syndromes. Opium, derived from the Greek word for "juice," is extracted from the latex sap of the opium poppy (Papaverum somniferum). The juice of the poppy is the source of some 20 different alkaloids of opium. These alkaloids of opioids can be divided into 2 chemical classes: phenanthrenes (morphine, codeine, and thebaine) and benzylisoquinolines (agents that do not interact with opioid receptors). PMID- 21785486 TI - Opioid abuse in cancer pain: report of two cases and presentation of an algorithm of multidisciplinary care. AB - BACKGROUND: The growing awareness of opioid abuse and addiction in the chronic pain population, along with increasing cancer survivorship, has heightened our awareness of this potential problem in the cancer patient. An increasing number of patients who abuse opioids have been identified in our clinical setting. OBJECTIVE: We present an algorithm of multidisciplinary care for the treatment of cancer patients at risk for abusing opioids. SETTING: Two illustrative patient examples were identified recently from our clinic. RESULTS: These 2 patient examples demonstrate our multidisciplinary approach to treatment. A discussion of safe prescribing principles adapted from the literature is presented. Also, a brief point of added complexity is introduced; specifically, ethical considerations due to the unique nature of cancer pain. LIMITATIONS: Although validation studies exist for the use of screening tools in patients with chronic noncancer pain, there have been no instrument validation studies on patients with cancer pain. The educational treatment model that we refer to regarding facilitating safe use of opioids also has not been studied on patients with cancer pain. Lastly, we express caution in generalizing our guidelines to patients with noncancer pain. Our patient population differs in the multiple co existing stressors and symptom burden associated with cancer. CONCLUSIONS: We have become increasingly aware of the problem of opioid abuse in the cancer pain population. With an approach to using safe prescribing principles adapted from chronic pain literature, and an ethically based multidisciplinary approach, clinicians can continue to treat pain successfully in the opioid-misusing cancer patient. We outline our approach in this article. PMID- 21785487 TI - Painful osseous metastases. AB - Up to 90% of patients with metastatic or advanced stage cancer will experience significant cancer-related pain. Approximately half or more of patients diagnosed with cancer may experience bone pain. It has been estimated that tumor metastases to the skeleton affect roughly 400,000 United States citizens annually. Carcinoma from breast, lung, and prostate cancers account for about 80% of secondary metastatic bone disease. Bone metastases may cause devastating clinical complications associated with dramatic reductions in quality of life, mobility, and independence as well as excruciating refractory pain. Associated complications from osseous metastases also present a substantial economic burden. Currently, there is still a significantly high number of patients suffering with unrelieved pain from osseous metastases. Treatments for painful osseous metastases may not only diminish pain, but may also improve quality of life and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events." Treatment strategies for painful osseous metastases include systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques (radiofrequency ablation (RFA) and cryoablation), bisphosphonates, chemotherapeutic agents, inhibitors of RANK-RANKL interaction (e.g., denosumab), hormonal therapies, interventional techniques (e.g., kyphoplasty), and surgical approaches. Although the mechanisms underlying the development of bone metastases are not completely understood, there appears to be important bi-directional interactions between the tumor and the bone microenvironment. A greater understanding of the pathophysiology of painful osseous metastases may lead to better and more selective targeted analgesic therapy. Additionally, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects. PMID- 21785488 TI - Introduction: hanafusa memorial issue. PMID- 21785489 TI - Introduction: hanafusa memorial issue, part 2. PMID- 21785490 TI - Introduction: The Changing Directions of p53 Research. PMID- 21785491 TI - Scanning electrochemical microscopy studies of micropatterned copper sulfide (Cu(x)S) thin films fabricated by a wet chemistry method. AB - Patterned copper sulfide (Cu(x)S) microstructures on Si (1 1 1) wafers were successfully fabricated by a relatively simple solution growth method using copper sulfate, ethylenediaminetetraacetate and sodium thiosulfate aqueous solutions as precursors. The Cu(x)S particles were selectively deposited on a patterned self-assembled monolayer of 3-aminopropyltriethoxysilane regions created by photolithography. To obtain high quality Cu(x)S films, preparative conditions such as concentration, proportion, pH and temperature of the precursor solutions were optimized. Various techniques such as optical microscopy, atomic force microscopy (AFM), X-ray diffraction, optical absorption and scanning electrochemical microscopy (SECM) were employed to examine the topography and properties of the micro-patterned Cu(x)S films. Optical microscopy and AFM results indicated that the Cu(x)S micro-pattern possessed high selectivity and clear edge resolution. From combined X-ray diffraction analysis and optical band gap calculations we conclude that Cu(9)S(5) (digenite) was the main phase within the resultant Cu(x)S film. Both SECM image and cyclic voltammograms confirmed that the Cu(x)S film had good electrical conductivity. Moreover, from SECM approach curve analysis, the apparent electron-transfer rate constant (k) in the micro-pattern of Cu(x)S dominated surface was estimated as 0.04 cm/s. The SECM current map showed high edge acuity of the micro-patterned Cu(x)S. PMID- 21785492 TI - Copper isotope fractionation during surface adsorption and intracellular incorporation by bacteria. AB - Copper isotopes may prove to be a useful tool for investigating bacteria-metal interactions recorded in natural waters, soils, and rocks. However, experimental data which attempt to constrain Cu isotope fractionation in biologic systems are limited and unclear. In this study, we utilized Cu isotopes (delta(65)Cu) to investigate Cu-bacteria interactions, including surface adsorption and intracellular incorporation. Experiments were conducted with individual representative species of Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) bacteria, as well as with wild-type consortia of microorganisms from several natural environments. Ph-dependent adsorption experiments were conducted with live and dead cells over the pH range 2.5-6. Surface adsorption experiments of Cu onto live bacterial cells resulted in apparent separation factors (Delta(65)Cu(solution-solid) = delta(65)Cu(solution) delta(65)Cu(solid)) ranging from +0.30/00 to +1.40/00 for B. subtilis and +0.20/00 to +2.60/00 for E. coli. However, because heat-killed bacterial cells did not exhibit this behavior, the preference of the lighter Cu isotope by the cells is probably not related to reversible surface adsorption, but instead is a metabolically-driven phenomenon. Adsorption experiments with heat-killed cells yielded apparent separation factors ranging from +0.30/00 to -0.690/00 which likely reflects fractionation from complexation with organic acid surface functional group sites. For intracellular incorporation experiments the lab strains and natural consortia preferentially incorporated the lighter Cu isotope with an apparent Delta(65)Cu(solution-solid) ranging from ~+1.00/00 to +4.40/00. Our results indicate that live bacterial cells preferentially sequester the lighter Cu isotope regardless of the experimental conditions. The fractionation mechanisms involved are likely related to active cellular transport and regulation, including the reduction of Cu(II) to Cu(I). Because similar intracellular Cu machinery is shared by fungi, plants, and higher organisms, the influence of biological processes on the delta(65)Cu of natural waters and soils is probably considerable. PMID- 21785505 TI - Is the prevalence of Down syndrome births in Hawai'i increasing? AB - PURPOSE: In response to a study published by the Centers for Disease Control and Prevention (CDC) in 2009, which indicated that the prevalence of Down syndrome births was increasing in the 10 regions studied, this study examined whether a similar trend was occurring in Hawai'i. METHODS: Data were obtained from the Hawai'i State Department of : Health Birth Defects Program for the years 1997 2005. The information was analyzed by numbers of live births and outcomes of Down syndrome pregnancies, by ratio of terminations to live births, by age of mother (< 35 years or >= 35 years), by maternal ethnicity, and by whether the baby was born with a congenital heart defect (a frequent concomitant condition of babies born with Down Syndrome). These results were compared with previously published studies on the prevalence of Down syndrome births and pregnancies in Hawai'i and were also compared with recently published data of the CDC. FINDINGS: THE STUDY FOUND THAT THE PREVALENCE OF DOWN SYNDROME : births for Hawai'i over the nine year period did not change significantly. Thus, this finding did not match the findings of the CDC study. Additionally, the data showed that the prevalence of congenital heart defects was higher in Hawai'i than in other areas. However, because of changes in the resources available to the Hawai'i Birth Defects Program, fully comparing in all respects data from the 1997-2005 period with studies conducted earlier in Hawai'i was not possible. CONCLUSIONS: THE DATA IDENTIFIED A NUMBER OF AREAS IN NEED OF FURTHER : study. These areas include the following: 1) an examination of the kinds of information and counseling given by primary care providers to women following a prenatal diagnosis of Down syndrome; 2) analysis of the characteristics, values, and choices made by these women to terminate the pregnancy or continue it to term; and 3) determination of why the prevalence of congenital heart defects appears higher among births of babies with Down syndrome in Hawai'i than elsewhere. PMID- 21785506 TI - Artesunate: investigational drug for the treatment of severe falciparum malaria in Hawai'i. AB - INTRODUCTION: There are hundreds of millions of cases of malaria each year worldwide resulting in a million deaths. These deaths are mostly due to Plasmodium falciparum. The only Federal Drug Administration approved treatment for severe malaria is intravenous quinidine gluconate. Intravenous quinidine is increasingly unavailable in the United States. In 2007, the Center for Disease Control and Prevention implemented an investigational new drug protocol to allow the use of intravenous artesunate for cases of severe malaria in the United States. The authors present such a case treated under this protocol at Tripler Army Medical Center, Hawai'i. CASE REPORT: A 49-year-old man presented to Tripler Army Medical Center, Hawai'i in February 2009 with a one-month history of fever, chills, and weight loss. He recently travelled to multiple malaria endemic areas. Physical examination was significant for fever and prostration. Laboratory studies revealed anemia, thrombocytopenia, and a high parasite load of Plasmodium falciparum. A strategic network was activated to obtain and administer intravenous artesunate. His condition rapidly improved as his parasitemia cleared. He was discharged after six days with no adverse medication effects and full recovery upon six-month follow-up. DISCUSSION: Our patient met the criteria for severe Plasmodium falciparum malaria. He was immediately treated with intravenous artesunate and manifested a quick and durable response to therapy. At present, intravenous artesunate is awaiting Federal Drug Administration approval but available via a strategic network controlled by the Centers for Disease Control and Prevention. This case highlights a common delay in diagnosis, importance of optimal prophylaxis, and attention to travel history as they relate to the development of severe malaria. PMID- 21785507 TI - Gastric volvulus, Borchardt's Triad, and Endoscopy: A Rare Twist. AB - The authors describe a case of gastric volvulus, which is a rare cause of gastric outlet obstruction. An 85-year-old man presented with nausea, vomiting, and epigastric pain. Admission abdominal radiograph demonstrated a grossly distended stomach with air-fluid levels. Multiple attempts at nasogastric tube placement failed. Endoscopy revealed a fluid-filled, tortuous stomach with a paraesophageal hernia, and the operator was unable to locate or pass the scope through the pylorus. Traditionally Borchardt's triad is believed to be diagnostic for acute gastric volvulus and consists of unproductive retching, epigastric pain and distention, and the inability to pass a nasogastric tube. The authors propose that the following features on endoscopy are highly suggestive of the most common type of volvulus (organoaxial): tortuous stomach, paraesophageal hernia, and inability to locate or pass the scope through the pylorus. PMID- 21785508 TI - Medical school hotline: harnessing technology for a 21st century medical education. PMID- 21785509 TI - UH cancer center hotline: life after cancer treatment: caring for cancer survivors. PMID- 21785510 TI - The weathervane. PMID- 21785511 TI - The Effects of Incorrect Modeling on Noise and Resolution Properties of ML-EM Images. AB - The effects of incorrect compensation for collimator blur in single-photon emission computed tomography (SPECT) images are studied in terms of the noise and resolution properties of the reconstructed images. Qualitative analysis of images of the Hoffman brain phantom reconstructed using nonlinear maximum-likelihood expectation maximization (ML-EM) show the behavior of longer noise correlations for high-pass filtered images. These qualitative observations are confirmed with more quantitative noise measures. The differences also appear in images reconstructed using linear Landweber iteration. However, the signal-to-noise ratio, in terms of the noise-equivalent quanta, remains largely unchanged. We conclude that the compensation model affects SPECT image properties, though the effect on human task performance remains to be studied. PMID- 21785512 TI - Helix formation in the polymer brush. AB - This work considers the physics of a brush formed by polymers capable of undergoing a helix-coil transition. A self-consistent field approximation for strongly stretched polymer chains is used in combination with a lattice model of the interaction energy in helix-coil mixtures. Crowding-induced chain stretching stabilizes helix formation at moderate tethering densities while high tethering density causes sufficiently strong stretching to unravel segments of the helix, resulting in distinct layers of monomer density and helical content. Compared to a random-coil brush at low-to-moderate tethering density, a helicogenic brush is less resistant to compression in the direction perpendicular to stretching due to easy alignment of helices and fewer unfavorable interactions between helical segments. At higher tethering density, the abovementioned stretch-induced decrease in helical content resists further compression. The proposed model is useful for understanding an emerging class of biomaterials that utilize helix forming polymer brushes to induce shape changes or to stabilize biofunctional helical peptide sequences. PMID- 21785513 TI - Development of Clinical Psychology and Mental Health Resources in Vietnam. AB - In this paper, we discuss development of the Vietnam National University graduate Clinical Psychology Program, which has the goal of training both Vietnamese researchers who will develop and evaluate culturally appropriate mental health treatments, as well as Vietnamese clinicians who will implement and help disseminate these evidence-based treatments. We first review the background situation in Vietnam regarding mental health, and its infrastructure and training needs, and discuss the process through which the decision was made to develop a graduate program in clinical psychology as the best approach to address these needs. We then review the development process for the program and its current status, and our focus on the schools as a site for service provision and mental health task shifting. Finally, we outline future goals and plans for the program, and discuss the various challenges that the program has faced and our attempts to resolve them. PMID- 21785514 TI - Depressed mood and speech in Chilean mothers of 51/2-year-old children. AB - Previous research on maternal speech and depression has focused almost exclusively on how depressed mothers talk to their infants and toddlers in the U.S. and U.K., two English-speaking countries. This study considered how depressed Spanish-speaking mothers from a Latin American country talk about their preschool-age children. Five-minute speech samples were provided by 178 Chilean mothers who were asked to talk about their 51/2-year-old children to a project psychologist. Maternal depressive symptomatology was measured by the Spanish language version of the Center for Epidemiologic Studies Depression Scale (CES D). In multivariate analysis of covariance (MANCOVA), higher maternal depressed mood showed statistically significant associations with the following maternal speech characteristics: more criticisms, less laughter, fewer medium pauses, less positive satisfaction with the child's behavior or characteristics, a rating of a negative overall relationship with the child, and more crying (suggestive trend). A structural equation model confirmed these findings and found an indirect effect between laughter and criticisms: mothers with higher depressed mood who laughed less criticized their children less. The findings illustrate that depressed mood adversely affects how a group of Chilean mothers speak about their children. PMID- 21785515 TI - ON IDENTIFIABILITY OF NONLINEAR ODE MODELS AND APPLICATIONS IN VIRAL DYNAMICS. AB - Ordinary differential equations (ODE) are a powerful tool for modeling dynamic processes with wide applications in a variety of scientific fields. Over the last 2 decades, ODEs have also emerged as a prevailing tool in various biomedical research fields, especially in infectious disease modeling. In practice, it is important and necessary to determine unknown parameters in ODE models based on experimental data. Identifiability analysis is the first step in determing unknown parameters in ODE models and such analysis techniques for nonlinear ODE models are still under development. In this article, we review identifiability analysis methodologies for nonlinear ODE models developed in the past one to two decades, including structural identifiability analysis, practical identifiability analysis and sensitivity-based identifiability analysis. Some advanced topics and ongoing research are also briefly reviewed. Finally, some examples from modeling viral dynamics of HIV, influenza and hepatitis viruses are given to illustrate how to apply these identifiability analysis methods in practice. PMID- 21785516 TI - Synthesis of function-oriented 2-phenyl-2H-chromene derivatives using L pipecolinic acid and substituted guanidine organocatalysts. AB - Organocatalytic domino oxa-Michael/aldol reactions between salicylaldehyde with electron deficient olefins are presented. We screened guanidine, 1,1,3,3 tetramethylguanidine (TMG) and L-pipecolinic acid as organocatalysts for this transformation. 3-Substituted 2-phenyl-2H-chromene derivatives are synthesized with high yields and with poor enantioselectivity (5-17% ee) using L-pipecolinic acid while TMG works well with cinnamaldehyde without using co-catalyst. These 3 substituted-2-phenyl-2H-chromene derivatives are further derivatized to synthesize triazole and biotin-containing chromene derivatives, to facilitate purification of protein targets. PMID- 21785517 TI - Synthesis and spectroscopic characterization of red-shifted spironaphthoxazine based optical switch probes. AB - Spironaphthoxazine (NISO) is an efficient optical switch probe that has applications in high contrast detection of Foerster resonance energy transfer (FRET) using optical lock-in detection (OLID). NISO exists in two distinct states spiro (SP) and merocyanine (MC) that can be independently controlled by using alternate irradiation with near ultraviolet and visible light. Unfortunately, the SP-state of NISO has an absorption centered at 350 nm, which may lead to phototoxic effects when manipulating the probe within a living cell. To overcome this problem we introduce new, red-shifted amino substituted NISO probes compared to NISO that undergo an efficient SP to MC transition in response to irradiation by using 405-nm light, which is less damaging to living cells. This study details the synthesis of amino-substituted NISO and their N-hydroxysuccinimide ester and maleimide derivatives and their use in generating covalent attached protein conjugates. This study also presents a characterization of the spectroscopic and optical switching properties of these red-shifted NISO probe in solution. PMID- 21785518 TI - Influence of Zr on structure, mechanical and thermal properties of Ti-Al-N. AB - Multinary Ti-Al-N thin films are used for various applications where hard, wear and oxidation resistant materials are needed. Here, we study the effect of Zr addition on structure, mechanical and thermal properties of Ti(1-x)Al(x)N based coatings under the guidance of ab initio calculations. The preparation of Ti(1-x z)Al(x)Zr(z)N by magnetron sputtering verifies the suggested cubic (NaCl-type) structure for x below 0.6-0.7 and z <= 0.4. Increasing the Zr content from z = 0 to 0.17, while keeping x at ~ 0.5, results in a hardness increase from ~ 33 to 37 GPa, and a lattice parameter increase from 4.18 to 4.29 A. The latter are in excellent agreement with ab initio data. Alloying with Zr also promotes the formation of cubic domains but retards the formation of stable wurtzite AlN during thermal annealing. This leads to high hardness values of ~ 40 GPa over a broad temperature range of 700-1100 degrees C for Ti(0.40)Al(0.55)Zr(0.05)N. Furthermore, Zr assists the formation of a dense oxide scale. After 20 h exposure in air at 950 degrees C, where Ti(0.48)Al(0.52)N is already completely oxidized, only a ~ 1 MUm thin oxide scale is formed on top of the otherwise still intact ~ 2.5 MUm thin film Ti(0.40)Al(0.55)Zr(0.05)N. PMID- 21785519 TI - Acculturation among Mexican-heritage preadolescents: A latent class analysis. AB - This study applies advanced conceptualization and measurement to an analysis of acculturation among 1,632 Mexican-heritage preadolescents. We assessed whether - and how - multiple measures combine to form a latent acculturation construct that groups individuals into classes; and determine how many and what classes (or types) of acculturation are experienced by this sample of 5(th) graders. Measures included attitudinal, behavioral, and linguistic acculturation, generation status, time in the U.S., ethnic identification, and contact with the culture of origin. The analysis identified five classes of acculturation, differing in size and characterized by specific measures of acculturation: less acculturated, moderately bicultural, strongly bicultural, highly acculturated, and marginalized. Although most youths fell into the first four classes, consonant with their exposure to American society, a small minority of youths fell into the last class. Despite substantial exposure to U.S. culture and recent exposure to Mexican culture, these youth showed little affinity for either culture. PMID- 21785520 TI - Automated image processing and analysis of cartilage MRI: enabling technology for data mining applied to osteoarthritis. AB - Osteoarthritis (OA) is a heterogeneous and multi-factorial disease characterized by the progressive loss of articular cartilage. Magnetic Resonance Imaging has been established as an accurate technique to assess cartilage damage through both cartilage morphology (volume and thickness) and cartilage water mobility (Spin lattice relaxation, T2). The Osteoarthritis Initiative, OAI, is a large scale serial assessment of subjects at different stages of OA including those with pre clinical symptoms. The electronic availability of the comprehensive data collected as part of the initiative provides an unprecedented opportunity to discover new relationships in complex diseases such as OA. However, imaging data, which provides the most accurate non-invasive assessment of OA, is not directly amenable for data mining. Changes in morphometry and relaxivity with OA disease are both complex and subtle, making manual methods extremely difficult. This chapter focuses on the image analysis techniques to automatically localize the differences in morphometry and relaxivity changes in different population sub groups (normal and OA subjects segregated by age, gender, and race). The image analysis infrastructure will enable automatic extraction of cartilage features at the voxel level; the ultimate goal is to integrate this infrastructure to discover relationships between the image findings and other clinical features. PMID- 21785521 TI - The Influence of On-Campus, Academic Year Undergraduate Research on STEM PhD Outcomes: Evidence from the Meyerhoff Scholarship Program. AB - The Meyerhoff Scholarship Program, which celebrated its 20(th) year in 2008, is considered a successful intervention program for increasing the number of underrepresented minorities who earn PhDs or MD/PhDs and pursue research careers in science, technology, engineering, and mathematics (STEM). This article examines the relationship between participation in one specific component of the Meyerhoff Scholarship Program-on-campus, academic year research-and the pursuit of a STEM PhD by thirteen cohorts of program participants. The results indicate that participation in on-campus, academic year research is associated with a substantial increase in the probability of pursuing a STEM PhD. They further suggest that the structure and intensity of the on-campus, academic year research experience matter. PMID- 21785522 TI - Housing Dependence and Intimate Relationships in the Lives of Low-Income Puerto Rican Mothers. AB - Using longitudinal ethnographic data from the Three-City Study, we examined the relationship between sixteen low-income Puerto Rican mothers' housing dependencies and their intimate partner relations. We traced mothers' dependent housing arrangements and entree to marital or cohabiting relationships from their teens through their procurement of independent housing while entering and maintaining intimate partner unions as adults. Findings indicated that various trigger factors led women out of their natal homes and into expedited cohabitation with romantic partners which frequently resulted in unstable unions in which mothers had little power and autonomy. As mothers became eligible for housing subsidies they obtained housing independent from their male partners, potentially increasing the propensity for greater relationship power. Housing independence, however, was not without problems. Spillover effects, such as shadowing partners, threatened housing stability and mothers' independence. The relevance of these findings for future research is discussed. PMID- 21785523 TI - Parents' Marital Distress, Divorce, and Remarriage: Links with Daughters' Early Family Formation Transitions. AB - We used data from the Add Health study to estimate the effects of parents' marital status and relationship distress on daughters' early family formation transitions. Outcomes included traditional transitions (marriage and marital births) and nontraditional transitions (cohabitation and nonmarital births). Relationship distress among continuously married parents was not related to any outcome. Offspring with single parents and remarried parents had an elevated risk of nonmarital births and nonmarital cohabitation. Offspring with remarried parents with a high-distress relationship had an elevated risk of early marriages and marital births. These results, combined with analyses of mediating variables, provide the strongest support for a modeling perspective, although some support also was found for a perspective based on escape from stress. PMID- 21785524 TI - How Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) Work: Cross Disciplinary Perspectives. AB - Evidence from multiple lines of research supports the effectiveness and practical importance of Alcoholics Anonymous and Narcotics Anonymous. Conference presenters discussed the relationship between 12-Step participation and abstinence among various populations, including adolescents, women, and urban drug users. Insight from the arts and humanities placed empirical findings in a holistic context. PMID- 21785525 TI - Tracing long-term vadose zone processes at the Nevada Test Site, USA. AB - The nuclear weapons testing programme of the USA has released radionuclides to the subsurface at the Nevada Test Site. One of these tests has been used to study the hydrological transport of radionuclides for over 25 years in groundwater and the deep unsaturated zone. Ten years after the weapon's test, a 16 year groundwater pumping experiment was initiated to study the mobility of radionuclides from that test in an alluvial aquifer. The continuously pumped groundwater was released into an unlined ditch where some of the water infiltrated into the 200 m deep vadose zone. The pumped groundwater had well characterized tritium activities that were utilized to trace water migration in the shallow and deep vadose zones. Within the near-surface vadose zone, tritium levels in the soil water are modelled by a simple one-dimensional, analytical wetting front model. In the case of the near-surface soils at the Cambric Ditch experimental site, water flow and salt accumulation appear to be dominated by rooted vegetation, a mechanism not included within the wetting front model. Simulation results from a two-dimensional vadose groundwater flow model illustrate the dominance of vertical flow in the vadose zone and the recharge of the aquifer with the pumped groundwater. The long-time series of hydrological data provides opportunities to understand contaminant transport processes better in the vadose zone with an appropriate level of modelling. PMID- 21785526 TI - Transition from exo- to endo- Cu absorption in CuSi(n) clusters: A Genetic Algorithms Density Functional Theory (DFT) Study. AB - The characterization and prediction of the structures of metal silicon clusters is important for nanotechnology research because these clusters can be used as building blocks for nano devices, integrated circuits and solar cells. Several authors have postulated that there is a transition between exo to endo absorption of Cu in Si(n) clusters and showed that for n larger than 9 it is possible to find endohedral clusters. Unfortunately, no global searchers have confirmed this observation, which is based on local optimizations of plausible structures. Here we use parallel Genetic Algorithms (GA), as implemented in our MGAC software, directly coupled with DFT energy calculations to show that the global search of CuSi(n) cluster structures does not find endohedral clusters for n < 8 but finds them for n >= 10. PMID- 21785527 TI - The role of affective experience in work motivation: Test of a conceptual model. AB - The purpose of this paper was to contribute to understanding of the crucial role of emotion in work motivation by testing a conceptual model developed by Seo, Barrett, and Bartunek (2004) that predicted the impacts of core affect on three behavioral outcomes of work motivation, generative-defensive orientation, effort, and persistence. We tested the model using an Internet-based investment simulation combined with an experience sampling procedure. Consistent with the predictions of the model, pleasantness was positively related to all three of the predicted indices. For the most part, these effects occurred indirectly via its relationships with expectancy, valence, and progress judgment components. Also as predicted by the model, activation was directly and positively related to effort. PMID- 21785528 TI - Novel interventional approaches for ALI/ARDS: cell-based gene therapy. AB - Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), continue to be a major cause of morbidity and mortality in critically ill patients. The present therapeutic strategies for ALI/ARDS including supportive care, pharmacological treatments, and ventilator support are still controversial. More scientists are focusing on therapies involving stem cells, which have self-renewing capabilities and differentiate into multiple cell lineages, and, genomics therapy which has the potential to upregulate expression of anti-inflammatory mediators. Recently, the combination of cell and gene therapy which has been demonstrated to provide additive benefit has opened up a new chapter in therapeutic strategy and provides a basis for the development of an innovative approach for the prevention and treatment of ALI/ARDS. PMID- 21785530 TI - Dissociation constant measurement using combination tapered fiber-optic biosensor (CTFOB) dip-probes. AB - The document reports a novel method of measuring dissociation constant (k(D)) of antibody-antigen interaction using evanescent wave based combination tapered fiber-optic biosensor (CTFOB) dip-probes. The method was demonstrated by measuring the dissociation constant of human Interleukin-6 (IL-6) and anti-IL-6 interaction. Sandwich immunoassay was used to generate fluorescence signal proportional to antigen-antibody conjugate pairs. A portable CCD based spectrometer setup was used to record spectral profile of the fluorescence signal. The measured value of dissociation constant k(D) for IL-6 and capture anti-IL-6 (clone MQ2-13A5) antibodies at room temperature is588 +/-19 pM . PMID- 21785529 TI - Design of Optimal Treatments for Neuromusculoskeletal Disorders using Patient Specific Multibody Dynamic Models. AB - Disorders of the human neuromusculoskeletal system such as osteoarthritis, stroke, cerebral palsy, and paraplegia significantly affect mobility and result in a decreased quality of life. Surgical and rehabilitation treatment planning for these disorders is based primarily on static anatomic measurements and dynamic functional measurements filtered through clinical experience. While this subjective treatment planning approach works well in many cases, it does not predict accurate functional outcome in many others. This paper presents a vision for how patient-specific multibody dynamic models can serve as the foundation for an objective treatment planning approach that identifies optimal treatments and treatment parameters on an individual patient basis. First, a computational paradigm is presented for constructing patient-specific multibody dynamic models. This paradigm involves a combination of patient-specific skeletal models, muscle tendon models, neural control models, and articular contact models, with the complexity of the complete model being dictated by the requirements of the clinical problem being addressed. Next, three clinical applications are presented to illustrate how such models could be used in the treatment design process. One application involves the design of patient-specific gait modification strategies for knee osteoarthritis rehabilitation, a second involves the selection of optimal patient-specific surgical parameters for a particular knee osteoarthritis surgery, and the third involves the design of patient-specific muscle stimulation patterns for stroke rehabilitation. The paper concludes by discussing important challenges that need to be overcome to turn this vision into reality. PMID- 21785531 TI - Quantitative Estimation of IL-6 in Serum/Plasma Samples Using a Rapid and Cost Effective Fiber-Optic dip-probe. AB - A rapid and cost-effective combination tapered fiber-optic biosensor (CTFOB) dip probe was used for quantitative estimation of interleukin (IL)-6 in serum/plasma samples. Sandwich immunoassay was used as the detection technique. Probes could successfully detect presence of IL-6 in two serum samples, non-neoplastic autoimmune patient (lupus) sample and lymphoma patient sample. The estimated amount of IL-6 in lupus patient sample was 4.8 +/- 0.9 pM and in lymphoma patient sample was 2 +/- 1 pM. It is demonstrated that the developed CTFOB dip-probe is capable of quantitative estimation of proteins in serum/plasma samples with high specificity. PMID- 21785532 TI - In vivo Near-IR Imaging of Occlusal Lesions at 1310-nm. AB - Several in vitro studies have demonstrated the potential for transillumination imaging and optical coherence tomography operating at 1310-nm for imaging caries lesions on tooth proximal and occlusal surfaces. Recently, we demonstrated that lesions on proximal surfaces could be imaged in vivo using NIR transillumination and that PS-OCT can be used in vivo to measure early demineralization on tooth buccal and occlusal surfaces. In this paper we report the first in vivo measurements using OCT and NIR imaging of occlusal lesions that have been scheduled for restoration. Occlusal lesions were chosen that were scheduled for restoration based on conventional diagnosis that consists of visual and tactile examination. Occlusal lesions were visible in the NIR. OCT looks promising for confirming the lateral spread of occlusal caries under the dentinal-enamel junction adjacent to fissures. These studies suggest that both near infrared transillumination imaging at 1310-nm and OCT provide valuable information about the severity of caries lesions. PMID- 21785533 TI - Repair of Artificial Lesions using an Acidic Remineralization Model Monitored with Cross - Polarization Optical Coherence Tomography. AB - It is difficult to completely remineralize carious lesions because diffusion into the interior of the lesion is inhibited as new mineral is deposited in the outermost layers. In previous remineralization studies employing polarization sensitive optical coherence tomography (PS-OCT), two models of remineralization were employed and in both models there was preferential deposition of mineral in the outer most layer. In this study we attempted to remineralize the entire lesion using an acidic remineralization model and demonstrate that this remineralization can be monitored using PS-OCT. Artificial lesions approximately 100-150 MUm in-depth were exposed to an acidic remineralization regimen and the integrated reflectivity from the lesions was measured before and after remineralization. Automated integration routines worked well for assessing the integrated reflectivity for the lesion areas after remineralization. Although there was a higher degree of remineralization, there was still incomplete remineralization of the body of the lesion. PMID- 21785535 TI - Potassium chloride injection still poses threats to patients. PMID- 21785534 TI - Bridging Token Identity Theory and Supervenience Theory Through Psychological Construction. PMID- 21785537 TI - New drugs/drug news. PMID- 21785536 TI - Severe drug shortages impose heavy costs on hospital pharmacies: senate bill might help ... or not. PMID- 21785538 TI - Naltrexone SR/Bupropion SR (Contrave): A New Approach to Weight Loss in Obese Adults. PMID- 21785540 TI - The 340B Discount Drug Program At Ozarks Medical Center: An Economic Stimulus Plan for Missouri. PMID- 21785539 TI - Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non-Small-Cell Lung Cancer. AB - After decades of empirical treatment, molecular subtypes of non-small-cell lung cancer (NSCLC) are now emerging that may enable us to target treatment for patients and increase the likelihood of response. Of the biomarkers under evaluation, gene mutations are gaining recognition as predictive markers for anti epidermal-growth factor receptor (EGFR) therapy. To date, unlike the situation in colorectal cancer, mutation of the v-Ki-Ras-2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has an inconclusive role in NSCLC and should not be used to exclude patients from anti-EGFR therapy. For first-line NSCLC therapy, EGFR mutation status constitutes a prudent test to identify patients who are most likely to benefit from EGFR-tyrosine kinase inhibitor therapy rather than from chemotherapy. In first-line maintenance and relapsed (second-line or third-line) settings, clinical data support the use of erlotinib (Tarceva), as currently indicated, without regard to evaluation of EGFR mutation status. All patient subsets have been shown to benefit with prolonged progression-free and overall survival. PMID- 21785541 TI - Treatment options for obesity and potential therapies on the horizon. PMID- 21785542 TI - Pharmaceutical approval update. PMID- 21785543 TI - American academy of dermatology. PMID- 21785544 TI - 11th European congress on osteoporosis and osteoarthritis and international liver congress 2011: 46th European association for the study of the liver. PMID- 21785545 TI - Immune globulin intravenous (human), 5% liquid gammaplex: for replacement therapy of primary humoral immunodeficiency. PMID- 21785546 TI - Fluorouracil mistake ends with a fatality: applying the lessons learned can save lives. PMID- 21785548 TI - New drugs/drug news. PMID- 21785547 TI - New medicare part d rule affects long-term-care pharmacies. PMID- 21785549 TI - Ulipristal Acetate (ella): A Selective Progesterone Receptor Modulator For Emergency Contraception. PMID- 21785551 TI - The Expanding Class of Non-Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV-1 Infection. PMID- 21785550 TI - Protease Inhibitors for Patients With HIV-1 Infection: A Comparative Overview. PMID- 21785553 TI - Pharmaceutical approval update. PMID- 21785552 TI - Digestive disease week 2011. PMID- 21785554 TI - A survey on managing multiple sclerosis: the managed care perspective. PMID- 21785555 TI - Histological chorioamnionitis is increased at extremes of gestation in stillbirth: a population-based study. AB - OBJECTIVE: To determine the incidence of histological chorioamnionitis and a fetal response in stillbirths in New South Wales (NSW), and to examine any relationship of fetal response to spontaneous onset of labour and to unexplained antepartum death. STUDY DESIGN: Population-based cohort study. Setting. New South Wales Australia. Population. All births between 2002 and 2004 with stillbirths reviewed and classified by the state perinatal mortality review committee. METHODS: Record linkage of the Midwives Data Collection and the Perinatal Death Database including placental histopathology and standardised cause of death classification. RESULTS: 952 stillbirths were included. The incidence of histopathological chorioamnionitis was 22.6%, with a bimodal distribution. A fetal inflammatory response was present in 10.1% and significantly correlated with spontaneous onset of labour. The absence of a fetal inflammatory response was strongly associated with unexplained antepartum death. CONCLUSIONS: The increased incidence of histological chorioamnionitis at extremes of gestation is confirmed in the largest dataset to date using population data. This has important implications for late gestation stillbirth as the percentage of unexplained stillbirths increases near term. PMID- 21785557 TI - Multiple method contraception use among African American adolescents in four US cities. AB - We report on African American adolescents' (N = 850; M age = 15.4) contraceptive practices and type of contraception utilized during their last sexual encounter. Respondents completed measures of demographics, contraceptive use, sexual partner type, and ability to select "safe" sexual partners. 40% endorsed use of dual or multiple contraceptive methods; a total of 35 different contraceptive combinations were reported. Perceived ability to select "safe" partners was associated with not using contraception (OR = 1.25), using less effective contraceptive methods (OR = 1.23), or hormonal birth control (OR = 1.50). Female gender predicted hormonal birth control use (OR = 2.33), use of less effective contraceptive methods (e.g., withdrawal; OR = 2.47), and using no contraception (OR = 2.37). Respondents' age and partner type did not predict contraception use. Adolescents used contraceptive methods with limited ability to prevent both unintended pregnancies and STD/HIV. Adolescents who believed their partners posed low risk were more likely to use contraceptive practices other than condoms or no contraception. Reproductive health practitioners are encouraged to help youth negotiate contraceptive use with partners, regardless of the partner's perceived riskiness. PMID- 21785556 TI - Aspects of prophylactic vaccination against cervical cancer and other human papillomavirus-related cancers in developing countries. AB - Cervical cancer and other human papillomavirus- (HPV-) related cancers are preventable, but preventive measures implemented in developing countries and especially in low-income rural regions have not been effective. Cervical cancer burden derived from sexually transmitted HPV infections is the heaviest in developing countries, and a dramatic increase in the number of cervical cancer cases is predicted, if no intervention is implemented in the near future. HPV vaccines offer an efficient way to prevent related cancers. Recently implemented school-based HPV vaccination demonstration programmes can help tackle the challenges linked with vaccine coverage, and access to vaccination and health services, but prevention strategies need to be modified according to regional characteristics. In urban regions WHO-recommended vaccination strategies might be enough to significantly reduce HPV-related disease burden, but in the rural regions additional vaccination strategies, vaccinating both sexes rather than only females when school attendance is the highest and applying a two-dose regime, need to be considered. From the point of view of both public health and ethics identification of the most effective prevention strategies is pivotal, especially when access to health services is limited. Considering cost effectiveness versus justice further research on optional vaccination strategies is warranted. PMID- 21785559 TI - Disinfection of the Access Orifice in NOTES: Evaluation of the Evidence Base. AB - Introduction. Appropriate prevention of infection is a key area of research in natural orifice translumenal endoscopic surgery (NOTES), as identified by the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). Methods. A review of the literature was conducted evaluating the evidence base for access orifice preparation/treatment in NOTES procedures in the context of infectious complications. Recommendations based on the Oxford Centre for Evidence-Based Medicine guidelines were made. Results. The most robust evidence includes several experimental randomised controlled trials assessing infectious complications in the transgastric approach to NOTES. Transvaginal procedures are long established for accessing the peritoneal cavity following disinfection with antiseptic. Only experimental case series for transcolonic and transvesical approaches are described. Conclusion. Grade C recommendation requiring no preoperative preparation can be made for the transgastric approach. Antiseptic irrigation is recommended for transvaginal (grade C) NOTES access, as is current practice. Further human trials need to be conducted to corroborate the current evidence base for transgastric closure. It is important that future trials are conducted in a methodologically robust fashion, with emphasis on clinical outcomes and standardisation of enterotomy closure and postoperative therapy. PMID- 21785558 TI - Performance evaluation of manual and automated (MagNA pure) nucleic acid isolation in HPV detection and genotyping using Roche Linear Array HPV Test. AB - Nucleic acids of human papillomavirus (HPV) isolated by manual extraction method (AmpliLute) and automated MagNA pure system were compared and evaluated with cytohistological findings in 253 women. The concordance level between AmpliLute and MagNA was very good 93.3% (kappa = 0.864, P < .0001). Overall HPVpositivity detected by AmpliLute was 57.3% (30.4% as single and 27% as multiple infections) in contrast to MagNA 54.5% (32% and 23%, resp.). Discrepant results observed in 25 cases: 11 MagNA(-)/AmpliLute(+), 10 of which had positive histology; 5 MagNA(+)/AmpliLute(-) with negative histology; 8 MagNA(+)/AmpliLute(+): in 7 of which AmpliLute detected extra HPV genotypes and 1 MagNA(invalid)/AmpliLute(+) with positive histology. Both methods performed well when compared against cytological (area under curve (AUC) of AmpliLute 0.712 versus 0.672 of MagNA) and histological diagnoses (AUC of AmpliLute 0.935 versus 0.877 of MagNA), with AmpliLute showing a slightly predominance over MagNA. However, higher sensitivities, specificities, and positive/negative predictive values were obtained by AmpliLute. PMID- 21785560 TI - The use of self-expanding plastic stents in the management of oesophageal leaks and spontaneous oesophageal perforations. AB - Leakage after oesophageal anastomosis or perforation remains a challenge for the surgeon. Traditional management has been operative repair or intensive conservative management. Both treatments are associated with prolonged hospitalisation and high morbidity and mortality rates. Self-expanding metallic stents have played an important role in the palliation of malignant oesophageal strictures and the treatment of tracheoesophageal fistulae. However, self expanding metal stents in benign oesophageal disease are associated with complications such as bleeding, food bolus impaction, stent migration, and difficulty in retrieval. The Polyflex stent is the only commercially available self-expanding plastic stent which has been used in the management of malignant oesophageal strictures with good results. This review will consider the literature concerning the use of self-expanding plastic stents in the treatment of oesophageal anastomotic leakage and spontaneous perforations of the oesophagus. PMID- 21785561 TI - Balanced Propofol Sedation in Patients Undergoing EUS-FNA: A Pilot Study to Assess Feasibility and Safety. AB - Introduction and aims. Balanced propofol sedation (BPS) administered by gastroenterologists has gained popularity in endoscopic procedures. Few studies exist about the safety of this approach during endosonography with fine needle aspiration (EUS-FNA). We assessed the safety of BPS in EUS-FNA. Materials and methods. 112 consecutive patients, referred to our unit to perform EUS-FNA, from February 2008 to December 2009, were sedated with BPS. A second gastroenterologist administered the drugs and monitorized the patient. Results. All the 112 patients (62 males, mean age 58.35) completed the examination. The mean dose of midazolam and propofol was, respectively, of 2.1 mg (range 1-4 mg) and 350 mg (range 180-400). All patients received oxygen with a mean flux of 4 liter/minute (range 2-6 liters/minute). The mean recovery time after procedure was 25 minutes (range 18-45 minutes). No major complications related to sedation were registered during all procedures. The oxygen saturation of all patients never reduced to less than 85%. Blood systolic pressure during and after the procedure never reduced to less than 100 mmHg. Conclusions. In our experience BPS administered by non-anaesthesiologists provided safe and successful sedation in patients undergoing EUS-FNA. PMID- 21785562 TI - Comparison of postoperative complications after endoscopic submucosal dissection: differences of insufflations and anesthesias. AB - Endoscopic submucosal dissection (ESD) has enabled the collective resection and increased the accuracy of pathological diagnosis. However, ESD requires a long operation time, which results in increased doses of analgesics/sedatives, and causes worsening of respiratory and hemodynamic statuses. To reduce postoperative complications, we have applied ESD with CO(2) insufflation and general anesthesia. This study included 50 patients who underwent ESD for early gastric cancer, 25 with air insufflation and intravenous anesthesia (Air/IV group), and the remaining 25 with CO(2) insufflation and general anesthesia (CO(2)/GA group). Postoperative enlarged feeling of the abdomen was observed only in 1 of 25 patients in the CO(2)/GA group (P = 0.0416). Postoperative severe unrest was observed in none of the patients in the CO(2)/GA group and in 4 of 25 (16%) patients in the Air/IV group (P = 0.0371). CO(2) insufflation and general anesthesia are useful in stabilizing intraoperative conditions and reducing postoperative complications. PMID- 21785563 TI - Pulsed Nano-Electrospray Ionization: Characterization of Temporal Response and Implementation with a Flared Inlet Capillary. AB - The temporal response of pulsed nano-electrospray ionization mass spectrometry (nano-ESI-MS) was studied and its influence on ion formation and detection was characterized. Rise and decay times for the mass resolved ion current were determined to be 20 +/- 3 msec and 61 +/- 5 msec, respectively, which led to a maximum pulse rate of 12 Hz. Pulsed nano-ESI operation was demonstrated from a multi-sprayer source controlled by a high voltage pulsing circuit constructed in house. The desired source mode of operation (e.g. pulsing or continuous) can be realized solely by controlling the voltage applied to each sprayer. PMID- 21785564 TI - Synergic Effect of Genistein and Daidzein on UVB-Induced DNA Damage: An Effective Photoprotective Combination. AB - The anti-inflammatory effects and antioxidant activities of individual isoflavones are well established although little is known about the photoprotective effect of their combination. The aim of this study was to investigate the photoprotective effects of different concentrations of genistein and daidzein individually or combined. We measured the expression levels of the cyclo-oxygenase-2 (COX-2) and growth arrest and DNA-damage inducible (Gadd45) genes, which are involved in inflammation and DNA repair, respectively, in BJ-5ta human skin fibroblasts irradiated with 60 mJ/cm(2) UVB. We also determined the cellular response to UVB-induced DNA damage by Comet assay. We report that genistein and daidzein when administered combined, and at a specific concentration and ratio, exerted a synergistic photoprotective effect that was greater than the effect obtained with each isoflavone alone. The results reported herein suggest that low concentrations of genistein and daidzein combined may be good candidate ingredients for protective agents against UV-induced photodamage. PMID- 21785565 TI - Preclinical studies with umbilical cord mesenchymal stromal cells in different animal models for muscular dystrophy. AB - Umbilical cord mesenchymal stromal cells (MSC) have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs), independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1) human umbilical cord tissue (hUCT) MSCs into the caudal vein of SJL mice; (2) hUCT and canine umbilical cord vein (cUCV) MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies. PMID- 21785566 TI - Clinical therapeutics in pregnancy. AB - Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy. PMID- 21785567 TI - Dampening Host Sensing and Avoiding Recognition in Pseudomonas aeruginosa Pneumonia. AB - Pseudomonas aeruginosa is an opportunistic pathogen and causes a wide range of acute and chronic infections. P. aeruginosa infections are kept in check by an effective immune surveillance in the healthy host, while any imbalance or defect in the normal immune response can manifest in disease. Invasive acute infection in the immunocompromised patients is mediated by potent extracellular and cell bound bacterial virulence factors. Life-threatening chronic infection in cystic fibrosis patients is maintained by pathogenic variants that contribute to evade detection and clearance by the immune system. Here, we reviewed the molecular basis of receptor-mediated recognition of P. aeruginosa and their role in initiating inflammation and the colonization. In addition, the consequence of the P. aeruginosa genetic adaptation for the antibacterial defence and the maintaining of chronic infection are discussed. PMID- 21785569 TI - Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents. AB - Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM) cell participation in vascular development have identified VEGF, SDF-1alpha, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway. PMID- 21785568 TI - Ceftaroline: A New Cephalosporin with Activity against Methicillin-Resistant Staphylococcus aureus (MRSA). AB - Microbial resistance has reached alarming levels, threatening to outpace the ability to counter with more potent antimicrobial agents. In particular, methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of skin and soft-tissue infections and PVL-positive strains have been associated with necrotizing pneumonia. Increasing reports of growing resistance to glycopeptides have been noted, further limiting the efficacy of standard antibiotics, such as vancomycin. Ceftaroline is a novel fifth-generation cephalosporin, which exhibits broad-spectrum activity against Gram-positive bacteria, including MRSA and extensively-resistant strains, such as vancomycin intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and vancomycin resistant S. aureus (VRSA). In addition to being an exciting new agent in the anti-MRSA armamentarium, ceftaroline provides efficacy against many respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Ceftaroline (600 mg intravenously every 12 hours) has been shown effective in phase III studies in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. To date, this unique antibiotic exhibits a low propensity for inducing resistance and has a good safety profile, although further post-marketing data and clinical experience are needed. In summary, ceftaroline provides an additional option for the management of complex multidrug resistant infections, including MRSA. PMID- 21785570 TI - Sequential dose-dense Doxorubicin and Ifosfamide in advanced soft-tissue sarcoma patients in an out-patient-basis schedule. AB - Aims. This phase II study explored activity/safety of front-line dose-dense chemotherapy in high-grade STS (soft tissue sarcoma) patients and tested ezrin as prognostic factor. Patients and Methods. The protocol consisted of three cycles of doxorubicin (DOXO) 30 mg/m(2) on days 1-3 every 2 weeks, followed by three cycles of ifosfamide (IFO) 2.5 g/m(2) two hours a day on days 1-5 every 3 weeks, with GCSF support. Ezrin was assessed immunohistochemically. Results. Twenty patients, 13 metastatic and 7 locally advanced, were enrolled. Median age was 39 years (25-60). Median dose intensities were 42 mg/m(2)/week and 3.6 g/m(2)/week for DOXO and IFO, respectively. Grade 3/4 toxicities occurred in 18 patients. Response rate was 15% (3 of 20) by RECIST. Patients younger than 45 years with locally advanced disease and synovial histology presented longer survival. A trend towards longer survival was observed among ezrin-positive patients. Conclusions. This dose-dense schedule should not be routinely used due to its high frequency of toxic events; however, a sequential strategy with DOXO and IFO may benefit selected patients and should be further explored with lower doses. The role of ezrin as a prognostic marker should be confirmed in a larger group of patients. PMID- 21785571 TI - Absolute concentration of free volume-type defects in ultrafine-grained Fe prepared by high-pressure torsion. AB - A maximum excess volume DeltaV/V ~ 1.9 * 10(-3) in ultrafine-grained Fe prepared by high-pressure torsion is determined by measurements of the irreversible length change upon annealing employing a high-resolution differential dilatometer. Since dislocations and equilibrium-type grain boundaries cannot fully account for the observed released excess volume, the present study yields evidence for a high concentration of free volume-type defects inherent to nanophase materials, which is considered to be the main source of their particular properties, such as strongly enhanced diffusivities. PMID- 21785572 TI - Distinct patterns of activation-dependent changes in conformational mobility between ERK1 and ERK2. AB - Hydrogen/deuterium exchange measurements by mass spectrometry (HX-MS) can be used to report localized conformational mobility within folded proteins, where exchange predominantly occurs through low energy fluctuations in structure, allowing transient solvent exposure. Changes in conformational mobility may impact protein function, even in cases where structural changes are unobservable. Previous studies of the MAP kinase, ERK2, revealed increases in HX upon activation occured at the hinge between conserved N- and C-terminal domains, which could be ascribed to enhanced backbone flexibility. This implied that kinase activation modulates interdomain closure, and was supported by evidence for two modes of nucleotide binding that were consistent with closed vs open conformations in active vs inactive forms of ERK2, respectively. Thus, phosphorylation of ERK2 releases constraints to interdomain closure, by modulating hinge flexibility. In this study, we examined ERK1, which shares 90% sequence identity with ERK2. HX-MS measurements of ERK1 showed similarities with ERK2 in overall deuteration, consistent with their similar tertiary structures. However, the patterns of HX that were altered upon activation of ERK1 differed from those in ERK2. In particular, alterations in HX at the hinge region upon activation of ERK2 did not occur in ERK1, suggesting that the two enzymes differ with respect to their regulation of hinge mobility and interdomain closure. In agreement, HX-MS measurements of nucleotide binding suggested revealed domain closure in both inactive and active forms of ERK1. We conclude that although ERK1 and ERK2 are closely related with respect to primary sequence and tertiary structure, they utilize distinct mechanisms for controlling enzyme function through interdomain interactions. PMID- 21785573 TI - Development of a Low-Cost SIA-Based Analyser for Water Samples. AB - An automated multiparametric water analyser was developed and evaluated. The system was based on Sequential Injection Analysis and featured a photometric detection system comprising a tricolour RGB LED source and a photodiode. A program compiled in Visual Basic was used to control the SIA flow system, the LEDs, and the data acquisition and processing. The program loads and executes methods written in ASCII and stored as text files. The system was capable of handling up to four methods simultaneously. When used to carry out methods based on the APHA standard methods, the figures of merit obtained were considered satisfactory for the purpose. The total cost was under US $4600. It was concluded that the analyser is appropriate for routine use and has potential for an increased number of simultaneous methods and for enhanced capabilities if new versions of the software are developed. PMID- 21785574 TI - Sulfolobus mutants, generated via PCR products, which lack putative enzymes of UV photoproduct repair. AB - In order to determine the biological relevance of two S. acidocaldarius proteins to the repair of UV photoproducts, the corresponding genes (Saci_1227 and Saci_1096) were disrupted, and the phenotypes of the resulting mutants were examined by various genetic assays. The disruption used integration by homologous recombination of a functional but heterologous pyrE gene, promoted by short sequences attached to both ends via PCR. The phenotypic analyses of the disruptants confirmed that ORF Saci_1227 encodes a DNA photolyase which functions in vivo, but they could not implicate ORF Saci_1096 in repair of UV- or other externally induced DNA damage despite its similarity to genes encoding UV damage endonucleases. The success of the gene-disruption strategy, which used 5' extensions of PCR primers to target cassette integration, suggests potential advantages for routine construction of Sulfolobus strains. PMID- 21785575 TI - Learning Hidden Markov Models for Regression using Path Aggregation. AB - We consider the task of learning mappings from sequential data to real-valued responses. We present and evaluate an approach to learning a type of hidden Markov model (HMM) for regression. The learning process involves inferring the structure and parameters of a conventional HMM, while simultaneously learning a regression model that maps features that characterize paths through the model to continuous responses. Our results, in both synthetic and biological domains, demonstrate the value of jointly learning the two components of our approach. PMID- 21785576 TI - Design and Implementation of Functional Nanoelectronic Interfaces With Biomolecules, Cells, and Tissue Using Nanowire Device Arrays. AB - Nanowire FETs (NWFETs) are promising building blocks for nanoscale bioelectronic interfaces with cells and tissue since they are known to exhibit exquisite sensitivity in the context of chemical and biological detection, and have the potential to form strongly coupled interfaces with cell membranes. We present a general scheme that can be used to assemble NWs with rationally designed composition and geometry on either planar inorganic or biocompatible flexible plastic surfaces. We demonstrate that these devices can be used to measure signals from neurons, cardiomyocytes, and heart tissue. Reported signals are in millivolts range, which are equal to or substantially greater than those recorded with either planar FETs or multielectrode arrays, and demonstrate one unique advantage of NW-based devices. Basic studies showing the effect of device sensitivity and cell/substrate junction quality on signal magnitude are presented. Finally, our demonstrated ability to design high-density arrays of NWFETs enables us to map signal at the subcellular level, a functionality not enabled by conventional microfabricated devices. These advances could have broad applications in high-throughput drug assays, fundamental biophysical studies of cellular function, and development of powerful prosthetics. PMID- 21785577 TI - A theoretical study of aqueous solvation of K comparing ab initio, polarizable, and fixed-charge models. AB - The hydration of K(+) is studied using a hierarchy of theoretical approaches, including ab initio Born-Oppenheimer molecular dynamics and Car-Parrinello molecular dynamics, a polarizable force field model based on classical Drude oscillators, and a nonpolarizable fixed-charge potential based on the TIP3P water model. While models based more directly on quantum mechanics offer the possibility to account for complex electronic effects, polarizable and fixed charges force fields allow for simulations of large systems and the calculation of thermodynamic observables with relatively modest computational costs. A particular emphasis is placed on investigating the sensitivity of the polarizable model to reproduce key aspects of aqueous K(+), such as the coordination structure, the bulk hydration free energy, and the self diffusion of K(+). It is generally found that, while the simple functional form of the polarizable Drude model imposes some restrictions on the range of properties that can simultaneously be fitted, the resulting hydration structure for aqueous K(+) agrees well with experiment and with more sophisticated computational models. A counterintuitive result, seen in Car-Parrinello molecular dynamics and in simulations with the Drude polarizable force field, is that the average induced molecular dipole of the water molecules within the first hydration shell around K(+) is slightly smaller than the corresponding value in the bulk. In final analysis, the perspective of K(+) hydration emerging from the various computational models is broadly consistent with experimental data, though at a finer level there remain a number of issues that should be resolved to further our ability in modeling ion hydration accurately. PMID- 21785578 TI - Hemangiopericytoma of maxilla in a pediatric patient: a case report. AB - The Hemangiopericytoma is a malignant vascular tumor arising from mesenchymal cells with pericytic differentiation. Hemangiopericytoma is most commonly seen in adults, and only 5% to 10% of cases occur in children. The tumor is extremely rare in the head and neck region (16%)1. Cytogenic abnormalities have been present in some hemangiopericytoma cases. Surgical resection remains the mainstay treatment. Adjuvant chemotherapy and radiotherapy is appropriate for cases of incomplete resections and life-threatening tumors particularly in children. Late relapses may occur and require long-term follow-up. A 4-year-old child patient with hemangiopericytoma of the maxilla presented with firm, recurrent, but painless jaw mass. Radiographic investigations revealed a poorly circumscribed radiolucency. The lesion biopsy showed well-circumscribed multiple lobules of tumor mass consisting of tightly packed, spindle-shaped cells. Chemotherapy and radiotherapy of the lesion was conducted. The role of the pediatric dental team is extensive in children with hemangiopericytoma, who require a regular dental review. The patient's oncologist should be immediately contacted if there is any suspicion of recurrence. PMID- 21785579 TI - The discovery of the fat-regulating phosphatidic acid phosphatase gene. AB - Phosphatidic acid phosphatase is a fat-regulating enzyme that plays a major role in controlling the balance of phosphatidic acid (substrate) and diacylglycerol (product), which are lipid precursors used for the synthesis of membrane phospholipids and triacylglycerol. Phosphatidic acid is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, secretion, and endocytosis. While this important enzyme has been known for several decades, its gene was only identified recently from yeast. This discovery showed the importance of phosphatidic acid phosphatase in lipid metabolism in yeast as well as in higher eukaryotes including humans. PMID- 21785580 TI - Increased expression of the tail-anchored membrane protein SLMAP in adipose tissue from type 2 Tally Ho diabetic mice. AB - The tail-anchored membrane protein, sarcolemmal membrane associated protein (SLMAP) is encoded to a single gene that maps to the chromosome 3p14 region and has also been reported in certain diabetic populations. Our previous studies with db/db mice shown that a deregulation of SLMAP expression plays an important role in type 2 diabetes. Male Tally Ho mice were bred to present with either normoglycemia (NG) or hyperglycemia (HG). Abdominal adipose tissue from male Tally Ho mice of the HG group was found to have a significantly lower expression of the membrane associated glucose transporter-4 (GLUT-4) and higher expression of SLMAP compared to tissue from NG mice. There were 3 isoforms expressed in the abdominal adipose tissue, but only 45 kDa isoform of SLMAP was associated with the GLUT-4 revealed by immunoprecipitation data. Knock down studies using SLMAP siRNA with adipocytes resulted in a significant reduction in SLMAP and a decrease in glucose uptake. Thus, SLMAP may be an important regulator of glucose uptake or involved in GLUT-4 fusion/translocation into the plasma membrane of mouse abdominal adipose tissue and changes in SLMAP expression are linked to hyperglycemia and diabetes. PMID- 21785582 TI - Systemic mastocytosis associated with splenic marginal zone lymphoma with villous lymphocytes. AB - The development of a second haematological disease during the course of systemic mastocytosis is a well-known phenomenon. In most of the cases, they consist of myelodysplasia or myeloproliferative disorders. The association with lymphoproliferative disorders has also been described, but it is uncommon and the relationship is not well established. We report a patient diagnosed with systemic mastocytosis who three years later developed a splenic marginal zone lymphoma with villous lymphocytes. PMID- 21785581 TI - Interaction between mitochondria and the endoplasmic reticulum: implications for the pathogenesis of type 2 diabetes mellitus. AB - Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated with beta-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca(2+) homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM. PMID- 21785583 TI - Risk factors for hepatitis C virus transmission obscure in nigerian patients. AB - Aim. To determine the prevalence of anti-HCV and risk factors associated with HCV infection in Nigerians. Materials and Method. Patients attending a general outpatient clinic were administered a structured questionnaire on the risk factors for HCV infection. They were also tested for anti-HCV using a third generation enzyme-linked immunosorbent assay. Result. The seroprevalence of anti HCV was 4.7%. Among the risk factors evaluated, none was found to be significantly associated with anti-HCV seropositivity. Conclusion. The risk factors associated with HCV infection in Nigerian patients are obscure. This warrants further studies on the epidemiology of this important cause of liver disease. PMID- 21785584 TI - Low-Radiation-Dose Modified Small Bowel CT for Evaluation of Recurrent Crohn's Disease. AB - Crohn's disease affects any part of the GI tract, commonly the terminal ileum. To decrease radiation exposure we developed a low-radiation-dose unenhanced CT (modified small Bowel CT, MBCT) to evaluate the small bowel using hyperdense oral contrast. Technique. MBCT was investigated in patients with pathologically proven Crohn's disease presenting with new symptoms from recurrent inflammation or stricture. After ethics board approval, 98 consecutive patients were retrospectively evaluated. Kappa values from two independent reviewers were calculated for presence of obstruction, active inflammation versus chronic stricture, and ancillary findings. Forty-two patients underwent surgery or colonoscopy within 3 months. Results. Kappa was 0.84 for presence of abnormality versus a normal exam and 0.89 for differentiating active inflammation from chronic stricture. Level of agreement for presence of skip areas, abscess formation, and fistula was 0.62, 0.75, and 0.78, respectively. In the subset with "gold standard" follow-up, there was 83% agreement. Conclusions. MBCT is a low radiation technique with good to very good interobserver agreement for determining presence of obstruction and degree of disease activity in patients with Crohn's disease. Further investigation is required to refine parameters of disease activity compared to CT enterography and small bowel follow through. PMID- 21785585 TI - The natural history and outcomes of the patients with carcinosarcoma involving kidney and renal pelvis. AB - Background. The objective of this paper was to examine the epidemiology, natural history, and prognostic factors of carcinosarcoma of the kidney and renal pelvis (CSKP) using population-based registry. Patients and Methods. Forty-three patients with CSKP, diagnosed between January 1973 and December 2007, were identified from the national Surveillance, Epidemiology, and End Results (SEER) database and reviewed. Results. 79% of all patients with known SEER stage were classified as having regional or distant stage; almost all the patients with known histology grade had poorly or undifferentiated histology. The median cancer specific survival was 6 months (95% CI 4-9). The 1-year cancer-specific survival rate for entire cohort was 30.2%. There were no differences in terms of age at diagnosis, histological grade, tumor stage on presentation, and frequency of nephrectomy between carcinosarcoma of kidney (CSK) or renal pelvis (CSP). In multivariate analysis, age at diagnosis, tumor stage, and year of diagnosis were found to be significant predictors for cancer-specific survival. Conclusion. CSKP commonly presented as high-grade, advanced stage disease, and was associated with a poor prognosis regardless of location. PMID- 21785586 TI - Role of KIT-Positive Interstitial Cells of Cajal in the Urinary Bladder and Possible Therapeutic Target for Overactive Bladder. AB - In the gastrointestinal tract, interstitial cells of Cajal (ICCs) act as pacemaker cells to generate slow wave activity. Interstitial cells that resemble ICCs in the gastrointestinal tract have been identified by their morphological characteristics in the bladder. KIT is used as an identification marker of ICCs. ICCs in the bladder may be involved in signal transmission between smooth muscle bundles, from efferent nerves to smooth muscles, and from the urothelium to afferent nerves. Recent research has suggested that not only the disturbance of spontaneous contractility caused by altered detrusor ICC signal transduction between nerves and smooth muscle cells but also the disturbance of signal transduction between urothelial cells and sensory nerves via suburothelial ICC may induce overactive bladder (OAB). Recent reports have suggested that KIT is not only a detection marker of these cells, but also may play a crucial role in the control of bladder function. Research into the effect of a c-kit receptor inhibitor, imatinib mesylate, on bladder function implies that KIT-positive ICCs may be therapeutic target cells to reduce bladder overactivity and that the blockage of c-kit receptor may offer a new therapeutic strategy for OAB treatment, although further study will be needed. PMID- 21785587 TI - Quality-on-Demand Compression of EEG Signals for Telemedicine Applications Using Neural Network Predictors. AB - A telemedicine system using communication and information technology to deliver medical signals such as ECG, EEG for long distance medical services has become reality. In either the urgent treatment or ordinary healthcare, it is necessary to compress these signals for the efficient use of bandwidth. This paper discusses a quality on demand compression of EEG signals using neural network predictors for telemedicine applications. The objective is to obtain a greater compression gains at a low bit rate while preserving the clinical information content. A two-stage compression scheme with a predictor and an entropy encoder is used. The residue signals obtained after prediction is first thresholded using various levels of thresholds and are further quantized and then encoded using an arithmetic encoder. Three neural network models, single-layer and multi-layer perceptrons and Elman network are used and the results are compared with linear predictors such as FIR filters and AR modeling. The fidelity of the reconstructed EEG signal is assessed quantitatively using parameters such as PRD, SNR, cross correlation and power spectral density. It is found from the results that the quality of the reconstructed signal is preserved at a low PRD thereby yielding better compression results compared to results obtained using lossless scheme. PMID- 21785588 TI - Perioperative intravascular fluid assessment and monitoring: a narrative review of established and emerging techniques. AB - Accurate assessments of intravascular fluid status are an essential part of perioperative care and necessary in the management of the hemodynamically unstable patient. Goal-directed fluid management can facilitate resuscitation of the hypovolemic patient, reduce the risk of fluid overload, reduce the risk of the injudicious use of vasopressors and inotropes, and improve clinical outcomes. In this paper, we discuss the strengths and limitations of a spectrum of noninvasive and invasive techniques for assessing and monitoring intravascular volume status and fluid responsiveness in the perioperative and critically ill patient. PMID- 21785589 TI - Allergic Responses Induced by a Fungal Biopesticide Metarhizium anisopliae and House Dust Mite Are Compared in a Mouse Model. AB - Biopesticides can be effective in controlling their target pest. However, research regarding allergenicity and asthma development is limited. We compared the ability of fungal biopesticide Metarhizium anisopliae (MACA) and house dust mite (HDM) extracts to induce allergic responses in BALB/c mice. The extracts were administered by intratracheal aspiration at doubling doses (2.5-80 MUg protein) 4X over a four-week period. Three days after the last exposure, serum and bronchoalveolar lavage fluid (BALF) were collected. The extracts' relative allergenicity was evaluated based on response robustness (lowest significant dose response compared to control (0 MUg)). MACA induced a more robust serum total IgE response than HDM. However, in the antigen-specific IgE assay, a similar dose of both MACA and HDM was required to achieve the same response level. Our data suggest a threshold dose of MACA for allergy induction and that M. anisopliae may be similar to HDM in allergy induction potential. PMID- 21785591 TI - Ethylene oxide: acute four-hour and one-hour inhalation toxicity testing in rats. AB - Ethylene oxide was tested on groups of rats for either 4-hour or 1-hour inhalation exposure, followed by 14 days of observation. Groups of five Sprague Dawley rats/sex were exposed, and clinical signs and mortality were recorded. Clinical signs noted included irregular breathing, absence of certain reflexes, and tremors. Rats that died had moderate to severe pulmonary congestion. The calculated LC(50) values, reported as ppm by volume (with 95% confidence limits), were as follows. 4-hour LC(50) values were 1972 (1887 to 2061) ppm for males; 1537 (1391 to 1698) ppm for females; 1741 (1655 to 1831) ppm for the combined sexes. The 1-hour LC(50) values were 5748 (5276 to 6262) ppm for males; 4439 (4034 to 4884) ppm for females; 5029 (4634 to 5459) ppm for the combined sexes. PMID- 21785590 TI - Oxidative toxicity in neurodegenerative diseases: role of mitochondrial dysfunction and therapeutic strategies. AB - Besides fluorine, oxygen is the most electronegative element with the highest reduction potential in biological systems. Metabolic pathways in mammalian cells utilize oxygen as the ultimate oxidizing agent to harvest free energy. They are very efficient, but not without risk of generating various oxygen radicals. These cells have good antioxidative defense mechanisms to neutralize these radicals and prevent oxidative stress. However, increased oxidative stress results in oxidative modifications in lipid, protein, and nucleic acids, leading to mitochondrial dysfunction and cell death. Oxidative stress and mitochondrial dysfunction have been implicated in many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and stroke-related brain damage. Research has indicated mitochondria play a central role in cell suicide. An increase in oxidative stress causes mitochondrial dysfunction, leading to more production of reactive oxygen species and eventually mitochondrial membrane permeabilization. Once the mitochondria are destabilized, cells are destined to commit suicide. Therefore, antioxidative agents alone are not sufficient to protect neuronal loss in many neurodegenerative diseases. Combinatorial treatment with antioxidative agents could stabilize mitochondria and may be the most suitable strategy to prevent neuronal loss. This review discusses recent work related to oxidative toxicity in the central nervous system and strategies to treat neurodegenerative diseases. PMID- 21785592 TI - Recognizing and preventing overexposure to methylmercury from fish and seafood consumption: information for physicians. AB - Fish is a valuable source of nutrition, and many people would benefit from eating fish regularly. But some people eat a lot of fish, every day or several meals per week, and thus can run a significant risk of overexposure to methylmercury. Current advice regarding methylmercury from fish consumption is targeted to protect the developing brain and nervous system but adverse health effects are increasingly associated with adult chronic low-level methylmercury exposure. Manifestations of methylmercury poisoning are variable and may be difficult to detect unless one considers this specific diagnosis and does an appropriate test (blood or hair analysis). We provide information to physicians to recognize and prevent overexposure to methylmercury from fish and seafood consumption. Physicians are urged to ask patients if they eat fish: how often, how much, and what kinds. People who eat fish frequently (once a week or more often) and pregnant women are advised to choose low mercury fish. PMID- 21785593 TI - Pancreatic cancer cell lines can induce prostaglandin e2 production from human blood mononuclear cells. AB - Accumulating evidence suggests an important role for cyclooxygenase-2 (COX-2) in the pathogenesis of a wide range of malignancies. The protumorigenic properties of COX-2 are generally thought to be mediated by its product, PGE(2), which is shown to promote tumor spread and growth by multiple mechanisms but most importantly through modulation of the local immune response in the tumor. Pancreatic tumor cells produce various amounts of PGE(2), some of them being even deficient in COX enzymes or other PGE(2) synthases. Here we describe that, beside pancreatic tumor cells or stromal fibroblasts, human peripheral blood mononuclear cells can also produce PGE(2) upon coculture with pancreatic cancer cells. Stimulating of cellular cPLA2 within PBMCs by secreted factors, presumably sPLA2, from tumor cells appeared crucial, while the direct contact between PBMCs and PDACs seemed to be dispensable for this effect. Our data is emphasizing the complex interactions participating in the formation of the tolerogenic immune milieu within pancreatic tumors. PMID- 21785594 TI - Titrimetric and spectrophotometric assay of oxcarbazepine in pharmaceuticals using N-bromosuccinimide and bromopyrogallol red. AB - Titrimetric and spectrophotometric methods are described for the determination of oxcarbazepine (OXC) in bulk drug and in tablets. The methods use N bromosuccinimide (NBS) and bromopyrogallol red (BPR) as reagents. In titrimetry (method A), an acidified solution of OXC is titrated directly with NBS using methyl orange as indicator. Spectrophotometry (method B) involves the addition of known excess of NBS to an acidified solution of OXC followed by the determination of the unreacted NBS by reacting with BPR and measuring the absorbance of the unreacted dye at 460 nm. Titrimetry allows the determination of 6-18 mg of OXC and follows a reaction stoichiometry of 1 : 1 (OXC : NBS), whereas spectrophotometry is applicable over the concentration range of 0.8-8.0 MUg mL( 1). Method B with a calculated molar absorptivity of 2.52 * 10(4) L mol(-1) cm( 1) is the most sensitive spectrophotometric method ever developed for OXC. The optical characteristics such as limits of detection (LOD), quantification (LOQ), and Sandell's sensitivity values are also reported for the spectrophotometric method. The accuracy and precision of the methods were studied on intraday and interday basis. The methods described could usefully be applied to routine quality control of tablets containing OXC. No interference was observed from common pharmaceutical adjuvants. Statistical comparison of the results with a reference method shows an excellent agreement and indicates no significant difference in accuracy and precision. The reliability of the methods was further ascertained by recovery studies in standard addition procedure. PMID- 21785595 TI - Direct Zinc Determination in Brazilian Sugar Cane Spirit by Solid-Phase Extraction Using Moringa oleifera Husks in a Flow System with Detection by FAAS. AB - This paper reports a method for the determination of zinc in Brazilian sugar cane spirit, (cachaca in Portuguese), using solid-phase extraction with a flow injection analysis system and detection by FAAS. The sorbent material used was activated carbon obtained from Moringa oleifera husks. Flow and chemical variables of the proposed system were optimized through multivariate designs. The factors selected were sorbent mass, sample pH, sample flow rate, and eluent concentration. The optimum extraction conditions were obtained using a sample pH of 4.0, a sample flow rate of 6.0 mL min(-1), 30.0 mg of sorbent mass, and 1.0 mol L(-1) HNO(3) as the eluent at a flow rate of 4.0 mL min(-1). The limit of detection for zinc was 1.9 MUg L(-1), and the precision was below 0.82% (20.0 MUg L(-1), n = 7). The analytical curve was linear from 2 to 50 MUg L(-1), with a correlation coefficient of 0.9996. The method developed was successfully applied to spiked Brazilian sugar cane spirit, and accuracy was assessed through recovery tests, with results ranging from 83% to 100%. PMID- 21785596 TI - Derivatization Ion Chromatography for the Determination of Monoethanolamine in Presence of Hydrazine in PHWR Steam-Water Circuits. AB - A simple, rapid and accurate method for the determination of monoethanolamine (MEA) in PHWR steam-water circuits has been developed. MEA is added in the feed water to provide protection against corrosion while hydrazine is added to scavenge dissolved oxygen. The quantitative determination of MEA in presence of hydrazine was accomplished using derivatization ion chromatography with conductometric detection in nonsuppressed mode. A Metrosep cation 1-2 analytical column and a Metrosep cartridge were used for cation separation. A mixture of 4 mM tartaric acid, 20% acetone and 0.05 mM HNO(3) was used as eluent. Acetone in the mobile phase leads to the formation of different derivatives with MEA and hydrazine. The interferences due Na(+) and NH(4) (+) were eliminated by adopting a simple pretreatment procedure employing OnGuard-H cartridge. The limit of detection limit of MEA was 0.1 MUg mL(-1) and the relative standard deviation was 2% for the overall method. The recovery of MEA added was in the range 95%-102%. The method was applied to the determination of MEA in steam generator water samples. PMID- 21785597 TI - Acute Immobilization Stress Modulate GABA Release from Rat Olfactory Bulb: Involvement of Endocannabinoids-Cannabinoids and Acute Stress Modulate GABA Release. AB - We studied the effects of cannabinoids and acute immobilization stress on the regulation of GABA release in the olfactory bulb. Glutamate-stimulated 3H-GABA release was measured in superfused slices. We report that cannabinoids as WIN55, 212-2, methanandamide, and 2-arachidonoylglycerol were able to inhibit glutamate- and KCl-stimulated 3H-GABA release. This effect was blocked by the CB1 antagonist AM281. On the other hand, acute stress was able per se to increase endocannabinoid activity. This effect was evident since the inhibition of stimulated GABA release by acute stress was reversed with AM281 and tetrahydrolipstatin. Inhibition of the endocannabinoid transport or its catabolism showed reduction of GABA release, antagonized by AM281 in control and stressed animals. These results point to endocannabinoids as inhibitory modulators of GABA release in the olfactory bulb acting through an autocrine mechanism. Apparently, stress increases the endocannabinoid system, modulating GABAergic synaptic function in a primary sensory organ. PMID- 21785598 TI - Loss of H2A.Z Is Not Sufficient to Determine Transcriptional Activity of Snf2 Related CBP Activator Protein or p400 Complexes. AB - The p400 and SRCAP (Snf2-related CBP activator protein) complexes remodel chromatin by catalyzing deposition of histone H2A.Z into nucleosomes. This remodeling activity has been proposed as a basis for regulation of transcription by these complexes. Transcript levels of p21 or Sp1 mRNAs after knockdown of p400 or SRCAP reveals that each regulates transcription of these promoters differently. In this study, we asked whether deposition of H2A.Z within specific nucleosomes by p400 or SRCAP dictates transcriptional activity. Our data indicates that nucleosome density at specific p21 or Sp1 promoter positions is not altered by the loss of either remodeling complex. However, knockdown of SRCAP or p400 reduces deposition of H2A.Z~50% into all p21 and Sp1 promoter nucleosomes. Thus, H2A.Z deposition is not targeted to specific nucleosomes. These results indicate that the deposition of H2A.Z by the p400 or SRCAP complexes is not sufficient to determine how each regulates transcription. This conclusion is further supported by studies that demonstrate a SRCAP(DeltaATP ) mutant unable to deposit H2A.Z has similar transcriptional activity as wild-type SRCAP. PMID- 21785599 TI - Diagnosis of Bilateral Tonsil Cancers via Staging PET/CT: Case Report and Review. AB - Diagnostic workup of metastatic head and neck squamous cell carcinoma of unknown primary site has traditionally included CT and/or MRI imaging and endoscopic biopsies. Routine bilateral tonsillectomy is highly controversial and the role of PET/CT is evolving, both for identification of potential primary sites and the detection of distant metastases. We report a case of cervical nodal metastasis of squamous cell carcinoma from an unknown primary site, in which dual-modality PET/CT led to the unexpected diagnosis of synchronous bilateral tonsillar cancers. In addition, PET/CT correctly distinguished pulmonary sarcoidosis from metastatic disease in this patient. PMID- 21785600 TI - Human pregnancy and parturition clinical management. PMID- 21785601 TI - Breast Cancer Profile in a Group of Patients Followed up at the Radiation Therapy Unit of the Yaounde General Hospital, Cameroon. AB - Objective. To describe the profile of breast cancer in the patients attending the radiation therapy unit of Yaounde General Hospital. Method. From 1989 to 2009, we conducted a descriptive retrospective study based on the register and medical records of patients. Results. During the study period, 531 breast cancer patients were recorded of which 0.75% were male. Age range was 18 to 82 years, with a mean of 45.17 years. Out of these, 66.1% were less than 50 years old and 31.9% less than 40. Self detection was the discovery method in most cases (95.34% of patients). Mean delay before presentation at hospital was 10.35 months, and 54.94% had used traditional medicine before medical evaluation. Metastasis and locally advanced breast cancer at diagnosis were present in 08.13% and 62.78%, respectively. Mastectomy was used in 88.08% of patients. Conclusion. The study reinforces the position occupied by late presentation and advanced stage at diagnosis of breast cancer profile in developing countries. PMID- 21785602 TI - Surgical treatment of endometrial cancer and atypical hyperplasia: a trend shift from laparotomy to laparoscopy. AB - Background. Laparoscopic hysterectomy has proved to be a safe alternative to open surgery in women with benign indications. Few studies compare laparotomy and laparoscopy in gynecologic oncology, and the objective of this study was to analyze the feasibility and development of laparoscopic surgery in endometrial cancer patients. Material and Methods. Records from all women having a hysterectomy due to premalignant or malignant endometrial changes during the years 2002-2009 were examined retrospectively. Results. A total of 521 hysterectomies were performed during the study period. Laparoscopy was performed in about 20% of the cases in the first two years, increasing to 83% in the last year of the period. Moreover, the laparoscopic technique was increasingly applied in older women, more obese women and in women with high-risk preoperative diagnosis, without increasing the complication rate. Conclusions. As for benign indications, laparoscopic hysterectomy in endometrial cancer patients should be preferred whenever possible. PMID- 21785603 TI - Harlequin syndrome in a case of toxic goitre: a rare association. AB - Harlequin syndrome (HS) is known to be associated with conditions like brain stem infarcts and superior mediastinal neurinoma. However, it has not been reported in association with autoimmune hyperthyroidism. We report a case of exacerbation of unilateral sweating in a patient with HS following the onset of toxic goitre. Previous reports have suggested that a tortuous inferior thyroid artery can produce neurovascular compression of the sympathetic chain which was not observed in our patient. Autoimmune aetiology for HS needs to be explored. Increased sweating in hyperthyroid patients needs to be assessed properly so as to prognosticate appropriately. PMID- 21785604 TI - Entamoeba gingivalis in Acute Osteomyelitis of the Mandible. AB - An 86-year-old woman presented with osteonecrosis of the mandible following bisphosphonate therapy for multiple myeloma, and underwent surgical debridement and multiple dental extractions. Histopathologic examination of the necrotic bone fragments revealed acute osteomyelitis with mixed flora and organisms morphologically consistent with Entamoeba gingivalis. In addition to oral scrapings and sputum, E. gingivalis has been identified in specimens obtained from the uterus, cervix, neck lymph nodes, and lung. It is rarely found in lesions of the head and neck. We present an unusual case of E. gingivalis in acute osteomyelitis of the mandible, following bisphosphonate therapy for multiple myeloma. To our knowledge, this is the first reported case of E. gingivalis in association with osteomyelitis. PMID- 21785605 TI - Severe fetal distress and umbilical cord strangulation. AB - We describe an extreme case of amniotic band syndrome, presented with fetal stress during labor and associated with strangulation of umbilical cord. PMID- 21785606 TI - A Rare Case of Secondary Bacterial Peritonitis from Clostridium perfringens in an Adult Patient with Noncirrhotic Ascites and a Krukenberg Tumor: Report of a Case. AB - Secondary bacterial peritonitis, in comparison to spontaneous, presents with a surgically treatable intraabdominal source for infection such as a gastrointestinal perforation or abscess and is nearly always polymicrobial. We present a rare case of secondary bacterial peritonitis from Clostridium perfringens in an adult patient with noncirrhotic ascites and a Krukenberg tumor. PMID- 21785607 TI - Testicular arteriovenous malformation: gray-scale and color Doppler ultrasonography features. AB - Intratesticular arteriovenous malformations (AVMs) are extremely rare benign incidental lesions of the testis. Ultrasonography (US) generally reveals a hypoechoic solid mass within the testicular parenchyma. We describe a patient with intratesticular AVM which was found incidentally during workup for infertility. The gray-scale and Doppler US appearance of an intratesticular AVM and the differential diagnosis have been presented. Based on the gray-scale, US appearance differentiation from malignant testicular tumors is difficult. Doppler US examination aids in the diagnosis by demonstrating the vascular nature of the tumor. PMID- 21785608 TI - Plasticity of cells and ex vivo production of red blood cells. AB - The supply of transfusable red blood cells (RBCs) is not sufficient in many countries. If transfusable RBCs could be produced abundantly from certain resources, it would be very useful. Our group has developed a method to produce enucleated RBCs efficiently from hematopoietic stem/progenitor cells present in umbilical cord blood. More recently, it was reported that enucleated RBCs could be abundantly produced from human embryonic stem (ES) cells. The common obstacle for application of these methods is that they require very high cost to produce sufficient number of RBCs that are applicable in the clinic. If erythroid cell lines (immortalized cell lines) able to produce transfusable RBCs ex vivo were established, they would be valuable resources. Our group developed a robust method to obtain immortalized erythroid cell lines able to produce mature RBCs. To the best of our knowledge, this was the first paper to show the feasibility of establishing immortalized erythroid progenitor cell lines able to produce enucleated RBCs ex vivo. This result strongly suggests that immortalized human erythroid progenitor cell lines able to produce mature RBCs ex vivo can also be established. PMID- 21785609 TI - Expression patterns of cancer-testis antigens in human embryonic stem cells and their cell derivatives indicate lineage tracks. AB - Pluripotent stem cells can differentiate into various lineages but undergo genetic and epigenetic changes during long-term cultivation and, therefore, require regular monitoring. The expression patterns of cancer-testis antigens (CTAs) MAGE-A2, -A3, -A4, -A6, -A8, -B2, and GAGE were examined in undifferentiated human embryonic stem (hES) cells, their differentiated derivatives, teratocarcinoma (hEC) cells, and cancer cell lines of neuroectodermal and mesodermal origin. Undifferentiated hES cells and embryoid body cells expressed MAGE-A3, -A6, -A4, -A8, and GAGEs while later differentiated derivatives expressed only MAGE-A8 or MAGE-A4. Likewise, mouse pluripotent stem cells also express CTAs of Magea but not Mageb family. Despite similarity of the hES and hEC cell expression patterns, MAGE-A2 and MAGE-B2 were detected only in hEC cells but not in hES cells. Moreover, our analysis has shown that CTAs are aberrantly expressed in cancer cell lines and display low tissue specificity. The identification of CTA expression patterns in pluripotent stem cells and their derivatives may be useful for isolation of abnormally CTA-expressing cells to improve the safety of stem-cell based therapy. PMID- 21785610 TI - Bacterial Isolates and Antibiotic Sensitivity among Gambian Children with Severe Acute Malnutrition. AB - Background. Establishing the pattern of infection and antimicrobial sensitivities in the local environment is critical to rational use of antibiotics and the development of management algorithms. Methods. Morbidity history and physical examination of 140 children with severe acute malnutrition were recorded. Their blood, stool, and urine samples were cultured and antibiotic sensitivity patterns determined for any bacterial pathogens isolated. Results. Thirty-eight children had a pathogen isolated from blood culture, 60% of which were considered contaminants. Coagulase negative staphylococcus was the predominant contaminant, while the major causes of bacteraemia were nontyphoidal Salmonella (13%), S. pneumoniae (10%), and E. coli (8%). E. coli accounted for 58% of the urinary isolates. No pathogen was isolated from stool. In vitro sensitivity by disk diffusion showed that 87.5% of the isolates were sensitive to ampicillin and/or gentamicin and 84.4% (27/32) to penicillin and/or gentamicin. Conclusions. A combination of ampicillin and gentamicin provides adequate antibiotic cover for severely malnourished children in The Gambia. PMID- 21785611 TI - Drug testing for newborn exposure to illicit substances in pregnancy: pitfalls and pearls. AB - Estimates of the prevalence of drug usage during pregnancy vary by region and survey tool used. Clinicians providing care to newborns should be equipped to recognize a newborn who has been exposed to illicit drugs during pregnancy by the effects the exposure might cause at the time of delivery and/or by drug testing of the newborn. The purpose of this paper is to provide an overview of the literature and assess the clinical role of drug testing in the newborn. Accurate recognition of a newborn whose mother has used illicit drugs in pregnancy cannot only impact decisions for healthcare in the nursery around the time of delivery, but can also provide a key opportunity to assess the mother for needed services. While drug use in pregnancy is not an independent predictor of the mother's ability to provide a safe and nurturing environment for her newborn, other issues that often cooccur in the life of a mother with a substance abuse disorder raise concerns for the safety of the discharge environment and should be assessed. Healthcare providers in these roles should advocate for unbiased and effective treatment services for affected families. PMID- 21785612 TI - Inhalation of ortho-phthalaldehyde vapor causes respiratory sensitization in mice. AB - Ortho-Phthalaldehyde (OPA) has been approved for high-level sterilization of heat sensitive medical instruments and is increasingly being used as a replacement in the healthcare industry for glutaraldehyde, a known sensitizer. Numerous case reports have been published indicating workers and patients experiencing respiratory problems, anaphylaxis, skin reactivity, and systemic antibody production. Our laboratory previously demonstrated that OPA is a dermal sensitizer in mice. The goal of the present study was to determine if OPA is a respiratory sensitizer following inhalation exposure. Mice were exposed to OPA vapor and airway and lymph nodes were examined for cytokine gene expression and alterations in lymphocyte populations. Inhalation of OPA for 3 days resulted in a concentration-dependent increase in lymphocyte proliferation, mainly B lymphocytes, in the draining lymph nodes. A secondary challenge of mice with OPA resulted in a dramatic increase in the population of B lymphocytes expressing IgE. Expression of Th2 (IL-4, IL-5, and IL-13) and anti/proinflammatory (IL-10, TNFalpha, and IL-1beta) cytokine genes was upregulated in the lymph nodes and the nasal mucosa. Mice exposed to the higher concentrations of OPA-produced OPA specific IgG(1) antibodies indicating systemic sensitization. These findings provide evidence that OPA has the potential to cause respiratory sensitization in mice. PMID- 21785613 TI - Haptenation: chemical reactivity and protein binding. AB - Low molecular weight chemical (LMW) allergens are commonly referred to as haptens. Haptens must complex with proteins to be recognized by the immune system. The majority of occupationally related haptens are reactive, electrophilic chemicals, or are metabolized to reactive metabolites that form covalent bonds with nucleophilic centers on proteins. Nonelectrophilic protein binding may occur through disulfide exchange, coordinate covalent binding onto metal ions on metalloproteins or of metal allergens, themselves, to the major histocompatibility complex. Recent chemical reactivity kinetic studies suggest that the rate of protein binding is a major determinant of allergenic potency; however, electrophilic strength does not seem to predict the ability of a hapten to skew the response between Th1 and Th2. Modern proteomic mass spectrometry methods that allow detailed delineation of potential differences in protein binding sites may be valuable in predicting if a chemical will stimulate an immediate or delayed hypersensitivity. Chemical aspects related to both reactivity and protein-specific binding are discussed. PMID- 21785614 TI - Asthma in the Elderly: Can We Distinguish It from COPD? AB - Asthma in older adults affects quality of life and results in a higher hospitalization rate and mortality. In common clinical practice, asthma in the elderly is underdiagnosed and undertreated or overdiagnosed and mistreated. The age-related reduction in perception of shortness of breath and the high incidence of comorbidities make the diagnosis and management more difficult and challenging for the physicians. Chronic obstructive pulmonary disease (COPD) is usually easy to distinguish from asthma, but sometimes the distinction from late-onset asthma in older patients, particularly in cigarette smokers, is difficult and may be impossible. Both diseases are characterized by the presence of airflow obstruction but have distinct pathogenesis, inflammatory pattern, and prognosis. The distinction between Asthma and COPD based simply on spirometric parameters is difficult especially in the elderly asthmatics. The combination of lung function testing, bronchial hyperresponsiveness (BHR) and atopy status, HRCT scans, and the newly developed biological techniques, allowing the assessment of biomarker profiles, could facilitate the distinction between these diseases. PMID- 21785615 TI - Tracking Exercise Motions of Older Adults Using Contours. AB - In this paper we describe the development of a novel markerless motion capture system and explore its use in documenting elder exercise routines in a health club. This system uses image contour tracking and swarm intelligence methods to track the location of the spine and shoulders during three exercises - treadmill, exercise bike, and overhead lateral pull-down. Validation results show that our method has a mean error of approximately 2 degrees when measuring the angle of the spine or shoulders relative to the horizontal. Qualitative study results demonstrate that our system is capable of providing important feedback about the posture and stability of elders while they are performing exercises. Study participants indicated that feedback from our system would add value to their exercise routines. PMID- 21785616 TI - Current state of type 1 diabetes immunotherapy: incremental advances, huge leaps, or more of the same? AB - Thus far, none of the preclinically successful and promising immunomodulatory agents for type 1 diabetes mellitus (T1DM) has conferred stable, long-term insulin independence to diabetic patients. The majority of these immunomodulators are humanised antibodies that target immune cells or cytokines. These as well as fusion proteins and inhibitor proteins all share varying adverse event occurrence and severity. Other approaches have included intact putative autoantigens or autoantigen peptides. Considerable logistical outlays have been deployed to develop and to translate humanised antibodies targeting immune cells, cytokines, and cytokine receptors to the clinic. Very recent phase III trials with the leading agent, a humanised anti-CD3 antibody, call into question whether further development of these biologics represents a step forward or more of the same. Combination therapies of one or more of these humanised antibodies are also being considered, and they face identical, if not more serious, impediments and safety issues. This paper will highlight the preclinical successes and the excitement generated by phase II trials while offering alternative possibilities and new translational avenues that can be explored given the very recent disappointment in leading agents in more advanced clinical trials. PMID- 21785620 TI - Locating the Acupoint Baihui (GV20) Beneath the Cerebral Cortex with MRI Reconstructed 3D Neuroimages. AB - Baihui (GV20) is one of the most important acupoints of the Du meridian (the government vessel) and is commonly used in neurology and psychiatry and as a distal point of anorectal disorders by general practitioners. The anatomical relationship between the scalp region of the acupoint and the underlying corresponding cortex remains obscure. In this study, we first prepared the indicator for MRI scanning on a GE 1.5 T excite machine in a mode suitable for 3D reconstruction. The 3D Avizo software system (version 6.0, Mercury Computer Systems, Inc., Germany) was then used for image processing and the resulting data subsequently analyzed using descriptive statistics and analysis of variance (ANOVA). The mean distance from the Baihui anterior to the central sulcus in the adult group was greater than that in the child group (22.7 +/- 2.2 and 19.7 +/- 2.2 mm, resp., P = .042), whereas in the child group the distance between the Baihui anterior and the precentral sulcus was greater than in the adult group (6.8 +/- 0.8 and 3.8 +/- 0.8 mm, resp., P < .001). This MRI presentation demonstrates that the location of Baihui (GV20) can be identified using the distance from the central or precentral sulcus. PMID- 21785619 TI - Myricetin Ameliorates Defective Post-Receptor Insulin Signaling via beta Endorphin Signaling in the Skeletal Muscles of Fructose-Fed Rats. AB - beta-Endorphin plays a major role in the amelioration of insulin resistance. The present study documents that myricetin (3,5,7,3', 4', 5'-hexahydroxyflavone) ameliorates insulin resistance by enhancing beta-endorphin production in insulin resistant rats. The rats were induced for insulin resistance by feeding them a diet containing 60% fructose for 6 weeks. The degree of insulin resistance was measured by the homeostasis model assessment of basal insulin resistance (HOMA IR). The plasma levels of insulin and beta-endorphin were measured by an enzyme linked immunosorbent assay. The insulin receptor-related signaling mediators in the soleus muscles of rats were evaluated by immunoprecipitation or immunoblotting. Myricetin was injected daily (1 mg kg(-1) per injection, thrice daily) for 14 days. Consequently, the high-glucose plasma levels in fructose-fed rats decreased significantly concomitant with an increase in plasma beta endorphin. The reduction of the elevated HOMA-IR index following treatment with myricetin was subsequently inhibited by the administration of beta-funaltrexamine hydrochloride (beta-FNA) at doses sufficient to block MU-opioid receptors (MOR). The myricetin treatment was also observed to affect the phosphorylation of the insulin receptor, insulin receptor substrate-1, Akt and Akt substrate of 160 kDa, with subsequent effects on glucose-transporter subtype 4 translocation, all of which were blocked by beta-FNA pretreatment. These results indicated that enhancement of beta-endorphin secretion, which in turn leads to peripheral MOR activation, is involved in the action of myricetin on the amelioration of impaired signaling intermediates downstream of insulin receptors. PMID- 21785618 TI - Pathological role of tonsillar B cells in IgA nephropathy. AB - Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale. PMID- 21785617 TI - T cell recognition of autoantigens in human type 1 diabetes: clinical perspectives. AB - Type 1 diabetes (T1D) is an autoimmune disease driven by the activation of lymphocytes against pancreatic beta-cells. Among beta-cell autoantigens, preproinsulin has been ascribed a key role in the T1D process. The successive steps that control the activation of autoreactive lymphocytes have been extensively studied in animal models of T1D, but remains ill defined in man. In man, T lymphocytes, especially CD8(+) T cells, are predominant within insulitis. Developing T-cell assays in diabetes autoimmunity is, thus, a major challenge. It is expected to help defining autoantigens and epitopes that drive the disease process, to pinpoint key functional features of epitope-specific T lymphocytes along the natural history of diabetes and to pave the way towards therapeutic strategies to induce immune tolerance to beta-cells. New T-cell technologies will allow defining autoreactive T-cell differentiation programs and characterizing autoimmune responses in comparison with physiologically appropriate immune responses. This may prove instrumental in the discovery of immune correlates of efficacy in clinical trials. PMID- 21785621 TI - Description of a sulfitobacter strain and its extracellular cyclodipeptides. AB - A marine bacterium M44 was separated from 30 m deep seawater in the East China Sea (26 degrees 28.3' N 122 degrees 29.0' E) in 2006. 16S rDNA gene sequence comparison showed that the strain M44 was a member of the genus Sulfitobacter and highly similar to KMM 3554(T). A series of experiments demonstrated that this strain M44 had many distinctive characteristics: its cells were gram-negative and mesophilic; its colonies were slightly yellowish, round, convex, and smooth; and it could grow at 10-28 degrees C, pH 6.0-10.0, and in the presence of 0-12.5% (w/v) NaCl; the optimum growth conditions were 25 degrees C and pH 7.0, and the optimum Na(+) concentration was 2.5%. In addition, strain M44 contained 18 : 1 omega7c, 11 methyl 18 : 1 omega7c and 16 : 0 fatty acids as major fatty acids, and the genomic DNA G+C content was 58.04 mol%. According to our results of the secondary metabolites, six cyclodipeptides were isolated from the strain M44, which were Cyclo (Val-Leu), Cyclo (Phe-Val), Cyclo (Phe-Leu), Cyclo (Leu-Ile), Cyclo (Phe-Ile), and Cyclo (Trp-Pro). It is the first study of secondary metabolites isolated from this genus. PMID- 21785623 TI - In Vitro Ultramorphological Assessment of Apoptosis on CEMss Induced by Linoleic Acid-Rich Fraction from Typhonium flagelliforme Tuber. AB - The plant Typhonium flagelliforme, commonly known as "rodent tuber" in Malaysia, is often used as a health supplement and traditional remedy for alternative cancer therapies, including leukemia. This study aimed to evaluate in vitro anti leukemic activity of dichloromethane extract/fraction number 7 (DCM/F7) from T. flagelliforme tuber on human T4 lymphoblastoid (CEMss) cell line. The DCM extract of tuber has been fractionated by column chromatography. The obtained fractions were evaluated for its cytotoxicity toward CEMss cells as well as human primary blood lymphocytes (PBLs). Assessment of apoptosis produced by the most active fraction was evaluated by various microscopic techniques and further confirmation of apoptosis was done by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Phytochemical screening was done by gas chromatography mass spectrometry (GC-MS). The results shows that 7 out of 12 fractions showed significant cytotoxicity against the selected cell line CEMss, in which fractions DCM/F7, DCM/F11 and DCM/F12 showed exceptional activity with 3, 5 and 6.2 MUg ml( 1), respectively. Further studies in the non-cancerous PBL exhibited significant selectivity of DCM/F7 compared to other fractions. Cytological observations showed chromatin condensation, cell shrinkage, abnormalities of cristae, membrane blebbing, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by double-staining of acridine orange (AO)/propidium iodide (PI), SEM and TEM. In addition, DCM/F7 has increased the cellular DNA breaks on treated cells. GC-MS revealed that DCM/F7 contains linoleic acid, hexadecanoic acid and 9 hexadecanoic acid. The present results indicate that T. flagelliforme possess a valuable anti-leukemic effect and was able to produce distinctive morphological features of cell death that corresponds to apoptosis. PMID- 21785624 TI - Study of the Anti-Proliferative Activity of 5-Substituted 4,7-Dimethoxy-1,3 Benzodioxole Derivatives of SY-1 from Antrodia camphorata on Human COLO 205 Colon Cancer Cells. AB - A set of 10 4,7-dimethoxy-1,3-benzodioxole derivatives based on a lead compound previously discovered by our group, SY-1, which was isolated from Antrodia camphorata, were evaluated for their in vitro inhibitory activity on human colorectal carcinoma cells (COLO 205). Structure-activity relationship studies of the 10 compounds indicated the importance of the chain length of the alkyl group at the 5-position, and the 2-propenyl substituent named "apiole" exhibited the most potent inhibitory activity. In the present study, we demonstrate that the SY 1 analogue "apiole" decreased the proliferation of COLO 205 cells, but not that of normal human colonic epithelial cells (FHC). The G0/G1 cell cycle arrest induced by apiole (75-225 MUM) was associated with significantly increased levels of p53, p21 and p27 and decreased levels of cyclin D1. Concerning COLO 205 cell apoptosis, apiole (>150 MUM) treatment significantly increased the levels of cleaved caspases 3, 8, 9 and bax/bcl-2 ratio and induced ladder formation in DNA fragmentation assay and sub-G1 peak in flow cytometry analysis. These findings suggest that apiole can suppress COLO 205 cell growth; however, the detailed mechanisms of these processes require further investigation. PMID- 21785622 TI - New perspectives on chinese herbal medicine (zhong-yao) research and development. AB - Synthetic chemical drugs, while being efficacious in the clinical management of many diseases, are often associated with undesirable side effects in patients. It is now clear that the need of therapeutic intervention in many clinical conditions cannot be satisfactorily met by synthetic chemical drugs. Since the research and development of new chemical drugs remain time-consuming, capital intensive and risky, much effort has been put in the search for alternative routes for drug discovery in China. This narrative review illustrates various approaches to the research and drug discovery in Chinese herbal medicine. Although this article focuses on Chinese traditional drugs, it is also conducive to the development of other traditional remedies and innovative drug discovery. PMID- 21785625 TI - Biological activities of chinese propolis and brazilian propolis on streptozotocin-induced type 1 diabetes mellitus in rats. AB - Propolis is a bee-collected natural product and has been proven to have various bioactivities. This study tested the effects of Chinese propolis and Brazilian propolis on streptozotocin-induced type 1 diabetes mellitus in Sprague-Dawley rats. The results showed that Chinese propolis and Brazilian propolis significantly inhibited body weight loss and blood glucose increase in diabetic rats. In addition, Chinese propolis-treated rats showed an 8.4% reduction of glycated hemoglobin levels compared with untreated diabetic rats. Measurement of blood lipid metabolism showed dyslipidemia in diabetic rats and Chinese propolis helped to reduce total cholesterol level by 16.6%. Moreover, oxidative stress in blood, liver and kidney was improved to various degrees by both Chinese propolis and Brazilian propolis. An apparent reduction in levels of alanine transaminase, aspartate transaminase, blood urea nitrogen and urine microalbuminuria-excretion rate demonstrated the beneficial effects of propolis in hepatorenal function. All these results suggested that Chinese propolis and Brazilian propolis can alleviate symptoms of diabetes mellitus in rats and these effects may partially be due to their antioxidant ability. PMID- 21785626 TI - Acupuncture May Stimulate Anticancer Immunity via Activation of Natural Killer Cells. AB - This article presents the hypothesis that acupuncture enhances anticancer immune functions by stimulating natural killer (NK) cells. It provides background information on acupuncture, summarizes the current scientific understanding of the mechanisms through which NK cells act to eliminate cancer cells, and reviews evidence that acupuncture is associated with increases in NK cell quantity and function in both animals and humans. The key contribution of this article involves the use of cellular immunology and molecular biological theory to interpret and synthesize evidence from disparate animal and human studies in formulating the 'acupuncture immuno-enhancement hypothesis': clinicians may use acupuncture to promote the induction and secretion of NK-cell activating cytokines that engage specific NK cell receptors that endogenously enhance anticancer immune function. PMID- 21785627 TI - Ameliorate Effects of Li-Fu Formula on IL-6-Mediated Cardiac Hypertrophy in Hamsters Fed with a Hyper-Cholesterol Diet. AB - Hypercholesterolemia diets are considered as major sources to cause cardiac hypertrophy. This study intends to evaluate the effects of Li-Fu formula on cardiac hypertrophy induced by hypercholesterolemia diet. Twenty-four male Golden Syrian hamsters were randomly divided into control, cholesterol and Li-Fu formula groups and fed with different experimental diets for 2 months. Histopathological analysis and western blotting were performed to measure the myocardial architecture, and various cardiac hypertrophy-associated molecules in the excised left ventricle from hamsters. The ratios of whole heart weight/body weight (BW) and left ventricle weight/BW were significantly higher in the cholesterol group but significantly lower in the Li-Fu formula group. The protein levels of both atrial natriuretic peptide and brain natriuretic peptide were significantly increased in the cholesterol group but significantly reduced in the Li-Fu formula group. Additionally, significantly increased interleukin-6, STAT3, MEK5, p-ERK5 and non-cardiomyocyte proliferate signal molecules such as p-MEK and p-ERK, were detected in the cholesterol group but significantly reduced in the Li-Fu formula group. Notably, no significant variations of inflammatory signaling molecules, including p-P38 and p-JNK, were detected in all groups. Our experimental results demonstrated the significant reductions of cardiac hypertrophy and related eccentric hypertrophy signaling, non-cardiomyocyte proliferate signaling in the excised left ventricle of hamsters from the Li-Fu formula. We suggested the protective effects of Li-Fu formula on cardiac hypertrophy that may be useful in prevention or treatment of hypertrophy-associated cardiovascular diseases. PMID- 21785628 TI - Anti-Atherogenic Activity of Ethanolic Fraction of Terminalia arjuna Bark on Hypercholesterolemic Rabbits. AB - Atherosclerosis which results from gradual deposition of lipids in medium and large arteries is a leading cause of mortality worldwide. Terminalia arjuna is a herb of Combretaceae family which contains hypolipidemic compounds and flavonoids with high antioxidative properties. This study was conducted to determine the effect of ethanolic fraction of T. arjuna on blood lipids and atherosclerosis in rabbits fed with high fat diet (HFD). Twenty New Zealand rabbits of either sex were randomly divided into five groups: the first two were normal diet group and HFD (21% fat) group and the remaining three groups received high cholesterol diet supplemented with standard drug (Atorvastatin 10 mg kg(-1) body weight), T. arjuna ethanolic fraction (100 and 200 mg kg(-1) body weight), respectively. The concentration of total cholesterol (TC), low density lipoprotein (LDL) cholesterol, triglycerides (TGs), very low density lipoprotein (VLDL) cholesterol and high density lipoprotein (HDL) cholesterol was determined in rabbits at the start of the experiment, at the 14th, 30th days and at the end of the study. Anti atherogenic index was calculated from the lipid profile of the rabbits before sacrifice. At the end of the experimental period, the aorta was removed for assessment of atherosclerotic plaques. Results show that T. arjuna significantly decreases TC, LDL and TG levels and increases HDL and lessens atherosclerotic lesion in aorta (P < .05). Hence T. arjuna extract can effectively prevent the progress of atherosclerosis. This is likely due to the effect of T. arjuna on serum lipoproteins and its antioxidant and anti-inflammatory properties. PMID- 21785629 TI - Assessment of Antioxidant Properties in Fruits of Myrica esculenta: A Popular Wild Edible Species in Indian Himalayan Region. AB - Crude extract of Myrica esculenta fruits, a wild edible species of Indian Himalayan Region, was evaluated for phenolic compounds and antioxidant properties. Results revealed significant variation in total phenolic and flavonoid contents across populations. Among populations, total phenolic content varied between 1.78 and 2.51 mg gallic acid equivalent/g fresh weight (fw) of fruits and total flavonoids ranged between 1.31 and 1.59 mg quercetin equivalent/g fw. Antioxidant activity determined by 2,2'-azinobis(3 ethylbenzothiazoline-6-sulphonic acid) radical scavenging, 1,1-diphenyl-2 picrylhydrazyl radical scavenging and ferric reducing antioxidant power (FRAP) exhibited considerable antioxidant potential and showed significant positive correlation with total phenolic and total flavonoids content. High performance liquid chromatography analysis revealed significant variation (P < .01) in phenolic compounds (i.e., gallic acid, catechin, hydroxybenzioc acid and rho coumaric acid) across populations. This study provides evidences to establish that consumption of M. esculenta fruits while providing relished taste would also help in reduction of free radicals. Therefore, this wild edible species deserves promotion in the region through horticulture and forestry interventions. PMID- 21785630 TI - Protective Effect of Anthocyanins Extract from Blueberry on TNBS-Induced IBD Model of Mice. AB - This study was carried out to evaluate the protective effect of anthocyanins extract of blueberry on trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) model of mice. The study employed female C57BL/6 mice (n = 50), and colitis was induced by intracolonic injection of 0.5 mg of TNBS dissolved in 50% ethanol-phosphate buffered solution. The mice were divided into five groups (n = 10): vehicle, TNBS control and anthocyanins groups that received different doses of anthocyanins extract (10, 20 and 40 mg kg(-1)) daily for 6 days. Both increase in body weight and diarrhea symptoms were monitored each day. After 6 days, the animals were killed, and the following parameters were assessed: colon length, morphological score, histological score and biochemical assay (NO, myeloperoxidase (MPO), interleukin (IL)-12, IL-10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma). The results showed that the anthocyanins extract of blueberry rendered strong protection against TNBS-induced colonic damage at a dosage of 40 mg kg(-1). When compared with the control, anthocyanins extract significantly prevented loss of body weight and ameliorated the scores of diarrhea, morphology and histology. Treatment with anthocyanins extract restored IL-10 excretion, as well as caused reduction in the levels of NO, MPO, IL-12, TNF-alpha and IFN-gamma. Our research revealed the protective effect of anthocyanins extract from blueberry on TNBS-induced experimental colitis in mice, as well as examined whether high levels of dietary blueberries would lower the risk or have protective effects on human IBD, which may require further investigation. PMID- 21785631 TI - Evaluation of Antioxidant and Cerebroprotective Effect of Medicago sativa Linn. against Ischemia and Reperfusion Insult. AB - Antioxidants have been the focus of studies for developing neuroprotective agents to be used in the therapy for stroke, which is an acute and progressive neurodegenerative disorder. Medicago sativa (MS) has a long tradition of use as ayurvedic and homoeopathic medicine in central nervous system disorders. The plant has been reported to have antioxidant, anti-inflammatory and antidiabetic effects. Therefore, the present study was designed to investigate the neuroprotective effect of methanol extract of MS on ischemia and reperfusion induced cerebral injury in mice. Bilateral carotid artery occlusion (BCAO) for 15 min followed by 24-h reperfusion, resulted in significant elevation in infarct size, xanthine oxidase (XO) activity, superoxide anion (O(*-) (2)) production and thiobarbituric acid-reactive substance (TBARS) levels, and significant depletion in endogenous antioxidant [reduced glutathione (GSH), superoxide dismutase (SOD) and total tissue sulfhydryl (T-SH) groups] systems in mice brain. Further, BCAO led to impairment in short-term memory and motor coordination. Pre-treatment with MS (100 or 200 mg kg(-1), p.o.) markedly reduced cerebral infarct size, XO, O(*-) (2) and TBARS levels, significantly restored GSH, SOD and T-SH levels and attenuated impairment in short-term memory and motor coordination. In addition, MS directly scavenged free radicals generated against a stable radical 1,1 diphenyl-2-picrylhydrazyl and O(*-) (2) generated in phenazine methosulphate nicotinamide adenine dinucleotide systems, and also inhibited XD/XO conversion and resultant O(*-) (2) production. The data from this study suggest that treatment with MS enhances the antioxidant defense against BCAO-induced global cerebral ischemia and exhibits neuroprotective activity. PMID- 21785632 TI - Acupuncture treatment of a patient with persistent allergic rhinitis complicated by rhinosinusitis and asthma. AB - A pathophysiologic relationship between allergic rhinitis and rhinosinusitis and asthma has long been suggested. However, few clinical studies of acupuncture have been conducted on these comorbid conditions. A 48-year-old male suffering from persistent allergic rhinitis with comorbid chronic rhinosinusitis and asthma since the age of 18 years was studied. He complained of nasal obstruction, sneezing, cough, rhinorrhea and moderate dyspnea. He occasionally visited local ear-nose-throat clinics for his nasal symptoms, but gained only periodic symptom relief. The patient was treated with acupuncture, infrared radiation to the face and electro-acupuncture. Needles were inserted at bilateral LI20, GV23, LI4 and EX-1 sites with De-qi. Electro-acupuncture was performed simultaneously at both LI20 sites and additional traditional Korean acupuncture treatments were performed. Each session lasted for 10 min and the sessions were carried out twice a week for 5 weeks. The patient's Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire score decreased from 38, at the beginning of treatment, to 23, 3 weeks after the last treatment. The Total Nasal Symptom Score was reduced from six (baseline) to five, 3 weeks after the last treatment. There was significant clinical improvement in the forced expiratory volume in 1 s-from 3.01 to 3.50 l with discontinuation of the inhaled corticosteroid, and no asthma-related complaints were reported. Further clinical studies investigating the effectiveness of acupuncture for the patients suffering from allergic rhinitis and/or rhinosinusitis with comorbid asthma are needed. PMID- 21785633 TI - Pulse width modulation electro-acupuncture on cardiovascular remodeling and plasma nitric oxide in spontaneously hypertensive rats. AB - This study was designed to investigate the effect of pulse width modulation electro-acupuncture (PWM-EA) on cardiovascular remodeling and nitric oxide (NO) in spontaneously hypertensive rats (SHR). Thirty-four male SHR were randomly divided into control, captopril, and two PWM-EA groups, which were treated with 350 Hz (SHR-350 Hz) and whole audio bandwith electro-acupuncture (SHR-WAB group) respectively, on the ST 36 point located on the outside of the hind leg. Systolic blood pressure (BP), plasma and myocardial NO were measured. Histological studies were also performed on the aortic wall and the left ventricle. The BP in the SHR 350 Hz, SHR-WAB and the captopril groups was lower than in the control group following the treatment (P < .05). The average aortic media wall thickness in the two electro-acupuncture groups was less than in the control group (P < .05). The left ventricle/heart weight ratio in the captopril and SHR-350 Hz groups was less than in the control group (P < .01), but was similar between the SHR-WAB and the control group (P > .05). The plasma and myocardium NO levels were elevated in the captopril and the SHR-350 Hz group (P < .05 and .01, resp.). The plasma level of NO in the SHR-WAB group was also higher than in the control group (P < .05). We concluded that pulse width modulation electro-acupuncture on the ST 36 point prevents the progression of hypertension and diminishes the cardiovascular remodeling in SHR. It also elevates plasma and cardiac NO in this animal model. PMID- 21785634 TI - Epigenetics in traditional chinese pharmacy: a bioinformatic study at pharmacopoeia scale. AB - Epigenetics is a phenomenon of heritable changes in the chromatin structure of a genomic region, resulting in a transcriptional silent or active state of the region over cell mitosis. Mounting evidence has demonstrated phenotypic consequence of alternations in the patterns of DNA methylation and histone modifications, two of the well-studied epigenetic mechanisms. The epigenome thus represents an interesting therapeutic target. Traditional Chinese medicine (TCM) is a system of therapies that has developed through empiricism for over 2100 years and has remained a popular alternative medicine in some Far East Asian populations. We searched 3294 TCM medicinals (TCMMs) containing 48 491 chemicals for chemicals that interact with the epigenetics-related proteins and found that 29.8% of the TCMMs are epigenome- and miRNA-modulating via, mainly, interactions with Polycomb group and methyl CpG-binding proteins. We analyzed 200 government approved TCM formulas (TCMFs) and found that a statistically significant proportion (99%) of them are epigenome- and miRNA-interacting. The epigenome and miRNA interactivity of the Monarch medicinals is found to be most prominent. Histone modifications are heavily exploited by the TCMFs, many of which are tonic. Furthermore, epigenetically, the Assistant medicinals least resemble the Monarch. We quantified the role of epigenetics in TCM prescription and found that epigenome- and miRNA-interaction information alone determined, to an extent of 20%, the clinical application areas of the TCMFs. Our results provide (i) a further support for the notion of the epigenomes as a drug target and (ii) a new set of tools for the design of TCM prescriptions. PMID- 21785635 TI - Revisiting the Sham: Is It all Smoke and Mirrors? AB - The misuse of sham controls in examining the efficacy or effectiveness of Complementary and Alternative Medicine has created numerous problems. The theoretical justification for incorporating a sham is questionable. The sham does not improve our control of bias and leads to relativistic data that, in most instances, has no appropriate interpretation with regards to treatment efficacy. Even the concept of a sham or placebo control in an efficacy trial is inherently paradoxical. Therefore, it is prudent to re-examine how we view sham controls in the context of medical research. Extreme caution should be used in giving weight to any sham-controlled study claiming to establish efficacy or safety. PMID- 21785636 TI - Influence of Oreocnide integrifolia (Gaud.) Miq on IRS-1, Akt and Glut-4 in Fat Fed C57BL/6J Type 2 Diabetes Mouse Model. AB - Oreocnide integrifolia (OI) leaves are used as folklore medicine by the people of northeast India to alleviate diabetic symptoms. Preliminary studies revealed hypoglycemic and hypolipidemic potentials of the aqueous leaf extract. The present study was carried out to evaluate whether the OI extract induces insulin secretion in vivo and in vitro and also whether it is mediated through the insulin-signaling pathway. The experimental set-up consisted of three groups of C57BL/6J mice strain: (i) control animals fed with standard laboratory diet, (ii) diabetic animals fed with a high-fat diet for 24 weeks and (iii) extract supplemented animals fed with 3% OI extract along with high-fat diet for 24 weeks. OI-extract supplementation lowered adiposity and plasma glucose and insulin levels. Immunoblot analysis of IRS-1, Akt and Glut-4 protein expressions in muscles of extract-supplemented animals revealed that glucoregulation was mediated through the insulin-signaling pathway. Moreover, immunostaining of pancreas revealed increased insulin immunopositive cells in OI-extract-treated animals. In addition, the insulin secretogogue ability of the OI extract was demonstrated when challenged with high glucose concentration using isolated pancreatic islets in vitro. Overall, the present study demonstrates the possible mechanism of glucoregulation of OI extract suggestive of its therapeutic potential for the management of diabetes mellitus. PMID- 21785637 TI - Clowns benefit children hospitalized for respiratory pathologies. AB - The study aims at evaluating health-generating function of humor therapy in a hospital ward hosting children suffering from respiratory pathologies. The main scope of this study is to investigate possible positive effects of the presence of a clown on both the clinical evolution of the on-going disease, and on some physiological and pain parameters. Forty-three children with respiratory pathologies participated in the study: 21 of them belonged to the experimental group (EG) and 22 children to the control group (CG). During their hospitalization, the children of the EG interacted with two clowns who were experienced in the field of pediatric intervention. All participants were evaluated with respect to clinical progress and to a series of physiological and pain measures both before and after the clown interaction. When compared with the CG, EG children showed an earlier disappearance of the pathological symptoms. Moreover, the interaction of the clown with the children led to a statistically significant lowering of diastolic blood pressure, respiratory frequency and temperature in the EG as compared with the control group. The other two parameters of systolic pressure and heart frequency yielded results in the same direction, without reaching statistical significance. A similar health-inducing effect of clown presence was observed on pain parameters, both by self evaluation and assessment by nurses. Taken together, our data indicate that the presence of clowns in the ward has a possible health-inducing effect. Thus, humor can be seen as an easy-to-use, inexpensive and natural therapeutic modality to be used within different therapeutic settings. PMID- 21785638 TI - Analysis of the Potential Topical Anti-Inflammatory Activity of Averrhoa carambola L. in Mice. AB - Inflammatory skin disorders, such as psoriasis and atopic dermatitis, are very common in the population; however, the treatments currently available are not well tolerated and are often ineffective. Averrhoa carambola L. (Oxalidaceae) is an Asian tree that has been used in traditional folk medicine in the treatment of several skin disorders. The present study evaluates the topical anti-inflammatory effects of the crude ethanolic extract of A. carambola leaves, its hexane, ethyl acetate, and butanol fractions and two isolated flavonoids on skin inflammation. Anti-inflammatory activity was measured using a croton oil-induced ear edema model of inflammation in mice. Topically applied ethanolic extract reduced edema in a dose-dependent manner, resulting in a maximum inhibition of 73 +/- 3% and an ID(50) value of 0.05 (range: 0.02-0.13) mg/ear. Myeloperoxidase (MPO) activity was also inhibited by the extract, resulting in a maximum inhibition of 60 +/- 6% (0.6 mg/ear). All of the fractions tested caused inhibition of edema formation and of MPO activity. Treatment with the ethyl acetate fraction was the most effective, resulting in inhibition levels of 75 +/- 5 and 54 +/- 8% for edema formation and MPO activity, respectively. However, treatment of mice with isolated compounds [apigenin-6-C-beta-l-fucopyranoside and apigenin-6-C-(2"-O alpha-l-rhamnopyranosyl)-beta-l-fucopyranoside] did not yield successful results. Apigenin-6-C-(2"-O-alpha-l-rhamnopyranosyl)-beta-l-fucopyranoside caused only a mild reduction in edema formation (28 +/- 11%). Taken together, these preliminary results support the popular use of A. carambola as an anti-inflammatory agent and open up new possibilities for its use in skin disorders. PMID- 21785639 TI - Curdione Plays an Important Role in the Inhibitory Effect of Curcuma aromatica on CYP3A4 in Caco-2 Cells. AB - Curcuma aromatica is a plant belonging to genus Curcuma of family Zingiberaceae and is widely used as supplements in Japan. Rhizomes of C. aromatica have curcumin as a major yellow pigment and curdione as a main ingredient of essential oils. In this study, we investigated the affect of C. aromatica on CYP3A4 using 1alpha,25-(OH)(2)-D(3)-treated Caco-2 clone cells. Caco-2 cells were treated with methanol extract (0.1 mg ml(-1)), its hexane soluble fraction (0.1 mg ml(-1)), curcumin (4 MUM) and curdione (20 MUM) for 72 hours. Nifedipine was used as a substrate of CYP3A4. Methanol extract, hexane fraction and curdione inhibited the formation of oxidized nifedipine by 50-70%, and curcumin showed no effect. The IC50s of methanol extract, hexane fraction and curdione to oxidized nifedipine formation were 21, 14 and 3.9 MUg ml(-1) (16.9 MUM), respectively. The content of curdione in methanol extract was 11.4%. Moreover, all of methanol extract, hexane fraction and curdione decreased CYP3A4 protein expression but had no affect on CYP3A4 mRNA expression. Our results showed that these drugs further decreased the CYP3A4 protein expression level after the protein synthesis was inhibited by cychroheximide. These findings suggest that curdione plays an important role in the CYP3A4 inhibitory activity of C. aromatica and curdione might inhibit the activity by accelerating the degradation of CYP3A4. PMID- 21785640 TI - A Preclinical Evaluation of Antrodia camphorata Alcohol Extracts in the Treatment of Non-Small Cell Lung Cancer Using Non-Invasive Molecular Imaging. AB - This study was carried out to provide a platform for the pre-clinical evaluation of anti-cancer properties of a unique CAM (complementary and alternative medicine) agent, Antrodia camphorata alcohol extract (ACAE), in a mouse model with the advantageous non-invasive in vivo bioluminescence molecular imaging technology. In vitro analyses on the proliferation, migration/invasion, cell cycle and apoptosis were performed on ACAE-treated non-small cell lung cancer cells, H441GL and control CGL1 cells. In vivo, immune-deficient mice were inoculated subcutaneously with H441GL followed by oral gavages of ACAE. The effect of ACAE on tumor progression was monitored by non-invasive bioluminescence imaging. The proliferation and migration/invasion of H441GL cells were inhibited by ACAE in a dose-dependent manner. In addition, ACAE induced cell cycle arrest at G0/G1 phase and apoptosis in H441GL cells as shown by flow cytometric analysis, Annexin-V immunoflourescence and DNA fragmentation. In vivo bioluminescence imaging revealed that tumorigenesis was significantly retarded by oral treatment of ACAE in a dose-dependent fashion. Based on our experimental data, ACAE contains anti-cancer properties and could be considered as a potential CAM agent in future clinical evaluation. PMID- 21785641 TI - San-Huang-Xie-Xin-Tang Prevents Rat Hearts from Ischemia/Reperfusion-Induced Apoptosis through eNOS and MAPK Pathways. AB - San-Huang-Xie-Xin-Tang (SHXT) is a traditional Chinese medication consisting of three herbs, namely Coptidis rhizome, Scutellariae radix and Rhei rhizome. This study aimed to examine the cardioprotective effects of SHXT in a rat model of acute myocardial apoptosis induced by ischemia/reperfusion (I/R). Vehicle (intravenous saline) or SHXT (intravenous or oral) was administered prior to I/R (occlusion of left coronary artery for 45 min followed by reperfusion for 2 h). In the vehicle group, myocardial I/R caused myocardial infarction with increased plasma cardiac enzymes, severe arrhythmia and mortality. Myocardial apoptosis was induced by I/R as evidenced by DNA ladder and Bcl-2/Bax ratio. In the SHXT group, we found that SHXT significantly reduced plasma levels of cardiac enzymes, arrhythmia scores (from 5 +/- 1 to 2 +/- 1, P < .01) and mortality rate (from 53 to 0%, P < .01). In addition, pretreatment with intravenous SHXT reduced the infarct size dose-dependently when compared with the vehicle group (10 mg kg(-1): 14.0 +/- 0.2 versus 44.5 +/- 5.0%, and 30 mg kg(-1): 6.2 +/- 1.2% versus 44.5 +/- 5.0%, both P < .01). Similarly, oral administration of SHXT reduced the infarct size dose-dependently. Furthermore, SHXT markedly decreased the apoptosis induced by I/R with increased Bcl-2/Bax ratio. Finally, we found that SHXT counteracted the I/R-induced downstream signaling, resulting in increased myocardial eNOS expression and plasma nitrite, and decreased activation of ERK1/2, p38 and JNK. These data suggest that SHXT has cardioprotective effects against I/R-induced apoptosis, and that these effects are mediated, at least in part, by eNOS and MAPK pathways. PMID- 21785642 TI - Cassia auriculata: Aspects of Safety Pharmacology and Drug Interaction. AB - Safety pharmacology studies help in identifying preclinical adverse drug reactions. We carried out routine safety pharmacology with focus on cardiovascular variables and pharmacokinetic herb-drug interaction studies on rats fed with standardized traditional hydro-alcoholic extract and technology based supercritical extract of Cassia auriculata for 12 weeks. Our studies indicate that both these extracts are pharmacologically safe and did not show any significant adverse reactions at the tested doses. The traditional hydro alcoholic extract did not show any significant effect on pharmacokinetics; however, the technology-based supercritical extract caused a significant reduction in absorption of metformin. Our results indicate the need to include pharmacokinetic herb-drug interaction studies as evidence for safety especially for technology-based extracts. PMID- 21785643 TI - Placebo analgesia, acupuncture and sham surgery. AB - Invasive procedures, such as surgery and acupuncture, are likely better than the others in terms of eliciting placebo analgesia. Understanding how invasive procedures can elicit enhanced placebo responses may provide new insights into mechanisms underlying placebo analgesia. In this essay, it is argued that sensory, cognitive and emotional factors are major determinants of the magnitude of placebo analgesia. Sham surgery and acupuncture are good examples of placebo interventions, which generate robust placebo responses through simultaneously manipulating such three factors. PMID- 21785644 TI - A Water-Soluble Polysaccharide from the Fruit Bodies of Bulgaria inquinans (Fries) and Its Anti-Malarial Activity. AB - A water-soluble polysaccharide (BIWS-4b) was purified from the fruit bodies of Bulgaria inquinans (Fries). It is composed of mannose (27.2%), glucose (15.5%) and galactose (57.3%). Its molecular weight was estimated to be 7.4 kDa (polydispersity index, Mw/Mn: 1.35). Structural analyses indicated that BIWS-4b mainly contains (1 -> 6)-linked, (1 -> 5)-linked and (1 -> 5,6)-linked beta-Galf units; (1 -> 4)-linked and non-reducing terminal beta-Glcp units; and (1 -> 2) linked, (1 -> 6)-linked, (1 -> 2,6)-linked and non-reducing terminal alpha-Manp units. When examined by the 4-day method and in a prophylactic assay in mice, BIWS-4b exhibited markedly suppressive activity against malaria while enhancing the activity of artesunate. Immunological tests indicated that BIWS-4b significantly enhanced macrophage phagocytosis and splenic lymphocyte proliferation in malaria-bearing mice and normal mice. The anti-malarial activity of BIWS-4b might be intermediated by enhancing immune competence and restoring artesunate-suppressed immune function. Thus, BIWS-4b is a potential adjuvant of anti-malaria drugs. PMID- 21785645 TI - Hydrotherapy for the treatment of pain in people with multiple sclerosis: a randomized controlled trial. AB - Background. Multiple sclerosis (MS) is a chronic demyelinating neurological disease. Several studies have reported that complementary and alternative therapies can have positive effects against pain in these patients. Objective. The objective was to investigate the effectiveness of an Ai-Chi aquatic exercise program against pain and other symptoms in MS patients. Methods. In this randomized controlled trial, 73 MS patients were randomly assigned to an experimental or control group for a 20-week treatment program. The experimental group underwent 40 sessions of Ai-Chi exercise in swimming pool and the control group 40 sessions of abdominal breathing and contraction-relaxation exercises in therapy room. Outcome variables were pain, disability, spasm, depression, fatigue, and autonomy, which were assessed before the intervention and immediately and at 4 and 10 weeks after the last treatment session. Results. The experimental group showed a significant (P < 0.028) and clinically relevant decrease in pain intensity versus baseline, with an immediate posttreatment reduction in median visual analogue scale scores of 50% that was maintained for up to 10 weeks. Significant improvements were also observed in spasm, fatigue, disability, and autonomy. Conclusion. According to these findings, an Ai-Chi aquatic exercise program improves pain, spasms, disability, fatigue, depression, and autonomy in MS patients. PMID- 21785646 TI - Effect of Mucuna pruriens Seed Extract Pretreatment on the Responses of Spontaneously Beating Rat Atria and Aortic Ring to Naja sputatrix (Javan Spitting Cobra) Venom. AB - Mucuna pruriens Linn. (velvet bean) has been used by native Nigerians as a prophylactic for snakebite. Rats pretreated with M. pruriens seed extract (MPE) have been shown to protect against the lethal and cardiovascular depressant effects of Naja sputatrix (Javan spitting cobra) venoms, and the protective effect involved immunological neutralization of the venom toxins. To investigate further the mechanism of the protective effect of MPE pretreatment against cobra venom toxicity, the actions of Naja sputatrix venom on spontaneously beating rat atria and aortic rings isolated from both MPE pretreated and untreated rats were studied. Our results showed that the MPE pretreatment conferred protection against cobra venom-induced depression of atrial contractility and atrial rate in the isolated atrial preparations, but it had no effect on the venom-induced contractile response of aortic ring preparation. These observations suggested that the protective effect of MPE pretreatment against cobra venom toxicity involves a direct protective action of MPE on the heart function, in addition to the known immunological neutralization mechanism, and that the protective effect does not involve action on blood vessel contraction. The results also suggest that M. pruriens seed may contain novel cardioprotective agent with potential therapeutic value. PMID- 21785647 TI - Cinnamomi ramulus Ethanol Extract Exerts Vasorelaxation through Inhibition of Ca Influx and Ca Release in Rat Aorta. AB - Contraction of vascular smooth muscle cells depends on the induction of cytosolic calcium ion (Ca(2+)) due to either Ca(2+) influx through voltage-gated Ca(2+) channels or to receptor-mediated Ca(2+) release from the sarcoplasmic reticulum. The present study investigated the vasorelaxation effect of Cinnamomi ramulus ethanol extract (CRE) and the possible mechanisms in rat aorta. CRE (0.1 mg/mL) relaxed vasoconstriction induced by phenylephrine (PE; 1 MUM) and angiotensin II (5 MUM). Preincubation with CRE significantly reduced the rat aortic contraction by addition of CaCl(2) in Ca(2+)-free Krebs solution and FPL64176 (10 MUM). Pretreatment with nifedipine (100 MUM) or verapamil (1 MUM) significantly reduced the CRE-mediated vasorelaxation of PE-induced vascular contraction. In addition, CRE also relaxed the vascular contraction caused by m-3M3FBS (5 MUg/mL), but U73122 (10 MUM) significantly inhibited the vasorelaxation of PE precontracted aortic rings. Furthermore, CRE significantly reduced the magnitude of PE- and caffeine (30 mM)-induced transient contraction. In vascular strips, CRE downregulated the expression levels of phosphorylated PLC and phosphoinositide 3 kinase elevated by PE or m-3M3FBS. These results suggest that CRE relaxes vascular smooth muscle through the inhibition of both Ca(2+) influx via L-type Ca(2+) channel and inositol triphosphate-induced Ca(2+) release from the sarcoplasmic reticulum. PMID- 21785648 TI - Bambusae caulis in Liquamen Suppresses the Expression of Thymus and Activation Regulated Chemokine and Macrophage-Derived Chemokine in Human Keratinocytes due to Antioxidant Effect. AB - Bambusae caulis in Liquamen (BCL), traditional herbal medicine used in East Asia, is known to have antioxidative and immune-regulating properties. We hypothesized that the potential antioxidant effects of BCL might suppress the production of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in human keratinocytes (HaCaT cell). The immune-regulating effect of BCL was demonstrated by antioxidant capacity using DPPH analysis and DCFH-DA analysis. We found that BCL had strong ROS scavenge effect in HaCaT cell. BCL also showed suppression of IFN-gamma-induced expression of TARC and MDC, activation of NF-kappaB, and, moreover, significant block of IFN-gamma-induced degradation and phosphorylation of IkappaB. However, it had no effects on phosphorylation of p38 MAPK. Collectively, these results suggest that BCL may have a therapeutic potential on skin disease such as atopic dermatitis by inhibiting Th2 chemokines which is due, at least in part, to its antioxidant capacities. PMID- 21785649 TI - Inhibitory effects of glycyrrhetinic Acid on DNA polymerase and inflammatory activities. AB - We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols alpha, beta, kappa, and lambda, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-alpha (TNF-alpha) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-kappaB (NF-kappaB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition. PMID- 21785650 TI - Ethanol Extract of Abnormal Savda Munziq, a Herbal Preparation of Traditional Uighur Medicine, Inhibits Caco-2 Cells Proliferation via Cell Cycle Arrest and Apoptosis. AB - Aims. Study the effect of Abnormal Savda Munziq (ASMq) ethanol extract on the proliferation, apoptosis, and correlative gene, expression in colon cancer cells (Caco-2) to elucidate the molecular mechanisms responsible for the anticancer property of Abnormal Savda Munziq. Materials and Methods. ASMq ethanol extract was prepared by a professional pharmacist. Caco-2 cells were treated with different concentration of ASMq ethanol extract (0.5-7.5 mg/mL) for different time intervals (48 and 72 h). Antiproliferative effect of ASMq ethanol extract was determined by MTT assay; DNA fragmentation was determined by gel electrophoresis assay; cell cycle analysis was detected by flow cytometer; apoptosis-related gene expression was detected by RT-PCR assay. Results. ASMq ethanol extract possesses an inhibition effect on Caco-2 cells proliferation, induction of cell apoptosis, cell cycle arrest in sub-G1 phase, and downregulation of bcl-2 and upregulation of Bax gene expression. Conclusion. The anticancer mechanism of ASMq ethanol extract may be involved in antiproliferation, induction of apoptosis, cell cycle arrest, and regulation of apoptosis-related gene expression such as bcl-2 and Bax activity pathway. PMID- 21785651 TI - Antidiabetic Activity of Gnidia glauca and Dioscorea bulbifera: Potent Amylase and Glucosidase Inhibitors. AB - Diabetes is a metabolic disorder affecting about 220 million people worldwide. One of the most critical complications of diabetes is post-prandial hyper glycemia (PPHG). Glucosidase inhibitor and alpha-amylase inhibitors are class of compounds that help in managing PPHG. Low-cost herbal treatment is recommended due to their lesser side effect for treatment of diabetes. Two plants with significant traditional therapeutic potential, namely, Gnidia glauca and Dioscorea bulbifera, were tested for their efficiency to inhibit alpha-amylase and alpha-glucosidase. Stem, leaf, and flower of G. glauca and bulb of D. bulbifera were sequentially extracted with petroleum ether, ethyl acetate, and methanol as well as separately with 70% ethanol. Petroleum ether extract of flower of G. glauca was found to inhibit alpha-amylase significantly (78.56%). Extracts were further tested against crude murine pancreatic, small intestinal, and liver glucosidase enzyme which revealed excellent inhibitory properties. alpha-glucosidase inhibition provided a strong in vitro evidence for confirmation of both G. glauca and D. bulbifera as excellent antidiabetic remedy. This is the first report of its kind that provides a strong biochemical basis for management of type II diabetes using G. glauca and D. bulbifera. These results provide intense rationale for further in vivo and clinical study. PMID- 21785653 TI - Parafalx angioleiomyoma: a case report and review of the literature. AB - Angioleiomyomas (ALMs) involving the central nervous system are exceedingly rare, and no ALM involving the parafalx region has ever been clinically reported. We report the first case of ALM involving the parafalx region on its surgical procedure and radiological feature. A 50-year-old man had a 6 month history of frontal headache and occasional seizure attacks. The radiological examination showed a parafalx occupation similar to meningioma. The tumour was very hypointense on T1 weighted magnetic resonance imaging (MRI) and hyperintense on T2 weighted MRI, which enhanced homogeneously with intravenous administration of gadolinium. The tumour was removed totally by sinusoidal transverse scalp incision and bilateral parafalx approach. To our surprise, the tumour was prominently debulked using bipolar shrinkage to coagulate the tumour feeding vessels, resulting in less bleeding during total removal of the tumour.. The lesion was confirmed as ALM by histological examination. The prognosis was good for the patient after surgery during the 18 month follow-up. PMID- 21785654 TI - The co-existence of CHARGE and myelodysplastic syndrome in a child. AB - We report the case of an 8-month-old female child with co-existence of CHARGE with myelodysplastic syndrome, which is not reported in the literature. The patient was treated with packed cell transfusion, laser photocoagulation for retinal detachment, and antimicrobials, and referred for bone marrow transplantation. PMID- 21785655 TI - Possible fenugreek induced haemolysis in a patient with previously unknown G6PD deficiency. AB - Glucose 6 phosphate dehydrogenase (G6PD) deficiency is the most common disease producing enzymopathy. People with G6PD deficiency cannot cope with oxidative stressors. These patients are asymptomatic until they develop a haemolytic crisis which presents as anaemia and jaundice. The agents known to cause haemolysis in these patients are: oxidant drugs, (primaquine, chloroquine and other anti malarials), antibiotics, (chloramphenicol, nitrofurantoin, sulphonamides, and all quinolone antibiotics). Chemicals to be avoided are moth balls (napththalene), aniline dyes, and some Chinese herbal medicine (San Chi, Chuan Lian). The classic presentation of exposure to Fava beans (legumes), causing oxidative haemolysis, has led G6PD deficiency to be also known as Favism. The patient we present here had no exposure to any of the known causes of oxidative haemolysis. Instead his precipitating cause strongly suggests raw fenugreek (T foenum-graecum L), a legume used as a herbal treatment for diabetes and previously not known to be a precipitant of haemolysis in G6PD deficiency. PMID- 21785652 TI - Socioeconomic Status and Coronary Heart Disease Risk: The Role of Social Cognitive Factors. AB - The aim of this study is to examine existing research on social cognitive factors that may, in part, mediate the relationship between socioeconomic status (SES) and coronary heart disease (CHD). We focus on how social status is 'carried' in the mental systems of individuals, and how these systems differentially affect CHD risk and associated behaviors. To this end, literatures documenting the association of various social cognitive factors (e.g., social comparison, perceived discrimination, and self-efficacy) with cardiovascular disease are reviewed as are literatures regarding the relationship of these factors to SES. Possible mechanisms through which social cognitions may affect health are addressed. In addition, directions for future research are discussed, and a model identifying the possible associations between social cognitive factors, SES, and coronary disease is provided. PMID- 21785656 TI - Neoplastic meningitis as the presenting manifestation of gastric adenocarcinoma. AB - A middle aged man presented with clinical signs of chronic meningitis, including bilateral hearing loss and progressive blindness. Lumbar puncture revealed a mild elevation in lymphocyte number, an elevation in protein levels, and diminished glucose levels, without malignant cells. Magnetic resonance imaging (MRI) T2 weighted seqeunces showed bilateral enhancement of the acoustic nerves. The aetiology of the chronic meningitis was revealed gastric cancer by gastroscopy, and micrometastasis by bone marrow trephine biopsy. Although cerebrospinal fluid (CSF) cytology was negative, neoplastic meningitis (NM) was diagnosed based on clinical and MRI data. The patient's condition worsened rapidly and he died shortly thereafter. Autopsy confirmed the presence of advanced gastric cancer (adenocarcinoma of signet-ring cell type) with pancreatic involvement, and NM with cancer cells on the meninges, but without infiltration tumour cells into underlying brain parenchyma. We conclude that NM as an initial symptom of gastric cancer is rare and ultimately fatal. PMID- 21785657 TI - Tension pneumatocoele in a child with an empyema. AB - A previously well 13-month-old child presented to our institution with a pneumonia which developed into a tension pneumatocoele. Management was conservative and the patient fully recovered. Streptococcus pneumoniae type 7F was isolated and is not covered by the current heptavalent vaccine. PMID- 21785658 TI - Patent foramen ovale and hypercoagulable state in the pathogenesis of acute thrombotic myocardial infarction. AB - Patent foramen ovale (PFO) is a known cause of cryptogenic stroke and, when associated with a condition of thrombophilia, its closure has been shown to reduce the recurrence of cerebral embolic events. Here we present a case of a young man, with a history of previous recurrent cerebral ischaemic episodes, that developed an inferior acute myocardial infarction (AMI) with angiographic evidence of thrombotic occlusion of the right coronary artery (RCA). Thrombus aspiration followed by balloon angioplasty was performed and, after 24 h of glycoprotein IIb/IIIa inhibitor infusion, thrombus was no longer evident at coronary angiography. Screening for thrombophilia revealed heterozygosis for prothrombin G20210A polymorphism. At transoesophageal echocardiography (TOE), a large PFO with right-to-left atrial shunt was present. Given the history of multiple thrombotic clinical events and the associated state of thrombophilia, transcatheter PFO closure was successfully performed. At 12 months of follow-up the patient was completely asymptomatic. PMID- 21785659 TI - Solitary fibrous tumour of the ethmoid sinuses and anterior fossa. AB - A 68-year-old woman presented with a 2 month history of progressive headache, left extremity weakness, and cognitive difficulties. Neuroimaging results demonstrated a macrocystic tumour attached to ethmoid sinuses and disclosed atypical findings. The tumour was totally removed. All the symptoms and signs ameliorated after surgery. Histological and immunohistochemical examinations led to a diagnosis of solitary fibrous tumour. A solitary fibrous tumour could be seen in various intracranial areas but ethmoid sinuses and anterior fossa are not an exceptional site. They appear as extra-axial tumours with a characteristic pattern on magnetic resonance imaging (MRI), but the cystic component is very unusual. Intracranial location and MRI features of this rare entity are presented and discussed along with various dura based tumours. PMID- 21785660 TI - Small bowel obstruction secondary to gastric adenocarcinoma. AB - A 77-year-old man presented with small bowel obstruction secondary to a solitary metastasis 7 years following resection of gastric carcinoma. At laparotomy, there was no evidence of local recurrence of gastric carcinoma and the liver was also noted to be grossly normal. Further exploration revealed the presence of a small bowel tumour in the ileum causing obstruction. A small bowel resection with side to-side anastomosis was performed. On microscopy, the appearance of the resected small bowel tumour was consistent with a metastasis from the previously resected gastric carcinoma. The patient made an uneventful recovery following surgery and was later referred for further oncology management. PMID- 21785661 TI - Question box: a tool for gathering information about HIV and AIDS. AB - Previous studies on knowledge of HIV transmission and prevention have used surveys. This study used the question box method to create a safe environment for collecting information on knowledge of HIV transmission and prevention. The aim was to encourage young people to ask questions about HIV, which they would otherwise not ask because of fear of being judged negatively, ridiculed, punished or stigmatized. Seven question boxes were placed at each community secondary school in Lilongwe Rural West District of Malawi. In total participants asked 394 questions. Six categories of questions emerged and included: general questions about HIV, sexual practices, perinatal transmission, other modes of transmission, contact/sharing items and prevention and condom use. The question box method created a safe environment for asking sensitive questions anonymously about HIV and AIDS. PMID- 21785662 TI - Thyrsiferol Inhibits Mitochondrial Respiration and HIF-1 Activation. AB - The cytotoxic marine red algal metabolite thyrsiferol (1) was found to inhibit hypoxia-induced hypoxia-inducible factor-1 (HIF-1) activation in T47D human breast tumor cells (66% inhibition at 3 MUM). Compound 1 also suppressed hypoxic induction of HIF-1 target genes (VEGF, GLUT-1) at the mRNA level, and displayed tumor cell line-selective time-dependent inhibition of cell viability/proliferation. Mechanistic studies revealed that 1 selectively suppressed mitochondrial respiration at Complex I (IC(50) 3 MUM). Thyrsiferol represents a prototypical, structurally unique electron transport chain inhibitor. The apparent rotenone-like activity may contribute to the observed cytotoxicity of 1 and play an important role in Laurencia chemical defense. PMID- 21785663 TI - Efficacy of latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass antibiotic treatment: a cluster-randomized trial. AB - The World Health Organization (WHO) recommends environmental improvements such as latrine construction in the integrated trachoma control strategy, SAFE. We report a cluster-randomized trial assessing the effect of intensive latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass treatment with antibiotics.Twenty-four communities in Goncha Seso Enesie woreda, Amhara Regional State, Ethiopia, were enumerated, and a random selection of 60 children aged 0- 9 years in each was monitored for clinical signs of trachoma and ocular chlamydial infection at baseline, 12 and 24 months. All community members were offered treatment with a single dose of oral azithromycin or topical tetracycline. After treatment, 12 subkebeles were randomized to receive intensive latrine promotion. Mean cluster ocular infection in the latrine and the non latrine arms were reduced from 45.5% (95% CI 34.1-56.8%) and 43.0% (95% CI 31.1 54.8%) respectively at baseline to 14.6% (95% CI 7.4-21.8%) and 14.8% (95% CI 8.9 20.8%) respectively at 24 months (P=0.93). Clinical signs fell from 72.0% (95% CI 58.2-85.5%) and 61.3% (95% CI 44.0-78.5%) at baseline to 45.8% (36.0-55.6%) and 48.5% (34.0-62.9%) respectively at 24 months (P=0.69). At 24 months, estimated household latrine coverage and use were 80.8% and 61.7% respectively where there had been intensive latrine promotion and 30.0% and 25.0% respectively in the single treatment only arm. We were unable to detect a difference in the prevalence of ocular chlamydial infection in children due to latrine construction. PMID- 21785664 TI - TREATMENT AND SURVIVAL PATTERNS IN RELATION TO MULTIMORBIDITY IN PATIENTS WITH LOCOREGIONAL BREAST AND COLORECTAL CANCER. AB - PURPOSE: To examine the effects of the occurrence and co-occurrence of comorbidities (COM), functional limitations (FL), and geriatric syndromes (GS) on treatment and outcomes in older cancer patients. MATERIALS AND METHODS: We used records from the Ohio Cancer Incidence Surveillance System linked with Medicare data, clinical assessment data from the home health care Outcomes and Assessment Information Set, and death certificate data. Our patient population included fee for-service HHC Medicare beneficiaries diagnosed with incident loco-regional breast or colorectal cancer in years 1999-2001 (n=1236). We grouped patients according to the presence of multimorbidity: (0): none of COM, FL, or GS; (1): occurrence - but no co-occurrence - of COM, FL, or GS; (2): co-occurrence of any two of COM, FL, and GS; and (3): co-occurrence of all three of COM, FL, and GS. Our outcomes were receipt of standard treatment, as well as overall survival (OS) and disease-specific survival (DSS) through 2005. Multivariable regression models were developed to analyze the independent association between multimorbidity and the outcomes, before and after adjusting for age. RESULTS: The effect of multimorbidity on our outcomes was attenuated considerably by age. Adjusting for age and compared with no multimorbidity (0), high multimorbidity (3) remained significantly and negatively associated with receipt of standard treatment (adjusted odds ratio: 0.57, 95% Confidence Interval (CI): 0.33, 0.97). Furthermore, high multimorbidity (3) was associated with increased hazard for OS, but not for DSS (adjusted hazard ratio and 95% CI: 2.15 (1.58, 2.93) for three entities). CONCLUSION: Multimorbidity is significantly and independently associated with cancer treatment and OS, but not DSS. PMID- 21785665 TI - The Sexuality of Childhood Sexual Abuse Survivors. AB - In this grounded theory study, a theoretical framework that depicts the process by which childhood sexual abuse (CSA) influences the sexuality of women and men survivors was constructed. Data were drawn from interview transcripts of 95 men and women who experienced CSA. Using constant comparison analysis, the researchers determined that the central phenomenon of the data was a process labeled Determining My Sexual Being, in which survivors moved from grappling with questions related to the nature, cause, and sexual effects of the abuse to laying claim to their own sexuality. Clinical implications are discussed. PMID- 21785666 TI - The Effect of Voice Output on the AAC-Supported Conversations of Persons with Alzheimer's Disease. AB - The purpose of this study was to determine whether the presence or absence of digitized 1-2 word voice output on a direct selection, customized augmentative and alternative communication (AAC) device would affect the impoverished conversations of persons with dementia. Thirty adults with moderate Alzheimer's disease participated in two personally relevant conversations with an AAC device. For 12 of the participants the AAC device included voice output. The AAC device was the FlexiboardTM containing 16 messages needed to discuss a favorite autobiographical topic chosen by the participant and his/her family caregivers. Ten-minute conversations were videotaped in participants' residences and analyzed for four conversational measures related to the participants' communicative behavior. Results show that AAC devices with digitized voice output depress conversational performance and distract participants with moderate Alzheimer's disease as compared to similar devices without voice output. There were significantly more 1-word utterances and fewer total utterances when AAC devices included voice output, and the rate of topic elaborations/initiations was significantly lower when voice output was present. Discussion about the novelty of voice output for this population of elders and the need to train elders to use this technology is provided. PMID- 21785667 TI - Using Amazon's Mechanical Turk for Annotating Medical Named Entities. AB - Amazon's Mechanical Turk (AMT) service is becoming increasingly popular in Natural Language Processing (NLP) research. In this poster, we report our findings in using AMT to annotate biomedical text extracted from clinical trial descriptions with three entity types: medical condition, medication, and laboratory test. We also describe our observations on AMT workers' annotations. PMID- 21785668 TI - Why Have College Completion Rates Declined? An Analysis of Changing Student Preparation and Collegiate Resources. AB - Rising college enrollment over the last quarter century has not been met with a proportional increase in college completion. Comparing the high school classes of 1972 and 1992, we show declines in college completion rates have been most pronounced for men who first enroll in less selective public universities and community colleges. We decompose the decline into the components due to changes in preparedness of entering students and due to changes in collegiate characteristics, including type of institution and resources per student. While both factors play some role, the supply-side characteristics are most important in explaining changes in college completion. (JEL I23). PMID- 21785669 TI - Examining the Factor Structure of Anxiety and Depression Symptom Items Among Adolescents in Santiago, Chile. AB - The co-occurrence of emotional disorders among adolescents has received considerable empirical attention. This study aims to contribute to the understanding of co-occurring anxiety and depression by examining the factor structure of the Youth Self-Report used with a sample of low-income adolescents from Santiago, Chile. Data from two independent, randomly selected subsamples were analyzed using exploratory and confirmatory factor analyses. Results indicate the best fit for the data is a two-factor model of anxiety and depression symptoms, which factors anxiety and depression into separate latent constructs. Because the findings show that anxiety and depression are not measured by the same factor in this international sample, the results imply that a valid and useful distinction exists between these constructs. That these constructs are found to be separate factors suggests that anxiety and depression may have separate etiologies and consequences, which might be best addressed by separate intervention components. These findings are consistent with the viewpoint that anxiety and depression constructs have similar emotional features and, despite sharing a common underlying internalizing disorder, distinct items capture aspects of each construct. PMID- 21785670 TI - Probing many-particle correlations in semiconductor quantum wells using double quantum-coherence signals. AB - Multidimensional analysis of coherent signals is commonly used in nuclear magnetic resonance to study correlations among spins. These techniques were recently extended to the femtosecond regime and applied to chemical, biological and semiconductor systems. In this work, we apply a two-dimensional correlation spectroscopy technique which employs double-quantum-coherence to investigate many body effects in a semiconductor quantum well. The signal is detected along the direction k(1)+ k(2)- k(3), where k(1), k(2) and k(3) are the pulse wave vectors in chronological order. We show that this signal is particularly sensitive to many-body correlations which are missed by time-dependent Hartree-Fock approximation. The correlation energy of two-exciton can be probed with a very high resolution arising from a two-dimensional correlation spectrum, where two exciton couplings spread the cross peaks along both axes of the 2D spectrum to create a characteristic highly resolved pattern. This level of detail is not available from conventional one-dimensional four-wave mixing or other two dimensional correlation spectroscopy signals such as the photo echo (-k(1)+ k(2)+ k(3)). PMID- 21785671 TI - Distributed source x-ray tube technology for tomosynthesis imaging. AB - Tomosynthesis imaging requires projection images from different viewing angles. Conventional systems use a moving xray source to acquire the individual projections. Using a stationary distributed x-ray source with a number of sources that equals the number of required projections, this can be achieved without any mechanical motion. Advantages are a potentially faster image acquisition speed, higher spatial and temporal resolution and simple system design. We present distributed x-ray sources based on carbon nanotube (CNT) field emission cathodes. The field emission cathodes deliver the electrons required for x-ray production. CNT emitters feature a stable emission at high current density, a cold emission, excellent temporal control of the emitted electrons and good configurability. We discuss the use of stationary sources for two applications: (i) a linear tube for stationary digital breast tomosynthesis (sDBT), and (ii) a square tube for on board tomosynthesis image-guided radiation therapy (IGRT). Results from high energy distributed sources up to 160kVp are also presented. PMID- 21785672 TI - NOVEL LEAD ZIRCONATE TITANATE COMPOSITE VIA FREEZING TECHNOLOGY FOR HIGH FREQUENCY TRANSDUCER APPLICATIONS. AB - Novel PZT-5A ceramic-polymer composite was prepared via freezing technology. This composite exhibited good dielectric and ferroelectric behaviors. At 1 kHz, the dielectric constant and the dielectric loss were 546 and 0.046, respectively, while the remnant polarization was 13.0 MUC/cm(2) at room temperature. The electromechanical coupling coefficient (k(t)) of PZT-5A composite was measured to be 0.54, which is similar to that of PZT piezoelectric ceramic. The piezoelectric coefficient (d(33)) of PZT-5A composite was determined to be ~250 pC/N. Using this composite, a 58MHz single element transducer with the bandwidth of 70% at 6dB was built, and the insertion loss was tested to be -29dB around the central frequency. PMID- 21785673 TI - The clinical utility of gene testing for Alzheimer's disease. AB - Alzheimer's disease (AD) is the largest cause of dementia, affecting 35.6 million people in 2010. Amyloid precursor protein, presenilin 1 and presenilin 2 mutations are known to cause familial early-onset AD, whereas apolipoprotein E (APOE) epsilon4 is a susceptibility gene for late-onset AD. The genes for phosphatidylinositol-binding clathrin assembly protein, clusterin and complement receptor 1 have recently been described by genome-wide association studies as potential risk factors for late-onset AD. Also, a genome association study using single neucleotide polymorphisms has identified an association of neuronal sortilin related receptor and late-onset AD. Gene testing, and also predictive gene testing, may be of benefit in suspected familial early-onset AD however it adds little to the diagnosis of late-onset AD and does not alter the treatment. We do not recommend APOE epsilon4 genotyping. PMID- 21785674 TI - Clinical, diagnostic and immunological characteristics of patients with possible neuroborreliosis without intrathecal Ig-synthesis against Borrelia antigen in the cerebrospinal fluid. AB - The diagnosis of neuroborreliosis is not always straightforward. Intrathecal immunoglobulin (Ig) synthesis against Borrelia antigen may not be detected, at least early in the disease course. Also other neurological and infectious diagnoses have to be considered. We have studied patients with clinical possible neuroborreliosis without intrathecal Ig synthesis against Borrelia antigen in the cerebrospinal fluid (CSF) (n=17). Diagnosis was based on typical clinical history and at least one of the following findings; mononuclear leucocytosis in the CSF (n=4); typical erythema migrans >5 cm in diameter in relation to debut of symptoms (n=8); prompt clinical response to antibiotic teratment (n=14). Also other possible diagnoses had to be excluded. Seventeen patients first investigated because of suspected neuroborreliosis but later confirmed with other diagnoses were used as controls. All patients had a lumbar puncture. Borrelia specific IFN-gamma and IL-4 secretion was investigated in peripheral blood (PBL) and CSF with an ELISPOT assay. Polymerase chain reaction (PCR) was used to reveal any Borrelia antigen in the CSF. Six of 17 patients with possible neuroborreliosis showed high IFN-gamma secretion in peripheral blood, otherwise we found no statistically significant differences between the groups. PCR did not reveal any Borrelia antigen in CSF. The diagnosis and treatment of possible but not confirmed neuroborreliosis is a clinical challenge. The clinical response to treatment may be the best option in these cases. PMID- 21785675 TI - Moyamoya syndrome in an adult with essential thrombocythemia. AB - Moyamoya syndrome is a rare cerebrovascular disorder characterized by progressive occlusion of the supraclinoid internal carotid artery and proximal portions of the anterior and middle cerebral arteries resulting in an extensive network of collateralized blood vessels and producing a characteristic angiographic appearance. Although the pathophysiology is unclear, hematologic disorders have been associated with development of the moyamoya syndrome. A case report is presented. A 29 year-old female with a history of essential thrombocythemia developed progressive ischemic strokes. Angiography revealed characteristic moyamoya changes and pathologic examination showed intimal hyperplasia with scant collagen fibers and myxoid change. This is the first reported case of moyamoya syndrome in an adult patient with essential thrombocythemia demonstrating histological findings that suggest a shared pathophysiology with moyamoya syndrome in sickle cell anemia. PMID- 21785676 TI - Amyotrophic lateral sclerosis: one or multiple causes? AB - The Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in the adulthood, and it is characterized by rapid and progressive compromise of the upper and lower motor neurons. The majority of the cases of ALS are classified as sporadic and, until now, a specific cause for these cases still is unknown. To present the different hypotheses on the etiology of ALS. It was carried out a search in the databases: Bireme, Scielo and Pubmed, in the period of 1987 to 2011, using the following keywords: Amyotrophic lateral sclerosis, motor neuron disease, etiology, causes and epidemiology and its similar in Portuguese and Spanish. It did not have consensus as regards the etiology of ALS. Researches demonstrates evidences as regards intoxication by heavy metals, environmental and occupational causes, genetic mutations (superoxide dismutase 1), certain viral infections and the accomplishment of vigorous physical activity for the development of the disease. There is still no consensus regarding the involved factors in the etiology of ALS. In this way, new research about these etiologies are necessary, for a better approach of the patients, promoting preventive programs for the disease and improving the quality of life of the patients. PMID- 21785677 TI - Influence of histocompatibility genes on disease susceptibility and treatment response in patients with relapsing-remitting multiple sclerosis treated with interferon beta-1a. AB - Multiple sclerosis (MS) is the most common, non-traumatic cause of neurological disability in young adults. The aim of this study was to investigate the influence of HLA class II alleles DRB1* and DQB1* on susceptibility to relapsing remitting (RR) MS and response to interferon (IFN) beta-1a treatment. A prospective observational study was conducted. Seventeen patients with clinically definite RRMS, attending a tertiary referral center for multiple sclerosis in Israel and receiving treatment with subcutaneous IFN beta-1a, 22 mcg three times weekly were recruited between December 1998 and February 2000 and observed for 12 months. HLA genotyping was performed and clinical characteristics (relapse rate and disability progression) assessed at baseline and after 12 months. HLA data for a healthy control group were also used for comparison. HLA and the success of treatment with IFN beta-1a in this group of RRMS patients were assessed. The frequency of DRB1*03 was six times higher in patients treated with IFN beta-1a than in the healthy control group (n=100): 29% (5/17) versus 5% (5/100), respectively. Additionally, DQB1*03 and DQB1*02 were present in 82% (14/17) and 41% (7/17) of RRMS patients, but in only 33% (33/100) and 18% (18/100) of control patients, respectively. A better response to IFN beta-1a treatment was seen in patients carrying these alleles than in patients without these alleles. Our results indicated that DRB1*03, DQB1*03 and DQB1*02 alleles may contribute to MS susceptibility and IFN beta-1a responsiveness, and warrant further verification in a larger population. PMID- 21785678 TI - Bioorthogonal chemical reporter methodology for visualization, isolation and analysis of glycoconjugates. AB - The recent development of metabolic oligosaccharide engineering combined with bioorthogonal reactions is providing unique opportunities to detect, image, and isolate glycoconjugates of living cells, tissues, and model organisms. In this methodology, exogenously-supplied non-natural sugars are fed to cells and employed by the biosynthetic machinery for the biosynthesis of neoglycoconjugates. In this way, reactive functional groups such as ketones, azides, and thiols have been incorporated into sialic acid, galactosamine, glucosamine, and fucose moieties of glycoconjugates. A range of bioorthogonal reactions have been described that functionalize the chemical 'tags' for imaging, isolation, and drug delivery. PMID- 21785681 TI - A morphological approach to the diagnosis of protozoal infections of the central nervous system. AB - Protozoal infections, though endemic to certain regions, can be seen all around the world, because of the increase in travel and migration. In addition, immunosuppression associated with various conditions, particularly with HIV infection, favors the occurrence of more severe manifestations and failure to respond to treatments. The CNS may be the only affected system; when not, it is often the most severely affected. Despite information obtained from clinical, laboratory, and imaging procedures that help to narrow the differential diagnosis of intracranial infections, there are cases that need confirmation with biopsy or autopsy. Predominant presentations are meningoencephalitis (trypanosomiasis), encephalopathy (cerebral malaria), or as single or multiple pseudotumoral enhancing lesions (toxoplasmosis, reactivated Chagas' disease). The immune reconstitution disease, resulting from enhancement of pathogen-specific immune responses after HAART, has altered the typical presentation of toxoplasmosis and microsporidiosis. In this paper, a morphological approach for the diagnosis of protozoal infections affecting the CNS (amoebiasis, cerebral malaria, toxoplasmosis, trypanosomiasis, and microsporidiosis) is presented. PMID- 21785679 TI - Targeted drug delivery across the blood-brain barrier using ultrasound technique. AB - Effective delivery of therapeutic agents into the brain can greatly improve the treatments of neurological and neurodegenerative diseases. Application of focused ultrasound facilitated by microbubbles has shown the potential to deliver drugs across the blood-brain barrier into targeted sites within the brain noninvasively. This review provides a summary of the technological background and principle, highlights of recent significant developments and research progress, as well as a critical commentary on the challenges and future directions in the field. This review also outlines and discusses the tasks that researchers face in order to successfully translate the technology into a clinical reality, including obtaining improved understanding of the mechanisms, demonstration of therapeutic efficacy and safety for specific applications, and development of methodology for rational design to achieve optimized and consistent outcomes. PMID- 21785680 TI - Digital imaging in cytopathology. AB - Rapid advances are occurring in the field of cytopathology, particularly in the field of digital imaging. Today, digital images are used in a variety of settings including education (E-education), as a substitute to multiheaded sessions, multisite conferences, publications, cytopathology web pages, cytology proficiency testing, telecytology, consultation through telecytology, and automated screening of Pap test slides. The accessibility provided by digital imaging in cytopathology can improve the quality and efficiency of cytopathology services, primarily by getting the expert cytopathologist to remotely look at the slide. This improved accessibility saves time and alleviates the need to ship slides, wait for glass slides, or transport pathologists. Whole slide imaging (WSI) is a digital imaging modality that uses computerized technology to scan and convert pathology and cytology glass slides into digital images (digital slides) that can be viewed remotely on a workstation using viewing software. In spite of the many advances, challenges remain such as the expensive initial set-up costs, workflow interruption, length of time to scan whole slides, large storage size for WSI, bandwidth restrictions, undefined legal implications, professional reluctance, and lack of standardization in the imaging process. PMID- 21785682 TI - From the bench to bedside: biological and methodology considerations for the future of companion diagnostics in nonsmall cell lung cancer. AB - Companion diagnostics are an emerging and exciting field in the care of oncology patients. These tests accompany standard diagnostic investigations in cancer patients and function as an aid in treatment decision making. A great number of new compounds are under clinical and laboratory testing in nonsmall cell lung cancer (NSCLC). As the variety of therapeutic options expands in the various settings of the disease, it becomes apparent that specific and sensitive molecular tests are necessary to define the subsets of patients who are going to derive clinical benefit. Testing for epidermal growth factor receptor (EGFR) somatic mutations for the appropriate administration of tyrosine kinase inhibitors is just the beginning. Anaplastic lymphoma kinase (ALK) fusion protein detection and molecular histology classification are promising candidate predictors for clinical benefit from crizotinib and pemetrexed, respectively. This paper summarizes such diagnostics and discusses unanswered questions concerning underlying biology and standardization issues. PMID- 21785683 TI - Amelioratory Effect of Nanoconjugated Vancomycin on Spleen during VRSA-Induced Oxidative Stress. AB - Objective. The aim of the present study was to evaluate the possible antioxidant effects of nanoconjugated vancomycin against VRSA infection on select makers of oxidative damage and antioxidant status in spleen. Methods. A coagulase-positive VRSA strain was used for this study. VRSA infection was developed in Swiss mice by intraperitoneal injection of 5 * 10(6) CFU/mL bacterial solutions. VRSA infected mice were treated with nanoconjugated vancomycin at its effective dose for 10 days. After decapitation, blood was used for determination of viable bacteria count and spleen was excised from control and experimental groups, homogenized and used for different biochemical estimations. Results. Nitrate level, myeloperoxidase activity, lipid peroxidation, protein oxidation, oxidized glutathione, and DNA fragmentation level were increased significantly (P < 0.05) in spleen of VRSA-infected group as compared to control group, and reduced glutathione level, activity of SOD, CAT, GPx, GR, and GST were decreased significantly (P < 0.05); which were increased or decreased significantly (P < 0.05) near to normal in nanoconjugated vancomycin-treated group. Conclusion. These findings suggest the potential use and beneficial role of nanoconjugated vancomycin against VRSA-infection-induced oxidative stress and DNA damage in spleen. PMID- 21785684 TI - Novel molecular markers of malignancy in histologically normal and benign breast. AB - To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and "budding-uninhibited-by benzimidazoles-1-homolog-beta" (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; N = 9) and high-grade molecular abnormality (HNB-HGMA; N = 9). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and BUB1B expression as H-scores (0-300). Increasing TOP2A, MCM2, and BUB1B protein expression from HNB LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA). In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers. PMID- 21785685 TI - Diagnosis and Molecular Characterization of Mycobacterium avium subsp. paratuberculosis from Dairy Cows in Colombia. AB - The objective of this study was the serological, bacteriological and molecular diagnosis, as well as the molecular characterization of Mycobacterium avium subsp. paratuberculosis (Map) in adult cows of five Colombian dairy herds. Serum samples were tested by an indirect absorbed enzyme-linked immunosorbent assay (ELISA-C). All fecal samples were tested by pooled culture. After that, fecal samples of Map positive pools were tested individually by culture and polymerase chain reaction (PCR). In one herd, slurry and tissue samples from one animal were also taken and tested by PCR and culture. Map isolates were analyzed by the Multilocus Short Sequence Repeat (MLSSR) and the Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) methods. ELISA produced positive results in 1.8% (6/329) of the animals and 40% (2/5) of the herds. Four fecal, two tissue, and two slurry samples from a herd were Map positive by culture and PCR. MLSSR and MIRU-VNTR revealed two different strain profiles among eight Map isolates recovered. This study reports the first molecular characterization of Map in one dairy herd in Colombia, the limitations for individual diagnosis of subclinical Map infections in cattle, and the usefulness of pooled fecal samples and environmental sampling for Map diagnosis. PMID- 21785686 TI - Mycobacteria in terrestrial small mammals on cattle farms in Tanzania. AB - The control of bovine tuberculosis and atypical mycobacterioses in cattle in developing countries is important but difficult because of the existence of wildlife reservoirs. In cattle farms in Tanzania, mycobacteria were detected in 7.3% of 645 small mammals and in cow's milk. The cattle farms were divided into "reacting" and "nonreacting" farms, based on tuberculin tests, and more mycobacteria were present in insectivores collected in reacting farms as compared to nonreacting farms. More mycobacteria were also present in insectivores as compared to rodents. All mycobacteria detected by culture and PCR in the small mammals were atypical mycobacteria. Analysis of the presence of mycobacteria in relation to the reactor status of the cattle farms does not exclude transmission between small mammals and cattle but indicates that transmission to cattle from another source of infection is more likely. However, because of the high prevalence of mycobacteria in some small mammal species, these infected animals can pose a risk to humans, especially in areas with a high HIV-prevalence as is the case in Tanzania. PMID- 21785687 TI - Protein C activity in dogs: adaptation of a commercial human colorimetric assay and evaluation of effects of storage time and temperature. AB - Objectives of this study were to adapt a commercial human protein C (PC) colorimetric assay for use in dogs and to investigate effects of various storage conditions. The human assay was modified by using pooled canine plasma for calibration and by increasing the activation time. PC activity was measured in fresh canine plasma and in plasma stored under various conditions. PC activity of some stored samples was significantly different from that of fresh plasma; however, differences were small. No difference was detected in samples stored under similar conditions but analyzed in different laboratories using similar methodology. Results of this study indicate that the human colorimetric assay is suitable for canine samples if pooled canine plasma is used for calibration, that Clinical and Laboratory Standards Institute sample storage guidelines developed for testing in humans are appropriate for dogs, and that comparisons of results from laboratories using similar methodology are legitimate. PMID- 21785688 TI - Transient non-autoimmune hyperthyroidism of early pregnancy. AB - It is characterized by chemical and sometimes clinical hyperthyroidism, without evidence of thyroid autoimmunity that resolves spontaneously by 16 weeks gestation without significant obstetrical complications. PMID- 21785690 TI - Can Levothyroxine Be Taken as Evening Dose? Comparative Evaluation of Morning versus Evening Dose of Levothyroxine in Treatment of Hypothyroidism. AB - 152 drug naive primary hypothyroid patients were divided into morning (Group 1) and evening (Group 2) dosing group and evaluated for change in biochemical profile, physical functioning and Quality of Life during the course of 12 weeks of study. At the end of 12 weeks 70 (90.90%) subjects in Group 1 and 72 (96%) in Group 2 achieved euthyroidism. On evaluation clinical symptoms and total clinical scores improved in both the groups at the end of 6 and 12 weeks. Significant improvement in thyroid profile was seen in both the groups at the end of 6 and 12 weeks (P value <.0001). On intergroup comparison, no significant difference in thyroid profile was seen at 6 and 12 weeks between the morning and the evening dose group. Similar dose of levothyroxine was required to achieve euthyroidism in both the groups. Though an early restoration of euthyroidism was seen in evening group, the difference when compared to the morning group was not statistically significant. On assessment of QoL, statistically significant improvement in various parameters was seen in both the groups. Hence, from the study we inferred that evening dose is as efficacious as morning dose and provides an alternate dosing regimen. PMID- 21785691 TI - Abnormalities of the first three steps of gait initiation in patients with Parkinson's disease with freezing of gait. AB - The purpose of this study was to investigate abnormalities of the first three steps of gait initiation in patients with Parkinson's disease (PD) with freezing of gait (FOG). Ten PD patients with FOG and 10 age-matched healthy controls performed self-generated gait initiation. The center of pressure (COP), heel contact positions, and spatiotemporal parameters were estimated from the vertical pressures on the surface of the force platform. The initial swing side of gait initiation was consistent among the trials in healthy controls but not among the trials in PD patients. The COP and the heel contact position deviated to the initial swing side during the first step, and the COP passed medial to each heel contact position during the first two steps in PD patients. Medial deviation of the COP from the first heel contact position had significant correlation with FOG questionnaire item 5. These findings indicate that weight shifting between the legs is abnormal and that medial deviation of the COP from the first heel contact position sensitively reflects the severity of FOG during the first three steps of gait initiation in PD patients with FOG. PMID- 21785689 TI - Thyroid disorders and diabetes mellitus. AB - Studies have found that diabetes and thyroid disorders tend to coexist in patients. Both conditions involve a dysfunction of the endocrine system. Thyroid disorders can have a major impact on glucose control, and untreated thyroid disorders affect the management of diabetes in patients. Consequently, a systematic approach to thyroid testing in patients with diabetes is recommended. PMID- 21785692 TI - The on-freezing phenomenon: cognitive and behavioral aspects. AB - Freezing of gait is a warning sign of Parkinson's disease. One could distinguish off-freezing, which is associated with dopaminergic therapy and to its titration, and it is clinically related to wearing-off phenomenon. Differently, the on freezing phenomenon seems to be related to a neural disruption of the frontal parietal-basal ganglia-pontine projections; clinically, it does not respond to therapy modifications or to different drug titration. In a group of patients with on-freezing, we have detected an alteration of focusing attention, an impairment of set-shifting, in addition to poor abstract reasoning and a reduction of planning. These aspects have been even more evident, when compared with the results obtained by a group of PD patients, without freezing. PMID- 21785693 TI - Cytotoxicity and induction of inflammation by pepsin in Acid in bronchial epithelial cells. AB - Introduction. Gastroesophageal reflux has been associated with chronic inflammatory diseases and may be a cause of airway remodelling. Aspiration of gastric fluids may cause damage to airway epithelial cells, not only because acidity is toxic to bronchial epithelial cells, but also since it contains digestive enzymes, such as pepsin. Aim. To study whether pepsin enhances cytotoxicity and inflammation in airway epithelial cells, and whether this is pH dependent. Methods. Human bronchial epithelial cells were exposed to increasing pepsin concentrations in varying acidic milieus, and cell proliferation and cytokine release were assessed. Results. Cell survival was decreased by pepsin exposure depending on its concentration (F = 17.4) and pH level of the medium (F = 6.5) (both P < 0.01). Pepsin-induced interleukin-8 release was greater at lower pH (F = 5.1; P < 0.01). Interleukin-6 induction by pepsin was greater at pH 1.5 compared to pH 2.5 (mean difference 434%; P = 0.03). Conclusion. Pepsin is cytotoxic to bronchial epithelial cells and induces inflammation in addition to acid alone, dependent on the level of acidity. Future studies should assess whether chronic aspiration causes airway remodelling in chronic inflammatory lung diseases. PMID- 21785694 TI - Modelling cost-effectiveness of biologic treatments based on disease activity scores for the management of rheumatoid arthritis in Spain. AB - Background. The objective of this simulation model was to assess the cost effectiveness of different biological treatment strategies based on levels of disease activity in Spain, in patients with moderate to severe active RA and an insufficient response to at least one anti-TNF agent. Methods. Clinically meaningful effectiveness criteria were defined using DAS28 scores: remission and Low Disease Activity State (LDAS) thresholds. Monte-Carlo simulations were conducted to assess cost-effectiveness over 2 years of four biological sequential strategies composed of anti-TNF agents (adalimumab, infliximab), abatacept or rituximab, in patients with moderate to severe active RA and an insufficient response to etanercept as first biological agent. Results. The sequential strategy including etanercept, abatacept and adalimumab appeared more efficacious over 2 years (102 days in LDAS) compared to the same sequence including rituximab as second biological option (82 days in LDAS). Cost-effectiveness ratios showed lower costs per day in LDAS with abatacept (427 ?) compared to rituximab as second biological option (508 ?). All comparisons were confirmed when using remission criteria. Conclusion. Model results suggest that in patients with an insufficient response to anti-TNF agents, the biological sequences including abatacept appear more efficacious and cost-effective than similar sequences including rituximab or cycled anti-TNF agents. PMID- 21785695 TI - Evidence for the immunosuppressive potential of calcineurin inhibitor-sparing regimens in liver transplant recipients with impaired renal function. AB - Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state. PMID- 21785697 TI - Short Communication: In Vitro Efficacy Testing of Praziquantel, Ivermectin, and Oxfendazole against Taenia Solium Cysts. AB - Oxfendazole is recommended as the drug of choice for treating porcine cysticercosis. The drug does not kill brain cysts and is not registered for use in pigs. Latest its safety in the recommended dose has been questioned. The aim of this study was to investigate two alternative anthelminthics. The efficacy of praziquantel and ivermectin was compared to oxfendazole In Vitro on Taenia solium. Cysts of T. solium were isolated from infected pork and incubated in culture media together with the drugs. The degree of evagination was used as effect measurement and determined after 6 hours. Praziquantel had a half maximal effective concentration (EC(50)) of value 0.006 +/- 0.001 MUg/mL. Ivermectin did not show any impact on the evagination in concentrations from 0.001 to 30 MUg/mL and neither did oxfendazole in concentrations from 0.001 to 50 MUg/mL. PMID- 21785699 TI - Validation of a diagnostic microarray for human papillomavirus: coverage of 102 genotypes. AB - Papillomaviruses have been implicated in a variety of human diseases ranging from common warts to invasive carcinoma of the anogenital mucosa. Existing assays for genotyping human papillomavirus are restricted to a small number of types. Here, we present a comprehensive, accurate microarray strategy for detection and genotyping of 102 human papillomavirus types and validate its use in a panel of 91 anal swabs. This array has equal performance to traditional dot blot analysis with the benefits of added genotype coverage and the ability to calibrate readout over a range of sensitivity or specificity values. PMID- 21785696 TI - Parasites or cohabitants: cruel omnipresent usurpers or creative "eminences grises"? AB - This paper presents many types of interplays between parasites and the host, showing the history of parasites, the effects of parasites on the outcome of wars, invasions, migrations, and on the development of numerous regions of the globe, and the impact of parasitic diseases on the society and on the course of human evolution. It also emphasizes the pressing need to change the look at the parasitism phenomenon, proposing that the term "cohabitant" is more accurate than parasite, because every living being, from bacteria to mammals, is a consortium of living beings in the pangenome. Even the term parasitology should be replaced by cohabitology because there is no parasite alone and host alone: both together compose a new adaptive system: the parasitized-host or the cohabitant-cohabited being. It also suggests switching the old paradigm based on attrition and destruction, to a new one founded on adaptation and living together. PMID- 21785700 TI - An unusual cause of dementia: essential diagnostic elements of corticobasal degeneration-a case report and review of the literature. AB - Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease. PMID- 21785701 TI - Genetic Association between Akt1 Polymorphisms and Alzheimer's Disease in a Japanese Population. AB - A recent paper reported that Abeta oligomer causes neuronal cell death through the phosphatidylinositol-3-OH kinase (PI3K)-Akt-mTOR signaling pathway. Intraneuronal Abeta, a main pathological finding of Alzheimer's disease (AD), is also known as inhibiting activation of Akt. This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the Akt1 gene are associated with AD. SNPs genotyped using TaqMan technology was analyzed using a case-control study design. Our case-control dataset consisted of 180 AD patients and 130 age matched controls. Although two SNPs showed superficial positive, Hardy-Weinberg equilibrium (HWE) tests, and linkage disequilibrium (LD) analyses suggested that genetic regions of the gene are highly polymorphic. We failed to detect any synergetic association among Akt1 polymorphisms, Apolipoprotein E (APO E), and AD. Further genetic studies are needed to clarify the relationship between the Akt1 and AD. PMID- 21785698 TI - Variables and strategies in development of therapeutic post-transcriptional gene silencing agents. AB - Post-transcriptional gene silencing (PTGS) agents such as ribozymes, RNAi and antisense have substantial potential for gene therapy of human retinal degenerations. These technologies are used to knockdown a specific target RNA and its cognate protein. The disease target mRNA may be a mutant mRNA causing an autosomal dominant retinal degeneration or a normal mRNA that is overexpressed in certain diseases. All PTGS technologies depend upon the initial critical annealing event of the PTGS ligand to the target RNA. This event requires that the PTGS agent is in a conformational state able to support hybridization and that the target have a large and accessible single-stranded platform to allow rapid annealing, although such platforms are rare. We address the biocomplexity that currently limits PTGS therapeutic development with particular emphasis on biophysical variables that influence cellular performance. We address the different strategies that can be used for development of PTGS agents intended for therapeutic translation. These issues apply generally to the development of PTGS agents for retinal, ocular, or systemic diseases. This review should assist the interested reader to rapidly appreciate critical variables in PTGS development and facilitate initial design and testing of such agents against new targets of clinical interest. PMID- 21785703 TI - Evaluating voting competence in persons with Alzheimer disease. AB - Voting by persons with dementia raises questions about their decision-making capacity. Methods specifically addressing voting capacity of demented people have been proposed in the US, but never tested elsewhere. We translated and adapted the US Competence Assessment Tool for Voting (CAT-V) to the Italian context, using it before 2006 elections for Prime Minister. Consisting of a brief questionnaire, this tool evaluates the following decision-making abilities: understanding nature and effect of voting, expressing a choice, and reasoning about voting choices. Subjects' performance was examined in relation to dementia severity. Of 38 subjects with Alzheimer's disease (AD) enrolled in the study, only three scored the maximum on all CAT-V items. MMSE and CAT-V scores correlated only moderately (r = 0.59; P < 0.0001) with one another, reflecting the variability of subjects' performance at any disease stage. Most participants (90%), although performing poorly on understanding and reasoning items, scored the maximum on the choice measure. Our results imply that voting capacity in AD is only roughly predicted by MMSE scores and may more accurately be measured by a structured questionnaire, such as the CAT-V. Among the decision-making abilities evaluated by the CAT-V, expressing a choice was by far the least affected by the dementing process. PMID- 21785702 TI - Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis. AB - Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Abeta) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg-19959) of various ages. Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis markers to be noticeably upregulated in Tg-19959 mice very early in the development of the disease. Knockdown of either one of BACE1 or BACE1-AS transcripts by continuous infusion of locked nucleic acid- (LNA-) modified siRNAs into the third ventricle over the period of two weeks caused concordant downregulation of both transcripts in Tg 19959 mice. Downregulation of BACE1 mRNA was followed by reduction of BACE1 protein and insoluble Abeta. Modulation of BACE1 and BACE1-AS transcripts also altered oligomeric Abeta aggregation pattern, which was in turn associated with an increase in neurogenesis markers at the RNA and protein level. Conclusion. We found alterations in the RNA and protein concentrations of several adult neurogenesis markers, as well as non-protein-coding BACE1-AS transcripts, in parallel with the course of beta-amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1-AS (thereby reducing Abeta production and plaque deposition), we were able to modulate expression of these neurogenesis markers. Our findings suggest a distortion of adult neurogenesis that is associated with Abeta production very early in amyloid pathogenesis. We believe that these alterations, at the molecular level, could prove useful as novel therapeutic targets and/or as early biomarkers of AD. PMID- 21785704 TI - Management of Hypertension among Patients with Coronary Heart Disease. AB - Evidence suggests that coronary heart disease (CHD) is the most common outcome of hypertension. Hypertension accelerates the development of atherosclerosis, and sustained elevation of blood pressure (BP) can destabilize vascular lesions and precipitate acute coronary events. Hypertension can cause myocardial ischemia in the absence of CHD. These cardiovascular risks attributed to hypertension can be reduced by optimal BP control. Although several antihypertensive agents exist, the choice of agent and the appropriate target BP for patients with CHD remain controversial. In this succinct paper, we examine the evidence and the mechanisms for the linkage between hypertension and CHD and we discuss the treatment options and the goals of therapy that are consistent with the report of the seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and American Heart Association scientific statement. We anticipate changes in the recommendations of the forthcoming JNC 8. PMID- 21785705 TI - Role of the Renin-Angiotensin system and aldosterone on cardiometabolic syndrome. AB - Aldosterone facilitates cardiovascular damage by increasing blood pressure and through different mechanisms that are independent of its effects on blood pressure. In this respect, recent evidence involves aldosterone in the pathogenesis of metabolic syndrome. Although this relationship is complex, there is some evidence suggesting that different factors may play an important role, such as insulin resistance, renin-angiotensin-aldosterone system, oxidative stress, sodium retention, increased sympathetic activity, levels of free fatty acids, or inflammatory cytokines and adipokines. In addition to the classical pathway by which aldosterone acts through the mineralocorticoid receptors leading to sodium retention, aldosterone also has other mechanisms that influence cardiovascular tissue remodelling. Finally, overweight and obesity promote the adrenal secretion of aldosterone, increasing the predisposition to type 2 diabetes mellitus. Further studies are needed to better establish therapeutic strategies that act on the blockade of mineralocorticoid receptor in the treatment and prevention of cardiovascular diseases related to the excess of aldosterone and the metabolic syndrome. PMID- 21785707 TI - Production and use of lipases in bioenergy: a review from the feedstocks to biodiesel production. AB - Lipases represent one of the most reported groups of enzymes for the production of biofuels. They are used for the processing of glycerides and fatty acids for biodiesel (fatty acid alkyl esters) production. This paper presents the main topics of the enzyme-based production of biodiesel, from the feedstocks to the production of enzymes and their application in esterification and transesterification reactions. Growing technologies, such as the use of whole cells as catalysts, are addressed, and as concluding remarks, the advantages, concerns, and future prospects of enzymatic biodiesel are presented. PMID- 21785708 TI - Immobilization of Erwinia sp. D12 Cells in Alginate-Gelatin Matrix and Conversion of Sucrose into Isomaltulose Using Response Surface Methodology. AB - Isomaltulose is a noncariogenic reducing disaccharide and also a structural isomer of sucrose and is used by the food industry as a sucrose replacement. It is obtained through enzymatic conversion of microbial sucrose isomerase. An Erwinia sp. D12 strain is capable of converting sucrose into isomaltulose. The experimental design technique was used to study the influence of immobilization parameters on converting sucrose into isomaltulose in a batch process using shaken Erlenmeyer flasks. We assessed the effect of gelatin and transglutaminase addition on increasing the reticulation of granules of Erwinia sp. D12 cells immobilized in alginate. Independent parameters, sodium alginate concentration, cell mass concentration, CaCl(2) concentration, gelatin concentration, and transglutaminase concentration had all a significant effect (P < 0.05) on isomaltulose production. Erwinia sp. D12 cells immobilized in 3.0% (w/v) sodium alginate, 47.0% (w/v) cell mass, 0.3 molL(-1) CaCl(2), 1.7% (w/v) gelatin and 0.15% (w/v) transglutaminase presented sucrose conversion into isomaltulose, of around 50-60% in seven consecutive batches. PMID- 21785706 TI - Acid phosphatases of budding yeast as a model of choice for transcription regulation research. AB - Acid phosphatases of budding yeast have been studied for more than forty years. This paper covers biochemical characteristics of acid phosphatases and different aspects in expression regulation of eukaryotic genes, which were researched using acid phosphatases model. A special focus is devoted to cyclin-dependent kinase Pho85p, a negative transcriptional regulator, and its role in maintaining mitochondrial genome stability and to pleiotropic effects of pho85 mutations. PMID- 21785709 TI - Three types of striational antibodies in myasthenia gravis. AB - Myasthenia gravis (MG) is caused by antibodies that react mainly with the acetylcholine receptor on the postsynaptic site of the neuromuscular junction. A wide range of clinical presentations and associated features allow MG to be classified into subtypes based on autoantibody status. Striational antibodies, which react with epitopes on the muscle proteins titin, ryanodine receptor (RyR), and Kv1.4, are frequently found in MG patients with late-onset and thymoma. Antititin and anti-RyR antibodies are determined by enzyme-linked immunosorbent assay or immunoblot. More recently, a method for the detection of anti-Kv1.4 autoantibodies has become available, involving 12-15% of all MG patients. The presence of striational antibodies is associated with more severe disease in all MG subgroups. Anti-Kv1.4 antibody is a useful marker for the potential development of lethal autoimmune myocarditis and response to calcineurin inhibitors. Detection of striational antibodies provides more specific and useful clinical information in MG patients. PMID- 21785710 TI - Male-male competition as a force in evolutionary diversification: evidence in haplochromine cichlid fish. AB - It has been suggested that intrasexual competition can be a source of negative frequency-dependent selection, causing agonistic character displacement and facilitating speciation and coexistence of (sibling) species. In this paper we synthesise the evidence that male-male and female-female competition contributes to cichlid diversification, showing that competition is stronger among same coloured individuals than those with different colours. We argue that intrasexual selection is more complex because there are several examples where males do not bias aggression towards their own type. In addition, sibling species or colour morphs often show asymmetric dominance relationships. We briefly discuss potential mechanisms that might promote the maintenance of covariance between colour and aggression-related traits even in the face of gene-flow. We close by proposing several avenues for future studies that might shed more light on the role of intrasexual competition in cichlid diversification. PMID- 21785711 TI - A chronological perspective on the acheulian and its transition to the middle stone age in southern Africa: the question of the fauresmith. AB - An understanding of the age of the Acheulian and the transition to the Middle Stone Age in southern Africa has been hampered by a lack of reliable dates for key sequences in the region. A number of researchers have hypothesised that the Acheulian first occurred simultaneously in southern and eastern Africa at around 1.7-1.6 Ma. A chronological evaluation of the southern African sites suggests that there is currently little firm evidence for the Acheulian occurring before 1.4 Ma in southern Africa. Many researchers have also suggested the occurrence of a transitional industry, the Fauresmith, covering the transition from the Early to Middle Stone Age, but again, the Fauresmith has been poorly defined, documented, and dated. Despite the occurrence of large cutting tools in these Fauresmith assemblages, they appear to include all the technological components characteristic of the MSA. New data from stratified Fauresmith bearing sites in southern Africa suggest this transitional industry maybe as old as 511-435 ka and should represent the beginning of the MSA as a broad entity rather than the terminal phase of the Acheulian. The MSA in this form is a technology associated with archaic H. sapiens and early modern humans in Africa with a trend of greater complexity through time. PMID- 21785712 TI - Augmentation index derived from peripheral arterial tonometry correlates with cardiovascular risk factors. AB - Background. Augmentation index (AIx) is traditionally obtained from pressure waveforms via arterial applanation tonometry. We sought to evaluate the association between AIx obtained from peripheral arterial tonometry (PAT) with cardiovascular risk factors (CRF) and coronary artery disease (CAD). Methods. 186 patients were enrolled in the study. The presence or absence of CRFs and CAD was assessed in each subject. AIx was calculated by an automated algorithm averaging pulse wave amplitude data obtained via PAT. Central blood pressures were assessed in a subset of patients undergoing clinically indicated cardiac catheterization. Results. An association was observed between AIx and age, heart rate, systolic blood pressure, mean arterial pressure, pulse pressure, body weight and body mass index. AIx was significantly lower in patients with <3 CRFs compared to those with >5 CRFs ( P = .02). CAD+ patients had significantly higher AIx compared to CAD- patients ( P = .008). Area under the ROC curve was 0.604 (P < .01). In patients undergoing cardiac catheterization, after adjusting for age, height and heart rate, AIx was a significant predictor of aortic systolic and pulse pressures (P < .05) Conclusion. AIx derived from PAT correlates with cardiac risk factors and CAD. It may be a useful measure of assessing overall risk for coronary artery disease. PMID- 21785713 TI - Stenting of anomalous left main coronary artery stenosis in an adult with a retroaortic course. AB - Coronary bypass graft has been the conventional treatment of choice in anomalous left man coronary artery stenosis. We are reporting an interesting case with anomalous left main coronary artery originating from right aortic sinus having retroaortic course complicated by significant atherosclerotic narrowing of the vessel and its percutaneous management. PMID- 21785714 TI - MicroRNA Expression Profile in CAD Patients and the Impact of ACEI/ARB. AB - Coronary artery disease (CAD) is the largest killer of males and females in the United States. There is a need to develop innovative diagnostic markers for this disease. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in important cellular processes, and we hypothesized that the miRNA expression profile would be altered in whole blood samples of patients with CAD. We performed a microarray analysis on RNA from the blood of 5 male subjects with CAD and 5 healthy subjects (mean age 53 years). Subsequently, we performed qRT-PCR analysis of miRNA expression in whole blood of another 10 patients with CAD and 15 healthy subjects. We identified 11 miRNAs that were significantly downregulated in CAD subjects (P < .05). Furthermore, we found an association between ACEI/ARB use and downregulation of several miRNAs that was independent of the presence of significant CAD. In conclusion, we have identified a distinct miRNA signature in whole blood that discriminates CAD patients from healthy subjects. Importantly, medication use may significantly alter miRNA expression. These findings may have significant implications for identifying and managing individuals that either have CAD or are at risk of developing the disease. PMID- 21785715 TI - Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier. AB - Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity. PMID- 21785716 TI - Usage, risk, and benefit of weight-loss drugs in primary care. AB - Purpose. To investigate the use of the weight-loss drugs rimonabant, sibutramine, and orlistat in primary care and to characterize the patients receiving the drugs. Methods. In this retrospective, descriptive study, 300 randomly selected patients having started weight-loss drug treatment at 15 primary care centres were investigated using the patient's medical records and their complete drug purchase data. Results. Even though 48% of the patients specifically demanded drug treatment, 77% continued treatment less than one year. 28% of rimonabant patients and 32% of sibutramine patients had a history of depression or antidepressant treatment. 41% of sibutramine patients had a history of hypertension and/or cardiovascular disease. 36% had no documented weight after treatment initiation. Conclusions. These results suggest that weight-loss drug treatment was often initiated upon patient request but was of limited clinical benefit as it was managed in a large portion of Swedish primary carecenters. PMID- 21785717 TI - Pregnancy after bariatric surgery: a review. AB - Maternal obesity is a major cause of obstetric morbidity and mortality. With surgical procedures to facilitate weight loss becoming more widely available and demanded and increasing number of women becoming pregnant after undergoing bariatric surgery, it is important and timely to consider the outcome of pregnancy following bariatric surgery. This paper aims to synthesize the current evidence regarding pregnancy outcomes after bariatric surgery. It concludes that bariatric surgery appears to have positive effects on fertility and reduces the risk of gestational diabetes and preeclampsia. Moreover, there appears to be a reduced incidence of fetal macrosomia post-bariatric procedure, although there remains uncertainty about the increased rates of small-for-gestational age and intrauterine growth restricted infants, as well as premature rupture of membranes in this group. A number of case reports highlight that pregnancy following bariatric surgery is not without complications and it must be managed as high risk by the multidisciplinary team. PMID- 21785718 TI - Nutrition and Iron Status of 1-Year Olds following a Revision in Infant Dietary Recommendations. AB - A previous study showed low iron status in 12-month-old Icelandic infants associated most strongly with cow's milk intake and growth. Infant dietary recommendations were revised in 2003. This study investigated nutrition and iron status in a new infant cohort. Subjects/Methods. Randomly selected infants were prospectively investigated for diet, anthropometry, and iron status (n = 110 141). Results. Breastfeeding initiation rate was 98%; 38% of 5-month olds were exclusively and 20% of 12-month olds partially breastfed. Formula was given to 21% of 6-month olds and 64% of 12-month olds, but cow's milk to 2.5% and 54.4% of 6- and 12-month olds, respectively. Iron depletion (serum ferritin < 12 MUg/L) affected 5.8%, 1.4% were also iron deficient (MCV < 74 fl), and none were anemic (Hb < 105 g/l). Iron status associated negatively with growth and breastfeeding duration and positively with meat and formula intake at 9-12 months, but not with cow's milk. Conclusion. Improved iron status might be explained by a shift from cow's milk to formula in the diet of Icelandic 6-12-month olds. Dietary changes altered associations between foods and iron status. PMID- 21785719 TI - Mental Health Treatment Involvement and Religious Coping among African American, Hispanic, and White Veterans of the Wars of Iraq and Afghanistan. AB - Although racial/ethnic differences have been found in the use of mental health services for depression in the general population, research among Veterans has produced mixed results. This study examined racial/ethnic differences in the use of mental health services among 148 Operation Enduring/Iraqi Freedom (OEF/OIF) Veterans with high levels of depression and posttraumatic stress disorder (PTSD) symptoms and evaluated whether religious coping affected service use. No differences between African American, Hispanic, and Non-Hispanic white Veterans were found in use of secular mental health services or religious counseling. Women Veterans were more likely than men to seek secular treatment. After controlling for PTSD symptoms, depression symptom level was a significant predictor of psychotherapy attendance but not medication treatment. African American Veterans reported higher levels of religious coping than whites. Religious coping was associated with participation in religious counseling, but not secular mental health services. PMID- 21785720 TI - Potential Antidepressant Role of Neurotransmitter CART: Implications for Mental Disorders. AB - Depression is one of the most prevalent and debilitating public health concerns. Although no single cause of depression has been identified, it appears that interaction among genetic, epigenetic, biochemical, environmental, and psychosocial factors may explain its etiology. Further, only a fraction of depressed patients show full remission while using current antidepressants. Therefore, identifying common pathways of the disorder and using that knowledge to develop more effective pharmacological treatments are two primary targets of research in this field. Brain-enriched neurotransmitter CART (cocaine- and amphetamine-regulated transcript) has multiple functions related to emotions. It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system, which is considered to have an important role in regulating mood. Notably, adolescents carrying a missense mutation in the CART gene exhibit increased depression and anxiety. Hence, CART peptide may be a novel promising antidepressant agent. In this paper, we summarize recent progress in depression and CART. In particular, we emphasize a new antidepressant function for CART. PMID- 21785721 TI - Evolution of Hepatitis B Virus in a Chronic HBV-Infected Patient over 2 Years. AB - Mutations in full-length HBV isolates obtained from a chronic HBV-infected patient were evaluated at three time points: 1 day, 6 months, and 31 months. While 5 nucleotides variation, and an 18 bp deletion of preS1 have been kept in during at least the first two years, C339T mutation occurring in the hydrophilic region of HBsAg and T770C that caused polymerase V560A substitution were the new point mutations found existing in sequenced clones of the 3rd time point. Internal deletion of coding region obviously appeared in the 3rd time point. The splicers included two new 5'-splice donors and three new 3'-splice acceptors besides the reported donors and acceptors and may have produced presumptive HBV spliced proteins or truncated preS proteins. ALT, HBeAg and viral DNA load varied during the follow-up years. These data demonstrated the diversity of genomes in HBV-infected patient during evolution. Combined with clinical data, the HBV variants discovered in this patient may contribute to viral persistence of infection or liver pathogenesis. PMID- 21785722 TI - SPECT Imaging of Epilepsy: An Overview and Comparison with F-18 FDG PET. AB - Epilepsy surgery is highly effective in treating refractory epilepsy, but requires accurate presurgical localization of the epileptogenic focus. Briefly, localization of the region of seizure onset traditionally dependents on seizure semiology, scalp EEG recordings and correlation with anatomical imaging modalities such as MRI. The introduction of noninvasive functional neuroimaging methods, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) has dramatically changed the method for presurgical epilepsy evaluation. These imaging modalities have become powerful tools for the investigation of brain function and are an essential part of the evaluation of epileptic patients. Of these methods, SPECT has the practical capacity to image blood flow functional changes that occur during seizures in the routine clinical setting. In this review we present the basic principles of epilepsy SPECT and PET imaging. We discuss the properties of the SPECT tracers to be used for this purpose and imaging acquisition protocols as well as the diagnostic performance of SPECT in addition to SPECT image analysis methods. This is followed by a discussion and comparison to F-18 FDG PET acquisition and imaging analysis methods. PMID- 21785724 TI - Involvement of phosphatases in proliferation, maturation, and hemoglobinization of developing erythroid cells. AB - Production of RBCs is triggered by the action of erythropoietin (Epo) through its binding to surface receptors (Epo-R) on erythroid precursors in the bone marrow. The intensity and the duration of the Epo signal are regulated by several factors, including the balance between the activities of kinesase and phosphatases. The Epo signal determines the proliferation and maturation of the precursors into hemoglobin (Hb)-containing RBCs. The activity of various protein tyrosine phosphatases, including those involved in the Epo pathway, can be inhibited by sodium orthovanadate (Na(3)VO(4), vanadate). Adding vanadate to cultured erythroid precursors of normal donors and patients with beta-thalassemia enhanced cell proliferation and arrested maturation. This was associated with an increased production of fetal hemoglobin (HbF). Increased HbF in patients with beta-hemoglobinopathies (beta-thalassemia and sickle cell disease) ameliorates the clinical symptoms of the disease. These results raise the possibility that specific and nontoxic inhibitors of phosphatases may be considered as a therapeutic modality for elevating HbF in patients with beta-hemoglobinopathies as well as for intensifying the Epo response in other forms of anemia. PMID- 21785725 TI - The Role of Seizure-Related SEZ6 as a Susceptibility Gene in Febrile Seizures. AB - Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related (SEZ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation in SEZ6 at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role for SEZ6 as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined. PMID- 21785726 TI - Acute renal failure, microangiopathic haemolytic anemia, and secondary oxalosis in a young female patient. AB - A 29-year old female presented with a one-week history of vomiting, diarrhoea, abdominal pain, and headache. On admission, she had acute renal failure requiring dialysis. Tests revealed a hemolytic anemia with thrombocytopenia. An initial diagnosis of thrombotic thrombocytopenic microangiopathy was made and plasma exchange was instigated. However, renal biopsy did not show thrombotic microangiopathy but instead revealed acute kidney injury with mild tubulointerstitial nephritis and numerous oxalate crystals, predominantly in the distal tubules. The patient had been taking large doses (>1100 mg daily) of vitamin C for many months. She also gave a history of sclerotherapy using injections of an ethylene glycol derivative for superficial leg veins. The patient completed five sessions of plasma exchange and was able to discontinue dialysis. She eventually achieved full renal recovery. She has now discontinued sclerotherapy and vitamin supplementation. PMID- 21785723 TI - Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. AB - Cell survival and apoptosis implicate an increasing complexity of players and signaling pathways which regulate not only the decision-making process of surviving (or dying), but as well the execution of cell death proper. The same complex nature applies to anoikis, a form of caspase-dependent apoptosis that is largely regulated by integrin-mediated, cell-extracellular matrix interactions. Not surprisingly, the regulation of cell survival, apoptosis, and anoikis furthermore implicates additional mechanistic distinctions according to the specific tissue, cell type, and species. Incidentally, studies in recent years have unearthed yet another layer of complexity in the regulation of these cell processes, namely, the implication of cell differentiation state-specific mechanisms. Further analyses of such differentiation state-distinct mechanisms, either under normal or physiopathological contexts, should increase our understanding of diseases which implicate a deregulation of integrin function, cell survival, and anoikis. PMID- 21785728 TI - Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats. AB - Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors. PMID- 21785727 TI - The Relation between Fructose-Induced Metabolic Syndrome and Altered Renal Haemodynamic and Excretory Function in the Rat. AB - This paper explores the possible relationships between dietary fructose and altered neurohumoral regulation of renal haemodynamic and excretory function in this model of metabolic syndrome. Fructose consumption induces hyperinsulinemia, hypertriglyceridaemia, insulin resistance, and hypertension. The pathogenesis of fructose-induced hypertension is dubious and involves numerous pathways acting both singly and together. In addition, hyperinsulinemia and hypertension contribute significantly to progressive renal disease in fructose-fed rats. Moreover, increased activity of the renin-angiotensin and sympathetic nervous systems leading to downregulation of receptors may be responsible for the blunted vascular sensitivity to angiotensin II and catecholamines, respectively. Various approaches have been suggested to prevent the development of fructose-induced hypertension and/or metabolic alteration. In this paper, we address the role played by the renin-angiotensin and sympathetic nervous systems in the haemodynamic alterations that occur due to prolonged consumption of fructose. PMID- 21785730 TI - Emergency caesarean section: influences on the decision-to-delivery interval. AB - RCOG/NICE guidelines recommend that, for fetal compromise in labour, delivery should be accomplished ideally within 30 minutes. In this study, we investigated the factors which affect the decision-to-delivery (DD) intervals for emergency caesareans. To achieve this, prospective data were collected for all grade 1 and 2 caesareans performed on a busy labour ward over 12 months. We found that the ratio of labouring women to midwives had a significant effect on the DD intervals, which were significantly prolonged when 1 : 1 care was not provided (P < 0.001). The observed effect resulted exclusively from a prolonged transfer time to theatre. General anesthesia use shortened the DD interval for grade 1 caesareans (P < 0.001) and was more likely to be used during the day shift (P < 0.009). We conclude that midwifery staffing levels and the form of anaesthesia employed influence on DD intervals for the most urgent caesarean sections. PMID- 21785729 TI - Alcohol consumption and risk of all-cause and cardiovascular disease mortality in men. AB - This study examined the association between consumption of alcoholic beverages and all-cause and cardiovascular disease (CVD) mortality in a cohort of men (n = 31,367). In the Cox proportional hazards model adjusted for age, year of examination, body mass index (BMI), smoking, family history of CVD, and aerobic fitness, there were no significant differences in risk of all-cause mortality across alcohol intake groups. Risk of CVD mortality was reduced 29% in quartile 1 (HR = 0.71, 95% confidence interval (CI): 0.53, 0.95) and 25% in quartile 2 (HR = 0.75, 95% CI: 0.58, 0.98). The amount of alcohol consumed to achieve this risk reduction was <6 drinks/week; less than the amount currently recommended. The addition of other potential confounders and effect modifiers including blood pressure, insulin sensitivity, lipid levels, and psychological variables did not affect the magnitude of association. Future research is needed to validate the current public health recommendations for alcohol consumption. PMID- 21785731 TI - Poly(amidoamine)-Cholesterol Conjugate Nanoparticles Obtained by Electrospraying as Novel Tamoxifen Delivery System. AB - A new poly(amidoamine)-cholesterol (PAA-cholesterol) conjugate was synthesized, characterized and used to produce nanoparticles by the electrospraying technique. The electrospraying is a method of liquid atomization that consists in the dispersion of a solution into small charged droplets by an electric field. Tuning the electrospraying process parameters spherical PAA-chol nanoparticles formed. The PAA-cholesterol nanoparticles showed sizes lower than 500 nm and spherical shape. The drug incorporation capacity was investigated using tamoxifen, a lipophilic anticancer drug, as model drug. The incorporation of the tamoxifen did not affect the shape and sizes of nanoparticles showing a drug loading of 40%. Tamoxifen-loaded nanoparticles exhibited a higher dose-dependent cytotoxicity than free tamoxifen, while blank nanoparticles did not show any cytotoxic effect at the same concentrations. The electrospray technique might be proposed to produce tamoxifen-loaded PAA-chol nanoparticle in powder form without any excipient in a single step. PMID- 21785733 TI - Epithelial ovarian carcinoma types and the coexistence of ovarian tumor conditions. AB - Objective. Ovarian carcinomas are presumed to arise within ovarian inclusion cysts or from a coexisting epithelial lesion in the ovary. Insight may be gained by relating different subtypes of ovarian cancer with the presence of coexisting tumor-like conditions. Methods. The Dutch nation-wide pathology database PALGA (Pathologisch Anatomisch Landelijk Geautomatiseerd Archief) identified the various histopathological subtypes of ovarian cancer in 824 patients diagnosed in 1996-2003, and recorded the presence of epithelial tumor conditions around the ovarian tumors. In addition, a PALGA database of all 153 consecutive patients referred to the Nijmegen University Medical Centre in 2007 for histopathological work-up was analyzed. Results. The prevalence of coexisting ovarian tumor conditions was 16.4% (135 out of 824 patients, (95% CI: 8.4%-24.4%)). The coexistence was highest for endometrioid, mucinous, clear cell, and borderline malignancies. The referral group revealed 35% (54 out of 153 patients, (95% CI: 28%-42%)) of coexisting epithelial ovarian tumor conditions. Conclusion. One in six patients with a malignant ovarian tumor has a coexisting epithelial tumor condition in the ovary, which is also rather frequently observed in the diagnostic work-up practice. PMID- 21785732 TI - Remodelling of membrane rafts expression in lung cells as an early sign of mechanotransduction-signalling in pulmonary edema. AB - Membrane rafts (MRs) are clusters of lipids, organized in a "quasicrystalline" liquid-order phase, organized on the cell surface and whose pattern of molecules and physicochemical properties are distinct from those of the surrounding plasma membrane. MRs may be considered an efficient and fairly rapid cell-activated mechanism to express or mask surface receptors aimed at triggering specific response pathways. This paper reports observations concerning the role of MRs in the control of lung extravascular water that ought to be kept at minimum to assure gas diffusion, supporting the hypothesis that MRs expression is a potential mechanism of sensing minor changes in the volume of extravascular water. We present the evidence that MRs expression specifically relates to signal transduction processes evoked by mechanical stimuli arising in the interstitial lung compartment when a small increase in extravascular volume occurs. We further hypothesize that a differential expression of MRs might also reflect the damage to precise components of the extracellular matrix caused by the perturbation in water balance and thus can trigger a molecule-oriented specific matrix remodelling. PMID- 21785734 TI - Smoking and cervical cancer. AB - Cervical cancer (CC) is the third most common cancer in women worldwide; however, CC is a preventable disease, and much effort should be done to prevent it. Persistence of high-risk HPV infection is the strongest epidemiologic risk factor for CC, however it is not sufficient for development of the disease it cofactors should be present. In 2004; IARC listed cervical cancer among those causally related to smoking. Smoking interferes with incidence and prevalence of HPV infection and is associated with cervical intraepithelial neoplasia and invasive CC. Multiple factors seem to intervene on cervical carcinogenesis related with tobacco, especially by direct local carcinogenic effect and local immunosuppression. Smoking addition is also closely related with other confounding factors, like unfavorable psychosocial events, systemic immunity, contraception, and nutrition, which got difficult epidemiologic evaluation of smoking role on cervical carcinogenesis. Smoking habits should be taken in account in clinical practice and in research concerning CC. PMID- 21785737 TI - Diabetes and cancer: is diabetes causally related to cancer? AB - Diabetes mellitus is a serious and growing health problem worldwide and is associated with severe acute and chronic complications. Moreover, epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer. Several studies indicate an association between diabetes and the risk of liver, pancreas, endometrium, colon/rectum, breast, and bladder cancer. Mortality is also moderately increased in subjects with diabetes. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in diabetic patients. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic as well as mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. The effect of diabetes treatment drugs, aside from metformin, on cancer is not conclusive. In order to fight the perfect storm of diabetes and cancer, strategies to promote primary prevention and early detection of these conditions are urgently needed. PMID- 21785735 TI - Maturation of the GABAergic transmission in normal and pathologic motoneurons. AB - gamma-aminobutyric acid (GABA) acting on Cl(-)-permeable ionotropic type A (GABA(A)) receptors (GABA(A)R) is the major inhibitory neurotransmitter in the adult central nervous system of vertebrates. In immature brain structures, GABA exerts depolarizing effects mostly contributing to the expression of spontaneous activities that are instructive for the construction of neural networks but GABA also acts as a potent trophic factor. In the present paper, we concentrate on brainstem and spinal motoneurons that are largely targeted by GABAergic interneurons, and we bring together data on the switch from excitatory to inhibitory effects of GABA, on the maturation of the GABAergic system and GABA(A)R subunits. We finally discuss the role of GABA and its GABA(A)R in immature hypoglossal motoneurons of the spastic (SPA) mouse, a model of human hyperekplexic syndrome. PMID- 21785739 TI - Mitochondrial dysfunction and insulin resistance: the contribution of dioxin-like substances. AB - Persistent organic pollutants (POPs) are known to cause mitochondrial dysfunction and this in turn is linked to insulin resistance, a key biochemical abnormality underlying the metabolic syndrome. To establish the cause and effect relationship between exposure to POPs and the development of the metabolic syndrome, Koch's postulates were considered. Problems arising from this approach were discussed and possible solutions were suggested. In particular, the difficulty of establishing a cause and effect relationship due to the vagueness of the metabolic syndrome as a disease entity was discussed. Recently a bioassay, aryl hydrocarbon receptor (AhR) trans-activation activity using a cell line expressing AhR-luciferase, showed that its activity is linearly related with the parameters of the metabolic syndrome in a population. This finding suggests the possible role of bioassays in the analysis of multiple pollutants of similar kinds in the pathogenesis of several closely related diseases, such as type 2 diabetes and the metabolic syndrome. Understanding the effects of POPs on mitochondrial function will be very useful in understanding the integration of various factors involved in this process, such as genes, fetal malnutrition and environmental toxins and their protectors, as mitochondria act as a unit according to the metabolic scaling law. PMID- 21785736 TI - Assortment of GABAergic plasticity in the cortical interneuron melting pot. AB - Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations. PMID- 21785738 TI - Clinical allogeneic and autologous islet cell transplantation: update. AB - Islet cell transplantation is categorized as a beta-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, beta-cell regeneration from human stem cells and gene induction of the naive pancreas represent the next generation of beta-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities. PMID- 21785740 TI - Chemerin: A Novel Link between Inflammation and Atherosclerosis? PMID- 21785741 TI - ATP-Sensitive Potassium Channel-Deficient Mice Show Hyperphagia but Are Resistant to Obesity. AB - BACKGROUND: The hypothalamus, the center for body weight regulation, can sense changes in blood glucose level based on ATP-sensitive potassium (K(ATP)) channels in the hypothalamic neurons. We hypothesized that a lack of glucose sensing in the hypothalamus affects the regulations of appetite and body weight. METHODS: To evaluate this hypothesis, the responses to glucose loading and high fat feeding for eight weeks were compared in Kir6.2 knock-out (KO) mice and control C57BL/6 mice, because Kir6.2 is a key component of the K(ATP) channel. RESULTS: The hypothalamic neuropeptide Y (NPY) analyzed one hour after glucose injection was suppressed in C57BL/6 mice, but not in Kir6.2 KO mice, suggesting a blunted hypothalamic response to glucose in Kir6.2 KO mice. The hypothalamic NPY expression at a fed state was elevated in Kir6.2 KO mice and was accompanied with hyperphagia. However, the retroperitoneal fat mass was markedly decreased in Kir6.2 KO mice compared to that in C57BL/6 mice. Moreover, the body weight and visceral fat following eight weeks of high fat feeding in Kir6.2 KO mice were not significantly different from those in control diet-fed Kir6.2 KO mice, while body weight and visceral fat mass were elevated due to high fat feeding in C57BL/6 mice. CONCLUSION: These results suggested that Kir6.2 KO mice showed a blunted hypothalamic response to glucose loading and elevated hypothalamic NPY expression accompanied with hyperphagia, while visceral fat mass was decreased, suggesting resistance to diet-induced obesity. Further study is needed to explain this phenomenon. PMID- 21785742 TI - Comparison of EGF with VEGF non-viral gene therapy for cutaneous wound healing of streptozotocin diabetic mice. AB - BACKGROUND: To accelerate the healing of diabetic wounds, various kinds of growth factors have been employed. It is the short half-life of administered growth factors in hostile wound beds that have limited wide-spread clinical usage. To overcome this limitation, growth factor gene therapy could be an attractive alternative rather than direct application of factors onto the wound beds. We administered two growth factor DNAs, epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) into a cutaneous wound on diabetic mice. We compared the different characteristics of the healing wounds. METHODS: Streptozotocin was injected intraperitoneally to induce diabetes into C57BL/6J mice. The ultrasound micro-bubble destruction method with SonoVue as a bubbling agent was used for non-viral gene delivery of EGF(828) and VEGF(165) DNAs. Each gene was modified for increasing efficacy as FRM-EGF(828) or minicircle VEGF(165). The degree of neoangiogenesis was assessed using qualitative laser Doppler flowmetry. We compared wound size and histological findings of the skin wounds in each group. RESULTS: In both groups, accelerated wound closure was observed in the mice receiving gene therapy compared with non treated diabetic control mice. Blood flow detected by laser doppler flowmetry was better in the VEGF group than in the EGF group. Wound healing rates and histological findings were more accelerated in the EGF gene therapy group than the VEGF group, but were not statistically significant. CONCLUSION: Both non-viral EGF and VEGF gene therapy administrations could improve the speed and quality of skin wound healing. However, the detailed histological characteristics of the healing wounds were different. PMID- 21785743 TI - The effect of an Angiotensin receptor blocker on arterial stiffness in type 2 diabetes mellitus patients with hypertension. AB - BACKGROUND: Hypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension. METHODS: We used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan. RESULTS: In the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels. CONCLUSION: Short-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect. PMID- 21785744 TI - Angiotensin II Inhibits Insulin Binding to Endothelial Cells. AB - BACKGROUND: Insulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance. METHODS: After treating bovine aortic endothelial cells with angiotensin II (ATII), we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR) on the cell membranes and in the cytosol. RESULTS: After treatment of 10(-7)M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05). ATII receptor blocker (eprosartan) dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05). At 200 uM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol. CONCLUSION: ATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium based mechanism. PMID- 21785745 TI - Relationship between Chemerin Levels and Cardiometabolic Parameters and Degree of Coronary Stenosis in Korean Patients with Coronary Artery Disease. AB - BACKGROUND: Chemerin is a novel adipokine that is associated with inflammation and adipogenesis. However, it remains unclear whether chemerin is involved in patients with cardiovascular disease. We investigated whether the serum chemerin levels of Korean patients with coronary artery disease correlated with specific cardiometabolic parameters. METHODS: In total, 131 patients, all of whom had coronary artery stenosis exceeding 50%, participated in this study. Their serum chemerin levels and cardiometabolic parameters were measured. The serum chemerin levels of two groups of patients were compared; those with one stenotic vessel (n=68) and those with multiple stenotic vessels, including left main coronary artery disease (n=63). RESULTS: Serum chemerin levels correlated positively with the degree of coronary artery stenosis and fasting glucose, triglyceride, total cholesterol, low density lipoprotein cholesterol, and high sensitive C-reactive protein levels. The group with multiple stenotic vessels, including left main disease, had higher chemerin levels than the group with one stenotic vessel (t= 2.129, P=0.035). Multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease (odds ratio, 1.018; confidence interval, 0.997 to 1.040; P=0.091). CONCLUSION: Serum chemerin levels have a significant correlation with several cardiometabolic risk factors and the degree of coronary artery stenosis in Korean patients with coronary artery disease. However, multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease. Additional investigations are necessary to fully elucidate the role of chemerin in cardiovascular disease. PMID- 21785746 TI - Prevalence of Diabetes Mellitus and Prediabetes in Dalseong-gun, Daegu City, Korea. AB - BACKGROUND: The aim of the present study was to determine the population-based prevalence of diabetes mellitus (DM) and prediabetes in a rural district of Daegu City, Korea. METHODS: Between August and November 2003, a community-based health survey of adults aged 20 years and older was performed in the rural district of Dalseong-gun in Daegu City. A total of 1,806 of all eligible individuals agreed to participate. Fasting plasma glucose was measured in all participants. Two hour oral glucose tolerance was measured in the 1,773 participants for whom there was neither an established diagnosis of DM nor evidence of DM according to fasting glucose levels. The prevalence of DM and prediabetes was determined according to the 2003 criteria of the American Diabetes Association. Subjects with prediabetes were classified into one of three categories of glucose intolerance: isolated impaired fasting glucose (IFG); isolated impaired glucose tolerance (IGT); or combined IFG and IGT. RESULTS: The prevalence of DM was 12.2%. The highest prevalence rates were observed in subjects in their seventies. A total of 34.7% of all subjects who were assigned a diagnosis of DM in the present study had not been diagnosed previously. The prevalence of prediabetes was 22.7%. The highest prevalence rates were observed in subjects in their fifties. CONCLUSION: The present study identified prevalence rates of 12.2% for DM (age-standardized prevalence rate [ASR], 6.8%), and 22.7% for prediabetes (ASR 18.5%). These results emphasize the need for community health promotion strategies to prevent or delay the onset of DM in individuals with prediabetes. PMID- 21785747 TI - Therapeutic target achievement in type 2 diabetic patients after hyperglycemia, hypertension, dyslipidemia management. AB - BACKGROUND: Our study group established "3H care" in 2002. The meaning of "3H care" attain and maintain adequate controls over hypertension, hyperlipidemia, and hyperglycemia in type 2 diabetic patients. This study evaluated the achievement of target goals after one year or more of "3H care" by specialists in our diabetic clinic. METHODS: This was a retrospective study of 200 type 2 diabetic patients who received "3H care" for one year or more in our diabetic clinic. We evaluated achievement of target goals for metabolic controls as suggested by the American Diabetes Association. RESULTS: Overall, 200 type 2 diabetes patients were enrolled, of whom 106 were males (53%) and 94 were females (47%). After one year of "3H care," the mean HbA1c was 7.2+/-1.5% and the percentage of patients achieving glycemic control (HbA1c <7%) was 51.8%. However only 32.2% of hypertensive patients achieved the recommended target. After one year of "3H care," the percentages of those who achieved the target value for dyslipidemia were 80.0% for total cholesterol, 66.3% for low density lipoprotein cholesterol, 57.9% for triglyceride, and 51.8% for high density lipoprotein cholesterol. The percentage that achieved all three targets level was only 4.4% after one year and 14.8% after two years. CONCLUSION: The results of this study demonstrate that only a minor proportion of patients with type 2 diabetes achieved the recommended goals despite the implementation of "3H care." It is our suggestion that better treatment strategies and methods should be used to control hypertension, hyperlipidemia and hyperglycemia. PMID- 21785748 TI - Small rice bowl-based meal plan for energy and marcronutrient intake in korean men with type 2 diabetes: a pilot study. AB - BACKGROUND: Koreans eat rice, which is usually served in a rice bowl. We investigated the effect of a meal plan using small rice bowls on the total energy intake (TEI) and the marcronutrient intake in Korean men with type 2 diabetes. METHODS: A total of 62 men with type 2 diabetes were divided by body mass index (BMI) (normal weight [NW], BMI<23 kg/m(2); overweight [OW], 23<=BMI<25 kg/m(2); obese [OB], BMI>=25 kg/m(2)) and proportions of carbohydrate intake to TEI (PCI) (low carbohydrate intake [LC], <55%; recommended carbohydrate intake [RC], >=55% and <=60%; high carbohydrate intake [HC], >60%). The 3-day dietary records were analyzed for TEI and proportions of macronutrients, before and 2 weeks after a small-sized (300 mL) rice bowl based education was given. RESULTS: There were no significant differences in the age and BMI within the sub-groups by BMI and PCI groups. In baseline, the ratio of TEI to recommended total energy intake (RTR) of OW and OB were higher than that of NW. The PCI of HC was higher than that of LC and alcohol intake of HC was lower than that of LC. After education, the reduction of RTREI in OB was higher than that in OW and NW. The reduction of PCI in HC was higher than that of LC. CONCLUSION: A small rice bowl based meal plan was effective for the reduction of energy intake and control of marcronutrient intake in Korean obese men with type 2 diabetes consuming a high carbohydrate diet. PMID- 21785749 TI - Factors associated with long-term oral hypoglycemic agent responsiveness in korean patients with type 2 diabetes mellitus. AB - BACKGROUND: This study was performed to determine the factors associated with long-term oral hypoglycemic agent (OHA) responsiveness in Korean type 2 diabetic patients. METHODS: Two groups of patients were selected among the type 2 diabetic patients who were followed for more than two years at a university hospital diabetes clinic. The OHA responsive group consisted of 197 patients whose HbA1c levels were maintained at <=7% with OHA for more than two years. The OHA failure group consisted of 180 patients whose HbA1c levels were >8% in spite of optimal combined OHA therapy or patients who required insulin therapy within the two years of the study. RESULTS: The OHA failure group had higher baseline values of fasting and postprandial glucose, HbA1c, and lower fasting, postprandial, and delta C-peptide compared to those of the OHA responsive group. The OHA failure group also had a higher proportion of female patients, longer diabetic duration, and more family history of diabetes. There were no significant differences in body mass index (BMI) or insulin resistance index between the two groups. Multiple logistic regression analysis showed that the highest quartile of baseline fasting, postprandial glucose, and HbA1c and the lowest quartile of postprandial and delta C-peptide were associated with an increased odds ratio of OHA failure after adjustment for age, sex, body mass index, and family history of diabetes. CONCLUSION: Lower baseline values of postprandial and delta C-peptide and elevated fasting glucose and HbA1c are associated with long-term OHA responsiveness in Korean patients with type 2 diabetes mellitus. PMID- 21785750 TI - Retrospective analysis on the efficacy, safety and treatment failure group of sitagliptin for mean 10-month duration. AB - BACKGROUND: To investigate the clinical results of sitagliptin (SITA) and the characteristics of the treatment failure group or of low responders to SITA. METHODS: A retrospective study of type 2 diabetic patients reviewed 99 cases, including 12 treatment failure cases, who stopped SITA because of worsening patients' condition, and 87 cases, who continued treatment over five visits (total 9.9+/-10.1 months) after receiving the prescription of SITA from December 2008 to June 2009. Subjects were classified as five groups administered SITA as an initial combination with metformin (MET), add-on to metformin or sulfonylurea, and switching from sulfonylurea or thiazolidinedione. The changes in HbA1c level from the first to last visit (DeltaHbA1c) in treatment maintenance group were subanalyzed. RESULTS: The HbA1c level was significantly reduced in four groups, including initial coadministration of SITA with metformin (DeltaHbA1c=-1.1%, P<0.001), add-on to MET (DeltaHbA1c=-0.6%, P=0.017), add-on to sulfonylurea (DeltaHbA1c=-0.5%, P<0.001), and switching from thiazolidinedione (DeltaHbA1c= 0.3%, P=0.013). SITA was noninferior to sulfonlyurea (DeltaHbA1c=-0.2%, P=0.63). There was no significant adverse effect. The treatment failure group had a longer diabeties duration (P=0.008), higher HbA1c (P=0.001) and fasting plasma glucose (P=0.003) compared to the maintenance group. Subanalysis on the tertiles of DeltaHbA1c showed that low-response to SITA (tertile 1) was associated with a longer diabetes duration (P=0.009) and lower HbA1c (P<0.001). CONCLUSION: SITA was effective and safe for use in Korean type 2 diabetic patients. However, its clinical responses and long-term benefit-harm profile is yet to be established. PMID- 21785751 TI - Letter: predictive clinical parameters for the therapeutic efficacy of sitagliptin in korean type 2 diabetes mellitus (diabetes metab j 2011;35:159-65). PMID- 21785752 TI - Response: predictive clinical parameters for the therapeutic efficacy of sitagliptin in korean type 2 diabetes mellitus (diabetes metab j 2011;35:159-65). PMID- 21785753 TI - Human liver xenotransplantation. PMID- 21785754 TI - Preventing Hepatitis B-induced Liver Cancer: Implications for Eliminating Health Disparities. AB - If the definition of eliminating of a health disparity were signified by the absence of any differences in incidence or mortality between a population's experiences with a health problem, then the only health disparity that has ever been eliminated is smallpox because with zero cases of smallpox in the world, no health disparities exist because of smallpox. The eradication of smallpox is perhaps the only historical example where the elimination of a health disparity has been achieved. Principles and lessons learned, particularly through the intersection of science and policy that could be applied to the elimination of other health disparities both domestically and internationally are proposed. PMID- 21785755 TI - Deformable Image Registration of Sliding Organs Using Anisotropic Diffusive Regularization. AB - Traditional deformable image registration imposes a uniform smoothness constraint on the deformation field. This is not appropriate when registering images visualizing organs that slide relative to each other, and therefore leads to registration inaccuracies. In this paper, we present a deformation field regularization term that is based on anisotropic diffusion and accommodates the deformation field discontinuities that are expected when considering sliding motion. The registration algorithm was assessed first using artificial images of geometric objects. In a second validation, monomodal chest images depicting both respiratory and cardiac motion were generated using an anatomically-realistic software phantom and then registered. Registration accuracy was assessed based on the distances between corresponding segmented organ surfaces. Compared to an established diffusive regularization approach, the anisotropic diffusive regularization gave deformation fields that represented more plausible image correspondences, while giving rise to similar transformed moving images and comparable registration accuracy. PMID- 21785756 TI - [Recommendations of the Latin-American network for the study and treatment of the neuropathic pain]. AB - Neuropathic pain (NP) is a kind of pain which is distinct from the somatic or visceral pain that the GP is used to assessing; the clinical profile and the response to treatment of this kind of pain are different. Given its high incidence in the population, it is important that the non-specialized physician should be capable of identifying it early and start treatment. This work attempts to summarize the clinical, diagnostic, pathophysiological and therapeutic aspects of NP to guide the non-specialized physician in the identification and initial treatment of patients suffering from NP. At the same time, the therapeutic options which are only available at centers specialized in the treatment of pain in patients who do not progress satisfactorily are also summarized. This work includes the updates published on the latest guidelines and recommendations, which have had a major impact worldwide. As background to this report, highly respected professionals from our field published in 2008 an important article in Spanish. This material sets out clinical, pathophysiological and diagnostic concepts which the authors of this work mostly agree with. On the other hand, we differ significantly in the therapeutic aspects. PMID- 21785757 TI - A novel membrane-permeant cADPR antagonist modified in the pyrophosphate bridge. AB - A concise method for the formation of cyclopyrophosphate of cIDPRE as well as sulfur and selenium-substituted pyrophosphate cIDPRE analogues (P(1)(S)-cIDPRE, P(1)(Se)-cIDPRE, P(2)(S)-cIDPRE and P(2)(Se)-cIDPRE) was reported and one of the P(S)-diastereoisomers, P(1)(S)-cIDPRE-1, is a novel membrane-permeant cADPR antagonist. PMID- 21785759 TI - Thieno[3,4-b]pyrazines and their applications to low band gap organic materials. AB - The application of fused-ring thieno[3,4-b]pyrazines in conjugated organic polymers has been found to be a powerful approach to the production of low band gap materials. While thieno[3,4-b]pyrazine-based materials date back to the early 1990s, significant advances in the preparation and scope of thieno[3,4-b]pyrazine based materials have been reported in recent years, primarily in response to the increasing demand for reduced band gap materials in photovoltaic devices. In this review, we provide an overview of thieno[3,4-b]pyrazines and their application to conjugated materials, highlighting in particular the recent advances in the breadth of thieno[3,4-b]pyrazine building blocks and the promise of tuning materials to achieve optimal properties for specific applications. PMID- 21785758 TI - Ultrasensitive quantification of mature microRNAs by real-time PCR based on ligation of a ribonucleotide-modified DNA probe. AB - It was first demonstrated that the DNA probe modified with ribonucleotides can be efficiently ligated by using miRNA as the template. With PCR amplification of the ligated DNA probe, as low as 0.2 fM target miRNAs can be detected with high specificity. PMID- 21785760 TI - A near-infrared reversible fluorescent probe for peroxynitrite and imaging of redox cycles in living cells. AB - BzSe-Cy is a small-molecule fluorescent probe containing Se, which can respond reversibly to changes in ONOO(-) or reduced ascorbate and exhibit high sensitivity and selectivity for ONOO(-). PMID- 21785761 TI - Alkyl chain engineering on a dithieno[3,2-b:2',3'-d]silole-alt dithienylthiazolo[5,4-d]thiazole copolymer toward high performance bulk heterojunction solar cells. AB - A new copolymer of dithienosilole and dithienylthiazolo[5,4-d]thiazole with a hexyl side chain on the 4-position of thiophene units was designed and synthesized. Polymer solar cells based on the polymer as a donor and PC(70)BM as an acceptor demonstrated a power conversion efficiency up to 5.88% with a high fill factor of 71.6%. PMID- 21785762 TI - Naphthodithiophene-2,1,3-benzothiadiazole copolymers for bulk heterojunction solar cells. AB - Two newly synthesized naphthodithiophene-based copolymers, PNB, exhibit a low optical bandgap of ~1.64 eV with which the solar cells fabricated from the blend of PNB and PC(71)BM afforded a power conversion efficiency of 5.3% with external quantum efficiency over 60% in a broad spectral range. PMID- 21785764 TI - Assembly of bicyclic or monocyclic clusters from [(eta5-C5Me5)2Mo2(MU3 S)4(CuMeCN)2]2+ with tetraphosphine or N,P mixed ligands: syntheses, structures and enhanced third-order NLO performances. AB - Reactions of the preformed cluster [(eta(5)-C(5)Me(5))(2)Mo(2)(MU(3) S)(4)Cu(2)(MeCN)(2)](ClO(4))(2) (1) with two tetraphosphine ligands, 1,4 N,N,N',N'-tetra(diphenylphosphanylmethyl)benzene diamine (dpppda) and N,N,N',N' tetra(diphenylphosphanylmethyl)ethylene diamine (dppeda), produced two bicyclic clusters {[(eta(5)-C(5)Me(5))(2)Mo(2)(MU(3)-S)(4)Cu(2)](2)(L)}(ClO(4))(4) (3: L = dpppda; 4: L = dppeda). Analogous reactions of 1 or [(eta(5) C(5)Me(5))(2)Mo(2)(MU(3)-S)(4)Cu(2)(MeCN)(2)](PF(6))(2) (2) with two N,P mixed ligands, N,N-bi(diphenylphosphanylmethyl)-2-aminopyridine (bdppmapy) and N diphenylphosphanylmethyl-4-aminopyridine (dppmapy), afforded two monocyclic clusters {[(eta(5)-C(5)Me(5))(2)Mo(2)(MU(3)-S)(4)Cu(2)](2)(L)(2)}X(4) (5: L = bdppmapy, X = ClO(4); 6: L = dppmapy, X = PF(6)). Compounds 3-6 were fully characterized by elemental analysis, IR spectra, UV-vis spectra, (1)H and (31)P{(1)H} NMR spectra, ESI-MS and single-crystal X-ray crystallography. In the tetracations of 3-6, two cubane-like [Mo(2)(MU(3)-S)(4)Cu(2)] cores are linked either by one dpppda or dppeda bridge to form a bicyclic structure or by a pair of bdppmapy or dppmapy bridges to afford a monocyclic structure. The third-order nonlinear optical (NLO) properties of 1 and 3-6 in MeCN were also investigated by femtosecond degenerate four-wave mixing (DFWM) technique with a 50 fs pulse width at 800 nm. Compounds 3-6 exhibited enhanced third-order NLO performances relative to that of 1. PMID- 21785763 TI - Biomimetic iron(III) complexes of N3O and N3O2 donor ligands: protonation of coordinated ethanolate donor enhances dioxygenase activity. AB - A series of iron(III) complexes 1-4 of the tripodal tetradentate ligands N,N bis(pyrid-2-ylmethyl)-N-(2-hydroxyethyl)amine H(L1), N,N-bis(pyrid-2-ylmethyl)-N (2-hydroxy- propyl)amine H(L2), N,N-bis(pyrid-2-ylmethyl)-N-ethoxyethanolamine H(L3), and N-((pyrid-2-ylmethyl)(1-methylimidazol-2-ylmethyl))-N-(2 hydroxyethyl)amine H(L4), have been isolated, characterized and studied as functional models for intradiol-cleaving catechol dioxygenases. In the X-ray crystal structure of [Fe(L1)Cl(2)] 1, the tertiary amine nitrogen and two pyridine nitrogen atoms of H(L1) are coordinated meridionally to iron(III) and the deprotonated ethanolate oxygen is coordinated axially. In contrast, [Fe(HL3)Cl(3)] 3 contains the tertiary amine nitrogen and two pyridine nitrogen atoms coordinated facially to iron(III) with the ligand ethoxyethanol moiety remaining uncoordinated. The X-ray structure of the bis(MU-alkoxo) dimer [{Fe(L5)Cl}(2)](ClO(4))(2)5, where HL is the tetradentate N(3)O donor ligand N,N bis(1-methylimidazol-2-ylmethyl)-N-(2-hydroxyethyl)amine H(L5), contains the ethanolate oxygen donors coordinated to iron(III). Interestingly, the [Fe(HL)(DBC)](+) and [Fe(HL3)(HDBC)X] adducts, generated by adding ~1 equivalent of piperidine to solutions containing equimolar quantities of iron(III) complexes 1-5 and H(2)DBC (3,5-di-tert-butylcatechol), display two DBC(2-)-> iron(III) LMCT bands (lambda(max): 1, 577, 905; 2, 575,915; 3, 586, 920; 4, 563, 870; 5, 557, 856 nm; Deltalambda(max), 299-340 nm); however, the bands are blue-shifted (lambda(max): 1, 443, 700; 2, 425, 702; 3, 424, 684; 4, 431, 687; 5, 434, 685 nm; Deltalambda(max), 251-277 nm) on adding 1 more equivalent of piperidine to form the adducts [Fe(L)(DBC)] and [Fe(HL3)(HDBC)X]. Electronic spectral and pH-metric titration studies in methanol disclose that the ligand in [Fe(HL)(DBC)](+) is protonated. The [Fe(L)(DBC)] adducts of iron(III) complexes of bis(pyridyl)-based ligands (1,2) afford higher amounts of intradiol-cleavage products, whereas those of mono/bis(imidazole)-based ligands (4,5) yield mainly the auto-oxidation product benzoquinone. It is remarkable that the adducts [Fe(HL)(DBC)](+)/[Fe(HL3)(DBC)X] exhibit higher rates of oxygenation affording larger amounts of intradiol-cleavage products and lower amounts of benzoquinone. PMID- 21785765 TI - A random copolymer based on dithienothiophene and diketopyrrolopyrrole units for high performance organic solar cells. AB - A random donor-acceptor semiconducting copolymer based on diketopyrrolopyrrole as the acceptor unit and dithienothiophene as the donor unit has been synthesized and characterized. Preliminary studies of BHJ solar cells based on this polymer with PC(71)BM showed a high PCE of above 5% under 100 mW cm(-2) AM1.5 solar illumination. PMID- 21785766 TI - Electrochemical detection of hepatitis C virus with signal amplification using BamHI endonuclease and horseradish peroxidase-encapsulated nanogold hollow spheres. AB - A novel electrochemical method to detect hepatitis C virus was developed based on site-specific cleavage of BamHI endonuclease and enzymatic signal amplification with horseradish peroxidase-encapsulated nanogold hollow spheres. PMID- 21785767 TI - Particle-bound polycyclic aromatic hydrocarbons in an urban, industrial and rural area in the western Mediterranean. AB - Particle-bound PAHs were measured at three sites in southeastern Spain (an urban background location, a suburban-industrial site in the vicinity of two cement plants and a rural area) in order to investigate the influence of the type of location on PAH concentrations. A clear influence of cement production on particulate PAH levels could not be established since for the urban background and suburban-industrial sites the average concentrations of total PAHs in the PM2.5 fraction were very similar (1.085 and 1.151 ng m(-3), respectively), with benzo[b+k]fluoranthene and chrysene as the predominant compounds. Diagnostic ratios, used to identify PAH emission sources, pointed to traffic as the main source of particulate PAH at both locations. As expected, PAH levels at the rural site were significantly lower (0.408 ng m(-3) in the PM10 fraction) due to increasing distance from the emission sources. PAH seasonal variations at the urban background and suburban-industrial sites were the same as reported in many previous studies. Average winter to summer ratios for total PAHs were 4.4 and 4.9 for the urban background and industrial sites, in that order. This seasonal cycle could be partially explained by the higher temperature and solar radiation during summer enhancing PAH evaporation from the particulate phase and PAH photochemical degradation, respectively. The study of PAH distribution between the fine and coarse fraction at the urban site revealed that on average around 80% of total PAHs were associated with fine particles. PMID- 21785768 TI - Photochemical control of bacterial signal processing using a light-activated erythromycin. AB - Bacterial cells control resistance to the macrolide antibiotic erythromycin using the MphR(A) repressor protein. Erythromycin binds to MphR(A), causing release of the PmphR promoter, activating expression of the 2'-phosphotransferase Mph(A). We engineered the MphR(A)/promoter system to, in conjunction with a light activatable derivative of erythromycin, enable photochemical activation of gene expression in E. coli. We applied this photochemical gene switch to the construction of a light-triggered logic gate, a light-controlled band-pass filter, as well as spatial and temporal control of gene expression. PMID- 21785769 TI - Applications of vectorized gold nanoparticles to the diagnosis and therapy of cancer. AB - This critical review focuses on the anti-cancer fight using gold nanoparticles (AuNPs) functionalized with chemotherapeutic drugs in so-called "complexes" (supramolecular assemblies) and "conjugates" (covalent assemblies) as vectors. There is a considerable body of recent literature on various tumor-imaging techniques using the surface plasmon band (SPB) and the "passive" and "active" vectorization of anti-cancer drugs. This article reviews the main concepts and the most recent literature data with emphasis on AuNP preparation, cytotoxicities and use in selective targeting of cancer cells with over-expressed receptors for diagnosis and therapy (108 references). PMID- 21785770 TI - Evaluation of cell-free tumour DNA and RNA in patients with breast cancer and benign breast disease. AB - High levels of DNA and RNA released by apoptotic and necrotic cells circulate in the blood of cancer patients. In the present study we determined the applicability of the quantification of nucleic acids and their genetic alterations as minimally invasive tool for breast cancer screening. The relative concentrations of DNA and RNA were determined in preoperative serum of 102 breast cancer patients, 32 patients with benign breast disease and 53 healthy women. The mean follow-up time of the cancer patients was 6.2 years. Loss of heterozygosity (LOH) at four polymorphic markers (D13S159, D13S280, D13S282 at region 13q31-33 and D10S1765 at PTEN region 10q23.31) was analyzed by PCR-based fluorescence microsatellite analyses using cell-free DNA. The serum levels of DNA (p = 0.016) and RNA (p = 0.001) could differentiate between healthy women and cancer patients, but could not discriminate malignant from benign breast lesions. A significant correlation of serum DNA with RNA levels was observed in all groups (p = 0.018). Increased serum DNA levels (but not RNA levels) in cancer patients were associated with a poorer overall (p = 0.021) and disease-free survival (p = 0.025). The occurrence of LOH at all markers significantly correlated with lymph node status (p = 0.026). In addition, the LOH frequency at D13S280 (p = 0.047) and D13S159 (p = 0.046) associated with overall and disease-free survival, respectively. In conclusion, the quantification of cell-free tumour DNA had diagnostic and prognostic values in breast cancer patients, and DNA loss at the region 13q31-33 may be an indication of lymphatic tumour cell spread. PMID- 21785771 TI - A Kagome layer-based 3D Mn(II) framework showing coexistence of spin-canting, spin-frustration, field-induced metamagnetic and spin-flop transitions. AB - A novel 3D Mn(II) coordination framework with Kagome sublattice, [Mn(3)(py)(2)(nip)(2)](n) (py(-) = 2-((1H-tetrazol-5-yl)methyl)pyridine and nip(2 ) = 5-nitroisophathalate), was in situ solvothermally synthesized and shows the coexistence of spin-canting, spin-frustration as well as field-induced metamagnetic and spin-flop transitions at 2.9 K. PMID- 21785772 TI - Effect of surface microstructure of TiO2 film from micro-arc oxidation on its photocatalytic activity: a HRTEM study. AB - Photocatalysis is a reaction that happens on the surface of catalysts around only several atomic layers. Therefore, the microstructure beneath the surface plays a key role for the improvement of photocatalytic property. In this paper, the microstructural variation of the TiO(2) film from micro-arc oxidation (MAO) was characterized by using a high resolution transmission electron microscopy (HRTEM), and the relationship between microstructures and photocatalytic activity was studied. The results revealed that: 1) The microstructural variation from the surface to the interior in the as-prepared film is as follows: an amorphous layer with thickness around 10-20 nm, an intermediate zone consisting of amorphous, anatase and few rutile TiO(2) phases with grain size about 12 nm, then the main structure consisting of anatase and few rutile TiO(2) phases with grain size around 20 nm. This variation was formed due to temperature gradient during MAO. 2) When the TiO(2) film was annealed at 450 degrees C for 12 h, the amorphous layer disappeared and crystallized into fine anatase grains, and, simultaneously, the grain size in the intermediate layer grew obviously from 12 nm into 18 nm, and the interior portion from 20 nm into 30 nm. 3) The photocatalysis experiments exhibited that photocatalytic activity of the post-annealed TiO(2) film was enhanced to more than twice that of the as-prepared TiO(2) film. Therefore, we propose that the crystallization of amorphous phase beneath the surface plays a key role for the improvement of its photocatalytic property. PMID- 21785773 TI - Mechanism of intramolecular catalysis in the hydrolysis of alkyl monoesters of 1,8-naphthalic acid. AB - Hydrolysis of alkyl 1,8-naphthalic acid monoesters 1a-d is subject to highly efficient intramolecular nucleophilic catalysis by the neighboring COOH group. The reactivity for the COOH reaction depends on the leaving group pK(a), with values of beta(LG) of -0.50, consistent with a mechanism involving rate determining breakdown of tetrahedral addition intermediates. The release of the steric strain of the peri-substitiuents in the highly reactive alkyl 1,8 naphthalic acid monoesters is fundamental to understand the observed special reactivity in this intramolecular reaction. DFT calculations show how the proton transfers involved in the cleavage of the neutral ester can be catalyzed by solvent water, thus facilitating the departure of poor alkoxide leaving groups. PMID- 21785774 TI - Quantitative detection of C-deuterated drugs by CARS microscopy and Raman microspectroscopy. AB - The introduction of carbon-deuterium (C-D) bonds into drug compounds by organic synthesis is a non-invasive labelling approach, which does not alter the chemical and physiological properties of the drug itself. C-deuterated drugs exhibit characteristic vibrational signatures in the C-D stretching region around 2100 2300 cm(-1), which avoids spectral interference with contributions from a complex biological environment. In this paper, the quantitative detection of C-deuterated drugs by Raman microspectroscopy and single-band CARS microscopy is examined. Concentration-dependent studies on drugs with aliphatic and aromatic C-D moieties were performed in a two-channel microfluidic chip, using the corresponding non deuterated (C-H) isotopologues as an internal reference. PMID- 21785775 TI - Functional supramolecular assemblies derived from dendritic building blocks. AB - Control of the structure and function of self-assembled materials has been a significant issue in many areas of nanoscience. Among many different types of building blocks, dendritic ones have shown interesting self-assembly behaviour and functional performances due to their unique shape and multiple functionalities. Dendritic building blocks exhibit unique self-assembly behaviour in diverse environments such as aqueous and organic solutions, solid-liquid interfaces, and thermotropic solid conditions. Tuning the balance between hydrophilic and hydrophobic parts, as well as the external conditions for self assembly, provides unique opportunities for control of supramolecular architectures. Furthermore, the introduction of suitable functional moieties into dendrons enables us to control self-assembly characteristics, allowing nanostructures to exhibit smart performances for electronic or biological applications. The self-assembly characteristics of amphiphilic dendrons under various conditions were investigated to elucidate how dendrons can assemble into nanoscopic structures and how these nanoassemblies exhibit unique properties. Well-defined nanostructures derived from self-assembly of dendrons provide an efficient approach for exhibition of unique functions at the nanoscale. This feature article describes the unique self-assembly characteristics of various types of dendritic building blocks and their potential applications as advanced materials. PMID- 21785776 TI - Unexpected isotopic effect of a deuteriumed countercation on the spin-Peierls type transitions in quasi-one-dimensional bis(maleonitriledithiolato)nickelate monoanion spin systems. AB - Two deuteriumed quasi-one-dimensional (quasi-1D) spin-Peierls-type compounds, 4-X benzylpyridinium-d(5) bis(maleo-nitriledithiolato)nickelate (the substituent X = Br or Cl), were structurally characterized. Compared with the corresponding non deuteration compounds, the transition temperature T(C) shifts to higher temperature. The isotopic effect of countercations on T(C) is probably related to the change of phonon frequency omega(0) and 'chemical pressure' resulted from the substitution of pyridine by pyridine-d(5). PMID- 21785777 TI - Radical C-glycosylation reaction of pyranosides with the 2,3-trans carbamate group. AB - Radical-mediated C-glycosylation of pyranosides with the 2,3-trans carbamate group was investigated. C-Glycosylation was achieved with high alpha-selectivity. PMID- 21785778 TI - Double layer capacitance of anode/solid-electrolyte interfaces. AB - The double layer of electrode/electrolyte interfaces plays a fundamental role in determining the performance of solid state electrochemical cells. The double layer capacitance is one of the most-studied descriptors of the double layer. This work examines a case study on lanthanum strontium vanadate (LSV)/yttria stabilized zirconia (YSZ) interfaces exposed in solid oxide fuel cell anode environment. The apparent double layer capacitance is obtained from impedance spectroscopy. The intrinsic double layer capacitance is evaluated based on Stern's method in conjunction with the Volta potential analysis across LSV/YSZ interfaces. Both the apparent and the intrinsic double layer capacitances exhibit right-skewed volcano patterns, when the interfaces are subjected to anodic biases from 0 to 150 mV. The apparent double layer capacitance is about one order of magnitude larger than the intrinsic double layer capacitance. This discrepancy roots in the inconsistent surface areas that are involved. This analysis of capacitance would provide a more realistic TPB estimate of a working solid-state electrochemical device. PMID- 21785779 TI - Modeling van der Waals interactions between proteins and inorganic surfaces from time-dependent density functional theory calculations. AB - In this work we show how the ab initio determination of van der Waals coefficients within time-dependent density functional theory can be used to build efficient and accurate atomistic models that describe the long-range interactions of proteins with other proteins and of proteins with semi-conducting surfaces. The model parameters are fitted so that they reproduce the ab initio van der Waals coefficients of amino acids and dipeptides. We then assess the quality of our results by comparing ab initio van der Waals coefficients for larger peptides with the coefficients yielded by the models. The different sets of parameters can be easily incorporated in current empirical force field methods, thus providing an essential ingredient for molecular dynamics simulations of proteins close to surfaces. PMID- 21785780 TI - New crystalline aluminum alkoxide oxide fluorides: evidence of the mechanism of the fluorolytic sol-gel reaction. AB - This study reports three new crystalline aluminum isopropoxide oxide fluorides with molar ratios of Al:F equal to 1:1 and 1:1.25. These are the first three representatives isolated without the incorporation of external donor molecules. Compound 1 Al(4)F(4)(MU(4)-O)(MU-O(i)Pr)(5)[H(O(i)Pr)(2)] contains a tetranuclear unit consisting of two different five fold coordinated AlFO(4)-units, with F exclusively in the terminal position. Compound 2, Al(4)F(4)(MU(4)-O)(MU O(i)Pr)(5)[H(O(i)Pr)(2)].Al(5)F(5)(MU(5)-O)(MU-O(i)Pr)(8), contains both a tetranuclear unit (as in 1) and a pentanuclear Al-unit. Al-atoms in the latter are five- and six fold coordinated. Compound 3, Al(16)F(20)(MU(4)-O)(4)(MU O(i)Pr)(20).2((i)PrOH), exhibits a slightly higher fluorination degree and contains an oligomeric chain of four F-linked tetranuclear Al-units. In addition to X-ray structure analysis, compound 1 was characterized by different solid state MAS NMR techniques, including (27)Al triple quantum MAS NMR and (1)H, (1)H >(13)C CP, (19)F and (27)Al MAS NMR. On the basis of the collected data, a reliable decomposition of (27)Al single pulse MAS NMR spectra and an unambiguous assignment of the resonances to the respective structural AlFO(4)-units are given. The new crystalline aluminum isopropoxide oxide fluorides are direct evidence of the fluorolytic sol-gel mechanism previously discussed. PMID- 21785781 TI - Ti(iv) doped WO3 nanocuboids: fabrication and enhanced visible-light-driven photocatalytic performance. AB - In this paper, we successfully fabricate Ti(iv) doped WO3 nanocuboids with controlled Ti(iv) contents through a facile, mild, aqueous-phase route. The characterizations clearly exhibit the optimum amount of the Ti(iv) dopant in under these conditions. The obtained photocatalyst shows excellent visible-light driven photocatalytic performance. It can decompose an organic dye within 70 min under visible-light irradiation. Such a large activity enhancement probably arises from the change of band structure. The results provide an efficient route for the design of photocatalysts with improved visible-light-driven photocatalytic activity as well as a promising material for use in solar cells, nanodevices, and other applications. PMID- 21785782 TI - A potential fortuitous binding of inhibitors of an inverting family GH9 beta glycosidase derived from isofagomine. AB - Using structural insight, the binding mode of isofagomine-derived inhibitors with family GH9 glycosidases is achieved via the study of Alicyclobacillus acidocaldarius (AaCel9A) endoglucanase. In contrast to what was observed in the first report using these compounds with inverting glycosidases from family GH6, these inhibitors do not adopt a distorted conformation in the active site. PMID- 21785783 TI - 3-Substituted-2,4-pentanedionates: ligands for photoactive supramolecular assemblies. AB - Synthetic routes for the construction of 3-substituted 2,4-pentadionate ligands are broadly surveyed. They involve sequential alkylation and arylation by numerous methods, including those based on reactions of coordinated ligands, and can provide access to various rationally designed ligands. Applications of such ligands in the synthesis of multichromophoric complexes are illustrated in some detail. Incorporation of 3-substituted 2,4-pentanedione units into mesomorphic and macromolecular structures is considered in relation to structural control of energy and electron transfer processes in photoactive systems. Aspects of the general supramolecular chemistry of complexes of 3-substituted-2,4-pentadionate ligands are briefly discussed to illustrate the utility of such species within the full range of 1,3-dionate chemistry. PMID- 21785784 TI - Acid properties of solid acid catalysts characterized by solid-state 31P NMR of adsorbed phosphorous probe molecules. AB - A brief review is presented on acidity characterization of solid acid catalysts by means of solid-state phosphor-31 magic-angle-spinning nuclear magnetic resonance ((31)P MAS NMR) spectroscopy using phosphor-containing molecules as probes. It is emphasized that such a simple approach using (31)P MAS NMR of adsorbed phosphorous probe molecules, namely trimethylphosphine (TMP) and trialkylphosphine oxides (R(3)PO), represents a unique technique in providing detailed qualitative and quantitative features, viz. type, strength, distribution, and concentration of acid sites in solid acid catalysts. In particular, it will be shown that when applied with a proper choice of probe molecules with varied sizes and results obtained from elemental analysis, the amounts and locations (intracrystalline vs. extracrystalline) of different types (Bronsted vs. Lewis) of acid sites may be determined. In addition, by incorporating the NMR results with that obtained from theoretical density functional theory (DFT) calculations, correlations between the (31)P chemical shifts (delta(31)P) and acidic strengths of Bronsted and Lewis acid sites may also be derived, facilitating a suitable acidity scale for solid acid catalysts. PMID- 21785785 TI - Selection of a synthetic glycan oligomer from a library of DNA-templated fragments against DC-SIGN and inhibition of HIV gp120 binding to dendritic cells. AB - We report the synthesis of a nucleic acid-encoded carbohydrate library, its combinatorial self-assembly into 37,485 pairs and a screen against DC-SIGN leading to the identification of consensus ligand motifs. A prototypical example from the selected pairs was shown to have enhanced binding. A dendrimer incorporating the selected motifs inhibited gp120's binding to dendritic cells with higher efficiency than mannan. PMID- 21785786 TI - Excited-state N-H...S hydrogen bond between indole and dimethyl sulfide: time dependent density functional theory study. AB - The intermolecular hydrogen bond N-H...S between indole and dimethyl sulfide is theoretically investigated. The formation of N-H...S hydrogen bonds between indole and dimethyl sulfide in ground and excited states is confirmed by the analysis of geometric structure, Mulliken charge, and infrared spectra. The result shows that the S(1) state of hydrogen bonded indole-Me(2)S is mainly a charger transfer state, while the S(2) state is a local excited state and also the state corresponding to the experiment. More importantly, it is demonstrated that the intermolecular hydrogen bond N-H...S of indole-Me(2)S is strengthened in the S(1) and S(2) states compared to that in ground state. Moreover, the strengthening of intermolecular N-H...S hydrogen bond in excited state induces the fluorescence emission peak of indole shifts to the red. These findings may provide insights for further study of N-H...S hydrogen bonds existing in many biomolecular systems. PMID- 21785787 TI - Hierarchical micro/nano structures of carbon composites as anodes for microbial fuel cells. AB - We demonstrate the utility of hierarchical micro/nano structures of electrically conductive carbon composites as anodes for microbial fuel cells (MFCs). To construct the hierarchical structures, carbon nanotubes (CNTs) were directly grown on micro-porous graphite felts at high densities. Using the CNT-modified felts as anodes, power outputs from MFCs were increased ~7 fold compared to those with bare graphite-felt anodes. We also show that this power improvement is sustainable even in MFCs operated with naturally occurring microbial communities. These results suggest the wide utility of the hierarchical micro/nano structures of conductive carbon composites for bio-electrochemical processes. PMID- 21785788 TI - Substituent effects on the rate of formation of azomethine ylides. A computational investigation. AB - The effect of substituents on the rate of conrotatory thermal cleavage of aziridine has been studied at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level and also using SCS-MP2 methodology. While the parent compound has a high free energy of activation (194.6 kJ mol(-1)), this value could be drastically lowered by substituent effects. Anionic species were found to be particularly effective in increasing the calculated reaction rate. The potential utility of this approach in 1,3-dipolar cycloaddition is discussed. PMID- 21785789 TI - Design, synthesis and photoactivation studies of fluorous photolabels. AB - Two fluorous diazirine photolabels were designed, synthesized and subjected to photoactivation studies. The photoactivation studies revealed an unexpected photoreaction when the fluorous tag was directly connected to the diazirine ring, leading to the formation of a fluorous alkene. The more efficient photolabel of the two was identified as a flexible precursor for target specific photoaffinity labels for fluorous proteomics by adding appropriate ligands depending on the target protein subset. As a proof of feasibility, mannose residues were added to the photolabel making it a potential photoaffinity label to tag proteins that bind mannose. PMID- 21785790 TI - Resonant dissociative electron attachments to cysteine and cystine. AB - Shape-resonant electron attachments to cysteine and cystine and the subsequent dissociation dynamics are investigated with the single-center expansion potential scattering calculations. Selectivity of the direct bond cleavage at a given resonant state or by the specific resonant state coupling is demonstrated with the one-dimensional complex potential energy curves of the temporary anion (cysteine)(-). The wave function of the lowest shape resonant state of the temporary anion (cystine)(-) distinctly shows the localized anti-bond (S-S)* character, implying that this disulfide bond can be easily broken due to the low energy electron resonant attachment. PMID- 21785791 TI - Pd-catalyzed cross-coupling reactions of alkyl halides. AB - Cross-coupling reactions have become indispensable tools for creating carbon carbon (or heteroatom) bonds in organic synthesis. Like in other important transition metal catalyzed reactions, such as metathesis, addition, and polymerization, unsaturated compounds are usually employed as substrates for cross-coupling reactions. However during the past decade, a great deal of effort has been devoted to the use of alkyl halides as saturated compounds in cross coupling reactions, which has resulted in significant progress in this undeveloped area by introducing new effective ligands. Many useful catalytic systems are now available for synthetic transformations based on C(sp(3)) C(sp(3)), C(sp(3))-C(sp(2)) and C(sp(3))-C(sp) bond formation as complementary methods to conventional C(sp(2))-C(sp(2)), C(sp(2))-C(sp) and C(sp)-C(sp) coupling. This tutorial review summarizes recent advances in cross-coupling reactions of alkyl halides and pseudohalides catalyzed by a palladium complex. PMID- 21785792 TI - Expeditious one-pot synthesis of C3-piperazinyl-substituted quinolines: key precursors to potent c-Met inhibitors. AB - An effective one-pot synthesis of quinolines bearing diverse C3-piperazinyl functions was developed by using a modified Friedlander's protocol. The method not only enables the synthesis of our early reported c-Met inhibitor on a large scale, but also provides a way to generate novel multi-substituted quinolines for further structure-activity relationship (SAR) study. PMID- 21785793 TI - Modular synthesis of 1-alpha- and 1-beta-(indol-2-yl)-2'-deoxyribose C nucleosides. AB - A simple two-step method for the selective preparation of anomerically pure 1alpha- and 1beta-(indol-2-yl)deoxyribose derivatives was developed. The synthesis was based on the Sonogashira reaction of 1alpha- and 1beta ethynyldeoxyribose and 2-haloanilines followed by a Pd-complex catalyzed cyclization to the corresponding indolyldeoxyribosides. PMID- 21785794 TI - Chiral N-tert-butanesulfinyl alpha,beta-unsaturated ketimine: a simple and highly effective olefin/sulfinimide hybrid ligand for asymmetric 1,4-additions. AB - One novel type of chiral olefin/sulfinimide hybrid ligands has been developed through a simple one-step condensation of alpha,beta-unsaturated ketones with tert-butanesulfinamide and utilized successfully for rhodium-catalyzed asymmetric conjugated additions to furnish the desired adducts in high yields with excellent ee's. PMID- 21785795 TI - Steady-state photoinduced absorption of CdSe/CdS octapod shaped nanocrystals. AB - Colloidal branched nanocrystals have been attracting increasing attention due to evidence of an interesting relationship between their complex shape and charge carrier dynamics. Herein, continuous wave photoinduced absorption (CW PIA) measurements of CdSe/CdS octapod-shaped nanocrystals are reported. CW PIA spectra show strong bleaching due to the one-dimensional (1D) CdS pod states (480 nm) and the zero-dimensional (0D) CdSe core states (690 nm). The agreement with previously reported ultrafast pump-probe experiments indicates that this strong bleaching signal may be assigned to state filling. Additional bleaching features at 520 and 560 nm are characterized by a longer lifetime and are thus ascribed to defect states, localized at the pod-core interface of the octapod, showing that some of the initially photogenerated carriers get quickly trapped into these long lived defect states. However, we remark that a relevant part of electrons remain untrapped: this opens up the opportunity to exploit octapod shaped nanocrystals in photovoltaics applications, as electron acceptor materials, considering that several efficient hole extracting materials are already available for the realization of a composite bulk heterojunction. PMID- 21785796 TI - DNA damage as a biomarker of genotoxic contamination in Mytilus galloprovincialis from the south coast of Portugal. AB - DNA damage was evaluated in the haemolymph of Mytilus galloprovincialis from nine sites along the south coast of Portugal using the comet assay. DNA damage was low, in the same range of sites considered to suffer low impact from genotoxic contaminants. Even so, differences between sites, seasons and genders were found. Highest values were in mussels from the main estuaries and the fishery harbour, reflecting higher genotoxin levels, whereas the lowest values can be used as a baseline for future work. Non-contaminant related factors (e.g. temperature and oxygen) were also shown to influence DNA damage. Between seasons, highest values were in summer related not only to the increase of tourism in this region (~10 fold), but also to temperature. Between genders, males were found to be more sensitive. The condition index was also generally higher in summer. Lipid peroxidation, another damage biomarker, was measured in gills to assess if there is any association between the responses of both biomarkers and if they are similarly affected by the same environmental conditions. LPO like DNA damage was higher in summer. This work confirms that DNA damage is a sensitive biomarker to discriminate genotoxic contamination, even in areas considered to suffer low impact from genotoxins. PMID- 21785797 TI - Construction of a long range p/n heterojunction with a pair of nanometre-wide continuous D/A phases. AB - A p/n heterojunction is the basic setup for light-electric conversion. It has been widely accepted that the ideal configuration for organic photovoltaics is formed by the joint of a pair of long-range continuous but nanometre-wide phases consisting of electron-donating (D) and -accepting (A) components, respectively. Such a p/n heterojunction can provide not only a large D/A interface essential to efficient photoinduced charge separation, but also the transportation pathways for both electrons and holes. This review article summarizes the present approaches including D-A double cables, diblock copolymers, and small molecular D A dyads and multiads, to construct such an ideal p/n heterojunction. Each approach is introduced by a few selected representative works, with highlights on their molecular design strategies and the relationship of chemical structure packing order-property. Such information would be useful for the next research in the field. PMID- 21785798 TI - Three-dimensional (3D) hydrodynamic focusing for continuous sampling and analysis of adherent cells. AB - A simple three-dimensional (3D) hydrodynamic focusing microfluidic device integrated with continuous sampling, rapid dynamic lysis, capillary electrophoretic (CE) separation and detection of intracellular content is presented. One of the major difficulties in microfluidic cell analysis for adherent cells is that the cells are prone to attaching to the channel surface. To solve this problem, a cross microfluidic chip with three sheath-flow channels located on both sides of and below the sampling channel was developed. With the three sheath flows around the sample solution-containing cells, the formed soft fluid wall prevents the cells from adhering to the channel surface. Labeled cells were 3D hydrodynamically focused by the sheath-flow streams and smoothly introduced into the cross-section one by one. The introduction of sheath-flow streams not only ensured single-cell sampling but avoided blockage of the sampling channel by adherent cells as well. The maximum rate for introduction of individual cells into the separation channel was about 151 cells min(-1). With electric field applied on the separation channel, the aligned cells were driven into the separation channel and rapidly lysed within 400 ms at the entry of the channel by sodium dodecylsulfate (SDS) added in the sheath-flow solution. The microfluidic system was evaluated by analysis of reduced glutathione (GSH) and reactive oxygen species (ROS) in single HepG2 cells. The average analysis throughput of ROS and GSH in single cells was 16-18 cells min(-1). PMID- 21785799 TI - Molecularly imprinted monolith coupled on-line with high performance liquid chromatography for simultaneous quantitative determination of cyromazine and melamine. AB - We report a novel method for simultaneous determination of cyromazine and melamine based on a molecularly imprinted monolith on-line coupled with high performance liquid chromatography (HPLC). The imprinted monolith was prepared by in situ polymerization using 2,4-diamino-6-undecyl-1,3,5-triazine (DAUTA) as a mimic template. Due to the better solubility of DAUTA in chloroform, hydrogen bonds were effectively developed between the template and the functional monomer and resulted in the formation of highly specific cavities in the obtained imprinted monolith. With methanol as the loading solvent, cyromazine and melamine were both selectively retained by the obtained imprinted monolith, while the nonspecific adsorption on the non-imprinted monolith was negligible. The imprinted monolithic column was on-line coupled with HPLC for purification and concentration of the two analytes from milk samples. To minimize the peak broadening during the on-line transfer of the analytes from the imprinted monolith to the following analytical column, a successive desorption program was developed for the elution step, which enabled on-line stacking of the target compounds before being analyzed by HPLC. Low detection limits of 0.12 MUg mL(-1) for melamine and 0.05 MUg mL(-1) for cyromazine were achieved with only 0.3 mL of milk sample and a low sensitivity HPLC-UVD instrument. The method may be further extended to detect other analytes of interest in a large variety of samples. PMID- 21785801 TI - Editorial--Analyst's special focus on emerging investigators. PMID- 21785800 TI - Non-invasive spatial visualization system of exhaled ethanol for real-time analysis of ALDH2 related alcohol metabolism. AB - A novel imaging system of ethanol in exhaled breath induced by acetaldehyde dehydrogenase (ALDH2)-related alcohol metabolism has been developed. The system provides an image of ethanol distribution as chemiluminescence (CL) on an enzyme immobilized support. The spatiotemporal change of CL generated by ethanol in exhaled breath after oral administration of ethanol was detected by employing an electron multiplier CCD (EM-CCD) camera, illustrated and analyzed. Prior to measurement of standard gaseous ethanol and ethanol in exhaled breath, the system was optimized by investigating the enzyme-immobilized supports, concentration of substrate and pH condition of Tris-HCl buffer solution. The ethanol skin patch test, a simple method as an indicator of ALDH2, was performed on healthy volunteers. Breath samples of 5 volunteers with ALDH2 (+) and 5 volunteers with ALDH2 (-) were used for exhaled ethanol analysis. Concentration-time profiles of exhaled ethanol obtained from all volunteers were analyzed over a period of 120 min after oral administration of ethanol (0.4 g per kg body weight) in the form of beer which contains 5% of alcohol. The results obtained from the system showed that the peaks of exhaled ethanol concentrations appeared at 30 min, which was considered as a rapid ethanol absorption phase following first-order kinetics. Exhaled ethanol concentrations of volunteers with ALDH2 (+) were lower than volunteers with ALDH2 (-) and the digestion of ethanol in volunteers with ALDH2 (+) was faster than in volunteers with ALDH2 (-). The eliminations were analyzed to follow zero-order kinetics with a rate constant for each group. PMID- 21785802 TI - Single-cell electrical lysis of erythrocytes detects deficiencies in the cytoskeletal protein network. AB - The network of erythrocyte cytoskeletal proteins significantly influences erythrocyte physical and biological properties. Here we show that the kinetics of erythrocyte lysis during exposure to an electric field is sensitively correlated with defects in the cytoskeletal network. Histograms compiled from single-cell electrical lysis data show characteristics of erythrocyte populations that are deficient in a specific cytoskeletal protein, revealing the presence of cell subpopulations. PMID- 21785803 TI - N-tosylhydrazones: versatile reagents for metal-catalyzed and metal-free cross coupling reactions. AB - Transition metal-catalyzed cross-coupling reactions have been established as one of the most powerful tools for the construction of C-C and C-X bonds. In this context, the development of novel metal-catalyzed cross-coupling processes that do not require stoichiometric organometallic reagents is particularly attractive. Recently, N-tosylhydrazones have emerged as a new type of versatile coupling partners for transition metal-catalyzed cross-coupling reactions as well as metal free cross-coupling reactions, and have attracted increasing attention. This tutorial review summarizes recent important developments in this area with N tosylhydrazones as versatile coupling partners. PMID- 21785804 TI - Synthesis, structure and redox properties of bis(cyclopentadienyl)dithiolene complexes of molybdenum and tungsten. AB - The compounds [Cp(2)M(S(2)C(2)(H)R)] (M = Mo or W; R = phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or quinoxalin-2-yl) and [Cp(2)Mo(S(2)C(2)(Me)(pyridin 2-yl)] have been prepared by a facile and general route for the synthesis of dithiolene complexes, viz. the reaction of [Cp(2)MCl(2)] (M = Mo or W) with the dithiolene pro-ligand generated by reacting the corresponding 4-(R)-1,3-dithiol-2 one with CsOH. These Mo compounds were reported previously (Hsu et al., Inorg. Chem. 1996, 35, 4743); however, the preparative method employed herein is more versatile and generates the compounds in good yield and all of the W compounds are new. Electrochemical investigations have shown that each compound undergoes a diffusion controlled one-electron oxidation (OX(I)) and a one-electron reduction (RED(I)) process; each redox change occurs at a more positive potential for a Mo compound than for its W counterpart. The mono-cations generated by chemical or electrochemical oxidation are stable and the structures of both components of the [Cp(2)Mo(S(2)C(2)(H)R)](+)/[Cp(2)Mo(S(2)C(2)(H)R)] (R = Ph or pyridin-3-yl) redox couples have been determined by X-ray crystallography. For each redox related pair, the changes in the Mo-S, S-C and C-C bond lengths of the {MoSCCS} moiety are generally consistent with OX(I) involving the loss of an electron from a pi orbital that is Mo-S and C-S antibonding and C-C bonding in character. These results have been interpreted successfully within the framework provided by DFT calculations accomplished for [Cp(2)M(S(2)C(2)(H)Ph)](n) (M = Mo or W; n = +1, 0 or -1). The HOMO of the neutral compounds is derived mainly from the dithiolene pi(3) orbital (65%); therefore, OX(I) is essentially a dithiolene-based process. The similarity of the potentials for OX(I) (ca. 30 mV) for analogous Mo and W compounds is consistent with this interpretation and the EPR spectra of each of the Mo cations show that the unpaired electron is coupled to the dithiolene proton but relatively weakly to (95,97)Mo. The DFT calculations indicate that the unpaired electron is more localised on the metal in the mono-anions than in the mono-cations. In agreement with this, the EPR spectrum of each of the Mo containing mono-anions manifests a larger (95,97)Mo coupling (A(iso)) than observed for the corresponding mono-cation and RED(I) for a W compound is significantly (ca. 300 mV) more negative than that of its Mo counterpart. [Cp(2)W(S(2)C(2)(H)(quinoxalin-2-yl))] is anomalous; RED(I) occurs at a potential ca. 230 mV more positive than expected from that of its Mo counterpart and the EPR spectrum of the mono-anion is typical of an organic radical. DFT calculations indicate that these properties arise because the electron is added to a quinoxalin-2-yl pi-orbital. PMID- 21785805 TI - Nitrate leaching to shallow groundwater systems from agricultural fields with different management practices. AB - Monitoring the concentration of NO(3)-N from agricultural fields to the subsurface and shallow ground water resources have received considerable interest worldwide, since agriculture has been identified as a major source of nitrate nitrogen (NO(3)-N) pollution of groundwater systems in intensively farmed watersheds. A study was conducted to quantify the impact of two tillage practices viz. chisel plow (CP) and no till (NT) with liquid swine manure application on nitrate leaching to the shallow ground water system under corn-soybean production system. This study is part of the long-term field experiments conducted at Iowa State University using completely randomized block design. The NO(3)-N concentrations in the shallow ground water were monitored at three depths viz., a network of subsurface drains at a depth of 1.2 m and piezometers at depths of 1.8 m and 2.4 m. Results of this study showed that the average NO(3)-N concentration during the study period was 16.1 mg l(-1), 14.4 mg l(-1) and 11.8 mg l(-1) at 1.2 m, 1.8 m and 2.4 m depths, respectively implying significant amount of NO(3)-N leaching past the subsurface drain depth of 1.2 m into the shallow groundwater but the NO(3)-N concentration decreases with the depth. The NO(3)-N concentrations in shallow groundwater were significantly higher under the chisel plow system in comparison with the no till method of tillage. Fall application of liquid swine manure caused more leaching in comparison with the spring application. Higher NO(3)-N concentration was observed under corn in comparison with the soybean plots. An in-depth analysis of the data showed a definite relationship between the NO(3)-N concentration in subsurface drain water at a depth of 1.2 m and shallow groundwater at depths of 1.8 m and 2.4 m depths. PMID- 21785806 TI - Engineered approaches to the stem cell microenvironment for cardiac tissue regeneration. AB - Micro- and nanoscale engineering approaches in medicine have the potential to recreate physiologically relevant stem cell microenvironments to enhance our understanding of stem cell behaviour and bring stem cell therapy closer to fruition. The realization of such advancements will impact a number of therapeutic applications, the most immediate of which may be the repair of heart tissue. Despite profound advances in creating physiologically relevant in vivo stem cell niches through the control of biochemical regulatory factors, further synergism of innovative techniques promise to elucidate the impact of a number of physical cues such as stem cell differentiation into cardiac cells, the electromechanical coupling among these cells, and the formation of bioengineered cardiac tissue grafts. This review examines the recent physiologically relevant micro- and nanoengineering efforts that have been made to address these factors. In Sections II and III, we introduce the traditional focuses of stem cell derived cardiac tissue: differentiation directed by transcription factors and structural cues within the stem cell niche. However, the majority of this review, Sections IV-VII, endeavours to highlight innovative and unconventional microscale engineering techniques that have employed topographic, biomaterial, microfluidic, mechanical, electrical, and optical stimulation for stem cell based cardiac tissue engineering. PMID- 21785807 TI - Inorganic nanostructures grown on graphene layers. AB - This article presents a review of current research activities on the hybrid heterostructures of inorganic nanostructures grown directly on graphene layers, which can be categorized primarily as zero-dimensional nanoparticles; one dimensional nanorods, nanowires, and nanotubes; and two-dimensional nanowalls. For the hybrid structures, the nanostructures exhibit excellent material characteristics including high carrier mobility and radiative recombination rate as well as long-term stability while graphene films show good optical transparency, mechanical flexibility, and electrical conductivity. Accordingly, the versatile and fascinating properties of the nanostructures grown on graphene layers make it possible to fabricate high-performance optoelectronic and electronic devices even in transferable, flexible, or stretchable forms. Here, we review preparation methods and possible device applications of the hybrid structures consisting of various types of inorganic nanostructures grown on graphene layers. PMID- 21785808 TI - Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. AB - The optimal regimen of the anticoagulant and antiplatelet therapies in patients with atrial fibrillation who have had a coronary stent is unclear. It is well recognised that "triple therapy" with aspirin, clopidogrel, and warfarin is associated with an increased risk of bleeding. National guidelines have not made specific recommendations given the lack of adequate data. In choosing the best antithrombotic options for a patient, consideration needs to be given to the risks of stroke, stent thrombosis and major bleeding. This document describes these risks, provides specific recommendations concerning vascular access, stent choice, concomitant use of proton-pump inhibitors and the use and duration of triple therapy following stent placement based upon the risk assessment. PMID- 21785810 TI - Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells. AB - B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hyper-mutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV-diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed >= 2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in lambda but not kappa isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs differed also from that in kappa-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between kappa and lambda isotype CLL clones and suggest an antigenic selection that, in kappa samples, operates against CDR variation. PMID- 21785809 TI - Overexpression of M3 muscarinic receptor is a novel strategy for preventing sudden cardiac death in transgenic mice. AB - The present study was designed to investigate the cardiac benefits of M3 muscarinic receptor (M3-mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K+ channel by microRNA-1 (miR 1) in a conditional overexpression mouse model. A cardiac-specific M3-mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M3-mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia reperfusion (I/R). By using whole-cell patch techniques, M3-mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K+ current. By using Western blot techniques, M3-mAChR overexpression also rescued the expression of the inward rectifying K+ channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M3 mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K+ current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death. PMID- 21785813 TI - Efficacy of indacaterol in the treatment of patients with COPD. AB - Effective bronchodilation is an important part of the management of patients with chronic obstructive pulmonary disease (COPD) and can improve breathlessness and ability to undertake physical activities. Indacaterol is a new once-daily, long acting inhaled bronchodilator for COPD. We review here the efficacy of indacaterol as a bronchodilator, including its impact upon symptoms and health status. The evidence reviewed comprises four placebo-controlled clinical studies of indacaterol treatment, three of which included treatment arms with one of the other long-acting inhaled bronchodilators (once-daily tiotropium or twice-daily salmeterol or formoterol), in 4,833 patients with moderate-to-severe COPD. Indacaterol had a bronchodilator effect significantly greater than formoterol and salmeterol, and similar to tiotropium. Its effect on symptoms and health status was similar or significantly greater than the other bronchodilators. The safety profile was similar to placebo. Once-daily indacaterol is an effective and beneficial maintenance bronchodilator treatment for patients with moderate-to severe COPD. PMID- 21785811 TI - Liraglutide prevents hypoadiponectinemia-induced insulin resistance and alterations of gene expression involved in glucose and lipid metabolism. AB - Liraglutide is a glucagonlike peptide (GLP)-1 analog that reduces blood glucose levels, increases insulin secretion and improves insulin sensitivity through mechanisms that are not completely understood. Therefore, we aimed to evaluate the metabolic impact and underlying mechanisms of liraglutide in a hypoadiponectinemia and high-fat diet (HFD)-induced insulin resistance (IR) model. Adiponectin gene targeting was achieved using adenovirus-transduced RNAi and was used to lower plasma adiponectin levels. Liraglutide (1 mg/kg) was given twice daily for 8 wks to HFD-fed apolipoprotein (Apo)E-/- mice. Insulin sensitivity was examined by a hyperinsulinemic-euglycemic clamp. Gene mRNA and protein expressions were measured by quantitative real-time polymerase chain reaction (PCR) and Western blot, respectively. Administration of liraglutide prevented hypoadiponectinemia-induced increases in plasma insulin, free fatty acids, triglycerides and total cholesterol. Liraglutide also attenuated hypoadiponectinemia-induced deterioration in peripheral and hepatic insulin sensitivity and alterations in key regulatory factors implicated in glucose and lipid metabolism. These findings demonstrated for the first time that liraglutide could be used to rescue IR induced by hypoadiponectinemia and HFD via regulating gene and protein expression involved in glucose and lipid metabolism. PMID- 21785814 TI - Rational development of telehealth to support primary care respiratory medicine: patient distribution and organisational factors. AB - AIMS: Telehealth may offer opportunities to support primary and secondary care of patients with respiratory disease. This study examined the potential for applying telehealth in a region of the UK by exploring the distribution of patients and examining attitudes to implementation of telehealth. METHODS: The distribution of patients with asthma, COPD, lung cancer and obstructive sleep apnoea (OSAS) in the NHS Highland Region (309,900 residents, 12,507 square miles) was determined from Quality and Outcomes Framework data and disease registers. Qualitative interviews with health professionals (n=20) focussing on the potential for telehealth in respiratory medicine were analysed using the Normalisation Process Model. RESULTS: The most remote general practices accounted for 40% of patients with asthma (7198/17822), 45% of those with COPD (2145/4721), 33% of lung cancer (199/605) and 35% of OSAS (169/489) patients. Urban figures were 28% of asthma patients, 26% of COPD patients, 25% of lung cancer and 31% of OSAS patients. Interviewees identified a range of telehealth applications they considered potentially beneficial including management, information and communication systems. However, they also identified challenges - mainly related to training, costs and infrastructure. CONCLUSIONS: Tailoring telehealth to support management of respiratory diseases in primary care requires knowledge of patient distribution, which will impact on the nature and feasibility of services. Individual and organisational capacities and attitudes are also likely to influence successful implementation. PMID- 21785815 TI - Our patients' fears may be getting the better of them: how do we deal with it? PMID- 21785816 TI - Piloting tele-monitoring in COPD: a mixed methods exploration of issues in design and implementation. AB - BACKGROUND: In 2008 NHS Lothian implemented a COPD tele-monitoring service incorporating a touch-screen computer for daily recording of symptoms and weekly oximetry and spirometry measurement. Data were transmitted by secure broadband link to a call centre where trained workers monitored data and contacted clinicians according to an agreed algorithm. AIMS: To explore the perceptions of patients and professionals about the pilot implementation of the COPD tele monitoring service. METHODS: In-depth interviews were undertaken with patients and professionals before and after installation of the tele-monitoring equipment. Interviews were recorded, transcribed and thematically analysed. Data on use of healthcare resources were obtained from primary care records. RESULTS: Twenty of the 27 patients in the pilot and 25 professionals participated. (n=55 interviews and one focus group). Patients were generally positive about the technology, which they perceived enabled earlier recognition of exacerbations and facilitated access to clinical advice. In contrast, clinicians had concerns about false positive symptom scores, difficulties in interpreting physiological data, overtreatment (reflected in a large increase in antibiotics and steroid prescribing), and an increased workload. CONCLUSIONS: Tele-monitoring was perceived by patients as improving access to professional care, but raised concerns for clinicians about possible over-treatment and how best to organise services to support the technology. PMID- 21785817 TI - Azacitidine induces demethylation of p16INK4a and inhibits growth in adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is one of the peripheral T-cell malignant neoplasms strongly associated with human T-cell leukemia virus type-I (HTLV-I). Although the viral transactivator protein Tax has been proposed to play a critical role in leukemogeneis, additional cellular events are required for the development of ATL. One of the genetic events of the disease is inactivation of tumor suppressor genes. The CDKN2A locus on chromosome 9p encodes 2 cell cycle regulatory proteins, p14ARF and p16INK4a, which share exon 2 using different reading frames. The p14ARF and p16INK4a genes have been implicated as tumor suppressor genes by their frequent mutation, deletion or promoter hypermethylation in a variety of human tumors. In this report, we describe the expression status of p14ARF and p16INK4a in 9 ATL cell lines (MT1, MT2, OKM3T, F6T, K3T, Oh13T, S1T, Su9T01 and HUT102). By reverse transcription polymerase chain reaction (RT-PCR), expression of p14ARF was not detected in one cell line (OKM3T), while expression of p16INK4a was not detected in 6 cell lines (OKM3T, MT1, MT2, Oh13T, S1T and Su9T01). In the OKM3T cell line, the shared exon 2 of the p14ARF/p16INK4a gene was deleted; however, the p16INK4a gene, was epigenetically inactivated in 5 other cells lines. In primary tumor cells obtained from ATL patients, p14ARF expression was absent in 6 of the 11 samples. We confirmed the methylation of the p16INK4a gene in MT1 and MT2 cells using the methylation-specific PCR (MSP) method. Treatment with 2.0 uM of Azacitidine (AZA), a demethylating agent, for 72 h restored p16INK4a transcript expression and induced growth inhibition in MT2 cells. Our results demonstrate that p16INK4a is epigenetically silenced in ATL. AZA offers a potential new therapeutic approach to improve the poor outcomes associated with ATL. PMID- 21785818 TI - A novel function of EpCAM in oral squamous cell carcinoma cells under anchorage independent conditions. AB - Epithelial cell adhesion molecule (EpCAM), involved in Ca2+-independent homotypic cell-cell adhesion in epithelial tissues, is overexpressed in several cancer types. Although studies investigating the function of EpCAM in cancers have shown that it plays a role in cell proliferation, invasion and metastasis, the overall function of EpCAM in cancer cells has remained elusive. Here, we report a novel function of EpCAM in multicellular aggregates (MCAs). EpCAM inhibition using RNA interference (RNAi) did not affect cell morphology, proliferation or expression of certain genes, including cyclin D1 in monolayer cultures of the human oral squamous cell carcinoma cell lines HSC-3 or HSC-4. However, in HSC-4 cells cultured as MCAs, suppression of EpCAM significantly reduced the expression levels of cyclin D1. Nuclear localization of the cyclin D1 protein was observed in MCAs of HSC-4 cells but not in MCAs of EpCAM knockdown HSC4 cells, suggesting that EpCAM regulates cyclin D1 expression and localization in HSC-4 cells under anchorage-independent conditions. We propose that targeting EpCAM might result in more efficient therapies under certain conditions of oral squamous cell carcinoma. PMID- 21785819 TI - Tumor-derived vascular endothelial growth factor (VEGF)-a facilitates tumor metastasis through the VEGF-VEGFR1 signaling pathway. AB - Vascular endothelial growth factor (VEGF) and its receptors are involved in carcinogenesis, invasion and tumor angiogenesis, but the underlying mechanism by which VEGF promotes tumor metastasis is poorly understood. In this study, we show that in cancer patients high expression of VEGF is correlated with metastasis, and anti-VEGF treatment (bevacizumab) has clinical effects on tumor metastasis. Two human lung carcinoma cell lines (A549 and SPCA1 cells) with distinct VEGF expression were injected intravenously through the lateral tail vein of SCID mice and a murine model was developed. We investigated the association between the expression of VEGF and tumor metastasis by microvessel density, immunohistochemistry and whole mount staining. At sacrifice, in the high VEGF expression A549 cell line group, the induced tumor was distinctively larger in size and multiple metastatic lesions were found in lung tissues. Two specific neutralizing anti-mouse VEGFR1 and VEGFR2 antibodies were administered to the tumor-bearing mice; anti-VEGFR1, but not anti-VEGFR2 treatment produced inhibitive effects on VEGF-induced tumor metastasis. These findings demonstrate that the VEGF-VEGFR1 signaling pathway is crucial for tumor metastasis and the blockade of VEGF-VEGFR1-induced metastasis may provide a novel approach for the prevention and treatment of tumor metastasis. PMID- 21785820 TI - Model examination of chemoprevention with retinoids in squamous cell carcinomas of the head and neck region and suitable biomarkers for chemoprevention. AB - The prognosis for patients with head and neck tumors (HNSCC) is poor, due among other things to the high-risk factor for locoregional recurrence and/or second primary tumors. Extensive studies on chemoprevention of oral pre-cancers to stop carcinogenesis and to prevent recurrence and/or second primary tumors have failed to reach the desired effects. The toxicity of retinoids (RA) for example limits their dosage. Biomarkers are used to evaluate the duration of therapy. In this study, cell culture models are used to demonstrate immunocytochemical expression of RA receptors (RAR, RXR), Ki-67 and p53 before and after all-trans retinoic acid (ATRA) treatment. Telomerase activity in PCR is used to assess the effectiveness of ATRA. Along with an RA-sensitive HNSCC cell line UM-SCC-35 we employed cell lines UM-SCC-14C and HaCaT. Our immunocytochemical examination produced no proof of a statistically significant change in expression of RARalpha, RARbeta or RXRgamma receptors after ATRA treatment, either in the cells of the sensitive UM-SCC-35 line or in HaCaT cells. The RARbeta and RXRgamma receptors showed increased expression after brief cell treatment of UM-SCC-14C. The reduced telomerase activity after prolonged treatment of the UM-SCC-35-cells with ATRA (as well as the reduced p53 expression) proved to be a biomarker for evaluating the success of therapy. Although XTT and MTT tests demonstrated that cell proliferation in UM-SCC-35 cells was inhibited after brief and extended RA influence, the immunocytological Ki-67 scores failed to confirm the inhibition. No reduction of p53 expression, of telomerase activity or of cell proliferation in the XTT and MTT test was detected in the RA-insensitive cell line UM-SCC-14C or in HaCaT cells. We also demonstrated the parameters used in examining the models in sections of carcinoma tissue and in control tissues from the head and neck region, so they can be examined in clinical chemopreventive studies on biopsy tissue. PMID- 21785821 TI - Androgen deprivation therapy affects BCL-2 expression in human prostate cancer. AB - BCL-2 is an integral protein of the external mitochondrial membrane that inhibits cell apoptotic death. We investigated the effect of androgen deprivation therapy (ADT) on BCL-2 expression in prostate cancer tissues. We studied BCL-2 expression in vivo in prostate cancer tissues obtained from patients who underwent radical prostatectomy after neoadjuvant ADT, by Northern and Western blot analysis, and immunohistochemistry. Moreover, gene transcriptional activity was also measured by nuclear run-on experiments. We demonstrated an increase of BCL-2 mRNA expression in patients who underwent neoadjuvant ADT for 1 month in comparison to patients who had not received any therapy. Moreover, we demonstrated that there were no significant modifications of BCL-2 mRNA levels in patients who underwent neoadjuvant ADT for 3 and 6 months. Furthermore, BCL-2 protein levels in patients who underwent neoadjuvant ADT for 1 month were upregulated in comparison to patients who had not received any therapy. Immunohistochemical analysis showed a strong positivity of prostate cells depending on ADT administration for 1 month. Finally, transcriptional activity was not modified in patients who underwent neoadjuvant ADT, suggesting the absence of hormonal regulation on BCL-2 gene expression at the transcriptional level. Our data show that short-term administration of ADT interferes with BCL-2 expression, suggesting that androgen mediated mechanisms may act through BCL-2-mediated apoptotic pathways. Moreover, since short-term ADT administration does not interfere with BCL-2 expression at the transcriptional level, the androgen-mediated mechanisms involving BCL-2 pathways, probably act at the post-transcriptional level. PMID- 21785822 TI - Anti-tumor activity of the proteasome inhibitor bortezomib in gastric cancer. AB - The prognosis of unresectable advanced gastric cancer has improved over the last decade due to advances in chemotherapy. However, molecular targeting in gastric cancer therapy has been poorly established and the 5-year survival rate is still <10%. The proteasome plays a pivotal role in the regulation of cell proliferation, apoptosis and differentiation in a variety of tumor cells. Bortezomib, a selective inhibitor of the proteasome, has prominent effects against several tumor types, including multiple myeloma. We examined the anti tumor effects of bortezomib on gastric cancer cells in vitro and in subcutaneously transplanted nude mice. We demonstrated that among seven types of gastric cancer cells examined, treatment with bortezomib induced both apoptotic and anti-proliferative effects, resulting in a reduction in cell survival rates. The induction of apoptosis was observed to be dependent on the inhibition of nuclear factor kappaB (NF-kappaB) activation and the subsequent production of reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) activation. Interestingly, we observed that those cells with high levels of NF-kappaB activity were resistant to bortezomib treatment. Additionally, we demonstrated that the activation of the extracellular signal-regulated kinase (ERK1/2) was inhibited following bortezomib treatment, which may contribute to its anti proliferative effects. We also observed anti-tumor effects of bortezomib in vivo. Bortezomib is a potential novel molecular targeting drug for the treatment of unresectable advanced gastric cancer. PMID- 21785823 TI - Three-dimensional culture promotes reconstitution of the tumor-specific hypoxic microenvironment under TGFbeta stimulation. AB - In vitro tumor growth in a three-dimensional (3D) architecture has been demonstrated to play an important role in biology not only for developmental organogenesis and carcinogenesis, but also for analyses on reconstitution and maintenance in a variety of biological environments surrounding the cells. In addition to providing architectural similarity to living organisms, 3D culture with a radial flow bioreactor (RFB) can also closely mimic the living hypoxic microenvironment under which specific organogenesis or carcinogenesis occurs. The findings of the present study under the RFB culture conditions show that cancer cells underwent a shift from aerobic to hypoxic energy metabolism, in addition to protein expression to maintain the 3D structure. In RFB-cultured cells, protein stability of hypoxia-inducible factor 1 (HIF1) alpha, a subunit of HIF1, was increased without upregulation of its mRNA. Under these conditions, PHD2, HIF prolyl-4-hydroxy-lase 2 and a HIF1 downstream enzyme, were stabilized without affecting the mRNA levels via downregulation of FK506-binding protein 8. PHD2 accumulation, which occurred concomitant with HIF1 stabilization, may have compensated for the lack of oxygen under hypoxic conditions to regulate the HIF levels. 3D-culture-induced overexpression of carbonic anhydrase (another representative HIF downstream enzyme) was found to occur independently of cell density in RFB--cultured cells, suggesting that the RFB provided an adequately hypoxic microenvironment for the cultured cells. From these results, it was hypothesized that the key factors are regulatory molecules, which stabilize and degrade HIF molecules, thereby activating the HIF1 pathway under a hypoxic milieu. PMID- 21785824 TI - Osteopontin regulates growth and migration of human nasopharyngeal cancer cells. AB - Naspharyngeal carcinoma (NPC) is a common malignant tumor. Radiotherapy is the main treatment for patients with early-stage NPC. Some chemotherapeutic methods have been used to delay the progression of NPC during the later stages. Osteopontin (OPN), a secreted phosphoglycoprotein, has been shown to be involved in cell proliferation, migration and invasion in a variety of tumor models. However, the effect of OPN on the proliferation and migration activity of human NPC cells is still unknown. In this study, we detected the expression of OPN in NPC CNE-2 cells, and investigated the roles of OPN in CNE-2 cells. Our results show that the down-regulation of OPN inhibits the growth and migration of CNE-2 cells. Additionally, our results indicate that the cell number in the G2 phase can be regulated by OPN. We further demonstrate that OPN shRNA down-regulates the expression of MMP-2 and MMP-9, and that OPN overexpression up-regulates the expression of MMP-2 and MMP-9. PMID- 21785825 TI - Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes. AB - Evidence supports that oxidative stress exerts significant effects on the pathogenesis of heart dysfunction. On the other hand, the presence of specific androgen receptor (AR) in mammalian cardiomyocytes implies that androgen plays a physiological role in cardiac function, myocardial injury and the regulation of the redox state in the heart. This study used the testicular feminized (Tfm) and castrated male mice to investigate the effects of testosterone deficiency, physiological testosterone therapy and AR on oxidative stress in cardiomyocytes. Tfm mice have a non-functional AR and reduced circulating testosterone levels. Male littermates and Tfm mice were separated into 5 experimental groups: non castrated littermate controls, castrated littermates, sham-operated Tfm, testosterone-treated castrated littermates and testosterone-treated sham-operated Tfm mice. Cardiomyocytes that were isolated from the left ventricle were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) enzyme activities, and malondialdehyde (MDA) levels. Additionally, mitochondrial DNA (mtDNA) deletion mutations were detected by nested PCR. The SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the proportion of mtDNA mutations were increased in castrated and sham-operated Tfm mice compared to control mice. However, an increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the proportion of mtDNA mutations in the mice that had received testosterone therapy. These changes were statistically similar in castrated and sham-operated Tfm mice after testosterone therapy. In conclusion, it is testosterone deficiency that induces oxidative stress in cardiomyocytes. Physiological testosterone therapy is able to suppress oxidative stress mediated via the AR-independent pathway. PMID- 21785826 TI - Microvascular architecture of early esophageal neoplasia. AB - Progress in magnifying endoscopy has allowed endoscopic atypia to be evaluated on the basis of the presence or the absence of microvascular hyperplasia in a tumor. We focused our attention on intra-epithelial papillary capillary loops (IPCLs) and studied 20 cases of esophageal neoplasia (IPCL type III, 10 cases; IPCL type IV, 10 cases) and 99 vessels (IPCL type III, 24 vessels; IPCL type IV, 75 vessels). We evaluated the histopathological findings and measured vessel caliber, distance from the basement membrane, distance between blood vessels and thickness of the epithelium. According to the Vienna classification, the histological findings in the 10 patients with IPCL type III lesions were classified as category 1 (negative for neoplasia/dysplasia) in 8 patients and category 3 (non-invasive low grade neoplasia) in 2 patients. The histological findings in the 10 patients with IPCL type IV lesions were classified as category 1 in 1 patient, category 3 in 4 patients and category 4 (non-invasive high grade neoplasia) in 5 patients. The vessel caliber of IPCL type IV lesions (mean, 5.9 +/- 2.7 um) was significantly larger than that of IPCL type III lesions (mean, 4.8 +/- 1.5 um) (P=0.013). The distance from the basement membrane of IPCL type IV lesions (mean, 99.9 +/- 34.4 um) was significantly greater than that of IPCL type III lesions (mean, 58.0 +/- 36.2 um) (P=1.52562E-06). The distance between blood vessels and the thickness of the epithelium did not differ significantly between IPCL type III and IPCL type IV lesions. Our results revealed that changes in vessels of IPCL type IV lesions involve two factors: increased vessel caliber and prolongation of IPCLs toward the surface. These vascular changes appear to be associated with increased atypia of blood vessels. PMID- 21785827 TI - Notch1 is involved in migration and invasion of human breast cancer cells. AB - The Notch pathway displays several functions related to tumor progression. Breast carcinomas commonly express Notch1, Notch2, Notch3 and Notch4 at variable levels and these are mainly involved in differentiation, proliferation and survival. Notch1 can also induce the invasion of breast cancer cells. However, the precise role and mechanism of Notch1 in tumor invasion remains unclear. In this report, we used small interference RNA technology to knock down the expression of Notch1, resulting in reduced migration and invasion of breast cancer cells. Meanwhile, F actin polymerization, which is essential for cellular generation of the forces needed for motility, was also impaired in Notch1 knockdown cells. We further investigated the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteases-2 (MMP-2) and MMP-9, and found that the expression of functional EMMPRIN and MMP-2 was significantly decreased in Notch1 knockdown cells, while the expression of MMP-9 was constant. Additionally, the silencing of Notch1 expression likewise impaired cell-to-matrix and cell-to-cell adhesion. Western blotting results showed that reduction of Notch1 levels impacted the phosphorylation of PAK, phosphorylation of Akt, phosphorylation of FAK, the phosphorylation of integrin beta1, ICAM-1 and beta-catenin. Collectively, these findings suggest that targeting Notch1 has important therapeutic value in breast cancer. PMID- 21785828 TI - The flavonoid Baohuoside-I inhibits cell growth and downregulates survivin and cyclin D1 expression in esophageal carcinoma via beta-catenin-dependent signaling. AB - Esophageal cancer is one of the most common malignancies and is associated with a dismal prognosis. Although treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We found that Baohuoside-I, a flavonoid extracted from a Chinese medicinal plant, exhibits anticancer activity. Here, we demonstrated that Baohuoside-I significantly inhibited Eca109 human esophageal squamous carcinoma cell proliferation and induced Eca109 cell apoptosis in vitro and in vivo. The growth inhibitory effect of Baohuoside-I on the Eca109 tumor cell line was examined by MTT assay; the induction of apoptosis was analyzed by flow cytometry. Eca109-luc cells were injected into the subcutaneous tissue of nude mice to establish xenograft tumors. Our results revealed that Baohuoside-I caused a dose- and time-dependent inhibition of cell growth and an induction of apoptosis. Furthermore, Baohuoside-I-treated cells were characterized by decreased expression of the beta-catenin gene and protein in the total cell lysates. Thus, the gene and protein expression of the downstream elements survivin and cyclin D1 was downregulated. To determine the precise inhibitory mechanisms involved, further in-depth in vivo studies of Baohuoside-I are warranted. Our study provides the first evidence that Baohuoside-I inhibits tumor growth and induces apoptosis by inhibiting beta-catenin-dependent signaling pathways. Thus, Baohuoside-I is a potential candidate in ESCC disease therapy. PMID- 21785829 TI - Epigenetic silencing of microRNA-373 plays an important role in regulating cell proliferation in colon cancer. AB - microRNAs (miRNA) are non-coding RNAs that negatively control gene expression by cleaving or inhibiting the translation of target gene mRNAs. We used a microarray based transcriptomic analysis to identify miRNA expression levels that changed in response to epigenetic factors. Specifically, we searched for increased expression of miRNAs prepared from colon cancer cell line DLD-1 after a 96-h treatment with 5 uM of 5-aza-2'-deoxycytidine (DAC). Among those identified, transient transfection of miRNA hsa-miR-373 resulted in cytostasis. In addition, bisulfate sequence analysis of the promoter regions of these miRNAs showed aberrant methylation in the cancer cells. In clinical colon samples, hsa-miR-373 was down-regulated in colon cancers (29/40, 72.5%) relative to control samples, whereas the purported oncogene RAB22A (a target gene of hsa-miR-373) was up regulated (24/40, 60%). Using methylation-specific PCR, we also observed aberrant methylation of hsa-miR-373 in colon cancers (35/40, 87.5%) relative to controls (8/40, 20%). Based on these results, we conclude that expression of hsa-miR-373 is down-regulated by aberrant methylation in colon cancer and that this miRNA may function by regulating expression of the oncogene RAB22A. PMID- 21785831 TI - Social information processing as a mediator between cognitive schemas and aggressive behavior in adolescents. AB - This longitudinal investigation assessed whether cognitive schemas of justification of violence, mistrust, and narcissism predicted social information processing (SIP), and SIP in turn predicted aggressive behavior in adolescents. A total of 650 adolescents completed measures of cognitive schemas at Time 1, SIP in ambiguous social scenarios at Time 1 and Time 2, and reactive aggression at Time 1, Time 2, and Time 3 to determine whether SIP measured at Time 2 mediated between the cognitive schemas measured at Time 1 and the aggressive behavior measured at Time 3. The results showed that each schema predicted different SIP components: Justification of violence predicted aggressive response access, narcissism predicted anger and aggressive response access, and mistrust predicted more hostile attributions and less anger. Only the SIP component of aggressive response access was directly associated with reactive aggression. The mediational model was quite similar for boys and girls although some paths, such as the association between aggressive response access and reactive aggression, were higher for boys. PMID- 21785830 TI - The effect of down regulation of calcineurin Aalpha by lentiviral vector-mediated RNAi on the biological behavior of small-cell lung cancer and its bone metastasis. AB - Bone is the third most common site of cancer metastasis. Over 30 to 40% of lung cancers can develop skeletal metastasis and no effective curative therapy exists in clinic cases. Previously we screened the different expression of proteins between SBC-5 cells and SBC-3 cells by proteomic study methods (MALDI-TOF/TOF-MS) and found that calcineurin (hereafter referred as Cn) overexpresses in SBC-5 which has special priority in metastasis to bone in a multiple-organ metastasis mice model. However the roles of Cn in osteotropism of SCLC remain to be elucidated. At present study, we decrease CnAalpha expression in SBC-5 by lentiviral vector-mediated RNAi and found that down regulation of CnAalpha gene expression can decrease the proliferation and colony formation rate, impede the cell cycle progression, reduce the cell migration and invasion, and inhibit cells adhering to bone matrix, but not change the apoptosis rate of SBC-5 in vitro. In vivo down or up regulation of CnAalpha gene expression can only decrease or increase the bone metastasis rate, but not affect the metastasis rate to the visceral organs. Our research reveals that CnAalpha is closely related to the osteotropism metastasis of SCLC and a candidate tumor promotor gene for developing bone metastases. PMID- 21785832 TI - Translating 'distress' and screening for emotional distress in multicultural cancer patients in Israel. AB - BACKGROUND: The adaptability of the distress thermometer (DT) to multicultural groups has rarely been assessed. AIMS: To assess DT adaptability to the Israeli population as a multicultural society. METHODS: Participants were 496 cancer patients. They were recruited for 3 days a week in 2009-2010 (97% response rate). Participants completed the DT, a problem list, Hospital Anxiety and Depression Scale (HADS), and the Brief Symptom Inventory (BSI-18). RESULTS: Receiver operating characteristic (ROC) curve analyses of DT scores yielded area under the curve (AUC) of 0.63 as against HADS and of 0.78 as against BSI-18. ROC analysis revealed that the optimal cutoff score was >= 3. It yielded sensitivity and specificity of 0.74 and 0.65, as against the HADS, and 0.64 and 0.64, as against the BSI-18. The Jewish participants reported higher distress than the Arab participants, and the ROC properties were markedly higher for the Jewish subgroup alone. CONCLUSIONS: The adapted DT was moderately efficient for detecting emotional distress in cancer patients in Israel. Cultural aspects related to distress should be taken into account for administration of the DT in multicultural societies. PMID- 21785833 TI - PROMIS Pediatric Anger Scale: an item response theory analysis. AB - PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS) aims to develop patient-reported outcome (PROs) instruments for use in clinical research. The PROMIS pediatrics (ages 8-17) project focuses on the development of PROs across several health domains (physical function, pain, fatigue, emotional distress, social role relationships, and asthma symptoms). The objective of the present study was to report on the psychometric properties of the PROMIS Pediatric Anger Scale. METHODS: Participants (n = 759) were recruited from public school settings, hospital-based outpatient, and subspecialty pediatrics clinics. The anger items (k = 10) were administered on one test form. A hierarchical confirmatory factor analytic model (CFA) was conducted to evaluate scale dimensionality and local dependence. Item response theory (IRT) analyses were then used to finalize the item scale and short form. RESULTS: CFA confirmed that the anger items are representative of a unidimensional scale, and items with local dependence were removed, resulting in a six-item short form. The IRT-scaled scores from summed scores and each score's conditional standard error were calculated for the new six-item PROMIS Pediatric Anger Scale. CONCLUSIONS: This study provides initial calibrations of the anger items and creates the PROMIS Pediatric Anger Scale, version 1.0. PMID- 21785835 TI - Differentiation and neuro-protective properties of immortalized human tooth germ stem cells. AB - Stem cells are considered to be promising therapeutic options in many neuro degenerative diseases and injuries to the central nervous system, including brain ischemia and spinal cord trauma. Apart from the gold standard embryonic and mesenchymal origin, human tooth germ stem cells (hTGSCs) have also been shown to enjoy the characteristics of mesenchymal stem cells (MSCs) and the ability to differentiate into adipo-, chondro-, osteo- and neuro-genic cells, suggesting that they might serve as potential alternatives in the cellular therapy of various maladies. Immortalization of stem cells may be useful to avoid senescence of stem cells and to increase their proliferation potential without altering their natural characteristics. This study evaluated the expression of stem cell markers, surface antigens, differentiation capacity, and karyotype of hTGSCs that have been immortalized by human telomerase reverse transcriptase (hTERT) or simian vacuolating virus 40 (SV40) large T antigen. These undying cells were also evaluated for their neuro-protective potential using an in vitro SH-SY5Y neuro blastoma model treated with hydrogen-peroxide or doxo-rubicin. Although hTGSC SV40 showed abnormal karyotypes, our results suggest that hTGSC-hTERT preserve their MSC characteristics, differentiation capacity and normal karyotype, and they also possess high proliferation rate and neuro-protective effects even at great passage numbers. These peculiars indicate that hTGSC-hTERT could be used as a viable model for studying adipo-, osteo-, odonto- and neuro-genesis, as well as neuro-protection of MSCs, which may serve as a springboard for potentially utilizing dental waste material in cellular therapy. PMID- 21785836 TI - Quinoprotein adducts accumulate in the substantia nigra of aged rats and correlate with dopamine-induced toxicity in SH-SY5Y cells. AB - Parkinson's disease (PD) is an age-dependent neurodegenerative disorder characterized by dopaminergic neuron loss in substantia nigra. Previous studies have implicated a role of dopamine oxidation in PD. Dopamine oxidation leads to the formation of dopamine quinone, which generates reactive oxygen species and covalently modifies cysteinyl proteins to form quinoprotein adduct. We compared quinoprotein adduct formation and lipid peroxidation in different brain regions of young and old rats. We found a prominent age-dependent accumulation of quinoprotein adducts in the substantia nigra, while no significant change of lipid peroxidation was detected in any brain regions of 2- to 15-month old rats. To determine whether quinoprotein adduct formation correlates with dopamine induced cytotoxicity, we analyzed dopamine treated SH-SY5Y cells and found a strong correlation between quinoprotein adduct formation and cytotoxicity. Together, our results indicate that quinoprotein adduct formation may play a role in the age-dependent selective vulnerability of dopaminergic neurons in PD. PMID- 21785837 TI - Are there other possible pathways for the renal protective effects of statins? PMID- 21785838 TI - Renal cocktail: too hard for a diabetic. AB - We herein report a case of a 67-year-old diabetic woman who presented with a history of fatigue for 1 month. Her investigations showed proteinuria, active urine sediment, p-ANCA positivity and worsened renal functions. A diagnosis of rapidly progressive glomerulonephritis was made. Renal biopsy revealed class V (membranous) lupus nephritis with superimposed ANCA-associated crescentic glomerulonephritis. She was treated with steroids and cyclophosphamide. Two months later, she presented with cytomegalovirus colitis and deep vein thrombosis of right leg. The case reflects an interesting renal pathology, and complications of the disease per se and its treatment. PMID- 21785839 TI - Rangeland and pasture monitoring: an approach to interpretation of high resolution imagery focused on observer calibration for repeatability. AB - Collection of standardized assessment and monitoring data is critically important for supporting policy and management at local to continental scales. Remote sensing techniques, including image interpretation, have shown promise for collecting plant community composition and ground cover data efficiently. More work needs to be done, however, evaluating whether these techniques are sufficiently feasible, cost-effective, and repeatable to be applied in large programs. The goal of this study was to design and test an image-interpretation approach for collecting plant community composition and ground cover data appropriate for local and continental-scale assessment and monitoring of grassland, shrubland, savanna, and pasture ecosystems. We developed a geographic information system image-interpretation tool that uses points classified by experts to calibrate observers, including point-by-point training and quantitative quality control limits. To test this approach, field data and high resolution imagery (~3 cm ground sampling distance) were collected concurrently at 54 plots located around the USA. Seven observers with little prior experience used the system to classify 300 points in each plot into ten cover types (grass, shrub, soil, etc.). Good agreement among observers was achieved, with little detectable bias and low variability among observers (coefficient of variation in most plots <0.5). There was a predictable relationship between field and image interpreter data (R (2) > 0.9), suggesting regression-based adjustments can be used to relate image and field data. This approach could extend the utility of expensive-to-collect field data by allowing it to serve as a validation data source for data collected via image interpretation. PMID- 21785840 TI - Ammonia emissions from a broiler farm: spatial variability of airborne concentrations in the vicinity and impact on adjacent woodland. AB - Agricultural NH(3) emissions affect air quality and influence the nitrogen cycle. In the subject study, NH(3) emissions from a broiler farm and the resulting atmospheric concentrations in the immediate vicinity during three growing cycles have been quantified. Additionally, vegetation along a transect in an adjacent woodland was analysed. The emissions were as high as 10 kg NH(3) h(-1) and the atmospheric concentrations ranged between 33 and 124 MUg NH(3) m(-3) per week in the immediate vicinity. Measurements of the atmospheric concentrations over 7 weeks showed a substantial decline of mean concentrations (based on a 3-week average) from ~13 to <3 MUg NH(3) m(-3), at 45- and 415-m distance from the farm. Vegetation surveys showed that nitrophilous species flourished when they grew closest to the farm (their occurrence sank proportionately with distance). A clearly visible damage of pine trees was observed within 200 m of the farm; this illustrated the significant impact of NH(3) emissions from agricultural sources on the sensitive ecosystem. PMID- 21785841 TI - Exploring the utility of Posidonia oceanica chlorophyll fluorescence as an indicator of water quality within the European Water Framework Directive. AB - The European Water Framework Directive commits partner countries to evolve uniform protocols for monitoring the environmental condition of natural water bodies, crucially integrating biological and ecological criteria from the associated ecosystems. This has encouraged considerable research on the development of bioindicator-based systems of water quality monitoring. A critical step towards this end is providing evidence that the proposed bioindicator system adequately reflects the human pressures to which a specific water body is submitted. Here we investigate the utility of pulse-amplitude-modulated (PAM) fluorometry, a fast, non-destructive and increasingly popular bioindicator-based method, in assessing water quality based on the widespread Mediterranean seagrass Posidonia oceanica, an important constituent of submersed benthic vegetation. Specifically, we evaluated the ability of PAM to discriminate between sites along a pre-established gradient of anthropogenic pressures and the consistency and reliability of PAM parameters across spatial scales. Our results show that the maximum quantum yield (Fv/Fm), representing the structural photosynthetic efficiency of the plant, responds significantly to the degree of site-level anthropogenic pressure. However, Fv/Fm values in our study increased with increasing pressure, in striking contrast with other studies that report declines in Fv/Fm values with increasing stress. A potential explanation for this discrepancy is that our study sites were influenced by multiple diffuse stressors (characteristic of most coastal waters) that could potentially interact with each other to influence Fv/Fm values in often unpredictable ways. The photosynthetic variables calculated from rapid light curves (ETR(max), maximum electron transport rate; alpha, initial slope of the curve; I (k), saturating irradiance), which represent an instant picture of the photosynthetic activity of the plant, were unable to clearly discriminate between sites subject to different anthropogenic pressures due to considerable small-scale variability. Taken together, these results suggest that even though PAM fluorometry may be a good candidate tool for monitoring water bodies in terms of costs and applicability, considerably more needs to be understood about how its parameters respond to real world stressors, particularly when they act in concert with each other. With our present understanding of seagrass photosynthetic responses to anthropogenic stress, it would be ill advised to employ PAM as anything but a complementary tool to validate environmental stress derived with other, more robust methodologies. PMID- 21785842 TI - Groundwater contamination evolution in the Guadiamar and Agrio aquifers after the Aznalcollar spill: assessment and environmental implications. AB - In 1998, the Agrio and Guadiamar rivers underwent an enormous environmental disaster caused by the rupture of the Aznalcollar tailings dam and the release of 6 hm(3) of pyrite sludge and acidic water. Both rivers run over recent alluvial materials which form a small-sized aquifer which is however important because underground water feeds the flow of the rivers. This work analyzes the state of groundwater 10 years after the spill. Before the dam failure, this aquifer was already contaminated in the zone nearest to the mine, to which the impact of the spill was added. Contamination levels in the alluvial aquifer of the Agrio River have decreased remarkably. However, they are still important, with acidic pH values and high concentrations of toxic elements (maximum values of 16 mg/L of Zn and 15 mg/L of Al). There are also important levels of contamination in the Guadiamar alluvial area closest to the mine, as well as in specific zones located further south. The concentration of toxic elements is mainly controlled by pH. The evolution of contaminant levels show a sharp decrease after the first years following the spill, followed by a subsequent stabilization. It is necessary to take measures for the recovery of the aquifer because, otherwise, groundwater will continue contributing contaminants into the Agrio and Guadiamar rivers. PMID- 21785843 TI - The potential of hydrodynamic damage to animal cells of industrial relevance: current understanding. AB - Suspension animal cell culture is now routinely scaled up to bioreactors on the order of 10,000 L, and greater, to meet commercial demand. However, the concern of the 'shear sensitivity' of animal cells still remains, not only within the bioreactor, but also in the downstream processing. As the productivities continue to increase, titer of ~10 g/L are now reported with cell densities greater than 2 * 10(7) cells/mL. Such high, and potentially higher cell densities will inevitably translate to increased demand in mass transfer and mixing. In addition, achieving productivity gains in both the upstream stage and downstream processes can subject the cells to aggressive environments such as those involving hydrodynamic stresses. The perception of 'shear sensitivity' has historically put an arbitrary upper limit on agitation and aeration in bioreactor operation; however, as cell densities and productivities continue to increase, mass transfer requirements can exceed those imposed by these arbitrary low limits. Therefore, a better understanding of how animal cells, used to produce therapeutic products, respond to hydrodynamic forces in both qualitative and quantitative ways will allow an experimentally based, higher, "upper limit" to be created to guide the design and operation of future commercial, large scale bioreactors. With respect to downstream hydrodynamic conditions, situations have already been achieved in which practical limits with respect to hydrodynamic forces have been experienced. This review mainly focuses on publications from both the academy and industry regarding the effect of hydrodynamic forces on industrially relevant animal cells, and not on the actual scale-up of bioreactors. A summary of implications and remaining challenges will also be presented. PMID- 21785845 TI - Beyond clinical guidelines: highly effective intravenous thrombolysis therapy in a 104-year-old patient with severe acute ischemic stroke. PMID- 21785846 TI - Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide induced oxidative stress, mitochondrial dysfunction and apoptosis. AB - Vascular disease is the leading cause of morbidity and mortality. Oxidative stress can cause endothelial cell apoptosis. Low insulin like growth factor-1 (IGF-1) has been linked to adverse risk profile and increased vascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, we undertook this study to investigate whether IGF-1 favorably affects oxidative-stress mediated apoptosis of vascular endothelial cells. Exposure to hydrogen peroxide induced apoptotic changes (e.g. DNA fragmentation, altered mitochondrial membrane potential and caspase-3 activity) in human umbilical vein endothelial cells (HUVECs) in a time dependent manner. Addition of IGF-1 blocked the oxidative-stress effect parallel to IGF-1 receptor (IGF-1R) expression, and silencing the IGF-1R with small interference RNA attenuated the IGF-1 influence. Our findings show that enhanced IGF-1 signaling inhibits oxidative-stress induced apoptosis in HUVECs by reducing mitochondrial dysfunction. Specifically the protective mechanism of IGF-1 involves preserving the mitochondrial membrane potential, maintaining the mitochondrial retention of cytochrome-c, and reducing caspase-3 activity. These results may have therapeutic implications in preventing/reducing vascular disease associated endothelial dysfunction. PMID- 21785847 TI - Dietary anthocyanins protect endothelial cells against peroxynitrite-induced mitochondrial apoptosis pathway and Bax nuclear translocation: an in vitro approach. AB - Anthocyanins have received increasing attention because of their relatively high intake in humans and wide range of potential health-promoting effects, including anti-atherogenic properties. Evidences support their vascular protective effects but the involved molecular mechanisms have not been well clarified. The endothelium seems to have a central role in atherogenesis and apoptosis is emerging as a crucial event in this disease progression. Following our previous work on the biochemical pathways underlying peroxynitrite-triggered apoptosis in endothelial cells, here we investigated potential mechanisms responsible for the cytoprotective actions of three common anthocyanins, namely cyanidin- delphinidin and pelargonidin-3-glucoside, against this process. Beyond their antioxidant properties, all these flavonoids, possessing either catecholic or monophenolic structures, were able to counteract peroxynitrite-induced apoptotic effects in endothelial cells through the inhibition of several crucial signaling cascades. Actually, pre-incubation of cells with 25 MUM anthocyanins prevented them from peroxynitrite-mediated apoptosis, which was evaluated by the loss of mitochondrial membrane potential, caspases-9 and-3 activation, the increase in cytoplasmatic Bax levels and the inactivation of the PI3 K/Akt pathway. Moreover, they counteracted the translocation of Bax into the nucleus, as observed by immunocytochemistry and immunoblot, an event shown for the first time in endothelial cells apoptotic process. Such cellular actions could not be inferred from their in vitro antioxidant properties. These results suggest a potential role of dietary anthocyanins in the modulation of several apoptotic signaling pathways triggered by peroxynitrite in endothelial cells, supporting mechanistically their health benefits in the context of prevention of endothelial dysfunction and, ultimately, of atherosclerosis. PMID- 21785848 TI - Loeys-Dietz syndrome: cardiovascular, neuroradiological and musculoskeletal imaging findings. AB - Loeys-Dietz syndrome (LDS) is an increasingly recognized autosomal-dominant connective tissue disorder with distinctive radiological manifestations, including arterial tortuosity/aneurysms, craniofacial malformations and skeletal abnormalities. LDS exhibits a more aggressive course than similar disorders, such as Marfan or the vascular subtype of Ehlers-Danlos syndrome, with morbidity and mortality typically resulting from complications of aortic/arterial dissections. Early diagnosis, short-interval follow-up imaging and prophylactic surgical intervention are essential in preventing catastrophic cardiovascular complications. This review focuses on the cardiovascular, neuroradiological and musculoskeletal imaging findings in this disorder and recommendations for follow up imaging. PMID- 21785849 TI - Medication neurotoxicity in children. AB - Medication neurotoxicity may have a variety of imaging manifestations in children. In this pictorial essay, we review the two most common brain injury patterns, posterior reversible encephalopathy syndrome (PRES) and acute toxic leukoencephalopathy (ATL). Proposed etiologies, salient features on neurological imaging, and methods for differentiating these entities and their implications will be discussed. Certain agents do not fall into these two broad patterns but instead characteristically involve central structures. We individually review several medications and their respective neurotoxic appearances including methotrexate, cyclosporine A, tacrolimus, metronidazole and vigabatrin. Diagnosis of medication neurotoxicity may be achieved by the combination of new-onset neurological deficits, recent initiation of a new therapy agent and distinctive findings on magnetic resonance imaging. Clinical and radiological improvement and/or resolution are frequently observed after the agent is discontinued. PMID- 21785850 TI - Paediatric thyroid carcinoma in disguise: papillary thyroid carcinoma presenting with thyrotoxicosis and diffuse goiter. AB - Abstract Papillary thyroid carcinoma is rare in children. Its clinical manifestation may deviate from that observed in adult patients. We present a 14 year-old girl with papillary thyroid carcinoma. We then discuss various distinctive sonographic signs that may aid diagnosis, and we discuss differences in clinical features between children and adults [added]. PMID- 21785851 TI - Imaging the Rex vein preoperatively using wedged hepatic venous portography. AB - BACKGROUND: Mesentericoportal bypass, the Rex shunt, restores the physiological hepatic portal flow and reduces the clinical sequelae of portal hypertension in children with extrahepatic portal vein obstruction (EHPVO). The preoperative evaluation includes an accurate assessment of the portal venous inflow and outflow. The former is readily assessed by ultrasound and MRI, while the outflow intrahepatic portal vein is harder to assess. PURPOSE: To assess the efficacy of wedged hepatic venous portography (WHVP) at detecting a patent Rex vein preoperatively in children with EHPVO who were considered for mesenterico-portal bypass. MATERIALS AND METHODS: A single-institution retrospective chart review was undertaken for children with EHPVO who had been considered for a mesoportal bypass between January 2001 and January 2010. RESULTS: Sixteen children were considered for mesoportal bypass, including four post reduced-size liver transplant patients. Ten children (63%) underwent WHVP. The Rex vein was clearly identified in 8/10 (80%). One Rex vein was seen at surgery but not demonstrated at WHVP. Six mesoportal bypasses were performed without WHVP, of which three (50%) were successful. CONCLUSION: WHVP had a sensitivity of more than 80% and specificity of 100% in the preoperative patency assessment of the Rex vein. PMID- 21785852 TI - Comparison of MR enterography and histopathology in the evaluation of pediatric Crohn disease. AB - BACKGROUND: While MR enterography (MRE) is commonly used to identify segments of bowel affected by Crohn disease in children, there is little data to support this practice. OBJECTIVE: To assess the ability of MRE to identify segments of small bowel and colon affected by pediatric Crohn disease using histopathology as the reference standard. MATERIALS AND METHODS: Pediatric MRE examinations performed between April 2009 and December 2010 were identified. Subjects were excluded if they did not have Crohn disease, if they had Crohn disease but no correlative histopathology within 2 months of imaging, or if they had undergone prior bowel resection. Pertinent MRE and histopathology reports were reviewed, and normal and abnormal bowel segments were documented. RESULTS: Thirty-two pediatric MRE examinations were identified with correlative histopathology. MRE had an overall sensitivity of 94% for detecting the presence of Crohn disease, in general. At the bowel segmental level, MRE had a sensitivity of 66%, specificity of 90%, positive predictive value of 85% and negative predictive value of 76%. The terminal ileum was abnormal by MRE in 11 of 15 (73%) subjects lacking a diagnostic biopsy of this bowel segment. CONCLUSION: MRE successfully identifies small bowel and colon segments affected by pediatric Crohn disease. PMID- 21785853 TI - Celecoxib for recurrent sclerouveitis after syphilitic panuveitis. A case report. AB - PURPOSE: To report a case of recurrent ocular inflammation after optimal therapy of bilateral syphilitic panuveitis responding to oral celecoxib. METHODS: A case report was conducted. RESULTS: A 76-year-old man presented with painful blurry vision in both eyes. Ocular examination disclosed bilateral panuveitis. Serological testing confirmed blood and cerebrospinal fluid syphilitic involvement. After 2 weeks of intravenous penicillin therapy, recurrent episodic sclerouveitis was observed. CONCLUSION: Ocular inflammation after healing of infectious uveitis is a rare ophthalmic sequela. In an immunocompetent patient, either re-infection or immune uveitis should be evoked. Non-steroidal therapeutic options, as celecoxib, could be a good option of treatment in such immune cases. PMID- 21785854 TI - The RNA profile of porcine parvovirus 4, a boca-like virus, is unique among the parvoviruses. AB - PPV4 transcribes its genome from a single promoter, and the RNAs are generated via alternate splicing coupled with alternate polyadenylation, a strategy similar to that of the bocaviruses; however, several differences were detected. The PPV4 ORF1 codes for four NS proteins, while the bocavirus ORF1 codes for 1-3 NS proteins. Whereas the VP1/VP2 capsid proteins of bocavirus are encoded by a single RNA, VP1 and VP2 of PPV4 are encoded by two separate RNAs. While ORF3 of PPV4 encodes two NP proteins, ORF3 of bocavirus codes for only one NP polypeptide. Taken together, PPV4 is unique among the parvoviruses. PMID- 21785855 TI - Construction of a replicon and an infectious cDNA clone of the Sofjin strain of the Far-Eastern subtype of tick-borne encephalitis virus. AB - Tick-borne encephalitis virus (TBEV) causes severe encephalitis in humans. The Sofjin-HO strain is the prototype strain of the TBEV Far-Eastern subtype and is highly pathogenic in a mouse model. In this study, we constructed replicons and infectious cDNA clones of the Sofjin-HO strain. The replication of the replicon RNA was confirmed, and infectious viruses were recovered from the infectious cDNA clone. The recombinant viruses showed similar virulence characteristics to those of the parental virus. While characterizing the replicon and infectious cDNA, several amino acid differences derived from cell culture adaptations were analysed. The amino acids differences at E position 496 and NS4A position 58 were found to affect viral replication. The Gly- or Ala-to-Glu substitution at E position 122 was shown to increase neuroinvasiveness in mice. These replicons and infectious cDNA clones are useful in revealing the viral molecular determinants involved in the replication and pathogenicity of TBEV. PMID- 21785856 TI - Psychiatric and demographic predictors of memory deficits in African Americans with schizophrenia: the moderating role of cultural mistrust. AB - Although African Americans are overrepresented among schizophrenia diagnoses, assessments of memory deficits in schizophrenia often do not consider issues of race, ethnicity, and culture. Digit span testing (DST) is often used to assess memory problems associated with schizophrenia. The purpose of the current study was to examine the effects of psychiatric symptoms and demographic background on the DST performances of 128 African American schizophrenic patients. It was hypothesized that level of cultural mistrust would moderate the relationship of psychiatric and demographic variables to memory deficits. The study involved the secondary analysis of data from the Culturally-Sensitive Diagnostic Interview Research Project. Different models of the relationship among predictor variables in their impact on DST performance were tested via structural equation modeling (SEM); and the moderating effects of level of cultural mistrust were evaluated with the best SEM model. The results supported the hypothesis that level of cultural mistrust moderates the relationship among variables in the SEM model. Specifically, psychiatric symptoms negatively impacted DST performance in the low cultural mistrust group, but they had no significant association to the memory deficits of the high cultural mistrust group. The pattern of findings for the effects of psychiatric symptoms on DST performance is consistent with the view of cultural mistrust as an adaptive mechanism in African Americans. One implication is that cultural factors should be taken into account when assessing memory deficits in African Americans with schizophrenia. PMID- 21785857 TI - Factors associated with differential uptake of seasonal influenza immunizations among underserved communities during the 2009-2010 influenza season. AB - Influenza vaccination coverage remains low and disparities persist. In New York City, a community-based participatory research project (Project VIVA) worked to address this issue in Harlem and the South Bronx by supplementing existing vaccination programs with non-traditional venues (i.e., community-based organizations). We conducted a 10 min survey to assess access to influenza vaccine as well as attitudes and beliefs towards influenza vaccination that could inform intervention development for subsequent seasons. Among 991 participants recruited using street intercept techniques, 63% received seasonal vaccine only, 11% seasonal and H1N1, and 26% neither; 89% reported seeing a health care provider (HCP) during the influenza season. Correlates of immunization among those with provider visits during the influenza season included being US-born, interest in getting the vaccine, concern about self or family getting influenza, an HCP's recommendation and comfort with government. Among those without an HCP visit, factors associated with immunization included being US born, married, interest in getting the vaccine, understanding influenza information, and concern about getting influenza. Factors associated with lack of interest in influenza vaccine included being born outside the US, Black and uncomfortable with government. In medically underserved areas, having access to routine medical care and understanding the medical implications of influenza play an important role in enhancing uptake of seasonal influenza vaccination. Strategies to improve vaccination rates among Blacks and foreign-born residents need to be addressed. The use of non-traditional venues to provide influenza vaccinations in underserved communities has the potential to reduce health disparities. PMID- 21785858 TI - Prevalence of hepatitis B infection among young and unsuspecting Hmong blood donors in the Central California Valley. AB - Chronic hepatitis B virus (HBV) infection may result in cirrhosis and/or hepatocellular carcinoma and is one of the leading causes of mortality in Asian Americans including Hmong Americans. The Central California Valley is home to a huge Hmong population. To date, the true prevalence of HBV among Hmong is largely unknown. The aim of this study was to contribute to the limited data on HBV prevalence and its trends in Hmong population in the Central California Valley. Between fiscal years 2006 and 2010, a total of 219, 450 voluntary donors were identified at Central California Blood Center in Fresno. Of these, 821 (399 males and 422 females) were Hmong donors. A cross-sectional review of the HBV (hepatitis B surface antigen) positivity among all donors was carried out. Prevalence estimates with 95% confidence intervals (CI) were calculated. Ninety two percent of Hmong donors were between age groups 16 and 35 years, and only 8% were >=36 years. The overall prevalence in Hmong was noted at 3.41% (95%CI 2.3 4.9) compared to 0.06% (95%CI 0.05-0.07) in donors of all ethnicities. The calculated prevalence could be an underestimate of the true HBV prevalence in Hmong as the study enrolled only healthy blood donors with predominant younger age (<=35 years) population. These results underscore the persistent burden of HBV infection and potentially increased risk of premature death even in the second generation Hmong community of the Central California Valley. This study reemphasizes the unequivocal need to develop robust preventive and treatment strategies for HBV in Hmong community. PMID- 21785859 TI - Amino acids exhibit anti-inflammatory effects in human monocytic leukemia cell line, THP-1 cells. AB - OBJECTIVE: The elemental diet is one of the effective therapies for inflammatory bowel disease. However, the mechanism remains unclear, and there have never been reports about the inhibitory effects of amino acids in human monocytes/macrophages. We investigated the inhibitory effects of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases, in human monocytes/macrophages. METHODS: We examined the inhibitory effects of cysteine, histidine or glycine on the induction of nuclear factor-kappaB (NF-kappaB) activation, expression of intracellular adhesion molecule-1 (ICAM-1, CD54) and production of interleukin-8 (IL-8) in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood mononuclear cells (PBMCs) stimulated with tumor necrosis factor-alpha (TNF-alpha). RESULTS: Cysteine, histidine and glycine significantly reduced the activation of NF-kappaB in THP-1 cells stimulated with TNF-alpha. In addition, cysteine and histidine significantly inhibited the expression of ICAM-1 and production of IL-8 in THP-1 cells and PBMCs. CONCLUSIONS: Our results suggest that cysteine and histidine exhibit anti-inflammatory effects in THP-1 cells, and may be responsible for the efficacy of treatment in inflammatory bowel diseases. PMID- 21785861 TI - The organization of upper limb physiological tremor. AB - The objectives of this study are (1) to assess the relationship between tremor displacement of different segments of the upper limb, (2) to assess whether an attempt to voluntarily reduce tremor amplitude affects this relationship. Twenty five young healthy participants were tested. Tremor of the finger, hand, arm and shoulder was assessed using laser displacement sensors while the upper limb was in a postural position. Results show strong correlations (r > 0.90), high coherence (>0.9) and in-phase movement between tremor displacement oscillations of different segments. The majority of finger tremor amplitude can be predicted by angular movement generated at the shoulder joint (r(2) > 0.86). Participants were able to voluntarily reduce tremor amplitude, but no change in the relationship between segments was observed. Tremor of all segments of the upper limb was mechanically driven by the angular movement generated at the shoulder joint. This study provides evidence that there is no compensatory organization of physiological tremor. This lays the groundwork to evaluate whether pathological tremors also lack this organization. PMID- 21785860 TI - Effects of epoprostenol and sildenafil on right ventricular function in hypoxic volunteers: a tissue Doppler imaging study. AB - Sildenafil and epoprostenol are effective therapies in pulmonary arterial hypertension (PAH). Both drugs increase cardiac output, which has been in part attributed to improved right ventricular (RV) contractility. We therefore used tissue Doppler imaging (TDI) to test whether sildenafil and epoprostenol might differently affect RV function in normal subjects before and after induction of acute hypoxic pulmonary hypertension. Ten healthy volunteers underwent this randomized, double-blind, placebo-controlled cross-over study. Echocardiographic measurements were obtained 60 min after the intake of a placebo or 50 mg sildenafil or under 8 ng/kg/min iv epoprostenol, in normoxia or after 60 min of hypoxic breathing (FIO(2) of 0.12). Right ventricular systolic function was assessed by systolic strain (epsilon), strain rate (SR), isovolumic contraction acceleration (IVA) and tricuspid annulus plane systolic excursion (TAPSE), and diastolic function by tricuspid annulus E/A ratio and isovolumic relaxation time related to RR interval (IRT/RR). Pulmonary artery pressure was calculated from the acceleration time of pulmonary flow and cardiac output from the left ventricular outflow tract flow-velocity. Hypoxia increased pulmonary vascular resistance (PVR) by 78%, did not affect indices of RV systolic function, decreased E/A and increased IRT/RR. Epoprostenol more than sildenafil increased cardiac output, apical epsilon and TAPSE, the latter in proportion to decreased PVR. In addition, apical SR was increased only by epoprostenol. None of the drugs affected IVA, basal SR, E/A and IRT/RR. These results are not suggestive of intrinsic positive inotropic effects of either sildenafil or epoprostenol at maximal doses tolerated by normal subjects. PMID- 21785862 TI - Outcome of HIV exposed infants: experience of a regional pediatric center for HIV in North India. AB - OBJECTIVE: To study the outcome of HIV exposed infants in terms of mortality, morbidity, nutritional status and HIV infection status. METHODS: Retrospective analysis of data on 162 HIV exposed infants registered at Regional Pediatric Center for HIV, Delhi and meeting the inclusion criteria, was done. RESULTS: Median age at presentation was 6 wk. 17.4% mothers were on ART while 44.1% received NVP prophylaxis. 61.7% babies received NVP prophylaxis. Thirty-three percent of infants were symptomatic at presentation. Feeding strategy followed was breast-feeding in 18.7%, replacement feeding 71.6% and mixed feeding 9.7%. At presentation, 50.6% infants were wasted, 48.8% stunted and 39.4% had microcephaly. A progressive increase in proportion of children with under nutrition, stunting and microcephaly was noted with increasing age at presentation. Of the enrolled infants, 81 (50%) were alive and under follow-up. Among these, HIV infection was excluded in 65 infants (80.2% of those alive, 40.1% of the cohort). Thirty-four (21%) infants died and 47 (29%) were lost to follow-up. HIV infection was diagnosed in 24 (14.8%, 14 definite, 10 presumed). Of these 13 were alive and on ART, while 11 died. HIV status was not ascertained for the infants lost to follow-up and 23 infants who died. CONCLUSIONS: HIV infection is being under-diagnosed during pregnancy. Exposed infants have a high mortality and high prevalence of malnutrition. There is an urgent need for standardizing care of exposed infants to promote follow-up and prevent mortality by offering feeding counseling and ensuring early infection detection. PMID- 21785863 TI - Single dose of 50 mg/kg clofibrate in jaundice of healthy term neonates: randomised clinical trial of efficacy and safety. AB - OBJECTIVE: To evaluate the effect of single oral dose of 50 mg/kg clofibrate in hyperbilirubinemia of term healthy neonates in Yazd, Iran. METHODS: A parallel single- blinded randomized clinical trial, conducted on 60 healthy term neonates admitted between July and December 2007 to Shahid Sadoughi Hospital. Inclusion criteria were neonates with gestation age of 38-42 wk, birth weight of 2500-4000 g, product of normal vaginal delivery, breast-fed and total serum bilirubin (TSB) level of 17-29.9 mg/dL. Neonates with sepsis, anemia, severe asphyxia, hemolytic diseases, major congenital anomalies, indirect hyperbilirubinemia and underlying hepatic disorders were excluded. Selection of patients was based on random allocation via table of random numbers and the patients distributed into two groups. In group one, 30 neonates were treated with phototherapy alone and in 30 of other group treatment done with single dose of 50 mg/kg clofibrate and phototherapy. The primary endpoint with respect to efficacy in reducing of TSB was achieving TSB to less than 14 mg/dL as measured at the beginning, 12, 24 and 48 h after the start of phototherapy. Secondary outcomes were hospital stay days, duration of phototherapy and side effects of treatments during hospital stay and on the second day after discharge. RESULTS: No significant differences were seen from the viewpoint of rout of delivery, gender, gestational age, birth weight, hemoglobin and bilirubin level at time of admission and weight in discharge time in the two groups. After 48 h of intervention, 27 (90%) neonates in clofibrate group and 15 (56.7%) in control group had TSB of less than 14 mg/dL (p 0.02). Mean TSB 12 h after treatment (mean +/- SD: 14.82 +/- 1.7 mg/dL vs. 16.67 +/- 1.77 mg/dL, P 0.001), 24 h after treatment (mean +/- SD: 11.97 +/- 2.92 mg/dL vs. 14.61 +/- 2.52 mg/dL, P 0.001) and 48 h after treatment (mean +/- SD: 7.91 +/- 2.45 mg/dL vs. 12.74 +/- 2.21 mg/dL, P 0.0001), mean of hospital stay days (mean +/- SD: 1.7 +/- 0.7 days vs. 3.2 +/- 1.2 days, P 0.03) and duration of phototherapy (mean +/- SD: 30.2 +/- 13.99 h vs. 46.2 +/- 15.58 h, P 0.001] were significantly lower in clofibrate group. Only loose stool was seen in two patients of clofibrate group and no significant difference was seen from view of safety of the treatments. CONCLUSIONS: A single dose of 50 mg/kg clofibrate in treatment of neonatal hyperbilirubinemia is effective, safe and cost effective in view of reducing hospital stay days. PMID- 21785864 TI - The effect of baclofen and diazepam on motor skill acquisition in healthy subjects. AB - Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing or decreasing ankle dorsiflexor torque. Subjects trained for a total of 30 min. Transcranial magnetic stimulation of the primary motor cortex leg area was applied to elicit motor evoked potentials in the anterior tibial muscle (TA). Coupling between populations of TA motor units was calculated in the frequency (coherence) domain during isometric dorsiflexion. Subjects receiving placebo showed statistically significant improvement in motor performance (q = 34.1, P = 0.014) accompanied by a statistically significant reduction in intramuscular coherence. Subjects receiving baclofen and diazepam conversely showed no progression in motor performance (P > 0.05), and the training was not accompanied by a decrease in intramuscular coherence. TA motor evoked potentials had significantly lower threshold following the training in the placebo group, whereas this was not the case in the treatment groups. These data indicate that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy. PMID- 21785865 TI - Effect of exposure to detergents and other chemicals on biomarkers of pulmonary response in exhaled breath from hospital cleaners: a pilot study. AB - PURPOSE: The main aim of the study was to provide evidence whether professional cleaning was associated with biomarkers of lung damage in non-invasively collected biological fluids (exhaled air and exhaled breath condensate--EBC). MATERIALS AND METHODS: This cross-sectional study involved 40 cleaners regularly exposed to cleaning detergents and 40 controls. The subjects completed a standard questionnaire from European Community Respiratory Health Survey (ECRHS II) and underwent a spirometry. Fractional exhaled nitric oxide (F(E)NO) was measured online, and pH, ammonium (NH(4) (+)), H(2)O(2) and 4-hydroxynonenal (4-HNE) were assayed in EBC. RESULTS: Among the cleaners, the frequency of asthma and rhinitis was, respectively, 2.5 and 20%. The most frequently reported symptoms were sneezing (27.5%), nasal and/or pharyngeal pruritus (25%), ocular pruritus (22.5%) and cough (22.5%). There were no significant differences in comparison with the control group. Median F(E)NO levels were higher in African than in Caucasian cleaners (21.5 [16.5-30.0] ppb and 18.0 [13.5-20.5] ppb; p < 0.05). H(2)O(2)-EBC (0.26 [0.09-0.53] MUM vs. 0.07 [0.04-0.15] MUM; p < 0.01), NH(4) (+)-EBC (857 [493-1,305] MUM vs. 541 [306-907] MUM; p < 0.01) and pH-EBC (8.17 [8.09-8.24] vs. 8.06 [7.81-8.10]; p < 0.01) were higher in the cleaners than in the controls. Finally, the cleaners showed significant correlations between pH-EBC and NH(4) (+)-EBC (r = 0.33, p < 0.05) and a weak correlation between 4-HNE-EBC and H(2)O(2)-EBC (r = 0.37, p < 0.05). CONCLUSION: The promising role of EBC analysis in biomonitoring of exposed workers was confirmed. It was also possible to identify the potential biomarkers of exposure to alkaline products (increased ammonium-EBC and pH-EBC levels) and potential biomarkers of oxidative stress (increased H(2)O(2)-EBC levels correlated with 4-HNE-EBC levels) in workers with no signs of airway diseases. PMID- 21785866 TI - Occupational exposures to asbestos, polycyclic aromatic hydrocarbons and solvents, and cancers of the oral cavity and pharynx: a quantitative literature review. AB - PURPOSE: The role of occupational risk factors in oral and pharyngeal cancer is not well known and is possibly underestimated. This quantitative review summarizes epidemiological findings on exposure to asbestos, polycyclic aromatic hydrocarbons and solvents, and cancers of the oral cavity and pharynx. METHODS: A systematic literature search was performed. We analyzed 63 publications: 8 from case-control studies and 55 from cohort studies. For agents with at least five available studies with homogenous exposure, a series of meta-analyses was conducted to provide quantitative pooled estimates of risks, using random effect models. RESULTS: Exposure to asbestos (meta-RR 1.25; 95% CI 1.10-1.42) and to polycyclic aromatic hydrocarbons (meta-RR 1.14; 95% CI 1.02-1.28) was found to be associated with oral and pharyngeal cancer risk. On the other hand, no association was found with exposure to solvents in general (meta-RR 0.98; 95% CI 0.77-1.23) but the strong heterogeneity between studies suggested differences in exposures. The small number of studies with homogeneous exposure did not allow meta-analyses for specific solvents. CONCLUSIONS: Future investigations should overcome common weaknesses of past studies, in terms of sample size, characterization of exposure, and classification of cancer sites. PMID- 21785867 TI - Polymer phosphorylases: clues to the emergence of non-replicative and replicative polymers. AB - Polymer formation is arguably one of the essential factors that allowed the emergence, stabilisation and spread of life on Earth. Consequently, studies concerning biopolymers could shed light on the origins of life itself. Of particular interest are RNA and polysaccharide polymers, the archetypes of the contrasting proposed evolutionary scenarios and their respective polymerases. Nucleic acid polymerases were hypothesised, before their discovery, to have a functional similarity with glycogen phosphorylase. Further identification and characterisation of nucleic acid polymerases; particularly of polynucleotide phosphorylase (PNPase), provided experimental evidence for the initial premise. Once discovered, frequent similarities were found between PNPase and glycogen phosphorylase, in terms of catalytic features and biochemical properties. As a result, PNPase was seen as a model of primitive polymerase and used in laboratory precellular systems. Paradoxically, however, these similarities were not sufficient as an argument in favour of an ancestral common polymerisation mechanism prior to polysaccharides and polyribonucleotides. Here we present an overview of the common features shared by polymer phosphorylases, with new proposals for the emergence of polysaccharide and RNA polymers. PMID- 21785868 TI - Time-course analysis of temporal preparation on central processes. AB - Participants usually respond faster to a response signal (RS) when this signal is preceded by a warning stimulus than when it is not. A question of theoretical importance is the locus of this facilitating effect within the information processing stream. Recently, Los and Schut (Cogn Psychol 57:20-55, 2008) suggested that temporal preparation acts on central processes while perception of the RS is under way. The present study provides a stochastic model (central preparation model, CPM) based on this hypothesis and presents three experiments testing this model. To track the complete time-course of temporal preparation, the warning signal could either precede or follow the RS. The data show some systematic deviation from the model's predictions, questioning CPM's assumption that temporal preparation acts only on central processes. An alternative mechanism of temporal preparation based on the parallel grains model [Miller and Ulrich (Cogn Psychol 46:101-151, 2003)] is discussed. PMID- 21785869 TI - Tumor budding and dedifferentiation in gallbladder carcinoma: potential for the prognostic factors in T2 lesions. AB - Dedifferentiation (DD) is often encountered in gallbladder carcinoma (GBC) and poor prognosis with budding (BD) has been reported for other malignancies. However, the features of DD and BD in GBC remain unclear. The purpose of this study was to clarify the features and prognostic potential of DD and BD in GBC. A total of 80 patients with GBC (excluding intramucosal cancer) were enrolled. DD was histopathologically evaluated as tumors in which the grade of the invasive front is higher than the grade at the surface. BD was defined as an isolated single cancer cell or a cluster of fewer than five cancer cells at the invasive front. Of the 80 patients, 47 (58.8%) were positive for BD and 33 (41.2%) were positive for DD. Both BD and DD correlated significantly with disease-specific survival in univariate analysis (P < 0.0001 and P = 0.0013, respectively), but they were not identified as independent prognostic factors by multivariate analysis. In univariate analysis according to T stage, both BD and DD correlated significantly with survival in patients with T2 (n = 32) tumor (P = 0.0011 and P = 0.0018, respectively), whereas no prognostic impact in patients with T1b (n = 8), T3 (n = 34), or T4 (n = 6) tumor. Both DD and BD are frequently observed in GBC and reflect prognosis, particularly for T2 lesions. Therefore, the status of BD and DD should be taken into consideration in pathological reports on GBC. PMID- 21785870 TI - Specific expression of ZO-1 and N-cadherin in rosette structures of various tumors: possible recapitulation of neural tube formation in embryogenesis and utility as a potentially novel immunohistochemical marker of rosette formation in pulmonary neuroendocrine tumors. AB - Neuroendocrine tumors can develop in various organs. All of these tumors are designated on the basis of their morphologic characteristics evident by light microscopy, and by immunohistochemistry for antigens such as synaptophysin, chromogranin-A, and CD56/NCAM. In the present study, we attempted to demonstrate the localization of Zonula occludens-1 (ZO-1) and N-cadherin in rosette structures of neuroendocrine tumors using immunohistochemistry and to clarify their specific distribution in rosettes in human pulmonary neuroendocrine tumors in comparison with various types of adenocarcinoma. Among 40 neuroendocrine tumors of the lung examined, 18 cases (45%) and 22 cases (55%) were positive for ZO-1 and N-cadherin, respectively. In addition, we divided the cases into two types: 16 cases of Flexner-type tumor and 24 cases of Homer-Wright-type tumor. We then determined the Rosette Index (RoI; the percentage fraction of rosette structures positive for ZO-1 or N-cadherin among the total number of rosette structures). The Flexner-type neuroendocrine tumors showed significantly higher levels of RoI in ZO-1 than the Homer-Wright-type neuroendocrine tumors (median; 38.8% vs 0%, p < 0.001). On the other hand, N-cadherin and ZO-1 were hardly detected in tubular adenocarcinomas in various organs, and their immunoreactivities differed significantly between adenocarcinoma and pulmonary neuroendocrine tumor (ZO-1, mean 0.23% vs 18%, p < 0.0001; N-cadherin, mean 0% vs 33%, p < 0.0001). In conclusion, expression of ZO-1 and N-cadherin may reflect the mechanisms leading to rosette formation in neuroendocrine tumors, which possibly recapitulate neural tube formation in embryogenesis and could represent a specific immunohistochemical marker for neuroendocrine carcinoma of the lung. PMID- 21785871 TI - Measuring health outcomes of adolescents: report from a pilot study. AB - There is a need to understand the practicality, validity and reliability of using utility measures with children and adolescents. We designed a pilot study in order to help guide the selection of an appropriate health-related quality-of life (HRQoL) questionnaire for adolescents to be used in the context of a large randomised controlled trial (RCT) of family therapy versus standard treatment for adolescents aged 11-17 years. The pilot study was carried out on a school sample of adolescents in the same age range as the RCT. Adolescents were asked to fill in three HRQoL questionnaires: the standard EQ-5D, the licensed Health Utilities Index HUI, and the child-friendly version of the standard EQ-5D: the EQ-5D for youth (EQ-5D-Y). This report explores the problems with the language and concepts embodied within those HRQoL questionnaires and open discussion regarding how we can value the health of adolescents for cost-utility analysis in a larger study. PMID- 21785872 TI - Online sex-seeking behaviors among men who have sex with men: implications for investigation and intervention. AB - To investigate factors associated with online sex-seeking behaviors among men who have sex with men (MSM) in Beijing, China. MSM participants were recruited from two cohort studies with multiple enrollment methods from November 2006 to February 2007 and from March to June 2008, respectively. Data collected included demographics and sexual behaviors. Of the 901 participants, 68.1% were single; 69.3% were non-Beijing residents; 94.4% considered themselves to be homosexual; 65.2% received college or higher levels of education; the median age was 26 years; 73.0% sought male sex partners via the Internet in the past 3 months; 66.2% had >=2 sex partners. Younger age, higher levels of education and having had >=2 male sex partners in the past 3 months were independently associated with seeking sex partners on the Internet. These findings indicate that Internet-based intervention programs could encourage younger high-risk MSM to use condoms and reduce their numbers of sexual partners. PMID- 21785873 TI - Development of the perceived risk of HIV scale. AB - Past studies have used various methods to assess perceived risk of HIV infection; however, few have included multiple items covering different dimensions of risk perception or have examined the characteristics of individual items. This study describes the use of Item Response Theory (IRT) to develop a short measure of perceived risk of HIV infection scale (PRHS). An item pool was administered by trained interviewers to 771 participants. Participants also completed the risk behavior assessment (RBA) which includes items measuring risky sexual behaviors, and 652 participants completed HIV testing. The final measure consisted of 8 items, including items assessing likelihood estimates, intuitive judgments and salience of risk. Higher scores on the PRHS were positively associated with a greater number of sex partners, episodes of unprotected sex and having sex while high. Participants who tested positive for HIV reported higher perceived risk. The PRHS demonstrated good reliability and concurrent criterion-related validity. Compared to single item measures of risk perception, the PRHS is more robust by examining multiple dimensions of perceived risk. Possible uses of the measure and directions for future research are discussed. PMID- 21785874 TI - Ventricular resynchronization is the principle mechanism of benefit with cardiac resynchronization therapy. AB - Although there is little debate over the fact that cardiac resynchronization therapy (CRT) can benefit the majority of patients selected with routine indications, the precise mechanism for improvement may be considered controversial. Among patients selected with New York Heart Association functional class III or IV symptoms, left ventricular ejection fraction <= 35% and electrocardiographic QRS widening of at least 120-130 ms, approximately 60-80% of patients improved depending on the definition of response used. Although a reasonable assumption is that electrocardiographic QRS widening is a surrogate for delays in regional ventricular mechanical activation, a large volume of data has demonstrated that there is a subset of patients with widened QRS complexes who have no significant mechanical dyssynchrony. The reason for dissociation of electrical dispersion and mechanical dyssynchrony is unknown presently, but many studies have demonstrated the association of dyssynchrony with favorable outcome following CRT. Perhaps more importantly, several imaging studies (principally by echocardiography) have shown the lack of baseline mechanical dyssynchrony to be as a marker for a less favorable outcome after CRT. Recently, the lack of dyssynchrony before CRT has been shown to be associated with a significantly lower long-term probability of freedom from death, heart transplantation, or left ventricular assist device placement. As further mechanistic evidence for the relationship of mechanical dyssynchrony and LV functional response to CRT, it has been suggested that patients who failed to improve their tissue Doppler measures of dyssynchrony after CRT have a lower chance of reverse remodeling. This topic has been muddled by technical difficulties in measurement of mechanical dyssynchrony by all imaging approaches, the confounding variable of scar in ischemic disease, and the widely variable definitions of response used by different investigators. However, the weight of evidence from a pathophysiological basis to the recent long-term patient outcome data strongly support the notion that resynchronization is the principle mechanism of benefit from CRT. PMID- 21785875 TI - Metal concentrations in two bioindicator fish species, Merlangius merlangus, Mullus Barbatus, captured from the West Black Sea coasts (Bartin) of Turkey. AB - The Black Sea is very vulnerable to originating from land based human activities and its health is equally dependent on the coastal and non-coastal states of its basin. Total concentrations of cadmium, copper, zinc, lead, nickel, aluminum, iron, manganese, boron and chromium concentrations were determined in Merlangius merlangus (whiting) and Mullus barbatus found in Amasra in the West Coast of the Black Sea (Turkey). The metal contents that were measured in head and muscle was expressed in MUg g(-1) wet weight. On average, while the highest Fe (344.25 MUg g(-1)), Mn (10.35 MUg g(-1)), Cr (0.96 MUg g(-1)) and Al (76.77 MUg g(-1)) concentrations were measured in the heads of M. merlangus and the highest Zn (77.99 MUg g(-1)), Cu(8.53 MUg g(-1)), B (44.83 MUg g(-1)), Ni (1.96 MUg g(-1)), Cd (0.40 MUg g(-1)) and Pb (6.80 MUg g(-1)) concentrations were detected in the muscles of M. merlangus. There were significant differences between metal levels of muscles in these two species. In terms of permissible levels reported by WHO FAO and TSE, there is not any risk for human consumption for both M. merlangus and M. barbatus, for Pb. PMID- 21785876 TI - Organochlorine pesticides in soils from a typical alluvial plain of the Yangtze River Delta region, China. AB - Residues of organochlorine pesticides (OCPs), dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane (HCH), their risks and affecting factors in 544 representative soils collected from a typical alluvial plain of the Yangtze River Delta region, China, were investigated. Mean concentrations of SigmaDDT and SigmaHCH in soils were 88.8 and 99 ng/g, respectively. Historical application of DDT and HCH were the major sources of their residues in soils. Concentrations of DDT in soils had relative greater levels of contamination, while concentrations of HCH were almost at safe levels. Residues of DDT and HCH in soils were affected by soil types as well as soil textures. PMID- 21785877 TI - Genotoxicity of fenpropathrin and fenitrothion on root tip cells of Vicia faba. AB - The genotoxicity of fenpropathrin and fenitrothion on root tip cells of Vicia faba was studied. The symptoms were investigated about the mitotic index, the micronucleus frequency and chromosomal aberration frequency of root tip cells of Vicia faba which were induced by different concentrations of fenpropathrin and fenitrothion (1 * 10(-10)-1 * 10(-2) g L(-1)). Results showed that fenpropathrin and fenitrothion could induce the micronucleus of root tip cells of Vicia faba. It occurred in a dose-dependent manner. Peaks were observed at 1 * 10( -6) g L( 1) fenpropathrin and 1 * 10(-4) g L(-1) fenitrothion, and micronucleus frequency reached 14.587 +/- 1.5110/00 and 14.164 +/- 1.6230/00, respectively. From 1 * 10( 10) g L(-1) to 1 * 10( -6) g L(-1) fenpropathrin and 1 * 10(-4) g L(-1) fenitrothion, the micronucleus frequency increased with the increase of the concentrations, but beyond this range, the micronucleus frequency decreased with the further increase of the concentrations. A similar trend was observed for mitotic index. Moreover, fenpropathrin and fenitrothion could induce various types of chromosome aberration, such as lagging chromosomes, chromosome fragment, chromosome bridge, multipolar, nuclear buds, karyorrhexis, etc. PMID- 21785878 TI - Combined effect of copper and cadmium on heavy metal ion bioaccumulation and antioxidant enzymes induction in Chlorella vulgaris. AB - The relationships between metal uptake and antioxidant enzyme activities or a response to membrane lipid peroxidation (i.e., malondialdehyde production) in Chlorella vulgaris exposed to Cu and Cd compounds singly and in combination were investigated. The results showed that bioaccumulation of a single metal was influenced by the presence of the other metal. The activities of superoxide dismutase and peroxidase increased to more than fivefold of the control after exposure to Cu(1.5 MUM) alone or to Cu(1.5 MUM) with Cd mixtures. Malondialdehyde levels in C. vulgaris also increased to approximately twofold of the control after exposure to high concentration of Cu(1.5 MUM) alone or to Cu and Cd mixtures. However, Cd alone did not significantly increase the levels of antioxidant enzymes or malondialdehyde. PMID- 21785879 TI - Comparative tissue distribution of heavy metals in house sparrow (Passer domesticus, Aves) in polluted and reference sites in Turkey. AB - Bioindicators are useful for environmental monitoring in ecosystems with pollution loads. We compared concentrations of selected 10 metals in 42 samples of House Sparrow in a polluted by thermal power plant and reference sites. We found mean tissue concentrations of some metals to be significantly higher in sparrows from the polluted area when compared to tissues from the reference site. In liver mean concentrations of Cu (35.85 +/- 17.22 mg kg(-1)) and Zn (101.76 +/- 26.38 mg kg(-1)) were significantly higher and concentration of Ni (0.43 +/- 0.49 mg kg(-1)) were significantly lower in sparrows from the polluted area (p<0.05). The concentration of Cu was significantly higher in muscle and liver at the polluted site. Gender did not seem to influence residue levels, of the elements studied, among sparrows with the exception of kidney cobalt concentrations; which were higher in female sparrows than in males (p<0.05, t=-2.409). PMID- 21785880 TI - Implementation of systematic neuromonitoring training for thyroid surgery. AB - Neural monitoring is increasingly applied to thyroid surgery and yet few surgeons have received formal training in intraoperative neuromonitoring (IONM). Standardized application of neural monitoring is an expected outcome of formal training programs in IONM. This study was designed to document a systematic training course that focuses on standardized state-of-art IONM knowledge. Seventeen 1-day courses were organized by the Department of Surgical Sciences, University of Insubria Medical School (Varese-Como, Italy), between 2009-2010. The course included didactic and practical training sessions. Some specific steps and checklist identified for courses included: knowledge of IONM technology and troubleshooting algorithms; IONM anesthetic perspectives, standards of IONM equipment set up and technique. A total of 75 trainees completed a questionnaire after completion of the respective courses. Questions probed demographic data, operative IONM experience and evaluation of course content. Data gathered showed that 97% of participants had no prior experience with the standardized approach of IONM technique (i.e. stimulation of the vagal nerve). The most useful parts of the course were judged to be (a) algorithms for perioperative IONM problem solving (30%), (b) live surgery with hands-on training (25%), (c) standardization of IONM technique (25%), and (d) IONM equipment set-up (20%). Poor reimbursement for hospital thyroid procedures is the main reason of limitation of IONM technology. The course offered participants novel knowledge and training and gave participants a systematic and standard approach to IONM technique. PMID- 21785881 TI - Intussusception of the small bowel secondary to an enterolith from a jejunal diverticulum. AB - We report a case of acute, small bowel obstruction secondary to intussusception caused by an enterolith from a jejunal diverticulum, in an elderly female with a history of chronic, intermittent abdominal pain. Diagnostic work-up of the patient included a computed tomographic (CT) scan which demonstrated the intussusception, but not the enterolith, which was characteristically radiolucent. A laparotomy was performed and the enterolith was found and delivered. A fistula between the gallbladder and small bowel was sought, but not found. Multiple diverticulae were found throughout the small bowel. Although small bowel diverticulosis is rare, it should be considered in the differential diagnosis of the acute abdomen and chronic abdominal pain, especially in those with known colonic diverticulosis, in whom this condition is more common. PMID- 21785882 TI - Development of a full body CAD dataset for computational modeling: a multi modality approach. AB - The objective of this study was to develop full body CAD geometry of a seated 50th percentile male. Model development was based on medical image data acquired for this study, in conjunction with extensive data from the open literature. An individual (height, 174.9 cm, weight, 78.6 +/- 0.77 kg, and age 26 years) was enrolled in the study for a period of 4 months. 72 scans across three imaging modalities (CT, MRI, and upright MRI) were collected. The whole-body dataset contains 15,622 images. Over 300 individual components representing human anatomy were generated through segmentation. While the enrolled individual served as a template, segmented data were verified against, or augmented with, data from over 75 literature sources on the average morphology of the human body. Non-Uniform Rational B-Spline (NURBS) surfaces with tangential (G1) continuity were constructed over all the segmented data. The sagittally symmetric model consists of 418 individual components representing bones, muscles, organs, blood vessels, ligaments, tendons, cartilaginous structures, and skin. Length, surface area, and volumes of components germane to crash injury prediction are presented. The total volume (75.7 * 103 cm(3)) and surface area (1.86 * 102 cm(2)) of the model closely agree with the literature data. The geometry is intended for subsequent use in nonlinear dynamics solvers, and serves as the foundation of a global effort to develop the next-generation computational human body model for injury prediction and prevention. PMID- 21785883 TI - Design, development, and analysis of a surrogate for pulmonary injury prediction. AB - Current anthropomorphic test devices (ATDs) measure chest acceleration and deflection to assess risk of injury to the thorax. This study presents a lung surrogate prototype designed to expand the injury assessment capabilities of ATDs to include a risk measure for pulmonary contusion (PC). The surrogate augments these existing measures by providing pressure data specific to the lung and its lobes. The prototype was created from a rendering of a 50th percentile male lung inflated to normal inspiration, obtained from clinical CT data. Surrogate size, lobe volume, and airway cross sections were selected to match the morphology of the lung. Elastomeric urethane was molded via rapid prototyping to create a functional prototype. Pressure sensors in each of the five terminal airways independently monitored pressure traces in the lobes during impacts to the surrogate. Software was created to analyze the surrogate impact pressure data, determine the lobe with the greatest pressure rise for a particular impact, and estimate the initial speed of surface deformation. Calibration testing indicates an approximately linear relationship between peak lobe pressure and surface impact speed. No type I or II errors were demonstrated during lobe detection testing. During repeatability testing, the standard deviation was between 2 and 4% of the mean peak pressure. Ongoing research will focus on correlating surrogate data, pressure pulses, or surface deformation, to risk functions for PC. PMID- 21785885 TI - Multilevel measurement of dimensions of collaborative functioning in a network of collaboratives that promote child and family well-being. AB - Evaluating collaboration between community partners presents a series of methodological challenges (Roussos and Fawcett in Annu Rev Public Health 21:369 402, 2000; Yin and Kaftarian 1997), one of which is selection of the appropriate level of analysis. When data are collected from multiple members of multiple settings, multilevel analysis techniques should be used. Multilevel confirmatory factor analysis (MCFA) is an analytic approach that incorporates the advantages of latent variable measurement modeling and multilevel modeling for nested data. This study utilizes MCFA on data obtained from an evaluation survey of collaborative functioning provided to members of 157 community collaboratives in Georgia. This study presents a well-fitting measurement model that includes five dimensions of collaborative functioning, and a structural component with individual- and collaborative-level covariates. Findings suggest that members' role and meeting attendance significantly predicted their assessment of collaboration at the individual level, and that tenure of collaborative leaders predicted the overall functioning of the collaborative at the collaborative level. Dimensionality of collaborative functioning and implications of potentially substantial measurement biases associated with selection of respondents are addressed. PMID- 21785884 TI - Hemodynamics and in-stent restenosis: micro-CT images, histology, and computer simulations. AB - A model that combines the results of in vivo experiment, 3D image data, and computer simulation has been developed. Twelve identical stents were implanted into six healthy pigs and explanted at a range of different post-recovery periods from 6 h to 28 days. The stented vessel segments were embedded in methacrylate resin for the preparation of transverse histological sections and imaged using ultra-high resolution micro-CT. The resulting CT data was used to reconstruct the 3D geometry of the stents and one case was used to inform a 3D computational fluid dynamic model. Derived hemodynamic parameters such as wall shear stress (WSS), axial WSS, and oscillatory shear index were correlated with the distribution of neointimal hyperplasia, assessed from histomorphometric analyses. The direct comparison of hemodynamic parameters and biological response supports the hypothesis that low and oscillatory WSS lead to a greater neointimal response within the stented region. Moreover, the realistic geometry obtained from micro CT images, characterized by proximal overexpansion and asymmetric deployment of the stent, leads to a markedly non-uniform distribution of WSS values and correlates with asymmetric neo-intimal growth. This correlation cannot be appreciated from studies of idealized geometries. PMID- 21785886 TI - [Urology and National Socialism. Paul Rosenstein 1875-1964, the disrupted biography of a Jewish urologist]. AB - The biography of Paul Rosenstein (1875-1964) serves as an example of the fate of a Jewish scientist at the beginning of the twentieth century in an area of conflict between the development of urology as a specialty at greater urban hospitals, professional achievements as a surgeon and scientist, drastic breaks during Nazi era and escape from Nazi terror via New York to Brazil. PMID- 21785887 TI - [Certified prostate cancer centers and second opinion centers for testicular cancer: successful models of uro-oncology cancer care]. AB - Establishment of organ site-specific cancer centers by the German Cancer Society (GCS) is part of the basic politically driven reform of oncology care in Germany. Since 2007 an increasing number of prostate cancer centers have been guided toward certification by the OnkoZert GmbH of the GCS. Currently 68 centers are certified and together with ongoing certification proceedings will amount to 81 prostate cancer centers, which cover about one fourth of cases of primary prostate cancer. Urology is of particular importance in the management of these centers. For the most part, urologists belonging to a clinical unit are the initiators of the certification process, thus ensuring that uro-oncology is firmly entrenched in the specialty with involvement of outpatient service providers. Fears that authority will be lost are unfounded as long as responsibility for this task is taken seriously and active use is made of the possibilities for creativity. A similarly important function is fulfilled by the testicular cancer centers that offer second opinion services, which were initiated by urology conjointly with German Cancer Aid to pursue the goal of quality assurance for this tumor entity and therefore likewise secure the position of this tumor in the realm of urologists. By applying such strategic approaches, urologists will succeed in sustainably safeguarding their future importance in a very competitive environment and in counteracting the encroachments of other specialties by exhibiting clear orientation. PMID- 21785888 TI - Image-based monitoring of magnetic resonance-guided thermoablative therapies for liver tumors. AB - Minimally invasive treatment options for liver tumor therapy have been increasingly used during the last decade because their benefit has been proven for primary and inoperable secondary liver tumors. Among these, radiofrequency ablation has gained widespread consideration. Optimal image-guidance offers precise anatomical information, helps to position interventional devices, and allows for differentiation between already-treated and remaining tumor tissue. Patient safety and complete ablation of the entire tumor are the overriding objectives of tumor ablation. These may be achieved most elegantly with magnetic resonance (MR)-guided therapy, where monitoring can be performed based on precise soft-tissue imaging and additional components, such as diffusion-weighted imaging and temperature mapping. New MR scanner types and newly developed sequence techniques have enabled MR-guided intervention to move beyond the experimental phase. This article reviews the current role of MR imaging in guiding radiofrequency ablation. Signal characteristics of primary and secondary liver tumors are identified, and signal alteration during therapy is described. Diffusion-weighted imaging (DWI) and temperature mapping as special components of MR therapy monitoring are introduced. Practical information concerning coils, sequence selection, and parameters, as well as sequence gating, is given. In addition, sources of artifacts are identified and techniques to decrease them are introduced, and the characteristic signs of residual tumor in T1-, T2-, and DWI are described. We hope to enable the reader to choose MR sequences that allow optimal therapy monitoring depending on the initial signal characteristics of the tumor as well as its size and location in the liver. PMID- 21785889 TI - A comparison of seminar and computer based training on the accuracy and reliability of raters using the Children's Global Assessment Scale (CGAS). AB - The aim of this study was to compare two methods to conduct CGAS rater training. A total of 648 raters were randomized to training (CD or seminar), and rated five cases before and 12 months after training. The ICC at baseline/end of study was 0.71/0.78 (seminar), 0.76/0.78 (CD), and 0.67/0.79 (comparison). There were no differences in training effect in terms of agreement with expert ratings, which speaks in favor of using the less resource-demanding CD. However, the effect was modest in both groups, and untrained comparison group improved of the same order of magnitude, which proposes more extensive training. PMID- 21785890 TI - Weather, water quality and infectious gastrointestinal illness in two Inuit communities in Nunatsiavut, Canada: potential implications for climate change. AB - Climate change is expected to cause changes in precipitation quantity, intensity, frequency and duration, which will subsequently alter environmental conditions and might increase the risk of waterborne disease. The objective of this study was to describe the seasonality of and explore associations between weather, water quality and occurrence of infectious gastrointestinal illnesses (IGI) in two communities in Nunatsiavut, Canada. Weather data were obtained from meteorological stations in Nain (2005-2008) and Rigolet (2008). Free-chlorine residual levels in drinking water were extracted from municipal records (2005 2008). Raw surface water was tested weekly for total coliform and E. coli counts. Daily counts of IGI-related clinic visits were obtained from health clinic registries (2005-2008). Analysis of weather and health variables included seasonal-trend decomposition procedures based on Loess. Multivariable zero inflated Poisson regression was used to examine potential associations between weather events (considering 0-4 week lag periods) and IGI-related clinic visits. In Nain, water volume input (rainfall + snowmelt) peaked in spring and summer and was positively associated with levels of raw water bacteriological variables. The number of IGI-related clinic visits peaked in the summer and fall months. Significant positive associations were observed between high levels of water volume input 2 and 4 weeks prior, and IGI-related clinic visits (P < 0.05). This study is the first to systematically gather, analyse and compare baseline data on weather, water quality and health in Nunatsiavut, and illustrates the need for high quality temporal baseline information to allow for detection of future impacts of climate change on regional Inuit human and environmental health. PMID- 21785891 TI - Relationship between age and drinking instructions on the modification of drinking behavior. AB - Making appropriate recommendations for safe drinking behavior among different age groups requires understanding of differences between young and older adults in following them. The purpose of this study was to investigate how drinking behavior in terms of drinking speed and bolus size differs between young and older adults following instructions to change drinking rate. Thirty young (mean age 24.7 years) and 30 older (mean age 66.9 years) healthy female participants were recruited. All participants drank water under different drinking instructions: "as they normally would", "as quickly as is comfortably possible", and "slowly". Results showed that when asked to drink quickly, both age groups increased drinking speed to a similar extent. When asked to drink slowly, older adults were unable to slow their drinking rate as much as young adults (P < .001). When drinking slowly, older adults had significantly larger bolus size than young adults'. These suggest that in a healthcare setting, the often prescribed advice to "drinking slowly" may be insufficient precaution for older patients. Prudence is suggested to carefully observe patients drinking after they've been asked to drink slowly, before making a clinical judgment if additional, more specific strategies may be indicated. PMID- 21785892 TI - Understanding the association of biomedical, psychosocial and behavioral risks with adverse pregnancy outcomes among African-Americans in Washington, DC. AB - This study investigates the relationship between adverse pregnancy outcomes in high-risk African American women in Washington, DC and sociodemographic risk factors, behavioral risk factors, and the most common and interrelated medical conditions occurring during pregnancy: diabetes, hypertension, preeclampsia, and Body Mass Index (BMI). Data are from a randomized controlled trial conducted in 6 prenatal clinics. Women in their 1st or 2nd trimester were screened for behavioral risks (smoking, environmental tobacco smoke exposure, depression, and intimate partner violence) and demographic eligibility. 1,044 were eligible, interviewed and followed through their pregnancies. Classification and Regression Trees (CART) methodology was used to: (1) explore the relationship between medical and behavioral risks (reported at enrollment), sociodemographic factors and pregnancy outcomes; (2) identify the relative importance of various predictors of adverse pregnancy outcomes; and (3) characterize women at the highest risk of poor pregnancy outcomes. The strongest predictors of poor outcomes were prepregnancy BMI, preconceptional diabetes, employment status, intimate partner violence, and depression. In CART analysis, preeclampsia was the first splitter for low birthweight; preconceptional diabetes was the first splitter for preterm birth (PTB) and neonatal intensive care admission; BMI was the first splitter for very PTB, large for gestational age, Cesarean section and perinatal death; employment was the first splitter for miscarriage. Preconceptional factors strongly influence pregnancy outcomes. For many of these women, the high risks they brought into pregnancy were more likely to impact their pregnancy outcomes than events during pregnancy. PMID- 21785893 TI - Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences. AB - Extensive evidence indicates that heme oxygenase-1 (HO-1) exerts potent cytoprotective effects in response to stress. Previous studies have shown that gene therapy with HO-1 protects against myocardial ischemia/reperfusion injury for up to 8 weeks after gene transfer. However, the long-term effects of HO-1 gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the HO-1 gene (rAAV/HO-1) that enables long-lasting transgene expression. Mice received injections in the anterior LV wall of rAAV/LacZ (LacZ group) or rAAV/HO 1 (HO-1 group); 1 year later, they were subjected to a 30-min coronary occlusion (O) and 4 h of reperfusion (R). Cardiac HO-1 gene expression was confirmed at 1 month and 1 year after gene transfer by immunoblotting and immunohistochemistry analyses. In the HO-1 group, infarct size (% of risk region) was dramatically reduced at 1 year after gene transfer (11.2 +/- 2.1%, n = 12, vs. 44.7 +/- 3.6%, n = 8, in the LacZ group; P < 0.05). The infarct-sparing effects of HO-1 gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (15.0 +/- 1.7%, n = 10). There were no appreciable changes in LV fractional shortening, LV ejection fraction, or LV end-diastolic or end-systolic diameter at 1 year after HO-1 gene transfer as compared to the age matched controls or with the LacZ group. Histology showed no inflammation in the myocardium 1 year after rAAV/HO-1-mediated gene transfer. These results demonstrate, for the first time, that rAAV-mediated HO-1 gene transfer confers long-term (1 year), possibly permanent, cardioprotection without adverse functional consequences, providing proof of principle for the concept of achieving prophylactic cardioprotection (i.e., "immunization against infarction"). PMID- 21785895 TI - Is bilateral lower limb lengthening appropriate for achondroplasia?: midterm analysis of the complications and quality of life. AB - BACKGROUND: Use of the Ilizarov technique for limb lengthening in patients with achondroplasia is controversial, with a high risk of complications balancing cosmetic gains. Although several articles have described the complications of this procedure and satisfaction of patients after surgery, it remains unclear whether lengthening improves the quality of life (QOL) of these patients. QUESTIONS/PURPOSES: We asked whether bilateral lower limb lengthenings with deformity correction in patients with achondroplasia would improve QOL and investigated the correlation between complication rate and QOL. PATIENTS AND METHODS: We retrospectively reviewed 22 patients (average age, 12.7 years) diagnosed with achondroplasia who underwent bilateral lower limb lengthenings between 2002 and 2005. These patients were compared with 22 patients with achondroplasia for whom limb lengthening was not performed. The two groups were assessed using the American Academy of Orthopaedic Surgeons (AAOS) lower limb, SF 36, and Rosenberg self-esteem scores. Minimum followup was 4.5 years (range, 4.5 6.9 years). RESULTS: Among the lengthening group, the average gain in length was 10.21 +/- 2.39 cm for the femur and 9.13 +/- 2.12 cm for the tibia. A total of 123 complications occurred in these 88 segments. The surgical group had higher Rosenberg self-esteem scores than the nonsurgical group although there were no differences in the AAOS and the SF-36 scores. The self-esteem scores decreased with the increase in the number of complications. CONCLUSIONS: Our data suggest that despite frequent complications, bilateral lower limb lengthening increases patients' QOL. We believe lengthening is a reasonable option in selected patients. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21785894 TI - Ciliate metallothioneins: unique microbial eukaryotic heavy-metal-binder molecules. AB - This article represents an updated review of ciliate metallothioneins (Tetrahymena species) including a comparative analysis with regard to well-known metallothioneins (MTs) from other organisms and discussion of their exclusive features. It opens with an introduction to ciliates, summarizing the main characteristics of these eukaryotic microorganisms and their use as cellular models to study metallothioneins and metal-eukaryotic cell interactions. It has been experimentally proved that at least three different metal resistance mechanisms exist in ciliates, of which bioaccumulation is the most studied. Structural comparative analysis reveals that Tetrahymena MTs have unique characteristics, such as longer length, a considerably higher cysteine content, different metal-MT stoichiometry values, the presence of new cysteine clusters, and a strictly conserved modular-submodular structure. Gene expression analysis reveals a multistress and differential response to diverse metals and other environmental stressors, which corroborates the classification of these MTs. An in silico analysis of the promoter sequences of some MT genes reveals the presence of conserved motifs that are probably involved in gene expression regulation. We also discuss the great advantages of the first ciliate whole-cell biosensors based on MT promoters from Tetrahymena thermophila to detect heavy metal ions in environmental samples. PMID- 21785896 TI - Incidence of patients with lower extremity injuries presenting to US emergency departments by anatomic region, disease category, and age. AB - BACKGROUND: The incidence of patients with lower extremity injuries presenting to emergency departments in the United States with respect to specific anatomic regions and disease categories is unknown. Such information might be used for injury prevention, resource allocation, and training priorities. QUESTIONS/PURPOSES: We determined the anatomic regions, disease categories, and circumstances that account for the highest incidence of leg problems among patients presenting to emergency departments in the United States. METHODS: We used the National Electronic Injury Surveillance System (NEISS) to obtain a probability sample of all lower extremity injuries treated at emergency departments during 2009. A total of 119,815 patients who presented to emergency departments with lower extremity injuries in 2009 were entered in the NEISS database. Patient and injury characteristics were analyzed. Incidence rates for various regions, disease categories, injuries, and age groups were calculated using US census data. RESULTS: We identified 112 unique combinations of disease categories and anatomic regions. Strains and sprains accounted for 36% of all lower extremity injuries. The injury with the greatest incidence was an ankle sprain (206 per 100,000; 95% confidence interval, 181-230). Younger patients were more likely to have ankle sprains, foot contusions/abrasions, and foot strains/sprains. Older patients were more likely to have lower trunk fractures and lower trunk contusions/abrasions. The most common incidence for injury was at home (45%). CONCLUSIONS: Given relatively low-acuity leg problems such as strains and sprains account for a substantial number of emergency department visits pertaining to leg problems, use of telephone triage, scheduled same or next-day urgent care appointments, and other alternatives to the traditional emergency room might result in better use of emergency healthcare resources. PMID- 21785897 TI - Excretion kinetics of urinary 3-hydroxybenzo[a]pyrene following dietary exposure to benzo[a]pyrene in humans. AB - Urinary 3-hydroxy-benzo[a]pyrene (3-OHBaP) is considered as an exposure marker for assessing carcinogenic risks as it is a metabolite of benzo[a]pyrene (BaP). A controlled human study was conducted to examine the kinetics of urinary 3-OHBaP after consuming charcoal-barbecued meat. Two feeding experiments were performed, with meat doses of 15 and 30 g/kg (experiments 1 and 2, respectively). All voided urine over 7 days was collected and analyzed. The background urinary 3-OHBaP concentration was 0.002-0.085 ng/g creatinine, with large inter-individual (80 100%) and intra-individual of (90-100%) variations. The background amount of 3 OHBaP excreted by the current subjects was 40-50 pg/day. The amounts of urinary 3 OHBaP excreted within 12 h post-exposure increased significantly (P < 0.05) from background only in experiment 1. The proportion of the administered BaP dose that was excreted as urinary 3-OHBaP within 12 h post-exposure was 0.006 and 0.0012% in experiments 1 and 2, respectively. The excretion ratio declined as the dose increased. Urinary 3-OHBaP can be used to assess dietary exposure to BaP, but it may be not suitable for low-dose scenarios because of the low urinary excretion proportion and high variability of the background. PMID- 21785898 TI - C-reactive protein and pain sensitivity: findings from female twins. AB - BACKGROUND: Systemic inflammation and pain sensitivity may contribute to the development and maintenance of chronic pain conditions. PURPOSE: We examined the relationship between systemic inflammation as measured by C-reactive protein (CRP) and cold pain sensitivity in 198 female twins from the University of Washington Twin Registry. We also explored the potential role of familial factors in this relationship. METHODS: Linear regression modeling with generalized estimating equations examined the overall and within-pair associations. RESULTS: Higher levels of CRP were associated with higher pain sensitivity ratings at pain threshold (p = 0.02) and tolerance (p = 0.03) after adjusting for age, body mass index, time to reach pain threshold or tolerance, and clinical pain status. The magnitude of the associations remained the same in within-pair analyses controlling for familial factors. CONCLUSIONS: The link between CRP and pain sensitivity may be due to non-shared environmental factors. CRP and pain sensitivity can be examined as potential biomarkers for chronic pain and other inflammatory conditions. PMID- 21785899 TI - Fatigue, depression, sleep, and activity during chemotherapy: daily and intraday variation and relationships among symptom changes. AB - BACKGROUND: Previous research suggests that cancer patients frequently experience multiple symptoms during chemotherapy; however, relationships among symptom changes are largely unknown. PURPOSE: The aim of the current study was to examine daily and intraday changes and interrelationships among fatigue, depression, and objectively measured disruptions in sleep and activity during chemotherapy. METHODS: Participants were 78 women with gynecologic cancer. Fatigue, depression, sleep, and activity were assessed the week before and the week after the participants' first three infusions. RESULTS: Significant changes in fatigue, depression, sleep, and activity were observed over time. Before infusions, increases in fatigue were associated with increases in depression. After infusions, increases in fatigue were associated with increases in depression and minutes awake at night, as well as decreases in daytime activity and regularity of sleep/activity patterns (ps < .05). CONCLUSIONS: This study is among the first to track daily and intraday changes in symptoms and interrelationships during chemotherapy. Results indicate that symptoms are interrelated and return to baseline levels after infusions. PMID- 21785900 TI - Optimising the use of bone-targeted agents in patients with metastatic cancers: a practical guide for medical oncologists. AB - Bone metastases can be associated with a significant worsening of patient morbidity and mortality. Bisphosphonates have been extensively researched and shown to delay the onset and reduce the incidence of complications from bone metastases. The most commonly used bisphosphonates are intravenous pamidronate, intravenous ibandronate, intravenous zoledronic acid and oral/intravenous clodronate. Several bone-targeted agents with innovative mechanisms of action are currently being developed. These include receptor activator of nuclear factor-kB ligand (RANKL) inhibitors, CCR1 inhibitors, Src inhibitors, DKK1-neutralising antibodies, activin antagonists and endothelin-1 inhibitors. In an era of individualised medicine, oncologists are being faced with an increasing number of questions when dealing with bone-targeted agents. These questions not only include the choice of which drug to use (i.e. bisphosphonates or RANKL inhibitor) but also the best treatment strategy to use. This review will provide medical oncologists with a practical guide to the use of bone-targeted agents. PMID- 21785901 TI - Attitudes about violence and involvement in peer violence among youth: findings from a high-risk community. AB - Peer violence perpetration and victimization are the most common types of violence among youth. This study determined the associations among violent attitudes toward peers, involvement in peer violence perpetration, and experience with peer violence victimization among boys and girls in a high-risk, urban community. Analyses were based on data from the 2004 Youth Violence Survey, which was administered to over 80% of public school students in grades 7, 9, 11, and 12 (N = 4,131) in a disadvantaged, urban, school district in the USA. Logistic regression analyses were conducted to test the associations between attitudes in support of violence and involvement in violent behaviors. Results show that among youth, attitudes supporting boys hitting boys significantly increased the odds of peer violence perpetration after controlling for potential confounders (adjusted odds ratio [AOR], 1.35; 95% confidence interval [CI] = 1.07, 1.72). However, stratified analyses for boys and girls show that attitudes supporting boys hitting boys increased the odds of peer violence perpetration for girls only after controlling for potential confounders (AOR, 1.49; 95% CI = 1.05, 2.13). The findings demonstrate that there are important differences between boys and girls in terms of their associations with violent attitudes and involvement in actual violent behaviors. However, additional research is needed to determine how attitude modifications can be incorporated into youth violence prevention programs. PMID- 21785902 TI - Can lymphatic vascular density be used in determining metastatic spreading potential of tumor in invasive ductal carcinomas? AB - Regional lymph node status is the primary parameter determining treatment strategies and prognoses in breast cancer. Lymphatic vessels in primary tumor tissue play a significant role in lymphatic metastasis. The aim of this study was to investigate the correlation of intra- and peritumoral lymphatic microvessel densities (LVD) with prognostic parameters in breast cancer, including lymphatic invasion (LI). Lymphangiogenesis was investigated using D2-40 monoclonal antibody in 69 invasive ductal carcinoma cases who underwent mastectomy and axillary lymph node dissection. Positively stained microvessels were counted at 400* in dense lymphatic vascular foci (hotspots). Tumor LI was established when at least one neoplastic cell cluster was clearly visible inside a D2-40-positive lymph vessel. Relationships were sought between clinicopathological parameters and mean LVD and LI in primary tumor tissue. Peritumoral LVD was markedly higher than intratumoral LVD (p < 0.001). No significant relationship was found between intratumoral LVD and clinicopathological parameters (p > 0.05). However, significant relationships were detected between peritumoral LVD and LVI [H&E] (p = 0.04), number of lymphatic invasion [n/mm2, D2-40] (p = 0.001), tumor size (p = 0.01), lymph node status (p = 0.03), and tumor stage (p = 0.04). The immunohistochemical determination of LI and LVD can contribute to the prediction of a tumor's biological behavior in invasive ductal carcinomas. Peritumoral LVD in primary tumor tissue is closely related to parameters influencing the prognosis of a tumor. PMID- 21785903 TI - Higher serum DPP-4 enzyme activity and decreased lymphocyte CD26 expression in type 1 diabetes. AB - Dipeptidyl peptidase-4 (DPP-4) is involved in the metabolism of peptide hormones, T-cell activation and proliferation. In type 1 diabetes mellitus (T1DM) beta-cell destruction involves a number of dysregulated T-cells. Our aim was to assess the serum DPP-4 activity and the lymphocyte membrane bound CD26 expression in patients with type 1 diabetes and healthy controls. Ninety-eight (T1DM: 48, F/M = 20/28, mean age: 34.4y; control: 50, F/M = 39/11 mean age: 32,4y) individuals were included. Fasting serum DPP-4 enzymatic activity, plasma glucose (FPG), CD26 expression on CD3+, CD4+ and CD8+ lymphocytes, HbA1c and body mass index (BMI) were assessed. ICA and GAD antibodies were assessed in the T1DM group. DPP-4 enzymatic activity was determined by kinetic enzyme assay, ICA and GAD were assessed by ELISA. Determination of the CD26 expression on CD3+, CD4+ and CD8+ lymphocytes was performed by flow-cytometric analysis. We found higher serum DPP 4 activity (Mean: T1DM: 30.069 U/L, control: 22.62 U/L, p < 0.0001) and decreased CD26 lymphocyte expression on all lymphocyte subpopulations in T1DM. Fasting serum DPP-4 activity was independent from the ICA or GAD status of patients with T1DM. Here we first present that the serum DPP-4 activity is increased and the lymphocyte membrane bound CD26 expression is decreased in type 1 diabetes. Decreased lymphocyte membrane bound CD26 expression in T1DM might be a novel part of the T-lymphocyte regulatory dysfunction observed in type 1 diabetes mellitus. These results might provide some basis for the clinical implication of DPP-4 inhibition in patients with T1DM. PMID- 21785904 TI - An efficient multiplex genotyping approach for detecting the major worldwide human Y-chromosome haplogroups. AB - The Y chromosome is paternally inherited and therefore serves as an evolutionary marker of patrilineal descent. Worldwide DNA variation within the non-recombining portion of the Y chromosome can be represented as a monophyletic phylogenetic tree in which the branches (haplogroups) are defined by at least one SNP. Previous human population genetics research has produced a wealth of knowledge about the worldwide distribution of Y-SNP haplogroups. Here, we apply previous and very recent knowledge on the Y-SNP phylogeny and Y-haplogroup distribution by introducing two multiplex genotyping assays that allow for the hierarchical detection of 28 Y-SNPs defining the major worldwide Y haplogroups. PCR amplicons were kept small to make the method sensitive and thereby applicable to DNA of limited amount and/or quality such as in forensic settings. These Y-SNP assays thus form a valuable tool for researchers in the fields of forensic genetics and genetic anthropology to infer a man's patrilineal bio-geographic ancestry from DNA. PMID- 21785905 TI - Studies on the phase I metabolism of the new designer drug 3-fluoromethcathinone using rabbit liver slices. AB - The metabolism of the novel designer drug 3-fluoromethcathinone (3-FMC), sold as "legal highs", was investigated in vitro via cryopreserved rabbit liver slices. The pharmacological properties and toxicological effects of 3-FMC and its metabolites are not known yet. It can be assumed that 3-FMC will cause effects similar to 4-methylmethcathinone (mephedrone) and methcathinone. For the metabolism studies, pretests were performed with rabbit liver slices incubated with kavain to evaluate optimal conditions. Finally, six known metabolites of kavain were revealed and therefore sufficient information about the suitability of the enzyme system of the rabbit liver slices was obtained. Under optimized conditions, 3-FMC was added to Krebs-Henseleit buffer, pH 7.4 containing NADPH and bicarbonate and incubated with a single rabbit liver slice at 37 degrees C. The metabolism was monitored at 5, 30 and 180 min, respectively. The metabolites formed via the former cryopreserved rabbit liver slices were examined by LC/MS TOF. Metabolites were identified by their exact masses and isotopic patterns. 3 Fluorocathinone, 3-fluorocathinone-imine, hydroxy-3-fluoromethcathinone and 3 fluoromethcathinone-diol were formed as the main metabolites. PMID- 21785906 TI - Is mobility in the labor market a solution to sustainable return to work for some sick listed persons? AB - AIM: The study aims to identify characteristics associated with long-term expectations of professional stability or mobility among recently sick-listed workers, and to study whether expectations of professional mobility and turnover intentions were associated with duration of sick leave. METHODS: A cross sectional study was performed on baseline measures in a prospective cohort study of patients who were granted sick leave due to musculoskeletal (MSD) or mental (MD) disorders. A total of 1,375 individuals fulfilled the inclusion criteria. A baseline questionnaire was sent by mail within 3 weeks of their first day of certified medical sickness; 962 individuals responded (70%). The main diagnosis was MSD in 595 (62%) individuals and MD in 367 (38%). RESULTS: Expectations of ability to remain in the present profession in 2 years was associated with better health and health-related resources, younger age, higher education, and better effort-reward balance. Effort-reward imbalance, MD, high burnout scores, and better educational and occupational position were associated with turnover intentions. Low expectations of ability to remain in the present profession defined two vulnerable groups with regard to RTW, those with no turnover intentions were older, had lower personal resources, more often had MSD, and slower RTW rate. Those with turnover intentions had a clear effort-reward imbalance and high burnout scores. CONCLUSIONS: The results of this explorative study underline the importance of differentiating RTW-interventions based on knowledge about the sick-listed person's resources in relation to the labor market and the work place, and their expectations of future employment and employability. PMID- 21785907 TI - Validation of the PHQ-15 for somatoform disorder in the occupational health care setting. AB - INTRODUCTION: Within the occupational health setting, somatoform disorders are a frequent cause of sick leave. Few validated screening questionnaires for these disorders are available. The aim of this study is to validate the PHQ-15 in this setting. METHODS: In a cross-sectional study of 236 sicklisted employees, we studied the performance of the PHQ-15 in comparison with the Mini International Neuropsychiatric Interview (MINI) as golden reference standard. We approached employees who were sick listed for a period longer than 6 weeks and shorter than 2 years for participation. This study was conducted on one location of a large occupation health service in the Netherlands, serving companies with more than 500 employees. All employees who returned the PHQ-15 were invited for the MINI interview. Specificity and sensitivity were calculated for optimal cut point and a receiver operating characteristic (ROC) was constructed. RESULTS: A total of 107 participants consented to participate in the MINI interview. A non-response analysis showed no significant differences between groups. According to the MINI, the prevalence of somatoform disorders was 21.5%, and the most frequent found disorder was a pain disorder. The PHQ-15 had an optimal cut point of 9 (patients scoring 9 or higher (>=9) were most likely to suffer from a somatoform disorder), with specificity and sensitivity equal to 61.9 and 56.5%, respectively. ROCs showed an area under the curve (AUC) of 0.63. CONCLUSION: The PHQ-15 shows moderate sensitivity but limited efficiency with a cut point of 9 and can be a useful questionnaire in the occupational health setting. PMID- 21785908 TI - Forearm bone mineral density in familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a comparative study. AB - Studies have shown that cancellous bone is relatively preserved in primary hyperparathyroidism (PHPT), whereas bone loss is seen in cortical bone. Familial hypocalciuric hypercalcemia (FHH) patients seem to preserve bone mineral in spite of hypercalcemia and often elevated plasma parathyroid hormone (PTH). The objective of this study was to compare total and regional forearm bone mineral density (BMD) in patients with PHPT and FHH and to examine if differences can be used to separate the two disorders. We included 63 FHH, and 121 PHPT patients in a cross-sectional study. We performed dual-energy X-ray absorptiometry scans of the forearm, hip and lumbar spine and measured a number of biochemical variables. PTH patients had significantly lower Z-scores in all parts of the forearm compared to FHH. This was also the case after adjustment for body mass index. When stratifying for age, gender and PTH, T-scores were still significantly lower in PHPT patients than in FHH patients at the total, the mid and the ultradistal forearm, but not at the proximal 1/3 forearm. In a multiple regression analysis BMD Z-score was lower in PHPT compared to FHH at the total forearm, the mid forearm and the ultradistal forearm but not the proximal forearm when adjusting for biochemical variables including PTH, 1,25(OH)(2)D and Ca(2+). These observations support that inactivating mutations in the CASR gene in bone cells in FHH may protect against forearm bone loss. Differences between the two groups in total or regional forearm BMD were inferior to the calcium/creatinine clearance ratio as a diagnostic tool to separate FHH from PHPT. PMID- 21785909 TI - Controversial topics in the management of displaced supracondylar humerus fractures in children. AB - The aim of our study was to review the literature looking for the up to date information regarding these controversial topics. An electronic literature search was performed using the Medline/PubMed database. A closed reduction attempt should always be done first. It is more important to engage both columns as well as divergence of the pins no matter whatever configuration is applied. Time to surgery seems to be not an important factor to increase the risk of complications as well as open reduction rate. Usually neurological injuries present a spontaneous recovery. If there is absent pulse, we should follow the algorithm associated with the perfusion of the hand. PMID- 21785910 TI - Guided growth for correction of knee flexion deformity: a series of four cases. AB - Fixed knee flexion deformity can present as an insidious and significant problem in diverse etiologies, most commonly in cerebral palsy. Traditional surgical intervention has included posterior capsulotomy and supracondylar femoral osteotomy, both of which carry significant associated morbidity and risks. In the skeletally immature patient, guided growth may be used to correct or substantially diminish the deformity. We are presenting our early experience encompassing four subjects who completed instrumented gait analysis both prior to and after distal femoral anterior guided growth (hemiepiphysiodesis). Changes in gait and function resulting from surgery in each individual are reported. Outcomes indicate improved knee range of motion and alleviation of crouch at the knee with secondary improvements in the ankle, hip and pelvis. Three subjects with initially slow gait velocity improved to within normal limits by demonstrating increased stride length. A measure of overall gait kinematics showed improvements in all limbs. Anterior guided growth (hemiepiphysiodesis) of the distal femur resulted in positive quantitative changes in all four patients, though degree and types of changes were variable in this small series. Encouraged by these findings, we now prefer guided growth to extension supracondylar osteotomy for the skeletally immature patient with fixed knee flexion deformity. PMID- 21785911 TI - Transiliac lengthening with posterior lumbar-iliac percutaneous fusion in sacral hemiagenesis. AB - Sacral agenesis is a term that applies to a wide range of developmental disorders of the lower portions of the spine and pelvis. Hemisacrum patients with all sacral segments present on one side of the spine, and decompensated lumbar rotoscoliosis, whit instability torac-pelvic that had transiliac lengthening of the lower extremity, accomplished by an innominate osteotomy with interposition of a rectangular iliac-bone graft in the osteotomy site, besides a posterior lumbar-iliac percutaneous fusion. We reported 5 adolescent patients, 2 men and 3 women, treated from 2000 to 2009, associated with average pelvic imbalance of 3.2 cm (2.5-4.5 cm) without other associated congenital anomalies. Patients classified as Vergara (Acta Ortop Mex 19:6-12, 2005) type IB unilateral partial agenesis of the sacrum, asymmetry of the pelvic ring there's a torac-pelvic cifoscoliotic deformity. Mean age was 12.2 years-old (range from 8.2 to 13.7). The mean follow-up was 7.2 years (from 2 to 8). The consolidation process of the osteotomy site was in an average of 6.4 (5-8.7 weeks) (P = 0.036). None of the patients presented family medical history of diabetes on their mothers. None residual femoral nerve palsy. The procedure offers postural correction at the level of the pelvis, low morbidity and no additional operations were required to achieve the surgical objective. Level of evidence Level IV, therapeutic study: Case series (no, or historical, control group), Prospective: The study was started before the first patient was enrolled. PMID- 21785912 TI - Non-impactor-based methods for sizing of aerosols emitted from orally inhaled and nasal drug products (OINDPs). AB - The purpose of this article is to review non-impactor-based methods for measuring particle size distributions of orally inhaled and nasal pharmaceutical aerosols. The assessment of the size distributions of sprays and aerosols from orally inhaled and nasal drug products by methods not involving multi-stage cascade impaction may offer significant potential advantages in terms of labor savings and reducing the risk for operator-related errors associated with complex-to undertake impactor-based methods. Indeed, in the case of nasal spray products, cascade impaction is inappropriate and alternative, and preferably non-invasive methods must be sought that minimize size-related bias associated with the measurement process for these relatively large droplets. This review highlights the options that are available to those involved with product quality assessments, providing guidance on relative strengths and weaknesses, as well as highlighting precautions that should be observed to minimize bias. The advent of Raman chemical imaging, which enables an estimate to be made of the proportion of each particle comprising active pharmaceutical ingredient(s) (APIs), necessitates a re-think about the value of classical microscopy image analysis as now being capable of providing API-relevant information from collected aerosols and sprays. PMID- 21785913 TI - Combination of neoadjuvant chemotherapy followed by surgical resection as a new strategy for WHO grade II gliomas: a study of cognitive status and quality of life. AB - Diffuse WHO grade II (GIIG) may be unresectable when involving critical structures. To assess the feasibility and functional tolerance (cognition and quality of life) of an original therapeutic strategy combining neoadjuvant chemotherapy followed by surgical resection for initially inoperable GIIG. Ten patients underwent Temozolomide for unresectable GIIG, as initial treatment or at recurrence after previous partial resection, due to invasion of eloquent areas or bi-hemispheric diffusion preventing a total/subtotal removal. Functional outcome after both treatments was assessed, with evaluation of seven cognitive domains. Chemotherapy induced tumor shrinkage (median volume decrease 38.9%) in ipsilateral functional areas in six patients and in the contralateral hemisphere in four. Only four patients had a 1p19q codeletion. The tumor shrinkage made possible the resection (mean extent of resection 93.3%, 9 total or subtotal removals) of initially inoperable tumors. Postoperatively, three patients had no deficits, while verbal episodic memory and executive functions were slightly impaired in seven patients. However, global quality of life was roughly preserved on the EORTC QLQ C30 + BN 20 (median score: 66.7%). Role functioning score was relatively reduced (median score: 66.7%) whereas KPS was preserved (median score: 90, range 80-100). Seven patients became seizure-free while three improved. This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances). Cognitive deficits seem mostly related to tumor location. Because KPS is not reliable enough, a detailed neuropsychological assessment should be systematically performed in GIIG. PMID- 21785915 TI - Association of polymorphisms in transforming growth factor-beta receptors with susceptibility to gastric cardia adenocarcinoma. AB - Both transforming growth factor-beta receptor I (TGFBR1) and receptor II (TGFBR2) are serine/threonine kinases and play important roles in TGF-beta/Smads signal pathway. The case-control study was performed to evaluate the possible association of Int7G24A and *6A polymorphisms of TGFBR1 and G-875A polymorphism of TGFBR2 with susceptibility to gastric cardia adenocarcinoma (GCA) in a population of North China. Polymerase-chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR methods were used respectively to detect the genotype of Int7G24A, *6A and G-875A in 468 GCA and 584 healthy controls. Immunohistochemistry method was used to determine the protein expression of TGFBR1 and TGFBR2. Family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing GCA. There were no differences in the genotype distribution of TGFBR1 *6A polymorphism among cases and controls. However, A allele of Int7G24A significantly elevated the risk of developing GCA (adjusted OR = 1.34, 95% CI 1.03-1.87) and A allele of G-875A significantly decreased the risk of developing GCA (adjusted OR = 0.73, 95% CI 0.49-0.92). When stratified for TNM stage, A allele of Int7G24A and G-875A allele carriers had a 1.41-fold (95% CI 1.05-1.98) increased and a 0.70-fold (95% CI 0.47-0.92) decreased risk of stage III and IV gastric cardia adenocarcinoma. The protein expression of TGFBR1 and TGFBR2 in GCA was not correlated with genotypes of them. In conclusions, TGFBR1 Int7G24A and TGFBR2 G-875A polymorphisms may play important roles in the risk of GCA in North China. PMID- 21785914 TI - Revisiting the role of molecular targeted therapies in patients with brain metastases. AB - Brain metastases (BM) are treated with surgical resection when feasible. Unfortunately this occurs only in a small subset of patients. The optimal treatment for patients with intracranial metastases non amenable to surgical resection has not been identified. Radiotherapy improves symptom control and survival but long-term local control has been poor. Conventional chemotherapies have generally produced disappointing results possibly due to their limited ability to penetrate the blood brain barrier. Therefore, newer treatments are required for patients with unresectable BM. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review we will present current data on targeted therapies that have been approved for the treatment of malignant tumours and we discuss the evidence of their use in patients with BM. PMID- 21785916 TI - Spatial and temporal transcriptomic analysis of the Arabidopsis thaliana-Botrytis cinerea interaction. AB - Plants activate an array of defence responses following recognition of pathogenic organisms. This study attempted to characterize at a transcriptional level, the defence responses of Arabidopsis thaliana after infection with Botrytis cinerea using microarrays. Alteration in transcript levels following infection was investigated in time (temporal) and space (spatial). A number of genes were up- and down-regulated specifically at 12 h, others at 24 h while others were up- and down-regulated at both time points. Similarly, some genes were specifically induced very close to the lesion while others in more distal tissue. Clustering of expression profiles resulting from other biotic and abiotic interactions with Arabidopsis indicated a large overlap in gene expression. This study highlighted a multitude of genes induced in Arabidopsis spatially and temporally following infection with B. cinerea providing an insight into key processes of defence against this pathogen. The plethora of altered genes identified are candidates for further investigation. PMID- 21785917 TI - Quantified visual scoring of metastatic melanoma patient treatment response using computed tomography: improving on the current standard. AB - To assess whether quantitative visual scoring (QVS) is a better early predictor of progression-free survival (PFS) in patients on chemotherapy for metastatic melanoma using CT than the currently used Response Evaluation Criteria in Solid Tumors (RECIST) standard. Retrospective evaluation of 65 consecutive patients with metastatic melanoma on treatment who had a baseline and follow-up CT after two cycles of therapy. QVS was used to code imaging findings on the radiology reports considering size change, brain metastases, new lesions, mixed lesion response, and the number of organ systems involved. RECIST 1.1 criteria placed patients in the progressive disease, stable disease, or partial response groups. Multiple regression analysis was used to correlate the various independent variables with PFS. The Cox hazard proportions ratio, median survival, and Kaplan Meier curves of the different prognostic groups were calculated. QVS of size change was found more sensitive in detecting patients deteriorating (57.1% versus 37.5%) or improving (23.8% versus 10.7%), more correlated with the median PFS for the deteriorating (1.8 versus 1.7 months), stable (5.6 versus 4.0 month), and improving (8.3 versus 5.5 months) categories and more predictive of PFS (Cox hazard proportion ratio of 3.070 versus 1.860) than RECIST 1.1 categorization. Multiple regression analysis demonstrated QVS of lesion size correlated most closely with PFS among the variables assessed (r = 0.519, p < 0.0001). QVS in this study was superior to standard RECIST categorization in terms of discriminating treated metastatic melanoma patients likely to have longer PFS. PMID- 21785918 TI - Optimal size of jejunal pouch as a reservoir after total gastrectomy: a single center prospective randomized study. AB - BACKGROUND: In order to improve a patient's quality of life after total gastrectomy, jejunal pouch reconstruction has been employed. However, little information exists regarding the optimal size of the jejunal pouch after total gastrectomy. METHODS: The study was designed as a single-center randomized trial in which the results of double-tract reconstruction with pouches of two different sizes were compared, i.e., short and long pouch double tract (SPDT and LPDT, respectively). We conducted a clinical assessment with standard questionnaire after surgery. The amount of residual food in the jejunal pouch was determined by endoscopy. RESULTS: No demographic differences were noted between the two groups. The eating capacity per meal was higher in the SPDT group than in the LPDT group. The postoperative weight loss 24 months after surgery was lower in SPDT group than that in the LPDT group. Although the incidence of early dumping symptoms was higher in the SPDT group, no difference was noted in the other postprandial abdominal symptoms between the two groups. CONCLUSIONS: We conclude that the optimal pouch should be relatively short, as a short pouch improves the eating capacity per meal and the weight loss ratio to the preoperative value. PMID- 21785919 TI - Quantification of skeletal blood flow and fluoride metabolism in rats using PET in a pre-clinical stress fracture model. AB - PURPOSE: Blood flow is an important factor in bone production and repair, but its role in osteogenesis induced by mechanical loading is unknown. Here, we present techniques for evaluating blood flow and fluoride metabolism in a pre-clinical stress fracture model of osteogenesis in rats. PROCEDURES: Bone formation was induced by forelimb compression in adult rats. (15)O water and (18)F fluoride PET imaging were used to evaluate blood flow and fluoride kinetics 7 days after loading. (15)O water was modeled using a one-compartment, two-parameter model, while a two-compartment, three-parameter model was used to model (18)F fluoride. Input functions were created from the heart, and a stochastic search algorithm was implemented to provide initial parameter values in conjunction with a Levenberg-Marquardt optimization algorithm. RESULTS: Loaded limbs are shown to have a 26% increase in blood flow rate, 113% increase in fluoride flow rate, 133% increase in fluoride flux, and 13% increase in fluoride incorporation into bone as compared to non-loaded limbs (p < 0.05 for all results). CONCLUSIONS: The results shown here are consistent with previous studies, confirming this technique is suitable for evaluating the vascular response and mineral kinetics of osteogenic mechanical loading. PMID- 21785920 TI - Diplorickettsia massiliensis as a human pathogen. AB - Diplorickettsia massiliensis has been recently isolated from Ixodes ricinus ticks. We screened 13,872 serum samples from patients in France with suspected tick-borne diseases and found three cases that had serological evidence of D. massiliensis infection; for one of these three cases, we obtained molecular evidence of an infection as well. PMID- 21785921 TI - Cardiovascular imaging in diabetes mellitus. PMID- 21785922 TI - A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging. AB - BACKGROUND: Regadenoson myocardial perfusion imaging (MPI) is a useful method for risk assessment. We hypothesized that the heart rate response (HRR) to regadenoson carries incremental prognostic information to that derived from perfusion pattern and left ventricular (LV) ejection fraction (EF). METHODS AND RESULTS: The study population included 1,156 (60 +/- 13 years, 46% women, 40% diabetes mellitus, 53% chronic kidney disease) patients. During a follow-up period of 22 +/- 5 months, 103 patients died (9%). Independent determinants of the HRR included age, gender, race, diabetes mellitus, coronary revascularization, LVEF, use of insulin and aldosterone antagonists. Decreasing HRR was associated with stepwise increase in mortality (log-rank P < .0001). In a Cox proportional model for mortality that adjusted for age, gender, diabetes mellitus, renal disease, and MPI findings, HRR in the lowest quartile was independently associated with fivefold increase in mortality compared to the highest quartile [HR 5.2, 95% CI 2.3-12.0, P < .0001]. Patients with a normal HRR had a relatively low annualized total mortality despite the presence of risk factors. The addition of HRR to traditional MPI findings had a net reclassification improvement of 15%, P = .02. CONCLUSION: A blunted HRR to regadenoson is an independent predictor of poor outcome, adds incremental value to MPI, and helps in better risk stratification. PMID- 21785923 TI - Differences between primary care physicians' and oncologists' knowledge, attitudes and practices regarding the care of cancer survivors. AB - BACKGROUND: The growing number of cancer survivors combined with a looming shortage of oncology specialists will require greater coordination of post treatment care responsibilities between oncologists and primary care physicians (PCPs). However, data are limited regarding these physicians' views of cancer survivors' care. OBJECTIVE: To compare PCPs and oncologists with regard to their knowledge, attitudes, and practices for follow-up care of breast and colon cancer survivors. DESIGN AND SUBJECTS: Mailed questionnaires were completed by a nationally representative sample of 1,072 PCPs and 1,130 medical oncologists in 2009 (cooperation rate = 65%). Sampling and non-response weights were used to calculate estimates to reflect practicing US PCPs and oncologists. MAIN MEASURES: PCPs and oncologists reported their 1) preferred model for delivering cancer survivors' care; 2) assessment of PCPs' ability to perform follow-up care tasks; 3) confidence in their knowledge; and 4) cancer surveillance practices. KEY RESULTS: Compared with PCPs, oncologists were less likely to believe PCPs had the skills to conduct appropriate testing for breast cancer recurrence (59% vs. 23%, P < 0.001) or to care for late effects of breast cancer (75% vs. 38%, P < 0.001). Only 40% of PCPs were very confident of their own knowledge of testing for recurrence. PCPs were more likely than oncologists to endorse routine use of non recommended blood and imaging tests for detecting cancer recurrence, with both groups departing substantially from guideline recommendations. CONCLUSION: There are significant differences in PCPs' and oncologists' knowledge, attitudes, and practices with respect to care of cancer survivors. Improving cancer survivors' care may require more effective communication between these two groups to increase PCPs' confidence in their knowledge, and must also address oncologists' attitudes regarding PCPs' ability to care for cancer survivors. PMID- 21785924 TI - Human-induced pluripotent stem cells as a source of hepatocyte-like cells: new kids on the block. PMID- 21785925 TI - Clinical validity of endoscopic submucosal dissection for submucosal invasive gastric cancer: a single-center study. AB - BACKGROUND: The 2010 Japanese Gastric Cancer Association guidelines for the treatment of submucosal invasive gastric cancer (SM-GC) specify size 30 mm or less, differentiated-dominant histology, lack of vessel involvement, and submucosal invasion of less than 500 MUm (SM1) as expanded criteria for curative endoscopic resection. Our purpose in this study was to confirm the validity of the expanded indications for curative endoscopic submucosal dissection (ESD) of SM-GC. METHODS: The study subjects were 173 patients with SM-GC resected by ESD at Hiroshima University Hospital between April 2002 and September 2010, including 99 patients for whom 3-plus years' follow-up information was available. Post-ESD outcomes were compared between cases of SM1-GC that met the expanded ESD criteria, those that did not, and SM2-GC cases. RESULTS: Complete resection was achieved for 93.2% of the SM1-GCs that met the expanded criteria. There was neither metastasis to lymph nodes or other organs nor local recurrence among the SM1-GCs. Disease-specific survival did not differ significantly between patients that were simply followed up after ESD and those that were treated by additional surgical resection. CONCLUSIONS: Our outcome data support the clinical validity of ESD without additional surgical resection for SM1-GCs that meet the expanded criteria. PMID- 21785926 TI - Multivisceral resection for gastric cancer: a systematic review. AB - BACKGROUND: The overall prognosis and survival of patients with advanced gastric cancer is generally poor. One of the most powerful predictors of outcomes in gastric cancer surgery is an R0 resection. However, the extent of the required surgical resection and the additional benefit of multivisceral resection (MVR) are controversial. METHODS: Electronic literature searches were conducted using Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1, 1998 to December 31, 2009. All search titles and abstracts were independently rated for relevance by a minimum of two reviewers. RESULTS: Seventeen studies were included in this review. Among the 1343 patients who underwent MVR, overall complication rates ranged from 11.8 to 90.5%. Perioperative mortality was found to be 0-15%. Pathological T4 disease was confirmed in 28.8-89% of patients. R0 resection and extent of nodal involvement were important predictors of survival in patients undergoing MVR. Patient outcomes may also be affected by the number of organs resected. CONCLUSIONS: Gastrectomy with MVR can be safely pursued in patients with locally advanced gastric cancer to achieve an R0 resection. MVR may not be beneficial in patients with extensive nodal disease. PMID- 21785927 TI - Second-line chemotherapy for gastric cancer: a new issue lies ahead in global trials. AB - Chemotherapy for gastric cancer has been advancing fairly well. It has been indicated that not only advances in first-line chemotherapy but also those in second-line chemotherapy have contributed to the prolongation of overall survival. The Arbeitsgemeinschaft Internistische Onkologie (AIO) study supports the idea that second-line chemotherapy is appropriate in patients with a good general condition. Also, the Japan Clinical Oncology Group (JCOG) integral analysis suggests that advances have been made in second-line chemotherapy. However, most recently reported studies of second-line chemotherapy have been conducted as small-scale phase II or retrospective trials. No randomized control trial to establish standard treatment has been reported. Which regimen is the most appropriate as second-line therapy must be investigated in the future. Currently, molecularly targeted agents for gastric cancer are being developed and tested in global trials. As a new issue in global trials, second-line chemotherapy has been emphasized. In recent global trials, subset analysis showed regional differences in overall survival. This was possibly associated with the regional differences in second-line chemotherapy. When developing new molecularly targeted agents for first-line chemotherapy, we cannot ignore the result that the proportion of patients in whom treatment was switched to second-line chemotherapy was high in Asia. In planning a global trial, this new issue should be sufficiently discussed. PMID- 21785928 TI - What's New in the Management of Bacterial Septic Arthritis? AB - Septic arthritis is a common rheumatological emergency requiring prompt diagnosis and treatment, since delays in management can lead to high morbidity and mortality. In this review article, we discuss the epidemiology and recent advances in knowledge of the pathogenesis of septic arthritis, with a special emphasis on various bacterial and host factors involved in mediating the inflammatory process and the potential for targeted therapy to modulate the immune response. Recent advances in laboratory and imaging techniques are reviewed along with treatment and potential new therapies. PMID- 21785929 TI - Soft tissue infections caused by marine bacterial pathogens: epidemiology, diagnosis, and management. AB - Skin and soft tissue infections (SSTIs) are one of the most common infection syndromes and may be caused by a large number of microorganisms. Some principles of aquatic injuries are different than those of land-based trauma. Wounds sustained in marine environment are exposed to a milieu of bacteria rarely encountered in different settings. These include Vibrio spp., Aeromonas spp., Shewanella spp., Erysipelothrix rhusiopathiae, Mycobacterium marinum, Streptococcus iniae, and other microbes. Failure to recognize and treat these uncommon pathogens in a timely manner may result in significant morbidity or death. These infections are frequently contracted as a result of recreational swimming, fishing injuries, or seafood handling. The spectrum of manifestations is wide, varying from cases of mild cellulitis, to severe life-threatening necrotizing fasciitis requiring radical surgery, to sepsis and death. This review will focus on the epidemiology, clinical manifestations, and treatment of SSTIs caused by the most important marine pathogens. PMID- 21785930 TI - Development of a low-cost sterilization biological indicator using Bacillus atrophaeus by solid-state fermentation. AB - The production of biological indicators involving bacterial sporulation and multi step downstream processes has been described. The goal of the present work was to use fermented material as the final product in a biological indicator, thereby reducing processing steps and costs. The performance of three different inexpensive supports (vermiculite, sand, and sugarcane bagasse) was assessed by determining Bacillus atrophaeus sporulation during solid-state fermentation and by assessing the direct use of the fermentation products in the subsequent steps of the process. All three supports allowed spore production of between 10(7) and 10(9) CFU g(-1). Sand proved to be the best inert support enabling the direct use of the fermented product due to its easy homogenization, filling properties, and compatibility with recovery medium. Bacterial adhesion to the sand surface was supported by biofilm formation. The resistance to sterilization of the dried fermentation product was evaluated. For dry-heat resistance (160 degrees C), the D value was 6.6 min, and for ethylene oxide resistance (650 mg/L), the D value was 6.5 min. The cost reduction of this process was at least 48%. No previous studies have been published on the application of sand as a support in solid state fermentation for the production of biological indicators. PMID- 21785932 TI - In situ sensor techniques in modern bioprocess monitoring. AB - New reactor concepts as multi-parallel screening systems or disposable bioreactor systems for decentralized and reproducible production increase the need for new and easy applicable sensor technologies to access data for process control. These sophisticated reactor systems require sensors to work with the lowest sampling volumes or, even better, to measure directly in situ, but in situ sensors are directly incorporated into a reactor or fermenter within the sterility barrier and have therefore to stand the sterilization procedures. Consequently, these in situ sensor technologies should enable the measurement of multi-analytes simultaneously online and in real-time at a low price for the robust sensing element. Current research therefore focuses on the implementation of noninvasive spectroscopic and optical technologies, and tries to employ them through fiber optics attached to disposable sensing connectors. Spectroscopic methods reach from ultraviolet to infrared and further comprising fluorescence and Raman spectroscopy. Also, optic techniques like microscopy are adapted for the direct use in bioreactor systems (Ulber et al. in Anal Bioanal Chem 376:342-348, 2003) as well as various electrochemical methods (Joo and Brown in Chem Rev 108:638 651, 2008). This review shows the variety of modern in situ sensing principles in bioprocess monitoring with emphasis on spectroscopic and optical techniques and the progress in the adaption to latest reactor concepts. PMID- 21785931 TI - Fungal enzyme sets for plant polysaccharide degradation. AB - Enzymatic degradation of plant polysaccharides has many industrial applications, such as within the paper, food, and feed industry and for sustainable production of fuels and chemicals. Cellulose, hemicelluloses, and pectins are the main components of plant cell wall polysaccharides. These polysaccharides are often tightly packed, contain many different sugar residues, and are branched with a diversity of structures. To enable efficient degradation of these polysaccharides, fungi produce an extensive set of carbohydrate-active enzymes. The variety of the enzyme set differs between fungi and often corresponds to the requirements of its habitat. Carbohydrate-active enzymes can be organized in different families based on the amino acid sequence of the structurally related catalytic modules. Fungal enzymes involved in plant polysaccharide degradation are assigned to at least 35 glycoside hydrolase families, three carbohydrate esterase families and six polysaccharide lyase families. This mini-review will discuss the enzymes needed for complete degradation of plant polysaccharides and will give an overview of the latest developments concerning fungal carbohydrate active enzymes and their corresponding families. PMID- 21785933 TI - OH-functionalized open-ended armchair single-wall carbon nanotubes (SWCNT) studied by density functional theory. AB - The structures of ideal armchair (5,5) single-wall carbon nanotubes (SWCNTs) of different lengths (3.7, 8.8, and 16.0 A for C(40)H(20), C(80)H(20), and C(140)H(20)) and with 1-10 hydroxyl groups at the end of the nanotube were fully optimized at the B3LYP/3-21G level, and in some cases at the B3LYP/6-31G level, and the energy associated with the attachment of the OH substituent was determined. The OH-group attachment energy was compared with the OH functionalization of phenanthrene and picene models and with previous results for zigzag (9.0) SWCNT systems. In comparison to zigzag SWCNTs, the armchair form is more (by about 5 to 10 kcal mol(-1)) reactive toward hydroxylation. PMID- 21785934 TI - Computer-assisted design for atenolol prodrugs for the use in aqueous formulations. AB - Based on stability studies on the drugs atenolol and propranolol and some of their derivatives it is believed that increasing the lipophilicity of the drug will lead to an increase in the stability of its aqueous solutions and will provide a prodrug system with the potential for releasing atenolol in a controlled manner. Using DFT theoretical calculations we have calculated an intramolecular acid catalyzed hydrolysis in nine maleamic (4-amino-4-oxo 2butenoic) acids (Kirby's N-alkylmaleamic acids), 1-9. The DFT calculations confirmed that the acid-catalyzed hydrolysis mechanism in these systems involves: (1) a proton transfer from the hydroxyl of the carboxyl group to the adjacent amide carbonyl carbon, (2) an approach of the carboxylate anion toward the protonated amide carbonyl carbon to form a tetrahedral intermediate; and (3) a collapse of the tetrahedral intermediate into products. Furthermore, DFT calculations in different media revealed that the reaction rate-limiting step depends on the reaction medium. In aqueous medium the rate-limiting step is the collapse of the tetrahedral intermediate whereas in the gas phase the formation of the tetrahedral intermediate is the rate-limiting step. Furthermore, the calculations establish that the acid-catalyzed hydrolysis efficiency is largely sensitive to the pattern of substitution on the carbon-carbon double bond. Based on the experimental t(1/2) (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1-9 we have calculated the t(1/2) values for the conversion of the two prodrugs to the parental drug, atenolol. The calculated t(1/2) values for ProD 1-2 are predicted to be 65.3 hours and 11.8 minutes, respectively. Thus, the rate by which atenolol prodrug undergoes cleavage to release atenolol can be determined according to the nature of the linker of the prodrug (Kirby's N-alkylmaleamic acids 1-9). PMID- 21785935 TI - De novo design of 7-aminocoumarin derivatives as novel falcipain-3 inhibitors. AB - The availability of the crystal structure of falcipain-3, knowledge of the peptides carrying the 7-aminocoumarin moiety as falcipain-3 ligands/substrates, and a need for new antimalarial agents stimulated us to look at the possibility of finding some novel falcipain-3 inhibitors. In this paper, we report the effect of substitution at the 7-amino position of the coumarin nucleus on the inhibition of falcipain-3, which is a well-validated antimalarial target. The de novo drug design was assisted by QSAR studies that shed light on the binding patterns of known and the newly designed inhibitors, thus taking this discovery process to the next level. PMID- 21785936 TI - Atomistic modeling of water diffusion in hydrolytic biomaterials. AB - One of the most promising applications of hydrolytically degrading biomaterials is their use as drug release carriers. These uses, however, require that the degradation and diffusion of drug are reliably predicted, which is complex to achieve through present experimental methods. Atomistic modeling can help in the knowledge-based design of degrading biomaterials with tuned drug delivery properties, giving insights on the small molecules diffusivity at intermediate states of the degradation process. We present here an atomistic-based approach to investigate the diffusion of water (through which hydrolytic degradation occurs) in degrading bulk models of poly(lactic acid) or PLA. We determine the water diffusion coefficient for different swelling states of the polymeric matrix (from almost dry to pure water) and for different degrees of degradation. We show that water diffusivity is highly influenced by the swelling degree, while little or not influenced by the degradation state. This approach, giving water diffusivity for different states of the matrix, can be combined with diffusion-reaction analytical methods in order to predict the degradation path on longer time scales. Furthermore, atomistic approach can be used to investigate diffusion of other relevant small molecules, eventually leading to the a priori knowledge of degradable biomaterials transport properties, helping the design of the drug delivery systems. PMID- 21785937 TI - Understanding the desensitizing mechanism of olefin in explosives: shear slide of mixed HMX-olefin systems. AB - We simulated the shear slide behavior of typical mixed HMX-olefin systems and the effect of thickness of olefin layers (4-22 A) on the behavior at a molecular level by considering two cases: bulk shear and interfacial shear. The results show that: (1) the addition of olefin into HMX can reduce greatly the shear sliding barriers relative to the pure HMX in the two cases, suggesting that the desensitizing mechanism of olefin is controlled dominantly by its good lubricating property; (2) the change of interaction energy in both systoles of shear slide is strongly dominated by van der Waals interaction; and (3) the thickness of olefin layers in the mixed explosives can influence its desensitizing efficiency. That is, the excessive thinness of olefin layers in the mixed explosive systems, for example, several angstroms, can lead to very high sliding barriers. PMID- 21785938 TI - Conformation analysis of a surface loop that controls active site access in the GH11 xylanase A from Bacillus subtilis. AB - Xylanases (EC 3.2.1.8 endo-1,4-glycosyl hydrolase) catalyze the hydrolysis of xylan, an abundant hemicellulose of plant cell walls. Access to the catalytic site of GH11 xylanases is regulated by movement of a short beta-hairpin, the so called thumb region, which can adopt open or closed conformations. A crystallographic study has shown that the D11F/R122D mutant of the GH11 xylanase A from Bacillus subtilis (BsXA) displays a stable "open" conformation, and here we report a molecular dynamics simulation study comparing this mutant with the native enzyme over a range of temperatures. The mutant open conformation was stable at 300 and 328 K, however it showed a transition to the closed state at 338 K. Analysis of dihedral angles identified thumb region residues Y113 and T123 as key hinge points which determine the open-closed transition at 338 K. Although the D11F/R122D mutations result in a reduction in local inter-intramolecular hydrogen bonding, the global energies of the open and closed conformations in the native enzyme are equivalent, suggesting that the two conformations are equally accessible. These results indicate that the thumb region shows a broader degree of energetically permissible conformations which regulate the access to the active site region. The R122D mutation contributes to the stability of the open conformation, but is not essential for thumb dynamics, i.e., the wild type enzyme can also adapt to the open conformation. PMID- 21785939 TI - Structure and electronic absorption spectra of nematogenic alkoxycinnamic acids - a comparative study based on semiempirical and DFT methods. AB - Structure of nematogenic p-n-Alkoxy cinnamic acids (nOCAC) with various alkyl chain carbon atoms (n = 2, 4, 6, 8) has been optimized using density functional B3LYP with 6-31+G (d) basis set using crystallographic geometry as input. Using the optimized geometry, electronic structure of the molecules has been evaluated using the semiempirical methods and DFT calculations. Molecular charge distribution and phase stability of these systems have been analyzed based on Mulliken and Lowdin population analysis. The electronic absorption spectra of nOCAC molecules have been simulated by employing DFT method, semiempirical CNDO/S and INDO/S parameterizations. Two types of calculations have been performed for model systems containing single and double molecules of nOCAC. UV-Visible spectra have been calculated for all single molecules. The UV stability of the molecules has been discussed in light of the electronic transition oscillator strength (f). The dimer complexes of higher homologues (n = 6, 8) have also been reported to enable the comparison between single and double molecules. PMID- 21785940 TI - Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells. AB - Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies. However, little is known about any effects of these drugs on the central nervous system. The aim of the present study was to analyze the effects of trichostatin A (TSA)--a broad-spectrum histone deacetylase inhibitor--on the transcriptional regulation of several genes involved in dopamine- and serotonergic neurotransmission. To this end, short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with TSA either alone or in combination with hypoxia, and mRNA levels of dopamine receptor D3 (DRD3) and D4 (DRD4), dopamine transporter (DAT), dopamine hydroxylase (DBH), dopamine receptor regulating factor (DRRF), catechol-O-methyltransferase (COMT), serotonin receptor 1A (HTR1A), monoamino oxidase A (MAO-A), serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 (TPH2) were determined by quantitative PCR. We found that TSA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes, implying that induction of these genes is not mediated directly by hypoxia inducible factor-1alpha. On the other hand, TSA dramatically upregulated the expression of DAT and SLC6A4 (45-fold and 15-fold, respectively), while transcript levels of MAO-A and COMT were significantly reduced (by 70% and by more than 90%, respectively). Induction of DAT protein expression was detected by western blotting. These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons. PMID- 21785941 TI - Hidden treasures in stem cells of indeterminately growing bilaterian invertebrates. AB - Indeterminate growth, the life-long growth without fixed limits, is typical of some evolutionarily very successful aquatic invertebrate groups such as the decapod crustaceans, bivalve molluscs and echinoderms. These animals enlarge their organs also in the adult life period and can regenerate lost appendages and organs, which is in sharp contrast to mammals and most insects. Interestingly, decapods, bivalves and echinoderms develop only rarely neoplastic and age-related diseases, although some species reach ages exceeding 100 years. Their stem cell systems must have co-evolved with these successful life histories suggesting possession of unknown and beneficial features that might open up new vistas in stem cell biology. Research of the last decade has identified several adult stem cell systems in these groups and also some mature cell types that are capable to dedifferentiate into multipotent progenitor cells. Investigation of stem and progenitor cells in indeterminately growing bilaterian invertebrates is assumed beneficial for basic stem cell biology, aquaculture, biotechnology and perhaps medicine. The biggest treasure that could be recovered in these animal taxa concerns maintenance of stem cell niches and fidelity of stem cell division for decades without undesirable side effects such as tumour formation. Uncovering of the underlying molecular and regulatory mechanisms might evoke new ideas for the development of anti-ageing and anti-cancer interventions in humans. PMID- 21785943 TI - An exploration of the associations of pregnancy and perinatal features with cytokines and tryptophan/kynurenine metabolism in children with attention-deficit hyperactivity disorder (ADHD). AB - Intra-individual variability of the characteristics of children with attention deficit hyperactivity (ADHD) may reflect compromised glial energy supply in the synapse. We reported recently that while serum levels of a glial marker, the cytokine S100B, were not seriously altered, levels of other cytokines and tryptophan metabolites were related to symptoms, attention and variability. Here, we explore with a regression analysis whether levels of these substances were associated with features of the index pregnancy of potential aetiological significance. Serum was taken from 35 children with DSM-IV ADHD (14 on medication) and 21 typically developing controls to measure 8 cytokines (S100B, IL-2, IL-6, IL-10, IL-13, IL-16, TNF-alpha and IFN-gamma) and 5 metabolites (Tryptophan, Kynurenine, Kynurenate [KA], 3-hydroxy-kynurenine [3HK] and 5 hydroxyindole acetic acid [5-HIAA]). The mothers received a 124-item questionnaire on features surrounding the pregnancy. (1) For children with ADHD, a shorter pregnancy and smaller birth weight were associated statistically with increased 3HK and IFN-gamma and for obstetric problems with decreased TNF-alpha levels. (2) Maternal smoking related to decreasing kynurenine and increasing 3HK and S100B levels in ADHD children. Paternal smoking was associated with increased tryptophan in the controls and increased IL-6 levels in ADHD children. (3) The taking of supplements often related to decreasing TNF-alpha, increasing IL-10 and lower 5-HIAA levels in the ADHD children. Less 5-HIAA but more tryptophan was associated with earlier and later life events, respectively. (4) Increased IL-16 and 5-HIAA levels in the ADHD group related to reports of poorer infant health. Unexpectedly, more child care (seafood and time together) in ADHD than healthy families was implicated by lower tryptophan levels and an altered balance of pro inflammatory cytokines. Across measures control families generally showed either non-significant associations or the opposite to those of the ADHD group. In ADHD children more than controls, the balance of potentially toxic or protective kynurenine metabolites and of pro- over anti-inflammatory cytokines may reflect the perinatal experience associated with stress, but not with maternal illness. PMID- 21785942 TI - Immediate unidirectional epigenetic reprogramming of NORs occurs independently of rDNA rearrangements in synthetic and natural forms of a polyploid species Brassica napus. AB - The dynamics of genome modification that occurred from the initial hybridization event to the stabilization of allopolyploid species remains largely unexplored. Here, we studied inheritance and expression of rDNA loci in the initial generations of Brassica napus allotetraploids (2n = 38, AACC) resynthesized from Brassica oleracea (2n = 18, CC) and B. rapa (2n = 20, AA) and compared the patterns to natural forms. Starting already from F1 generation, there was a strong uniparental silencing of B. oleracea genes. The epigenetic reprogramming was accompanied with immediate condensation of C-genome nucleolar organizer region (NOR) and progressive transgeneration hypermethylation of polymerase I promoters, mainly at CG sites. No such changes were observed in the A-genome NORs. Locus loss and gains affecting mainly non-NOR loci after the first allotetraploid meiosis did not influence established functional status of NORs. Collectively, epigenetic and genetic modifications in synthetic lines resemble events that accompanied formation of natural allopolyploid species. PMID- 21785944 TI - Robust bronchoscope motion tracking using sequential Monte Carlo methods in navigated bronchoscopy: dynamic phantom and patient validation. AB - PURPOSE: Accurate and robust estimates of camera position and orientation in a bronchoscope are required for navigation. Fusion of pre-interventional information (e.g., CT, MRI, or US) and intra-interventional information (e.g., bronchoscopic video) were incorporated into a navigation system to provide physicians with an augmented reality environment for bronchoscopic interventions. METHODS: Two approaches were used to predict bronchoscope movements by incorporating sequential Monte Carlo (SMC) simulation including (1) image-based tracking techniques and (2) electromagnetic tracking (EMT) methods. SMC simulation was introduced to model ambiguities or uncertainties that occurred in image- and EMT-based bronchoscope tracking. Scale invariant feature transform (SIFT) features were employed to overcome the limitations of image-based motion tracking methods. Validation was performed on five phantom and ten human case datasets acquired in the supine position. RESULTS: For dynamic phantom validation, the EMT-SMC simulation method improved the tracking performance of the successfully registered bronchoscopic video frames by 12.7% compared with a hybrid-based method. In comparisons between tracking results and ground truth, the accuracy of the EMT-SMC simulation method was 1.51 mm (positional error) and 5.44 degrees (orientation error). During patient assessment, the SIFT-SMC simulation scheme was more stable or robust than a previous image-based approach for bronchoscope motion estimation, showing 23.6% improvement of successfully tracked frames. Comparing the estimates of our method to ground truth, the position and orientation errors are 3.72 mm and 10.2 degrees , while those of our previous image-based method were at least 7.77 mm and 19.3 degrees . The computational times of our EMT- and SIFT-SMC simulation methods were 0.9 and 1.2 s per frame, respectively. CONCLUSION: The SMC simulation method was developed to model ambiguities that occur in bronchoscope tracking. This method more stably and accurately predicts the bronchoscope camera position and orientation parameters, reducing uncertainties due to problematic bronchoscopic video frames and airway deformation during intra-bronchoscopy navigation. PMID- 21785945 TI - Evaluation of the experiences of family members whose deceased relative donated tissues at the NHSBT dedicated donation facility in Speke, Liverpool. AB - Donation of human tissue for transplant and research has historically been facilitated within the hospital mortuary. In 2006 NHSBT Tissue Services opened the Dedicated Donation Facility [DDF], the first facility in the UK dedicated to the donation of tissues under strictly controlled conditions. Nine family members who had agreed and experienced the transfer of their deceased relative to the DDF for tissue donation participated in a service evaluation applying qualitative data collection methods and framework analysis. The evaluation aimed to: understand the decision-making process of family members who agreed to their deceased relative being moved to the DDR for tissue donation; identify any concerns that family members had; gather the views of family members regarding the 'service' provided to them by NHSBT Tissue Services. Family members were unaware of the possibility of tissue donation. The process of reasoning behind both agreeing to tissue donation and movement of the deceased to the DDF by family members was fundamentally, 'the benefit to others' that tissue donation would bring, and fulfilling the wishes of the deceased [when known]. Family decision making was facilitated by: (i) a positive rapport with the requester, (ii) satisfaction with the information provided to the family about what would happen, and (iii) trust in that what was being said would happen. Family members were satisfied with the service provided to them by Tissue Services and confident in agreeing to the transfer of their deceased relative to the dedicated facility for tissue donation. PMID- 21785946 TI - Association between carotid plaque composition assessed by multidetector computed tomography and cerebral embolism after carotid stenting. AB - INTRODUCTION: We aimed to assess the relationship between atherosclerotic carotid plaque composition analyzed using multidetector computed tomography (MDCT) and the appearance of new ischemic lesions detected by diffusion-weighted images (DWI) after carotid artery stenting (CAS). METHODS: We quantitatively and qualitatively analyzed plaque characteristics in carotid arteries using MDCT before CAS in 19 patients. Carotid plaques were expediently subdivided into four components with Hounsfield unit (HU) values of <0, 0-60, 60-130, and >600. The incidence of distal embolism was evaluated with DWI. Pearson's correlation analyses were used to assess the association between plaque composition and the incidence of cerebral embolization. RESULTS: Fifteen patients (79%) demonstrated new DWI lesions after CAS. High-signal DWIs were noted as follows: one in six patients, 2 ~ 5 in five patients, 6 ~ 10 in two patients, and >10 in two patients. The mean volumes of the plaque components for HU < 0, 0-60, 60-130, and >600 were 5.4, 200, 260, and 59 mm(3), respectively. There was a strong correlation between the number of high-signal DWI lesions in the ipsilateral side and the plaque volume of HU < 0 (r = 0.927; P < 0.0001). There was a moderate correlation between the number of high-signal DWI lesions and the plaque volume of HU 0-60 (r = 0.568; P = 0.0099) and the sum total of HU < 0 and HU 0-60 (r = 0.609; P = 0.0047). CONCLUSIONS: Quantitative and qualitative tissue characterization of carotid plaques using MDCT might be a useful predictor for silent ischemic lesions after CAS. PMID- 21785947 TI - Myosin IIB deficiency in embryonic fibroblasts affects regulators and core members of the par polarity complex. AB - Wild-type (WT) and myosin heavy chain IIB null [MHCIIB (-/-)] embryonic fibroblasts were used as an experimental model to assess the role of the isoform B of myosin II (MII) in the regulation of the cell shape and intrinsic polarity. Genetic ablation of MHCIIB causes a persistent albeit, unstable protrusive activity in embryonic fibroblasts (Lo et al. in Nonmuscle myosin IIB is involved in the guidance of fibroblast migration. Mol Biol Cell 15:982-989, 2004). Here, we show that MHCIIB-deficient fibroblasts are characterized by a sustained guanine nucleotide exchange factor (GEF)-dependent activation of the small GTPase Rac-1 that is responsible for the continual lamellipodium formation. Moreover, we observed a sustained PKC-zeta activation and an increased association of cortactin with the plasma membrane in the MHCIIB (-/-) cells that were also dependent on GEF-mediated Rac-1 activation. Rac-1 activation and its downstream effects were induced in WT fibroblasts by inhibiting MII ATPase and crosslinking activities, suggesting that an altered actin-MII interaction favours Rac-1 activation, regardless of the MII isoform implicated. In addition, we found MIIB isoform-specific effects that were independent of Rac-1 activation. MHCIIA interacts with cortactin whereas MHCIIB does not. By contrast, MHCIIB interacts with Lgl1, a member of the Scribble/Dlg/Lgl polarity complex, whereas MHCIIA does not. MHCIIB (-/-) fibroblasts exhibited deregulated endogenous levels of the Par polarity complex members, Par3 and Par6. Together, the data show that MHCIIB deficiency causes imbalances in signalling pathways that are responsible for cell polarity determination. The results suggest that these pathways are targets of MIIB in the regulation of the cell's shape and polarity. PMID- 21785948 TI - Dietary fiber and grain consumption in relation to head and neck cancer in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Dietary fiber and grain consumption may reduce the risk of head and neck cancer; however, the epidemiological evidence is limited. We investigated this relationship in the National Institutes of Health (NIH)-AARP Diet and Health Study. METHODS: Cox proportional hazards models were used to calculate multivariable hazard ratios (HR) and 95% confidence intervals (CI) to investigate dietary fiber and grain intake in relation to head and neck cancer. RESULTS: During approximately 11 years of follow-up, 1,867 (401 women/1,466 men) cases of head and neck cancer were diagnosed. Our data indicated that the relationship between fiber and grain intake and head and neck cancer is modified by sex (p interactions < 0.001 and 0.001, respectively). Women with higher intake of total fiber and total grains had a lower risk of head and neck cancer (HR (10 g/day) = 0.77, 95% CI = 0.64-0.93; HR (serving/1,000 kcal) = 0.89, 95% CI = 0.80-0.99, respectively); this inverse relation was consistent across subtypes of fiber and grains. Conversely in men, the inverse associations were weaker and nonsignificant. CONCLUSIONS: In the largest prospective cohort study to investigate this relation to date, intake of total fiber and grain foods was inversely associated with head and neck cancer incidence among women, but not among men. PMID- 21785949 TI - The Aspergillus nidulans CENP-E kinesin KipA is able to dimerize and to move processively along microtubules. AB - Kinesin molecular motors serve a variety of cellular functions usually in dynamic processes. One characteristic feature of many kinesins is their ATP-dependent processive movement along polymerized microtubules. However, many kinesins work as stationary polymerases or depolymerases. Therefore, it needs to be determined for each motor, whether it moves processively along microtubules or not. The Schizosaccharomyces pombe kinesin-7, Tea2, has been shown to be involved in cell end marker transportation towards the cortex to organize the actin cytoskeleton. In human, kinesin 7 promotes microtubule polymerization. In Aspergillus nidulans, the machinery for determining growth directionality is conserved, but there is no evidence yet that kinesin 7, KipA is potentially involved in the transportation of the cell end marker proteins, TeaA or TeaR or newly identified proteins such as KatA. We expressed KipA in Escherichia coli and determined the catalytic properties of this kinesin. Here we show that KipA is an active ATPase, which is able to dimerize and move processively along microtubules with a speed of 9.48 MUm/min. PMID- 21785950 TI - Psychotherapy research needs theory. Outline for an epistemology of the clinical exchange. AB - This paper provides an analysis of a basic assumption grounding the clinical research: the ontological autonomy of psychotherapy-based on the idea that the clinical exchange is sufficiently distinguished from other social objects (i.e. exchange between teacher and pupils, or between buyer and seller, or interaction during dinner, and so forth). A criticism of such an assumption is discussed together with the proposal of a different epistemological interpretation, based on the distinction between communicative dynamics and the process of psychotherapy-psychotherapy is a goal-oriented process based on the general dynamics of human communication. Theoretical and methodological implications are drawn from such a view: It allows further sources of knowledge to be integrated within clinical research (i.e. those coming from other domains of analysis of human communication); it also enables a more abstract definition of the psychotherapy process to be developed, leading to innovative views of classical critical issues, like the specific-nonspecific debate. The final part of the paper is devoted to presenting a model of human communication--the Semiotic Dialogical Dialectic Theory--which is meant as the framework for the analysis of psychotherapy. PMID- 21785951 TI - SNP marker diversity in common bean (Phaseolus vulgaris L.). AB - Single nucleotide polymorphism (SNP) markers have become a genetic technology of choice because of their automation and high precision of allele calls. In this study, our goal was to develop 94 SNPs and test them across well-chosen common bean (Phaseolus vulgaris L.) germplasm. We validated and accessed SNP diversity at 84 gene-based and 10 non-genic loci using KASPar technology in a panel of 70 genotypes that have been used as parents of mapping populations and have been previously evaluated for SSRs. SNPs exhibited high levels of genetic diversity, an excess of middle frequency polymorphism, and a within-genepool mismatch distribution as expected for populations affected by sudden demographic expansions after domestication bottlenecks. This set of markers was useful for distinguishing Andean and Mesoamerican genotypes but less useful for distinguishing within each gene pool. In summary, slightly greater polymorphism and race structure was found within the Andean gene pool than within the Mesoamerican gene pool but polymorphism rate between genotypes was consistent with genepool and race identity. Our survey results represent a baseline for the choice of SNP markers for future applications because gene-associated SNPs could themselves be causative SNPs for traits. Finally, we discuss that the ideal genetic marker combination with which to carry out diversity, mapping and association studies in common bean should consider a mix of both SNP and SSR markers. PMID- 21785952 TI - Leptomeningeal metastases from breast cancer: intrinsic subtypes may affect unique clinical manifestations. AB - Leptomeningeal metastasis (LM) usually occurs late during the course of breast cancer. The aim of this study was to characterize the clinical features and outcomes of LM based on breast cancer subtypes in conjunction with brain parenchymal metastases. A retrospective study was performed of breast cancer patients with LM, who received palliative management at Samsung Medical Center between 1995 and 2008. Among the 272 metastatic breast cancer patients with central nervous system (CNS) involvement, 68 patients with LM were identified. The median age was 46 years (range, 24-72 years). The median survival duration from LM to death (LM-OS) was 4.5 months (range, 0.2-26.4 months). Patients surviving for 12 or more months were rarer among triple negative (TN) patients compared to other subtypes (21.7% for HR + ve vs. 27.8% for HER2 + ve vs. 72.7% for TN, P = 0.217). Death caused by CNS involvement appeared to be much more common in TN than in other subtypes (0% for HR + ve vs. 36% for HER2 + ve vs. 64% for TN, P = 0.060). Median survival time from distant metastasis was significantly different among the three groups (28.3 vs. 29.1 vs. 11.8 months, P < 0.0001). However, median survival time from LM did not differ (4.1 vs. 5.9 vs. 3.8 months, P = 0.226). Characteristic manifestations and treatment outcomes of LM may be affected by the unique biology of breast cancer intrinsic subtypes. The different roles of active combined treatment modalities including both systemic chemotherapy and local treatment modalities should be considered to improve outcomes. PMID- 21785953 TI - Unchanged serum viral load and liver function during tocilizumab treatment in a patient with rheumatoid arthritis and hepatitis C virus infection. PMID- 21785954 TI - Behcet's disease and IgA nephropathy. AB - Although Behcet's disease (BD) is a kind of systemic disease, renal involvement is rare, especially IgA nephropathy (IgAN). Renal manifestations in BD range from mild urinary abnormalities to glomerulonephritis with persistent renal failure, which includes minimal change disease, proliferative glomerulonephritis, rapidly crescentic glomerulonephritis, renal amyloidosis and IgA nephropathy. Amyloidosis seems to be the most common type of renal lesion in BD, and several cases of nephrotic syndrome secondary to amyloidosis have been documented. Co-occurrence of BD and IgA nephropathy has only been reported in only few cases. We describe two patients with the rare association of BD and IgAN. We suggested that it is important to periodically perform renal function assessment in patients with BD, through urinalysis and measurement of serum creatinine for detecting any abnormality and providing an early adequate treatment. PMID- 21785955 TI - Rising hospitalization rates of Kawasaki Disease in Chile between 2001 and 2007. AB - Incidence of Kawasaki disease (KD) varies geographically, with highest rates in East Asia and comparatively lower rates in Europe and United States. Population based epidemiologic studies of KD in Latin American countries have not been done. The purpose of this study is to determine demographic characteristics, hospitalization rates and estimated incidence of KD in Chile. We performed a retrospective review of national hospital discharge databases between 2001 and 2007 for patients younger than 18 years of age with KD (ICD10 code M30.3). Seven hundred and eighty-six hospitalizations with discharge diagnosis of KD were identified, representing 0.03% of hospitalizations. Median age of diagnosis was 1 year, and 85% of patients were younger than 5 years. Male-to-female ratio was 1.6:1. Highest hospitalization rates occurred in late winter/spring (August November) with a smaller peak in summer (March). KD-associated hospitalization rate was 7.6 per 100,000 children younger than 5 years (95% CI 7.0-8.1). Hospitalization rates increased 47% between 2001-2004 and 2005-2007 periods: 6.3 (95% CI 5.6-7.0) to 9.3 (95% CI 8.3-10.3), (P < 0.001). Estimated incidence of KD, assuming 10% readmission rates, was 6.8 (95% CI 6.3-7.4), increasing from 5.7 (95% CI 5.0-6.3) in 2001-2004 to 8.4 (95% CI 7.4-9.3) in 2005-2007 (P < 0.001). In conclusion, demographic characteristics of Chilean patients with KD are similar to international data. There has been an increase in hospitalization rates and estimated incidence of KD in Chile between 2001 and 2007. This may reflect a true increase in cases or improved awareness. PMID- 21785956 TI - Efficacy of a multidisciplinary treatment program in patients with severe fibromyalgia. AB - The purpose of this study was to evaluate the efficacy of a multidisciplinary treatment program in patients severely affected by fibromyalgia. Thirty-four fibromyalgia patients were randomly divided into two groups. The control group: 17 women who continued their medical treatment and participated in four educational sessions and the experimental group that included 17 patients who besides the former medical treatment also underwent a weekly 1-h session program for 8 weeks including massage therapy, ischemic pressure on the 18 tender points, aerobic exercise and thermal therapy. At the beginning of the program, there were no significant differences between the two groups in any of the parameters. At the end of treatment, there was a significant improvement in the experimental group in the following items: vitality, social functioning, grip strength and the 6-min walk test. At 1 month after the end of treatment, the experimental group showed significant differences in overall health perception, social functioning, grip strength and the 6-min walk test. At that time, considering the threshold for clinical efficacy set at an improvement of 30% or above for the analyzed variables, 25% of the patients met the requirement for improvement of the following: number of symptoms: Visual Analogic Scale for fatigue, Fibromyalgia Impact Questionnaire and Beck Anxiety Inventory. In conclusion, patients with severe manifestations of fibromyalgia can obtain improvement with a short-term, low-cost and simple-delivery multidisciplinary program. However, additional studies including higher numbers of patients are needed to confirm the beneficial effect of this treatment program. PMID- 21785957 TI - Association of Fcgamma receptor IIIA variant with a subset of anti-topoisomerase I-positive patients in systemic sclerosis: a descriptive pilot study. AB - Hypothesizing a pathophysiological role of anti-topoisomerase I antibodies (anti topo I) through autoantibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxic effectors expressing receptors for the Fc portion of IgG in systemic sclerosis (SSc), 267 SSc patients (56 with anti-topo I and 102 with anti centromere antibodies (ACA)) were genotyped for the functional FCGR3A-V158F polymorphism. A descriptive analysis of patients according to their clinical and immunological status and FCGR3A-158 V/F genotypes was performed using multiple correspondence analysis. This descriptive analysis revealed an association between the FCGR3A-158 VV genotype and the presence of anti-topo I. By contrast, no relationship was found between FCGR3A polymorphism and the presence of ACA. SSc patients with anti-topo I appear to be more frequently homozygous for the high-affinity FcgammaRIIIA-coding allele, suggesting that some autoantibodies may be pathogenic through ADCC. PMID- 21785958 TI - Urticaria and dermographism in patients with adult-onset Still's disease. AB - Adult-onset Still's disease (AOSD) patients typically present with arthralgia, fever, lymphadenopathy and a transient salmon maculopapular rash. Only approximately 25 cases of AOSD with urticaria were described in the literature. In this article, the authors report three additional cases of AOSD with urticarial and dermographic lesions who had a good clinical response to glucocorticoid and antihistamines. A review of the literature concerning this issue is also herein written. PMID- 21785959 TI - Coexistent tumor necrosis factor receptor-associated periodic fever syndrome and Ehlers-Danlos syndrome. AB - A 32-year-old Caucasian woman had periodic fevers, skin disease, polyarthralgia and hypermobile joints that were consistent with tumor necrosis factor receptor associated periodic fever syndrome confirmed with a finding of R92Q missense mutation of the TNFRSFA1 gene with Ehlers-Danlos hypermobility type syndrome. They are both autosomal dominant disorders, and their coexistence suggests that they could share some phenotypic features that may require special consideration in management. Conceivably, they could share common gene mutations although no such data are available. PMID- 21785960 TI - Use of glycosylated ferritin assay to aid the diagnosis of adult-onset Still's disease: a local laboratory experience in Hong Kong. PMID- 21785961 TI - Successful use of etanercept for the treatment of Reiter's syndrome: a case report and review of the literature. AB - The treatment of severe and refractory cases of reactive arthritis is not well defined. There is a limited data about the use of tumor necrosis factor-alpha (TNF-alpha) blockers in reactive arthritis. Herein is a description of a patient with severe case of Chlamydia trachomatis-related reactive arthritis that was refractory to nonsteroidal anti-inflammatory drugs, sulfasalazine, prednisone, and methotrexate and was successfully treated with etanercept. PMID- 21785962 TI - Bilateral orbital Erdheim-Chester disease treated with 12 weekly administrations of VNCOP-B chemotherapy: a case report and a review of literature. AB - Erdheim-Chester disease (ECD) is a non-Langerhans' cells histiocytosis of unknown etiology, which generally presents with long bones involvement, even if extraskeletal lesions may be frequently recognized. As a consequence of its rarity, there is no consensus concerning the best standard of care for affected patients. We present the case of a 53-year-old woman with bilateral orbital histologically documented ECD, presenting with an important thickening and swelling of the periorbital tissue and massive involvement of lateral rectal muscles, as documented by magnetic resonance. The patient was successfully addressed to 12 cycles of a weekly lymphoma-designed chemotherapy regimen, including etoposide, mitoxantrone, cyclophosphamide, vincristine, bleomycin, and prednisone (VNCOP-B regimen). Periorbital lesions reduced during the courses of chemotherapy, along with a regression to normal appearance of the extrinsic ocular musculature. This appears as an effective and well-tolerated first-line treatment option for ECD patients, due to the possibility of maintaining an adequate dose intensity, with also a concomitant continuous steroid administration. PMID- 21785964 TI - Dominant responses with conservation of T-cell receptor usage in the CD8+ T-cell recognition of a cancer testis antigen peptide presented through HLA-Cw7 in patients with multiple myeloma. AB - Cancer testis antigens exhibit physiological expression within germ cells and are frequently expressed in malignant tissue. Interestingly, immunological tolerance to cancer testis proteins does not appear to be established, and the expression of CTAg proteins within malignant cells can therefore lead to induction of cellular and humoral immunity. A considerable body of evidence now indicates that CD8-specific immunity plays an important role in the control of cancer cell growth, and a number of vaccine studies are in progress to boost CTAg-specific cellular immune responses. We have previously identified CTAg-specific immune responses in patients with multiple myeloma and reported that recognition of the MAGE-A1(289-298) peptide, which is described as being restricted by HLA-B*0702, was the most frequent response seen with our peptide panel. Here, we studied seven CD8+ T-cell clones specific for this peptide which were isolated from three patients with myeloma at several time-points. The affinity of peptide recognition was high with 50% maximal interferon-gamma production observed at a peptide concentration of 10(-10) M and variation of only one order of magnitude between the affinities of the clones. Importantly, all the clones were able to recognise and kill multiple myeloma cell lines. Interestingly, one patient did not express HLA-B*0702, but three clones from this patient recognised the MAGE-A1(289-298) peptide on a lymphoblastoid cell line (LCLs) expressing HLA-Cw7, and we now show evidence that the MAGE-A1(289-298) peptide is expressed and recognised through Cw7. The T-cell receptor gene usage was determined in five clones and showed conserved features in both the alpha and the beta chain genes indicating correlation between T-cell receptor usage and peptide specificity of cancer testis antigen-specific T-cell clones. PMID- 21785963 TI - Tobacco dependence treatment for Korean Americans: preliminary findings. AB - The study was conducted to examine the relative effectiveness of cognitive behavior therapy with a cultural tailoring intervention compared to brief medication management. The study used a two-arm randomized controlled trial in which participant assignment was stratified by gender. The intervention condition received eight weekly 40-min individualized counseling sessions of culturally tailored cognitive behavior therapy, while the control condition received eight weekly 10-min individualized counseling sessions of medication management. Both conditions received nicotine patches for 8 weeks. Data were collected at baseline and at four follow-up points (one and 4 weeks, and three and 6 months post-quit). Treatment outcomes were presented as an intention-to-treat analysis. Thirty Korean immigrants participated in the study. At 6-month follow-up, 57.1% of participants in the intervention and 18.8% of participants in the control had 7 day point prevalence abstinence (odds ratio = 5.8, 95% confidence interval = 1.12 26.04, P = 0.04). Participants' self-reported abstinence was biochemically verified with exhaled carbon monoxide and salivary cotinine levels. A combination of the culturally tailored cognitive behavior therapy and nicotine replacement therapy had a better treatment outcome compared to brief medication management. The promising result suggests a need to further test the intervention in larger samples and longer follow-up assessments before it can be adapted in clinical settings. PMID- 21785965 TI - [Nailing of fractures of the femoral neck in the elderly]. PMID- 21785966 TI - Alginate scaffold for organ culture of cryopreserved-thawed human ovarian cortical follicles. AB - PURPOSE: To compare macroporous alginate scaffolds with Matrigel for culturing frozen-thawed human primordial follicles in organ culture. METHODS: Twelve girls/women donated ovarian tissue. One tissue sample was fixed immediately after thawing (uncultured samples). Slices were cultured for 2 weeks on either Matrigel or on alginate scaffolds with a serum-free culture medium. Growth evaluation consisted of follicular counts and classification, immunohistochemistry and measurement of 17beta-Estradiol (E(2)) production. RESULTS: The number of developing follicles was significantly higher in alginate scaffold-cultured samples than on Matrigel with a concomitant decrease in the number of primordial follicles in alginate scaffold-cultured samples than uncultured samples. The number of atretic follicles after 1 week was significantly higher in the Matrigel cultured samples than in the alginate scaffold cultured samples. E(2) production was similar in both groups. CONCLUSIONS: Three dimensional alginate scaffolds are a promising putative in vitro technology for developing human primordial follicles. PMID- 21785967 TI - A robust method for ventriculomegaly detection from neonatal brain ultrasound images. AB - Ventriculomegaly is the most commonly detected abnormality in neonatal brain. It can be defined as a condition when the human brain ventricle system becomes dilated. This in turn increases the intracranial pressure inside the skull resulting in progressive enlargement of the head. Sometimes it may also cause mental disability or death. For these reasons early detection of ventriculomegaly has become an important task. In order to identify ventriculomegaly from neonatal brain ultrasound images, we propose an automated image processing based approach that measures the anterior horn width as the distance between medial wall and floor of the lateral ventricle at the widest point. Measurement is done in the plane of the scan at the level of the intraventricular foramina. Our study is based on neonatal brain ultrasound images in the midline coronal view. In addition to ventriculomegaly detection, this work also includes both cross sectional and longitudinal study of anterior horn width of lateral ventricles. Experiments were carried out on brain ultrasound images of 96 neonates with gestational age ranging from 26 to 39 weeks and results have been verified with the ground truth provided by doctors. Accuracy of the proposed scheme is quite promising. PMID- 21785968 TI - ECC-based grouping-proof RFID for inpatient medication safety. AB - Several papers were proposed in which symmetric cryptography was used to design RFID grouping-proof for medication safety in the Journal of Medical Systems. However, if we want to ensure privacy, authentication and protection against the tracking of RFID-tags without losing system scalability, we must design an asymmetric cryptography-based RFID. This paper will propose a new ECC-based grouping-proof for RFID. Our ECC-based grouping-proof reduces the computation of tags and prevents timeout problems from occurring in n-party grouping-proof protocol. Based on asymmetric cryptography, the proposed scheme is practical, secure and efficient for medication applications. PMID- 21785969 TI - MESA: the NIH-sponsored study that validates atherosclerosis imaging for primary prevention. AB - Coronary artery calcium (CAC) score correlates strongly with the burden of atherosclerotic plaques in the coronary arteries. It is the strongest predictor of future coronary events in asymptomatic individuals, being stronger than all traditional risk factors combined. It is also a better predictor of future events than carotid intima-media thickness (CIMT) measurement for the prediction of coronary artery disease but slightly weaker than CIMT for the prediction of cerebrovascular events such as stroke. These findings have been validated by the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective epidemiologic study sponsored by the National Institutes of Health (NIH) investigating the prevalence, correlates, and progression of atherosclerosis in an asymptomatic, ethnically diverse population. That is why the US national guidelines have recently elevated their recommendation levels to Class IIa for use of CAC and CIMT in risk stratification of the asymptomatic intermediate-risk population. PMID- 21785970 TI - Bile aspiration cytology in diagnosis of bile duct carcinoma: factors associated with positive yields. AB - BACKGROUND/PURPOSE: In bile duct carcinoma (BDC) patients, bile aspiration cytology (BAC) is an established method for cytodiagnosis. However, almost all previous reports investigated the biliary strictures caused not only by BDC but also by gallbladder and pancreatic carcinomas. Therefore, BAC in BDC patients only has not yet been investigated sufficiently. The aim of this study was to evaluate the actual sensitivity of BAC and to evaluate the factors that affect positive yields of BAC in patients with defined BDC. METHODS: Data on 47 consecutive patients with definite BDC, who underwent BAC via endoscopic nasobiliary drainage (ENBD) or percutaneous transhepatic cholangiodrainage (PTCD), were retrospectively collected. Fourteen factors were studied for association with positive BAC. RESULTS: The number of cytological samplings ranged from 1 to 14 times. The cumulative diagnostic yield was 72.3% (34/47), and 32 positive results were obtained at a maximum of six samplings. Independent factors associated with positive BAC were perihilar location, stricture length >= 2 cm, and macroscopic papillary type. CONCLUSION: In BDC patients with ENBD or PTCD, repeated BAC is useful, and six times was the optimum number of repeat samplings. Although the sensitivity of BAC is not sufficient for the preoperative diagnosis of malignant biliary stricture, the three independent factors noted above predict positive yields and indicate whether or not BAC should be repeated up to six times. PMID- 21785971 TI - Estradiol-mediated suppression of CYP1B1 expression in mouse MA-10 Leydig cells is independent of protein kinase A and estrogen receptor. AB - Estrogens have multifaceted roles in mammalian testis. In the present study, we focused on estradiol as a potential regulator of testicular cytochrome P450 1B1 (CYP1B1) expression and investigated the possible mechanisms involved in the estradiol-mediated suppression. CYP1B1 protein levels were measured in the testes of rats that were treated with 17beta-estradiol benzoate (1.5 mg/kg) at different stages of development. In addition, CYP1B1 mRNA levels were measured in mouse MA 10 Leydig tumor cells treated with (a) various concentrations of 17beta-estradiol benzoate, (b) 17beta-estradiol benzoate in the presence of exogenous luteinizing hormone (LH), or (c) 17beta-estradiol benzoate in the presence of ICI 182,780, a competitive steroidal antagonist of estrogen receptors (ERs). Treatment of neonatal, pubertal, or adult rats with 17beta-estradiol benzoate was associated with a reduction of approximately 90% in testicular CYP1B1 protein content compared to age-matched controls. Treatment of MA-10 cells with 17beta-estradiol benzoate (10-500 nM) produced a concentration- and time-dependent decrease in CYP1B1 mRNA levels, but had no effect on LH receptor mRNA levels or on protein kinase A (PKA) activity. However, 17beta-estradiol benzoate (10-500 nM), regardless of the concentration tested, failed to attenuate the LH-elicited increase in CYP1B1 mRNA or PKA activity in MA-10 cells that were co-treated with LH and estradiol. Similarly, ICI 182,780 (10-1000 uM) did not reverse the suppressive effect of estradiol on CYP1B1 mRNA expression in MA-10 cells co treated with estradiol and ICI 182,780. The results indicate that downregulation of testicular CYP1B1 by estradiol was independent of PKA activity and was not mediated by ERs in MA-10 cells. PMID- 21785972 TI - Generation and application of anti-ouabain IgY antibodies. AB - Ouabain is a bioactive hapten and is very difficult to be accurately quantified because of the lack of useful reagents. Furthermore, where ouabain is produced in the adrenal glands has not been identified. In this study, ouabain-BSA was generated for immunizing the laying hens to generate ouabain-specific IgY antibodies in chicken eggs. The anti-ouabain IgY antibodies were detected in eggs 1 week after the last immunization and their concentrations increased with time. The highest concentrations of anti-ouabain IgY antibodies reached at 1:10,240 for ELISA 5 weeks after immunization and maintained for 4 weeks in chicken eggs. Following PEG precipitation, an average of 8.5 mg of anti-ouabain IgY antibodies with a purity of 87.6% was achieved from a single egg. Further analysis revealed that the anti-ouabain IgY antibodies had little immunoreactivity to hydrocortisone, dexamethasone, cedilanid, and digoxin, indicating their high specificity, and the purified IgY antibodies effectively detected endogenous ouabain in the cytoplasm of cells predominately in the zona reticularis of rat and human adrenal glands, indicating their high immunoreactivity. Given that IgY has an unique structure and bioactive features, the generated anti-ouabain IgY antibodies may be used as a new reagent for accurately quantifying ouabain in biological studies. PMID- 21785973 TI - Using an evolutionary algorithm to determine the parameters of a biologically inspired model of head direction cells. AB - A biologically inspired model of head direction cells is presented and tested on a small mobile robot. Head direction cells (discovered in the brain of rats in 1984) encode the head orientation of their host irrespective of the host's location in the environment. The head direction system thus acts as a biological compass (though not a magnetic one) for its host. Head direction cells are influenced in different ways by idiothetic (host-centred) and allothetic (not host-centred) cues. The model presented here uses the visual, vestibular and kinesthetic inputs that are simulated by robot sensors. Real robot-sensor data has been used in order to train the model's artificial neural network connections. The main contribution of this paper lies in the use of an evolutionary algorithm in order to determine the values of parameters that determine the behaviour of the model. More importantly, the objective function of the evolutionary strategy used takes into consideration quantitative biological observations reported in the literature. PMID- 21785974 TI - Association of PPAR polymorphisms with cytokine levels in allergic rhinitis. AB - Our aim was to study the association of Pro12Ala and exon6 C161T polymorphisms of PPARgamma and intron7 G/C polymorphisms of PPAR-alpha with clinical symptoms, peak nasal inspiratory flow values, serum soluble TNF-alpha, TNF-R1, Fas, Fas ligand and IgE concentrations in patients with seasonal allergic rhinitis during and after pollen season. We performed a follow-up study of 66 Hungarian patients with seasonal allergic rhinitis and 180 healthy referent subjects. We used PCR RFLP technique and ELISA. The distribution of mutant alleles of PPAR-gamma and alpha did not differ in patients and referent subjects. Patients carrying the mutant 12Ala, exon6 161T alleles of PPAR-gamma and intron7 C allele of PPAR-alpha had significantly higher clinical symptom score values, TNF-alpha and IgE levels and lower peak nasal inspiratory flow values during and after pollen season. The results indicated that nuclear receptors PPAR-gamma and PPAR-alpha are involved in the regulation of inflammatory mediator production in patients with seasonal allergic rhinitis and polymorphisms of the receptors are very likely to contribute to the heterogeneity of clinical and immunological parameters of allergic patients. PMID- 21785975 TI - Predictive validity of MRI in detecting and following cholesteatoma. AB - High recurrence rate of the middle ear cholesteatoma requires regular postoperative follow-up. This study evaluated data from the patients investigated with DW MRI to ascertain (1) the strength of the technique in detecting primary, and residual recurrent cholesteatoma, and (2) its accuracy in differentiating cholesteatoma from postoperative tissue changes. The diagnostic accuracy of two different DW imaging (EPI and non-EPI) techniques was evaluated. The data have been collected prospectively from 33 consecutive patients with either primary cholesteatoma, or with suspicious symptoms for potential cholesteatoma recurrence. The findings from non-EPI (HASTE) DW MR and EPI DW MR images were blindly compared with those obtained during a primary or secondary surgery. Preoperative non-EPI (HASTE) DWI pointed to a cholesteatoma in 25 out of 33 patients. In this subgroup, cholesteatoma were confirmed also by the surgery. In five cases, the non-EPI (HASTE) DWI did not show a cholesteatoma in the temporal bone, which agreed with the surgical findings. Three misclassifications were made by non-EPI (HASTE) DWI, all in the subgroup of patients indicated for primary surgery. The resulting pooled sensitivity of non-EPI (HASTE) DW imaging for diagnosing cholesteatoma in our study amounted to 96.15% (95% confidence interval (CI) 80.36-99.9), specificity was 71.43% (95% CI 29.04-96.33). Positive predictive value was 92.59% (95% CI 75.71-99.09) and negative predictive value 83.33% (95% CI 35.88-99.58). In conclusion, we recommend the non-EPI (HASTE) DW MRI as a valid method for diagnosing cholesteatoma and follow-up after cholesteatoma surgery. PMID- 21785976 TI - Expanding cancer prevention education to national and international audiences: the National Cancer Institute's Principles and Practice of Cancer Prevention and Control annual summer course. AB - The Summer Curriculum in Cancer Prevention has been sponsored by the National Cancer Institute's Cancer Prevention Fellowship Program for over two decades. This curriculum includes a 4-week course entitled "Principles and Practice of Cancer Prevention and Control." The ultimate goal of this course is to present the most current cancer prevention research to a diverse workforce of researchers and practitioners eager to address the current challenges in this field. The course covers the current status of cancer prevention research and practice, ranging from epidemiology and clinical practice, and from basic to behavioral science research. It is comprised of lectures grouped into nine modules representing broad and specific topics relevant to cancer prevention. Course participants come from a broad cross-section of career stages, professions, and research interests, and are from across the USA and other countries. Over time and in response to feedback from participants, the course has developed to meet the needs and expectations of this diverse audience, and may serve as a model for those interested in cancer prevention education and training in other countries. PMID- 21785979 TI - Perianal abscess and fistula-in-ano in children: clinical characteristic, management and outcome. AB - PURPOSE: The aims of this study are to evaluate the clinical characteristics of perianal abscess and fistula-in-ano in children, and to assess our experience in treatment, and to identify factors that affected the clinical outcomes. METHODS: A retrospective review of children with perianal abscess and fistula-in-ano was carried out in a tertiary care children's hospital from January 2005 to December 2010. Demographic information of the patients, localization of the lesions, treatment procedures, microbial organisms in pus, usage of antibiotics, abscess recurrence, development of fistula-in-ano, and duration of symptoms were recorded. Patients with systemic diseases and inflammatory bowel diseases were excluded from the study. RESULTS: A total of 158 children (146 males, 12 females) treated for perianal abscess and fistula-in-ano with a median age of 7.2 months (ranging 16 days to 18 years) were eligible for the study. Initial examination of the 136 patients revealed perianal abscess and 22 patients with fistula-in-ano. Primary treatment was incision and drainage (I/D) for the fluctuating perianal abscess (73.5%), and local care for the spontaneously (S/D) drained abscess (26.5%) with or without antibiotic therapy. Patients were divided into two groups according to age distribution, 98 of the patients were younger than 12 months, and 60 were older than 12 months of age. There was no significant difference in sex distribution, localization of the lesions, treatment procedures, recurrence of abscess and fistula-in-ano formation between the two age groups (p > 0.05). Recurrence rates (27% in I/D and 30.6% in S/D, p > 0.05) and development of fistula-in-ano (20% in I/D and 27.8 in S/D, p > 0.05) were not significant I/D and S/D groups. Kind of the microorganisms in pus swaps did not effect the fistula-in-ano formation. Usage of antibiotics significantly reduced the development of fistula-in-ano (p = 0.001), but did not effect the recurrence of perianal abscess (p > 0.05). The mean follow-up period was 10.6 +/- 8.6 months. While the 9 of the overall 52 fistula-in-ano (22 initial, 30 after abscess treatment) were resolved spontaneously, 43 of the remaining needed surgical intervention (fistulotomy/fistulectomy). CONCLUSIONS: Although management of perianal abscess is still controversial, simple drainage of the perianal abscess with additional antibiotic therapy reduces the development of fistula-in-ano. Fistula-in-ano within children has a chance of spontaneous resolution thus the immediate surgical intervention should be avoided. PMID- 21785978 TI - Environmental exposures and rheumatoid arthritis risk. AB - In addition to rapidly burgeoning data regarding novel genetic risk factors, a growing list of environmental exposures have been implicated in rheumatoid arthritis (RA) susceptibility. Cigarette smoking is chief among the many environmental exposures implicated in disease risk, accounting for approximately one in six new cases of RA, with recent results underscoring the central importance of select gene-smoking interactions in RA development. In this review, we examine data linking several environmental exposures with RA risk, including cigarette smoking, other air pollutants and occupational exposures, reproductive/hormonal influences, alcohol consumption, select infections leading to periodontal disease, and dietary factors. Where applicable, we review the current understanding of biologic mechanisms linking these environmental factors to disease risk. PMID- 21785980 TI - From single biobanks to international networks: developing e-governance. AB - The future holds the possibility to link and network biobanks, existing biorepositories and reference databases for research purposes in ways that have not been possible before. There is the potential to develop 'research portals' that will enable researchers to access these research resources that are located around the globe with the click of a mouse. In this paper, I will argue that our current governance system for research is unable to provide all of the oversight and accountability mechanisms that are required for this new way of doing research that is based upon flows of data across international borders. For example, our current governance framework for research is nationally based, with a complex system of laws, policies and practice that can be unique to a jurisdiction. It is also evident that many of the nationally based governance bodies in this field do not have the legal powers or expertise to adjudicate on the complex issues, such as privacy and disclosure risks that are raised by cross border data sharing. In addition, the conceptual underpinning of this research governance structure is based on the "one researcher, one project, one jurisdiction" model. In the conclusion of this paper, I lay out some preliminary ideas as to how this system has to change to accommodate research that is based on networks. I suggest that a move to digital governance mechanisms might be a start to making research governance systems more appropriate for the 21st century. PMID- 21785977 TI - Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic organ systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors. PMID- 21785981 TI - Combination of oral non-absorbable and intravenous antibiotics versus intravenous antibiotics alone in the prevention of surgical site infections after colorectal surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Oral non-absorbable antibiotics work by decreasing intraluminal bacterial content after mechanical bowel preparation. The advantage of adding oral non-absorbable antibiotics to intravenous antibiotics to decrease surgical site infection (SSI) after colorectal surgery is not well known. We conducted a meta-analysis of randomized controlled trials (RCT) comparing the effectiveness of combined oral non-absorbable and intravenous antibiotics versus intravenous antibiotics alone in reducing the incidence of SSI following colorectal surgery. METHOD: We included RCT comparing a combination of oral non-absorbable antibiotics and intravenous antibiotics to intravenous antibiotics alone in order to prevent SSI after colorectal surgery. Outcomes assessed included postoperative infectious complications, such as surgical wound infections (SWI) defined as a combination of superficial and deep SSI, organ-space infections and anastomotic dehiscence. RESULTS: Sixteen RCT published between 1979 and 2007 were included in the meta-analysis. The overall analyses indicated that patients randomly assigned to an oral non-absorbable antibiotic in addition to an intravenous antibiotic had a reduced risk of SWI (RR: 0.57 [95% CI: 0.43-0.76], p = 0.0002) compared with participants receiving only intravenous antibiotics. The use of oral non absorbable antibiotics in addition to intravenous antibiotics had no significant effect on organ-space infections (RR: 0.71 [95% CI: 0.43-1.16], p = 0.2) or the risk of anastomotic leak (RR: 0.63 [95% CI: 0.28-1.41], p = 0.3). CONCLUSION: Our meta-analysis shows that a combination of oral non-absorbable antibiotics and intravenous antibiotics significantly lowers the incidence of SWI compared with intravenous antibiotics alone. In light of our results, the use of oral non absorbable antibiotics in colorectal surgery should be encouraged. PMID- 21785982 TI - Increased number of B-cells in the red pulp of the spleen in ITP. AB - Platelets are targeted by autoantibodies and destroyed in the reticuloendothelial system in the spleen, liver and bone marrow in patients with immune thrombocytopenia (ITP). Other mechanisms such as destruction by cytotoxic T-cells and defective production of platelets in the bone marrow also exist. Splenectomy normalizes the platelet count in 70% of ITP patients, however, precious little is known about the spleen in this disease. Our aim was therefore to investigate the splenic morphology and especially the number and localization of splenic leukocytes in patients with ITP and controls and to evaluate factors predicting outcome of splenectomy. Spleen sections from 29 ITP patients and 11 individuals splenectomized due to trauma were analyzed by immunohistochemistry. All except one of the ITP patients had a normalized platelet count 12 months after splenectomy and the platelet count was inversely correlated with age. ITP patients had an increased number of B-cells in the red pulp. The number of white pulp B-cells and number of T-cells in both compartments was unchanged. In conclusion, B-cells are increased in the red pulp of the spleen and together with cytotoxic T-cells, helper T-cells and macrophages line the sinusoids enabling the immunological attack on platelets in ITP. PMID- 21785983 TI - Improvement of L-arginine production by overexpression of a bifunctional ornithine acetyltransferase in Corynebacterium crenatum. AB - Ornithine acetyltransferase (EC 2.3.1.35; OATase) gene (argJ) from the L-arginine producing mutant Corynebacterium crenatum SYPA5-5 was cloned, sequenced, and expressed in Escherichia coli BL21 (DE3). Analysis of the argJ sequence revealed that the argJ coded a polypeptide of 388 amino acids with a calculated molecular weight of 39.7 kDa. In this study, the function of the OATase (argJ) of C. crenatum SYPA5-5 has been identified as a conserved ATML sequence for the autolysis of the protein to alpha- and beta-subunits. When the argJ regions corresponding to the alpha- and beta-subunits were cloned and expressed separately in E. coli BL21, OATase activities were abolished. At the same time, a functional study revealed that OATase from C. crenatum SYPA5-5 was a bifunctional enzyme with the functions of acetylglutamate synthase (EC 2.3.1.1, NAGS) and acetylornithine deacetylase (EC 3.5.1.16, AOase) activities. In order to investigate the effects of the overexpression of the argJ gene on L: -arginine production, the argJ gene was inserted into pJCtac to yield the recombinant shuttle plasmid pJCtac-argJ and then transformed into C. crenatum SYPA5-5. The results showed that the engineered strains could not only express more OATase (90.9%) but also increase the production of L: -arginine significantly (16.8%). PMID- 21785984 TI - Titanium release in serum of patients with different bone fixation implants and its interaction with serum biomolecules at physiological levels. AB - Increased concentrations of circulating metal-degradation products derived from the use of Ti orthopaedic implants may have deleterious biological effects over the long term. Therefore, there is an increasing need to establish the basal level of Ti in the serum of the population (exposed and non-exposed) with appropriate highly sensitive techniques and strategies. With this aim, we have developed a quantitative strategy for the determination of total Ti concentration in human serum samples by isotope dilution analysis using a double-focussing inductively coupled plasma mass spectrometer. Minimizing sample handling and therefore contamination issues, we obtained detection limits of about 0.05 MUg L( 1) Ti working at medium resolution (m/Deltam 4000). Such extremely good sensitivity permitted us to establish the range of Ti concentration in serum of 40 control individuals (mean 0.26 MUg L(-1)) and also to compare it with the level in exposed patients with different Ti metal implants. On the other hand, Ti transport "in vivo" studies have been enabled by online coupling of liquid chromatography (anion-exchange) separation and double-focussing inductively coupled plasma mass spectrometry for sensitive detection of Ti. The development of a postcolumn isotope dilution strategy permitted quantitative characterization of the Ti-transporting biomolecules in human serum. The results for unspiked serum revealed that 99.8% of the Ti present in this fluid is bound to the protein transferrin, with column recoveries greater than 95%. PMID- 21785985 TI - Diversity and composition of sulfate- and sulfite-reducing prokaryotes as affected by marine-freshwater gradient and sulfate availability. AB - Sulfate- and sulfite-reducing prokaryotes (SSRP) communities play a key role in both sulfur and carbon cycles. In estuarine ecosystems, sulfate concentrations change with tides and could be limited in tidal freshwater reach or deep sediments. In a subtropical estuary of northern Taiwan in December 2007, we examined the compositional changes of SSRP communities. We examined three sites: from the lower estuarine brackish-water reach (site GR and mangrove vegetation site, GM) to the upper estuarine tidal freshwater reach (site HR), as well as from surface to a 50-cm depth. The partial sequence of sulfite reductase (dsrB) genes was used as a molecular marker of SSRP, linked to polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE) techniques. SSRP communities of the DGGE profiles varied with sites according to one-way analyses of similarities (Global R = 0.69, P = 0.001). Using cluster analysis, the DGGE profile was found to show site-specific clusters and a distinct depth zonation (five, six, and two SSRP communities at the GM, GR, and HR sites, respectively). SSRP composition was highly correlated to the combination of salinity, reduced sulfur, and total organic carbon contents (BIO-ENV analysis, r ( s ) = 0.56). After analyzing a total of 35 dsrB sequences in the DGGE gel, six groups with 15 phylotypes were found, which were closely related to marine-freshwater gradient. Moreover, sequences neighboring sulfite-reducing prokaryotes were observed, in addition to those affiliated to sulfate-reducing prokaryotes. Four phylotypes harvested in HR resembled the genus Desulfitobacterium, a sulfite-reducing prokaryote, which failed to use sulfate as an electron acceptor and were active in freshwater and sulfate-limited habitat. The other five phylotypes in the HR reach belonged to the sulfate-reducing prokaryotes of the genera Desulfatiferula, Desulfosarcina, Desulfovibrio, and Desulfotomaculum, which appeared to tolerate low salinity and low sulfate supply. SSRP phylotypes at the mangrove-vegetated GM site (five phylotypes in two groups) were phylogenetically less diverse, when compared with those at the non-mangrove-vegetated GR site (three phylotypes in three groups) and the tidally influenced freshwater HR site (nine phylotypes in five groups). Phylotypes found at GR and GM were all affiliated to marine sulfate reducing prokaryote strains of the genera Desulfofaba, Desulfobotulus, Desulfatiferula, Desulfosarcina, and Desulfotomaculum. Notably, a phylotype recorded in the surface sediment at GR resembled the genus Desulfobulbus, which was recorded from freshwater environment consisting of the freshwater input at GR during ebb tides. PMID- 21785986 TI - Categories of glucose tolerance and continuous glycemic measures and mortality. AB - We investigated the association of undiagnosed diabetes, previously known diabetes and prediabetes (WHO 1999 classification) with all-cause and cause specific mortality in an older German population. Previous study results for mortality in patients with very low levels of HbA1c, fasting plasma glucose (FPG), and 2-h plasma glucose (2hPG) are still inconclusive. Thus we have extended the analyses to continuous measures of glycemia. A total of 1,466 subjects aged 55-74 years from the population-based KORA survey S4 (conducted from 1999 to 2001) were included in our observational mortality study (152 subjects with previously known diabetes, and 1,314 further subjects who underwent oral glucose tolerance tests). Mortality was followed up for a maximum of 10.0 years (median follow-up 8.8 years). A total of 180 (12.3%) of the 1,466 subjects have died during the follow-up period. The age- and sex-adjusted hazard ratios for all-cause mortality were 2.6 (95%CI, 1.7-3.8) for known diabetes, 2.8 (95%CI, 1.7-4.4) for undiagnosed diabetes, and 1.1 (95%CI, 0.8-1.7) for prediabetes [reference: normal glucose tolerance (NGT)]. After multivariable adjustment, undiagnosed diabetes was associated with 3.0-fold increased cancer mortality, 1.1 fold increased cardiovascular mortality, and 4.7-fold increased non-cancer, non cardiovascular mortality compared with NGT. For HbA1c, FPG, and 2hPG, J-shaped associations with all-cause mortality were observed. Undiagnosed diabetes is associated with increased all-cause, cancer, and non-cancer non-cardiovascular mortality, but not with cardiovascular mortality in this older population. All cause mortality in undiagnosed diabetes is similar to that in previously known diabetes but much higher than mortality in prediabetes and NGT. PMID- 21785987 TI - Solution NMR structure of MED25(391-543) comprising the activator-interacting domain (ACID) of human mediator subunit 25. AB - The solution NMR structure of protein MED25(391-543), comprising the activator interacting domain (ACID) of subunit 25 of the human mediator, is presented along with the measurement of polypeptide backbone heteronuclear 15N-{1H} NOEs to identify fast internal motional modes. This domain interacts with the acidic transactivation domains of Herpes simplex type 1 (HSV-1) protein VP16 and the Varicella-zoster virus (VZV) major transactivator protein IE62, which initiate transcription of viral genes. The structure is similar to the beta-barrel domains of the human protein Ku and the SPOC domain of human protein SHARP, and provides a starting point to understand the structural biology of initiation of HSV-1 and VZV gene activation. Homology models built for the two ACID domains of the prostate tumor overexpressed (PTOV1) protein using the structure of MED25(391 543) as a template suggest that differential biological activities of the ACID domains in MED25 and PTOV1 arise from modulation of quite similar protein-protein interactions by variable residues grouped around highly conserved charged surface areas. PMID- 21785988 TI - Transformation of alfalfa chloroplasts and expression of green fluorescent protein in a forage crop. AB - The ability to transform chloroplasts in multiple species is important for improving agricultural traits. Chloroplast transformation of alfalfa (Medicago sativa L.), a useful forage plant with high market value, was achieved using a vector carrying aadA and gfp genes being introduced into the chloroplasts of alfalfa via particle bombardment using leaves and calli as explants. Resistant somatic embryos were generated and developed into plantlets from explants. The transformation efficiency was 1.3% for callus explants and 2.7% for leaf explants. PCR and Southern blotting analyses revealed that the foreign genes were integrated into the transformed chloroplast genome. The occurrence of GFP was further confirmed by fluorescence microscopy. Expression of foreign genes in alfalfa chloroplasts is therefore possible, and provides a novel means for genetic improvement of agronomically important traits and production of value added proteins. PMID- 21785989 TI - Use of Pichia fermentans and Candida sp. strains for the biological treatment of stored olive mill wastewater. AB - Of 105 isolates screened for growth on plates containing olive mill wastewater (OMW), five were selected and identified as Pichia fermentans (Y1, Y4) and Candida sp. (Y2, Y11, and Y18). On the basis of their ability to use phenol at 716 mg l(-1), strains Y2 (15% reduction) and Y4 (18% reduction) were then used to detoxify stored OMW under various operational conditions. Yeast treatment of OMW increased the pH and, in the best conditions (aeration and no glucose addition), the COD decreased (47%) and phytotoxicity was also decreased (56%) probably due to the changes in the composition of phenolic compounds. PMID- 21785990 TI - The effects of moderately high temperature on zeaxanthin accumulation and decay. AB - Moderately high temperature reduces photosynthetic capacities of leaves with large effects on thylakoid reactions of photosynthesis, including xanthophyll conversion in the lipid phase of the thylakoid membrane. In previous studies, we have found that leaf temperature of 40 degrees C increased zeaxanthin accumulation in dark-adapted, intact tobacco leaves following a brief illumination, but did not change the amount of zeaxanthin in light-adatped leaves. To investigate heat effects on zeaxanthin accumulation and decay, zeaxanthin level was monitored optically in dark-adapted, intact tobacco and Arabidopsis thaliana leaves at either 23 or 40 degrees C under 45-min illumination. Heated leaves had more zeaxanthin following 3-min light but had less or comparable amounts of zeaxanthin by the end of 45 min of illumination. Zeaxanthin accumulated faster at light initiation and decayed faster upon darkening in leaves at 40 degrees C than leaves at 23 degrees C, indicating that heat increased the activities of both violaxanthin de-epoxidase (VDE) and zeaxanthin epoxidase (ZE). In addition, our optical measurement demonstrated in vivo that weak light enhances zeaxanthin decay relative to darkness in intact leaves of tobacco and Arabidopsis, confirming previous observations in isolated spinach chloroplasts. However, the maximum rate of decay is similar for weak light and darkness, and we used the maximum rate of decay following darkness as a measure of the rate of ZE during steady-state light. A simulation indicated that high temperature should cause a large shift in the pH dependence of the amount of zeaxanthin in leaves because of differential effects on VDE and ZE. This allows for the reduction in DeltapH caused by heat to be offset by increased VDE activity relative to ZE. PMID- 21785991 TI - Effects of the measuring light on the photochemistry of the bacterial photosynthetic reaction center from Rhodobacter sphaeroides. AB - The bacterial reaction center (RC) has become a reference model in the study of the diverse interactions of quinones with electron transfer complexes. In these studies, the RC functionality was probed through flash-induced absorption changes where the state of the primary donor is probed by means of a continuous measuring beam and the electron transfer is triggered by a short intense light pulse. The single-beam set-up implies the use as reference of the transmittance measured before the light pulse. Implicit in the analysis of these data is the assumption that the measuring beam does not elicit the protein photochemistry. At variance, measuring beam is actinic in nature at almost all the suitable wavelengths. In this contribution, the analytical modelling of the time evolution of neutral and charge-separated RCs has been performed. The ability of measuring light to elicit RC photochemistry induces a first order growth of the charge-separated state up to a steady state that depends on the light intensity and on the occupation of the secondary quinone (Q(B)) site. Then the laser pulse pumps all the RCs in the charge-separated state. The following charge recombination is still affected by the measuring beam. Actually, the kinetics of charge recombination measured in RC preparation with the Q(B) site partially occupied are two-exponential. The rate constant of both fast and slow phases depends linearly on the intensity of the measuring beam while their relative weights depend not only on the fractions of RC with the Q(B) site occupied but also on the measuring light intensity itself. PMID- 21785992 TI - Chronic diarrhea and malabsorption due to hypogammaglobulinemia: a report on twelve patients. AB - Hypogammaglobulinemic sprue (HGS), which may predispose to infection, is uncommon. Twelve patients (all men; median age 29 years, 15-50) with HGS (4%) of 296 with chronic small bowel diarrhea and malabsorption syndrome (MAS) during a 10-year period were analyzed. Treatment of HGS was delayed due to misdiagnosis as intestinal tuberculosis (n = 7) and diarrhea-predominant irritable bowel syndrome (n = 1). All had diarrhea and weight loss (median loss 12 Kg). Associated conditions were clubbing, bronchiectasis, and seizure (2 patients each), and hypothyroidism (n = 1). Laboratory parameters were urinary D-xylose median 0.46 g/5 g/5 h (range 0.2-1.6; normal >= 1), fecal fat 11.9 g/day (3.8-16.7; normal <= 7 g), serum IgA, IgG, and IgM: 23.5 mg/dL (17-114; normal 90-450), 584 mg/dL (145 1051; normal 800-1800), and 23 (0-40.3; normal 60-280). IgA, IgG, and IgM were low in 10, 10, and 11, respectively. Duodenal biopsy was normal in 6 patients and showed partial villous atrophy in 6 and nodular lymphoid hyperplasia in two. Associated infections were giardiasis (n = 1), disseminated strongyloidiasis (1), small intestinal bacterial overgrowth (3), septicemia (2), and septic arthritis (1). Two patients died of sepsis, five are well on immunoglobulin and specific anti-infective treatment, and five are lost to follow up. Approximately 4% patients with MAS have hypogammaglobulinemia, which is often associated with infection and is diagnosed late. PMID- 21785993 TI - Shedding light on the epidemiology of gastroesophageal reflux disease in India--a big step forward. PMID- 21785994 TI - Questionnaire based gastroesophageal reflux disease (GERD) assessment scales. AB - Questionnaire based assessment scales for gastroesophageal reflux disease (GERD) have been utilized for assessment of the patient's symptomatology, assessment of symptom severity and frequency, assessment of health-related quality of life and for assessment of response to treatment. A multitude of unidimensional and multidimensional questionnaires exist for making symptom assessment and monitoring quality of life in GERD. Many of the scales meet some of the parameters of an ideal evaluative GERD specific assessment instrument. Yet, there are certain shortcomings and challenges which are faced in development of GERD questionnaires. This review discusses the features of an ideal symptom assessment instrument, examines the strengths and weaknesses of currently available questionnaires. PMID- 21785995 TI - Outcomes of hypoplastic left heart syndrome in low-birth-weight patients. AB - The objective of this study was to assess outcomes of hypoplastic left heart syndrome (HLHS) patients weighing <= 2.5 kg throughout staged palliation. We performed a single-center retrospective review. Abstracted data included gestational age, birth weight, presence of noncardiac anomalies, and survival through Fontan. Fifty-two patients met inclusion criteria, with a median birth weight of 2.14 kg and gestational age of 36 weeks. Five patients received comfort care only. Of 47 patients who underwent initial surgical palliation, 51% survived to initial hospital discharge. Birth weight and gestational age (GA) were similar between survivors and nonsurvivors. Compared with survivors, risk factors for death prior to initial hospital discharge were as follows: small for GA (P = 0.005), noncardiac anomalies (P = 0.04), need for post-perative extracorporeal membrane oxygenation (P = 0.0004), and conversion from initial palliation to Sano shunt (n = 5, no survivors). Operative survival following Stage 2 palliation was 91% (21/23) and 94% after Fontan (17/18). Overall survival for palliated patients from birth through Fontan was 36%. Low-birth-weight neonates with HLHS have poor overall survival through the Fontan operation, with highest mortality following Stage 1 palliation. Being small for GA and the presence of noncardiac anomalies are important preoperative risk factors for early mortality. PMID- 21785997 TI - Passive water control at the surface of a superhydrophobic lichen. AB - Some lichens have a super-hydrophobic upper surface, which repels water drops, keeping the surface dry but probably preventing water uptake. Spore ejection requires water and is most efficient just after rainfall. This study was carried out to investigate how super-hydrophobic lichens manage water uptake and repellence at their fruiting bodies, or podetia. Drops of water were placed onto separate podetia of Cladonia chlorophaea and observed using optical microscopy and cryo-scanning-electron microscopy (cryo-SEM) techniques to determine the structure of podetia and to visualise their interaction with water droplets. SEM and optical microscopy studies revealed that the surface of the podetia was constructed in a three-level structural hierarchy. By cryo-SEM of water-glycerol droplets placed on the upper part of the podetium, pinning of the droplet to specific, hydrophilic spots (pycnidia/apothecia) was observed. The results suggest a mechanism for water uptake, which is highly sophisticated, using surface wettability to generate a passive response to different types of precipitation in a manner similar to the Namib Desert beetle. This mechanism is likely to be found in other organisms as it offers passive but selective water control. PMID- 21785996 TI - Pathogenesis of the tauopathies. AB - Microtubule-associated protein tau is the most commonly misfolded protein in human neurodegenerative diseases, where it becomes hyperphosphorylated and filamentous. Mutations in MAPT, the tau gene, cause approximately 5% of cases of frontotemporal dementia. They are frequently accompanied by parkinsonism. The existence of MAPT mutations has established that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. However, most tauopathies are not inherited in a dominant manner. The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary. This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept. PMID- 21785998 TI - A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer. AB - PURPOSE: The objective of this trial was to evaluate the clinical effects of sorafenib, a multi-targeted kinase inhibitor, in combination with androgen receptor blockade in patients with castration-resistant prostate cancer. METHODS: This was a multicenter, two-stage, phase 2 trial. Eligible patients had rising PSA, minimal symptoms and were chemotherapy-naive. Sorafenib 400 mg twice daily was administered with bicalutamide 50 mg once daily on a 28-day cycle. The primary endpoint was PSA response (>= 50% decline) or stable disease >= 6 months. RESULTS: 39 patients were enrolled including eight without clinical evidence of metastases. Eighteen (47%) patients have had either a PSA response or stable disease >= 6 months. PSA declines of >= 50% occurred in 12 (32%) of 38 assessable patients, including seven of 27 patients (26%) with prior anti-androgen use. Median time to treatment failure was 5.5 months (95%CI = 4.8.1-8.3). Grade >= 3 adverse events included fatigue, skin rash, and hand-foot syndrome. CONCLUSIONS: PSA declines and stable disease were observed with a combination of sorafenib and bicalutamide including in patients previously progressing on bicalutamide. Strategies to combine multi-targeted kinase inhibitors with hormonal therapies warrant further study in patients with CRPC. PMID- 21785999 TI - The broad challenge of public engagement in science: commentary on: "Constitutional moments in governing science and technology". AB - Timely public engagement in science presents a broad challenge. It includes more than research into the ethical, legal and social dimensions of science and state initiated citizen's participation. Introducing a public perspective on science while safeguarding its public value involves a diverse set of actors: natural scientists and engineers, technology assessment institutes, policy makers, social scientists, citizens, interest organisations, artists, and last, but not least, politicians. PMID- 21786000 TI - Is human enhancement also a personal matter? AB - Emerging technologies are increasingly used in an attempt to "enhance the human body and/or mind" beyond the contemporary standards that characterize human beings. Yet, such standards are deeply controversial and it is not an easy task to determine whether the application of a given technology to an individual and its outcome can be defined as a human enhancement or not. Despite much debate on its potential or actual ethical and social impacts, human enhancement is not subject to any consensual definition. This paper proposes a timely and much needed examination of the various definitions found in the literature. We classify these definitions into four main categories: the implicit approach, the therapy-enhancement distinction, the improvement of general human capacities and the increase of well-being. After commenting on these different approaches and their limitations, we propose a definition of human enhancement that focuses on individual perceptions. While acknowledging that a definition that mainly depends on personal and subjective individual perceptions raises many challenges, we suggest that a comprehensive approach to define human enhancement could constitute a useful premise to appropriately address the complexity of the ethical and social issues it generates. PMID- 21786001 TI - Takayasu arteritis in pregnancy: an analysis from eastern India. AB - OBJECTIVE: Takayasu's Arteritis (TA) is a rare inflammatory disease of medium and large size arteries that affects women of reproductive age. This study aims to highlight the antenatal management and analyze the obstetric outcome in women with TA. METHODS: This retrospective study was carried out in the Department of O&G, Cardiology and Rheumatology--IPGME&R, Kolkata from June 2002 to July 2010. Sixteen patients with 29 pregnancy events were compared with 60 matched controls. RESULTS: Clinical presentation of study population at admission included unequal or absent pulse, hypertension, congestive cardiac failure, retinopathy, aortic regurgitation and cerebrovascular accident (CVA). Mode of delivery was cesarean in 20 pregnancies (71.49%) and vaginal in nine pregnancies (31.03%). Significant maternal complications included pregnancy induced hypertension (100 vs. 1.66%; P < 0.001), preeclampsia (92.85 vs. 0%; P < 0.001), postpartum hemorrhage (17.24 vs. 1.66%; P < 0.001) and preterm labor (17.24 vs. 3.33%; P < 0.001). One maternal mortality was present due to CVA. Neonatal outcome showed 26 live births with increased incidence of intrauterine growth restriction (51.72 vs. 1.66%; P < 0.001) and neonates requiring NICU admissions (58.62 vs. 5.0%; P < 0.001). CONCLUSION: Although conception was spontaneous in all these pregnancies, antenatal and intrapartum control of blood pressure played a pivotal role in pregnancy outcome. High rate of operative interference was present. All subsequent pregnancies had similar outcome due to slow progression of the disease. Although pregnancy was complicated by hypertension and its sequelae, successful outcome could be achieved with timely admission, judicious medication and multidisciplinary approach. PMID- 21786002 TI - Multiple myeloma and pregnancy: a case report and literature review. AB - PURPOSE: Multiple myeloma, a hematological malignancy generally affecting elderly people, was diagnosed at the beginning of the pregnancy of a 33-year-old woman. We carried out a literature review in order to evaluate the consequences of this cancer on pregnancy and of pregnancy on multiple myeloma, as to determine the specific follow-up required. METHODS: A systematic search for articles of interest published between 1949 and 16 November 2010 was performed in MEDLINE, SCOPUS and EMBASE, using the words "multiple myeloma" and "pregnancy". We identified 398 publications of potential interest, 20 of which were selected and included in the analysis. RESULTS: The selected articles included 26 cases. No specific risk factors were identified in pregnant women. The most common presentations were bone pain and/or anemia, as in the general population. Pregnancy seemed to have no effect on multiple myeloma progression. Most pregnancies went to term, with only two medical terminations and six cesareans performed before term, due to the severity of the cancer. No effect of the cancer or its treatment by chemotherapy during pregnancy was found in the children. CONCLUSION: Pregnancy does not seem to be contraindicated in women with multiple myeloma. Nevertheless, the management of pregnant patients with multiple myeloma is a diagnostic, therapeutic and social challenge, requiring a multidisciplinary approach and regular follow-up. Decisions should be taken based on the severity of the disease, its prognosis and maternal choice. PMID- 21786003 TI - [Livedoid vasculopathy. Pathogenesis, diagnosis and treatment of cutaneous infarction]. AB - Livedo vasculopathy is a chronic recurrent disease of the cutaneous circulation and is characterized by episodic occurrence of painful ulcerations of the lower leg. These heal slowly leaving small porcelain-white scars called atrophie blanche. Recent research has shown that livedoid vasculopathy is a coagulation disorder classified as a vasculopathy different from inflammatory vasculitis. Distinguishing between the disorders enhances the pathophysiologic understanding and supports the therapeutic rationale. The prevention of irreversible residual scarring is the main goal in treating cutaneous infarction; prompt treatment is required. PMID- 21786004 TI - [How the sun ages our skin. The dermis as the driving force]. AB - Extrinsic factors (= environmentally induced skin aging) lead to both epidermal and dermal changes. Recent investigations have shown that the dermis plays the decisive role, at least for skin aging caused by ultraviolet (UV) radiation. Exposure to UV radiation results in an accumulation of damage to the mitochondrial DNA of dermal fibroblasts and thus an altered gene expression of the affected cells, which chronically drives both the dermal (e.g., wrinkle formation) and epidermal (atrophy, barrier dysfunction) aging process. This knowledge is currently being used to develop highly effective cosmetic strategies to reverse the skin aging process. PMID- 21786005 TI - A retrospective analysis of extended-interval dosing and the impact on bisphosphonate compliance in the US Military Health System. AB - This study evaluated whether patients treated with bisphosphonates in the US Military Health System were more compliant with treatment given monthly versus weekly. While medication compliance did improve with treatment given monthly, overall compliance with bisphosphonates was still suboptimal suggesting the need for further strategies to improve compliance with treatment for osteoporosis. INTRODUCTION: The study objective was to evaluate the relationship between bisphosphonate dosing interval and medication compliance among new users initiating oral bisphosphonates. METHODS: We conducted a retrospective observational cohort study of administrative claims data in the US Military Health System to examine medication compliance among 22,363 new users of oral bisphosphonates starting weekly (68%) or monthly (32%) therapy. Medication compliance during the first year of treatment was measured using two methods: (1) medication possession ratio (MPR) with compliance defined as >=80% of days covered and (2) time to first gap of more than 30 days following initiation. Logistic regression and a proportional hazards model were used to detect differences in medication compliance between cohorts. RESULTS: After the first year of therapy, 57% of subjects were not compliant with bisphosphonates (MPR <80%), while 84% experienced a gap in treatment of more than 30 days. After adjustment for study covariates, the odds of a patient being compliant with treatment was 21% higher among monthly users compared to weekly users (OR 1.207, 95% confidence interval (CI) 1.119-1.257). Similarly, the risk of experiencing a 30-day gap in treatment was 6% lower among monthly users compared to weekly users (HR 0.934, 95% CI 0.905-0.964). CONCLUSIONS: Patients receiving oral bisphosphonates on a monthly basis showed higher rates of medication compliance compared to weekly dosing in our study. However, compliance with bisphosphonates among all new users was suboptimal, suggesting the need for improved strategies to enhance compliance with oral bisphosphonates in the US Military Health System. PMID- 21786006 TI - Differences in structural geometrical outcomes at the neck of the proximal femur using two-dimensional DXA-derived projection (APEX) and three-dimensional QCT derived (BIT QCT) techniques. AB - Structural geometric parameters at neck of the proximal femur were obtained using DXA-derived hip structural analysis (APEX 3) and quantitative computed tomography derived (BIT QCT) techniques in 237 elderly females. Linear correlations for parameters ranged from 0.45 to 0.90. The average value of the subperiosteal width, as determined by the two techniques, was the same; variables dependent on mass measurements were different. INTRODUCTION: There has been increasing interest in using bone structural geometry to assess bone fragility to complement bone mineral mass. The objective of this study is to compare structural geometrical differences between "2D" DXA-derived and "3D" QCT-derived techniques in unselected clinical cases. METHODS: All 237 females had both DXA and QCT assessments of femoral neck structural geometry. Variables compared were areal bone mineral density, cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), averaged cortical thickness (Ct), endosteal width (ESW), subperiosteal width (W), and buckling ratio (BR). RESULTS: Correlation of femoral neck variables ranged from 0.45 for ESW to 0.90 for CSA. APEX 3 and BIT QCT-derived femoral neck W values were numerically similar. However CSA, CSMI, Z and Ct values measured by APEX 3 were higher and ESW and BR values were lower than corresponding BIT QCT. CONCLUSIONS: 2D DXA structural analysis of neck of femur is related to but different from same parameters calculated from true 3D images obtained by CT. Femoral neck size values are similar for DXA and QCT, but structural geometrical variables dependent on mass calibration standards, location of neck ROI and mathematical derivation techniques are different. PMID- 21786007 TI - Destruction of salivary and lacrimal glands by Th1-polarized reaction in a model of secondary Sjogren's syndrome in lupus-prone female NZB * NZWF(1) mice. AB - T helper (Th)1/Th2 balance determines the direction of some kinds of autoimmune diseases. The involvement of acini areas by CD4(+) helper T(Th) cell subset in submandibular and lacrimal glands are largely unknown in secondary Sjogren's syndrome (sSjS) with systemic lupus erythematosus (SLE). Submandibular and lacrimal glands were examined immunopathologically in lupus-prone female NZB * NZW(B/W)F(1) mice, model for human sSjS with SLE. Dacryoadenitis and sialoadenitis with renal failure developed with age. Infiltration of lymphoid cells (lymphocytes and plasma cells) expanded from the periductal areas in striated ducts to the acini, and the isolated foci in the acini were observed in those organs. The destruction of duct and acini epithelium, including the myoepithelium, was induced by interferon (IFN)-gamma(+) and IgG2a(+) lymphoid cells, but not by interleukin(IL)-4(+), IL-5(+), IL-13(+), and IgG1(+) lymphoid cells. Compared with IL-5 and IL-13, high values of IFN-gamma were produced systemically at various ages. Also local expression of IFN-gamma mRNA was higher than that of IL-4 mRNA. The result suggests that the acini destruction in submandibular and lacrimal glands may be induced by systemic and local Th1 cell dominant reactions in lupus-prone B/WF(1) mice with sSjS. PMID- 21786008 TI - Anterior interosseous nerve compression syndrome: is there a role for endoscopy? AB - BACKGROUND: Anterior interosseous nerve syndrome is characterized by paralysis of the flexor digitorum profundus, the flexor pollicis longus and the pronator quadratus muscles without sensory loss. Extended exploration of the anterior interosseous nerve is the surgical treatment of choice. The present study evaluates the feasibility of an endoscopic approach for nerve decompression. METHODS: Preparation of the anterior interosseous nerve was performed in ten human cadaver arms. Subsequently, one female patient suffering from anterior interosseous nerve syndrome was endoscopically operated on. FINDINGS: A skin incision of 3-4 cm in the proximal direction was made at the forearm, and the median nerve was visualized between the pronator teres muscle and the flexor digitorum superficialis. Subsequently, the anterior interosseus nerve branch was identified, followed distally and decompressed under endoscopic view. The procedure could be accomplished in all cases under endoscopic view. Due to the very steep surgical angle, a branch of the anterior interosseus nerve was injured in one cadaver case. In all other cases, no adverse effects were observed. In the clinical case, the anterior interosseus nerve was endoscopically identified and decompressed, but a skin incision of 5 cm was required. CONCLUSIONS: The results demonstrate that an endoscopic decompression of the anterior interosseus nerve is possible. Several difficulties occurred: Due to the depth of the surgical approach, especially in case of bulky muscles and very small skin incisions, the view is limited, harboring a higher risk of nerve injury. With more experience and specially designed endoscopes, application of this technique in anterior interosseus nerve compression syndrome might become more feasible. PMID- 21786009 TI - Analysis of epidermal lipids in normal and atopic dogs, before and after administration of an oral omega-6/omega-3 fatty acid feed supplement. A pilot study. AB - Alterations of the lipid expression in the skin of human and canine atopic subjects may be one of the key factors in the disease development. We have analyzed the ultrastructure of the clinically uninvolved skin of atopic dogs and compared it with the lipid composition of their tape-stripped stratum corneum (SC). The effect of a 2 month treatment of atopic dogs by food supplementation with a mixture of essential fatty acids was evaluated on skin samples taken before and after the treatment period. Electron microscopy revealed that the non lesional skin of atopic dogs exhibited an abnormal and largely incomplete structure of the lamellar lipids with little cohesion between the corneocyte strata. The SC of atopic dogs was characterized by a significant decrease in the lipid content when compared to the healthy controls. Following oral supplementation with the mixture of essential fatty acids, the overall lipid content of the SC markedly increased. This feature was observed both with the free and, most importantly, with the protein-bound lipids (cholesterol, fatty acids and ceramides), the latter constituting the corneocyte-bound scaffold for ordinate organisation of the extracellular lipid bi-layers. Indeed, the semi quantitative electron microscopy study revealed that the treatment resulted in a significantly improved organization of the lamellar lipids in the lower SC, comparable to that of the healthy dogs. Our results indicate the potential interest of long-term alimentary supplementation with omega-6 and omega-3 essential fatty acids in canine atopic dermatitis. PMID- 21786010 TI - Regeneration of extrahepatic bile ducts by tissue engineering with a bioabsorbable polymer. AB - With the widespread adoption of laparoscopic cholecystectomy and living-donor liver transplantation in recent years, complications involving the biliary system, stenosis in particular, are increasing. Various invasive and non-invasive techniques are now available for the treatment of biliary stenosis, but all are compromised by a high risk of recurrence and other problems. As a potential solution, our group has developed a bioabsorbable polymer (BAP) tube for implantation as a bypass graft. In the study reported here, we implanted this BAP tube and confirmed bile duct regeneration at the graft site after the tube had been degraded and absorbed into the body. We briefly describe our findings on extrahepatic biliary tissue regeneration, focusing on the possibility of its clinical application. This artificial bile duct may promote the development of novel treatments for biliary disease. PMID- 21786011 TI - A novel prognostic model for extranodal natural killer/T-cell lymphoma. AB - Natural killer (NK)/T-cell lymphoma is a rare neoplasm with heterogeneous clinical behaviors. This study aimed to devise a prognostic model specifically for extranodal NK/T-cell lymphoma, providing risk stratification in affected patients. A total of 146 patients newly diagnosed with extranodal NK/T-cell lymphoma were retrospectively analyzed. Independent predictors of survival were determined by Cox regression analysis. The estimated 5-year overall survival rate for all patients was 41.9%. Both the International Prognostic Index and Korean NK/T-cell lymphoma Prognostic Index were prognostic in univariate analysis. The majority of our patients were in the low-risk International Prognostic Index and Korean NK/T-cell lymphoma Prognostic Index category (with no or one adverse factor), but both of these two prognostic models had no discriminating power within the subgroup of these patients. Absolute lymphocyte count at diagnosis, B symptoms, and advanced stage were independently predicted poorer survival. Cox analysis yielded a novel prognostic model based on these three parameters that categorized patients into one of three risk groups: Group 1 (57 cases, 39.0%), no adverse factors; Group 2 (43 cases, 29.5%), one adverse factor; and Group 3 (46 cases, 31.5%), two or three adverse factors. Five-year overall survival was 71.6% for Group 1, 55.5% for Group 2, and 0% for Group 3 (P < 0.0001). The novel prognostic model balanced the distribution of patients into different risk groups with better predictive discrimination. It may be useful to stratify patients with extranodal NK/T-cell lymphoma into different risk groups and provide more information for treatment selection. PMID- 21786012 TI - The expression of epidermal growth factor receptor and Ki67 in primary and relapse nasopharyngeal cancer: a micro-evidence for anti-EGFR targeted maintenance therapy. AB - Epidermal growth factor receptor (EGFR) was expressed widely in NPC. The aim of this study was to investigate the difference of expression of EGFR and Ki67 in primary and recurrence of NPC to supply a micro-evidence of anti-EGFR targeted maintenance therapy for NPC. A retrospective review of 40 patients with clinical stages I-IV b was performed. Chemoradiation was included chemotherapy with fluorouracil plus cisplatin and irradiation for primary and lymph draining regions. All patients were verified tumor locoregional relapse with/or without distant metastasis by CT or MRI after combined CRT by primary and recurrence biopsies. The correlation between EGFR and Ki67 expression inspected by immunohistochemistry was analyzed. The difference of time to recurrence grouped by different expressions of EGFR and Ki67 was compared by log-rank test. The median follow-up time was 20.0 months +/- 2.70 (range 23-71). EGFR and Ki67 expression in primary was not significantly different with recurrent focus. A strong significant correlation between EGFR and Ki67 molecules expression was obtained in primary (r = 0.573; P = 0.001) and in recurrent focus (r = 0.698; P = 0.000). A significantly shorter time to locoregional relapse in patients with positive expression of EGFR than patients with negative EGFR expression in primary (P = 0.010) and in relapse (P = 0.022). There was no significant difference of EGFR and Ki67 expression in primary and recurrence tumor expression. The time to relapse was significantly shorter in high expression of EGFR, which might supply micro-evidence to anti-EGFR targeted maintenance therapy for those patients with EGFR overexpression in primary tumor. PMID- 21786013 TI - A preliminary study on the expression of tumor-associated glycoprotein-72 in human gliomas. AB - Tumor-associated glycoprotein-72 (TAG-72) is a high molecular weight tumor associated glycoprotein, which is known to be overexpressed in various human tumors, but its expression in glioma tissues is unknown. Therefore, the aim of this study was to investigate whether TAG-72 is present in glioma and to evaluate the correlation between TAG-72 expression and the severity of the malignancy of this tumor. Immunohistochemistry and Western blot were used to investigate the expression of TAG-72 protein, respectively, in 152 patients with gliomas. There were 90 men and 62 women (mean age 50.6 +/- 11.8 years). Astrocytoma was found in 130 patients and glioblastoma in 22. No TAG-72 expression was found in the non cancerous brain tissues. TAG-72 protein expression was identified in 80 patients with glioma (52.6%). The expression level of TAG-72 protein was increased from gliomas with low grades to those with high grades. The highest mean value of TAG 72 protein was found in patients with glioblastoma (P < 0.01), whereas the lowest mean values were found in those with grade I astrocytoma (P < 0.01). Our results provide convincing evidence for the first time that the expression of TAG-72 is up-regulated in human gliomas. The expression levels of TAG-72 in gliomas were associated with the severity of the tumor. Whether positive TAG-72 protein expression can be used as a predictor for prognosis of the patients or as a therapeutic target for glioma requires further investigation. PMID- 21786014 TI - Towards optimum chest compression performance during constant peak displacement cardiopulmonary resuscitation. AB - The aim of this study is to determine the conditions necessary to achieve optimum chest compression (CC) performance during constant peak displacement cardiopulmonary resuscitation (CPR). This was accomplished by first performing a sensitivity analysis on a theoretical constant peak displacement CPR CC model to identify the parameters with the highest sensitivity. Next, the most sensitive parameters were then optimized for net sternum-to-spine compression depth, using a two-variable non-linear least squares method. The theoretical CC model was found to be most sensitive to: thoracic stiffness, maximum sternal displacement, CC rate, and back support stiffness. Based on a two-variable, non-linear least squares analysis to optimize the model for the net sternum-to-spine compression depth during constant peak displacement CPR, it was found that the optimum ranges for the CC rate and back support stiffness are between 40-120 cpm and 241.0 1198.5 Ncm-1, respectively. Clinically, this suggests that current ERC guidelines for the CC rate during peak displacement CPR are appropriate; however, practitioners should be aware that the stiffness of the back support surfaces found in many hospitals may be sub-optimal and should consider using a backboard or a concrete floor to enhance CPR effectiveness. PMID- 21786015 TI - Cardiac oxygen supply is compromised during the night in hypertensive patients. AB - The enhanced heart rate and blood pressure soon after awaking increases cardiac oxygen demand, and has been associated with the high incidence of acute myocardial infarction in the morning. The behavior of cardiac oxygen supply is unknown. We hypothesized that oxygen supply decreases in the morning and to that purpose investigated cardiac oxygen demand and oxygen supply at night and after awaking. We compared hypertensive to normotensive subjects and furthermore assessed whether pressures measured non-invasively and intra-arterially give similar results. Aortic pressure was reconstructed from 24-h intra-brachial and simultaneously obtained non-invasive finger pressure in 14 hypertensives and 8 normotensives. Supply was assessed by Diastolic Time Fraction (DTF, ratio of diastolic and heart period), demand by Rate-Pressure Product (RPP, systolic pressure times heart rate, HR) and supply/demand ratio by A(dia)/A(sys), with A(dia) and A(sys) diastolic and systolic areas under the aortic pressure curve. Hypertensives had lower supply by DTF and higher demand by RPP than normotensives during the night. DTF decreased and RPP increased in both groups after awaking. The DTF of hypertensives decreased less becoming similar to the DTF of normotensives in the morning; the RPP remained higher. A(dia)/A(sys) followed the pattern of DTF. Findings from invasively and non-invasively determined pressure were similar. The cardiac oxygen supply/demand ratio in hypertensive patients is lower than in normotensives at night. With a smaller night-day differences, the hypertensives' risk for cardiovascular events may be more evenly spread over the 24 h. This information can be obtained noninvasively. PMID- 21786016 TI - Differential remodeling responses of cerebral and skeletal muscle arterioles in a novel organ culture system. AB - Evidence suggests that maladaptive changes in the cerebral microcirculation may contribute to ischemia in numerous diseases. We sought, therefore, to develop an ex vivo organ culture system to study early changes in cerebral arteriolar structure and function, and to compare associated findings to those for non cerebral arterioles. Pilot studies revealed that rabbit cerebral arterioles maintained contractility longer when cultured in media containing rabbit-specific plasma rather than fetal bovine serum. Cerebral and skeletal muscle arterioles were cultured in a pressure myograph for 5 days; maximum dilatory and contractile responses were measured at 0, 1, 3, and 5 days. Passive properties were preserved in cerebral arterioles over the entire culture period, although skeletal muscle arterioles underwent constrictive remodeling. Cerebral arterioles also maintained a myogenic capability over the entire culture period, albeit at progressively larger diameters, whereas the skeletal muscle arterioles did so only over 3 days. Culture in rabbit serum, which contains numerous growth factors and clotting factors, did not induce or increase inward remodeling in cerebral or skeletal arterioles. These results suggest inherent, organ-specific differences in arteriolar remodeling, and that extensive results in the literature on non cerebral arterioles should not be extrapolated to predict responses in the cerebral microcirculation. PMID- 21786017 TI - The response of Corylus avellana L. phenology to rising temperature in north eastern Slovenia. AB - Knowledge of plant-weather relationships can improve crop management, resulting in higher quality and more stable crop yields. The annual timing of spring phenophases in mid-latitudes is largely a response to temperature, and reflects the thermal conditions of previous months. The effect of air temperature on the variability of hazelnut (Corylus avellana L.) phenophases (leafing, flowering) was investigated. Meteorological and phenological data for five cultivars were analysed over the periods 1969-1979 (P1) and 1994-2007 (P2) in Maribor, Slovenia. Phenological data series were correlated strongly to the temperature of the preceding months (R(2): 0.64-0.98) and better correlated to daily maximum and mean temperatures than to daily minimum temperatures. About 75% of phenophases displayed a tendency towards earlier appearance and a shorter flowering duration during P2, which could be explained by the significant temperature changes (+0.3 degrees C/decade) from December to April between 1969 and 2007. An increase in air temperature of 1 degrees C caused an acceleration in leafing by 2.5-3.9 days, with flowering showing higher sensitivity since a 1 degrees C increase promoted male flowering by 7.0-8.8 days and female flowering by 6.3-8.9 days. The average rate of phenological change per degree of warming (days earlier per +1 degrees C) did not differ significantly between P1 and P2. An estimation of chilling accumulation under field conditions during 1993-2009, between 1 November and 28 February, showed that all four of these months contributed approximately similar amounts of accumulated chilling units. The growing degree days (GDD) to flowering were calculated by an estimated base temperature of 2 degrees C and 1 January as a starting date, given the most accurate calculations. In general, thermal requirements were greater in P2 than in P1, although this difference was not significant. Longer-time series data extended to other agricultural and wild plants would be helpful in tracking possible future changes in phenological responses to local climate. PMID- 21786018 TI - First case of gastrointestinal mucormycosis in an immunocompromised patient with gallbladder and duodenum involvement. PMID- 21786019 TI - On the nature of CS and US representations in Pavlovian learning. AB - A significant problem in the study of Pavlovian conditioning is characterizing the nature of the representations of events that enter into learning. This issue has been explored extensively with regard to the question of what features of the unconditioned stimulus enter into learning, but considerably less work has been directed to the question of characterizing the nature of the conditioned stimulus. This article introduces a multilayered connectionist network approach to understanding how "perceptual" or "conceptual" representations of the conditioned stimulus might emerge from conditioning and participate in various learning phenomena. The model is applied to acquired equivalence/distinctiveness of cue effects, as well as a variety of conditional discrimination learning tasks (patterning, biconditional, ambiguous occasion setting, feature discriminations). In addition, studies that have examined what aspects of the unconditioned stimulus enter into learning are also reviewed. Ultimately, it is concluded that adopting a multilayered connectionist network perspective of Pavlovian learning provides us with a richer way in which to view basic learning processes, but a number of key theoretical problems remain to be solved, particularly as they relate to the integration of what we know about the nature of the representations of conditioned and unconditioned stimuli. PMID- 21786020 TI - Micronutrient status in lactating mothers before and after introduction of fortified flour: cross-sectional surveys in Maela refugee camp. AB - BACKGROUND: Deficiency of micronutrients is common in refugee populations. OBJECTIVES: Identify deficiencies and whether provided supplements and wheat flour fortified with 10 micronutrients impacts upon status among breast-feeding women from Maela refugee camp. METHODS: Two sequential cross-sectional studies were conducted in different groups of lactating mothers at 12 weeks postpartum. The first survey was before and the second 4-5 months after micronutrient fortified flour (MFF) had been provided to the camp (in addition to the regular food basket). Iron status and micronutrients were measured in serum, whole blood, and in breast milk samples. RESULTS: Iron and zinc deficiency and anemia were highly prevalent while low serum retinol and thiamine deficiency were rarely detected. Iron and zinc deficiency were associated with anemia, and their proportions were significantly lower after the introduction of MFF (21 vs. 35% with soluble transferrin receptor (sTfR) >8.5 mg/L, P = 0.042, and 50 vs. 73% with serum zinc <0.66 mg/L, P = 0.001). Serum sTfR, whole-blood thiamine diphosphate (TDP) and serum beta-carotene were significant predictors (P < 0.001) of milk iron, thiamine and beta-carotene, respectively. Lower prevalence of iron deficiency in the MFF group was associated with significantly higher iron and thiamine in breast milk. CONCLUSIONS: High whole-blood TDP and breast milk thiamine reflected good compliance to provided thiamine; high prevalence of iron deficiency suggested insufficient dietary iron and low acceptance to ferrous sulfate supplements. MFF as an additional food ration in Maela refugee camp seemed to have an effect in reducing both iron and zinc deficiency postpartum. PMID- 21786022 TI - The demographic drivers of local population dynamics in two rare migratory birds. AB - The exchange of individuals among populations can have strong effects on the dynamics and persistence of a given population. Yet, estimation of immigration rates remains one of the greatest challenges for animal demographers. Little empirical knowledge exists about the effects of immigration on population dynamics. New integrated population models fitted using Bayesian methods enable simultaneous estimation of fecundity, survival and immigration, as well as the growth rate of a population of interest. We applied this novel analytical framework to the demography of two populations of long-distance migratory birds, hoopoe Upupa epops and wryneck Jynx torquilla, in a study area in south-western Switzerland. During 2002-2010, the hoopoe population increased annually by 11%, while the wryneck population remained fairly stable. Apparent juvenile and adult survival probability was nearly identical in both species, but fecundity and immigration were slightly higher in the hoopoe. Hoopoe population growth rate was strongly correlated with juvenile survival, fecundity and immigration, while that of wrynecks strongly correlated only with immigration. This indicates that demographic components impacting the arrival of new individuals into the populations were more important for their dynamics than demographic components affecting the loss of individuals. The finding that immigration plays a crucial role in the population growth rates of these two rare species emphasizes the need for a broad rather than local perspective for population studies, and the development of wide-scale conservation actions. PMID- 21786021 TI - The Kruppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice. AB - AIMS/HYPOTHESIS: Mutations in GLIS3, which encodes a Kruppel-like zinc finger transcription factor, were found to underlie sporadic neonatal diabetes. Inactivation of Glis3 by gene targeting in mice was previously shown to lead to neonatal diabetes, but the underlying mechanism remains largely unknown. We aimed to elucidate the mechanism of action of GLIS family zinc finger 3 (GLIS3) in Glis3 ( -/- ) mice and to further decipher its action in in-vitro systems. METHODS: We created Glis3 ( -/- ) mice and monitored the morphological and biochemical phenotype of their pancreatic islets at different stages of embryonic development. We combined these observations with experiments on Glis3 expressed in cultured cells, as well as in in vitro systems in the presence of other reconstituted components. RESULTS: In vivo and in vitro analyses placed Glis3 upstream of Neurog3, the endocrine pancreas lineage-defining transcription factor. We found that GLIS3 binds to specific GLIS3-response elements in the Neurog3 promoter, activating Neurog3 gene transcription both directly, and synergistically with hepatic nuclear factor 6 and forkhead box A2. CONCLUSIONS/INTERPRETATION: These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice. PMID- 21786023 TI - Narrowband ultraviolet B phototherapy and serum folic acid level. PMID- 21786024 TI - Backbone NMR resonance assignments of the nucleotide binding domain of the ABC multidrug transporter LmrA from Lactococcus lactis in its ADP-bound state. AB - LmrA from Lactococcus lactis is a multidrug transporter and a member of the ATP binding cassette (ABC) transporter family. ABC transporters consist of a transmembrane domain (TMD) and a nucleotide binding domain (NBD). The NBD contains the highly conserved signature motifs of this transporter superfamily. In the case of LmrA, the TMD and the NBD are expressed as a single polypeptide. LmrA catalyzes the extrusion of hydrophobic compounds including antibiotics from the cell membrane at the expense of ATP hydrolysis. ATP binds to the NBD, where binding and hydrolysis induce conformational changes that lead to the extrusion of the substrate via the TMD. Here, we report the (1)H, (13)C and (15)N backbone chemical shift assignments of the isolated 263 amino acid containing NBD of LmrA in its ADP bound state. PMID- 21786025 TI - Effect of dietary beta carotene on cerebral aneurysm and subarachnoid haemorrhage in the brain apo E-/- mice. AB - Atherosclerosis will lead to stenosis/occlusion in the lumen of various arteries of living body. This can lead various conditions including myocardial infarction, cerebral infarction/aneurysm and peripheral artery disease. Ang II is believed to be an important regulatory peptide involved in maintaining cardiovascular homeostasis and pathogenesis of various cardiovascular diseases. Matrix metalloproteinase's (MMPs), adhesion molecules and plasminogen systems are involved in the inflammatory reaction of various blood vessels as well as pathogenesis of cerebro vasuclar disease in apo E(-/-) mice during angiotensin II injection. The present study analyses the role of ang II in development of cerebral aneurysm and also evaluated the mRNA levels of MMPs, adhesion molecules, plasminogen systems and peroxisome proliferators-associated receptors in the brain of apo E(-/-) mouse during the progression of cerebral aneurysm and ischemic conditions. Also, this study evaluates the role of dietary beta carotene on cerebrovascular disease. Serum total cholesterol (TC), Low density lipoprotein (LDL) and triglyceride (TG) levels were significantly increased in angiotensin II treated animals and further beta carotene supplementation reduces TC but does not affect the triglyceride and LDL levels. Circulating levels of macrophages were significantly increased in angiotensin treated animals and further beta carotene supplementation significantly reduced the circulating macrophages. Cerebro meningeous aneurysm, subarachnoid haemorrhage, multiple foci of infarction, necrosis and infiltration of inflammatory cells were observed in the cerebral hemispheres of ang II treated animals, however, infarction size were reduced and no aneurysm, inflammatory foci was observed in beta carotene treated animals. Real time analysis showed down regulation of mRNA levels of MMP 2, uPA, PAI, PPAR A, MCSF1 and up regulation of tPA and MCP-1 in the brain during the progression of cerebral aneurysm and beta carotene supplementation to bring to normal expression levels of all the candidate genes for cerebrovascular diseases. Based on above results, Ang II may induced cerebral aneurysm, ischemia/infarction on brain through RAS system by down regulating the mRNA levels of MMP 2, uPA, PAI, PPAR-A, MCSF1 and up regulating tPA and MCP-1 and beta carotene attenuates the disease condition and bring down to normal expression levels of above genes. PMID- 21786026 TI - Antigenic specificity and expression of a natural idiotope on human pentameric and hexameric IgM polymers. AB - Natural antibodies (NAbs) are present in circulation even before the exposure to antigen and they exert various biological functions. They are polyreactive and mainly represented by immunoglobulin M (IgM), which is the first antibody produced in an ongoing immune response to infection and/or immunization. IgM is always secreted as a polymer with predominant pentameric structure, although other polymeric forms such as hexamer can be also formed. The biological functions of hexameric IgM are still not known and it is proposed that its existence as a NAb could be deleterious. However, the nature of IgM hexamers has not been investigated yet. In this paper, we have tested the expression of natural idiotope and antigenic specificities of pentameric and hexameric IgM polymers originating from sera of patients with Waldenstrom's macroglobulinemia, as well as patients suffering from recurrent urinary bacterial infections. We demonstrate that although pentameric IgM polymers can exist as natural and immune antibodies, IgM hexamers are exclusively immune and do not exist as NAbs. PMID- 21786027 TI - Genetic inferences about the population dynamics of codling moth females at a local scale. AB - Estimation of demographic parameters is important for understanding the functioning of natural populations and the underlying ecological and evolutionary processes that may impact their dynamics. Here, we used sibship assignment methods to shed light on the local dynamics of codling moth females in eight orchards in a 90-ha domain near Valence, France. Based on full-sib inference among 1,063 genotyped moths, we estimated (1) the effective number of females that had offspring, (2) their fertility and (3) the distribution of their oviposition sites within and among orchards. The average number of females in all the orchards increased between the first (~130) and the second (~235) annual generations. The average fertilities of the females were similar at each generation according to the host plant considered (apple, pear, or walnut), but differed between commercial (~10) and non-treated (~25) apple orchards. Females mainly clustered their eggs on contiguous trees along orchard borders, but they also occasionally dispersed their eggs among different orchards independently of the cultivated host plants or the inter-orchard distances (up to 698 m) during the second annual generation. The mean distance between two oviposition sites was 30 m. Sibship estimates of both the effective number of females and the inter orchard migration rates (~5%) were in agreement with the observed genetic differentiation among the eight orchards (0.006 < F ( st ) < 0.013). These results confirm and extend previous field and laboratory observations in Cydia pomonella, and they demonstrate that sibship assignments based on genetic data are an interesting alternative to mark-release-recapture methods for inferring insect population dynamics. PMID- 21786028 TI - Post-glacial evolution of Panicum virgatum: centers of diversity and gene pools revealed by SSR markers and cpDNA sequences. AB - Switchgrass (Panicum virgatum), a central and Eastern USA native, is highly valued as a component in tallgrass prairie and savanna restoration and conservation projects and a potential bioenergy feedstock. The purpose of this study was to identify regional diversity, gene pools, and centers-of-diversity of switchgrass to gain an understanding of its post-glacial evolution and to identify both the geographic range and potential overlap between functional gene pools. We sampled a total of 384 genotypes from 49 accessions that included the three main taxonomic groups of switchgrass (lowland 4x, upland 4x, and upland 8x) along with one accession possessing an intermediate phenotype. We identified primary centers of diversity for switchgrass in the eastern and western Gulf Coast regions. Migration, drift, and selection have led to adaptive radiation in switchgrass, creating regional gene pools within each of the main taxa. We estimate that both upland-lowland divergence and 4x-to-8x polyploidization within switchgrass began approximately 1.5-1 M ybp and that subsequent ice age cycles have resulted in gene flow between ecotype lineages and between ploidy levels. Gene flow has resulted in "hot spots" of genetic diversity in the southeastern USA and along the Atlantic Seaboard. PMID- 21786029 TI - [Evaluation of the "initiative pain-free clinic" for quality improvement in postoperative pain management. A prospective controlled study]. AB - AIM: Demonstration of improved postoperative pain management by implementation of the S3 guidelines on treatment of acute perioperative and posttraumatic pain, by the integrated quality management concept "quality management acute pain" of the TUV Rheinland or by participation in the benchmark project "Quality improvement in postoperative pain management" (QUIPS). METHODS: A prospective controlled study (pre-post design) was carried out in hospitals with various levels of care comparing three hospital groups (n = 17/7/3, respectively). Group 1: participation in the QUIPS project (intraclinic and interclinic comparison of outcome data of postoperative pain treatment), group 2: participation in the quality management acute pain program (certified by TUV Rheinland), group 3: control group with no involvement in either of the two concepts. In all three groups, an anonymous data collection was performed consisting of patient-reported pain intensity, side effects, pain disability and patient satisfaction. Pain therapy intervention was carried out only in group 2 by an integrated quality management concept (certification project: Quality management acute pain) with a package of measures to improve structure, process and outcome quality. RESULTS: The TUV Rheinland certified clinics (group 2) showed a significant improvement in the pre-post comparison (before versus after certification) in the areas maximum pain (from visual analogue scale VAS 4.6 to 3.7), stress pain (5.3 to 3.9), pain related impairment (proportion of patients with pain-linked decreased mobility and movement 26% to 16.1%, coughing and breathing 23.1% to 14.3%) and patient satisfaction (from 13.2 to 13.7; scale 0 completely unsatisfied, 15 very satisfied). The clinics with participation in QUIPS for 2 years also showed a significant improvement in stress pain (numeric rating scale NRS for pain 4.5 to 4.2), pain-linked-limitation of coughing and breathing (28% to 23.6%), and patient satisfaction (from 11.9 to 12.4). There were no differences in postoperative nausea and vomiting between any of the groups. CONCLUSIONS: The main objective of the certification concept quality management acute pain as a tool for the successful implementation of the S3 guidelines on treatment of acute perioperative and posttraumatic pain, led to a significant improvement in patient outcome. Participation in QUIPS is an ideal supplement to TUV Rheinland certification and can be recommended as a benchmarking tool to evaluate outcome. PMID- 21786030 TI - Dissociation between medial frontal negativity and cardiac responses in the ultimatum game: Effects of offer size and fairness. AB - In the present study, we examined the role of fairness and offer size on brain and cardiac responses in the ultimatum game (UG). Twenty healthy volunteers played the role of responder in a computerized version of the UG in which the fairness and size of the offers were systematically varied. Both fairness and size of the offer influenced the acceptance rates in a predictable way, leading to fewer accepted unfair and low offers. Only unfair high, but not unfair low offers were accompanied by a medial frontal negativity. An unexpected stronger cardiac deceleration to fairer offers was found, which was not affected by the size of the offers. Cardiac and electrocortical measures showed a different relation with performance, and both measures were correlated only modestly. This dissociation between cardiac responses and brain potentials is discussed in terms of a possible differential sensitivity to effects of stimulus probability and violation of the social rules. PMID- 21786031 TI - Engineering [Ln(DPA)3] 3- binding sites in proteins: a widely applicable method for tagging proteins with lanthanide ions. AB - Paramagnetic relaxation enhancements from unpaired electrons observed in nuclear magnetic resonance (NMR) spectra present powerful long-range distance restraints. The most frequently used paramagnetic tags, however, are tethered to the protein via disulfide bonds, requiring proteins with single cysteine residues for covalent attachment. Here we present a straightforward strategy to tag proteins site-specifically with paramagnetic lanthanides without a tether and independent of cysteine residues. It relies on preferential binding of the complex between three dipicolinic acid molecules (DPA) and a lanthanide ion (Ln(3+)), [Ln(DPA)(3)](3-), to a pair of positively charged amino acids whose charges are not compensated by negatively charged residues nearby. This situation rarely occurs in wild-type proteins, allowing the creation of specific binding sites simply by introduction of positively charged residues that are positioned far from glutamate or aspartate residues. The concept is demonstrated with the hnRNPLL RRM1 domain. In addition, we show that histidine- and arginine-tags present binding sites for [Ln(DPA)(3)](3-). PMID- 21786032 TI - Quantitative and dynamic expression profile of premature and active forms of the regional ADAM proteins during chicken brain development. AB - The ADAM (A Disintegrin and Metalloprotease) family of transmembrane proteins plays important roles in embryogenesis and tissue formation based on their multiple functional domains. In the present study, for the first time, the expression patterns of the premature and the active forms of six members of the ADAM proteins - ADAM9, ADAM10, ADAM12, ADAM17, ADAM22 and ADAM23 - in distinct parts of the developing chicken brain were investigated by quantitative Western blot analysis from embryonic incubation day (E) 10 to E20. The results show that the premature and the active forms of various ADAM proteins are spatiotemporally regulated in different parts of the brain during development, suggesting that the ADAMs play a very important role during embryonic development. PMID- 21786033 TI - Yeast two-hybrid and itc studies of alpha and beta spectrin interaction at the tetramerization site. AB - Yeast two-hybrid (Y2H) and isothermal titration calorimetry (ITC) methods were used to further study the mutational effect of non-erythroid alpha spectrin (alphaII) at position 22 in tetramer formation with beta spectrin (betaII). Four mutants, alphaII-V22D, V22F, V22M and V22W, were studied. For the Y2H system, we used plasmids pGBKT7, consisting of the cDNA of the first 359 residues at the N terminal region of alphaII, and pGADT7, consisting of the cDNA of residues 1697 2145 at the C-terminal region of betaII. Strain AH109 yeast cells were used for colony growth assays and strain Y187 was used for beta-galactosidase activity assays. Y2H results showed that the C-terminal region of betaII interacts with the N-terminal region of alphaII, either the wild type, or those with V22F, V22M or V22W mutations. The V22D mutant did not interact with betaII. For ITC studies, we used recombinant proteins of the alphaII N-terminal fragment and of the erythroid beta spectrin (betaI) C-terminal fragment; results showed that the K(d) values for V22F were similar to those for the wild-type (about 7 nM), whereas the K(d) values were about 35 nM for V22M and about 90 nM for V22W. We were not able to detect any binding for V22D with ITC methods. This study clearly demonstrates that the single mutation at position 22 of alphaII, a region critical to the function of nonerythroid alpha spectrin, may lead to a reduced level of spectrin tetramers and abnormal spectrin-based membrane skeleton. These abnormalities could cause abnormal neural activities in cells. PMID- 21786034 TI - Protective effect of intermedin on myocardial cell in a rat model of severe acute pancreatitis. AB - Severe acute pancreatitis (SAP) is a common disease with a poor prognosis. Heart failure is one cause of SAP patient death. Intermedin (IMD) is a potent endogenous cardio-protective substance. Administration of exogenous IMD showed beneficial effects in cardiovascular diseases. The aim of this study was to investigate the myocardial damage in SAP and to determine the therapeutic potential of IMD for SAP. Using an SAP rat model, we examined endogenous IMD expression following SAP induction, and determined the effect of IMD on myocardial function, histological morphology, apoptosis-related gene expression, and prognosis. Our results indicated that the cardiac function and histological structure were significantly disrupted in SAP rats. Infusion of exogenous IMD significantly preserved cardiac function and ameliorated myocardial damage. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) revealed that myocardial apoptosis was extensively present in SAP rats, and IMD infusion led to increased expression of the prosurvival factor Bcl-2, but decreased pro-apoptotic factors Bax and caspase-3. In addition, IMD infusion also reversed the change of IMD receptor systems in SAP rat heart tissue. Furthermore, we found that IMD infusion greatly decreased mortality of SAP rats. In conclusion, administration of SAP produced therapeutic effects in SAP through modulating apoptotic and pro-survival gene expression, inhibiting myocardial apoptosis, preserving cardiac function, and a useful therapeutic agent for SAP, and provides us an insight for a clinical trial of IMD for treating human severe acute pancreatitis. PMID- 21786035 TI - The use of a human papillomavirus 18 promoter for tissue-specific expression in cervical carcinoma cells. AB - The use of tissue-specific promoter elements in the treatment of cervical cancer has been explored in this paper. The P(105) promoter of human papillomavirus 18 (HPV18) was utilised to direct tissue-specific expression in a number of cell types. Expression was examined in three cervical carcinoma cell lines: HeLa (HPV18 positive), SiHa (HPV16 positive), and C33A cells (HPV negative); the epithelial cell line, H1299; and the foetal fibroblast cell line, MRC5, utilising a luciferase expression vector. Expression was highest in the cervical cell lines by a factor of at least 80. The effect of a number of mutations in the P(105) promoter on expression levels was examined. Three deletion constructs of the long control region (LCR) were investigated: an 800 bp fragment (LCR800), a 400 bp fragment (LCR400), and a 200 bp fragment (LCR200), as well as the full length product LCR of HPV18 (LCR1000). The LCR800 construct of the HPV18 P(105) promoter had the highest level of expression in the cervical cell lines and was also highest in the HPV18-positive HeLa cell line. Site-directed mutagenesis was then employed on the LCR800 construct to create four further constructs that each had inactivating mutations in one of the four E2 binding sites (E2BSs). Overall, this study indicated that the LCR800 construct of the HPV18 P(105) promoter could be utilised as a tissuerestricted promoter in cervical cancer cells. PMID- 21786036 TI - Perinatal sources of mesenchymal stem cells: Wharton's jelly, amnion and chorion. AB - Recently, stem cell biology has become an interesting topic, especially in the context of treating diseases and injuries using transplantation therapy. Several varieties of human stem cells have been isolated and identified in vivo and in vitro. Ideally, stem cells for regenerative medical application should be found in abundant quantities, harvestable in a minimally invasive procedure, then safely and effectively transplanted to either an autologous or allogenic host. The two main groups of stem cells, embryonic stem cells and adult stem cells, have been expanded to include perinatal stem cells. Mesenchymal stem cells from perinatal tissue may be particularly useful in the clinic for autologous transplantation for fetuses and newborns, and after banking in later stages of life, as well as for in utero transplantation in case of genetic disorders.This review highlights the characteristics and therapeutic potential of three human mesenchymal stem cell types obtained from perinatal sources: Wharton's jelly, the amnion, and the chorion. PMID- 21786037 TI - Treatment trials in aging and mild cognitive impairment. AB - There are currently no FDA-approved therapies for mild cognitive impairment (MCI) as no treatment trial to date has convincingly demonstrated a significant effect on cognition or symptom progression. Whether the problem lies with the evaluated compounds, drugs previously shown to have therapeutic benefit in Alzheimer disease (AD), or the clinical trial designs themselves, remains unclear. However, future trials will likely need to use strategies to enrich for more homogeneous samples with appropriate biological characteristics at entry, define optimal treatment durations, and develop highly sensitive assessments and reliable outcomes with the power to detect change and treatment benefit in mildly impaired subjects. PMID- 21786038 TI - Adjacent segment degeneration after instrumented posterolateral lumbar fusion: a prospective cohort study with a minimum five-year follow-up. AB - PURPOSE: To (1) clarify the role of various risk factors in the development of ASD, (2) compare instrumentation configuration with the development of ASD, (3) correlate the radiological incidence of ASD and its clinical outcome and (4) compare the clinical outcome between patients with radiological evidence of ASD and without ASD. METHODS: This study prospectively examined 74 consecutive patients who underwent instrumented lumbar/lumbosacral fusion for degenerative disease with a minimum follow-up of 5 years. Among the patients, 68 were enrolled in the study. All of the patients had undergone preoperative radiological assessment and postoperative radiological assessment at regular intervals. The onset and progression of ASD changes were evaluated. The patients were divided in two groups: patients with radiographic evidence of ASD (group 1) and patients without ASD changes (group 2). Comprehensive analysis of various risk factors between group 1 and group 2 patients was performed. The Visual Analog Scale (VAS) was used to evaluate the clinical outcome and the functional outcome was evaluated using the Oswestry Disability Index (ODI) before and after surgery along with radiological assessment. RESULTS: Radiographic ASD occurred in 20.6% (14/68) of patients. Preoperative disc degeneration at an adjacent segment was a significant risk factor for ASD. Other risk factors such as the age of a patient at the time of surgery, gender, preoperative diagnosis, length of fusion, instrumentation configuration, sagittal alignment and lumbar or lumbosacral fusion were not significant risk factors for the development of ASD. There was no correlation between ASD and its clinical outcome as determined at the final follow-up session. In addition, clinical outcome of patients with ASD and without ASD were not comparable. CONCLUSIONS: Patients with preoperative disc degeneration at an adjacent segment were more at risk for the development of ASD. Other risk factors including instrumentation configuration were not significantly associated with ASD. There was no correlation between both the radiological development of ASD and its clinical outcome and the clinical outcome of patients with and without ASD. PMID- 21786039 TI - Evaluation of autologous platelet concentrate for intertransverse lumbar fusion. AB - INTRODUCTION: The aim of the study was to analyze if the adding of autologous platelet concentrate (APC) to a mixture of local autograft plus tricalcium phosphate and hidroxiapatite (TCP/HA) would improve the fusion rate in posterolateral lumbar fusion. MATERIALS AND METHODS: A prospective, controlled, blinded, non-randomized clinical trial was carried out in 107 patients affected by degenerative lumbar pathology. The study group consisted of 67 patients, in which autologous platelet concentration was added to a mixture of autologous local bone graft and TCP/HA. A control group of 40 patients with same pathology and surgical technique but without APC addition was used to compare the fusion mass obtained. By means of plain X-rays, a blinded evaluation of the intertransverse fusion mass quality at twelve and twenty-four months was made according to type A (bilateral uniform mass), type B (unilateral uniform mass) and type C (irregular or lack bilateral mass). Patients with type C were regarded as pseudoarthrosis. RESULTS: In the study group 17 patients had lack or irregular fusion mass (25.4%) versus three patients in the control group (7.5%), which was statistically significant. CONCLUSIONS: This study shows that the adding of autologous platelet concentration to a mixture of autologous bone graft plus TCP/HA has decreased our rates of posterolateral lumbar fusion. PMID- 21786040 TI - Role of viscosity in influencing the glass-forming ability of organic molecules from the undercooled melt state. AB - PURPOSE: Understanding the critical factors governing the crystallization tendency of organic compounds is vital when assessing the feasibility of an amorphous formulation to improve oral bioavailability. The objective of this study was to investigate potential links between viscosity and crystallization tendency for organic compounds from the undercooled melt state. METHODS: Steady shear rate viscosities of numerous compounds were measured using standard rheometry as a function of temperature through the undercooled melt regime. Data for each compound were fit to the Vogel-Tamman-Fulcher (VTF) equation; kinetic fragility via strength parameter (D) was determined. RESULTS: Compounds with high crystallization tendencies exhibited lower melt viscosities than compounds with low crystallization tendencies. A correlation was observed between rate of change in viscosity with temperature and crystallization tendency, with slowly crystallizing compounds exhibiting larger increases in viscosity as temperature decreased below T(m). Calculated strength parameters indicated all compounds were kinetically fragile liquids; thus, kinetic fragility may not accurately assess glass-forming ability from undercooled melt state. CONCLUSIONS: A link was observed between the viscosity of a compound through the undercooled melt regime and its resultant crystallization tendency, indicating viscosity is a critical parameter to fully understand crystallization tendency of organic compounds. PMID- 21786041 TI - Morphological and molecular analysis of Ornithonyssus spp. (Acari: Macronyssidae) from small terrestrial mammals in Brazil. AB - Based on chaetotaxy of the dorsal shield, the taxonomic status of many species of Ornithonyssus has been considered invalid, resulting in the synonymy of all Brazilian Ornithonyssus from small terrestrial wild mammals into one of the following four species: Ornithonyssus bacoti (Hirst, 1913), Ornithonyssus matogrosso (Fonseca, 1954), Ornithonyssus pereirai (Fonseca, 1935) or Ornithonyssus wernecki (Fonseca, 1935). Despite the revision of this genus in 1980, including all known species worldwide, the knowledge of Ornithonyssus in Brazil has not progressed for more than 40 years. Considering the potential importance of these haematophagous mites in transmitting rickettsial disease agents to animals and humans, we have revised Ornithonyssus species collected from small mammals in Brazil by means of morphological and molecular studies. Types and other material deposited in the Acari Collection of the Instituto Butantan (IBSP) were examined in addition to recently collected specimens. Morphological and genetic analysis of the 16S rDNA mitochondrial gene revealed that small terrestrial mammals in Brazil are parasitized by six species of Ornithonyssus mites: Ornithonyssus brasiliensis (Fonseca, 1939), O. matogrosso, O. monteiroi (Fonseca, 1941), O. pereirai, O. vitzthumi (Fonseca, 1941), and O. wernecki. An illustrated key to females of the valid Brazilian species of Ornithonyssus is included, based on optical and scanning electron microscopy. PMID- 21786042 TI - High-grade optical polydimethylsiloxane for microfluidic applications. AB - Commercially available polydimethylsiloxane (PDMS) elastomers, such as Sylgard 184(r) are widely used in soft lithography and for microfluidic applications. These PDMS elastomers contain fillers to enhance their mechanical stability. The reinforcing fillers, often sub-micrometer small SiO(2) particles, tend to aggregate, swell with water, and thereby become cognoscible in a way that can strongly interfere with the visualization of micro-scale events taking place next to PDMS structures. As PDMS microfluidics are often used for studying cells and micro-/nanoparticles and for creating/handling nanodroplets, it has become highly desirable to employ a PDMS having high optical quality and that allows microscopy observation without artifacts. Here, we present a PDMS formulation that is free of fillers and has sufficiently low viscosity to perform a filtration step of the mixed prepolymers before curing. By molding a bi-layer microfluidic network (MFN), composed of a thin filler-free PDMS layer and a thicker Sylgard 184(r) backing layer, PDMS MFNs featuring both high optical quality and mechanical stability, can be fabricated. PMID- 21786044 TI - The first Neurocritical Care Research Conference: a great starting point. PMID- 21786043 TI - Impact of tracheostomy timing on outcome after severe head injury. AB - BACKGROUND: The influence of tracheostomy timing on outcome after severe head injury remains controversial. METHODS: The investigation was based on data prospectively collected by the Pennsylvania Trauma Society Foundation statewide trauma registry from January 1990 until December 2005. RESULTS: 3,104 patients met criteria for inclusion in the study (GCS <= 8 and tracheostomy). Early Tracheostomy Group (ETG) patients, defined as tracheostomy performed during hospital days 1-7, were more likely to be functionally independent at discharge (adjusted odds ratio (OR) 1.45, 95% confidence interval (CI), 1.16-1.82, P = 0.001) and have a shorter length of stay (adjusted OR 0.23, 95% CI, 0.20-0.28, P < 0.0001). However, Late Tracheostomy Group (LTG) patients, defined as tracheostomy performed >7 days after admission, were approximately twice as likely to be discharged alive (adjusted OR 2.12, 95% CI, 1.60-2.82, P < 0.0001). Using a Composite Outcome Scale, which combined these three measures, there was a non-significant trend toward a higher likelihood of a poor outcome in LTG patients. When this analysis was repeated using only those patients in relatively good condition on admission, LTG patients were found to be approximately 50% less likely to have a good outcome (adjusted OR 0.46, 95% CI, 0.28-0.73, P = 0.001) when compared to ETG patients. CONCLUSIONS: These results indicate a complex relationship between tracheostomy timing and outcome, but suggest that a strategy of early tracheostomy, particularly when performed on patients with a reasonable chance of survival, results in a better overall clinical outcome than when the tracheostomy is performed in a delayed manner. PMID- 21786045 TI - Neurocritical care nursing research priorities. AB - The science of nursing has long been discussed as a blending of the art and science of caring, and nursing research builds the evidence of support for nursing practice. Nurses and nursing care are key to successful neurocritical care research endeavors. Ideally nursing care should be evidence based and supported by solid research. The goal of nursing research is to expand the knowledge of caring for patients. Within the scope of nursing research, the priorities for research in neurocritical care should support this goal. In this manuscript, we discuss what we believe are the priorities of neurocritical care nursing research, the obstacles, and some possible solutions. PMID- 21786047 TI - Behaviour of crossbred does and their kids at parturition under extensive and intensive conditions. AB - Data from 82 kiddings from mixed-breed (native x dairy goats) goats reared on rangeland (n = 47) or confinement (n = 35) were used to determine the influence of various factors on length of labour, standing of newborn kids and time to first suckling in pluriparous goats. Both groups were mated at the same time to bucks of the same genotype in February. During the kidding time in July, the goats were monitored for 24 h in order to register parturition traits and kid birth weight and body measurements. For all goats, blood samples were collected at parturition in order to establish the nutritional state of goats. Grazing goats had lower body weight and body condition score (P < 0.01) than pen-fed goats, as well as lower values for some blood metabolites indicative of low body energy reserves. For both grazing and pen-fed goats, the majority of kiddings (>93%) occurred during daylight hours. No kiddings were registered from 2300 to 0500 hours. No effects of height at withers, thoracic circumference and sex of kids at birth were found to influence length of labour. Labour was shorter (P < 0.01) for pen-fed does than grazing goats (10.6 +/- 1.18 min vs. 15.4 +/- 1.2 min; mean +/- SD). The length of parturition was considerably longer (P < 0.05) for twin-bearing does than for single-bearing does (16.6 +/- 1.76 min vs. 11.2 +/ 0.81 min, respectively). The interval between parturition and standing of kids was shorter (P < 0.05) for kids from litters weighing >3.3 kg (entire litter) than kids from litters with <3.3 kg (22.7 +/- 1.82 min vs. 31.1 +/- 2.76 min). Time to first suckling was longer (P < 0.05) for kids delivered from pen-fed does than kids from grazing does (57.8 +/- 7.57 min vs. 42.9 +/- 3.05 min). These results confirm that, independently of type of production system (intensive or extensive), kiddings of does are concentrated during daylight hours. These results also indicate that conformation of kids does not alter duration of labour, and that nutritional stress of goats during gestation (extensive conditions) does not interfere with the neonate's level of alertness and arousal. PMID- 21786046 TI - Hemodynamic management of subarachnoid hemorrhage. AB - Hemodynamic augmentation therapy is considered standard treatment to help prevent and treat vasospasm and delayed cerebral ischemia. Standard triple-H therapy combines volume expansion (hypervolemia), blood pressure augmentation (hypertension), and hemodilution. An electronic literature search was conducted of English-language papers published between 2000 and October 2010 that focused on hemodynamic augmentation therapies in patients with subarachnoid hemorrhage. Among the eligible reports identified, 11 addressed volume expansion, 10 blood pressure management, 4 inotropic therapy, and 12 hemodynamic augmentation in patients with unsecured aneurysms. While hypovolemia should be avoided, hypervolemia did not appear to confer additional benefits over normovolemic therapy, with an excess of side effects occurring in patients treated with hypervolemic targets. Overall, hypertension was associated with higher cerebral blood flow, regardless of volume status (normo- or hypervolemia), with neurological symptom reversal seen in two-thirds of treated patients. Limited data were available for evaluating inotropic agents or hemodynamic augmentation in patients with additional unsecured aneurysms. In the context of sparse data, no incremental risk of aneurysmal rupture has been reported with the induction of hemodynamic augmentation. PMID- 21786048 TI - Influence of tongue inspection during cysticercosis diagnosis on some behavioral and physiological stress measures in pigs (Sus scrofa domestica). AB - To evaluate the level of stress induced by the tongue inspection method during cysticercosis diagnosis in pigs at 60 and 90 kg, 27 animals were assigned to one of three experimental groups. In the first group (T1), pigs were held with a snout noose. In addition, animals in T2 were subjected to tongue inspection, while in T0, none of the procedures described above were performed. Resistance to be handled and serum cortisol concentration were higher (P < 0.05) than those from T0 in T1 and T2 groups, for 60- and 90-kg pigs. Time to return to the feeder observed the same pattern than previous variables in 60-kg pigs, but T1 and T0 were similar (P > 0.05) for the heavier animals. T2 did not build up a significant amount of stress with respect to T1, where only more (P > 0.05) vocalizations were emitted by 90-kg pigs. It was concluded that the use of snout noose induces major changes in some behavioral and physiological measures of stress in swine, while the opening of the mouth including tongue inspection does not contribute significantly to this effect. PMID- 21786049 TI - Effect of crossbreeding on fertility, hatchability and embryonic mortality of Nigerian local chickens. AB - A total of 970 eggs were collected from matings involving three genotypes of Nigerian local chickens (Normal-feathered, Frizzle-feathered and Naked neck) and one exotic broiler breeder strain (Anak Titan) to evaluate the effect of crossbreeding on fertility, hatchability and embryonic mortality. Mating was achieved through artificial insemination. Sire genotype significantly (P < 0.05) affected percent fertility and percent dead-in-shell. Naked neck sire genotype had the highest dead-in-shell (19.5%) with the least being 7.5% for Frizzle feathered chickens. Frizzle-feathered sire genotype had the highest fertility (90.5%) and hatchability (91.4%). Dam genotype had a significant effect (P < 0.01) on fertility and hatchability, with Anak Titan dam having the highest fertility and hatchability of 88.2% and 94.6%, respectively. Fertility and hatchability were significantly (P < 0.05) influenced by the interactive effect of sire and dam genotypes with Frizzle-feathered * Anak Titan having 98.5% fertility and 96.8% hatchability. Both straight and reciprocal crosses involving Frizzle-feathered genotype and Anak Titan resulted in higher mean values for fertility and hatchability when compared to crosses involving the other two local chicken genotypes. This result suggests that the use of the Frizzle-feathered genotype appears to be more desirable in fertility and hatchability trials. PMID- 21786050 TI - Reporting results after bariatric surgery: reproducibility of predicted body mass index. AB - BACKGROUND: There is a controversy about the best way to report results after bariatric surgery. Several indices have been proposed over the years such as percentage of total weight loss (%TWL), percentage of excess weight loss (%EWL), and percentage of excess body mass index loss (%EBMIL). More recently, it has been suggested to individualize the body mass index (BMI) goal to be achieved by the patients (predicted BMI-PBMI). The objective was to assess the reproducibility of this PBMI in our service. METHODS: In this retrospective study, we assessed the %TWL, %EWL, %EBMIL (with expected BMI of 25 kg/m2), and %EBMIL (with PBMI) over 4 years of observation in two groups of patients: BMI <50 kg/m2 and BMI >=50 kg/m2. RESULTS: The medical records of 403 patients were studied. From 18 to 42 months after surgery, %TWL was higher in the superobese group, whereas %EWL was similar for the two groups. %EBMIL was higher in less obese patients up to 24 months and similar thereafter. In contrast, %EBMIL with PBMI was greater in the superobese group, although it never reached the 100% goal. CONCLUSIONS: We conclude that %EBMIL results according to PBMI were not reproducible in our institution. There is a need to elaborate a new easy-to obtain and reproducible index. PMID- 21786051 TI - Evaluation of motility changes after laparoscopic sleeve gastrectomy using magnetic resonance imaging. PMID- 21786053 TI - Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations. AB - In the present study, genotype-phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation. PMID- 21786054 TI - Clinical characteristics of tension-type headache in the neurological clinic of a university hospital in China. AB - The aim of this study was to investigate the clinical characteristics and patterns of diagnosis and treatment of patients with tension-type headache in the neurology outpatient clinic of a university hospital in China. This cross sectional study was conducted in the neurological clinic of a tertiary care hospital in Chongqing between March 2010 and May 2010. All consecutive patients with the chief complaint of headache were asked to complete a face-to-face interview with physicians. A questionnaire for collecting data of headache patients was completed by a qualified physician. Headache diagnosis was made by physicians according to the criteria of the second edition of the International Classification of Headache Disorders. A total of 399 patients were diagnosed as having tension-type headache, around two-thirds of them (66.9%) were female and the mean age was 44.8 +/- 12.8 years. Approximately, half of the patients were diagnosed as suffering from chronic tension-type headache. Of all tension-type headache sufferers, 64.9% had consulted a physician for headache in the previous year, and only 22 patients (5.6%) had received a physician diagnosis of tension type headache. A total of 41.4% of patients took analgesic for acute treatment and 13.3% were considered to have medication overuse, however, none had ever used any preventative medications. In conclusion, many tension-type headache patients did not receive a physician diagnosis of tension-type headache or effective treatment in the neurological clinic. Tension-type headache remains underrecognized in China. Better education among physicians is needed so as to improve the diagnosis and treatment of tension-type headache. PMID- 21786055 TI - Increased anteversion of press-fit femoral stems compared with anatomic femur. AB - BACKGROUND: With contemporary canal-filling press-fit stems, there is no adjustability of stem position in the canal and therefore the canal anatomy determines stem version. Stem version will affect head/neck impingement, polyethylene wear from edge loading, and hip stability, but despite this, the postoperative version of a canal-filling press-fit stem is unclear. QUESTIONS/PURPOSES: Is there a difference between the version of the nonoperated femur and the final version of a canal-filling press-fit femoral component? Could a difference create an alignment problem for the hip replacement? METHODS: Sixty four hips were studied with fluoroscopy and 46 nonarthritic and 41 arthritic hips were studied with MRI. A standardized fluoroscopic technique for determining preoperative and postoperative femoral version was developed with the patient supine on a fracture table undergoing supine total hip arthroplasty. To validate the methods, the results were compared with two selected series of axial MRI views of the hip comparing the version of the head with the version of the canal at the base of the neck. RESULTS: For the operated hips, the mean anatomic hip version was less than the stem version: 18.9 degrees versus 27.0 degrees . The difference on average was 8.1 degrees of increased anteversion (SD, 7.4 degrees ). Both MRI series showed the femoral neck was more anteverted on average than the femoral head, thereby explaining the operative findings. CONCLUSION: With a canal-filling press-fit femoral component there is wide variation of postoperative component anteversion with most stems placed in increased anteversion compared with the anatomic head. The surgical technique may need to adjust for this if causing intraoperative impingement or instability. PMID- 21786056 TI - Mark B. Coventry Award: synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. AB - BACKGROUND: C-reactive protein (CRP) serum assays are a standard element of the diagnostic workup for periprosthetic joint infection (PJI). However, because CRP is a marker for systemic inflammation, this test is not specific to PJI. QUESTIONS/PURPOSES: Our purpose was to assess whether synovial fluid and serum assays alone could differentiate between infected and uninfected revision knee arthroplasties and to determine which of these methods had the greatest diagnostic accuracy. METHODS: We collected synovial fluid specimens from 66 patients undergoing revision total knee arthroplasty. Patients were judged uninfected or infected by standardized criteria. Synovial CRP levels were measured using an individual CRP assay (15 samples; 10 infected, five uninfected) and a multiplex immunoassay platform (59 samples; 25 infected, 34 uninfected). Results from preoperative standard serum CRP assays conducted were also collected (55 samples; 25 infected, 30 uninfected). Sensitivity, specificity, and receiver operating characteristic curve analyses were performed for each assay with a diagnosis of infection based on previously established criteria. RESULTS: Synovial CRP concentrations differed between infected and uninfected joints in the multiplex and serum analyses. The area under the curve was 0.84 for the individual assay, 0.91 for the multiplex assay, and 0.88 for the serum CRP assay. Sensitivity and specificity were 70.0% and 100.0% for the individual enzyme linked immunosorbent assay, 84.0% and 97.1% for the multiplex assay, and 76.0% and 93.3% for the serum CRP assay. CONCLUSIONS: An assay measuring CRP in synovial fluid may be more accurate in diagnosing PJI than the standard serum CRP assay. We believe such an assay holds promise as a new diagnostic marker for PJI. PMID- 21786057 TI - Reliability and validity of the Portuguese version of the Stroke Impact Scale 2.0 (SIS 2.0). AB - OBJECTIVE: To test the reliability and validity of the Portuguese version of the Stroke Impact Scale 2.0 (SIS 2.0). METHODS: Two samples (N = 448 and N = 50) of stroke patients attending physical therapy were evaluated. The Portuguese versions of the SIS 2.0 and Chedoke-McMaster Stroke Assessment (CMSA), and a set of individual patient characteristics were the measures used. RESULTS: Reliability was good with Cronbach's alpha coefficients ranging from 0.83 to 0.96, and intraclass correlation coefficients (ICC) between 0.70 and 0.95 for the SIS 2.0 domains. Construct validity was supported by 6 predefined hypotheses involving expected correlations between SIS 2.0 domains, CMSA dimensions and age. An additional predefined hypothesis was also confirmed, with subjects without complications during hospitalization obtaining significantly higher scores in 7 of the 8 SIS 2.0 domains (P < 0.05). CONCLUSION: The Portuguese SIS 2.0 evidenced suitable psychometric characteristics in terms of reliability and validity. PMID- 21786058 TI - Use of the PedsQL in childhood intermittent exotropia: estimates of feasibility, internal consistency reliability and parent-child agreement. AB - PURPOSE: To evaluate the PedsQLs performance in children with intermittent exotropia (X[T]) in terms of feasibility, internal consistency, floor-ceiling effects and levels of parent-child agreement. METHODS: Children with X(T) aged <12 years were recruited from 26 UK Hospital Eye Clinics/Orthoptic Departments. QOL was assessed using child (n = 166) and proxy (n = 392) versions of the PedsQLv4. Feasibility was assessed by percentage of missing responses; internal consistency by Cronbach's alpha and agreement by Bland-Altman plots and intraclass correlations. Analyses included age and gender comparisons. RESULTS: Missing response rates were no higher than 1.8%. Cronbach's alpha reached >= 0.70 on all but one parent-rated scale and on most child-rated Total, Psychosocial Summary and Social Functioning scales, but was <0.70 on most child-rated Physical, Emotional and School Functioning scales. On parent-rated scales, there were no floor effects; ceiling effects reached 27-56% in parents' Physical, Social and School Functioning. On child-rated scales, there were 0-1% floor effects and 0-28% ceiling effects. Parent-child agreement was fair to poor and varied by child's gender. CONCLUSIONS: Proxy-rated PedsQLs demonstrated good internal consistency/feasibility in parents of children with X(T); child-rated reports appeared acceptable, although caution is advised regarding Physical, Emotional and School Functioning scales in younger children. Low-fair agreement between proxy and self-ratings is common in paediatric QOL assessment, reiterating the importance of obtaining both perspectives. We encourage future studies to explore the influence of child's age and gender, and the relationship of the proxy respondent. PMID- 21786059 TI - Liver abscess after liver metastasectomy is a poor prognostic factor in patients with colorectal cancer. AB - PURPOSE: More and more complications of extensive hepatic resection are being encountered in patients treated for liver metastases from colorectal cancer. This study aimed to determine the impact of liver abscess after hepatic resection on overall survival (OS) and the role of adjuvant chemotherapy. METHODS: This is a retrospective study of 252 patients treated by liver metastasectomy between 2001 and 2010. RESULTS: The 5-year survival rate was 55.8%. Twenty-one (8.3%) patients developed liver abscess after liver metastasectomy. Multivariate analysis identified the size of liver metastasis, surgical margin, and the presence of liver abscess as significant prognostic factors. Patients (whether or not they developed liver abscess after hepatic resection) had similar progression-free survival (median, 9.8 vs. 12.4 months, P = 0.476), but patients who developed liver abscess had significantly shorter OS (26.6 vs. 76.0 months, P = 0.004). Subsequent adjuvant therapy significantly improved OS in these patients (16.9 vs. 38.5 months, P = 0.032). CONCLUSIONS: Liver abscess after liver metastasectomy is an independent prognostic factor, and adjuvant chemotherapy is warranted in those patients who develop liver abscess. PMID- 21786060 TI - Depression is associated with prolonged and complicated recovery following colorectal surgery. AB - BACKGROUND: There are little data regarding the impact of depression on outcomes after gastrointestinal surgery. We hypothesize that depression would be associated with prolonged hospital stay and changes in discharge disposition for patients undergoing colon and rectal surgery. METHODS: We identified 292,191 patients undergoing colon and rectal surgery using the 2008 Nationwide Inpatient Sample. We used multivariate regression to evaluate the effect of depression on length of stay and discharge disposition. RESULTS: A preoperative diagnosis of depression was present in 20,039 (6.9%) patients. Mean length of stay for those with depression (10.4 days, 95% confidence interval (CI) 10.04-10.76) was significantly longer than for patients without depression (9.64 days, 95% CI 9.48 9.81). After adjusting for cofounders, depression still predicted an increase in length of stay. Additionally, depressed patients were less likely to resume normal function at discharge, as 40% required either home health or time in a skilled facility following discharge from the acute care hospital. CONCLUSIONS: Among patients undergoing colorectal surgery, depression is associated with a significantly prolonged hospital stay and higher likelihood of requiring skilled nursing assistance after discharge. Further research into the mechanism underlying these differences and potential treatment strategies among depressed patients is warranted. PMID- 21786061 TI - Laparoscopic treatment of epiphrenic diverticula: preoperative evaluation and surgical technique. How I do it. AB - INTRODUCTION: Traditionally, epiphrenic diverticula have been managed through a left thoracotomy. With the advancement of minimally invasive techniques, a laparoscopic approach has gained widespread popularity. Unfortunately, the preoperative evaluation of patients with epiphrenic diverticula, and their surgical management, is still not well characterized. DISCUSSION: The goal of this article is to illustrate our approach to patients with epiphrenic diverticula in terms of preoperative evaluation and surgical technique. The final discussion will focus on the evidence-based rationale for our preoperative assessment and surgical approach. PMID- 21786062 TI - Roles of VEGF-C and Smad4 in the lymphangiogenesis, lymphatic metastasis, and prognosis in colon cancer. AB - BACKGROUND/AIMS: We combined two different signal pathways on transforming growth factor beta1 (TGF-beta1)-Smad and vascular endothelial growth factor C (VEGF C)/VEGF receptors for exploring changes in pathway members and their influence on lymphangiogenesis and clinicopathological features. MATERIALS AND METHODS: Expression of TGF-beta1, TGF-betaRII, Smad4, VEGF-C, and VEGFR-3 was immunohistochemically evaluated in 147 colon cancer patients who were followed up for 5 years. RESULTS: Lymphatic vessel density in colon cancer tissues was significantly higher than in normal colonic tissues. Smad4 expression negatively correlated with lymphatic vessel count and VEGF-C expression. VEGF-C expression positively correlated with lymphatic vessel count. Analysis using the Kaplan Meier method indicated that patients with VEGF-C-positive tumors had significantly shorter overall survival and tumor-free survival time than those with VEGF-C-negative tumors. Patients with Smad4-negative tumors had significantly shorter overall survival and tumor-free survival time than those with Smad4-positive tumors. CONCLUSIONS: Both Smad4 and VEGF-C are involved in lymphangiogenesis and lymphatic metastasis. Smad4 and VEGF-C expression may be clinically useful indicators for prognostic evaluation in colon cancer patients. PMID- 21786063 TI - Endoscopic transmural drainage of peripancreatic fluid collections: outcomes and predictors of treatment success in 211 consecutive patients. AB - OBJECTIVES: Endoscopy is a minimally invasive technique for the drainage of peripancreatic fluid collections. This study evaluated the clinical outcomes and predictors of treatment success in consecutive patients undergoing endoscopic transmural drainage of peripancreatic fluid collections. METHODS: This is a retrospective study of patients who underwent endoscopic drainage of peripancreatic fluid collections over 7 years. Prior to drainage, an ERCP was attempted for stent placement in all patients with a pancreatic duct leak. Drainages were performed using conventional endoscopy or endoscopic ultrasound. Transmural stents and/or drainage catheters were deployed and endoscopic necrosectomy was undertaken when required. Data on clinical outcomes and complications were collected prospectively. RESULTS: A total of 211 patients underwent drainage of peripancreatic fluid collections that was classified as pseudocyst in 45%, abscess in 28%, and necrosis in 27%. Mean diameter of the fluid collection was 100.6 mm, and 34.5% of patients had pancreatic duct stent placement. Median duration of follow-up was 356 days. Treatment success was 85.3% and was higher for pseudocyst and abscess compared to necrosis (93.5% vs. 63.2%, p < 0.0001). Complications were encountered in 17 patients (8.5%) and was higher for drainage of necrosis than pseudocyst or abscess (15.8% vs. 5.2%, p = 0.02). Treatment success was more likely for patients with pseudocyst or abscess than necrosis (adjusted OR = 7.6, 95% CI [2.9, 20.1], p < 0.0001) when adjusted for serum albumin and white cell count, type of endoscopic modality or accessory used, pancreatic duct stenting, luminal compression, size and location of fluid collection. CONCLUSIONS: Endoscopic therapy is a highly effective technique for the management of patients with non-necrotic peripancreatic fluid collections. PMID- 21786066 TI - Molecular evidence for person-to-person transmission of a novel subtype in Giardia duodenalis assemblage B at the rehabilitation institution for developmentally disabled people. AB - Giardia duodenalis was found in three patients and a health care worker at a rehabilitation institution for developmentally disabled people. The four isolates were genotyped and subtyped by multilocus homology searching and phylogenetic analyses of the following four loci: glutamate dehydrogenase (gdh), triosephosphate isomerase (tpi), and beta-giardin (bg) as variable loci, and elongation factor 1 alpha (ef1alpha) as a conserved locus. The partial sequences, gdh (709 bp), tpi (526 bp), bg (724 bp), and ef1alpha (680 bp) of four isolates obtained were mutually identical, and the isolates were found to be a novel subtype in sub-assemblage BIV, strongly indicating that person-to-person transmission by a single subtype occurred at the institution. PMID- 21786065 TI - Mitochondrial antioxidants alleviate oxidative and nitrosative stress in a cellular model of sepsis. AB - PURPOSE: Mitochondrial dysfunction plays a key role in sepsis. METHODS: We used a sepsis model of human endothelial cells (HUVEC) to study mitochondrial function during normoxic (21% O(2)) and hypoxic (1% O(2)) conditions. RESULTS: When stimulated with a LPS cocktail, HUVEC displayed an increase of nitric oxide (NO) in normoxic and hipoxic conditions, being higher at 21% O(2). LPS-activation for 24 h at 1% O(2) increased ROS production, which was reversed with the mitochondrial antioxidant Mitoquinone (MQ) and Glutathione Ethyl Ester (GEE). Activated cells displayed diminished mitochondrial O(2) consumption with specific inhibition of Complex I, accompanied by increase in tyrosine nitration and Type II NOS protein expression, effects which were recovered by antioxidants and/or with L-NAME. These parameters varied with O(2) environment, namely inhibition of respiration observed in both O(2) environments at 24 h was very similar, whereas O(2) consumption rate fell earlier in 1% O(2)-exposed cells. While no significant differences were detected at earlier time points, at 24 h tyrosine nitration was higher in normoxic vs. hypoxic cells. CONCLUSIONS: Mitochondria are heavily implicated in sepsis. Mitochondrial antioxidants provide a mechanistic model for the development of potential therapies. PMID- 21786067 TI - Light and electron microscopy observations of embryogenesis and egg development in the human liver fluke, Opisthorchis viverrini (Platyhelminthes, Digenea). AB - Eggs of most species digenean flukes hatch in the external environment to liberate larvae that seek and penetrate a snail intermediate host. Those of the human liver flukes, Opisthorchis viverrini, hatch within the gastrointestinal canal of their snail hosts. While adult parasites are primarily responsible for the pathology in cases of human opisthorchiasis, their eggs also contribute by inducing granulomata and in serving as nidi for gallstone formation. In view of the peculiar biology of O. viverrini eggs and their contribution to pathology, we investigated embryogenesis in this species by light and transmission electron microscopy. Egg development was traced from earliest stages of coalescence in the ootype until full embryonation in the distal region of the uterus. Fully mature eggs were generally impermeable to resin and could not be examined by conventional electron microscopy methods. However, the use of high-pressure freezing and freeze-substitution fixation of previously fixed eggs enabled the internal structure of mature eggs, particularly the subshell envelopes, to be elucidated. Fertilization occurs in the ootype, and the large zygote is seen therein with a single spermatozoon wrapped around its plasma membrane. As the zygote begins to divide, the spent vitellocytes are pushed to the periphery of the eggs, where they progressively degrade. The early eggshell is formed in the ootype by coalescing eggshell precursor material released by approximately six vitelline cells. The early eggs have a thinner eggshell and are larger than, but lack the characteristic shape of, mature eggs. Characteristic shell ornamentation, the "muskmelon" appearance of eggs, appears after eggshell polymerization in the ootype. Pores are not present in the shell of O. viverrini eggs. The inner and outer envelopes are poorly formed in this species, with the outer envelope evident beneath the eggshell at the opercular pole of the mature egg. The miracidium has a conical anterior end that lacks the distinctive lamellar appearance of the terebratorium of other digeneans, such as the schistosomes. The miracidium is richly glandular, containing an apical gland in the anterior end, large cephalic gland, and posterior secretory glands. Each gland contains a secretory product with different structure. The paucity of vitelline cells associating with eggs, the reduced size of eggs, and reduced complexity of the extraembryonic envelopes are interpreted as adaptations to the peculiar hatching biology of the miracidia. PMID- 21786068 TI - Recombinant Wolbachia surface protein (WSP)-induced T cell responses in Wuchereria bancrofti infections. AB - Human lymphatic filariasis is a debilitating parasitic disease characterized by downregulation of the host's immune response in asymptomatic carriers along with profound hyperreactivity in chronic patients apart from putatively immune endemic normals. The endosymbiont Wolbachia, a bacterium of filarial nematodes has received much attention as possible chemotherapeutic target and its involvement in disease pathogenesis. The role of recombinant Wolbachia surface protein (rWSP), one of the most abundantly expressed proteins of the endosymbiont, in modulating cell-mediated immune responses in patients harboring Wuchereria bancrofti infections was evaluated in the current study. rWSP-induced lymphoproliferation with peripheral blood mononuclear cells suggested an impaired proliferative response in asymptomatic microfilaremic (MF) and symptomatic chronic pathology (CP) patients compared to endemic normals (EN). This was further supported by a significantly diminished expression of CD69 along with elevated levels of CD127 and CD62L in filarial patients (MF and CP) compared to EN. Further, rWSP induced the expression of regulatory T cell markers CTLA-4 and CD25 along with suppressor cytokines IL-10 and TGF-beta in MF and CP patients compared to EN. However, the rWSP-stimulated expression of IFN-gamma was diminished significantly in filarial patients compared to endemic normals. Thus, these findings suggest that WSP may also contribute to the suppression of immune responses seen in filarial patients. PMID- 21786069 TI - Serum paraoxonase-1 (PON-1) genotype and exposure to organophosphorous insectides -is there a high-risk population? AB - The Health Studies Branch (HSB) is responsible for responding to domestic and international requests for assistance with suspected and known environmental associated public health threats as well as pursuing original environmental research. The HSB employs personnel with a wide variety of educational backgrounds and professional training including epidemiology, medicine, toxicology, statistics, and other environmental public health-related disciplines. This wide range of expertise is necessary to address the broad scope of potential environmental health threats. HSB scientists conduct studies on environmental exposures. Recent examples include the following: mercury exposure in children living in large urban areas, exposure to brevetoxins and microcystins arising from harmful algal blooms, and occupational exposures to pesticides. This article will present a brief description of an ongoing study of insecticide exposure and paraoxonase-1 (PON-1) genotype in banana plantation workers in Chinandega, Nicaragua. We will then discuss the enzyme PON-1 and its potential role in organophosphate insecticide metabolism and toxicity. PMID- 21786070 TI - Object-centered reference systems and human spatial memory. AB - The present study investigated the role of object-centered reference systems in memories of objects' locations. Participants committed to memory the locations and orientations of either 11 human avatars (Experiment 1) or 11 animal models (Experiment 2) displayed in a desktop virtual environment and then completed judgments of relative directions, in which they pointed to objects from imagined vantage points corresponding to the locations of the objects. Results showed that, with avatars, performance was better when the imagined heading was congruent with the facing direction of the avatar located at the imagined vantage point. With animal models, no such facilitation was found. For both types of stimuli, performance was better for the learning view than for the novel 135 degrees view. Results demonstrate that memories of the locations of objects are affected by object-centered reference systems and are consistent with conjectures that spatial memories are hierarchies of spatial reference systems, with higher levels corresponding to larger scales of space. PMID- 21786071 TI - Fast-specific tomography imaging via Cerenkov emission. AB - PURPOSE: Development of more tumor-specific radiopharmaceuticals is not enough; to understand the disease, we must study data modeling. Although fluoro-18 deoxyglucose positron emission tomography can map a multi-peak distribution of trace radioisotopes, optical tomography should also be able to redirect the distribution. PROCEDURES: Multi-view image acquisition of small animals injected with 2-deoxy-2-[(18)F]fluoro-D: -glucose began with X-ray computed tomography scanning and Cerenkov luminescence imaging. After fusion processing, utilization of the geometric row scaling and L (1/2) regularization operator effectively generates in vivo Cerenkov luminescence tomography images with the SP(3) forward model. RESULTS: The identification is confirmed by the comparison between tumor specific tomography from Cerenkov emission and the radioactivity measured in vitro. CONCLUSION: The proposed technique can quickly localize the mobility of radionuclides and uptake by organs, which provides an imaging methodology in oncology. PMID- 21786072 TI - Prolonged biventricular assist device support as a bridge to heart transplantation. AB - We report a case in which long-term biventricular assist device (BiVAD) support enabled successful heart transplantation. The patient was diagnosed with dilated cardiomyopathy at age 11. She underwent implantation of a Toyobo LVAD, tricuspid valvuloplasty and annuloplasty at age 15. Right heart bypass (RHB) was established using a centrifugal pump. Right ventricular function showed no improvement during a ten-day period, and RHB was switched to a Toyobo RVAD on postoperative day (POD) 11. Because of poor oxygenation, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was instituted. She was weaned from V-V ECMO on POD 14. She was brought to the United States on POD 189 under BiVAD support, and underwent heart transplantation on POD 199. She was discharged 4 months later. Two years after heart transplantation, she remained in New York Heart Association class one without rejection. PMID- 21786073 TI - Evaluation of computer-assisted quantification of carotid artery stenosis. AB - The purpose of this study was to evaluate the influence of advanced software assistance on the assessment of carotid artery stenosis; particularly, the inter observer variability of readers with different level of experience is to be investigated. Forty patients with suspected carotid artery stenosis received head and neck dual-energy CT angiography as part of their pre-interventional workup. Four blinded readers with different levels of experience performed standard imaging interpretation. At least 1 day later, they performed quantification using an advanced vessel analysis software including automatic dual-energy bone and hard plaque removal, automatic and semiautomatic vessel segmentation, as well as creation of curved planar reformation. Results were evaluated for the reproducibility of stenosis quantification of different readers by calculating the kappa and correlation values. Consensus reading of the two most experienced readers was used as the standard of reference. For standard imaging interpretation, experienced readers reached very good (k = 0.85) and good (k = 0.78) inter-observer variability. Inexperienced readers achieved moderate (k = 0.6) and fair (k = 0.24) results. Sensitivity values 80%, 91%, 83%, 77% and specificity values 100%, 84%, 82%, 53% were achieved for significant area stenosis >70%. For grading using advanced vessel analysis software, all readers achieved good inter-observer variability (k = 0.77, 0.72, 0.71, and 0.77). Specificity values of 97%, 95%, 95%, 93% and sensitivity values of 84%, 78%, 86%, 92% were achieved. In conclusion, when supported by advanced vessel analysis software, experienced readers are able to achieve good reproducibility. Even inexperienced readers are able to achieve good results in the assessment of carotid artery stenosis when using advanced vessel analysis software. PMID- 21786074 TI - MicroRNA: implications in HIV, a brief overview. AB - MicroRNAs (miRNAs) are 20-22 nucleotide length noncoding RNA molecules that represent key regulators of many normal cellular functions. miRNAs undergo two processing steps which transform a long primary transcript into the mature miRNA. Available literatures demonstrate the association between alterations in the expression of miRNAs and the progression of numerous human disorders. Even though significant advances have been made, many fundamental questions about their expression and function still remain unanswered. Identifying factors that block the negative action of drugs of abuse on the miRNAs could help in identifying new therapeutic strategies. In this review, we briefly discuss the importance of miRNAs on HIV, strategies used by virus to avoid the cells' antiviral miRNA defenses, and how HIV might control and regulate host cell genes by encoding viral miRNAs. PMID- 21786075 TI - Progressive multifocal leukoencephalopathy associated with isolated CD8+ T lymphocyte deficiency mimicking tumefactive MS. PMID- 21786076 TI - A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings. AB - Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naive individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naive individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance. PMID- 21786079 TI - From the editors' desk: valuing health and primary care. PMID- 21786078 TI - Early detection of neuropathophysiology using diffusion-weighted magnetic resonance imaging in asymptomatic cats with feline immunodeficiency viral infection. AB - HIV infection results in a highly prevalent syndrome of cognitive and motor disorders designated as HIV-associated dementia (HAD). Neurologic dysfunction resembling HAD has been documented in cats infected with strain PPR of the feline immunodeficiency virus (FIV), whereas another highly pathogenic strain (C36) has not been known to cause neurologic signs. Animals experimentally infected with equivalent doses of FIV-C36 or FIV-PPR, and uninfected controls were evaluated by magnetic resonance diffusion-weighted imaging (DW-MRI) and spectroscopy (MRS) at 17.5-18 weeks post-infection, as part of a study of viral clade pathogenesis in FIV-infected cats. The goals of the MR imaging portion of the project were to determine whether this methodology was capable of detecting early neuropathophysiology in the absence of outward manifestation of neurological signs and to compare the MR imaging results for the two viral strains expected to have differing degrees of neurologic effects. We hypothesized that there would be increased diffusion, evidenced by the apparent diffusion coefficient as measured by DW-MRI, and altered metabolite ratios measured by MRS, in the brains of FIV PPR-infected cats relative to C36-infected cats and uninfected controls. Increased apparent diffusion coefficients were seen in the white matter, gray matter, and basal ganglia of both the PPR and C36-infected (asymptomatic) cats. Thalamic MRS metabolite ratios did not differ between groups. The equivalently increased diffusion by DW-MRI suggests similar indirect neurotoxicity mechanisms for the two viral genotypes. DW-MRI is a sensitive tool to detect neuropathophysiological changes in vivo that could be useful during longitudinal studies of FIV. PMID- 21786077 TI - Methamphetamine toxicity and its implications during HIV-1 infection. AB - Over the past two decades methamphetamine (MA) abuse has seen a dramatic increase. The abuse of MA is particularly high in groups that are at higher risk for HIV-1 infection, especially men who have sex with men (MSM). This review is focused on MA toxicity in the CNS as well as in the periphery. In the CNS, MA toxicity is comprised of numerous effects, including, but not limited to, oxidative stress produced by dysregulation of the dopaminergic system, hyperthermia, apoptosis, and neuroinflammation. Multiple lines of evidence demonstrate that these effects exacerbate the neurodegenerative damage caused by CNS infection of HIV perhaps because both MA and HIV target the frontostriatal regions of the brain. MA has also been demonstrated to increase viral load in the CNS of SIV-infected macaques. Using transgenic animal models, as well as cultured cells, the HIV proteins Tat and gp120 have been demonstrated to have neurotoxic properties that are aggravated by MA. In addition, MA has been shown to exhibit detrimental effects on the blood-brain barrier (BBB) that have the potential to increase the probability of CNS infection by HIV. Although the effects of MA in the periphery have not been as extensively studied as have the effects on the CNS, recent reports demonstrate the potential effects of MA on HIV infection in the periphery including increased expression of HIV co-receptors and increased expression of inflammatory cytokines. PMID- 21786081 TI - Posttraumatic stress disorder and trauma characteristics are correlates of premenstrual dysphoric disorder. AB - Posttraumatic stress disorder (PTSD) is often comorbid with premenstrual dysphoric disorder (PMDD) in women; however, it is unclear whether this relationship is driven by the trauma that may lead to PTSD or if PTSD is uniquely associated with PMDD. In this study, we examine trauma and PTSD as independent correlates of PMDD. Researchers conducted a cross-sectional, secondary data analysis of 3,968 female participants (aged 18-40) of the Collaborative Psychiatric Epidemiology Surveys. Women who had a history of trauma with PTSD (odds ratio, OR = 8.14, 95% confidence interval, CI = 3.56-18.58) or a history of trauma without PTSD (OR = 2.84, 95% CI = 1.26-6.42) were significantly more likely than women with no history of trauma to report PMDD. This graded relationship was also observed in association with premenstrual symptoms. Among trauma survivors, PTSD was independently associated with PMDD, although characteristics of participants' trauma history partially accounted for this association. Our study demonstrated that trauma and PTSD were independently associated with PMDD and premenstrual symptoms. Clinicians should be aware that women who present with premenstrual symptomatology complaints may also have a history of trauma and PTSD that needs to be addressed. This pattern of comorbidity may complicate the treatment of both conditions. PMID- 21786080 TI - Alterations of ubiquitylation and sumoylation in conventional renal cell carcinomas after the Chernobyl accident: a comparison with Spanish cases. AB - We determined whether ubiquitylation and sumoylation processes are involved in conventional renal cell carcinogenesis associated with chronic, long-term, persistent low doses of ionizing radiation (IR) in patients living for more than 20 years in cesium-137 ((137)Cs)-contaminated areas after the Chernobyl accident in Ukraine. To this end, we assessed the immunohistochemical expression of ubiquitin (Ub), SUMO1, SUMO E2 conjugating enzyme Ubc9, and the cell cycle regulators p53, mdm2, and p14(ARF) in 38 conventional renal cell carcinomas from Ukrainian patients with different degrees of radiation exposure after the Chernobyl accident. As control cases, 18 conventional renal carcinoma (cRCC) tissues from a Spanish cohort were analyzed. No significant differences between the Ukrainian and Spanish groups were found regarding Ub overexpression, although being higher in the Ukrainian cases. Furthermore, this expression was inversely associated with SUMO1 and Ubc9, with no correlation with tumor nuclear grade. There was also a direct relationship between Ubc9 and inflammatory response. These findings do not allow us to consider the immunohistochemical expression of ubiquitylation and sumoylation as valuable markers for discriminating the effects of long-term, low-dose IR exposure in cRCC carcinogenesis. PMID- 21786082 TI - Renal transplantation in infants and small children. AB - There are still concerns about renal transplantation in small children. The aim of this study was to identify prenatal data, underlying diseases, patient and graft survival, graft function and growth in young renal transplant recipients at our center. A retrospective analysis was performed on 50 kidney transplants performed during the period 1981-2008 in children weighing <13 kg. Their median age at transplantation was 1.4 (range 0.4-3.7) years and the median weight was 9.5 (3.4-12.1) kg. The underlying diseases were congenital in 88% of the patients and acquired in 12%. Ten-year patient survival was 88% (82% before 1998 and 95% since 1998). Ten-year graft survival was 82% (75 and 95%, respectively). Graft function (glomerular filtration rate) deteriorated from a mean of 75-48 ml/min/1.73 m(2) within 10 years. There was rapid catch-up growth within the first years post-transplant, from a median height of -2.44 standard deviation score (SDS) at transplantation to -0.74 SDS after 3 years. In small children, patient and graft survival were as good as those in older children. Renal function deteriorated during the first years post-transplant but stabilized within a few years. In most children, there was a substantial improvement in growth within the first years after transplantation. PMID- 21786083 TI - Quantifying the effects of iodine contrast media on standardised uptake values of FDG PET/CT images: an anthropomorphic phantom study. AB - This study aimed to quantify the amount of change in Standardised Uptake Values (SUVs) of PET/CT images by simulating the set-up as closely as possible to the actual patient scanning. The experiments were conducted using an anthropomorphic phantom, which contained an amount of radioactivity in the form of Fluorodeoxyglucose (FDG) in a primary plastic test tube and one litre saline bags, including the insertion of bony structures and another two test tubes containing different concentrations of iodine contrast media. Standard scanning protocols were employed for the PET/CT image acquisition. The highest absolute differences in the SUVmax and SUVmean values of the saline bags were found to be about 0.2 and 0.4, respectively. The primary test tube showed the largest change of 1.5 in both SUVs; SUV max and SUVmean. However, none of these changes were found to be statistically significant. The clinical literature also contains no evidence to suggest that the changes of this magnitude would change the final diagnosis. Based on these preliminary data, we propose that iodine contrast media can be used during the CT scan of PET/CT imaging, without significantly affecting the diagnostic quality of this integrated imaging modality. PMID- 21786085 TI - Contralateral axial lateropulsion and ocular tilt reaction in a cerebello-lateral medullary-spinal stroke. PMID- 21786084 TI - Effects of instrumental insemination and insemination quantity on Dufour's gland chemical profiles and vitellogenin expression in honey bee queens (Apis mellifera). AB - Honey bee queens (Apis mellifera) mate in their early adult lives with a variable number of males (drones). Mating stimulates dramatic changes in queen behavior, physiology, gene expression, and pheromone production. Here, we used virgin, single drone- (SDI), and multi-drone- (MDI) inseminated queens to study the effects of instrumental insemination and insemination quantity on the pheromone profiles of the Dufour's gland, and the expression of the egg-yolk protein, vitellogenin, in the fat body. Age, environmental conditions, and genetic background of the queens were standardized to specifically characterize the effects of these treatments. Our data demonstrate that insemination and insemination quantity significantly affect the chemical profiles of the Dufour's gland secretion. Moreover, workers were more attracted to Dufour's gland extract from inseminated queens compared to virgins, and to the extract of MDI queens compared to extract of SDI queens. However, while there were differences in the amounts of some esters between MDI queens and the other groups, it appears that the differences in behavioral responses were elicited by subtle changes in the overall chemical profiles rather than dramatic changes in specific individual chemicals. We also found a decrease in vitellogenin gene expression in the fat body of the MDI queens, which is negatively correlated with the quantities of Dufour's gland content. The possible explanations of this reduction are discussed. PMID- 21786086 TI - Forced confabulation affects memory sensitivity as well as response bias. AB - A signal detection analysis assessed the extent to which forced confabulation results from a change in memory sensitivity (d(a)), as well as response criterion (beta). After viewing a crime video, participants answered 14 answerable and 6 unanswerable questions. Those in the voluntary guess condition had a "don't know" response option; those in the forced guess condition did not. One week later, the same questions were answered using a recognition memory test that included each participant's initial responses. As was predicted, on both answerable and unanswerable questions, participants in the forced guess condition had significantly lower response criteria than did those who voluntarily guessed. Furthermore, on both answerable and unanswerable questions, d(a) scores were also significantly lower in the forced than in the voluntary guess condition. Thus, the forced confabulation effect is a real memory effect above and beyond the effects of response bias; forcing eyewitnesses to guess or speculate can actually change their memory. PMID- 21786087 TI - Tryptase activates isolated adult cardiac fibroblasts via protease activated receptor-2 (PAR-2). AB - Protease activated receptor-2 (PAR-2) derived cycloxygenase-2 (COX-2) was recently implicated in a cardiac mast cell and fibroblast cross-talk signaling cascade mediating myocardial remodeling secondary to mechanical stress. We designed this study to investigate in vitro assays of isolated adult cardiac fibroblasts to determine whether binding of tryptase to the PAR-2 receptor on cardiac fibroblasts will lead to increased expression of COX-2 and subsequent formation of the arachodonic acid metabolite 15-d-Prostaglandin J(2) (15-d PGJ(2)). The effects of tryptase (100 mU) and co-incubation with PAR-2 inhibitor peptide sequence FSLLRY-NH(2) (10(-6)M) on proliferation, hydroxyproline concentration, 15-d-PGJ(2) formation and PAR-2/COX-2 expression were investigated in fibroblasts isolated from 9 week old SD rats. Tryptase induced a significant increase in fibroproliferation, hydroxyproline, 15-d-PGJ(2) formation and PAR-2 expression which were markedly attenuated by FSLLRY. Tryptase-induced changes in cardiac fibroblast function utilize a PAR-2 dependent mechanism. PMID- 21786088 TI - Primary extranodal histiocytic sarcoma of lumbar spine. AB - A 17-year-old male patient presented with lower back pain and weakness of lower limbs. On radiological investigation, a destructive bony lesion involving the third lumbar vertebra was seen associated with soft tissue extension and an extradural component. The lesion was surgically excised in view of the rapidly progressing symptoms. The histologic diagnosis was histiocytic sarcoma. Further investigations did not reveal any other lesion elsewhere. The case is being presented in view of the uncommon occurrence of a primary extranodal histiocytic sarcoma of the lumbar spine, which simulated a primary bone tumor. PMID- 21786089 TI - Cardiac involvement in Wegener's granulomatosis resistant to induction therapy. AB - OBJECTIVES: The aim of the study was to assess cardiac involvement in patients with Wegener's granulomatosis (WG), who failed to achieve remission following >6 months induction therapy for life or organ threatening disease. METHODS: Eleven WG patients (eight males, mean age 47 +/- 13 years), who failed to achieve remission despite >6 months induction therapy, underwent transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR). RESULTS: Cardiac involvement was present in 9 (82%) patients. Regional wall motion abnormalities were found in two individuals, but none had left ventricular (LV) ejection fraction <50%. Nine patients had late gadolinium enhancement (LGE) lesions involving LV myocardium and right ventricle free wall was involved in four patients. LGE lesions were found in subepicardial, midwall and subendocardial LV myocardial layers. CMR revealed myocarditis in six patients. Patients with myocarditis had a higher number of LV segments with LGE (5.2 +/- 3.4 vs 1.0 +/- 1.2, p = 0.03) and more frequent diastolic dysfunction by TTE (5 vs 0, p = 0.02) than those without. Pericardial effusion was observed in five patients, while localized pericardial thickening in six patients. CONCLUSIONS: In WG resistant to >6 months induction therapy cardiac involvement is frequent and is characterized by foci of LGE lesions and signs of myocardial inflammatory process. PMID- 21786090 TI - p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naive prostate cancer. AB - Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX 2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naive PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP. PMID- 21786091 TI - Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer's disease measured by pulsed arterial spin labeling MRI. AB - Alzheimer's disease (AD) and mild cognitive impairment (MCI), the transitional clinical stage between cognition in normal aging and dementia, have been linked to abnormalities in brain perfusion. Pulsed arterial spin labeling (PASL) is a magnetic resonance imaging (MRI) technique for evaluating brain perfusion. The present study aimed to determine regional perfusion abnormalities in 19 patients with mild dementia in AD and 24 patients with MCI as compared to 24 cognitively healthy elderly controls using PASL. In line with nuclear imaging methods, lower perfusion in patients with MCI and AD was found mainly in the parietal lobe, but also in angular and middle temporal areas as well as in the left middle occipital lobe and precuneus. Our data imply that PASL may be a valuable instrument for investigating perfusion changes in the transition from normal aging to dementia and indicate that it might become an alternative to nuclear imaging techniques in AD diagnostics. PMID- 21786092 TI - Efficacy of cone-beam computed tomography during transcatheter arterial chemoembolization for hepatocellular carcinoma. AB - Cone-beam computed tomography (CBCT) using a flat-panel detector is an alternative method of obtaining cross-sectional images. This technique is now being used during transcatheter arterial chemoembolization (TACE) for inoperable hepatocellular carcinoma (HCC). Several CBCT techniques are performed to detect HCC lesions: CBCT during portography (CBCTAP), CBCT during hepatic arteriography (CBCTHA), CBCT after iodized oil injection (LipCBCT), CBCT during arteriography (CBCTA) of extrahepatic collaterals. Almost all HCC lesions can be detected using these CBCT images. Three-dimensional arteriography using maximum intensity projection from CBCTHA images can identify the tumor-feeding branch. In particular, this technique is useful when the tumor stain cannot be demonstrated on arteriography. In addition, dual-phase CBCTHA can improve the diagnostic accuracy for hypervascular HCCs because corona enhancement can be detected around the tumor. To monitor the embolized area during TACE, selective CBCTHA or LipCBCT at the embolization point is useful. Two sequential CBCT scans without and with contrast material injection is also useful to confirm each embolized area of two vessels. Furthermore, CBCTA can prevent nontarget embolization. Although the image quality of CBCT is low compared to that of conventional CT, CBCT provides useful information that helps perform TACE for HCCs safely and effectively. PMID- 21786093 TI - Assessment of renal impairment by non-contrast-enhanced conventional magnetic resonance imaging: comparison with 99mTc-DTPA renography. AB - PURPOSE: The aim of this study was to determine whether non-contrast-enhanced magnetic resonance imaging (MRI) can detect three levels of renal impairment by evaluating the differences and agreement with (99m)Tc-diethylenetriamine pentaacetic acid (DTPA) renography. MATERIALS AND METHODS: A total of 28 patients with kidney disease were enrolled in the study. MRI findings, including visual corticomedullary differentiation (CMD) on T1- and T2-weighted imaging (T1WI, T2WI), cortical irregularity, the number of renal cysts, and the volume of the kidney, were evaluated for individual kidneys and pairs of kidneys. The differences and agreement between MRI findings and the three levels of renal impairment based on the glomerular filtration rate (GFR) measured using (99m)Tc DTPA renography were analyzed. RESULTS: All MRI findings except the number of renal cysts in pairs of kidneys were consistent with the patient's classification. The agreement between the patient's classifications based on GFR and that based on the visual CMD on T1WI and T2WI was almost perfect or substantial in both individual kidneys and pairs of kidneys. CONCLUSION: Non contrast-enhanced MRI was capable of distinguishing three levels of renal function, including serious renal impairment. PMID- 21786094 TI - Initial experience with computed tomographic colonography applied for noncolorectal cancerous conditions. AB - PURPOSE: The aim of this study was to asses retrospectively the performance of computed tomography colonography (CTC) for noncolorectal cancerous conditions. MATERIAL AND METHODS: A total of 44 patients with non-colorectal cancerous conditions underwent CTC. We researched the indications for CTC or present illness and evaluated the CTC imaging findings. We assessed whether diagnosis by CTC reduced conventional colonoscopic examinations. RESULTS: A total of 47 examinations were performed in 44 patients. The indications for CTC or a present illness were as follows: 15 patients with impossible or incomplete colonoscopy, 7 with diverticular disease, 6 with malignancy (noncolorectal cancer), 6 with Crohn's disease, 4 suspected to have a submucosal tumor on colonoscopy, 2 with ischemic colitis, and 4 with various other diseases. Colonic findings were diagnosed on CTC in 36 examinations, and extracolonic findings were identified in 35 of 44 patients. In all, 17 patients had undergone colonoscopy previously, 9 (52.9%) of whom did not require further colonoscopy by CTC. Five patients underwent colonoscopy after CTC. CONCLUSION: The indications for CTC were varied for patients with noncolorectal cancerous conditions. CTC examinations could be performed safely. Unlike colonoscopy or CT without preparation, CTC revealed colonic and extracolonic findings and may reduce the indication of colonoscopy in patients with noncolorectal cancerous conditions. PMID- 21786095 TI - Role of 11C-choline positron emission tomography/computed tomography in evaluating patients affected by prostate cancer with suspected relapse due to prostate-specific antigen elevation. AB - PURPOSE: The aim of this study was to evaluate the accuracy of (11)C-choline positron emission tomography/computed tomography (PET/CT) in restaging patients affected by prostate cancer and suspected relapse due to prostate-specific antigen (PSA) increase. We also aimed to determine a PSA cutoff that is most suited to the study in terms of best compromise between sensitivity and specificity. Secondary endpoints were a comparison between (11)C-choline PET/CT and histological results, clinical findings, and radiological imaging (CT and magnetic resonance imaging). MATERIALS AND METHODS: We retrospectively evaluated 210 patients (median +/- SD age 70 +/- 7 years) affected by prostate cancer who underwent (11)C-choline PET/CT. RESULTS: (11)C-choline PET/CT imaging was positive in 116 (55.2%) patients and negative in 94 (44.8%). Receiver operating characteristic (ROC) analysis showed that the highest accuracy (sensitivity 76.8%, specificity 92.5%) for the whole population was achieved when the PSA level of 1.26 ng/ml level was used as the cutoff value for interpreting the results (P = 0.0001 and the area under the ROC curve AUC 0.897). For patients treated with surgery or surgery plus radiotherapy the cutoff was 0.81 ng/ml (sensitivity 73.2%, specificity 86.1%). For patients treated with radiotherapy alone, the cutoff was 2.0 ng/ml (sensitivity 81.8%, specificity 92.9%). CONCLUSION: Our results indicate that (11)C-choline PET/CT is a useful diagnostic tool in patients affected by prostate cancer and a relapsed PSA level. The highest accuracy for all patients is obtained with a PSA cutoff level of 1.26 ng/ml, above which the imaging study is performed (0.81 ng/ml for patients treated with surgery or surgery plus radiotherapy and 2.0 ng/ml for patients treated with radiotherapy alone). PMID- 21786096 TI - Determination of a standard deviation that could minimize radiation exposure in an automatic exposure control for pulmonary thin-section computed tomography. AB - PURPOSE: The aim of this study was to determine a standard deviation (SD) that most reduces the radiation dose without sacrificing the diagnostic accuracy of thin-section computed tomography (CT) for clinical use. MATERIALS AND METHODS: A total of 120 patients were examined by multidetector CT. They were assigned to one of four SD groups: 8, 9, 11, and 12. Each SD group consisted of 30 patients. The CT images of the same patients with SD10 that had formerly been examined were used for comparison. Two radiologists independently evaluated the degrees of image noise and diagnostic acceptability of the pulmonary diseases using a point score grading system. We compared the scores between each SD and the SD10 group. RESULTS: Generally, image noise was significantly more prominent in the higher-SD groups. The mean score of diagnostic acceptability was significantly lower in the SD12 group (4.2 +/- 1.6) than in the SD10 group (4.6 +/- 1.1) group (P < 0.001), whereas no difference was present between the SD8 (4.9 +/- 0.7), SD9 (4.8 +/- 1.0), and SD11 (4.4 +/- 1.5) groups and the SD10 group (4.7 +/- 1.1, 4.6 +/- 1.4, 4.6 +/- 1.1, respectively). CONCLUSION: Thin-section CT with SD12 is not acceptable. SD11 seems to be the setting with the lowest radiation dose while providing acceptable imaging quality for pulmonary thin-section CT. PMID- 21786098 TI - Correlations between computed tomography findings and clinical manifestations of Streptococcus pneumoniae pneumonia. AB - PURPOSE: The aim of this study was to characterize the imaging features and compare computed tomography (CT) findings with clinical features of patients with Streptococcus pneumoniae pneumonia. MATERIALS AND METHODS: We retrospectively reviewed 75 patients (44 men, 31 women; mean age 67 years) diagnosed with S. pneumoniae pneumonia who underwent chest CT scanning at our institution between January 2007 and August 2008. Diagnoses were based on detection of the S. pneumoniae antigen in urine. RESULTS: Chest CT scans revealed abnormalities in all patients. The predominant opacity patterns were an airspace pneumonia pattern (48%) and a bronchopneumonia pattern (48%), followed by an interstitial pneumonia pattern (4%). Consolidation was observed most frequently (84%) followed by ground glass opacity (82.7%), bronchial wall thickening (61.3%), and centrilobular nodules (49.3%). Airway dilatation (21.6%), pleural effusion (33.3%), lymphadenopathy (34.8%), and pulmonary emphysema (21.3%) were also observed. Pulmonary emphysema was significantly less frequent in patients with the bronchopneumonia pattern than in those without (p = 0.007). The clinical features and CT findings did not differ significantly. CONCLUSION: CT image analysis showed that patients with S. pneumoniae pneumonia exhibited the bronchopneumonia and airspace pneumonia patterns with equal frequency. Bronchopneumonia pattern was less common in patients with preexisting emphysema. PMID- 21786097 TI - Comparison of diagnostic and prognostic capabilities of 18F-FDG-PET/CT, 131I scintigraphy, and diffusion-weighted magnetic resonance imaging for postoperative thyroid cancer. AB - PURPOSE: The first aim of this study was to compare the detectability of metastasis of postoperative differentiated thyroid cancer (DTC) among (131)I whole body scintigraphy (IWBS), fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), and diffusion-weighted magnetic resonance imaging (DWI). The second aim was to clarify the association between the image pattern and prognosis. MATERIALS AND METHODS: We evaluated 70 postoperative DTC patients on both a patient basis and an organ basis (lymph nodes, lung, bone), and we analyzed the correlation between the image pattern and the prognosis. RESULTS: For the patient-basis analysis, the detectability by IWBS, PET/CT, and DWI was 67.1%, 84.2%, and 57.6%, respectively. IWBS provided complementary information to that provided by PET/CT in 11 of 70 (15.7%) cases. For the organ-basis analysis, IWBS was the best detector for lymph node metastasis (72.4%). PET/CT was superior to IWBS for detecting metastasis of bone (85.7% vs. 71.4%) and lung (94.1% vs. 62.7%). For the correlation analysis, PET and DWI positivity were the factors predicting a poor prognosis. CONCLUSION: PET/CT was the best modality for detecting metastases in postoperative DTC patients, although IWBS provided complementary information. Because PET/CT and DWI gave similar information (e.g., positivity) suggesting poor prognoses, the combination of IWBS and DWI might be the method of choice for monitoring postoperative DTC. PMID- 21786100 TI - Real-time axial motion detection and correction for single photon emission computed tomography using a linear prediction filter. AB - PURPOSE: We have developed an algorithm for real-time detection and complete correction of the patient motion effects during single photon emission computed tomography. The algorithm is based on a linear prediction filter (LPC). MATERIALS AND METHODS: The new prediction of projection data algorithm (PPDA) detects most motions-such as those of the head, legs, and hands-using comparison of the predicted and measured frame data. When the data acquisition for a specific frame is completed, the accuracy of the acquired data is evaluated by the PPDA. If patient motion is detected, the scanning procedure is stopped. After the patient rests in his or her true position, data acquisition is repeated only for the corrupted frame and the scanning procedure is continued. RESULTS: Various experimental data were used to validate the motion detection algorithm; on the whole, the proposed method was tested with approximately 100 test cases. The PPDA shows promising results. CONCLUSION: Using the PPDA enables us to prevent the scanner from collecting disturbed data during the scan and replaces them with motion-free data by real-time rescanning for the corrupted frames. As a result, the effects of patient motion is corrected in real time. PMID- 21786099 TI - Usefulness of diffusion-weighted imaging of breast tumors: quantitative and visual assessment. AB - PURPOSE: We evaluated the usefulness of quantitative and visual assessment of diffusion-weighted imaging (DWI) of breast tumors to distinguish malignant from benign tumors. MATERIALS AND METHODS: The DWI findings of 106 breast lesions (15 benign, 91 malignant) were retrospectively analyzed. The mean apparent diffusion coefficient (ADC) value for each lesion was calculated using b values of 250, 500, 750, and 1000 s/mm(2) as a quantitative assessment. We visually evaluated the signal intensity of each breast lesion on the basis of a spinal signal intensity in DWI (b = 1000 s/mm(2)) and compared the mean ADC values using a threshold mean ADC +1.65 * standard deviation (SD) for malignant and benign breast lesions. Obviously strong signal intensity of the lesion relative to that of the spinal cord on DWI signifies malignancy. RESULTS: The mean ADC value for benign lesions (1.50 +/- 0.38 * 10(-3) mm(2)/s) was significantly higher than that for malignant lesions (0.98 +/- 0.19 * 10(-3) mm(2)/s), with 94.5% sensitivity, 80% specificity, and 92.5% accuracy. Sensitivity for visual assessment was 91.5%, specificity was 33.3%, and total accuracy was 82.5%. CONCLUSION: ADC values, but not visual assessment, may be useful for differentiating benign and malignant breast tumors. PMID- 21786101 TI - Rosette-forming glioneuronal tumor of the fourth ventricle with bilateral olivary degeneration. AB - Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle has been recognized as a new type of glioneuronal tumor. RGNTs are typically located in the infratentorial midline with involvement of the fourth ventricle. They occasionally involve the aqueduct and/or vermis. RGNTs of unusual anatomical sites or those with unusual findings have been reported. The present case reports describe RGNT of the fourth ventricle with bilateral olivary degeneration. It is important to accumulate imaging findings and biological behaviors of RGNTs given the limited number of cases. PMID- 21786102 TI - Hypertensive crisis due to contrast-enhanced computed tomography in a patient with malignant pheochromocytoma. AB - A 63-year-old man underwent computed tomography (CT) using intravenous low osmolar iodine contrast medium (LOCM) 6 days after undergoing high-dose (131)I MIBG therapy for metastatic pheochromocytoma. Immediately after the CT examination, his blood pressure increased to 260/160 mmHg (from 179/101 mmHg before the examination). Phentolamine mesilate was administered, and the blood pressure rapidly went back to normal. Although hypertensive crisis after administration of LOCM is rare, this case suggests that high-dose (131)IMIBG therapy may be a risk factor for hypertensive crisis after administration of intravenous LOCM. PMID- 21786103 TI - Ultrasonographic elastography of the breast using acoustic radiation force impulse technology: preliminary study. AB - PURPOSE: The aim of this study was to investigate the clinical usefulness of acoustic radiation force impulse (ARFI) imaging for the differential diagnosis of breast lesions. MATERIALS AND METHODS: We studied 40 solid mass lesions from a total of 40 patients (age range 29-67 years, mean 50 years). There were 18 benign lesions and 22 malignant tumors. ARFI imaging was performed using Virtual Touch tissue imaging. We examined the possibility of lesions seen on B-mode images being visually confirmed on ARFI images. When the lesion was visually confirmed, the lesions that were bright or dark inside were classified into patterns 1 and patterns 3, respectively. The lesions that failed to be visually confirmed were classified as pattern 2. RESULTS: There were 3 pattern 1 lesions and 7 pattern 2 lesions; all of these lesions were benign. The remaining 8 benign lesions and 22 malignant lesions were determined to be pattern 3. The negative predictive value was 100%. CONCLUSION: ARFI imaging is a potentially promising ultrasonographic technique for the differential diagnosis of breast lesions, particularly complicated cysts without a cystic component on B-mode images. PMID- 21786105 TI - Single nucleotide polymorphisms predict symptom severity of autism spectrum disorder. AB - Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single nucleotide polymorphisms (SNPs) can predict symptom severity of autism spectrum disorder (ASD). We divided 118 ASD children into a mild/moderate autism group (n = 65) and a severe autism group (n = 53), based on the Childhood Autism Rating Scale (CARS). For each child, we obtained 29 SNPs of 9 ASD-related genes. To generate predictive models, we employed three machine-learning techniques: decision stumps (DSs), alternating decision trees (ADTrees), and FlexTrees. DS and FlexTree generated modestly better classifiers, with accuracy = 67%, sensitivity = 0.88 and specificity = 0.42. The SNP rs878960 in GABRB3 was selected by all models, and was related associated with CARS assessment. Our results suggest that SNPs have the potential to offer accurate classification of ASD symptom severity. PMID- 21786106 TI - Localized Aurora B activity spatially controls non-kinetochore microtubules during spindle assembly. AB - Efficient spindle assembly involves the generation of spatial cues around chromosomes that locally stabilize microtubule (MT) plus-ends. In addition to the small GTPase Ran, there is evidence that Aurora B kinase might also generate a spatial cue around chromosomes but direct proof for this is still lacking. Here, we find that the Aurora B substrate MCAK localizes to MT plus-ends throughout the mitotic spindle, but its accumulation is strongly reduced on MT plus-ends near chromatin, suggesting that a signal emanating from chromosomes negatively regulates MCAK plus-end binding. Indeed, we show that Aurora B is the kinase responsible for producing this chromosome-derived signal. These results are the first to visualize spatially restricted Aurora B kinase activity around chromosomes on an endogenous substrate and explain how Aurora B could spatially control the dynamics of non-kinetochore MTs during spindle assembly. PMID- 21786107 TI - Molecular identification of the microbial diversity in two sequencing batch reactors with activated sludge. AB - The diversity of the microbial community was identified in two lab-scale, ideally mixed sequencing batch reactors which were run for 115 days. One of the reactors was intermittently aerated (2 h aerobically/2 h anaerobically) whereas the other was consistently aerated. The amount of biomass as dry matter, the degradation of organic carbon determined by chemical oxygen demand and nitrogen-degradation activity were followed over the operation of the two reactors and did not show significant differences between the two approaches at the end of the experiment. At this point, the composition of the microbial community was determined by a terminal restriction fragment length polymorphism approach using multiple restriction enzymes by which organisms were retrieved to the lowest taxonomic level. The microbial composition was then significantly different. The species richness was at least five-fold higher in the intermittently aerated reactor than in the permanently kept aerobic approach which is in line with the observation that ecosystem disturbances result in higher diversity. PMID- 21786108 TI - Impact of sulphate-reducing bacteria on the performance of engineering materials. AB - Microbiologically Influenced Corrosion (MIC) is an electrochemical corrosion influenced by the presence/action of biological agents such as, but not limited to, bacteria. One of the key elements of MIC is sulphate-reducing bacteria (SRB). There are still many misunderstandings about these bacteria, their role in the deterioration of engineering materials and their importance over other types of corrosion-related micro-/macro-organisms. SRB do not require oxygen, yet they can be found in oxygenated environments; they are capable of tolerating a relative wide range of temperature, pH, chloride concentration and pressure values. Not only can SRB have deteriorating impact on engineering materials, they are also capable of inducing harm to health and agriculture. In this paper, after reviewing facts and figures regarding ecological and economical impacts of corrosion in general and MIC, in particular, the central concept of MIC, that is, biofilm formation and its deterioration mechanisms and the role of SRB in such mechanisms are described. Also, the possible enhancing role of SRB on stress corrosion cracking of steels and the controversial concept of no relationship between the number of SRB and corrosion rate are addressed and reviewed. PMID- 21786109 TI - Evaluation of time, attendance of medical staff, and resources during radiotherapy for head and neck cancer patients: the DEGRO-QUIRO trial. AB - INTRODUCTION: A number of national and international societies have published recommendations regarding the required equipment and manpower that is assumed to be necessary to treat a specific number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating their recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancer treated by radiotherapy. The results of the examinations of radiotherapy in head and neck cancer (HNC) patients are presented in this manuscript. PATIENTS AND METHODS: Four radiation therapy centers (University of Jena, University of Erlangen, University of Dusseldorf and the community hospital of Neuruppin) participated in this prospective study. Working time of the different occupational groups and room occupancies for the core procedures of radiotherapy in HNC were prospectively documented during a 4-month period and subsequently statistically analyzed. RESULTS: The time needed per patient varied considerably between individual patients and between centers for all evaluated procedures. Room occupancy, presence of technicians, and overall medical staff times were 21 min, 26 min, and 42 min, respectively, for planning CT with i.v. contrast medium (n = 79), and 23 min, 44 min, and 51 min respectively, for planning CT without contrast medium (n = 45). Definition of the target volume (n = 91) was the most time consuming procedure for the physicians taking 1 h 45 min on average. Medical physicists spent a mean time of 3 h 8 min on physical treatment planning (n = 97) and 1 h 8 min on authorization of the treatment plan (n = 71). Treatment simulations (n = 185) required an average room occupancy of 23 min, and a mean technicians presence of 47 min. The mean room occupancy (n = 84) was 24 min for the first radiotherapy including portal imaging associated with a mean presence of the technicians of 53 min. For routine radiotherapy sessions (n = 2,012) and routine radiotherapy sessions including portal imaging (n = 407), mean room occupancies were 13 min and 16 min, respectively. The presence of increasing number of technicians was significantly associated with shorter room occupancy. IMRT including portal imaging (n = 213) required an average room occupancy of 24 min and a mean technician time of 48 min. CONCLUSION: The data presented here allow an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average head and neck cancer patient treated with a specific number of fractions. However, one has to be aware that a number of necessary and time consuming activities were not evaluated in the present study. PMID- 21786110 TI - Prostate image-guided radiotherapy by megavolt cone-beam CT. AB - PURPOSE: To test megavolt cone-beam CT (MV-CBCT) in order to evaluate setup errors in prostate radiotherapy. PATIENTS AND METHODS: The setup of 9 patients was verified weekly by electronic portal imaging (EPI) and MV-CBCT, both per formed in the same treatment session. EPI were compared with digitally reconstructed radiographies (DRRs). MV-CBCTs were matched to simulation CTs by manual registration based on bone markers (BMR), by manual registration based on soft tissues (STR) - rectum, bladder, and seminal vesicles - and by automatic registration (AR) performed by a mutual information algorithm. Shifts were evaluated along the three main axes: anteroposterior (AP), craniocaudal (CC), and laterolateral (LL). Finally, in 4 additional patients showing intraprostatic calcifications, the calcification mismatch error was used to evaluate the three MV-CBCT matching methods. RESULTS: A total of 50 pairs of orthogonal EPIs and 50 MV-CBCTs were analyzed. Assuming an overall tolerance of 2 mm, no significant differences were observed comparing EPI vs BMR in any axis. A significant difference (p < 0.001) was observed along the AP axis comparing EPI vs AR and EPI vs STR. On the calcification data set (22 measures), the calcification mismatch along the AP direction was significantly lower (p < 0.05) after STR than after BMR or AR. CONCLUSION: Bone markers were not an effective surrogate of the target position and significant differences were observed comparing EPI or BMR vs STR, supporting the assessment of soft tissue position by MVCBs to verify and correct patient setup in prostate radiotherapy. PMID- 21786111 TI - Patterns of care and course of symptoms in palliative radiotherapy: a multicenter pilot study analysis. AB - BACKGROUND AND PURPOSE: To evaluate patterns of care as well as effectiveness and side effects of palliative treatment in four German radiation oncology departments. PATIENTS AND METHODS: All referrals in four German radiation oncology departments (two university hospitals, one academic hospital, one private practice) were prospective documented for 1 month in 2008 (2 months at one of the university hospitals). In palliatively irradiated patients, treatment aims and indications as well as treated sites and fractionation schedules were recorded. In addition, symptoms and side effects were analyzed with standardized questionnaires before and at the end of radiotherapy. RESULTS: During the observation period, 603 patients underwent radiation therapy in the four centers and 153 (24%, study population) were treated with palliative intent. Within the study, patients were most frequently treated for bone (34%) or brain (27%) metastases. 62 patients reported severe or very severe pain, 12 patients reported severe or very severe dyspnea, 27 patients reported neurological deficits or signs of cranial pressure, and 43 patients reported a poor or very poor sense of well-being. The most frequent goals were symptom relief (53%) or prevention of symptoms (46%). Life prolongation was intended in 37% of cases. A wide range of fractionation schedules was applied with total doses ranging from 3-61.2 Gy. Of the patients, 73% received a slightly hypofractionated treatment schedule with doses of > 2.0 Gy to <= 3.0 Gy per fraction and 12% received moderate to highly hypofractionated therapy with doses of > 3.0 Gy to 8.0 Gy. Radiation therapy led to a significant improvement of well-being (35% of patients) and reduction of symptoms, especially with regard to pain (66%), dyspnea (61%), and neurological deficits (60%). Therapy was very well tolerated with only 4.5% grade I or II acute toxicities being observed. Unscheduled termination was observed in 19 patients (12%). CONCLUSIONS: Palliative radiation therapy is effective in reducing symptoms, increases subjective well-being, and has minimal side effects. More studies are necessary for subgroup analyses and for clarifying the different goals in palliative radiotherapy. PMID- 21786112 TI - Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival: results of a retrospective study. AB - PURPOSE: The optimal dose for salvage radiotherapy (SRT) after radical prostatectomy (RP) is still not defined. It should be at least 66 Gy. In the present study, the suitability of PSA regression as a selection criterion for an SRT dose escalation to 70.2 Gy was examined. PATIENTS AND METHODS: Between 1997 and 2007, 301 prostate cancer patients received SRT after RP at the Charite - University Medicine Berlin, Campus Benjamin Franklin. None of the patients had antihormone therapy prior to SRT. A total of 234 patients received 66.6 Gy. From 2002 on, 67 patients with a PSA decrease during SRT were irradiated with 70.2 Gy. The influence of this selection and dose escalation on freedom from biochemical progression (bNED) was analyzed. RESULTS: The median follow-up of the whole group was 30 months, the median pre-SRT PSA was 0.28 ng/ml. Of the patients, 27% (82/301) developed biochemical progression, 31% from the 66.6 Gy cohort (73/292) and 13% from the 70.2 Gy cohort (9/67) (p = 0.01). The calculated 2-years bNED was 74% for the whole group, 88% vs. 71% after 70.2 Gy and 66.6 Gy, respectively (p = 0.01). In a multivariate analysis, the total dose (p = 0.017), the re achievement of an undetectable PSA after SRT (p = 0.005), and the infiltration of the seminal vesicles (p = 0.049) were independent parameters of bNED. CONCLUSION: Our analysis suggests that patient selection during SRT for a dose escalation to 70.2 Gy can improve the freedom from biochemical progression in patients with SRT after RP. PMID- 21786113 TI - Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients. AB - PURPOSE: More than 80% of patients with breast cancer undergoing postsurgical radiotherapy (RT) will develop radiodermatitis and approximately 10% of these patients show grade 3 lesions. Side effects may reduce the patient's compliance and can be limiting factors to follow RT protocols. Therefore, there is a high need for more effective prophylactic treatments. In this study, a silymarin-based cream (Leviaderm((r))) was tested in comparison to our standard of care (SOC) at the involved site. METHODS: A total of 101 patients were evaluated after breast conserving surgery followed by RT with 50.4 Gy plus boost 9-16 Gy. Of these, 51 patients were treated with the silymarin-based cream. In addition, 50 patients were documented receiving a panthenol-containing cream interventionally, if local skin lesions occurred. The acute skin reactions were classified according to the RTOG and VAS (Visual Analogue Scale) scores. RESULTS: The median time to toxicity was prolonged significantly with silymarin-based cream (45 vs. 29 days (SOC), p < 0.0001). Only 9.8% of patients using silymarin-based cream showed grade 2 toxicity in week 5 of RT in comparison to 52% with SOC. At the end of RT, 23.5% of patients in the silymarin-based study group developed no skin reactions vs. 2% with SOC, while grade 3 toxicity occurred only in 2% in the silymarin-based arm compared to 28% (SOC). CONCLUSIONS: Silymarin-based cream Leviaderm((r)) may be a promising and effective treatment for the prevention of acute skin lesions caused by RT of breast cancer patients. To confirm the results of this nonrandomized, observational trial, this component should be tested in larger multicenter studies in this setting. PMID- 21786114 TI - A preliminary study on metal and nutrient concentrations in running water systems in southern New Caledonia. AB - Metal and nutrient concentrations were measured in five running water sampling sites of New Caledonia. Metal concentrations were homogeneous (Ni; 22.7-50.6 MUg L(-1)) or not (Fe; 37-749 MUg L(-1)). Concentrations of Ni, Cr, Fe were high, including high dissolved fractions (up to 47.8, 70.8 and 417 MUg L(-1), respectively). Concentrations of anthropogenic metals (Ag, As, Cd, Cu, Pb, Sb, V, Zn) were low (maximum: total Cu, 0.6 MUg L(-1)). The contamination of waters is presumably due to soil weathering and mining activities. Metal concentrations and phosphate depletion (<0.04 MUmol L(-1)) suggest constrained conditions for the development of aquatic life. PMID- 21786115 TI - Malnutritional neuropathy under intestinal levodopa infusion. AB - Levodopa/Carbidopa intestinal gel infusion (LCIG) for Parkinson's disease is under debate to provoke polyneuropathy (PNP). In our cohort of 20 thus treated patients, two developed debilitating axonal PNP with deficient pyridoxin and folate levels, and marginal cobalamin. Homocysteine was highly elevated. The neuropathies responded to vitamin replacement. We assume that LCIG can provoke PNP most likely of malnutritional origin. To avoid this side effect, the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary. PMID- 21786116 TI - Comment: should we diagnose MCI in Parkinson disease? PMID- 21786117 TI - The possible role of the kynurenine pathway in anhedonia in adolescents. AB - To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders. PMID- 21786118 TI - Polyarthritis and posterior interosseous nerve palsy associated with gastric carcinoma. AB - Cancer polyarthritis is a very rare condition. Here, we present a case of cancer polyarthritis, who also had mononeuritis simplex as a manifestation of paraneoplastic neuralgic syndrome. A 71-year-old man, who initially presented symmetrical polyarthritis and unilateral posterior interosseous nerve palsy, was subsequently diagnosed to have gastric cancer. Total gastrectomy was performed, and his polyarthritis and the palsy simultaneously disappeared within 2 weeks after the resection. His gastric cancer was found to be metastasized to his liver 16 months after the total gastrectomy; however, the polyarthritis and the palsy did not recurrent throughout his course. The polyarthritis in this case was diagnosed as a cancer polyarthritis from its features. On the other hand, the isolated posterior interosseous nerve palsy in this case met the diagnostic criteria for paraneoplastic neurological syndrome. This case was also unique in that the manifestations of paraneoplastic syndromes did not recur even after the metastasis of the primary cancer, suggesting that some specific clones in the cancer were responsive to the manifestations of paraneoplastic syndromes. Our case suggested that relapse of the manifestations of paraneoplastic syndromes may not always herald the recurrence of primary or metastatic tumour, and other tumour markers and signs should be periodically followed to search for the recurrence of the tumours. PMID- 21786119 TI - Pitfalls on paleopathological interpretations in the visual arts: commentary about the article "Evidences of rheumatic disorders and orthopedics practices in Moche art". PMID- 21786120 TI - Primary Sjogren's syndrome in Moroccan patients: characteristics, fatigue and quality of life. AB - Our aim was to evaluate fatigue and quality of life (QoL) in Moroccan patients with primary Sjogren's syndrome (PSS) and determine their correlates with disease related parameters. Fifty-seven consecutive patients with PSS according to the American-European Consensus group (AEGG) criteria were included. Demographic, clinical, biological and immunological characteristics for all patients were collected. Xerostomia was demonstrated by histological grading of lower lip glandular biopsy. A Schirmer test was performed to measure lachrymal flow. Oral, ocular, skin, vaginal and tracheal dryness were evaluated by using a visual analogue scale (VAS). Fatigue was assessed by the Multidimensional assessment of fatigue (MAF) and the QoL by using the generic instrument: SF-36. 90% of our patients were women. The mean age of patients was 53.73 +/- 7.69 years, and the mean disease duration was 5.38 +/- 4.11 years. The mean oral dryness was 68.38 +/ 20.29, and the mean ocular dryness was 51.91 +/- 14.03. The mean total score of the MAF was 26.73 +/- 8.33, and 87.5% of our patients experienced severe fatigue. Also, physical and mental domains of QoL were altered in a significant way, and the severity of fatigue had a negative impact on SF-36 scores. MAF and SF-36 scores were correlated with the delay of diagnosis, the intensity of xerostomia and the activity of joint involvement. A low socioeconomic and educational level had a negative impact on fatigue scores and QoL. Histological grading of lower lip glandular biopsy, immunological status and the severity of systemic involvement had no correlations with fatigue scores or the alteration of QoL. Patients receiving antidepressant have lesser fatigue and those receiving Methotrexate have better SF-36 scores. In our data, there was a high prevalence of fatigue in Moroccan patients with PSS associated with altered QoL. Severe fatigue and reduced QoL seem to be related to the severity of joint involvement, xerostomia and both educational and socioeconomic levels. Also, treatment with methotrexate and antidepressant seems to improve patients' living and QoL. An appropriate therapeutic intervention for depression and articular manifestations in PSS should be applied to improve patients' living. PMID- 21786121 TI - Amyloid deposition in rheumatoid arthritis of the hip. AB - The aim of this study was to examine the frequency of amyloid deposition in patients with end-stage rheumatoid arthritis (RA) of the hip. The impact on the clinical situation and the RA severity regarding the inflammation was analyzed. Fifty patients with RA who consecutively underwent total hip replacement were prospectively evaluated. X-rays of the patients were analyzed radiologically (Larsen score) to quantify the radiological changes. A clinical score (Harris Hip Score) was preoperatively calculated from every patient. A laboratory set of inflammation markers (erythrocyte sedimentation rate, CRP, serum amyloid A-SAA, electrophoresis) was measured in every patient the day before the operation. Specimens of bone and cartilage from the femoral head and of the capsule were obtained from every patient intraoperatively for histological evaluation. A histological grading was performed. In patients with amyloid deposits, the subtypes were characterized immunohistologically. Ninety-two percent of the patients had raised SAA in the blood samples, but the only amyloid subtype was ATTR. No correlation was found for any other measured item, such as inflammation signs in the blood samples, the histological grading, the radiological or the clinical score. Amyloid plays a role in inflammatory joint destruction processes in RA with raised SAA values, but the amyloid deposits in the joint are of a different subtype. Thus, these amyloid deposits can be considered as minor pathologic significance. A correlation to the radiological and histological changes was ruled out by our study. As in degenerative arthritis, ATTR amyloid deposits may be an incidental finding in aged joints. PMID- 21786122 TI - Mycophenolate mofetil treatment in two children with severe polyarteritis nodosa refractory to immunosuppressant drugs. AB - Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small- and medium-sized arteries with multiorgan involvement, rarely reported in childhood. Despite aggressive treatment with the combination of corticosteroids and cytotoxic agents, the overall prognosis is poor in most patients. We report on two siblings, now 15- and 14-year-old, affected with childhood onset PAN, refractory to multiple therapies, who showed rapid clinical and laboratory improvement when mycophenolate mofetil was introduced. The relationship between the administration of this immunosuppressant agent and the reduced disease activity is confirmed by the sustained absence of disease flares over 4 years of treatment. PMID- 21786123 TI - How sequence learning creates explicit knowledge: the role of response-stimulus interval. AB - Destrebecqz and Cleeremans (Psychon bull rev 8:343-350, 2001; Attention and implicit learning. John Benjamins Publishing Company, Amsterdam, pp 181-213, 2003) reported that increasing the response-stimulus interval (RSI) during incidental sequence learning improved participants' ability to discriminate old and new sequences in a recognition test. However, the original experimental design confounded RSI effects during training and test. I therefore repeated the experiment with an improved design in which RSI was varied systematically during the training phase and the recognition task. Participants learned a sequence of response locations either incidentally or intentionally. As a result, sequence recognition was not affected by the RSI manipulations in the group of incidental learners. With intentional learning instructions, recognition was unaffected by training RSI, but a long RSI in the test phase improved recognition performance over a short RSI. Response latencies while executing the test sequences indicated no effect of training RSI on sequence learning. However, sequence knowledge was expressed more readily when the RSI in the test phase matched the RSI in the training phase. PMID- 21786124 TI - HIDA, percutaneous transhepatic cholecysto-cholangiography and liver biopsy in infants with persistent jaundice: can a combination of PTCC and liver biopsy reduce unnecessary laparotomy? AB - BACKGROUND: Historically, HIDA is the initial diagnostic test in the evaluation of biliary atresia (BA). Non-excreting HIDA scans can yield false-positive results leading to negative laparotomy. OBJECTIVE: Cholestatic infants must be evaluated promptly to exclude biliary atresia (BA) and other treatable hepatic conditions. Intraoperative cholangiogram (IOC) is the gold standard for diagnosing BA, but requires surgical intervention. Percutaneous transhepatic cholecysto-cholangiography (PTCC) and liver biopsy are less invasive and have been described in small case series. We hypothesized that PTCC and liver biopsy effectively exclude BA, thus avoiding unnecessary IOC. MATERIALS AND METHODS: Retrospective review of cholestatic infants who underwent PTCC, biopsy or cholescintigraphy at a tertiary children's hospital from August 1998 to January 2009. Group differences were evaluated and the receiver operator curve and safety of PTCC determined. RESULTS: One-hundred twenty-eight cholestatic infants were reviewed. Forty-six (36%) underwent PTCC. Forty-one out of 46 (89%) had simultaneous PTCC and liver biopsy. PTCC was completed successfully in 19/23 (83%) children despite a small or absent GB on initial US. Negative laparotomy rate was 1/6 (17%) for simultaneous PTCC/liver biopsy. Complications occurred in 4/46 including bleeding (n=2), fever with elevated transaminases (n=1) and oxygen desaturations (n=1). CONCLUSION: PTCC, particularly when performed in combination with simultaneous liver biopsy, effectively excludes BA in cholestatic infants with acceptable morbidity. PTCC can frequently be performed when a contracted gallbladder is seen on initial US exam. Negative laparotomy rate is lowest when PTCC is coupled with simultaneous liver biopsy. PMID- 21786125 TI - Combined respiratory and cardiac triggering improves blood pool contrast-enhanced pediatric cardiovascular MRI. AB - BACKGROUND: Contrast-enhanced cardiac MRA suffers from cardiac motion artifacts and often requires a breath-hold. OBJECTIVE: This work develops and evaluates a blood pool contrast-enhanced combined respiratory- and ECG-triggered MRA method. MATERIALS AND METHODS: An SPGR sequence was modified to enable combined cardiac and respiratory triggering on a 1.5-T scanner. Twenty-three consecutive children referred for pediatric heart disease receiving gadofosveset were recruited in HIPAA-compliant fashion with IRB approval and informed consent. Children underwent standard non-triggered contrast-enhanced MRA with or without suspended respiration. Additionally, a free-breathing-triggered MRA was acquired. Triggered and non-triggered studies were presented in blinded random order independently to two radiologists twice. Anatomical structure delineation was graded for each triggered and non-triggered acquisition and the visual quality on triggered MRA was compared directly to that on non-triggered MRA. RESULTS: Triggered images received higher scores from each radiologist for all anatomical structures on each of the two reading sessions (Wilcoxon rank sum test, P < 0.05). In direct comparison, triggered images were preferred over non-triggered images for delineating cardiac structures, with most comparisons reaching statistical significance (binomial test, P < 0.05). CONCLUSION: Combined cardiac and respiratory triggering, enabled by a blood pool contrast agent, improves delineation of most anatomical structures in pediatric cardiovascular MRA. PMID- 21786126 TI - Gd-DOTA administration at MRI in children younger than 18 months of age: immediate adverse reactions. AB - BACKGROUND: There is a paucity of evidence with regard to the safety of contrast medium administration at MRI in neonates and infants. PURPOSE: To assess immediate adverse reactions in children younger than 18 months of age during routine clinical utilization of gadoteric acid (Gd-DOTA) in a cohort of patients with nonselected indications. MATERIALS AND METHODS: One hundred and four neonates and infants were enrolled in a postmarketing survey with Gd-DOTA (Dotarem, Guerbet, Roissy, France) from a single pediatric hospital. A standardized questionnaire was used to collect the patient information. RESULTS: All included children, ages 3 days to 18 months, received one injection of Gd DOTA (volume 0.6-4 ml). No immediate adverse event was reported. CONCLUSION: This postmarketing study involving neonates and infants suggests a favorable safety profile of Gd-DOTA in routine practice. PMID- 21786127 TI - The relationship between a coiled morphology and Mbl in alkaliphilic Bacillus halodurans C-125 at neutral pH values. AB - The facultative alkaliphilic Bacillus halodurans C-125 can grow in a pH range from 6.8 to 10.8. The morphology of the cells grown at pH values above 7.5 is rod shaped, whereas, that gown at pH values less than 7.5 is coiled. Cytoplasmic membrane staining revealed that this coiled morphology was formed not by one filamentous cell, but by many chained bent/non-bent cells. Prokaryotic actin and tubulin homologs (MreB, Mbl MreBH, and FtsZ, respectively) are known to function as bacterial cytoskeleton proteins. The transcription levels of ftsZ, mreB, and mreBH genes were hardly affected by growth pH. However, the level of the mbl gene was significantly decreased at neutral pH values. Moreover, the expression level of the Mbl protein at pH 7.0 was about one-fourth of that at pH 10. Immunofluorescence microscopy (IFM) showed that the Mbl protein was localized as a helical structure in the rod-shaped cell grown at pH 10, whereas a helical structure was not observed in the cells grown at pH 7.0. Fluorescent vancomycin staining showed insertion of new peptidoglycan strands of sidewalls occurred in the cells grown at pH 7.0. These data suggested that a decrease in the expression level of the Mbl protein can influence the morphology of B. halodurans C-125 grown at pH 7.0 without influencing insertion of new peptidoglycan strands. PMID- 21786128 TI - Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease. AB - WRN is a RecQ helicase with an associated exonuclease activity important in DNA metabolism, including DNA replication, repair and recombination. In humans, deficiencies in WRN function cause the segmental progeroid Werner syndrome (WS), in which patients show premature onset of many hallmarks of normal human ageing. At the cellular level, WRN loss results in rapid replicative senescence, chromosomal instability and sensitivity to various DNA damaging agents including the topoisomerase inhibitor, camptothecin (CPT). Here, we investigate the potential of using either transient or stable WRN knockdown as a means of sensitising cells to CPT. We show that targeting WRN mRNA for degradation by either RNAi or hammerhead ribozyme catalysis renders human fibroblasts as sensitive to CPT as fibroblasts derived from WS patients, and furthermore, we find altered cell cycle transit and nucleolar destabilisation in these cells following CPT treatment. Such WS-like phenotypes are observed despite very limited decreases in total WRN protein, suggesting that levels of WRN protein are rate-limiting for the cellular response to camptothecin. These findings have major implications for development of anti-WRN agents that may be useful in sensitising tumour cells to clinically relevant topoisomerase inhibitors. PMID- 21786129 TI - Bile acids as colon carcinogens and coffee ingredients as antagonists. PMID- 21786130 TI - Artificial gravity with ergometric exercise can prevent enhancement of popliteal vein compliance due to 4-day head-down bed rest. AB - Changes of venous compliance may contribute in part to postflight orthostatic intolerance. The purpose of the present study was to determine whether intermittent artificial gravity exposure with ergometric exercise could prevent venous compliance changes in the lower limbs due to simulated weightlessness. Twelve healthy male volunteers were exposed to simulated microgravity for 4 days of head-down bed rest (HDBR). Six subjects were randomly loaded 1.0-2.0 Gz intermittent artificial gravity (at foot level) with 40 W of ergometric workload every day (countermeasure group, CM). The six others served as the control (CON group). Venous compliance was estimated by measuring the corresponding change of cross-sectional area (CSA) of popliteal vein at each minute of various venous occlusion pressure stages. Basal CSA was significantly lower after bed rest in the control group, and preserved in the countermeasure group. The percent increase in the CSA of CON group was significantly greater almost at each minute of various venous cuff pressures after bed rest than before. Compliance of popliteal vein of CON group was significant greater when 40, 60 and 80 mmHg cuff pressure applied after bed rest than before of CON group. In conclusions, a 4-day simulated weightlessness leads to increase of popliteal venous compliance; centrifuge-induced artificial gravity with ergometric exercise can prevent enhancement of popliteal venous compliance due to 4-day head-down tilt bed rest, the effect of the countermeasure on compliance might involve changes in venous filling and changes in venous structure. PMID- 21786131 TI - Direct cytotoxicity evaluation of 63S bioactive glass and bone-derived hydroxyapatite particles using yeast model and human chondrocyte cells by microcalorimetry. AB - In this study, the cytotoxicity evaluation of prepared 63S bioactive glass and bone-derived hydroxyapatite particles with yeast and human chondrocyte cells was carried out using isothermal micro-nano calorimetry (IMNC), which is a new method for studying cell/biomaterial interactions. Bioactive glass particles were made via sol-gel method and hydroxyapatite was obtained from bovine bone. Elemental analysis was carried out by XRF and EDXRF. Amorphous structure of the glass and completely crystalline structure of HA were detected by XRD analysis. Finally, the cytotoxicity of bioactive glass and bone-derived HA particles with yeast and cultured human chondrocyte cells was evaluated using IMNC. The results confirmed the viability, growth and proliferation of human chondrocyte cells in contact with 63S bioactive glass, and bone-derived HA particles. Also the results indicated that yeast model which is much easier to handle, can be considered as a good proxy and can provide a rapid primary estimate of the ranges to be used in assays involving human cells. All of these results confirmed that IMNC is a convenient method which caters to measuring the cell-biomaterial interactions alongside the current methods. PMID- 21786132 TI - Mesoporous silica nanoparticle-functionalized poly(methyl methacrylate)-based bone cement for effective antibiotics delivery. AB - Poly(methyl methacrylate)-based bone cements are functionalized with mesoporous silica nanoparticles (MSN) to enable a highly efficient and sustained release of antibiotics to reduce the risk of post-operative joint infection. To overcome the limited drug release of 5% for only 1 day with the current commercial-grade bone cements, a 8 wt% MSN-formulated bone cement is able to increase the drug release efficiency by 14-fold and sustain the release for up to 80 days. The loaded MSN is suggested to build up an effective network of rod-shaped silica particles with uniformly arranged nanoporous channels, which is responsible for the effective drug diffusion and extend time-release to the external surfaces. MSN has no detrimental effect on the critical weight-bearing bending modulus and compression strength of bone cement. In vitro assay test results show a much sustained antibacterial effect and low cytotoxicity of MSN demonstrating the potential applicability of MSN-formulated bone cement. PMID- 21786133 TI - Long-term in vivo response to citric acid-based nanocomposites for orthopaedic tissue engineering. AB - The disadvantages of current bone grafts have triggered the development of a variety of natural and synthetic bone substitutes. Previously, we have described the fabrication, characterization, and short-term tissue response of poly(1,8 octanediol-co-citrate) (POC) with 60 weight % hydroxyapatite nanocrystals (POC HA) at 6 weeks. In order to better understand the clinical potential, longer term effects, and the biodegradation, biocompatibility, and bone regenerative properties of these novel nanocomposites, POC-HA, POC, and poly-L-lactide (PLL) were implanted in osteochondral defects in a rabbit model and assessed at 26 weeks. Explants were stained with Masson Goldner Trichrome and the fibrous capsule and tissue ingrowth measured. In addition, the bone-implant and bone cartilage response of POC-HA, POC, and PLL were assessed through histomorphometry and histological scoring. Upon histological evaluation, both POC-HA and POC implants were biocompatible, but PLL implants were surrounded by a layer of leukocytes at 26 weeks. In addition, due to the degradation properties of POC-HA, tissue grew into the implant and had the highest area of tissue ingrowth although not statistically significant. Histomorphometric analyses supported a similar osteoid, osteoblast, and trabecular bone surface area among all implants although the fibrous capsule thickness was the largest for POC. Moreover, histological scoring demonstrated comparable scores among all three groups of the articular cartilage and subchondral bone. This study provides the long-term bone and cartilage response of novel, citric acid-based nanocomposites and their equivalence to FDA-approved biomaterials. Furthermore, we provide new insights and further discussion of these nanocomposites for orthopaedic applications. PMID- 21786134 TI - Solvent and melting induced microspheres sintering techniques: a comparative study of morphology and mechanical properties. AB - In this work we propose a bottom up approach founded on the assembly of building blocks by solvent induced microparticle sintering to realize multifunctional polymer scaffolds with predefined pore dimension and fully percolative pathway, able to include interspersing microdepot for the release of bioactive molecules. The aim of this study was to develop a versatile method of microspheres sintering based on the partial dissolution of the surface of adjacent microparticles and to compare it with melting induced microspheres sintering, just developed in a previous work. The two techniques were compared in terms of morphology, porosity and mechanical properties. The high potential of customizing the sintering process by the proper selection of the sintering techniques as well as microparticles with different features (e.g., material, size, shape, inner porosity) allows obtaining a wide pattern of micro/nanostructures with bio inspired mechanical response so satisfying all basic requirements of a "smart" scaffold for bone tissue engineering. PMID- 21786135 TI - Neuronal discharge patterns in the globus pallidus pars interna in a patient with Parkinson's disease and hemiballismus secondary to subthalamotomy. AB - Alterations in the basal ganglia-thalamocortical "motor" circuit activity, have been proposed to explain many features associated with hypokinetic and hyperkinetic movement disorders. We describe the firing pattern of the globus pallidus pars interna in a Parkinson disease's patient who developed Hemichorea Ballismus subsequent to ipsilateral subthalamotomy, and compare findings to those from PD patients submitted to pallidotomy while in the OFF-medication state. Single units obtained from extracellular recordings were extracted and mean discharge frequency, interspike interval and coefficient of variation (defined as Tonicity Score) were computed. Discharge density histograms, analysis of distribution and spectral analysis were also performed. Mean firing frequency showed no significant difference between PD patients in the OFF state and the patient we report. However, a significant difference in tonicity was found for this patient characterized by a regular, non-bursting firing pattern. The findings indicate that in HB caused by lesions to STN in the parkinsonian state, GPi firing rates can be similar to and firing pattern more regular than those observed in GPi of PD patients OFF-medication with intact STN. PMID- 21786137 TI - Prediction of protein-protein interactions between Ralstonia solanacearum and Arabidopsis thaliana. AB - Ralstonia solanacearum is a devastating bacterial pathogen that has an unusually wide host range. R. solanacearum, together with Arabidopsis thaliana, has become a model system for studying the molecular basis of plant-pathogen interactions. Protein-protein interactions (PPIs) play a critical role in the infection process, and some PPIs can initiate a plant defense response. However, experimental investigations have rarely addressed such PPIs. Using two computational methods, the interolog and the domain-based methods, we predicted 3,074 potential PPIs between 119 R. solanacearum and 1,442 A. thaliana proteins. Interestingly, we found that the potential pathogen-targeted proteins are more important in the A. thaliana PPI network. To facilitate further studies, all predicted PPI data were compiled into a database server called PPIRA (http://protein.cau.edu.cn/ppira/). We hope that our work will provide new insights for future research addressing the pathogenesis of R. solanacearum. PMID- 21786136 TI - Wine flavor and aroma. AB - The perception of wine flavor and aroma is the result of a multitude of interactions between a large number of chemical compounds and sensory receptors. Compounds interact and combine and show synergistic (i.e., the presence of one compound enhances the perception of another) and antagonistic (a compound suppresses the perception of another) interactions. The chemical profile of a wine is derived from the grape, the fermentation microflora (in particular the yeast Saccharomyces cerevisiae), secondary microbial fermentations that may occur, and the aging and storage conditions. Grape composition depends on the varietal and clonal genotype of the vine and on the interaction of the genotype and its phenotype with many environmental factors which, in wine terms, are usually grouped under the concept of "terroir" (macro, meso and microclimate, soil, topography). The microflora, and in particular the yeast responsible for fermentation, contributes to wine aroma by several mechanisms: firstly by utilizing grape juice constituents and biotransforming them into aroma- or flavor impacting components, secondly by producing enzymes that transform neutral grape compounds into flavor-active compounds, and lastly by the de novo synthesis of many flavor-active primary (e.g., ethanol, glycerol, acetic acid, and acetaldehyde) and secondary metabolites (e.g., esters, higher alcohols, fatty acids). This review aims to present an overview of the formation of wine flavor and aroma-active components, including the varietal precursor molecules present in grapes and the chemical compounds produced during alcoholic fermentation by yeast, including compounds directly related to ethanol production or secondary metabolites. The contribution of malolactic fermentation, ageing, and maturation on the aroma and flavor of wine is also discussed. PMID- 21786138 TI - Understanding errors in diagnostic radiology: proposal of a classification scheme and application to emergency radiology. AB - Errors in image interpretation are a common problem in diagnostic radiology. Although many published articles provide trainees with the means to correctly interpret imaging studies, they do not provide a framework for understanding why and how errors occur. In this article, we propose a classification system that allows categorization of errors, which we hope can serve as a basis for peer review, self-education, and quality improvement programs. Our scheme incorporates elements of a classification system proposed by previous authors but also includes novel categories. In this article, we show the usefulness of our scheme by applying it to a specific, and particularly problematic, diagnosis in emergency radiology, namely that of dural sinus thrombosis. PMID- 21786139 TI - Evaluation of the topographical surface changes and roughness of zirconia after different surface treatments. AB - The purpose of this study was to investigate the surface morphology and roughness of zirconia after different surface treatments. Eighty sintered zirconia specimens were divided into four groups (n = 20) according to the surface treatments received: no treatment, erbium:yttrium-aluminum-garnet (Er:YAG) laser irradiation (400 mJ, 10 Hz, 4 W, 100 MPS, distance: 1 mm), tribochemical silica coating with 30 MUm aluminum oxide (Al(2)O(3)) modified by silica, and air abrasion with 110 MUm Al(2)O(3) particles. After the surface treatments, the surface roughness (Ra in MUm) of the specimens was evaluated using a surface texture measuring instrument. Surface morphology of a specimen from each group was evaluated with atomic force microscope (AFM) and scanning electron microscope (SEM) analyses. The surface roughness values were statistically analyzed by the Kruskal-Wallis and Mann-Whitney U tests (p = 0.05). All of the surface treatments produced rougher surfaces than the control group (p < 0.005). While there were no significant differences between the surface roughness of laser and silica groups (p > 0.05). SEM and AFM analyses revealed changes in surface topography after surface treatments, especially in the laser group with the formation of rare pits and in the silica and air abrasion groups with the formation of microretentive grooves. According to the results of the statistical and microscopic analyses, all of the surface treatments can be used for roughening zirconia prior to cementation; however, air abrasion is the most effective surface treatment to obtain micromechanical retention. PMID- 21786140 TI - Microhardness and polymerization shrinkage of flowable resins that are light cured using a blue laser. AB - This study evaluated the microhardness and polymerization shrinkage of flowable resins that are cured using different light sources. Seven flowable resins and two light sources (diode-pumped solid-state (DPSS) laser (LAS) and Optilux 501 (OP)) were chosen for the study. To evaluate the microhardness, a mold (height: 2 mm, inner diameter: 4 mm) was filled with resin and then light cured. The microhardness was measured at the top and bottom surfaces after aging for 24 h. The level of polymerization shrinkage was evaluated for 130 s (during and after the light curing) by measuring the dimensions of the cylindrical shape resin filling. The light intensity of the LAS and OP was approximately 520 mW/cm(2) and 800 mW/cm(2), respectively. The data for the microhardness and polymerization shrinkage were analyzed statistically. The microhardness (Hv) of the specimens at the top and bottom surface ranged from 25.3 +/- 0.6 to 55.3 +/- 1.0 and 28.0 +/- 2.6 to 63.0 +/- 2.3, respectively. Admira flow, Grandio flow, and Filtek Z350 flow showed a slightly higher microhardness at the bottom surface than that at the top surface. The degree of polymerization shrinkage (MUm) of the specimens ranged from 30.5 +/- 1.3 to 45.9 +/- 0.6 for LAS and from 35.1 +/- 1.5 to 47.1 +/ 1.0 for OP. The values obtained using LAS and OP showed a statistical difference, but in many cases, the difference between the absolute values was minor. PMID- 21786141 TI - The incidence of lymphocytic thyroid infiltration and Hashimoto's thyroiditis increased in patients operated for benign goiter over a 31-year period. AB - The incidence of Hashimoto's thyroiditis (HT) seems to have increased over the last several decades. Since there is a lack of recent studies in the literature that evaluate this phenomenon on a histological basis, we aimed to assess the incidence of lymphocytic thyroid infiltration (LTI) in our large surgical patient collective over a 31-year period. In our study, a total of 1,050 patients who had undergone uni- or bilateral thyroid surgery for benign goiter were included (150 patients in each group, during 1979 to 2009). The stored histological sections of the removed thyroid specimens were re-analyzed, including routine grading of LTI severity on a scale of 0-4, according to Williams and Doniach. Positive correlations were seen for the incidences of LTI grading (0-4) (r = 0.077, p = 0.013) and HT (r = 0.044, p = 0.078) over the years. Furthermore, when comparing the years 1979-1989 and 1994-2009, i.e., before and after the second iodine prophylaxis had been introduced in Austria, a higher incidence of HT was found for the later years (2 out of 450, 0.4%, vs. 6 out of 600, 1.0%, respectively; p < 0.0001). In conclusion, the data demonstrate that the incidence of LTI and HT has increased substantially over the last 31 years. PMID- 21786142 TI - Genetic basis of cystinosis in Turkish patients: a single-center experience. AB - We report the molecular findings for the CTNS gene in 12 Turkish cystinosis patients aged 7-29 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Cystinosis was diagnosed at age 1 month to 9 years. Seven patients reached end-stage renal failure at ages ranging from 6.5 to 15 years. Whereas three of the remaining five have renal Fanconi syndrome with proteinuria, two have had kidney failure of varying degrees. Molecular analyses involved an initial multiplex polymerase chain reaction (PCR) to determine the presence or absence of the 57-kb northern European founder deletion in CTNS, followed by sequencing of the ten coding exons of CTNS. Comprehensive mutation analysis verified that none of the 12 patients carried the common 57-kb deletion. We identified four previously reported nucleotide variations associated with cystinosis and five new variants: a 10-kb deletion, three missense variants, and a nucleotide substitution in a potential branch point site of intron 4. This study is the first molecular analysis of Turkish cystinosis patients and provides guidance for the molecular diagnosis of cystinosis in this population. PMID- 21786143 TI - Lessons from common markers of tumor-initiating cells in solid cancers. AB - Tumor-initiating cells (TICs) have emerged as the driving force of carcinomas, which appear as hierarchically structured. TICs as opposed to the tumor bulk display tumor forming potential, which is linked to a certain degree of self renewal and differentiation, both major features of stem cells. Markers such as CD44, CD133, CD24, EpCAM, CD166, Lgr5, CD47, and ALDH have been described, which allow for the prospective enrichment of TICs. It is conspicuous that the same markers allow for an enrichment of TICs in various entities and, on the other hand, that different combinations of these markers were independently reported for the same tumor entity. Potential functions of these markers in the regulation of TIC phenotypes remained somewhat neglected although they might give insights in common molecular themes of TICs. The present review discusses major TIC markers with respect to their function and potential contributions to the tumorigenic phenotype of TICs. PMID- 21786145 TI - Effects of working memory load on performance and cardiovascular activity in younger and older workers. AB - BACKGROUND: Working memory (WM) declines with ageing, and this may cause problems in older workers who have to do complex work requiring WM. PURPOSE: We tested the assumption that an increase in WM load negatively affects performance and results in impaired cardiovascular adaptation to changing task demands in older workers relative to younger ones. METHOD: Thirty-three younger (29 +/- 3 years) and 32 older (55 +/- 3 years) workers had to perform a visual 0-back (low WM load) and 2 back (high WM load) task. Heart rate (HR), heart rate variability (HRV), beat-to beat blood pressure (BP) and baroreflex were registered. RESULTS: In the high WM load condition, older adults responded more slowly and less accurately than younger adults, while no age effects in the low WM load condition were found. Older workers showed a higher systolic blood pressure (SBP) reactivity to high WM load as well as a diminished post-task recovery of SBP and HRV than younger workers. Factor analysis demonstrated a close relationship between HR, baroreflex and HRV and their modulation by a common factor ("vagal tone") in the younger group. By contrast, HR was more related to the "sympathetic" factor in the older group. CONCLUSION: The data suggest that older workers as compared with younger ones are impaired in tasks requiring WM, which is accompanied by enhanced cardiovascular "costs" in terms of increased SBP and reduced vagal control over HR. PMID- 21786144 TI - Specification of neuronal and glial subtypes from human pluripotent stem cells. AB - Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide a dynamic tool for revealing early embryonic development, modeling pathological processes, and developing therapeutics through drug discovery and potential cell replacement. The first step toward the utilities of human PSCs is directed differentiation to functionally specialized cell/tissue types. Following developmental principles, human ESCs, and lately iPSCs, have been effectively differentiated to region- and/or transmitter-specific neuronal and glial types, including cerebral glutamatergic, striatal gamma-aminobutyric acid (GABA)-ergic, forebrain cholinergic, midbrain dopaminergic, and spinal motor neurons, as well as astrocytes and oligodendrocytes. These studies also reveal unique aspects of human cell biology, including intrinsically programmed developmental course, differential uses of transcription factors for neuroectoderm specification, and distinct responses to extracellular signals in regulating cell fate. Such information will be instrumental in translating biological findings to therapeutic development. PMID- 21786146 TI - Round ligament lipoma mimicking acute appendicitis in a 24-week pregnant female: a case report. AB - An exhaustive search of the literature using the Pub Med database revealed no reports of round ligament lipomas mimicking acute appendicitis in pregnant patients. There are relatively few articles on round ligament lipomas and even less on round ligament lipomas during pregnancy. This case report is on a 27-year old 24-week pregnant female who presented with signs and symptoms similar to acute appendicitis who in fact had a large right pelvic round ligament lipoma that was causing her pain. PMID- 21786147 TI - Bilateral inguinal hernia repair. PMID- 21786148 TI - Outcome of components separation for contaminated complex abdominal wall defects. AB - BACKGROUND: Contaminated large abdominal wall defects can pose a formidable challenge to the surgeon. This study compared the outcome of components separation (CS) for complex ventral defects with or without contamination. METHODS: A retrospective review was conducted of all patients who underwent CS over an 8-year period. Pre-operative factors such as the presence/absence of contamination were analyzed for their effect on length of hospitalization, readmission rate, post-operative complications, re-intervention rate, and long term recurrence. RESULTS: A total of 34 patients was analyzed. There were 18 males (53%) with a mean age of 57 years. Mean body mass index was 31 kg/m(2). Seventeen patients (50%) had prior repair (mean 2.1 repairs per patient, median 2). Mean size of abdominal defect was 255 cm(2). Out of the 34 patients, 13 had infected or contaminated defects, including 5 patients with infected mesh. Length of stay was longer in the contaminated group (11.1 vs 3.1 days, P < 0.01). A higher complication rate was noted in the setting of contamination (77 vs 38%, P = 0.03). During a mean follow-up of 47 months, no difference was noted in the re intervention rate (38 vs 29%, P = 0.70) or long-term recurrence rate of the defect (8 vs 5%, P = 1.0) (contaminated vs non-contaminated group, respectively). CONCLUSIONS: CS is a good option for closure of large contaminated complex abdominal wall defects. Despite an increased risk of postoperative complications and longer hospitalization length, long-term outcomes are favorable. PMID- 21786149 TI - L-2-oxothiazolidine-4-carboxylate influence on age- and heat exposure-dependent redox changes in rat's blood plasma. AB - In the present study, we investigated both the age- and heat exposure-related redox changes of blood plasma by analyzing GSH, thiol status and carbonyl groups. Our results clearly indicated that the plasma redox balance shifted toward oxidation during both aging and acute heat exposure. To further confirm this age- and heat exposure-related redox shift, we quantified the changes in thiol content. The total thiol level was found to be significantly decreased in the aged group. A similar pattern can be explained by low levels of serum GSH in old rats compared to young rats. The significance of the present study are the data showing increased oxidative stress in plasma during aging, attributed to a decrease in major antioxidant components in serum. OTC treatment, in relation to C=O regarded as a marker of oxidative damage was probably much more effective in increasing of GSH synthesis than in prevention of protein oxidation. PMID- 21786150 TI - Cerebral hyperperfusion syndrome remains under-recognized. PMID- 21786151 TI - High lipoprotein(a) serum levels in three CADASIL families. PMID- 21786152 TI - Person centred care and shared decision making: implications for ethics, public health and research. AB - This paper presents a systematic account of ethical issues actualised in different areas, as well as at different levels and stages of health care, by introducing organisational and other procedures that embody a shift towards person centred care and shared decision-making (PCC/SDM). The analysis builds on general ethical theory and earlier work on aspects of PCC/SDM relevant from an ethics perspective. This account leads up to a number of theoretical as well as empirical and practice oriented issues that, in view of broad advancements towards PCC/SDM, need to be considered by health care ethics researchers. Given a PCC/SDM-based reorientation of health care practice, such ethics research is essential from a quality assurance perspective. PMID- 21786154 TI - High site fidelity and low site connectivity in temperate salt marsh fish populations: a stable isotope approach. AB - Adult and juvenile fish utilise salt marshes for food and shelter at high tide, moving into adjacent sublittoral regions during low tide. Understanding whether there are high levels of site fidelity for different species of coastal fish has important implications for habitat conservation and the design of marine protected areas. We hypothesised that common salt marsh fish species would demonstrate a high site fidelity, resulting in minimal inter-marsh connectivity. Carbon ((13)C) and nitrogen ((15)N) stable isotope ratios of larvae and juveniles of five common salt marsh fish (Atherina presbyter, Chelon labrosus, Clupea harengus, Dicentrarchus labrax, Pomatoschistus microps), seven types of primary producer and seven secondary consumer food sources were sampled in five salt marshes within two estuary complexes along the coast of south-east England. Significant differences in (13)C and (15)N signatures between salt marshes indicated distinct sub-populations utilising the area of estuary around each salt marsh, and limited connectivity, even within the same estuary complex. (15)N ratios were responsible for the majority of inter-marsh differences for each species and showed similar site-specific patterns in ratios in primary producers, secondary consumers and fish. Fish diets (derived from isotope mixing models) varied between species but were mostly consistent between marsh sites, indicating that dietary shifts were not the source of variability of the inter-marsh isotopic signatures within species. These results demonstrate that for some common coastal fish species, high levels of site fidelity result in individual salt marshes operating as discrete habitats for fish assemblages. PMID- 21786153 TI - Discrimination of 'driver' and 'passenger' HPV in tonsillar carcinomas by the polymerase chain reaction, chromogenic in situ hybridization, and p16(INK4a) immunohistochemistry. AB - Human papillomavirus (HPV) positive tonsillar squamous cell carcinoma (TSCC) is associated with a favorable clinical outcome. However, the HPV detected in a given tumor may be causal (driver HPV) or an incidental bystander (passenger HPV). There is a need to discriminate these forms of HPV in TSCCs to understand their impact on HPV as a biomarker for use in TSCC patient management. This study has compared the polymerase chain reaction (PCR), chromogenic in situ hybridization (CISH), and p16(INK4a) immunohistochemistry in the assessment of HPV status in TSCC. Archival specimens of TSCC from thirty patients were investigated. HPV was detected by PCR in 25/30 (83.3%) tumors; HPV16 (70.0%) and HPV52 (6.7%) were the most common types. HPV was corroborated by CISH in 22/25 (88.0%) specimens; integrated HPV was implicated by the presence of punctate signals in each of these cases. p16(INK4a) staining was found in 20/22 (90.9%) HPV PCR positive samples; two PCR/CISH HPV positive cases were p16(INK4a) negative and two HPV negative samples were p16(INK4a) positive. These data suggest that a minority of HPV positive TSCCs are positive for passenger HPV and that two or more assays may be required for diagnosing driver HPV status. Further studies are required to exam whether oropharyngeal tumors positive for passenger HPV have a less favorable prognosis than tumors that are driver HPV positive. The clinical significance of TSCCs that test HPV negative/p16(INK4a) positive, PCR and CISH HPV positive/p16 (INK4a) negative, or PCR HPV positive/p16 (INK4a) and CISH negative, also requires further investigation. PMID- 21786155 TI - Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. AB - AIMS/HYPOTHESIS: Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined. RESULTS: Administration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation. CONCLUSIONS/INTERPRETATION: Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins. PMID- 21786157 TI - Complete mitochondrial genome sequence of the spinyhead croaker Collichthys lucidus (Perciformes, Sciaenidae) with phylogenetic considerations. AB - The complete mitochondrial genome of the spinyhead croaker Collichthys lucidus was determined using long-PCR and primer walking methods. It is a circular molecule of 16,451 bp in length with a standard set of 22 tRNAs, 2 rRNAs, 13 protein-coding genes as well as a non-coding control region in the same order as those of the other bony fishes. C. lucidus mitogenome exhibited a clear strand specific bias in nucleotide composition, as evidence by a GC- skew of the H strand of -0.319. The strand-specific bias was also reflected in the codon usage of genes oriented in opposite directions. All tRNA genes except for tRNA( Ser(AGY)) harbored the typical cloverleaf secondary structures and possessed anticodons that matched the vertebrate mitochondrial genetic code. Contrary to the typical structure of control region consistig of TAS, central, and CSB domains, there were no central conserved blocks available in C. lucidus mitogenome. Despite extensive studies based on both morphology and molecules, phylogenetic position of C. lucidus with Sciaenidae is still controversial. Our phylogenetic results provided more evidence to support previous morphological studies and consistently placed C. lucidus as a sister taxon to Collichthys niveatus, with both of these taxa forming the monophyletic Collichthys. PMID- 21786156 TI - Molecular characterization of a cucumber nitrate reductase (CsNR) gene under NO(3) (-) stress. AB - Nitrate reductase is a key enzyme in the overall process of nitrate assimilation by plants. A full-length cDNA clone encoding nitrate reductase (NR; EC 1.6.6.1) was isolated from cucumber (Cucumis sativus L.) by RT-PCR and RACE techniques. The NR of cucumber (CsNR), a full-length cDNA sequence of 3032 bp contains an open reading frame of 2748 bp encoding 915 amino acids. The deduced 915 amino acid sequence showed high identities with NR from other plants. Quantitative real time PCR analysis indicated that CsNR expression was different in root, stem, leaf, flower and mature fruit tissues. CsNR transcript level and nitrate reductase activity (NRA) was down-regulated and the change in NO(3) (-) concentration showed a negative trend with NRA in leaves when subjected to the 182 mM NO(3) (-) treatment. However, the CsNR transcript level was up-regulated in roots by 182 mM NO(3) (-) treatment. Furthermore, NRA in roots lagged behind CsNR expression and there was no obvious lag of NRA in leaves. This study found that in roots, there was no obvious relationship between NRA and NO(3) (-) content. These results indicated that NRA was not only controlled by the level of CsNR mRNA and there was an obvious negative relationship between NO(3) (-) content and NRA in leaves but not in roots. PMID- 21786158 TI - NUDT6, the FGF-2's antisense gene, showed associations with fat deposition related traits in pigs. AB - The nudix (nucleoside diphosphate linked moiety X)-type motif 6 (Nudt6) belongs to the cytosolic Nudix hydrolase family genes, and it has been identified as a fibroblast growth factor 2 (Fgf-2)'s anti-sense gene in humans and rats, and can regulate Fgf-2 stability by its 3' un-translated region (UTR) of mRNA. Here we cloned two completed mRNA of porcine NUDT6 variant transcripts and then analyzed the overlapping relationships of 3'UTR ends between NUDT6 and FGF-2 genes. The expression patterns of NUDT6 were detected in heart, liver, spleen, lung, kidney, muscle and fat tissues, suggesting a widespread mRNA expression of this gene in pigs. The real-time PCR results revealed the reverse expression patterns of NUDT6 and FGF-2 in Tongcheng and Yorkshire pig's tissues including heart, live, spleen, lung, kidney and fat tissues. A C/T single nucleotide polymorphism in NUDT6 was genotyped in two experimental populations, and the association analyses revealed that it was significantly associated with intramuscular fat percentage (P < 0.01) and intramuscular lipid (P < 0.05) in experiment population 1, and it was significantly associated with percentage of leaf and caul fat (P < 0.05), percentage of leaf fat (P < 0.05), proportion of lean and bone of the ham (P < 0.05) in experimental population 2. The findings from this study could offer new evidences that NUDT6 maybe a candidate gene for fat deposition in pigs. PMID- 21786159 TI - Association of two porcine reproductive and respiratory syndrome virus (PRRSV) receptor genes, CD163 and SN with immune traits. AB - CD163 and sialoadhesin (SN) were reported as two essential receptors for the porcine reproductive and respiratory syndrome virus. To investigate the relationship between these two genes and porcine immunity, we assigned porcine CD163 and SN respectively to SSC5q21-q24 and SSC17q23 by IMpRH. Expression profiles revealed that CD163 and SN were ubiquitously expressed in ten tissues, and were expressed highly in lymph gland, spleen and liver, which implied the potential functions of CD163 and SN in immunity. Moreover, a single nucleotide polymorphism (SNP) c.3534C>T was found in 3'-UTR of the CD163 gene and association analysis showed that this gene was significantly associated with the IgG content in blood (P < 0.05). A novel missense mutation c.878A>G located in exon4 of the SN gene which caused the amino acid transition from histidine to arginine was detected, and it was significantly associated with the WBC count in the peripheral blood (P < 0.05). These results provided fundamental evidence for CD163 and SN as two functional candidate genes affecting immunity in pigs. PMID- 21786160 TI - Sequence-structural features and evolutionary relationships of family GH57 alpha amylases and their putative alpha-amylase-like homologues. AB - The glycoside hydrolase family 57 (GH57) contains alpha-amylase and a few other amylolytic specificities. It counts ~400 members from Archaea (1/4) and Bacteria (3/4), mostly of extremophilic prokaryotes. Only 17 GH57 enzymes have been biochemically characterized. The main goal of the present bioinformatics study was to analyze sequences having the clear GH57 alpha-amylase features. Of the 107 GH57 sequences, 59 were evaluated as alpha-amylases (containing both GH57 catalytic residues), whereas 48 were assigned as GH57 alpha-amylase-like proteins (having a substitution in one or both catalytic residues). Forty-eight of 59 alpha-amylases were from Archaea, but 42 of 48 alpha-amylase-like proteins were of bacterial origin. The catalytic residues were substituted in most cases in Bacteroides and Prevotella by serine (instead of catalytic nucleophile glutamate) and glutamate (instead of proton donor aspartate). The GH57 alpha-amylase specificity has thus been evolved and kept enzymatically active mainly in Archaea. PMID- 21786161 TI - Estimation of the diagnostic accuracy of the glyco-C and US9 gene-based polymerase chain reaction technique for the detection of bovine Herpesvirus type 5 DNA in decomposed brain suspension from a slaughter house using Bayesian analysis, Brazil. AB - Brazil represents the greatest beef producer among tropical countries, and the major obstacle for meat international trade is sanitary problems especially closely related to viral encephalitis. The goal of this study was to estimate the accuracy of the glycol and US9 gene-based polymerase chain reactions (PCRs) for the detection of bovine Herpesvirus type 5 (BoHV-5) from decomposed brain samples (n = 95). For this purpose, a latent-class (bayesian) approach was used. Sensitivity (Se) was estimated to be 70% (95% probability interval, 40-80) and specificity (Sp) 100% in the statistical analysis for both PCRs used. Accordingly, a minimum of >=40% of the calves was estimated to harbor BoHV-5 DNA even after 72 h of decomposition at room temperature. It was concluded that US9 gene-based PCR could also be considered a cost-effective alternative in sanitary programmers. However, given the importance of veterinary diagnoses, PCR-positive samples should be further confirmed through in vitro isolation and/or sequencing. PMID- 21786162 TI - Feed intake and utilization in sheep fed graded levels of dried moringa (Moringa stenopetala) leaf as a supplement to Rhodes grass hay. AB - The effects of feeding graded levels of dried moringa (Moringa stenopetala) leaf on intake, body weight gain (BWG), digestibility and nitrogen utilization were studied using male sheep (BW of 13.8 +/- 0.12 kg). Six sheep were randomly allocated to each of the four treatment diets: Rhodes grass (Chloris gayana) hay offered ad libitum (T1), hay + 150 g moringa leaf (T2), hay + 300 g moringa leaf (T3), hay + 450 g moringa leaf (T4) were offered daily. A 7-day digestibility trial and an 84-day growth experiments were conducted. Dry matter (DM), organic matter (OM) and crude protein (CP) intakes increased (P < 0.05) with increasing levels of moringa leaf in the diets. Sheep fed T2, T3 and T4 diets gained (P < 0.05) 40.2, 79.1 and 110.1 g/head/day, respectively, while the control group (T1) lost weight (-13.3 g/head/day). The apparent digestibilities of DM, OM, neutral detergent fibre and acid detergent fibre were similar (P > 0.05) among treatments. The digestibility of dietary CP increased (P < 0.05) with increasing levels of moringa leaf, but there was no significant difference between T2 and T3 diets. The nitrogen (N) intake and urinary N excretion increased (P < 0.05) with increasing levels of moringa leaf. The N retention was highest (P < 0.05) for 450 g moringa leaf supplementation. The control group was in a negative N balance. Supplementing a basal diet of Rhodes grass hay with dried moringa leaves improved DM intake, BWG and N retention. It is concluded that M. stenopetala can serve as a protein supplement to low-quality grass during the dry season under smallholder sheep production system. PMID- 21786163 TI - Non-invasive pulmonary perfusion assessment in young patients with cystic fibrosis using an arterial spin labeling MR technique at 1.5 T. AB - OBJECT: To assess lung perfusion in young patients with cystic fibrosis (CF) using an arterial spin labeling (ASL) technique. MATERIALS AND METHODS: Perfusion imaging was performed in 5 healthy volunteers and 33 pediatric patients (13 +/- 5 years) with CF using an ASL technique. Image quality was evaluated on a five point scale (1 = excellent). Quantitative perfusion maps were calculated based on the modified Bloch equations. Perfusion differences between volunteers and CF patients and regional differences between lobes were analyzed using Student's t test. The association of perfusion values and forced expiratory volume in 1 s (FEV1) was analyzed using univariate regression analysis. RESULTS: Mean lung perfusion was 698 +/- 67 ml/100g/min (range: 593-777 ml/100g/min) in volunteers and 526 +/- 113 ml/100g/min (range: 346-724 ml/100g/min) in CF patients. Median image quality was 2 in volunteers and 3 in CF patients. In CF patients, significantly lower perfusion was observed in the upper lobes compared to healthy volunteers. Mean perfusion values significantly correlated with FEV1 (r = 0.84, P < 0.0001). CONCLUSION: ASL perfusion imaging provides lung perfusion assessment in young CF patients. This non-invasive functional imaging technique is worth being evaluated in the clinical monitoring of CF patients. PMID- 21786164 TI - Duration of wound fluid secretion from chronic venous leg ulcers is critical for interleukin-1alpha, interleukin-1beta, interleukin-8 levels and fibroblast activation. AB - Wound fluid collected from chronic wounds may be used as a simple gauge of the processes taking place in the tissue. There is lack of information on the optimal conditions for wound fluid procurement. We have studied possible diurnal variations and duration of wound fluid accumulation using retentive hydrophobic foam on the levels of prototypic cytokines [interleukin (IL)-1alpha, IL-1beta], a chemokine (IL-8) and proteinases [matrix metalloproteinase (MMP)-9] in 23 chronic venous leg ulcer patients. Bioactivity of 1 and 24 h wound fluids, and serum was also compared. There were no significant temporal changes in the levels of the above-mentioned four proteins, when comparing three consecutive 8-h intervals starting from 0800 that in turn did not differ significantly with the 24-h collection levels. IL-1alpha, IL-1beta and IL-8 levels were higher (p < 0.05) in 24 h compared with 1 h wound fluids, whereas MMP-9 levels were insensitive to the length of collection. The 24 h wound fluids did not elicit DNA synthesis in adult human dermal fibroblasts in contrast to the 1 h wound fluids (p = 0.046) and serum (p = 0.036). The polyurethane foam alone had no significant effects on the concentration of the examined analytes. The length of collection is critical when monitoring cytokine/chemokine and bioactivity levels of chronic wound fluid. The removal of accumulating unfavorable factors in chronic wound fluid may be important in wound management. PMID- 21786165 TI - Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways. AB - Celastrol, a plant triterpene has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. In the present report, we investigated the effect of celastrol on proliferation of various cancer cell lines. The mechanism, by which this triterpene exerts its apoptotic effects, was also examined in detail. We found that celastrol inhibited the proliferation of wide variety of human tumor cell types including multiple myeloma, hepatocellular carcinoma, gastric cancer, prostate cancer, renal cell carcinoma, head and neck carcinoma, non-small cell lung carcinoma, melanoma, glioma, and breast cancer with concentrations as low as 1 MUM. Growth inhibitory effects of celastrol correlated with a decrease in the levels of cyclin D1 and cyclin E, but concomitant increase in the levels of p21 and p27. The apoptosis induced by celastrol was indicated by the activation of caspase-8, bid cleavage, caspase-9 activation, caspase-3 activation, PARP cleavage and through the down regulation of anti-apoptototic proteins. The apoptotic effects of celastrol were preceded by activation of JNK and down-regulation of Akt activation. JNK was needed for celastrol-induced apoptosis, and inhibition of JNK by pharmacological inhibitor abolished the apoptotic effects. Overall, our results indicate that celastrol can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and down-regulation of anti-apoptotic protein expression. PMID- 21786166 TI - A neonatal brain MR image template of 1 week newborn. AB - PURPOSE: Magnetic resonance imaging (MRI) is often used to detect and treat neonatal cerebral disorders. However, neonatal MR image interpretation is limited by intra- and inter-observer variability. To reduce such variability, a template based computer-aided diagnosis system is being developed, and several methods for creating templates were evaluated. METHOD: Spatial normalization for each individual's MR images is used to accommodate the individual variation in brain shape. Because the conventional normalization uses as adult brain template, it can be difficult to analyze the neonatal brain, as there are large difference between the adult brain and the neonatal brain. This article investigates three approaches for defining a neonatal template for 1-week-old newborns for diagnosing neonatal cerebral disorders. The first approach uses an individual neonatal head as the template. The second approach applies skull stripping to the first approach, and the third approach produces a template by averaging brain MR images of 7 neonates. To validate the approaches, the normalization accuracy was evaluated using mutual information and anatomical landmarks. RESULTS: The experimental results of 7 neonates (revised age 5.6 +/- 17.6 days) showed that normalization accuracy was significantly higher with the third approach than with the conventional adult template and the other two approaches (P < 0.01). CONCLUSION: Three approaches to neonatal brain template matching for spinal normalization of MRI scans were applied, demonstrating that a population average gave the best results. PMID- 21786167 TI - Actin cytoskeleton in the extra-ovular embryo sac of Utricularia nelumbifolia (Lentibulariaceae). AB - The actin cytoskeleton in the mature female gametophyte of angiosperms has been examined in only a few dicot and monocot species. The main purposes of this study were to identify how the actin cytoskeleton is arranged in the mature extra ovular embryo sac in Utricularia nelumbifolia (Lentibulariaceae). We found that the extra-ovular part of the central cell has a well-developed actin cytoskeleton: actin microfilaments formed of long strands which run longitudinally or transversally to the long axis of the embryo sac. The exerted part of the central cell, which is exposed to the environment of the ovary chamber, is highly vacuolated and in the thin peripheral cytoplasm possesses a complicated network of actin microfilaments. The epidermal cells of the placenta that are in contact with the extra-ovular part of the embryo sac are crushed. The ultrastructure data of these cells are presented. We detected the accumulation of the actin cytoskeleton between the micropylar parts of the synergids and the extra-ovular part of central cell. This actin accumulation is unusual because in typical angiosperms the micropylar parts of the synergids form the apex of the female gametophyte. PMID- 21786168 TI - Centrins in unicellular organisms: functional diversity and specialization. AB - Centrins (also known as caltractins) are conserved, EF hand-containing proteins ubiquitously found in eukaryotes. Similar to calmodulins, the calcium-binding EF hands in centrins fold into two structurally similar domains separated by an alpha-helical linker region, shaping like a dumbbell. The small size (15-22 kDa) and domain organization of centrins and their functional diversity/specialization make them an ideal system to study protein structure-function relationship. Here, we review the work on centrins with a focus on their structures and functions characterized in unicellular organisms. PMID- 21786169 TI - Valproic acid induced differentiation and potentiated efficacy of taxol and nanotaxol for controlling growth of human glioblastoma LN18 and T98G cells. AB - Glioblastoma shows poor response to current therapies and warrants new therapeutic strategies. We examined the efficacy of combination of valproic acid (VPA) and taxol (TX) or nanotaxol (NTX) in human glioblastoma LN18 and T98G cell lines. Cell differentiation was manifested in changes in morphological features and biochemical markers. Cell growth was controlled with down regulation of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NF-kappaB), phospho-Akt (p-Akt), and multi-drug resistance (MDR) marker, indicating suppression of angiogenic, survival, and multi-drug resistance pathways. Cell cycle analysis showed that combination therapy (VPA and TX or NTX) increased the apoptotic sub G1 population and apoptosis was further confirmed by Annexin V-FITC/PI binding assay and scanning electron microscopy. Combination therapy caused activation of caspase-8 and cleavage of Bid to tBid and increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF). Upregulation of calpain and caspases (caspase-9 and caspase-3) and substrate degradation were also detected in course of apoptosis. The combination of VPA and NTX most effectively controlled the growth of LN18 and T98G cells. Therefore, this combination of drugs can be used as an effective treatment for controlling growth of human glioblastoma cells. PMID- 21786170 TI - Gelsolin in cerebrospinal fluid as a potential biomarker of epilepsy. AB - Gelsolin is an actin regulatory protein that generally distributed in a wide variety of body tissues, especially the brain tissues and cerebrospinal fluid. In this study we found that lumbar CSF-gelsolin concentrations markedly decreased in epileptic patients by enzyme linked immunosorbent assay. In order to help judge the result, we determined gelsolin expression in temporal lobe tissues of patients with temporal lobe epilepsy using double-label immunofluorescence to location and using western blot to quantitation. Then we observed that gelsolin was co-expressed with microtubule-associated protein-2 in axons and cytoplasms of neurons and gelsolin protein level was also down-regulated in temporal lobe tissues of epileptic patients. Our findings suggested that CSF-gelsolin level might reflect the alteration of gelsolin in brain tissue of epileptic patients and CSF-gelsolin seems to be a potential biomarker for epilepsy. PMID- 21786171 TI - Prospective, longitudinal study of plastic bronchitis cast pathology and responsiveness to tissue plasminogen activator. AB - Plastic bronchitis (PB) is a rare disease that often occurs in patients with congenital heart disease (CHD) who have undergone staged single-ventricle palliation. It is characterized by the formation of rubbery "casts" in the airways. PB treatment frequently includes inhaled tissue plasminogen activator (tPA). However, the efficacy of tPA to reduce cast burden is unknown. This is further complicated by our lack of knowledge of cast composition. We obtained spontaneously expectorated PB casts from children (n = 4) with CHD and one adult patient with idiopathic PB. Pathological assessment was made from paraffin preserved samples. Casts were treated with phosphate-buffered saline (PBS) or tPA. Cast response to tPA was assessed by changes in cast weight and the production of fibrin D-dimer. Independent of dose, tPA reduced cast weight compared with PBS-treatment (P = 0.001) and increased D-dimer levels. Histological staining showed that PB casts from all patients were composed of fibrin and contained notable numbers of lymphocytes. Cast composition did not change over time. Collectively, these data support that in our PB patients, casts are composed of fibrin and are responsive to tPA treatment. This makes inhaled tPA a potentially viable option for symptomatic relief of PB while we work to unravel the complexity of PB pathogenesis. PMID- 21786173 TI - Hairy roots cultures from different Solanaceous species have varying capacities to produce E. coli B-subunit heat-labile toxin antigen. AB - The gene encoding enterotoxigenic Escherichia coli B-subunit heat-labile toxin (LTB) antigen was co-transformed into hairy root cultures of Nicotiana tabacum (tobacco), Solanum lycopersicum (tomato) and Petunia parodii (petunia) under the CaMV35S promoter. Tobacco and petunia roots contained ~65-70 MUg LTB g(-1) tissue whilst hairy roots of tomato contained ~10 MUg LTB g(-1). Antigen at ~600 ng ml( 1) was detected in growth medium of tobacco and petunia. Tobacco roots with higher LTB levels showed growth retardation of ~80% whereas petunia hairy roots with similar levels of LTB showed only ~35% growth retardation, relative to vector controls. Regeneration of plants from LTB-containing tobacco hairy roots was readily achieved and re-initiated hairy roots from greenhouse-grown plants showed similar growth and LTB production characteristics as the original hairy root cultures. PMID- 21786172 TI - Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors. AB - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q (2) = 0.696 and r (2) = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q (2) = 0.711 and r (2) = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r (2) (pred) values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials. PMID- 21786174 TI - To fuse or not to fuse in lumbar degenerative spondylolisthesis: do baseline symptoms help provide the answer? AB - INTRODUCTION: Clinical symptoms in lumbar degenerative spondylolisthesis (LDS) vary from predominantly radiating pain to severe mechanical low back pain. We examined whether the outcome of surgery for LDS varied depending on the predominant baseline symptom and the treatment administered [decompression with fusion (D&F) or decompression alone (D)]. METHODS: 213 consecutive patients (69 +/- 9 years; 155f, 58 m) participated. Inclusion criteria were LDS, maximum three affected levels, no previous surgery at the affected level, and D (N = 56) or D&F (N = 157) as the operative procedure. Pre-op and at 12 months' follow-up (FU), patients completed the multidimensional Core Outcome Measures Index (COMI) including 0-10 leg-pain (LP) and LBP scales. At 12 months' FU, patients rated global outcome which was then dichotomised into "good" and "poor". RESULTS: Pre operatively, LBP and COMI scores were significantly worse (p < 0.05) in the D&F group than in the D group. The improvement in COMI at 12 months' FU was significantly greater for D&F than for D (p < 0.001) and was not influenced by the patient's declared "main problem" at baseline (back pain, leg pain, or neurological disturbances) (p > 0.05). There was a higher proportion (p = 0.01) of "good" outcomes at 12 months' FU in D&F (86%) than in D (70%). Multiple regression analysis, controlling for possible confounders, revealed treatment group to be the only significant predictor of outcome (adding fusion = better outcome). DISCUSSION: Our study indicated that LDS patients showed better patient based outcome with instrumented fusion and decompression than with decompression alone, regardless of baseline symptoms. This may be due to the fact that the underlying slippage as the cause of the stenosis is better addressed with fusion. PMID- 21786175 TI - Primary intracranial plasma cell granulomas presenting as malignant neoplasms. AB - Plasma cell granuloma (PCG) is an uncommon non-neoplastic mass lesion of unknown etiology. It is characterized by a polyclonal proliferation of chronic inflammatory cells, mostly mature plasma and other mononuclear cells. PCGs arising in the central nervous system are particularly rare. We report two additional cases of intracranial PCG exclusively involving the brain parenchyma. A 47 year-old woman, presenting with partial motor seizures and fluent aphasia, underwent complete excision of a well-demarcated, enhancing left parietal mass. The second patient was a 56 year-old man presenting with headaches and right sided weakness who underwent stereotactic biopsy of an ill-defined, heterogeneously enhancing lesion in the left basal ganglia. Immunohistochemical analysis of surgical specimens showed polyclonal plasma cells and mature lymphocytes but no etiological agent. A histopathologic diagnosis of intracranial PCG was made in both cases. PCG should be part of the differential diagnosis of enhancing mass lesions of the brain. The etiology and natural history of these tumor-like lesions is not fully understood. Complete surgical excision appears to be curative. Lesions where total resection is not possible may benefit from adjuvant treatment including corticosteroids and possibly radiation therapy. PMID- 21786176 TI - Extinction context as a conditioned inhibitor. AB - Two lick suppression experiments using rats were conducted to determine whether extinction of a punctate excitor in a particular context would result in that context becoming a conditioned inhibitor, as defined by passing both summation and retardation tests. The role of extinction trial spacing was investigated as a possible determinant of whether the extinction context would become inhibitory. Experiment 1 demonstrated that, although inhibition was evident using either massed or spaced extinction trials, spaced trials reduced measurable inhibition as assessed by the summation test, but trial spacing had no influence on retardation test performance. Experiment 2 confirmed Experiment 1's conclusions while controlling for the influence of latent inhibition on the retardation test. In Experiment 2, the context proved inhibitory only following massed extinction trials. These data suggest that, at least with select parameters, an extinction context can become inhibitory. PMID- 21786177 TI - Population pharmacokinetic-pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter. AB - Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10 min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia's formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure-response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (E (max)) models. For QTcF, the model was characterized by a typical E (max) of 20.3 ms, and by a vernakalant median effective concentration dependent (EC50) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E (max) of 3.05 mmHg and EC50 of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP. PMID- 21786178 TI - Urgent surgery is needed when cyst enlarges in terminal myelocystoceles. AB - PURPOSE: The phenomenon of cyst enlargement in terminal myelocystocele (TMC) patients has been mentioned in the literature. However, its clinical significance has not been clarified in depth. We reviewed TMC patients who had experienced cyst enlargement during the preoperative period to determine the correlation with symptomatic progression. We sought to determine the optimal surgical strategy for such patients. METHODS: Of eight patients who were operated on for TMC from 1991 to 2009, four patients that showed cyst enlargement before the operation were reviewed. A retrospective review of medical recordings, radiological imaging, and other evaluations for neurologic status was done, focusing on the temporal neurological changes that correlated with the cyst enlargement. RESULTS: Each of the four patients with cyst enlargement showed concurrent progression of neurologic symptoms, two by motor weakness and two by neurogenic bladder. In only one case, early detection and prompt surgery were possible, and this patient showed dramatic improvement in muscle strength after the surgery. The progression of neurologic deterioration was arrested postoperatively for the other three patients. CONCLUSIONS: Hence, cyst enlargement in a TMC patient should be considered as a warning for neurologic deterioration, and the operation should be performed expediently to prevent impairment in neurologic function. PMID- 21786179 TI - Comparative study of the immunohistochemical expression of tissue inhibitors of metalloproteinases 1 and 2 between clearly invasive carcinomas and "in situ" trophoblast invasion. AB - Tissue inhibitors of metalloproteinases (TIMPs) play an important role in extracellular matrix homeostasis by regulating MMP activity. Although they were initially considered inhibitors of tumor growth and metastasis, recently their role in cancer progression has been controversial. The aim of our study was to compare the immunohistochemical expression of TIMP1 and TIMP2 between an uncontrollably invasive phenomenon (cancer) and an "in situ" process (trophoblast invasion) in an effort to assess any differential role of these molecules between these two distinct phenomena and therefore to understand better their contribution in cancer invasion and migration. We performed an immunohistochemical analysis of 50 carcinomas (colorectal, gastric, breast, pulmonary, and renal) and 40 first trimester gestations. The marker expression was evaluated semiquantitatively, separately in cancer parenchymal and trophoblastic cells as well as in malignant stromal and decidual cells, according to a percentage scale (0, <10, 10-50, and >50%) and according to staining intensity (0, +, ++, and +++). Our results showed that there was no statistically significant difference in TIMP1 expression between cancer parenchymal cells and trophoblastic cells. On the other hand, TIMP1 was expressed more often in decidual cells than in cancer stromal cells. Immunostaining for TIMP2 was more extensive and intense both in trophoblastic and decidual cells than in cancer parenchymal and stromal cells, respectively. The reduced expression of TIMP2 in metastatic carcinomas by comparison with non-metastatic gestation specimens underlines its importance in cancer invasion and migration. On the other hand, TIMP1 was more expressed in decidua than cancer stroma, but at the same time showed no statistically significant difference between cancer parenchyma and trophoblasts, highlighting its multifunctional activity in cancer progression. PMID- 21786180 TI - miR-203 expression predicts outcome after liver transplantation for hepatocellular carcinoma in cirrhotic liver. AB - Many recent studies have shown the utility of microRNAs (miRs) as cancer-related biomarkers. The aim of the present study was to evaluate the correlation between miR-203 expression and prognosis of patients with hepatocellular carcinoma (HCC) and cirrhosis after liver transplantation (LT). Sixty-six HCC samples from patients who had undergone LT were examined for miR-203 expression using quantitative reverse transcription-polymerase chain reaction. The data were correlated with clinicopathological parameters and prognosis. Patient survival was analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used for multivariate analysis of prognostic factors. We found that miR-203 expression was low in tumor tissues of patients (n = 16) with post-LT HCC recurrence in comparison with those in patients with non-recurrence (n = 50) (P = 0.003). Patients with higher miR-203 expression had significantly better recurrence-free survival (RFS) and overall survival (OS) (P = 0.016 for RFS; P = 0.014 for OS). Multivariate analysis revealed that high-miR-203 expression was an independent predictor of good prognosis (HR 0.202, P = 0.006 for RFS; HR 0.332, P = 0.013 for OS). Our results suggest that miR-203 could be a novel prognostic marker in HCC patients who have undergone LT and might also be a potential therapeutic target. PMID- 21786181 TI - A plea for the wider use of CRT-P in candidates for cardiac resynchronisation therapy. AB - Spectacular developments have taken place, in the last 10 years, in the device based management of heart failure (HF). Patients presenting with chronic HF may benefit from a device implanted with a view to: (1) resynchronise the pump function of a discoordinated failing heart or (2) prevent sudden arrhythmic death by automatic cardioversion or defibrillation. This "point-of-view" article reviews the large amount of information gathered in the past 10 years on the use of cardiac resynchronisation therapy (CRT), with or without cardioverter defibrillator (ICD), and puts in perspective the advisability of using one, the other or both treatments in distinct patient subsets. There is currently no strong scientific evidence supporting the systematic implantation of CRT-ICD (CRT D) instead of CRT pacemakers (CRT-P). Plain common sense should limit the prescription of these costly and complicated devices to patients in need of secondary prevention of ventricular arrhythmias or, for primary prevention, in younger patients without major concomitant illnesses. The preferential choice of CRT-P for the remainder of ambulatory patients in New York Heart Association (NYHA) functional class III or IV is currently acceptable. Because of insufficient data regarding the performance of CRT-P in patients presenting in NYHA functional class I or II, CRT-D is currently the device of choice for this sub-population. PMID- 21786182 TI - Realizing the potential of ecosystem services: a framework for relating ecological changes to economic benefits. AB - Increasingly government agencies are seeking to quantify the outcomes of proposed policy options in terms of ecosystem service benefits, yet conflicting definitions and ad hoc approaches to measuring ecosystem services have created confusion regarding how to rigorously link ecological change to changes in human well-being. Here, we describe a step-by-step framework for producing ecological models and metrics that can effectively serve an economic-benefits assessment of a proposed change in policy or management. A focus of the framework is developing comparable units of ecosystem goods and services to support decision-making, even if outcomes cannot be monetized. Because the challenges to translating ecological changes to outcomes appropriate for economic analyses are many, we discuss examples that demonstrate practical methods and approaches to overcoming data limitations. The numerous difficult decisions that government agencies must make to fairly use and allocate natural resources provides ample opportunity for interdisciplinary teams of natural and social scientists to improve methods for quantifying changes in ecosystem services and their effects on human well-being. This framework is offered with the intent of promoting the success of such teams as they support managers in evaluating the equivalency of ecosystem service offsets and trades, establishing restoration and preservation priorities, and more generally, in developing environmental policy that effectively balances multiple perspectives. PMID- 21786183 TI - Trends of forest dynamics in tiger landscapes across Asia. AB - Protected areas (PAs) are cornerstones of biodiversity conservation, but small parks alone cannot support wide-ranging species, such as the tiger. Hence, forest dynamics in the surrounding landscapes of PAs are also important to tiger conservation. Tiger landscapes often support considerable human population in proximity of the PA, sometimes within the core itself, and thus are subject to various land use activities (such as agricultural expansion and road development) driving habitat loss and fragmentation. We synthesize information from 27 journal articles in 24 tiger landscapes to assess forest-cover dynamics in tiger-range countries. Although 29% of the PAs considered in this study have negligible change in overall forest cover, approximately 71% are undergoing deforestation and fragmentation. Approximately 58% of the total case studies have human settlements within the core area. Most changes-including agricultural expansion, plantation, and farming (52%), fuelwood and fodder collection (43%), logging (38%), grazing (38%), and tourism and development (10%)-can be attributed to human impacts largely linked to the nature of the management regime. This study highlights the need for incorporating new perspectives, ideas, and lessons learned locally and across borders into management plans to ensure tiger conservation in landscapes dominated by human activities. Given the increasing isolation of most parks due to agricultural, infrastructural, and commercial developments at the periphery, it is imperative to conduct planning and evaluation at the landscape level, as well as incorporate multiple actors and institutions in planning, instead of focusing solely on conservation within the PAs as is currently the case in most tiger parks. PMID- 21786184 TI - DNA sequence variation of the tobacco cutworm, Spodoptera litura (Lepidoptera: Noctuidae), determined by mitochondrial A+T-rich region and nuclear ITS2 sequences. AB - In an effort to gain greater insight into the nature of the population genetic structure of the pest insect Spodoptera litura (Lepidoptera: Noctuidae), tobacco cutworms were collected from six Korean and five Chinese localities, and their mitochondrial A+T-rich region and nuclear internal transcribed spacer 2 (ITS2) were cloned and sequenced. The A+T-rich region and nuclear ITS2 provided a maximum sequence divergence of 2.88 and 1.82%, respectively. Overall, a low level of genetic fixation (F(ST) = 0-0.02965 in the A+T-rich region and 0-0.34491 in ITS2) and no discernible isolated population were noted among most S. litura populations. Along with these results, the absence of genetic variance between Korea and China indicates a profound interrelation of the S. litura populations in the two countries, consistent with the current notion that S. litura has sufficient flight capacity for dispersal. PMID- 21786185 TI - Fibrinolysis is down-regulated in mouse collagen-induced arthritis, but its normalization does not alleviate the course of disease. AB - OBJECTIVE: Down-regulation of fibrinolysis and increased fibrin deposition in joints are hallmarks of rheumatoid arthritis (RA), and are believed to be involved in disease progression. The mouse model of collagen-induced arthritis (CIA) closely resembles RA and has been used to explore mechanism and treatments of RA, but neither the fibrinolytic system nor pro-fibrinolytic therapies were investigated in CIA. MATERIALS AND METHODS: Plasmin activity, levels of plasminogen activator inhibitor (PAI-1), D-dimer, and IL-6 were measured in plasma of CIA mice. Fibrin deposition and PAI-1 levels were also measured in inflamed joints. Mice were treated with plasminogen activators uPA (urokinase type plasminogen activator) or tPA (tissue-type plasminogen activator). Effects of treatment on disease severity and fibrinolytic system were assessed. RESULTS: CIA caused decrease in plasmin activity, accompanied by increase in PAI-1 levels, in both blood and inflamed joints. This resulted in massive fibrin deposition in synovium. PAI-1 levels correlated negatively with plasmin activity and positively with IL-6. Treatments with uPA and tPA improved plasmin activity and removed fibrin deposits in inflamed joints. However, disease severity remained unchanged. CONCLUSIONS: Fibrinolytic changes in CIA parallel changes in RA, making CIA a suitable model to study fibrinolysis in RA. Normalization of plasmin activity in CIA after treatment with plasminogen activators had no effect on disease severity. PMID- 21786186 TI - Applying mixed methods to pretest the Pressure Ulcer Quality of Life (PU-QOL) instrument. AB - PURPOSE: Pretesting is key in the development of patient-reported outcome (PRO) instruments. We describe a mixed-methods approach based on interviews and Rasch measurement methods in the pretesting of the Pressure Ulcer Quality of Life (PU QOL) instrument. METHODS: We used cognitive interviews to pretest the PU-QOL in 35 patients with pressure ulcers with the view to identifying problematic items, followed by Rasch analysis to examine response options, appropriateness of the item series and biases due to question ordering (item fit). We then compared findings in an interactive and iterative process to identify potential strengths and weaknesses of PU-QOL items, and guide decision-making about further revisions to items and design/layout. RESULTS: Although cognitive interviews largely supported items, they highlighted problems with layout, response options and comprehension. Findings from the Rasch analysis identified problems with response options through reversed thresholds. CONCLUSIONS: The use of a mixed-methods approach in pretesting the PU-QOL instrument proved beneficial for identifying problems with scale layout, response options and framing/wording of items. Rasch measurement methods are a useful addition to standard qualitative pretesting for evaluating strengths and weaknesses of early stage PRO instruments. PMID- 21786190 TI - Ca2+: a versatile master key for intracellular signaling cascades. PMID- 21786187 TI - Alterations in platelet function and cell-derived microvesicles in recently menopausal women: relationship to metabolic syndrome and atherogenic risk. AB - A woman's risk for metabolic syndrome (MS) increases at menopause, with an associated increase in risk for cardiovascular disease. We hypothesized that early menopause-related changes in platelet activity and concentrations of microvesicles derived from activated blood and vascular cells provide a mechanistic link to the early atherothrombotic process. Thus, platelet functions and cellular origin of blood-borne microvesicles in recently menopausal women (n = 118) enrolled in the Kronos Early Estrogen Prevention Study were correlated with components of MS and noninvasive measures of cardiovascular disease [carotid artery intima medial thickness (CIMT), coronary artery calcium (CAC) score, and endothelial reactive hyperemic index (RHI)]. Specific to individual components of the MS pentad, platelet number increased with increasing waist circumference, and platelet secretion of ATP and expression of P-selectin decreased with increasing blood glucose (p = 0.005) and blood pressure (p < 0.05), respectively. Waist circumference and systolic blood pressure were independently associated with monocyte- and endothelium-derived microvesicles (p < 0.05). Platelet-derived and total procoagulant phosphatidylserine-positive microvesicles, and systolic blood pressure correlated with CIMT (p < 0.05), but not with CAC or RHI. In summary, among recently menopausal women, specific platelet functions and concentrations of circulating activated cell membrane-derived procoagulant microvesicles change with individual components of MS. These cellular changes may explain in part how menopause contributes to MS and, eventually, to cardiovascular disease. PMID- 21786191 TI - The plasma membrane calcium pump in the hearing process: physiology and pathology. AB - Mammalian cells express four different plasma membrane Ca(2+) ATPases. Two of them (PMCA1 and PMCA4) are expressed ubiquitously, and are considered housekeeping isoforms. Two (PMCA2 and PMCA4) have tissue restricted distribution. They are abundantly expressed in the brain and in nervous tissue-derived cell types. The primary transcripts of all PMCAs undergo alternative splicing, generating a large number of additional isoforms. Splicing occurs at site A, in the N-terminal moiety of the pump, and at site C, within the C-terminal calmodulin binding domain: The pumps are canonical targets of calmodulin stimulation. The site C insertion leads to a truncation of the pump about 50 residues short of the original C-terminal. One of the pumps (PMCA2) has special properties: It displays high activity even in the absence of the natural activator calmodulin, and has a particularly complex pattern of alternative splicing at both sites A and C. A variant of the PMCA2 pump containing an insert at site A and truncated C-terminally is the resident isoform of the pump in the stereocilia of hair cells of the inner ear. It exports Ca(2+) to the endolymph that bathes the stereocilia less efficiently than the full length, non-inserted PMCA2 pump. The proper functioning of hair cells demands the precise maintenance of the Ca(2+) balance between hair cells and the endolymph. Disturbances in the balance affect the process of mechano-electrical transduction, which depends on the ability of the stereociliar bundle to deflect in response to sound waves. The tip links that organize the bundle are formed by the Ca(2+) binding protein cadherin 23 and by protocadherin 15: Disturbances of the Ca(2+) binding by cadherin 23 and/or of the ability of the PMCA2 variant of the stereocilia to export Ca(2+) to the endolymph generate hearing loss phenotypes. Such phenotypes have now been described in mice and humans. In some cases they are linked to mutations of both cadherin 23 and the PMCA2 pump, but in other cases they may be generated by mutations of particular severity in only one of the two proteins. The PMCA2 defect that leads to deafness has now been analyzed molecularly: It affects the long range, unstimulated ability of PMCA2 to export Ca(2+). PMID- 21786192 TI - Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps. AB - The plasma membrane calcium ATPases (PMCA) are a family of genes which extrude Ca(2+) from the cell and are involved in the maintenance of intracellular free calcium levels and/or with Ca(2+) signalling, depending on the cell type. In the cardiovascular system, Ca(2+) is not only essential for contraction and relaxation but also has a vital role as a second messenger in signal transduction pathways. A complex array of mechanisms regulate intracellular free calcium levels in the heart and vasculature and a failure in these systems to maintain normal Ca(2+) homeostasis has been linked to both heart failure and hypertension. This article focuses on the functions of PMCA, in particular isoform 4 (PMCA4), in the heart and vasculature and the reported links between PMCAs and contractile function, cardiac hypertrophy, cardiac rhythm and sudden cardiac death, and blood pressure control and hypertension. It is becoming clear that this family of calcium extrusion pumps have essential roles in both cardiovascular health and disease. PMID- 21786193 TI - Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling. AB - The concept advanced by Berridge and colleagues that intracellular Ca(2+)-stores can be mobilized in an agonist-dependent and messenger (IP(3))-mediated manner has put Ca(2+)-mobilization at the center stage of signal transduction mechanisms. During the late 1980s, we showed that Ca(2+)-stores can be mobilized by two other messengers unrelated to inositol trisphosphate (IP(3)) and identified them as cyclic ADP-ribose (cADPR), a novel cyclic nucleotide from NAD, and nicotinic acid adenine dinucleotide phosphate (NAADP), a linear metabolite of NADP. Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms. Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum, while that of NAADP is the two pore channel in endolysosomes.As cADPR and NAADP are structurally and functionally distinct, it is remarkable that they are synthesized by the same enzyme. They are thus fraternal twin messengers. We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and, through homology, found its mammalian homolog, CD38. Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion, susceptibility to bacterial infection, to social behavior of mice through modulating neuronal oxytocin secretion. We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis. This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components. PMID- 21786194 TI - The structural biology of ryanodine receptors. AB - Ryanodine receptors are ion channels that allow for the release of Ca(2+) from the endoplasmic or sarcoplasmic reticulum. They are expressed in many different cell types but are best known for their predominance in skeletal and cardiac myocytes, where they are directly involved in excitation-contraction coupling. With molecular weights exceeding 2 MDa, Ryanodine Receptors are the largest ion channels known to date and present major challenges for structural biology. Since their discovery in the 1980s, significant progress has been made in understanding their behaviour through multiple structural methods. Cryo-electron microscopy reconstructions of intact channels depict a mushroom-shaped structure with a large cytoplasmic region that presents many binding sites for regulatory molecules. This region undergoes significant motions during opening and closing of the channel, demonstrating that the Ryanodine Receptor is a bona fide allosteric protein. High-resolution structures through X-ray crystallography and NMR currently cover ~11% of the entire protein. The combination of high- and low resolution methods allows us to build pseudo-atomic models. Here we present an overview of the electron microscopy, NMR, and crystallographic analyses of this membrane protein giant. PMID- 21786195 TI - Physiological roles of NAADP-mediated Ca2+ signaling. AB - Nicotinic acid dinucleotide phosphate (NAADP) is unique amongst Ca(2+) mobilizing messengers in that its principal function is to mobilize Ca(2+) from acidic organelles. Early studies indicated that it was likely that NAADP activates a novel Ca(2+) release channel distinct from the well characterized Ca(2+) release channels on the (sarco)-endoplasmic reticulum (ER), inositol trisphosphate and ryanodine receptors. In this review, we discuss the emergence of a novel family of endolysosomal channels, the two-pore channels (TPCs), as likely targets for NAADP, and how molecular and pharmacological manipulation of these channels is enhancing our understanding of the physiological roles of NAADP as an intracellular Ca(2+) mobilizing messenger. PMID- 21786196 TI - Actin, more than just a housekeeping protein at the scene of fertilization. AB - Since the first demonstration of sperm entry into the fertilized eggs of Mediterranean sea urchin Paracentrotus lividus by Hertwig (1876), enormous progress and insights have been made on this topic. However, the precise molecular mechanisms underlying fertilization are largely unknown. The two most dramatic changes taking place in the zygote immediately after fertilization are: (i) a sharp increase of intracellular Ca(2+) that initiates at the sperm interaction site and traverses the egg cytoplasm as a wave, and (ii) the concomitant dynamic rearrangement of the actin cytoskeleton. Traditionally, this has been studied most extensively in the sea urchin eggs, but another echinoderm, starfish, whose eggs are much bigger and transparent, has facilitated experimental approaches using microinjection and fluorescent imaging methodologies. Thus in starfish, it has been shown that the sperm-induced Ca(2+) increase in the fertilized egg can be recapitulated by several Ca(2+)-evoking second messengers, namely inositol 1,4,5-trisphosphate (InsP3), cyclic ADP-ribose (cADPr) and nicotinic acid adenine dinucleotide phosphate (NAADP), which may play distinct roles in the generation and propagation of the Ca(2+) waves. Interestingly, it has also been found that the dynamic rearrangement of the actin cytoskeleton in the fertilized eggs plays pivotal roles in guiding monospermic sperm entry and in the fine modulation of the intracellular Ca(2+) signaling. As it is well known that Ca(2+) regulates the structure of the actin cytoskeleton, our finding that Ca(2+) signaling can be reciprocally affected by the state of the actin cytoskeleton raises an intriguing possibility that actin and Ca(2+) signaling may form a 'positive feedback loop' that accelerates the downstream events of fertilization. Perturbation of the cortical actin networks also inhibits cortical granules exocytosis. Polymerizing actin bundles also compose the 'acrosome process,' a tubular structure protruding from the head of fertilizing sperm. Hence, actin, which is one of the most strictly conserved proteins in eukaryotes, modulates almost all major aspects of fertilization. PMID- 21786197 TI - Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis. AB - Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Abeta) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca(2+)) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of gamma secretase involved in generation of Abeta peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca(2+) leak channels, independent of gamma-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca(2+) leak function activity and Ca(2+) overload in the ER. These results provided potential explanation for abnormal Ca(2+) signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca(2+) leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article. PMID- 21786198 TI - Early calcium dysregulation in Alzheimer's disease: setting the stage for synaptic dysfunction. AB - Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process. Amyloid plaques, neurofibrillary tangles and neuronal loss, though characteristic of AD, are late stage markers whose impact on the most devastating aspect of AD, namely memory loss and cognitive deficits, are still unclear. Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline. One common element that presents with several features of AD is disrupted neuronal calcium signaling. Increased intracellular calcium levels are functionally linked to presenilin mutations, ApoE4 expression, amyloid plaques, tau tangles and synaptic dysfunction. In this review, we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease. PMID- 21786199 TI - Distinctive characteristics and functions of multiple mitochondrial Ca2+ influx mechanisms. AB - Intracellular Ca(2+) is vital for cell physiology. Disruption of Ca(2+) homeostasis contributes to human diseases such as heart failure, neuron degeneration, and diabetes. To ensure an effective intracellular Ca(2+) dynamics, various Ca(2+) transport proteins localized in different cellular regions have to work in coordination. The central role of mitochondrial Ca(2+) transport mechanisms in responding to physiological Ca(2+) pulses in cytosol is to take up Ca(2+) for regulating energy production and shaping the amplitude and duration of Ca(2+) transients in various micro-domains. Since the discovery that isolated mitochondria can take up large quantities of Ca(2+) approximately 5 decades ago, extensive studies have been focused on the functional characterization and implication of ion channels that dictate Ca(2+) transport across the inner mitochondrial membrane. The mitochondrial Ca(2+) uptake sensitive to non-specific inhibitors ruthenium red and Ru360 has long been considered as the activity of mitochondrial Ca(2+) uniporter (MCU). The general consensus is that MCU is dominantly or exclusively responsible for the mitochondrial Ca(2+) influx. Since multiple Ca(2+) influx mechanisms (e.g. L-, T-, and N-type Ca(2+) channel) have their unique functions in the plasma membrane, it is plausible that mitochondrial inner membrane has more than just MCU to decode complex intracellular Ca(2+) signaling in various cell types. During the last decade, four molecular identities related to mitochondrial Ca(2+) influx mechanisms have been identified. These are mitochondrial ryanodine receptor, mitochondrial uncoupling proteins, LETM1 (Ca(2+)/H(+) exchanger), and MCU and its Ca(2+) sensing regulatory subunit MICU1. Here, we briefly review recent progress in these and other reported mitochondrial Ca(2+) influx pathways and their differences in kinetics, Ca(2+) dependence, and pharmacological characteristics. Their potential physiological and pathological implications are also discussed. PMID- 21786200 TI - Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein. AB - ALG-2 (a gene product of PDCD6) is a 22-kD protein containing five serially repetitive EF-hand structures and belongs to the penta-EF-hand (PEF) family, including the subunits of typical calpains. ALG-2 is the most conserved protein among the PEF family members and its homologs are widely found in eukaryotes. X ray crystal structures of various PEF proteins including ALG-2 have common features: presence of eight alpha-helices and dimer formation via paired EF5s that are positioned in anti-parallel orientation. ALG-2 forms a homodimer and a heterodimer with its closest paralog peflin. Like calmodulin, a well-known four EF-hand protein, ALG-2 interacts with various proteins in a Ca(2+)-dependent fashion, but the binding motifs are completely different. With some exceptions, ALG-2-interacting proteins commonly contain Pro-rich regions, and ALG-2 recognizes at least two distinct Pro-containing motifs: PPYP(X)nYP (X, variable; n=4 in ALIX and PLSCR3) and PXPGF (represented by Sec31A). A shorter alternatively spliced isoform, lacking two residues and designated ALG 2(DeltaGF122), does not bind ALIX but maintains binding capacity to Sec31A. X-ray crystal structural analyses have revealed that binding of calcium ions induces the configuration of the side chain of R125 so that it opens Pocket 1, which accepts PPYP, but Pocket 1 remains closed in the case of ALG-2(DeltaGF122). ALG-2 dimer has two ligand-binding sites, each in a monomer molecule, and appears to function as a Ca(2+)-dependent adaptor protein to either stabilize a preformed complex or to bridge two proteins on scaffolds in systems of the endosomal sorting complex required for transport (ESCRT) and ER-to-Golgi transport. PMID- 21786202 TI - Building the DREAM interactome. AB - DREAM/calsenilin/KChIP3 is a calcium binding protein of the neuronal calcium sensor superfamily. DREAM interacts with DRE (downstream regulatory element) sites in the DNA to regulate transcription and with many proteins to exert specialized functions in different subcellular compartments. Work from different laboratories has identified a growing list of interacting proteins that constitutes the DREAM interactome. The knowledge of these interactions has greatly contributed to the understanding of the various physiological functions of DREAM. PMID- 21786201 TI - STIM1 and Orai1: novel targets for vascular diseases? AB - The past five years have witnessed the discovery of the endoplasmic reticulum calcium (Ca(2+)) sensor STIM1 and the plasma membrane Ca(2+) channel Orai1 as the bona fide molecular components of the store-operated Ca(2+) entry (SOCE) and the Ca(2+) release-activated Ca(2+) current (I (CRAC)). It has been known for two decades that SOCE and I (CRAC) are required for lymphocyte activation as evidenced by severe immunodeficient phenotypes in patients lacking I (CRAC). In recent years however, studies have uncovered expression of STIM1 and Orai1 proteins in various tissues and described additional roles for these proteins in physiological functions and pathophysiological conditions. Here, we will summarize novel findings pertaining to the role of STIM1 and Orai1 in the vascular system and discuss their potential use as targets in the therapy of vascular disease. PMID- 21786204 TI - Compatible GLRaV-3 viral infections affect berry ripening decreasing sugar accumulation and anthocyanin biosynthesis in Vitis vinifera. AB - Virus infections in grapevine cause important economic losses and affect fruit quality worldwide. Although the phenotypic symptoms associated to viral infections have been described, the molecular plant response triggered by virus infection is still poorly understood in Vitis vinifera. As a first step to understand the fruit changes and mechanisms involved in the compatible grapevine virus interaction, we analyzed the berry transcriptome in two stages of development in the red wine cultivar Cabernet Sauvignon infected with Grapevine leaf-roll-associated virus-3 (GLRaV-3). Analysis of global gene expression patterns indicate incomplete berry maturation in infected berries as compared to uninfected fruit suggesting viral infection interrupts the normal berry maturation process. Genes with altered expression in berries harvested from GLRaV 3-infected vines as compared to uninfected tissue include anthocyanin biosynthesis and sugar metabolism genes. The reduction in transcript accumulation for sugar and anthocyanin metabolism during fruit development is consistent with a dramatic reduction in anthocyanin biosynthesis as well as reduced sugar levels in berries, a hallmark phenotypic change observed in virus infected grapevines. Analysis of key regulatory factors provides a mechanism for the observed gene expression changes. Our results provide insight into commonly observed phenotypic alterations in virus infected vines and the molecular mechanisms associated with the plant response to the virus during berry ripening. PMID- 21786205 TI - Self-reported cancer rates in two rural areas of West Virginia with and without mountaintop coal mining. AB - Mountaintop coal mining in the Appalachian region in the United States causes significant environmental damage to air and water. Serious health disparities exist for people who live in coal mining portions of Appalachia, but little previous research has examined disparities specifically in mountaintop mining communities. A community-based participatory research study was designed and implemented to collect information on cancer rates in a rural mountaintop mining area compared to a rural non-mining area of West Virginia. A door-door health interview collected data from 773 adults. Self-reported cancer rates were significantly higher in the mining versus the non-mining area after control for respondent age, sex, smoking, occupational history, and family cancer history (odds ratio = 2.03, 95% confidence interval = 1.32-3.13). Mountaintop mining is linked to increased community cancer risk. Efforts to reduce cancer and other health disparities in Appalachia must focus on mountaintop mining portions of the region. PMID- 21786206 TI - Oral cancer in India: an epidemiologic and clinical review. AB - Oral cancer is one of the most fatal health problems faced by the mankind today. In India, because of cultural, ethnic, geographic factors and the popularity of addictive habits, the frequency of oral cancer is high. It ranks number one in terms of incidence among men and third among women. Several factors like tobacco and tobacco related products, alcohol, genetic predisposition and hormonal factors are suspected as possible causative factors. Hence the study was designed to determine the prevalence of Oral Cancer in patients who attended the outpatient department, at Bharati Vidyapeeth Deemed University Dental College Sangli India during a period of 24 months in 2009-2010. Further various modes of tobacco and alcohol consuming habit were assessed along with the site of occurrence of oral cancer. About 35,122 subjects belonging to a semi-urban district of Sangli in Western Maharashtra (India) were screened. Tobacco and alcohol consumption was the common habit among the study population. Out of these about 112 cases showed Oral Cancer. The prevalence of Oral Cancer was 1.12%. Statistical analysis was done using the SPSS software 11. The findings in the present study reveal a high prevalence of Oral Cancer and a rampant misuse of variety of addictive substances in the community. Close follow up and systematic evaluation is required in this population. Education about ill effects of tobacco and alcohol consumption is necessary at a broader scale. There is an urgent need for awareness programs involving the community health workers, dentists and allied medical professionals. PMID- 21786207 TI - American Indian community leader and provider views of needs and barriers to mammography. AB - Breast cancer incidence is rising and mortality is disproportionately high among American Indians and Alaska Natives, yet screening rates remain low. Using community-based participatory research, we conducted interviews with community leaders (n = 13) and providers from the Indian Health Service, tribal clinics, and urban safety-net clinics (n = 17). Participants in both groups identified similar needs, including culturally-appropriate mammography education, use of Native elders as patient navigators, and an emphasis on preventive care. Pertinent barriers included culturally-specific issues (e.g., historic mistrust and gender roles), cost, transportation, and fear of mammography and potential results. The results reflect the struggles of promoting mammography across diverse populations. PMID- 21786208 TI - In vitro activity of ceftobiprole and seven other antimicrobial agents against invasive Streptococcus pneumoniae isolates in Spain. AB - The in vitro activity of ceftobiprole was compared with that of seven antimicrobial agents against invasive Streptococcus pneumoniae isolated from adult patients (>15 years old). Characterization of erythromycin-resistant strains and serotype distribution of all pneumococci were also evaluated. Seventy invasive S. pneumoniae strains were isolated from December 2007 to January 2009. Serotyping was carried out by Quellung reaction. Antibiotic susceptibility was tested by broth microdilution (CLSI guidelines). The comparator agents were penicillin, cefotaxime, erythromycin, clindamycin, telithromycin, tetracycline and moxifloxacin. Phenotypic characterization of macrolide resistance was performed by the double disk method. Macrolide resistance genes [erm(B) and mef(A/E)] and the promoter of erm(B) were detected by PCR. Twenty-five different serotypes were detected of which 87% were non-PCV7 types. The percentages of resistance to erythromycin, clindamycin and tetracycline were 20%, 8.6% and 16%, respectively. A penicillin MIC >=0.12 mg/L was observed in 14 of the 70 invasive pneumococci strains. The cefotaxime and ceftobiprole MIC(50)/MIC(90) of these 14 strains were 1/4 and 0.03/1 mg/L, respectively. Ceftobiprole showed higher in vitro activity than penicillin and cefotaxime with all isolates being inhibited by <=1 mg/L. Its high in vitro activity should make ceftobiprole a very promising drug for the treatment of pneumococcal infections. PMID- 21786203 TI - Synaptic effects induced by alcohol. AB - Ethanol (EtOH) has effects on numerous cellular molecular targets, and alterations in synaptic function are prominent among these effects. Acute exposure to EtOH activates or inhibits the function of proteins involved in synaptic transmission, while chronic exposure often produces opposing and/or compensatory/homeostatic effects on the expression, localization, and function of these proteins. Interactions between different neurotransmitters (e.g., neuropeptide effects on release of small molecule transmitters) can also influence both acute and chronic EtOH actions. Studies in intact animals indicate that the proteins affected by EtOH also play roles in the neural actions of the drug, including acute intoxication, tolerance, dependence, and the seeking and drinking of EtOH. This chapter reviews the literature describing these acute and chronic synaptic effects of EtOH and their relevance for synaptic transmission, plasticity, and behavior. PMID- 21786209 TI - Betel nut extract and arecoline block insulin signaling and lipid storage in 3T3 L1 adipocytes. AB - According to several population-based studies, betel nut chewing is associated with metabolic syndrome and diabetes in British South Asians and Taiwanese. However, the underlying molecular mechanism is not yet clear. Arecoline is an alkaloid-type natural product found in betel nuts. Our aim was to clarify the influence of betel nut extract and arecoline on lipid accumulation and insulin signaling in adipocytes. We found that betel nut extract and arecoline blocked lipid storage in 3T3-L1 adipocytes. The possible mechanism may function by inhibiting the expression of the insulin receptor, glucose transporter-4, fatty acid synthase, and the lipid droplet proteins perilipin and adipophilin. In addition, betel nut extract and arecoline increased the basal level of IRS-1 serine(307) phosphorylation and decreased insulin-stimulated IRS-1 tyrosine, Akt, and PI3 kinase phosphorylation. In conclusion, betel nut extract and arecoline have diabetogenic potential on adipocytes that may result in insulin resistance and diabetes at least in part via the obstruction of insulin signaling and the blockage of lipid storage. PMID- 21786210 TI - Liver resection for advanced or aggressive colorectal cancer metastases in the era of effective chemotherapy: a review. AB - Liver surgery has been known to cure metastatic colorectal cancer in a small proportion of patients. However, advances in procedural technique and chemotherapy now allow more patients to have safe, potentially curative surgery. Here we review surgery for unresectable colorectal liver metastases using an expert multidisciplinary approach. With multidisciplinary management of patients with effective chemotherapy that can downstage metastases, more patients with previously inoperable disease can benefit from surgery. Portal vein embolization results in hypertrophy of the future liver remnant; on occasions, combining embolization with staged liver resection permits potentially curative surgery for patients previously unable to survive resection. However, increasing use of chemotherapy has raised awareness of potential hepatotoxicity and other deleterious effects of cytotoxic agents. Prolonged prehepatectomy chemotherapy therefore can reduce resectability even using a 2-stage procedure. Suitable timing of surgery for unresectable liver metastases during chemotherapy is critical. Because of advances in chemotherapy, colorectal cancer, like ovarian cancer, can now show survival benefit from maximum surgical debulking. Benefit from such maximum hepatic debulking surgery for metastatic colorectal disease is uncertain, but likely. Surgery in isolation may be approaching technical limits, but is now likely to help more patients because of the success of complementary strategies, particularly newer chemotherapy and targeted therapy. Expert individualized multidisciplinary treatment planning and problem-solving is essential. PMID- 21786211 TI - Phase I study of irinotecan by 24-h intravenous infusion in combination with 5 fluorouracil in metastatic colorectal cancer. AB - BACKGROUND: This study was intended to ascertain the feasibility of a combination therapy with irinotecan by 24-h intravenous infusion (24-h CPT-11) and 5 fluorouracil (5-FU) for patients with metastatic colorectal cancer, to estimate the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD), to determine the recommended dose (RD) for the Phase II study, and to evaluate the efficacy of the combination therapy. METHODS: The dosage regimen was as follows: CPT-11 was given by 24-h CPT-11 on day 1, followed by 24-h intravenous infusion of 5-FU on day 2. This regimen was repeated every 2 weeks. The dose of CPT-11 was escalated in five steps from 50 to 75, 100, 125, or 150 mg/m(2) (levels 1-5), whereas the dose of 5-FU was fixed at 800 mg/m(2). RESULTS: Twenty-six patients were recruited for this study, and 25 of the 26 patients were eligible for the assessment. The DLTs of 24-h CPT-11/5-FU therapy included grade 3 diarrhea in 1 patient treated at level 1, and grade 3 neutropenia in 1 patient and grade 4 neutropenia in 1 patient at level 4. In level 5, in 3 cases the next administration could not be done for 22 days or more as a consequence of anorexia. Thus, the level 5 was made a MTD and the level 4 was made a RD. The main side effects of grade 3 or higher, although nausea/vomiting occurred, were mild and tolerable in severity overall. The overall response rate was 24.0% (6PR/25). CONCLUSION: This study suggests that 24-h CPT-11/5-FU therapy is feasible and effective for treatment of metastatic colorectal cancer. PMID- 21786212 TI - The effects of the 2009 dust storm on emergency admissions to a hospital in Brisbane, Australia. AB - In September 2009 an enormous dust storm swept across eastern Australia. Dust is potentially hazardous to health as it interferes with breathing, and previous dust storms have been linked to increased risks of asthma and even death. We examined whether the 2009 Australian dust storm changed the volume or characteristics of emergency admissions to hospital. We used an observational study design, using time series analyses to examine changes in the number of admissions, and case-only analyses to examine changes in the characteristics of admissions. The admission data were from the Prince Charles Hospital, Brisbane, between 1 January 2009 and 31 October 2009. There was a 39% increase in emergency admissions associated with the storm (95% confidence interval: 5, 81%), which lasted for just 1 day. The health effects of the storm could not be detected using particulate matter levels. We found no significant change in the characteristics of admissions during the storm; specifically, there was no increase in respiratory admissions. The dust storm had a short-lived impact on emergency hospital admissions. This may be because the public took effective avoidance measures, or because the dust was simply not toxic, being composed mainly of soil. Emergency departments should be prepared for a short-term increase in admissions during dust storms. PMID- 21786214 TI - Cardioprotective effect of 3-iodothyronamine in perfused rat heart subjected to ischemia and reperfusion. AB - 3-iodothyronamine (T(1)AM) is an endogenous compound which shares structural and functional features with biogenic amines and is able to interact with a specific class of receptors, designed as trace amine associated receptors. T(1)AM has significant physiological effects in mammals and produces a reversible, dose dependent negative inotropic and chronotropic effect in heart. The aim of the present study was to investigate if T(1)AM is able to reduce irreversible tissue injury in isolated rat hearts subjected to ischemia and reperfusion, as evaluated by triphenyltetrazolium chloride staining. We observed that T(1)AM reduced infarct size at concentrations (125 nM to 12.5 MUM) which did not produce any significant hemodynamic action. The dose-response curve was bell-shaped and peaked at 1.25 MUM. T(1)AM-induced cardioprotection was completely reversed by the administration of chelerythrine and glibenclamide, suggesting a protein kinase C and K (ATP) (+) -dependent pathway, while it was not additive to the protection induced by cyclosporine A, suggesting modulation of mitochondrial permeability transition. At cardioprotective concentration, T(1)AM reduced the time needed for cardiac attest during ischemia, but it did not affect sarcoplasmatic reticulum Ca(2+) handling, as demonstrated by unaltered ryanodine receptor binding properties. In conclusion, in isolated rat heart T(1)AM produces a cardioprotective effect which is mediated by a protein kinase C and K (ATP) (+) -dependent pathway and is probably linked to modulation of mitochondrial permeability transition and/or ischemic arrest time. PMID- 21786213 TI - Abdominal surgical incision induces remote preconditioning of trauma (RPCT) via activation of bradykinin receptors (BK2R) and the cytochrome P450 epoxygenase pathway in canine hearts. AB - OBJECTIVE: Recently, a novel observation was made in which nonischemic trauma at a site remote from the heart produced by a transverse abdominal incision resulted in a marked reduction of infarct size (IS) in the mouse heart via activation of sensory nerve fibers in the skin and subsequent activation of bradykinin 2 receptors (BK2R). This phenomenon was termed remote preconditioning of trauma (RPCT). Since RPCT may have potential clinical implications we attempted to confirm these findings in a large animal model, the dog. The epoxyeicosatrienoic acids (EETs) have also recently been shown to be antinociceptive and have been shown to mimic ischemic preconditioning (IPC) and postconditioning (POC) in dogs, therefore, we tested the role of the EETs in RPCT. METHODS: Anesthetized adult mongrel dogs of either sex were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion followed by 3 h of reperfusion. In all groups except the controls (no slit), a transverse slit (9 cm) was applied to the abdominal wall of the dog being careful to only slit the skin. Subsequently, 15 min after the slit the heart was subjected to the ischemia/reperfusion protocol. RESULTS: In the control dogs, the IS as a percent of the area at risk (AAR) was 22.5 +/- 2.4%, whereas in the dogs subjected to the slit alone the IS/AAR was reduced to 9.2 +/- 1.2% (*P < 0.01). The BR2R blocker, HOE 140 (50 ug/kg, iv) given 10 min prior to the slit, completely abolished the protective effects of RCPT as did pretreatment with 14,15-EEZE, a putative EET receptor blocker or pretreatment with the selective EET synthesis inhibitor, MSPPOH. CONCLUSIONS: These results suggest that BK and the EETs share cardioprotective properties in a large animal model of RPCT. PMID- 21786215 TI - Nuclear factor-kappaB: a key regulator in health and disease of lungs. AB - Rel/NF-kappaB transcription factors play a key role in modulating the response of immunoregulatory genes including cytokines and chemokines, cell adhesion molecules, acute phase proteins, and anti-microbial peptides. Furthermore, an array of genes important for angiogenesis, tumor invasion and metastasis is also regulated by nuclear factor-kappaB (NF-kappaB). Close association of NF-kappaB with inflammation and tumorigenesis makes it an attractive target for basic research as well as for pharmaceutical industries. Studies involving various animal and cellular models have revealed the importance of NF-kappaB in pathobiology of lung diseases. This review (a) describes structures, activities, and regulation of NF-kappaB family members; (b) provides information which implicates NF-kappaB in pathogenesis of pulmonary inflammation and cancer; and (c) discusses information about available synthetic and natural compounds which target NF-kappaB or specific components of NF-kappaB signal transduction pathway and which may provide the foundation for development of effective therapy for lung inflammation and bronchogenic carcinomas. PMID- 21786217 TI - Polyphenols, ethnomedicine, and benefit sharing. PMID- 21786216 TI - Investigation of amygdala volume in men with the fragile X premutation. AB - Premutation fragile X carriers have a CGG repeat expansion (55 to 200 repeats) in the promoter region of the fragile X mental retardation 1 (FMR1) gene. Amygdala dysfunction has been observed in premutation symptomatology, and recent research has suggested the amygdala as an area susceptible to the molecular effects of the premutation. The current study utilizes structural magnetic resonance imaging (MRI) to examine the relationship between amygdala volume, CGG expansion size, FMR1 mRNA, and psychological symptoms in male premutation carriers without FXTAS compared with age and IQ matched controls. No significant between group differences in amygdala volume were found. However, a significant negative correlation between amygdala volume and CGG was found in the lower range of CGG repeat expansions, but not in the higher range of CGG repeat expansions. PMID- 21786219 TI - Indomethacin in pregnancy: applications and safety. AB - Preterm labor (PTL) is a major cause of neonatal morbidity and mortality worldwide. Among the available tocolytics, indomethacin, a prostaglandin synthetase inhibitor, has been in use since the 1970s. Recent studies have suggested that prostaglandin synthetase inhibitors are superior to other tocolytics in delaying delivery for 48 hours and 7 days. However, increased neonatal complications including oligohydramnios, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the patent ductus arteriosus have been reported with the use of indomethacin. Indomethacin has been also used in women with short cervices as well as in those with idiopathic polyhydramnios. This article describes the mechanism of action of indomethacin and its clinical applications as a tocolytic agent in women with PTL and cerclage and its use in the context of polyhydramnios. The fetal and neonatal side effects of this drug are also summarized and guidelines for its use are proposed. PMID- 21786218 TI - The relationship between maternal body mass index and tobacco use on small-for gestational-age infants. AB - We sought to estimate the association between prepregnancy body mass index (BMI) and small-for-gestational-age (SGA) neonates and to determine if there is a synergistic effect of tobacco use on SGA across all BMI strata. We performed a retrospective cohort study of 65,104 patients seen for second-trimester ultrasound. BMI was categorized into underweight, normal weight, overweight, and obese. SGA was defined as birth weight <10th percentile and <5th percentile. Univariable and multivariable logistic regression analyses were used to evaluate the association between BMI and SGA. Stratified analyses and tests for effect modification were performed to evaluate for a potential synergistic effect between tobacco use and abnormal prepregnancy BMI on SGA. After controlling for potential confounders, underweight BMI was associated with an increased risk for SGA <10th percentile (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.5 to 2.1), while overweight (aOR 0.7, 95% CI 0.7 to 0.8) and obese BMIs (aOR 0.6, 95% CI 0.5 to 0.7) were associated with a decreased risk of SGA. There was no effect modification of tobacco use on the risk of SGA across all BMI categories. Although both tobacco and underweight BMI are independently associated with SGA, there was no evidence of synergism. Continued emphasis on both smoking cessation and maintenance of normal prepregnancy BMI remains paramount to decreasing the incidence of SGA. PMID- 21786220 TI - Tea triterpenoidal saponins from the roots of Camellia sinensis have inhibitory effects against alcohol dehydrogenase. AB - Ten new polyhydroxyolean-12-ene pentacyclic triterpenoidal saponins, named rogchaponins 1-10, were isolated from the methanolic extract of the roots of Camellia sinensis by a series of chromatographic methods (silica gel flash column and C18 MPLC followed by C18 HPLC). Their structures were established by 1D and 2D-NMR techniques along with IR and HR-TOF-MS. Rogchaponins R4 ( 4) and R5 (5) showed inhibitory activities against yeast alcohol dehydrogenase (ADH) with IC (50) values of 16.1 +/- 3.2 and 15.4 +/- 3.3 uM, respectively. A 4-methylpyrazole positive control exhibited an IC (50) of 2750 +/- 50 uM. However, the saponins showed no inhibitory activity against yeast aldehyde dehydrogenase (ALDH). PMID- 21786221 TI - Biochemical mechanism of modulation of human P-glycoprotein by stemofoline. AB - The resistance to chemotherapeutic drugs by cancer cells is considered to be one of the major obstacles for success in the treatment of cancer. A major mechanism underlying this multidrug resistance is the overexpression of P-glycoprotein (P gp), resulting in insufficient drug delivery to the tumor sites. A previous study has shown that stemofoline, an alkaloid isolated from Stemona burkillii, could enhance the sensitivity of chemotherapeutics in a synergistic fashion. In the present study, we have focused on the effect of stemofoline on the modulation of P-gp function in a multidrug resistant human cervical carcinoma cell line (KB V1). The effects of stemofoline on a radiolabeled drug, [(3)H]-vinblastine, and fluorescent P-gp substrates, rhodamine 123 and calcein-AM accumulation or retention were investigated to confirm this finding. Stemofoline could increase the accumulation or retention of radiolabeled drugs or fluorescent P-gp substrates in a dose-dependent manner. For additional studies on drug-P-gp binding, P-gp ATPase activity was stimulated by stemofoline in a concentration dependent manner. More evidence was offered that stemofoline inhibits the effect on photoaffinity labeling of P-gp with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner. These data indicate that stemofoline may interact directly with P-gp and inhibit P-gp activity, whereas stemofoline has no effect on P-gp expression. Taken together, the results exhibit that stemofoline possesses an effective MDR modulator, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells. PMID- 21786222 TI - Neurosurgery in Wurzburg until World War II. AB - The institution of German neurosurgery as an autonomous surgical specialty, starting in Wurzburg in 1934, is closely linked to the names of Fritz Konig and Wilhelm Tonnis. They were acting at a time when the global economic crisis and a consolidating Nazi dictatorship caused a cascade of alarming changes in political and social life. On the one hand it is fascinating to see how the restless work and energy of Tonnis managed to build up the first independent neurosurgical unit in Germany and to tighten efficient international connections all over the world within a few years. On the other hand-from a present-day perspective-it is difficult to understand how his strive towards a specialist's success, in contrast to that of Otfrid Foerster, was barely affected by the threatening political development, until the Second World War stopped his plans and ideas for many years. PMID- 21786223 TI - Cost analysis of near-infrared spectroscopy tissue oximetry for monitoring autologous free tissue breast reconstruction. AB - Free flap monitoring typically requires specialized nursing that can increase medical costs. This study uses near-infrared spectroscopy (NIRS) tissue oximetry to monitor free tissue breast reconstruction. We hypothesize this practice will reduce medical costs by eliminating the need for specialized nursing. From August 2006 to January 2010, women undergoing unilateral free tissue breast reconstruction were enrolled and admitted postoperatively to either the surgical intensive care unit (ICU) or floor. Each underwent continuous monitoring using NIRS tissue oximetry and intermittent clinical examination with surface Doppler ultrasonography. Patient demographics, comorbidities, perioperative details, and financial data were recorded. There were 50 patients studied, all with abdominal based flaps (25 per group). There were no statistically significant differences in patient demographics, comorbidities, mean flap weight, ischemia time, or length of stay between the ICU and floor groups. Four flaps had vascular complications, all detected by NIRS tissue oximetry. Comparison of hospital costs showed an average reduction of $1937 per patient when monitored on the surgical floor (P = 0.036). NIRS tissue oximetry is a sensitive and reliable monitoring tool, eliminating the need for specialized nursing care. The effect is decreased cost structure and increased hospital contribution margin for autologous free tissue breast reconstruction. PMID- 21786224 TI - [Surgical treatment of pulmonary carcinoids - ten-year results]. AB - INTRODUCTION: Carcinoids are malignant neuro-endocrine tumours occurring in the bronchopulmonary location in about 25 %, and accounting for approximately 2 % of all pulmonary tumours. MATERIAL AND METHODS: Our retrospective analysis included 27 patients, 14 men and 13 women, mean age 58.4 years, treated from 2000 to 2009 for carcinoids in bronchopulmonary locations. The tumour manifested clinically in 52 % of the cases, the most common symptom being cough; one tumour manifested as carcinoid syndrome. All patients underwent fibrobronchoscopy that was positive in 20 cases (74.1 %). Pre-surgery histological diagnoses were made in 13 patients (48.1 %). Chest CT scans were carried out in 26 patients, and the investigation failed to detect the expected pathological process in 2 of the patients. Octreoscans were carried out in 12 patients, and were successful in identifying a primary neuroendocrine tumour in 75 %. RESULTS: All patients in the sample underwent rad-ical surgical therapy; the most common surgical procedure was lobectomy (70.4 %). Perioperative morbidity and mortality were zero. Typical carcinoids were found in 20 cases while 7 cases were atypical carcinoids, 20 tumours were located centrally. 74 % of the tumours were consistent with stage I A disease. Mean follow-up period was 47 (range: 6-134) months. Local recurrences were observed in 2 patients (7.4 %), but the tumour disseminated in 4 patients (14.8 %). Two patients (7.4 %) died during the follow-up period. Overall five year survival in the sample was 92.3 %, 90.9 % in the typical carcinoid group and 100 % for atypical carcinoids. We found a statistically significant association between disease-free interval and histological type of the tumour; the risk of progression was 8 times higher in -patients with atypical carcinoids compared to patients with typical carcinoids (Log-Rank-Test: p-value = 0.0049). CONCLUSION: Radical surgical treatment of bronchopulmonary carcinoids is the optimum therapeutic approach that results in the best results both regarding perioperative morbidity and mortality and regarding long-term survival of the patients. PMID- 21786225 TI - p-Aminophenol and p-paraphenylenediamine induce injury and apoptosis of human HK 2 proximal tubular epithelial cells. AB - BACKGROUND: There is rapidly accumulating evidence that use of oxidized hair dye causes various forms of nephrotoxic injury. However, the regulation and implication of the nephrotoxic injury resulting from p-aminophenol (PAP) and p paraphenylenediamine (PPD), the main components of oxidized hair dye, remain unknown. METHODS: To clarify the effect of PAP and PPD, we analyzed the proliferation, lactate dehydrogenase (LDH) levels, apoptosis and subsequent mRNA levels of caspase-3 in HK-2 cells stimulated with different concentrations of PAP or PPD. Cell proliferation was assessed by MTT assay. The production of LDH was determined by Hitachi 7170 biochemical analyzer. The apoptosis of cell was analyzed using flow cytometry and scanning electron microscopy. The mRNA levels of caspase-3 were quantitatively measured by real-time PCR. RESULTS: The proliferation of HK-2 cells was significantly inhibited by PAP, PPD and each mixed with hydrogen peroxide (H2O2). The level of apoptosis of HK-2 cells, the mRNA levels of caspase-3 and LDH production by PAP or PPD stimulation was significantly higher than controls or after H2O2. A typical apoptotic morphological change was observed under electron microscopy in response to PAP or PPD. CONCLUSION: It appears that caspase-3 may play a key role in the nephrotoxic injury resulting from PAP, PPD or its oxidized form. PMID- 21786226 TI - Aliskiren: the first direct renin inhibitor available for clinical use. AB - The idea of blocking the renin-angiotensin system (RAS) with the inhibition of the enzymatic activity of renin has been pursued for half a century, but it became a reality only recently, with the synthesis of aliskiren, the first direct renin inhibitor available for clinical use. The upstream blockade of the system induced by aliskiren, in combination with its unique pharmacological properties (inhibiting potency, high plasma concentration, long half-life and preferential partitioning in the kidney) makes this compound the ideal tool to achieve a complete blockade of the RAS. Consistent with expectations, present evidence indicates that aliskiren, at the licensed dosages of 150-300 mg/day, lowers blood pressure to the same extent as other first-line antihypertensive agents, with the additional advantage of a longer duration of action which persists for several days after the cessation of treatment. Moreover, aliskiren was found to act synergically not only with diuretics but also with other drug classes, including angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. In addition, results of recent clinical trials have shown that aliskiren possesses cardiovascular and renal protective properties which may contribute to the beneficial effects of this drug beyond the reduction of blood pressure. Finally, aliskiren has an excellent, placebo-like tolerability profile, a feature which is very relevant for improving compliance of patients. PMID- 21786227 TI - What would we like to know, and what do we not know about fibroblast growth factor 23? AB - Recently, a new view of the molecular mechanisms of phosphate homeostasis and secondary hyperparathyroidism pathogenesis has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. FGF23 is a 32-kDa peptide secreted by the osteocytes involved in the control of phosphate homeostasis and calcitriol metabolism. FG23 is constantly elevated in advanced chronic kidney disease (CKD) patients, and recent studies have indicated that high levels are associated with the progression of CKD and with higher mortality rates in hemodialysis patients. In the CKD population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary hyperparathyroidism, by inducing a resistance of the parathyroid glands to FGF23, and to be associated with higher mortality risk in incident hemodialysis patients. FGF23 appears to be involved in bone metabolism, but a direct effect of FGF23 on bone disease in humans has not yet been elucidated, even if the inhibitory effect of FGF23 on osteoblast activity that has been described in animal models and hereditary rickets is clearly connected with FGF23 deficiency. The association between altered levels of FGF23 and bone disease could be mainly due to the dysregulation of phosphate-handling and vitamin D metabolism, more than to a direct antiosteoblastic activity of FGF23. FGF23 appears to be a new biomarker, which is independently associated with several cardiovascular risk factors such as endothelial dysfunction, arterial stiffness and left ventricular hypertrophy, in the general population as well as in early CKD. All of the above have been related to cardiovascular and general mortality. Until now, we know that elevated FGF23 levels in dialysis patient are associated with several cardiovascular adverse outcomes mentioned above; the clinical relevance of high FGF23 values in dialysis patients remains unclear, because therapy with active vitamin D sterols further increases FGF23 levels but, on the other hand, is associated with a survival benefit in dialysis patients. This paradox highlights the need for future prospective randomized trials to evaluate the correlation between vitamin D therapy and FGF23 levels in dialysis patients. In the clinical setting, there are still different FGF23 actions that need investigation. In this sense, increased knowledge of mineral metabolism disorder alterations in CKD may be used to improve diagnostics and select future treatments. PMID- 21786228 TI - Determinism and liabilities in a complicated transrectal prostate biopsy: what is what. AB - We report the case of a 53-year-old man suffering from the contemporary onset of penile Mondor's disease and high-flow priapism 10 days after a transrectal prostate biopsy. We analyzed whether these pathological conditions were causally related to the biopsy, and the role of urologist regarding the onset of one or both the diseases. Critically evaluating the clinical picture and the procedure used for the biopsy, we were able to recognize a connection between the office procedure and the onset of the high-flow priapism, otherwise than for penile Mondor's disease. Our report is of value for urologists, making them aware of such possible complications, and for forensic experts that might have to deal with similar cases, as it demonstrates only a partial involvement of urologist in this clinical setting. PMID- 21786229 TI - [Sporadic case of desmoid tumor in outcomes of lombotomic nephrectomy]. AB - The desmoid tumor is a rare tumor with an incidence of 2-4 cases per million people each year, and represents 0.03% of all cancers. The tumor is composed of fibrous tissue that produces masses of well-differentiated hard elastic consistency. According to their site of onset, the desmoid tumors are classified in abdominal, intra-abdominal, and extra-abdominal. The abdominal cases develop inside the abdominal muscles of the abdominal wall upright, especially in women in their 2nd - 4th decade of life, particularly in those who have been pregnant. METHODS: A 66-year-old patient underwent nephrectomy in 2006 for the detection of a massive tumor in the right kidney (EI: pT1bNx). The patient came to our observation for the radiological tracking (CT) of a solid lesion of 4 cm below the right arch, 2 years after surgery. For this reason it was decided to refer the patient to a series of percutaneous biopsies. The report describes a histologic lesion of fibromatosis. After one year a new CT exam showed a significant increase of the size of the lesion, with a diameter of 11.6 x 7.9 cm, and abdominal involvement to ascending colon. Given the discrepancy between the CT data and the histological report, it was decided to refer the patient to a lombotomic exploration and the subsequent removal of the lesion, which appeared of hard, elastic consistency and well capsulated. The final histology test confirmed the fibromatosis lesion. CONCLUSIONS: The desmoid tumor is a rare tumor characterized by the proliferation of fibrotic tissue. The tumor is composed of well-differentiated fibrous tissue and has a hard-elastic consistency. Regarding the development of dermoid tumors, several risk factors were identified, including extra-abdominal fibromatosis, genetic factors, endocrine factors. Other causes may arise from trauma or abdominal injury in surgical outcomes of appendectomy, laparotomy and other surgical scars (scar fibromatosis) or genetic predisposing factors. The surgical resection of dermoid tumors should be the therapy of choice, complete and radical, to cover the possible excision of a wide margin of surrounding structures concerned, and those arrangements should ensure a low rate of relapse. However, in cases of inoperable cancer due to extension, anti-estrogen therapy may have an important therapeutic and well-tolerated effect, besides being relatively non-toxic, even at high doses. A close follow-up is indicated, however, and warmly recommended. PMID- 21786230 TI - [Insignificant prostate cancer: charateristics and predictive factors]. AB - INTRODUCTION: The widespread screening for PSA has contributed to the increased incidence of prostate cancer (PCa), mostly identifying disease at earlier stages. Many of these patients will probably not require treatment because of the indolent course of the disease. The European Randomized Study of Screening for Prostate Cancer (ERSPC) has showed that 1410 men needed to be screened and 48 prostatectomies performed to prevent death. The aim of this study was to evaluate predictive factors of insignificant PCa in our experience. MATERIALS AND METHODS: We analyzed various preoperative clinical and biopsy findings of 225 consecutive patients who underwent prostatectomy from October 2007 to June 2010. The indication for biopsy was placed in presence of an abnormal rectal examination and/or suspected transrectal ultrasound and/or PSA >4 ng/ml. We consider insignificant a tumor with a volume <=5% of the entire gland with a Gleason score <= 6, with no grades 4 or 5 and organ confined. RESULTS: The prevalence of potentially insignificant PCa in our experience was 12%. The preoperative findings of patients with insignificant PCa were significantly more favorable than the remaining cases with PCa not insignificant. Multivariate analysis did not reveal any independent predictors. CONCLUSIONS: In our experience, in a population not screened for PCa, we have not identified any factors that can predict with certainty the insignificant nature of a tumor and, therefore, useful to start a patient on an active surveillance program. PMID- 21786231 TI - [Comparison of low-power laser and ultrasound litotripsy in the management of middle-distal ureteral stones]. AB - OBJECTIVE: To compare the success rates and complications of ultrasound and low power Holmium laser-assisted ureteroscopy (URS) in managing middle-distal ureteral stones. MATERIALS AND METHODS: We retrospectively analyzed the records of 90 patients with middle-distal ureteral stones who underwent ureteroscopic lithotripsy at our institution from May 2006 to April 2010. 45 patients were treated with ultrasound (mean size 6.7 mm), 45 patients with low-power Holmium laser (mean size 7.4 mm). The same ureteroscope (9.5/8ch rigid-Storz) was used to treat all the patients. Patients were monitored before the hospital discharge with abdominal radiograph and ultrasonography, and as outpatients after 3 months with abdominal radiograph, ultrasonography and urography in selected cases. RESULTS: We obtained a complete immediate fragmentation of stones in 27/45 (60%) patients with ultrasound, and in 36/45 (80%) patients after laser treatment. A proximal migration of stones was observed in 12/45 (26.8%) patients with ultrasound and 3/45 (6.6) with laser. We observed a ureteral perforation after laser treatment and no patient developed urosepsis. 6/45 (13.3%) patients who were treated with ultrasound underwent auxiliary therapy such as alkalizing therapy, 9/45 (20%) patients a second ureteroscopy, 9/45 (20%) a shockwave lithotripsy. No patient underwent an auxiliary shockwave treatment after laser, 6/45 (13.4%) patients underwent a second ureteroscopy. Operating time (20.33 vs 28.85 minutes) and hospitalization (3.6 vs 5.1 days) were shorter with laser if compared with ultrasound treatment. CONCLUSION: In our study the fragmentation rates of Holmium laser-assisted ureteroscopy were significantly better than with ultrasound in the middle-distal ureteral stones management. We did not have relevant complications using both procedures, and the need for auxiliary procedures was significantly less for Holmium laser-assisted ureteroscopy when compared with ultrasound. PMID- 21786232 TI - [High-intensity focused ultrasound (HIFU): our experience in the treatment of prostate cancer relapsing after radiotherapy]. AB - The aim of the study is to evaluate the safety and efficacy of high-intensity focused ultrasound (HIFU) treatment in patients with local prostate cancer recurrence after radiotherapy. From February 2009 to June 2010, 14 patients with prostate cancer recurrence after radiotherapy were selected for HIFU treatment; all patients had a positive TRUS-guided biopsy and the absence of distant metastases was confirmed by computer tomography, PET choline or bone scintigraphy. We classified all patients in 3 groups using D'Amico's classification: 4 patients high risk (PSA >20 ng/ml - 8<= Gleason Score<= 10 - clinical stage>=T2c), 8 patients intermediate risk (10 PSAnadir+1.2ng/ml) or after adjuvant therapy introduction. All complications were recorded. Of the 14 patients selected, 12 patients underwent HIFU treatments; 2 patients were excluded because of rectal strictures induced by radiotherapy. At a mean 13 months' follow-up, biochemical success rate was obtained in 1 of the high risk patients and in 5 of the low and intermediate risk patients; 1 man died for a disease not correlated with prostate cancer recurrence. Complications included urinary tract infection, acute urinary retentions, urethral strictures and light stress incontinence. In our experience salvage HIFU is a safe treatment option for local relapse after radiotherapy; its efficacy depends on a careful patient selection. PMID- 21786233 TI - [From lab to clinical activity: adrenergic receptors and human uro-genital tissues]. AB - BACKGROUND: Nowadays translational medicine is acquiring a more and more important role in connecting laboratory experimental results on human tissues to clinical findings and drug employment. We want to underline the importance of in vitro studies, which have been extensively performed on animal organs, but few studies have been performed on human tissues. Nevertheless, a more accurate result when compared to the in vivo use of drugs can be given only by testing the very same human tissues in a lab. We related clinical treatments of different pathologies with the results obtained in laboratory studying in vitro fragments of human organs extracted during surgery exposed to different mediators and drugs. METHODS: Fragments of urethers, bladder (detrusorial muscle and bladder neck muscle fibers), corpora cavernosa, and vas deferens were extracted during demolitive surgery trying not to traumatize the tissue, in order to keep it alive and not to ruin its contractile fibers. The fragments were then put into polisaline solution and, once in the laboratory, fixed on suitable isolated organ support, fixed at one side of the thermostatic pool and on the other side connected to a digital monitoring system. The contractility was then studied after adding different mediators. RESULTS: The urethers have shown a stronger response to NE and PGF2a, with a different contractility in their distal part due to a major concentration of alpha-receptors; the bladder neck has also shown a strong contractile response to NE and PGF2a, and is inhibited by alpha-blockers; the bladder detrusor, instead, responds to ACH (acetylcholine) and PGF2a; the vas deferens shows a different type of contractility in the prostatic part compared to the epididimary part when stimulated with noradrenaline and PGF2a; the corpora cavernosa respond to NE and PGF2a. CONCLUSIONS: The results obtained after stimulating the fragments can explain and prove the receptorial activity of inner mediators and of commonly used drugs which have, for years, been used empirically; the simplicity and repetitivity of the method can be considered and used not only to research the physiological functioning of different organs, but also the functioning of new drugs before testing them on patients, being more reliable and accurate than tests on animal tissues. This experimental work has shown that using human tissues in testing specific mediators is the most reliable laboratory method. PMID- 21786234 TI - [Did the staging of renal neoplasm improve with time? Retrospective study on a cohort of 2000 patients]. AB - OBJECTIVES: During the last 3 decades ultrasonographic and cross-sectional imaging techniques have been widely adopted in the pre-operative staging of renal masses with a progressive technological refinement. The aim of this study is to evaluate if, according to such a change, the accuracy of pre-operative staging is getting better. MATERIALS AND METHODS: A retrospective analysis of 1935 patients, surgically treated at our Institute since 1983 for a renal neoplasm, has been carried out. Dividing the experience in 2 periods, before and after the year 2000, the diagnostic tools adopted during pre-operative staging and their accuracy have been evaluated by a comparison with the post-operative data (accuracy=true positive+true negative/total number of cases), also taking into account each single aspect of staging (dimension of tumor, local extension, venous invasion, lymphnodal and distant metastasis). RESULTS AND DISCUSSION: 994 patients have been treated before 2000, and 941 afterwards. During time, a progressive reduction in the use of urography and, on the other hand, a diffusion of chest CT have been observed, whereas NMR maintained a similar and limited field of application in both periods. During time, the overall accuracy of staging has not significantly improved (69.5% vs 72.3%, p=0.18), but a slightly better staging of distant (93.9% vs 96.7%, p=0.01) and lymphnodal metastasis (90.9% vs 94.8%, p=0.01) can be found. CONCLUSIONS: The pre-operative staging of renal cancer has not really improved during the last 3 decades, in spite of the availability of more precise radiological tools. Anyway, due to the diffusion of CT scan, a slightly better definition of lymphnodal and distant metastasis can be observed. This fact could play a role in indicating a targeted therapy for advanced disease, especially in the light of a neo-adjuvant setting. PMID- 21786235 TI - [Impact of overactive bladder on sexual function in women]. AB - INTRODUCTION: Overactive Bladder (OAB) and Urge Urinary Incontinence (UUI) are both debilitating and bothersome conditions. OAB negatively impact on women's quality of life affecting their own ability and personal relationships. Our aim has been to evaluate how OAB and UUI affect women's sexual function and the possible role of antimuscarinic drugs in improving their sexual condition. MATERIALS AND METHODS: From January 2009 to May 2010, 58 women diagnosed with OAB filled in the self-administered questionnaires: Female Sexual Function Index (FSFI), the short form of Urogenital Distress Inventory (UDI-6) and the Incontinence Impact Questionnaire (IIQ-7). 33 of them (57%) reported a FSFI score<26,55 and were treated with Solifenacin 5mg. they were re-evaluated with the same questionnaires after three months of therapy. RESULTS: The mean FSFI score of 33 patients affected by Female Sexual Disfunction (FSD) was 21,8 (range: 18,6-25,7). The six domains designed to address different aspects of female sexual dysfunctions, sexual desire, satisfaction, orgasm, arousal, lubrication and related pain symptoms, were altered in 48, 33, 21, 15, 12 and 8% of the patients respectively. In 70% of the patients, FSFI score improved of a mean of 5,4 after three months of therapy; UDI-6 and IIQ-7 decreased from 56,3 and 59,9 to 47,6 and 50,2, respectively. Considering women with UUI + OAB or OAB alone, we reported a significant improvement of urinary symptoms and women sexual condition after three months of therapy. CONCLUSION: OAB syndrome was found to cause greater deterioration in women sexual function. Antimuscarinic drugs are the mainstay of pharmacologic treatment of OAB able to improve urinary symptoms, enhance quality of life and female sexual condition. PMID- 21786236 TI - [The association of Serenoa repens, lycopene and selenium is superior to Serenoa repens alone in reducing benign prostatic hyperplasia]. AB - Serenoa repens (SeR) is frequently associated with other natural compounds, such as lycopene (Ly), a carotenoid, and selenium (Se), an essential trace element, to increase its therapeutic activity in benign prostatic hyperplasia (BPH). The LY Se-SeR association has a greater and stronger anti-inflammatory activity than SeR alone. In addition, the LY-Se-SeR combination is more effective than SeR alone in reducing prostate weight and hyperplasia, augmenting apoptosis, and reducing cell proliferation and growth factor expression. This experimental evidence suggests that Ly-Se-SeR association is superior to SeR alone in reducing benign prostate growth. PMID- 21786237 TI - [The repressed Eros in urology]. PMID- 21786238 TI - [Prostiva RF therapy (transurethral needle ablation): evaluation of results from 127 patients]. AB - AIMS OF STUDY: Following the latest guidelines, management of LUTS/BPH includes not only conventional prostatic surgery, but also the minimally invasive treatment (MIT) of symptoms, with great attention given to improvement in the quality of life. One such MIT for BPH is the Prostiva RF Therapy (Transurethral Needle Ablation). The aim of the study was to evaluate the results obtained from 127 patients (pts) treated with Prostiva. MATERIALS AND METHODS: The Prostiva RF Therapy is a MIT indicated in the treatment of BPH<50 gr with no median lobe and with PSA inside normal limits. This procedure employs low-level radio frequency energy delivered from a generator. From October 2004 to January 2009 120 pts (mean age: 64 years) were treated with Prostiva RF Therapy at two Italian centers. International Prostate Symptom Score (I-PSS), Quality of life (QoL) and Index of Erectile Dysfunction (IIEF5) were compared between baseline and last follow-up. RESULTS: Mean FU was 27 months +/- 24. At baseline, the mean prostate size was 36.62+/-16 gr. At enrollment, 70 of 120 pts (58%) were under pharmacological treatment for BPH. 102 pts were treated under spinal anesthesia and 18 under local anesthesia. The total average time of the procedure was 28'. The average number of ablations was 5. Uroflowmetry showed a significant improvement in 67% of pts. 63% reported overall satisfaction with I-PSS and QoL improvement. 25% pts needed further therapies (15% pharmacological, 10% TURP). There were no serious complications, 12% needed prolonged catheterization (max 7 days), 6% experienced transient irritation (max 2 weeks), 5 pts experienced transitory ejaculation disorders, and 1 pt anejaculation. There were no significant differences in IIEF -5 either before or after the procedure. CONCLUSIONS: In our experience the PT was effective in 66% of treated patients. The procedure was easy, safe and feasible to be carried out under local anesthesia. PMID- 21786239 TI - [US-guided percutaneous radio frequency in kidney cancer: our experience]. AB - The radio frequency ablation of kidney cancer showed satisfactory results at a short follow-up with the use of a new RF generator system. Radio frequency is an alternative procedure with the intention of producing heat damage to tissue by electromagnetic energy. METHODS: From January 2009 to July 2010, at our operative unit, ten patients (age range: 50-83 years) underwent percutaneous radio frequency. All tumors were primitive without secondarism. The lesion diameter ranged from 15 to 35 mm. Only in two cases the treatment was open due to difficulties in finding the lesion. RESULTS: At six months' treatment, two patients had a complete remission and one patient an incomplete one; at eight months, five patients are with a complete remission and one patient with complete remission; at twelve months, one patient showed an incomplete remission. CONCLUSIONS: There are no studies with a long-term follow-up and it is prudent to limit this therapy to those patients who can not undergo surgical treatment. A correct post-operative imaging evaluation is essential to ensure an effective treatment. PMID- 21786240 TI - Establishing the learning curve for a tunneled dialysis catheter placement. AB - PURPOSE: To determine how many procedures a surgical trainee requires before they are able to place a tunneled double-lumen dialysis catheter safely on their own. METHODS: Surgical trainees unfamiliar with the procedure received a pre-operative briefing in which we explained 1) why, how, and in what particular order each operational step should be executed and 2) what the possible pitfalls/complications are. Next, an experienced surgeon demonstrated the procedure with the trainee scrubbed-in as their assistant. The trainee then performed all successive procedures, while the supervising surgeon acted as a silent observer and intervened only when an error was made. We recorded all errors as well as near misses and noted if they were severe, recurrent or unanticipated. At least three procedures were required but training was continued until less than three errors were made. RESULTS: Ten trainees were included in the study. On average, a trainee made 11.9 mistakes during 3.4 procedures in a time span of 28.2 days. Only three trainees performed their last procedure flawlessly. The number of errors decreased exponentially from the first procedure onwards (P<.001). A statistically significant correlation was found between the number of mistakes and the number of days since the last procedure (P<.035). Unanticipated errors most frequently involved erroneous fluoroscopy interpretation, flushing with blood-contaminated saline, and incorrect volume injection for the heparin lock. CONCLUSIONS: A theoretically well-prepared surgical trainee should be able to perform the placement of a tunneled dialysis catheter safely after four procedures. Training is more efficient when procedures follow each other quickly. PMID- 21786241 TI - Identification of risk factors for catheter-related thrombosis in patients with totally implantable venous access ports in the forearm. AB - PURPOSE: To identify risk factors for the development of catheter-related thrombosis (CRT) in patients with totally implantable venous access ports (TIVAP) in the forearm, and to analyze the effect of prophylaxis and treatment. METHODS: We retrospectively identified 200 patients (94 men, 106 women, mean age 57.7 +/ 14 y) with TIVAP implantation in the forearm between 3/2010 and 11/2010. Type, number of punctures and sonographically defined diameter of the accessed vein were analyzed. Chemotherapy administered prior to the implantation procedure and history of thrombo-embolic events were assessed. Thrombo-embolic prophylaxis (TEP) following port implantation and treatment as well as course of CRT were analyzed. RESULTS: Twenty-one patients (10.5%) were diagnosed with CRT. Accessed vessels and mean diameter were basilic (n=150, 3.7 mm), brachial (n=39, 3.5 mm) and cephalic (n=11, 3.5 mm) vein. Neither type nor vessel diameter had effect on CRT development (P>.05). Implantation in the left forearm resulted in a significantly higher rate of CRT (P=.04). Ninety-five patients (47.5%) received chemotherapy and 30 patients (15.0%) had a history of thrombosis prior to implantation; both had no effect on development of CRT. Low molecular weight heparin (LMWH) was prescribed in 94/200 patients (47.0%) and had no effect on development of CRT (P>.05). Therapeutic anticoagulation with LMWH resulted in clinical improvement in 12/21 patients (57.4%). CONCLUSIONS: TIVAPs of the forearm may be associated with a certain rate of early and late CRT. The simplest vein to puncture should be selected for vascular access. Thrombo-embolic prophylaxis appears to be rather ineffective for prevention of CRT. PMID- 21786242 TI - Intrapleural migration of a percutaneous transhepatic hemodialysis catheter. AB - Percutaneous transhepatic catheters are a form of nonconventional access for patients requiring hemodialysis. We report a complication of these catheters which has not been previously described in the literature. The mechanism for intrapleural migration and a way to avoid this potential complication are discussed. PMID- 21786243 TI - Delayed percutaneous closure of the subclavian artery after inadvertent placement of a hemodialysis catheter. PMID- 21786244 TI - Technique for a single-time correction of arteriovenous fistula aneurysm in conjuction with creation of a new venous drainage pathway. AB - Aneurysm and stenosis are among the most frequent complications of an arteriovenous fistula (AVF) for hemodialysis. The occurrence of the two kinds of problem may be found in one and the same patient, affecting the use of the AVF and even rendering its use impossible. We report the technique used for correction of a patient's aneurysmal dilations of radio-cephalic AVF and stenosis after the aneurysmal segment, with an increase in post-punction bleeding during the hemodialysis sessions. This was treated with resection and aneurysmorrhaphy associated with the preparation of a new anastomosis with the brachial vein. PMID- 21786245 TI - Blood flow measurements during hemodialysis vascular access interventions- catheter-based thermodilution or Doppler ultrasound? AB - PURPOSE: To test the clinical performance of catheter-based thermodilution and Doppler ultrasound of the feeding brachial artery for blood flow measurements during hemodialysis vascular access interventions. METHODS: Thirty patients with arteriovenous fistulas who underwent 46 interventions had access blood flow measured before and after every procedure. Two methods, catheter-based thermodilution and Doppler ultrasound, were compared to the reference method of ultrasound dilution. Catheter-based thermodilution and Doppler ultrasound were performed during the endovascular procedures while flow by ultrasound dilution was determined within three days of the procedure. The methods were compared using regression analysis and tested for systematic bias. RESULTS: Failure to position the thermodilutional catheter correctly was observed in 8 out of 46 (17%) pre-intervention measurements. Post-intervention measurements and ultrasound measurements were feasible in all patients. The average level of agreement was good when comparing catheter-based thermodilution to ultrasound dilution. However, blood flow by ultrasound dilution may differ by +/-130 mL/min (+/-22%) at a flow level of 600 mL/min by thermodilution. Results from Doppler ultrasound displayed a moderate level of agreement on average when compared to ultrasound dilution. Blood flow by ultrasound dilution may differ by +/-160 mL/min (+/-27%) at a flow level of 600 mL/min by Doppler ultrasound. No systematic bias was detected by either method. CONCLUSIONS: On average, results from catheter-based thermodilution were more in agreement with results from the ultrasound dilution technique compared to Doppler ultrasound. However, considering the cost and the high technical failure rate of the thermodilutional system, we recommend the use of ultrasound. PMID- 21786246 TI - Successful repair of a ruptured arterio-venous fistula aneurysm with femoral vein autograft. PMID- 21786247 TI - Is CD133 a biomarker for cancer stem cells of colorectal cancer and brain tumors? A meta-analysis. AB - BACKGROUND: CD133 has been used to identify normal and cancer stem cells from several different tissues. Nowadays some researchers have reported that CD133 expression was not restricted to cancer stem cells (CSCs) of colorectal cancer and brain tumors, and CD133-negative subsets could also initiate tumors. We therefore performed a meta-analysis to assess the value of CD133 as a biomarker of CSCs for colorectal cancer and brain tumors. METHODS: A Medline search was performed to identify relevant studies for the analysis. The meta-analysis was done using RevMan 5.0 software. Outcome measures were colony formation rate and xenotransplanted tumor formation rate. RESULTS: Fifteen identified studies were available for analysis. For in vitro tests, there were no significant differences in the colony formation rates between CD133-positive and CD133-negative cells for colorectal cancer and brain tumors. For in vivo tests, the xenotransplanted tumor formation rate showed a significant difference between CD133-positive cells and CD133-negative cells in colorectal cancer only, corresponding to a risk difference of 0.40 (95%CI: 0.07, 0.73). Samples (cell lines versus tissues), applied biomarkers (combined versus single), and injection site were included as factors in sensitivity analyses, but the results were very inconsistent. CONCLUSIONS: CD133 may not be suitable as a universe biomarker in identifying CSCs of colorectal cancer and brain tumors. Additional studies are necessary to further delineate its role. PMID- 21786248 TI - Overexpression of GLUT1 in colorectal cancer is independently associated with poor prognosis. AB - BACKGROUND: To investigate the expression of glucose transporter 1 (GLUT1) in colorectal cancer (CRC) and its relationship to clinicopathological variables. METHODS: The expression of GLUT1 in 163 primary tumors together with the corresponding normal mucosa, and 36 liver metastases was examined using real-time PCR. RESULTS: The mean value of GLUT1 was higher in primary tumors (50.390 +/- 68.648) than in the corresponding normal mucosa (20.437 +/- 28.703, p<0.0001), while there was no significant difference in GLUT1 expression between CRC and liver metastasis (50.390 +/- 68.648 vs 52.277 +/- 52.482, p=0.190). In CRCs, GLUT1 expression was higher in poorly differentiated than in well and moderately differentiated tumors (p=0.022), and higher in stage III + IV than in stage I + II tumors (p=0.035). The patients with high-expressed GLUT1 had a worse prognosis than those with low-expressed GLUT1 independently of gender, age, tumor site, stage and differentiation (p=0.026, RR 2.737, 95% CI 1.126-6.651) in stage I-III CRCs. In liver metastasis, GLUT1 expression was higher in larger tumors than in smaller ones (p=0.025). CONCLUSIONS: Overexpression of GLUT1 in stage I-III CRCs was independently associated with poor prognosis. PMID- 21786249 TI - Acute kidney injury due to rhabdomyolysis in narcotic drug users. AB - BACKGROUND: Regular or illegal drugs and toxins are the most frequent non physical causes of rhabdomyolysis (RM) in peacetime. Acute kidney injury (AKI) is a serious and, sometimes, fatal complication of RM. It occurs in 8-20% of RM incidents. METHODS: In this prospective study we evaluated the severity of RM and AKI in narcotic drug users. From January 2001 to December 2007, 21 patients (17 males, mean age 27.8+/-4.8 years) with RM associated with AKI were classified into two groups: 11 heroin users (HU) and 10 non-heroin users (NHU). The severity of RM was evaluated by estimation, on admission, of serum creatine phosphokinase (CPK), serum glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), phosphate (PO4 ) and calcium (Ca) and by the presence of paraplegia (PPL). The severity of AKI during hospitalization was evaluated by estimation of serum creatinine (CR), the presence of oligoanuria (OA), the days of hospitalization (DH), the total of hemodialysis treatments (THD) and the number of patients who received blood transfusions (BT). RESULTS: RM was much more severe in HU than in NHU. Mean SGOT, CPK, LDH, and P values on admission were higher in HU. Hypocalcemia was statistically more severe in HU. Nine HU were admitted with PPL vs. 1 NHU. Serum CR levels were higher and oligoanuria was much more common in HU. HU had a longer hospitalization period and underwent a bigger number of HT. More HU took BT. CONCLUSIONS: The results of this study suggest that both RM and ARF are more severe in HU than in NHU possibly due to an additional myotoxic effect of heroin. PMID- 21786250 TI - Apheresis as rescue therapy in a severe case of sudden hearing loss. AB - A 23-year-old man complained of progressive left ear hearing loss and tinnitus and was unsuccessfully treated with steroids and mannitol. Four months later he presented with sudden, severe, asymmetrical, bilateral sensorineural hearing loss. The results of the laboratory workup were normal except for antinuclear autoantibodies. Auditory brain stem responses showed absent peak and interpeak latencies on both sides. The combination of plasma exchange with high doses of steroids resulted in a definite improvement. Plasmapheresis combined with steroid administration can be used as second-line therapy in idiopathic, sudden sensorineural hearing loss. PMID- 21786251 TI - Euthyroid sick syndrome and nutritional status are correlated with hyposelenemia in hemodialysis patients. AB - BACKGROUND: Maintenance hemodialysis (HD) patients have altered levels of thyroid hormone (TH) in euthyroid sick syndrome, along with low T3 levels and several nutritional metabolic disturbances. Selenium (Se) is an essential trace element for living organisms, which has been shown to play a major role in thyroid hormone levels and the nutritional metabolism. The aims of the present study were to assess the changes in serum levels of selenium and their correlation with disorders of the endocrine and nutritional metabolism in HD patients. METHODS: Fifty-three uremic patients with hemodialysis were evaluated; 30 healthy volunteers served as controls. Baseline serum concentrations of total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), and free thyroxine (FT4) were determined by radioimmunoassay (RIA). Serum levels of thyroid-stimulating hormone (TSH) and intact parathyroid hormone (iPTH) were measured by a sensitive immunoradiometric assay (IRMA). Serum selenium was analyzed using Hitachi Z- 2000 polarized Zeeman atomic absorption spectrometry. Other metabolic variables were measured in all patients and control subjects. Multiple correlation analysis was performed among variables. RESULTS: Higher serum triglyceride, LDL-C, ApoB and lower albumin, HDL-C levels were found in subjects with HD. Mean serum selenium concentration was significantly lower in the HD group than in the control group (p<0.01). The levels of serum TT3 and FT3 in HD patients were significantly lower than in healthy control subjects (p<0.01; p<0.05, respectively), but TT4, FT4 and TSH were not different. However, serum iPTH levels were significantly higher in patients than in controls (p<0.01). In the group of HD patients, serum selenium levels were significantly positively correlated with albumin, HDL-C, TT3 and FT3 ; and negatively correlated with triglyceride (TG), LDL-C, ApoB and iPTH. Both serum TT3 and FT3 levels were significantly positively correlated with HDL-C; and negatively correlated with TG, LDL-C and ApoB. CONCLUSIONS: These data suggest that hyposelenemia in HD patients correlated with euthyroid sick syndrome with low T3 levels, and nutritional status with hyperlipidemia and hypoalbuminemia which might be involved in dysfunction in the endocrine and nutrition metabolism in dialysis patients. PMID- 21786252 TI - Surgical therapy of end-stage heart failure: understanding cell-mediated mechanisms interacting with myocardial damage. AB - Worldwide, cardiovascular disease results in an estimated 14.3 million deaths per year, giving rise to an increased demand for alternative and advanced treatment. Current approaches include medical management, cardiac transplantation, device therapy, and, most recently, stem cell therapy. Research into cell-based therapies has shown this option to be a promising alternative to the conventional methods. In contrast to early trials, modern approaches now attempt to isolate specific stem cells, as well as increase their numbers by means of amplifying in a culture environment. The method of delivery has also been improved to minimize the risk of micro-infarcts and embolization, which were often observed after the use of coronary catheterization. The latest approach entails direct, surgical, trans-epicardial injection of the stem cell mixture, as well as the use of tissue engineered meshes consisting of embedded progenitor cells. PMID- 21786253 TI - Video evaluation of the kinematics and dynamics of the beating cardiac syncytium: an alternative to the Langendorff method. AB - Many important observations and discoveries in heart physiology have been made possible using the isolated heart method of Langendorff. Nevertheless, the Langendorff method has some limitations and disadvantages such as the vulnerability of the excised heart to contusions and injuries, the probability of preconditioning during instrumentation, the possibility of inducing tissue edema, and high oxidative stress, leading to the deterioration of the contractile function. To avoid these drawbacks associated with the use of a whole heart, we alternatively used beating mouse cardiac syncytia cultured in vitro in order to assess possible ergotropic, chronotropic, and inotropic effects of drugs. To achieve this aim, we developed a method based on image processing analysis to evaluate the kinematics and the dynamics of the drug-stimulated beating syncytia starting from the video recording of their contraction movement. In this manner, in comparison with the physiological no-drug condition, we observed progressive positive ergotropic, positive chronotropic, and positive inotropic effects of 10 uM isoproterenol (beta-adrenergic agonist) and early positive ergotropic, negative chronotropic, and positive inotropic effects of 10 uM phenylephrine (alpha-adrenergic agonist), followed by a late phase with negative ergotropic, positive chronotropic, and negative inotropic trends. Our method permitted a systematic study of in vitro beating syncytia, producing results consistent with previous works. Consequently, it could be used in in vitro studies of beating cardiac patches, as an alternative to Langendorff's heart in biochemical and pharmacological studies, and especially when the Langendorff technique is inapplicable (e.g., in studies about human cardiac syncytium in physiological and pathological conditions, patient-tailored therapeutics, and syncytium models derived from induced pluripotent/embryonic stem cells with genetic mutations). Furthermore, the method could be helpful in heart tissue engineering and bioartificial heart research to "engineer the heart piece by piece." In particular, the proposed method could be useful in the identification of a suitable cell source, in the development and testing of "smart" biomaterials, and in the design and use of novel bioreactors and microperfusion systems. PMID- 21786254 TI - Nafamostat mesilate as an anticoagulant during continuous veno-venous hemodialysis: a three-year retrospective cohort study. AB - INTRODUCTION: Although nafamostat mesilate, a synthetic serine protease inhibitor, has been commonly used in Japan as an anticoagulant during continuous renal replacement therapy (CRRT), its clinical utility has not been well determined. The aim of this study was to evaluate the efficacy (filter survival) and safety (bleeding complications) of nafamostat mesilate in CRRT for acute kidney injury (AKI) among critically ill patients. METHODS: We retrospectively studied consecutive patients with AKI treated with continuous veno-venous hemodialysis and nafamostat mesilate from April 2005 to March 2008. Demographic, clinical and laboratory data were extracted from the clinical chart. RESULTS: Fifty-eight patients were enrolled in this study (45 males with an average age of 66+/-15 years). The median filter survival was 21.8 h (range: 2.8-55.5 h), and the mean was 20.8+/-8.4 h. Only 38 out of 181 filters (21%) were interrupted because of filter failure within 24 hours and 89 filters (49%) were electively renewed within 24 hours. Activated partial thromboplastin time was elevated especially during the first 24 hours (46.7+/-13.1 s at baseline versus 73.9+/ 24.3 s at day 1; ANOVA p<0.01). Hematocrit level was kept around 30% and did not change significantly (ANOVA p=0.69). No patients experienced major bleeding while treated with CRRT. CONCLUSIONS: Nafamostat mesilate provided sufficient filter survival without causing major bleeding complications despite the prolongation of APTT. PMID- 21786258 TI - Pyomyositis and septic hip arthritis due to bacteroides fragilis. A case report. AB - Bacteroides fragilis is a rare cause of pyomyositis or septic arthritis. We present the case of a 74-year-old otherwise healthy male who presented with fever and right hip pain ten days after a course of intramuscular injections. Magnetic resonance imaging (MRI) showed septic arthritis of the right hip joint and pyomyositis of the right gluteus minimus muscle. Blood cultures and pus aspirated from the muscle grew Bacteroides fragilis. The patient was treated successfully with surgical debridement and metronidazole, administered for six weeks intravenously and five weeks orally. Simultaneous pyomyositis and hip septic arthritis due to Bacteroides fragilis is rare, but should be considered possible after intramuscular injections. PMID- 21786255 TI - Interactions of human embryonic stem cell-derived neural progenitors with an electrospun nanofibrillar surface in vitro. AB - Stem cell technology combined with nano-scaffold surfaces provides a new tool for better induction involved in cell lineage differentiations and therefore for central nervous system repair. This study was undertaken to investigate appropriate neural cell-substrate interactions. Neural progenitors (NPs) were established from human embryonic stem cells (hESCs), as a first step, using an adherent system and a defined medium supplemented with a combination of factors. Next, the behavior of hESC-derived NPs (hESC-NPs) was evaluated on a synthetic, randomly oriented, three-dimensional nanofibrillar matrix composed of electrospun polyamide nanofibers (Ultra-WebTM) using a variety of experimental approaches. We have demonstrated that homogenous, expandable, and self-renewable NPs can be easily generated from hESCs; they can express related markers Nestin, Sox1, and Pax6; and they can undergo multipotency differentiation to neurons and glials. Functionally, NPs cultured on nanofibers demonstrated an increase in the rate of migration, proliferation, morphology, and neurite length when compared with NPs cultured on two-dimensional culture surfaces. The results suggest that topographical features of the extracellular matrix of the cell environment have paved the way for a better understanding of human neuronal development, thus allowing for future clinical applications. PMID- 21786259 TI - Medical management of osteonecrosis of the hip: a review. AB - Osteonecrosis or avascular necrosis (AVN) of the hip is a progressive disease mainly affecting adults in their third, fourth or fifth decade of life. Studies into the natural history of the disease suggest that femoral head collapse occurs within 2-3 yrs with associated degenerative changes and at that stage arthroplasty is the most reliable treatment option. Therefore prevention of femoral head collapse is highly desirable in this young patient group. In early stage disease, before femoral head collapse (Ficat and Arlet stage 1-3) core decompression of the femoral head is currently the most widely used procedure to try to relieve intraosseous pressure in the femoral head and restore blood supply.Greater understanding of the pathogenesis of osteonecrosis has led to research into non-surgical management of early stages of the disease, including pharmacological and biophysical treatments.There may be a reduction in symptoms and evidence of prevention of disease progression following some non-surgical treatments. Further studies are needed, including trials comparing medical management with surgical intervention. PMID- 21786260 TI - Comment on "Minimally invasive management of unstable proximal femoral extracapsular fractures using reverse LISS femoral locking plates". PMID- 21786261 TI - Relationship between the McPherson classification and complications after hip spacer implantation. AB - The implantation of antibiotic-loaded cement spacers is established in the treatment of late hip joint infections, and the McPherson staging system has been widely used in this context. The aim of our study was to evaluate the relationship between the McPherson classification and complications at the site of hip spacer implantation. 60 patients were retrospectively identified who fulfilled our inclusion criteria. Using the McPherson classification, 12 patients were categorised as IIIA1, 4 as IIIA2, 19 as IIIB1, 7 as IIIB2, 12 as IIIC1, and 6 as IIIC2. Complications recorded were infection-associated, mechanical, systemic, general, and mortality. Statistical analysis was performed by means of the Mantel-Haenszel and the exact Fisher tests. In relation to complications with respect to the systemic host grade, the Mantel-Haenszel test revealed significant differences regarding only the emergence of a draining sinus. In relation to complications with respect to the local extremity grade, the exact Fisher test revealed significant differences regarding only the emergence of wound healing complications. All other complications showed no significant differences. The McPherson classification, in association with an increasing number of comorbidities, indicates a higher risk of occurrence of a postoperative draining sinus, whereas the grade of compromised local tissues is associated with wound healing complications. Improvement of the general medical condition of patients between stages as well as an anatomical dissection and closure of the wound may lead to a decreased incidence of these complications. PMID- 21786263 TI - Metal-on-metal hip resurfacing with uncemented fixation of the femoral component. A minimum 2 year follow up. AB - The current generation of metal-on-metal hip resurfacing designs has largely been characterized by cemented femoral fixation using a cementless cup. We present the clinical results of 135 entirely uncemented metal-on-metal hip resurfacing procedures. The primary outcome measures were revision for any cause and the Oxford hip score at the latest follow up. The average length of followup was 2.9 years. The mean Oxford hip score was 18.4 and no patient required revision of either component during the study period. Uncemented femoral fixation may be comparable to fixation with cement in metal-on-metal hip resurfacing. PMID- 21786265 TI - Phacoemulsification in a patient with small pupil and a large iris cyst. AB - PURPOSE: Peripheral iris cysts are generally asymptomatic and nonprogressive. They are usually located in the inferotemporal quadrant of the anterior segmen:, most commonly in the iridociliary sulcus. We report our management strategy in a patient with small pupil and a large iris cyst. METHOD: Retrospective, case report. RESULTS: A 65-year-old man was referred, reporting blurred vision OS. Best-corrected visual acuity (BCVA) was 6/12 OD and 6/48 OS. Anterior chamber (AC) examination OS revealed an iris cyst protruding inferotemporally occupying almost one-third of AC volume. Intraocular pressure (IOP) was 32 mmHg OS and 19 mmHg OD. Aspiration with a 27-G cannula, without cyst resection, was performed. Phacoemulsification and intraocular lens implantation were uneventful. The BCVA improved to 6/9 1 week postoperatively and to 6/6 a month later. In the first postoperative visit, IOP dropped to 16 mmHg. The cyst was significantly decreased in size. Six months postoperatively, BCVA remained unchanged while AC examination revealed that the cyst remained in place with no signs of enlargement. CONCLUSIONS: In this case, cyst aspiration was elected as a treatment procedure that led to significant decrease in size. This management option, combined with an uncomplicated cataract extraction procedure, resulted in an excellent visual and a positive anatomic outcome. PMID- 21786266 TI - Fundus autofluorescence patterns in type 2A idiopathic juxtafoveolar retinal telangiectasis. AB - PURPOSE: To describe fundus autofluorescence (FAF) patterns in patients with type 2A idiopathic juxtafoveolar retinal telangiectasia (IJRT). METHODS: We reviewed FAF images, color photographs, and fluorescein angiography (FA) images of 30 eyes from 16 patients with type 2A IJRT. Eyes with presence of subretinal neovascularization or any other retinal pathology were excluded. All the imaging modalities were obtained with a Heidelberg Retina Angiograph (HRA) confocal laser scanning system. RESULTS: The mean age of the patients was 50.7 years, 68.5% female. At baseline, the median best-corrected visual acuity was 20/50. Loss of normal foveal hypoautofluorescence was noted in 93.3% of eyes. All the eyes showed hypoautofluorescence corresponding to intraretinal crystals and pigment clumps. Increased FAF around the pigments was noted in 93.3% of eyes. Increased FAF corresponding to the angiographic leakage from telangiectatic and nontelangiectatic areas was noted in 86.6% of eyes and 80% of eyes, respectively. CONCLUSIONS: Loss of foveal hypoautofluorescence and increased FAF corresponding to the nontelangiectatic angiographic leakage areas were predominant features. Fundus autofluorescence patterns corresponding to color photography and FA findings may further add to the understanding of morphologic alterations in type 2A nonproliferative IJRT at early stages. PMID- 21786267 TI - Clinical presentation and surgical outcomes in primary myopic macular hole retinal detachment. AB - PURPOSE: To describe the clinical presentation of primary macular hole retinal detachment (MHRD) secondary to high myopia and to evaluate the surgical outcomes. METHODS: Nine eyes of 9 patients with primary myopic MHRD (axial length =26.5 mm) were enrolled. A standardized surgical protocol was performed using vitrectomy with preservative-free triamcinolone acetonide-assisted internal limiting membrane (ILM) peeling and silicone oil tamponade and were followed for at least 6 months from the first surgery. RESULTS: There were 6 women and 3 men with a median age of 52 years. Six (66.6%) patients presented with inferior bullous configuration and 3 had subtotal retinal detachment. The mean preoperative refractive error (spherical equivalent) and mean axial length was 12 +/- 3.553 D (range 8.50-19.50) and 28.13 +/- 1.65 mm (range 26.50-31.50), respectively. The patients were followed up for a period of at least 6 months. The retina was attached and macular hole closed in all the eyes. There was significant visual acuity improvement from mean preoperative visual acuity of logMAR 1.85 +/- 0.11 (range 1.76-1.93) to postoperative visual acuity of logMAR 0.95 +/- 0.14 (range 0.84-1.06) (p<0.001). CONCLUSIONS: Retinal detachment in highly myopic eyes can often be secondary to a macular hole with predominance of inferior bullous configuration and primary vitrectomy with ILM peeling with silicone oil tamponade results in good anatomic and functional outcomes. PMID- 21786268 TI - Evaluation of collagen crosslinking in keratoconus eyes with Kera intracorneal ring implantation. AB - PURPOSE: To assess the outcome of collagen crosslinking (CXL) in keratoconus eyes after implantation of Kera intracorneal ring segments. PATIENTS AND METHODS: Twenty-one eyes of 13 patients with mild to moderate degree of keratoconus were included in this study. All eyes had uneventful surgery for Kera intracorneal ring segment implantation followed by collagen CXL treatment after at least 3 months of the implantation. Inclusion criteria were absence of corneal scarring and corneal thickness higher than 400 mm. Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), spherical equivalent and cylinder refraction, and the mean keratometric (K) values were evaluated preoperatively and postoperatively. RESULTS: The mean age was 21.36 +/- 4.46 years (range 16-28). Mean time between implantation of Kera ring and CXL was 4.56 +/- 3.2 months. The mean baseline UCVA and BCVA were 0.05 +/- 0.02 and 0.18 +/- 0.1, respectively; after Kera ring, the mean UCVA and BCVA were 0.23 +/- 0.17 and 0.39 +/- 0.18 (p=0.000), respectively. Collagen CXL after Kera ring resulted in an additional change in UCVA and BCVA to become 0.23 +/- 0.17 (p=0.951) and 0.41 +/- 0.18 (p=0.08), respectively. Also, CXL results in an additional change in spherical equivalent, cylindrical, and mean keratometric values. The decrease in spherical equivalent, cylindrical, and mean keratometric value was 2.8 D (p<0.05), 2.1 D (p<0.05), and 2.5 D (p<0.05), respectively, after Kera ring treatment. An additional decrease of 0.11 D (p>0.05), 0.01 D (p>0.05), and 0.09 D (p>0.05) was obtained after CXL in each respective parameter. CONCLUSIONS: Collagen CXL has an additive effect after Kera ring implantation and may be considered as an enhancement/stabilizing procedure. PMID- 21786270 TI - Collagen crosslinking for ectasia following PRK performed in excimer laser assisted keratoplasty for keratoconus. AB - PURPOSE: To report the results of corneal collagen crosslinking (CXL) in a patient with corneal ectasia developed after excimer laser-assisted lamellar keratoplasty for keratoconus and a secondary photorefractive keratectomy (PRK) for residual refractive error. METHODS: A 33-year-old woman, who had originally been treated for keratoconus in the right eye by excimer laser-assisted lamellar keratoplasty, subsequently had her residual ametropia treated by topographically guided, transepithelial excimer laser PRK. Five years after PRK, the patient developed corneal ectasia showing concomitant visual changes of best spectacle corrected visual acuity (BSCVA) reduced to 20/33 with a refraction of -6.00 +6.00 * 30. The minimum corneal thickness at the ectasia apex was 406 um. A treatment of riboflavin-UVA-induced corneal CXL was performed on the right eye. RESULTS: Two years after the CXL treatment, the right eye improved to 20/20 BSCVA with a refraction of plano +1.00 * 50 while exhibiting a clear lamellar graft. CONCLUSIONS: Corneal CXL provided safe and effective management of ectasia developed after excimer laser-assisted lamellar keratoplasty and PRK. PMID- 21786271 TI - Analgesic effect of etoricoxib (Arcoxia(r)) 120 mg during retinal laser photocoagulation. AB - PURPOSE: Panphotocoagulation reduces the risk of vision loss in proliferative diabetic retinopathy. However, not many patients tolerate this treatment well due to pain. Therefore, we evaluated the analgesic effect of etoricoxib during photocoagulation in patients with proliferative diabetic retinopathy. METHODS: A prospective, randomized, double-blind study was conducted on 44 consecutive patients eligible for panphotocoagulation due to proliferative diabetic retinopathy. During the first panphotocoagulation session, both groups were treated without medication. During the following session, the control group received a placebo pill while the other group received etoricoxib 120 mg. Both groups took the medicines 1 hour before the treatment. After each session, the patients quantified the level of pain on a subjective visual scale. RESULTS: A total of 52 patients were selected for the study and the data of 44 patients were analyzed. In the control group, the average level of pain in the first session was 7.68 (standard deviation 1.70), dropping to an average of 7.32 (standard deviation 1.39) after ingestion of placebo. Therefore, there was no statistical difference (p = 0.1187). In contrast, the average level of pain without the drug in the group taking etoricoxib 120 mg was 7.95 (standard deviation 1.46) vs 5.18 (standard deviation 1.65) with the drug, a significant statistical difference (p<0.001). CONCLUSIONS: Etoricoxib 120 mg reduces pain and can be used before panphotocoagulation. Data show that the medication is more effective against pain during photocoagulation than placebo. PMID- 21786272 TI - Localized foveal detachment in a patient with central retinal artery occlusion with cilioretinal sparing. AB - PURPOSE: To report the optical coherence tomography (OCT) findings of acute central retinal artery occlusion (CRAO) with cilioretinal sparing. METHODS: Optical coherence tomography findings in a 45-year-old man with CRAO with cilioretinal sparing were evaluated. RESULTS: Optical coherence tomography disclosed diffuse thickening of the neurosensory retina in the perifoveolar area. Increased reflectivity was noted in the inner retinal layers. The hyporeflectivity is observed in the outer retina including the outer neurosensory retina. The photoreceptors are not seen because of the shadowing effect. A localized foveal detachment composed of a dome-shaped retinal elevation over a nonreflective cavity with minimal shadowing of the underlying tissues was seen. CONCLUSIONS: The OCT findings showed that besides the usual OCT findings in acute CRAO, the presence of a cilioretinal artery might lead to the leakage of fluid into the subfoveal space leading to localized detachment. PMID- 21786274 TI - Patients with neovascular age-related macular degeneration in Spain display a high cardiovascular risk. AB - PURPOSE: Cardiovascular disease and its risk factors may have a significant role in the development of neovascular age-related macular degeneration (NV-AMD). This study aims to assess the impact of these factors in this population and define their level of cardiovascular risk according to the Framingham model. METHODS: This was a cross-sectional, observational, multicenter study that included patients aged 50 years or older who attended ophthalmic centers for the diagnosis or follow-up of NV-AMD. Information collected included demographic and AMD data, a complete history of cardiovascular disease and its risk factors, lipid profile, blood pressure, and treatment history. RESULTS: The study population consisted of 901 patients, predominantly Caucasian, with a mean age of 75.7 years, receiving anti-vascular endothelial growth factor therapy for their NV-AMD in 77.7% of the cases. Blood pressure measurement during the study visit and lipid analyses revealed poor control in 67.7% and 93.3% of the patients, respectively. Hypertension was the most prevalent cardiovascular risk factor (77.7%), followed by a history of cardiac disease or other forms of atherosclerotic disease (53.8%). Diabetes was present in 28% of the subjects. The study population was considered a high-risk population according to the National Cholesterol Education Program Expert Panel Clinical Guidelines (NCEP ATP III), with a probability of a cardiovascular event in 10 years of 19.3% according to the Framingham model. CONCLUSIONS: This NV-AMD population is associated with a significant cardiovascular risk, and the Framingham model can help us identify those subjects with higher risk levels in order to improve their overall management. PMID- 21786273 TI - Graves' orbitopathy: extraocular muscle/total orbit area ratio is positively related to the Clinical Activity Score. AB - BACKGROUND AND OBJECTIVE: Both extraocular muscle (EOM) and orbital fat are involved in Graves' orbitopathy (GO) but their enlargement might occur with a different temporal pattern. Two GO subtypes have been described, one with predominant EOM enlargement and the other with prevalent fat tissue involvement. We longitudinally investigated the EOM in patients with GO and their relationship with clinical activity. PATIENTS AND METHODS: By using commercial software with a segmentation technique, we calculated from computed tomography (CT) scan EOM coronal area (CA) and total orbit coronal area (TOA) in 23 control subjects and in 32 patients with GO. The latter were studied both at presentation and 18 months later. Superior, lateral, inferior, and medial EOM areas and TOA were selected by 3 different contiguous CT slices: A, B, and C, chosen at globe pole tangent and 2 and 4 mm backward. The Clinical Activity Score (CAS) was also measured. RESULTS: Orbital EOM CA/TOA ratio (OM/TOA ratio) after 18 months decreased in most patients with GO, indicating that EOM area decrement contributed significantly to OM/TOA ratio reduction. Clinical Activity Score decrease was significantly correlated to the OM/TOA ratio decrease. CONCLUSIONS: An easy method to measure CA of EOM and orbit allowed us to observe that in most patients with GO the OM/TOA ratio decreases with time, suggesting that macroscopic EOM involvement occurs initially and resolves as the other clinical signs and symptoms of the disease resolve, as indicated by the significant OM/TOA ratio correlation with CAS. PMID- 21786275 TI - Bilateral choroidal neovascularization associated with bilateral ABCA4 gene mutation. AB - PURPOSE: To describe a case of ABCA4 gene mutation (G1961E) associated with bilateral choroidal neovascularization (CNV) treated with intravitreal ranibizumab injections. METHODS: A 52-year-old man with bilateral CNV associated with ABCA4 gene mutation underwent complete ophthalmologic examination over a 30 month follow-up and was treated with intravitreal ranibizumab injections on an as needed basis. RESULTS: Baseline best-corrected visual acuity (BCVA) was 20/32 in the right eye (RE) and 20/63 in the left eye (LE). Two small CNVs with juxtafoveal location were detectable in the RE, whereas a single subfoveal CNV was visible in the LE. Overall, 6 and 9 intravitreal ranibizumab injections were administered in RE and LE, respectively, during the 30-month follow-up. At the end of the follow-up, BCVA was 20/100 in the RE and 20/200 in the LE. CONCLUSIONS: This case report reveals that ABCA4 gene mutation may be complicated by multiple and bilateral CNVs. Intravitreal injection of ranibizumab can achieve temporary CNV stabilization, but cannot guarantee complete quiescence over a long term follow-up. Other therapeutic approaches could be necessary to accomplish visual acuity preservation. PMID- 21786276 TI - Photosensitizers form in histidine buffer and mediate the photodegradation of a monoclonal antibody. AB - Fluorescent light (FL) photodegradation of a monoclonal antibody (mAb) formulated in histidine buffer is mediated by histidine-derived photosensitizers that accumulate and greatly increase with light exposure. Histidine-derived photosensitizers are the primary mediators of Trp photooxidation. FL photodegradation requires light exposure and is pH dependent. It is significantly reduced or eliminated by buffer exchanges, by oxygen depletion, or at pH values greater than 7. Antibody-fragment MS ion counts reveal that oxidation of a single light chain Trp in CDR1 correlates with binding loss. Multiple heavy chain methionines oxidize, but poorly correlate with binding loss. Photosensitizers extracted from photo-aged histidine buffer are potent mediators of FL photodegradation including oxidation and, to a lesser degree, fragmentation and aggregation of the mAb. These photosensitizers absorb visible light and have neutral mass of 187.1- 386.1 Da. They are also fluorescent with ex/em at 360/450 nm. When spiked into histidine or MES buffered mAb formulations they produce a concentration dependent and pronounced increase in FL-photodegradation; however, no oxidation or loss of antibody function occurs in the dark and hydrogen peroxide does not oxidize Trp. The major component is consistent with histidine oxidation to 6a-hydroxy-2-oxo-octahydro-pyrollo[2,3-d]imidazole-5-carboxylic acid. Photosensitizer levels measured in the formulation prior to light exposure, are linearly related to the FL-photodegradation observed and can predict degradation in photostability testing. PMID- 21786277 TI - Frailty models: Applications to biomedical and genetic studies. AB - In survival analysis, frailty models are potential choices for modeling unexplained heterogeneity in a population. This tutorial presents an overview and general framework of frailty modeling and estimation for multiplicative hazards models in the context of biomedical and genetic studies. Other topics in frailty models, such as diagnostic methods for model adequacy and inference in frailty models, are also discussed. Examples of analyses using multivariate frailty models in a non-parametric hazards setting on biomedical datasets are provided, and the implications of choosing to use frailty and relevance to genetic applications are discussed. PMID- 21786278 TI - Subgroup identification based on differential effect search--a recursive partitioning method for establishing response to treatment in patient subpopulations. AB - We propose a novel recursive partitioning method for identifying subgroups of subjects with enhanced treatment effects based on a differential effect search algorithm. The idea is to build a collection of subgroups by recursively partitioning a database into two subgroups at each parent group, such that the treatment effect within one of the two subgroups is maximized compared with the other subgroup. The process of data splitting continues until a predefined stopping condition has been satisfied. The method is similar to 'interaction tree' approaches that allow incorporation of a treatment-by-split interaction in the splitting criterion. However, unlike other tree-based methods, this method searches only within specific regions of the covariate space and generates multiple subgroups of potential interest. We develop this method and provide guidance on key topics of interest that include generating multiple promising subgroups using different splitting criteria, choosing optimal values of complexity parameters via cross-validation, and addressing Type I error rate inflation inherent in data mining applications using a resampling-based method. We evaluate the operating characteristics of the procedure using a simulation study and illustrate the method with a clinical trial example. PMID- 21786279 TI - Monitoring binary outcomes using risk-adjusted charts: a comparative study. AB - Monitoring binary outcomes when evaluating health care performance has recently become common. Classical statistical methodologies such as cumulative sum (CUSUM) charts have been refined and used for this purpose. For instance, the risk adjusted CUSUM chart (RA-CUSUM) for monitoring binary outcomes was proposed for monitoring 30-day mortality following cardiac surgery. The RA-CUSUM inherits optimality properties of the original CUSUM charts in the sense of signaling early when there is change. However, although the RA-CUSUM is a powerful monitoring tool, it will always eventually signal a change with probability 1 even when there is no real change. In other words, the probability of a type I error for the RA-CUSUM is 1. It also turns out that, because of the skewed distribution of the run lengths of the RA-CUSUM, the median is often well below the mean, and as a consequence more than half of all its false alarms occur before the designed average run length. In addition, when the change to be detected occurs at a later time in the series of observations being monitored, the rate of false alarms increases, and the RA-CUSUM may not be appropriate. Therefore, if the price of false alarms is high, it is preferable to use methods that control the rate of false alarms. In this paper, we propose alternative sequential curtailed and risk-adjusted charts that control the type I error rate in the context of monitoring 30-day mortality following cardiac surgery. We explore the merits of each of these methodologies in terms of average run lengths as well as in terms of type I error probabilities, and we compare them to the RA CUSUM chart. We illustrate the methodologies by using data on monitoring performance of seven surgeons from a medical center. PMID- 21786280 TI - Semiparametric transformation models for joint analysis of multivariate recurrent and terminal events. AB - Recurrent event data occur in many clinical and observational studies, and in these situations, there may exist a terminal event such as death that is related to the recurrent event of interest. In addition, sometimes more than one type of recurrent events may occur, that is, one may encounter multivariate recurrent event data with some dependent terminal event. For the analysis of such data, one must take into account the dependence among different types of recurrent events and that between the recurrent events and the terminal event. In this paper, we extend a method for univariate recurrent and terminal events and propose a joint modeling approach for regression analysis of the data and establish the finite and asymptotic properties of the resulting estimates of unknown parameters. The method is applied to a set of bivariate recurrent event data arising from a long term follow-up study of childhood cancer survivors. PMID- 21786281 TI - Characterizing global statistical significance of spatiotemporal hot spots in magnetoencephalography/ electroencephalography source space via excursion algorithms. AB - Identifying brain regions with high differential response under multiple experimental conditions is a fundamental goal of functional imaging. In many studies, regions of interest (ROIs) are not determined a priori but are instead discovered from the data, a process that requires care because of the great potential for false discovery. An additional challenge is that magnetoencephalography/electroencephalography sensor signals are very noisy, and brain source images are usually produced by averaging sensor signals across trials. As a consequence, for a given subject, there is only one source data vector for each condition, making it impossible to apply testing methods such as analysis of variance. We solve these problems in several steps. (1) To obtain within-condition uncertainty, we apply the bootstrap across trials, producing many bootstrap source images. To discover 'hot spots' in space and time that could become ROIs, (2) we find source locations where likelihood ratio statistics take unusually large values. We are not interested in isolated brain locations where a test statistic might happen to be large. Instead, (3) we apply a clustering algorithm to identify sources that are contiguous in space and time where the test statistic takes an 'excursion' above some threshold. Having identified possible spatiotemporal ROIs, (4) we evaluate global statistical significance of ROIs by using a permutation test. After these steps, we check performance via simulation, and then illustrate their application in a magnetoencephalography study of four-direction center-out wrist movement, showing that this approach identifies statistically significant spatiotemporal ROIs in the motor and visual cortices of individual subjects. PMID- 21786282 TI - Extended mixture factor analysis model with covariates for mixed binary and continuous responses. AB - Finite mixture factor analysis provides a parsimonious model to explore latent group structures of high-dimensional data. In this modeling framework, we can explore latent structures for continuous responses. However, dichotomous items are often used to define latent domains in practice. This paper proposes an extended finite mixture factor analysis model with covariates to model mixed continuous and binary responses. We use a Monte Carlo expectation-maximization (MCEM) algorithm to estimate the model. In the E step, closed-form solutions are not available for the conditional expectation of complete data log likelihood, so it is approximated by sample means, which are in turn generated by the Gibbs sampler from the joint conditional distribution of latent variables. To monitor the convergence of the MCEM algorithm, we use bridge sampling to calculate the log likelihood ratio of two successive iterations. We adopt a diagnostic plot of the log likelihood ratio against iterations for monitoring the convergence of the MCEM algorithm. We compare different models based on BIC, in which we approximate the observed data log likelihood by using a Monte Carlo method. We investigate the computational properties of the MCEM algorithm by simulation studies. We use a real data example to illustrate the practical usefulness of the model. Finally, we discuss limitations and possible extensions. PMID- 21786283 TI - Assessing covariate imbalance in meta-analysis studies. AB - The main goal of meta-analysis is to combine data across studies or data sets to obtain summary estimates. In this paper, the novelty is to propose a statistical tool to assess a possible covariate imbalance in baseline variables to investigate similarity of trials. We conducted the detection of the covariate imbalance, first, through some graphical comparison of the empirical cumulative distribution functions or ECDFs, which are built by putting together arms or trials according to some risk factor, and second, through some non-parametric tests such as the Kolmogorov-Smirnov and the Anderson-Darling tests. To overcome the huge presence of ties, we conducted the statistical tests on perturbed versions of the original data sets. The applications concern two real meta analyses of RCTs: the first one, on interferon-alpha treatment of chronic hepatitis C, with 107 studies involved, and the second one, on cholesterol lowering treatment with statins, with 14 studies involved. The applications allow for analysis of both when risk factors reflecting demographic or clinical differences in experimental and control arms are balanced or not and when there are structural differences between the levels of some study variables, in order to proceed eventually with the pooling of the studies. We developed our suggestion, which is a quantitative way to assess combinability in meta-analysis, only with respect to RCTs, but it could be applied to a minor extent to non-RCTs. PMID- 21786284 TI - Multiple imputation for completion of a national clinical audit dataset. AB - The Myocardial Ischaemia National Audit Project (MINAP) is a register of heart attacks covering 234 acute admitting hospitals in England and Wales. It is used to assess the extent to which hospitals are attaining the government targets for patients with heart attacks (myocardial infarction). MINAP is therefore of national importance in coronary care and of potential international importance for research. As with most observational databases, there is missing data in MINAP, which has the potential to bias statistical analyses. In this paper, we use multiple imputation to reduce the impact of missing data and we give details of how our imputation scheme was implemented. The key contribution of this paper is the provision of multiply completed datasets, suited to a range of analyses, that can be used to make efficient inferences without the distractions of missing data. Our work will assist MINAP in achieving its priority goal of providing useful data with which to analyse patient care. PMID- 21786285 TI - A quasi F-test for functional linear models with functional covariates and its application to longitudinal data. AB - Functional linear models are useful in analyzing data from designed experiments and observational studies with functional responses, as well as longitudinal data with a large number of repeated measures on each subject. We propose a quasi F test for functional linear models with functional covariates and outcomes. We develop a numerical procedure and an efficient approximation for computing p values, and present a simple way to test individual predictors. For illustration, we apply the proposed procedure to a longitudinal depression data set with repeatedly measured methamphetamine use as a predictor. We conduct a simulation study to assess the size and the power of the test. PMID- 21786286 TI - Modeling continuous diagnostic test data using approximate Dirichlet process distributions. AB - There is now a large literature on the analysis of diagnostic test data. In the absence of a gold standard test, latent class analysis is most often used to estimate the prevalence of the condition of interest and the properties of the diagnostic tests. When test results are measured on a continuous scale, both parametric and nonparametric models have been proposed. Parametric methods such as the commonly used bi-normal model may not fit the data well; nonparametric methods developed to date have been relatively complex to apply in practice, and their properties have not been carefully evaluated in the diagnostic testing context. In this paper, we propose a simple yet flexible Bayesian nonparametric model which approximates a Dirichlet process for continuous data. We compare results from the nonparametric model with those from the bi-normal model via simulations, investigating both how much is lost in using a nonparametric model when the bi-normal model is correct and how much can be gained in using a nonparametric model when normality does not hold. We also carefully investigate the trade-offs that occur between flexibility and identifiability of the model as different Dirichlet process prior distributions are used. Motivated by an application to tuberculosis clustering, we extend our nonparametric model to accommodate two additional dichotomous tests and proceed to analyze these data using both the continuous test alone as well as all three tests together. PMID- 21786287 TI - Renal impairment, hemoglobinuria, and hemoglobinemia among patients with idiopathic thrombocytopenic purpura. AB - Renal impairment (RI) and events potentially leading to RI were reported in idiopathic thrombocytopenic purpura (ITP) patients with specific medications. This study was conducted to estimate the incidence rate (IR) of RI, hemoglobinuria and hemoglobinemia (HE) and characterize baseline risk factors in ITP and ITP-free patients. Incident ITP and matched non-ITP patients were identified from an electronic medical record database from 1990 to 2002. ITP patients were classified by the treatment first received (initiators) or ever received (users). All cohorts were followed for study outcomes. IRs were calculated and standardized by age and gender. A total of 881 ITP and 4,496 ITP free patients yielded 3,044 and 16,006 person-years, respectively. The ITP cohort had a slightly higher prevalence of autoimmune diseases and infections than the ITP-free cohort. The IR (/10,000 person-years) for RI, hemoglobinuria and HE was 14.2, 35.7, and 7.1 in the ITP cohort; 10.0, 48.8, and 0 in the ITP-free cohort; and 18.3, 37.1, and 6.1 in untreated ITP patients, respectively. The risk of RI, HE or hemoglobinuria was not found to differ substantially between ITP and non ITP patients or across ITP treatments. PMID- 21786289 TI - Prevalence of monoclonal gammopathy of undetermined significance in an elderly urban Korean population. AB - Research on the epidemiology of monoclonal gammopathy of undetermined significance (MGUS) is limited in Korea. The aim of this study was to determine the prevalence and characteristics of MGUS in an elderly urban Korean population. A random sample of 1118 Korean elders was selected from residents aged 65 years or older living in Seongnam, Korea 1 year from August 2005. We obtained plasma samples remaining after scheduled tests for the Korean Longitudinal Study on Health and Aging. The mean age of the study population was 72 years (range, 65-97 years). To screen for MGUS, immunofixation and free light-chain (FLC) assays were performed. Age-adjusted and gender-adjusted MGUS prevalence rates in 680 responders were estimated as 3.3% [95% confidence interval (CI) = 2.0-4.6%], and the estimated age-adjusted prevalence of MGUS was 4.3% in men (95% CI = 1.9-6.6%) and 2.6% in women (95% CI = 1.0-4.2%). Abnormal FLC ratios were detected in 10% of MGUS cases. Multivariate analysis of 945 participants revealed that significant risk factors for MGUS included advanced age, male sex, hyperproteinemia, increased erythrocyte sedimentation rate, and abnormal FLC ratio. MGUS is less prevalent among elderly Koreans (3.3%) than other races. This is the first study to estimate the prevalence of MGUS in the Korean elderly population. Our findings should be confirmed with additional studies analyzing follow-up samples from 2010. PMID- 21786288 TI - An evaluation of concurrent G6PD (A-) deficiency and sickle cell trait in Malian populations of children with severe or uncomplicated P. falciparum malaria. PMID- 21786290 TI - NerveCenter: July 2011. PMID- 21786291 TI - NerveCenter: messages from the brain at rest. PMID- 21786293 TI - Medical student learning in the preclinical curriculum: many steps behind a rapidly moving world. PMID- 21786294 TI - Got milk? PMID- 21786295 TI - Open-label surgical trials for Parkinson disease: time for reconsideration. PMID- 21786296 TI - Current concepts and management of glioblastoma. AB - Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice. PMID- 21786297 TI - Gestational vitamin D and the risk of multiple sclerosis in offspring. AB - OBJECTIVE: Vitamin D may have a protective role in the etiology of multiple sclerosis (MS), but the effect of gestational vitamin D on adult onset MS has not been studied. METHODS: In 2001, 35,794 mothers of participants of the Nurses' Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse daughters. We studied the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and their daughters' risk of developing MS. RESULTS: MS was diagnosed in 199 women. The relative risk of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted rate ratio (RR) of MS was 0.62 (95% confidence interval [CI], 0.40-0.95; p trend = 0.001) for nurses whose mothers consumed 2 to 3 glasses of milk per day compared with those whose mothers consumed <3 glasses per month, and 0.57 (95% CI, 0.35-0.91; p trend = 0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH)D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles, the adjusted RR was 0.59; (95% CI, 0.37-0.92; p trend = 0.002). INTERPRETATION: Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in offspring. PMID- 21786298 TI - Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity. AB - OBJECTIVE: It is still unclear whether chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS), because substantial methodological differences have been claimed by Zamboni to account for the lack of results of other groups. Furthermore, the potential role of venous malformations in influencing MS severity has not been fully explored. This information is particularly relevant, because uncontrolled surgical procedures are increasingly offered to MS patients to treat their venous stenoses. METHODS: In the present study, CCSVI was studied in 84 MS patients and in 56 healthy subjects by applying the Zamboni method for CCSVI identification. RESULTS: We found no significant differences (p = 0.12) in CCSVI frequency between MS and control subjects. Furthermore, no differences were found between CCSVI-positive and CCSVI-negative patients in terms of relevant clinical variables such as disease duration, time between onset and first relapse, relapsing or progressive disease course, and risk of secondary progression course. Statistically significant differences were not found between CCSVI-positive and CCSVI-negative MS subjects by analyzing direct measures of disability such as mean Expanded Disability Status Scale (EDSS) (p = 0.07), mean progression index (p > 0.1), and mean MS severity score (p > 0.1). The percentage of subjects who reached EDSS 4.0 and 6.0 milestones was not different among CCSVI-negative and CCSVI-positive subjects, and no significant correlation was found between severity of disability and number of positive CCSVI criteria. INTERPRETATION: Our results indicate that CCSVI has no role in either MS risk or MS severity. PMID- 21786299 TI - Intravenous autologous bone marrow mononuclear cells for ischemic stroke. AB - OBJECTIVE: Cellular therapy is an investigational approach for stroke. Mononuclear cells (MNCs) from the bone marrow reduce neurological deficits in animal stroke models. We determined if autologous MNC infusion was feasible and safe in patients with ischemic stroke. METHODS: We conducted an open-label prospective study of a bone marrow harvest followed by readministration of autologous MNCs in 10 patients, 18 to 80 years old, with acute middle cerebral artery ischemic stroke. Bone marrow was aspirated from the iliac crest, and MNCs were separated at a Good Manufacturing Practices facility and administered intravenously up to a maximum of 10 million cells/kg. The harvest and infusion had to occur between 24 and 72 hours after stroke. Patients were monitored for 6 months. RESULTS: Bone marrow aspiration was successfully completed in all patients. Eight received 10 million cells/kg, and 2 received >=7 million cells/kg. There were no significant adverse events related to harvest or infusion. Two patients had infarct expansion between enrollment and harvest and underwent hemicraniectomy after cell infusion. One patient died at 40 days due to a pulmonary embolism related to the stroke. There were no study-related severe adverse events. Median National Institutes of Health Stroke Scale score was 13 before harvest, 8 at 7 days, and 3 at 6 months. At 6 months, all surviving patients had shifted down by at least 1 point on the modified Rankin Scale compared to day 7. Seven of 10 patients achieved a Barthel Index >=90. INTERPRETATION: This study suggests that a bone marrow harvest and reinfusion of autologous MNCs were safe and feasible in acute stroke patients. PMID- 21786300 TI - Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. AB - OBJECTIVE: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X adrenoleukodystrophy (X-ALD). METHODS: X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X ALD. RESULTS: Here, we prove the capability of the antioxidants N-acetyl cysteine, alpha-lipoic acid, and alpha-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests. INTERPRETATION: We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. PMID- 21786302 TI - Glial gap junctional communication involvement in hippocampal damage after middle cerebral artery occlusion. AB - OBJECTIVE: Most patients with stroke caused by middle cerebral artery occlusion (MCAO) show cognitive deficit that is generally regarded as resulting from damage to the cerebral cortex rather than the hippocampus. Whether MCAO induces hippocampal damage and whether this contributes to the cognitive defects remains unclear. Here we investigate the hippocampal damage and its correlation to cognitive defects after exclusively unilateral MCAO and the underlying mechanism for that damage. METHODS: Patients were assessed for hippocampal damage by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), and the Mini Mental-Status Evaluation (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess for cognitive defects. RESULTS: We provide the first evidence that patients with exclusively unilateral MCAO showed hippocampal damage characterized by an infarct-size-independent atrophy and alterations in neuronal and glial metabolites in the ipsilateral hippocampus, in parallel with cognitive impairment. Rodent MCAO also induced delayed shrinkage and pyramidal neuronal death in the ipsilateral hippocampus and an impairment of hippocampal-dependent spatial memory. Blocking Gap junctional communication (GJC) with carbenoxolone or downregulation of connexin43 (Cx43) significantly increased the survival of the pyramidal neurons in the ipsilateral hippocampus and improved behavioral scores. Furthermore, Cx43 heterozygous mice showed reduced shrinkage and metabolite abnormality in ipsilateral hippocampus after MCAO. INTERPRETATION: Astroglial GJC plays a significant role in MCAO-induced remote hippocampal damage and cognitive impairment. It might be possible to improve the cognition in patients with MCAO by manipulating interastrocytic communication via the gap junction channels. PMID- 21786301 TI - Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy. AB - OBJECTIVE: While inflammatory pain is well described in skeletal muscle, neuropathic muscle pain remains to be clarified. We used 3 well-established rodent models of peripheral neuropathy to evaluate for muscle pain. METHODS: In rats exposed to either of 2 neurotoxic cancer chemotherapies, paclitaxel or oxaliplatin, or to alcohol consumption, we assessed the evolution of mechanical hyperalgesia in skeletal muscle and skin, in the same animal. To explore the involvement of protein kinase C epsilon (PKCepsilon), a second messenger implicated in some forms of neuropathic pain, antisense oligodeoxynucleotides (AS ODNs) or mismatch ODNs (MM-ODNs) for PKCepsilon were administered intrathecally. RESULTS: Rats submitted to models of chemotherapy-induced and alcohol-induced neuropathy developed persistent muscle hyperalgesia, which evolved in parallel in muscle and skin. The administration of PKCepsilon AS, which has been shown to mediate cutaneous hyperalgesia in paclitaxel and ethanol models of neuropathic pain, also inhibited muscle hyperalgesia induced by these agents. Stopping AS-ODN was associated with the reappearance of hyperalgesia at both sites. The AS-ODN to PKCepsilon treatment was devoid of effect in both muscle and skin in the oxaliplatin neuropathy model. INTERPRETATION: Our results support the suggestion that neuropathic muscle pain may be a greater clinical problem than generally appreciated. PMID- 21786305 TI - Closed loop communication to prevent delay in recombinant tissue plasminogen activator administration. PMID- 21786307 TI - Functional changes in hypothalamic hamartoma neurons and gelastic epilepsy. PMID- 21786308 TI - Faciobrachial dystonic attacks: seizures or movement disorder? PMID- 21786311 TI - Cerebrospinal fluid analysis in the 2010 revised McDonald's multiple sclerosis diagnostic criteria. PMID- 21786313 TI - Improving uncertainty analysis in kinetic evaluations using iteratively reweighted least squares. AB - Kinetic parameters of environmental fate processes are usually inferred by fitting appropriate kinetic models to the data using standard nonlinear least squares (NLS) approaches. Although NLS is appropriate to estimate the optimum parameter values, it implies restrictive assumptions on data variances when the confidence limits of the parameters must also be determined. Particularly in the case of degradation and metabolite formation, the assumption of equal error variance is often not realistic because the parent data usually show higher variances than those of the metabolites. Conventionally, such problems would be tackled by weighted NLS regression, which requires prior knowledge about the data errors. Instead of implicitly assuming equal error variances or giving arbitrary weights decided by the researcher, we use an iteratively reweighted least squares (IRLS) algorithm to obtain the maximum likelihood estimates of the model parameters and the error variances specific for the different species in a model. A study with simulated data shows that IRLS gives reliable results in the case of both unequal and equal error variances. We also compared results obtained by NLS and IRLS, with probability distributions of the parameters inferred with a Markov Chain Monte-Carlo (MCMC) approach for data from aerobic transformation of different chemicals in soil. Confidence intervals obtained by IRLS and MCMC are consistent, whereas NLS leads to very different results when the error variances are distinctly different between different species. Because the MCMC results can be assumed to reflect the real parameter distribution imposed by the observed data, we conclude that IRLS generally yields more realistic estimates of confidence intervals for model parameters than NLS. PMID- 21786315 TI - Advantages of isovolemic hemodilution-red cell exchange therapy to prevent recurrent stroke in sickle cell anemia patients. AB - Chronic simple hypertransfusion (every 3 to 4 weeks) effectively prevents secondary stroke in children with sickle cell anemia but leads to iron overload despite chelation therapy. Conventional red blood cell exchange (C-RBCx) has advantages over simple transfusion: no net iron gain and less frequent hospital visits. However, C-RBCx requires more red blood cell units, an apheresis instrument and skilled personnel; it is also more expensive. We developed a modified procedure where isovolemic hemodilution precedes RBCx (IHD-RBCx) to decrease RBC units required and to increase the interval between procedures. Twenty patients underwent IHD-RBCx over a period of 7 years. IHD-RBCx required 11% fewer RBC units and increased inter-procedure interval from 37 to 53 days compared to C-RBCx. The median number of annual procedures decreased from 9.8 to 7.0 per patient, resulting in estimated savings of more than $4.5 million over 10 years for 20 patients while providing improved care. Five patients have discontinued chelation therapy; three while on C-RBCx and two while on IHD-RBCx. No adverse events occurred related to the isovolemic hemodilution phase and no patients had recurrent stroke. IHD-RBCx is a safe, efficient, and cost effective therapy for secondary prevention of stroke in patients with sickle cell anemia. PMID- 21786314 TI - Mobilization of endocrine-disrupting chemicals and estrogenic activity in simulated rainfall runoff from land-applied biosolids. AB - Municipal biosolids are commonly applied to land as soil amendment or fertilizer as a form of beneficial reuse of what could otherwise be viewed as waste. Balanced against this benefit are potential risks to groundwater and surface water quality from constituents that may be mobilized during storm events. The objective of the present study was to characterize the mobilization of selected endocrine-disrupting compounds, heavy metals, and total estrogenic activity in rainfall runoff from land-applied biosolids. Rainfall simulations were conducted on soil plots amended with biosolids. Surface runoff and leachate was collected and analyzed for the endocrine-disrupting compounds bisphenol A, 17alpha ethynylestradiol, triclocarban, triclosan, octylphenol, and nonylphenol; a suite of 16 metals; and estrogenic activity via the estrogen receptor-mediated chemical activated luciferase gene expression (ER-CALUX) bioassay. Triclocarban (2.3-17.3 ng/L), triclosan (<51-309 ng/L), and octylphenol (<4.9-203 ng/L) were commonly detected. Chromium (2.0-22 ug/L), Co (2.5-10 ug/L), Ni (28-235 ug/L), Cu (14-110 ug/L), As (1.2-2.7 ug/L), and Se (0.29-12 ug/L) were quantifiable over background levels. Triclosan, Ni, and Cu were detected at levels that might pose some risk to aquatic life, though levels of metals in the biosolids were well below the maximum allowable regulatory limits. The ER-CALUX results were mostly explained by background bisphenol A contamination and octylphenol in runoff, although unknown contributors or matrix effects were also found. PMID- 21786316 TI - Mucosal healing of esophageal involvement of Crohn's disease with granulocyte/monocyte adsorption. AB - We report a case of a 16-year-old male who suffered from Crohn's disease (CD) with esophageal involvement, showing remarkable improvement with granulocyte/monocyte adsorption (GMA). The patient had been diagnosed as ileocolic CD and was treated with 5-aminosalicylate. He was admitted to our hospital with symptoms of fever, diarrhea, and odynophagia. Endoscopic examinations revealed that the exacerbation of ileocolic ulcers, and advent of ulcers in esophagus. Because of the patient's refusal to receive corticosteroids, immunomodulators, or biologics, he underwent GMA twice a week. After 10 sessions of GMA, he entered remission with significant decrease in clinical activity. In addition, endoscopic examinations showed remarkable improvement of ileocolic ulcers and disappearance of esophageal lesions. No adverse events were observed. GMA could be effective for manifestations of CD in gastrointestinal tract other than ileum or colon. PMID- 21786317 TI - Outcomes of previously healthy pediatric patients with fulminant sepsis-induced multisystem organ failure receiving therapeutic plasma exchange. AB - BACKGROUND: Fulminant sepsis-induced multisystem organ failure (MSOF) in pediatric patients carries substantial morbidity and mortality. Therapeutic plasma exchange (TPE) has been reported to be beneficial in sepsis-induced MSOF. We evaluated the outcomes of previously healthy children with fulminant sepsis induced MSOF receiving TPE. MATERIALS AND METHODS: Previously healthy pediatric ICU patients who underwent TPE for MSOF due to fulminant bacterial sepsis were retrospectively reviewed. Eleven patients (three females and eight males) with age ranging 8 months to 14 years were identified (eight meningococcemia and three other infections). All patients received daily TPE with fresh frozen plasma (FFP) as replacement fluid. Organ failure index (OFI-maximum score = 6) was assessed daily for 7 days. RESULTS: A median of 4 TPE (1-14) were performed. Improvements in organ function and platelet count occurred in most patients with 2-4 TPE treatments. All 10 patients who were alive had reduced OFI to 2 by day 7 of initial TPE and were all fully recovered (survival rate = 10/11, 91%). The only death occurred in a patient who died the same day after his first TPE treatment, which was initiated 24 h after development of MSOF. The 10 survivors underwent early initiation of TPE (median 5.3 h) after the onset of MSOF. CONCLUSIONS: > TPE may contribute to a better outcome in previously healthy pediatric patients with fulminant sepsis-induced MSOF, especially if instituted early in the course of multiorgan failure. PMID- 21786318 TI - Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. AB - Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption. PMID- 21786319 TI - Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone-active hormones. AB - Weight loss therapy to improve health in obese older adults is controversial because it causes further bone loss. Therefore, it is recommended that weight loss therapy should include an intervention such as exercise training (ET) to minimize bone loss. The purpose of this study was to determine the independent and combined effects of weight loss and ET on bone metabolism in relation to bone mineral density (BMD) in obese older adults. One-hundred-seven older (age >65 years) obese (body mass index [BMI] >= 30 kg/m(2) ) adults were randomly assigned to a control group, diet group, exercise group, and diet-exercise group for 1 year. Body weight decreased in the diet (-9.6%) and diet-exercise (-9.4%) groups, not in the exercise (-1%) and control (-0.2%) groups (between-group p < 0.001). However, despite comparable weight loss, bone loss at the total hip was relatively less in the diet-exercise group (-1.1%) than in the diet group ( 2.6%), whereas BMD increased in the exercise group (1.5%) (between-group p < 0.001). Serum C-terminal telopeptide (CTX) and osteocalcin concentrations increased in the diet group (31% and 24%, respectively), whereas they decreased in the exercise group (-13% and -15%, respectively) (between-group p < 0.001). In contrast, similar to the control group, serum CTX and osteocalcin concentrations did not change in the diet-exercise group. Serum procollagen propeptide concentrations decreased in the exercise group (-15%) compared with the diet group (9%) (p = 0.04). Serum leptin and estradiol concentrations decreased in the diet (-25% and -15%, respectively) and diet-exercise (-38% and 13%, respectively) groups, not in the exercise and control groups (between-group p = 0.001). Multivariate analyses revealed that changes in lean body mass (beta = 0.33), serum osteocalcin (beta = -0.24), and one-repetition maximum (1-RM) strength (beta = 0.23) were independent predictors of changes in hip BMD (all p < 0.05). In conclusion, the addition of ET to weight loss therapy among obese older adults prevents weight loss-induced increase in bone turnover and attenuates weight loss-induced reduction in hip BMD despite weight loss-induced decrease in bone-active hormones. PMID- 21786320 TI - Is greater lumbar vertebral BMD associated with more disk degeneration? A study using uCT and discography. AB - It is well documented that osteoarthritis is associated with greater BMD in peripheral extremities. Yet the relationship between vertebral BMD and disk degeneration (DD) remains controversial in the lumbar spine, which may be due largely to the inadequacies of BMD and DD measures. Aiming to clarify the association between vertebral BMD and adjacent DD, we studied 137 cadaveric lumbar vertebrae and 209 corresponding intervertebral disks from the spines of 48 white men aged 21 to 64 years. DD was evaluated using discography. The vertebrae were scanned using a micro-computed tomography (uCT) system to obtain volumetric BMD for the whole vertebra, the vertebral body, the vertebral body excluding osteophytes, and the vertebral body excluding osteophytes and endplates. A random effects model was used to examine the association between the different definitions of vertebral BMD and adjacent DD. No significant association was found between the BMD of the whole vertebra and adjacent DD. However, when the posterior elements were excluded, there was a significant association between greater vertebral body BMD and more severe degeneration in the disk cranial to the vertebra. This association remained after further excluding osteophytes and endplates from the vertebral body BMD measurements. Also, a trend of greater BMD of the vertebral body associated with more adjacent DD was evident. These results clarify the association between vertebral BMD and DD and specifically indicate that it is higher BMD of the vertebral body, not the entire vertebra, that is associated with more severe adjacent DD. This association may be obscured by the posterior elements and is not confounded by osteophytes and endplate sclerosis. PMID- 21786321 TI - Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. AB - Bone undergoes remodeling consisting of osteoclastic bone resorption followed by osteoblastic bone formation throughout life. Although the effects of bone morphogenetic protein (BMP) signals on osteoblasts have been studied extensively, the function of BMP signals in osteoclasts has not been fully elucidated. To delineate the function of BMP signals in osteoclasts during bone remodeling, we deleted BMP receptor type IA (Bmpr1a) in an osteoclast-specific manner using a knock-in Cre mouse line to the cathepsin K locus (Ctsk(Cre/+);Bmpr1a(flox/flox), designated as Bmpr1a(DeltaOc/DeltaOc)). Cre was specifically expressed in multinucleated osteoclasts in vivo. Cre-dependent deletion of the Bmpr1a gene occurred at 4 days after cultivation of bone marrow macrophages obtained from Bmpr1a(DeltaOc/DeltaOc) with RANKL. These results suggested that Bmpr1a was deleted after formation of osteoclasts in Bmpr1a(DeltaOc/DeltaOc) mice. Expression of bone-resorption markers increased, thus suggesting that BMPRIA signaling negatively regulates osteoclast differentiation. Trabeculae in tibia and femurs were thickened in 3.5-, 8-, and 12-week-old Bmpr1a(DeltaOc/DeltaOc) mice. Bone histomorphometry revealed increased bone volume associated with increased osteoblastic bone-formation rates (BFR) in the remodeling bone of the secondary spongiosa in Bmpr1a(DeltaOc/DeltaOc) tibias at 8 weeks of age. For comparison, we also induced an osteoblast-specific deletion of Bmpr1a using Col1a1-Cre. The resulting mice showed increased bone volume with marked decreases in BFR in tibias at 8 weeks of age. These results indicate that deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, thus suggesting that BMPR1A signaling in osteoclasts regulates coupling to osteoblasts by reducing bone-formation activity during bone remodeling. PMID- 21786323 TI - Urinary kappa and lambda immunoglobulin light chains in normoalbuminuric type 2 diabetes mellitus patients. AB - BACKGROUND AND AIM: Kidney disease is one of the major chronic microvascular complications of diabetes. Tubular involvement may precede glomerular involvement and the appearance of microalbuminuria. The aim of the study was to evaluate quantitatively immunoglobulin light chains (IgLCs), kappa and lambda excretion in the urine of patients with type 2 diabetes mellitus with normoalbuminuria and with microalbuminuria compared to control group. RESULTS: Urinary IgLCs levels of the control group were significantly lower than diabetic patients with normoalbuminuria and diabetic patients with albuminuria. IgLCs were significantly associated with the duration of disease and negatively with estimated glomerular filtration rate. CONCLUSION: Type 2 diabetic patients can have significantly raised concentrations of urinary IgLCs before microalbuminuria or renal disease occurs. Further investigations are recommended to assess LC evaluation in the early management of diabetic renal disease. PMID- 21786322 TI - Determining the molecular mechanism of inactivation by chemical modification of triosephosphate isomerase from the human parasite Giardia lamblia: a study for antiparasitic drug design. AB - Giardiasis, the most prevalent intestinal parasitosis in humans, is caused by Giardia lamblia. Current drug therapies have adverse effects on the host, and resistant strains against these drugs have been reported, demonstrating an urgent need to design more specific antigiardiasic drugs. ATP production in G. lamblia depends mainly on glycolysis; therefore, all enzymes of this pathway have been proposed as potential drug targets. We previously demonstrated that the glycolytic enzyme triosephosphate isomerase from G. lamblia (GlTIM), could be completely inactivated by low micromolar concentrations of thiol-reactive compounds, whereas, in the same conditions, the activity of human TIM (HuTIM) was almost unaltered. We found that the chemical modification (derivatization) of at least one Cys, of the five Cys residues per monomer in GlTIM, causes this inactivation. In this study, structural and functional studies were performed to describe the molecular mechanism of GlTIM inactivation by thiol-reactive compounds. We found that the Cys222 derivatization is responsible for GlTIM inactivation; this information is relevant because HuTIM has a Cys residue in an equivalent position (Cys217). GlTIM inactivation is associated with a decrease in ligand affinity, which affects the entropic component of ligand binding. In summary, this work describes a mechanism of inactivation that has not been previously reported for TIMs from other parasites and furthermore, we show that the difference in reactivity between the Cys222 in GlTIM and the Cys217 in HuTIM, indicates that the surrounding environment of each Cys residue has unique structural differences that can be exploited to design specific antigiardiasic drugs. PMID- 21786324 TI - Serum amyloid-A levels in neonatal necrotizing enterocolitis. AB - We aimed to evaluate serum levels of serum amyloid-A (SAA) both in the diagnosis and monitoring the treatment response of necrotizing enterocolitis (NEC). Forty five preterm neonates were enrolled in the study, including 15 infants with NEC, 15 with sepsis, and 15 healthy preterm infants. Pre- and posttreatment serum SAA levels were measured. Among patients with NEC, 11 had stage 1 and 4 had stage 2 disease according to the modified Bell's staging criteria. Baseline SAA levels of the infants with NEC were significantly higher than controls (P=0.013) and were significantly lower than those with sepsis (P=0.004). When infants with stage 1 and stage 2 NEC were analyzed separately, baseline SAA levels of the infants with stage 2 NEC were significantly higher than controls (P=0.027) than those with stage 1 NEC (P=0.018), but similar to those with sepsis. There was a trend that baseline SAA levels were also correlated with the Bell stage (r=0.501, P=0.057). Posttreatment SAA levels significantly decreased in infants with sepsis (P=0.002). Pre- and posttreatment SAA levels were similar in patients with stage 1 and 2 NEC. In conclusion, SAA rises in early stages of NEC and may aid in diagnosis as a serum marker. PMID- 21786325 TI - TGF-beta1 serum concentration as a complementary diagnostic biomarker of lung cancer: establishment of a cut-point value. AB - Lung cancer is a malignant disease with increasing mortality rates. Cytokines play a role in normal cell growth regulation and differentiation and are also implicated in malignant disease. Among these cytokines, Transforming Growth Factor beta type 1 (TGF-beta1) acts as a tumor promoter in malignant cells. Several clinical studies have found high levels of TGF-beta1 in various cancer types. The aim of this study was to establish a TGF-beta1 cut-off point as a complementary diagnostic tool in lung cancer detection. Therefore, 72 clinically well-characterized individuals were studied, 41 lung cancer patients and 31 healthy subjects. Serum TGF-beta1 concentration was measured by an enzyme-linked immunosorbent assay (ELISA). We compared statistically the serum TGF-beta1 concentration between both groups with analysis of variance, linear regression and receiver operating curve analysis. We observed that lung cancer patients produced higher TGF-beta1 levels than healthy individuals (37,225+/-9,436 vs. 28,416+/-9,324 pg/ml, P<0.001). The cut-point diagnostic value was 30,500 pg/ml with 80.5% sensitivity, 64.5% specificity and odds ratio: 7.5, 95% CI: 2.6-21.8. CONCLUSIONS: We found significantly higher TGF-beta1 levels in lung cancer patients than in healthy individuals. We propose the measurement of serum TGF beta1 levels as a complementary diagnostic test in lung cancer detection. PMID- 21786326 TI - Unusual false-positive case of urinary screening for buprenorphine. AB - Buprenorphine is a centrally acting analgesic drug that is administered for the management of opioid dependence and as an analgesic drug for the treatment of chronic pain. The growing use of this substance has determined an increased need for laboratory testing for either detection and confirmation of the illicit use or monitoring compliance as a substitution therapy for opioid dependence. We describe here the case of urinary sample adulteration with exogenous buprenorphine (6,952 ng/ml), which has led to afalse-positive immunoassay test result (14.9 ng/ml) on a subsequent sample due to a phenomenon of instrumental carry-over. This unusual case confirms the importance to take into account adulteration when screening urines for buprenorphine in patients undergoing substitution therapy for opioid dependence, routinely perform a confirmation assay on positive samples, and rule out instrumental carry-over. PMID- 21786327 TI - Clinical significance of simultaneous determination of serum tryptophan and tyrosine in patients with lung cancer. AB - BACKGROUND: To explore the clinical significance of serum tyrosine (Tyr) and tryptophan (Trp) in patients with lung cancer, we used a simple and efficient method of high-performance liquid chromatography with fluorescence detection (HPLC-FD) that simultaneously measured serum Trp and Tyr contents. METHODS: The concentrations of Tyr and Trp were measured simultaneously by HPLC-FD in the sera of 80 patients with lung cancer and 120 healthy controls. RESULTS: Trp concentrations were significantly lower in patients with lung cancer than in healthy controls (39.26+/-5.44 vs. 49.93+/-5.43 umol/l, respectively; P<0.01), whereas in Tyr concentrations there were no differences with healthy controls (65.38+/-7.94 vs.66.40+/-8.55 umol/l, respectively; P>0.05). In addition, patients in the adenocarcinoma group had significantly lower Trp and Tyr concentrations than those in squamous cell carcinoma group. There was no difference between the early stage and advanced stage of lung cancer. CONCLUSIONS: Determination of serum Trp and Tyr concentrations can be employed to assist the diagnosis of the histotypes of lung cancer and tumor stage. Tyr and Trp as indexes on the lung cancer diagnostic sensitivity, specificity were 54.9, 62.9% and 82.4, 92.1%, Trp is an important and special index for lung cancer diagnosis of which the specificity of diagnosis of lung cancer is more than 92%. PMID- 21786328 TI - Evaluation of alpha-iduronidase in dried blood spots is an accurate tool for mucopolysaccharidosis I diagnosis. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the alpha-L-iduronidase (IDUA), which leads to the accumulation of glycosaminoglycans in lysosomes. MPS I patients present a spectrum ranging from a severe to an attenuated phenotype. Once clinical suspicion is present, diagnosis of MPS I can be performed by enzyme activity determination and/or molecular analysis. The aim of this study was to establish a reference interval value to IDUA activity using a dried blood spots (DBS) assay and to evaluate whether this assay could be a secure tool to diagnose MPS I patients. RESULTS: IDUA activity range on HV DBS samples were 1.40-7.78 umol/l blood/hr. Regarding the validation group, 11 of the 36 individuals clinically suspected of MPS I had the diagnosis confirmed by DBS and reference assay (leukocytes). When we considered the new proposed cutoff value of 1.5 umol/l blood/hr, the sensitivity, specificity, and predictive values were 100%. CONCLUSIONS: Our results strongly suggest that the determination of IDUA activity using a DBS assay is a secure tool for MPS I diagnosis. However, it is extremely important to assure that all recommendations for collection, transport, and storage are correctly followed to guarantee the quality of the samples. PMID- 21786329 TI - Ischemia-modified albumin as a biochemical marker in children with neuroblastoma and soft tissue sarcomas. AB - In this study, the levels of ischemia-modified albumin (IMA) in pediatric oncology patients with soft tissue sarcomas (STSs) and neuroblastoma (NB) were analyzed. To date, there have been no studies concerning IMA in these groups of patients. Ninety-nine children with STSs and NB were analyzed from 2006 to 2009, and 30 healthy children were also enrolled in the study. IMA levels were measured throughout treatment in all patients. The levels of IMA in all cancer patients (mean 116.8+/-39.3 U/ml), in patients with STSs (mean 119.8+/-27.5 U/ml), and in patients with NB (mean 114.6+/-36.6 U/ml) were significantly higher than in the control patients (mean 87.3+/-38.3 U/ml; P=0.0013, 0.0066, and 0.0164, respectively). IMA levels increased before and during the treatment compared with levels in the controls. The determination of IMA levels in pediatric oncology patients with poor prognoses from STSs and NB may play an important role in predicting response to therapy and overall outcome. PMID- 21786330 TI - Evolving methods for single nucleotide polymorphism detection: Factor V Leiden mutation detection. AB - BACKGROUND: The many techniques used to diagnose the Factor V Leiden (FVL) mutation, the most common hereditary hypercoagulation disorder in Eurasians, and the most frequently requested genetic test reflect the evolving strategies in protein and DNA diagnosis. METHODS: Here, molecular methods to diagnose the FVL mutation are discussed. RESULTS: Protein-based detection assays include the conventional functional activated protein C resistance coagulation test and the recently reported antibody-mediated sensor detection; and DNA-based assays include approaches that use electrophoretic fractionation e.g., restriction fragment length polymorphism, denaturing gradient gel electrophoresis, and single stranded conformational PCR analysis, DNA hybridization (e.g., microarrays), DNA polymerase-based assays, e.g., extension reactions, fluorescence polarization template-directed dye-terminator incorporation, PCR assays (e.g., amplification refractory mutation system, melting curve analysis using real-time quantitative PCR, and helicase-dependent amplification), DNA sequencing (e.g., direct sequencing, pyrosequencing), cleavase-based Invader assay and ligase-based assays (e.g., oligonucleotide ligation assay and ligase-mediated rolling circle amplification). CONCLUSION: The method chosen by a laboratory to diagnose FVL not only depends on the available technical expertise and equipment, but also the type, variety, and extent of other genetic disorders being diagnosed. PMID- 21786331 TI - Serum paraoxonase-1 activities and oxidative status in patients with plaque-type psoriasis with/without metabolic syndrome. AB - OBJECTIVE: Psoriasis is a chronic immune-mediated inflammatory skin disease associated with metabolic syndrome, which is made up of a cluster of disorders, including obesity, diabetes mellitus, dyslipidemia, and cardiovascular disease. The aim of this study was to investigate serum paraoxonase-1 activities and oxidative status parameters in patients with plaque-type psoriasis with or without metabolic syndrome. METHODS: In this study, patients with plaque-type psoriasis with (n=25) or without (n=27) metabolic syndrome, according to the criteria of the International Diabetes Federation (IDF), were matched for age and sex to an equally sized control group (n=25). RESULTS: In patients without metabolic syndrome, serum paraoxonase and arylesterase activities showed mean decreases of 29 and 6%, respectively, whereas in patients with metabolic syndrome, the mean decreases in the enzymes' activities were 35 and 11%, respectively, compared with those in the control group. Serum total antioxidant capacity and total oxidant status were not statistically significant in any of the three groups. Multiple linear regression analysis revealed that HDL cholesterol and log-transformed triglyceride were independent variables for serum arylesterase activity and that fasting glucose and diastolic blood pressure were independent variables for serum paraoxonase activity. CONCLUSIONS: These results suggest that according to the criteria of the IDF, the significant decrease observed in serum paraoxonase activity was independent of the metabolic syndrome in patients with mild-to-moderate plaque-type psoriasis, whereas the significant decrease in serum arylesterase activity was associated with the metabolic syndrome. PMID- 21786332 TI - Cutoff level to detect heterozygous alpha 1 antitrypsin deficiency in Turkish population. AB - BACKGROUND: Alpha 1 antitrypsin (AT) deficiency is a hereditary disorder leading to the defective defence system against neutrophil elastasis in lung and accumulation of insoluble heterodimer AT molecules in hepatocytes. Knowledge of the prevalence of AT deficiency in each country is important to organize the public health policy. The aim of this study is to determine the prevalence of AT deficiency in Turkish population and to define the cutoff value of AT level in serum to detect heterozygous AT deficient subjects. MATERIALS AND METHODS: Serum samples from 1,203 healthy blood donors were used, attending the Blood Bank of Hacettepe Medical Faculty. Isoelectric focusing method for determining PIM, PIS, and PIZ alleles and rate immune nephelometry for measuring the level of AT in serum were used. RESULTS: Out of 1,203 healthy blood donors enrolled, 1,164 (%96.8) had normal variant PI MM allelee, 9 (%0.7) PI MZ, 7 (%0.6) PI MS, 6 (%0.5) MF, and 17 (%1.4) PI M? (unidentified variants with existing standards). Most individuals (89.6%) with low AT level (cutoff <100 mg/dl) in serum were positive for PI MM allele. The cutoff value to investigate PI MZ was 100.5 mg/dl, which had PPV and NPV of 5.0 and 99.9%, respectively. AT deficiency is a rare hereditary disorder in asymptomatic healthy Turkish blood donors. Although the cutoff value of 100.5 mg/dl for AT level in serum was able to detect heterozygous AT deficiency in the healthy population, this finding should be conformed to case control studies. PMID- 21786333 TI - Detection of the JAK2 mutation in myeloproliferative neoplasms by asymmetric PCR with unlabeled probe and high-resolution melt analysis. AB - BACKGROUND: Several methods have been established to detect the JAK2 V617F mutation, a frequent event involved in the pathogenesis of myeloproliferative neoplasms (MPNs). High-resolution melt (HRM) analysis is a newly established technique without the requirement of any gel-based post-PCR handling. METHODS: An asymmetric PCR with unlabeled specific probe was developed and combined to HRM analysis o screen for JAK2 V617F mutation. RESULTS: Heterozygous mutation was easily distinguished from homozygous JAK2 for the obvious shape change. Homozygous JAK2 mutant can be also well separated from wild-type JAK2 in the presence of internal temperature calibrators. The easily recognizable and maximal sensitivity of HRM analysis was 5% for the detection of JAK2 V617F mutation, higher than 25% of direct sequencing. In the test of blind screening of 223 samples (111 Ph- MPNs, 60 Ph+ chronic myeloid leukemia, and 52 acute myeloid leukemia), JAK2 V617F mutations were found in 78 (70%) patients with MPNs, but in none with chronic and acute myeloid leukemia. HRM analysis of all cases was fully concordant with the results of PCR-RFLP and direct sequencing. CONCLUSIONS: The HRM method with unlabeled probe could be used as convenient, sensitive and reliable diagnostic test for detection of JAK2 V617F mutation. PMID- 21786334 TI - Correlation of Chlamydia and Chlamydophila spp. IgG and IgM antibodies by microimmunofluorescence with antigen detection methods. AB - Correlation of serologic titers for Chlamydia trachomatis with other tests has been based on direct fluorescence antibody (DFA) testing and culture, but not on nucleic acid-based tests that are used for screening. We retrospectively reviewed the specificity of antibodies against C. trachomatis, Chlamydia psittaci, and Chlamydophila pneumoniae by microimmunofluorescence (MIF) when compared with DFA, culture, nucleic acid probe, and transcription-mediated amplification. Over a 6 year period, 226 cases had both MIF and one of these other methods performed for comparison. Agreement between C. trachomatis antigen or nucleic acid detection and MIF results was 87% (197/226). C. trachomatis serology had a negative predictive value of 98%, and 10.6% of cases were positive by serology and negative by antigen testing. Of the 13 patients who had a positive C. trachomatis antigen or nucleic acid test result, 9 had IgG and/or IgM titers highest against C. trachomatis, 3 had IgG titers highest against C. pneumoniae, and 1 had undetectable titers for the three chlamydial species. Twenty-five patients had positive IgG and/or IgM titers to C. trachomatis but negative antigen test results. Serologic testing can increase the sensitivity of detecting C. trachomatis infections. PMID- 21786335 TI - Chronic exposure to nanosized, anatase titanium dioxide is not cyto- or genotoxic to Chinese hamster ovary cells. AB - Titanium dioxide nanoparticles (nano-TiO(2) ) are widely used in cosmetics, skin care products, paints, and water treatment processes. Disagreement remains regarding the safety of nano-TiO(2) , and little epidemiological data is available to provide needed resolution. Most studies have examined effects using acute exposure experiments with relatively few studies using a chronic exposure design. We examined cyto- and genotoxicity in CHO-K1 cells following 60 days of continuous exposure to defined levels of nano-TiO(2) (0, 10, 20, or 40 MUg/ml). Oxidative stress increased in a concentration-dependent manner in short- (2 days) and long-term cultures, but long-term cultures had lower levels of oxidative stress. The primary reactive oxygen species appeared to be superoxide, and ROS indicators were lowered with the addition of superoxide dismutase (SOD). No cyto- or genotoxic effects were apparent using the XTT, trypan-blue exclusion, and colony-forming assays for viability and the Comet and Hprt gene mutation assays for genotoxicity. Nano-TiO(2) increased the percentage of cells in the G2/M phase of the cell cycle, but this effect did not appear to influence cell viability or cell division. Cellular Ti content was dose-dependent, but chronically exposed cells had lower amounts than acutely exposed cells. CHO cells appear to adapt to chronic exposure to nano-TiO(2) and detoxify excess ROS possibly through upregulation of SOD in addition to reducing particle uptake. PMID- 21786336 TI - Repetitive exposure to zinc oxide nanoparticles induces dna damage in human nasal mucosa mini organ cultures. AB - Data on the toxicological properties of zinc oxide nanoparticles (ZnO-NPs) is incomplete. ZnO-NPs may enter humans via inhalation or ingestion. The aim of the current study was to evaluate ZnO-NP-induced genotoxicity in three-dimensional (3D) mini organ cultures (MOCs) of human nasal mucosa following repeated exposure to ZnO-NP and regeneration. Nasal MOCs of 10 patients and ZnO-NPs were cultivated for one week and then characterized by electron microscopy. Nasal MOCs were partially covered by ciliated epithelium after one week of cultivation. ZnO-NPs were distributed to the cytoplasm and the nucleus. MOCs were exposed once, twice, or three times to 0.1 or 5 MUg/ml of ZnO-NPs for 1 hr per exposure and were then evaluated for cytotoxicity and genotoxicity. MOCs were cultivated for 24 hr after the triple ZnO-NP exposure to allow for regeneration. ZnO-NP exposure did not result in significant cytotoxicity or apoptosis, as determined by trypan blue exclusion and caspase-3 activity, respectively. A significant increase in DNA damage was detected following repetitive exposure compared to single exposure to ZnO-NPs at 5 MUg/ml, but not 0.1 MUg/ml ZnO-NPs. At both concentrations of ZnO NP, DNA fragmentation increased after 24 hr of regeneration. In contrast, DNA damage which was induced by the positive control, methyl methanesulfonate, was significantly reduced after 24-hr regeneration. Thus, our results suggest that repetitive exposure to low concentrations of ZnO-NPs results in persistent or ongoing DNA damage. PMID- 21786337 TI - Key studies used to support cancer risk assessment questioned. AB - This paper reassessed studies conducted under the leadership of Drosophila geneticist Curt Stern which played a pivotal role in the acceptance of the linear dose-response model by the U.S. National Academy of Sciences Biological Effects of Atomic Radiation (BEAR) I Committee and the subsequent generalization of their recommendations on the linearity dose-response paradigm for ionizing radiation and chemically induced cancer. The analysis finds serious concerns and flaws in important aspects of these experiments, their assessment, and interpretation. Of particular concern was the failure of Stern's group to provide the necessary and promised experimental documentation to support the findings of three critical summarized experiments published as a brief technical note in Science. While this analysis questions the validity of the reported findings and their interpretations, it raises an even more serious concern about the process by which leaders in the radiation genetics community accepted such findings without requiring the necessary documentation and then used this information to support the acceptance of the linear dose-response in public policy matters as affected by risk assessment practices that have continued to the present. PMID- 21786339 TI - Antigenotoxic activity of naturally occurring furanocoumarins. AB - This study was designed to investigate the antigenotoxic effects of a series of naturally occurring furanocoumarins (NOFs) including isoimperatorin, imperatorin, (+)-oxypeucedanin, (+)-byakangelicol, and (+)-byakangelicine on antigenotoxic activities against genotoxicity induced by carcinogens [furylfuramide and N methyl-N'-nitro-N-nitrosoguanidine], and procarcinogens 2-[2-(acetylamino)-4 amino-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-4) and 2 amino-3,4-dimethyl-3H-imidazo-[4,5-f] quinoline (MeIQ)] to genotoxic metabolites catalyzed by rat S9 or rat and human recombinant cytochrome P450 (CYP) 1As by using the umu test based on SOS response. Five different NOFs, which were found in the human diets, strongly inhibited the umuC induction by procarcinogens, but did not be affected by carcinogens. Notably, isoimperatorin and (+)-byakangelicol were found to be potent inhibitors on the metabolic activation of PBTA-4 and MeIQ to genotoxic metabolites catalyzed by rat and human CYP1A1, or rat and human CYP1A2, respectively. In addition, to elucidate the mechanism of their antigenotoxic effects against procarcinogens, the effects of NOFs on rat and human CYP1A1- or rat and human CYP1A2-related enzyme activities of 7 ethoxyresorufin-O-deethylase (EROD) were also investigated. Reduction of the EROD activities by some of the NOFs with IC(50) values of 0.23-20.64 MUM was found to be due to strong inhibition of CYP1A1 and CYP1A2 dependent monooxygenases. Furthermore, the mechanism of inhibitions by NOFs on human CYP1A1 and CYP1A2 was analyzed by means of Dixon plots plus Cornish-Bowden plots. The kinetic studies of inhibition types revealed that these compounds inhibited the human CYP1A1 and CYP1A2 a variety of modes rather than by a uniform one. Moreover, experiments with a two-stage incubation indicated that NOFs, except for imperatorin, inhibited human CYP1A1 in a mechanism-based manner, but directly inhibited human CYP1A2. This data suggest that certain NOFs, to which humans are exposed in the diet, may be capable of affecting the metabolic activation of procarcinogens due to inhibitions of CYP1A1 and CYP1A2 enzymes. PMID- 21786340 TI - Solid-state circular dichroism and hydrogen bonding: absolute configuration of massarigenin A from Microsphaeropsis sp. AB - Massarigenin A (1) and papyracillic acids A (2) and B (3) were isolated from the endophytic fungus Microsphaeropsis sp. Their structures were elucidated by multidimensional nuclear magnetic resonance spectroscopy; the structure of massarigenin A (1) was also confirmed by X-ray crystallography. The absolute configuration of massarigenin A (1) was established by means of circular dichroism (CD) spectroscopy and time-dependent density functional theory (TDDFT) calculations. The impact of intermolecular hydrogen bonds detected in the crystal packing of 1 on CD spectra measured in the solid state was also investigated. PMID- 21786338 TI - XRCC1 coordinates disparate responses and multiprotein repair complexes depending on the nature and context of the DNA damage. AB - XRCC1 is a scaffold protein capable of interacting with several DNA repair proteins. Here we provide evidence for the presence of XRCC1 in different complexes of sizes from 200 to 1500 kDa, and we show that immunoprecipitates using XRCC1 as bait are capable of complete repair of AP sites via both short patch (SP) and long patch (LP) base excision repair (BER). We show that POLbeta and PNK colocalize with XRCC1 in replication foci and that POLbeta and PNK, but not PCNA, colocalize with constitutively present XRCC1-foci as well as damage induced foci when low doses of a DNA-damaging agent are applied. We demonstrate that the laser dose used for introducing DNA damage determines the repertoire of DNA repair proteins recruited. Furthermore, we demonstrate that recruitment of POLbeta and PNK to regions irradiated with low laser dose requires XRCC1 and that inhibition of PARylation by PARP-inhibitors only slightly reduces the recruitment of XRCC1, PNK, or POLbeta to sites of DNA damage. Recruitment of PCNA and FEN-1 requires higher doses of irradiation and is enhanced by XRCC1, as well as by accumulation of PARP-1 at the site of DNA damage. These data improve our understanding of recruitment of BER proteins to sites of DNA damage and provide evidence for a role of XRCC1 in the organization of BER into multiprotein complexes of different sizes. PMID- 21786341 TI - Chiral superstructures of insulin amyloid fibrils. AB - Hydrodynamic forces are capable of inducing structural order in dispersed solid phases, and of causing symmetry-breaking when chiral crystals precipitate from an achiral liquid phase. Until it was observed upon vortex-assisted fibrillation of insulin, such behavior had been thought to be confined to few unbiological systems. In this paper we are discussing chiroptical properties of two chiral variants of insulin amyloid, termed +ICD and -ICD, which form during the process of chiral bifurcation in vortexed solutions of aggregating insulin. As conventional measurements of circular dichroism of solid, anisotropic substances are particularly vulnerable to overlapping influences of linear birefringence and linear dichroism, we have employed complementary tools including dedicated universal chiroptical spectrophotometer to rule out such artifacts. We propose that the strong chiroptical properties of +ICD and -ICD insulin fibrils are an aspect of genuine superstructural chirality of amyloid fibrils and of powerful excitonic couplings taking place within them. A comparison of thioflavin T complexes with fibrils formed by insulin and polyglutamic acid suggests that the extrinsic Cotton effect stemming from the level of single twisted dye molecules is weaker, although diagnostically useful, and cannot account for the overall magnitude of ICD of the dye bound to +/-ICD insulin amyloid. PMID- 21786342 TI - Infrared photodetectors based on reduced graphene oxide and graphene nanoribbons. AB - The use of reduced graphene oxide (RGO) and graphene nanoribbons (GNRs) as infrared photodetectors is explored, based on recent results dealing with solar cells, light-emitting devices, photodetectors, and ultrafast lasers. IR detection is demonstrated by both RGO and GNRs in terms of the time-resolved photocurrent and photoresponse. The responsivity of the detectors and their functioning are presented. PMID- 21786343 TI - Molecular-shape-controlled photovoltaic performance probed via soluble pi conjugated arylacetylenic semiconductors. AB - The synthesis and characterization of a new series of anthracene-based derivatives and their use as donors in bulk-heterojunction solar cells is reported. It is found that when using well-defined building blocks in constructing the chromophore, the donor molecular shape dramatically affects organic photovoltaic (OPV) performance in a previously unrecognized way. PMID- 21786344 TI - Efficient heterojunction photovoltaic cell utilizing nanocomposites of lead sulfide nanocrystals and a low-bandgap polymer. PMID- 21786345 TI - Ultrathin multifunctional oxide coatings for lithium ion batteries. PMID- 21786346 TI - Monolithic integration of arrays of single-walled carbon nanotubes and sheets of graphene. AB - Sheets of graphene and arrays of single-walled carbon nanotubes (SWNTs) are formed separately using chemical vapor deposition techniques onto different optimized growth substrates. Techniques of transfer printing provide a route to integration, yielding two terminal devices and transistors in which patterned structures of graphene form the electrodes and the SWNTs arrays serve as the semiconducting channels. PMID- 21786347 TI - Bio-inspired complementary photoconductor by porphyrin-coated silicon nanowires. PMID- 21786348 TI - Site-specific transfer-printing of individual graphene microscale patterns to arbitrary surfaces. PMID- 21786349 TI - High-performance and highly durable inverted organic photovoltaics embedding solution-processable vanadium oxides as an interfacial hole-transporting layer. AB - Inverted OPV devices based on sol-gel derived vanadium oxides (VOx ) as an interfacial layer are demonstrated. The VOx shows excellent characteristics as a hole-transporting and protecting layer. The constructed devices exhibit enhanced performance with the studied polymers and are highly durable under accelerated conditions for long time periods. PMID- 21786350 TI - trans-1,2-Bis(N-methylimidazol-2-yl)ethylene: towards building blocks for 2D fabrics and MML-type 1D molecular strands. PMID- 21786351 TI - Multivalued logic gates based on DNA. PMID- 21786352 TI - Divergent heparin oligosaccharide synthesis with preinstalled sulfate esters. AB - Traditional chemical synthesis of heparin oligosaccharides first involves assembly of the full length oligosaccharide backbone followed by sulfation. Herein, we report an alternative strategy in which the O-sulfate was introduced onto glycosyl building blocks as a trichloroethyl ester prior to assembly of the full length oligosaccharide. This allowed divergent preparation of both sulfated and non-sulfated building blocks from common advanced intermediates. The O sulfate esters were found to be stable during glycosylation as well as typical synthetic manipulations encountered during heparin oligosaccharide synthesis. Furthermore, the presence of sulfate esters in both glycosyl donors and acceptors did not adversely affect the glycosylation yields, which enabled us to assemble multiple heparin oligosaccharides with preinstalled 6-O-sulfates. PMID- 21786353 TI - Distinguishing carbones from allenes by complexation to AuCl. AB - Quantum chemical calculations have been performed for the dicoordinated carbon compounds C(PPh(3))(2), C(NHC(Me))(2), R(2) C=C=CR(2) (R = H, F, NMe(2)), C(3)O(2), C(CN)(2)(-) and N-methyl-substituted N-heterocyclic carbene (NHC(Me)). The geometries of the complexes in which the dicoordinated carbon molecules bind as ligands to one and two AuCl moieties have been optimized and the strength and nature of the metal-ligand interactions in the mono- and diaurated complexes were investigated by means of energy decomposition analysis. The goal of the study is to elucidate the differences in the chemical behavior between carbones, allenes and carbenes. The results show that carbones bind one and two AuCl species in eta(1) fashion, whereas allenes bind them in eta(2) fashion. Compounds with latent divalent carbon(0) character can coordinate in more than one way, with the dominant mode indicating the degree of carbone or allene character. The calculated structures of the mono- and diaurated tetraaminoallenes (TAAs) reveal that TAAs exhibit a chameleon-like behavior: The bonding situation in the equilibrium structure is best described as allene [(R(2)N)(2)]C=C=C[(NR(2))(2)] in which the central carbon atom is a tetravalent C(IV) species, but the reactivity suggests that TAAs should be considered as divalent C(0) compounds C{C[(NR(2))(2)]}(2), that is, as "hidden" carbones. Carbon suboxide binds one AuCl preferentially in the eta(1) mode, whereas the equilibrium structures of the eta(1)- and eta(2)-bonded diaurated complex are energetically nearly degenerate. The doubly negatively charged isoelectronic carbone C(CN)(2)(2-) binds one and two AuCl very strongly in characteristic eta(1) fashion. The N-heterocyclic carbene complex, [NHC(Me)(AuCl)], possesses a high bond dissociation energy (BDE) for the splitting off of AuCl. The diaurated NHC adduct, [NHC(Me)(AuCl)(2)], has two eta(1)-bonded AuCl moieties that exhibit aurophilic attraction, which yield a moderate bond strength that might be large enough for synthesizing the complex. The BDE for the second AuCl in [NHC(Me)(AuCl)(2)] is clearly smaller than the values for the second AuCl in doubly aurated carbone complexes. PMID- 21786355 TI - Abstracts of the 25th Anniversary Symposium of the Protein Society. Boston, Massachusetts, USA. July 23-27, 2011. PMID- 21786356 TI - Mechanics of Homeotropically Ordered Smectic-A Elastomers with Global Oblate Chain Conformation. AB - Smectic-A elastomers combine one-dimensional translational order of rod-like segments with the rubber elasticity of a polymer network. In recent years, detailed investigations were carried out on elastomers showing a global prolate chain conformation. In this communication, the first experiments on fluorinated SA elastomers exhibiting a global oblate chain conformation are presented, where the polymer chains are on average compressed along the layer normal of the lamellar phase structure. The mechanical anisotropy is studied by means of thermoelastic experiments and stress-strain measurements. For the first time, the layer compression modulus B of smectic elastomers is directly measured. B is significantly larger as compared to conventional low molar mass liquid crystals and decreases significantly with increasing local disorder introduced by the isotropic crosslinker. PMID- 21786354 TI - Accurate noninvasive measurement of cell size and compartment shape anisotropy in yeast cells using double-pulsed field gradient MR. AB - The accurate characterization of pore morphology is of great interest in a wide range of scientific disciplines. Conventional single-pulsed field gradient (s PFG) diffusion MR can yield compartmental size and shape only when compartments are coherently ordered using q-space approaches that necessitate strong gradients. However, double-PFG (d-PFG) methodology can provide novel microstructural information even when specimens are characterized by polydispersity in size and shape, and even when anisotropic compartments are randomly oriented. In this study, for the first time, we show that angular d-PFG experiments can be used to accurately measure cellular size and shape anisotropy of fixed yeast cells employing relatively weak gradients. The cell size, as measured by light microscopy, was found to be 5.32 +/- 0.83 um, whereas the results from noninvasive angular d-PFG experiments yielded a cell size of 5.46 +/ 0.45 um. Moreover, the low compartment shape anisotropy of the cells could be inferred from experiments conducted at long mixing times. Finally, similar experiments were conducted in a phantom comprising anisotropic compartments that were randomly oriented, showing that angular d-PFG MR provides novel information on compartment eccentricity that could not be accessed using conventional methods. Angular d-PFG methodology seems to be promising for the accurate estimation of compartment size and compartment shape anisotropy in heterogeneous systems in general, and biological cells and tissues in particular. PMID- 21786359 TI - Self-Assembly Pluronic and beta-Cyclodextrin to Hollow Nanospheres for Enhanced Gene Delivery. AB - This paper studies a kind of hollow nanospheres prepared by self-assembly beta cyclodextrins (beta-CDs) and poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide) (pluronic F127) for gene delivery. It was found that this kind of hollow nanospheres enable load PEI10K/DNA and the resulting F127?NH2 ?betaCD/(PEI10K/DNA) with 0.08 ug/well DNA display equal or higher gene delivery capability compared to PEI10K/DNA with 1 ug/well DNA in the absence or presence of serum. The cytotoxicity of the nanospheres was over 100 times lower than that of PEI10K. PMID- 21786360 TI - Reversible Photoinduced Switching of Permeability in a Cast Non-Porous Film Comprising Azobenzene Liquid Crystalline Polymer. AB - Permeation characteristics of an azobenzene-containing liquid crystalline (LC) non-porous film are investigated using a metallic corrosion method. Thin films (300 nm) are fabricated by the solution casting of an azobenzene side-chain LC polymer on freshly polished carbon steel coupons. Coated coupons are treated under the following conditions: a) gradual annealing at a cooling rate lower than 1 degrees C . min(-1) from 150 degrees C (above its Tg ) to room temperature, and b) irradiation at 465 nm (20 mW . cm(-2) ) with either circularly polarized light (CPL) or non-polarized light (NPL). The morphology of these films is characterized using X-ray diffraction, polarized optical microscopy, and transmission measurements. The results suggest that the annealing treatment resulted in the formation of a polydomain structure consisting of locally ordered small smectic domains that lack mutual orientation. Ordered micro domains are surrounded by disordered phases. CPL and NPL irradiation generates a monodomain orientated structure and an isotropic liquid crystal glass, respectively. The permeability of these non-porous films treated by CPL, NPL, and annealing are found to be 6.14 * 10(-4) , 1.92 * 10(-2) , and 1.56 * 10(-3) cm(3) . m(-2) . d(-1) . An orientation-dependent structure model is constructed to explain the permeation phenomenon, considering the ordered phase is impermeable, only the disordered phase is accessible to penetrating molecules. Fast switching of gas permeation is demonstrated by alternative irradiation of the film with CPL and NPL, which results in an approximately 30-fold difference in the permeability of the non-porous film. PMID- 21786361 TI - Synthesis and Photovoltaic Properties of a Thienylenevinylene and Diketopyrrolopyrrole Copolymer with High Mobility. AB - A novel donor-acceptor-type polymer with a low band-gap that alternates electron rich thienylenevinylene groups with electron-deficient diketopyrrolopyrrole (DPP) units (PETVTDPP) has been synthesized by Pd-catalyzed Stille cross-coupling polymerization. The polymer shows a broad absorption band of wavelengths that range from 330 to 900 nm, and a low band-gap value of 1.43 eV. The field-effect mobility of an organic thin-film transistor based on this polymer is 0.05 cm(2 ) . Vs(-1) . Bulk-heterojunction solar cells using a mixture of PETVTDPP and PC[71] BM for the active layer show a power conversion efficiency (PCE) of 1.94% under simulated AM 1.5 G solar irradiation at 100 mW . cm(-2) . PMID- 21786362 TI - Immortalization of swine umbilical vein endothelial cells (SUVECs) with the simian virus 40 large-T antigen. AB - Implementation of the swine umbilical vein endothelial cells (SUVECs) model in vitro can be instrumental in determining the biology of endothelial cells. We have generated an immortalized endothelial cell line, G-1410, using Simian virus 40 T-antigen (SV40 T-ag) primarily to overcome the short life span before the onset of senescence and high variability among enzymatically isolated cells of primary cultures. Fast proliferating cells were selected from cultures and, after a fifth passage, examined for the presence of the SV40 T-ag by PCR and immunocytochemistry. Phase contrast and transmission electron microscopy revealed that G-1410 cells did not differ morphologically from SUVECs. The G-1410 cells exhibited positive staining for vascular endothelial (VE)-cadherin and von Willebrand factor (vWF), and formed capillary-like tube structures on Matrigel. Despite the strong oncogenic signal provided by SV40 T-ag, these transformed G 1410 cells have remained karyotypically normal and non-tumorigenic. G-1410 cells also responded to stimulation with VEGF, FGF-2, and newborn calf serum. Moreover, G-1410 cells showed elevated expression of VEGF120, VEGF164 (VEGF-A), and FGF-2 at both mRNA and protein levels. In conclusion, based on the cytological and functional evaluation of the newly obtained immortalized cell line, it can be concluded that G-1410 cells provide a useful tool for studying the effects of VEGF and FGF systems, and other signal transduction pathways related to angiogenesis. PMID- 21786363 TI - Indistinguishable transcriptional profiles between in vitro- and in vivo-produced bovine fetuses. AB - During the past several decades, in vitro fertilization (IVF) has been increasingly used both in animal production and human infertility treatment. Animals derived from in vitro manipulation are occasionally associated with abnormal offspring syndrome (AOS) and other developmental abnormalities. By studying gene expression of in vitro-produced (IVP) embryos/animals, we gain an indicator of how well this procedure mimics the in vivo environment. Most previous studies of this nature have focused on only a few genes at a time or have been limited to studying the pre-implantation stage; a global view of how gene transcription may be influenced by in vitro procedures during fetal development has yet to be ascertained. To this end, we collected liver and placental tissue samples from IVP and in vivo control bovine fetuses at days 90 and 180 of gestation. We used a bovine 13K oligonucleotide microarray to investigate the transcriptional profiles in both tissues from IVP fetuses, and compared them with those of their age-matched in vivo counterparts. Surprisingly, in both liver and placental tissues, the transcriptional profiles between IVP and control fetuses, at either 90 or 180 days of gestation, were indistinguishable. A total of 879 genes were found to be significantly regulated during liver development from 90 to 180 days of gestation, but there were no gene expression changes in the placental tissue during this developmental period. Quantitative real-time RT-PCR on 11 selected genes confirmed these results. Our results have certain implications for IVF technologies, both in agriculture and in human medicine. PMID- 21786364 TI - Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure. AB - OBJECTIVE: There is little evidence on comparative effectiveness of individual angiotensin receptor blockers (ARBs) in patients with chronic heart failure (CHF). This study compared four ARBs in reducing risk of mortality in clinical practice. METHODS: A retrospective analysis was conducted on a national sample of patients diagnosed with CHF from 1 October 1996 to 30 September 2002 identified from Veterans Affairs electronic medical records, with supplemental clinical data obtained from chart review. After excluding patients with exposure to ARBs within the previous 6 months, four treatment groups were defined based on initial use of candesartan, valsartan, losartan, and irbesartan between the index date (1 October 2000) and the study end date (30 September 2002). Time to death was measured concurrently during that period. A marginal structural model controlled for sociodemographic factors, comorbidities, comedications, disease severity (left ventricular ejection fraction), and potential time-varying confounding affected by previous treatment (hospitalization). Propensity scores derived from a multinomial logistic regression were used as inverse probability of treatment weights in a generalized estimating equation to estimate causal effects. RESULTS: Among the 1536 patients identified on ARB therapy, irbesartan was most frequently used (55.21%), followed by losartan (21.74%), candesartan (15.23%), and valsartan (7.81%). When compared with losartan, after adjusting for time-varying hospitalization in marginal structural model, candesartan (OR = 0.79, 95%CI = 0.42-1.50), irbesartan (OR = 1.17, 95%CI = 0.72-1.90), and valsartan (OR = 0.98, 95%CI = 0.45-2.14) were found to have similar effectiveness in reducing mortality in CHF patients. CONCLUSION: Effectiveness of ARBs in reducing mortality is similar in patients with CHF in everyday clinical practice. PMID- 21786365 TI - Functional consequences and structural interpretation of mutations of human choline acetyltransferase. AB - Choline acetyltransferase (ChAT; EC 2.3.1.6) catalyzes synthesis of acetylcholine from acetyl-CoA (AcCoA) and choline in cholinergic neurons. Mutations in CHAT cause potentially lethal congenital myasthenic syndromes associated with episodic apnea (ChAT-CMS). Here, we analyze the functional consequences of 12 missense and one nonsense mutations of CHAT in 11 patients. Nine of the mutations are novel. We examine expression of the recombinant missense mutants in Bosc 23 cells, determine their kinetic properties and thermal stability, and interpret the functional effects of 11 mutations in the context of the atomic structural model of human ChAT. Five mutations (p.Trp421Ser, p.Ser498Pro, p.Thr553Asn, p.Ala557Thr, and p.Ser572Trp) reduce enzyme expression to less than 50% of wild type. Mutations with severe kinetic effects are located in the active-site tunnel (p.Met202Arg, p.Thr553Asn, and p.Ala557Thr) or adjacent to the substrate binding site (p.Ser572Trp), or exert their effect allosterically (p.Trp421Ser and p.Ile689Ser). Two mutations with milder kinetic effects (p.Val136Met and p.Ala235Thr) are also predicted to act allosterically. One mutation (p.Thr608Asn) below the nucleotide binding site of CoA enhances dissociation of AcCoA from the enzyme-substrate complex. Two mutations introducing a proline residue into an alpha-helix (p.Ser498Pro and p.Ser704Pro) impair the thermal stability of ChAT. PMID- 21786366 TI - Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy. AB - By combining exome sequencing in conjunction with genetic mapping, we have identified the first mutation in large mitochondrial ribosomal protein MRPL3 in a family of four sibs with hypertrophic cardiomyopathy, psychomotor retardation, and multiple respiratory chain deficiency. Affected sibs were compound heterozygotes for a missense MRPL3 mutation (P317R) and a large-scale deletion, inherited from the mother and the father, respectively. These mutations were shown to alter ribosome assembly and cause a mitochondrial translation deficiency in cultured skin fibroblasts resulting in an abnormal assembly of several complexes of the respiratory chain. This observation gives support to the view that exome sequencing combined with genetic mapping is a powerful approach for the identification of new genes of mitochondrial disorders. PMID- 21786368 TI - Immunity against a therapeutic xenoprotein/Fc construct delivered by gene transfer is reduced through binding to the inhibitory receptor FcgammaRIIb. AB - BACKGROUND: Therapeutic xenoproteins are immunogenic and can induce neutralizing antibodies. When delivered by intramuscular injection of a plasmid vector, this mimics classical DNA vaccination. To demonstrate this, we chose Exendin-4 (Ex4), which is a glucagon-like peptide-1 mimetic xenoprotein in clinical use for treating type 2 diabetes. We constructed an Ex4 and mouse immunoglobulin (Ig)G1 Fc fusion fragment (Ex4/Fc), and hypothesized that it would have minimal immunogenicity as a result of its capacity to bind the inhibitory Fc receptor FcgammaRIIb expressed by B lymphocytes. METHODS: Plasmid vectors encoding Ex4/Fc constructs, with wild-type or mutant Fc, were injected intramuscularly into mice, and local electroporation was applied to enhance gene transfer. Gene transfer was performed in both wild-type and FcgammaRIIb knockout mice. Antibody production was detected in serum by an enzyme-linked immunosorbent assay. RESULTS: Recombinant Ex4/Fc bound only to B cells expressing FcgammaRIIb. This binding was dependent on a motif in the Fc region, which we mutated to abolish binding (Ex4/Fcmut). Ex4 antibody was detected in mice treated with Ex4, as well as Ex4/Fcmut, but not in those treated with Ex4/Fc. Thus, wild-type Fc was associated with reduced immunogenicity. To confirm this was related to the presence of inhibitory Fc receptors, we also performed experiments in FcgammaRIIb null mice. Mice lacking this receptor produced antibodies against all Ex4 constructs, including the wild-type Fc (Ex4/Fc). CONCLUSIONS: The present study shows that inhibitory FcgammaRIIb receptors interacting with the wild-type IgG1 Fc reduce immunity against Ex4/Fc, suggesting an approach for reducing the immunogenicity of therapeutic proteins in the context of gene therapy. PMID- 21786367 TI - Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects. AB - Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC(IGF)), to promote these seed and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC(IGF) or traceable MSC(IGF)-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1(-/-)) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (MUCT), and histological analyses. We found that systemically transplanted MSC(IGF) through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC(IGF) to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1(-/-) mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1(-/-) left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC(IGF) in fracture repair and potentially to treat nonunions. PMID- 21786369 TI - Generation of melamine polymer condensates upon hypergolic ignition of dicyanamide ionic liquids. PMID- 21786370 TI - Transmembrane domain peptide/peptide nucleic acid hybrid as a model of a SNARE protein in vesicle fusion. PMID- 21786371 TI - exo-Selective asymmetric Diels-Alder reaction of 2,4-dienals and nitroalkenes by trienamine catalysis. PMID- 21786372 TI - The 3D solution structure of thurincin H, a bacteriocin with four sulfur to alpha carbon crosslinks. PMID- 21786373 TI - Towards highly active and robust alkyne metathesis catalysts: recent developments in catalyst design. PMID- 21786374 TI - Distribution pattern of length, length uniformity, and density of TiO3(2-) quantum wires in an ETS-10 crystal revealed by laser-scanning confocal polarized micro-Raman spectroscopy. PMID- 21786375 TI - Protein-like oligomerization of carbohydrates. PMID- 21786376 TI - Magnesium-mediated benzothiazole activation: a room-temperature cascade of C-H deprotonation, C-C coupling, ring-opening, and nucleophilic addition reactions. AB - Ligand domin(o)ated: In contrast to the straightforward deprotonation of benzothiazole using Grignard reagents, treatment of benzothiazole with 1 leads to a novel type of activation. The initial magnesiation initiates an unstoppable domino reaction of C-C coupling, ring opening, nucleophilic addition, and deprotonation to give 2. THF=tetrahydrofuran. PMID- 21786377 TI - Cyclopropyl iminium activation: reactivity umpolung in enantioselective organocatalytic reaction design. PMID- 21786378 TI - Fluorescence properties of 8-(2-pyridyl)guanine "2PyG" as compared to 2 aminopurine in DNA. AB - Because of their environment-sensitive fluorescence quantum yields, base analogues such as 2-aminopurine (2AP), 6-methylisoxanthopterin (6-MI), and 3 methylisoxanthopterin (3-MI) are widely used in nucleic-acid folding and catalysis assays. Emissions from these guanine mimics are quenched by base stacking interactions and collisions with purine residues. Fluorescent base analogues that remain highly emissive in folded nucleic acids can provide sensitive means to differentiate DNA/RNA structures by participating in energy transfer from proximal ensembles of unmodified nucleobases. The development of new, highly emissive guanine mimics capable of proper base stacking and base pairing interactions is an important prerequisite to this approach. Here we report a comparison of the most commonly used probe, 2-aminopurine (2AP), to 8-(2 pyridyl)-2'-deoxyguanosine (2PyG). The photophysical properties of these purine derivatives are very different. 2PyG exhibits enhanced fluorescence quantum yields upon its incorporation into folded nucleic acids--approximately 50-fold brighter fluorescence intensity than 2AP in the context of duplex DNA. Due to its bright fluorescence and compatibility with proper DNA folding, 2PyG can be used to accurately quantify energy-transfer efficiencies, whereas 2AP is much less sensitive to structure-specific trends in energy transfer. When using nucleoside monomers, Stern-Volmer plots of 2AP fluorescence revealed upward curvature of F(0) /F upon titration of guanosine monophoshate (GMP), whereas 2PyG exhibited unusual downward curvature of F(0) /F that resulted in a recovery of fluorescence at high GMP concentrations. These results are consistent with the trends observed for 2PyG- and 2AP-containing oligonucleotides, and furthermore suggest that solutions containing high concentrations of GMP can, in some ways, mimic the high local nucleobase densities of folded nucleic acids. PMID- 21786379 TI - The ribosome meets synthetic biology. PMID- 21786380 TI - Identification of a gene cluster that initiates azasugar biosynthesis in Bacillus amyloliquefaciens. PMID- 21786381 TI - Spin-orbit coupling in phosphorescent iridium(III) complexes. AB - We study the excited states of two iridium(III) complexes with potential applications in organic light-emitting diodes: fac-tris(2 phenylpyridyl)iridium(III) [Ir(ppy)(3)] and fac-tris(1-methyl-5-phenyl-3-n-propyl [1,2,4]triazolyl)iridium(III) [Ir(ptz)(3)]. Herein we report calculations of the excited states of these complexes from time-dependent density functional theory (TDDFT) with the zeroth-order regular approximation (ZORA). We show that results from the one-component formulation of ZORA, with spin-orbit coupling included perturbatively, accurately reproduce both the results of the two-component calculations and previously published experimental absorption spectra of the complexes. We are able to trace the effects of both scalar relativistic correction and spin-orbit coupling on the low-energy excitations and radiative lifetimes of these complexes. In particular, we show that there is an indirect relativistic stabilisation of the metal-to-ligand charge transfer (MLCT) states. This is important because it means that indirect relativistic effects increase the degree to which SOC can hybridise singlet and triplet states and hence plays an important role in determining the optical properties of these complexes. We find that these two compounds are remarkably similar in these respects, despite Ir(ppy)(3) and Ir(ptz)(3) emitting green and blue light respectively. However, we predict that these two complexes will show marked differences in their magnetic circular dichroism (MCD) spectra. PMID- 21786382 TI - Relationship between intracellular Ca2+ and ROS during fluoride-induced injury in SH-SY5Y cells. AB - The mechanisms underlying the neurotoxicology of endemic fluorosis still remain obscure. To explore lactate dehydrogenase (LDH) leakage, intracellular Ca2+ concentration ([Ca2+]i ) and reactive oxygen species (ROS) production induced by fluoride, human neuroblastoma (SH-SY5Y) cells were incubated with sodium fluoride (NaF, 20, 40, 80 mg/L) for 24 h, with 40 mg/L NaF for 3, 6, 12, 18, 24 h, and N acetyl-L-cysteine (NAC), ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N' tetraacetic acid (EGTA), 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) alone or combined with fluoride (40 mg/L) respectively for 12 h in vitro. The results showed that the LDH levels in the 40 and 80 mg/L fluoride-treated groups were significantly higher than that of the control group (in the test level of 0.05, the difference were statistical significance). [Ca2+]i and ROS reached a peak at 3 h and 12 h respectively after exposure to 40 mg/L fluoride. Fluoride coincubated with NAC (antioxidant) dramatically decreased ROS and LDH levels compared with the fluoride only group (in the test level of 0.05, the difference were statistical significance). However, fluoride-induced increase in [Ca2+]i was not affected by NAC. BAPTA-AM (intracellular calcium chelator) markedly lowered fluoride-induced increase of [Ca2+]i , ROS and LDH levels while EGTA (extracellular calcium chelator) have no effects on them. These results indicate that fluoride-related Ca2+ release from the site of intracellular calcium storage causes the elevation of ROS contributing to the cytotoxicity in SH-SY5Y cells. PMID- 21786383 TI - cDNA microarray analysis of the gene expression of murine leukemia RAW 264.7 cells after exposure to propofol. AB - Propofol (2,6-diisopropylphenol) is the most extensively used general anesthetic sedative agent and it is employed in clinical patients. It has been shown that propofol exhibits anticancer activities. However, there is no available information to address propofol-induced cytotoxic effects and affected gene expressions on murine leukemia cells. Therefore, we investigated the effects of propofol on the levels of protein and gene expression, which are associated with apoptotic death in mouse leukemia RAW 264.7 cells in vitro. Results indicated that propofol induced cell morphological changes, cytotoxicity, and induction of apoptosis in RAW 264.7 cells in vitro. Western blot analysis demonstrated that propofol promoted Fas, cytochrome c, caspase-9 and -3 active form and Bax levels, but inhibited Bcl-xl protein level which led to cell apoptosis. Furthermore, cDNA microarray assay indicated that propofol significantly enhanced 5 gene expressions (Gm4884; Gm10883; Lce1c; Lrg1; and LOC100045878) and significantly suppressed 26 gene expressions (Gm10679; Zfp617; LOC621831; LOC621831; Gm5929; Snord116; Gm3994; LOC380994; Gm5592; LOC380994; Gm4638; LOC280487; Gm4638; Tex24; A530064D06Rik; BC094916; EG668725; Gm189; Hist2h3c2; Gm8020; Snord115; Gm3079; Olfr198; Tdh; Snord115; and Olfr1249). Based on these observations, propofol altered apoptosis-related proteins might result from induction of apoptotic gene expression and inhibition of cell growth gene expression, which finally led to apoptosis in a mouse leukemia cell line (RAW 264.7) in vitro. PMID- 21786384 TI - Induction of reactive oxygen species in chlamydomonas reinhardtii in response to contrasting trace metal exposures. AB - The toxicity of metals to organisms is, in-part, related to the formation of reactive oxygen species (ROS) in cells and subsequent oxidative stress. ROS are by-products of normal respiration and photosynthesis processes in organisms, but environmental factors, like metal exposure, can stimulate excess production. Metals involved in several different mechanisms such as Haber-Weiss cycling and Fenton-type reactions can produce ROS. Some metals, such as Cd, may contribute to oxidative stress indirectly by depleting cellular antioxidants. We investigated the measurement of ROS as a sensitive biomarker of metal toxicity (that could possibly be implemented in a biotic ligand model for algae) and we compared ROS induction in response to several contrasting transition metals (Cu, V, Ni, Zn, and Cd). We also compared the ROS response to glutathione and growth toxicity endpoints measured in a previous study. The cell-permeable dye, 2'7'dichlorodihydrofluorescein diacetate, was used as a probe to detect formation of ROS in Chlamydomonas reinhardtii cells. Metal-exposed cells were incubated with the fluorescent dye in a 96-well plate and monitored over 5.5 h. A dose response of ROS formation was observed with Cu exposure in the range of 20-500 nM. Cu produced more ROS compared with either Zn or Cd (both nonredox active metals). The redox-active metal V produced increased ROS with increased concentration. The measurement of ROS may be a useful indicator of Cu toxicity, but the signal to noise ratio was better for the glutathione endpoint assay. PMID- 21786385 TI - Cytogenetic effects of commercial formulations of deltamethrin and/or thiacloprid on Wistar rat bone marrow cells. AB - Deltamethrin (DEL) and thiacloprid (THIA) are two insecticides that are widely used in agriculture either separately or in combination. Studies on genotoxicity and cytotoxicity of TIA and the mixture of DEL and THIA insecticides have not been reported so far. Therefore, we investigated the cytotoxic and genotoxic effects of commercial formulations DEL and/or THIA in rat bone marrow cells, using mitotic index (MI), micronucleus (MN) and chromosome aberrations (CA) assay. In vivo cytokinesis-block micronucleus (CBMN) assay using cytochalasin-B in bone marrow cells was performed for the first time in this study. Rats were orally gavaged with a single dose of DEL (15 mg/kg), THIA (112.5 mg/kg) or DEL + THIA (15 + 112.5 mg/kg) for 24 h (acute treatments), or DEL (3 mg/kg/day), THIA (22.5 mg/kg/day) or DEL + THIA (3 + 22.5 mg/kg/day) for 30 days (subacute treatments). A corn oil vehicle control group and cyclophosphamide (50 mg/kg) positive control group were also included. All DEL and/or THIA treatments significantly decreased MI and binucleated (BN) cell numbers, and significantly increased CA, as compared to the vehicle control group. The results of CBMN assay indicated that the combination of DEL and THIA for both treatment times and the 30-day treatment with THIA alone caused a significant increase in micronucleus formation in BN cells. The present findings indicated the combined exposure of DEL and THIA showed genotoxic and cytotoxic effects more than those of individual exposure of DEL or THIA in rat bone marrow cells. PMID- 21786386 TI - Evaluation of DNA damage and cytotoxicity induced by three commonly used organophosphate pesticides individually and in mixture, in rat tissues. AB - Organophosphate pesticides are among the most widely used synthetic chemicals for controlling a wide variety of pests. Chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) are among the most extensively used organophosphate (OP) pesticides. The main target of action of OP compounds is the central and peripheral nervous system, although it has also been postulated that these compounds in both acute and chronic intoxication, disturb the redox processes and thus induce oxidative stress. The excessive generation of reactive oxygen species (ROS) causes damage to all vital macromolecules including lipids, proteins, and DNA. This study was aimed to investigate the genotoxicity and cytotoxicity of CPF, MPT, and MLT when given singly or in combination. The DNA damage was measured by alkaline single-cell gel electrophoresis or comet assay and expressed as DNA damage index. The results showed that both acute and chronic exposure with CPF, MPT, and MLT, caused significantly marked DNA damage in rat tissues namely, liver, brain, kidney, and spleen, when measured 24 hour posttreatment. It was also observed that MPT caused highest level of DNA damage and brain was maximally affected by these OP compounds. When these pesticides were given in mixture, the damage was not the sum of damage caused by individual pesticide, confirming that these pesticides do not potentiate the toxicity of each other. When the DNA damage was measured 48 and 72 hour posttreatment, the damage was partially repaired. Pesticide exposure also caused histopathological changes in rat tissues. PMID- 21786387 TI - Evaluation of factors associated with cadmium exposure and kidney function in the general population. AB - Cadmium (Cd) is a nonessential toxic metal which is widely distributed in the environment. The general population is exposed to low levels of Cd and the kidney is the organ most sensitive to Cd toxicity. This study was performed to simultaneously evaluate Cd exposure, kidney function, and oxidative stress biomarkers in the general population. A total of 643 adults were interviewed to document demographic characteristics, lifestyles, past-medical history, and diet during the last 24 h. We estimated daily Cd intake based on the diet of study subjects who had not been exposed to Cd occupationally. Whole blood and urine samples were collected and analyzed to determine Cd concentrations and kidney function indices (beta2 -microglobulin [beta2-MG], N-acetyl-beta-D glucosaminidase [NAG], metallothionein [MT]). The oxidative stress index (malondialdehyde [MDA]) was determined from the urine. The daily Cd intake from diet was established as 7.07 MUg/day. The mean concentration of Cd measured in the blood was 1.22 MUg/L and urine was 0.95 MUg/g creatinine. The concentrations of Cd in blood and urine were higher in females than in males. The blood levels of Cd were affected by sex, age, and smoking, and urine Cd was influenced by sex, age, and blood Cd. The urine Cd was positively correlated with MT, NAG activity, and MDA in females, but with NAG only in males. The blood Cd was associated with MT in males. Increased NAG activity was observed when Cd in urine reached 1.0 MUg Cd/g creatinine and was also affected by age, hypertension, and diabetes mellitus. Urinary MT only responded to Cd in urine or blood. In summary, exposure to Cd in the general population was influenced by various factors including sex, age, and smoking habits. Such exposure might eventually cause tubular damage in the kidneys through the oxidative stress mechanism, and females might be more susceptible than males to Cd exposure under the environment. PMID- 21786388 TI - How can we miss you, if you will never leave? Biodegradable stents. PMID- 21786389 TI - Take that, stent nihilists: additional evidence for the benefits of coronary stenting. PMID- 21786390 TI - He who can, does; he who does, teaches. PMID- 21786391 TI - GenousTM endothelial progenitor cell capturing stent: thrombus-resistant but vulnerable to restenosis. PMID- 21786392 TI - Measuring the lumen with conductance: are we looking at a breakthrough technology? PMID- 21786393 TI - Mending the torn coronary artery. PMID- 21786394 TI - Murphy's law and us. PMID- 21786395 TI - Transcatheter valve implantation within failed tricuspid valve surgical bioprostheses. PMID- 21786396 TI - Technique of arterial femoral puncture, safe in, safe out. PMID- 21786397 TI - Percutaneous left ventricular assist devices--still waiting for the final word. PMID- 21786398 TI - Alcohol septal ablation via a subendocardial approach: acute effects in an animal model. PMID- 21786399 TI - Round pegs for not round holes: the challenge of percutaneous repair of paravalvular regurgitation. PMID- 21786400 TI - One-year results of the INSPIRE trial with the novel MGuard stent: serial analysis with QCA and IVUS. AB - BACKGROUND: The newly developed balloon-expandable Mguard stent system, a combination of an ultra-thin polymer mesh sleeve attached to the external surface of a BMS, was conceived to provide embolic protection during PCI of SVG and thrombus-containing lesions. Although the acute results (<30 days) have pointed to the efficacy of this novel device, few is known about its long-term performance. METHODS: The present article address the 1-year clinical results of a cohort of 30 patients enrolled in the INSPIRE trial. Inclusion critiria was de novo lesions in SVG or native vessels with angiographic evidence of instability with potential to provoke flow disturbances and/or distal embolization. The primary endpoint (incidence of MACE-composite of cardiac death, nonfatal MI, and TLR) up to 30 days of the procedure has already been published. Secondary endpoints here presented included in-stent late lumen loss (QCA), % of stent obstruction (IVUS) at 6 months and combined MACE at 1 year. QCA and IVUS were performed by independent corelabs. RESULTS: Mean population age was 63 years with 38% of diabetics. Overall, 55% presented with ACS and 57% of lesions were located in SVG. Most lesions had complex morphology including the presence of thrombus (26%) and ulceration (20%). Distal/proximal protection devices were not used. Preprocedural QCA data showed lesion length and reference vessel diameter of 12.0 +/- 4.5 mm and 3.0 +/- 0.5 mm. The MGuard stent was successfully delivered in all cases and final TIMI-3 was achieved in 100% with no MACE up to 30 days. At 6 months, in-stent late loss and % of stent obstruction were 1.0 +/- 0.4 mm and 28.5 +/- 15.6%. Up to 1 year there was no case of cardiac death, two MI (one Q wave and one non-Q-wave) and six cases of ischemia-driven TLR. Of note, there was no case of definite/probable stent thorombosis. CONCLUSIONS: In this series of patients treated with MGuard stent, the novel device showed no midterm efficacy and safety concerns. PMID- 21786401 TI - Unusual complication of pacemaker implantation/revision: secondary endocarditis due to fracture and embolization of an introducer sheath. AB - We report a 48-year-old male with a rare complication of pacemaker revision fracture, migration, and secondary endocarditis due to a venous introducer sheath. We illustrate the possible mechanism of injury and discuss approaches to management. PMID- 21786402 TI - Mouse strains for the ubiquitous or conditional overexpression of the Flii gene. AB - The gelsolin related actin binding protein, Flii, is able to regulate wound healing; mice with decreased Flii expression show improved wound healing whereas mice with elevated Flii expression exhibit impaired wound healing. In both mice and humans Flii expression increases with age and amelioration of FLII activity represents a possible therapeutic strategy for improved wound healing in humans. Despite analysis of Flii function in a variety of organisms we know little of the molecular mechanisms underlying Flii action. Two new murine alleles of Flii have been produced to drive constitutive or tissue-specific expression of Flii. Each strain is able to rescue the embryonic lethality associated with a Flii null allele and to impair wound healing. These strains provide valuable resources for ongoing investigation of Flii function in a variety of biological processes. PMID- 21786404 TI - Pattern of bacterial and fungal infections in the first 3 months after pediatric living donor liver transplantation: an 11-year single-center experience. AB - Infection after pediatric living donor liver transplantation (LDLT) is a major cause of morbidity and mortality. Here, we sought to determine the incidence, timing, location, and risk factors for bacterial and fungal infections. We retrospectively investigated infection for 3 postoperative months in 345 consecutive pediatric patients (56.2% were females) who underwent primary LDLT at Kyoto University Hospital, Japan. A total of 179 patients (51.9%) developed at least 1 bacterial and/or fungal infection episode, with an infection rate of 2.5 per patient. The predominant infection site was the surgical site (52%). Most of the bacterial and fungal infection occurred within the first month. Enterococcus species followed by multidrug-resistant Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus were the predominant bacterial pathogens. All fungal isolates were Candida species. Prolonged preoperative hospital stay more than 7 days (P = 0.025) and bile leak (P = 0.047) were independent predictors of bacterial infection. Preoperative ascites (P = 0.009) and prolonged insertion of intravascular catheters (P = 0.001) independently predicted fungal infections. Bacterial and fungal infections were responsible for 42.9% of the causes of death in our study. To avoid bacterial and fungal infections after LDLT, broader spectrum prophylaxis to cover the range of organisms seen in these infections should be considered as a more favorable treatment regimen to prevent prophylaxis failure, especially for patients with a preoperative hospital stay more than 7 days or operative complications in the form of a bile leak. Early drain removal and prophylactic antifungal drugs should be considered for patients with preoperative ascites. Cooperation between attending physicians and infectious disease physicians can improve the outcome of patients after LDLT. PMID- 21786403 TI - Stella-Cre mice are highly efficient Cre deleters. AB - Cre-loxP recombination is widely used for genetic manipulation of the mouse genome. Here, we report generation and characterization of a new Cre line, Stella Cre, where Cre expression cassette was targeted to the 3' UTR of the Stella locus. Stella is specifically expressed in preimplantation embryos and in the germline. Cre-loxP recombination efficiency in Stella-Cre mice was investigated at several genomic loci including Rosa26, Jak2, and Npm1. At all the loci examined, we observed 100% Cre-loxP recombination efficiency in the embryos and in the germline. Thus, Stella-Cre mice serve as a very efficient deleter line. PMID- 21786405 TI - Recreation as a developmental experience. Issue editors' notes. PMID- 21786407 TI - Leisure, recreation, and play from a developmental context. AB - Participation in activities and experiences defined as play, recreation,and leisure has important developmental implications for youth. Elements and characteristics of leisure experiences contribute directly to the development of identity, autonomy, competence,initiative, civic duty, and social connections. Whether in informal or formal, appropriately structured and organized programs,leisure experiences can help facilitate adolescent development in these areas. For example, one of the defining elements of leisure is that it is characterized by free choice and self-determination. Programs that promote leadership, choice, autonomy, and initiative can help adolescents deal with developmental challenges associated with this age group. Leisure experiences can also promote civic engagement and provide important peer-to-peer, peer to-adult, and peer-to-community connections. The social context of leisure is important to adolescent development in that it provides opportunities to learn empathy, loyalty, and intimacy in their group activities, as well as to negotiate with peers, resolve conflict,and work together for communal goals. In addition, adolescents often report positive emotional experiences in leisure, which can serve as a relief from the stress they feel in other areas of their lives and contribute to positive psychological adjustment and well-being. A case study is used to show how planned, purposive programs can be used as critical components of efforts to contribute to adolescent development. PMID- 21786408 TI - Positive youth development within a family leisure context: youth perspectives of family outcomes. AB - Although a variety of recreation programs provide valuable settings for youth development and should continue, the home should be considered the first and perhaps the most essential context for positive youth development. Family leisure experiences are purposively or intentionally planned by invested adults (parents) to create and maintain meaningful relationships and provide supportive opportunities for their children to learn skills and develop behaviors that will not only strengthen current family life but ultimately contribute to their overall positive development. The article presents family leisure research from a youth perspective and sets out the implications of the role of home-based core types of leisure that families engage in. PMID- 21786409 TI - Back to the future: The potential relationship between leisure and education. AB - There is a long, documented history of the relationships among leisure, recreation, and education dating back to Greek philosophy.Originally there was little differentiation among the terms as they were presented as a unified process for youth and human development. Over time, each of these fields has developed, and their definitions have been shaped and reshaped. Using some of the original conceptions from Aristotle and Plato, coupled with foundational premises suggested by Dewey, this article frames current youth development efforts in a historical context. The authors suggest that perhaps what the separate professions might define as high-quality leisure, recreation, and educational experiences still maintain links among each. They further suggest that planned experiences with increasing levels of coordination can strengthen these links and develop an "education-for-leisure" perspective among participating youth and the choices they make. Self-determination theory (SDT) refers to the autonomy in choosing a particular behavior or action. Youth development opportunities that make connections between the content of a regular school day and choice of activity during out-of-school time can inculcate self-determined leisure choices that are productive. Planned and intentional educational experiences expand the possibilities for productive recreational choices. This article therefore proposes a framework for increasing levels of coordination among educational and recreational entities so that participating youth can develop and adopt an education-for-leisure disposition. PMID- 21786410 TI - Recreation as a component of the community youth development system. AB - In an era of fragmented school systems and budget cuts, many educators and youth leaders seeking to solve the problems that youth face are turning to out-of school-time programs. In many communities, these programs are seen as essential in the development of youth into fully functioning adults. One such area of the out-of-school-time sector is the provision of recreation services. Recreational services have a vital role in connecting youth to their communities, as well as enabling youth and adult allies to improve challenging conditions. This chapter outlines the historical role that recreation has played in community youth development programs and shows how community youth development has evolved. It then looks at how organizations in three communities--the Youthline Outreach Mentorship program in Minneapolis, a 4-H initiative in Parker City, Texas, and the Hockey Is for Everyone program--have successfully applied the theoretical knowledge. Best practices from these programs illustrate that the role of recreation in community youth development is changing. No longer are recreation programs about providing just "fun and games." Recreation organizations are now placing more value on the development of the community as a whole, in addition to the individual well-being of young people. PMID- 21786411 TI - Youth development and the camp experience. AB - The organized camp experience has been an important part of the lives of children, youth, and adults for over 150 years. The camp experience is a way for young people to explore and search for an authenticity often missing in other parts of their lives that contributes to their healthy transition into adulthood. Over the past decade, tremendous growth in the volume and rigor of camp-related research has occurred, facilitated by a targeted research agenda conducted by the American Camp Association. This agenda was founded on three national research projects conducted between 2003 and 2007: a study to identify the developmental outcomes of the camp experience, a benchmarking study of the youth development supports and opportunities provided through camp experiences, and a program improvement project directed toward enhancing supports and opportunities provided by camps. The findings from these research projects suggest that camp experiences promote developmental outcomes in both campers and staff and that camps provide the supports and opportunities needed for positive youth development. This article explores the developmental outcomes of the camp experience and the characteristics of the supports and opportunities afforded by camp experiences, including settings, structures, and programs and activities, as a way to provide a clearer understanding of camp as a positive youth development setting. Innovations and opportunities in research related to the provision of quality camp experiences are also considered. PMID- 21786412 TI - Outdoor-based play and reconnection to nature: a neglected pathway to positive youth development. AB - Throughout history, outdoor-based play and the connection to nature have been recognized as important contributors to a happy life and healthy development. At times, however, play and nature have been neglected and viewed as frivolous and wasteful. In the early twentieth century, the first play movement took place to get children out of the factories and back outdoors to play. Now, a century later, factors including twenty-four-hour media,stranger danger, and overscheduling of children's time have resulted in a level of play deprivation that is contributing to a host of social, emotional, and physical problems. This article draws on recent research that shows that as many as 40 percent of America's schools have eliminated or significantly reduced recess. Also, children and adolescents are spending an average of fifty-three hours each week in front of screen media, and only 31 percent of mothers report that their children play outside as frequently as they did as children. The deficits in outdoor-based play that arise from these lifestyles have resulted in significant increases in emotional and psychological disorders, decreased capacity to deal with stressors, and decreased physical fitness. This article describes specific organizations and programs that address the problem of play deprivation and reconnection to the outdoors. PMID- 21786413 TI - Adventure-based programming: exemplary youth development practice. AB - Despite functioning on the periphery of academic scholarship, theory development, and rigorous science, the better adventure-based programs are functioning at the forefront of professional youth practices. This article links the core elements and processes of adventure programs to the literature on positive youth development and quality youth programming. Contemporary work on developmental systems theory, developmental cascades, and initiative are well aligned with the historical, philosophical, and pro-grammatic roots of adventure education. In addition, adventure programs afford some powerful experiences by way of distinct features such as isolation, dosage, different physical environments, holistic approaches, social experiences, and program novelty. This combination of features often provides a microcosm for youth to live, learn, experiment, and grow. Despite the strengths in prototypical adventure programs, they remain less accessible and are not easily delivered to many youth. Although there are clearly differences in adventure program and other youth activities, many of the qualities of adventure programs can be included in a broader and more accessible spectrum of youth opportunities. This article thus explains the congruency between the literature on positive youth development and adventure programs and generalizes current tenets of adventure programs to the broader context of youth practice. It is time to recognize the important role that adventure programs play for many youth and fully embrace what these diverse and successful programs can teach the general field of positive youth development. PMID- 21786414 TI - A competency-based approach to preparing staff as recreation and youth development leaders. AB - Youth development professionals and parks and recreation professionals often are charged with providing services to youth. However, the approach of each can be quite different as recreation is a primary focus for recreation professionals and part of many services offered by youth development specialists. Despite the differences, these two groups of professionals can learn a great deal from each other. This article examines youth development and staff training with examples from the field and suggests how youth development professionals can learn from recreation professionals and vice versa. It suggests that parks and recreation professionals can strengthen degree programs, accreditation, certification, and continuing education by incorporating specific youth development competencies established by the National Collaboration for Youth. For their part, youth development professionals can learn from parks and recreation professionals how to enhance recreation programming as part of their services by gaining an understanding of program design, program and activity leadership, and administrative practices. With much debate over whether more education or more experience is a better path for those working with youth, the authors suggest that a combination of both will adhere to the quality of staff. Staff gain further knowledge and skill from academic preparation at the undergraduate and graduate levels, field-based training through jobs and internships, and continuing education courses specializing in youth development competencies and recreation-based competencies set within a youth development environment. PMID- 21786415 TI - Reframing recreation as a public policy priority. AB - Recreation has the potential to be an important public policy priority; however, it must be reframed to address critical policy priorities. Few policymakers understand the value and benefits of recreation, requiring practitioners and advocates to closely connect recreation to issues of concern to policymakers. A significant policy opportunity to expand recreational opportunities for children and youth lies in the area of education, including the reauthorization of the Elementary and Secondary Education Act. By educating policymakers on the myriad outcomes that can result from quality recreational experiences, including the ways in which recreation can support the education of children and youth, solid,incremental progress can be made in positioning recreation as a public policy priority. PMID- 21786416 TI - Estimating the future decline of wild coho salmon populations resulting from early spawner die-offs in urbanizing watersheds of the Pacific Northwest, USA. AB - Since the late 1990 s, monitoring efforts evaluating the effectiveness of urban stream restoration projects in the greater metropolitan area of Seattle, Washington, USA, have detected high rates of premature mortality among adult coho salmon (Oncorhynchus kisutch) in restored spawning habitats. Affected animals display a consistent suite of symptoms (e.g., disorientation, lethargy, loss of equilibrium, gaping, fin splaying) that ultimately progresses to death on a timescale of a few hours. Annual rates of prespawn mortality observed over multiple years, across several drainages, have ranged from approximately 20% to 90% of the total fall run within a given watershed. Current weight-of-evidence suggests that coho prespawn mortality is caused by toxic urban stormwater runoff. To evaluate the potential consequences of current and future urbanization on wild coho salmon, we constructed life-history models to estimate the impacts of prespawn mortality on coho populations and metapopulations. At the low (20%) and high (90%) ends of the range of observed mortality, model results indicated the mean time to extinction of localized coho populations in 115 and 8 y, respectively. The presence of productive source populations (i.e., unaffected by prespawn mortality) within a metapopulation reduced local extinction risk. However, as more populations within a metapopulation become affected by spawner die-offs prior to spawning, the source population's productivity declined. These simple models demonstrate the potential for rapid losses from coho populations in urbanizing watersheds. Because the models do not account for possible impacts of toxic runoff to other coho life stages, they likely underestimate the cumulative impacts of nonpoint source pollution on wild populations. PMID- 21786417 TI - In vivo ultra-fast photoacoustic flow cytometry of circulating human melanoma cells using near-infrared high-pulse rate lasers. AB - The circulating tumor cells (CTCs) appear to be a marker of metastasis development, especially, for highly aggressive and epidemically growing melanoma malignancy that is often metastatic at early stages. Recently, we introduced in vivo photoacoustic (PA) flow cytometry (PAFC) for label-free detection of mouse B16F10 CTCs in melanoma-bearing mice using melanin as an intrinsic marker. Here, we significantly improve the speed of PAFC by using a high-pulse repetition rate laser operating at 820 and 1064 nm wavelengths. This platform was used in preclinical studies for label-free PA detection of low-pigmented human CTCs. Demonstrated label-free PAFC detection, low level of background signals, and favorable safety standards for near-infrared irradiation suggest that a fiber laser operating at 1064 nm at pulse repetition rates up to 0.5 MHz could be a promising source for portable clinical PAFC devices. The possible applications can include early diagnosis of melanoma at the parallel progression of primary tumor and CTCs, detection of cancer recurrence, residual disease and real-time monitoring of therapy efficiency by counting CTCs before, during, and after therapeutic intervention. Herewith, we also address sensitivity of label-free detection of melanoma CTCs and introduce in vivo CTC targeting by magnetic nanoparticles conjugated with specific antibody and magnetic cells enrichment. PMID- 21786418 TI - Leukoflow: multiparameter extended white blood cell differentiation for routine analysis by flow cytometry. AB - Differential white blood cell count (dWBC) is a frequently used diagnostic tool. For most patient samples an automated blood counter produces a five-part differential count. If this dWBC does not meet pre-set criteria, microscopic dWBC is performed. Microscopy is labor intensive and requires sustained training of technicians. Inter-observer variation and statistical variation are significant, due to limited numbers of cells counted. Flow cytometry is a candidate reference method for dWBC. Advantages are immunological definitions and large number of measured cells. Our goal was to replace (part of) the microscopic dWBC by a flow cytometric dWBC, that gives additional information on blasts, myeloid precursors, and lymphocyte subsets. We designed a cocktail of antibodies (CD4, CD14, CD34, CD16, CD56, CD19, CD45, CD138, CD3, and CD71) combined with a gating strategy and flow cytometric protocol for easy identification of leukocyte populations. This assay, called Leukoflow, requires low sample volume, has few manual handling steps, and a potential turn-around-time shorter than 2 h. We determine percentages and absolute concentrations of at least 13 different cell populations. For quantification of normoblasts a second flow cytometric staining was designed. We compared microscopic dWBC with that of the automated blood counter and Leukoflow for normal and abnormal blood samples. Leukoflow results correlate well with the automated blood counter for leukocytes, neutrophils, eosinophils, monocytes, and lymphocytes. Correlation with manual dWBC is lower. Blast counts reported by Leukoflow suffer less from inter-observer variation compared to manual dWBC. In addition to microscopic or cytometric dWBC-techniques T-lymphocytes, CD4-T-lymphocytes, B-lymphocytes, NK-cells, myeloid progenitors, plasma cells, and blasts are determined by Leukoflow. These populations give potential useful clinical information and are subject for future studies focusing on the additional clinical value. Leukoflow is a highly interesting and promising technique for clinical laboratories. PMID- 21786420 TI - Multiplatform comparison of multiplexed bead arrays using HPV genotyping as a test case. AB - While previous studies have investigated the utility of Luminex technology in comparison to other standard techniques, there have been few studies directly comparing different bead-based assays. A key barrier to establishing Luminex technology in research or clinical laboratories is the apparent need to purchase not only encoded bead sets but also the Luminex instrument. However, as flow cytometry instrumentation continues to improve in sensitivity and in the number and diversity of detection parameters, a diverse range of bead-based assays is likely to emerge. Human papillomavirus (HPV) genotyping requires multiplexed analysis of 10-100 individual genotypes per sample, which is well suited to bead based assays whilst technically challenging and costly for related technologies (e.g., qPCR). Here we performed an unbiased technical comparison between Luminex technology and our in-house 3-mercaptopropyl trimethoxysilane ("MPS") bead platform, which has been designed for integration with generic cytometry instruments. In genotyping 200 clinical samples, we compared the two bead assays against the goldstandard Roche Line Blot (RLB) assay, and both performed well in receiver-operator characteristic (ROC) curve analysis. We also show instrument based differences are a significant factor in comparing the methods, which needs to be considered in future comparative studies. These multi-platform analyses are important in establishing the validity of new methods, as well as highlighting specific advantages and disadvantages of the assays for specific applications. PMID- 21786419 TI - Modular anti-EGFR and anti-Her2 targeting of SK-BR-3 and BT474 breast cancer cell lines in the presence of ErbB receptor-specific growth factors. AB - Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor- and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR 3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRG-caused compensation of Lapatinib induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. PMID- 21786421 TI - Topography-induced cell adhesion to Acr-sP(EO-stat-PO) hydrogels: the role of protein adsorption. AB - Topographic surface patterning of intrinsically non-adhesive P(EO-stat-PO)-based hydrogels can lead to the adhesion and spreading of fibroblasts. Explanations for this unexpected behavior are discussed, particularly with regard to non-specific protein adsorption from the serum-supplemented culture medium. The presence of serum proteins is shown to be essential for adhesion. Adsorption of plasma and ECM proteins (Fibronectin (FN) and Vitronectin (VN)) to the hydrogels is possible. The effect of VN on initial cell adhesion is analyzed in detail. It appears that VN is the main serum component that is crucial for initial cell adhesion to PEG and that surface topography is essential for further, durable adhesion establishment, and spreading. PMID- 21786423 TI - Bacterial display in combinatorial protein engineering. AB - Technologies for display of recombinant protein libraries are today essential tools in many research-intensive fields, such as in the drug discovery processes of biopharmaceutical development. Phage display is still the most widely used method, but alternative systems are available and are becoming increasingly popular. The most rapidly expanding of the alternative systems are the cell display-based technologies, offering innovative strategies for selection and characterization of affinity proteins. Most investigations have focused on eukaryotic yeast for display of protein libraries, but similar systems are also being developed using prokaryotic hosts. This review summarizes the field of bacterial surface display with a strong emphasis on library applications for generation of new affinity proteins. The main focus will be on the most recent progress of the work on primarily Escherichia coli, but also on studies using a recently developed system for display on Gram-positive Staphylococcus carnosus. In addition, general strategies for combinatorial protein engineering using cell display are discussed along with the latest developments of new methodologies with comparisons to mainly phage display technology. PMID- 21786424 TI - Bioprocess monitoring by marker gene analysis. AB - The optimization and the scale up of industrial fermentation processes require an efficient and possibly comprehensive analysis of the physiology of the production system throughout the process development. Furthermore, to ensure a good quality control of established bioprocesses, on-line analysis techniques for the determination of marker gene expression are of interest to monitor the productivity and the safety of bioprocesses. A prerequisite for such analyses is the knowledge of genes, the expression of which is critical either for the productivity or for the performance of the bioprocess. This work reviews marker genes that are specific indicators for stress- and nutrient-limitation conditions or for the physiological status of the bacterial production hosts Bacillus subtilis, Bacillus licheniformis and Escherichia coli. The suitability of existing gene expression analysis techniques for bioprocess monitoring is discussed. Analytical approaches that enable a robust and sensitive determination of selected marker mRNAs or proteins are presented. PMID- 21786422 TI - Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function. AB - The Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium (Ep) and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumour suppressor (TS). In stark contrast, using various measures, we found that Runx3 expression is undetectable in GIT Ep. Employing a variety of biochemical and genetic techniques, including analysis of Runx3-GFP and R26LacZ/Runx3(Cre) or R26tdTomato/Runx3(Cre) reporter strains, we readily detected Runx3 in GIT embedded leukocytes, dorsal root ganglia, skeletal elements and hair follicles. However, none of these approaches revealed detectable Runx3 levels in GIT Ep. Moreover, our analysis of the original Runx3(LacZ/LacZ) mice used in the previously reported study failed to reproduce the GIT expression of Runx3. The lack of evidence for Runx3 expression in normal GIT Ep creates a serious challenge to the published data and undermines the notion that Runx3 is a TS involved in cancer pathogenesis. PMID- 21786425 TI - Exfoliated nanosheets of layered perovskite KCa2Nb3O10 as an inorganic liquid crystal. PMID- 21786426 TI - Efficient control for the cationic platinum(II)-catalyzed concise synthesis of two types of fused carbocycles with angular oxygen functionality. PMID- 21786427 TI - Using checklists in a gross anatomy laboratory improves learning outcomes and dissection quality. AB - Checklists have been widely used in the aviation industry ever since aircraft operations became more complex than any single pilot could reasonably remember. More recently, checklists have found their way into medicine, where cognitive function can be compromised by stress and fatigue. The use of checklists in medical education has rarely been reported, especially in the basic sciences. We explored whether the use of a checklist in the gross anatomy laboratory would improve learning outcomes, dissection quality, and students' satisfaction in the first-year Human Structure didactic block at Mayo Medical School. During the second half of a seven-week anatomy course, dissection teams were each day given a hardcopy checklist of the structures to be identified during that day's dissection. The first half of the course was considered the control, as students did not receive any checklists to utilize during dissection. The measured outcomes were scored on four practice practical examinations and four dissection quality assessments, two each from the first half (control) and second half of the course. A student satisfaction survey was distributed at the end of the course. Examination and dissection scores were analyzed for correlations between practice practical examination score and checklist use. Our data suggest that a daily hardcopy list of anatomical structures for active use in the gross anatomy laboratory increases practice practical examination scores and dissection quality. Students recommend the use of these checklists in future anatomy courses. PMID- 21786428 TI - Developing observational skills and knowledge of anatomical relationships in an art and anatomy workshop using plastinated specimens. AB - One of the strong trends in medical education today is the integration of the humanities into the basic medical curriculum. The anatomy program is an obvious choice for using the humanities to develop professionalism and ethical values. They can also be used to develop close observational skills. Many medical schools have developed formal art observation training in conjunction with nearby art museums to enhance the visual diagnostic skills of their medical students. We report here on an art and anatomy workshop that paired medical and art students who did drawing exercises from plastinated anatomical specimens and the animated face to hone observational skills. Each member of the pair brought a different perspective and expertise to the work that allowed each to be a mentor to the other. The workshop had three sessions: the first involved drawings of plastinated specimens that allowed an intimate experience with authentic human material; the second involved drawings of the human face; and the third included examination of anatomical texts of important anatomist-artists, a lecture on contemporary artists whose work involves anatomy, and a film demonstrating the facial muscles. We propose workshops such as these will help students increase their ability to detect details. This will assist the medical student in developing diagnostic skills for identifying disease and the art student in using the human body as subject. We further propose that these programs will help students develop humanistic sensitivities and provide an outlet for expression of the emotional aspects of dealing with disease and mortality. PMID- 21786429 TI - The diverse utility of wet prosections and plastinated specimens in teaching gross anatomy in New Zealand. AB - Anatomical education has traditionally used cadaveric material to study the human body, with both wet prosections and plastinated (PP) material commonly utilized. However, the frequency of use of these different preparation modes in a tertiary institution has not been previously examined. An audit of PP use in the Department of Anatomy and Structural Biology at the University of Otago was performed for 2009, assessing the number of courses, variety, and number of PP used throughout 2009. Results indicate the unique and diverse nature of PP utilization and are discussed with reference to their relative strengths and weaknesses. Such information is useful to those wishing to initiate or maintain programs that involve the teaching of human anatomy with cadaveric material. PMID- 21786430 TI - Orthopedic resident anatomy review course: a collaboration between anatomists and orthopedic surgeons. AB - A challenge for new residents and senior residents preparing for board examinations is refreshing their knowledge of basic science disciplines, such as human gross anatomy. The Department of Orthopaedics at the University of Utah School of Medicine has for many years held an annual Orthopedic Resident Anatomy Review Course during the summer months for all of its residents. The primary purpose of the course is to renew competencies in basic science disciplines so that incoming residents more quickly reach a level of functional proficiency and to afford senior residents a platform to teach their junior colleagues. Before 2005, this course was conducted with minimal participation from anyone outside of the Department of Orthopaedics. Many of the residents voiced concerns that the educational benefits were not proportionate to the time invested. To improve the teaching of orthopedic-related anatomy, an educational collaboration between the Departments of Neurobiology and Anatomy and Orthopaedics was established in 2004 and continues to the present time. The major objectives of refining the course pedagogy, developing a Course Manual and Dissection Guide, and evaluating the results by administering a course survey questionnaire are described in this article. Implementation of all facets of the revised course has resulted in better participation by orthopedic faculty and more favorable reviews by the participating residents. Based on current levels of interest and positive comments from course participants, the Anatomy and Orthopedic faculty course directors plan to continue to develop course materials and pedagogy. PMID- 21786431 TI - Unite Rhumatologique des Affections de la Main (URAM) scale: development and validation of a tool to assess Dupuytren's disease-specific disability. AB - OBJECTIVE: To our knowledge, no functional outcome measure has been developed and validated for Dupuytren's disease. We aimed to develop and validate a patient reported functional outcome measure for Dupuytren's disease. METHODS: Patients with Dupuytren's disease (n = 9) and medical experts (n = 7) provided input and opinions about limiting activities that were difficult to perform because of Dupuytren's disease for item generation. The provisional scale was studied in an independent sample of patients (n = 85) for item reduction according to response distribution, reliability, redundancy, and loading in a 1-factor solution. The final scale was evaluated as follows: reliability using Cronbach's alpha coefficient and test-retest intraclass correlation coefficient from the previous 85-patient population, and construct validity and responsiveness after needle aponeurotomy in another independent 53-patient sample. For construct validity, convergent validity and divergent validity were tested. The clinically important change was estimated relative to a 1-point categorical change on the Tubiana scale. RESULTS: A 52-item provisional scale was generated and reduced to the final 9-item scale called the Unite Rhumatologique des Affections de la Main (URAM) scale (total score 0-45). The scale showed good to excellent reliability and suitable construct validity. The URAM score improved after needle aponeurotomy: the standardized effect size was 0.56. The estimated clinically important change of the URAM scale was 2.9 points. CONCLUSION: We provide the first patient-reported functional measure for Dupuytren's disease. The URAM scale demonstrated suitable psychometric properties, and is short and convenient enough for easy use in daily practice and in clinical studies. PMID- 21786432 TI - Paclitaxel delivery to brain tumors from hydrogels: a computational study. AB - Malignant gliomas are aggressive forms of primary brain tumors characterized by a poor prognosis. The most successful treatment so far is the local implantation of polymer carriers (Gliadel(r) wafers) for the sustained release of carmustine. To improve the effectiveness of local drug treatment, new polymer carriers and pharmacological agents are currently being investigated. Of particular interest is a set of novel thermo-gelling polymers for the controlled release of hydrophobic drugs such as paclitaxel (e.g., OncoGelTM). Herein, we use computational mass transport simulations to investigate the effectiveness of paclitaxel delivery from hydrogel-forming polymer carriers. We found similar (within 1-2 mm) therapeutic penetration distances of paclitaxel when released from these hydrogels as compared with carmustine released from Gliadel(r) wafers. Effective therapeutic concentrations were maintained for >30 days for paclitaxel when released from the hydrogel as compared with 4 days for carmustine released from Gliadel(r) wafers. Convection in brain tissue prevented the formation of a uniform drug concentration gradient around the implant. In addition, the surface area to volume ratio of the gel is an important factor that should be considered to maintain a controlled release of paclitaxel within the degradation lifetime of the polymer matrix. PMID- 21786433 TI - Are you "tilting at windmills" or undertaking a valid clinical trial? AB - In this review, several aspects surrounding the choice of a therapeutic intervention and the conduct of clinical trials are discussed. Some of the background for why human studies have evolved to their current state is also included. Specifically, the following questions have been addressed: 1) What criteria should be used to determine whether a scientific discovery or invention is worthy of translation to human application? 2) What recent scientific advance warrants a deeper understanding of clinical trials by everyone? 3) What are the different types and phases of a clinical trial? 4) What characteristics of a human disorder should be noted, tracked, or stratified for a clinical trial and what inclusion /exclusion criteria are important to enrolling appropriate trial subjects? 5) What are the different study designs that can be used in a clinical trial program? 6) What confounding factors can alter the accurate interpretation of clinical trial outcomes? 7) What are the success rates of clinical trials and what can we learn from previous clinical trials? 8) What are the essential principles for the conduct of valid clinical trials? PMID- 21786434 TI - A randomized study assessing the effects of pretreatment with cilostazol on periprocedural myonecrosis after percutaneous coronary intervention. AB - PURPOSE: It is unknown whether cilostazol pretreatment reduces postprocedural myonecrosis (PPMN). Cilostazol pretreatment reduces PPMN after percutaneous coronary intervention (PCI). MATERIALS AND METHODS: A total of 120 patients with stable angina scheduled for elective PCI were randomly assigned to a 7-day pretreatment with Cilostazol (200 mg/day) or to a control group. Creatine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels were measured at baseline and at 6 and 24 hours after PCI. The primary end-point was the occurrence of PPMN, defined as any CK-MB elevation above the upper normal limit (UNL). Aspirin and clopidogrel were co-administered for 7 days before PCI, and resistance to these agents was then assayed using the VerifyNow System. RESULTS: There was no difference in baseline characteristics between the final analyzable cilostazol (n=54) and the control group (n=56). Despite a significantly greater % inhibition of clopidogrel in the cilostazol group (39+/-23% versus 25+/-22%, p=0.003), the incidence of PPMN was similar between the cilostazol group (24%) and the control group (25%, p=1.000). The rate of CK-MB elevation at >=3 times UNL was also similar between the two groups (6% versus 5%, p=0.583). The incidence of cTnI increase over the UNL or to 3 times the UNL was not different between the two groups. There was no significant difference in terms of the rate of adverse events during follow- up, although the cilostazol group showed a tendency to have a slightly higher incidence of entry site hematoma. CONCLUSION: This trial demonstrated that adjunctive cilostazol pretreatment might not significantly reduce PPMN after elective PCI in patients with stable angina. PMID- 21786435 TI - Application of magnetic resonance imaging and magnetic resonance angiography as diagnostic measures for the first attack of suspected cerebrovascular diseases in Korea. AB - PURPOSE: No precise data are available showing how magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) can be applied to diagnosis for the first attack of a suspected cerebrovascular disease in Korea. The purpose of this study was to evaluate the application level of MRI and MRA as diagnostic tools and the related factors to the use of these techniques. MATERIALS AND METHODS: This study used the health benefit claim data of 89,890 patients who were hospitalized for the first time due to suspected cerebrovascular disease in 2007 without having visited medical institutions as an outpatient or inpatient from 2003 to 2006. RESULTS: Of the 89,890 cases, 28.4% took both MRI and MRA, 10.7% took only MRI and 6.9% took only MRA. The related factors identified in the multivariate logistic regression analysis were gender, type of insurance, type of medical institution, type of department, duration of hospitalization, and type of disease. CONCLUSION: This study showed that the application level of MRI and MRA as diagnostic measures for the first attack of a suspected cerebrovascular diseases varied depending on several factors. It is necessary to study more accurate levels of computerized tomography (CT), computerized tomography angiography (CTA), MRI or MRA as measures to diagnose a first attack of suspected cerebrovascular disease. PMID- 21786436 TI - Cytochrome P450 2C19 polymorphism is associated with reduced clopidogrel response in cerebrovascular disease. AB - PURPOSE: Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease. MATERIALS AND METHODS: We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism. RESULTS: A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0+/-84.9) were significantly lower than those of intermediate and poor metabolizers (237.9+/-88.0, 302.2+/-58.9). The percent inhibition of extensive metabolizers (44.6+/-21.8) was significantly higher than that of intermediate and poor metabolizers (30.5+/-21.5, 14.0+/-13.4). CONCLUSION: Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation. PMID- 21786437 TI - The positive association between peripheral blood cell counts and bone mineral density in postmenopausal women. AB - PURPOSE: Accumulating evidence has shown a close connection between hematopoiesis and bone formation. Our aim was to evaluate the association between peripheral blood cell counts and bone mineral density (BMD) in a sample of postmenopausal women. MATERIALS AND METHODS: Three hundreds thirty eight healthy postmenopausal women who underwent BMD measurement during their health check-up were investigated. BMD was measured by dual energy X-ray asorptiometry at L1-L4 spine, femoral neck and total proximal femur. BMD was expressed as a T-score: among T scores obtained from three different sites (L1-L4 spine, femoral neck and total proximal femur), the lowest T-score was considered to be the subject's T-score. RESULTS: The prevalence of osteopenia and osteoporosis diagnosed by T-score in the study participants were 49.4% (167/338) and 5.0% (17/338), respectively. Peripheral blood white blood cell (WBC), red blood cell (RBC) and platelet counts had significant positive correlations with T-scores (p<0.001) upon simple linear regression analysis. A multiple linear regression analysis, after controlling of confounders including age, body weight, systolic blood pressure, alkaline phosphatase and creatinine, showed that WBC (beta=0.127; standard error=0.043; p=0.014), RBC (beta=0.192; standard error=0.139; p<0.001) and platelet (beta=0.097; standard error=0.001; p=0.050) counts still had significant positive association with T-scores. CONCLUSION: The study results showed a positive relationship between blood cell counts and bone mineral density in postmenopausal women, supporting the idea of a close connection between hematopoiesis and bone formation. The study results also suggest that blood cell counts could be a putative marker for estimating BMD in postmenopausal women. PMID- 21786438 TI - Impact of obesity on metabolic syndrome among adolescents as compared with adults in Korea. AB - PURPOSE: This study aimed to estimate the prevalence of metabolic syndrome (MetS) in adolescents and adults and to compare the impact of body mass index (BMI) on MetS between adolescents and adults in Korea. MATERIALS AND METHODS: Data were used from 6,186 subjects aged 10 years or more who representatively participated in the Third Korean National Health and Nutrition Examination Survey. Body composition, blood test, and health behavioral factors were measured. We used the definition of MetS from the modified the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) for adolescents and the NCEP-ATP III for adults. RESULTS: The prevalence of MetS was 6.4 (95% CI 4.5-8.4) and 22.3 (95% CI 20.8-23.8) in adolescents and adults, respectively. The prevalence of MetS among normal, overweight and obese body types for both adolescents and adults differed significantly (p<0.001). After adjustment for covariates, the odds ratios (ORs) of obese and overweight body types on MetS compared with normal BMI in adolescents were 28.1 (95% CI 11.4-69.1) and 8.7 (95% CI 2.3-33.1), respectively. The ORs of obesity on MetS were 32.0 (95% CI 7.5-136.9), 32.2 (95% CI 12.8-80.8), 16.2 (95% CI 9.4-27.9), 7.6 (95% CI 4.7-12.2) and 9.9 (95% CI 6.8-14.6) for subjects in their 20's, 30's, 40's, 50's and older than 60, in order. CONCLUSION: We found that the prevalence of MetS increased with age and was more prevalent in males. Moreover, the group younger than 39 years of age had a higher chance of having MetS than the group older than 40 years of age. Weight control is more vital in the earlier stages of life for the prevention and management of MetS. PMID- 21786439 TI - Clinicopathological characteristics in combined hepatocellular cholangiocarcinoma: a single center study in Korea. AB - PURPOSE: Combined hepatocellular-cholangiocarcinoma (CHCC) is an uncommon form of cancer, and its clinicopathological features have rarely been reported in detail. This study was undertaken to evaluate the clinicopathological characteristics and prognostic factors of CHCC. MATERIALS AND METHODS: The clinicopathological features of patients diagnosed with CHCC at Severance Hospital between January 1996 and December 2007 were retrospectively studied by comparing them with the features of patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC) who had undergone a hepatic resection during the same period. RESULTS: Forty three patients diagnosed with CHCC were included in this study (M : F=35 : 8, median age, 55 years). According to the parameters of the American Joint Committee on Cancer staging, there were 6 (14.0%), 9 (20.9%), 25 (58.1%), and 3 (7.0%) patients with stages I, II, III, and IV cancer, respectively. Thirty-two of the 43 patients underwent resection with curative intent. After resection, 27 patients (84.4%) had tumor recurrence during the follow-up period of 18 months (range: 6-106 months), and the median time to recurrence was 13 months. Overall median survival periods after hepatic resection of CHCC, HCC and CC were 34, 103 and 38.9 months, respectively (p<0.001). The median overall survival for all patients with CHCC was 21 months, and the 5-year survival rate was 18.1%. The presence of portal vein thrombosis and distant metastasis were independent prognostic factors of poor survival. CONCLUSION: Even after curative hepatic resection, the presence of a cholangiocellular component appeared to be a poor prognostic indicator in patients with primary liver cancer. PMID- 21786440 TI - Localized resectable genitourinary sarcoma in adult Korean patients: experiences at a single center. AB - PURPOSE: To evaluate the clinicopathological characteristics and prognosis of localized resectable genitourinary sarcomas in adults. MATERIALS AND METHODS: Between September, 1996 and November, 2008, 18 consecutive cases of adults (12 men and 6 women; median age 48.8 years) who were treated for primary genitourinary sarcomas were identified. The following variables were analyzed: patient age, gender, body mass index, American Society of Anesthesiologists (ASA) score, primary organ, tumor histology, size, necrosis, Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade, and surgical margin positivity. Recurrence- free survival and disease-specific survival were the study end points. RESULTS: The most common presenting symptom was a palpable mass (six cases, 33.3%), the most common site was the kidney (six cases, 33.3%), and the most common histological subtype was leiomyosarcoma (eight patients, 44.4%). Complete resection with negative surgical margins was achieved in 13 patients (72.2%). The median follow-up period was 49.9 months (range 6.4 to 147.6). The recurrence- free survival rates at 1, 3, and 5 years were 81.6%, 66.5%, and 66.5%, respectively. Recurrence-free survival only associated significantly with ASA score (p=0.018). The disease-specific survival rate at 1, 3, and 5 years was 88.9%, 76.2%, and 67.7%, respectively. Disease-specific survival was associated significantly only with FNCLCC grade (p=0.042). CONCLUSION: Although genitourinary sarcomas in adults are a rare group of tumors with a poor prognosis, some patients may have a favorable prognosis. Our findings suggest that FNCLCC grade is the most important prognostic factor for these patients. PMID- 21786441 TI - Palpation device for the identification of kidney and bladder cancer: a pilot study. AB - PURPOSE: To determine the ability of a novel palpation device to differentiate between benign and malignant tissues of the kidney and bladder by measuring tissue elasticity. MATERIALS AND METHODS: A novel palpation device was developed, mainly composed of a micromotor, a linear position sensor, a force transducer, and a hemisphere tip and cylindrical body probe. Motion calibration as well as performance validation was done. The tissue elasticity of both benign and malignant tissues of the kidney and bladder was measured using this device. A single investigator performed the ex-vivo palpation experiment in twelve kidneys and four bladder specimens. Malignant tissues were made available from partial nephrectomy specimens and radical cystectomy specimens. Palpations for benign renal parenchyma tissue were carried out on nephroureterectomy specimens while non-involved areas in the radical cystectomy specimens were used for benign bladder samples. Elastic modulus (Young's modulus) of tissues was estimated using the Hertz-Sneddon equation from the experimental results. These were then compared using a t-test for independent samples. RESULTS: Renal cell carcinoma tissues appear to be softer than normal kidney tissues, whereas tissues from urothelial carcinoma of the bladder appear to be harder than normal bladder tissues. The results from renal cell carcinoma differed significantly from those of normal kidney tissues (p=0.002), as did urothelial carcinoma of the bladder from normal bladder tissues (p=0.003). CONCLUSION: Our novel palpation device can potentially differentiate between malignant and benign kidney and bladder tissues. Further studies are necessary to verify our results and define its true clinical utility. PMID- 21786442 TI - The bacterial protein azurin enhances sensitivity of oral squamous carcinoma cells to anticancer drugs. AB - PURPOSE: Surgical therapy is the primary treatment for oral cancer, but it can cause facial distortion. Therefore, if anticancer drugs are effective against oral cancer, they may be used preferentially. However, oral squamous carcinoma cells (OSCCs) are resistant to these drugs, so finding a way to enhance the sensitivity of these cells to anticancer drugs is important. The bacterial protein azurin is known to selectively enter cancer cells and induce apoptosis. In this study, we show the anticancer effect of azurin in OSCC. MATERIALS AND METHODS: OSCC cell line (YD-9) was subjected to azurin treatment. Cell viability, morphology and protein expression levels were monitored after treatment of azurin. Cells were also subjected to combination treatment of azurin with either 5-fluorouracil or etopside. RESULTS: Azurin-treated cells showed decreased cell viability accompanied by apoptotic phenotypes including morphological change, DNA breakage, and increases in p53 and cyclin B1 protein levels. Combination treatment of azurin with other anti-tumor agents caused an increase in sensitivity to anticancer drugs in azurin-treated YD-9 cells. CONCLUSION: Azurin has a strong synergistic anticancer effect on oral cancer cells when it is used along with anticancer drugs. PMID- 21786443 TI - Prognostic implications of the NIH consensus criteria in children with chronic graft-versus-host disease. AB - PURPOSE: In this study, we analyzed a cohort of children with chronic graft versus-host disease (GvHD) according to the NIH consensus classification (NCC) in order to observe whether global assessment at diagnosis correlates with GvHD specific endpoints. We then studied the clinical course of these patients, specifically with regards to episodes of GvHD exacerbation requiring treatment escalation. MATERIALS AND METHODS: Recipients of either allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from January 2006 to August 2008 at the Department of Pediatrics, The Catholic University of Korea were evaluated for chronic GvHD, which was diagnosed according to the NCC. The course of chronic GvHD in these patients was then followed. RESULTS: Of 59 evaluable patients, 23 developed chronic GvHD for a cumulative incidence of 39.3%. Upon multivariate analysis, previous acute GvHD (>=grade II) had a significant impact on chronic GvHD incidence. With a median duration of systemic treatment for chronic GvHD of 501 days, no significant relationship was found between initial global severity of chronic GvHD and either duration of immunosuppressive treatment or final clinical response to treatment. Fifteen patients (65%) experienced at least one episode of chronic GvHD exacerbation during the period of follow-up, with a median of four exacerbations in the subgroup of patients who experienced such events. Lung GvHD resulted in the highest number of exacerbations per diagnosed patient, followed by oral GvHD. CONCLUSION: Analysis of this small cohort indicates that global assessment as proposed by the NCC may have limited correlations with GvHD-specific endpoints, possibly due to the favorable response of children to treatment. PMID- 21786444 TI - Endobronchial aspergilloma: report of 10 cases and literature review. AB - PURPOSE: A retrospective investigation of the clinical and radiologic features as well as the bronchoscopic appearance was carried out in patients with endobronchial aspergilloma. MATERIALS AND METHODS: Ten patients with endobronchial aspergilloma diagnosed by bronchoscopy and histological examination were identified at the Gyeongsang University Hospital of Korea, from May 2003 to May 2009. RESULTS: The patients included 9 men and 1 woman, and the age of the patients ranged from 36 to 76 (median, 58 years). The associated diseases or conditions were: previous pulmonary tuberculosis in 7 patients, lung cancer in 2 patients, pulmonary resection in 1 patient, and foreign body of the bronchus in 1 patient. The chest radiologic finding showed fibrotic changes as a consequence of previous tuberculosis infection in 6 patients and a mass-like lesion in 2 patients. Two patients had a co-existing fungus ball, and an endobronchial lesion was suspected in only 2 patients on the CT scan. The bronchoscopic appearance was a whitish to yellow necrotic mass causing bronchial obstruction in 7 patients, foreign body with adjacent granulation tissue and whitish necrotic tissue in 1 patient, whitish necrotic tissue at an anastomosis site in 1 patient, and a protruding mass with whitish necrotic tissue in 1 patient. CONCLUSION: An endobronchial aspergilloma is a rare presentation of pulmonary aspergilosis and is usually incidentally found in immunocompetent patients with underlying lung disease. It usually appears as a necrotic mass causing bronchial obstruction on bronchoscopy and can be confirmed by biopsy. PMID- 21786445 TI - Further increases in carbapenem-, amikacin-, and fluoroquinolone-resistant isolates of Acinetobacter spp. and P. aeruginosa in Korea: KONSAR study 2009. AB - PURPOSE: The increasing prevalence of antimicrobial resistant bacteria has become a serious worldwide problem. The aim of this study was to analyze antimicrobial resistance data generated in 2009 by hospitals and commercial laboratories participating in the Korean Nationwide Surveillance of Antimicrobial Resistance program. MATERIALS AND METHODS: Susceptibility data were collected from 24 hospitals and two commercial laboratories. In the analysis, resistance did not include intermediate susceptibility. Duplicate isolates were excluded from the analysis of hospital isolates, but not from the commercial laboratory isolates. RESULTS: Among the hospital isolates, methicillin-resistant Staphylococcus aureus, penicillin G-nonsusceptible Streptococcus pneumoniae based on meningitis breakpoint, and ampicillin- resistant Enterococcus faecium remained highly prevalent. The proportion of vancomycin-resistant E. faecium gradually increased to 29%. Ceftazidime-resistant Escherichia coli and Klebsiella pneumoniae increased to 17% and 33%, respectively, and fluoroquinolone-resistant K. pneumoniae, Acinetobacter spp. and Pseudomonas aeruginosa increased to 33%, 67% and 39%, respectively. Amikacin-resistant Acinetobacter spp. increased to 48%. Imipenem-resistant Acinetobacter spp. and P. aeruginosa increased to 51% and 26%, respectively. Higher resistance rates were observed in intensive care unit (ICU) isolates than in non-ICU isolates among the isolates from hospitals. Resistance rates were higher in hospital isolates than in clinic isolates among the isolates from commercial laboratories. CONCLUSION: Among the hospital isolates, ceftazidime-resistant K. pneumoniae and fluoroquinolone- resistant K. pneumoniae, Acinetobacter spp., and P. aeruginosa further increased. The increase in imipenem resistance was slight in P. aeruginosa, but drastic in Acinetobacter spp. The problematic antimicrobial-organism combinations were much more prevalent among ICU isolates. PMID- 21786446 TI - Results from over one year of follow-up for absorbable mesh insertion in partial mastectomy. AB - PURPOSE: Recently, several clinicians have reported the advantages of simplicity and cosmetic satisfaction of absorbable mesh insertion. However, there is insufficient evidence regarding its long-term outcomes. We have investigated the surgical complications and postoperative examination from the oncologic viewpoint. MATERIALS AND METHODS: From February 2008 to March 2009, 34 breast cancer patients underwent curative surgery with absorbable mesh insertion in Samsung Medical Center. Patient characteristics and follow up results including complications, clinical and radiological findings were retrospectively investigated. RESULTS: The mean age of the study population was 50.1+/-8.9 years old (range 31-82) with a mean tumor size of 3+/-1.8 cm (range 0.8-10.5), and the excised breast tissue showed a mean volume of 156.1+/-99.8 mL (range 27-550). Over the median follow-up period of 18+/-4.6 months (range 3-25), mesh associated complications, including severe pain or discomfort, edema, and recurrent fluid collection, occurred in nine patients (26.5%). In three cases (8.8%), recurrent mastitis resulted in mesh removal or surgical intervention. In the postoperative radiologic survey, the most common finding was fluid collection, which occurred in five patients (16.1%), including one case with organizing hematoma. Fat necrosis and microcalcifications were found in three patients (9.7%). CONCLUSION: Absorbable mesh insertion has been established as a technically feasible, time saving procedure after breast excision. However, the follow-up results showed some noticeable side effects and the oncologic safety of the procedure is unconfirmed. Therefore, we suggest that mesh insertion should be considered only in select cases and should be followed-up carefully. PMID- 21786447 TI - Effects of multiple drilling on the ischemic capital femoral epiphysis of immature piglets. AB - PURPOSE: This study investigated the effects of multiple drilling on the immature capital femoral epiphysis following ischemic injury in a piglet model. MATERIALS AND METHODS: Ischemic necrosis of capital femoral epiphysis was induced bilaterally in 12 piglets using a cervical ligation method. Three weeks later, medial, central, and lateral 3 drill holes were made on the left femoral head using 0.062" K-wire. At 3, 6, 9, and 12 weeks following the multiple drilling, femoral heads were harvested from each three piglets. On histologic examination, percent of revascularization, percent of osteoblast surface, capital femoral epiphyseal quotient and proximal femoral growth plate height were evaluated. Untreated right femoral heads served as control. RESULTS: While percent of revascularization of left capital femoral epiphysis with multiple drilling was significantly higher than untreated control side (p<0.001), percent of osteoblast surface, capital femoral epiphyseal quotient and proximal femoral growth plate height showed no significant difference. CONCLUSION: This study indicates that multiple drilling could promote revascularization of ischemic capital femoral epiphysis, and multiple drilling does not appear to produce bony physeal bars at short-term, if using small diameter drill. However, multiple drilling alone does not seem to prevent femoral head deformity or to promote new bone formation. PMID- 21786448 TI - Limb angular deformity correction using Dyna-ATC: surgical technique, calculation method, and clinical outcome. AB - PURPOSE: Dyna-ATC is a unilateral external fixator with angulator, lengthener, and translator, which allows for angular correction and compensation of the secondary displacement during angular correction. The purpose of this study is to introduce surgical technique and calculation methods and to evaluate the clinical outcome of angular deformity correction using Dyna-ATC. MATERIALS AND METHODS: The amounts of secondary displacement were calculated with the distances between axis of correction of angulation, Center of Rotational Angulation, and osteotomy and the amount of angular deformity. The rate of angular correction was determined to distract the corticotomy at 1 mm/day. Clinical and radiographic evaluation was performed on 13 patients who underwent deformity correction using Dyna-ATC. There were 8 proximal tibia vara, 1 tibia valga, 2 varus and 4 valgus deformities on distal femur. One patient underwent pelvic support femoral reconstruction. Concomitant lengthening was combined in all femur cases. Mean age at surgery was 17.5 years (7 to 64). RESULTS: All but one achieved bony healing and normal alignment with the index procedure. Mean mechanical axis deviation improved from 31.9 mm to 3.0 mm. The average amount of angular correction was 11.0 degrees on tibiae and 10.0 degrees on femora. The average length gain on femora was 6.4 cm, and the healing index averaged to 1.1 mo/cm. One patient underwent quadricepsplasty and one patient had three augmentation surgeries due to poor new bone formation. CONCLUSION: We believe that Dyna-ATC is a useful alternative to bulky ring fixators for selective patients with angular deformity less than 30 degrees in the coronal plane around the knee joint. PMID- 21786449 TI - CT evaluation of vocal cord paralysis due to thoracic diseases: a 10-year retrospective study. AB - PURPOSE: To discuss computed tomography (CT) evaluation of the etiology of vocal cord paralysis (VCP) due to thoracic diseases. MATERIALS AND METHODS: From records from the past 10 years at our hospital, we retrospectively reviewed 115 cases of VCP that were evaluated with CT. Of these 115 cases, 36 patients (23 M, 13 F) had VCP due to a condition within the thoracic cavity. From these cases, we collected the following information: sex, age distribution, side of paralysis, symptom onset date, date of diagnosis, imaging, and primary disease. The etiology of VCP was determined using both historical information and diagnostic imaging. Imaging procedures included chest radiograph, CT of neck or chest, and esophagography or esophagoscopy. RESULTS: Thirty-three of the 36 patients with thoracic disease had unilateral VCP (21 left, 12 right). Of the primary thoracic diseases, malignancy was the most common (19, 52.8%), with 18 of the 19 malignancies presenting with unilateral VCP. The detected malignant tumors in the chest consisted of thirteen lung cancers, three esophageal cancers, two metastatic tumors, and one mediastinal tumor. We also found other underlying etiologies of VCP, including one aortic arch aneurysm, five iatrogenic, six tuberculosis, one neurofibromatosis, three benign nodes, and one lung collapse. A chest radiograph failed to detect eight of the 19 primary malignancies detected on the CT. Nine patients with lung cancer developed VCP between follow-ups and four of them were diagnosed with a progression of malignancy upon CT evaluation of VCP. CONCLUSION: CT is helpful for the early detection of primary malignancy or progression of malignancy between follow-ups. Moreover, it can reveal various non-malignant causes of VCP. PMID- 21786450 TI - Cytological results of ultrasound-guided fine-needle aspiration cytology for thyroid nodules: emphasis on correlation with sonographic findings. AB - PURPOSE: To compare the cytological results of ultrasound-guided fine-needle aspiration (US-FNA) cytology of thyroid nodules to sonographic findings and determine whether US findings are helpful in the interpretation of cytological results. MATERIALS AND METHODS: Among the thyroid nodules that underwent US-FNA cytology, we included the 819 nodules which had a conclusive diagnosis. Final diagnosis was based on pathology from surgery, repeated FNA cytology or follow-up of more than one year. Cytological results were divided into five groups: benign, indeterminate (follicular or Hurthle cell neoplasm), suspicious for malignancy, malignant, and inadequate. US findings were categorized as benign or suspicious. Cytological results and US categories were analyzed. RESULTS: Final diagnosis was concluded upon in 819 nodules based on pathology (n=311), repeated FNA cytology (n=204) and follow-up (n=304), of which 634 were benign and 185 were malignant. There were 560 benign nodules, 141 malignant nodules, 49 nodules with inadequate results, 21 with indeterminate results, and 48 that were suspicious for malignancy. The positive and negative predictive values of the US categories were 59.1% and 97.0%, and those of the cytological results were 93.7% and 98.9%. The US categories were significantly correlated with final diagnosis in the benign (p=0.014) and suspicious for malignancy (p<0.001) cytological result groups, but not in the inadequate and indeterminate cytological results groups. The false positive and negative rates of cytological results were 1.9% and 3.2%. CONCLUSION: Sonographic findings can be useful when used alongside cytological results, especially in nodules with cytological results that are benign or suspicious for malignancy. PMID- 21786451 TI - Rapid identification of thrombocytopenia-associated multiple organ failure using red blood cell parameters and a volume/hemoglobin concentration cytogram. AB - Thrombocytopenia-associated multiple organ failure (TAMOF) has a high mortality rate when not treated, and early detection of TAMOF is very important diagnostically and therapeutically. We describe herein our experience of early detection of TAMOF, using an automated hematology analyzer. From 498,390 inpatients, we selected 12 patients suspected of having peripheral schistocytosis, based on the results of red blood cell (RBC) parameters and a volume/hemoglobin concentration (V/HC) cytogram. We promptly evaluated whether the individual patients had clinical manifestations and laboratory findings were consistent with TAMOF. Plasma exchanges were then performed for each patient. All 12 patients had TAMOF. The mean values of RBC parameters were significantly higher in all of the patients than with the reference range, however, 3 patients had % RBC fragments within the reference range. The mean value of ADAMTS-13 activity was slightly lower in patients compared with the reference range. Of the 12 patients, remission was obtained in 9 patients (75%) within 4 to 5 weeks using plasma exchanges. Three patients died. An increased percentage of microcytic hyperchromic cells with anisocytosis and anisochromia indicated the presence of schistocytes, making it an excellent screening marker for TAMOF. Identification of TAMOF with RBC parameters and a V/HC cytogram is a facile and rapid method along with an automated hematology analyzer already in use for routine complete blood cell counting test. PMID- 21786453 TI - Unexpected sudden death of a 19-year-old female with congenital single coronary artery ostium during exertion. AB - Coronary artery anomalies are associated often with myocardial ischemia or sudden cardiac death. A 19-year-old woman who participated in an exertive game lost consciousness upon one such exertion. She was taken to a hospital where she died on the same day. An autopsy revealed that she had bifurcated coronary arteries, which arose from one coronary ostium in the left sinus of Valsalva. The right coronary artery arose from the left sinus and traveled between the aorta and the pulmonary trunk. The heart as well as the cardiac conduction system depended exclusively on the single coronary artery ostium for oxygenated blood supply, and the unbalanced blood distribution on her exertion probably led to sudden cardiac death. The case highlights the medicolegal importance of unexpected sudden cardiac death related to an anomalous origin of the coronary arteries. PMID- 21786452 TI - IL-10 is predominantly produced by CD19(low)CD5(+) regulatory B cell subpopulation: characterisation of CD19 (high) and CD19(low) subpopulations of CD5(+) B cells. AB - IL-10 production by CD19(+)CD5(+) B cells was investigated, by determining the expression levels of CD19, a classical B cell marker. Peripheral mononuclear cells were stained with fluorescence-conjugated anti-CD5, anti-CD19, anti-IL-10, and Annexin V. Interestingly, IL-10-producing B cells were found to be localised within the CD19(low)CD5(+) B cell subset. Apoptotic changes were also observed mainly in CD19(low) cells among B cells. Thus, CD5(+) B cells should be classified as CD19(high) and CD19(low) cells, and the immunological significance of CD19 for the IL-10 production by CD5(+) B cells requires further studies. PMID- 21786454 TI - Rapidly aggravated dissecting flap by angiography during percutaneous stent placement for acute isolated superior mesenteric artery dissection. AB - Acutely aggravated dissecting flap and consequent occlusion of the superior mesenteric artery (SMA) by simple contrast passage during initial angiography for percutaneous stent placement is a uncommon event, which usually is not reported. After analysis of many factors that underlie development of such complications, we present herein one case of successful treatment of isolated SMA dissection and its complications with favorable outcomes during 25 months follow-up after percutaneous stent placement. PMID- 21786455 TI - A case of pseudomembranous colitis after voriconazole therapy. AB - This is a case report on a 35-year-old man with acute myelogenous leukemia who presented fever and intermittent mucoid loose stool to the emergency center. He had been taking voriconazole for invasive pulmonary aspergillosis. The flexible sigmoidoscopy was consistent with the diagnosis of pseudomembranous colitis. PMID- 21786456 TI - Invasive aspergillosis arising from ureteral aspergilloma. AB - Ureteral obstruction may develop in immunocompromised patients with an Aspergillus fungal infection. Infections can progress to invasive aspergillosis, which is highly lethal. We report a case of a 56-year-old man with alcoholic cirrhosis of the liver and diabetes. He had ureteral aspergilloma, discovered as a saprophytic whitish mass. It was treated by ureteroscopic removal, however, he refused antifungal treatment. His condition progressed to invasive aspergillosis, and died from sepsis and hepatorenal syndrome. PMID- 21786457 TI - RE: Pulmonary hypertension associated with use of phentermine? PMID- 21786459 TI - Refractory anemia with ring sideroblasts masked by iron deficiency anemia. PMID- 21786458 TI - HCV-specific T-cell responses in HIV/hepatitis C virus-coinfected patients on highly active antiretroviral therapy are comparable to those observed in hepatitis C virus-monoinfected individuals. AB - BACKGROUND: Cellular responses against hepatitis C virus (HCV) are impaired in HIV/HCV-coinfected patients showing uncontrolled viral replication and immune suppression. Very few studies have explored to what extent HCV-specific response improves as a consequence of control of HIV replication by highly active antiretroviral therapy. We compared HCV-specific T-cell responses between HIV/HCV coinfected patients, showing complete viral suppression, and HCV-monoinfected patients. METHODS: HCV-specific T-cell responses were examined in 50 interferon naive patients with chronic hepatitis C: 27 HCV-mono-infected and 23 HIV/HCV coinfected on highly active antiretroviral therapy and undetectable HIV load. Production of interferon-gamma and tumor necrosis factor-alpha was simultaneously measured in response to genotype-matched overlapping peptides spanning the whole HCV proteome by flow cytometry. Differences between groups were tested using nonparametric tests. RESULTS: More than half of patients presented CD4+ (60%) or CD8+ (57%) response to at least one HCV protein with no significant differences between both groups. Intensity and breadth of response were also similar between groups. The functional profile of response was represented, in both groups, mainly by monofunctional subsets, although there were some differences between CD4+ and CD8+ T-cell response. CD8+ response was mediated almost exclusively by monofunctional interferon-gamma+ cells, whereas bifunctional interferon-gamma+ tumor necrosis factor-alpha+ cells showed a moderate contribution to CD4+ response. Most of the CD8+ response was mediated by interferon-gamma, whereas tumor necrosis factor-alpha was the highest contributor to CD4+ response. CONCLUSIONS: Our study demonstrates that in HIV/HCV-coinfected patients with maximal HIV suppression under highly active antiretroviral therapy, several characteristics of anti-HCV T-cell response are similar to those found in HCV monoinfected patients, suggesting that control of HIV replication might improve HCV-specific T-cell response in HIV/HCV-coinfected patients. PMID- 21786461 TI - Bibliography. Pediatric anesthesia. Current world literature. PMID- 21786460 TI - Predictors and outcomes of HIV-infected antiretroviral-naive patients with discordant responses to combination antiretroviral treatment in Asian and Australian populations: results from APHOD. PMID- 21786462 TI - Bibliography. Anesthesia and medical disease. Current world literature. PMID- 21786463 TI - CD4+CD25(high) Treg cells in peripheral blood during remission and exacerbation of allergic asthma in children. AB - AIM: To determine the percentage of CD4+CD25(high) Treg cells in peripheral bloodCD4+ T cells of allergic asthmatic children during disease remission and exacerbation. METHODS: Peripheral blood mononuclear cells (PBMC) and serum samples were collected from 6- to 11-year-old children with mild-to-moderate allergic asthma (n = 34)and from healthy controls (n = 15). CD4+CD25(high) T cells in PBMC were detected by flow cytometry. Total and specific IgE in serum were analysed by enzyme-amplified chemiluminescence, and IL-2 was measured by ELISA. RESULTS: There was no significant difference in CD4+CD25(high) T-cell proportions between asthmatic children in exacerbation and remission as compared with controls.CD4+CD25(high) T-cell percentages were not correlated with total and specific IgE. IL-2 was elevated in both disease remission and exacerbation but did not correlate significantly with CD4+CD25(high) T-cell percentages. CONCLUSION: CD4+CD25(high) T-cell proportion in the peripheral blood of total CD4+T cells is not reduced in children with allergic IgE-mediated asthma and does not differ between disease remission and exacerbation. PMID- 21786464 TI - Bibliography. Infectious arthritis and immune dysfunction. Current world literature. PMID- 21786465 TI - Bibliography. Metabolic bone disease. Current world literature. PMID- 21786466 TI - Minnesota: Medicine and materials. PMID- 21786468 TI - Breaking free from nicotine dependence. A combination of strategies boosts the odds of success. PMID- 21786469 TI - Medications for Alzheimer's disease. Benefits of currently approved drugs are limited, but research continues. PMID- 21786470 TI - Treating intermittent explosive disorder. Emerging data show medication and cognitive behavioral therapy may help some patients. PMID- 21786471 TI - Large study finds that the combination of diabetes and depression ups mortality risk. PMID- 21786472 TI - Commentary. A biomarker for PTSD risk? PMID- 21786473 TI - "To surrender himself, in perfectly liberal inquiry": Walter Pater, many sidedness, and the conversion novel. AB - This essay uses Walter Pater's "Marius the Epicurean" (1885) to explore why certain Victorian liberals preferred to see religion as a matter of collective inheritance rather than personal belief. Recent commentators have portrayed the Protestant emphasis on individual conversion as one of the foundations of liberal individualism. Pater's liberalism, however, sees radical breakage with the past as a threat to the humanist ideal of many-sidedness and instead imagines the path of a rich individuality as running precisely through a surrender to the inscriptions of cultural heritage. Indeed, Pater virtually transforms the idea of self-culture into that of ethnographic culture, with the detached aesthete becoming a participant-observer who can both submit to the determinations of history and reflect on them through an anthropological lens. PMID- 21786474 TI - England's approach to improving end-of-life care: a strategy for honoring patients' choices. AB - In the U.S. health care system, and in those of many other countries, the care of dying patients is generally not performed well, with pain and other distress frequently undertreated and patients' preferences not respected. England's evidence-based End of Life Care Strategy could prove instructive. This issue brief discusses the origins, content, and implementation of the Strategy, as well as its potential impact. Both England and the United States struggle with similar challenges, including looking beyond the province of hospice and palliative-care specialists and initiating palliative services before the patient's final days. Aspects of the English approach that may be useful in the United States include strategies to help physicians recognize when patients are entering a trajectory that may end in death, the use of "death at home" as a metric for measuring progress, improving the skills of clinical and caregiving personnel through Web based training, and developing a national improvement pathway. PMID- 21786475 TI - Weight watchers. PMID- 21786476 TI - Abortion curriculum in undergraduate medical education is an issue of civic professionalism. PMID- 21786477 TI - Editorial: welcome...and farewell. PMID- 21786478 TI - Making of a popular debate: the "Indian forester" and the emerging agenda of state forestry in India, 1875-1904. PMID- 21786479 TI - Transition zones: changing landscapes and local authority in south-west Bengal, 1880s-1920s. PMID- 21786480 TI - [Revised Surviving Sepsis Campaign Guidelines and therapy for severe sepsis]. PMID- 21786481 TI - [Treatment strategy using amphotericin B liposome for cases of fungal pneumonia associated with hematological malignancy]. PMID- 21786482 TI - [Life saving treatment using amphotericin B liposome for a case with fungal meningitis due to orbital cellulitis]. PMID- 21786483 TI - [Collagenous colitis as cause of chronic diarrhea in ten-year-old child]. PMID- 21786484 TI - What have you learned today? PMID- 21786485 TI - 'Pay it forward' through publication. PMID- 21786486 TI - Care of the patient with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS), a complex, neurodevelopmental genetic disorder with an estimated incidence of 7 in 10,000-29,000 people, is found in all races and both genders. It is the most commonly identified genetic cause of obesity. A multidisciplinary approach to managing PWS is highlighted, along with elements that should be included in a treatment plan, to help nurses deliver comprehensive care to meet the complex biopsychosocial needs of adults with PWS. PMID- 21786487 TI - Caring for migrant farm workers on medical-surgical units. AB - Over 3 million migrant farm workers are employed in the United States. Many factors place them at risk for work-related disease and injury. Knowledge of workers' health issues can prepare medical-surgical nurses to anticipate and meet the needs of this underserved population. PMID- 21786488 TI - The Ruby Red Slipper Program: an interdisciplinary fall management program in a community academic medical center. AB - Falls are a common, yet serious complication for hospitalized patients. The Ruby Red Slipper Program is an interdisciplinary fall management program that includes development and education of unit-based fall management teams. Initial outcomes demonstrated significant reductions in falls. PMID- 21786489 TI - Maintaining patency with packed red blood cell infusions: comparison of IV normal saline infusion vs. normal saline syringe method. AB - As blood products are being used more judiciously, registered nurses need to develop practices to facilitate the effective administration of these products. The study results suggest both the syringe push method and the continuous infusion method of normal saline provide adequate line patency during packed red blood cell infusions through peripheral catheters. PMID- 21786490 TI - Turning the nightmare of complex regional pain syndrome into a time of healing, renewal, and hope. AB - Complex regional pain syndrome is a lifelong chronic pain disorder. The medical treatment and nursing interventions, which can turn this nightmare into a time of healing, renewal, and hope, are described. PMID- 21786491 TI - Educating staff nurses on diabetes: knowledge enhancement. AB - Evidence-based practice education of staff nurses has the potential to improve knowledge and ultimately the care of hospitalized diabetic patients. The value and knowledge enhancement of a diabetes education program for nurses working in a Heart and Vascular Institute in an academic medical center is described. PMID- 21786492 TI - Biological disease modifying anti-rheumatic drugs. PMID- 21786493 TI - Hyperthyroidism. PMID- 21786494 TI - Random assignment. PMID- 21786495 TI - [Is emigration necessary to be able to work as a real emergency physician?]. PMID- 21786496 TI - [Lack of silence. The open-plan office--a growing occupational environmental problem]. PMID- 21786497 TI - [Strengthened support for statin therapy as secondary prevention. Doubtful evidence for more intensive lowering of cholesterol levels]. PMID- 21786498 TI - [Target levels for LDL cholesterol are put out of the running. Cholesterol should be lowered maximally in high cardiovascular risk]. PMID- 21786499 TI - [Prediction of postoperative pain gives new possibilities. Tailored pain relief can prevent development of prolonged severe pain]. PMID- 21786500 TI - [Kidney care--a web-based registry tool and decision support. Good for follow up and therapy evaluation in metastazing renal cancer]. PMID- 21786501 TI - [The responsibility for medications list should be clear. Swedish Drug Committees (LOK) has published guidelines]. PMID- 21786502 TI - [Melanoma diagnostics and other laboratory tests: Use the available tools to show that the results are correct!]. PMID- 21786503 TI - [More money can make matters worse]. PMID- 21786504 TI - [Hiprex in favour again?]. PMID- 21786505 TI - [School health service--a guarantee for children's health]. PMID- 21786506 TI - [Compulsory psychiatric care contra the zero vision for suicide]. PMID- 21786507 TI - [Difficult therapeutic decision making in treatment of children with oesophageal atresia and trisomy of chromosome 18 - comments by geneticist, surgeon, neonatologist, paediatrician and anaesthesiologist]. AB - Oesophageal atresia is a congenital defect of alimentary tract concerning the interruption of oesophagus with or without connection with the trachea. Its incidence is 1:3000-3500 of live-born. Associated anomalies including genetic disorders occur in 50% of patients. Edwards syndrome which is trisomy of chromosome 18 with poor prognosis. The incidence of Edwards syndrome is 1:5000 of live-born. About 5% of these children live more than 1 year. The aim of this article is a retrospective analysis of the course of treatment of newborn with oesophageal atresia and Edwards syndrome and making of therapeutic decision. The authors from different medical specializations: clinical genetics, paediatric surgery, paediatrics and neonatology, paediatric intensive care and palliative medicine, have undertaken a discussion regarding surgical treatment of children with oesophageal atresia and chromosomal, lethal syndrome. PMID- 21786508 TI - [Characteristics of extracranial malignant germ cell tumours in two age groups of children (0-10 and 10-18 years). Multicentre experiences]. AB - In order to assess if any differences exist in children germ cell tumours depending on age, we compared some features of germ cell tumours in two age groups:younger than 10 and between 11 and 18 years. MATERIAL AND METHODS: Data of 146 patients with germ cell tumours treated in 15 Polish paediatric oncology departments between 1995 and 2005 were evaluated. They were divided into two groups: 76 children 0-10 years old (group I) and 70 patients 11-18 years old (group II). Tumour morphology, sex of patients, primary tumour and metastases localization, disease stage, biochemical markers, treatment response, disease relapse and long survival were analyzed. Every patient was treated according to the TGM 95 protocol. RESULTS: In group 1, 67 tumours were assessed histologically. 64%t tumours had homogenous structure with yolk sac tumour in predominance and 36% were mixed. Yolk sac tumour (YST) or teratoma as components of mixed tumours were the most commonly found. In older group 64 tumours were examined, 41% were homogenous, and seminoma/dysgerminoma predominated. In 59% mixed tumours the most common components were YST embryonal carcinoma and teratoma. The most common primary site in group I was the sacrococcygeal region while in group II - the gonads. Disseminated disease was recognized mostly in older children. Among two evaluated serum markers, AFP was increased mostly in younger patients (76% vs 44%), and 3HCG in older group (40% vs 9%). Treatment response was comparable in both groups. Two relapses were observed in each group. Poor outcome was noted in 17/140 analyzed patients: 9 (12%) in group I and 8 (11%) in group II. In 12 of patients with poor outcome the cause of death was progression and in 5 of them - treatment complications. CONCLUSIONS: 1. Germ cell tumours in younger and older children differ in histology, primary localization and serum level of biochemical markers. 2. In older patients germ cell tumours are recognized more frequently in advanced clinical stages. 3. Treatment response was comparable in both groups. 4. There is a need to analyze the intensity of chemotherapy to precise the adequate risk groups according to primary treatment response. PMID- 21786509 TI - [Evaluation of selected cytokines in children and adolescents with osteosarcoma at diagnosis - preliminary report]. AB - BACKGROUND: Osteosarcoma (OS) is the most frequent primary malignant bone tumour, mainly affecting children in the first and second decade of life. Causes of the disease are still unknown and reaction of the immune system on its development is very individual. Particular emphasis must be placed on the role of cytokines in the immunoregulatory and coordinating function and tumour cell disruption. Knowledge about cytokines concentration in serum, regarding mechanisms of oncogenesis, may have prognostic significance for the further course of OS in children. The aim of study was evaluation of IL-2, IL-4, IL-8, IFN-gamma, and TNF a concentrations in children with osteosarcoma at diagnosis. MATERIALS AND METHODS: The study was performed on the group of44 children with osteosarcoma, aged from 6 to 20 years (average 14.9 years; median 15.0 years). 22 children ofthesame age (median 14.5years) without neoplastic disease and active inflammatory state formed the control group. Investigations were performed before the therapy. The inclusion criteria were: diagnosis of primary osteosarcoma, upper or lower limbs tumour localization, patients who were not treated by chemo- or radiotherapy before biopsy patients' age at diagnosis was 6-20 years. Concentrations of selected cytokines were analyzed in peripheral blood with using ELISA method with 99.8% sensitivity and 99,5% specificity. RESULTS: In children with osteosarcoma, at diagnosis the following concentration of peripheral blood cytokines (medians) was observed: IL-2 10.7 pg/ml (min-max: 0.0-894.0); IFN-gamma 1,3 pg/ml (min-max: 0.2-147); TNF-alpha 28.3 pg/ml (min-max: 0.0-188.8); IL-4 2.0 pg/ml (min-max: 0.0-32.0); IL-8 13.5 pg/ml (min-max: 0.0-2154.0). A large scatter among individual children results was found. Analysis of cytokines concentration showed significant statistical differences between patients with OS and the control group in case of IL-4 (p=0.005) and IL-8 (p=0.01). CONCLUSIONS: Results of studies obtained at diagnosis did not give a specific answer about the prognosis and further course of OS disease in patients in the developmental age. Big differences in cytokines concentration in children and youth with OS might be associated with individual biological variation and individual reaction to the development of neoplastic disease and further studies in this direction are needed - before the start of cytostatic therapy and in therapy monitoring. PMID- 21786510 TI - [Vaccinations in children with idiopathic nephrotic syndrome]. AB - Idiopathic nephrotic syndrome is the most common glomerulopathy diagnosed in children. Pathogenesis of the syndrome, frequent hospitalizations and immunosuppressive treatment cause that children with this disease belong to the high risk group in relation to frequency and severity of infection. It is therefore essential to take into consideration the vaccination of these patients. The immunization of a child may be connected with several complications including the relapse or exacerbation of the basic disease. There is still too little data which vaccinations are safe, in which period of the disease the child can be vaccinated and what is the influence of the used treatment on its efficiency. The study shows the present state of knowledge concerning the usage of some obligatory and recommended vaccinations in the group of children with idiopathic nephrotic syndrome. PMID- 21786511 TI - [Size of testes and epididymes in boys up to 17 years of life assessed by ultrasound method and method of external linear measurements]. AB - AIMS: 1. Determination of the size of testes and epididymes on the right and left side, in healthy boys in various age groups with use of non-invasive ultrasound examination method and the method of external linear measurements. 2. Determination of age, when intensive growth of testicular and epididymal size starts. 3. Determination whether there are statistically significant differences between the size of the right and the left testis, as well as between the right and left epididymis. 4. Evaluation of the ultrasound method and method of external linear measurements in their use for scientific investigations. MATERIAL AND METHODS: 309 boys, aged from 1 day to 17 years of life, treated in the Clinical Department of Paediatric Surgery and Traumatology of the Medical University in Lublin from 2009 to 2010 due to diseases needed to be treated surgically, but not the scrotum, were examined in this study. No pathologies influencing the development of genital organs were found in these boys. Dimension of the testes was studied with ultrasound method and with method of external linear measurements. Dimension of epididymes was only examined with ultrasound method. In every age group the author calculated mean arithmetical values for: testiscular length, thickness, width and volume, as well as epididymal depth and basis. With consideration of standard deviation (X+/-1 SD) it was possible to define the range of dimension of healthy testes and epididymes and their change with age. Final dimensions of the right and left testis as well as of the right and left epididymis were compared. Dimensions of the testis on the same side of body acquired with the ultrasound method and acquired with the method of external linear measurements were compared. Statistical work-up with Wilcoxon test for two dependent groups was implemented. RESULTS OF STUDIES: Ultrasound evaluation pointed to intensive 2.5-times increase in testicular length and width, and 2 times increase in testicular thickness in boys aged 10 to 17 years. Mean volume of neonatal testis is 0.35 ml. From 10th year of life, the testicular volume increases 10-times from 1.36 ml to 12.83 ml in 17th year of life. Depth of epididymis measured with ultrasound method is always greater than its basis. Both these dimensions increase quickly from the 10th year of life. Measurements done with the caliper on the average overestimate testicular length by 5.7 mm, its thickness by 2.9 mm and its width by 1.4 mm, comparing with ultrasound method. There were no statistically important differences between dimension of the right and left testis. Differences between dimension of the right and left epididymis are statistically significant. CONCLUSIONS: 1. Age is the main factor influencing testicular size in boys. 2. Intensive growth of testes starts in the 10th year of life, of epididymes in 12th year of life. 3. Testicular volume is the most precise description of its size. There are no statisticallysignificant differences between volume of the right and left testis. Differences between dimension, described by the depth and basis of the right and left epididymis are statistically significant. 4. Ultrasound method and method of external linear measurements with the caliper have similar diagnostic value in comparing the size of both testes. 5. Measurements of testicular size with ultrasound method have much greater value for detail evaluation than the method of external linear measurements with the caliper, which does not regard thickness of the skin and testicular coats, as well as the epididymal head which is often situated on the upper end of the testis. PMID- 21786512 TI - [Chlamydophila pneumoniae infections in younger children. Experience of one centre. Preliminary report]. AB - BACKGROUND: Very few recent Polish data are available on the epidemiology of Chlamydophil pneumoniae (C. pneumoniae) as causative agent among paediatric patients, hospitalized with respiratory tract disorders. Extending these data would serve as rationale for empirical antimicrobial therapy. The aim of the study was to evaluate the frequency of C. pneumoniae infections in younger children hospitalized with prolonged cough and/or prolonged pneumonia. MATERIAL AND METHODS: 110 children, aged 0.3-7.0 yrs., hospitalized from January 1st to March 3 1st 2009 for the above reasons were retrospectively enrolled in the study. Diagnosis of C. pneumoniae was based on ELISA IgM antibodies positive test. Patients with ambiguous IgM titre were excluded from further study (n=12). RESULTS: Of 98 finally investigated children, C. pneumoniae infection was found in 28 patients (28.5%) with the highest frequency in February 2009 (15 cases). It was diagnosed more frequentlyin toddlers (over 1.73 yrs. of age) than in infants and youngest children (p=0,014; OR=4,10 95%C1=1,4-12,0). In patients with active C pneumoniae infection WBC were significantly lower (p=0,001), but within normal range (8647/mm3, +/- SD: 3247/mm3). Other factors such as sex, clinical symptoms and some chosen laboratory markers did not differ significantly between subgroups of sero-positive/sero-negative patients. CONCLUSIONS: Performed analysis suggests a significant role of C. pneumoniae etiology in younger children with prolonged respiratory tract symptoms and can be a useful tool in empirical antibacterial treatment. Further studies for a longer period, larger groups of patients and additional confirmation of sero-positive cases are needed. PMID- 21786513 TI - [Influence of natural boosters on long-term immunity against hepatitis B]. AB - BACKGROUND: Incidence of hepatitis B in Poland decreased significantly after implementation of routine immunization in infants. Natural boosters may influence the long-term post vaccination immunity in countries, where endemicity is high. In areas of low incidence this influence may be limited. The aim of the study was to analyze the influence of risk factors for HBV infection (potential natural boosters) on long-term post vaccination immunity against hepatitis B and the possibilityof HBVinfection in previously vaccinated individuals. PATIENTS AND METHODS: In 130 children aged 10-12years, vaccinated with 4 doses ofrecombinantvaccine against hepatitis B in infancy, exposure to risk factors for HBV infection (infection in family members including mother, hospitalization, surgical interventions, blood transfusion, dental treatment, piercing, tattooing) was analyzed. Markers of HBVinfection (anti-HBc and HBsAg) and humoral immunity against hepatitis B were determined. Protective level of anti-HBs antibodies was defined as > or =10 IU/1. RESULTS: Statistically significant influence of dental treatment (p<0.02) andsurgicalinterventions (p<0.05) on possessing very high anti HBs titer (> or = 1000 IU/) was revealed, which indicates that these factors act as natural boosters. Children, who previously received blood transfusion, statistically more frequently did not have protective level of anti-HBs (p<0.0 I). In all 6 children with confirmed HBV infection there was exposure to risk factors for infection in anamnesis. In children with chronic hepatitis B (positive HBsAg) statistically significantly more frequently surgical interventions were performed (p<0.05). CONCLUSIONS: I. Despite of low incidence of hepatitis B in Poland, natural boosters, especially dental and surgical treatment, may stimulate the post vaccination immunity. 2. Blood transfusion is currently not a source of infection, however, children who received blood transfusion in the neonatal period, may require control of immunization efficacy or a booster dose. 3. HBVinfection and chronic hepatitis B may occur in previously vaccinated children, especially if they underwent surgical intervention. PMID- 21786514 TI - [Diagnostic problems in a 17-year-old patient with gastrointestinal manifestations of Fabry disease]. AB - Fabry disease is a rare X-linked recessive lysosomal storage disorder caused by deficiency of lysosomal enzyme alpha-galactosidase, which leads to accumulation of globotriasylceramides (GL-3) in visceral tissues and vascular endothelium, causing multi-organ failure. We presenta case of Fabry disease in a 17-year-old patient with mainly gastrointestinal manifestations, diagnosed 10 years after the manifestation of first symptoms. Significant and progressive weight loss with abdominal pain and vomiting, leading to cachexia, were observed in early childhood. The patient was investigated for non-inflammatory bowel diseases, Raynaud syndrome, polimyositis, mitochondrial cytopathies, intestinal lypodystrophies and others. The symptoms of intenstinal pseudo-obstruction syndrome were observed and surgical treatment was instituted because of necrosis of the colon. There was progressive cachexia and parenteral nutrition had to be instituted. Finally, plasma alpha-galactosidase was measured, and its deficit confirmed Fabry disease. In conclusion gastrointestinal symptoms in the course of Fabry disease can obscure other characteristic symptoms, may be prodromal and leading. Heart and renal failure may not occur in children. Unexplained abdominal pain and malnutrition may be gastrointestinal manifestations of metabolic disorders. PMID- 21786515 TI - Evaluation of sCD30 level in maternal serum in pregnancies complicated by severe preeclampsia. AB - BACKGROUND: Our study was a continuation of the research on the immunological pathology and changes associated with pregnancy complicated by preeclampsia. The aim of this study was to compare the levels of soluble CD30 in maternal serum in the group of women with preeclamptic pregnancy and in the control group of normotensive healthy pregnant women. MATERIAL AND METHODS: The study was carried out in 50 patients with pregnancies complicated bysevere preeclampsia (Pre group). The control group consisted of 34 healthy normotensive pregnant patients with singleton uncomplicated pregnancies (group K). Maternal serum soluble CD30 concentrations were estimated using a sandwich ELISA assay. There were no statistically significant differences in gravidity, parity, maternal age, body height and BMI in patient profiles between groups. Maternal weight was lower in the control group of patients than in the group of preeclamptic patients. Systolic and diastolic blood pressure and mean arterial blood pressure were higher in the study group ofpreeclamptic pregnant women than in the control group. RESULTS: The levels of maternal serum soluble CD30 in preeclamptic women did not differ in comparison with healthy controls. The mean values were 21.257+/ 10.304 ng/mL in the Pre group compared with 21.806+/-11.076 ng/mL in the control group. CONCLUSIONS: Since preeclampsia is not associated with a fall of the maternal soluble CD30 level it can not constitute a measure of improving diagnostic and therapeutic management. PMID- 21786516 TI - [Thermal comfort in preterm babies. Infra-red colour thermography findings. Preliminary report]. AB - OBJECTIVE: To assess the thermal comfort of clinically stable neonates with normal body temperature by using infra-red colour thermography (THY). MATERIAL AND METHODS: 32 babies were enrolled in the study. The axillary temperature was maintained in the range 36.6-37.0 degrees C and the air temperature in the incubator remained within the neutral range according to Hey and Katz. Temperature distribution was measured by THY The abdomen and foot skin temperature, as well as the difference between both parameters were recorded. Thermal comfort for THY was defined as a difference between core and peripheral temperatures (Deltat) in the range of 1 to 2 degrees C. RESULTS: Thermal comfort defined according to THY criterion was fulfilled only in 12 patients (37.5%). We found Deltat< 1 degree C in 14 patients (43.8%), and Deltat>2 degrees C in 6 patients (6.3%). Thermal comfort defined by standard care varied from founded by THY p<0.0001. High foot temperature >or=35.0 degrees C in THY was found as a determinant for Deltat< 10 degrees C. Multivariate logistic regression analysis found gestational age <30 weeks to be connected with the risk of hyperthermia [odds ratio 8.4 (95% Cl 1.2-61.2). CONCLUSIONS: We concluded that there is a risk for hyperthermia in prenaturely, immature babies when nursed in standard neutral temperature. Infra-red colour thermography gives additional information which can be used for further studies on determination of optimal thermal comfort in newborn. PMID- 21786517 TI - [Evaluation of sick neonates' medical interventions in maternity units before transport to reference centres]. AB - BACKGROUND: Interhospital transfer of the sick neonate should be an integral part of neonatal intensive care. However, it is essential that the referring hospital is able to provide the appropriate standard of care from birth up to the point of transfer. OBJECTIVE: To evaluate the quality of medical interventions before interhospital transport of sick neonates. MATERIAL AND METHODS: Retrospective study based on review of all transport records of530 neonates who were transported at the Neonatal Intensive Care Unit (NICU) in 2006. The examined variables included medical interventions in the maternity unit and transport team interventions before and during the transport. RESULTS: During the study period there was as a total of 530 transfers to Neonatology Departments, 325 of them (61.32%) were transferred to the NICU and 205 (38.68%) to the Special Care Unit. Within the group of neonates transported to the NICU, 51 (15.7%) infants had hypothermia, 65 (20%) had no venous access before the transport. The most common form of respiratory therapy was oxygen therapy (89 (27.4%) neonates), followed by mechanical ventilation (65 (20%) and NCPAP ventilation (50 (15.4%) infants). As a result of transport team interventions the number of children with hypothermia decreased to 27 (8.3%). Peripheral intravenous devices were inserted in 52 (16%) neonates. The number of infants transported on mechanical ventilation increased to 115 (35.4%), 56 (17.2%) babies received NCPAP and 53 (16.3%) were on supplemental oxygen. The highest number of transport team interventions was found in the group of extremely low birth weight infants. CONCLUSIONS: Inadequate medical preparation of sick neonates in maternity hospital for interhospital transport was the reason for the high incidence of transport team interventions before moving the neonate to the NICU. PMID- 21786518 TI - [Ileus due to adhesions as a consequence of abdominal surgery in childhood - analysis of 94 cases]. AB - INTRODUCTION: Ileus due to adhesions is a common postoperative complication. However, there are only rare reports of this condition occuring in children. The aim of this study was to determinate the risk of incidence of intestinal adhesion ileus in children after abdominal operations. MATERIAL AND METHODS: Retrospective studies were carried out on a group of 94 children operated in the Department of Pediatric Surgery and Urology of the Polish Mother's Memorial Hospital - Research Institute in Lodz in the years 1996-2005, in whom adhesions were found on relaparotomy. The following parameters were analysed:indication for operation age at first laparotomy, timeintervalbetweenl aparotomyandrelaparotomy, localization and extent of adhesions, complications after adhesiolysis, indications for relaparotomy. RESULTS: Among 1987 children in whom laparotomy was performed, in 94 intestinal adhesions were found. The majority of relaparatomies were performed in the first 6 months after the primary operation. CONCLUSIONS: Adhesive bowel obstruction is a frequent and serious complication after laparotomy especially in the neonatal period. It occurs most frequently in the 6 months after the primary operation. PMID- 21786519 TI - [The Phelan-McDermid syndrome (22q13 microdeletion) - case report]. AB - Sub telomeric aberrations area frequent cause of child developmental delay. Because ofa non-characteristic course and great variation of patients' appearance in most of the subtelomeric microdeletion syndromes, diagnosis of dysmorphic features is difficult. Phelan-McDermid syndrome (22q 13 microdeletion syndrome) is characterized by generalized hypotonia, global psychomotor development delay, absent or delayed speech development and autistic behaviour. The paper describes a 4-year-old child with the 22q13 microdeletion diagnosed using MLPA and FISH methods. PMID- 21786520 TI - [Avascular necrosis of the femoral head in a patient with severe aplastic anaemia]. AB - Avascular necrosis (AVN) is a pathological condition associated with numerous processes. Most frequent causes of ischaemia of the femoral head include trauma, corticosteroid therapy, radiation therapy, alcoholism, Gaucher's disease, systemic lupus erythematosus, rheumatoid arthritis. Corticosteroid therapy is considered the most frequent risk factor for developing avascular necrosis. In this paper we report a case of a 19-year old female patient who developed avascular necrosis of the right femoral head following treatment of severe aplastic anaemia. Clinical symptoms included groin pain and fever, painful abduction and internal rotation, tenderness over the right hip joint. The plain X ray was not specific. However magnetic resonance imaging of the hip revealed changes characteristic for avascular necrosis. Conservative treatment was administrated. Two years after the onset of first clinical symptoms the patient is able to walk without pain, although the range of motion of the right hip joint is partially diminished. We evaluated the possible risk factors of AVN, diagnostic methods and prognosis. The onset of avascular necrosis should be considered as one of the relevant complications in patients with severe aplastic anaemia following immunosuppressive treatment. PMID- 21786521 TI - [Late manifestation of congenital diaphragmatic hernia - case report]. AB - Congenital diaphragmatic hernia (CDH) in most cases presents immediately or within hours after birth with signs of respiratory failure: dyspnea, tachypnea, and cyanosis. Late presentation of CDH (beyond the neonatal period) is less common and represents true diagnostic challenge. Diagnosis of the defect is difficult. Symptoms are non-specific and can be misleading. Late onset of this anomaly must be considered in the differential diagnosis of chronic gastrointestinal or respiratory symptoms. The aim of this report is a case of 17 year old boy with delayed presentation of congenital diaphragmatic hernia. PMID- 21786522 TI - How to adopt the European diploma in anaesthesiology as the National Board Examination in Anaesthesiology and intensive therapy--from Euro (Euro) to EDA I- three-year experience in Poland. PMID- 21786523 TI - [Comparison of atracurium, cisatracurium and vecuronium during anaesthesia for laparoscopic surgery]. AB - BACKGROUND: The aim of the study was to compare the intubating conditions, onset time, and duration of action of atracurium, cisatracurium, and vecuronium, when used for muscle relaxation in laparoscopic surgery with carbon dioxide inflation. In trying to find an "ideal" relaxant we compared the relative potency of these drugs, and also measured pH, PaCO2 and skin temperature. METHODS: Ninety-five ASA I and II patients were randomly allocated to three groups, to receive atracurium (I), cisatracurium (II), or vecuronium (III), during propofol/fentanyl anaesthesia. Neuromuscular transmission was monitored using accelerography (TOF GUARD). Patients were intubated after the injection of 0.5 mg kg-1 atracurium (I), 0.1 mg kg(-1) cisatracurium (II), or 0.1 mg kg(-1) vecuronium (III). Muscle relaxation was maintained with incremental doses of 0.1 0.2 mg kg(-1) and 0.03 mg kg(-1) of the relaxants respectively, given after a second response to TOF stimulation was noted. Recovery time was defined as the time from a maximal block (TOF=0) to spontaneous recovery of TOF 75%. RESULTS: Conditions for performing tracheal intubation were noted to be excellent in groups I and III, and good in group II. The mean recovery time was significantly shorter in groups II and III, than in group I. No significant correlations were found between the duration of neuromuscular blockade and pH, PaCO2 or palm skin temperature. CONCLUSIONS: Vecuronium, besides providing excellent conditions for tracheal intubation, had the fastest onset time and optimal duration of action. We found the drug to be the most suitable for laparoscopic surgery. PMID- 21786524 TI - [Effect of pre-emptive pregabalin on pain intensity and morphine requirement after hysterectomy]. AB - BACKGROUND: Pregabalin, an antiepileptic and chronic pain medication, has been used by various authors for preoperative analgesia. We have assessed the effect of pre-emptive administration of the drug to patients scheduled for elective abdominal hysterectomy. METHODS: Seventy-four ASA I and II patients were included in this prospective, double blind study. They were randomised to receive 75, 150, or 300 mg of pregabalin, or 7.5 mg of midazolam as a placebo, one hour before anaesthesia and surgery. Anaesthesia was induced with propofol and maintained with sevoflurane or desflurane. Fentanyl was used for analgesia and rocuronium for muscle relaxation. Immediately after surgery, patients received morphine intravenously in 2 mg increments until the NRS score was below 3. This was then followed by PCA. RESULTS: Morphine consumption and pain scores were only significantly lower in the 300 mg pregabalin group, when compared to the placebo and other treatment groups; there were no differences between placebos and lower doses of pregabalin. CONCLUSION: We conclude that pre-emptive administration of 300 mg pregabalin reduces postoperative pain and morphine consumption. Further studies on higher doses would appear to be justified. PMID- 21786525 TI - [Pre-emptive ketoprofen for postoperative pain relief after urologic surgery]. AB - BACKGROUND: Effective multimodal postoperative analgesia is one of determinants of patient satisfaction after successful surgery. Following the recommendations of non-steroidal antiinflammatory agents (NSAIDs) for pre-emptive analgesia, we assessed the efficacy of ketoprofen administered before urological surgery. METHODS: Fifty-two ASA I and II adult patients, scheduled for elective urologic procedures under general anaesthesia, were enrolled in this prospective, double blind study. They were randomized to receive intravenously either 100 mg ketoprofen or placebo (0.9% saline), one hour before the procedure, and at 8, 24, 36 and 48 h after. Pethidine was given for rescue analgesia. VAS was used for pain scoring. RESULTS: Pain scores were similar in both groups and identified as severe (VAS >4) during the first 48 h after surgery. There was no difference in the number of patients requiring rescue pethidine analgesia, mostly required during the first 12 postoperative hours. CONCLUSION: Pre-emptive analgesia with intravenous ketoprofen was ineffective in patients undergoing urological surgery. PMID- 21786526 TI - [Results of severe sepsis treatment--two years of experience in a single centre]. AB - BACKGROUND: Treatment of severe sepsis (SS) is a major challenge for an ITU, because of the high mortality. The severity of 55 is scored according to the number of organ systems that have failed. We analysed the results of treatment of SS in the ITU of the Upper Silesian Medical Centre, and compared them to previously reported data obtained from other centres. METHODS: Between 2008 and 2009, 45 SS cases were treated. Demographic data, laboratory tests and therapeutic routines were analysed. RESULTS: The overall mortality rate was 58%. There was a positive correlation between mortality, male gender and advanced age. The most common initial sources of infection were the respiratory system and abdominal cavities. Serious metabolic disturbance and central nervous system failure markedly affected prognosis. In 56% of cases, five or more organ systems were affected, DISCUSSION: Survival in SS is related to the number of affected organ systems. All patients were admitted in critical condition requiring respiratory and inotropic support. Despite strict application of the Surviving Sepsis Campaign (SSC) recommendations and a relatively short time from diagnosis to commencement of adequate treatment, the mortality rate was found to be higher than the European average, but comparable to that from the Polish registry. CONCLUSIONS: Advanced age, male gender and intraperitoneal pathology worsened the prognosis in SS. Mortality was directly related to the number of organ systems involved, and the number of coexistent diseases. An interdisciplinary approach during diagnosis and a reduced time to the start of intensive treatment are essential for survival. Ready access to updated databases on SS enables regular reviews of the results of treatment and improvement of algorithms. PMID- 21786527 TI - [Knowledge of BLS and AED resuscitation algorithm amongst medical students- preliminary results]. AB - BACKGROUND: Early recognition of cardiac arrest (CA) and immediate commencement of resuscitation, may increase the survival rate among CA victims. We therefore conducted a survey among medical students to assess their knowledge of BLS and AED. METHODS: The audit was performed among students, most of whom had completed at least one first aid course and those who had not done a first-aid course at all. The ERC-recommended questionnaire 2005 was used for the survey. RESULTS: One hundred and sixty five students completed the survey. Most of them recognized the usefulness of basic resuscitation algorithms and the use of AEDs. 88% of students recognized the importance offirst aid courses, and 91.6% would undertake them again. Despite obvious enthusiasm and self-declared adequate knowledge, 45.7% of the audited students were not familiar with the guidelines and answered wrongly to more than 6 of 12 questions in the questionnaire. The vast majority of the first year medical students were not familiar with the algorithms. CONCLUSION: We conclude that general knowledge of resuscitation algorithms among medical students is inadequate, and regular refresher courses are essential. PMID- 21786528 TI - [Congenital pseudocholinesterase deficiency]. AB - BACKGROUND: Congenital pseudocholinesterase (pChe) deficiency is a rare genetic abnormality which may lead to prolonged duration of action of muscle relaxants that are hydrolysed by pChe. We describe two cases in which mivacurium resulted in neuromuscular block lasting several hours. CASE REPORTS: Two non-related male patients, aged 26 and 7 years, scheduled for elective ENT surgery, received propofol, desflurane, remifentanil and mivacurium. At the end of the surgery it was not possible to reverse the neuromuscular blockade, and there were no responses to TOF or post-tetanic stimulation. Neuromuscular transmission returned spontaneously after 7, and 4 h, respectively. Postoperative assay revealed severe pChe deficiency in both patients, with values of 3393 UL(-1)and 2558 UL(-1), respectively (normal range 5100-11700 UL(-1). Family screening confirmed the presence of pChe deficiency in both cases. CONCLUSION: In any case of unexpected prolonged muscle relaxation after mivacurium, pChe deficiency should be considered and its activity measured.When confirmed, careful family screening is mandatory. PMID- 21786529 TI - [Haemorrhagic shock complicating acute pancreatitis]. AB - BACKGROUND: Acute pancreatitis may be accompanied by a number of complications. They include diffuse peritonitis, intra-abdominal and retroperitoneal abscesses, and severe haemorrhage. These complications are the cause of approximately 50% of all deaths in acute pancreatitis. CASE REPORT: A 33-year-old man was admitted to ITU with septic shock, due to acute pancreatitis and necrosis after multiple surgeries. On the fifth day after admission, his condition deteriorated due to respiratory distress and massive bleeding from the splenic region requiring surgical packing. On the next day, the bleeding became critical. More than 2000 mL of blood was evacuated from the peritoneal cavity, the bleeding site was re packed, and the patient was transfused with RBCs, FFP and 0.04 mg kg(-1) of recombinant factor VIIa concentrate. This resulted in haemostasis, however the subsequent clinical course was complicated by septic shock, perforation of the transverse colon and peritonitis. The patient eventually recovered and was discharged home after 105 days in hospital. CONCLUSION: Multifactorial management of acute pancreatitis is essential; in cases of severe haemorrhage, surgical packing and administration of recombinant factor VIIa concentrate are key components of successful treatment. PMID- 21786530 TI - [Pneumocephalus and pneumorrhachis after chest wall injury]. AB - Pneumocephalus and pneumorrhachis are rare findings, and may result from a variety of causes, including severe asthma or trauma. We describe a case, where intracranial and intraspinal air was found after trauma to the chest wall. CASE REPORT: A 24-yr-old patient suffered multiple trauma in a traffic accident, including a closed head injury and bursting fractures of theTh 7, 8 and 9 vertebral bodies with laceration of the spinal cord. Reposition of the spinal column was complicated by wound infection and septic shock. Intraoperatively, accidental extubation led to migration of gastric contents and was complicated by possible rupture of the oesophagus. Postoperative CT scan revealed the presence of air within the mediastinum, cranium and the entire spinal canal. The osteosynthetic material was removed, and the air quickly reabsorbed. The paraplegic patient was discharged from ITU in a satisfactory condition. DISCUSSION: The most probable cause of the complication was traumatic rupture of the oesophagus and penetration of air via lacerated dura mater, to the spinal canal and the cranium. Conservative treatment was successful and led to complete (beside paraplegia) recovery. PMID- 21786531 TI - [Reduction of intraoperative bleeding during functional endoscopic sinus surgery]. AB - Functional endoscopic sinus surgery (FESS) is a surgical procedure, during which all necessary manipulations are performed while using a fibreoptic camera. The endoscope is inserted together with the surgical instruments, through the nasal cavity. During the surgery, bleeding has to be minimized, since even a small amount of blood may completely obstruct vision via the endoscope. Various approaches have been used to secure a dry operating field; among them are: topical vasoconstrictors, Fowler's position, alpha-and beta-adrenergic blockade, and preoperative steroids. All these methods are far from being effective and are associated with significant side effects. The recently approved approach to this problem is to combine total intravenous anaesthesia using propofol and remifentanil, together with esmolol. With the heart rate reduced to 60 bpm, excellent operative conditions can be achieved with moderate hypotension (MAP 65 mm Hg-8.7 kPa). Altered microcirculation and a low cardiac output are the principal underlying mechanisms in these cases. PMID- 21786532 TI - [Selected techniques of regional anaesthesia for orthopaedic surgery]. AB - Central blocks, continuous subarachnoid-epidural anaesthesia, including combined spinal-epidural anaesthesia (CSE) are used for long and painful procedures of lower limbs. They provide quick and good-quality anaesthesia as well as satisfactory postoperative analgesia. After their administration, ambulation is quick and rehabilitation instituted early, which is essential for the postoperative course of orthopaedic procedures. Peripheral blocks are an excellent alternative, especially in patients at high perioperative risk, who require anticoagulants. The novel techniques of location of peripheral nerves and plexuses, i.e., nerve stimulation- and ultrasound-guidance, improve the efficacy of blocks and shorten the duration of anaesthesia. Moreover, they improve safety and comfort of patients. PMID- 21786533 TI - Effects of preservation media on in vitro maturation of porcine oocytes. AB - The effects of preservation media for ovaries on in vitro maturation of porcine oocytes was studied. The cumulus-oocyte complexes (COCs) obtained from ovaries that had been preserved in three different media at various temperatures for different time intervals were cultured in the M199 maturation medium. The preservation media used were 0.9% saline solution, BCS (Braun-Collins solution) and Dulbecco's phosphate buffered saline solution (PBS). Mature oocytes obtained from the ovaries preserved in three preservation media for 8 h were electrically activated. The activated oocytes were then cultured in the NCSU23 embryo culture medium for 16 h to observe activation, or for 144 h to observe embryo development. It was found that the preservation temperature significantly affected maturation of the porcine oocytes. A preservation temperature of about 25 degrees C showed an optimal maturation rate for a preservation time of 8 h for the three preservation media. Although the preservation temperature was a major factor influencing the maturation rate, different preservation media at 25 degrees C for 8 h also significantly affected the maturation rate, activation rate and embryo development. Among these three preservation media, PBS exhibited the highest cleavage rate indicating that PBS should be a better preservation medium for porcine ovaries at 25 degrees C for 8 h or longer periods. PMID- 21786534 TI - Effects of L-arginine and NG-nitro L-arginine methyl ester (L-NAME) on ischemia/reperfusion injury of skeletal muscle, small and large intestines. AB - This study analyzed the effects of L-arginine and non-specific nitric oxide (NO) synthase blocker (L-NAME) on structural and metabolic changes in experimental ischemia/reperfusion injury in the rat. Histopathological evaluation of rat tissues after reperfusion was also performed. The animals were divided into four groups: [1] nonischemic control, [2] ischemia 4 hrs/repefusion 30, 60, 120 min, [3] ischemia/reperfusion after L-arginine administration, [4] ischemia/reperfusion, after L-arginine, and L-NAME. L-arginine (500 mg/kg) and L NAME (75 micromol/rat/day) were administrated orally for 5 days before experiment. Concentrations of free radicals, CD-62P, CD-54 and malonyl dialdehyde (MDA) in tissues, and MDA and NO levels in sera were determined. Free radical levels significantly increased in reperfused skeletal muscle, small and large intestines. In large bowel, reperfusion increased MDA levels and evoked a rise of endotoxin level while NO levels decreased. Histological studies showed an increase in the number of lymphocytes in both intestines. Administration of L arginine reduced leukocyte adherence associated with ischemia-repefusion injury, decreased the levels of free radicals and MDA in the examined tissues, and inhibited the release of endotoxins into blood. L-arginine-treated animals showed higher serum NO levels and reduced leukocyte bowel infiltration. Concomitant L NAME administration reduced serum NO and tissue free radical [corrected] levels, but did not affect intestinal leukocyte infiltration. L-arginine could ameliorate intestinal ischemia/reperfusion injury and constitute a possible protective mechanism by decreasing neutrophil-endothelial interactions, stimulating free radical scavenging and reducing lipid peroxidation. PMID- 21786535 TI - Contribution of non-inactivating Na+ current induced by oxidizing agents to the firing behavior of neuronal action potentials: experimental and theoretical studies from NG108-15 neuronal cells. AB - The effects of chemical injury with oxidizing agents on voltage-gated Na+ current (I(Na)) in differentiated NG108-15 neuronal cells were investigated in this study. In whole-cell patch-clamp recordings, the challenge of these cells with t butyl hydroperoxide (t-BHP; 1 mM) decreased the peak amplitude of I(Na) with no modification in the current-voltage relationship. It caused a slowing of current inactivation, although there was no alteration in the activation time course of I(Na). Cell exposure to t-BHP also increased a non-inactivating I(Na) (I(Na(NI)) elicited by long-lasting ramp pulses. The t-BHP-induced increase of I(Na(NI)) was reversed by a further application of riluzole (10 microM) or oxcarbazepine (10 microM). When I(Na) was elicited by simulated waveforms of action potentials (APs), during exposure to t-BHP, the amplitude of this inward current was diminished, accompanied by a reduction in inactivation/deactivation rate and an increase in current fluctuations. Under current-clamp recordings, addition of t BHP (0.3 mM) enhanced AP firing in combination with clustering-like activity and sub-threshold membrane oscillations. In the simulation study, when the fraction of non-inactivating Na(v) channels was elevated, the simulated window component of I(Na) in response to a long-lasting ramp pulse was reduced; however, the persistent I(Na) was markedly enhanced. Moreover, when simulated firing of APs was generated from a modeled neuron, changes of AP firing caused by the increased fraction of non-inactivating Na(v) channels used to mimic the t-BHP actions were similar to the experimental observations. Taken together, it is anticipated that the effects of oxidizing agents on I(Na(NI)) could be an important mechanism underlying their neurotoxic actions in neurons or neuroendocrine cells occurring in vivo. PMID- 21786536 TI - Blood glucose level and survival in streptozotocin-treated human chymase transgenic mice. AB - A growing body of evidence suggests the potential role of chymase in organ injury in diabetes. We investigated blood glucose levels and survival in transgenic mice carrying the human chymase gene (Tg). Intraperitoneal injections of streptozotocin (STZ) (200, 100, 75 and 50 mg/kg in total, i.p.) were given to uninephrectomized Tg mice and wild-type C57BL/6 (BL) mice. Before STZ injection, the Tg mice had significantly lower body weights and slightly higher systolic blood pressure as compared with the BL mice. STZ-treated Tg mice showed significantly higher postprandial blood glucose levels as compared with the STZ treated BL mice. The survival prevalence of STZ-treated Tg mice was zero, whereas BL mice showed a value of 40% until 42 days. STZ (100, 75 or 50 mg/kg, i.p.) treated Tg mice also showed a similar pattern as compared with the STZ-treated BL mice. These data suggest that human chymase contributes to blood glucose levels and mortality during the progression of diabetes. PMID- 21786537 TI - Effects of citalopram on cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naive rats. AB - Recent studies have shown that learning and memory capacity is disturbed in depressive patients, and it is important to reveal the effects of antidepressant drugs on cognitive function in depressive patients with memory problems. Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used drugs for the treatment of disorders related to serotonergic dysfunction like depression and anxiety. Contradictory findings exist regarding the effects of SSRIs on memory. The aim of this study is to investigate whether citalopram affects memory in various models of learning and memory tasks in rats. Citalopram (at 20 and 50 mg/kg) significantly shortened the retention latency in the passive avoidance test and prolonged the transfer latency on the second day at 10 and 50 mg/kg doses in the elevated plus-maze test. Citalopram also significantly increased the number of errors (at the 10 mg/kg dose) and prolonged the latency values compared to the control group in both reference and working memory trials in the three-panel runway test. Citalopram also impaired reference memory trials of animals at the 20 mg/kg dose. In conclusion, citalopram impaired cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naive rats. These effects might be related to serotonergic and nitrergic mechanisms, which need to be investigated in further studies. PMID- 21786538 TI - Mediation of vagal cardioinhibitory responses by glutamatergic receptors in the caudal medulla of turtles. AB - Our previous studies showed that electrical stimulation of the nuclei ambiguous (NA) or dorsomotor nuclei of the vagus (DMV) complex in the brain stem of spontaneously breathing pond turtles (Cyclemys fiavomarginata), anesthetized with chloralose (4 mg/100 g) and urethane (40 mg/100 g), produced a marked slowing or even cessation of the heart rate, and resulted in an immediate fall of blood pressure. Results of the present study further demonstrated that the cardioinhibitory responses could also be elicited by microinjection of monosodium glutamate (0.2-20 nl, 50 mM) into the NA/DMV complex in turtles. A two-barrel glass micropipette held in a manipulator was connected to a pneumatic pressure pump for microinjection. The glutamate-induced cardioinhibitory responses could be significantly reduced in a dose-dependent manner by pretreatment with AP-5 (a NMDA receptor antagonist, at 1-8 nmole) or CNQX (a non-NMDA receptor antagonist; at 0.1-0.8 nmole) 20 min before glutamate administration. Histochemical verification by injecting horseradish peroxidase into the cervical vagus nerves revealed that retrogradely labeled glutamatergic neurons in the NA/DMV complex were observed. These results suggest that glutamatergic receptors in the caudal medulla may mediate vagal cardioinhibitory responses in the turtle. PMID- 21786539 TI - Effect of passive repetitive isokinetic training on cytokines and hormonal changes. AB - It is well known that muscle strength and power are important factors in exercise. Plyometrics is designed to gain muscle strength and power in a shock method. The passive repetitive isokinetic (PRI) machine is developed for plyometrics. The present study aims to understand the effect of ten-week PRI training in different intensities on human plasma concentration cytokines as well as hormonal changes. Thirty young male subjects were enrolled into the ten-week PRI training program and were divided randomly into traditional, low- and high intensity PRI training groups. Blood samples were obtained before, during, after and 1-, 2-, 3-, 5- and 7-day (D) post-training. The plasma concentrations of cytokines and hormones were measured by an enzyme-linked immunosorbent assay (ELISA). Elevated plasma IL-2 was found in the subjects in all the training programs. Significant increases of proinflammatory cytokines IL-1beta and TNF alpha were observed at post 7 D in the high-intensity PRI training (29.5 +/- 4.4 and 515.8 +/- 127.1 pg/ml, respectively). No significance in differences in the plasma concentration of IL-6 was observed in the traditional and low-intensity PRI training. Significant elevation of IL-6 was found at post 5 D in high intensity PRI training. Higher plasma IL-6 concentration was observed at post 3 and 5 D in high-intensity PRI training compared to low-intensity PRI training (P < 0.05). Significant elevation of plasma IL-15 during (week 6) and after (post 0 D) was observed in low-intensity PRI training. Also, there were differences between low-intensity PRI training and traditional training at post 0, 2, 3, and 5 D. The plasma concentration of cortisol was decreased to the lowest value (118.0 +/- 17.3 ng/ml) at post 0 D in traditional training, then returned to the baseline (220.5 +/- 19.1 ng/ml). In the high-intensity PRI training, but not in the low-intensity PRI training, the cortisol level dropped from 224.9 +/- 25.8 ng/ml at post 0 D down to the 123.2 +/- 22.6 ng/ml at post 1 D. Significant differences were found at post 1 and 5 D between low- and high-intensity PRI training, and post 0, 1, 2, and 3 D between traditional and high-intensity PRI training. Significant increased testosterone was found post 0, 1, 2, and 3 D in traditional training. Higher plasma testosterone was observed during and the recovery period in low-intensity, but not in high-intensity, PRI training. In conclusion, high-intensity PRI training could induce the proinflammatory cytokines, i.e., IL-1beta and TNF-alpha, and decrease plasma cortisol in the recovery period. PMID- 21786540 TI - [Prevention of complications and emphasis on early rehabilitation after total joint arthroplasy]. PMID- 21786541 TI - [Early rehabilitation after simultaneously bilateral total knee arthroplasty]. AB - OBJECTIVE: To investigate the principle and methods of preoperative and postoperative rehabilitation for simultaneous bilateral total knee arthroplasty. METHODS: From January 2005 to June 2008, 72 patients (144 knees) were reviewed in the study, including 33 males and 39 females, ranging in age from 46 to 78 years, with an average age of 69 years. There were 54 patients with osteoarthritis, 17 patients with RA, and 1 patient with traumatic osteoarthritis, including 10 cases (15 knees) of fixed varus deformity more than 30 degree and 6 cases (8 knees) of fixed vagus deformity more than 15 degree. Rehabilitation protocol was made for preoperative, early postoperative and late postoperative stages. Patients were encouraged to initiate the exercises at the early postoperative stage on the premise of multimodal analgesia. Knee function and pain were evaluated using WOMAC and VAS pain scores. Lower limb embolism was determined by ultrasonic scan and pulmonary embolism was diagnosed by clinical manifestation and D-dimer level. RESULTS: Sixty-nine patiets (138 knees) were followed up at 2 d preoperatively and the second day, 1, 2, 8 and 24 weeks postoperatively. The average postoperative WOMAC and VAS score were significantly lower than preoperative levels,while the postoperative knee ROM and 6 min walking distance were evidently higher than the preoperative ones, respectively. One hundred and twenty-eight knees achieved full extension and flexion more than 90 degree at 2 weeks postoperatively, and 135 knees reached 110 degree in flexion. Unilateral lower limb embolism was found in 2 cases (2 knees) and bilateral ones were found in 1 case (2 knees). No pulmonary embolism was confirmed. CONCLUSION: Rehabilitation protocols should be made for preoperative, early postoperative and late postoperative stages of simultaneous bilateral knee arthroplasty. Patients should be encouraged to exercise at the early postoperative stage on the premise of multimodal analgesia, in order to improve knee function and reduce edema. PMID- 21786542 TI - [Medium-term therapeutic evaluation of an uncemented femoral component]. AB - OBJECTIVE: To study the clinical and radiographic results of tatal hip arthroplasty (THA) with an uncemented femoral component after 6 to 10 years follow-up, and to investigate factors effecting their efficacy. METHODS: From January 2000 to December 2003, 58 patients were treated with primary total hip arthroplasty. Among the patients, 27 patients were male and 31 patients were female, ranging in age from 25 to 73 years, with an average of 56 years. The 58 patients were clinically and radiographically followed up including before operation, postoperative 1.5, 3, 6 and 12 months, and then once a year. Therapeutic evaluation was measured by using Harris scoring system. The incidence of osteolysis around the components in different Gruen zones was radiologically determined. The data were analyzed by SPSS 16.0 software. RESULTS: All the patients were followed up, and the duration ranged from 6 to 10 years, with a mean of 8.2 years. The Harris hip score of the patients improved from preoperative mean of (54.0 +/- 7.8) to (88.3 +/- 6.1) at the latest follow-up. There were 32 patients with an excellent result, 22 good, 3 fair and 1 poor. Radiological analysis showed that 48 patients had stable bone in growth, 10 patients got stable fibrous in growth and nobody showed unstable fixation with aseptic loosening. Subsidence (1 to 3 mm) was observed in 4 patients. Osteolysis of the femoral cortex was seen in 4 patients without progressive development, and the latest follow-up radiographs showed a significantly greater incidence of osteolysis in Gruen zone I, VI, VII compared with others (P = 0.031). All the patients with low Harris score had received prostheses which were undersized in the intramedullary canal, and these differences were statistically significant. CONCLUSION: The uncemented femoral component has good medium-term clinical follow up results because of high stability and no aseptic loosening. PMID- 21786543 TI - [Case-control study on acute colonic pseudo-obstruction after total hip or knee arthroplasty]. AB - OBJECTIVE: To investigate the incidence, predisposing factors and therapeutic modalities of acute colonic pseudo-obstruction (ACPO) in patients after total hip arthroplasties (THA) and total knee arthroplasties (TKA). METHODS: From January 2006 to December 2009, 12 patients with ACPO after THA and TKA operation were investigated retrospectively,who were viewed as the ACPO group. There were 10 males and 2 females with an average age of (78 +/- 12) years in the ACPO group. Other 853 patients without ACPO after THA and TKA operation were viewed as the control group treated at the same period. The incidence of ACPO was calculated. The clinical data were collected and compared between the two groups including patient age, gender, procedure, anesthetic class, clinical presentation, radiographic findings, duration from index surgery to diagnosis of ACPO, treatment, postoperative mobilization time, and length of hospital stay. RESULTS: The incidence of ACPO was 1.4%. The incidence of primary THA (1.3%) was higher than that of primary TKA (0.4%); the incidence of hip and knee revisions (5.0%) was higher than that of primary THA and TKA (1.0%); there was no difference in incidence between hip revisions (5.5%) and knee revisions (4.0%). The mean age was (78 +/- 12) years old in ACPO group and (71 +/- 13) in the control group. The male/female ratio was 5:1 in ACPO group and 2:3 in control group. There were statistical differences in mean age and gender ratio between the two groups. No association was found with respect to anesthetic class. On average, ACPO occurred at 2.5 days after index surgery. The abdominal distention occurred in all 12 cases, nausea or vomiting in 8 cases and abdominal pain in 3 cases. Radiographically cecal dilation occurred in all cases and intestinal dilation in 3 cases. All patients initially were treated conservatively with immediate cessation of oral intake,a nasogastric tube and oral mineral oil. Three patients received a rectal tube. Only 1 patient required endoscopic decompression. There were no deaths after ACPO in the series. Mean mobilization time after surgery averaged (5.0 +/- 2.2) days in ACPO group compared with (2.5 +/- 1.1) days in the control group. Mean hospital stay averaged (16.5 +/- 6.4) days in ACPO group compared with (10.5 +/- 4.5) days in the control group. There were statistical differences in mean mobilization time after surgery and mean hospital stay between two groups. CONCLUSION: ACPO mainly happened in old male patients. The majority cases response to conservative treatment and their prognoses are good. But ACPO will delay mobilization time after surgery and increase hospital stay. PMID- 21786544 TI - [Case-control study on the effect of ulinastatin on postoperative complications in elderly patients undergoing hip joint replacement]. AB - OBJECTIVE: To evaluate the preventive effects of ulinastatin (Uti) on postoperative complications in elderly patients undergoing hip joint replacement. METHODS: From Angust 2009 to June 2010, 160 elderly patients undergoing selective hip joint replacement with ASA I to II were assessed according to American Society of Anesthesiologists classification, including 81 males and 79 females ranging in age from 65 to 83 years (mean 73.9 years). All the patients were divided into 2 groups according to random number table (80 patients in each group): control group (group C) and ulinastatin group (group U). The patients in Group U received intravenous injection of ulinastatin with a dose of 10,000 U/kg before skin incision,and then with dose of 5000 U/kg respectively at 1, 2 and 3 days after operatio. The patients in Group C received the same volume of normal saline instead of ulinastatin. Blood samples were taken preoperatively,at the end of surgery and 1, 2, 3 days after operation for determination of ALT, AST, Scr, BUN and Plasma D-dimer. Deep vein thrombosis and postoperative cognitive dysfunction (POCD) were also examined through color Doppler ultrasonography and neuroeognirive assessment on the postoperative 3 days respectively. RESULTS: Compared with the preoperative values, the contents of ALT, AST, Scr, BUN and plasma D-dimer in each group all increased. Compared with group C,the values of ALT, AST, Scr, BUN and plasma D-dimer decreased markedly (P < 0.05). The incidence rate of DVT and POCD was 0 and 3.75% in group U, which were lower than those of patients in the group C (40%, 27.5%) respectively. CONCLUSION: Intravenous infusion of ulinastatin during operation can protect important organ function, correct blood hypercoagulability, lower the occurrence of DVT and POCD, and prevent the postoperative complications in some degree. PMID- 21786545 TI - [Clinical significance and expression of the inflammatory cytokines (IL-1, IL-2, IL-6 and IL-10) in blood serum of the patients after total hip replacement]. AB - OBJECTIVE: To evaluate the changes in the expressions of the inflammatory cytokines (IL-1, IL-2, IL-6 and IL-10) in blood serum of the patients after total hip replacement (THR). METHODS: From February 2010 to June 2010, thirty patients undergone primary total hip arthroplasty in one side including 18 male and 12 female with the mean age of (58.4 +/- 6.6) years (ranged from 52 to 70 years). Twenty patients were Ficat II type,and 10 patients were Ficat III type. The contents of IL-1, IL-2, IL-6 and IL-10 in blood serum were detected on the day before operation and 1 to 3 days after operation respectively by ELISA. At the same time, the content of C reactive protein was also detected, and the results were statistically analyzed. RESULTS: The contents of IL-1, IL-6 and IL-10 in the serum of patients at the first day after THR were significantly higher than those before operation (t = 2.62, 3.51, 2.21, P < 0.05), and reached the peak at 1 to 3 days after operations, then subsequently decreased. However, the content of IL-2 in the serum of patients after operation was obvious lower (t = 2.16, P < 0.05),and recovered to normal level gradually. CONCLUSION: It is the key time of treatment at 1 to 3 days after THR. Monitoring IL-1, IL-2, IL-6 and IL-10 after operation in time, and monitoring life sign at the same time could sensitively observe the effect of treatment and forecast the trend of diseases in patients. PMID- 21786546 TI - [Prognostic significance of hidden blood loss in total hip arthroplasty (THA)]. AB - OBJECTIVE: To explore the prognostic significance of hidden blood loss in total hip arthroplasty. METHODS: From May 2008 to July 2009, Harris hip score was used to evaluate the functions of 71 patients undergoing single side total hip arthroplasty (including 47 males and 24 females with a mean age of 68.3 years, ranged from 48 to 75 years). The blood loss in the operation was analyzed to study the correlation between hidden blood loss and the functional rehabilitation. RESULTS: All 71 patients undergoing THA were involved in the result analysis. The mean total blood loss was 1473 ml and the hidden blood loss was 545 ml (37%). Hidden blood loss significantly correlated with functional rehabilitation (P = 0.001), but there were no correlations between functional rehabilitation and age, gender, operative limb of patients (P = 0.067, 0.527, 0.926, 0.072). CONCLUSION: Hidden blood loss maybe a useful prognostic information contributing to the functional rehabilitation of total hip arthroplasty. PMID- 21786547 TI - [Treatment of tibial nonunion with interlocking intramedullary nail and bone grafting in high-altitude: a report of 45 cases]. PMID- 21786548 TI - [Classification of pilon fractures by computed tomography and its guide to clinical treatment]. AB - OBJECTIVE: To introduce a method of three-column classifications for Pilon fractures and observe clinical utility on column fixation. METHODS: From June 2007 to March 2010,a total of 27 patients (29 ankles, 26 males and 1 female,ranging in age from 23 to 59 years, with an average of 33.1 years) with Pilon fractures were treated through column fixation by using semitubular plates or screws with anteromedial, anterior, posterolateral,posteromedial approach. And postoperative follow up were carried out. RESULTS: The mean follow up was 17.5 months(ranged,5 to 33 months). According to the Mazur ankle grading system, the outcome was excellent in 20, good in 4 and fair in 5 ankles. Patients in this group did not have complications of wound dehiscence, deep infection, osteomyelitis, nonunion, ankylosis, and joint instability. CONCLUSION: Based on the three-column classification, the clinical results for the treatment of Pilon fractures demonstrate the rationality and efficiency of this method. PMID- 21786549 TI - [Case-control study on combined therapy for preventing postsurgery stiffness after elbow fracture]. AB - OBJECTIVE: To research the efficacy,security and necessity of combined therapy for preventing postsurgery stiffness after elbow fracture. METHODS: From May 2009 to April 2010, 60 patients with elbow fractures treated by operation were randomly divided into two groups: combined therapy group and past procedure group. Thirty patients in the combined therapy group,including 12 males and 18 females, ranging in age from 23 to 63 years, averaged (43.53 +/- 7.74) years old; 15 patients had two parts fractures, including humeral intercondylar fractures combined with olecroanon and (or) ulna coronoid process fractures in 8 cases, fractures of exterior and interior humeral condyle combined with capitulum radius in 3 cases, fractures of olecroanon and ulna coronoid process in 3 cases, fractures of olecroanon and capitulum radius in 1 case; other 15 patients had one part fractures, including fractures of exterior or interior humeral condyle in 8 cases,fractures of olecroanon or ulna coronoid process in 6 cases, fractures of capitulum radius in 1 patient. Thirty patients in the past procedure group,including 11 males and 19 females, ranging in age from 24 to 67 years, averaged (46.13 +/- 6.22) years; 15 patients had two parts fractures, including fractures of humeral intercondylar fracture combined with olecroanon and(or) ulna coronoid process in 7 cases, fractures of exterior and interior humeral condyle combined with capitulum radius in 2 cases,fractures of olecroanon and ulna coronoid process in 5 cases,fractures of humeral intercondylar fracture combined with capitulum radius in 1 patient; 15 pa- tients had one part fracture, including fractures of exterior or interior humeral condyle in 6 cases, fractures of olecroanon or ulna coronoid process in 8 cases, fractures of capitulum radius in 1 patient; the patients in the past procedure group were treated with past procedure methods. Mayo Elbow Performance Score (including gmotion of elbow joint) and security (using X-ray to recheck displacement fracture, internal fixation failure and heterotopic ossification) were evaluated at postoperative 6 months. From 2002 to 2006, 30 patients were reviewed as historical control group, including 17 males and 13 females, ranging in age from 27 to 62 years, averaged (47.17 +/- 7.83) years; 15 patients had two parts fractures, including fractures of humeral intercondylar combined with olecroanon and(or) ulna coronoid process in 7 cases, fractures of exterior and interior humeral condyle combined with capitulum radius in 1 case, fractures of olecroanon and ulna coronoid process in 6 cases, fractures of ulna coronoid process and capitulum radius in 1 case; 15 patients had one part fractures,including fractures of exterior or interior humeral condyle in 9 cases, fractures of olecroanon or ulna coronoid process in 5 cases,fractures of capitulum radius in 1 case. The Mayo Elbow Performance Score of the patients in historical control group was evaluated retrospectively at postoperative 6 months and the results were compared with that of past procedure group. RESULTS: Mayo score of combined therapy group was (91.00 +/- 7.81)surpassed to (76.83 +/- 10.71) of the past procedure group and (73.17 +/- 1.99) of historical control group (F = 24.98, P < 0.05). The range of motion of elbow was (102.40 +/- 9.16) degrees of combined therapy group surpassed to (83.57 +/- 6.21) degrees of the past procedure group (t = 9.325, P < 0.05). There were no internal fixation loose,obvious fracture displacement and heterotopic ossification in each X-ray examination of patients in the combined therapy group. The Mayo score of historical control group was (73.17 +/- 11.99), showing no significant differences when compared with (76.83 +/- 10.71) of the past procedure group (LSD, P = 0.172). CONCLUSION: Combined therapy including different stage, different method combination and different subject to practice to prevent postsurgery stiffness after elbow fracture is effect, security and necessity. PMID- 21786550 TI - [Case-control study on two different methods in the treatment of Bennett fractures]. AB - OBJECTIVE: To compare the clinical outcomes between two different methods in the treatment of Bennett fractures. METHODS: From May 2005 to June 2009, 31 patients with Bennett fractures were treated with gypsum and percutaneous fragment pin fixation. In gypsum fixation group,there were 17 cases including 12 males and 5 females with an average age of (43.9-5.7) years; according to Buechler classification: 3 cases were I region fracture, 11 cases were II region fracture, 3 cases were III region fracture. In percutaneous fragment pin fixation group,there were 14 cases including 8 males and 6 females with an average age of (45.6 +/- 6.1) years; according to Buechler classification: 3 cases were I region fracture, 9 cases were II region fracture and 2 cases were II region fracture. The observing and comparing items of the two groups included: (1) length of stay, time of fracture healing,failure of fixation; (2) postoperative radiographs comparison according to method of Kjaer-Petersen; (3) cannon scores used for outcome measurement. RESULTS: All the patients in the two groups were followed up, the duration ranged from 6 to 15 months,with an average of (9.0 +/- 3.5) months. The length of stay were (7.0 +/- 2.5) d in gypsum fixation group and (9.0 +/- 3.9) d in percutaneous fragment pin fixation group with statistically significant differences (P < 0.05). The postoperative reduction quality according to method of Kjaer-Petersen, in gypsum fixation group:4 patients got an excellent result, 8 good and 5 poor; in percutaneous fragment pin fixation group,the above data were 8, 6 and 0 respectively;there were statistically significant differences (P < 0.05 ) between the two groups. The time of fracture healing were (6.0 +/- 0.5) weeks in gypsum fixation group and (6.0 +/- 1.9) weeks in percutaneous fragment pin fixation group with no statistically significant differences (P > 0.05). Cannon scores were evaluated at postoperative 3 months,in gypsum fixation group: 6 patients got an excellent result, 8 good and 3 fair; in percutaneous fragment pin fixation group,the above data were 8, 5 and 1 respectively; there were no statistically significant differences (P > 0.05) between two groups. Two patients had fracture re-displacement in gypsum fixation group, and no failure cases in percutaneous fragment pin fixation group. CONCLUSION: There are satisfied therapeutic effects in two different methods for the treatment of Bennett fractures. However, gypsum fixation has advantage of easy to operate and atraumatic, but unstability and easy to displacement; percutaneous fragment pin fixation has advantage of fixed solidly and better in functional rehabilitation, but big in surgical trauma and long in length of stay. PMID- 21786551 TI - [Treatment of adult early femur head necrosis with the tantalum screw]. AB - OBJECTIVE: To investigate a new method for the treatment adult early femur head necrosis in order to avoid further collapse and necrosis and improve the clinical symptoms. METHODS: From January 2009 to June 2010, 10 hips of 9 patients, including 7 males and 2 females, aged from 29 to 63 years old (averaged 44.1), with femur head necrosis were treated with implantation of the tantalum screw. The X-ray film, CT scan and MRI were performed before operation. According to Steinberg staging, stage I was in 1 case (1 hip), stage II a in 4 cases(5 hips), stage II b in 4 cases (4 hip). With the C-arm X-ray conducted guide, wire was drilled into the center of femur head necrosis regions from the greater trochanter bottom, hollow bodkin enlarged marrow along the guide wire, scraped necrosis sequestrum, transplanted bone if necessary,then implantated the appropriate tantalum screw to prop up the articular surface. The patients were followed up at 3rd, 6th, 9th month postoperatively, the clinical effects were evaluated according to the JOA criteria, and the changes of the femoral head were observed by X-rays. RESULTS: The mean operative time was 50 min (ranged from 40 to 60 min); the mean blood loss was 80 ml (ranged from 60 to 100 ml). There was no complications, such as postoperative infection, fracture, deep vein thrombosis and so on. All patients were followed up more than 9 months. No aggravation in collapse and necrosis were found by regular X-ray examination. Post-operative JOA score increased month by month. JOA scores increased obviously from preoperative (31.30 +/- 19.63) to (54.10 +/- 13.20), (69.90 +/- 15.04), (87.00 +/- 8.83) at the 3,6,9 months after operation, respectively. CONCLUSION: The tantalum screw implantation is simple and effective for the treatment of adult early femur head necrosis, and can effectively avoid collapse of necrotic area, the results were satisfactory in the near future. PMID- 21786552 TI - [Modified manipulative reduction and fixation for the treatment of ankle fractures accompanied by lateral dislocation of talus: a report of 38 cases]. PMID- 21786553 TI - [Case-control study on transverse carpal ligament resection for the prevention of delayed carpal tunnel syndrome after distal radius fracture]. AB - OBJECTIVE: To investigate the effects of open reduction by palm side for the distal radius fracture and T shape plate internal fixation with simultaneous anterior transverse carpal ligament resection for the prevention of delayed carpal tunnel syndrome after operation. METHODS: From March 2000 to March 2007, 32 patients (8 males and 24 females, ranging in age from 46 to 66 years) with distal radius fracture were treated with open reduction by palm side and T shape plate internal fixation with simultaneous anterior transverse carpal ligament resection; while 30 patients (7 males and 23 females,ranging in age from 45 to 65 years) only with open reduction by palm side and T shape plate internal fixation. The incidences of delayed carpal tunnel syndrome between the two groups were compared. RESULTS: Among 32 patients treated with open reduction by palm side and T shape plate internal fixation with anterior transverse carpal ligament resection, 3 patients had delayed carpal tunnel syndrome; while in 30 patients treated with open reduction by palm side and T shape plate internal fixation, 10 patients had delayed carpal tunnel syndrome. There was significant statistically difference (P < 0.05%). CONCLUSION: Simultaneous anterior transverse carpal ligament resection can effectively prevent the delayed carpal tunnel syndrome occurrence for the distal radius fracture with open reduction by palm side. PMID- 21786554 TI - [Treatment of primary frozen shoulder with manipulation under anesthesia combined with arthroscopy]. AB - OBJECTIVE: To study the feasibility and effectiveness of manipulation under anesthsia combined with arthroscopy for the treatment of primary frozen shoulder. METHODS: Thirty-four patients with primary frozen shoulder were treated from January 2006 to March 2009, including 20 males and 14 females with an average age of (56 +/- 3.6) years(ranged from 43 to 62 years). The course of the disease ranged from 9 to 13 months, with a mean time of 11.3 months. All the patient were treated with manipulation under anesthsia combined with arthroscopy. The synovitis of the biceps tendon and the rotator interval was thermo-coagulated, and limited synoviectomy was performed. Subacromial bursoscopy was applied to the patients after glenohumeral arthroscopy. Secondly radiofrequency electrode was used to coagulate bleeding and manipulative relax was performed. All the patients started active and passive postoperative rehabilitation from 1st day after treatment and were followed up for an average of 18.9 months (ranged from 13 to 32 months). The range of motion (ROM) of shoulder joint and feeling of pain calculated by Constant score system were compared before and after the operation. RESULTS: The post-operative feeling of pain according to Constant score system at 12 months after operation(total 15 points) was (13 +/- 1.58), which was different from that of pre-operative score of (5 +/- 2.60) (P < 0.01). As compared with pre operative conditions, the motion of shoulder revealed significant improvement at different postoperative stages (P < 0.05). The total post-operative score according to Constant score system at 12 months after operation was (86 +/- 11.20), which was higher than that of pre-operative score of (27 +/- 2.40) (P < 0.01). CONCLUSION: Manipulation under anesthsia combined with arthroscopy is an effective, optimal, minimal invasive management with high clinical value for primary frozen shoulder. PMID- 21786555 TI - [Study on early stage operation for Denis II sacral fracture accompanied by neurological damage]. AB - OBJECTIVE: To study therapeutic effects of early stage operation for type I sacral fracture accompanied by neurological damage. METHODS: Twelve patients with type II sacral fracture accompanied by neurological damage were reviewed in the study from March 2008 to March 2010, including 8 males and 4 females. Final diagnosis was given according to the evaluation of physical examination, X-ray, CT and MRI. Operations were performed 6 to 14 days after injury, averaged 9 days. According to Denis classification of sacral fracture, 12 patients were Type H . Eight patients suffered from severe anterior sacral foramen transformation with invasion of fragments on nerve root were treated with decompression, open reduction and internal fixation. Other 4 patients were treated with open reduction and internal fixation. RESULTS: During the following-up period, ranging from 6 to 24 months, all the patients attained bony union and 11 patients got nerve function recovery to different degrees. According to criterion of Gibbons, the average preoperative score was (1.50 +/- 0.67); the average postoperative score was(2.67 +/- 0.49); there were statistically significant differences in the above index between preoperation and postoperation (P < 0.05). CONCLUSION: Early stage operation for type II sacral fracture accompanied by neurological damage usually achieves satisfactory results. PMID- 21786556 TI - [CT and MRI in diagnosis of avascular necrosis of the vertebral body]. AB - OBJECTIVE: To evaluate the value of CT and MRI in the diagnosis of avascular necrosis of the vertebral body (ANV). METHODS: Twelve ANV patients were retrospectively analysed by their medical history, clinic manifestation, CT and MRI. Twelve AVN patients were treated with percutaneous vertebroplasty (PVP). The pain level of each patient was assessed, both before and after the procedure, using a visual analogue scale (VAS). RESULTS: All the patients had ANV in the thoracolumbar spine. The intravertebral vaccum phenomenon (VP), with gas or fluid like collection, was seen on computed tomographic (CT) images and magnetic resonance images (MRI). In the early stages, the VP zone was characterized by fluid-like collection, and was low intensity on T1, high intensity on T2. In the latter stages, the margin of VP zone had sclerotic change on CT scan. VAS score decreased from preoperative (9.08 +/- 0.76) to (2.33 +/- 1.43) at 3 days after PVP. CONCLUSION: ANV must be considered as a possible diagnosis of VP secondary to osteoporotic vertebral fractures. Both CT and MRI could provide reliable diagnostic proof for ANV. PVP is proved to be an effective and safe procedure for the treatment of ANV, and could provid quick pain relief. PMID- 21786557 TI - [Meta-analysis of studies on mortality of early surgery vs. delayed surgery for patients with femoral neck fractures]. AB - OBJECTIVE: Current guidelines indicate that surgery for femoral neck fracture should be performed within 24 hours. But the effect of early surgery on mortality was not consistent with each other. This study is to explore the effect of early surgery on the risk of death among elderly patients with femoral neck fracture. METHODS: By searching Medline, PubMed, CENTRAL (the Cochrane central register of controlled trials), CBM, CNKI and VIP et al, published documents about studies of early surgery VS delayed surgery on mortality for femoral neck fractures were collected. The data were analysised by using statistic software Stata 11.0. Random or fixed effect models were applied to conduct meta analysis on the study results, the combined relative risk (RR) and the 95% confidence interval (CI) were calculated as well. RESULTS: Six cohort studies and 8 430 patients were included in the combined analysis,which indicated that 64% death risk was observed in the early surgery group compared to the delayed surgery group (RR = 0.64, 95% CI: 0.55-0.73, P = 0.000). The death was divided into two subgroups: one was early death with 30 days and the other was late death after 6 months. For the early death, there was no statistic significance between early surgery and delayed surgery (RR = 0.93, 95% CI: 0.69-1.18, P = 0.076). And for the late death, only 59% death risk was observed in the early surgery group (RR = 0.59, 95% CI: 0.49-0.69, P = 0.000) compared to the delayed surgery group. CONCLUSION: Early surgery was associated with a lower risk of death for femoral neck fracture patients. PMID- 21786558 TI - [Kimura disease: a case report and review of relative literatures]. PMID- 21786559 TI - [Influence of the unevenness of articular surface on the osteochondral repair]. AB - OBJECTIVE: To investigate whether the unevenness of articular surface would affect the osteochondral repair. METHODS: Eight Shanghai Chongming 6-months-old masculine goats with a mean weight of 25 kg were used in this study. Different unevenness, which were 0.5 mm, 1.0 mm, 2.0 mm protrude or concavity, were created on the weight-bearing portion of the medial femoral condyles of the goats. The goats were sacrificed 12 weeks later and were observed with the general observation, HE staining and transmission electron microscope. To evaluate the microscopic morphology, a histological grading scale described by O'Driscoll, Keeley and Salter was used. RESULTS: The general observation and HE staining showed that the unevenness of 0.5 mm or 1.0 mm protrudes or concavity could be repaired to get the surface smooth on the whole. The transmission electron microscope showed that the reparative tissues were the same as the normal cartilage. The 2.0 mm depth couldn't be repaired satisfactorily. The transmission electron microscope showed that the fiber bundle proliferated and the chondrocytes degenerated. The scores of the 2.0 mm depth were significantly lower than that of the 0.5 mm or 1.0 mm (P < 0.05). CONCLUSION: The unevenness could have an influence on the repair. The limited unevenness could be repaired by itself. PMID- 21786560 TI - [P75 neurotrophin receptor mRNA sequential expression and significance after Cauda equina compression in rats]. AB - OBJECTIVE: To observe the mRNA expression of p75NTR (p75 neurotrophin receptor) and the amount of neuronal cells apoptosis in lumbar-sacral spinal cord at different time points after the acute cauda equina compression in rats and to explore their correlation. METHODS: Sixty adult female Sprague Dawley(SD) rats were randomly divided into the normal control group and the compression groups. The acute cauda equine compression model was established as placing a silicon gel rubber at L(3,4) level of the vertebral canal which represented about 70% to 80% compression to the cross section. The whole L(1,2) level of spinal cords were harvested at 1, 3, 5, 7, 14, 28 d after operation in compression group. Tunel method was applied to observe cell apoptosis and RT-PCR was used to detect the p75NTR mRNA expression. SPSS 13.0 statistical software was adopted to help analysis. RESULTS: In the compression group, both the nerve cells apoptosis and the p75 mRNA expression existed the trend of low-high-low synchronally compared with the control group, there was a significant difference (P < 0.05) among comprssion groups at different time points,there was a significant difference in changes (P < 0.05). p75NTR of mRNA expression and lumbosacral nerve cells apoptosis was in a positive correlation. CONCLUSION: After acute cauda equina compression, p75NTR mRNA expression is closely related to the neuronal apoptosis, which plays an important role in the molecular mechanism of the CES. PMID- 21786561 TI - [The first exploration of a minimally invasive lysis subcutaneouly for the treatment of gluteal muscle contracture based on relatively safe region around standard injection point of gluteal muscle]. AB - OBJECTIVE: To explore the solution of choosing the minimally invasive incision site for gluteal muscle contracture patient based on standard injection point of gluteal muscle. METHODS: from September 2008 to August 2010, 25 patients (14 males and 11 females with an average of 16.5 years, ranging from 12 to 26 years) with injected gluteal muscle contracture were prospectively studied. The course of disease was from 6 to 12 years. Firstly, the connective skin Surface line from anterior superior iliac spine to coccyx (line AD) was delineated and the point (point O) was marked out as the standard gluteal muscle injection site which was on the one-third of the distance from the anterior superior iliac spine(point A) to the coccyx (point D). Secondly, the anterior and posterior edge lines of surface projection of the gluteal muscle contracture banding (line a, line p) were delineated. Thirdly, the distance from B to O and C to O (B is the point of intersection of line a and line AD,C is the point of intersection of line P and line AD)were measured which was the intersection of line a,p and line AD to point O. Lastly, the minimally invasive surgery was operformed via the skin entry of point C. RESULTS: OB = (0 +/- 0.76) cm, OC = (2.86 +/- 0.78) cm, BC = (2.86 +/- 1.01) cm,the mean postoperative drainage was less than 10 ml,there was no nerve damage,hematoma and other complications. All patients achieved the function of squatting in 4 to 6 days. CONCLUSION: The solution of choosing the minimally invasive incision site based on standard injection point of gluteal muscle has advantages of positioning precisely,handling easily, recoverying quickly, less trauma and safety, etc. PMID- 21786562 TI - [Research on the osteogenic ability of 3-Ds interconnected porous titanium]. AB - OBJECTIVE: To evaluate the osteogenic ability of the three-dimensional interconnected porous titanium(TDIPT) coated with bonelike apatite, by the test of the culture of osteoblast in vitro. METHODS: The pure TDIPT was prepared by the high temperature insostatic pressing (HIP) and was divided into two groups. One group of TDIPT was dipped into the 1.5 simulated body fluid (1.5 SBF) and developed the TDIPT coated with bone-like apatite (The test group). Another group was control group (pure TDIPT). The porous titanium of the two groups were all made into standard parts (5 mm x 5 mm x 4 mm) and placed into the 24-hole plates. The osteoblasts were extracted from SD rat. After the primary culture and subculture of the osteoblast in vitro, the osteoblasts were inoculated into the samples in the 24-pole plate and cultured continually. MTT Cell Proliferation Assay was done on the 1st, 3rd, 5th, 7th and 9th day respectively after inoculating. The ALP activity was tested on the 7th, 14th and 21st day, respectively. The collected data were analyzed by use of the student t test. RESULTS: The MTT value and the ALP activity increased with the increasing of the culture time in the two group, but those of the test group was more significant than those of the control group (P < 0.05). Moreover, the osteoblast tachyauxesis and stable adhesion were observed in test group by SEM at the 7th day after culturing. CONCLUSION: The bioactivity of the TDIPT improves significantly after coating with the bone-like apatite onto the surface of the TDIPT. PMID- 21786563 TI - [Treatment of ulna olecranon fractures with coarse silk suture for the fixation of triceps aponeurosis: a report of 28 cases]. PMID- 21786564 TI - [Value of spiral CT examination for diagnosis of occult fracture of ankle and foot]. AB - OBJECTIVE: To investigate the value of spiral CT examination for diagnosis occult fracture of the patients with negative result of X-ray examination and with high suspicion of fractures,so as to reduce misdiagnosis. METHODS: From January 2007 to June 2010, 31 patients with ankle trauma performed spiral CT examination, including 18 males and 13 females, ranging in age from 21 to 67 years, with a mean of 35 years. The main symptoms of the patients included ankle pain, local swelling, obvious tenderness and activity limitation. All the patients had negative results of X-ray examination. RESULTS: The spiral CT examination revealed 11 patients with fractures, involving a total of 17 points. Single fracture were found in 6 cases,and multiple fractures were found in 5 cases. Among single fractures, the lateral malleolus fracture was found in 1 case, talus fracture was found in 1 case, scaphoid fracture was found in 1 case, the fracture of the base of 5th metatarsal base was found in 1 case and calcaneal fractures were found in 2 cases. Within multiple fractures,internal and lateral malleolus fracture were found in 1 case; medial malleolus, calcaneus and talus fractures were found in 1 case; talus and scaphoid fractures were found in 1 case; the fractures of 1st and 2nd cuneiform bone were found in 1 case; the 2nd and 3rd metatarsal base fracture was found in 1 case. CONCLUSION: For the patients with negative X-ray examination and high suspicion of fractures,the spiral CT examination is needed, which could significantly improve the detection rate of occult fractures, and provide imaging basis for clinical treatment and judicial identify. PMID- 21786565 TI - [Treatment of calcaneal avulsion fractures with twinfix suture anchors fixation]. AB - OBJECTIVE: For the calcaneal avulsion fracture, the current method is more commonly used screws or Kirschner wire to fix fracture fragment. This article intended to explore the feasibility and clinical efficacy for the treatment of avulsion fractures with TwinFix suture anchors. METHODS: From July 2007 to November 2010, 21 patients were reviewed, including 15 males and 6 females, ranging in age from 49 to 65 years,with a mean of 58.7 years. Twelve patients had nodules in the right heel and 9 patients had nodules in the left heel. All the patients had closed fractures. The typical preoperative symptoms of the patients included pain in the upper heel and weak in heel lift. Body examination results: palpable sense of bone rubbing in the back of the heel, and swelling in the heel. Surgery treatment with TwinFix suture anchors performed as follows : to fix TwinFix suture anchors into the calcaneal body, then to drill the fracture block, to make the double strand suture through the fracture holes, to knot the suture eachother to fix the block, and to use stitch to fix the remaining suture in the Achilles tendon in order to improve the block fixation. The criteria of the AOFAS Foot and Ankle Surgery by the United States Association of ankle-rear foot functional recovery was used to evaluate the Achilles tendon. RESULTS: Total average score was (95.5 +/- 3.12) points, including pain items of(38.5 +/- 2.18) points,the average score of functional items of (49.5 +/- 3.09) points,and power lines of 10 points in all patients. Twenty-one patients got an excellent result, 16 good and 5 poor. CONCLUSION: The methods of treatment for the calcaneal avulsion fractures with TwinFix suture anchors is a simple operation, and have excellent clinical effect, which is worthy of promotion. PMID- 21786566 TI - [Simple posterior dislocation of ankle joint: a report of 1 case]. PMID- 21786567 TI - [Biomechanical study on the posterior screw fixation in the lower cervical spine]. AB - So far, the fixation in the lower cervical spine through posterior approach technology has commonly been used, besides the lateral screw and pedicle screw techniques, transarticular screw and laminar screw techniques have being paid more attention recently. This article introduced four screw fixation ways in the lower cervical spine through posterior approach and reviewed the recent biomechanics studies of four screw fixation techniques. The biomechanics study includes stabilization, pollout strength, insertion technique, and screw characteristic and so on. Lateral screw and pedicle screw techniques have become an effective internal fixation way for the lower cervical spine instability because of their superior stabilization and higher pollout strength. Transarticular screw fixation has become a new way to fix the lower cervical spine through posterior approach, which has widely surgical indications. Besides, this technique is relatively safe, simple and has achieved favorable curative effect in clinic. Laminar screw fixation technique is rarely used in clinic, but the study of anatomy and biomechanics confirmed that this technique can be applied as a salvage technique in clinic. Above four techniques of the screw fixation in the lower cervical spine through posterior approach have advantages and disadvantages, respectively, and the application in clinic is different. Through the biomechanics study of these techniques will contribute to the development of the techniques of the screw fixation in the lower cervical spine through posterior approach and guide the clinical work effectively. PMID- 21786568 TI - [Hyperuricemia as a component of cardiorenal syndrome]. AB - The role of hyperuricemia as a cardiovascular and renal risk factor and approaches to its correction are discussed. PMID- 21786569 TI - [The level of endothelin-1 and reactivity of skin microvessels in patients with early stages of chronic kidney disease]. AB - AIM: To evaluate endothelin-1 (ET-1) levels and to characterize reflex vasomotor reactions of skin vessels in distant exposure to cold in patients with chronic kidney disease (CKD) of stage I and II. MATERIAL AND METHODS: Glomerular filtration rate (GFR) was calculated by MDRD formula for 40 healthy subjects (mean age 39.2 +/- 2.0 years) and 147 CKD patients (mean age 41.4 +/- 1.8 years). All the patients were also exposed to the cold test (a modified variant). RESULTS: Patients with CKD stage I demonstrated a 35.1% fall in blood flow rate (Qas) in response to cold stimulus, patients of stage II--a 42.2% fall, healthy patients--a 19.3%. CKD patients of stage I and II retained a Qas fall for 3 min after exposure to cold, while healthy subjects resumed skin blood circulation immediately after exposure to cold. Blood plasma ET-1 concentration in healthy subjects was 0.239 +/- 0.055 fmol/ml, in stage I CKD patients--0.334 +/- 0.066 fmol/l, in stage II CKD patients--0.422 +/- 0.041 fmol/l. Relationships were found between ET-1 level and GFR (Rs = 0.242; p < 0.05), 24 h proteinuria (Rs = 0.375; p < 0.003) and Qas% in the cold test (Rs = -0.389; p < 0.003) as well as time of recovery of the background Qas (Rs = -0.311; p < 0.003). CONCLUSION: Dysfunction of autonomic nervous system at early stages of CKD may arise by means of activation of ET-1 synthesis in response to enhancement of sympathetic impacts. PMID- 21786570 TI - [Estimation of podocyte dysfunction by nephrinuria severity in proteinuric forms of chronic glomerulonephritis]. AB - AIM: To evaluate severity of nephrinuria (NU) as a marker of podocyte dysfunction (PD) in patients with proteinuric forms of chronic glomerulonephritis (CGN) and to specify efficacy of this test for assessment of activity and prognosis of CGN. MATERIAL AND METHODS: We examined 74 CGN patients: 18 with inactive nephritis (group 1), 18--with subnephrotic proteinuria (group 2), 38--with nephrotic syndrome--NS (group 3). The control group consisted of 10 healthy subjects. Urinary excretion of nephrin was studied with indirect enzyme immunoassay. A response to immunosuppressive treatment (IST) was studied in 23 NS patients depending on a baseline NU level. RESULTS: An NU level was higher in patients with proteinuric forms of CGN (groups 2 and 3) than in inactive disease and in healthy subjects, in NS patients significantly higher than in less severe proteinuria. NU was significantly higher in arterial hypertension, in persistent NS. Remission of NS was achieved within 6 months of treatment in 9 of 11 (82%) patients with a baseline NU level < 17 ng/ml. Eight from 12 (67%) patients with high NU did not respond to IST conducted for 9 months to 2 years. ROC-curve construction showed that NU assessment in NS patients has high informative value in assessment of prognosis and efficacy of treatment in 6 months to come. CONCLUSION: The NU test in CGN patients is an informative diagnostic test allowing prognosis of a response to IST and assessment of PD severity. PMID- 21786571 TI - [Determination of urinary markers of proteolysis/fibrinolysis and fibroangiogenesis in the kidney in hypertensive patients]. AB - AIM: To determine clinical significance of urinary biomarkers of proteolysis/fibrinolysis and fibroangiogenesis in essential hypertension (EH). MATERIAL AND METHODS: Examination of the kidneys was made in 71 patients with EH degree 1-3. Renal function was assessed by 24-h albuminuria, calculated glomerular filtration rate (GFR) by Cockroft-Golt. Early signs of renal damage were microalbuminuria--MAU (diurnal albuminuria 30-300 mg/day), reduction of GFR (< 90 ml/min/1.73 m2). EH patients with hypercreatininemia and GFR under 60 ml/min/1.73m2 corresponding to stage III of chronic kidney disease were not included in the study. An additional nephropathy marker was an elevated index of resistance of interlobular renal arteries (RI > 0.65) as shown by dopplerometry. ELISA examined urinary biomarkers of intercellular and cell-matrix interactions in the kidney in EHpatients and healthy controls (n = 12). RESULTS: MAU was detected in 54 (76%) of 71 EH patients, elevated RI > 0.65--in 37 (52%) patients. Urinary biomarkers of proteolysis/fibrinolysis and fibroangiogenesis were higher in EH patients then in the controls. Urinary excretion of PAI-1, TGF-beta1, VEGF and collagen of type IV in EH patients with MAU was significantly higher than in patients with normoalbuminuria. A strong direct correlation between MAU and the rest above urinary biomarkers was found as well as between urinary excretion of collagen IV and RI. An inverse negative relationship was seen between RI and GFR. CONCLUSION: Renal impairment in EHpatients is a progressive disorder. Each stage of this process has its own clinicodiagnostic markers. Urinary biomarkers ofproteolysis/fibrinolysis and fibroangiogenesis in the kidney are informative for monitoring of early HNP. PMID- 21786572 TI - [Association of gene TP53 polymorphic marker Pro72Arg with clinical characteristics of chronic glomerulonephritis]. AB - AIM: To study association of gene TP53 polymorphic marker Pro72Arg coding synthesis of p53 protein with onset, course and progress of chronic glomerulonephritis (CGN). MATERIAL AND METHODS: We examined 126 patients (63 males and 63 females, mean age 38.8 +/- 13.2 years) with CGN duration 13.0 +/- 9.1 years. When analyzing genetic predisposition to CGN, we compared incidence rate of alleles/genotypes of polymorphic marker Pro72Arg of gene TP53 in CGN patients and 69 controls free of renal disease. CGN clinical features were assessed retrospectively including analysis of nephritis onset, clinical and morphological variants. The course of CGN was analysed by changes in severity of hypertension, persistence of proteinuria > 3 g/day during 6 months and longer, conduction of immunosuppressive therapy and response to it. In analysis of progression rate, doubling of blood creatinine was considered as an end point. We used polymerase chain reaction with analysis of restriction fragment length for identification of alleles of Pro 72Arg polymorphic marker of TP53 gene. RESULTS: Distribution of the genotypes of the above polymorphic marker in CGN patients and in controls did not significantly differ. Depending on Pro allele carriage, CGN patients were divided into two groups: Arg/Arg group (59 carriers of genotype Arg/Arg) and Pro group (63 patients with genotype Arg/Pro and 4 with genotype Pro/Pro). Carriage of Pro allele of gene TP53 was associated with high CGN activity at onset, presence of arteriolosclerosis and IgA deposits in kidney biopsy. Patients with genotype Arg/Arg more frequently developed nephritic syndrome without renal dysfunction syndrome. CONCLUSION: We have discovered association of gene TP53 polymorphic marker Pro72Arg with clinical manifestations of CGN. Carriers of Pro allele more often have signs of active glomerular inflammation and vascular impairment with renal dysfunction while carriers of Arg/Arg genotype more frequently demonstrate isolated nephritic syndrome. PMID- 21786573 TI - [Cycloferon administration in chronic pyelonephritis: changes in interferon status]. AB - AIM: To detect correlations between changes in interferon (INF) system and a course of chronic pyelonephritis (CP), to ascertain a corrective effect of cyclopheron in combined treatment with antibacterial drugs. MATERIAL AND METHODS: We examined 30 CP patients in different periods of the disease: group 1 had latent CP without laboratory evidence for exacerbation, group 2 had CP exacerbation treated with antibiotics, group 3 had exacerbation given basic treatment and cyclopheron by a standard scheme. All the patients were examined for interferon status, patients of groups 2 and 3 were examined once more after therapy. RESULTS: Patients of all the groups showed diminished ability of blood leukocytes to produce IFN, especially IFN-gamma. Cyclopheron addition to antibacterial therapy significantly stimulated production of IFN alpha and gamma by blood cells compared to basic therapy. Examination of 5 patients after 1-year follow-up detected preserved ability of blood cells to produce IFN and reduce the number of exacerbations after combined treatment with cyclopheron. CONCLUSION: Administration of cyclopheron in combination with standard antibacterial treatment results in persistent correction of IFN status. PMID- 21786574 TI - [Comparative characteristics of hemostasis system in patients with endstage renal disease admitted for urgent and elective hemodialysis]. AB - AIM: To evaluate parameters of hemostasis system in patients with end-stage renal disease (ESRD) with consideration of elective or urgent start of dialysis treatment. MATERIAL AND METHODS: A total of 47 patients with ESRD entered the study. They were divided into two groups depending on urgent (group 1) or elective (group 2) start of hemodialysis. Group 1 consisted of 31 patients (13 female, 18 male) aged 18-86 years, group 2 - of 16 patients (9 female, 7 male) aged 36-79 years. The patients were comparable by ESRD causes. Clinical and laboratory findings were compared: activated partial thromboplastin time, prothrombin time, levels of fibrinogen, soluble complexes fibrin-monomers (SCFM). RESULTS: Azotemia, hyperkalemia and anemia were close to similar. Group 1 patients had more severe alterations of nutrition status and fat metabolism, marked hyperhydration and hypervolemia, arterial hypertension, more frequent neurological and infectious complications, symptoms of enteritis. Thrombotic complications developed in 51.5%, thromboses of the vascular access in 45% in group 1 vs group 2 which demonstrated only one type of thrombotic complications - thromboses of primary arteriovenous fistula (in 1 patient, 6.25%). Hemorrhagic complications were absent in group 2, in group 1 these developed 5 times less frequently than thromboses. Platelet count was significantly less (p = 0.001) in group 1 than in group 2. Hyperfibrinogenemia occurred in about 65% patients of group 1 and in 46% in group 2. SCFM levels were elevated in both groups, but in group 1 these levels were by 50% higher than in group 2 (p = 0.005). This evidences for stronger activation of intravascular coagulation in patients on urgent hemodialysis. CONCLUSION: ESRD patients admitted for urgent hemodialysis had more severe uremic syndrome with stronger activation of blood coagulation than patients admitted for elective hemodialysis. Frequency of thrombosis in patients admitted for urgent hemodialysis was 8.3 times higher than in patients admitted for elective hemodialysis. PMID- 21786575 TI - [Left ventricular hypertrophy in end-stage renal disease and its possible regression as a result of correction of anemia and arterial hypertension]. AB - AIM: To ascertain mechanisms of development of left ventricular hypertrophy (LVH) and possible cardioprotective action of anemia correction in patients with end stage renal disease. MATERIAL AND METHODS: A total of 98 patients (53 females and 45 males aged 49.4 +/- 14 years) on hemodialysis participated in the study. The patients were examined clinically with estimation of the levels of parathormone, calcium, phosphorus, erythrocytic indices, serum ferritin, blood transferrin. Echocardiography with dopplerography on Aloka-4000 unit were made. Left ventricular geometry was assessed by J. Gottdiener classification. Therapeutic policy aimed at correction of anemia, arterial hypertension, phosphorus-calcium metabolism. RESULTS: The patients were treated and followed up for 18 months. The examination was done before treatment, 12 and 18 months later. After the trial the patients were divided into 4 groups depending on the results obtained on LVH development. Blood pressure, hemoglobin, echocardiographic parameters changed according to the patient's group. After 18 months of observation and treatment with erythropoietin and iron preparations, ACE inhibitors, angiotensin II receptor blockers, beta-adrenoblockers, drugs regulating phosphorus-calcium metabolism some cases were seen of reduction of systolic blood pressure, achievement of target hemoglobin level, regression of LVH. CONCLUSION: Combined treatment of hemodialysis patients including antianemic, antihypertensive drugs promoted improvement of LVH or its regression in some cases. PMID- 21786576 TI - [The role of leptin, adiponectin and insulin-resistance markers in development of early stages of chronic kidney disease and atherosclerosis of carotid arteries in obese patients]. AB - AIM: To characterize clinicopathogenetically factors influencing development of early chronic kidney disease (CKD) and impairment of other target organs in obese patients. MATERIAL AND METHODS: The examination of 86 obese patients (64 males and 22 females, mean age 44 +/- 11 years) included standard clinical tests, test for albuminuria, calculation of glomerular filtration rate (GFR) by MDRD formula, ultrasound investigation of the carotid arteries to detect atherosclerotic lesion of the carotid arteries, assessment of insulin resistance - IR (plasma concentration of insulin before meal and blood C-peptide, HOMA-index), test for plasma adipokinins (leptin, adiponectin). RESULTS: Significant direct correlations were found between blood plasma leptin concentration, body mass index (BMI), plasma concentration of insulin and C-peptide, HOMA index, adiponectinemia and albuminuria. CKD patients have significantly higher than patients free of CKD levels of IR markers, waist circumference, BMI, leptinemia (38.2 +/- 28.8 and 21.6 +/- 19.8 ng/ml, respectively; p < 0.01). Obstructive sleep apnea syndrome was associated with higher IR and albuminuria, significantly lower estimated GFR (81 +/- 2 and 95 +/- 2 ml/min/1.73 m2, respectively; p < 0.05). Ultrasound evidence for atherosclerotic lesions of the carotid arteries was associated with a significant increase in blood plasma concentration of C peptide, reduction of adiponectinemia (14.9 +/- 10.8 and 32.5 +/- 22.5 mcg/ml; p < 0.01), a rise in proportion fasting insulinemia/adiponectinemia (1.6 +/- 1.2 and 0.6 +/- 0.8, respectively; p < 0.05) and reduction of estimated GFR (86 +/- 19 and 102 +/- 25 ml/min/1.73 m2, respectively; p = 0.001). CONCLUSION: In obesity, CKD at early stages develops in parallel with atherosclerotic lesion of the carotid arteries, which correlates with progression of leptinemia, IR and attenuation of organ-protecting properties of adiponectin. PMID- 21786577 TI - [Efficacy of levosimendan vs dopamine in patients with resistant cardiac failure]. AB - AIM: Effects of levosimendan treatment compared to dopamine treatment on a clinical course, central hemodynamics and prognosis in patients with resistant cardiac failure (RCF). MATERIAL AND METHODS: A total of 30 RCF patients (16 females and 14 males aged 50-80 years) were divided into two groups. Patients of group 1 received inotropic drug levosimendan intravenously in the initial dose 12 24 mcg/kgfor 10 min with subsequent 24-hour infusion in a dose 0.1 mcg/kg/min. Patients of group 2 received dopamine intravenously for 24 hours in a mean dose 2.2 mcg/kg/min. The patients were followed up for 6 months. RESULTS: In group 1 cardiac failure regressed earlier than in group 2. Left ventricular performance index after infusion hour 1 increased from 2.9 to 3.3 (kg.m)/m2, in group 2 it decreased from 2.6 to 2.3 (kg.m)/m2; p = 0.028). To infusion hour 24 this index in group 1 was 3.2 (kg.m)/m2, in group 2--2.6 (kg.m)/m2. Cardiac index (CI) in group 1 increased from 23 l/min/m2 at infusion min 1 to 2.7 l/min/ m2 after 10 min of infusion and 29 l/min/m2 after 24 hours, i.e. there was a 26% rise (p = 0.025). In group 2 the CI rise was insignificant--from 2.4 to 2.5 l/min/m2. To the end of levosimendan injection, systemic vascular resistance fell from 1520.9 to 1174.6 dyne.s.cm(-5) (p = 0.031), in group 2 no significant changes were seen. Hospital mortality in group 1 was 1 patient, in group 2--6 patients. CONCLUSION: Inotropic treatment in RCF patients with levosimendan vs dopamine produces earlier regress of cardiacfailure symptoms, better improvement of myocardial contractivity, is associated with a good prognosis. PMID- 21786578 TI - [Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage]. AB - AIM: To investigate frequency of carriage of genetic polymorphisms CYP2C9 and VKORC1 in patients with venous thromboembolic complications (VTEC) in Moscow population given warfarin treatment and effects of this carriage on stability of anticoagulation and frequency of hemorrhagic complications (HC) in warfarin treatment. MATERIAL AND METHODS: The study included 111 patients with the history of deep vein thrombosis and/ or pulmonary artery thromboembolism. All the patients received non-fractionated or low-molecular heparin for at least 5 days, then warfarin (target INR 2.0-3.0). Warfarin dose was selected empirically. Gene CYP2C9 and VKORC1 polymorphisms were studied. HC were endpoints. RESULTS: Genotype CYP2C9*1/*1 (a "wild" type) was detected in 94 (84.7%) patients. Of other genotypes - heterozygotes CYP2C9*1/*2 (4.5%) and CYP2C9*1/*3 (10.8%). Genotyping by VKORC1 detected genotype GG (a wild type) in 42.3%, genotype GA--in 48.6%, genotype AA--in 9.1% patients. A mean warfarin dose, supporting an adequaite INR, was asspciated with both genotype CYP2C9 and VKORC1. Warfarin doses were highest in carriers of wile genotypes CYP2C9 and VKORC1 (6,9 and 8,8 mg/day), the lowest--in patients with genotypes CYP2C9*1/*3 and VKORC1 (4,5 and 4,0 mg/day). The carriers of polymorphisms CYP2C9*1/*3 and VKORC1 showed less stable anticoagulation vs carriers of allele variants CYP2C9*1/*1, CYP2C9*1/*2 and genotypes GG, GA VKORC1. An HC rate depended, as a rule, on carriage of genotypes CYP2C9*1/*3 and AA VKORC1. The highest risk of HC was associated with genotype CYP2C9*1/*3. The results of multifactorial regression analysis also indicated that carriage of genotype CYP2C9*1/*3, a female gender and the range of INR in warfarin treatment > or = 2,66 are independent predictors of HC in VTEC patients on warfarin treatment. CONCLUSION: Carriage of gene CYP2C9 and VKORC1 polymorphisms affects suppoting dose of warfarin and rate of hemorrhage in patients with VTEC in Moscow population. Frequency of HC is the highest in carriers of genotypes CYP2C9*1/*3 and AA VKORC1, they need minimal supporting dose of warfarin. Carriage of genotype CYP2C9*1/*3 in line with a female gender and instability of INR is an independent predictor of HC in VTEC patients in Moscow population on warfarin treatment. PMID- 21786579 TI - [Obesity and chronic kidney disease]. AB - Obesity and overweight are now characterized as epidemics. It is shown that body overweight is associated with functional and structural changes in the kidneys. The results of epidemiological studies indicate that obesity can be the risk factor of chronic kidney disease (CKD) irrespective of the presence or absence of diabetes, arterial hypertension and other comorbidities. Manifestations of renal pathology in obese persons include microalbuminuria and proteinuria, hyperfiltration or impaired renal function. Glomerulomegaly and focal segmental glomerulosclerosis are the most typical structural signs of obesity-related nephropathy. More evidence is accumulated on the link between CKD in obesity and abnormalities in adypokine secretion (hyperleptinemia, lack of adiponectin), activation of rennin-angiotensin system, chronic inflammation, endothelial dysfunction, lipid accumulation, impaired renal hemodynamics and diminished nephron number related to body mass. A decrease of body weight following lifestyle modification or bariatric surgery leads to reduction in albuminuria and eliminates hyperfiltration in obese subjects. Thus, prevention and treatment of obesity may reduce CKD incidence in general population. PMID- 21786580 TI - [The role of D2 vitamin metabolite paricalcitol in nephroprotective strategy in chronic disease of the kidneys]. AB - Calcitriol is important in nephroprotective strategy in chronic disease of the kidneys (CDK). However, its long-term use often results in hypercalciemia with metastatic calcification. Compared to calcitriol, paricalcitol (zemplar)- metabolite of vitamin D2--leads to hypercalciemia less frequently, has a more potent nephroprotective effect and more rapidly decreases blood levels of parathyroid hormone. Paricalcitol in combination with lozartan has more pronounced nephroprotective effect. Morphological analysis detected inhibition of development of glomerulosclerosis and tubulointerstitial fibrosis. A cardioprotective effect of paricalcitol manifests with reduction of mortality from cardiovascular complications both at CDKpredialysis stage and in regular hemodialysis. PMID- 21786581 TI - [Bronchial asthma and gastroesophageal reflux disease: view of the clinician and pathophysiologist]. AB - Combination of bronchial asthma (BA) with gastroesophageal reflux disease (GRD) is now most prevalent among combined pathology of the respiratory and gastrointestinal tracts. Interaction of these diseases is stated basing on clinical picture and pathogenetic aspects of BA development in the presence of GRD and GRD in the presence of BA. Development of combined affection of gastrointestinal and respiratory tracts occurs in secondary immunodeficiency. Main lines of the paradigm of macrophage phenotypes M1/M2 and mechanisms of alternative development of the immune response Th1/Th2 in combination of GRD with BA are presented. Investigation of macrophage functional activity and Th1/ Th2 balance gives ground for development of the method of macrophage phenotype reprogramming which is a promising approach to effective treatment of combined pathology of the respiratory tract and upper gastrointestinal tract including cases resistant to pharmacological treatment. PMID- 21786582 TI - [A model of the human arterial system]. PMID- 21786583 TI - [An analyzer of kinematic parameters of human gait based on a laser distance meter]. PMID- 21786584 TI - [A robot manipulator for vascular surgery viewed from the perspective of the bioengineering system theory]. PMID- 21786585 TI - [Patient monitoring during mechanotherapy based on electrocutaneous impedance measurement]. PMID- 21786586 TI - [An experimental neural-network cardiac analyzer]. PMID- 21786587 TI - [Analysis of the measurement accuracy of devices used for calibration testing of blood pressure and pulse monitors]. PMID- 21786588 TI - [Assessment of RR-intervalogram instability]. PMID- 21786589 TI - [Contactless measurement of tolerant and intolerant intraocular pressure]. PMID- 21786590 TI - [Use of the orbita apparatus for correction of prolonged disorders of tissue perfusion]. PMID- 21786591 TI - [Emerging and reemerging infections of Northern Eurasia: global implications]. AB - This paper presents selected results of the studies on emerging and reemerging infections caried out in D I Ivanovsky Research Institute of Virology with special reference to comprehensive ecological, virological, and molecular-genetic analysis of the following viruses: California encephalaitis serocomplex, West Nile fever, highly virulent avian influenza A virus (H5N 1), and new pandemic influenza A vires (HIN1). Special attention is given to the role of emerging and reemerging infections at the territory of Northern Eurasia in national and world wide epidemiological cataclysms and their prognostication for minimizing their consequences based on monitoring pathogen evolution. PMID- 21786593 TI - [Genotypic structure of the genus influenza A virus]. AB - The modern classification of influenza A viruses (Orthomyxoviridae, Influenza A virus) at the subtype and genotype levels is presented. The former data on epidemic (pandemic), epizootic, and historical influenza A strains are revised in the context of the new nomenclature of whole-genome genotypes. PMID- 21786592 TI - [Taxonomic structure of Orthomyxoviridae: current views and immediate prospects]. AB - Analysis of taxonomic structure of Orthomyxoviridae was undertaken in view of its anticipated evolution. Four concepts of circulation of influenza A viruses in the biosphere are discussed, viz. anthrponose, zooanthroponose, metastrongilose, and protozoan. All of them may be considered in the framework of the general zooantroponose concept. Influenza B and C viruses can not be regarded as strictly anthroponose. Comparative molecular-genetic analysis of the genus Thogotovirus provides a basis for the designation of Thogoto and Batken-Dhori as independent geni. It is speculated that t he proof of transmission of Isaviruses by copepods Caligus elongates and Lepeophtheirus salmonis (Crustacea: Copepoda) may open up a new line of developments in arborvirology since crustacean vectors of viruses have never been described before. PMID- 21786594 TI - [Molecular diagnostics of influenza]. AB - The review is concerned with molecular diagnostic tools for influenza A viruses. Test systems based on PCR, real-time PCR, IEA, sequenation, and microchip-based methods are discussed as applied at this Institute for comprehensive monitoring influenza A viruses. PMID- 21786595 TI - [Etiotropic therapy of influenza: lessons from the last pandemic]. AB - Analysis of the experience gained during the last pandemic of 'swine' influenza A (H1N1) sw1 is presented with reference to clinical studies and etiotropic therapy. The mechanism of development of severe pneumonia as a result of mutations at the binding site of hemagglutinin receptor enhancing a2'-3' sialoside specificity and pneumotropism of the virus is described. The data on the efficiency of Ingavirin, a new Russian antiviral for the treatment of influenza, are reported. PMID- 21786597 TI - [Characteristic of the new Khatanga virus genotype]. AB - Complete nucleotide sequence of the S-segment and partial sequences of M- and L segments (981 and 1005 nucleotide respectively) have been determined in 20 strains of California encephalitis serocomplex, isolated in Yakitiya, Sakhalin, and Kamchatka. The phylogenetic analysis ofgenomic S-, M-, and L-segments showed that all 20 strains are related to Khatanga virus (La Cross subtype of California encephalitis serotype). Eight strains belong to group 2 of Khatanga virus while the remaining 12 make up a new (third) genetic group of this virus having original S- and M-segments and L-segment similar to that of the second group. PMID- 21786596 TI - [Arborviruses of the California encephalitis serogroup 1N Russia and their contribution to infectious pathology]. AB - This review focuses on arborviral infections associated with California serocomplex (Bunyaviridae, Orthobunyavirus). Results of relevant eco epidemiological and clinical studies in Russia are presented suggesting the ubiquitious nature of diseases caused by viruses of the California encephalitis serocomplex (Inko, Tahyna, Snowshoe Hare). The etiologic structure of these diseases in taiga and mixed woods of the European part and Western Siberia is dominated by the Inco virus and in southern regions by Tahina. The diseases have a well apparent seasonal pattern (July-August) in agreement with the peak summer activity of the pathogens. Two clinical forms of pathology are distinguished, influenza-like and generalized, the latter affecting lungs, kidneys, liver, and CNS. The Inco virus plays a key role in pathogenesis of the generalized form affecting CNS. PMID- 21786598 TI - [Recombinant monoclonal antibodies for the treatment and prevention of viral infections]. AB - Recombinant monoclonal antibodies (mAB) are a new class of medicinal preparations with the potential for wide application to the treatment of viral infections. Marked progress in the development of therapeutic mAB against respiratory syncytial influenza A viruses, West Nile virus, and some others has been achieved in recent years in contrast to HIV and hepatitis C pathogens. The main obstacle hampering this work is great heterogeneity and diversity of these viruses. Gene engineering technologies make it possible to modify mAB, modulate their efficacy, and create bi-specific mAB. This review presents data on the development and prospects for the application of mAB to prevent and treat viral infections. PMID- 21786599 TI - [Contribution of professor A. A. Baranov to the development of preventive pediatric medicine in Russia]. PMID- 21786600 TI - [Main trends in children's health dynamics in the Russian Federation. Search for problem solutions]. AB - Dynamics of main characteristics of children's health (morbidity, disablement and mortality rates) for the last 15 years is followed up. Results of analysis of official statistics and relevant scientific research are reported. The most important factors influencing children's health in the course of development are discussed. Medico-social implications of deterioration and stabilization of selected health indices are considered. Main strategies for the solution of current problems related to children's health protection, improvement and repair are outlined. PMID- 21786601 TI - [Medico-prophylactic foundations of the safety of information and communication technologies used in educational institutions]. AB - The problems pertaining to the safety of information and communication technologies used in the spheres of education and leisure activities of children and adolescents are discussed. The relevant risk factors are identified. Results of physiological and hygienic studies for substantiating regulations of continuous work with a personal computer are presented taking into account the children's age and hygienic requirements to electronic teaching aids. PMID- 21786602 TI - [Biological therapy in pediatric rheumatology]. AB - This article presents the unique experience of Research Centre of Children's Health in the treatment of 438 children with juvenile rheumatoid arthritis using biological preparations, viz. infliximab (270), adalimumab (55), ethanercept (25), rituximab (74), and tocilizumab (34). It is shown that differential biological therapy, unlike treatment with classical immunodepressants (methotrexate, cyclosporine, leflunomide, etc.), permits to achieve clinico laboratory remission in 70% and markedly decrease activity of the disease in 20% of the patients within 1 year after the onset. It is concluded that treatment with gene-engineered drugs improves the quality of life of the children and their families, normal growth and development of the patients and affects prognosis of this formerly incurable chronic autoimmune disease. PMID- 21786604 TI - [Neurorehabilitation in pediatrics]. AB - The main principles of long-term rehabilitation of children and adolescents with cerebral paralysis, related neurologic disorders, aftereffects of a neuroinfection, and some rare genetically determined diseases are the earliest possible initiation of remedial measures and the regular combined use of different forms of rehabilitative treatment. The proposed approach allowed to reduce severity of motor and speech disturbances and improve social and cognitive functions in 50.5% of the patients. Quality of life of the patients and their families also improved; healthy infants were born in 98 (19%) families. PMID- 21786603 TI - [Modern technologies for diagnostics and therapy of inflammatory intestinal diseases in children]. AB - The paper presents currently available scientific information on epidemiology of inflammatory intestinal diseases (IID), immunogenetics, pathogenesis and new methods for diagnostics of Crohn's disease and non-specific ulcerative colitis. Results of original studies on the prevalence of polymorphous variants of different genes responsible for the development of inflammatory processes in children with these pathologies are considered. Therapeutic modalities for children with IID are discussed. Treatment with infliximab resulted in clinical remission in 82% of the children with resistant forms of IID. PMID- 21786605 TI - [High-tech methods in pediatric surgery]. AB - Scientific and technical progress resulting in the introduction of high technologies in medicine radically changed the concept of surgical treatment of children. It is currently based on low-traumatic and minimally invasive methods for surgical intervention. High-tech surgical interventions implies the availability of modern sophisticated equipment and adequate anesthesiological support with comprehensive intraoperative monitoring all vitally important parameters. In the postoperative period, part of the patients need adequate (sometimes long-term) parenteral feeding with the application of long-term Broviak catheters and Space B-Braun systems. The use of this equipment in our Centre makes possible surgical treatment of children at a qualitatively new (low traumatic and minimally invasive) level and reduce the duration of surgery by 50% compared with traditional methods. PMID- 21786606 TI - [Hereditary thrombophilia in children: current views of etiology and pathogenesis]. AB - This review is focused on the role of genetic factors in etiology and pathogenesis of thrombophilia in adults and children. Their knowledge permits to elucidate the main causes of this pathology and choose adequate measures for its prevention. PMID- 21786607 TI - [Laboratory diagnosis of atherosclerotic plaque damage in patients with coronary heart disease: PAPP-A (a review of literature)]. AB - Vascular inflammation is a major pathogenetic factor for the progression of an atherosclerotic process and for the development of destructive plaque changes. Now an active search is under way for markers to diagnose acute coronary syndrome at the early stage of development. The paper discusses the role of markers of inflammation and endogenous destruction in the development of atherosclerotic plaque instability. Pregnancy-associated plasma protein A (PAPP-A) is its most promising marker. It may be used to stratify the risk of cardiovascular complications in coronary heart disease and to assess their prognosis. PMID- 21786608 TI - [Clinical and laboratory detection of phenotypic characteristics in patients with high hypertriglyceridemia]. AB - The purpose of the study was to define the values of clinical and biochemical (phenotypic) differences in 2 groups of patients: 1) those with moderate (< or =4.5 mmol/l) blood triglyceride (TG) levels and 2) those with high (more than 4.5 mmol/l) blood TG levels and to reveal significant parameters of a diagnostic algorithm for primary and secondary forms of hypertriglyceridemia (HTG). Ninety six (54%) patients females) with a TG level of more than 2.3 mmol/l were examined. The age was 12 to 71 years (median [quartiles] 50 years [41-61 years]); women accounted for 54%. The patients had the following diseases: coronary heart disease (CHD) (44.89%), myocardial infarction (13.5%), arterial hypertension (87.9%). The diagnosis of HTG included an algorithm for the clinical, biochemical, and clinicogenealogical examination of patients. Biochemical blood analysis involved lipoprotein parameters: cholesterol, triglycerides, low-density lipoprotein cholesterol, lipid electrophoresis, apolipoproteins Al, B-100, E, and C-III. The data were processed using the statistical packages STATISTICA 6.0 and SPSS 17.0. Comparison revealed no age- and gender-related differences in the parameters between Groups 1 and 2 There was a significant correlation between the high levels of TG and the following indicators: total cholesterol, chylomicrones, lipoprotein(a), LP-E , LP B:E, LP C-III4, and LP C-III, smoking (a risk factor) and with the indicators of other metabolic disturbances--total C, chylomicrones, lipoprotein(a), LP-E-total, LP B:E, LP-C3-total, and LP-C3, which determined the impact of nutrition had a hereditary predisposition through the polygenic mechanisms of gene expression under the influence of a number of factors. Pancreatitis was found to be implicated in the development of HTG. Higher TG levels correlated with the parameters, the diagnosis of which reveals additional metabolic disturbances via environmental and polygenic mechanisms PMID- 21786609 TI - [Current possibilities of cytological assay in the study of pleural and peritoneal exudates]. AB - Serous exudates were studied by immunoperoxidase and immunofluorescence immunocytochemical assays and by laser flow cytofluorimetry. The current high tech techniques detect sparse tumor complexes in the exudates at the early metastatic stages, which are undetectable by the routine cytological assay, and also reduce the hyperdiagnosis of the tumor process. The use of a set of immunocytochemical markers can specify the source of metastatic spread when the primary tumor focus is not found. Fluorescence immunocytochemistry of the exudates has been shown to be highly effective and rapid during emergency intraoperative studies to clarify the extent of the tumor process. PMID- 21786610 TI - [Capabilities of immunophenotyping of soft tissue sarcomas on cytosmears: results of examination of 57 tumors]. AB - Analysis of the results of examining 57 primary and metastatic soft tissues tumors has shown the principal capabilities of immunophenotyping in the cytosmears for differential diagnosis, the determination of histogenesis, and the assessment of their prolferative activity. Its major benefit is short response time and easiness to use. All results were assessed by comparison with the data of immunohistochemical study on paraffin sections. PMID- 21786611 TI - [Experimental quality assessment of APTT-control reagent kits in the study of plasma with varying Factor VIII activity]. AB - An investigation into activated partial thromboplastin time (APTT) in the plasma samples with varying Factor VIII activities has determined the following parameters of the quality of APTT-control reagent kits: coefficient of variation, linearity, sensitivity, and detection. The kit is shown to meet GOST P 51352-99 requirements. The determination of the validity coefficient of approximation has proven a directly proportional functional relationship of the APTT values to the Factor VIII activity in the bilogarithmic coordinate system. The kit may be used to diagnose hemophilia A and Willebrand disease. PMID- 21786612 TI - [Principles of the calculation of blood corpuscles in biological fluids, by using slide trays]. AB - Counting blood corpuscles in biological fluids, by using slide trays is a current, rapid, and convenient method. For their adequate calculation, it is necessary to know the volume of biological material under the chamber array of a slide tray, the total volume of the chamber in microl, and the degree of biological material concentration. When the Nechiporenko test reveals single urinary costs, it is recommended to count the latter in the whole chamber of a slide tray, followed by division of their count by the total volume of the chamber in microl. All required data must be given in an instruction for slide trays. PMID- 21786613 TI - [Current methods for serological diagnosis of syphilis]. AB - The paper gives information on novel diagnostic tests based on immunoblotting and immunochromatographic methods used to detect antibodies against Treponema pallidum. Whether these tests should be incorporated into an algorithm of the current serological diagnosis of syphilis is discussed. PMID- 21786614 TI - [An overview of methods for determining bilirubin in human blood and tissues]. AB - The paper gives a literature overview of biochemical methods for determining bilirubin and its fractions in human blood and other biological fluids and tissues. The methods using diazo reagents and reagents that oxidize bilirubin to beliverdin are considered. Reagent-free and transcutaneous methods for determination of bilirubin in neonatal infants are considered separately. PMID- 21786615 TI - [Practical recommendations for the use of coagulometers]. AB - The paper describes the basic stages of operation on APH2-02, APH2-02-P, and APH4 02-P coagulometers. The operating sequence is considered when carrying out the prothrombin test, the most common coagulology test in the laboratories of Russia. In addition, recommendations are given, which allow the most typical errors to be avoided. PMID- 21786616 TI - [Platelet melatonin levels in healthy donors]. AB - A convenient and reliable enzyme immunoassay of platelet melatonin has been developed using the Melatonin ELISA kits (IBL Hamburg GmBH). The proposed methods permit the quantitative determination of platelet melatonin, which opens up new prospects for using this indicator for diagnostic purposes. PMID- 21786617 TI - [Immunomodulators in therapy for chronic virus hepatitis C]. AB - The authors present the results of their investigations of clinical and immunological characteristics in chronic viral hepatitis C (CVHC). Cellular and humoral immunological parameters and cytokine profile, including the interferon status, were studied in relation to the activity of the process. Statistically significant clinical laboratory and immunological differences were found in patients (CVHC) receiving various treatment options. The clinical efficacy of immunomodulators of the groups of aminophthalhydrazides (galavit, tamerit) and muramyl peptides (glymuride) in the combination therapy of CVHC was evaluated. PMID- 21786618 TI - [GM1-dot-EIA for the detection of toxin-producing Vibrio cholerae strains]. AB - A new variant of enzyme immunoassay (EIA) has been developed on the basis of GM1 gangliosides to detect the toxin-producing Vibrio cholerae strains--GM1-dot-EIA. Experiments were run using a nitrocellulose membrane to bind GM1 gangliosides and polyclonal antitoxic serum to detect cholerogen. GM1-dot-EIA testing identified cholera toxin in 11 of 13 supernatants of V. cholerae eltor ctx(+) strains isolated from man and in 3 of 7 supernatants of V. cholerae eltor ctx(+) strains isolated from water. These data agree with those obtained in CM1-EIA. There was no reaction with the supernatants of other microorganisms. The sensitivity of the technique was 10 ng/ml. Thus, the simple and specific GM1-dot-EIA may be recommended to detect toxin-producing V cholerae strains isolated from man and water. PMID- 21786620 TI - [Introduction of quality systems into laboratory medicine: methodological aspects]. AB - The paper considers the problems of introducing the quality management systems (QMS) according to GOST R ISO 9001-2001 in the health care facilities of different forms of property and departmental subordination. It gives examples of successfully putting QMS into practice in the companies that manufacture products for laboratory diagnosis in accordance with the Russian and international standardization principles. Methods are presented for training the staff of the facilities in the QMS principles and making a dialogue between laboratories and customers. PMID- 21786619 TI - [Laboratory tests in the diagnosis of feral herd infections]. AB - Immunological laboratory tests play an important role in establishing the depth of extent of this or that infectious disease. Scheduled immunological monitoring (serological screening) is made to find out whether there are antibodies (Abs) against the causative agents of individual feral herd infections. The immunological examination is aimed at detecting Abs against the pathogens of infectious diseases of bacterial (Ixodes tick-borne borrelioses, tularemia, leptospiroses, human granulocytic anaplasmosis), viral (hemorrhagic fever with renal syndrome, tick-borne viral encephalitis, West Nile fever), and rickettsial (Q-fever) etiologies. The performed serological screening could yield data on the practically widespread of hemorrhagic fever with renal syndrome in the Ulyanovsk Region and show high rates of Abs to Ixodes tick-borne borrelioses (5.75), coxiellosis (3.7%), and human granulocytic anaplasmosis (4.3%). PMID- 21786621 TI - [Monoclonal antibodies with high virus-neutralizing activity against pandemic influenza virus A/llV-Moscow/01/2009 (H1N1)swl]. AB - The authors have obtained a panel of 7 monoclonal antibodies (MAbs) against pandemic influenza virus A/IIV-Moscow/01/2009 (HIN1)swl isolated in Russia. One MAb is directed to a NP protein linear epitope and interacts with all the influenza A viruses under study. Six other MAbs are directed to H1 hemagglutinin conformation-dependent determinants and detect homologous virus in the hemagglutination-inhibition test, enzyme immunoassay, immunofluorescence and virus neutralization tests. MAbs differentiate pandemic influenza viruses A(H1N1)swl from seasonal influenza A(H1N1), A(H3N2), and B viruses. The high neutralizing activity of MAbs permits their use to study the fine antigen structure of influenza virus hemagglutinin and to differentiate the A(H1N1) pandemic influenza viruses and offers promise for obtaining humanized antibodies in order to make specific prevention and treatment of influenza. PMID- 21786623 TI - [Aprotinin-induced inhibition of pandemic influenza virus A(H1N1) reproduction]. AB - Infectivity of pandemic influenza virus A(H1N1) infectivity is shown to be activated through proteolytic cleavage of hemagglutinin HA0 --> HA1 + HA2 during virus propagation in the human intestinal cell line Caco-2 and chicken embryonated eggs. Injection of aprotinin, a natural serine protease inhibitor, into the liquid culture or allantoic cavity of chicken embryos inhibited the proteolysis of the viral HA0 and suppressed the proteolytic activation of the synthesized virus and its multicycle replication. These data allow aprotinin to be recommended as an antiviral drug for the treatment of swine influenza in humans. PMID- 21786622 TI - [Immunogenicity of inactivated subunit adsorbed monovalent vaccine against influenza A/California/7/2009 (H1N1) strain]. AB - The immunogenicity of Pandeflu subunit vaccine against influenza A/California/7/2009 (H1N1) was evaluated in 70 healthy volunteers aged 18 to 60 years. The vaccine was intramuscularly injected twice at an interval of 28 days. Each dose (0.5 ml) contains A(HIN1) influenza virus hemagglutinin (15 +/- 2.2 microg), aluminum hydroxide (Denmark) (0.475 +/- 0.075 microg), and the preservative thiomerosal (merthiolate) (50 +/- 7.5 microg). The level of antibodies was determined in the microneutralization assay. After administration of two doses of the vaccine at a 28-day interval, the geometric mean antibody titer (GMAT) reached 1:21.1 with a further increase to 1:30 (the baseline GMAT) was 1:6.1). The frequencies of seroconversion and seroprotection were 71.4 and 59.2%, respectively; the antibody increase factor was 4.92, which meets the CPMP criteria. The administration of the vaccine did not result in adverse reactions in the postvaccination period. PMID- 21786624 TI - [Restriction analysis of genome composition of live influenza vaccine]. AB - Live attenuated cold-adapted influenza vaccine (LIV) has been used in Russia for over 50 years and proved to be safe and effective. Currently, Russian reassortant LAIV is based on influenza AILeningrad/134/17/57 (H2N2) and B/USSR/60/69 Master Donor Viruses (MDVs) which are cold-adapted (ca), temperature-sensitive (ts), and attenuated (att), respectively. The MDVs are used to generate attenuated reassortant vaccine viruses containing the surface antigens of current wild type (wt) influenza A (HINI) and A (H3N2) viruses and wt influenza B virus. The ca/ts/att phenotype of these viruses limits replication in the upper respiratory tract. Reassortment typically yields numerous viruses with different genome constellations, rapid screening is needed to select proper vaccine viruses. In this study, screening of reassortant vaccine strains for live attenuated influenza vaccine generated from currently circulating influenza A and B viruses by RFLP assay is described. PMID- 21786625 TI - [Analysis of the prevalence of CCR5 coreceptor antagonist resistance mutations among HIV-1 variants in Russia]. AB - The authors studied the prevalence of mutations associated with resistance to the CCRS coreceptor antagonists maraviroc and vicriviroc in Russia. Most (93.6%) patients infected with HIV-1 genetic subtype A (IDU-A), predominant in the CIS countries, were found to have maraviroc resistance mutations. These mutations appear to reflect the natural genome polymorphism characteristic of the variant IDU-A. Maraviroc resistance mutations were of limited occurrence (2.8%) among the samples of virus subtype B in Russia. There were no vicriviroc resistance mutations in both the HIV-1 genetic variant IDU-A and the samples of virus subtype B. There is a need for further clinical studies evaluating the real impact of these mutations on the efficacy of maraviroc in patients infected with the HIV-1 genetic variant IDU-A. PMID- 21786626 TI - [Retherapy with lamivudine in hbeag-negative chronic hepatitis B patients unresponsive to interferon/peginterferon treatment]. AB - The paper gives data on retherapy with lamivudine in seven HBeAg-negative chronic hepatitis B patients previously unresponsive to interferon-alpha and peginterferon-alpha2b therapy (6 unresponsive patients and 1 with recurrence). Prior to lamivudine therapy, hepatic biopsy and HBV genotyping were carried out and the baseline level of viremia and the presence of YMDD mutations were determined in all the patients. Its therapeutic efficiency was based on viremia level and AIAT activity at 6, 12, 18, and 24 weeks of treatment. Six of the 7 patients, including 2 receiving peginterferon-a2a, achieved a virological response. Trends in viremia within the first 12 weeks of treatment were a major factor to assess the virological response. Positive predictors during retreatment with lamivudine are discussed. PMID- 21786627 TI - [Interaction of the Siberian and Far Eastern subtypes of tick-borne encephalitis virus in mammals with mixed infection. Competition of the subtypes in acute and inapparent infection]. AB - Long-term monitoring of natural tick-borne encephalitis virus (TBEV) populations could reveal the change of TBEV subtypes, the displacement of the Far Eastern (FE) subtype, and its substitution for the Siberian (Sib) subtype. Acute and inapparent mixed infections were studied in Syrian hamsters to understand this phenomenon. The animals were inoculated with the Sib subtype and then with the FE one of TBEV (JQ845440-YaroslavI-Aver-08 and Fj214132-Kemerovo-Phateev-1954 strains). The inapparent form developed more frequently in mixed infection. Viral progeny was genotyped by reverse transcription polymerase chain reaction and hybridization fluorescence detection using genotype-specific probes. Independent reproduction of strains in the brain gave way to competition. The FE subtype dominated in hamster youngsters with acute infection. The Sib subtype had selective benefits in asymptomatic infection (adult hamsters infected intracerebrally and subcutaneously and youngsters infected subcutaneously). The competition of the subtypes was imperfect. PMID- 21786628 TI - [Specific humoral immunity after single immunization with mumps vaccine: data of a 3-year follow-up]. AB - The level and spectrum of humoral specific immunity were studied in 60 volunteers immunized with Russian mumps vaccine. Specific IgG levels were measured by enzyme immunoassay (EIA) and neutralization test using the Leningrad-3 (L-3) mumps virus (MV) vaccine strain and 5 heterologous MV strains of various genotypes (A, B, C, D, and H). The maximum functional activity of antibodies was recorded at an average of 18 months postvaccination. Within 3 years after vaccination, starting at 6 months, specific IgG neutralized all 6 MV strains having varying activity in relation to the genotype. Neutralizing titers (NT) against the L-3 strain were 1.3-1.7-fold higher than those against heterologous MV strains throughout the follow-up. Despite a tendency towards lower specific IgG levels, within 3 years postvaccination, EIA IgG titers remained to be 2.5 -log, L-3 strain HT were -log, or more, and the titers against 5 heterologous MV strains were 2 -log2 or more in all the volunteers. PMID- 21786629 TI - [Analysis of the polymorphic variants of the PDE4D gene in patients with acute stroke in the Moldavian population]. AB - The risk of the ischemic stroke is mediated by both environmental and genetic factors. Recent studies of DeCode group identified the risk of polymorphisms for ischemic stroke in the phosphodiesterase 4D gene (PDE4D). The goal of this study was to explore the role of two variants of the gene encoding PDE4D [SNP41 (rs152312) and SNP87 (rs2910829)] in the Moldavian patients with ischemic stroke and in control. No significant association with ischemic stroke was observed with SNP41 and 87. PMID- 21786630 TI - [Genetic characterization of the Brucella melitensis isolates from Mongolia, Russia, and Azerbaijan]. AB - The goal of this work was to provide comparative genetic characterization of the human and animal Brucella melitensis isolates from Mongolia, Russia and Azerbaijan using current molecular-genetic typing methods. MATERIALS AND METHODS: Twenty eight Mongolian (n = 18), Russian (n = 6), and Azerbaijan (n = 4) human and animal Brucella melitensis isolates were studied using 2 molecular typing methods based on PCR for differential species and biovar specific ORF (open reading frames) molecular targets and MLVA (multiple locus variable number tandem repeats analysis) using primers to 12 known loci. RESULTS: The PCR was used for differential molecular targets (all B. melitensis isolates) were characterized as the B. melitensis biovar 2. The MLVA revealed 7 identical and 5 variable MLVA loci. All the isolates were classified into 25 genotypes using the dendrogram on the data of 12 loci and the cluster related to reference strain B. melitensis 63/9 biovar 2. The B. melitensis isolates having related MLVA genotypes were connected to Mongolian, Russian and Azerbaijan regions. The circulation for two B. melitensis isolates to not typical hosts as camel and yak was demonstrated using molecular typing methods. CONCLUSION: The genetic characterization of twenty eight B. melitensis isolates from different geographical regions in Mongolia, Russia, and Azerbaijan recognized genetic relationships. On the other hand, the MLVA has high discrimination power with a resulting Hunter and Gaston discriminatory index (HGDI) of 0.9841 revealing genetic diversity for the isolates forming of 25 MLVA genotypes. To improve the system of the brucellosis surveillance in Russia MLVA typing of B. melitensis isolates are necessary to investigate from the Siberian (Republics Tuva, Buryatia, and Irkutsk region) and South (Republics Dagestan, Kalmykia, and Stavropol region) Districts having frontier areas with Mongolia and Azerbaijan. PMID- 21786631 TI - [Genetic features of Borrelia miyamotoi transmitted by Ixodes persulcatus]. AB - The definition and molecular typing of Borrelia miyamotoi transmitted by the Ixodes persuccatus ticks was based on the partial sequencing of the 16S rRNA, p66, and glpQ genes. All the B. miyamotoi analyzed sequences of the 16S rRNA, glpQ, and p66 gene fragments from I. persulcatus were identical and had 99.9-100% similarity to corresponding genes of the B. miyamotoi strain FR64b isolated in Japan. The analyzed amino acid sequences revealed that the 66 protein B. miyamotoi in the site corresponding to the surface-exposed domain contained considerable difference from the Borrelia hermsii, the typical member tick-born relapsing fever, as from Borrelia lonestari transmitted by the Ixodes ticks. PMID- 21786632 TI - [Study of the heterogeneity of 16s rRNA gene and groESL operone in the dna samples of Anaplasma phagocytophilum, Ehrlichia muris, and "Candidatus Neoehrlichia mikurensis" determined in the Ixodes persulcatus ticks in the area of Urals, Siberia, and far east of Russia]. AB - A total of 3552 Ixodes persulcatus from Sverdlovsk, Chelyabinsk, Novosibirsk, Irkutsk regions and Khabarovsk Territory were examined on the Ehrlichia and Anaplasma presence by nested PCR based on the 16S rRNA gene. Both Anaplasma phagocytophilum and Ehrlichia muris DNA were found in I. persulcatus in all studied regions. A. Phagocytophilum was detected in 1.3-6.3% of ticks and E. muris - in 2.0-14.1% of ticks. Moreover, "Candidatus Neoehrlichia mikurensis" DNA was found in 8 ticks collected in Novosibirsk, Irkutsk Regions and Khabarovsk Territory. Partial nucleotide sequences of 16S rRNA gene and groESL operone (1240 1300 bp) were determined for 65 samples of A. Phagocytophilum, 17 samples of E. muris and 4 samples of "Candidatus Neoehrlichia mikurensis". Nucleotide sequences of 16S rRNA gene and groESL operone of E. muris and "Candidatus Neoehrlichia mikurensis" were shown to be highly conservative, and nucleotide sequences of groESL operone of both E. muris and "Candidatus Neoehrlichia mikurensis" differed from the sequences found previously in other species of Ixodid tick. On the basis of analysis of the 16S rRNA gene and groESL operone sequences it was concluded that all revealed samples A. Phagocytophilum could be divided into 2 groups. GroESL operone sequences of A. Phagocytophilum from the first group were identical to each other but significantly differed from the known groESL operone sequences (less than 98.2% of similarity), whereas their 16S rRNA gene sequences were identical to the sequence of widely distributed and pathogenic for human A. Phagocytophilum genetic variant (CAHU-HGEl, GenBank AF093788) or differed from it by a single nucleotide substitution. The nucleotide sequences of groESL operone of A. Phagocytophilum from the second group differed from each other by 1-4 nucleotides and were closely related (99.2-99.4% of similarity) to the sequences of groESL operone ofA. phagocytophilum isolates found in Europe in Ixodes ricinus and roe deer. The nucleotide sequences of the 16S rRNA gene of A. Phagocytophilum from the second group were most similar to the sequence of the rare A. Phagocytophilum genetic variant previously found only in China (GenBank DQ342324). PMID- 21786634 TI - [Fourth international school on molecular genetics for young scientists "GENOMICS and cell biology"]. PMID- 21786635 TI - [Conclusion of participants of Coordination Conference "Specifying national programs on liquidating diseases connected with exposure to asbestos-containing dust"]. PMID- 21786633 TI - [Comparison of protective properties of the smallpox DNA-vaccine based on the variola virus A30L gene and its variant with modified codon usage]. AB - Efficacy of candidate DNA-vaccines based on the variola virus natural gene A30L and artificial gene A30Lopt with modified codon usage, optimized for expression in mammalian cells, was tested. The groups of mice were intracutaneously immunized three times with three-week intervals with candidate DNA-vaccines: pcDNA_A30L or pcDNA_A30Lopt, and in three weeks after the last immunization all mice in the groups were intraperitoneally infected by the ectromelia virus K1 strain in 10 LD50 dose for the estimation of protection. It was shown that the DNA-vaccines based on natural gene A30L and codon-optimized gene A30Lopt elicited virus, thereby neutralizing the antibody response and protected mice from lethal intraperitoneal challenge with the ectromelia virus with lack of statistically significant difference. PMID- 21786636 TI - [Program on liquidating diseases connected with exposure to asbestos-containing dust, over 2011-2025 and for further period (Project)]. PMID- 21786637 TI - [Comparative analysis of mortality among population of industrial mono-cities in Sverdlovsky region]. AB - The article covers comparative analysis of mortality causes and levels, with special consideration of mortality with malignancies, among dwellers of Asbest (enterprise forming company town - Pulbic Corporation "Uralasbest" - world leader in extraction and concentration of chrysotile asbestos) and Kamensk-Uralsky (enterprises forming company town - non-ferrous metallurgy plants), agricultural agea and population of Sverdlovsk region over 10 years (1997-2006). Major attention was paid to influence of dust containing chrysotile asbestos fibers. PMID- 21786638 TI - [Evaluating death risk in cohort of workers with long length of service, engaged into extraction and concentration of chrysotile asbesto]. AB - The article covers data on evaluating mortality risk with all causes, separate disease classes and entities, with special consideration of malignancies varying in localization, when compared with reference regions, as well as in connection with age, dose, duration since first contact, smoking and presence of pulmonary X ray changes in members of cohort formed within Russian-American-Finnish project "Studies of work conditions and health state of workers engaged into asbestos deposits of Siberia (1995-1997). PMID- 21786639 TI - [Regulation and methodic background for safe controlled usage of chrysotile asbestos in Russia]. AB - The article covers main results of regulation and methodic background for safe controlled usage of chrysotile asbestos in Russia. The authors consider that now Russian Federation has contemporary regulation and methodic background aimed to safe, controlled and responsible usage of chrysotile asbestos. The background covers all stages of complete industrial cycle of chrysotile from its extraction to utilization. PMID- 21786640 TI - [The evolution of sleep circadian cycle and telencephalo-diencephalic interaction in vertebrates]. AB - The modem representations of wakefulness-sleep cycle evolution and the data about dynamics of reactivity of activating and inhibition neurotransmitter systems of the forebrain, converging in striatum, in cold- and warm-blooded vertebrates are considered. The data about dynamics of immune reactivity of vasopressin- and oxytocinergic cells of paraventricular and supraoptical hypothalamic nuclei is presented. On the basis of the obtained results, the idea of the leading role of telencephalo-diencephalic interactions in activation of somnogenic processes and their possible mechanisms is advanced. PMID- 21786641 TI - [Thermophysiology of the paradoxical sleep]. AB - Data on interactions between the paradoxical sleep (PS) and thermoregulation under thermo-comfortable and extreme conditions (in high and low temperatures, forced and spontaneous fasting, acclimation to cold and acclimation to natural winter conditions) are reviewed. The hypothesis of the PS role in synchronising and endogenous "kindling" of the visceral function ultradian rhythms is substantiated. Some new data are presented on entering torpor as a phenomenon of the "dramatic" neuronal plasticity. PMID- 21786643 TI - [Neurophysiological, neurochemical, autonomous and chronobiological basics of sleep medicine]. AB - The review discusses various mechanisms of the rapidly growing problem of Sleep Medicine. The "Sleep-wakefulness" cycle is a continuum of different functional states and the diseases that these states might prompt to manifest themselves in various ways. In these cases, we must say that change produces the conditions of disease manifestation rather than the disease itself. The paper describes the dynamics of the autonomous parameters during sleep, emphasizes the role and importance of chronobiological aspects of the "sleep-wakefulness" cycle. The holographic principle of the operation I sleep cycle is described which persists even in the cerebral stroke. From the standpoint of neurochemistry, modern hypnotics and drugs of the nearest future can be divided into 2 groups: proS (pro sleep)--for sleeping, and antiW (anti-wakefulness)--vs. wakefulness. PMID- 21786642 TI - [The sleep and the visceral function control]. AB - The review focuses on rapidly growing body of data indicating that disturbances of the natural sleep and sleep deprivation lead to various visceral disorders. The review mentions consequences of sleep disturbances on the gastro-intestinal system, cardio-vascular and respiratory, immune, endocrine and reproductive functions. In order to establish the functional link between the sleep and the visceral health it is proposed that during sleep the central nervous system including all cortical areas switches from the processing of the exteroceptive information to the processing of the interoceptive information. Review of the studies, which offer the direct confirmation of this hypothesis, is presented. PMID- 21786644 TI - [Changes of breathing during sleep in normal condition and in neurological alterations on different levels of respiratory regulation]. AB - Disturbances of the rhythm and depth of the respiratory movements during sleep are common phenomena among healthy individuals. These disturbances could manifest themselves as apnoea, hypopnoea or some pathological types of breathing not affecting human wellbeing and functioning. When the quantity of breathing disturbances exceeds the specified threshold the clinical syndromes of sleep disordered breathing appear, each of them having their own clinical features and ways of pathogenesis. 343 patients (162 males and 181 females) with different forms of neurological lesions which could affect respiratory regulation on cerebral, spinal, neural and muscular levels were studied. It was found that the most prominent sleep breathing disturbances develop with the damage on a central level of respiratory regulation. There was certain specificity in the occurrence of different types of disordered breathing depending on the level of impact. PMID- 21786646 TI - [Sleep and stress]. AB - Stress is one of the main factors influencing sleep. Sleep could be considered as the adaptive mechanism including the stress defence. In the article, changes of the human night structure under the influence of stress are discussed. Specific and unspecific reaction of sleep parameters reflecting stress influences of different modalities, the pole of personality factors, and the methods of increasing the adaptive forces of the human through sleep normalization are described. PMID- 21786645 TI - [Genetics of sleep]. AB - Main achievements in general and molecular genetics of sleep, especially NREM sleep, are regarded. Among them, discovery of such heredity disorders, as FFI, FASPS and DSPS, the finding of genetic hallmarks of sleep EEG, etc. PMID- 21786647 TI - [Early ontogenesis of fish and of commercial invertebrates as a problem of developmental biology]. PMID- 21786648 TI - [Dynamics of numbers of commercial fish in early ontogenesis in different areas of the Central-Eastern Atlantic]. AB - Changes in the quantitative composition of mass fish species at early stages of ontogenesis in different areas of the Central-Eastern Atlantic (CEA) in warm and cold seasons in 1994-2008 were analyzed in the paper. The most widespread representatives of ichthyocenosis of CEA were: European pilchard (Sardina pilchardus), common scad (Trachurus trachurus), round sardinella (Sardinella aurita), and West-African scad (Trachrus trecae). The data obtained indicate that, within the economic zone of Morocco, fluctuations of numbers at early stages of development in European pilchard and common scad are close over the entire water area under consideration (36 degrees-21 degrees N). The regularities of fluctuations of the numbers of ichthyoplankton are similar to the interannual changes in the biomass of fish in the area of Morocco. In the area of Mauritania (21 degrees-16 degrees N), fluctuations of numbers of the early stages of development of commercial fish cannot be unambiguously correlated with changes in the biomass of adult fish. It is known that, in the economic zone of Mauritania, there are Senegal-Mauritanian populations of round sardinella and West-African scad that inhabit waters of different states and are not completely assessed by our surveys. Therefore, no obvious relation was observed between the considered data. PMID- 21786649 TI - [Influence of development pace on pharyngeal teeth formula in Abramis brama (L.) bream: experimental data]. AB - An experiment on acceleration and retardation of ontogenesis with thyroid manipulation has revealed direct changes in definitive dentition of pharyngeal bones in Abramis brama bream. As development pace accelerates, the number of teeth reduces to the formula 5-4. When development pace slows down, this number increases to the formula 6-5. Moreover, an additional minor row of teeth (1.6 5.1, 2.6-5.2) is formed. The observed changes transcend typical changes happening in nature. It is assumed that heterochronies provoke changes in the number of teeth. PMID- 21786650 TI - [Influence of lecithotrofic feeding on growth and development of larvae of freshwater shrimp Macrobrachium rosenbergii]. AB - In the giant freshwater shrimp Macrobrachium rosenbergii (De Man), lecithotrofic feeding was discovered at the zoea I stage, and facultative lecithotrofic feeding was found at the zoea II stage. Cases of the completion of the first two stages without feeding were detected. However, a delay in feeding at the zoea II stage caused the inhibition of the growth and development of larvae. In this connection, we recommend to introduce food to the aquaculture of the giant freshwater shrimp on the end of the first day after hatching, when the first zoea II larvae emerge. PMID- 21786651 TI - [Reproductive potential of the Eastern Baltic cod Gadus morhua callarias L. population]. AB - Trends in interannual variation in maturation and spawning terms of various age cohorts in the Eastern Baltic cod population in 1997-2009 were studied. Specific features in the age structure of the mature population part that were established by the end of the first decade of the 21st century were clarified. The role of cod age cohorts in the current population reproduction was considered taking into account the data on cod recruitment and fecundity. PMID- 21786652 TI - [Spawning and early ontogenesis of the littoral polychaete Namanereis littoralis (Grube, 1876) (Nereididae, Namanereidinae)]. AB - For the first time, under laboratory conditions, development of the polychaete Namanereis littoralis (Grube, 1876) is investigated. Under conditions of the Sea of Japan, its reproduction occurs in July and is confined to the season of monsoon rains. Fertilization is external. Spawning manifests no epitocous transformations. Fecundity is low, ovicells are rich in yolk, and development is nonpelagic, lecithotrophic, embryonized, characterized by a high rate--5-8 days- and occurs in mucous clutches up to hatching of benthic juveniles. Temperature and salinity optima of development are 22-27 degrees C and 16-21 per thousand, respectively, characterizing the species as subtropical brackish-water by its origin. Archaic and specialized traits are noted in the early ontogenesis of N. littoralis. PMID- 21786653 TI - [Assessment of production of eggs of Eastern Baltic cod (Gadus morhua callarias L.) on the basis of long-term ichthyoplankton data]. AB - Proceeding from long-term data on the numbers of eggs of cod in ichthyoplankton, the total annual production of cod eggs at four main spawning grounds of the Baltic Sea was calculated. It was shown that the long-term fluctuations of cod egg production were positively related to the dynamics of the volume of waters coming to the Baltic Sea in years of the North Sea advections. It is suggested that this dependence was determined by a set of adaptations providing the extension of cod reproduction upon the improvement of the environment. PMID- 21786654 TI - [Functional development of chemosensory systems in the ontogeny of fish]. AB - Regularities of the functional development of chemosensory systems in the ontogeny of fish has been studied, i.e., the olfactory system, the taste system, and the common chemical sense. The olfactory system begins to function and provides response of juveniles to chemical signals before the taste system. Embryos that have hatched from coating but that do not yet feed exhibit nonspecialized motor responses to olfactory stimuli already. Immediately after the transition to exogenous nutrition, olfactory sensitivity to signals which elicit defensive and feeding behavioral responses begins to form and the ability to differentiate between similar odors develops. The reception of a limited number of taste stimuli occurs in the larvae during the transition to exogenous nutrition. With age, the spectrum of effective taste substances expands and the time spent on the definition of palatability by juvenile fishes reduces. Functional development of individual components of the taste system arises heterochronously, i.e., the outer (extraoral) form of taste reception arises earlier and more rapidly, and the buccal (intraoral) form of taste reception arises slower. No information is available about the functional development of the common chemical sense in the ontogeny of fish. It is assumed that the function of the chemosensory system arises in fish in early larval instar. PMID- 21786656 TI - [Ontogenetic causes and mechanisms for formation of differences in number of fish scales]. AB - Fish scale cover forms in late ontogenesis. Therefore, the conditions of development significantly affect its characteristics (number of scales). This study is aimed at considering the influence of external and internal factors on variation of the number of scales in fish. Acceleration of development results in decrease of the number of scales, while it increases with deceleration. Experiments on regulation of thyroid status of fish showed that the certain mechanism of alteration of the number of scales is related with heterochrony, such as a shift of the laying period of scale cover. Accelerated development is caused by early scale development at smaller body length, while decelerated development is characterized with later scale development and greater body length. Data considering heterochrony as the possible reason for deviations in the number of scales in related fish species are represented. Moreover, alterations of the distance between scales (morphogenetic calculation) can serve as another alteration mechanism of the number of scales in fish (especially phyletically far species). PMID- 21786655 TI - [Effect of hormonal compounds on embryogenesis of the pond snail Lymnaea stagnalis (L., 1758)]. AB - Effect of preparations ofa peptide nature (pituitrin and oxytocin) and of a steroid nature (progesterone and hydrocortisone) on embryonic development of freshwater gastropod Lymnaea stagnalis (Mollusca, Gastropoda, Pulmonata) is described. The hormonal preparations used, which differed in chemical nature and physiological activity, may render diverse effects on embryogenesis of the studied mollusk. Of neurohormones, pituitrin rendered the most noticeable and principally stimulating effect. Oxytocin was incorporated in regulatory processes much later and its effect on the rate of realization of particular stages depended more on the quality of occurring changes. In final stages of development, this hormone principally inhibited growth and development of embryos. The female sex hormone progesterone rendered an expressed stimulatory effect, especially notable in later developmental stages of embryos. The hormone hydrocortisone stimulated initial stages of embryogenesis. Its effect was almost not expressed in the final stages. The discovered differences seem to be related both to the functional specificity of the investigated compounds and to specific traits of mechanisms of realization of their effects. A hypothesis is formulated: in gastropods, similarly to vertebrates, the hormones are systemic embryonic and postnatal inducers of differentiation processes. PMID- 21786657 TI - [Effect of food availability in early ontogenesis on the rate of growth and numbers of bream Abramis brama L. (Cypriniformes, Cyprinidae) in Kursh Bay of the Baltic Sea]. AB - On the basis of studies of zooplankton and ichthyoplankton in the coastal zone of Kursh Bay of the Baltic Sea, zooplankton production accessible for juveniles of bream Abramis brama L. at early stages of ontogenesis, degree of removal of food resources, and food availability of juveniles of the bream that was reflected in the rate of growth were calculated. It is concluded that the removal of more than 60% of production of food zooplankton by bream juveniles leads to an increase of their mortality at early stages and a decrease in the rate of increase in the body weight. PMID- 21786658 TI - [Dynamics of glucocorticoids in the ontogenesis of freshwater crawfish Astacus leptodactylus Esch]. AB - Dynamics of changes in glucocorticoid (hydrocortisone and corticosterone) levels was studied in the ontogenesis of freshwater crawfish Astacus Leptodactylus Esch. It was shown that steroid concentrations increase during the embryogenesis period. Decrease in the glucocorticoid levels during postembryonic development is most probably related to the stabilization of young fish growth and the attainment of hormone levels typical for adult individuals. The correlation ofglucocorticoid levels with physiological-biochemical changes at different stages of ontogenesis indicates that these steroids play an essential role in the regulation of freshwater crawfish vital functions. PMID- 21786659 TI - [Adaptive specific features of energy metabolism in fish ontogenesis]. AB - A review of data on the pattern of change of the intensity of oxygen consumption during early ontogenesis of different fish species (rainbow trout, loach, zebrafish, carp, and grass carp) is provided. It has a similar pattern: this index increases in the period of embryonic and larval development and, after passing of larvae to an active feeding, it begins to gradually decline. This dynamics is determined by specific features of an increase in the rate of oxygen uptake and body weight in the course of early stages of fish ontogenesis. For determining optimal temperature conditions of development, a method of total (for a definite stage of development) oxygen uptake was suggested, which makes it possible to determine minimal energy expenditures necessary for the process of a particular stage of embryogenesis to take place. Analysis of temperature dependence of kinetic properties of enzymes with reference to the Michaelis constant (Km) for lactate dehydrogenase demonstrated that minimal Km, corresponding to maximal enzyme-substrate affinity, for embryos of different fish species differs in correspondence with differences in temperature conditions of development of these species in nature. For embryos of one species developing at changing temperature conditions (salmonids), this index changes in accordance with a temperature drift in nature. PMID- 21786660 TI - [Estimating survival of thrushes: modeling capture-recapture probabilities]. AB - The stochastic modeling technique serves as a way to correctly separate "return rate" of marked animals into survival rate (phi) and capture probability (p). The method can readily be used with the program MARK freely distributed through Internet (Cooch, White, 2009). Input data for the program consist of "capture histories" of marked animals--strings of units and zeros indicating presence or absence of the individual among captures (or sightings) along the set of consequent recapture occasions (e.g., years). Probability of any history is a product of binomial probabilities phi, p or their complements (1 - phi) and (1 - p) for each year of observation over the individual. Assigning certain values to parameters phi and p, one can predict the composition of all individual histories in the sample and assess the likelihood of the prediction. The survival parameters for different occasions and cohorts of individuals can be set either equal or different, as well as recapture parameters can be set in different ways. There is a possibility to constraint the parameters, according to the hypothesis being tested, in the form of a specific model. Within the specified constraints, the program searches for parameter values that describe the observed composition of histories with the maximum likelihood. It computes the parameter estimates along with confidence limits and the overall model likelihood. There is a set of tools for testing the model goodness-of-fit under assumption of equality of survival rates among individuals and independence of their fates. Other tools offer a proper selection among a possible variety of models, providing the best parity between details and precision in describing reality. The method was applied to 20-yr recapture and resighting data series on 4 thrush species (genera Turdus, Zoothera) breeding in the Yenisei River floodplain within the middle taiga subzone. The capture probabilities were quite independent of observational efforts fluctuations while differing significantly between the species and sexes. The estimates of adult survival rate, obtained for the Siberian migratory populations, were lower than those for sedentary populations from both the tropics and intermediate latitudes with marine climate (data by Ricklefs, 1997). Two factors, the average temperature influencing birds during their annual movements, and climatic seasonality (temperature difference between summer and winter) in the breeding area, fit the latitudinal pattern of survival most closely (R2 = 0.90). Final survival of migrants reflects an adaptive life history compromise for use of superabundant resources in breeding area at the cost of avoidance of severe winter conditions. PMID- 21786661 TI - [Monoxenous and heteroxenous parasites of fish manipulate behavior of their hosts in different ways]. AB - Adaptive host manipulation hypothesis is usually supported by case studies on trophically transmitted heteroxenous endoparasites. Trematodes and cestodes are among efficient manipulators of fish, their common intermediate hosts. In this review paper, new data on modifications of host fish behavior caused by monoxenous ectoparasitic crustaceans are provided together with a review of effects caused by heteroxenous parasites. Differences in modifications of host behavior caused by heteroxenous and monoxenous parasites are discussed. Manipulation by heteroxenous parasites enhances availability of infected fish to predators--definitive hosts of the parasites. Fine-tuned synchronization of modified anti-predator behavior with a certain phase of the trematode Diplostomum spathaceum development in the eyes of fish, their second intermediate host, was shown. Modifications of behavior are habitat specific. When juvenile salmonids are in the open water, parasites impair their cooperative anti-predator behavior; in territorial bottom-dwelling salmonids, individual defense behavior such as sheltering is the main target of manipulation. It was shown that monoxenous ectoparasitic crustaceans Argulus spp. decreased motor activity, aggressiveness and increased shoal cohesiveness of infected fish. Such a behavior facilitates host and mate searching in these parasites, which often change their hosts, especially during reproduction. Reviewed experimental data suggest that heteroxenous parasites manipulate their host mainly through impaired defense behavior, e.g. impairing shoaling in fish. Alternatively, monoxenous parasites facilitate shoaling that is profitable for both parasites and hosts. Coordination of modified host behavior with the parasite life cycle, both temporal and spatial, is the most convincing criterion of the adaptive value of host manipulation. PMID- 21786662 TI - [Episodic electric discharges in the course of social interactions: an example of Asian clariid catfish]. AB - Function of weak electric discharges is conclusively proved only for two fish orders - Mormyriformes and Gymnotiformes. Every specimen of the two groups emits electric discharges continuously or quite regularly for location, orientation and communication. The function of weak episodic electric discharges in other groups of weakly electric fish - Rajiformes, Uranoscopidae and Siluriformes, remains the puzzle since Darwin. Recent experiments made it possible to expand the list of weakly electric fish with episodic discharges. The range of behavioral situations accompanied with electric emission has been expanded as well. For instance, Asian catfish, Clarias macrocephalus, emit episodic discharges while in aggressive and spawning behavior. Asian catfish females emit the special burst of electrical discharges as a part of mating ritual. This burst cannot serve as an invitation to spawning or synchronization of reproductive products release, because females emit it after the sperm ejection. If females would need males' help for eggs release, it could be suggested that discharges assist in their mutual efforts. Since the electric field strength near fish is higher than fish's non-specialized electrical sensitivity thresholds, other hypotheses are possible. For example, it could be suggested that electric fields would make sperm or eggs more active. To proceed in our conception about episodic discharges function, new hardware and software are needed. PMID- 21786663 TI - [Nonlinear population dynamics: complication in the age structure influences transition-to-chaos scenarios]. AB - The work continues a series of studies on the evolution of a natural population of explicitly seasonal organisms. Model analyses have revealed relationships between the duration of ontogenesis and the pattern of temporal dynamics in size of an isolated population (i.e., the structure and dimensionality of the chaotic attractors). For nonlinear models of age-structured population dynamics (under long-lasting ontogenesis), increase in the reproductive potential is shown to result in the chaotic attractors whose structure and dimensionality changes in response to variations in the model parameters. When the ontogenesis becomes longer and more complicated, it does not, "on the average", augment the level of chaos in the attractors observed. There are wide enough regions in the space of the birth and death parameter values that provide for windows in the chaotic dynamics where the total or partial regularization occurs. PMID- 21786664 TI - [Genetic genealogy: history and methodology]. AB - The review surveys the development and the current state of genetic genealogy, a branch of science dealing with the history of individuals, families, and kins using molecular genetic methods. The main milestones in the development of genetic genealogy are established: the appearance of essential prerequisites (development of DNA genotyping and forensic techniques of evaluating biological kinship); the first publications on the topic in the late 1990s; the establishment of commercial companies, periodicals, and noncommercial organizations dealing with this subject. The theory and practical applications of dating individuals back to the most recent common ancestors on the basis of Y chromosomal amd mitochondrial DNA data are briefly considered. PMID- 21786665 TI - [Identification and molecular genetic characterization of the polytene chromosome interbands in Drosophila melanogaster]. AB - Being inserted into the polytene chromosome interbands, P transposable elements integrated in the genome of Drosophila produce new bands, enabling their use as markers of interband positions on the physical map. Molecular genetic analysis of 13 interbands marked as described showed that in most cases these regions were represented by intergenic spacers and by 5' noncoding regions of the genes. The interband regions consist of unique chromatin type whose decondensation is not obviously associated with transcription. In addition, interbands are enriched with the specific CHRIZ protein. Comparison of chromosomal protein sets and histone modifications in the polytene chromosome interband regions and in the corresponding sequences of the diploid cell chromosomes demonstrated their complete similarity relative these characteristics. In both cell types, interband regions contained open chromatin markers, including RNA polymerase II, ORC, GAF, TRX, and acetylated histones. At the same time, these regions appeared to be depleted of the repressed chromatin proteins, PC, E(Z), H3K9Me3, H3K27Me3, and some others. The similarity between interband chromosomal regions from different cell types is also manifested in the sets of DNAse I hypersensitive sites, which proved to be hot spots for transposon insertions. Our results suggest that band interband structure is a fundamental principle of the interphase chromosome organization. PMID- 21786666 TI - [Gene RAD31 is identical to gene MEC1 of yeast Saccharomyces cerevisiae]. AB - The earlier identified gene RAD31 was mapped on the right arm of chromosome II in the region of gene MEC1 localization. Epistatic analysis demonstrated that the rad31 mutation is an allele of the MEC1 gene, which allows further designation of the rad31 mutation as mec1-212. Mutation mec1-212, similar to deletion alleles of this gene, causes sensitivity to hydroxyurea, disturbs the check-point function, and suppresses UV-induced mutagenesis. However, this mutation significantly increases the frequency of spontaneous canavanine-resistance mutations induced by disturbances in correcting errors of DNA replication and repair, which distinguishes it from all identified alleles of gene MEC1. PMID- 21786667 TI - [Genetic differentiation in plants of the genus Cypripedium from Russia inferred from allozyme data]. AB - Ten gene loci of nine enzyme systems (PGI, 6-PGD, NADHD, SKDH, GDH, PGM, DIA, ADH, GOT-1, and GOT-2) were analyzed in Cypripedium calceolus, C. macranthon, C. shanxiense, and C. ventricosum plants from the south of the Russian Far East. Alleles of loci 6-PGD, NADHD, GDH, ADH, GOT-1, and PGIproved to be diagnostic for C. calceolus and C. macranthon. Plants of C. shanxiense from Primorye and Sakhalin Island were monomorphic at all of the loci examined, and their allelic structure can be regarded as diagnostic for the species. The allelic structure for fragments of the C. calceolus population from the western and eastern parts of the species range differed in two loci, PGl and SKDH: alleles absent in C. calceolus plants from the western part of the range occurred at a high frequency in the plants of this species from the eastern part of the range (28 and 55 plants or 41% and 68%, respectively). These alleles were found in C. shanxiense. The genetic structure of C. shanxiense was similar to that of C. calceolus from the eastern part of the range, i.e., the region when these species are sympartic. The additional alleles in C. calceolus from the eastern part of the range might have appeared as a result of hybridization with C. shanxiense. Our results indicate that C. calceolus plants occuring on the territory of Russia form two groups that represent two different units of genetic diversity preservation. We suggest that C. x ventricosum plants in southern Primorye were formed by hybridization between C. macranthon and C. calceolus x C. shanxiense hybrids. Thus, they differ from plants inhabiting the Urals and West Siberia, which originated by hybridization between C. macranthon and C. calceolus. The population of C. x ventricosum presumably also consists of two plant groups differing in genetic structure, which should be regarded as two different units of preservation of this taxon. PMID- 21786668 TI - [The role of chromosomes from homeologous group 5 in regulation of grain hardness and protein content in substitution lines of common wheat cultivar Saratovskaya 29]. AB - Genetic regulation of grain hardness and protein content in intervarietal substitution lines for chromosomes of homeologous group 5 was examined. Common wheat cultivar Saratovskaya 29 with high bread-backing properties served as the recipient. Donors of chromosomes 5A and 5D were 18 cultivars with variable traits examined, including high-protein cultivars (Atlas 66 and Diamant 2), and soft grain cultivars (Ul'yanovka and Chinese Spring). Analysis of substitution lines pointed to a substantial effect of chromosome 5D on the regulation of both traits. It was demonstrated that as a result of intervarietal substitution for chromosome 5D from donor cultivars Ul'yanovka and Chinese Spring, the endosperm softness was increased compared to the recipient cultivar Saratovskaya 29. Substitution lines Saratovskaya 29/Atlas 66 5D and Saratovskaya 29/Diamant 2 5D were characterized by high grain protein content, as well as by high endosperm softness. In addition, the line Saratovskaya 29/Novosibirskaya 67 5D, characterized by grain hardness higher than in Saratovskaya 29, was isolated. In the lines with intervarietal substitution of chromosome 5A, grain protein content was found to be lower than in recipient cultivar Saratovskaya 29. PMID- 21786669 TI - [Fruit set variation associated with apozygotic reproduction in sugar beet (Beta vulgaris l.)]. AB - Fruit set upon apozygotic reproduction was studied for four years in the msSOAN-5 pollen-sterile inbred sugar beet line. The progenies obtained from pollen-sterile plants by apozygotic reproduction had both fruits with normal seeds and parthenocarpic fruits without seeds, which was not an occasional event. Growth conditions proved to strongly affect the fruit set and seed quality. For instance, water deficiency during early plant development increased the proportion ofparthenocarpic seeds. Waiter deficiency combined with a lower temperature during flowering additionally caused a substantial decrease in the total number of fruits. Under the same growth conditions, related accessions did not differ in seed productivity, but varied in the proportion of normal (with seeds) and parthenocarpic (without seeds) fruits. PMID- 21786670 TI - [Polymorphism of microsatellite loci in cultivars and species of pear (Pyrus L.)]. AB - Using five SSR markers, polymorphism ofmicrosatellite loci was examined in 46 cultivars and five species of pear (Pyrus ussuriensis, P. bretscgneideri, P. pyraster, and P. elaegnifolia). Most of the accessions examined demonstrated the presence of unique allele sets. The degree of relationship between Russian and Western European pear cultivar was established. It was demonstrated that P. ussuriensis and its first generation progeny were genetically distant from typical cultivars of P. communis, as well as from the P. communis x P. ussuriensis hybrids of later generations. SSR estimates of the cultivar relatedness were shown to correlate with the corresponding pedigree-based estimates. A number of SSR alleles specific to P. ussuriensis were identified. Based on the analysis of microsatellite loci, the allelic composition was determined for each cultivar examined. These data can serve as a molecular certificate of the cultivar. PMID- 21786671 TI - [Associations between 60 SNPs identified by APEX microarray and growth rate, meatiness and selection index in boars]. AB - A total of 312 boars (201 Landrace and 111 Large White) were genotyped with a custom-made low throughput genotyping microarray (called SNiPORK) based on array primer extension (APEX) technology. The results were used to association studies between genotyped SNP markers and daily gains, meat content and selection index. Among the 60 SNP markers analyzed, 14 of them showed statistically significant associations between the genotype and the level of at least one trait. In order to find extremely beneficial or unfavorable intergenic diplotype combinations, 5 SNP markers were selected: CASTA499C, MYF6 T255C, PKLR C384T, SFRSI C1146T and TNNT3T 153C, which showed statistically significant associations at P or = 16 years old) with laboratory-confirmed CM from January - December 2007 at Hlabisa Hospital--a district hospital in northern KwaZulu-Natal. OUTCOME MEASURES: Inpatient mortality and associated risk factors were analysed. The proportion alive and on antiretroviral therapy (ART) at 2 years was determined by linkage to the HIV treatment programme. RESULTS: One hundred and four individuals were identified with laboratory diagnosis of CM; 74/104 (71.2%) with complete records were included in the analysis. Inpatient mortality was high (40.5%) and was significantly associated with reduced conscious level (aHR 3.09, 95% CI 1.30 - 7.33) and absence of headache (aHR 0.33 for headache, 95% CI 0.13 - 0.87). Only 8 individuals (10.8% of all study subjects) were alive and receiving ART 2 years after the CM episode. CONCLUSIONS: Long-term outcomes of CM are poor in routine practice. Interventions to strengthen linkage to HIV treatment and care and continuation of secondary fluconazole prophylaxis are critical. PMID- 21786730 TI - Loss to follow-up in a community clinic in South Africa--roles of gender, pregnancy and CD4 count. AB - BACKGROUND: Faith-based organisations have expanded antiretroviral therapy (ART) in community clinics across South Africa. Loss to follow-up (LTFU), however, limits the potential individual and population treatment benefits and optimal care. OBJECTIVE: To identify patient characteristics associated with LTFU 6 months after starting ART in a large community clinic. METHODS: Patients initiating ART between April 2004 and October 2006 in one South African Catholic Bishops' Conference HIV treatment clinic who had at least one follow-up visit were included and routinely monitored every 6 months after ART initiation. Standardised instruments were used to collect data. Rates of LTFU over time were estimated by the Kaplan-Meier method. The Cox proportional hazard regression examined the impact of age, baseline CD4 count, baseline HIV RNA, gender and pregnancy status on LTFU. RESULTS: Data from 925 patients (age >14 years, median age 36 years, 70% female, of whom 16% were pregnant) were included: 51 (6%) were lost to follow-up 6 months after ART initiation. Younger age (< or = 30 years) (hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.05 - 4.38) and pregnancy for women (HR 3.75, 95% CI 1.53 - 9.16) were significantly associated with higher LTFU rates. When stratified by baseline CD4 count, gender and pregnancy status, pregnant women with lower baseline CD4 counts (< or = 200 cells/microl) had 6.06 times the hazard (95% CI 2.20 - 16.71) of LTFU at 6 months compared with men. CONCLUSIONS: HIV-infected pregnant women initiating ART were significantly more likely to be lost to follow-up in a community clinic in South Africa. Urgent interventions to successfully retain pregnant women in care are needed. PMID- 21786731 TI - Provider-initiated HIV testing increases access of patients with HIV-associated tuberculosis to antiretroviral treatment. AB - BACKGROUND: Timely initiation of antiretroviral treatment (ART) is a critical component of the case management of patients with HIV-associated tuberculosis (TB) and advanced immunodeficiency. We sought to determine the impact of the introduction of provider-initiated HIV-testing in TB clinics in 2005 on subsequent referrals of patients with HIV-associated TB at a community-based ART service in Cape Town. METHODS: Retrospective analysis of an ART cohort database (2002 - 2008) stratified by calendar periods. RESULTS: Between 2002 and 2008, 3 770 ART-naive adults enrolled in the ART service. Overall, 27.4% of these patients had been referred from TB clinics with a diagnosis of HIV-associated TB. This proportion increased from 16.0% of referrals in the period 2002 - 2005 prior to the introduction of provider-initiated HIV testing, to 34.7% in 2007 - 2008 (p<0.001). The median duration of TB treatment completed prior to referral decreased from 3 months to 1 month (p<0.001) and patients enrolled with higher median CD4 cell counts (71 cells/microl v. 95 cells/microl; p<0.001). Moreover, the proportion with recurrent TB epiSodes decreased from 8.6% to 3.2% (p<0.001). CONCLUSIONS: Introduction of provider-initiated HIV testing by the TB control programme was temporally associated with a major increase in referrals of patients with HIV-associated TB to this ART service, a progressive decline in referral delay, improvements in baseline CD4 cell counts, and fewer recurrent TB episodes. Such trends are likely to be associated with improved survival, and these data strongly support this HIV-testing strategy. PMID- 21786732 TI - Outbreak of Rift Valley fever affecting veterinarians and farmers in South Africa, 2008. AB - BACKGROUND: During 2008, Rift Valley fever (RVF) virus re-emerged in South Africa as focal outbreaks in several provinces. AIMS: To investigate an outbreak affecting cattle farmers and farm workers, and the staff and students of a veterinary school, assess the prevalence of infection during the outbreak, document the clinical presentation of cases, and identify potential risk factors. METHODS: We conducted a cross-sectional serological survey of exposed veterinarians and farmers, who were examined to determine the presence of current or recent illness. Blood specimens were collected for virus isolation, nucleic acid detection and serology. A subset was interviewed using a standardised questionnaire to obtain data on recent exposures and risk factors for infection. RESULTS: Of 53 participants potentially exposed to infected domestic ruminants, 15% had evidence of recent infection and 4% evidence of past exposure to the RVF virus. The prevalence of acute infection was 21% in veterinarians compared with 9% in farmers and farm workers. After a mean incubation period of 4.3 days, the most frequent symptoms experienced included myalgia (100%), headache (88%) and malaise (75%). No asymptomatic cases were identified. Transmission, by direct contact with infected animals was the major risk factor in these professional groups. Performing animal autopsies was significantly associated with acute infection (risk ratio 16.3, 95% confidence interval 2.3 - 114.2). CONCLUSIONS: Increased risks associated with veterinary practices highlight a need for the use of personal protective equipment, and identify veterinarians as a primary target group for future vaccination. PMID- 21786733 TI - Prostate cancer among different racial groups in the Western Cape: presenting features and management. AB - OBJECTIVES: We aimed to compare the presenting features and management of prostate cancer among different racial groups. PATIENTS AND METHODS: We studied all patients diagnosed with prostate cancer at the Urological Oncology Clinic, Tygerberg Hospital, from January 1995 to December 2005. Most presented symptomatically as PSA screening is not readily available in the referral area of the hospital. Race was self-defined as white, coloured or black. Statistical analysis was performed using Student's t-test or Fisher's exact test, where appropriate. A two-tailed p-value <0.05 was accepted as statistically significant. RESULTS: There were 901 patients: 291 (32.3%) white, 539 (59.8%) coloured and 71 (7.9%) black. Mean age at presentation was significantly higher in the white than the coloured and black groups (69.7, 67.9 and 68.9 years, respectively). Grade 1 adenocarcinoma was most common in the white (37%) and coloured groups (38%), and grade 2 was most common in the black group (39%). There was a significantly lower percentage of patients with T3-4 disease at diagnosis in the white group (47%) than the coloured (61%) and black (62%) groups. Mean serum PSA at diagnosis was significantly higher in the black than the coloured and white groups (766.1,673.3 and 196.1 ng/ml, respectively). Potentially curative therapy (radical prostatectomy or radiotherapy) was chosen by 31% of white, 23% of coloured and only 12% of black patients. The mean duration of follow-up was significantly shorter in the black than in the white or coloured groups (24.0, 31.5 and 35.0 months, respectively). CONCLUSIONS: Black men presented with higher grade and stage disease and higher serum PSA, received potentially curative treatment less often, and had a shorter follow-up (probably owing to shorter survival) than the white and coloured groups. Greater prostate cancer awareness and education among patients and physicians and more widespread use of PSA screening of presymptomatic men at risk of prostate cancer is needed. PMID- 21786734 TI - [The challenge to the tobacco component of the Evin law is rejected]. PMID- 21786735 TI - [Emergency departments: do they have any future in West Africa? Example of the Principal Hospital of Dakar]. AB - The principal hospital of Dakar is a military institution whose interest in endemic tropical disease is well established in Western Africa. Since the beginning of the 21st century, this institution began to offer emergency care with the opening of the emergency department (Service d'Accueil des Urgences [SAUD in 2000. This 2007-2008 study aimed to determine the exact place of this ward within the institution. An analysis of patient trajectories and referrals shows that with nearly 40,000 emergency cases per year, the SAU was responsible for one-third of all hospital consultations and hospitalizations. Two-thirds of patients whose condition was urgent were hospitalized in the intensive care unit or surgical department. For these patients, the system proves to be efficient. For the patients whose condition was not urgent, twice the number of patients than those remaining on site were transferred to another hospital. For patients who remained on site, one-third were placed in the mother and baby care department, another third remained in the emergency department's short-stay unit (Unite d'Hospitalisation de Courte Duree) and the remaining third were moved to other wards, medical wards taking 18% of the whole. Thus, the medical ward recruited 12% of their patients in the SAU. This study shows two models of care in the hospital: the traditional one, rooted in direct recruitment; and the emergency one, politically established during the 2000s as a modern evolution of this health institution, which appears to be population-based, emergency centered and respectful of equity in health access. These two models question the institutional policy and the success of its recent evolution toward emergency issues. PMID- 21786736 TI - [Seasonal and pandemic A (H1N1) 2009 influenza vaccination coverage among health care workers in a French university hospital]. AB - The aim of this study was to highlight the perceived risk, behavioural changes and acceptance of the seasonal and pandemic (H1N1) 2009 influenza vaccine by healthcare workers in a French teaching hospital. We surveyed healthcare workers from the Angers French teaching hospital (CHU) using a cross-sectional intercept design during phase 5A of the French National Plan for the Prevention and Control of the 2009 "Pandemic Influenza". Professionals were asked to take the survey in their workplace from November 2009 to February 2010. The primary endpoint was immunization coverage among healthcare workers who had contact with at-risk patients. Among the 532 workers responding, 22.3% were vaccinated against seasonal influenza and 36.5% against H1N1 influenza. The immunization coverage rate was significantly higher among physicians. For seasonal influenza, the 2 most-cited reasons for vaccination were "to protect the patient" and "to avoid getting sick"; arguments against vaccination were "I never get the flu" or "getting vaccinated is inconvenient and takes too long". For the pandemic A (H1N1) 2009 flu, the arguments for vaccination were "to protect the patient" and "to protect the family"; arguments against vaccination were linked to vaccine safety. Vaccination coverage against seasonal influenza was lower than that reported in the literature, possibly because of the time required between vaccination for pandemic (H1N1) 2009 influenza and seasonal influenza and the priority often given to vaccination against H1N1. This study emphasizes the lack of perception of pandemic (H1N1) 2009 influenza severity and lack of understanding about the process of developing the seasonal and H1N1 influenza vaccines. Concerns about safety, the possibility of side effects and the vaccine development process need to be addressed. An information campaign stressing the necessity for healthcare workers to be vaccinated must be strengthened. PMID- 21786737 TI - [Mortality from cancer in Tunisia: calculating years of life lost]. AB - This work, conducted in Tunisia, aimed to calculate the number of years of life lost due to premature death caused by cancer. The data were based on mortality statistics (2006) provided by the national surveillance system of causes of death and involved calculations proposed by the World Health Organization. A total of 105,205 deaths due to cancer were recorded, 61,550 for males and 43,655 for females. The cancers were mostly of the lung and upper respiratory-digestive tract for men and breast and cervix for women. These results should prompt the health care system to emphasize tobacco control, the promotion of healthy eating and physical activity, as well as screening for breast and cervical cancer. PMID- 21786738 TI - [Diabetes plans in six European countries and in Canada]. AB - Seventeen of the 27 European Union countries have established programs and initiatives to counteract the increasing rate of diabetes in Europe. Luxembourg has not instituted such an initiative at a national level but is considering a national scheme. This article presents several national diabetes policies from other states. The information in these national schemes can be used to assist in the development of a national diabetes program in Luxembourg. Seven national diabetes programs, from The Netherlands, England, Austria, Germany, France, Belgium and Canada, were analyzed. We aimed to identify the most important principles underlying these programs and what makes them successful. The national health policies encompass 3 dimensions: psychological, social and economic. Some key determinants were identified. The most successful diabetes programs promote quality of care and services, early detection and the autonomy of people through the patient's therapeutic education. Other identified determinants are the establishment of an efficient information system, enabling people with diabetes to have access to excellent services and educational information. The system also allows health professionals to easily follow up their diabetes patients and provides a tool for evaluating and developing multidisciplinary competences for professionals. PMID- 21786739 TI - [The World Initiative for the Eradication of Poliomyelitis: a long road full of pitfalls]. AB - The World Initiative for the Eradication of Poliomyelitis (IMEP), launched in 1988, is based on two strategies: mass vaccination with oral polio vaccine (OPV) and surveillance of acute flaccid paralysis (AFP). The disease incidence was reduced by 99%, but eradication, originally scheduled for 2000, has still not been reached in 2010, and four countries continue to be endemic (India, Pakistan, Afghanistan and Nigeria). The obstacles to eradication are the difficulty in reaching all children to be vaccinated, especially in areas of insecurity; the imperfections of OPV--irregular efficacy and genetic instability; and the limitations of surveillance in detecting only the paralytic form of the disease, which often remains asymptomatic. The repeated postponements of the ending of the initiative, which greatly increased the cost of IMEP, spark debate about the actual feasibility of eradication and justification to continue funding in a difficult global economic context, so the initiative remains without significant impact on indicators of the Millennium Goals for Development. PMID- 21786740 TI - [Selective free health care in sub-Saharan Africa: an opportunity for strengthening health systems?]. AB - As the idealistic deadline of the Millennium Development Goals (MDGs), 2015, looms ever closer, some are calling for user fees abolition. In many African countries, this involves targeting groups considered vulnerable. However, operational problems have surfaced in the experiences of some of the pioneering West African countries. We identified various health system bottlenecks. These challenges are also starting points and opportunities to strengthen health care systems in Africa through making changes such as significantly increasing health care funding, improving the reliability of funding, making equity a health policy priority, adopting "New Public Management" types of reforms, ensuring the supply and quality of inputs, making efforts to reinforce the systemic components of the health sector, and improving the quality and quantity of evaluations undertaken in the health sector. PMID- 21786741 TI - Genotoxicity and endocrine-disruption potentials of sediment near an oil spill site: two years after the Hebei Spirit oil spill. AB - The Hebei Spirit oil spill episode (December 7, 2007) has affected the western coastal area of South Korea; however, there is limited information on the potential toxicity of the oil spill to the ecosystem or humans. The potential toxicity of sediments collected from the affected area (n = 22) 2 years after the spill was evaluated. Acute lethal toxicity tests using Vibrio fischeri and Moina macrocopa and tests for genotoxicity and alteration of steroidogenesis using chicken DT40 cells and H295R cells, respectively, were conducted. Both crude and weathered oil extracts were evaluated in order to link the observed toxicity in the sediment extracts to the oil spill. Whereas toxicity to bacteria and daphnids was observed in only two elutriate samples, 10 of the 22 sediment extracts showed genotoxic potential in DT40 cells. The mechanisms of genotoxicity involved nucleotide excision repair (XPA(-/)), homologous recombination (RAD54(-/-)), and translesion synthesis pathways (REV3(-/-)). In addition, nine sediment extracts caused significantly greater production of E2 in H295R cells, and significant up regulation of CYP19, CYP11B2, and 3betaHSD2 by sediment extracts was observed. The pattern of toxicities observed in both crude and weathered oil samples was similar to that observed in the sediment extracts. The genotoxicicity and endocrine-disruption potential of the sediment extracts suggest a need for long term followup for such toxicity in humans and wildlife in this area. PMID- 21786742 TI - Application of an integrated community analysis approach for microbial source tracking in a coastal creek. AB - High fecal indicator bacterial (FIB) concentrations signal urban coastal water quality impairments that can threaten public health. However, FIB (total and fecal coliform plus Enterococcus sp.) concentrations are not specific to human waste, and thus, microbial source tracking (MST) is employed to assess public health risks and remediation alternatives. Currently, water quality diagnosis requires several simultaneous MST assays. Relatively unexplored is a community analysis approach for MST where the overall microbial community composition is compared, through multivariate analysis, to link sources and sinks of microbial pollution. In this research, an urban coastal creek and drain sampling transect, previously diagnosed as human-waste-contaminated, were evaluated for bacterial community composition relative to fecal sources; a laboratory spiking study was also performed to assess method sensitivity and specificity. Multivariate statistical analysis of community profiles clearly distinguished different fecal sources, indicated a high sensitivity for sewage spikes, and confirmed creek contamination sources. This work demonstrates that molecular microbial community analysis combined with appropriate multivariate statistical analyses is an effective addition to the MST tool box. PMID- 21786743 TI - Conformations of trimethyl phosphite: a matrix isolation infrared and ab initio study. AB - The conformations of trimethyl phosphite (TMPhite) were studied using matrix isolation infrared spectroscopy. TMPhite was trapped in a nitrogen matrix using an effusive source maintained at two different temperatures (298 and 410 K) and a supersonic jet source. The experimental studies were supported by ab initio computations performed at the B3LYP/6-31++G** level. Computations identified four minima for TMPhite, corresponding to conformers with C(1)(TG(+/-)G(+/-)), C(s)(TG(+)G(-)), C(1)(G(+/-)TT), and C(3)(G(+/-)G(+/-)G(+/-)) structures, given in order of increasing energy. Computations of the transition state structures connecting the C(s)(TG(+)G(-)) and C(1)(G(+/-)TT) conformers to the global minimum C(1)(TG(+/-)G(+/-)) structure were also carried out. The barriers for the interconversion of C(s)(TG(+)G(-)) and C(1)(G(+/-)TT) to the ground state C(1)(TG(+/-)G(+/-)) conformer were 0.2 and 0.6 kcal/mol, respectively. Comparison of conformational preferences of TMPhite with the related carbon compound, trimethoxymethane, and the organic phosphate, trimethyl phosphate, was also made using natural bond orbital analysis. PMID- 21786744 TI - Sewage exfiltration as a source of storm drain contamination during dry weather in urban watersheds. AB - Separating storm drains and sanitary sewers is expected to control sewage pollution, for example, from combined sewer overflows, and to reduce excessive stormwater flow to wastewater treatment plants. However, sewage contamination has been found in such separated storm drain systems in urban areas during dry weather flow. To determine whether transmission of sewage is occurring from leaking sanitary sewers directly to leaking separated storm drains, field experiments were performed in three watersheds in Santa Barbara, CA. Areas with high and low risks for sewage exfiltration into storm drains were identified, and rhodamine WT (RWT) dye pulses were added to the sanitary sewers. RWT was monitored in nearby storm drain manholes using optical probes set up for unattended continuous monitoring. Above-background RWT peaks were detected in storm drains in high-risk areas, and multiple locations of sewage contamination were found. Sewage contamination during the field studies was confirmed using the human-specific Bacteroidales HF183 and Methanobrevibacter smithii nifH DNA markers. This study is the first to provide direct evidence that leaking sanitary sewers can directly contaminate nearby leaking storm drains with untreated sewage during dry weather and suggests that chronic sanitary sewer leakage contributes to downstream fecal contamination of coastal beaches. PMID- 21786745 TI - Monitoring the in vitro enzyme-mediated degradation of degradable poly(ester amide) for controlled drug delivery by LC-ToF-MS. AB - To scrutinize materials for specific biomedical applications, we need sensitive and selective analytical methods that can give more insight into the process of their biodegradation. In the present study, the enzymatic degradation of multiblock poly(ester amide) based on natural amino acids, such as lysine and leucine, was performed with serine proteases (alpha-chymotrypsin (alpha-CT) and proteinase K (PK)) in phosphate-buffered saline solution at 37 degrees C for 4 weeks. Fully and partially degraded water-soluble products were analyzed by liquid chromatography hyphenated with time-of-flight mass spectrometry using an electrospray interface (LC-ESI-ToF-MS). Tracking the release of monomeric and oligomeric products into the enzyme media during the course of enzymatic degradation revealed the preferences of alpha-CT and PK toward ester and amide bonds: both alpha-CT and PK showed esterase and amidase activity. Although within the experimental time frame up to 30 and 15% weight loss was observed in case of alpha-CT and PK, respectively, analysis by size exclusion chromatography showed no change in the characteristic molecular-weight averages of the remaining polymer. This suggests that the enzymatic degradation occurs at the surface of this biomaterial. A sustained and linear degradation over a period of 4 weeks supports the potential of this class of poly(ester amide)s for drug delivery applications. PMID- 21786746 TI - A palladium-catalyzed vinylcyclopropane (3+2) cycloaddition approach to the Melodinus alkaloids. AB - A palladium-catalyzed (3+2) cycloaddition of a vinylcyclopropane and a beta nitrostyrene is employed to rapidly assemble the cyclopentane core of the Melodinus alkaloids. The ABCD ring system of the natural product family is prepared in six steps from commercially available materials. PMID- 21786747 TI - Synthesis, crystal and electronic structures, and properties of the new pnictide semiconductors A2CdPn2 (A = Ca, Sr, Ba, Eu; Pn = P, As). AB - A series of ternary Zintl phases, Ca(2)CdP(2), Ca(2)CdAs(2), Sr(2)CdAs(2), Ba(2)CdAs(2), and Eu(2)CdAs(2), have been synthesized through high temperature metal flux reactions, and their structures have been characterized by single crystal X-ray diffraction. They belong to the Yb(2)CdSb(2) structure type and crystallize in the orthorhombic space group Cmc2(1) (No. 36, Z = 4) with cell dimensions of a = 4.2066(5), 4.3163(5), 4.4459(7), 4.5922(5), 4.4418(9) A; b = 16.120(2), 16.5063(19), 16.904(3), 17.4047(18), 16.847(4) A; c = 7.0639(9), 7.1418(8), 7.5885(11), 8.0526(8), 7.4985(16) A for Ca(2)CdP(2) (R1 = 0.0152, wR2 = 0.0278), Ca(2)CdAs(2) (R1 = 0.0165, wR2 = 0.0290), Sr(2)CdAs(2) (R1 = 0.0238, wR2 = 0.0404), Ba(2)CdAs(2) (R1 = 0.0184, wR2 = 0.0361), and Eu(2)CdAs(2) (R1 = 0.0203, wR2 = 0.0404), respectively. Among these, Ca(2)CdAs(2) was found to form with another closely related structure, depending on the experimental conditions- monoclinic space group Cm (No. 8, Z = 10) with lattice constants a = 21.5152(3) A, b = 4.30050(10) A, c = 14.3761(2) A and beta = 110.0170(10) degrees (R1 = 0.0461, wR2 = 0.0747). UV/vis optical absorption spectra for both forms of Ca(2)CdAs(2) show band gaps on the order of 1.0 eV, suggesting semiconducting properties, which have also been confirmed through electronic band structure calculations based on the density-functional theory. Results from differential scanning calorimetry measurements probing the thermal stability and phase transitions in the two Ca(2)CdAs(2) polymorphs are discussed. Magnetic susceptibility measurements for Eu(2)CdAs(2), indicating divalent Eu(2+) cations, are presented as well. PMID- 21786748 TI - Effects of gene-environmental interaction on noise-induced hearing threshold levels for high frequencies (HTLHF). AB - In this study we assessed the interaction between glutathione S-transferase (GST) genetic polymorphisms and noise exposures, with regard to their effect on the hearing threshold levels for high frequencies (HTLHF). Research participants comprised 347 male workers, and each participant's cumulative noise exposure was determined using a job-exposure matrix. Approximately 64.6% of the participants' exposure in L(eq-8 h) was above 90 dBA. The mean HTLHF was 32.1 dB. A significant dose-response relationship was found between noise exposure and HTLHF. We further converted the estimated total noise exposure level over each participant's job history to a noise exposure level that corresponded to a 40-year exposure (L(eq 40y)). After we had adjusted the results for age, we found that workers carrying GSTM1 null, GSTT1 null, and GSTP1 Ile(105)/Ile(105) genotypes were susceptible to the HTLHF when their L(eq-40y) were above 90 dBA. Therefore, GST genetic polymorphisms might affect HTLHF only when workers are exposed to high noise levels. PMID- 21786749 TI - Comment on "A sulfonium cation intermediate in the mechanism of methionine sulfoxide reductase B: a DFT study". PMID- 21786750 TI - Physiological and molecular effect assessment versus physico-chemistry based mode of action schemes: Daphnia magna exposed to narcotics and polar narcotics. AB - Structural analogues are assumed to elicit toxicity via similar predominant modes of action (MOAs). Currently, MOA categorization of chemicals in environmental risk assessment is mainly based on the physicochemical properties of potential toxicants. It is often not known whether such classification schemes are also supported by mechanistic biological data. In this study, the toxic effects of two groups of structural analogues (alcohols and anilines) with predefined MOA (narcotics and polar narcotics) were investigated at different levels of biological organization (gene transcription, energy reserves, and growth). Chemical similarity was not indicative of a comparable degree of toxicity and a similar biological response. Categorization of the test chemicals based on the different biological responses (growth, energy use, and gene transcription) did not result in a classification of the predefined narcotics versus the predefined polar narcotics. Moreover, gene transcription based clustering profiles were indicative of the observed effects at higher level of biological organization. Furthermore, a small set of classifier genes could be identified that was discriminative for the clustering pattern. These classifier genes covaried with the organismal and physiological responses. Compared to the physico-chemistry based MOA classification, integrated biological multilevel effect assessment can provide the necessary MOA information that is crucial in high-quality environmental risk assessment. Our findings support the view that transcriptomics tools hold considerable promise to be used in biological response based mechanistic profiling of potential (eco)toxicants. PMID- 21786751 TI - Differential display system with vertebrate-common degenerate oligonucleotide primers: uncovering genes responsive to dioxin in avian embryonic liver. AB - To assess possible impacts of environmental pollutants on gene expression profiles in a variety of organisms, we developed a novel differential display system with primer sets that are common in seven vertebrate species, based on degenerate oligonucleotide-primed PCR (DOP-PCR). An 8-mer inverse repeat motif was found in most transcripts from the seven vertebrates including fish to primates with detailed transcriptome information; more than 10,000 motifs were recognized in common in the transcripts of the seven species. Among them, we selected 275 common motifs that cover about 40-70% of transcripts throughout these species, and designed 275 DOP-PCR primers that were common to seven vertebrate species (common DOP-PCR primers). To detect genes responsive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing embryos, differential display with common DOP-PCR primers was applied to embryonic liver of two avian species, the chicken (Gallus gallus) and the common cormorant (Phalacrocorax carbo), which were exposed in ovo to TCDD. The cDNA bands that showed differences between the control and TCDD-treated groups were sequenced and the mRNA expression levels were confirmed by real-time RT-PCR. This approach succeeded in isolating novel dioxin-responsive genes that include 10 coding genes in the chicken, and 1 coding gene and 1 unknown transcript in the cormorant, together with cytochrome P450 1As that have already been well established as dioxin markers. These results highlighted the usefulness of systematically designed novel differential display systems to search genes responsive to chemicals in vertebrates, including wild species, for which transcriptome information is not available. PMID- 21786753 TI - Comproportionation of cationic and anionic tungsten complexes having an N heterocyclic carbene ligand to give the isolable 17-electron tungsten radical CpW(CO)2(IMes)(*). AB - A series consisting of a tungsten anion, radical, and cation, supported by the N heterocyclic carbene 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) and spanning formal oxidation states W(0), W(I), and W(II), has been synthesized, isolated, and characterized. Reaction of the hydride CpW(CO)(2)(IMes)H with KH and 18-crown-6 gives the tungsten anion [CpW(CO)(2)(IMes)](-)[K(18-crown-6)](+). Electrochemical oxidation of [CpW(CO)(2)(IMes)](-) in MeCN (0.2 M (n)Bu(4)N(+)PF(6)(-)) is fully reversible (E(1/2) = -1.65 V vs Cp(2)Fe(+*/0)) at all scan rates, indicating that CpW(CO)(2)(IMes)(*) is a persistent radical. Hydride transfer from CpW(CO)(2)(IMes)H to Ph(3)C(+)PF(6)(-) in MeCN affords [cis CpW(CO)(2)(IMes)(MeCN)](+)PF(6)(-). Comproportionation of [CpW(CO)(2)(IMes)](-) with [CpW(CO)(2)(IMes)(MeCN)](+) gives the 17-electron tungsten radical CpW(CO)(2)(IMes)(*). This complex shows paramagnetically shifted resonances in the (1)H NMR spectrum and has been characterized by IR spectroscopy, low temperature EPR spectroscopy, and X-ray diffraction. CpW(CO)(2)(IMes)(*) is stable with respect to disproportionation and dimerization. NMR studies of degenerate electron transfer between CpW(CO)(2)(IMes)(*) and [CpW(CO)(2)(IMes)]( ) are reported. DFT calculations were carried out on CpW(CO)(2)(IMes)H, as well as on related complexes bearing NHC ligands with N,N' substituents Me (CpW(CO)(2)(IMe)H) or H (CpW(CO)(2)(IH)H) to compare to the experimentally studied IMes complexes with mesityl substituents. These calculations reveal that W-H homolytic bond dissociation energies (BDEs) decrease with increasing steric bulk of the NHC ligand, from 67 to 64 to 63 kcal mol(-1) for CpW(CO)(2)(IH)H, CpW(CO)(2)(IMe)H, and CpW(CO)(2)(IMes)H, respectively. The calculated spin density at W for CpW(CO)(2)(IMes)(*) is 0.63. The W radicals CpW(CO)(2)(IMe)(*) and CpW(CO)(2)(IH)(*) are calculated to form weak W-W bonds. The weakly bonded complexes [CpW(CO)(2)(IMe)](2) and [CpW(CO)(2)(IH)](2) are predicted to have W-W BDEs of 6 and 18 kcal mol(-1), respectively, and to dissociate readily to the W centered radicals CpW(CO)(2)(IMe)(*) and CpW(CO)(2)(IH)(*). PMID- 21786755 TI - Comment on "Effects of triclocarban, triclosan, and methyl triclosan on thyroid hormone action and stress in frog and mammalian culture systems". PMID- 21786754 TI - Ecotoxicogenomics to support ecological risk assessment: a case study with bisphenol A in fish. AB - Effects of bisphenol A (BPA) on ovarian transcript profiles as well as targeted end points with endocrine/reproductive relevance were examined in two fish species, fathead minnow (Pimephales promelas) and zebrafish (Danio rerio), exposed in parallel using matched experimental designs. Four days of waterborne exposure to 10 MUg BPA/L caused significant vitellogenin induction in both species. However, zebrafish were less sensitive to effects on hepatic gene expression and steroid production than fathead minnow and the magnitude of vitellogenin induction was more modest (i.e., 3-fold compared to 13,000-fold in fathead minnow). The concentration-response at the ovarian transcriptome level was nonmonotonic and violated assumptions that underlie proposed methods for estimating hazard thresholds from transcriptomic results. However, the nonmonotonic profile was consistent among species and there were nominal similarities in the functions associated with the differentially expressed genes, suggesting potential activation of common pathway perturbation motifs in both species. Overall, the results provide an effective case study for considering the potential application of ecotoxicogenomics to ecological risk assessments and provide novel comparative data regarding effects of BPA in fish. PMID- 21786756 TI - Interconversion study in 1,4-substituted six-membered cyclohexane-type rings. Structure and dynamics of trans-1,4-dibromo-1,4-dicyanocyclohexane. AB - Cyclohexane is an extremely flexible molecule that oscillates, at room temperature, between two clearly distinct and extreme conformations that cannot be distinguished at room temperature; so much so that the NMR spectrum is a single line that includes all 12 protons be they axial or equatorial. This raises the interesting question as to what happens when there are equal substituents at the 1 and 4 carbon atoms of the ring. Therefore substitution in the 1,4-positions in the cyclohexane ring has been the subject of considerable interest because some form of interconversion between extreme conformations could lead to the existence of a rather unusual behavior. To study this problem, the interconversion in (di- or tetra-1,4)-substituted six-membered cyclohexane-type rings, trans-1,4-dibromo-1,4-dicyanocyclohexane, was found to be a particularly suitable candidate. Although X-ray diffraction studies on the crystalline solid found the molecule to be centrosymmetric, it still shows a significant dipole moment MU in solution, as determined with a procedure that leads to the vapor phase values of MU. Furthermore, the low magnetic field proton NMR spectrum at ambient temperature appears as a single line, a situation that changes with increasing field intensity and different solvents. Both these effects are attributed to dynamics, because small distortions can easily disrupt the exact cancellation of the individual dipoles (which are quite strong) associated with each end of the molecule. The molecule can exist in two forms, with both the bromines in an axial geometry or both in an equatorial position. Interconversion between these forms is observed, as in the parent cyclohexane. The single NMR line observed at low magnetic fields is due to fast exchange and requires that the two forms have roughly equal populations. Spectra obtained at low temperature confirm this, and variable-temperature studies allow measurement of the rates, leading to an enthalpy of activation of 62 kJ mol(-1). More details of the interconversion are provided by some new calculation methods. Even for a relatively small molecule like this, calculation of a full potential energy surface is prohibitive. However, methods are now available to follow the molecule along the reaction coordinate in quite an efficient way. The results of these calculations lead to an extremely detailed picture of chair-chair interconversion in a di- and tetrasubstituted six-membered ring of the cyclohexane family. PMID- 21786757 TI - Asymmetric aza-[3+3] annulation in the synthesis of indolizidines: an unexpected reversal of regiochemistry. AB - An enantioselective and diastereoselective aza-[3+3] annulation of pyrrolidine based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines. PMID- 21786758 TI - Optimizing the operation of a two-phase anaerobic digestion system digesting grass silage. AB - This paper examines the optimization of an existing two-phase anaerobic digestion process using grass silage as a feedstock. The system comprises 6 leach beds connected to an upflow anaerobic sludge blanket (UASB). The existing system produced 305 L CH(4) kg(-1) VS added at an overall retention time of 42 days (6 leach beds emptied and fed sequentially every 7 days in series). The desired improvements were a reduction in retention time with increased methane production. It was noted in the existing system that biogas production and COD levels fell off in the last 2 days of each 7-day cycle. Thus the first change involved reduction in retention time to 30 days (6 leach beds fed sequentially every 5 days in series). This lead to a slight improvement in methane production (310 L CH(4) kg(-1) VS added). The second change was effected by separation of flows to the first stage (leach beds) and the second stage (UASB) through addition of an extra pump to optimize leaching. This led to an increase in CH(4) production (341 L CH(4) kg(-1) VS). The overall improvement from the existing system was an increase of 11.8% in methane production and a reduction in size or retention time of 40% (42 days decreased to 30 days retention time). PMID- 21786760 TI - Organic triplet sensitizer library derived from a single chromophore (BODIPY) with long-lived triplet excited state for triplet-triplet annihilation based upconversion. AB - Triplet-triplet annihilation (TTA) based upconversions are attractive as a result of their readily tunable excitation/emission wavelength, low excitation power density, and high upconversion quantum yield. For TTA upconversion, triplet sensitizers and acceptors are combined to harvest the irradiation energy and to acquire emission at higher energy through triplet-triplet energy transfer (TTET) and TTA processes. Currently the triplet sensitizers are limited to the phosphorescent transition metal complexes, for which the tuning of UV-vis absorption and T(1) excited state energy level is difficult. Herein for the first time we proposed a library of organic triplet sensitizers based on a single chromophore of boron-dipyrromethene (BODIPY). The organic sensitizers show intense UV-vis absorptions at 510-629 nm (epsilon up to 180,000 M(-1) cm(-1)). Long-lived triplet excited state (tau(T) up to 66.3 MUs) is populated upon excitation of the sensitizers, proved by nanosecond time-resolved transient difference absorption spectra and DFT calculations. With perylene or 1-chloro 9,10-bis(phenylethynyl)anthracene (1CBPEA) as the triplet acceptors, significant upconversion (Phi(UC) up to 6.1%) was observed for solution samples and polymer films, and the anti-Stokes shift was up to 0.56 eV. Our results pave the way for the design of organic triplet sensitizers and their applications in photovoltaics and upconversions, etc. PMID- 21786759 TI - Prevalence of anaerobic ammonium-oxidizing bacteria in contaminated groundwater. AB - Anaerobic ammonium-oxidizing (anammox) bacteria perform an important step in the global nitrogen cycle: anaerobic oxidation of ammonium and reduction of nitrite to form dinitrogen gas (N(2)). Anammox organisms appear to be widely distributed in natural and artificial environments. However, their roles in groundwater ammonium attenuation remain unclear and only limited biomarker-based data confirmed their presence prior to this study. We used complementary molecular and isotope-based methods to assess anammox diversity and activity occurring at three ammonium-contaminated groundwater sites: quantitative PCR, denaturing gradient gel electrophoresis, sequencing of 16S rRNA genes, and (15)N-tracer incubations. Here we show that anammox performing organisms were abundant bacterial community members. Although all sites were dominated by Candidatus Brocadia-like sequences, the community at one site was particularly diverse, possessing four of five known genera of anammox bacteria. Isotope data showed that anammox produced up to 18 and 36% of N(2) at these sites. By combining molecular and isotopic results we have demonstrated the diversity, abundance, and activity of these autotrophic bacteria. Our results provide strong evidence for their important biogeochemical role in attenuating groundwater ammonium contamination. PMID- 21786761 TI - Prediction of the dissociation constant pKa of organic acids from local molecular parameters of their electronic ground state. AB - A quantum chemical method has been developed to estimate the dissociation constant pK(a) of organic acids from their neutral molecular structures by employing electronic structure properties. The data set covers 219 phenols (including 29 phenols with intramolecular H-bonding), 150 aromatic carboxylic acids, 190 aliphatic carboxylic acids, and 138 alcohols, with pK(a) varying by 16 units (0.38-16.80). Optimized ground-state geometries employing the semiempirical AM1 Hamiltonian have been used to quantify the site-specific molecular readiness to donate or accept electron charge in terms of both charge-associated energies and energy-associated charges, augmented by an ortho substitution indicator for aromatic compounds. The resultant regression models yield squared correlation coefficients (r(2)) from 0.82 to 0.90 and root-mean-square errors (rms) from 0.39 to 0.70 pK(a) units, corresponding to an overall (subset-weighted) r(2) of 0.86. Simulated external validation, leave-10%-out cross-validation and target value scrambling demonstrate the statistical robustness and prediction power of the derived model suite. The low intercorrelation with prediction errors from the commercial ACD package provides opportunity for a consensus model approach, offering a pragmatic way for further increasing the confidence in prediction significantly. Interestingly, inclusion of calculated free energies of aqueous solvation does not improve the prediction performance, probably because of the limited precision provided by available continuum-solvation models. PMID- 21786762 TI - Polymer-anchored peroxo compounds of vanadium(V) and molybdenum(VI): synthesis, stability, and their activities with alkaline phosphatase and catalase. AB - We generated a series of new polymer-bound peroxo complexes of vanadium(V) and molybdenum(VI) of the type [VO(O(2))(2)(sulfonate)]-PSS [PSS = poly(sodium 4 styrene sulfonate)] (PV(3)), [V(2)O(2)(O(2))(4)(carboxylate)VO(O(2))(2)(sulfonate)]-PSSM [PSSM = poly(sodium styrene sulfonate-co-maleate)] (PV(4)), [Mo(2)O(2)(O(2))(4)(carboxylate)]-PA [PA = poly(sodium acrylate)] (PMo(1)), [MoO(O(2))(2)(carboxylate)]-PMA [PMA = poly(sodium methacrylate)] (PMo(2)), and [MoO(O(2))(2)(amide)]-PAm [PAm = poly(acrylamide)] (PMo(3)) by reacting V(2)O(5) (for PV(3) and PV(4)) or H(2)MoO(4) (for PMo(1), PMo(2), and PMo(3)) with H(2)O(2) and the respective water-soluble macromolecular ligand at pH 5-6. The compounds were characterized by elemental analysis (CHN and energy-dispersive X-ray spectroscopy), spectral studies (UV-vis, IR, (13)C NMR, (51)V NMR, and (95) Mo NMR), thermal (TGA) as well as scanning electron micrographs (SEM), and EDX analysis. It has been demonstrated that compounds retain their structural integrity in solutions of a wide range of pH values and are approximately 100 times weaker as substrate to the enzyme catalase relative to H(2)O(2), its natural substrate. The effect of the title compounds, along with previously reported compounds [V(2)O(2)(O(2))(4)(carboxylate)]-PA (PV(1)) and [VO(O(2))(2)(carboxylate)]-PMA (PV(2)) on rabbit intestine alkaline phosphatase (ALP) has been investigated and compared with the effect induced by the free diperoxometallates viz. Na[VO(O(2))(2)(H(2)O)] (DPV), [MoO(O(2))(2)(glycine)(H(2)O)] (DMo(1)), and [MoO(O(2))(2)(asparagine)(H(2)O)] (DMo(2)). It has been observed that although all the compounds tested are potent inhibitors of the enzyme, the polymer-bound and neat complexes act via distinct mechanisms. Each of the macromolecular compounds is a classical noncompetitive inhibitor of ALP. In contrast, the action of neat pV and heteroligand pMo compounds on the enzyme function is consistent with a mixed type of inhibition. PMID- 21786764 TI - Dissolution of lamellar phases. AB - Dissolution of surfactant liquid crystals is an important process both at the manufacturing stage of surfactant based formulated products and during their use. Dissipative particle dynamics simulations were employed to study the production of surfactant-oil-water systems under both temperature and water quenches. Upon the dissolution of a high concentration lamellar phase surfactant, wormlike micelles are formed, which differ from the spherical micelles produced at the same concentration with a temperature quench. The surfactant molecules have a tendency to remain within their initially formed lamellar phase sheets and just rearrange into wormlike micelles. When a hydrophobic additive (oil) is added to the initial system, longer cylindrical micelles are formed, with the creation of some spherical micelles under dissolution. These micelles detach from the long cylinders as a result of their natural oscillations. PMID- 21786765 TI - One- and two-photon live cell imaging using a mutant SNAP-Tag protein and its FRET substrate pairs. AB - A small molecule-assisted protein labeling strategy based on a mutant SNAP-Tag (mSNAP) and its FRET substrate pairs has been developed. Both one- and two-photon fluorescence microscopic experiments were successfully demonstrated in living cells. PMID- 21786766 TI - Three-dimensional atomic imaging of colloidal core-shell nanocrystals. AB - Colloidal core-shell semiconductor nanocrystals form an important class of optoelectronic materials, in which the exciton wave functions can be tailored by the atomic configuration of the core, the interfacial layers, and the shell. Here, we provide a trustful 3D characterization at the atomic scale of a free standing PbSe(core)-CdSe(shell) nanocrystal by combining electron microscopy and discrete tomography. Our results yield unique insights for understanding the process of cation exchange, which is widely employed in the synthesis of core shell nanocrystals. The study that we present is generally applicable to the broad range of colloidal heteronanocrystals that currently emerge as a new class of materials with technological importance. PMID- 21786763 TI - Investigating endogenous peptides and peptidases using peptidomics. AB - Rather than simply being protein degradation products, peptides have proven to be important bioactive molecules. Bioactive peptides act as hormones, neurotransmitters, and antimicrobial agents in vivo. The dysregulation of bioactive peptide signaling is also known to be involved in disease, and targeting peptide hormone pathways has been a successful strategy in the development of novel therapeutics. The importance of bioactive peptides in biology has spurred research to elucidate the function and regulation of these molecules. Classical methods for peptide analysis have relied on targeted immunoassays, but certain scientific questions necessitated a broader and more detailed view of the peptidome--all the peptides in a cell, tissue, or organism. In this review we discuss how peptidomics has emerged to fill this need through the application of advanced liquid chromatography--tandem mass spectrometry (LC MS/MS) methods that provide unique insights into peptide activity and regulation. PMID- 21786767 TI - Highly efficient synthesis of phenols by copper-catalyzed hydroxylation of aryl iodides, bromides, and chlorides. AB - 8-Hydroxyquinolin-N-oxide was found to be a very efficient ligand for the copper catalyzed hydroxylation of aryl iodides, aryl bromides, or aryl chlorides under mild reaction conditions. This methodology provides a direct transformation of aryl halides to phenols and to alkyl aryl ethers. The inexpensive catalytic system showed great functional group tolerance and excellent selectivity. PMID- 21786768 TI - New Fe3+/Cr3+ perovskites with anomalous transport properties: the solid solution La(x)Bi(1-x)Fe(0.5)Cr(0.5)O3 (0.4 <= x <= 1). AB - In this work, the sol-gel synthesis, structural characterization, and transport properties of a new solid solution of the general formula La(x)Bi(1 x)Fe(0.5)Cr(0.5)O(3) (0.4 <= x <= 1) are presented. The solubility limit x has been determined and variation of the lattice parameters measured through profile fitting. The cell parameters, space group, and atomic positions, as obtained by the Rietveld refinement of X-ray diffraction data, are reported. This analysis and electron diffraction studies as well do not reveal any evidence of Fe/Cr ordering. Regarding the transport properties, magnetic and electric characterizations are described. The electrical response with the temperature and frequency has been studied, and a "positive temperature coefficient" for the resistivity has been found for temperatures between 270 and 400 degrees C. The magnetic behavior is striking because, for all materials studied, zero-field cooling curves appear above field-cooling ones, an anomalous feature that is interpreted as being due to complex ferromagnetic/antiferromagnetic interactions in the B perovskite sublattice. PMID- 21786769 TI - Computer simulations of homogeneous nucleation of benzene from the melt. AB - Nucleation is the key step in crystallization by which the molecules (or atoms or ions) aggregate together, find the right relative orientations, and start to grow to form the final crystal structure. Since nucleation is an activated step involving a large gap in time scales between molecular motions and the nucleation event itself, nucleation must be studied using rare events methods. We employ a technique developed previously in our group known as aimless shooting [Peters, B.; Trout, B. L. J. Chem. Phys., 2006, 125, 054108], which is based on transition path sampling, to generate reactive trajectories between the disordered and ordered phases of benzene. Using the likelihood maximization algorithm, we analyze the aimless shooting trajectories to identify the key order parameters or collective variables to describe the reaction coordinate for the nucleation of benzene from the melt. We find that the local bond orientation and local relative orientation order parameters are the most important collective variables in describing the reaction coordinate for homogeneous nucleation from the melt, as compared to cluster size and space-averaged order parameters. This study also demonstrates the utility of recently developed order parameters for molecular crystals [Santiso, E. E.; Trout, B. L. J. Chem. Phys., 2011, 134, 064109]. PMID- 21786770 TI - Tandem cyclization-Michael reaction by combination of metal- and organocatalysis. AB - The use of a catalytic amount of platinum complexes (1 mol %) was found to be compatible with different organocatalysts (DABCO or the Jorgensen-Hayashi catalyst) that were used in the functionalization of various activated methylenes. By this method, a series of lactones with C-3 quaternary centers and substitution at C-5 were prepared. PMID- 21786771 TI - Ultrafast nonradiative decay of electronically excited States of malachite green: ab initio calculations. AB - We have investigated the nonradiative deactivation process of malachite green in the singlet excited states, S(1) and S(2), by high-level ab initio quantum chemical calculations using the CASPT2//CASCF approach. The deactivation pathways connecting the Franck-Condon region and conical intersection regions are identified. The initial population in the S(1) state is on a flat surface and the relaxation involves a rotation of phenyl rings, which leads the molecule to reach the conical intersection between the S(1) and S(0) states, where it efficiently decays back to the ground state. There exists a small barrier connecting the Franck-Condon and conical intersection regions on the S(1) potential energy surface. The decay mechanism from the S(2) state also involves the twisting motion of phenyl rings. In contrast to the excitation to the S(1) state, the initial population is on a downhill ramp potential and the barrierless relaxation through the rotation of substituted phenyl rings is expected. During the course of relaxation, the molecule switches to the S(1) state at the conical intersection between S(2) and S(1), and then it decays back to the ground state through the intersection between S(1) and S(0). In relaxation from both S(1) and S(2), large distortion of phenyl rings is required for the ultrafast nonradiative decay to the ground state. PMID- 21786772 TI - Separating electrophilicity and Lewis acidity: the synthesis, characterization, and electrochemistry of the electron deficient tris(aryl)boranes B(C6F5)(3 n)(C6Cl5)n (n = 1-3). AB - A new family of electron-deficient tris(aryl)boranes, B(C(6)F(5))(3 n)(C(6)Cl(5))(n) (n = 1-3), has been synthesized, permitting an investigation into the steric and electronic effects resulting from the gradual replacement of C(6)F(5) with C(6)Cl(5) ligands. B(C(6)F(5))(2)(C(6)Cl(5)) (3) is accessed via C(6)Cl(5)BBr(2), itself prepared from donor-free Zn(C(6)Cl(5))(2) and BBr(3). Reaction of C(6)Cl(5)Li with BCl(3) in a Et(2)O/hexane slurry selectively produced B(C(6)Cl(5))(2)Cl, which undergoes B-Cl exchange with CuC(6)F(5) to afford B(C(6)F(5))(C(6)Cl(5))(2) (5). While 3 forms a complex with H(2)O, which can be rapidly removed under vacuum or in the presence of molecular sieves, B(C(6)Cl(5))(3) (6) is completely stable to refluxing toluene/H(2)O for several days. Compounds 3, 5, and 6 have been structurally characterized using single crystal X-ray diffraction and represent the first structure determinations for compounds featuring B-C(6)Cl(5) bonds; each exhibits a trigonal planar geometry about B, despite having different ligand sets. The spectroscopic characterization using (11)B, (19)F, and (13)C NMR indicates that the boron center becomes more electron-deficient as n increases. Optimized structures of B(C(6)F(5))(3 n)(C(6)Cl(5))(n) (n = 0-3) using density functional theory (B3LYP/TZVP) are all fully consistent with the experimental structural data. Computed (11)B shielding constants also replicate the experimental trend almost quantitatively, and the computed natural charges on the boron center increase in the order n = 0 (0.81) < n = 1 (0.89) < n = 2 (1.02) < n = 3 (1.16), supporting the hypothesis that electrophilicity increases concomitantly with substitution of C(6)F(5) for C(6)Cl(5). The direct solution cyclic voltammetry of B(C(6)F(5))(3) has been obtained for the first time and electrochemical measurements upon the entire series B(C(6)F(5))(3-n)(C(6)Cl(5))(n) (n = 0-3) corroborate the spectroscopic data, revealing C(6)Cl(5) to be a more electron-withdrawing group than C(6)F(5), with a ca. +200 mV shift observed in the reduction potential per C(6)F(5) group replaced. Conversely, use of the Guttmann-Beckett and Childs' methods to determine Lewis acidity on B(C(6)F(5))(3), 3, and 5 showed this property to diminish with increasing C(6)Cl(5) content, which is attributed to the steric effects of the bulky C(6)Cl(5) substituents. This conflict is ascribed to the minimal structural reorganization in the radical anions upon reduction during cyclic voltammetric experiments. Reduction of 6 using Na((s)) in THF results in a vivid blue paramagnetic solution of Na(+) [6](*-); the EPR signal of Na(+)[6](*-) is centered at g = 2.002 with a((11)B) 10G. Measurements of the exponential decay of the EPR signal (298 K) reveal [6](*-) to be considerably more stable than its perfluoro analogue. PMID- 21786773 TI - A density functional theory study of the Nef-isocyanide reaction: mechanism, influence of parameters and scope. AB - The Nef reaction between isocyanides and acyl chlorides is studied at the M06 2X/6-311+G(d,p) level of theory in toluene. After proving that the reaction follows a concerted mechanism instead of an addition-elimination path, we study the influences of the solvent, the isocyanide, the acyl moiety and the leaving group on the energy profile of the reaction. The calculated data can be rationalized with the pK(a) of the leaving group, or more generally with the population of the oxygen lone pairs of the acyl moiety. PMID- 21786774 TI - Atmospheric chemistry of 2,3-pentanedione: photolysis and reaction with OH radicals. AB - The kinetics of the overall reaction between OH radicals and 2,3-pentanedione (1) were studied using both direct and relative kinetic methods at laboratory temperature. The low pressure fast discharge flow experiments coupled with resonance fluorescence detection of OH provided the direct rate coefficient of (2.25 +/- 0.44) * 10(-12) cm(3) molecule(-1) s(-1). The relative-rate experiments were carried out both in a collapsible Teflon chamber and a Pyrex reactor in two laboratories using different reference reactions to provide the rate coefficients of 1.95 +/- 0.27, 1.95 +/- 0.34, and 2.06 +/- 0.34, all given in 10(-12) cm(3) molecule(-1) s(-1). The recommended value is the nonweighted average of the four determinations: k(1) (300 K) = (2.09 +/- 0.38) * 10(-12) cm(3) molecule(-1) s( 1), given with 2sigma accuracy. Absorption cross sections for 2,3-pentanedione were determined: the spectrum is characterized by two wide absorption bands between 220 and 450 nm. Pulsed laser photolysis at 351 nm was used and the depletion of 2,3-pentanedione (2) was measured by GC to determine the photolysis quantum yield of Phi(2) = 0.11 +/- 0.02(2sigma) at 300 K and 1000 mbar synthetic air. An upper limit was estimated for the effective quantum yield of 2,3 pentanedione applying fluorescent lamps with peak wavelength of 312 nm. Relationships between molecular structure and OH reactivity, as well as the atmospheric fate of 2,3-pentanedione, have been discussed. PMID- 21786775 TI - Chiral sulfinamide/achiral sulfonic acid cocatalyzed enantioselective protonation of enol silanes. AB - The application of chiral sulfinamides and achiral sulfonic acids as a cocatalyst system for enantioselective protonation reactions is described. Structurally simple, easily accessible sulfinamides were found to induce moderate-to-high ee's in the formation of 2-aryl-substituted cycloalkanones from the corresponding trimethylsilyl enol ethers. PMID- 21786776 TI - Stereocontrolled synthesis of substituted bicyclic ethers through oxy-Favorskii rearrangement: total synthesis of (+/-)-communiol E. AB - The potential of the oxy-Favorskii rearrangement to form branched cis-fused bicyclic ethers was explored. Both tertiary and quaternary centers were constructed in highly stereospecific manners. Methanol and primary amines were effective nucleophiles for the rearrangement. The total synthesis of (+/-) communiol E was achieved based on this method. PMID- 21786779 TI - N-halamine copolymers for use in antimicrobial paints. AB - A series of copolymers containing units of a novel hydantoinylacrylamide and the sodium salt of 2-(acrylamido)-2-methylpropanesulfonic acid have been synthesized. The homopolymer of the hydantoinylacrylamide compound was insoluble in water, while the copolymers with the sulfonic acid sodium salt were water dispersible/soluble, with the solution becoming completely transparent when the feed ratio for the copolymer contained 7 parts of the hydantoin moiety to 3 parts of the sodium sulfonate moiety. The polymers were added into a commercial water based latex paint, and upon drying, the painted surfaces treated with the water miscible copolymers were rendered antimicrobial following chlorination with dilute household bleach. The chlorinated homopolymer failed to provide an antimicrobial property for the paint because of its tendency to isolate into aggregates in the paint, while the completely miscible copolymers were capable of 6-log inactivation of Staphylococcus aureus and Escherichia coli O157:H7 within 5 min of contact time. PMID- 21786780 TI - Insights into the reaction mechanism of the prolyl-acyl carrier protein oxidase involved in anatoxin-a and homoanatoxin-a biosynthesis. AB - Anatoxin-a and homoanatoxin-a are two potent cyanobacterial neurotoxins. We recently reported the identification of the gene cluster responsible for the biosynthesis of these toxins as well as the in-vitro reconstitution of the first steps of this biosynthesis. We now report experimental evidence supporting the proposed reaction mechanism of AnaB, a flavoprotein homologous to acyl-CoA dehydrogenase. AnaB catalyzes the two-electron oxidation of prolyl-AnaD, which is proline linked to the acyl carrier protein holo-AnaD, to dehydroprolyl-AnaD using oxygen as the second substrate. AnaB is thus an oxidase. By using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we have identified and characterized dehydroprolyl-AnaD, the AnaB product. We estimated an apparent catalytic constant of 1 min(-1) for AnaB catalysis. We synthesized several deuterium-labeled prolines and enzymatically transformed them into their corresponding prolyl-AnaD. These deuterium-labeled prolyl-AnaDs were oxidized in the presence of AnaB, and the deuterium labeling in the remaining substrate and in the product was determined by LC-MS/MS. The data supported a reaction mechanism starting with a rapid enolization followed by a slow oxidation to give the conjugated imine, which in turn was isomerized to pyrroline-5-carboxyl-AnaD. We also showed that cis- and trans-4-fluoro-L-prolyl-AnaD and 3,4-dehydro-L prolyl-AnaD were transformed into pyrrole-2-carboxyl-AnaD by AnaB. Thus, the 4 fluoro-analogues experienced a beta-elimination supporting the AnaB-catalyzed aza allylic isomerization. We identified by sequence alignment the AnaB active site base, Glu244. We produced, purified, and characterized the E244A AnaB mutant, which is inactive, supporting the catalytic role of E244 as a base. PMID- 21786781 TI - Ion induced dipole clusters H(n)- (3 <= n-odd <= 13): density functional theory calculations of structure and energy. AB - We investigate anew the possible equilibrium geometries of ion induced dipole clusters of hydrogen molecular ions, of molecular formula H(n)(-) (3 <= n-odd <= 13). Our previous publications [Sapse, A. M.; et al. Nature 1979, 278, 332; Rayez, J. C.; et al., J. Chem. Phys. 1981, 75, 5393] indicated these molecules would have a shallow minimum and adopt symmetrical geometries that accord with the valence shell electron pair repulsion (VSEPR) rules for geometries defined by electron pairs surrounding a central point of attraction. These earlier calculations were all based upon Hartree-Fock (HF) calculations with a fairly small basis of atomic functions, except for the H3(-) ion for which configuration interaction (CI) calculations were carried out. A related paper [Hirao, K.; et al., Chem. Phys. 1983, 80, 237] carried out similar calculations on the same clusters, finding geometries similar to our earlier calculations. However, although that paper argued that the stabilization energy of negative ion clusters H(n)(-) is small, vibration frequencies for the whole set of clusters was not reported, and so a definitive assertion of a true equilibrium was not present. In this paper we recalculate the energetics of the ion induced dipole clusters using density function theory (DFT) B3LYP method calculations in a basis of functions (6-311++G(d,p)). By calculating the vibration frequencies of the VSEPR geometries, we prove that in general they are not true minima because not all the resulting frequencies correspond to real values. By searching the energy surface of the B3LYP calculations, we find the true minimum geometries, which are surprising configurations and are perhaps counterintuitive. We calculate the total energy and binding energy of the new geometries. We also calculate the bond paths associated with the quantum theory of atoms in molecules (QTAIM). The B3LYP/6-311++G(d,p) results, for each molecule, deliver bond paths that radiate between each polarized H2 molecule and the polarizing H(-) ion. PMID- 21786782 TI - Comment on color loss in ethanolic solutions of chlorophyll a. PMID- 21786784 TI - Real-time observation of impurity diffusion in silicon nanowires. AB - Solid-state diffusion of the transition metal impurities, gold (Au), nickel (Ni), and copper (Cu), in silicon (Si) nanowires was studied by in situ transmission electron microscopy. Compared to diffusion in a bulk crystal, Au diffusion is extremely slow when the amount of metal is limited but significantly enhanced when an unlimited supply is available. Cu and Ni diffusion leads to rapid silicide formation but slows considerably with physical encapsulation by a volume restricting carbon shell. PMID- 21786785 TI - NMR-based metabolomics reveals that conjugated double bond content and lipid storage efficiency in HepG2 cells are affected by fatty acid cis/trans configuration and chain length. AB - In the present study the metabolic response to various fatty acids was investigated in HepG2 cells by using a (1)H NMR-based approach. To elucidate the effect of cis/trans configuration, the cells were exposed to either oleic acid (C18:1 cis-9), elaidic acid (C18:1 trans-9), vaccenic acid (C18:1 trans-11), linoleic acid (C18:2), or palmitic acid (C16:0), and multivariate data analysis revealed a strong effect of fatty acid on the lipophilic metabolite fraction. Inspection of the spectra revealed that the difference between the observed responses could be ascribed to the appearance of resonances from conjugated double bonds (5.65, 5.94, and 6.28 ppm) in cells exposed to vaccenic acid, revealing that vaccenic acid upon uptake by the HepG2 cells is converted into a conjugated fatty acid. Upon exposure of the HepG2 cells to either butyric acid (C4:0), caproic acid (C6:0), lauric acid (C12:0), myristic acid (C14:0), or palmitic acid (C16:0), an effect of fatty acid length was also evident, and data indicated that short-chain fatty acids (C4-C6) are immediately converted, whereas medium-long-chain fatty acids (C12-16) are incorporated into triglycerides and deposited in the cells. In conclusion, the present study demonstrates that (1)H NMR spectroscopy is a useful method for studying the uptake of fatty acids in in vitro cells. PMID- 21786783 TI - Antibiotics as signal molecules. PMID- 21786786 TI - Growth of straight InAs-on-GaAs nanowire heterostructures. AB - One of the main motivations for the great interest in semiconductor nanowires is the possibility of easily growing advanced heterostructures that might be difficult or even impossible to achieve in thin films. For III-V semiconductor nanowires, axial heterostructures with an interchange of the group III element typically grow straight in only one interface direction. In the case of InAs-GaAs heterostructures, straight nanowire growth has been demonstrated for growth of GaAs on top of InAs, but so far never in the other direction. In this article, we demonstrate the growth of straight axial heterostructures of InAs on top of GaAs. The heterostructure interface is sharp and we observe a dependence on growth parameters closely related to crystal structure as well as a diameter dependence on straight nanowire growth. The results are discussed by means of accurate first principles calculations of the interfacial energies. In addition, the role of the gold seed particle, the effect of its composition at different stages during growth, and its size are discussed in relation to the results observed. PMID- 21786788 TI - Spontaneous phase and morphology transformations of anodized titania nanotubes induced by water at room temperature. AB - We report a spontaneous phase transformation of titania nanotubes induced by water at room temperature, which enables the as-anodized amorphous nanotubes to be crystallized into anatase mesoporous nanowires without any other post treatments. These mesoporous TiO(2) nanomaterials have a markedly improved surface area, about 5.5 times than that of the as-anodized TiO(2) nanotubes, resulting in a pronounced enhanced photocatalytic activity. The present approach not only allows a flexible control over the morphology of TiO(2) nanostructures but can fundamentally eliminate the need for high temperature operations for crystallizing amorphous TiO(2). PMID- 21786787 TI - Bioactivity-guided fractionation for the butyrylcholinesterase inhibitory activity of furanocoumarins from Angelica archangelica L. roots and fruits. AB - Isolation and identification of the inhibitors of butyrylcholinesterase (BChE), obtained from the extracts of roots and fruits of Angelica archangelica L., are reported. Our results confirmed the weak inhibitory effect of Angelica roots on acetylcholinesterase activity. BChE inhibition was much more pronounced at a concentration of 100 MUg/mL for hexane extracts and attained a higher rate than 50%. The TLC bioautography guided fractionation and spectroscopic analysis led to the isolation and identification of imperatorin from the fruit's hexane extract and of heraclenol-2'-O-angelate from the root's hexane extract. Both compounds showed significant BChE inhibition activity with IC(50) = 14.4 +/- 3.2 MUM and IC(50) = 7.5 +/- 1.8 MUM, respectively. Only C8-substituted and C5-unsubstituted furanocoumarins were active, which could supply information about the initial structures of specific BChE inhibitors. PMID- 21786789 TI - An unexpected oxidation of unactivated methylene C-H using DIB/TBHP protocol. AB - An in situ generated hypervalent iodine species, bis(tert butylperoxy)iodobenzene, was used as a peroxy radical source for the oxidation of unreactive, remote, and isolated alkyl (cyclic or aliphatic) esters and amides to the corresponding keto compounds under very mild conditions. PMID- 21786790 TI - Oxidative coupling as a biomimetic approach to the synthesis of scytonemin. AB - The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations in its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated in a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4 dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin. PMID- 21786791 TI - Simultaneous quantification of multiple nucleic acid targets using chemiluminescent probes. AB - A novel method is described for simultaneous detection and quantification of attomoles or a few femtomoles of two (or potentially more) nucleic acid targets, without need for amplification. The technique depends on spectral-temporal resolution of chemiluminescence emitted from independent hybridization-induced chemiluminescent signal probes. The probes are internally quenched except in the presence of their specific targets, thereby allowing detection limits up to 10,000 times lower than with fluorescent probes. This is sufficient to obviate the need for amplification in many cases. The utility of the technique has been demonstrated by use of resolvable N-linked acridinium and 2,7-dimethoxyacridinium ester labeled probes in a homogeneous assay for sensitive and simultaneous independent quantification of pan-bacterial and pan-fungal target sequences in seawater. PMID- 21786792 TI - Continuous lipid bilayers derived from cell membranes for spatial molecular manipulation. AB - Progress with respect to enrichment and separation of native membrane components in complex lipid environments, such as native cell membranes, has so far been very limited. The reason for the slow progress can be related to the lack of efficient means to generate continuous and laterally fluid supported lipid bilayers (SLBs) made from real cell membranes. We show in this work how the edge of a hydrodynamically driven SLB can be used to induce rupture of adsorbed lipid vesicles of compositions that typically prevent spontaneous SLB formation, such as vesicles made of complex lipid compositions, containing high cholesterol content or being derived from real cell membranes. In particular, upon fusion between the moving edge of a preformed SLB and adsorbed vesicles made directly from 3T3 fibroblast cell membranes, the membrane content of the vesicles was shown to be efficiently transferred to the SLB. The molecular transfer was verified using cholera toxin B subunit (CTB) binding to monosialoganglioside receptors (G(M1) and G(M3)), and the preserved lateral mobility was confirmed by spatial manipulation of the G(M1/M3)-CTB complex using a hydrodynamic flow. Two populations of CTB with markedly different drift velocity could be identified, which from dissociation kinetics data were attributed to CTB bound with different numbers of ganglioside anchors. PMID- 21786793 TI - Synthesis and biological activities of (R)- and (S)-N-(4-Methoxyphenyl)-N,2,6 trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride as potent cytotoxic antitubulin agents. AB - (R,S)-1 is a potent antimitotic compound. (R)-1.HCl and (S)-1.HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88 fold more potent than the (R)-isomer. PMID- 21786794 TI - Infrared study of the bacterial autoinducer N-hexanoyl-homoserine lactone (C6 HSL) in the gas-phase, water, and octanol solutions. AB - The N-hexanoyl-homoserine lactone (C6-HSL) molecule has been investigated by means of infrared multiphoton dissociation (IRMPD) and Fourier-transform infrared spectroscopy (FT-IR) under different conditions in an attempt to mimic biological situations encountered in communication between bacteria for quorum sensing. The protonated molecular ion was studied in the gas-phase that corresponds to a solvent-free situation somewhat analogous to that encountered in the receptor. The simulation of the IRMPD spectrum of the isolated ion was then conducted by means of quantum chemistry calculations in vacuum. In the case of the neutral species, the FT-IR spectra were recorded in D(2)O, mimicking the cytosolic and extracellular media as well as in 1-octanol that is often used for simulation of cell membranes. The interpretation was conducted by considering a C6-HSL molecule in its endo or exo conformation hydrogen-bonded to, respectively, six D(2)O and four 1-octanol molecules. A satisfying agreement with the experimental FT-IR studies conducted in solution at room temperature was obtained as long as a continuum IEFPCM model was added to the explicit solvent environment. PMID- 21786795 TI - Green synthesis of gold nanoparticles using glycerol-incorporated nanosized liposomes. AB - There has been enormous interest in the last decade in development methods for the inorganic synthesis of metallic nanoparticles of desired sizes and shapes because of their unique properties and extensive applications in catalysis, electronics, plasmonics, and sensing. Here we report on an environmentally friendly, one-pot synthesis of metallic nanoparticles, which avoids the use of organic solvents and requires mild experimental conditions. The developed method uses liposomes as nanoreactors, where the liposomes were prepared by encapsulating chloroauric acid and exploited the use of glycerol, incorporated within the lipid bilayer as well as in its hydrophilic core, as a reducing agent for the controlled preparation of highly homogeneous populations of gold nanoparticles. The effects of temperature, the presence of a capping agent, and the concentration of glycerol on the size and homogeneity of the nanoparticles formed were investigated and compared with solution-based glycerol-mediated nanoparticle synthesis. Well-distributed gold nanoparticle populations in the range of 2-8 nm were prepared in the designed liposomal nanoreactor with a clear dependence of the size on the concentration of glycerol, the temperature, and the presence of a capping agent whereas large, heterogeneous populations of nanoparticles with amorphous shapes were obtained in the absence of liposomes. The particle morphology and sizes were analyzed using transmission electron microscopy imaging, and the liposome size was measured using photon correlation spectroscopy. PMID- 21786796 TI - Analysis of hydrogen-bond interaction potentials from the electron density: integration of noncovalent interaction regions. AB - Hydrogen bonds are of crucial relevance to many problems in chemistry, biology, and materials science. The recently developed NCI (noncovalent interactions) index enables real-space visualization of both attractive (van der Waals and hydrogen-bonding) and repulsive (steric) interactions based on properties of the electron density. It is thus an optimal index to describe the interplay of stabilizing and destabilizing contributions that determine stable minima on hydrogen-bonding potential-energy surfaces (PESs). In the framework of density functional theory, energetics are completely determined by the electron density. Consequently, NCI will be shown to allow quantitative treatment of hydrogen-bond energetics. The evolution of NCI regions along a PES follows a well-behaved pattern which, upon integration of the electron density, is capable of mimicking conventional hydrogen-bond interatomic potentials. PMID- 21786797 TI - beta-Galactosidase fluorescence probe with improved cellular accumulation based on a spirocyclized rhodol scaffold. AB - We identified a rhodol bearing a hydroxymethyl group (HMDER) as a suitable scaffold for designing fluorescence probes for various hydrolases. HMDER shows strong fluorescence at physiological pH, but phenolic O-alkylation of HMDER results in a strong preference for the spirocyclic form, which has weak fluorescence. As a proof of concept, we utilized this finding to develop a new fluorescence probe for beta-galactosidase. This probe has favorable characteristics for imaging in biological samples: it has good cellular permeability, and its hydrolysis product is well-retained intracellularly. It could rapidly and clearly visualize beta-galactosidase activity in cultured cells and in Drosophila melanogaster tissue, which has rarely been achieved with previously reported fluorescence probes. PMID- 21786799 TI - Microscale liquid dynamics and the effect on macroscale propagation in pillar arrays. AB - Liquid dynamics in micropillar arrays have received significant fundamental interest and have offered opportunities for the development of advanced microfluidic, thermal management, and energy-harvesting devices. However, a comprehensive understanding of complex liquid behavior and the effect on macroscopic propagation rates in micropillar arrays is needed. In this work, we investigated the microscopic sweeping behavior of the liquid front along the spreading direction in micropillar arrays where the sweeping distance scales with the one-fifth power of time. We explain the scaling with a simplified model that captures the capillary pressure gradient at the liquid front. Furthermore, we show that such microscopic dynamics is the mechanism that decreases the macroscopic propagation rate. This effect is a result of the reduction in the interfacial energy difference used to generate the capillary pressure, which is explained with an energy-based model and corroborated with experiments. The results indicate the importance of accounting for the microscopic dynamics of the liquid on microstructured surfaces, particularly in sparse geometries. PMID- 21786798 TI - Nitrogen kinetic isotope effects for the monoamine oxidase B-catalyzed oxidation of benzylamine and (1,1-(2)H2)benzylamine: nitrogen rehybridization and CH bond cleavage are not concerted. AB - Nitrogen kinetic isotope effects for the oxidation of benzylamine and (1,1 (2)H(2))benzylamine by recombinant human monoamine oxidase B show that cleavage of the CH bond is not concerted with rehybridization of the nitrogen atom. PMID- 21786800 TI - Role of ion flux on alignment of carbon nanofibers synthesized by DC plasma on transparent insulating substrates. AB - A key factor to the implementation of devices with vertically aligned carbon nanofibers (VACNFs) is fundamental understanding of how to control fluctuations in the growth direction of the fibers. Here we demonstrate synthesis of VACNF on transparent and insulating substrates by continuous direct current (DC) plasma for realization of cellular interface suitable for transmission optical microscopy. To maintain continuous glow discharge above the substrate, a metal grid electrode layer (Cr) was deposited over silica with windows of exposed silica ranging in size from 200 MUm to 1 mm. This electrode geometry allows for synthesis of VACNFs even within an insulating window. This observation and the observed trends in the alignment of nanofibers in the vicinity of grid electrodes have indicated that the alignment does not correspond to the direction of the electric field at the substrate level, contrary to previously proposed alignment mechanism. Computational modeling of the plasma with this grid cathode geometry has shown that nanofiber alignment trends follow calculated ion flux direction rather than electrical field. The new proposed alignment mechanism is that ion sputtering of the carbon film on a catalyst particle defines the growth direction of the nanofibers. With this development, fiber growth direction can be better manipulated through changes in ionic flux direction, opening the possibility for growth of nanofibers on substrates with unique geometries. PMID- 21786801 TI - Synthesis and characterization of a series of highly fluorogenic substrates for glutathione transferases, a general strategy. AB - Glutathione transferases (GSTs) are used in biotechnology applications as fusion partners for facile purification and are also overexpressed in certain tumors. Consequently, there is a need for sensitive detection of the enzymes. Here we describe a general strategy for the synthesis and characterization of novel fluorogenic substrates for GSTs. The substrates were synthesized by introducing an electrophilic sulfonamide linkage to fluorescent molecules containing an amino group [e.g., 2,4-dinitrobenzenesulfonamide (DNs) derivatives of coumarin, cresyl violet, and rhodamine]. The derivatives were essentially nonfluorescent, and upon GST catalyzed cleavage of the dinitrobenzenesulfonamide, free fluorophore is released (and 1-glutathionyl-2,4-dinitrobenzene + SO(2)). All the coumarin-, cresyl violet- and rhodamine-based fluorogenic probes turned out to be good substrates for most GSTs, especially for GSTA(1-1), in terms of strong fluorescence increases (71-1200-fold), high k(cat)/K(m) values (10(4)-10(7) M(-1) s(-1)) and significant rate enhancements (10(6)-10(9)-fold). The substrates were successfully applied to quantitate very low levels of GST activity in cell extracts and DNs-cresyl violet was also successfully applied to the imaging of microsomal MGST(1) activity in living cells. The cresyl violet stained cells retained their fluorescence after fixation, which is a very useful property. In summary, we describe a general and versatile strategy to generate fluorogenic GST substrates, some of them providing the most sensitive assays so far described for GSTs. PMID- 21786802 TI - Synthesis and characterization of fluorescent pyrrolyldipyrrinato Sn(IV) complexes. AB - A series of neutral, 5-coordinate pyrrolyldipyrrinato Sn(IV) complexes have been synthesized via reaction of a pyrrolyldipyrrin, or its corresponding hydrochloride salt, with dibutyltin or diphenyltin oxide. The complexes are structurally unique in that all three nitrogen atoms of the pyrrolyldipyrrinato ligand bind to the tin center, making these complexes the first examples of pyrrolyldipyrrins behaving as LX(2) ligands. The complexes are highly fluorescent, exhibiting fluorescence quantum yields between 0.28 and 0.61, and display interesting preliminary biological activity. PMID- 21786804 TI - Temperature effects on the rovibrational spectra of pyrene-based PAHs. AB - Absorption infrared spectra have been computed for a variety of polycyclic aromatic hydrocarbon molecules of the pyrene family, taking into account anharmonicity and temperature effects, rovibrational quantization, and couplings. The energy levels are described by a second-order perturbative expansion of the rovibrational Hamiltonian in the vibrational and rotational quantum numbers, as relevant for a symmetric-top molecule, with ingredients obtained from quantum chemistry calculations. Multicanonical Monte Carlo simulations are carried out to compute bidimensional IR intensity histograms as a function of total energy and vibrational frequency, which then provide the absorption spectrum at arbitrary temperatures via a Laplace transformation. The main spectral features analyzed for neutral, anionic, and cationic pyrene indicate a strong dependence on temperature, in agreement with existing laboratory experiments, and a significant contribution of rotational degrees of freedom to the overall broadenings. The spectral shifts and broadenings reveal some sensitivity of anharmonicities to the charge and protonation states and, in the case of protonated pyrene and pyrenyl cation, on possible isomers and between aromatic and aliphatic C-H bands. Implications of the present work to the general issue of interstellar emission features are discussed. PMID- 21786803 TI - Design, synthesis, and biological evaluation of triazolo-pyrimidine derivatives as novel inhibitors of hepatitis B virus surface antigen (HBsAg) secretion. AB - The high levels of hepatitis B virus (HBV) surface antigen (HBsAg)-bearing subviral particles in the serum of chronically infected individuals play an important role in suppressing HBV-specific immune response and are only mildly affected by the current small molecule therapies. Thus, a therapy that specifically reduces HBsAg serum levels could be used in combination therapy with nucleos(t)ide drugs or permit therapeutic vaccination for the treatment of HBV infection. Herein, we report the design, synthesis, and evaluation of novel triazolo-pyrimidine inhibitors (1, 3, and 4) of HBsAg cellular secretion, with activity against drug-resistant HBV variants. Extensive SAR led to substantial improvements in the EC(50) of the parent compound, 5 (HBF-0259), with the best being 3c, with EC(50) = 1.4 +/- 0.4 MUM, SI >= 36. The lead candidates, both 1a (PBHBV-001) and 3c (PBHBV-2-15), were well-tolerated in both normal and HBV transgenic mice and exhibited acceptable pharmacokinetics and bioavailability in Sprague-Dawley rats. PMID- 21786806 TI - Effect of nitrate, perchlorate, and water on uranyl(VI) speciation in a room temperature ionic liquid: a spectroscopic investigation. AB - Room-temperature ionic liquids form potentially important solvents in novel nuclear waste reprocessing methods, and the solvation, speciation, and complexation behaviors of lanthanides and actinides in these solvents are of great current interest. In the study reported here, the coordination environment of uranyl(VI) in solutions of the room-temperature ionic liquid 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][Tf(2)N]) containing perchlorate, tetrabutylammonium nitrate, and water was investigated using Raman, ATR-FTIR, and NMR spectroscopies in order to better understand the role played in uranyl(VI) solution chemistry in room-temperature ionic liquids by water and other small, weakly complexing ligands. The (2)H NMR chemical shift for water in a solution of uranyl perchlorate hexahydrate in [EMIM][Tf(2)N] appears at 6.52 ppm, indicating that water is coordinated to uranyl(VI). A broad nu(OH) stretching mode at 3370 cm(-1) in the ATR-FTIR spectrum shows that this coordinated water is engaged in hydrogen bonding with water molecules in a second coordination sphere. A significant upfield shift in the (2)H NMR signal for water and the appearance of distinct nu(as)(HOH) (at 3630 cm(-1)) and nu(s)(HOH) (at 3560 cm(-1)) vibrational bands in the ATR-FTIR spectra show that coordinated water is displaced by nitrate upon formation of the UO(2)(NO(3))(2) and UO(2)(NO(3))(3)(-) complexes. The Raman spectra indicate that perchlorate complexed to uranyl(VI) is also displaced by nitrate. Our results indicate that perchlorate and water, though weakly complexing ligands, do have a role in uranyl(VI) speciation in room-temperature ionic liquids and that Raman, infrared, and NMR spectroscopies are valuable additions to the suite of tools currently used to study the chemical behavior of uranyl(VI)-ligand complexes in these solvents. PMID- 21786805 TI - Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11beta hydroxysteroid dehydrogenase type 1. AB - Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11beta-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000* selectivity over 11beta-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge. PMID- 21786807 TI - Purified phenolics from hydrothermal treatments of biomass: ability to protect sunflower bulk oil and model food emulsions from oxidation. AB - The phenolic fractions released during hydrothermal treatment of selected feedstocks (corn cobs, eucalypt wood chips, almond shells, chestnut burs, and white grape pomace) were selectively recovered by extraction with ethyl acetate and washed with ethanol/water solutions. The crude extracts were purified by a relatively simple adsorption technique using a commercial polymeric, nonionic resin. Utilization of 96% ethanol as eluting agent resulted in 47.0-72.6% phenolic desorption, yielding refined products containing 49-60% w/w phenolics (corresponding to 30-58% enrichment with respect to the crude extracts). The refined extracts produced from grape pomace and from chestnut burs were suitable for protecting bulk oil and oil-in-water and water-in-oil emulsions. A synergistic action with bovine serum albumin in the emulsions was observed. PMID- 21786808 TI - Probing highly efficient photoisomerization of a bridged azobenzene by a combination of CASPT2//CASSCF calculation with semiclassical dynamics simulation. AB - Mechanism of phototriggered isomerization of azobenzene and its derivatives is of broad interest. In this paper, the S(0) and S(1) potential energy surfaces of the ethylene-bridged azobenzene (1) that was recently reported to have highly efficient photoisomerization were determined by ab initio electronic structure calculations at different levels and further investigated by a semiclassical dynamics simulation. Unlike azobenzene, the cis isomer of 1 was found to be more stable than the trans isomer, consistent with the experimental observation. The thermal isomerization between cis and trans isomers proceeds via an inversion mechanism with a high barrier. Interestingly, only one minimum-energy conical intersection was determined between the S(0) and S(1) states (CI) for both cis -> trans and trans -> cis photoisomerization processes and confirmed to act as the S(1) -> S(0) decay funnel. The S(1) state lifetime is ~30 fs for the trans isomer, while that for the cis isomer is much longer, due to a redistribution of the initial excitation energies. The S(1) relaxation dynamics investigated here provides a good account for the higher efficiency observed experimentally for the trans -> cis photoisomerization than the reverse process. Once the system decays to the S(0) state via CI, formation of the trans product occurs as the downhill motion on the S(0) surface, while formation of the cis isomer needs to overcome small barriers on the pathways of the azo-moiety isomerization and rotation of the phenyl ring. These features support the larger experimental quantum yield for the cis -> trans photoisomerization than the trans -> cis process. PMID- 21786809 TI - Superlattice of rodlike virus particles formed in aqueous solution through like charge attraction. AB - Rodlike tobacco mosaic virus (TMV) has been found to assemble into a 2D superlattice in aqueous solution with hexagonally packed structures in the presence of Ba(2+) through like-charge attraction whereas lower-Z divalent ions such as Zn(2+), Cd(2+), Mg(2+), and Ca(2+) induce only liquidlike ordering. The molar ratio between Ba(2+) and TMV is a crucial parameter in the formation of the superlattice. There is a critical molar ratio of Ba(2+) to TMV at which TMV exhibits a transition from a nonordered colloidal state to an ordered crystalline state. It is also found that the superlattice is formed regardless of the pH and TMV concentration within the range studied. PMID- 21786811 TI - Ultrafast coloring-bleaching performance of nanoporous WO3-SiO2 gasochromic films doped with Pd catalyst. AB - The gasochromic performance and durability of WO(3)-based films can be improved by doping SiO(2) particles within WO(3) matrix forming nanoporous supporting network and dispersing Pd catalyst inside films with enhanced catalytic activity. Nanoporous WO(3)-SiO(2) composite films loaded with Pd catalyst were prepared by sol-gel dip-coating process and served as an active chromogenic layer to fabricate a double-glazed gasochromic device. The structure, morphology, optical properties and gasochromic performance of WO(3)-SiO(2) films were fully investigated. The WO(3)-SiO(2) films exhibit excellent gasochromic performance with ultrafast coloring rate of 14.8% per second (%/s) (WO(3): 2.84%/s) and bleaching rate of 44.1%/s (WO(3): 7.18%/s). The transmittance changed between 17.8 and 74.6% during coloring-bleaching cycles, and totally reversibility and stability were achieved. PMID- 21786810 TI - Solid-state NMR spectroscopy provides atomic-level insights into the dehydration of cartilage. AB - An atomic-level insight into the functioning of articular cartilage would be useful to develop prevention strategies and therapies for joint diseases such as osteoarthritis. However, the composition and structure of cartilage and their relationship to its unique mechanical properties are quite complex and pose tremendous challenges to most biophysical techniques. In this study, we present an investigation of the structure and dynamics of polymeric molecules of articular cartilage using time-resolved solid-state NMR spectroscopy during dehydration. Full-thickness cartilage explants were used in magic-angle spinning experiments to monitor the structural changes of rigid and mobile carbons. Our results reveal that the dehydration reduced the mobility of collagen amino acid residues and carbon sugar ring structures in glycosaminoglycans but had no effect on the trans-Xaa-Pro conformation. Equally interestingly, our results demonstrate that the dehydration effects are reversible, and the molecular structure and mobility are restored upon rehydration. PMID- 21786813 TI - Interaction of ionic surfactants with cornea-mimicking anionic liposomes. AB - The interaction of surface-active molecules with lipid bilayers is ubiquitous both in biological systems and also in several technological applications. Here we explore the interaction of ionic surfactants with liposomes whose composition mimics the ocular epithelia. In this study, liposomes with a composition mimicking ocular epithelia are loaded with calcein dye above the self-quenching concentration. The liposomes are then exposed to surfactants, and the rate of dye leaked from the liposomes due to the interaction of surfactants is measured. Both cationic and anionic surfactants at various concentrations and ionic strengths are explored. Results show that the liposome bilayer permeability to the dye increases on exposure to the surfactants, leading to the release of the dye trapped in the core. However, the dye release stops after a finite time, suggesting a transient increase in permeability followed by healing. The leakage profiles exhibit two different timescales for the cationic surfactant but only one timescale for the anionic surfactant. The total dye leakage increases with surfactant concentration, and at a given concentration, the dye leakage is significantly higher for the cationic surfactants. The timescale for the healing decreases with increasing surfactant concentration, and increasing ionic strength increases the dye leakage for the anionic surfactant. These results show that the surfactant binding to the lipid bilayer increases the permeability while the bilayers heal likely because of the surfactant jump from the outer to the inner leaflet and/or rearrangement into tighter aggregates. PMID- 21786812 TI - Noncovalent polymerization of mesogens crystallizes lysozyme: correlation between nonamphiphilic lyotropic liquid crystal phase and protein crystal formation. AB - Crystallization of proteins is important for fundamental studies and biopharmaceutical development but remains largely an empirical science. Here, we report the use of organic salts that can form a class of unusual nonamphiphilic lyotropic liquid crystals to crystallize the protein lysozyme. Certain nonamphiphilic organic molecules with fused aromatic rings and two charges can assemble into stable thread-like noncovalent polymers that may further form liquid crystal phases in water, traditionally termed chromonic liquid crystals. Using five of these mesogenic molecules as additives to induce protein crystallization, we discover that molecules that can form liquid crystal phases in water are highly effective at inducing the crystal formation of lysozyme, even at concentrations significantly lower than that required for forming liquid crystal phases. This result reveals an example of inducing protein crystallization by the molecular assembly of the additives, and is consistent with a new mechanism by which the strong hydration of an assembly process provides a gradual means to compete for the water molecules to enable solvated proteins to form crystals. PMID- 21786814 TI - Determination of the physical properties of room temperature ionic liquids using a Love wave device. AB - In this work, we have shown that a 100 MHz Love wave device can be used to determine whether room temperature ionic liquids (RTILs) are Newtonian fluids and have developed a technique that allows the determination of the density-viscosity product, rhoeta, of a Newtonian RTIL. In addition, a test for a Newtonian response was established by relating the phase change to insertion loss change. Five concentrations of a water-miscible RTIL and seven pure RTILs were measured. The changes in phase and insertion loss were found to vary linearly with the square root of the density-viscosity product for values up to (rhoeta)(1/2) ~ 10 kg m(-2) s(-1/2). The square root of the density-viscosity product was deduced from the changes in either phase or insertion loss using glycerol as a calibration liquid. In both cases, the deduced values of rhoeta agree well with those measured using viscosity and density meters. Miniaturization of the device, beyond that achievable with the lower-frequency quartz crystal microbalance approach, to measure smaller volumes is possible. The ability to fabricate Love wave and other surface acoustic wave sensors using planar metallization technologies gives potential for future integration into lab-on-a-chip analytical systems for characterizing ionic liquids. PMID- 21786815 TI - Quantitative proteomic analysis of the heat stress response in Clostridium difficile strain 630. AB - Clostridium difficile is a serious nosocomial pathogen whose prevalence worldwide is increasing. Postgenomic technologies can now be deployed to develop understanding of the evolution and diversity of this important human pathogen, yet little is known about the adaptive ability of C. difficile. We used iTRAQ labeling and 2D-LC-MS/MS driven proteomics to investigate the response of C. difficile 630 to a mild, but clinically relevant, heat stress. A statistically validated list of 447 proteins to which functional roles were assigned was generated, allowing reconstruction of central metabolic pathways including glycolysis, gamma-aminobutyrate metabolism, and peptidoglycan biosynthesis. Some 49 proteins were significantly modulated under heat stress: classical heat shock proteins including GroEL, GroES, DnaK, Clp proteases, and HtpG were up-regulated in addition to several stress inducible rubrerythrins and proteins associated with protein modification, such as prolyl isomerases and proline racemase. The flagellar filament protein, FliC, was down-regulated, possibly as an energy conservation measure, as was the SecA1 preprotein translocase. The up-regulation of hydrogenases and various oxidoreductases suggests that electron flux across these pools of enzymes changes under heat stress. This work represents the first comparative proteomic analysis of the heat stress response in C. difficile strain 630, complementing the existing proteomics data sets and the single microarray comparative analysis of stress response. Thus we have a benchmark proteome for this pathogen, leading to a deeper understanding of its physiology and metabolism informed by the unique functional and adaptive processes used during a temperature upshift mimicking host pyrexia. PMID- 21786816 TI - Selective homogeneous hydrogenation of biogenic carboxylic acids with [Ru(TriPhos)H]+: a mechanistic study. AB - Selective hydrogenation of biogenic carboxylic acids is an important transformation for biorefinery concepts based on platform chemicals. We herein report a mechanistic study on the homogeneously ruthenium/phosphine catalyzed transformations of levulinic acid (LA) and itaconic acid (IA) to the corresponding lactones, diols, and cyclic ethers. A density functional theory (DFT) study was performed and corroborated with experimental data from catalytic processes and NMR investigations. For [Ru(TriPhos)H](+) as the catalytically active unit, a common mechanistic pathway for the reduction of the C?O functionality in aldehydes, ketones, lactones, and even free carboxylic acids could be identified. Hydride transfer from the Ru-H group to the carbonyl or carboxyl carbon is followed by protonation of the resulting Ru-O unit via sigma bond metathesis from a coordinated dihydrogen molecule. The energetic spans for the reduction of the different functional groups increase in the order aldehyde < ketone < lactone ~ carboxylic acid. This reactivity pattern as well as the absolute values are in full agreement with experimentally observed activities and selectivities, forming a rational basis for further catalyst development. PMID- 21786817 TI - Assessment of the determination of azodicarbonamide and its decomposition product semicarbazide: investigation of variation in flour and flour products. AB - Azodicarbonamide, as a bleaching agent and improving agent, is a permitted food additive in certain countries and can be determined by high-performance liquid chromatography. However, it partially degrades with the heat of processing to form trace amounts of semicarbazide, which shows carcinogenicity and also has been shown to cause tumors. The concentration of semicarbazide in azodicarbonamide-treated flour was determined by isotope dilution ((13)C, (15)N(2)-semicarbazide) liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS). The quantification was obtained utilizing the homologous internal standard. The limits of detection were 1 mg/kg for azodicarbonamide and 0.5 * 10(-3) mg/kg for semicarbazide. The rates of recovery were 82.3-103.1% for azodicarbonamide and 72.4-116.5% for semicarbazide. This study prepared four different types of flour products to investigate the variation of semicarbazide. The concentration of semicarbazide in all types of flour products is higher than that in flour, and the concentration of semicarbazide in outside of flour products is slightly higher than that in the inside. As the problem of food safety hazard aggravates daily, we should be more concerned about food security and human health. PMID- 21786818 TI - 1,2-BN cyclohexane: synthesis, structure, dynamics, and reactivity. AB - BN/CC isosterism has emerged as a viable strategy to increase the structural diversity of carbon-based compounds. We present the first synthesis and characterization of the parent 1,2-BN cyclohexane, the BN-isostere of cyclohexane. 1,2-BN cyclohexane is an air- and water-stable compound that cleanly forms a trimer with release of dihydrogen when thermally activated. We also demonstrate that 1,2-BN cyclohexane has a lower activation barrier for ring inversion than cyclohexane due to BN/CC isosterism. PMID- 21786819 TI - Tetrarhena-heterocycle from the palladium-catalyzed dimerization of Re2(CO)8(MU SbPh2)(MU-H) exhibits an unusual host-guest behavior. AB - The six-membered heavy atom heterocycles [Re(2)(CO)(8)(MU-SbPh(2))(MU-H)](2), 5, and Pd[Re(2)(CO)(8)(MU-SbPh(2))(MU-H)](2), 7, have been prepared by the palladium catalyzed ring-opening cyclo-dimerization of the three-membered heterocycle Re(2)(CO)(8)(MU-SbPh(2))(MU-H), 3. The palladium atom that lies in the center of the heterocycle 7 was removed to yield 5. The palladium removal was found to be partially reversible leading to an unusual example of host-guest behavior. A related dipalladium complex Pd(2)Re(4)(CO)(16)(MU(4)-SbPh)(MU(3)-SbPh(2))(MU Ph)(MU-H)(2), 6, was also formed in these reactions of palladium with 3. PMID- 21786820 TI - Facile identification of phosphorylation sites in peptides by radical directed dissociation. AB - Identification of phosphorylation sites is of interest due to their importance in protein regulation; however, the identification of the exact sites of this modification is not always easily obtained due to the dynamic nature of phosphorylation and the challenges faced during mass spectrometric analysis. Herein we elaborate on our previous communication (Diedrich, J. K.; Julian, R. R. J. Am. Chem. Soc. 2008, 130, 12212-12213) describing a novel technique for assignment of phosphorylation in a site-specific and facile manner. Phosphorylation sites are selectively modified through beta elimination followed by Michael addition chemistry to install a photolabile group. Photodissociation with 266 nm light yields homolytic cleavage at the modification site, generating a beta radical which is poised to fragment the peptide backbone. Dissociation primarily yields d-type ions at the previously phosphorylated residue, allowing facile identification. Radical directed fragmentation also occurs in smaller abundances at neighboring residues. The mechanisms behind this selective radical fragmentation are presented and the utility is discussed. Fragmentation is shown to be independent of charge state allowing analysis of a wide variety of peptide sequences including peptides with multiple phosphorylation sites. A comparison of this technique is made with collision induced dissociation (CID) and electron capture dissociation (ECD) for representative peptides. PMID- 21786821 TI - Assembly and targeting of liposomal nanoparticles encapsulating quantum dots. AB - Quantum dots (QDs) are attracting intense interest as fluorescence labeling agents for biomedical imaging because biocompatible coatings and relatively nontoxic rare earth metal QDs have emerged as possible options. QD photoemissions are bright, of narrow wavelength range, and very stable. We sought to encapsulate QDs within targeted PEGylated liposomes to reduce their propensity for liver uptake and to amplify the already strong QD emission signal. A novel lipid-QD conjugate initialized a process by which lipids in solution coalesced around the QDs. The liposomal structure was confirmed with size measurements, SEM, and IR spectroscopy. PEGylated QD liposomes injected into a xenograft tumor model largely cleared from the body within 24 h. Residual liver labeling was low. Targeted QD liposomes exhibited robust tumor labeling compared with controls. This study highlights the potential of these near IR emitting QD liposomes for preclinical/clinical applications. PMID- 21786822 TI - Antiplasmodial and antitrypanosomal activity of pyrethrins and pyrethroids. AB - In a screen of 1800 plant and fungal extracts for antiplasmodial, antitrypanosomal, and leishmanicidal activity, the n-hexane extract of Chrysanthemum cinerariifolium (Trevir.) Vis. flowers showed strong activity against Plasmodium falciparum. We isolated the five pyrethrins [i.e., pyrethrin II (1), jasmolin II (2), cinerin II (3), pyrethrin I (4), and jasmolin I (5)] from this extract. These were tested together with 15 synthetic pyrethroids for their activity against P. falciparum and Trypanosoma brucei rhodesiense and for cytotoxicity in rat myoblast L6 cells. The natural pyrethrins showed antiplasmodial activity with IC(50)s between 4 and 12 MUM, and antitrypanosomal activity with IC(50)s from 7 to 31 MUM. The pyrethroids exhibited weaker antiplasmodial and antitrypanosomal activity than the pyrethrins. Both pyrethrins and pyrethroids showed moderate cytotoxicity against L6 cells. Pyrethrin II (1) was the most selective antiplasmodial compound, with a selectivity index of 24. PMID- 21786823 TI - Interaction of ionic liquids ions with natural cyclodextrins. AB - The interaction of natural alpha-, beta-, and gamma-cyclodextrins (CDs) with 14 hydrophobic ionic moieties of ionic liquids (ILs) was systematically examined in dilute aqueous solutions using isothermal titration microcalorimetry (ITC) and NMR spectroscopy. The studied cationic and anionic moieties involved some recently developed heavily fluorinated structures, as well as some others of common use. To isolate the effect of a given ion, the measurements were performed on salts containing the hydrophobic IL ion in question and a complexation inactive counterion. Additional ITC experiments on ILs whose both cation and anion can interact appreciably with the CD cavity demonstrated that to resolve the effect of individual ions from such data is generally a tricky task and confirmed the superiority of the isolation strategy adopted for the purpose throughout this work. The binding constant, enthalpy and entropy determined at 298.15 K for the 1:1 (ion:CD) inclusion complex formation range in broad limits, being 0 < K < 2 * 10(5), 0 < -Delta(r)H degrees /(kJ.mol(-1)) < 44, and -28 < TDelta(r)S degrees /(kJ.mol(-1)) < 14, respectively. The stabilities of complexes of perfluorohexyl bearing ions with beta-CD belong to the highest ever observed with natural CDs in water. The established binding affinity scales were discussed in both thermodynamic and molecular terms. The concepts of hydrophobic interaction and guest-host size matching supported by simple molecular modeling proved useful to rationalize the observed widely different binding affinities and suggest possible binding modes. Enthalpy and entropy contributions to the stability of the ion-CD complexes were found to compensate each other considerably obeying more or less the linear compensation relationship marked by existing literature data on binding other guests to natural CDs. As outliers to this pattern, the most stable complexes of -C(6)F(13) bearing ions with beta-CD were found to receive an enhanced inherent entropy stabilization due to extraordinarily high extent of desolvation occurring in the course of binding. PMID- 21786824 TI - Copper(I)-catalyzed regioselective propargylic substitution involving Si-B bond activation. AB - The silicon nucleophile generated by copper(I)-catalyzed Si-B bond activation allows several gamma-selective propargylic substitutions. The regioselectivity (gamma:alpha ratio) is strongly dependent on the propargylic leaving group. Chloride is superior to oxygen leaving groups in linear substrates (gamma:alpha > 99:1), and it is only the phosphate group that also shows promising regiocontrol (gamma:alpha = 90:10). That leaving group produces superb gamma-selectivity (gamma:alpha > 99:1) in alpha-branched propargylic systems, and enantioenriched substrates react with excellent central-to-axial chirality transfer. PMID- 21786825 TI - Transition-metal-free alkynylation of aryl chlorides. AB - Two sets of conditions have been developed for a base-mediated, transition-metal free alkynylation of aryl chlorides that proceeds via benzyne intermediates. The first set of conditions involves the use of TMPLi base in a pentane/THF mixture at 25 degrees C. The second set involves use of a metal alkoxide base in dioxane at elevated temperature. Reasonable functional group tolerance has been observed. Fluoro, trifluoromethyl, silyl, cyano, and alcohol functionalities are compatible with the reaction conditions. PMID- 21786826 TI - A Cu@Au nanoparticle-based colorimetric competition assay for the detection of sulfide anion and cysteine. AB - As an extension of our previous work, which described the unique ability of the core/shell Cu@Au nanoparticle (NP) to selectively recognize iodide, (1) herein, we wish to report the development of an alternatively sensitive and selective colorimetric detection for sulfide anion and cysteine based upon the Cu@Au NP by a competition avenue. In the absence of sulfide anion or cysteine, iodide can induce an appreciable color change of the Cu@Au NP solution from purple to red by transforming the clusters of NP to single, nearly spherical, and larger ones. However, the transformation is severely interfered by the presence of sulfide or cysteine because of a higher binding strength of the S-Au bond than the I-Au one. As a result, the clear purple-to-red color change induced by iodide is affected as a correlation with the concentration of sulfide or cysteine. By taking advantage of this fact, we can detect a concentration of 3 MUM for sulfide and 0.4 MUM for cysteine with the naked eye or 0.3 MUM (10 ppb) for sulfide and 50 nM (6 ppb) for cysteine aided by a UV/vis spectrometer. Given the detrimental effect of hydrogen sulfide and the biological importance of cysteine, the assay may become useful in the environment monitoring, water quality inspection and biomedical diagnosis as well. PMID- 21786827 TI - Observation of the Fano resonance in gold nanorods supported on high-dielectric constant substrates. AB - Fano resonances in plasmonic nanostructures, characterized by their asymmetric resonance spectral profile, are currently attracting much interest due to their potential applications in biological sensing, metamaterials, photoswitching, and nonlinear optical devices. In this study, we report on the observation of the Fano resonance in Au nanorods induced by their coupling with the supporting substrate. For Au nanorods having a large size and deposited on a substrate with a large dielectric constant, the strong nanorod-substrate coupling gives rise to a Fano line shape on the far-field scattering spectrum. Electrodynamic calculations reveal that the Fano resonance originates from the interference of a broad octupolar and a narrow quadrupolar plasmon mode of the nanorod. Such an interaction is enabled by the strong image charges induced by substrates with high dielectric constants. Moreover, the Fano resonance is very sensitive to the nanorod-substrate spacing. When the spacing is experimentally increased to be larger than ~8 nm, the Fano resonance disappears. These results will be important not only for understanding the interference of different plasmon modes in plasmonic systems but also for developing a number of plasmon-based optical and optoelectronic devices. PMID- 21786828 TI - Nanoparticle-based biocompatible and targeted drug delivery: characterization and in vitro studies. AB - Paclitaxel nanoparticles (PAX NPs) prepared with the size of 110 +/- 10 nm and zeta potential of -40 +/- 3 mV were encapsulated in synthetic/biomacromolecule shell chitosan, dextran-sulfate using a layer-by-layer self-assembly technique. Zeta potential measurements, analysis of X-ray photoelectron spectroscopy, and scanning electron microscopy confirmed the successful adsorption of each layer. Surface modifications of these core-shell NPs were performed by covalently conjugating with poly(ethylene glycol) (H(2)N-PEG-carboxymethyl, M(w) 3400) and fluorescence labeled wheat germ agglutinin (F-WGA) to build a biocompatible and targeted drug delivery system. 32% of PAX was released from four bilayers of biomacromolecule assembled NPs within 8 h as compared with >85% of the drug released from the bare NPs. Moreover, high cell viability with PEG conjugation and high binding capacity of WGA-modified NPs with Caco-2 cells were observed. This biocompatible and targeted NP-based drug delivery system, therefore, may be considered as a potential candidate for the treatment of colonic cancer and other diseases. PMID- 21786829 TI - Stability effects on CO2 adsorption for the DOBDC series of metal-organic frameworks. AB - Metal-organic frameworks with unsaturated metal centers in their crystal structures, such as Ni/DOBDC and Mg/DOBDC, are promising adsorbents for carbon dioxide capture from flue gas due to their high CO(2) capacities at subatmospheric pressures. However, stability is a critical issue for their application. In this paper, the stabilities of Ni/DOBDC and Mg/DOBDC are investigated. Effects of steam conditioning, simulated flue gas conditioning, and long-term storage on CO(2) adsorption capacities are considered. Results show that Ni/DOBDC can maintain its CO(2) capacity after steam conditioning and long term storage, whereas Mg/DOBDC does not. Nitrogen isotherms for Mg/DOBDC show a drop in surface area after steaming, corresponding to the decrease in CO(2) adsorption, which may be caused by a reduction of unsaturated metal centers in its structure. Conditioning with dry simulated flue gas at room temperature only slightly affects CO(2) adsorption in Ni/DOBDC. However, introducing water vapor into the simulated flue gas further reduces the CO(2) capacity of Ni/DOBDC. PMID- 21786832 TI - Nanomedicine for cancer: lipid-based nanostructures for drug delivery and monitoring. AB - Recent advances in nanotechnology, materials science, and biotechnology have led to innovations in the field of nanomedicine. Improvements in the diagnosis and treatment of cancer are urgently needed, and it may now be possible to achieve marked improvements in both of these areas using nanomedicine. Lipid-coated nanoparticles containing diagnostic or therapeutic agents have been developed and studied for biomedical applications and provide a nanomedicine strategy with great potential. Lipid nanoparticles have cationic headgroups on their surfaces that bind anionic nucleic acids and contain hydrophobic drugs at the lipid membrane and hydrophilic drugs inside the hollow space in the interior. Moreover, researchers can design nanoparticles to work in combination with external stimuli such as magnetic field, light, and ionizing radiation, which adds further utility in biomedical applications. In this Account, we review several examples of lipid based nanoparticles and describe their potential for cancer treatment and diagnosis. (1) The development of a lipid-based nanoparticle that included a promoter-enhancer and transcriptional activator greatly improved gene therapy. (2) The addition of a radiosensitive promoter to lipid nanoparticles was sufficient to confer radioisotope-activated expression of the genes delivered by the nanoparticles. (3) We successfully tailored lipid nanoparticle composition to increase gene transduction in scirrhous gastric cancer cells. (4) When lipophilic photosensitizing molecules were incorporated into lipid nanoparticles, those particles showed an increased photodynamic cytotoxic effect on the target cancer. (5) Coating an Fe(3)O(4) nanocrystal with lipids proved to be an efficient strategy for magnetically guided gene-silencing in tumor tissues. (6) An Fe(16)N(2)/lipid nanocomposite displayed effective magnetism and gene delivery in cancer cells. (7) Lipid-coated magnetic hollow capsules carried aqueous anticancer drugs and delivered them in response to a magnetic field. (8) Fluorescent lipid-coated and antibody-conjugated magnetic nanoparticles detected cancer-associated antigen in a microfluidic channel. We believe that the continuing development of lipid-based nanomedicine will lead to the sensitive minimally invasive treatment of cancer. Moreover, the fusion of different scientific fields is accelerating these developments, and we expect these interdisciplinary efforts to have considerable ripple effects on various fields of research. PMID- 21786834 TI - Lewis acid catalyzed reactions of chiral imidazolidinones and oxazolidinones: insights on the role of the catalyst. AB - The mechanism proposed by Evans to justify the selectivity obtained in Lewis acid catalyzed Diels-Alder reactions of cyclopentadiene with acyloxazolidinones has been generalized and used in the rationalization of selectivities obtained in many other systems. However, we recently proposed an alternative mechanism, on the basis of open-chain mono- and bicomplexes, that avoids the need for chelates and explains the selectivity obtained by Evans. In this manuscript we apply our proposal to the catalyzed conjugated addition of amines to acylimidazolidinones, reported by Cardillo, and we clearly show that aluminum chelates are not involved in the reaction, as they induce no selectivity, while Cardillo observed high experimental selectivities. Our data equally show that bicomplexes with carbonyl parallel orientation, proposed by Cardillo to justify the experimental selectivity with nonchelating Lewis acids, indeed induce the opposite selectivity and have also to be dismissed. On the other hand, our mechanistic proposal allows for the full rationalization of the data obtained by Cardillo with aluminum, boron, or zinc Lewis acids and supports our previous proposal on DA cycloadditions of dienes to Evans chiral auxiliary derivatives. PMID- 21786833 TI - Dual-label STED nanoscopy of living cells using photochromism. AB - We demonstrate live-cell STED microscopy of two protein species using photochromic green fluorescent proteins as markers. The reversible photoswitching of two markers is implemented so that they can be discerned with a single excitation and STED wavelength and a single detection channel. Dual-label STED microscopy is shown in living mammalian cells. PMID- 21786835 TI - Palladium-catalyzed decarboxylative coupling of potassium nitrophenyl acetates with aryl halides. AB - A palladium-catalyzed decarboxylative cross-coupling of potassium 2- and 4 nitrophenyl acetates with aryl chlorides and bromides has been developed. Because the nitro group can be readily converted to many other functional groups, the new reaction provides a useful method for the preparation of diverse 1,1-diaryl methanes and their derivatives. PMID- 21786836 TI - Organocatalytic asymmetric sulfa-Michael addition of thiols to 4,4,4 trifluorocrotonates. AB - The first asymmetric sulfa-Michael addition of thiols to 4,4,4 trifluorocrotonates for the construction of a stereogenic center bearing a unique trifluoromethyl group and a sulfur atom has been achieved in high yields and excellent enantioselectivities with a 1 mol % bifunctional organocatalyst. Subsequent transformation led to the expedient preparation of enantioenriched thiochroman-4-one and the key intermediate of the potent inhibitor of MMP-3, (R) gamma-trifluoromethyl gamma-sulfone hydroxamate. PMID- 21786837 TI - Characterization of the phosphoproteome in androgen-repressed human prostate cancer cells by Fourier transform ion cyclotron resonance mass spectrometry. AB - Androgen-repressed human prostate cancer, ARCaP, grows and is highly metastatic to bone and soft tissues in castrated mice. The molecular mechanisms underlying the aberrant responses to androgen are not fully understood. Here, we apply state of-the-art mass spectrometry methods to investigate the phosphoproteome profiles in ARCaP cells. Because protein biological phosphorylation is always substoichiometric and the ionization efficiency of phosphopeptides is low, selective enrichment of phosphorylated proteins/peptides is required for mass spectrometric analysis of phosphorylation from complex biological samples. Therefore, we compare the sensitivity, efficiency, and specificity for three established enrichment strategies: calcium phosphate precipitation (CPP), immobilized metal ion affinity chromatography (IMAC), and TiO(2)-modified metal oxide chromatography. Calcium phosphate precipitation coupled with the TiO(2) approach offers the best strategy to characterize phosphorylation in ARCaP cells. We analyzed phosphopeptides from ARCaP cells by LC-MS/MS with a hybrid LTQ/FT-ICR mass spectrometer. After database search and stringent filtering, we identified 385 phosphoproteins with an average peptide mass error of 0.32 +/- 0.6 ppm. Key identified oncogenic pathways include the mammalian target of rapamycin (mTOR) pathway and the E2F signaling pathway. Androgen-induced proliferation inhibitor (APRIN) was detected in its phosphorylated form, implicating a molecular mechanism underlying the ARCaP phenotype. PMID- 21786838 TI - Surveillance and monitoring for chronic diseases: a vital investment. PMID- 21786839 TI - Building a foundation for better health: the role of the Aadhaar number. PMID- 21786840 TI - Blind transbronchial needle aspiration without an on-site cytopathologist: experience of 473 procedures. AB - BACKGROUND: Transbronchial needle aspiration (TBNA) is an established procedure for sampling the mediastinal lymph nodes. Data reported from India are limited on this routine procedure. We describe our experience of the efficacy, diagnostic accuracy and safety of TBNA. METHODS: We retrospectively reviewed all TBNAs done at our centre between 2006 and 2009. Under local anaesthesia, accessible lymph node stations were sampled thrice without fluoroscopy and without an on-site cytopathologist. Data are presented in a descriptive manner. RESULTS: A total of 4513 diagnostic bronchoscopies were done, of which 473 (10.5%) underwent TBNA. There were 297 men (63%) and 176 women (37%) with a mean (SD) age of 46.2 (13.98) years. The most common clinical diagnoses were sarcoidosis (50.5%), lung cancer (26.8%), tuberculosis (8.7%) and others (14%). The overall efficacy of TBNA in sampling a mediastinal/hilar lymph node was 72%. The accuracy of TBNA in achieving a pathological diagnosis was 40.4%, whereas the diagnostic yield of a successful procedure was 56.8% (lymph nodes were successfully sampled in 193 of 340 procedures). The most common diagnoses on cytology were sarcoidosis and lung cancer. In patients with a clinical diagnosis of lung cancer, the diagnostic accuracy of TBNA was 46.5% (59 of 127), whereas in patients with sarcoidosis it was 38.1% (91 of 239). TBNA provided an additional diagnostic yield in 5.6% (12 of 215) of patients with sarcoidosis who also underwent transbronchial lung biopsy. There were no periprocedural complications. CONCLUSION: Blind TBNA is a safe and effective procedure that can be routinely done in the bronchoscopy suite. PMID- 21786841 TI - Health-promoting school initiative in Ashram schools of Wardha district. AB - BACKGROUND: We studied the effect of a health-promoting school-based intervention for disadvantaged children in the residential Ashram schools of rural Wardha, Maharashtra. METHODS: At baseline, 1287 children in 10 Ashram schools were examined using a locally adapted Global School-based Student Health Survey questionnaire. The haemoglobin level of all children was estimated using the haemoglobin colour scale. Body mass index and physical activity score for each child were calculated. The intervention was carried out through school health committees. After 1 year, 1226 children were examined using the same questionnaire. RESULTS: There was significant improvement in personal hygiene and reduction in hygiene-related morbidity among the children. The median haemoglobin level of the children increased from 10.7 g/dl to 11.4 g/dl. There was also a significant increase in the proportion of children with body mass index that was normal for age (5th-85th percentile) from 32.2% to 38.5%. CONCLUSION: The need based participatory health-promoting school initiative for disadvantaged children in Ashram schools led to an improvement in their personal hygiene and health. PMID- 21786842 TI - Avoiding negative appendectomies in rural surgical practice: is C-reactive protein estimation useful as a diagnostic tool? AB - BACKGROUND: Appendectomy is one of the most frequently performed abdominal operations in rural surgical practice. In spite of various preoperative investigations to aid in the diagnosis, the rate of negative appendectomies is 15%-30%. Qualitative C-reactive protein (CRP) estimation is an inexpensive diagnostic test which can be done in small laboratories using a simple kit. We studied the value of estimating the CRP level in diagnosing acute appendicitis and reducing negative appendectomies. METHODS: Patients who had been clinically diagnosed with acute appendicitis and planned for appendectomy, were selected by purposive sampling. Leucocyte counts, CRP level estimation and ultrasonography of the abdomen were done preoperatively. The sensitivity, specificity, predictive value, diagnostic accuracy, false-positive and false-negative rates, and likelihood ratios were calculated for various components of the diagnosis. RESULTS: Of the 238 patients, 193 had histological evidence of acute appendicitis. When the diagnosis was based on the consultant's decision, the overall negative appendectomy rate was 18.9%. CRP level estimation yielded a sensitivity of 98% (95% CI 95%-100%) and specificity of 87% (95% CI 73%-94%). A positive CRP value was associated with acute appendicitis (p<0.0001). Adding CRP to the diagnostic work-up increased the sensitivity to 100% (95% CI 98%-100%) and diagnostic accuracy to 92% (95% CI 87%- 95%), and would have reduced negative explorations to 3%. CONCLUSION: CRP estimation complements the clinical diagnosis by a consultant surgeon, and should be included in the diagnostic work-up of appendicitis. CRP estimation is inexpensive and does not add an undue burden to the cost of management. PMID- 21786843 TI - Changing trends of services used as first contact by patients with mental health problems. AB - BACKGROUND: In the past, traditional faith healers and practitioners of alternative medicine have often been reported to be the first source of contact for Indian patients with mental health problems. However, over the past few decades, this trend seems to be changing. METHOD: Using a semi-structured questionnaire, we assessed 200 new patients at a psychiatric outpatient service in a general hospital for the first service contact used by them for their mental health problems. RESULTS: Psychiatrists, non-psychiatric physicians, traditional faith healers and practitioners of alternative medicine were the first service contact for 91 (45.5%), 88 (44%), 16 (8%) and 5 (2.5%) patients, respectively. Patients suffering from severe mental illnesses were more likely to choose a psychiatrist as the first contact, whereas those with neurotic, stress-related and organic mental disorders contacted a non-psychiatric physician. CONCLUSION: In the current scenario, psychiatrists and nonpsychiatric physicians serve as the first service contact for most patients with mental health problems in India, though traditional faith healers and practitioners of alternative medicine are contacted by a minority. PMID- 21786844 TI - Lithium-induced sinus node dysfunction at therapeutic serum levels. AB - Lithium-induced cardiotoxicity, though rare at therapeutic levels, has been reported frequently in overdoses. We report a patient who developed sinus bradycardia while being treated with lithium carbonate even though the serum lithium levels were within the therapeutic range. It reversed following withdrawal of lithium and did not reappear with subsequent treatment with valproate. PMID- 21786845 TI - Clinical applications of probiotics in gastrointestinal disorders in children. AB - Probiotics are widely used in promoting human health and adjunctive therapy of human disease. Many clinical trials and research studies have shown benefits of probiotics. We review the literature associated with the clinical applications of probiotics in paediatric diseases, including necrotizing enterocolitis, infantile colic, infectious diarrhoea or gastrointestinal infection, antibiotic-associated diarrhoea, constipation, lactose intolerance, inflammatory bowel disease, irritable bowel syndrome and functional abdominal pain. We also summarize the representative probiotics that are commonly used in paediatric diseases. PMID- 21786846 TI - Vitamin A supplementation does not improve maternal survival. PMID- 21786847 TI - Diffuse traumatic brain injury: do we have an answer? PMID- 21786848 TI - Second-hand smoke: a first hand problem! PMID- 21786849 TI - Career choices of undergraduate medical students. AB - BACKGROUND: Many factors influence the career choices of undergraduate medical students. We sought to identify the career choices of medical students in an Indian medical college and what influenced these choices. METHODS: We conducted a questionnaire-based cross-sectional survey. We included medical students of all semesters at a medical college. The sociodemographic data, first choice of career on the day of the questionnaire and rating of 34 factors influencing choices were recorded. RESULTS: Two hundred and eighty-two questionnaires were analysed. The most preferred career choices were medicine and surgery, followed by orthopaedics; 3 students each chose obstetrics and gynaecology, and anaesthesia; none chose community medicine. Second-semester students made choices before and the rest after joining medical college. Significantly, senior students were disinclined to take up surgery (p=0.003), preferring orthopaedics instead (p=0.017). 'Personal interest' was rated by 80% of students as important in influencing their choice, followed by stability (58%), reputation of the specialty (56%) and lifestyle (55%). CONCLUSION: The career choices of medical students at our institution were biased against some subjects. Often, choices develop during the course. Role modelling by faculty during departmental postings could be a factor influencing choice. PMID- 21786850 TI - Non-health determinants of health and healthcare in Delhi. AB - With only 0.05% of the total area of the country, Delhi is home to 1.34% of India's population. This creates enormous pressure on natural and man-made resources, and generates situations in which non-health determinants may take precedence over the conventional determinants directly associated with health and healthcare. With the rising advocacy on social determinants of health, several of these factors may rightly seem to be part of the broader territory of health related variables, and in that context, they may be designated as conventional non-medical determinants. We discuss some more visible domains, such as demography, migration and floating population; the physical and biological environment; economic determinants; social determinants; legislation and enforcement, and underscore some less explored yet critical domains of the determinants related to culture, governance and politics. What emerges as a compelling reality is a wide differential in physical environment, urban planning and access to infrastructural inputs between the privileged and marginalized areas of Delhi. Inequities in physical quality of life are so gross that even a value-neutral, official narrative betrays them helplessly. We propose actionable areas to address some of the pressing non-health determinants of health and healthcare. PMID- 21786851 TI - Limitations of the study of calcium profile in the fasting stage and without a tourniquet. PMID- 21786852 TI - Revised Hippocratic Oath. PMID- 21786853 TI - Validity of MCQ tests. PMID- 21786855 TI - Balancing rational care with consumer beliefs: tightrope walking. PMID- 21786856 TI - Medical research output in India: where are we? PMID- 21786857 TI - Supreme Court delivers historic judgment on Aruna Shanbaug case. PMID- 21786858 TI - USA launches plan to fight prescription drug abuse. PMID- 21786860 TI - New negotiations with Europe may threaten India's ability to export generic drugs to countries that need them the most. PMID- 21786861 TI - Vibrato and tremor extent spectrum: algorithm and applications. AB - This work investigated the measurement of vibrato and tremor extent values. Related works have not explored the possibility of measuring extent in the spectra of fundamental frequency (f(0)) low-frequency undulations. It is shown here that by canceling average (DC) values and baseline drifts of f(0) contours, as well as weighting the respective spectra by the time window DC value, extent measures can be promptly obtained in the frequency domain. The method is illustrated with measurements from synthetic and human data. PMID- 21786862 TI - Toward optimizing stream fusion in multistream recognition of speech. AB - A multistream phoneme recognition framework is proposed based on forming streams from different spectrotemporal modulations of speech. Phoneme posterior probabilities were estimated from each stream separately and combined at the output level. A statistical model of the final estimated posterior probabilities is used to characterize the system performance. During the operation, the best fusion architecture is chosen automatically to maximize the similarity of output statistics to clean condition. Results on phoneme recognition from noisy speech indicate the effectiveness of the proposed method. PMID- 21786863 TI - Influence of impression of vehicle styling on loudness of acceleration sounds in cabin. AB - The influence of participants' impressions of vehicle styling on the loudness of acceleration sounds was investigated. A series of images of luxury or sporty vehicles was presented to the participants as acceleration sounds were being replayed. The results indicated that participants who were frequent drivers felt that the sound associated with luxury vehicles was louder than that associated with sporty vehicles. However, participants who rarely drove perceived almost no difference between the loudness of the two vehicles types. Thus, the loudness was shown to depend on both the participants' impression of the vehicle and their driving frequency. PMID- 21786864 TI - Estimation of pressure-particle velocity impedance measurement uncertainty using the Monte Carlo method. AB - The pressure-particle velocity (PU) impedance measurement technique is an experimental method used to measure the surface impedance and the absorption coefficient of acoustic samples in situ or under free-field conditions. In this paper, the measurement uncertainty of the the absorption coefficient determined using the PU technique is explored applying the Monte Carlo method. It is shown that because of the uncertainty, it is particularly difficult to measure samples with low absorption and that difficulties associated with the localization of the acoustic centers of the sound source and the PU sensor affect the quality of the measurement roughly to the same extent as the errors in the transfer function between pressure and particle velocity do. PMID- 21786865 TI - Temporal integration of loudness measured using categorical loudness scaling and matching procedures. AB - Temporal integration of loudness of 1 kHz tones with 5 and 200 ms durations was assessed in four subjects using two loudness measurement procedures: categorical loudness scaling (CLS) and loudness matching. CLS provides a reliable and efficient procedure for collecting data on the temporal integration of loudness and previously reported nonmonotonic behavior observed at mid-sound pressure level levels is replicated with this procedure. Stimuli that are assigned to the same category are effectively matched in loudness, allowing the measurement of temporal integration with CLS without curve-fitting, interpolation, or assumptions concerning the form of the loudness growth function. PMID- 21786866 TI - Postnatal development of cochlear microphonic and compound action potentials in a precocious species, Chinchilla lanigera. AB - The development of sound-evoked responses in Chinchilla lanigera was studied from postnatal ages P0-1 (first 24 h) to adult. Cochlear microphonic (CMs) and compound action potentials (CAPs), representing ensemble sound-evoked activities of hair cells and auditory nerve fibers, respectively, were present as early as age P0-1. The data indicate that CM thresholds and sensitivities were generally adult-like (i.e., fall into adult ranges) at birth, but suprathreshold CM amplitudes remained below adult ranges through P28. CAP thresholds reached adult like values between P7-P14, but the suprathreshold CAP amplitude continued to increase until ~P28. The results confirm the auditory precociousness of the chinchilla. PMID- 21786867 TI - Stoneley waves in three-layered cylindrical solid media. AB - This paper considers the propagation of Stoneley modes along the interfaces of three-layered concentric cylindrical solid media in order to assist in the design of ultrasonic transmission rods. The phase velocity dispersion curves and amplitude distributions are numerically analyzed. The modes are analogous to non dispersive Stoneley waves and are confined to the vicinities of the two interfaces at high frequency. A key finding is that the peak amplitude location for each mode transfers between the two interfaces as a function of frequency. A simplified model is introduced, giving the peak amplitude locations of each mode in different frequency ranges efficiently. PMID- 21786868 TI - English-learning infants' perception of word stress patterns. AB - Adult speakers of different free stress languages (e.g., English, Spanish) differ both in their sensitivity to lexical stress and in their processing of suprasegmental and vowel quality cues to stress. In a head-turn preference experiment with a familiarization phase, both 8-month-old and 12-month-old English-learning infants discriminated between initial stress and final stress among lists of Spanish-spoken disyllabic nonwords that were segmentally varied (e.g. ['nila, 'tuli] vs [lu'ta, pu'ki]). This is evidence that English-learning infants are sensitive to lexical stress patterns, instantiated primarily by suprasegmental cues, during the second half of the first year of life. PMID- 21786869 TI - Evolution of statistical properties for a nonlinearly propagating sinusoid. AB - The nonlinear propagation of a pure sinusoid is considered using time domain statistics. The probability density function, standard deviation, skewness, kurtosis, and crest factor are computed for both the amplitude and amplitude time derivatives as a function of distance. The amplitude statistics vary only in the postshock realm, while the amplitude derivative statistics vary rapidly in the preshock realm. The statistical analysis also suggests that the sawtooth onset distance can be considered to be earlier than previously realized. PMID- 21786870 TI - Some normative data on lip-reading skills (L). AB - The ability to obtain reliable phonetic information from a talker's face during speech perception is an important skill. However, lip-reading abilities vary considerably across individuals. There is currently a lack of normative data on lip-reading abilities in young normal-hearing listeners. This letter describes results obtained from a visual-only sentence recognition experiment using CUNY sentences and provides the mean number of words correct and the standard deviation for different sentence lengths. Additionally, the method for calculating T-scores is provided to facilitate the conversion between raw and standardized scores. This metric can be utilized by clinicians and researchers in lip-reading studies. This statistic provides a useful benchmark for determining whether an individual's lip-reading score falls within the normal range, or whether it is above or below this range. PMID- 21786871 TI - Sound field separation with a double layer velocity transducer array (L). AB - In near-field acoustic holography sound field separation techniques make it possible to distinguish between sound coming from the two sides of the array. This is useful in cases where the sources are not confined to only one side of the array, e.g., in the presence of additional sources or reflections from the other side. This paper examines a separation technique based on measurement of the particle velocity in two closely spaced parallel planes. The purpose of the technique is to recover the particle velocity radiated by a source in the presence of disturbing sound from the opposite side of the array. The technique has been examined and compared with direct velocity based reconstruction, as well as with a technique based on the measurement of the sound pressure and particle velocity. The double layer velocity method circumvents some of the drawbacks of the pressure-velocity based reconstruction, and it can successfully recover the normal velocity radiated by the source, even in the presence of strong disturbing sound. PMID- 21786872 TI - Comparison of echolocation clicks from geographically sympatric killer whales and long-finned pilot whales (L). AB - The source characteristics of biosonar signals from sympatric killer whales and long-finned pilot whales in a Norwegian fjord were compared. A total of 137 pilot whale and more than 2000 killer whale echolocation clicks were recorded using a linear four-hydrophone array. Of these, 20 pilot whale clicks and 28 killer whale clicks were categorized as being recorded on-axis. The clicks of pilot whales had a mean apparent source level of 196 dB re 1 MUPa pp and those of killer whales 203 dB re 1 MUPa pp. The duration of pilot whale clicks was significantly shorter (23 MUs, S.E.=1.3) and the centroid frequency significantly higher (55 kHz, S.E.=2.1) than killer whale clicks (duration: 41 MUs, S.E.=2.6; centroid frequency: 32 kHz, S.E.=1.5). The rate of increase in the accumulated energy as a function of time also differed between clicks from the two species. The differences in duration, frequency, and energy distribution may have a potential to allow for the distinction between pilot and killer whale clicks when using automated detection routines for acoustic monitoring. PMID- 21786873 TI - Application of acoustic feedback to target detection in a waveguide: experimental demonstration at the ultrasonic scale. AB - People are familiar with the acoustic feedback phenomenon, which results in a loud sound that is heard when a musician plays an electric instrument directly into a speaker. Acoustic feedback occurs when a source and a receiver are connected both acoustically through the propagation medium and electrically through an amplifier, such that the amplified received signal is continuously re emitted by the source. The acoustic feedback can be initiated from a continuous sine wave. When the emitter and the receiver are in phase, resonance is obtained, which appears to be highly sensitive to any fluctuation of the propagation medium. Another procedure consists in initiating the acoustic feedback from a continuous loop of ambient noise. It then generates an unstable self-sustained feedback oscillator (SFO) that is tested here as a method for monitoring temperature fluctuations of a shallow-water oceanic environment. The goal of the present study is to reproduce and study the SFO at the laboratory scale in an ultrasonic waveguide. The experimental results demonstrate the potential applications of the SFO for the detection of a target in the framework of the acoustic-barrier problem in shallow-water acoustics. PMID- 21786875 TI - Frequency response and design parameters for differential microbarometers. AB - The study of infrasound is experiencing a renaissance since it was chosen as a verification technique for the Comprehensive Nuclear-Test-Ban Treaty. Source identification is one of the main topics of research which involves detailed knowledge on the source time function, the atmosphere as medium of propagation, and the measurement system. Applications are also foreseen in using infrasound as passive probe for the upper atmosphere, taking the field beyond its monitoring application. Infrasound can be conveniently measured with differential microbarometers. An accurate description of the instrument response is an essential need to be able to attribute the recorded infrasound to a certain source or atmospheric properties. In this article, a detailed treatment is given of the response of a differential microbarometer to acoustic signals. After an historical introduction, a basic model for the frequency response is derived with its corresponding poles and zeros. The results are explained using electric analogs. In addition, thermal conduction is added to the model in order to capture the transition between adiabatic and isothermal behavior. Also discussed are high-frequency effects and the effect of external temperature variations. Eventually, the design parameters for differential microbarometers are derived. PMID- 21786874 TI - Acoustic shock wave propagation in a heterogeneous medium: a numerical simulation beyond the parabolic approximation. AB - Numerical simulation of nonlinear acoustics and shock waves in a weakly heterogeneous and lossless medium is considered. The wave equation is formulated so as to separate homogeneous diffraction, heterogeneous effects, and nonlinearities. A numerical method called heterogeneous one-way approximation for resolution of diffraction (HOWARD) is developed, that solves the homogeneous part of the equation in the spectral domain (both in time and space) through a one-way approximation neglecting backscattering. A second-order parabolic approximation is performed but only on the small, heterogeneous part. So the resulting equation is more precise than the usual standard or wide-angle parabolic approximation. It has the same dispersion equation as the exact wave equation for all forward propagating waves, including evanescent waves. Finally, nonlinear terms are treated through an analytical, shock-fitting method. Several validation tests are performed through comparisons with analytical solutions in the linear case and outputs of the standard or wide-angle parabolic approximation in the nonlinear case. Numerical convergence tests and physical analysis are finally performed in the fully heterogeneous and nonlinear case of shock wave focusing through an acoustical lens. PMID- 21786876 TI - A displacement-pressure finite element formulation for analyzing the sound transmission in ducted shear flows with finite poroelastic lining. AB - In the present work, the propagation of sound in a lined duct containing sheared mean flow is studied. Walls of the duct are acoustically treated with absorbent poroelastic foams. The propagation of elasto-acoustic waves in the liner is described by Biot's model. In the fluid domain, the propagation of sound in a sheared mean flow is governed by the Galbrun's equation. The problem is solved using a mixed displacement-pressure finite element formulation in both domains. A 3D implementation of the model has been performed and is illustrated on axisymmetric examples. Convergence and accuracy of the numerical model are shown for the particular case of the modal propagation in a infinite duct containing a uniform flow. Practical examples concerning the sound attenuation through dissipative silencers are discussed. In particular, effects of the refraction effects in the shear layer as well as the mounting conditions of the foam on the transmission loss are shown. The presence of a perforate screen at the air-porous interface is also considered and included in the model. PMID- 21786877 TI - Failure of the Ingard-Myers boundary condition for a lined duct: an experimental investigation. AB - This paper deals with experimental investigation of the lined wall boundary condition in flow duct applications such as aircraft engine systems or automobile mufflers. A first experiment, based on a microphone array located in the liner test section, is carried out in order to extract the axial wavenumbers with the help of an "high-accurate" singular value decomposition Prony-like algorithm. The experimental axial wavenumbers are then used to provide the lined wall impedance for both downstream and upstream acoustic propagation by means of a straightforward impedance education method involving the classical Ingard-Myers boundary condition. The results show that the Ingard-Myers boundary condition fails to predict with accuracy the acoustic behavior in a lined duct with flow. An effective lined wall impedance, valid whatever the direction of acoustic propagation, can be suitably found from experimental axial wavenumbers and a modified version of the Ingard-Myers condition with the form inspired from a previous theoretical study [Auregan et al., J. Acoust. Soc. Am. 109, 59-64 (2001)]. In a second experiment, the scattering matrix of the liner test section is measured and is then compared to the predicted scattering matrix using the multimodal approach and the lined wall impedances previously deduced. A large discrepancy is observed between the measured and the predicted scattering coefficients that confirms the poor accuracy provided from the Ingard-Myers boundary condition widely used in lined duct applications. PMID- 21786878 TI - Modal depth function estimation using time-frequency analysis. AB - Acoustic propagation in shallow water is characterized by a set of depth dependent modes, the modal depth functions, which propagate in range according to their horizontal wavenumbers. For inversion purposes, modal depth function estimation in shallow water is an issue when the environment is not known. Classical methods that provide blind mode estimation rely on the singular value decomposition of the received field at different frequencies over a vertical array of transducers. These methods require that the vertical array spans the full water column. This is obviously a strong limitation for the application of such methods in an operational context. To overcome these shortcomings, this study proposes to replace the spatial diversity constraint by a frequency diversity condition, and thus considers the case of a field emanating from an impulsive source. Indeed, because of the discrete nature of the wavenumber spectrum and due to their dispersive behavior, the modes are separated in the time-frequency domain. This phenomenon enables the design of a modal filtering scheme for signals received on a single receiver. In the case of a vertical receiver array, the modal contributions can be isolated for each receiver even when using a partial water column spanning array. This method thus eliminates the receiving constraints of classical methods of modal depth function estimation, although it imposes the use of an impulsive source. The developed algorithm is benchmarked on numerical simulations and validated on laboratory experimental data recorded in an ultrasonic waveguide. Practical applications are also discussed. PMID- 21786879 TI - A modal Wentzel-Kramers-Brillouin approach to calculating the waveguide invariant for non-ideal waveguides. AB - The frequency dependence of a waveguide's Green's function can be summarized by a single parameter known as the waveguide invariant, beta. Although it has been shown analytically that beta~1 for ideal waveguides, numerical and experimental results have shown that beta~1 for many realistic shallow water waveguides as well. There is not much prior work explaining why the non-uniformities present in realistic sound speed profiles sometimes have such a small effect on the value of beta. This paper presents a method for calculating beta using a modal Wentzel Kramers-Brillouin (WKB) description of the acoustic field, which reveals a straightforward relationship between the sound speed profile and beta. That relationship is used to illustrate why non-uniformities in the sound speed profile sometimes have such a small effect on beta and under what circumstances the non-uniformities will have a large effect on beta. The method uses implicit differentiation and thus does not explicitly solve for the horizontal wavenumbers of the modes, making it applicable to waveguides with arbitrary sound speed profiles and fluid bottom halfspaces. Several examples are given, including an analytic estimate of beta in a Pekeris waveguide. PMID- 21786880 TI - Estimating the instantaneous velocity of randomly moving target swarms in a stratified ocean waveguide by Doppler analysis. AB - Doppler analysis has been extensively used in active radar and sonar sensing to estimate the speed and direction of a single target within an imaging system resolution cell following deterministic theory. For target swarms, such as fish and plankton in the ocean, and raindrops, birds and bats in the atmosphere, multiple randomly moving targets typically occupy a single resolution cell, making single-target theory inadequate. Here, a method is developed for simultaneously estimating the instantaneous mean velocity and position of a group of randomly moving targets within a resolution cell, as well as the respective standard deviations across the group by Doppler analysis in free-space and in a stratified ocean waveguide. While the variance of the field scattered from the swarm is shown to typically dominate over the mean in the range-velocity ambiguity function, cross-spectral coherence remains and maintains high Doppler velocity and position resolution even for coherent signal processing algorithms such as the matched filter. For pseudo-random signals, the mean and variance of the swarms' velocity and position can be expressed in terms of the first two moments of the measured range-velocity ambiguity function. This is shown analytically for free-space and with Monte-Carlo simulations for an ocean waveguide. PMID- 21786881 TI - An algorithm for the localization of multiple interfering sperm whales using multi-sensor time difference of arrival. AB - In this paper an algorithm is described for the localization of individual sperm whales in situations where several near-by animals are simultaneously vocalizing. The algorithm operates on time-difference of arrival (TDOA) measurements observed at sensor pairs and assumes no prior knowledge of the TDOA-whale associations. In other words, it solves the problem of associating TDOAs to whales. The algorithm is able to resolve association disputes where a given TDOA measurement may fit to more than one position estimate and can handle spurious TDOAs. The algorithm also provides estimates of Cramer-Rao lower bound for the position estimates. The algorithm was tested with real data using TDOA estimates obtained by cross correlating click-trains. The click-trains were generated by a separate algorithm that operated independently on each sensor to produce click-trains corresponding to a given whale and to reject click-trains from reflected propagation paths. PMID- 21786882 TI - Resonance blocking and passing effects in two-dimensional elastic waveguides with obstacles. AB - Resonance localization of wave energy in two-dimensional (2D) waveguides with obstacles, known as a trapped mode effect, results in blocking of wave propagation. This effect is closely connected with the allocation of natural resonance poles in the complex frequency plane, which are in fact the spectral points of the related boundary value problem. With several obstacles the number of poles increases in parallel with the number of defects. The location of the poles in the complex frequency plane depends on the defect's relative position, but the gaps of transmission coefficient plots generally remain in the same frequency ranges as for every single obstacle separately. This property gives a possibility to extend gap bands by a properly selected combination of various scatterers. On the other hand, a resonance wave passing in narrow bands associated with the poles is also observed. Thus, while a resonance response of a single obstacle works as a blocker, the waveguide with several obstacles becomes opened in narrow vicinities of nearly real spectral poles, just as it is known for one-dimensional (1D) waveguides with a finite number of periodic scatterers. In the present paper the blocking and passing effects are analyzed based on a semi-analytical model for wave propagation in a 2D elastic layer with cracks or rigid inclusions. PMID- 21786883 TI - A comparison of stochastic and effective medium approaches to the backscattered signal from a porous layer in a solid matrix. AB - This paper reports a study of the backscattering behavior of a solid layer containing randomly spaced spherical cavities in the long wavelength limit. The motivation for the work arises from a need to model the responses of porous composite materials in ultrasonic NDE procedures. A comparison is made between models based on a summation over discrete scatterers, which show interesting emergent properties, and an integral formulation based on an ensemble average, and with a simple slab effective medium approximation. The similarities and differences between these three models are demonstrated. A simple quantitative criterion is established which sets the maximum frequency at which ensemble average or equivalent homogeneous medium models can represent echo signal generation in a porous layer for given interpore spacing, or equivalently, given pore size and concentration. PMID- 21786884 TI - Experimental investigation on reversal of secondary Bjerknes force between two bubbles in ultrasonic standing wave. AB - The direction of the secondary Bjerknes force between a free bubble and an attached bubble was experimentally investigated. The behavior of the two bubbles in an ultrasonic standing wave of 27 kHz was observed using an imaging system with a high-speed video camera. It was demonstrated experimentally that the direction of the force reversed at a specific separation distance between the two bubbles, which was defined as the threshold distance. The threshold distance changed with the radius of the attached bubble. In addition, a theoretical calculation was performed using a previously derived model that coupled the vibrations of two free bubbles [Ida, Phys. Lett. A 297, 210-217 (2002)]. The experiment data for the threshold distance qualitatively agreed with the theoretical predictions, except when the separation distance was very small. Then, it was discovered that the free bubble became trapped near the attached bubble when the separation distance between the two bubbles was very small. This indicated that a stable equilibrium point for the separation distance exists that cannot be predicted by the theoretical model. PMID- 21786886 TI - On the sound fields of infinitely long strips. AB - Exact solutions are derived for sound radiation from four kinds of infinitely long strips: namely a rigid strip in a baffle of finite width, a resilient strip in free space, and a resilient or rigid strip in an infinite baffle. In one limit, the strip in a finite baffle becomes a rigid strip in free space and in the other, a line source in a finite baffle. Here "rigid" means that the surface velocity is uniform, whereas "resilient" means that the surface pressure is uniform, and the strip is assumed to have zero mass or stiffness, as if a force were driving the acoustic medium directly. According to the Babinet-Bouwkamp principle, radiation from a resilient strip in an infinite baffle is equivalent to diffraction of a plane wave through a slit in the same. Plots are shown for the radiation impedances, far-field directivity patterns, and on-axis pressure responses of the four kinds of strip. A simple relationship between the radiation admittance of the rigid strip in an infinite baffle and the resilient strip in free space is presented. The two-dimensional rectangular wave functions developed in this paper can be applied to related problems. PMID- 21786885 TI - Theoretical prediction of the onset of thermoacoustic instability from the experimental transfer matrix of a thermoacoustic core. AB - The aim of this paper is to propose a method to predict the onset conditions of the thermoacoustic instability for various thermoacoustic engines. As an accurate modeling of the heat exchangers and the stack submitted to a temperature gradient is a difficult task, an experimental approach for the characterization of the amplifying properties of the thermoacoustic core is proposed. An experimental apparatus is presented which allows to measure the transfer matrix of a thermoacoustic core under various heating conditions by means of a four microphone method. An analytical model for the prediction of the onset conditions from this measured transfer matrix is developed. The experimental data are introduced in the model and theoretical predictions of the onset conditions are compared with those actually observed in standing-wave and traveling-wave engines. The results show good agreement between predictions from the model and experiments. PMID- 21786887 TI - Acoustic emission localization in complex dissipative anisotropic structures using a one-channel reciprocal time reversal method. AB - This paper presents an imaging method for the localization of the impact point in complex anisotropic structures with diffuse field conditions, using only one passive transducer. The proposed technique is based on the reciprocal time reversal approach (inverse filtering) applied to a number of waveforms stored into a database containing the experimental Green's function of the structure. Unlike most acoustic emission monitoring systems, the present method exploits the benefits of multiple scattering, mode conversion, and boundaries reflections to achieve the focusing of the source with high resolution. Compared to a standard time reversal approach, the optimal refocusing of the back propagated wave field at the impact point is accomplished through a "virtual" imaging process. The robustness of the inverse filtering technique is experimentally demonstrated on a dissipative stiffened composite panel and the source position can be retrieved with a high level of accuracy in any position of the structure. Its very simple configuration and minimal processing requirements make this method a valid alternative to the conventional imaging Structural Health Monitoring systems for the acoustic emission source localization. PMID- 21786888 TI - Active noise attenuation in ventilation windows. AB - The feasibility of applying active noise control techniques to attenuate low frequency noise transmission through a natural ventilation window into a room is investigated analytically and experimentally. The window system is constructed by staggering the opening sashes of a spaced double glazing window to allow ventilation and natural light. An analytical model based on the modal expansion method is developed to calculate the low frequency sound field inside the window and the room and to be used in the active noise control simulations. The effectiveness of the proposed analytical model is validated by using the finite element method. The performance of the active control system for a window with different source and receiver configurations are compared, and it is found that the numerical and experimental results are in good agreement and the best result is achieved when the secondary sources are placed in the center at the bottom of the staggered window. The extra attenuation at the observation points in the optimized window system is almost equivalent to the noise reduction at the error sensor and the frequency range of effective control is up to 390 Hz in the case of a single channel active noise control system. PMID- 21786889 TI - Total annoyance from an industrial noise source with a main spectral component combined with a background noise. AB - When living close to an industrial plant, people are exposed to a combination of industrial noise sources and a background noise composed of all the other noise sources in the environment. As a first step, noise annoyance indicators in laboratory conditions are proposed for a single exposure to an industrial noise source. The second step detailed in this paper involves determining total annoyance indicators in laboratory conditions for ambient noises composed of an industrial noise source and a background noise. Two types of steady and permanent industrial noise sources are studied: low frequency noises with a main spectral component at 100 Hz, and noises with a main spectral component in middle frequencies. Five background noises are assessed so as to take into account different sound environments which can usually be heard by people living around an industrial plant. One main conclusion of this study is that two different analyses are necessary to determine total annoyance indicators for this type of ambient noise, depending on the industrial noise source composing it. Therefore, two total annoyance indicators adapted to the ambient noises studied are proposed. PMID- 21786890 TI - Particle motion measured at an operational wind turbine in relation to hearing sensitivity in fish. AB - The effect of sound pressure on the hearing of fish has been extensively investigated in laboratory studies as well as in field trials in contrast to particle motion where few studies have been carried out. To improve this dearth of knowledge, an instrument for measuring particle motion was developed and used in a field trial. The particle motion is measured using a neutrally buoyant sphere, which co-oscillates with the fluid motion. The unit was deployed in close vicinity to a wind turbine foundation at Utgrunden wind farm in the Baltic Sea. Measurements of particle motion were undertaken at different distances from the turbine as well as at varying wind speeds. Levels of particle motion were compared to audiograms for cod (Gadus morhua L.) and plaice (Pleuronectes platessa L.). PMID- 21786891 TI - On the acoustic properties of parallel arrangement of multiple micro-perforated panel absorbers with different cavity depths. AB - The acoustic properties of a compound micro-perforated panel (MPP) absorber array are investigated. The absorber array consists of three parallel-arranged MPP absorbers with different cavity depths. A finite element procedure is used to simulate its acoustic behaviors under normal incidence. Experimental studies are carried out to verify the numerical simulations. Due to different reactance matching conditions in the absorber array, strong local resonance occurs and the corresponding local resonance absorption dominates. Compared with single MPP absorber, the absorber array requires lower acoustic resistance for good absorption performance, and the resonance frequencies shift due to inter resonator interactions. The different acoustic resistance requirement is explained by considering the reduced effective perforation rate of the MPP in the absorber array. The performance of the absorber array varies with the sizes and spatial arrangement of the component absorbers. When the distance between component absorbers is larger than a quarter-wavelength, the above-mentioned parallel absorption mechanism diminishes. In the experimental study, the normal incidence absorption coefficients of a prototype MPP absorber array are tested. The measured results compare well with the numerical predictions. The experimental study also shows that although other absorption mechanisms may exist, dissipation by the MPP is dominant in the MPP absorber array. PMID- 21786892 TI - Evaluation of speech transmission in open public spaces affected by combined noises. AB - In the present study, the effects of interference from combined noises on speech transmission were investigated in a simulated open public space. Sound fields for dominant noises were predicted using a typical urban square model surrounded by buildings. Then road traffic noise and two types of construction noises, corresponding to stationary and impulsive noises, were selected as background noises. Listening tests were performed on a group of adults, and the quality of speech transmission was evaluated using listening difficulty as well as intelligibility scores. During the listening tests, two factors that affect speech transmission performance were considered: (1) temporal characteristics of construction noise (stationary or impulsive) and (2) the levels of the construction and road traffic noises. The results indicated that word intelligibility scores and listening difficulty ratings were affected by the temporal characteristics of construction noise due to fluctuations in the background noise level. It was also observed that listening difficulty is unable to describe the speech transmission in noisy open public spaces showing larger variation than did word intelligibility scores. PMID- 21786893 TI - Equal autophonic level curves under different room acoustics conditions. AB - The indirect auditory feedback from one's own voice arises from sound reflections at the room boundaries or from sound reinforcement systems. The relative variations of indirect auditory feedback are quantified through room acoustic parameters such as the room gain and the voice support, rather than the reverberation time. Fourteen subjects matched the loudness level of their own voice (the autophonic level) to that of a constant and external reference sound, under different synthesized room acoustics conditions. The matching voice levels are used to build a set of equal autophonic level curves. These curves give an indication of the amount of variation in voice level induced by the acoustic environment as a consequence of the sidetone compensation or Lombard effect. In the range of typical rooms for speech, the variations in overall voice level that result in a constant autophonic level are on the order of 2 dB, and more than 3 dB in the 4 kHz octave band. By comparison of these curves with previous studies, it is shown that talkers use acoustic cues other than loudness to adjust their voices when speaking in different rooms. PMID- 21786894 TI - Sound radiation from an aperture in a rectangular enclosure under low modal conditions. AB - This paper investigates both theoretically and experimentally the sound radiation from an aperture placed in an enclosure wall for the particular case of low modal sound field. The incidence field is composed of the enclosed sound field, which is calculated using the theoretical modal model presented. The transmitted sound is calculated by the Rayleigh radiation equation after continuity conditions have been applied in the aperture plane, assuming the condition of a thin wall. The model is experimentally validated by measuring the directivity and sound pressure radiated from an aperture in the side of a rectangular box. Because the walls of the enclosure are not rigid, an experimental procedure to determine its admittance is also presented. The experiments have been carried out for the first four modes of the enclosed sound field, and good agreement is found between the theoretical and experimental results. These results indicate that the admittance of the aperture, its radiation efficiency, and its directivity are all functions of the predominant mode shape, and the frequency, as well as the location and shape, of the aperture relative to the predominant enclosed mode shape. PMID- 21786895 TI - Multi-input multi-output underwater communications over sparse and frequency modulated acoustic channels. AB - This paper addresses multi-input multi-output (MIMO) communications over sparse acoustic channels suffering from frequency modulations. An extension of the recently introduced SLIM algorithm, which stands for sparse learning via iterative minimization, is presented to estimate the sparse and frequency modulated acoustic channels. The extended algorithm is referred to as generalization of SLIM (GoSLIM). The sparseness is exploited through a hierarchical Bayesian model, and because GoSLIM is user parameter free, it is easy to use in practical applications. Moreover this paper considers channel equalization and symbol detection for various MIMO transmission schemes, including both space-time block coding and spatial multiplexing, under the challenging channel conditions. The effectiveness of the proposed approaches is demonstrated using in-water experimental measurements recently acquired during WHOI09 and ACOMM10 experiments. PMID- 21786896 TI - Psychometric functions for pure-tone frequency discrimination. AB - The form of the psychometric function (PF) for auditory frequency discrimination is of theoretical interest and practical importance. In this study, PFs for pure tone frequency discrimination were measured for several standard frequencies (200 8000 Hz) and levels [35-85 dB sound pressure level (SPL)] in normal-hearing listeners. The proportion-correct data were fitted using a cumulative-Gaussian function of the sensitivity index, d', computed as a power transformation of the frequency difference, Deltaf. The exponent of the power function corresponded to the slope of the PF on log(d')-log(Deltaf) coordinates. The influence of attentional lapses on PF-slope estimates was investigated. When attentional lapses were not taken into account, the estimated PF slopes on log(d') log(Deltaf) coordinates were found to be significantly lower than 1, suggesting a nonlinear relationship between d' and Deltaf. However, when lapse rate was included as a free parameter in the fits, PF slopes were found not to differ significantly from 1, consistent with a linear relationship between d' and Deltaf. This was the case across the wide ranges of frequencies and levels tested in this study. Therefore, spectral and temporal models of frequency discrimination must account for a linear relationship between d' and Deltaf across a wide range of frequencies and levels. PMID- 21786897 TI - On the mechanisms involved in the recovery of envelope information from temporal fine structure. AB - Three experiments were designed to provide psychophysical evidence for the existence of envelope information in the temporal fine structure (TFS) of stimuli that were originally amplitude modulated (AM). The original stimuli typically consisted of the sum of a sinusoidally AM tone and two unmodulated tones so that the envelope and TFS could be determined a priori. Experiment 1 showed that normal-hearing listeners not only perceive AM when presented with the Hilbert fine structure alone but AM detection thresholds are lower than those observed when presenting the original stimuli. Based on our analysis, envelope recovery resulted from the failure of the decomposition process to remove the spectral components related to the original envelope from the TFS and the introduction of spectral components related to the original envelope, suggesting that frequency- to amplitude-modulation conversion is not necessary to recover envelope information from TFS. Experiment 2 suggested that these spectral components interact in such a way that envelope fluctuations are minimized in the broadband TFS. Experiment 3 demonstrated that the modulation depth at the original carrier frequency is only slightly reduced compared to the depth of the original modulator. It also indicated that envelope recovery is not specific to the Hilbert decomposition. PMID- 21786898 TI - The effect of lip-reading on primary stream segregation. AB - Lip-reading has been shown to improve the intelligibility of speech in multitalker situations, where auditory stream segregation naturally takes place. This study investigated whether the benefit of lip-reading is a result of a primary audiovisual interaction that enhances the obligatory streaming mechanism. Two behavioral experiments were conducted involving sequences of French vowels that alternated in fundamental frequency. In Experiment 1, subjects attempted to identify the order of items in a sequence. In Experiment 2, subjects attempted to detect a disruption to temporal isochrony across alternate items. Both tasks are disrupted by streaming, thus providing a measure of primary or obligatory streaming. Visual lip gestures articulating alternate vowels were synchronized with the auditory sequence. Overall, the results were consistent with the hypothesis that visual lip gestures enhance segregation by affecting primary auditory streaming. Moreover, increases in the naturalness of visual lip gestures and auditory vowels, and corresponding increases in audiovisual congruence may potentially lead to increases in the effect of visual lip gestures on streaming. PMID- 21786899 TI - Generating partially correlated noise--a comparison of methods. AB - There are three standard methods for generating two channels of partially correlated noise: the two-generator method, the three-generator method, and the symmetric-generator method. These methods allow an experimenter to specify a target cross correlation between the two channels, but actual generated noises show statistical variability around the target value. Numerical experiments were done to compare the variability for those methods as a function of the number of degrees of freedom. The results of the experiments quantify the stimulus uncertainty in diverse binaural psychoacoustical experiments: incoherence detection, perceived auditory source width, envelopment, noise localization/lateralization, and the masking level difference. The numerical experiments found that when the elemental generators have unequal powers, the different methods all have similar variability. When the powers are constrained to be equal, the symmetric-generator method has much smaller variability than the other two. PMID- 21786900 TI - Binaural image position distributions for phase-shifted low frequency tone bursts. AB - This experiment was designed to yield precise measures of the statistical properties of perceived sound images. Results are reported for listeners' judgments of intracranial sound image lateral positions in response to binaural tone burst stimuli (250 Hz, 50 ms) with varying interaural phase differences, conditional on the absence or presence of a (left or right) reference monaural tone burst (also 250 Hz, 50 ms) ending 500 ms prior to the test signal. The monaural-reference shifted the position distributions toward the opposite side of the head. The position distribution variance and skewness depended on the mean of the position distribution, not on the interaural phase difference of the stimulus. The standard deviation increased as the mean moved laterally from midline. Near the midline the position distributions were skewed ipsilaterally. Near either ear they were skewed toward the midline. The results suggest that the most important noise limiting performance originates central to brainstem coincidence detector networks. PMID- 21786901 TI - The effect of hearing impairment on localization dominance for single-word stimuli. AB - Localization dominance (one of the phenomena of the "precedence effect") was measured in a large number of normal-hearing and hearing-impaired individuals and related to self-reported difficulties in everyday listening. The stimuli (single words) were made-up of a "lead" followed 4 ms later by a equal-level "lag" from a different direction. The stimuli were presented from a circular ring of loudspeakers, either in quiet or in a background of spatially diffuse babble. Listeners were required to identify the loudspeaker from which they heard the sound. Localization dominance was quantified by the weighting factor c [B.G. Shinn-Cunningham et al., J. Acoust. Soc. Am. 93, 2923-2932 (1993)]. The results demonstrated large individual differences: Some listeners showed near-perfect localization dominance (c near 1) but many showed a much reduced effect. Two thirds (64/93) of the listeners gave a value of c of at least 0.75. There was a significant correlation with hearing loss, such that better hearing listeners showed better localization dominance. One of the items of the self-report questionnaire ("Do you have the impression of sounds being exactly where you would expect them to be?") showed a significant correlation with the experimental results. This suggests that reductions in localization dominance may affect everyday auditory perception. PMID- 21786902 TI - Effect of source spectrum on sound localization in an everyday reverberant room. AB - Two experiments explored how frequency content impacts sound localization for sounds containing reverberant energy. Virtual sound sources from thirteen lateral angles and four distances were simulated in the frontal horizontal plane using binaural room impulse responses measured in an everyday office. Experiment 1 compared localization judgments for one-octave-wide noise centered at either 750 Hz (low) or 6000 Hz (high). For both band-limited noises, perceived lateral angle varied monotonically with source angle. For frontal sources, perceived locations were similar for low- and high-frequency noise; however, for lateral sources, localization was less accurate for low-frequency noise than for high-frequency noise. With increasing source distance, judgments of both noises became more biased toward the median plane, an effect that was greater for low-frequency noise than for high-frequency noise. In Experiment 2, simultaneous presentation of low- and high-frequency noises yielded performance that was less accurate than that for high-frequency noise, but equal to or better than for low-frequency noise. Results suggest that listeners perceptually weight low-frequency information heavily, even in reverberant conditions where high-frequency stimuli are localized more accurately. These findings show that listeners do not always optimally adjust how localization cues are integrated over frequency in reverberant settings. PMID- 21786903 TI - The effects of age and cochlear hearing loss on temporal fine structure sensitivity, frequency selectivity, and speech reception in noise. AB - Temporal fine structure (TFS) sensitivity, frequency selectivity, and speech reception in noise were measured for young normal-hearing (NHY), old normal hearing (NHO), and hearing-impaired (HI) subjects. Two measures of TFS sensitivity were used: the "TFS-LF test" (interaural phase difference discrimination) and the "TFS2 test" (discrimination of harmonic and frequency shifted tones). These measures were not significantly correlated with frequency selectivity (after partialing out the effect of audiometric threshold), suggesting that insensitivity to TFS cannot be wholly explained by a broadening of auditory filters. The results of the two tests of TFS sensitivity were significantly but modestly correlated, suggesting that performance of the tests may be partly influenced by different factors. The NHO group performed significantly more poorly than the NHY group for both measures of TFS sensitivity, but not frequency selectivity, suggesting that TFS sensitivity declines with age in the absence of elevated audiometric thresholds or broadened auditory filters. When the effect of mean audiometric threshold was partialed out, speech reception thresholds in modulated noise were correlated with TFS2 scores, but not measures of frequency selectivity or TFS-LF test scores, suggesting that a reduction in sensitivity to TFS can partly account for the speech perception difficulties experienced by hearing-impaired subjects. PMID- 21786904 TI - Extracting the invariant model from the feedback paths of digital hearing aids. AB - Feedback whistling is a severe problem with hearing aids. A typical acoustical feedback path represents a wave propagation path from the receiver to the microphone and includes many complicated effects among which some are invariant or nearly invariant for all users and in all acoustical environments given a specific type of hearing aids. Based on this observation, a feedback path model that consists of an invariant model and a variant model is proposed. A common acoustical-pole and zero model-based approach and an iterative least-square search-based approach are used to extract the invariant model from a set of impulse responses of the feedback paths. A hybrid approach combining the two methods is also proposed. The general properties of the three methods are studied using artificial datasets, and the methods are cross-validated using the measured feedback paths. The results show that the proposed hybrid method gives the best overall performance, and the extracted invariant model is effective in modeling the feedback path. PMID- 21786905 TI - Comparing spatial tuning curves, spectral ripple resolution, and speech perception in cochlear implant users. AB - Spectral ripple discrimination thresholds were measured in 15 cochlear-implant users with broadband (350-5600 Hz) and octave-band noise stimuli. The results were compared with spatial tuning curve (STC) bandwidths previously obtained from the same subjects. Spatial tuning curve bandwidths did not correlate significantly with broadband spectral ripple discrimination thresholds but did correlate significantly with ripple discrimination thresholds when the rippled noise was confined to an octave-wide passband, centered on the STC's probe electrode frequency allocation. Ripple discrimination thresholds were also measured for octave-band stimuli in four contiguous octaves, with center frequencies from 500 Hz to 4000 Hz. Substantial variations in thresholds with center frequency were found in individuals, but no general trends of increasing or decreasing resolution from apex to base were observed in the pooled data. Neither ripple nor STC measures correlated consistently with speech measures in noise and quiet in the sample of subjects in this study. Overall, the results suggest that spectral ripple discrimination measures provide a reasonable measure of spectral resolution that correlates well with more direct, but more time consuming, measures of spectral resolution, but that such measures do not always provide a clear and robust predictor of performance in speech perception tasks. PMID- 21786906 TI - Acoustic temporal modulation detection and speech perception in cochlear implant listeners. AB - The goals of the present study were to measure acoustic temporal modulation transfer functions (TMTFs) in cochlear implant listeners and examine the relationship between modulation detection and speech recognition abilities. The effects of automatic gain control, presentation level and number of channels on modulation detection thresholds (MDTs) were examined using the listeners' clinical sound processor. The general form of the TMTF was low-pass, consistent with previous studies. The operation of automatic gain control had no effect on MDTs when the stimuli were presented at 65 dBA. MDTs were not dependent on the presentation levels (ranging from 50 to 75 dBA) nor on the number of channels. Significant correlations were found between MDTs and speech recognition scores. The rates of decay of the TMTFs were predictive of speech recognition abilities. Spectral-ripple discrimination was evaluated to examine the relationship between temporal and spectral envelope sensitivities. No correlations were found between the two measures, and 56% of the variance in speech recognition was predicted jointly by the two tasks. The present study suggests that temporal modulation detection measured with the sound processor can serve as a useful measure of the ability of clinical sound processing strategies to deliver clinically pertinent temporal information. PMID- 21786907 TI - A theoretical model of the pressure field arising from asymmetric intraglottal flows applied to a two-mass model of the vocal folds. AB - A theoretical flow solution is presented for predicting the pressure distribution along the vocal fold walls arising from asymmetric flow that forms during the closing phases of speech. The resultant wall jet was analyzed using boundary layer methods in a non-inertial reference frame attached to the moving wall. A solution for the near-wall velocity profiles on the flow wall was developed based on a Falkner-Skan similarity solution and it was demonstrated that the pressure distribution along the flow wall is imposed by the velocity in the inviscid core of the wall jet. The method was validated with experimental velocity data from 7.5 times life-size vocal fold models, acquired for varying flow rates and glottal divergence angles. The solution for the asymmetric pressures was incorporated into a widely used two-mass model of vocal fold oscillation with a coupled acoustical model of sound propagation. Asymmetric pressure loading was found to facilitate glottal closure, which yielded only slightly higher values of maximum flow declination rate and radiated sound, and a small decrease in the slope of the spectral tilt. While the impact on symmetrically tensioned vocal folds was small, results indicate the effect becomes more significant for asymmetrically tensioned vocal folds. PMID- 21786908 TI - Direct-numerical simulation of the glottal jet and vocal-fold dynamics in a three dimensional laryngeal model. AB - An immersed-boundary method based flow solver coupled with a finite-element solid dynamics solver is employed in order to conduct direct-numerical simulations of phonatory dynamics in a three-dimensional model of the human larynx. The computed features of the glottal flow including mean and peak flow rates, and the open and skewness quotients are found to be within the normal physiological range. The flow-induced vibration pattern shows the classical "convergent-divergent" glottal shape, and the vibration amplitude is also found to be typical for human phonation. The vocal fold motion is analyzed through the method of empirical eigenfunctions and this analysis indicates a 1:1 modal entrainment between the "adduction-abduction" mode and the "mucosal wave" mode. The glottal jet is found to exhibit noticeable cycle-to-cycle asymmetric deflections and the mechanism underlying this phenomenon is examined. PMID- 21786909 TI - Context-specific acoustic differences between Peruvian and Iberian Spanish vowels. AB - This paper examines four acoustic properties (duration F0, F1, and F2) of the monophthongal vowels of Iberian Spanish (IS) from Madrid and Peruvian Spanish (PS) from Lima in various consonantal contexts (/s/, /f/, /t/, /p/, and /k/) and in various phrasal contexts (in isolated words and sentence-internally). Acoustic measurements on 39 speakers, balanced by dialect and gender, can be generalized to the following differences between the two dialects. The vowel /a/ has a lower first formant in PS than in IS by 6.3%. The vowels /e/ and /o/ have more peripheral second-formant (F2) values in PS than in IS by about 4%. The consonant /s/ causes more centralization of the F2 of neighboring vowels in IS than in PS. No dialectal differences are found for the effect of phrasal context. Next to the between-dialect differences in the vowels, the present study finds that /s/ has a higher spectral center of gravity in PS than in IS by about 10%, that PS speakers speak slower than IS speakers by about 9%, and that Spanish-speaking women speak slower than Spanish-speaking men by about 5% (irrespective of dialect). PMID- 21786910 TI - The mutual roles of temporal glimpsing and vocal characteristics in cocktail party listening. AB - At a cocktail party, listeners must attend selectively to a target speaker and segregate their speech from distracting speech sounds uttered by other speakers. To solve this task, listeners can draw on a variety of vocal, spatial, and temporal cues. Recently, Vestergaard et al. [J. Acoust. Soc. Am. 125, 1114-1124 (2009)] developed a concurrent-syllable task to control temporal glimpsing within segments of concurrent speech, and this allowed them to measure the interaction of glottal pulse rate and vocal tract length and reveal how the auditory system integrates information from independent acoustic modalities to enhance recognition. The current paper shows how the interaction of these acoustic cues evolves as the temporal overlap of syllables is varied. Temporal glimpses as short as 25 ms are observed to improve syllable recognition substantially when the target and distracter have similar vocal characteristics, but not when they are dissimilar. The effect of temporal glimpsing on recognition performance is strongly affected by the form of the syllable (consonant-vowel versus vowel consonant), but it is independent of other phonetic features such as place and manner of articulation. PMID- 21786911 TI - Laminar cortical dynamics of conscious speech perception: neural model of phonemic restoration using subsequent context in noise. AB - How are laminar circuits of neocortex organized to generate conscious speech and language percepts? How does the brain restore information that is occluded by noise, or absent from an acoustic signal, by integrating contextual information over many milliseconds to disambiguate noise-occluded acoustical signals? How are speech and language heard in the correct temporal order, despite the influence of contexts that may occur many milliseconds before or after each perceived word? A neural model describes key mechanisms in forming conscious speech percepts, and quantitatively simulates a critical example of contextual disambiguation of speech and language; namely, phonemic restoration. Here, a phoneme deleted from a speech stream is perceptually restored when it is replaced by broadband noise, even when the disambiguating context occurs after the phoneme was presented. The model describes how the laminar circuits within a hierarchy of cortical processing stages may interact to generate a conscious speech percept that is embodied by a resonant wave of activation that occurs between acoustic features, acoustic item chunks, and list chunks. Chunk-mediated gating allows speech to be heard in the correct temporal order, even when what is heard depends upon future context. PMID- 21786913 TI - Effects of spectral smearing and temporal fine-structure distortion on the fluctuating-masker benefit for speech at a fixed signal-to-noise ratio. AB - Normal-hearing listeners receive less benefit from momentary dips in the level of a fluctuating masker for speech processed to degrade spectral detail or temporal fine structure (TFS) than for unprocessed speech. This has been interpreted as evidence that the magnitude of the fluctuating-masker benefit (FMB) reflects the ability to resolve spectral detail and TFS. However, the FMB for degraded speech is typically measured at a higher signal-to-noise ratio (SNR) to yield performance similar to normal speech for the baseline (stationary-noise) condition. Because the FMB decreases with increasing SNR, this SNR difference might account for the reduction in FMB for degraded speech. In this study, the FMB for unprocessed and processed (TFS-removed or spectrally smeared) speech was measured in a paradigm that adjusts word-set size, rather than SNR, to equate stationary-noise performance across processing conditions. Compared at the same SNR and percent-correct level (but with different set sizes), processed and unprocessed stimuli yielded a similar FMB for four different fluctuating maskers (speech-modulated noise, one opposite-gender interfering talker, two same-gender interfering talkers, and 16-Hz interrupted noise). These results suggest that, for these maskers, spectral or TFS distortions do not directly impair the ability to benefit from momentary dips in masker level. PMID- 21786912 TI - Learning a novel phonological contrast depends on interactions between individual differences and training paradigm design. AB - Studies evaluating phonological contrast learning typically investigate either the predictiveness of specific pretraining aptitude measures or the efficacy of different instructional paradigms. However, little research considers how these factors interact--whether different students learn better from different types of instruction--and what the psychological basis for any interaction might be. The present study demonstrates that successfully learning a foreign-language phonological contrast for pitch depends on an interaction between individual differences in perceptual abilities and the design of the training paradigm. Training from stimuli with high acoustic-phonetic variability is generally thought to improve learning; however, we found high-variability training enhanced learning only for individuals with strong perceptual abilities. Learners with weaker perceptual abilities were actually impaired by high-variability training relative to a low-variability condition. A second experiment assessing variations on the high-variability training design determined that the property of this learning environment most detrimental to perceptually weak learners is the amount of trial-by-trial variability. Learners' perceptual limitations can thus override the benefits of high-variability training where trial-by-trial variability in other irrelevant acoustic-phonetic features obfuscates access to the target feature. These results demonstrate the importance of considering individual differences in pretraining aptitudes when evaluating the efficacy of any speech training paradigm. PMID- 21786915 TI - Benefit of temporal fine structure to speech perception in noise measured with controlled temporal envelopes. AB - Previous studies have assessed the importance of temporal fine structure (TFS) for speech perception in noise by comparing the performance of normal-hearing listeners in two conditions. In one condition, the stimuli have useful information in both their temporal envelopes and their TFS. In the other condition, stimuli are vocoded and contain useful information only in their temporal envelopes. However, these studies have confounded differences in TFS with differences in the temporal envelope. The present study manipulated the analytic signal of stimuli to preserve the temporal envelope between conditions with different TFS. The inclusion of informative TFS improved speech-reception thresholds for sentences presented in steady and modulated noise, demonstrating that there are significant benefits of including informative TFS even when the temporal envelope is controlled. It is likely that the results of previous studies largely reflect the benefits of TFS, rather than uncontrolled effects of changes in the temporal envelope. PMID- 21786914 TI - Perceptual weighting of the envelope and fine structure across frequency bands for sentence intelligibility: effect of interruption at the syllabic-rate and periodic-rate of speech. AB - Listeners often only have fragments of speech available to understand the intended message due to competing background noise. In order to maximize successful speech recognition, listeners must allocate their perceptual resources to the most informative acoustic properties. The speech signal contains temporally-varying acoustics in the envelope and fine structure that are present across the frequency spectrum. Understanding how listeners perceptually weigh these acoustic properties in different frequency regions during interrupted speech is essential for the design of assistive listening devices. This study measured the perceptual weighting of young normal-hearing listeners for the envelope and fine structure in each of three frequency bands for interrupted sentence materials. Perceptual weights were obtained during interruption at the syllabic rate (i.e., 4 Hz) and the periodic rate (i.e., 128 Hz) of speech. Potential interruption interactions with fundamental frequency information were investigated by shifting the natural pitch contour higher relative to the interruption rate. The availability of each acoustic property was varied independently by adding noise at different levels. Perceptual weights were determined by correlating a listener's performance with the availability of each acoustic property on a trial-by-trial basis. Results demonstrated similar relative weights across the interruption conditions, with emphasis on the envelope in high-frequencies. PMID- 21786916 TI - Detection thresholds for gaps, overlaps, and no-gap-no-overlaps. AB - Detection thresholds for gaps and overlaps, that is acoustic and perceived silences and stretches of overlapping speech in speaker changes, were determined. Subliminal gaps and overlaps were categorized as no-gap-no-overlaps. The established gap and overlap detection thresholds both corresponded to the duration of a long vowel, or about 120 ms. These detection thresholds are valuable for mapping the perceptual speaker change categories gaps, overlaps, and no-gap-no-overlaps into the acoustic domain. Furthermore, the detection thresholds allow generation and understanding of gaps, overlaps, and no-gap-no overlaps in human-like spoken dialogue systems. PMID- 21786917 TI - Automatic estimation of voice onset time for word-initial stops by applying random forest to onset detection. AB - The voice onset time (VOT) of a stop consonant is the interval between its burst onset and voicing onset. Among a variety of research topics on VOT, one that has been studied for years is how VOTs are efficiently measured. Manual annotation is a feasible way, but it becomes a time-consuming task when the corpus size is large. This paper proposes an automatic VOT estimation method based on an onset detection algorithm. At first, a forced alignment is applied to identify the locations of stop consonants. Then a random forest based onset detector searches each stop segment for its burst and voicing onsets to estimate a VOT. The proposed onset detection can detect the onsets in an efficient and accurate manner with only a small amount of training data. The evaluation data extracted from the TIMIT corpus were 2344 words with a word-initial stop. The experimental results showed that 83.4% of the estimations deviate less than 10 ms from their manually labeled values, and 96.5% of the estimations deviate by less than 20 ms. Some factors that influence the proposed estimation method, such as place of articulation, voicing of a stop consonant, and quality of succeeding vowel, were also investigated. PMID- 21786918 TI - Perception of musical and lexical tones by Taiwanese-speaking musicians. AB - This study explored the relationship between music and speech by examining absolute pitch and lexical tone perception. Taiwanese-speaking musicians were asked to identify musical tones without a reference pitch and multispeaker Taiwanese level tones without acoustic cues typically present for speaker normalization. The results showed that a high percentage of the participants (65% with an exact match required and 81% with one-semitone errors allowed) possessed absolute pitch, as measured by the musical tone identification task. A negative correlation was found between occurrence of absolute pitch and age of onset of musical training, suggesting that the acquisition of absolute pitch resembles the acquisition of speech. The participants were able to identify multispeaker Taiwanese level tones with above-chance accuracy, even though the acoustic cues typically present for speaker normalization were not available in the stimuli. No correlations were found between the performance in musical tone identification and the performance in Taiwanese tone identification. Potential reasons for the lack of association between the two tasks are discussed. PMID- 21786919 TI - A methodological and preliminary study on the acoustic effect of a trumpet player's vocal tract. AB - A methodological study is presented to examine the acoustic role of the vocal tract in playing the trumpet. Preliminary results obtained for one professional player are also shown to demonstrate the effectiveness of the method. Images of the vocal tract with a resolution of 0.5 mm (2 mm in thickness) were recorded with magnetic resonance imaging to observe the tongue posture and estimate the vocal-tract area function during actual performance. The input impedance was then calculated for the player's air column including both the supra- and subglottal tracts using an acoustic tube model including the effect of wall losses. Finally, a time-domain blowing simulation by Adachi and Sato [J. Acoust. Soc. Am. 99, 1200 1209 (1996)] was performed with a model of the lips. In this simulation, the oscillating frequency of the lips was slightly affected by using different shapes of the vocal tract measured for the player. In particular, when the natural frequency of the lips was gradually increased, the transition to the higher mode occurred at different frequencies for different vocal-tract shapes. Furthermore, simulation results showed that the minimum blowing pressure required to attain the lip oscillation can be reduced by adjusting the vocal-tract shape properly. PMID- 21786920 TI - Radiation efficiency of a guitar top plate linked with edge or corner modes and intercell cancellation. AB - This paper was based on a theoretical framework to determine strong and weak radiation by a guitar top plate, vibrating through deflections hard to analyze: multipolar mode shapes. The air-structure interaction was examined in terms of edge modes or corner modes, and considering even or odd number modes. A numerical model was implemented and experimentally calibrated, exhibiting several advantages exploring the coupling between vibratory and acoustic waves in a top plate. Two analyses were applied detecting high or low radiation efficiency for the structure. First, the addition of volume velocity for odd numbers of poles and cancellation for even numbers were examined. In fact, both behaviors can happen at the same time, as it was shown for a corner radiator case used as an example. Second, the ratio between bending and acoustic wavenumbers was explored. To illustrate the importance of this ratio, some theoretical features of a more efficient radiator than the corner mode were exposed in an edge mode example. Labeling multipolar mode shapes as efficient or inefficient radiators showed to be a useful alternative analyzing the top plate behavior. It can be applied knowing the nodal lines of the vibration pattern and estimating the bending and acoustic wavelengths. PMID- 21786921 TI - Classification of behavior using vocalizations of Pacific white-sided dolphins (Lagenorhynchus obliquidens). AB - Surface behavior and concurrent underwater vocalizations were recorded for Pacific white-sided dolphins in the Southern California Bight (SCB) over multiple field seasons spanning 3 years. Clicks, click trains, and pulsed calls were counted and classified based on acoustic measurements, leading to the identification of 19 key call features used for analysis. Kruskal-Wallis tests indicated that call features differ significantly across behavioral categories. Previous work had discovered two distinctive click Types (A and B), which may correspond to known subpopulations of Pacific white-side dolphins in the Southern California Bight; this study revealed that animals producing these different click types also differ in both their behavior and vocalization patterns. Click Type A groups were predominantly observed slow traveling and milling, with little daytime foraging, while click Type B groups were observed traveling and foraging. These behavioral differences may be characteristic of niche partitioning by overlapping populations; coupled with differences in vocalization patterns, they may signify that these subpopulations are cryptic species. Finally, random forest decision trees were used to classify behavior based on vocalization data, with rates of correct classification up to 86%, demonstrating the potential for the use of vocalization patterns to predict behavior. PMID- 21786922 TI - Measuring body length of male sperm whales from their clicks: the relationship between inter-pulse intervals and photogrammetrically measured lengths. AB - Sperm whales (Physeter macrocephalus) emit short, broadband clicks which often include multiple pulses. The time interval between these pulses [inter-pulse interval (IPI)] represents the two-way time for a pulse to travel between the air sacs located at either end of the sperm whale's head. The IPI therefore, is a proxy of head length which, using an allometric relationship, can be used to estimate total body length. Previous studies relating IPI to an independent measure of length have relied on very small sample sizes and manual techniques for measuring IPI. Sound recordings and digital stereo photogrammetric measurements of 21 individuals were made off Kaikoura, New Zealand, and, in addition, archived recordings of whales measured with a previous photogrammetric system were reanalyzed to obtain a total sample size of 33 individuals. IPIs were measured automatically via cepstral analysis implemented via a software plug-in for pamguard, an open-source software package for passive acoustic monitoring. IPI measurements were highly consistent within individuals (mean CV=0.63%). The new regression relationship relating IPI (I) and total length (T) was found to be T=1.258I+5.736 (r(2)=0.77, p<0.001). This new regression provides a better fit than previous studies of large (> 11 m) sperm whales. PMID- 21786923 TI - Noise-induced temporary threshold shift and recovery in Yangtze finless porpoises Neophocaena phocaenoides asiaeorientalis. AB - In Yangtze finless porpoises Neophocaena phocaenoides asiaeorientalis, the effects of fatiguing noise on hearing thresholds at frequencies of 32, 45, 64, and 128 kHz were investigated. The noise parameters were: 0.5-oct bandwidth, -1 to +0.5 oct relative to the test frequency, 150 dB re 1 MUPa (140-160 dB re 1 MUPa in one measurement series), with 1-30 min exposure time. Thresholds were evaluated using the evoked-potential technique allowing the tracing of threshold variations with a temporal resolution better than 1 min. The most effective fatiguing noise was centered at 0.5 octave below the test frequency. The temporary threshold shift (TTS) depended on the frequencies of the fatiguing noise and test signal: The lower the frequencies, the bigger the noise effect. The time-to-level trade of the noise effect was incomplete: the change of noise level by 20 dB resulted in a change of TTS level by nearly 20 dB, whereas the tenfold change of noise duration resulted in a TTS increase by 3.8-5.8 dB. PMID- 21786925 TI - Optimization of pulsed focused ultrasound exposures for hyperthermia applications. AB - Hyperthermic temperatures, with potential applications in drug/gene delivery and chemo/radio sensitization, may be generated in biological tissues by applying focused ultrasound (FUS) in pulsed mode. Here, a strategy for optimizing FUS exposures for hyperthermia applications is proposed based on theoretical simulations and in vitro experiments. Initial simulations were carried out for tissue-mimicking phantoms, and subsequent thermocouple measurements allowed for validation of the simulation results. Advanced simulations were then conducted for an ectopic, murine xenograft tumor model. The ultrasound exposure parameters investigated in this study included acoustic power (3-5 W), duty cycle (DC) (10% 50%), and pulse repetition frequency (PRF) (1-5 Hz), as well as effects of tissue perfusion. The thermocouple measurements agreed well with simulation outcomes, where differences between the two never exceeded 1.9%. Based on a desired temperature range of 39-44 degrees C, optimal tumor coverage (40.8% of the total tumor volume) by a single FUS exposure at 1 MHz was achieved with 4 W acoustic power, 50% DC, and 5 Hz PRF. Results of this study demonstrate the utility of a proposed strategy for optimizing pulsed-FUS induced hyperthermia. These strategies can help reduce the requirement for empirical animal experimentation, and facilitate the translation of pulsed-FUS applications to the clinic. PMID- 21786924 TI - Two-dimensional shear wave speed and crawling wave speed recoveries from in vitro prostate data. AB - The crawling wave experiment was developed to capture a shear wave induced moving interference pattern that is created by two harmonic vibration sources oscillating at different but almost the same frequencies. Using the vibration sonoelastography technique, the spectral variance image reveals a moving interference pattern. It has been shown that the speed of the moving interference pattern, i.e., the crawling wave speed, is proportional to the shear wave speed with a nonlinear factor. This factor can generate high-speed artifacts in the crawling wave speed images that do not actually correspond to increased stiffness. In this paper, an inverse algorithm is developed to reconstruct both the crawling wave speed and the shear wave speed using the phases of the crawling wave and the shear wave. The feature for the data is the application to in vitro prostate data, while the features for the algorithm include the following: (1) A directional filter is implemented to obtain a wave moving in only one direction; and (2) an L(1) minimization technique with physics inspired constraints is employed to calculate the phase of the crawling wave and to eliminate jump discontinuities from the phase of the shear wave. The algorithm is tested on in vitro prostate data measured at the Rochester Center for Biomedical Ultrasound and University of Rochester. Each aspect of the algorithm is shown to yield image improvement. The results demonstrate that the shear wave speed images can have less artifacts than the crawling wave images. Examples are presented where the shear wave speed recoveries have excellent agreement with histology results on the size, shape, and location of cancerous tissues in the glands. PMID- 21786981 TI - Behavior of water molecules near monolayer-protected clusters with different terminal segments of ligand. AB - Molecular dynamics simulations are performed to investigate the behavior of water molecules near gold monolayer protected clusters (MPCs) with two different types of surfactant, HS(CH(2))(5)(OCH(2)CH(2))(2)COOH (type1) and HS(CH(2))(11)COOH (type2). The effects of the different moieties of the two ligands on the local structure of the water molecules are quantified by means of the reduced density profiles of oxygen and hydrogen atoms, and the hydrogen bond statistics. The adsorption characteristics of water molecules are evaluated by means of their residence time near the MPCs. The results show that the hydrophilic oligo (ethylene glycol) segment increases the number of water molecules, which penetrate the protective layer of MPC. As a result, the inter-water hydrogen bond network in the protective layer of type1 MPC is stronger than that in the protective layer of the type2 MPC. It is shown that the presence of interfacial hydrogen bonds increases the adsorption of water molecules near the MPCs and therefore constrains the motion of MPCs. As a result, the residence time of the water molecules adjacent to the type1 MPC is longer than that of the molecules adjacent to the type2 MPC. PMID- 21786980 TI - Communication: Momentum-resolved quantum interference in optically excited surface states. AB - Surface states play essential roles in condensed matter physics, e.g., as model two-dimensional (2D) electron gases and as the basis for topological insulators. Here, we demonstrate quantum interference in the optical excitation of 2D surface states using the model system of C(60)/Au(111). These surface states are transiently populated and probed in a femtosecond time- and angle-resolved two photon photoemission experiment. We observe quantum interference within the excited populations of these surface states as a function of parallel momentum vector. Such quantum interference in momentum space may allow one to control 2D transport properties by optical fields. PMID- 21786982 TI - Optimized energy landscape exploration using the ab initio based activation relaxation technique. AB - Unbiased open-ended methods for finding transition states are powerful tools to understand diffusion and relaxation mechanisms associated with defect diffusion, growth processes, and catalysis. They have been little used, however, in conjunction with ab initio packages as these algorithms demanded large computational effort to generate even a single event. Here, we revisit the activation-relaxation technique (ART nouveau) and introduce a two-step convergence to the saddle point, combining the previously used Lanczos algorithm with the direct inversion in interactive subspace scheme. This combination makes it possible to generate events (from an initial minimum through a saddle point up to a final minimum) in a systematic fashion with a net 300-700 force evaluations per successful event. ART nouveau is coupled with BigDFT, a Kohn-Sham density functional theory (DFT) electronic structure code using a wavelet basis set with excellent efficiency on parallel computation, and applied to study the potential energy surface of C(20) clusters, vacancy diffusion in bulk silicon, and reconstruction of the 4H-SiC surface. PMID- 21786983 TI - Quantum diffusive dynamics of macromolecular transitions. AB - We study the role of quantum fluctuations of atomic nuclei in the real-time dynamics of non-equilibrium macro-molecular transitions. To this goal we introduce an extension of the dominant reaction pathways formalism, in which the quantum corrections to the classical overdamped Langevin dynamics are rigorously taken into account to order h(2). We first illustrate our approach in simple cases, and compare with the results of the instanton theory. Then we apply our method to study the C7(eq) -> C7(ax) transition of alanine dipeptide. We find that the inclusion of quantum fluctuations can significantly modify the reaction mechanism for peptides. For example, the energy difference which is overcome along the most probable pathway is reduced by as much as 50%. PMID- 21786984 TI - Efficient quantum trajectory representation of wavefunctions evolving in imaginary time. AB - The Boltzmann evolution of a wavefunction can be recast as imaginary-time dynamics of the quantum trajectory ensemble. The quantum effects arise from the momentum-dependent quantum potential--computed approximately to be practical in high-dimensional systems--influencing the trajectories in addition to the external classical potential [S. Garashchuk, J. Chem. Phys. 132, 014112 (2010)]. For a nodeless wavefunction represented as psi(x, t) = exp(-S(x, t)/h) with the trajectory momenta defined by ?S(x, t), analysis of the Lagrangian and Eulerian evolution shows that for bound potentials the former is more accurate while the latter is more practical because the Lagrangian quantum trajectories diverge with time. Introduction of stationary and time-dependent components into the wavefunction representation generates new Lagrangian-type dynamics where the trajectory spreading is controlled improving efficiency of the trajectory description. As an illustration, different types of dynamics are used to compute zero-point energy of a strongly anharmonic well and low-lying eigenstates of a high-dimensional coupled harmonic system. PMID- 21786985 TI - Theory of multichromophoric coherent resonance energy transfer: a polaronic quantum master equation approach. AB - The approach of second order time local quantum master equation in the polaron picture, which has been employed for a theory of coherent resonance energy transfer, is extended for general multichromophore systems. Explicit expressions for all the kernel and inhomogeneous terms are derived, which can be calculated by any standard numerical procedure. The theory is then applied to a model of donor-bridge-acceptor system moderately coupled to bosonic bath. The results are compared with those based on the theory of Forster's resonance energy transfer. It is shown that coherently coupled multichromophores can speed up the transfer of energy substantially and in a way insensitive to the disorder. PMID- 21786986 TI - Implementation of pseudopotential in the G3 theory for molecules containing first , second-, and non-transition third-row atoms. AB - Compact effective pseudopotential (CEP) is adapted in the G3 theory providing a theoretical alternative referred to as G3CEP for calculations involving the first , second-, and non-transition third-row elements. These modifications tried to preserve as much as possible the original characteristics of G3. G3CEP was used in the study of 247 enthalpies of formation, 22 atomization energies, 104 ionization potentials, 63 electron affinities, and 10 proton affinities, resulting in the calculation of 446 species for the first-, second-, and third row atoms. The final average total absolute deviation was of 1.29 kcal mol(-1) against 1.16 kcal mol(-1) from all-electron G3 for the same calculations. The CPU time has been reduced by 7% to 56%, depending on the size of the molecules and the type of atoms considered. PMID- 21786987 TI - Ab initio calculations on the excited states of Na3 cluster to explore beyond Born-Oppenheimer theories: adiabatic to diabatic potential energy surfaces and nuclear dynamics. AB - We perform ab initio calculation using quantum chemistry package (MOLPRO) on the excited states of Na(3) cluster and present the adiabatic PESs for the electronic states 2(2)E' and 1(2)A(1)', and the non-adiabatic coupling (NAC) terms among those states. Since the ab initio calculated NAC elements for the states 2(2)E' and 1(2)A(1)' demonstrate the numerical validity of so called "Curl Condition," such states closely form a sub-Hilbert space. For this subspace, we employ the NAC terms to solve the "adiabatic-diabatic transformation (ADT)" equations to obtain the functional form of the transformation angles and pave the way to construct the continuous and single valued diabatic potential energy surface matrix by exploiting the existing first principle based theoretical means on beyond Born-Oppenheimer treatment. Nuclear dynamics has been carried out on those diabatic surfaces to reproduce the experimental spectrum for system B of Na(3) cluster and thereby, to explore the numerical validity of the theoretical development on beyond Born-Oppenheimer approach for adiabatic to diabatic transformation. PMID- 21786988 TI - Simulating structural transitions by direct transition current sampling: the example of LJ38. AB - Reaction paths and probabilities are inferred, in a usual Monte Carlo or molecular dynamic simulation, directly from the evolution of the positions of the particles. The process becomes time-consuming in many interesting cases in which the transition probabilities are small. A radically different approach consists of setting up a computation scheme where the object whose time evolution is simulated is the transition current itself. The relevant timescale for such a computation is the one needed for the transition probability rate to reach a stationary level, and this is usually substantially shorter than the passage time of an individual system. As an example, we show, in the context of the "benchmark" case of 38 particles interacting via the Lennard-Jones potential ("LJ(38)" cluster), how this method may be used to explore the reactions that take place between different phases, recovering efficiently known results, and uncovering new ones with small computational effort. PMID- 21786989 TI - Size evolution study of "molecular" and "atom-in-cluster" polarizabilities of medium-size gold clusters. AB - A study on static polarizabilities for a family of gold clusters (Au(n), n = 6, 12, 20, 34, 54) is presented. For each cluster, a density functional theory perturbation theory calculation was performed to compute the cluster polarizability and the polarizability of each atom in the cluster using Bader's "quantum theory of atoms in molecules" formalism. The cluster polarizability tensor, alpha(cluster), is expressed as a sum of the atom-in-molecule tensors, alpha(cluster)=?(Omega)alpha(Omega). A strong quadratic correlation (R(2) = 0.98) in the isotropic polarizability of atoms in the cluster and their distance to the cluster center of mass was observed. The cluster polarizabilities are in agreement with previous calculations. PMID- 21786990 TI - Implementation of screened hybrid density functional for periodic systems with numerical atomic orbitals: basis function fitting and integral screening. AB - We present an efficient O(N) implementation of screened hybrid density functional for periodic systems with numerical atomic orbitals (NAOs). NAOs of valence electrons are fitted with gaussian-type orbitals, which is convenient for the calculation of electron repulsion integrals and the construction of Hartree-Fock exchange matrix elements. All other parts of Hamiltonian matrix elements are constructed directly with NAOs. The strict locality of NAOs is adopted as an efficient two-electron integral screening technique to speed up calculations. PMID- 21786991 TI - Harmonic electron correlation operator. AB - An appealing way to model electron correlation within the single determinant wave function formalism is through the expectation value of a linear two-electron operator. For practical reasons, it is desirable for such an operator to be universal, i.e., not depend on the positions and types of nuclei in a molecule. We show how a perturbation theory applied to a hookium atom provides for a particular form of a correlation operator, hence called the harmonic correlation operator. The correlation operator approach is compared and contrasted to the traditional ways to describe electron correlation. To investigate the two electron approximation of this operator, we apply it to many-electron hookium systems. To investigate the harmonic approximation, we apply it to the small atomic systems. Directions of future research are also discussed. PMID- 21786992 TI - Constrained-pairing mean-field theory. V. Triplet pairing formalism. AB - Describing strong (also known as static) correlation caused by degenerate or nearly degenerate orbitals near the Fermi level remains a theoretical challenge, particularly in molecular systems. Constrained-pairing mean-field theory has been quite successful, capturing the effects of static correlation in bond formation and breaking in closed-shell molecular systems by using singlet electron entanglement to model static correlation at mean-field computational cost. This work extends the previous formalism to include triplet pairing. Additionally, a spin orbital extension of the "odd-electron" formalism is presented as a method for understanding electron entanglement in molecules. PMID- 21786993 TI - A global, high accuracy ab initio dipole moment surface for the electronic ground state of the water molecule. AB - A highly accurate, global dipole moment surface (DMS) is calculated for the water molecule using ab initio quantum chemistry methods. The new surface is named LTP2011 and is based on all-electron, internally contracted multireference configuration interaction, including size-extensivity corrections in the aug-cc pCV6Z basis set. Dipoles are computed as energy derivatives and small corrections due to relativistic effects included. The LTP2011 DMS uses an appropriate functional form that guarantees qualitatively correct behaviour even for most high energies configuration (up to about 60,000 cm(-1)), including, in particular, along the water dissociation channel. Comparisons with high precision experimental data show agreement within 1% for medium-strength lines. The new DMS and all the ab initio data are made available in the supplementary material. PMID- 21786994 TI - Identifying low variance pathways for free energy calculations of molecular transformations in solution phase. AB - Improving the efficiency of free energy calculations is important for many biological and materials design applications, such as protein-ligand binding affinities in drug design, partitioning between immiscible liquids, and determining molecular association in soft materials. We show that for any pair potential, moderately accurate estimation of the radial distribution function for a solute molecule is sufficient to accurately estimate the statistical variance of a sampling along a free energy pathway. This allows inexpensive analytical identification of low statistical error free energy pathways. We employ a variety of methods to estimate the radial distribution function (RDF) and find that the computationally cheap two-body "dilute gas" limit performs as well or better than 3D-RISM theory and other approximations for identifying low variance free energy pathways. With a RDF estimate in hand, we can search for pairwise interaction potentials that produce low variance. We give an example of a search minimizing statistical variance of solvation free energy over the entire parameter space of a generalized "soft core" potential. The free energy pathway arising from this optimization procedure has lower curvature in the variance and reduces the total variance by at least 50% compared to the traditional soft core solvation pathway. We also demonstrate that this optimized pathway allows free energies to be estimated with fewer intermediate states due to its low curvature. This free energy variance optimization technique is generalizable to solvation in any homogeneous fluid and for any type of pairwise potential and can be performed in minutes to hours, depending on the method used to estimate g(r). PMID- 21786995 TI - Symmetry exploitation in closed-shell coupled-cluster theory with spin-orbit coupling. AB - In the present work, we report exploitation of spatial symmetry in calculations of ground state energy and analytic first derivatives of closed-shell molecules based on our previously developed coupled-cluster (CC) approach with spin-orbit coupling. Both time-reversal symmetry and spatial symmetry for D(2h) and its subgroups are exploited in the implementation. The symmetry of a certain spin case for the amplitude, intermediate, or density matrix is determined by the symmetry of the corresponding spin functions and the direct product decomposition method is employed in computations involving these quantities. The reduction in computational effort achieved through the use of spatial symmetry is larger than the order of the molecular single point group. Symmetry exploitation renders application of the CC approaches with spin-orbit coupling to larger closed-shell molecules containing heavy elements with high accuracy. PMID- 21786996 TI - Analysis of self-consistency effects in range-separated density-functional theory with Moller-Plesset perturbation theory. AB - Range-separated density-functional theory combines wave function theory for the long-range part of the two-electron interaction with density-functional theory for the short-range part. When describing the long-range interaction with non variational methods, such as perturbation or coupled-cluster theories, self consistency effects are introduced in the density functional part, which for an exact solution requires iterations. They are generally assumed to be small but no detailed study has been performed so far. Here, the authors analyze self consistency when using Moller-Plesset-type (MP) perturbation theory for the long range interaction. The lowest-order self-consistency corrections to the wave function and the energy, that enter the perturbation expansions at the second and fourth order, respectively, are both expressed in terms of the one-electron reduced density matrix. The computational implementation of the latter is based on a Neumann series which, interestingly, even though the effect is small, usually diverges. A convergence technique, which perhaps can be applied in other uses of Neumann series in perturbation theory, is proposed. The numerical results thus obtained show that, in weakly bound systems, self-consistency can be neglected since the long-range correlation does not affect the density significantly. Although MP is not adequate for multireference systems, it can still be used as a reliable analysis tool. Though the density change is not negligible anymore in such cases, self-consistency effects are found to be much smaller than long-range correlation effects (less than 10% for the systems considered). For that reason, a sensible approximation might be to update the short-range energy functional term while freezing its functional derivative, namely, the short-range local potential, in the wave function optimization. The accuracy of such an approximation still needs to be assessed. PMID- 21786997 TI - Field-free molecular orientation enhanced by two dual-color laser subpulses. AB - In this paper, we theoretically show that the field-free molecular orientation created by a single dual-color laser pulse can be significantly enhanced by separating it into two time-delayed dual-color subpulses. It is indicated that the maximum enhancement of the molecular orientation created by two time-delayed dual-color subpulses can be achieved with their intensity ratio of about 1:2 and by simultaneously applying the second one at the beginning of the rotational wave packet rephasing or the end of the rotational wave packet dephasing induced by the first one. It is also shown that the enhancement or suppression of the molecular orientation can be coherently manipulated by varying the relative phase between the fundamental field and its second harmonic field of the second dual color subpulse, and its enhancement is obtained around half rotational period. PMID- 21786999 TI - On the rotational temperature and structure dependence of electric field deflection experiments: a case study of germanium clusters. AB - Molecular beam electric field deflection experiments offer a probe to the structural and dielectric properties of isolated particles in the gas phase. However, their quantitative interpretation is still a formidable task. Despite the benefits of this method, the analysis of the deflection behavior is often complicated by various experimental and theoretical problems, including the amount of energy stored in internal and rotational modes of the deflected particle and the amount of structural asymmetry. In this contribution, we address these issues by discussing the experimentally observed field-induced deflection of Ge(9), Ge(10), and Ge(15) clusters in comparison to quantum mechanical and classical deflection models. Additionally, we derive simple formulas to describe how the molecular beam deflection depends on the rotational temperature and the symmetry of the particle. Based on these results, we discuss to what extend molecular beam electric field deflection experiments can be used as a tool for structure determination of isolated clusters in the gas phase. PMID- 21786998 TI - Analyzing velocity map images to distinguish the primary methyl photofragments from those produced upon C-Cl bond photofission in chloroacetone at 193 nm. AB - We use a combination of crossed laser-molecular beam scattering experiments and velocity map imaging experiments to investigate the three primary photodissociation channels of chloroacetone at 193 nm: C-Cl bond photofission yielding CH(3)C(O)CH(2) radicals, C-C bond photofission yielding CH(3)CO and CH(2)Cl products, and C-CH(3) bond photofission resulting in CH(3) and C(O)CH(2)Cl products. Improved analysis of data previously reported by our group quantitatively identifies the contribution of this latter photodissociation channel. We introduce a forward convolution procedure to identify the portion of the signal, derived from the methyl image, which results from a two-step process in which C-Cl bond photofission is followed by the dissociation of the vibrationally excited CH(3)C(O)CH(2) radicals to CH(3) + COCH(2). Subtracting this from the total methyl signal identifies the methyl photofragments that result from the CH(3) + C(O)CH(2)Cl photofission channel. We find that about 89% of the chloroacetone molecules undergo C-Cl bond photofission to yield CH(3)C(O)CH(2) and Cl products; approximately 8% result in C-C bond photofission to yield CH(3)CO and CH(2)Cl products, and the remaining 2.6% undergo C-CH(3) bond photofission to yield CH(3) and C(O)CH(2)Cl products. PMID- 21787000 TI - Geometrical and substituent effects in conical intersections: linking chemical structure and photoreactivity in polyenes. AB - The knowledge of the intersection space topography of electronic states is essential for deciphering and predicting photoinduced reactions. Michl and Bonacic-Koutecky developed a two-electron two-orbital model that allowed first systematic studies of the chemical origin of conical intersections in strongly polar systems. We generalize this approach to arbitrary functionalized and unfunctionalized polyene systems. For the extended model, a set of mathematical conditions for the formation of conical intersections are derived. These conditions are translated into geometrical motions and electronic effects, which help to explain and predict the structure and energetics of conical intersections. A three-step strategy for the conceptual search of conical intersections is outlined. Its universal validity is demonstrated using the textbook example cyclohexadiene and its functionalized derivative trifluoromethyl indolylfulgide, a chromophore studied for possible application as a molecular switch. PMID- 21787001 TI - Hyperfine interactions in the A3Phi4 and X3Phi4 states of iridium monofluoride, IrF. AB - Laser induced-fluorescence spectra of the 1-0 band of the A(3)Phi(4)-X(3)Phi(4) transition of iridium monofluoride, IrF, have been obtained at near natural linewidth resolution using supersonic molecular beam techniques. The spectra show a complex, clearly resolved hyperfine structure which has significant contributions from the magnetic and quadrupole hyperfine terms in (193)Ir and (191)Ir, both with I = 3/2, and the fluorine magnetic hyperfine term (I = 1/2). The spectra of both (193)IrF and (191)IrF isotopologues have been assigned and analyzed. The hyperfine structure was interpreted with the aid of atomic hyperfine parameters, which were used to determine the configurational composition of the ground state and to estimate the individual molecular hyperfine parameters. PMID- 21787002 TI - The diatomic dication CuZn2+ in the gas phase. AB - In the present combined experimental and theoretical study we report the observation of the novel gas-phase dication CuZn(2+) and provide some theoretical insight into the electronic binding of this exotic metastable molecule and its formation mechanism. Using mass spectrometry we have detected four isotopomer signals of CuZn(2+) at half-integer m/z values for ion flight times of about 14 MUs. CuZn(2+) was unambiguously identified by its isotopic abundance. High current energetic Ar(+) ion bombardment of a brass surface was used for its production. Subsequent dication formation was found to take place in the ion extraction region of our mass spectrometer several tens of microns in front of the sputtered brass surface. The dication formation mechanism appears to be resonant electron transfer in soft gas-phase collisions between sputter-ejected singly charged CuZn(+) molecular ions and incoming Ar(+) projectiles. This conclusion is supported by our theoretical study that obtained an ionization energy of CuZn(+) of 15.75 eV, in excellent agreement with both the experimental and calculated ionization energy of Ar (15.76 and 15.67 eV, respectively). The ground state of CuZn(2+) is found to be a metastable one with a very shallow potential well at an internuclear equilibrium distance of about 2.7 A the dissociation energy being very difficult to estimate. Interestingly, spin-orbit corrections are found to be necessary to get an adequate description of the metastable state of CuZn(2+), whereas relativistic corrections have no effects on neutral CuZn nor on CuZn(+). PMID- 21787003 TI - Excited-state intramolecular proton transfer reaction modulated by low-frequency vibrations: an effect of an electron-donating substituent on the dually fluorescent bis-benzoxazole. AB - Excited-state intramolecular proton transfer (ESIPT) reaction has been studied in a molecule showing dual fluorescence, the 2,5-bis(2-benzoxazolyl)-4-methoxyphenol (BBMP), and its isotopomers, where the methoxy, and alternatively, the OH group has been deuterated. Attention is focused on the influence of electron donating OCH(3) substituent on fast excited state reaction. Comparison between the resonance-enhanced multiphoton ionization spectrum and the laser-induced excitation of the primary and phototautomeric emissions has been done. The geometry, electron density distribution, vibrational structure as well as the potential energy profiles in the S(0) and S(1) states of four possible rotameric forms of BBMP were calculated with application of the density functional theory (DFT). It allowed identifying the most probable conformer and assessing the role of low-frequency motions for the ESIPT efficiency. PMID- 21787004 TI - RG+ formation following photolysis of NO-RG via the A-X transition: a velocity map imaging study. AB - Kr(+) and Xe(+) formation following photodissociation of NO-RG (RG = Kr or Xe) molecules via the A-X electronic transition in the 44,150-44,350 cm(-1) region has been investigated using velocity map imaging. Nuclear kinetic energy release (nKER) spectra indicate that the NO cofragment is produced in multiple vibrational states of the electronic ground state, with a high degree of rotational excitation. Photofragment angular distributions and nKERs are consistent with photo-induced charge transfer at the two-photon level followed by dissociative ionization at the three-photon level. RG(+) angular distributions showing highly parallel character relative to the laser polarization axis are indicative of a high degree of molecular alignment in the dissociating species. PMID- 21787005 TI - Electronic states and spin-orbit splitting of lanthanum dimer. AB - Lanthanum dimer (La(2)) was studied by mass-analyzed threshold ionization (MATI) spectroscopy and a series of multi-configuration ab initio calculations. The MATI spectrum exhibits three band systems originating from ionization of the neutral ground electronic state, and each system shows vibrational frequencies of the neutral molecule and singly charged cation. The three ionization processes are La(2)(+) (a(2)?(g)(+)) <- La(2) (X(1)?(g)(+)), La(2)(+) (b(2)Pi(3/2, u)) <- La(2) (X(1)?(g)(+)), and La(2)(+) (b(2)Pi(1/2, u)) <- La(2) (X(1)?(g)(+)), with the ionization energies of 39,046, 40,314, and 40,864 cm(-1), respectively. The vibrational frequency of the X(1)Sigma(g)(+) state is 207 cm(-1), and those of the a(2)Sigma(g)(+), b(2)Pi(3/2, u) and b(2)Pi(1/2, u) are 235.7, 242.2, and 240 cm(-1). While X(1)Sigma(g)(+) is the ground state of the neutral molecule, a(2)Sigma(g (+) and b(2)Pi(u) are calculated to be the excited states of the cation. The spin-orbit splitting in the b(2)Pi(u) ion is 550 cm(-1). An X(4)Sigma(g)(-) state of La(2)(+) was predicted by theory, but not observed by the experiment. The determination of a singlet ground state of La(2) shows that lanthanum behaves differently from scandium and yttrium. PMID- 21787006 TI - Can quasiclassical trajectory calculations reproduce the extreme kinetic isotope effect observed in the muonic isotopologues of the H + H2 reaction? AB - Rate coefficients for the mass extreme isotopologues of the H + H(2) reaction, namely, Mu + H(2), where Mu is muonium, and HeMU + H(2), where HeMU is a He atom in which one of the electrons has been replaced by a negative muon, have been calculated in the 200-1000 K temperature range by means of accurate quantum mechanical (QM) and quasiclassical trajectory (QCT) calculations and compared with the experimental and theoretical results recently reported by Fleming et al. [Science 331, 448 (2011)]. The QCT calculations can reproduce the experimental and QM rate coefficients and kinetic isotope effect (KIE), k(Mu)(T)/k(HeMU)(T), if the Gaussian binning procedure (QCT-GB)--weighting the trajectories according to their proximity to the right quantal vibrational action--is applied. The analysis of the results shows that the large zero point energy of the MuH product is the key factor for the large KIE observed. PMID- 21787007 TI - Re-entrant phase behaviour of network fluids: a patchy particle model with temperature-dependent valence. AB - We study a model consisting of particles with dissimilar bonding sites ("patches"), which exhibits self-assembly into chains connected by Y-junctions, and investigate its phase behaviour by both simulations and theory. We show that, as the energy cost epsilon(j) of forming Y-junctions increases, the extent of the liquid-vapour coexistence region at lower temperatures and densities is reduced. The phase diagram thus acquires a characteristic "pinched" shape in which the liquid branch density decreases as the temperature is lowered. To our knowledge, this is the first model in which the predicted topological phase transition between a fluid composed of short chains and a fluid rich in Y-junctions is actually observed. Above a certain threshold for epsilon(j), condensation ceases to exist because the entropy gain of forming Y-junctions can no longer offset their energy cost. We also show that the properties of these phase diagrams can be understood in terms of a temperature-dependent effective valence of the patchy particles. PMID- 21787009 TI - Sound dispersion and attenuation in concentrated H2SO4 by visible and ultraviolet Brillouin spectroscopy. AB - The acoustic properties of highly concentrated H(2)SO(4) are investigated performing visible and ultraviolet Brillouin scattering measurements. We analyzed the isotropic and anisotropic spectra of this molecular liquid in a wide temperature and exchanged wavector range in order to study the evolution of its sound velocity and viscosity. This allows us to extract the parameters required to describe its viscoelastic relaxation behavior. We found that the behavior of the hydrodynamic parameters of this molecular liquid shares some similarities with that of water indicating a rather high increase of sound velocity if compared to that measured by ultrasonics. PMID- 21787008 TI - Nanostructural organization in carbon disulfide/ionic liquid mixtures: molecular dynamics simulations and optical Kerr effect spectroscopy. AB - In this paper, the nanostructural organization and subpicosecond intermolecular dynamics in the mixtures of CS(2) and the room temperature ionic liquid (IL) 1 pentyl-3-methylimidazolium bis{(trifluoromethane)sulfonyl}amide ([C(5)mim][NTf(2)]) were studied as a function of concentration using molecular dynamics (MD) simulations and optical heterodyne-detected Raman-induced Kerr effect spectroscopy. At low CS(2) concentrations (<10 mol.% CS(2)/IL), the MD simulations indicate that the CS(2) molecules are localized in the nonpolar domains. In contrast, at higher concentrations (>=10 mol.% CS(2)/IL), the MD simulations show aggregation of the CS(2) molecules. The optical Kerr effect (OKE) spectra of the mixtures are interpreted in terms of an additivity model with the components arising from the subpicosecond dynamics of CS(2) and the IL. Comparison of the CS(2)-component with the OKE spectra of CS(2) in alkane solvents is consistent with CS(2) mainly being localized in the nonpolar domains, even at high CS(2) concentrations, and the local CS(2) concentration being higher than the bulk CS(2) concentration. PMID- 21787010 TI - Spatio-temporal anomalous diffusion in heterogeneous media by nuclear magnetic resonance. AB - In this paper, we describe nuclear magnetic resonance measurements of water diffusion in highly confined and heterogeneous colloidal systems using an anomalous diffusion model. For the first time, temporal and spatial fractional exponents, alpha and MU, introduced within the framework of continuous time random walk, are simultaneously measured by pulsed gradient spin-echo NMR technique in samples of micro-beads dispersed in aqueous solution. In order to mimic media with low and high level of disorder, mono-dispersed and poly dispersed samples are used. We find that the exponent alpha depends on the disorder degree of the system. Conversely, the exponent MU depends on both bead sizes and magnetic susceptibility differences within samples. The new procedure proposed here may be a useful tool to probe porous materials and microstructural features of biological tissue. PMID- 21787011 TI - Structure and thermodynamics of hard-core Yukawa fluids: thermodynamic perturbation approaches. AB - The thermodynamic perturbation theories, which are based on the power series of a coupling constant (lambda-expansion), have been proposed for studying the structural and thermodynamic properties of a hard-core Yukawa (HCY) fluid: one (A1-approximation) is the perturbation theory based on the hard-sphere repulsion as a reference system. The other (A2-approximation) is the perturbation theory based on the reference system which incorporates both the repulsive and short range attractive interactions. The first-order mean-spherical approximation (FMSA) provided by Tang and Lu [J. Chem. Phys. 99, 9828 (1993)] has been employed for investigating the thermodynamic properties of a HCY fluid using the alternative method via the direct correlation function. The calculated results show that (i) the A1 and A2 approximations are in excellent agreements with previous computer simulation results in the literature and compare with the semi empirical works of Shukla including the higher-order free energy terms, (ii) the A1 and A2 approximations are better than the FMSA and the mean-spherical approximation, (iii) the A2-approximation compares with the A1-approximation, even though the perturbation effect of an A2-approximation is much smaller than that of an A1-approximation, and that (iv) the FMSA study is particularly of advantage in providing the structure and thermodynamics in a simple and analytic manner. PMID- 21787012 TI - Atomic decomposition of the protein solvation free energy and its application to amyloid-beta protein in water. AB - We report the development of an atomic decomposition method of the protein solvation free energy in water, which ascribes global change in the solvation free energy to local changes in protein conformation as well as in hydration structure. So far, empirical decomposition analyses based on simple continuum solvation models have prevailed in the study of protein-protein interactions, protein-ligand interactions, as well as in developing scoring functions for computer-aided drug design. However, the use of continuum solvation model suffers serious drawbacks since it yields the protein free energy landscape which is quite different from that of the explicit solvent model and since it does not properly account for the non-polar hydrophobic effects which play a crucial role in biological processes in water. Herein, we develop an exact and general decomposition method of the solvation free energy that overcomes these hindrances. We then apply this method to elucidate the molecular origin for the solvation free energy change upon the conformational transitions of 42-residue amyloid-beta protein (Abeta42) in water, whose aggregation has been implicated as a primary cause of Alzheimer's disease. We address why Abeta42 protein exhibits a great propensity to aggregate when transferred from organic phase to aqueous phase. PMID- 21787013 TI - Heat conduction in chain polymer liquids: molecular dynamics study on the contributions of inter- and intramolecular energy transfer. AB - In this paper, the molecular mechanisms which determine the thermal conductivity of long chain polymer liquids are discussed, based on the results observed in molecular dynamics simulations. Linear n-alkanes, which are typical polymer molecules, were chosen as the target of our studies. Non-equilibrium molecular dynamics simulations of bulk liquid n-alkanes under a constant temperature gradient were performed. Saturated liquids of n-alkanes with six different chain lengths were examined at the same reduced temperature (0.7T(c)), and the contributions of inter- and intramolecular energy transfer to heat conduction flux, which were identified as components of heat flux by the authors' previous study [J. Chem. Phys. 128, 044504 (2008)], were observed. The present study compared n-alkane liquids with various molecular lengths at the same reduced temperature and corresponding saturated densities, and found that the contribution of intramolecular energy transfer to the total heat flux, relative to that of intermolecular energy transfer, increased with the molecular length. The study revealed that in long chain polymer liquids, thermal energy is mainly transferred in the space along the stiff intramolecular bonds. This finding implies a connection between anisotropic thermal conductivity and the orientation of molecules in various organized structures with long polymer molecules aligned in a certain direction, which includes confined polymer liquids and self organized structures such as membranes of amphiphilic molecules in water. PMID- 21787014 TI - Temperature dependence of ice critical nucleus size. AB - We present a molecular dynamics study of ice growth from supercooled water. By performing a series of simulations with different initial conditions, we have quantitative established the relationship existing between the critical nucleus size and the temperature. The results show that ice embryos containing hundreds or thousands of molecules are needed for the system to crystallize macroscopically, even at high degrees of supercooling. Our findings explain the difficulty in observing spontaneous ice nucleation in atomistic simulations and the relative ease with which water droplets can be supercooled under controlled experiments. PMID- 21787015 TI - Solvent effects on the conformation of DNA dodecamer segment: a simulation study. AB - Different solvent temperatures with five kinds of counterions are used to investigate solvent effects on the DNA microscopic structure. The dodecamer d (CGCGAATTCGCG) DNA segment is merged into the solvents and its conformation transition is studied with the molecular dynamics simulations in detail. For the simple point charge model of water molecule with Na(+) counterions, as temperature increases from 200 K to 343 K, the duplex DNA changes from stiff B form to a state between A form and B form, which we define as mixed (A-B) structure, with a double helix unwinding. To study the counterions effects, other four alkali cations, Li(+), K(+), Rb(+), or Cs(+) ions, are substituted for Na(+) ions at 298 K and 343 K, respectively. For the cases of Li(+), Rb(+), and Cs(+) ions, the duplex DNA becomes more flexible with sugar configuration changing form C2'-endo to C1'-endo type and the width and depth of minor groove at CpG and GpC steps moving towards A values, as the mass of the counterions decreasing. For the case of K(+) ions, DNA-K(+) interaction widens the width of minor and major grooves at ApA steps and TpT steps, respectively. It seems that the light ions (Li(+) or Na(+)) prefer to interact with the free phosphate oxygen atoms while the heavier ions (Rb(+) and Cs(+)) strongly interact with the base pairs. PMID- 21787016 TI - Stacking in sediments of colloidal hard spheres. AB - We use computer simulations to investigate the crystallization dynamics of sedimenting hard spheres in large systems (hundreds of thousands of particles). We show that slow sedimentation results primarily in face-centered cubic (fcc) stacked crystals, instead of random hexagonal close packed or hexagonal close packed (hcp) crystals. We also find slanted stacking faults, in the fcc regions. However, we attribute the formation of fcc to the free energy difference between fcc and hcp and not to the presence of these slanted stacking faults. Although the free energy difference between hcp and fcc per particle is small (only 10(-3) times the thermal energy), it can become considerable, when multiplied by the number of particles in each domain. The ratio of fcc to hcp obtained from dynamic simulations is in excellent agreement with well-equilibrated Monte Carlo simulations, in which no slanted stacking faults were found. Our results explain a range of experiments on colloids, in which the amount of fcc increases upon lowering the sedimentation rate or decreasing the initial volume fraction. PMID- 21787017 TI - Kinetic aspects of the thermostatted growth of ice from supercooled water in simulations. AB - In experiments, the growth rate of ice from supercooled water is seen to increase with the degree of supercooling, that is, the lower the temperature, the faster the crystallization takes place. In molecular dynamics simulations of the freezing process, however, the temperature is usually kept constant by means of a thermostat that artificially removes the heat released during the crystallization by scaling the velocities of the particles. This direct removal of energy from the system replaces a more realistic heat-conduction mechanism and is believed to be responsible for the curious observation that the thermostatted ice growth proceeds fastest near the melting point and more slowly at lower temperatures, which is exactly opposite to the experimental findings [M. A. Carignano, P. B. Shepson, and I. Szleifer, Mol. Phys. 103, 2957 (2005)]. This trend is explained by the diffusion and the reorientation of molecules in the liquid becoming the rate-determining steps for the crystal growth, both of which are slower at low temperatures. Yet, for a different set of simulations, a kinetic behavior analogous to the experimental finding has been reported [H. Nada and Y. Furukawa, J. Crystal Growth 283, 242 (2005)]. To clarify this apparent contradiction, we perform relatively long simulations of the TIP4P/Ice model in an extended range of temperatures. The temperature dependence of the thermostatted ice growth is seen to be more complex than was previously reported: The crystallization process is very slow close to the melting point at 270 K, where the thermodynamic driving force for the phase transition is weak. On lowering the temperature, the growth rate initially increases, but displays a maximum near 260 K. At even lower temperatures, the freezing process slows down again due to the reduced diffusivity in the liquid. The velocity of the thermostatted melting process, in contrast, shows a monotonic increase upon raising the temperature beyond the normal melting point. In this case, the effects of the increasing thermodynamic driving force and the faster diffusion at higher temperatures reinforce each other. In the context of this study, we also report data for the diffusion coefficient as a function of temperature for the water models TIP4P/Ice and TIP4P/2005. PMID- 21787018 TI - The non-equilibrium charge screening effects in diffusion-driven systems with pattern formation. AB - The effects of non-equilibrium charge screening in mixtures of oppositely charged interacting molecules on surfaces are analyzed in a closed system. The dynamics of charge screening and the strong deviation from the standard Debye-Huckel theory are demonstrated via a new formalism based on computing radial distribution functions suited for analyzing both short-range and long-range spacial ordering effects. At long distances the inhomogeneous molecular distribution is limited by diffusion, whereas at short distances (of the order of several coordination spheres) by a balance of short-range (Lennard-Jones) and long-range (Coulomb) interactions. The non-equilibrium charge screening effects in transient pattern formation are further quantified. It is demonstrated that the use of screened potentials, in the spirit of the Debye-Huckel theory, leads to qualitatively incorrect results. PMID- 21787019 TI - Chemical speciation of adsorbed glycine on metal surfaces. AB - Experimental studies have reported that glycine is adsorbed on the Cu(110) and Cu(100) surfaces in its deprotonated form at room temperature, but in its zwitterionic form on Pd(111) and Pt(111). In contrast, recent density functional theory (DFT) calculations indicated that the deprotonated molecules are thermodynamically favored on Cu(110), Cu(100), and Pd(111). To explore the source of this disagreement, we have tested three possible hypotheses. Using DFT calculations, we first show that the kinetic barrier for the deprotonation reaction of glycine on Pd(111) is larger than on Cu(110) or Cu(100). We then report that the presence of excess hydrogen would have little influence on the experimentally observed results, especially for Pd(111). Lastly, we perform Monte Carlo simulations to demonstrate that the aggregates of zwitterionic species on Pt(111) are energetically preferred to those of neutral species. Our results strongly suggest that the formation of aggregates with relatively large numbers of adsorbed molecules is favored under experimentally relevant conditions and that the adsorbate-adsorbate interactions in these aggregates stabilize the zwitterionic species. PMID- 21787020 TI - Site-specific intermolecular interaction in alpha-phase crystalline films of phthalocyanines studied by soft x-ray emission spectroscopy. AB - The local electronic structures of crystalline and amorphous films of zinc phthalocyanine (ZnPc) and metal-free phthalocyanine (H(2)Pc) have been studied by soft x-ray emission spectroscopy (XES). We found a clear crystalline structure dependence of the elastic-peak shape in the resonant XES spectra. The elastic peaks of both ZnPc and H(2)Pc are found to show an asymmetric shape due to resonant inelastic x-ray scattering (RIXS) at the nitrogen sites for the alpha crystalline films, but not for the amorphous films. The observed RIXS feature is ascribed to the charge transfer excitation due to the Raman-active intermolecular interaction, which dominates the excited-electron dynamics in alpha-crystalline phthalocyanine films. PMID- 21787021 TI - In situ investigation of the early stage of TiO2 epitaxy on (001) SrTiO3. AB - We report on a systematic study of the growth of epitaxial TiO(2) films deposited by pulsed laser deposition on Ti-terminated SrTiO(3) (001) single crystals. By using in situ reflection high energy electron diffraction, low energy electron diffraction, x-ray photoemission spectroscopy, and scanning probe microscopy, we show that the stabilization of the anatase (001) phase is preceded by the growth of a few nanometers thick pseudomorphic Sr(x)TiO(2+y) (x, y < 1) intermediate layer. The data demonstrate that the formation of this intermediate phase is related to the activation of a long range Sr migration from the SrTiO(3) substrate into the film. Our results enrich the phase diagram of the Sr-Ti-O system under epitaxial strain opening a route for the study of the electronic and dielectric properties of the reported Sr-deficient SrTiO(3) phase. PMID- 21787022 TI - Concentration dependent refractive index of a binary mixture at high pressure. AB - In the present work binary mixtures of varying concentrations of two miscible hydrocarbons, 1,2,3,4-tetrahydronaphtalene (THN) and n-dodecane (C12), are subjected to increasing pressure up to 50 MPa in order to investigate the dependence of the so-called concentration contrast factor (CF), i.e., (?n/?c)(p, T), on pressure level. The refractive index is measured by means of a Mach Zehnder interferometer. The setup and experimental procedure are validated with different pure fluids in the same pressure range. The refractive index of the THN C12 mixture is found to vary both over pressure and concentration, and the concentration CF is found to exponentially decrease as the pressure is increased. The measured values of the refractive index and the concentration CFs are compared with values obtained by two different theoretical predictions, the well known Lorentz-Lorenz formula and an alternative one proposed by Looyenga. While the measured refractive indices agree very well with predictions given by Looyenga, the measured concentration CFs show deviations from the latter of the order of 6% and more than the double from the Lorentz-Lorenz predictions. PMID- 21787023 TI - Quantum chemical analysis of the unfolding of a penta-glycyl 3(10)-helix initiated by HO(?), HO2(?), and O2(-?). AB - In this study, the thermodynamic functions of hydrogen abstraction from the C(alpha) and amide nitrogen of Gly(3) in a homo-pentapeptide (N-Ac-GGGGG-NH(2); G5) by HO(?), HO(2)(?), and O(2)(-?) were computed using the Becke three parameter Lee-Yang-Parr (B3LYP) density functional. The thermodynamic functions, standard enthalpy (DeltaH degrees ), Gibbs free energy (DeltaG degrees ), and entropy (DeltaS degrees ), of these reactions were computed with G5 in the 3(10) helical (G5(Hel)) and fully-extended (G5(Ext)) conformations at the B3LYP/6 31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the conductor-like polarizable continuum model implicit water model. H abstraction is more favorable at the C(alpha) than at the amide nitrogen. The secondary structure of G5 affects the bond dissociation energy of the H-C(alpha), but has a negligible effect on the dissociation energy of the H-N bond. The HO(?) radical is the strongest hydrogen abstractor, followed by HO(2)(?), and finally O(2)(-?). The secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by disabling the potential electron delocalization at the C(alpha), which is possible when G5 is in the extended conformation. The unfolding of the peptide radicals is more favorable than the unfolding of G5(Hel); however, only the HO(?) can initiate the unfolding of G5(Hel) and the formation of G5(Ext)(?). These results are relevant to peptides that are prone to undergoing transitions from helical structures to beta-sheets in the cellular condition known as "oxidative stress" and the results are discussed in this context. PMID- 21787024 TI - Role of loop entropy in the force induced melting of DNA hairpin. AB - Dynamics of a single stranded DNA, which can form a hairpin have been studied in the constant force ensemble. Using Langevin dynamics simulations, we obtained the force-temperature diagram, which differs from the theoretical prediction based on the lattice model. Probability analysis of the extreme bases of the stem revealed that at high temperature, the hairpin to coil transition is entropy dominated and the loop contributes significantly in its opening. However, at low temperature, the transition is force driven and the hairpin opens from the stem side. It is shown that the elastic energy plays a crucial role at high force. As a result, the force-temperature diagram differs significantly with the theoretical prediction. PMID- 21787025 TI - Does amino acid sequence determine the properties of Abeta dimer? AB - The effect of random reshuffling of amino acids on the properties of dimers formed by Abeta peptides is studied using replica exchange molecular dynamics and united atom implicit solvent model. We show that thermodynamics of dimer assembly and the dimer globule-like state are not affected by sequence permutation. Furthermore, sequence reshuffling does not change the distributions of non-local interactions and, to a large extent, amino acids in the dimer volume. To rationalize these results, we demonstrate that Gaussian statistics applies surprisingly well to the end-to-end distances of the peptides in the dimer implying that non-bonded interactions between distant along the chain amino acids are effectively screened. This observation suggests that peptides in the dimer behave as ideal chains in polymer melt, in which amino acids lose their "identity" and therefore the memory of sequence position. As a result large-scale properties of the dimer become universal or sequence independent. Comparison of our simulations with the prior theoretical studies and their implications for experiments are discussed. PMID- 21787026 TI - Theory of crosslinked bundles of helical filaments: intrinsic torques in self limiting biopolymer assemblies. AB - Inspired by the complex influence of the globular crosslinking proteins on the formation of biofilament bundles in living organisms, we study and analyze a theoretical model for the structure and thermodynamics of bundles of helical filaments assembled in the presence of crosslinking molecules. The helical structure of filaments, a universal feature of biopolymers such as filamentous actin, is shown to generically frustrate the geometry of crosslinking between the "grooves" of two neighboring filaments. We develop a coarse-grained model to investigate the interplay between the geometry of binding and mechanics of both linker and filament distortion, and we show that crosslinking in parallel bundles of helical filaments generates intrinsic torques, of the type that tend to wind the bundle superhelically about its central axis. Crosslinking mediates a non linear competition between the preference for bundle twist and the size-dependent mechanical cost of filament bending, which in turn gives rise to feedback between the global twist of self-assembled bundles and their lateral size. Finally, we demonstrate that above a critical density of bound crosslinkers, twisted bundles form with a thermodynamically preferred radius that, in turn, increases with a further increase in crosslinking bonds. We identify the stiffness of crosslinking bonds as a key parameter governing the sensitivity of bundle structure and assembly to the availability and affinity of crosslinkers. PMID- 21787028 TI - Attitudes of Florida pharmacists toward implementing a state prescription drug monitoring program for controlled substances. AB - BACKGROUND: As of May 23, 2011, 35 states had an operational prescription drug monitoring program (PDMP), and 13 additional states, including Florida in 2009, had passed legislation to implement a PDMP. PDMPs, electronic databases that collect and track designated data on controlled substances and other commonly abused medications, are intended to serve as a tool for health care practitioners when prescribing and dispensing controlled substances to reduce drug abuse and diversion. In an analysis of 1,268 drug-caused deaths from January through June 2010 in Florida, the top 3 prescription drugs included the controlled substances oxycodone (56%), alprazolam (35%), and methadone (26%), all of which would be subject to reporting in Florida's PDMP when implemented. Because pharmacists are the health care professionals most affected by PDMP reporting requirements, evaluating their attitudes about PDMP implementation is important. OBJECTIVES: To assess Florida pharmacists' attitudes toward implementing a PDMP in the state. METHODS: This was a cross-sectional study conducted in Florida between February 2010 and June 2010 prior to the implementation of the proposed PDMP. A random sample of 5,000 of approximately 26,000 pharmacists licensed in Florida was invited to participate in a voluntary and anonymous 10-question self-administered mail survey of which 4 survey items assessed pharmacists' attitudes towards implementing a PDMP in the state. RESULTS: Of the 5,000 pharmacists contacted by mail, 911 (18.2%) completed the survey, of whom 836 responded to the items assessing opinions about PDMPs and provided practice site information. A majority of pharmacists across all practice settings agreed or strongly agreed with the statements that a PDMP "should be implemented in Florida" (chain 84.0%, hospital 74.2%, independent 77.9%, and other 71.1%) and that a PDMP would decrease "the incidence of doctor shopping" if implemented (chain 80.8%, hospital 67.2%, independent 71.7%, and other 63.3%). A majority of pharmacists across all practice settings disagreed or strongly disagreed with the statements that they would be "discouraged to dispense controlled substances" by the PDMP (chain 61.4%, hospital 50.0%, independent 60.2%, and other 63.8%) and that PDMP implementation would be "an invasion of patients' privacy" (chain 80.3%, hospital 67.7%, independent 67.3%, and other 69.3%). CONCLUSION: In a small-sample survey, a majority of Florida pharmacists across all practice settings were in favor of implementing a PDMP in Florida. This is the first study to examine Florida pharmacists' attitudes toward PDMP implementation, and the results should prompt future analyses of relevant outcomes, such as drug abuse, drug-related mortality, and doctor shopping. PMID- 21787029 TI - Promoting interprofessional collaboration: pharmacy students teaching current and future prescribers about Medicare Part D. AB - BACKGROUND: Nearly all health professional students and prescribers, regardless of specialty, will care for older adults who are enrolled in or eligible for the Medicare Part D prescription drug benefit. Given the growing numbers of older adults, the increased burden of chronic disease, and the escalating costs of health care, health professional students and prescribers across disciplines should learn strategies to promote cost-effective prescribing and collaborate with pharmacists who are experts in medication use and costs. OBJECTIVE: To describe and evaluate the impact of a statewide peer education program in which selected students at 7 California schools of pharmacy delivered a clinically relevant lecture on Part D to a multidisciplinary audience of health professional students and prescribers. METHODS: Trained pharmacy students delivered a case based lecture on Medicare Part D to other health professional students and prescribers throughout the state of California. An 11-item survey designed to evaluate (a) self-assessed Part D knowledge, (b) opinion of pharmacists' roles on the health care team, (c) intent to collaborate with pharmacists, and (d) awareness of cost-savings strategies to reduce patients' out-of-pocket drug costs was administered before and after the lecture. Pre-lecture versus post-lecture results were tested for statistical significance using the Wilcoxon signed-rank test with Bonferroni adjustment of alpha to 0.004 because of multiple comparisons. RESULTS: From October 2008 through May 2010, trained students from 7 pharmacy schools gave 58 presentations to a total of 1,490 current or future prescribers, including 304 nurse practitioner students and 279 resident physicians. At baseline pre-lecture, self-rated knowledge of Medicare Part D was generally poor; only 4.9% of respondents strongly agreed that "I understand the Medicare Part D benefit," and 6.6% strongly agreed that they could "identify key Medicare Part D resources to help my patients." Nine of 11 survey items showed statistically significant improvement (P less than 0.001), including all 4 items in the Part D knowledge domain and all 5 items in the intent-to-collaborate domain (e.g., "I consult with pharmacists and/or pharmacy students about drug costs"). Outcomes were similar across the 7 schools. CONCLUSION: At pre-lecture baseline, self-reported deficits in knowledge about Part D policy and drug cost savings resources and strategies existed among medical, nursing and physician assistant students, resident physicians, and other health professionals. A pharmacy student-led peer education lecture can be used to bridge this gap, resulting in timely dissemination of geriatrics health policy information and increased awareness of pharmacists' roles and expertise in pharmaceutical health policy and patient care. PMID- 21787030 TI - Prevalence and predictors of utilization of community pharmacy generic drug discount programs. AB - BACKGROUND: Since 2006, select pharmacies in the United States have been offering programs where prescriptions for certain generic medications can be filled at very low cost (e.g., a 30-day supply for $4). However, limited knowledge exists on the characteristics of patients who have used these services. OBJECTIVE: To examine the prevalence of use of community pharmacy generic drug discount programs and the characteristics of patients using these programs. METHODS: Two cross-sectional surveys of patients in a university-affiliated health system general medicine clinic were conducted over an approximately 4-week period in the summers of 2008 and 2010. The survey measured self-reported information in 3 parts: a listing of current medications, questions about program use, and patient demographics. The survey was administered to patients as they were waiting to see their physicians with a research assistant on-site for assistance and to collect the completed surveys. Medications listed by patients were classified as acute or chronic by pharmacists on the research team. Descriptive statistics (Pearson chi square or Student's t-tests) were used to compare subjects across years and between groups of discount program users and nonusers. Logistic regression models were constructed to identify significant predictors of program use, testing demographic factors, prescription drug coverage, number of medications, monthly out-of-pocket payments, and year of the survey. RESULTS: The convenience sample included 414 individuals overall, 203 in 2008 and 211 in 2010. After excluding respondents who did not answer all survey questions, the sample size was 311 (n = 148 in 2008 and 163 in 2010). The sample was mostly Caucasian; most patients had prescription coverage; and a large majority of medications filled were for chronic use. Patient characteristics were similar in the 2 groups except for a higher mean number of self-reported medications in 2010 than 2008 (4.2 vs. 3.4, respectively, P = 0.01). Use of a discount medication program was reported by 52 (31.9%) of those surveyed in 2010 compared with 7 (4.7%) in 2008 (P less than 0.001). When both groups were combined, factors associated with use of generic drug discount programs included filling prescriptions for a higher number of medications (odds ratio [OR] =1.13, 95% CI =1.01-1.27, P =0.036) and the year of the survey (OR for 2010 =9.02, 95% CI =3.8221.29). Differences in program use were also observed among categories of age and income. CONCLUSIONS: Over a 2-year period, there was an increase in the use of discount generic medication programs in this university clinic population. Patients who take more prescription medications are more likely to choose such plans, and differences in program use were observed between ranges of age and income. More extensive analysis is needed to better predict patient use of such services. PMID- 21787031 TI - Clinical pharmacist intervention and the proportion of diabetes patients attaining prevention objectives in a multispecialty medical group. AB - BACKGROUND: Clinical practice recommendations from American Diabetes Association (ADA) include specific prevention goals intended to reduce the risk of diabetic complications. The Healthy People 2010 (HP2010) initiative, updated to Healthy People 2020, proposes similar objectives for improvement of clinical measures and outcomes in patients with diabetes. Clinical pharmacists are gaining an increasing role in providing diabetes management services, including collaborative practice in medical groups. OBJECTIVE: To compare the rates of attainment of diabetes prevention goals described by the ADA 2009 guidelines and the HP2010 initiative for patients receiving clinical pharmacist interventions in a collaborative practice diabetes clinic versus patients receiving usual care. METHODS: The setting is a primary care clinic affiliated with a 140-physician multispecialty medical group in the upper Midwest. Diabetes patients were identified from electronic medical records by ICD-9-CM diagnosis codes 250.00 through 250.99 for dates of service in the 12-month period from January 1, 2007, through December 31, 2007. Study subjects had to be aged 18 years or older and have at least 2 visits to a primary care physician (PCP) or the pharmacist managed diabetes clinic during 2007. Descriptive statistics and chi-square analysis were utilized. RESULTS: Of 7,068 patients at least 18 years of age with at least 1 diabetes diagnosis code for a medical encounter in 2007, 1,298 (18.4%) had a least 1 visit in the pharmacist-managed diabetes clinic, and 321 patients (4.5%) had 2 or more visits. These 321 patients were compared with 321 patients stratified by gender and randomly selected from 3,022 patients who had at least 2 visits with a PCP and no visits in the pharmacist-managed diabetes clinic in 2007. Nine of the 14 HP2010 objectives (64.3%) were attained in the intervention group compared with 7 of 14 (50.0%) in the usual care group. For patients with hypertension at baseline, 44.6% (120/269) in the intervention group versus 48.0% (123/256) in the usual care group achieved goal blood pressure (P = 0.430). The low-density lipoprotein (LDLC) goal ( less than 100 milligrams per deciliter) was achieved in 76.0% of patients in the intervention group (244/321) versus 59.2% (190/321) in usual care (P less than 0.001). Fewer patients in the intervention group achieved hemoglobin A1c less than 7% (50.8%, n =163/321) compared with usual care (71.0%, n = 228/321, P less than 0.001). The proportions of patients with influenza and pneumococcal vaccinations were higher in the intervention group versus the usual care group for 3 of 4 comparisons by age, but neither group met the target goals. CONCLUSIONS: Patients who were seen by the clinical pharmacists met more of the preventive care objectives recommended by the ADA 2009 and HP2010 initiatives; however, more patients in usual care met the A1c goal compared with pharmacist-managed patients. The absence of baseline values for A1c, blood pressure, and LDL-C prevented longitudinal assessment of the effects of this clinical pharmacist intervention. PMID- 21787032 TI - The pursuit of transparency and quality improvement in cost-effectiveness analysis - a case study in disease-modifying drugs for the treatment of multiple sclerosis. AB - Cost-effectiveness analysis (CEA) can be a powerful analytic tool for assessing the value of health care interventions when used in conjunction with efficacy, safety, and other supporting data in an evidence-based decision making environment. CEA is commonly defined in terms of the comparison of costs, expressed in monetary units, with outcomes that may be expressed in a variety of ways. One of the most common forms of CEA compares costs in monetary units with outcomes quantified in nonmonetary units (e.g., cancer avoided, death avoided, or successfully treated patient). Cost-utility analysis (CUA) is a form of CEA that compares costs in monetary units with outcomes quantified as a multidimensional measure of effectiveness (e.g., utilities that are used to estimate quality adjusted life-years [QALYs]). Cost benefit analysis (CBA), another form of CEA that is used less frequently, compares costs and benefits (i.e., outcomes) both of which are quantified in monetary units. Overall, there has been an increasing trend in the use of CEA (CEA, CUA, and CBA) to inform decision making. This trend can be implicitly measured by the frequency of published CEAs over time. PMID- 21787033 TI - Does medicalization of life imperil health? Expanding indications for diagnosis and treatment of chronic "disease". PMID- 21787034 TI - Drug use evaluation of endocrine therapy in women with breast cancer in a Chinese hospital. PMID- 21787035 TI - Relapse dynamics during smoking cessation: recurrent abstinence violation effects and lapse-relapse progression. AB - Smoking cessation is a process that unfolds over time and is characterized by intermittent lapses. We used parametric recurrent event survival analyses to better understand the dynamic relationship between a set of Abstinence Violation Effect (AVE, Marlatt & Gordon, 1985) responses to lapsing and subsequent lapse relapse progression. Participants were 203 smokers who achieved abstinence and responded to items assessing three core components of the AVE (internal attribution, abstinence self-efficacy and guilt) following a total of 1,001 lapse episodes in near real time. Neither self-blame, self-efficacy, nor guilt following participants' first lapse predicted relapse. Controlling for responses to their first lapse, responses to each additional lapse did prospectively predict lapse progression, such that drops in self-efficacy were associated with accelerated progression to a subsequent lapse (HR = 1.09, CI = 1.02-1.15), while increases in internal attributions of blame actually protected against lapsing (HR = 0.98, CI = 0.97-0.99). Treatment with nicotine patches slowed recurrent lapse progression (HR = 0.58, CI = 0.48-0.70), but this effect dissipated over multiple lapses, and was moderated by elevated ratings of postlapse guilt (HR = 1.08, CI = 1.01-1.18), which predicted accelerated progression within the active patch group, while protecting against lapse in the placebo group. Results highlight the dynamic nature of lapse responses during smoking cessation, indicating that self-efficacy predicts progression from one lapse to the next, while attributions of self-blame and guilt influenced progression in unexpected ways. PMID- 21787036 TI - Beyond positive psychology? Toward a contextual view of psychological processes and well-being. AB - The field of positive psychology rests on the assumption that certain psychological traits and processes are inherently beneficial for well-being. We review evidence that challenges this assumption. First, we review data from 4 independent longitudinal studies of marriage revealing that 4 ostensibly positive processes-forgiveness, optimistic expectations, positive thoughts, and kindness can either benefit or harm well-being depending on the context in which they operate. Although all 4 processes predicted better relationship well-being among spouses in healthy marriages, they predicted worse relationship well-being in more troubled marriages. Then, we review evidence from other research that reveals that whether ostensibly positive psychological traits and processes benefit or harm well-being depends on the context of various noninterpersonal domains as well. Finally, we conclude by arguing that any movement to promote well-being may be most successful to the extent that it (a) examines the conditions under which the same traits and processes may promote versus threaten well-being, (b) examines both healthy and unhealthy people, (c) examines well being over substantial periods of time, and (d) avoids labeling psychological traits and processes as positive or negative. PMID- 21787038 TI - 2010 annual report of the American Psychological Association. AB - This report presents the 2010 annual report of the American Psychological Association (APA). It provides the highlights of the association's and individual directorate's activities to APA members. APA continued it's efforts to advance psychological practice and ensure the public's access to high-quality psychological services, apply psychological science and expertise to pressing social issues, fulfill the goals of APA's new strategic plan, and increase the public's understanding of psychology as a science and STEM (science, technology, engineering, and mathematics) discipline. PMID- 21787037 TI - Training the brain: practical applications of neural plasticity from the intersection of cognitive neuroscience, developmental psychology, and prevention science. AB - Prior researchers have shown that the brain has a remarkable ability for adapting to environmental changes. The positive effects of such neural plasticity include enhanced functioning in specific cognitive domains and shifts in cortical representation following naturally occurring cases of sensory deprivation; however, maladaptive changes in brain function and development owing to early developmental adversity and stress have also been well documented. Researchers examining enriched rearing environments in animals have revealed the potential for inducing positive brain plasticity effects and have helped to popularize methods for training the brain to reverse early brain deficits or to boost normal cognitive functioning. In this article, two classes of empirically based methods of brain training in children are reviewed and critiqued: laboratory-based, mental process training paradigms and ecological interventions based upon neurocognitive conceptual models. Given the susceptibility of executive function disruption, special attention is paid to training programs that emphasize executive function enhancement. In addition, a third approach to brain training, aimed at tapping into compensatory processes, is postulated. Study results showing the effectiveness of this strategy in the field of neurorehabilitation and in terms of naturally occurring compensatory processing in human aging lend credence to the potential of this approach. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 21787039 TI - Biased information processing in the escalation paradigm: information search and information evaluation as potential mediators of escalating commitment. AB - Escalation of commitment denotes decision makers' increased reinvestment of resources in a losing course of action. Despite the relevance of this topic, little is known about how information is processed in escalation situations, that is, whether decision makers who receive negative outcome feedback on their initial decision search for and/or process information biasedly and whether these biases contribute to escalating commitment. Contrary to a widely cited study by E. J. Conlon and J. M. Parks (1987), in 3 experiments, the authors found that biases do not occur on the level of information search. Neither in a direct replication and extension of the original study with largely increased test power (Experiment 1) nor under methodologically improved conditions (Experiments 2 and 3) did decision makers responsible for failure differ from nonresponsible decision makers with regards to information search, and no selective search for information supporting the initial decision or voting for further reinvestment was observed. However, Experiments 3 and 4 show that the evaluation of the previously sought information is biased among participants who were responsible for initiating the course of action. Mediation analyses show that this evaluation bias in favor of reinvestment partially mediated the responsibility effect on escalation of commitment. PMID- 21787040 TI - Unlocking the black box: exploring the link between high-performance work systems and performance. AB - With a growing body of literature linking systems of high-performance work practices to organizational performance outcomes, recent research has pushed for examinations of the underlying mechanisms that enable this connection. In this study, based on a large sample of Welsh public-sector employees, we explored the role of several individual-level attitudinal factors--job satisfaction, organizational commitment, and psychological empowerment--as well as organizational citizenship behaviors that have the potential to provide insights into how human resource systems influence the performance of organizational units. The results support a unit-level path model, such that department-level, high-performance work system utilization is associated with enhanced levels of job satisfaction, organizational commitment, and psychological empowerment. In turn, these attitudinal variables were found to be positively linked to enhanced organizational citizenship behaviors, which are further related to a second-order construct measuring departmental performance. PMID- 21787041 TI - Social regulation of serotonin in the auditory midbrain. AB - The neuromodulator serotonin regulates auditory processing and can increase within minutes in response to stimuli like broadband noise as well as nonauditory stressors. Little is known about the serotonergic response in the auditory system to more natural stimuli such as social interactions. Using carbon-fiber voltammetry, we measured extracellular serotonin in the auditory midbrain of resident male mice during encounters with a male intruder. Serotonin increased in the inferior colliculus (IC) over the course of a 15 minute interaction, but not when mice were separated with a perforated barrier. Several behaviors, including the amount of immobility and anogenital investigation performed by the resident, were correlated with the serotonergic response. Multiple intrinsic factors associated with individual mice also correlated with the serotonergic response. One of these was age: older mice had smaller serotonergic responses to the social interaction. In a second interaction, individual identity predicted serotonergic responses that were highly consistent with those in the first interaction, even when mice were paired with different intruders. Serotonin was also significantly elevated in the second social interaction relative to the first, suggesting a role for social experience. These findings show that during social interaction, serotonin in the IC is influenced by extrinsic factors such as the directness of social interaction and intrinsic factors including age, individual identity, and experience. PMID- 21787042 TI - Rat behavior in go/no-go and two-alternative choice odor discrimination: differences and similarities. AB - To elucidate the cognitive structures of animals, neuroscientists use several behavioral tasks. Therefore, it is imperative to have a firm understanding of each task's behavioral parameters in order to parse out possible task effects. We compare two operant discrimination tasks (Go/No-Go: GNG; Two-Alternative Choice: TAC) that are commonly used in olfactory research. Past research has suggested that solving the two tasks requires divergent cognitive strategies. One hypothesis is that the two tasks differ in how an animal optimizes reward rate by means of a speed-accuracy trade-off (SAT). If this is true, then changing tasks could give researchers an additional tool to understand animal cognition. However, no study has systematically analyzed the two tasks in parallel using odor stimuli. Using standardized training protocols, we test GNG and TAC in parallel. Our protocols allow us to isolate the stimulus sampling period from a general reaction time period. We find that the two tasks do not differ with regard to the stimulus sampling period and conclude that the two tasks do not differ in the amount of time it takes an animal to perform a discrimination. Instead, tasks differ in the time it takes to make an overt behavioral response, with GNG showing shorter periods than TAC. We also find no evidence of rats using either task-specific or intertrial interval-dependent SAT schema in order to optimize reward rate. We show that similarities between dependent variables, with the possible exception of response delay, appear to be under experimenter control. PMID- 21787043 TI - Impulsivity as a mediating mechanism between early-life adversity and addiction: theoretical comment on Lovic et al. (2011). AB - Early-life adversity, impulsivity, and dopaminergic function have all been implicated in adult drug addiction. The article by Lovic, Keen, Fletcher, and Fleming in this issue further elucidates this relationship by demonstrating that early-life adversity can increase impulsivity and decrease behavioral flexibility in adulthood. Recent literature suggests that these results are likely due to structural and functional changes in regions such as the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), as well as altered dopamine activity. Impulsivity and behavioral inflexibility can increase susceptibility to addiction, and in turn, chronic substance abuse can impair the neurocircuitry underlying behavioral inhibition. Thus, early-life adversity may act as an entry point into a feed-forward spiral of impulsivity and addiction via the dysfunction of regions such as the OFC, NAc, and mesolimbic dopamine. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21787045 TI - Effects of multisystemic therapy through midlife: a 21.9-year follow-up to a randomized clinical trial with serious and violent juvenile offenders. AB - OBJECTIVE: Although current evidence suggests that the positive effects of multisystemic therapy (MST) on serious crime reach as far as young adulthood, the longer term impact of MST on criminal and noncriminal outcomes in midlife has not been evaluated. In the present study, the authors examined a broad range of criminal and civil court outcomes for serious and violent juvenile offenders who participated on average 21.9 (range = 18.3-23.8) years earlier in a clinical trial of MST (C. M. Borduin et al., 1995). METHOD: Participants were 176 individuals who were originally randomized to MST or individual therapy (IT) during adolescence and averaged 3.9 arrests for felonies prior to treatment. Arrest, incarceration, and civil suit data were obtained in middle adulthood when participants were on average 37.3 years old. RESULTS: Intent-to-treat analyses showed that felony recidivism rates were significantly lower for MST participants than for IT participants (34.8% vs. 54.8%, respectively) and that the frequency of misdemeanor offending was 5.0 times lower for MST participants. In addition, the odds of involvement in family-related civil suits during adulthood were twice as high for IT participants as for MST participants. CONCLUSIONS: The present study represents the longest follow-up to date of an MST clinical trial and demonstrates that the positive impact of an evidence-based youth treatment such as MST can last well into adulthood. Implications of the authors' findings for policymakers and service providers are discussed. PMID- 21787046 TI - Risk for suicidal ideation in the U.S. Air Force: an ecological perspective. AB - OBJECTIVE: Suicidal members of the U.S. military often fail to disclose their suicidal urges and behaviors. Military suicide prevention efforts may therefore be enhanced if they also target less stigmatized psychosocial factors that may decrease risk of suicidality. In keeping with Bronfenbrenner's (1977, 1994) model, this study simultaneously examined 4 ecological levels (i.e., individual, family, workplace, and community) of factors variously associated with increased or decreased risk for suicidal ideation. METHOD: Active-duty U.S. Air Force members (N = 52,780; 79.3% male; 79.2% non-Hispanic White; mean age = 31.78 years, SD = 7.38) completed the 2006 Community Assessment survey (a biennial, anonymous survey conducted at 82 U.S. Air Force bases worldwide), including the Centers for Disease Control and Prevention's (2008) 5-item measure of past-year suicidality along with scales assessing an array of potential predictors. RESULTS: The 1-year rate of suicidal ideation, defined as (a) more than rarely thinking about suicide or (b) ever seriously considering suicide, was approximately 4%. In multivariate models, for men and women, individual- (depressive symptoms and alcohol problems), family- (relationship satisfaction and intimate partner victimization), workplace- (hours worked), and community level (social support) variables were retained in the final model. However, some sex differences in retained predictors were noted (e.g., men: dissatisfaction with the U.S. Air Force way of life; women: workplace relationship satisfaction and financial stressors). CONCLUSIONS: Addressing depressive symptoms and alcohol use, facilitating healthy relationship functioning, and increasing job satisfaction and social support may aid military suicide prevention efforts. These findings illustrate the importance of attending to multiple levels of potential influence when designing integrated suicide prevention and intervention programs. PMID- 21787047 TI - Sudden gains in prolonged exposure for children and adolescents with posttraumatic stress disorder. AB - OBJECTIVE: Our objective was to examine sudden gains during developmentally adjusted prolonged exposure for posttraumatic stress disorder (PTSD) among children and adolescents. We hypothesized that sudden gains would be detected and would be predictive of treatment outcome and follow-up. METHOD: Sixty-three youngsters (ages 8-17) completed a developmentally adjusted protocol for the treatment of pediatric PTSD (Foa, Chrestman, & Gilboa-Schechtman, 2008). Participants' posttraumatic and depressive symptoms were assessed before each treatment session, as well as at approximately 3 and 12 months after treatment termination. We measured posttraumatic symptoms with the Child PTSD Symptom Scale (Foa, Johnson, Feeny, & Treadwell, 2001) and measured depressive symptoms with the Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) and the Children's Depression Inventory (Kovacs, 1981, 1982). RESULTS: Sudden gains were found among 49.2% of participants and constituted 48.6% of the total reduction in posttraumatic symptoms. Compared to individuals who did not experience sudden gains, individuals who experienced sudden gains reported lower levels of posttraumatic symptoms, F(1, 61) = 14.4, p < .001, and depressive symptoms, F(1, 61) = 7.9, p < .01, at treatment termination. Differences in posttraumatic symptoms were maintained during both follow-up periods. CONCLUSIONS: Sudden gains are common in pediatric prolonged exposure for PTSD and are predictive of long-term outcome. Treatment planning can benefit from consideration of the intraindividual course of improvement, and treatment development may be enriched by understanding the mechanisms responsible for sudden gains. PMID- 21787048 TI - A communication-based intervention for nonverbal children with autism: what changes? Who benefits? AB - OBJECTIVE: This article examines the form and function of spontaneous communication and outcome predictors in nonverbal children with autism following classroom-based intervention (Picture Exchange Communication System [PECS] training). METHOD: 84 children from 15 schools participated in a randomized controlled trial (RCT) of PECS (P. Howlin, R. K. Gordon, G. Pasco, A. Wade, & T. Charman, 2007). They were aged 4-10 years (73 boys). Primary outcome measure was naturalistic observation of communication in the classroom. Multilevel Poisson regression was used to test for intervention effects and outcome predictors. RESULTS: Spontaneous communication using picture cards, speech, or both increased significantly following training (rate ratio [RR] =1.90, 95% CI [1.46, 2.48], p < .001; RR = 1.77, 95% CI [1.35, 2.32], p < .001; RR = 3.74, 95% CI [2.19, 6.37], p < .001, respectively). Spontaneous communication to request objects significantly increased (RR = 2.17, 95% CI [1.75, 2.68], p < .001), but spontaneous requesting for social purposes did not (RR = 1.34, 95% CI [0.83, 2.18], p = .237). Only the effect on spontaneous speech persisted by follow-up (9 months later). Less severe baseline autism symptomatology (lower Autism Diagnosis Observation Schedule [ADOS] score; C. Lord et al., 2000) was associated with greater increase in spontaneous speech (RR = 0.90, 95% CI [0.83, 0.98], p = .011) and less severe baseline expressive language impairment (lower ADOS item A1 score), with larger increases in spontaneous use of speech and pictures together (RR = 0.62, 95% CI [0.44, 0.88], p = .008). CONCLUSION: Overall, PECS appeared to enhance children's spontaneous communication for instrumental requesting using pictures, speech, or a combination of both. Some effects of training were moderated by baseline factors. For example, PECS appears to have increased spontaneous speech in children who could talk a little at baseline. PMID- 21787049 TI - Depression and delinquency covariation in an accelerated longitudinal sample of adolescents. AB - OBJECTIVES: The current study tested opposing predictions stemming from the failure and acting out theories of depression-delinquency covariation. METHOD: Participants included a nationwide longitudinal sample of adolescents (N = 3,604) ages 12 to 17. Competing models were tested with cohort-sequential latent growth curve modeling to determine whether depressive symptoms at age 12 (baseline) predicted concurrent and age-related changes in delinquent behavior, whether the opposite pattern was apparent (delinquency predicting depression), and whether initial levels of depression predict changes in delinquency significantly better than vice versa. RESULTS: Early depressive symptoms predicted age-related changes in delinquent behavior significantly better than early delinquency predicted changes in depressive symptoms. In addition, the impact of gender on age-related changes in delinquent symptoms was mediated by gender differences in depressive symptom changes, indicating that depressive symptoms are a particularly salient risk factor for delinquent behavior in girls. CONCLUSION: Early depressive symptoms represent a significant risk factor for later delinquent behavior- especially for girls--and appear to be a better predictor of later delinquency than early delinquency is of later depression. These findings provide support for the acting out theory and contradict failure theory predictions. PMID- 21787050 TI - Empirically guided coordination of multiple evidence-based treatments: an illustration of relevance mapping in children's mental health services. AB - OBJECTIVE: Despite substantial progress in the development and identification of psychosocial evidence-based treatments (EBTs) in mental health, there is minimal empirical guidance for selecting an optimal set of EBTs maximally applicable and generalizable to a chosen service sample. Relevance mapping is a proposed methodology that addresses this problem through structured comparison of client characteristics in a service sample to participant characteristics from studies of EBTs. METHOD: The authors demonstrate the feasibility of relevance mapping using data from 1,781 youths in a statewide mental health system and a study data set including 437 randomized clinical trials. Relevance mapping (a) reveals who is "coverable" by any EBT, under different definitions of matches between study participants and clients, and (b) identifies minimum sets of treatments needed to serve maximum numbers of clients, across different levels of analysis for defining treatment operations. RESULTS: In the illustration sample, all problems targeted by the study data set review were fully coverable when matching only required clients to have the same problem as EBT study participants. At the other extreme, when matching also required age, gender, ethnicity, and setting, the percentage of noncoverable youths increased to 86% in this sample. Two minimal sets of only 8 EBTs were identified that, when added to the one EBT already in place in that system, covered 100% of coverable youths when matching required problem, age, and gender. CONCLUSIONS: This methodology offers promise for the empirically guided selection and coordination of EBTs, thereby addressing one aspect of the gap between knowledge and practice. PMID- 21787044 TI - Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. AB - Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease. PMID- 21787051 TI - Foster placement disruptions associated with problem behavior: mitigating a threshold effect. AB - OBJECTIVE: Placement disruptions have adverse effects on foster children. Identifying reliable predictors of placement disruptions might assist in the allocation of services to prevent disruptions. There were two objectives in this study: (a) to replicate a prior finding that the number of daily child problem behaviors at entry into a new foster home predicts subsequent placement disruptions in foster preschoolers and (b) to determine whether this association is mitigated by a treatment foster care intervention. METHOD: Problem behavior and placement disruptions were examined in 60 children in regular foster care (age range = 3.10-5.91 years [M = 4.34, SD = 0.83], 58.3% male, 93.4% Caucasian) and 57 children in a treatment foster care program (age range = 3.01-6.78 years [M = 4.54, SD = 0.86], 49.1% male, 82.5% Caucasian). Using the Parent Daily Report Checklist (Chamberlain & Reid, 1987), a brief telephone interview, foster caregivers reported problem behavior 6 times over 3 months. Placement disruptions were tracked over 12 months. RESULTS: The regular foster care children with 5 or fewer problem behaviors were at low risk for disruption, but their risk increased 10% for each additional behavior (p = .013). The intervention appeared to mitigate this "threshold effect"; number of problem behaviors did not predict risk of placement disruption in the treatment foster care group (p = .63). CONCLUSIONS: These findings replicate previous evidence linking child problem behavior to placement disruptions and further highlight the need for early preventative interventions. PMID- 21787052 TI - Cognitive behavioral treatment of PTSD in residents of battered women's shelters: results of a randomized clinical trial. AB - OBJECTIVE: This study was designed to explore the acceptability, feasibility, and initial efficacy of a new shelter-based treatment for victims of intimate partner violence (IPV; i.e., Helping to Overcome PTSD through Empowerment [HOPE]). METHOD: A Phase I randomized clinical trial comparing HOPE (n = 35) with standard shelter services (SSS) (n = 35) was conducted. Primary outcome measures included the Clinician-Administered PTSD Scale (CAPS; D. D. Blake et al., 1995) and the Conflict Tactic Scales-Revised (M. A. Straus, S. L. Hamby, S. Boney-McCoy, & D. B. Sugarman, 1996). Participants were followed at 1-week, 3- and 6-months postshelter. RESULTS: Participants reported HOPE to be credible and indicated a high degree of satisfaction with treatment. Only 2 women withdrew from treatment. Both intent to treat (ITT) and minimal attendance (MA) analyses found that HOPE treatment relative to SSS was significantly associated with a lower likelihood of reabuse over the 6-month follow-up period (OR = 5.1, RR = 1.75; OR = 12.6, RR = 3.12, respectively). Results of hierarchical linear model analyses found a significant treatment effect for emotional numbing symptom severity in the ITT sample, t(67) = -2.046, p < .05, and significant treatment effects for effortful avoidance symptom severity, t(49) = -2.506, p < .05, and arousal symptom severity, t(49) = -2.04, p < .05, in the MA sample. Significant effects were also found for depression severity, empowerment, and social support. CONCLUSIONS: Results support the acceptability and feasibility of HOPE and suggest that HOPE may be a promising treatment for IPV victims in shelter. However, results also suggest that modifications to HOPE may be required to improve treatment outcomes. PMID- 21787053 TI - An introduction to the 2011 National Multicultural Conference & Summit keynote addresses. AB - This article provides and introduction to the 2011 National Multicultural Conference & Summit Keynote Addresses. The authors explain that they chose to focus on the tension and possibilities within multicultural psychology at the seventh biennial National Multicultural Conference & Summit (NMCS), which was held on January 27-28, 2011, at The Westin-Seattle Hotel. During the 2-day conference, nearly 900 attendees engaged with one another and heard from experts in the field as we focused on the theme, "Unification through Diversity: Bridging Psychological Science & Practice in the Public Interest. Two key sets of presentations are highlighted. PMID- 21787054 TI - Is multicultural psychology a-scientific?: diverse methods for diversity research. AB - This article asks, and answers three separate questions: What is multicultural psychology? What is psychological science? Are multicultural psychology and (empirical/positivist) psychological science incompatible? A brief overview of the history of science is provided emphasizing the emancipatory impulses behind a modernist, empirical, positivist approach to science. It is argued that such an approach is not incompatible with multicultural psychology. The author concludes that multicultural psychological will be strengthened if psychologists draw upon both qualitative and quantitative methods, including those that come from a positivist tradition, when investigating psychological and social issues as they affect diverse populations. PMID- 21787055 TI - Is psychological science a-cultural? AB - The history of psychological science, as it has intersected with ethnoracial, cultural, and other marginalized domains of group difference, is replete with disinterest, dismissal, or denigration of these diverse forms of psychological experience. This has led some to wonder whether psychological science is a cultural, or even anti-cultural in orientation. Assessment of this provocative proposition first requires exploration of three composite questions: (1) What is culture?, (2) What is science?, and (3) What is psychological science? Based on brief consideration of these composite questions--which are remarkably complex in their own right--I argue that psychological science is not, has never been, and indeed cannot in principle be a-cultural. Instead, like all forms of knowing, psychological science emerges at particular historical moments to achieve particular goals that are motivated by particular interests. Throughout much of the history of psychological science, these goals and interests were tied to ideologically suspect agendas that contemporary psychologists are right to repudiate. The interesting question becomes whether psychology's knowledge practices can be disentangled from this earlier ideological contamination to furnish the discipline with viable methods. I propose that psychological science can in fact be so disentangled; nevertheless, the resulting methods are never adopted or deployed outside of culturally constituted interests, objectives, and motivations, thereby requiring ongoing critical engagement with the subtexts of disciplinary knowledge production. In fact, there seem to be important ways in which psychology's scientific aspirations hobble disciplinary inquiry into the human condition that has motivated multicultural psychologists to consider alternative paradigms of inquiry. PMID- 21787056 TI - Toward ethnocultural diversification of higher education. AB - Attitudes toward ethnocultural diversification in higher education mirror attitudes toward paying taxes. Dissenters are opposed to paying taxes or to ethnocultural diversification. Passive Supporters value the benefits of taxes or ethnocultural diversification, but pay taxes or engage in diversity efforts only when required to do so. Active Supporters pay taxes or support diversity efforts even if they are not required to do so. Mandatory approaches to decrease the resistance of Dissenters to ethnocultural diversification may be necessary, whereas compelling voluntary approaches may be useful to mobilize Passive Supporters. Solutions need to be tailored to the needs of European Americans and persons of color. This article offers a conceptual framework for future research and interventions. PMID- 21787057 TI - Observed parenting behavior with teens: measurement invariance and predictive validity across race. AB - Previous reports supporting measurement equality between European American and African American families have often focused on self-reported risk factors or observed parent behavior with young children. This study examines equality of measurement of observer ratings of parenting behavior with adolescents during structured tasks; mean levels of observed parenting; and predictive validity of teen self-reports of antisocial behaviors and beliefs using a sample of 163 African American and 168 European American families. Multiple-group confirmatory factor analyses supported measurement invariance across ethnic groups for four measures of observed parenting behavior: prosocial rewards, psychological costs, antisocial rewards, and problem solving. Some mean-level differences were found: African American parents exhibited lower levels of prosocial rewards, higher levels of psychological costs, and lower problem solving when compared to European Americans. No significant mean difference was found in rewards for antisocial behavior. Multigroup structural equation models suggested comparable relationships across race (predictive validity) between parenting constructs and youth antisocial constructs (i.e., drug initiation, positive drug attitudes, antisocial attitudes, problem behaviors) in all but one of the tested relationships. This study adds to existing evidence that family-based interventions targeting parenting behaviors can be generalized to African American families. PMID- 21787058 TI - A longitudinal examination of early adolescence ethnic identity trajectories. AB - Early adolescence is marked by transitions for adolescents, and is also a time for identity exploration. Ethnic identity is an essential component of youths' sense of self. In this study we examined the trajectories of ethnic identity for adolescents from ethnic minority backgrounds during a 4-year period. Six latent class trajectories were identified in the study: the majority of adolescents (41.8%) displayed growth in ethnic identity over 4 years, followed by 30.1% whose high levels of ethnic identity remained stable, then by those who experienced moderate decreases in ethnic identity (10.8%). Another class of adolescents (7.3%) showed significant declines in ethnic identity level, followed by 5.5% of adolescents with significant increases, and finally by 4.5% of adolescents with low stable levels of ethnic identity during this developmental period. The classes differed by ethnicity, and adolescents with increasing high levels of ethnic identity reported better parent-child relationships. Findings and implications are discussed. PMID- 21787059 TI - The perceived ethnic discrimination questionnaire--community version: validation in a multiethnic Asian sample. AB - This study evaluated the validity and reliability of the Perceived Ethnic Discrimination Questionnaire-Community Version (PEDQ-CV) Lifetime Exposure scale in a multiethnic Asian sample (N = 509). The 34-item scale measures perceived interpersonal racial/ethnic discrimination and includes four subscales assessing different types of discrimination: Social Exclusion, Stigmatization, Discrimination at Work/School, and Threat/Aggression. The Lifetime Exposure scale demonstrated excellent reliability across the full group and in all major subgroups. Subscales displayed good reliability across the full group and moderate-to-good reliability in each subgroup. The Lifetime Exposure scale was significantly correlated with the depression and anxiety subscales of the SCL-90 R, providing preliminary evidence of construct validity. The data suggest the Lifetime Exposure scale, previously validated in Black and Latino adults, is also appropriate for use with Asian samples, and can be used to examine both within group and between-groups differences in discrimination. PMID- 21787060 TI - Development and initial validation of the internalization of Asian American stereotypes scale. AB - This research consists of four studies on the initial reliability and validity of the Internalization of Asian American Stereotypes Scale (IAASS), a self-report instrument that measures the degree Asian Americans have internalized racial stereotypes about their own group. The results from the exploratory and confirmatory factor analyses support a stable four-factor structure of the IAASS: Difficulties with English Language Communication, Pursuit of Prestigious Careers, Emotional Reservation, and Expected Academic Success. Evidence for concurrent and discriminant validity is presented. High internal-consistency and test-retest reliability estimates are reported. A discussion of how this scale can contribute to research and practice regarding internalized stereotyping among Asian Americans is provided. PMID- 21787061 TI - Perceived discrimination and mental health symptoms among Black men with HIV. AB - People living with HIV (PLWH) exhibit more severe mental health symptoms, including depression and posttraumatic stress disorder (PTSD) symptoms, than do members of the general public. We examined whether perceived discrimination, which has been associated with poor mental health in prior research, contributes to greater depression and PTSD symptoms among HIV-positive Black men who have sex with men (MSM), who are at high risk for discrimination from multiple stigmatized characteristics (HIV-serostatus, race/ethnicity, sexual orientation). A total of 181 Black MSM living with HIV completed audio computer-assisted self-interviews (ACASI) that included measures of mental health symptoms (depression, PTSD) and scales assessing perceived discrimination due to HIV-serostatus, race/ethnicity, and sexual orientation. In bivariate tests, all three perceived discrimination scales were significantly associated with greater symptoms of depression and PTSD (i.e., reexperiencing, avoidance, and arousal subscales; all p values < .05). The multivariate model for depression yielded a three-way interaction among all three discrimination types (p < .01), indicating that perceived racial discrimination was negatively associated with depression symptoms when considered in isolation from other forms of discrimination, but positively associated when all three types of discrimination were present. In multivariate tests, only perceived HIV related discrimination was associated with PTSD symptoms (p < .05). Findings suggest that some types of perceived discrimination contribute to poor mental health among PLWH. Researchers need to take into account intersecting stigmata when developing interventions to improve mental health among PLWH. PMID- 21787062 TI - Demanding kin relations and depressive symptoms among low-income African American women: mediating effects of self-esteem and optimism. AB - Association of demanding kin relations, depressive symptoms, self-esteem, and optimism was assessed among 130 low-income African American women. Demanding relations with kin were positively associated with depressive symptoms and negatively linked to self-esteem and optimism. Self-esteem and optimism were negatively associated with depressive symptoms and mediated the association of demanding relations with kin and women's depressive symptoms. Findings were discussed in terms of the detrimental effects of demanding social relations with kin and the possible role that other relationships may play in compensating for poor relations with extended family. PMID- 21787063 TI - A multigroup confirmatory factor analysis of the Patient Health Questionnaire-9 among English- and Spanish-speaking Latinas. AB - Depression is a significant problem for ethnic minorities that remains understudied partly due to a lack of strong measures with established psychometric properties. One screening tool, the Patient Health Questionnaire-9 (PHQ-9), which was developed for use in primary care has also gained popularity in research settings. The reliability and validity of the PHQ-9 has been well established among predominantly Caucasian samples, in addition to many minority groups. However, there is little evidence regarding its utility among Hispanic Americans, a large and growing cultural group in the United States. In this study, we investigated the reliability and structural validity of the PHQ-9 in Hispanic American women. A community sample of 479 Latina women from southern California completed the PHQ-9 in their preferred language of English or Spanish. Cronbach's alphas suggested that there was good internal consistency for both the English- and Spanish-language versions. Structural validity was investigated using multigroup confirmatory factor analysis. Results support a similar one factor structure with equivalent response patterns and variances among English- and Spanish-speaking Latinas. These results suggest that the PHQ-9 can be used with confidence in both English and Spanish versions to screen Latinas for depression. PMID- 21787066 TI - Racial dialogues: challenges faculty of color face in the classroom. AB - Research on the experiences of faculty of color in predominantly White institutions (PWIs) suggests that they often experience the campus climate as invalidating, alienating, and hostile. Few studies, however, have actually focused on the classroom experiences of faculty of color when difficult racial dialogues occur. Using Consensually Qualitative Research, eight faculty of color were interviewed about their experiences in the classroom when racially tinged topics arose. Three major findings emerged. First, difficult racial dialogues were frequently instigated by the presence of racial microaggressions delivered toward students of color or the professor. Dialogues on race were made more difficult when the classrooms were diverse, when heated emotions arose, when there was a strong fear of self-disclosure, and when racial perspectives differed. Second, all faculty experienced an internal struggle between balancing their own values and beliefs with an attempt to remain objective. This conflict was often described as exhausting and energy-depleting. Third, faculty of color described both successful and unsuccessful strategies in facilitating difficult dialogues on race that arose in the course of their teaching. These findings have major implications for how PWIs can develop new programs, policies, and practices that will aid and support colleagues of color. PMID- 21787065 TI - Holistic reasoning on the other side of the world: validation of the analysis holism scale in Mexicans. AB - The universality of cognitive processes has been called into question. Research suggests that individuals from Eastern cultures (e.g., China, Korea) when compared to individuals from Western cultures (e.g., the United States) prefer to reason holistically. This line of research has not been extended to cultural groups far removed from cultures traditionally surveyed in cross-cultural research such as Hispanics. We conducted two studies to understand: 1) the generalizability of the construct of holistic reasoning in Mexicans, and 2) the preferred reasoning style of Mexicans when compared to U.S. Americans. Results support the generalization of the factor structure of holistic reasoning as originally hypothesized by Choi, Koo, and Choi (2007). The results of Study 2 suggest that Mexicans scored higher than U.S. Americans on certain aspects of holistic reasoning. PMID- 21787064 TI - A cultural adaptation of motivational interviewing to address heavy drinking among Hispanics. AB - Although the need for cultural adaptations is often noted in addiction research, there are few templates to guide the process. The rationale for a social contextual framework to culturally adapt motivational interviewing for an immigrant heavy drinking Latino population in the U.S. Northeast is presented. The aim of the pilot study was to obtain data on acceptability of this approach. Participant responses to the adaptation were examined qualitatively and quantitatively in a preliminary study. Participants recruited from the community met criteria for risky drinking (men, >=5 drinks/occasion or >=14 drinks/week; women, >=4 drinks/occasion or >=7 drinks/week). Participants (n = 25) who completed baseline assessments and a culturally adapted brief motivational interview (CAMI) were asked to complete a qualitative exit interview to give feedback on their interview experience. Participants reported being highly engaged with treatment (M = 3.58 on a scale of 1-4, SD = .50), and felt very satisfied with treatment (M = 3.58 on a scale of 1-4, SD = .93). Nearly all (95%) reported that understanding their culture was important to understanding their drinking behavior. Results support the acceptability and relevance of this adaptation from participants' perspectives. PMID- 21787069 TI - On the border: young adults with LGBQ parents navigate LGBTQ communities. AB - Little research has examined the perspectives of young adults with lesbian, gay, bisexual, transgender, and queer (LGBTQ) parents, particularly in relation to their identification with the LGBTQ community. To address this gap, we conducted a qualitative study of 42 young adults (ages 18-29) who were raised by LGBQ parents. We found that participants often described their sense of belonging to the LGBTQ community as shifting over the life course. Some participants, particularly those whose parents had always been out, felt connected to the LGBTQ community as children. Of these, most maintained those connections over time. However, some increasingly deidentified with the LGBTQ community, which they sometimes attributed to their own heterosexual identification. Others, particularly those whose parents came out later in life, described a lack of connection to the LGBTQ community as children. Of these, most became increasingly identified with the community, which they often attributed to their own and their parents' increasing sense of comfort with their parents' sexuality. Heterosexual participants who sought out LGBTQ-oriented groups in young adulthood sometimes encountered resistance from these groups, whereby participants' reasons for wanting to become involved were not readily apparent or appreciated. Our findings highlight the need for practitioners to understand the complex and often changing role of the LGBTQ community in the lives of young adults with LGBQ parents. PMID- 21787071 TI - A longitudinal examination of coach and peer motivational climates in youth sport: implications for moral attitudes, well-being, and behavioral investment. AB - Embedded in achievement goal theory (Ames, 1992; Meece, Anderman, & Anderman, 2006), this study examined how perceptions of coach and peer motivational climate in youth sport predicted moral attitudes, emotional well-being, and indices of behavioral investment in a sample of British adolescents competing in regional leagues. We adopted a longitudinal perspective, taking measures at the middle and the end of a sport season, as well as at the beginning of the following season. Multilevel modeling analyses showed that perceptions of task-involving peer and coach climates were predictive of more adaptive outcomes than were perceptions of ego-involving peer and coach climates. Predictive effects differed as a function of time and outcome variable under investigation. The results indicate the importance of considering peer influence in addition to coach influence when examining motivational climate in youth sport. PMID- 21787070 TI - Integration of the brief behavioral activation treatment for depression (BATD) into a college orientation program: depression and alcohol outcomes. AB - College freshmen face a variety of academic and social challenges as they adjust to college life that can place them at risk for a number of negative outcomes, including depression and alcohol-related problems. Orientation classes that focus on teaching incoming students how to better cope with college-oriented stress may provide an opportunity to prevent the development of these adjustment problems. This article outlines a program based on behavioral activation that can be integrated into college orientation programs to provide a more comprehensive orientation experience. Data are presented from an initial pilot study in which 71 first-semester freshman at the University of Maryland participated in a 15 week, 2 hr per week orientation class (n = 37 in the behavioral activation enhanced orientation classes and n = 34 in the control orientation as usual classes). Students' depression and alcohol use were evaluated at the beginning, middle, and end of the course. Results indicated a Time * Group interaction such that problem drinking (but not consumption) was significantly reduced across assessments in the behavioral activation classes and largely unchanged in the standard classes. No difference was observed in depression scores; however, fairly low depression scores across the 3 time points may have limited the opportunity to observe any meaningful impact of the orientation classes on depression. The authors conclude with a discussion of the implications of their findings for preventing adjustment problems among incoming college students and future directions. PMID- 21787072 TI - Changing emotion dynamics: individual differences in the effect of anticipatory social stress on emotional inertia. AB - Emotional inertia-the degree to which people's feelings carry over from one moment to the next-is an important property of the temporal dynamics of emotions. Thus far, emotional inertia has only been examined as a stable, trait-like characteristic. However, internal or external events (e.g., stress) may trigger changes in people's emotion dynamics, particularly among individuals with heightened sensitivity to such events. The current study investigated how emotional inertia is influenced by the anticipation of social stress, and how this effect is moderated by individual differences in depression, self-esteem, and fear of negative evaluation. We measured participants' (n = 71) emotional inertia in daily life using experience sampling before and after experimentally manipulating anticipatory social stress. Consistent with previous research, psychological maladjustment was associated with higher emotional inertia during "normal" daily life. However, when anticipating a socially stressful event, levels of emotional inertia dropped, particularly among participants scoring high on depression and fear of negative evaluation and low on self-esteem. These results demonstrate that emotion dynamics can vary as a function of contextual factors and identify moderators of such variation. PMID- 21787073 TI - Basic emotions elicited by odors and pictures. AB - The sense of olfaction is often reported to have a special relationship with emotional processing. Memories triggered by olfactory cues often have a very emotional load. On the other hand, basic negative or positive emotional states should be sufficient to cover the most significant functions of the olfactory system including ingestion, hazard avoidance, and social communication. Thus, we investigated whether different basic emotions can be evoked in healthy people through the sense of olfaction. We asked 119 participants which odor evokes one of the six basic emotions (happiness, disgust, anger, anxiety, sadness, and surprise); another 97 participants were asked about pictures evoking those emotions. The results showed that almost every participant could name an olfactory elicitor for happiness or disgust. Olfactory elicitors of anxiety were reported less frequently, but they were still reported by three-quarters of the participants. However, for sadness and anger only about half of the participants reported an olfactory elicitor, whereas significantly more named a visual cue. Olfactory emotion elicitors were mainly related to the classes of culture, plants, and food, and visual emotion elicitors were largely related to humans. This data supports the hypothesis that in the vast majority of people, few differentiated emotions can be elicited through the olfactory channel. These emotions are happiness, disgust, and anxiety. PMID- 21787074 TI - Interactions between cognition and emotion during response inhibition. AB - Cognition and emotion interact to determine ongoing behaviors. In this study, we investigated the interaction between cognition and emotion during response inhibition using the stop-signal task. In Experiment 1, low-threat stop-signals comprising fearful and happy face pictures were employed. We found that both fearful and happy faces improved response inhibition relative to neutral ones. In Experiment 2, we employed high-threat emotional stimuli as stop signals, namely stimuli previously paired with mild shock. In this case, inhibitory performance was impaired relative to a neutral condition. We interpret these findings in terms of the impact of emotional stimuli on early sensory/attentional processing, which resulted in improved performance (Experiment 1), and in terms of their impact at more central stages, which impaired performance (Experiment 2). Taken together, our findings demonstrate that emotion can either enhance or impair cognitive performance depending on the emotional potency of the stimuli involved. PMID- 21787075 TI - Daily variability in working memory is coupled with negative affect: the role of attention and motivation. AB - Across days, individuals experience varying levels of negative affect, control of attention, and motivation. We investigated whether this intraindividual variability was coupled with daily fluctuations in working memory (WM) performance. In 100 days, 101 younger individuals worked on a spatial N-back task and rated negative affect, control of attention, and motivation. Results showed that individuals differed in how reliably WM performance fluctuated across days, and that subjective experiences were primarily linked to performance accuracy. WM performance was lower on days with higher levels of negative affect, reduced control of attention, and reduced task-related motivation. Thus, variables that were found to predict WM in between-subjects designs showed important relationships to WM at the within-person level. In addition, there was shared predictive variance among predictors of WM. Days with increased negative affect and reduced performance were also days with reduced control of attention and reduced motivation to work on tasks. These findings are in line with proposed mechanisms linking negative affect and cognitive performance. PMID- 21787076 TI - Feeling bad about being sad: the role of social expectancies in amplifying negative mood. AB - Our perception of how others expect us to feel has significant implications for our emotional functioning. Across 4 studies the authors demonstrate that when people think others expect them not to feel negative emotions (i.e., sadness) they experience more negative emotion and reduced well-being. The authors show that perceived social expectancies predict these differences in emotion and well being both more consistently than-and independently of-personal expectancies and that they do so by promoting negative self-evaluation when experiencing negative emotion. We find evidence for these effects within Australia (Studies 1 and 2) as well as Japan (Study 2), although the effects of social expectancies are especially evident in the former (Studies 1 and 2). We also find experimental evidence for the causal role of social expectancies in negative emotional responses to negative emotional events (Studies 3 and 4). In short, when people perceive that others think they should feel happy, and not sad, this leads them to feel sad more frequently and intensely. PMID- 21787077 TI - Mapping emotions through time: how affective trajectories inform the language of emotion. AB - The words used to describe emotions can provide insight into the basic processes that contribute to emotional experience. We propose that emotions arise partly from interacting evaluations of one's current affective state, previous affective state, predictions for how these may change in the future, and the experienced outcomes following these predictions. These states can be represented and inferred from neural systems that encode shifts in outcomes and make predictions. In two studies, we demonstrate that emotion labels are reliably differentiated from one another using only simple cues about these affective trajectories through time. For example, when a worse-than-expected outcome follows the prediction that something good will happen, that situation is labeled as causing anger, whereas when a worse-than-expected outcome follows the prediction that something bad will happen, that situation is labeled as causing sadness. Emotion categories are more differentiated when participants are required to think categorically than when participants have the option to consider multiple emotions and degrees of emotions. This work indicates that information about affective movement through time and changes in affective trajectory may be a fundamental aspect of emotion categories. Future studies of emotion must account for the dynamic way that we absorb and process information. PMID- 21787078 TI - Negative triangles: simple geometric shapes convey emotional valence. AB - It has been suggested that downward pointing triangles convey negative valence, perhaps because they mimic an underlying primitive feature present in negative facial expressions (Larson, Aronoff, and Stearns, 2007). Here, we test this proposition using a flanker interference paradigm in which participants indicated the valence of a central face target, presented between two adjacent distracters. Experiment 1 showed that, compared with face flankers, downward pointing triangles had little influence on responses to face targets. However, in Experiment 2, when attentional competition was increased between target and flankers, downward pointing triangles slowed responses to positively valenced face targets, and speeded them to negatively valenced targets, consistent with valence-based flanker compatibility effects. These findings provide converging evidence that simple geometric shapes may convey emotional valence. PMID- 21787079 TI - No emotional "pop-out" effect in natural scene viewing. AB - It has been shown that attention is drawn toward emotional stimuli. In particular, eye movement research suggests that gaze is attracted toward emotional stimuli in an unconscious, automated manner. We addressed whether this effect remains when emotional targets are embedded within complex real-world scenes. Eye movements were recorded while participants memorized natural images. Each image contained an item that was either neutral, such as a bag, or emotional, such as a snake or a couple hugging. We found no latency difference for the first target fixation between the emotional and neutral conditions, suggesting no extrafoveal "pop-out" effect of emotional targets. However, once detected, emotional targets held attention for a longer time than neutral targets. The failure of emotional items to attract attention seems to contradict previous eye-movement research using emotional stimuli. However, our results are consistent with studies examining semantic drive of overt attention in natural scenes. Interpretations of the results in terms of perceptual and attentional load are provided. PMID- 21787080 TI - Patients' communication with doctors: a randomized control study of a brief patient communication intervention. AB - In research on doctor-patient communication, the patient role in the communication process has received little attention. The dynamic interactions of shared decision making and partnership styles which involve active patient communication are becoming a growing area of focus in doctor-patient communication. However, patients rarely know what makes "good communication" with medical providers and even fewer have received coaching in this type of communication. In this study, 180 patients were randomly assigned to either an intervention group using a written communication tool to facilitate doctor patient communication or to standard care. The goal of this intervention was to assist patients in becoming more effective communicators with their physicians. The physicians and patients both rated the quality of the communication after the office visit based on the patients' knowledge of their health concerns, organizational skills and questions, and attitudes of ownership and partnership. The results supported that patients in the intervention group had significantly better communication with their doctors than patients in the standard care condition. Physicians also rated patients who were in the intervention group as having better overall communication and organizational skills, and a more positive attitude during the office visit. This study supports that helping patients structure their communication using a written format can facilitate doctor-patient communication. Patients can become more adept at describing their health concerns, organizing their needs and questions, and being proactive, which can have a positive effect on the quality of the doctor-patient communication during outpatient office visits. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21787081 TI - Finding the heart of medical family therapy: a content analysis of medical family therapy casebook articles. AB - In an effort to identify the essential ingredients of medical family therapy, a content analysis of 15 peer-reviewed case studies in medical family therapy was conducted. The case studies were published from 1996 to 2007 in Families, Systems, & Health. Through a qualitative content analysis, three main themes emerged that describe the essence of the practice of medical family therapy: (1) The patient's multisystemic experience of disease, (2) treatment is about caring, not just caregiving, and (3) elevating the patient as collaborator in the care team. PMID- 21787082 TI - Publication bias in psychological science: prevalence, methods for identifying and controlling, and implications for the use of meta-analyses. AB - The issue of publication bias in psychological science is one that has remained difficult to address despite decades of discussion and debate. The current article examines a sample of 91 recent meta-analyses published in American Psychological Association and Association for Psychological Science journals and the methods used in these analyses to identify and control for publication bias. Of the 91 studies analyzed, 64 (70%) made some effort to analyze publication bias, and 26 (41%) reported finding evidence of bias. Approaches to controlling publication bias were heterogeneous among studies. Of these studies, 57 (63%) attempted to find unpublished studies to control for publication bias. Nonetheless, those studies that included unpublished studies were just as likely to find evidence for publication bias as those that did not. Furthermore, authors of meta-analyses themselves were overrepresented in unpublished studies acquired, as compared with published studies, suggesting that searches for unpublished studies may increase rather than decrease some sources of bias. A subset of 48 meta-analyses for which study sample sizes and effect sizes were available was further analyzed with a conservative and newly developed tandem procedure of assessing publication bias. Results indicated that publication bias was worrisome in about 25% of meta-analyses. Meta-analyses that included unpublished studies were more likely to show bias than those that did not, likely due to selection bias in unpublished literature searches. Sources of publication bias and implications for the use of meta-analysis are discussed. PMID- 21787083 TI - A 2 * 2 taxonomy of multilevel latent contextual models: accuracy-bias trade-offs in full and partial error correction models. AB - In multilevel modeling, group-level variables (L2) for assessing contextual effects are frequently generated by aggregating variables from a lower level (L1). A major problem of contextual analyses in the social sciences is that there is no error-free measurement of constructs. In the present article, 2 types of error occurring in multilevel data when estimating contextual effects are distinguished: unreliability that is due to measurement error and unreliability that is due to sampling error. The fact that studies may or may not correct for these 2 types of error can be translated into a 2 * 2 taxonomy of multilevel latent contextual models comprising 4 approaches: an uncorrected approach, partial correction approaches correcting for either measurement or sampling error (but not both), and a full correction approach that adjusts for both sources of error. It is shown mathematically and with simulated data that the uncorrected and partial correction approaches can result in substantially biased estimates of contextual effects, depending on the number of L1 individuals per group, the number of groups, the intraclass correlation, the number of indicators, and the size of the factor loadings. However, the simulation study also shows that partial correction approaches can outperform full correction approaches when the data provide only limited information in terms of the L2 construct (i.e., small number of groups, low intraclass correlation). A real-data application from educational psychology is used to illustrate the different approaches. PMID- 21787084 TI - Bayes factor approaches for testing interval null hypotheses. AB - Psychological theories are statements of constraint. The role of hypothesis testing in psychology is to test whether specific theoretical constraints hold in data. Bayesian statistics is well suited to the task of finding supporting evidence for constraint, because it allows for comparing evidence for 2 hypotheses against each another. One issue in hypothesis testing is that constraints may hold only approximately rather than exactly, and the reason for small deviations may be trivial or uninteresting. In the large-sample limit, these uninteresting, small deviations lead to the rejection of a useful constraint. In this article, we develop several Bayes factor 1-sample tests for the assessment of approximate equality and ordinal constraints. In these tests, the null hypothesis covers a small interval of non-0 but negligible effect sizes around 0. These Bayes factors are alternatives to previously developed Bayes factors, which do not allow for interval null hypotheses, and may especially prove useful to researchers who use statistical equivalence testing. To facilitate adoption of these Bayes factor tests, we provide easy-to-use software. PMID- 21787085 TI - Workaholic and work engaged employees: dead ringers or worlds apart? AB - Building on Deci and Ryan's Self-Determination Theory and Meijman and Mulder's Effort-Recovery Model, the present study examined the nature, antecedents, and consequences of working hard (i.e., workaholism and work engagement) in a Dutch convenience sample of 1,246 employees. A confirmatory factor analysis showed that workaholism and work engagement were two largely independent concepts. Crossing these two concepts yielded four types of workers: workaholic employees, engaged employees, engaged workaholics, and nonworkaholic/nonengaged employees. MANOVA and subsequent ANOVAs were used to compare these four groups regarding their motivation, working hours, and levels of burnout. As expected, study results revealed that workaholic employees were driven by controlled motivation, whereas engaged employees were driven by autonomous motivation. Engaged workaholics were driven by both controlled and autonomous motivation. In addition, the results revealed that engaged workaholics spent most time on working. Unlike workaholic employees, engaged workaholics did not experience the highest levels of burnout, suggesting that high engagement may buffer the adverse consequences of workaholism. The present study emphasizes the importance of differentiating among at least three categories of employees who work hard: workaholic employees, engaged employees, and-for the first time-engaged workaholics. PMID- 21787087 TI - Age differences in processing fluctuations in postural control across trials and across days. AB - Postural control performances of 18 younger and 18 older adults were repeatedly measured on 45 weekdays with five trials per day. This design made it possible to dissociate between long-term trends and processing fluctuations in the sensorimotor domain at moment-to-moment, trial-to-trial, and day-to-day levels. Older adults fluctuated more than younger adults at all timescales. Age differences in trial-to-trial and day-to-day processing fluctuations were reduced but remained statistically significant when controlling for fluctuations on faster timescales. We concluded that age differences in intraindividual fluctuations at the longer timescales are in part related to age differences in low-level system robustness, suggesting a cascade of effects across multiple timescales. PMID- 21787086 TI - The association between change in cognitive ability and cause-specific mortality in a community sample of older adults. AB - While there is consistent evidence that initial levels of cognitive ability predict mortality, there is mixed evidence for a relationship between changes in cognition and mortality. There have been few studies that have examined whether the level and slope of cognitive performance is predictive of subsequent mortality from all causes or from cardiovascular disease, stroke, heart disease, respiratory disease, or cancer. This study aimed to assess whether the level and slope of cognitive ability were associated with all-cause or cause-specific mortality. A cohort of 896 community-based elderly people in Australia was interviewed four times over 12 years, with vital status followed for up to 17 years. Of these, 592 participants completed two or more interviews and were included in survival models of six mortality outcomes. Cognitive change in five domains of ability was estimated using latent growth models. Poorer initial processing speed or verbal fluency was significantly associated with greater all cause and/or cardiovascular mortality. In addition, declines in global ability were associated with greater all-cause, cardiovascular, and heart disease mortality. Vocabulary and episodic memory were not associated with mortality, and none of the cognitive tests significantly predicted respiratory or cancer mortality. Initial levels of cognitive ability tended to be better predictors of subsequent mortality than were changes in ability. The results suggest that vascular events may be largely responsible for the overall relationship between cognition and mortality. PMID- 21787088 TI - Cognitive mechanisms of false facial recognition in older adults. AB - Older adults show elevated false alarm rates on recognition memory tests involving faces in comparison to younger adults. It has been proposed that this age-related increase in false facial recognition reflects a deficit in recollection and a corresponding increase in the use of familiarity when making memory decisions. To test this hypothesis, we examined the performance of 40 older adults and 40 younger adults on a face recognition memory paradigm involving three different types of lures with varying levels of familiarity. A robust age effect was found, with older adults demonstrating a markedly heightened false alarm rate in comparison to younger adults for "familiarized lures" that were exact repetitions of faces encountered earlier in the experiment, but outside the study list, and therefore required accurate recollection of contextual information to reject. By contrast, there were no age differences in false alarms to "conjunction lures" that recombined parts of study list faces, or to entirely new faces. Overall, the pattern of false recognition errors observed in older adults was consistent with excessive reliance on a familiarity-based response strategy. Specifically, in the absence of recollection older adults appeared to base their memory decisions on item familiarity, as evidenced by a linear increase in false alarm rates with increasing familiarity of the lures. These findings support the notion that automatic memory processes such as familiarity remain invariant with age, while more controlled memory processes such as recollection show age-related decline. PMID- 21787089 TI - Age-related influences on lexical selection and orthographic encoding during homophone spelling. AB - Two experiments investigated age differences in how semantic, syntactic, and orthographic factors influence the production of homophone spelling errors in sentence contexts. Younger and older adults typed auditorily presented sentences containing homophone targets (e.g., blew) that were categorized as having a regular spelling (EW) or an irregular spelling (UE). In Experiment 1, homophones were preceded by an unrelated word, a semantic prime that was congruent with the target's meaning in the sentence (e.g., wind), or a semantic prime incongruent with the target's meaning (e.g., sky) and instead related to the competitor homophone. Experiment 2 manipulated the target's part of speech, where target and competitor homophones shared or differed in part of speech. For both age groups, significant semantic priming occurred, where homophone errors decreased following congruent semantic primes and increased following incongruent primes. However, priming only occurred when homophones shared part of speech. Further, both age groups made more errors on homophones with an irregular than a regular spelling, and this regularity effect was smaller for older adults when homophones shared part of speech. Contrary to many spoken production tasks, older adults made fewer errors overall than younger adults. These findings demonstrate age preservation in lexical selection but age differences in orthographic encoding, resulting in older adults producing fewer errors because of reduced activation to competitor homophones. These findings also illustrate that syntactic factors, such as part of speech, can influence the spellings of individual words. PMID- 21787090 TI - Co-occurring mental health and substance use problems in offenders: implications for risk assessment. AB - We undertook a secondary data analysis to study issues relevant to co-occurring mental health and substance disorder in a combined sample of offenders (N = 3,197). Using the Personality Assessment Inventory, we compared the frequency of depressive, traumatic stress, and personality disorder symptom elevations across offenders with and without substance problems, identified the extent to which co occurring problems were accompanied by risk factors for suicide and aggression, and tested for gender differences. Offenders with substance problems were more likely than others to have increased mental health problems and risk factors for suicide or aggression. Women with substance problems, compared with men, had higher depression, traumatic stress, and borderline features, in addition to lower antisocial features. The frequency with which suicide and aggression risk factors were associated with mental health problems was generally similar across men and women. Measurement issues relevant to co-occurring disorder and risk assessment are discussed. PMID- 21787092 TI - Assessing implicit motivational orientations in couple relationships: the Partner Related Agency and Communion Test (PACT). AB - The Partner-Related Agency and Communion Test (PACT) was developed to measure implicit agentic and communal needs in the domain of couple relationships through content analyses of fantasy stories. Study 1 (N = 125) confirmed that the new thematic coding system captured experimentally induced differences in partner related motivation and showed expected relations with D. G. Winter's (1994) motive scoring system. Study 2 confirmed the discriminant and incremental validity of the implicit partner-related needs compared with self-report measures of the Big Five traits and adult attachment in a sample of 499 couples. In addition, dyadic analyses revealed expected associations of the partner-related needs with relationship satisfaction as experienced by oneself and by one's partner. The studies lend initial support to the validity of the relationship specific needs for agency and communion as assessed by the PACT and introduce dyadic data analyses to the study of implicit motives. PMID- 21787091 TI - Validity of the Externalizing Spectrum Inventory in a criminal offender sample: relations with disinhibitory psychopathology, personality, and psychopathic features. AB - The Externalizing Spectrum Inventory (ESI; Krueger, Markon, Patrick, Benning, & Kramer, 2007) provides a self-report based method for indexing a range of correlated problem behaviors and traits in the domain of deficient impulse control. The ESI organizes lower order behaviors and traits of this kind around higher order factors encompassing general disinhibitory proneness, callous aggression, and substance abuse. In the current study, we used data from a male prisoner sample (N = 235) to evaluate the validity of ESI total and factor scores in relation to external criterion measures consisting of externalizing disorder symptoms (including child and adult antisocial deviance and substance-related problems) assessed via diagnostic interviews, personality traits assessed with self-reports, and psychopathic features as assessed with both interviews and self reports. Results provide evidence for the validity of the ESI measurement model and point to its potential usefulness as a referent for research on the neurobiological correlates and etiological bases of externalizing proneness. PMID- 21787093 TI - The merit of meritocracy. AB - We argue that the preference for the merit principle is a separate construct from hierarchy-legitimizing ideologies (i.e., system justification beliefs, prejudice, social dominance orientation), including descriptive beliefs that meritocracy currently exists in society. Moreover, we hypothesized that prescriptive beliefs about merit should have a stronger influence on reactions to the status quo when hierarchy-legitimizing ideologies are weak (vs. strong). In 4 studies, participants' preference for the merit principle and hierarchy-legitimizing ideologies were assessed; later, the participants evaluated organizational selection practices that support or challenge the status quo. Participants' prescriptive and descriptive beliefs about merit were separate constructs; only the latter predicted other hierarchy-legitimizing ideologies. In addition, as hypothesized, among participants who weakly endorsed hierarchy-legitimizing ideologies, the stronger their preference for the merit principle, the more they opposed selection practices that were perceived to be merit violating but the more they supported practices that were perceived to be merit restoring. In contrast, those who strongly endorsed hierarchy-legitimizing ideologies were always motivated to support the status quo, regardless of their preference for the merit principle. PMID- 21787094 TI - The past makes the present meaningful: nostalgia as an existential resource. AB - The present research tested the proposition that nostalgia serves an existential function by bolstering a sense of meaning in life. Study 1 found that nostalgia was positively associated with a sense of meaning in life. Study 2 experimentally demonstrated that nostalgia increases a sense of meaning in life. In both studies, the link between nostalgia and increased meaning in life was mediated by feelings of social connectedness. Study 3 evidenced that threatened meaning increases nostalgia. Study 4 illustrated that nostalgia, in turn, reduces defensiveness following a meaning threat. Finally, Studies 5 and 6 showed that nostalgia disrupts the link between meaning deficits and compromised psychological well-being. Collectively, these findings indicate that the provision of existential meaning is a pivotal function of nostalgia. PMID- 21787095 TI - Predicting employment status at 2 years' postdischarge from spinal cord injury rehabilitation. AB - OBJECTIVES: This exploratory study examined the extent to which postinjury employment was predictable when patients were followed up 2 years' postdischarge from a specialist Spinal Cord Injury (SCI) Unit. PARTICIPANTS AND DESIGN: Seventy two individuals with SCI for whom there were discharge Functional Independence Measure (FIM) scores, 60 complete sets of data were available for Discriminant Function Analysis. RESULTS: Using a combination of variables assessed prior to or shortly after discharge from rehabilitation, complemented by psychosocial variables assessed at the time of follow-up, moderate classification accuracy was achieved with respect to employment status at the 2-year follow-up period (72%), with the set of predictor variables being more accurate at predicting those subsequently in paid employment (83%) than those not (67%). CONCLUSIONS: The main implication of the study results is that nontraditional variables (i.e., variables other than injury and demographic variables), including, particularly, contextual environmental variables such as community integration, access to transport, and social support, are worthy of further research, especially because many of these are amenable to rehabilitation program interventions, and thus may facilitate the attainment of enhanced rates of postdischarge employment among those living with SCI. PMID- 21787096 TI - Development and validation of the Caregiver Empowerment Scale: a resource for working with family caregivers of persons with traumatic brain injury. AB - OBJECTIVE: To use multitrait analysis to determine the measurement structure of the Caregiver Empowerment Scale (CES). PARTICIPANTS: An American sample of 87 adult primary family caregivers of persons with traumatic brain injury (TBI). RESULTS: A four-factor structure was identified including factor 1 (Advocacy Self Efficacy), factor 2 (Community Self-Efficacy), factor 3 (Caregiver Self Efficacy), and factor 4 (Personal Self-Efficacy). CONCLUSIONS: The CES provides clinicians and researchers a means to assess self-perceived coping abilities of family caregivers of persons with TBI. PMID- 21787097 TI - Integrating behavioral-motive and experiential-requirement perspectives on psychological needs: a two process model. AB - Psychological need theories offer much explanatory potential for behavioral scientists, but there is considerable disagreement and confusion about what needs are and how they work. A 2-process model of psychological needs is outlined, viewing needs as evolved functional systems that provide both (a) innate psychosocial motives that tend to impel adaptive behavior and (b) innate experiential requirements that when met reinforce adaptive behavior and promote mental health. The literature is reviewed to find support for 8 hypotheses derived from this model: that certain basic psychosocial motives are present at birth; that successful enactment of these motives supports the functioning and wellness of all humans; that individual differences in these motives develop in childhood; that these strong motive dispositions tend to produce the satisfying experiences they seek; that motive dispositions do not moderate the effect of motive-corresponding need satisfaction on well-being but do moderate the effect of assigned goal-type on rated self-concordance for those goals; that need dissatisfaction and need satisfaction correspond to the separable behavioral motive and experiential-reward aspects of needs; and that motives and needs can become decoupled when chronic dissatisfaction of particular requirements warps or depresses the corresponding motives, such that the adaptive process fails in its function. Implications for self-determination theory and motive disposition theory are considered. PMID- 21787098 TI - Response rate and reinforcement rate in Pavlovian conditioning. AB - Four experiments used delay conditioning of magazine approach in rats to investigate the relationship between the rate of responding, R, to a conditioned stimulus (CS) and the rate, r, at which the CS is reinforced with the unconditioned stimulus (US). Rats were concurrently trained with four variable duration CSs with different rs, either as a result of differences in the mean CS US interval or in the proportion of CS presentations that ended with the US. In each case, R was systematically related to r, and the relationship was very accurately characterized by a hyperbolic function, R = Ar/(r +c). Accordingly, the reciprocal of these two variables-response interval, I (= 1/R), and CS-US interval, i (= 1/r) - were related by a simple affine (straight line) transformation, I = mi+b. This latter relationship shows that each increment in the time that the rats had to wait for food produced a linear increment in the time they waited between magazine entries. We discuss the close agreement between our findings and the Matching Law (Herrnstein, 1970) and consider their implications for both associative theories (e.g., Rescorla & Wagner, 1972) and nonassociative theories (Gallistel & Gibbon, 2000) of conditioning. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21787099 TI - Summation of reinforcement rates when conditioned stimuli are presented in compound. AB - Three experiments used delay conditioning of magazine approach in rats to examine the summation of responding when two conditioned stimuli (CSs) are presented together as a compound. The duration of each CS varied randomly from trial-to trial around a mean that differed between the CSs. This meant that the rats' response rate to each CS was systematically related to the reinforcement rate of that CS, but remained steady as time elapsed during the CS (Harris & Carpenter, 2011; Harris, Gharaei, & Pincham, 2011). When the rats were presented with a compound of two CSs that had been conditioned separately, they responded more during the compound than during either of the CSs individually. More significantly, however, in all three experiments, the rats responded to the compound at the same rate as they responded to a third CS that had been reinforced at a rate equal to the sum of the reinforcement rates of the two CSs in compound. We discuss the implications of this finding for associative models (e.g., Rescorla & Wagner, 1972) and rate-based models (Gallistel & Gibbon, 2000) of conditioning. PMID- 21787101 TI - Chess masters show a hallmark of face processing with chess. AB - Face processing has several distinctive hallmarks that researchers have attributed either to face-specific mechanisms or to extensive experience distinguishing faces. Here, we examined the face-processing hallmark of selective attention failure--as indexed by the congruency effect in the composite paradigm- in a domain of extreme expertise: chess. Among 27 experts, we found that the congruency effect was equally strong with chessboards and faces. Further, comparing these experts with recreational players and novices, we observed a trade-off: Chess expertise was positively related to the congruency effect with chess yet negatively related to the congruency effect with faces. These and other findings reveal a case of expertise-dependent, facelike processing of objects of expertise and suggest that face and expert-chess recognition share common processes. PMID- 21787100 TI - Quantity judgments of auditory and visual stimuli by chimpanzees (Pan troglodytes). AB - Many species can choose between two visual sets of stimuli on the basis of quantity. This is true when sets are both visible, or are presented one set at a time or even one item at a time. However, we know comparatively little about how well nonhuman animals can compare auditory quantities. Here, three chimpanzees (Pan troglodytes) chose between two sets of food items when they only heard each item fall into different containers rather than seeing those items. This method prevented the chimpanzees from summing the amount of visible food they saw because there were no visual cues. Chimpanzees performed well, and their performance matched that of previous experiments with regard to obeying Weber's law. They also performed well with comparisons between a sequentially presented auditory set and a fully visible set, demonstrating that duration of presentation was not being used as a cue. In addition, they accommodated empty sets into these judgments, although not perfectly. Thus, chimpanzees can judge auditory quantities in flexible ways that show many similarities to how they compare visual quantities. PMID- 21787102 TI - Should social savvy equal good spatial skills? The interaction of social skills with spatial perspective taking. AB - Real-world perspective-taking problems frequently involve interactions among individuals, suggesting a potential social element to this seemingly spatial problem. Previous studies have suggested that the agency of the target in a perspective-taking task might influence reasoning. This hypothesis is tested directly by manipulating whether one takes the perspective of a potential agent or an object. The results were striking: Even though no overall differences in performance were observed with and without agents, performance was differentially associated with social skills. In particular, participants with better social skills were more accurate than less social peers when the target was a potential agent, whereas no such relationship was observed when the target was an object. These results suggest that bringing domain-specific investigations to bear on real-world problems requires understanding how that domain exists in the broader context of interacting skills and biases. PMID- 21787104 TI - The weight of time: affordances for an integrated magnitude system. AB - In five experiments we explored the effects of weight on time in different action contexts to test the hypothesis that an integrated magnitude system is tuned to affordances. Larger magnitudes generally seem longer; however, Lu and colleagues (2009) found that if numbers were presented as weights in a range heavy enough to affect lifting, the "larger seems longer" effect was enhanced, but it was eliminated with weights too light to affect lifting. Experiments 1 and 2 revealed that actually lifting kilogram and gram weights had effects parallel to symbolized weights, suggesting that Lu et al.'s task implicitly evoked a lifting context. Experiments 3 and 4 showed that weights too heavy (e.g., tons) or too light to be discriminated by lifting, but relevant to other affordances (e.g., grams of a toxin) had effects on time as large or larger than for kilograms. Experiment 5 showed that the effect for grams in a toxicology context did not generalize to the lifting task of Experiment 2. Weight appears to integrate with other magnitudes when it is relevant to meaningful actions, including but not limited to lifting. PMID- 21787105 TI - Are pictures good for learning new vocabulary in a foreign language? Only if you think they are not. AB - The current study explored whether new words in a foreign language are learned better from pictures than from native language translations. In both between subjects and within-subject designs, Swahili words were not learned better from pictures than from English translations (Experiments 1-3). Judgments of learning revealed that participants exhibited greater overconfidence in their ability to recall a Swahili word from a picture than from a translation (Experiments 2-3), and Swahili words were also considered easier to process when paired with pictures rather than translations (Experiment 4). When this overconfidence bias was eliminated through retrieval practice (Experiment 2) and instructions warning participants to not be overconfident (Experiment 3), Swahili words were learned better from pictures than from translations. It appears, therefore, that pictures can facilitate learning of foreign language vocabulary--as long as participants are not too overconfident in the power of a picture to help them learn a new word. PMID- 21787103 TI - Neural mechanisms of interference control underlie the relationship between fluid intelligence and working memory span. AB - Fluid intelligence (gF) and working memory (WM) span predict success in demanding cognitive situations. Recent studies show that much of the variance in gF and WM span is shared, suggesting common neural mechanisms. This study provides a direct investigation of the degree to which shared variance in gF and WM span can be explained by neural mechanisms of interference control. The authors measured performance and functional magnetic resonance imaging activity in 102 participants during the n-back WM task, focusing on the selective activation effects associated with high-interference lure trials. Brain activity on these trials was correlated with gF, WM span, and task performance in core brain regions linked to WM and executive control, including bilateral dorsolateral prefrontal cortex (middle frontal gyrus; BA9) and parietal cortex (inferior parietal cortex; BA 40/7). Interference-related performance and interference related activity accounted for a significant proportion of the shared variance in gF and WM span. Path analyses indicate that interference control activity may affect gF through a common set of processes that also influence WM span. These results suggest that individual differences in interference-control mechanisms are important for understanding the relationship between gF and WM span. PMID- 21787106 TI - Basic processes in reading: the effect of interletter spacing. AB - Reading is acutely sensitive to the amount of space between letters within a string. In the present investigation, we explore the impairment caused by increasing interletter spacing when reading single words and nonwords aloud. Specifically, 2 hypotheses are tested: (a) whether increasing interletter spacing induces serial processing while reading aloud and (b) whether this serial processing results from an increased reliance on a serial sublexical mechanism similar to that implemented in dual route models of reading. Implications of the present results for understanding basic processes in reading are discussed with particular reference to different types of serial processing in reading aloud and the role of attention in reading. PMID- 21787107 TI - On the plasticity of the survival processing effect. AB - Nairne, Thompson, and Pandeirada (2007) discovered a strong and rather general memory advantage for word material processed in a survival-related context. One possible explanation of this effect conceives survival processing as a special form of encoding: Nature specifically "tuned" our memory systems to process and remember fitness-relevant information. We tested this explanation by studying whether the survival processing effect is robust against encoding manipulations that do not affect the fitness relevance of information. Three experiments replicated a strong survival processing effect under standard conditions but showed that the mnemonic benefit of survival processing diminishes or even vanishes when participants focus on a single problem (Experiments 1 and 2) or technique (Experiment 3) of survival. We argue that it is not survival processing per se that facilitates recall but the richness and distinctiveness with which information is encoded. PMID- 21787108 TI - Using mobile clinics to deliver HIV testing and other basic health services in rural Malawi. AB - CONTEXT: The majority of Malawians are impoverished and primarily dependant on subsistence farming, with 85% of the population living in a rural area. The country is highly affected by HIV and under-resourced rural health centers struggle to meet the government's goal of expanding HIV testing, antiretroviral treatment, and other basic services. ISSUE: This report describes the work of two four-wheel drive mobile clinics launched in 2008 to fill an identified service gap in the remote areas of Mulanje District, Malawi. The program was developed by an international non-governmental organization, Global AIDS Interfaith Alliance (GAIA), and the Mulanje District Health Office, with funding from the Elizabeth Taylor HIV/AIDS Foundation. The clinics provide: (1) rapid HIV testing and treatment referral; (2) diagnosis and treatment of malaria; (3) sputum collection for TB screening; (4) diagnosis and treatment of sexually transmitted and opportunistic infections; and (5) pre-natal care. The clinic vehicles provide medical supplies and personnel (a clinical officer, nurse, and nurse aide) to set up clinics in community buildings such as churches or schools. LESSONS LEARNED: In such a project, the implementation process and schedule can be affected by medication, supply chain and infrastructural issues, as well as governmental and non-governmental requirements. Timelines should be sufficiently flexible to accommodate unexpected delays. Once established, service scheduling should be flexible and responsive; for instance, malaria treatment rather than HIV testing was most urgently needed in the season when these services were launched. Assessing the impact of healthcare delivery in Malawi is challenging. Although mobile clinic and the government Health Management Information System (HMIS) data were matched, inconsistent variables and gaps in data made direct comparisons difficult. Data collection was compromised by the competing demand of high patient volume; however, rather than reducing the burden on existing health centers, the data suggest that the mobile clinics provided services for people who otherwise may not have attended a health center. The GAIA mobile clinics were integrated into a catchment area through a community participation model, allowing point-of-care primary health services to be provided to thousands of people in remote rural villagers. Strong relationships have been forged with local community leaders and with Malawi Ministry of Health officers as the foundation for long-term sustainable engagement and eventual integration of services into Health Ministry programs. PMID- 21787109 TI - 'I am part of the community but...' The changing context of rural living for persons with advanced cancer and their families. AB - INTRODUCTION: Older rural persons who are receiving palliative care experience multiple co-existing transitions that can be distressing. These transitions do not occur in a vacuum, but occur in a context that reflects the uniqueness of rural living and the complexities of end of life in rural settings. The context or situation (geographical, physical, and social) in which an experience occurs influences the way people view and interpret the world around them; this contextual perspective contributes greatly to perceptions held by rural residents. PURPOSE: The purpose of this study was to explore the context in which older rural patients receiving palliative care and their families experience transitions. Following a study of the transition experiences of older rural palliative patients, an in-depth interpretive description analysis was conducted specific to the context in which the participants' transitions occurred. METHODS: Twenty-seven open-ended, individual, audio-taped, qualitative interviews were conducted and 4 focus group discussions were held to gather data. Individual audio-taped interviews were conducted with six older rural persons with advanced cancer and 10 bereaved (post-death) family caregivers. Four focus groups were conducted with 12 palliative care healthcare professionals. Participants were recruited from 3 rural health regions in a western Canadian province classified as one of the most 'rural' Canadian provinces. All interviews were transcribed verbatim, coded, and analyzed using Thorne's interpretive description qualitative approach. RESULTS: From the data analysis four themes emerged: (1) community connectedness/isolation; (2) lack of accessibility to care; (3) communication and information issues; and (4) independence/dependence. Participants described feelings of being connected to the community at the same time as they also reported feeling isolated. They described their value of independence at the same time as finding themselves becoming increasingly dependent on others. At times this value of independence interfered with their seeking and accessing needed health or supportive care. They perceived their lack of access to health care resulted in little or no choice in where they die. CONCLUSIONS: These findings reveal that the rural context has a major impact on the types of community support and healthcare services needed by older persons with advanced disease and their families. With advanced disease, the participants' sense of solitude became one of isolation, and with increasing dependence on others, they needed more connection and support from others. The findings reflected a more complex view of rural aging and dying than has been cited in the literature to date. This study suggests there is a need to renegotiate community supports and the independence available to persons with advanced disease as they undergo multiple transitions near the end of life. PMID- 21787110 TI - Clinical decision-making of rural novice nurses. AB - INTRODUCTION: Nurses in rural settings are often the first to assess and interpret the patient's clinical presentations. Therefore, an understanding of how nurses experience decision-making is important in terms of educational preparation, resource allocation to rural areas, institutional cultures, and patient outcomes. METHODS: Theory development was based on the in-depth investigation of 12 novice nurses practicing in rural critical access hospitals in a north central state. This grounded theory study consisted of face-to-face interviews with 12 registered nurses, nine of whom were observed during their work day. The participants were interviewed a second time, as a method of member checking, and during this interview they reviewed their transcripts, the emerging themes and categories. Directors of nursing from both the research sites and rural hospitals not involved in the study, experienced researchers, and nurse educators facilitated triangulation of the findings. RESULTS: 'Sociocentric rationalizing' emerged as the central phenomenon and referred to the sense of belonging and agency which impacted the decision-making in this small group of novice nurses in rural critical access hospitals. The observed consequences, which were conceptualized during the axial coding process and were derived from observations and interviews of the 12 novice nurses in this study include: (1) gathering information before making a decision included assessment of: the credibility of co-workers, patients' subjective and objective data, and one's own past and current experiences; (2) conferring with co-workers as a direct method of confirming/denying decisions being made was considered more realistic and expedient than policy books and decision trees; (3) rural practicum clinical experiences, along with support after orientation, provide for transition to the rural nurse role; (4) involved directors of nursing served as both models and protectors of novice nurses placed in high accountability positions early in their careers. These novice nurses were often working with a limited staff, while managing an ever-changing census and acuity of patients. The significance of interdependence and welcoming relationships with their co-workers and directors of nursing was pivotal in the clinical decision-making process. CONCLUSIONS: Despite access to a number of resources at their disposal (including policy books, decision trees, standing orders, textbooks, and in some cases internet resources), the 12 nurses in this study indicated collaboration with co-workers was a major means of facilitating their decision-making. Rural novice nurses require facilitation of social skills as much as critical thinking skills both within their programs of nursing and during their new employee orientation; however, decision-making must be guided by more experienced nurses who are willing to mentor novice nurses and advise them to to reflect upon their decisions as they care for patients using evidenced based practice. In a rural setting, this is especially important because novice nurses are tasked early in their career with decision-making, which often involves ill-structured problems set in dynamic and changing environments, in high-stakes situations where patient safety is a concern. PMID- 21787111 TI - A hypertension gene: are we there yet? AB - Cardiovascular diseases are the leading cause of death worldwide. Essential hypertension is a major risk factor for the development of other cardiovascular diseases and is caused by a combination of environmental and genetic factors, with up to 50% of blood pressure variance currently attributed to an individual's genetic makeup. By studying genes that cause monogenic forms of hypertension and pathways relevant to blood pressure control, a number of polymorphisms have been identified that increase an individual's risk of developing high blood pressure. We report on candidate gene association studies and genome-wide association studies that have been performed to date in the field of hypertension research. It is becoming clear that for the majority of people there is no single gene polymorphism that causes hypertension, but rather a number of common genetic variants, each having a small effect. Using pharmacogenomics to personalize the treatment of hypertension holds promise for achieving and sustaining normotensive pressures quickly, while minimizing the risk of adverse reactions and unwanted side-effects. This will decrease the risk of stroke and myocardial infarction in individuals and lead to a reduced burden of disease upon society as a whole. PMID- 21787112 TI - Intersections of epigenetics, twinning and developmental asymmetries: insights into monogenic and complex diseases and a role for 3D facial analysis. AB - For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena. PMID- 21787113 TI - The Ets transcription factor ELF5 functions as a tumor suppressor in the kidney. AB - Renal cell carcinoma is an important clinical disease with poorly understood etiology. ELF5 is an epithelial-specific member of the Ets family of transcription factors, characterized by the 80 amino acid Ets domain that binds the purine-rich GGAA/T Ets motif found in the promoter regions of a variety of genes. Since ELF5 is highly expressed in kidney and has been postulated to function as a tumor suppressor, at least in the context of the breast, we investigated its role in kidney cancer. In renal cell carcinoma ELF5 expression was consistently decreased in tumor samples versus normal. ELF5 mRNA was decreased in 94% of lesions tested and ELF5 protein was undetectable in 40/40 kidney-derived carcinomas. Re-expression of the ELF5 gene in 786-O renal carcinoma cells suppressed their tumorigenic capacity in vitro and in vivo. This work is the first to suggest that ELF5 has tumor suppressor activity in the kidney. PMID- 21787114 TI - Kallikrein-related peptidase 3 (KLK3/PSA) single nucleotide polymorphisms and ovarian cancer survival. AB - There is substantial evidence suggesting a role for hormone-regulated kallikrein related peptidases (KLKs) in carcinogenesis and tumour metastasis. KLKs are considered to have potential as prognostic biomarkers for hormone dependent cancers, particularly ovarian cancer. The purpose of this study was to evaluate the association between Kallikrein-related peptidase 3 (KLK3) gene single nucleotide polymorphisms (SNPs) located in hormone response elements and ovarian cancer survival. DNA samples were analyzed from 304 Australian women diagnosed with epithelial ovarian cancer. The KLK3 rs266882 and rs11084033 SNPs were genotyped by the Sequenom iPLEX Mass Array platform. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models. An association was observed with ovarian cancer survival for homozygote carriers of the rare allele of rs11084033 (adjusted HR 2.12, 95% CI 1.08-4.15). This finding is consistent with bioinformatic analysis predicting the rs11084033 rare allele to be responsible for the loss of a confirmed androgen response element, and with published expression data suggesting that aggressive ovarian cancers show decreased KLK3 tumor expression. The rs11084033 has potential prognostic significance in ovarian cancer. However, this finding requires replication, and further investigation regarding the functional significance of rs11084033 and correlated SNPs. PMID- 21787115 TI - CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk. AB - Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer. PMID- 21787116 TI - An additional case of the recurrent 15q24.1 microdeletion syndrome and review of the literature. AB - We report a 9-year-old girl with 3 Mb interstitial deletion of chromosome 15q24 identified by oligonucleotide array comparative hybridization. She is of Chinese ancestry and shared some typical features of previously reported 15q24 deletion cases such as mild dysmorphism with developmental and speech delay. She also had mild hearing loss that was reported in one other case. We compared all 19 cases that are identified from array-CGH. The deletion occurred within an 8.3 Mb region from 15q23 to 15q24.3. The minimum overlapping deleted region is less than 0.5 Mb from 72.3 Mb to 72.7 Mb. The functions of the nine annotated genes within the region and how they might contribute to the microdeletion phenotype are discussed. PMID- 21787117 TI - Use of Bayes' formula to make a genetic risk estimate. AB - Izabella and her partner sought pre-implantation genetic diagnosis (PGD) because Izabella had retinoblastoma due to a deletion in chromosome 13 and they want to have children not at genetic risk of retinoblastoma. Fortunately, Izabella's tumor was unilateral and was treated successfully and she is well. Izabella's chromosome abnormality is mosaic with 70% of lymphocytes having the deletion. This mosaicism may not be present in Izabella's ovaries. The couple went through PGD on two occasions and 13 embryos were tested. None had the deleted chromosome 13. IVF and PGD failed to produce a pregnancy. The couple wished to know what the experience provides as to the risk to their offspring: in particular, does it indicate a risk low enough to be acceptable if they go ahead with a natural pregnancy instead of another resort to PGD? Also, the couple did not want prenatal diagnosis. The situation therefore requires an estimate of the probability that an embryo will have the deletion. Counseling is problematic because there is no obvious way of selecting a prior probability from which to compute a Bayesian estimate of risk. Two solutions are offered, depending on the amount of information available about genes transmitted from the maternal grandparents. PMID- 21787118 TI - Evaluation of satisfaction of parents with the use of videoconferencing for a pediatric genetic consultation. AB - Telegenetics is a new development in the service delivery of Genetic Services in Australia. This project was designed to establish if it was an acceptable alternative to a face-to-face consultation in the genetic assessment of intellectual disability, including morphological assessment, of the patient. Ten children from two outreach clinics in rural NSW who were referred by their pediatrician were assessed by a single geneticist via telehealth and then seen again face-to-face as a 'gold standard'. Satisfaction surveys were then sent to both the parents and the referring pediatricians. After the face-to-face appointment, the clinical geneticist reviewed the recordings of both the transmitted footage and the high definition footage that was sent separately. There were very few morphological findings missed by the telegenetic assessments. The discrepancies that were noted could decrease in frequency as staff become more familiar with the methods. The parents of the patients reported no problem with the cameras and telehealth. They would have preferred face-to-face appointment but would be happy to have the telehealth appointment if it meant being seen earlier. This pilot study suggests that clinical genetic diagnostic assessment could be performed by telemedicine. PMID- 21787119 TI - Abstracts for the 35th Human Genetics Society Of Australasia annual scientific meeting, Gold Coast, Australia July 31-August 3, 2011. PMID- 21787122 TI - Osteolytic presentation of pediatric acute megakaryoblastic leukemia. PMID- 21787120 TI - Defining genome maintenance pathways using functional genomic approaches. AB - Genome maintenance activities including DNA repair, cell division cycle control, and checkpoint signaling pathways preserve genome integrity and prevent disease. Defects in these pathways cause birth defects, neurodegeneration, premature aging, and cancer. Recent technical advances in functional genomic approaches such as expression profiling, proteomics, and RNA interference (RNAi) technologies have rapidly expanded our knowledge of the proteins that work in these pathways. In this review, we examine the use of these high-throughput methodologies in higher eukaryotic organisms for the interrogation of genome maintenance activities. PMID- 21787123 TI - Thrombosis in children with acute lymphoblastic leukemia treated at a tertiary care center in Lebanon: revisiting the role of predictive models. AB - The incidence of symptomatic venous thromboembolism (VTE) in children receiving therapy for acute lymphoblastic leukemia (ALL) varies widely and is protocol dependent. The authors herein report the incidence and potential risk factors for VTE in children with ALL while being treated on a uniform protocol at a single tertiary care center in Lebanon. The authors also examine necessary modifications in a recently published model before it could predict VTE in their patients. PMID- 21787121 TI - Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy. AB - For several decades, lipid biologists have investigated how sphingolipids contribute to physiology, cell biology, and cell fate. Foremost among these discoveries is the finding that the bioactive sphingolipids ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have diverse and often opposing effects on cell fate. Interestingly, these bioactive sphingolipids can be interconverted by just a few enzymatic reactions. Therefore, much attention has been paid to the enzymes which govern these reactions with a disproportionate amount of focus on the enzyme sphingosine kinase 1 (SK1). Several studies have found that tissue expression of SK1 correlates with cancer stage, chemotherapy response, and tumor aggressiveness. In addition, overexpression of SK1 in multiple cancer cell lines increases their resistance to chemotherapy, promotes proliferation, allows for anchorage independent growth, and increases local angiogenesis. Inhibition of SK1 using either pharmacological inhibitors or by crossing SK1 null mice has shown promise in many xenograft models of cancer, as well as several genetic and chemically induced mouse models of carcinogenesis. Here, we review the majority of the evidence that suggests SK1 is a promising target for the prevention and/or treatment of various cancers. Also, we strongly advocate for further research into basic mechanisms of bioactive sphingolipid signaling, and an increased focus on the efficacy of SK inhibitors in non xenograft models of cancer progression. PMID- 21787124 TI - Not all hemangiomas are benign--epithelioid hemangioendothelioma: an aggressive vascular lesion in children. PMID- 21787125 TI - Seroconversion status after single dose and double doses of varicella vaccination in children with leukemia. AB - Although varicella is a benign self-limiting disease in healthy children, it can be fatal when it occurs in immunocompromised hosts. Despite that immunosuppressed children are suggested to require 2 doses of vaccine to achieve seroconversion, conflicting results are reported in the literature. The aim of this study was to investigate the seroconversion status and mean antibody titers at first year after single dose and double doses of varicella vaccination in acute lymphoblastic leukemia patients. Patients with leukemia in remission for at least 1 year who were seronegative for varicella-zoster virus immunoglobulin G (IgG) were vaccinated. Titers above the cutoff level (0.65) were accepted as seroconversion. Seventeen patients were vaccinated with single dose whereas 24 patients were vaccinated with double doses. Mean prevaccination antibody titers were 0.56 +/- 0.05 in patients with single dose and 0.51 +/- 0.08 in patients with double doses (P > .05, Student t test). The mean antibody titers at first year were 0.61 +/- 0.05 in patients with single-dose vaccination (P > .05, Wilcoxon signed-rank test) and 1.48 +/- 0.04 in patients with double doses (P < .001, Wilcoxon signed-rank test). Seroconversion after single-dose vaccination was achieved in 29% of patients (n = 5/17) and in 75% of patients with double doses (n = 18/24) at first year (P = .004, chi-square test). These results suggest that seroconversion after single-dose vaccination might not persist at first year in malignancy patients. Double doses should be applied in order to provide long-term seroconversion. PMID- 21787126 TI - Effect of transitioning from extended-release methylphenidate onto osmotic, controlled-release methylphenidate in children/adolescents with ADHD: results of a 3-month non-interventional study. AB - BACKGROUND: To explore the clinical outcomes of children/adolescents with ADHD who transitioned from extended-release methylphenidate (ER MPH, Medikinet Retard) to osmotic release oral system (OROS) MPH (Concerta). Medikinet Retard is a registered trade name of Medice, Bad Iserlohn, Germany. Concerta is a registered trade name of Janssen-Cilag GmbH, Neuss, Germany. METHODS: This prospective, non interventional study included patients aged 6 to 18 years with a confirmed diagnosis of ADHD who experienced insufficient clinical response and/or poor tolerability on ER MPH. Patients transitioned onto OROS MPH and were followed for 12 weeks. Symptoms, functional outcome, health-related quality of life, safety and tolerability were assessed. RESULTS: 180 patients were included in the intention-to-treat analysis. The mean ER MPH dose before switching was 28.2 mg/day; mean OROS MPH starting dose was 38.1 mg/day, increasing to 41.2 mg/day at the final visit. Mean treatment duration was 79.49 +/- 24.22 days (median 85; range 7-136). Several symptomatic and functional outcomes under OROS MPH treatment changed from baseline and included the Conners' Parent Rating Scale (CPRS; -11.7 +/- 11.3; p < 0.0001), C-GAS (12.3 +/- 15.2; p < 0.0001) and ILC-LQ0 28 (parents' rating 2.9 +/- 4.3 and patients' rating 2.8 +/- 3.8; both p < 0.0001). Improvements in social interactions, playing with other children, doing household chores, or school homework, going to bed, and behavior towards visitors/at visits were noted (p < 0.0001). Approximately 40% of patients reported better sleep quality and appetite (p < 0.0001), and 72.8% expressed satisfaction with OROS MPH therapy compared to previous ER MPH. OROS MPH was well tolerated; the most common AEs after switching, with an incidence >2% and possibly related to therapy, were involuntary muscle contractions (tics; 8.9%), insomnia (7.2%) and anorexia (5.0%). No relevant changes in body weight or vital signs were observed. Three patients reported four serious AEs, but none were considered related to OROS MPH. Limitations included those associated with the uncontrolled, open-label design, possible inclusion bias and non-validation of the CPRS in a German population. CONCLUSIONS: Transitioning onto OROS MPH improved functionality, symptom control and decreased burden of disease in patients with ADHD who had insufficient response to, and/or poor tolerability of ER MPH. Similarly, care givers benefited from patients' treatment and reported significant reduction in their burden of disease and improvement of their quality of life upon the child's transition onto OROS MPH. PMID- 21787127 TI - Long-term raloxifene for postmenopausal osteoporosis. AB - BACKGROUND: Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, raloxifene 60 mg/day (raloxifene) is intended to be used for long term treatment (treatment >3 years). SCOPE: We review available information concerning long-term use of raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE). FINDINGS: The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, raloxifene lowered markers of bone turnover to a premenopausal reference interval. Biopsies from three patients treated with raloxifene for 8 years showed normal bone and bone cells and double label in all specimens. Invasive breast cancer risk is a clinical consideration in postmenopausal women with osteoporosis, and invasive breast cancer risk reduction was the primary endpoint in CORE. In MORE and CORE, the benefit of raloxifene versus placebo in incidence of invasive breast cancer increased with greater duration of therapy up to 8 years. CONCLUSIONS: The long term use of raloxifene has been evaluated through changes in fracture risk reduction, BMD, markers of bone turnover, iliac crest bone biopsies, and invasive breast cancer risk reduction. PMID- 21787129 TI - The effect of intracytoplasmic sperm injection on the early hCG level in twin pregnancies. AB - OBJECTIVES: Since it has been suggested that intracytoplasmic sperm injection (ICSI) might impair the early development of embryos and twin pregnancies have physiologically different aspects from singleton pregnancies, we aimed to investigate the effect of ICSI on the human chrionic gonadotropin (hCG) levels in twin pregnancies. METHODS: A total of 220 clinical pregnancies which underwent controlled ovarian hyperstimulation and in vitro fertilization/ICSI were analyzed retrospectively. RESULTS: In twin pregnancies, the mean number of retrieved oocytes and estradiol (E2) levels on hCG day were significantly higher in ICSI group in spite of lower dose of gonadotropin. The hCG levels according to insemination method did not demonstrate any difference after adjustment for age of patient and partner, BMI, treatment regimens, serum E2 on hCG day, number of oocytes retrieved and date of sampling. CONCLUSIONS: The hCG values according to fertilization methods were not significantly different both in twin pregnancies with adjustment for confounders. PMID- 21787131 TI - Allergic contact dermatitis: effect of age. AB - The relationship between allergic contact dermatitis (ACD) and age has not been well documented. We searched for articles and textbooks based on age-ACD relationship and evaluated relevant data. The frequency of skin reactions to allergens increased with age in some studies, whereas others showed no definite effect. This might be caused by variations in study design, genetic factors or by external influences such as from different regions and environmental exposure. In general, investigators agree that elderly patients were more likely to have multiple contact allergies than younger persons. This may be because of the frequent use of topical medicaments and having a longer time for potential allergen exposure. However, a review of marketed transdermal products for ACD shows a very low incidence, and no age-related effects were reported. One exception to this low incidence of ACD is the transdermal product, Catapres TTS((r)) (clonidine), which has a reported incidence rate of ~16%. The generally low incidence of ACD in marketed products and the conflicting findings in the prevalence of specific age-related ACD indicate the need for further investigation as to the proclivity for developing new sensitivities with age. PMID- 21787134 TI - Differentiation capacity of human chondrocytes embedded in alginate matrix. AB - Healing capacity of cartilage is low. Thus, cartilage defects do not regenerate as hyaline but mostly as fibrous cartilage which is a major drawback since this tissue is not well adapted to the mechanical loading within the joint. During in vitro cultivation in monolayers, chondrocytes proliferate and de-differentiate to fibroblasts. In three-dimensional cell cultures, de-differentiated chondrocytes could re-differentiate toward the chondrogenic lineage and re-express the chondrogenic phenotype. The objective of this study was to characterize the mesenchymal stem cell (MSC) potential of human chondrocytes isolated from articular cartilage. Furthermore, the differentiation capacity of human chondrocytes in three-dimensional cell cultures was analyzed to target differentiation direction into hyaline cartilage. After isolation and cultivation of chondrogenic cells, the expression of the MSC-associated markers: cluster of differentiation (CD)166, CD44, CD105, and CD29 was performed by flow cytometry. The differentiation capacity of human chondrocytes was analyzed in alginate matrix cultured in Dulbecco?s modified eagle medium with (chondrogenic stimulation) and without (control) chondrogenic growth factors. Additionally, the expression of collagen type II, aggrecan, and glycosaminoglycans was determined. Cultivated chondrocytes showed an enhanced expression of the MSC-associated markers with increasing passages. After chondrogenic stimulation in alginate matrix, the chondrocytes revealed a significant increase of cell number compared with unstimulated cells. Further, a higher synthesis rate of glycosaminoglycans and a positive collagen type II and aggrecan immunostaining was detected in stimulated alginate beads. Human chondrocytes showed plasticity whilst cells were encapsulated in alginate and stimulated by growth factors. Stimulated cells demonstrated characteristics of chondrogenic re-differentiation due to collagen type II and aggrecan synthesis. PMID- 21787137 TI - Effect of dialect on identification and severity of speech impairment in Indigenous Australian children. AB - This study investigated the effect of dialectal difference on identification and rating of severity of speech impairment in children from Indigenous Australian backgrounds. The speech of 15 Indigenous Australian children identified by their parents/caregivers and teachers as having 'difficulty talking and making speech sounds' was assessed using the Diagnostic Evaluation of Articulation and Phonology. Fourteen children were identified with speech impairment on the Diagnostic Evaluation of Articulation and Phonology using Standard Australian English (AusE) as the target pronunciation; whereas 13 were identified using Australian Aboriginal English (AAE) as the target. There was a statistically significant decrease in seven children's severity classification and a statistically significant increase in all children's percentage of consonants, vowels and phonemes correct when comparing AAE with AusE. Features of AAE used by the children included /h/ insertion and deletion, primary stress on the first syllable and diphthongs alternating with short clear vowels. It is important that speech-language pathologists consider children's dialect as one component of culturally and linguistically appropriate services. PMID- 21787136 TI - Quantitative determination of morphological and territorial structures of articular cartilage from both perpendicular and parallel sections by polarized light microscopy. AB - In order to investigate the three-dimensional structure of the collagen fibrils in articular cartilage, full-thickness canine humeral cartilage was microtomed into perpendicular sections that included both the articular surface and the subchondral bone and approximately 100 successive parallel sections that were each 6 microm thick and from a different cartilage depth. Each section was imaged using polarized light microscopy with a 5x objective (2.0 microm pixel size), generating two quantitative images (angle and retardation). Selected sections were also imaged using a 40x objective (0.25 microm pixel size). At an increased depth from the articular surface, the angle and retardation results in the perpendicular sections showed the well-known 90 degrees change in fibril orientation between the surface and the deep cartilage. In contrast, the retardation results of the parallel sections decreased from the articular surface and remained approximately 0 through most of the radial zones, while the angle results of the parallel sections only changed about 30 degrees. The territorial matrix morphology surrounding 61 chondrocyte clusters was quantified by its length, aspect ratio, and orientation. The cellular clusters in the surface cartilage were ellipsoidal in both parallel and perpendicular sections. In the radial zone, the cellular clusters were oriented in vertical columns in the perpendicular sections and as circular groupings in the parallel sections. This orthogonal imaging technique could provide a better understanding of the three dimensional territorial and interterritorial fibrils in articular cartilage, the disturbance of which could signify the onset of degenerative cartilage diseases such as osteoarthritis. PMID- 21787135 TI - The effects of adipokines on cartilage and meniscus catabolism. AB - Obesity is one of the primary risk factors for osteoarthritis. Increased adiposity is associated not only with alterations in joint loading, but also with increased systemic and joint concentrations of adipose tissue-derived cytokines, or "adipokines", that promote a state of chronic, low-grade inflammation that may act in concert with other cytokines in the joint to increase joint degeneration. However, the direct effect of adipokines, such as leptin, visfatin, and interleukin-6 (IL-6), on joint tissues, such as articular cartilage and meniscus, are not fully understood. In this study, we examined the hypothesis that these adipokines act synergistically with interleukin-1 (IL-1) to increase catabolism and the production of proinflammatory mediators in cartilage and meniscus. Explants of porcine cartilage and meniscus were treated with physiologically relevant concentrations of leptin, IL-6, or visfatin, alone or in combination with IL-1. Visfatin and IL-1 promoted the catabolic degradation of both cartilage and meniscus, as evidenced by increased metalloproteinase activity, nitric oxide production, and proteoglycan release. However, leptin or IL-6 at physiologic concentrations had no effect on the breakdown of these tissues. These findings suggest that the effects of obesity-induced osteoarthritis may not be through a direct effect of leptin or IL-6 on cartilaginous tissues, but support a potential role for increased visfatin levels in this regard. These data provide an important first step in understanding the role of adipokines in regulating cartilage and meniscus metabolism; however, these adipokines may have different effects in the context of the whole joint and must be evaluated further. PMID- 21787128 TI - Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. PMID- 21787138 TI - Inflectional morphology in cri du chat syndrome--a case study. AB - This study examined morphological skills in a girl with cri du chat syndrome, addressing three questions: (1) To what extent does the subject inflect words? (2) To what extent are words inflected correctly? (3) To what extent do the inflected words reflect productive morphological rules, and to what extent can they be considered to be rote-learned? The study draws on two sources of data: a corpus of spontaneous utterances collected when the subject was 14 years old and her performance on a past tense elicitation test at 11;10 and 16;5. It was found that most inflectional forms in the nominal, verbal, pronominal and adjectival paradigms of the target language were attested in the corpus. These forms were in all but a few instances inflected correctly. The most frequent inflection errors were infinitive for present, past or past participle in verbs and wrong gender in determiners. Furthermore, performance on the elicitation test indicated some knowledge of productive inflectional rules of the target language, despite relatively poor phonetic, phonological and syntactic skills. PMID- 21787139 TI - Testing the language of German cerebral palsy patients with right hemispheric language organization after early left hemispheric damage. AB - Language functions are generally represented in the left cerebral hemisphere. After early (prenatally acquired or perinatally acquired) left hemispheric brain damage language functions may be salvaged by reorganization into the right hemisphere. This is different from brain lesions acquired in adulthood which normally lead to aphasia. Right hemispheric reorganized language (RL) is not associated with obvious language deficits. In this pilot study we compared a group of German-speaking patients with left hemispheric brain damage and RL with a group of matched healthy controls. The novel combination of reliable language lateralization as assessed by neuroimaging (functional magnetic resonance imaging) and specific linguistic tasks revealed significant differences between patients with RL and healthy controls in both language comprehension and production. Our results provide evidence for the hypothesis that RL is significantly different from normal left hemispheric language. This knowledge can be used to improve counselling of parents and to develop specific therapeutic approaches. PMID- 21787143 TI - Consonant inventories in the spontaneous speech of young children: a bootstrapping procedure. AB - Consonant inventories are commonly drawn to assess the phonological acquisition of toddlers. However, the spontaneous speech data that are analysed often vary substantially in size and composition. Consequently, comparisons between children and across studies are fundamentally hampered. This study aims to examine the effect of sample size on the resulting consonant inventories. A spontaneous speech corpus of 30 Dutch-speaking 2-year-olds was used. The results indicate that in order to construct and compare inventories reliably, they should be drawn from speech samples that are equally large. A new consonant inventory procedure is introduced. The implementation of this procedure demonstrates considerably less variation in inventory size across children and word positions than reported previously. This finding has important implications for clinical studies that constructed and compared inventories of typically and atypically developing children without normalizing the sample size. PMID- 21787142 TI - Voice onset time of voiceless bilabial and velar stops in 3-year-old bilingual children and their age-matched monolingual peers. AB - This study investigates aspects of voice onset time (VOT) of voiceless bilabial and velar stops in monolingual and bilingual children. VOT poses a special challenge for bilingual Spanish- and English-speaking children because although this VOT distinction exists in both languages, the values differ for the same contrast across Spanish and English. Twenty-four 3-year-olds participated in this study (8 bilingual Spanish-English, 8 monolingual Spanish and 8 monolingual English). The VOT productions of /p/ and /k/ in syllable-initial stressed singleton position were compared across participants. Non-parametric statistical analyses were performed to examine differences (1) between monolinguals and bilinguals and (2) between English and Spanish. The main findings of the study were that monolingual and bilingual children generally differed on VOT in English, but not in Spanish. No statistically significant differences were found between the Spanish and the English VOT of the bilingual children, but the VOT values did differ significantly for monolingual Spanish- versus monolingual English-speaking participants. Our findings were interpreted in terms of Flege's Speech Learning Model, finding possible evidence for equivalence classification. PMID- 21787144 TI - The birth and growth of a scientific journal. AB - Clinical Linguistics & Phonetics (CLP) and its namesake field have accomplished a great deal in the last quarter of a century. The success of the journal parallels the growth and vitality of the field it represents. The markers of journal achievement are several, including increased number of journal pages published annually; greater diversity of topics related to the core mission of the journal; expanding cross-language coverage; and healthy interactions among editors, reviewers and contributors; and - for better or worse - journal impact factors. A journal is in a competitive dynamic with other journals that share its general domain of scholarship, which is a major reason why an apparent imbalance may emerge in the topic content of any particular journal. The content of a journal is determined by the nature and number of submitted manuscripts. As far as linguistic content goes, CLP's centre of gravity appears to have been mostly in phonology and phonetics, but certainly not to the exclusion of syntax, semantics and pragmatics. The clinical scope is broad, both in terms of concepts and types of disorder. CLP has secured its place among journals in the field, and it is an outlet of choice for many researchers throughout the world. PMID- 21787145 TI - Clinical linguistics: its past, present and future. AB - Historiography is a growing area of research within the discipline of linguistics, but so far the subfield of clinical linguistics has received virtually no systematic attention. This article attempts to rectify this by tracing the development of the discipline from its pre-scientific days up to the present time. As part of this, I include the results of a survey of articles published in Clinical Linguistics & Phonetics between 1987 and 2008 which shows, for example, a consistent primary focus on phonetics and phonology at the expense of grammar, semantics and pragmatics. I also trace the gradual broadening of the discipline from its roots in structural linguistics to its current reciprocal relationship with speech and language pathology and a range of other academic disciplines. Finally, I consider the scope of clinical linguistic research in 2011 and assess how the discipline seems likely develop in the future. PMID- 21787146 TI - An ultrasonographic investigation of cleft-type compensatory articulations of voiceless velar stops. AB - Ultrasound imaging was used to investigate the articulation of the voiceless velar stop [k] in five speakers with compensatory articulation related to cleft palate. The perceptual evaluation of the acoustic realization and the visual assessment of the tongue movement for the target sound were made by three examiners. The analysis revealed a variety of different compensatory strategies that included glottal stops, pharyngeal stops, midpalatal stops and glottal and velar co-productions. One patient produced palatal click sounds together with a midpalatal stop. The ultrasound imaging also revealed covert articulatory movements that would have been missed in a purely perceptual analysis. The analysis of the ultrasound images points to subphonemic aspects of cleft-type compensatory articulation that are important to understand for speech therapy. PMID- 21787147 TI - On the unity of children's phonological error patterns: distinguishing symptoms from the problem. AB - This article compares the claims of rule- and constraint-based accounts of three seemingly distinct error patterns, namely, Deaffrication, Consonant Harmony and Assibilation, in the sound system of a child with a phonological delay. It is argued that these error patterns are not separate problems, but rather are symptoms of a larger conspiracy to avoid word-initial coronal stops. The clinical implications of these findings are also considered. PMID- 21787148 TI - Transcribing speech: practicalities, philosophies and prophesies. AB - This article outlines the main practical and philosophical developments which have contributed to current approaches to phonetic transcription. Particular contributions from scholars in the field are highlighted as seminal in shaping transcription work. Consideration is also given to the ways in which insights from clinical transcription impact upon the analysis of non-clinical data. Finally, the trends which look set to emerge in future transcription practice and research are speculated upon. PMID- 21787149 TI - Effect size in clinical phonology. AB - The purpose of this article is to motivate the use of effect size (ES) for single subject research in clinical phonology, with an eye towards meta-analyses of treatment effects for children with phonological disorders. Standard mean difference (SMD) is introduced and illustrated as one ES well suited to the multiple baseline (MBL) design and evaluation of generalization learning, both of which are key to experimental studies in clinical phonology. PMID- 21787150 TI - IPD3 controls the formation of nitrogen-fixing symbiosomes in pea and Medicago Spp. AB - A successful nitrogen-fixing symbiosis requires the accommodation of rhizobial bacteria as new organelle-like structures, called symbiosomes, inside the cells of their legume hosts. Two legume mutants that are most strongly impaired in their ability to form symbiosomes are sym1/TE7 in Medicago truncatula and sym33 in Pisum sativum. We have cloned both MtSYM1 and PsSYM33 and show that both encode the recently identified interacting protein of DMI3 (IPD3), an ortholog of Lotus japonicus (Lotus) CYCLOPS. IPD3 and CYCLOPS were shown to interact with DMI3/CCaMK, which encodes a calcium- and calmodulin-dependent kinase that is an essential component of the common symbiotic signaling pathway for both rhizobial and mycorrhizal symbioses. Our data reveal a novel, key role for IPD3 in symbiosome formation and development. We show that MtIPD3 participates in but is not essential for infection thread formation and that MtIPD3 also affects DMI3 induced spontaneous nodule formation upstream of cytokinin signaling. Further, MtIPD3 appears to be required for the expression of a nodule-specific remorin, which controls proper infection thread growth and is essential for symbiosome formation. PMID- 21787151 TI - Schwann cell proliferation and macrophage infiltration are evident at day 14 after painful cervical nerve root compression in the rat. AB - Although it is known that different types of nerve root insults can produce radicular pain, it is not known whether the neuronal and Schwann cell pathologies in the nerve root vary between inflammation-induced nerve root injury and traumatic compression. This study examined the extent of Wallerian degeneration and associated cellular repair processes in the nerve root in the context of mechanical hyperalgesia resulting from different modes of painful nerve root injury. The C7 dorsal nerve root underwent a transient 10 gram-force compression (10 g), inflammation-induced irritation by chromic gut exposure (Cg), or a combination of those stimuli (10 g+Cg). Fourteen days after injury when hyperalgesia remained, immunohistochemical analysis revealed upregulation of substance P, robust macrophage infiltration, myelin degeneration and debris removal, and a significant increase in the number of myelinating Schwann cells (Krox20-positive) in the compressed roots (10 g, 10 g+Cg). Cg alone also produced hyperalgesia, despite being associated with intact myelin. Unilateral exposure to chromic material induced bilateral increases in macrophages and Krox20-positive Schwann cells in the nerve roots, and substance P expression in the dorsal root ganglion (DRG) neurons. Results suggest that despite similar sensitivity, the extent of infiltrating macrophages and repopulated Schwann cells varies for pain from mechanical and/or chemical nerve root injury. Although these different cellular mechanisms may explain pain, they may also only reflect varying injury etiologies. PMID- 21787152 TI - Renoprotective effect of grape seed extract against oxidative stress induced by gentamicin and hypercholesterolemia in rats. AB - RATIONALE: Kidneys are dynamic organs and represent one of the major systems maintaining the body homeostasis; they are affected by many chemicals and drugs. Grape seed extract (GSE) has been targeted to prevent drug-induced renal toxicity. OBJECTIVES: This study investigates the possible renoprotective effect of GSE against oxidative stress, renal impairment, and hypercholesterolemia (HC) induced by gentamicin (GM) and cholesterol-enriched diet. Seventy adult male Wistar rats (160 +/- 10 g) were divided into seven groups: (1) served as control, (2) GSE, (3) GM, (4) GSE + GM, (5) hypercholesterolemic (HC) group, (6) GM + HC group, and (7) GM + HC + GSE. Kidney functions, inflammatory mediators, cytokines, lipid profile, nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and oxidative and antioxidative stress parameters were assessed in all groups. MAIN FINDINGS: GM induced renal dysfunction, which was exacerbated by the presence of HC as confirmed by laboratory determinations. Administration of GSE attenuated the renal toxicity evidenced in significant reduction in elevated kidney function, inflammatory cytokines as well as lipid profile, NO, cGMP, enzymatic, and nonenzymatic antioxidants. CONCLUSION: Administration of GSE simultaneously with GM attenuated oxidative stress, diminished renal toxicity, and improved lipid profile induced by GM and HC. PMID- 21787153 TI - Results of 4-year analysis of conversion from calcineurin inhibitors to mTOR inhibitors in renal transplant patients: single-center experience. AB - In this retrospective study, 83 patients were accepted. Mammalian target of rapamycin (mTOR) group consisting of 37 patients were converted from calcineurin inhibitors (CNI), and the control group included 46 patients (initially CNI receiving patients). As a control-match of each mTOR inhibitor patient, the succeeding patient with transplantation who continued CNI therapy was chosen. All patients received CNI, MMF, and prednisolone as an immunosuppressive therapy initially. In comparison of two groups, there was no significant difference between sex, donor organ source, donor organ ischemia time, or mismatches. However, mean age between groups was significantly different (mTOR group: 48.3 +/ 12, CNI group: 38.6 +/- 11, p < 0.001). Decision of conversion to mTOR inhibitors in 30 patients was made by biopsy. The reasons for conversion were determined as CNI nephrotoxicity in 15 patients, chronic allograft nephropathy in 15 patients, malignancy in 6 patients, and renal artery stenosis in 1 patient. Basal glomerular filtration rates (GFRs) were markedly lower in mTOR group than in CNI group (38.8 mL/min vs. 72.7 mL/min). At the end of 48-month follow-ups, GFR increased from 38 mL/min to 54 mL/min in mTOR group; however, it decreased to 53 mL/min from 72 mL/min in CNI group. There was no difference left between the two groups in GFR after 4-year follow-up. Hyperlipidemia was higher in mTOR group. Acute rejection rates were similar. Cytomegalovirus (CMV) disease was more prevalent in CNI group. Graft failure developed due to secondary reasons, causing mortality in both groups. We suggest that conversion to mTOR inhibitors maintains and improves graft functions well. PMID- 21787154 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Improving access to kidney transplant information has increased preemptive living kidney donation. AB - Transplantation provides the best outcomes and quality of life for people with end-stage renal disease and therefore offers the optimum treatment of choice. Preemptive living donor (LD) transplantation is an increasingly preferable alternative to dialysis as transplantation outcomes indicate lower morbidity and mortality rates and greater graft and patient survival rates compared to those who are transplanted after dialysis has commenced. Despite nursing and medical teams giving information to patients regarding transplantation and living donation, the number of people coming forward for preemptive transplant work-up remained limited. Changing the format, environment, and quality of information given to patients and families seemed necessary in order to increase the number of preemptive transplants. Our data show that we have improved the access to the information seminars with attendance rising from 5 to 15 attendees per seminar (3 per year) in 2005 to average 65 attendees per seminar (6 per year) in 2010. By expanding the access to information for patients, their families and friends, living donation has increased with a growth in the proportion of preemptive LD transplants from 28% (23/81) in 2006 to 44% in 2010 (29/66; p = 0.05). We can conclude that expanding the pool accessing information has increased the number of preemptive (LD) transplants in our center. PMID- 21787155 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Adolescents with chronic kidney disease and their need for online peer mentoring: a qualitative investigation of social support and healthcare transition. AB - Adolescents with chronic kidney disease (CKD) tend to be isolated from peers who also have CKD, develop non-adherent behavior with treatment recommendations, and consequently are at higher risk for poor health outcomes such as transplant rejection. At the same time, patients in this age group tend to be technologically savvy and well-versed in using Internet-based communication tools to connect with other people. In this study, we conducted semi-structured interviews among adolescents with CKD to assess their information needs and their interest in using a CKD-oriented peer-mentoring website that we are developing, kTalk.org. We interviewed 17 adolescents with CKD, ages 14-18 years old, to learn about (1) any concerns regarding transition from pediatric to adult care teams; and (2) their interest in using the Internet as a source for disease-related information and as a social networking tool for finding and interacting with their peers. The interviews were digitally recorded, transcribed, and qualitatively analyzed. Results showed that (1) the adolescent participants are commonly concerned about transitioning to an adult clinic; (2) they are isolated from peers with the same medical condition who are of similar age; (3) they are frequent Facebook users and are highly interested in exploring the possibility of using an online community website, such as kTalk.org, to discover and communicate with peers and peer mentors; and (4) there exist divergent opinions regarding if an online community of adolescent CKD patients should be open to the public. PMID- 21787156 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Do medical trainees receive adequate training in the management of acute kidney injury? AB - There has been increased interest in acute kidney injury (AKI) over the past decade following the recognition of the association of relatively small rises in serum creatinine with worse patient outcomes. This association has resulted in newly proposed definitions in AKI based on changes in serum creatinine. In 2009, the National Confidential Enquiry into Patient Outcomes and Death Adding Insult to Injury AKI study reported that only 50% of patients who died with a diagnosis of AKI received good care. The study identified multiple deficiencies and made a number of recommendations which included improving the training of undergraduate and postgraduate trainees in the management of AKI. The aim of the evaluation was to try and identify the perception of medical trainees in Leeds Teaching Hospitals of the training they had received on AKI. A simple questionnaire was used and captured the views of 73 trainees (including 13 final-year medical students). The evaluation indicated that the majority of trainees were unaware of newly proposed definitions of AKI, and many trainees felt that the training they had received in AKI was inadequate for their needs. Following this evaluation, we have made a number of changes to the training that is delivered to both undergraduate and postgraduate trainees in Leeds on the management of AKI. PMID- 21787157 TI - Elective and emergency surgery in chronic hemodialysis patients. AB - PURPOSE: Aim of this study was to report our experience in elective and emergency surgery on chronic hemodialysis (CH) patients for end-stage renal disease (ESRD). METHODS: All patients on CH for ESRD who underwent various surgical procedures in our unit within the past 9-year period (2001-2010) were included in this study. These patients were divided into two groups according to the type of surgery performed: elective or emergency. Demographic data, indications for surgery, primary causes of ESRD, surgical procedures, postoperative complications, and mortality rates were studied. RESULTS: Of 130 patients, 121 underwent elective surgery while 10 were addressed for emergency operation. In the elective surgery group, the most common diseases were secondary hyperparathyroidism, kidney diseases, cholelithiasis, and diabetic foot gangrene. Complications occurred in nine patients (morbidity rate, 7%) and only one patient died (mortality rate, 0.8%). In the emergency surgery group, the most common diseases were diabetic foot gangrene and obstructed sigmoid colon cancer. In this group, complications occurred in seven patients (total morbidity rate, 70%) and two patients died (mortality rate, 20%). CONCLUSIONS: Elective surgery in patients on CH for ESRD can be performed with acceptable surgical risks provided careful preoperative preparation, intraoperative, and postoperative precautions are taken. PMID- 21787158 TI - Coenzyme Q10 and its relation with oxidant and antioxidant system markers in patients with end-stage renal disease. AB - RATIONALE AND OBJECTIVES: Oxidative stress is increased in chronic kidney disease (CKD) patients and end-stage renal disease (ESRD) patients undergoing dialysis treatment. Coenzyme Q(10) (CoQ(10)) is a ubiquitous and strong antioxidant. Role of CoQ(10) is not fully evaluated in renal patients. We aimed to investigate the relationship of CoQ(10) with oxidant and antioxidant system markers in patients with renal disease. MATERIAL AND METHODS: Forty patients with CKD (stages 3-5) who were managed conservatively without dialysis treatment, 40 hemodialysis, and 60 chronic ambulatory peritoneal dialysis (CAPD) patients were included in the study. Biochemical and whole blood analyses were done using hospital auto analyzers from stored samples. Serum CoQ(10), malondialdehyde (MDA), superoxide dismutase (SOD), and antioxidant activity (AOA) levels were determined. MAIN FINDINGS: There was no difference among the groups in terms of serum CoQ(10) levels. However, other components of antioxidant system, namely, SOD and AOA were significantly higher in CAPD patients when compared to CKD patients. MDA levels were not significantly different among the groups. PRINCIPAL CONCLUSION(S): The results of this study showed no difference among CKD, CAPD, and hemodialysis patients in terms of serum CoQ(10) levels. PMID- 21787159 TI - Differences in bio-incompatibility among four biocompatible dialyzer membranes using in maintenance hemodialysis patients. AB - BACKGROUND: Following the introduction of modified cellulosic and then synthetic membrane dialyzers, it was realized that the dialyzer bio-incompatibility depends on the membrane composition. We designed a prospective, randomized, cohort study of 6 months to determine several parameters of biocompatibility in maintenance hemodialysis (MHD) patients treated with four different membrane dialyzers. METHODS: There were 60 MHD patients enrolled in the study. In baseline, synthetic low-flux dialyzer, polysulfone (PS) membrane was used in all patients for at least 3 months. Then the patients were randomly divided into three groups according to different dialyzer membranes. Synthetic high-flux dialyzer group, polyethersulfone membrane, cellulose triacetate (CTA) high-flux membrane, and synthetic low-flux dialyzer, polymethylmethacrylate (PMMA) membrane were used in 6 months. A new dialyzer was used for each study treatment, and there was no dialyzer reuse. The biocompatibility markers and solutes removal markers were detected repeatedly at different time points. RESULTS: The blood levels of highly sensitive C reactive protein, interleukin (IL)-1beta, and interleukin (IL)-13 showed no difference among different groups at al time points. However, the blood complement levels and white blood cell counts were significantly different among three groups. When the dialyzers changed from PS to PMMA membrane, C3a levels and white blood cell counts changed significantly (p < 0.05). Moreover, the changes of C5a levels were significantly different between group CTA and group PMMA in month 3 (p < 0.05). CONCLUSION: There were much more differences on bio incompatibility among different dialyzer membranes. PMID- 21787160 TI - Impact of immunofluorescence on the histological pattern of pediatric kidney biopsies from northern Pakistan. AB - Kidney biopsy is an investigation for diagnosis and prognosis of a variety of nephritides. It also influences therapeutic options. Immunofluorescence (IMF) greatly adds in identifying the pathologies which may not be obvious on light microscopy (L/M), such as IgM, IgA nephropathy, pauci-immune glomerulonephritis, and anti-glomerular basement membrane disease. We present here data of 170 pediatric kidney biopsies from July 2005 to December 2009 from Department of Nephrology and Hypertension, Lady Reading Hospital, Peshawar, Pakistan. The study was undertaken to see whether IMF would alter the histological pattern of pediatric kidney biopsies and to compare these data with an earlier data from our department of 415 pediatric kidney biopsies done over 7-year period from 1998 to 2005, which were analyzed with L/M alone. Out of 170 kidney biopsies using L/M and IMF, IgM turns out to be most common pattern (20%), followed by minimal change disease (MCD) (17.05%), focal and segmental glomerulosclerosis (FSGS) (15.88%), chronic sclerosing glomerulonephritis (Chr. sclerosing GN) (12.35%), mesangio proliferative glomerulonephritis (MPGN) (7.65%), mesangio capillary glomerulonephritis (MCGN) (6.47%), membranous glomerulonephritis (Mem. GN) (5.29%), IgA nephropathy (5.29%), cresentic glomerulonephritis (Cres. GN) (3.53%), lupus nephritis (2.96%), and others (3.53%). Comparing these results of 170 cases with 415 renal biopsies without IMF, IgM dominated the histological pattern in IMF group whereas MCD followed by FSGS and MPGN were prominent in group without IMF. Therefore, variation in the overall histological pattern with IMF technique proved statistically significant (p < 0.0001). Addition of IMF has altered the frequency of MCD, a change from 24% (100/415) to 17% (29/170), FSGS from 18.3% (76/415) to 15.88% (27/170), and MPGN from 17.35% (72/415) to 7.65% (13/170). PMID- 21787161 TI - Does early initiation of continuous renal replacement therapy affect outcome: experience in a tertiary care center. AB - BACKGROUND: Acute kidney injury (AKI) requiring dialysis commonly occurs in critically ill patients and is associated with high mortality. Factors impacting outcomes of individuals with AKI who underwent continuous renal replacement therapy (CRRT), including early versus late initiation and duration of CRRT, were examined. METHODS: Survival and recovery of renal function for patients with AKI in the intensive care unit were retrospectively examined over a 7-year period. Factors associated with mortality and renal recovery were analyzed based on severity of illness as defined by Cleveland Clinic Foundation (CCF) score. Univariate and multivariate logistic regression analysis with backward elimination was performed to determine the most significant risk factors. RESULTS: Of patients who underwent CRRT, 230/330 met inclusion criteria. During index admission 112/230 (48.7%) patients died. Median survival was 15.5 days [95% confidence interval (12.0, 18.0)]. Among survivors, renal recovery occurred in 84/118 (71.2%). Renal recovery overall was observed in 90/230 subjects (39.13%). A higher baseline CCF score correlated with higher mortality and lower probability of renal recovery. Patients initiated on CRRT > 6 days after AKI diagnosis had significantly higher mortality compared with those initiated earlier (odds ratio = 11.66, p = 0.0305). Patients receiving CRRT >10 days had a higher mortality rate compared with those with shorter exposure (71.3% vs. 45.5%, respectively, p = 0.012). CONCLUSIONS: CRRT remains an important dialysis modality in hemodynamically unstable patients with AKI. Mortality in these patients continues to be high. Renal recovery is high in survivors. Delay in initiation and length of CRRT exposure may portend poorer prognosis. PMID- 21787162 TI - Palliative medicine referral in patients undergoing continuous renal replacement therapy for acute kidney injury. AB - BACKGROUND: Referral patterns for palliative medicine consultation (PMC) by intensivists for patients requiring continuous renal replacement therapy (CRRT) have not been studied. METHODS: We retrospectively analyzed clinical data on patients who received CRRT in a tertiary referral center between 1999 and 2006 to determine timeliness and effectiveness of PMC referrals and mortality rate as a surrogate for safety among patients receiving CRRT for acute kidney injury. RESULTS: Over one-fifth (21.1%) of the 230 CRRT patients studied were referred for PMC (n = 55). PMC was requested on average after median of 15 hospital and 13 intensive care unit (ICU) days. Multivariate regression analysis revealed no association between mortality risk and PMC. Total hospital length of stay for patients who died after PMC referral was 18.5 (95% CI = 15-25) days compared with 12.5 days (95% CI = 9-17) for patients who died without PMC referral. ICU care for patients who died and received PMC was longer than for patients with no PMC [11.5 (95% CI = 9-15) days vs. 7.0 (95% CI = 6-9) days, p < 0.01]. CRRT duration was longer for patients who died and received PMC referral than for those without PMC [5.5 (95% CI = 4-8) vs. 3.0 (95% CI = 3-4) days; p < 0.01]. CONCLUSIONS: PMC was safe, but referrals were delayed and ineffective in optimizing the utilization of intensive care in patients receiving CRRT. A proactive, "triggered" referral process will likely be necessary to improve timeliness of PMC and reduce duration of non-beneficial life-sustaining therapies. PMID- 21787163 TI - Garlic extract ameliorates renal and cardiopulmonary injury in the rats with chronic renal failure. AB - Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species and cytokine release. We aimed to investigate the possible protective and antioxidant effects of aqueous garlic extract (AGE) in a rat model of CRF. Male Sprague-Dawley rats were randomly assigned as either CRF group with 5/6 reduction in the renal mass or sham operated control group. CRF group received either saline or AGE (250 mg/kg/day/1 mL) orally for 3 weeks. At the end of the 3 weeks, rats were decapitated and trunk blood was collected. Creatinine, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) activity, and TNF-alpha and IL-1beta levels were measured in the serum samples, while malondialdehyde (MDA), glutathione (GSH) levels, and myeloperoxidase (MPO) activity were determined in the kidney, lung, and heart samples. CRF caused significant decreases in tissue GSH, which were accompanied with significant increases in MDA levels and MPO activities, while the circulating levels of the LDH activity, creatinine, BUN, TNF-alpha, and IL-1beta were elevated. AGE treatment alleviated CRF-induced oxidative changes in the injured tissues, while CRF-induced elevations in the blood levels of the pro inflammatory cytokines and LDH were reduced. In conclusion, CRF-induced oxidative tissue injury occurs via the activation of pro-inflammatory mediators and by neutrophil infiltration into tissues and that the protective effects of garlic on CRF-induced injury can be attributed to its ability to inhibit neutrophil infiltration and pro-inflammatory mediators. These findings suggest that garlic, as a supplementary to diet, may have a potential therapeutic use in delimitating the systemic oxidant effects of CRF on remote organs. PMID- 21787164 TI - Insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme gene in steroid-resistant nephrotic syndrome for children: a genetic association study and meta-analysis. AB - An assessment of the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with steroid-resistant nephrotic syndrome (SRNS) risk in children is still controversial. A meta-analysis was performed to evaluate the relation between ACE gene polymorphisms and SRNS susceptibility. The relevant studies were screened from electronic database and eligible investigations were synthesized using meta-analysis methods. Seven investigations were identified for the analysis of association between ACE I/D gene polymorphism and SRNS risk in children, including five in Asians, one in Caucasians, and one in Africans. There was not a markedly positive association between D allele or DD genotype and SRNS susceptibility in Asians (OR = 1.60, p = 0.26; OR = 1.90, p = 0.38) and for Caucasian population (OR = 0.92, p = 0.86; OR = 0.27, p = 0.22). However, an association of D allele with SRNS susceptibility was observed (OR = 4.67, p = 0.003) in Africans, but not for DD genotype (OR = 6.00, p = 0.05). Interestingly, II genotype seemed to play a positive role against SRNS onset for Asians and African children (OR = 0.51, p = 0.02; OR = 0.07, p = 0.02), but not for Caucasians (OR = 0.33, p = 0.30). In conclusion, our results indicate that D allele or DD homozygous might not be a significant genetic molecular marker for the development of SRNS in Asians and Caucasian children. However, D allele seemed be associated with SRNS risk for Africans but DD genotype did not. PMID- 21787165 TI - Chronic renal disorder after a nuclear crisis: a brief review. AB - A present global public health concern is the adverse effect from nuclear leakage crisis in Japan. Based on the previous data on a previous famous nuclear crisis, Chernobyl crisis, the chronic renal disorder in affected population is an interesting topic in nephrology. Here, the author briefly reviews and discusses on the chronic renal disorder and nuclear denotation. Disturbance to the renal cell, alteration of renal function, and disorder of nephrological system in offsprings of exposed subjects are the three main focused topics. PMID- 21787166 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. E-pediatric nephrology in India. AB - New tools such as blogs, social media networks, and audio and video podcasts in Web 2.0 have allowed better exchange of information among physicians across distances. The medical world has started embracing this new technology as it emerges. Wikis, blogs, and podcasts carry the potential of complementing, improving, and adding new collaborative dimensions to the health education currently in existence. There is a need for physicians in all specialities to adopt the new Web 2.0 technologies. This review features the innovative use of internet in disseminating renal education in Pediatric Nephrology in India. PMID- 21787168 TI - Simvastatin administration ameliorates neurobehavioral consequences of subarachnoid hemorrhage in the rat. AB - In the present study we assessed the neuroprotective effects of simvastatin in a rodent model of experimental subarachnoid hemorrhage (SAH). Based on recent data showing the role of statins not only in lowering the level of cholesterol but also in preventing cardiac and cerebrovascular damage in risk population, and in decreasing vasospasm and delayed ischemia after aneurysmal SAH, we investigated the neuroprotective effects of intraperitoneal administration of simvastatin (40 mg/kg/day for 5 consecutive days) in Sprague-Dawley rats 30 min after SAH, as compared to vehicle-treated SAH animals. We employed a battery of well characterized tests to assess memory, learning, motivational, balance, and behavioral performances. On days 1-4 post-SAH, simvastatin-treated rats have significantly improved beam balance scores (days 1-2, p<0.001; days 3-4, p<0.01), beam balance times (days 1-4, p<0.01), and latency to traverse the beam (days 1 3, p<0.01; day 2, p<0.005; day 4, p<0.0001) in comparison with control groups that, conversely, were not protected against SAH-related body weight changes. These results demonstrate that the administration of simvastatin may represent a beneficial therapeutic approach able to reduce post-SAH cognitive dysfunction. PMID- 21787169 TI - MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort. AB - The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07 2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted. PMID- 21787170 TI - CYP2D plays a major role in berberine metabolism in liver of mice and humans. AB - Berberine is a widely used plant extract for gastrointestinal infections, and is reported to have potential benefits in treatment for diabetes and hypercholesterolemia. It has been suggested that interactions between berberine containing products and cytochromes P450 (CYPs) exist, but little is known about which CYPs mediate the metabolism of berberine in vivo. In this study, berberine metabolites in urine and feces of mice were analyzed, and the role that CYPs play in producing these metabolites were characterized in liver microsomes from mice (MLM) and humans (HLM), as well as recombinant human CYPs. Eleven berberine metabolites were identified in mice, including 5 unconjugated metabolites, mainly in feces, and 6 glucuronide and sulfate conjugates, predominantly in urine. Three novel berberine metabolites were observed. Three unconjugated metabolites of berberine were produced by MLM, HLM, and recombinant human CYPs. CYP2D6 was the primary recombinant human CYP producing these metabolites, followed by CYP1A2, 3A4, 2E1 and CYP2C19. The metabolism of berberine in MLM and HLM was decreased the most by a CYP2D inhibitor, and moderately by inhibitors of CYP1A and 3A. CYP2D plays a major role in berberine biotransformation, therefore, CYP2D6 pharmacogenetics and potential drug-drug interactions should be considered when berberine is used. PMID- 21787167 TI - Emerging imaging tools for use with traumatic brain injury research. AB - This article identifies emerging neuroimaging measures considered by the inter agency Pediatric Traumatic Brain Injury (TBI) Neuroimaging Workgroup. This article attempts to address some of the potential uses of more advanced forms of imaging in TBI as well as highlight some of the current considerations and unresolved challenges of using them. We summarize emerging elements likely to gain more widespread use in the coming years, because of 1) their utility in diagnosis, prognosis, and understanding the natural course of degeneration or recovery following TBI, and potential for evaluating treatment strategies; 2) the ability of many centers to acquire these data with scanners and equipment that are readily available in existing clinical and research settings; and 3) advances in software that provide more automated, readily available, and cost-effective analysis methods for large scale data image analysis. These include multi-slice CT, volumetric MRI analysis, susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), arterial spin tag labeling (ASL), functional MRI (fMRI), including resting state and connectivity MRI, MR spectroscopy (MRS), and hyperpolarization scanning. However, we also include brief introductions to other specialized forms of advanced imaging that currently do require specialized equipment, for example, single photon emission computed tomography (SPECT), positron emission tomography (PET), encephalography (EEG), and magnetoencephalography (MEG)/magnetic source imaging (MSI). Finally, we identify some of the challenges that users of the emerging imaging CDEs may wish to consider, including quality control, performing multi-site and longitudinal imaging studies, and MR scanning in infants and children. PMID- 21787172 TI - Engineering a high throughput axon injury system. AB - Several key biological mechanisms of traumatic injury to axons have been elucidated using in vitro stretch injury models. These models, however, are based on the experimentation of single cultures keeping productivity slow. Indeed, low yield has hindered important and well-founded investigations requiring high throughput methods such as proteomic analyses. To meet this need, we engineered a multi-well high throughput injury device to accelerate and accommodate the next generation of traumatic brain injury research. This modular system stretch injures neuronal cultures in either a 24-well culture plate format or 6 individual wells simultaneously. Custom software control allows the user to accurately program the pressure pulse parameters to achieve the desired substrate deformation and injury parameters. Analysis of the pressure waveforms showed that peak pressure was linearly related to input pressure and valve open times and that the 6- and 24-well modules displayed rise times, peak pressures, and decays with extremely small standard deviations. Data also confirmed that the pressure pulse was distributed evenly throughout the pressure chambers and therefore to each injury well. Importantly, the relationship between substrate deformation and applied pressure was consistent among the multiple wells and displayed a predictable linear behavior in each module. These data confirm that this multi well system performs as well as currently used stretch injury devices and can undertake high throughput studies that are needed across the field of neurotrauma research. PMID- 21787171 TI - Comparison of acute and chronic traumatic brain injury using semi-automatic multimodal segmentation of MR volumes. AB - Although neuroimaging is essential for prompt and proper management of traumatic brain injury (TBI), there is a regrettable and acute lack of robust methods for the visualization and assessment of TBI pathophysiology, especially for of the purpose of improving clinical outcome metrics. Until now, the application of automatic segmentation algorithms to TBI in a clinical setting has remained an elusive goal because existing methods have, for the most part, been insufficiently robust to faithfully capture TBI-related changes in brain anatomy. This article introduces and illustrates the combined use of multimodal TBI segmentation and time point comparison using 3D Slicer, a widely-used software environment whose TBI data processing solutions are openly available. For three representative TBI cases, semi-automatic tissue classification and 3D model generation are performed to perform intra-patient time point comparison of TBI using multimodal volumetrics and clinical atrophy measures. Identification and quantitative assessment of extra- and intra-cortical bleeding, lesions, edema, and diffuse axonal injury are demonstrated. The proposed tools allow cross correlation of multimodal metrics from structural imaging (e.g., structural volume, atrophy measurements) with clinical outcome variables and other potential factors predictive of recovery. In addition, the workflows described are suitable for TBI clinical practice and patient monitoring, particularly for assessing damage extent and for the measurement of neuroanatomical change over time. With knowledge of general location, extent, and degree of change, such metrics can be associated with clinical measures and subsequently used to suggest viable treatment options. PMID- 21787173 TI - Clot lysis time in platelet-rich plasma: method assessment, comparison with assays in platelet-free and platelet-poor plasmas, and response to tranexamic acid. AB - Fibrinolysis dysfunctions cause bleeding or predisposition to thrombosis. Platelets contain several factors of the fibrinolytic system, which could up or down regulate this process. However, the temporal relationship and relative contributions of plasma and platelet components in clot lysis are mostly unknown. We developed a clot lysis time (CLT) assay in platelet-rich plasma (PRP-CLT, with and without stimulation) and compared it to a similar one in platelet-free plasma (PFP) and to another previously reported test in platelet-poor plasma (PPP). We also studied the differential effects of a single dose of tranexamic acid (TXA) on these tests in healthy subjects. PFP- and PPP-CLT were significantly shorter than PRP-CLT, and the three assays were highly correlated (p < 0.0001). PFP- and PPP-, but more significantly PRP-CLT, were positively correlated with age and plasma PAI-1, von Willebrand factor, fibrinogen, LDL-cholesterol, and triglycerides (p < 0.001). All these CLT assays had no significant correlations with platelet aggregation/secretion, platelet counts, and pro-coagulant tests to explore factor X activation by platelets, PRP clotting time, and thrombin generation in PRP. Among all the studied variables, PFP-CLT was independently associated with plasma PAI-1, LDL-cholesterol, and triglycerides and, additionally, stimulated PRP-CLT was also independently associated with plasma fibrinogen. A single 1 g dose of TXA strikingly prolonged all three CLTs, but in contrast to the results without the drug, the lysis times were substantially shorter in non-stimulated or stimulated PRP than in PFP and PPP. This standardized PRP-CLT may become a useful tool to study the role of platelets in clot resistance and lysis. Our results suggest that initially, the platelets enmeshed in the clot slow down the fibrinolysis process. However, the increased clot resistance to lysis induced by TXA is overcome earlier in platelet-rich clots than in PFP or PPP clots. This is likely explained by the display of platelet pro-fibrinolytic effects. Focused research is needed to disclose the mechanisms for the relationship between CLT and plasma cholesterol and its potential pathophysiologic and clinical relevance. PMID- 21787174 TI - Nitric oxide and peroxynitrite platelet levels in gestational hypertension and preeclampsia. AB - The aim of the study was to investigate platelet nitric oxide (NO) pathways in women with Gestational Hypertension (GH), Preeclampsia (PE) and Controls. Platelet NO(x) and peroxynitrite (ONOO(-)) levels, inducible (iNOS) and endothelial nitric oxide synthase (eNOS) and Nitrotyrosine expression (N-Tyr) in 30 women with GH, 30 with PE and 30 healthy pregnant controls, age, parity and gestational age-matched, were assessed. Platelet NO(x) and ONOO(-) levels were significantly higher in GH and PE vs. Controls, with higher levels in GH vs. PE. At the same way, iNOS and N-Tyr were significantly higher in GH and PE vs. Controls, with higher levels in GH vs. PE. Since GH expressed higher amount of NO metabolites and higher activation of iNOS compared to PE, we can hypothesize that the severity of hypertensive pathology is almost not related to only NO metabolism, this research confirmed that GH and PE are associated with marked changes in NO pathways; it is not easy to understand if they could be interpreted as causes or consequence of these pathologic states. PMID- 21787175 TI - Prasugrel resistance: fact or fiction. AB - Prasugrel is a third-generation thienopyridine that inhibits ADP-induced platelet activation by irreversibly blocking the P2Y12 receptor. Given in healthy volunteers in dosages used clinically, it invariably inhibits platelet aggregation. When administered in patients, it has been shown to result in a faster, more consistent and stronger inhibition of platelet aggregation compared with the most widely used clopidogrel. However, cases of inadequate platelet inhibition or of the so-called 'resistance' to prasugrel have been occasionally reported. The focus of this review is prasugrel resistance prevalence, mechanisms and potential clinical implications. PMID- 21787176 TI - A navigation system for percutaneous needle interventions based on PET/CT images: design, workflow and error analysis of soft tissue and bone punctures. AB - Percutaneous needle intervention based on PET/CT images is effective, but exposes the patient to unnecessary radiation due to the increased number of CT scans required. Computer assisted intervention can reduce the number of scans, but requires handling, matching and visualization of two different datasets. While one dataset is used for target definition according to metabolism, the other is used for instrument guidance according to anatomical structures. No navigation systems capable of handling such data and performing PET/CT image-based procedures while following clinically approved protocols for oncologic percutaneous interventions are available. The need for such systems is emphasized in scenarios where the target can be located in different types of tissue such as bone and soft tissue. These two tissues require different clinical protocols for puncturing and may therefore give rise to different problems during the navigated intervention. Studies comparing the performance of navigated needle interventions targeting lesions located in these two types of tissue are not often found in the literature. Hence, this paper presents an optical navigation system for percutaneous needle interventions based on PET/CT images. The system provides viewers for guiding the physician to the target with real-time visualization of PET/CT datasets, and is able to handle targets located in both bone and soft tissue. The navigation system and the required clinical workflow were designed taking into consideration clinical protocols and requirements, and the system is thus operable by a single person, even during transition to the sterile phase. Both the system and the workflow were evaluated in an initial set of experiments simulating 41 lesions (23 located in bone tissue and 18 in soft tissue) in swine cadavers. We also measured and decomposed the overall system error into distinct error sources, which allowed for the identification of particularities involved in the process as well as highlighting the differences between bone and soft tissue punctures. An overall average error of 4.23 mm and 3.07 mm for bone and soft tissue punctures, respectively, demonstrated the feasibility of using this system for such interventions. The proposed system workflow was shown to be effective in separating the preparation from the sterile phase, as well as in keeping the system manageable by a single operator. Among the distinct sources of error, the user error based on the system accuracy (defined as the distance from the planned target to the actual needle tip) appeared to be the most significant. Bone punctures showed higher user error, whereas soft tissue punctures showed higher tissue deformation error. PMID- 21787177 TI - Epidemiology, severity classification, and outcome of moderate and severe traumatic brain injury: a prospective multicenter study. AB - Changes in the demographics, approach, and treatment of traumatic brain injury (TBI) patients require regular evaluation of epidemiological profiles, injury severity classification, and outcomes. This prospective multicenter study provides detailed information on TBI-related variables of 508 moderate-to-severe TBI patients. Variability in epidemiology and outcome is examined by comparing our cohort with previous multicenter studies. Additionally, the relation between outcome and injury severity classification assessed at different time points is studied. Based on the emergency department Glasgow Coma Scale (GCS), 339 patients were classified as having severe and 129 as having moderate TBI. In 15%, the diagnosis differed when the accident scene GCS was used for classification. In hospital mortality was higher if severe TBI was diagnosed at both time points (44%) compared to moderate TBI at one or both time points (7-15%, p<0.001). Furthermore, 14% changed diagnosis when a threshold (>=6 h) for impaired consciousness was used as a criterion for severe TBI: In-hospital mortality was<5% when impaired consciousness lasted for<6 h. This suggests that combining multiple clinical assessments and using a threshold for impaired consciousness may improve the classification of injury severity and prediction of outcome. Compared to earlier multicenter studies, our cohort demonstrates a different case mix that includes a higher age (mean=47.3 years), more diffuse (Traumatic Coma Databank [TCDB] I-II) injuries (58%), and more major extracranial injuries (40%), with relatively high 6 month mortality rates for both severe (46%) and moderate (21%) TBI. Our results confirm that TBI epidemiology and injury patterns have changed in recent years whereas case fatality rates remain high. PMID- 21787180 TI - Acetylcholinesterase inhibition and locomotor function after motor-sensory cortex impact injury. AB - Traumatic brain injury (TBI) induces transient or persistent dysfunction of gait and balance. Enhancement of cholinergic transmission has been reported to accelerate recovery of cognitive function after TBI, but the effects of this intervention on locomotor activity remain largely unexplored. The hypothesis that enhancement of cholinergic function by inhibition of acetylcholinesterase (AChE) improves locomotion following TBI was tested in Sprague-Dawley male rats after a unilateral controlled cortical impact (CCI) injury of the motor-sensory cortex. Locomotion was tested by time to fall on the constant speed and accelerating Rotarod, placement errors and time to cross while walking through a horizontal ladder, activity monitoring in the home cages, and rearing behavior. Assessments were performed the 1st and 2nd day and the 1st, 2nd, and 3rd week after TBI. The AChE inhibitor physostigmine hemisulfate (PHY) was administered continuously via osmotic minipumps implanted subcutaneously at the rates of 1.6-12.8 MUmol/kg/day. All measures of locomotion were impaired by TBI and recovered to initial levels between 1 and 3 weeks post-TBI, with the exception of the maximum speed achievable on the accelerating Rotarod, as well as rearing in the open field. PHY improved performance in the accelerating Rotarod at 1.6 and 3.2 MUmol/kg/day (AChE activity 95 and 78% of control, respectively), however, higher doses induced progressive deterioration. No effect or worsening of outcomes was observed at all PHY doses for home cage activity, rearing, and horizontal ladder walking. Potential benefits of cholinesterase inhibition on locomotor function have to be weighed against the evidence of the narrow range of useful doses. PMID- 21787181 TI - Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. AB - Radiotherapy is commonly employed to treat cancers of the head and neck and is increasingly used to treat other central nervous system (CNS) disorders. Exceeding the radiation tolerance of normal CNS tissues can result in sequelae contributing to patient morbidity and mortality. Animal studies and clinical experience suggest that neuroinflammation plays a role in the etiology of these effects; however, detailed characterization of this response has been lacking. Therefore, a dose-time investigation of the neuroinflammatory response after single-dose cranial irradiation was performed using C57BL/6 mice. Consistent with previous reports, cranial irradiation resulted in multiphasic inflammatory changes exemplified by increased transcript levels of inflammatory cytokines, along with glial and endothelial cell activation. Cranial irradiation also resulted in acute infiltration of neutrophils and a delayed increase in T cells, MHC II-positive cells, and CD11c-positive cells seen first at 1 month with doses >= 15 Gy. CD11c-positive cells were found almost exclusively in white matter and expressed MHC II, suggesting a "mature" dendritic cell phenotype that remained elevated out to 1 year postirradiation. Our results indicate that cranial irradiation leads to persistent neuroinflammatory changes in the C57BL/6 mouse brain that includes unique immunomodulatory cell populations. PMID- 21787182 TI - Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure. AB - The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation related mortality from cardiovascular disease. PMID- 21787183 TI - HZE 56Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase. AB - Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage. PMID- 21787184 TI - Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. AB - The potential superiority of hypertonic saline (HTS) over mannitol (MTL) for control of intracranial pressure (ICP) following traumatic brain injury (TBI) is still debated. Forty-seven severe TBI patients with increased ICP were prospectively recruited in two university hospitals and randomly treated with equiosmolar infusions of either MTL 20% (4 mL/kg; n=25 patients) or HTS 7.5% (2 mL/kg; n=22 patients). Serum sodium, hematocrit, ICP, arterial blood pressure, cerebral perfusion pressure (CPP), shear rate, global indices of cerebral blood flow (CBF) and metabolism were measured before, and 30 and 120 min following each infusion during the course of illness. Outcome was assessed at 6 months. Both HTS and MTL effectively and equally reduced ICP levels with subsequent elevation of CPP and CBF, although this effect was significantly stronger and of longer duration after HTS and correlated with improved rheological blood properties induced by HTS. Further, effect of HTS on ICP appeared to be more robust in patients with diffuse brain injury. In contrast, oxygen and glucose metabolic rates were left equally unaffected by both solutions. Accordingly, there was no significant difference in neurological outcome between the two groups. In conclusion, MTL was as effective as HTS in decreasing ICP in TBI patients although both solutions failed to improved cerebral metabolism. HTS showed an additional and stronger effect on cerebral perfusion of potential benefit in the presence of cerebral ischemia. Treatment selection should therefore be individually based on sodium level and cerebral hemodynamics. PMID- 21787185 TI - The future of psychiatric pharmacogenomics. PMID- 21787187 TI - Continuous un-SERT-ainty of 5-HTTLPR. PMID- 21787188 TI - Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group. AB - One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study. PMID- 21787189 TI - Interstitial lung disease in gefitinib-treated Japanese patients with non-small cell lung cancer: genome-wide analysis of genetic data. AB - AIM: To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib. MATERIALS & METHODS: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case-control study component ('CCS'; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher's exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests. RESULTS: The CCS data provided some false discovery rate evidence that the significance of top ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene-gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses. CONCLUSION: Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research. PMID- 21787190 TI - Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity related complications. AB - Second-generation antipsychotics can greatly improve symptoms of psychosis spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient's risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation. PMID- 21787191 TI - Transporter-mediated drug-drug interactions. AB - Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed. PMID- 21787193 TI - Clinical implementation of pharmacogenetics: a nonrepresentative explorative survey to participants of WorldPharma 2010. AB - Despite the fast-growing literature and the emerging support from regulatory drug agencies, the translation of pharmacogenetics (PGx) into the clinic is still rather limited; it seems that many existing challenges are yet to be overcome prior to an extensive adoption of PGx-based diagnostics. This article describes the results of an explorative nonrepresentative survey that attempted to evaluate the perceived status quo of, and the obstacles facing, PGx implementation in clinical practice in countries with emerging and developing economies versus countries with advanced economies. This study is a useful starting point to help gain better insight into the international, rather than merely the regional, barriers facing the lag in PGx implementation in the clinic. A more transparent picture about these priorities can be constructed through conducting a similar study on a more representative sample of respondents/participants. PMID- 21787195 TI - Clinical options after failure of allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies. AB - Disease recurrence is the single most common cause of death after allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Disease status and chemosensitivity at the time of transplantation, as well as the development of graft-versus-host disease (GVHD), are factors known to influence the risk of relapse post-HSCT. Both acute and chronic GVHD have been associated with decreased relapse rates; however, owing to toxicity, overall survival is not consistently improved in these patients. Furthermore, there is a transient period of immunodeficiency after HSCT, which may permit residual malignant cells to proliferate early in the post-transplant course, before the donor immune system can establish a graft-versus-tumor response. Patients who fail an initial HSCT have an extremely poor outcome; therefore, maneuvers to prevent, identify and treat recurrent disease as early as possible in these situations are necessary. Strategies to distinguish graft-versus-tumor from GVHD, to enhance both general and disease-specific immune reconstitution after transplantation, and to increase donor-mediated anti-host immune reactions are being investigated in clinical trials. Single agent nontoxic post-HSCT chemotherapy, cellular therapies and second allogeneic HSCT using reduced intensity regimens are among the modalities under investigation. PMID- 21787192 TI - Pharmacogenomics of cisplatin-induced ototoxicity. AB - Cisplatin ototoxicity affects different individuals in a widely variable manner. These variations are likely to be explained by genetic differences among those affected. It would be highly advantageous to identify genetic variants that predispose to cisplatin ototoxicity in order to minimize the risk to susceptible subgroups. Although this area of research is very important, only a few studies have rigorously examined the genetic basis for cisplatin-induced susceptibility to hearing loss. This article addresses recent progress in clarifying the incidence of cisplatin ototoxicity and the risk factors and controversies regarding the identification of genetic variants associated with cisplatin induced hearing loss. PMID- 21787196 TI - Differential effects of HOXB4 and NUP98-HOXA10hd on hematopoietic repopulating cells in a nonhuman primate model. AB - Expansion of hematopoietic stem cells (HSCs) is beneficial in settings where HSC numbers are limited, such as cord blood transplantation. The human homeobox transcription factor HOXB4 has been shown to enhance stem cell expansion in several experimental models. We have shown previously that HOXB4 overexpression in monkey CD34(+) cells has a dramatic effect on expansion and engraftment of short-term repopulating cells. Here, we wished to compare the effects of HOXB4 and another candidate gene, NUP98-HOXA10hd (NA10hd). We used a competitive repopulation assay in pigtailed macaques to study engraftment of CD34(+) cells modified with gammaretroviral HOXB4YFP or NA10hdGFP. We found that HOXB4YFP contributed more to early hematopoiesis (<30 days), whereas NA10hdGFP contributed more to later hematopoiesis. In each case, we observed two distinct peaks in engraftment of NA10hd-transduced cells, one within 20 days post transplant and another after 5-6 months. Analysis of CD14(+), CD3(+), and CD20(+) subsets confirmed that higher percentages of cells of each lineage were derived from NA10hdGFP(+) progenitors than from HOXB4YFP(+) progenitors. In conclusion, we show that HOXB4 and NA10hd both have a significant impact on hematopoietic reconstitution; however, these effects are differential and therefore may offer complementary strategies for HSC expansion. PMID- 21787197 TI - Influence of chin height on perceived attractiveness in the orthognathic patient, layperson, and clinician. AB - OBJECTIVE: To determine an objective and quantitative evaluation of how severity of chin height variations influence perceived attractiveness. MATERIALS AND METHODS: The chin height of an idealized male and female frontal facial image was altered in 2.5-mm increments from -12.5 to 22.5 mm (male images) and from -10 to 20 mm (female images). These images were rated on a seven-point Likert scale by a preselected group of pretreatment orthognathic patients, clinicians, and laypeople. RESULTS: The classical lower facial proportional canon of upper lip height as one third (33.3%), lower lip height as one third (33.3%) and chin height as one third (33.3%) of lower anterior face height (LAFH) may be used as an "ideal" proportional ratio. However, chin height variations within a given proportional range are largely unnoticed, ie, from approximately 30% chin height in relation to LAFH (male and female) up to approximately 40% (males) and 50% (females) chin height in relation to LAFH. Additionally, surgery is only desired with greater variations in chin height: greater than 50% and less than 20%-23% of LAFH in males, and greater than 58% and less than 20%-22% of LAFH in females. Patients and clinicians are more critical than laypeople, but no significant differences were found between clinicians and patients. CONCLUSIONS: In relation to the classical canon, surgical correction of chin height deformities are desired with chin height greater than 50% and less than 20%-23% of LAFH in males, and greater than 58% and less than 20%-22% of LAFH in females. PMID- 21787198 TI - Altered mandibular growth under functional posterior displacement in rats. AB - OBJECTIVE: To test the null hypothesis that there is no difference in mandibular growth between growing rats with posterior functional mandibular displacement and growing rats without functional mandibular displacement. MATERIALS AND METHODS: Twenty female Wistar rats (5 weeks old) were randomized into two groups: (1) control and (2) mandible posterior displacement in the occluded condition induced by an occlusal guiding appliance. After 8 weeks all animals were sacrificed, cone beam computed tomography scan images of the heads were taken using the classic I CAT, and acrylic rapid-prototyped templates of the mandibles were constructed. Mandibular length, ramus height, and intercondylar distance were measured. Mandibular length and ramus height were submitted to the two-way analysis of variance, while intercondylar distance was analyzed by nonpaired Student's t test. RESULTS: Mandibular length was bigger (P < .0001) in the control than in the experimental group, but no significant difference was found between the left and right sides (P = .9380). No significant differences were observed for ramus height and intercondylar distance. CONCLUSIONS: The results of this study demonstrated that functional posterior displacement of the mandible in growing rats resulted in shorter mandibular length. PMID- 21787199 TI - Ultrasound enhances the healing of orthodontically induced root resorption in rats. AB - OBJECTIVE: To examine the effect of low-intensity pulsed ultrasound (LIPUS) on orthodontically induced root resorption in rats. MATERIALS AND METHODS: Sixty four male Wistar rats were divided randomly and equally into four groups (n = 16 rats each). The rats were untreated (negative control) or treated with orthodontic tooth movement without (positive control) or with LIPUS at 100 or 150 MW/cm(2) (LIPUS-treated groups). An initial force of 100 g was applied to the areas between the upper right central incisors and the first molars of the rats for 10 days. Eight rats were randomly chosen from each group, and the root resorption index (RRI) was determined with scanning electron microscopy (SEM). Upper first molar-centered mesial-distal tissue slices were generated from the upper first molars and peridentium of the remaining eight rats from each group. Specimen slices were analyzed with hematoxylin-eosin and tartrate-resistant acid phosphatase staining, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) immunohistochemistry, and optical microscopy. Analyses of cell number, densitometry, and one-way analysis of variance were performed. RESULTS: The LIPUS-treated groups displayed decreased RRI values, decreased osteoclast numbers and activity levels, and increased OPG/RANKL expression ratios. High-power SEM revealed reparative cementum in the LIPUS treated samples. CONCLUSION: LIPUS regulates osteoclast differentiation via the OPG/RANKL ratio, evoking a reparative effect on orthodontically induced root resorption in rats. PMID- 21787200 TI - Do enamel microabrasion and casein phosphopeptide-amorphous calcium phosphate affect shear bond strength of orthodontic brackets bonded to a demineralized enamel surface? AB - OBJECTIVE: To evaluate and compare the effects of enamel microabrasion, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and their combination on the shear bond strength (SBS) of orthodontic brackets bonded to demineralized enamel surface. MATERIALS AND METHODS: One hundred human first premolar teeth were randomly allocated to one of five groups. Group I was considered as the control of other groups. For the remaining groups, demineralization was performed via solutions. In group II, brackets were directly bonded to the demineralized enamel surface. CPP-ACP was applied in group III, microabrasion was performed in group IV, and both microabrasion and CPP-ACP application were performed in group V. The specimens were tested for SBS. Bond failures were scored according to the Adhesive Remnant Index (ARI). Analysis of variance and Tukey tests were used to compare the SBS of the groups. ARI scores of the groups were evaluated with a G test. The statistical significance was set at P <. 05 level. RESULTS: Statistically significant difference was found among the five investigated groups (F = 111.870; P < .001). The SBS of groups II and IV were significantly lower than the other groups. No statistically significant difference was found among groups I (control; mean 24.1 +/- 4.1 MPa), III (mean 22.0 +/- 3.6 MPa), and V (mean 24.3 +/- 1.9 MPa). Microabrasion and combination with CPP-ACP showed higher SBS compared to the control group. The differences between ARI scores of the groups were statistically significant (P < .001). CONCLUSION: CPP-ACP pretreatment, microabrasion of the enamel, and the combination of these two methods improve the bonding to demineralized enamel. PMID- 21787202 TI - Reforming the regulations governing research with human subjects. PMID- 21787201 TI - Cumulative head impact burden in high school football. AB - Impacts to the head are common in collision sports such as football. Emerging research has begun to elucidate concussion tolerance levels, but sub-concussive impacts that do not result in clinical signs or symptoms of concussion are much more common, and are speculated to lead to alterations in cerebral structure and function later in life. We investigated the cumulative number of head impacts and their associated acceleration burden in 95 high school football players across four seasons of play using the Head Impact Telemetry System (HITS). The 4-year investigation resulted in 101,994 impacts collected across 190 practice sessions and 50 games. The number of impacts per 14-week season varied by playing position and starting status, with the average player sustaining 652 impacts. Linemen sustained the highest number of impacts per season (868); followed by tight ends, running backs, and linebackers (619); then quarterbacks (467); and receivers, cornerbacks, and safeties (372). Post-impact accelerations of the head also varied by playing position and starting status, with a seasonal linear acceleration burden of 16,746.1g, while the rotational acceleration and HIT severity profile burdens were 1,090,697.7 rad/sec(2) and 10,021, respectively. The adolescent athletes in this study clearly sustained a large number of impacts to the head, with an impressive associated acceleration burden as a direct result of football participation. These findings raise concern about the relationship between sub-concussive head impacts incurred during football participation and late-life cerebral pathogenesis, and justify consideration of ways to best minimize impacts and mitigate cognitive declines. PMID- 21787203 TI - Efficacy of adalimumab in the treatment of psoriasis: a retrospective study of 15 patients in daily practice. AB - BACKGROUND: Adalimumab is a fully human IgG1 monoclonal antibody that binds to tumor necrosis factor (TNF), a key proinflammatory cytokine involved in the pathogenesis of psoriasis. OBJECTIVE: A single-center, retrospective study was conducted to assess the efficacy and safety of adalimumab in patients with moderate to severe psoriasis in daily practice. METHODS: The medical records of 15 patients with moderate to severe psoriasis treated with adalimumab during a 1 year period were reviewed. Previous conventional systemic treatments or other biological agents were unsuccessful. All patients received subcutaneous injections of an initial dose of adalimumab (80 mg) at week 0 followed by adalimumab (40 mg) every other week. RESULTS: A 75% improvement in the Psoriasis Area and Severity Index (PASI 75) score was achieved by 80% of patients at week 24 and by 73.3% of patients at week 48. Moreover, 13.3% of patients were almost completely cleared (PASI 90) at week 48. At 24 weeks, adalimumab therapy increased significantly a patient's quality of life as assessed by the Dermatology Life Quality Index (DLQI) (p = 0.001). The Nail Psoriasis Severity Index (NAPSI) decreased from a mean (SD) of 18.9 (12.2) to 8.2 (4.7) (p = 0.001) at week 24. Palmoplantar psoriasis decreased from a mean score of 1.1 (1.3) to 0.5 (0.9) (p = 0.026) and scalp involvement from a mean of 2.5 (1.2) to 1.1 (1.0) (p = 0.002) at week 24. Out of 11 patients with pruritus at the pre-treatment visit, this symptom had completely disappeared in nine of them after 24 weeks of treatment. CONCLUSIONS: Treatment with adalimumab proved to be effective for the management of chronic moderate to severe plaque-type psoriasis in patients whose disease had been refractory to systemic conventional therapies or other biologic agents. PMID- 21787204 TI - Using magnetic resonance imaging for early assessment of submucous cleft palate: a case report. AB - Surgical correction for submucous cleft palate is generally indicated in the presence of velopharyngeal inadequacy. Clinical assessment of velopharyngeal inadequacy requires that the child is able to produce a connected speech sample, which can yield a delay in treatment decisions that extends through a critical period of speech and language development. A perceptual speech assessment and intraoral examination are traditionally the most important methods of establishing a diagnosis of submucous cleft palate. The purpose of this case report is to demonstrate the use of magnetic resonance imaging as a diagnostic tool to provide early identification and an indication of surgical treatment for an individual born with a submucous cleft palate. The magnetic resonance images indicated a discontinuous levator veli palatini muscle sling arrangement with attachment of the muscle bundles onto the hard palate. Surgery was performed at 16 months and postsurgical speech evaluations demonstrated normal resonance and age-appropriate speech. PMID- 21787205 TI - Factors predictive of complex Mohs surgery cases. AB - BACKGROUND: Mohs surgery allows excision of skin cancer in a tissue-sparing fashion that minimizes recurrence risk. While the indications for Mohs surgery are well established, factors predictive of complex Mohs cases are less studied. OBJECTIVE: To determine patient, tumor, and surgeon characteristics associated with complex Mohs cases. METHODS: A retrospective review was performed for a 3 year period (7/2006-6/2009) to identify Mohs cases requiring >=4 stages ("complex"), and a control population requiring <=3 stages ("non-complex"). Surgical logs for four fellowship-trained Mohs surgeons were reviewed. RESULTS: 77 complex cases (51 academic practice vs. 26 private practice) were compared with 154 control cases (102 academic practice vs. 52 private practice). There were no significant differences in patient age, gender, immunosuppression, academic (2.7% complex) versus private practice (3.5% complex), or surgeons' years of experience. Factors associated with complexity included: recurrent tumors (p < 0.001; odds ratio (OR) 6.88; 95% confidence interval (CI) 2.8-17); basal cell carcinoma (BCC) with infiltrative or morpheaform histology (p = 0.0019; OR 3.0; 95% CI 1.5-6.3); tumors of the nose (p = 0.0168; OR 2.05; 95% CI 1.1-3.7), especially nasal tip (p = 0.0103; OR 3.68; 95% CI 1.3-10.6) and ear (p = 0.0178; OR 3.0; 95% CI 1.2-7.9), especially helix (p = 0.00744; OR 5.9; 95% CI 1.5-22.7); tumors with pre-operative size >1 cm (p = 0.018; OR 2.0; 95% CI 1.1 3.6); and tumors involving >1 cosmetic subunit (p = 0.0072; OR 5.0; 95% CI 1.5 16.7). Complex tumors had greater post-operative area (10.6 +/- 1.3 vs. 3.6 +/- 0.7 cm2; p < 0.0001), and more often required flap/graft repair (p < 0.0001; OR 6.9; 95% CI 3.7-13.1). LIMITATIONS: A retrospective study representing a single geographic area. CONCLUSIONS: Mohs cases are similar in complexity whether in academic or private practice. Recurrent/aggressive histology tumors, tumors >1 cm, and tumors on the nose or ear are more likely to prove surgically complex. Advanced knowledge of these factors may be useful pre-operatively as Mohs surgeons plan their scheduled cases. PMID- 21787206 TI - Ustekinumab for the treatment of HIV psoriasis. PMID- 21787207 TI - Efficacy of low-dose acitretin in the treatment of psoriasis. AB - OBJECTIVES: Clinical experience favors low doses of acitretin to reduce adverse events but still maintain efficacy. We revisited the pivotal acitretin trials to compare the efficacy of high- versus low-dose acitretin. MATERIALS AND METHODS: We analyzed data from two large randomized trials which had an 8-week, double blinded (DB), placebo-controlled phase followed by a 16-week open-label (OL) phase. During the DB phase, patients received placebo, 10, 25, 50, or 75 mg of acitretin daily. Dose adjustment was allowed during the OL phase, during which high-dose treatment was defined as approximately 50 mg/day and low-dose as approximately 25 mg/day. Primary end points were improvement of psoriasis based on investigator static global assessment (ISGA) and reduction in affected body surface area (BSA). RESULTS: At the end of the OL phase (week 24), treatment success rates were similar among all groups (29%-33%)--with the exception of the group receiving low-dose treatment for both DB and OL phases (47% success). Decrease in BSA was also highest in this group (73% vs. 28% to 54%). CONCLUSION: Individualization of acitretin dosing is crucial to minimize side effects and should lead to improved adherence and efficacy. This analysis supports the utility of low-dose acitretin for psoriasis over extended treatment periods. PMID- 21787208 TI - Hemorrhage secondary to interforaminal implant surgery: anatomical considerations and report of a case. AB - Understanding the anatomy of the floor of mouth is very important as severe submandibular hemorrhages are life threatening. This case report illustrates the potential hemorrhage consequences of implant surgery within the interforaminal region. The highly vascularized interforaminal region is susceptible to hemorrhage, which can be induced simply by instruments causing vascular trauma. The risk of intraoperative bleeding can be minimized by painstaking preoperative clinical and radiological examination but cannot be averted as it is inherent in the underlying anatomy of the region. PMID- 21787209 TI - Stress distribution around maxillary anterior implants as a factor of labial bone thickness and occlusal load angles: a 3-dimensional finite element analysis. AB - The purpose of this study was to evaluate the influence of the stress/strain distribution in buccal bone of an anterior maxillary implant using 3 bone thicknesses under 5 different loading angles. Different testing conditions incorporating 3 buccal bone thicknesses, 3 bone compositions, and 5 loading angles of an anterior maxillary implant were applied in order to investigate the resultant stress/strain distribution with finite element analysis. The maximum equivalent stress/strain increased with the decreasing of loading angle relative to the long axis. In addition to loading angle, bone quality and quantity also influenced resultant stress distribution. Dental practitioners should consider combinations of bone composition, diameter, and load angulations to predict success or failure for a given implant length and diameter. PMID- 21787210 TI - The comparison of treatment with clobetasol propionate 0.05% and topical pimecrolimus 1% treatment in the treatment of alopecia areata. AB - BACKGROUND: Alopecia areata (AA) is a non-scarring hair loss. OBJECTIVE: We aimed the comparison of clobetasol propionate and pimecrolimus efficiency and tolerability in the treatment of AA. METHODS: The study included a total of 100 consecutive patients with AA. Patients were randomized into four groups. 30 patients used 1% pimecrolimus cream, 30 patients used 0.05% clobetasol propionate cream, 20 patients used petrolatum as placebo. Scalp of 20 patients was divided into two equal areas and one area was treated with 1% pimecrolimus cream and the other area with 0.05% clobetasol propionate cream. RESULTS: At week 12 of treatment, the recovery rate of the pimecrolimus group was 53.73 +/- 44.49 and the recovery score was 3.63 +/- 2.07; that of the clobetasol propionate group was 47.00 +/- 44.80 and the recovery score was 3.33 +/- 2.20; that of the placebo group was 35.50 +/- 40.53 and the recovery score was 2.75 +/- 1.88. There was no statistically significant difference among the groups in terms of the percentage of recovery and the recovery score (p < 0.05). CONCLUSION: In conclusion, we detected that topical pimecrolimus treatment is as effective as topical corticosteroids and is superior to topical corticosteroids in terms of side effects in the treatment of AA. PMID- 21787211 TI - Phospholipases and cationic peptides inhibit Cryptosporidium parvum sporozoite infectivity by parasiticidal and non-parasiticidal mechanisms. AB - The apicomplexan parasite Cryptosporidium parvum is an important cause of diarrhea in humans and cattle, and it can persistently infect immunocompromised hosts. No consistently effective parasite-specific pharmaceuticals or immunotherapies for control of cryptosporidiosis are presently available. The innate immune system represents the first line of host defense against a range of infectious agents, including parasitic protozoa. Several types of antimicrobial peptides and proteins, collectively referred to herein as biocides, constitute a major effector component of this system. In the present study, we evaluated lactoferrin, lactoferrin hydrolysate, 5 cationic peptides (lactoferricin B, cathelicidin LL37, indolicidin, beta-defensin 1, beta-defensin 2), lysozyme, and 2 phospholipases (phospholipase A2, and phosphatidylinositol-specific phospholipase C) for anti-cryptosporidial activity. The biocides were evaluated either alone or in combination with 3E2, a monoclonal antibody (MAb) against C. parvum that inhibits sporozoite attachment and invasion. Sporozoite viability and infectivity were used as indices of anti-cryptosporidial activity in vitro. All biocides except lactoferrin had a significant effect on sporozoite viability and infectivity. Lactoferrin hydrolysate and each of the 5 cationic peptides were highly parasiticidal and strongly reduced sporozoite infectivity. While each phospholipase also had parasiticidal activity, it was significantly less than that of lactoferrin hydrolysate and each of the cationic peptides. However, each phospholipase reduced sporozoite infectivity comparably to that observed with lactoferrin hydrolysate and the cationic peptides. Moreover, when 3 of the cationic peptides (cathelicidin LL37, beta-defensin 1, and beta-defensin 2) were individually combined with MAb 3E2, a significantly greater reduction of sporozoite infectivity was observed over that by 3E2 alone. In contrast, reduction of sporozoite infectivity by a combination of either phospholipase with MAb 3E2 was no greater than that by 3E2 alone. These collective observations suggest that cationic peptides and phospholipases neutralize C. parvum by mechanisms that are predominantly either parasiticidal or non-parasiticidal, respectively. PMID- 21787212 TI - Genetic characterization of Protostrongylus shiozawai from Japanese serows (Capricornis crispus). AB - Protostrongylus shiozawai (Nematoda: Strongylida) infection is known to occur in the lungs of wild Japanese serows (Capricornis crispus) and, to date, has been classified only by its morphological characteristics, as well as host specificity. To characterize P. shiozawai genetically, a partial sequence of the second internal transcribed spacer (ITS-2) region was determined and compared with those of related nematodes. Our subsequent classification of P. shiozawai based on phylogenetic analysis was consistent with the current classification. Phylogenetic analysis also showed that P. shiozawai is more closely related to Protostrongylus stilesi than to Protostrongylus rufescens. PCR using genetic markers in the ITS-2 region should provide a useful tool for expanded studies of P. shiozawai and other Protostrongylus species. PMID- 21787213 TI - Scanning electron microscopy and molecular characterization of a new Haplosporidium species (Haplosporidia), a parasite of the marine gastropod Siphonaria pectinata (Mollusca: Gastropoda: Siphonariidae) in the Gulf of Mexico. AB - Based on scanning electron microscopy and the small subunit ribosomal RNA (SSU rRNA), Haplosporidium tuxtlensis n. sp. (Haplosporidia), a parasite found in the visceral tissues of the false limpet Siphonaria pectinata (Linnaeus, 1758), is described. The spores are ellipsoidal (3.61 +/- 0.15 um * 2.69 +/- 0.19 um), with a circular lid (2.94 +/- 0.5 um) representing the operculum. The spore wall bears filaments occurring singly, or in clusters, of 2 to 8, fusing distally. Phylogenetic relationships of H. tuxtlensis n. sp. were assessed with other described species using the SSU rRNA sequence. Haplosporidium tuxtlensis n. sp. is sister taxon to Haplosporidium pickfordi Barrow, 1961. The morphological characteristics (spore wall structure, shape, size, and filament structure) and the unique host identity corroborate it as a new species. Additionally, this is the first record of Haplosporidia infecting striped false limpets in the Gulf of Mexico. PMID- 21787214 TI - Photodynamic therapy in the treatment of extensive Bowen's disease. AB - BACKGROUND: Surgical excision is the preferred method of eradicating Bowen's disease (BD). Photodynamic therapy (PDT) has been successfully used for treatment of actinic keratosis, basal cell carcinoma, and BD. OBJECTIVE: Our aim was to evaluate the efficacy and tolerability of PDT for treatment of extensive BD. METHOD: Eighteen patients with 23 biopsy-proven BD lesions were treated with PDT. We defined as extensive those lesions large than 3 cm. Methyl aminolevulinate cream was applied for 3 h before illumination with an light emitting diode light source at a wavelength of 630 nm (energy density of 37 J/cm2). Treatment was repeated 1 week later. RESULTS: After 12 weeks of treatment, 22 of 23 BD lesions (90%) showed complete clinical response. Only three lesions recurred after a follow-up period of 12 months. Cosmetic outcome at 12 months was good or excellent in 94% of patients. CONCLUSION: Methyl aminolevulinate PDT is an effective treatment option for extensive BD with excellent cosmesis. PMID- 21787215 TI - Ribosomal DNA sequence characterization of Maritrema cf. eroliae Yamaguti, 1939 (Digenea: Microphallidae) and its life cycle. AB - The microphallid Maritrema eroliae parasitizes shore birds in marine ecosystems while its larval stages infect mud snails and crustacean hosts. Because it is difficult to morphologically distinguish between larvae of M. eroliae and other microphallids co-occurring in the same habitat, partial nucleotide sequences of the ribosomal DNA (rDNA), including the 28S and 18S in addition to complete sequences of ITS1 and ITS2, were scrutinized. This analysis was used to establish the snail-crab link in the life cycle of M. cf. eroliae . The rDNA 28S, 18S, and ITS sequences of metacercariae from the crab Xantho exaratus and sporocysts from the snail Clypeomorus bifasciata were compared. Sequence alignment demonstrated that the sporocyst and metacercaria may belong to M. eroliae and suggested a new second intermediate host for M. eroliae , the crab X. exaratus . The phylogenetic positions of the larval stages were determined by comparing the 28S, 18S, and ITS sequences with those of other trematodes available in GenBank. The phylogenetic trees confirmed the position of M. cf. eroliae within the Microphallidae and found it to be closely related to Maritrema heardi and Maritrema neomi. The present study represents the first molecular study correlating the larval stages in the life cycle of M. cf. eroliae using partial sequences of 28S and 18S in addition to complete ITS1 and ITS2 sequences. Furthermore, the sequences elucidated the evolutionary relationship of M. cf. eroliae to other microphallids. PMID- 21787216 TI - Seroprevalence of Toxoplasma gondii infection in Tibetan sheep in Tibet, China. AB - In the present investigation, the seroprevalence of Toxoplasma gondii antibodies in 455 Tibetan sheep in Tibet, China, was examined using an indirect hemagglutination test. Of these, 26 (5.7%) Tibetan sheep were seropositive at the cut-off of 1:64 serum dilution. The seroprevalence ranged from 2.2% to 8.9% among Tibetan sheep of <1-yr-old, 1-3-yr-old, and >3-yr-old, but the differences among the age groups were not significant (P > 0.05). The prevalence in male Tibetan sheep (2.8%) was lower than that in female Tibetan sheep (6.6%), but the difference was not statistically significant (P > 0.05). The results of this survey indicated the presence of T. gondii infection in Tibetan sheep, which may cause economic losses to the local livestock industry and which poses a potential threat to human health in this area. PMID- 21787217 TI - A retrospective study of the efficacy of a new intense pulsed light for the treatment of photoaging: report of 70 cases. AB - BACKGROUND: Intense pulsed light (IPL) system incorporating optimal pulse technology has been developed to enhance the efficacy and safety of the treatment of photoaging. However, there are few clinical studies on the treatment of photoaging using the novel IPL. OBJECTIVE: To determine the efficacy and safety of a new IPL for the treatment of photoaging. MATERIAL AND METHODS: We performed a retrospective study and reviewed photoaged skin lesions from 70 patients who were treated with IPL between May 2010 and February 2011. Two independent dermatologists performed assessment of global scores for photoaging. Patients were asked to rate the results and to report any adverse effects by phone interview. RESULTS: The main problems of patients offered treatment were dyspigmentation, wrinkle, skin roughness, and telangiectasia. The patients received four to five treatments at 3- to 4-week intervals. After three to four treatments, 77.1% and 74% of patients experienced improvements in overall and pigmentation, respectively. 59 patients responded the phone interview expressing satisfaction of treatment. 89.8% of patients rated their overall improvement as excellent or good. No one reported severe adverse reaction. CONCLUSION: The novel IPL is an effective and safe treatment option for photoaged skin. PMID- 21787218 TI - Progress in the placebo debate for homeopathy? PMID- 21787219 TI - An exploratory study on scientific investigations in homeopathy using medical analyzer. AB - BACKGROUND: The action of homeopathic medicines, in ultra-high dilution, is not directly observable. An attempt was made to explore autonomic response of selective homeopathic medicines, in healthy persons, using Medical Analyzer System (Electronics Division, Bhabha Atomic Research Centre, Mumbai, India). OBJECTIVE: The objective of the study was to observe the action of homeopathic medicines on physiologic variability of heart rate and blood flow. MATERIAL AND METHODS: Pre- and postinterventional variability spectra of heart rate and blood flow of 77 subjects were recorded with the Medical Analyzer System, administering homeopathic preparations of Aconitum napellus (6c, 10M), Arsenicum album (200c, 1M), Gelsemium sempervirens (200c, 1M), Phosphorus (200c, 1M), Pulsatilla nigricans (200c) and Sulphur (200c, 1M) versus placebo control. The amplitude of the peaks viz. low-frequency, medium-frequency, and high-frequency was measured for postintervention analysis. An increase in the amplitude of any valid peak by 100% or a decrease by 50% was considered as significant change. RESULTS: Aconitum napellus produced a response in heart rate variability (HRV) with 30c potency and in blood flow variability with 1M potency. Sulphur 200c and 1M, Gelsemium 200c and Pulsatilla 200c, produced a 62.5% response in HRV against the placebo response of 16.6%. Gelsemium, Phosphorus, and Sulphur produced a response in blood flow variability with a 1M potency, similar to the response of Aconitum napellus 1M. CONCLUSIONS: These data suggest that it is possible to record the response of homeopathic medicines on physiologic parameters of the autonomic nervous system. PMID- 21787220 TI - 17beta-Estradiol and interferon tau interact in the regulation of the immune response in a model of experimental autoimmune orchitis. AB - Immunoregulatory activity of type I interferons (IFNs) and estrogen is convergent in some cases of autoimmune disorders. The aim of our study was to determine whether a potent interaction of IFN and estradiol (E2) has an influence on immune response and estrogen receptor alpha (ER-?) expression in antigen-presenting cells in a model of experimental autoimmune orchitis (EAO). C3H/He/W male mice were immunized with testicular germ cells (TGCs) and orally treated with interferon tau (IFN-?), E2, or both simultaneously. The delayed-type hypersensitivity reaction was intensified after the administration of either IFN ? or E2, but their co-administration had no effect. IFN-? treatment increased immunoglobulin G2a (IgG2a) and decreased IgG1 levels of TGC-specific antibodies, whereas E2 abolished the effects of the used cytokine. The total splenic cellularity and the number of spleen CD11c+MHC II+ and F4/80+MHC II? cells were increased after IFN-? treatment, whereas E2 antagonized this effect. After IFN-? administration the level of ER-? was significantly higher in F4/80+MHC II? cells, whereas E2 had no effect. However, the administration of E2 significantly reduced the ER-? level in F4/80+MHC II+ and CD11c+MHC II+ cells in comparison with the IFN-??treated groups. In the EAO model, the type I IFN and E2 cooperated at the general and cellular levels of immune response, but E2 treatment usually abolished the effects exerted by the cytokine. PMID- 21787221 TI - Cytokines in autoimmune uveitis. AB - Autoimmune uveitis is a complex group of sight-threatening diseases that arise without a known infectious trigger. The disorder is often associated with immunological responses to retinal proteins. Experimental models of autoimmune uveitis targeting retinal proteins have led to a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and have provided a template for the development of novel therapies. The disease in humans is believed to be T cell-dependent, as clinical uveitis is ameliorated by T cell targeting therapies. The roles of T helper 1 (Th1) and Th17 cells have been major topics of interest in the past decade. Studies in uveitis patients and experiments in animal models have revealed that Th1 and Th17 cells can both be pathogenic effectors, although, paradoxically, some cytokines produced by these subsets can also be protective, depending on when and where they are produced. The major proinflammatory as well as regulatory cytokines in uveitis, the therapeutic approaches, and benefits of targeting these cytokines will be discussed in this review. PMID- 21787223 TI - Celiac disease: progress towards diagnosis and definition of pathogenic mechanisms. AB - The current issue of the International Reviews of Immunology is dedicated entirely to Celiac Disease (CD). Recent development of additional biomarkers and diagnostics resulted in a sharp revision of the prevalence of this condition, with a previously unrecognized subclinical occurrence in the adult population. This was paralleled by groundbreaking progress in understanding its molecular pathogenesis: while gluten-derived peptides activate the innate immunity, post translationally modified gluten elicits an adaptive immunity. These arms amplify each other, resulting in a self- perpetuating autoimmune condition, influenced by disturbances of the gut flora and mucus chemistry. The process evolves dramatically in a subset of patients with vulnerable immune homeostasis (eg. Treg cells) explaining the progressive, aggravating syndrome in the clinically overt version of CD. In depth understanding of the pathogenesis of CD thus creates the premises of developing novel, more accurate animal models that should support a rationale development of new prophylactic and therapeutic interventions. PMID- 21787222 TI - The role of cytokines in the pathogenesis and treatment of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by a defect in immune tolerance and exacerbated by both the innate and adaptive arms of the immune response. SLE-associated immune hyperactivity can be detected systemically as elevations in levels of cytokines along with their upregulated receptors expressed by hematopoietic cells. Importantly, increased levels of cytokines and their receptors can be observed in target organs, and it is clear that they have important roles in disease pathogenesis. Recent therapeutic strategies have focused on proximal cytokines, such as interferon alpha, interleukin (IL)-1, IL-6, and tumor necrosis factor as a result of the efficacious use of biologic agents for intervention in rheumatoid arthritis and other autoimmune diseases. Despite the recent advances in understanding the cytokine networks involved in autoimmune diseases and more specifically in SLE, the diagnosis and prognosis of lupus remain a challenge. Lupus is heterogeneous and unpredictable; moreover, the frequency and severity of flares can be difficult to determine and treat. A better understanding of the regulation of expression of key cytokines and their receptors can likely provide important clues to the pathogenic mechanisms underlying specific forms of SLE, and pave the way toward more effective therapeutics. PMID- 21787224 TI - An update on the diagnostics of celiac disease. AB - In celiac disease, highly sensitive and specific serum endomysial and transglutaminase 2 antibody tests are widely used in identifying patients for diagnostic endoscopy and small-bowel biopsy. In addition, the recently developed deamidated gliadin peptide antibody tests show promise in celiac disease diagnostics. In view of these apparent problems attending the diagnostic gold standard, gluten-induced small-bowel mucosal villous atrophy with crypt hyperplasia, other diagnostic approaches beyond conventional histology have been introduced. Furthermore, the diagnostic criteria for celiac disease are currently under revision with an eye also to noninvasive diagnostic strategies. PMID- 21787225 TI - Important lessons derived from animal models of celiac disease. AB - Several animal models have been recently developed to recapitulate various components of the complex process that is celiac disease. In addition to the increasing diversity of murine models there are now monkey models of celiac disease. Mouse strains and protocols have been developed that are now just beginning to address the complex interactions among the innate and adaptive immune responses to gluten, as well as gluten-dependent autoimmunity in celiac disease. The most important conclusion that these models have provided us with so far is that while all three components (innate gluten sensitivity, adaptive gluten sensitivity, and autoimmunity) are independent phenomena, all are necessary for celiac disease to develop. PMID- 21787227 TI - New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. AB - Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. It is one of the most common lifelong disorders on a worldwide basis. Celiac enteropathy is the final consequence of an abnormal immune reaction, showing features of both an innate and an adaptive response to gluten prolamins. The clinical spectrum is wide, including cases with either typical intestinal or atypical extraintestinal features, and silent forms. The only available treatment consists in dietary exclusion of grains containing gluten. New pharmacological treatment are currently under scrutiny. PMID- 21787226 TI - Unraveling the ties between celiac disease and intestinal microbiota. AB - Celiac disease is a multifactorial disorder that involves interactions between genetic and environmental factors. Gluten proteins are responsible for the symptoms of celiac disease, but other environmental factors that influence the intestinal ecosystem, including the milk-feeding type and gastrointestinal infections, may also play a role. Moreover, intestinal dysbiosis, characterized by increased Gram-negative bacteria and reduced bifidobacteria, has been detected in celiac disease patients. This review summarizes current knowledge of the associations between the intestinal microbiota and celiac disease and its possible modes of action in pathogenesis. Deeper understanding of these interactions can help redefine how this disorder is investigated. PMID- 21787228 TI - Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database. AB - BACKGROUND: Dietary fish oil supplements are increasingly used as an alternative to prescription-grade omega-3 fatty acids (P-OM3) for the treatment of hypertriglyceridemia. The content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in these supplement products varies widely and may result in a suboptimal response. The aim of this study was to review marketed fish oil supplements and to develop a reference for clinicians to compare products. METHODS: The National Library of Medicine Herbal Supplement Database was systematically searched using fish oil, EPA, DHA, and omega-3 fatty acid as search terms. Daily doses needed to achieve the Food and Drug Administration (FDA)-approved dose (RxDose) (3,360 mg of combined EPA and DHA) were calculated from the milligrams of EPA and DHA per serving, and suggested retail prices were used to calculate monthly cost of each product. A "usage criteria" was set to highlight products at the RxDose with a monthly cost of <$50, daily servings <8, daily amount of vitamins A and D less than or equal to the U.S. Dietary Reference Intake upper limit defined as 10,000 and 4,000 IU, respectively, and if the product was U.S. Pharmacopeia verified. RESULTS: A total of 163 products were identified, and 102 nonliquid and liquid products met our entry criteria. The median amount of EPA and DHA per serving in the nonliquid products was 216 mg and 200 mg, respectively, and the median number of servings at the RxDose was 11.2 at a median monthly cost of $63.49. The median amount of EPA (460 mg) and DHA (400 mg) per serving in the liquid products was higher than the nonliquid products. Thus, the median number of servings at the RxDose was only 3.6 teaspoons and the median monthly cost of $13.60. Only 22% of products met our "usage criteria." CONCLUSIONS: The amount of EPA and DHA per recommended serving in these products was highly variable. Clinicians should heighten their scrutiny in terms of selection of the appropriate product. PMID- 21787229 TI - Dynamic signals for hair follicle development and regeneration. AB - Hair follicles form during embryonic development and, after birth, undergo recurrent cycling of growth, regression, and relative quiescence. As a functional mini-organ, the hair follicle develops in an environment with dynamic and alternating changes of diverse molecular signals. Over the past decades, genetically engineered mouse models have been used to study hair follicle morphogenesis and significant advances have been made toward the identification of key signaling pathways and the regulatory genes involved. In contrast, much less is understood in signals regulating hair follicle regeneration. Like hair follicle development, hair follicle regeneration probably relies on populations of stem cells that undergo a highly coordinated and stepwise program of differentiation to produce the completed structure. Here, we review recent advances in the understanding of the molecular signals underlying hair follicle morphogenesis and regeneration, with a focus on the initiation of the primary hair follicle structure placode. Knowledge about hair follicle morphogenesis may help develop novel therapeutic strategies to enhance cutaneous regeneration and improve wound healing. PMID- 21787230 TI - Comparative proteomic analysis of human somatic cells, induced pluripotent stem cells, and embryonic stem cells. AB - Induced pluripotent stem cells (iPSCs) are somatic cells that have been reprogrammed to a pluripotent state via introduction of defined transcription factors. iPSCs are a valuable resource for regenerative medicine, but whether iPSCs are identical to embryonic stem cells (ESCs) remains unclear. In this study, we performed comparative proteomic analyses of human somatic cells [human newborn foreskin fibroblasts (hFFs)], human iPSCs (hiPSCs) derived from hFFs, and H9 human ESCs (hESCs). We reprogrammed hFFs to a pluripotent state using 4 core transcription factors: Oct4 (O), Sox2 (S), Klf4 (K), and c-Myc (M). The proteome of hiPSCs induced by 4 core transcription factors was relatively similar to that of hESCs. However, several proteins, including dUTPase, GAPDH, and FUSE binding protein 3, were differentially expressed between hESCs and hiPSCs, implying that hiPSCs are not identical to hESCs at the proteomic level. The proteomes of iPSCs induced by introducing 3, 5, or 6 transcription factors were also analyzed. Our proteomic profiles provide valuable insight into the factors that contribute to the similarities and differences between hESCs and hiPSCs and the mechanisms of reprogramming. PMID- 21787231 TI - Adjuvant properties of Cytosine-phosphate-guanosine oligodeoxynucleotide in combination with various polycations in an ovalbumin-vaccine model. AB - Oligonucleotides containing CpG motifs (cytosine-phosphate-guanosine oligodeoxynucleotide [CpG ODN]) display strong immunostimulatory effects, and polycations have been previously reported as cellular delivery system. In the present study, we investigated the adjuvant properties of combinations of a CpG ODN with various polycations (poly-arginine, poly-lysine, poly-histidine, or chitosan) in an ovalbumin vaccination model. We showed that, when combined to CpG ODN, poly-arginine and poly-histidine, but not poly-lysine or chitosan, enhanced efficiently both the IgG antibody production and the number of splenocytes secreting interferon-gamma after stimulation with a CD8+ T cell-restricted peptide. Interestingly, CpG ODN-poly-arginine, which was the most efficient, compared favorably to the complete Freund's adjuvant and aluminium salts and induced no local toxicity, making this combination a very attractive adjuvant for vaccines. PMID- 21787233 TI - The biological effects of lung-derived mediators on the liver. AB - Despite the use of lung-protective mechanical ventilation (MV), the mortality of patients with acute lung injury remains at 30 to 40%, predominantly due to multiorgan failure. The objective of this study was to determine the biological significance of lung-derived mediators on peripheral organ inflammation. The authors utilized an isolated perfused mouse lung model of lipopolysaccharide (LPS)-induced lung inflammation and protective MV to collect lung-derived mediators. Aliquots of perfusate from these animals (or appropriate controls) were then injected intravenously into a cohort of normal animals whose livers were subsequently assessed in vivo using intravital video microscopy. Perfusate from LPS-inflamed lungs contained significantly higher concentrations of inflammatory mediators than perfusate from saline-instilled lungs. Assessment of livers in the second cohort of animals 120 minutes after perfusate injection revealed decreased sinusoidal blood flow, leukocytosis, and increased cell death in those receiving perfusate from LPS-inflamed lungs compared to perfusate from saline controls. There were no differences between control animals that received pure perfusate or pure LPS mixed with perfusate. These results showed that lung derived mediators had a significant biological effect on nonpulmonary organs within a short period of time after administration. Therapies targeting these mediators may prevent multiorgan failure and death in patients with acute lung injury. PMID- 21787232 TI - Long-term systemic myostatin inhibition via liver-targeted gene transfer in golden retriever muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients. PMID- 21787234 TI - Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). AB - ABSTRACT MicroRNAs (miRNAs) are a class of small, noncoding RNAs that posttranscriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. Accumulating evidence suggests that miRNAs may play a role in chemoresistance and may be involved in the modulation of some drug resistance related pathways in cancer cells. Here, the authors investigated the possible role of miRNAs in the development of drug resistance in lung cancer cell line. The results showed that 14 miRNAs were presented significantly (>2-fold), including up-regulation of 9 miRNAs and down-regulation of 5 miRNAs in A549/DDP cell line, compared with the parental A549 cell line. Up-regulation of miR-138 increased the sensitivity of A549/DDP cells to cisplatin in in vitro drug sensitivity assay, and increased apoptosis assessed by flow cytometry. The authors also found that excision repair cross-complementation group 1 (ERCC1) was negatively regulated by miR-138 and that down-regulation of ERCC1 at the protein level largely correlated with elevated levels of miR-138 in A549/DDP cells. Taken together, these findings suggest that miR-138 could play an important role in the development of cisplatin resistance in non-small cell lung cancer (NSCLC). PMID- 21787236 TI - Treatment of hypertension in patients 85 years of age or older: a J-BRAVE substudy. AB - Whether the strict control of blood pressure (BP) of patients with hypertension who are aged 85 years or older is beneficial is unclear. The Japan's Benidipine Research on Antihypertensive Effects in the Elderly study is a prospective, observational 3-year study to evaluate the safety and effectiveness of treatment with a calcium channel blocker benidipine in 8897 hypertensive patients aged 65 years or older as a post-marketing surveillance. We examined the relationship between the achieved BP and cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) in a subgroup of 415 patients aged 85 years or older (mean age 88 years). BP decreased significantly from 165 +/- 14/84 +/- 10 mmHg to 130 +/- 11/71 +/- 10 mmHg during treatment in patients with a treated systolic BP (SBP) < 140 mmHg (n = 230) and BP decreased significantly from 169 +/ 16/86 +/- 12 mmHg to 143 +/- 13/75 +/- 10 mmHg in those with a treated SBP >= 140 mmHg (n = 185). There was a nonsignificant trend toward a lower rate of cardiovascular events and higher rate of total death in patients with a treated SBP < 140 mmHg. On-treatment SBP >= 160 mmHg is tended to associate with a higher incidence of cardiovascular events. There was no significant difference in the incidence of adverse reactions between the controlled BP group (3.04%) and the less well controlled BP group (3.24%). In conclusion, although this study was not powered for definitive conclusion, there was a nonsignificant trend toward a lower rate of cardiovascular events and higher total death in patients aged 85 years or older with a treated SBP < 140 mmHg. PMID- 21787237 TI - Exam anxiety induces significant blood pressure and heart rate increase in college students. AB - To investigate the relationship between the anxiety and blood pressure (BP) and heart rate (HR) increase in peri-exam period. Sixty-four college students(20.0 +/ 0.1 year old) were included in this study. The BP and HR were measured in the morning and in the evening for 3 days during the prereview (ba), review, and exam periods. The BP and HR increase amplitudes (HRIA) of review and exam periods were from the difference of corresponding values and basic values, and the BPIA/baBP and HRIA/baHR were calculated. All of the students completed the Self-Rating Anxiety score (SAS) questionnaire the first day of the exam period. Scores over 50 points were used as the standard for anxiety. From the prereview to exam periods, the BP and HR increased gradually. The exam SBPIA (4.3 +/- 1.3 vs. 0.3 +/- 0.5 mmHg, P < 0.05) and DBPIA (4.4 +/- 1.5 vs. 1.0 +/- 0.5 mmHg, P < 0.05) were significantly higher in the anxiety group than in the no-anxiety group. The SBPIA/DBPIA and HRIA showed a similar profile also(9.7 +/- 2.1 vs. 1.9 +/- 0.9 bpm, P < 0.05). Strong positive correlations were found between the SAS score and BPIA and HRIA both in the review and exam period. The smoking group and family hypertension group had higher anxiety score; meanwhile, their exam BPIAs and HRIAs were significantly higher than their corresponding group. The BP and HR increase in the review and exam period, anxiety is an important factor of BP and HR increase. PMID- 21787235 TI - Green tea epigallo-catechin-galleate ameliorates the development of obliterative airway disease. AB - Lung transplantation has the worst outcome compared to all solid organ transplants due to chronic rejection known as obliterative bronchiolitis (OB). Pathogenesis of OB is a complex interplay of alloimmune-dependent and independent factors, which leads to the development of inflammation, fibrosis, and airway obliteration that have been resistant to therapy. The alloimmune independent inflammatory pathway has been the recent focus in the pathogenesis of rejection, suggesting that targeting this may offer therapeutic benefits. As a potent anti-inflammatory agent, epigallo-catechin-galleate (EGCG), a green tea catechin, has been very effective in ameliorating inflammation in a variety of diseases, providing the rationale for its use in this study in a murine heterotopic tracheal allograft model of OB. Mice treated with EGCG had reduced inflammation, with significantly less neutrophil and macrophage infiltration and significantly reduced fibrosis. On further investigation into the mechanisms, inflammatory cytokines keratinocyte (KC), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-alpha), involved in neutrophil recruitment, were reduced in the EGCG-treated mice. In addition, monocyte chemokine monocyte chemoattractant protein-1 (MCP-1) was significantly reduced by EGCG treatment. Antifibrotic cytokine interferon-gamma-inducible protein-10 (IP-10) was increased and profibrotic cytokine transforming growth factor-beta (TGF-beta) was reduced, further characterizing the antifibrotic effects of EGCG. These findings suggest that EGCG has great potential in ameliorating the development of obliterative airway disease. PMID- 21787238 TI - Repair of recurrent cleft palate with free vastus lateralis muscle flap. AB - A 6-year-old girl presented with a large recalcitrant oronasal fistula after bilateral cleft lip and palate repair and numerous secondary attempts at fistula closure. Incomplete palmar arches precluded a free radial forearm flap. A free vastus lateralis muscle flap was successfully transferred. No fistula recurrence was observed at 18 months. There was no perceived thigh weakness. The surgical scar healed inconspicuously. Free flaps should no longer be considered the last resort for treatment of recalcitrant fistulas after cleft palate repair. A free vastus lateralis muscle flap is an excellent alternative, and possibly a superior option, to other previously described free flaps. PMID- 21787239 TI - Normative nasalance scores for the Malay language. AB - OBJECTIVE: To establish normative nasalance scores for a set of newly developed stimuli in Malay. DESIGN: Cross-sectional study. PARTICIPANTS: Participants were 150 native speakers of Malay aged 6 years to 12 years. METHOD: All consented participants were initially screened to identify any overt difficulties relating to hearing, voice quality, resonance, or speech and language skills. Participants who passed the screen read or repeated each stimulus, and nasalance scores were recorded. RESULTS: The mean nasalance score for the Oral passage was 13.86% (SD = 5.11, 95% CI = 13.04 to 14.68), 60.28% (SD = 6.99, 95% CI = 59.15 to 61.41) for the Nasal Passage, and 27.72% (SD = 4.74, 95% CI = 26.96 to 28.49) for the Set of Sentences. CONCLUSION: Despite small variations, the overall mean nasalance scores in Malay are consistent with published norms in other languages. Age and sex differences were observed but clinically not relevant. PMID- 21787240 TI - New beta-glucan inhibitors as antifungal drugs. AB - INTRODUCTION: New classes of synthetic and semi-synthetic beta-glucan inhibitors have recently emerged, providing analogs that, in some cases, have been proven to have a high degree of activity against fungi, offering the prospect of alternatives to the commercially available lipopeptide/echinocandin agents caspofungin, micafungin and anidulafungin. AREA COVERED: This review covers applications disclosing compound classes that include synthetic pyridazinone analogs, bicyclic heteroaryl ring compounds, aniline derivates, and semi synthetic echinocandin and enfumafungin derivatives. MK-3118 is an analog of the natural product enfumafungin that, in particular, shows promise as it has a spectrum of activity comparable with caspofungin but has the advantageous property of oral bioavailability. EXPERT OPINION: The diversity of chemical classes in the present review, which have demonstrable activity against beta glucan and the prospect of oral bioavailability, offers hope that safe and effective antifungal drugs will emerge and be commercialized. Of particular note, the Merck compound MK-3118, with solid evidence of efficacy based on preclinical data, has moved into clinical trials. PMID- 21787241 TI - Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn's disease. AB - INTRODUCTION: Human mesenchymal stem cells (Prochymal brand of remestemcel-L) have been developed for experimental use in Crohn's disease and other conditions. Mesenchymal stems cells (MSCs) have been shown to inhibit inflammatory responses of innate and adaptive immune cells as well as have reparative effects on inflamed tissues. Promising preliminary therapeutic results of MSCs on gastrointestinal graft-versus-host disease have lead to Phase III trials for active Crohn's disease. AREAS COVERED: This review examines the discovery and characterization of mesenchymal stem cells, their immune effects, their use in animal models of disease, the production and administration of remestemcel-L and the published results of trials of remestemcel-L and alternative MSCs in Crohn's disease. EXPERT OPINION: The Prochymal brand of remestemcel-L represents the successful pharmaceutical development of mesenchymal stem cells for potential therapy in human disease. While preliminary results show promise of this therapy in terms of efficacy and safety, robust trials confirming efficacy results, explanation of the mechanism of response and estimates of effect compared to other biologics and immunosuppressants will be needed before this is an approved and widely accepted therapy. PMID- 21787242 TI - Abacavir and lamivudine for the treatment of human immunodeficiency virus. AB - INTRODUCTION: The introduction of combination antiretroviral therapy (cART) in 1996 dramatically changed the survival and the quality of life of people living with human immunodeficiency virus (HIV). Viral replication can be controlled by using a combination of more than 30 licensed drugs. Despite the fact that many advances have been made in the last 20 years of experience with antiretrovirals, certain needs remain to be addressed, such as the presence of chronic inflammation, the long-term side effects of newly introduced drugs and eradication. Abacavir (ABC) and lamivudine (3TC) are licensed in a fixed-dose combination to be administered once daily with other antiretroviral agents for the treatment of HIV. AREAS COVERED: This article provides an extensive review of the evidence on the combination of ABC 600 mg and 3TC 300 mg. Specifically, it discusses the chemistry-- including the phrarmacodynamics, resistance to treatment, pharmacokinetics and metabolism--and formulations available. It also looks at clinical efficacy, including safety and tolerability. EXPERT OPINION: In the last few years, new data regarding human leukocyte antigen (HLA) B*5701 testing to prevent the hypersensitivity reaction due to ABC have been presented, providing a landmark in the management of adverse events in HIV, and later a previously unexpected correlation of the recent exposure to ABC with an increased risk of cardiovascular disease. This review presents the current situation with regard to the long-term efficacy and safety data on the ABC/3TC combination. PMID- 21787243 TI - Antimalarial activity in Xylocarpus granatum (Koen). AB - The antimalarial activity of Xylocarpus granatum fruits and their active constituents gedunin and xyloccensin-I were investigated using an in vitro model in this study. The chloroform fraction of X. granatum fruits was found to show promising antimalarial activity using an in vitro model of Plasmodium falciparum. On purification of the active fraction, four pure compounds were isolated and characterised, namely gedunin, photogedunin, xyloccensin-I and palmitic acid. Out of these only gedunin and xyloccensin-I were found to show activity equivalent to the parent active fraction in vitro model. PMID- 21787244 TI - Bilateral redundancy gain and callosal integrity in a man with callosal lipoma: a diffusion-tensor imaging study. AB - We investigated whether abnormalities in the structural organization of the corpus callosum in the presence of curvilinear lipoma are associated with increased facilitation of response time to bilateral stimuli, an effect known as the redundancy gain (RG). A patient (A.J.) with a curvilinear lipoma of the corpus callosum, his genetically-identical twin, and age-matched control participants made speeded responses to luminant stimuli. Structural organization of callosal regions was assessed with diffusion-tensor imaging. A.J. was found to have reduced structural integrity in the splenium of the corpus callosum and produced a large RG suggestive of neural summation. PMID- 21787245 TI - Driving ability in stroke patients with residual visual inattention: a case study. AB - Driving ability of three patients having a right hemisphere infarct and residual visual inattention was examined. The neuropsychological examination included the Peripheral Perception Test and the Signal Detection Test from the Vienna Test System, and the Behavioural Inattention Test (BIT). Driving ability was assessed with an on-road evaluation. The patients had no neglect based on the BIT and had normal visual fields, but they showed slightly poorer visual search on the left side. All patients passed the official on-road driving test and were considered capable of driving. This study raises the question if acute neglect can recover to a degree in which driving may be possible. PMID- 21787246 TI - Through the eyes of the own-race bias: eye-tracking and pupillometry during face recognition. AB - People are generally better at remembering faces of their own race than faces of a different race, and this effect is known as the own-race bias (ORB) effect. We used eye-tracking and pupillometry to investigate whether Caucasian and Asian face stimuli elicited different-looking patterns in Caucasian participants in a face-memory task. Consistent with the ORB effect, we found better recognition performance for own-race faces than other-race faces, and shorter response times. In addition, at encoding, eye movements and pupillary responses to Asian faces (i.e., the other race) were different from those to Caucasian faces (i.e., the own race). Processing of own-race faces was characterized by more active scanning, with a larger number of shorter fixations, and more frequent saccades. Moreover, pupillary diameters were larger when viewing other-race than own-race faces, suggesting a greater cognitive effort when encoding other-race faces. PMID- 21787247 TI - The color of touch: a case of tactile-visual synaesthesia. AB - We report a single-case study, EB, who experiences synaesthetic sensations of color from tactile stimulation. Developmental synaesthesia is typically characterized by the consistency of synaesthetic pairings over time, in that stimuli tend to generate the same synaesthetic responses on different occasions. Here we demonstrate that EB's touch-color associations are significantly more consistent over time compared to a group of non-synaesthete controls, but that this comes in the face of surprisingly high consistency among non-synaesthetes themselves, for certain tactile stimuli. We show, too, that EB's touch-color correspondences are guided by an implicit rule system, and that this system is shared by non-synaesthetes. Both synaesthetes and non-synaesthetes are sensitive to tactile qualities such as smoothness and softness, and these qualities are systematically related to the luminance and chroma of associated colors. PMID- 21787248 TI - Openness to psychological explanations and treatment among people with fibromyalgia versus rheumatoid arthritis. AB - OBJECTIVE: The classic perspective in the psychosomatic literature is that patients with medically unexplained syndromes do not acknowledge psychologically based causes for their conditions and will not engage in psychological treatments. These assumptions were tested by contrasting the illness models and reported treatment experiences of individuals with fibromyalgia (FM), a syndrome with a currently unknown organic origin, with those of individuals with rheumatoid arthritis (RA), a 'legitimate' (i.e. organic) condition. METHOD: 193 patients with FM and 176 with RA completed measures assessing their views about the causes of their condition, the treatments they had used and their judged effectiveness. RESULTS: Contrary to prediction, compared to patients with RA, patients with FM were more likely to endorse psychological causes for their condition and reported having used more psychological management approaches. Moreover, patients with FM considered psychological approaches to be more effective than narcotics. CONCLUSION: These findings indicate that patients with FM do not react defensively to the implication of psychogenic causes. Rather, as a group, they tend to acknowledge both the psychosocial influences on and the effectiveness of psychological management approaches for their condition. PMID- 21787249 TI - Neuroprotective effect of Manasamitra vatakam against aluminium induced cognitive impairment and oxidative damage in the cortex and hippocampus of rat brain. AB - Manasamitra vatakam (MMV) has long been used as a traditional medicine in India for the treatment of psychosomatic diseases, anxiety neurosis, and stress. The present study was designed to examine the neuroprotective effect of MMV against aluminum (Al)-induced memory impairment and oxidative damage in rats. Neurotoxicity was induced by the administration of Al [100 mg/kg body weight (b.w.) per oral (p.o.)/day] to Wistar albino rats for 90 days. Al administration induced neurotoxicity as well as oxidative stress by affecting the active avoidance and memory impairment, as well as altering antioxidants, such as HSP70 protein, superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase, and acetylcholinesterase. It was observed that the administration of MMV (100 mg/kg b.w./p.o./day) along with AlCl(3) improves memory performance and antioxidant activity against Al-induced neurotoxicity in rats. In conclusion, these data suggest that MMV can prevent brain damage from Al-induced neurotoxicity in rats and thus can be used as a neuroprotective agent. PMID- 21787251 TI - Examining the structure of emotional intelligence at the item level: new perspectives, new conclusions. AB - Despite twenty years of research, many unknowns remain regarding the Mayer Salovey (e.g., 1997) model of emotional intelligence (EI) and the validity of tests that have been designed to measure it. Evidence relevant to the internal structure of EI has come mainly from factor-analytic studies of the MSCEIT and the MEIS, utilising parcelled task scores rather than individual test items. This approach has several deficiencies: in addition to the loss of item-level information, it results in an insufficient number of observed variables per factor and an inability to separate structural sources of local item dependence (i.e., method variance) from construct-related variance. The present study (N=707) employed multidimensional item response modelling to investigate the dimensional structure of the MSCEIT, at the item level, for the first time. It is shown that item format and the specific choice of task explain far more of the variance in response patterns than does the hypothesised dimensional structure of EI, to the point that there is no empirical reason to prefer a higher-dimensional model of EI over a unidimensional model. It is argued that the advantage of an item-level perspective can be fundamental, rather than merely incremental. PMID- 21787252 TI - Spatial and seasonal variations in the stable C isotope composition of dissolved inorganic carbon and in physico-chemical water parameters in the Plitvice Lakes system. AB - Plitvice Lakes waters were collected at 14 sampling points, including springs, tributaries and lakes, for the period 2002-2007. The results of the physical and chemical conditions of calcite precipitation as well as the delta(13)C values of dissolved inorganic carbon (DIC) were used to study the processes influencing calcite precipitation. Significant differences between spring, lake and stream waters as well as changes in the downstream direction were observed. The correlation between delta(13)C(DIC) values and physico-chemical conditions for calcite precipitation showed that calcite precipitates in lake waters which are oversaturated with respect to CaCO(3) (I (sat) values 4-10) and with delta(13)C(DIC) values between-11.5 and-8.5 0/00. In spring waters, the delta(13)C(DIC) values were more negative, from-14 to-12 0/00, and I (sat) values of 1-2 indicated that equilibrium conditions for calcite precipitation were not attained. The downstream increase in delta(13)C(DIC) correlated with the increase in the delta(13)C values of calcite in the lake sediments, suggesting that the freshwater calcite was mainly of autochthonous origin and precipitated within the water column in isotopic equilibrium with DIC. PMID- 21787250 TI - Fluid shear stress alters the hemostatic properties of endothelial outgrowth cells. AB - Surface endothelialization is an attractive means to improve the performance of small diameter vascular grafts. While endothelial outgrowth cells (EOCs) are considered a promising source of autologous endothelium, the ability of EOCs to modulate coagulation-related blood activities is not well understood. The goal of this study was to assess the role of arterial flow conditions on the thrombogenic phenotype of EOCs. EOCs derived from baboon peripheral blood, as well as mature arterial endothelial cells from baboons, were seeded onto adsorbed collagen, then exposed to physiologic levels of fluid shear stress. For important hemostatic pathways, cellular responses to shear stress were characterized at the gene and protein level and confirmed with a functional assay for activated protein C (APC) activity. For EOCs, fluid shear stress upregulated gene and protein expression of anticoagulant and platelet inhibitory factors, including thrombomodulin, tissue factor pathway inhibitor, and nitric oxide synthase 3 (eNOS). Fluid shear stress significantly altered the functional activity of EOCs by increasing APC levels. This study demonstrates that fluid shear stress is an important determinant of EOC hemostatic properties. Accordingly, manipulation of EOC phenotype by mechanical forces may be important for the development of thrombo-resistant surfaces on engineered vascular implants. PMID- 21787253 TI - Fighting down the scourge, building up the church: organisational constraints in religious involvement with HIV/AIDS in Mozambique. AB - Religious organisations (ROs) are often said to play an important role in mitigating the impact of HIV/AIDS. Yet, limitations of that role have also been acknowledged. While most of the literature has focused on ideological and individual-level implications of religion for HIV/AIDS, in this study we shift the focus to the organisational factors that shape and constrain ROs' involvement in both HIV prevention and HIV/AIDS care and support. Using primarily qualitative data collected in a predominantly Christian area in southern Mozambique, we show that the organisational vitality of a RO as determined by its membership size and its relationships with other churches and with governmental and non-governmental agencies is a pervasive priority of RO leaders. Therefore, all church activities, including those related to HIV/AIDS, are instrumentalised by the religious leadership to achieve the church's organisational aims--maintaining and growing its membership, safeguarding the often precarious coexistence with other churches, and enhancing its standing vis-a-vis the government and powerful non governmental organisations. As a result, the effectiveness of ROs' involvement in HIV/AIDS prevention and assistance is often compromised. PMID- 21787254 TI - The bumpy road to socialise nature: sex education in Japan. AB - This study was prompted by an empirical puzzle: why is sex education in schools so underdeveloped in Japan compared to many other industrialised societies? On the one hand, formal pedagogy under state policy is conservative, emphasising reproductive and prophylactic purposes rather than a comprehensive understanding of sexuality. On the other hand, however, Japan has a highly visible sexual environment where a variety of commercial sex activities are tolerated and even encouraged. The aim of the paper is to provide an integrated picture of these apparently contradictory trends by examining the nexus of political, economic and sociocultural factors that affect sex education in contemporary Japan. PMID- 21787255 TI - Gendered HIV risk patterns among polygynous sero-discordant couples in Uganda. AB - Stable serodiscordant relationships and sexual concurrency are pathways that contribute to the HIV epidemic in sub-Saharan Africa. However whether polygyny imparts the same risks as informal concurrent relationships remains an open research question. Using data collected at enrollment from a cohort study of sero discordant couples, this analysis investigates how polygynous relationships differ from those involving only a single female spouse and whether men involved in polygynous partnerships are more likely to report HIV-risk behaviour than those in single spouse partnerships. Of 444 enrolled couples, 111 (25%) were polygynous and 333 (75%) were single-spouse partnerships. We found that polygynous men were more likely to report controlling sexual decision-making and to report any unprotected sex with unknown sero-status partner. After controlling for potential confounders, polygynous men were still more likely to report unprotected sex with an unknown sero-status partner. In this sample of sero discordant couples we found indication of excess HIV-risk behaviour among men involved in polygynous relationships. PMID- 21787256 TI - Making sense of abstinence: social representations in young Africans' HIV-related narratives from six countries. AB - Despite the prominence of abstinence promotion in HIV prevention for young Africans, there is little documentation concerning its reception and interpretation. With the purpose of informing programmatic practice, we examined how young Africans from six countries with contrasting HIV prevalence rates make sense of abstinence. 'Scenarios from Africa' scriptwriting contests invite young people to contribute ideas for short films about HIV. Using thematic narrative based approaches, we analyzed a stratified random sample of these narratives written in 2005 by young women and men aged 10-24 years from Senegal, Burkina Faso, South-East Nigeria, Kenya, Namibia and Swaziland. Abstinence was considerably more prominent as a theme in the samples from SE Nigeria, Kenya and Swaziland. It was articulated in relation to conservative Christian sexual morality and in opposition to condom use with particular intensity in SE Nigeria, with stigmatising implications for non-abstainers. However, cross-national commonalities were more striking than differences. Examples of non-stigmatising pro-abstinence messaging highlighted the appeal of discourses of romantic love and future plans across countries and demographic characteristics. The analysis yielded contextual understanding, youth-driven ideas and recommendations to inform comprehensive HIV-prevention efforts. PMID- 21787259 TI - Risk factors associated with retained placenta after cesarean delivery. AB - OBJECTIVES: Retained placenta after cesarean delivery (RPAC) is a rare phenomenon that has not been previously studied in detail. The objective of our study was to identify potential risk factors that predispose to the development of this obstetrical complication. METHODS: We performed a retrospective case-control study comparing 20 cases of RPAC with 40 matched controls, using logistic regression models to test likely risk factors. RESULTS: RPAC occurred in 0.16% of cesarean deliveries in our population. The crude odds ratio (OR) of RPAC was increased in patients who had preterm delivery (PTD) (OR=9.06, 95% CI: 2.04 40.29), conceived with artificial reproductive technology (ART) (OR=5.03, 95% CI: 1.24-20.40), and carried multiples (OR=18.89, 95% CI: 2.29-151.23). Conversely, for each week of gestation the odds of RPAC decreased by 0.57 (95% CI: 0.40 0.82). CONCLUSIONS: Earlier gestational age, PTD, use of ART and multiples are associated with increased OR of RPAC. PMID- 21787260 TI - Outcome of severe intrapartum acidemia diagnosed with fetal scalp blood sampling. AB - AIM: To analyze short-term neonatal outcome and the sampling to delivery interval in cases with severe intrapartum acidemia diagnosed with fetal scalp blood sampling (FBS). METHODS: This is a secondary analysis of data from a trial of 2992 women, who were, when indicated, randomized to either lactate or pH analyses by FBS. Median and 95(th) centile values for lactate analyses were 2.9 mmol/L and 6.6 mmol/L, respectively. Corresponding pH values were 7.30 and 7.17. We defined severe intrapartum acidemia as lactate >6.6 mmol/L or pH <7.17. Outcome measures were cord artery pH <7.00, Apgar <7 at 5 min, hypoxic ischemic encephalopathy and time interval from FBS to delivery. RESULTS: Severe intrapartum acidemia was present in 85/1355 (6.3%) cases with lactate analyses and in 69/1008 (6.8%) cases with pH analyses. Cord artery pH <7.00 occurred in 12/154 (7.8%), Apgar <7 at 5 min in 16/154 (10.4%) and hypoxic ischemic encephalopathy in 4/154 (2.6%) of the cases. There were no differences in outcomes between the two groups. However, delivery was expedited more rapidly in the pH management group (median 16 vs. 21 min; P=0.01). CONCLUSION: Severe neonatal morbidity occurred in 10% or less in this high-risk group. FBS is an early marker of intrapartum hypoxia and can be used to prevent severe birth acidemia. Lactate might be an earlier marker than pH in the hypoxic process. PMID- 21787261 TI - Clinical and pathological features of testicular diffuse large B-cell lymphoma: a heterogeneous disease. AB - Most testicular lymphomas are of diffuse large B-cell (DLBCL) type with an outcome inferior to nodal DLBCL. Within an apparently homogeneous group of testicular DLBCLs, small cell components, plasmacytoid differentiation and lymphoepithelial lesions (LELs), features of extranodal marginal zone lymphoma (eMZL), can be identified. The aim of this study was to define the histological features of testicular DLBCL and correlate this with their clinical behavior and outcome. Thirty-six patients with testicular DLBCL (Ann Arbor stage I/II) were identified through the databases of two Dutch regional cancer registries, diagnosed between 1981 and 1999. Follow-up for patients alive was more than 10 years. Medical records and pathology specimens were reviewed. eMZL features were found in 53% of the cases of localized stage testicular DLBCL. Compared to patients with "pure" DLBCL, patients with DLBCL with eMZL features presented more often with stage I disease, normal lactate dehydrogenase, smaller tumors and absence of B-symptoms, and they responded more favorably to initial treatment. Their median survival was 48 months versus 12 months for "pure" DLBCL (p = 0.87). Features of eMZL were commonly identified in testicular DLBCL and they correlated with a more favorable clinical presentation and better response to initial therapy. However, these differences did not reach statistical significance due to small numbers. PMID- 21787262 TI - Genomic aberrations affecting the outcome of immunodeficiency-related diffuse large B-cell lymphoma. AB - The objective of this study was to evaluate the prognostic impact of genomic regions in a series of human immunodeficiency virus (HIV)-related diffuse large B cell lymphomas (HIV-DLBCLs) and post-transplant DLBCLs (PT-DLBCLs) analyzed by genome-wide DNA profiling. Minimal common regions (MCRs) were estimated on genomic profiles obtained using Affymetrix Human Mapping 250k Nsp I arrays and tested for their impact on clinical outcome by univariate analysis on 36 PT DLBCLs, 19 HIV-DLBCLs and, as a control group, 149 DLBCLs arising in immunocompetent individuals (IC-DLBCLs). PT-DLBCL and HIV-DLBCL presented a similar outcome. Immunodeficiency-related DLBCL (ID-DLBCL) had a worse overall survival (OS) than IC-DLBCL. Seven MCRs showed a statistical impact on OS in PT DLBCL and four in HIV-DLBCL. Among these, the presence of gains at 1q or at 18q defined a group of patients with PT-DLBCL with a very poor outcome (p < 0.0001). The presence of del(3p14.2) or of + 2p23.1 identified a group of HIV-DLBCLs with a very poor outcome (p = 0.0072). It was concluded that genomic aberrations affecting outcome differ between ID-DLBCL and IC-DLBCL and are also dependent on the type of acquired immunodeficiency. PMID- 21787263 TI - Overview of SLC22A and SLCO families of drug uptake transporters in the context of cancer treatments. AB - The effectiveness of many anticancer agents is dependent on their disposition to the intracellular space of cancerous tissue. Accumulation of anticancer drugs at their sites of action can be altered by both uptake and efflux transport proteins, however the majority of research on the disposition of anticancer drugs has focused on drug efflux transporters and their ability to confer multidrug resistance. Here we review the roles of uptake transporters of the SLC22A and SLCO families in the context of cancer therapy. The many first-line anticancer drugs that are substrates of organic cation transporters (OCTs) organic cation/carnitine transporters (OCTNs) and organic anion- transporting polypeptides (OATPs) are summarized. In addition, where data is available a comparison of the localization of drug uptake transporters in healthy and cancerous tissues is provided. Expression of drug uptake transporters increases the sensitivity of cancer cell lines to anticancer substrates. Furthermore, early observational studies have suggested a causal link between drug uptake transporter expression and positive outcome in some cancers. Quantification of drug transporters by mass spectrometry will provide an essential technique for generation of expression data during future observational clinical studies. Screening of drug uptake transporter expression in primary tumors may help differentiate between susceptible and resistant cancers prior to therapy. PMID- 21787264 TI - Pharmacokinetic and pharmacogenetic predictive markers of irinotecan activity and toxicity. AB - After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed. PMID- 21787265 TI - Clinical pharmacokinetic and metabolism of PET radiotracers for imaging P glycoprotein in chemoresistant tumor of colorectal cancer. AB - The pharmacological treatment of colorectal tumour leads to MultiDrug Resistance due to overexpression of several ABC transporters such as P-glycoprotein and some Multidrug associated Resistance Proteins (MRPs) that are able to efflux the chemotherapeutic agent out of the cell. A strategy to reverse MDR is the co administration of antineoplastic agent with a P-glycoprotein inhibitor. These inhibitors are an useful tool for investigating, by PET, the expression and the activity of P-gp and MRPs that are overexpressed in chemoresistant colorectal tumor cells. In this review will be focused the aspect on P-gp and MRPs ligands employed as PET radiotracers considering their pharmacokinetic pharmacodynamic profile and their selectivity towards ABC transporters involved in chemoresistant cell of colorectal tumour. PMID- 21787266 TI - Alternative spliced variants as biomarkers of colorectal cancer. AB - Surgical resection and adjuvant therapy, which mainly involves 5-fluorouracil (5 FU), irinotecan (CPT-11), oxaliplatin (LOHP) chemotherapy and recently targeted therapy, are the most common treatments of colorectal cancer (CRC). As to improve the therapeutic efficacy and assist with therapeutic decisions, there is an urgent need for prognostic and predictive molecular biomarkers. Recent evidence demonstrates that aberrations in alternative splicing process of cancer will provide candidate biomarkers for cancers to meet this need. In this review, we outline the fundamental mechanism of alternative splicing that plays a major role in protein diversity, and summarize the relationship between imbalance alternative splicing with cancer. Moreover, several alternative spliced variants and cancer-specific splicing events at the mRNA level in CRC, which may serve as diagnostic, predictive, prognostic markers of CRC, are also discussed. These specific splice variants or the RNA splicing machinery will be new, potential targets for the treatment of CRC that offers a specific site of anti-cancer chemotherapy. PMID- 21787267 TI - The impact of folate status on the efficacy of colorectal cancer treatment. AB - Over the past three decades, numerous reports have addressed several aspects of drug resistance phenomena. However, little is known regarding the impact that dietary components and nutritional supplements have on the mechanisms of resistance that malignant cells develop to chemotherapeutic agents. The increased fortification of cereals, grains and bread with folic acid (FA) has resulted in a marked rise in folate levels in blood and tissues. Vitamin fortification that includes FA is rather commonly used by cancer patients, but FA is also used to protect against pemetrexed induced side effects in the treatment of non-small cell lung cancer and mesothelioma or that of the antifolate methotrexate in rheumatoid arthritis. Moreover, the reduced folate leucovorin (LV, 5 formyltetrahydrofolate) is also used along with 5-fluorouracil in the treatment of colorectal cancer. Likewise, LV is used to reduce toxicity of methotrexate in the treatment of leukemia. FA can also increase efficacy of unrelated regimens, containing cisplatin. Hence there is growing evidence that dietary supplements as folic acid, can mimic, intensify, or attenuate the effects of unrelated chemotherapeutic agents. The aim of this review is to highlight some new insights in the cellular and molecular mechanisms affected by folate status, leading to chemotherapy resistance, especially towards antifolates in colorectal cancer treatment. This encompasses the effect of folate status on drug export, as well as on the increased expression of mutated target enzymes involved in folate metabolism and on the augmentation of cellular folate pools that impair polyglutamylation of antifolates, ultimately affecting treatment efficacy. PMID- 21787268 TI - Predicting efficacy and toxicity in the era of targeted therapy: focus on anti EGFR and anti-VEGF molecules. AB - The treatment of solid malignancies includes various target drugs, such as monoclonal antibodies and tyrosine kinase inhibitors, which exert their effect alone or in combination with chemotherapy. The main part of these molecules have a target on proteins of EGFR and VEGF pathways. The particular toxicity profile and the financial impact, deriving from the application of these agents in cancer treatment, prompted a lot of researches to define predictive factors of their efficacy. Various biomarker were identified among the components of the targeted pathways. However just few studies allowed to identify specific factors to predict the toxicity of these drugs. In this review EGFR and VEGF-related pathways are described, most relevant clinical findings about target therapy applications are exposed and the clinical impact of predictive factors of efficacy and toxicity are discussed. PMID- 21787269 TI - DNA copy number profiles correlate with outcome in colorectal cancer patients treated with fluoropyrimidine/antifolate-based regimens. AB - For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5 FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy. PMID- 21787270 TI - Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients. AB - Fluoropyrimidines and oxaliplatin continued to be the mainstay of therapeutic regimens in the treatment of colorectal cancer (CRC). For this reason, pharmacokinetic and metabolism of these drugs were analyzed and the identification of accurate and validated predictive, prognostic and toxicity markers became necessary to develop an effective therapy adapted to the patient's molecular profile, while minimizing life-threatening toxicities. In this review, we discuss literature data, defining predictive and prognostic markers actually identified in the treatment of CRC. We analyzed predictive markers of fluoropyrimidines effectiveness, principally for 5-Fluorouracil (5- FU) and also for oral fluoropyrimidines, as thymidylate Synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), methylenetetrahydrofolate reductase (MTHFR), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), microsatellite instability. DPD represent the more studied 5-FU toxicity marker, followed by TS and OPRT. Oxaliplatin effectiveness is principally regulated by nucleotide excision repair (NER) pathway, including excision repair cross-complementation group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XDP). The major oxaliplatin toxicity marker is represented by glutathione S-transferase (GST). All these results are based principally on retrospective studies. The future challenge became to validate molecular markers and their association with clinical outcomes in prospective trials, refining technologic platforms and bioinformatics to accommodate the complexity of the multifaceted molecular map that may determine outcome, and determining CRC patients most likely to benefit from therapeutic interventions tailored specifically for them. PMID- 21787271 TI - Biomarkers of chemotherapeutics efficacy and toxicity in colorectal cancer. PMID- 21787272 TI - KIR molecules: recent patents of interest for the diagnosis and treatment of several autoimmune diseases, chronic inflammation, and B-cell malignancies. AB - There has been rapidly increasing interest in innate immunity in recent years. Natural killer (NK) cells are cytotoxic lymphocytes that constitute a major component of the innate immune system. NK cells are mainly modulated through different receptors and cytokines. The killer immunoglobulin-like receptors (KIRs) represent the largest category of NK cell receptors. KIR function is mainly regulated by binding both classical MHC I (human leukocyte antigen, HLA A, B and C) and also non-classical MHC. Some KIRs are specific to certain HLA subtypes. Questions about how the NK cells sense self-antigen, infection, and altered cells, and how a protective immune response can be induced are being answered at the molecular level. Research has revealed the central role of innate immunity in the pathogenesis of many autoimmune and inflammatory diseases, as well as B-cell malignancies, with the emergence of recent developments for KIR characterization, disease monitoring, and treatment. In this paper, we report three recent patents focused on KIR applications: the first one is targeted at the determination of the complex KIR haplotypes by using next generation sequencing; the second patent represents a practical approach for genotyping and treatment of the main KIR-related autoimmune and chronic inflammatory diseases; and the last patent describes the possible contributions of KIR to promising combination immunotherapies. PMID- 21787273 TI - An analysis of federal circuit discrimination: the evolution of the written description requirement vis-a-vis DNA and biotechnological inventions concerns for synthetic biology. AB - The Federal Circuit uses particular patent doctrines as policy levers to control the nature of the nation's patent output. To this end, the Court will actively discriminate in it's application of the Patent Act, depending on the nature of the technology before it. One example of such a lever is the written description doctrine. Most recently, the court has looked to this doctrine in an effort to limit the scope of biotechnology patents in general and DNA patents in particular. This paper provides a cursory review of this law regarding the enigmatic written description requirement, examining particularly its history and purposes. It then examines some of the recent cases that allude to the Federal Circuit's particular efforts in the biotechnology industry. Finally, it presents a potentially problematic technology for future implementation of discriminatory practices by the court. PMID- 21787274 TI - Editorial: Focal adhesion kinase signaling in cancer--Part II. PMID- 21787275 TI - Nanoparticles in oncology: the new theragnostic molecules. AB - Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover, cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently, nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapy and diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context of the current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and application of nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findings with respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recent prospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system and apoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drug discovery. PMID- 21787276 TI - Development of focal adhesion kinase inhibitors in cancer therapy. AB - Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase implicated in cancer progression, and plays a vital role in integrating environmental signals from growth factors, extracellular matrix and mechanical forces. As a scaffolding protein, FAK interacts and regulates the activity of many signaling kinases including Src, VEGFR-3, p53, PI3k and IGF-1R. In turn, FAK activity is modulated by a complex network of regulators that presents a number of therapeutic approaches to targeting FAK in cancer therapy. The ATP competitive inhibitors binds directly to FAK kinase domain to abrogate multiple downstream signaling pathways, and this class of agents lead the way in FAK inhibitor clinical development. CFAK-C4 and Y15 represents a novel class of non-ATP dependant, allosteric inhibitors that interrupt protein-protein interactions to achieve anti cancer effects. The optimal approach to targeting FAK for cancer therapy is currently under investigation. Preliminary efficacy signals from early-phase trials suggest that FAK inhibitors may be best used in combination therapy. In addition to determining dosing schedules that is tolerable by patients, future clinical studies should include mechanistic-based pharmacodynamic studies to determine the biological active dose and explore potential predictive markers. In summary, a rich pipeline of FAK-targeting agents is entering clinical development and has the potential of improving the lives of cancer patients. PMID- 21787278 TI - Design and synthesis of N-phosphoryl peptide modified podophyllotoxin derivatives as potent anticancer agents. AB - A series of novel compounds with N-phosphoryl peptide modification at the C-4 position on podophyllotoxin were synthesized and evaluated for their cytotoxicity in vitro against K562 cell lines. Among these compounds 5c, 5f and 5k exhibited better cytotoxicity (IC(50) = 5.5 uM, 2.1 uM, and 3.1 uM, respectively) than podophyllotoxin and etoposide. Further study on compound 5f using flow cytometry analysis indicated that the anti-tumor effect might be due to the induction of apoptosis. PMID- 21787277 TI - Clinical importance and potential use of small molecule inhibitors of focal adhesion kinase. AB - Since its first description Focal Adhesion Kinase (FAK), a cytoplasmatic tyrosine kinase, has been implicated in the formation and progression of solid and liquid malignant tumors. Therefore orally available selective small molecule inhibitors of FAK have been developed, three of them (PF-562-271, PF-04554878 and GSK2256098) are already in clinical testing. This review discusses the recent data obtained from these Phase 1 trials. We also discuss available data on the mechanisms of action of these inhibitors in carcinogenesis and demonstrate that FAK plays an important role in neoangiogenesis which is a crucial step in cancer growth. PMID- 21787279 TI - The potent antiplasmodial calmodulin-antagonist trifluoperazine inhibits plasmodium falciparum calcium-dependent protein kinase 4. AB - Due to their critical involvement in the execution of the malaria parasite developmental pattern both in the mosquito vector and in the human host, Plasmodium calcium-dependent protein kinases (CDPKs) are considered promising candidates for the development of new tools to block malaria transmission. We report here that the phenothiazine trifluoperazine non-competitively inhibits Plasmodium falciparum CDPK4 in the micromolar range while other calmodulin antagonists only marginally affect the enzyme activity, and we propose the inhibition mechanism. Our results demonstrate that selective enzyme inhibition is achievable by targeting its calmodulin-like domain. This observation could be exploited for the discovery of innovative phenothiazine-based CDPK inhibitors of potential medical interest. PMID- 21787280 TI - A solution study of the interaction of the Cu(II) ions with HisGlyGlyTrp tetrapeptide and its evaluation as superoxide dismutase mimetic complex. AB - The superoxide anion radical is a highly reactive toxic species produced during the metabolic processes. A number of copper (II) complexes with amino acids and peptides are known to show superoxide dismutase (SOD) like activity. The design and application of synthetic low molecular weight metal complexes as SOD mimics have received considerable attention during the last decade. A variety of di- and tri-peptides containing histidyl residue in different positions have been employed to bind Cu(II) and to show the activity. But reports on Cu(II) complex with tetra-peptide having histidine amino acid in this regard are limited. As the HGGGW peptide having His at its N-terminal is reported to be a potential moiety for Cu(2+) binding, in the present work the synthesis of HisGlyGlyTrp peptide and its complexation with copper (II) ions has been reported. The interaction of synthesized peptide with Cu(II) was studied by electron spray ionization-mass spectrometer (ESI-MS) and UV-Vis spectroscopic methods. The species distribution was studied by combined spectrophotometric and potentiometric methods. The studies were performed at 25 +/- 0.1 degrees C with constant ionic strength (u = 0.1 M NaNO(3)) in aqueous solution using Bjerrum-Calvin's pH-titration technique as adopted by Irving and Rossotti for binary systems. The solution studies suggested that the pH of the medium play important role in the different species formation of the copper complexes. Species distribution curves indicate that Cu complexation takes place at all physiological pH values from 3-11. The resultant copper (II) peptide complex at physiological pH was tested for superoxide dismutase activity using standard NBT method. The complex has SOD activity with the IC(50) value of 1.32 uM. PMID- 21787281 TI - Purification, cDNA clone and recombinant expression of foot protein-3 from Mytilus coruscus. AB - Mussels Mytilus coruscus can adhere to various solid surface in the presence of moisture. Mussel foot protein-3 (mfp-3) has been suggested as the main adhesive protein in the plaques closest to the adhesion interface and been the focus of substantial biomaterials development research within the last decade. The byssal plaques of M. coruscus were accumulated and variants of a family known as mcofp3 (Mytilus coruscus foot protein 3) were purified from acetic acid/urea extracts of plaques, with their N-terminal sequences determined thereafter. The cDNA sequence coding for the mcofp3 precursor was obtained from M. coruscus foot cDNA library. These precursors contain a putative signal peptide of 24 residues, a mature peptide sequence of 41-56 amino acids rich in Tyr, Gly, Pro, and Asn. The recombinant mcofp3 fused with a hexa-histidine affinity ligand was successfully expressed through an Escherichia coli expression system, and the recombinant mcofp3 was purified using affinity chromatography followed by reverse phase high performance liquid chromatography (HPLC). The DOPA content and adhesive properties of purified recombinant mcofp3 with or without tyrosinase modification were compared with the native mcofp3. These assays showed that recombinant mcofp3 has significant adhesive ability and may be useful as a bioadhesive in medical or underwater environments. PMID- 21787282 TI - Predicting thermophilic proteins with pseudo amino acid composition:approached from chaos game representation and principal component analysis. AB - Comprehensive knowledge of thermophilic mechanisms about some organisms whose optimum growth temperature (OGT) ranges from 50 to 80 degrees C degree plays a major role for helping to design stable proteins. How to predict function-unknown proteins to be thermophilic is a long but not fairly resolved problem. Chaos game representation (CGR) can investigate hidden patterns in protein sequences, and also can visually reveal their previously unknown structures. In this paper, using the general form of pseudo amino acid composition to represent protein samples, we proposed a novel method for presenting protein sequence to a CGR picture using CGR algorithm. A 24-dimensional vector extracted from these CGR segments and the first two PCA features are used to classify thermophilic and mesophilic proteins by Support Vector Machine (SVM). Our method is evaluated by the jackknife test. For the 24-dimensional vector, the accuracy is 0.8792 and Matthews Correlation Coefficient (MCC) is 0.7587. The 26-dimensional vector by hybridizing with PCA components performs highly satisfaction, in which the accuracy achieves 0.9944 and MCC achieves 0.9888. The results show the effectiveness of the new hybrid method. PMID- 21787283 TI - Phosphorylation of a heme-regulated eukaryotic initiation factor 2alpha kinase enhances the interaction with heat-shock protein 90 and substantially upregulates kinase activity. AB - Heme-regulated eukaryotic initiation factor 2alpha kinase (HRI) functions under conditions of heme shortage caused by blood diseases such as erythropoietic protoporphyria and beta-thalassemia, and retains the heme:globin ratio at 1:1 by sensing the heme concentration in reticulocytes. This HRI function is regulated by various factors including autophosphorylation and protein-protein interactions. A heat-shock protein controls HRI function, however, the molecular mechanism of catalytic regulation of HRI by the heat-shock protein is unclear. In the present study, we examined the interactions of HRI with a heat-shock protein, Hsp90, under various conditions, using a pull-down assay and measuring catalytic activity. It was found that [1] an interaction between Hsp90 and phosphorylated HRI was evident, whereas no interaction was observed between Hsp90 and HRI dephosphorylated by treatment with lambda protein phosphatase; [2] Hsp90 enhanced the kinase activity of phosphorylated HRI but not dephosphorylated HRI, but this enhancement was not observed in the presence of heme; and, [3] autophosphorylation of HRI was not influenced by Hsp90. Therefore, we propose that autophosphorylation of HRI is critical for catalytic regulation by Hsp90 under heme-shortage conditions. PMID- 21787284 TI - Naturally plant-derived compounds: role in bone anabolism. AB - From a nutritional point of view, several factors are involved in ensuring optimal bone health. The most documented of these are calcium and vitamin D. However, it is now well acknowledged that some phytochemicals, also known as phytonutrients, which are plant-based compounds that are present in our daily diet, can positively regulate a number of physiological functions in mammalian systems involved in chronic diseases such as osteoporosis. Indeed, emerging data in animal models of postmenopausal osteoporosis has shown that exposure to some of these naturally plant-derived compounds (e.g. flavonoids) positively influences bone metabolism through preserved bone mineral density. In vitro experiments with bone cells have reported cellular and molecular mechanisms of phytonutrients involved in bone metabolism. Indeed, phytonutrients and especially polyphenols can act on both osteoblasts and osteoclasts to modulate bone metabolism, a balance between both cell type activities being required for bone health maintenance. To date, most studies investigating the effects of polyphenols on osteoblast cells have reported involvement of complex networks of anabolic signalling pathways such as BMPs or estrogen receptor mediated pathways. This review will report on the interaction between phytochemicals and bone metabolism in cell or animal models with a particular focus on the molecular mechanisms involved in the bone anabolic response. PMID- 21787285 TI - Activin receptor signaling: a potential therapeutic target for osteoporosis. AB - Current antiresorptive therapies not only prevent bone loss by decreasing osteoclastic bone resorption but also inhibit bone formation. Dual anabolic antiresorptive agents may be required to cure severe osteoporosis by preventing further bone loss and increasing bone mass to normal levels. Recent studies have demonstrated that activin signaling plays a crucial role in the skeleton. Activins, like other TGF-beta superfamily members, transduce their signals through type I and II receptor serine/threonine kinases. The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor (ALK4 and/or ALK7), which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins. Activin signaling is down-regulated by inhibins, follistatin and other proteins, which antagonize activin signaling by a variety of mechanisms. A soluble chimeric protein composed of the extracellular domain of ActRIIA fused to IgG-Fc binds to circulating ligands such as activin A and prevents signaling through the endogenous receptor. In cynomolgus monkeys, the ActRIIA soluble receptor increases bone volume by decreasing bone resorption and increasing bone formation, leading to enhanced mechanical strength and bone quality. In addition, a single dose of the soluble ActRIIA-Fc fusion protein increased serum BSALP and PINP and decreased serum CTX and TRACP 5b in postmenopausal women. These data provide evidence of a dual anabolic antiresorptive effect of the soluble ActRIIA Fc fusion protein in the skeleton. Therefore, targeting activin receptor signaling may be useful for therapeutic intervention in osteoporosis. PMID- 21787286 TI - Potential anti-catabolic and anabolic properties of strontium ranelate. AB - Osteoporosis is a major public health problem for adults above 55 years of age, which leads to an increase in bone fragility. Last decade has witnessed remarkable advances in molecular biology and genetics that led to detailed understanding of the bone remodeling cycle and new therapeutic targets for its treatment have emerged. Thus, besides classical approach (vitamin D and calcium administration, bisphosphonates, oestrogen, raloxifene), new therapeutic agents such as parathyroid hormone (PTH) compounds, anti-RANKL antibodies and strontium ranelate are or will be increasingly used in the treatment of osteoporosis. In this review, we have presented the importance and therapeutic potential of strontium ranelate as a dual agent in the current treatment of osteoporosis. PMID- 21787287 TI - Antagonizing the calcium-sensing receptor: towards new bone anabolics? AB - With a rise in the aging population, the global osteoporosis market represents a major unmet need and one of the greatest challenges for the pharmaceutical companies. Currently bisphosphonates constitute the mainstay antiosteoporotic treatment. They inhibit osteoclast-dependent bone resorption, and substantially reduce the risk of vertebral and non-vertebral fractures. However, bisphosphonates are only marginally effective in subjects with significant loss of bone mineral density. Furthermore, safety concerns have recently been raised due to an increased risk of low-energy fractures associated with long-term bisphosphonate treatment; hence the need for new osteoanabolic drugs. Transient fluctuations in plasma parathyroid hormone (PTH) are a well-established bone anabolic stimulus and efforts have aimed at identifying new medical therapies that can reduce the risk of vertebral and non-vertebral fractures and increase bone mineral density through modifications of circulating PTH. Two approaches have recently emerged in the search for new bone anabolics: a) administration of exogenous PTH, and b) administration of compounds, which evoke transient release of endogenous PTH, namely calcilytics. This review will focus on the potential use of PTH modifying agents as the new osteoanabolics. PMID- 21787288 TI - Prostaglandin E(2) receptors as potential bone anabolic targets - selective EP4 receptor agonists. AB - Prostaglandin E(2) is known to be a potent metabolite in bone biology. Its effects are mediated via four receptor subtypes with different properties, effects and mechanisms of action. The EP2 and EP4 receptors have been extensively investigated as bone anabolic therapy targets in the literature. The aim of this review was to analyse the available evidence supporting the use of selective agonists for those receptors for anabolic bone application purposes. Although several studies report on the presence of the EP2 receptor in several cell types, efforts to directly confirm the presence of this receptor in human bone cells have not been successful. The EP4 receptor however has been identified in human bone cells and its significant role in bone biology has been demonstrated with the use of selective agonists, antagonists and transgenic small animals. The use of selective EP4 agonists reversed established osteoporotic changes, enhanced the boneimplant interface strength and was shown to have a synergistic effect when used with other bone cell targeting pharmacological agents such as BMP-2 and bisphosphonates. Further elucidation of the side-effect profile of prostanoid and non-prostanoid agonists is required for these agents to proceed towards clinical applications. PMID- 21787289 TI - Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent. AB - Normal bone homeostasis is the result of a cross-talk between the anabolic axis (osteoblast differentiation) and catabolic axis (osteoclast remodeling). A disruption of this tightly regulated relationship leads to imbalanced bone turnover which ultimately results in diseases of the skeleton. Given that the majority of disease states are characterized by an inadequate renewal of osteoblasts, and the canonical wingless (Wnt) pathway is critical for their differentiation from progenitors, this represents an intriguing target for bone therapy. This mini-review focuses on the different options available for pharmaceutical enhancement of osteogenic differentiation through targeting the various proteins involved in Wnt signaling. PMID- 21787290 TI - The role of BMPs in bone anabolism and their potential targets SOST and DKK1. AB - Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs' role in bone formation is well known, the current clinical data supporting their effectiveness are not robust, possibly in part because BMPs affect bone resorption as well. BMPs can reduce bone mass by inducing osteoclastogenesis via the RANKL-OPG pathway, which is a critical regulator of osteoclasts by osteoblasts. BMPs have both bone anabolic and catabolic effects by affecting multiple cell types in bone such as mesenchymal cells, chondrocytes, osteoblasts, osteoclasts, and endothelial cells. We recently generated an osteoblast-targeted deletion of BMP signaling using a Cre-loxP strategy and found that BMP signaling in osteoblasts can inhibit Wnt signaling through the Wnt inhibitors DKK1 and SOST. Loss-of-function of either DKK1 or SOST, which are downstream targets of BMPs, causes a high bone mass phenotype in humans and mice, suggesting an importance of DKK1 and SOST for bone mass regulation. There are many bone anabolic effectors that control bone mass such as BMPs, PTH, and Wnt inhibitors. This article will focus on BMPs' effects on bone anabolism and propose a potential network of the bone mass mediators BMPs, PTH, and SOST. We believe it is important to understand this network to guide the clinical application of bone anabolic agents. PMID- 21787291 TI - Insulin-like growth factor-I molecular pathways in osteoblasts: potential targets for pharmacological manipulation. AB - The insulin-like growth factors (IGFs) are the most abundant growth factors stored in bone and produced by osteoblasts. IGF-I is an important regulator of osteoblast function and required for optimal bone development and maintenance. IGF-I can act in an endocrine, paracrine or autocrine manner and is regulated by a family of six IGF binding proteins (IGFBPs). The IGFBPs are often found bound to IGF-I in the circulation or complexed with IGF-I in osteoblasts. IGFBP-3 and 5 are known stimulators of IGF-I actions, whereas IGFBP-1, -2, -4 and -6 are known inhibitors of IGF-I action in bone. Once IGF-I binds to its receptor (type 1 IGF receptor) it initiates a complex signaling pathway including the phosphoinositol 3-kinase (PI3-K)/3-PI-dependent kinase (PDK)-1/Akt pathway and the Ras/Raf/mitogen-activated protein (MAP) kinase pathway which stimulate cell function and/or survival. Based on the critical role for IGF-I in osteoblasts, it is a logical candidate for anabolic therapy. However, systemic administration of IGF-I is not cell specific and a limited number of long term experiments have been completed to date. Several recent findings indicate that many of the IGFBPs and specific proteins in the IGF-I signaling pathways are also potent anabolic factors in regulating osteoblast function. This review will focus on the role of these factors in mediating IGF-I action in osteoblasts and how they may serve as potential targets to stimulate osteoblast function and bone formation. PMID- 21787293 TI - Anabolic effects of intermittent PTH on osteoblasts. AB - Intermittent parathyroid hormone (iPTH) is the only FDA-approved therapy for bone loss due to conditions such as osteoporosis that increases bone formation by osteoblasts; all other therapies approved for osteoporosis block bone resorption by osteoclasts. The anabolic effects of iPTH are likely due to a combination of multiple mechanisms, including induction of immediate-early genes, increased expression and/or activity of essential osteoblast transcription factors, and downregulation of anti-osteogenic proteins, such as sclerostin. In contrast, continuous administration of PTH induces bone loss primarily due to up-regulation of RANKL expression and inhibition of osteoprotegerin expression. PMID- 21787292 TI - Insulin like growth factor-I: a critical mediator of the skeletal response to parathyroid hormone. AB - This review focuses on the mechanisms by which PTH stimulates both osteoblast and osteoclast function, emphasizing the critical role that IGF-I plays in these processes. After reviewing the current literature on the skeletal actions of PTH and the modulation of IGF action on bone by the different IGF-binding proteins, the review then examines studies from mouse models in which IGF-I or its receptor have been selectively deleted in different cells of the skeletal system, in particular osteoprogenitors, mature osteoblasts, and osteoclasts. Mice in which IGF-I production has been deleted from all cells are deficient in both bone formation and bone resorption with few osteoblasts or osteoclasts in bone in vivo, reduced osteoblast colony forming units, and an inability of either the osteoblasts or osteoclast precursors to support osteoclastogenesis in vitro. Mice in which the IGF-I receptor is specifically deleted in mature osteoblasts have a mineralization defect in vivo, and bone marrow stromal cells from these mice fail to mineralize in vitro. Mice in which the IGF-I receptor is deleted in osteoprogenitor cells have a marked reduction in osteoblast proliferation and differentiation leading to osteopenia. Finally mice lacking the IGF-I receptor in their osteoclasts have increased bone and decreased osteoclast formation. PTH fails to stimulate bone formation in the mice lacking IGF-I or its receptor in osteoblasts or enhance the signaling between osteoblasts and osteoclasts through RANKL/RANK and Ephrin B2/Eph B4, emphasizing the role IGF-I signaling plays in cell-communication per se and as stimulated by PTH. PMID- 21787294 TI - Molecular and pharmacological aspects of existing and experimental bone anabolic therapies. PMID- 21787296 TI - Molecular targeted therapy of gastrointestinal cancer. PMID- 21787295 TI - Viral and non-viral approaches for transient delivery of mRNA and proteins. AB - The transient delivery of gene products (RNA or proteins) is not a biotechnological invention but rather an evolutionarily conserved process underlying and regulating a variety of biological functions. On the basis of insights into the underlying mechanisms, several viral and cell-based approaches have been developed for the delivery of RNA or proteins. Prominent applications include the induction of major biological or therapeutic effects on the basis of "hit-and-run" mechanisms, such as vaccination, cell fate modification (reprogramming, differentiation), control of cell trafficking, enhancement of cell regeneration, and genome engineering using sequence-specific recombinases or nucleases. Ideally, procedures for delivery of RNA or proteins should be targeted to specific cells, overcome biophysical hurdles without harming cellular integrity, circumvent the various alarm signals of the innate immune system, allow dose-controlled delivery of functional biomacromolecules, and avoid the induction of an adaptive immune response. Here we review the current state of approaches for the delivery of mRNA and proteins with a focus on RNA viruses, virus-like particles including retrovirus particle-mediated transfer of mRNA or proteins, extracellular vesicles, and cell-penetrating peptides. The basic concepts and recent advances are put into perspective in the context of potential limitations of the technologies and strategies to overcome cellular barriers and defense mechanisms. PMID- 21787297 TI - Computational methods for identification of functional residues in protein structures. AB - The recent accumulation of experimentally determined protein 3D structures combined with our ability to computationally model structure from amino acid sequence has resulted in an increased importance of structure-based methods for protein function prediction. Two types of methods for function prediction have been proposed: those that can accurately predict overall biochemical or biological roles of a protein and those that predict its functional residues. Here, we review approaches used for the computational identification of functional residues in protein structures and summarize their applications to a wide variety of problems in functional proteomics, such as the prediction of catalytic residues, post-translational modifications, or nucleic acid-binding sites. We examine four different problems in order to perform a comparison between several recently proposed methods and, finally, conclude by identifying limitations and future challenges in this field. PMID- 21787298 TI - Cellular automata and its applications in protein bioinformatics. AB - With the explosion of protein sequences generated in the postgenomic era, it is highly desirable to develop high-throughput tools for rapidly and reliably identifying various attributes of uncharacterized proteins based on their sequence information alone. The knowledge thus obtained can help us timely utilize these newly found protein sequences for both basic research and drug discovery. Many bioinformatics tools have been developed by means of machine learning methods. This review is focused on the applications of a new kind of science (cellular automata) in protein bioinformatics. A cellular automaton (CA) is an open, flexible and discrete dynamic model that holds enormous potentials in modeling complex systems, in spite of the simplicity of the model itself. Researchers, scientists and practitioners from different fields have utilized cellular automata for visualizing protein sequences, investigating their evolution processes, and predicting their various attributes. Owing to its impressive power, intuitiveness and relative simplicity, the CA approach has great potential for use as a tool for bioinformatics. PMID- 21787299 TI - Structural protein descriptors in 1-dimension and their sequence-based predictions. AB - The last few decades observed an increasing interest in development and application of 1-dimensional (1D) descriptors of protein structure. These descriptors project 3D structural features onto 1D strings of residue-wise structural assignments. They cover a wide-range of structural aspects including conformation of the backbone, burying depth/solvent exposure and flexibility of residues, and inter-chain residue-residue contacts. We perform first-of-its-kind comprehensive comparative review of the existing 1D structural descriptors. We define, review and categorize ten structural descriptors and we also describe, summarize and contrast over eighty computational models that are used to predict these descriptors from the protein sequences. We show that the majority of the recent sequence-based predictors utilize machine learning models, with the most popular being neural networks, support vector machines, hidden Markov models, and support vector and linear regressions. These methods provide high-throughput predictions and most of them are accessible to a non-expert user via web servers and/or stand-alone software packages. We empirically evaluate several recent sequence-based predictors of secondary structure, disorder, and solvent accessibility descriptors using a benchmark set based on CASP8 targets. Our analysis shows that the secondary structure can be predicted with over 80% accuracy and segment overlap (SOV), disorder with over 0.9 AUC, 0.6 Matthews Correlation Coefficient (MCC), and 75% SOV, and relative solvent accessibility with PCC of 0.7 and MCC of 0.6 (0.86 when homology is used). We demonstrate that the secondary structure predicted from sequence without the use of homology modeling is as good as the structure extracted from the 3D folds predicted by top performing template-based methods. PMID- 21787300 TI - Small open reading frames: current prediction techniques and future prospect. AB - Evidence is accumulating that small open reading frames (sORF, <100 codons) play key roles in many important biological processes. Yet, they are generally ignored in gene annotation despite they are far more abundant than the genes with more than 100 codons. Here, we demonstrate that popular homolog search and codon-index techniques perform poorly for small genes relative to that for larger genes, while a method dedicated to sORF discovery has a similar level of accuracy as homology search. The result is largely due to the small dataset of experimentally verified sORF available for homology search and for training ab initio techniques. It highlights the urgent need for both experimental and computational studies in order to further advance the accuracy of sORF prediction. PMID- 21787301 TI - Machine learning algorithms for predicting protein folding rates and stability of mutant proteins: comparison with statistical methods. AB - Machine learning algorithms have wide range of applications in bioinformatics and computational biology such as prediction of protein secondary structures, solvent accessibility, binding site residues in protein complexes, protein folding rates, stability of mutant proteins, and discrimination of proteins based on their structure and function. In this work, we focus on two aspects of predictions: (i) protein folding rates and (ii) stability of proteins upon mutations. We briefly introduce the concepts of protein folding rates and stability along with available databases, features for prediction methods and measures for prediction performance. Subsequently, the development of structure based parameters and their relationship with protein folding rates will be outlined. The structure based parameters are helpful to understand the physical basis for protein folding and stability. Further, basic principles of major machine learning techniques will be mentioned and their applications for predicting protein folding rates and stability of mutant proteins will be illustrated. The machine learning techniques could achieve the highest accuracy of predicting protein folding rates and stability. In essence, statistical methods and machine learning algorithms are complimenting each other for understanding and predicting protein folding rates and the stability of protein mutants. The available online resources on protein folding rates and stability will be listed. PMID- 21787302 TI - Solvent and lipid accessibility prediction as a basis for model quality assessment in soluble and membrane proteins. AB - On-going efforts to improve protein structure prediction stimulate the development of scoring functions and methods for model quality assessment (MQA) that can be used to rank and select the best protein models for further refinement. In this work, sequence-based prediction of relative solvent accessibility (RSA) is employed as a basis for a simple MQA method for soluble proteins, and subsequently extended to the much less explored case of (alpha helical) membrane proteins. In analogy to soluble proteins, the level of exposure to the lipid of amino acid residues in transmembrane (TM) domains is captured in terms of the relative lipid accessibility (RLA), which is predicted from sequence using low-complexity Support Vector Regression models. On an independent set of 23 TM proteins, the new SVR-based predictor yields correlation coefficient (CC) of 0.56 between the predicted and observed RLA profiles, as opposed to CC of 0.13 for a baseline predictor that utilizes TMLIP2H empirical lipophilicity scale (with standard deviations of about 0.15). A simple MQA approach is then defined by ranking models of membrane proteins in terms of consistency between predicted and observed RLA profiles, as a measure of similarity to the native structure. The new method does not require a set of decoy models to optimize parameters, circumventing current limitations in this regard. Several different sets of models, including those generated by fragment based folding simulations, and decoys obtained by swapping TM helices to mimic errors in template based assignment, are used to assess the new approach. Predicted RLA profiles can be used to successfully discriminate near native models from non-native decoys in most cases, significantly improving the separation of correct and incorrectly folded models compared to a simple baseline approach that utilizes TMLIP2H. As suggested by the robust performance of a simple MQA method for soluble proteins that utilizes more accurate RSA predictions, further significant improvements are likely to be achieved. The steady growth in the number of resolved membrane protein structures is expected to yield enhanced RLA predictions, facilitating further efforts to improve de novo and template based prediction of membrane protein structure. PMID- 21787303 TI - On the relationship between catalytic residues and their protein contact number. AB - Due to advances in structural biology, an increasing number of protein structures of unknown function have been deposited in Protein Data Bank (PDB). These proteins are usually characterized by novel structures and sequences. Conventional comparative methodology (such as sequence alignment, structure comparison, or template search) is unable to determine their function. Thus, it is important to identify protein's function directly from its structure, but this is not an easy task. One of the strategies used is to analyze whether there are distinctive structure-derived features associated with functional residues. If so, one may be able to identify the functional residues directly from a single structure. Recently, we have shown that protein weighted contact number is related to atomic thermal fluctuations and can be used to derive motional correlations in proteins. In this report, we analyze the weighted contact-number profiles of both catalytic residues and non-catalytic residues for a dataset of 760 structures. We found that catalytic residues have distinct distributions of weighted contact numbers from those of non-catalytic residues. Using this feature, we are able to effectively differentiate catalytic residues from other residues with a single optimized threshold value. Our method is simple to implement and compares favourably with other more sophisticated methods. In addition, we discuss the physics behind the relationship between catalytic residues and their contact numbers as well as other features (such as residue centrality or B-factors) associated with catalytic residues. PMID- 21787304 TI - Structural models of protein-DNA complexes based on interface prediction and docking. AB - Protein-DNA interactions are the physical basis of gene expression and DNA modification. Structural models that reveal these interactions are essential for their understanding. As only a limited number of structures for protein-DNA complexes have been determined by experimental methods, computation methods provide a potential way to fill the need. We have developed the DISPLAR method to predict DNA binding sites on proteins. Predicted binding sites have been used to assist the building of structural models by docking, either by guiding the docking or by selecting near-native candidates from the docked poses. Here we applied the DISPLAR method to predict the DNA binding sites for 20 DNA-binding proteins, which have had their DNA binding sites characterized by NMR chemical shift perturbation. For two of these proteins, the structures of their complexes with DNA have also been determined. With the help of the DISPLAR predictions, we built structural models for these two complexes. Evaluations of both the DNA binding sites for 20 proteins and the structural models of the two protein-DNA complexes against experimental results demonstrate the significant promise of our model-building approach. PMID- 21787305 TI - Conotoxin superfamily prediction using diffusion maps dimensionality reduction and subspace classifier. AB - Conotoxins are disulfide-rich small peptides that are invaluable channel-targeted peptides and target neuronal receptors, which have been demonstrated to be potent pharmaceuticals in the treatment of Alzheimer's disease, Parkinson's disease, and epilepsy. Accurate prediction of conotoxin superfamily would have many important applications towards the understanding of its biological and pharmacological functions. In this study, a novel method, named dHKNN, is developed to predict conotoxin superfamily. Firstly, we extract the protein's sequential features composed of physicochemical properties, evolutionary information, predicted secondary structures and amino acid composition. Secondly, we use the diffusion maps for dimensionality reduction, which interpret the eigenfunctions of Markov matrices as a system of coordinates on the original data set in order to obtain efficient representation of data geometric descriptions. Finally, an improved K local hyperplane distance nearest neighbor subspace classifier method called dHKNN is proposed for predicting conotoxin superfamilies by considering the local density information in the diffusion space. The overall accuracy of 91.90% is obtained through the jackknife cross-validation test on a benchmark dataset, indicating the proposed dHKNN is promising. PMID- 21787306 TI - Molecular surface representation using 3D Zernike descriptors for protein shape comparison and docking. AB - The tertiary structures of proteins have been solved in an increasing pace in recent years. To capitalize the enormous efforts paid for accumulating the structure data, efficient and effective computational methods need to be developed for comparing, searching, and investigating interactions of protein structures. We introduce the 3D Zernike descriptor (3DZD), an emerging technique to describe molecular surfaces. The 3DZD is a series expansion of mathematical three-dimensional function, and thus a tertiary structure is represented compactly by a vector of coefficients of terms in the series. A strong advantage of the 3DZD is that it is invariant to rotation of target object to be represented. These two characteristics of the 3DZD allow rapid comparison of surface shapes, which is sufficient for real-time structure database screening. In this article, we review various applications of the 3DZD, which have been recently proposed. PMID- 21787307 TI - Neural network pairwise interaction fields for protein model quality assessment and ab initio protein folding. AB - In order to use a predicted protein structure one needs to know how good it is, as the utility of a model depends on its quality. To this aim, many Model Quality Assessment Programs (MQAP) have been developed over the last decade, with MQAP also being assessed at the CASP competition. We present a new knowledge-based MQAP which evaluates single protein structure models. We use a tree representation of the Calpha trace to train a novel Neural Network Pairwise Interaction Field (NN-PIF) to predict the global quality of a model. NN-PIF allows fast evaluation of multiple structure models for a single sequence. In our tests on a large set of structures, our networks outperform most other methods based on different and more complex protein structure representations in global model quality prediction. Moreover, given NN-PIF can evaluate protein conformations very fast, we train a separate version of the model to gauge its ability to fold protein structures ab initio. We show that the resulting system, which relies only on basic information about the sequence and the Calpha trace of a conformation, generally improves the quality of the structures it is presented with and may yield promising predictions in the absence of structural templates, although more research is required to harness the full potential of the model. PMID- 21787308 TI - A sampling-based method for ranking protein structural models by integrating multiple scores and features. AB - One of the major challenges in protein tertiary structure prediction is structure quality assessment. In many cases, protein structure prediction tools generate good structural models, but fail to select the best models from a huge number of candidates as the final output. In this study, we developed a sampling-based machine-learning method to rank protein structural models by integrating multiple scores and features. First, features such as predicted secondary structure, solvent accessibility and residue-residue contact information are integrated by two Radial Basis Function (RBF) models trained from different datasets. Then, the two RBF scores and five selected scoring functions developed by others, i.e., Opus-CA, Opus-PSP, DFIRE, RAPDF, and Cheng Score are synthesized by a sampling method. At last, another integrated RBF model ranks the structural models according to the features of sampling distribution. We tested the proposed method by using two different datasets, including the CASP server prediction models of all CASP8 targets and a set of models generated by our in-house software MUFOLD. The test result shows that our method outperforms any individual scoring function on both best model selection, and overall correlation between the predicted ranking and the actual ranking of structural quality. PMID- 21787309 TI - Machine learning models in protein bioinformatics. PMID- 21787310 TI - The mitochondrial citrate carrier: a new player in inflammation. AB - The mitochondrial CIC (citrate carrier) catalyses the efflux of citrate from the mitochondrial matrix in exchange for cytosolic malate. In the present paper we show that CIC mRNA and protein markedly increase in lipopolysaccharide-activated immune cells. Moreover, CIC gene silencing and CIC activity inhibition significantly reduce production of NO, reactive oxygen species and prostaglandins. These results demonstrate for the first time that CIC has a critical role in inflammation. PMID- 21787311 TI - Phosphoinositides and the regulation of tubular-based endosomal sorting. AB - From the pioneering work of Mabel and Lowell Hokin in the 1950s, the biology of this specific isomer of hexahydroxycyclohexane and its phosphorylated derivatives, in the form of inositol phosphates and phosphoinositides, has expanded to fill virtually every corner of cell biology, whole-organism physiology and development. In the present paper, I give a personal view of the role played by phosphoinositides in regulating the function of the endosomal network, and, in so doing, highlight some of the basic properties through which phosphoinositides regulate cell function. PMID- 21787312 TI - Models of dementia: an introductory overview. AB - The analysis of the molecular development of AD (Alzheimer's disease) is technically challenging, due to the chronic nature of the disease, the lack of early and definitive clinical diagnosis, and the fact that the abnormal molecular pathology occurs in the brain. Therefore appropriate animal models of AD are essential if we are to dissect the processes leading to molecular pathology, and ultimately to test the efficacy of potential therapies before clinical studies. Unfortunately, there is controversy over the benefits of the available models, the only consensus of opinion being that no perfect model currently exists. The investigation of animal models is extremely costly and time-consuming, therefore researchers tend to focus on one or two models. For scientists entering the AD research field, it can be difficult to identify the most appropriate model for their needs. Therefore the Models of Dementia: the Good, the Bad and the Future Biochemical Society Focused Meeting provided a platform for discussion and debate on the use and limitations of current models, the most appropriate methods for their characterization and identification of the most pressing needs of the field in general. PMID- 21787313 TI - Intraneuronal Abeta as a trigger for neuron loss: can this be translated into human pathology? AB - In the present review, we summarize the current achievements of modelling early intraneuronal Abeta (amyloid beta-peptide) accumulation in transgenic mice with the resulting pathological consequences. Of special importance will be to discuss recent developments and the translation of the results to AD (Alzheimer's disease). N-terminally truncated AbetapE3 (Abeta starting with pyroglutamate at position 3) represents a major fraction of all Abeta peptides in the brain of AD patients. Recently, we generated a novel mAb (monoclonal antibody), 9D5, that selectively recognizes oligomeric assemblies of AbetapE3 and demonstrated the potential involvement of oligomeric AbetapE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost non-detectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal staining was observed. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Abeta levels and stabilized behavioural deficits. In summary, we have demonstrated that intraneuronal Abeta is a valid risk factor in model systems and AD patients. This feature of AD pathology was successful in identifying novel low-molecular-mass oligomeric Abeta-specific antibodies for diagnosis and therapy. PMID- 21787314 TI - A BACwards glance at neurodegeneration: molecular insights into disease from LRRK2, SNCA and MAPT BAC-transgenic mice. AB - BAC (bacterial artificial chromosome)-transgenic mice expressing a transgene from an entire genomic locus under the control of the native promoter offer the opportunity to generate more accurate genetic models of human disease. The present review discusses results of recent studies investigating PD (Parkinson's disease) and tauopathies using BAC-transgenic mice carrying either the LRRK2 (leucine-rich repeat kinase 2), alpha-synuclein (SNCA) or MAPT (microtubule associated protein tau) genes. In all lines, expression of the WT (wild-type) gene resulted in physiologically relevant protein expression. The effect of expressing the mutant form of a gene varied depending on the mouse strain or the particular disease mutation used, although it was common to see either neurochemical or behavioural differences in these animals. Overall, BAC technology offers an exciting opportunity to generate a wide range of new animal models of human-disease states. PMID- 21787315 TI - Mitochondrial beta-amyloid in Alzheimer's disease. AB - It is well established that the intracellular accumulation of Abeta (amyloid beta peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Abeta can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Abeta, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Abeta accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Abeta; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD-Abeta interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay. PMID- 21787316 TI - FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease. AB - The lack of reliable translational procedures applicable to both patients and experimental models are a major obstacle for the advancement of basic research as well as for the development of therapeutics. This is particularly relevant to neurodegenerative disorders such as AD (Alzheimer's disease), where the predictive validity of animal models and procedures applied preclinically have met with little success. Two approaches available for human diagnostics are currently experiencing major advancements in preclinical research: in vivo imaging using MRI (magnetic resonance imaging) or PET (positron-emission tomography) and recordings of brain electrical activity via surface EEG (electroencephalogram). The present paper reviews the results obtained so far in rodent AD models, and summarizes advantages and disadvantages of such procedures. PMID- 21787317 TI - Axon-glial disruption: the link between vascular disease and Alzheimer's disease? AB - Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline. PMID- 21787318 TI - Assessing the contribution of inflammation in models of Alzheimer's disease. AB - Inflammation has long been proposed as having a role in AD (Alzheimer's disease), although it remains unclear whether inflammation represents a cause or consequence of AD. Evidence from the clinical setting in support of a role for inflammation in AD includes increased expression of inflammatory mediators and microglial activation in the post-mortem AD brain. Also, epidemiological studies on AD patients under long-term treatment with non-steroidal anti-inflammatory drugs suggest some benefits, although recent prospective trials showed no effect. Furthermore, in AD patients, infection and other systemic inflammatory events worsen symptoms. Finally, several inflammatory genes are associated with increased risk of AD. Therefore, to elucidate the underlying mechanisms of AD and the role of inflammation, researchers have turned to experimental models and here we present a short overview of some key findings from these studies. Activation of microglia is seen in various transgenic models of AD, with both a protective role and a detrimental role being ascribed to it. Early microglial activation is probably beneficial in AD, through phagocytosis of amyloid beta-peptide. At later stages however, pro-inflammatory cytokine release from microglia could contribute to neuronal demise. A better understanding of microglial phenotype at the various stages of AD is therefore still required. Although most studies suggest a detrimental role for pro-inflammatory cytokines such as interleukin-1 and tumour necrosis factor in AD, contradictory findings do exist. Age-related and differential cellular expression of these inflammatory mediators is probably a key determinant of their exact contribution to AD. In conclusion, there is no doubt that inflammatory processes are part of the pathophysiology of AD, but a better understanding of the exact contribution at different stages of the disease process is still required before appropriate treatment strategies can be devised. PMID- 21787319 TI - Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. AB - Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by beta-amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization. PMID- 21787320 TI - Systemic inflammation and Alzheimer's disease. AB - A number of studies demonstrate disturbances of the central innate immune system in AD (Alzheimer's disease). In animal and human studies, there is evidence of close communication between systemic and central innate immune systems. Animal models of neurodegeneration show evidence of an exaggerated central innate immune response following systemic inflammation. Clinical studies of AD show evidence of increased cognitive decline and exaggerated sickness behaviour in response to systemic inflammation. Recognition of this communication pathway offers alternative explanations for a number of recognized risk factors in the development and progression of AD and highlights the potential of the manipulation of systemic innate immunity as a novel therapeutic approach. PMID- 21787321 TI - Hippocampal synaptic activity, pattern separation and episodic-like memory: implications for mouse models of Alzheimer's disease pathology. AB - The present review summarizes converging evidence from animal and human studies that an early target of amyloid pathology is synaptic activity in the DG (dentate gyrus)/CA3 network. We briefly review the computational significance of the DG/CA3 network in the encoding of episodic memory and present new evidence that the CA3/DG pattern of activation is compromised in a mouse model of amyloid pathology. In addition, we present a new behavioural method to test the prediction that amyloid-related synaptic pathology will disrupt the formation of an integrated episodic-like (what, where and when) memory in mice. PMID- 21787322 TI - Alzheimer's disease genetics: lessons to improve disease modelling. AB - In the present review, we look back at the recent history of GWAS (genome-wide association studies) in AD (Alzheimer's disease) and integrate the major findings with current knowledge of biological processes and pathways. These topics are essential for the development of animal models, which will be fundamental to our complete understanding of AD. PMID- 21787323 TI - Can neurodegeneration be separated from neuropathological hallmarks of chronic idiopathic human neurodegenerative disease? A perspective from modelling! AB - Chronic neurodegenerative disease is characterized by extensive regional loss of neurons in the brain and neuropathological hallmarks in surviving neurones. Genetic modelling by overexpression of hallmark proteins does not produce extensive neurodegeneration, whereas genetic deletion of neuronal 26S proteasomes does, as well as some hallmarks of human disease. PMID- 21787324 TI - The amyloid cascade hypothesis has misled the pharmaceutical industry. AB - The pharmaceutical industry has invested a great deal of time and finance in the development of therapeutics targeting amyloid generation, signalling and plaque stability. This has been based on the amyloid cascade hypothesis which states that abnormal amyloid precursor protein processing and the formation of amyloid plaques is the central process in the development of the symptoms of Alzheimer's disease. However, most clinical trials in this area have been disappointing; therefore the attendees of the Models of Dementia: the Good, the Bad and the Future meeting were given the opportunity to openly debate the proposal 'the amyloid cascade has misled the pharmaceutical industry', with the main contributions from Professor John Hardy and Professor John Mayer. The present article is a representation of the debate. PMID- 21787325 TI - Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models. AB - ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65 80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Abeta (amyloid beta peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects. PMID- 21787326 TI - Modelling early responses to neurodegenerative mutations in mice. AB - Considering the many differences between mice and humans, it is perhaps surprising how well mice model late-onset human neurodegenerative disease. Models of Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Huntington's disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes. However, there are also major differences. To extrapolate from mouse models to human disease, we need to understand how these differences relate to intrinsic limitations of the mouse system and to the effects of transgene overexpression. In the present paper, we use examples from an amyloid-overexpression model and a mutant-tau-knockin model to illustrate what we learn from each type of approach and what the limitations are. Finally, we discuss the further contributions that knockin and similar approaches can make to understanding pathogenesis and how best to model disorders of aging in a short lived mammal. PMID- 21787327 TI - 'Alzheimer-like' pathology in a murine model of arterial hypertension. AB - Genetic AD (Alzheimer's disease) accounts for only few AD cases and is almost exclusively associated with increased amyloid production in the brain. Instead, most patients are affected with the sporadic form of AD and typically have altered clearance mechanisms. The identification of factors that influence the onset and progression of sporadic AD is a key step towards understanding its mechanism(s) and developing successful therapies. An increasing number of epidemiological studies describe a strong association between AD and cardiovascular risk factors, particularly hypertension, that exerts detrimental effects on the cerebral circulation, favouring chronic brain hypoperfusion. However, a clear demonstration of a pathophysiological link between cardiovascular risk factors and AD aetiology is still missing. To increase our knowledge of the mechanisms involved in the brain's response to hypertension and their possible role in promoting amyloid deposition in the brain, we have performed and investigated in depth different murine models of hypertension, induced either pharmacologically or mechanically, leading in the long term to plaque formation in the brain parenchyma and around blood vessels. In the present paper, we review the major findings in this particular experimental setting that allow us to study the pathogenetic mechanisms of sporadic AD triggered by vascular risk factors. PMID- 21787328 TI - Systemic inflammation and delirium: important co-factors in the progression of dementia. AB - It is widely accepted that inflammation plays some role in the progression of chronic neurodegenerative diseases such as AD (Alzheimer's disease), but its precise role remains elusive. It has been known for many years that systemic inflammatory insults can signal to the brain to induce changes in CNS (central nervous system) function, typically grouped under the syndrome of sickness behaviour. These changes are mediated via systemic and CNS cytokine and prostaglandin synthesis. When patients with dementia suffer similar systemic inflammatory insults, delirium is a frequent consequence. This profound and acute exacerbation of cognitive dysfunction is associated with poor prognosis: accelerating cognitive decline and shortening time to permanent institutionalization and death. Therefore a better understanding of how delirium occurs during dementia and how these episodes impact on existing neurodegeneration are now important priorities. The current review summarizes the relationship between dementia, systemic inflammation and episodes of delirium and addresses the basic scientific approaches currently being pursued with respect to understanding acute cognitive dysfunction during aging and dementia. In addition, despite there being limited studies on this subject, it is becoming increasingly clear that infections and other systemic inflammatory conditions do increase the risk of AD and accelerate the progression of established dementia. These data suggest that systemic inflammation is a major contributor to the progression of dementia and constitutes an important clinical target. PMID- 21787329 TI - The role of mutant TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. AB - TDP-43 (TAR DNA-binding protein 43) has been identified as a key protein of ubiquitinated inclusions in brains of patients with ALS (amyotrophic lateral sclerosis) or FTLD (frontotemporal lobar degeneration), defining a new pathological disease spectrum. Recently, coding mutations have been identified in the TDP-43 gene (TARDBP), which further confirmed the pathogenic nature of the protein. Today, several animal models have been generated to gain more insight into the disease-causing pathways of the FTLD/ALS spectrum. This mini-review summarizes the current status of TDP-43 models, with a focus on mutant TDP-43. PMID- 21787330 TI - Distant cousins: genomic and sequence diversity within the BPI fold-containing (BPIF)/PLUNC protein family. AB - PLUNC (palate, lung and nasal epithelium clone) proteins make up the largest branch of the BPI (bactericidal/permeability-increasing protein)/LBP (lipopolysaccharide-binding protein) family of lipid-transfer proteins. PLUNCs make up one of the most rapidly evolving mammalian protein families and exhibit low levels of sequence similarity coupled with multiple examples of species specific gene acquisition and gene loss. Vertebrate genomes contain multiple examples of genes that do not meet our original definition of what is required to be a member of the PLUNC family, namely conservation of exon numbers/sizes, overall protein size, genomic location and the presence of a conserved disulfide bond. This suggests that evolutionary forces have continued to act on the structure of this conserved domain in what are likely to be functionally important ways. PMID- 21787331 TI - An expanded family of proteins with BPI/LBP/PLUNC-like domains in trypanosome parasites: an association with pathogenicity? AB - Trypanosomatids are protozoan parasites that cause human and animal disease. Trypanosoma brucei telomeric ESs (expression sites) contain genes that are critical for parasite survival in the bloodstream, including the VSG (variant surface glycoprotein) genes, used for antigenic variation, and the SRA (serum resistance-associated) gene, which confers resistance to lysis by human serum. In addition, ESs contain ESAGs (expression-site-associated genes), whose functions, with few exceptions, have remained elusive. A bioinformatic analysis of the ESAG5 gene of T. brucei showed that it encodes a protein with two BPI (bactericidal/permeability-increasing protein)/LBP (lipopolysaccharide-binding protein)/PLUNC (palate, lung and nasal epithelium clone)-like domains and that it belongs to a multigene family termed (GR)ESAG5 (gene related to ESAG5). Members of this family are found with various copy number in different members of the Trypanosomatidae family. T. brucei has an expanded repertoire, with multiple ESAG5 copies and at least five GRESAG5 genes. In contrast, the parasites of the genus Leishmania, which are intracellular parasites, have only a single GRESAG5 gene. Although the amino acid sequence identity between the (GR)ESAG5 gene products between species is as low as 15-25%, the BPI/LBP/PLUNC-like domain organization and the length of the proteins are highly conserved, and the proteins are predicted to be membrane-anchored or secreted. Current work focuses on the elucidation of possible roles for this gene family in infection. This is likely to provide novel insights into the evolution of the BPI/LBP/PLUNC-like domains. PMID- 21787332 TI - Ovocalyxin-36 and other LBP/BPI/PLUNC-like proteins as molecular actors of the mechanisms of the avian egg natural defences. AB - The chicken egg possesses physical and chemical barriers to protect the embryo from pathogens. OCX-36 (ovocalyxin-36) was suggested to be a 36 kDa eggshell specific protein that is secreted by the regions of the oviduct responsible for eggshell formation. Its expression is strongly up-regulated during shell calcification. This protein was also detected in vitelline membrane and expressed in gut tissues. Analysis of the OCX-36 protein sequence revealed that OCX-36 is related to the BPI (bactericidal permeability-increasing proteins)/LBP [LPS (lipopolysaccharide)-binding proteins]/PLUNC (palate, lung and nasal epithelium clone) superfamily, and that there are strong similarities between the exon/intron organization of the mammalian LBP/BPI and the avian OCX-36 genes. A recent study revealed that OCX-36 originates from a tandem duplication of an ancestral BPI/LBP/PLUNC gene, after the divergence of birds and mammals. Its antimicrobial activity was recently investigated and it was shown that OCX-36 binds to LPS from Escherichia coli. High-throughput methodologies have led to the identification of approximately 1000 new egg proteins. Among these are LBP/BPI proteins that might play a role in the natural defences of the egg to protect the embryo during its development in the external milieu, and may function to keep the table egg free of pathogens. The function of these BPI-like molecules is the subject of intense research to characterize their putative LPS-binding properties and antimicrobial activity. PMID- 21787333 TI - Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily. AB - We present the BPIFAn/BPIFBn systematic nomenclature for the PLUNC (palate lung and nasal epithelium clone)/PSP (parotid secretory protein)/BSP30 (bovine salivary protein 30)/SMGB (submandibular gland protein B) family of proteins, based on an adaptation of the SPLUNCn (short PLUNCn)/LPLUNCn (large PLUNCn) nomenclature. The nomenclature is applied to a set of 102 sequences which we believe represent the current reliable data for BPIFA/BPIFB proteins across all species, including marsupials and birds. The nomenclature will be implemented by the HGNC (HUGO Gene Nomenclature Committee). PMID- 21787334 TI - Plasma PLTP (phospholipid-transfer protein): an emerging role in 'reverse lipopolysaccharide transport' and innate immunity. AB - Plasma PLTP (phospholipid-transfer protein) is a member of the lipid transfer/LBP [LPS (lipopolysaccharide)-binding protein] family, which constitutes a superfamily of genes together with the short and long PLUNC (palate, lung and nasal epithelium clone) proteins. Although PLTP was studied initially for its involvement in the metabolism of HDL (high-density lipoproteins) and reverse cholesterol transport (i.e. the metabolic pathway through which cholesterol excess can be transported from peripheral tissues back to the liver for excretion in the bile), it displays a number of additional biological properties. In particular, PLTP can modulate the lipoprotein association and metabolism of LPS that are major components of Gram-negative bacteria. The delayed association of LPS with lipoproteins in PLTP-deficient mice results in a prolonged residence time, in a higher toxicity of LPS aggregates and in a significant increase in LPS induced mortality as compared with wild-type mice. It suggests that PLTP may play a pivotal role in inflammation and innate immunity through its ability to accelerate the 'reverse LPS transport' pathway. PMID- 21787335 TI - Old and new findings on lipopolysaccharide-binding protein: a soluble pattern recognition molecule. AB - LBP [LPS (lipopolysaccharide)-binding protein] was discovered approximately 25 years ago. Since then, substantial progress has been made towards our understanding of its function in health and disease. Furthermore, the discovery of a large protein family sharing functional and structural attributes has helped in our knowledge. Still, key questions are unresolved, and here an overview on the old and new findings on LBP is given. LBP is an acute-phase protein of the liver, but is also synthesized in other cells of the organism. While LBP is named after the ability to bind to LPS of Gram-negative bacteria, it also can recognize other bacterial compounds, such as lipopeptides. It has been shown that LBP is needed to combat infections; however, the main mechanism of action is still not clear. New findings on natural genetic variations of LBP leading to functional consequences may help in further elucidating the mechanism of LBP and its role in innate immunity and disease. PMID- 21787336 TI - Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy. AB - BPI (bactericidal/permeability-increasing protein) is a 55 kDa anti-infective molecule expressed in neutrophil and eosinophil granules and on some epithelial cells. BPI's high affinity for the lipid A region of endotoxin targets its opsonizing, microbicidal and endotoxin-neutralizing activities towards Gram negative bacteria. Several immunocompromised patient populations demonstrate BPI deficiency, including newborns, those with anti-neutrophil cytoplasmic antibodies (as in cystic fibrosis and HIV infection) and those exposed to radiochemotherapy. BPI may be replenished by administering agents that induce its expression or by administration of recombinant BPI congeners, potentially shielding BPI-deficient individuals against Gram-negative bacterial infection, endotoxemia and its toxic sequelae. PMID- 21787337 TI - Structural and biophysical insight into cholesteryl ester-transfer protein. AB - CETP (cholesteryl ester-transfer protein) is essential for neutral lipid transfer between HDL (high-density lipoprotein) and LDL (low-density lipoprotein) and plays a critical role in the reverse cholesterol transfer pathway. In clinical trials, CETP inhibitors increase HDL levels and reduce LDL levels, and therefore may be used as a potential treatment for atherosclerosis. In this review, we cover the analysis of CETP structure and provide insights into CETP-mediated lipid transfer based on a collection of structural and biophysical data. PMID- 21787338 TI - The BPI-like/PLUNC family proteins in cattle. AB - Members of the protein family having similarity to BPI (bactericidal/permeability increasing protein) (the BPI-like proteins), also known as the PLUNC (palate, lung and nasal epithelium clone) family, have been found in a range of mammals; however, those in species other than human or mouse have been relatively little characterized. Analysis of the BPI-like proteins in cattle presents unique opportunities to investigate the function of these proteins, as well as address their evolution and contribution to the distinct physiology of ruminants. The present review summarizes the current understanding of the nature of the BPI-like locus in cattle, including the duplications giving rise to the multiple BSP30 (bovine salivary protein 30 kDa) genes from an ancestral gene in common with the single PSP (parotid secretory protein) gene found in monogastric species. Current knowledge of the expression of the BPI-like proteins in cattle is also presented, including their pattern of expression among tissues, which illustrate their independent regulation at sites of high pathogen exposure, and the abundance of the BSP30 proteins in saliva and salivary tissues. Finally, investigations of the function of the BSP30 proteins are presented, including their antimicrobial, lipopolysaccharide-binding and bacterial aggregation activities. These results are discussed in relation to hypotheses regarding the physiological role of the BPI-like proteins in cattle, including the role they may play in host defence and the unique aspects of digestion in ruminants. PMID- 21787339 TI - PLUNC: a multifunctional surfactant of the airways. AB - PLUNC (palate, lung and nasal epithelium clone) protein is an abundant secretory product of epithelia throughout the mammalian conducting airways. Despite its homology with the innate immune defence molecules BPI (bactericidal/permeability increasing protein) and LBP (lipopolysaccharide-binding protein), it has been difficult to define the functions of PLUNC. Based on its marked hydrophobicity and expression pattern, we hypothesized that PLUNC is an airway surfactant. We found that purified recombinant human PLUNC exhibited potent surfactant activity by several different measures, and experiments with airway epithelial cell lines and primary cultures indicate that native PLUNC makes a significant contribution to the overall surface tension in airway epithelial secretions. Interestingly, we also found that physiologically relevant concentrations of PLUNC-inhibited Pseudomonas aeruginosa biofilm formation in vitro without acting directly as a bactericide. This finding suggests that PLUNC protein may inhibit biofilm formation by airway pathogens, perhaps through its dispersant properties. Our data, along with reports from other groups on activity against some airway pathogens, expand on an emerging picture of PLUNC as a multifunctional protein, which plays a novel role in airway defences at the air/liquid interface. PMID- 21787340 TI - Latherin and other biocompatible surfactant proteins. AB - Horses and other equids are unusual in producing protein-rich sweat for thermoregulation, a major component of which is latherin, a highly surface active, non-glycosylated protein that is a member of the PLUNC (palate, lung and nasal epithelium clone) family. Latherin produces a significant reduction in water surface tension at low concentrations (<=1 mg/ml), and probably acts as a wetting agent to facilitate evaporative cooling through a thick, waterproofed pelt. Latherin binds temporarily to hydrophobic surfaces, and so may also have a disruptive effect on microbial biofilms. It may consequently have a dual role in horse sweat in both evaporative cooling and controlling microbial growth in the pelt that would otherwise be resourced by nutrients in sweat. Latherin is also present at high levels in horse saliva, where its role could be to improve mastication of the fibrous diet of equids, and also to reduce microbial adherence to teeth and oral surfaces. Neutron reflection experiments indicate that latherin adsorbs to the air/water interface, and that the protein undergoes significant conformational change and/or partial unfolding during incorporation into the interfacial layer. PMID- 21787341 TI - Distribution of human PLUNC/BPI fold-containing (BPIF) proteins. AB - Although gene expression studies have shown that human PLUNC (palate, lung and nasal epithelium clone) proteins are predominantly expressed in the upper airways, nose and mouth, and proteomic studies have indicated they are secreted into airway and nasal lining fluids and saliva, there is currently little information concerning the localization of human PLUNC proteins. Our studies have focused on the localization of three members of this protein family, namely SPLUNC1 (short PLUNC1), SPLUNC2 and LPLUNC1 (long PLUNC1). Western blotting has indicated that PLUNC proteins are highly glycosylated, whereas immunohistochemical analysis demonstrated distinct patterns of expression. For example, SPLUNC2 is expressed in serous cells of the major salivary glands and in minor mucosal glands, whereas SPLUNC1 is expressed in the mucous cells of these glands. LPLUNC1 is a product of a population of goblet cells in the airway epithelium and nasal passages and expressed in airway submucosal glands and minor glands of the oral and nasal cavities. SPLUNC1 is also found in the epithelium of the upper airways and nasal passages and in airway submucosal glands, but is not co-expressed with LPLUNC1. We suggest that this differential expression may be reflected in the function of individual PLUNC proteins. PMID- 21787342 TI - Dual host-defence functions of SPLUNC2/PSP and synthetic peptides derived from the protein. AB - PSP (parotid secretory protein)/SPLUNC2 (short palate, lung and nasal epithelium clone 2) is expressed in human salivary glands and saliva. The protein exists as an N-glycosylated and non-glycosylated form and both appear to induce agglutination of bacteria, a major antibacterial function for salivary proteins. Both forms of PSP/SPLUNC2 bind LPS (lipopolysaccharide), suggesting that the protein may also play an anti-inflammatory role. Based on the predicted structure of PSP/SPLUNC2 and the location of known antibacterial and anti-inflammatory peptides in BPI (bactericidal/permeability-increasing protein) and LBP (LPS binding protein), we designed GL13NH2 and GL13K, synthetic peptides that capture these proposed functions of PSP/SPLUNC2. GL13NH3 agglutinates bacteria, leading to increased clearance by macrophages and reduced spread of infection in a plant model. GL13K kills bacteria with a minimal inhibitory concentration of 5-10 MUg/ml, kills bacteria in biofilm and retains activity in 150 mM NaCl and 50% saliva. Both peptides block endotoxin action, but only GL13K appears to bind endotoxin. The peptides do not cause haemolysis, haemagglutination in serum, inhibit mammalian cell proliferation or induce an inflammatory response in macrophages. These results suggest that the GL13NH2 and the modified peptide GL13K capture the biological activity of PSP/SPLUNC2 and can serve as lead compounds for the development of novel antimicrobial and anti-inflammatory peptides. PMID- 21787343 TI - Bioinformatics of the TULIP domain superfamily. AB - Proteins of the BPI (bactericidal/permeability-increasing protein)-like family contain either one or two tandem copies of a fold that usually provides a tubular cavity for the binding of lipids. Bioinformatic analyses show that, in addition to its known members, which include BPI, LBP [LPS (lipopolysaccharide)-binding protein)], CETP (cholesteryl ester-transfer protein), PLTP (phospholipid-transfer protein) and PLUNC (palate, lung and nasal epithelium clone) protein, this family also includes other, more divergent groups containing hypothetical proteins from fungi, nematodes and deep-branching unicellular eukaryotes. More distantly, BPI like proteins are related to a family of arthropod proteins that includes hormone binding proteins (Takeout-like; previously described to adopt a BPI-like fold), allergens and several groups of uncharacterized proteins. At even greater evolutionary distance, BPI-like proteins are homologous with the SMP (synaptotagmin-like, mitochondrial and lipid-binding protein) domains, which are found in proteins associated with eukaryotic membrane processes. In particular, SMP domain-containing proteins of yeast form the ERMES [ER (endoplasmic reticulum)-mitochondria encounter structure], required for efficient phospholipid exchange between these organelles. This suggests that SMP domains themselves bind lipids and mediate their exchange between heterologous membranes. The most distant group of homologues we detected consists of uncharacterized animal proteins annotated as TM (transmembrane) 24. We propose to group these families together into one superfamily that we term as the TULIP (tubular lipid-binding) domain superfamily. PMID- 21787345 TI - The bactericidal/permeability-increasing protein (BPI) in the innate defence of the lower airways. AB - The human BPI (bactericidal/permeability-increasing protein), stored in primary azurophilic granula of neutrophil granulocytes and produced by mucosal epithelia, has been known for decades to bind LPS (lipopolysaccharide) with very high affinity and to efficiently kill Gram-negative bacteria. Thus BPI potentially represents a central component of the innate immune system to directly combat microbes and modulate subsequent adaptive immune responses. Especially in the lungs, which are frequently exposed to a variety of inhaled pathogens, antimicrobial innate defence molecules such as BPI, are of exceptional relevance. In the present review, we highlight possible functions of BPI during acute pneumonia and CF (cystic fibrosis)-associated chronic infections in the lung. PMID- 21787344 TI - LBP/BPI proteins and their relatives: conservation over evolution and roles in mutualism. AB - LBP [LPS (lipopolysaccharide)-binding protein] and BPI (bactericidal/permeability increasing protein) are components of the immune system that have been principally studied in mammals for their involvement in defence against bacterial pathogens. These proteins share a basic architecture and residues involved in LPS binding. Putative orthologues, i.e. proteins encoded by similar genes that diverged from a common ancestor, have been found in a number of non-mammalian vertebrate species and several non-vertebrates. Similar to other aspects of immunity, such as the activity of Toll-like receptors and NOD (nucleotide-binding oligomerization domain) proteins, analysis of the conservation of LBPs and BPIs in the invertebrates promises to provide insight into features essential to the form and function of these molecules. This review considers state-of-the-art knowledge in the diversity of the LBP/BPI proteins across the eukaryotes and also considers their role in mutualistic symbioses. Recent studies of the LBPs and BPIs in an invertebrate model of beneficial associations, the Hawaiian bobtail squid Euprymna scolopes' alliance with the marine luminous bacterium Vibrio fischeri, are discussed as an example of the use of non-vertebrate models for the study of LBPs and BPIs. PMID- 21787346 TI - Functional roles of SPLUNC1 in the innate immune response against Gram-negative bacteria. AB - PLUNC (palate, lung and nasal epithelium clone)-associated gene originally referred to one gene, but now has been extended to represent a gene family that consists of a number of genes with peptide sequence homologies and predicted structural similarities. PLUNC-like proteins display sequence homology with BPI (bactericidal/permeability-increasing protein), a 456-residue cationic protein produced by precursors of polymorphonuclear leucocytes that have been shown to possess both bactericidal and LPS (lipopolysaccharide)-binding activities. The human PLUNC is also known as LUNX (lung-specific X protein), NASG (nasopharyngeal carcinoma-related protein) and SPURT (secretory protein in upper respiratory tract). The gene originally named PLUNC is now recognized as SPLUNC1. Its gene product SPLUNC1 is a secretory protein that is abundantly expressed in cells of the surface epithelium in the upper respiratory tracts and secretory glands in lung, and in the head and the neck region. The functional role of SPLUNC1 in innate immunity has been suggested but not clearly defined. The present review describes recent findings that support antimicrobial and anti-inflammatory functions of SPLUNC1 in Gram-negative bacteria-induced respiratory infection. PMID- 21787347 TI - The molecular biology of inflammatory bowel diseases. AB - IBDs (inflammatory bowel diseases) are a group of diseases affecting the gastrointestinal tract. The diseases are multifactorial and cover genetic aspects: susceptibility genes, innate and adaptive responses to inflammation, and structure and efficacy of the mucosal protective barrier. Animal models of IBD have been developed to gain further knowledge of the disease mechanisms. These topics form an overlapping background to enable an improved understanding of the molecular features of these diseases. A series of articles is presented based on the topics covered at the Biochemical Society Focused Meeting The Molecular Biology of Inflammatory Bowel Diseases. PMID- 21787348 TI - The opposing roles of IL-21 and TGFbeta1 in chronic inflammatory bowel disease. AB - There are large numbers of T-cells in the mucosa of the intestine in healthy individuals. The stimulus for their presence is the normal gut microbiota. For unknown reasons, in patients with IBD (inflammatory bowel disease), there is inappropriate and chronic activation of mucosal T-cells which leads to gut damage and severe morbidity. In one form of IBD, namely Crohn's disease, the T-cells are probably responding to the microbiota. T-cell survival in the gut wall is dependent on pro-inflammatory cytokines and antibody-mediated inhibition of one of these cytokines, TNFalpha (tumour necrosis factor alpha), has shown efficacy in patients, thus encouraging investigations of other ways to control mucosal T cell responses. In the present paper, we give a brief review of T-cell immunology in IBD and then discuss how two particular cytokines, namely IL-21 (interleukin 21), which is generally pro-inflammatory and important in gut T-cell survival and in maintaining Th17 cells, and TGFbeta1 (transforming growth factor beta1), which is generally immunosuppressive, play opposing roles in gut inflammation. PMID- 21787349 TI - Bacteria in the pathogenesis of inflammatory bowel disease. AB - Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge. PMID- 21787350 TI - Nutritional influences on the gut microbiota and the consequences for gastrointestinal health. AB - The human colonic microbiota degrades dietary substrates that are indigestible in the upper GIT (gastrointestinal tract), releasing bacterial metabolites, some of which are important for gut health. Advances in molecular biology techniques have facilitated detailed analyses of the composition of the bacterial community resident in the lower GIT. Such analyses have indicated that more than 500 different bacterial species colonize an individual, and that, although there is much functional consistency in the resident bacterial groups, there is considerable inter-individual variation at the species/strain level. The bacterial community develops during early childhood until it reaches an adult like composition. Whereas colonization and host factors influence the species composition, dietary factors also have an important impact, with specific bacterial groups changing in response to specific dietary interventions. Since bacterial species have different metabolic activities, specific diets have various consequences for health, dependent on the effect exerted on the bacterial population. PMID- 21787351 TI - Role of faecal gas analysis for the diagnosis of IBD. AB - The diagnosis of IBD (inflammatory bowel disease) is based on the clinical evaluation of symptoms and signs leading to a series of investigations. The investigations used are often unpleasant for patients; they are invasive, costly and potentially dangerous. Patients often report that the odour of flatus, or the gas emitted from faeces, is abnormal during a flare of their IBD. Our group has characterized the VOCs (volatile organic compounds) in the headspace gas emitted from faecal samples from healthy subjects, from patients with infectious diarrhoea and from those with Crohn's disease or ulcerative colitis, both in relapse and remission. Painstaking analysis of gas chromatography-MS data (VOC profiling) has revealed patterns of compounds that are strongly associated with specific infectious diseases and with IBD. These compounds represent a change in the microflora and/or the metabolism of bacteria and/or the epithelium in disease states. These profiles offer a potential for rapid non-invasive assessment of a range of infectious and non-infectious gastrointestinal diseases. The study of VOCs may lead to a better understanding of the pathogenesis of IBD. PMID- 21787352 TI - Intestinal secretory cell ER stress and inflammation. AB - Data from animal models and human inflammatory bowel diseases have implicated the ER (endoplasmic reticulum) stress pathway in intestinal inflammation. We have characterized the development of inflammation in Winnie mice in which ER stress arises due to a single missense mutation in the MUC2 mucin produced by intestinal goblet cells. This model has allowed us to explore the genesis of inflammation ensuing from a single gene polymorphism affecting secretory cells. In these mice, a proportion of MUC2 misfolds during biosynthesis, leading to ER stress and activation of the unfolded protein response. Winnie mice develop spontaneous complex progressive inflammation that is most severe in the distal colon. Inflammation involves TH1, TH2 and TH17 T-cells, with a progressive development of a TH17-dominated response, but also involves innate immunity, in a pattern not dissimilar to human colitis. Experimental inhibition of tolerance in this model severely exacerbates colitis, demonstrating active effective suppression of inflammation. Even though the misfolding of MUC2 is a consequence of an inherited mutation, as inflammation develops, the molecular markers of ER stress increase further and goblet cell pathology becomes worse, suggesting that inflammation itself exacerbates ER stress. PMID- 21787353 TI - Genetic relationships between A20/TNFAIP3, chronic inflammation and autoimmune disease. AB - A20 [also known as TNFAIP3 (tumour necrosis factor alpha-induced protein 3)] restricts and terminates inflammatory responses through modulation of the ubiquitination status of central components in NF-kappaB (nuclear factor kappaB), IRF3 (interferon regulatory factor 3) and apoptosis signalling cascades. The phenotype of mice with full or conditional A20 deletion illustrates that A20 expression is essential to prevent chronic inflammation and autoimmune pathology. In addition, polymorphisms within the A20 genomic locus have been associated with multiple inflammatory and autoimmune disorders, including SLE (systemic lupus erythaematosis), RA (rheumatoid arthritis), Crohn's disease and psoriasis. A20 has also been implicated as a tumour suppressor in several subsets of B-cell lymphomas. The present review outlines recent findings that illustrate the effect of A20 defects in disease pathogenesis and summarizes the identified A20 polymorphisms associated with different immunopathologies. PMID- 21787354 TI - Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases. AB - IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD. PMID- 21787355 TI - Intestinal inflammation and the enterocyte transportome. AB - Diarrhoea is a hallmark of intestinal inflammation. The mechanisms operating in acute inflammation of the intestine are well characterized and are related to regulatory changes induced by inflammatory mediators such as prostaglandins, cytokines or reactive oxygen species, along with leakage due to epithelial injury and changes in permeability. In chronic colitis, however, the mechanisms are less well known, but it is generally accepted that both secretory and absorptive processes are inhibited. These disturbances in ionic transport may be viewed as an adaptation to protracted inflammation of the intestine, since prolonged intense secretion may be physiologically unacceptable in the long term. Mechanistically, the changes in transport may be due to adjustments in the regulation of the different processes involved, to broader epithelial alterations or frank damage, or to modulation of the transportome in terms of expression. In the present review, we offer a summary of the existing evidence on the status of the transportome in chronic intestinal inflammation. PMID- 21787356 TI - Role of oxidative stress and antioxidant enzymes in Crohn's disease. AB - There is increasing interest in oxidative stress being a potential aetiological factor and/or a triggering factor in Crohn's disease, rather than a concomitant occurrence during the pathogenesis of the disease. Recent research has shown that the immune mononuclear cells of Crohn's disease patients are induced to produce hydrogen peroxide (H2O2). Similarly, the regulation of antioxidant enzymes during disease in these cells has been unravelled, showing that SOD (superoxide dismutase) activity and GPx (glutathione peroxidase) activity is increased during active disease and returns to normal in remission phases. However, catalase remains constantly inhibited which supports the idea that catalase is not a redox sensitive enzyme, but a regulator of cellular processes. ROS (reactive oxygen species) can be produced under the stimulus of different cytokines such as TNFalpha (tumour necrosis factor alpha). It has been shown in different experimental models that they are also able to regulate apoptosis and other cellular processes. The status of oxidative stress elements in Crohn's disease and their possible implications in regulating cellular processes are reviewed in the present paper. PMID- 21787357 TI - Impeded protein folding and function in active inflammatory bowel disease. AB - The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD. PMID- 21787360 TI - Induction of an incomplete autophagic response by cancer-preventive geranylgeranoic acid (GGA) in a human hepatoma-derived cell line. AB - GGA (geranylgeranoic acid) is a natural polyprenoic acid, derivatives of which has been shown to prevent second primary hepatoma. GGA induces mitochondria mediated PCD (programmed cell death), which may be relevant to cancer prevention. To gain further insights into GGA-induced PCD, autophagy processes were examined in human hepatoma-derived HuH-7 cells. Treatment of HuH-7/GFP (green fluorescent protein)-LC3 cells with GGA induced green fluorescent puncta in the cytoplasm within 30 min and their massive accumulation at 24 h. After 15 min of GGA treatment, a burst of mitochondrial superoxide production occurred and LC3beta-I was appreciably converted into LC3beta-II. GGA-induced early stages of autophagy were unequivocally confirmed by electron-microscopic observation of early/initial autophagic vacuoles. On the other hand, LC3beta-II as well as p62/SQSTM1 (sequestosome 1) continuously accumulated and co-localized in the cytoplasmic puncta after GGA treatment. Furthermore, GGA treatment of HuH-7/mRFP (monomeric red fluorescent protein)-GFP-LC3 cells showed yellow fluorescent puncta, whereas glucose deprivation of the cells gave red fluorescent puncta. These results strongly suggest that GGA induces the initial phase of autophagy, but blocks the maturation process of autolysosomes or late stages of autophagy, insomuch that GGA provides substantial accumulation of autophagosomes under serum-starvation conditions in human hepatoma cells. PMID- 21787361 TI - The proteome of cytosolic lipid droplets isolated from differentiated Caco-2/TC7 enterocytes reveals cell-specific characteristics. AB - BACKGROUND INFORMATION: Intestinal absorption of alimentary lipids is a complex process ensured by enterocytes and leading to TRL [TAG (triacylglycerol)-rich lipoprotein] assembly and secretion. The accumulation of circulating intestine derived TRL is associated with atherosclerosis, stressing the importance of the control of postprandial hypertriglyceridaemia. During the postprandial period, TAGs are also transiently stored as CLDs (cytosolic lipid droplets) in enterocytes. As a first step for determining whether CLDs could play a role in the control of enterocyte TRL secretion, we analysed the protein endowment of CLDs isolated by sucrose-gradient centrifugation from differentiated Caco-2/TC7 enterocytes, the only human model able to secrete TRL in culture and to store transiently TAGs as CLDs when supplied with lipids. Cells were analysed after a 24 h incubation with lipid micelles and thus in a state of CLD-associated TAG mobilization. RESULTS: Among the 105 proteins identified in the CLD fraction by LC-MS/MS (liquid chromatography coupled with tandem MS), 27 were directly involved in lipid metabolism pathways potentially relevant to enterocyte-specific functions. The transient feature of CLDs was consistent with the presence of proteins necessary for fatty acid activation (acyl-CoA synthetases) and for TAG hydrolysis. In differentiated Caco-2/TC7 enterocytes, we identified for the first time LPCAT2 (lysophosphatidylcholine acyltransferase 2), involved in PC (phosphatidylcholine) synthesis, and 3BHS1 (3-beta-hydroxysteroid dehydrogenase 1), involved in steroid metabolism, and confirmed their partial CLD localization by immunofluorescence. In enterocytes, LPCAT2 may provide an economical source of PC, necessary for membrane synthesis and lipoprotein assembly, from the lysoPC present in the intestinal lumen. We also identified proteins involved in lipoprotein metabolism, such as ApoA-IV (apolipoprotein A-IV), which is specifically expressed by enterocytes and has been proposed to play many functions in vivo, including the formation of lipoproteins and the control of their size. The association of ApoA-IV with CLD was confirmed by confocal and immunoelectron microscopy and validated in vivo in the jejunum of mice fed with a high-fat diet. CONCLUSIONS: We report for the first time the protein endowment of Caco-2/TC7 enterocyte CLDs. Our results suggest that their formation and mobilization may participate in the control of enterocyte TRL secretion in a cell specific manner. PMID- 21787362 TI - alphav integrin processing interferes with the cross-talk between alphavbeta5/beta6 and alpha2beta1 integrins. AB - BACKGROUND INFORMATION: Previous studies have reported that cross-talk between integrins may be an important regulator of integrin-ligand binding and subsequent signalling events that control a variety of cell functions in many tissues. We previously demonstrated that alphavbeta5/beta6 integrin represses alpha2beta1 dependent cell migration. The alphav subunits undergo an endoproteolytic cleavage by protein convertases, whose role in tumoral invasion has remained controversial. RESULTS: Inhibition of convertases by the convertase inhibitor alpha1-PDX (alpha1-antitrypsin Portland variant), leading to the cell-surface expression of an uncleaved form of the alphav integrin, stimulated cell migration toward type I collagen. Under convertase inhibition, alpha2beta1 engagement led to enhanced phosphorylation of both FAK (focal adhesion kinase) and MAPK (mitogen activated protein kinase). This outside-in signalling stimulation was associated with increased levels of activated beta1 integrin located in larger than usual focal-adhesion structures and a cell migration that was independent of the PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) pathway. CONCLUSIONS: The increase in cell migration observed upon convertases inhibition appears to be due to the up-regulation of beta1 integrins and to their location in larger focal-adhesion structures. The endoproteolytic cleavage of alphav subunits is necessary for alphavbeta5/beta6 integrin to control alpha2beta1 function and could thus play an essential role in colon cancer cell migration. PMID- 21787363 TI - How mathematics warp biology: round-off of umbilical cord blood gas case value decimals distorts calculation of metabolic acidosis at birth. AB - OBJECTIVE: To illustrate the impact on settling neonatal metabolic acidosis diagnosis by rounding off pH and base deficit (BD) case value decimals. DESIGN: Comparative study. SETTING: University maternity units. SAMPLE: Umbilical cord arterial blood gas values from 18 831 newborns. MAIN OUTCOME MEASURES: Prevalences of pH <7.05 and metabolic acidosis diagnosis (pH <7.05 plus BD >12.0 mmol/L). METHODS: Calculation of BD from pH and pCO(2) values, and calculating the prevalences of metabolic acidosis before and after rounding off three-decimal values to two or one decimals. The 'round to half even' and 'round half up' round off rules were used for digit 5. RESULTS: Arterial pH was <=7.049 in 339 newborns (1.8%). In 27 (8.0%) pH was 7.045-7.049, rounded off to 7.05 when truncated to two decimals (crude vs. round-off values; McNemar's test, p<0.000001). Depending on round-offs of pH case value decimals before or after calculation of BD, and round-offs of resulting three-decimal BD values to one decimal, metabolic acidosis 'disappeared' or 'appeared' in eight of 75 metabolic acidosis cases (10.7%). With different modes of calculation, the number of metabolic acidosis cases varied between 75 and 71 cases (p>=0.1). CONCLUSION: Due to pH and BD case value decimal round-offs, a diagnostic discrepancy of acidotic pH values occurred in 8%, and of metabolic acidosis diagnosis in 10.7% of cases. A drift of a dichotomy parameter value cut-off due to decimal round-offs will result in a shift in distribution of positive and negative cases in a population sample. PMID- 21787364 TI - Assessment of the health status of 2,499 dermatological outpatients using the 12 item Medical Outcomes Study Short Form (SF-12) questionnaire. AB - BACKGROUND: In dermatological research and clinical practice it is important to evaluate the burden of the disease. OBJECTIVE: To assess whether the 12-item Short Form of the Medical Outcomes Study (SF-12) could yield a valid description of the health status of a large number of dermatological outpatients. METHODS: The SF-12 and the 12-item General Health Questionnaire (GHQ-12) were utilized. Questionnaires were self-completed by the outpatients in the waiting rooms. At the end of the visit the dermatologists recorded the diagnosis and the evaluation of the clinical severity. RESULTS: Data were complete for 2499 patients. We observed a reduction in the Physical Component Summary score (PCS-12) with increasing age, while the Mental Component Summary score (MCS-12) was stable. PCS 12 and MCS-12 scores were worse in women. Twenty-three per cent of patients were identified as GHQ-12 positive. GHQ-12-positive patients ('cases') had lower PCS 12 and MCS-12 scores compared with GHQ-12-negative patients (mean +/- SD, PCS-12: 47.9 +/- 10.8 vs. 52.2 +/- 6.6; MCS-12: 35.2 +/- 10.2 vs. 50.9 +/- 78.3, respectively). High correlations between the MCS-12 score and the GHQ-12 were documented overall (-0.690, P < 0.001) and for single skin diseases. CONCLUSIONS: The impact of dermatological diseases is high for the mental components of health status; the mean scores for MCS-12 were low, and lower in patients identified as GHQ-12 'cases'. The picture of the general health status of patients with skin diseases given by the SF-12 allows meaningful comparisons both within dermatological conditions and with diseases in other specialties, as well as within categories of clinical severity and psychological well-being in single skin conditions. PMID- 21787366 TI - The follicular triad: a pathological clue to the diagnosis of early frontal fibrosing alopecia. PMID- 21787365 TI - Obstetric outcome for women who received individualized treatment for fear of childbirth during pregnancy. AB - OBJECTIVE: To compare obstetric outcomes for women with fear of childbirth who received counseling during pregnancy with women without fear of childbirth. DESIGN: Descriptive, retrospective case-control study. SETTING: University Hospital, Linkoping, Sweden. SAMPLE: 353 women who were referred to a unit for psychosocial obstetrics and gynecology because of fear of childbirth constituted the index group and 579 women without fear of childbirth formed a reference group. METHODS. Data were collected from standardized antenatal and delivery records. MAIN OUTCOME MEASURES: Delivery data. RESULTS: Elective cesarean sections (CS) were more frequent in the index group (p<0.001). Induction of delivery was also more common among the women with fear of childbirth (16.5 compared with 9.6%, p<0.001). Women with fear of childbirth who were scheduled for vaginal delivery were more often delivered by emergency CS (p=0.007). Elective CS was more common among the parous women with fear of childbirth and instrumental delivery was more common among nulliparous women with fear of childbirth. There were no differences in complications during pregnancy, delivery or postpartum between the two groups. CONCLUSION: Fear of childbirth is a predisposing factor for emergency and elective CS even after psychological counseling. Maximal effort is necessary to avoid traumatizing deliveries and negative experiences, especially for nulliparous women. PMID- 21787367 TI - Prevalence of dermatoporosis in elderly French hospital in-patients: a cross sectional study. PMID- 21787369 TI - Understanding attraction stimuli of the cat flea, Ctenocephalides felis, in non chemical control methods. AB - Comparisons were conducted of flea catches of four commercially available flea traps in the laboratory and under field conditions, in both rural and urban locations. The results clearly showed the My Flea TrapTM, which utilizes an intermittent light to attract fleas, to be far superior in trapping ability to the three continuous light traps; it caught up to 23 times as many fleas as the other traps. Altering the lighting mechanism to provide continuous rather than intermittent light significantly decreased the number of fleas captured. In addition, the use of a green filter significantly increased trapping efficiency, whereas the addition of a heat source had no apparent effect. PMID- 21787368 TI - The determinants of periorbital skin ageing in participants of a melanoma case control study in the U.K. AB - BACKGROUND: Skin ageing is said to be caused by multiple factors. The relationship with sun exposure is of particular interest because the detrimental cutaneous effects of the sun may be a strong motivator to sun protection. We report a study of skin ageing in participants of an epidemiological study of melanoma. OBJECTIVES: To determine the predictors of periorbital cutaneous ageing and whether it could be used as an objective marker of sun exposure. METHODS: Photographs of the periorbital skin in 1341 participants were graded for wrinkles, degree of vascularity and blotchy pigmentation and the resultant data assessed in relation to reported sun exposure, sunscreen use, body mass index (BMI), smoking and the melanocortin 1 receptor (MC1R) gene status. Data were analysed using proportional odds regression. RESULTS: Wrinkling was associated with age and heavy smoking. Use of higher sun-protection factor sunscreen was protective (P = 0.01). Age, male sex, MC1R variants ('r', P=0.01; 'R', P=0.02), higher reported daily sun exposure (P=0.02), increased BMI (P=0.01) and smoking (P=0.02) were risk factors for hypervascularity. Blotchy pigmentation was associated with age, male sex, higher education and higher weekday sun exposure (P=0.03). More frequent sunscreen use (P=0.02) and MC1R variants ('r', P=0.03; 'R', P=0.001) were protective. CONCLUSIONS: Periorbital wrinkling is a poor biomarker of reported sun exposure. Vascularity is a better biomarker as is blotchy pigmentation, the latter in darker-skinned individuals. In summary, male sex, sun exposure, smoking, obesity and MC1R variants were associated with measures of cutaneous ageing. Sunscreen use showed some evidence of being protective. PMID- 21787371 TI - Effect of repeated microwave disinfections on bonding of different commercial teeth to resin denture base. AB - OBJECTIVE: To verify the influence of repeated microwave disinfections on the shear bond strength of two commercial types of teeth to acrylic resin, when the ridge lap surfaces were unmodified, bur abraded, bur grooved or etched by monomer. MATERIAL AND METHODS: Eighty specimens (n = 10) were adhered to the tooth ridge lap surface, polymerised in a water bath at 74 degrees C for 9 h. Microwaved specimens were individually immersed in 150 ml of water and submitted to five simulated disinfections in a microwave oven calibrated at 650 W for 3 min. Control specimens were not microwave treated. Shear bond strength tests were performed in an Instron machine with a cross-speed of 1 mm/min. The fracture load values were transformed into shear bond strength as a function of the bonding area (0.28 cm(2)). Data were submitted to ANOVA and Tukey's test (alpha = 0.05). Fractured areas were classified as adhesive, cohesive (resin or tooth) or mixed failures. RESULTS: Repeated microwave disinfections increased the shear strength of the tooth/resin bond. Mechanical retention in microwaved and non-microwaved procedures improved the shear bond strength. CONCLUSIONS: The different commercial types of teeth influenced shear bond strength values, with Biotone teeth showing the lower values. PMID- 21787370 TI - Do assistive devices, training, and workload affect injury incidence? Prevention efforts by nursing homes and back injuries among nursing assistants. AB - AIMS: This paper is a report of a study of association between workplace injuries experienced by nursing assistants in nursing homes in the United States and four factors that may affect injury rates: initial nursing assistant training, training at the current facility, lifting devices, and time to execute daily duties. BACKGROUND: High injury rates among nursing personnel have been reported in multiple settings across countries. The existing literature is divided on the effectiveness of training and assistive devices in reducing injury rates among nursing assistants. METHODS: We examined associations between whether or not the nursing assistant has experienced an injury and four key factors: quality of initial injury prevention training, injury prevention training at current facility, lift availability and whether or not the nursing assistant has sufficient time to complete resident activities of daily living. We estimated a survey-weighted logit model using 2004 National Nursing Assistant Survey data. RESULTS/FINDINGS: The odds of an injury in the past year were lower among nursing assistants who reported always having a lift available when needed (41% lower odds), available facility training to reduce workplace injuries (39%), and sufficient time to complete resident activities of daily living (35%). Quality of initial training to prevent work injuries was not significantly associated with injury status. CONCLUSION: Regions without widespread access to lifting devices may be able to reduce injury rates by increasing the availability of lifting devices. The potential for reductions in injury rates in the United States is greatest from improving training and ensuring adequate time for resident care, as most facilities currently have lifts available. PMID- 21787372 TI - Parental psychological well-being and cognitive development of very low birth weight infants at 2 years. AB - AIM: To assess the associations between cognitive development of very low birth weight (VLBW) infants and measures of parental psychological well-being. METHODS: In this prospective cohort study, 182 VLBW infants born 1/2001-12/2006 at the Turku University Hospital, Finland, were followed up. At 2 years corrected age, cognitive development of the child was assessed using the Mental Development Index of Bayley Scales, and both parents filled in validated questionnaires defining parental psychological well-being (Beck Depression Inventory, Parenting Stress Index and Sense of Coherence Scale). RESULTS: The cognitive delay of the infant was associated with paternal symptoms of depression (p = 0.007) and parenting stress (p = 0.03). Mothers of the infants with cognitive delay reported increased parenting stress related to the difficulty to accept the child (p = 0.001). Weak sense of coherence predicted depressive symptoms in both parents (p < 0.0001). CONCLUSION: Even if the fathers of VLBW infants experienced depressive symptoms less often than the mothers, the ability of the fathers to cope was significantly associated with the cognitive development of the infant. In addition, the fathers reported more parenting stress if the infant had a cognitive delay. The mothers reported more parenting stress related to accepting the VLBW infant with cognitive delay. PMID- 21787373 TI - Molecular evidence of HIV-1 transmission in 20 Korean individuals with haemophilia: phylogenetic analysis of the vif gene. AB - To assess whether a genetic relationship exists between the viruses infecting HIV positive patients with haemophilia and those infecting plasma donors, we determined the vif sequences in 169 individuals, including 20 haemophilia patients, 3 plasma donors, and 146 local controls. Twenty haemophilia patients were diagnosed with HIV-1 at 1-2 years after exposure to factor IX (FIX) manufactured in Korea, beginning in 1989-1990. Plasma samples from donors O and P were used to manufacture clotting factors including FIX used to treat the 20 haemophiliacs. The vif gene from frozen stored serum samples obtained 1-3 years after diagnosis was amplified by RT-PCR, and subjected to direct sequencing. Phylogenetic analysis revealed that vif sequences from 128 of the samples (including haemophilia patients and donors) belonged to the Korean subclade of HIV-1 subtype B (KSB). Sequences from 41 other participants were identified as subtype B, but outside the Korean subclade. Sequences of the vif gene from donors O and P plus the 20 individuals with haemophilia comprised two subclusters within KSB. In addition, signature pattern analysis disclosed the presence of conserved nucleotides at two positions in donors and haemophiliacs only. Together with information on KSB, dates of plasma donations and seroconversion of haemophilia patients, our results suggest that the haemophiliacs examined here became infected by viruses in the domestic clotting factor used for treatment. PMID- 21787374 TI - Assessment of the dynamics of the physiological states of Lactococcus lactis ssp. cremoris SK11 during growth by flow cytometry. AB - AIMS: The aim of this study was to improve knowledge about the dynamics of the physiological states of Lactococcus lactis ssp. cremoris SK11, a chain-forming bacterium, during growth, and to evaluate whether flow cytometry (FCM) combined with fluorescent probes can assess these different physiological states. METHODS AND RESULTS: Cellular viability was assessed using double labelling with carboxyfluorescein diacetate and propidium iodide. FCM makes it possible to discriminate between three cell populations: viable cells, dead cells and cells in an intermediate physiological state. During exponential and stationary phases, the cells in the intermediate physiological state were culturable, whereas this population was no longer culturable at the end of the stationary phase. CONCLUSIONS, AND IMPACT OF THE STUDY: We introduced a new parameter, the ratio of the means of the fluorescence cytometric index to discriminate between viable culturable and viable nonculturable cells. Finally, this work confirms the relevance of FCM combined with two fluorescent stains to evaluate the physiological states of L. lactis SK11 cells during their growth and to distinguish viable cells from viable but not culturable cells. PMID- 21787375 TI - Acculturative type is associated with breastfeeding duration among low-income Latinas. AB - We sought to assess the relationship between acculturative type and breastfeeding outcomes among low-income Latinas, utilising a multidimensional assessment of acculturation. We analysed data derived from a breastfeeding peer counselling randomised trial. Acculturation was assessed during pregnancy using a modified Acculturation Rating Scale for Mexican Americans scale. Analyses were restricted to Latinas who completed the acculturation scale and had post-partum breastfeeding data (n = 114). Cox survival analyses were conducted to evaluate differences in breastfeeding continuation and exclusivity by acculturative type. Participants were classified as integrated-high (23.7%, n = 27), traditional Hispanic (36.8%, n = 42), integrated-low (12.3%, n = 14) and assimilated (27.2%, n = 31). The integrated-low group was significantly more likely to continue breastfeeding than the traditional Hispanic, assimilated, and integrated-high groups (P < 0.05, P < 0.05, and P < 0.01, respectively). The traditional Hispanic group was marginally more likely to continue breastfeeding than the integrated high group (P = 0.06). Breastfeeding continuation rates vary significantly between acculturative types in this multinational, low-income Latina sample. Multidimensional assessments of acculturation may prove useful in better tailoring future breastfeeding promotion interventions. PMID- 21787376 TI - Intein lacking conserved C-terminal motif G retains controllable N-cleavage activity. AB - A split-intein consists of two complementary fragments (N-intein and C-intein) that can associate to carry out protein trans-splicing. The Ssp GyrB S11 split intein is an engineered unconventional split-intein consisting of a 150-amino acid N-intein and an extremely small six-amino-acid C-intein, which comprises the conserved intein motif G. Here, we show that fusion proteins containing the 150 amino-acid N-intein could be triggered to undergo controllable N-cleavage in vitro when the six-amino-acid C-intein or a derivative thereof was added as a synthetic peptide in trans. More importantly, we discovered, unexpectedly, that the 150-amino-acid N-intein could be induced by strong nucleophiles to undergo N cleavage in vitro, and in Escherichia coli cells, in the absence of the motif G containing six-amino-acid C-intein. This finding indicated that the first step of the protein splicing mechanism (acyl shift) could occur in the absence of the entire motif G. Extensive kinetic analyses revealed that both the motif G residues and the Ser+1 residue positively influenced N-cleavage rate constants and yields. The 150-amino-acid N-intein could also tolerate various unrelated sequences appended to its C-terminus without disruption of the N-cleavage function, suggesting that the catalytic pocket of the intein has considerable structural flexibility. Our findings reveal interesting insights into intein structure-function relationships, and demonstrate a new and potentially more useful method of controllable, intein-mediated N-cleavage for protein engineering applications. PMID- 21787377 TI - Synergy between the N-terminal and C-terminal domains of Mycobacterium tuberculosis HupB is essential for high-affinity binding, DNA supercoiling and inhibition of RecA-promoted strand exchange. AB - The occurrence of DNA architectural proteins containing two functional domains derived from two different architectural proteins is an interesting emerging research theme in the field of nucleoid structure and function. Mycobacterium tuberculosis HupB, unlike Escherichia coli HU, is a two-domain protein that, in the N-terminal region, shows broad sequence homology with bacterial HU. The long C-terminal extension, on the other hand, contains seven PAKK/KAAK motifs, which are characteristic of the histone H1/H5 family of proteins. In this article, we describe several aspects of HupB function, in comparison with its truncated derivatives lacking either the C-terminus or N-terminus. We found that HupB binds a variety of DNA repair and replication intermediates with K(d) values in the nanomolar range. By contrast, the N-terminal fragment of M. tuberculosis HupB (HupB(MtbN)) showed diminished DNA-binding activity, with K(d) values in the micromolar range, and the C-terminal domain was completely devoid of DNA-binding activity. Unlike HupB(MtbN) , HupB was able to constrain DNA in negative supercoils and introduce negative superhelical turns into relaxed DNA. Similarly, HupB exerted a robust inhibitory effect on DNA strand exchange promoted by cognate and noncognate RecA proteins, whereas HupB(MtbN), even at a 50-fold molar excess, had no inhibitory effect. Considered together, these results suggest that synergy between the N-terminal and C-terminal domains of HupB is essential for its DNA-binding ability, and to modulate the topological features of DNA, which has implications for processes such as DNA compaction, gene regulation, homologous recombination, and DNA repair. PMID- 21787378 TI - Embryonic stem-cell-preconditioned microenvironment induces loss of cancer cell properties in human melanoma cells. AB - The cancer microenvironment affects cancer cell proliferation and growth. Embryonic stem (ES)-preconditioned 3-dimensional (3-D) culture of cancer cells induces cancer cell reprogramming and results in a change in cancer cell properties such as differentiation and migration in skin melanoma. However, the mechanism has not yet been clarified. Using the ES-preconditioned 3-D microenvironment model, we provide evidence showing that the ES microenvironment inhibits proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. We also found that the ES microenvironment suppresses telomerase activity and thereby induces senescence in SK-MEL-28 cells. Furthermore, we observed that gremlin, an antagonist of BMP4, is secreted from ES cells and plays an important role in cellular senescence. Knocking down gremlin in the ES microenvironment increases proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. Taken together, these results demonstrated that gremlin is a crucial factor responsible for abrogating melanoma properties in the ES-preconditioned 3 D microenvironment. PMID- 21787379 TI - Risk assessment of the introduction of H5N1 highly pathogenic avian influenza as a tool to be applied in prevention strategy plan. AB - Risks of the introduction of highly pathogenic avian influenza (HPAI) H5N1 through migratory birds to the main wintering site for wild birds in southern Brazil and its consequences were assessed. Likelihoods were estimated by a qualitative scale ranging from negligible to high. Northern migrants that breed in Alaska and regularly migrate to South America (primary Charadriiformes) can have contact with birds from affected areas in Asia. The likelihood of the introduction of HPAI H5N1 through migratory birds was found to be very low as it is a probability conditioned to successful transmission in breeding areas and the probabilities of an infected bird migrating and shedding the virus as far as southern Brazil. The probability of wild species becoming exposed to H5N1 infected birds is high as they nest with northern migrants from Alaska, whereas for backyard poultry it is moderate to high depending on proximity to wetlands and the presence of species that could increase the likelihood of contact with wild birds such as domestic duck. The magnitude of the biological and economic consequences of successful transmission to poultry or wild birds would be low to severe depending on the probability of the occurrence of outbreak scenarios described. As a result, the risk estimate is greater than negligible, and HPAI H5N1 prevention strategy in the region should always be carefully considered by the veterinary services in Brazil. PMID- 21787380 TI - Food of the dogs. PMID- 21787381 TI - An integrated strategy for identification of both sharp and broad peaks from next generation sequencing data. AB - A novel integrative approach has been developed by Lieb and colleagues for analyzing genome-wide datasets of different chromatin-binding factors and epigenetic states that exhibit both sharp and diffuse signals on the genome. PMID- 21787382 TI - Sex lethal and upstream ORFs: a bait-and-trap system for ribosomes. AB - An upstream ORF cooperates with Sex lethal to inhibit msl-2 translation during Drosophila sex determination, a biological principle with potentially broad application in gene regulation. PMID- 21787383 TI - Value of scar imaging and inotropic reserve combination for the prediction of segmental and global left ventricular functional recovery after revascularisation. AB - BACKGROUND: This study sought to prospectively and directly compare three cardiovascular magnetic resonance (CMR) viability parameters: inotropic reserve (IR) during low-dose dobutamine (LDD) administration, late gadolinium enhancement transmurality (LGE) and thickness of the non-contrast-enhanced myocardial rim surrounding the scar (RIM). These parameters were examined to evaluate their value as predictors of segmental left ventricular (LV) functional recovery in patients with LV systolic dysfunction undergoing surgical or percutaneous revascularisation. The second goal of the study was to determine the optimal LDD CMR- and LGE-CMR-based predictor of significant (>= 5%) LVEF improvement 6 months after revascularisation. METHODS: In 46 patients with chronic coronary artery disease (CAD) (63 +/- 10 years of age, LVEF 35 +/- 8%), wall motion and the above mentioned CMR parameters were evaluated before revascularisation. Wall motion and LGE were repeatedly assessed 6 months after revascularisation. Logistic regression analysis models were created using 333 dysfunctional segments at rest. RESULTS: An LGE threshold value of 50% (LGE50) and a RIM threshold value of 4 mm (RIM4) produced the best sensitivities and specificities for predicting segmental recovery. IR was superior to LGE50 for predicting segmental recovery. When the areas under the ROC curves is compared, the combined viability prediction model (LGE50 + IR) was significantly superior to IR alone in all analysed sets of segments, except the segments with an LGE from 26% to 75% (p = 0.08). The RIM4 model was not superior to the LGE50 model. A myocardial segment was considered viable if it had no LGE or had any LGE and produced IR during LDD stimulation. ROC analysis demonstrated that >= 50% of viable segments from all dysfunctional and revascularised segments in a patient predict significant improvement in LVEF with a 69% sensitivity and 70% specificity (AUC 0.7, p = 0.05). The cut-off of >= 3 viable segments was a less useful predictor of significant global LV recovery. CONCLUSIONS: LDD-CMR is superior to LGE-CMR as a predictor of segmental recovery. The advantage is greatest in the segments with an LGE from 26% to 75%. The RIM cut-off value of 4 mm had no superiority over the LGE cut-off value of 50% in predicting the segmental recovery. Patients with >= 50% of viable segments from all dysfunctional and revascularised had a tendency to improve LVEF by >= 5% after revascularisation. PMID- 21787384 TI - Characteristics of HIV-infected women and factors associated with HCV seropositivity in the Republic of Georgia. AB - BACKGROUND: The aim of this study was to describe the extent of the HIV epidemic among women in the Republic of Georgia and to identify factors associated with HCV co-infection in this population. FINDINGS: All women aged >=18 years who were diagnosed with HIV between 1989 and 2006 were identified through the National HIV/AIDS surveillance database. Medical records were reviewed for demographic characteristics, risk factors and HCV serostatus. A total of 249 women were identified. Only 4% declared injection drug use (IDU); sex work was reported by 9%. Substantial risk factors were identified among the women's sexual partners, nearly 69% of whom were IDUs, 84% were HIV positive and 66% HCV positive. Seventeen percent of women were seropositive for HCV. Factors significantly associated with HCV seropositivity in bivariate analyses among non-IDU women were partner IDU+ [Prevalence ratio (PR): 4.5 (95% CI: 1.4, 14.2)], and partner HCV+ [PR: 7.2 (95% CI: 1.8, 29.5)]. CONCLUSIONS: The HIV epidemic in the Republic of Georgia is closely tied to the IDU community. Evidence-based interventions targeting IDU and partners of IDU are urgently required to halt the spread of the HIV epidemic in the country. PMID- 21787386 TI - Development of Taenia pisiformis in golden hamster (Mesocricetus auratus). AB - The life cycle of Taenia pisiformis includes canines as definitive hosts and rabbits as intermediate hosts. Golden hamster (Mesocricetus auratus) is a rodent that has been successfully used as experimental model of Taenia solium taeniosis. In the present study we describe the course of T. pisiformis infection in experimentally infected golden hamsters. Ten females, treated with methyl prednisolone acetate were infected with three T. pisiformis cysticerci each one excised from one rabbit. Proglottids released in faeces and adults recovered during necropsy showed that all animals were infected. Eggs obtained from the hamsters' tapeworms, were assessed for viability using trypan blue or propidium iodide stains. Afterwards, some rabbits were inoculated with eggs, necropsy was performed after seven weeks and viable cysticerci were obtained. Our results demonstrate that the experimental model of adult Taenia pisiformis in golden hamster can replace the use of canines in order to study this parasite and to provide eggs and adult tapeworms to be used in different types of experiments. PMID- 21787385 TI - ZINBA integrates local covariates with DNA-seq data to identify broad and narrow regions of enrichment, even within amplified genomic regions. AB - ZINBA (Zero-Inflated Negative Binomial Algorithm) identifies genomic regions enriched in a variety of ChIP-seq and related next-generation sequencing experiments (DNA-seq), calling both broad and narrow modes of enrichment across a range of signal-to-noise ratios. ZINBA models and accounts for factors that co vary with background or experimental signal, such as G/C content, and identifies enrichment in genomes with complex local copy number variations. ZINBA provides a single unified framework for analyzing DNA-seq experiments in challenging genomic contexts. PMID- 21787387 TI - Women receive more trials of noninvasive ventilation for acute respiratory failure than men: a nationwide population-based study. AB - INTRODUCTION: Previous studies in western countries have observed that women are less likely than men to receive intensive care and mechanical ventilation (MV). We aimed to investigate whether the gender difference also exists in Asian populations and in the provision of different types of MV including invasive (INV) and noninvasive ventilation (NIV). METHODS: We analyzed all adult hospital patients between 2005 and 2007 in the claims data from 1,000,000 randomly selected people in the Taiwan National Health Insurance Research Database. NIV only was defined as patients receiving NIV as the only ventilator treatment during hospitalization. Gender difference was assessed using multivariable analyses with/without considering a hospital cluster effect by generalized estimating equations models. Subgroup analyses for gender difference in NIV use were performed using propensity score matching method. RESULTS: Of the 128,327 patients enrolled, 53.8% were men, 9.2% received intensive care and 5.2% used MV. After adjusting for potential confounders, women were less likely than men to receive intensive care (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.73-0.82) and MV (aOR 0.84, 95% CI 0.78-0.91). Among MV patients, 6.8% received NIV-only; the proportion of which was higher in women than in men (8.6% vs. 5.7%, P < 0.001). After controlling for confounders and a cluster effect, women remained more likely to receive NIV-only (aOR 1.61, 95% CI 1.32-1.96). Subgroup analyses showed that patients with underlying congestive heart failure (CHF) had the highest difference in the provision of NIV-only (female-to-male aOR 2.76, 95% CI 1.38-5.53). A hospital cluster effect on the gender difference in NIV use was found in patients with diseases other than chronic obstructive pulmonary disease and CHF. CONCLUSIONS: Gender differences existed not only in the provision but also in the types of MV. Further studies are needed to understand why gender differences occur. PMID- 21787388 TI - Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. AB - BACKGROUND: Monocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown. The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma. METHODS: Prostate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n = 171), adjacent non neoplastic tissues (n = 135), PIN lesions (n = 40) and normal prostatic tissue (n = 14). Protein expression was correlated with patients' clinicopathologic characteristics. RESULTS: In the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence. CONCLUSIONS: Our data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer. PMID- 21787389 TI - Ultrafast nano-oscillators based on interlayer-bridged carbon nanoscrolls. AB - We demonstrate a viable approach to fabricating ultrafast axial nano-oscillators based on carbon nanoscrolls (CNSs) using molecular dynamics simulations. Initiated by a single-walled carbon nanotube (CNT), a monolayer graphene can continuously scroll into a CNS with the CNT housed inside. The CNT inside the CNS can oscillate along axial direction at a natural frequency of tens of gigahertz. We demonstrate an effective strategy to reduce the dissipation of the CNS-based nano-oscillator by covalently bridging the carbon layers in the CNS. We further demonstrate that such a CNS-based nano-oscillator can be excited and driven by an external AC electric field, and oscillate at more than 100 GHz. The CNS-based nano-oscillators not only offer a feasible pathway toward ultrafast nano-devices but also hold promise to enable nanoscale energy transduction, harnessing, and storage (e.g., from electric to mechanical). PMID- 21787390 TI - Strength and tempo of selection revealed in viral gene genealogies. AB - BACKGROUND: RNA viruses evolve extremely quickly, allowing them to rapidly adapt to new environmental conditions. Viral pathogens, such as influenza virus, exploit this capacity for evolutionary change to persist within the human population despite substantial immune pressure. Understanding the process of adaptation in these viral systems is essential to our efforts to combat infectious disease. RESULTS: Through analysis of simulated populations and sequence data from influenza A (H3N2) and measles virus, we show how phylogenetic and population genetic techniques can be used to assess the strength and temporal pattern of adaptive evolution. The action of natural selection affects the shape of the genealogical tree connecting members of an evolving population, causing deviations from the neutral expectation. The magnitude and distribution of these deviations lends insight into the historical pattern of evolution and adaptation in the viral population. We quantify the degree of ongoing adaptation in influenza and measles virus through comparison of census population size and effective population size inferred from genealogical patterns, finding a 60-fold greater deviation in influenza than in measles. We also examine the tempo of adaptation in influenza, finding evidence for both continuous and episodic change. CONCLUSIONS: Our results have important consequences for understanding the epidemiological and evolutionary dynamics of the influenza virus. Additionally, these general techniques may prove useful to assess the strength and pattern of adaptive evolution in a variety of evolving systems. They are especially powerful when assessing selection in fast-evolving populations, where temporal patterns become highly visible. PMID- 21787391 TI - The virtual supermarket: an innovative research tool to study consumer food purchasing behaviour. AB - BACKGROUND: Economic interventions in the food environment are expected to effectively promote healthier food choices. However, before introducing them on a large scale, it is important to gain insight into the effectiveness of economic interventions and peoples' genuine reactions to price changes. Nonetheless, because of complex implementation issues, studies on price interventions are virtually non-existent. This is especially true for experiments undertaken in a retail setting. We have developed a research tool to study the effects of retail price interventions in a virtual-reality setting: the Virtual Supermarket. This paper aims to inform researchers about the features and utilization of this new software application. RESULTS: The Virtual Supermarket is a Dutch-developed three dimensional software application in which study participants can shop in a manner comparable to a real supermarket. The tool can be used to study several food pricing and labelling strategies. The application base can be used to build future extensions and could be translated into, for example, an English-language version. The Virtual Supermarket contains a front-end which is seen by the participants, and a back-end that enables researchers to easily manipulate research conditions. The application keeps track of time spent shopping, number of products purchased, shopping budget, total expenditures and answers on configurable questionnaires. All data is digitally stored and automatically sent to a web server. A pilot study among Dutch consumers (n = 66) revealed that the application accurately collected and stored all data. Results from participant feedback revealed that 83% of the respondents considered the Virtual Supermarket easy to understand and 79% found that their virtual grocery purchases resembled their regular groceries. CONCLUSIONS: The Virtual Supermarket is an innovative research tool with a great potential to assist in gaining insight into food purchasing behaviour. The application can be obtained via an URL and is freely available for academic use. The unique features of the tool include the fact that it enables researchers to easily modify research conditions and in this way study different types of interventions in a retail environment without a complex implementation process. Finally, it also maintains researcher independence and avoids conflicts of interest that may arise from industry collaboration. PMID- 21787392 TI - Community mobilisation with women's groups facilitated by Accredited Social Health Activists (ASHAs) to improve maternal and newborn health in underserved areas of Jharkhand and Orissa: study protocol for a cluster-randomised controlled trial. AB - BACKGROUND: Around a quarter of the world's neonatal and maternal deaths occur in India. Morbidity and mortality are highest in rural areas and among the poorest wealth quintiles. Few interventions to improve maternal and newborn health outcomes with government-mandated community health workers have been rigorously evaluated at scale in this setting.The study aims to assess the impact of a community mobilisation intervention with women's groups facilitated by ASHAs to improve maternal and newborn health outcomes among rural tribal communities of Jharkhand and Orissa. METHODS/DESIGN: The study is a cluster-randomised controlled trial and will be implemented in five districts, three in Jharkhand and two in Orissa. The unit of randomisation is a rural cluster of approximately 5000 population. We identified villages within rural, tribal areas of five districts, approached them for participation in the study and enrolled them into 30 clusters, with approximately 10 ASHAs per cluster. Within each district, 6 clusters were randomly allocated to receive the community intervention or to the control group, resulting in 15 intervention and 15 control clusters. Randomisation was carried out in the presence of local stakeholders who selected the cluster numbers and allocated them to intervention or control using a pre generated random number sequence. The intervention is a participatory learning and action cycle where ASHAs support community women's groups through a four phase process in which they identify and prioritise local maternal and newborn health problems, implement strategies to address these and evaluate the result. The cycle is designed to fit with the ASHAs' mandate to mobilise communities for health and to complement their other tasks, including increasing institutional delivery rates and providing home visits to mothers and newborns. The trial's primary endpoint is neonatal mortality during 24 months of intervention. Additional endpoints include home care practices and health care-seeking in the antenatal, delivery and postnatal period. The impact of the intervention will be measured through a prospective surveillance system implemented by the project team, through which mothers will be interviewed around six weeks after delivery. Cost data and qualitative data are collected for cost-effectiveness and process evaluations. STUDY REGISTRATION: ISRCTN: ISRCTN31567106. PMID- 21787394 TI - A spatial analysis of variations in health access: linking geography, socio economic status and access perceptions. AB - BACKGROUND: This paper analyses the relationship between public perceptions of access to general practitioners (GPs) surgeries and hospitals against health status, car ownership and geographic distance. In so doing it explores the different dimensions associated with facility access and accessibility. METHODS: Data on difficulties experienced in accessing health services, respondent health status and car ownership were collected through an attitudes survey. Road distances to the nearest service were calculated for each respondent using a GIS. Difficulty was related to geographic distance, health status and car ownership using logistic generalized linear models. A Geographically Weighted Regression (GWR) was used to explore the spatial non-stationarity in the results. RESULTS: Respondent long term illness, reported bad health and non-car ownership were found to be significant predictors of difficulty in accessing GPs and hospitals. Geographic distance was not a significant predictor of difficulty in accessing hospitals but was for GPs. GWR identified the spatial (local) variation in these global relationships indicating locations where the predictive strength of the independent variables was higher or lower than the global trend. The impacts of bad health and non-car ownership on the difficulties experienced in accessing health services varied spatially across the study area, whilst the impacts of geographic distance did not. CONCLUSIONS: Difficulty in accessing different health facilities was found to be significantly related to health status and car ownership, whilst the impact of geographic distance depends on the service in question. GWR showed how these relationships were varied across the study area. This study demonstrates that the notion of access is a multi-dimensional concept, whose composition varies with location, according to the facility being considered and the health and socio-economic status of the individual concerned. PMID- 21787393 TI - Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen. AB - BACKGROUND: Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. RESULTS: We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met. CONCLUSION: Altogether, MMP-19 exhibits an anti angiogenic effect on endothelial cells via generation of angiostatin-like fragments. PMID- 21787395 TI - Physicians' propensity to collaborate and their attitude towards EBM: a cross sectional study. AB - BACKGROUND: The healthcare management literature states that physicians often coordinate their activities within and between organizations through social networks. Previous studies have also documented the relationship between professional networks and physicians' attitudes toward evidence-based medicine (EBM). The present study sought associations between physicians' self-reported attitudes toward EBM and the formation of inter-physician collaborative network ties. METHODS: Primary data were collected from 297 clinicians at six hospitals belonging to one of the largest local health units of the Italian National Health Service. Data collection used a survey questionnaire that inquired about professional networks and physicians' characteristics. Social network analysis was performed to describe inter-physician professional networks. Multiple regression quadratic assignment procedures were performed to assess the relationship between self-reported attitudes toward EBM and clinicians' propensity to collaborate. RESULTS: Physicians who reported similar attitudes toward EBM were more likely to exchange information and advice through collaborative relationships (beta = 0.0198; p < 0.05). Similarities in other characteristics, such as field of specialization (beta = 0.1988; p < 0.01), individual affiliations with hospital sites (beta = 0.0845; p < 0.01), and organizational clinical directorates (beta = 0.0459; p < 0.01), were also significantly related to physicians' propensity to collaborate. CONCLUSIONS: Communities of practice within healthcare organizations are likely to contain separate clusters of physicians whose members are highly similar. Organizational interventions are needed to foster heterophily whenever multidisciplinary cooperation is required to provide effective health care. PMID- 21787396 TI - Acute appendicitis in preschoolers: a study of two different populations of children. AB - OBJECTIVE: To assess the incidence and the risk factors implicated in acute appendicitis in preschoolers in our region. METHODS: Over a 7-year period, 352 children underwent appendectomy for suspected acute appendicitis. Of these, data for 23 children were excluded because no inflammation of the appendix was found on subsequent histology. Of the remaining 329, 82 were <= 5 years old (i.e., preschool children) and 247 were 5-14 years old. These two groups of children were further divided according to their religion into Muslims and Christian Orthodox: 43 of the children aged <= 5 years were Muslims and 39 were Christian Orthodox. A household questionnaire was designed to collect data concerning age, gender, type of residence area, living conditions, vegetable consumption, and family history of surgery for acute appendicitis as preschool children. The removed appendices were also assessed histologically for the amount of lymphoid tissue. RESULTS: Acute appendicitis of preschoolers developed more frequently in Muslims (39.4%) than in Christians (17.7%; p < 0.001). The lack of inside toilet facilities at home, overcrowded living conditions, living in rural areas, and the amount of appendix lymphoid tissue were significantly more frequent among the Muslim preschool children (p < 0.05), while there were no statistically significant differences between Muslim and Christian children with regard to gender, the family history of acute appendicitis, or the vegetable consumption (p > 0.05). CONCLUSIONS: In our region, the percentage of preschool-aged Muslim children with acute appendicitis was remarkably high. One possible explanation for this finding could be the higher amount of lymphoid tissue in the wall of the appendix in Muslim preschool children together with their low standard of hygiene. PMID- 21787397 TI - Polydatin up-regulates Clara cell secretory protein to suppress phospholipase A2 of lung induced by LPS in vivo and in vitro. AB - BACKGROUND: Lung injury induced by lipopolysaccharide (LPS) remains one of the leading causes of morbidity and mortality in children. The damage to membrane phospholipids leads to the collapse of the bronchial alveolar epithelial barrier during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Phospholipase A2 (PLA2), a key enzyme in the hydrolysis of membrane phospholipids, plays an important traumatic role in pulmonary inflammation, and Clara cell secretory protein (CCSP) is an endogenous inhibitor of PLA2. Our previous study showed that polydatin (PD), a monocrystalline extracted from a traditional Chinese medicinal herb (Polygonum cuspidatum Sieb, et Zucc), reduced PLA2 activity and sPLA2-IIA mRNA expression and mitigated LPS-induced lung injury. However, the potential mechanism for these effects has not been well defined. We have continued to investigate the effect of PD on LPS-induced expression of CCSP mRNA and protein in vivo and in vitro. RESULTS: Our results suggested that the CCSP mRNA level was consistent with its protein expression. CCSP expression was decreased in lung after LPS challenge. In contrast, PD markedly increased CCSP expression in a concentration-dependent manner. In particular, CCSP expression in PD-pretreated rat lung was higher than in rats receiving only PD treatment. CONCLUSION: These results indicated that up regulation of CCSP expression causing inhibition of PLA2 activation may be one of the crucial protective mechanisms of PD in LPS-induced lung injury. PMID- 21787398 TI - Chromosomal painting and ZW sex chromosomes differentiation in Characidium (Characiformes, Crenuchidae). AB - BACKGROUND: The Characidium (a Neotropical fish group) have a conserved diploid number (2n = 50), but show remarkable differences among species and populations in relation to sex chromosome systems and location of nucleolus organizer regions (NOR). In this study, we isolated a W-specific probe for the Characidium and characterized six Characidium species/populations using cytogenetic procedures. We analyzed the origin and differentiation of sex and NOR-bearing chromosomes by chromosome painting in populations of Characidium to reveal their evolution, phylogeny, and biogeography. RESULTS: A W-specific probe for efficient chromosome painting was isolated by microdissection and degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) amplification of W chromosomes from C. gomesi. The W probe generated weak signals dispersed on the proto sex chromosomes in C. zebra, dispersed signals in both W and Z chromosomes in C. lauroi and, in C. gomesi populations revealed a proximal site on the long arms of the Z chromosome and the entire W chromosome. All populations showed small terminal W probe sites in some autosomes. The 18S rDNA revealed distinctive patterns for each analyzed species/population with regard to proto sex chromosome, sex chromosome pair, and autosome location. CONCLUSIONS: The results from dual-color fluorescence in situ hybridization (dual-color FISH) using W and 18S rDNA probes allowed us to infer the putative evolutionary pathways for the differentiation of sex chromosomes and NORs, from structural rearrangements in a sex proto chromosome, followed by gene erosion and heterochromatin amplification, morphological differentiation of the sex chromosomal pair, and NOR transposition, giving rise to the distinctive patterns observed among species/populations of Characidium. Biogeographic isolation and differentiation of sex chromosomes seem to have played a major role in the speciation process in this group of fish. PMID- 21787399 TI - Algometry with a clothes peg compared to an electronic pressure algometer: a randomized cross-sectional study in pain patients. AB - BACKGROUND: Hypersensitivity of the central nervous system is widely present in pain patients and recognized as one of the determinants of chronic pain and disability. Electronic pressure algometry is often used to explore aspects of central hypersensitivity. We hypothesized that a simple pain provocation test with a clothes peg provides information on pain sensitivity that compares meaningfully to that obtained by a well-established electronic pressure algometer. "Clinically meaningful" was defined as a medium (r = 0.3-0.5) or high (r > 0.5) correlation coefficient according to Cohen's conventions. METHODS: We tested 157 in-patients with different pain types. A calibrated clothes peg was applied for 10 seconds and patients rated the pain intensity on a 0 to 10 numerical rating scale. Pressure pain detection threshold (PPdt) and pressure pain tolerance threshold (PPtt) were measured with a standard electronic algometer. Both methods were performed on both middle fingers and ear lobes. In a subgroup of 47 patients repeatability (test-retest reliability) was calculated. RESULTS: Clothes peg values correlated with PPdt values for finger testing with r = -0.54 and for earlobe testing with r = -0.55 (all p-values < 0.001). Clothes peg values also correlated with PPtt values for finger testing with r = -0.55 (p < 0.001). Test-retest reliability (repeatability) showed equally stable results for clothes peg algometry and the electronic algometer (all r-values > 0.89, all p-values < 0.001). CONCLUSIONS: Information on pain sensitivity provided by a calibrated clothes peg and an established algometer correlate at a clinically meaningful level. PMID- 21787400 TI - Rare variants in the ATM gene and risk of breast cancer. AB - INTRODUCTION: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved. METHODS: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants. RESULTS: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant. CONCLUSIONS: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2. PMID- 21787401 TI - Low physical fitness is a strong predictor of health problems among young men: a follow-up study of 1411 male conscripts. AB - BACKGROUND: Military service in Finland is compulsory for male citizens and annually about 90% of 19-year-old men enter into the service. Approximately 15% of them are discharged due to medical reasons constituting a group of young men who are at risk of being marginalised in society. The purpose of the study was to evaluate predictive associations between medical discharge from the compulsory military service and various intrinsic risk factors, including socio-economic, health, health behavior, and physical fitness outcomes. METHODS: We followed four successive cohorts of conscripts who formed a representative sample of Finnish young men (18-28 years old, median age 19 yrs) for 6 months. To exclude injuries and illnesses originating before the onset of service, conscripts discharged from the service at the medical screenings during the 2-week run-in period were excluded from the analyses. Data regarding medical discharge were charted from computerised patient records. Predictive associations between medical discharge and intrinsic risk factors were examined using multivariate Cox's proportional hazard models. RESULTS: Of 1411 participants, 9.4% (n = 133) were discharged prematurely for medical reasons, mainly musculoskeletal (44%, n = 59) and mental and behavioral (29%, n = 39) disorders. Low levels of physical fitness assessed with a 12-min running test (hazard ratio [HR] 3.3; 95% confidence interval [CI]: 1.7-6.4), poor school success (HR 4.6; 95% CI: 2.0-11.0), poor self-assessed health (HR 2.8; 95% CI: 1.6-5.2), and not belonging to a sports club (HR 4.9; 95% CI: 1.2-11.6) were most strongly associated with medical discharge in a graded manner. The present results highlight the need for an improved pre-enlistment examination and provide a new means of identifying young persons with a high risk for discharge. CONCLUSIONS: The majority of the observed risk factors are modifiable. Thus preventive measures and programs could be implemented. The findings suggest that increasing both aerobic and muscular fitness is a desirable goal in a pre-training program before entering military service. Attention to appropriate waist circumference and strategies addressing psychological well being may strengthen the preventive program. Optimally the effectiveness of these programs should be tested in randomized controlled intervention studies. PMID- 21787403 TI - Lessons from the business sector for successful knowledge management in health care: a systematic review. AB - BACKGROUND: The concept of knowledge management has been prevalent in the business sector for decades. Only recently has knowledge management been receiving attention by the health care sector, in part due to the ever growing amount of information that health care practitioners must handle. It has become essential to develop a way to manage the information coming in to and going out of a health care organization. The purpose of this paper was to summarize previous studies from the business literature that explored specific knowledge management tools, with the aim of extracting lessons that could be applied in the health domain. METHODS: We searched seven databases using keywords such as "knowledge management", "organizational knowledge", and "business performance". We included articles published between 2000-2009; we excluded non-English articles. RESULTS: 83 articles were reviewed and data were extracted to: (1) uncover reasons for initiating knowledge management strategies, (2) identify potential knowledge management strategies/solutions, and (3) describe facilitators and barriers to knowledge management. CONCLUSIONS: KM strategies include such things as training sessions, communication technologies, process mapping and communities of practice. Common facilitators and barriers to implementing these strategies are discussed in the business literature, but rigorous studies about the effectiveness of such initiatives are lacking. The health care sector is at a pinnacle place, with incredible opportunities to design, implement (and evaluate) knowledge management systems. While more research needs to be done on how best to do this in healthcare, the lessons learned from the business sector can provide a foundation on which to build. PMID- 21787402 TI - Quantification of codon selection for comparative bacterial genomics. AB - BACKGROUND: Statistics measuring codon selection seek to compare genes by their sensitivity to selection for translational efficiency, but existing statistics lack a model for testing the significance of differences between genes. Here, we introduce a new statistic for measuring codon selection, the Adaptive Codon Enrichment (ACE). RESULTS: This statistic represents codon usage bias in terms of a probabilistic distribution, quantifying the extent that preferred codons are over-represented in the gene of interest relative to the mean and variance that would result from stochastic sampling of codons. Expected codon frequencies are derived from the observed codon usage frequencies of a broad set of genes, such that they are likely to reflect nonselective, genome wide influences on codon usage (e.g. mutational biases). The relative adaptiveness of synonymous codons is deduced from the frequency of codon usage in a pre-selected set of genes relative to the expected frequency. The ACE can predict both transcript abundance during rapid growth and the rate of synonymous substitutions, with accuracy comparable to or greater than existing metrics. We further examine how the composition of reference gene sets affects the accuracy of the statistic, and suggest methods for selecting appropriate reference sets for any genome, including bacteriophages. Finally, we demonstrate that the ACE may naturally be extended to quantify the genome-wide influence of codon selection in a manner that is sensitive to a large fraction of codons in the genome. This reveals substantial variation among genomes, correlated with the tRNA gene number, even among groups of bacteria where previously proposed whole-genome measures show little variation. CONCLUSIONS: The statistical framework of the ACE allows rigorous comparison of the level of codon selection acting on genes, both within a genome and between genomes. PMID- 21787404 TI - Colorectal carcinoma: nucleosomes, carcinoembryonic antigen and ca 19-9 as apoptotic markers; a comparative study. AB - BACKGROUND: Colorectal carcinoma is a common and often fatal disease in which methods of early detection and monitoring are essential. The present study was conducted for measuring serum levels of nucleosomes, carcinoembryonic antigen (CEA) and CA 19-9 in patients newly diagnosed with colorectal carcinoma and confirmed by clinicopathological study. METHOD: Thirty subjects were included in the current study: six normal subjects as a control group with mean age (45.6 +/- 7.9) and twenty four colorectal carcinoma patients with mean age (46.9 +/- 15.6), which were classified pathologically according to the degree of malignant cell differentiation into well differentiated (group I), moderately differentiated (group II) and poorly differentiated (group III). Fasting venous blood samples were collected preoperative. RESULTS: The results revealed a significant increase in serum level of nucleosomes in patients with poorly differentiated tumors versus patients with well differentiated tumors (p = 0.041). The levels of CEA and CA19-9 showed no significant increase (p = 0.569 and 0.450, respectively). CONCLUSION: In conclusion, serum level of nucleosomes provides a highly sensitive and specific apoptotic marker for colorectal carcinoma. PMID- 21787405 TI - Effect of alpha-linolenic acid on endoplasmic reticulum stress-mediated apoptosis of palmitic acid lipotoxicity in primary rat hepatocytes. AB - BACKGROUND: Hepatic inflammation and degeneration induced by lipid depositions may be the major cause of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of saturated and unsaturated fatty acids (FA) on apoptosis in primary rat hepatocytes. METHODS: The primary rat hepatocytes were treated with palmitic acid and/or alpha-linolenic acid in vitro. The expression of proteins associated with endoplasmic reticulum (ER) stress, apoptosis, caspase-3 levels were detected after the treatment. RESULTS: The treatment with palmitic acid produced a significant increase in cell death. The unfolded protein response (UPR)-associated genes CHOP, GRP78, and GRP94 were induced to higher expression levels by palmitic acid. Co-treatment with alpha linolenic acid reversed the apoptotic effect and levels of all three indicators of ER stress exerted by palmitic acid. Tunicamycin, which induces ER stress produced similar effects to those obtained using palmitic acid; its effects were also reversed by alpha-linolenic acid. CONCLUSIONS: alpha-Linolenic acid may provide a useful strategy to avoid the lipotoxicity of dietary palmitic acid and nutrient overload accompanied with obesity and NAFLD. PMID- 21787406 TI - A protocol for enumeration of aquatic viruses by epifluorescence microscopy using AnodiscTM 13 membranes. AB - BACKGROUND: Epifluorescence microscopy is a common method used to enumerate virus like particles (VLP) from environmental samples and relies on the use of filter membranes with pore sizes < 0.02 MUm; the most commonly used protocols employ 25 mm AnodiscTM membranes with a built-in support ring. Other filters with small pore sizes exist, including the 13 mm AnodiscTM membranes without a support ring. However, the use of these membranes for viral enumeration has not been previously reported. RESULTS: Here we describe a modified protocol for 13 mm Anodisc membranes that uses a custom filter holder that can be readily constructed in individual investigators' laboratories from commercially available Swinnex(r) filter holders. We compared VLP concentrations obtained from phage lysates and seawater samples using both Anodisc membranes, as well as NucleporeTM small pore size membranes (0.015 or 0.030 MUm). The 13 mm Anodisc membranes gave comparable estimates of VLP abundance to those obtained with the 25 mm Anodisc membranes when similar staining methods were employed. Both Nuclepore membranes typically gave an order of magnitude lower VLP abundance values for environmental samples. CONCLUSIONS: The 13 mm Anodisc membranes are less costly and require smaller sample volumes than their 25 mm counterpart making them ideal for large-scale studies and sample replication. This method increases the options of reliable approaches available for quantifying VLP from environmental samples. PMID- 21787407 TI - Rapeseed and milk protein exhibit a similar overall nutritional value but marked difference in postprandial regional nitrogen utilization in rats. AB - BACKGROUND: Rapeseed is an emerging and promising source of dietary protein for human nutrition and health. We previously found that rapeseed protein displayed atypical nutritional properties in humans, characterized by low bioavailability and a high postprandial biological value. The objective of the present study was to investigate the metabolic fate of rapeseed protein isolate (RPI) and its effect on protein fractional synthesis rates (FSR) in various tissues when compared to a milk protein isolate (MPI). METHODS: Rats (n = 48) were given a RPI or MPI meal, either for the first time or after 2-week adaptation to a MPI or RPI based diet. They were divided in two groups for measuring the fed-state tissue FSR 2 h after the meal (using a flooding dose of 13C-valine) and the dietary N postprandial distribution at 5 h (using 15N-labeled meals). RESULTS: RPI and MPI led to similar FSR and dietary nitrogen (N) losses (ileal and deamination losses of 4% and 12% of the meal, respectively). By contrast, the dietary N incorporation was significantly higher in the intestinal mucosa and liver (+36% and +16%, respectively) and lower in skin (-24%) after RPI than MPI. CONCLUSIONS: Although RPI and MPI led to the same overall level of postprandial dietary N retention in rats (in line with our findings in humans), this global response conceals marked qualitative differences at the tissue level regarding dietary N accretion. The fact that FSR did not however differed between groups suggest a differential modulation of proteolysis after RPI or MPI ingestion, or other mechanisms that warrant further study. PMID- 21787408 TI - Effect of mesoporous silica under Neisseria meningitidis transformation process: environmental effects under meningococci transformation. AB - BACKGROUND: This study aimed the use of mesoporous silica under the naturally transformable Neisseria meningitidis, an important pathogen implicated in the genetic horizontal transfer of DNA causing a escape of the principal vaccination measures worldwide by the capsular switching process. This study verified the effects of mesoporous silica under N. meningitidis transformation specifically under the capsular replacement. METHODS: we used three different mesoporous silica particles to verify their action in N. meningitis transformation frequency. RESULTS: we verified the increase in the capsular gene replacement of this bacterium with the three mesoporous silica nanoparticles. CONCLUSION: the mesouporous silica particles were capable of increasing the capsule replacement frequency in N. meningitidis. PMID- 21787409 TI - Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities. AB - BACKGROUND: Enrichment of loci by DNA hybridization-capture, followed by high throughput sequencing, is an important tool in modern genetics. Currently, the most common targets for enrichment are the protein coding exons represented by the consensus coding DNA sequence (CCDS). The CCDS, however, excludes many actual or computationally predicted coding exons present in other databases, such as RefSeq and Vega, and non-coding functional elements such as untranslated and regulatory regions. The number of variants per base pair (variant density) and our ability to interrogate regions outside of the CCDS regions is consequently less well understood. RESULTS: We examine capture sequence data from outside of the CCDS regions and find that extremes of GC content that are present in different subregions of the genome can reduce the local capture sequence coverage to less than 50% relative to the CCDS. This effect is due to biases inherent in both the Illumina and SOLiD sequencing platforms that are exacerbated by the capture process. Interestingly, for two subregion types, microRNA and predicted exons, the capture process yields higher than expected coverage when compared to whole genome sequencing. Lastly, we examine the variation present in non-CCDS regions and find that predicted exons, as well as exonic regions specific to RefSeq and Vega, show much higher variant densities than the CCDS. CONCLUSIONS: We show that regions outside of the CCDS perform less efficiently in capture sequence experiments. Further, we show that the variant density in computationally predicted exons is more than 2.5-times higher than that observed in the CCDS. PMID- 21787410 TI - Mild hypoglycemia is independently associated with increased mortality in the critically ill. AB - INTRODUCTION: Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear. METHODS: Prospectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint. RESULTS: We analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively. CONCLUSIONS: Mild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality. PMID- 21787412 TI - Vaughan-Jackson-like syndrome as an unusual presentation of Kienbock's disease: a case report. AB - INTRODUCTION: Kienbock's disease is a condition of osteonecrosis of the lunate bone in the hand, and most patients present with a painful and sometimes swollen wrist with a limited range of motion in the affected wrist. Vaughan-Jackson syndrome is characterized by the disruption of the digital extensor tendons, beginning on the ulnar side with the extensor digiti minimi and extensor digitorum communis tendon of the small finger. It is most commonly associated with rheumatoid arthritis. We describe a case of a patient with an unusual presentation of Kienbock's disease with symptoms similar to those of Vaughan Jackson syndrome. CASE PRESENTATION: A 40-year-old man of Indian ethnic origin with no known history of trauma presented to our clinic with a ten-day history of an inability to extend his right little and ring fingers with associated pain in his right wrist. He was being treated with long-term steroids but had no other significant medical history. His examination revealed an inability to extend the metacarpal and phalangeal joints of the right ring and little fingers with localized tenderness over the lunate bone. Spontaneous disruption of the extensor tendons was diagnosed clinically and, after radiological investigation, was confirmed to be secondary to dorsal extrusion of the fragmented lunate bone. The patient underwent surgical repair of the tendons and had a full recovery afterward. CONCLUSION: Kienbock's disease, though rare, is an important cause of spontaneous extensor tendon rupture. The original description of Vaughan-Jackson syndrome was of rupture of the extensor tendons of the little and ring fingers caused by attrition at an arthritic inferior radioulnar joint. We describe a case of a patient with Kienbock's disease that first appeared to be a Vaughan-Jackson like syndrome. PMID- 21787411 TI - Identification of a human immunodominant T-cell epitope of mycobacterium tuberculosis antigen PPE44. AB - BACKGROUND: Recently our group has identified a novel antigen of Mycobacterium tuberculosis, protein PPE44, belonging to the "PPE protein" family. Although its role in infection is largely unknown, PPE44-specific immune responses were detected in mice infected with M. tuberculosis; moreover, immunization of mice with PPE44 subunit vaccines resulted in protective efficacy comparable to the one afforded by BCG against M. tuberculosis (Romano et al., Vaccine 26, 6053-6063, 2008). RESULTS: In the present paper, we investigated anti-PPE44 T-lymphocyte responses during human infection by evaluating the frequency of PPE44-specific interferon (IFN)-gamma-secreting cells by ELISpot and flow cytometry in a small cohort of healthy subjects that had proven positive to PPD (PPD+) in vitro, in patients with active tuberculosis, in subjects vaccinated with BCG and in unvaccinated, PPD- healthy controls. We showed IFN-gamma+ T cell immune responses to recombinant PPE44 in at least a very high proportion of PPD+ individuals tested and, to a lower extent, in subjects vaccinated with BCG. By the use of a panel of overlapping synthetic 20-mer peptides spanning the PPE44 primary amino acid sequence, we identified a strong CD4+ T-cell epitope, encompassed by peptide p1L (VDFGALPPEVNSARMYGGAG), in the NH2-terminus of the PPE44 molecule at the amino acid position 1-20. Conversely, our experiments did not provide evidence of a significant IFN-gamma+ CD4+ T cell response to PPE44 or its immunodominant peptide p1L in most (7 out of 8) patients with active TB. CONCLUSIONS: Our data suggest an important immunological role of PPE44 and its immunodominant epitope p1L that could be useful in the design of anti-tuberculosis vaccines and in the immunological diagnosis of M. tuberculosis infection. PMID- 21787413 TI - Desmoid tumor of the abdominal wall: a case report. AB - INTRODUCTION: Desmoid tumors are rare lesions without any metastatic potential but a strong tendency to invade locally and to recur. These tumors are associated with women of fertile age, especially during and after pregnancy. CASE PRESENTATION: The case of a desmoid tumor of the anterior abdominal wall in a 40 year-old Caucasian man with no relevant family history is presented, describing its appearance on computed tomography and ultrasonography. The patient, who presented with a painless mass in the left anterolateral abdomen, had a history of previous urgent abdominal surgery after a shotgun injury two years earlier. Radical resection of the affected abdominal wall musculature was performed, and the defect was reconstructed with polypropylene mesh. CONCLUSION: The diagnosis of desmoid tumor should be strongly considered even in male patients with an abdominal mass and a history of previous abdominal surgery. The goal of its treatment is complete tumor excision and avoidance of the development of complications such as hernia. PMID- 21787414 TI - Progressive obtundation in a young woman with bilateral corpus striatum infarction: a case report. AB - BACKGROUND: Bilateral ischemic infarction involving the corpus striatum is a rare event which usually results from global cerebral hypoxia, intoxications, and drug abuse. CASE PRESENTATION: We report a 28 year old Caucasian woman who presented with progressive obtundation and later development of severe expressive dysphasia and Parkinsonism after sustaining ischemic stroke of both corpora striata. Hemorrhagic transformation developed on day four of admission. CONCLUSION: This is a rare case of bilateral basal ganglia infarction with hemorrhagic transformation in a young patient. Our patient's work up did not reveal any cause behind this stroke; however, advanced investigations (such as genetic testing and conventional angiography) were not done. The damage resulted in motor dysphasia and Parkinsonism. Neither dystonia nor other involuntary movements developed, and cognitive function was not assessed because of the language disorder. PMID- 21787415 TI - The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. AB - INTRODUCTION: Intervertebral disc (IVD) degeneration is associated with proteolytic degradation of the extracellular matrix, and its repair requires both the production of extracellular matrix and the downregulation of proteinase activity. These properties are associated with several growth factors. However, the use of growth factors in clinical practice is limited by their high cost. This cost can be circumvented using synthetic peptides, such as Link N, which can stimulate the synthesis of proteoglycan and collagen by IVD cells in vitro. The purpose of the present study was to evaluate the effect of Link N in vivo in a rabbit model of IVD degeneration. METHODS: New Zealand white rabbits received annular puncture in two lumbar discs. Two weeks after puncture, both punctured discs of each rabbit were injected with either Link N or saline. After 2 weeks, nine rabbits were euthanized and the annulus fibrosus (AF) and nucleus pulposus (NP) of Link N-injected and saline-injected IVDs were removed and used to prepare total RNA. Following reverse transcription, quantitative PCR was performed for aggrecan, COL2A1, COL1A1, ADAMTS-4, ADAMTS-5 and MMP-3. After 12 weeks, 19 rabbits were euthanized and the injected IVDs were removed for biochemical and histological analysis. Proteinase K digests were analyzed for DNA and sulfated glycosaminoglycan content. Disc height was monitored radiographically biweekly. RESULTS: Following needle puncture, disc height decreased by about 25% over 2 weeks, and was partially restored by Link N injection. Puncture of the IVD resulted in a trend towards decreased proteoglycan content in both the NP and AF, and a trend towards partial restoration following Link N injection, although under the time course used this did not achieve statistical significance. Link N did not alter the DNA content of the discs. Link N injection led to a significant increase in aggrecan gene expression and a significant decrease in proteinase gene expression in both the NP and AF, when compared with saline alone. CONCLUSIONS: When administered to the degenerate disc in vivo, Link N stimulated aggrecan gene expression and downregulated metalloproteinase expression, and there was a trend towards increased proteoglycan content of the disc, in both the NP and AF. These are features needed for any agent designed to stimulate disc repair. In principle, therefore, Link N supplementation could be an option for treating disc degeneration. PMID- 21787416 TI - Rapid optimization of gene dosage in E. coli using DIAL strains. AB - BACKGROUND: Engineers frequently vary design parameters to optimize the behaviour of a system. However, synthetic biologists lack the tools to rapidly explore a critical design parameter, gene expression level, and have no means of systematically varying the dosage of an entire genetic circuit. As a step toward overcoming this shortfall, we have developed a technology that enables the same plasmid to be maintained at different copy numbers in a set of closely related cells. This provides a rapid method for exploring gene or cassette dosage effects. RESULTS: We engineered two sets of strains to constitutively provide a trans-acting replication factor, either Pi of the R6K plasmid or RepA of the ColE2 plasmid, at different doses. Each DIAL (different allele) strain supports the replication of a corresponding plasmid at a constant level between 1 and 250 copies per cell. The plasmids exhibit cell-to-cell variability comparable to other popular replicons, but with improved stability. Since the origins are orthogonal, both replication factors can be incorporated into the same cell. We demonstrate the utility of these strains by rapidly assessing the optimal expression level of a model biosynthetic pathway for violecein. CONCLUSIONS: The DIAL strains can rapidly optimize single gene expression levels, help balance expression of functionally coupled genetic elements, improve investigation of gene and circuit dosage effects, and enable faster development of metabolic pathways. PMID- 21787417 TI - Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib. AB - BACKGROUND: Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet derived growth factor receptors (PDGFRs)-alpha and -beta, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome. METHODS: Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT). RESULTS: At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF C or sKIT, were partially or completely reversed during the first 2-week off treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS. CONCLUSIONS: Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00247676. PMID- 21787418 TI - Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis. AB - INTRODUCTION: To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. METHODS: Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO(2)) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay. RESULTS: 4-HNE levels pre/post anti TNF-alpha therapy were inversely correlated with in vivo tpO(2) (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO(2) levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found. CONCLUSIONS: High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-alpha treatment. PMID- 21787419 TI - The minimal kinome of Giardia lamblia illuminates early kinase evolution and unique parasite biology. AB - BACKGROUND: The major human intestinal pathogen Giardia lamblia is a very early branching eukaryote with a minimal genome of broad evolutionary and biological interest. RESULTS: To explore early kinase evolution and regulation of Giardia biology, we cataloged the kinomes of three sequenced strains. Comparison with published kinomes and those of the excavates Trichomonas vaginalis and Leishmania major shows that Giardia's 80 core kinases constitute the smallest known core kinome of any eukaryote that can be grown in pure culture, reflecting both its early origin and secondary gene loss. Kinase losses in DNA repair, mitochondrial function, transcription, splicing, and stress response reflect this reduced genome, while the presence of other kinases helps define the kinome of the last common eukaryotic ancestor. Immunofluorescence analysis shows abundant phospho staining in trophozoites, with phosphotyrosine abundant in the nuclei and phosphothreonine and phosphoserine in distinct cytoskeletal organelles. The Nek kinase family has been massively expanded, accounting for 198 of the 278 protein kinases in Giardia. Most Neks are catalytically inactive, have very divergent sequences and undergo extensive duplication and loss between strains. Many Neks are highly induced during development. We localized four catalytically active Neks to distinct parts of the cytoskeleton and one inactive Nek to the cytoplasm. CONCLUSIONS: The reduced kinome of Giardia sheds new light on early kinase evolution, and its highly divergent sequences add to the definition of individual kinase families as well as offering specific drug targets. Giardia's massive Nek expansion may reflect its distinctive lifestyle, biphasic life cycle and complex cytoskeleton. PMID- 21787420 TI - Changing patterns of malaria during 1996-2010 in an area of moderate transmission in southern Senegal. AB - BACKGROUND: Malaria is reportedly receding in different epidemiological settings, but local long-term surveys are limited. At Mlomp dispensary in south-western Senegal, an area of moderate malaria transmission, year-round, clinically suspected malaria was treated with monotherapy as per WHO and national policy in the 1990s. Since 2000, there has been a staggered deployment of artesunate amodiaquine after parasitological confirmation; this was adopted nationally in 2006. METHODS: Data were extracted from clinic registers for the period between January 1996 and December 2010, analysed and modelled. RESULTS: Over the 15-year study period, the risk of malaria decreased about 32-times (from 0.4 to 0.012 episodes person-year), while anti-malarial treatments decreased 13-times (from 0.9 to 0.07 treatments person-year) and consultations for fever decreased 3-times (from 1.8 to 0.6 visits person-year). This was paralleled by changes in the age profile of malaria patients so that the risk of malaria is now almost uniformly distributed throughout life, while in the past malaria used to concern more children below 16 years of age. CONCLUSIONS: This study provides direct evidence of malaria risk receding between 1996-2010 and becoming equal throughout life where transmission used to be moderate. Infection rates are no longer enough to sustain immunity. Temporally, this coincides with deploying artemisinin combinations on parasitological confirmation, but other contributing causes are unclear. PMID- 21787421 TI - Training trainers in health and human rights: implementing curriculum change in South African health sciences institutions. AB - BACKGROUND: The complicity of the South African health sector in apartheid and the international relevance of human rights as a professional obligation prompted moves to include human rights competencies in the curricula of health professionals in South Africa. A Train-the-Trainers course in Health and Human Rights was established in 1998 to equip faculty members from health sciences institutions nationwide with the necessary skills, attitudes and knowledge to teach human rights to their students. This study followed up participants to determine the extent of curriculum implementation, support needed as well as barriers encountered in integrating human rights into health sciences teaching and learning. METHODS: A survey including both quantitative and qualitative components was distributed in 2007 to past course participants from 1998-2006 via telephone, fax and electronic communication. RESULTS: Out of 162 past participants, 46 (28%) completed the survey, the majority of whom were still employed in academic settings (67%). Twenty-two respondents (48%) implemented a total of 33 formal human rights courses into the curricula at their institutions. Respondents were nine times more likely (relative risk 9.26; 95% CI 5.14-16.66) to implement human rights education after completing the training. Seventy-two extracurricular activities were offered by 21 respondents, many of whom had successfully implemented formal curricula. Enabling factors for implementation included: prior teaching experience in human rights, general institutional support and the presence of allies - most commonly coworkers as well as deans. Frequently cited barriers to implementation included: budget restrictions, time constraints and perceived apathy of colleagues or students. Overall, respondents noted personal enrichment and optimism in teaching human rights. CONCLUSION: This Train-the-Trainer course provides the historical context, educational tools, and collective motivation to incorporate human rights educational initiatives at health sciences institutions. Increased implementation of human rights instruction, both formally and extracurricularly, has demonstrated the training's significance not only within academic institutions but more broadly across the health sector. Coworkers are vital allies in teaching human rights to health sciences students, helping to alleviate institutional barriers. Training fellow staff members and those in key leadership roles is noted as vital to the sustainability of human rights education. PMID- 21787422 TI - Time and frequency domain analysis of heart rate variability in cattle affected by bovine spongiform encephalopathy. AB - BACKGROUND: Heart rate variability (HRV) analysis is a method to assess the function of the autonomic nervous system. Brainstem nuclei that influence HRV are affected by vacuolar changes and accumulation of disease-associated prion protein (PrPd) in bovine spongiform encephalopathy (BSE) resulting in clinical signs suggestive of an increased parasympathetic tone. It was hypothesised that BSE in cattle causes changes in the autonomic nervous system; this was tested by comparing HRV indices derived from 1048 electrocardiograms, which were recorded from 51 naturally or experimentally infected cattle with BSE confirmed by postmortem tests, 321 clinical suspect cases or cattle inoculated with potentially infectious tissue without disease confirmation and 78 BSE-free control cattle. FINDINGS: Statistically significant differences were found for low or high frequency power, their normalised values and ratio when the last recording prior to cull or repeated recordings were compared but only between male and female cattle of the three groups and not between groups of the same gender, even though BSE cases of each gender appeared to be more nervous during the recording. The same findings were made for heart rate, deviation from the mean RR interval and vasovagal tonus index when repeated recordings were compared. BSE cases with severe vacuolar changes in the parasympathetic nucleus of the vagus nerve had a significantly lower low:high frequency power ratio but not a lower heart rate than BSE cases with mild vacuolation, whereas severity of vacuolar changes in the solitary tract nucleus or intensity of PrPd accumulation in both nuclei did not appear to have any affect on either index. Abnormalities in the electrocardiogram were detected in 3% of the recordings irrespective of the BSE status; sinus arrhythmia was present in 93% of the remaining recordings. CONCLUSIONS: HRV analysis was not useful to distinguish BSE-positive from BSE negative cattle grouped by gender, and HRV indices appeared to be mainly influenced by gender. There is agreement with earlier studies that vacuolar changes in the brainstem may be associated with an increased parasympathetic tone in BSE and that abnormalities in an electrocardiogram can be detected in cattle without evidence of heart disease. PMID- 21787423 TI - Identification of genomic indels and structural variations using split reads. AB - BACKGROUND: Recent studies have demonstrated the genetic significance of insertions, deletions, and other more complex structural variants (SVs) in the human population. With the development of the next-generation sequencing technologies, high-throughput surveys of SVs on the whole-genome level have become possible. Here we present split-read identification, calibrated (SRiC), a sequence-based method for SV detection. RESULTS: We start by mapping each read to the reference genome in standard fashion using gapped alignment. Then to identify SVs, we score each of the many initial mappings with an assessment strategy designed to take into account both sequencing and alignment errors (e.g. scoring more highly events gapped in the center of a read). All current SV calling methods have multilevel biases in their identifications due to both experimental and computational limitations (e.g. calling more deletions than insertions). A key aspect of our approach is that we calibrate all our calls against synthetic data sets generated from simulations of high-throughput sequencing (with realistic error models). This allows us to calculate sensitivity and the positive predictive value under different parameter-value scenarios and for different classes of events (e.g. long deletions vs. short insertions). We run our calculations on representative data from the 1000 Genomes Project. Coupling the observed numbers of events on chromosome 1 with the calibrations gleaned from the simulations (for different length events) allows us to construct a relatively unbiased estimate for the total number of SVs in the human genome across a wide range of length scales. We estimate in particular that an individual genome contains ~670,000 indels/SVs. CONCLUSIONS: Compared with the existing read-depth and read-pair approaches for SV identification, our method can pinpoint the exact breakpoints of SV events, reveal the actual sequence content of insertions, and cover the whole size spectrum for deletions. Moreover, with the advent of the third-generation sequencing technologies that produce longer reads, we expect our method to be even more useful. PMID- 21787424 TI - Clinical evaluation of cardiac effects of experimental doxycycline overdosing in healthy calves. AB - BACKGROUND: Cardiac morphologic and functional changes consistent with cardiomyopathy have been reported in field cases of calves with accidental doxycycline overdosing. The purpose of this study was to evaluate clinically the cardiac effects of an experimentally-induced doxycycline overdosing in healthy calves. Twelve 2 months-old healthy Belgian Blue calves were studied. Six of them (group 1) received the normal dose (5 mg/kg, BID) and the six others (group 2) received five times the normal dose (25 mg/kg, BID) of oral doxycycline for five consecutive days (D1 to D5). Each calf was clinically examined daily. Measurement of serum AST, CK, Iso-CKs and LDH activities and an echocardiographic examination were performed before (D0) and one day after (D6) the last doxycycline administration. An ECG tracing was recorded at D0, D4, and D6. RESULTS: In both groups, no clinical, blood, echocardiographic or electrocardiographic changes suggestive of a cardiomyopathy were observed. Only a decreased appetite was observed in the calves of the group 2 between D3 and D6. CONCLUSIONS: This trial failed to reproduce cardiac changes reported in accidental doxycycline-poisoning in calves, suggesting that high doses of doxycycline may not be the only etiologic factor of the cardiomyopathy reported in the field cases. PMID- 21787425 TI - Polysaccharides from Agaricus bisporus and Agaricus brasiliensis show similarities in their structures and their immunomodulatory effects on human monocytic THP-1 cells. AB - BACKGROUND: Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. Crude mushroom extracts have been tested without detailed chemical analyses of its polysaccharide content. For the present study we decided to chemically determine the carbohydrate composition of semi purified extracts from 2 closely related and well known basidiomycete species, i.e. Agaricus bisporus and A. brasiliensis and to study their effects on the innate immune system, in particular on the in vitro induction of pro-inflammatory cytokines, using THP-1 cells. METHODS: Mushroom polysaccharide extracts were prepared by hot water extraction and precipitation with ethanol. Their composition was analyzed by GC-MS and NMR spectroscopy. PMA activated THP-1 cells were treated with the extracts under different conditions and the production of pro-inflammatory cytokines was evaluated by qPCR. RESULTS: Semi-purified polysaccharide extracts of A. bisporus and A. brasiliensis (= blazei) were found to contain (1->6),(1->4)-linked alpha-glucan, (1->6)-linked beta-glucan, and mannogalactan. Their proportions were determined by integration of 1H-NMR signs, and were considerably different for the two species. A. brasiliensis showed a higher content of beta-glucan, while A. bisporus presented mannogalactan as its main polysaccharide. The extracts induced a comparable increase of transcription of the pro-inflammatory cytokine genes IL-1beta and TNF-alpha as well as of COX-2 in PMA differentiated THP-1 cells. Pro-inflammatory effects of bacterial LPS in this assay could be reduced significantly by the simultaneous addition of A. brasiliensis extract. CONCLUSIONS: The polysaccharide preparations from the closely related species A. bisporus and A. brasiliensis show major differences in composition: A. bisporus shows high mannogalactan content whereas A. brasiliensis has mostly beta-glucan. Semi-purified polysaccharide extracts from both Agaricus species stimulated the production of pro-inflammatory cytokines and enzymes, while the polysaccharide extract of A. brasiliensis reduced synthesis of these cytokines induced by LPS, suggesting programmable immunomodulation. PMID- 21787426 TI - Centrilobular emphysema combined with pulmonary fibrosis results in improved survival: a response. AB - Better survival in combined pulmonary fibrosis and emphysema than in lone pulmonary fibrosis: bias or reality? A response to Centrilobular emphysema combined with pulmonary fibrosis results in improved survival by Todd et al., Fibrogenesis & Tissue Repair 2011, 4:6.Please see related letter http://fibrogenesis.com/content/4/1/17. PMID- 21787427 TI - Survival in pulmonary fibrosis combined with emphysema: likely defined by characteristics of specific patient subpopulations. AB - Authors' Reply to letter from Cottin et al.Please see related letter http://www.fibrogenesis.com/content/4/1/16. PMID- 21787428 TI - Association between plasma metabolites and gene expression profiles in five porcine endocrine tissues. AB - BACKGROUND: Endocrine tissues play a fundamental role in maintaining homeostasis of plasma metabolites such as non-esterified fatty acids and glucose, the levels of which reflect the energy balance or the health status of animals. However, the relationship between the transcriptome of endocrine tissues and plasma metabolites has been poorly studied. METHODS: We determined the blood levels of 12 plasma metabolites in 27 pigs belonging to five breeds, each breed consisting of both females and males. The transcriptome of five endocrine tissues i.e. hypothalamus, adenohypophysis, thyroid gland, gonads and backfat tissues from 16 out of the 27 pigs was also determined. Sex and breed effects on the 12 plasma metabolites were investigated and associations between genes expressed in the five endocrine tissues and the 12 plasma metabolites measured were analyzed. A probeset was defined as a quantitative trait transcript (QTT) when its association with a particular metabolic trait achieved a nominal P value < 0.01. RESULTS: A larger than expected number of QTT was found for non-esterified fatty acids and alanine aminotransferase in at least two tissues. The associations were highly tissue-specific. The QTT within the tissues were divided into co expression network modules enriched for genes in Kyoto Encyclopedia of Genes and Genomes or gene ontology categories that are related to the physiological functions of the corresponding tissues. We also explored a multi-tissue co expression network using QTT for non-esterified fatty acids from the five tissues and found that a module, enriched in hypothalamus QTT, was positioned at the centre of the entire multi-tissue network. CONCLUSIONS: These results emphasize the relationships between endocrine tissues and plasma metabolites in terms of gene expression. Highly tissue-specific association patterns suggest that candidate genes or gene pathways should be investigated in the context of specific tissues. PMID- 21787429 TI - Carbon-assisted growth and high visible-light optical reflectivity of amorphous silicon oxynitride nanowires. AB - Large amounts of amorphous silicon oxynitride nanowires have been synthesized on silicon wafer through carbon-assisted vapor-solid growth avoiding the contamination from metallic catalysts. These nanowires have the length of up to 100 MUm, with a diameter ranging from 50 to 150 nm. Around 3-nm-sized nanostructures are observed to be homogeneously distributed within a nanowire cross-section matrix. The unique configuration might determine the growth of ternary amorphous structure and its special splitting behavior. Optical properties of the nanowires have also been investigated. The obtained nanowires were attractive for their exceptional whiteness, perceived brightness, and optical brilliance. These nanowires display greatly enhanced reflection over the whole visible wavelength, with more than 80% of light reflected on most of the wavelength ranging from 400 to 700 nm and the lowest reflectivity exceeding 70%, exhibiting performance superior to that of the reported white beetle. Intense visible photoluminescence is also observed over a broad spectrum ranging from 320 to 500 nm with two shoulders centered at around 444 and 468 nm, respectively. PMID- 21787430 TI - Campylobacter jejuni dsb gene expression is regulated by iron in a Fur-dependent manner and by a translational coupling mechanism. AB - BACKGROUND: Many bacterial extracytoplasmic proteins are stabilized by intramolecular disulfide bridges that are formed post-translationally between their cysteine residues. This protein modification plays an important role in bacterial pathogenesis, and is facilitated by the Dsb (disulfide bond) family of the redox proteins. These proteins function in two parallel pathways in the periplasmic space: an oxidation pathway and an isomerization pathway. The Dsb oxidative pathway in Campylobacter jejuni is more complex than the one in the laboratory E. coli K-12 strain. RESULTS: In the C. jejuni 81-176 genome, the dsb genes of the oxidative pathway are arranged in three transcriptional units: dsbA2 dsbB-astA, dsbA1 and dba-dsbI. Their transcription responds to an environmental stimulus - iron availability - and is regulated in a Fur-dependent manner. Fur involvement in dsb gene regulation was proven by a reporter gene study in a C. jejuni wild type strain and its isogenic fur mutant. An electrophoretic mobility shift assay (EMSA) confirmed that analyzed genes are members of the Fur regulon but each of them is regulated by a disparate mechanism, and both the iron-free and the iron-complexed Fur are able to bind in vitro to the C. jejuni promoter regions. This study led to identification of a new iron- and Fur-regulated promoter that drives dsbA1 gene expression in an indirect way. Moreover, the present work documents that synthesis of DsbI oxidoreductase is controlled by the mechanism of translational coupling. The importance of a secondary dba-dsbI mRNA structure for dsbI mRNA translation was verified by estimating individual dsbI gene expression from its own promoter. CONCLUSIONS: The present work shows that iron concentration is a significant factor in dsb gene transcription. These results support the concept that iron concentration - also through its influence on dsb gene expression - might control the abundance of extracytoplasmic proteins during different stages of infection. Our work further shows that synthesis of the DsbI membrane oxidoreductase is controlled by a translational coupling mechanism. The dba expression is not only essential for the translation of the downstream dsbI gene, but also Dba protein that is produced might regulate the activity and/or stability of DsbI. PMID- 21787431 TI - Cognitive behaviour therapy in medication-treated adults with ADHD and persistent symptoms: a randomized controlled trial. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) in adulthood is not fully treated by psychopharmacological treatment alone. The main aim of the current study was to evaluate a newly developed cognitive behaviour therapy (CBT) based group programme, the Reasoning and Rehabilitation for ADHD Youths and Adults (R&R2ADHD), using a randomized controlled trial. METHODS: 54 adults with ADHD already receiving psychopharmacological treatment were randomly allocated to an experimental (CBT/MED) treatment condition (n = 27) and a 'treatment as usual' (TAU/MED) control condition (n = 27) that did not receive the CBT intervention. The outcome measures were obtained before treatment (baseline), after treatment and at three month follow-up and included ADHD symptoms and impairments rated by independent assessors, self-reported current ADHD symptoms, and comorbid problems. RESULTS: The findings suggested medium to large treatment effects for ADHD symptoms, which increased further at three month follow-up. Additionally, comorbid problems also improved at follow-up with large effect sizes. CONCLUSIONS: The findings give support for the effectiveness of R&R2ADHD in reducing ADHD symptoms and comorbid problems, an improving functions associated with impairment. The implications are that the benefits of R&R2ADHD are multifaceted and that combined psychopharmacological and CBT based treatments may add to and improve pharmacological interventions. TRIAL REGISTRATION: ACTRN12611000533998 (http://www.ANZCTR.org.au/ACTRN12611000533998.aspx). PMID- 21787432 TI - Development of a practical tool to measure the impact of publications on the society based on focus group discussions with scientists. AB - BACKGROUND: A 'societal impact factor' that complements the scientific impact factor would contribute to a more comprehensive evaluation of scientific research. In order to develop a practical tool for its assessment, it is important to learn about perceptions of scientists on how to measure a societal impact factor. METHODS: This qualitative study presents the development of a practical tool to measure the societal impact of publications based on 8 focus group discussions with 24 biomedical scientists at the Medical University Vienna between May 2008 and May 2009. Topics focused on (1) features of an ideal tool, (2) criteria that should be considered in the assessment, and (3) the identification of practical pitfalls. In an iterative exercise involving the repeated application of the drafted tool to scientific papers, criteria for the assessment were refined. A small-scale exercise to evaluate the tool in terms of its comprehensibility, relevance and practicability was conducted using questionnaires for 6 external experts in leading positions of public health, and yielded acceptable results. RESULTS: The tool developed consists of three quantitative dimensions, that is (1) the aim of a publication, (2) the efforts of the authors to translate their research results, and, if translation was accomplished, (3) (a) the size of the area where translation was accomplished (regional, national or international), (b) its status (preliminary versus permanent) and (c) the target group of the translation (individuals, subgroup of population, total population). CONCLUSIONS: Focus group discussions with scientists suggested that the societal impact factor of a publication should consider the effect of the publication in a wide set of non-scientific areas, but also the motivation behind the publication, and efforts by the authors to translate their findings. The proposed tool provides some valuable insights for further research and practical applications in the topic area. PMID- 21787433 TI - The effects of polyunsaturated fatty acids in alcohol dependence treatment--a double-blind, placebo-controlled pilot study. AB - BACKGROUND: The lipid fraction of cell membranes consists of polyunsaturated fatty acids (PUFAS), and chronic alcohol use alters it, modifying its permeability, what might contribute for the dysfunctional metabolism observed in the central nervous system of alcohol dependent patients. Therefore, the supplementation of PUFAS can be an important adjuvant in alcoholism treatment. METHODS: This was a placebo controlled, double blind, randomized study where, 80 alcohol dependent patients, according to DSM-IV, were allocated in four groups with 20 patient each: 'PUFAS', 'Naltrexone', 'Naltrexone + PUFAS' and 'Placebo'. Those substances were administered for 90 days and scales were applied to assess patients craving (OCDS) and alcohol dependence severity (SADD) at baseline and after 90 days. PUFAS serum levels were assessed before and after treatment by high performance liquid chromatography assay. RESULTS: Forty-three patients completed the trial. There was a significant improvement over time on drinking days, SADD and OCDS scores in all groups (p < 0.001). The drinking days comparison between groups did not show statistical significant difference. The same effect was observed for compulsion (OCDS) and severity of dependence scale (SADD). The serum levels of PUFAS increased in all the supplemented groups after treatment, although not significantly. CONCLUSIONS: The oral supplementation of 2 g PUFAS for 3 months did not significantly differ from placebo in reducing the amount of alcohol ingestion, or OCDS and SADD scores in a group of alcohol dependent patient. TRIAL REGISTRATION: NCT01211769. PMID- 21787434 TI - Community participation for malaria elimination in Tafea Province, Vanuatu: part II. Social and cultural aspects of treatment-seeking behaviour. AB - BACKGROUND: Early diagnosis and prompt effective case management are important components of any malaria elimination strategy. Tafea Province, Vanuatu has a rich history of traditional practices and beliefs, which have been integrated with missionary efforts and the introduction of modern constructions of health. Gaining a detailed knowledge of community perceptions of malarial symptomatology and treatment-seeking behaviours is essential in guiding effective community participation strategies for malaria control and elimination. METHOD: An ethnographic study involving nine focus group discussions (FGD), 12 key informant interviews (KII) and seven participatory workshops were carried out on Tanna Island, Vanuatu. Villages in areas of high and low malaria transmission risk were selected. Four ni-Vanuatu research officers, including two from Tanna, were trained and employed to conduct the research. Data underwent thematic analysis to examine treatment-seeking behaviour and community perceptions of malaria. RESULTS: Malaria was perceived to be a serious, but relatively new condition, and in most communities, identified as being apparent only after independence in 1980. Severe fever in the presence of other key symptoms triggered a diagnosis of malaria by individuals. Use of traditional or home practices was common: perceived vulnerability of patient and previous experience with malaria impacted on the time taken to seek treatment at a health facility. Barriers to health care access and reasons for delay in care-seeking included the availability of health worker and poor community infrastructure. CONCLUSION: Due to programme success of achieving low malaria transmission, Tafea province has been identified for elimination of malaria by 2012 in the Government of Vanuatu Malaria Action Plans (MAP). An effective malaria elimination programme requires interactions between the community and its leaders, malaria workers and health providers for success in diagnosis and prompt treatment. As malaria becomes more uncommon, utilizing unique motivators for communities to seek early diagnosis and treatment is important, particularly as other health conditions that cause fevers become increasingly more common. The design of these interventions are dependent upon robust understanding of community perceptions of disease, and the evolving nature of these perceptions. PMID- 21787435 TI - Endotoxin-free purification for the isolation of bovine viral diarrhoea virus E2 protein from insoluble inclusion body aggregates. AB - BACKGROUND: Protein expression in Escherichia coli may result in the recombinant protein being expressed as insoluble inclusion bodies. In addition, proteins purified from E. coli contain endotoxins which need to be removed for in vivo applications. The structural protein, E2, from Bovine Viral Diarrhoea Virus (BVDV) is a major immunogenic determinant, and is an ideal candidate as a subunit vaccine. The E2 protein contains 17 cysteine residues creating difficulties in E. coli expression. In this report we outline a procedure for successfully producing soluble and endotoxin-free BVDV E2 protein from inclusion bodies (IB). RESULTS: The expression of a truncated form of BVDV-E2 protein (E2-T1) in E. coli resulted in predominantly aggregated insoluble IB. Solubilisation of E2-T1 with high purity and stability from IB aggregates was achieved using a strong reducing buffer containing 100 mM Dithiothreitol. Refolding by dialysis into 50 mM Tris (pH 7.0) containing 0.2% Igepal CA630 resulted in a soluble but aggregated protein solution. The novel application of a two-phase extraction of inclusion body preparations with Triton X-114 reduced endotoxin in solubilised E2-T1 to levels suitable for in vivo use without affecting protein yields. Dynamic light scattering analyses showed 37.5% of the protein was monomeric, the remaining comprised of soluble aggregates. Mice immunised with E2-T1 developed a high titre antibody response by ELISA. Western hybridisation analysis showed E2-T1 was recognised by sera from immunised mice and also by several BVDV-E2 polyclonal and monoclonal antibodies. CONCLUSION: We have developed a procedure using E. coli to produce soluble E2-T1 protein from IB, and due to their insoluble nature we utilised a novel approach using Triton X-114 to efficiently remove endotoxin. The resultant protein is immunogenic and detectable by BVDV-E2 specific antibodies indicating its usefulness for diagnostic applications and as a subunit vaccine. The optimised E. coli expression system for E2-T1 combined with methodologies for solubilisation, refolding and integrated endotoxin removal presented in this study should prove useful for other vaccine applications. PMID- 21787436 TI - Expression of core antigen of HCV genotype 3a and its evaluation as screening agent for HCV infection in Pakistan. AB - BACKGROUND: Pakistan is facing a threat from hepatitis C infection which is increasing at an alarming rate throughout the country. More specific and sensitive screening assays are needed to timely and correctly diagnose this infection. METHODS: After RNA extraction from specimen (HCV-3a), cDNA was synthesized that was used to amplify full length core gene of HCV 3a. After verification through PCR, DNA sequencing and BLAST, a properly oriented positive recombinant plasmid for core gene was digested with proper restriction enzymes to release the target gene which was then inserted downstream of GST encoding DNA in the same open reading frame at proper restriction sites in multiple cloning site of pGEX4t2 expression vector. Recombinant expression vector for each gene was transformed in E. coli BL21 (DE3) and induced with IPTG for recombinant fusion protein production that was then purified through affinity chromatography. Western blot and Enzyme Linked Immunosorbant Assay (ELISA) were used to detect immuno-reactivity of the recombinant protein. RESULTS: The HCV core antigen produced in prokaryotic expression system was reactive and used to develop a screening assay. After validating the positivity (100%) and negativity (100%) of in-house anti-HCV screening assay through a standardized panel of 200 HCV positive and 200 HCV negative sera, a group of 120 serum specimens of suspected HCV infection were subjected to comparative analysis of our method with commercially available assay. The comparison confirmed that our method is more specific than the commercially available assays for HCV strains circulating in this specific geographical region of the world and could thus be used for HCV screening in Pakistan. CONCLUSION: In this study, we devised a screening assay after successful PCR amplification, isolation, sequencing, expression and purification of core antigen of HCV genotype 3a. Our developed screening assay is more sensitive, specific and reproducible than the commercially available screening assays in Pakistan. PMID- 21787437 TI - Preparation and Characterization of Mesoporous Zirconia Made by Using a Poly (methyl methacrylate) Template. AB - Superfine powders of poly (methyl methacrylate) (PMMA) have been prepared by means of an emulsion polymerization method. These have been used as templates in the synthesis of tetragonal phase mesoporous zirconia by the sol-gel method, using zirconium oxychloride and oxalic acid as raw materials. The products have been characterized by infrared spectroscopy, X-ray diffraction analysis, transmission electron microscopy, N2adsorption-desorption isotherms, and pore size distribution. The results indicate that the average pore size was found to be 3.7 nm. PMID- 21787438 TI - Idiopathic aortitis: an underrecognized vasculitis. AB - Aortitis is a general term denoting inflammation of the aortic wall. Various infectious and non-infectious diseases can be complicated by aortitis; in addition, isolated idiopathic aortitis has also been described. In a 12-year nationwide Danish population-based study, the prevalence of aortitis among 1,210 resected thoracic aorta samples was 6.1%, with nearly three-quarters of cases being idiopathic. Identified risk factors for aortitis included advanced age, a history of connective tissue disease, diabetes mellitus, and heart valve pathology. As in virtually all pathological studies, this study has a bias toward reporting the most severe cases of aortitis requiring surgical repair. PMID- 21787439 TI - MicroRNAs in systemic rheumatic diseases. AB - MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease. PMID- 21787440 TI - The lung as a possible target for the immune reaction in myositis. AB - Interstitial lung disease is a common manifestation of autoimmune myositis that confers significant morbidity and mortality. The vulnerability of the lung may offer insight into the etiology of this autoimmune disease. The frequency and patterns of lung injury vary based on the autoantibody. Antibodies against the aminoacyl-tRNA synthetases and melanoma differentiation-induced gene-5 are frequently associated with interstitial lung disease. Although the mechanisms underlying these associations have not been fully elucidated, emerging data highlight the importance of autoantigen expression and conformation in the target tissue (lung and muscle, in this case), as well as identifying relevant amplifying pathways (such as regeneration). PMID- 21787442 TI - Towards a data sharing Code of Conduct for international genomic research. AB - Data sharing is increasingly regarded as an ethical and scientific imperative that advances knowledge and thereby respects the contributions of the participants. Because of this and the ever-increasing amount of data access requests currently filed around the world, three groups have decided to develop data sharing principles specific to the context of collaborative international genomics research. These groups are: the international Public Population Project in Genomics (P3G), an international consortium of projects partaking in large scale genetic epidemiological studies and biobanks; the European Network for Genetic and Genomic Epidemiology (ENGAGE), a research project aiming to translate data from large-scale epidemiological research initiatives into relevant clinical information; and the Centre for Health, Law and Emerging Technologies (HeLEX). We propose seven different principles and a preliminary international data sharing Code of Conduct for ongoing discussion. PMID- 21787441 TI - Microarrays in the 2010s: the contribution of microarray-based gene expression profiling to breast cancer classification, prognostication and prediction. AB - Breast cancer comprises a collection of diseases with distinctive clinical, histopathological, and molecular features. Importantly, tumors with similar histological features may display disparate clinical behaviors. Gene expression profiling using microarray technologies has improved our understanding of breast cancer biology and has led to the development of a breast cancer molecular taxonomy and of multigene 'signatures' to predict outcome and response to systemic therapies. The use of these prognostic and predictive signatures in routine clinical decision-making remains controversial. Here, we review the clinical relevance of microarray-based profiling of breast cancer and discuss its impact on patient management. PMID- 21787444 TI - Revisiting widowhood in later life: changes in patterns and profiles, advances in research and understanding. AB - This analysis reviews the ways in which both the experience of widowhood in old age and the nature of research on widowhood have changed since the publication of the book Widowhood in Later Life in 1991. Patterns of decline in widowhood in both its duration and incidence in later life are examined. Widowhood research has advanced conceptually by moving beyond understanding widowhood solely in terms of role loss. Life course perspectives, and concepts of multiple narratives and of resilience, have also contributed to the field. New methodologies, including prospective and longitudinal designs involving larger data sets, and more in-depth qualitative studies, have advanced our understanding of complexities and variations in widowhood. These include issues of gender and ethnocultural diversity, as well as the intersection of wealth, health, and class. This article also examines how patterns of labour force affiliation, social policy, and the changing nature of marriage shape widowhood in later life. PMID- 21787445 TI - The influence of water and humidity on the hatching of Nematodirus battus eggs. AB - This paper examines the influence of water on the ecology of the eggs of Nematodirus battus, with a view to estimating the importance of including rainfall in mathematical models of parasite abundance. The literature suggests that, under pasture conditions, the availability of moisture is unlikely to be limiting for egg development, while eggs and infective larvae are highly resistant to desiccation. In the presented experiment, eggs that had been kept in salt sludges at 95% and 70% RH and were subsequently put at 15 degrees C produced only a mildly accelerated, but not a mass, hatch, in the first few days after return to water. Eggs kept at higher osmotic pressures died. Mass hatching of infective larvae, described at pasture when spells of rain follow periods of drought, is unlikely to occur as the result of a sudden water influx into eggs. Since water is not necessary for migration of infective larvae from the soil on to grass, such peaks in larval abundance are more likely to arise from the effects of temperature on hatching of eggs. PMID- 21787446 TI - Autogenic Training as a behavioural approach to insomnia: a prospective cohort study. AB - BACKGROUND: Insomnia is commonly associated with chronic health problems. Behavioural and cognitive factors often perpetuate a vicious cycle of anxiety and sleep disturbance, leading to long-term insomnia. National Institute for Health and Clinical Excellence currently recommends behavioural approaches before prescribing hypnotics. Behavioural approaches aim to treat underlying causes, but are not widely available. Research usually includes patients diagnosed with insomnia rather than secondary, co-morbid sleep- related problems. AIM: To examine the effectiveness of autogenic training (AT) as a non-drug approach to sleep-related problems associated with chronic ill health. DESIGN: Prospective pre- and post-treatment cohort study. SETTING: AT centre, Royal London Hospital for Integrated Medicine, University College London Hospitals NHS Foundation Trust. METHODS: All patients referred for AT from April 2007 to April 2008 were invited to participate. Participants received standard 8-week training, with no specific focus on sleep. Sleep questionnaires were administered at four time points, 'Measure Your Medical Outcome Profile' (MYMOP) and Hospital Anxiety and Depression Scale, before and after treatment. Results before and after treatment were compared. Camden and Islington Community Local Research and Ethics Committee approved the study. RESULTS: The AT course was completed by 153 participants, of whom 73% were identified as having a sleep-related problem. Improvements in sleep patterns included: sleep onset latency (P = 0.049), falling asleep quicker after night waking (P < 0.001), feeling more refreshed (P < 0.001) and more energised on waking (P = 0.019). MYMOP symptom, well-being, anxiety and depression scores significantly improved (all P < 0.001). CONCLUSION: This study suggests that AT may improve sleep patterns for patients with various health conditions and reduce anxiety and depression, both of which may result from and cause insomnia. Improvements in sleep patterns occurred despite, or possibly due to, not focusing on sleep during training. AT may provide an approach to insomnia that could be incorporated into primary care. PMID- 21787447 TI - Painful leg ulcers: community nurses' knowledge and beliefs, a feasibility study. AB - BACKGROUND: Leg ulceration presents a significant health-care problem for patients and it is likely to be associated with pain. Poorly managed persistent pain may lead to insomnia, depression and suicidal ideation. To manage leg ulcer pain effectively, it is necessary first to assess pain, but there is little evidence of this activity in the literature. This study aimed to explore community nurses' knowledge and beliefs about the management of painful leg ulceration. METHOD: A feasibility study surveyed the knowledge and views of a sample of community nurses in the North of England, United Kingdom. Data were collected using a postal questionnaire. RESULTS: A total of 115 completed questionnaires were returned (response rate = 32%). The majority of the respondents were female (n = 102, 91.8%). The nurses in this clinical study claimed to be aware of the pain that patients with leg ulceration may experience. Over 90% of the patients were aware of the key consequences of this pain, including insomnia, depression, social isolation and others. However, over one third of the nurses reported that they had not received pain management training. Approximately one half reported not assessing pain appropriately. Nurses reported using pain triggers and severity to diagnose aetiology and complications of leg ulceration. CONCLUSION: This study suggested inadequate pain management practices despite the fact that there were a significant number of the nurses who were aware of the associated pain and possible outcomes. Pain assessment was lacking, suggesting a lack of formal pain assessment procedures. They described not using effective pain management techniques and were aware of their need for education in this area. PMID- 21787448 TI - Impact of maternal supplementation with probiotics during pregnancy on atopic eczema in childhood--a meta-analysis. AB - In the present study, we sought to conduct a literature review of randomised, double-blind, placebo-controlled trials, which assessed the impact of probiotics intake during pregnancy on the development of eczema in children. A meta-analysis was conducted for comparison of the development of atopic eczema in children whose mothers took probiotics during pregnancy v. placebo. Study selection, quality appraisal and data extraction were performed independently and in duplicate. The studies were rated according to their size in order to calculate the influence of individual studies on the meta-analysis. A total of seven randomised, double-blind, placebo-controlled trials, published between 2001 and 2009, were selected from the PubMed and Ovid databases for the meta-analysis. The meta-analysis was performed with statistical software Stata/SE11.0. The completed meta-analysis of the seven studies shows a significant risk reduction for atopic eczema in children aged 2-7 years by the administration of probiotics during pregnancy (reduction 5.7 %; P = 0.022). However, this effect was only significant for lactobacilli (reduction 10.6 %; P = 0.045), but not for a mixture of various bacterial strains as probiotics (difference 3.06 %, P = 0.204). In conclusion, the meta-analysis shows that the administration of lactobacilli during pregnancy prevents atopic eczema in children aged from 2 to 7 years. However, a mixture of various bacterial strains does not affect the development of atopic eczema, independent of whether they contain lactobacilli or not. PMID- 21787450 TI - Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome. AB - The mechanisms implicated in the LDL-cholesterol (LDL-C)-lowering effects of the Mediterranean-type diet (MedDiet) are unknown. The present study assessed the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on surrogate markers of cholesterol absorption, synthesis and clearance using plasma phytosterols, lathosterol and proprotein convertase subtilisin/kexin-9 (PCSK9) concentrations, respectively, in men with the metabolic syndrome. The subjects' diet (n 19, 24-62 years) was first standardised to a baseline North American control diet (5 weeks) followed by a MedDiet (5 weeks), both under weight-maintaining isoenergetic feeding conditions. The participants then underwent a 20-week free-living energy restriction period (10 (sd 3) % reduction in body weight, P < 0.01), followed by the consumption of the MedDiet (5 weeks) under controlled isoenergetic feeding conditions. The LDL-C lowering effect of the MedDiet in the absence of weight loss ( - 9.9 %) was accompanied by significant reductions in plasma PCSK9 concentrations ( - 11.7 %, P < 0.01) and in the phytosterol:cholesterol ratio ( - 9.7 %, P < 0.01) compared with the control diet. The addition of weight loss to the MedDiet had no further impact on plasma LDL-C concentrations and on these surrogate markers of LDL clearance and cholesterol absorption. The present results suggest that the MedDiet reduces plasma LDL-C concentrations primarily by increasing LDL clearance and reducing cholesterol absorption, with no synergistic effect of body weight loss in this process. PMID- 21787449 TI - Protein restriction during pregnancy induces hypertension in adult female rat offspring--influence of oestradiol. AB - We previously reported that gestational dietary protein restriction in rats causes sex-related differences in development of blood pressure (BP) in the offspring, which is more pronounced in males than in females. As such effects may depend on sex hormones, we investigated the role of oestradiol in the development of hypertension in female offspring of protein-restricted dams. Female offspring of pregnant rats fed normal (20 %) or protein-restricted (6 %) casein diets throughout pregnancy were kept either intact, ovariectomised or ovariectomised with oestradiol supplementation. BP, Plasma oestradiol and testosterone levels, and vascular oestrogen receptor (ER) were examined. BP was significantly higher and plasma oestradiol levels were significantly lower ( - 34 %) in intact protein restricted female offspring compared to corresponding controls. Further decrease in oestradiol levels by ovariectomy exacerbated hypertension in the protein restricted females, with an earlier onset and more prominent elevation in BP compared to controls. Oestradiol supplementation in ovariectomised protein restricted females significantly reversed ovariectomy-induced hypertension but did not normalise BP to control levels. The hypertensive protein-restricted females have reduced vascular ERalpha expression that was unaffected by ovariectomy or oestradiol replacement. In addition, testosterone levels were significantly higher by 2.4-, 3.4- and 2.8-fold in intact, ovariectomised and oestradiol-replaced protein-restricted females compared to corresponding controls. The present data show that: (1) hypertension in protein-restricted adult female offspring is associated with reduced plasma oestradiol levels; (2) oestradiol protects and limits the severity of hypertension in protein-restricted females and contributes to sexual dimorphism; (3) oestradiol replacement fails to completely reverse hypertension, which may be related to limited availability of vascular ERalpha receptors and/or increased circulating testosterone levels. PMID- 21787451 TI - Protective effects of fractional extracts from Panellus serotinus on non alcoholic fatty liver disease in obese, diabetic db/db mice. AB - Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialised countries. Various mushrooms have been used in Eastern folk medicine for the treatment of lifestyle diseases. We previously found that the dietary intake of powdered whole Panellus serotinus (Mukitake) alleviates NAFLD in obese, diabetic db/db mice. In the present study, we investigated the influence of Mukitake fractional extracts on the development of NAFLD in db/db mice. A significant reduction in the hepatic TAG content, macrovesicular hepatocytes and activities of key enzymes for de novo synthesis of the fatty acid was observed in both the water-soluble Mukitake extract (WE) diet and the ethanol soluble Mukitake extract (EE) diet groups compared with the control diet group of the db/db mice. The serum level of monocyte chemoattractant protein-1 (MCP-1), which is known to exacerbate insulin resistance, was significantly decreased in the WE group. On the other hand, the serum level of adiponectin, which plays a protective role against the metabolic syndrome, was significantly increased in the EE group. Additionally, differential analysis between Mukitake and Shiitake, mycelia from the same family, using liquid chromatography time-of-flight MS technology revealed that only seven and five compounds exist in WE and EE from Mukitake, respectively. In conclusion, the present study demonstrated that Mukitake displays at least two different physiological actions that alleviate NAFLD: one through the reduction in inflammatory damage by its suppression in MCP 1 production and the other through an increase in level of serum adiponectin and the prevention of visceral fat accumulation. PMID- 21787452 TI - More citations, but a fall in impact factor. PMID- 21787453 TI - Effects of yeast cell walls on performance and immune responses of cyclosporine A treated, immunosuppressed broiler chickens. AB - The present study was conducted to investigate the effects of dietary yeast (Saccharomyces cerevisiae) cell walls (YCW) from the yeast extract industry on performance and immune function of cyclosporine A (CSA)-treated, immunosuppressed broiler chickens. A total of 240 day-old male broilers were allocated randomly into four treatments: (1) non-challenged control; (2) non-challenged control+0.3 % YCW; (3) CSA-challenged group; (4) CSA-challenged+0.3 % YCW. On days 1-4 and 22 25 of age, broilers were subcutaneously injected with CSA or sterile saline. The results showed that supplementation of YCW significantly improved daily weight gain (DWG) during the starter (days 1-21, P < 0.01), finisher (days 22-42, P < 0.01) and overall (days 1-42, P < 0.05) periods compared with the control birds, but had no effect on feed conversion ratio (FCR, P>0.05). Compared with the CSA treated birds, YCW alleviated the decrease of DWG (P < 0.01) and increase of FCR (P < 0.05) caused by CSA challenge at different periods and cumulatively. On days 21 and 42, YCW mitigated the CSA-induced decrease of peripheral blood lymphocyte blastogenic response (P < 0.01). In addition, YCW improved the relative weights of the bursa of Fabricius (P < 0.01) and thymus (P < 0.01) and up-regulated the splenic expression of pro-inflammatory cytokines IL-1beta (P < 0.01) and IL-6 (P < 0.01) on day 42 compared with the CSA-treated birds. These results indicate that YCW supplementation has beneficial effects in attenuating the immunosuppressive effects of CSA challenge, therefore improving growth performance of broiler chickens. PMID- 21787454 TI - The effects of 12-week psyllium fibre supplementation or healthy diet on blood pressure and arterial stiffness in overweight and obese individuals. AB - Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of the metabolic syndrome and they are both powerful independent predictors of cardiovascular risk. A high-fibre diet has been correlated with lower BMI and a lower incidence of hyperlipidaemia, CVD, hypertension and diabetes. The present randomised, parallel-design study compared the effects of fibre intake from a healthy diet v. fibre supplement diets on blood pressure (BP) and vascular function over 12 weeks. Overweight and obese adults were randomised to one of three groups: control (with placebo), fibre supplement (FIB) or healthy eating group with placebo (HLT). Systolic blood pressure (SBP) was lower in the FIB group compared with the control group at week 6, but not at week 12. However, SBP was lower in the HLT group compared with control group at week 12. At week 6, the FIB group presented lower diastolic blood pressure and augmentation index compared with the control group, but this result did not persist to the end of the study. The present study did not show any improvements in BP or vascular function in overweight and obese individuals with psyllium fibre supplementation over 12 weeks of intervention. However, a healthy diet provided the greatest improvements in BP in overweight and obese subjects. Further research with hypertensive individuals is necessary to elucidate whether increased fibre consumption in the form of psyllium supplementation may provide a safe and acceptable means to reduce BP, vascular function and the risk of developing CVD. PMID- 21787455 TI - The anti-metastatic efficacy of beta-ionone and the possible mechanisms of action in human hepatocarcinoma SK-Hep-1 cells. AB - beta-Ionone (BI), a precursor for carotenoids, is widely distributed in fruit and vegetables. Recent in vitro studies have demonstrated the potential anti metastatic effects of BI, but the mechanisms underlying such actions are not clear. Because liver cancer is the most endemic cancer in Taiwan and in a large region of the world, we hereby investigate the anti-metastatic effects of BI and its mechanisms of actions in a highly metastatic human hepatocarcinoma SK-Hep-1 cells. We show that incubation of cells with BI (1-50 MUm) for 24 and 48 h significantly inhibited cell invasion, migration and adhesion. Mechanistically, incubation of cells with BI (1-50 MUm) for 24 h resulted in the following: (1) significant inhibition of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase type plasminogen activator activities, (2) up-regulation of protein expression of the tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and plasminogen activator inhibitor-1, (3) down-regulation of the expression of migration-related proteins, including focal adhesion kinase (FAK), phosphorylated form of FAK, Rho, Rac1 and Cdc42 and (4) up-regulation of the expression of nm23-H1 protein (P < 0.05). Overall, the results show that BI effectively inhibits the metastasis of SK-Hep-1 cells, and this effect involves the regulation of gene expression and signal pathways related to invasion and migration. PMID- 21787456 TI - Glycaemic response to barley porridge varying in dietary fibre content. AB - The interest in barley as a food is increasing worldwide because of its high dietary fibre (DF) content and low glycaemic index (GI). DF in cereals may prove beneficial in improving blood glucose response in the long term. However, a dose dependent effect of insoluble fibre on reducing postprandial blood glucose levels is yet to be proven. The objective of the present study was to determine the glycaemic response to two barley porridges prepared from whole barley grains varying in fibre content. In two separate non-blind randomised crossover trials, ten human subjects consumed barley porridge with 16 g/100 g and 10 g/100 g fibre content provided in different serving sizes (equivalent to 25 and 50 g available carbohydrate). The glycaemic response to both barley porridges was significantly lower than the reference glucose (P < 0.05). There was no significant difference between the glucose areas under the curve or GI for the two barley porridges. We concluded that irrespective of the difference in total fibre content or serving size of barley porridges, their GI values did not differ significantly. PMID- 21787457 TI - Chronic total occlusion by stent fracture in Kawasaki disease: is recanalisation possible? AB - Despite various medications for Kawasaki disease, a small number of children have been undergoing interventions for severe coronary artery complications. Transcatheter intervention is a feasible alternative to coronary artery bypass grafting in a patient with chronic totally occluded lesion after Kawasaki disease, even by stent fracture. PMID- 21787458 TI - Catheter closure of coronary sinus atrial septal defect using Amplatzer Septal Occluder. AB - Coronary sinus defect is a rare type of atrial septal defect. We report two patients who had a coronary sinus atrial septal defect without persistent left superior caval vein, where the orifice of the coronary sinus was closed using the Amplatzer Septal Occluder. The procedure was successful, without any complications including conduction disturbance. PMID- 21787459 TI - Tetralogy of Fallot with double aortic arch. PMID- 21787460 TI - Effects of periconceptional undernutrition on maternal taurine concentrations in sheep. AB - Taurine has an important role in numerous physiological processes, including many aspects of fetal development such as development of the pancreas and brain, and requirements increase during pregnancy. Periconceptional undernutrition has long term effects on pancreas and brain function of the offspring, but the effects on maternal taurine economy are unknown. We, therefore, studied the effects of different periods of periconceptional undernutrition on maternal plasma and urine taurine concentrations before and during pregnancy. Four groups of singleton bearing ewes were studied (n 10-11): controls fed ad libitum, and groups undernourished from 60 d before until mating (PreC), from 2 d before mating until 30 d after mating (PostC) or from 60 d before until 30 d after mating (Pre+PostC). In PreC ewes, plasma taurine concentrations remained at control levels for the first 30 d, and then decreased through the remainder of undernutrition, but recovered by 30 d after mating; urinary taurine excretion was low at mating, but recovered similarly. In PostC ewes, plasma taurine concentrations recovered after 2 weeks despite ongoing undernutrition; urinary taurine excretion had recovered by 30 d after mating. Pre+PostC ewes followed the same pattern as PreC for the first 60 d, but plasma taurine concentrations and urinary excretion recovered slowly, and did not reach the control levels until 97 d. These data suggest that different periods of mild periconceptional undernutrition in sheep have different but substantial effects on maternal taurine homoeostasis. These effects may be one mechanism by which maternal periconceptional undernutrition alters development of the offspring with implications for adult health. PMID- 21787462 TI - [Objective recognition of the indication of liver transplantation]. PMID- 21787463 TI - [Basic connotation and development orientation of emergency medicine]. PMID- 21787461 TI - Assembly and disassembly of a retinal cholinergic network. AB - In the few weeks prior to the onset of vision, the retina undergoes a dramatic transformation. Neurons migrate into position and target appropriate synaptic partners to assemble the circuits that mediate vision. During this period of development, the retina is not silent but rather assembles and disassembles a series of transient circuits that use distinct mechanisms to generate spontaneous correlated activity called retinal waves. During the first postnatal week, this transient circuit is comprised of reciprocal cholinergic connections between starburst amacrine cells. A few days before the eyes open, these cholinergic connections are eliminated as the glutamatergic circuits involved in processing visual information are formed. Here, we discuss the assembly and disassembly of this transient cholinergic network and the role it plays in various aspects of retinal development. PMID- 21787464 TI - [Perioperative monitoring and control of hyperglycemia during deep hypothermic circulatory arrest]. AB - OBJECTIVE: To observe the trend of change in perioperative blood glucose level in patients undergoing deep hypothermic circulatory arrest (DHCA), in order to evaluate the influencing factors of inciting hyperglycemia and the clinical effects of insulin control. METHODS: In the Department of Cardiothoracic Surgery of Changhai Hospital, 176 patients underwent aortic operation under DHCA from January 2000 to January 2010. Blood glucose, arterial blood gas and lactate levels were determined at four time points, including pre-cardiopulmonary bypass (CPB), pre-DHCA, post-DHCA, and at admission to intensive care unit (ICU). Hyperglycemia after surgery was controlled at the level of 6-8 mmol/L by intermittent subcutaneous injection or intravenous micropump injection of insulin. At the same time, the cumulative amount of insulin within 24 hours after surgery was recorded. RESULTS: The blood glucose (mmol/L) level at pre-DHCA time point was significantly higher than that of pre-CPB (9.62 +/- 1.79 vs. 5.04 +/- 1.401,P<0.05), and the blood glucose level was further elevated at the time point of post-DHCA (14.91 +/- 2.36,P<0.01) and in-ICU (15.32 +/- 2.47) compared with that of pre-CPB (P<0.01). The level of blood glucose elevation was positively correlated with blood lactate level. One hundred and thirty-four patients (76.1%) insulin was given with intravenous micropump due to poor effect of intermittent subcutaneous injection of insulin in controlling blood glucose. Among whom 30 patients (17.0%) developed the phenomenon of insulin resistance. Perioperative hyperglycemia during DHCA was associated with old age (>= 50 years old), primary hypertension, serious aortic valve disease, diabetes or coronary heart disease, emergency operation, CPB time >= 3 hours and DHCA time >= 45 minutes. The cumulative amount of insulin within 24 hours after surgery was increased significantly. The results of blood glucose (mmol/L) in-ICU were as follows : age >= 50 years old or < 50 years old (18.66 +/- 2.52 vs. 12.90 +/- 2.27); hypertension with and without (18.98 +/- 2.55 vs. 12.31 +/- 2.34); serious aortic valve disease with and without (19.59 +/- 2.95 vs. 12.13 +/- 2.23); diabetes with and without (20.62 +/- 1.76 vs. 11.75 +/- 1.11); coronary heart disease with and without (19.77 +/- 2.98 vs. 12.01 +/- 2.02); emergency operation with and without (19.78 +/- 1.97 vs. 12.23 +/- 1.38); CPB time >= 3 hours or < 3 hours (19.86 +/- 1.89 vs. 11.70 +/- 1.15); DHCA time >= 45 minutes or < 45 minutes (19.92 +/- 1.88 vs. 11.64 +/- 1.12), and all of them should statistical difference (all P < 0.05). The cumulative amount of insulin (U) within 24 hours after surgery was as follows: age >= 50 years old or < 50 years old (169.5 +/- 56.6 vs. 110.2 +/- 38.5); hypertension with and without (171.6 +/- 64.0 vs. 104.8 +/- 34.3); aortic valve disease with and without (171.4 +/- 36.8 vs. 109.4 +/- 27.6); diabetes with and without (202.5 +/- 46.7 vs. 100.4 +/- 31.5); coronary heart disease with and without (178.5 +/- 38.6 vs. 104.6 +/- 26.4 ); emergency operation with and without (178.3 +/- 35.7 vs. 102.7 +/- 26.8); CPB time >= 3 hours or < 3 hours (168.6 +/- 37.2 vs. 107.3 +/- 27.5); DHCA time >= 45 minutes or < 45 minutes (172.5 +/- 36.1 vs. 105.4 +/- 28.7), and all of them showed significant statistical difference (all P < 0.05). and all of them showed significant statistical difference (all P < 0.05). CONCLUSION: DHCA may cause significant increase in perioperative blood glucose and lactate, and even may lead to insulin resistance. Patients often require continuous intravenous administration of large doses of insulin. Perioperative hyperglycemia during DHCA is related to many factors, which should be considered in control of blood glucose. PMID- 21787465 TI - [Comparison of measuring energy expenditure with indirect calorimetry and traditional estimation of energy expenditure in patients in intensive care unit]. AB - OBJECTIVE: To compare measurement of energy expenditure (MEE) by indirect calorimetry (IC) with traditional estimation of energy expenditure (EEE), to provide a basis for energy supplementary for critically ill patients. METHODS: Using self-controlled study,the energy expenditure of 57 intensive care unit (ICU) patients was measured by IC. Meanwhile, EEE was also calculated using the following equations : Harris-Benedict (HB), HB*factor , or 104.6 kJ/kg. Body weight were calculated using actual body weight (ABW) or ideal body weight (IBW). If body mass index (BMI)<18.4 kg/m(2) it was considered as underweight , and the IBW was selected from the IBW table. The potential adequacy of estimated energy was assayed by ratio of EEE/MEE. RESULTS: There was significant difference in MEE by IC and EEE by HB, HB*factor and 104.6 kJ/kg [(6 335 +/- 1 004) kJ, (9 125 +/- 1 795) kJ, (7 188 +/- 1 029) kJ vs. (7 753 +/- 1 439) kJ ,P<0.05 or P<0.01]. There was significant difference between EEE by HB*factor and 104.6 kJ/kg (P<0.01) , and EEE by 104.6 kJ/kg*ABW , and the latter was closer to MEE. Underfeeding would occur in most ICU patients if HB equation was used [100% (4/4) in underweight patients and 73.59% (39/53) in normal weight (BMI 18.5-23.9 kg/m(2))]. EEE as calculated by 104.6 kJ/kg*IBW was reasonable in the underweight patients 100% ( 4/4 ), but EEE in the patients with normal weight by using HB*factor or 104.6 kJ/kg*ABW resulted in significant underfeeding [39.62% (21/53) and 43.39% (23/53)] or overfeeding [24.53% (13/53) and 13.22% (7/53)]. CONCLUSION: EEE derived from the equations was extremely inaccurate and may result in significant underfeeding or overfeeding in individuals. On the basis of this study we would recommend IC for measuring energy expenditure in ICU patients. Otherwise , the equations of 104.6 kJ/kg*IBW in underweight and 104.6 kJ/kg*ABW in normal weight patients may be reasonable. PMID- 21787466 TI - [Peri-operative characteristics of cerebral oxygen metabolism in patients with encephalopathy after orthotopic liver transplantation]. AB - OBJECTIVE: To investigate the feature of cerebral oxygen metabolism during peri operative stage of orthotopic liver transplantation (OLT), in order to identify the difference between the patients with or without complicating encephalopathy after OLT, and the relationship between the cerebral oxygen metabolism and encephalopathy after OLT. METHODS: Thirty patients undergoing OLT were studied. The patients were divided into two groups according to occurrence or not of encephalopathy after OLT: encephalopathy group and non-encephalopathy group. Blood samples were taken from radial artery and jugular vein simultaneously for blood gas analysis before operation, 25 minutes after onset of anhepatic phase, 30 minutes after graft reperfusion , 3 hours after graft reperfusion , and 24 hours after graft reperfusion. Cerebral arterial oxygen content (CaO(2)), oxygen content of jugular vein blood (CjvO(2)), cerebral arterial-venous oxygen content difference (Ca-jvO(2)), cerebral oxygen extraction ratio (CERO(2)) and cerebral blood flow/cerebral metabolic rate of oxygen ratio (CBF/CMRO(2)) were calculated, and the levels of blood glucose and lactic acid were recorded. RESULTS: There were 11 patients (36.7%) complicated by encephalopathy after OLT. The quantity of red blood cell infusion, blood loss and the dosage of noradrenalin in encephalopathy group were significantly larger compared with non-encephalopathy group. The overall tendency of change in cerebral oxygen metabolism index was about the same for both groups, while CaO(2) and Ca-jvO(2) at 25 minutes after onset of anhepatic phase, 30 minutes after graft reperfusion and 3 hours after graft reperfusion , and CERO(2) at 30 minutes after graft reperfusion and 3 hours after graft reperfusion were significantly decreased compared with those before operation [CaO(2) (ml/L) in encephalopathy group: 132.4 +/- 23.5 , 125.9 +/- 17.6, 133.4 +/- 11.1 vs. 148.5 +/- 28.8, in non-encephalopathy group: 135.7 +/- 22.4, 130.5 +/- 20.0, 139.9 +/- 21.2 vs. 148.9 +/- 28.2; Ca-jvO(2) (ml/L) in encephalopathy group: 42.9 +/- 13.2, 31.4 +/- 12.3 , 32.3 +/- 6.5 vs. 52.9 +/- 23.5, in non-encephalopathy group: 33.0 +/- 14.1, 26.6 +/- 9.1, 30.6 +/- 10.3 vs. 50.2 +/- 23.2; CERO(2) in encephalopathy group: (24.9 +/- 9.7)%, (24.4 +/- 5.5)% vs. (35.4 +/- 11.5)%, in non-encephalopathy group: (20.6 +/- 7.3)%, (21.9 +/- 7.0)% vs. (33.4 +/- 13.1)%, all P < 0.05], and they returned to the levels before operation at 24 hours after graft reperfusion. Jugular venous oxygen saturation (SjvO(2)) and CBF/CMRO(2) ratio were significantly increased at 30 minutes after graft reperfusion and 3 hours after graft reperfusion compared with the levels before operation [SjvO(2) in encephalopathy group: 0.838 +/- 0.105, 0.835 +/- 0.065 vs. 0.709 +/- 0.125, in non-encephalopathy group: 0.854 +/- 0.074, 0.824 +/ 0.074 vs. 0.713 +/- 0.138; CBF/CMRO(2) ratio in encephalopathy group: 37.8 +/- 16.6, 31.9 +/- 6.8 vs. 20.9 +/- 6.7 , in non-encephalopathy group: 37.8 +/- 14.1, 35.7 +/- 13.7 vs. 24.3 +/- 14.0, all P <0.05], and they returned to the levels before operation at 24 hours after graft reperfusion. The overall tendency of change in blood glucose and lactic acid was about the same in both groups, while the levels of blood glucose increased significantly from anhepatic phase to 24 hours after graft reperfusion compared with the levels before operation , and the levels of lactic acid increased significantly from anhepatic phase to 3 hours after graft reperfusion compared with the levels before operation and returned to the levels before operation at 24 hours after graft reperfusion. CONCLUSION: There are significant changes in the features of cerebral oxygen metabolism during OLT, but there is no difference between encephalopathy group and non encephalopathy group. The occurrence of encephalopathy can be attributed to many factors, so the prevention and treatment should be comprehensive considered. PMID- 21787467 TI - [Protective effect of polyenylphosphatidyl choline on liver in rat with sepsis]. AB - OBJECTIVE: To investigate the protective effect of polyenylphosphatidyl choline (PPC) on liver in rat with sepsis. METHODS: A total of 50 healthy male SD rats were randomly divided into four groups according to random number table: normal control group (NS group, n=10), sepsis model group (LPS group, n=15), PPC control group (PPC group, n=10) and PPC protection group (P+L group, n=15). A single dose of lipopolysaccharide (LPS) 6 mg/kg was injected to the peritoneal cavity to reproduce the sepsis model, while in NS group and PPC group, same volume of normal saline was used. PPC 10 ml/kg (232.5 mg/kg) was injected 24 hours and 6 hours before LPS via the tail vein in PPC group and P+L group, while in NS group and LPS group 5% glucose solution in the same volume was given. Behavioral changes and mortality rate of rats were recorded, and all survived rats were sacrificed 24 hours after LPS injection. Venous blood was taken for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) determination. Ratios of liver weight/body weight (L/Wb) and wet weight/dry weight of liver (W/D) were calculated. Histopathology changes in liver tissue were observed with hematoxylin eosin (HE) stain, and intercellular adhesion molecule-1 (ICAM-1) expression with instant two-step immunohistochemistry. RESULTS: Twenty-four hours after LPS injection (LPS group), the rats became lethargic, with less activity and drinking, while rats in P+L group, showed much better mental status, water intake and activity than LPS group. The mortality rate of P+L group was significantly lower than that of LPS group [6.7% (1/15) vs. 46.7% (7/15),P<0.05]. Compared with LPS group, rats in P+L group had lower levels of plasma ALT and AST, L/Wb, W/D , and liver ICAM-1 positive expression ratio [ALT (U/L): 157.71 +/- 32.63 vs. 225.63 +/- 43.47; AST (U/L): 53.21 +/- 13.85 vs. 85.25 +/- 18.91; L/Wb: (4.09 +/- 0.28)% vs. (4.50 +/- 0.25)%; W/D : 3.52 +/- 0.27 vs. 3.84 +/- 0.18; ICAM-1 positive expression ratio: 35.7% (5/14) vs. 87.5 (7/8),P<0.05 or P <0.01]. All parameters were normal in NS group and PPC group, and no statistical significance was observed between them (all P >0.05). LPS-injection led to severe inflammatory reaction in hepatic tissue , including obvious edema of hepatic parenchymal cells, exudation and aggregation of inflammatory cells, while in P+L group, these morphological changes were milder than that in LPS group but more obvious than that of NS group. CONCLUSION: Pre-treatment of rats with PPC alleviates progressive inflammatory disturbances of hepatic tissue caused by endotoxin injection, and it attenuates liver edema and ICAM-1 expression, protects liver function and decreases mortality rate in rats with sepsis. PMID- 21787468 TI - [Expression and significance of beta adrenergic receptors in a model of left ventricular mechanical unloading]. AB - OBJECTIVE: To study the expression and significance of beta adrenergic receptors mRNA in a model of left ventricular mechanical unloading, and explore the change in cardiomyocyte in molecular level after left ventricular unloading. METHODS: Heart failure was reproduced in Lewis rats by ligating left anterior descending (LAD) artery. After 4 weeks, the failing hearts and right lungs were heterotopically transplanted into the abdomen of the recipients by anastomosing their ascending aorta to the recipients' descending aorta in the heart transplantation group. Two weeks after transplantation, heart weight, left ventricular weight, myocyte diameter and myocardial fibrosis were determined , and beta adrenergics receptors mRNA expression was essayed by real-time polymerase chain reaction (PCR). Seven normal Lewis rats served as control. RESULTS: The weight of the enlarged heart, left ventricular weight and myocyte diameter of the failing hearts were decreased to normal after transplantation. The levels of beta1- and beta2- adrenergic receptors mRNA expression were significantly lowered in heart failure group compared with that of normal group(0.09 +/- 0.03 vs. 0.18 +/- 0.04, 0.07 +/- 0.06 vs. 0.12 +/- 0.02, both P <0.05). The level of beta2- adrenergic receptor mRNA expression in heart transplantation group (0.11 +/- 0.05) rose to normal (P>0.05), but beta1- adrenergic receptor mRNA expression (0.08 +/- 0.06) was lower in heart transplantation group than that in normal group (P<0.05). CONCLUSION: Myocardium reverse remodeling after left ventricular unloading is accompanied by the change in cardiomyocyte in molecular level , such as the change in beta adrenergic receptors , which may involve in the improvement of heart function after being supported by left ventricular assist device. PMID- 21787469 TI - [Changes in haemodynamics and electrolytes during perioperative period of living donor liver transplantation in children and their preventive measures]. AB - OBJECTIVE: To explore the preventive measures of disturbances of haemodynamics and electrolytes by observing their changes during perioperative period of living donor liver transplantation in children. METHODS: Twenty children who had undergone living donor liver transplantation operation were enrolled in the study, their haemodynamics and electrolyte parameters before operation and on the 1, 3, 5 and 7 days after the operation were monitored and analyzed. RESULTS: Compared with levels before operation , systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) significantly increased on the 1, 3, 5 and 7 days after the operation [SBP(mm Hg, 1 mm Hg=0.133 kPa): 106.60 +/- 9.58, 116.75 +/- 9.11, 117.95 +/- 12.15, 116.45 +/- 8.73 vs. 92.75 +/- 6.72,DBP(mm Hg): 63.85 +/- 10.33, 70.70 +/- 10.98, 70.90 +/- 12.92, 74.65 +/- 15.51 vs. 53.95 +/- 12.43,MAP (mm Hg):78.15 +/- 9.30, 85.30 +/- 9.44, 85.35 +/- 13.85, 85.90 +/- 13.94 vs. 66.45 +/- 8.83, all P <0.05], but the heart rate (HR, bpm)was significant lowered only on 5 days after the operation (102.80 +/- 26.08 vs. 117.25 +/- 19.25,P<0.05). Blood Na(+) (mmol/L)level rose significantly on the 1 day after the operation (146.52 +/- 5.89 vs. 139.36 +/- 3.91,P<0.01). On the same day, blood K(+) and Ca(2+) were declined significantly [K(+) (mmol/L): 3.36 +/- 0.44 vs. 4.12 +/- 0.68, Ca(2+) (mmol/L): 1.15 +/- 0.15 vs. 1.23 +/- 0.06,P<0.01 and P <0.05], but there was no obvious change in them on 3, 5 and 7 days. Significant decrease in blood Mg(2+) (mmol/L) was found on the 1, 3, 5 and 7 days after the operation (0.69 +/- 0.11, 0.64 +/- 0.10, 0.58 +/- 0.10, 0.72 +/- 0.17 vs. 0.84 +/- 0.10,P<0.05 or P <0.01). CONCLUSION: Hypertension is the main haemodynamics change during perioperative period of living donor liver transplantation in children, and the levels of electrolytes are not stable in early postoperative period of liver transplantation. Early diagnosis and treatment of hypertension is important for children to recover from operation , and it is also important to maintain normal levels of electrolytes to obtain a successful liver transplantation. PMID- 21787470 TI - [Analysis of incidence and risk factor in hospitalized patients with acute kidney injury]. AB - OBJECTIVE: To investigate the epidemiology and the risk factors of acute kidney injury (AKI) in hospitalized patients in order to help clinicians better understand and prevent AKI. METHODS: All patients hospitalized in Renji Hospital of Shanghai Jiao Tong University, which is a three-level General Hospital in Shanghai, during January to December of 2008 were screened by Lab Administration Network. Study group was comprised of the patients with full clinical data of AKI, as defined by Acute Kidney Injury Network (AKIN). The incidence, etiology and distribution characteristics of hospitalized patients with AKI were retrospectively analyzed. Logistic regression analysis was used to investigate the risk factors in severity of AKI. RESULTS: Nine hundred and thirty-four patients suffering from AKI for 1 001 episodes were enrolled. The incidence of AKI in hospitalized patients was 2.4% (934/38 734). The ratio of male to female was 1.88:1. The mean age was (60.82 +/- 16.94) years old. Higher incidence was seen with an increase in age. Three hundred and thirty-one(35.4%) patients with AKI were found in medical department, 592(63.4%) patients in surgical department and 11(1.2%) patients in department of gynecologic and obstetrics. Analysis of the causes of AKI showed that pre-AKI accounted for 52.0%, followed by renal parenchyma AKI (44.7%) and postrenal AKI (3.3%). The most common reason for AKI was acute tubular necrosis (ATN, 37.5%), followed by absolute (33.6%) and relative inadequacy of blood volume (13.4%). Multivariate logistic regression analysis showed that chronic kidney disease (CKD) [odds ratio (OR)=2.085, 95% confidence interval (95%CI): 1.536-2.830,P<0.01], renal injurious drugs (OR=1.438, 95%CI: 1.087-1.901 ,P<0.05), and failure of organs other than kidney (OR=1.327, 95%CI: 1.014-1.737,P<0.05) were independent risk factors for stage II III AKI. CONCLUSION: AKI is one of the most common clinical syndromes in hospitalized patients. With the increase of age, the incidence increases gradually. The most common reasons for hospitalized AKI are pre-AKI and ATN. CKD, renal injurious drugs and failure of other organs are independent risk factors of medium to serious AKI. PMID- 21787471 TI - [Clinical study of the new intelligent determination and analysis system for glomerular filtration rate]. AB - OBJECTIVE: To discuss the clinical application value of determining glomerular filtration rate(GFR) with the new intelligent determination and analysis system for GFR (B&G System). METHODS: GFR of 216 hospitalized patients suffering from the different diseases was determined accurately by clearance rate of (99m)Tc diethylene triamine pentaacetic acid ((99m)Tc-DTPA) (Tc-GFR), and the serum creatinine (SCr) and blood urea nitrogen (BUN) were also determined. At the same time GFR was determined by B&G system and Robert formula (B&G-GFR, Robert-GFR), and creatinine clearance rate (CCr) and GFR were calculated by Cockcroft/Gault formula(CG-CCr-GFR). All the results were compared, and correlation analysis was done for the three groups of data. RESULTS: Among 216 patients, B&G-GFR and Tc GFR in 106 patients with renal insufficiency and 110 patients with normal renal function showed no significant difference (ml . min(-1). 1.73 m(-2): 29.13 +/- 18.96 vs. 32.28 +/- 25.03, 121.13 +/- 49.79 vs. 118.48 +/- 43.25, both P >0.05), while Robert-GFR (ml . min(-1) . 1.73 m(-2): 21.45 +/- 15.67, 93.54 +/- 30.01) and CG-CCr-GFR (ml . min(-1) . 1.73 m(-2): 11.87 +/- 8.69, 86.27 +/- 21.44)were significantly lower than Tc-GFR (P<0.05 or P <0.01 ). The values of B&G-GFR, Robert-GFR, CG-CCr-GFR and Tc-GFR in renal insufficiency group (ml . min(-1) . 1.73 m(-2) :6.15 +/- 14.07, 13.83 +/- 11.36, 23.41 +/- 24.34) were respectively significantly lower than that of normal renal function group (ml . min(-1) . 1.73 m(-2):7.65 +/- 6.54, 24.94 +/- 13.24, 32.21 +/- 21.81, all P <0.05). B&G-GFR, Robert-GFR, and CG-CCr-GFR of both groups were positively correlated with Tc-GFR (P<0.05 or P <0.01), but negatively correlated with SCr (P<0.05 or P <0.01). CONCLUSION: B&G-GFR, Robert-GFR and CG-CCr-GFR , to a certain extent, do accurately reflect GFR. However, B&G-GFR is more accurate than others, and it can take the place of Tc-GFR clinically. B&G system has the advantage of accuracy, simplicity, speed, safety and low-price compared with other methods for the determination of GFR, and it warrants popularization. PMID- 21787472 TI - [Impact of therapeutic time on the prognosis in critically ill patients with acute renal failure who needed renal replacement therapy]. AB - OBJECTIVE: To investigate the impact of therapeutic time on the prognosis in critically ill patients with acute renal failure (ARF) who needed renal replacement therapy (RRT), and to analyze the risk factors of death. METHODS: All data were retrieved from the Database of Early Diagnosis and Treatment in Acute Renal Failure in Shanghai. Eighty-eight patients were collected with 56 males and 32 females who accepted continuous veno-venous hemofiltration (CVVH). The mean age was (55.73 +/- 16.33) years old. Patients were divided into two groups according to therapeutic time: short time group (6-12 hours, n=49) and long time group (>12 hours, n=39). The differences between two groups before and after treatment were compared. Kaplan-Meier survival analysis, the Log-rank test was performed to evaluate the prognosis of ARF patients on 15, 30 and 60 days. Cox regression analysis was performed to evaluate the risk factors affected the patient survival. RESULTS: There were no significant difference of age, surgery, chronic kidney disease (CKD), diabetes, multiple organ failure (MOF) and severity of disease between two groups before treatment. Compared with that before treatment, blood pH, HCO(-)(3) were increased, and K(+), blood urea nitrogen (BUN), serum creatinine (SCr) were decreased after treatment (all P <0.05). There were no significant difference of Na(+) concentration and heart rate (HR), mean arterial pressure (MAP) after treatment. Kaplan-Meier survival analysis showed the survival rate of short time group and long time group were 64.4% vs. 51.4%, 52.8% vs. 46.2% and 50.4% vs.41.0% on 15, 30 and 60 days respectively. No significant difference in survival rate was noted (P=1.234). Cox regression analysis showed that the independent risk factors of short time mortality were diabetes [hazard ratio (HR)=2.134, 95% confidence interval (95%CI) 1.093 4.167,P<0.05] and MOF(HR 1.564, 95%CI 1.233-1.984,P<0.01). CONCLUSION: The mortality of ARF in critical ill patients remains high, despite accepted renal replacement therapy. The therapeutic time of CVVH may not affect the patient survival not with standing the duration of renal replacement therapy. In our group, diabetes and MOF were the independent risk factors of patients death. PMID- 21787473 TI - [The effect of low-dose hydrocortisone on the expression of glucocorticoid receptor alpha of the septic kidney and its protective effect on kidney in rat]. AB - OBJECTIVE: To investigate the protective effect and mechanism of low dose glucocorticoid(GC) on sepsis induced acute kidney injury(AKI) in rat. METHODS: Eighty healthy Wistar male rats were randomly divided into sham group (n=10), AKI model group (AKI group, n=35)and hydrocortisone treatment group(HC group, n=35),according to random digital table. Septic AKI model was reproduced using cecal ligation and puncture (CLP). After the procedure hydrocortisone 6 mg/kg was injected via sublingual vein in HC group. At 24 hours after the procedure, blood was obtained and the animals were sacrificed in all groups. Pathological changes in the kidney were observed with hematoxylin eosin (HE) staining. The expressions of glucocorticoid receptor alpha (GR-alpha) and nuclear transcription factor KappaB (NF-KappaB) in the kidney were assessed by immunohistochemistry. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (IL-1beta, IL 6,IL-10) in the plasma were determined by enzyme-linked immunosorbent assay(ELISA). RESULTS: 1 The difference in survival rates in AKI group and HC group showed no statistical significance (42.8% vs. 48.6%,P>0.05). 2 Renal tubular epithelial cells were swollen and exfoliated, with loss and vacuolation of tubular brush border under light microscope in AKI group. Pathological changes in renal tubules in HC group were alleviated. 3 Compared with AKI group, the expression of GR-alpha was increased [absorbance (A) value: 0.35 +/- 0.05 vs. 0.25 +/- 0.05,P<0.01] and the expression of NF-KappaB was decreased in HC group (A value: 0.23 +/- 0.04 vs.0.34 +/- 0.04,P<0.01). Compared with AKI group, the levels of TNF-alpha, IL-1beta, IL-6 were lowered [TNF-alpha (ng/L): 94.25 +/- 7.96 vs. 118.24 +/- 6.63; IL-1beta (ng/L): 19.14 +/- 1.99 vs. 28.91 +/- 6.81; IL 6 (ng/L): 66.32 +/- 1.99 vs. 85.70 +/- 11.54; all P <0.01] and the level of IL-10 (ng/L) was elevated (98.33 +/- 6.68 vs. 88.59 +/- 7.34,P<0.01) in HC group. CONCLUSION: A low dose of hydrocortisone can inhibit the activity of NF-KappaB, possibly by means of increasing the expression of renal GR-alpha in septic rats. Accordingly it reduces the production of pro-inflammatory factors which participate in sepsis. So it effectively inhibits inflammation in sepsis and protects the kidney in septic rats. PMID- 21787474 TI - [Effect of Xuebijing injection on T helper 17 and CD4+ CD25+ regulatory T cells in patients with sepsis]. AB - OBJECTIVE: To study the level and significance of T helper 17 (Th17) and CD4(+) CD25(+) regulatory T cells (Treg) in peripheral blood of patients with sepsis and to evaluate the effects of Xuebijing injection on them. METHODS: 1 Sixty-four patients with sepsis in intensive care unit (ICU) of Anhui Provincial Hospital were divided into three groups: sepsis group (n=26), severe sepsis group (n=21), and septic shock group (n=17). Eighteen healthy individuals served as controls. The comparison in the expression of Th17 and CD4(+)CD25(+) Treg within groups and the correlation between their levels and the severity of sepsis was made. 2 Sixty four patients were also randomly divided into two groups: routine group (n=25, received routine bundle treatment) and Xuebijing treatment group (n=39, received bundle treatment + Xuebijing treatment). Patients in Xuebijing treated group were given 50 ml Xuebijing injection two times per day in addition to routine bundle treatment. Seven days constituted one course of treatment. The expressions of Th17 and CD4(+) CD25(+) Treg of 64 patients on the 1 day and 7 days after treatment were detected by flow cytometry. The effects of Xuebijing injection on the patients were evaluated. RESULTS: 1 The expression rate of Th17 and CD4(+)CD25(+) Treg was (0.84 +/- 0.29)% and (0.43 +/- 0.20)% respectively in control group, and they were lower than that of patients with sepsis (P<0.05). The expression rate of Th17 was higher in severe sepsis group [(3.18 +/- 0.84)%] than that of other two groups (P <0.05). Moreover , The expression rate of CD4(+)CD25(+) Treg was highest [(3.28 +/- 0.76)%] in septic shock group (P<0.05) , and it was positive correlated with acute physiology and chronic health evaluation II (APACHEII) score and blood lactate (r(1)=0.519, r(2)=0.451, both P =0.01) in all 64 patients. 2 Compared with routine group, our study indicated that Xuebijing injection could reduce the abnormal expression of Th17 [(1.72 +/- 0.69)% vs. (2.35 +/- 0.81)%,P<0.05] and CD4(+)CD25(+) Treg [(1.78 +/- 1.00)% vs. (2.30 +/- 0.85)%,P<0.05] and decrease length of stay in ICU [(4.7 +/- 2.6) days vs. (7.5 +/- 4.3) days,P=0.002]. It also lowered 28-day mortality of patients with sepsis, but the difference between two groups was not significant (20.5% vs. 28.0%,P>0.05). CONCLUSION: The expression of Th17 and CD4(+)CD25(+) Treg was increased in sepsis patients and was positively correlated with severity of sepsis, suggesting that they may play an important role in pathogenesis of sepsis. Xuebijing injection could decrease the abnormal expression of Th17 and CD4(+) CD25(+) Treg and tend to decrease the fatality rate of sepsis. PMID- 21787475 TI - [Clinical analysis and discussion of causes of central pontine myelinolysis occurring early after liver transplantation]. PMID- 21787476 TI - [Effect of Rhubarb administered via different routes on blood inflammatory cytokines levels of patients with severe acute pancreatitis]. PMID- 21787479 TI - The effect of QMix, an experimental antibacterial root canal irrigant, on removal of canal wall smear layer and debris. PMID- 21787481 TI - Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: a case report. PMID- 21787483 TI - Cone-beam computed tomography evaluation of maxillary sinusitis. AB - INTRODUCTION: Dental pain originating from the maxillary sinuses can pose a diagnostic problem. Periapical lesion development eliciting inflammatory changes in the mucosal lining can cause the development of a sinusitis. The purpose of this study was to describe the radiographic characteristics of odontogenic maxillary sinusitis as seen on cone-beam computed tomography (CBCT) scans and to determine whether any tooth or any tooth root was more frequently associated with this disease. METHODS: Eighty-two CBCT scans previously identified as showing maxillary sinus pathosis were examined for sinusitis of odontogenic origin in both maxillary sinuses. RESULTS: One hundred thirty-five maxillary sinusitis instances with possible odontogenic origin were detected. Of these, 37 sinusitis occurrences were from nonodontogenic causes, whereas 98 instances were tooth associated with some change in the integrity of the maxillary sinus floor. The average amount of mucosal thickening among the sinusitis cases was 7.4 mm. Maxillary first and second molars were 11 times more likely to be involved than premolars, whereas either molar was equally likely to be involved. The root most frequently associated with odontogenic sinusitis is the palatal root of the first molar followed by the mesiobuccal root of the second molar. CONCLUSIONS: Changes in the maxillary sinuses appear associated with periapical pathology in greater than 50% of the cases. Maxillary first or second molar teeth are most often involved, and individual or multiple roots may be implicated in the sinusitis. The use of CBCT scans can provide the identification of changes in the maxillary sinus and potential causes of the sinusitis. PMID- 21787482 TI - Dental magnetic resonance imaging: making the invisible visible. AB - INTRODUCTION: Clinical dentistry is in need of noninvasive and accurate diagnostic methods to better evaluate dental pathosis. The purpose of this work was to assess the feasibility of a recently developed magnetic resonance imaging (MRI) technique, called SWeep Imaging with Fourier Transform (SWIFT), to visualize dental tissues. METHODS: Three in vitro teeth, representing a limited range of clinical conditions of interest, imaged using a 9.4T system with scanning times ranging from 100 seconds to 25 minutes. In vivo imaging of a subject was performed using a 4T system with a 10-minute scanning time. SWIFT images were compared with traditional two-dimensional radiographs, three dimensional cone-beam computed tomography (CBCT) scanning, gradient-echo MRI technique, and histological sections. RESULTS: A resolution of 100 MUm was obtained from in vitro teeth. SWIFT also identified the presence and extent of dental caries and fine structures of the teeth, including cracks and accessory canals, which are not visible with existing clinical radiography techniques. Intraoral positioning of the radiofrequency coil produced initial images of multiple adjacent teeth at a resolution of 400 MUm. CONCLUSIONS: SWIFT MRI offers simultaneous three-dimensional hard- and soft-tissue imaging of teeth without the use of ionizing radiation. Furthermore, it has the potential to image minute dental structures within clinically relevant scanning times. This technology has implications for endodontists because it offers a potential method to longitudinally evaluate teeth where pulp and root structures have been regenerated. PMID- 21787484 TI - Instrument separation analysis of multi-used ProTaper Universal rotary system during root canal therapy. AB - INTRODUCTION: The purpose of this study was to identify the influential factors responsible for clinical instrument separation of reused ProTaper Universal rotary instruments (Dentsply Maillefer, Ballaigues, Switzerland). METHODS: Six thousand one hundred fifty-four root canals in 2,654 teeth were prepared using ProTaper Universal files in endodontic clinics. Separation incidence was determined based on the number of treated teeth or canals. Data were collected including the size of fractured instrument, the length and location of a broken segment within the root canal, and the curvature of canal. The chi-square test and independent samples t test were used to determine the statistical significance. RESULTS: The overall instrument separation incidences were 2.6% according to the number of teeth and 1.1% according to the canal number, respectively. Separation incidences according to the number of teeth or canals were significantly higher (P < .05) in molars than those in premolars or anterior teeth. Because of its largest diameter, F3 file presented the highest separation incidence according to the number of teeth (1.0%) or canals (0.4%); 47.5% instrument separation of mandibular molars and 61.5% instrument separation of maxillary molars happened in the mesiobuccal canals. Moreover, 91.4% fragments were located in the apical third of root canals, and 54.2% instrument separation occurred in severely curved canals. There was a significant difference (P < .05) in the mean fracture length between shaping (2.42 +/- 0.73 mm) and finishing files (3.32 +/- 0.73 mm). CONCLUSIONS: Separation incidence according to the canal number is more reliable than that according to the number of teeth because of the variable canal number in different teeth. The tooth type, rotary file size, canal location, and anatomy were correlated with the instrument separation of reused ProTaper Universal files. PMID- 21787485 TI - Relationship between smoking and endodontic variables in hypertensive patients. AB - INTRODUCTION: The aim of this study was to investigate the relationship between smoking and the prevalence of apical periodontitis and root canal treatment in hypertensive patients. METHODS: In a cross-sectional study, the records of 100 hypertensive patients, 50 smokers and 50 nonsmokers, were examined. Periapical status of all teeth was assessed by using the periapical index score. RESULTS: Apical periodontitis in 1 or more teeth was found in 92% of smoker patients and in 44% of nonsmoker subjects (P=.000; odds ratio [OR], 16.8; 95% confidence interval [CI], 4.6-61.3). One or more root-filled teeth were found in 58% and 20% of smoker and nonsmoker subjects, respectively (P < .01; OR, 5.5; 95% CI, 2.3 13.5). Among smoker hypertensive patients, 6% of the teeth had apical periodontitis, whereas in the nonsmoker subjects, 2% of teeth were affected (P < .01; OR, 3.3; 95% CI, 2.0-5.4). The percentage of root-filled teeth in the smoker and nonsmoker groups was 3.6% and 1.2%, respectively (P < .01; OR, 2.9; 95% CI, 1.6-5.5). CONCLUSIONS: The prevalence of apical periodontitis and root canal treatment was significantly higher in smoker hypertensive patients compared with nonsmoker subjects. PMID- 21787486 TI - Detection of vertical root fractures by using cone-beam computed tomography: a clinical study. AB - INTRODUCTION: Vertical root fractures of teeth (VRFs) often pose a diagnostic dilemma because of the difficulty in detection of these in intraoral radiographs except in certain cases with very distinct clinical findings. This often leads to unwarranted extraction of the tooth. Cone-beam computed tomography (CBCT) produces three-dimensional images and allows precise visualization and evaluation of VRFs or cracks in extracted teeth, as reported previously. This clinical pilot study was designed to determine the diagnostic accuracy of noninvasive CBCT for detection of suspected VRFs in endodontically treated teeth by using exploratory surgery to confirm the presence or absence of a fracture. METHODS: Thirty-two teeth in 29 patients with clinical signs and symptoms suggestive of VRF were included in the study after informed consent was obtained. They underwent a limited area CBCT evaluation. All CBCT studies were blinded, and 2 board certified oral and maxillofacial radiologists assessed the presence or absence of VRF through sequential evaluation of the three-dimensional volume. Subjects underwent surgical exploration as part of treatment, which helped establish the presence or absence of VRF. RESULTS: Pearson correlation coefficient by using surgical finding to confirm presence/absence of fracture was 0.602, positive predictive value was 91%, and negative predictive value was 67%. The sensitivity was 88%, and specificity was 75%. CONCLUSIONS: This study revealed the superior diagnostic accuracy of CBCT for detection of VRF. PMID- 21787487 TI - Comparative evaluation of platelet-rich plasma and guided tissue regeneration membrane in the healing of apicomarginal defects: a clinical study. AB - INTRODUCTION: The aim of the study was to compare the healing responses of platelet-rich plasma (PRP), PRP + a collagen sponge, and a collagen membrane used as guided tissue regeneration (GTR) materials for the treatment of apicomarginal defects. METHODS: Thirty patients with suppurative chronic apical periodontitis and apicomarginal communication were selected and allocated randomly into three groups according to the barrier technique to be used during periradicular surgery: the collagen membrane group, the PRP group, and the PRP + collagen sponge group. Clinical and radiographic measurements were determined at baseline and every 3 months after surgery up to 1 year. Cases were defined as healed when no clinical signs or symptoms were present, and radiographs showed complete or incomplete (scar tissue) healing of previous radiolucencies. RESULTS: The PRP and PRP + collagen sponge groups depicted 83.33% and 88.89% healing, respectively, in terms of combined clinical-radiographic healing as compared with 80% in the collagen membrane group. All the three treatments showed highly significant (P < .05) reductions in the periodontal pocket depth (PD), the clinical attachment level (CAL), the gingival margin position (GMP), the size of the periapical lesion, the percentage reduction of the periapical rarefactions, and periapical healing. No significant differences between the three groups were evident for these parameters (P > .05). CONCLUSIONS: GTR applied to apicomarginal defects using PRP or PRP + collagen sponge lead to similar enhancements of the clinical outcome of periradicular surgery in terms of periapical healing, gain of periodontal support, PD reduction, and PRP may be an alternative treatment for GTR membrane in the treatment of apicomarginal defects. PMID- 21787488 TI - Midkine expression in human periapical granulomas. AB - INTRODUCTION: The expression of midkine (MK), a heparin-binding growth factor, is increased in various human tumors, making it a promising tumor marker and target for tumor therapy. MK is also related to the regulation of the development and etiology of chronic or autoimmune diseases; however, the involvement of MK in apical periodontitis has never been examined. This study compared the localization of MK-expressing cells and MK messenger RNA expression in periapical granulomas with healthy gingival tissues. METHODS: Periapical lesions were removed surgically from chronic apical periodontitis patients, and serial tissue sections were stained with hematoxylin-eosin. The lesions diagnosed as periapical granulomas pathologically were examined by immunohistochemistry using human MK monoclonal antibodies. MK messenger RNA expression was also detected using real time polymerase chain reaction analysis. Healthy gingival tissues were analyzed in the same manner. RESULTS: MK was expressed by inflammatory cells, such as macrophages, lymphocytes, and neutrophils, as well as by endothelial cells in periapical granulomas but not in healthy gingival tissues. The MK-expressing inflammatory cells were seen adjacent to blood vessels, which contained MK expressing endothelial cells, suggesting the interaction of MK among these cells during the process of inflammatory cell infiltration. Quantitative analysis of MK messenger RNA expression revealed that periapical granulomas expressed significantly more MK than healthy gingival tissues. CONCLUSIONS: These findings suggest that MK is involved in the pathogenesis of periapical granulomas. PMID- 21787489 TI - A comparative study of using a combination of calcium chloride and mineral trioxide aggregate as the pulp-capping agent on dogs' teeth. AB - INTRODUCTION: The addition of some chemicals to mineral trioxide aggregate (MTA) may improve the physical properties of the biomaterial. The aim of this study was to compare a combination of MTA with/without CaCl(2) as pulp-capping agents in dogs' teeth. METHODS: The dental pulp of 32 teeth in four dogs were exposed and capped with either MTA or MTA/CaCl(2). After 2 months, the animals were sacrificed, and the teeth were prepared for histological evaluation. Pulpal response to the two capping materials was evaluated in terms of necrosis, inflammation, and formation of a calcified bridge. The chi-square test was used for data analysis. RESULTS: Histological results showed a higher percentage of inflammation and necrosis and a lower percentage of calcified bridge formation in MTA/CaCl(2) samples compared with MTA; however, the differences were not statistically significant (P > .05). CONCLUSIONS: The addition of CaCl(2) to MTA pulp-capping agent did not improve the properties of this biomaterial. PMID- 21787490 TI - A micro-computed tomographic analysis of maxillary lateral incisors with radicular grooves. AB - INTRODUCTION: The radicular groove is clinically significant due to its relevance to onset of inflammatory processes in the periodontal tissues. This study examined anatomic features of radicular grooves by using micro-computed tomography (micro-CT) scans. METHODS: Eleven extracted permanent maxillary lateral incisors with radicular grooves were collected from a native Chinese population and were scanned by micro-CT scans. The specimens were reconstructed three-dimensionally by software Mimics 10.01 (Materialise, Leuven, Belgium). The grooves were classified into three types on the basis of severity. RESULTS: Three specimens presented type I grooves (apically not beyond the coronal third of the root); five specimens showed a type II groove (beyond coronal third, corresponding to a normal or simple root canal), and three showed a type III groove (beyond the coronal third, corresponding to a complex root canal system). The developing groove could be located at the mesial (three teeth), distal (six teeth) and medial (one tooth) aspect of the root. In one specimen double grooves were found (a mesial and a distal). All specimens with type I grooves had normal root canal configuration. A cross-sectional teardrop-like canal was seen in a specimen with a type II groove. The C-shaped canal, invagination canal, and additional root with secondary canal were observed in specimens with type III grooves. CONCLUSIONS: Understanding the anatomic features of the radicular groove is essential for successful dental treatment. PMID- 21787491 TI - Biocompatibility of two novel root repair materials. AB - INTRODUCTION: The purpose of the present study was to evaluate the biocompatibility of 2 root-end filling materials, Endosequence Root Repair Material Putty (ERRM Putty) and Paste (ERRM Paste) and compare them with gray mineral trioxide aggregate (MTA). METHODS: ERRM Putty, ERRM Paste, MTA, intermediate restorative material (IRM), and Cavit G were tested. For cytotoxicity assay, human gingival fibroblasts were incubated for 1, 3, and 7 days with extracts of varying concentrations from materials set for 2 days or 7 days. Cell viability was evaluated by methyl-thiazol-tetrazolium (MTT) assay. For cell adhesion assay, materials set for 7 days were examined under scanning electron microscope directly after setting, after incubation in cell culture medium for 7 days, and after incubation in gingival fibroblast suspension at a density of 5 * 10(4) cells/well for 2 and 7 days. The constituents of crystals formed on surface of materials were determined by energy dispersive analysis by x ray. RESULTS: Cell viability was significantly correlated with the type of material, setting time, and incubation time (P < .001 for all parameters). ERRM Putty and ERRM Paste displayed similar cell viabilities to MTA at all experimental conditions, except that fresh samples of ERRM Paste showed slightly lower cell viabilities than MTA. Cell viabilities with IRM and Cavit G were significantly lower than with the other 3 materials (P < .001). Similar surface crystallographic features and cell adhesion were observed on ERRM Paste, ERRM Putty, and MTA. CONCLUSIONS: ERRM Putty and ERRM Paste displayed similar in vitro biocompatibility to MTA. PMID- 21787492 TI - Hypoxia promotes mineralization of human dental pulp cells. AB - INTRODUCTION: Dental pulp can be exposed to hypoxic conditions in case of trauma or inflammation. Dental pulp cells (DPCs) have mineralization potential, which plays a key role in pulp repair and reparative dentinogenesis process. Little information is available about DPC mineralization in hypoxic condition. The purpose of this study was to assess the influence of hypoxia on DPC mineralization to pave the way for a better understanding of dental pulp regeneration and reparative dentin formation. METHODS: Human DPCs were obtained by using tissue explant technique in vitro and cultured in normoxia (20% O(2)) or hypoxia (5% O(2)). Cell viability was investigated by methyl-thiazol-tetrazolium assay. Cell mineralization was assessed by von Kossa staining and alizarin red S staining. Important mineral genes such as osteocalcin (OCN), dentin matrix acidic phosphoprotein-1 (DMP-1), bone sialoprotein (BSP), and dentin sialophosphoprotein (DSPP) were determined by real-time polymerase chain reaction. RESULTS: Cell viability of DPCs increased more in hypoxia than in normoxia from day 3 to day 5. Von Kossa staining and alizarin red S staining showed DPCs in hypoxia had higher mineralization activity than in normoxia. Expression of mRNAs for OCN, DMP-1, BSP, and DSPP was greater in hypoxia than in normoxia. CONCLUSIONS: These results imply that hypoxia promotes DPC mineralization. PMID- 21787493 TI - An in vitro evaluation of the growth of human periodontal ligament fibroblasts after exposure to a 4-META-containing methacrylate-based endodontic sealer. AB - INTRODUCTION: In this study we evaluated the cytotoxic effects of MetaSEAL, a 4 META-containing meth-acrylate-based endodontic sealer, on human periodontal ligament (HPDL) fibroblasts. There are a limited number of studies on the cytotoxic effects of MetaSEAL, and there are no studies on the cytotoxic effects of MetaSEAL on cells it might come into contact with in vivo. METHODS: MetaSEAL concentrations of 25, 50, 100, 200, 400, and 800 MUg/mL were exposed to HPDL fibroblast cultures and evaluated at 1, 3, 7, 14, and 21 days. Controls included untreated cells and cells treated with ethanol, the vehicle for MetaSEAL suspension. Crystal violet staining in 24-well plates and the fluorescence-based CyQUANT Cell Proliferation Assay in 96-well plates assessed fibroblast viability. RESULTS: Significant cytotoxicity against HPDL growth by MetaSEAL was both time- and concentration-dependent. At day 1 there were no significant cytotoxic effects, whereas by day 3, 800 MUg/mL concentration, by day 7, 200, 400, and 800 MUg/mL concentrations, and by day 14, 50, 100, 200, 400, and 800 MUg/mL concentrations were significantly cytotoxic. By day 21, all concentrations were significantly cytotoxic. These findings were confirmed by both the crystal violet and CyQUANT assays. CONCLUSIONS: MetaSEAL endodontic sealer has increasing HPDL cytotoxicity with both concentration and time exposure. PMID- 21787494 TI - Assessment of hemostatic efficacy and osseous wound healing using HemCon dental dressing. AB - INTRODUCTION: Obtaining hemostasis in the surgical crypt during periradicular surgery is essential. It allows for improved visibility and contributes to a dry environment suitable for the placement of moisture-sensitive root-end filling material. Although current materials may not be moisture sensitive during setting, hemostasis is important for proper placement of root-end filling materials during apical surgery. A new hemostatic agent, HemCon dental dressing (Patterson Dental, St Paul, MN), may improve upon the efficacy of wound healing and hemostasis both in extent and time. The aim of this study was to evaluate the hemostatic effect of HemCon in osseous wound sites and evaluate the wound healing potential and percentage of new bone formation in osseous crypts treated with HemCon. METHODS: A split-mouth design was used with random allocation of sham and experimental sites in 12 rabbits. In experimental sites, either HemCon or 15.5% ferric sulfate was applied to osseous crypts created with a round bur. Hemostatic efficacy was evaluated using predetermined scores. Rabbits were sacrificed at 21 days, and tissues were harvested and prepared for histologic evaluation. A blinded pathologist scored samples relative to inflammation. The percentage of new bone deposition was calculated using NIS Elements software (Nikon Instruments Inc, Melville, NY). RESULTS: There was no statistical significant difference in hemostatic efficacy or wound healing between HemCon and ferric sulfate (P > .05). The HemCon group showed a significantly higher percentage of new bone deposition compared with the controls (P < .01). CONCLUSIONS: HemCon shows promise as an adjunct to the endodontic surgical armamentarium. PMID- 21787496 TI - Effects of leukemia inhibitory factor on proliferation and odontoblastic differentiation of human dental pulp cells. AB - INTRODUCTION: The purpose of this study was to determine whether the leukemia inhibitory factor (LIF) is expressed in human dental tissue and exerts its effect on proliferation and odontoblastic differentiation of the dental pulp cells (DPCs). METHODS: An immunohistochemical assay was used to detect the expression of LIF and leukemia inhibitory factor receptor (LIFR) in the human dental pulp. The proliferation of DPCs was examined by culturing human primary DPCs in the presence of LIF with different doses or the neutralizing antibody to LIF. Western blot was performed to assay the phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (Stat3) in the presence or absence of LIF and/or AG 490, a specific inhibitor of Jak2. The odontoblastic differentiation of DPCs was determined using the alkaline phosphatase (ALP) activity assay, quantification of bone sialoprotein (BSP) and dentin sialophosphoprotein (DSPP) gene expression, and mineralization nodule formation. RESULTS: LIF and LIFR were present in the odontoblasts and DPCs. LIF induced proliferation of DPCs, which was inhibited by the LIF neutralizing antibody and AG 490. LIF induced phosphorylation of Jak2 and Stat3 but not in the presence of the AG490. ALP activity of DPCs, in the absence or presence of mineralization induction medium, was inhibited by LIF. Furthermore, the mineralization nodule formation and the expression of BSP and DSPP were inhibited by LIF. This inhibition on differentiation was attenuated by the AG490. CONCLUSIONS: LIF and LIFR are expressed in the human dental pulp. LIF promotes the proliferation of DPCs, and the odontoblastic differentiation is inhibited via the Jak2-Stat3 signaling pathway. PMID- 21787495 TI - Blockade of TLR2 inhibits Porphyromonas gingivalis suppression of mineralized matrix formation by human dental pulp stem cells. AB - INTRODUCTION: Human dental pulp stem/progenitor cells (hDPSC) can differentiate into odontoblast-like cells and express dentin sialophosphoprotein (DSPP) and osteocalcin (OCN); thus, they may be used to regenerate dentin. However, residual bacterial components in the root canal may suppress this activity. PURPOSE: This study investigated the effect of a Porphyromonas gingivalis component on the expression of DSPP and OCN by stimulated hDPSCs and the influence of blockade of TLR2-mediated P. gingivalis host recognition. METHODS: Stimulated hDPSCs were exposed to varying concentrations of P. gingivalis lipopolysaccharide (LPS), and the expression of DSPP and OCN was measured. Similar groups of stimulated hDPSCs were exposed to TLR2 blocking agents before exposure to LPS. RESULTS: hDPSCs exposed to 5, 10, and 20 MUg/mL LPS exhibited a dose-dependent reduction in the expression of DSPP (3.19 +/- 0.18, 2.60 +/- 0.49, and 1.15 +/- 0.29, respectively) and OCN (3.51 +/- 1.18, 2.60 +/- 0.67 and 1.66 +/- 0.89, respectively). The expression of DSPP and OCN after exposure to 20 MUg/mL of LPS was significantly lower than measured for unexposed stimulated cells (analysis of variance and post hoc Tukey test, P < .05). The blockade of TLR2 using an extra- and intracellular agent affected DSPP (4.67 +/- 0.97 and 5.29 +/- 1.66, respectively) and OCN (5.25 +/- 1.69 and 5.82 +/- 2.38, respectively) expression at levels comparable to stimulated cells unexposed to 20 MUg/mL LPS (6.32 +/- 2.47 and 4.70 +/- 1.60 for DSPP and OCN, respectively). CONCLUSIONS: The suppressing effect of P. gingivalis on mineralized matrix formation by hDPSCs is confirmed, and this suppression can be moderated by TLR2 blockade. PMID- 21787497 TI - The effect of temperature and pH variations on the surface tension of EDTA solutions. AB - INTRODUCTION: Surface tension of a liquid is one of the major factors that affect the wetting of a solid. The reduction in surface tension could improve the contact of irrigants with the dentinal walls of the root canal system. This in vitro study was conducted to evaluate the effect of pH and temperature variations on the surface tension of EDTA solutions. METHODS: Three solutions, 17% EDTA, REDTA, and EDTA-T, were prepared and adjusted to have a pH of 5.5, 7.5, and 10.5. The surface tension of the test solutions was measured at 22 degrees C by the pendant drop technique, and the measurement was repeated after heating the solution at 37 degrees C. Differences among the experimental groups were statistically analyzed using three-way analysis of variance followed by the Bonferroni test for pair-wise comparison. RESULTS: The results of this study showed that there were significant differences in the surface tension values of solutions depending on the pH and temperature (P < .001). The surface tension level of the EDTA solution dramatically decreased when surfactant was added to the EDTA solution in both pH and temperature variations (P < .001). The increased temperature significantly altered the surface tension value at a pH of 5.5 of all EDTA solutions, at a pH of 7.5 of EDTA and REDTA solutions, and at a pH of 10.5 of only REDTA solution (P < .01). CONCLUSIONS: It was concluded that the surface tension of EDTA with and without surfactant is influenced by pH and temperature. PMID- 21787498 TI - In vitro resistance to fracture of roots obturated with Resilon or gutta-percha. AB - INTRODUCTION: There have been varied results from studies comparing postendodontic fracture resistance between teeth obturated with Resilon or gutta percha. This study was performed to evaluate the fracture resistance of roots obturated by using Resilon (RealSeal system) or gutta-percha (with AH Plus sealer). METHODS: Eighty extracted human mandibular single-rooted premolars stored in 10% formalin were used in the study. They were prepared by using a crown-down technique, debrided with NaOCl, ethylenediaminetetraacetic acid, and sterile water and divided into 4 groups. Obturation was performed by using the lateral condensation method. The negative control group consisted of unfilled specimens, and the positive control group consisted of those obturated with flowable, dual-cure composite resin. All root specimens were stored for 2 weeks in 100% humidity to allow complete setting of the sealer. Each specimen was mounted in acrylic in a polyvinyl ring and tested for fracture resistance with the Universal testing machine. The loading fixture of the machine was mounted with its spherical tip aligned with the center of the canal opening of each root. A vertical loading force was applied until it fractured the root. The force values were subjected to statistical analysis including analysis of variance and Fisher least significant difference testing. RESULTS: Teeth obturated with Resilon were more resistant to fracture than those obturated with gutta-percha. The difference was found to be highly significant (P=.00001). CONCLUSIONS: Resilon increased the resistance to fracture of single-rooted teeth in vitro. PMID- 21787499 TI - Effect of light-emitting diode photopolymerization modes on the push-out bond strength of a methacrylate-based sealer. AB - INTRODUCTION: The objective of this study was to investigate and compare the effect of different light-emitting diode (LED) polymerization modes on the bond strength of a methacrylate-based sealer used with Resilon or gutta-percha. METHODS: Forty extracted single-rooted teeth were sectioned off below the cementoenamel junction, and the root canals were instrumented by using rotary instruments to ISO #30/0.06 taper. The roots were randomly assigned into 1 of the following groups for root canal obturation: (1) RealSeal + Resilon and (2) RealSeal + gutta-percha. In each group, specimens were further subgrouped according to the LED polymerization mode used to cure RealSeal: (1) standard (20 seconds of maximum intensity) and (2) exponential (5 seconds of exponential power increase, followed by 15 seconds of maximum intensity). Specimens were stored in 100% humidity for 1 week at 37 degrees C. Push-out test was performed at a crosshead speed of 1 mm/min on 2-mm-thick root slices obtained from coronal to apical direction. Multivariate analysis of variance and Tukey tests were used for statistical analysis of the data (P=.05). Failure modes were examined under the scanning electron microscope. RESULTS: The tested polymerization modes had no significant effect on the bond strength values (P > .05). RealSeal + gutta-percha yielded significantly greater bond strength than RealSeal + Resilon (P < .05). In all groups, the bond strength values decreased significantly from coronal to apical direction (P < .05). Adhesive failure at the sealer-dentin interface was the predominant fracture mode. CONCLUSIONS: The exponential photopolymerization mode had no significant advantage over the standard regimen in terms of dentin bond strength. PMID- 21787500 TI - Removal of surgical smear layer. AB - INTRODUCTION: During apicoectomy and retrograde cavity preparation, a smear layer, which contains microorganisms and necrotic pulpal tissues, is formed on the dentinal surfaces cut by the instruments. Bacteria can survive and proliferate inside or below the smear layer. The purpose of this study was to evaluate in vitro two different procedures for the removal of the smear layer in retrocavities prepared with ultrasonic retrotips. METHODS: Twenty-eight single rooted teeth were cleaned, shaped, and obturated with gutta-percha and sealer. The apical 3 mm of each root were cut with a carbide bur, and retrograde cavities were prepared with ProUltra ultrasonic retrotips (Maillefer Dentsply, Baillagues, Switzerland) at a depth of 3 mm. Teeth in group A were treated with a gel of 35% orthophosphoric acid for 15 seconds, and teeth in group B were treated with a gel of 24% EDTA at a neutral pH for 2 minutes. The samples were prepared for scanning electron microscopic observation and scored for the presence of the smear layer on the retrocavity walls. RESULTS: Eighty percent of the teeth in group A showed an optimal degree of cleanliness of the walls, with dentinal tubules completely open. The majority of analyzed samples coming from group B showed dentinal tubules covered with the smear layer. CONCLUSIONS: The analysis of the samples showed that orthophosphoric acid is more effective than EDTA in removing surgical smear layer even with less time of action. PMID- 21787501 TI - Visualization of irrigant flow and cavitation induced by Er:YAG laser within a root canal model. AB - INTRODUCTION: Laser-activated irrigation (LAI) has recently been introduced as an innovative method for root canal irrigation. However, there is limited information about the cleaning mechanism of an Er:YAG laser. In this study, we visualized the action of laser-induced bubbles and fluid flow in vitro to better understand the physical mechanisms underlying LAI. METHODS: An Er:YAG laser was equipped with a novel cone-shaped tip with a lateral emission rate of approximately 80%. Laser light was emitted at a pulse energy of 30, 50, or 70 mJ (output energy: 11, 18, or 26 mJ) and a repetition rate of 1 or 20 pulses per second, without air or water spray. Fluid flow dynamics in a root canal model were observed by using glass-bead tracers under a high-speed camera. Moreover, laser-induced bubble patterns were visualized in both free water and the root canal model. RESULTS: Tracers revealed high-speed motion of the fluid. A full cycle of expansion and implosion of vapor and secondary cavitation bubbles were clearly observed. In free water, the vapor bubble expanded for 220 microseconds, and its shape resembled that of an apple. In the root canal model, the vapor bubble expanded in a vertical direction along the canal wall, and bubble expansion continued for >=700 microseconds. Furthermore, cavitation bubbles were created much more frequently in the canal model than in free water. CONCLUSIONS: These results suggest that the cleaning mechanism of an Er:YAG laser within the root canal might depend on rapid fluid motion caused by expansion and implosion of laser-induced bubbles. PMID- 21787502 TI - pH, calcium ion release, and setting time of an experimental mineral trioxide aggregate-based root canal sealer. AB - INTRODUCTION: An experimental mineral trioxide aggregate sealer (MTAS) has been developed for use as a root canal sealer. The aim of this study was to evaluate the setting time, pH, and calcium ion release of MTAS compared with white Portland cement (CPB-40; Votorantin Cimentos, Camargo Correa SA, Pedro Leopoldo, MG, Brazil), white MTA Angelus (MTA; Angelus, Londrina, PR, Brazil), and AH Plus (Dentsply DeTrey, Konstanz, Germany). METHODS: For the evaluation of setting time, each material was analyzed using Gilmore-type needles. Polyethylene tubes with the materials were immersed in distilled water for the measurement of pH (digital pH meter) and calcium release (atomic absorption spectrophotometry). The evaluations were performed at 3, 6, 12, 24, and 48 hours and 7, 14, and 28 days. Data were analyzed by analysis of variance and the Tukey test at 5% significance level. RESULTS: MTAS showed higher calcium release at all experimental periods, a greater increase in pH up to 48 hours and the longest setting time. CONCLUSIONS: MTAS presented favorable properties for its indication as a root canal sealer. PMID- 21787503 TI - Comparison of two techniques for assessing the shaping efficacy of repeatedly used nickel-titanium rotary instruments. AB - INTRODUCTION: The shaping capacity of nickel-titanium (NiTi) rotary instruments is often assessed by photographic or micro-computed tomography (micro-CT) measurements, and these instruments are often used more than once clinically. This study was conducted to compare photographic and micro-CT measurements and to assess if the repeated use of NiTi instruments affected the shape of canal preparation. METHODS: Ten new sets of ProTaper Universal instruments (Dentsply Maillefer, Ballaigues, Switzerland) were used in 60 resin blocks simulating curved root canals. Groups 1 to 6 (n=10) represented the first to sixth use of the instrument, respectively. Digitized images of the prepared blocks were taken in both mesiodistal (MD) and buccolingual (BL) directions and area measurements (mm(2)) were calculated using AutoCAD (Autodesk Inc, San Rafael, CA). The volumes of the same prepared canals were measured using micro-CT (mm(3)). Statistical analysis was performed to detect differences between photographic and volumetric measurements and differences between uses. RESULTS: Two-way repeated-measures analysis of variance revealed significant differences between groups (P < .001). Regarding measurement type, there were no significant differences between BL and MD measurements, but there were significant differences between micro-CT and BL measurements (P < .001) and micro-CT and MD measurements (P=.001). Significant differences were also noted between uses. CONCLUSIONS: Within the limitations of the present study, micro-CT scanning is more discriminative of the changes in canal space associated with repeated instrument use than photographic measurements. Canal preparations are significantly smaller after the third use of the same instrument. PMID- 21787504 TI - Effects of a novel hydration accelerant on the biological and mechanical properties of white mineral trioxide aggregate. AB - INTRODUCTION: The objective of this study was to investigate the antibacterial, biocompatibility, and mechanical properties of mineral trioxide aggregate (MTA) set using a calcium lactate gluconate (CLG) solution. METHODS: ProRoot white MTA (WMTA) (Dentsply Tulsa Dental, Tulsa, OK) was used as the control group; MTA-like cement was prepared by mixing Portland cement/bismuth oxide/calcium sulfate (75/20/5) as the experiment group. A solution of 23.1 wt% CLG was used as a hydration accelerant and was compared with deionized water (DDW). Changes in pH values, antibacterial properties, in vitro cell viability, and diametral tensile strength (DTS) of the hydrated cements were assessed. RESULTS: Like WMTA, pH values for the MTA-like cement set using DDW and the CLG solution showed minor but statistically significant differences (P < .05). The antibacterial effects of hydrated specimens set by DDW and CLG against Streptococcus mutans assessed with an in vitro tube dilution test showed a significant difference in the early hydration time but no significant difference after 60 minutes (P > .05). A mouse osteoblastic cell (MC3T3-E1)-based MTT assay revealed that WMTA set using CLG had significantly higher cell viability than that set using DDW (P < .05). The DTS test for hydrated MTA-like cement with different liquids showed a significant difference on day 1 but no statistical difference on day 21. CONCLUSIONS: The results suggest that using a CLG solution as the hydration accelerant may enhance the biocompatibility but not compromise WMTA's antibacterial and mechanical properties. PMID- 21787505 TI - Evaluation of photodynamic therapy using a light-emitting diode lamp against Enterococcus faecalis in extracted human teeth. AB - INTRODUCTION: Photodynamic therapy (PDT) with high-power lasers as the light source has been proven to be effective in disinfecting root canals. The aim of this study was to evaluate the antimicrobial effect of PDT using toluidine blue O (TBO) and a low-energy light-emitting diode (LED) lamp after the conventional disinfection protocol of 6% NaOCl. METHODS: Single-rooted extracted teeth were cleaned, shaped, and sealed at the apex before incubation with Enterococcus faecalis for 2 weeks. Roots were randomly assigned to five experimental groups and three control groups. Dentin shavings were collected from the root canals of all groups with a #50/.06 rotary file, colony-forming units were determined, and the bacterial survival rate was calculated for each treatment. RESULTS: The bacterial survival rate of the NaOCl/TBO/light group (0.1%) was significantly lower (P < .005) than the NaOCl (0.66%) and TBO/light groups (2.9%). CONCLUSIONS: PDT using TBO and a LED lamp has the potential to be used as an adjunctive antimicrobial procedure in conventional endodontic therapy. PMID- 21787506 TI - The effect of three rotational speed settings on torque and apical force with vortex rotary instruments in vitro. AB - INTRODUCTION: Both the number of rotations in curved canals and torque are related to fracture resistance of nickel-titanium rotaries via the respective mechanisms of brittle and flexural failure. Increased rotational speed (rotations per minute [RPM]) may lead to higher cutting ability and could overcompensate for increased fatigue. The impact of three RPM settings on peak torque (Nmm) and apically directed force (N) during root canal preparation were investigated in vitro. METHODS: S-shaped canals in plastic blocks (n = 12/group) were instrumented with Vortex rotaries (Dentsply Tulsa Dental, Tulsa, OK) sizes #15 to 30 with a .04 taper. Rotaries were used in a manufacturer-recommended sequence: #30, 25, and 20 in a crown-down approach progressively deeper into the canal, #15 to the working length, and apical enlargement with sizes 20 and 25 to WL. A total of 216 preparation procedures were performed using a custom testing platform. RPM was set at 200, 400, or 600; automated axial feed mirrored clinical handling, resulting in two in-and-out movements, each to preset insertion depths. Torque and apical force were continuously recorded and peak values statistically contrasted using analysis of variances. RESULTS: No file fractures were observed in any of the three experimental groups. Peak torques and forces varied by instrument size and were highest at 200 RPM for all sizes; torque and force were reduced by 32% and 48%, respectively, at 400 RPM (P < .001). Increasing RPM to 600 did not result in further reductions. The number of discernible peaks for torque (threshold: 0.3 Nmm) and force (threshold: 0.2 N) significantly decreased from 200 RPM to 400 RPM and did not decrease further with 600 RPM. CONCLUSIONS: Under the present experimental conditions, rotational speed had a significant impact on preparation with Vortex rotaries, with instruments at 400 RPM generating less torque and force compared with 200 RPM. PMID- 21787507 TI - A comparative study of the effects of three root-end filling materials on proliferation and adherence of human periodontal ligament fibroblasts. AB - INTRODUCTION: The present in vitro study was conducted with the aim of evaluating and comparing the cytotoxic effects of three root-end filling materials, ProRoot mineral trioxide aggregate (ProRoot MTA; Dentsply Tulsa Dental, Memphis, TN), MTA Angelus (Angelus, Londrina, Brazil), and a modified zinc oxide-eugenol cement (Super-EBA; Bosworth Co, Skokie, IL) on human periodontal ligament (PDL) fibroblasts. METHODS: PDL cells were cultured in an mineral trioxide aggregate (MTA)- or a Super-EBA-conditioned medium to assess the viability as determined by the trypan blue exclusion assay. The proliferation of the cells was recorded, and the cellular morphology was observed by confocal microscopy. Moreover, PDL cell aggregates were cultured on the substrate surfaces to assess cell adhesion. RESULTS: ProRoot MTA was found to be the most biocompatible material, whereas Super-EBA was found to be the most cytotoxic material because it significantly inhibited the cell growth and adherence on its. In the presence of ProRoot MTA, the PDL cell proliferation was almost unaltered. MTA Angelus was found to be more cytotoxic than ProRoot MTA, offering, however, excellent scaffold properties for the adhesion of cell aggregates. CONCLUSIONS: Under the conditions of the present study, it seems that commercially available forms of MTA may behave in different ways regarding their proliferative effect on human PDL fibroblasts. ProRoot MTA appears to be the most biocompatible of the three tested materials when considering use for root-end endodontic microsurgery. PMID- 21787508 TI - Influence of root canal taper on its cleanliness: a scanning electron microscopic study. AB - INTRODUCTION: Taper is a factor that determines final root canal dimensions and, consequently, the dimensions of the space for the cleaning action of irrigants. Therefore, the aim of the present study was to investigate the influence of taper on root canal cleanliness. METHODS: Root canals of 45 mandibular incisors were divided into 3 groups and prepared with GT rotary files to apical preparation size 30 and final taper 0.04, 0.06, and 0.08, respectively. Irrigation with 2.5% NaOCl was performed after each file. The final irrigation sequence was 10 mL 17% ethylenediaminetetraacetic acid, followed by 10 mL 2.5% NaOCl and 10 mL saline solution. The presence of debris and smear layer on root canal walls was evaluated under the scanning electron microscope with the use of a 4-category scale system. RESULTS: The presence of debris was minimal in all groups. Statistical analysis for the presence of smear layer showed no significant differences between the groups, whereas a significant difference was detected between the apical and middle thirds of each group. CONCLUSIONS: Under the conditions of this study, root canal preparation with tapers 0.04, 0.06, or 0.08 did not affect canal cleanliness. Debris removal was almost complete for all tapers, whereas smear layer was not removed, especially from the apical part of the canals. PMID- 21787509 TI - Embolia cutis medicamentosa (Nicolau syndrome) after endodontic treatment: a case report. AB - INTRODUCTION: Embolia cutis medicamentosa (Nicolau syndrome) is a rare iatrogenic event of tissue necrosis after intramuscular or intraarticular application of cristalloid suspensions. Clinically, it presents as a livid discoloration of the skin, local pain, and signs of inflammation. METHODS: This article presents the first case of Nicolau syndrome after the endodontic application of calcium hydroxide paste into the distal root canal of tooth 18. The patient presented to the Department for Maxillofacial Surgery and hospitalized for several days. RESULTS: The application of calcium hydroxide paste led to a thrombosis of the inferior alveolar artery and various branches of the maxillary artery. A definite necrosis of the left-side infraorbital skin area and concomitant hypaesthesia of the infraorbital nerve and of the mental nerve were observed. CONCLUSIONS: Calcium hydroxide paste is appropriate for the medicamentous treatment of root canals, but is not suitable to stanch bleeding from periapical arteries. PMID- 21787510 TI - Mandibular first molar with six separate canals. AB - INTRODUCTION: Many anatomical variations can occur within the mandibular first molar. Commonly, 3-4 canals are located, but as many as 6-7 canals have been reported. METHODS: This report describes a case of a mandibular first molar with 6 separate canals (3 mesial and 3 distal) that was instrumented with conventional hand and rotary files and obturated by using a hybrid warm vertical compaction technique. RESULTS: Recall examination as far as 3 years post-treatment found no sensitivity to percussion or palpation and recall radiographs after treatment show resolution of the previous apical periodontitis. CONCLUSIONS: The existence of such teeth as these underlies the importance of looking for additional canals. PMID- 21787511 TI - Eight months of clinical experience with the Self-Adjusting File system. AB - INTRODUCTION: The Self-Adjusting File (SAF) system (ReDent-Nova, Ra'anana, Israel) has been recently introduced for the simultaneous instrumentation and irrigation of root canals. The SAF is claimed to adapt itself three dimensionally to the root canal, including its cross-section. It is operated with a continuous flow of sodium hypochlorite that is delivered into the root canal through the hollow file and claimed to be activated by sonic agitation of the irrigant. Our aim was to present for the first time clinical cases prepared with the SAF system and to describe a clinical classification of canals, according to their difficulty, with recommendations for endodontic treatment sequences for each category. METHODS: This report is based on the experience of a single endodontist, who used the system to treat more than 50 consecutive primary endodontic cases over the prior 8 months. RESULTS: A clinical classification was developed which enabled the operator to select a treatment protocol for easy and optimal glide path preparation to be effectively used with the SAF file in the various root canals encountered in the clinical environment. CONCLUSIONS: Clinical classification of canal difficulty makes root canal treatment sequences with the SAF simple and predictable. Many types of cases can be treated with the SAF system although a novice user is advised to advance slowly along the learning curve from simpler to more complicated canals. PMID- 21787514 TI - The 2011 IOM report on vitamin D and calcium requirements for north america: clinical implications for providers treating patients with low bone mineral density. AB - Vitamin D is an essential nutrient for skeletal mineralization and maintenance of bone mass. Most healthy individuals can meet their vitamin D requirements through dietary means, modest supplementation and solar exposure for short periods of time. The serum level of 25OHD that determines adequacy is 20 ng/ml, which corresponds with consumption of 6-800 IU of vitamin D per day, according to the Institute of Medicine review. There is still debate about whether higher doses of vitamin D are required for treating patients with osteoporosis. PMID- 21787515 TI - Vitamin D and common sense. PMID- 21787516 TI - Trends in dual-energy X-ray absorptiometry in the United States, 2000-2009. AB - After a decade of policies encouraging dual-energy X-ray absorptiometry (DXA) use, Medicare incrementally decreased reimbursement for non-facility-based DXAs, effective 2007. This study quantifies trends in central DXA use before and after the reimbursement change. Using 2000-2009 claims data, we selected subjects aged 50+yr with Medicare supplemental or commercial insurance. The central site DXA test (using CPT codes) rate was calculated within each calendar quarter as the number of patients with a DXA test divided by the total number of patients. Piecewise linear regression was used to quantify change in DXA rates coincident with the 2007 reimbursement reductions. During 2000-2009, slightly over 5 million DXA tests were conducted. Annual rates for females with Medicare steadily increased until 2007, when they leveled off; a similar pattern was observed for the commercially insured. Regression modeling showed that pre-2007 rates increased annually by 0.76% (0.72-0.80) and 0.76% (0.70-0.82) among those with Medicare supplemental and commercial insurance, respectively, and over 2007-2009, rates changed annually by +0.07% (-0.05% to 0.19%) and -0.12% (-0.29% to 0.04%), respectively. During 2007-2009, there were 3.1 (2.4-3.8) and 4.0 (3.1-4.9) fewer tests per 100 person years for females with Medicare supplemental and commercial insurance, respectively, than would have been expected based on the pre-2007 trend. The post-2007 DXA rate was lower than what would have been expected had the observed trend of increasing annual DXA rates from 2000 to 2007 continued unabated beyond the Medicare reimbursement change in 2007. Continuing to provide access to DXA testing for women at increased risk of osteoporosis is important to providing high-quality care for metabolic bone disease in the United States. PMID- 21787518 TI - Quantitative ultrasound normative reference data for community-dwelling white and black females in the United States. AB - Quantitative ultrasound (QUS) race-specific normative reference data are not available for accurate calculation of Z-scores. The primary aims of this study were (1) to develop a race-specific QUS reference database for white and black females and to compare estimated fracture risk between these 2 racial groups and (2) to compare stiffness index (SI) values of white females in this study to manufacturer-obtained values. Subjects included 1111 females (31% black), aged 20 85 yr (52 +/- 19 yr), with a mean SI score of 93.7 +/- 20.1. White females, aged 20-39 yr (n=213), were used to calculate T-scores, whereas Z-scores were age and race specific. Black females had significantly higher SI scores than white females (p<0.001). White females aged 50+ yr in this study had significantly higher SI scores compared with manufacturer-derived values. Results highlight the need for population- and race-specific normative data when using QUS as a screening tool for identifying high fracture risk. PMID- 21787517 TI - Long-term versus short-term precision of dual-energy X-ray absorptiometry scans and the impact on interpreting change in bone mineral density at follow-up. AB - We hypothesized that increased time between repeat scans would be a critical factor resulting in long-term precision (LTP) being greater than short-term precision (STP) because time erases the short-term mind's eye memory of positioning that makes STP easy to perform. In 2 prospective studies, STP, in which repeat scans were performed within minutes, was compared with LTP in the same patients in whom repeat scans were separated by 3-10 d (n=35) or 2-12 mo (n=30). The first baseline scan and the follow-up scan were used to calculate LTP. Rigorous exclusion criteria were applied to patients returning 2-12 mo after baseline to avoid the effects of biological change that could affect bone mineral density (e.g., bisphosphonate treatment). Results showed that LTP was significantly greater than STP irrespective of whether the interval between baseline was short (3-10d) or averaged 188 d. For example, LTP for left femoral neck (LFN) was 0.017 g/cm(2) with 3-10d separating follow-up from baseline, with STP being 0.007 g/cm(2) (duplicate scans at baseline, Day 1). For the second prospective cohort, LTP for LFN when the mean follow-up interval was 188 d was 0.024 g/cm(2); STP in the same patients was 0.009 g/cm(2) (p<0.05 by F test). A sampling of patients returning for follow-up to an osteoporosis clinic was used to evaluate the impact of using LTP vs STP to interpret change. The use of a least significant change value based on LTP (rather than STP) resulted in significantly fewer patients having "significant" change at follow-up and eliminated discrepancies in which BMD apparently increased at 1 skeletal site but decreased at another. We conclude that (1) time is the primary variable accounting for the difference between STP and LTP, and (2) STP underestimates true dual-energy X-ray absorptiometry variability, resulting in overdiagnosis of change at follow-up. PMID- 21787573 TI - Developmental immunotoxicity and the importance of controlling for litter effects. PMID- 21787574 TI - Frequency of chromosomal aberrations in peripheral lymphocytes of tannery workers in Brazil. AB - To evaluate the incidence of chromosomal aberrations (CA) in peripheral lymphocytes of workers chronically exposed to chemical hazards in a tannery in Franca, Sao Paulo, Brazil. The exposed group consisted of 10 male workers employed in the same tannery. The duration of work in the tannery ranged from 5 months to 14 years. The control group consisted of 10 males without a history of exposure to chemicals or other potentially genotoxic substances. A total of 100 well-spread metaphases were analyzed per subject. The frequency of CA was higher in the exposed group than in the control group. Smoking had a significant effect on the frequency of CA in both the control and the exposed groups. Chronic occupational exposure of tannery workers represents a relevant risk factor for the development of diseases associated with genetic damage. PMID- 21787575 TI - Mercury distribution in neonatal rat brain after intrauterine methylmercury exposure. AB - Methylmercuric chloride (MMC) was orally administered to pregnant Wistar rats from gestational day 6 (G6) for 5 consecutive days. After delivery, the neonatal rats were decapitated and the cerebrum, cerebellum and hippocampus were excised on postnatal day (PND) 1, 7, 14, 21, 30 to determine total Hg contents and concentrations (six per stage). Both total Hg contents and concentrations in all the three regions increased as exposure dose increased and declined as postnatal time prolonged. Interestingly, differences of total Hg content between cerebrum and hippocampus at each time-point were significant (P<0.05). In the meantime, considering the Hg concentration, while no differences were observed before PND14 (P<0.05) among the three regions, Hg concentration in hippocampus was significantly higher than in cerebrum after that time period (P<0.05). We demonstrated that MeHg could pass through the placental and blood-brain barriers in a dose-dependent manner. Moreover, we found mercury redistribution occurred in offspring brain following the prolongation of postnatal time. The hippocampus was the major target of MeHg accumulation. PMID- 21787576 TI - Myricetin suppresses oxidative stress-induced cell damage via both direct and indirect antioxidant action. AB - We evaluated the cytoprotective effect of myricetin on oxidative stress damaged cells by assessment of the scavenging effect of reactive oxygen species (ROS) and the activities of antioxidant enzymes. Myricetin showed the scavenging effect of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals on intracellular ROS. In addition, myricetin restored the activity and protein expression of cellular antioxidant defense enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) reduced by hydrogen peroxide (H(2)O(2)) treatment. H(2)O(2)-induced cellular DNA and lipid damages, and myricetin was found to prevent the DNA damage shown by inhibition of DNA tail and it decreased nuclear phospho-histone H2A.X expression, which are both markers for DNA strand breakage. Membrane lipid peroxidation was also attenuated as shown by inhibition of TBARS formation and of fluorescence intensity of diphenyl-1-pyrenylphosphine (DPPP). These results suggest that myricetin protects cells against H(2)O(2)-induced cell damage via inhibition of ROS generation and activation of antioxidant enzymes. PMID- 21787577 TI - Xenobiotic metabolism of bank vole (Myodes glareolus) exposed to PCDDs. AB - Previous studies in bank vole (Myodes glareolus) and field vole (Microtus agrestis) living at the old sawmill area contaminated by chlorinated dibenzo-p dioxins and -furans (PCDD/Fs) showed that these two relatively close species have a significant difference in their body burden of PCDD/Fs, bank voles having significantly higher concentrations. The aim of this study was to clarify more comprehensively the basic xenobiotic metabolism in wild bank voles and examine whether PCDD exposure would affect xenobiotic metabolism in bank voles more generally. The activity of cytochrome P450 enzymes was studied by fluorometric analyzes as well as by the aid of an earlier developed N-in-one CYP-selective activity cocktail, and immunoblotting assay. Several CYP-associated activities were considerably and statistically significantly elevated in the liver of animals living in the contaminated area. Increases in several CYP1A- and CYP2A/B associated activities are probably due to the exposure to variable dioxin- and PCB-class inducers. The results of this comprehensive screening seemed to be in agreement with the existing knowledge of CYP enzyme induction by dioxin-like substances. PMID- 21787578 TI - Neurotoxic effect of the herbicide paraquat on ascidian larvae. AB - Paraquat is an herbicide widely used in agriculture, that proved to have toxic effect on many animal models. Moreover, it is considered a potential etiologic factor of Parkinson's disease. Ascidians are invertebrate chordates, whose larval central nervous system shares basic structural homologies with the vertebrate one. Ascidian larvae exposed to paraquat developed specific alterations of the CNS, that were characterized by histological and immunohistochemical analysis. Tyrosine hydroxylase (TH) expression was examined by "in situ" hybridization. A decrease of dopamine content in anterior CNS of treated larvae was observed. In combined treatments with paraquat and l-ascorbic acid, a common anti-oxidant, the severity of the malformations was significantly reduced, confirming that the oxidative stress is involved in the toxicity mechanism of paraquat on ascidians. For its sensitivity to paraquat and its simple chordate body plan, ascidian larva is a promising animal model to further investigate the molecular mechanism of paraquat neurotoxicity. PMID- 21787579 TI - High-dose dibutyl phthalate improves performance of F1 generation male rats in spatial learning and increases hippocampal BDNF expression independent on p-CREB immunocontent. AB - Dibutyl phthalate (DBP), an important representative of endocrine disrupting chemical, is suspected of affecting the cognitive function of humans and animals. In this study, effects of DBP on maze performance in male rats were evaluated by spatial learning tasks; the effects of DBP on the expression of brain-derived neurotrophic factor (BDNF) were also analyzed in both mRNA and mature protein levels in the hippocampus, with intent to investigate the possible mechanism underlying the behavioral findings. Pregnant Wistar rats were treated orally by gavage with 0, 25, 75, 225 and 675mgDBP/kgBW/day from gestational day (GD) 6 to postnatal day (PND) 21, and then the weaned offspring continued receiving the same treatment till PND 28. We found that male pups treated with high-dose DBP showed enhancement in spatial acquisition in a Morris water maze during PNDs 30 33, and displayed better retention of spatial memory in a probe trial after a reverse trail during PNDs 60-62. Real-time PCR and western blotting analysis of the hippocampus from DBP-treated male rats on PND 21 revealed an increase in BDNF expression, compared to the vehicle-matched control. BDNF variant III, a transcription promoted by active CREB (i.e. p-CREB), as well as the immunocontent of p-CREB, was scarcely altered by the treatment. Our results suggest that developmental treatment with high-dose DBP improves spatial memory in male rats, and this effect may be related to an increase in BDNF expression in the hippocampus in a p-CREB independent route. PMID- 21787580 TI - Diclofenac-enriched artificial sediment induces oxidative stress in Hyalella azteca. AB - Diclofenac is a nonsteroidal anti-inflammatory drug widely used in Mexico where it is sold over the counter. It enters water bodies through municipal and industrial discharges, posing a risk to water systems and aquatic organisms. Diclofenac-enriched artificial sediment was used to evaluate the toxicity of this pharmaceutical on the sentinel species Hyalella azteca, using oxidative stress biomarkers in order to determine if the set of tests used in this study is a suitable early damage biomarker. The median lethal concentration (72-h LC(50)) was determined and oxidative stress was evaluated using lipid peroxidation, protein carbonyl content to evaluate oxidized protein content, and the activity of superoxide dismutase, catalase, and glutathione peroxidase. All biomarkers were significantly altered. Diclofenac induces oxidative stress in H. azteca and the set of tests used (lipid peroxidation, protein carbonyl content, antioxidant enzyme activities) constitutes an adequate early damage biomarker for evaluating the toxicity of this pharmaceutical group in aquatic species. PMID- 21787581 TI - Influence of cypermethrin toxicity on ionic regulation and gill Na(+)/K(+)-ATPase activity of a freshwater teleost fish Cyprinus carpio. AB - The effects of acute and sublethal toxicity of cypermethrin, a synthetic pyrethroid insecticide on plasma electrolytes (Na(+), K(+) and Cl(-)) levels and gill Na(+)/K(+)-ATPase activity in a common carp Cyprinus carpio were examined. The 24h LC(50) value of cypermethrin for C. carpio was 1.86ppm. During acute exposure, cypermethrin caused adverse effects in the form of hyponatreima, hypokalemia and hypochloremia and inhibition of gill Na(+)/K(+)-ATPase activity. In sublethal exposure to cypermethrin (0.186ppm for 35 days), plasma Na(+) was decreased throughout the exposure period except 7th day whereas plasma K(+) level was increased up to 28th day, then declined. However, plasma Cl(-) level was decreased. Likewise, gill Na(+)/K(+)-ATPase activity was decreased as the exposure period extended. The present study indicates that cypermethrin was highly toxic to freshwater fish and ion levels in blood as measured by specific ion concentrations (Na(+), K(+) and Cl(-)) and changes in gill Na(+)/K(+)-ATPase activity may represent a sensitive and useful nonspecific biomarkers of chemical exposure and effects. PMID- 21787582 TI - Inhibitory effect of morin on DMH-induced biochemical changes and aberrant crypt foci formation in experimental colon carcinogenesis. AB - Morin is a flavonoid present in fruits and Chinese herbs, exhibits various beneficial biological activities. There are numerous evidence suggesting that total dietary fat intake is generally associated with early promotion of colon cancer, the alterations in the lipid profile is important for malignant transformation and tumor development and carbohydrate moieties of glycoproteins reflect the stage of cancer. Aberrant crypt foci (ACF) consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancer. Our aim was to study the inhibitory effect morin on aberrant crypt foci and alterations in the levels of lipids, and glycoconjugates in experimental rat colon cancer. Group 1 served as control, groups 2 and 4 received 50mg/kg b.w. morin orally everyday for 30 weeks. Groups 3 and 4 were given subcutaneous injection of 1,2-dimethylhydrazine (DMH) 20mg/kg b.w. for the first 15 weeks. Administration of morin at the dose of 50mg/kg b.w., significantly suppressed the formation of ACF its multiplicity and lowered levels of serum and tissue lipids, cholesterol-phospholipid ratio, glycoconjugate and also increased the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase). These results indicate that morin has a protective effect against DMH-induced colon carcinogenesis. PMID- 21787583 TI - Bioenergetics and DNA alteration of normal human fibroblasts by hexavalent chromium. AB - The effects of hexavalent chromium on mitochondria of normal human fibroblasts were investigated through the measurement of oxygen consumption, and its genotoxic effect through the analysis of chromium DNA adducts and oxidative DNA lesions. ROS production was also quantified. Chromium diminished oxygen consumption by cells in a concentration-dependent manner (IC(50)=66+/-8MUM). This effect can be attributed to an alteration in mitochondrial functions, leading to defective glucose catabolism. The Comet assay, performed with and without the lesion-specific enzyme formamidopyrimidine-DNA glycosylase (Fpg), highlighted the extent of oxidative DNA base damage. DNA base damage was induced with low concentrations (0.5-3MUM) of Cr(VI), whereas bioenergetic disturbance was only observed at higher concentrations (20-500MUM). PMID- 21787584 TI - Protective effect of Corchorus olitorius leaves against arsenic-induced oxidative stress in rat brain. AB - The present study was undertaken to evaluate the protective effect of an aqueous extract of Corchorus olitorius leaves (AECO) against NaAsO(2) induced brain toxicity in experimental rats. The animals exposed to NaAsO(2) (10mg/kg, p.o.) for 10 days exhibited a significant inhibition (p<0.01) of superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase and reduced glutathione levels in rat brain. In addition, the toxin increased (p<0.01) the levels of oxidized glutathione and thiobarbituric acid reactive substances in the brain tissue of experimental rats. Treatment with AECO (50 and 100mg/kg, p.o.) for 15 days prior to arsenic intoxication significantly improved antioxidant markers in a dose dependant manner. Histological studies on the ultrastructural changes of brain tissue supported the protective activity of the AECO. The results suggest that treatment with AECO prior to arsenic intoxication has a significant role in protecting animals from arsenic-induced toxicity. PMID- 21787585 TI - Role of vitamin E in preventing acute mercury toxicity in rat. AB - We have examined the effect of both pre- and post-treatment of vitamin E on mercury induced acute toxicity in rats. Mercury (12MUmol/kg b.w., single intraperitoneal injection) resulted in oxidative injury and metallothionein mRNA expression together with alterations in tissue histology and accumulation of mercury in the body organs. The ameliorating potential of vitamin E (24MUmol/kg b.w., single intraperitoneal injection) was observed in mercury administered rats. Our findings indicate that vitamin E provides complete protection from mercury toxicity in the liver with both pre- and post-treatments. As mercury is nephrotoxic and neurotoxic, it is interesting to note that post-treatment of vitamin E showed more protection in the kidney compared to pre-treatment. In brain tissue, partial protection was observed on oxidative stress parameters. Our results thus suggest that post-treatment with vitamin E could be more beneficial than pre- treatment in mercury intoxication. PMID- 21787586 TI - Response of human DNA polymerase iota promoter to N-methyl-N'-nitro-N nitrosoguanidine. AB - Human Pol iota is a highly distributed, low-fidelity DNA polymerase lacking intrinsic exonuclease proofreading activity, thus its effects are strictly regulated. We predicted and cloned the promoter region of the human POLI gene. Successively, by transfection of deletion constructs of the POLI promoter, we demonstrated that the regions -848/-408 and -30/+215 contained positive regulatory elements, and the region +215/+335 had proximal promoter activity. Overexpression of Sp1 significantly increased the transcriptional activity of the promoter, and mutation of the Sp1 site reversed Sp1-induced promoter transactivation. Quantitative RT-PCR showed that POLI mRNA expression was up regulated in human amnion FL cells treated by the carcinogen N-methyl-N'-nitro-N nitrosoguanidine (MNNG). Reporter gene assays demonstrated that MNNG also significantly increased the transcriptional activity of the predicted promoter ( 848/+335) and the proximal promoter (+215/+335). However, the promoter with the Sp1 site mutation had no response to MNNG treatment, suggesting that Sp1 plays an important role in the transcriptional regulation of the POLI gene stimulated by MNNG. Our data suggest that abnormal regulation of Pol iota may be involved in the mutagenesis and carcinogenesis induced by environmental chemicals. PMID- 21787587 TI - Effects of maternal cadmium administration on development of monoaminergic, GABAergic and glutamatergic systems. AB - The effects of maternal exposure to 10mgCd/l (as cadmium acetate) in drinking water during gestation and lactation on the development of monoaminergic and aminoacidergic systems were studied in discrete brain areas of the pups: striatum, cerebral cortex, dorsal hippocampus and basal-medial hypothalamus. Hippocampal levels of serotonin and 5-hydroxyindolacetic acid were significantly reduced in rats exposed to Cd whereas the dopamine content was not significantly affected by Cd. Glutamate concentration decreased in hypothalamus and increased in hippocampus, while gamma-aminobutiric acid content decreased only in cerebral cortex. The present results demonstrate that maternal exposure to 10mg/l of Cd leads to neurochemical disturbances on serotoninergic and aminoacidergic systems during development. PMID- 21787588 TI - Histopathological and proteomic analysis of hepatic tissue from adult male zebrafish exposed to 17beta-estradiol. AB - 17beta-Estradiol (E2) is known to contribute significantly a large extent to the estrogenicity in aquatic system. In the present study, two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MALDI-TOF-TOF MS), combined with histopathological analysis, was used to screen hepatic responses in adult male zebrafish. Eight proteins were found to be up-regulated more than 2-fold, whereas five protein spots were down-regulated more than 2-fold after 1nM E2 treatment for 14 days, which had caused histological effects in zebrafish livers. These differentially expressed proteins accounted for a variety of cellular biological processes, such as response to oxidative stress, cell surface receptor-linked signal transduction, oxidation-reduction and cellular calcium ion homeostasis. The results demonstrated that E2 comprehensively influenced a variety of cellular and biological processes in zebrafish. Moreover, the proteomic responses elicited in zebrafish allow us to better understand the underlying mechanisms of endocrine disrupting chemicals (EDCs)-induced toxicity fully. PMID- 21787589 TI - Role of micronutrients against dimethylmercury intoxication in male rats. AB - Mercury is one of the most toxic non-radioactive heavy metals. Chelation therapy has been the basis for the medical treatment of mercury poisoning. Male albino rats were administered dimethylmercury (1.5mg/kg) orally for 21 days. Chelation therapy with N-acetyl cysteine along with combination of antioxidants viz. zinc and selenium was given for 5 days after 24h of toxicant administration. All animals were sacrificed after 48h of last treatment and various blood biochemical parameters were performed. Toxicant caused rise in bilirubin, gamma-GT, cholesterol, triglycerides, urea, creatinine, the uric acid content with a decline in albumin. A significant elevation was observed in LPO content and mercury concentration, along with concomitant decline in GSH levels after toxicant administration in liver, kidney and brain. Noticeable fall was also observed in AChE enzyme. Histopathological analysis was consistent with the biochemical observations and led to conclude that combination therapy provided protection against mercury toxicity. PMID- 21787590 TI - Oxidative and nitrosative stress in experimental rat liver fibrosis: Protective effect of taurine. AB - Taurine (TAU) has protective effects on experimental liver fibrosis. The present study investigates whether benefits of TAU are mediated through attenuation of oxidative and nitrosative stresses. Liver fibrosis was induced in male Wistar rats by simultaneous administration of iron (0.5%, w/w) and ethanol (6g/kg/day) for 60 days consecutively. Significant increases in thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides, protein carbonyl content and loss of non-protein, protein and total thiols were observed in the liver of iron plus alcohol-fed rats. Nitrosative stress was marked by increased levels of S nitrosothiols and decreased nitrite content. Accumulation of nitrated and oxidatively modified proteins in liver was further evidenced by immunohistochemical localization with specific antibodies for 4-hydroxynonenol (4 HNE), 3-nitrotyrosine (3-NT) and dinitrophenol (DNP). Decrease in mitochondrial ion-transport enzymes and disturbances in calcium and iron levels were also observed in these rats. TAU administration (2% (w/v) in drinking water) significantly reduced the levels of lipid hydroperoxides, TBARS, protein carbonyl with concomitant elevation in thiol levels. The presence of 4-HNE, 3-NT and DNP protein adducts was minimal. TAU also improved mitochondrial enzyme activities and regulated iron and calcium levels. These results show that the restorative effect of taurine in fibrosis involves amelioration of protein and lipid damage by decreasing oxidative and nitrosative stresses. PMID- 21787591 TI - The effects of maternal exposure to food additive E341 (tricalcium phosphate) on foetal development of rats. AB - E341 (tricalcium phosphate) (TCP) is commonly used as a food additive and also as a nutritional supplement. To evaluate the possible developmental effects, female Wistar rats were treated with E341 (TCP) by oral gavage during pregnancy. There were three groups of each containing five rats. Rats in Groups I-III were fed with standard diet, oil and E341 (TCP) 175mg/kg body weight during gestation days (GD 0-20) respectively. We assessed foetal body lengths and weights and also made morphometric examination of placenta and umbilical cord. The placental weights of E341 (TCP) group (Group III) were found to be decreased statistically. According to skeletal stainings of foetuses, lengths of left ulna (28.3%), right femur (29.8%), left femur (34.9%) and diameter of the skull of y-axis were significantly decreased (12.3%) in E341 (TCP) treatment groups. There was an increase in trans-umbilical diameter in treatment group (14%). This is the first study in which developmental effects of E341 (TCP) have ever evaluated. The results suggest that prenatal development of rats during gestation is sensitive to E341 (TCP) exposure. PMID- 21787592 TI - Humic acid enhances the cytotoxic effects of arsenic trioxide on human cervical cancer cells. AB - Cervical cancer is the second leading cancer affecting women, and recent studies have demonstrated arsenic trioxide (As(2)O(3)) has therapeutic effects on cervical cancer by promoting apoptosis and inhibiting metastasis in vitro and in vivo. Humic acid (HA) possesses various pharmacologic properties, including anti inflammatory, anti-neoplastic, and anti-proliferative effects by inducing apoptosis. We examined the growth inhibition properties and the combined effects of HA and As(2)O(3) in human cervical adenocarcinoma cell lines. Our results shown both As(2)O(3) and HA-induced inhibition of cell growth, most likely by ROS mediated cell damage and activation of the apoptosis pathway, and HA enhanced the anti-proliferative action of As(2)O(3) in HeLa and SiHa cells, which reduced the LC(50) about 57.62 or 73.52% (300MUg HA/mL) to 83.67 or 79.03% (500MUg HA/mL), respectively. This study is relevant to the development of chemotherapeutic approaches using As(2)O(3) in treating human cervical cancer. PMID- 21787593 TI - CYP1A1 and CYP3A4 polymorphic variations in Delhi population of Northern India. AB - Cytochrome P450 (CYP) 1A1 and CYP3A4 are important phase I xenobiotic metabolizing enzymes involved in the metabolism of numbers of toxins, endogenous hormones and pharmaceutical drugs. Polymorphisms in these phase I genes can alter enzyme activity and are known to be associated with cancer susceptibility related to environmental toxins and hormone exposure. Their genotypes may also display ethnicity dependent population frequencies. The present study was aimed to determine the frequencies of commonly known functional polymorphisms of CYP1A1 and CYP3A4 in North Indian population. Allelic frequency of CYP1A1 polymorphisms, m1, m2 and m4 were observed to be 40.3, 31.2 and 0% respectively. Frequency of CYP3A4*1B polymorphism was 0%. We observed inter as well as intra ethnic variation in the distribution of frequency of these polymorphisms. Analysis of polymorphisms in these genes might help in predicting the risk of cancer. Our results emphasize the need for more such studies in "high risk populations". PMID- 21787594 TI - In vitro toxicity of silica nanoparticles in myocardial cells. AB - In the present study, toxicities of silica nanoparticles with sizes of 21 and 48nm were assessed in myocardial H9c2(2-1) cells using the methylthiazolyldiphenyl-tetrazolium bromide reduction and lactate dehydrogenase assays. Cell injuries were characterized by morphological changes using hematoxylin and eosin staining. Reactive oxygen species, malondialdehyde and glutathione were measured to evaluate the levels of oxidative stress. To elucidate mechanisms, cell cycle distributions and the expressions of p53, p21 and Bax were also analyzed. Results showed that silica nanoparticles produced cytotoxicities in size, dose (0.1-1.6mg/ml) and time (12, 24, 36 and 48h exposure) dependent manners. Moreover, the particles caused oxidative stress, induced G1 phase arrest and upregulated levels of p53 and p21. Taken together, these data suggested that cell injuries were triggered by the generation of oxidative stress; p53 and p21 mediated G1 phase arrest is a potential mechanistic pathway of silica nanoparticles induced damage in H9c2(2-1) cells. PMID- 21787595 TI - Blood selenium, glutathione peroxidase activity and antioxidant supplementation of subjects exposed to arsenic via drinking water. AB - This work investigated serum selenium (Se) and glutathione peroxidase (GPx) levels in 25 Croatian subjects exposed to high levels of As from drinking water (median As level in urine: 620.74MUg/g creatinine) and 25 controls (32.98MUg/g creatinine). The exposed group had lower (p<0.001) median serum Se and GPx levels (Se: 82.34MUg/l vs 59.02MUg/l; GPx: 45.99U/g hemoglobin vs 38.38U/g hemoglobin). A subsample of 20 exposed subjects took part in a 2-month antioxidant supplementation trial which increased median GPx activity from 30.71 to 40.98U/g hemoglobin (p=0.041) and reduced total urinary As median from 680.15 to 501.96MUg/g creatinine (p=0.051). The effect of selected catalase (-262C>T) and GPx1 (-593C>T) gene polymorphisms was also examined. The low Se status and GPx activity may heighten risk of adverse health effects, especially in genetically predisposed individuals. The outcome of antioxidant treatment indicates modulation of As metabolism and oxidative stress, relevance of which needs further research. PMID- 21787596 TI - Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells. AB - Oxidative stress is a known mechanism induced, among other things, by arsenic toxicity. As a response, the cell triggers the synthesis of antioxidant and stress response elements like glutathione and heme oxygenase. Alpha-lipoic acid (ALA) is a well-known antioxidant that confers protection to oxidative stress conditions. We analyzed the effect of ALA pretreatment on Nrf2-responsive gene expression of HepG2 cells exposed to As(3+). Cells were treated with 5mM ALA and 8h later exposed to 50MUM As(3+) for 24h, analyzing MTT-activity, glutathione content, Nrf2 induction and antioxidant gene expression. As(3+) increased glutathione (154%), heme oxygenase, glutamate cystein ligase, modifier subunit and metallothionein (35-fold, 10-fold and 9-fold, respectively). ALA prevented the strong expression of heme oxygenase by As(3+) exposure (from 35- to 5-times of control cells), which correlated with the reduction of Nrf2 observed in As(3+) group. ALA pretreatment can down-modulate the response mediated by Nrf2 and provide protection to As(3+) exposed HepG2 cells. PMID- 21787597 TI - Chemical characterisation and cytotoxic effects in A549 cells of urban-air PM10 collected in Torino, Italy. AB - Human type II alveolar cells (A549) were exposed to aqueous- and organic-solvent PM10 extracts to evaluate their effects on cell proliferation, proinflammatory cytokine release and cytotoxicity (assayed by lactate dehydrogenase, LDH, activity). PM10 samples collected in Torino (northwest Italy) were analysed for inorganic chemical species (bioavailable iron and secondary particulates) and endotoxins, which are potentially inflammatory promoters in human airways. During the sampling period, PM10 concentration was 55.4+/-39.1MUg/m(3), secondary particles constituted 42+/-9% of the PM10 total mass, and bioavailable iron concentration was 0.078+/-0.095MUg/m(3). PM10 inhibits cell proliferation and induces both IL-6 and LDH release in a dose- and time-dependent manner, with a seasonal trend. The different effects of aqueous and organic PM10 extracts demonstrate the importance of particle composition for the induction of cytotoxic effects on A549 cells. A first comparison between the biological effects induced by PM10 extracts and PM10 components was performed. PMID- 21787598 TI - Quercetin protects rat liver against lead-induced oxidative stress and apoptosis. AB - Quercetin, a flavonoid, effectively improved the lead-induced histology changes including structure damage and leukocyte infiltration in rat liver. The present study was designed to explore the protective mechanism of quercetin against lead induced hepatic injury. We found that quercetin markedly decreased the MDA and H(2)O(2) levels and lowered the GSH/GSSG ratio in the liver of lead-treated rat. Moreover, quercetin markedly restored Cu/Zn-SOD, Mn-SOD, CAT and GPx activities and upregulated mRNA expression levels of these proteins in the liver of lead treated rat. Western blot analysis showed that quercetin significantly inhibited apoptosis by modulating the ratio of Bax to Bcl-2 expression and suppressing the expression of phosphorylated JNK1/2 and cleaved caspase-3 in the liver of lead treated rat. In conclusion, these data suggest that quercetin protects the rat liver from lead-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and inhibiting apoptosis. PMID- 21787599 TI - Ecotoxicological investigation of CeO(2) and TiO(2) nanoparticles on the soil nematode Caenorhabditis elegans using gene expression, growth, fertility, and survival as endpoints. AB - In this study, the potential harmful effect of cerium dioxide (CeO(2)), and titanium dioxide (TiO(2)) nanoparticles on the environment was investigated using Caenorhabditis elegans ecotoxicity tests. Multiple toxic endpoints, such as stress-response gene expression, growth, fertility, and survival, were analyzed in C. elegans, in response to the CeO(2) and TiO(2) exposure. To investigate relationship between sizes of nanoparticles and toxicity, C. elegans were exposed to nanoparticles to the different sizes of nanoparticles (15, 45nm for CeO(2) and 7, 20nm for TiO(2)). An increase in the expression of the cyp35a2 gene, decrease in fertility and survival parameters were observed in the 15 and 45nm of CeO(2) and in the 7nm of TiO(2) nanoparticles exposed to C. elegans. Gene knock-down experiment using RNA interference (RNAi) suggested that physiological level disturbances may be related with the cyp35a2 gene expression. Smaller sized nanoparticles (7nm of TiO(2) and 15nm of CeO(2)) seemed to be more toxic than larger sized ones (20nm of TiO(2) and 45nm of CeO(2)) on the observed toxicity. The size-dependent effect in CeO(2) and TiO(2) nanoparticles-induced toxicity needs to be investigated under more detailed experimental settings with the various sizes of nanoparticles. Further studies on the mechanism by which CeO(2) and TiO(2) nanoparticles affect cyp35a2 gene expression, fertility, and survival are warranted to better understand the CeO(2) and TiO(2) nanoparticles-induced ecotoxicity in C. elegans, as are studies with the causal relationships between these parameters. Overall results suggest that CeO(2) and TiO(2) nanoparticles have a potential for provoking ecotoxicity on C. elegans and the data obtained from this study can comprise a contribution to knowledge of the ecotoxicology of nanoparticles in C. elegans, about which little data are available. PMID- 21787600 TI - Enhancement of FcERI-mediated degranulation response in the rat basophilic leukemia cell line RBL2H3 by the fluorosurfactants perfluorooctanoic acid and perfluorooctane sulfonate. AB - The effect of two fluorosurfactants, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), on degranulation of rat basophilic leukemia RBL2H3 cells was investigated. PFOA and PFOS promoted IgE-mediated release of granule components of RBL2H3 cells at 10-300MUM. At low concentrations (<30MUM), the fluorosurfactants failed to induce degranulation, but promoted IgE-mediated degranulation without affecting cell viability. The absence of extracellular Ca(2+) removed the promoting effect of the fluorosurfactants on IgE-mediated degranulation. On the other hand, the fluorosurfactants at high concentrations (>100MUM) induced release of granule components without IgE-mediated activation in parallel with cell death. Pretreatment of tetradecanoyl-phorbol-acetate, a protein kinase C activator, inhibited both the promoting effect of the fluorosurfactants at low concentration on IgE-mediated degranulation and cell death-associated granule component release by high concentration of the fluorosurfactants. These findings indicate that PFOA and PFOS affect granule component release of mast cells by two different mechanisms, namely enhancement of active degranulation machinery at low concentrations and cell lysis at high concentrations. PMID- 21787601 TI - Association study between sick building syndrome and polymorphisms of seven human detoxification genes in the Japanese. AB - Sick building syndrome (SBS) is a chronic disorder caused by exposure to diverse indoor environmental or chemical pollutants. This study examined the association between seven detoxification genes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTP1, and NAT2) and SBS in the Japanese population. One hundred eighty patients with SBS and 401 healthy controls were enrolled in this study. We examined the prevalence for total of eleven genetic polymorphisms of detoxification genes. However, no statistically significant differences in allele and genotype frequency distributions of eleven genetic polymorphisms of these detoxification genes were found between patients and controls. On this basis, we conclude that the polymorphisms that we assessed for the detoxification genes do not contribute to the etiology of SBS. PMID- 21787602 TI - Neurotoxic effects in patients poisoned with organophosphorus pesticides. AB - In this paper we review neurotoxic disorders appearing in patients poisoned with organophosphorus pesticides. These compounds cause four important neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP) and chronic organophosphate-induced neuropsychiatric disorder (COPIND). Compared to the cholinergic syndrome, that causes millions of cases of poisoning each year, other disorders involve much smaller numbers of patients. The review is focused on the neurotoxic effects appearing after acute and chronic exposure to organophosphates with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy. PMID- 21787603 TI - Effects of fish cytochromes P450 inducers and inhibitors on difloxacin N demethylation in kidney of Chinese idle (Ctenopharyngodon idellus). AB - Cytochromes P450 (CYPs) play key roles in drug metabolism which are widely distributed in kidney in aquatic organisms. CYP(s) mainly catalyzed the N demethylation reaction of difloxacin (DIF) biotransformation to sarafloxacin (SAR). However, limited information is available about CYP investigation in fish. In order to supply useful information on CYP(s) characterization for DIF N demethylation, the present study assessed the effects of fish potent CYP inducers and inhibitors on DIF N-demethylation and the inductive and inhibitive enzyme kinetics in kidney of Chinese idle (Ctenopharyngodon idellus) by reversed-phase high-performance liquid chromatography (RP-HPLC). Results demonstrated that the amounts of SAR formation pretreated by beta-naphthoflavone (BNF) increased by 1.1 fold and alpha-naphthoflavone (ANF) inhibited SAR formation level by 0.6-fold at the third day. Enzymatic parameters V(max) and Cl(int) of DIF N-demethylase were increased by 0.56- and 0.38-fold due to beta-naphthoflavone (BNF) pretreatment. DIF N-demethylation inhibition by varying ANF concentrations represented a mixed type inhibition with the value of the inhibition constants (K(i)) 12.9mg/kg. BNF and ANF are the separate typical inducer and inhibitor for CYP1A in fish. Thus, we suggest that CYP1A may be responsible for DIF N-demethylation in kidney. This study provides instructive information to ensure treatment success in fisheries medication with two or more drugs. PMID- 21787604 TI - Evaluation of lead and mercury neurotoxic health risk by resident children in the Obuasi municipality, Ghana. AB - This study assesses neurotoxic effects associated with exposure to lead and mercury in borehole, tap and surface water by resident children in the Obuasi municipality in accordance with USEPA risk assessment guidelines. From the results of the study, the hazard quotient for oral ingestion of mercury in tap water in Obuasi is 7.4 and 15 respectively via both central tendency exposure (CTE) and reasonable maximum exposure (RME) parameters, respectively. This means that approximately 7 and 15 (by both CTE and RME parameters, respectively) resident children in Obuasi are likely to show neurologic effects associated with exposure to mercury and lead such as increased nervousness, loss of memory and/or decrease in concentration, impaired writing ability and tremor. PMID- 21787605 TI - Pre-treatment with mild UV irradiation increases the resistance of nematode Caenorhabditis elegans to toxicity on locomotion behaviors from metal exposure. AB - UV irradiation at 10J/m(2)/min induced a mild toxicity on locomotion behaviors and stress response in Caenorhabditis elegans. Pre-treatment with UV irradiation at 10J/m(2)/min at L2-larva stage prevented the formation of locomotion behavioral defects, and activated a noticeable reduction of stress response and oxidative damage in 50 and 100MUM metal (Hg, Pb, and Cr) exposed nematodes. Pre treatment with UV irradiation at 20J/m(2)/min caused a significant decrease of locomotion behaviors in metal exposed nematodes, and pre-treatment with mild UV irradiation could not prevent the formation of locomotion behavioral defects in 200MUM metal exposed nematodes. Moreover, the adaptive response to toxicity on locomotion behaviors induced by metal exposure was not formed in mev-1 mutants. Therefore, pre-treatment to mild UV irradiation activates the cross-adaptation response to toxicity on locomotion behaviors induced by metal exposure, and this kind of adaptive response may be under the control of MEV-1 function. PMID- 21787606 TI - In vitro cytotoxicity and antioxidant activities of five medicinal plants of Malvaceae family from Cameroon. AB - The potential antiproliferative and antioxidant activities of extracts from five medicinal plants from Cameroon were evaluated in vitro on HepG-2 cells. The results showed the significant decrease of the viability of the cells in a concentration-dependent manner. According to the IC(50) obtained, the extracts of S. acuta (461.53+/-0.23) and U. lobata (454.93+/-0.12) showed significant antiproliferative activity. At fixed concentration (250MUgmL(-1)), extracts demonstrated higher antiproliferative activity (67.05%; 65.42%), (52.62%; 56.64%) and (32.98%; 36.85%) respectively during 24, 48 and 72h. Extracts of S. cordifolia and V. album demonstrated significant antiproliferative property after 48h while S. rhombifolia exhibited weak cytotoxicity. The results of the antioxidant properties showed that theses extracts induced significantly increase of SOD, CAT and GsT activity after 48h. Taken together, the results extracts showed that of S. acuta and U. lobata may be a promising alternative to synthetic substances as natural compound with high antiproliferative and antioxidant activities. PMID- 21787607 TI - Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro. AB - Akebia saponin D is a typical bioactive triterpenoid saponin isolated the rhizome of Dipsacus asper Wall. Our previous studies demonstrated that the oral bioavailability of akebia saponin D was very low, but the underlying mechanisms remained unknown. The present study aims to investigate the intestinal absorptive characteristics of akebia saponin D as well as the absorptive transport behavior influenced by co-administration of three absorption-enhancing agents and three efflux protein inhibitors using an in vitro everted gut sac method and an in situ intestinal perfusion model. The results showed that akebia saponin D had a quite limited intestinal permeability, and there was a non-linear increase in transepithelial transportation with increasing concentrations of akebia saponin D. The absorption of akebia saponin D was intestinal segment selective and the small intestine was the best absorptive site. Among three absorption promoters, borneol could significantly improve the permeability of akebia saponin D across ileum, while Tween-80 and DMSO had almost no absorption-enhancing effect. In addition, verapamil, probenecid and pantoprazole in the perfusates were used in this study as modulators of transporters such as P-glycoprotein, MRPs and BCRP in the intestinal mucosa, respectively. The results exhibited that the ileal permeability of akebia saponin D was markedly elevated by the co-administration of probenecid, indicating that akebia saponin D may be likely a substrate of MRPs. The above-mentioned results suggest that akebia saponin D has a poor intestinal absorption not only due to its poor transepithelial permeability but also owing to the contribution of efflux transporters such as MRPs in the intestine. PMID- 21787608 TI - Effects of low, moderate and relatively high chronic exposure to cadmium on long bones susceptibility to fractures in male rats. AB - The study investigated the risk of the femur and tibia fractures on a male rat model of low, moderate and relatively high human exposure to cadmium (1, 5 and 50mg Cd/l in drinking water for 12 months). Bone mineral density (BMD) and biomechanical properties at the proximal and distal femur, and femoral and tibial diaphysis as well as the bone content of mineral and organic components, were evaluated. The exposure to 1mg Cd/l caused only very subtle changes in biomechanical properties at the femoral neck and distal femur. In the rats treated with 5mg Cd/l, a decrease in the distal femur BMD (by 5.5%) and enhanced vulnerability to fracture at the femoral neck, distal femur, and tibia diaphysis were observed. At the highest Cd treatment, the BMD decreased (by 6.5-11%) and the biomechanical properties weakened at all regions of the femur and tibia. Moreover, a decrease in the femur and tibia content of mineral components (by 11.5% and 10%, respectively) and the tibia content of organic components (by 7%) was noted. The results seem to indicate that low chronic exposure to Cd can have no influence on the bone resistance to fracture, whereas moderate (and particularly relatively high) exposure seriously increases the risk of fracture of long bones in males. The observations, together with our findings on an analogous female rat model, provide evidence that males are less vulnerable to Cd induced demineralization and weakening of biomechanical properties of the femur and tibia than females. PMID- 21787609 TI - Salsolinol, a catechol neurotoxin, induces modification of ferritin: Protection by histidine dipeptide. AB - 1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), an endogenous neurotoxin present in the mammalian brain, is known to perform a role in the pathogenesis of Parkinson's disease. In this study, we evaluated oxidative modifications of ferritin occurring after incubation with salsolinol. When ferritin was incubated with salsolinol, protein aggregation increased in a time dependent manner. Free radical scavengers inhibited this salsolinol-mediated ferritin modification. The exposure of ferritin to salsolinol also results in the generation of protein carbonyl compounds and the formation of dityrosine. The results of this study show that free radicals may perform a pivotal role in salsolinol-mediated ferritin modification. Histidine dipeptides, such as carnosine, have been proposed to function as antioxidant agents in vivo. In this study, we also attempted to determine whether the histidine dipeptides, carnosine and N-acetyl-carnosine, could prevent salsolinol-mediated oxidative modification of ferritin. Our results showed that both carnosine and N-acetyl-carnosine significantly reduced ferritin aggregation. Both compounds effectively inhibited the formation of both carbonyl compounds and dityrosine. These results suggest that carnosine derivatives can, indeed, protect against salsolinol-mediated ferritin modification, as the consequence of free radical-scavenging activity. PMID- 21787610 TI - Disposition kinetics of selenium in healthy volunteers following therapeutic shampoo treatment. AB - This study was aimed at documenting the kinetic time courses of selenium (Se) in accessible biological matrices of volunteers following controlled applications of therapeutic shampoo containing Se, to better elucidate the mechanisms by which shampoo-Se accumulates in hair and hence estimate the contribution of this source to total Se body burden. Ten healthy volunteers were exposed to Se-shampoo three times a week over a month. Blood, hair and toenail concentrations along with daily urinary excretions were repeatedly measured over an 18-month period following the onset of application. Over the entire study period, blood concentrations of Se (range: 127-233MUg/l) and daily urinary excretions (range: 11.9-150MUg/d) remained within baseline range of the general population. Conversely, during shampoo application, mean Se concentrations in hair reached transitional levels of 89MUg/g while, following cessation of treatment, a mono exponential decrease was observed with a mean half-life of 4.5 weeks. Two of the volunteers also exhibited an increase in toenail concentrations of Se during the study period. Results show that Se-shampoo does not contribute significantly to total Se body burden, as assessed from blood and urine levels. Differences observed between blood and urine time courses as compared to hair profiles and the presence of Se on hair grown before treatment indicates an adsorption on hair; however, the gradual decrease in Se concentrations in successive centimeters of hair grown following the application period suggests a concomitant absorption from the scalp during treatment with subsequent excretion in hair. PMID- 21787611 TI - HSP110 expression is induced by cadmium exposure but is dispensable for cell survival of mouse NIH3T3 fibroblasts. AB - The effects of cadmium exposure on the expression of HSP110 were examined in mouse NIH3T3 fibroblasts. Following exposure to cadmium chloride, the level of HSP110 and HSP70 proteins increased after 3h and remained elevated at 24h. Similarly, their mRNA levels increased markedly in response to cadmium exposure. Treatment with 10MUM mercury chloride, another toxic metal compound, also induced expression of HSP110; however, HSP110 expression was not induced in cells exposed to the same concentration of manganese chloride, zinc chloride, or lead chloride for 6 or 24h. Silencing of HSP110 expression using short-interference RNA did not affect cadmium-induced cellular damage. These results show that cadmium exposure induces the expression of high molecular weight chaperone HSP110 as well as the well-known HSP70, but indicate that HSP110 does not play a major role in cell survival following cadmium exposure. PMID- 21787612 TI - Impaired endothelial function assessed by flow-mediated vasodilatation in workers occupationally exposed to lead. AB - The aim of the study was to examine endothelial function in workers occupationally exposed to lead by means of FMD (flow-mediated dilatation). 44 men professionally exposed to lead, smelters and refiners, employees working at copper smelter and control group of 41 healthy men were enrolled into the study. Within the group of men occupationally exposed to lead the absolute increase in diameter after ischaemia (BAD, brachial artery diameter) and flow-mediated dilation were statistically less significant when compared to those of the control group. There was a negative linear correlation between FMD and lead concentration in copper smelters (r=-0.64). Multivariate backward step-wise regression analysis showed that blood lead concentration in copper smelters independently influenced the impairment of endothelial function expressed as decreased FMD value. In conclusion, results of our study suggest that endothelial function assessed by flow-mediated dilatation was impaired in workers occupationally exposed to lead. PMID- 21787613 TI - Subacute toxicity of p,p'-DDT on rat thyroid: Hormonal and histopathological changes. AB - The purpose of this study is to assess the effect of p,p'-DDT on thyroid activity of male Wistar rats. Pesticide was administered intraperitoneally (i.p.) for 10 consecutive days at doses of 50 and 100mg/kg/day. At the end of the treatment, the endpoints examined included serum total levels of triiodothyronine (T(3)), total thyroxine (T(4)), and thyroid stimulating hormone (TSH). Thyroid gland histopathology and tissue metabolism of thyroid hormone (T(4) UDP glucuronyltransferase UDP-GT and 5'-deiodinases) were determined. DDT treatment altered thyroid function namely by increasing hepatic excretion of T(4) glucuronide. At the dose of 50mg/kg it decreased T(4) circulating levels and increased thyroid 5'-deiodinase type I (5'-D-I) and brown adipose tissue (BAT) 5' deiodinase type II (5'-D-II) activities but it did not affect liver 5'-D-I activity which might contribute to the maintenance of the serum T(3) level. Treatment with 100mgDDT/kg decreased serum thyroid hormone concentration and tissue 5'-D-I activity without affecting BAT 5'-D-II activity. Gland histomorphological analysis showed hyperplasia and squamous metaplasia with abundant colloid. These observations associated to the elevated serum TSH levels and gland hypertrophy suggest that DDT exposure induced an hypothyroidism state with a colloid goiter in rats. PMID- 21787614 TI - Polymorphisms and functional differences in aryl hydrocarbon receptors (AhR) in Japanese field mice, Apodemus speciosus. AB - Dioxins, which are unintentionally generated toxic pollutants, exert a variety of adverse effects on organisms. The majority of these effects, which include teratogenesis, immunosuppression, tumor promotion, and endocrine disruption, are mediated through aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. Genetic variations in AhR result in different survivability under exposure to dioxin contamination, which might affect the genetic structure of wildlife populations through differential susceptibility to dioxin exposure. The aim of this study was to clarify the polymorphisms of AhR in Japanese field mice, Apodemus speciosus, and their functional differences in order to develop a molecular indicator for dioxin sensitivity. Wild Japanese field mice had abundant polymorphisms in AhR coding region. Seventy-one single nucleotide polymorphisms, 27 of which occur amino acid substitutions, and consequently 49 alleles were identified in 63 individuals. In the functional analysis of AhR variants using transient reporter assays, a Gln to Arg mutation at amino acid 799 exhibited a significant decrease in the level of transactivational properties (p=0.015) which might modify the dioxin susceptibility of an individual. PMID- 21787615 TI - Fluoride induces vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aortas. AB - We hypothesized that fluoride induces vascular contraction through activation of the RhoA/Rho kinase pathway in isolated rat aortas. Rat aortic rings were mounted in organ baths and contracted with sodium fluoride (NaF). We measured the amount of GTP-RhoA as well as vascular tension. We also determined the level of phosphorylation of the myosin light chain (MLC(20)), myosin phosphatase targeting subunit 1 (MYPT1) and PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17kDa (CPI17). In both physiological salt solution and Ca(2+)-free solution, NaF increased vascular tension and MLC(20) phosphorylation in dose-dependent manners. NaF increased not only phosphorylation level of MYPT1(Thr855) and CPI17(Thr38), but also the amount of GTP-RhoA. Both H1152 and Y27632, inhibitors of Rho kinase, but not Ro31-8220, an inhibitor of PKC, attenuated NaF-induced contraction and phosphorylation level of MLC(20), MYPT1(Thr855) and CPI17(Thr38). In conclusion, fluoride induces vascular contraction through activation of the RhoA/Rho kinase pathway. PMID- 21787616 TI - Effects of repeated exposure to decabrominated diphenyl ether (BDE-209) on mice nervous system and its self repair. AB - Decabrominated diphenyl ether (BDE-209) is widely used as brominated flame retardants (BFRs). In order to investigate its direct neurotoxic effects on mice and its self repair, mice were repeatedly exposured to BDE-209. Different concentrations of BDE-209 (0, 0.1, 40, 80 and 160mg/kgbw/d) were administered daily to CD-1 Swiss mice by gavage for 15, 30 and 60 days. Body and brain weights were recorded after the exposure. And the self repair was studied. Levels of acetylcholinesterase (TchE), superoxide dismutase (SOD) and malonic dialdehyde (MDA) in brain were analyzed. Experimental results suggested that the nervous system was permanently damaged by BDE-209 through the cholinergic system enzyme. PMID- 21787617 TI - Protection of DNA and membrane from gamma-radiation induced damage by the extract of Acorus calamus Linn.: An in vitro study. AB - Acorus calamus, an ethnomedicinally important plant, was investigated for its protecting activity against radiation induced DNA and membrane damage. The in vitro free radical scavenging activity of the extract (water:ethanol, 1:1) of A. calamus was studied by parameters viz DPPH (1,1-diphenyl-2-picryl-hydrazyl) radical scavenging activity, hydroxyl radical scavenging activity, and superoxide radical scavenging activity. Membrane damage due to radiation exposure was measured as the peroxidation of lipids in terms of thiobarbituric acid reacting substance (TBARS). The in vitro DNA damage was monitored by assessing the radiation induced relaxation of supercoiled plasmid DNA (pBR322). Damage to cellular DNA induced by gamma-radiation (6Gy) was monitored by alkaline single cell gel electrophoresis or comet assay in murine cells and human peripheral blood leukocytes. Enhancement of DNA repair mechanism was also monitored. The extract effectively scavenged free radicals in a concentration dependent manner. Presence of A. calamus extract during irradiation prevented peroxidation of membrane lipids in mouse liver homogenate. It helped to reduce the disappearance of the covalently closed circular (ccc) form of plasmid DNA following exposure to gamma-radiation. Also the A. calamus extract effectively protected DNA from radiation induced strand breaks and enhanced the DNA repair process. Hence A. calamus extract can be used as a good source of natural radioprotecting agent. PMID- 21787618 TI - Effects of chronic aluminum exposure on memory through multiple signal transduction pathways. AB - OBJECTIVE: To investigate the effects of chronic aluminum (Al) exposure on memory of rats by recording long-term potentiation (LTP) induction in CA1 region of Schaffer collateral (SC) of hippocampus and observing the changes of key LTP induction-related kinases. METHODS: Forty weaned Wistar rats were divided into 4 groups ad libitum, each group 10 rats. Three groups were fed with 0.2%, 0.4% and 0.6% AlCl(3) in drinking water for three months individually to set up the aluminum exposure models and the rest group was the control. After behavioral test, electrophysiological recordings were made at area CA1 from hippocampal SC branch followed by biochemical examination for several key kinases involved in LTP induction and formation. RESULTS: Chronic exposure of Al significantly decrease the activities of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) and reduced the expression levels of extracellular signal-regulated kinases (ERK1/2) and Ca(2+)-calmodulin dependent protein kinase II (CaMKII) in hippocampus, attenuating the population spike (PS) amplitude of LTP from the hippocampal CA1 region, causing impaired memory abilities of rats. CONCLUSIONS: Aluminum accumulation in the hippocampus affects several crucial kinases involved in LTP induction and formation, resulting in impairment of memory. PMID- 21787619 TI - Reference values for hair minerals of Polish students. AB - In the present work, reference values for the content of elements in human hair were elaborated. The population chosen for the study was a group of students in Polish urban area, which served as a representative group of a population of 20 years old individuals living in Europe. The content of 36 elements (essential (B, Ca, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, P, S, Si, Sn, V, Zn), toxic (Al, As, Cd, Hg, Ni, Pb, Sb, Tl) elements and others (Ag, Ba, Bi, Ce, La, Li, Rb, Sr, Ti, Y, Zr)) was determined in hair sampled from 117 subjects. Hair were digested with nitric acid in microwave oven in closed Teflon bombs and underwent multielemental analysis for the content of macroelements by ICP-OES and for micro- and trace elements by ICP-MS. Reference ranges were determined and considered as the values between 10th and 90th percentile. It was assumed that the values of the extreme low and high 10% in the population reflected mineral imbalance. In the population, a group of females and males was distinguished, and also a group of women which tinted their hair was separated. This enabled to point out the differences in hair mineral content between genders and for tinted and non-tinted hair. Statistical significance of differences was found for several elements, for which separate reference values were elaborated. This concerned the following elements: Ba, Ca, Cu, K, La, Mg, Mn, Si, Sr and Ti. In the interpretation of the level of these elements it is necessary to take into consideration both sex and artificial coloring. Also ratios between elements were evaluated - between nutritive (Ca/Mg, Ca/P, Na/K, Zn/Cu) and nutritive vs. toxic (Zn/Cd, Zn/Pb). In this case the differences were detected only for Ca/P ratio. This shows that perhaps in the future, inter-element ratios rather than the absolute levels of elements would be considered for the interpretation of the results of mineral analysis of hair. PMID- 21787620 TI - Involvement of mitochondrial ATP-sensitive potassium channels in etomidate preconditioning-induced protection in human myeloid HL-60 cells. AB - Exposure of HL-60 cells, a human myeloid cell line, to 500MUM etomidate for 24h reduced cell viability and increased nitric oxide production and mitochondrial permeability transition pore (mPTP) opening. Preconditioning (1h) with 1MUM etomidate 4h before exposure to the 500MUM dose of etomidate attenuated those detrimental effects. The mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel) inhibitor 5-hydroxydecanoic acid reduced the etomidate preconditioning effects. The mitoK(ATP) channel opener diazoxide attenuated the mPTP opening caused by the large dose of etomidate. Our results suggest that etomidate can induce a preconditioning effect that may involve mitoK(ATP) channel activation. PMID- 21787621 TI - UV-B induced thymocytes apoptosis blocked by dicyclodextrinyl ditelluride-A GPX mimic. AB - Apoptosis is known to occur after ultraviolet-B (UV-B) radiation. It was found that UV-B could induce cell apoptosis and change cell cycle progression. After exposure to 100J/m(2) of UV-B, pre-G1 phase thymocytes were increased significantly and S phase thymocytes were decreased significantly. UV-B could also induce lipid peroxidation of thymocytes to have their MDA amount increased. These phenomena could be explained by production of reactive oxygen species (ROS), which were induced by UV-B radiation. In this study, we examined the protective effect of dicyclodextrinyl ditelluride (2-TeCD), the glutathione peroxidase (GPX, EC 1.11.1.9) mimics, on thymocytes apoptosis induced by UV-B radiation. The experimental results showed that 2-TeCD protects thymocytes from apoptosis. Moreover, 2-TeCD inhibits lipid peroxidation of thymocytes and displayed great antioxidant ability. Furthermore, 2-TeCD blocks the accumulation of wild-type-p53 (wt-p53) tumor-suppressor gene product caused by UV-B radiation. PMID- 21787622 TI - Characteristics of Escherichia coli biofilm production, genetic typing, drug resistance pattern and gene expression under aminoglycoside pressures. AB - In our studies, qualitative (scanning electron microscope) and semi-quantitative (modified crystal violet staining method) methods had been used to evaluate Escherichia coli biofilm-forming ability. Broth microdilution method and enterobacterial repetitive intergenic consensus-based PCR (ERIC-PCR) were performed to study E. coli drug resistance pattern and genetic typing. Based on the results above, we studied the correlation between biofilm-forming ability phenotype, drug resistance pattern and genetic typing in E. coli. Real-time qPCR (qRT-PCR) was used to reveal mRNA expression level of E. coli biofilm related multiple antibiotics resistance genes (acrA, agn43, csgA, csgD, ompF and pgaA) under different concentrations of four aminoglycoside pressures. Our results showed that: (i) forty-nine out of 64 strains of E. coli (76.56%) showed significant production of biofilm and most of them performed weak biofilm-forming ability; (ii) ERIC-PCR showed that there was significant correlation between biofilm-forming ability and genotype; while there was weak correlation between biofilm-forming ability and drug resistance patterns based upon the results of semi-quantitative method and antibiotics susceptibility test; (iii) qRT-PCR revealed mRNA expression of acrA, agn43, csgA, csgD, ompF and pgaA genes changed accordingly by stimulation of different concentrations of four aminoglycosides. PMID- 21787623 TI - Free radical scavenging, antioxidant enzymes and wound healing activities of leaves extracts from Clerodendrum infortunatum L. AB - Three successive extracts of Clerodendrum infortunatum L. leaves have been studied for their potential as antioxidants in 1,1-diphenyl-2-picrylhydrazyl (DPPH) model. The scavenging activity of ethanol extract was found to be high when compared to petroleum ether and chloroform extracts. Hence, it was selected to evaluate the beneficial properties using in vitro and in vivo models. The antioxidant and its protective effects against CCl(4) induced oxidative stress in rats were significantly high. Further, to validate the traditional therapeutic claim, wound healing activity of the plant extracts was also carried out. Among the three extracts tested the petroleum ether and ethanol extracts exhibited a significant response. The presence of high antioxidant and pharmacological properties correlates to the total phenolic contents in the plant Clerodendrum infortunatum L. PMID- 21787624 TI - Biomarker responses in the bivalve (Chlamys farreri) to exposure of the environmentally relevant concentrations of lead, mercury, copper. AB - Water samples collected from Bohai Bay were determined to describe the distributions of lead, mercury, and copper in this area, indicating that mean values of the three metals were 1.63MUg/L, 4.85*10(-2)MUg/L, and 2.68MUg/L, respectively. Only lead exceeded the first class limit of seawater quality standard in China. Then, antioxidant enzymes, lipid peroxidation, and metabolic enzymes were investigated in bivalves (Chlamys farreri), exposed to three metals at the environmental concentration levels obtained from our investigation. Significantly reduced SOD, CAT and GPx activities, in lead-exposed group were observed and resulted in obvious lipid peroxidation. In contrast, mercury and copper did not show such clear oxidative stresses. In consistent with the oxidative stress variations, exposed only to lead caused a great inhibition on EROD activity. Multi-biomarker responses in bivalve when exposed to lead at the environmentally relevant concentration in Bohai Bay suggested that lead may possess a potential risk in this area. PMID- 21787625 TI - Effects of atrazine and chlorpyrifos on acetylcholinesterase and Carboxylesterase in brain and muscle of common carp. AB - The aim of this study was to investigate the effects of chlorpyrifos (CPF), atrazine (ATR) and the mixture of them on acetylcholinesterase (AChE) and carboxylesterase (CbE) in brain and muscle of common carp, respectively. 220 carps were averagely divided into 11 groups according to the different treatments and concentration, including the exposure and recovery experiments. The activities of AChE and CbE of the brain and muscle were determined at the end of the exposure and the recovery. The results showed that in the control group, the specific enzymatic activities in the brain were higher than that in the muscle. The activities of AChE and CbE in the exposure groups were significantly lower than that in the control group except for the CbE activity in the ATR low-dose group. There was a negative dose-response relationship between the activities of AChE and CbE and the pesticides concentration. The activities of AChE and CbE in the recovery groups were significantly higher than that in the exposure group except for the CbE activity in the ATR low-dose group, AChE activity in the high dose group of the mixture of ATR and CPF, and AChE activity of the brain in the CPF high-dose group. The results suggested that: (1) brain AChE may be considered as a very sensitive and early biomarker of exposure to CPF, ATR, or the mixture of ATR and CPF, (2) brain CbE may be used as a secondary biomarker for evaluating the exposure to CPF, ATR, or the mixture of ATR and CPF and (3) the change of the AChE and CbE activities caused by the mixture of ATR and CPF was more sensitive than that caused by the ATR or CPF alone. PMID- 21787626 TI - Tanghinigenin from seeds of Cerbera manghas L. induces apoptosis in human promyelocytic leukemia HL-60 cells. AB - Tanghinigenin, a cardiac glycoside, is isolated from the seeds of Cerbera manghas L. In this study, we demonstrated that tanghinigenin reduced the viability of human promyelocytic leukemia HL-60 cells in a time- and dose-dependent manner, and efficiently induced apoptosis in HL-60 cells as evidenced by the Annexin V/PI binding assay, DNA fragmentation and AO/EB staining studies. In addition, stimulation of HL-60 cells with tanghinigenin induced a series of intracellular events including the activation of caspase-3, -8, and -9, as well as up regulation of Fas and FasL protein level. Taken together, caspase activation and Fas/FasL interaction was found to be involved in tanghinigenin-induced HL-60 cell apoptosis. PMID- 21787627 TI - Genistein inhibits osteolytic bone metastasis and enhances bone mineral in nude mice. AB - In this study, the effective activity of genistein on osteolytic bone metastasis and bone mineral was investigated. Female BALB/c-nu/nu mice were injected with estrogen receptor-negative human breast cancer cells, MDA-MB-231, into left cardiac ventricle to form osteolytic bone metastases, and administered genistein subcutaneously after radiologically small but defined osteolytic metastases had been observed (protocol 1), simultaneously with cancer cells inoculation (protocol 2) and prophylactically 7 days before inoculation of cancer cells (protocol 3). In all protocols, genistein (10mg/kg/day) markedly reduced the number and volume of osteolytic bone metastases assessed by radiography and the number of osteoclasts. Furthermore, histomorphometrical analysis revealed that genistein markedly increased trabecular area (Tb.Ar%), trabecular thickness (Tb.Th) and trabecular number (Tb.N), and decreased trabecular separation (Tb.Sp). These results thus demonstrate that genistein could inhibit osteolytic bone metastases, suppress bone resorption, increase bone mass and improve bone microstructure in bone metastases of breast cancer. PMID- 21787628 TI - Probing the molecular mechanism of C.I. Acid red 73 binding to human serum albumin. AB - The molecular mechanism of C.I. Acid red 73 binding to human serum albumin (HSA) was investigated by spectroscopy and molecular docking procedures. The molecular docking results indicated that subdomain IB of HSA was the main active binding site for C.I. Acid red 73. The spectroscopic experiment results showed that the mechanism of the interaction between C.I. Acid red 73 and HSA was dominantly initiated by complex formation and the number of binding site (n) was 1.71 at 298K. The molecular docking study and thermodynamic analysis suggested that the forces acting was predominantly hydrophobic and hydrogen bond interactions. Far UV circular dichroism (CD) spectroscopy also revealed that the conformation of the HSA changed slightly after C.I. Acid red 73 bound to the HSA. The mean distance between the bound dye and the Trp residue is 3.28nm as calculated from Forster energy transfer. PMID- 21787629 TI - Acute toxicity study of the interaction between titanium dioxide nanoparticles and lead acetate in mice. AB - Titanium dioxide (TiO(2)) is one kind of widely used nanoparticle, which was used as a solid-phase extraction to preconcentrated and measured of lead (Pb) in river water and seawater. However the interaction of nanoparticle TiO(2) and Pb was unknown. The aim of this study is to investigate the potential acute toxicity of the interaction between nanoparticle TiO(2) (50 and 120nm) and lead acetate (PbAC) in adult mice. The animals were randomly divided into six groups: a control group and five treatment groups (TiO(2)-50, TiO(2)-120, PbAC, TiO(2) 50+PbAC and TiO(2)-120+PbAC groups). Suspensions of TiO(2) (5g/kg body weight), PbAC (500mg/kg body weigh) and TiO(2) (5g/kg body weight)+PbAC (500mg/kg body weigh) were administrated to mice via oral gavage, respectively. Seven days later, the animals were sacrificed after being anesthetized by ether. There were no significant changes of the body weight coefficients of liver, kidney and brain. However, the results of liver function and nephrotoxicity examination revealed that there were serious damages to liver and kidney between the group treated with the mix suspension and the one with TiO(2). After the mix suspension treatment, ROS levels were significantly increased in liver but not in kidney, cortex and hippocampus. There were no increase of MDA levels in these tissues, and no activity reductions of SOD and GSH-Px in liver and kidney but in the cortex and hippocampus. Therefore, though our results have not suggested that TiO(2) particle and PbAC have a synergistic acute toxicity in mice after oral administration, PbAC may increase the acute toxicity of TiO(2) nanoparticle in some degree. The potential toxic mechanism maybe related with oxidative damages. PMID- 21787630 TI - Leaf and root extracts of Moricandia arvensis protect against DNA damage in human lymphoblast cell K562 and enhance antioxidant activity. AB - Four extracts were prepared from the roots and leaves of Moricandia arvensis: root chloroform extract (ChlR), leaf chloroform extract (ChlL), root ethyl acetate extract (EAR) and leaf ethyl acetate extract (EAL). The genotoxic and antigenotoxic properties of these extracts were investigated by assessing the induction and inhibition of the genotoxicity induced by the direct-acting mutagen, hydrogen peroxide (H(2)O(2)), using the "Comet assay." It appears that none of the different extracts produces a genotoxic effect, except the highest tested concentrations of the leaf extracts which were capable to eliciting DNA damage. Human lymphoblast cells K562 were pretreated with different concentrations of each extracts and then treated by H(2)O(2), for the antigenotoxic study. The results showed that all extracts inhibited the genotoxicity induced by H(2)O(2) and particularly ChlR (42.5MUg/ml) and ChlL (65MUg/ml) extracts. In addition, antioxidant potential study of root and leaf extracts using different antioxidant tests indicated that root extracts possess a potent antioxidant activity through namely their capacity to transfer electrons. PMID- 21787631 TI - Sea cucumber, Stichopus japonicus ethyl acetate fraction modulates the lipopolysaccharide induced iNOS and COX-2 via MAPK signaling pathway in murine macrophages. AB - The sea cucumber Stichopus japonicus is an important food and traditional medicine in Asian countries. However, ethyl acetate solvent fraction of S. japonicus (SCEA-F) is largely unknown for its anti-inflammatory activity and related molecular mechanisms. In this study, effect of SCEA-F on inflammation was investigated in LPS stimulated RAW264.7 cells. SCEA-F significantly inhibited the productions of NO and PGE(2) by inhibiting iNOS and COX-2 at their protein and gene levels. The production and the gene transcription of pro-inflammatory cytokines are also inhibited. The responsible molecular signaling for these inhibitory actions was found to be through suppression of the phosphorylation of MAPK molecules; ERK and p38 MAPK. These results indicate that SCEA-F inhibits LPS induced inflammatory response via blocking of MAPK signaling pathway in murine macrophages, thus demonstrated its in vitro anti-inflammatory potential. Therefore it could be suggested that SCEA-F could be effectively used in functional food preparations. PMID- 21787632 TI - Frequency distribution of GSTM1 and GSTT1 null allele in Pakistani population and risk of disease incidence. AB - Glutathione-S-transferases, GSTM1 and GSTT1 play a significant role in detoxification and bioactivation of a broad range of xenobiotic compounds known to be mutagenic and/or carcinogenic. Deletion polymorphisms of these glutathione transferases (GSTM1 and GSTT1) predispose individuals to environmental carcinogenic compounds. Although a number of studies have shown the relationship between GSTM1 and/or GSTT1 deletion polymorphism and different cancers, these findings cannot be extrapolated to other populations due to intra- and inter ethnic variability. In order to assess the impact of differential ethnicity on the occurrence of different cancers in local population due to GSTM1, or GSTT1 deletion polymorphism, 111 healthy male and female individuals of different age groups from Southern Punjab, Pakistan were genotyped using a multiplex polymerase chain reaction. From the results it is obvious that null alleles of GSTM1 and GSTT1 genes were found in 45% and 23% individuals, respectively. In 5% of individuals' simultaneous deletion of both GSTM1 and GSTT1 genes were observed. Frequency of GSTM1 null allele is in concordance with those documented for Chinese, Caucasians, Mongolian, and Japanese populations. However, a significantly higher frequency for GSTT1 null was reported in Chinese and Japanese population as compared to Pakistani population. It is the first ever report on frequency of GSTM1 and GSTT1 null allele in Pakistani population which demonstrate the impact of ethnicity and provide basis for future epidemiological and clinical studies. PMID- 21787633 TI - Measurements of genotoxic potential of cadmium in different tissues of fresh water climbing perch Anabas testudineus (Bloch), using the comet assay. AB - The present investigation was undertaken to study the induction of DNA damage by CdCl(2) in freshwater climbing perch Anabas testudineus (Bloch) using alkaline single cell gel electrophoresis (comet assay). The DNA damage was measured in the tissue of gill, kidney and liver as the percentage of DNA in comet tails and comet heads in the tissue of the fish specimens exposed to 0.1, 1.0, 2.0mgL(-1) concentrations of CdCl(2). It was found that at all the concentrations of CdCl(2), the liver tissue exhibited significantly (p<0.01) higher DNA damage, followed by kidney and gill tissue. The DNA damage was found to be concentration dependent, with the highest DNA damage at 2mgL(-1) concentration, followed by 1.0 and 0.1mgL(-1). At the concentration of 2mgL(-1) of CdCl(2), the tail and head DNA of liver tissue were 38.81% and 59.49%, in kidney tissue the values were 32.37% and 64.66% whereas in gill tissue the values were 31.30% and 66.40% respectively. This study conclude that comet assay can be used for in vivo laboratory experiment using fish as model for screening the genotoxic potential of cadmium. PMID- 21787634 TI - Reactivation of VX-inhibited AChE by novel oximes having two oxygen atoms in the linker. AB - Two newly developed AChE reactivators possessing two oxime groups in 4-position of the pyridinium rings with linkers CH(2)O(CH(2))(2)OCH(2) and CH(2)O(CH(2))(4)OCH(2) were tested for their potency to reactivate VX-inhibited AChE. Their reactivation potency was compared with currently available oximes such as pralidoxime, obidoxime and HI-6. Appropriate constants (affinity towards the intact and inhibited enzyme, reactivation rate) characterizing the reactivation process were determined. According to the data obtained, a new oxime with CH(2)O(CH(2))(2)OCH(2) linker reached as high reactivation potency as HI-6. The percentage of reactivation of the oxime with CH(2)O(CH(2))(2)OCH(2) linker was comparable to that of obidoxime at a concentration 10(-3)M. Hence, these oximes may be worthy of future development for the treatment of nerve agent intoxications, especially, with lipophilic agents such as soman and cyclosarin. PMID- 21787635 TI - Toxicokinetics of pyrethroid metabolites in male and female rats. AB - The toxicokinetic characteristics of 3-phenoxybenzyl alcohol (3PBAlc) and 3 phenoxybenzaldehyde (3PBAld; metabolites of pyrethroid [PYR] after 25mg/kg, single intravenous administration), were investigated in male and female rats. The systemic clearance (Cl) of 3PBAlc in females (0.403+/-0.040l/h/kg) was significantly larger than that of males (0.227+/-0.036l/h/kg). The plasma concentration-time curve of 3PBAld decreased gradually and then increased again 1 and 2h after injection, suggesting the effect of enterohepatic circulation. The present study characterized the elimination and distribution of PYR metabolites and suggests that gender-related difference exists in the toxicokinetics of 3PBAlc and 3PBAld in rats. PMID- 21787636 TI - Brain noradrenaline changes in rats prenatally exposed to ozone. AB - In the present study we considered the possible impairment of developmental noradrenergic maturity of the cerebellum, cerebral cortex and pons at 10-, 20- and 30-day-old rats arising from mothers subjected to 1ppm ozone concentration during pregnancy. The noradrenaline concentration was found to be significantly reduced in the cerebellum during the study, while in the cerebral cortex and the pons it was found to be reduced at days 10 and 30 respectively as compared to controls. We concluded that prenatal exposure of 1.0ppm ozone causes embryonic/fetal changes manifested in postnatal levels of noradrenaline concentrations in the brains of rats. PMID- 21787637 TI - Calculating the dermal flux of chemicals with OELs based on their molecular structure: An attempt to assign the skin notation. AB - Our objectives included calculating the permeability coefficient and dermal penetration rates (flux value) for 112 chemicals with occupational exposure limits (OELs) according to the LFER (linear free-energy relationship) model developed using published methods. We also attempted to assign skin notations based on each chemical's molecular structure. There are many studies available where formulae for coefficients of permeability from saturated aqueous solutions (K(p)) have been related to physicochemical characteristics of chemicals. The LFER model is based on the solvation equation, which contains five main descriptors predicted from chemical structure: solute excess molar refractivity, dipolarity/polarisability, summation hydrogen bond acidity and basicity, and the McGowan characteristic volume. Descriptor values, available for about 5000 compounds in the Pharma Algorithms Database were used to calculate permeability coefficients. Dermal penetration rate was estimated as a ratio of permeability coefficient and concentration of chemical in saturated aqueous solution. Finally, estimated dermal penetration rates were used to assign the skin notation to chemicals. Defined critical fluxes defined from the literature were recommended as reference values for skin notation. The application of Abraham descriptors predicted from chemical structure and LFER analysis in calculation of permeability coefficients and flux values for chemicals with OELs was successful. Comparison of calculated K(p) values with data obtained earlier from other models showed that LFER predictions were comparable to those obtained by some previously published models, but the differences were much more significant for others. It seems reasonable to conclude that skin should not be characterised as a simple lipophilic barrier alone. Both lipophilic and polar pathways of permeation exist across the stratum corneum. It is feasible to predict skin notation on the basis of the LFER and other published models; from among 112 chemicals 94 (84%) should have the skin notation in the OEL list based on the LFER calculations. The skin notation had been estimated by other published models for almost 94% of the chemicals. Twenty-nine (25.8%) chemicals were identified to have significant absorption and 65 (58%) the potential for dermal toxicity. We found major differences between alternative published analytical models and their ability to determine whether particular chemicals were potentially dermotoxic. PMID- 21787638 TI - Ameliorative effect of curcumin on hepatotoxicity induced by chloroquine phosphate. AB - India is one of the most endemic areas, where malaria predominates and its control has become a formidable task. Chloroquine phosphate (CQ) on account of its rapid action on blood schizontocide of all the malarial parasite strains has become the most widely prescribed drug for prophylaxis and treatment of malaria. Toxicity of CQ is most commonly encountered at therapeutic and higher doses of treatment. Thus, the present study was undertaken to evaluate the protective effect of Curcumin, a herbal antioxidant obtained from Curcuma longa, on hepatic biochemical and histopathological status of CQ induced male mice. Swiss albino male mice were administered oral doses of CQ (100mg/kg body wt., 200mg/kg body wt. and 300mg/kg body wt.) and CQ+curcumin (300mg/kg body wt.+80mg/kg body wt.) for 45 days. A withdrawal of high dose treatment for 45 days was also studied. Administration of CQ brought about a significant decrease in Protein content with a decline in SDH, ATPase and ALKase activities, whereas ACPase activity was found to be significantly increased following CQ treatment. Antioxidant enzyme SOD registered a significant reduction as opposed to TBARS which was found to be elevated in a significant manner in the CQ treated groups as compared to control. Gravimetric indices (body weight and organ weight) declined significantly following CQ treatment. Administration of curcumin exhibited significant reversal of CQ induced toxicity in hepatic tissue. Protein content, SDH, ATPase, ALKase, ACPase, SOD, TBARS, body weight and organ weight were found to be comparable to that of control group after curcumin administration. Thus, obtained results led us to conclude the curative potential of curcumin against CQ induced hepatotoxicity. PMID- 21787639 TI - Risk assessment induced by knapsack or conventional motor sprayer on pesticides applicators and farm workers in cotton season. AB - Fakous Province in the Sharkia Governorate constitutes one of the largest agricultural areas in Egypt. The majority of people in this province rely on subsistence agriculture. In the cotton cultivation season the continuous application of pesticides is commonly used to increase agricultural productivity, using different types of spraying equipment. In this study a cohort of 210 intensive agricultural pesticide applicators and farm workers from Sawada and Akyad Elkepplia villages in Fakous Province were assessed according to the type of spraying equipment they used. Conventional motor (300l/feddan or 0.42ha) and knapsack motor sprayer (20l/feddan) were commonly used by farmers. Contamination on applicators was detected on head, body (thorax/abdomen) and legs at different percentages according to the spraying tools. The recorded results revealed that contamination with pesticides due to knapsack motor sprayers 0.76% on head, 4.8% on body and 5.8% on legs; however, conventional motor sprayers induce contamination of 3.6% on head, 23.7% on body and 29.1% on legs. Several criteria for estimating pesticide contamination by previous delivery systems were used. The most important reference biomarker was serum acetyl cholinesterase (AchE) depression. Sprayers showed changes in serum glucose levels as well as reduced erythrocytic glutathione levels (GSH). However, an increase in both total serum protein and albumin was recorded also, alongside elevation in lipid peroxidation biomarker malondialdehyde (MDA). Changes in serum biochemistry regarding enzymes reflecting cytotoxicity were also recorded, such as inhibition of alanine aminotransferase (ALT) and glutathione-S-transferase (GST). An increase in aspartate aminotransferase (AST) and glutathione reductase (GR) was observed particularly in conventional motor sprayers. Changes in enzymes activities found in this study are linked to the adverse health effects related to chronic pesticide toxicity that may lead to pathophysiological diseases, cancer or neurodegenerative disorders, which warrants further investigation. PMID- 21787640 TI - Erythrocyte antioxidants enzymes imbalance following subcutaneous pyrethroid treatments in rats of different sex. AB - Permethrin and deltamethrin are insecticides used all over the world in agriculture to control pests. The aim of this work is to investigate the effects of subcutaneous permethrin and/or deltamethrin treatments on erythrocyte antioxidant enzymes activity in rats of different sex. The results obtained show that permethrin decreases SOD and GPx activity in female rats, while it increases SOD activity in male rats. Deltamethrin treatment reduces GPx activity in male rats, while permethrin has a similar effect but only for short time treatments. A catalase activity decrease was observed in both sexes following pyrethroid treatment but when both the pyrethroids were administrated in male rats, the enzyme activity has increased. In conclusion, this study points out for the first time the importance of rat gender on erythrocyte antioxidant enzymes, which are influenced not only by the length and the type of insecticide treatment but importantly by sex. PMID- 21787641 TI - Metal deposition and functional neurotoxicity in rats after 3-6 weeks nasal exposure by two physicochemical forms of manganese. AB - Airborne manganese represents a major risk of nervous system damage first of all in industrial settings. The resulting effects may depend on the dose and physicochemical form of Mn. To compare the effect of soluble and nanoparticulate Mn, adult male rats received daily instillation of MnCl(2) solution or MnO(2) nanoparticle suspension (dose: 2.53mg Mn per rat) into the nasal cavity for 3 and 6 weeks. At the end of treatment, spontaneous open field motility was tested, electrophysiological recording was done in anesthesia, and brain tissue Mn level was determined. Metal level increase in the rats' brain, body weight gain reduction, and decrease of open field motility was significant in the MnCl(2), but not nano-Mn, treated rats. Most evoked cortical activity parameters were significantly altered in both groups, but spontaneous cortical activity spectrum only in the rats receiving MnCl(2). There was fair correlation between brain Mn levels and certain neuro-functional parameters, underlining the causal relationship. Electrophysiological tests might be more sensitive to the effects of Mn than general toxicological or neurobehavioral tests. PMID- 21787642 TI - Anti-allergic effects and mechanisms of action of the ethanolic extract of Angelica gigas in dinitrofluorobenzene-induced inflammation models. AB - To confirm the anti-allergic effects of the ethanolic extract of Angelica gigas (EAG), the levels of ear erythema, ear weight, vascular leakage, heamatology, tumor-necrosis factor-alpha, interleukin-6 and immunoglobulin E from mice sensitized with 2,4-dinitroflurorobenzene were examined. The results showed that EAG reduced ear erythema and ear weight; we also found that Evan's blue leakage decreased. Furthermore, the levels of interleukin-6 and immunoglobulin E in the serum were significantly inhibited. In RAW264.7 cells, EAG drastically inhibited the mRNA levels of inducible nitric oxide synthease, tumor-necrosis factor-alpha and macrophage inflammatory protein-1beta, suggesting that EAG may inhibit the release of pro-inflammatory cytokines and acute neutrophilic inflammation. Western blot analysis showed that EAG inhibited nuclear factor-kappaB- and extracelullar signal-regulated protein kinase-dependent inflammatory pathways. Interestingly, EAG effectively inhibited the release of beta-hexosaminidase, a granule marker from mast cells. Taken together, our results demonstrate that EAG inhibits focal and systemic inflammatory and allergic reactions, and holds great promise for the treatment of several inflammatory diseases. PMID- 21787643 TI - Ginseng saponin metabolite induces apoptosis in MCF-7 breast cancer cells through the modulation of AMP-activated protein kinase. AB - Previous studies have shown that the ginseng saponin metabolite, Compound K (20-O d-glucopyranosyl-20(S)-protopanaxadiol, IH901), suppresses proliferation of various cancers and induces apoptosis. AMP-activated protein kinase (AMPK) is a sensor of cellular energy states and is involved in apoptosis of cancer cells. We hypothesized that Compound K may exert cytotoxicity in MCF-7 human breast cancer cells through modulation of AMPK, followed by a decrease in cyclooxygenase-2 (COX 2) expression. Compound K inhibited cell growth, induced apoptosis via generation of reactive oxygen species (ROS), as well as decreasing COX-2 expression and prostaglandin E(2) (PGE(2)) levels. These effects of Compound K were induced via an AMPK-dependent pathway and were abrogated by a specific AMPK inhibitor. These results suggest that Compound K induced apoptosis by modulating AMPK-COX-2 signaling in MCF-7 human breast cancer cells. PMID- 21787644 TI - Protective effect of desloratadine against oxidative stress in human erythrocytes in vitro. AB - Desloratadine (DCL) is a non-sedating antihistamine approved for the treatment of allergic rhinitis or chronic idiopathic urticaria. The objective of this study was to evaluate the potential protective effect of DCL against oxidative stress in human erythrocytes in vitro. Human erythrocytes were oxidized by a water soluble radical generators-2,2' azobis (2-amidinopropane) hydrochloride (AAPH; 20, 50mM) or tert-butyl hydroperoxide (TBHP; 0.5mM) and the protective effects of DCL (2, 5, 7, 10 and 26MUM) on selected oxidative stress markers were investigated. Erythrocytes were divided into aliquots. The first aliquot was incubated for 2h at 37 degrees C with AAPH or TBHP. The other test aliquots were preincubated with selected concentrations of DCL for 30min and followed by AAPH or TBHP incubation for 2h. Malondialdehyde (MDA) content, catalase (CAT) and superoxide dismutase (SOD) activities, as well as hemolysis percentage (H) were measured in all erythrocyte samples. The influence of solvent (0.5% ethanol) on the parameters studied was also checked. Pretreatment with DCL (7, 10, 26MUM) could prevent TBHP-induced increase in MDA formation in a concentration-dependent manner. DCL has no influence on CAT activity and it significantly enhanced SOD activity compared to AAPH treatment samples at 7, 10, 26MUM. DCL (26MUM) also reduced the hemolytic effect on erythrocytes when compared to the erythrocytes exposed to oxidants only. These results suggest a beneficial effect of DCL as an antioxidant, which might be an additional explanation of its therapeutic action. PMID- 21787645 TI - Hydrophobic double walled carbon nanotubes interaction with phopholipidic model membranes: (1)H-, (2)H-, (31)P NMR and ESR study. AB - The interactions of carbon nanotubes synthesized by catalytic chemical vapour deposition with phospholipidic bilayers, mimicking biological membranes, have been investigated using solid state (31)P- and (2)H NMR, (1)H- and (31)P NMR in liquids and ESR studies. It was found that carbon nanotubes can integrate the bilayer, depending on the overall cohesion of the membrane used. Whereas no direct interaction can be observed in small unilamellar vesicles or directly in the presence of short-chained phospholipids, carbon nanotubes incorporate into the membrane of multibilayers. The result is a significant 2-3K lowering of the transition temperature in multibilayers of dimyristoyl lecithins, which is more markedly associated with increased fluidity in the most superficial part of the membrane below the transition temperature (292-300K range). However, no ionophoric property was found on large unilamellar vesicles. PMID- 21787646 TI - Effects of combined vanadate and magnesium treatment on erythrocyte antioxidant defence system in rats. AB - The effect of vanadate and magnesium treatment on erythrocyte defence system was studied in outbred 2-month-old, albino male Wistar rats (14 rats/each group) which daily received: Group I (Control)-deionized water to drink; Group II-water solution of sodium metavanadate (NaVO(3); SMV) at a concentration of 0.125mgV/mL; Group III-water solution of magnesium sulfate (MgSO(4); MS) at a concentration of 0.06mgMg/mL, Group IV-water solution of SMV-MS at the same concentrations over a 12-week time. The fluid intake and the concentration of reduced glutathione (GSH) as well as the activity of Cu, Zn-superoxide dismutase (Cu, Zn-SOD), catalase (CAT) and glutathione reductase (GR) were significantly decreased in the rats receiving SMV alone (Group II) or in combination with MS (Group IV) compared with Groups I and III. The cellular glutathione peroxidase (cGSH-Px) activity was unchanged in all the treated groups. The activity of glutathione S-transferase (GST) fell in the animals in Group II, compared with the rats in Groups I, III and IV; whereas in the rats in Group III its activity was higher than in the control animals. These results showed that V (as SMV) consumed by the rats with drinking water at a dose of 12mgV/kg b.w./24h for 12 weeks may attenuate defence system in rats' erythrocytes (RBCs), which is probably a consequence of vanadium pro-oxidant potential. Therefore, reactive oxygen species (ROS) are suggested to be involved in the alterations in antioxidant defence system in these cells. Mg (as MS) at the dose ingested (6mgMg/kg b.w./24h) at co-exposure to SMV was not able to counteract its deleterious effect. The results also provide evidence that V-Mg interactions may be involved in the decrease of erythrocyte GR activity and Mg concentration in the plasma under concomitant treatment with both metals at the doses of 12.6mgV and 6mgMg/kg b.w./24h. PMID- 21787647 TI - Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. AB - Toxicity of nanoparticles depends on many factors including size, shape, chemical composition, surface area, surface charge, and others. In this study, we compared the toxicity of different sized-silver nanoparticles (AgNPs) which are being widely used in consumer products due to its unique antimicrobial activity. When mice were treated with AgNPs 1mg/kg for 14 days by oral administration, small sized AgNPs (22nm, 42nm, and 71nm) were distributed to the organs including brain, lung, liver, kidney, and testis while large-sized AgNPs (323nm) were not detected in those tissues. The levels of TGF-beta in serum were also significantly increased in the treated group of small-sized AgNPs but not in large-sized AgNPs. In addition, B cell distribution was increased in small-sized AgNPs but not in large-sized-AgNPs by the phenotype analysis. However, body weight or in the ratio of organ/body weight were not different between the control group and all the AgNPs-treated groups. The repeated-dose toxicity of AgNPs (42nm) was also investigated in mice by oral administration for 28 days. By the administration of AgNPs (0.25mg/kg, 0.50mg/kg, 1.00mg/kg), adverse impacts on liver and kidney were observed in a high dose-treated group (1.00mg/kg), when determined by blood chemistry and histipathological analysis. Cytokines including IL-1, IL-6, IL-4, IL-10, IL-12, and TGF-beta were also increased in a dose dependent manner by repeated oral administration. In addition, B cell distribution in lymphocyte and IgE production were increased. Based on these results, it is suggested that repeated oral administration of nano-sized AgNPs may cause organ toxicity and inflammatory responses in mice. PMID- 21787648 TI - Pyridoxine mitigates cadmium induced hepatic cytotoxicity and oxidative stress. AB - Therapeutic potential of pyridoxine (vit B6) was evaluated against cadmium induced hepatic cytotoxicity in culture and oxidative stress in rats. Nonmalignant "Chang" liver cell culture was exposed to Cd (cadmium chloride) that produced cytotoxicity in terms of increase in cell growth inhibition rate, alanine aminotransferase, lactate dehydrogenase and lipid peroxidation, which was significantly mitigated by pyridoxine in a concentration dependent manner. Acute exposure to Cd (6.5mg/kg body weight; ip once only) produced a condition of hepatic oxidative stress by substantially increasing lipid peroxidation and oxidized glutathione level along with corresponding decrease in reduced glutathione and various antioxidant enzymes, i.e., superoxide dismutase, catalase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase. Cadmium administration significantly increased the leakage of liver marker enzymes in serum, i.e., transaminases, alkaline phosphatase and lactate dehydrogenase. Therapy with pyridoxine after 3h of Cd administration decreased the release of serum transaminases, alkaline phosphatase and lactate dehydrogenase towards control. Administration of pyridoxine inhibited lipid peroxidation and formation of oxidized glutathione, increased the reduced glutathione level and restored the activities of aforesaid antioxidant enzymes towards control. The observations clearly demonstrated that pyridoxine treatment mitigates cadmium induced hepatic cytotoxicity and oxidative stress and provides evidence that it may be used clinically against Cd-induced hepatic toxicity. PMID- 21787649 TI - Antioxidant intervention compensates oxidative stress in blood of subjects exposed to emissions from a coal electric-power plant in South Brazil. AB - In the process of energy generation, particulate matter (PM) emissions derived from coal combustion expose humans to serious occupational diseases, which are associated with overgeneration of reactive oxygen species (ROS). The purpose of the present study is to better understand the relations between PM exposure derived from a coal electric-power plant and the oxidative damage in subjects (n=20 each group) directly (working at the burning area) or indirectly (working at the office or living in the vicinity of the electric-power plant=group of residents) exposed to airborne contamination, before and after daily supplementation with vitamins C (500mg) and E (800mg) during six months, which were compared to non-exposed subjects (control group). Several biomarkers of oxidative stress were examined such as levels of thiobarbituric acid reactive substances (TBARS), protein carbonyls (PC), protein thiols (PT) and vitamin E in plasma, levels of reduced glutathione (GSH) in whole blood, and of activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) in red cells. Before supplementation, TBARS and PC levels were significantly increased, levels of GSH and vitamin E were decreased, while the activities of SOD and CAT were increased in workers groups and GST were increased in all groups in compared to controls. After the antioxidant supplementation essentially all these biomarkers were normalized to control levels. The antioxidant intervention was able to confer a protective effect of vitamins C and E against the oxidative insult associated with airborne contamination derived from coal burning of an electric power plant. PMID- 21787650 TI - The neurotoxic effects of monocrotophos on the formation of the serotonergic nervous system and swimming activity in the larvae of the sea urchin Hemicentrotus pulcherrimus. AB - The neurotoxicity of monocrotophos (MCP) in the development of the serotonergic nervous system and swimming activity of larvae of the sea urchin, Hemicentrotus pulcherrimus, was examined. Lethal dose 50% of MCP was 43MUg/ml. Overall morphology was not affected in larvae that received up to 30MUg/ml of MCP soon after fertilization until the 53h post-fertilization pluteus stage. However, while 70+/-0.6% of larvae in 5MUg/ml MCP swam actively, the proportion decreased to 30+/-1.7% in 30MUg/ml MCP. Accordingly, immunoblotting indicated that MCP decreased the relative intensity of immunoreaction of serotonin receptor protein. Whole-mount immunohistochemistry indicated that MCP inhibited serotonergic axon growth, reduced the number of serotonergic cells at the apical ganglion, and perturbed formation of the serotonin receptor cell network. The present study demonstrated that sea urchin larva is a useful model for evaluating the working mechanism of environmental toxicants in neurogenesis and behavior. PMID- 21787651 TI - The effect of dietary habits on mineral composition of human scalp hair. AB - In the present work, hair mineral analysis of 117 individuals was carried out. The subjects were asked to fill a questionnaire concerning their dietary habits. The content of minerals in hair was determined by ICP-OES (macroelements) and ICP MS technique (micro-, toxic and other trace elements). The results were elaborated statistically by Statisticaver. 8.0. It was found that consuming highly processed food causes increased levels of e.g. Na and P in hair, intake of slimming preparation resulted in increased content of Al, Cr, Ti, taking in laxative agents caused lower level of Pb (this element was probably eliminated by other excretory routes). Individuals which declared the use of analgesic agents had more Si in their hair. Drinking coffee was related with higher level of Al, Ni, S and Ti and lower Pb in hair. Drinking tea caused reduction in the level of Hg. These results show that hair mineral content reflects exposure of elements from the diet. PMID- 21787652 TI - Effects of prenatal and postnatal exposure to a low dose of bisphenol A on behavior and memory in rats. AB - Endocrine disruptors (EDs) are increasingly common chemicals in the environment. Bisphenol A (BPA), used to manufacture polycarbonate plastics, is an ED recognized for its estrogenic, anti-estrogenic, and anti-androgenic effects. Behavior is considered a vital characteristic for an animal's life cycle. This study evaluated the effect of exposure to low doses of BPA during pregnancy and/or lactation on several aspects of rat behavior, including memory, locomotion, and the exploratory instinct. Pups at 16 weeks of age (females and males) were divided into groups according to the mother's exposure to BPA (40MUg/kg/day): CON (vehicle only); PRE (during pregnancy); LAC (during lactation); PRE-LAC (during both pregnancy and lactation). In the PRE-LAC group, exposure to BPA impaired both short-term (STM) and long-term memory (LTM) in inhibitory avoidance and the object recognition task, and also affected locomotor activity and spatial memory. Some sex-specific behavioral characteristics disappeared in the LAC group. Sex-specific memory and behavior impairment were caused by BPA exposure during brain organogenesis and differentiation. PMID- 21787653 TI - Inhibition of cadmium-induced apoptosis by glutathione S-transferase P1 via mitogen-activated protein kinases and mitochondrial pathways. AB - Cadmium is a well-known toxic metal for the kidney. Glutathione S-transferase P1 (GSTP1) plays an important role in the detoxification and xenobiotics metabolism. Here, we investigated whether GSTP1 affected Cd(2+)-induced apoptotic cell death in human embryonic kidney cell line (HEK) 293 cells. We showed that in HEK293 cells, silencing of GSTP1 expression through RNA interference reinforced the loss in cell viability induced by Cd(2+). Overexpression of GSTP1 inhibited loss of mitochondrial membrane potential, prevented cytochrome c release from mitochondria and caspase-3 activation, inhibited mitogen-activated protein kinases (MAPKs) including ERK, JNK and p38, and suppressed apoptosis induced by Cd(2+). The oligonucleosomal DNA fragmentation assay also demonstrated that overexpression of GSTP1 by adenovirus infection prevented Cd(2+)-induced apoptosis in primary renal tubule cells. Our data suggest that GSTP1 was an endogenous inhibitor of Cd(2+)-induced apoptosis. PMID- 21787654 TI - Endocrine disrupting chemicals-Linking internal exposure to vitellogenin levels and ovotestis in Abramis brama from Dutch surface waters. AB - The exposure of male bream from three Dutch freshwater locations to endocrine disrupting compounds (EDCs) and corresponding effects are described in this study. Fish specimen displaying reproductive disorders associated with high levels of plasma vitellogenin (VTG) concentrations and occurrence of ovotestis (OT) were investigated. To provide information on the full spectrum of EDCs in fish tissue, adipose tissue samples of individual fish were analyzed for nearly 130 chemicals targeting different compound classes (bisphenols, alkylphenols, pesticides, polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), hydroxylated polychlorinated biphenyls (OH PCBs), polybrominated diphenyl ethers (PBDEs) and biphenyls (PBBs)) and steroid hormones. To establish whether tissue from specimen with reproductive disorders shows a spectrum of EDCs that is qualitatively and quantitatively different from that of controls free of symptoms, bioassay-directed fractionation was performed using the recombinant yeast estrogen screen (YES), the E-Screen bioassay, the human sulfotransferase 1E1 (SULT1E1) inhibition assay, and the coumestrol-based estrogen receptor alpha (ERalpha) high resolution screening (HRS) assay. No differences in estrogenicity could be observed between the cases and controls and steroidal estrogens accounted for the majority of estrogenicity found in the complex mixtures. In this study, the combination of the different assays employed to measure total estrogenicity and the SULT1E1 inhibition does not predict the outcome of unwanted physiological effects, however, it can be used to determine the presence of EDCs in fish samples and their estrogenic effects. PMID- 21787655 TI - Analytical methods for determining metabolites of polycyclic aromatic hydrocarbon (PAH) pollutants in fish bile: A review. AB - The determination of polycyclic aromatic hydrocarbon (PAH) metabolites in bile can serve as a tool for assessing environmental PAH exposure in fish. Biliary PAH metabolite levels can be measured using several analytical methods, including simple fluorescence assays (fixed fluorescence detection or synchronous fluorescence spectrometry); high-performance liquid chromatography with fluorescence detection (HPLC-F); gas chromatography-mass spectrometry (GC-MS) after deconjugation, extraction and derivatization of the bile sample, and finally by advanced liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) methods. The method alternatives are highly different both with regard to their analytical performance towards different PAH metabolite structures as well as in general technical demands and their suitability for different monitoring strategies. In the present review, the state-of-the-art for these different analytical methods is presented and the advantages and limitations of each approach as well as aspects related to analytical quality control and inter-laboratory comparability of data and availability of certified reference materials are discussed. PMID- 21787656 TI - Effect of conjugated linoleic acid (CLA) on lipid profile and liver histology in laboratory rats fed high-fructose diet. AB - The objective of the study was to assess the effect of CLA on serum lipid profile, plasma malondialdehyde and liver histology in Wistar rats fed high fructose diet. Eighteen rats were randomly assigned to three experimental groups and fed for the next 21 days. The experimental diets were: I, Control; II, Fructose (63.2% of fructose); and III, CLA+Fructose (1% CLA and 63.2% of fructose). The experimental treatments had no effect on body weight of the rats. The LDL+VLDL cholesterol, TG and liver weight were significantly increased in animals fed Fructose. MDA concentrations were significantly increased in rats fed Fructose diet but CLA+Fructose diet had no effect on this marker. In the same line, the histological examination of the livers showed a series of morphological alterations, notably hepatic steatosis in animals fed high-fructose diet. No signs of the steatosis in rats fed CLA+Fructose diet were observed. In conclusion, CLA in high-fructose diet, decreases serum LDL+VLDL and TG and plasma MDA concentrations as well as liver weight and liver cholesterol, thus opposing the effects of high-fructose diet and showing a potential antiatherogenic effect. Similarly, dietary CLA fed at 1% level (w/w) in high-fructose diet, prevented steatosis observed histologically in livers of rats fed high-fructose diets. PMID- 21787657 TI - Effects of beta-cypermethrin on male rat reproductive system. AB - To study adverse effects and underlying mechanisms of beta-cypermethrin (beta cyp) on male reproductive system, the 15-day intact male adult Sprague-Dawley (SD) rats assay was used as an in vivo test. Male adult SD rats were treated by oral gavage with 0, 15 and 30mgbeta-cyp/kgBW for 15 days. After 15-day treatments, the testes, epididymis and seminal vesicles were excised and weighed, respectively. One testis was used for testicular sperm head counts, and the other was for immunohistochemistry test to characterize the expression of androgen receptors (ARs). There were substantial decreases of both sperm head counts and daily sperm production after beta-cyp exposure. The expression of AR decreased significantly in rats treated with 15 and 30mgbeta-cyp/kgBW, and the gray scale pixel values in the three groups (0, 15 and 30mgbeta-cyp/kgBW) were 113.79+/ 13.58, 96.09+/-5.95 and 77.27+/-5.44, respectively. These findings suggested beta cyp has significant adverse effects on the reproductive system. Reducing the expression of AR is a potential mechanism of decreased sperm production caused by beta-cyp. PMID- 21787658 TI - In vitro effect of the antimalarial drug proguanil hydrochloride on viability and DNA damage in human peripheral blood lymphocytes. AB - This study aimed to evaluate the effect of proguanil, a chemical substance used for treatment and prevention of malaria on viability and DNA integrity in human lymphocytes in vitro. Two different concentrations of proguanil obtained from the plasma concentrations were used: 130ng/ml used for prophylactic treatment and 520ng/ml used in treatment of malaria. Testing was done with and without metabolic activation. Viability of lymphocytes decreased in time and dose dependent manner. Comet assay parameters showed similar effects, indicating that some damage to DNA molecule can occur. Frequency of sister chromatid exchanges did not show significant deviation from the control samples. As for the proliferation kinetics no significant changes were noticed. Since majority of DNA damaging effect is induced after metabolic activation it is to be concluded that activity of proguanil is dependent upon the active metabolite cycloguanil and that monitoring should be conducted especially among frequent travellers. PMID- 21787659 TI - Quercetin protects the rat kidney against oxidative stress-mediated DNA damage and apoptosis induced by lead. AB - Quercetin, a flavonoid, effectively improved the lead-induced histology changes including structure damage and leukocyte infiltration in rat kidney. The present study was designed to explore the protective mechanism of quercetin against lead induced oxidative DNA damage and apoptosis in rat kidney. We found that quercetin markedly decreased the ROS level and lowered the GSH/GSSG ratio in the kidney of lead-treated rat. The increase of 8-hydroxydeoxyguanosine level in the kidney of lead-treated rat was effectively suppressed by quercetin. Furthermore, quercetin markedly restored Cu/Zn-SOD, CAT and GPx activities in the kidney of lead-treated rat. TUNEL assay showed that lead-induced apoptosis in rat kidney was significantly inhibited by quercetin, which might be attributed to its antioxidant property. In conclusion, these results suggested that quercetin could protect the rat kidney against lead-induced injury by improving renal function, attenuating histopathologic changes, reducing ROS production, renewing the activities of antioxidant enzymes, decreasing DNA oxidative damage and apoptosis. PMID- 21787660 TI - Protective effect of reduced glutathione on the liver injury induced by acute omethoate poisoning. AB - Omethoate is an organophosphate insecticide with high toxicity. The aim of this study was to investigate the protective effect of exogenous reduced glutathione (GSH) on omethoate-induced liver injury. Sprague-Dawley rats were randomly divided into three groups: control, OM (omethoate poisoning), and OM+GSH (omethoate poisoning treated with GSH). The activities of acetylcholinesterase (AChE), aspartate aminotransferase (AST), alanine aminotransferase (ALT) in plasma, free organophosphate (FOP) in the liver were determined, and the histopathological changes in the liver were observed. Furthermore, TNF-alpha and NO in liver homogenate were assayed. The results showed that AChE activity was significantly inhibited by omethoate, but was not altered by GSH treatment. GSH was able to prevent hepatocellular edema and fatty degeneration, decrease liver FOP, attenuate the increased AST and ALT activity, and decline the increase of TNF-alpha and NO induced by omethoate. These results indicate GSH can attenuate liver injury, and suggest that GSH may be administered to protect the organ from injury in patients with acute organophosphate poisoning. PMID- 21787661 TI - Investigation of anti-microbial activity of catechin on Escherichia coli growth by microcalorimetry. AB - Catechin is a major monomer of Chinese Rhubarb. Chinese Rhubarb has been claimed to have a therapeutic value as a bacteriostatic drug. It is also known that total rhubarb anthraquinone mixture and its individual components such as emodin are the effective components. However, the catechins component in Chinese Rhubarb such as catechin has not been characterized. In the present study, the power-time curves of Escherichia coli growth were obtained and the action on them by addition of catechin in different concentrations in vitro were studied by microcalorimetry. The results suggest E. coli growth is inhibited by catechin in a dose-dependent manner starting from the concentration of 0.05 to 1.6mgmL(-1). The correspondence analysis reveals k(2) and P(2) are the significant parameters to evaluate the anti-microbial effect. Microcalorimetry is a useful tool to evaluate the anti-microbial effect with its sensitive and significant quantitative information. PMID- 21787662 TI - Curcumin protects against cypermethrin-induced genotoxicity in rats. AB - Cypermethrin is a synthetic pyrethroid insecticide used worldwide in agriculture, home pest control, protection of foodstuff and disease vector control. The aim of the present study was to investigate the protective effect of curcumin on cypermethrin-induced genotoxicity in rats. Administration of cypermethrin (25mg/kg, p.o.) for 28 days resulted in significant increase in the frequency of micronuclei formation in bone marrow cells and DNA damage in blood cells. Curcumin (100mg/kg, p.o.) administration caused significant reduction in micronuclei formation and, marked reduction in DNA damage. The present study revealed that presence of curcumin could diminish cypermethrin-induced genotoxicity in rats. PMID- 21787663 TI - Air pollutants: the key stages in the pathway towards the development of cardiovascular disorders. AB - Air pollution has been one of the significant risks to human health. Various studies indicate that ambient particulate matter in air pollution is most strongly allied to increased morbidity and mortality due to their link with cardiovascular adverse events. The mechanisms leading to these harmful effects on the cardiovascular system have not been defined clearly but several hypotheses have been proposed that elucidate the direct and indirect effects of air pollution. Adverse cardiovascular events such as thrombosis, vascular dysfunction, atherosclerosis, myocardial infarction and disturbance in cardiac autonomic control are thought to be linked with air pollution. Recently, an association has also been found between cardiac hypertrophy and air pollution. The present review focuses on highlighting the implications of air pollution in deteriorating cardiac health. PMID- 21787664 TI - Chemopreventive efficacy of Wedelia calendulaceae against 20-methylcholanthrene induced carcinogenesis in mice. AB - Present study reports the chemopreventive effect of methanol extract of Wedelia calendulaceae (MEWC) against 20-methylcholanthrene (20-MC) induced carcinogenesis in Swiss albino mice. MEWC was administered orally at 250 and 500 mg/kg body weight for 90 consecutive days after 24h of single subcutaneous administration of 20-MC (200 MUg) in mice and observed for 15 weeks to record tumor incidence (fibrosarcoma) and survival. After 15 weeks the mice were sacrificed for the estimation of hematological profiles and liver biochemical parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). MEWC treatment markedly reduced tumor incidence and prolonged life span of sarcoma bearing mice as compared to 20 MC control. Hematological profiles were significantly (p<0.001) restored to normal levels in MEWC treated mice. MEWC treatment significantly (p<0.001) modulated the aforesaid liver biochemical parameters as compared to 20-MC control. Therefore, W. calendulaceae possess remarkable chemopreventive efficacy in Swiss mice. PMID- 21787665 TI - Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) alleviates benzo[a]pyrene-7,8-diol-9,10-epoxide induced cell cycle arrest and apoptosis in human cells. AB - Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) is a carcinogen causing bulky-adduct DNA damage and inducing extensive cell responses regulating cell cycle, cell survival and apoptosis. However, the mechanism of cellular responses to BPDE exposure is not fully understood. In this study, we demonstrated the involvement of the phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) in the cellular response to BPDE exposure and addressed the role of eIF2alpha phosphorylation in the regulation of the cellular stress. Phosphorylation of eIF2alpha was induced in a normal human FL amnion epithelial cell line, and the expression of ATF4, a conserved downstream transcriptional factor of eIF2alpha phosphorylation, was up-regulated after BPDE exposure; however, the four known primary kinases for eIF2alpha phosphorylation (GCN2, HRI, PKR, and PERK) were not found activated. While BPDE induced severe cell cycle arrest and apoptosis and decreased cell viability in FL cells, salubrinal, a selective inhibitor of eIF2alpha dephosphorylation, maintained the eIF2alpha phosphorylation and attenuated cell cycle arrest and apoptosis and promoted cell survival. The findings reveal that when BPDE causes cellular damages, it induces eIF2alpha phosphorylation as well, which produces a pro-survival and anti apoptotic effect to alleviate the cellular damages. Thus, the present study proposes a new cellular defensive mechanism during the environmental mutagen and carcinogen attack. PMID- 21787666 TI - Effects of lanthanum, cerium, and neodymium on the nuclei and mitochondria of hepatocytes: accumulation and oxidative damage. AB - The aim of this study was to investigate the contents of lanthanum (La), cerium (Ce), and neodymium (Nd) that accumulate in nuclei and mitochondria isolated from the liver and their corresponding potential oxidative damage effects on nuclei and mitochondria. Five-week-old male imprinting control region (ICR) mice were exposed to chlorides of La, Ce, or Nd by oral gavage with one of three doses: 10, 20, or 40 mg/kgBW/day for 6 weeks. The concentrations of administered elements in hepatocyte nuclei and mitochondria were determined with inductively coupled plasma-mass (ICP-MS) spectrometry. The accumulation of La, Ce, and Nd in hepatocyte nuclei and mitochondria gradually increased in a dose-dependent manner with exposure to the elements, although the concentrations of La, Ce, and Nd in hepatocyte mitochondria were lower than those in their counterpart nuclei. In hepatocyte nuclei, superoxide dismutase (SOD) and catalase (CAT) activities decreased, whereas glutathione peroxidase (GPx) activity, glutathione (GSH) and malondialdehyde (MDA) levels increased. In hepatocyte mitochondria, SOD, CAT, and GPx activities and GSH levels were significantly decreased, and MDA levels were significantly increased. These results suggest that La, Ce, and Nd presumably enter hepatocytes and mainly accumulate in the nuclei and induce oxidative damage in hepatic nuclei and mitochondria. PMID- 21787667 TI - Oxidative stress induced by thyroid dysfunction in rat erythrocytes and heart. AB - The aim of this study was to determine whether the effects of thyroid dysfunction induce oxidative stress in the blood and heart of male Wistar rats. Rats were randomly divided into three groups: group I served as control rats. Group II was treated daily with 0.05% benzythiouracile (BTU) administered in drinking water. Rats of group III have received l-thyroxine sodium salt (0.0012%), in drinking water. The results showed that thyroid dysfunction rats had poor growth performance. On the other hand, in hyperthyroid rats, a marked decrease compared with control occurred of some hematological parameters such red blood cell number (RBC), haemoglobin (Hb) concentration and haematocrit (Ht). There was also a significant increase in erythrocyte numbers and heart TBARS concentrations in hypothyroid rats compared with control. These results were associated with a fall in the total antioxidant status (TAS) in the serum of the hyperthyroid rats. Alteration of the antioxidant system in the hypo-/hyperthyroidism-induced rats was confirmed by the significant increase of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and a decline in glutathione (GSH) content in both tissues were detected in hyperthyroid group compared to controls. On the other hand, serum transaminase activities (aspartate transaminase (AST); alanine transaminase (ALT)) were elevated indicating hepatic cellular damage after treatment with exogenous L-thyroxine. Moreover, serum lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT) and creatine phosphokinase (CPK) activities were increased in the hyperthyroidism rats. These results indicated that excessive thyroxin (long term) ingestion had an adverse effect on animal health and performance. We conclude that thyroid dysfunction induces oxidative stress and modifies some biochemical parameters of erythrocytes, heart and liver disease; our results show the occurrence of a state of oxidizing stress in relation to hyperthyroidism. PMID- 21787668 TI - Protective effect of the methanolic extract from Duchesnea indica against oxidative stress in vitro and in vivo. AB - Duchesnea indica (Rosaceae family) is herb used extensively in traditional Chinese medicine. In this study we investigated its protective activity against hydrogen peroxide (H(2)O(2))-induced cytotoxicity in human skin fibroblast (CCD 986Sk) cells and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced H(2)O(2) in the skin of hairless mice. Pretreatment of CCD-986Sk cells with methanolic extract of D. indica (DIM) improved the cell viability, enhanced activity of catalase, and decreased the leakage of lactate dehydrogenase (LDH) and the levels of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS) in H(2)O(2) injured cells. Furthermore, DIM inhibited cell apoptosis and Bax expression induced by H(2)O(2). In addition, the level of H(2)O(2) stimulated by TPA was decreased by DIM in the skin of hairless mice. These results suggest that DIM offers protection against oxidative stress in vitro and in vivo, and this ability suggests potential use for protection against oxidation-induced skin damage. PMID- 21787669 TI - Diagnostic assay of trace lead in an ex vivo tissue using a combination electrode. AB - A voltametric diagnosis of trace lead was performed using macro type combination sensors of fluorine-doped graphite pencil electrodes (FPE). Two pencils were used as the reference and auxiliary instead of expensive Ag/AgCl standards and Pt counters. Under optimized conditions, a square wave (SW) stripping working curve was attained at 10-70 mg/L and a micro range of 10-70 MUg/L. The developed sensor was not only inexpensive but also had a fast (90-s) accumulation time. An analytical detection limit of 10 MUg/L was obtained. The results were applied to an ex vivo tissue and an artificial turf. PMID- 21787670 TI - Altered BRCA1 and BRCA2 responses and mutation of BRCA1 gene in mice exposed chronically and transgenerationally to aqueous extract of betel nut (AEBN). AB - The Brca1 and Brca2 tumor suppressor genes are involved in the maintenance of genomic integrity as they facilitate error free DNA repair. This study was designed to understand the role of Brca1 and Brca2 in betel nut (BN) induced chronic and transgenerational carcinogenesis in mice. Young male and female Swiss Albino mice were chronically as well as transgenerationally exposed to aqueous extract of betel nut (AEBN) in drinking water (2 mg ml(-1)) for up to 24 weeks. In chronically exposed mice, the levels of Brca1 and Brca2 proteins were elevated to approximately 1.4-fold over the age matched controls after 2 weeks of exposure to AEBN, followed by a decline below the controls. In transgenerationally exposed mice, both Brca1 and Brca2 proteins remained below the controls from the onset of AEBN exposure and rapidly declined further, indicating a loss of tumor suppressor protection. Nucleotide sequencing of exon 11 of Brca1 and exon 27 of Brca2 did not reveal mutation in liver nodules of chronically exposed mice, while a G -> C mutation Brca1 was observed in liver nodules as well as in solid tumors developing in transgenerationally exposed mice. Thus, the genomic instability arising due to the lowering in the levels of Brca1 and Brca2 proteins and mutation in exon 11 of Brca1 gene contributed to the increased risk of cancer in mice exposed transgenerationally to AEBN. PMID- 21787671 TI - Multi-endpoint toxicities on Chinese rare minnow (Gobiocypris rarus) fed with different diets. AB - To compare the effects of three diets, rare minnow was fed with three diets from 30 dph to mature period. The activities of EROD, PROD, SOD and GST were measured in the WBHs as well as Vtg and TBARS concentrations at 60 dph. The rest fish were fed until adulthood for breeding studies. The group A served as the control group. It was found that Vtg, GST and EROD were significantly increased in the groups B and C, but SOD, TBARS and PROD levels were significantly increased only in the group C. In the adulthood, Vtg was significantly induced in the males in the group C. In generation F1, inhibition of CAT D activities and decrease of reproductive success were only found in pellet A group, but not in pellet B group. These findings indicate that the selection of diet is extremely important to assure veracity of the experiment results. PMID- 21787672 TI - Zearalenone activates pregnane X receptor, constitutive androstane receptor and aryl hydrocarbon receptor and corresponding phase I target genes mRNA in primary cultures of human hepatocytes. AB - The mycotoxin zearalenone (ZEN) is found worldwide as a contaminant in cereals and grains. ZEN subchronic and chronic toxicities are dominated by reproductive disorders in different mammalian species which have made ZEN established mammalian endocrine disrupter. Over the last 30 years of ZEN biotransformation study, the toxin was thought to undergo reductive metabolism only, with the generation in several species of alpha- and beta-isomers of zearalenol. However, recent investigations have noticed that the mycoestrogen is prone to oxidative metabolism leading to hydroxylation of ZEN though the involvement of different cytochromes P450 (CYPs) isoforms. The aim of the present study was to further explore the effect of ZEN on regulation of some CYPs using primary cultures of human hepatocytes. For this aim, using real time RT-PCR, we monitored in a first time, the effect of ZEN on mRNA levels of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AhR), nuclear receptors known to be involved in the regulation of some CYPs. In a second time, we looked for ZEN effect on expression of PXR, CAR and AhR corresponding phase I target genes (CYP3A4, CYP3A5, CYP2B6, CYP2C9, CYP1A1 and CYP1A2). Finally, we realised the luciferase assay in HepG2 treated with the toxin and transiently transfected with p-CYP3A4-Luc in the presence of a hPXR vector or transfected with p-CYPA1 Luc.Our results clearly showed that ZEN activated human PXR, CAR and AhR mRNA levels in addition to some of their phase I target genes mainly CYP3A4, CYP2B6 and CYP1A1 and at lesser extent CYP3A5 and CYP2C9 at ZEN concentrations as low as 0.1 MUM. PMID- 21787673 TI - Pubertal exposure to bisphenol A disrupts behavior in adult C57BL/6J mice. AB - Bisphenol A (BPA) is a widespread endocrine disrupting chemical that influences adult physiology and behavior after perinatal exposure. However, it is not clear if pubertal exposure to BPA exerts hormone dependent effects on behaviors. Using C57BL/6J mice, we sought to determine how pubertal exposure to BPA affects locomotion, exploration, anxiety and sociability in adulthood. Compared to controls, pubertal exposure to BPA or E(2) (17beta-estradiol) significantly altered female exploratory and anxiety behavior. Moreover, BPA and E(2)-treated female mice displayed increased levels of affiliation to female stimulus mice and decreased levels of affiliation to male stimulus mice; while our control males showed affiliation preference to female stimulus. These results indicate that pubertal exposure to BPA or E(2) may masculinize female social and emotional behavior. PMID- 21787674 TI - Selenium supplementation ameliorates static magnetic field-induced disorders in antioxidant status in rat tissues. AB - The aim of this study was to investigate the effect of selenium supplementation on the antioxidant enzymatic system (such as GPx, GR and SOD), GSH and selenium level in liver, kidney, muscle and brain of static magnetic field (SMF) exposed rats. Male adult rats were divided into control rats (n=6), SMF-exposed rats (128 mT; 1h/day for 5 days), selenium-treated rats (Na(2)SeO(3), 0.2mg/l, in drinking water for 4 weeks) and co-exposed rats (selenium for 4 weeks and SMF during the last 5 consecutive days). Sub-acute exposure to SMF induces a decrease of selenium levels in kidney, muscle and brain. Our results also revealed a decrease of GPx activities in kidney and muscle. By contrast, SMF exposure increased total GSH levels and total SOD activities in liver, while glutathione reductase activity is unaffected. Selenium supplementation in SMF-exposed rats restored selenium levels in kidney, muscle and brain and elevated the activities of GPx in kidney and muscle to those of control group. In the liver, selenium supplementation failed to bring down the elevated levels of total GSH and SOD activity. Our investigations suggested that sub-acute exposure to SMF altered the antioxidant response by decreasing the level of total selenium in kidney, muscle and brain. Interestingly, selenium supplementation ameliorates antioxidant capacity in rat tissues exposed to SMF. PMID- 21787675 TI - Arsenic-induced hepatic mitochondrial toxicity in rats and its amelioration by dietary phosphate. AB - The present study was aimed to test the hypothesis that inorganic phosphate may reduce arsenic toxicity by decreasing its intestinal transference. Co administration of inorganic phosphate (6.56 M) and arsenic (6.07 mM) in the intestinal loops of rats, in situ, caused significant reduction of arsenic transference. Short-term arsenic exposure (3mg/kg body weight/day for 30 days) caused liver damage evidenced by activities of liver enzymes and necroinflammatory changes. These effects of arsenic were coupled with enhanced mitochondrial swelling, inhibition of cytochrome c oxidase, Ca(2+)-ATPase, a decrease in mitochondrial calcium content, changes in indices of hepatic mitochondrial oxidative stress and iNOS expression. Arsenic also increased hepatic caspase 3 activity and DNA fragmentation. All these apoptosis-related molecular changes caused by arsenic could be alleviated by supplementation with inorganic phosphate, which likely suggests a protective role of phosphate against arsenic-induced hepatotoxic changes. PMID- 21787676 TI - Effects of paraoxon on neuronal and lymphocytic cholinergic systems. AB - The cholinergic system in lymphocytes is hypothesized to be a key target for neurotoxic organophosphates (OPs). The present study determined the comparative effects of paraoxon, the active metabolite of OP-parathion, which is detected in the human neuroblastoma line, SH-SY5Y, and leukemic T-lymphocytes, MOLT-3, in vitro. Paraoxon induced cytotoxic effects in a dose- and time-dependent manner in both cells. Further, the paraoxon-induced modulatory effects were comparable despite different cell types, including over-expression of N-terminus acetylcholinesterase (N-AChE) protein, a marker of apoptosis, down-regulations of mRNA encoding M1, M2, and M3 muscarinic acetylcholine receptors (mAChRs), and induction in expression of c-Fos gene, an indication of certain mAChR subtype(s) activation. Furthermore, the non-selective cholinergic antagonist atropine partially attenuated the paraoxon-induced N-AChE and c-Fos activations in both types of cells. These results provide initial and additional information that OPs may similarly induce neuro- and immuno-toxic effects through mAChRs activation, and they underline the potential of using lymphocytes for assessing OPs-induced neurotoxicity. PMID- 21787677 TI - Protective effect of the glial cell line-derived neurotrophic factor (GDNF) on human mesencephalic neuron-derived cells against neurotoxicity induced by paraquat. AB - Paraquat is a cationic herbicide that causes acute cell injury by undergoing redox cycling. Oxidative stress is thought to be the crucial mechanism invoked by this redox-cycling compound. The cytotoxicity of paraquat was examined in an immortalized human mesencephalic neuron-derived cell line. The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction activity was examined as cytotoxicity indicator. Cells were seeded with densities at inoculation of 5 * 10(4)cells/ml and 10 * 10(4)cells/ml, and paraquat was added 24h later to give final concentrations from 10 to 500 MUM. At 24 and 48 h of treatment, mitochondrial activity was determined with the MTT assay. To further understand the effect of paraquat exposure on human mesencephalic neuron-derived cells, the cells were differentiated and similar experiments were carried out. Supplementation of culture medium with dibutyryl cyclic AMP and GDNF significantly increased the resistance of the cultures to the paraquat-mediated cytotoxicity. These results confirm that GDNF confers protection against paraquat mediated cytotoxicity and show that immortalized human mesencephalic neuron derived cells are an adequate in vitro system for evaluating the cytoprotective effects of GDNF on oxidative injury caused by xenobiotics. PMID- 21787678 TI - Therapeutic efficiency of succimer used with calcium and ascorbic acid in the treatment of mild lead-poisoning. AB - The aim of this study was to explore therapeutic efficiency of succimer used with calcium and ascorbic acid in the treatment of mildly lead-poisoned mice and preschool children. Mice were exposed to lead by drinking water, and then treated with saline solution, 50mg/kg body weight (b.w.) succimer, 100mg/kg b.w. succimer, or 50mg/kg b.w. succimer plus calcium and ascorbic acid by gavage. Seventy-two children aged 48-72 months were randomly assigned into combined treatment or nutritional intervention group. Lead levels in blood and bone were analyzed by atomic absorption spectrophotometry. Activities of aminolevulinic acid dehydratase (ALAD) in blood were determined by colorimetric method. Results of animal experiment showed that succimer used alone could reduce lead levels in blood and bone and reverse activities of ALAD in blood, however, a better therapeutic efficiency in mobilizing bone lead could be achieved by succimer used with calcium and ascorbic acid. Findings from the clinical study showed that reduction of blood lead levels (BLLs) between the end and initiation of therapy in the combined treatment group was significantly greater than that in the nutritional intervention group. Percentage of children with BLLs less than 10MUg/dL at the end of therapy and the eighth week after therapy in the combined treatment group was significantly higher than that in the nutritional intervention group. In conclusion, combined use of succimer with calcium and ascorbic acid seemed to be a choice in the treatment of mildly lead poisoned children. PMID- 21787679 TI - Protective role of taurine against genotoxic damage in mice treated with methotrexate and tamoxfine. AB - The genotoxic actions of anti-neoplastic drugs can lead to the development of secondary cancers in patients in extended remission. One of the most attractive approaches to disease prevention involves the use of natural antioxidants to protect tissue against toxic injury. We investigated the modulatory effects of exogenously administered taurine, on the genotoxicity of two well known anti neoplastic drugs methotrexate (MTX) and tamoxifen (TAM) in Swiss albino mice. The animals were randomly divided into six groups consisting of ten mice each. Two groups were received single intraperitoneal injection of MTX (10 mg/kgb.wt.) and TAM (50 mg/kgb.wt.) to induce genotoxicity. Two other groups were treated orally with taurine (100 mg/kgb.wt.) for nine days prior to MTX and TAM administration. A vehicle treated control group and taurine control groups were also included. The protective effects of taurine were monitored by apoptosis assays and level of reduced glutathione (GSH), a key antioxidant, in liver, chromosomal aberrations in somatic and germ cells as well as sperm count, motility and morphology. The results indicated that taurine pre-treatment showed significant increment in the levels of GSH content, reduction in DNA fragmentation and ladder formation in hepatic tissue, suggesting the antioxidant activity of taurine may reduce the toxic effects of MTX and TAM. Treatment with taurine showed also significant reduction in the frequency of chromosomal aberrations in both somatic and germ cells. Moreover, it increases sperm count and motility, and decreases the incidence of sperm abnormalities. In conclusion, it appears that taurine protects against anti-neoplastic drugs-induced genotoxicity in somatic and germ tissues and may be of therapeutic potential in alleviating the risk of secondary tumors in chemotherapy. PMID- 21787680 TI - Up-regulation of hypoxia-inducible factor-1 alpha by cobalt chloride prevents hearing loss in noise-exposed mice. AB - Since hypoxia-inducible factor-1alpha (HIF-1alpha) is the key transcription factor that enables cells to survive in hypoxia, we have investigated whether an upregulation of HIF-1alpha prevents the noise-induced hearing loss in BALB/c hybrid mice, which were intraperitoneally injected with CoCl(2) (a HIF-1alpha inducer) and exposed to white band noise with 120 dB peak equivalent sound pressure level for 3h once daily for 3 days. In the CoCl(2) treatment group, HIF 1alpha was found to be up-regulated in the cochlear tissues and the hearing loss was largely prevented. Histologically, the loss of sensory hair cells was also significantly lower in the CoCl(2) treatment group than the Control group. However, YC-1 (a HIF-1alpha inhibitor) attenuated the preventive effect of CoCl(2) on the noise-induced hearing loss. These results suggest that HIF-1alpha plays a crucial role in the prevention against noise trauma in the inner ear. PMID- 21787681 TI - The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentration in Thai bus drivers. AB - Polycyclic aromatic hydrocarbons (PAHs) are associated with an increased cancer risk. CYP1A1 and GSTs enzymes are important in metabolism of PAHs. Genetic polymorphisms of these enzymes are responsible for enzyme activity and concentration variation. The objectives of this study were to evaluate association of 1-OHP concentration with genetic polymorphisms of CYP1A1 and GSTs in Thai bus drivers. The results showed that 1-OHP levels in bus drivers were significantly higher than that in the control group. Significant difference in 1 OHP was found between smokers and non-smokers, in only bus drivers. Significantly increasing of 1-OHP levels were observed in bus drivers with CYP1A1 MspI and exon 7 variants. Whereas, bus drivers with GSTP1 Val and GSTM1 null genotypes showed decreasing in excretion of 1-OHP. No association between 1-OHP and polymorphisms of GSTT1 was found. This study indicated that 1-OHP concentrations were associated with exposure to air pollution, cigarette smoking and polymorphisms of CYP1A1, GSTM1 and GSTP1 genes. PMID- 21787682 TI - Elevated serum neopterin levels in acetaminophen-induced liver injury. AB - Neopterin is synthesized in macrophage/Kupffer cells by interferon-gamma and other cytokines. This study aimed to evaluate the utility of using neopterin as a biomarker of acetaminophen (APAP)-induced liver injury. Wistar rats, randomly divided into two groups (APAP and normal), received APAP (1.0 g/kg) and distilled water, respectively, by gastric tube. The APAP group had a higher degree of liver necrosis than the control group. The APAP group also had significantly higher serum neopterin levels than the normal group. Serum neopterin levels correlated with serum AST, ALT activities, and degree of necrosis. This study demonstrates the preclinical utility of neopterin as a biomarker for the animal model of APAP induced liver injury. Further research studies are required to determine the preclinical opportunities of using neopterin as a marker of APAP-induced liver injury. PMID- 21787683 TI - Intrastriatal manganese chloride exposure causes acute locomotor impairment as well as partial activation of substantia nigra GABAergic neurons. AB - Our previous studies showed chronic exposure to manganese chloride (Mn) causes locomotor impairment and lesion of dopaminergic neurons in substantia nigra (SN). But effects of acute Mn exposure on locomotor ability, SN dopaminergic and GABAergic neurons were not clear. In the current study, Mn was injected into the striatum of GAD(67)-GFP mice. Twenty-four hours after injection, locomotor ability was quantitatively evaluated with behavioral tests (rotarod test and open field test). Meanwhile, the numbers of dopaminergic and GABAergic neurons were counted through immunofluorescent staining for TH and GFP respectively, and activations of dopaminergic and GABAergic neurons were evaluated by double immunofluorescent labeling for TH/Fos and GFP/Fos, respectively. Behavioral tests showed a significant locomotor impairment 24h after Mn injection. The numbers of SN dopaminergic and GABAergic neurons were not altered significantly 24h after Mn injection; however, some of SN GABAergic neurons were activated and dopaminergic neurons were left inactivated. In addition, there were still a large number of Mn activated neurons that fell into neither dopaminergic nor GABAergic criteria. Our data suggested that activation of SN GABAergic neurons but not lesion of dopaminergic neurons, which was found to play an important role in the Mn-induced chronic neurotoxicity in our previous studies, contributed partially to Mn induced acute locomotor impairment. Therefore we come to the conclusion that Mn exposure can induce acute or chronic neurotoxicity via different neuronal elements. PMID- 21787684 TI - Aluminum nanoparticle exposure in L1 larvae results in more severe lethality toxicity than in L4 larvae or young adults by strengthening the formation of stress response and intestinal lipofuscin accumulation in nematodes. AB - Toxicity of Al(2)O(3)-NPs, as compared to that of Al(2)O(3), to L1-larval, L4 larval or young adult nematodes was evaluated. When exposure was performed at L1 larval stage, the significant increases of lethality, stress response, and intestinal lipofuscin autofluorescence were observed in 6.3-203.9 mg/L of Al(2)O(3)-NPs exposed nematodes. In contrast, when exposure was performed at L4 larval or young adult stage, the significant increases of lethality and intestinal lipofuscin autofluorescence were observed in 12.7-203.9 mg/L of Al(2)O(3)-NPs exposed nematodes, and the significant inductions of stress response were detected in 25.5-203.9 mg/L of Al(2)O(3)-NPs exposed nematodes. Moreover, the lethality was significantly correlated with the stress response and the intestinal lipofuscin autofluorescence in Al(2)O(3)-NPs exposed nematodes. These data imply that Al(2)O(3)-NPs exposure in L1 larvae causes more severe lethality toxicity than in L4 larvae or young adults by strengthening the formation of stress response and intestinal lipofuscin accumulation in nematodes. PMID- 21787685 TI - Regulation of thyroid hormone related genes mRNA expression by exogenous T3 in larvae and adult Chinese rare minnow (Gobiocypris rarus). AB - In this study, the expression time and profiles of thyroid hormone receptor alpha (tralpha), type I and II deiodinase enzymes (d1 and d2), transthyretin (ttr), sodium iodide symporter (nis), and thyrotropin-releasing hormone receptor (trhr) genes in Chinese rare minnow (Gobiocypris rarus) were determined using real-time PCR. Meanwhile, the changes of these genes were investigated by exogenous T(3) (3.8 nM) in larvae and adult fish. The retardation of swim bladder development and growth inhibition were observed for larvae, and the transcription of tralpha, d1, d2, nis, and trhr was significantly down-regulated at the end of exposure (21 d). In adults, a down-regulation of tralpha, d1, nis, and trhr mRNA levels occurred at 7th or 14th day of exposure, but returned back to their normal levels similar to control at the end of exposure. The down-regulation of gene mRNA expression could serve as a compensatory mechanism for the activation of thyroid system. PMID- 21787686 TI - Differential accumulation levels in the brain of rats exposed to the endocrine disruptor 4-tert-octylphenol (OP). AB - Octylphenol (OP) is an endocrine-disrupting chemical that accumulates in various organs. It has also been shown to exert noxious effects on the central nervous system. In the present study, we measured in Sprague-Dawley rats the degree of OP accumulation in different areas of the brain and investigated the effect of OP in pain modulation. Two groups of male Sprague-Dawley rats were treated for 20 days with 50mg/kg BW/day of OP (group 1) or vehicle (group 2). At the end of the treatment, the formalin test was performed to evaluate the effect of OP exposure on pain. Soon after, rats were sacrificed, and the accumulation of OP in the cerebral cortex, hippocampus, hypothalamus, cerebellum, thalamus, striatum, mesencephalus and ventral hindbrain was measured by HPLC analysis. The results showed a greater accumulation of OP in the cerebral cortex compared to all the other areas; there was also more accumulation in the cerebellum compared to the mesencephalus and thalamus. No accumulation was found in the striatum. These results suggest that there is a preferential accumulation of OP in different areas of the brain with consequences to neural behaviour. On the contrary, experiments on facial grooming did not show significant effects of OP on pain. PMID- 21787687 TI - Effect of the exposure to metal lead on the regenerative ability of Lumbriculus variegatus (Oligochaeta). AB - Lumbriculus variegatus is a recommended species for use in sediment toxicity tests and is known to have a remarkable power of segmental regeneration. Here, we tested the effects of a chemical stressor on the regenerative ability of L. variegatus and investigated the potential of regenerative ability as an additional new parameter in standard toxicity tests. The worms were cut into two equal segments, and exposed to various concentrations of lead. Two assays were performed: one with sediment spiked with lead and the other with water spiked with lead. The endpoints were segmental regeneration, survival and behaviour. Regenerative ability was clearly affected by exposure to lead-contaminated sediment and lead-contaminated water. Organisms exposed to lead grew more slowly than those not exposed; worms exposed to contaminated water showed higher mortalities than those exposed to contaminated sediment. Results showed that L. variegatus' regenerative ability, as a developmental test parameter, is more sensitive than mortality. PMID- 21787688 TI - Anthocyanins isolated from the purple-fleshed sweet potato attenuate the proliferation of hepatic stellate cells by blocking the PDGF receptor. AB - During the process of liver fibrosis, hepatic stellate cells (HSCs) play a critical role in the increased formation and reduced degradation of extracellular matrix in the liver. We investigated the anti-proliferative effects of an anthocyanin fraction (AF), isolated from the purple-fleshed sweet potato, on platelet-derived growth factor (PDGF)-BB-dependent signaling pathways in HSC-T6 cells. HSC proliferation plays a pivotal role in liver fibrogenesis. The AF suppressed HSC activation, including PDGF-induced proliferation and alpha-smooth muscle actin (alpha-SMA) expression. Additionally, AF inhibited PDGF-BB-induced Akt and ERK1/2 phosphorylation. AF inhibited the phosphorylation level of PDGF receptor-beta (PDGFR-beta) following PDGF-BB stimulation, providing a mechanism for the inhibition of AF-mediated kinase. These results suggest that AF suppresses HSC proliferation by blocking PDGFR-beta signaling, inhibiting Akt and ERK1/2 activation and alpha-SMA expression. PMID- 21787689 TI - Antimutagenic, antigenotoxic and antioxidant activities of phenolic-enriched extracts from Teucrium ramosissimum: combination with their phytochemical composition. AB - The evaluation of the mutagenic and antimutagenic actions of extracts obtained from aerial part of Teucrium ramosissimum was assayed using the Salmonella typhimurium assay system. The effect of the same extracts on genotoxicity and SOS response induced by aflatoxin B(1) as well as nitrofurantoin was investigated in a bacterial assay system, i.e., the SOS chromotest with Escherichia coli PQ37. The different extracts showed no mutagenicity when tested with Salmonella typhimurium strains TA100, TA98 and TA1535 either with or without S9 mix. In contrast, our results prove that T. ramosissimum extracts possess antimutagenic effects against sodium azide, aflatoxin B1, benzo[a]pyrene and 4-nitro-o phenylenediamine. Moreover, the T. ramosissimum tested extracts exhibited no genotoxicity either with or without the external S9 activation mixtures. However, all the extracts significantly decreased the genotoxicity induced by aflatoxin B(1) and nitrofurantoin. The result obtained by the Ames test confirms those of SOS chromotest. Antioxidant capacity of the tested extracts was evaluated using the enzymatic (xanthine/xanthine oxidase assay) and the non enzymatic (NBT/riboflavine, DPPH and ABTS assays) systems. All extracts exhibited high antioxidant activity except the chloroform and the methanol extracts in DPPH and NBT/riboflavine assays respectively. Our results underline the potential of T. ramosissimum to avoid mutations and also its antioxidant potential. PMID- 21787690 TI - Mitochondria protection of baicalein against oxidative damage via induction of manganese superoxide dismutase. AB - This study investigated the cytoprotective effect of baicalein (5,6,7 trihydroxyflavone) against oxidative stress-induced mitochondrial dysfunction. Electron spin resonance (ESR) spectrometry revealed that baicalein showed significant scavenging effects on superoxide radicals and hydroxyl radicals. When H(2)O(2) treatment induces an increase in mitochondrial reactive oxygen species (ROS), baicalein treatment decreased high level of ROS. Baicalein significantly reduced alteration of Bcl-2 family proteins, the release of cytochrome c from mitochondria into the cytosol via inhibition of mitogen-activated protein kinase kinase-4 (MKK4/SEK1) and c-Jun NH(2)-terminal kinase (JNK) cascades induced by H(2)O(2) treatment. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in mitochondria against oxidative stress. Baicalein restored both MnSOD protein expression and activity, which were abolished by H(2)O(2) treatment. The transcription factor NF-E2-related factor 2 (Nrf2) is a critical regulator of MnSOD, achieved by binding to the antioxidant response element (ARE). Baicalein restored nuclear Nrf2 protein expression and its ARE binding activity, which were abolished by H(2)O(2) treatment. These studies demonstrate that baicalein attenuates mitochondrial oxidative stress by activating Nrf2 mediated MnSOD induction. PMID- 21787691 TI - Toxicological evaluation of Pterocaulon polystachyum extract: a medicinal plant with antifungal activity. AB - Pterocaulon polystachyum DC is a native species to southern Brazil, Paraguay, Uruguay and northeastern Argentina. It is utilized to treat animal problems popularly diagnosed as "mycoses". The antifungal and amebicidal activity of its hexane extract has been previously reported, although there are no studies confirming the safety of this plant for therapeutic purposes to date. Hence, this study investigates the toxic effects of a hexane extract of Pterocaulon polystachyum administered as acute and subacute oral treatments. After acute treatment the extract caused alterations in biochemical parameters, morphological alterations in tissues and was genotoxic, according to the comet assay; neither mortality nor visible signs of lethality were seen in mice. Similarly subacute treatment caused important differences in biochemical parameters and tissues, between control and treated groups. The results also revealed genotoxicity in kidney tissue, though no mutagenicity was detected by the micronucleus test. No animal died during the treatment period. PMID- 21787692 TI - Assessment of chromosomal aberrations, micronuclei and proliferation rate index in peripheral lymphocytes from Tunisian nurses handling cytotoxic drugs. AB - Anti-neoplastic agents are widely used in the treatment of cancer and some non neoplastic diseases. These drugs have been proved to be mutagens, carcinogens and teratogens. To check the eventual effects of anti-cancer drugs on occupationally exposed Tunisian nurses, we used chromosomal aberration assay and micronucleus assay. Both parameters have been used to evaluate cellular DNA damage in the biological monitoring of occupationally exposed workers and each assay has its own aim .We used the proliferation rate index to evaluate the cytotoxic effect of antineoplastic drugs in exposed nurses. The frequency of binucleated micronucleated cells was significantly higher in nurses handling cytostatic drugs than in control. We detected also a significant increase of structural chromosomal aberrations. Control subjects generally had significantly higher values of proliferation rate index compared to expose ones. Our results confirm the genotoxic and the cytotoxic effects of antineoplastic drugs in blood lymphocytes circulation. This study points to the necessity to work under more safe and controlled conditions during the preparation and the administration of anti-cancer drugs. PMID- 21787693 TI - Nuclear factor-kappaB inhibitors alleviate nivalenol-induced cytotoxicity in HL60 cells. AB - Tricothecene mycotoxins, such as nivalenol, are toxic to leukocytes. To elucidate the molecular mechanism of nivalenol toxicity, we investigated the involvement of nuclear factor-kappaB (NF-kappaB) in nivalenol-induced cytotoxicity in HL60 cells using the NF-kappaB inhibitors pyrrolidinedithiocarbamate (PDTC) and dexamethasone. Cells were treated with the chemicals for 24h before assays were performed. Nivalenol elicited interleukin (IL)-8 secretion. IL-8 secretion was lower in cells concomitantly treated with nivalenol and NF-kappaB inhibitors than with nivalenol alone. Nivalenol reduced monocyte chemotactic protein (MCP)-1 secretion. MCP-1 secretion was higher in cells concomitantly treated with nivalenol and NF-kappaB inhibitors than with nivalenol alone. NF-kappaB inhibitors thus alleviated the effects of nivalenol, indicating that NF-kappaB is important for nivalenol-caused changes in cytokine secretion. Nivalenol hindered cell proliferation, and dexamethasone reduced this effect, suggesting that NF kappaB contributes to cell proliferation. Thus, it appears that NF-kappaB is involved in nivalenol-induced toxicity in HL60 cells. PMID- 21787694 TI - Environmental and occupational exposure to lead as a potential risk factor for cardiovascular disease. AB - We have evaluated current knowledge on relations between environmental and occupational exposure to lead with a strong emphasis on cardiovascular disease risk factors, such as the influence of lead compounds on lipid disturbances and arterial blood pressure. In addition, "novel" biochemical and vascular risk factors for cardiovascular diseases were discussed, as well as the combination of lead exposure and genetic predisposition to cardiovascular diseases. Occupationally and educationally, awareness of the unfavourable effects of lead on cardiovascular diseases risk factors should be emphasised. Indeed, accurate identification of the various mechanisms that might account for the effects of lead on the cardiovascular system should be of the highest priority in this field of research. PMID- 21787695 TI - DNA damage and cholinesterase activity in occupational workers exposed to pesticides. AB - The present study was designed to evaluate genotoxicity, acetyl cholinesterase (AChE) activity, hepatic and renal toxicity in occupational workers exposed to mixture of pesticides (n=70) with same number of healthy subjects as controls. The mean comet tail DNA % (TD %) and tail moment (TM) were used to measure DNA damage, while AChE activity and other biochemical parameters such as markers of nephrotoxicity (urea and creatinine) and hepatotoxicity (AST, ALT and ALP) were measured as biomarkers for toxicity due to exposure of pesticides. The occupational workers were continuously exposed to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion on a regular interval as per usage and activity. The comet assay using lymphocytes of exposed workers showed significantly higher TD percentage value (60.43% vs. 31.86%, p<0.001) and TM value (14.48 MUm vs. 6.42 MUm, p<0.001) in occupational workers as compared to controls. AChE activity in erythrocytes was found to be decreased (3.45 KAU/L vs. 9.55 KAU/L in controls, p<0.001) and associated with the duration of exposure to pesticides used by the workers. Enzyme levels for hepatic and renal functions were also found significantly different in occupational workers than healthy controls (p<0.001). These results suggest that the exposure to mixture of pirimiphos methyl, chlorpyrifos, temephos and malathion may induce DNA damage, decrease in AChE activity, hepatotoxicity as well as nephrotoxicity. Periodic biomonitoring of these biomarkers along with imparting education and training to occupational workers for safe application of pesticides is recommended for its potential hazards. PMID- 21787696 TI - The effect of Laminaria japonica polysaccharides on the recovery of the male rat reproductive system and mating function damaged by multiple mini-doses of ionizing radiations. AB - To evaluate the radiation-protect effects of Laminaria japonica polysaccharides (LJP) on male reproductive system damage and mating dysfunction induced by multiple mini-dose ionizing radiations, male rats were administrated with radiation and/or LJP. Results showed that mating function (such as erection, mount and ejaculation), sperm count and survival rate in LJP group were significantly better than the corresponding model group after the radiation. The testis organ coefficient, GSH (glutathione) content, serum sex hormones (luteinizing hormone, follicle-stimulating hormone, testosterone and estradiol) levels improved while MDA (malondialdehyde) content decreased. In addition, SOD (superoxide dismutase), GSH-PX (glutathione peroxidase), LDH (lactate dehydrogenase) activities were enhanced while testicular tissue damage was reduced, 14 days after the cessation of radiation; all indicators in the LJP group were similar to the control group. Our results suggest that, LJP has some promoting effects on the recovery of the reproductive system and mating dysfunction induced by radiation. PMID- 21787697 TI - Dynamic analysis of exposure to aluminum and an acidic condition on bone formation in young growing rats. AB - The toxic effects of exposure to aluminum (Al) in an acidic condition on bone formation in young growing rats were studied. Wistar rats were divided randomly into Al-treated group (100mg Al(3+)/L; pH 5.6) and control group (distilled water). Al-treated rats showed lower body weight, lower serum pH, higher accumulation of Al, in addition to disordered metabolism of calcium and phosphorus compared with control rats. The levels of parathyroid hormone, calcitonin, osteocalcin, procollagen carboxy-terminal propeptide and bone alkaline phosphatase were significantly lower in the Al-treated group than in the control group from days 90, 30, 60, 60 and 90, respectively. The bone mineral density of the distal and proximal femoral metaphysis was significantly lower in the Al-treated group than in the control group on days 120 and 150. These findings suggest that long-term Al exposure in an acidic condition inhibits bone formation and induces bone loss in young growing animals. PMID- 21787698 TI - Protective effect of selenium on aluminium-induced oxidative stress in mouse liver in vivo. AB - The aim of the study was to evaluate possible protective effects of selenium (Se) against systemic aluminium (Al) toxicity and the redox status of mouse liver after short-term (16 h) exposure to Al in vivo. BALB/c mice were injected i.p. with AlCl(3) (25mg Al(3+) per kg of body mass) or/and Na(2)SeO(3) (1.25mg Se per kg of body mass). The 4-fold increased activity of ALT in serum showed systemic hepatotoxicity that Se could not prevent by competitive mechanisms. The protective effects of Se could only be observed on intracellular oxidative stress events as determined by glutathione status. Exposure to Al leads to the decrease in the total glutathione (GSH(tot)) and GSH/GSSG redox ratio to about 50% of the control. Upon co-exposure to Se+Al, the concentration of GSH(tot) and the redox ratio was restored to the control values. Our results indicate that Se did not have a protective effect on Al-linked liver toxicity, but did ameliorate intracellular oxidative stress processes mediated by glutathione. PMID- 21787699 TI - Effects of cytochrome P450 1A substrate (difloxacin) on enzyme gene expression and pharmacokinetics in crucian carp (hybridized Prussian carp). AB - Cytochrome P450s (CYPs) play a prominent role in drug metabolism and biotransformation which are distributed in liver of aquatic animals. However, limited information is available about CYP genes involved in drug metabolism in fish. In the present study, we explore CYP1A characterization for DIF metabolism. Firstly, we cloned and characterized the full-length cDNA sequence of a CYP1A gene from crucian carp (hybridized Prussian carp), the predicted protein sequence for CYP1A comprise 496 amino acids. The heme-binding region of the CYP1A, encompassing the amino acid sequence GLGKRRCIG, which is identical to the same region of other homologues. Secondly, we studied the difloxacin (DIF) kinetics and the effects of DIF on their corresponding CYP1A mRNA levels in liver of crucian carp. CYP1A1 mRNA expression was analyzed by real-time PCR, and DIF concentration was determined by reversed-phase high-performance liquid chromatography (RP-HPLC). Results showed that the concentration of DIF in liver reached its peak (67.70 mg kg(-1)) at 0.5h, while the CYP1A1 gene expression was at the lowest point. CYP1A mRNA was down-regulated by 6.5 mg ml(-1) DIF in the liver of crucian carp. Thus, our work confirmed that DIF is both the substrate and inhibitor of CYP1A. The information provided a model for the potential utility of gene expression analysis and drug metabolization in fish. PMID- 21787700 TI - Mutagenic and genotoxic assessment of atrazine-based herbicide to freshwater fish Channa punctatus (Bloch) using micronucleus test and single cell gel electrophoresis. AB - The mutagenic and genotoxic effect of 'Rasayanzine', an atrazine herbicide, was carried out in fish Channa punctatus using micronucleus and single cell gel electrophoresis (SCGE) assays. Three sub-lethal concentrations of the test material viz., SL-I (1/5th LC(50)=~8.48 mgL(-1)), SL-II (1/8th LC(50)=~5.30 mgL( 1)) and SL-III (1/10th LC(50)=~4.24 mgL(-1)) were calculated using LC(50) value and the fish specimens were exposed to these concentrations. Erythrocyte and gill cells were sampled on day 0, 1, 3, 5, 7, 14, 21, 28 and 35 of exposure for assessment of micronuclei induction in blood erythrocytes and DNA damage using SCGE assay in both blood erythrocytes and gill cells. Significant effects (p<0.01) for both concentration and time of exposure were observed in treated fish. Micronuclei induction in erythrocytes was highest (8.4 mgL(-1)) on day 7 of exposure. The highest level of DNA damage in the SCGE was observed in both tissues on day 5 at all concentrations followed by gradual non-linear decline. This study further confirmed that the micronucleus and SCGE assays are useful in determining potential genotoxicity of water pollutants and might be appropriate as part of monitoring program. PMID- 21787701 TI - Toxicological responses to acute mercury exposure for three species of Manila clam Ruditapes philippinarum by NMR-based metabolomics. AB - The Manila clam (Ruditapes philippinarum) has been considered a good sentinel species for metal pollution monitoring in estuarine tidal flats. Along the Bohai coast of China, there are dominantly distributed three species of clams (White, Liangdao Red and Zebra in Yantai population) endowed with distinct tolerances to environmental stressors. In this study, adductor muscle samples were collected from both control and acute mercury exposed White, Liangdao Red and Zebra clams, and the extracts were analyzed by NMR-based metabolomics to compare the metabolic profiles and responses to the acute mercury exposure to determine the most sensitive clam species capable of acting as abioindicator for heavy metal pollution monitoring. The major abundant metabolites in the White clam sample were branched-chain amino acids (leucine, isoleucine and valine), lactate, arginine, aspartate, acetylcholine, homarine and ATP/ADP, while the metabolite profile of Zebra clam sample comprised high levels of glutamine, acetoacetate, betaine, taurine and one unidentified metabolite. For the Liangdao Red clam sample, the metabolite profile relatively exhibited high amount of branched-chain amino acids, arginine, glutamate, succinate, acetylcholine, homarine and two unassigned metabolites. After 48h exposure of 20MUgL(-1) Hg(2+), the metabolic profiles showed significant differences between three clam species, which included increased lactate, succinate, taurine, acetylcholine, betaine and homarine and decreased alanine, arginine, glutamine, glutamate, acetoacetate, glycine and ATP/ADP in White clam samples, and elevated succinate, taurine and acetylcholine, and declined glutamine, glycine, and aspartate in Liangdao Red clam samples, while the increased branched-chain amino acids, lactate, succinate, acetylcholine and homarine, and reduced alanine, acetoacetate, glycine and taurine were observed in the Zebra clam samples. Overall, our findings showed that White clams could be a preferable bioindicator for the metal pollution monitoring based on the more sensitive metabolic changes in the adductor muscle compared with other two (Liangdao Red and Zebra) clam species. PMID- 21787702 TI - Effect of propetamphos on the male rats reproductive system. AB - The present study aimed at defining the testicular toxicity of propetamphos. Mature male albino rats (5-6 months old) were treated with propetamphos orally at doses of 0, 0.18, 0.38, 0.75, 1.5 and 3mg/kg/day for 60 consecutive days. Propetamphos at a dose of 0.38 mg/kg/day significantly reduced the sperm motility only. At 0.75 mg/kg/day sperm count, sperm motility, plasma testosterone level and activity of sorbiol dehydrogenase (SDH) were significantly reduced and sperm morphological abnormalities were significantly increased. At 1.5mg/kg/day weight of testes, seminal vesicle and epididymis were reduced dose dependently whereas, at 3mg/kg/day, weight of prostate gland and activities of acid phosphatase (ACP) and glucose-6-P-dehydrogenase (G6PDH) were decreased significantly. On histopathological examination indicated toxicity of propetamphos on testes depending on dose and observed at doses higher than 0.38 mg/kg/day. These results indicate testicular toxicity of propetamphos at dose of 0.38 mg/kg/day or higher in male albino rats. PMID- 21787703 TI - Chokeberry (Aronia melanocarpa) juice modulates 7,12-dimethylbenz[a]anthracene induced hepatic but not mammary gland phase I and II enzymes in female rats. AB - Chokeberry is a rich source of procyanidins known to have several types of biological activity including anticarcinogenic potential in experimental models. In this study we examined the effect of chokeberry juice on the hepatic and mammary gland carcinogen metabolizing enzyme expression altered by the polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene (DMBA). Sprague-Dawley rats were gavaged with chokeberry juice (8 ml/kg b.w.) for 28 consecutive days. DMBA was administered i.p. on the 27th and the 28th days. Pretreatment with chokeberry juice reduced the activity of CYP1A1 and increased that of CYP2B involved in metabolic activation/detoxication of DMBA in rat liver, as well as expression and activity of phase II enzymes. Chokeberry juice had no effect on these parameters in the mammary gland and DMBA induced DNA damage in rat blood cells. These results together with our earlier observations indicate that metabolic alterations induced by chokeberry feeding are tissue specific and depend on the class of carcinogen. PMID- 21787704 TI - Assessment of seasonal and sex-related variability of biomarkers in carp (Cyprinus carpio L.) from Karakaya Dam Lake, Turkey. AB - This study examines seasonal changes in the activities of selected biomarkers in carp (Cyprinus carpio L.) from Karakaya Dam Lake and evaluates the influence of gender and environmental factors on those activities. Physicochemical characteristics of water were evaluated in the lakewater. Fish were sampled on seasonal basis, and liver ethoxyresorufin-O-deethylase (EROD), glutathione-S transferase, glutathione reductase, plasma lactate dehydrogenase, aspartate and alanine aminotransferase, and brain acetylcholinesterase (AChE) activities were assayed. Plasma vitellogenin level and hepatosomatic index and condition factors were also determined. Strong seasonal variations were observed but there were no gender differences among selected markers. The highest vitellogenin level of male fish was detected as 606ng/mL which represents the estrogenicity of water in the lake in September 2005. In addition, the seasonal changes of some biomarkers such as EROD and AChE showed that the lake may be at risk of pollution by some xenobiotics arising from agricultural and/or industrial activities. PMID- 21787705 TI - Liver and heart toxicity due to 90-day oral exposure of ICR mice to N,N dimethylformamide. AB - N,N-dimethylformamide (DMF) is a colorless liquid with a faint amine odor, which is widely used in the world. DMF exposure may induce adverse effects on liver, but few studies showed damage to heart after exposure to DMF. In the present study, DMF was administered to ICR mice with the doses of 0.32, 0.63 and 1.26 g/kg of body weight by gavage for 90 days. The increase in the relative liver weight is accompanied with the presence of the centrilobular hepatocellular hypertrophy as well as increased serum levels of aspartate transaminase (AST) and alanine transaminase (ALT). An increase of malondialdehyde (MDA) level was shown in liver homogenate, while superoxide dismutase (SOD) and glutathione (GSH) activities decreased. Heart damage was also shown in mice exposed to DMF for 90 days, although pathological examination showed only slight inflammatory cell infiltration. Increased levels of serum lactate dehydrogenase (LDH), isoenzymes of creatine kinase (CK-MB) and cardiac troponin I (cTnI) were shown. Increased level of MDA was also shown in heart homogenate, in contrast with the decreased activity of SOD. These data suggested that the administration of DMF could induce liver and heart injuries and oxidative stress was involved in the toxic effects. PMID- 21787707 TI - Modulation of phase-II enzyme activities in benzene treated ovariectomized rats. AB - The aim of the study was to determine the influence of ovariectomy on phase II enzymes viz. glutathione-S-transferase (GST), glutathione peroxidase (GPX) and catalase (CAT) in liver and kidney of female rats treated with benzene. The results showed the significant decrease of the GST and GPX activity in benzene treated rats after ovariectomy. However progesterone supplementation stimulated the activity of GST and GPX in liver and kidney of benzene treated non ovariectomized and ovariectomized rats. Progesterone supplementation to benzene treated ovariectomized rats helps to gain in CAT activity. Our results on DNA damage using single cell gel electrophoresis also confirmed our findings on antioxidant enzymes. The results showed that lack of protective progesterone against benzene toxicity is reflected in alterations in antioxidant enzyme activities. However progesterone therapy to benzene treated ovariectomized rats results in activating the antioxidant defence system. Since female workers are engaged in industrial sector, these results are important from occupational health point of view. Benzene exposure affects their reproductive health. Nevertheless, it could be modulated by suitable hormonal therapy. PMID- 21787706 TI - The effect of oxime reactivators on muscarinic receptors: functional and binding examinations. AB - The antidotal treatment of organophosphorus poisoning is still a problematic issue since no versatile antidote has been developed yet. In our study, we focused on an interesting property, which does not relate to the reactivation of inhibited acetylcholinesterase (AChE) of some oximes, but refers to their anti muscarinic effects which may contribute considerably to their treatment efficacy. One standard reactivator (HI-6) and two new compounds (K027 and K203) have been investigated for their antimuscarinic properties. Anti-muscarinic effects were studies by means of an in vitro stimulated atrium preparation (functional test), the [(3)H]-QNB binding assay and G-protein coupled receptor assay (GPCR, beta Arrestin Assay). Based on the functional data HI-6 demonstrates the highest anti muscarinic effect. However, only when comparing [(3)H]-QNB binding results and GPCR data, K203 shows a very promising compound with regard to anti-muscarinic potency. The therapeutic impact of these findings has been discussed. PMID- 21787708 TI - Alterations in Ca2+ homeostasis and oxidative damage induced by ethion in erythrocytes of Wistar rats: ameliorative effect of vitamin E. AB - Organophosphate (OP) insecticides have been reported to induce oxidative stress due to lipid peroxidation and alteration in defense mechanisms. It is known that calcium content in erythrocytes plays a very important in normal physiology of cells. Erythrocytes are a very convenient model to understand the susceptibility of membrane to oxidative damage induced by various xenobiotic compounds. The aim of present study was to investigate the effects of ethion induced oxidative damage, alterations in membrane bound enzymes and Ca(2+) homeostasis and a possible protective role of vitamin E. Adult male albino rats of Wistar strain were orally administered ethion and vitamin E daily for 28 days. Animals were randomly divided into four groups: control; ethion treated (2.7 mg/kgbw/day); vitamin E treated (50mg/kg of bw/day); ethion+vitamin E treated. The animals were sacrificed after 7, 14, 21 and 28 days. Erythrocyte membranes were prepared and analyzed for protein, lipid peroxidation (LPO) and membrane bound ATPases. Furthermore, Ca(2+) homeostasis as function of time and concentration was evaluated in erythrocytes. The results from the present study show that in vivo administration of ethion resulted in oxidative damage to erythrocyte membranes as evident by increased lipid peroxidation. The increased LPO following ethion intoxication was accompanied by significant decrease in the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase and disturbed Ca(2+)homeostasis in erythrocytes. Furthermore, vitamin E treatment had a beneficial effect by decreasing lipid peroxidation; partially restoring activities of membrane bound ATPases and Ca(2+) homeostasis. The present study suggests that ethion exerts its toxic effect by increasing LPO, altering the activity of membrane bound enzymes and disturbing Ca(2+) homeostasis. Vitamin E treatment ameliorated the toxic effects of ethion suggesting its role as a potential antioxidant. PMID- 21787709 TI - Diuron exposure induces systemic and organ-specific toxicity following acute and sub-chronic exposure in male Wistar rats. AB - Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a substitute urea herbicide widely used on agricultural crops with potential mutagenic, teratogenic, reproductive and carcinogenic effects. Nonetheless, its toxic potential on the immune system needs a detailed assessment. Thus, in order to evaluate the adverse effect of this herbicide on lymphohematopoietic organs and macrophage activity, male Wistar rats were orally treated with Diuron at 125, 1250 and 2500 ppm for 14, 28 or 90 days. General signs of toxicity were observed in Diuron-treated groups (1250 and 2500 ppm), including reduced food intake and body weight gain, as well as higher relative weights for spleen, kidneys and liver (28 and 90-day toxicity studies) and elevated serum levels of ALT, albumin, total protein, creatinine and urea (28-day toxicity study). Diuron exposure caused a severe depletion of splenic white pulp compartments and cellularity, followed by a decreased number of CD4(+) T lymphocytes, increased extramedullary hematopoiesis and deposition of hemosiderin in red pulp. Despite alteration in macrophage spreading, the macrophagic activity was not significantly affected by the herbicide. Under these experimental conditions, the results suggest that Diuron exerts systemic and target-organ toxicity, mainly at higher concentration. PMID- 21787710 TI - Immunopotentiation and antitumor effects of a ginsenoside Rg3-fortified red ginseng preparation in mice bearing H460 lung cancer cells. AB - Antitumor effects of a ginsenoside Rg(3)-fortified red ginseng preparation (Rg(3) RGP) were investigated in human non-small cell lung carcinoma (H460) cells using in vitro cytotoxicity assay and in vivo nude mouse xenograft model. Immunomodulatory effects of the preparation were also assessed by measuring the facilitating activities on the nitric oxide (NO) release from peritoneal macrophages, in vitro and in vivo lymphocyte proliferation, and the carbon clearance from circulating blood. In a cell level, Rg(3)-RGP exerted H460 cytotoxicity and facilitated splenocyte proliferation at very high concentrations, without affecting NO production. However, oral administration of Rg(3)-RGP (100-300 mg/kg) enhanced carbon particle-phagocytic index of blood macrophages up to 360-397% of control value. In addition, Rg(3)-RGP significantly increased the splenocyte proliferation (23% at 100mg/kg). In tumor-bearing mice, 28-day oral treatment with Rg(3)-RGP (100mg/kg) remarkably suppressed the tumor growth, leading to the decrease of the tumor volume and weight by 30-31%, which was comparable to the effect (27-29% reduction) of doxorubicin (2mg/kg at 3-day intervals). While Rg(3)-RGP did not cause adverse effects, intravenous injection of doxorubicin markedly decreased body and testes weights, and exhibited severe depletion of spermatogenic cells in the atrophic seminiferous tubules. These results indicate that Rg(3)-RGP exerts antitumor activities via indirect immunomodulatory actions, without causing adverse effects as seen in doxorubicin. PMID- 21787711 TI - Anti-proliferative and apoptotic effects of the novel taspine derivative tas41 in the Caco-2 cell line. AB - Taspine was screened and isolated for the first time from Radix et Rhizoma Leonticis. Tas41 is a novel taspine derivative. We investigated the effects of tas41 on proliferation of the Caco-2 cell line using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT), a fluorescence-activated cell sorter (FACS), enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR) and western blotting (WB). Changes in the cell cycle, apoptosis, activation of caspase-3, caspase-8 and caspase-9, and expressions of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) were investigated after Caco-2 cells were treated with tas41. At the same time, expressions of apoptosis protein bcl-2 and bax were determined. Tas41 was found to induce apoptosis in a concentration-dependent manner as confirmed by DNA fragmentation analysis, TUNEL assay and flow cytometry. Protein and mRNA expressions of EGF, VEGF, CDK2, bcl-2 and bax were evaluated by ELISA, WB and RT PCR. Tas41 had a better anti-proliferative effect than taspine on Caco-2 cells. A DNA ladder and apoptosis was observed, and the increased apoptotic activity by tas41 was accompanied by a decrease in the expression of VEGF protein and mRNA. The activities of caspase-3, caspase-8 and caspase-9 were significantly increased in cells treated with tas41 compared with those in the control group. In addition, protein and mRNA expressions of bcl-2 were decreased, and protein and mRNA expressions of bax were increased. These findings demonstrate that tas41 can inhibit the proliferation of, and induce apoptosis in, Caco-2 cells by activating caspase-3, caspase-8 and caspase-9, downregulating the expressions of VEGF, upregulating the ratio of bax/bcl-2. PMID- 21787712 TI - Study on the association between environmental cadmium exposure, cytochrome P450 mediated 20-HETE, heme-oxygenase-1 polymorphism and hypertension in Thai population residing in a malaria endemic areas with cadmium pollution. AB - The aims of the study were to investigate (i) the effects of environmental cadmium (Cd) on hypertension, biological markers of renal dysfunction and renal cytochrome P450-mediated arachidonate metabolism; and (ii) the association between genetic polymorphism of heme oxygenase-1 (HO-1) and hypertension and Cd induced renal injury in the exposed Thai population. The study was conducted in adult subjects residing in Cd-contaminated malaria endemic areas of Mae Sot District, Thailand. All subjects were randomly selected and consistently distributed for sex, age and residential areas. Blood and urinary Cd levels were not significantly different between the case (hypertensive) and control (matched pair normotensive) groups. While other renal dysfunction biomarkers were comparable between the two groups, urinary microalbumin, urinary 20-hydroxy 5,8,11,14-eicosatetraenoic acid (20-HETE) and serum creatinine were siginificantly higher in the hypertensive group. Only N-acetyl-beta glucosaminidase (NAG) showed positive correlation with Cd in hypertensive and normotensive group. With respect to heme oxygenase-1 (HO-1) polymorphism, the frequencies of (GT)(n) alleles were similar in both case and control groups. The frequency of SL genotype was significantly higher in the control group, whereas the frequency of ML genotype was significantly higher in the case group. Although no significant difference between 20-HETE and NAG levels in various HO-1 genotypes was found, a trend of increase in 20-HETE and NAG levels was observed in subjects carrying longer (GT)(n) repeats. Results from the present study provide no clear evidence on the direct effects of environmental Cd on high blood pressure development in the non-occupational exposed Thai population. Furthermore, the indirect effect of Cd through HO-1 (genetic polymorphism and prevalence of long GT(n) repeats) and 20-HETE was inconclusive. Based on the data obtained in the present investigation further studies should be performed which use a larger sample size and effectively control for confounding. This should provide more definitive evidence of the relationship between Cd exposure and high blood pressure. PMID- 21787713 TI - Evaluation of radioprotective efficacy and possible mechanism of action of Aloe gel. AB - The present study was undertaken to determine the optimum effective dose, dose reduction factor (DRF) and possible mechanism of action of Aloe gel. Three different doses of gel (250, 500 and 750 mg/kg body weight) were tested against 8 Gy induced damage in Swiss albino mice. A dose of 750 mg/kg body weight of Aloe was found the most effective while, 250 mg/kg body weight was the least effective in providing protection, as observed in the form of higher concentrations of blood GSH and vitamin C and lower level of serum LPO than irradiated animals at 1h post irradiation and higher percent of survivors up to day 30 post irradiation. Treatment of mice with Aloe before irradiation with different doses of gamma radiation (6-12 Gy) delayed the onset and reduced the severity of signs of radiation sickness. The LD(50/30) was calculated as 6.77 and 10 Gy for untreated irradiated and Aloe treated irradiated animals, respectively and its dose reduction factor was also calculated as 1.47. Aloe gel scavenged the free radicals, DPPH*, ABTS(+*) and NO in a concentration dependent manner in vitro and therefore, scavenging of free radicals seems to be its important mechanism of action. PMID- 21787714 TI - Development of nano alpha-ketoglutarate nebulization formulation and its pharmacokinetic and safety evaluation in healthy human volunteers for cyanide poisoning. AB - Development of nano alpha-ketoglutarate (A-KG) nebulization formulation for neutralization of inhaled cyanide ion toxicity. Objectives of the present study were to (a) develop a novel A-KG nebulization formulation against cyanide poisoning, particularly hydrogen cyanide gas (b) validate its respiratory fraction in vitro and in vivo, and (c) create its pharmacokinetic data in human volunteers. The formulation was optimized on the basis of particle size of aerosolized droplets after nebulization in 6 volunteers. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized A-KG after radiolabeling it with Technetium-99m. The formulation was optimized using 30% ethanol-saline with particle size in the range of 300-500 nm. In vitro and in vivo studies showed that drug nebulization resulted in a significant respirable fraction of 65 +/- 0.6% with whole lung deposition of 13 +/- 1%. Human pharmacokinetic data was derived in 6 healthy human volunteers with peak serum concentration (C(max)) of 39 +/- 3 MUg/ml, while the area under curve (AUC) after inhalation was 376 +/- 23 MUg * h/ml indicating that the drug was rapidly and completely absorbed when targeted directly to lungs. Significant lung deposition of A-KG was achieved with the developed formulation. The formulation appears to have several advantages, including the potential of neutralizing inhaled CN(-) ions in the lungs themselves. It is a safe and efficacious procedure, suitable for hospital or ambulance use in accidental cyanide poisoning cases, or as a preventive approach for fire-rescue teams. PMID- 21787715 TI - In Salvia miltiorrhiza, phenolic acids possess protective properties against amyloid beta-induced cytotoxicity, and tanshinones act as acetylcholinesterase inhibitors. AB - Radix Salvia miltiorrhiza (RSM), a traditional Chinese medicinal herb, has been alleged to possess therapeutic effects against senile dementia, also known as Alzheimer's disease (AD). However, the effects of the major components in RSM on cytotoxicity induced by amyloid-beta peptide (Abeta) and on acetylcholinesterase activity have not been studied in depth to date. In this report, the effects of RSM aqueous/ethanol extracts, total polyphenols, total tanshinones and 3 phenolic compounds against toxicity mediated by Abeta(25-35) were tested with PC-12 cells. The results showed that Abeta(25-35)-induced cytotoxicity was revised by RSM aqueous/ethanol extracts and total polyphenols and that danshensu and salvianolic acid B could protect PC-12 cells by blocking Abeta(25-35)-induced Ca(2+)-intake, lactate dehydrogenase release, cell viability decrease and apoptosis. In addition, the activities of RSM extracts and relevant constituents in their inhibition of acetylcholinesterase were investigated using rat brain homogenates as an enzyme resource. Galanthamine hydrobromide, an accepted acetylcholinesterase inhibitor, was employed as a positive control agent. Our preliminary studies demonstrated that RSM ethanol extract, total tanshinones, tanshinone I and dihydrotanshinone I had remarkable inhibition effects on acetylcholinesterase in vitro. These findings suggest that both tanshinones and polyphenols in RSM are the active constituents responsible for the beneficial effects of this herb in AD treatment. PMID- 21787716 TI - Role of carbon monoxide in impaired endothelial function mediated by acute second hand tobacco, incense, and candle smoke exposures. AB - The aim of this study was to determine if carbon monoxide (CO) is responsible for acute adverse cardiovascular effects of different sources of smoke: second-hand tobacco smoke (SHS), incense and candle smoke. Endothelial function was tested using flow-mediated dilation (FMD) in pigs and was shown to be sensitive to nitric oxide synthase blockade. Subsequent experiments showed that FMD was significantly impaired compared to sham-exposed pigs at 30 min after a 30-min exposure to all three sources of smoke. In contrast, SHS significantly increased systolic, diastolic and pulse pressures compared to sham-exposure, while both incense and candle smoke exposure had no effect. The FMD impairment correlated well with CO levels in the exposure chamber, but not total particulates or venous CO-hemoglobin. Therefore, this study suggests a gas phase component of smoke that accompanies CO, but not CO itself, is responsible for acute endothelial dysfunction after SHS, incense or candle smoke exposure. PMID- 21787717 TI - Ganoderma applanatum terpenes protect mouse liver against benzo(alpha)pyren induced oxidative stress and inflammation. AB - Ganoderma applanatum terpenes (GAT) have been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of GAT against benzo(a)pyrene (BaP) induced oxidative stress and inflammation in mouse liver, and explored the potential mechanism of its action. Our data showed that GAT significantly decreased levels of ALT and AST in serum and the liver histological injury in BaP-treated mice. GAT markedly decreased the levels of ROS, MDA and lowered the GSH/GSSG ratio in the liver of BaP-treated mice. Furthermore, GAT markedly inhibited the BaP-induced increase of Cu/Zn-SOD, CAT, GPx and GST activities in the mouse liver. Western blot analysis showed that GAT significantly inhibited inflammation by pressing the expression of IL-1beta and COX-2 and inhibiting NF-kappaB translocation in the liver of BaP-treated mice. In conclusion, these results suggested that GAT could protect the mouse liver against BaP-induced injury by improving hepatic function, attenuating histopathologic changes, decreasing levels of ROS and MDA, renewing the activities of antioxidant enzymes and suppressing inflammatory response. PMID- 21787718 TI - Cadmium-induced up-regulation of aldo-keto reductase 1C3 expression in human nasal septum carcinoma RPMI-2650 cells: Involvement of reactive oxygen species and phosphatidylinositol 3-kinase/Akt. AB - Cadmium is a well-known toxic metal and occupational exposure to it is associated with lung cancer. In probing the possible non-genotoxic molecular targets of cadmium-induced nasal toxicity, we performed an mRNA differential display analysis for cadmium-treated human nasal septum carcinoma RPMI-2650 cells. Cadmium (>= 0.5 MUM) inhibited the cell proliferation. The intracellular ROS levels were induced by cadmium treatment. In addition, cadmium elicited the AKR1C3 expression. The cadmium-induced increase in AKR1C3 protein levels was suppressed by N-acetylcysteine (NAC) and, to a lesser extent, PI3K inhibitor (Ly294002). Cells pretreated with Ly294002 were more resistant to cadmium toxicity than control. The increase in AKR1C3 protein level was accompanied by an increase in the nuclear transcription factor Nrf2. Overall, our data suggest that cadmium-induced ROS cause up-regulation of AKR1C3 expression, at least partially via the activation of PI3K-related intracellular signaling pathways, and Nrf2 activation, thereby contributing to an adaptive intracellular response to cadmium toxicity. PMID- 21787720 TI - Toxicokinetics of naringin, a putative antitussive, after 184-day repeated oral administration in rats. AB - The toxicokinetic characteristics of naringin were investigated in rats that had been orally administered naringin extract, a candidate for oral treatment of cough, prepared from Citrus grandis "Tomentosa", at 50, 250, or 1250 mg/kg/day in a repeated-dose study for 1, 32, 93, or 184 days. Increased values of the mean systemic exposure were approximately proportional to increases in dose levels during all collection intervals; no saturation was observed. No significant differences in mean systemic exposure were observed between male and female rats. Results provide a reference for interpretation of toxicology findings and relevance to clinical safety issues. PMID- 21787719 TI - Effects of flour bleaching agent on mice liver antioxidant status and ATPases. AB - Benzoyl peroxide (BPO) is a strong oxidizing agent and widely used as flour bleaching agent. However their potential risk of liver damage is unknown. The aim of this study was to investigate the effects of BPO on mice liver antioxidant status and ATPases according to the actual amount of BPO in flour from Jinan, China. The results showed that the maximum concentration of BPO reached up to 284.6 mg/kg and content of BPO mainly ranged from 0 to 240 mg/kg. Therefore, four groups of mice were gavaged daily with BPO at doses of 0, 50, 100, 200mg/kg b.w./d for 42 days, respectively. In liver tissue, superoxide dismutase (SOD) activity was significantly decreased, while the content of malondialdehyde (MDA) significantly increased following BPO exposure at 200mg/kg b.w. BPO significantly decreased the Mg(2+)-ATPase and Ca(2+)-ATPase activities of the liver at 200mg/kg b.w. BPO, at all of the doses assayed, produced non-significant effects on glutathione peroxidase (GSH-Px) and Na(+)K(+)-ATPase activities. Experimental results suggested that BPO had certain adverse effects on antioxidant status and the activities of Mg(2+)-ATPase and Ca(2+)-ATPase of liver tissue. PMID- 21787721 TI - Histopathological changes in gill, liver and kidney of neotropical fish Colossoma macropomum exposed to paraquat at different temperatures. AB - This work focused on the histological alterations in gill, liver and kidney of fish Colossoma macropomum exposed to different temperatures (18 degrees C, 29 degrees C, 35 degrees C) with 10mg/L of herbicide Paraquat (PQ), during 21 days. The fish exhibited histopathological changes in these tissues; the most important alteration in gills was telangiectasis. Liver showed debris accumulation inside cytoplasm hepatocytes, karyolysis, karyohesis and a decrease in the size of sinusoids. Hyperplasia of melanomacrophagic centers (MMC) and an increase in basophils were observed in kidney. The lesion inducing by PQ and the damage in tissue depended of temperature exposure fish. The severity of lesions clearly differed among organs with the liver showing the most extensive damages followed in order by the kidney and gills. In PQ/18 degrees C group it was observed the changes in the pattern of lesions, with kidney showing higher damage followed gills and liver. PMID- 21787722 TI - The effect of aging and an ovariectomy operation on the level of phosphorylated CaM kinase II in the hippocampus of female mice prenatally exposed to diethylstilbestrol. AB - The effects of aging and an ovariectomy operation on the brain-disrupting actions caused by prenatal exposure to diethylstilbestrol (DES) were studied in mice. In the young DES-exposed female mice, the level of hippocampal phosphorylated CaM kinase II (pCaMKII) was not changed. However, at 8 months, the level of hippocampal pCaMKII in the DES-exposed female mice significantly increased compared to control. Moreover, the ovariectomy significantly increased the level of pCaMKII in the hippocampus but not the cortex of DES-exposed female mice. These findings suggest that the influence of prenatally-exposed DES on the hippocampal pCaMKII may be affected by the endogenous female sex hormones such as estrogen. PMID- 21787723 TI - DNA adduct variations in non-smoking crop farmers: potential relationship with occupational exposure to pesticides? AB - Genotoxic impact of the occupational exposure was measured in farmers from Normandy, France. White blood cell DNA-adduct levels were measured for 116 non smoking French crop farmers, using the (32)P-postlabelling method. A single blood sample was collected per farmer, at a randomised period of the year. Significantly higher bulky DNA-adduct levels were observed for samples collected from April to July, compared with samples collected during the other months. Agricultural practices were not significantly different between these two groups of farmers, but interestingly, the mean and the median duration without exposure to pesticides were significantly shorter for farmers sampled between April and July. These data, obtained in a homogeneous population of farmers, indicate a genotoxic impact for a sub-group, with a potential association with the use of pesticides. From the rest of the group, this study also gives for the first time additional information on the background fluctuations of this biomarker over the year. PMID- 21787724 TI - Exposure to metals from orthodontic appliances by hair mineral analysis. AB - The aim of the present work was to investigate the exposure of patients to metals released from orthodontic appliances in situ. The paper reports the results of biocompatibility studies of orthodontic appliances by an in vivo method using hair sampled from the group of patients (N = 28) and a control group (N = 18). The mean content of metals (Ni, Cr, Mn, Fe) in hair that were hypothesized to be systemically absorbed from stainless steel, was provided. The highest difference between the groups was found for Ni (39% higher level in hair of patients), Mn (18%), Fe (4.1%), Cr (2.5%), as calculated by a new dimensionless metal release coefficient (alpha). The second coefficient defined in the present work (beta) corresponded to the difference in the mean content of elements between the groups. The coefficient was the highest for Fe, subsequently Ni, Mn and Cr. None of the differences was statistically significant. For each group and a given element, ranges between 10th and 90th percentile were determined. The upper value of the range differed the mostly between the groups for Ni (82.5%) showing that stainless steel of orthodontic appliance can be the source of exposure to this element. The difference was also identified for Mn (26.5%). For Cr and Fe, the lower value of the range was elevated. It was noted that 22% of patients undergoing orthodontic treatment had elevated levels of Ni in hair. A correlation matrix between the content of the elements in hair was calculated. Statistically significant correlations were found between Cr and Fe, showing similar sources of exposure. Multiple regression analysis showed the dependence of Ni content (dependent variable) on the level of Co and Mg (synergism) and V (antagonism). PMID- 21787725 TI - Myocardial oxidative stress following sub-chronic and chronic oral cadmium exposure in rats. AB - We investigated the effect of oral cadmium intoxication on the antioxidant/prooxidant status in serum and heart. Wistar rats, separated into four groups, that received: (1) tap water for 60 days (control); (2), (3) and (4) Cd(2+) (15 ppm)-containing water, during 15, 30 and 60 days, respectively. Lipoperoxidation increased in serum and heart of group 4. Circulating paraoxonase 1 activity was higher in groups 2 and 3. Protein carbonyl-groups increased while total and reduced glutathione levels decreased in the heart after 15 days of cadmium intoxication. Cardiac catalase activity was higher in groups 3 and 4 but glutathione peroxidase activity diminished in the heart of all poisoned groups. Superoxide dismutase transcript levels as well as Nrf2 expression also increased in the heart of groups 2 and 3, while gp91phox and p47phox mRNA levels rose only in group 3. We suggest cadmium intoxication modifies antioxidant/prooxidant ratio in serum and heart in a time-of-exposure-dependent way. PMID- 21787726 TI - Concentration and reference interval of trace elements in human hair from students living in Palermo, Sicily (Italy). AB - Trace element contents in specimens of hair collected from 137 children aged 11 13 years old, living in Palermo (Sicily, Italy) were determined by ICP-MS. This work reports analytical data for the following 19 elements: Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn. The most abundant chemical elements were zinc and copper (Zn > Cu), with concentrations exceeding 10 MUg/g (Zn = 189.2 MUg/g; Cu = 22.9 MUg/g). Other elements with concentrations greater than 1 MUg/g were, in order of abundance, Al>Sr>Ba>Pb. The remaining elements were all below 1 MUg/g. The average elemental concentrations in hair were statistically compared by Kolmogorov-Smirnov's test taking children's gender into account. Al, Ba, Cr, Li, Rb, Sb, Sr, V and Zn were statistically different according to gender, with significance p < 0.001. This study thus confirms the need for hair analysis to differentiate female data from those of males. IUPAC coverage intervals and coverage uncertainties for trace elements in the analysed hair samples are also reported. PMID- 21787727 TI - Effect of BDE-209 on glutathione system in Carassius auratus. AB - In this study, the oxidative stress induced by deca-polybromodiphenyl ether (BDE 209) was investigated in livers of Carassius auratus. Six groups of fish were exposed to blank and 0, 0.004, 0.04, 0.4, 4 MUM BDE-209 (in 0.1% DMSO) for 1, 4, 7, 10, 13 d, respectively. The following oxidative stress markers were analyzed: reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidases (GPx) and glutathione S-transferases (GSTs). No significant difference was observed in the content of GSH over the whole period of exposure (p > 0.05). Increases in hepatic GR and GPx activities were in concomitant with the decrease in GST activity. GR activity was induced after 1 d exposure, while GPx activity reached maximum at 4 d after exposure to 0.04 MUM BDE-209 and GST activity was significantly inhibited at 7-13 d in all the treatment groups (0.004-4 MUM group). PMID- 21787728 TI - Cadmium and exposure to stress increase aggressive behavior. AB - Environmental toxicants and stress influence the health and behavior of people from different parts of the world. In the present study, aggressive behavior was evaluated in rats exposed to cadmium (Cd) for four weeks and subjected to immobilization stress (IS) based on the resident/intruder paradigm. Latency to the first bite (LB), total number of attacks (NA), total duration of attack manifestations (DAM), and a composite aggression score (CAS) were used to assess aggressiveness. Cadmium concentrations in the blood and the brain were determined. We observed that the parameters of aggressiveness were not altered by either Cd or IS when administered separately. However, animals exposed to Cd+IS had increased NA, DAM, and CAS. Cadmium was detected in the blood and the brain after treatment and Cd+IS exposure modified Cd distribution in these tissues. These results suggest that exposure to low levels of Cd associated with stress may lead to increased aggressiveness in rats. PMID- 21787729 TI - Bone mineral density is related with previous renal dysfunction caused by cadmium exposure. AB - Relationship between bone mineral density (BMD) and previous renal dysfunction caused by cadmium exposure was investigated. A total of 457 persons, living in polluted and control areas, were followed up in this study. The inhabitants living in exposure areas ceased ingesting cadmium-contaminated rice in 1996. Blood and urinary cadmium levels and BMD in 1998 and 2006 were measured. Urinary N-acetyl-beta-d-glucosaminidase and albumin determined in 1998 and 2006 were used to evaluate kidney status. BMD of subjects with tubular damage was significant lower than those without damage in female (p < 0.05). The prevalence of osteoporosis was significantly different between those with and without kidney damage (p = 0.003, in total population; p = 0.039, in female) and those with and without tubular damage (p = 0.0005, in total population; p = 0.007, in female). The results suggested that BMD was correlated with previous kidney impairment caused by cadmium exposure, especially to tubular damage and especially for female. PMID- 21787730 TI - Nrf2-mediated adaptive response to cadmium-induced toxicity involves protein kinase C delta in human 1321N1 astrocytoma cells. AB - Cadmium (Cd) is a toxic heavy metal, and exposure to Cd causes a range of changes within the cell. At high concentrations, Cd causes damage to cells via a range of mechanisms. At low concentrations, Cd can stimulate expression of genes that are part of an adaptive response. In this study, we have used the astrocytoma cell line 1321N1 as a model to investigate the induction of protective enzymes in response to Cd. We have shown that expression of NAD(P)H:quinone oxidoreductase and haem oxygenase enzymes are induced as the protein level by -fold and -fold, and in response to 5 and 10 MUM Cd. Levels of NQO1 and HO1 mRNA are also increased by -fold and -fold following 24h exposure to 5 and 10 MUM cadmium. An increase in the nuclear accumulation of the transcription factor Nrf2 was also observed following Cd treatment. Through the use of the protein kinase C inhibitor bisindolylmaleimide (VIII) acetate we have demonstrated the involvement PKC in the Nrf2-mediated response of 1321N1 cells to 5-10 MUM Cd. We have also shown through the used of 10 MUM rottlerin that PKCdelta is the isoform responsible for mediating this response. PMID- 21787731 TI - Chemical composition and antimicrobial activity of the essential oil of Rosemary. AB - The composition of the essential oil of Rosemary was analyzed by gas chromatography-mass spectrometry (GC-MS). 22 components, which constitute 97.41% of the oil, were identified. The major constituents were 1,8-Cineole (26.54%) and alpha-Pinene (20.14%). Minimum inhibitory concentrations (MICs), minimal bactericidal concentration (MBC) and time-kill dynamic processes against three Gram-positive bacteria (Staphylococcus epidermidis, Staphylococcus aureus and Bacillus subtilis), three Gram-negative bacteria (Proteus vulgaris, Pseudomonas aeruginosa and Escherichia coli) and two fungi (Candida albicans and Aspergillus niger) were determined for the oil, 1,8-Cineole and alpha-Pinene. The oil showed pronounced antibacterial and antifungal activity than 1,8-Cineole and alpha Pinene against all of the tested microbes. Furthermore, the survival rates and morphological changes of S. aureus after treatment with different concentrations of the essential oil were assessed by flow cytometry (FCM) and atomic force microscopy (AFM). PMID- 21787732 TI - Purification and characterization of carbonic anhydrase from the teleost fish Dicentrarchus labrax (European seabass) liver and toxicological effects of metals on enzyme activity. AB - Carbonic anhydrase (EC 4.2.1.1; CA) was purified and characterized from the liver of the teleost fish Dicentrarchus labrax (European seabass) for the first time. The purification procedure consisted of a single step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The enzyme was purified 78.8-fold with a yield of 46%, and a specific activity of 751.72U/mg proteins. It has an optimum pH at 7.5; an optimum temperature at 25 degrees C; an optimum ionic strength at 10mM and a stable pH at 8.5. The kinetic parameters of this enzyme were determined for its esterase activity, with 4-nitrophenyl acetate (NPA) as substrate and the purified enzyme had an apparent K(M) and V(max) values of 0.44 mM and 0.249 MUmolxmin(-1), respectively. The following metals, Al(+3), Cu(+2), Pb(+2), Co(+3), Ag(+1), Zn(+2) and Hg(+2) showed inhibitory effects on the enzyme. Al(+3) and Cu(+2) exhibited the strongest inhibitory action. Pb(+2) was moderate inhibitor, whereas other metals showed weaker actions. All tested metals inhibited the enzyme in a competitive manner. Our findings indicate that these metals inhibit the fish enzyme in a similar manner to other alpha-CAs from mammals investigated earlier, but the susceptibility to various metals differ between the fish and mammalian enzymes. Our results also demonstrate that these metals might be dangerous at low micromolar concentrations for fish CA enzymes. PMID- 21787733 TI - Asoxime (HI-6) impact on dogs after one and tenfold therapeutic doses: assessment of adverse effects, distribution, and oxidative stress. AB - Asoxime (HI-6) is a well known oxime reactivator used for counteracting intoxication by nerve agents. It is able to reactivate acetylcholinesterase (AChE) inhibited even by sarin or soman. The present experiment was aimed to determine markers of oxidative stress represented by thiobarbituric acid reactive substances and antioxidants represented by ferric reducing antioxidant power, reduced and oxidized glutathione in a Beagle dog model. Two groups of dogs were intramuscularly exposed to single (11.4 mg/kg.b.wt.) or tenfold (114 mg/kg.b.wt.) human therapeutically doses of HI-6. HI-6 affinity for AChE in vitro was evaluated in a separate experiment. Complete serum biochemistry and pharmacokinetics were also performed with significant alteration in blood urea nitrogen, creatine phosphokinase, glucose and triglycerides. Blood samples were collected before HI-6 application and after 30, 60, and 120 min. The overall HI-6 impact on organism is discussed. PMID- 21787734 TI - Acute and twenty-eight days repeated oral dose toxicity study of besifloxacin in Wistar albino rats. AB - The purpose of this study was to investigate the potential acute and 28-day repeated oral toxicities of besifloxacin (BAF) in Wistar albino rats. In oral acute and repeated dose study, BAF was administered to both sex of rats, at dose levels of 0, 300, 600, 900 mg/kg/day and 0, 100, 200, 500 mg/kg/day, respectively. In the acute study, total white blood cell (WBC) (male, 43.74%; female, 42.60%) and total bilirubin (T-BIL) (male, 80%; female, 60%) were significantly increase, total protein (TP) (male, 23.24%; 27.80%) was significantly decreased, and significant incidence of pericholangitis (male, 83.33%; female, 75%) was shown in males and females of high-dose groups. In repeated oral dose toxicity study, similar type effects were also observed after serum hematological and serum biochemical analysis, whereas additionally sever hepatic injury and focal ulceration in gastric mucosa also observed in high dose groups of both sexes after histopathological analysis. However these toxic effects of besifloxacin were transient and reversible and no-observed adverse effect level (NOAEL) were 300 mg/kg/day for acute and 100 mg/kg/day for repeated dose toxicity study, respectively. PMID- 21787735 TI - Study on acute toxicity and structure-activity relationship of Daphnia magna exposed to naphthoquinones. AB - The acute toxicities of the six naphthoquinone compounds on Daphnia magna (D. magna) at 48 h were classified as harmful, toxic, and very toxic. The results indicated that logP played an important part in the toxicity of compounds to organism. And 1-carbonyl or the other hydrophobic substituents of the naphthoquinone compounds are likely to mediate the binding of the compound to the target via hydrogen bonding and hydrophobic interactions. Our results provided a foundation for further investigation using 3D-QSAR and HQSAR to evaluate the aquatic ecological risk and the mechanism of toxicity of naphthoquinones. PMID- 21787736 TI - Histochemical changes in muscle of rats exposed subchronically to low doses of heavy metals. AB - Heavy metals are ubiquitous in the environment and exposure through food and water as well as occupational sources can constitute a potential threat to human health. The mechanisms of heavy metal damage include the production of free radicals that alter mitochondrial activity, affecting cellular types like neurons and muscular fibres. We examined whether rats exposed subchronically via drinking water to low doses of heavy metals can produce alterations in muscle. Results showed that the proportion of ragged red fibres increased in muscle of rats exposed to lead and thallium, likewise slight changes in enzymatic activity of muscular fibres were also observed. PMID- 21787737 TI - Students prescribing emergency drug infusions utilising smartphones outperform consultants using BNFCs. AB - OBJECTIVE: To compare the use of a drugs calculator on a smartphone with use of the British National Formulary for Children (BNFC) for accuracy, speed and confidence of prescribing in a simulated paediatric emergency. DESIGN: 28 doctors and 7 medical students in a paediatric department of a District General Hospital, were asked to prescribe both a dopamine infusion and an adrenaline infusion for a hypotensive child. For one calculation they used the BNFC as their reference source and for the other they used the 'PICU Calculator' on the iPhone. RESULTS: The drugs calculator on the smartphone was more accurate than the BNFC, with 28.6% of participants being able to correctly prescribe an inotropic infusion using the BNFC and 100% of participants being able to do so using the drugs calculator on the smartphone (p<0.001). The smartphone calculator was 376% quicker than the BNFC with the mean time saved being 5 min and 17s per participant (p<0.001). Participants were more confident in their prescription when using the drugs calculator on the smartphone with a mean confidence score of 8.5/10 compared with 3.5/10 when using the BNFC (p<0.001). CONCLUSIONS: Utilising the smartphone was significantly more accurate and faster, with prescribers more confident in their calculations, than use of the BNFC. This applied irrespective of clinical experience with medical students utilising the smartphone technology outperforming Consultant Paediatricians when they used the BNFC. PMID- 21787738 TI - Vasopressin for cardiac arrest: meta-analysis of randomized controlled trials. AB - BACKGROUND: Prior meta-analyses-reported results of randomised controlled trials (RCTs) published between 1997 and 2004 failed to show any vasopressin-related benefit in cardiac arrest. Based on new RCT-data and a hypothesis of a potentially increased vasoconstricting efficacy of vasopressin, we sought to determine whether the cumulative, current evidence supports or refutes an overall and/or selective benefit for vasopressin regarding sustained restoration of spontaneous circulation (ROSC), long-term survival, and neurological outcome. METHODS: Two reviewers independently searched PubMed, EMBASE, and Cochrane Database for RCTs assigning adults with cardiac arrest to treatment with a vasopressin-containing regimen (vasopressin-group) vs adrenaline (epinephrine) alone (control-group) and reporting on long-term outcomes. Data from 4475 patients in 6 high-methodological quality RCTs were analyzed. Subgroup analyses were conducted according to initial cardiac rhythm and time from collapse to drug administration (T(DRUG))<20 min. RESULTS: Vasopressin vs. control did not improve overall rates of sustained ROSC, long-term survival, or favourable neurological outcome. However, in asystole, vasopressin vs. control was associated with higher long-term survival {odds ratio (OR)=1.80, 95% confidence interval (CI)=1.04-3.12, P=0.04}. In asystolic patients of RCTs with average T(DRUG)<20 min, vasopressin vs. control increased the rates of sustained ROSC (data available from 2 RCTs; OR=1.70, 95% CI=1.17-2.47, P=0.005) and long-term survival (data available from 3 RCTs; OR=2.84, 95% CI=1.19-6.79, P=0.02). CONCLUSIONS: Vasopressin use in the resuscitation of cardiac arrest patients is not associated with any overall benefit or harm. However, vasopressin may improve the long-term survival of asystolic patients, especially when average T(DRUG) is <20 min. PMID- 21787739 TI - Resuscitation feedback and targeted education improves quality of pre-hospital resuscitation in Scotland. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality and serious neurological morbidity in Europe. Recent studies have demonstrated the adverse physiological consequences of poor resuscitation technique and have shown that quality of cardiopulmonary resuscitation (CPR) is a critical determinant of outcome from OHCA. Telemetry of the defibrillator transthoracic impedance (TTI) trace can objectively measure quality of pre-hospital resuscitation. This study aims to analyse the impact of targeted resuscitation feedback and training on quality of pre-hospital resuscitation. METHODS: Prospective, single centre, cohort study over 13 months (1st December 2009-31st December 2010). Baseline pre-hospital resuscitation data was gathered over a 3 month period. Modems (n=40) were fitted to defibrillators on ambulance vehicles. Following a resuscitation attempt, the event was sent via telemetry and the TTI trace analysed. Outcome measures were time spent performing chest compressions, compression rate, the interval required to deliver a defibrillator shock and use of automatic or manual cardiac rhythm analysis. Targeted resuscitation classes were introduced and all ambulance crews received feedback following a resuscitation attempt. Pre-hospital resuscitation quality pre and post intervention were compared. RESULTS: 111 resuscitation traces were analysed. Mean hands-on-chest time improved significantly following feedback and targeted resuscitation training (73.0% vs 79.3%, p=0.007). There was no significant change in compression rate during the study period. There was a significant reduction in median time-to-shock interval from 20.25s (IQR 15.50-25.50s) to 13.45 s (IQR 2.25 22.00 s) (p=0.006). Automatic rhythm recognition fell from 50% to 28.6% (p=0.03) following intervention. CONCLUSION: Telemetry and analysis of the TTI trace following OHCA allows objective evaluation of the quality of pre-hospital resuscitation. Targeted resuscitation training and ambulance feedback improves the quality of pre-hospital resuscitation. Further studies are required to establish possible survival benefit from this technique. PMID- 21787740 TI - What is the relationship between the Glasgow coma scale and airway protective reflexes in the Chinese population? AB - AIM: To describe the relationship of gag and cough reflexes to Glasgow coma score (GCS) in Chinese adults requiring critical care. METHOD: Prospective observational study of adult patients requiring treatment in the trauma or resuscitation rooms of the Emergency Department, Prince of Wales Hospital, Hong Kong. A long cotton bud to stimulate the posterior pharyngeal wall (gag reflex) and a soft tracheal suction catheter were introduced through the mouth to stimulate the laryngopharynx and elicit the cough reflex. Reflexes were classified as normal, attenuated or absent. RESULTS: A total of 208 patients were recruited. Reduced gag and cough reflexes were found to be significantly related to reduced GCS (p=0.014 and 0.002, respectively). Of 33 patients with a GCS<=8, 12 (36.4%) had normal gag reflexes and 8 (24.2%) had normal cough reflexes. 23/62 (37.1%) patients with a GCS of 9-14 had absent gag reflexes, and 27 (43.5%) had absent cough reflexes. In patients with a normal GCS, 22.1% (25/113) had absent gag reflexes and 25.7% (29) had absent cough reflexes. CONCLUSIONS: Our study has shown that in a Chinese population with a wide range of critical illness (but little trauma or intoxication), reduced GCS is significantly related to gag and cough reflexes. However, a considerable proportion of patients with a GCS<=8 have intact airway reflexes and may be capable of maintaining their own airway, whilst many patients with a GCS>8 have impaired airway reflexes and may be at risk of aspiration. This has important implications for airway management decisions. PMID- 21787742 TI - Ethyl-glucuronide and ethyl-sulfate in placental and fetal tissues by liquid chromatography coupled with tandem mass spectrometry. AB - The aim of this study was to develop a method for the determination of ethyl glucuronide (EtG) and ethyl-sulfate (EtS), two direct ethanol metabolites, in early placental and fetal human tissues, as potential biomarkers of transplacental ethanol transfer from the mother to the fetus. Placental and fetal tissue samples were obtained from women undergoing voluntary termination of pregnancy at 12 weeks of gestation. Samples were deproteinized and directly injected into a liquid chromatography coupled with tandem mass spectrometry (LC MS/MS) system. Limits of detection of 13.0 and 23.0 pmol/g and lower limits of quantification of 22.0 and 40.0 pmol/g were reached for EtG and EtS, respectively. Inter- and intraday imprecision and accuracy were always lower than 15%. The method was applied to 70 samples (35 placentas and 35 fetal tissues). Of 35 samples, 4 samples collected from 4 women tested positive for EtG and EtS, always showing higher concentrations for EtG. The placenta/fetal tissue ratio for EtG was 2.9 +/- 0.9, whereas EtS showed a ratio of 1.7 +/- 0.7. Preliminary results suggest that these metabolites are present in both tissues. Further studies should now corroborate the hypothesis, not yet confirmed, that transplacental transfer of ethanol takes place not only for the parent compound but also for EtG and EtS. PMID- 21787741 TI - Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12. AB - Gestational choriocarcinoma is a malignant trophoblastic tumor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma tumorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell-1 (iC3-1) cells, generated from HTR8/SVneo human trophoblastic cells retrovirally transduced with activated H-RAS (HRASV12). The iC3-1 cells exhibited constitutive activation of the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC3-1 cells and parental HTR8/SVneo cells revealed that iC3-1 cells expressed matrix metalloproteinases, epithelial-mesenchymal transition related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC3-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcinoma. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma. PMID- 21787743 TI - Structural models of the manganese complex of photosystem II and mechanistic implications. AB - Photosynthetic water oxidation and O2 formation are catalyzed by a Mn4Ca complex bound to the proteins of photosystem II (PSII). The catalytic site, including the inorganic Mn4CaO(n)H(x) core and its protein environment, is denoted as oxygen evolving complex (OEC). Earlier and recent progress in the endeavor to elucidate the structure of the OEC is reviewed, with focus on recent results obtained by (i) X-ray spectroscopy (specifically by EXAFS analyses), and (ii) X-ray diffraction (XRD, protein crystallography). Very recently, an impressive resolution of 1.9A has been achieved by XRD. Most likely however, all XRD data on the Mn4CaO(n)H(x) core of the OEC are affected by X-ray induced modifications (radiation damage). Therefore and to address (important) details of the geometric and electronic structure of the OEC, a combined analysis of XRD and XAS data has been approached by several research groups. These efforts are reviewed and extended using an especially comprehensive approach. Taking into account XRD results on the protein environment of the inorganic core of the Mn complex, 12 alternative OEC models are considered and evaluated by quantitative comparison to (i) extended-range EXAFS data, (ii) polarized EXAFS of partially oriented PSII membrane particles, and (iii) polarized EXAFS of PSII crystals. We conclude that there is a class of OEC models that is in good agreement with both the recent crystallographic models and the XAS data. On these grounds, mechanistic implications for the O-O bond formation chemistry are discussed. This article is part of a Special Issue entitled: Photosystem II. PMID- 21787744 TI - Effects of synaptotagmin 2 on membrane fusion between liposomes that contain SNAREs involved in exocytosis in mast cells. AB - Mast cells play a pivotal role in allergic responses. Antigen stimulation causes elevation of the intracellular Ca(2+) concentration, which triggers the exocytotic release of inflammatory mediators such as histamine. Recent research, including our own, has revealed that SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins such as syntaxin-3, -4, SNAP-23, and VAMP-8 are involved in exocytosis. Although exocytosis in mast cells is Ca(2+) dependent, the target molecule that interacts with Ca(2+) is not clear. Synaptotagmin is a Ca(2+) sensor and regulates exocytosis in neuronal cells. However, the role of synaptotagmin 2, a member of the synaptotagmin family, in exocytosis in mast cells remains controversial. In this study, we investigated the role of synaptotagmin 2 by a liposome-based fusion assay. SNARE proteins (SNAP-23, syntaxin-3, VAMP-8) and synaptotagmin 2 were expressed in Escherichia coli and purified as GST-tagged or His-tagged fusion proteins. These SNARE proteins were incorporated by a detergent dialysis method. Membrane fusion between liposomes was monitored by fluorescence resonance energy transfer between fluorescent-labeled phospholipids. In the presence of Ca(2+), low synaptotagmin 2 concentration inhibited membrane fusion between SNARE-containing liposomes, while high synaptotagmin 2 concentration enhanced membrane fusion. This enhancement required phosphatidylserine as a membrane component. These results suggest that synaptotagmin 2 regulates membrane fusion of SNARE-containing liposomes involved in exocytosis in mast cells, and that this regulation is dependent on synaptotagmin 2 concentration, Ca(2+), and phosphatidylserine. PMID- 21787745 TI - Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption. AB - The cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coli lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE C16:0/C18:1. PMID- 21787746 TI - DODAB:monoolein-based lipoplexes as non-viral vectors for transfection of mammalian cells. AB - DNA/Cationic liposome complexes (lipoplexes) have been widely used as non-viral vectors for transfection. Neutral lipids in liposomal formulation are determinant for transfection efficiency using these vectors. In this work, we studied the potential of monoolein (MO) as helper lipid for cellular transfection. Lipoplexes composed of pDNA and dioctadecyldimethylammonium bromide (DODAB)/1-monooleoyl-rac glycerol (MO) at different molar ratios (4:1, 2:1 and 1:1) and at different cationic lipid/DNA ratios were investigated. The physicochemical properties of the lipoplexes (size, charge and structure), were studied by Dynamic Light Scattering (DLS), Zeta Potential (zeta) and cryo-transmission electron microscopy (cryo-TEM). The effect of MO on pDNA condensation and the effect of heparin and heparan sulphate on the percentage of pDNA release from the lipoplexes were also studied by Ethidium Bromide (EtBr) exclusion assays and electrophoresis. Cytotoxicity and transfection efficiency of these lipoplexes were evaluated using 293T cells and compared with the golden standard helper lipids 1,2-dioleoyl-sn glycero-3-hosphoethanolamine (DOPE) and cholesterol (Chol) as well as with a commercial transfection agent (LipofectamineTM LTX). The internalization of transfected fluorescently-labeled pDNA was also visualized using the same cell line. The results demonstrate that the presence of MO not only increases pDNA compactation efficiency, but also affects the physicochemical properties of the lipoplexes, which can interfere with lipoplex-cell interactions. The DODAB:MO formulations tested showed little toxicity and successfully mediated in vitro cell transfection. These results were supported by fluorescence microscopy studies, which illustrated that lipoplexes were able to access the cytosol and deliver pDNA to the nucleus. DODAB:MO-based lipoplexes were thus validated as non toxic, efficient lipofection vectors for genetic modification of mammalian cells. Understanding the relation between structure and activity of MO-based lipoplexes will further strengthen the development of these novel delivery systems. PMID- 21787748 TI - Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation. AB - The cyclin-dependent kinase (CDK) inhibitor p21 plays key roles in p53-dependent DNA-damage responses, i.e., cell cycle checkpoints, senescence, or apoptosis. p21 might also play a role in DNA repair. p21 foci arise at heavy-ion-irradiated DNA double-strand break (DSB) sites, which are mainly repaired by nonhomologous DNA end-joining (NHEJ). However, no mechanisms of p21 accumulation at double-strand break (DSB) sites have been clarified in detail. Recent works indicate that Ku70 and Ku80 are essential for the accumulation of other NHEJ core factors, e.g., DNA PKcs, XRCC4 and XLF, and other DNA damage response factors, e.g., BRCA1. Here, we show that p21 foci arise at laser-irradiated sites in cells from various tissues from various species. The accumulation of EGFP-p21 was detected in not only normal cells, but also transformed or cancer cells. Our results also showed that EGFP-p21 accumulated rapidly at irradiated sites, and colocalized with the DSB marker gamma-H2AX and with the DSB sensor protein Ku80. On the other hand, the accumulation occurred in Ku70-, Ku80-, or DNA-PKcs-deficient cell lines and in human papillomavirus 18-positive cells, whereas the p21 mutant without the PCNA binding region (EGFP-p21(1-146)) failed to accumulate at the irradiated sites. These findings suggest that the accumulation of p21, but not functional p53 and the NHEJ core factors, is dependent on PCNA. These findings also suggest that the accumulation activity of p21 at DNA damaged sites is conserved among human and animal cells, and p21 is a useful tool as a detection marker of DNA damaged sites. PMID- 21787747 TI - Molecular characterization and identification of surrogate substrates for diacylglycerol lipase alpha. AB - Diacylglycerol lipase alpha is the key enzyme in the formation of the most prevalent endocannabinoid, 2-arachidonoylglycerol in the brain. In this study we identified the catalytic triad of diacylglycerol lipase alpha, consisting of serine 472, aspartate 524 and histidine 650. A truncated version of diacylglycerol lipase alpha, spanning residues 1-687 retains complete catalytic activity suggesting that the C-terminal domain is not required for catalysis. We also report the discovery and the characterization of fluorogenic and chromogenic substrates for diacylglycerol lipase alpha. Assays performed with these substrates demonstrate equipotent inhibition of diacylglycerol lipase alpha by tetrahydrolipastatin and RHC-20867 as compared to reactions performed with the native diacylglycerol substrate. Thus, confirming the utility of assays using these substrates for identification and kinetic characterization of inhibitors from pharmaceutical collections. PMID- 21787749 TI - Thrombin induces MCP-1 expression through Rho-kinase and subsequent p38MAPK/NF kappaB signaling pathway activation in vascular endothelial cells. AB - Thrombin has been shown to increase expression of chemokines such as monocyte chemoattractant protein 1 (MCP-1) in endothelial cells, leading to the development of atherosclerosis. However, the precise mechanism of this induction remains unknown. In the present study, we investigated whether the small G protein RhoA, and its effector, Rho-kinase are involved in MCP-1 induction by thrombin in endothelial cells. Y-27632, a specific Rho-kinase inhibitor, potently inhibited MCP-1 induction by thrombin. Y-27632 significantly decreased the chemotactic activity of thrombin-stimulated supernatants of endothelial cells on monocytes. Importantly, fasudil, a specific Rho-kinase inhibitor, attenuated MCP 1 gene expression in the aorta of db/db mice. Y-27632 attenuated thrombin mediated phosphorylation of p38MAPK and p65, indicating that Rho-kinase mediates thrombin-induced MCP-1 expression through p38MAPK and NF-kappaB activation. Our findings demonstrate that the Rho/Rho-kinase signaling pathway plays a critical role in thrombin-mediated MCP-1 expression and function, and suggest that Rho/Rho kinase may be an important target in the development of new therapeutic strategies for atherosclerosis. PMID- 21787750 TI - Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein. AB - The vast majority of physiological processes in living cells are mediated by protein-protein interactions often specified by particular protein sequence motifs. PDZ domains, composed of 80-100 amino acid residues, are an important class of interaction motif. Among the PDZ-containing proteins, glutaminase interacting protein (GIP), also known as Tax Interacting Protein TIP-1, is unique in being composed almost exclusively of a single PDZ domain. GIP has important roles in cellular signaling, protein scaffolding and modulation of tumor growth and interacts with a number of physiological partner proteins, including Glutaminase L, beta-Catenin, FAS, HTLV-1 Tax, HPV16 E6, Rhotekin and Kir 2.3. To identify the network of proteins that interact with GIP, a human fetal brain cDNA library was screened using a yeast two-hybrid assay with GIP as bait. We identified brain-specific angiogenesis inhibitor 2 (BAI2), a member of the adhesion-G protein-coupled receptors (GPCRs), as a new partner of GIP. BAI2 is expressed primarily in neurons, further expanding GIP cellular functions. The interaction between GIP and the carboxy-terminus of BAI2 was characterized using fluorescence, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy assays. These biophysical analyses support the interaction identified in the yeast two-hybrid assay. This is the first study reporting BAI2 as an interaction partner of GIP. PMID- 21787751 TI - The Seryl-tRNA synthetase/tRNASer acceptor stem interface is mediated via a specific network of water molecules. AB - tRNAs are aminoacylated by the aminoacyl-tRNA synthetases. There are at least 20 natural amino acids, but due to the redundancy of the genetic code, 64 codons on the mRNA. Therefore, there exist tRNA isoacceptors that are aminoacylated with the same amino acid, but differ in their sequence and in the anticodon. tRNA identity elements, which are sequence or structure motifs, assure the amino acid specificity. The Seryl-tRNA synthetase is an enzyme that depends on rather few and simple identity elements in tRNA(Ser). The Seryl-tRNA-synthetase interacts with the tRNA(Ser) acceptor stem, which makes this part of the tRNA a valuable structural element for investigating motifs of the protein-RNA complex. We solved the high resolution crystal structures of two tRNA(Ser) acceptor stem microhelices and investigated their interaction with the Seryl-tRNA-synthetase by superposition experiments. The results presented here show that the amino acid side chains Ser151 and Ser156 of the synthetase are interacting in a very similar way with the RNA backbone of the microhelix and that the involved water molecules have almost identical positions within the tRNA/synthetase interface. PMID- 21787752 TI - ErbB2 down-regulates microRNA-205 in breast cancer. AB - Gene amplification and protein overexpression of erbB2 (Her2/neu) has been observed in approximately 20-30% of breast cancers. ErbB2-positive breast cancer is tend to be more aggressive than other types of breast cancer and therefore further investigation on the signaling pathways of erbB2 is needed for the therapeutic target for breast cancer treatment. Here we report that microRNA-205 (miR-205), a molecule also reported to be associated with breast cancer, is negatively regulated by erbB2 overexpression. Breast epithelial cells exogenously overexpressed with erbB2 decreased the expression of miR-205, whereas increased the expression of cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6). The decreased expression of miR-205 slightly increased by the transfection of erbB2 siRNA into the erbB2-overexpressing breast cancer epithelial cells. Overexpression of erbB2 enabled breast epithelial cells to grow anchorage-independently in soft agar, and the transfection of the precursor of miR-205 into the cells leaded to the decrease in the ability to grow in soft agar. These results suggest that down regulation of miR-205 in erbB2-overexpressing breast epithelial cells is essential for erbB2-induced tumorigenesis, and miR-205 may have the potential to be a novel important alternative therapeutic target for erbB2-positive breast cancer. PMID- 21787753 TI - EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic adenocarcinoma cells. AB - Human pancreatic cancer is currently one of the fifth-leading causes of cancer related mortality with a 5-year survival rate of less than 5%. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative therapeutic strategies. Increasing evidence suggests an association of carcinogenesis and chronic inflammation. Because IL-1 plays a crucial role in inflammation-associated carcinogenesis, we analyzed the biological effects of IL-1 and its modulation by the chemopreventive green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the human pancreatic adenocarcinoma cell line Colo357. Proinflammatory IL-6 and PGHS-2 as well as proangiogenic IL-8 and VEGF were induced by IL-1, whereas the secretion of invasion-promoting MMP-2 remained unaffected. IL-1 responsiveness and constitutive MMP-2 release in Colo357 were downregulated by EGCG in a dose- and time-dependent manner. Moreover, EGCG reduced cell viability via induction of apoptosis in Colo357. Since EGCG effects on cytokine production precede reduction in cell viability, we hypothesize that these findings are not only a result of cell death but also depend on alterations in the IL-1 signaling cascade. In this context, we found for the first time an EGCG-induced downregulation of the IL-1RI expression possibly being caused by NF-kappaB inhibition and causative for its inhibitory action on the production of tumorigenic factors. Thus, our data might have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in high-risk patients with human pancreatic carcinoma. PMID- 21787754 TI - Heteroplasmic mitochondrial disease in Dictyostelium discoideum. AB - The bewildering complexity of the relationship between genotype and phenotype in human mitochondrial diseases has delayed an understanding of the related cytopathological mechanisms. To explore the relationship between mitochondrial dysfunction in Dictyostelium discoideum and the related cytopathologies, we determined whether the phenotypic outcomes were similar regardless of which D. discoideum mitochondrial gene was targeted for disruption. The disruption of the mitochondrial genes resulted in a similar pattern of phenotypes to those caused by other mitochondrial defects. These include impairment of phototaxis, multicellular development and growth on plates and in liquid medium. As the reduced growth rates could have been due to defective phagocytic or macropinocytic nutrient uptake, these processes were tested but found to be unaffected. Since mitochondria have been associated with Legionella pathogenesis of human macrophages, it was also determined if mitochondrially diseased Dictyostelium strains were better or worse than healthy cells at supporting the growth of Legionella pneumophila. The results revealed that the mitochondrially diseased strains supported greater L. pneumophila growth than the wild type Dictyostelium strain (AX2). Quantitative Northern blotting showed a significant reduction in the level of expression of the entire mitochondrial genome, regardless of which mitochondrial gene was targeted for disruption, suggesting a generalized deficiency in mitochondrial gene expression and function. The phenotypic outcomes were the same as those shown previously to result from chronic hyperactivity of the energy-sensing protein kinase, AMPK, after knockdown of mitochondrial chaperonin 60. PMID- 21787757 TI - What we have learned from crystal structures of proteins to receptor function. AB - The activity of ligand gated channels is crucial for proper brain function and dysfunction of a single receptor subtype have led to neurological impairments ranging from benign to major diseases such as epilepsy, startle diseases, etc. Molecular biology and crystallography allowed the characterization at the atomic scale of the first four transmembrane ligand gated channels and of proteins sharing a high degree of homology with the neurotransmitter-binding domain. Gaining an adequate knowledge of the structural features of the ligand binding pocket led to the possibilities of developing virtual screening based approaches and probing in silico the docking of very large numbers of molecules. Development of new computing tools further extended such possibilities and rendered possible the screening of the chemical universe database GDB-11, which contains all possible organic molecules up to 11 atoms of C, N, O and F. In the case of the nicotinic acetylcholine receptors molecules identified using such screening methods were synthesized and characterized in binding assays and their pose determined in crystal structure with the acetylcholine binding protein. However, in spite of these thorough approaches, functional studies revealed that these molecules had a greater affinity for the pore domain of the channel and acted as open channel blocker rather than binding site antagonist. In this work, we discuss the potential and current limitations of how progresses made with the crystal structures of ligand gated channels, or ligand binding proteins, can be used in combination with virtual screening and functional assays, to identify novel compounds. PMID- 21787756 TI - Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. AB - Prostate cancer (PCa) is one of the most deadly malignancies among men in the United States. Although localized prostate cancer can be effectively treated via surgery or radiation, metastatic disease is usually lethal. Recent evidence suggests that the development and progression of human prostate cancer involves complex interplay between epigenetic alterations and genetic defects. We have recently demonstrated that Nrf2, a master regulator of cellular antioxidant defense systems, was epigenetically silenced during the progression of prostate tumorigenesis in TRAMP mice. The aim of this study is to investigate the potential of curcumin (CUR), a dietary compound that we have reported to be able to prevent the development of prostate cancer in TRAMP mice, as a DNA hypomethylation agent. Using bisulfite genomic sequencing (BGS), treatment of TRAMP C1 cells we showed that CUR reversed the methylation status of the first 5 CpGs in the promoter region of the Nrf2 gene. Methylation DNA immunoprecipitation (MeDIP) analysis revealed that CUR significantly reduced the anti-mecyt antibody binding to the first 5 CpGs of the Nrf2 promoter, corroborated the BGS results. Demethylation of Nrf2 was found to be associated with the re-expression of Nrf2 and one of its downstream target gene, NQO-1, one of the major anti-oxidative stress enzymes, both at the mRNA and protein levels. Taken together, our current study suggests that CUR can elicit its prostate cancer chemopreventive effect, potentially at least in part, through epigenetic modification of the Nrf2 gene with its subsequent induction of the Nrf2-mediated anti-oxidative stress cellular defense pathway. PMID- 21787758 TI - Linear ubiquitination in NF-kappaB signaling and inflammation: What we do understand and what we do not. AB - Despite its small size, ubiquitin is one of the most versatile signaling molecules in the cell and affects distinct cellular processes. It forms the building block of a repertoire of posttranslational modifications of cellular proteins, ranging from the attachment of a single ubiquitin to ubiquitin chains of different linkage. Proteins that contain ubiquitin chain-specific ubiquitin binding domains recognize different types of ubiquitination and determine the mode of signaling of modified proteins. Polyubiquitin chains were thought to be formed only by the conjugation of the ubiquitin C-terminal Gly to one of the seven internal Lys residues of another ubiquitin. However, the C-terminal Gly was recently shown to also link to the N-terminus of another ubiquitin to form head to-tail polyubiquitin chains, which is referred to as linear ubiquitination. These linear linkages can be assembled and conjugated to another protein by an E3 ligase complex known as LUBAC, and are recognized by a particular ubiquitin binding domain known as UBAN. Both have been implicated in the regulation of TNF induced NF-kappaB signaling, which induces the expression of a wide range of proteins that mediate many biological processes including inflammation and cell survival. We discuss the molecular players and mechanisms that determine the specificity and outcome of linear ubiquitination in NF-kappaB signaling, as well as future directions and challenges ahead. PMID- 21787755 TI - Naturally-expressed nicotinic acetylcholine receptor subtypes. AB - Nicotinic acetylcholine receptors (nAChRs) warrant attention, as they play many critical roles in brain and body function and have been implicated in a number of neurological and psychiatric disorders, including nicotine dependence. nAChRs are composed as diverse subtypes containing specific combinations of genetically distinct subunits and that have different functional properties, distributions, and pharmacological profiles. There had been confidence that the rules that define ranges of assembly partners for specific subunits were well-established, especially for the more prominent nAChR subtypes. However, we review here some newer findings indicating that nAChRs having largely the same, major subunits exist as isoforms with unexpectedly different properties. Moreover, we also summarize our own studies indicating that novel nAChR subtypes exist and/or have distributions not heretofore described. Importantly, the nAChRs that exist as new isoforms or subtypes or have interesting distributions require alteration in thinking about their roles in health and disease. PMID- 21787759 TI - OATP1B1/1B3 activity in plated primary human hepatocytes over time in culture. AB - Primary human hepatocytes are widely used as an in vitro model for evaluation of drug metabolism and transport. However, it has been shown that the gene expression of many drug-metabolizing enzymes and transporters change in culture. The aim of the present study was to evaluate the activity of organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) in plated primary human hepatocytes over time in culture. The uptake kinetics of the OATP1B1/1B3 substrate [(3)H]-estradiol-17beta-d-glucuronide was determined in cells from five donors. An extensive and variable decrease in OATP1B1/1B3 activity and/or increase in passive diffusion was observed over time. Already after 6h in culture, the OATP1B1/1B3 activity was not possible to determine in liver cells from one donor, while after 24h, the uptake activity was not measurable in one additional donor. In the other three, the decrease in CL(int) (V(max)/K(m)) values ranged from 15% to 86% after 24h in culture compared to the values measured at 2h. Visual examination of OATP1B1 protein expression by confocal microscopy showed localization to the plasma membrane as expected, and an extensive decrease in OATP1B1 expression over time in culture supported the decline in activity. The significant reduction in SLCO1B1 and SLCO1B3 gene expression over time determined by RT-PCR also supported the loss of OATP1B1/1B3 activity. In conclusion, plated primary human hepatocytes are useful as an in vitro model for OATP1B1/1B3-mediated uptake studies, but the culture time may substantially change the uptake kinetics. PMID- 21787760 TI - Understanding SOS (Son of Sevenless). AB - Son of Sevenless (SOS) was discovered in Drosophila melanogaster. Essential for normal eye development in Drosophila, SOS has two human homologues, SOS1 and SOS2. The SOS1 gene encodes the Son of Sevenless 1 protein, a Ras and Rac guanine nucleotide exchange factor. This protein is composed of several important domains. The CDC25 and REM domains provide the catalytic activity of SOS1 towards Ras and the histone fold DH/PH (Dbl homology and Pleckstrin homology) domains function, in tandem, to stimulate GTP/GDP exchange for Rac. In contrast to Ras, there have been few studies that implicate SOS1 in human disease and, initially, less attention was given to this gene. However, mutations in SOS1 have been reported recently in Noonan syndrome and in type 1 hereditary gingival fibromatosis. Although, there have been very few studies that focus on the regulation of this important gene by physiological or exogenous factors, we recently found that the SOS1 gene was induced by the environmental toxin, dioxin, and that this effect was mediated by the aryl hydrocarbon receptor (AhR). These recent observations raise the possibility that alterations in the expression of the SOS1 gene and, consequently, in the activity of the SOS1 protein may affect toxicological endpoints and lead to clinical disease. These possibilities, thus, have stimulated much interest in SOS1 recently. In this article, we review the functions of SOS1 and the evidence for its roles in physiology and pathology across species. PMID- 21787761 TI - p63 in tooth development. AB - Recent findings have shown that the development of teeth involves a complex sequence of molecular events in which the p53 family member p63 is involved. Indeed, mice lacking p63 do not have teeth and humans bearing mutations in p63 suffer developmental syndromes that affect tooth morphology and number. Several isoforms of p63 have been described: the use of two different promoters produces longer TAp63 isoforms, or shorter, 5' truncated isoforms known as DeltaNp63. The 3' end of primary transcripts is then subject to alternative splicing resulting in three additional isoforms: alpha (alpha), beta (beta) and gamma (gamma). Tooth development relies mainly on the activity of the N-terminally truncated DeltaNp63 isoforms. Here we review the experimental evidence for the involvement of DeltaNp63 in tooth development through its ability to sustain the molecular signalling that orchestrates epithelial-mesenchymal interaction. PMID- 21787762 TI - Administration of carnosine in the treatment of acute spinal cord injury. AB - L-Carnosine is an endogenously synthesized dipeptide composed of beta-alanine and L-histidine. It acts as a free radical scavenger and possesses antioxidant properties. L-Carnosine reduces proinflammatory and profibrotic cytokines such as transforming growth factor-beta (TGF-beta), interleukin (IL)-1, and tumor necrosis factor (TNF)-alpha in different experimental settings. In the present study, we investigated the efficacy of L and D-carnosine on the animal model of spinal cord injury (SCI). The spinal cord was exposed via a four-level T5-T8 laminectomy and SCI was produced by extradural compression of the spinal cord at level T6-T7 using an aneurysm clip with a closing force of 24 g. Treatment with D carnosine (150 mg/kg administered i.p., 1 h and 6h, after SCI), but not L carnosine significantly decreased (a) the degree of spinal cord inflammation and tissue injury (histological score), (b) neutrophil infiltration (myeloperoxidase activity), (c) nitrotyrosine formation, inducible NO synthase (iNOS) and Hsp70 expression, (d) proinflammatory cytokines, and (e) apoptosis (TUNEL staining, Fas ligand, Bax, and Bcl-2 expression). Furthermore, D-carnosine (150 mg/kg administered i.p., 1 h and 6 h, after SCI) significantly ameliorated the loss of limb function (evaluated by motor recovery score). Taken together, our results demonstrate the strong difference between L-carnosine and D-carnosine. The result strongly suggests that D-carnosine treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. PMID- 21787763 TI - Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets. AB - Malignant pleural mesothelioma (MPM) is an aggressive chemotherapy-resistant cancer. Up-regulation of epidermal growth factor receptor (EGFR) plays an important role in MPM development and EGFR-tyrosine kinase inhibitors (TKIs) may represent novel therapeutic options. We tested the effects of the EGFR TKIs gefitinib and erlotinib and TKIs targeted to other growth factors (VEGFR and PDGFR), in comparison to standard antineoplastic agents, in two human MPM cell lines, IST-Mes2 and ZL55. All drugs showed IC(50) values in the micromolar range: TKIs induced cytostatic effects at concentrations up to the IC(50,) while conventional drug growth-inhibitory activity was mainly cytotoxic. Moreover, the treatment of IST-Mes2 with TKIs (gefitinib and imatinib mesylate) in combination with cisplatin and gemcitabine did not show additivity. Focusing on the molecular mechanisms underlying the antiproliferative and pro-apoptotic effects of EGFR TKIs, we observed that gefitinib induced the formation and stabilization of inactive EGFR homodimers, even in absence of EGF, as demonstrated by EGFR B(max) and number of sites/cell. The analysis of downstream effectors of EGFR signaling demonstrated that EGF-induced proliferation, reverted by gefitinib, involved ERK1/2 activation, independently from Akt pathway. Gefitinib inhibits MPM cell growth and survival, preventing EGF-dependent activation of ERK1/2 pathway by blocking EGFR-TK phosphorylation and stabilizing inactive EGFR dimers. Along with the molecular definition of TKIs pharmacological efficacy in vitro, these results may contribute to delve deep into the promising but still controversial role for targeted and conventional drugs in the therapy of MPM. PMID- 21787764 TI - Assessment of clinical performance without adequate analytical validation: A prescription for confusion. AB - OBJECTIVES: Lp-PLA2 is a biomarker with promise for predicting cardiac risk. The lack of reproducible results has limited its use. In evaluating a new reagent kit, we investigated conditions for optimal reproducibility. METHODS: The Auto PLAC reagents were evaluated on the Cobas instrument. Performance characteristics, stability, and population ranges were determined. RESULTS: Analytical performance characteristics replicated manufacturer's claims. The stability profile of the analyte was unusual, with increasing results observed with storage at 4 degrees C or -20 degrees C. Only storage at -70 degrees C gave acceptable stability. Population median values with properly preserved samples were much lower than the cut off previously validated for increased risk. CONCLUSIONS: It is postulated that variability in specimen handling was a major contributor to the lack of traceability of the current reagents to the earlier clinical studies demonstrating its utility. We are now unsure how to identify reliable criteria for result interpretation. PMID- 21787765 TI - A screen for hoxb1-regulated genes identifies ppp1r14al as a regulator of the rhombomere 4 Fgf-signaling center. AB - Segmentation of the vertebrate hindbrain into multiple rhombomeres is essential for proper formation of the cerebellum, cranial nerves and cranial neural crest. Paralog group 1 (PG1) hox genes are expressed early in the caudal hindbrain and are required for rhombomere formation. Accordingly, loss of PG1 hox function disrupts development of caudal rhombomeres in model organisms and causes brainstem defects, associated with cognitive impairment, in humans. In spite of this important role for PG1 hox genes, transcriptional targets of PG1 proteins are not well characterized. Here we use ectopic expression together with embryonic dissection to identify novel targets of the zebrafish PG1 gene hoxb1b. Of 100 genes up-regulated by hoxb1b, 54 were examined and 25 were found to represent novel hoxb1b regulated hindbrain genes. The ppp1r14al gene was analyzed in greater detail and our results indicate that Hoxb1b is likely to directly regulate ppp1r14al expression in rhombomere 4. Furthermore, ppp1r14al is essential for establishment of the earliest hindbrain signaling-center in rhombomere 4 by regulating expression of fgf3. PMID- 21787767 TI - Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome. AB - Cancer stem cells (CSCs) play an important role in the recurrence and drug resistance of cancer. Isolation and characterization of CSCs from ovarian cancer samples may help to provide novel diagnostic and therapeutic targets in the management of recurrent disease and drug resistance in ovarian cancer. Here, we developed a xenograft model in which cells from 14 samples of human ovarian serous adenocarcinoma tissue or ascites were implanted in immunodeficient mice to test the tumorigenic potential of different populations of ovarian cancer cells. We identified and isolated the tumorigenic cells as CD117(+)Lineage(-) from three different xenografts. As few as 10(3) cells with the CD117(+)Lineage(-) phenotype, which comprise <2% of the xenograft tumor cells, were able to regenerate tumors in a mouse model, a 100-fold increase in tumorigenic potential compared to CD117(-)Lineage(-) cells. The tumors that arose from purified CD117(+)Lineage(-) cells reproduced the original tumor heterogeneity and could be serially generated, demonstrating the ability to self-renew and to differentiate, two defining properties of stem cells. Furthermore, immunohistochemistry analysis of 25 patients with advanced ovarian serous adenocarcinoma revealed positive immunostaining for CD117 in 40% (10 of 25) of patients. CD117 expression was statistically correlated with resistance to conventional chemotherapy (P=0.027). In conclusion, our study demonstrates that human ovarian cancer cells with the CD117(+) phenotype possess the unique properties of CSCs, including self-renewal, differentiation, a high tumorigenic potential, and chemoresistance. Future studies designed to target CD117(+) cancer cells may identify more attractive and effective therapies for treatment of ovarian cancer. PMID- 21787766 TI - miR-196 regulates axial patterning and pectoral appendage initiation. AB - Vertebrate Hox clusters contain protein-coding genes that regulate body axis development and microRNA (miRNA) genes whose functions are not yet well understood. We overexpressed the Hox cluster microRNA miR-196 in zebrafish embryos and found four specific, viable phenotypes: failure of pectoral fin bud initiation, deletion of the 6th pharyngeal arch, homeotic aberration and loss of rostral vertebrae, and reduced number of ribs and somites. Reciprocally, miR-196 knockdown evoked an extra pharyngeal arch, extra ribs, and extra somites, confirming endogenous roles of miR-196. miR-196 injection altered expression of hox genes and the signaling of retinoic acid through the retinoic acid receptor gene rarab. Knocking down rarab mimicked the pectoral fin phenotype of miR-196 overexpression, and reporter constructs tested in tissue culture and in embryos showed that the rarab 3'UTR is a miR-196 target for pectoral fin bud initiation. These results show that a Hox cluster microRNA modulates development of axial patterning similar to nearby protein-coding Hox genes, and acts on appendicular patterning at least in part by modulating retinoic acid signaling. PMID- 21787768 TI - Hepatic response to aluminum toxicity: dyslipidemia and liver diseases. AB - Aluminum (Al) is a metal toxin that has been implicated in the etiology of a number of diseases including Alzheimer's, Parkinson's, dialysis encephalopathy, and osteomalacia. Al has been shown to exert its effects by disrupting lipid membrane fluidity, perturbing iron (Fe), magnesium, and calcium homeostasis, and causing oxidative stress. However, the exact molecular targets of aluminum's toxicity have remained elusive. In the present review, we describe how the use of a systems biology approach in cultured hepatoblastoma cells (HepG2) allowed the identification of the molecular targets of Al toxicity. Mitochondrial metabolism is the main site of the toxicological action of Al. Fe-dependent and redox sensitive enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) are dramatically decreased by Al exposure. In an effort to compensate for diminished mitochondrial function, Al-treated cells stabilize hypoxia inducible factor-1alpha (HIF-1alpha) to increase ATP production by glycolysis. Additionally, Al toxicity leads to an increase in intracellular lipid accumulation due to enhanced lipogenesis and a decrease in the beta-oxidation of fatty acids. Central to these effects is the alteration of alpha-ketoglutarate (KG) homeostasis. In Al-exposed cells, KG is preferentially used to quench ROS leading to succinate accumulation and HIF-1alpha stabilization. Moreover, the channeling of KG to combat oxidative stress leads to a reduction of l-carnitine biosynthesis and a concomitant decrease in fatty acid oxidation. The fluidity and interaction of these metabolic modules and the implications of these findings in liver-related disorders are discussed herein. PMID- 21787769 TI - Stem cell self-renewal in intestinal crypt. AB - As a rapidly cycling tissue capable of fast repair and regeneration, the intestinal epithelium has emerged as a favored model system to explore the principles of adult stem cell biology. However, until recently, the identity and characteristics of the stem cell population in both the small intestine and colon has remained the subject of debate. Recent studies based on targeted lineage tracing strategies, combined with the development of an organotypic culture system, have identified the crypt base columnar cell as the intestinal stem cell, and have unveiled the strategy by which the balance between proliferation and differentiation is maintained. These results show that intestinal stem cells operate in a dynamic environment in which frequent and stochastic stem cell loss is compensated by the proliferation of neighboring stem cells. We review the basis of these experimental findings and the insights they offer into the mechanisms of homeostatic stem cell regulation. PMID- 21787770 TI - Regulation of ciliary beat frequency by the nitric oxide signaling pathway in mouse nasal and tracheal epithelial cells. AB - OBJECTIVES: Our purpose was to investigate the role of the nitric oxide (NO) signaling pathway in the regulation of ciliary beat frequency (CBF) in mouse nasal and tracheal epithelial cells. METHODS: We studied the effects of the NO donor l-arginine (L-Arg) and specific inhibitors of the NO signaling pathway on CBF of both nasal and tracheal epithelial cells by using high-speed digital microscopy. We also examined eNOS, sGC beta, PKG I and acetylated alpha tubulin expression in native mouse nasal and tracheal epithelium using immunohistochemical methods. RESULTS: L-Arg significantly increased CBF of cultured nasal and tracheal epithelial cells, and the effects were blocked by pretreatment with N(G)-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor, with LY-83583, a sGC inhibitor, or with KT-5823, a PKG inhibitor. Positive immunostaining for NO signaling molecules including eNOS, sGC beta and PKG I was observed in either nasal or tracheal ciliated epithelium. CONCLUSION: NO plays a role in regulating CBF of mouse respiratory epithelial cells via a eNOS-NO-sGC beta-cGMP-PKG I pathway. PMID- 21787771 TI - Anterior-posterior asymmetry in iris mechanics measured by indentation. AB - Indentation and histological analysis of the porcine iris were done to assess the relative stiffness of the anterior (stroma) and posterior (dilator and sphincter) layers. The dimensions of the constituent structures were documented histologically by staining with a monoclonal anti-human alpha-smooth muscle actin antibody to determine the location of the stroma, sphincter, and dilator. Intact porcine irides (4-8 h post-mortem) were bisected into two equal C-shaped halves to indent both surfaces. Indentation experiments were performed using a 1 mm cylindrical indenter tip. The load-displacement curve for each experiment was used to estimate effective instantaneous and equilibrium moduli for the anterior and posterior surfaces of the tissue. A total of 18 irides (9 pairs) with 3-5 indentations per iris surface was performed. The average thickness of the samples was 550 MUm; the indentation depth was limited to 60-100 MUm depending on the thickness of the sample at each point. Posterior surface indentation gave larger forces than anterior, with the resulting instantaneous modulus of 6.0 +/- 0.6 kPa versus 4.0 +/- 0.5 kPa (mean +/- 95% CI, n = 45, p < 0.001) and equilibrium modulus of 4.4 +/- 0.9 versus 2.3 +/- 0.3 (p = 0.007). The stress-relaxation analysis revealed that the anterior surface had a shorter relaxation time (121.31 +/- 6.84 s) than the posterior surface (210.61 +/- 9.41 s, p = 0.03), perhaps due to the permeability of the stroma. Recognizing that our effective modulus calculations in this study did not account for heterogeneity, viscoelasticity, or poroelasticity, we conclude that the posterior components of the iris - dilator, pigment epithelium, and sphincter - are on average stiffer than the stroma and anterior border layer. PMID- 21787772 TI - Crystal structure of human MTH1 and the 8-oxo-dGMP product complex. AB - MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9A) and its complex with the product 8-oxo-dGMP (1.8A). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design. PMID- 21787773 TI - Inadvertently discovered round mass in mesentery. PMID- 21787774 TI - An unusual cause of fibrostenotic terminal ileal disease. PMID- 21787775 TI - Living in a dangerous world decreases maternal care: a study in serotonin transporter knockout mice. AB - Adverse early experiences can profoundly influence the adult behavioral profile. When pregnant and lactating mice are confronted with soiled bedding of unfamiliar males (UMB), these stimuli signal the danger of infanticide and thus simulate a "dangerous world". In a previous study, offspring of UMB treated mothers were shown to display increased anxiety-like behavior and reduced exploratory locomotion as adults, compared to mice treated with neutral bedding (NB, "safe environment"). The aim of this study was to elucidate the mechanisms conveying these effects of living in a "dangerous world" to offspring behavior. We hypothesized the mother to be the major link and focused on the influence of UMB on maternal stress hormones and behavior. Thus, we investigated fecal corticosterone metabolites (CM) and maternal care of pregnant and lactating mice either treated with NB or UMB. The offspring were subsequently tested for their anxiety-like and exploratory behavior. Mothers treated with UMB showed a significantly higher increase of fecal CM following the initial treatment, than NB treated mothers, indicating that the odor cues of potentially infanticidal males represented an ethologically relevant stimulus. Whereas the hormonal stress response habituated, living in a "dangerous world" led to a distinct and consistent reduction of maternal care behavior, particularly concerning the duration of licking and grooming the pups. Surprisingly, we could not confirm our former findings of altered phenotypes in the offspring of UMB treated mothers. In summary, we hypothesize that the frequently described effects of early life adversity on the offspring's behavioral profile are mediated primarily by maternal care in altricial rodents. PMID- 21787776 TI - Pathogenic bacteria prime the induction of Toll-like receptor signalling in human colonic cells by the Gal/GalNAc lectin Carbohydrate Recognition Domain of Entamoeba histolytica. AB - In mixed intestinal infections with Entamoeba histolytica trophozoites and enteropathogenic bacteria, which are wide-spread in areas of endemic amoebiasis, interaction between the pathogens could be an important factor in the occurrence of invasive disease. It has been reported that exposure of human colonic cells to enteropathogenic bacteria increased trophozoite adherence to the cells and their subsequent damage. We report here that the Carbohydrate Recognition Domain (CRD) of the amoebic Gal/GalNAc lectin binds to Toll-like receptors TLR-2 and TLR-4 in human colonic cells, activating the "classic" signalling pathway of these receptors. Activation induced expression of TLR-2 and TLR-4 mRNAs and the mRNAs of pro-inflammatory cytokines, as well as an increase in the corresponding proteins. Direct correlation was observed between the increased expression of TLRs and pro-inflammatory cytokines, the enhanced adhesion of trophozoites to the cells and the inflicted cell damage. When cells were exposed to pathogenic bacteria Staphylococcus aureus (Gram+) or Shigella dysenteriae (Gram-), elements of an innate immune response were induced. CRD by itself elicited a similar cell response, while exposure to a commensal Escherichia coli had a null effect. Pre exposure of the cells to pathogenic bacteria and then to CRD rendered an inflammatory-like microenvironment that after addition of trophozoites facilitated greater cell destruction. Our results suggest that CRD is recognised by human colonic cells as a pathogen-associated-molecular-pattern-like molecule and as such can induce the expression of elements of an innate immune response. In the human host, an exacerbated inflammatory environment, derived from pathogen interplay, may be an important factor for development of invasive disease. PMID- 21787777 TI - Early activated Th-1 type and dominantly diverse natural killer T (CD3+CD161+Valpha24-) cells in bone marrow among visceral leishmaniasis patients. AB - Lipid antigens of Leishmania donovani-like lipophosphoglycans (LPG) are demonstrated to be a potent ligand for natural killer T (NKT) cell activation. Little is known about the phenotype or function of these cells and their trafficking pattern to the bone marrow (BM) of visceral leishmaniasis (VL) patients. Their precise role in humans still requires pathological validation. The study included 42 parasitologically confirmed patients (mean age 24.80+/ 16.26 years; range 3-70 years; 25 males and 17 females), 33 healthy contact subjects (family/non-family members) and normal BM specimens (NBM; n=9). Enumeration of NKT cells and quantification of parasites (before and after therapy) were performed for the recruited patients. Results established that non CD1d restricted, diverse cells are the dominant population among resident but not enriched NKT (CD3+CD161+) cells at the disease site (BM). Expression profiles for various markers are indicative of their early activated (CD69+, CD62L(low), CD11a(high)) CCR5+ phenotype at the BM. Functionally, BM-derived NKT cells were dominantly producing IFN-gamma in response to L. donovani antigen in vitro. Given these observations, these data indicate that CD3+CD161+ diverse NKT cells are heterogeneous in function and of the dominant Th-1 phenotype at the disease site. PMID- 21787778 TI - Applications and performance of monoclonal antibodies to human tartrate resistant acid phosphatase. AB - BACKGROUND: Tartrate-resistant acid phosphatase (TRACP) is an enzyme common to cells of the mononuclear phagocyte system and a clinically relevant biomarker for osteoclasts and inflammatory macrophages. The purpose was to assess applications and performance of six anti-TRACP monoclonal antibodies. METHODS: Mab9C5, 14G6, 162, 203, 220, and 89 were used as capture and detection antibodies in quantitative immunoassay, and for western blot (WB), immunoprecipitation, and immunohistochemistry of paraffin sections containing chronic inflammatory infiltrates. The clinical performance of mab14G6 for immunoassay of serum TRACP5b activity was compared to two commercial kit methods. RESULTS: Mab9C5 is useful for WB and immunohistochemistry methods only. Mab14G6, 162, and 203 are useful for quantitative immunoassay and immunoprecipitation, however, mab203 causes inactivation of enzymatic activity. Mab220 and 89 are specific for TRACP5a and useful in all applications. Mab14G6 has similar clinical sensitivity and specificity as two commercial methods. CONCLUSIONS: TRACP is an important marker in osteoimmunology. Specific antibodies with unique specificity for TRACP isoforms and defined applications will be valuable for clinical evaluation of bone metabolic, inflammatory and autoimmune diseases and will aid in basic research of TRACP biochemistry and biology. PMID- 21787779 TI - Absolute and percent CD4+ T-cell enumeration by flow cytometry using capillary blood. AB - INTRODUCTION: CD4+ T-cell counting is usually performed on whole blood obtained from standard venipuncture. Venipuncture requires expertise, results in discomfort and generates biological waste. Capillary blood could be used to measure the levels of CD4+ T-cell in children, elderly and very ill patients. We studied the agreement between CD4+ T-cell counts and percent generated using venous blood with those obtained with capillary blood in HIV-infected adults and children in a resource-limited tropical setting. METHODS: This cross-sectional study consecutively enrolled a total of 152 adult and pediatric HIV-positive patients attending two outpatient clinics in Maputo City, Mozambique. We recruited individuals presenting for their routine clinical follow-up that included the determination of CD4+ T-cell counts in peripheral blood. For each subject, peripheral blood specimens were obtained by both venipuncture and finger prick. Specimens were tested using two flow cytometers, the FACSCount and the FACSCalibur. RESULTS: Absolute CD4+ T-cell counts obtained using capillary blood were in close agreement with those from venous blood both on the FACSCalibur (absolute bias=+12.3 cells/mm3, limits of agreement: -259.2 to +283.9, R2=0.96) and the FACSCount (absolute bias=+16.1 cells/mm3, limits of agreement: -209.2 to +241.5, R2=0.97). Percent CD4+ T-cell counts were measured only on the FACSCalibur also showed a good agreement with a bias of +0.6% and limits of agreement of -3.1 to +4.3. CONCLUSIONS: Absolute CD4+ T-cell counts and percent generated using capillary blood are in close agreement with those from venous blood. Point-Of-Care assays and standard flow cytometers can be deployed in a tiered laboratory network where both venous and capillary blood collection can be used for CD4+ T-cell enumeration. PMID- 21787780 TI - Potential roles of recombinant acetylcholine receptor alpha subunit 1-211 in immunoadsorbent and DNA immunization. AB - The open reading frame of the alpha-subunit (amino acids 1-211) of human muscle nicotinic acetylcholine receptor (hAChR(alpha211)) was inserted into eukaryotic expression vector of pPIC9K to form a recombinant plasmid. After transformation and expression, the target protein rhAChR(alpha211) (recombinant hAChR(alpha211)) was secretively expressed in recombinant strain P. pastoris GS115/pPIC9K hAChR(alpha211) with a yield of 25 mg/L. rhAChR(alpha211) was purified by Q Sepharose column and gel filtration chromatography. Furthermore, the purified protein was coupled with CNBr-actived Sepharose 4B to form a special immunoadsorbent. By this immunoadsorbent, the removal rate for AChRAb in two myasthenia gravis (MG) patient sera reached 84% and 94%, respectively. The DNA fragment of hAChR(alpha211) was cloned into shuffle vector of pcDNA3.0 to form the recombinant plasmid pcDNA-hAChR(alpha211). Then the gene vaccine was directly injected intramuscularly into C57BL/6 mice. After immunization, the corresponding antibody, AChRAb, was detected in mice sera by ELISA. The target gene could be re amplified by PCR in muscle, liver, spleen and kidney of immunized mice. It provides rapid and efficient methods to remove specific acetylcholine receptor antibody from the patient's sera and establish an animal model of myasthenia gravis by recombinant hAChR(alpha211) immunization. PMID- 21787781 TI - Improvement of anti-Burkholderia mouse monoclonal antibody from various phage displayed single-chain antibody libraries. AB - To improve anti-Burkholderia monoclonal antibody (MAb) binding affinity, six single chain variable fragments (scFvs) constructed previously were used as scaffolds to construct large highly-diversified phage-displayed mouse scFv random and domain libraries. First, we employed random mutagenesis to introduce random point mutations into entire variable regions, generating six random libraries. Additionally, the oligonucleotide-directed mutagenesis was targeted on complementarity-determining region 3 (CDR3) from each variable region of heavy (VH) and light chains (VL) derived from six scFvs, and generated eighteen domain libraries including six VH CDR3, six VL CDR3, and six combined VH/VL CDR3 mutated domains, respectively. We collected high scFvs binders through panning experiment over the large (size ~1 * 109) random and domain libraries. The quality of the libraries was validated by successful selection of high-affinity clones. Random mutagenesis generated many mutant scFv clones having more than one amino acid changes around framework regions, but not many in CDRs. Surprisingly, the resulting eight higher scFv binders were selected from CDR3 mutations, but not from random mutations. Six of them resulted from CDR3 mutations of light chain, except for two scFvs from heavy chain, showing both Burkholderia pseudomallei and Burkholderia mallei had preferentially influenced the VL CDR3. Furthermore, all eight higher scFvs converted to full format human IgG1 antibodies were expressed transiently in 293T cell line. Five chimeric MAbs showed improved higher binding activity, as much as 0.2-0.3 at O.D. 405 nm, than positive control MAbs. These libraries could be valuable sources for selection of anti-Burkholderia antibodies and discovery of the relevant epitope(s) for developing effective vaccines or therapeutics. PMID- 21787782 TI - AMP-activated protein kinase and metabolic regulation in cold-hardy insects. AB - Winter survival for many insects depends on cold hardiness adaptations as well as entry into a hypometabolic diapause state that minimizes energy expenditure. We investigated whether AMP-activated protein kinase (AMPK) could be involved in this adaptation in larvae of two cold-hardy insects, Eurosta solidaginis that is freeze tolerant and Epiblema scudderiana that uses a freeze avoidance strategy. AMPK activity was almost 2-fold higher in winter larvae (February) compared with animals collected in September. Immunoblotting revealed that phosphorylation of AMPK in the activation loop and phosphorylation of acetyl-CoA carboxylase (ACC), a key target of AMPK, were higher in Epiblema during midwinter whereas no seasonal change was seen in Eurosta. Immunoblotting also revealed a significant increase in ribosomal protein S6 phosphorylation in overwintering Epiblema larvae, and in both Eurosta and Epiblema, phosphorylation of eukaryotic initiation factor 4E-binding protein-1 dramatically increased in the winter. Pyruvate dehydrogenase (PDH) E1alpha subunit site 1 phosphorylation was 2-fold higher in extracts of Eurosta larvae collected in February versus September while PDH activity decreased by about 50% in Eurosta and 80% in February Eurosta larvae compared with animals collected in September. Glycogen phosphorylase phosphorylation was 3-fold higher in Epiblema larvae collected in February compared with September and also in these animals, triglyceride lipase activity increased by 70% during winter. Overall, our study suggests a re-sculpting of metabolism during insect diapause, which shifted to a more catabolic poise in freeze-avoiding overwintering Epiblema larvae, possibly involving AMPK. PMID- 21787783 TI - Salivary gland transcriptome analysis in response to sugar feeding in malaria vector Anopheles stephensi. AB - In this study, we analyzed a small scale transcriptome of salivary glands in sugar fed female mosquitoes. Thirty five percent of the transcripts could not be assigned a function. Some of them may code for salivary gland specific products involved in sugar feeding. We identified and characterized two new putative cDNAs encoding a sugar transporter and a cAMP generating DAPIT (Diabetes-Associated proteins in insulin sensitive tissues). Down regulation of these two cDNAs in response to blood feeding suggest that both AsST and AsDAPIT salivary genes may specifically be involved in the facilitation of sugar metabolism and energy production. The inability to absorb or digest sugar may cause organ failure, improper functioning of nervous system, behavioral disorder and death. Further functional characterization of theses putative transcripts is under investigation to examine their role in the mosquito salivary glands. PMID- 21787784 TI - Early ion-channel remodeling and arrhythmias precede hypertrophy in a mouse model of complete atrioventricular block. AB - Complete atrioventricular block (CAVB) and related ventricular bradycardia are known to induce ventricular hypertrophy and arrhythmias. Different animal models of CAVB have been established with the most common being the dog model. Related studies were mainly focused on the consequences on the main repolarizing currents in these species, i.e. IKr and IKs, with a limited time point kinetics post-AVB. In order to explore at a genomic scale the electrical remodeling induced by AVB and its chronology, we have developed a novel model of CAVB in the mouse using a radiofrequency-mediated ablation procedure. We investigated transcriptional changes in ion channels and contractile proteins in the left ventricles as a function of time (12h, 1, 2 and 5 days after CAVB), using high-throughput real time RT-PCR. ECG in conscious and anesthetized mice, left ventricular pressure recordings and patch-clamp were used for characterization of this new mouse model. As expected, CAVB was associated with a lengthening of the QT interval. Moreover, polymorphic ventricular tachycardia was recorded in 6/9 freely-moving mice during the first 24h post-ablation. Remarkably, myocardial hypertrophy was only evident 48 h post-ablation and was associated with increased heart weight and altered expression of contractile proteins. During the first 24 hours post CAVB, genes encoding ion channel subunits were either up-regulated (such as Nav1.5, +74%) or down-regulated (Kv4.2, -43%; KChIP2, -47%; Navbeta1, -31%; Cx43, -29%). Consistent with the transient alteration of Kv4.2 expression, I(to) was reduced at day 1, but restored at day 5. In conclusion, CAVB induces two waves of molecular remodeling: an early one (<=24 h) leading to arrhythmias, a later one related to hypertrophy. These results provide new molecular basis for ventricular tachycardia induced by AV block. PMID- 21787785 TI - Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target. AB - The retinoblastoma tumor suppressor (Rb) plays a key role in cell cycle control and is linked to various types of human cancer. Rb binds to the LxCxE motif, present in a number of cellular and viral proteins such as AdE1A, SV40 large T antigen and human papillomavirus (HPV) E7, all instrumental in revealing fundamental mechanisms of tumor suppression, cell cycle control and gene expression. A detailed kinetic study of RbAB binding to the HPV E7 oncoprotein shows that an LxCxE-containing E7 fragment binds through a fast two-state reaction strongly favored by electrostatic interactions. Conversely, full-length E7 binds through a multistep process involving a pre-equilibrium between E7 conformers, a fast electrostatically driven association step guided by the LxCxE motif and a slow conformational rearrangement. This kinetic complexity arises from the conformational plasticity and intrinsically disordered nature of E7 and from multiple interaction surfaces present in both proteins. Affinity differences between E7N domains from high- and low-risk types are explained by their dissociation rates. In fact, since Rb is at the center of a large protein interaction network, fast and tight recognition provides an advantage for disruption by the viral proteins, where the balance of physiological and pathological interactions is dictated by kinetic ligand competition. The localization of the LxCxE motif within an intrinsically disordered domain provides the fast, diffusion-controlled interaction that allows viral proteins to outcompete physiological targets. We describe the interaction mechanism of Rb with a protein ligand, at the same time an LxCxE-containing model target, and a paradigmatic intrinsically disordered viral oncoprotein. PMID- 21787786 TI - Synthetic antibodies designed on natural sequence landscapes. AB - We present a method for synthetic antibody library generation that combines the use of high-throughput immune repertoire analysis and a novel synthetic technology. The library design recapitulates positional amino acid frequencies observed in natural antibody repertoires. V-segment diversity in four heavy (V(H)) and two kappa (V(kappa)) germlines was introduced based on the analysis of somatically hypermutated donor-derived repertoires. Complementarity-determining region 3 length and amino acid designs were based on aggregate frequencies of all V(H) and V(kappa) sequences in the data set. The designed libraries were constructed through an adaptation of a novel gene synthesis technology that enables precise positional control of amino acid composition and incorporation frequencies. High-throughput pyrosequencing was used to monitor the fidelity of construction and characterize genetic diversity in the final 3.6*10(10) transformants. The library exhibited Fab expression superior to currently reported synthetic approaches of equivalent diversity, with greater than 93% of clones observed to successfully display both a correctly folded heavy chain and a correctly folded light chain. Genetic diversity in the library was high, with 95% of 7.0*10(5) clones sequenced observed only once. The obtained library diversity explores a comparable sequence space as the donor-derived natural repertoire and, at the same time, is able to access novel recombined diversity due to lack of segmental linkage. The successful isolation of low- and subnanomolar-affinity antibodies against a diverse panel of receptors, growth factors, enzymes, antigens from infectious reagents, and peptides confirms the functional viability of the design strategy. PMID- 21787787 TI - Crystal structure of the cytoplasmic N-terminal domain of subunit I, a homolog of subunit a, of V-ATPase. AB - Subunit "a" is associated with the membrane-bound (V(O)) complex of eukaryotic vacuolar H(+)-ATPase acidification machinery. It has also been shown recently to be involved in diverse membrane fusion/secretory functions independent of acidification. Here, we report the crystal structure of the N-terminal cytosolic domain from the Meiothermus ruber subunit "I" homolog of subunit a. The structure is composed of a curved long central alpha-helix bundle capped on both ends by two lobes with similar alpha/beta architecture. Based on the structure, a reasonable model of its eukaryotic subunit a counterpart was obtained. The crystal structure and model fit well into reconstructions from electron microscopy of prokaryotic and eukaryotic vacuolar H(+)-ATPases, respectively, clarifying their orientations and interactions and revealing features that could enable subunit a to play a role in membrane fusion/secretion. PMID- 21787789 TI - Crystal structure of crotoxin reveals key residues involved in the stability and toxicity of this potent heterodimeric beta-neurotoxin. AB - The crystal structure of crotoxin, a potent presynaptic neurotoxin from Crotalus durissusterrificus, was solved at 1.35 A resolution. It shows the architecture of the three disulfide-linked polypeptide chains (alpha, beta, and gamma) of the acidic subunit CA noncovalently complexed with the basic phospholipase A(2) (PLA(2)) subunit CB. The unique structural scaffold of the association of the CA and CB subunits indicates that posttranslational cleavage of the pro-CA precursor is a prerequisite for the assembly of the CA-CB complex. These studies provide novel structural insights to explain the role of the CA subunit in the mechanism of action of crotoxin. The crystal structure of the highly toxic and stable CA(2)CBb complex crystallized here allows us to identify key amino acid residues responsible for significant differences in the pharmacological activities of the two classes of crotoxin complexes. In particular, we show that critical residues Trp31 and Trp70 of the CBb subunit establish intermolecular polar contacts with Asp99 and Asp89, respectively, of the beta-chain of CA(2) and contribute to the stability and toxicity of the CA(2)CBb complex. These interactions also lead to decreased PLA(2) activity by partially blocking substrate access to the catalytic dyad and by masking several interfacial binding surface residues important for PLA(2) interaction with phospholipids. Identification of the binding interface between the CA subunits and the CB subunits of crotoxin is important for the structure-based design of antineurotoxic inhibitors. Since crotoxin displays numerous physiological functions, including antitumoral properties, knowledge of its three-dimensional structure will be useful for the understanding of these diverse effects. PMID- 21787788 TI - The determinants that govern microtubule assembly from the atomic structure of GTP-tubulin. AB - Tubulin alternates between a soluble curved structure and a microtubule straight conformation. GTP binding to alphabeta-tubulin is required for microtubule assembly, but whether this triggers conversion into a straighter structure is still debated. This is due, at least in part, to the lack of structural data for GTP-tubulin before assembly. Here, we report atomic-resolution crystal structures of soluble tubulin in the GDP and GTP nucleotide states in a complex with a stathmin-like domain. The structures differ locally in the neighborhood of the nucleotide. A loop movement in GTP-bound tubulin favors its recruitment to the ends of growing microtubules and facilitates its curved-to-straight transition, but this conversion has not proceeded yet. The data therefore argue for the conformational change toward the straight structure occurring as microtubule specific contacts are established. They also suggest a model for the way the tubulin structure is modified in relation to microtubule assembly. PMID- 21787790 TI - A mathematical model to distinguish sociological and biological susceptibility factors in disease transmission in the context of H1N1/09 influenza. AB - The pandemic H1N1/09 influenza virus differs from seasonal influenza in its greater prevalence among younger individuals. It is well known that younger individuals interact with one another and society as a whole more than older individuals, suggesting that this could account for the skewed prevalence. However, the observed skewed disease prevalence could also be due to a lesser biological vulnerability (cross-immunity or partial immunity) in the older generation. We develop an age-structured, compartmental mathematical model to quantify the degree to which the skewed disease prevalence among younger individuals is due to a lesser biological vulnerability in the older generation. The model incorporates synthetic data regarding sociological interaction between different age groups generated from the simulation software EpiSims, which allows a clear distinction of the sociological and biological susceptibility effects on the transmission rate of the disease. After fitting the model to available data, we quantify the degree of biological susceptibility of five age groups in the population of the United States. Our model indicates that individuals over the age of 60 are 1/15 as susceptible to H1N1/09 influenza as those under 30 years of age. The key feature in the model is separating social contact factors of disease transmission from biological ones. PMID- 21787791 TI - Multiobjective H2/Hinfinity synthetic gene network design based on promoter libraries. AB - Some current promoter libraries have been developed for synthetic gene networks. But an efficient method to engineer a synthetic gene network with some desired behaviors by selecting adequate promoters from these promoter libraries has not been presented. Thus developing a systematic method to efficiently employ promoter libraries to improve the engineering of synthetic gene networks with desired behaviors is appealing for synthetic biologists. In this study, a synthetic gene network with intrinsic parameter fluctuations and environmental disturbances in vivo is modeled by a nonlinear stochastic system. In order to engineer a synthetic gene network with a desired behavior despite intrinsic parameter fluctuations and environmental disturbances in vivo, a multiobjective H(2)/H(infinity) reference tracking (H(2) optimal tracking and H(infinity) noise filtering) design is introduced. The H(2) optimal tracking can make the tracking errors between the behaviors of a synthetic gene network and the desired behaviors as small as possible from the minimum mean square error point of view, and the H(infinity) noise filtering can attenuate all possible noises, from the worst-case noise effect point of view, to achieve a desired noise filtering ability. If the multiobjective H(2)/H(infinity) reference tracking design is satisfied, the synthetic gene network can robustly and optimally track the desired behaviors, simultaneously. First, based on the dynamic gene regulation, the existing promoter libraries are redefined by their promoter activities so that they can be efficiently selected in the design procedure. Then a systematic method is developed to select an adequate promoter set from the redefined promoter libraries to synthesize a gene network satisfying these two design objectives. But the multiobjective H(2)/H(infinity) reference tracking design problem needs to solve a difficult Hamilton-Jacobi Inequality (HJI)-constrained optimization problem. Therefore, the fuzzy approximation method is employed to simplify the HJI-constrained optimization problem to an equivalent linear matrix inequality (LMI)-constrained optimization problem, which can be easily solved by selecting an adequate promoter set from the redefined promoter libraries using the LMI toolbox in Matlab. Based on the confirmation of in silico design examples, we can select an adequate promoter set from the redefined promoter libraries to achieve the multiobjective H(2)/H(infinity) reference tracking design. The proposed method can reduce the number of trial-and-error experiments in selecting an adequate promoter set for a synthetic gene network with desired behaviors. With the rapid increase of promoter libraries, this systematic method will accelerate progress of synthetic biology design. PMID- 21787792 TI - Wide-field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber. AB - The rodent dorsal window chamber is a widely used in vivo model of the microvasculature. The model consists of a 1cm region of exposed microvasculature in the rodent dorsal skin that is immobilized by surgically implanted titanium frames, allowing the skin microvasculature to be visualized. We describe a detailed protocol for surgical implantation of the dorsal window chamber which enables researchers to perform the window chamber implantation surgery. We further describe subsequent wide-field functional imaging of the chamber to obtain hemodynamic information in the form of blood oxygenation and blood flow on a cm size region of interest. Optical imaging techniques, such as intravital microscopy, have been applied extensively to the dorsal window chamber to study microvascular-related disease and conditions. Due to the limited field of view of intravital microscopy, detailed hemodynamic information typically is acquired from small regions of interest, typically on the order of hundreds of MUm. The wide-field imaging techniques described herein complement intravital microscopy, allowing researchers to obtain hemodynamic information at both microscopic and macroscopic spatial scales. Compared with intravital microscopy, wide-field functional imaging requires simple instrumentation, is inexpensive, and can give detailed metabolic information over a wide field of view. PMID- 21787794 TI - Proprioceptive recalibration following prolonged training and increasing distortions in visuomotor adaptation. AB - Reaching with misaligned visual feedback of the hand leads to reach adaptation (motor recalibration) and also results in partial sensory recalibration, where proprioceptive estimates of hand position are changed in a way that is consistent with the visual distortion. The goal of the present study was to explore the relationship between changes in sensory and motor systems by examining these processes following (1) prolonged reach training and (2) training with increasing visuomotor distortions. To examine proprioceptive recalibration, we determined the position at which subjects felt their hand was aligned with a reference marker after completing three blocks of reach training trials with a cursor that was rotated 30 degrees clockwise (CW) for all blocks, or with a visuomotor distortion that was increased incrementally across the training blocks up to 70 degrees CW relative to actual hand motion. On average, subjects adapted their reaches by 16 degrees and recalibrated their sense of felt hand position by 7 degrees leftwards following the first block of reach training trials in which they reached with a cursor that was rotated 30 degrees CW relative to the hand, compared to baseline values. There was no change in these values for the 30 degrees training group across subsequent training blocks. However, subjects training with increasing levels of visuomotor distortion showed increased reach adaptation (up to 34 degrees leftward movement aftereffects) and sensory recalibration (up to 15 degrees leftwards). Analysis of motor and sensory changes following each training block did not reveal any significant correlations, suggesting that the processes underlying motor adaptation and proprioceptive recalibration occur simultaneously yet independently of each other. PMID- 21787793 TI - Impact of chronic hypercortisolemia on affective processing. AB - Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD. Twenty one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy control subjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated. CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CS group, greater activation in left dorsal anterior cingulate was related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD. This article is part of a Special Issue entitled 'Anxiety and Depression'. PMID- 21787795 TI - The attention network of the human brain: relating structural damage associated with spatial neglect to functional imaging correlates of spatial attention. AB - Functional imaging studies of spatial attention regularly report activation of the intraparietal sulcus (IPS) and dorsal premotor cortex including the frontal eye fields (FEF) in tasks requiring overt or covert shifting of attention. In contrast, lesion-overlap studies of patients with spatial neglect - a syndrome characterized by severe impairments of spatial attention - show that the critical damage concerns more ventral regions, comprising the inferior parietal lobule, the temporal-parietal junction (TPJ), and the superior temporal gyrus. We performed voxel-based lesion-symptom mapping of 29 right-hemisphere stroke patients, using several performance indices derived from a cueing task as measures of spatial attention. In contrast to previous studies, we focused our analyses on eight regions of interest defined according to results of previous functional imaging studies. A direct comparison of neglect with control patients revealed that neglect was associated with damage to the TPJ, the middle frontal gyrus, and the posterior IPS. The latter region was also a significant predictor of the degree of contralesional slowing of target detection and the extent to which ipsilesional distracters captured attention of neglect patients. Finally, damage to the FEF and posterior IPS was negatively correlated with the tendency of neglect patients to orient attention toward behaviourally relevant distracters. These findings support the results of functional imaging studies of spatial attention and provide evidence for a network account of neglect, according to which attentional selection of relevant environmental stimuli and the reorienting of attention result from dynamic interactions between the IPS, the dorsal premotor cortex, and the TPJ. PMID- 21787797 TI - Inhibition of food intake induced by acute stress in rats is due to satiation effects. AB - Acute mild stress induces an inhibition of food intake in rats. In most studies, the cumulative daily food intake is measured but this only provides a quantitative assessment of ingestive behavior. The present study was designed to analyze the reduction in food intake induced by acute stress and to understand which behavioral and central mechanisms are responsible for it. Two different stressors, restraint stress (RS) and forced swimming stress (FSS), were applied acutely to male Wistar rats. We first measured corticosterone and ACTH in plasma samples collected immediately after acute RS and FSS in order to validate our stress models. We measured food intake after RS and FSS and determined meal patterns and behavioral satiety sequences. The expressions of CRF, NPY and POMC in the hypothalamus were also determined immediately after acute RS and FSS. The rise in corticosterone and ACTH levels after both acute RS and FSS validated our models. Furthermore, we showed that acute stress induced a reduction in cumulative food intake which lasted the whole day for RS but only for the first hour after FSS. For both stressors, this stress-induced food intake inhibition was explained by a decrease in meal size and duration, but there was no difference in ingestion speed. The behavioral satiety sequence was preserved after RS and FSS but grooming was markedly increased, which thus competed with, and could reduce, other behaviors, including eating. Lastly, we showed that RS induced an increase in hypothalamic POMC expression. These results suggest that acute stress may affect ingestive behavior by increasing satiation and to some extent by enhancing grooming, and this may be due to stimulation of the hypothalamic POMC neurons. PMID- 21787798 TI - Synthesis of steroid-ferrocene conjugates of steroidal 17-carboxamides via a palladium-catalyzed aminocarbonylation--copper-catalyzed azide-alkyne cycloaddition reaction sequence. AB - Steroids with the 17-iodo-16-ene functionality were converted to ferrocene labeled steroidal 17-carboxamides via a two step reaction sequence. The first step involved the palladium-catalyzed aminocarbonylation of the alkenyl iodides with prop-2-yn-1-amine as the nucleophile in the presence of the Pd(OAc)(2)/PPh(3) catalyst system. In the second step, the product N-(prop-2 ynyl)-carboxamides underwent a facile azide-alkyne cycloaddition with ferrocenyl azides in the presence of CuSO(4)/sodium ascorbate to produce the steroid ferrocene conjugates. The new compounds were obtained in good yield and were characterized by (1)H and (13)C NMR, IR, MS and elemental analysis. PMID- 21787796 TI - Tracking cognitive fluctuations with multivoxel pattern time course (MVPTC) analysis. AB - The posterior parietal cortex, including the medial superior parietal lobule (mSPL), becomes transiently more active during acts of cognitive control in a wide range of domains, including shifts of spatial and nonspatial visual attention, shifts between working memory representations, and shifts between categorization rules. Furthermore, spatial patterns of activity within mSPL, identified using multivoxel pattern analysis (MVPA), reliably distinguish between different acts of control. Here we describe a novel multivoxel pattern-based analysis that uses fluctuations in cognitive state over time to reveal inter regional functional connectivity. First, we used MVPA to model patterns of activity in mSPL associated with shifting or maintaining spatial attention. We then computed a multivoxel pattern time course (MVPTC) that reflects, moment-by moment, the degree to which the pattern of activity in mSPL more closely matches an attention-shift pattern or a sustained-attention pattern. We then entered the MVPTC as a regressor in a univariate (i.e., voxelwise) general linear model (GLM) to identify voxels whose BOLD activity covaried with the MVPTC. This analysis revealed several regions, including the striatum of the basal ganglia and bilateral middle frontal gyrus, whose activity was significantly correlated with the MVPTC in mSPL. For comparison, we also conducted a conventional functional connectivity analysis, entering the mean BOLD time course in mSPL as a regressor in a univariate GLM. The latter analysis revealed correlations in extensive regions of the frontal lobes but not in any subcortical area. The MVPTC analysis provides greater sensitivity (e.g., revealing the striatal-mSPL connectivity) and greater specificity (i.e., revealing more-focal clusters) than a conventional functional connectivity analysis. We discuss the broad applicability of MVPTC analysis to a variety of neuroimaging contexts. PMID- 21787799 TI - The steroid metabolome in lamotrigine-treated women with epilepsy. AB - BACKGROUND: Epilepsy in women may be associated with reproductive disorders and alterations in serum steroid levels. Some steroids can be induced by epilepsy and/or treatment with antiepileptic drugs; however, there are still limited data available concerning this effect on the levels of other neuroactive steroid metabolites such as 3a-hydroxy-5a/b-reduced androstanes. AIM: To evaluate steroid alterations in women with epilepsy (WWE) on lamotrigine monotherapy. SUBJECTS AND METHODS: Eleven WWE and 11 age-matched healthy women underwent blood sampling in both phases of their menstrual cycles (MCs). The steroid metabolome, which included 30 unconjugated steroids, 17 steroid polar conjugates, gonadotropins, and sex hormone-binding globulin (SHBG), was measured using gas chromatography mass spectrometry (GC-MS) and radioimmunoassay (RIA). RESULTS: WWE had lower cortisol levels (status p<0.001), but elevated levels of unconjugated 17 hydroxypregnenolone (status p<0.001). Progesterone was higher in the follicular menstrual phase (FP) in WWE than in the controls (status*menstrual phase p<0.05, Bonferroni multiple comparisons p<0.05), whereas 17-hydroxyprogesterone was higher in WWE in both menstrual phases (status p<0.001). The steroid conjugates were mostly elevated in WWE. The levels of 5alpha/beta-reduced androstanes in WWE that were significantly higher than the controls were etiocholanolone (status p<0.001), 5alpha-androstane-3alpha,17beta-diol (status p<0.001), and the 5alpha/beta-reduced androstane polar conjugates (status p<0.001). CONCLUSIONS: WWE showed a trend toward higher circulating 3alpha-hydroxy-5alpha/beta-reduced androstanes, increased activity of 17alpha-hydroxylase/17,20 lyase in the Delta(5)-steroid metabolic pathway, and increased levels of the steroid polar conjugates. PMID- 21787800 TI - Zootoxic effects of reduviid Rhynocoris marginatus (Fab.) (Hemiptera: Reduviidae) venomous saliva on Spodoptera litura (Fab.). AB - Rhynocoris marginatus is a predominant and potential reduviid predator of many economically important pests in India. The venomous saliva (VS) was collected by milking method and diluted with HPLC grade water to prepare different concentrations (200, 400, 600, 800 and 1000ppm). The VS from R. marginatus was found to be toxic and the LD(50) of the VS in Spodoptera litura third instar were 768 and 929ppm at 48 and 96h for microinjection and oral toxicity studies, respectively. Level of hydrolase and detoxification enzymes significantly decreased in a dose-dependent manner after treating the host with VS for 96h. A decrease in carbohydrate (21%) and lipid (46%) contents and an increase in the protein content (50%) were prominent in the experimental category. The VS reduced the relative growth rate, approximate digestibility, efficiency of conversion of ingested and digested food of S. litura in the oral toxicity study. Salivary venom inhibits the haemocytes from aggregation and affects spreading behavior of haemocytes separated from the fifth stadium larvae of S. litura. The result showed that VS toxins caused mortality, changed the nutritional indices, and altered the levels of macromolecule quantity and digestive enzymes of S. litura. We concluded that the VS of R. marginatus is venomous to a prey species, S. litura. PMID- 21787801 TI - Towards a visual recognition threshold: new instrument shows humans identify animals with only 1ms of visual exposure. AB - The human visual system is very adept at extracting categorical information from complex scenes with only the briefest of exposure. Here we show that information from visual scenes can be processed to the level of identification with formally unattainable, ultra-brief (1ms) presentations. This brief presentation time is afforded by a new instrument, the light-emitting diode (LED) tachistoscope, in which a liquid crystal display (LCD) is illuminated externally by a brief LED flash after LCD steady-state is reached, such that image onset and offset timing can be precisely controlled. Photographs of animals were presented with or without backgrounds for 1ms and 10ms. The results indicate that visual recognition of objects benefits from presenting them in isolation rather than with a background at smaller (1ms) durations. In both conditions, however, animals could be recognised at 1ms at least 83% of the time, possibly due to iconic memory and top-down, feedback mechanisms. PMID- 21787803 TI - A non-invasive method to isolate the neuronal linage from the nasal epithelium from schizophrenic and bipolar diseases. AB - Brain imaging and histopathological studies suggest that neurodevelopmental anomalies play a key role in the etiology of schizophrenia (SZ) and bipolar disorder (BD). New neuron formation and maturation occur in human olfactory epithelium throughout life. Therefore, the olfactory epithelium has been proposed as a model to study alterations in neurodevelopment, particularly in some psychiatric diseases. However, former studies were done with olfactory epithelium biopsies taken post mortem or under anesthesia from patients with SZ and BD. In this work we have developed a new method to obtain viable neural precursors by exfoliation of the anterior region of the medial lateral turbinate of the nasal cavity from healthy controls, and ambulatory patients. Cells were propagated to establish neural precursor banks. Thawed cells showed cytoskeletal phenotypes typical of developing neurons. They also conserved the ability to differentiate in presence of 2mM dibutyril-cyclic adenosine monophosphate, and maintained voltage-operated Ca(2+) currents in culture. Moreover, proportions of neuronal maturation stages were maintained in cultured exfoliates obtained from SZ and BD patients. Data support that neural precursors obtained from a nasal exfoliate are an excellent experimental model to later approach studies on biomarkers, neural development and cellular alterations in the pathophysiology of SZ and BD. PMID- 21787804 TI - Antiherpetic activity of a sulfated polysaccharide from Agaricus brasiliensis mycelia. AB - Sulfated polysaccharides are good candidates for drug discovery in the treatment of herpetic infections. Agaricus brasiliensis (syn A. subrufescens, A. blazei) is a Basidiomycete fungus native to the Atlantic forest region of Southeastern Brazil. Herein we report the chemical modification of a polysaccharide extracted from A. brasiliensis mycelia to obtain its sulfated derivative (MI-S), which presented a promising inhibitory activity against HSV-1 [KOS and 29R (acyclovir resistant) strains] and HSV-2 strain 333, with selectivity indices (SI = CC50/IC50) higher than 439, 208, and 562, respectively. The mechanisms underlying this inhibitory activity were scrutinized by plaque assay with different methodological strategies. MI-S had no virucidal effects, but inhibited HSV-1 and HSV-2 attachment, penetration, and cell-to-cell spread, as well as reducing the expression of HSV-1 ICP27, UL42, gB, and gD proteins. MI-S also presented synergistic antiviral effect with acyclovir. These results suggest that MI-S presents multiple modes of anti-HSV action. PMID- 21787805 TI - Determining shoal membership: a comparison between momentary and trajectory-based methods. AB - Miller and Gerlai proposed two methods for determining shoal membership in Danio rerio, one based on momentary mean inter-individual distances and the other on post hoc analysis of the trajectories of nearest-neighbor distances. We propose a method based on momentary nearest-neighbor distances and compare the three methods using simulation. In general, our method yielded results that were more similar to their second method than their first one, and is computationally simpler. PMID- 21787806 TI - The function of dopaminergic neural signal transmission in auditory pulse perception: evidence from dopaminergic treatment in Parkinson's patients. AB - Auditory pulse perception, which is the perception of relatively salient and regularly appearing events in an acoustic sequence, is a necessary function in humans and has been suggested to rely on basal ganglia function. Our study investigated the effect dopamine depletion has on the auditory pulse perception in Parkinson's disease (PD). We examined PD patients and healthy seniors in this study, and all participants performed a pulse perception task and a motor control task. The pulse perception task consisted of a two alternative forced choice task in which subjects had to identify stimuli as metrical or non-metrical. We tested PD patients before and after the administration of l-3,4-dihydroxyphenylalanin (l DOPA). The healthy control group performed the same tasks twice. PD patients that were dopamine depleted performed the pulse perception task equally well and as fast as did the healthy control group. However, after the administration of l DOPA, PD patients performed the pulse perception task significantly faster than they did before the pharmacological intervention, which showed that pulse perception can be modulated by dopaminergic stimulation. These findings indicate that pulse perception relies on dopaminergic mechanisms but is not affected by dopamine depletion in the early stages of PD. PMID- 21787807 TI - A role for p38 mitogen-activated protein kinase in early post-embryonic development of Schistosoma mansoni. AB - The importance of p38 mitogen-activated protein kinase (p38 MAPK) to Schistosoma mansoni miracidium to mother-sporocyst development was investigated. Western blotting revealed that phosphorylation (activation) of p38 MAPK was low in larvae after 4h development in vitro but increased markedly during transformation, with ~2.7- and ~3.7-fold increases after 19h and 28h culture, respectively. Immunohistochemistry of larvae undergoing transformation revealed activated p38 MAPK associated with regions including the tegument, neural mass and germinal cells. Inhibition of larval p38 MAPK with SB203580 reduced significantly the rate of development of miracidia to mother sporocysts, whereas activation of p38 MAPK with anisomycin had the opposite effect. These results provide insight into p38 MAPK signalling in schistosomes and support a role for p38 MAPK in the early post embryonic development of S. mansoni. PMID- 21787802 TI - Psychoneuroimmunology in pregnancy: immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development. AB - It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development. PMID- 21787808 TI - Biological and conformational evaluation of angiotensin II lactam bridge containing analogues. AB - Angiotensin II (AII) is the active octapeptide product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. In an attempt to establish the AII-receptor-bound conformation of this octapeptide, we designed conformationally constrained analogues by scanning the entire AII sequence with an i-(i+2) and i-(i+3) lactam bridge consisting of an Asp-(Xaa)(n)-Lys scaffold. Most analogues presented low agonistic activity when compared to AII in the different bioassays tested. The exceptions are cyclo(0-1a) [Asp(0), endo (Lys(1a))]-AII (1) and [Asp(0), endo-(Lys(1a))]-AII (2), both of which showed activity similar to AII. Based on peptide 1 and the analogue cyclo(3-5)[Sar(1), Asp(3), Lys(5)]-AII characterized by Matsoukas et al., we analyzed the agonistic and antagonistic activities, respectively, through a new monocyclic peptide series synthesized by using the following combinations of residues as bridgehead elements for the lactam bond formation: D- or L-Asp combined with D- or L-Lys or L-Glu combined with L-Orn. Six analogues showed an approximately 20% increase in biological activity when compared with peptide (1) and were equipotent to AII. In contrast, six analogues presented antagonistic activity. These results suggest that the position of the lactam bridge is more important than the bridge length or chirality for recognition of and binding to the angiotensin II AT1-receptor. PMID- 21787809 TI - Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. AB - Infection or cell damage triggers the release of pro-inflammatory cytokines such as interleukin(IL)-1alpha or beta and tumor necrosis factor (TNF)alpha which are key mediators of the host immune response. Following their identification and the elucidation of central signaling pathways, recent results show a highly complex crosstalk between various cytokines and their signaling effectors. The molecular mechanisms controlling signaling thresholds, signal integration and the function of feed-forward and feedback loops are currently revealed by combining methods from biochemistry, genetics and in silico analysis. Increasing evidence is mounted that defects in information processing circuits or their components can be causative for chronic or overshooting inflammation. As progress in biosciences has always benefitted from the use of well-studied model systems, research on inflammatory cytokines may function as a paradigm to reveal general principles of signal integration, crosstalk mechanisms and signaling networks. PMID- 21787810 TI - Sterilization of biological pathogens using supercritical fluid carbon dioxide containing water and hydrogen peroxide. AB - Novel noninvasive techniques for the removal of biological contaminants to generate clean or sterile materials are in demand by the medical, pharmaceutical and food industries. The sterilization method described here uses supercritical fluid carbon dioxide (SF-CO(2)) containing 3.3% water and 0.1% hydrogen peroxide (v/v/v) to achieve from four to eight log viability reduction of all tested microbial species, including vegetative cells, spores and biofilms. The sterilization method employs moderate pressure and temperature (80 atm, 50 degrees C) and a short (30-minute) treatment time. The procedure kills various opportunistic pathogens that often persist in biofilm structures, fungal spores commonly associated with nosocomial infections, and Bacillus pumilus SAFR-032 endospores that are notoriously hard to eradicate by conventional sterilization techniques. PMID- 21787811 TI - Auditory N1 as a change-related automatic response. AB - To test the hypothesis that the N1 component of auditory evoked potentials (AEPs) is one form of the change-related response elicited by an abrupt change in sound pressure from a silent background, two AEP experiments were conducted. Change-N1 was evoked by a test stimulus at 70dB following a 3-s conditioning stimulus of 0 69dB. On-N1 was evoked by the test sound alone at various sound pressures. As the physical difference between stimuli increased, the amplitude of Change-N1 increased, and the latency shortened. The amplitude and latency of On-N1 showed a similar pattern to the Change-N1 response. These results support the idea that On N1 is a change-related component elicited by a sound pressure change. PMID- 21787812 TI - Sensory stimuli induce nuclear translocation and phosphorylation of nuclear factor kappa B in primary sensory neurons of mice. AB - Nuclear factor kappa B (NF-kappaB) is a transcription factor, which is translocated to the nucleus when activated. Herein, we demonstrate immunohistochemically that electrical, chemical, and thermal stimuli, applied to the skin of mice, all induced nuclear translocation and phosphorylation of NF kappaB in dorsal root ganglia (DRG) neurons. The latency of this response was short, with effects observable in as little as 3min following stimulation. Few nuclear phospho-NF-kappaB-positive neurons were observed in DRG innervating unstimulated regions. These results suggest somatosensory stimuli quickly induce NF-kappaB-mediated gene transcription in DRG, and phospho-NF-kappaB could be a suitable histological marker for activated DRG neurons. PMID- 21787813 TI - Thoracotomy reduces intrinsic brain movement caused by heartbeat and respiration: a simple method to prevent motion artifact for in vivo experiments. AB - Recent technical advances in electrophysiological recording and functional imaging from the brain of living animals have promoted our understandings of the brain function, but these in vivo experiments are still technically demanding and often suffer from spontaneous pulsation, i.e., brain movements caused by respiration and heartbeat. Here we report that thoracotomy suppresses the motion artifact to a practically negligible level. This simple method will be useful in a wide variety of in vivo experiments, such as patch-clamp physiology, and optical imaging of neurons, glial cell, and blood vessels. PMID- 21787814 TI - Genetic manipulation of butyrate formation pathways in Clostridium butyricum. AB - Clostridium butyricum is one of the commonly used species for fermentative hydrogen production. While producing H2, it can produce acids (lactic, acetic and butyric acids) and CO2, as well as a small amount of ethanol. It has been proposed that elimination of competing pathways, such as the butyrate formation pathway, should increase H2 yields in Clostridium species. However, the application of this strategy has been hindered by the unavailability of genetic tools for these organisms. In this study, we successfully transferred a plasmid (pMTL007) to C. butyricum by inter-specific conjugation with Escherichia coli and disrupted hbd, the gene encoding beta-hydroxybutyryl-CoA dehydrogenase in C. butyricum. Fermentation data showed that inactivation of hbd in C. butyricum eliminated the butyrate formation pathway, resulting in a significant increase in ethanol production and an obvious decrease in H2 yield compared with the wild type strain. However, under low partial pressure of H2, the hbd-deficient strain showed increased H2 production with the simultaneous decrease of ethanol production, indicating that H2 production by C. butyricum may compete for NADH with the ethanol formation pathway. Together with the discovery of a potential bifurcating hydrogenase, this study extends our understanding of the mechanism of H2 production by C. butyricum. PMID- 21787815 TI - Biodegradable nanocomposite microparticles as drug delivering injectable cell scaffolds. AB - Injectable cell scaffolds play a dual role in tissue engineering by supporting cellular functions and delivering bioactive molecules. The present study aimed at developing biodegradable nanocomposite microparticles with sustained drug delivery properties thus potentially being suitable for autologous stem cell therapy. Semi-crystalline poly(l-lactide/dl-lactide) (PLDL70) and poly(l-lactide co-glycolide) (PLGA85) were used to prepare nanoparticles by the double emulsion method. Uniform and spherical nanoparticles were obtained at an average size of 270-300 nm. The thrombin receptor activator peptide-6 (TRAP-6) was successfully loaded in PLDL70 and PLGA85 nanoparticles. During the 30 days' release, PLDL70 nanoparticles showed sustainable release with only 30% TRAP-6 released within the first 15 days, while almost 80% TRAP-6 was released from PLGA85 nanoparticles during the same time interval. The release mechanism was found to depend on the crystallinity and composition of the nanoparticles. Subsequently, mPEG-PLGA nanocomposite microparticles containing PLDL70 nanoparticles were produced by the ultrasonic atomization method and evaluated to successfully preserve the intrinsic particulate properties and the sustainable release profile, which was identical to that of the nanoparticles. Good cell adhesion of the human fibroblasts onto the nanocomposite microparticles was observed, indicating the desired cell biocompatibility. The presented results thus demonstrate the development of nanocomposite microparticles tailored for sustainable drug release for application as injectable cell scaffolds. PMID- 21787816 TI - Highly selective in-vivo imaging of tumor as an inflammation site by ROS detection using hydrocyanine-conjugated, functional nano-carriers. AB - Previously, the optical imaging of chitosan-functionalized, Pluronic-based nano carriers by Cy5.5 conjugation revealed a good tumor targeting characteristic of the nano-carriers in vivo [J. Control. Release, 147 (2010) 109-117]. However, in spite of the relatively strong signal from tumor site, they also showed strong fluorescence signals from other organs, especially liver. Thus, for the detection of pathological sites, the direct use of the Cy5.5-conjugated nano-carriers is limited due to significant background signals associated with non-specific delivery of the probes. To overcome this limitation, in this study, we prepared hydrocyanine-conjugated and chitosan-functionalized Pluronic-based nano-carriers (Hydrocyanine-NC) that can detect ROS in pathological sites. The reduction of cyanine to hydrocyanine of the nano-carriers resulted in complete disappearance of fluorescence emission, and the fluorescence could be recovered by ROS-induced re-oxidization. Hydrocyanine-NC could detect various ROS including superoxide anion (O(2)(-)) and hydroxyl radical (OH(-)) in a dose-dependent manner. Hydrocyanine-NC was also stable in serum-containing media and did not show acute cytotoxicity. Hydrocyanine-NC developed strong fluorescence by the intracellular ROS formation in LPS-stimulated macrophage cells in vitro. As an in-vivo inflammation site imaging, SCC7 tumor-bearing mice were optically monitored after the i.v. injection of the dye-conjugated nano-carriers. When non-reduced, cyanine conjugated and chitosan-functionalized Pluronic-based nano-carriers (Cyanine-NC) were injected, strong fluorescence emission was observed from the abdominal area as well as from the tumor site, and it remained over 2days. In contrast, in the case of Hydrocyanine-NC, the initially very weak fluorescence emission from the abdominal area disappeared over time whereas the fluorescence emission from the tumor site was similar to that of Cyanine-NC. Therefore, the re-oxidation of Hydrocyanine-NC by ROS in vivo specifically eliminated the background signals from non-specific delivery of the probes, but it produced fluorescence emission strong enough to monitor the target inflammation site selectively. PMID- 21787817 TI - Protein kinase A inhibition modulates the intracellular routing of gene delivery vehicles in HeLa cells, leading to productive transfection. AB - Cellular entry of nanoparticles for drug- and gene delivery relies on various endocytic pathways, including clathrin- and caveolae-mediated endocytosis. To improve delivery, i.e., the therapeutic and/or cell biological impact, current efforts are aimed at avoiding processing of the carriers along the degradative clathrin-mediated pathway towards lysosomes, and promoting that along the caveolae-mediated pathway. Here, we demonstrate the effective internalization of branched polyethylenimine polymers (BPEI), complexed with nucleic acids, by HeLa cells along both pathways. However, transfection efficiency or nuclear ODN delivery primarily occurs via the caveolae-mediated pathway, along which delivery into lysosomes is avoided. Interestingly, inhibition of intracellular protein kinase A (PKA) activity modulates the intracellular trafficking of both poly- and lipoplexes along the clathrin-mediated pathway by impeding trafficking into the late endosomal/lysosomal compartments, thus avoiding degradation. In case of BPEI polyplexes this promotes their transfection efficiency by 2-3 fold. Evidence excludes early endosomes as a major site for BPEI-mediated release/delivery. Rather, we identify a novel compartment, tentatively characterized as a transferrin(-)/rab9(-)/LAMP1(-) compartment, to which cargo within the clathrin mediated pathway of endocytosis is rerouted upon inhibition of PKA, and which may act as an alternative and effective site of cargo release in gene delivery. Our findings offer new opportunities for improving gene delivery by non-viral based nanoparticles. PMID- 21787819 TI - Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. AB - Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil(r)) and paclitaxel (Taxol(r)). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D. PMID- 21787820 TI - Expression of an optimized Argopecten purpuratus antimicrobial peptide in E. coli and evaluation of the purified recombinant protein by in vitro challenges against important plant fungi. AB - Antimicrobial peptides (AMP) have been widely described in several organisms from different kingdoms. We recently designed and evaluated a synthetic version of an AMP isolated and characterized from Argopecten purpuratus hemocytes. This study describes the generation of a chimaeric gene encoding for Ap-S, the use of this construct to transform E. coli strain BL21, and the evaluation of the purified recombinant Ap-S (rApS) as an antifungal agent. The proposed gene coding for rAp S consists of 93 nucleotides arranged downstream from the IPTG-inducible T7 promoter. The best synthesis conditions were obtained after E. coli cultivation at 26 degrees C for 3h, which allowed for the production of an rAp-S-enriched fraction containing the peptide at 249MUM. Mass spectrometry analysis of the purified rAp-S (3085.80Da) showed the addition of a glycine residue on its N terminal end derived from vector design and peptide purification. The purified rApS fraction was assayed for antifungal activity by direct addition of purified rApS elution to potato dextrose agar media at a final concentration of 81nM. These assays showed important growth inhibitions of both biotrophic (Fusarium oxysporum, Trichoderma harzianum) and necrotrophic (Botrytis cinerea, Alternaria spp.) fungi in that the hyphae structures and spore count were affected in all cases. The strategy of cloning and expressing rAp-S in E. coli, the high yield obtained and its successful use for controlling pathogenic fungi suggest that this molecule could be applied to agricultural crops using various management strategies. PMID- 21787818 TI - PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma. AB - Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG(5k)-CA(8) and PEG(2k)-CA(4)) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG(2k)-CA(4) micelles, compared to PEG(5k)-CA(8) micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B-lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG(2k)-CA(4) micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated that both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG(2k)-CA(4) micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil(r)) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX. PMID- 21787821 TI - The proton gradient of secretory granules and glutamate transport in blood platelets during cholesterol depletion of the plasma membrane by methyl-beta cyclodextrin. AB - Glutamate transport in blood platelets resembles that in brain nerve terminals because platelets contain neuronal Na(+)-dependent glutamate transporters, glutamate receptors in the plasma membrane, vesicular glutamate transporters in secretory granules, which use the proton gradient as a driving force, and can release glutamate during aggregation/activation. The acidification of secretory granules and glutamate transport were assessed during acute treatment of isolated platelets with cholesterol-depleting agent methyl-beta-cyclodextrin (MbetaCD). Confocal imaging with the cholesterol-sensitive fluorescent dye filipin showed a quick reduction of cholesterol level in platelets. Using pH-sensitive fluorescent dye acridine orange, we demonstrated that the acidification of secretory granules of human and rabbit platelets was decreased by ~15% and 51% after the addition of 5 and 15mM MbetaCD, respectively. The enrichment of platelet plasma membrane with cholesterol by the application of complex MbetaCD-cholesterol (1:0.2) led to the additional accumulation of acridine orange in secretory granules indicating an increase in the proton pumping activity of vesicular H(+)-ATPase. MbetaCD did not evoke release of glutamate from platelets that was measured with glutamate dehydrogenase assay. Flow cytometric analysis did not reveal alterations in platelet size and granularity in the presence of MbetaCD. These data showed that the dissipation of the proton gradient of secretory granules rather than their exocytosis caused MbetaCD-evoked decrease in platelet acidification. Thus, the depletion of plasma membrane cholesterol in the presence of MbetaCD changed the functional state of platelets affecting storage capacity of secretory granules but did not evoke glutamate release from platelets. PMID- 21787823 TI - WITHDRAWN: Letter to the Editor. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21787824 TI - RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection. AB - In order to achieve host cell entry, the apicomplexan parasite Neospora caninum relies on the contents of distinct organelles, named micronemes, rhoptries and dense granules, which are secreted at defined timepoints during and after host cell entry. It was shown previously that a vaccine composed of a mixture of three recombinant antigens, corresponding to the two microneme antigens NcMIC1 and NcMIC3 and the rhoptry protein NcROP2, prevented disease and limited cerebral infection and transplacental transmission in mice. In this study, we selected predicted immunogenic domains of each of these proteins and created four different chimeric antigens, with the respective domains incorporated into these chimers in different orders. Following vaccination, mice were challenged intraperitoneally with 2 * 10(6)N. caninum tachzyoites and were then carefully monitored for clinical symptoms during 4 weeks post-infection. Of the four chimeric antigens, only recNcMIC3-1-R provided complete protection against disease with 100% survivors, compared to 40-80% of survivors in the other groups. Serology did not show any clear differences in total IgG, IgG1 and IgG2a levels between the different treatment groups. Vaccination with all four chimeric variants generated an IL-4 biased cytokine expression, which then shifted to an IFN-gamma-dominated response following experimental infection. Sera of recNcMIC3 1-R vaccinated mice reacted with each individual recombinant antigen, as well as with three distinct bands in Neospora extracts with similar Mr as NcMIC1, NcMIC3 and NcROP2, and exhibited distinct apical labeling in tachyzoites. These results suggest that recNcMIC3-1-R is an interesting chimeric vaccine candidate and should be followed up in subsequent studies in a fetal infection model. PMID- 21787822 TI - Inferior quantitative and qualitative immune responses to pneumococcal conjugate vaccine in infants with nasopharyngeal colonization by Streptococcus pneumoniae during the primary series of immunization. AB - BACKGROUND: Heightened immunogenicity, measured one month after the primary series of pneumococcal conjugate vaccine (PCV), in African children was previously hypothesized to be due to increased rates of nasopharyngeal pneumococcal colonization during early infancy. METHODS: We analyzed the effect of selected vaccine-serotype (6B, 19F and 23F) nasopharyngeal colonization prior to the first PCV dose or when colonized for the first time prior to the second or third (2nd/3rd) PCV dose on serotype quantitative and qualitative antibody responses. RESULTS: Colonization prior to receiving the first PCV was associated with lower geometric mean antibody concentrations (GMCs) one month after the third dose of PCV and six months later to the colonizing-serotype. Colonized infants also had lower geometric mean titers (GMTs) on opsonophagocytosis activity assay (OPA) and a lower proportion had titers >= 8 against the colonizing serotypes (19F and 23F) post vaccination. Colonization occurring only prior to the 2nd/3rdPCV dose was also associated with lower GMCs and OPA GMTs to the colonizing-serotype. The effect of colonization with serotypes 19F and 23F prior to PCV vaccination had a greater effect on a lower proportion of colonized infants having OPA titers >= 8 than the effect of colonization on the lower proportion with antibody >= 0.35 MUg/ml. CONCLUSION: Infant nasopharyngeal colonization at any stage before completing the primary series of PCV vaccination was associated with inferior quantitative and qualitative antibody responses to the colonizing-serotype. PMID- 21787825 TI - Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine. AB - BACKGROUND: Shigella flexneri 2a lipopolysaccharide 50 is a nasally delivered subunit vaccine consisting of a macromolecular complex composed of LPS, IpaB, IpaC and IpaD. The current study examined vaccine safety and immunogenicity across a dose range and the clinical performance of a new intranasal delivery device. METHODS: Volunteers (N=36) were randomized to receive vaccine via the DolphinTM (Valois of America, Congers, New York) intranasal spray device at one of three doses (240, 480, and 690 MUg) on days 0, 14, and 28. Another group (N=8) received the 240 MUg dose via pipette. Vaccine safety was actively monitored and antigen-specific humoral and mucosal immune responses were determined. RESULTS: There were no serious adverse events and the majority of adverse events (98%) were mild. Antibody secreting cells (ASC), plasma, and mucosal immune responses to Shigella antigens were detected at all three dose levels with the 690 MUg dose inducing the highest magnitude and frequency of responses. Vaccination with comparable doses of Invaplex 50 via the DolphinTM resulted in higher plasma and ASC immune responses as compared to pipette delivery. CONCLUSION: In this trial the S. flexneri 2a Invaplex 50 vaccine was safe, well-tolerated and induced robust levels of antigen-specific intestinal IgA and ASC responses. The spray device performed well and offered an advantage over pipette intranasal delivery. PMID- 21787826 TI - Nanoparticle conjugation and pulmonary delivery enhance the protective efficacy of Ag85B and CpG against tuberculosis. AB - Vaccines that drive robust T-cell immunity against Mycobacterium tuberculosis (Mtb) are needed both for prophylactic and therapeutic purposes. We have recently developed a synthetic vaccine delivery platform with Pluronic-stabilized polypropylene sulfide nanoparticles (NPs), which target lymphoid tissues by their small size (~ 30 nm) and which activate the complement cascade by their surface chemistry. Here we conjugated the tuberculosis antigen Ag85B to the NPs (NP Ag85B) and compared their efficacy in eliciting relevant immune responses in mice after intradermal or pulmonary administration. Pulmonary administration of NP Ag85B with the adjuvant CpG led to enhanced induction of antigen-specific polyfunctional Th1 responses in the spleen, the lung and lung-draining lymph nodes as compared to soluble Ag85B with CpG and to the intradermally-delivered formulations. Mucosal and systemic Th17 responses were also observed with this adjuvanted NP formulation and vaccination route, especially in the lung. We then evaluated protection induced by the adjuvanted NP formulation following a Mtb aerosol challenge and found that vaccination with NP-Ag85B and CpG via the pulmonary route displayed a substantial reduction of the lung bacterial burden, both compared to soluble Ag85B with CpG and to the corresponding intradermally delivered formulations. These findings highlight the potential of administrating NP-based formulations by the pulmonary route for TB vaccination. PMID- 21787827 TI - Natural products and the search for novel vaccine adjuvants. AB - Vaccines that protect against intracellular infections such as malaria, Leishmania and Chlamydia require strong cellular responses based on CD4(+) T cells and CD8(+) T cells in addition to antibodies. Such cell-mediated responses can be potentiated with adjuvants. However, very few adjuvants have been licensed for use in humans; thus there is an urgent need for the discovery of new non toxic adjuvants in order to produce more efficacious vaccines. Until recently, the mechanisms of how adjuvants worked remained largely unknown, but, it is becoming clearer that many function via host germline-encoded pattern recognition receptors (PRRs) expressed by most immune and non-immune cells. Most PRRs sense infection and transmit a series of signals that ultimately lead to the development of immunity. PRR mediated signalling can be harnessed to search for new vaccine adjuvants. Dendritic cells (DCs) express many PRRs and are remarkably effective at directing T cell immunity. Natural products (NPs) have been the basis of many drugs and are a rich source of immune activators and/or regulators of the immune response. Here we review PRRs in the context of NPs and propose the use of DCs as biological probes to help identify novel immune type molecules and adjuvants within collections of NPs. PMID- 21787828 TI - Comparative efficacy of pre-erythrocytic whole organism vaccine strategies against the malaria parasite. AB - Despite major efforts over the past 50 years to develop a malaria vaccine, no product has been licensed yet. Irradiated sporozoites are the benchmark for an experimental live-attenuated malaria vaccine that induces potent protection against re-infection in humans and animal models. Lasting protection can also be elicited by parasite attenuation via tailored genetic modification or drug cover leading to renewed interest in whole-organism vaccination strategies. In this study, we systematically compared the protective efficacy of different whole organism vaccination approaches in the Plasmodium berghei/C57bl/6 rodent malaria model. We applied blood stage parasitemia and quantitative RT-PCR of liver parasite loads as two complementary primary endpoints of a malaria challenge infection. We were able to demonstrate similar potency of genetic attenuation, i.e., uis3(-) and p36p(-) parasites, and prophylactic drug cover, i.e., azithromycin, pyrimethamine, primaquine and chloroquine, during sporozoite exposure in comparison to irradiated sporozoites. Importantly, when animals were covered with the antibiotic azithromycin during sporozoite exposure we observed superior protection. On the other end, immunizations with heat-killed and over irradiated sporozoites failed to confer any detectable protection. Together, we show that systematic pre-clinical evaluation and quantification of vaccine efficacy is vital for identification of the most potent whole organism anti malaria vaccine strategy. PMID- 21787829 TI - MDCK cell line with inducible allele B NS1 expression propagates delNS1 influenza virus to high titres. AB - Influenza A viruses lacking the gene encoding the non-structural NS1 protein (delNS1) have potential use as live attenuated vaccines. However, due to the lack of NS1, virus replication in cell culture is considerably reduced, prohibiting commercial vaccine production. We therefore established two stable MDCK cell lines that show inducible expression of the allele B NS1 protein. Upon induction, both cell lines expressed NS1 to about 1000-fold lower levels than influenza virus-infected cells. Nevertheless, expression of NS1 increased delNS1 virus titres to levels comparable to those obtained with an isogenic virus strain containing an intact NS1 gene. Recombinant NS1 expression increased the infectious virus titres 244 to 544-fold and inhibited virus induced apoptosis. However, NS1 expression resulted in only slightly, statistically not significant, reduced levels of interferon-beta production. Thus, the low amount of recombinant NS1 is sufficient to restore delNS1 virus replication in MDCK cells, but it remains unclear whether this occurs in an interferon dependent manner. In contrast to previous findings, recombinant NS1 expression did not induce apoptosis, nor did it affect cell growth. These cell lines thus show potential to improve the yield of delNS1 virus for vaccine production. PMID- 21787831 TI - Antioxidant acitivity of low molecular weight hyaluronic acid. AB - Two polysaccharides, low molecular weight hyaluronic acid-1 (LMWHA-1) and LMWHA 2, with their molecular weight of 1.45*10(5) and 4.52*10(4)Da, respectively, were prepared from high molecular weight hyaluronic acid (HA,1.05*10(6)Da). LMWHA-1, LMWHA-2 and HA were studied for their antioxidant activities. In vitro antioxidant assay, LMWHA showed strong inhibition of lipid peroxidation and scavenging activities of hydroxyl radical, moderate 1,1-diphenyl-2-picryldydrazyl radical and superoxide anion scavenging activity. In addition, the LMWHA-1 exhibited much stronger antioxidant activity than LMWHA-2 and HA. For antioxidant testing in vivo, LMWHA-1, LMWHA-2 and HA were orally administrated over a period of 7days in a cyclophosphamide(CY) induced immunosuppressed mice model. As results, administration of LMWHA was able to overcome CY-induced immunosuppression and significantly raised the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity (TAOC) in immunosuppressed mice. The results showed that the LMWHA, possessing pronounced free radical scavenging and antioxidant activities. PMID- 21787833 TI - Exonization of transposed elements: A challenge and opportunity for evolution. AB - Protein-coding genes are composed of exons and introns flanked by untranslated regions. Before the mRNA of a gene can be translated into protein, the splicing machinery removes all the intronic regions and joins the protein-coding exons together. Exonization is a process, whereby genes acquire new exons from non protein-coding, primarily intronic, DNA sequences. Genomic insertions or point mutations within DNA sequences often generate alternative splice sites, causing the splicing system to include new sequences as exons or to elongate existing exons. Because the alternative splice sites are not as efficient as the originals the new variants usually constitute a minor fraction of mature mRNAs. While the prevailing original splice variant maintains functionality, the additional sequence, free from selection pressure, evolves a new function or eventually vanishes. If the new splice variant is advantageous, selection might operate to optimize the new splice sites and consequently increase the proportion of the alternative splice variant. In some instances, the original splice variant is completely replaced by constitutive splicing of the new form. Because of the fortuitous presence of internal splice site-like structures within their sequences, portions of transposed elements frequently serve as modules of exonization. Their recruitment requires a long and versatile optimization process involving multiple changes over a time span of millions, even hundreds of millions, of years. Comparisons of corresponding genes and mRNAs in phylogenetically related species enables one to chronologically reconstruct such changes, from ancient ancestors to living species, in a stepwise manner. We will review this process using three different exemplary cases: (1) the evolution of a constitutively spliced mammalian-wide repeat (MIR), (2) the evolution of an alternative exon 1 from an alternative 5'-extended primary transcript containing an Alu element, and (3) a rare case of the stepwise exoniztion of an Alu element derived sequence mediated by A-to-I RNA editing. PMID- 21787832 TI - Hexachlorobenzene induces deregulation of cellular growth in rat liver. AB - Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the biosphere. The aim of the present study was to investigate the effect of HCB on the homeostasis of liver cell growth, analyzing parameters of cell proliferation and apoptosis, in HCB (0.1, 1, 10 and 100 mg/kg body weight)-treated rats, during 4 weeks. Cell proliferation and ERK1/2 phosphorylation, associated with survival mechanisms, were increased at HCB 100 mg/kg. The pesticide increased the number of apoptotic cells, and the activation of caspase-3, -9 and -8, in a dose dependent manner, suggesting that HCB-induced apoptosis is mediated by caspases. Increased Fas and FasL protein levels indicate that the death receptor pathway is also involved. This process is associated with decreased Bid, and increased cytosolic cytochrome c protein levels. Transforming growth factor-beta1 (TGF beta1) intervenes in apoptotic and/or proliferative processes in hepatocytes. TGF beta1 cDNA and protein levels are dose-dependently increased, suggesting that this cytokine might be involved in HCB-induced dysregulation of cell proliferation and apoptosis. In conclusion, this study reports for the first time that HCB induces loss of the homeostatic balance between cell growth and cell death in rat liver. Induced apoptosis occurs by mechanisms involving signals emanating from death receptors, and the mitochondrial pathway. PMID- 21787835 TI - Inhibition of Bcl3 gene expression mediates the anti-proliferative action of estrogen in pituitary lactotrophs in primary culture. AB - In addition to their well-known stimulatory action, estrogens have an anti proliferative effect. The present study was undertaken to investigate the mechanism by which 17beta-estradiol (E2) inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation in vitro in the rat pituitary lactotroph, a typical estrogen-responsive cell. E2 treatment of pituitary cells did not change levels of IGF-1-induced phosphorylation of proliferation-related protein kinases such as Erk1/2 and Akt. We performed global gene expression profiling by DNA microarray analysis and identified 177 genes regulated by E2 in the presence of IGF-1. These results were verified by quantitative real time PCR. The estrogen-regulated genes included several NFkappaB family related genes. As pharmacological inhibition of the NFkappaB pathway blocked IGF-1-induced lactotroph proliferation, we chose to investigate whether one NFkappaB pathway gene, Bcl3, was involved in the anti proliferative action of E2. RNA interference-mediated knockdown of Bcl3 expression attenuated IGF-1-induced lactotroph proliferation. Even minimal induced overexpression of Bcl3 blocked the anti-proliferative action of E2. In contrast, Nfkb2, another E2-downregulated protein, required maximal overexpression to block the anti-proliferative action of E2. These results suggest that inhibition of Bcl3 expression is involved in the anti-proliferative action of estrogens in pituitary lactotrophs in culture. PMID- 21787836 TI - Activins and activin antagonists in the prostate and prostate cancer. AB - Activins are members of the TGF-beta super-family. There are 4 mammalian activin subunits (beta(A), beta(B), beta(C) and beta(E)) that combine to form functional proteins. The role of activin A (beta(A)beta(A)) is well characterized and known to be a potent growth and differentiation factor. Two of the activin subunits (beta(C) and beta(E)) were discovered more recently and little is known about their biological functions. In this review the evidence that activin-beta(C) is a significant regulator of activin A bioactivity is presented and discussed. It is concluded that activin-beta(C), like other antagonists of activin A, is an important growth regulator in prostate health and disease. PMID- 21787837 TI - Cb1 receptor-mediated signaling emerges as a novel lead to evidence-based treatment development for stress-related psychopathology. PMID- 21787834 TI - Clocks on top: the role of the circadian clock in the hypothalamic and pituitary regulation of endocrine physiology. AB - Recent strides in circadian biology over the last several decades have allowed researchers new insight into how molecular circadian clocks influence the broader physiology of mammals. Elucidation of transcriptional feedback loops at the heart of endogenous circadian clocks has allowed for a deeper analysis of how timed cellular programs exert effects on multiple endocrine axes. While the full understanding of endogenous clocks is currently incomplete, recent work has re evaluated prior findings with a new understanding of the involvement of these cellular oscillators, and how they may play a role in constructing rhythmic hormone synthesis, secretion, reception, and metabolism. This review addresses current research into how multiple circadian clocks in the hypothalamus and pituitary receive photic information from oscillators within the hypothalamic suprachiasmatic nucleus (SCN), and how resultant hypophysiotropic and pituitary hormone release is then temporally gated to produce an optimal result at the cognate target tissue. Special emphasis is placed not only on neural communication among the SCN and other hypothalamic nuclei, but also how endogenous clocks within the endocrine hypothalamus and pituitary may modulate local hormone synthesis and secretion in response to SCN cues. Through evaluation of a larger body of research into the impact of circadian biology on endocrinology, we can develop a greater appreciation into the importance of timing in endocrine systems, and how understanding of these endogenous rhythms can aid in constructing appropriate therapeutic treatments for a variety of endocrinopathies. PMID- 21787838 TI - Neuregulin-1 prevents amyloid beta-induced impairment of long-term potentiation in hippocampal slices via ErbB4. AB - Neuregulin-1 (NRG1) participates in numerous neurodevelopmental processes and plasticity of the brain. Despite this, little is known about its role in Alzheimer's disease (AD). Amyloid beta (Abeta) peptide is generally believed to play a critical role in the pathogenesis of AD. The present study examined the effect of synthetic Abeta1-42 peptides on long-term potentiation (LTP) in the CA1 region of mice hippocampal slices, a cellular model of learning and memory. We found that application of a test dose of Abeta1-42 (200 nM) significantly inhibited the development of LTP without affecting basal synaptic transmission. Pretreatment with NRG1 effectively prevented Abeta1-42-induced impairment of LTP, an effect that was dose-dependent. This LTP-restoring action of NRG1 was almost completely abolished by blocking ErbB4, a key NRG1 receptor, suggesting that NRG1 acts through ErbB4 to exert its protective action on LTP. The present study thus provides the first demonstration that NRG1/ErbB4 protects against Abeta-induced hippocampal LTP impairment, suggesting that NRG1 may be a promising candidate for the treatment of early-stage AD. PMID- 21787839 TI - Impact of the NCAM derived mimetic peptide plannexin on the acute cellular consequences of a status epilepticus. AB - Plannexin represents a NCAM-derived peptide mimicking trans-homophilic NCAM interaction, which proved to exert neuroprotective effects in vitro. The effect of plannexin was evaluated in a rat status epilepticus model. As expected, prolonged seizure activity resulted in a pronounced cell loss in hippocampal subregions. The comparison between the vehicle- and plannexin-treated animals with status epilepticus did not reveal neuroprotective effects of plannexin on mature neurons. However, treatment with plannexin partially prevented the reduction in the number of doublecortin-labeled neuronal progenitor cells, which was evident 48h following status epilepticus. In conclusion, the data might give first evidence that plannexin can protect immature neurons in vivo. Future studies are necessary to evaluate whether disease-modifying or preventive effects are observed in models of epileptogenesis. PMID- 21787840 TI - Partial rescue of NT-3 null mutant phenotype by a PDGF-beta regulated transgene. AB - The phenotype of neurotrophin-3 (NT-3) null mutant mice is characterized by sensory ataxia and early postnatal death. Previous analysis revealed a severe depletion of peripheral sensory, sympathetic and parasympathetic neurons. Most of the deficits are established early during embryonic development. Whereas absence of proprioceptive afferents can explain the sensory ataxia, the reasons for early postnatal death are unclear. To circumvent the limitations imposed by early mortality of null mutants we generated mouse line expressing NT-3 transgenes driven by the platelet-derived growth factor beta-chain (PDGF-beta) promoter, which is known to be active in neurons and mesenchyme derivatives. Mice carrying one or two PDGF-NT3 transgenes on a background null for wildtype NT-3 were generated by crossing with an NT-3 null strain. Although still ataxic, mice from this cross could survive for periods longer than a year. Histological analysis revealed a limited rescue of muscle spindles and parvalbumin immunoreactive sensory neurons. PMID- 21787841 TI - The interrelationship between ligand binding and self-association of the folate binding protein. The role of detergent-tryptophan interaction. AB - BACKGROUND: The folate binding protein (FBP) regulates homeostasis and intracellular trafficking of folic acid, a vitamin of decisive importance in cell division and growth. We analyzed whether interrelationship between ligand binding and self-association of FBP plays a significant role in the physiology of folate binding. METHODS: Self-association behavior of apo- and holo-FBP was addressed through size exclusion chromatography, SDS-PAGE, mass spectrometry, surface plasmon resonance and fluorescence spectroscopy. RESULTS: Especially holo-FBP exhibits concentration-dependent self-association at pH 7.4 (pI), and is more prone to associate into stable complexes than apo-FBP. Even more pronounced was the tendency to complexation between apo-FBP and holo-FBP in accord with a model predicting association between apo and holo monomers [19]. This will lead to removal of apo monomers from the reaction scheme resulting in a weak incomplete ligand binding similar to that observed at FBP concentrations <10nM. The presence of synthetic and natural detergents normalized folate binding kinetics and resulted in appearance of monomeric holo-FBP. Fluorescence spectroscopy indicated molecular interactions between detergent and tryptophan residues located in hydrophobic structures of apo-FBP which may participate in protein associations. GENERAL SIGNIFICANCE: Self-association into multimers may protect binding sites, and in case of holo-FBP even folate from biological degradation. High-affinity folate binding in body secretions, typically containing 1-10nM FBP, requires the presence of natural detergents, i.e. cholesterol and phospholipids, to avoid complexation between apo- and holo-FBP. PMID- 21787842 TI - How accentuation influences semantic short-term memory representations during on line speech processing: an event-related potential study. AB - In the present study, the ERP (event-related brain potentials) technique was used to investigate how accentuation influences the semantic short-term memory representations during on-line speech processing, and how this accentuation effect interacts with the distance of accentuation in the speech signal. Chinese spoken sentences were used as stimuli. The sentences included two critical words: Noun1 and Noun2, with the ERP time-locked to Noun2. During sentence comprehension, when the listener hears Noun2, he needs to retrieve Noun1 from the working memory and integrate it with Noun2. We manipulated the (de-)accentuation of Noun1 and the semantic relationship between Noun1 and Noun2 by changing Noun1 in the sentence context. Moreover, we manipulated the distance of accentuation (distance between Noun1 and Noun2) by changing the syntactic structure of the sentences. The results revealed a significant main effect of semantic relatedness, indicating that the low semantic relatedness condition elicited a larger N400 than the high semantic relatedness condition. Importantly, there was a significant two-way interaction between semantic relatedness and accentuation and a significant three-way interaction between semantic relatedness, accentuation, and distance. Further analysis demonstrated that, the semantic relatedness effect was modulated by accentuation in the long-distance sentences, but not in the short-distance sentences. That is, in the long-distance sentences, the semantic relatedness effect reached significance only when the to-be integrated expression in the preceding sentence context was accented; however, in the short-distance sentences, the semantic relatedness effects reached significance regardless of the presence or absence of accentuation. The results indicated that, during on-line speech processing, accentuation can enhance the corresponding information's semantic short-term memory representation, and that the effect of accentuation on semantic short-term memory is somewhat flexible and shows up only when the words in the speech signal were far apart. PMID- 21787844 TI - Neuromagnetic responses reveal the cortical timing of audiovisual synchrony. AB - Multisensory processing involving visual and auditory inputs is modulated by their relative temporal offsets. In order to assess whether multisensory integration alters the activation timing of primary visual and auditory cortices as a function of the temporal offsets between auditory and visual stimuli, a task was designed in which subjects had to judge the perceptual simultaneity of the onset of visual stimuli and brief acoustic tones. These were presented repeatedly with three different inter-stimulus intervals that were chosen to meet three perceptual conditions: (1) physical synchrony perceived as synchrony by subjects (SYNC); (2) physical asynchrony perceived as asynchrony (ASYNC); (3) physical asynchrony perceived ambiguously (AMB, i.e. 50% perceived as synchrony, 50% as asynchrony). Magnetoencephalographic activity was recorded during crossmodal sessions and unimodal control sessions. The activation of primary visual and auditory cortices peaked at a longer latency for the crossmodal conditions as compared to the unimodal conditions. Moreover, the latency in the auditory cortex was longer in the SYNC than in the ASYNC condition, whereas in the visual cortex the latency in the AMB condition was longer than in the ASYNC condition. These findings suggest that multisensory processing affects temporal dynamics already in primary cortices, that such activity can differ regionally and can be sensitive to the temporal offsets of multisensory inputs. In addition, in the AMB condition the conscious awareness of asynchrony might be associated to a later activation of the primary auditory cortex. PMID- 21787843 TI - Functional reorganization of the presynaptic dopaminergic terminal in parkinsonism. AB - Whether dopamine (DA) release is compensated during the presymptomatic phase of Parkinson's disease (PD) is controversial. Here we use in vivo voltammetry in the parkinsonian rat and an electrical stimulation protocol established to fatigue nigrostriatal dopaminergic (DAergic) neurons to investigate the plasticity of DA release mechanisms. Amplitudes of evoked voltammetric signals recorded in intact rat striata decreased with repetitive, high-frequency stimulation (60 Hz, every 5 min/60 min). Strikingly, DA levels were maintained during an identical "fatiguing" protocol in 6-hydroxydopamine-lesioned (<40% denervation) striata in the absence of enhanced DA synthesis. In contrast, more severely lesioned striata (>55% denervation) also appeared to sustain DA release, however, this was demonstrated in the presence of enhanced synthesis. Sustained release was replicated in intact animals after irreversible blockade of the dopamine transporter (DAT) via RTI-76, implicating neuronal uptake as a trigger. We further demonstrate through kinetic analysis that lesions and compromised uptake target a "long-term" (time constant of minutes) presynaptic depression, which underlies the maintenance of release. Taken together, our findings identify a denervation-induced maintenance of DA release that was independent of activated synthesis and driven by altered uptake. This novel neuroadaptation may contribute to early preclinical normalization of function and help resolve discrepant findings regarding compensatory changes in DA release during progression of the parkinsonian state. PMID- 21787845 TI - N400 solution effect of Chinese character fragments: an orthographic neighborhood size effect. AB - In this study, event-related brain potentials (ERPs) elicited by fragments of Chinese single-character words were simultaneously recorded while participants completed a delayed character-matching task as fast as possible, wherein probe characters were matched with their prior fragments. The number of solutions for such fragments was manipulated. Results indicate that fragments completed with several characters elicited greater N400 than did fragments with a single solution. Behavioral results demonstrated that "multiple-solution" responses were slower and had lower accuracy rates than the "one-solution" responses. In this article, both behavioral and N400 solution-effects are interpreted to provide evidence that supports the interactive activation model (IAM) but counters the efficacy of serial search models. PMID- 21787846 TI - Bioactive saponins from the fruits of Aesculus pavia L. AB - Continued chemical investigation on the fruits of Aesculus pavia L. resulted in theisolation and identification of two new oleanolic acid saponins, namely vaccaroside A (1) andvaccaroside B (2). The isolated furostanol saponins were evaluated for cytotoxic activity againsthuman normal amniotic and human lung carcinoma cell lines using neutral red and MTT assays.In vitro experiments showed significant cytotoxicity in a dose dependent manner with IC50 valuesin the range of 27.80-79.02 MUM. PMID- 21787847 TI - Two new chalcone glycosides from the stems of Entada phaseoloides. AB - Two new chalcone glycosides 4'-O-(6"-O-galloyl-beta-d-glucopyranosyl)-2',4 dihydroxychalcone (1) and 4'-O-(6"-O-galloyl-beta-d-glucopyranosyl)-2'-hydroxy-4 methoxychalcone (2) together with one known chalcone glycoside 4'-O-beta-d glucopyranosyl-2'-hydroxy-4-methoxychalcone (3) were isolated from the stems of Entada phaseoloides. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis, including HSQC, HMBC, (1)H-(1)H COSY, and chemical evidences. This is the first report of chalcone-type compounds isolated from the genus Entada. PMID- 21787848 TI - Pharmacokinetics and tissue distribution of schizonepetin in rats. AB - Schizonepetin, a natural monoterpene from Herba Schizonepetae, is a potential antiviral agent. In this paper, a simple, rapid and sensitive HPLC-UV method was first developed and validated for the determination of schizonepetin in rat plasma and tissue homogenates after oral and intravenous administration. The results showed that schizonepetin was absorbed and eliminated rapidly, and its oral absolute bioavailability in rats achieved about 75%. The drug distributed widely in various tissues of rats, and had no long-term accumulation in vivo. The research provides reliable scientific data for designing drug treatment regimens of schizonepetin. PMID- 21787849 TI - Effect of epoxides and alpha-methylene-gamma-lactone skeleton of sesquiterpenes from yacon (Smallanthus sonchifolius) leaves on caspase-dependent apoptosis and NF-kappaB inhibition in human cercival cancer cells. AB - The present study investigated the cytotoxicity of enhydrin (1), uvedalin (2) and sonchifolin (3) in cervical cancer cells. We have found that SLs 1-3 in doses in range of 0.22-10 MUM inhibited cell proliferation and induced apoptosis in both a dose- and time-dependent fashion. A significant cell death induction was supported by morphological studies. The apoptotic effect is associated with caspase-3/7 activation and NF-kB inhibition. Interestingly, enhydrin possessing two epoxide units was found to be the most cytotoxic compound. Therefore it can be assumed that number of epoxides and existence of alpha-methylene-gamma-lactone moiety are essential for the acceleration of apoptosis. PMID- 21787850 TI - Studies on antidepressant and antinociceptive effects of ethyl acetate extract from Piper laetispicum and structure-activity relationship of its amide alkaloids. AB - Piper laetispicum C.DC. (Piperaceae), is an endemic climbing, glabrous plant distributed in the southern part of China. A novel alkaloid amide, Laetispicine, from it has been proven to possess antidepressant activity. In this present study, antidepressant and antinociceptive effects of the ethyl acetate extract (EAE) of P. laetispicum have been studied in forced swimming, open field, acetic acid writhing and formalin tests in KM mice. A significantly antidepressant-like effect was showing at doses of higher than 60 mg/kg, which was not due to an increase in locomotive activity. The EAE also presented an analgesic effect, in our studies. At lower doses (30 mg/kg) the antinociceptive effect was likely mediated via peripheral inflammation and changes in central processing, and at higher doses (120 mg/kg) that was due to both central and peripheral pathways. We also quantitatively analyzed the major components of EAE by HPLC and approached the structure-activity relationship between structure of amide alkaloids and its antidepressant activities. The antidepressant effective components of EAE might be Leatispiamide A and Laetispicine. In their molecular structures, the isolated double bond from benzene ring and conjugated double bond located at 2-3 and 4-5 were necessary for its antidepressant activity. PMID- 21787851 TI - Transcriptional repression by the proximal exonic region at the human TERT gene. AB - In humans, the enzyme telomerase (hTERT) is responsible for the synthesis of new repeat sequences at the telomeres of chromosomes. Although active in early embryogenesis, the hTERT gene is transcriptionally silenced in almost all somatic cells in the adult, but is aberrantly re-activated in over 90% of human cancers. The molecular mechanisms responsible for repression of this gene are thought to involve the transcription factor CTCF. In this study, we bioinformatically identify putative CTCF binding sites in the hTERT proximal exonic region (PER) and determine their functional relevance in mediating transcriptional silencing at this gene. Tests using a reporter gene assay in HeLa cancer cells demonstrate that a sub-region of the PER exhibits strong transcriptional repressive activity. This repression is independent of the previously identified CTCF binding site near the transcriptional start site of the hTERT gene. In addition, site directed mutagenesis of three predicted CTCF binding sites, including a previously characterized in vivo site in exon 2, does not result in a loss of the repression mediated by the PER. The results from this study indicate that expression of the hTERT gene in HeLa cells is regulated by sequences in the PER. This transcriptional control is mediated through additional regulatory molecular mechanisms, independent of CTCF binding. PMID- 21787852 TI - Temporary effect of postharvest UV-C irradiation on gene expression profile in tomato fruit. AB - To obtain an overall view on gene expression during the early stage (24 h) of tomato fruit in response to postharvest UV-C irradiation (4 kJ/m(2)), we performed a microarray analysis by using Affymetrix Tomato Genechip. The results showed that 274 and 403 genes were up- or down-regulated, respectively, more than two folds in postharvest tomato fruit irradiated with UV-C as compared with that in control fruit. The up-regulated genes mainly involve in signal transduction, defense response and metabolism. Conversely, genes related to cell wall disassembly, photosynthesis and lipid metabolism were generally down-regulated. These results opened ways to probe into the molecular mechanisms of the effects of postharvest UV-C irradiation on increased disease resistance, delayed softening, better quality maintenance and prolonged postharvest life in tomato fruit. PMID- 21787853 TI - Time-dependent variation in the biodistribution of C60 in rats determined by liquid chromatography-tandem mass spectrometry. AB - We examined the biodistribution of C(60) in rats after tail vein administration using LC-MS/MS. C(60) was detected in various tissues, such as brain, kidneys, liver, lungs, and spleen of rats. On the other hand, no C(60) was found in blood. The highest C(60) concentration was observed in the lungs, followed by spleen, liver, kidneys, and brain. These results suggested that C(60) injected in the tail vein could be filtered by lung capillary vessels and accumulate in the lungs prior to being distributed to other tissues. Moreover, C(60) not being detected in the blood indicates that clearance of C(60) from the blood by filtration might effectively occur in the lungs. The time-dependent variation in the biodistribution of C(60) was evaluated. A time-dependent decrease in C(60) concentrations was observed in all tissues, except spleen. Moreover, a decreasing trend of C(60) levels differed among tissues, which could be due to differences in accumulation. These results suggest that unmodified C(60) and/or C(60) metabolites by metabolic enzymes could be excreted into feces and/or urine. In further studies, the metabolic and excretion pathways of C(60) should be evaluated to understand the toxicokinetics of C(60). PMID- 21787854 TI - A quality by design (QbD) case study on liposomes containing hydrophilic API: I. Formulation, processing design and risk assessment. AB - The purpose of this study was to extend QbD principles to liposomal drug products containing a hydrophilic active pharmaceutical ingredient (API) to demonstrate both the feasibility and the advantages of applying QbD concepts to liposome based complex parenteral controlled release systems. The anti-viral drug Tenofovir was selected as a model compound. Desired properties for two of the key liposome drug product qualities, namely the particle size and drug encapsulation efficiency, were defined and evaluated. It was observed that the liposome preparation process significantly affects liposome particle size, and this resulted in considerable variation in the drug encapsulation efficiency. Lipid chain length did not have a significant effect on drug encapsulation efficiency. However, lipid concentration did affect the drug encapsulation efficiency with higher lipid concentrations resulting in higher drug encapsulation. The use of risk assessment in this study assisted the identification of eight high risk factors that may impact liposome drug encapsulation efficiency and particle size. PMID- 21787855 TI - Effects of Rubus coreanus extract on visual processes in bullfrog's eye. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Rubus coreanus (Rosaceae) is traditionally used as an aphrodisiac, astringent, restorative and tonic in Asian countries. It is advised for treating diseases related to liver, kidney and urinary dysfunction, premature greying, blurred vision, infertility, impotence and premature ejaculation. Additionally, there is a long history of different parts of the plants being used in the treatment of ophthalmic diseases. However, no scientific studies have been undertaken to determine the effects of Rubus coreanus in visual processes of the vertebrate retina. AIM OF STUDY: The purpose of the present study was to investigate the positive effects of Rubus coreanus extracts on visual processes in the vertebrate's eye. MATERIALS AND METHODS: Electroretinogram (ERG) techniques were used to record the responses from a bullfrog's eye cup preparations. Active pharmacological agents were used to block specific receptors in the retina and to leave others unaffected. Lipid peroxidation in the retina was generated by adding FeSO(4)+Na-ascorbate. RESULTS: It was observed that both dark- and light-adapted ERG b-wave peak amplitude significantly increases with Rubus coreanus treatment. It was found that Rubus coreanus acts as a retinal neural antagonist but not as GABA receptor antagonist. Rubus coreanus treatment lowered the duration of rhodopsin regeneration. The results obtained indicated that Rubus coreanus protects against lipid peroxidation drop off ERG amplitude in retina. CONCLUSION: Based on results obtained, it is suggested that Rubus coreanus can potentially improve visual sensitivity and can be used to treat pathophysiological conditions of eye. PMID- 21787856 TI - Isolation of narciprimine from Cyrtanthus contractus (Amaryllidaceae) and evaluation of its acetylcholinesterase inhibitory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Plants of the family Amaryllidaceae are used widely in traditional medicine in South Africa. Several of these, including representatives of the genus Cyrtanthus find use in the treatment of mental illness and age-related dementia. AIM OF THE STUDY: Based on the distribution of central nervous system-activating alkaloidal constituents within the genus Cyrtanthus, Cyrtanthus contractus was here explored for such compounds which could interact with acetylcholinesterase (AChE), of significance in the progression of neurodegeneration associated with Alzheimer's disease. MATERIALS AND METHODS: The known phenanthridone alkaloid narciprimine was isolated via column chromatography of the ethanolic extract of bulbs of Cyrtanthus contractus. The structure of the compound was determined by high field 2D NMR and mass spectroscopic techniques. The classical method of Ellman et al. was used in the determination of AChE inhibitory activity. RESULTS: The isolation of narciprimine from Cyrtanthus contractus is a landmark find since it has previously only been identified in Zephyranthes, Narcissus and Lycoris, genera endemic to the Americas, Europe and Asia, respectively. Narciprimine exhibited micromolar inhibitory activity (IC(50) 78.9) against the enzyme acetylcholinesterase. CONCLUSION: This work represents the first isolation of narciprimine from an African Amaryllidaceae species, which may be of chemotaxonomic significance. The AChE inhibitory activity of narciprimine, taken together with activities of other structurally similar inhibitors within the series affords further insight to the structural details of the lycorine alkaloid acetylcholinesterase inhibitory pharmacophore. PMID- 21787857 TI - Application of chicken egg yolk immunoglobulins in the control of terrestrial and aquatic animal diseases: a review. AB - Oral administration of chicken egg yolk immunoglobulin (IgY) has attracted considerable attention as a means of controlling infectious diseases of bacterial and viral origin. Oral administration of IgY possesses many advantages compared with mammalian IgG including cost-effectiveness, convenience and high yield. This review presents an overview of the potential to use IgY immunotherapy for the prevention and treatment of terrestrial and aquatic animal diseases and speculates on the future of IgY technology. Included are a review of the potential application of IgY for the treatment of livestock diseases such as mastitis and diarrhea, poultry diseases such as Salmonella, Campylobacteriosis, infectious bursal disease and Newcastle disease, as well as aquatic diseases like shrimp white spot syndrome virus, Yersina ruckeri and Edwardsiella tarda. Some potential obstacles to the adoption of IgY technology are also discussed. PMID- 21787858 TI - Molecular mechanisms involved in the adaptive response to cadmium-induced apoptosis in human myelomonocytic lymphoma U937 cells. AB - We examined the molecular mechanisms involved in the adaptive response to cadmium (Cd)-induced apoptosis in human myelomonocytic lymphoma U937 cells. When U937 cells were treated with 50 MUM cadmium chloride (CdCl2) for 12 h, significant apoptosis occurred. This was associated with an increase in intracellular reactive oxygen species (ROS), sustained phosphorylation of JNK, activation of caspase-3, a decrease in Mcl-1 (anti-apoptotic Bcl-2 proteins), and increases in Bim, Noxa and tBid (a pro-apoptotic protein under the Bcl-2 family). No apoptosis occurred when the cells were treated with 1 MUM CdCl2 for 72 h. However, pretreatment with low-dose CdCl2 dramatically altered the sensitivity of the cells to 50 MUM CdCl2 with inhibition of apoptosis. Concomitantly, there were significant decreases in the generation of intracellular ROS and the activation of JNK. Pretreatment with 1 MUM CdCl2 also attenuated the decrease in Mcl-1 and the increases in Bim, Noxa and tBid induced by 50 MUM CdCl2. In conclusion, pretreatment with low-dose Cd inhibited apoptosis induced by high-dose Cd. The mechanism involves inhibition of intracellular ROS generation and JNK activation, and modulating the balance between the expression of Mcl-1 and its binding partners, Bim, Noxa and tBid. PMID- 21787859 TI - The neuroimmune changes induced by cohabitation with an Ehrlich tumor-bearing cage mate rely on olfactory information. AB - Cohabitation for 14 days with Ehrlich tumor-bearing mice was shown to increase locomotor activity, to decrease hypothalamic noradrenaline (NA) levels, to increase NA turnover and to decrease innate immune responses and decrease the animals' resistance to tumor growth. Cage mates of a B16F10 melanoma-bearer mice were also reported to show neuroimmune changes. Chemosignals released by Ehrlich tumor-bearing mice have been reported to be relevant for the neutrophil activity changes induced by cohabitation. The present experiment was designed to further analyze the effects of odor cues on neuroimmune changes induced by cohabitation with a sick cage mate. Specifically, the relevance of chemosignals released by an Ehrlich tumor-bearing mouse was assessed on the following: behavior (open-field and plus maze); hypothalamic NA levels and turnover; adrenaline (A) and NA plasmatic levels; and host resistance induced by tumor growth. To comply with such objectives, devices specifically constructed to analyze the influence of chemosignals released from tumor-bearing mice were employed. The results show that deprivation of odor cues released by Ehrlich tumor-bearing mice reversed the behavioral, neurochemical and immune changes induced by cohabitation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. Our results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion. PMID- 21787860 TI - Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. AB - Growing evidence suggests that adult-born granule cells integrate into hippocampal networks and are required for proper cognitive function. Although neuroinflammation is involved in many disorders associated with cognitive impairment, it remains unknown whether it impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Under similar behavioral conditions, exploration-induced expression of the immediate-early gene Arc in hippocampal cells has been linked to cellular activity observed by electrophysiological recording. By detecting exploration-induced Arc protein expression, we investigated whether neuroinflammation alters the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Neuroinflammation was induced in rats by intra-cerebroventricular infusion of lipopolysaccharide for 28 days. Animals received bromodeoxyuridine injections starting on day 29 (5 days) and were euthanized two months later. Persistent lipopolysaccharide-induced neuroinflammation was reliably detected by microglial activation in the hippocampus. Neuroinflammation did not impact the number of adult-born neurons but did alter their migration pattern through the granule cell layer. There was a positive correlation between the density of activated microglia and alterations in the fraction of existing granule neurons expressing Arc, suggesting that neuroinflammation induced a long-term disruption of hippocampal network activity. The proportion of adult-born neurons expressing behaviorally induced Arc was significantly lower in lipopolysaccharide-treated rats than in controls. This observation supports the fact that neuroinflammation significantly impacts adult-born neurons recruitment into hippocampal networks encoding spatial information. PMID- 21787861 TI - Dinitrosyliron complexes are the most abundant nitric oxide-derived cellular adduct: biological parameters of assembly and disappearance. AB - It is well established that nitric oxide ((*)NO) reacts with cellular iron and thiols to form dinitrosyliron complexes (DNIC). Little is known, however, regarding their formation and biological fate. Our quantitative measurements reveal that cellular concentrations of DNIC are proportionally the largest of all (*)NO-derived adducts (900 pmol/mg protein, or 45-90 MUM). Using murine macrophages (RAW 264.7), we measured the amounts, and kinetics, of DNIC assembly and disappearance from endogenous and exogenous sources of (*)NO in relation to iron and O(2) concentration. Amounts of DNIC were equal to or greater than measured amounts of chelatable iron and depended on the dose and duration of (*)NO exposure. DNIC formation paralleled the upregulation of iNOS and occurred at low physiologic (*)NO concentrations (50-500 nM). Decreasing the O(2) concentration reduced the rate of enzymatic (*)NO synthesis without affecting the amount of DNIC formed. Temporal measurements revealed that DNIC disappeared in an oxygen-independent manner (t(1/2)=80 min) and remained detectable long after the (*)NO source was removed (>24 h). These results demonstrate that DNIC will be formed under all cellular settings of (*)NO production and that the contribution of DNIC to the multitude of observed effects of (*)NO must always be considered. PMID- 21787862 TI - Inhibition of human breast cancer Matrigel invasion by Streptolysin O activation of the EGF receptor ErbB1. AB - Streptolysin O (SLO) is a protein cytotoxin derived from Group A beta-hemolytic streptococci that associates with membranes and permeabilizes cells. Oxidation inactivates SLO, eliminating the characteristic hemolytic and cytotoxic activities. However, oxidized SLO produces beneficial therapeutic effects in vivo on scleroderma, scar formation and wound healing. Here we report that oxidized SLO also significantly inhibited invasion by human metastatic breast cancer MDA MB-231 cells through Matrigel in an in vitro model of metastatic disease. This dose-dependent response corresponded to selective SLO activation of epidermal growth factor receptor (EGFR) ErbB1. SLO and EGF were equally selective in activation of EGFR, but EGF elicited larger relative increases in phosphorylation at various sites, especially pronounced for Tyr845. Addition of SLO did not affect either ERK1/2 or Akt kinases and altered the expression of only 10 of 84 metastasis-related genes in MDA-MB-231 cells. Neither SLO nor EGF promoted growth of several human breast cancer cell lines. Knockdown of EGFR by siRNA ablated the inhibitory effect of SLO on cancer cell invasion, showing SLO selectively activated ErbB1 kinase to reduce invasion without increasing cell growth. The results suggest SLO might have promise as a new therapy to inhibit metastasis. PMID- 21787863 TI - Molecular machinery of macroautophagy and its deregulation in diseases. AB - Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation. This process begins with the assembly of protein complexes on isolation membrane to initiate the formation of autophagosome, followed by its nucleation, elongation and maturation. Fusion of autophagosomes with lysosomes then leads to degradation of the cargo. In the past decade, significant advances have been made on the identification of molecular players that are implicated in various stages of macroautophagy. Post-translational modifications of macroautophagy regulators have also been demonstrated to be critical for the selective targeting of cytoplasmic contents into autophagosomes. In addition, recent demonstration of distinct macroautophagy regulators has led to the identification of different subtypes of macroautophagy. Since deregulation of macroautophagy is implicated in diseases including neurodegenerative disorders, cancers and inflammatory disorders, understanding the molecular machinery of macroautophagy is crucial for elucidating the mechanisms by which macroautophagy is deregulated in these diseases, thereby revealing new potential therapeutic targets and strategies. Here we summarize current knowledge on the regulation of mammalian macroautophagy machineries and their disease-associated deregulation. PMID- 21787865 TI - Non-destructive analysis of tablet coatings with optical coherence tomography. AB - Optical coherence tomography (OCT) is a non-invasive analysis technique allowing fast and high-quality cross-sectional imaging of scattering media. OCT is based on the physical phenomenon of low coherence interferometry and is thus well suited to image layered structures. In this paper, high-speed spectral domain OCT was used for the characterization of pharmaceutical tablet coatings, sampled at different stages of an industrial drum spray coating process, comprising tablets with a coating thickness ranging from uncoated to a target coating thickness of about 70 MUm. In addition to the OCT investigation of layer thickness and homogeneity, tablet weight gain and tablet diameters were determined on a single tablet level. Scanning electron microscopy (SEM) was applied for referencing the coating thickness obtained with OCT. We demonstrated that OCT allows rapid evaluation of coating properties, such as thickness and homogeneity independently from variations of the tablet core. In contrast to indirect methods, deviations observed with OCT can be related directly to the coating properties. Furthermore, for an extended morphological coating characterization, three dimensional images were reconstructed. Pending further developments, the high axial resolution and fast data acquisition rate of OCT has the potential for highly accurate, fast and low-cost coating control during and after manufacturing. PMID- 21787864 TI - Glucose-6-phosphate isomerase deficiency results in mTOR activation, failed translocation of lipin 1alpha to the nucleus and hypersensitivity to glucose: Implications for the inherited glycolytic disease. AB - Inherited glucose-6-phosphate isomerase (GPI) deficiency is the second most frequent glycolytic erythroenzymopathy in humans. Patients present with non spherocytic anemia of variable severity and with neuromuscular dysfunction. We previously described Chinese hamster (CHO) cell lines with mutations in GPI and loss of GPI activity. This resulted in a temperature sensitivity and severe reduction in the synthesis of glycerolipids due to a reduction in phosphatidate phosphatase (PAP). In the current article we attempt to describe the nature of this pleiotropic effect. We cloned and sequenced the CHO lipin 1 cDNA, a gene that codes for PAP activity. Overexpression of lipin 1 in the GPI-deficient cell line, GroD1 resulted in increased PAP activity, however it failed to restore glycerolipid biosynthesis. Fluorescence microscopy showed a failure of GPI deficient cells to localize lipin 1alpha to the nucleus. We also found that glucose-6-phosphate levels in GroD1 cells were 10-fold over normal. Lowering glucose levels in the growth medium partially restored glycerolipid biosynthesis and nuclear localization of lipin 1alpha. Western blot analysis of the elements within the mTOR pathway, which influences lipin 1 activity, was consistent with an abnormal activation of this system. Combined, these data suggest that GPI deficiency results in an accumulation of glucose-6-phosphate, and possibly other glucose-derived metabolites, leading to activation of mTOR and sequestration of lipin 1 to the cytosol, preventing its proper functioning. These results shed light on the mechanism underlying the pathologies associated with inherited GPI deficiency and the variability in the severity of the symptoms observed in these patients. PMID- 21787866 TI - Functional and metabolic characterization of hemocytes of the green mussel, Perna viridis: in vitro impacts of temperature. AB - The green mussel, Perna viridis, is a bivalve mollusk native to Asia and was recently introduced to Florida, USA. Since its first observation in 1999 in Tampa Bay, Florida, green mussel population has expanded considerably, to reach the Atlantic coast of Florida, Georgia and South Carolina. Most of currently available studies about the ecology and biology of green mussels were performed in the Indian and Pacific oceans. Very recently, it has been suggested that due to a weak low temperature resistance, green mussels might have already reached the Northern edge of their distribution in the USA. However, there is currently an obvious lack of data about the adaptation capacities of Perna viridis to environmental conditions in Florida, especially at the physiological and cellular levels. In the present work, we determined and characterized the populations of circulating hemocytes, and the cellular components of hemolymph involved in various physiological functions, including immunity. Two main populations were characterized, hyalinocytes and granulocytes. Granulocytes accounted for 60% of circulating cells, and displayed higher phagocytic capacities, lysosomal content and basal oxidative metabolism than hyalinocytes. Hemocyte parameters were not influenced by the size of green mussels. In addition, hemocytes were subjected to acute temperature challenges (10, 20 and 30 degrees C) and their immune-related functions and metabolism analyzed. Our results showed that 10 degrees C represent a stressful condition for the Floridian green mussels, as depicted by a low phagocytosis capacity and an increase of oxidative metabolism. PMID- 21787867 TI - Distribution of M-channel subunits KCNQ2 and KCNQ3 in rat hippocampus. AB - Neuronal M-channels are low threshold, slowly activating and non-inactivating, voltage dependent K(+) channels that play a crucial role in controlling neuronal excitability. The native M-channel is composed of heteromeric or homomeric assemblies of subunits belonging to the Kv7/KCNQ family, with KCNQ2/3 heteromers being the most abundant form. KCNQ2 and KCNQ3 subunits have been found to be expressed in various neurons in the central and peripheral nervous system of rodents and humans. Previous evidence shows preferential localization of both subunits to axon initial segments, somata and nodes of Ranvier. In this work, we show the distribution and co-localization of KCNQ2 and KCNQ3 subunits throughout the hippocampal formation, via immunostaining experiments on unfixed rat brain slices and confocal microscopy. We find intense localization and colocalization to the axonal initial segment in several regions of the hippocampus, as well as staining for non-neuronal cells in the area of the lateral ventricle. We did not observe colocalization of KCNQ2 or KCNQ3 with the presynaptic protein, synaptophysin. PMID- 21787869 TI - A neural basis for interindividual differences in the McGurk effect, a multisensory speech illusion. AB - The McGurk effect is a compelling illusion in which humans perceive mismatched audiovisual speech as a completely different syllable. However, some normal individuals do not experience the illusion, reporting that the stimulus sounds the same with or without visual input. Converging evidence suggests that the left superior temporal sulcus (STS) is critical for audiovisual integration during speech perception. We used blood-oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to measure brain activity as McGurk perceivers and non-perceivers were presented with congruent audiovisual syllables, McGurk audiovisual syllables, and non-McGurk incongruent syllables. The inferior frontal gyrus showed an effect of stimulus condition (greater responses for incongruent stimuli) but not susceptibility group, while the left auditory cortex showed an effect of susceptibility group (greater response in susceptible individuals) but not stimulus condition. Only one brain region, the left STS, showed a significant effect of both susceptibility and stimulus condition. The amplitude of the response in the left STS was significantly correlated with the likelihood of perceiving the McGurk effect: a weak STS response meant that a subject was less likely to perceive the McGurk effect, while a strong response meant that a subject was more likely to perceive it. These results suggest that the left STS is a key locus for interindividual differences in speech perception. PMID- 21787870 TI - Phonological manipulation between speech perception and production activates a parieto-frontal circuit. AB - Repetition has been shown to activate the so-called 'dorsal stream', a network of temporo-parieto-frontal areas subserving the mapping of acoustic speech input onto articulatory-motor representations. Among these areas, a region in the posterior Sylvian fissure at the temporo-parietal boundary (also called 'area Spt') has been suggested to play a central role particularly with increasing computational demands on phonological processing. Most of the relevant evidence stems from tasks requiring metalinguistic processing. To date, the relevance of area Spt in natural phonological operations based on implicit linguistic knowledge has not yet been investigated. We examined two types of phonological processes assumed to be lateralized differently, i.e., the processing of syllabic stress versus subsyllabic segmental processing. In two ways, subjects modified an auditorily presented pseudoword before reproducing it overtly: (a) by a prosodic manipulation involving a stress shift across syllable boundaries, (b) by a segmental manipulation involving a vowel substitution. Manipulation per se was expected to engage area Spt. Segmental compared to prosodic processing was expected to reveal predominantly left lateralized activation, while prosodic compared to segmental processing was expected to result in bilateral or right lateralized activation. Contrary to expectation, activation in area Spt did not vary with increased phonological processing demand. Instead, area Spt was engaged regardless of whether subjects simply repeated a pseudoword or performed a phonological manipulation before reproduction. However, for both segmental and prosodic stimuli, reproduction after manipulation (compared to repetition) activated the left intraparietal sulcus and left inferior frontal cortex. We propose that these parieto-frontal regions are recruited when the task requires phonological manipulation over and above the more automated transfer of auditory into articulatory verbal codes, which appears to involve area Spt. When directly contrasted with prosodic manipulation, segmental manipulation resulted in increased activation predominantly in left inferior frontal areas. This may be due to an increased demand on phonological sequencing operations at the subsyllabic phoneme level. Contrasted with segmental manipulations, prosodic manipulation did not result in increased activation, which may be due to a lower degree of morphosyntactic and to syllable-level processing. PMID- 21787868 TI - Study factors influencing ventricular enlargement in schizophrenia: a 20 year follow-up meta-analysis. AB - A meta-analysis was performed on studies employing the ventricular-brain ratio to compare schizophrenic subjects to that of normal controls. This was a follow-up to a similar meta-analysis published in 1992 in which study-, in addition to clinical-, factors were found to contribute significantly to the reported difference between patients with schizophrenia and controls. Seventy-two (N=72) total studies were identified from the peer reviewed literature, 39 from the original meta-analysis, and 33 additional studies published since which met strict criteria for inclusion and analysis - thus representing ~30 years of schizophrenia ventricular enlargement research. Sample characteristics from schizophrenics and controls were coded for use as predictor variables against within sample VBR values as well as for between sample VBR differences. Additionally, a number of factors concerning how the studies were conducted and reported were also coded. Obtained data was subjected to unweighted univariate as well as multiple regression analyses. In particular, results indicated significant differences between schizophrenics and controls in ventricular size but also the influence of the diagnostic criteria used to define schizophrenia on the magnitude of the reported VBR. This suggests that differing factors of the diagnostic criteria may be sensitive to ventricular enlargement and might be worthy of further examination. Interestingly, we observed an inverse relationship between VBR difference and the number of co-authors on the study. This latter finding suggests that larger research groups report smaller VBR differences and may be more conservative or exacting in their research methodology. Analyses weighted by sample size provided identical conclusions. The effects of study factors such as these are helpful for understanding the variation in the size of the reported differences in VBR between patients and controls as well as for understanding the evolution of research on complex clinical syndromes employing neuroimaging morphometrics. PMID- 21787871 TI - The sound of size: crossmodal binding in pitch-size synesthesia: a combined TMS, EEG and psychophysics study. AB - Crossmodal binding usually relies on bottom-up stimulus characteristics such as spatial and temporal correspondence. However, in case of ambiguity the brain has to decide whether to combine or segregate sensory inputs. We hypothesise that widespread, subtle forms of synesthesia provide crossmodal mapping patterns which underlie and influence multisensory perception. Our aim was to investigate if such a mechanism plays a role in the case of pitch-size stimulus combinations. Using a combination of psychophysics and ERPs, we could show that despite violations of spatial correspondence, the brain specifically integrates certain stimulus combinations which are congruent with respect to our hypothesis of pitch size synesthesia, thereby impairing performance on an auditory spatial localisation task (Ventriloquist effect). Subsequently, we perturbed this process by functionally disrupting a brain area known for its role in multisensory processes, the right intraparietal sulcus, and observed how the Ventriloquist effect was abolished, thereby increasing behavioural performance. Correlating behavioural, TMS and ERP results, we could retrace the origin of the synesthestic pitch-size mappings to a right intraparietal involvement around 250 ms. The results of this combined psychophysics, TMS and ERP study provide evidence for shifting the current viewpoint on synesthesia more towards synesthesia being at the extremity of a spectrum of normal, adaptive perceptual processes, entailing close interplay between the different sensory systems. Our results support this spectrum view of synesthesia by demonstrating that its neural basis crucially depends on normal multisensory processes. PMID- 21787872 TI - Reproductive mode evolution in nematodes: insights from molecular phylogenies and recently discovered species. AB - The Phylum Nematoda has long been known to contain a great diversity of species that vary in reproductive mode, though our understanding of the evolutionary origins, causes and consequences of nematode reproductive mode change have only recently started to mature. Here we bring together and analyze recent progress on reproductive mode evolution throughout the phylum, resulting from the application of molecular phylogenetic approaches and newly discovered nematode species. Reproductive mode variation is reviewed in multiple free-living, animal-parasitic and plant-parasitic nematode groups. Discussion ranges from the model nematode Caenorhabditis elegans and its close relatives, to the plant-parasitic nematodes of the Meloidogyne genus where there is extreme variation in reproductive mode between and even within species, to the vertebrate-parasitic genus Strongyloides and related genera where reproductive mode varies across generations (heterogony). Multiple evolutionary transitions from dioecous (obligately outcrossing) to hermaphroditism and parthenogenesis in the phylum are discussed, along with one case of an evolutionary transition from hermaphroditism to doioecy in the Oscheius genus. We consider the roles of underlying genetic mechanisms in promoting reproductive plasticity in this phylum, as well as the potential evolutionary forces promoting transitions in reproductive mode. PMID- 21787873 TI - Phylogeny of iguanian lizards inferred from 29 nuclear loci, and a comparison of concatenated and species-tree approaches for an ancient, rapid radiation. AB - Iguanian lizards form a diverse clade whose members have been the focus of many comparative studies of ecology, behavior, and evolution. Despite the importance of phylogeny to such studies, interrelationships among many iguanian clades remain uncertain. Within the Old World clade Acrodonta, Agamidae is sometimes found to be paraphyletic with respect to Chamaeleonidae, and recent molecular studies have produced conflicting results for many major clades. Within the largely New World clade Pleurodonta, relationships among the 12 currently recognized major subclades (mostly ranked as families) have been largely unresolved or poorly supported in previous studies. To clarify iguanian evolutionary history, we first infer phylogenies using concatenated maximum likelihood (ML) and Bayesian analyses of DNA sequence data from 29 nuclear protein-coding genes for 47 iguanian and 29 outgroup taxa. We then estimate a relaxed-clock Bayesian chronogram for iguanians using BEAST. All three methods produce identical topologies. Within Acrodonta, we find strong support for monophyly of Agamidae with respect to Chamaeleonidae, and for almost all relationships within agamids. Within Pleurodonta, we find strong Bayesian support for almost all relationships, and strong ML support for some interfamilial relationships and for monophyly of almost all families (excepting Polychrotidae). Our phylogenetic results suggest a non-traditional biogeographic scenario in which pleurodonts originated in the Northern Hemisphere and subsequently spread southward into South America. The pleurodont portion of the tree is characterized by several very short, deep branches, raising the possibility of deep coalescences that may confound concatenated analyses. We therefore also use 27 of these genes to implement a coalescent-based species-tree approach for pleurodonts. Although this analysis strongly supports monophyly of the pleurodont families, interfamilial relationships are generally different from those in the concatenated tree, and support is uniformly poor. However, a species-tree analysis using only the seven most variable loci yields higher support and more congruence with the concatenated tree. This suggests that low support in the 27 gene species-tree analysis may be an artifact of the many loci that are uninformative for very short branches. This may be a general problem for the application of species-tree methods to rapid radiations, even with phylogenomic data sets. Finally, we correct the non-monophyly of Polychrotidae by recognizing the pleurodont genus Anolis (sensu lato) as a separate family (Dactyloidae), and we correct the non-monophyly of the agamid genus Physignathus by resurrection of the genus Istiurus for the former Physignathus lesueurii. PMID- 21787874 TI - Effects of monolaurin on ruminal methanogens and selected bacterial species from cattle, as determined with the rumen simulation technique. AB - Before being able to implement effective ruminal methane mitigation strategies via feed supplementation, the assessment of side effects on ruminal fermentation and rumen microbial populations is indispensable. In this respect we investigated the effects of monolaurin, a methane-mitigating lipid, on methanogens and important carbohydrate-degrading bacteria present in ruminal fluid of dairy cattle in continuous culture employing the rumen simulation technique. In six experimental runs, each lasting for 10 days, four diets with different carbohydrate composition, based on hay, maize, wheat and a maize-wheat mixture, either remained non-supplemented or were supplemented with monolaurin and incubated in a ruminal-fluid buffer mixture. Incubation liquid samples from days 6 to 10 of incubation were analyzed with relative quantitative polymerase chain reaction (qPCR) of 16S rRNA genes to assess monolaurin-induced shifts in specific rumen microbial populations in relation to the corresponding non-supplemented diets. Monolaurin completely inhibited Fibrobacter succinogenes in all diets while the response of the other cellulolytic bacteria varied in dependence of the diet. Megasphaera elsdenii remained unaffected by monolaurin in the two diets containing maize, but was slightly stimulated by monolaurin with the wheat and largely with the hay diet. The supply of monolaurin suppressed Methanomicrobiales below the detection limit with all diets, whereas relative 16S rRNA gene copy numbers of Methanobacteriales increased by 7-fold with monolaurin in case of the hay diet. Total Archaea were decreased by up to over 90%, but this was significant only for the wheat containing diets. Thus, monolaurin exerted variable effects mediated by unknown mechanisms on important ruminal microbes involved in carbohydrate degradation, along with its suppression of methane formation. The applicability of monolaurin for methane mitigation in ruminants thus depends on the extent to which adverse effects on carbohydrate-degrading bacteria actually impair the supply of digested carbohydrates to the animal. PMID- 21787875 TI - Human microbial ecology: lactobacilli, probiotics, selective decontamination. AB - Health care-associated infections are closely associated with different medical interventions which interrupt the balance of human microbiota. The occasional predominance of opportunistic pathogens may lead to their translocation into the lymph nodes and bloodstream, causing endogenous (primary or secondary) hospital infections. The question is raised as to if there is a possibility for prevention of the imbalance of GI microbiota during medical interventions in critically ill patients. Prophylactic selective decontamination of the digestive tract (SDD) simultaneously applies three to four different antimicrobials for the suppression of enteric aerobic microbes, which are potentially pathogenic microorganisms. However, there is no convincing evidence that the indigenous beneficial intestinal microbiota are preserved, resulting in reduced mortality of high-risk patients. In this overview, we have evaluated the antimicrobial treatment guidelines of the Infectious Diseases Society of America (IDSA) for intra abdominal infections in adults and seniors according to their safety for different Lactobacillus spp. The data from our group and in the literature have shown that all tested lactobacilli strains (nearly one hundred) were insusceptible to metronidazole while different species of lactobacilli of the three fermentation groups expressed particular antibiotic susceptibility to vancomycin, cefoxitin, ciprofloxacin and some new tetracyclines. We have relied on microbial ecology data showing that the GI tracts of adults and the elderly are simultaneously colonised at least with several (four to a maximum of 12) Lactobacillus species expressing variable intrinsic insusceptibility to the aforementioned antimicrobials, according to the provided data in table. This finding offers the possibility of preserving the colonisation of the intestine with some beneficial lactobacilli during antimicrobial treatment in critically ill patients with health care-associated infections. Several probiotic Lactobacillus spp. strains are intrinsically resistant to antimicrobials and can be used during antibacterial therapy, however, their application as an additive to antimicrobial treatment in critically ill patients needs to be investigated in well-designed clinical trials. PMID- 21787876 TI - Phaeohyphomycosis caused by Alternaria infectoria presenting as multiple vegetating lesions in a renal transplant patient. AB - The genus Alternaria is one of the most common black moulds and appears to be increasing as a causative agent of subcutaneous phaeohyphomycosis, particularly among immunosuppressed patients. A 53-year-old patient who had received a kidney transplant presented with multiple verrucous lesions on the distal extremities. Positive histopathology and cultures, in addition to rDNA ITS region sequencing, identified the fungal isolate as Alternaria infectoria. Oral itraconazole was administered for 10 months. A follow-up at 15 months demonstrated no signs of infection. Clinical manifestations of cutaneous alternariosis vary significantly and only a few cases have been described in the literature. Although optimal treatment options remain controversial, this case of phaeohyphomycosis was successfully treated with itraconazole monotherapy. PMID- 21787877 TI - [Nematophagous fungi used for the biological control of gastrointestinal nematodes in livestock and administration routes]. AB - The control of gastrointestinal nematodes relies at present mostly on antihelmintic treatments using synthetic molecules. This approach, however, has led to the appearance of resistance to some types of antihelmintics which, together with the need to cut down on the use of chemicals, has fostered the development of other control methods, such as biological control, which is the use of living organisms that are naturally antagonistic to an unwanted species. Among the natural enemies of nematode parasitic larvae is the microfungus Duddingtonia flagrans. Research has shown the ability of this fungus to reduce the number of nematode larvae in faeces, the ability of its chlamydospores to survive the passage through the gastrointestinal tract of livestock and, moreover, to keep its germinative ability, thus facilitating the development of formulations. The present review looks at the species currently used and the different ways of administering already tested nematophagous fungi. PMID- 21787878 TI - Interleukin 24 as a novel potential cytokine immunotherapy for the treatment of Mycobacterium tuberculosis infection. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global health problem. Interleukin 24 (IL-24) is a novel tumor suppressor and a unique member of the IL-10 family of cytokines. However, the in vivo immunological consequences of this cytokine's activity during Mtb infection are still unknown. We found that IL-24 concentration was significantly decreased in the sera of TB patients, and Mtb infection suppressed IL-24 expression of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, we used a mouse infection model utilizing the virulent Mtb H37Rv strain to demonstrate that the administration of exogenous IL-24 had a protective effect against the bacteria. We found that IL-24 could activate human CD8(+) T cells, driving CD8(+) T cells to produce interferon-gamma (IFN-gamma) and counteract TB. This activity was found to be dependent on early involvement of neutrophils in the mouse model. IL 24 strongly stimulated IFN-gamma production mainly by signaling through the IL-24 receptors of human CD8(+) T cells. IL-12 secretion from neutrophils in response to IL-24 treatment might be a minor factor in activating human CD8(+) T cells to secrete IFN-gamma. Suppression of IL-24 expression by Mtb infection might enhance susceptibility to infection and promote the development of chronic TB. This new information could potentially stimulate the development of a new cytokine-based immunotherapeutic approach using IL-24 to stimulate immunity against TB. PMID- 21787880 TI - Ultrastructural changes in the third-stage, infective larvae of ruminant nematodes treated with sainfoin (Onobrychis viciifolia) extract. AB - Plants rich in condensed tannins are an alternative to chemical anthelmintics to control gastrointestinal nematodes (GINs) in ruminants. Previous functional studies have shown that sainfoin extracts affect the two forms of infective larvae (L3), ensheathed and exsheathed. However, the mechanisms of action remain unknown. The aim of this study was thus to compare ultrastructural changes in ensheathed and exsheathed L3 of two GIN species after in vitro contact with sainfoin extracts using transmission electron microscopy. The main changes identified were an alteration of the hypodermis, the presence of numerous vesicles in the cytoplasm and degeneration and/or death of muscular and intestinal cells. The changes suggested similar and nonspecies-specific lesions in the two nematode species. Comparison of the modifications found in the ensheathed vs. exsheathed L3s revealed different locations of the main cellular changes depending on the larval form. It is hypothesized that these spatial differences in lesions are mainly influenced by the presence of the sheath which favors contact between the active compounds and either the cuticle or the digestive tract. Overall, our observations suggest that the functional changes observed in the biology of GIN L3s after contact with sainfoin extracts are mediated through a direct mode of action, i.e. different interactions between the bioactive plant metabolites and the nematode structure depending on the route of contact. PMID- 21787879 TI - Reproductive and developmental toxicity of formaldehyde: a systematic review. AB - Formaldehyde, the recently classified carcinogen and ubiquitous environmental contaminant, has long been suspected of causing adverse reproductive and developmental effects, but previous reviews were inconclusive, due in part, to limitations in the design of many of the human population studies. In the current review, we systematically evaluated evidence of an association between formaldehyde exposure and adverse reproductive and developmental effects, in human populations and in vivo animal studies, in the peer-reviewed literature. The mostly retrospective human studies provided evidence of an association of maternal exposure with adverse reproductive and developmental effects. Further assessment of this association by meta-analysis revealed an increased risk of spontaneous abortion (1.76, 95% CI 1.20-2.59, p=0.002) and of all adverse pregnancy outcomes combined (1.54, 95% CI 1.27-1.88, p<0.001), in formaldehyde exposed women, although differential recall, selection bias, or confounding cannot be ruled out. Evaluation of the animal studies including all routes of exposure, doses and dosing regimens studied, suggested positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mechanisms underlying formaldehyde-induced reproductive and developmental toxicities, including chromosome and DNA damage (genotoxicity), oxidative stress, altered level and/or function of enzymes, hormones and proteins, apoptosis, toxicogenomic and epigenomic effects (such as DNA methylation), were identified. To clarify these associations, well-designed molecular epidemiologic studies, that include quantitative exposure assessment and diminish confounding factors, should examine both reproductive and developmental outcomes associated with exposure in males and females. Together with mechanistic and animal studies, this will allow us to better understand the systemic effect of formaldehyde exposure. PMID- 21787882 TI - The mammalian ABC transporter ABCA1 induces lipid-dependent drug sensitivity in yeast. AB - ABCA1 belongs to the A class of ABC transporter, which is absent in yeast. ABCA1 elicits lipid translocation at the plasma membrane through yet elusive processes. We successfully expressed the mouse Abca1 gene in Saccharomyces cerevisiae. The cloned ABCA1 distributed at the yeast plasma membrane in stable discrete domains that we name MCA (membrane cluster containing ABCA1) and that do not overlap with the previously identified punctate structures MCC (membrane cluster containing Can1p) and MCP (membrane cluster containing Pma1p). By comparison with a nonfunctional mutant, we demonstrated that ABCA1 elicits specific phenotypes in response to compounds known to interact with membrane lipids, such as papuamide B, amphotericin B and pimaricin. The sensitivity of these novel phenotypes to the genetic modification of the membrane lipid composition was studied by the introduction of the cho1 and lcb1-100 mutations involved respectively in phosphatidylserine or sphingolipid biosynthesis in yeast cells. The results, corroborated by the analysis of equivalent mammalian mutant cell lines, demonstrate that membrane composition, in particular its phosphatidylserine content, influences the function of the transporter. We thus have reconstituted in yeast the essential functions associated to the expression of ABCA1 in mammals and characterized new physiological phenotypes prone to genetic analysis. This article is a part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). PMID- 21787881 TI - High sensitivity quantitative lipidomics analysis of fatty acids in biological samples by gas chromatography-mass spectrometry. AB - Historically considered to be simple membrane components serving as structural elements and energy storing entities, fatty acids are now increasingly recognized as potent signaling molecules involved in many metabolic processes. Quantitative determination of fatty acids and exploration of fatty acid profiles have become common place in lipid analysis. We present here a reliable and sensitive method for comprehensive analysis of free fatty acids and fatty acid composition of complex lipids in biological material. The separation and quantitation of fatty acids are achieved by capillary gas chromatography. The analytical method uses pentafluorobenzyl bromide derivatization and negative chemical ionization gas chromatography-mass spectrometry. The chromatographic procedure provides base line separation between saturated and unsaturated fatty acids of different chain lengths as well as between most positional isomers. Fatty acids are extracted in the presence of isotope-labeled internal standards for high quantitation accuracy. Mass spectrometer conditions are optimized for broad detection capacity and sensitivity capable of measuring trace amounts of fatty acids in complex biological samples. . PMID- 21787884 TI - Analysis of mitochondrial genome revealed a rare 50 bp deletion and substitutions in a family with hypertension. AB - We have sequenced the complete mtDNA of a family with hypertension (HT), type 2 diabetes (T2D) and coronary artery disease (CAD). Our analysis revealed two novel mutations (C3519T, G13204A); of which G13204A replaces valine to isoleucine. In silico analysis of a rare missense mutation (T8597C) showed a deleterious effect. We also observed a 50bp deletion (m.298_347del50) in the hypervariable region II (HVSII) of all the individuals, who had a common maternal lineage. This (50bp) deletion was not found in 17,785 individuals from different ethnic populations of India or in a variety of different disease phenotypes. We predict that the mtDNA mutations might be responsible for the HT. Analysis of POLG (polymerase gamma) gene revealed 14 variants which might be responsible for some of the mtDNA mutations seen in this family. PMID- 21787885 TI - Regulation and protection of mitochondrial physiology by sirtuins. AB - The link between sirtuin activity and mitochondrial biology has recently emerged as an important field. This conserved family of NAD(+)-dependent deacetylase proteins has been described to be particularly involved in metabolism and longevity. Recent studies on protein acetylation have uncovered a high number of acetylated mitochondrial proteins indicating that acetylation/deacetylation processes may be important not only for the regulation of mitochondrial homeostasis but also for metabolic dysfunction in the context of various diseases such as metabolic syndrome/diabetes and cancer. The functional involvement of sirtuins as sensors of the redox/nutritional state of mitochondria and their role in mitochondrial protection against stress are hereby described, suggesting that pharmacological manipulation of sirtuins is a viable strategy against several pathologies. PMID- 21787883 TI - Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial. AB - Infertility afflicts 15% of couples who wish to conceive. Despite intensive evaluation of both male and female partners, the etiology may remain unknown leading to a diagnosis of unexplained infertility. For such couples, treatment often entails ovulation induction (OI) with fertility medications coupled with intrauterine insemination. Complications of this therapy include ovarian hyperstimulation syndrome and creation of multiple gestation pregnancies, which can be complicated by preterm labor and delivery, and the associated neonatal morbidity and expense of care for preterm infants. The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study is designed to assess whether OI in couples with unexplained infertility with an aromatase inhibitor produces mono-follicular development in most cycles, thereby reducing multiple gestations while maintaining a comparable pregnancy success rate to that achieved by OI with either gonadotropins or clomiphene citrate. These results will provide future guidance of therapy for couples with unexplained infertility, and if comparable pregnancy rates are achieved with a substantial reduction in multiple gestations, the public health benefit will be considerable. PMID- 21787886 TI - Time course of lung inflammatory and fibrogenic responses during protective mechanical ventilation in healthy rats. AB - This study aimed to assess pulmonary inflammatory and fibrogenic responses and their impact on lung mechanics and histology in healthy rats submitted to protective mechanical ventilation for different experimental periods. Eighteen Wistar rats were randomized to undergo open lung-mechanical ventilation (OL-MV) for 1, 6 or 12 h. Following a recruitment maneuver, a decremental PEEP trial was performed and PEEP set according to the minimal respiratory system static elastance. Respiratory system, lung, and chest-wall elastance and gas-exchange were maintained throughout the 12 h experimental period. Histological lung injury score remained low at 1 and 6 h, but was higher at 12 h due to overinflation. A moderate inflammatory response was observed with a distinct peak at 6h. Compared to unventilated controls, type I procollagen mRNA expression was decreased at 1 and 12h, while type III procollagen expression decreased throughout the 12h experimental period. In conclusion, OL-MV in healthy rats yielded overinflation after 6 h even though respiratory elastance and gas-exchange were preserved for up to 12 h. PMID- 21787887 TI - High altitude simulation, substance P and airway rapidly adapting receptor activity in rabbits. AB - To investigate whether there is a change in airway rapidly adapting receptor (RAR) activity during high altitude exposure, rabbits were placed in a high altitude simulation chamber (barometric pressure, 429 mm Hg). With 12 h exposure, when there was pulmonary congestion, an increase in basal RAR activity was observed. With 36 h exposure, when there was alveolar edema, there was a further increase in basal RAR activity. In these backgrounds, there was an increase in the sensitivity of the RARs to substance P (SP). To assess whether there was an increase in lung SP level, neutral endopeptidase activity was determined which showed a decrease in low barometric pressure exposed groups. It is concluded that along with the SP released, pulmonary congestion and edema produced, respectively by different durations of low barometric pressure exposure cause a progressive increase in RAR activity which may account for the respiratory symptoms reported in climbers who are unacclimatized. PMID- 21787888 TI - Thermodynamic analysis of ionizable groups involved in the catalytic mechanism of human matrix metalloproteinase 7 (MMP-7). AB - Human matrix metalloproteinase 7 (MMP-7) exhibits a broad bell-shaped pH dependence with the acidic and alkaline pK(e) (pK(e1) and pK(e2)) values of about 4 and 10. In this study, we estimated the ionizable groups involved in its catalytic mechanism by thermodynamic analysis. pK(a) of side chains of L-Asp, L Glu, L-His, L-Cys, L-Tyr, L-Lys, and L-Arg at 25-45 degrees C were determined by the pH titration of amino-acid solutions, from which their enthalpy changes, ?H degrees , of deprotonation were calculated. pK(e1) and pK(e2) of MMP-7 at 15-45 degrees C were determined in the hydrolysis of (7-methoxycoumarin-4-yl)acetyl-L Pro-L-Leu-Gly-L-Leu-[N(3)-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl]-L-Ala-L-Arg NH(2), from which ?H(o) for pK(e1) and pK(e2) was calculated. The ?H(o) for pK(e1) (-20.6+/-6.1kJmol(-1)) was similar to that for L-Glu (-23.6+/-5.8kJmol( 1)), and the ?H(o) for pK(e2) (89.9+/-4.0kJmol(-1)) was similar to those for L Arg (87.6+/-5.5kJmol(-1)) and L-Lys (70.4+/-4.4kJmol(-1)). The mutation of the active-site residue Glu198 into Ala completely abolished the activity, suggesting that Glu198 is the ionizable group for pK(e1). On the other hand, no arginine or lysine residues are found in the active site of MMP-7. We proposed a possibility that a protein-bound water is the ionizable group for pK(e2). PMID- 21787889 TI - Modular poly(ethylene glycol) scaffolds provide the ability to decouple the effects of stiffness and protein concentration on PC12 cells. AB - This research focused on developing a modular poly(ethylene glycol) (PEG) scaffold, assembled from PEG microgels and collagen I, to provide an environment to decouple the chemical and mechanical cues within a three-dimensional scaffold. We first characterized the microgel fabrication process, examining the size, polydispersity, swelling ratio, mesh size and storage modulus of the polymer particles. The resulting microgels had a low polydispersity index, PDI=1.08, and a diameter of ~1.6 MUm. The mesh size of the microgels, calculated from the swelling ratio, was 47.53 A. Modular hydrogels (modugels) were then formed by compacting N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride/N hydroxysuccinimidyl group-activated microgels with PEG-4arm-amine and 0, 1, 10, or 100 MUg ml(-1) collagen. The stiffness (G(*)) of the modugels was not significantly altered with the addition of collagen, allowing for modification of the chemical environment independent from the mechanical properties of the scaffold. PC12 cell aggregation increased in modugels as collagen concentrations increased and cell viability in modugels was improved over bulk PEG hydrogels. Overall, these results indicate that further exploration of modular scaffolds formed from microgels could allow for a better understanding of the relationship between the chemical and mechanical properties and cellular behavior. PMID- 21787890 TI - Charcot-Marie-Tooth caused by a copy number variation in myelin protein zero. AB - INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The majority has a duplication of the peripheral myelin protein 22. CMT is otherwise caused by point mutations or small insertions/deletions in one of the 44 known CMT genes. METHODS AND RESULTS: Conventional sequencing of six CMT genes were followed by Multiplex Ligation dependent Probe Amplification (MLPA), array Comparative Genomic Hybridization (aCGH) and breakpoint analysis in a large Norwegian CMT pedigree. Affected had an extra copy of the myelin protein zero (MPZ) gene. CONCLUSION: To our knowledge this is the first non-peripheral myelin protein 22 copy number variation to cause Charcot-Marie-Tooth disease. PMID- 21787892 TI - Cibacron Blue and proteomics: the mystery of the platoon missing in action. AB - The use of Cibacron Blue columns (HiTrapBlue) in proteome analysis for removal of plasma albumin, for facilitating biomarker discovery, has not borne any fruit. In fact, the visibility of low-abundance proteins was obscured. It is here reported that, upon albumin sequestering from plasma, there is adsorption, via hydrophobic interaction, of a substantial number of plasma proteins, which are lost for subsequent analysis if the blue resin is eluted via an ion shock (2 M NaCl) or with a somewhat more robust eluant (5 M urea, 2 M thiourea, 2% CHAPS, 2% sulphobetain 3-10) as recommended by manufacturers. Such treatments, in fact, release at most 25 to 30 unique gene products, including albumin. If, however, the Affigel-Blue resin, after elution with either of the two above eluants, is further eluted with boiling 4% SDS in 25 mM DTT, all the missing proteins (amounting to at least 112 unique species) are desorbed and biomarker analysis can be conducted in a correct way. It is also suggested that such blue-resin treatment could be coupled to ProteoMiner adsorption, this coupled treatment further enhancing the chances of success for discovery of low-abundance proteins. PMID- 21787891 TI - A comparative proteome analysis links tyrosine kinase 2 (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C). AB - Tyrosine kinase 2 (Tyk2) is an integral part of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway which relays intracellular signals of various cytokines. Tyk2 crucially contributes to host defense mechanisms against microbial pathogens and to tumor surveillance but also facilitates immune pathologies. Here we investigated the impact of Tyk2 on the macrophage proteome using the synthetic double-stranded RNA analog polyinosinic acid-polycytidylic acid (poly(I:C)) as a mimicry of viral infections. By means of 2D-DIGE in connection with PMF obtained by MALDI-MS and sequence tag determination by MS/MS we unambiguously identified eighteen protein spots corresponding to sixteen distinct proteins that are regulated by poly(I:C) and differentially expressed between wildtype (WT) and Tyk2-deficient macrophages. The majority of these proteins are functionally assigned to cellular immune responses and to metabolism. We show for selected metabolic enzymes, i.e. triosephosphate isomerase (TIM), ATP-citrate synthase (ACLY) and long-chain-fatty acid-CoA ligase 4 (ACSL4), that Tyk2 affects protein expression transcriptionally and post-transcriptionally. We furthermore confirm the involvement of Tyk2 in the regulation of lipid and carbohydrate metabolism at the level of metabolites. Taken together, our results provide new evidence for important functions of Tyk2 at the molecular interface between innate immunity and cellular metabolism. PMID- 21787893 TI - Analysis of the variability of human normal urine by 2D-GE reveals a "public" and a "private" proteome. AB - The characterization of the normal urinary proteome is steadily progressing and represents a major interest in the assessment of clinical urinary biomarkers. To estimate quantitatively the variability of the normal urinary proteome, urines of 20 healthy people were collected. We first evaluated the impact of the sample conservation temperature on urine proteome integrity. Keeping the urine sample at RT or at +4 degrees C until storage at -80 degrees C seems the best way for long term storage of samples for 2D-GE analysis. The quantitative variability of the normal urinary proteome was estimated on the 20 urines mapped by 2D-GE. The occurrence of the 910 identified spots was analysed throughout the gels and represented in a virtual 2D gel. Sixteen percent of the spots were found to occur in all samples and 23% occurred in at least 90% of urines. About 13% of the protein spots were present only in 10% or less of the samples, thus representing the most variable part of the normal urinary proteome. Twenty proteins corresponding to a fraction of the fully conserved spots were identified by mass spectrometry. In conclusion, a "public" urinary proteome, common to healthy individuals, seems to coexist with a "private" urinary proteome, which is more specific to each individual. PMID- 21787894 TI - Unequal blood pressures: a manifestation of subclavian steal. PMID- 21787897 TI - Is hyponatremia a marker or a mediator? PMID- 21787898 TI - Multimodality evaluation of a rare intracardiac tumor: cardiac hemangioma. PMID- 21787899 TI - Is migraine a modifiable risk factor for ischemic stroke? Potentially not. PMID- 21787900 TI - Medical therapy versus myocardial revascularization in chronic coronary syndrome and stable angina. AB - Coronary artery disease is a leading cause of death in the United States. Angina is encountered frequently in clinical practice. Effective management of patients with coronary artery disease and stable angina should consist of therapy aimed at symptom control and reduction of adverse clinical outcomes. Therapeutic options for angina include antianginal drugs: nitrates, beta-blockers, calcium channel blockers, ranolazine, and myocardial revascularization. Recent trials have shown that although revascularization is slightly better in controlling symptoms, optimal medical therapy that includes aggressive risk factor modification is equally effective in reducing the risk of future coronary events and death. On the basis of the available data, it seems appropriate to prescribe optimal medical therapy in most patients with coronary artery disease and stable angina, and reserve myocardial revascularization for selected patients with disabling symptoms despite optimal medical therapy. PMID- 21787901 TI - Plasma interleukin-10 levels and adverse outcomes in acute coronary syndrome. AB - PURPOSE OR BACKGROUND: Interleukin (IL)-10 is an immunoregulatory cytokine that is produced by a variety of cell types, such as macrophages and activated monocytes. IL-10 possesses numerous anti-inflammatory, anti-thrombotic and anti atherosclerotic properties. Furthermore, patients with acute coronary syndrome have been demonstrated to have reduced levels of IL-10 compared to their stable counterparts. For these reasons, it has been proposed that IL-10 plays a protective role in both atherogenesis and plaque vulnerability. However, 2 short term studies on the prognostic utility of IL-10 in patients with acute coronary syndrome have provided conflicting results, with one study showing that reduced levels of IL-10 were predictors of adverse outcomes and another showing that elevated levels predicted poor outcomes. The objective of the present study was to investigate the long-term prognostic significance of baseline IL-10 levels in patients with acute coronary syndrome. METHODS: Baseline plasma IL-10 levels were measured in 193 well-characterized male patients with acute coronary syndrome who were referred for coronary angiography and followed prospectively for 5 years for the development of major adverse cardiovascular events. RESULTS: After controlling for a variety of baseline variables (including established biomarkers such as high-sensitivity C-reactive protein and N-terminal-pro-B-type natriuretic peptide), plasma IL-10 levels (whether analyzed as a continuous variable or as a categorical variable using receiver operating characteristic-derived cut point) were a strong and independent predictor of the composite outcome of death or non fatal myocardial infarction when using a Cox proportional hazards model. CONCLUSIONS: These data demonstrate that, despite biologic plausibility for IL-10 as being a cardioprotective cytokine, elevated baseline plasma levels of IL-10 are a strong and independent predictor of long-term adverse cardiovascular outcomes in patients with acute coronary syndrome. PMID- 21787902 TI - N-terminal pro B-type natriuretic peptide in the early evaluation of suspected acute myocardial infarction. AB - BACKGROUND: Myocardial ischemia is a strong trigger of N-terminal pro-B-type natriuretic peptide (NT-proBNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that NT-proBNP might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. METHODS: In a prospective multicenter study, NT-proBNP was measured at presentation in 658 consecutive patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality. RESULTS: Acute myocardial infarction was the adjudicated final diagnosis in 117 patients (18%). NT-proBNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other final diagnoses (median 886 pg/mL vs 135 pg/mL, P <.001). The diagnostic accuracy of NT-proBNP for acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval [CI], 0.75-0.83). When added to cardiac troponin T, NT-proBNP significantly increased the AUC from 0.89 (95% CI, 0.84 0.93) to 0.91 (95% CI, 0.88-0.94; P=.033). Cumulative 24-month mortality rates were 0% in the first, 1.3% in the second, 8.3% in the third, and 23.3% in the fourth quartile of NT-proBNP (P <.001). NT-proBNP (AUC 0.85, 95% CI, 0.81-0.89) predicted all-cause mortality independently of and more accurately than both cardiac troponin T (AUC 0.66, 95% CI, 0.58-0.74; P <.001) and the Thrombolysis in Myocardial Infarction risk score (AUC 0.79, 95% CI, 0.74-0.84; P <.001). Net reclassification improvement (Thrombolysis in Myocardial Infarction vs additionally NT-proBNP) was 0.188 (P <.009), and integrated discrimination improvement was 0.100 (P <.001). CONCLUSIONS: Use of NT-proBNP improves the early diagnosis and risk stratification of patients with suspected acute myocardial infarction. PMID- 21787903 TI - Trends in outpatient transthoracic echocardiography: impact of appropriateness criteria publication. AB - BACKGROUND: The impact of the 2007 American College of Cardiology Foundation Transthoracic Echocardiography Appropriateness Criteria on trends in appropriateness is unknown. Therefore, we sought to identify the appropriateness of outpatient transthoracic echocardiography pre- and postpublication of this document. METHODS: The 2007 Appropriateness Criteria were used to classify outpatient echocardiographic studies at an academic medical center during October 2000 and October 2008. The patient's electronic medical record was used to identify echocardiographic indication and appropriateness. RESULTS: From October 2000 to October 2008, there was an 85% increase in outpatient echocardiographic volume. Using the Appropriateness Criteria, there was no significant change in inappropriate referrals (13% and 15%, P=.58). Sixty-five studies (12%) were referred for indications "not addressed" by the document, with an increase (7% to 15%, P=.012) from 2000 to 2008. In a second analysis, incorporating the 2008 Valve Guidelines, an increase was demonstrated in the total number of studies that could be classified, but there was no significant change in the proportion of inappropriate referrals (P=.50). There remained a significant increase (3% to 10%, P=.009) in the proportion of indications "not addressed" by either guideline. CONCLUSION: From October 2000 to October 2008, we experienced a near doubling of outpatient echocardiographic volume, with no significant change in the percent of inappropriate referrals despite interim publication of the Appropriateness Criteria document. In addition, there was an increase in echocardiographic referrals for "not addressed" indications. Future efforts are needed both to refine the Appropriateness Criteria to include unaddressed indications and to promote its effective implementation. PMID- 21787904 TI - Isolated aerobic exercise and weight loss: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Aerobic exercise is a common nonpharmacological intervention for the management of obesity. However, the efficacy of isolated aerobic exercise at promoting weight loss is unclear. We conducted a systematic review and meta analysis to evaluate the efficacy of isolated aerobic exercise programs in overweight and obese populations. METHODS: We searched for published randomized controlled trial reports of aerobic exercise through January 20, 2010. Trials with an isolated aerobic exercise intervention were included. A random-effect model was used to synthesize the results of each intervention. RESULTS: We identified 14 trials involving 1847 patients. The duration of aerobic exercise programs ranged from 12 weeks to 12 months. Results were pooled for programs with 6-month duration and programs with 12-month duration. Six-month programs were associated with a modest reduction in weight (weighted mean difference [WMD]=-1.6 kg; 95% confidence interval [CI], -1.64 to -1.56) and waist circumference (WMD= 2.12 cm; 95% CI, -2.81 to -1.44). Twelve-month programs also were associated with modest reductions in weight (WMD=-1.7 kg; 95% CI, -2.29 to -1.11) and waist circumference (WMD=-1.95 cm; 95% CI, -3.62 to -0.29). CONCLUSION: Moderate intensity aerobic exercise programs of 6-12 months induce a modest reduction in weight and waist circumference in overweight and obese populations. Our results show that isolated aerobic exercise is not an effective weight loss therapy in these patients. Isolated aerobic exercise provides modest benefits to blood pressure and lipid levels and may still be an effective weight loss therapy in conjunction with diets. PMID- 21787905 TI - Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review. AB - OBJECTIVE: Post-thrombotic syndrome causes considerable morbidity. The Home-LITE study showed a lower incidence of post-thrombotic syndrome and venous ulcers after 3 months of treating deep vein thrombosis with the low-molecular-weight heparin tinzaparin versus oral anticoagulation. This systematic review examined whether long-term treatment of deep vein thrombosis using low-molecular-weight heparin, rather than oral anticoagulation, reduces development of post-thrombotic syndrome. METHODS: We identified 9 articles comparing treatment of deep vein thrombosis using long-term low-molecular-weight heparin with any comparator, which reported outcomes relevant to the post-thrombotic syndrome assessed >= 3 months post-deep vein thrombosis. RESULTS: Pooled analysis of 2 studies yielded an 87% risk reduction with low-molecular-weight heparin in the incidence of venous ulcers at >= 3 months (P = .019). One study showed an overall odds ratio of 0.77 (P = .001) favoring low-molecular-weight heparin for the presence of 8 patient-reported post-thrombotic syndrome signs and symptoms. Pooled analysis of 5 studies showed a risk ratio for low-molecular-weight heparin versus oral anticoagulation of 0.66 (P < .0001) for complete recanalization of thrombosed veins. CONCLUSION: These results support the lower incidence of post-thrombotic syndrome and venous ulcers observed in Home-LITE. Long-term treatment with low molecular-weight heparin rather than oral anticoagulation after a deep vein thrombosis may reduce or prevent development of signs and symptoms associated with post-thrombotic syndrome. Post-thrombotic syndrome and associated acute ulcers may develop more rapidly after deep vein thrombosis than previously recognized. PMID- 21787908 TI - What kind of people: obesity stigma and inequities. PMID- 21787906 TI - Attributable risk estimate of severe psoriasis on major cardiovascular events. AB - BACKGROUND: Recent studies suggest that psoriasis, particularly if severe, may be a risk factor for major adverse cardiac events, such as myocardial infarction, stroke, and mortality from cardiovascular disease. We compared the risk of major adverse cardiac events between patients with psoriasis and the general population and estimated the attributable risk of severe psoriasis. METHODS: We performed a cohort study in the General Practice Research Database. Severe psoriasis was defined as receiving a psoriasis diagnosis and systemic therapy (N=3603). Up to 4 patients without psoriasis were selected from the same practices and start dates for each patient with psoriasis (N=14,330). RESULTS: Severe psoriasis was a risk factor for major adverse cardiac events (hazard ratio 1.53; 95% confidence interval, 1.26-1.85) after adjusting for age, gender, diabetes, hypertension, tobacco use, and hyperlipidemia. After fully adjusted analysis, severe psoriasis conferred an additional 6.2% absolute risk of 10-year major adverse cardiac events. CONCLUSION: Severe psoriasis confers an additional 6.2% absolute risk of a 10-year rate of major adverse cardiac events compared with the general population. This potentially has important therapeutic implications for cardiovascular risk stratification and prevention in patients with severe psoriasis. Future prospective studies are needed to validate these findings. PMID- 21787907 TI - Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis. AB - BACKGROUND: The mechanism of osteoporosis with fracture secondary to mastocytosis is little known, and its treatment is poorly codified. METHODS: Ten patients with a mean age of 52.5 years with systemic mastocytosis and osteoporotic fractures were treated with interferon alpha 1.5 million U 3 times per week, combined with monthly pamidronate infusions (1 mg/kg) for 2 years, followed by pamidronate infusions every 3 months. RESULTS: Before treatment, the mean number of vertebral fractures was 3.5, spinal T-score was -3+/-1, hip T-score was -1.9+/-0.7, serum C terminal telopeptide was 357+/-258 pg/mL (N=80-800), bone alkaline phosphatase was 20+/-3.2 IU (N=8-25), and tryptase was 49+/-36 MUg/mL (N<10). Interferon alpha was discontinued in 2 patients because of poor tolerance. Mean follow-up was 60 months. No patient developed a fracture under treatment. In the 8 patients treated with interferon alpha and pamidronate, the mean annual increase in spinal bone mineral density was 12.6%+/-5.6% and 1.93% in hip bone mineral density. Serum C-terminal telopeptide decreased by 66%, bone alkaline phosphatase decreased by 25%, and tryptase decreased by 34%. In the 2 patients treated with pamidronate alone, mean annual bone mineral density increase was 2.4%+/-0.1% at the spine and 0%+/-01% at the hip. CONCLUSION: Osteoporosis secondary to mastocytosis mainly affects trabecular bone, and markers of bone remodeling are normal. Combined treatment with low doses of interferon and pamidronate markedly increased bone density. PMID- 21787909 TI - Some low homogenization pressures improve certain probiotic characteristics of yogurt culture bacteria and Lactobacillus acidophilus LA-K. AB - Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus salivarius ssp. thermophilus, and Lactobacillus acidophilus are dairy cultures widely used in the manufacture of cultured dairy products. Commonly used homogenization pressures in the dairy industry are 13.80 MPa or less. It is not known whether low homogenization pressures can stimulate bacteria to improve their probiotic characteristics. Objectives were to determine the effect of homogenization at 0, 3.45, 6.90, 10.34, and 13.80 MPa on acid tolerance, bile tolerance, protease activity, and growth of L. delbrueckii ssp. bulgaricus LB-12, S. salivarius ssp. thermophilus ST-M5, and L. acidophilus LA-K. The cultures were individually inoculated in cool autoclaved skim milk (4 degrees C) and homogenized for 5 continuous passes. Growth and bile tolerance of samples were determined hourly for 10h of incubation. Acid tolerance was determined every 20 min for 120 min of incubation. Protease activity was determined at 0, 12, and 24h of incubation. All homogenization pressures studied improved acid tolerance of L. delbrueckii ssp. bulgaricus LB-12 but had no beneficial effect on protease activity and had negative effects on growth and bile tolerance. A pressure of 6.90 MPa improved acid tolerance, bile tolerance, and protease activity of S. salivarius ssp. thermophilus ST-M5, but none of the homogenization pressures studied had an effect on its growth. Homogenization pressures of 13.80 and 6.90 MPa improved acid tolerance and bile tolerance, respectively, of L. acidophilus LA-K but had no effect on protease activity and its growth. Some low homogenization pressures positively influenced some characteristics of yogurt culture bacteria and L. acidophilus LA-K. Culture pretreatment with some low homogenization pressures can be recommended for improvement of certain probiotic characteristics. PMID- 21787910 TI - Antioxidative effects of whey protein on peroxide-induced cytotoxicity. AB - Myoblastic toxicity is a major adverse effect caused by reactive oxygen species (ROS) when exercising heavily. Although protection or alleviation of ROS toxicity can be achieved by administration of antioxidant vitamins such as vitamin E and vitamin C, their protective effect remains controversial. Thus, alternative natural antioxidants may be potential candidates for foods for athletes. In this research, we investigated the antioxidative effect of whey protein against hydrogen peroxide (H(2)O(2)) toxicity using C(2)C(12) myoblasts. Whey protein pre incubation prevented the decrease in cell viability after H(2)O(2) treatment. The production of 8-hydroxydeoxyguanosine associated with DNA oxidative damage was also inhibited by the whey protein pre-incubation. Endogenous antioxidant defense, such as glutathione, catalase, and superoxide dismutase activity, was also modulated by the antioxidant. At the same time, enhanced mRNA expression levels of heme oxygenase-1 and NADPH quinone oxidoreductase-1 were observed in cells pre-incubated with whey protein before H(2)O(2) abuse. These findings suggest that whey protein improved the antioxidant capacity against acute oxidative stress through multiple pathways and this protein may serve as an alternative source of antioxidants for prevention of athletic injuries caused by ROS. PMID- 21787911 TI - Effect of liquid retentate storage on flavor of spray-dried whey protein concentrate and isolate. AB - The objective of this study was to determine the effects of holding time of liquid retentate on flavor of spray-dried whey proteins: Cheddar whey protein isolate (WPI) and Mozzarella 80% whey protein concentrate (WPC80). Liquid WPC80 and WPI retentate were manufactured and stored at 3 degrees C. After 0, 6, 12, 24, and 48h, the product was spray-dried (2kg) and the remaining retentate held until the next time point. The design was replicated twice for each product. Powders were stored at 21 degrees C and evaluated every 4 mo throughout 12 mo of storage. Flavor profiles of rehydrated proteins were documented by descriptive sensory analysis. Volatile components were analyzed with solid phase microextraction coupled with gas chromatography mass spectrometry. Cardboard flavors increased in both spray-dried products with increased retentate storage time and cabbage flavors increased in WPI. Concurrent with sensory results, lipid oxidation products (hexanal, heptanal, octanal) and sulfur degradation products (dimethyl disulfide, dimethyl trisulfide) increased in spray-dried products with increased liquid retentate storage time, whereas diacetyl decreased. Shelf stability was decreased in spray-dried products from longer retentate storage times. For maximum quality and shelf life, liquid retentate should be held for less than 12h before spray drying. PMID- 21787912 TI - The effect of substitution of NaCl with KCl on chemical composition and functional properties of low-moisture Mozzarella cheese. AB - The effect of NaCl substitution with KCl on chemical composition, organic acids profile, soluble calcium, and functionality of low-moisture Mozzarella cheese (LMMC) was investigated. Functionality (meltability and browning), organic acids profile, and chemical composition were determined. Chemical composition showed no significant difference between experimental cheeses at same storage period, and same salt treatment. Meltability of LMMC salted with 3NaCl:1KCl, 1NaCl:1KCl, and 1NaCl:3KCl was higher compared with only NaCl (control). The amount of soluble Ca and P increased significantly during storage, with no significant difference between salt treatments. Organic acids profile did not differ between salt treatments at the same storage time. PMID- 21787913 TI - Proteolysis of low-moisture Mozzarella cheese as affected by substitution of NaCl with KCl. AB - The proteolytic and ACE inhibitory activities of low-moisture Mozzarella cheese (LMMC) as affected by partial substitution of NaCl with KCl were investigated. Experimental LMMC were made and salted with 4 salt mixtures: NaCl only (control), 3NaCl:1KCl, 1NaCl:1KCl, and 1NaCl:3KCl, and then proteolytic activity and angiotensin-converting enzyme inhibitory activity were determined. Salt treatment significantly affected angiotensin-converting enzyme inhibitory activity and phosphotungstic acid-soluble N of LMMC during storage. Water-soluble N, trichloroacetic acid-soluble N, lactic acid bacteria population, and total free amino acids were unaffected during storage. Nonetheless, water-soluble N and trichloroacetic acid-soluble N increased significantly during storage within a salt treatment. Peptide profiles and urea-PAGE gels did not differ between experimental cheeses at the same storage time. PMID- 21787914 TI - Anaerobic digestion of dairy manure influenced by the waste milk from milking operations. AB - It is not uncommon that a significant amount of milk from milking operations is discharged to manure digesters on dairy farms. To understand the effect of milk on the digester performance, experiments using batch digesters (500-mL flasks) were carried out in this study to co-digest milk and dairy manure at different milk levels for biogas production and pollutant reduction, and a total of 8 treatments were examined [i.e., control (without milk) and 1, 3, 5, 7, 9, 14, and 19% milk additions]. The temperature for all digesters was maintained at 37+/-0.5 degrees C throughout the experimental period, which was 28 d. The results showed that co-digesting milk with dairy manure could increase biogas productivity, with the percent cumulative biogas volume increased by 5.6, 16.3, 26.5, 40.8, 50.2, 79.9, and 103.8%, as compared with the control, for milk addition of 1, 3, 5, 7, 9, 14, and 19% (vol/vol), respectively. However, the CH(4) content in the biogas decreased slightly as the milk content increased (from 66.5% for the control to 63.5% for 19% milk treatment), implying that the added milk could promote CO(2) production. To avoid that, the milk content in the manure should be controlled below 3%. A linear relationship for the total biogas volume produced with the milk content in the manure was revealed, with a correlation coefficient of 0.99. An improved removal efficiency of chemical oxygen demand was observed for milk treated digesters. Good linear regressions between the total biogas production and the percent chemical oxygen demand decrease and the substrate carbon/nitrogen ratio were also obtained (correlation coefficients: 0.93 and 0.99, respectively). Besides, co-digestion of dairy manure and milk was found to improve substrate solids breakdown, but had little effect on percent volatile fatty acid decrease. In summary, the waste milk co-digested with dairy manure may not cause negative effects on anaerobic digester performance. PMID- 21787915 TI - Simultaneous detection of cow and buffalo species in milk from China, India, and Pakistan using multiplex real-time PCR. AB - Asian countries are major producers of cow and buffalo milk. For quality and authenticity purposes, a multiplex real-time PCR assay was developed to specifically and simultaneously detect DNA from these 2 bovine species. Targeting the cytochrome b gene of mitochondrial DNA, common PCR primers amplified a 105-bp fragment, and 2 fluorescent probes specific to either cow or buffalo were designed for their identification. Specificity was successfully tested on 6 other species, including sheep and goat, and sensitivity reached 1% of cow DNA in buffalo DNA and vice versa. As an evaluation, the method was tested using 119 freeze-dried Asian milk samples from regional industrial milk facilities. Although these samples did not cover the entire Asian zone, the multiplex assay indicated that approximately 20% of the samples (mainly from India) showed high levels of cross-contamination of cow milk by buffalo milk, and vice versa. Fast, sensitive, and straightforward, this method is fit-for-purpose for the authenticity control of Asian milk. PMID- 21787916 TI - Angiotensin-converting enzyme inhibitory activity in Mexican Fresco cheese. AB - The objective of this study was to evaluate if Mexican Fresco cheese manufactured with specific lactic acid bacteria (LAB) presented angiotensin I-converting enzyme inhibitory (ACEI) activity. Water-soluble extracts (3 kDa) obtained from Mexican Fresco cheese prepared with specific LAB (Lactococcus, Lactobacillus, Enterococcus, and mixtures: Lactococcus-Lactobacillus and Lactococcus Enterococcus) were evaluated for ACEI activity. Specific peptide fractions with high ACEI were analyzed using reverse phase-HPLC coupled to mass spectrometry for determination of amino acid sequence. Cheese containing Enterococcus faecium or a Lactococcus lactis ssp. lactis-Enterococcus faecium mixture showed the largest number of fractions with ACEI activity and the lowest half-maximal inhibitory concentration (IC(50); <10 MUg/mL). Various ACEI peptides derived from beta casein [(f(193-205), f(193-207), and f(193-209)] and alpha(S1)-casein [f(1-15), f(1-22), f(14-23), and f(24-34)] were found. The Mexican Fresco cheese manufactured with specific LAB strains produced peptides with potential antihypertensive activity. PMID- 21787917 TI - Reservoir and routes of transmission of Enterobacter sakazakii (Cronobacter spp.) in a milk powder-producing plant. AB - Several outbreaks of Cronobacter spp. (Enterobacter sakazakii) have been described as food-borne illness in neonates and infants. Powdered infant formula has been identified as a source of infection, especially in hospital nurseries, where a bulk of formula nutrient is prepared for the whole day and instructions for preparation are not always followed correctly. Neonates who are underweight or immunosuppressed are especially at risk for an E. sakazakii infection. Considering that milk powder is the main ingredient of powdered infant formula, we analyzed the incidence and distribution of E. sakazakii in a milk powder producing plant. We looked specifically at the spray-drying towers and roller dryers. Selected isolates from samples taken from the environment and final product were typed by pulsed-field gel electrophoresis to investigate the epidemiology of the organism within the production area of the plant. Seven pulsed-field gel electrophoresis types were detected in the spray-drying area, which presumably entered the plant through an aperture for process air and an improperly controlled roller shutter. Furthermore, textile filters for exhaust air of both the spray-drying towers were identified as internal reservoirs of the pathogen. For economic reasons, powder from the textile filters is reintroduced into the product flow; this can contaminate the final product. For the production of milk powder to be used as an ingredient of powdered infant formula, it was suggested to terminate the process of reintroducing the filtered powder into the product flow. A second transmission route was identified in the roller dryer section of the factory. It could be shown that contaminated milk concentrate could pass the process unheated, thus leading to a contamination of the product with E. sakazakii. PMID- 21787918 TI - Analysis of the economically optimal voluntary waiting period for first insemination. AB - The voluntary waiting period (VWP) is defined as the time between parturition and the time at which the cow is first eligible for insemination. Determining the optimal VWP from field data is difficult and unlikely to happen. Therefore, a Monte-Carlo dynamic-stochastic simulation model was created to calculate the economic effects of different VWP. The model is dynamic and uses time steps of 1 wk to simulate the reproductive cycle (ovulation, estrous detection, and conception), the occurrence of postpartum disorders, and the lactation curve. Inputs of the model were chosen to reflect the situation of Dutch dairy cows. In the model, we initially created a cow of a randomly selected breed, parity, month of calving, calf status of last calving, and expected 305-d milk yield. The randomly varied variables were based upon relevant distributions and adjusted for cow statuses. The lactation curve was modeled by Wood's function. The economic input values in the analysis included: cost of milk production (?0.07 to ?0.20 per kg), calf price (?35 to ?150 per calf), AI cost (?7 to ?24 per AI), calving management cost (?137 to ?167 per calving), and culling cost, expressed as the retention pay-off (?118 to ?1,117). A partial budget approach was used to calculate the economic effect of varying the VWP from 7 to 15 wk postpartum, using a VWP of 6 wk as reference. Per iteration, the VWP with either the lowest economic loss or the maximum profit was determined as the optimal VWP. The optimal VWP of most cows (90%) was less than 10 wk. On average, every VWP longer than 6 wk gave economic losses. Longer VWP were in particular optimal for the first parity of breeds other than Holstein-Friesian, cows calving in winter with low milk production, high milk persistency, delayed peak milk yield time, a delayed time of first ovulation, or occurrence of a postpartum disorder, and while costs of milk production are low and costs for AI are high. PMID- 21787919 TI - Strategies for time of culling in control of paratuberculosis in dairy herds. AB - Effect of time for culling cows infected with Mycobacterium avium ssp. paratuberculosis on prevalence and profitability was identified through simulations. Seven test-and-cull strategies with different culling criteria and no attempts to close infection routes were compared with strategies with (1) no control and (2) closure of infection routes and no culling. The effects on true prevalence and gross margin were evaluated in a herd with typical reproduction management (heat detection rate of 38%). This was repeated in a herd with poor reproduction management (heat detection rate of 28%), because poor reproduction leads to lack of replacement animals, which was hypothesized to affect the economic effects of culling. Effects of varying prices of milk, replacement heifers, and hourly wages were also evaluated. The simulated results predicted that immediate culling after the first positive antibody ELISA test would be the most effective culling strategy to reduce prevalence. However, closing transmission routes was even more effective in reducing the prevalence. In the first 3 to 6 yr, all test-and-cull strategies reduced gross margin by US$5 to 55/stall per year. These losses were fully compensated by increased gross margin in yr 6 to 19. In the short run (7 yr with typical reproduction and 10 yr with poor reproduction), it was most profitable to cull test-positive cows when their milk yield decreased below 85% of that expected according to their parity and lactation stage, especially in herds with poor reproduction management. However, this strategy only stabilized the prevalence and did not reduce it. In the long term (>7 yr from implementation of a strategy), it was most profitable to cull cows immediately or as soon as possible after testing positive the first time. Varying milk prices did not affect the ranking between the different culling strategies. Increased market price (20%) of replacement heifers made all culling strategies less profitable and made culling based on a milk yield criterion the most profitable culling strategy for a longer period (11 to 13 yr). A 20% reduction in heifer price made immediate culling after a positive test the most profitable strategy overall in herds with typical reproduction, and after 9 yr in herd with poor reproduction. To conclude, the ideal culling strategy depends on the aim of intervention, the time horizon, and the reproductive capabilities combined with prices of replacement animals. PMID- 21787920 TI - The relationship between dairy cow hygiene and somatic cell count in milk. AB - Corporal hygiene is an important indicator of welfare for dairy cows and is dependent on facilities, climate conditions, and the behavior of the animals. The objectives of this study were to describe how the hygiene conditions of dairy cows vary over time and to assess whether a relationship exists between hygiene and somatic cell count (SCC) in milk. Monthly hygiene evaluations were conducted on lactating cows in 2 dairy farms for 9 consecutive months, totaling 3,554 evaluations from 545 animals. Hygiene was measured using a 4-point scoring system (very clean, clean, dirty, and very dirty) for 4 areas of the animal's body (leg, flank, abdomen, and udder) and combining these scores to generate a composite cleanliness score. A total of 2,218 milk samples was analyzed from 404 cows to determine SCC and somatic cell linear scores (SCLS). Individual variation was observed in the hygiene of cows throughout the year, with the highest proportion of clean cows being observed in August and the lowest in January. In spite of this seasonal variation, approximately half (55.62%) of the cows displayed consistent cleanliness scores, with 45.86% of them remaining consistently clean (very clean or clean) and 9.76% remaining dirty (very dirty or dirty) over the course of the study. The very clean cows had the lowest SCLS, followed by the clean, dirty, and very dirty cows (no statistically significant differences were found between the latter 2 groups). The most critical months for cow hygiene were those with the greatest rainfall, when a reduction in the welfare of cows and higher SCC values were observed. The evaluation and control of dairy cow hygiene are useful in defining management strategies to reduce problems with milk and improve the welfare of the animals. PMID- 21787921 TI - Association of standing and lying behavior patterns and incidence of intramammary infection in dairy cows milked with an automatic milking system. AB - The standing and lying behavior patterns of dairy cows, particularly the length of time cows spend standing after milking, have the potential to influence the incidence of intramammary infection (IMI). The objectives were to describe the standing and lying behavior patterns of cows milked with an automatic milking system (AMS) and to determine how these patterns relate to the incidence of IMI. One hundred and eleven lactating Holstein dairy cows were monitored over a 4-mo period. These cows were kept in a sand-bedded freestall barn with 2 pens, each with a free cow traffic AMS. Feed was delivered once daily, and pushed up 2 to 3 times daily. Quarter milk samples were collected for bacteriological culture from each cow once every 4 wk. A new IMI was defined as a positive culture sample following a negative culture. For 7 d before each of the last 3 milk samplings, standing and lying behavior, and times of milking and feed manipulation (feed delivery and push up) were recorded. Daily lying time and lying bout length were negatively related with milk yield (r=-0.23 and -0.20, respectively) and milking frequency (r=-0.32 and -0.20, respectively); milk yield was positively related to milking frequency (r=0.58). Feed manipulation near the time cows were milked (1h before 2h after) resulted in the longest post-milking standing times (mean=86 min; 95% confidence interval=78, 94 min), whereas feed manipulation occurring outside that time frame resulted in shorter post-milking standing times. Over the study period, 171 new IMI were detected. Of these new IMI detected, those caused by coagulase-negative staphylococci were the only ones associated with post milking standing time; as post-milking standing time increased past 2.5h after milking, the odds of acquiring a new IMI tended to also increase. In summary, standing and lying behavior patterns of cows milked with an AMS were affected by both feed manipulation and their milking activity. Further, the post-milking standing time of cows milked with an AMS can be managed by providing fresh feed, as well as by pushing up feed, frequently throughout the day. Finally, cows that spend long periods of time (>2.5h) standing following milking may be at higher risk of acquiring a new CNS IMI. PMID- 21787922 TI - Effect of solar radiation and flaxseed supplementation on milk production and fatty acid profile of lactating ewes under high ambient temperature. AB - The objectives of this study were to evaluate the effects of protection from solar radiation and whole flaxseed supplementation on milk yield and milk fatty acid profile in lactating ewes exposed to high ambient temperature. The experiment was conducted during summer and involved 40 ewes divided into 4 groups. The ewes were either exposed (not offered shade) or protected from solar radiation (offered shade). For each solar radiation treatment, ewes were supplemented with whole flaxseed or not. Milk samples from each ewe were collected at the morning and afternoon milking every week, and analyzed for pH, total protein, casein, fat, and lactose content, somatic cell count, and renneting parameters (clotting time, rate of clot formation, and clot firmness after 30 min). At the beginning of the experiment, and then at d 23 and 44, milk samples were analyzed for milk fatty acids using gas chromatography. Flaxseed supplementation significantly increased milk yield, fat, protein, and casein yields, and somatic cell count, and increased fat and lactose contents of milk. A decrease of saturated fatty acids from C6:0 to C16:0 and an increase of C18:1 trans-11 and C18:2 cis-9,trans-11 was observed in milk from flaxseed-supplemented ewes. Flaxseed supplementation decreased saturated fatty acids content and increased total monounsaturated fatty acids content, the total content of isomers of conjugated linoleic acid, and polyunsaturated fatty acids content in milk. Flaxseed also increased the alpha-linolenic acid content of milk. As a result, milk from supplemented groups showed an increase in n-3 fatty acid content. Flaxseed supplementation decreased short-chain and medium-chain fatty acids, and increased long-chain fatty acid content of milk. On average, flaxseed supplementation increased the C18:2 cis-9,trans-11/C18:1 trans-11 Delta(9) desaturase index starting from d 23 of the experiment, in correspondence with the highest C18:2 cis-9,trans-11 content of milk from flaxseed-supplemented ewes. Flaxseed decreased atherogenic and thrombogenic indices of milk. Protection from solar radiation during summer did not improve yield and composition of ewe milk. Nevertheless, milk from ewes exposed to solar radiation showed decreased long chain fatty acid and polyunsaturated fatty acids contents, and in particular, decreased vaccenic acid, rumenic acid, and total conjugated linoleic acid contents. PMID- 21787923 TI - Lactoperoxidase activity in milk is correlated with somatic cell count in dairy cows. AB - Lactoperoxidase (LPO) is a milk protein with antimicrobial function. The present study was undertaken to examine the correlation between LPO activity and somatic cell count (SCC) in milk to use LPO activity as an indicator of mastitis. Composite milk of 36 cows and quarter milk of 3 cows were collected once per week from 0 to 300 d postpartum and twice per day for 1 wk, respectively. For the measurement of LPO activity, milk was mixed with tetramethylbenzidine solution and incubated at 37 degrees C for 30 min, followed by the measurement of optical density. When only milk with low SCC (132+/-12*10(3) cells/mL) was used, a significant decrease in LPO activity was detected in primiparous cows from 0 to 4 mo postpartum. Lactoperoxidase activities of primiparous cows in mo 1, 2, and 3 postpartum were significantly higher than those in multiparous cows. When composite milk was divided based on LPO activity, the SCC was significantly higher in the groups with LPO activity >5 and from 3 to 3.9 U/mL in the second- and fourth-parity cows, respectively, compared with the group with LPO activity <2U/mL. Extremely high SCC were found in the >=fifth-parity cows, even in low-LPO activity groups. In the case of quarter milk, higher LPO activity was associated with increased SCC in all 3 cows. The percentage of quarter milk samples with high SCC (4,062+/-415*10(3) cells/mL) increased with an increase in the LPO activity. The percentage of quarter milk samples with high SCC was 50.0 to 100% in the milk with LPO activity >=5 U/mL. These results indicate that the correlation of LPO activity to the SCC in bovine milk may point to the potential use of the former as an indicator of SCC. PMID- 21787924 TI - Effects of providing total mixed rations indoors and on pasture on the behavior of lactating dairy cattle and their preference to be indoors or on pasture. AB - Grazing is considered a normal behavior for dairy cattle, although they may not be able to meet their nutritional requirements from grazing alone, and so to sustain higher yields requires access to a total mixed ration (TMR). The study aim was to provide dairy cows with access to TMR indoors and on pasture to establish influence on behavior and preference for each location. The study took place from August to November, 2009, using 36 late-lactation Holstein-Friesian dairy cows. The cows were allocated to 1 of 3 26-d study periods (n=12*3). Within each period the cows were further divided into a control (n=6) or treatment (n=6) group using a crossover design, where the cows were changed between the control and treatment group after 13 d. Treatment cows had access to TMR indoors and on pasture, whereas control cows only had access to TMR indoors. Following a.m. and p.m. milkings the cows were taken to a point equidistant between indoors and pasture and given the choice of going to pasture (1.5 ha) or to a freestall barn. Between milkings the cows had free access between the locations. Initial choice was recorded and a video camera was used to record time spent in each location. Behavior observations were recorded to establish how the cows spent their time during the day. To determine what factors influenced preference, weather conditions, milk yield, body condition score, and lameness were recorded. Initially, the cows chose indoors following milking (96.4+/-0.80%). Overall, the cows expressed a partial preference for pasture (71.1+/-1.82%), which was different from 100, 50, and 0%. Study period influenced preference with cows spending less time on pasture as the season progressed (86.7 vs. 68.3 vs. 58.3% for study periods 1, 2, and 3, respectively). Providing the cows with TMR outdoors did not affect pasture use, but resulted in an increase in TMR intake of 2.2+/-0.41 kg of dry matter/d. The cows spent more time on pasture as the temperature-humidity index indoors (55.6+/-0.92) and outdoors (54.6+/-0.82) increased, but rainfall and milk yield did not influence preference. Cows with lameness score >1.5 spent more time indoors (35.4+/-4.52 vs. 25.2+/-2.64% for cows with >1.5 vs. <=1.5 lameness score, respectively). In conclusion, the cows expressed a partial preference for pasture, which was not influenced by providing TMR on pasture. PMID- 21787925 TI - Analysis of the influence of variation factors on electrical conductivity of milk in Murciano-Granadina goats. AB - The aim of this study was to obtain further knowledge on electrical conductivity (EC) of milk as a tool for detecting mastitis in goats. The effect of farm, parity, stage of lactation, and health status of the glands on EC, and the somatic cell count (SCC) of milk was analyzed. Additionally, relationships between EC and chemical composition and SCC were studied. Finally, characteristics of EC and SCC (sensitivity and specificity) as diagnostic tests used to detect mastitis were studied. One hundred and five Murciano-Granadina goats were enrolled in the study. Milk samples (by gland) were collected monthly for 7 mo on 3 farms in the southeastern Spain. To establish the health status, milk samples were aseptically collected before milking by gland. Foremilk (by gland) was collected to analyze EC, SCC, and chemical composition. Glands were classified according to the health status as free of mastitis, bacterial mastitis, or unspecific mastitis. The effects of farm, parity, and stage of lactation, as well as the interactions between health status and parity, parity and stage of lactation, and health status and stage of lactation were associated with EC. Changes in the milk's chemical composition (particularly of chloride ions) explained most of the variance in EC (R(2)=0.91). The strongest association between EC and SCC was found at SCC >2*10(6) cells/mL (r=0.42). The use of a single EC threshold for all animals and farms for detecting mastitis led to limited results for mastitis detection, which, in any case, favors negative predictive values over positive predictive values. This study revealed that factors, other than the health status, affecting EC hamper the use of an EC threshold for mastitis detection with sufficient specificity on all animals. Any detection system based on EC of milk should consider these factors, as well as specific variations for each of the animals. PMID- 21787926 TI - Short communication: reference values for blood parameters in Holstein dairy cows: effects of parity, stage of lactation, and season of production. AB - Confidence intervals for blood parameters used for nutritional and metabolic profile testing in cattle were calculated for clinically normal lactating Holstein cows, taking into account the effects of parity, stage of lactation, and season. Blood samples were collected from 740 cows in 33 Italian dairy herds according to a predefined protocol. Herds were visited during summer and the following winter, sampling 12 lactating cows at each visit (4 primiparous and 8 multiparous). Six cows were selected from the early-lactation group (days in milk: 10 to 89) and the other 6 were selected from the mid-lactation group (days in milk: 90 to 215). Cow selection criteria excluded animals clinically exposed to periparturient diseases as well as animals not considered in good health by a veterinary clinical examination. For each blood variable, outliers were identified and discarded. Data were then analyzed for their Gaussian distribution and variables with not normal distribution were log-transformed to adjust for lack of normality. Herd mean values were calculated for each blood parameter according to 3 main classification factors: parity (primiparous vs. multiparous), stage of lactation (early vs. mid) and season of production (summer vs. winter). The resulting data set was statistically analyzed using a mixed model with the fixed effects of these factors, their interactions, and the random effect of herd. General 95% confidence intervals were calculated for blood variables that showed a relevant herd variance component such as albumin, triglycerides, aspartate, urea, glucose, alanine aminotransferase, lactate dehydrogenase, direct and total bilirubin, calcium, magnesium, and potassium. For the remaining parameters, specific confidence intervals were calculated for each level of the significant main factors. Parity affected blood concentration of total protein, globulin, creatinine, alkaline phosphatase, gamma glutamyl transferase, creatinine kinase, and phosphorus. Blood nonesterified fatty acids, aspartate aminotransferase, gamma glutamyl transferase, creatinine kinase and cholesterol were influenced by stage of lactation. The season of production had a significant effect on total protein, globulin, creatinine, alkaline phosphatase, phosphorus, sodium, and chlorine. The outcomes of this work will improve the accuracy of the biochemical profile as a tool for dairy practitioners to assess the metabolic status of lactating Holstein cows. PMID- 21787927 TI - Effect of lactic acid bacteria inoculant and beet pulp addition on fermentation characteristics and in vitro ruminal digestion of vegetable residue silage. AB - The objective of this study was to determine the effect of beet pulp (BP) and lactic acid bacteria (LAB) on silage fermentation quality and in vitro ruminal dry matter (DM) digestion of vegetable residues, including white cabbage, Chinese cabbage, red cabbage, and lettuce. Silage was prepared using a small-scale fermentation system, and treatments were designed as control silage without additive or with BP (30% fresh matter basis), LAB inoculant Chikuso-1 (Lactobacillus plantarum, 5mg/kg, fresh matter basis), and BP+LAB. In vitro incubation was performed using rumen fluid mixed with McDougall's artificial saliva (at a ratio of 1:4, vol/vol) at 39 degrees C for 6h to determine the ruminal fermentability of the vegetable residue silages. These vegetable residues contained high levels of crude protein (20.6-22.8% of DM) and moderate levels of neutral detergent fiber (22.7-33.6% of DM). In all silages, the pH sharply decreased and lactic acid increased, and the growth of bacilli, coliform bacteria, molds, and yeasts was inhibited by the low pH at the early stage of ensiling. The silage treated with BP or LAB had a lower pH and a higher lactic acid content than the control silage. After 6h of incubation, all silages had relatively high DM digestibility (38.6-44.9%); in particular, the LAB-inoculated silage had the highest DM digestibility and the lowest methane production. The vegetable residues had high nutritional content and high in vitro DM digestibility. Also, both the addition of a LAB inoculant and moisture adjustment with BP improved the fermentation quality of the vegetable residue silages. In addition, LAB increased DM digestibility and decreased ruminal methane production. PMID- 21787928 TI - Effects of supplementation with 2-hydroxy-4-(methylthio)-butanoic acid isopropyl ester on splanchnic amino acid metabolism and essential amino acid mobilization in postpartum transition Holstein cows. AB - The present study aimed to investigate the effects of 2-hydroxy-4-(methylthio) butanoic acid isopropyl ester (HMBi) supplementation on splanchnic AA metabolism, essential AA (EAA) mobilization, and plasma AA status in postpartum transition dairy cows. The EAA mobilization was calculated by difference: EAA excretion in milk protein - net portal absorption of EAA or net splanchnic release of EAA. Eight Holstein cows fitted with permanent indwelling catheters in the hepatic portal vein, hepatic vein, mesenteric vein, and an artery in the dry period preceding second parturition were used in the study. Cows were randomly allocated to 1 of 4 treatments in a 2*2 factorial arrangement with factor 1: control (calcium carbonate) versus HMBi [1.5 g of HMBi/kg of dry matter (DM)] and factor 2: high dietary ethanol (19 g/kg of DM) versus high dietary propanol (16 g/kg of DM). Only factor 1 data are presented. Treatments were administered in 4 total mixed rations and initiated on the day of parturition. Cows were sampled 14 d before expected parturition and 4, 15, and 29 d after parturition. Supplementation with HMBi tended to increase milk fat content but not fat yield, tended to impose a slower rate of decrease in milk casein content with increasing days in milk (DIM), prevented the decrease in plasma Met associated with parturition for control, reduced plasma concentration of Ser, tended to reduce plasma concentrations of Gly and His, and tended to increase hepatic uptake of Met postpartum. Cows excreted 248+/-18 g more EAA in the milk at 4 DIM than was released from splanchnic tissues. The EAA deficiency decreased as lactation progressed and was not affected by HMBi supplementation. It was estimated that 4,700+/-600 g of EAA from extra-splanchnic tissues were secreted in milk protein during the first 29 DIM. Extra-splanchnic EAA mobilization can be crucial to sustain milk protein yield in the postpartum transition period and HMBi is a fast working Met source that can improve Met status of postpartum transition cows. PMID- 21787929 TI - Contribution of exopeptidases to formation of nonprotein nitrogen during ensiling of alfalfa. AB - The experiment was conducted to investigate the exopeptidase classes in alfalfa (Medicago sativa L.) leaves, and to determine their contribution to the formation of nonprotein nitrogen (NPN) components during ensiling. Six classes of inhibitors that included bestatin (aminopeptidase inhibitor), potato carboxypeptidase inhibitor (PCI, carboxypeptidase inhibitor), 1,10-phenanthroline (dipeptidase inhibitor), diprotin A (dipeptidyl-peptidase inhibitor), butabindide (tripeptidyl-peptidase inhibitor), and dipeptide Phe-Arg (peptidyl-dipeptidase inhibitor) were used. To determine the contribution of each exopeptidase to the formation of NPN products, aqueous extracts of fresh alfalfa were fermented to imitate the proteolytic process of ensiled alfalfa and to ensure that each class of exopeptidase inhibitor would have immediate contact with the proteases in the alfalfa extract. Five classes of exopeptidases; namely, aminopeptidase, carboxypeptidase, dipeptidase, dipeptidyl-peptidase, and tripeptidyl-peptidase, were shown to be present in alfalfa leaves, each playing a different role in alfalfa protein degradation. Aminopeptidase, carboxypeptidase, and dipeptidase were the main exopeptidases contributing to the formation of NH(3)-N. Among the 5 exopeptidases, tripeptidyl-peptidase appeared to be the principal exopeptidase in hydrolyzing forage protein into peptides, whereas carboxypeptidase and dipeptidase appeared to be more important in contributing to the formation of amino acid-N. Dipeptidyl-peptidase and tripeptidyl-peptidase did not play a role in the formation of NH(3)-N or amino acid-N. Dipeptidase, carboxypeptidase, and tripeptidyl-peptidase were the principal exopeptidases for hydrolyzing forage protein into NPN during ensilage, and treatment with a mixture of the 5 inhibitors reduced the total NPN concentration in the fermented alfalfa extract to about 45% of that in the control after 21 d of fermentation. PMID- 21787930 TI - Fatty acid intake alters growth and immunity in milk-fed calves. AB - The aim of the present study was to determine the effect of supplementing milk replacer (MR) with NeoTec4 (Provimi North America, Brookville, OH), a commercially available blend of butyric acid, coconut oil, and flax oil, on calf growth, efficiency, and indices of immune function. In trial 1a, 48 male Holstein calves were fed either a control MR that contained only animal fat or the same MR with NeoTec4 (treatment) along with free-choice starter. The MR (28.7% crude protein, 15.6% fat) was fed at an average of 1 kg of dry matter (DM)/d. In trial 1b, weaned calves from trial 1a were all fed dry starter for 28 d without NeoTec4 (phase 1), and then half the calves were fed NeoTec4 for 28 d (phase 2). In trial 2, 40 male Holstein calves were fed a control MR with lard, coconut oil, and soy lecithin or the same MR supplemented with NeoTec4 (treatment). The MR (22.8% crude protein, 18.9% fat) was fed at an average of 1 kg of DM/d; no starter was fed. In trial 1a, NeoTec4 improved average daily gain, feed intake, and feed efficiency, reduced the number of days that calves experienced scours, and reduced the medical treatments for clostridium sickness. In trials 1a and 2, NeoTec4 altered the inflammatory response to vaccination with Pasteurella at 5 wk of age and to challenge with Salmonella toxin at less than 2 wk of age (fed NeoTec4 for 6 d), as observed by reduced hyperthermia and hypophagia, and altered the tumor necrosis factor-alpha response. In addition, NeoTec4 enhanced the response in IL-4 and globular protein estimates postchallenge and enhanced titers for bovine viral diarrhea and respiratory parainfluenza-3. Postchallenge serum concentrations of albumin were lower and urea nitrogen concentrations were greater in control calves than in calves fed NeoTec4. In trial 1b, performance did not differ during the first 28 d when no calves received NeoTec4, but calves receiving NeoTec4 in the second 28 d had greater average daily gain and feed efficiency. We conclude that supplementation of MR with NeoTec4 alters some immune and inflammatory responses, including increasing titers to bovine viral diarrhea and respiratory parainfluenza-3 vaccinations, reduces scours, reduces medical treatments for clostridium sickness, and improves growth rates and feed efficiency. PMID- 21787931 TI - Grazing management and supplementation effects on forage and dairy cow performance on cool-season pastures in the southeastern United States. AB - Cool-season annual forages provide high-quality herbage for up to 5 mo in the US Gulf Coast states, but their management in pasture-based dairy systems has received little attention. Objectives of this study were to evaluate pasture and animal responses when lactating Holstein cows (n=32, mean DIM=184+/-21) grazed either N-fertilized rye (Secale cereale L.)-annual ryegrass (Lolium multiflorum Lam.) mixed pastures or rye-annual ryegrass-crimson clover (Trifolium incarnatum L.)-red clover (Trifolium pratense L.) pastures at 2 stocking rates (5 vs. 2.5 cows/ha) and 2 rates of concentrate supplementation [0.29 or 0.40 kg of supplement (as is)/kg of daily milk production]. Two cows paired by parity (one multiparous and one primiparous) were assigned randomly to each pasture. The 2 * 2 * 2 factorial arrangement of treatments was replicated twice in a completely randomized design. Forage mixture and supplementation rate did not affect milk production during three 28-d periods. Greater milk production occurred at the low (19.7 kg/d) than the high (14.7 kg/d) stocking rate during periods 2 and 3, but production was similar during period 1. Despite lower production per cow, milk production per hectare was generally greater at the high stocking rate (81.6 vs. 49.5 kg/ha). Generally, greater pregraze herbage mass on pastures at the lower stocking rate (1,400 vs. 1,150 kg/ha) accounted for greater herbage allowance. Both forage (8.0 vs. 5.9 kg/d) and total (14.1 vs. 11.6) organic matter intake were greater at the low stocking rate. Cows fed less supplement had greater forage organic matter intake (8.0 vs. 6.1 kg/d). Greater herbage mass was associated with the greater intake and subsequent greater milk production. Differences in forage nutritive value, blood metabolites and milk composition, although showing some response to treatments, may not be of sufficient magnitude to affect choice of pasture species or other management practices. Animal performance was not improved by adding clovers to mixed cool-season grass pastures like those in this study. Stocking rate had a major effect on pasture and animal performance. During the cool season, supplementation with concentrates should be planned based on estimated energy intake from forages to achieve optimum milk production and ensure maintenance of body condition. PMID- 21787932 TI - Effects of the percentage of concentrate on rumen fermentation, nutrient digestibility, plasma metabolites, and milk composition in mid-lactation goats. AB - The aim of this work was to study the effects of the dietary percentage of concentrate on patterns of intake, the evolution of rumen fermentation characteristics and plasma metabolites after a meal, nutrient digestibility, and milk production and composition in a medium-term trial in dairy goats. These effects have been well studied in dairy cattle but seldom in goats. Thirteen ruminally and duodenally cannulated dairy goats (95+/-4 d in milk) fed ad libitum were used in this study. Goats were assigned to 1 of 2 dietary treatments: high concentrate (70% concentrate on dry matter basis) or a low-concentrate (35%) total mixed rations. The experiment was conducted over a period of 10 wk, including 3 wk of adaption to the diets. Patterns of intake, rumen fermentation characteristics, and plasma metabolites after a meal and fatty acids profile of milk fat were compared at the onset and at the end of the experiment. The increase in dietary percentage of concentrate decreased rumen pH, acetate to propionate ratio, ammonia-N concentration, and plasma urea concentration. The percentage of concentrate did not affect total volatile fatty acid concentrations. The high-concentrate diet increased the rate of intake during the morning meal at the onset of the experiment, whereas it decreased total dry matter intake and the rate of intake during the morning meal at the end of the experiment. The high-concentrate diet resulted in greater organic matter digestibility. Raw milk yield and protein yield were greater in goats fed the high-concentrate diet, whereas fat yield was not affected by dietary treatments. The milk fat content was lower in goats fed the high-concentrate diet. Proportions of the trans-C18:1 isomer relative to total fatty acids in milk were higher with the high-concentrate diet, but no modification of the proportion of total trans-C18:1 was detected, in particular no shift from trans-11 C18:1 to trans-10 C18:1 was observed. Further, the isomer trans-10,cis-12 C18:2 was not detected. Data from this study could be used for a new modeling approach or to improve existing models. PMID- 21787933 TI - Effect of applying bacterial inoculants containing different types of bacteria to corn silage on the performance of dairy cattle. AB - This study examined the effect of applying different bacterial inoculants to corn silage at the time of ensiling on the performance of lactating dairy cows. Corn plants were harvested at 35% dry matter (DM), chopped, and ensiled in 2.4-m-wide bags after application of (1) no inoculant (CON); (2) Biotal Plus II (B2) containing Pediococcus pentosaceus and Propionibacteria freudenreichii; (3) Buchneri 40788 (BUC) containing Lactobacillus buchneri; or (4) Buchneri 500 (B500) containing Pediococcus pentosaceus and L. buchneri. All inoculants were supplied by Lallemand Animal Nutrition (Milwaukee, WI). Each of the 4 silages was included in separate total mixed rations consisting of 44% corn silage, 50% concentrate, and 6% alfalfa hay (DM basis). Fifty-two lactating Holstein cows were stratified according to milk production and parity and randomly assigned at 22 d in milk to the 4 dietary treatments. Cows were fed for ad libitum consumption and milked twice daily for 49 d. Dietary treatment did not affect intakes (kg/d) of DM (20.0), crude protein (CP; 3.7), neutral detergent fiber (NDF; 5.7), or acid detergent fiber (ADF; 3.6), or digestibility (%) of DM (73.9) or CP (72.4). However, NDF digestibility was lower in cows fed B2 compared with those fed other diets (45.3 vs. 53.0%). Consequently, cows fed B2 had lower digestible NDF intake (kg/d) than those fed other diets (2.5 vs. 3.0 kg/d). Dietary treatment did not affect milk yield (32.3 kg/d), efficiency of milk production (1.61), concentrations of milk fat (3.18%) and protein (2.79%), or yields of milk fat (1.03 kg/d) and protein (1.26 kg/d). Inoculant application to corn silage did not affect milk yield or feed intake of cows. PMID- 21787934 TI - Effects of ruminal ammonia and butyrate concentrations on reticuloruminal epithelial blood flow and volatile fatty acid absorption kinetics under washed reticulorumen conditions in lactating dairy cows. AB - The effect of reticuloruminal epithelial blood flow on the absorption of propionate as a volatile fatty acid (VFA) marker in 8 lactating Holstein cows was studied under washed rumen conditions. The cows were surgically prepared with ruminal cannulas and permanent catheters in an artery and mesenteric, right ruminal, and hepatic portal veins. The experiment was designed with 2 groups of cows: 4 cows adapted to high crude protein (CP) and 4 to low CP. All cows were subjected to 3 buffers: butyric, ammonia, and control in a randomized replicated 3 * 3 incomplete Latin square design. The buffers (30 kg) were maintained in a temporarily emptied and washed rumen for 40 min. The initial concentration of VFA was 84.2 mmol/L. Butyrate was increased from 4 to 36 mmol/L in butyric buffer by replacement of acetate, and ammonia (NH(3)) was increased from 2.5 to 22.5 mmol/L in ammonia buffer by replacement of NaCl. Increasing amounts of deuterium oxide (D(2)O) were added to the buffers as the order of buffer sequence increased (6, 12, and 18 g of D(2)O). Ruminal clearance of D(2)O was used to estimate epithelial blood flow. To increase accuracy of the epithelial blood flow estimates, data of ruminal liquid marker (Cr-EDTA), and initial and final buffer volumes were fitted to a dynamic simulation model. The model was used to estimate ruminal liquid passages, residual liquid, and water influx (saliva and epithelia water) for each combination of cow and buffer (n=24). Epithelial blood flow increased 49+/-11% for butyric buffer compared with control. The ruminal disappearance of propionate (marker VFA) was affected by buffer and followed the same pattern as for epithelial blood flow. The correlation between ruminal disappearance of propionate and epithelial blood flow (r=0.56) indicates that the removal of propionate can be limited by epithelial blood flow. The ruminal disappearance of propionate increased 30+/-12% for the butyric compared with ammonia buffer and 12.5+/-8% when compared with control. The net portal flux of propionate increased 32+/-6% in butyric compared with control. In conclusion, rumen epithelial blood flow is positively correlated with ruminal disappearance of propionate and affects the kinetics of ruminal VFA absorption. PMID- 21787935 TI - Dietary molasses increases ruminal pH and enhances ruminal biohydrogenation during milk fat depression. AB - Feeding high-concentrate diets has the potential to cause milk fat depression, but several studies have suggested that dietary sugar can increase milk fat yield. Two experiments were conducted to evaluate the ability of dietary molasses to prevent milk fat depression in the presence of a 65% concentrate diet. In trial 1, molasses replaced corn grain at 0, 2.5, or 5% of diet dry matter in diets fed to 12 second-lactation Holstein cows (134+/-37 d in milk) in a 3*3 Latin square design. Trial 1 demonstrated that replacing up to 5% of dietary dry matter from corn with molasses had positive effects on de novo fatty acid synthesis, increasing the yield of short- and medium-chain fatty acids during diet-induced milk fat depression. Increasing inclusion rate of molasses increased milk fat concentration, but decreased milk yield and milk protein yield. Trial 2 used 7 ruminally cannulated, multiparous, late-lactation Holstein cows (220+/-18 d in milk) to evaluate effects of dietary molasses on ruminal parameters and milk composition, and also to assess whether increased metabolizable protein supply would alter these responses. Cows were randomly assigned to a dietary treatment sequence in a crossover split plot design with 0 and 5% molasses diets. Dietary treatments were fed for 28 d, with 16 d for diet adaptation, and the final 12 d for 2 abomasal infusion periods in a crossover arrangement. Abomasal infusions of water or AA (5 g of l-Met/d+15 g of l-Lys-HCl/d+5 g of l-His-HCl-H(2)O/d) were administered 3 times daily for 5 d, with 2 d between infusion periods. Administration of AA had no effect on concentration or yield of any milk components. Addition of molasses increased milk fat concentration (2.71 vs. 2.94+/-0.21%), but had no effect on yields of milk fat or protein. Dietary molasses decreased total volatile fatty acid concentration (141 vs. 133+/-4.6mM), decreased the molar proportion of propionate, and increased the molar proportion of butyrate in ruminal fluid. Molasses also increased ruminal pH (5.73 vs. 5.87+/ 0.06), decreased the yield of trans-10 C18:1, and increased the yield of trans-11 C18:1 in milk fat. These data provide evidence that molasses may promote mammary de novo fatty acid synthesis in cows fed high-energy rations by moderating ruminal pH and altering ruminal fatty acid biohydrogenation pathways. PMID- 21787936 TI - Effectiveness of extruded rapeseed associated with an alfalfa protein concentrate in enhancing the bovine milk fatty acid composition. AB - Linseed and rapeseed, good sources of 18:3 n-3 and cis9-18:1, respectively, have been shown to improve the bovine milk fatty acid (FA) profile. However, rapeseed, unlike linseed, has little effect on the concentration of 18:3 n-3 in milk fat. Alfalfa protein concentrate (APC), besides being a valuable protein source for milk production, contains lipids rich in 18:3 n-3. Therefore, this experiment aimed at (1) evaluating the transfer efficiency of unsaturated FA (UFA), especially 18:3 n-3, of APC to bovine milk fat, and (2) evaluating whether extruded rapeseed (ER) associated with APC is as effective as extruded linseed (EL) in enhancing the bovine milk fat composition. Six lactating Holstein cows were used in a replicated 2 * 2 Latin square design with 2 iso-energy, iso nitrogen and iso-FA corn silage-based diets (EL and ER-APC) and two 21-d periods. Extruded linseed, as main UFA source, was included in the first diet, whereas ER, as main UFA source, and APC, as supplemental 18:3 n-3, were included in the second diet. Diets were distributed as a restricted total mixed ration. Compared with the EL diet, the ER-APC diet, where ER was associated with APC, increased milk concentration of 18:3 n-3 (1.18 vs. 1.31% of FA) and cis9-18:1 (18.35 vs. 20.01% of FA). The apparent transfer efficiency of 18:3 n-3 from diet to milk was almost twice as much for the ER-APC diet than for the EL diet (7.4 vs. 3.8% of intake). Extruded linseed accounted for 84% of 18:3 n-3 provided in the EL diet, whereas ER and APC accounted for 33 and 38% of 18:3 n-3 provided in the ER-APC diet, respectively. Because both EL and ER underwent extrusion in similar conditions, these results suggest that 18:3 n-3 of EL in the EL diet and ER in the ER-APC diet were subjected to more extensive ruminal biohydrogenation than 18:3 n-3 of APC in the ER-APC diet. This experiment shows that corn silage-based diets supplemented with ER as the main UFA source, associated with APC as supplemental 18:3 n-3, are as effective as corn silage-based diets supplemented with EL as the main UFA source, in increasing bovine milk UFA and 18:3 n-3 contents. Furthermore, at similar levels of dietary incorporation, this experiment shows that the ruminal bypass of 18:3 n-3 is higher for APC compared with EL. PMID- 21787937 TI - Effect of rumen-protected choline on performance, blood metabolites, and hepatic triacylglycerols of periparturient dairy cattle. AB - The effects of a dietary supplement of rumen-protected choline on feed intake, milk yield, milk composition, blood metabolites, and hepatic triacylglycerol were evaluated in periparturient dairy cows. Thirty-eight multiparous cows were blocked into 19 pairs and then randomly allocated to either one of 2 treatments. The treatments were supplementation either with or without (control) rumen protected choline. Treatments were applied from 3 wk before until 6 wk after calving. Both groups received the same basal diet, being a mixed feed of grass silage, corn silage, straw, and soybean meal, and a concentrate mixture delivered through transponder-controlled feed dispensers. For all cows, the concentrate mixture was gradually increased from 0 kg/day (wk -3) to 0.9 kg of dry matter (DM)/d (day of calving) and up to 8.1 kg of DM/d on d 17 postcalving until the end of the experiment. Additionally, a mixture of 60 g of a rumen-protected choline supplement (providing 14.4 g of choline) and of 540 g of soybean meal or a (isoenergetic) mixture of 18 g of palm oil and 582 g of soybean meal (control) was offered individually in feed dispensers. Individual feed intake, milk yield, and body weight were recorded daily. Milk samples were analyzed weekly for fat, protein, and lactose content. Blood was sampled at wk -3, d 1, d 4, d 7, d 10, wk 2, wk 3, and wk 6 and analyzed for glucose, nonesterified fatty acids, and beta hydroxybutyric acid. Liver biopsies were taken from 8 randomly selected pairs of cows at wk -3, wk 1, wk 4, and wk 6 and analyzed for triacylglycerol concentration. We found that choline supplementation increased DM intake from 14.4 to 16.0 kg/d and, hence, net energy intake from 98.2 to 109.1 MJ/d at the intercept of the lactation curve at 1 day in milk (DIM), but the effect of choline on milk protein yield gradually decreased during the course of the study. Choline supplementation had no effect on milk yield, milk fat yield, or lactose yield. Milk protein yield was increased from 1.13 to 1.26 kg/d at the intercept of the lactation curve at 1 DIM, but the effect of choline on milk protein yield gradually decreased during the course of the study. Choline supplementation was associated with decreased milk fat concentration at the intercept of the lactation curve at 1 DIM, but the effect of choline on milk fat concentration gradually decreased as lactation progressed. Choline supplementation had no effect on energy-corrected milk yield, energy balance, body weight, body condition score, and measured blood parameters. Choline supplementation decreased the concentration of liver triacylglycerol during the first 4 wk after parturition. Results from this study suggest that hepatic fat export in periparturient dairy cows is improved by choline supplementation during the transition period and this may potentially decrease the risk for metabolic disorders in the periparturient dairy cow. PMID- 21787938 TI - Persistency of methane mitigation by dietary nitrate supplementation in dairy cows. AB - Feeding nitrate to dairy cows may lower ruminal methane production by competing for reducing equivalents with methanogenesis. Twenty lactating Holstein-Friesian dairy cows (33.2+/-6.0 kg of milk/d; 104+/-58 d in milk at the start of the experiment) were fed a total mixed ration (corn silage-based; forage to concentrate ratio 66:34), containing either a dietary urea or a dietary nitrate source [21 g of nitrate/kg of dry matter (DM)] during 4 successive 24-d periods, to assess the methane-mitigating potential of dietary nitrate and its persistency. The study was conducted as paired comparisons in a randomized design with repeated measurements. Cows were blocked by parity, lactation stage, and milk production at the start of the experiment. A 4-wk adaptation period allowed the rumen microbes to adapt to dietary urea and nitrate. Diets were isoenergetic and isonitrogenous. Methane production, energy balance, and diet digestibility were measured in open-circuit indirect calorimetry chambers. Cows were limit-fed during measurements. Nitrate persistently decreased methane production by 16%, whether expressed in grams per day, grams per kilogram of dry matter intake (DMI), or as percentage of gross energy intake, which was sustained for the full experimental period (mean 368 vs. 310+/-12.5 g/d; 19.4 vs. 16.2+/-0.47 g/kg of DMI; 5.9 vs.4.9+/-0.15% of gross energy intake for urea vs. nitrate, respectively). This decrease was smaller than the stoichiometrical methane mitigation potential of nitrate (full potential=28% methane reduction). The decreased energy loss from methane resulted in an improved conversion of dietary energy intake into metabolizable energy (57.3 vs. 58.6+/-0.70%, urea vs. nitrate, respectively). Despite this, milk energy output or energy retention was not affected by dietary nitrate. Nitrate did not affect milk yield or apparent digestibility of crude fat, neutral detergent fiber, and starch. Milk protein content (3.21 vs. 3.05+/-0.058%, urea vs. nitrate respectively) but not protein yield was lower for dietary nitrate. Hydrogen production between morning and afternoon milking was measured during the last experimental period. Cows fed nitrate emitted more hydrogen. Cows fed nitrate displayed higher blood methemoglobin levels (0.5 vs. 4.0+/-1.07% of hemoglobin, urea vs. nitrate respectively) and lower hemoglobin levels (7.1 vs. 6.3+/-0.11 mmol/L, urea vs. nitrate respectively). Dietary nitrate persistently decreased methane production from lactating dairy cows fed restricted amounts of feed, but the reduction in energy losses did not improve milk production or energy balance. PMID- 21787939 TI - Effect of parity and stage of lactation on feed sorting behavior of lactating dairy cows. AB - The objectives of this study were to determine if feed sorting differs between primiparous (PP) and multiparous (MP) cows, if sorting changes from the period of peak lactation to peak dry matter intake (DMI), and whether feed sorting affects efficiency of production. Data on DMI, milk production, feed sorting (particle size of offered and refused feed), and energy status (plasma nonesterified fatty acid, beta-hydroxybutyrate, insulin and glucose concentration) were collected on 30 PP and 30 MP lactating Holstein dairy cows, individually housed and fed in tie stalls, during 3 wk (wk 2, 6, and 10) over 10 wk of a lactation study. Cows averaged 53, 81, and 109+/-10 d in milk (DIM) at the beginning of each of the 3 recording weeks. To determine sorting, feed samples were separated with a particle separator that had 3 screens (19, 8, and 1.18 mm) and a bottom pan, resulting in 4 fractions (long, medium, short, fine). Over the study period, MP cows consumed more DM and produced more milk than did the PP cows, but had similar efficiency of production (kg of milk/kg of DMI), and similar levels of plasma indicators of energy status. Across the study period, DMI increased, whereas milk yield decreased, resulting in decreased efficiency of milk production as cows moved further into lactation. All cows had higher nonesterified fatty acid and lower insulin concentrations in plasma at 53 DIM compared with at 81 and 109 DIM, suggesting they were mobilizing more body fat at that earlier stage of lactation. Across periods, all cows sorted against the longest ration particles, did not sort the medium ration particles, and sorted for fine ration particles; as a result, all cows consumed less neutral detergent fiber (NDF) and physically effective NDF (proportion of NDF retained on the 19- and 8-mm screens of the particle separator) than predicted. Greater selection against the longest ration particles was associated with greater efficiency of milk production; however, this sorting pattern also tended to be associated with lower milk fat percentage. The extent of the observed sorting against the longest, physically effective ration particles and for the finest ration particles was greater for PP cows than for MP cows across all 3 observation periods. Feed sorting remained consistent in cows across the DIM evaluated in this study and that this sorting behavior can affect the efficiency of milk production as well as milk fat percentage. Further, PP cows engage in more sorting of their ration than MP cows. PMID- 21787940 TI - Effects of supplementation with yeast culture and enzymatically hydrolyzed yeast on performance of early lactation dairy cattle. AB - One hundred fifty multiparous cows were balanced to 1 of 3 treatments (2 pens/trt) according to previous lactation 305-d mature equivalent yield to evaluate supplementation with yeast culture (YC; A-Max, Vi-COR, Mason, IA) and YC plus enzymatically hydrolyzed yeast (YC+EHY; Celmanax, Vi-COR) on production performance in dairy cattle. Cows entered pens at calving and remained through 14 wk postpartum. Treatment assignment to pens was random throughout the barn. Pens were identical in layout and each contained an exit alley to eliminate feed and animal mixing. The 3 treatments were control: nonsupplemented; YC: control diet with YC (56 g/d); and YC+EHY: control diet plus YC and EHY (28 g/d). Mean pen dry matter intake was similar across treatments. Cows supplemented with YC and YC+EHY produced more milk, fat-corrected milk, and energy-corrected milk than control cows (1.4 and 1.6, 1.6 and 1.8, 1.7 and 1.9 kg, respectively). Treatments YC and YC+EHY did not differ. Milk fat and lactose percentages were not affected by treatment. Milk protein percentage was higher for cows supplemented with YC+EHY than for those on YC and control treatments (2.98, 2.93, and 2.91%, respectively) with control and YC-supplemented cows not being different from each other. Differences in fat and protein yields were primarily reflective of milk yield. Treatment had no effect on milk urea nitrogen. No differences in the incidence of metabolic health were observed; however, cases of clinical mastitis for YC+EHY were less than half those for control and YC during wk 8 to 14 on trial. Somatic cell count was higher for cows fed control and YC diets compared with YC+EHY, primarily during wk 8 to 14 on trial. Supplementation of early lactation cows with YC improved milk production performance; furthermore, EHY supplementation improved milk protein percentage and mammary gland health. PMID- 21787941 TI - Effect of replacing solvent-extracted canola meal with high-oil traditional canola, high-oleic acid canola, or high-erucic acid rapeseed meals on rumen fermentation, digestibility, milk production, and milk fatty acid composition in lactating dairy cows. AB - The objective of this experiment was to investigate the effects of replacing conventional, solvent-extracted canola meal (control; CTRL) with high oil content; conventional, mechanically extracted canola meal (CMEC); high-oleic, low polyunsaturated fatty acid (FA) canola meal (HOLL); and high-erucic acid, low glucosinolate rapeseed meal (RPS) on rumen function, digestibility, milk production, and milk FA composition in lactating dairy cows. The experimental design was a replicated 4*4 Latin square with 8 lactating dairy cows. Four of the cows were ruminally cannulated. All oilseed meals were included at approximately 12 to 13% of dietary dry matter (DM). Crude protein and fat concentrations (% of DM) of the meals were 43 and 3.1%, 32.8 and 16.1%, 45.2 and 13.7%, and 34.3 and 17.9% for CTRL, CMEC, HOLL, and RPS, respectively. All diets were formulated to supply net energy of lactation in excess of requirements. The CMEC and RPS diets were predicted to be about 1% deficient in metabolizable protein. Relative to the CTRL, inclusion of high-oil seed meals in the diet lowered ruminal acetate concentration and the molar acetate:propionate ratio and decreased DM intake. Milk yield generally followed DM intake and was lower for CMEC and RPS than the CTRL. Treatments had no effect on milk composition, other than an increase in milk urea nitrogen concentration for HOLL. Fat-corrected milk (3.5%) feed efficiency was increased by HOLL and RPS compared with CTRL. Urinary urea nitrogen losses were increased by HOLL, which, as a consequence, increased the ammonia-emitting potential of manure. The ratio of milk N-to-N intake was greater for CMEC and RPS. Replacing solvent-extracted canola meal with the high-oil meal decreased milk fat 12:0, 14:0, 16:0, and total saturated FA content and enhanced cis-9 18:1 and total monounsaturated FA concentrations. Relative to the CTRL, canola increased total trans FA in milk, whereas inclusion of HOLL in the diet increased trans-11 18:1 and cis-9, trans-11 CLA content. The RPS increased milk fat cis-13 22:1 content from 0.07 to 2.33 g/100g of FA. In conclusion, HOLL or RPS, which are likely to come from small-scale biodiesel plants where oil is cold pressed without hexane extraction, fed at levels at or above 12 to 13% of dietary DM may decrease feed intake and milk production, but can be used to alter milk FA composition in lactating dairy cows. PMID- 21787942 TI - Short communication: effects of supplementation with pomegranate seed pulp on concentrations of conjugated linoleic acid and punicic acid in goat milk. AB - The effects of feeding pomegranate seed pulp (PSP) on milk yield, milk composition, fatty acid profiles of milk fat, and blood metabolites were examined in this study. During a pretrial period, 27 multiparous southern Khorasan (Iran) cross-bred goats were fed a similar diet and dry matter intake, milk yield, and milk composition were recorded. After adaptation and based on pretrial records, the goats were randomly assigned to 1 of 3 experimental diets and were housed in individual stalls. Experimental diets included 0, 6, or 12% of PSP (dry matter basis) and were fed as total mixed rations ad libitum for a 45-d period. Diets were formulated to be isonitrogenous and isocaloric. Supplementation of PSP did not affect dry matter intake or average daily gain of goats. Milk yield was not affected by inclusion of PSP in the diet. Milk fat concentration of goats fed diets with 6 and 12% PSP increased, but milk fat yield, milk protein concentration, and milk solids-not-fat concentration of goats were not affected by diets. Feeding PSP did not affect blood glucose, cholesterol, urea N, triglyceride, or lipoproteins. Feeding goats a diet containing 12% PSP modified the milk fatty acid profile, including conjugated linoleic, punicic, and vaccenic acids. PMID- 21787943 TI - Bimodality and the genetics of milk flow traits in the Italian Holstein-Friesian breed. AB - The overall goal of this study was to investigate milk flow traits in Italian Holstein-Friesian cows and, in particular, the bimodality of milk flow, defined as delayed milk ejection at the start of milking. Using a milkometer, 2,886 records were collected from 133 herds in northern Italy from 2001 to 2007. All records included 5 time-period measurements for milk flow, somatic cell score (SCS), milk yield, 8 udder type traits, and the presence or absence of bimodality in milk flow. Genetic parameters were estimated using linear animal models for continuous traits such as milk flow, udder type, SCS, and milk production, whereas bimodality was analyzed as a categorical trait. With the exception of decreasing time (which had a very small heritability value of 0.06), heritability values for milk flow traits were moderate, ranging from 0.10 (ascending time) to 0.41 (maximum milk flow). In addition, moderate to high genetic correlations were estimated between total milking time and other time measures (from 0.78 to 0.87), and among time flow traits (from 0.62 to 0.91). The decreasing time was the trait most genetically correlated with udder type traits, with correlation values of 0.92 with rear udder height, 0.85 with rear udder width, and 0.73 with teat placement. Large udders with strong attachments were also associated with greater milk production. Heritability estimated for bimodality was 0.43, and its genetic correlation with milk flow traits and SCS indicated a sizable genetic component underlying this trait. Bimodality was negatively associated with milk production; shorter milking times and greater peak milk levels were genetically correlated with more frequent bimodal flows, indicating that faster milk release would result in an increase in bimodal patterns. The negative genetic correlation of bimodality with SCS (-0.30) and the genetic correlation between milk flow traits and SCS suggest that the relationship between milkability and SCS is probably nonlinear and that intermediate flow rates are optimal with respect to mastitis susceptibility. Quicker milk flow over a shorter period would increase the frequency of bimodal curves in milking, whereas the correlation between bimodality and both ascending and descending time was less clear. PMID- 21787944 TI - Effect of type traits on functional longevity of Czech Holstein cows estimated from a Cox proportional hazards model. AB - Relationships between conformation traits and functional longevity in Holstein cows were evaluated using survival analysis. Functional longevity was defined as the number of days between the first calving and culling; that is, length of productive life. The data set consisted of 116,369 Holstein cows that first calved from 2003 to 2008. All cows used in the analysis were scored for conformation between d 30 and d 210 of their first lactation. The data included 48% censored records. Analyses were done separately for 20 linear descriptive type traits, 6 composite traits, and height at sacrum measured in centimeters. Cox proportional hazard models were fitted to analyze data. The hazard function was described as the product of a baseline hazard function and the time independent effects of age at first calving and sire (random), and the time dependent effects of stage of lactation and lactation number, herd, year and season, herd size, and 305-d milk production. The strongest relationship between a composite trait and functional longevity was for dairy form, followed by udder and final score. Among the descriptive type traits, the strongest relationships with longevity were found for body condition score, angularity, traits related to udder attachment, and udder depth. Foot and leg traits showed substantially lower effect on functional longevity, and the effect of foot angle was minimal. Functional longevity declined with decreased body condition score of cows. Cows with deep udders had significantly lower functional survival compared with cows with shallow udders. In addition, weak central ligament was associated with significant reduction of cow longevity. For dairy form and angularity, cows classified as very good were the worst with respect to longevity, whereas cows classified as poor were the best. An intermediate optimum was evident for rear legs rear view and rear legs set (side view), whereas cows with sickled legs had lower longevity than cows with straighter legs. PMID- 21787945 TI - Ex situ conservation of Holstein-Friesian cattle: comparing the Dutch, French, and US germplasm collections. AB - Holstein-Friesian (HF) gene bank collections were established in France, the Netherlands, and the United States to conserve genetic diversity for this breed. Genetic diversity of HF collections within and between countries was assessed and compared with active male HF populations in each country by using pedigree data. Measures of genetic diversity such as probability of gene origin inbreeding and kinship were calculated. The cryobanks have captured substantial amounts of genetic diversity for the HF compared with the current populations. A substantial part of the US, French, and Dutch collections seems to be genetically similar. On the other hand, the US collection in particular represents an interesting reservoir of HF genes of the past. Gene banks can play an important role in conserving genetic diversity within livestock breeds over time, and may support industry in the future when needed. PMID- 21787946 TI - Use of female information in dairy cattle genomic breeding programs. AB - Genomic selection has the potential to increase the accuracy of selection and, therefore, genetic gain, as well as reducing the rate of inbreeding, yet few studies have evaluated the potential benefit of the contribution of females in genomic selection programs. The objective of this study was to determine the effect on genetic gain, accuracy of selection, generation interval, and inbreeding, of including female genotypes in a genomic selection breeding program. A population of approximately 3,500 females and 500 males born annually was simulated and split into an elite and commercial tier representation of the Irish national herd. Several alternative breeding schemes were evaluated to quantify the potential benefit of female genomic information within dairy breeding schemes. Results showed that the inclusion of female phenotypic and genomic information can lead to a 3-fold increase in the rate of genetic gain compared with a traditional BLUP breeding program and decrease the generation interval of the males by 3.8 yr, while maintaining a reasonable rate of inbreeding. The accuracy of the selected males was increased by 73% in the final 3 yr of the genomic schemes compared with the traditional BLUP scheme. The results of this study have several implications for national breeding schemes. Although an investment in genotyping a large population of animals is required, these costs can be offset by the greater genetic gain achievable through the increased accuracy of selection and decreased generation intervals associated with genomic selection. PMID- 21787947 TI - A genome scan for quantitative trait loci affecting body conformation traits in Spanish Churra dairy sheep. AB - A genome scan for chromosomal regions influencing body conformation traits was conducted for a population of Spanish Churra dairy sheep following a daughter design. A total of 739 ewes from 11 half-sib sire families were included in the study. The ewes were scored for the 5 linear traits used in the breeding scheme of the Churra breed to assess body conformation: stature, rear legs-rear view, foot angle, rump width, and general appearance. All the animals, including the 11 sires, were genotyped for 181 microsatellite markers evenly distributed across the 26 sheep autosomes. Using the yield deviations of the raw scores adjusted for fixed factors as phenotypic measurements, a quantitative trait loci (QTL) analysis was performed on the basis of a multi-marker regression method. Seven suggestive QTL were identified on chromosomes Ovis aries (OAR)2, OAR5, OAR16, OAR23, and OAR26, but none reached a genome-wise significance level. Putative QTL were identified for all of the traits analyzed, except for general appearance score. The suggestive QTL showing the highest test statistic influenced rear legs rear view and was localized on OAR16, close to the growth hormone receptor coding gene, GHR. Some of the putative linkage associations reported here are consistent with previously reported QTL in cattle for similar traits. To the best of our knowledge, this study provides the first report of QTL for body conformation traits in dairy sheep; further studies will be needed to confirm and redefine the linkage associations reported herein. It is expected that future genome-wide association analyses of larger families will help identify genes underlying these putative genetic effects and provide useful markers for marker-assisted selection of such functional traits. PMID- 21787948 TI - Genetic analyses of protein yield in dairy cows applying random regression models with time-dependent and temperature x humidity-dependent covariates. AB - Data used in the present study included 1,095,980 first-lactation test-day records for protein yield of 154,880 Holstein cows housed on 196 large-scale dairy farms in Germany. Data were recorded between 2002 and 2009 and merged with meteorological data from public weather stations. The maximum distance between each farm and its corresponding weather station was 50 km. Hourly temperature humidity indexes (THI) were calculated using the mean of hourly measurements of dry bulb temperature and relative humidity. On the phenotypic scale, an increase in THI was generally associated with a decrease in daily protein yield. For genetic analyses, a random regression model was applied using time-dependent (d in milk, DIM) and THI-dependent covariates. Additive genetic and permanent environmental effects were fitted with this random regression model and Legendre polynomials of order 3 for DIM and THI. In addition, the fixed curve was modeled with Legendre polynomials of order 3. Heterogeneous residuals were fitted by dividing DIM into 5 classes, and by dividing THI into 4 classes, resulting in 20 different classes. Additive genetic variances for daily protein yield decreased with increasing degrees of heat stress and were lowest at the beginning of lactation and at extreme THI. Due to higher additive genetic variances, slightly higher permanent environment variances, and similar residual variances, heritabilities were highest for low THI in combination with DIM at the end of lactation. Genetic correlations among individual values for THI were generally >0.90. These trends from the complex random regression model were verified by applying relatively simple bivariate animal models for protein yield measured in 2 THI environments; that is, defining a THI value of 60 as a threshold. These high correlations indicate the absence of any substantial genotype * environment interaction for protein yield. However, heritabilities and additive genetic variances from the random regression model tended to be slightly higher in the THI range corresponding to cows' comfort zone. Selecting such superior environments for progeny testing can contribute to an accurate genetic differentiation among selection candidates. PMID- 21787949 TI - Optimal strategies for the use of genomic selection in dairy cattle breeding programs. AB - The objective of the present study was to conduct a stochastic simulation study on the possible benefits of an application of genomic selection in dairy cattle breeding programs according to a variety of selection schemes. In addition, the heritability of the trait in question, the accuracy of genomic breeding values, and the number of animals to be genotyped were varied. Specifically, the question of genotyping males, females, or both, was addressed. Selection schemes were compared with a young bull breeding program. The main criterion for comparison was the average of true breeding values of selected young males to be used as replacements for artificial insemination bulls. Stochastic simulations were run with 50 repetitions each to generate individuals with phenotypes, breeding values estimated by BLUP, and true breeding values. Genomic breeding values were generated from true breeding values with defined accuracy. Examined scenarios included a group of selection schemes that featured genotyping of parents of future bulls only. Such schemes can be viewed as improvements of young bull programs, and they were found to be competitive with or superior to a classical young bull program. However, a genomic breeding program usually involves at least genotyping young male candidates. A second group of selection schemes reflected this requirement. Scenarios in this group were found to be superior over the young bull program by 1.0 to 1.2 standard deviations of the average true breeding value of young male candidates. Within this group of scenarios, one scheme referred to an ideal situation under which genotypes for male calves were available without limitation. Using the average of true breeding values as the criterion for comparison, this idealistic scenario was competitive with other scenarios only if the reliability of genomic breeding values was larger than 0.50. Conventionally, not all males available will have genotypes, and the 2 most promising scenarios included a preselection step for dams of future bulls. This preselection step can be based on conventional BLUP estimated breeding values for bull dams, because differences with a scheme under which both parents and the resulting male offspring are genotyped were marginal. Genotyping of young male candidates should be the focus of activities of today's breeding organizations. PMID- 21787950 TI - Phenotypic and genetic variability of production traits and milk fatty acid contents across days in milk for Walloon Holstein first-parity cows. AB - The objective of this study was to assess the phenotypic and genetic variability of production traits and milk fatty acid (FA) contents throughout lactation. Genetic parameters for milk, fat, and protein yields, fat and protein contents, and 19 groups and individual FA contents in milk were estimated for first-parity Holstein cows in the Walloon Region of Belgium using single-trait, test-day animal models and random regressions. Data included 130,285 records from 26,166 cows in 531 herds. Heritabilities indicated that de novo synthesized FA were under stronger genetic control than FA originating from the diet and from body fat mobilization. Estimates for saturated short- and medium-chain individual FA ranged from 0.35 for C4:0 to 0.44 for C8:0, whereas those for monounsaturated long-chain individual FA were lower (around 0.18). Moreover, de novo synthesized FA were more heritable in mid to late lactation. Approximate daily genetic correlations among traits were calculated as correlations between daily breeding values for days in milk between 5 and 305. Averaged daily genetic correlations between milk yield and FA contents did not vary strongly among FA (around -0.35) but they varied strongly across days in milk, especially in early lactation. Results indicate that cows selected for high milk yield in early lactation would have lower de novo synthesized FA contents in milk but a slightly higher content of C18:1 cis-9, indicating that such cows might mobilize body fat reserves. Genetic correlations among FA emphasized the combination of FA according to their origin: contents in milk of de novo FA were highly correlated with each other (from 0.64 to 0.99). Results also showed that genetic correlations between C18:1 cis-9 and other FA varied strongly during the first 100 d in milk and reinforced the statement that the release of long-chain FA inhibits FA synthesis in the mammary gland while the cow is in negative energy balance. Finally, results showed that the FA profile in milk changed during the lactation phenotypically and genetically, emphasizing the relationship between the physiological status of cow and milk composition. PMID- 21787951 TI - Marker-assisted breeding value estimation for mastitis resistance in Finnish Ayrshire cattle. AB - Marker-assisted breeding value estimation is expected to increase the accuracy of estimated breeding values, especially for traits with low heritability. Several quantitative trait loci (QTL) have been found for somatic cell score and clinical mastitis. The objective of this study was to demonstrate marker-assisted breeding value estimation, combining data of genotyped and ungenotyped animals in a large pedigree population using either identical-by-descent (IBD) or identical-by-state (IBS) haplotypes for some previously identified QTL regions for somatic cell score and clinical mastitis in Finnish Ayrshire cattle. For both methods, QTL variances were estimated based on daughter yield deviations of genotyped bulls. The QTL explained only a small proportion of genetic variance, especially with IBS haplotypes. Using IBD haplotypes gave more reranking of bulls and cows than using IBS haplotypes. Cross-validation showed no increase in predictive ability when using IBS haplotypes compared with conventional breeding value estimation, whereas a decrease in predictive ability was observed with IBD haplotypes. Furthermore, computing time was lower and convergence was better with IBS haplotypes than with IBD haplotypes. In this study on mastitis resistance in Finnish Ayrshire, conventional breeding value estimation would be advocated because of the lack in improvement of accuracy and predictive ability when using marker-assisted breeding value estimation. However, in situations where IBS haplotypes would explain 10 to 20% or more of the genetic variance, marker assisted breeding value estimation with IBS haplotypes may yield greater accuracy and predictive ability than conventional breeding value estimation. PMID- 21787952 TI - Differential expression of heat shock protein genes and their splice variants in bovine preimplantation embryos. AB - Heat shock proteins (HSP) are among the first proteins produced during embryonic development and are crucial to cell function; their activities include folding, unfolding, transport, and localization of proteins and differentiation and regulation of the embryonic cell cycle. Although HSP have been extensively studied in humans and mice, limited information exists on the roles of these genes in bovine embryos. As such, the objectives of this study were to profile the expression of HSP and their splice variants in bovine embryos (degenerates vs. blastocysts) and to carry out association analysis with fertility traits. Quantitative real time PCR analysis revealed differences in expression that ranged from 1.5- to 7.6-fold in degenerate embryos compared with blastocysts. Interestingly, all members of the HSP40 family were found to be upregulated in degenerate embryos. Analysis of current bovine Ensembl data showed that 13 HSP genes have 1 transcript each, 2 genes have 2 transcripts each, and 2 have 3 transcripts each. Some splice variants show differential expression between degenerate embryos and blastocysts, whereas others were not expressed at all in embryos, which implies different functions of these transcripts in embryonic development. The most significant differentially expressed genes were further investigated for association with fertility and development traits. Single nucleotide polymorphisms in DNAJC15 and DNAJC27 were found to be associated with blastocyst rate and fertilization rate, respectively. Collectively, the roles of HSP in fertilization and early development of cattle embryos are important. PMID- 21787953 TI - Prediction of beta-lactoglobulin genotypes based on milk Fourier transform infrared spectra. AB - beta-Lactoglobulin (beta-LG) genotypes are associated with differences in bovine milk protein composition. Therefore, beta-LG genotypes are of direct relevance for the dairy industry. In this study, we predicted beta-lactoglobulin genotypes based on routinely recorded milk Fourier transform infrared spectra using 500 calibration samples. The results show that 76% of the cows carrying the beta-LG AA genotype, 80% of the cows carrying the beta-LG AB genotype, and 66% of the cows carrying the beta-LG BB genotype were predicted correctly. Furthermore, the prediction of beta-LG genotypes based on Fourier transform infrared spectra showed a repeatability of 0.85. We discuss how the combined use of predicted beta LG genotypes, pedigree information, and beta-LG genotypes derived using other methods could lead to further improvement in the percentage of correctly predicted beta-LG genotypes. The presented methodology is easy and inexpensive and could ultimately provide beta-LG genotypes at the individual cow level. PMID- 21787955 TI - Multiple-trait genomic evaluation of linear type traits using genomic and phenotypic data in US Holsteins. AB - Currently, the USDA uses a single-trait (ST) model with several intermediate steps to obtain genomic evaluations for US Holsteins. In this study, genomic evaluations for 18 linear type traits were obtained with a multiple-trait (MT) model using a unified single-step procedure. The phenotypic type data on up to 18 traits were available for 4,813,726 Holsteins, and single nucleotide polymorphism markers from the Illumina BovineSNP50 genotyping Beadchip (Illumina Inc., San Diego, CA) were available on 17,293 bulls. Genomic predictions were computed with several genomic relationship matrices (G) that assumed different allele frequencies: equal, base, current, and current scaled. Computations were carried out with ST and MT models. Procedures were compared by coefficients of determination (R(2)) and regression of 2004 prediction of bulls with no daughters in 2004 on daughter deviations of those bulls in 2009. Predictions for 2004 also included parent averages without the use of genomic information. The R(2) for parent averages ranged from 10 to 34% for ST models and from 12 to 35% for MT models. The average R(2) for all G were 34 and 37% for ST and MT models, respectively. All of the regression coefficients were <1.0, indicating that estimated breeding values in 2009 of 1,307 genotyped young bulls' parents tended to be biased. The average regression coefficients ranged from 0.74 to 0.79 and from 0.75 to 0.80 for ST and MT models, respectively. When the weight for the inverse of the numerator relationship matrix (A(-1)) for genotyped animals was reduced from 1 to 0.7, R(2) remained almost identical while the regression coefficients increased by 0.11-0.26 and 0.12-0.23 for ST and MT models, respectively. The ST models required about 5s per iteration, whereas MT models required 3 (6) min per iteration for the regular (genomic) model. The MT single step approach is feasible for 18 linear type traits in US Holstein cattle. Accuracy for genomic evaluation increases when switching ST models to MT models. Inflation of genomic evaluations for young bulls could be reduced by choosing a small weight for the A(-1) for genotyped bulls. PMID- 21787954 TI - Genomic and pedigree-based genetic parameters for scarcely recorded traits when some animals are genotyped. AB - Genetic parameters were estimated using relationships between animals that were based either on pedigree, 43,011 single nucleotide polymorphisms, or a combination of these, considering genotyped and non-genotyped animals. The standard error of the estimates and a parametric bootstrapping procedure was used to investigate sampling properties of the estimated variance components. The data set contained milk yield, dry matter intake and body weight for 517 first lactation heifers with genotypes and phenotypes, and another 112 heifers with phenotypes only. Multivariate models were fitted using the different relationships in ASReml software. Estimates of genetic variance were lower based on genomic relationships than using pedigree relationships. Genetic variances from genomic and pedigree relationships were, however, not directly comparable because they apply to different base populations. Standard errors indicated that using the genomic relationships gave more accurate estimates of heritability but equally accurate estimates of genetic correlation. However, the estimates of standard errors were affected by the differences in scale between the 2 relationship matrices, causing differences in values of the genetic parameters. The bootstrapping results (with genetic parameters at the same level), confirmed that both heritability and genetic correlations were estimated more accurately with genomic relationships in comparison with using the pedigree relationships. Animals without genotype were included in the analysis by merging genomic and pedigree relationships. This allowed all phenotypes to be used, including those from non-genotyped animals. This combination of genomic and pedigree relationships gave the most accurate estimates of genetic variance. When a small data set is available it might be more advantageous for the estimation of genetic parameters to genotype existing animals, rather than collecting more phenotypes. PMID- 21787956 TI - Genetic parameters of coagulation properties, milk yield, quality, and acidity estimated using coagulating and noncoagulating milk information in Brown Swiss and Holstein-Friesian cows. AB - The aim of this study was to estimate heritabilities of rennet coagulation time (RCT) and curd firmness (a(30)) and their genetic correlations with test-day milk yield, composition (fat, protein, and casein content), somatic cell score, and acidity (pH and titratable acidity) using coagulating and noncoagulating (NC) milk information. Data were from 1,025 Holstein-Friesian (HF) and 1,234 Brown Swiss (BS) cows, which were progeny of 54 HF and 58 BS artificial insemination sires, respectively. Milk coagulation properties (MCP) of each cow were measured once using a computerized renneting meter and samples not exhibiting coagulation within 31 min after rennet addition were classified as NC milk. For NC samples, RCT was unobserved. Multivariate analyses, using Bayesian methodology, were performed to estimate the genetic relationships of RCT or a(30) with the other traits and statistical inference was based on the marginal posterior distributions of parameters of concern. For analyses involving RCT, a right censored Gaussian linear model was used and records of NC milk samples, being censored records, were included as unknown parameters in the model implementing a data augmentation procedure. Rennet coagulation time was more heritable [heritability (h(2))=0.240 and h(2)=0.210 for HF and BS, respectively] than a(30) (h(2)=0.148 and h(2)=0.168 for HF and BS, respectively). Milk coagulation properties were more heritable than a single test-day milk yield (h(2)=0.103 and h(2)=0.097 for HF and BS, respectively) and less heritable than milk composition traits whose heritability ranged from 0.275 to 0.275, with the only exception of fat content of BS milk (h(2)=0.108). A negative genetic correlation, lower than 0.85, was estimated between RCT and a(30) for both breeds. Genetic relationships of MCP with yield and composition were low or moderate and favorable. The genetic correlation of somatic cell score with RCT in BS cows was large and positive and even more positive were those of RCT with pH and titratable acidity in both breeds, ranging from 0.80 to 0.94. Including NC milk information in the data affected the estimated correlations and decreased the uncertainty associated with the estimation process. On the basis of the estimated heritabilities and genetic correlations, enhancement of MCP through selective breeding with no detrimental effects on yield and composition seems feasible in both breeds. Milk acidity may play a role as an indicator trait for indirect enhancement of MCP. PMID- 21787957 TI - Short communication: statistical models for the analysis of coagulation traits using coagulating and noncoagulating milk information. AB - Aims of this study were to propose statistical models for the analysis of rennet coagulation time (RCT) suitable for making use of coagulating and noncoagulating (NC) milk information, to estimate heritabilities and to obtain rank correlations for sire merit. A total of 1,025 Holstein cows (progeny of 54 sires) reared in 34 herds were milk-sampled once. Data were analyzed using 4 alternative models: a standard linear (SLM), a right-censored linear Gaussian (CLM), a survival (SUM), and a threshold (THM) model. Model SLM analyzed coagulated milk records only, whereas analysis with CLM or SUM considered information of NC samples as censored records. Model THM analyzed occurrence of milk coagulation as a dichotomous trait. An artificial censoring scenario with an endpoint at 18 min (SET18) was considered after the rearrangement of the timeframe originally used for the observation of RCT (SET31). Heritabilities ranged from 0.12 to 0.25. Correlations of sire rankings ranged from 0.23 to 0.92. Differences in sire rankings between SLM and CLM or SUM increased when the proportion of NC records increased. Correlations between sire rankings obtained for SET31 and SET18 were high for CLM and SUM, indicating that rankings provided by these models tended to be stable even when a large fraction of samples with observed RCT was re-classified as NC milk. Results indicate that CLM and SUM are more suitable than SLM and THM for the analysis of coagulation ability when data contain NC milk information. PMID- 21787958 TI - Short communication: expression and alternative splicing of POU1F1 pathway genes in preimplantation bovine embryos. AB - Early embryo loss is a major contributing factor to cow infertility and that 70 to 80% of this loss occurs between d 8 and 16 postfertilization. However, little is known about the molecular mechanisms and the nature of genes involved in normal and abnormal embryonic development. Moreover, information is limited on the contributions of the genomes of dams and of embryos to the development and survival of preimplantation embryos. We hypothesized that proper gene expression level in the developing embryo is essential for embryo survival and pregnancy success. As such, the characterization of expression profiles in early embryos could lead to a better understanding of the mechanisms involved in normal and abnormal embryo development. To test this hypothesis, 2 d-8 embryo populations (degenerate embryos and blastocysts) that differed in morphology and developmental status were investigated. Expression levels of POU1F1 pathway genes were estimated in 4 sets of biological replicate pools of degenerate embryos and blastocysts. The OPN and STAT5A genes were found to be upregulated in degenerate embryos compared with blastocysts, whereas STAT5B showed similar expression levels in both embryo groups. Analysis of splice variants of OPN and STAT5A revealed expression patterns different from the total expression values of these genes. As such, measuring expression of individual transcripts should be considered in gene expression studies. PMID- 21787959 TI - Short communication: effect of mutation age on genomic predictions. AB - Genomic selection relies on the whole-genome evaluation of single nucleotide polymorphisms (SNP), some of them linked to quantitative trait loci (QTL). Although statistical methodology has been developed for the analysis of genomic data, little is known about the performance of SNP association studies when trying to capture variability from QTL mutations of different ages. Within this context, the influence of mutation age was analyzed under a simulation design, assuming presence or absence of selection on mutant QTL alleles. Focusing on a unique chromosome with a single QTL located in the proximal end, the performance of the genomic selection analyses was evaluated in terms of standardized mean square error (MSE). For all simulation scenarios, MSE was highest for the youngest mutations. The MSE was progressively reduced with mutation age under random mating and soft selection, and reached its maximum performance with the oldest mutations. On the other hand, moderate and strong selection caused a quick reduction of the MSE from youngest mutations to mutations arising in generations 920 to 939, thus resulting in a progressive increase for older mutations. In both cases, very young mutations escaped from genomic selection analyses, releasing a relevant amount of genetic variability that could not be captured and used in genomic selection programs. This demonstrated the need for new analytical approaches to model relevant and recent sources of variation; if captured, these young mutations could substantially contribute to current breeding schemes. PMID- 21787960 TI - Short communication: refinement of genetic regions associated with Mycobacterium avium subspecies paratuberculosis tissue infection and tolerance to Johne's disease. AB - Johne's disease is a highly transmissible bacterial disease caused by Mycobacterium avium ssp. paratuberculosis (MAP). The objective of this study was to refine the locus associated with MAP tissue infection and the locus associated with tolerance to Johne's disease. Using a genome-wide association analysis, single nucleotide polymorphisms associated with MAP tissue infection and tolerance to Johne's disease on Bos taurus autosome (BTA)3 and BTA15, respectively, have previously been identified. A 235-kb region on BTA3 was evaluated with 42 single nucleotide polymorphisms, and a 193-kb region on BTA15 was evaluated with 54 single nucleotide polymorphisms in a group of 209 Holstein cows. Using a single marker association analysis and haplotype tests, we refined a region of 10.6 kb on BTA3 as being associated with MAP tissue infection and a region of 6.5 kb on BTA15 as being associated with tolerance to Johne's disease. PMID- 21787961 TI - Comparison of bulk-tank standard plate count and somatic cell count for Wisconsin dairy farms in three size categories. AB - The objective of this study was to evaluate possible claims by advocates of small scale dairy farming that milk from smaller Wisconsin farms is of higher quality than milk from larger Wisconsin farms. Reported bulk tank standard plate count (SPC) and somatic cell count (SCC) test results for Wisconsin dairy farms were obtained for February to December, 2008. Farms were sorted into 3 size categories using available size-tracking criteria: small (<=118 cows; 12,866 farms), large (119-713 cattle; 1,565 farms), and confined animal feeding operations (>=714 cattle; 160 farms). Group means were calculated (group=farm size category) for the farms' minimum, median, mean, 90th percentile, and maximum SPC and SCC. Statistical analysis showed that group means for median, mean, 90th percentile, and maximum SPC and SCC were almost always significantly higher for the small farm category than for the large farm and confined animal feeding operations farm categories. With SPC and SCC as quality criteria and the 3 farm size categories of <=118, 119 to 713, and >=714 cattle, the claim of Wisconsin smaller farms producing higher quality milk than Wisconsin larger farms cannot be supported. PMID- 21787962 TI - Nutrition and metabolism of the surgical patient, Part II. PMID- 21787963 TI - Nutrition and metabolism of the surgical patient, Part II. PMID- 21787964 TI - Total parenteral nutrition and cancer: from the beginning. AB - The early development of total parenteral nutrition and its evolution as an adjunct to the nutritional, metabolic, and antineoplastic therapy of cancer patients is described. Examples related to the sine wave of responses to new data and discovery are placed in context to understand better past, present, and how and where to proceed in the future to achieve optimal results from multimodal comprehensive management of patients with malignancies. Practical and philosophic thoughts are proffered to justify continued, intensified, logical, controlled clinical studies directed toward establishing the most rational, safe, and effective use of total parenteral nutrition in treating patients with cancer. PMID- 21787965 TI - The relationships of nutrients, routes of delivery, and immunocompetence. AB - Malnutrition has marked consequences on surgical outcomes. Adequate nutrition is important for the proper functioning of all organ systems, particularly the immune system. Determination of the type and amount of nutrient supplementation and the appropriate route of nutrient delivery is essential to bolster the immune system and enhance the host's response to stress. Correct administration of immunonutrients could lead to reductions in patient morbidity following major surgery, trauma, and critical illness. PMID- 21787966 TI - Nutrition and gut immunity. AB - The human intestine contains huge amounts of nonpathologic bacteria surviving in an environment that is beneficial to both the host and the bacterial populations. When short pauses in oral intake occur with minimal alterations in the mucosa microbial interface, critical illness, with its attendant acidosis, prolonged gastrointestinal tract starvation, exogenous antibiotics, and breakdown in mucosal defenses, renders the host vulnerable to bacterial challenge and also threatens the survival of the bacteria. This review examines the altered innate and adaptive immunologic host defenses that occur as a result of altered oral or enteral intake and/or injury. PMID- 21787967 TI - Contributions of intestinal bacteria to nutrition and metabolism in the critically ill. AB - Important advances in the study of bacteria associated with the human gastrointestinal tract have significant implications for clinicians striving to meet the metabolic and nutritional needs of critically ill patients. This article offers a broad overview of the importance of the host-microbe relationship, discusses what is currently known about the role of gut microbes in nutrition and metabolism in the healthy human host, reviews how gut microbes are affected by critical illness, and discusses interventions that have already been used to manipulate the gut microbiome in patients in the intensive care unit. PMID- 21787968 TI - Nutritional support of surgical patients with inflammatory bowel disease. AB - Patients with inflammatory bowel disease (IBD) in need of surgery are often malnourished, which in turn increases the risk for postoperative complications. Malnutrition in IBD patients who must undergo surgery is due to the disordered activity of the diseased intestine, decreased dietary intake, and adverse effects of potent medications. IBD operations predispose patients to both macronutrient and micronutrient deficiencies. If the gut can be used safely it is the preferential route for feeding, though preoperative and postoperative parenteral nutrition remains a viable alternative for severely malnourished patients. New nutrient therapies include immunonutrition, fish oils, and probiotics. PMID- 21787969 TI - Nutritional support in acute and chronic pancreatitis. AB - Nutritional support can have a significant beneficial impact on the course of moderate to severe acute pancreatitis. Enteral nutrition is preferred, with emphasis on establishment of jejunal access; however, parenteral nutrition can also be of value if intestinal failure is present. Early initiation of nutritional support is critical, with benefits decreasing rapidly if begun after 48 hours from admission. Severe malnutrition in chronic pancreatitis can be avoided or treated with dietary modifications or enteral nutrition. PMID- 21787970 TI - The surgical treatment of type two diabetes mellitus. AB - Since the discovery that gastric bypass surgery leads to the rapid reversal of type 2 diabetes mellitus in morbidly obese patients, researchers have been searching for possible mechanisms to explain the result. The significance of bariatric surgery is twofold. It offers hope and successful therapy to the severely obese; those with T2DM, sleep apnea, or polycystic ovary disease; and others plagued by the comorbidities of the metabolic syndrome. This article examines four surgical procedures and their outcomes. PMID- 21787971 TI - Nutritional support of the obese and critically ill obese patient. AB - With the dramatic increase in the prevalence of obesity worldwide and in the United States, it is virtually certain that clinicians will be caring for bariatric and obese nonbariatric patients in increasing numbers. This patient population presents several difficulties from the medical and surgical management perspectives. In particular, nutrition of the bariatric patient and critically ill obese patient is challenging. A clear understanding of the nutritional assessment and unique management strategies available for the bariatric and the critically ill obese patient is essential to provide them with the safest and most effective care. PMID- 21787972 TI - Nutritional considerations in adult cardiothoracic surgical patients. AB - The importance of the preoperative nutritional status of cardiothoracic surgical patients in determining outcomes is demonstrated and discussed. Demographic, anthropometric, and biochemical changes in patients undergoing cardiothoracic surgery increase the importance of identifying those at risk for postoperative complications resulting from malnutrition. The interrelationships of chronic heart failure, cardiac cachexia, nutritional status, and nutritional support are identified and emphasized. The complexities of myocardial energetics and metabolism are outlined together with the nutrient needs for patients undergoing cardiac, pulmonary, or other intrathoracic operative procedures. PMID- 21787973 TI - Nutrition management of geriatric surgical patients. AB - Surgery in geriatric patients is accompanied by increases in morbidity and mortality, increases in functional abnormalities and poor outcomes, and increases in severe malnutrition, compared with surgery of similar magnitude in nongeriatric patients. Hospitalized elderly patients are at significant risk of presenting with, or developing, protein-energy and other nutrient deficiencies. However, nutritional assessment of older geriatric patients, 65 to 100 years of age, is a challenging task because of lack of adequate age-specific reference data in this diverse and heterogeneous population. Dietary counseling and conscientious, aggressive nutritional support are required for optimal metabolic and surgical care of this age group. PMID- 21787974 TI - Overview of enteral and parenteral feeding access techniques: principles and practice. AB - The importance of adequate nutrition has long been established in the surgical patient population. Enteral nutrition provides the safest, most cost-effective approach with endoscopic and surgical options for permanent access. Parenteral nutrition should be reserved for patients in whom enteral nutrition is contradicted. This article summarizes the routes of access for both enteral and parenteral nutrition as well as the indications, procedural pearls, and complications associated with each approach. PMID- 21787975 TI - Home parenteral nutrition support for intestinal failure. AB - Home parenteral nutrition is a life-saving treatment for many patients with intestinal failure. Expert placement and care of the vascular access device reduces the incidence of access-related complications. Careful monitoring of fluid, electrolyte, and macronutrient and micronutrient status can minimize major organ dysfunction and metabolic complications. A multidisciplined, integrated nutrition support team can allow patients with intestinal failure who need home parenteral nutrition maintain a near-normal life. PMID- 21787976 TI - Nutritional supplements in the surgical patient. AB - This article presents an overview of the current knowledge, status, and use of supplements by patients before surgical operations, together with the benefits expected of the supplements by the patients. The indications, potential advantages and disadvantages, and the relationships with various aspects of the preoperative preparation and postoperative management of surgical patients are discussed, with emphasis on the significant percentage of this population that is deficient in fundamental nutrients. Recent revisions and recommendations for some of the macronutrients are presented, together with a summary of federal regulations and an oversight of supplements. PMID- 21787977 TI - Historical highlights of the development of enteral nutrition. AB - The most significant events and discoveries regarding the development of enteral nutrition (EN) dating back to 1500 BC are chronicled. A more detailed description and discussion of subsequent more recent progress during the past two decades is focused primarily on 3 of the most dynamic areas of endeavor: tight glycemic control; timing and combining of EN and total parenteral nutrition to meet early target nutrition goals in intensive care unit patients; and the role, advances, and future of immunonutrition. An abridged classification of solutions for enteral feeding, and a brief outline of key prudent oral dietary guidelines are also presented. PMID- 21787978 TI - Illness and identity. PMID- 21787979 TI - Quiz page August 2011: lithium-induced nephrotic syndrome. PMID- 21787980 TI - Obesity and the epidemiology and prevention of kidney disease: waist circumference versus body mass index. PMID- 21787981 TI - Bridging the care gap around dialysis initiation: is CKD education part of the solution? PMID- 21787983 TI - Increased plasma levels of tacrolimus after ingestion of green tea. PMID- 21787984 TI - Multidetector computed tomography of spinal trauma: a pictorial review. AB - Spinal trauma is 1 of the major causes of disability that commonly affects young adults, and radiologists play a crucial role in the evaluation of acutely traumatized patients. With the advent of multidetector computed tomography (MDCT), the algorithm of imaging of spinal trauma has changed dramatically and MDCT is now established as the imaging modality of choice for the diagnosis of spinal trauma. The appearance on MDCT of the spinal injury depends on the mechanism of the injury, which also determines the stability of the injury. This pictorial essay describes the MDCT appearances, mechanism, and stability of commonly encountered traumatic spinal injuries. PMID- 21787982 TI - Progression of CKD in Hispanics: potential roles of health literacy, acculturation, and social support. AB - Hispanics are the fastest growing minority group in the United States, and compared with non-Hispanic whites, they have a higher incidence of end-stage renal disease. Examining novel factors that may explain this disparity in progression of chronic kidney disease (CKD) in Hispanics is urgently needed. Interpersonal and patient-centered characteristics, including health literacy, acculturation, and social support, have been shown to affect health outcomes in patients with other chronic diseases. However, these characteristics have not been well studied in the context of CKD, particularly in relation to disease knowledge, attitudes, and behaviors. In this report, we examine the potential roles of these factors for CKD progression in Hispanics and propose targeted therapeutic interventions. PMID- 21787985 TI - Musculoskeletal manifestations of hemophilia: imaging features. AB - The purpose of this pictorial assay is to demonstrate the imaging features of the various musculoskeletal manifestations of hemophilia, an X-linked disorder. Depending on the site of recurrent bleeding, musculoskeletal manifestation can be in the form of hemophilic arthropathy and/or soft tissue, intraosseous, or subperiosteal pseudotumors. Radiography, sonography, computed tomography, and especially magnetic resonance imaging help in the evaluation of hemophilic arthropathy and pseudotumors, providing accurate diagnosis, thus avoiding inadvertent procedures and related complications. Treatment includes replacement of clotting factors either continuously or when indicated, radionuclide or open synovectomy in cases of disabling arthropathy. PMID- 21787986 TI - Atypical tumors of the rectum with pathologic correlation. AB - Although the majority of rectal masses are histologically characterized as adenocarcinoma, there is a wide spectrum of rare, but specific, neoplastic processes that can involve the rectum and present with rectal bleeding. Knowledge of their existence and protean imaging features is crucial for accurate diagnosis and appropriate management. This review article describes the clinical, imaging, and histopathologic characteristics of several pathologically proven rectal lesions, including rectal carcinoid, rectal gastrointestinal stromal tumor, rectal cavernous hemangioma, primary anorectal melanoma, primary rectal lymphoma, and rectal metastases. PMID- 21787987 TI - Carbon dioxide as an intravascular imaging agent: review. AB - Patients with renal impairment and/or contrast allergies pose a challenge with regard to diagnostic evaluations. CO(2) may serve as a suitable alternative intravascular contrast agent in these patients with arteriographic applications, including evaluation of peripheral vascular disease, and venographic applications, such as transjugular intrahepatic portosystemic shunt procedure, to name a few. Unique properties of CO(2), such as low viscosity, lack of an allergic reaction, and renal toxicity, have afforded it its diagnostic capabilities. However, certain properties of CO(2) also pose a technical challenge in terms of its delivery. Although it remains a relatively safe alternative contrast agent, potential adverse effects have been reported and exist. PMID- 21787988 TI - Invited commentary. Crisis checklists for the operating room: development and pilot testing. PMID- 21787989 TI - Discussion. Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution. PMID- 21787990 TI - Mounting evidence supports universal surveillance for MRSA in preoperative patients. PMID- 21787991 TI - Another perspective on motorcycle helmet use. PMID- 21787993 TI - The Shah's spleen. PMID- 21787994 TI - The Shah's spleen. PMID- 21787996 TI - The Shah's spleen. PMID- 21787998 TI - Resolving the M-cell debate: why and how. PMID- 21788000 TI - A common denominator in analyzing data. PMID- 21787999 TI - HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). PMID- 21788001 TI - Visual information and rubber hand embodiment differentially affect reach-to grasp actions. AB - During the "rubber hand illusion" (RHI) participants feel touch originating from an artificial hand, which is felt to belong to the own body. The perceived location of the real hand is shifted towards the location of the artificial hand. However, evidence as to whether the RHI is accompanied by alterations of hand action is mixed. We found that the perceived size of one's own hand was affected by the size of the artificial hand that was used to elicit the illusion. Moreover, we tested a possible transfer of the RHI to a reach-to-grasp action. We observed that hand transport (i.e., reach) errors after RHI induction were independent of artificial hand size, showing that the parameter which is important for these reaching errors is the hand's perceived location. Results thus show that the RHI affects not only perceptual, but also action processing. In contrast, grip aperture was affected by artificial hand size independent of the RHI, suggesting that visual information about hand size affects grasping independent of embodiment of the artificial hand. Grip size increased with artificial hand size; this effect is explained by a higher reliance on proprioceptive information during blind reaching after receiving distorted visual information. PMID- 21788002 TI - Is the outcome of laparoscopic incisional hernia repair affected by defect size? A prospective study. AB - BACKGROUND: This study was performed to determine if defect size after laparoscopic incisional hernia repair is predictive of recurrence during the long term follow-up evaluation. METHODS: We performed a prospective clinical study on 310 patients who underwent laparoscopic incisional hernia repair to identify predictable risk factors for hernia recurrence. Univariate and multivariate Cox regression analysis were used. The defect size was analyzed with curve receiver operating characteristic curve. RESULTS: The overall recurrence rate was 6% after an average follow-up period of 60 months. On univariate analysis of the defect size (categories: <10 cm, 10-12 cm, and >15 cm), obesity, previous repairs, hernia location, surgical time, hospital stay, morbidity, and recurrences were significantly different (P < .001). By multivariate analysis, only obesity and defect size were independent prognostic factors (P < .001). CONCLUSIONS: The predictive value of defect size is shown. Patients with large defects have a higher risk of recurrence. Our study recommends reserving the laparoscopic technique for hernias not exceeding 10 cm in size, where it can be put to better use. PMID- 21788003 TI - Short and long-term results of the Karydakis flap versus the Limberg flap for treating pilonidal sinus disease: a prospective randomized study. AB - BACKGROUND: Pilonidal sinus is a common disease that mostly affects young people. Although various surgical techniques have been described for treating sacrococcygeal pilonidal disease (SPD), controversy still exists as to the best surgical technique. The purpose of this study was to compare the efficiency and short-term and long-term results of the Karydakis flap with that of the Limberg flap for treating SPD. METHODS: In this prospective randomized study, 269 patients with SPD were recruited to undergo either the Karydakis flap (n = 135) or the Limberg flap (n = 134) procedure between September 2004 and September 2008. RESULTS: The mean operative time for the Karydakis group (42.32 +/- 8.64 minutes) was shorter than that for the Limberg group (50.14 +/- 6.96 minutes) (P = .01). The complication rate for the Karydakis group (n = 15 [11.1%]) was lower than that for the Limberg group (n = 28 [20.8%]) (P = .029). The visual analogue scale score for postoperative pain at the operation site on the 30th day was lower in the Karydakis group than in the Limberg group (2.22 +/- 1.01 vs 3.23 +/- 1.14, P = .01). The visual analogue scale score for satisfaction with the cosmetic appearance of the scars in the Karydakis group was 7.08 +/- 1.75, whereas it was 3.16 +/- 1.40 in the Limberg group at the 3rd month (P = .01). Length of hospital stay was significantly shorter in the Karydakis group than in the Limberg group (3.40 +/- .94 vs 3.8 +/- 1.19 days, P = .03). Only 4 patients in the Karydakis group developed recurrence (3%), whereas 9 patients (6.9%) did so in the Limberg group (P = .151). CONCLUSIONS: The Karydakis flap procedure should be chosen instead of the Limberg flap for treating uncomplicated SPD because of its lower postoperative complication rate, lower pain scores, shorter operation time and length of hospital stay, and good cosmetic satisfaction. However, no differences existed between the 2 surgical procedures in terms of recurrence prevention. PMID- 21788004 TI - So you want to be a neurosurgeon: a career resource guide for successful navigation. AB - Neurosurgery is not just about head injuries and brain tumors. It is a specialty that currently stands at the forefront of biomedical and technological developments. Modern neurosurgery requires not only creativity and perseverance on behalf of your patients but also clinical acumen, surgical judgment, and technical expertise. This career resource guides the reader through the pathway to a practice in neurosurgery. PMID- 21788005 TI - Laparoscopic revision of failed antireflux surgery: a systematic review. AB - BACKGROUND: Laparoscopic antireflux surgery is an accepted treatment for persistent gastroesophageal reflux but about 4% of patients will eventually require revision surgery. METHODS: We searched The Cochrane Collaboration, Medline, and EMBASE databases, augmented by Google Scholar and PubMed related articles from January 1, 1990, to November 22, 2010. Twenty studies met the inclusion criteria, reporting on 930 surgeries. RESULTS: The mean surgical duration was 166 minutes and conversion to open revision fundoplication was required in 7% of cases. Complications were reported in 14% of cases and the mean length of stay varied between 1.2 and 6 days. A good to excellent result was reported for 84% of surgeries and 5% of patients required a further revisional procedure. CONCLUSIONS: Laparoscopic revision antireflux surgery appears to be feasible and safe, but subject to somewhat greater risk of conversion, higher morbidity, longer hospital stay, and poorer outcomes than primary laparoscopic fundoplication. PMID- 21788006 TI - The surgical management of abdominal pain in the multiple myeloma patient. AB - BACKGROUND: The purpose of this retrospective study was to characterize the presentation, treatment, and outcomes of patients with multiple myeloma requiring surgical evaluation for abdominal pain. METHODS: Medical records of patients with myeloma and abdominal pain evaluated by surgery over a period of 18 months were examined. RESULTS: Twenty-one patients underwent surgical evaluation, with 23 diagnoses. Neutropenic enterocolitis (n = 5 [22%]) and ileus (n = 4 [17%]) were common diagnoses. Eleven patients (52%) were neutropenic. Peritonitis was noted in only 1 patient. Eastern Cooperative Oncology Group performance status was either 3 or 4 in most patients (67%). Surgery was performed in 5 patients. The 90 day mortality rate for all patients was 43%, with all deaths secondary to sepsis in patients managed without surgery. CONCLUSIONS: Patients with myeloma requiring surgical evaluation for abdominal pain have a unique differential diagnosis, with notable findings at presentation including the presence of cytopenia, lack of peritoneal signs, and low performance status. PMID- 21788007 TI - The effect of increased hip flexion using stirrups on lower-extremity venous flow: a prospective observational study. AB - BACKGROUND: Patient positioning during surgeries for colorectal cancer may represent an unrecognized risk factor for deep venous thrombosis. METHODS: Twelve healthy control patients were positioned supine with knee flexion at 90 degrees . Duplex ultrasound examined common femoral vein (CFV) and proximal femoral vein diameter, peak systolic velocity, and volume flow with hip flexion at 0 degrees , 30 degrees , 60 degrees , and 90 degrees . Data were analyzed using the paired t test. RESULTS: In the CFV, hip flexion to 90 degrees was associated with a significant increase in mean volume flow when compared with hip flexion at 0 degrees (.59 vs .36 L/min; P = .05) and 30 degrees (.59 vs .35 L/min; P = .038). In both the CFV and proximal femoral vein, increased hip flexion was associated with significantly reduced vessel diameter and increased peak systolic velocity. CONCLUSIONS: Intraoperative positioning of the lower extremities represents a modifiable risk factor for deep venous thrombosis. When stirrups are used, hip flexion of 90 degrees maximizes venous drainage from the legs. PMID- 21788008 TI - A positive intramammary lymph node does not mandate a complete axillary node dissection. AB - BACKGROUND: We hypothesized that even in the face of a positive intramammary lymph node (IMLN) a negative axillary sentinel lymph node (SLN) reliably stages the axilla and complete axillary lymph node dissection (CALND) can be avoided. METHODS: A literature search identified 386 publications that included IMLNs and SLN biopsies. Patients with a positive IMLN and negative axillary SLN who underwent a CALND were included. A review of our database was also performed. RESULTS: Twenty-one cases in the literature met our criteria. A review of our database resulted in 2 additional cases. Twenty-three patients were identified who had a positive IMLN, negative axillary SLN biopsy, and underwent a CALND. In all cases, the CALND was negative. CONCLUSIONS: An axillary SLN biopsy accurately represents the disease status of the axilla in cases with a positive IMLN. CALND can be avoided in the setting of a positive IMLN and a negative axillary SLN biopsy. PMID- 21788009 TI - Transfusion increases the risk for vasoplegia after cardiac operations. AB - BACKGROUND: Perioperative vasoplegia is associated with increased morbidity. Red blood cell (RBC) transfusion increases plasma concentrations of inflammatory mediators, possibly contributing to the development of vasoplegia. We investigated the prevalence of mild and profound postoperative vasoplegia, identified factors associated with its development, and examined the role of RBC and component transfusion on the occurrence of postoperative vasoplegia. METHODS: Between January 1, 2000, and January 1, 2007, 25,960 patients underwent on-bypass cardiac surgical procedures. The incidence of vasoplegia was defined as (1) mild vasoplegia requiring norepinephrine infusion for blood pressure support on the day of operation and postoperative day 1, and (2) profound vasoplegia requiring vasopressin, with or without concomitant norepinephrine infusion, on the day of operation and postoperative day 1. Separate logistic regression models were used to model risk factors for development of mild and profound vasoplegia. RESULTS: RBC transfusion increased risk-adjusted odd ratios (ORs) of developing mild vasoplegia (1.07 [95% confidence limits (CL), 1.05, 1.10]; p<0.001) and profound vasoplegia (1.38 [1.31, 1.46] p<0.001). The risk-adjusted ORs (95% CL) for mild vasoplegia and profound vasoplegia were similarly increased by fresh-frozen plasma (OR, 1.24 [1.10, 1.41], p<0.001; and OR, 1.20 [1.13, 1.29], p<0.001) and platelet transfusion (OR, 1.39 [1.25, 1.54], p<0.001; and OR, 1.22 [1.14, 1.31], p<0.001), respectively. CONCLUSIONS: Red blood cells, fresh-frozen plasma, and platelet transfusion increased the prevalence of vasoplegia. RBC transfusion exhibited a dose-dependent response for developing vasoplegia with each RBC unit transfused. Further investigation is necessary to determine whether prophylactic use of vasopressor support in the setting of transfusion can ameliorate risk and effect outcomes. PMID- 21788010 TI - Long-term functional analysis of the atrioventricular valve in patients undergoing single ventricle palliation. AB - BACKGROUND: Presently, there are wide variations in cardiac anatomies requiring single ventricular palliation and these variations may have an impact on the incidence of atrioventricular valve regurgitation. METHODS: In all, 363 patients underwent single ventricular palliation (1978 to 2008). Hearts were first classified into single right ventricle (156), single left ventricle (140), and two ventricles (63); and secondly into single mitral (90), single tricuspid (64), two separate valves (110), and common atrioventricular valves (95). RESULTS: The incidence of atrioventricular valve regurgitation and the necessity of repair were the highest with common atrioventricular valves, followed by tricuspid and mitral valves (p < 0.0001). The success rate (postoperative regurgitation of mild or less) of repair was similar (p = 0.9800). Estimated survival for patients having moderate or greater atrioventricular valve regurgitation was similar to the rest of the patients (p = 0.8705). Patients were more likely to have progressive mitral regurgitation in the presence of both mitral and tricuspid valves, compared with single mitral valve (p = 0.0207). There were 2 patients who had severe mitral regurgitation; both had a nonsystemic left ventricle isolated from the circulation by malposition of the great arteries and restrictive/remote ventricular septal defect. In contrast, coexisting mitral valves reduced the incidence of potential tricuspid regurgitation (p = 0.0012). CONCLUSIONS: If performed properly, atrioventricular valve repair may neutralize the risk of regurgitation regardless of the valve morphology. The effort to incorporate the mitral valve into the systemic circulation may be important to reduce tricuspid regurgitation. The effort to decompress a nonsystemic left ventricle, if present, may be important to avoid unfavorable ventricular interactions on the mitral valve. PMID- 21788011 TI - Social anxiety and the effects of negative self-imagery on emotion, cognition, and post-event processing. AB - Numerous studies have shown that social phobia patients experience negative self impressions or images during social situations. Clark and Wells (1995) posited that such negative self-images are involved in the maintenance of social phobia. Thus, the present study investigated the effects of negative self-imagery on cognition and emotion during and following a brief social situation. Specifically, high and low socially anxious participants (N = 77) were instructed to hold either a negative or control self-image as they engaged in a brief speech. Participants then rated their anxiety, performance, cognitions, and focus of attention. Twenty-four hours later, they returned to the laboratory and completed questionnaires assessing the amount of post-event processing (PEP) they engaged in. The results showed that, irrespective of the level of social anxiety or depressive symptoms, participants that held the negative self-image experienced higher levels of anxiety, were more self-focused, experienced more negative thoughts, rated their anxiety as more visible, appraised their performance more negatively, and engaged in more negative and less positive PEP than participants that held the control self-image. Collectively the results indicate that negative imagery is causally involved in the maintenance of social phobia, as well as in the generation of social anxiety among non-anxious individuals. PMID- 21788012 TI - Improving access to psychological treatments: lessons from developing countries. AB - Even though psychological treatments have been advocated as treatments for a range of mental disorders by the WHO for scaling up through primary care globally, the vast majority of potential beneficiaries are unable to access these treatments. Two major barriers impede the path between evidence based treatments and improved access: the lack of skilled human resources and the acceptability of treatments across cultures. This essay synthesizes the experiences of programs which developed and evaluated psychological treatments for depression in three resource poor developing countries. These programs addressed the human resource barrier by training lay or community health workers to deliver the treatments and addressed the acceptability barrier by systematically adapting the treatment to contextual factors. All programs demonstrated significant benefits in recovery rates when compared with usual care demonstrating the effectiveness of the approach. The implications for these experiences to improving access to psychological treatments in the global context are discussed. PMID- 21788013 TI - Novel O-glycosidic gossypol isomers and their bioactivities. AB - Novel glycosidic gossypol analogs, 7,7'-gossypol diglucoside tetraacetate GS1, 6,7'-gossypol diglucoside tetraacetate GS2, 7,7'-gossypol diglycoside GS1', 6,7' gossypol diglycoside GS2' were obtained by the ultrasound-assisted reaction of the potassium salt of gossypol with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide under PTC conditions and were fully characterized by 1D NMR ((1)H NMR, (13)C NMR, DEPT, 1D NOE), 2D NMR (HMBC, HMQC), FTIR, HRMS and HPLC. The anticancer activities, cytotoxic effects as well as anti-trypanosomal activities of these novel glycosidic gossypols were explored and suggest that gossypol glycosides could be used to develop new candidates for anticancer drugs and anti trypanosomal agents. PMID- 21788014 TI - Effect of 1,25(OH)(2)D(3) on rat peritoneal mesothelial cells treated with high glucose plus lipopolysaccharide. AB - 1,25(OH)(2)D(3), the active metabolite of vitamin D(3), its activity is not limited to mineral and skeletal homeostasis. In recent years, there has been increasing evidence pointing to the role of its activity in the regulation of cell proliferation, cell differentiation and immunomodulation. Here we report lipopolysaccharide (LPS), a glycolipid that is produced and secreted by gram negative bacteria during peritonitis, plus high glucose (HG) can significantly inhibit mesothelial cell viability while induce more apoptosis in rat peritoneal mesothelial cells (RPMC). Pretreatment with 1,25(OH)(2)D(3) can reverse the above effect in a concentration dependent manner. HG plus LPS can down-regulate the levels of both mRNA and protein of VDR, and up-regulate the expression of TGF beta1 and TNF-alpha in RPMC, which can also be effectively reversed by pretreatment with 1,25(OH)(2)D(3). The above results suggest that HG plus LPS may induce changes in RPMC's viability and apoptosis, leading to peritoneal injury. 1,25(OH)(2)D(3) can reverse the inhibition of cell viability, the increase of apoptotic rate and induction of fibrosis related cytokine TGF-beta1 and TNF-alpha by HG plus LPS in RPMC, thus protect peritoneal membrane. PMID- 21788016 TI - The radiology report--are we getting the message across? AB - The radiology report is the primary method of communication between radiologist and referrer. Despite this, radiologists receive very little formal training regarding the structure of the radiology report and also its importance as a medico-legal document. We present a review of radiology reporting, highlighting the importance of report structure and language with the purpose of helping radiologists improve the clarity, brevity, pertinence, and readability of reports. We encourage radiologists to avoid hedging and strive to improve communication with referring clinicians. PMID- 21788015 TI - Proteomic biosignatures for monocyte-macrophage differentiation. AB - We used pulsed stable isotope labeling of amino acids in cell culture (pSILAC) to assess protein dynamics during monocyte-macrophage differentiation. pSILAC allows metabolic labeling of newly synthesized proteins. Such de novo protein production was evaluated from 3 to 7 days in culture. Proteins were identified by liquid chromatography-tandem mass spectrometry then quantified by MaxQuant. Protein protein linkages were then assessed by Ingenuity Pathway Analysis. Proteins identified were linked to cell homeostasis, free radical scavenging, molecular protein transport, carbohydrate metabolism, small molecule chemistry, and cell morphology. The data demonstrates specific biologic events that are linked to monocyte transformation in a defined biologic system. PMID- 21788017 TI - Identification and adaptive neural network control of a DC motor system with dead zone characteristics. AB - In this paper, an adaptive control approach based on the neural networks is presented to control a DC motor system with dead-zone characteristics (DZC), where two neural networks are proposed to formulate the traditional identification and control approaches. First, a Wiener-type neural network (WNN) is proposed to identify the motor DZC, which formulates the Wiener model with a linear dynamic block in cascade with a nonlinear static gain. Second, a feedforward neural network is proposed to formulate the traditional PID controller, termed as PID-type neural network (PIDNN), which is then used to control and compensate for the DZC. In this way, the DC motor system with DZC is identified by the WNN identifier, which provides model information to the PIDNN controller in order to make it adaptive. Back-propagation algorithms are used to train both neural networks. Also, stability and convergence analysis are conducted using the Lyapunov theorem. Finally, experiments on the DC motor system demonstrated accurate identification and good compensation for dead-zone with improved control performance over the conventional PID control. PMID- 21788018 TI - Maternal mortality in Greece, 1996-2006. AB - OBJECTIVE: To present retrospective data for maternal deaths in Greece from 1996 to 2006. METHODS: Demographic information and information on the causes of death was provided by the Hellenic Statistical Authority. Maternal deaths were assessed by cause of death, maternal age, and place of residence. The maternal mortality ratio (MMR) was estimated and expressed as the number of deaths per 100,000 live births. RESULTS: From 1996 to 2006, 29 deaths were attributed to pregnancy and childbirth, yielding a total MMR of 2.63. The leading cause of direct deaths was hemorrhage and that of indirect deaths was cardiac disease. There was a borderline significant decline in the MMR during the study period. The MMR was significantly higher at the extremes of the reproductive age range. CONCLUSION: Maternal mortality in Greece is low; however, no formal data have been published since 1996. Knowledge of the causes of maternal death can lead to the prevention of maternal deaths and safer motherhood. PMID- 21788019 TI - Ethnic differences in systemic inflammation: an investigation of C-reactive protein levels among Moroccan, Turkish and Dutch groups in the Netherlands. AB - OBJECTIVE: C-reactive protein (CRP) is a sensitive, non-specific systemic marker for inflammation and tissue damage in the human body and independently associated with incident cardiovascular disease (CVD) and traditional CVD risk factors. The aim of this study is to describe and analyse ethnic differences in CRP levels between Turkish, Moroccan and ethnic Dutch groups. METHODS: Data were collected in the setting of a general health survey, in Amsterdam, the Netherlands, in 2004. From 1219 adults information on physical and psychological health, lifestyle and demographic background was obtained via health interviews. In a physical examination, measurements of anthropometry and blood pressure were performed. Blood samples were collected and high-sensitive CRP was determined. RESULTS: Mean CRP levels, excluding acute inflammation, were higher among Turkish migrants (men: 2.1mg/l; women: 2.9mg/l) and Moroccan women (2.9mg/l) compared to the Dutch (men: 1.7mg/l; women: 2.3mg/l). 'High CVD risk' CRP levels (3mg/l>=CRP>=10mg/l) were also more prevalent in these groups. Ethnic differences in mean CRP levels persisted after controlling for sex, age, BMI and smoking. Ethnic differences in 'high CVD risk' CRP levels were attenuated by controlling for traditional CVD risk factors in men, but not in women. CONCLUSION: Their relatively high CRP levels put Turkish and female Moroccan migrants at higher risk of future cardiovascular events, especially women. Known determinants cannot explain ethnic differences in mean CRP levels. Traditional CVD determinants account for ethnic differences in 'high CVD risk' CRP levels among men, but not women. PMID- 21788020 TI - Mediterranean diet for combating the metabolic syndrome. PMID- 21788021 TI - Modelling of elution-extrusion counter-current chromatography using perfect replacement approach. AB - Basing on the perfect replacement approach the equilibrium cell model is developed to describe the separation process in elution-extrusion counter-current chromatography (EECCC). As is known, EECCC consists of three steps: classical elution, sweeping elution, and extrusion. The perfect replacement approach means that during sweeping elution step, the mobile phase contained in the column moves and interacts with the "old" stationary phase in the same mode as during the classical elution step; the "new" and "old" stationary phases do not mix; and after the contacting with the mobile phase the concentration of solutes in the "old" stationary phase remains constant and this stationary phase volume is pushed ahead to the exit of the column. Equations are presented allowing the simulation of the chromatogram of solutes eluted from the column with the mobile phase during the elution period and the chromatogram of solutes pushed out of the column with the stationary phase during the extrusion period of EECCC. These equations can help to choose the optimal conditions for conducting elution extrusion counter-current chromatography. PMID- 21788022 TI - Some theoretical and practical aspects in the separation of humic substances by combined liquid chromatography methods. AB - Permanent need to understand nature, structure and properties of humic substances influences also separation methods that are in a wide scope used for fractionation, characterization and analysis of humic substances (HS). At the first glance techniques based on size-exclusion phenomena are the most useful and utilized for relating elution data to the molecular mass distribution of HS, however, with some limitations and exceptions, respectively, in the structural investigation of HS. The second most abundant separation mechanism is reversed phase based on weak hydrophobic interactions beneficially combined with the step gradients inducing distinct features in rather featureless analytical signal of HS. Relatively great effort is invested to the developments of immobilized-metal affinity chromatography mimicking chelate-forming properties of HS as ligands in the environment. Surprisingly, relatively less attention is given to the ion-ion interactions based ion-exchange chromatography of HS. Chromatographic separation methods play also an important role in the examination of interactions of HS with pesticides. They allow us to determine binding constants and the other data necessary to predict the mobility of chemical pollutants in the environment. HS is frequently adversely acting in analytical procedures as interfering substance, so more detailed information is desired on manifestation of its numerous properties in analytical procedures. The article topic is covered by the review emphasizing advances in the field done in the period of last 10 years from 2000 till 2010. PMID- 21788023 TI - Reaction-induced phase separation of bis(triethoxysilyl)ethane upon sol-gel polymerization in acidic conditions. AB - While organically bridged alkoxysilane precursors such as bis(triethoxysilyl)ethane (BTESE) find increasing use in materials synthesis, their polymerization still has not been subject to detailed kinetic investigations. One factor complicating the measurement and interpretation of the behavior of these monomers is their tendency to aggregate during polymerization into small clusters or particles. Here, the phase behavior and kinetics of BTESE during polymerization in acidic water-ethanol solutions are investigated in situ using (29)Si NMR spectroscopy. Based on macroscopic observation of the colloidal stability of the reacting solutions, a ternary pseudo-phase diagram is constructed and solutions that seem from a macroscopic point of view to be favorable for kinetic investigation are probed in situ using (29)Si NMR. However, even when the solutions remain optically clear, the polymerization mixtures are sometimes prone to gradual loss of NMR signal. The rate of signal loss is found to be dependent on the initial composition as well as the pH of the reacting mixtures. We speculate that this phenomenon is caused by microphase separation of reaction intermediates formed early in the polymerization process. This phenomenon is likely to affect the formation and distribution of oligomers in the solution that eventually react together to form a material. PMID- 21788024 TI - Hydrophilicity/porous structure-tuned, SiO2/polyetherimide-coated polyimide nonwoven porous substrates for reinforced composite proton exchange membranes. AB - Porous substrate-reinforced composite proton exchange membranes have drawn considerable attention due to their promising application to polymer electrolyte membrane fuel cells (PEMFCs). In the present study, we develop silica (SiO(2)) nanoparticles/polyetherimide (PEI) binders-coated polyimide (PI) nonwoven porous substrates (referred to as "S-PI substrates") for reinforced composite membranes. The properties of S-PI substrates, which crucially affect the performance of resulting reinforced composite membranes, are significantly improved by controlling the hygroscopic SiO(2) particle size. The 40 nm S-PI substrate (herein, 40 nm SiO(2) particles are employed) shows the stronger hydrophilicity and highly porous structure than the 530 nm S-PI substrate due to the larger specific surface area of 40 nm SiO(2) particles. Based on the comprehensive understanding of the S-PI substrates, the structures and performances of the S-PI substrates-reinforced composite membranes are elucidated. In comparison with the 530 nm S-PI substrate, the hydrophilicity/porous structure-tuned 40 nm S-PI substrate enables the impregnation of a large amount of a perfluorosulfonic acid ionomer (Nafion), which thus contributes to the improved proton conductivity of the reinforced Nafion composite membrane. Meanwhile, the reinforced Nafion composite membranes effectively mitigate the steep decline of proton conductivity with time at low humidity conditions, as compared to the pristine Nafion membrane. This intriguing finding is further discussed by considering the unusual features of the S-PI substrates and the state of water in the reinforced Nafion composite membranes. PMID- 21788025 TI - Adsorption of several gases on flexible metal organic framework [Cu(dhbc)2(4,4' bpy)].H2O. AB - The adsorption of ten gases on the flexible metal organic framework material [Cu(dhbc)(2)(4,4'-bpy)].H(2)O (Cu(db)) has been measured over a wide range of temperatures and pressures. The gate opening condition and driving force behind gate adsorption for Cu(db) were discussed by examining the adsorption isotherms. The adsorption isotherms for each adsorbate can be generalized to a characteristic curve using the adsorption potential energy (epsilon) and the adsorption volume. The adsorption potential (epsilon(gate)) at gate opening is almost constant over a wide range of temperatures; thus, the gate pressure at a desired temperature can be deduced using the epsilon(gate) evaluated from one adsorption isotherm. The gate opening capacity of the gases was arranged in the order: CO(2)?N(2)O>C(2)H(4)?Xe>CH(4)>CO>O(2)>Ar?N(2)>H(2), which is governed by the interaction energy between the outer surface of Cu(db) and the adsorbate. It is suggested that the gate effect is brought about when the integral interaction energy of adsorbates with the Cu(db) surface exceeds a defined limit correlating with the pi-pi stacking energy of Cu(db) layers. PMID- 21788026 TI - Synthesis of 3D porous ferromagnetic NiFe2O4 and using as novel adsorbent to treat wastewater. AB - Three dimensions (3D) porous NiFe(2)O(4) is synthesized by a sol-gel method using egg white. The obtained NiFe(2)O(4) shows both good ferromagnetic properties and high adsorption capacity. The porous NiFe(2)O(4) shows good adsorption properties for organic dyes (Methylene Blue (138.50 mg/g), Fuchsine Red (14.61 mg/g), Methyl Violet (19.06 mg/g)) and heavy metal ions (Cu (II) (55.83 mg/g), Cr (VI) (36.95 mg/g) and Ni (II) (37.02 mg/g)) due to its 3D interconnected porous structure. The maximum adsorption of Methylene Blue (MB) fit the pseudo-second-order model and Langmuir isotherm equation well. More interestingly, the ferromagnetic NiFe(2)O(4) can be separated under a magnetic field conveniently and keeps high removal efficiency (>97%) during seven reusable cycles. These results suggest that the porous NiFe(2)O(4) is a promising favorable and reusable adsorbent. PMID- 21788027 TI - UV-curable low surface energy fluorinated polycarbonate-based polyurethane dispersion. AB - UV-curable low surface energy fluorinated polycarbonate-based polyurethane dispersions were synthesized by incorporating a hydroxy-terminated perfluoropolyether (PFPE) into the soft segment of polyurethane. The effects of the PFPE content on the UV-curing behavior, physical, surface, thermal properties and refractive index were investigated. The UV-curing behavior was analyzed by photo-differential scanning calorimetry. The surface free energy of the UV-cured film, which is related to the water or oil repellency, was calculated from contact angle measurements using the Lewis acid-base three liquids method. The surface free energy decreased significantly with increasing fluorine concentration because PFPE in the soft segment was tailored to the surface and produced a UV-cured film with a hydrophobic fluorine enriched surface, as confirmed by X-ray photoelectron spectroscopy. With increasing the fluorine content, the refractive indices of UV-cured films decreased. However, the UV curing rate and final conversion was decreased with increasing contents of PFPE, which resulted in the decrease of the glass transition temperature (T(g)), crosslink density, tensile strength and surface hardness. PMID- 21788028 TI - Interrelations between charging, structure and electrokinetics of nanometric polyelectrolyte films. AB - Streaming current, surface conductivity and swelling data of poly(acrylic acid) (PAA) and poly(ethylene imine) (PEI) thin films are analyzed on the basis of the theory for diffuse soft interfaces (J.F.L. Duval, R. Zimmermann, A. L. Cordeiro, N. Rein, C. Werner, Langmuir 25 (2009) 10691). Focus is put on ways to unravel the electroosmotic and migration contributions of the measured surface conductivity, which is crucial for appropriate electrokinetic analysis of films carrying high densities of dissociable groups. Results demonstrate that the osmotically-driven swelling of the PAA films with increasing pH is accompanied by an increase in diffuseness for the interphasial polymer segment density distribution. This heterogeneity is particularly marked at low ionic strength with a non-monotonous dependence of the streaming current on pH and the presence of a maximum at pH~6.5. The analysis of the PEI films evidences heterogeneous swelling with lowering pH, i.e. upon protonation of the amine groups. The characteristic decay length in the interphasial PEI segment density distribution is found to be nearly independent of the pH, which is in line with the moderate swelling determined by ellipsometry. A critical discussion is given on the strengths and limitations of electrokinetics/surface conductivity for quantifying the coupled electrohydrodynamic and structural properties of moderately to highly swollen polyelectrolyte thin films. PMID- 21788029 TI - Silicon dioxide hollow microspheres with porous composite structure: synthesis and characterization. AB - In this paper, a strategy for hollow porous silica microspheres with ideally flower structure is presented. SiO(2)/PAM hybrid composite microspheres with porous were synthesized by the reaction that the porous polyacrylamide (PAM) micro-gels immersed in tetraethoxysilane (TEOS) anhydrous alcohol solution and water in a moist atmosphere, with ammonium hydroxide as a catalyst. The SiO(2) hollow microspheres with porous were obtained after calcination of the composite microspheres at 550 degrees C for 4 h. The morphology, composition, and crystalline structure of the microspheres were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermo-gravimetric analysis (TGA), Fourier transform infrared spectroscopy (FI-IR), and X-ray diffraction (XRD), N(2) absorption analysis, respectively. The results indicated that the obtained hollow porous SiO(2) microspheres were a perfect flower structure. PMID- 21788030 TI - Functionalization of tungsten oxide into MWCNT and its application for sunlight induced degradation of rhodamine B. AB - A composite of multi-walled carbon nanotube/tungsten oxide (MWCNT/WO(3)) has been successfully synthesized. The prepared composite was characterized by X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), high resolution transmission electron microscopy (HRTEM) and Fourier transform infrared spectroscopy (FTIR). The catalytic activity was investigated by rhodamine B degradation under solar irradiation. The influence of various degradation parameters such as solar illumination time, initial dye concentration, dosage and pH was investigated. It was found that the composite exhibits an enhanced photocatalytic activity as compared with WO(3) and a mechanical mixture of MWCNTs and WO(3). The enhancement in photocatalytic performance of the MWCNT/WO(3) composite has been explained based on adsorption ability and electron transportation as a result of a strong interaction between WO(3) and MWCNTs. Besides, MWCNTs acts as dispersing agent preventing WO(3) from agglomerating during the catalytic process, providing a high active surface area of the catalyst. A reasonable mechanism for the enhanced reactivity was proposed. PMID- 21788031 TI - Optimization of Co2+ ions removal from water solutions via polymer enhanced ultrafiltration with application of PVA and sulfonated PVA as complexing agents. AB - The paper presents the results of the studies of UF-complexation process applied for the removal of Co(2+) ions from water solutions. As binding agents for cobalt ions, the PVA polymer (M(w)=10,000) and its sulfonated form, synthesized in the laboratory, have been used. The method of experimental design and response surface methodology have been employed to find out the optimal conditions for the complexation process and to evaluate the interaction between the input variables, i.e., initial cobalt concentration, pH and amount of the polymer used, expressed as a polymer/Co(2+) ratio r. The data collected by the designed experiments showed that sulfonation of polymer has improved significantly the binding ability of PVA. The optimal conditions of cobalt ions complexation established by response surface model for non-sulfonated PVA polymer have been found to be as follows: the initial concentration of Co(2+)=5.70 mg L(-1), the ratio between polymer and metal ions, r=8.58 and pH=5.93. The removal efficiency of Co(2+) in these conditions was 31.81%. For sulfonated PVA polymer, the optimal conditions determined are as follows: initial concentration of [Co(2+)](0)=10 mg L(-1), r=1.2 and pH=6.5. For these conditions, a removal efficiency of 99.98% has been determined. The experiments showed that Co(2+) removal ability of sulfonated PVA was much higher than its non-sulfonated precursor. Although the polymer concentrations used in the tests with sulfonated PVA were approximately ten times lower than the non-sulfonated one, the removal efficiency of cobalt ions was significantly higher. PMID- 21788032 TI - Design, rationale, and initiation of the Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial: a report from the Cardiothoracic Surgical Trials Network. AB - OBJECTIVE: Patients with coronary artery disease complicated by moderate ischemic mitral regurgitation have demonstrably poorer outcome than do patients with coronary artery disease but without mitral regurgitation. The optimal treatment of this condition has become increasingly controversial, and a randomized trial evaluating current practices is warranted. METHODS: We describe the design and initial execution of the Cardiothoracic Surgical Trials Network Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial. RESULTS: This is an ongoing prospective, multicenter, randomized, controlled clinical trial designed to test the safety and efficacy of mitral repair in addition to coronary artery bypass grafting in the treatment of moderate ischemic mitral regurgitation. CONCLUSIONS: The results of the Cardiothoracic Surgical Trials Network Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial will provide long-awaited information on controversial therapies for this morbid disease process. PMID- 21788033 TI - A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. AB - PURPOSE: We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. MATERIALS AND METHODS: Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle stimulating hormone responses, and prostate specific antigen failure and progression-free survival. RESULTS: During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. CONCLUSIONS: Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin releasing hormone agonist. PMID- 21788034 TI - Extraperitoneal laparoscopic Millin prostatectomy using finger enucleation. AB - PURPOSE: We evaluated the feasibilty, safety and results of extraperitoneal laparoscopic Millin prostatectomy using finger enucleation through an additional 1 cm suprapubic incision. MATERIALS AND METHODS: A total of 66 consecutive laparoscopic simple prostatectomies were performed with this technique in men with symptomatic bladder outflow obstruction and a prostate gland larger than 70 cc on transrectal ultrasound. Data such as operating time, intraoperative blood loss, transfusion rate, complications, catheterization period, hospitalization time and surgical specimen weight were prospectively collected and evaluated. Preoperative and 3-month postoperative International Prostate Symptom Score and urinary flow rates were used to assess the surgical outcome. RESULTS: Average operating time was 55 minutes with a mean estimated blood loss of 200 ml. No blood transfusion was necessary, and no conversion, complications or mortality was present. The mean postoperative catheterization period was 7.3 days with a mean hospital stay of 5.2 days. Mean enucleated tissue weight was 85.5 gm. At 3 months postoperatively the International Prostate Symptom Score improved to a mean of 5.8 (from a mean preoperative score of 29.5) while maximum urine flow improved to a mean of 18.5 ml per second (from a mean preoperative rate of 5.8 ml per second). CONCLUSIONS: This procedure is safe and fast with excellent functional outcomes. However, prolonged catheterization and hospitalization are still required. PMID- 21788035 TI - Predicting the probability of 90-day survival of elderly patients with bladder cancer treated with radical cystectomy. AB - PURPOSE: Despite the increased morbidity and mortality of radical cystectomy in elderly individuals with bladder cancer numerous studies show that surgery can provide a survival benefit. We sought to better identify patients at substantial risk for postoperative mortality. MATERIALS AND METHODS: We evaluated 220 consecutive patients 75 years old or older treated with radical cystectomy for bladder cancer at a single institution from 2000 to 2008. The analytical cohort comprised 169 patients with complete preoperative data available. A Cox proportional hazards model was used to determine the value of precystectomy clinical information to predict 90-day survival after radical cystectomy. Results were used to create a nomogram predicting the probability of 90-day survival after radical cystectomy. The model was then subjected to 200 bootstrap resamples for internal validation. RESULTS: Of the 220 patients 28 (12.7%) died within 90 days of surgery. Older age (HR 2.30, 95% CI 1.22-4.32) and lower preoperative albumin (HR 2.50, 95% CI 1.40-4.45) were significant predictors of 90-day mortality. We developed a nomogram based on patient age, clinical stage, Charlson comorbidity index and albumin to predict the likelihood of 90-day mortality with 75% accuracy. Internal validation showed a bootstrap adjusted concordance index of 71%. CONCLUSIONS: We developed a nomogram that provides individualized risk estimations to predict the probability of 90-day mortality, potentially enhancing preoperative counseling and providing clinicians with an added tool to individualize treatment decisions in this challenging patient population. These data suggest that albumin is a strong predictor of postoperative mortality and show the importance of assessing this variable before surgery. PMID- 21788036 TI - Peer review: "a critique of the critics". PMID- 21788037 TI - Imaging for staging prostate cancer--too much or not enough? PMID- 21788039 TI - The origin and significance of Randall's plaque in nephrolithiasis. PMID- 21788038 TI - Expanded prostate cancer index composite for clinical practice: development and validation of a practical health related quality of life instrument for use in the routine clinical care of patients with prostate cancer. AB - PURPOSE: Measuring the health related quality of life of patients with prostate cancer in routine clinical practice is hindered by the lack of instruments enabling efficient, real-time, point of care scoring of multiple health related quality of life domains. Thus, we developed an instrument for this purpose. MATERIALS AND METHODS: The Expanded Prostate Cancer Index Composite for Clinical Practice is a 1-page, 16-item questionnaire that we constructed to measure urinary incontinence, urinary irritation, and the bowel, sexual and hormonal health related quality of life domains. We eliminated conceptually overlapping items from the 3-page Expanded Prostate Cancer Index Composite-26 and revised the questionnaire format to mirror the AUA symptom index, thereby enabling practitioners to calculate health related quality of life scores at the point of care. We administered the Expanded Prostate Cancer Index Composite for Clinical Practice to a new cohort of patients with prostate cancer in community based and academic oncology, radiation, and urology practices to evaluate instrument validity as well as ease of use in clinical practice. RESULTS: A total of 175 treated and 132 untreated subjects with prostate cancer completed the Expanded Prostate Cancer Index Composite for Clinical Practice. The domain scores of the Expanded Prostate Cancer Index Composite for Clinical Practice correlated highly with the respective domain scores from longer versions of the Expanded Prostate Cancer Index Composite (r>=0.93 for all domains). The Expanded Prostate Cancer Index Composite for Clinical Practice showed high internal consistency (Cronbach's alpha 0.64-0.84) and sensitivity to prostate cancer treatment related effects (p<0.05 in each of 5 health related quality of life domains). Patients completed the Expanded Prostate Cancer Index Composite for Clinical Practice efficiently (96% in less than 10 minutes and with 11% missing items). It was deemed very convenient by clinicians in 87% of routine clinical encounters and clinicians accurately scored completed questionnaires 94% of the time. CONCLUSIONS: The Expanded Prostate Cancer Index Composite for Clinical Practice is a valid instrument that enables patient reported, health related quality of life to be measured efficiently and accurately at the point of care, and thereby facilitates improved emphasis and management of patient reported outcomes. PMID- 21788040 TI - Is repeat transurethral resection needed for minimally invasive T1 urothelial cancer? Pro. PMID- 21788041 TI - Is prostatitis a vascular disease? PMID- 21788043 TI - Regional collaboration to improve radiographic staging practices among men with early stage prostate cancer. AB - PURPOSE: We describe findings from a Urological Surgery Quality Collaborative project focused on improving the use of radiographic staging in men with newly diagnosed prostate cancer. MATERIALS AND METHODS: From May 2009 through September 2010 Urological Surgery Quality Collaborative surgeons collected uniform data for men with newly diagnosed prostate cancer. During this period we implemented 3 phases of data collection. Unlike the baseline phase, the second and third rounds were preceded by collaborative quality improvement interventions, including comparative performance feedback, and review and dissemination of clinical guidelines. We evaluated the use of bone scans and computerized tomography across prostate cancer risk strata, Urological Surgery Quality Collaborative practice locations, and before and after quality improvement interventions. RESULTS: We collected data for 858 men with prostate cancer. Based on the D'Amico classification 44%, 39% and 17% of the men had low, intermediate and high risk cancer, respectively. Overall 25% and 22% of patients underwent staging with a bone scan or computerized tomography, respectively, ordered by a Urological Surgery Quality Collaborative urologist. Urological Surgery Quality Collaborative practices differed significantly in their baseline use of bone scans and computerized tomography for men with low and intermediate risk cancer (p<0.01). Compared with baseline practice patterns (31% bone scans, 28% computerized tomography), urologists in Urological Surgery Quality Collaborative practices ordered fewer bone and computerized tomography scans in post-intervention phases 2 (23%, 21%) and 3 (16%, 13%) of data collection (p<0.01), including a significant reduction in the use of these studies in patients with low and intermediate risk cancer (p<0.05). CONCLUSIONS: Following collaborative feedback on baseline use and review of clinical guidelines, urologists in Urological Surgery Quality Collaborative practices dramatically reduced variations in practice patterns and improved adherence with recommended staging practices. PMID- 21788042 TI - The effect of age on the morbidity of kidney surgery. AB - PURPOSE: Previous reports of the morbidity of renal surgery have been primarily from academic tertiary referral centers and, thus, they may not reflect general clinical practice. We determined the effect of age and comorbidity on in-hospital surgical morbidity for radical and partial nephrectomy on a population level. MATERIALS AND METHODS: Data were obtained from a Canadian national discharge abstract database. From April 1998 to March 2008 information was available on 20,286 radical and 4,292 partial nephrectomies. Complications were identified using specific ICD-9 and 10 diagnosis and procedure codes. Complication rates were estimated by procedure type and by various explanatory variables, including patient age and Charlson comorbidity score. Multivariate logistic regressions were constructed for radical and partial nephrectomy to determine associations between explanatory variables and complications. RESULTS: Overall complications developed in 34.1% of radical and 34.3% of partial nephrectomy cases. Patients were more likely to have cardiac, respiratory, vascular and surgical complications after radical nephrectomy while they were more likely to experience genitourinary and nephrectomy specific complications after partial nephrectomy. On multivariate logistic regression after radical and partial nephrectomy complications increased with age and Charlson score. After adjusting for other covariates patients with a Charlson score of greater than 2 were approximately 6 times more likely to experience a complication than patients with a Charlson score of 0 for radical and partial nephrectomy (OR 6.22, 95% CI 5.18-7.48 and OR 5.68, 95% CI 3.72-8.66, respectively). CONCLUSIONS: In our population based study radical nephrectomy and partial nephrectomy were associated with higher morbidity than previously reported, particularly in the elderly population and in patients with comorbidity. PMID- 21788044 TI - Coronary artery revascularization and the risk of death in men with prostate cancer. AB - PURPOSE: We investigated whether the decrease in death from cardiovascular disease, a major competing risk, explains the observed increase in prostate cancer specific mortality before 1992. MATERIALS AND METHODS: Between 1991 and 2006, 1,880 men with known cardiovascular disease underwent radiation therapy for prostate cancer and were followed until July 2008. Cox regression multivariable analysis was performed to assess whether known prostate cancer prognostic factors, history of coronary artery revascularization for cardiovascular disease, age, Charlson comorbidity score and prostate cancer treatment were associated with the risk of death. RESULTS: Despite a significantly higher Charlson comorbidity score (p<0.001) due to a higher rate of prior myocardial infarction, the risk of death was significantly lower (adjusted hazard ratio 0.63, 95% CI 0.49-0.82, p<0.001) in men who underwent revascularization. High grade prostate cancer contributed significantly to the risk of death in men who underwent revascularization (AHR 1.74, 95% CI 1.04-2.91, p=0.04) but not in those who did not (AHR 1.18, 95% CI 0.88-1.58, p=0.27). CONCLUSIONS: The availability of and appropriate selection for revascularization may explain the increase in prostate cancer specific mortality before 1992. Men with cardiovascular disease in whom revascularization was not appropriate could consider active surveillance of prostate cancer because the increased risk of death was not associated with high grade prostate cancer. PMID- 21788045 TI - SEER coding standards result in underestimation of positive surgical margin incidence at radical prostatectomy: results of a systematic audit. AB - PURPOSE: SEER (Surveillance, Epidemiology and End Results) is the leading source of population level data on prostate cancer, including the positive surgical margin incidence at radical prostatectomy. Recently studies showed wide ranges in positive surgical margin rates among individual registries, which we hypothesized was the result of coding inaccuracies. Thus, we systematically audited SEER prostate cancer data. MATERIALS AND METHODS: The New Mexico Tumor Registry, a SEER core registry, was queried for incident prostate cancer cases in 2007 that met certain criteria, including 1) adenocarcinoma histology, 2) malignant behavior and 3) radical prostatectomy as the first course of therapy. Pathological stage codes were audited by examining original radical prostatectomy pathology reports in accordance with SEER coding guidelines. The incidence and sites of positive surgical margins were critically analyzed. RESULTS: Of the 305 cases that met all study inclusion criteria with complete source documents available 92 (30%) were coded incorrectly. The most common error was failure to properly account for surgical margin status (46 of 92 cases or 50%). The incidence of positive surgical margins in organ confined disease cases was 13% by SEER coding rules but 28% by a more clinical definition of positive surgical margins (p<0.001). In organ confined cases positive surgical margins occurred principally at the apex but in nonorgan confined cases most were multifocal. CONCLUSIONS: In this SEER registry 30% of radical prostatectomy cases in 2007 were coded inaccurately. SEER coding guidelines result in underestimating the positive surgical margin incidence. Clinicians and investigators should recognize the limitations of tumor registry data on positive surgical margins. PMID- 21788046 TI - Effects of increased cross-sectional imaging on the diagnosis and prognosis of adrenocortical carcinoma: analysis of the National Cancer Database. AB - PURPOSE: We assessed whether incidental screening due to imaging performed for other purposes has resulted in earlier detection or better outcomes in patients with adrenocortical carcinoma. MATERIALS AND METHODS: We used the National Cancer Database to assemble a cohort diagnosed with adrenocortical carcinoma from 1985 to 2007. Trends in the distribution of grouped tumor sizes were assessed with the Cochran-Armitage chi-square test. Relative 5-year survival rates were calculated for cases diagnosed through 2002. RESULTS: Median survival in the full cohort of 4,275 patients was 24 months. Localized adrenocortical carcinoma accounted for 43.9% of cases. No stage migration was noted with time. No statistical trends were noted in tumor size changes during the years in patients who underwent surgery for localized disease (p=0.32). No improvement was observed in 5-year survival during the period (p>0.1). CONCLUSIONS: In this cohort of patients with adrenocortical carcinoma, which is to our knowledge the largest cohort reported to date, 43.9% presented with localized disease. No shift was noted toward lower stage or smaller tumor size in a 22-year period despite the advent of abdominal imaging and its resulting incidental screening of the adrenal gland. These data contrast with the well documented stage and size migration of tumors of the kidney, a neighboring retroperitoneal organ. Furthermore, no improvement in survival was noted. As such, better risk stratification of patients with adrenal incidentaloma, while improving treatment efficacy for those with proven adrenocortical carcinoma, is an essential clinical and epidemiological task. PMID- 21788047 TI - Office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. AB - PURPOSE: Multiple studies have shown significant prostate cancer detection for repeat biopsy. However, the best approach regarding core number and location remains controversial. Transrectal saturation biopsy is believed to increase cancer detection but to our knowledge no studies comparing it to 12 to 14-core extended biopsy have been published. We compared saturation and extended repeat biopsy protocols after initially negative biopsy. MATERIALS AND METHODS: A total of 1,056 men underwent prostate biopsy after initially negative biopsy. The extended biopsy group included 393 men with 12 to 14-core repeat biopsy. The saturation biopsy group included 663 men with 20 to 24-core repeat biopsy. We analyzed demographics and prostate cancer between the 2 groups. We compared prostate cancer detection in patients with previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia as well as the risk of detecting clinically insignificant tumors. RESULTS: Prostate cancer was detected in 315 of the 1,056 patients (29.8%). Saturation biopsy detected almost a third more cancers (32.7% vs 24.9%, p=0.0075). In patients with a benign initial biopsy saturation biopsy achieved significantly greater prostate cancer detection (33.3% vs 25.6%, p=0.027). For previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia there was a trend toward higher prostate cancer detection rate in the saturation group but it did not attain statistical significance (31.2% vs 23.3%, p=0.13). Of 315 positive biopsies 119 (37.8%) revealed clinically insignificant cancer (40.1% vs 32.6%, p=0.2). CONCLUSIONS: Compared to extended biopsy, office based saturation biopsy significantly increases cancer detection on repeat biopsy. The potential for increased detection of clinically insignificant cancer should be weighed against missing significant cases. PMID- 21788048 TI - Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. AB - PURPOSE: We describe the safety of sipuleucel-T using an integrated analysis of 4 randomized, controlled studies in patients with prostate cancer. MATERIALS AND METHODS: Adverse events, survival data and laboratory evaluations were examined for common, rare and latent events. RESULTS: In 5% or more of sipuleucel-T cases some adverse events were reported at a rate at least twice that in controls, including chills in 53.1%, pyrexia in 31.3%, headache in 18.1%, myalgia in 11.8%, influenza-like illness in 9.7% and hyperhidrosis in 5.0%. These events generally occurred within 1 day of infusion, were grade 1 or 2 in severity and resolved in 2 days or less. The incidence of serious adverse events reported was 24.0% in sipuleucel-T cases and 25.1% in controls. Grade 3 or greater adverse events were reported within 1 day of infusion in 40 of 601 sipuleucel-T cases (6.7%) and 7 of 303 controls (2.3%). The incidence rate of reported cerebrovascular events was 3.5% for sipuleucel-T cases and 2.6% in controls. CONCLUSIONS: Sipuleucel-T therapy in patients with prostate cancer has a side effect profile that is characterized by mild to moderate, short-term, reversible adverse events. There was no evidence of a treatment related increase in autoimmune complications or secondary malignancies after treatment with sipuleucel-T. Sipuleucel-T can be administered safely in the outpatient setting. PMID- 21788049 TI - Changes in prostate specific antigen in hypogonadal men after 12 months of testosterone replacement therapy: support for the prostate saturation theory. AB - PURPOSE: We measured prostate specific antigen after 12 months of testosterone replacement therapy in hypogonadal men. MATERIALS AND METHODS: Data were collected from the TRiUS (Testim(r) Registry in the United States), an observational registry of hypogonadal men on testosterone replacement therapy (849). Participants were Testim naive, had no prostate cancer and received 5 to 10 gm Testim 1% (testosterone gel) daily. RESULTS: A total of 451 patients with prostate specific antigen and total testosterone values were divided into group A (197 with total testosterone less than 250 ng/dl) and group B (254 with total testosterone 250 ng/dl or greater). The groups differed significantly in free testosterone and sex hormone-binding globulin, but not in age or prostate specific antigen. In group A but not group B prostate specific antigen correlated significantly with total testosterone (r=0.20, p=0.005), free testosterone (r=0.22, p=0.03) and sex hormone-binding globulin (r=0.59, p=0.002) at baseline. After 12 months of testosterone replacement therapy, increase in total testosterone (mean+/-SD) was statistically significant in group A (+326+/-295 ng/dl, p<0.001; final total testosterone 516+/-28 ng/dl) and group B (+154+/-217 ng/dl, p<0.001; final total testosterone 513+/-20 ng/dl). After 12 months of testosterone replacement therapy, increase in prostate specific antigen was statistically significant in group A (+0.19+/-0.61 ng/ml, p=0.02; final prostate specific antigen 1.26+/-0.96 ng/ml) but not in group B (+0.28+/-1.18 ng/ml, p=0.06; final prostate specific antigen 1.55+/-1.72 ng/ml). The average percent prostate specific antigen increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall the greatest prostate specific antigen was observed after 1 month of treatment and decreased thereafter. CONCLUSIONS: Patients with baseline total testosterone less than 250 ng/dl were more likely to have an increased prostate specific antigen after testosterone replacement therapy than those with baseline total testosterone 250 ng/dl or greater, supporting the prostate saturation hypothesis. Clinicians should be aware that severely hypogonadal patients may experience increased prostate specific antigen after testosterone replacement therapy. PMID- 21788050 TI - Factors affecting response to bacillus Calmette-Guerin plus interferon for urothelial carcinoma in situ. AB - PURPOSE: The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guerin plus interferon-alpha therapy in patients with urothelial carcinoma in situ. MATERIALS AND METHODS: We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guerin plus interferon-alpha therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette Guerin naive and those with previous exposure to failed bacillus Calmette-Guerin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guerin plus interferon-alpha response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guerin failure pattern, courses and maintenance, and prior chemotherapy. RESULTS: The complete response rate at 3 and 6 months in naive vs previously failed bacillus Calmette Guerin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guerin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guerin naive patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019). CONCLUSIONS: Factors associated with a poor response to bacillus Calmette-Guerin plus interferon-alpha therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guerin failures and a bacillus Calmette-Guerin failure pattern. PMID- 21788051 TI - Hospital and surgical caseload are predictors of comprehensive surgical treatment for bladder cancer: a population based study. AB - PURPOSE: In patients with nonmetastatic muscle invasive bladder cancer, radical cystectomy and pelvic lymph node dissection represent a comprehensive surgical treatment. We tested the hypothesis that radical cystectomy performed at a high caseload hospital and/or by a high caseload surgeon is more likely to include pelvic lymph node dissection. MATERIALS AND METHODS: We identified 12,274 patients with bladder cancer treated with radical cystectomy between 1998 and 2007 within the Nationwide Inpatient Sample. Univariable and multivariable analyses tested the relationship between hospital and surgical caseload at radical cystectomy, and the pelvic lymph node dissection rate. Generalized estimating equation models were used to adjust for clustering among hospitals and surgeons. RESULTS: Overall 70% of patients received comprehensive surgical treatment defined as radical cystectomy and pelvic lymph node dissection. The pelvic lymph node dissection rate was 63% vs 67% vs 80% for low vs intermediate vs high annual hospital caseload tertiles, respectively (p<0.001). The pelvic lymph node dissection rate was 64% vs 68% vs 80% for low vs intermediate vs high annual surgical caseload tertiles, respectively (p<0.001). On multivariable analyses and after adjusting for clustering, annual hospital caseload and annual surgical caseload were independent predictors of the pelvic lymph node dissection rate. CONCLUSIONS: Our findings indicate that a potentially comprehensive surgical treatment, defined as radical cystectomy with pelvic lymph node dissection, is only offered to a subset of patients. Annual hospital caseload and annual surgical caseload represent important determinants of potentially comprehensive bladder cancer surgery. Efforts should be made to ensure that virtually all patients with bladder cancer receive comprehensive surgical treatment. PMID- 21788052 TI - Utilization trends in prostate cancer therapy. AB - PURPOSE: We determined therapeutic trends in the management of adenocarcinoma of the prostate, and in the case of intensity modulated radiation therapy we investigated whether site of service influenced those trends. MATERIALS AND METHODS: A variety of CPT codes to treat adenocarcinoma of the prostate were extracted from the Medicare Part B 5% sample for the years 2006 to 2008 inclusive. Data were stratified by year, type of service and, in the case of radiation therapy, site of service. Treatment trends were calculated by indexing the total number of Medicare beneficiaries receiving a service against needle biopsies of the prostate. RESULTS: The percentage of Medicare beneficiaries receiving therapy indexed to needle biopsies of the prostate increased from 43.8% in 2006 to 49.0% in 2008. Trends in radiation and surgery were similar with 11.5% and 13% increases in each modality, respectively. Total Medicare beneficiaries receiving intensity modulated radiation therapy and laparoscopic radical prostatectomy increased by 25.4% and 22.1%, respectively, while Medicare beneficiaries treated with open radical prostatectomy and 3-dimensional conformal radiation therapy decreased by 27.9% and 37.6%, respectively. The pattern of use for intensity modulated radiation therapy was similar in physician office and hospital facility settings, increasing from 7.3% to 11.1% and 8.3% to 11.3% of Medicare beneficiaries indexed to needle biopsies of the prostate receiving intensity modulated radiation therapy at these sites in 2008, respectively. CONCLUSIONS: Treatment trends in surgery and radiation strongly favor newer technologies, and in the case of intensity modulated radiation therapy, utilization trends for treatment of adenocarcinoma of the prostate are similar across all sites of service. PMID- 21788053 TI - How much imaging is necessary in patients with multicystic dysplastic kidneys? PMID- 21788054 TI - Surgical access for electrical stimulation of the pudendal and dorsal genital nerves in the overactive bladder: a review. AB - PURPOSE: The anatomy of the pudendal nerve and its nerve branches, especially the dorsal nerve of the penis and clitoris (dorsal genital nerves), and the clinical application of electrical stimulation of these nerves in patients with overactive bladder syndrome and detrusor overactivity are reviewed. MATERIALS AND METHODS: A literature search was performed using the PubMed(r) database and reference lists of relevant studies to obtain articles concerning the anatomy as well as the electrical stimulation of the pudendal nerve and its nerve branches in patients with overactive bladder syndrome. RESULTS: According to the anatomy, electrical stimulation of the pudendal nerve and the dorsal genital nerves to suppress involuntary detrusor contractions is possible at several sites along their course from the sacral nerves to the penis or clitoris. The nerves are accessible by minimally invasive percutaneous methods. Stimulation of the pudendal nerve and dorsal genital nerves effectively increases bladder capacity, and inhibits involuntary detrusor contractions and overactive bladder symptoms. CONCLUSIONS: More clinically applied studies are recommended for stimulation of the dorsal genital nerves to assess its value and feasibility because most studies have been performed in an acute and experimental setting. The preferred type of electrode is not known, but if wire electrodes can be implanted and fixated well by a minimally invasive procedure, cuff electrodes are not necessary. Before deciding on continuous or conditional stimulation, chronic clinical studies are recommended because acute studies remain inconclusive. The feasibility of conditional stimulation depends on the availability of a reliable and clinically applicable detrusor activity sensor. PMID- 21788055 TI - Prognostic significance of tumor volume in radical prostatectomy and needle biopsy specimens. AB - PURPOSE: This review addresses the controversies that persist relating to the prognosis and reporting of tumor volume in adenocarcinoma of the prostate. MATERIALS AND METHODS: A search was performed using the MEDLINE database and referenced lists of relevant studies to obtain articles addressing the quantification of cancer on radical prostatectomy and needle biopsy. RESULTS: In the 2010 TNM classification system T2 tumor at radical prostatectomy is subdivided into pT2a (unilateral tumor occupying less than 1/2 a lobe), pT2b (unilateral tumor greater than 1/2 a lobe) and pT2c (bilateral tumor). This pathological substaging of T2 disease fails on several accounts. In most studies pT2b disease almost does not exist. By the time a tumor is so large that it microscopically occupies more than 1/2 a lobe, in the majority of cases there is bilateral (pT2c) tumor. An even greater flaw of the substaging system for stage pT2 disease is the lack of prognostic significance. In reporting pathologically organ confined cancer, it should be merely noted as pT2 without further subclassification. The data are conflicting as to the independent prognostic significance of objective measurements of tumor volume in radical prostatectomy specimens. The most likely explanation for the discordant results lies in the strong correlation of tumor volume with other prognostic markers such as extraprostatic extension and positive margins. In studies where it is statistically significant on multivariate analysis, it is unlikely that knowing tumor volume improves prediction of prognosis beyond routinely reported parameters to the degree that it would be clinically useful for an individual patient. An alternative is to record tumor volume as minimal, moderate or extensive, which gives some indication to the urologist as to the extent of disease. Not only does providing an objective measurement not add useful prognostic information beyond what is otherwise routinely reported by the pathologist, but many objective measurements done in routine practice will likely not be an accurate indicator of the true tumor volume. There is also a lack of consensus regarding the best method of measuring tumor length when there are multiple foci in a single core separated by benign intervening prostatic stroma. Some pathologists, this author included, consider discontinuous foci of cancer as if it was 1 uninterrupted focus, the rationale being that these discontinuous foci are undoubtedly the same cancer going in and out of the plane of section. Measuring the cancer from where it starts to where it ends on the core gives the minimal length of cancer in the prostate. Others measure each focus individually, and the sum of these measurements is considered the cancer length on the core. Quantifying cancer with an ocular micrometer to record the total length or percent length of cancer is time-consuming, and the data are conflicting whether this is superior to other, simpler methods and whether any potential differences in predictive accuracy would translate into changes in clinical management. It is recommended that at a minimum the number of positive cores be recorded, unless fragmented involved cores preclude evaluation, along with at least 1 other more detailed measurement such as the percent of core involvement or length of cancer. CONCLUSIONS: Consensus has been reached on some of the issues relating to quantifying tumor volume in prostate cancer, such as the lack of utility of substaging pT2 disease. Other questions such as whether to include or subtract intervening benign prostate tissue on prostate needle cores will require additional studies. Finally, matters such as the need to quantify cancer at radical prostatectomy or which method of quantifying cancer on needle biopsy is superior will likely remain contentious due to the close interrelationship and redundancy of prognostic variables. PMID- 21788056 TI - Baseline heavy metals and metalloid values in blood of loggerhead turtles (Caretta caretta) from Baja California Sur, Mexico. AB - Environmental pollution due to heavy metals is having an increased impact on marine wildlife accentuated by anthropogenic changes in the planet including overfishing, agricultural runoff and marine emerging infectious diseases. Sea turtles are considered sentinels of ecological health in marine ecosystems. The objective of this study was to determine baseline concentrations of zinc, cadmium, copper, nickel, selenium, manganese, mercury and lead in blood of 22 clinically healthy, loggerhead turtles (Caretta caretta), captured for several reasons in Puerto Lopez Mateos, Baja California Sur, Mexico. Zinc was the most prevalent metal in blood (41.89 MUg g-1), followed by Selenium (10.92 MUg g-1). The mean concentration of toxic metal Cadmium was 6.12 MUg g-1 and 1.01MUg g-1 respectively. Mean concentrations of metals followed this pattern: Zn>Se>Ni>Cu>Mn>Cd>Pb and Hg. We can conclude that blood is an excellent tissue to measure in relatively non-invasive way baseline values of heavy metals in Caretta caretta. PMID- 21788057 TI - Acoustic Radiation Force Impulse-Imaging for the evaluation of the thyroid gland: a limited patient feasibility study. AB - PURPOSE: Real-time tissue elastography, a qualitative elastography method, has shown promising results in the diagnostic work up of thyroid nodules. However, to our knowledge no study has evaluated a quantitative elastography method in the thyroid gland. The present study is a feasibility study evaluating Acoustic Radiation Force Impulse-Imaging, a novel quantitative elastography method in the thyroid gland. METHODS: ARFI-imaging involves the mechanical excitation of tissue using short-duration acoustic pulses to generate localized displacements in tissue. The displacements induce a lateral shear-wave propagation which is tracked using multiple laterally positioned ultrasound "tracking" beams. Inclusion criteria were: thyroid nodules >=1cm, non-functioning or hypo functioning on radionuclide scanning, and cytological/histological assessment of thyroid nodule as reference method. All patients received conventional ultrasound, and examination of the thyroid gland including Power Doppler Ultrasound using a 9MHz linear transducer, in addition real-time elastography (RTE) was performed at 9MHz frequency and ARFI-imaging was performed at 4MHz using Siemens (ACUSON S2000) B-mode-ARFI combination transducer. RESULTS: Sixty nodules in 55 patients were analyzed. Three nodules were papillary carcinoma. The stiffer the tissue the faster the shear wave propagates. The results obtained indicated that the shear wave velocity in thyroid lobes ranged between 0.5 and 4.9m/s. The median velocity of ARFI-imaging in the healthy nodule-free thyroid gland, as well as in benign and malignant thyroid nodules was 1.98m/s (range: 1.20-3.63m/s), 2.02m/s (range: 0.92-3.97m/s), and 4.30m/s (range: 2.40-4.50m/s), respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p=0.018) or benign thyroid nodules (p=0.014) on the other hand. Specificity of ARFI-imaging for the differentiation of benign and malignant thyroid nodules was comparable with RTE (91-95%). CONCLUSIONS: ARFI can be performed in the thyroid tissue with reliable results. PMID- 21788058 TI - Ultrasonic measurements of particle retention by a porous medium. AB - Ultrasound transmission and reflection are utilized to characterize the particle retention in depth of fluid-saturated porous samples under a flow of silt solution. The effect of the concentration of particles in the fluid is investigated via measurements of "comparison coefficients" which are the ratio of the Fourier transforms of the reflected (transmitted) signals before and after the particle flow. Numerical computations of the latter coefficients using Biot Stoll's theory are compared to the experimental data. The frequential evolution of physical parameters such as bulk and shear moduli are sought. To this end, a gradient descent algorithm is utilized to minimize the differences between the experimental and calculated comparison coefficients. Several concentrations of suspended particles are investigated to check the validity of this inversion method and a good agreement between theory and experiments is observed. PMID- 21788059 TI - Metal sorption by peat and algae treated peat: kinetics and factors affecting the process. AB - The article presents a new approach that can be used for the purification of water contaminated by heavy metals. The treatment of peat with microalgae showed to be an effective way of increasing metal uptake by peat. Metal sorption was studied for a multimetal solution containing Cu, Cd, Ni, Zn, Cd, and Pb. Cu and Pb were found to be the metals having the highest affinity to peat. Water hardness has a strong effect on the uptake of borderline metals (Cd, Ni, Zn, Cd) from a solution. The use of algae for peat treatment resulted in less time to reach an equilibrium (24 h vs. 72 h for pure peat), and the effect of water hardness (Ca2+) on metal uptake was considerably reduced. Both peat and algal treated peat were able to take up metals from rather acidic solutions (pH 3.0). pH had less influence on the metal uptake compared with water hardness. The affinity of heavy metals to peat was the following: Pb>Cu>Ni>Cd>Zn>Co. It slightly changed to Pb>Cu>Ni>Cd~Co~Zn when the combined sorbent, peat treated with microalga, was applied. PMID- 21788060 TI - Qualitative analysis of volatile organic compounds on biochar. AB - Qualitative identification of sorbed volatile organic compounds (VOCs) on biochar was conducted by headspace thermal desorption coupled to capillary gas chromatographic-mass spectrometry. VOCs may have a mechanistic role influencing plant and microbial responses to biochar amendments, since VOCs can directly inhibit/stimulate microbial and plant processes. Over 70 biochars encompassing a variety of parent feedstocks and manufacturing processes were evaluated and were observed to possess diverse sorbed VOC composition. There were over 140 individual chemical compounds thermally desorbed from some biochars, with hydrothermal carbonization (HTC) and fast pyrolysis biochars typically possessing the greatest number of sorbed volatiles. In contrast, gasification, thermal or chemical processed biochars, soil kiln mound, and open pit biochars possessed low to non-detectable levels of VOCs. Slow pyrolysis biochars were highly variable in terms of their sorbed VOC content. There were no clear feedstock dependencies to the sorbed VOC composition, suggesting a stronger linkage with biochar production conditions coupled to post-production handling and processing. Lower pyrolytic temperatures (?350 degrees C) produced biochars with sorbed VOCs consisting of short carbon chain aldehydes, furans and ketones; elevated temperature biochars (>350 degrees C) typically were dominated by sorbed aromatic compounds and longer carbon chain hydrocarbons. The presence of oxygen during pyrolysis also reduced sorbed VOCs. These compositional results suggest that sorbed VOCs are highly variable and that their chemical dissimilarity could play a role in the wide variety of plant and soil microbial responses to biochar soil amendment noted in the literature. This variability in VOC composition may argue for VOC characterization before land application to predict possible agroecosystem effects. PMID- 21788061 TI - Levels of PCDD/Fs and DL-PCBs in selected foods and estimated dietary intake for the local residents of Luqiao and Yuhang in Zhejiang, China. AB - Polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) were measured by high resolution gas chromatograph/high resolution mass spectrometer (HRGC/HRMS) in six food groups from Luqiao (LQ) where the e-waste has been recycled and from Yuhang (YH) where the agriculture dominates in Zhejiang Province in China. The total WHO-TEQ values of PCDD/Fs and DL-PCBs in selected foods from LQ were significantly much higher than those from YH. The highest level of the total WHO-TEQ was in crucian carp (10.87 pg g(-1) w.w.) followed by duck (3.77 pg g(-1) w.w.), hen eggs (2.80 pg g( 1) w.w.), chicken (2.43 pg g(-1) w.w.), rice (0.08 pg g(-1) w.w.) and vegetables (0.022 pg g(-1) w.w.) in LQ. By contrast, the highest levels were measured in duck (0.74 pg g(-1) w.w.) followed by hen eggs (0.69 pg g(-1) w.w.), crucian carp (0.55 pg g(-1) w.w.), chicken (0.44 pg g(-1) w.w.), vegetables (0.002 pg g(-1) w.w.) and rice (0.0002 pg g(-1) w.w.) in YH, respectively. The monthly intake of PCDD/Fs and DL-PCBs for the local residents was 401.75 pg WHO-TEQ g(-1) w.w. in LQ, which is above the provisional tolerable monthly intake (PTMI) set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). We determined a monthly intake of 37.13 pg WHO-TEQ g(-1)w.w. in YH, which is below the PTMI. Crucian carp was the predominant contributor to the estimated monthly intake (EMI), accounting for 67.74% and 36.51% in LQ and YH, respectively. High levels of PCDD/Fs and DL PCBs in selected foods indicate severe contamination of these pollutants in the e waste recycling site. PMID- 21788062 TI - A hominin scaphoid from Sterkfontein, Member 4: morphological description and first comparative phenetic 3D analyses. PMID- 21788063 TI - Slow improvements of metal exposure, health- and breeding conditions of pied flycatchers (Ficedula hypoleuca) after decreased industrial heavy metal emissions. AB - The environment around metal industries, such as smelters, is often highly contaminated due to continuous deposition of metals. We studied nest box breeding populations of pied flycatchers (Ficedula hypoleuca) in a well-studied pollution gradient from a sulfide ore smelter in Northern Sweden, after reduced aerial metal emissions (by 93-99%) from the smelter. The deposition of arsenic, cadmium, copper and zinc (based on moss samples) reflected the reduced emissions fairly well. However, nestling pied flycatchers had similar concentrations of these elements and mercury in tissues (bone, liver and blood) and feces in the 2000s, as in the 1980s, when the emissions were substantially higher. The exposure to high metal concentrations in the close vicinity of the smelter resulted in inhibited ALAD activities, depressed hemoglobin and hematocrit levels and increased mortality of nestlings. Our results indicate that in the highly contaminated environment around the smelter, nestlings reflected the slowly cycling soil pool, rather than the atmospheric deposition, and the concentration in soils plays an important role for the response of pied flycatchers to reduced atmospheric deposition. PMID- 21788064 TI - Reduced production of IFN-gamma and LT-alpha is associated with successful prednisone therapy in patients with acquired hemophilia A: a pilot study. AB - Glucocorticoids (GC) are a standard treatment for acquired hemophilia A (AH). Although the optimal treatment regimen and duration of GC's is unknown, measurement of sub-clinical immune responses may help direct therapeutic decision making. To study the helpfulness of this approach, three male patients diagnosed with AH were treated with prednisone. The therapy resulted in inhibitor elimination in two out of the three individuals. During the treatment, peripheral mononuclear cells were isolated at different time points and stimulated in vitro. The expression of IFN-gamma and LT-alpha were monitored at both the protein and the mRNA levels. The amount of IFN-gamma and LT-alpha were markedly reduced by the time of inhibitor disappearance in the patients responding to GC therapy but remained high in the non-responder until cyclophosphamide was added. This study suggests that the secretion level of IFN-gamma and/or LT-alpha could be a predictive marker of prednisone responsiveness. PMID- 21788065 TI - Aspirin treatment influences platelet-related inflammatory biomarkers in healthy individuals but not in acute stroke patients. AB - OBJECTIVES: Platelet-leukocyte aggregation is believed to contribute to acute thrombotic events. While the effect of aspirin on platelet-to-platelet aggregation is well established, the impact of the drug on pro-inflammatory platelet function remains equivocal. Thus we investigated the effect of aspirin on selected platelet-related inflammatory biomarkers in both acute ischaemic stroke patients and healthy volunteers. METHODS: Using five-colour flow cytometry the platelet surface expression of CD62P and CD40L and subpopulations of leukocyte-platelet aggregates were assessed in 63 acute stroke patients and 40 healthy volunteers at baseline and after a 10-day period of aspirin intake at a daily dose of 150 mg. Simultaneously the plasma levels of soluble CD62P and CD40L, serum level of TxB(2), and whole blood impedance platelet aggregation under arachidonic acid (AA) stimulation were investigated. RESULTS: No differences in values of studied platelet-related inflammatory biomarkers in both resting platelets and those activated with TRAP after 10-day treatment with aspirin were confirmed in stroke subjects. In healthy individuals the resting platelet expression of CD62P, plasma level of soluble CD62P and percentage of circulating monocyte-platelet aggregates were lower after the aspirin intake period (P=0.009; P=0.04; P=0.004, respectively). In both studied groups serum level of TxB(2) and platelet aggregation under AA stimulation were lower than before treatment (P<0.001). CONCLUSION: Despite effective inhibition of COX-1 dependent platelet aggregation, aspirin does not influence the platelet alpha granule-derived inflammatory mediators and monocyte-platelet aggregation in acute stroke subjects, although it does in healthy individuals. PMID- 21788066 TI - Low TWEAK expression is correlated to the progression of squamous cervical carcinoma. AB - OBJECTIVE: To investigate the correlation of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its specific receptor fibroblast growth factor inducible immediate-early response protein 14 (Fn14) to cervical carcinogenesis by examining TWEAK/Fn14 expression levels or locations in different cervical tissues and cells. METHODS: TWEAK/Fn14 mRNA expressions were detected by quantitative real-time PCR in total of 120 cervical samples including normal, precancerous and cancerous tissues, while protein expressions were detected by immunofluorescent staining and western blot in both tissues and cell lines. Correlation between TWEAK expression levels to cancer progression and clinicopathologic features was statistically analyzed. RESULTS: The TWEAK expression was significantly decreased while Fn14 expression was increased in carcinoma and cervical intraepithelial neoplasm (CIN) specimens compared with that in normal control specimens. A similar trend of TWEAK/Fn14 expression was also observed in cervical cell lines. In addition, TWEAK expression decreased further along with the interstitial depth of invasion (P<0.05) and tumor grade (P<0.05), suggesting that TWEAK acts rather on local cancer tissue infiltration. CONCLUSION: TWEAK/Fn14 pathway may play a role in the development of squamous cervical carcinoma, in which the reduced level of TWEAK could promote the progression and invasion of cervical cancer. An increase in Fn14 may reflect a compensatory response to decreased TWEAK and may provide a novel therapeutic target for human cervical cancer treatment or a biomarker for cervical cancer diagnosis. PMID- 21788067 TI - Biota: sediment partitioning of aluminium smelter related PAHs and pulp mill related diterpenes by intertidal clams at Kitimat, British Columbia. AB - The question of polycyclic aromatic hydrocarbon (PAH) bioavailability and its relationship to specific PAH sources with different PAH binding characteristics is an important one, because bioavailability drives PAH accumulation in biota and ultimately the biochemical responses to the PAH contaminants. The industrial harbour at Kitimat (British Columbia, Canada) provides an ideal location to study the bioavailability and bioaccumulation of sediment hydrocarbons to low trophic level biota. Samples of soft shell clams (Mya arenaria) and intertidal sediment collected from multiple sites over six years at various distances from an aluminium smelter and a pulp and paper mill were analysed for 106 PAHs, plant diterpenes and other aromatic fraction hydrocarbons. Interpretation using PAH source ratios and multivariate data analysis reveals six principal hydrocarbon sources: PAHs in coke, pitch and emissions from anode combustion from the aluminium smelter, vascular plant terpenes and aromatised terpenes from the pulp and paper mill, petroleum PAHs from shipping and other anthropogenic activities and PAHs from natural plant detritus. Harbour sediments predominantly contain either pitch or pyrogenic PAHs from the smelter, while clams predominantly contain plant derived PAHs and diterpenes from the adjacent pulp mill. PAHs from the smelter have low bioavailability to clams (Biota-Sediment Accumulation Factors; BSAFs <1 for pitch and coke; <10 for anode combustion, decreasing to ~0.1 for the mass 300 and 302 PAHs), possibly due to binding to pitch or soot carbon matrices. Decreases in PAH isomer ratios between sediments and clams likely reflect a combination of variation in uptake kinetics of petroleum PAHs and compound specific metabolism, with the importance of petroleum PAHs decreasing with increasing molecular weight. Plant derived compounds exhibit little natural bioaccumulation at reference sites, but unsaturated and aromatised diterpenes released from resins by industrial pulping processes are readily accumulated by the clams (BSAFs >500). Thus while most of the smelter associated PAHs in sediments may not be bioavailable to benthic organisms, the plant terpenes (including retene, totarol, ferruginol, manool, dehydroabietane and other plant terpenes that form the chemical defence mechanism of conifers) released by pulp mills are bioavailable and possess demonstrated toxic properties. The large scale release of plant terpenes by some of the many pulp mills located in British Columbia and elsewhere represents a largely undocumented risk to aquatic biota. PMID- 21788069 TI - Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery. AB - Targeted delivery of therapeutic nanoparticles in a disease-specific manner represents a potentially powerful technology especially when treating infiltrative brain tumors such as gliomas. We developed a nanoparticulate drug delivery system decorated with AS1411 (Ap), a DNA aptamer specifically binding to nucleolin which was highly expressed in the plasma membrane of both cancer cells and endothelial cells in angiogenic blood vessels, as the targeting ligand to facilitate anti-glioma delivery of paclitaxel (PTX). Ap was conjugated to the surface of PEG-PLGA nanoparticles (NP) via an EDC/NHS technique. With the conjugation confirmed by Urea PAGE and XPS, the resulting Ap-PTX-NP was uniformly round with particle size at 156.0 +/- 54.8 nm and zeta potential at -32.93 +/- 3.1 mV. Ap-nucleolin interaction significantly enhanced cellular association of nanoparticles in C6 glioma cells, and increased the cytotoxicity of its payload. Prolonged circulation and enhanced PTX accumulation at the tumor site was achieved for Ap-PTX-NP, which eventually obtained significantly higher tumor inhibition on mice bearing C6 glioma xenografts and prolonged animal survival on rats bearing intracranial C6 gliomas when compared with PTX-NP and Taxol((r)). The results of this contribution demonstrated the potential utility of AS1411 functionalized nanoparticles for a therapeutic application in the treatment of gliomas. PMID- 21788070 TI - A starch-based microparticulate system dedicated to diagnostic and therapeutic nuclear medicine applications. AB - The aim of this work was to develop a new microparticulate system able to form a complex with radionuclides with a high yield of purity for diagnostic or therapeutic applications. Owing to its properties potato starch was chosen as starting material and modified by oxidization and coupling of a ligand (polyamine) enabling modified starch to chelate radionuclides. The choice of suitable experiments was based on a combination of a Rechtschaffner experimental design and a surface response design to determine the influence of experimental parameters and to optimize the final product. Starch-based microparticle formulations from the experimental plans were compared and characterized through particle size analysis, scanning electron microscopy, elemental analysis and, for the most promising formulations, by in vitro labeling stability studies and determination of free polyamine content or in vivo imaging studies. The mechanism of starch-based microparticle degradation was identified by means of size measurements. The results of the Rechtschaffner design showed the positive qualitative effect of the temperature and the duration of coupling reaction whereas surface response analysis clearly showed that, by increasing the oxidization level and starch concentration, the nitrogen content in the final product is increased. In vitro and in vivo characterization led to identification of the best formulation. With a size around 30 MUm, high radiochemical purity (over 95%) and a high signal-to-noise ratio (over 600), the new starch-based microparticulate system could be prepared as ready-to-use kits and sterilized without modification of its characteristics, and thus meet the requirement for in vivo diagnostic and therapeutic applications. PMID- 21788068 TI - Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche. AB - Human livers have maturational lineages of cells within liver acini, beginning periportally in stem cell niches, the canals of Hering, and ending in polyploid hepatocytes pericentrally and cholangiocytes in bile ducts. Hepatic stem cells (hHpSCs) in vivo are partnered with mesenchymal precursors to endothelia (angioblasts) and stellate cells, and reside in regulated microenvironments, stem cell niches, containing hyaluronans (HA). The in vivo hHpSC niche is modeled in vitro by growing hHpSC in two-dimensional (2D) cultures on plastic. We investigated effects of 3D microenvironments, mimicking the liver's stem cell niche, on these hHpSCs by embedding them in HA-based hydrogels prepared with Kubota's Medium (KM), a serum-free medium tailored for endodermal stem/progenitors. The KM-HA hydrogels mimicked the niches, matched diffusivity of culture medium, exhibited shear thinning and perfect elasticity under mechanical loading, and had predictable stiffness depending on their chemistry. KM-HA hydrogels, which supported cell attachment, survival and expansion of hHpSC colonies, induced transition of hHpSC colonies towards stable heterogeneous populations of hepatic progenitors depending on KM-HA hydrogel stiffness, as shown by both their gene and protein expression profile. These acquired phenotypes did not show morphological evidence of fibrotic responses. In conclusion, this study shows that the mechanical properties of the microenvironment can regulate differentiation in endodermal stem cell populations. PMID- 21788071 TI - Theranostic systems assembled in situ on demand by host-guest chemistry. AB - Theranostic systems have been explored extensively for a diagnostic therapy in the forms of polymer conjugates, implantable devices, and inorganic nanoparticles. In this work, we report theranostic systems in situ assembled by host-guest chemistry responding to a request. As a model theranostic system on demand, cucurbit[6]uril-conjugated hyaluronate (CB[6]-HA) was synthesized and decorated with FITC-spermidine (spmd) and/or formyl peptide receptor like 1 (FPRL1) specific peptide-spmd by simple mixing in aqueous solution. The resulting (FITC-spmd and/or peptide-spmd)@CB[6]-HA was successfully applied to the bioimaging of its target-specific delivery to B16F1 cells with HA receptors and its therapeutic signal transduction with elevated Ca(2+) and phosphor extracellular signal-regulated kinase (pERK) levels in FPRL1-expressing human breast adenocarcinoma (FPRL1/MCF-7) cells. Finally, we could confirm in vitro and in vivo stability of the highly specific host-guest interaction. The on-demand theranostic platform technology using host-guest chemistry can be exploited for various bioimaging, biosensing, drug delivery, and tissue engineering applications. PMID- 21788072 TI - Angiotensin III stimulates ERK1/2 mitogen-activated protein kinases and astrocyte growth in cultured rat astrocytes. AB - Angiotensin (Ang) III is a biologically active metabolite of Ang II with similar effects and receptor binding properties as Ang II. Most Ang III studies delineate physiological effects of the peptide but, the intracellular pathways leading to the actions are unknown and are a focus of these studies. We investigated in cultured brainstem and cerebellum rat astrocytes whether Ang III stimulates ERK1/2 mitogen activated protein (MAP) kinases and astrocyte growth. Ang III significantly stimulated ERK1/2 MAP kinases in a dose- and time-dependent manner. The maximal stimulation occurred with 100 nM Ang III (2.8+/-0.3 and 2.3+/-0.1 fold over basal, in brainstem and cerebellum astrocytes, respectively). This stimulation occurred as early as 1 min, and was sustained for at least 15 min. Moreover, inhibition of the ERK1/2 MAP kinase pathway by 10 MUM PD98059 attenuated Ang III-induced ERK1/2 phosphorylation. Ang III induction of ERK1/2 occurred via stimulation of the Ang AT(1) receptor since pretreatment with 10 MUM Losartan, a selective AT(1) receptor blocker, prevented Ang III-induced ERK1/2 phosphorylation. The selective AT(2) Ang receptor blocker PD123319 was ineffective. Comparable to Ang II, Ang III also stimulated astrocyte growth in a concentration-dependent manner, an effect that occurred via activation of the AT(1) receptor as well. These findings suggest that Ang III has similar effects as Ang II in astrocytes since it rapidly stimulates the phosphorylation of the ERK1/2 MAP kinases and induces astrocyte proliferation through activation of the AT(1) receptor. These studies are important in establishing signaling pathways for Ang III and provide validation of the central role of Ang III. PMID- 21788073 TI - Immunomodulatory role of substance P in the wall lizard Hemidactylus flaviviridis: an in vitro study. AB - Present in vitro investigation for the first time in ectotherms demonstrated the immunomodulatory role of substance P in the wall lizard Hemidactylus flaviviridis. Substance P inhibited the percentage phagocytosis and phagocytic index of lizard splenic phagocytes. Inhibitory effect of substance P was completely blocked by NK-1 receptor antagonist spantide I, indicating the NK-1 receptor mediated action. Further, NK-1 receptor-coupled downstream signaling cascade involved in controlling phagocytosis was explored using inhibitors of adenylate cyclase (SQ 22536) and protein kinase A (H-89). Both the inhibitors, in a concentration-related manner decreased the suppressive effect of substance P on phagocytosis. In addition, substance P treatment caused an increase in intracellular cAMP level in splenic phagocytes. Taken together, it can be suggested that substance P via NK-1 receptor-coupled AC-cAMP-PKA pathway modulated the phagocytic activity of splenic phagocytes in wall lizards. PMID- 21788074 TI - Plasmablastic lymphoma: are more intensive regimens needed? PMID- 21788075 TI - Cytokine antibody array analysis in brain and periphery of scrapie-infected Tg338 mice. AB - Scrapie is a prion-associated transmissible spongiform encephalopathy (TSE) of sheep and goats, and frequently serves as a comparative model for other prion diseases, such as chronic wasting disease and bovine spongiform encephalopathy. TSEs are unique neurologic disorders that do not appear to be accompanied by robust systemic immunologic responses. mRNA data suggest that cytokines are involved in scrapie progression. In this study, brain tissue, mesenteric lymph nodes, splenic tissue and serum from ovinized mice were screened for 62 cytokine and cytokine-related proteins at pre-clinical and clinical points of infection. Expression patterns were compared to brain histology and clinical presentation. Increased cytokine expression in the brain and periphery were noted in scrapie positive animals before histologic changes or clinical signs were evident. Of the 62 proteins examined, only IL-10 and TIMP-1 were consistently expressed at increased levels in the serum throughout infection. These cytokines could suggest future targets for biomarkers of infection and may, as well, provide insight into the biologic dynamics of prion-associated neurologic diseases. PMID- 21788076 TI - Time trade-off procedure for measuring health utilities loss with human papillomavirus-induced diseases: a multicenter, retrospective, observational pilot study in Italy. AB - BACKGROUND: The economic evaluation of any human papillomavirus (HPV) vaccination strategy requires the measurement of clinical benefits (quality-adjusted life years [QALY]) gained to reflect both the increase in life expectancy and the economic benefits associated with an effective intervention. OBJECTIVE: The purpose of this pilot study was to investigate the feasibility of a standardized time trade-off (TTO) procedure to quantify utilities loss in health states affected by HPV-induced pathologies in Italy. METHODS: This multicenter, retrospective, observational, cross-sectional study was designed to elicit data on utilities in a cohort of women with a histologically confirmed diagnosis of high-grade cervical intraepithelial neoplasias (CIN2-3). An algorithm for the computerized administration of a TTO questionnaire was developed for the standardized elicitation of data on health utilities in CIN2-3, anogenital warts, and invasive cervical cancer. The European Quality of Life-5 Dimensions (EQ-5D) questionnaire was used to assess the respondents' baseline perception of their health conditions. The correlation between utilities and age, time from conization to questionnaire administration, and EQ-5D score, was tested using the Spearman rank correlation coefficient (rho) as a measure of validity. RESULTS: Of 42 enrolled patients, 36 responded (85.7%) (mean [SD] age, 37.2 [9.0] years). The women's perception of their health state was high (mean [SD] EQ-5D score, 0.93 [0.10]). The mean utility values were 0.73 (0.22), 0.71 (0.35), and 0.02 (0.08) for CIN2-3, anogenital warts, and invasive cervical cancer, respectively. Based on rho values, none of the 3 HPV-induced pathologies considered was significantly correlated with utility. Nonsignificant variability was found among utilities elicited for anogenital warts (range, 0.54 [0.47] to 0.79 [0.27]); this variability was a limitation of this pilot study and was likely the result of the limited sample size. CONCLUSIONS: Based on the findings from this pilot study, a TTO standardized procedure is expected to be feasible and appropriate for assessing utilities in patients affected by HPV-related diseases and for cost effectiveness analyses of cervical cancer prevention in Italy. PMID- 21788077 TI - Latanoprost systemic exposure in pediatric and adult patients with glaucoma: a phase 1, open-label study. AB - OBJECTIVE: To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose. DESIGN: Phase 1, open-label, multicenter study. PARTICIPANTS: Pediatric patients of 3 age groups (<3, 3-<12, and 12-<18 years) and adults (>=18 years) receiving latanoprost ophthalmic solution 0.005% once daily in 1 or both eyes for >=2 weeks. INTERVENTION: Latanoprost was administered in both eyes each morning post screening. Subjects returned 3 to 28 days later for evaluation of plasma concentrations, withholding morning latanoprost. At the clinic, a single drop of latanoprost ophthalmic solution was instilled into both eyes. Plasma latanoprost acid concentrations were collected predose and 5, 15, 30, and 60 minutes after administration. MAIN OUTCOME MEASURES: Latanoprost acid plasma exposure. RESULTS: The evaluable PK analysis set included data from 39 of 47 enrolled subjects. The median peak plasma concentration value was higher in the <3-year age group (166 pg/ml) versus other groups (49, 16, and 26 pg/ml for the 3-<12-year, 12-<18-year, and >=18-year age groups, respectively). The median area under the concentration time curve from zero to last measurable concentration value was also higher in the <3-year age group (2716 pg/min/ml) versus other groups (588, 106, and 380 pg/min/ml for the 3-<12-year, 12-<18-year, and >=18-year age groups, respectively). Latanoprost acid was rapidly eliminated from the blood, with plasma concentrations undetectable within 10 to 30 minutes postdose in all but the <3-year age group. There were no discontinuations or dose reductions due to adverse events or treatment-emergent adverse events. CONCLUSIONS: Latanoprost acid systemic exposure was higher in younger children versus adolescents and adults, attributed primarily to lower body weight and smaller blood volume. Latanoprost acid was eliminated rapidly in all age groups and resulted in only a brief period of systemic exposure after once-daily dosing. Higher systemic exposure was not accompanied by adverse events, and on the basis of extrapolation of safety data from adults, this pilot study suggests an adequate safety margin for systemic adverse effects with use of the adult topical dose of latanoprost in pediatric patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references. PMID- 21788078 TI - Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. AB - OBJECTIVE: To study the clinical course of herpes zoster ophthalmicus (HZO) and to compare the demographics, treatments, and outcomes in patients aged <60 years versus patients aged >=60 years at the time of diagnosis. DESIGN: Retrospective chart review of all 112 patients presenting for management of HZO from January 1, 2008 to December 31, 2008. PARTICIPANTS: A total of 112 patients (58 aged <60 years and 54 aged >60 years) at the time of HZO onset. INTERVENTIONS: Anterior segment complications, treatments, and surgical procedures were documented at 3 months, 6 months, and 1 year, and then annually for the remainder of the follow up period. MAIN OUTCOME MEASURES: Intraocular pressure, inflammation, steroid use, surgical procedures, anterior segment complications, post-herpetic neuralgia, and delayed herpes zoster pseudodendrites. RESULTS: Equal numbers of patients were affected with HZO in the younger and older age groups (51.8%, n = 58 vs. 48.2%, n = 54, respectively, P = 0.69). The most common decade of HZO onset was between 50 and 59 years. Younger patients were more likely to be healthy compared with older patients (P = 0.05). Delayed herpes zoster pseudodendrites were more common in the younger patients (36.7% vs. 16.7%, P = 0.03). The mean number of flares per patient-years was significantly higher in the younger patients (z test, P = 0.024). Post-herpetic neuralgia, neurotrophic keratopathy, and secondary infectious keratitis were more frequent in the older patients (P = 0.05). Prevalence of corneal perforation, corneal thinning, cataract formation, and glaucoma was similar between the 2 groups. Most patients in both groups (84.2% of younger patients and 89.5% of older patients) were taking topical steroids 3 years after referral for HZO. CONCLUSIONS: Herpes zoster ophthalmicus affects individuals aged younger than and older than 60 years in similar numbers, with the most common decade of onset between age 50 and 59 years. Younger patients had more episodes of delayed pseudodendritiform keratitis and flares of inflammation compared with older patients, who had more problems related to neurotrophic keratopathy. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21788079 TI - Risk factors for four-year incident visual impairment and blindness: the Los Angeles Latino Eye Study. AB - PURPOSE: To identify independent risk factors for incident visual impairment (VI) and monocular blindness. DESIGN: Population-based prospective cohort study. PARTICIPANTS: A total of 4658 Latinos aged 40 years in the Los Angeles Latino Eye Study (LALES). METHODS: A detailed history and comprehensive ophthalmologic examination was performed at baseline and at the 4-year follow-up on 4658 Latinos aged >=40 years from Los Angeles, California. Incident VI was defined as best corrected visual acuity (BCVA) of <20/40 and >20/200 in the better-seeing eye at the 4-year follow-up examination in persons who had a BCVA of >=20/40 in the better-seeing eye at baseline. Incident monocular blindness was defined as BCVA of <=20/200 in 1 eye at follow-up in persons who had a BCVA >20/200 in both eyes at baseline. Sociodemographic and clinical risk factors identified at the baseline interview and examination and associated with incident VI and loss of vision were determined using multivariable regression. Odds ratios (ORs) were calculated for those variables that were independently associated with VI and monocular blindness. MAIN OUTCOME MEASURES: Odds ratios for various risk factors for incident VI and monocular blindness. RESULTS: Independent risk factors for incident VI were older age (70-79 years, OR 4.8; >=80 years OR 17.9), unemployment (OR 3.5), and diabetes mellitus (OR 2.2). Independent risk factors for monocular blindness were being retired (OR 3.4) or widowed (OR 3.7) and having diabetes mellitus (OR 2.1) or any ocular disease (OR 5.6) at baseline. Persons with self-reported excellent/good vision were less likely to develop VI or monocular blindness (OR 0.4-0.5). CONCLUSIONS: Our data highlight that older Latinos and Latinos with diabetes mellitus or self-reported eye diseases are at high risk of developing vision loss. Furthermore, being unemployed, widowed, or retired confers an independent risk of monocular blindness. Interventions that prevent, treat, and focus on the modifiable factors may reduce the burden of vision loss in this fastest growing segment of the US population. PMID- 21788080 TI - Sunken eyes, sagging brain syndrome: bilateral enophthalmos from chronic intracranial hypotension. AB - PURPOSE: To explain the mechanism for acquired enophthalmos after ventriculoperitoneal shunting (VPS). DESIGN: Case series and a case-control study. PARTICIPANTS AND CONTROLS: Four study patients with bilateral enophthalmos after VPS and 10 control subjects. METHODS: Case description of 4 study patients. Calculated orbital volumes for 2 study patients were compared with controls using the Wilcoxon rank-sum test. MAIN OUTCOME MEASURES: Exophthalmometry measurements and total orbital and fat volumes. RESULTS: Patient 1 is a 25-year-old man who presented with progressive enophthalmos 3 years after VPS for traumatic intracranial bleeding. Imaging demonstrated upward expansion of the orbital roof and evidence of intracranial hypotension. The intracranial pressure (ICP) was 20 mm H2O. The enophthalmos improved after shunt revision. Patient 2 is a 19-year old man who presented with progressive enophthalmos 18 months after VPS for traumatic intracranial hemorrhage. Patient 3 is a 38-year-old woman who presented with bilateral enophthalmos 15 years after VPS after a ruptured aneurysm. Imaging showed orbital expansion. Patient 4 is a 16-year-old man who presented with severe enophthalmos 5 years after a VPS for aneurysm-related hemorrhage. Imaging demonstrated orbital enlargement and findings of intracranial hypotension. Intracranial pressure ranged between -200 and 0 mm H2O. Shunt revision improved the enophthalmos. Total orbital volumes were significantly greater in the study patients than in the controls. Control subjects (5 male, 5 female, ages 23-45 years) had an average right orbital volume of 24.6 +/- 3.3 cm3 (n = 10). In comparison, the right orbital volumes of patients 1 and 3 were 32.6 and 32.1 cm3. Similar results were found for the left orbits (23.9 +/- 2.7 cm3 [control average] vs. 35.9 and 32.6 cm3). In patient 1, the post-shunt volumes increased 14% (right) and 23% (left) from pre-shunt volumes. In contrast, orbital fat volume was not statistically significantly different between the control group and enophthalmic patients (right orbit control mean 7.94 +/- 3.1 cm3 [n = 10] vs. 7.9 and 9.8 cm3; left orbit control mean 7.88+3.1 cm3 vs. 9.2 and 10.0 cm3). CONCLUSIONS: Enophthalmos after VPS results primarily from chronic intracranial hypotension. Low ICP causes expansion of orbital volume with no fat atrophy. In such patients, shunt revision with a pressure-regulating valve to correct intracranial hypotension should be considered. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21788081 TI - Vascular tumors of the conjunctiva in 140 cases. AB - OBJECTIVE: To report clinical and histopathologic features of vascular tumors of the conjunctiva. DESIGN: Retrospective, noninterventional case series. PARTICIPANTS: A total of 140 patients. INTERVENTION: None. MAIN OUTCOME MEASURES: Tumor diagnosis, anatomic location, clinical features, management, and histopathology. RESULTS: There were 140 vascular tumors of the conjunctiva with 93% benign and 7% malignant. The specific diagnoses included lymphangioma/lymphangiectasis (n = 54, 36%), pyogenic granuloma (n = 31, 22%), capillary hemangioma (n = 20, 14%), Kaposi's sarcoma (n = 10, 7%), acquired sessile hemangioma (n = 10, 7%), racemose hemangioma (n = 7, 5%), varix (n = 4, 3%), cavernous hemangioma (n = 3, 2%), and glomangioma (n = 1, <1%). The lesions were unilateral in 89% and discovered at median age of 41 years. Bilateral lesions included lymphangiectasia, Kaposi's sarcoma, and racemose hemangioma. All tumors were typically found in adults with the exception of capillary hemangioma (<1 year) and glomangioma (16 years). The median tumor diameter was 6 mm, with the largest median diameter (15 mm) with Kaposi's sarcoma and (12 mm) glomangioma and capillary hemangioma and the smallest median diameter (3 mm) with cavernous hemangioma. The most common anatomic sites included bulbar conjunctiva, which was extralimbal in 80 patients (57%), limbal in 19 patients (14%), tarsal conjunctiva in 27 patients (19%), and forniceal conjunctival in 24 patients (17%). Clinical features included cystic component in 24% of patients (seen with lymphangioma, glomangioma, and varix), well-defined margins in 64% of patients, and feeder vessels in 39% of patients. CONCLUSIONS: A variety of vascular tumors can occur in both children and adults at various anatomic locations in the conjunctiva. They tend to occur unilaterally on the bulbar conjunctiva, and the majority of tumors are benign. PMID- 21788082 TI - Affective intensity and lability: heritability in adult male twins. AB - BACKGROUND: Inability to monitor and self-regulate heightened levels of affect lability and affect intensity is associated with a range of mood, anxiety, and personality disorders, psychosomatic symptoms and socially maladaptive behaviors. Despite the importance of these aspects of affective regulation, there are no twin study data to shed light on the genetic and environmental components of these constructs. METHODS: Affective Lability Scale (ALS) and Affect Intensity Measure (AIM) questionnaires were administered to 796 male twins in the Vietnam Era Twin Registry and subjected to twin and model-fitting analyses. Complete data were available from 182 monozygotic and 119 dizygotic twin pairs. RESULTS: Biometrical genetic model-fitting estimates indicated that additive genetic influence accounted for 40% of the variance in affect intensity and 25% of the variance in the ALS subscale assessing anxiety-depression mood shifts. Nonadditive genetic influence was indicated for ALS subscales measuring shifts between normal mood and depression (29%) and anger (27%), respectively. There was negligible evidence of shared environmental influence on affect measures. In contrast, estimates of nonshared environmental influences ranged from 52% to 74%. LIMITATIONS: Female were not included in this study due to the nature of the twin cohort. Data from subjects in a population cohort may not generalize to clinical populations. Measures of environment were not included. CONCLUSIONS: These results provide evidence for moderate heritability of affect intensity and specific measures of affect lability. Individual differences in mood regulation may represent phenotypic variation in a core psychobiologic vulnerability (e.g., neurotransmitter systems). PMID- 21788083 TI - Association of catechol-O-methyltransferase variants with duloxetine response in major depressive disorder. AB - Single-nucleotide and diplotype associations with 17-item Hamilton Depression Rating Scale (HAMD(17)) total score changes were examined, based on catechol-O methyltransferase (COMT) rs165599 status in duloxetine-treated, self-identified white patients with major depressive disorder. COMT rs165737 and a diplotype containing COMT rs165599 and COMT rs165737 were associated with HAMD(17) total score changes. PMID- 21788084 TI - Self-assessment of psychological stress in schizophrenia: Preliminary evidence of reliability and validity. AB - Heightened stress sensitivity is a common characteristic of schizophrenia and may be predictive of clinical and functional outcomes. However, systematic assessment is not part of routine clinical practice. This study investigated the reliability and predictive values of two versions of a new scale for the assessment of psychological stress in psychosis (Psychological Stress Index; PSI). Thirty-seven patients with schizophrenia/schizoaffective disorder and 30 healthy controls completed a battery of self-report measures at baseline and 4-8 weeks for test retest. Thirty-four patients were followed up at 12 months. Both of the 18-item and 9-item PSI demonstrated good levels of reliability and could significantly discriminate patients from healthy controls. Both versions showed moderate convergence with self-report and clinician ratings of depression and anxiety, and superior predictive validity of 12-month follow-up clinical and functional outcomes compared to an existing measure of stress (Perceived Stress Scale). The clinical usefulness of the PSI is supported by its predictive power on cross sectional and longitudinal outcome. The PSI-9 performed as well as, if not better than, the PSI-18 in this study, but further evaluation is warranted for more conclusive comparison. PMID- 21788085 TI - Regulation of interleukin-1 in acute brain injury. AB - Inflammation is a complex vascular response that has evolved to eliminate infection and to repair injured tissue. It is subject to tight regulatory control of its initiation and resolution. Failure of an inflammatory response to resolve has become recognised as a major contributor to the pathology of diverse diseases (including acute brain injuries). Interleukin-1 (IL-1) is a pro-inflammatory cytokine and key contributor to damage after acute brain injury. Understanding the regulation of IL-1 production is vital for the development of new drug targets and therapies. In recent years, there have been major advances in how we understand the resolution of inflammatory responses, and in how IL-1 is regulated after injury. Advances are summarised here in the context of addressing how dampening the inflammatory response and actions of IL-1 provides a strategy for reducing damage after acute brain injury such as stroke. PMID- 21788087 TI - Familal left ventricular hypertrabeculation (noncompaction) is myopathic. AB - BACKGROUND: Left-ventricular hypertrabeculation/noncompaction(LVHT) is a cardiac abnormality of unknown aetiology, frequently associated with arrhythmias, heart failure, and embolism. In most cases LVHT is associated with neuromuscular disorders (NMDs) or other rare non-neuromuscular genetic syndromes. Occasionally, LVHT occurs familiarly. METHODS AND RESULTS: Invited for a cardiologic investigation were all first-degree relatives of index patients with LVHT who attended the cardiologic department. Altogether 25 relatives of 15 index patients from 15 families were investigated. Three members each were investigated in 3 families, 2 patients each in 4 families and 1 member each in 8 families. Among the 25 relatives from the 15 families, LVHT was found in 4 of them. Accordingly, familial LVHT was detected in 4 of the 15 investigated families (27%). Among the 4 relatives with LVHT, extension and morphology were similar to the appropriate index patient in 2 families. A NMD was diagnosed in three of the four relatives (75%) with familial LVHT. One relative without LVHT presented with a history of Fallot's tetralogy, and two relatives each presented with thickening of the left ventricular myocardium. CONCLUSIONS: LVHT is familial in at least 27% of the patients with LVHT. LVHT may differ between relatives in some of the patients with familial LVHT. Familial LVHT is associated with a NMD in the majority of the cases. Relatives of LVHT patients may present with cardiac abnormalities other than LVHT. PMID- 21788086 TI - Pattern separation in the hippocampus. AB - The ability to discriminate among similar experiences is a crucial feature of episodic memory. This ability has long been hypothesized to require the hippocampus, and computational models suggest that it is dependent on pattern separation. However, empirical data for the role of the hippocampus in pattern separation have not been available until recently. This review summarizes data from electrophysiological recordings, lesion studies, immediate-early gene imaging, transgenic mouse models, as well as human functional neuroimaging, that provide convergent evidence for the involvement of particular hippocampal subfields in this key process. We discuss the impact of aging and adult neurogenesis on pattern separation, and also highlight several challenges to linking across species and approaches, and suggest future directions for investigation. PMID- 21788088 TI - Structural and functional uncoupling of liver performance in the Fontan circulation. AB - BACKGROUND: The liver is known to be structurally abnormal in long-standing Fontan circulation. The degree of liver dysfunction associated with such abnormalities is however largely unknown. We assessed structural changes (serum fibrosis markers) and function (indocyanine green clearance (ICG)) in Fontan patients. METHODS: 21 stable Fontan patients were prospectively assessed and compared with 8 histologically proven compensated viral cirrhotic patients. All subjects had standard liver profile, "Enhanced Liver Fibrosis" (ELF) score (including hyaluronic acid, aminoterminal type III procollagen peptide P3NP and tissue inhibitor of metalloproteinase TIMP-1 levels), and ICG using the LiMON Device. Plasma disappearance rate (PDR) and 15-minute retention (R15) were recorded after ICG infusion. RESULTS: Indocyanine clearance and retention (PDR and R15) were similar between Fontan and compensated cirrhotic patients (17 +/- 5 vs 18 +/- 6 (p=0.75) and 11 +/- 10 vs 10 +/- 10 (p=0.75)), as was degree of fibrosis (7.97 +/- 1.16 vs 9.0 +/- 1.43, p=NS). There was a positive correlation between PDR and ELF (R=0.77, p=0.028) as well as R15 and ELF (R=0.905, p=0.002) in the viral cirrhotics but not in the Fontan group. (R=-0.243, p=0.302; and R=0.226, p=0.338). PDR (17 +/- 5) and R15 (11 +/- 10) were not significantly different in Fontan as compared with the established cirrhotics. CONCLUSIONS: Fontan patients have similar global hepatic function and fibrosis as compared with viral cirrhotic patients. However in Fontan patients, fibrosis was not closely correlated with global liver function, whereas viral cirrhotic patients exhibited a close correlation between function and fibrosis. PMID- 21788089 TI - Acute absolute vasodilatation is associated with a lower vascular wall stiffness in pulmonary arterial hypertension. AB - BACKGROUND: Acute vasoreactivity testing (VT) is considered mandatory in the diagnostic work-up of patients with pulmonary arterial hypertension (PAH). We studied the relation between the acute absolute arterial vasodilatation and the severity of vascular remodeling estimated by intravascular ultrasound (IVUS) in patients with idiopathic PAH. METHODS: Simultaneous right heart catheterization and IVUS of the pulmonary artery (PA) were performed both in basal conditions and during short-term intravenous epoprostenol infusion in nineteen idiopathic PAH patients. Pulmonary vascular resistance (PVRi) and capacitance indexes (stroke volume/pulse pressure, Cp), were calculated. Local pulsatility was estimated by IVUS (IVUSp) (systolic-diastolic lumen area/diastolic lumen area*100; sA-dA/dA) and PA stiffness was assessed by the elastic modulus (E: pulse pressure/IVUSp). RESULTS: Epoprostenol infusion (11+/-2ng/kg/min) determined a real vasodilatation (increment of dA>10%) in six patients. This vasodilation group presented on average significantly higher cardiac index, stroke volume index and Cp, and lower PVRi and IVUSp (P<0.05), with a lower E (P=0.08). Three patients were responders according to the actual criteria, but only one showed a real vasodilator response. Baseline E below the median value (<=190mm Hg) was able to differentiate patients with an acute vasodilator response (sensibility 83%, specificity 73%, area under ROC 0.81; P<0.05). Neither E nor vasodilator response is correlated with delta mean PA pressure and PVRi. CONCLUSIONS: Patients with higher IVUSp and lesser E displayed an absolute PA vasodilation during VT with epoprostenol. The patients with a positive VT according to actual criteria do not necessarily have a real vasodilatation on intravascular ultrasound. PMID- 21788090 TI - Sero-epidemiology of peste des petits ruminants (PPR) in Pakistan. AB - A sero survey was conducted during 2005-2006 to estimate the sero prevalence of PPR in the small ruminant population of Pakistan. A total of 2798 samples were collected including goats (1979) and sheep (819) from villages in 27 randomly selected districts. These were tested by cELISA for PPRV and true prevalence estimates were calculated by Rogan and Gladen estimator. Overall, 1273 (45.5%) were found positive; 980 (49.5%) of 1979 samples from goats and 293 (35.8%) of 819 serum samples from sheep were positive. The true sero-prevalence of PPR was estimated to be 48.5% (95% CI, 46.6-50.3), and 52.9% (95% CI, 50.7-55.1) and 37.7 (95% CI, 34.4-41.0) for goats and sheep, respectively. PPR virus is widely distributed all across Pakistan and has become an endemic infection of small ruminants. Since it is one of the leading causes of morbidity and mortality in small ruminants, it poses a serious threat to food security and the rural economy in Pakistan. PMID- 21788091 TI - Persistent spatial clusters of plasmacytosis among Danish mink farms. AB - Aleutian disease (Plasmacytosis) is caused by the Aleutian mink disease virus (AMDV), an autonomous parvovirus and affects many mustelid species, including the American mink (Neovisonvison). In Denmark, an eradication program reduced the prevalence of test-positive farms from 100% in 1976 to 15% in 1996. Nevertheless, the disease persists in the Vendsyssel district of Northern Jutland, despite the eradication efforts. In this study, we used spatial epidemiological analysis to test for spatial autocorrelation of the distribution of farms positive for the disease. We investigated 2375 farms in Denmark (342 of which were located in the Vendsyssel district), during the period 2000-2008. For the purpose of our study, a farm was considered positive when, on any test conducted in a year, at least three animals were tested positive. To detect spatial clusters, we performed a retrospective analysis with spatial scan statistics. We performed one analysis for each of the nine years (2000-2008). A separate analysis was conducted with only the farms in Vendsyssel included. The spatial cluster analysis revealed a significant cluster throughout the time period studied in Northern Jutland. The only exception was 2002 when an outbreak was detected in the southern part of Jutland, and not in the north. The farm-level prevalence of the disease in Denmark was highest in this year, suggesting that the outbreak in the south could have masked the persistent signal from the north; the northern cluster was still significant when analysing only the Vendsyssel populations. These results confirm that Northern Jutland continues to have a significantly higher number of cases than expected if the disease was randomly distributed. PMID- 21788092 TI - Bioluminescence imaging: progress and applications. AB - Application of bioluminescence imaging has increased tremendously in the past decade and has significantly contributed to core conceptual advances in biomedical research. This technology provides valuable means for monitoring of different biological processes in immunology, oncology, virology and neuroscience. In this review, we discuss current trends in bioluminescence and its application in different fields with an emphasis on cancer research. PMID- 21788093 TI - Factors associated with carcass contamination by Campylobacter at slaughterhouse in cecal-carrier broilers. AB - A study was conducted in 2009 to identify risk factors of Campylobacter spp. transmission from the digestive tract to the carcasses of standard broilers (slaughter age: 37 day, carcass weight: 1.3 kg on average). Counts of Campylobacter were performed on pools of 10 ceca and 10 neck-skins from 108 Campylobacter ceca-positive batches in three slaughterhouses. Technical and health data also was collected on the broilers: age, size, carcass weight (mean and standard deviation), condemnation rate, mortality rate and nature of treatment during the rearing period. Cecal counts varied from 4.8 to 10.2 log(10) cfu/g. In seventeen batches (15.7%), the skin count was below the detection limit. In the 91 batches with positive neck-skin test results, the counts varied from 2.0 to 5.2 log(10) cfu/g. Standard deviation of carcass weight, condemnation rate, slaughter rate and cecal count were significantly lower and growth rate higher in the 17 batches where neck-skin results were not detected positive. Multivariate analysis showed that batches with higher standard deviation of carcass weight were 5 to 9 fold more at risk of having detectable carcass contamination. Among the 91 positive neck-skin batches, only slaughter rate and cecal counts were found to have a significant but limited effect on the level of neck-skin contamination. As far as body weight homogeneity may be affected by disease, better health control can contribute to a reduction of the contamination of the broiler carcasses in Campylobacter carrier batches. PMID- 21788095 TI - Methyl jasmonate-induced defense responses are associated with elevation of 1 aminocyclopropane-1-carboxylate oxidase in Lycopersicon esculentum fruit. AB - It has been known that methyl jasmonate (MeJA) interacts with ethylene to elicit resistance. In green mature tomato fruits (Lycopersicon esculentum cv. Lichun), 0.02mM MeJA increased the activity of 1-aminocyclopropane-1-carboxylate oxidase (ACO), and consequently influenced the last step of ethylene biosynthesis. Fruits treated with a combination of 0.02 MeJA and 0.02 alpha-aminoisobutyric acid (AIB, a competitive inhibitor of ACO) exhibited a lower ethylene production comparing to that by 0.02mM MeJA alone. The increased activities of defense enzymes and subsequent control of disease incidence caused by Botrytis cinerea with 0.2mM MeJA treatment was impaired by AIB as well. A close relationship (P<0.05) was found between the activity alterations of ACO and that of chitinase (CHI) and beta-1,3-glucanase (GLU). In addition, this study further detected the changes of gene expressions and enzyme kinetics of ACO to different concentrations of MeJA. LeACO1 was found the principal member from the ACO gene family to respond to MeJA. Accumulation of LeACO1/3/4 transcripts followed the concentration pattern of MeJA treatments, where the largest elevations were reached by 0.2mM. For kinetic analysis, K(m) values of ACO stepped up during the experiment and reached the maximums at 0.2mM MeJA with ascending concentrations of treatments. V(max) exhibited a gradual increase from 3h to 24h, and the largest induction appeared with 1.0mM MeJA. The results suggested that ACO is involved in MeJA-induced resistance in tomato, and the concentration influence of MeJA on ACO was attributable to the variation of gene transcripts and enzymatic properties. PMID- 21788094 TI - Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy. AB - BACKGROUND: Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and copper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy. METHODS: From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival. RESULTS: Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P<0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P=0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P<0.01). CONCLUSION: This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC. PMID- 21788096 TI - Bacteria misagglutination in legionella surveillance programmes. PMID- 21788097 TI - Giant cell arteritis--an incidental finding. AB - Giant cell arteritis is a systemic, inflammatory, and vascular syndrome that requires early diagnosis and immediate management because of the risk of loss of vision. Local symptoms include headache, scalp tenderness, jaw claudication, visual disturbances, and scalp necrosis. Systemic symptoms include weight loss, fever, malaise, fatigue, and polymyalgia rheumatica. We describe a case that was identified histologically as an incidental finding after excision of a basal cell carcinoma from the parietal area of the scalp. A search of PubMed and Medline using the keywords "giant cell arteritis", and "incidental histopathological diagnosis" returned no similar previously published cases in the head and neck. We present this as an unusual and interesting case. PMID- 21788099 TI - "Over-foreignization" or "unused potential"? A critical review of migrant health in Germany and responses toward unauthorized migration. AB - Persons of migrant background, a highly heterogeneous group, now comprise one fifth of the total population in Germany. However, delayed and conflicted responses to social inclusion have resulted in clear deficits in the health care system, with few serious attempts to assess migrants' profiles and needs. This article provides a critical review based on meta-analysis of literature indexed in MEDLINE, a qualitative review of German medical and nursing curricula, and original ethnographic data. It examines discourses and practices embedded within larger national debates on migrant integration and their specific manifestations in the health sector in order to explain the current situation of unauthorized migrants. The historical arc of the last fifty years can be viewed as a progression of key themes based on interrelated concepts of deservingness and selective investment. Relative deservingness is evident in differential social positioning and access to resources, resulting in selective investment and decades of continued social inequality. PMID- 21788098 TI - Litigation in National Health Service oral and maxillofacial surgery: review of the last 15 years. AB - Litigation claims are increasing in medicine but we know of little detailed analysis of those published concerning oral and maxillofacial surgery (OMFS) despite information being freely available from the NHS Litigation Authority (NHSLA) under the Freedom of Information Act. We obtained information from the NHSLA on clinical and non-clinical negligence claims in OMFS from April 1995 to August 2010, and analysed the data with outcomes and a further breakdown of subspecialty. During the period 318 claims relating to OMFS were registered. As expected, because of the high volume of patients treated, the highest number of claims related to dentoalveolar surgery and minor oral surgery. The total amount paid out was in excess of L5 million, and the highest claim (more than L300,000) during the period was for misdiagnosis of an oral cancer. Litigation in OMFS is increasing, as is the number of cases that necessitate compensation by the NHSLA. We discuss the trends and implications. PMID- 21788100 TI - Evaluating the response of two high yielding Indian rice cultivars against ambient and elevated levels of ozone by using open top chambers. AB - A continuous increase in the background level of tropospheric ozone (O(3)) has become a major challenge for present and future agricultural productivity at worldwide. Present study was designed to assess the impact of ambient (present) and elevated (future) concentrations of O(3) on two cultivars of Indian rice (Oryza sativa L. cvs Malviya dhan 36 and Shivani). Shoot and root lengths, number of leaves and total leaf area were severely affected by both ambient and elevated concentrations of O(3). Photosynthetic rate, stomatal conductance and photosynthetic efficiency (F(v)/F(m)) were also reduced by O(3) with more drastic effects under elevated levels of O(3). Leaf proteome showed reduction of some major proteins due to O(3). Pollen viability, viable florets plant(-1) and economic yield also showed significant negative impact under O(3)-exposure in both the test cultivars. The experimental findings depict that both the cultivars of rice demonstrate differential response against O(3), and it may help the plant breeders in selection of resistant cultivars for the area having higher concentrations of O(3). PMID- 21788101 TI - The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway. AB - Autophagy is designated as type II programmed cell death and may confer a tumor suppressive function. Our previous studies have shown that XIAP-associated factor 1 (XAF1) induced apoptosis and inhibited tumor growth in gastric cancer cells. In this study, we investigated the effect of XAF1 on the induction of autophagy in gastric cancer cells. We found that adenovirus vector-mediated XAF1 (adeno-XAF1) expression markedly induced autophagy, upregulated the level of Beclin-1 and inhibited phospho-Akt and phospho-p70S6K in gastric cancer cells. The downregulation of Beclin 1 or 3-methyladenine treatment suppressed adeno-XAF1 induced autophagy, but significantly enhanced adeno-XAF1-induced apoptosis. A pan caspase inhibitor prevented adeno-XAF1-induced apoptosis, but significantly increased adeno-XAF1-induced autophagy. Furthermore, adeno-XAF1 induced autophagy in xenograft tumor and inhibited tumor growth. Our results document that adeno XAF1 induces autophagy through upregulation of Beclin 1 expression and inhibition of Akt/p70S6K pathway, and reveal a new mechanism of XAF1 tumor suppression. PMID- 21788102 TI - Anti-angiogenic effect of Tanshinone IIA involves inhibition of matrix invasion and modification of MMP-2/TIMP-2 secretion in vascular endothelial cells. AB - Tanshinone IIA (Tan IIA) is one of the major lipophilic components of Salvia miltiorrhiza Bunge reported to exhibit anti-carcinogenic effect. In the present study, we further evaluated the anti-angiogenic effect of Tan IIA using the chorioallantoic membrane (CAM) in chicken embryos and human umbilical vascular endothelial cells (HUVECs). Tan IIA was confirmed to inhibit in vivo angiogenesis by CAM assay. Tan IIA also exhibited in vitro anti-angiogenic effects as demonstrated by tube formation assay, transwell migration assay and TNF-alpha induced matrix invasion assay. The mRNA expressions of matrix metalloproteinase 2, -3, -9, -14 (MMP-2, -3, -9, -14), tissue inhibitor of metalloproteinase-2 (TIMP-2) and reversion-inducing cysteine-rich protein with kazal motifs (RECK) were not affected by Tan IIA as analyzed by reverse transcription polymerase chain reaction (RT-PCR). However, the extracellular matrix metalloproteinase-2 (MMP-2) activity was found to be reduced dose-dependently by Tan IIA as determined by gelatin zymography. Results from western blot analysis and ELISA further demonstrated the dose-dependent decrease of MMP-2 and increase of TIMP-2 secretion from cytosol of vascular endothelial cells simultaneously after Tan IIA treatment. Together, the present study confirmed the anti-angiogenic effects of Tan IIA both in vivo and in vitro. Our results also demonstrated that Tan IIA could modulate the secretion of MMP-2 and TIMP-2 in an opposite way and resulted in the decreased MMP-2 activity of vascular endothelial cells. PMID- 21788103 TI - Arsenic oxide targets stem cell marker CD133/prominin-1 in gallbladder carcinoma. AB - CD133+ tumor cells are responsible for the initiation, propagation and recurrence of tumors, which raises the question of how to effectively target CD133+ tumor cells. Arsenic trioxide (As2O3) has considerable efficacy in treating solid tumors with induction of apoptosis. Here, we found that purified CD133+ gallbladder carcinoma cells are highly resistant to conventional chemotherapy. However, As2O3 effectively induces CD133+ gallbladder carcinoma cells apoptosis. Treatment with As2O3 reduces CD133 expression at transcriptional levels. Furthermore, the ectopic expression of CD133 attenuated the apoptotic effect of As2O3 on cells through activation of AKT signaling pathways. Collectively, As2O3 effectively targets CD133 in gallbladder carcinoma, providing a new mechanism of As2O3-induced cell apoptosis and a better understanding of drug resistance in gallbladder carcinoma. PMID- 21788104 TI - Intracoronary transplantation of genetically modified mesenchymal stem cells, a novel method to close muscular ventricular septal defects. AB - Muscular ventricular septal defects remain a challenge despite the progress in surgical and interventional closure of ventricular septal defects. Our hypothesis was inspired by the fact that more than two thirds of children with muscular ventricular septal defects experienced spontaneous closure. Therefore, we intend to induce the spontaneous closure of muscular ventricular septal defects by means of targeted intracoronary injection of mesenchymal stem cells which are genetically modified to enhance myocardial hypertrophy. The transplantation of bone marrow derived cells has been observed to be effective in improving tissue recovery and ameliorating cardiac function in patients and animal models with ischemic heart disease, acute myocarditis and dilated cardiomyopathy. We expect that the targeted intracoronary transplantation of genetically modified mesenchymal stem cells could enhance the tissue generation and myocardial hypertrophy simultaneously, which may lead to the closure of muscular ventricular septal defects in a way that imitate the spontaneous closure of ventricular septal defects. PMID- 21788105 TI - Hypothesis: everyday products induce multiple sclerosis. PMID- 21788106 TI - Application of tissue microarray for atherectomized tissues from peripheral arterial disease. AB - It is not easy to apply tissue microarray (TMA) to atherectomized tissues from peripheral arterial disease because of their physical properties. We introduce a new TMA application technique for atherectomized tissues. Using a pre-made plastic TMA cassette and TMA punch device, we successfully made the TMA block containing 40 vertically oriented atherectomized tissue samples from 10 patients. The histogram of surface areas of tissue cores in the TMA showed a bell-shaped distribution, whereas that of conventionally embedded tissues showed wide distribution. This finding suggests that the TMA method might be a better way of vertical embedding than the conventional method. A TMA block prepared by our method enabled a simultaneous evaluation of the histopathology of vertically oriented atherectomized tissues and the correlation between them with intravascular ultrasound image. In addition, this new method might be applied to various tissues in different ways. PMID- 21788107 TI - The effect of chondroitinase on nerve regeneration following composite tissue allotransplantation. AB - PURPOSE: To improve the degree of functional return and sensibility provided by composite tissue allotransplantation, enhanced nerve regeneration is essential. Chondroitin sulfate proteoglycans are found in the extracellular matrix of nerves and inhibit regenerating axons after injury. Treatment with chondroitinase to remove chondroitin sulfate proteoglycans has been shown to improve nerve regeneration in isolated nerve graft and transection-and-repair models. This study assesses the efficacy of chondroitinase as a neurotherapeutic agent in the setting of composite tissue allotransplantation. METHODS: Adult Lewis rats received either orthotopic hind limb transplants from Brown Norway rat donors (n = 12) or sciatic nerve transection and repair (n = 6). Following approximation of the sciatic nerve, half the animals received intraneural injections of chondroitinase in saline and the other half received intraneural injections of saline alone. Five weeks after transplantation, we killed the animals and analyzed nerves with nonbiased quantitative nerve histomorphometry. One day after transection and repair, we killed animals and harvested sciatic nerves for immunohistochemical staining of cleaved chondroitin sulfate proteoglycans epitope and laminin. We used unpaired t-tests for statistical analysis. RESULTS: Distal to the suture line, chondroitinase-treated animals demonstrated statistically greater total number of fibers and nerve density compared with controls. There were no statistically significant differences in fiber number or nerve density proximal to the suture line or in fiber widths. We observed staining of cleaved chondroitin sulfate proteoglycan epitopes only in treated animals, with no differences observed in the degree of laminin staining. CONCLUSIONS: Intraneural injection of chondroitinase cleaved inhibitory chondroitin sulfate proteoglycans without disrupting proregenerative laminin and resulted in enhanced nerve regeneration after composite tissue allotransplantation. Studies at later time points are needed to assess whether this enhanced nerve regeneration will produce improved functional return. PMID- 21788109 TI - A woman's journey through the reproductive, transitional and postmenopausal periods of life: impact on cardiovascular and musculo-skeletal risk and the role of estrogen replacement. AB - Sex hormones are fundamental for female development and they are important physiologically to maintain the health and normal functioning of several organs such as the brain, heart and bone. It is now clear that the hormonal changes that occur during a woman's life, particularly her estrogen status, can modulate disease activity. This is especially true for cardiovascular and musculo-skeletal diseases, which are two leading causes of morbidity and mortality in women. With the general aging of the population they represent a serious and growing public health concern. Estrogen synthesis and blood levels fluctuate during a woman's life and in this review three broad periods will be considered: reproductive phase, transition and postmenopausal phase. Generally speaking, women in the reproductive phase of their life are at low risk of cardiovascular and musculo skeletal disorders. However, the onset of menopause and the loss of ovarian function is associated with a significant increase in the prevalence of diseases such as coronary heart disease, osteoarthritis and osteoporosis. The prevalence of these debilitating diseases continues to increase through the postmenopausal period. Estrogen replacement is an obvious treatment approach to counter the problems associated with the loss of ovarian function and subsequent estrogen deficiency. Overall, oral and transdermal estrogen replacement are similarly effective in relieving menopausal symptoms and disorders that manifest during this period of a woman's life. Transdermal estrogen may be preferable in older women because of its lower thrombogenic potential. In this journey through a woman's life current best evidence relating to cardiovascular and musculo skeletal risk will be reviewed in line with well documented management strategies. PMID- 21788110 TI - Cerebrospinal fluid apolipoprotein E levels in subacute sclerosing panencephalitis. AB - Neurofibrillary tangles (NFTs) have been shown in 20% of subacute sclerosing panencephalitis (SSPE) cases. NFTs contain paired helical filaments formed by hyperphosphorylated tau. The intraneuronal tau metabolism and the rate of formation of paired helical filaments can be regulated by interactions between tau and isoforms of Apolipoprotein E (Apo E). Tau binds in vitro to Apo E3, interferes with the hyperphosphorylation of tau and may reduce the formation of NFTs. We investigated cerebrospinal fluid (CSF) Apo E levels in SSPE (n=37) and age-matched control (n=38) groups. The median level of total Apo E and Apo E4 were lower in the SSPE than the control group (p<0.001 and p=0.002). On the other hand, median Apo E3 level (0.28+/-0.23 MUg/ml) was higher in the SSPE group (p<0.001). Such elevated levels of ApoE3 might play a role in controlling the formation of NFTs in SSPE. Because NFT-associated neurodegeneration is a slow process, comparison of the long-term clinical course of SSPE cases with high and low Apo E3 levels might provide further understanding or the role of these molecules in this disease, and help the planning of neuroprotective treatment. PMID- 21788111 TI - Preliminary study of ultrasonographic tissue quantification of the breast using the acoustic radiation force impulse (ARFI) technology. AB - PURPOSE: To investigate the shear wave velocity of normal breast tissue and breast lesion using acoustic radiation force impulse (ARFI) technology. MATERIALS AND METHODS: This retrospective study was conducted with the approval of the institutional review board. Shear wave velocity was measured using a linear array transducer with a bandwidth of 4-9 MHz and Virtual Touch tissue quantification (Siemens Medical Solutions, Mountain View, CA, USA) in 50 patients. First, the values of the shear wave velocity were determined in the normal tissues. Then, the changes in the shear wave velocity while applying external compression on the breast were determined. For the differential diagnosis of breast lesions, the shear wave velocities of 30 mass lesions (13 benign and 17 malignant lesions) classified as BI-RADS category 4 were measured. RESULTS: The mean shear wave velocities in the subcutaneous fat and the mammary gland parenchyma were 2.66 m/s and 3.03 m/s, respectively (p=0.0006). The mean shear wave velocity measured while applying external compression was 3.33 m/s for subcutaneous fat (p<0.0001), and 3.84 m/s for the mammary gland parenchyma (p<0.0001). In 4 of malignant cases, the shear wave velocity was not indicated (displayed as X.XX; unmeasurable state). The mean shear wave velocity of the 13 malignant lesions (4.49 m/s) was higher than that of benign lesions (2.68 m/s) (p<0.01). CONCLUSIONS: ARFI tissue quantification is thought to be a potentially promising ultrasound technique for the diagnosis of breast lesions, but further investigation is required to identify the most appropriate method of measurement. PMID- 21788113 TI - Predictors of outcome after elective endovascular abdominal aortic aneurysm repair and external validation of a risk prediction model. AB - INTRODUCTION: Endovascular abdominal aortic aneurysm (AAA) repair (EVAR) has been associated with lower operative mortality and morbidity than open surgery but comparable long-term mortality and higher delayed complication and reintervention rates. Attention has therefore been directed to identifying preoperative and operative variables that influence outcomes after EVAR. Risk-prediction models, such as the EVAR Risk Assessment (ERA) model, have also been developed to help surgeons plan EVAR procedures. The aims of this study were (1) to describe outcomes of elective EVAR at the Royal Brisbane and Women's Hospital (RBWH), (2) to identify preoperative and operative variables predictive of outcomes after EVAR, and (3) to externally validate the ERA model. METHODS: All elective EVAR procedures at the RBWH before July 1, 2009, were reviewed. Descriptive analyses were performed to determine the outcomes. Univariate and multivariate analyses were performed to identify preoperative and operative variables predictive of outcomes after EVAR. Binomial logistic regression analyses were used to externally validate the ERA model. RESULTS: Before July 1, 2009, 197 patients (172 men), who were a mean age of 72.8 years, underwent elective EVAR at the RBWH. Operative mortality was 1.0%. Survival was 81.1% at 3 years and 63.2% at 5 years. Multivariate analysis showed predictors of survival were age (P = .0126), American Society of Anesthesiologists (ASA) score (P = .0180), and chronic obstructive pulmonary disease (P = .0348) at 3 years and age (P = .0103), ASA score (P = .0006), renal failure (P = .0048), and serum creatinine (P = .0022) at 5 years. Aortic branch vessel score was predictive of initial (30-day) type II endoleak (P = .0015). AAA tortuosity was predictive of midterm type I endoleak (P = .0251). Female sex was associated with lower rates of initial clinical success (P = .0406). The ERA model fitted RBWH data well for early death (C statistic = .906), 3-year survival (C statistic = .735), 5-year survival (C statistic = .800), and initial type I endoleak (C statistic = .850). CONCLUSIONS: The outcomes of elective EVAR at the RBWH are broadly consistent with those of a nationwide Australian audit and recent randomized trials. Age and ASA score are independent predictors of midterm survival after elective EVAR. The ERA model predicts mortality-related outcomes and initial type I endoleak well for RBWH elective EVAR patients. PMID- 21788114 TI - The transition from custom-made to standardized multibranched thoracoabdominal aortic stent grafts. AB - OBJECTIVE: The purpose of this study was to compare the branch morphology and short-term outcome of endovascular aneurysm repair using multibranched thoracoabdominal custom-made stent grafts (CSGs) vs standard stent grafts (SSGs). METHODS: Data on patient demographics, aortic morphology, component use, and outcome were collected prospectively. Final branch length (cuff to target artery orifice) and branch angle (cuff orientation to target artery orientation) were determined using 3-D reconstruction of computed tomographic angiograms (CTAs). RESULTS: Between January 2008 and March 2010, 28 patients underwent endovascular aneurysm repair using 14 CSGs and 14 SSGs. Two patients were excluded from analysis: one patient in the CSG group had yet to undergo CTA, and one patient in the SSG group had crossed renal branches due to problems traversing a previously reconstructed aortic arch. All the stent grafts were implanted successfully. There were no perioperative deaths. There were no statistically significant differences between the CSG (n = 13) and SSG (n = 13) groups in terms of patient age (74.4 +/- 7.9 years vs 73.5 +/- 6.0 years), aneurysm diameter (66.1 +/- 9.0 mm vs 71.2 +/- 9.0 mm), operative time (311 +/- 94 minutes vs 286 +/- 57 minutes), fluoroscopy time (108 +/- 43 minutes vs 101 +/- 30 minutes), contrast volume (98 +/- 39 minutes vs 91 +/- 27 minutes), blood loss (458 +/- 205 mL vs 433 +/- 193 mL), mean branch angle (22.8 +/- 19.0 degrees vs 22.0 +/- 17.6 degrees), or branch length (25.3 +/- 12.1 mm vs 23.4 +/- 10.2 mm). CONCLUSION: The substitution of SSG for CSG had no effect on the complexity of the procedure, the branch morphology, or the perioperative outcome. The availability of an off the-shelf SSG will broaden the application of endovascular thoracoabdominal aortic aneurysm repair by eliminating manufacturing delays. PMID- 21788115 TI - Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1. AB - Pregnancy modulates autoimmune diseases through diverse and still incompletely defined mechanisms, in part operating at the decidua-placenta interface. To assess the immunological contribution of placenta, we administered mouse placental proteins to a mouse model of autoimmune hypophysitis, a disease known to be strongly associated with pregnancy. Emulsified placental proteins suppressed both the cellular and humoral aspects of hypophysitis. Suppression was specific to self antigens and not seen when two foreign antigens, tetanus toxoid or tuberculin purified protein derivative, were used. Proteomic analysis revealed high levels of soluble TNF receptor 1 in placenta, suggesting that blockade of the TNF-alpha pathway was a mechanism of disease suppression. Placentas derived from mice deficient in TNF receptor 1 lost the ability to suppress hypophysitis. Notably, hypophysitis suppression was seen only when the TNF-alpha pathway was blocked locally, at the site of immunization, and not systemically. These findings provide evidence that placenta contributes to the immune tolerance of pregnancy by locally inhibiting the TNF-alpha pathway. PMID- 21788116 TI - Apathy, cognitive deficits and functional impairment in schizophrenia. AB - INTRODUCTION: Apathy has been repeatedly highlighted as a core component of negative symptoms especially with regard to functional outcome of schizophrenia. The purpose of this study was to explore the relationships between apathy, cognitive deficits, and psychosocial functioning in chronic patients with schizophrenia. METHODS: Thirty-six chronic patients with schizophrenia and an equal number of matched healthy participants were assessed with the clinician version of Apathy Evaluation Scale (AES-C) along with a comprehensive battery of neuropsychological measures. Functioning was assessed with the Personal and Social Performance scale (PSP) and other symptoms were measured with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. RESULTS: Apathy was strongly and specifically associated with poorer performance on executive tests in patient group. AES-C was significantly correlated with PSP total score as well as its subscales for social useful activities, personal and social relationships, and self-care. Multiple regression analysis revealed that apathy was the most robust predictor of current psychosocial functioning, accounting for 70% of the variance in functioning, independently of co-existent cognitive deficits. Moreover, executive dysfunction did not predict functional impairment, independently of the effect of apathy. CONCLUSION: Our findings confirm that apathy has a stronger relationship to functional impairment than cognitive deficits on a cross-sectional basis in schizophrenia. Moreover, they suggest that apathy and executive dysfunction might represent different manifestations of the same syndrome, probably sharing a common neural substrate. PMID- 21788117 TI - An essential role of RNA editing enzyme ADAR1 in mouse skin. PMID- 21788118 TI - Validation of the dimensionality emergence assay for the measurement of innate anxiety in laboratory mice. AB - The open field test is a common tool to measure innate anxiety in rodents. In the usual configuration of this test the animal is forced to explore the open arena and its behavior includes both anxiety and non-anxiety responses. However, the open arena is generally small and allows only limited expression of exploratory behavior. The recently developed dimensionality emergence assay in which an animal is housed in a home cage with free access to a large circular arena elicits graded exploration and promises to serve as a more ethological test of anxiety. Here we examined the predictive validity of this assay for anxiety related measures in mice. First, we compared their behavior in the presence or absence of access to the home cage and found that mice with access to the home cage exhibited a gradual build-up in exploration of the arena while those without did not. Then we identified behavioral measures that responded to treatment with the anxiolytic drug diazepam. Diazepam altered several classical measures of innate anxiety, such as distance traveled and thigmotaxis, but also led to a dose dependent acceleration of the build-up as reflected in a significantly reduced latency to attain several exploratory landmarks. Finally, we tested the utility of the dimensionality emergence assay in assessing alterations in innate anxiety reported in mice carrying a knockout allele for the serotonin 1A receptor (Htr1a). Our findings support the validity of the dimensionality emergence assay as a method to extract an expanded repertoire of behavioral measures for the assessment of anxiety in laboratory mice. PMID- 21788119 TI - Colloids engineering and filtration to enhance the sensitivity of paper-based biosensors. AB - Paper-based biosensors represent a disruptive technology by providing instantaneous and low-cost diagnostics for health and environmental applications. The lack of sensitivity can be an obstacle for this technology to compete with traditional analytical instrumentations. Aiming to improve the sensitivity of a paper-based colorimetric biosensor, we have applied colloids engineering in combination with filtration to lower the paper substrate backgrounds and optimize the immobilization of bio-molecules on paper. A model system consisting of an enzyme, alkaline phosphatase (ALP), and an inorganic colloid, calcium carbonate (CC), flocculated by a cationic dimethylamino-ethyl-methacrylate polyacrylamide (CPAM), demonstrated that the optimized CC flocs are best for enhancing the detecting sensitivity of ALP. The CC floc structure on paper was optimized by modulating its structure in suspension. Subsequently, the filtration process and the wicking ability of paper enabled to freeze the deposited CC structure inherited from the suspension. The incorporation of biomolecules into the CC before immobilizing on paper through filtration provided not only a better microenvironment, but also a higher surface density of immobilized biomolecules. The ALP detection limit of 117 fmol per zone (5mm circle) in the current study was fifty times lower than that of the common soaking method for biomolecule immobilization. The minimum amount of biomolecules per unit substrate area required for detection was lowered by over an order of magnitude, compared with spotting methods (i.e. inkjet printing). The improvement was also demonstrated by the steepest slope of standard curve, the lowest background, and the highest activity of the bioactive paper probed with the diluted BCIP/NBT liquid substrates. PMID- 21788120 TI - Study of silver nanoparticle-hemoglobin interaction and composite formation. AB - Nanoscience is now an expanding field of research and finds potential application in biomedical area, but it is limited due to lack of comprehensive knowledge of the interactions operating in nano-bio system. Here, we report the studies on the interaction and formation of nano-bio complex between silver nanoparticle (AgNP) and human blood protein hemoglobin (Hb). We have employed several spectroscopic (absorption, emission, Raman, FTIR, CD, etc.) and electron diffraction techniques (FE-SEM and HR-TEM) to characterize the Hb-AgNP complex system. Our results show the Hb-AgNP interaction is concentration and time dependent. The AgNP particle can attach/come closer to heme, tryptophan, and amide as well aromatic amine residues. As a result, the Hb undergoes conformational change and becomes unfolded through the increment of beta-sheet structure. The AgNP-Hb can form charge-transfers (CT) complex where the Hb-heme along with the AgNP involved in the electron transfer mechanism and form Hb-AgNP assembled structure. The electron transfer mechanism has been found to be dependent on the size of silver particle. The overall study is important in understanding the nano-bio system and in predicting the avenues to design and synthesis of novel nano-biocomposite materials in material science and biomedical area. PMID- 21788121 TI - A formal approach to the analysis of clinical computer-interpretable guideline modeling languages. AB - OBJECTIVE: To develop proof strategies to formally study the expressiveness of workflow-based languages, and to investigate their applicability to clinical computer-interpretable guideline (CIG) modeling languages. METHOD: We propose two strategies for studying the expressiveness of workflow-based languages based on a standard set of workflow patterns expressed as Petri nets (PNs) and notions of congruence and bisimilarity from process calculus. Proof that a PN-based pattern P can be expressed in a language L can be carried out semi-automatically. Proof that a language L cannot provide the behavior specified by a PNP requires proof by exhaustion based on analysis of cases and cannot be performed automatically. The proof strategies are generic but we exemplify their use with a particular CIG modeling language, PROforma. To illustrate the method we evaluate the expressiveness of PROforma against three standard workflow patterns and compare our results with a previous similar but informal comparison. RESULTS: We show that the two proof strategies are effective in evaluating a CIG modeling language against standard workflow patterns. We find that using the proposed formal techniques we obtain different results to a comparable previously published but less formal study. We discuss the utility of these analyses as the basis for principled extensions to CIG modeling languages. Additionally we explain how the same proof strategies can be reused to prove the satisfaction of patterns expressed in the declarative language CIGDec. CONCLUSION: The proof strategies we propose are useful tools for analysing the expressiveness of CIG modeling languages. This study provides good evidence of the benefits of applying formal methods of proof over semi-formal ones. PMID- 21788122 TI - Current opinion of aromatase inhibitor-induced arthralgia in breast cancer in the UK. AB - AIMS: Aromatase inhibitors are now a standard of care in the management of hormone-responsive early breast cancer in postmenopausal women. The troublesome side-effect of arthralgia remains a distinct clinical problem, with limited data on its aetiology and management. The aim of this questionnaire study was to evaluate the opinion of UK breast cancer clinicians on the importance of this treatment side effect. MATERIALS AND METHODS: In 2009, a questionnaire was sent to 772 breast surgeons and oncologists who manage breast cancer within the UK. The questionnaire evaluated the importance, investigation, management and the need for guidelines for aromatase inhibitor-induced arthralgia (AIA). RESULTS: Four hundred and sixteen (54%) returned questionnaires were suitable for analysis. By specialty, 234 (56%) were completed by breast surgeons, 134 (32%) by clinical oncologists, 45 (11%) by medical oncologists and one by a general surgeon. Three hundred and eighty-three (92%) specialists graded the importance of AIA as either very important or important; 211 (51%) did not know the aetiology of AIA; 280 (68%) did not perform bloods; 254 (61%) did not request radiology and 251 (60%) felt management was the responsibility of the oncologists. Three hundred and forty-nine (84%) considered that their practice would benefit from national guidelines. CONCLUSION: This questionnaire has highlighted that AIA is a major patient concern. Further research, educational initiatives and guidance are needed to improve the management of this treatment complication. PMID- 21788123 TI - Adverse cardiac remodeling due to maternal low protein diet is associated with alterations in expression of genes regulating glucose metabolism. AB - BACKGROUND AND AIMS: We have previously shown that a maternal low protein (LP) diet during pregnancy in the rat results in adverse ventricular remodeling and contractile deficiencies of the neonatal rat heart. Since pathological cardiac hypertrophy is associated with increased expression of genes involved in glucose handling, this study was undertaken to examine if maternal LP diet alters the expression of genes encoding for some key components of glucose metabolism and uptake, and of the insulin receptor (IR) signal transduction in the heart of male offspring. METHODS AND RESULTS: We determined the effect of maternal LP and normal diet (90 and 180 g/casein/kg respectively) on IR beta-subunit, insulin receptor substrate (IRS)-1, phosphotyrosyl protein phosphatase (PTP) 1B, GLUT4 and phosphatidylinositol (PI) 3-kinase in male rat offspring at 24 h and at 1, 4 and 8 wks post-partum. Quantitative real-time RT-PCR revealed significant age dependent increases in the expression of IR beta-subunit, IRS-1, PTP1B, GLUT4 and PI3-kinase in the LP group with concomitant increases in corresponding protein abundance at 4 wks of age. These changes were associated with increases in left ventricular (LV) internal diameters as well as increases in LV wall thickness. CONCLUSION: A maternal LP diet can induce increases in the gene expression and protein levels of key components of glucose metabolism and the IR signal transduction pathway in the neonatal rat heart, which may be related to accelerated energy supply, demand and utilization for ventricular remodeling due to compromised contractile performance during early life. PMID- 21788124 TI - Neuronal or inducible nitric oxide synthase (NOS) expression level is not involved in the different susceptibility to nigro-striatal dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) between C57BL/6 and BALB/c mice. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces severe degeneration of dopaminergic (DA-ergic) neurons when administrated to C57BL/6 mice, but such lesions are not observed in BALB/c mice. To clarify the factors which influence such marked strain differences in the susceptibility to MPTP, the involvement of neuronal NOS (nNOS) and inducible NOS (iNOS) was investigated. MPTP was intraperitoneally (ip) administrated to adult C57BL/6 (highly sensitive) and BALB/c (resistant) mice. Immunohistochemical analysis using an antibody to tyrosine hydroxylase (TH) showed a significant decrease in TH-immunopositive areas in the striatum and TH-positive cells in the substantia nigra pars compacta (SNpc) of MPTP-treated C57BL/6 mice at 1 and 7 days (d) after administration, compared to control C57BL/6 mice. On the other hand, MPTP-treated BALB/c mice showed no significant changes. By Western blot analysis, TH, MAO-B, DAT, nNOS and iNOS protein expression levels were examined in intact and MPTP-treated mice. Intact BALB/c mice showed higher DAT protein expression in the striatum and TH protein expression in the midbrain than intact C57BL/6 mice. In addition, MPTP treated BALB/c mice showed a more significant increase of MAO-B expression than MPTP-treated C57BL/6 mice at 12 h. The increase of nNOS and iNOS protein expressions in MPTP-treated BALB/c mice was more pronounced in the striatum and midbrain than in MPTP-treated C57BL/6 mice at 12 h and 2 d. These results indicate that MAO-B, DAT, nNOS or iNOS expression levels do not influence the different strain susceptibility to MPTP. PMID- 21788125 TI - Antifungal activity of Coriandrum sativum essential oil, its mode of action against Candida species and potential synergism with amphotericin B. AB - The increasing incidence of drug-resistant pathogens and toxicity of existing antifungal compounds has drawn attention towards the antimicrobial activity of natural products. The aim of the present study was to evaluate the antifungal activity of coriander essential oil according to classical bacteriological techniques, as well as with flow cytometry. The effect of the essential oil upon germ tube formation, seen as an important virulence factor, and potential synergism with amphotericin B were also studied. Coriander essential oil has a fungicidal activity against the Candida strains tested with MLC values equal to the MIC value and ranging from 0.05 to 0.4% (v/v). Flow cytometric evaluation of BOX, PI and DRAQ5 staining indicates that the fungicidal effect is a result of cytoplasmic membrane damage and subsequent leakage of intracellular components such as DNA. Also, concentrations bellow the MIC value caused a marked reduction in the percentage of germ tube formation for C. albicans strains. A synergetic effect between coriander oil and amphotericin B was also obtained for C. albicans strains, while for C. tropicalis strain only an additive effect was observed. This study describes the antifungal activity of coriander essential oil on Candida spp., which could be useful in designing new formulations for candidosis treatment. PMID- 21788126 TI - Antidepressant effect and pharmacological evaluation of standardized extract of flavonoids from Byrsonima crassifolia. AB - Byrsonima crassifolia (Malpighiaceae) has been used in traditional medicine for the treatment of some mental-related diseases; however, its specific neuropharmacological activities remain to be defined. The present study evaluates the anxiolytic, anticonvulsant, antidepressant, sedative effects produced by the extracts of Byrsonima crassifolia, and their influence on motor activity in ICR mice. Additionally, we determine the acute toxicity profiles of the Byrsonima crassifolia extracts and the presence of neuroactive constituents. Our results show that the methanolic extract of Byrsonima crassifolia produces a significant (P<0.05) antidepressant effect in the forced swimming test in mice at 500 mg/kg dose. However, it does not possess anxiolytic, sedative, or anticonvulsant properties, and does not cause a reduction of mice locomotion (P>0.05). Although the main compound of the methanolic extract was identified as quercetin 3-O xyloside (12 mg/kg), our findings suggest that flavonoids, such as rutin (4.4 mg/kg), quercetin (1.4 mg/kg) and hesperidin (0.7 mg/kg), may be involved in the antidepressant effects. To the best of our knowledge, the present study constitutes the first report on the presence of the flavonoids with neuropharmacological activity rutin and hesperidin in Byrsonima crassifolia. In conclusion, the present results showed that the methanolic extract standardized on flavonoids content of Byrsonima crassifolia possesses potential antidepressant like effects in the FST in mice, and could be considered as relatively safe toxicologically with no deaths of mice when orally administered at 2000 mg/kg. PMID- 21788127 TI - Effects of particle characteristics on magnetic immunoassay in a thin channel. AB - The effects of size and porosity of particles on magnetic immunoassay in a thin channel were studied. Experimental parameters were investigated and compared using a model immunoassay complex of carcinoembryonic antigen (CEA)/anti-CEA. The rate constant for the affinity reaction between functional particles increased as the size of magnetic nanoparticles (800-80 nm) decreased. The affinity reaction between functional particles had no significant effect on the sizes of microparticles (1.0-4.4 MUm) at commonly used thin channel flow-rates of 0.001 0.025 ml/min. Competitive and sandwich reactions of CEA/anti-CEA were studied for CEA detection. Microparticles of different porosities produced similar linear ranges of detection and limits of detection. The limits of detection for CEA were 0.29 pg/ml and 0.21 pg/ml for competitive and sandwich reactions, respectively. The linear ranges of detection were from 0.49 pg/ml to 4.9 ng/ml for both competitive and sandwich reactions. The detection limits were lower, and the linear ranges were wider than those of literature. There was a 9% difference in CEA detection measurements between competitive and sandwich magnetic immunoassay. The measurements of two magnetic immunoassays differed by less than 13% from the ELISA reference measurements. The running time was less than 30 min. Magnetic immunoassay in a thin channel has great potential for biochemical analysis and immunoassay-related applications. PMID- 21788128 TI - Previous extensive sun exposure and subsequent vitamin D production in patients with basal cell carcinoma of the skin, has no protective effect on internal cancers. AB - BACKGROUND: It has been suggested that sunlight through production of vitamin D might have a protective effect on a number of internal cancers. Consequently, in spite of the well known skin cancer risks, some researchers advocate more exposure to ultraviolet radiation, supported by the solarium industry. We estimated the risk of internal cancer before the patient contracted a basal cell carcinoma (BCC) of the skin, the most common cancer in white populations and strongly associated with extensive sun exposure. METHODS: A nested case control study was undertaken in the whole Swedish population. 115,016 patients with BCC and 987,893 controls were linked to population based registers. FINDINGS: The cases had an increased risk of getting another form of cancer before the BCC diagnosis: odds ratio (OR)=1.84; 95% confidence interval (CI) 1.81-1.86. This risk was mainly due to skin cancer: OR=4.95; 95% CI 4.81-5.09 but also non-skin cancer risk was elevated: OR=1.37; 95% CI 1.35-1.39. We adjusted the estimates for age, level of income, occupational status in national censuses, place of living and sex, where appropriate. Of the cancers specifically suggested to be related to vitamin D status: colon, prostate, breast, and ovary cancer, all had slightly increased ORs whilst for pancreatic and gastric cancer no increased OR was found. INTERPRETATION: Patients with BCC, a proxy for extensive sun exposure, run an increased risk of other forms of cancer prior to the diagnosis of BCC. The findings in this study contradict that vitamin D production through extensive sun exposure has any protective effect on internal cancer but emphasise the increased risk for skin cancer. PMID- 21788129 TI - False-positive screening results in the European randomized study of screening for prostate cancer. AB - BACKGROUND: Screening for prostate cancer (PC) with prostate-specific antigen (PSA) has been shown to decrease mortality, but has adverse effects, such as false-positive (FP) screening results. We describe the frequency of FP results and assess their relation to subsequent screening attendance, test results and prostate cancer risk in a large randomized trial. MATERIALS AND METHODS: We included data from five centres of the European Randomized Study of Screening for Prostate Cancer, altogether over 61,000 screened men. Men were screened with PSA test at a 2-7 year interval depending on the centre; PSA cut-off was 3.0-4.0 ng/ml. A positive screen with no histologically confirmed PC in biopsy within 1 year was defined as an FP result. RESULTS: Of the 61,604 men who were screened at least once, 17.8% had one or more FP result(s). Almost 20% of men who participated at all screening rounds had one or more FP result(s). More than half of the men with an FP result had another FP if screened again. Men with FP results had a fourfold risk of PC at subsequent screen (depending on the round, 10.0% versus 2.6-2.7% of men with negative screen, risk ratio 3.8-3.9). The PCs following an FP result were in 92.8% of cases localised and low-grade versus 90.4% following a screen-negative result. CONCLUSIONS: Our results show that FP results are common adverse effects in PC screening, as they affect at least one in six screened men. False-positive men are more prone to be diagnosed with PC but are also likely to have consistently high PSA levels. PMID- 21788130 TI - Determinants of successful implementation of population-based cancer screening programmes. AB - To facilitate the future implementation of population-based cancer screening programmes in European countries, we summarised the experience gained from existing programmes across Europe. We listed points that citizens, advocacy groups, politicians, health planners, and health professionals should consider when planning, implementing and running population based cancer screening programmes. The list is general and is applicable to breast, cervical and colorectal cancer screening. It is based on evidence presented in the three European Union guidelines on quality assurance in cancer screening and diagnosis, supplemented with other literature and expert experience presented at a European Science Advisory Network for Health workshop. The implementation of a cancer screening programme should be divided into the following seven phases: (1) before planning, (2) planning, (3) feasibility testing, (4) piloting or trial implementation, (5) scaling up from pilot to service, (6) running of full-scale programme, and (7) sustainability. For each phase, a substantial number of specified conditions have to be met. Successful implementation of a cancer screening programme requires societal acceptance and local ownership along with the best evidence-based practise and verification of adequate performance in each phase of implementation. PMID- 21788132 TI - Sentinel lymph node micrometastasis in human breast cancer: an update. AB - INTRODUCTION: The advent of sentinel lymph node biopsy (SLNB) and advances in histopathological and molecular analysis techniques have been associated with an increase in micrometastasis (MM) detection rate. However, the clinical significance of sentinel lymph node micrometastasis (SLN MM) continues to be a subject of much debate. In this article we review the literature concerning SLN MM, with particular emphasis on the prognostic significance of SLN MM. The controversies regarding histopathological assessment, clinical relevance and management implications are also discussed. METHODS: Literature review facilitated by Medline and PubMed databases. Cross referencing of the obtained articles was used to identify other relevant studies. RESULTS: Published studies have reported divergent and rather conflicting results regarding the clinical significance and implications of axillary lymph node (ALN) MM in general and SLN MM in particular. Some earlier studies demonstrated no associations, however most recent studies have found SLN MM to be an indicator of poorer prognosis and to be associated with non-SLN involvement. The use of adjuvant chemotherapy and/or hormonal manipulation therapy is associated with an improved survival in patients with SLN MM. Complete ALND may be safely omitted provided that adjuvant systemic therapy recommendations are equal to patients with node-positive disease. However, optimal management of SLN MM is yet to conclude. Furthermore, the identification of MM remains largely dependent on the analytical technique employed and the use of immunohistochemistry (IHC) increases the detection rate of SLN MM. Discrepancies in the histopathological interpretation of TNM classification of SLN tumour burden do exist. Published studies were non randomized and have significant limitations including a small sample size, limited follow-up period, and lack of standardization and reproducibility of pathological examination of the SLN. CONCLUSION: Patients with SLN MM have a poorer prognosis than those who are SLN negative. Therapeutic recommendations regarding patients with SLN MM should be taken in the context of multidisciplinary team setting and in selected cases of SLN MM, complete ALND may be safely omitted. A better reproducibility of pathological interpretation of the TNM classification is required so that future therapeutic guidelines can be applied without confusion. PMID- 21788131 TI - Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. AB - BACKGROUND: Mutations of NRAS and BRAF have been described in Caucasian melanomas. However, the status and the clinical significance of BRAF and NRAS mutations in the Asian population have not been investigated on a large scale. METHODS: Melanoma samples (n=432) were analysed for mutations in exons 11 and 15 of the BRAF gene, and exons 1 and 2 of the NRAS gene in genomic DNA by polymerase chain reaction (PCR) amplification and Sanger sequencing. Mutations of BRAF and NRAS genes were correlated to clinicopathologic features and prognosis of the patients. RESULTS: The incidence of somatic mutations within the BRAF and NRAS genes was 25.5% (110/432) and 7.2% (31/432), respectively. Among the 110 patients with BRAF mutations, 98 patients (89.1%) had V600E mutations. Melanomas without chronic sun-induced damage (Non-CSD) were more likely (P<0.01) to show BRAF mutations while NRAS mutation frequency was unbiased between melanoma subtypes. Patients with genetic mutations in BRAF (P<0.01) or NRAS (P=0.04) gene are more likely to have ulceration as compared to patients without BRAF or NRAS mutations, respectively. Both BRAF (P=0.003) and NRAS mutations (P=0.031) are inversely correlated to overall survival. CONCLUSIONS: BRAF mutation is frequent while mutations in NRAS gene are rare. The most prevalent BRAF mutation type is V600E. Patients with mutations in BRAF or NRAS gene are frequently present with ulceration, and mutation in BRAF or NRAS gene is indicator for poor prognosis. Our study may warrant a clinical trial of kinase inhibitors targeting BRAF V600E in Chinese and Asian melanoma patients. PMID- 21788133 TI - Optimization of fermentable sugar production from rape straw through hydrothermal acid pretreatment. AB - Operational conditions for the hydrolysis of rape straw were optimized using the combined severity index (CS), which combines the effects of time, temperature, and acid concentration into a single parameter. The sugar recovery yield was 77.8% of the theoretical yield at a value of CS=1.3. A maximum concentration of xylose of 7.22 g/L was obtained when the straw was treated for 10 min at a low reaction temperature (150 degrees C) and high acid concentration (pH 1.17). The pentose-rich hydrolyzate exhibited a low concentration of fermentation-inhibiting compounds. The concept of CS can be conveniently and effectively applied for optimization of pretreatments. PMID- 21788134 TI - Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain. AB - Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 MUM), inhibited Stat3-Stat3 protein interactions (IC(50)=19 MUM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 MUM, respectively). PMID- 21788135 TI - Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14beta dihydroxy-4,5alpha-epoxy-6beta-[(4'-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists. AB - Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy 6beta-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor. PMID- 21788137 TI - N-Arylalkyl-2-azaadamantanes as cage-expanded polycarbocyclic sigma (sigma) receptor ligands. AB - A series of racemic N-arylalkyl-2-azaadamantan-1-ols (9-15) and the corresponding deoxygenated, achiral N-arylalkyl-2-azaadamantanes (23-29) were synthesized and screened in competition binding assays against a panel of CNS targets. Adamantyl hemiaminals 9-15 displayed generally low affinity for both sigma(1) (K(i) values= 294-1950 nM) and sigma(2) receptors (K(i) values=201-1020 nM), and negligible affinity for 42 other CNS proteins. Deoxygenation of 9-15 to give the corresponding achiral azaadamantanes 23-29 greatly improved affinity for sigma(1) (K(i) values=8.3-239 nM) and sigma(2) receptors (K(i) values=34-312 nM). PMID- 21788136 TI - Synthesis and antimicrobial activity of N1-benzyl or N1-benzyloxy-1,6-dihydro 1,3,5-triazine-2,4-diamines. AB - The emergence and spread of multidrug-resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis are generating a threat to public health worldwide. In the current study, a series of N(1)-benzyl and N(1)-benzyloxy-1,6 dihydro-1,3,5-triazine-2,4-diamine derivatives were synthesized and investigated for their antimicrobial activity against S. aureus, and Mycobacterium smegmatis which is taxonomically related to M. tuberculosis. Most of the compounds exhibited good activity against M. smegmatis as determined by comparison of diameters of the zone of inhibition of test compounds and standard antibiotics. Compound 7o showed potent antimycobacterial activity against M. smegmatis without mammalian DHFR inhibition liability. The results from this study indicate that 1 benzyl derivatives of 1,6-dihydro-1,3,5-triazine-2,4-diamines may be used as lead compounds for the discovery of antimycobacterial agents. PMID- 21788138 TI - Synthesis and biological evaluation of (+/-)-benzhydrol derivatives as potent non nucleoside HIV-1 reverse transcriptase inhibitors. AB - A series of (+/-)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC(50) values less than 1 MUM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild-type HIV-1 with an EC(50) value of 0.12 MUM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A(17) (K103N+Y181C) with EC(50) values lower than 5 MUM. In addition, the binding modes with RT and the preliminary structure-activity relationships of these derivatives were also explored for further chemical modifications. PMID- 21788140 TI - Analysis of the role of Mg2+ on conformational change and target recognition by ciliate Euplotes octocarinatus centrin. AB - The binding of Mg(2+) with the Euplotes octocarinatus centrin (EoCen) and the effect of Mg(2+) on the binding of EoCen with the peptide melittin were examined by spectroscopic methods. In this study, it was found that Mg(2+) may bind with Ca(2+)-binding sites, at least partly, on EoCen, which displays ~10-fold weaker affinity than Ca(2+). In the presence of Mg(2+), Ca(2+)-saturated EoCen undergoes significant conformational changes resulting in decreased exposure of hydrophobic surfaces on the protein. Additionally, excess Mg(2+) did not change the stoichiometry, but rather reduced the affinity of EoCen to melittin. The Mg(2+) dependent decrease in the affinities of EoCen to melittin is an intrinsic property of Mg(2+), rather than a nonspecific ionic effect. The inhibitory effect of Mg(2+) on the formation of complexes between EoCen and melittin may contribute to the specificity of EoCen in target activation in response to cellular Ca(2+) concentration fluctuations. PMID- 21788139 TI - Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads. AB - Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC(50) values of 3.2 and 4.1 MUM. Synthetic exploration of hit 59 (IC(50)=4.1 MUM) yielded 25 lead inhibitors with the best illustrating IC(50) of 3.0 MUM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts. PMID- 21788141 TI - Endovascular stent graft repair of aortic dissection type B extending to the aortic arch. AB - OBJECTIVE: To analyse our experience with endovascular stent graft repair of descending aorta dissections that require supraaortic branch vessel revascularisation. DESIGN: Retrospective study. METHODS: From 2001 to 2009, 22 consecutive patients with the above dissections were retrospectively analysed. Inclusion requirement: aortic landing zone proximal to the left subclavian artery of less than 15 mm. Hybrid, scalloped or fenestrated endovascular stent grafts were selected based on dissection characteristics. Annual follow-up visits (median 27.1 months) included computed tomography angiography. End points include progressive pathology, complications and survival rates. RESULTS: Surgery was successful in all except for one operative complication. Two patients died within 30 days after surgery, one to cerebral infarction and the other to myocardial infarction. No postoperative complications occurred in the remaining patients. Thrombosis formed in the aortic false lumen of the graft exclusion segment in all patients. The maximum diameter of this segment decreased in 18 patients and was stable in two. In 19 patients, blood flow remained in the false lumen distal to the exclusion area not covered by stent. Patency was seen at mid- and long-term follow-up, without proximal endoleak, graft displacement or deaths. CONCLUSION: Endovascular stent graft methods show promise in endovascular stent graft repair of proximal descending aortic dissections involving the distal arch. PMID- 21788142 TI - On the validation of toe blood pressure measurements. PMID- 21788143 TI - Total endovascular debranching of the aortic arch. AB - BACKGROUND: Significant morbidity and mortality are related to conventional aortic replacement surgery. Endovascular debranching techniques, fenestrated or branched endografts are time consuming and costly. OBJECTIVE: We alternatively propose to use endovascular approach with parallel grafts for debranching of aortic arch. METHODS: Under general anesthesia, 12 F sheaths were inserted in the femoral, axillary and common carotid arteries for vascular accesses. ViaBahn grafts 10 - 15 cm in length were placed into the aortic arch from right common carotid, left common carotid and left axillary arteries, until the tip of each graft reached into the ascending aorta. Through one femoral artery, the aortic stent -graft was positioned and delivered. Soon after, the parallel grafts were sequentially delivered. Self-spanding Wallstents(R) were used for parallel grafts reinforcement. Ballooning was routinely used for parallel grafts and rarely for aortic graft. RESULTS: This technique was used in 2 cases. The first one was a lady with 72 years old, with an aortic retrograde dissection from left subclavian artery and involving remaining arch branches. Through right common carotid artery a stent-graft was placed in the ascending aorta and through the left common carotid artery a ViaBahn was inserted parallel to the former. A thoracic endograft then covered all the aortic arch dissection extending into the ascending aorta close to the sinu -tubular junction. The second case was a 82 year old male patient with a 7 cm aortic arch aneurysm. Through both common carotid arteries ViaBahn grafts were introduced and positioned into the ascending aorta. Soon after, the deployment of the thoracic stent graft covered all parallel grafts of the aortic arch, excluding the aneurysm. Both cases did not have neurologic or cardiac complications and were discharged 10 days after the procedure. CONCLUSIONS: This technique may be a good minimal invasive off-the shelf technical option for aortic arch ''debranching''. More data and further improvements are required before this promising technique can be widely advocated. PMID- 21788144 TI - TEVAR in acute complicated type B dissection-ammunition for complex aortic pathology. PMID- 21788146 TI - Hemiconvulsion-hemiplegia-epilepsy syndrome in South African children: insights from a retrospective case series. AB - INTRODUCTION: Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a recognized sequel of febrile partial status in children younger than 4 years. OBJECTIVE: To describe the clinical features, neuroradiology and outcome in 8 South African children with HHE syndrome. METHOD: A retrospective descriptive study of 8 consecutive cases of HHE syndrome presenting to tertiary hospitals in the Western Cape over a 2 year period. RESULTS: The median age of onset of convulsive status was 16 months (range: 9-36 months). Gender distribution was equal. The duration of the initial episode of status exceeded 2 h in all children. All children were reported to have been developmentally normal prior to the onset of the first seizure and none previously suffered seizures or had a family history of febrile seizures and epilepsy. In 7 of the 8 cases the initial seizure was not associated with fever or preceding illness. Imaging demonstrated cerebral hemiatrophy in all and additional crossed cerebellar atrophy in 2 children. Moderate to severe intellectual disability ensued in the majority of children. The severity of the intellectual disability correlated with the degree of the motor deficit and occurred irrespective of the cerebral hemisphere involved. CONCLUSION: In contrast to developed countries, HHE syndrome is still prevalent in South Africa. The neurological morbidity in South African children is significant and highlights the need for improved emergency care of status epilepticus. PMID- 21788147 TI - Polydispersity index of polymers revealed by DOSY NMR. AB - The polydispersity of a polymer chain is usually measured by its polydispersity index (PDI). In this study we present a method which allows to estimate the PDI of linear polymers from a simple diffusion experiment. The approach is based on the differential diffusion profile observed for the main polymer chain signal versus the extremity signal. From this difference, a statistical analysis of the DOSY spectrum allows the PDI to be estimated accurately, to the condition that the Flory coefficient of the polymer chain is known. Alternatively, the mass average molar mass Mw and the number average molar mass Mn can be extracted separately from the same spectrum. Results on PEO mixes reveal that, using this new method, PDI can be estimated with a very good accuracy. This method can easily be applied to almost any kind of linear polymers. PMID- 21788149 TI - Synthesis of novel amorphous calcium carbonate by sono atomization for reactive mixing. AB - Droplets of several micrometers in size can be formed in aqueous solution by atomization under ultrasonic irradiation at 2 MHz. This phenomenon, known as atomization, is capable of forming fine droplets for use as a reaction field. This synthetic method is called SARM (sono atomization for reactive mixing). This paper reports on the synthesis of a novel amorphous calcium carbonate formed by SARM. The amorphous calcium carbonate, obtained at a solution concentration of 0.8 mol/dm(3), had a specific surface area of 65 m(2)/g and a composition of CaCO(3)*0.5H(2)O as determined using thermogravimetric/differential thermal analysis (TG-DTA). Because the ACC had a lower hydrate composition than conventional amorphous calcium carbonate (ACC), the ACC synthesized in this paper was very stable at room temperature. PMID- 21788148 TI - Dependencies of multi-component T2 and T1rho relaxation on the anisotropy of collagen fibrils in bovine nasal cartilage. AB - Both NMR spectroscopy and MRI were used to investigate the dependencies of multi component T2 and T1rho relaxation on the anisotropy of bovine nasal cartilage (BNC). The non-negative least square (NNLS) method and the multi-exponential fitting method were used to analyze all experimental data. When the collagen fibrils in nasal cartilage were oriented at the magic angle (55 degrees ) to the magnetic field B0, both T2 and T1rho were single component, regardless of the spin-lock field strength or the echo spacing time in the pulse sequences. When the collagen fibrils in nasal cartilage were oriented at 0 degrees to B0, both T2 and T1rho at a spin-lock field of 500 Hz had two components. When the spin lock field was increased to 1000 Hz or higher, T1rho relaxation in nasal cartilage became a single component, even when the specimen orientation was 0 degrees . These results demonstrate that the specimen orientation must be considered for any multi-component analysis, even for nasal cartilage that is commonly considered homogenously structured. Since the rapidly and slowly relaxing components can be attributed to different portions of the water population in tissue, the ability to resolve different relaxation components could be used to quantitatively examine individual molecular components in connective tissues. PMID- 21788150 TI - An accurate, fast and robust method to generate patient-specific cubic Hermite meshes. AB - In-silico continuum simulations of organ and tissue scale physiology often require a discretisation or mesh of the solution domain. Cubic Hermite meshes provide a smooth representation of anatomy that is well-suited for simulating large deformation mechanics. Models of organ mechanics and deformation have demonstrated significant potential for clinical application. However, the production of a personalised mesh from patient's anatomy using medical images remains a major bottleneck in simulation workflows. To address this issue, we have developed an accurate, fast and automatic method for deriving patient specific cubic Hermite meshes. The proposed solution customises a predefined template with a fast binary image registration step and a novel cubic Hermite mesh warping constructed using a variational technique. Image registration is used to retrieve the mapping field between the template mesh and the patient images. The variational warping technique then finds a smooth and accurate projection of this field into the basis functions of the mesh. Applying this methodology, cubic Hermite meshes are fitted to the binary description of shape with sub-voxel accuracy and within a few minutes, which is a significant advance over the existing state of the art methods. To demonstrate its clinical utility, a generic cubic Hermite heart biventricular model is personalised to the anatomy of four patients, and the resulting mechanical stability of these customised meshes is successfully demonstrated. PMID- 21788151 TI - Association of -308 TNF-alpha promoter polymorphism with clinical aggressiveness in patients with head and neck squamous cell carcinoma. AB - Genetic polymorphisms in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene are involved in the regulation of the expression levels of its cytokine. Besides, these polymorphisms have been associated with the clinical behaviour of cancer. We investigated the -308 promoter region polymorphisms of the TNF-alpha gene and its association with the clinicopathological factors of a head and neck squamous cell carcinoma (HNSCC) sample. Furthermore, we analysed the impact of all the variables on the overall survival of patients. A sample of HNSCC (n=89) was evaluated. Clinicopathological factors and overall survival data were gathered. The TNF-alpha gene was analysed by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Data analyses were performed by using bivariate and multivariate statistical tests. Significance was set at p<0.05. HNSCC subjects carrying the A allele (GA/AA) exhibited associations with poor performance status (OR=2.82, p=0.039), lesions located on posterior areas (OR=4.02, p=0.002), and large-size tumours (OR=2.91, p=0.015). Subjects carrying only AA genotype exhibited association with poor performance status (OR=6.667, p=0.007). A worse overall survival was noted in subjects with large tumours (OR=4.87, p=0.005) and locoregional metastatic disease (OR=2.50, p=0.018). Our data suggests that the presence of the A allele/AA haplotype in HNSCC individuals might contribute to the higher clinical aggressiveness of malignant disease. PMID- 21788152 TI - New research horizons in vector-transmission of plant viruses. AB - Understanding the mechanisms controlling vector-transmission of plant viruses requires integrating information from at least three different viewpoints: virus vector interactions, plant-vector interactions and virus-plant interactions. While some of these aspects have been covered by past and present investigations, others have been bypassed completely, because of technical bottlenecks or conceptual lacunas. Here, we highlight recent advances and needs in hitherto poorly documented aspects of vector transmission, such as characterization of the vector molecules responsible for initial viral recognition, and the role of vector saliva in inoculation and initial onset of infection in a new plant. We also propose and discuss some novel conceptual and complementary questions that are opening up fascinating new horizons in this field. We explore the possible existence of viral morphs with specific properties that facilitate acquisition by vectors, and discuss the dynamics/genetics of such viral subpopulations, which could differentiate and specialize in different host compartments. PMID- 21788153 TI - Interaction of polyamidoamine (PAMAM) succinamic acid dendrimers generation 4 with human serum albumin. AB - Dendrimers, a relatively new group of highly branched three dimensional polymers, are intensively investigated to use them in biomedical and physicochemical sciences. Their specific architecture gives them the ability to interact with many different types of molecules. In our studies the interaction between PAMAM succinamic acid dendrimers generation 4 (PAMAM-SAH G4) and human serum albumin (HSA) was examined. Experiments showed that a single molecule of a HSA can bind approximately 6 particles of dendrimers. The fluorescence studies demonstrated that dendrimers lead to a decrease in protein fluorescence but changes in fluorescence anisotropy were not observed. Alterations in the spectrum of circular dichroism indicated changes in the secondary protein structure. The results clearly show that this generation of dendrimers possesses a strong ability to interact with human serum albumin. PMID- 21788154 TI - Influence of operational parameters on photocatalytic degradation of a genotoxic azo dye Acid Violet 7 in aqueous ZnO suspensions. AB - The photocatalytic degradation of a genotoxic azo dye Acid Violet 7 (AV 7) using ZnO as a photocatalyst in aqueous solution has been investigated under UV irradiation. The degradation is higher with UV/ZnO process than with UV/TiO(2) P25 process at pH 9. The effects of different parameters such as pH of the solution, amount of catalyst, initial dye concentration and the influence of cations, anions and oxidants on photodegradation of AV 7 were analyzed. Addition of oxidants except H(2)O(2) has no significant effect on degradation. The degradation of AV 7 follows pseudo-first order kinetics according to the Langmuir Hinshelwood model. The degradation of AV 7 has also been confirmed by COD and CV measurements. PMID- 21788155 TI - Study on the sonodynamic activity and mechanism of promethazine hydrochloride by multi-spectroscopic techniques. AB - In this paper, the bovine serum albumin (BSA) was selected as a target molecule, the sonodynamic damage to protein in the presence of promethazine hydrochloride (PMT) and its mechanism were studied by the means of absorption, fluorescence and circular dichroism (CD) spectra. The results of hyperchromic effect of absorption spectra and quenching of intrinsic fluorescence spectra indicate that the ultrasound-induced BSA molecules damage is enhanced by PMT. The damage degree of BSA molecules increases with the increase of ultrasonic irradiation time and PMT concentration. The results of synchronous fluorescence, three-dimensional fluorescence and CD spectra confirmed that the synergistic effects of ultrasound and PMT induced the damage of BSA molecules. The results of oxidation-extraction photometry with several reactive oxygen species (ROS) scavengers indicate that the damage of BSA molecules could be mainly due to the generation of ROS and both (1)O(2) and OH are the important mediators of the ultrasound-induced BSA molecules damage in the presence of PMT. PMID- 21788156 TI - Estimation of sigma- and pi-donor properties of heterocyclic thioamides by spectroscopic and magnetic resonance methods. AB - The charge-transfer complexes (CTC) of few thioamide: 1-methylimidazoline-2 thione (MMI), 3-methyl-1-ethoxycarbonilimidazoline-2-thione (Carb), 5 methylbenzimidazoline-2-thione (BIZ), benzothiazoline-2-thione (BTZ), benzoxazoline-2-thione (BOZ) as sigma-donors and diiodine as sigma-acceptor were studied by spectroscopic methods (UV/Vis, (1)H NMR). CTC formation constants of thioamides with diiodine were determined using the function of the average-iodine number. The charge-transfer complexes of thioamides as pi-donors with tetracyanoethylene (TCNE) as pi-electron acceptor, were studied by UV spectroscopy in dichloromethane and chloroform solutions. The mechanism of interaction MMI and Carb with TCNE have been studied by EPR spectroscopy. Spectral characteristics and formation constants are discussed in the terms of electron donor affinity of thioamides and the nature of the organic solvent used. The ionization potentials of donors were estimated from the CT transition energies of their complexes. The photolytic equilibrium constants of five thioamides are determined using pH-metric titrations. PMID- 21788158 TI - Motivation, psychopathology, locus of control, and quality of life in women with epileptic and nonepileptic seizures. AB - To examine factors that may potentially aid in the differential diagnosis and subsequent tailoring of treatment for patients with epileptic (ES) and psychogenic nonepileptic (PNES) seizures, thirty female patients with PNES and 51 female patients with temporal lobe epilepsy were assessed in the areas of motivation, psychopathology, health-related locus of control (HRLOC), and health related quality of life (HRQOL). The two groups demonstrated equivalent levels of motivation, clinically elevated yet comparable mood symptoms, and no general differences in HRLOC. Despite similar mood disturbances in both groups, the participants with PNES had a later age of seizure onset, exhibited greater personality disturbances, attributed more control over their condition to nonphysicians, and endorsed a greater negative impact of their seizures on physical and emotional aspects of HRQOL. Preliminary analyses suggest that chronic anxiety and overall HRQOL may be core discriminators between these seizure groups. Addressing such issues may prove useful in tailoring more specific treatments for these etiologically disparate conditions. PMID- 21788159 TI - Preferential DNA damage prevention by the E. coli AidB gene: A new mechanism for the protection of specific genes. AB - aidB is one of the four genes of E. coli that is induced by alkylating agents and regulated by Ada protein. Three genes (ada, alkA, and alkB) encode DNA repair proteins that remove or repair alkylated bases. However, the role of AidB remains unclear despite extensive efforts to determine its function in cells exposed to alkylating agents. The E. coli AidB protein was identified as a component of the protein complex that assembles at strong promoters. We demonstrate that AidB protein preferentially binds to UP elements, AT rich transcription enhancer sequences found upstream of many highly expressed genes, several DNA repair genes, and housekeeping genes. AidB allows efficient transcription from promoters containing an UP element upon exposure to a DNA methylating agent and protects downstream genes from DNA damage. The DNA binding domain is required to target AidB to specific genes preferentially protecting them from alkylation damage. However, deletion of AidB's DNA binding domain does not prevent its antimutagenic activity, instead this deletion appears to allow AidB to function as a cytoplasmic alkylation resistance protein. Our studies identify the role of AidB in alkylating agent exposed cells and suggest a new cellular strategy in which a subset of the genome is preferentially protected from damage by alkylating agents. PMID- 21788160 TI - Application of a validated ultra performance liquid chromatography-tandem mass spectrometry method for the quantification of darunavir in human plasma for a bioequivalence study in Indian subjects. AB - A simple, precise and rapid ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the quantification of darunavir, a protease inhibitor, using darunavir-d9 as internal standard (IS). The method involved liquid-liquid extraction of darunavir and IS in methyl-tert-butyl ether from 50 MUL human plasma. The chromatographic separation was achieved on an Acquity UPLC BEH C18 (50 mm * 2.1mm, 1.7 MUm particle size) analytical column under gradient conditions, in a run time of 1.6 min. The precursor -> product ion transitions for darunavir (m/z 548.1 -> 392.0) and IS (m/z 557.1 -> 401.0) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The method was extensively validated for its selectivity, sensitivity, carryover check, linearity, precision and accuracy, reinjection reproducibility, recovery, matrix effect, ion suppression/enhancement, stability and dilution integrity. The linearity of the method was established in the concentration range of 1.0-5000 ng/mL. The mean relative recovery for darunavir (100.8%) and IS (89.8%) from spiked plasma samples was consistent and reproducible. The application of this method for routine measurement of plasma darunavir concentration was demonstrated by a bioequivalence study conducted in 40 healthy Indian subjects for a 600 mg tablet formulation along with 100mg ritonavir as booster under fast and fed conditions. To demonstrate the reproducibility in the measurement of study data, an incurred sample reanalysis was done with 400 subject samples and the % change in concentration was within +/- 12%. PMID- 21788161 TI - Periorbital necrotising fasciitis following cutaneous herpes zoster. AB - Necrotising fasciitis is a rare severe infection of the soft tissues and deep fascia, which is associated with a significant level of mortality. Involvement of the head and neck is uncommon, and necrotising fasciitis of the periorbital area even rarer. We present a case of bilateral periorbital necrotising fasciitis following shingles in an otherwise healthy immunocompetent patient. PMID- 21788162 TI - Primary reconstruction of the umbilicus, using two rectangular subcutaneous pedicle flaps. PMID- 21788163 TI - Effects of green foam, black foam and gauze on contraction, blood flow and pressure delivery to the wound bed in negative pressure wound therapy. AB - BACKGROUND: Negative pressure wound therapy (NPWT) contracts the wound and alters the microvascular blood flow in the wound edge, which may be crucial in promoting wound healing. The aim of the present study was to examine these biological effects in the wound edge using different types of wound fillers. METHODS: Wounds were created on the backs of pigs and filled with green foam, black foam or gauze. Dressings for NPWT were then applied. The immediate effects of continuous NPWT, including pressure transmission to the wound bed and microvascular blood flow (using laser Doppler velocimetry), were studied in eight pigs that were anaesthetised for 12 h. In another eight pigs, wound contraction was studied during 72 h of NPWT. RESULTS: Pressure transduction to the wound bed was similar through green foam, black foam and gauze, with only small pressure drop. Wound contraction was more pronounced for green and black foam than for gauze. Blood flow was found to decrease 0.5 cm from the wound edge and increase 2.5 cm from the wound edge. The increase in blood flow was similar with all wound fillers, while the decrease was less pronounced with gauze than with both foams. CONCLUSIONS: The biological effects of NPWT depend on the type of wound filler. Green and black foam have similar effects, while gauze results in less pronounced wound contraction and hypoperfusion. NPWT may be tailored to the individual wound type to optimise the effects and minimise the complications by choosing different wound fillers. PMID- 21788164 TI - Discussion: 'Predicting spontaneous preterm birth' by Esplin et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Esplin MS, Merrell K, Goldenberg R, et al; the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units. Proteomic identification of serum peptides predicting subsequent spontaneous preterm birth. Am J Obstet Gynecol 2011;204:391.e1-8. PMID- 21788166 TI - Making the best match: can we select the right residents for obstetrics and gynecology and for our own programs? PMID- 21788167 TI - Marry old and new guidelines. AB - Gestational diabetes mellitus is associated with increased neonatal morbidities and higher cesarean delivery rates; women with gestational diabetes mellitus are at increased risk for type II diabetes mellitus later in life. The current recommendation for screening includes a glucose tolerance test either early in pregnancy and/or at 24-28 weeks' gestation followed by a diagnostic 100-g oral 3 hour glucose tolerance test with a rate of 5%. The results of a large prospective observational study (HAPO study) and 2 randomized trials lead the International Association of Diabetes in Pregnancy Study Group to recommend a 1-stage screening and diagnosis method that includes a 75-g 2-hour glucose tolerance test that will result in an 18% gestational diabetes mellitus rate. However, there is uncertainty about the clinical implications of the adoption of the latter recommendation. PMID- 21788168 TI - Staying with old guidelines. AB - Gestational diabetes mellitus is associated with increased neonatal morbidities and higher cesarean delivery rates; women with gestational diabetes mellitus are at increased risk for type II diabetes mellitus later in life. The current recommendation for screening includes a glucose tolerance test either early in pregnancy and/or at 24-28 weeks' gestation followed by a diagnostic 100-g oral 3 hour glucose tolerance test with a rate of 5%. The results of a large prospective observational study (HAPO study) and 2 randomized trials lead the International Association of Diabetes in Pregnancy Study Group to recommend a 1-stage screening and diagnosis method that includes a 75-g 2-hour glucose tolerance test that will result in an 18% gestational diabetes mellitus rate. However, there is uncertainty about the clinical implications of the adoption of the latter recommendation. PMID- 21788172 TI - ICRP Publication 113. Radiological protection education in medicine: an essential but often missing element. PMID- 21788170 TI - Perinatal risk indicators for long-term neurological morbidity among preterm neonates. AB - OBJECTIVE: Many obstetric interventions are performed to improve long-term neonatal outcome. However, long-term neonatal outcome is usually not a primary outcome because it is time-consuming and expensive. The aim of this project was to identify different perinatal risk indicators and to develop prediction models for neurologic morbidity at 2 and 5 years of age. STUDY DESIGN: Data from a Dutch cohort study of preterm and small-for-gestational-age infants was used. Neonates who were born in The Netherlands in 1983 with a gestational age of <34 weeks and without congenital abnormalities were included (n = 753). Infants were divided in 3 groups: no handicap, minor handicap, and major handicap. RESULTS: Common risk indicators for major handicaps at 2 and 5 years of age were male sex (odds ratio, 2.7 and 3.0, respectively), seizures after >=2 days of life (odds ratio, 5.8 and 5.8, respectively), and intracranial hemorrhage (odds ratio, 3.8 and 2.6, respectively). CONCLUSION: In this cohort, male sex, intracranial hemorrhage, and seizures seem to be important risk indicators for long-term neurologic morbidity. PMID- 21788173 TI - ICRP Publication 113. Education and training in radiological protection for diagnostic and interventional procedures. PMID- 21788177 TI - Localizing heart sounds in respiratory signals using singular spectrum analysis. AB - Respiratory sounds are always contaminated by heart sound interference. An essential preprocessing step in some of the heart sound cancellation methods is localizing primary heart sound components. Singular spectrum analysis (SSA), a powerful time series analysis technique, is used in this paper. Despite the frequency overlap of the heart and lung sound components, two different trends in the eigenvalue spectra are recognizable, which leads to find a subspace that contains more information about the underlying heart sound. Artificially mixed and real respiratory signals are used for evaluating the performance of the method. Selecting the appropriate length for the SSA window results in good decomposition quality and low computational cost for the algorithm. The results of the proposed method are compared with those of well-established methods, which use the wavelet transform and entropy of the signal to detect the heart sound components. The proposed method outperforms the wavelet-based method in terms of false detection and also correlation with the underlying heart sounds. Performance of the proposed method is slightly better than that of the entropy based method. Moreover, the execution time of the former is significantly lower than that of the latter. PMID- 21788178 TI - Multiscale causal connectivity analysis by canonical correlation: theory and application to epileptic brain. AB - Multivariate Granger causality is a well-established approach for inferring information flow in complex systems, and it is being increasingly applied to map brain connectivity. Traditional Granger causality is based on vector autoregressive (AR) or mixed autoregressive moving average (ARMA) model, which are potentially affected by errors in parameter estimation and may be contaminated by zero-lag correlation, notably when modeling neuroimaging data. To overcome this issue, we present here an extended canonical correlation approach to measure multivariate Granger causal interactions among time series. The procedure includes a reduced rank step for calculating canonical correlation analysis (CCA), and extends the definition of causality including instantaneous effects, thus avoiding the potential estimation problems of AR (or ARMA) models. We tested this approach on simulated data and confirmed its practical utility by exploring local network connectivity at different scales in the epileptic brain analyzing scalp and depth-EEG data during an interictal period. PMID- 21788179 TI - An SSVEP-based BCI using high duty-cycle visual flicker. AB - Steady-state visual-evoked potential (SSVEP)-based brain-computer interfaces (BCIs) have generated significant interest due to their high information transfer rate (ITR). Due to the amplitude-frequency characteristic of the SSVEP, the flickering frequency of an SSVEP-based BCI is typically lower than 20 Hz to achieve a high SNR. However, a visual flicker with a flashing frequency below the critical flicker-fusion frequency often makes subjects feel flicker jerky and causes visual discomfort. This study presents a novel technique using high duty cycle visual flicker to decrease user's visual discomfort. The proposed design uses LEDs flashing at 13.16 Hz, driven by flickering sequences consisting of repetitive stimulus cycles with a duration T (T = 76 ms). Each stimulus cycle included an ON state with a duration T(ON) and an OFF state with a duration T(OFF) (T = T(ON) + T(OFF)), and the duty cycle, defined as T(ON)/T, varied from 10.5% to 89.5%. This study also includes a questionnaire survey and analyzes the SSVEPs induced by different duty-cycle flickers. An 89.5% duty-cycle flicker, reported as a comfortable flicker, was adopted in a phase-tagged SSVEP system. Six subjects were asked to sequentially input a sequence of cursor commands with the 25.08-bits/min ITR. PMID- 21788180 TI - Multiscale FEM modeling of vascular tone: from membrane currents to vessel mechanics. AB - Regulation of vascular tone is a complex process that remains poorly understood. Here, we present our recent efforts for the development of physiologically realistic models of arterial segments for the analysis of vasoreactivity in health and disease. Multiscale modeling integrates intracellular and cell membrane components into whole-cell models of calcium and membrane potential dynamics. Single-cell models of vascular cells are combined into a multicellular model of the vascular wall, and vessel wall biomechanics are integrated with calcium dynamics in the smooth muscle layer. At each scale, continuum models using finite element method can account for spatial heterogeneity in calcium signaling and for nonuniform deformations of a vessel segment. The outlined approach can be used to investigate cellular mechanisms underlying altered vasoreactivity in hypertension. PMID- 21788181 TI - Design of a bone-attached parallel robot for percutaneous cochlear implantation. AB - Access to the cochlea requires drilling in close proximity to bone-embedded nerves, blood vessels, and other structures, the violation of which can result in complications for the patient. It has recently been shown that microstereotactic frames can enable an image-guided percutaneous approach, removing reliance on human experience and hand-eye coordination, and reducing trauma. However, constructing current microstereotactic frames disrupts the clinical workflow, requiring multiday intrasurgical manufacturing delays, or an on-call machine shop in or near the hospital. In this paper, we describe a new kind of microsterotactic frame that obviates these delay and infrastructure issues by being repositionable. Inspired by the prior success of bone-attached parallel robots in knee and spinal procedures, we present an automated image-guided microstereotactic frame. Experiments demonstrate a mean accuracy at the cochlea of 0.20 +/- 0.07 mm in phantom testing with trajectories taken from a human clinical dataset. We also describe a cadaver experiment evaluating the entire image-guided surgery pipeline, where we achieved an accuracy of 0.38 mm at the cochlea. PMID- 21788182 TI - Adaptive multiscale entropy analysis of multivariate neural data. AB - Multiscale entropy (MSE) has been widely used to quantify a system's complexity by taking into account the multiple time scales inherent in physiologic time series. The method, however, is biased toward the coarse scale, i.e., low frequency components due to the progressive smoothing operations. In addition, the algorithm for extracting the different scales is not well adapted to nonlinear/nonstationary signals. In this letter, we introduce adaptive multiscale entropy (AME) measures in which the scales are adaptively derived directly from the data by virtue of recently developed multivariate empirical mode decomposition. Depending on the consecutive removal of low-frequency or high frequency components, our AME can be estimated at either coarse-to-fine or fine to-coarse scales over which the sample entropy is performed. Computer simulations are performed to verify the effectiveness of AME for analysis of the highly nonstationary data. Local field potentials collected from the visual cortex of macaque monkey while performing a generalized flash suppression task are used as an example to demonstrate the usefulness of our AME approach to reveal the underlying dynamics in complex neural data. PMID- 21788183 TI - Robust automatic knee MR slice positioning through redundant and hierarchical anatomy detection. AB - Diagnostic magnetic resonance (MR) image quality is highly dependent on the position and orientation of the slice groups, due to the intrinsic high in-slice and low through-slice resolutions of MR imaging. Hence, the higher speed, accuracy, and reproducibility of automatic slice positioning, make it highly desirable over manual slice positioning. However, imaging artifacts, diseases, joint articulation, variations across ages and demographics as well as the extremely high performance requirements prevent state-of-the-art methods, such as volumetric registration, to be an off-the-shelf solution. In this paper, we address all these issues through an automatic slice positioning framework based on redundant and hierarchical learning. Our method has two hallmarks that are specifically designed to achieve high robustness and accuracy. 1) A redundant set of anatomy detectors are learned to provide local appearance cues. These detections are pruned and assembled according to a distributed anatomy model, which captures group-wise spatial configurations among anatomy primitives. This strategy brings about a high level of robustness and works even if a large portion of the target is distorted, missing, or occluded. 2) The detectors are learned and invoked in a hierarchical fashion, with each local detection scheduled and iterated according to its intrinsic invariance property. This iterative alignment process is shown to dramatically improve alignment accuracy. The proposed system is extensively validated on a large dataset including 744 clinical MR scans. Compared to state-of-the-art methods, our method exhibits superior performance in terms of robustness, accuracy, and reproducibility. The methodology is general and can be applied to other anatomies and other imaging modalities. PMID- 21788184 TI - A combined manifold learning analysis of shape and appearance to characterize neonatal brain development. AB - Large medical image datasets form a rich source of anatomical descriptions for research into pathology and clinical biomarkers. Many features may be extracted from data such as MR images to provide, through manifold learning methods, new representations of the population's anatomy. However, the ability of any individual feature to fully capture all aspects morphology is limited. We propose a framework for deriving a representation from multiple features or measures which can be chosen to suit the application and are processed using separate manifold-learning steps. The results are then combined to give a single set of embedding coordinates for the data. We illustrate the framework in a population study of neonatal brain MR images and show how consistent representations, correlating well with clinical data, are given by measures of shape and of appearance. These particular measures were chosen as the developing neonatal brain undergoes rapid changes in shape and MR appearance and were derived from extracted cortical surfaces, nonrigid deformations, and image similarities. Combined single embeddings show improved correlations demonstrating their benefit for further studies such as identifying patterns in the trajectories of brain development. The results also suggest a lasting effect of age at birth on brain morphology, coinciding with previous clinical studies. PMID- 21788185 TI - Medial-based deformable models in nonconvex shape-spaces for medical image segmentation. AB - We explore the application of genetic algorithms (GA) to deformable models through the proposition of a novel method for medical image segmentation that combines GA with nonconvex, localized, medial-based shape statistics. We replace the more typical gradient descent optimizer used in deformable models with GA, and the convex, implicit, global shape statistics with nonconvex, explicit, localized ones. Specifically, we propose GA to reduce typical deformable model weaknesses pertaining to model initialization, pose estimation and local minima, through the simultaneous evolution of a large number of models. Furthermore, we constrain the evolution, and thus reduce the size of the search-space, by using statistically-based deformable models whose deformations are intuitive (stretch, bulge, bend) and are driven in terms of localized principal modes of variation, instead of modes of variation across the entire shape that often fail to capture localized shape changes. Although GA are not guaranteed to achieve the global optima, our method compares favorably to the prevalent optimization techniques, convex/nonconvex gradient-based optimizers and to globally optimal graph theoretic combinatorial optimization techniques, when applied to the task of corpus callosum segmentation in 50 mid-sagittal brain magnetic resonance images. PMID- 21788186 TI - Online identification of nonlinear spatiotemporal systems using kernel learning approach. AB - The identification of nonlinear spatiotemporal systems is of significance to engineering practice, since it can always provide useful insight into the underlying nonlinear mechanism and physical characteristics under study. In this paper, nonlinear spatiotemporal system models are transformed into a class of multi-input-multi-output (MIMO) partially linear systems (PLSs), and an effective online identification algorithm is therefore proposed by using a pruning error minimization principle and least square support vector machines. It is shown that many benchmark physical and engineering systems can be transformed into MIMO-PLSs which keep some important physical spatiotemporal relationships and are very helpful in the identification and analysis of the underlying system. Compared with several existing methods, the advantages of the proposed method are that it can make full use of some prior structural information about system physical models, can realize online estimation of the system dynamics, and achieve accurate characterization of some important nonlinear physical characteristics of the system. This would provide an important basis for state estimation, control, optimal analysis, and design of nonlinear distributed parameter systems. The proposed algorithm can also be applied to identification problems of stochastic spatiotemporal dynamical systems. Numeral examples and comparisons are given to demonstrate our results. PMID- 21788187 TI - Discriminative graph embedding for label propagation. AB - In many applications, the available information is encoded in graph structures. This is a common problem in biological networks, social networks, web communities and document citations. We investigate the problem of classifying nodes' labels on a similarity graph given only a graph structure on the nodes. Conventional machine learning methods usually require data to reside in some Euclidean spaces or to have a kernel representation. Applying these methods to nodes on graphs would require embedding the graphs into these spaces. By embedding and then learning the nodes on graphs, most methods are either flexible with different learning objectives or efficient enough for large scale applications. We propose a method to embed a graph into a feature space for a discriminative purpose. Our idea is to include label information into the embedding process, making the space representation tailored to the task. We design embedding objective functions that the following learning formulations become spectral transforms. We then reformulate these spectral transforms into multiple kernel learning problems. Our method, while being tailored to the discriminative tasks, is efficient and can scale to massive data sets. We show the need of discriminative embedding on some simulations. Applying to biological network problems, our method is shown to outperform baselines. PMID- 21788188 TI - Nonlinear identification with local model networks using GTLS techniques and equality constraints. AB - Local model networks approximate a nonlinear system through multiple local models fitted within a partition space. The main advantage of this approach is that the identification of complex nonlinear processes is alleviated by the integration of structured knowledge about the process. This paper extends these concepts by the integration of quantitative process knowledge into the identification procedure. Quantitative knowledge describes explicit dependences between inputs and outputs and is integrated in the parameter estimation process by means of equality constraints. For this purpose, a constrained generalized total least squares algorithm for local parameter estimation is presented. Furthermore, the problem of proper integration of constraints in the partitioning process is treated where an expectation-maximization procedure is combined with constrained parameter estimation. The benefits and the applicability of the proposed concepts are demonstrated by means of two illustrative examples and a practical application using real measurement data. PMID- 21788189 TI - Toward dynamic image mosaic generation with robustness to parallax. AB - Mosaicing is largely dependent on the quality of registration among the constituent input images. Parallax and object motion present challenges to image registration, leading to artifacts in the result. To reduce the impact of these artifacts, traditional image mosaicing approaches often impose planar scene constraints or rely on purely rotational camera motion or dense sampling. However, these requirements are often impractical or fail to address the needs of all applications. Instead, taking advantage of depth cues and a smooth transition criterion, we achieve significantly improved mosaicing results for static scenes, coping effectively with nontrivial parallax in the input. We extend this approach to the synthesis of dynamic video mosaics, incorporating foreground/background segmentation and a consistent motion perception criterion. Although further additions are required to cope with unconstrained object motion, our algorithm can synthesize a perceptually convincing output, conveying the same appearance of motion as seen in the input sequences. PMID- 21788190 TI - Bayesian estimation for optimized structured illumination microscopy. AB - Structured illumination microscopy is a recent imaging technique that aims at going beyond the classical optical resolution by reconstructing high-resolution (HR) images from low-resolution (LR) images acquired through modulation of the transfer function of the microscope. The classical implementation has a number of drawbacks, such as requiring a large number of images to be acquired and parameters to be manually set in an ad-hoc manner that have, until now, hampered its wide dissemination. Here, we present a new framework based on a Bayesian inverse problem formulation approach that enables the computation of one HR image from a reduced number of LR images and has no specific constraints on the modulation. Moreover, it permits to automatically estimate the optimal reconstruction hyperparameters and to compute an uncertainty bound on the estimated values. We demonstrate through numerical evaluations on simulated data and examples on real microscopy data that our approach represents a decisive advance for a wider use of HR microscopy through structured illumination. PMID- 21788191 TI - Combining head pose and eye location information for gaze estimation. AB - Head pose and eye location for gaze estimation have been separately studied in numerous works in the literature. Previous research shows that satisfactory accuracy in head pose and eye location estimation can be achieved in constrained settings. However, in the presence of nonfrontal faces, eye locators are not adequate to accurately locate the center of the eyes. On the other hand, head pose estimation techniques are able to deal with these conditions; hence, they may be suited to enhance the accuracy of eye localization. Therefore, in this paper, a hybrid scheme is proposed to combine head pose and eye location information to obtain enhanced gaze estimation. To this end, the transformation matrix obtained from the head pose is used to normalize the eye regions, and in turn, the transformation matrix generated by the found eye location is used to correct the pose estimation procedure. The scheme is designed to enhance the accuracy of eye location estimations, particularly in low-resolution videos, to extend the operative range of the eye locators, and to improve the accuracy of the head pose tracker. These enhanced estimations are then combined to obtain a novel visual gaze estimation system, which uses both eye location and head information to refine the gaze estimates. From the experimental results, it can be derived that the proposed unified scheme improves the accuracy of eye estimations by 16% to 23%. Furthermore, it considerably extends its operating range by more than 15 degrees by overcoming the problems introduced by extreme head poses. Moreover, the accuracy of the head pose tracker is improved by 12% to 24%. Finally, the experimentation on the proposed combined gaze estimation system shows that it is accurate (with a mean error between 2 degrees and 5 degrees ) and that it can be used in cases where classic approaches would fail without imposing restraints on the position of the head. PMID- 21788192 TI - Single-image refocusing and defocusing. AB - In this paper, we present a postprocessing method to tackle the single-image refocusing-and-defocusing problem. The proposed method can accomplish the tasks of focus-map estimation and image refocusing and defocusing. Given an image with a mixture of focused and defocused objects, we first detect the edges and then estimate the focus map based on the edge blurriness, which is depicted explicitly by a parametric model. The image refocusing problem is addressed in a blind deconvolution framework, where the image prior is modeled by using both global and local constraints. In particular, we correct the defocused blurry edges to sharp ones with the aid of the parametric edge model and then render this cue as a local prior to ensure the sharpness of the refocused image. Experimental results demonstrate that the proposed method performs well in producing visually plausible images with different focus effects from a single input. PMID- 21788193 TI - An online learning approach to occlusion boundary detection. AB - We propose a novel online learning-based framework for occlusion boundary detection in video sequences. This approach does not require any prior training and instead "learns" occlusion boundaries by updating a set of weights for the online learning Hedge algorithm at each frame instance. Whereas previous training based methods perform well only on data similar to the trained examples, the proposed method is well suited for any video sequence. We demonstrate the performance of the proposed detector both for the CMU data set, which includes hand-labeled occlusion boundaries, and for a novel video sequence. In addition to occlusion boundary detection, the proposed algorithm is capable of classifying occlusion boundaries by angle and by whether the occluding object is covering or uncovering the background. PMID- 21788194 TI - Lookup-table-based gradient field reconstruction. AB - In computer vision, there are many applications, where it is advantageous to process an image in the gradient domain and then reintegrate the gradient field: important examples include shadow removal, lightness calculation, and data fusion. A serious problem with this approach is that the reconstruction step often introduces artefacts-commonly, smoothed and smeared edges-to the recovered image. This is a result of the inherent ill-posedness of reintegrating a nonintegrable field. Artefacts can be diminished but not removed, by using complex to highly complex reintegration techniques. Here, we present a remarkably simple (and on the face of it naive) algorithm for reconstructing gradient fields. Suppose we start with a multichannel original, and from it derive a (possibly one of many) 1-D gradient field; for many applications, the derived gradient field will be nonintegrable. Here, we propose a lookup-table-based map relating the multichannel original to a reconstructed scalar output image, whose gradient best matches the target gradient field. The idea, at base, is that if we learn how to map the gradients of the multichannel original onto the desired output gradient, and then using the lookup table (LUT) constraint, we effectively derive the mapping from the multichannel input to the desired, reintegrated, image output. While this map could take a variety of forms, here we derive the best map from the multichannel gradient as a (nonlinear) function of the input to each of the target scalar gradients. In this framework, reconstruction is a simple equation-solving exercise of low dimensionality. One obvious application of our method is to the image-fusion problem, e.g., the problem of converting a color or higher-D image into grayscale. We will show, through extensive experiments and complementary theoretical arguments, that our straightforward method preserves the target contrast as well as do complex previous reintegration methods, but without artefacts, and with a substantially cheaper computational cost. Finally, we demonstrate the generality of the method by applying it to gradient field reconstruction in an additional area, the shading recovery problem. PMID- 21788195 TI - Observer-Based Adaptive Fuzzy Backstepping Control for a Class of Stochastic Nonlinear Strict-Feedback Systems. AB - In this paper, two adaptive fuzzy output feedback control approaches are proposed for a class of uncertain stochastic nonlinear strict-feedback systems without the measurements of the states. The fuzzy logic systems are used to approximate the unknown nonlinear functions, and a fuzzy state observer is designed for estimating the unmeasured states. On the basis of the fuzzy state observer, and by combining the adaptive backstepping technique with fuzzy adaptive control design, an adaptive fuzzy output feedback control approach is developed. To overcome the problem of "explosion of complexity" inherent in the proposed control method, the dynamic surface control (DSC) technique is incorporated into the first adaptive fuzzy control scheme, and a simplified adaptive fuzzy output feedback DSC approach is developed. It is proved that these two control approaches can guarantee that all the signals of the closed-loop system are semi globally uniformly ultimately bounded (SGUUB) in mean square, and the observer errors and the output of the system converge to a small neighborhood of the origin. A simulation example is provided to show the effectiveness of the proposed approaches. PMID- 21788196 TI - Adaptive Neural Control of Pure-Feedback Nonlinear Time-Delay Systems via Dynamic Surface Technique. AB - This paper is concerned with robust stabilization problem for a class of nonaffine pure-feedback systems with unknown time-delay functions and perturbed uncertainties. Novel continuous packaged functions are introduced in advance to remove unknown nonlinear terms deduced from perturbed uncertainties and unknown time-delay functions, which avoids the functions with control law to be approximated by radial basis function (RBF) neural networks. This technique combining implicit function and mean value theorems overcomes the difficulty in controlling the nonaffine pure-feedback systems. Dynamic surface control (DSC) is used to avoid "the explosion of complexity" in the backstepping design. Design difficulties from unknown time-delay functions are overcome using the function separation technique, the Lyapunov-Krasovskii functionals, and the desirable property of hyperbolic tangent functions. RBF neural networks are employed to approximate desired virtual controls and desired practical control. Under the proposed adaptive neural DSC, the number of adaptive parameters required is reduced significantly, and semiglobal uniform ultimate boundedness of all of the signals in the closed-loop system is guaranteed. Simulation studies are given to demonstrate the effectiveness of the proposed design scheme. PMID- 21788197 TI - Informing selection of nanomaterial concentrations for ToxCast in vitro testing based on occupational exposure potential. AB - BACKGROUND: Little justification is generally provided for selection of in vitro assay testing concentrations for engineered nanomaterials (ENMs). Selection of concentration levels for hazard evaluation based on real-world exposure scenarios is desirable. OBJECTIVES: Our goal was to use estimates of lung deposition after occupational exposure to nanomaterials to recommend in vitro testing concentrations for the U.S. Environmental Protection Agency's ToxCastTM program. Here, we provide testing concentrations for carbon nanotubes (CNTs) and titanium dioxide (TiO2) and silver (Ag) nanoparticles (NPs). METHODS: We reviewed published ENM concentrations measured in air in manufacturing and R&D (research and development) laboratories to identify input levels for estimating ENM mass retained in the human lung using the multiple-path particle dosimetry (MPPD) model. Model input parameters were individually varied to estimate alveolar mass retained for different particle sizes (5-1,000 nm), aerosol concentrations (0.1 and 1 mg/m3), aspect ratios (2, 4, 10, and 167), and exposure durations (24 hr and a working lifetime). The calculated lung surface concentrations were then converted to in vitro solution concentrations. RESULTS: Modeled alveolar mass retained after 24 hr is most affected by activity level and aerosol concentration. Alveolar retention for Ag and TiO2 NPs and CNTs for a working lifetime (45 years) exposure duration is similar to high-end concentrations (~ 30 400 MUg/mL) typical of in vitro testing reported in the literature. CONCLUSIONS: Analyses performed are generally applicable for providing ENM testing concentrations for in vitro hazard screening studies, although further research is needed to improve the approach. Understanding the relationship between potential real-world exposures and in vitro test concentrations will facilitate interpretation of toxicological results. PMID- 21788198 TI - Environmental impact on vascular development predicted by high-throughput screening. AB - BACKGROUND: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCastTM project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. OBJECTIVE: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. METHODS: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. RESULTS: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. CONCLUSIONS: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways. PMID- 21788199 TI - Influence of the severity of obstructive sleep apnea on nocturnal heart rate indices and its association with hypertension. AB - OBJECTIVE: Both heart rate (HR) and blood pressure parameters provide important information on the pathophysiology of the cardiovascular regulatory mechanisms, and are mainly affected by the autonomic nervous system. We sought to clarify whether the severity of obstructive sleep apnea (OSA) affects nocturnal HRs and whether there is a relationship between nocturnal HRs and the presence of hypertension. METHODS: We retrospectively reviewed medical records of all patients who performed nocturnal polysomnography with monitoring of HRs, and examined whether there is a relationship among the nocturnal HRs, the severity of OSA and the presence of hypertension. RESULTS: A total of 540 patients were included in the study. Nocturnal mean and maximal HRs were significantly higher in severe OSA group than in moderate (p=0.002 and p>0.05 in females; p<0.049 and p=0.044, in males, respectively) and mild OSA groups (p<0.001 and p=0.003, respectively in females, p<0.001 and p=0.004, respectively in males); and there was a positive correlation between the nocturnal mean HR and apnea-hypopnea index (Pearson's p=0.504, p<0.001 in female group; Pearson's p=0.254, p<0.001 in male group) and again the nocturnal mean HR and the presence of HT (Spearman's p=0.090, p=0.394 in female group; Spearman's p=0.272, p<0.001 in male group) in both gender groups. CONCLUSION: We found that nocturnal mean and maximal HRs to be associated with severity of OSA and the presence of hypertension. We speculated that increased nocturnal mean and maximal HRs caused by sympathetic nervous system activation in OSA might be one of the mechanisms in explaining the hypertension and OSA association. PMID- 21788200 TI - Tricuspid annular motion in right coronary artery-related acute inferior myocardial infarction with or without right ventricular involvement. AB - OBJECTIVE: Tricuspid annular movement and velocities before and after thrombolytic therapy were investigated for the detection of right ventricular (RV) involvement in RCA (right coronary artery)-related acute inferior myocardial infarction (IMI). METHODS: Patients with RCA-related acute IMI were evaluated for this pilot prospective cohort study. Annular movement was measured by TAPSE (tricuspid annular plane systolic excursion), and annular velocities were measured by tissue Doppler echocardiography. Data collected before and after thrombolysis and angiography. Diagnosis of RV myocardial infarction (RVMI) was defined by co-presence of electrocardiographic and angiographic criteria. Chi square and Student's t-tests were used in statistical analysis. RESULTS: Thirty one patients were included. Before thrombolysis, annular velocities and TAPSE were found significantly higher in patients without RVMI than in patients with RVMI. Comparison of tricuspid systolic velocity (Sa) and movement before and after thrombolytic therapy in patients without RVMI revealed no significant difference (21.6+/-2.1 mm vs. 21.8+/-2.0 mm p>0.05 and 136.1+/-8.8 mm/s vs. 137.5+/-9.0 mm/s p>0.05, for TAPSE and Sa respectively). Contrarily, in patients with RVMI, TAPSE and systolic velocity increased significantly after thrombolysis compared with pre-thrombolysis (16.2+/-2.0 mm vs. 17.6+/-1.8 mm p=0.001 and 110.0+/-12.6 mm/s vs. 113.08+/-12.7 mm/s p=0.027 for TAPSE and Sa respectively). Diastolic velocities did not change significantly after thrombolysis in patients with RVMI. CONCLUSION: Tricuspid annular movement and velocity measurement by echocardiography may contribute to echocardiographic diagnosis of RV involvement in RCA-related IMI. Patients without RVMI have significantly higher annular velocities and TAPSE than in patients with RVMI before thrombolysis. Only in IMI patients with RVMI, significant increases in TAPSE and Sa were observed after thrombolysis. PMID- 21788201 TI - Neutrophil gelatinase-associated lipocalin levels in right and left heart failure: an observational study. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is a novel marker for early detection of renotubular deterioration. Despite the limited data concerning the NGAL in heart failure (HF), significance of NGAL in right-sided HF remains unknown. We assessed serum and urinary NGAL in left and right-sided HF due to non-ischemic cardiomyopathy (NICMP) and severe pulmonary arterial hypertension (PAH). METHODS: In this cross-sectional observational study, we compared three groups; 35 patients with NICMP, 28 patients with PAH and 27 healthy controls. None had a serum creatinine >=1.5 mg/dL. Plasma brain natriuretic peptide (BNP) levels, estimated glomerular filtration rate (eGFR) by Cockroft-Gault (CG) and Modification of Diet in Renal Disease Study formulas, echocardiographic measures of left and right ventricles (LV, RV) and non-invasive measurement of cardiac index (CI) by echocardiography and impedance cardiography were assessed. Differences among the groups for continuous variables were evaluated by the ANOVA and the Kruskal-Wallis test as appropriate. The Chi-square test was used for comparison of categorical variables. RESULTS: Despite eGFR with CG formula was lower in NICMP and PAH subsets as compared to those in controls (102+/-27 and 99.4+/-29.4 vs 122.4+/-25.9 mL/min, p<0.05 and p<0.005 in order), serum NGAL [141 (113-151), 174 (130-192) and 132 (95-181) ng/mL] and urinary NGAL [15 (12-18), 15 (12-22) and 13 (8-18) ng/mL] levels were not different among groups (p=0.15 and p=0.35, respectively). CONCLUSION: Despite the mildly impaired eGFR in left-sided HF due to NICMP and right-sided HF due to PAH, neither serum, nor urinary NGAL levels are elevated in these patients. PMID- 21788202 TI - Evaluation of the effects of chronic biomass fuel smoke exposure on peripheral endothelial functions: an observational study. AB - OBJECTIVE: To evaluate the effect of chronic biomass fuel (BMF) smoke exposure on peripheral endothelial functions. METHODS: Forty-seven healthy subjects who have been exposed to BMF smoke since birth (mean age 31.6+/-6.8 years, 21 male) were enrolled in the present cross-sectional observational study. The control group consisted of 32 healthy subjects (mean age 27.9+/-4.4 years, 11 male). The carotid intima media thickness (CIMT), flow associated dilatation (FAD %) and endothelium independent vasodilatation (GTN %) were assessed in all subjects. The carotid CIMT was defined as the distance between the leading edge of the lumen intima and the media-adventitia interfaces. FAD % was defined as the percentage change in the internal diameter of the brachial artery during reactive hyperemia related to the baseline. GTN % was defined as the change in diameter in response to the application of 400 ug of glyceril trinitrate relative to the baseline scan at the end of the fourth minute. Statistical analysis was performed using Student's t-test, Chi-square test and Spearman rank order correlation analysis. RESULTS: The average exposure time of the subjects to biomass fuel smoke was 31.7+/-6.6 years. They have been exposed to dung inhalation products meanly 8.3+/ 1.8 months in a year seasonally. The average daily exposure time was 15.7+/-3.3 hours. CIMT values of the two groups were not statistically different from each other (0.47+/-0.09 vs. 0.49+/-0.06 mm, p=0.138). However, a markedly reduced FAD % was determined in the study group (5.06+/-4.95 vs. 10.7+/-4.64, p<0.001). And GTN % of the BMF exposed group was significantly lower than the control group (14.41+/-8.47 vs. 21.85+/-7.87, p<0.001). CONCLUSION: FAD % and GTN % are markedly reduced in the individuals who have been exposed to BMF smoke inhalation products. Therefore, chronic BMF smoke exposure may be a risk factor for the development of endothelial dysfunction. PMID- 21788203 TI - Application of Healthy Heart program in the two semi-rural areas in Eskisehir. AB - OBJECTIVE: The purpose of this study was to raise awareness of people in two semi rural regions of Eskisehir in terms of cardiovascular diseases (CVD) risk factors and to promote related heart-healthy behaviors. METHODS: The study was a semi experimental intervention and featured as a two-phase design. In the first phase of the study, participants received visits at home. Individuals in intervention and control areas were given a participation form that indicated the Framingham Risk Score (FRS). Other training materials were distributed throughout the intervention area. The second phase was planned as a nested case- control study. The first phase included 2.766 persons and the second phase included 778 persons. In the evaluation of the data the Pearson Chi-square and Student's t-test for independent samples, Mc-Nemar Chi-square and the paired t-test for dependent samples were applied. RESULTS: During the first phase, the frequency of FRS metrics above 10% was 26.2% for males, 18.1% for females in the intervention area, 22.9% for males, and 14.9% for females in the control area. There was no difference between males and females in terms of scoring for control and intervention areas (p>0.05). Based on the FRS data, the second phase revealed a decrease of 15.4% in males (p<0.001) and 10.2% in females (p<0.001) in the intervention area and an increase of 8.2% in males (p=0.011) and 3.8% in females (p=0.078) in the control area. CONCLUSION: In this study, teaching individuals who were older than twenty years of age about cardiac health seemed to be an effective method for decreasing CVD risk factors. PMID- 21788204 TI - Involvement of galectin-3 in cadmium-induced cardiac toxicity. AB - OBJECTIVE: Accumulation of the wide spread environmental toxin cadmium (Cd) in tissues results in toxicity. Heart is one of the most effected tissues. Cd exposure induces inflammation in effected tissues. The present study was focused to evaluate roles of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in Cd toxicity and their relationships with galectin-3 levels. METHODS: In this experimental study, male Wistar rats were divided randomly to control and experimental groups. Experimental group was exposed to Cd at the dose of 15 ppm for 8 weeks (n=10/group). Inflammatory status in hearts was evaluated with measurement of tissue TNF-alpha and IL-6 levels. Histopathological examination of heart was carried out by light microscopy. Heart tissue caspase-3 level was used to identify apoptosis. Tissue galectin-3 level was evaluated by ELISA. Statistical difference between groups was evaluated by unpaired Student t-test, correlation was analyzed by Pearson's test. RESULTS: Heart sizes were increased after Cd toxicity. A significant increase in galectin-3 tissue levels was seen after Cd toxicity, this was accompanied with a significant increase in the TNF alpha (control: 402+/-39, Cd: 793+/-26 pg/g tissue, p<0.001) and IL-6 (control: 150+/-78, Cd: 325+/-65 pg/g tissue, p<0.001) levels. Histopathological examination under light microscope suggested a combination of ongoing necrosis and apoptosis. Increased caspase-3 levels were measured after Cd toxicity (control: 12+/-2, Cd: 18+/-3 pmol/ug/min, p<0.001). CONCLUSION: Chronic Cd administration induces inflammation and apoptosis in rat hearts. Cadmium causes increased galectin-3 production from heart tissue. The formation of TNF-alpha due to Cd exposure may likely trigger this mechanism. PMID- 21788205 TI - [Controversial issues in colorectal screening in Hungary: conflict of clinical and public health viewpoints]. AB - In Hungary, mortality rates from colorectal cancer are dramatically high, therefore the reduction by population screening as a public health measure is considered as one of the priorities of National Public Health Program. In the beginning, a human-specific immunological test was applied in the "model programs", as a screening tool, to detect the occult blood in the stool; compliance was 32% in average. However, the objectives of the model programs have not been achieved, because, among other reasons, a debate on the method of choice and the strategy to follow have divided the professional public opinion. In this study the debated issues are critically discussed, being convinced that, at present, population screening seems to be the most promising way to alleviate the burden of colorectal cancer. PMID- 21788206 TI - [Role of nipple sparing mastectomy in modern breast surgery]. AB - Recently an increasing number of reports of clinical experience have been published on nipple-sparing mastectomy. By the preservation of uninvolved skin and the nipple areola complex, this surgical technique greatly facilitates immediate reconstruction and optimal aesthetic outcome. However, the procedure raises serious oncologic concerns regarding the risk of an occult or a newly formed primary tumor due to parenchyma left behind in the nipple and the retroareola. Despite the ever increasing popularity of the method, there is still no evidence based confirmation to it. According to data from scientific literature on nipple-sparing mastectomy, there is no straightforward consequence to be drawn on oncologic safety; therefore the procedure is not generally considered to be alternative to standard mastectomy. In the indication of risk reduction, justification of the intervention seems to be well supported, and is expected to foster a greater rate of acceptance of surgical prophylaxis in patients with higher risk diseases. The procedure should be carried out possibly in the framework of clinical trials, in well selected patients with suitable preoperative and postoperative examinations, applying precise techniques and adequate patient education, according to international guidelines. Further long term results are needed to form a substantive expert opinion. Authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in Hungarian language. PMID- 21788207 TI - [Association of the Scientific Societies of Hungarian Medical Doctors (MORTESZ) was founded 80 years ago]. AB - After the First World War the professional medical societies in Hungary, which have already organized themselves nationwide, started to operate independently from each other. In that time came the idea to create another association above the others to gather them together while retaining their independent functioning. The Association of the Scientific Societies of Hungarian Medical Doctors (MORTESZ), established in 1931, became the nationwide forum for many medical associations. It also organized the first Hungarian Medical Grand-Week which became the annual meeting of the medical society. In the first year the cooperation only consisted of a common topic of two or three associations presented in the "Grand-Week". From year 1935, reports were appointed annually that each professional association could comment on. The proceedings of the "Grand-Week" were published yearly as appendices of the Hungarian Medical Journal. After the Second World War the activities of the independent associations were shut down by the authorities. The scientific and professional associations could continue their work as sections inside of the Doctors and Health Workers' Union. In 1966 the situation was solved thanks to the initiative of the Trade Union, the Department of Medicine and the Medical Section of the Hungarian Academy of Sciences which resulted in the foundation of the Association of the Hungarian Medical Societies (MOTESZ) which continues to gather together the collective work of many scientific associations and carries out tasks of general interest since then, similarly to the now 80-years-old MORTESZ. PMID- 21788208 TI - [GMO-free constitution]. PMID- 21788210 TI - Outcomes and risk prediction model for peripheral arterial disease in patients with stable coronary artery disease. AB - We used the National Heart, Lung, and Blood Institute Limited Access Dataset of Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) Trial (n = 8290) which included patients with stable coronary artery disease (CAD) and preserved ejection fraction (>40%). We identified risk factors for the development of critical peripheral arterial disease (PAD; those needing angioplasty, bypass grafting, or aneurysm repair) and formulated a risk score by multivariate analyses. A total of 220 patients (2.8%) developed critical PAD over a mean follow-up of 4.7 years. Significant predictors of critical PAD were history of intermittent claudication, smoking, hypertension (HTN), coronary artery bypass grafting (CABG), diabetes, age, serum cholesterol, and body mass index (BMI). Incident critical PAD was associated with increased composite outcome of cardiovascular death, myocardial infarction, percutaneous transluminal coronary angioplasty, or CABG (hazard ratio 1.82, 95% CI 1.50-2.22, P < .001). Risk assessment using our score may identify CAD patients at risk for critical PAD events. PMID- 21788211 TI - RNAG: a new Gibbs sampler for predicting RNA secondary structure for unaligned sequences. AB - MOTIVATION: RNA secondary structure plays an important role in the function of many RNAs, and structural features are often key to their interaction with other cellular components. Thus, there has been considerable interest in the prediction of secondary structures for RNA families. In this article, we present a new global structural alignment algorithm, RNAG, to predict consensus secondary structures for unaligned sequences. It uses a blocked Gibbs sampling algorithm, which has a theoretical advantage in convergence time. This algorithm iteratively samples from the conditional probability distributions P(Structure | Alignment) and P(Alignment | Structure). Not surprisingly, there is considerable uncertainly in the high-dimensional space of this difficult problem, which has so far received limited attention in this field. We show how the samples drawn from this algorithm can be used to more fully characterize the posterior space and to assess the uncertainty of predictions. RESULTS: Our analysis of three publically available datasets showed a substantial improvement in RNA structure prediction by RNAG over extant prediction methods. Additionally, our analysis of 17 RNA families showed that the RNAG sampled structures were generally compact around their ensemble centroids, and at least 11 families had at least two well separated clusters of predicted structures. In general, the distance between a reference structure and our predicted structure was large relative to the variation among structures within an ensemble. AVAILABILITY: The Perl implementation of the RNAG algorithm and the data necessary to reproduce the results described in Sections 3.1 and 3.2 are available at http://ccmbweb.ccv.brown.edu/rnag.html CONTACT: charles_lawrence@brown.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21788212 TI - Arrests for child pornography production: data at two time points from a national sample of U.S. law enforcement agencies. AB - This study collected information on arrests for child pornography (CP) production at two points (2000-2001 and 2006) from a national sample of more than 2,500 law enforcement agencies. In addition to providing descriptive data about an understudied crime, the authors examined whether trends in arrests suggested increasing CP production, shifts in victim populations, and challenges to law enforcement. Arrests for CP production more than doubled from an estimated 402 in 2000-2001 to an estimated 859 in 2006. Findings suggest the increase was related to increased law enforcement activity rather than to growth in the population of CP producers. Adolescent victims increased, but there was no increase in the proportion of arrest cases involving very young victims or violent images. Producers distributed images in 23% of arrest cases, a proportion that did not change over time. This suggests that much CP production may be primarily for private use. Proactive law enforcement operations increased, as did other features consistent with a robust law enforcement response. PMID- 21788213 TI - Mediating factors associated with pedestrian injury in children with attention deficit/hyperactivity disorder. AB - OBJECTIVE: Unintentional injury is the leading cause of pediatric mortality. One leading cause of unintentional injury is pedestrian injury. Children with developmental disabilities, particularly those with attention deficit/hyperactivity disorder-combined type (ADHD-C) seem to have increased pedestrian injury risk. This study examined (1) the differences in pedestrian behavior between children with ADHD-C and normally developing comparison children and (2) the mediating factors that might link ADHD-C with pedestrian injury risk. PATIENTS AND METHODS: A total of 78 children aged 7 to 10 years (39 children with ADHD-C diagnoses and 39 age- and gender-matched typically developing children) participated. The main outcome measure was pedestrian behavior, as measured in a semi-immersive, interactive, virtual pedestrian environment. Key pedestrian variables related to different aspects of the crossing process were identified: (1) before the cross (ie, evaluating aspects of the crossing environment); (2) making the cross (ie, deciding to cross and initiating movement); and (3) safety of the cross (ie, safety within the pedestrian environment after the decision to cross was made). RESULTS: Children with ADHD-C chose riskier pedestrian environments to cross within (F(1,72) = 4.83; P < .05). No significant differences emerged in other aspects of the crossing process. Executive function played a mediating role in the relationship between ADHD-C and the safety of the cross. CONCLUSIONS: Children with ADHD-C seem to display appropriate curbside pedestrian behavior but fail to process perceived information adequately to permit crossing safely. PMID- 21788214 TI - Health supervision for children with Down syndrome. AB - These guidelines are designed to assist the pediatrician in caring for the child in whom a diagnosis of Down syndrome has been confirmed by chromosome analysis. Although a pediatrician's initial contact with the child is usually during infancy, occasionally the pregnant woman who has been given a prenatal diagnosis of Down syndrome will be referred for review of the condition and the genetic counseling provided. Therefore, this report offers guidance for this situation as well. PMID- 21788215 TI - Emergency evaluation of children when sexual assault is suspected. PMID- 21788216 TI - Development of a screening tool for pediatric sexual assault may reduce emergency department visits. AB - OBJECTIVE: To define the characteristics of a novel screening tool used to identify which prepubertal children should potentially receive an initial evaluation for alleged sexual assault in a nonemergent setting. METHODS: Electronic medical records were retrospectively reviewed from 2007 to 2008. Visits with a chief complaint or diagnosis of alleged sexual assault for patients aged 12 years or younger were identified. Complete records, those with no evaluation before pediatric emergency-department arrival, and those with child advocacy center follow-up were included. Records were reviewed to answer the following: (1) Did the incident occur in the past 72 hours, and was there oral or genital to genital/anal contact? (2) Was genital or rectal pain, bleeding, discharge, or injury present? (3) Was there concern for the child's safety? (4) Was an unrelated emergency medical condition present? An affirmative response to any of the questions was considered a positive screen (warranting immediate evaluation); all others were considered negative screens. Those who had positive physical examination findings of anogenital trauma or infection, a change in custody, or an emergency medical condition were defined as high risk (having a positive outcome). RESULTS: A total of 163 cases met study criteria; 90 of 163 (55%) patients had positive screens and 73 of 163 (45%) had negative screens. No patients with negative screens were classified as high risk. The screening tool has sensitivity of 100% (95% confidence interval: 93.5-100.0). CONCLUSIONS: This screening tool may be effective for determining which children do not require emergency-department evaluation for alleged sexual assault. PMID- 21788217 TI - Forensic evidence collection and DNA identification in acute child sexual assault. AB - OBJECTIVE: To describe forensic evidence findings and reevaluate previous recommendations with respect to timing of evidence collection in acute child sexual assault and to identify factors associated with yield of DNA. METHODS: This was a retrospective review of medical and legal records of patients aged 0 to 20 years who required forensic evidence collection. RESULTS: Ninety-seven of 388 (25%) processed evidence-collection kits were positive and 63 (65%) of them produced identifiable DNA. There were 20 positive samples obtained from children younger than 10 years; 17 of these samples were obtained from children seen within 24 hours of the assault. Three children had positive body samples beyond 24 hours after the assault, including 1 child positive for salivary amylase in the underwear and on the thighs 54 hours after the assault. DNA was found in 11 children aged younger than 10 years, including the child seen 54 hours after the assault. Collection of evidence within 24 hours of the assault was identified as an independent predictor of DNA detection. CONCLUSIONS: Identifiable DNA was collected from a child's body despite cases in which: evidence collection was performed >24 hours beyond the assault; the child had a normal/nonacute anogenital examination; there was no reported history of ejaculation; and the victim had bathed and/or changed clothes before evidence collection. Failure to conduct evidence collection on prepubertal children beyond 24 hours after the assault will result in rare missed opportunities to identify forensic evidence, including identification of DNA. PMID- 21788218 TI - Automated dose-rounding recommendations for pediatric medications. AB - BACKGROUND: Although pediatric electronic prescribing systems are increasingly being used in pediatric care, many of these systems lack the clinical decision support infrastructure needed to calculate a safe and effective rounded medication dose. This infrastructure is required to facilitate tailoring of established dosing guidance while maintaining the medication's therapeutic intent. OBJECTIVE: The goal of this project was to establish best practices for generating an appropriate medication dose and to create an interoperable rounding knowledge base combining best practices and dose-rounding information. METHODS: We interviewed 19 pediatric health care and pediatric pharmacy experts and conducted a literature review. After using these data to construct initial rounding tolerances, we used a Delphi process to achieve consensus about the rounding tolerance for each commonly prescribed medication. RESULTS: Three categories for medication-rounding philosophy emerged from our literature review: (1) medications for which rounding is used judiciously to retain the intended effect; (2) medications that are rounded with attention to potential unintended effects; and (3) medications that are rarely rounded because of the potential for toxicity. We assigned a small subset of medications to a fourth category inadequate data-for which there was insufficient information to provide rounding recommendations. For all 102 medications, we were able to arrive at a consensus recommendation for rounding a given calculated dose. CONCLUSIONS: Results of this study provide the pediatric information technology community with a primary set of recommended rounding tolerances for commonly prescribed drugs. The interoperable knowledge base developed here can be integrated with existing and developing electronic prescribing systems, potentially improving prescribing safety and reducing cognitive workload. PMID- 21788219 TI - Collection of forensic evidence from pediatric victims of sexual assault. AB - OBJECTIVE: To determine the time period after sexual assault of a child that specimens may yield evidence using DNA amplification. Secondary questions included the comparative laboratory yields of body swabs versus other specimens, and the correlation between physical findings and laboratory results. PATIENTS AND METHODS: Data from evidence-collection kits from children 13 years and younger were reviewed. Kits were screened for evidence using traditional methods, and DNA testing was performed for positive specimens. Laboratory data were compared with historical information. RESULTS: There were 277 evidence-collection kits analyzed; 151 were collected from children younger than 10; 222 kits (80%) had 1 or more positive laboratory screening test, of which 56 (20%) tested positive by DNA. The time interval to collection was <24 hours for 30 of the 56 positive kits (68% positives with a documented time interval), and 24 (43% of all positive kits) were positive only by nonbody specimens. The majority of children with DNA were aged 10 or older, but kits from 14 children younger than 10 also had a positive DNA result, of which 5 were positive by a body swab collected between 7 and 95 hours after assault. Although body swabs were important sources of evidence for older children, they were significantly less likely than nonbody specimens to yield DNA among children younger than 10 (P = .002). There was no correlation between physical findings and laboratory evidence. CONCLUSIONS: Body samples should be considered for children beyond 24 hours after assault, although the yield is limited. Physical examination findings do not predict yield of forensic laboratory tests. PMID- 21788220 TI - A randomized controlled trial of propranolol for infantile hemangiomas. AB - OBJECTIVE: Propranolol hydrochloride is a safe and effective medication for treating infantile hemangiomas (IHs), with decreases in IH volume, color, and elevation. METHODS: Forty children between the ages of 9 weeks and 5 years with facial IHs or IHs in sites with the potential for disfigurement were randomly assigned to receive propranolol or placebo oral solution 2 mg/kg per day divided 3 times daily for 6 months. Baseline electrocardiogram, echocardiogram, and laboratory evaluations were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed at each visit. Children younger than 6 months were admitted to the hospital for monitoring after their first dose at weeks 1 and 2. Efficacy was assessed by performing blinded volume measurements at weeks 0, 4, 8, 12, 16, 20, and 24 and blinded investigator scoring of photographs at weeks 0, 12, and 24. RESULTS: IH growth stopped by week 4 in the propranolol group. Significant differences in the percent change in volume were seen between groups, with the largest difference at week 12. Significant decrease in IH redness and elevation occurred in the propranolol group at weeks 12 and 24 (P = .01 and .001, respectively). No significant hypoglycemia, hypotension, or bradycardia occurred. One child discontinued the study because of an upper respiratory tract infection. Other adverse events included bronchiolitis, gastroenteritis, streptococcal infection, cool extremities, dental caries, and sleep disturbance. CONCLUSION: Propranolol hydrochloride administered orally at 2 mg/kg per day reduced the volume, color, and elevation of focal and segmental IH in infants younger than 6 months and children up to 5 years of age. PMID- 21788222 TI - Near elimination of varicella deaths in the US after implementation of the vaccination program. AB - OBJECTIVE: Varicella has been preventable by vaccination in the United States since 1995. Previous studies reported a 66% decline in mortality rate during the first 6 years of the program. Since then, vaccination coverage has increased substantially. We updated the analysis of US varicella mortality for 2002-2007 and assessed the impact of the first 12 years of the US varicella vaccination program on varicella deaths. METHODS: National data on deaths for which varicella was listed as an underlying or contributing cause were obtained from the Mortality Multiple Cause-of-Death records from the US National Center for Health Statistics. We calculated the age-adjusted and age-specific mortality rates for 2002-2007 and trends since the prevaccine years. RESULTS: During the 12 years of the mostly 1-dose US varicella vaccination program, the annual average mortality rate for varicella listed as the underlying cause declined 88%, from 0.41 per million population in 1990-1994 to 0.05 per million population in 2005-2007. The decline occurred in all age groups, and there was an extremely high reduction among children and adolescents younger than 20 years (97%) and among subjects younger than 50 years overall (96%). In the last 6 years analyzed (2002-2007), a total of 3 deaths per age range were reported among children aged 1 to 4 and 5 to 9 years, compared with an annual average of 13 and 16 deaths, respectively, during the prevaccine years. CONCLUSIONS: The impressive decline in varicella deaths can be directly attributed to successful implementation of the 1-dose vaccination program. With the current 2-dose program, there is potential that these most severe outcomes of a vaccine-preventable disease could be eliminated. PMID- 21788221 TI - Consent for emergency medical services for children and adolescents. AB - Parental consent generally is required for the medical evaluation and treatment of minor children. However, children and adolescents might require evaluation of and treatment for emergency medical conditions in situations in which a parent or legal guardian is not available to provide consent or conditions under which an adolescent patient might possess the legal authority to provide consent. In general, a medical screening examination and any medical care necessary and likely to prevent imminent and significant harm to the pediatric patient with an emergency medical condition should not be withheld or delayed because of problems obtaining consent. The purpose of this policy statement is to provide guidance in those situations in which parental consent is not readily available, in which parental consent is not necessary, or in which parental refusal of consent places a child at risk of significant harm. PMID- 21788223 TI - Maternal-fetal intervention and fetal care centers. AB - The past 2 decades have yielded profound advances in the fields of prenatal diagnosis and fetal intervention. Although fetal interventions are driven by a beneficence-based motivation to improve fetal and neonatal outcomes, advancement in fetal therapies raises ethical issues surrounding maternal autonomy and decision-making, concepts of innovation versus research, and organizational aspects within institutions in the development of fetal care centers. To safeguard the interests of both the pregnant woman and the fetus, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics make recommendations regarding informed consent, the role of research subject advocates and other independent advocates, the availability of support services, the multidisciplinary nature of fetal intervention teams, the oversight of centers, and the need to accumulate maternal and fetal outcome data. PMID- 21788224 TI - A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. AB - BACKGROUND: Pagibaximab, a human chimeric monoclonal antibody developed against lipoteichoic acid, was effective against staphylococci preclinically and seemed safe and well tolerated in phase 1 studies. OBJECTIVE: To evaluate the clinical activity, pharmacokinetics, safety, and tolerability of weekly pagibaximab versus placebo infusions in very low birth weight neonates. PATIENTS AND METHODS: A phase 2, randomized, double-blind, placebo-controlled study was conducted at 10 NICUs. Patients with a birth weight of 700 to 1300 g and 2 to 5 days old were randomly assigned to receive 3 once-a-week pagibaximab (90 or 60 mg/kg) or placebo infusions. Blood was collected for pharmacokinetics, bacterial killing, and safety analyses. Adverse event and clinical outcome data were collected. RESULTS: Eighty-eight patients received pagibaximab at 90 (n = 22) or 60 (n = 20) mg/kg or placebo (n = 46). Groups were not different in demography, mortality, or morbidity. Pagibaximab demonstrated linear pharmacokinetics, a 14.5-day half life, and nonimmunogenicity. Definite staphylococcal sepsis occurred in 0%, 20%, and 13% (P < .11) and nonstaphylococcal sepsis occurred in 0%, 10%, and 15% (P < .15) of patients in the 90 mg/kg, 60 mg/kg, and placebo groups, respectively. In all patients with staphylococcal sepsis, estimated or observed pagibaximab levels were <500 MUg/mL (target level) at infection. CONCLUSIONS: Three once-a-week 90 or 60 mg/kg pagibaximab infusions, in high-risk neonates, seemed safe and well tolerated. No staphylococcal sepsis occurred in infants who received 90 mg/kg. Target levels were only consistently achieved after 2 to 3 doses. Dose optimization should enhance protection. PMID- 21788225 TI - Outcome and prognostic features in opsoclonus-myoclonus syndrome from infancy to adult life. AB - OBJECTIVE: Opsoclonus-myoclonus syndrome (OMS) is a serious and often chronically disabling neurologic illness with onset in early childhood. Our aim was to identify long-term neurologic sequelae of OMS and predictors for disease outcome. METHODS: We retrospectively assessed the case records of 101 patients diagnosed with OMS over a 53-year period. Clinical data were obtained from medical record review; we documented age at onset, severity of symptoms, response to treatment, and neurocognitive sequelae. RESULTS: Overall, 21% of the patients had a neuroblastoma detected; however, in those born after 1990, this figure rose to 40%. Sixty-one percent of the patients had a chronic-relapsing course, 32% experienced several acute exacerbations, and 7% had a monophasic course. At the most recent review, 60% had residual motor problems, 66% speech abnormalities, 51% learning disability, and 46% behavior problems. One-third of the patients had normal intellectual outcome and cessation of symptoms. A severe initial presentation predicted a chronic disease course (odds ratio [OR]: 2.77 [95% confidence interval (CI): 1.47-5.23]; P = .002) and later learning disability (OR: 2.03 [95% CI: 1.08-3.79]; P = .026). Those with cognitive impairment were younger at disease onset (15.0 vs 19.5 months; P = .029). A chronic-relapsing disease course was associated with motor (P < .001), speech (P = .001), cognitive (P < .001), and behavior (P = .006) problems. CONCLUSIONS: OMS is a chronic and debilitating illness; those with severe initial symptoms and those who are very young at disease onset are at increased risk of developing long-term sequelae. It is important for affected children to be identified early, because they might benefit from targeted immunomodulating therapy in specialist centers. PMID- 21788226 TI - School outcomes of children with special health care needs. AB - OBJECTIVE: To examine the associations between having a special health care need and school outcomes measured as attendance, student engagement, behavioral threats to achievement, and academic achievement. PARTICIPANTS AND METHODS: A total of 1457 children in the fourth through sixth grades from 34 schools in 3 school districts and their parents provided survey data; parents completed the Children With Special Health Care Needs Screener. School records were abstracted for attendance, grades, and standardized achievement test scores. RESULTS: Across 34 schools, 33% of children screened positive for special health care needs. After adjusting for sociodemographic and school effects, children with special health care needs had lower motivation to do well in school, more disruptive behaviors, and more frequent experiences as a bully victim. They experienced significantly lower academic achievement, as measured by grades, standardized testing, and parental-assessed academic performance. These findings were observed for children who qualified as having a special health care need because they had functional limitations attributed to a chronic illness or a behavioral health problem but not for those who qualified only because they took prescription medications. CONCLUSIONS: Specific subgroups of children with special health care needs are at increased risk for poor school outcomes. Health and school professionals will need to collaborate to identify these children early, intervene with appropriate medical and educational services, and monitor long term outcomes. PMID- 21788227 TI - Enterococcus ureasiticus sp. nov. and Enterococcus quebecensis sp. nov., isolated from water. AB - Three enterococcal isolates, CCRI-16620, CCRI-16986(T) and CCRI-16985(T), originating from water were characterized using morphological, biochemical and molecular taxonomic methods. 16S rRNA gene sequence analysis classified all three strains in the Enterococcus faecalis species group. The phylogenetic tree of 16S rRNA gene sequences showed that the three isolates form two separate branches. The first branch is represented by strains CCRI-16620 and CCRI-16986(T) and the second branch by strain CCRI-16985(T). Further sequence analysis of the housekeeping genes rpoA (encoding RNA polymerase alpha subunit), pheS (phenylalanyl-tRNA synthase), tufA (elongation factor Tu) and atpD (ATP synthase beta-subunit) as well as the results of amplified fragment length polymorphism (AFLP) DNA fingerprinting and DNA-DNA hybridization experiments confirmed the distinct status of these strains. Moreover, biochemical tests allowed phenotypic differentiation of the strains from the other species of the E. faecalis species group. On the basis of the results obtained, the names Enterococcus ureasiticus sp. nov. (type strain CCRI-16986(T) = CCUG 59304(T) = DSM 23328(T) = LMG 26304(T)) and Enterococcus quebecensis sp. nov. (type strain CCRI-16985(T) = CCUG 59306(T) = DSM 23327(T) = LMG 26306(T)) are proposed for the two hitherto undescribed species. PMID- 21788228 TI - Herbaspirillum canariense sp. nov., Herbaspirillum aurantiacum sp. nov. and Herbaspirillum soli sp. nov., isolated from volcanic mountain soil, and emended description of the genus Herbaspirillum. AB - Three Gram-negative, motile and slightly curved rod-shaped bacteria, strains SUEMI03(T), SUEMI08(T) and SUEMI10(T), were isolated from an old volcanic mountain soil on Tenerife (Canary Islands). The three strains were related phylogenetically to Herbaspirillum seropedicae. 16S rRNA gene sequence similarity was 99.2-99.6 % among strains SUEMI03(T), SUEMI08(T) and SUEMI10(T), which presented 97.5, 97.8 and 97.7 % identity, respectively, with respect to H. seropedicae DSM 6445(T). The three strains grew optimally in TSB at 28 degrees C and contained summed features 3 (C(16:1)omega6c and/or C(16:1)omega7c) and 8 (C(18:1)omega6c and/or C(18:1)omega7c) and C(16:0) as major cellular fatty acids. The DNA G+C contents of strains SUEMI03(T), SUEMI08(T) and SUEMI10(T) were 61.6, 60.4 and 61.9 mol%, respectively. Strains SUEMI03(T), SUEMI08(T) and SUEMI10(T) presented less than 60 % interstrain DNA relatedness and less than 30 % relatedness with respect to H. seropedicae DSM 6445(T). In spite of their common geographical origin, the three strains isolated in this study presented several phenotypic differences, presenting phenotypic profiles highly divergent from that of H. seropedicae. Therefore, we propose that the strains isolated in this study represent three novel species of the genus Herbaspirillum, named Herbaspirillum canariense sp. nov. (type strain SUEMI03(T) = LMG 26151(T) = CECT 7838(T)), Herbaspirillum aurantiacum sp. nov. (type strain SUEMI08(T) = LMG 26150(T) = CECT 7839(T)) and Herbaspirillum soli sp. nov. (type strain SUEMI10(T) = LMG 26149(T) = CECT 7840(T)). PMID- 21788229 TI - Aspergillus affinis sp. nov., a novel ochratoxin A-producing Aspergillus species (section Circumdati) isolated from decomposing leaves. AB - Two ochratoxin A (OTA)-producing Aspergillus isolates, recently collected from submerged riparian decomposing leaves in Italy, were found to have a similar morphology to Aspergillus cretensis (subgenus Circumdati, section Circumdati). However, marked differences emerged between these two novel isolates and A. cretensis as the former displayed different colony features and had larger vesicles, metulae, phialides and conidia, as well as a distinct sclerotial form and size. In order to determine the taxonomic status and to infer the evolutionary relationships of these two morphologically identical isolates, a molecular phylogenetic analysis was performed on all the officially recognized lineages in the section Circumdati. The DNA sequences and the deduced amino acid residues from the nuclear loci were analysed. Both rRNA and protein coding genes were assessed, which are widely used to differentiate taxa belonging to genus Aspergillus at various evolutionary levels. The 5.8S rDNA gene and internal transcribed spacers (ITS), the D1/D2 domains of the 28S rDNA gene, a region of the tubulin beta chain gene (benA) and part of the calmodulin gene (cmd) were amplified by PCR and then sequenced. The analysis of the rRNA regions and of the benA and cmd sequence data indicated that the two isogenic isolates belonged to a genetically distinct OTA-producing species of the genus Aspergillus. The isolates are proposed as representing a novel species, Aspergillus affinis sp. nov., with the type strain ATCC MYA-4773T=CBS 129190=417). Phylogenetically, A. affinis sp. nov. appeared to be very closely related to A. cretensis, from which it could be distinguished by means of a morphological trait analysis. PMID- 21788231 TI - Response to 'updating the international research agenda for sport injury prevention research'. PMID- 21788230 TI - Attention should be paid to preventing knee injury in tai chi exercise. PMID- 21788232 TI - Patient safety incidents associated with obesity: a review of reports to the National Patient Safety Agency and recommendations for hospital practice. AB - BACKGROUND: The incidence and prevalence of obesity are increasing world wide. In the UK, obesity governmental strategy has primarily focused on prevention measures, with less focus on the demands of treating obese patients in hospital. Increasing service demand by obese patients coupled with a lack of adequate provision for care of these patients may lead to an increase in patient safety incidents. By classifying patient safety incidents associated with obesity reported to the National Patient Safety Agency, this report aims to identify areas for improvement in the quality and safety of care of the obese patient. METHODS: A search of the National Reporting and Learning System database was conducted for all incidents caused by or relating to obesity for the period 1 January 2005 to 31 August 2008. The keywords 'obesity', 'overweight', 'BMI' (body mass index), and 'bariatric' were used. The relevant free text fields of the resulting set of incidents were then searched for the terms designed to isolate incidents occurring in anaesthesia, critical care, and surgery. Reported incidents were analysed and subsequently categorised to identify incident themes. Levels of harm were also established. RESULTS: 555 patient safety incidents were identified; 388 met inclusion criteria for analysis. 148 incidents were related to assessment, diagnosis or treatment, 213 related to infrastructure and 27 related to staffing. The majority of incidents were classified as no or low harm. Three deaths were reported, all within the domain of anaesthesia. CONCLUSIONS: This report identifies that the majority of safety incidents associated with obesity were related to infrastructure, suggesting that there is inadequate provision in place for the care of obese patients. While levels of harm were mostly low, the occurrence of incidents resulting in severe harm or death highlights the specific dangers associated with the care of the obese patient. A global approach to improving the safety of care delivery for obese patients is recommended, including obesity specific training, management structures, care pathways, and equipment provisioning.Further planning and development of operation policies is needed to ensure the safe delivery of healthcare to obese patients in the future. PMID- 21788233 TI - Republished editorial: What public policies have been more effective in promoting rational prescription of drugs? PMID- 21788234 TI - Republished review: Cardiac stem cell therapy: progress from the bench to bedside. AB - In the rush to assess the role of stem cell therapy for cardiovascular disease the details of translation are easily overlooked. This review summarises the progress to date in translating the exciting preclinical results of cardiac repair into man and considers the questions that this area of research has stimulated about the challenges of moving from bench to bedside. PMID- 21788235 TI - Republished error management: Paediatric dosing errors before and after electronic prescribing. AB - OBJECTIVE: To compare the incidence and severity rating of dose prescribing errors before and after the implementation of a commercially available electronic prescribing system at a tertiary care children's hospital. METHODS: Dose errors were identified using prescription review to detect errors. Severity rating was determined by five judges using a validated, reliable scoring tool. The mean score for each error was used as an index of severity. RESULTS: Dose prescribing errors occurred in 88 of the 3939 (2.2%) items prescribed for outpatients and inpatients, and on discharge prescriptions prior to the implementation of electronic prescribing (EP). After EP, there were 57 dose errors in 4784 (1.2%) items prescribed (1% absolute reduction (p<0.001 chi(2) test; 95% CI of difference in proportions -1.6% to -0.5%)). A decrease in the severity rating of dose errors was also seen: dose errors with potentially minor outcomes 35/3939 (0.89%) pre vs 21/4784 (0.44%) post (95% CI of difference in proportions -0.8% to -0.11%, p=0.009 chi(2) test); moderate outcome 46/3939 (1.17%) pre vs 33/4784 (0.69%) post (95% CI of difference in proportions -0.91% to -0.08, p=0.019, chi(2) test); severe outcome: 7/3939 (0.18%) pre vs 3/4784 (0.06%) post (95% CI of difference in proportions -0.31% to +0.04, p=0.11, chi(2) test). CONCLUSION: Electronic prescribing appears to reduce rates of dosing errors in paediatrics, but larger studies are required to assess the effect on the severity of these errors and in different settings. PMID- 21788236 TI - What is good supervision? PMID- 21788237 TI - Critiquing critical care paramedics. PMID- 21788238 TI - The C-MAC videolaryngoscope for prehospital emergency intubation. PMID- 21788239 TI - Bedside testing for myasthenia gravis: the ice-test. AB - A 67-year-old man presented to the acute medical take with a history of droopy eyelids and difficulty swallowing. A diagnosis of myasthenia gravis was suspected from the clinical history. The patient's symptoms were progressive, raising concerns of aspiration pneumonia or respiratory compromise if untreated. Definitive diagnosis of myasthenia gravis relies upon a combination of serological and electrophysiological investigations, the results of which are not immediately available in an acute situation. Bedside tests are therefore of practical clinical importance to enable prompt and effective initiation of treatment, particularly where critical symptoms are present. The ice-test is a straightforward and non-invasive investigation with a high sensitivity for myasthenia gravis and is a useful alternative to edrophonium testing. It is especially helpful in patients with cardiac and respiratory co-morbidities for whom acetylcholinesterase inhibitors are contraindicated. We describe a case where this simple bedside test successfully expedited the correct treatment and improved patient care. PMID- 21788241 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Can inflammatory markers distinguish streptococcal from viral tonsillitis? AB - A short-cut review was performed to evaluate whether inflammatory markers such as C reactive protein (CRP), erythrocyte sedimentation rate (ESR), white cell count (WCC) and procalcitonin (PCT) are able to discriminate between streptococcal and viral tonsillitis, enabling a reduction in the overuse of antibiotics. Eight studies with a total of 1031 participants were found. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that WCC, CRP and PCT levels are higher in patients with streptococcal tonsillitis compared to patients with tonsillitis or pharyngitis without group A streptococcus isolated from a throat swab. Which of these markers has the best test performance characteristics requires further study. PMID- 21788243 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Which intraosseous device is best in the prehospital setting? AB - A short cut review was carried out to establish which intraosseous device is best for use in the prehospital environment. A total of 2100 papers were found using the reported search, of which 2 represented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. The clinical bottom line is that traditional manual intraosseous infusion devices have better success rates and faster insertion times compared with semi-automatic intraosseous infusion devices in the prehospital setting. PMID- 21788244 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Evidence exists to guide thromboembolic prophylaxis in ambulatory patients with temporary lower limb immobilisation. AB - A short-cut review was carried out to establish whether patients requiring lower limb immobilisation should have thromboprophylaxis. A total of 148 papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that ambulatory patients with temporary lower leg immobilisation who are over 50, in a rigid cast, non-weight bearing or with a severe injury should be considered as an at risk group for venous thromboembolism (VTE). If there are any other current proven VTE risk factors, patients should be considered as high risk. PMID- 21788245 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Management of adult patients with icatibant in hereditary angioedema. AB - A short-cut review was carried out to establish whether icatibant is effective in the treatment of hereditary angioedema. A total of 168 papers were found using the reported search, of which one represented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of this best paper are tabulated. The clinical bottom line is there is promising evidence for the use of the bradykinin receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema. PMID- 21788246 TI - An atypical but dangerous presentation of chest pain. PMID- 21788248 TI - A randomized placebo-controlled cross-over study using a low frequency magnetic field in the treatment of fatigue in multiple sclerosis. AB - BACKGROUND: Fatigue is one of the most common disabling symptoms in multiple sclerosis (MS). There is growing evidence in the literature for beneficial effects of magnetic fields on different MS symptoms and this has been reported to be beneficial in patients with MS, especially those with fatigue. OBJECTIVES: The aim of the study was to assess the effects on primary fatigue with a pulsed systemic low frequency magnetic field by means of clinical scales in a population of MS subjects. METHODS: Randomized double-blind cross-over trial with 50 MS subjects with primary fatigue who were recruited among those followed as outpatients at the AISM Rehabilitation Centre, Genova, Italy. Subjects were randomized into two groups: magnetic field group and sham therapy group and evaluated with the Modified Fatigue Impact Scale (MFIS), the Fatigue Severity Scale (FSS), VAS and Time Walking Test 10 meter (TWT10m.) at the time points of the study. Each group received both sham therapy and magnetic field therapy with a wash-out period of 5 months. Subjects were treated for 24 min per session, three times per week, for 8 weeks. Statistical analysis was performed using multivariate analysis. RESULTS: Results showed a statistically significant improvement in MFIS Physical Score for T0-T1 (p < 0.05) for TIME but not for TREATMENT and TIME*TREATMENT factors. No statistically significant differences were found for all other parameters considered in the study. CONCLUSIONS: Exposure to a low frequency magnetic field, within the parameters of this treatment protocol, has no advantage over sham exposure in reducing the impact of fatigue. PMID- 21788249 TI - Focal multiple sclerosis lesions abound in 'normal appearing white matter'. AB - BACKGROUND: The 'normal appearing white matter' (NAWM) in multiple sclerosis (MS) is known to be abnormal using quantitative magnetic resonance (MR) techniques. The aetiology of the changes in NAWM remains debatable. OBJECTIVE: To investigate whether high-field and ultra high-field T(1)-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) MRI enables detection of MS white matter lesions in areas defined as NAWM using high-field T(2)-weighted fluid attenuation inversion recovery (FLAIR) MRI; that is, to ascertain whether undetected lesions are likely contributors to the burden of abnormality in similarly defined NAWM. METHODS: Fourteen MS patients underwent MRI scans using 3T FLAIR and MPRAGE and 7 Tesla (7T) MPRAGE sequences. Independent observers identified lesions on 3T FLAIR and (7T and 3T) MPRAGE images. The detection of every individual lesion was then compared for each image type. RESULTS: We identified a total of 812 white matter lesions on 3T FLAIR. Using 3T MPRAGE, 186 additional lesions were detected that were not detected using 3T FLAIR. Using 7T MPRAGE, 231 additional lesions were detected that were not detected using 3T FLAIR. CONCLUSIONS: MRI with 3T and 7T MPRAGE enables detection of MS lesions in areas defined as NAWM using 3T FLAIR. Focal MS lesions contribute to the abnormalities known to exist in the NAWM. PMID- 21788251 TI - Expectation, satisfaction, and predictors of dropout in cardiac rehabilitation. AB - BACKGROUND: Despite the evidence of benefit many patients fail to adhere to cardiac rehabilitation (CR). This study aims at describing the rate, reasons, and predictors of dropout from CR, as well as expectations und satisfaction among participants. METHODS: Prospective analysis of demographic, medical, and psychosocial data in a large cohort of consecutive participants of outpatient CR. RESULTS: Between 1999 and 2008, 2521 consecutive patients were enrolled in CR and complete data for analysis were available in 2371 patients. Diagnoses were coronary heart disease in 85%, valvular heart disease in 15%, and other in 10%. Mean age was 59.7 +/- 11.4 years; 85% were male. Specific expectations towards CR were identified in a subgroup of participants and satisfaction was high in 75% of patients. Early dropout was noted in 305 patients (12.9%); reasons for dropout were cardiac in 39 (1.7%) and non-cardiac in 266 (11.2%). Significant differences between dropouts vs. completers were: peak exercise capacity (116 +/- 41 vs. 123 +/- 39 Watt, p = 0.003); body mass index (28 +/- 7 vs. 27 +/- 4 kg/m(2), p = 0.04); prevalence of diabetes (18 vs. 13%, p = 0.011); smoking (32 vs. 16%, p < 0.001); being professionally active (24 vs. 34%, p = 0.007); widowhood (8 vs. 3%, p = 0.04); higher education (37.5 vs. 46.4%, p = 0.003); white collar work (21 vs. 27%, p = 0.012); and scales of a quality-of-life score (p < 0.02). Multivariate analysis revealed low exercise capacity, high body mass index, smoking, diabetes, and widowhood to be significant independent predictors for early dropout. CONCLUSION: In the present study we demonstrated a low rate of mainly non-cardiac dropout from outpatient CR in motivated and largely satisfied participants. In order to improve adherence, early attention and close supportive counselling is recommended in patients with low exercise capacity and those who are obese, diabetic, smokers, or bereaved of a partner. PMID- 21788250 TI - Rat Ace allele variation determines susceptibility to AngII-induced renal damage. AB - INTRODUCTION: Ace b/l polymorphism in rats is associated with differential tissue angiotensin-converting enzyme (ACE) expression and activity, and susceptibility to renal damage. Same polymorphism was recently found in outbred Wistar rat strain with b allele accounting for higher renal ACE, and provided a model for studying renin-angiotensin-aldosterone system (RAAS) response behind the innate high or low ACE conditions. METHODS: We investigated the reaction of these alleles on chronic angiotensin II (AngII) infusion. Wistar rats were selected to breed male homozygotes for the b (WU-B) or l allele (WU-L) (n = 12). For each allele, one group (n = 6) received AngII infusion via an osmotic minipump (435 ng/kg/min) for 3 weeks. The other group (n = 6) served as a control. RESULTS: WU B had higher ACE activity at baseline then WU-L. Interestingly, baseline renal ACE2 expression and activity were higher in WU-L. AngII infusion induced the same increase in blood pressure in both genotypes, no proteinuria, but caused tubulo interstitial renal damage with increased alpha-SMA and monocyte/macrophage influx only in WU-B (p < 0.05). Low ACE WU-L rats did not develop renal damage. CONCLUSION: AngII infusion causes proteinuria-independent renal damage only in rats with genetically predetermined high ACE while rats with low ACE seemed to be protected against the detrimental effect of AngII. Differences in renal ACE2, mirroring those in ACE, might be involved. PMID- 21788252 TI - Behavioural disorders, disability and quality of life in Parkinson's disease. AB - BACKGROUND: although non-motor symptoms of Parkinson's disease (PD) are known to adversely affect disability and health-related quality of life, the impact that specific disorders of reward and motivation have remains unclear. Impulse control disorders are more likely in those with a younger disease onset although there is no strong evidence to date that apathy is related to age of onset or correlated with a longer duration of disease. OBJECTIVE: to examine the effects of apathy and impulse controls disorders on disability and health-related quality of life. METHODS: a total of 99 non-demented participants with PD (35 with impulse control disorders, 26 with apathy and 38 with neither behavioural complication) were assessed using the Unified Parkinson's Disease Rating Scale (Activities of Daily Living component) and the Schwab-England scale to evaluate disability, and the PDQ (eight items) to assess quality of life. RESULTS: quality of life was reduced in both behavioural groups compared with participants without either condition. Disability was greater in the group with apathy. Variation in disability score (56%, P < 0.001) was explained by greater levels of apathy, depression, motor impairment and longer disease duration. Variation in quality of life score (54%, P < 0.001) was explained by higher levels of impulsivity, depression, dopaminergic load, motor complications, working memory problems and younger age at onset. CONCLUSION: apathy and impulsivity negatively impact on disability and health-related quality of life, emphasising the importance of effective diagnosis and management of these PD-related behavioural disturbances. PMID- 21788253 TI - Profile-statistical periodicity of DNA coding regions. AB - Novel methods for identifying a new type of DNA latent periodicity, called latent profile periodicity or latent profility, are used to search for periodic structures in genes. These methods reveal two distinct levels of organization of genetic information encoding. It is shown that latent profility in genes may correlate with specific structural features of their encoded proteins. PMID- 21788254 TI - Factors affecting the age at diagnosis of autism spectrum disorders in Nova Scotia, Canada. AB - While early diagnosis of autism spectrum disorders (ASD) is essential for ensuring timely access to early intervention services, there is limited existing literature investigating factors that delay this diagnosis. This population-based cohort study explored the age at which children in Nova Scotia, Canada, are diagnosed with ASDs and the factors associated with this age. Children diagnosed with an ASD between January 1992 and December 2005 were identified from a cohort of live births in the province between 1990 and 2002. Demographic and clinical variables were extracted from population-based perinatal and administrative health databases and evaluated as predictors of age at ASD diagnosis. Of 122,759 live births, 884 cases of ASDs were identified during the study period. The median age at diagnosis within the cohort was 4.6 years. In adjusted linear regression analysis, a one year increase in maternal age at delivery was associated with a 0.06 decrease in age at ASD diagnosis (p= .0007). Children who were residents of Halifax County received their diagnoses 0.52 years later than residents of other counties (p= .0054). A diagnosis of attention deficit/hyperactivity disorder (ADHD) was associated with a 1.29-year increase in age at diagnosis (p< .0001). These results suggest that potential exists for improving early detection of ASDs in the province. Future research in this field has the potential to contribute to our understanding of the causal pathways linking the demographic and clinical variables we have identified and the age at diagnosis of ASDs. PMID- 21788255 TI - Fatigue, wellbeing and parental self-efficacy in mothers of children with an autism spectrum disorder. AB - Raising a child with an Autism Spectrum Disorder (ASD) presents significant challenges for parents that potentially have a impact on their health and wellbeing. The current study examined the extent to which parents experience fatigue and its relationship to other aspects of wellbeing and parenting. Fifty mothers of children with an ASD aged 2-5 years participated in the study. Compared with mothers of typically developing children, mothers of children with an ASD reported significantly higher fatigue, with overall scores in the moderate range. Factors associated with high levels of fatigue were poor maternal sleep quality, a high need for social support and poor quality of physical activity. Fatigue was also significantly related to other aspects of wellbeing, including stress, anxiety and depression, and lower parenting efficacy and satisfaction. The need for interventions to specifically target parental fatigue and its impact on families affected by ASDs both in the short and long term is clearly indicated. PMID- 21788256 TI - The impact of the Advancing Social-communication And Play (ASAP) intervention on preschoolers with autism spectrum disorder. AB - This study evaluates an intervention targeting social-communication and play skills (Advancing Social-communication And Play; ASAP) implemented by school staff in a public preschool setting. With increases in enrollment of children with autism spectrum disorder (ASD) in school systems, establishing the effectiveness and feasibility of interventions implemented in school settings is important. In clinical settings, interventions targeting social-communication and play behaviors have increased these skills and impacted later language abilities. Results of this single-case design study indicated the ASAP intervention had a positive impact on social-communication and play skills for three preschoolers with ASD. All participants showed either increases in frequency or more stability in targeted behaviors. Social validity results provide additional support for the use of ASAP with preschoolers with ASD. PMID- 21788257 TI - Will medicine ever be able to halt the process of ageing? PMID- 21788258 TI - Improving the disclosure of medical incidents. PMID- 21788259 TI - Old age and the city. PMID- 21788261 TI - Some experiments involving animals require greater scrutiny, say scientists. PMID- 21788260 TI - Patients' and family members' views on how clinicians enact and how they should enact incident disclosure: the "100 patient stories" qualitative study. AB - OBJECTIVES: To investigate patients' and family members' perceptions and experiences of disclosure of healthcare incidents and to derive principles of effective disclosure. DESIGN: Retrospective qualitative study based on 100 semi structured, in depth interviews with patients and family members. SETTING: Nationwide multisite survey across Australia. PARTICIPANTS: 39 patients and 80 family members who were involved in high severity healthcare incidents (leading to death, permanent disability, or long term harm) and incident disclosure. Recruitment was via national newspapers (43%), health services where the incidents occurred (28%), two internet marketing companies (27%), and consumer organisations (2%). MAIN OUTCOME MEASURES: Participants' recurrent experiences and concerns expressed in interviews. RESULTS: Most patients and family members felt that the health service incident disclosure rarely met their needs and expectations. They expected better preparation for incident disclosure, more shared dialogue about what went wrong, more follow-up support, input into when the time was ripe for closure, and more information about subsequent improvement in process. This analysis provided the basis for the formulation of a set of principles of effective incident disclosure. CONCLUSIONS: Despite growing prominence of open disclosure, discussion about healthcare incidents still falls short of patient and family member expectations. Healthcare organisations and providers should strengthen their efforts to meet patients' (and family members') needs and expectations. PMID- 21788262 TI - Israeli court allows amputation of child's hand against wishes of mother. PMID- 21788263 TI - Partner and sister ask High Court for permission to let "minimally aware" woman die. PMID- 21788264 TI - Application of wedged foot orthosis effectively reduces pain in runners with pronated foot: a randomized clinical study. AB - OBJECTIVE: To examine the effects of foot orthosis intervention during a 60 minute running test in pronated-foot runners with overuse knee or foot pain during running. DESIGN: A randomized, controlled design. SETTING: Sports gym. PARTICIPANTS: Twenty-four runners with pronated foot who experienced pain over anterior knee or foot region during running were recruited and randomized into the treatment, or the control, group. INTERVENTIONS: A soft insole with a semi rigid rearfoot medial wedge was given to the treatment group, and a soft insole without corrective posting was applied to the control group. OUTCOME MEASURES: The immediate and short-term effects of orthosis application on incidence of pain, pain intensity and onset time were evaluated using the 60-minutes treadmill test. RESULTS: Immediately after wearing the foot orthosis, pain incidence reduced in the treatment group but not in the control group (P = 0.04). After two weeks, seven (58%) subjects in the treatment group and one (8%) in the control group were free of pain during the test (P = 0.01). The pain intensity score decreased significantly after orthosis application, from 35.5 to 17.2 (immediate effect, P = 0.014), then to 12.3 (short-term effect, P < 0.001). CONCLUSION: The rearfoot medially-wedged insole was a useful intervention for preventing or reducing painful knee or foot symptoms during running in runners with pronated foot. PMID- 21788265 TI - Long-term rehabilitation for chronic stroke arm movements: a randomized controlled trial. AB - OBJECTIVE: We investigated the effect of long-term practice on motor improvements in chronic stroke patients. DESIGN: Randomized parallel group controlled study. SETTING: Motor Behavior Laboratory, University of Florida. SUBJECTS: Eighteen individuals who experienced a stroke more than nine months prior to enrolling. INTERVENTIONS: The treatment interventions were bilateral arm movements coupled with active neuromuscular stimulation on the impaired arm for both practice duration groups. The short-term group received one treatment protocol, whereas, over 16 months, the long-term practice group completed 10 treatment protocols. All protocol sessions were 6 hours long (90 minutes 1 day/week/4 weeks) and were separated by 22 days. MAIN OUTCOME MEASURES: Repeated data collection on three primary outcome measures (i.e. Box and Block test, fractionated reaction times, and sustained force production) evaluated motor capabilities across rehabilitation times. RESULTS: Mixed design ANOVAs (Group * Retention Test: 2 * 4; Group * Retention Test * Arm Condition: 2 * 4 * 2) revealed improved motor capabilities for the long-term practice duration group on each primary measure. At the 16-month delayed retention test, when compared to the short-term group, the long-term group demonstrated: (a) more blocks moved (43 v 32), (b) faster premotor reaction times (158 v 208 ms), and (c) higher force production (75 v 45 N). CONCLUSION: Sixty hours of rehabilitation over 16 months provided by various bilateral arm movements and coupled active stimulation improved motor capabilities in chronic stroke. PMID- 21788266 TI - Does physiotherapy based on the Bobath concept, in conjunction with a task practice, achieve greater improvement in walking ability in people with stroke compared to physiotherapy focused on structured task practice alone?: a pilot randomized controlled trial. AB - OBJECTIVE: To compare the short-term effects of two physiotherapy approaches for improving ability to walk in different environments following stroke: (i) interventions based on the Bobath concept, in conjunction with task practice, compared to (ii) structured task practice alone. DESIGN: Randomized controlled trial. SETTING: Two rehabilitation centres Participants: Twenty-six participants between four and 20 weeks post-stroke, able to walk with supervision indoors. INTERVENTIONS: Both groups received six one-hour physiotherapy sessions over a two-week period. One group received physiotherapy based on the Bobath concept, including one hour of structured task practice. The other group received six hours of structured task practice. OUTCOME MEASURES: The primary outcome was an adapted six-minute walk test, incorporating a step, ramp and uneven surface. Secondary measures were gait velocity and the Berg Balance Scale. Measures were assessed before and after the intervention period. RESULTS: Following the intervention, there was no significant difference in improvement between the two groups for the adapted six-minute walk test (89.9 (standard deviation (SD) 73.1) m Bobath versus 41 (40.7) m task practice, P = 0.07). However, walking velocity showed significantly greater increases in the Bobath group (26.2 (SD 17.2) m/min versus 9.9 (SD = 12.9) m/min, P = 0.01). No significant differences between groups were recorded for the Berg Balance Scale (P = 0.2). CONCLUSION: This pilot study indicates short-term benefit for using interventions based on the Bobath concept for improving walking velocity in people with stroke. A sample size of 32 participants per group is required for a definitive study. PMID- 21788267 TI - Potential effectiveness of three different treatment approaches to improve minimal to moderate arm and hand function after stroke--a pilot randomized clinical trial. AB - OBJECTIVE: To test a study design and explore the feasibility and potential effects of conventional neurological therapy, constraint induced therapy and therapeutic climbing to improve minimal to moderate arm and hand function in patients after a stroke. METHOD: A pilot study with six-month follow-up in patients after stroke with minimal to moderate arm and hand function admitted for inpatient rehabilitation was performed. Participants were randomly allocated to one of three treatment approaches. Main outcomes were improvement of arm and hand function and adverse effects. RESULTS: 283 patients with stroke were screened for inclusion over a two-year period, out of which fourtyfour were included. All patients could be treated according to the protocol. Improvement of arm and hand function was significantly higher in conventional neurological therapy and constraint induced therapy compared with therapeutic climbing at discharge, and at six months follow-up (P < 0.05, effect size = 0.56-0.76). No significant differences in arm and hand function were observed between constraint induced therapy and conventional neurological therapy. Constraint induced therapy participants were significantly less at risk of developing shoulder pain at six months follow-up compared with the other participants (P < 0.05, effect size = 0.82 and 1.79, respectively). CONCLUSIONS: The study design needs adaptation to accommodate the stringent inclusion criteria leading to prolonged study duration. Constraint induced therapy seems to be the optimal approach to improve arm and hand function and minimize the risk of shoulder pain for patients with minimal to moderate arm hand function after stroke in the intermediate term. PMID- 21788268 TI - Guidance on minimally important clinical difference and trial size is needed. PMID- 21788270 TI - Feel the anxiety about examining patients and do it anyway. PMID- 21788269 TI - Another plausible explanation for mist inhaler's toxicity. PMID- 21788271 TI - Protecting children from mobile phone radiation. PMID- 21788274 TI - Competition could substantially benefit healthcare. PMID- 21788278 TI - James Malone-Lee responds to the media flurry over safety of anticholinergic drugs in elderly people. PMID- 21788280 TI - Anticoagulation and antiplatelet therapy in implantation of electrophysiological devices. AB - The growing implantations of electrophysiological devices in the context of increasing rates of chronic antithrombotic therapy in cardiovascular disease patients underscore the importance of an effective periprocedural prophylactic strategy for prevention of bleeding complications. In this review, we provide a concise overview of the data regarding anticoagulation and antiplatelet therapy in arrhythmia device surgery. Also, we critically discuss risk factors and procedural parameters that are potentially associated with haemorrhagic untoward events in this setting. Of note, current evidence suggests that heparin bridging therapy in patients on chronic anticoagulation and dual-antiplatelet therapy are associated with increased risk of pocket haematoma formation. Continuation of oral anticoagulation and short-term interruption of clopidogrel with aspirin maintenance in eligible patients, respectively, represent promising strategies with an acceptable safety profile. Besides the perioperative management of antithrombotic therapy, some extra supportive measures may also reduce the incidence of haematomas. High-risk cases should be better treated by experienced operators in high-volume centres. More randomized studies are needed to elucidate the exact role of particular antithrombotic therapy protocols. Finally, the recently accumulated data on this subject should be incorporated into the professional guidelines regarding arrhythmia device therapy. PMID- 21788283 TI - Iliac artery occlusion with "oxbow lake" formation following stent deployment in a tortuous external iliac artery during EVAR: a case report. AB - In this case report, we describe a complication that we term the "oxbow lake" deformity. This phenomenon occurs when a tortuous elongated external iliac artery segment is artificially straightened by an iliac stent resulting in kinking and compression of a redundant loop with lumen compromise. We describe the anatomy, corrective treatment, and outcome. This occurrence is potentially foreseeable with tortuous vascular anatomy and recognition can allow appropriate management planning avoiding complications for the patient. PMID- 21788282 TI - Obesity is not an independent risk factor for adverse perioperative and long-term clinical outcomes following open AAA repair or EVAR. AB - OBJECTIVES: Moderate (body mass index [BMI] >=30) and morbid obesity (BMI >=35) is increasing at an alarming rate in vascular surgery patients. The objective of this study was to determine the impact of obesity on perioperative and long-term clinical outcomes following open abdominal aortic aneurysm (AAA) repair or endovascular aneurysm repair (EVAR). METHODS: This review includes patients that underwent open AAA repair (n = 403) or EVAR (n = 223) from 1999 to 2009. Specific patient characteristics such as comorbid diseases, medications, and body mass index (BMI) were assessed. Specific perioperative outcomes such as length of stay, myocardial infarctions, and mortality were reviewed. In addition, long-term outcomes such as rates of reintervention, permanent renal dysfunction, and mortality beyond 30 days were also assessed. RESULTS: The incidence of obesity in open AAA patients was 25.3% (documented incidence 1.5%) and for EVAR was 24.6% (documented incidence 4%). Moderate and morbid obesity was associated with longer intensive care unit (ICU) admissions for both open AAA or EVAR patients (P < .05). However, no significant differences in perioperative outcomes in terms of overall length of stay, myocardial infarction, acute renal failure, wound infections, or mortality were noted between obese and nonobese patients underoing open AAA repair or EVAR (P > .05). Similarly, moderate and morbid obesity was not associated with significant differences in rates of reintervention, permanent renal dysfunction, and mortality beyond 30 days for patients undergoing open AAA repair or EVAR (P > .05). CONCLUSIONS: The results of this study indicate that moderate and morbid obesity are not independently associated with adverse perioperative and long-term clinical outcomes for patients undergoing open AAA repair or EVAR. Therefore, either open AAA repair or EVAR can be accomplished safely in moderately obese and morbidly obese patients. PMID- 21788284 TI - Attentiveness in care: towards a theoretical framework. AB - The purpose of this article is to shape a theoretical framework of attentiveness in care, which may function as a background to study attentiveness in a health care setting empirically. More insight into the functions, forms, and aspects of attentiveness in a particular health care setting is important, as there is a lack of indicators and criteria that enable a sharp picture of the caring side of health provision. The concept of attentiveness and its relation to care have seldom been examined thoroughly and broadly. This article argues that attentiveness is constitutive for good care, as it can create a space in which a relationship may arise. PMID- 21788285 TI - Editorial: What do we know about dignity in care? PMID- 21788286 TI - Iranian nurses and hospitalized teenagers' views of dignity. AB - Respect for human dignity is a basic and crucial component of nursing care. Illness with restricted physical ability and being confined to bed can compromise the dignity of patients. The views of adolescents regarding dignity in care have not previously been researched. This article details a descriptive-analytic study in which survey data was collected from all nurses and compared with a convenience sample of 180 hospitalized adolescents in two hospitals in Iran. The data was analyzed with SPSS software. A significant difference between nurses and hospitalized ill adolescents' perceptions was identified in relation to: understanding the importance of privacy (p < 0.001); observance of privacy (p < 0.001); importance of interaction between nurses and patients (p = 0.019); and the observance of interaction between nurses and patients (p < 0.001). Attention to adolescents' views about dignity can help nurses to improve quality of care for this group. PMID- 21788281 TI - Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. AB - BACKGROUND: Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS: For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS: Different growth factors such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-beta perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS: Growth factors play an important role in the mechanisms involved in myometrial patho-physiology. PMID- 21788287 TI - Futile cardiopulmonary resuscitation for the benefit of others: an ethical analysis. AB - It has been reported as an ethical problem within prehospital emergency care that ambulance professionals administer physiologically futile cardiopulmonary resuscitation (CPR) to patients having suffered cardiac arrest to benefit significant others. At the same time it is argued that, under certain circumstances, this is an acceptable moral practice by signalling that everything possible has been done, and enabling the grief of significant others to be properly addressed. Even more general moral reasons have been used to morally legitimize the use of futile CPR: That significant others are a type of patient with medical or care needs that should be addressed, that the interest of significant others should be weighed into what to do and given an equal standing together with patient interests, and that significant others could be benefited by care professionals unless it goes against the explicit wants of the patient. In this article we explore these arguments and argue that the support for providing physiologically futile CPR in the prehospital context fails. Instead, the strategy of ambulance professionals in the case of a sudden death should be to focus on the relevant care needs of the significant others and provide support, arrange for a peaceful environment and administer acute grief counselling at the scene, which might call for a developed competency within this field. PMID- 21788288 TI - Citizenship and autonomy in acquired brain injury. AB - In ethical theory, different concepts of autonomy can be distinguished. In this article we explore how these concepts of autonomy are combined in theory in the citizenship paradigm, and how this turns out in the practice of care for people with acquired brain injury. The stories of a professional caregiver and a client with acquired brain injury show that the combination of various concepts of autonomy in practice leads to tensions between caregivers and clients. These dynamics are discussed from a care ethics perspective, stressing the importance of relationships and interdependence, as well as paying attention to various, sometimes conflicting, perspectives in a deliberative dialogue. PMID- 21788289 TI - The hierarchy of values in Jewish bioethics. AB - This article describes how ethical issues in health are approached and resolved within the framework of Jewish bioethics. Its main purpose is to explore the range of sources and methodologies used to determine the appropriate hierarchy of values for various ethical scenarios. Its major thrust is to illustrate how a divinely based but humanly negotiated ethical code stands firm upon 'red flag' principles, while at the same time, allowing for 'shades of gray' flexibility informed by given contexts. It provides significant insights and practical tools that can be instrumental in decision making for nurses and other health providers of all faiths. The following ethical domains are addressed: respect for patient autonomy, truth-telling and allocation of resources. PMID- 21788290 TI - Cultural competence: reflections on patient autonomy and patient good. AB - Terms such as 'cultural competence' and 'transcultural nursing' have comfortably taken their place in the lexicon of health care. Their high profile is a reflection of the diversity of western societies and health care's commitment to provide care that is responsive to the values and beliefs of all who require treatment. However, the relationship between cultural competence and familiar ethical concepts such as patient autonomy has been an uneasy one. This article explores the moral foundations of cultural competence, ultimately locating them in patient autonomy and patient good. The discussion of patient good raises questions about the moral relevance of a value's rootedness in a particular culture. I argue that the moral justification for honoring cultural values has more to do with the fact that patients are strongly committed to them than it does with their cultural rootedness. Finally, I suggest an organizational approach to cultural competence that emphasizes overall organizational preparedness. PMID- 21788291 TI - Moral learning in psychiatric rehabilitation. AB - The purpose of this article is to illustrate moral learning in persons with a psychiatric disability who participated in a nursing intervention, called the photo-instrument. This intervention is a form of hermeneutic photography. The findings are based on a multiple case study of 42 patients and additional interviews with eight of them. Photo groups were organized within three settings of psychiatric services: ambulatory as well as clinical, all situated in the Netherlands. Data were analysed according to hermeneutic and semiotic principles. Two cases are presented. Findings show that voice and face are concepts that help to identify elements of moral learning in the rehabilitation process of persons with a psychiatric disability. During the process patients become more aware of their responsibilities towards themselves and others. PMID- 21788292 TI - Case commentary: Baby John. PMID- 21788293 TI - Prevalence of faecal carriage of Enterobacteriaceae with NDM-1 carbapenemase at military hospitals in Pakistan, and evaluation of two chromogenic media. AB - OBJECTIVES: To determine the prevalence and antimicrobial susceptibility of carbapenemase-producing Enterobacteriaceae among hospitalized patients and outpatients attending two military hospitals in Rawalpindi, Pakistan, and to compare the performance of two chromogenic culture media for the isolation of these organisms. METHODS: Stool samples from 200 distinct patients were cultured on MacConkey agar and subsequently on two chromogenic media-Colorex KPC and a prototype chromogenic medium, ID Carba-designed for the isolation of carbapenemase-producing Enterobacteriaceae. All Gram-negative isolates growing on either chromogenic medium were investigated for carbapenemases by phenotypic and molecular methods. Producers were subjected to susceptibility testing with 40 antimicrobials by VITEK 2 or agar dilution. RESULTS: In total, 64 NDM-1-positive isolates of Enterobacteriaceae, belonging to seven distinct species, were recovered from 37 (18.5%) of the stool samples. No other carbapenemase types were confirmed. Nineteen positive samples were identified among 70 from inpatients (prevalence 27.1%) and there were 18 positive samples among 130 from outpatients (prevalence 13.8%). Fifty-six isolates (87.5%) harbouring the NDM-1 enzyme were recovered on ID Carba compared with 41 isolates (64.1%) on Colorex KPC (P = 0.012). Multidrug resistance was prevalent, but no pan-resistant isolates were found, with most isolates susceptible in vitro to colistin (97%), mecillinam (95%), fosfomycin (94%), tigecycline (89%) and nitrofurantoin (78%). CONCLUSIONS: This study shows a high prevalence of multidrug-resistant Enterobacteriaceae with the NDM-1 enzyme in Rawalpindi. The new chromogenic medium, ID Carba, was more sensitive than Colorex KPC and has potential as a screening medium for isolation of Enterobacteriaceae harbouring the NDM-1 enzyme. PMID- 21788294 TI - Patient safety attitudes and behaviors of graduating medical students. AB - As North American medical schools reformulate curricula in response to public calls for better patient safety, surprisingly little research is available to explain and improve the translation of medical students' knowledge and attitudes into desirable patient safety behaviors in the clinical setting. A total of 139 fourth-year medical students at Virginia Commonwealth University, School of Medicine, 96% of the 2010 graduating class, completed the Attitudes toward Patient Safety Questionnaire and a self-report of safety behaviors. The students were exposed to informal discussions of patient safety concepts but received no formal patient safety curriculum. Most students recognized errors and responded with attitudes supportive of patient safety but desired behaviors were less common. In particular, errors went unreported, owing, in part, to the relationships of power and social influence undergirding the traditional authority gradient in the culture of medicine. A deeper understanding of patient safety attitudes, behavior, and medical culture is required to better inform instructional design decisions that influence desired patient safety behaviors and improve patient care. PMID- 21788295 TI - Promoting recovery and preventing drug-related mortality: competing risks? PMID- 21788296 TI - A comparative analysis of the outcome of flexor tendon repair in the index and little fingers: does the little finger fare worse? AB - The clinical and hand therapy notes of 180 patients who had single digit flexor tendon repairs in zones I and II from January 2000 to December 2004 were reviewed. Data from 60 index and 108 little fingers at 5 weeks, 8 weeks and 12 weeks follow-up visits were included. In zone I injuries, there was a statistically significant difference in flexion contracture (worse in the little fingers ) at all follow-up points. Although the range of motion and percentage of patients in the excellent category of the Strickland and Glogovac criteria were greater in the index finger group than the little finger for zone I and II injuries, these differences were not statistically significant. The rupture rate was also higher in the little finger group. PMID- 21788297 TI - Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase. AB - Suppression of TSH release from the hypothyroid thyrotrophs is one of the most rapid effects of 3,3',5'-triiodothyronine (T(3)) or thyroxine (T(4)). It is initiated within an hour, precedes the decrease in TSHbeta mRNA inhibition and is blocked by inhibitors of mRNA or protein synthesis. TSH elevation in primary hypothyroidism requires both the loss of feedback inhibition by thyroid hormone in the thyrotrophs and the positive effects of TRH. Another event in this feedback regulation may be the thyroid hormone-mediated induction of the TRH inactivating pyroglutamyl peptidase II (PPII) in the hypothalamic tanycytes. This study compared the chronology of the acute effects of T(3) or T(4) on TSH suppression, TRH mRNA in the hypothalamic paraventricular nucleus (PVN), and the induction of tanycyte PPII. In wild-type mice, T(3) or T(4) caused a 50% decrease in serum TSH in hypothyroid mice by 5 h. There was no change in TRH mRNA in PVN over this interval, but there was a significant increase in PPII mRNA in the tanycytes. In mice with genetic inactivation of the type 2 iodothyronine deiodinase, T(3) decreased serum TSH and increased PPII mRNA levels, while T(4) treatment was ineffective. We conclude that the rapid suppression of TSH in the hypothyroid mouse by T(3) occurs prior to a decrease in TRH mRNA though TRH inactivation may be occurring in the median eminence through the rapid induction of tanycyte PPII. The effect of T(4), but not T(3), requires the type 2 iodothyronine deiodinase. PMID- 21788298 TI - Benign post-esophagectomy gastrocardiac fistula. AB - The development of a gastrocardiac fistula is a rare complication following retrosternal gastric conduit creation. We report a case of a 64-year-old male who presented three years after esophagectomy with massive hematemesis. A fistulous connection between his gastric conduit and right ventricle was identified and successfully treated. Although the patient had an atypical presentation and lacked most of the commonly cited risk factors, the combination of peptic ulcer disease and Candida overgrowth resulted in the formation of a gastrocardiac fistula. Adherence to treatment principles including prompt surgical intervention, adequate coverage of the repair, and antimicrobial therapy against Candida species provides the highest likelihood of success in addressing this potentially lethal disease process. PMID- 21788299 TI - Thymoma within a giant congenital thymic cyst. AB - Congenital thymic cysts are very rare and mostly asymptomatic mediastinal lesions. Thymoma within such cysts is even more uncommon and has so far hardly been described. We report on a 41-year-old male with a World Health Organization type B1 thymoma within the wall of a huge unilocular thymic cyst. Because of the possible coexistence of typical congenital thymic cyst and thymoma, we recommend surgical resection both for establishing the diagnosis and for definite treatment. PMID- 21788300 TI - Permanent pacemaker implantation after transapical transcatheter aortic valve implantation. AB - The aim of the study was to determine the incidence of permanent pacemaker implantation (PPMI) in a cohort of 358 patients undergoing transapical aortic valve implantation (TAVI) using a balloon-expandable prosthesis between April 2008 and March 2011. After excluding patients who had had a previous PPMI (n=36; 10%), the study group consisted of 322 patients. These were divided into two groups: patients who required PPMI (PPM group) and patients who did not require it (non-PPM group). Preoperative, perioperative and one-year follow-up data were collected prospectively. Twenty (6.2%) patients required PPMI. Previous implantation of an aortic prosthesis (P=non-significant), previous coronary artery bypass grafting (P=0.05) and coronary artery disease (P<0.005) were more common in the non-PPM group. On logistic regression, only patient age seemed to be correlated to PPMI (P=0.05, odds ratio 1.08; CI 0.9-1.1). There was no difference in survival rate between the groups after 30 days (PPM group 95%, non PPM group 93.6%). Similarly, the survival rate did not differ after one year (PPM group 84%, non-PPM group 80.9%; P=0.3). The PPMI rate after transapical TAVI using a balloon-expandable prosthesis is thus low, and has no impact on early and follow-up mortality. PMID- 21788301 TI - Compromised cardiac function in exercising teenagers with pectus excavatum. AB - Patients with pectus excavatum complain about fatigue, tachypnea, discomfort and dyspnea, but the existence of an equivalent underlying pathophysiology has been questioned. We investigated 75 teenagers (49 pectus excavatum patients and 26 age matched controls) at rest and during bicycle exercise at submaximal exercise levels. At rest cardiac function was determined using echocardiography. During rest and exercise, cardiac output, heart rate and aerobic exercise capacity were measured using photo-acoustic gas-rebreathing technique for non-invasive determination of the cardiopulmonary function. At rest, no cardiac differences were found between control subjects and patients with pectus excavatum. During submaximal exercise, cardiac index was lower 6.6(6.3-7.0) l/min/m(2) among the pectus patients as compared to the control subjects 8.0(7.3-8.8) l/min/m(2), P=0.0001. The lower cardiac output among the pectus patients was due to a lower stroke index 42(39-45) ml/beat/m(2) as compared to controls 54(44-64) ml/beat/m(2), P=0.0022, whereas heart rate was unchanged. Cardiac function is significantly impaired at submaximal exercise level compared to healthy age matched controls. PMID- 21788303 TI - Normothermic total arch replacement without hypothermic circulatory arrest to treat aortic distal arch aneurysm in a patient with cold agglutinin disease. AB - Cold agglutinin disease although rare, can lead to serious complications for patients undergoing cardio-thoracic surgery, especially when cardiopulmonary bypass is applied under hypothermic circulatory arrest. We describe normothermic total arch replacement without hypothermic circulatory arrest in a patient with cold agglutinin disease. The patient tolerated all procedures well and did not develop cerebral ischemia due to surgical maneuvers or thrombotic or haemolytic complications due to cold agglutinin disease. Although endovascular aortic repair is the first choice under such complex conditions, this method could also serve as an alternative strategy when endovascular aortic repair is precluded. PMID- 21788302 TI - Preoperative carriage and postoperative same-species sternal wound infection after cardiac surgery. AB - Sternal wound infection (SWI) after cardiac surgery remains an important problem. Prediction of pathogens involved in such infection could guide antibiotics. From April 1, 2006 to December 31, 2008, retrospectively, we evaluated the diagnostic value of preoperative methicillin-sensible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) or multi-drug resistant Gram-negative bacillus (MDRGNB) carriage to predict same-pathogens involved in postoperative SWI. All patients referred for elective cardiac surgery were screened using multisite (nares, axillae, rectal) sampling at admission to detect MSSA, MRSA, and MDRGNB. Of the 1895 patients addressed, 425 patients (22.4%) were colonized at admission. Preoperative carriers more frequently developed SWI than non carriers, respectively, 11% vs. 5.5% (P<0.05). Because of the small sample, MDRGNB carriers could not be analyzed. For prediction of MSSA SWI with preoperative MSSA carriage, the area under the receiver operating characteristic (ROC) curve was 0.720 (95% confidence interval (CI), 0.364-0.796) and 0.710 (95% CI, 0.623-0.787) for prediction of MRSA SWI with preoperative MRSA carriage. Preoperative MSSA carriage is frequent but preoperative MRSA or MDRGNB carriage remains infrequent. The ability of preoperative carriage to predict a same pathogen-postoperative SWI was low and should not be used to guide empirical antibiotherapy. PMID- 21788304 TI - How does successful bridging with ventricular assist device affect cardiac transplantation outcome? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The issue was to determine the impact of bridge-to-transplant ventricular assist device support on survival after cardiac transplantation. Altogether 428 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The treatment options for patients with advanced heart failure or those with deteriorating end organ function on maximal medical therapy are limited to intravenous inotropes and mechanical assistance with intra-aortic balloon pump (IABP) or ventricular assist device (VAD). Studies exploring the effect of VADs on post-transplant mortality have yielded conflicting results. The Registry of the International Society for Heart and Lung Transplantation continues to identify mechanical support as a risk factor for decreased survival after transplantation. A limitation of this report is that the multivariable adjustment uses variables recorded not at the time of device implant but at the time of transplant. Some of the recipient characteristics thus may be altered by the device implant. Compared with the previous reports the latest data show improvement in post-transplant survival in the recent era. In addition, the excess risk appears to be limited to the early post-transplant period. Experienced centers consistently report outstanding post-transplant results with left ventricular assist device (LVAD) bridging. Of the 12 papers seven showed no difference in survival, and five showed a reduced survival. In the papers showing no difference, one year survival averaged from 85% in supported patients to 87% in non-supported patients. In papers reporting a difference in outcome, one year averaged survival was 74% in LVAD recipients compared to 90% in non-bridged patients. Decreased survival is associated with patients suffering from dilated cardiomyopathy, transplanted within two weeks of LVAD implantation and bridged to transplantation before 2003 as opposed to patients transplanted more recently. Based on the available evidence we conclude that in selected patients survival after heart transplantation in patients bridged with VAD is comparable to those who did not receive the device. PMID- 21788305 TI - Perceived emotional support and frequent social contacts are associated with greater knowledge of stroke warning signs: evidence from two cross-sectional us population surveys. AB - Public knowledge of acute stroke symptoms is a goal of public health policy. Similarly, general health knowledge is a hypothesized pathway for the salutary effects of social ties. This study examined the association of stroke warning sign knowledge with the quantity (number of recent social contacts) and/or quality (perceived emotional support) of social ties in two population-based cross-sectional surveys (Ns = 33,326 and 80,454). Both higher levels of emotional support and more frequent social contacts were independently associated with greater stroke warning sign knowledge. Social isolation is a novel marker of poor knowledge of stroke warning signs. PMID- 21788306 TI - The reluctance to burden others as a value in end-of-life decision making: a source of inaccuracy in substituted judgment. AB - Most patients are decisionally incapacitated at the end of life, leaving final treatment decisions to proxies, whose substituted judgment is often inaccurate. We investigated the reluctance to burden others (RBO), a commonly cited patient value, as a possible source of proxy inaccuracy. In a sample of 202 elders and their proxies, elders responded to three burden-related questions and the Life prolonging Treatment Preferences Questionnaire. Proxies used substituted judgment to respond to the same questions. Although RBO predicted treatment preferences for both elders and proxies, elders rated RBO significantly more important than did proxies. In addition, larger elder-proxy differences in RBO were associated with more inaccurate substituted judgment. PMID- 21788307 TI - Identification of a plant aminopeptidase with preference for aromatic amino acid residues as a novel member of the prolyl oligopeptidase family of serine proteases. AB - Genome analysis has indicated that plants, like animals, possess a variety of protease genes. However, bulk of putative proteases has not been characterized at the enzyme level. In this article, a novel enzyme that hydrolyses phenylalanyl-4 methylcoumaryl 7-amide (phenylalanyl-MCA) was purified from cotyledons of daikon radish by ammonium sulphate fractionation and successive chromatography with DEAE cellulose, phenyl-Sepharose, Sephacryl S-200 and Mini-Q. The molecular mass of the enzyme was estimated to be 78 kDa by SDS-PAGE under reducing conditions and 74 kDa by gel filtration, indicating that the enzyme is a monomer. The deduced amino acid sequence from the cDNA nucleotide sequence indicated that the enzyme is an orthologue of Arabidopsis unidentified protein, acylpeptide hydrolase-like protein (AHLP; UniProt ID: Q9FG66) belonging to the prolyl oligopeptidase (POP) family of a serine-type peptidase predicted from genetic information. Good substrates identified for the enzyme include phenylalanyl-MCA, tyrosyl-MCA and enkephalin. Neither acylamino acid-releasing activity nor endopeptidase activity was detected. The enzyme cleaved enkephalin (YGGFM, YGGFL), whereas, BAM-12 P (YGGFMRRVGRPE) and dynorphin A (YGGFLRRIRPKLK) were not digested. These results suggested that the enzyme possesses strict size selectivity of substrate. We propose the name 'tyrosyl aminopeptidase' for the uncharacterized protein AHLP. PMID- 21788308 TI - Status of RASSF1A in uveal melanocytes and melanoma cells. AB - RASSF1A gene, found at the 3p21.3 locus, is a tumor suppressor gene frequently hypermethylated in human cancers. In this study, we report that compared with melanocytes in normal choroid, RASSF1A is downregulated in uveal melanoma samples and in uveal melanoma cell lines. LOH at 3p21.3 was detected in 50% of uveal melanoma. Moreover, methylation of the RASSF1A promoter was detected in 35 of 42 tumors (83%) and RASSF1A was also weakly expressed at the mRNA level. These data indicate that LOH at the RASSF1A locus or RASSF1A promoter methylation may partly account for the suppression of RASSF1A expression observed in uveal melanoma. Furthermore, following ectopic expression in three RASSF1A-deficient melanoma cell lines (OCM-1, Mel270, and 92.1), RASSF1A weakly reduces cell proliferation and anchorage-independent growth of uveal melanoma cells without effect on ERK1/2 activation, cyclin D1 and p27(Kip1) expression. This study explored biological functions and underlying mechanisms of RASSF1A in the ERK1/2 pathway in normal uveal melanocytes. We showed that siRNA-mediated depletion of RASSF1A increased ERK1/2 activation, cyclin D1 expression, and also decreased p27(Kip1) expression in normal uveal melanocytes. Moreover, that the depletion of RASSF1A induced senescence-associated beta-galactosidase activity and increased p21(Cip1) expression suggests that RASSF1A plays a role in the escape of cellular senescence in normal uveal melanocytes. Interestingly, we found that RASSF1A was epigenetically inactivated in long-term culture of uveal melanocytes. Taken together, these data show that depletion of RASSF1A could be an early event observed during senescence of normal uveal melanocytes and that additional alterations are acquired during malignant transformation to uveal melanoma. PMID- 21788309 TI - Programmed intermittent epidural bolus versus continuous epidural infusion for labor analgesia: the effects on maternal motor function and labor outcome. A randomized double-blind study in nulliparous women. AB - BACKGROUND: Programmed intermittent epidural anesthetic bolus (PIEB) technique may result in reduced total local anesthetic consumption, fewer manual boluses, and greater patient satisfaction compared with continuous epidural infusion (CEI). In this randomized, double-blind study, we compared the incidence of motor block and labor outcome in women who received PIEB or CEI for maintenance of labor analgesia. The primary outcome variable was maternal motor function and the secondary outcome was mode of delivery. METHODS: Nulliparous, term women with spontaneous labor and cervical dilation <4 cm were eligible to participate in the study. Epidural analgesia was initiated and maintained with a solution of levobupivacaine 0.0625% with sufentanil 0.5 MUg/mL. After an initial epidural loading dose of 20 mL, patients were randomly assigned to receive PIEB (10 mL every hour beginning 60 minutes after the initial dose) or CEI (10 mL/h, beginning immediately after the initial dose) for the maintenance of analgesia. Patient-controlled epidural analgesia (PCEA) using a second infusion pump with levobupivacaine 0.125% was used to treat breakthrough pain. The degree of motor block was assessed in both lower extremities using the modified Bromage score at regular intervals throughout labor; the end point was any motor block in either limb. We also evaluated PCEA bolus doses and total analgesic solution consumption. RESULTS: We studied 145 subjects (PIEB = 75; CEI = 70). Motor block was reported in 37% in the CEI group and in 2.7% in the PIEB group (P < 0.001; odds ratio = 21.2; 95% CI: 4.9-129.3); it occurred earlier (P = 0.008) (hazard ratio = 7.8; 95% CI: 1.9-30.8; P = 0.003) and was more frequent at full cervical dilation in the CEI group (P < 0.001). The incidence of instrumental delivery was 20% for the CEI group and 7% for the PIEB group (P = 0.03). Total levobupivacaine consumption, number of patients requiring additional PCEA boluses, and mean number of PCEA boluses per patient were lower in the PIEB group (P < 0.001). No differences in pain scores and duration of labor analgesia were observed. CONCLUSIONS: Maintenance of epidural analgesia with PIEB compared with CEI resulted in a lower incidence of maternal motor block and instrumental vaginal delivery. PMID- 21788311 TI - The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations. AB - BACKGROUND: In the immature brain, neuronal Ca2+ oscillations are present during a time period of high plasticity and regulate neuronal differentiation and synaptogenesis. In this study we examined the long-term blockade of hippocampal Ca2+ oscillations, the role of the N-methyl-D-aspartate (NMDA) receptors and the effects of S(+)-ketamine on neuronal synapsin expression. METHODS: Hippocampal neurons were incubated at day 15 in culture with the specific NMDA receptor antagonists dizocilpine (MK 801, 100 MUM) or S(+)-ketamine (3 MUM to 25 MUM) for 24 hours. Terminal-deoxynucleotidyl-transferase (TUNEL) and activated caspase3 were used to detect apoptotic neurons. Ca2+ oscillations were detected after loading the neurons with the Ca2+-sensitive dye fura-2AM, and dual wavelength excitation fluorescence microscopy was performed. Ca2+/calmodulin kinase II (CaMKII) was measured using Western blots. Synapsin was identified with confocal antisynapsin immunofluorescence. RESULTS: Blocking the NMDA receptor with MK 801 or 25 MUM S(+)-ketamine resulted in a significant increase in apoptotic neurons. MK 801 led to a significant increase in cytosolic Ca2+ concentration and reduction of the amplitude and frequency of the Ca2+ oscillations. Similar to MK 801, the long-term application of S(+)-ketamine resulted in a significant increase in cytosolic Ca2+ concentration 24 hours after washout. This was associated with a down-regulation of the CaMKII and a reduction of the synapsin 24 hours after washout. CONCLUSION: Neuronal Ca2+ oscillations mediate neuronal differentiation and synaptogenesis via activating CaMKII. By acting via the NMDA receptor, S(+)-ketamine exerts its toxic effect through the suppression of neuronal Ca2+ oscillations, down-regulation of the CaMKII, and consecutively reduced synaptic integrity. PMID- 21788310 TI - Lidocaine attenuates the development of diabetic-induced tactile allodynia by inhibiting microglial activation. AB - BACKGROUND: Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated. METHODS: To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ injection. On day 21, microglial accumulation and p38 mitogen-activated protein kinase activation in the dorsal horn were evaluated. In vitro, the effects of lidocaine on cell viability, chemotactic response to monocyte chemotactic protein-1, and induction of proinflammatory mediators were examined in interferon (IFN)-gamma-stimulated primary microglial cells. RESULTS: Continuous systemic administration of lidocaine in the early progression of tactile allodynia produced long-lasting analgesic effects in STZ-treated mice. Lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells in the dorsal horn. In vitro, lidocaine down-regulated IFN-gamma-induced gene induction of inducible oxide synthase and interleukin-1beta. Pretreatment with lidocaine significantly reduced chemotactic response to monocyte chemotactic protein-1 of IFN-gamma activated microglial cells. CONCLUSION: Lidocaine alleviates STZ-induced tactile allodynia, possibly by modulating the p38 pathway in spinal microglial cells. Inhibiting microglial activation by lidocaine treatment early in the course of diabetes-induced neuropathy represents a potential therapeutic strategy for tactile allodynia. PMID- 21788312 TI - Nitrous oxide paradoxically modulates slow electroencephalogram oscillations: implications for anesthesia monitoring. AB - BACKGROUND: Nitrous oxide (N(2)O) is one of the oldest analgesics/adjuvant agents still in use today; however, its effects on the human electroencephalogram (EEG) remain unclear. It has been proposed that N(2)O may enhance higher-frequency EEG activity (often indicative of alert states and cognition) duration sedation. This possibly paradoxical effect has been used to explain the failure of many EEG monitors to capture the effects of N(2)O on patient state during anesthesia. To better understand the poor efficacy of current EEG approaches to monitoring N(2)O action, we quantitatively studied the sole effect of N(2)O on the resting EEG in healthy volunteers using multichannel EEG recordings under noise-minimized laboratory conditions. METHODS: Healthy male volunteers were administered 20% (n = 10), 40% (n = 10), or 60% (n = 5) inspired N(2)O mixed with oxygen during noise shielded EEG recordings. N(2)O was administered over a 20-minute period involving a 5-minute equilibration period and 5-minute washout. EEG spectral edge frequency (95%), median power frequency, total power, and band-limited power (delta, , alpha, beta, and gamma) were used as quantitative EEG parameters. The changes in these EEG parameters were quantified throughout N(2)O inhalation and compared between predrug baseline, peak drug effect, and washout. RESULTS: Quantification of changes in spectral power during N(2)O inhalation showed only minor changes in estimates of spectral edge and median power frequency, whereas significant reductions in total power were observed at frontal sites during peak gas effect (P = 0.001; mean reduction [95% confidence interval]: 41.90 MUV(2) [18.19-65.61 MUV(2)]) that rebounded during N(2)O washout. Such changes in total power were driven by shifts in low-frequency power (delta/), which were most elevated at frontal sites. CONCLUSION: Rather than directly enhancing high-frequency EEG power (beta or gamma bands), N(2)O seems to preserve the awake features of resting EEG (alpha band) and suppress power in those bands in which increases are typically associated with sedation/hypnosis (delta and ). These data suggest that N(2)O's suppression of low-frequency EEG power may help to explain previously reported difficulties in attempting to monitor patient state with the EEG during anesthesia involving N(2)O. Because increases in low-frequency power typically indicate increasing anesthesia, N(2)O's suppression of such activity and its rebound during washout would paradoxically influence EEG monitoring parameters. Therefore, correcting for such effects is expected to improve future monitoring methods. PMID- 21788313 TI - Cardiac axis-oriented full-volume data acquisition in real-time three-dimensional transesophageal echocardiography to facilitate on-cart analysis. AB - We propose a useful method to acquire a full-volume dataset that allows for efficient assessment of cardiac structures by real-time 3-dimensional transesophageal echocardiography (3DTEE). In our method, bicommissural full volume acquisition, the dataset is acquired with the X-Y-Z axes aligned along the lines connecting the mitral commissures, the mitral annular center to the left ventricular apex, and the mitral anterior-posterior ends, respectively. The image dataset obtained using this method not only allows for visualization of en face images of the cardiac structures, but box cropping of the dataset also provides useful sectional images that are the analogues of the standard 2DTEE views. Our method can potentially standardize 3D image orientation of the cardiac structures and facilitate intraoperative on-cart analysis in real-time 3DTEE. PMID- 21788315 TI - Commentary: recombinant activated factor VII: the controversial conundrum regarding its off-label use. PMID- 21788316 TI - The impact of anesthesia on glycine absorption in operative hysteroscopy: a randomized controlled trial. AB - BACKGROUND: Operative hysteroscopy requires the use of a distension medium and its absorption can lead to serious consequences from intravascular volume overload and water intoxication. We compared the impact of 2 types of anesthesia (general anesthesia and local anesthesia with sedation) on the absorption of glycine solution in operative hysteroscopy. METHODS: A randomized controlled trial was conducted over a 17-month period. Eligible patients undergoing operative hysteroscopy for abnormal uterine bleeding were randomized in 2 groups: a general anesthesia group and a local anesthesia with sedation group. The primary outcome was the median absorption of the glycine solution (10th-90th percentile) measured with an automated tandem canister system. Secondary outcomes included incidence of absorption >1000 mL, discontinued surgery because of excessive absorption, median change in serum sodium, postoperative hyponatremia, and patients' postoperative quality of life at 24 hours (8-item Short Form Health Survey questionnaire). Nonparametric analyses (Mann-Whitney U test, chi(2) test, and Fisher exact test) were used. RESULTS: Of 142 eligible patients, 95 agreed to participate and were randomized. Women who underwent general anesthesia had a higher median absorption of the glycine solution (10th-90th percentile) compared with women who underwent local anesthesia with sedation (480 mL [76-1300 mL] vs 253 mL [70-728 mL]; P = 0.005). General anesthesia was also associated with a higher rate of glycine solution absorption (>1000 mL [20% vs 4%; P = 0.009]) and a more rapid rate of decrease in serum sodium (>=10 mEq/L [8% vs 0%; P = 0.005]) than local anesthesia with sedation. Postoperative quality of life measures as rated by the patients were comparable between the 2 groups. CONCLUSION: Compared with general anesthesia, local anesthesia with sedation is associated with less glycine absorption and should be considered the preferred method of anesthesia for operative hysteroscopy. PMID- 21788314 TI - Validation and insights of anesthetic action in an early vertebrate network: the isolated lamprey spinal cord. AB - BACKGROUND: The lamprey spinal cord is a well-characterized vertebrate network that could facilitate our understanding of anesthetic action. We tested several hypotheses concerning the lamprey's clinical application to anesthesia, and the sites/mechanisms of anesthetic action. METHODS: In isolated lamprey spinal cords, minimum immobilizing concentrations (MICs) were determined for halothane, isoflurane, sevoflurane, desflurane, propofol, or the nonimmobilizer F6 (1,2 dichlorohexafluorocyclobutane), applied during D-glutamate-induced fictive swimming or noxious tail stimulation. Isoflurane and propofol effects on fictive swimming were tested in the presence and absence of strychnine and/or picrotoxin. RESULTS: Volatile anesthetic MICs were clinically comparable. Isoflurane MIC for fictive swimming and noxious stimulus-evoked movement were the same. F6 did not produce immobility, but decreased the amplitude and phase lag of fictive swimming. Isoflurane decreased fictive swimming cycle frequency, amplitude, autocorrelation, rostrocaudal phase lag, and coherence. Strychnine and picrotoxin elicited only disorganized motor activity under isoflurane and caused small increases in MIC. The effects of propofol differed from isoflurane for all locomotor rhythm variables except amplitude. The propofol MIC was much larger in lampreys compared with mammals. However, picrotoxin reversed propofol-induced immobility by reinitiating coordinated locomotor activity and increasing MIC>8 fold. CONCLUSIONS: The lamprey spinal cord is a relevant and tractable vertebrate network model for anesthetic action. Isoflurane disrupts interneuronal locomotor networks. gamma-Aminobutyric acid A and glycine receptors have marginal roles in isoflurane-induced immobility in lampreys. Propofol's selective gamma aminobutyric acid A receptor-mediated immobilizing mechanism is conserved in lampreys. The differential immobilizing mechanisms of isoflurane versus propofol reflect those in mammals, and further suggest different network modes of immobilizing action. PMID- 21788317 TI - A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. AB - BACKGROUND: Diagnosing postoperative heparin-induced thrombocytopenia (HIT) in cardiothoracic surgical patients is complicated because of the profound thrombocytopenia that occurs with cardiopulmonary bypass (CPB). CPB predisposes patients to develop a frequent incidence of antibodies directed against platelet factor 4 (PF4)/heparin complexes and HIT. The sensitivity of readily available antibody immunoassays is high, but specificity is quite low. The use of both a clinical probability score and rapid laboratory immunoassay has been shown to increase specificity, which is of particular importance in the CPB setting. Prompt diagnosis is crucial because cessation of heparin and treatment with alternative anticoagulation can reduce the risk of thromboembolic events. METHODS: We retrospectively reviewed records from cardiothoracic surgical patients whose serum was tested with both the serotonin release assay (SRA) and the PF4/heparin immunoassay from January 2007 through December 2010. We assigned a high, intermediate, or low clinical "4Ts" probability score that quantifies thrombocytopenia, timing of platelet decrease, and thrombotic complications in each patient. We then compared the clinical score and the PF4/heparin immunoassay against the "gold standard" diagnostic test, the SRA. RESULTS: The sensitivity and specificity for PF4/heparin optical density >0.40 were 100% and 26%, respectively. Sensitivity and specificity for the diagnosis of HIT with a combination of PF4/heparin optical density >0.40 and high/intermediate 4Ts score were 100% and 70%, respectively. The negative predictive value was 100% for low 4Ts score. CONCLUSIONS: We demonstrated that the use of the 4Ts clinical score combined with the PF4/heparin immunoassay for HIT diagnosis increases the sensitivity and specificity of HIT testing compared with the PF4/heparin immunoassay alone. Furthermore, with an intermediate 4Ts score and positive PF4/heparin antibody test, a confirmatory platelet activation assay such as the SRA is necessary. Physicians treating patients after cardiothoracic surgery should recognize the need for an antibody test and confirmation with a platelet activation assay with even moderate clinical probability of HIT. PMID- 21788318 TI - The effect of a new water-soluble sedative-hypnotic drug, JM-1232(-), on long term potentiation in the CA1 region of the mouse hippocampus. AB - BACKGROUND: JM-1232(-) {(-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl 3,5,6,7-tetrahydrocyclopenta[f]isoindol-1(2H)-one} is a new water-soluble sedative-hypnotic drug with affinity for the benzodiazepine binding site on gamma aminobutyric acid A receptors. The effects of JM-1232(-) on synaptic transmission in the brain are not known. In the present study, we investigated the effects of JM-1232(-) on synaptic transmission, synaptic plasticity (i.e., long-term potentiation [LTP] and paired-pulse facilitation), and excitatory/inhibitory postsynaptic currents (EPSCs/IPSCs) of pyramidal neurons in the CA1 region of mouse hippocampal slices. METHODS: We recorded Schaffer collateral-evoked field excitatory postsynaptic potentials and EPSCs and IPSCs of pyramidal neurons using whole-cell patch-clamp techniques in the CA1 region of mouse hippocampal slices. RESULTS: JM-1232(-) had no significant effect on the field excitatory postsynaptic potentials. Application of JM-1232(-) for 20 minutes before theta burst stimulation dose dependently impaired LTP. JM-1232(-) impaired paired-pulse facilitation. The benzodiazepine antagonist flumazenil abolished the inhibitory effect of JM-1232(-) on LTP and paired-pulse facilitation. JM-1232(-) had no effect on Schaffer collateral stimulation-evoked EPSCs, whereas it potentiated the amplitude and prolonged the decay of evoked IPSCs in CA1 pyramidal neurons. Flumazenil blocked the effect of JM-1232(-) on the amplitude and decay of evoked IPSCs. JM-1232(-) suppressed the action potential discharge in the CA1 pyramidal neurons during theta-burst stimulation, which was reversed by flumazenil. CONCLUSION: JM-1232(-) enhances synaptic inhibition and impairs LTP and paired pulse facilitation in area CA1 of the mouse hippocampus. These effects were mediated by benzodiazepine binding sites on gamma-aminobutyric acid A receptors. PMID- 21788319 TI - Point-of-care electronic prompts: an effective means of increasing compliance, demonstrating quality, and improving outcome. AB - BACKGROUND: Incentives based on quality indicators such as the Surgical Care Improvement Project core measures (SCIP 1) encourage implementation of evidence based guidelines consistently into clinical practice. Information systems with point-of-care electronic prompts (POCEPs) can facilitate adoption of processes and benchmark performance. We evaluated the effectiveness of POCEPs on rates of antibiotic administration within 60 minutes of surgical incision and effect on outcome in a prospective observational trial. METHODS: SCIP 1 compliance and the corresponding outcome variable (surgical site infection [SSI]) were examined prospectively over 2 consecutive 6-month periods before (A) and after (B) POCEPs implementation at a regional health system. Secondary analysis extended the observation to two 12-month periods (A' and B'). A 2-year (C and D) sustainability phase followed. RESULTS: The 19,744 procedures included 9127 and 10,617 procedures before (A) and after (B) POCEPs implementation, respectively. POCEPs increased compliance with SCIP indicators in period B by 31% (95% CI, 30.0%-32.2%) from 62% to 92% (P < 0.001) and were associated with a sustainable, contemporaneous decrease in the incidence of SSI from 1.1% to 0.7% (P = 0.003; absolute risk reduction, 0.4%; 95% CI, 0.1%-0.7%). Secondary and sustainability analysis revealed that compliance rates remained >95% with mean SSI rates lower for all periods compared with pre-POCEPs SSI rates (0.8%, 0.7%, and 0.5% vs 1.1%; P < 0.001). CONCLUSIONS: POCEPs increased compliance with SCIP indicators by >30% and were associated with a 0.4% absolute risk reduction in the incidence of SSI. POCEPs may be useful to modulate provider behavior and demonstrate intraoperative quality and value. PMID- 21788320 TI - The intrathecally administered kappa-2 opioid agonist GR89696 and interleukin-10 attenuate bone cancer-induced pain through synergistic interaction. AB - BACKGROUND: Although bone cancer-related pain is one of the most disruptive symptoms in patients with advanced cancer, patients are often refractory to pharmacological treatments; thus, more effective treatments for bone cancer pain are needed. We evaluated the analgesic efficacy of and interaction between intrathecal GR89696, a kappa(2)-opioid receptor agonist, and interleukin (IL)-10 in a rat model of bone cancer pain. METHODS: The rat model of bone cancer pain was produced by right tibia intramedullary injection of rat breast cancer cells, and an intrathecal catheterization was performed. Ten days later, a paw withdrawal threshold to mechanical stimulus by von Frey hairs was measured using the up-down method, after intrathecal administration of GR89696 and IL-10. The interaction between the 2 drugs was also evaluated using an isobolographic analysis. RESULTS: Intrathecal GR89696 and IL-10 significantly increased the paw withdrawal threshold of the cancer cell-implanted rat, in a dose-dependent manner, with 50% effective dose values (95% confidence interval) of 50.78 MUg (31.80-80.07MUg) and 0.83 MUg (0.59-1.15 MUg), respectively. Isobolographic analysis revealed a synergistic interaction between intrathecal GR89696 and IL 10. CONCLUSIONS: Intrathecally administered GR89696 and IL-10 attenuated bone cancer-induced pain, and the 2 drugs interacted synergistically in the spinal cord. These results raise the intriguing possibility of kappa(2)-opioid receptor agonists and IL-10 as a new therapeutic approach for the management of bone cancer-associated pain. PMID- 21788321 TI - Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. AB - BACKGROUND: The involvement of the L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in antinociception has been implicated as a molecular mechanism of antinociception produced by several antinociceptive agents, including MU-, kappa-, or delta-opioid receptor agonists, nonsteroidal analgesics, cholinergic agonist, and alpha2C adrenoceptor agonist. In this study, we investigated whether ketamine, a dissociative anesthetic N-methyl-D-aspartate receptor antagonist, was also capable of activating the L-arginine/NO/cGMP pathway and eliciting peripheral antinociception. METHODS: The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were locally administered into the right hindpaw of male Wistar rats. RESULTS: Ketamine (10, 20, 40, 80 MUg/paw) elicited a local antinociceptive effect that was antagonized by the nonselective NOS inhibitor L NOARG (12, 18, and 24 MUg/paw) and by the selective neuronal NOS inhibitor L-NPA (12, 18, and 24 MUg/paw). In another experiment, we used the inhibitors L-NIO and L-NIL (24 MUg/paw) to selectively inhibit endothelial and inducible NOS, respectively. These 2 drugs were ineffective at blocking the effects of the peripheral ketamine injection. In addition, the level of nitrite in the homogenized paw indicated that exogenous ketamine is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ (25, 50, and 100 MUg/paw) blocked the action of ketamine, and the cGMP-phosphodiesterase inhibitor zaprinast (50 MUg/paw) enhanced the antinociceptive effects of low-dose ketamine (10 MUg/paw). CONCLUSIONS: Our results suggest that ketamine stimulates the L arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects. PMID- 21788323 TI - Abstracts of the 2011 Annual Meeting of the Society for Technology in Anesthesia (STA). January 12-15, 2011. Las Vegas, Nevada, USA. PMID- 21788322 TI - The interaction between antidepressant drugs and the pain-relieving effect of spinal cord stimulation in a rat model of neuropathy. AB - BACKGROUND: Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. On the basis of our previous studies on the mode of action of SCS, intrathecal administration of subeffective doses of certain drugs has been shown to enhance the pain-relieving effect in patients with SCS. Antidepressants have a well-established beneficial effect in neuropathic pain. We performed the present study to examine potential synergistic or antagonistic effects on SCS of antidepressants: amitriptyline (tricyclic antidepressant), fluoxetine (selective serotonin reuptake inhibitor), and milnacipran (selective serotonin/noradrenaline reuptake inhibitor). METHODS: In rats, the effect of SCS on mechanical hypersensitivity after peripheral nerve injury was assessed in awake, freely moving animals. Antidepressants were administered intrathecally. RESULTS: When combining SCS with subeffective doses of amitriptyline or milnacipran, the suppressive effect of SCS on the mechanical hypersensitivity was enhanced in comparison with that obtained with SCS alone. There was no detectable effect of fluoxetine. No signs of an antagonistic effect of the drugs on the SCS effect were observed. CONCLUSIONS: These findings suggest a possible clinical application with a combination of SCS and a tricyclic antidepressant or selective serotonin/noradrenaline reuptake inhibitor drug in cases in which SCS per se has proven inefficient. PMID- 21788324 TI - Phenylephrine and tangible bias. PMID- 21788325 TI - Mind the gap. PMID- 21788327 TI - Describing oneself: what anesthesiology residency applicants write in their personal statements. PMID- 21788328 TI - Patent ductus arteriosus revisited: myths and misconceptions. PMID- 21788329 TI - Proscribing the use of albumin in the head-injured patient is not warranted. PMID- 21788330 TI - The relationship between ropivacaine infusions and postoperative falls after joint replacement: where is the evidence? PMID- 21788331 TI - How old is your "bougie"? PMID- 21788332 TI - The hidden cost of variability. PMID- 21788333 TI - Challenges in interpreting joined allelic combinations of OPRM1 and COMT genes. PMID- 21788334 TI - PAPD5, a noncanonical poly(A) polymerase with an unusual RNA-binding motif. AB - PAPD5 is one of the seven members of the family of noncanonical poly(A) polymerases in human cells. PAPD5 was shown to polyadenylate aberrant pre ribosomal RNAs in vivo, similar to degradation-mediating polyadenylation by the noncanonical poly(A) polymerase Trf4p in yeast. PAPD5 has been reported to be also involved in the uridylation-dependent degradation of histone mRNAs. To test whether PAPD5 indeed catalyzes adenylation as well as uridylation of RNA substrates, we analyzed the in vitro properties of recombinant PAPD5 expressed in mammalian cells as well as in bacteria. Our results show that PAPD5 catalyzes the polyadenylation of different types of RNA substrates in vitro. Interestingly, PAPD5 is active without a protein cofactor, whereas its yeast homolog Trf4p is the catalytic subunit of a bipartite poly(A) polymerase in which a separate RNA binding subunit is needed for activity. In contrast to the yeast protein, the C terminus of PAPD5 contains a stretch of basic amino acids that is involved in binding the RNA substrate. PMID- 21788336 TI - Coupled dynamics of bistable distant motion displays. AB - This study explores the extent to which a display changing periodically in perceptual interpretation through smooth periodic physical changes-an inducer-is able to elicit perceptual switches in an intrinsically bistable distant probe display. Four experiments are designed to examine the coupling strength and bistable dynamics with displays of varying degree of ambiguity, similarity, and symmetry-in motion characteristics-as a function of their locations in visual space. The results show that periodic fluctuations of a remote inducer influence a bistable probe and regulate its dynamics through coupling. Coupling strength mainly depends on the relative locations of the probe display and the contextual inducer in the visual field, with stronger coupling when both displays are symmetrical around the vertical meridian and weaker coupling otherwise. Smaller effects of common fate and symmetry are also found. Altogether, the results suggest that long-range interhemispheric connections, presumably involving the corpus callosum, are able to synchronize perceptual transitions across the vertical meridian. If true, bistable dynamics may provide a behavioral method to probe interhemispheric connectivity in behaving human. Consequences of these findings for studies using stimuli symmetrical around the vertical meridian are evaluated. PMID- 21788335 TI - Defining the Mer1 and Nam8 meiotic splicing regulons by cDNA rescue. AB - Meiosis-specific pre-mRNA splicing in budding yeast embraces multiple pre-mRNA targets grouped into regulons defined by their genetic requirements for vegetatively optional splicing factors (e.g., splicing enhancer Mer1 and the U1 snRNP subunit Nam8) or snRNA modifications (trimethylguanosine caps). Here, we genetically demarcate a complete meiotic splicing regulon by the criterion of cDNA bypass of the requirement for the governing splicing regulators to execute sporulation. We thereby show that the Mer1 and Nam8 regulons embrace four essential pre-mRNAs: MER2, MER3, SPO22, and AMA1. Whereas Nam8 also regulates PCH2 splicing, PCH2 cDNA is not needed for sporulation by nam8Delta diploids. Our results show that there are no essential intron-containing RNAs missing from the known roster of Mer1 and Nam8 targets. Nam8 is composed of three RRM domains, flanked by N-terminal leader and C-terminal tail segments. We find that the RRM2 and RRM3 domains, and their putative RNA-binding sites, are essential for yeast sporulation, whereas the leader, tail, and RRM1 modules are not. PMID- 21788337 TI - Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. AB - Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TM(Pro) mice expressing a mutant form of TM with reduced thrombin affinity and TM(LeD) mice lacking the N-terminal lectin-like domain. Studies of TM(Pro) mice revealed that TM is a powerful determinant of hematogenous metastasis. TM(Pro) mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TM(Pro) mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination. PMID- 21788338 TI - The mismatch repair pathway functions normally at a non-AID target in germinal center B cells. AB - Deficiency in Msh2, a component of the mismatch repair (MMR) system, leads to an approximately 10-fold increase in the mutation frequency in most tissues. By contrast, Msh2 deficiency in germinal center (GC) B cells decreases the mutation frequency at the IgH V region as a dU:dG mismatch produced by AID initiates modifications by MMR, resulting in mutations at nearby A:T base pairs. This raises the possibility that GC B cells express a factor that converts MMR into a globally mutagenic pathway. To test this notion, we investigated whether MMR corrects mutations in GC B cells at a gene that is not mutated by AID. Strikingly, we found that GC B cells accumulate 5 times more mutations at a reporter gene than during the development of the mouse. Notably, the mutation frequency at this reporter gene was approximately 10 times greater in Msh2(-/-) compared with wild-type GC B cells cells. In contrast to the V region, the increased level of mutations at A:T base pairs in GC B cells was not caused by MMR. These results show that in GC B cells, (1) MMR functions normally at an AID insensitive gene and (2) the frequency of background mutagenesis is greater in GC B cells than in their precursor follicular B cells. PMID- 21788339 TI - T cell-independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist. AB - Memory B cells are involved in long-term maintenance of antibody-dependent immunologic disorders. Therefore, it is essential to understand how the restimulation of FVIII-specific memory B cells in hemophilia A with FVIII inhibitors is regulated. We asked whether concurrent activation of the innate immune system by an agonist for toll-like receptor (TLR) 7 is able to facilitate the differentiation of FVIII-specific memory B cells in the absence of T-cell help. TLR7 recognizes single-stranded RNA as contained in RNA viruses such as influenza, Sendai, and Coxsackie B viruses. Our results indicate that highly purified murine memory B cells do not differentiate into FVIII-specific antibody secreting cells in the presence of FVIII and the TLR7 agonist when cultured in the absence of CD4(+) T cells. However, CD11c(+) dendritic cells facilitate the T cell-independent differentiation of FVIII-specific memory B cells but only in the presence of FVIII and the TLR7 agonist. In contrast to T cell-dependent restimulation, the antibody response after T cell-independent restimulation of FVIII-specific memory B cells is skewed toward IgG2a, an antibody subclass that is efficient in activating the complement system and in inducing Fc-receptor mediated effector functions, both are required for effective immune responses against pathogens. PMID- 21788340 TI - Hypoxia-inducible factor-1 drives annexin A2 system-mediated perivascular fibrin clearance in oxygen-induced retinopathy in mice. AB - Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2) gene through the direct action of the hypoxia-inducible factor-1 complex. We show, in addition, that A2 stabilizes its binding partner, p11, and promotes OIR related angiogenesis by enabling clearance of perivascular fibrin. Adenoviral mediated restoration of A2 expression restores neovascularization in the oxygen primed Anxa2(-/-) retina and reinstates plasmin generation and directed migration in cultured Anxa2(-/-) endothelial cells. Systemic depletion of fibrin repairs the neovascular response to high oxygen treatment in the Anxa2(-/-) retina, whereas inhibition of plasminogen activation dampens angiogenesis under the same conditions. These findings show that the A2 system enables retinal neoangiogenesis in OIR by enhancing perivascular activation of plasmin and remodeling of fibrin. These data suggest new potential approaches to retinal angiogenic disorders on the basis of modulation of perivascular fibrinolysis. PMID- 21788342 TI - The adoption of embryos in Malta: acting in the interest and welfare of a child in embryonic form? PMID- 21788341 TI - Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome. AB - Reduced gene dosage of ribosomal protein subunits has been implicated in 5q- myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q- syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome. PMID- 21788343 TI - Cilengitide induces autophagy-mediated cell death in glioma cells. AB - We studied the effect of the integrin inhibitor cilengitide in glioma cells. Cilengitide induced cell detachment and decreased cell viability, and induction of autophagy followed by cell apoptosis. In addition, cilengitide decreased the cell renewal of glioma stem-like cells (GSCs). Inhibition of autophagy decreased the cytotoxic effect of cilengitide. Pretreatment of glioma cells and GSCs with cilengitide prior to gamma-irradiation resulted in a larger increase in autophagy and a more significant decrease in cell survival. We found that cilengitide induced autophagy collectively in glioma cells, xenografts, and GSCs, which contributed to its cytotoxic effects and sensitized these cells to gamma radiation. PMID- 21788344 TI - RNA interference targeting survivin exerts antitumoral effects in vitro and in established glioma xenografts in vivo. AB - Malignant glioma represents the most common primary adult brain tumor in Western industrialized countries. Despite aggressive treatment modalities, the median survival duration for patients with glioblastoma multiforme (GBM), the highest grade malignant glioma, has not improved significantly over past decades. One promising approach to deal with GBM is the inactivation of proteins essential for survival or progression of glioma cells by means of RNA interference (RNAi) techniques. A likely candidate for an RNAi therapy of gliomas is the inhibitor of apoptosis protein survivin. Survivin is involved in 2 main cellular processes cell division and inhibition of apoptosis. We show here that stable RNAi of survivin induced polyploidy, apoptosis, and impaired proliferation of human U343 MG, U373-MG, H4, and U87-MG cells and of primary glioblastoma cells. Proteome profiler arrays using U373-MG cells identified a novel set of differentially expressed genes upon RNAi-mediated survivin knockdown. In particular, the death receptor TRAIL R2/DR5 was strongly upregulated in survivin-depleted glioma cells, inducing an enhanced cytotoxic response of allogeneic human NK cells. Moreover, an experimental in vivo therapy using polyethylenimine (PEI)/siRNA complexes for survivin knockdown efficiently blocked tumor growth of established subcutaneous U373-MG tumors and enhanced survival of NMRI(nu/nu) mice orthopically transplanted with U87-MG cells. We conclude that survivin is functionally relevant in gliomas and that PEI-mediated exogenous delivery of siRNA targeting survivin is a promising strategy for glioblastoma therapy. PMID- 21788345 TI - Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. AB - The differences in function, location, and migratory pattern of conventional dendritic cells (cDC) and plasmacytoid DCs (pDC) not only point to specialized roles in immune responses but also signify additive and interdependent relationships required to clear pathogens. We studied the in vivo requirement of cross-talk between cDCs and pDCs for eliciting antitumor immunity against in situ released tumor antigens in the absence or presence of the Toll-like receptor (TLR) 9 agonist CpG. Previous data indicated that CpG boosted tumor-specific T cell responses after in vivo tumor destruction and increased survival after tumor rechallenges. The present study shows that cDCs are indispensable for cross presentation of ablation-released tumor antigens and for the induction of long term antitumor immunity. Depletion of pDCs or applying this model in type I IFN receptor-deficient mice abrogated CpG-mediated responses. CD8alpha(+) cDCs and the recently identified merocytic cDCs were dependent on pDCs for CpG-induced upregulation of CD80. Moreover, DC transfer studies revealed that merocytic cDCs and CD8alpha(+) cDCs were most susceptible to pDC help and subsequently promoted tumor-free survival in a therapeutic setting. By transferring wild-type pDCs into TLR9-deficient mice, we finally showed that TLR9 expression in pDCs is sufficient to benefit from CpG as an adjuvant. These studies indicate that the efficacy of CpG in cancer immunotherapy is dependent on cross-talk between pDCs and specific subsets of cDCs. PMID- 21788347 TI - Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer. AB - Histone H2A.Z (H2A.Z) is an evolutionarily conserved H2A variant implicated in the regulation of gene expression; however, its role in transcriptional deregulation in cancer remains poorly understood. Using genome-wide studies, we investigated the role of promoter-associated H2A.Z and acetylated H2A.Z (acH2A.Z) in gene deregulation and its relationship with DNA methylation and H3K27me3 in prostate cancer. Our results reconcile the conflicting reports of positive and negative roles for histone H2A.Z and gene expression states. We find that H2A.Z is enriched in a bimodal distribution at nucleosomes, surrounding the transcription start sites (TSSs) of both active and poised gene promoters. In addition, H2A.Z spreads across the entire promoter of inactive genes in a deacetylated state. In contrast, acH2A.Z is only localized at the TSSs of active genes. Gene deregulation in cancer is also associated with a reorganization of acH2A.Z and H2A.Z nucleosome occupancy across the promoter region and TSS of genes. Notably, in cancer cells we find that a gain of acH2A.Z at the TSS occurs with an overall decrease of H2A.Z levels, in concert with oncogene activation. Furthermore, deacetylation of H2A.Z at TSSs is increased with silencing of tumor suppressor genes. We also demonstrate that acH2A.Z anti-correlates with promoter H3K27me3 and DNA methylation. We show for the first time, that acetylation of H2A.Z is a key modification associated with gene activity in normal cells and epigenetic gene deregulation in tumorigenesis. PMID- 21788346 TI - Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. AB - One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment. PMID- 21788348 TI - Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor-alpha. AB - Spinal application of TNFalpha induces both allodynia and hyperalgesia, and at least part of the pronociceptive effects of TNFalpha have been suggested as due to the impaired function of spinal inhibitory neurons (disinhibition). The present study explores the effects of TNFalpha on the signalling phenotype of spinal GABAergic neurons identified in transgenic mice expressing green fluorescent protein at the glutamic acid decarboxylase 67 (GAD67) promoter. Acute application of TNFalpha directly inhibits the excitability of a subset of GAD67(+) spinal neurons. TNFalpha-induced inhibition was dependent on the activation of p38 mitogen-activated protein kinase (MAPK) within these GAD67(+) neurons. TNFalpha receptor 1 (TNFR1) but not receptor 2 (TNFR2) was identified on spinal GAD67(+) neurons, suggesting that TNFalpha signals through TNFR1. Voltage clamp recordings of GAD67(+) neurons indicated that the inhibitory effect of TNFalpha was through suppression of the hyperpolarization-activated cation current (I(h)). This study defines a novel mechanism of spinal disinhibition mediated by a TNFalpha-TNFR1-p38 pathway within GABAergic inhibitory interneurons. PMID- 21788349 TI - Recovery of proprioceptive feedback from nerve crush. AB - Sensorimotor functions are restored by peripheral nerve regeneration with greater success following injuries that crush rather than sever the nerve. Better recovery following nerve crush is commonly attributed to superior reconnection of regenerating axons with their original peripheral targets. The present study was designed to estimate the fraction of stretch reflex recovery attributable to functional recovery of regenerated spindle afferents. Recovery of the spindle afferent population was estimated from excitatory postsynaptic potentials evoked by muscle stretch (strEPSPs) in motoneurons. These events were measured in cats that were anaesthetized, so that recovery of spindle afferent function, including both muscle stretch encoding and monosynaptic transmission, could be separated from other factors that act centrally to influence muscle stretch-evoked excitation of motoneurons. Recovery of strEPSPs to 70% of normal specified the extent of overall functional recovery by the population spindle afferents that regained responsiveness to muscle stretch. In separate studies, we examined recovery of the stretch reflex in decerebrate cats, and found that it recovered to supranormal levels after nerve crush. The substantial disparity in recovery between strEPSPs and stretch reflex led us to conclude that factors in addition to recovery of spindle afferents make a large contribution in restoring the stretch reflex following nerve crush. PMID- 21788350 TI - Computational analyses of intravascular tracer washout reveal altered capillary level flow distributions in obese Zucker rats. AB - Intravascular tracer washout data obtained from gastrocnemius muscle of lean Zucker rats (LZRs) and obese Zucker rats (OZRs) were analysed to investigate flow distributions in the OZR, a model of non-atherosclerotic peripheral vascular disease. A computer model used to simulate the network washout curves was developed based on experimentally observed relative dispersions in large vessels and asymmetrical flow distributions at bifurcations in dichotomous microvascular networks. The model results of simulations were compared to experimental washout data of (125)I-labelled albumin, an intravascular tracer, to uncover flow distributions on the arterial-network and capillary levels. The lean and obese Zucker rats demonstrated distinct capillary-level flow distributions, with higher dispersion and significantly more low-flow capillaries in the OZRs than in the LZRs. Targeted pharmacological treatments against identified sites of vascular dysfunction in OZRs (adrenoreceptor blockade with phentolamine, antioxidant treatment with Tempol and thromboxane receptor antagonism with SQ-29548) were shown to improve the capillary-level flow distributions in treated OZRs toward distributions determined in control LZRs. Combination therapy with multiple pharmacological interventions resulted in a greater degree of recovery. This study demonstrates that the enhanced perfusion heterogeneity at arteriole bifurcations is a potential mechanism underlying perfusion-demand mismatching in OZRs, and suggests that amelioration of this dysfunction must involve a multi faceted interventional approach. PMID- 21788351 TI - (-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. AB - The flavanol (-)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (-)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water-exercise (W-Ex), (3) (-) epicatechin ((-)-Epi), and (4) (-)-epicatechin-exercise ((-)-Epi-Ex). Animals received 1 mg kg(-1) of (-)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (~50%) and enhanced in situ muscle fatigue resistance (~30%) were observed with (-)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (-) epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (-)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (-)-epicatechin alone. These findings indicate that (-)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (-)-epicatechin and its potential clinical application as an exercise mimetic. PMID- 21788353 TI - Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate resistant prostate cancer progressing after first-line docetaxel: CUOG trial P 06c. AB - PURPOSE: Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy. PATIENTS AND METHODS: Men were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC). RESULTS: Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13 (23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90% or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients, respectively. Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients, respectively. Low serum CLU levels during treatment showed superior survival for patients based on modeling with proportional hazard regression with a time-dependent covariate and different landmarks. CONCLUSIONS: Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of custirsen with taxane therapy is ongoing. PMID- 21788352 TI - Purinergic modulation of preBotzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine. AB - ATP signalling in the CNS is mediated by a three-part system comprising the actions of ATP (and ADP) at P2 receptors (P2Rs), adenosine (ADO) at P1 receptors (P1Rs), and ectonucleotidases that degrade ATP into ADO. ATP excites preBotzinger complex (preBotC) inspiratory rhythm-generating networks where its release attenuates the hypoxic depression of breathing. Its metabolite, ADO, inhibits breathing through unknown mechanisms that may involve the preBotC. Our objective is to understand the dynamics of this signalling system and its influence on preBotC networks. We show that the preBotC of mouse and rat is sensitive to P2Y(1) purinoceptor (P2Y(1)R) activation, responding with a >2-fold increase in frequency. Remarkably, the mouse preBotC is insensitive to ATP. Only after block of A(1) ADORs is the ATP-evoked, P2Y(1)R-mediated frequency increase observed. This demonstrates that ATP is rapidly degraded to ADO, which activates inhibitory A(1)Rs, counteracting the P2Y(1)R-mediated excitation. ADO sensitivity of mouse preBotC was confirmed by a frequency decrease that was absent in rat. Differential ectonucleotidase activities are likely to contribute to the negligible ATP sensitivity of mouse preBotC. Real-time PCR analysis of ectonucleotidase isoforms in preBotC punches revealed TNAP (degrades ATP to ADO) or ENTPDase2 (favours production of excitatory ADP) as the primary constituent in mouse and rat, respectively. These data further establish the sensitivity of this vital network to P2Y(1)R-mediated excitation, emphasizing that individual components of the three-part signalling system dramatically alter network responses to ATP. Data also suggest therapeutic potential may derive from methods that alter the ATP-ADO balance to favour the excitatory actions of ATP. PMID- 21788354 TI - Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers. AB - PURPOSE: Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers. EXPERIMENTAL DESIGN: A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software. RESULTS: Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P = 0.0005), ACOT11 (P = 0.0001), PCDHGA12 (P = 0.0001), CA3 (P = 0.0002), and PTGDR (P = 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity. CONCLUSIONS: We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer. PMID- 21788355 TI - Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. AB - PURPOSE: Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. EXPERIMENTAL DESIGN: In vitro dose-response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. RESULTS: In vitro, topotecan caused a dose dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug-drug interaction. CONCLUSION: Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors. PMID- 21788356 TI - Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. AB - PURPOSE: In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high affinity FcgammaRIIIA. EXPERIMENTAL DESIGN: The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the FcgammaRIIIA polymorphism (CD16). RESULTS: Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (FcgammaR) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, FcgammaRs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers. CONCLUSION: These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies. PMID- 21788357 TI - Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. AB - PURPOSE: Bevacizumab targets VEGF-A and has proved beneficial in glioma patients, improving clinical symptoms by the reduction of tumor edema. However, it remains controversial whether or not bevacizumab exerts antitumor effects in addition to (and potentially independent of) its effects on tumor vessels, and it is unknown what doses are needed to achieve this. EXPERIMENTAL DESIGN: We established a novel orthotopic glioma mouse model that allowed us to simultaneously study the kinetics of the morphologic and functional vascular changes, tumor growth, and the viability of individual tumor cells during the course of anti-VEGF therapy in the same microscopic tumor region in real-time. Three doses of bevacizumab were compared, a subclinical dose and two clinical doses (medium and high). RESULTS: Low (subclinical) doses of bevacizumab led to a significant reduction of the total vascular volume without affecting tumor cell viability or the overall tumor growth rates. Medium and high doses triggered a similar degree of vascular regression but significantly decreased tumor growth and prolonged survival. Remaining vessels revealed morphologic features of vascular normalization, reduced permeability, and an increase in blood flow velocity; the latter was dose dependent. We observed an uncoupling of the antitumoral and the antivascular effects of bevacizumab with the high dose only, which showed the potential to cause microregional glioma cell regression. In some tumor regions, pronounced glioma cell regression occurred even without vascular regression. In vitro, there was no effect of bevacizumab on glioma cell proliferation. CONCLUSIONS: Regression of glioma cells can occur independently from vascular regression, suggesting that high doses of bevacizumab have indirect anticancer cell properties in vivo. PMID- 21788358 TI - Echocardiographic indices do not reliably track changes in left-sided filling pressure in healthy subjects or patients with heart failure with preserved ejection fraction. AB - BACKGROUND: In select patient populations, Doppler echocardiographic indices may be used to estimate left-sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important because it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure. METHODS AND RESULTS: Forty-seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects, and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e' and E/Vp) were measured at two baselines and during 4 preload altering maneuvers: lower body negative pressure 15 mm Hg; lower body negative pressure -30 mm Hg; rapid saline infusion of 10 to 15 mL/kg; and rapid saline infusion of 20 to 30 mL/kg. A random coefficient mixed model regression of PCWP versus E/e' and PCWP versus E/Vp was performed for (1) a composite of all data points and (2) a composite of all data points within each of the 3 groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mm Hg. For E/e', the composite random effects mixed model regression was PCWP=0.58*E/e'+7.02 (P<0.001), confirming the weak but significant relationship between these 2 variables. Individual subject linear regression slopes (range, -6.76 to 11.03) and r(2) (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP=1.95*E/Vp+7.48 (P=0.005); once again, individual subject linear regression slopes (range, -16.42 to 25.39) and r(2) (range, 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. CONCLUSIONS: Within individual subjects the noninvasive indices E/e' and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF. PMID- 21788359 TI - Crystal structure of a beta-prism II lectin from Remusatia vivipara. AB - The crystal structure of a beta-prism II (BP2) fold lectin from Remusatia vivipara, a plant of traditional medicinal value, has been determined at a resolution of 2.4 A. This lectin (RVL, Remusatia vivipara lectin) is a dimer with each protomer having two distinct BP2 domains without a linker between them. It belongs to the "monocot mannose-binding" lectin family, which consists of proteins of high sequence and structural similarity. Though the overall tertiary structure is similar to that of lectins from snowdrop bulbs and garlic, crucial differences in the mannose-binding regions and oligomerization were observed. Unlike most of the other structurally known proteins in this family, only one of the three carbohydrate recognition sites (CRSs) per BP2 domain is found to be conserved. RVL does not recognize simple mannose moieties. RVL binds to only N linked complex glycans like those present on the gp120 envelope glycoprotein of HIV and mannosylated blood proteins like fetuin, but not to simple mannose moieties. The molecular basis for these features and their possible functional implications to understand the different levels of carbohydrate affinities in this structural family have been investigated through structure analysis, modeling and binding studies. Apart from being the first structure of a lectin to be reported from the Araceae/Arum family, this protein also displays a novel mode of oligomerization among BP2 lectins. PMID- 21788360 TI - Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. AB - BACKGROUND: In premenopausal women with hormone receptor-positive breast cancer (BC), 5 years of tamoxifen is recommended. Little is known about reasons for interruption in this population. The aim was to estimate the incidence of tamoxifen interruption and its correlates among younger women. PATIENTS AND METHODS: Using a prospective cohort Elippse 40 of women with BC aged <= 40 diagnosed between 2005 and 2008, we studied 196 women. Tamoxifen interruption was defined as two or more consecutive months without dispensed prescription of tamoxifen, based on pharmacy refill database. Two periods were studied: between tamoxifen initiation and 16 months after BC diagnosis, and between 16 and 28 months. RESULTS: Among women treated with tamoxifen, 42% interrupted within the first 2 years of treatment. During the first period, treatment interruptions were associated with a lack of understandable information about endocrine treatment and insufficient social support. During the second period, another set of factors were associated with interruption: treatment side-effects, no longer fearing cancer relapse, lack of social support, no opportunity to ask questions at the time of diagnosis, and fewer treatment modalities. CONCLUSIONS: Improving information and patient-provider relationship might prevent interruption. Particular attention should be paid to women with little social support. PMID- 21788361 TI - Characterization of the phosphate starvation-induced glycerol-3-phosphate permease gene family in Arabidopsis. AB - Phosphate (Pi) deficiency is one of the leading causes of loss in crop productivity. Plants respond to Pi deficiency by increasing Pi acquisition and remobilization involving organic and inorganic Pi transporters. Here, we report the functional characterization of a putative organic Pi transporter, Glycerol-3 phosphate permease (G3Pp) family, comprising five members (AtG3Pp1 to -5) in Arabidopsis (Arabidopsis thaliana). AtG3Pp1 and AtG3Pp2 showed 24-and 3-fold induction, respectively, in the roots of Pi-deprived seedlings, whereas Pi deficiency-mediated induction of AtG3Pp3 and -4 was evident in both roots and shoots. Furthermore, promoter-beta-glucuronidase (GUS) fusion transgenics were generated for AtG3Pp2 to -5 for elucidation of their in planta role in Pi homeostasis. During Pi starvation, there was a strong expression of the reporter gene driven by AtG3Pp4 promoter in the roots, shoots, anthers, and siliques, whereas GUS expression was specific either to the roots (AtG3Pp3) or to stamens and siliques (AtG3Pp5) in other promoter-GUS fusion transgenics. Quantification of reporter gene activities further substantiated differential responses of AtG3Pp family members to Pi deprivation. A distinct pattern of reporter gene expression exhibited by AtG3Pp3 and AtG3Pp5 during early stages of germination also substantiated their potential roles during seedling ontogeny. Furthermore, an AtG3Pp4 knockdown mutant exhibited accentuated total lateral root lengths under +phosphorus and -phosphorus conditions compared with the wild type. Several Pi starvation-induced genes involved in root development and/or Pi homeostasis were up-regulated in the mutant. A 9-fold induction of AtG3Pp3 in the mutant provided some evidence for a lack of functional redundancy in the gene family. These results thus reflect differential roles of members of the G3Pp family in the maintenance of Pi homeostasis. PMID- 21788362 TI - Analysis of a range of catabolic mutants provides evidence that phytanoyl coenzyme A does not act as a substrate of the electron-transfer flavoprotein/electron-transfer flavoprotein:ubiquinone oxidoreductase complex in Arabidopsis during dark-induced senescence. AB - The process of dark-induced senescence in plants is not fully understood, however, the functional involvement of an electron-transfer flavoprotein/electron transfer flavoprotein:ubiquinone oxidoreductase (ETF/ETFQO), has been demonstrated. Recent studies have revealed that the enzymes isovaleryl-coenzyme A (CoA) dehydrogenase and 2-hydroxyglutarate dehydrogenase act as important electron donors to this complex. In addition both enzymes play a role in the breakdown of cellular carbon storage reserves with isovaleryl-CoA dehydrogenase being involved in degradation of the branched-chain amino acids, phytol, and lysine while 2-hydroxyglutarate dehydrogenase is exclusively involved in lysine degradation. Given that the chlorophyll breakdown intermediate phytanoyl-CoA accumulates dramatically both in knockout mutants of the ETF/ETFQO complex and of isovaleryl-CoA dehydrogenase following growth in extended dark periods we have investigated the direct importance of chlorophyll breakdown for the supply of carbon and electrons during this process. For this purpose we isolated three independent Arabidopsis (Arabidopsis thaliana) knockout mutants of phytanoyl-CoA 2-hydroxylase and grew them under the same extended darkness regime as previously used. Despite the fact that these mutants accumulated phytanoyl-CoA and also 2 hydroxyglutarate they exhibited no morphological changes in comparison to the other mutants previously characterized. These results are consistent with a single entry point of phytol breakdown into the ETF/ETFQO system and furthermore suggest that phytol is not primarily metabolized by this pathway. Furthermore analysis of isovaleryl-CoA dehydrogenase/2-hydroxyglutarate dehydrogenase double mutants generated here suggest that these two enzymes essentially account for the entire electron input via the ETF complex. PMID- 21788363 TI - Responses of legume versus nonlegume tropical tree seedlings to elevated CO2 concentration. AB - We investigated responses of growth, leaf gas exchange, carbon-isotope discrimination, and whole-plant water-use efficiency (W(P)) to elevated CO(2) concentration ([CO(2)]) in seedlings of five leguminous and five nonleguminous tropical tree species. Plants were grown at CO(2) partial pressures of 40 and 70 Pa. As a group, legumes did not differ from nonlegumes in growth response to elevated [CO(2)]. The mean ratio of final plant dry mass at elevated to ambient [CO(2)] (M(E)/M(A)) was 1.32 and 1.24 for legumes and nonlegumes, respectively. However, there was large variation in M(E)/M(A) among legume species (0.92-2.35), whereas nonlegumes varied much less (1.21-1.29). Variation among legume species in M(E)/M(A) was closely correlated with their capacity for nodule formation, as expressed by nodule mass ratio, the dry mass of nodules for a given plant dry mass. W(P) increased markedly in response to elevated [CO(2)] in all species. The ratio of intercellular to ambient CO(2) partial pressures during photosynthesis remained approximately constant at ambient and elevated [CO(2)], as did carbon isotope discrimination, suggesting that W(P) should increase proportionally for a given increase in atmospheric [CO(2)]. These results suggest that tree legumes with a strong capacity for nodule formation could have a competitive advantage in tropical forests as atmospheric [CO(2)] rises and that the water-use efficiency of tropical tree species will increase under elevated [CO(2)]. PMID- 21788364 TI - Purification and biochemical characterization of a novel ecto-apyrase, MP67, from Mimosa pudica. AB - We have previously reported the presence of an apyrase in Mimosa pudica. However, only limited information is available for this enzyme. Thus, in this study, the apyrase was purified to homogeneity. The purified enzyme had a molecular mass of around 67 kD and was able to hydrolyze both nucleotide triphosphate and nucleotide diphosphate as substrates. The ratio of ATP to ADP hydrolysis velocity of the purified protein was 0.01 in the presence of calcium ion, showing extremely high substrate specificity toward ADP. Thus, we designated this novel apyrase as MP67. A cDNA clone of MP67 was obtained using primers designed from the amino acid sequence of trypsin-digested fragments of the protein. In addition, rapid amplification of cDNA ends-polymerase chain reaction was performed to clone a conventional apyrase (MpAPY2). Comparison of the deduced amino acid sequences showed that MP67 is similar to ecto-apyrases; however, it was distinct from conventional apyrase based on phylogenetic classification. MP67 and MpAPY2 were expressed in Escherichia coli, and the recombinant proteins were purified. The recombinant MP67 showed high substrate specificity toward ADP rather than ATP. A polyclonal antibody raised against the recombinant MP67 was used to examine the tissue distribution and localization of native MP67 in the plant. The results showed that MP67 was ubiquitously distributed in various tissues, most abundantly in leaves, and was localized to plasma membranes. Thus, MP67 is a novel ecto-apyrase with extremely high substrate specificity for ADP. PMID- 21788365 TI - Rudiger Klein: reading the guideposts for axon guidance. Interview by Caitlin Sedwick. PMID- 21788366 TI - Evolution: Tracing the origins of centrioles, cilia, and flagella. AB - Centrioles/basal bodies (CBBs) are microtubule-based cylindrical organelles that nucleate the formation of centrosomes, cilia, and flagella. CBBs, cilia, and flagella are ancestral structures; they are present in all major eukaryotic groups. Despite the conservation of their core structure, there is variability in their architecture, function, and biogenesis. Recent genomic and functional studies have provided insight into the evolution of the structure and function of these organelles. PMID- 21788367 TI - Septin GTPases spatially guide microtubule organization and plus end dynamics in polarizing epithelia. AB - Establishment of epithelial polarity requires the reorganization of the microtubule (MT) cytoskeleton from a radial array into a network positioned along the apicobasal axis of the cell. Little is known about the mechanisms that spatially guide the remodeling of MTs during epithelial polarization. Septins are filamentous guanine triphosphatases (GTPases) that associate with MTs, but the function of septins in MT organization and dynamics is poorly understood. In this paper, we show that in polarizing epithelia, septins guide the directionality of MT plus end movement by suppressing MT catastrophe. By enabling persistent MT growth, two spatially distinct populations of septins, perinuclear and peripheral filaments, steer the growth and capture of MT plus ends. This navigation mechanism is essential for the maintenance of perinuclear MT bundles and for the orientation of peripheral MTs as well as for the apicobasal positioning of MTs. Our results suggest that septins provide the directional guidance cues necessary for polarizing the epithelial MT network. PMID- 21788368 TI - Repeated cleavage failure does not establish centrosome amplification in untransformed human cells. AB - We tested whether cleavage failure as a transient event establishes an incidence of centrosome amplification in cell populations. Five rounds of ~30% cytochalasin induced cleavage failure in untransformed human cell cultures did not establish centrosome amplification in the short or long terms. The progeny of binucleate cells progressively dropped out of the cell cycle and expressed p53/p21, and none divided a fourth time. We also tested whether cleavage failure established centrosome amplification in transformed cell populations. Tetraploid HCT116 p53( /-) cells eventually all failed cleavage repeatedly and ceased proliferating. HeLa cells all died or arrested within four cell cycles. Chinese hamster ovary cells proliferated after cleavage failure, but five rounds of induced cleavage failure produced a modest increase in the incidence of centrosome amplification in the short term, which did not rise with more cycles of cleavage failure. This incidence dropped to close to control values in the long term despite a 2-6% rate of spontaneous cleavage failure in the progeny of tetraploid cells. PMID- 21788369 TI - High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. AB - Phosphatidylserine (PS) plays a central role in cell signaling and in the biosynthesis of other lipids. To date, however, the subcellular distribution and transmembrane topology of this crucial phospholipid remain ill-defined. We transfected cells with a GFP-tagged C2 domain of lactadherin to detect by light and electron microscopy PS exposed on the cytosolic leaflet of the plasmalemma and organellar membranes. Cytoplasmically exposed PS was found to be clustered on the plasma membrane, and to be associated with caveolae, the trans-Golgi network, and endocytic organelles including intraluminal vesicles of multivesicular endosomes. This labeling pattern was compared with the total cellular distribution of PS as visualized using a novel on-section technique. These complementary methods revealed PS in the interior of the ER, Golgi complex, and mitochondria. These results indicate that PS in the lumenal monolayer of the ER and Golgi complex becomes exposed cytosolically at the trans-Golgi network. Transmembrane flipping of PS may contribute to the exit of cargo from the Golgi complex. PMID- 21788370 TI - A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization. AB - A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues. PMID- 21788371 TI - Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons. AB - Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid-mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ~40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca(2+) influx or Ca(2+)/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca(2+)/CaM-dependent signaling pathway. PMID- 21788372 TI - STIM1L is a new actin-binding splice variant involved in fast repetitive Ca2+ release. AB - Cytosolic Ca(2+) signals encoded by repetitive Ca(2+) releases rely on two processes to refill Ca(2+) stores: Ca(2+) reuptake from the cytosol and activation of a Ca(2+) influx via store-operated Ca(2+) entry (SOCE). However, SOCE activation is a slow process. It is delayed by >30 s after store depletion because stromal interaction molecule 1 (STIM1), the Ca(2+) sensor of the intracellular stores, must form clusters and migrate to the membrane before being able to open Orai1, the plasma membrane Ca(2+) channel. In this paper, we identify a new protein, STIM1L, that colocalizes with Orai1 Ca(2+) channels and interacts with actin to form permanent clusters. This property allowed the immediate activation of SOCE, a characteristic required for generating repetitive Ca(2+) signals with frequencies within seconds such as those frequently observed in excitable cells. STIM1L was expressed in several mammalian tissues, suggesting that many cell types rely on this Ca(2+) sensor for their Ca(2+) homeostasis and intracellular signaling. PMID- 21788373 TI - The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population. AB - BACKGROUND: Genome-wide association studies identified the FTO (fat mass and obesity gene) gene as an important determinant of body weight. More recently, the FTO gene was reported to be associated with other outcomes, including major risk factors for chronic kidney disease (CKD). We investigated the role of this gene in the risk of end-stage renal disease (ESRD) caused by CKD. METHODS: We conducted two large population-based case-control studies of ESRD. Study 1 compared 984 haemodialysed patients with ESRD with 2501 participants in the Czech post-MONICA study; Study 2 compared 1188 patients included in a kidney transplantation programme for ESRD with 6681 participants in the Czech HAPIEE study. The frequencies of the FTO rs17817449 single nucleotide polymorphism genotype were compared between cases and controls. RESULTS: The FTO rs17817449 genotype was significantly associated with CKD in both studies (P-values 0.00004 and 0.006, respectively). In the pooled data, the odds ratios of CKD for GG and GT, versus TT genotype, were 1.37 (95% confidence interval 1.20-1.56) and 1.17 (1.05-1.31), respectively (P for trend <0.0001). Among haemodialysed and kidney transplant patients, the onset of ESRD in GG homozygotes was 3.3 (P = 0.012) and 2.5 (P = 0.032) years, respectively, earlier than in TT homozygotes. CONCLUSIONS: These two large independent case-control studies in the general population found robust associations between the FTO rs17817449 polymorphism and the ESRD. The results suggest that the morbidities associated with the FTO gene include CKD. PMID- 21788374 TI - Variation in formulary adherence in general practice over time (2003-2007). AB - OBJECTIVE: To study trends and variation in adherence to the main national formulary for the 20 most prevalent health problems in Dutch general practice over a 5-year period (2003-07). METHODS: Routine electronic medical records from a pool of 115 representative general practices were linked to the main national formulary. Analyses included over 2 million prescriptions for 246 391 patients. The outcome variable was whether or not the prescribed medication was congruent with recommendations in the national formulary. Trends and variation were analysed using three-level multilevel logistic regression analyses (general practice, patient, and prescription). RESULTS: The percentage of formulary adherent prescriptions for the 20 most prevalent health problems was 73-76% between 2003 and 2007. The percentage varied considerably between guidelines. Lowest adherence rates were found for acute bronchitis and acute upper respiratory infection. Interpractice variation was constant over time. CONCLUSIONS: General practice information networks are useful for monitoring general patterns of formulary on a year-to-year basis. Formulary adherence is stable over time but varies across diagnoses, patients and general practices. In the past decade, efforts have been made to increase the level of formulary adherent prescribing. These general efforts managed to stabilize (variation in) adherence in a field where many other initiatives (e.g. by pharmaceutical companies) are undertaken to influence prescribing behaviour. PMID- 21788375 TI - Cell division and cell elongation in the coleoptile of rice alcohol dehydrogenase 1-deficient mutant are reduced under complete submergence. AB - BACKGROUND AND AIMS: When rice seeds germinate under complete submergence, only the coleoptile elongates efficiently. It has been reported previously that coleoptile elongation is reduced in the rice alcohol dehydrogenase 1 (ADH1) deficient mutant, reduced adh activity (rad). The aim of this study was to elucidate how expressions of genes responsible for coleoptile elongation are affected by the ADH1 deficiency in the rad mutant under submergence. METHODS: To identify genes whose expressions are changed in the rad coleoptile at an early stage in germination (i.e. 1 d after imbibition), coleoptiles of the rad mutant and its wild type (WT) were isolated by laser microdissection, and their mRNA levels were examined with a microarray. KEY RESULTS: The microarray analysis identified 431 genes whose transcript levels were different between rad and WT. Interestingly, among the down-regulated genes in the rad coleoptile, 17.5 % were cell division-related genes and 5.1 % were cell elongation-related genes. It was found that cell division started at 1 d after imbibition and then gradually ceased, whereas in the WT coleoptile cell elongation started between 1 d and 2 d after imbibition and then continued. However, neither cell division nor cell elongation actively occurred in the rad coleoptile, in which the amounts of ATP were reduced. CONCLUSIONS: These results indicate that cell division, as well as cell elongation, occur during coleoptile elongation in rice under complete submergence, and that the reduced ATP levels caused by the ADH1 deficiency repress both of them, thereby impairing coleoptile elongation in the rad mutant under submerged conditions. PMID- 21788376 TI - Chloroplast to chromoplast transition in tomato fruit: spectral confocal microscopy analyses of carotenoids and chlorophylls in isolated plastids and time lapse recording on intact live tissue. AB - BACKGROUND AND AIMS: There are several studies suggesting that tomato (Solanum lycopersicum) chromoplasts arise from chloroplasts, but there is still no report showing the fluorescence of both chlorophylls and carotenoids in an intermediate plastid, and no video showing this transition phase. METHODS: Pigment fluorescence within individual plastids, isolated from tomato fruit using sucrose gradients, was observed at different ripening stages, and an in situ real-time recording of pigment fluorescence was performed on live tomato fruit slices. KEY RESULTS: At the mature green and red stages, homogenous fractions of chloroplasts and chromoplasts were obtained, respectively. At the breaker stage, spectral confocal microscopy showed that intermediate plastids contained both chlorophylls and carotenoids. Furthermore, an in situ real-time recording (a) showed that the chloroplast to chromoplast transition was synchronous for all plastids of a single cell; and (b) confirmed that all chromoplasts derived from pre-existing chloroplasts. CONCLUSIONS: These results give details of the early steps of tomato chromoplast biogenesis from chloroplasts, with the formation of intermediate plastids containing both carotenoids and chlorophylls. They provide information at the sub-cellular level on the synchronism of plastid transition and pigment changes. PMID- 21788378 TI - Small increase in substratum [corrected] pH causes the dieback of one of Europe's most common lichens, Lecanora conizaeoides. AB - BACKGROUNDS AND AIMS: Lecanora conizaeoides was until recently western and central Europe's most abundant epiphytic lichen species or at least one of the most common epiphytes. The species is adapted to very acidic conditions at pH values around 3 and high concentrations of SO(2) and its derivatives formed in aqueous solution, and thus spread with increasing SO(2) deposition during the 19th and 20th centuries. With the recent decrease of SO(2) emissions to nearly pre-industrial levels within 20 years, L. conizaeoides declined from most of its former range. If still present, the species is no longer the dominant epiphyte, but is occurring in small densities only. The rapid spread of the L. conizaeoides in Europe from an extremely rare species to the probably most frequent epiphytic lichen and the subsequent rapid dieback are unprecedented by any other organism. The present study aimed at identifying the magnitude of deacidification needed to cause the dieback of the lichen. METHODS: The epiphytic lichen diversity and bark chemistry of montane spruce forests in the Harz Mountains, northern Germany, were studied and the results were compared with data recorded with the same methods 13 15 years ago. KEY RESULTS: Lecanora conizaeoides, which was the dominant epiphyte of the study area until 15 years ago, is still found on most trees, but only with small cover values of <=1 %. The bark pH increased by only 0.4 pH units. CONCLUSIONS: The data suggest that only slight deacidification of the substratum causes the breakdown of the L. conizaeoides populations. Neither competitors nor parasites of L. conizaeoides that may have profited from reduced SO(2) concentrations are likely causes of the rapid dieback of the species. PMID- 21788377 TI - Development of SSR and gene-targeted markers for construction of a framework linkage map of Catharanthus roseus. AB - BACKGROUND AND AIMS: Catharanthus roseus is a plant of great medicinal importance, yet inadequate knowledge of its genome structure and the unavailability of genomic resources have been major impediments in the development of improved varieties. The aims of this study were to develop co dominant sequence-tagged microsatellite sites (STMS) and gene-targeted markers (GTMs) and utilize them for the construction of a framework intraspecific linkage map of C. roseus. METHODS: For simple sequence repeat (SSR) isolation, a genomic library enriched for (GA)(n) repeats was constructed from C. roseus 'Nirmal' (CrN1). In addition, GTMs were also designed from 12 genes of the TIA (terpenoid indole alkaloid) pathway - the medicinally most significant pathway in C. roseus. An F(2) mapping population was also generated by crossing two diverse accessions of C. roseus CrN1 (Nirmal)*CrN82 (Kew). KEY RESULTS: A new set of 314 STMS markers and 64 GTMs were developed in this study. A segregating F(2) mapping population consisting of 111 F(2) individuals was generated. For generating the linkage map, a set of 423 co-dominant markers (378 newly developed and 45 published earlier) were screened for polymorphism between the parental genotypes, of which 134 were identified to be polymorphic. A total of 114 markers were mapped on eight linkage groups that spanned a 632.7 cM region of the genome with an average marker distance of 5.55 cM. Further, the mechanism of hypervariability at the gene-targeted loci was investigated at the sequence level. CONCLUSIONS: For the first time, a large array of STMS markers and GTMs was generated in the model medicinal plant C. roseus. Moreover, the first microsatellite marker-based linkage map was described in this study. Together, these will serve as a foundation for future genomics studies related to quantitative trait loci analysis and molecular breeding in C. roseus. PMID- 21788379 TI - Functional and phenotypic characteristics of alternative activation induced in human monocytes by interleukin-4 or the parasitic nematode Brugia malayi. AB - Human monocytes from patients with patent filarial infections are studded with filarial antigen and express markers associated with alternative activation of macrophages (MPhi). To explore the role of filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microfilariae (mf) of Brugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 [IL-4]) or classically (macrophage colony-stimulating factor [MCSF]) activated MPhi. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MPhi but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4(+) and CD8(+) T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. In contrast to results with MCSF-cultured monocytes, exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted filarial products skew monocytes similarly. PMID- 21788380 TI - Human monocytes promote Th1 and Th17 responses to Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children. Human immunity to pneumococcal infections has been assumed to depend on anticapsular antibodies. However, recent findings from murine models suggest that alternative mechanisms, dependent on T helper cells, are also involved. Although the immunological events in which T helper cells contribute to acquired immunity have been studied in mice, little is known about how these responses are generated in humans. Therefore, we examined bacterial and host factors involved in the induction of Th1 and Th17 responses, using a coculture model of human monocytes and CD4(+) T cells. We show that monocytes promote effector cytokine production by memory T helper cells, leading to a mixed Th1/Th17 (gamma interferon [IFN-gamma]/interleukin-17 [IL-17]) profile. Both T helper cytokines were triggered by purified pneumococcal peptidoglycan; however, the balance between the two immune effector arms depended on bacterial viability. Accordingly, live pneumococci triggered a Th1-biased response via monocyte production of IL-12p40, whereas heat-killed pneumococci triggered a Th17 response through TLR2 signaling. An increased understanding of human T helper responses is essential for the development of novel pneumococcal vaccines designed to elicit cell-mediated immunity. PMID- 21788381 TI - Serine/threonine protein kinase Stk is required for virulence, stress response, and penicillin tolerance in Streptococcus pyogenes. AB - Genes encoding one or more Ser/Thr protein kinases have been identified recently in many bacteria, including one (stk) in the human pathogen Streptococcus pyogenes (group A streptococcus [GAS]). We report that in GAS, stk is required to produce disease in a murine myositis model of infection. Using microarray and quantitative reverse transcription-PCR (qRT-PCR) studies, we found that Stk activates genes for virulence factors, osmoregulation, metabolism of alpha glucans, and fatty acid biosynthesis, as well as genes affecting cell wall synthesis. Confirming these transcription studies, we determined that the stk deletion mutant is more sensitive to osmotic stress and to penicillin than the wild type. We discuss several possible Stk phosphorylation targets that might explain Stk regulation of expression of specific operons and the possible role of Stk in resuscitation from quiescence. PMID- 21788382 TI - Interferon regulatory transcription factor 3 protects mice from uterine horn pathology during Chlamydia muridarum genital infection. AB - Mice with the type I interferon (IFN) receptor gene knocked out (IFNAR KO mice) or deficient for alpha/beta IFN (IFN-alpha/beta) signaling clear chlamydial infection earlier than control mice and develop less oviduct pathology. Initiation of host IFN-beta transcription during an in vitro chlamydial infection requires interferon regulatory transcription factor 3 (IRF3). The goal of the present study was to characterize the influence of IRF3 on chlamydial genital infection and its relationship to IFN-beta expression in the mouse model. IRF3 KO mice were able to resolve infection as well as control mice, overcoming increased chlamydial colonization and tissue burden early during infection. As previously observed for IFNAR KO mice, IRF3 KO mice generated a potent antigen-specific T cell response. However, in contrast to IFNAR KO mice, IRF3 KO mice exhibited unusually severe dilatation and pathology in the uterine horns but normal oviduct pathology after infection. Although IFN-beta expression in vivo was dependent on the presence of IRF3 early in infection (before day 4), the IFN-independent function of IRF3 was likely driving this phenotype. Specifically, early during infection, the number of apoptotic cells and the number of inflammatory cells were significantly less in uterine horns from IRF3 KO mice than in those from control mice, despite an increased chlamydial burden. To delineate the effects of IFN-beta versus IRF3, neutralizing IFN-beta antibody was administered to wild type (WT) mice during chlamydial infection. IFN-beta depletion in WT mice mimicked that in IFNAlphaR KO mice but not that in IRF3 KO mice with respect to both chlamydial clearance and reduced oviduct pathology. These data suggest that IRF3 has a role in protection from uterine horn pathology that is independent of its function in IFN-beta expression. PMID- 21788384 TI - Mutagenic analysis of the Clostridium difficile flagellar proteins, FliC and FliD, and their contribution to virulence in hamsters. AB - Although toxins A and B are known to be important contributors to the acute phase of Clostridium difficile infection, the role of colonization and adherence to host tissues in the overall pathogenesis of these organisms remains unclear. Consequently, we used the recently introduced intron-based ClosTron gene interruption system to eliminate the expression of two reported C. difficile colonization factors, the major flagellar structural subunit (FliC) and the flagellar cap protein (FliD), to gain greater insight into how flagella and motility contribute to C. difficile's pathogenic strategy. The results demonstrate that interrupting either the fliC or the fliD gene results in a complete loss of flagella, as well as motility, in C. difficile. However, both the fliC and fliD mutant strains adhered better than the wild-type 630Deltaerm strain to human intestine-derived Caco-2 cells, suggesting that flagella and motility do not contribute to, or may even interfere with, C. difficile adherence to epithelial cell surfaces in vitro. Moreover, we found that the mutant strains were more virulent in hamsters, indicating either that flagella are unnecessary for virulence or that repression of motility may be a pathogenic strategy employed by C. difficile in hamsters. PMID- 21788383 TI - Functional characterization of EpsC, a component of the type II secretion system, in the pathogenicity of Vibrio vulnificus. AB - EpsC, one of the components comprising the type II secretion system (T2SS), was isolated from a human-pathogenic bacterium, Vibrio vulnificus, to evaluate its role in eliciting virulence. An espC-deleted mutant of V. vulnificus displayed a reduced cytotoxicity to the human cell line HEp-2 and an attenuated virulence in a mouse model. This mutant exhibited dramatic defects in the secretion of diverse extracellular proteins, such as outer membrane proteins, transporters, and the known secreted factors, notably, a hemolysin (VvhA) and an elastase (VvpE). A defect in its secretion of proteins was restored by in trans complementation of the intact epsC gene. Analyses of cellular fractions revealed that VvhA and VvpE of the DeltaepsC mutant were not excreted outside the cell but were present mainly in the periplasmic space. Examination of a V. vulnificus mutant deficient in TolC, a component of the T1SS, showed that it is not involved in the secretion of VvhA and VvpE but that it is necessary for the secretion of another major toxin of V. vulnificus, RtxA. Therefore, the T2SS is required for V. vulnificus pathogenicity, which is mediated by at least two secreted factors, VvhA and VvpE, via facilitating the secretion and exposure of these factors to host cells. PMID- 21788385 TI - Heat-labile- and heat-stable-toxoid fusions (LTR192G-STaP13F) of human enterotoxigenic Escherichia coli elicit neutralizing antitoxin antibodies. AB - Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of diarrheal disease in humans and animals. Adhesins and enterotoxins, including heat-labile (LT) and heat-stable (STa) toxins, are the key virulence factors. Antigenic adhesin and LT antigens have been used in developing vaccines against ETEC diarrhea. However, STa has not been included because of its poor immunogenicity and potent toxicity. Our recent study showed that porcine-type STa toxoids became immunogenic and elicited neutralizing anti-STa antibodies after being genetically fused to a full-length porcine-type LT toxoid, LT(R192G) (W. Zhang et al., Infect. Immun. 78:316-325, 2010). In this study, we mutated human-type LT and STa genes, which are highly homologous to porcine-type toxin genes, for a full-length LT toxoid (LT(R192)) and a full-length STa toxoid (STa(P13F)) and genetically fused them to produce LT192-STa13 toxoid fusions. Mice immunized with LT192-STa13 fusion antigens developed anti-LT and anti-STa IgG (in serum and feces) and IgA antibodies (in feces). Moreover, secretory IgA antibodies from immunized mice were shown to neutralize STa and cholera toxins in T-84 cells. In addition, we fused the STa13 toxoid at the N terminus and C terminus, between the A1 and A2 peptides, and between the A and B subunits of LT192 to obtain different fusions in order to explore strategies for enhancing STa immunogenicity. This study demonstrated that human-type LT192-STa13 fusions induce neutralizing antitoxin antibodies and provided important information for developing toxoid vaccines against human ETEC diarrhea. PMID- 21788387 TI - Differential expression and characterization of a member of the mucin-associated surface protein family secreted by Trypanosoma cruzi. AB - We describe the characterization, purification, expression, and location of a 52 kDa protein secreted during interaction between the metacyclic form of Trypanosoma cruzi and its target host cell. The protein, which we have named MASP52, belongs to the family of mucin-associated surface proteins (MASPs). The highest levels of expression of both the protein and mRNA occur during the metacyclic and bloodstream trypomastigote stages, the forms that infect the vertebrate host cells. The protein is located in the plasma membrane and in the flagellar pockets of the epimastigote, metacyclic, and trypomastigote forms and is secreted into the medium at the point of contact between the parasite and the cell membrane, as well as into the host-cell cytosol during the amastigote stage. IgG antibodies specific against a synthetic peptide corresponding to the catalytic zone of MASP52 significantly reduce the parasite's capacity to infect the host cells. Furthermore, when the protein is adsorbed onto inert particles of bentonite and incubated with a nonphagocytic cell culture, the particles are able to induce endocytosis in the cells, which seems to demonstrate that MASP52 plays a role in a process whereby the trypomastigote forms of the parasite invade the host cell. PMID- 21788386 TI - Coinfection with Enterohepatic Helicobacter species can ameliorate or promote Helicobacter pylori-induced gastric pathology in C57BL/6 mice. AB - To investigate how different enterohepatic Helicobacter species (EHS) influence Helicobacter pylori gastric pathology, C57BL/6 mice were infected with Helicobacter hepaticus or Helicobacter muridarum, followed by H. pylori infection 2 weeks later. Compared to H. pylori-infected mice, mice infected with H. muridarum and H. pylori (HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (P < 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected with H. hepaticus and H. pylori (HhHp mice) developed more severe gastric pathology at 6 MPI (P = 0.01), with a HAI at 11 MPI (P = 0.8) similar to that of H. pylori-infected mice. H. muridarum-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [Il-1beta], gamma interferon [Ifn-gamma], and tumor necrosis factor-alpha [Tnf-alpha]) cytokines at both time points and Th17 (Il-17A) cytokine mRNA levels at 6 MPI in murine stomachs compared to those of H. pylori-infected mice (P < 0.01). Coinfection with H. hepaticus also suppressed H. pylori-induced elevation of gastric Th1 cytokines Ifn-gamma and Tnf-alpha (P < 0.0001) but increased Th17 cytokine mRNA levels (P = 0.028) at 6 MPI. Furthermore, mRNA levels of Il-17A were positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>H. pylori>HmHp) (at 6 MPI, r2 = 0.92, P < 0.0001; at 11 MPI, r2 = 0.82, P < 0.002). Despite disparate effects on gastritis, colonization levels of gastric H. pylori were increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-H. pylori-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity of H. pylori-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses to H. pylori infection. PMID- 21788388 TI - Neurotrophin receptor TrkC is an entry receptor for Trypanosoma cruzi in neural, glial, and epithelial cells. AB - Trypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated by T. cruzi surface trans-sialidase, also known as parasite derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used by T. cruzi to enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant to T. cruzi became highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore, trkC transfection conferred an ~3.0-fold intracellular growth advantage. Sialylation deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive to T. cruzi after transfection with the trkC gene. Additionally, NT-3 specifically blocked T. cruzi infection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blocked T. cruzi infection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected by T. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broad T. cruzi infection both in vitro and in vivo. PMID- 21788389 TI - Pneumolysin with low hemolytic activity confers an early growth advantage to Streptococcus pneumoniae in the blood. AB - Streptococcus pneumoniae is a leading cause of human diseases such as pneumonia, bacteremia, meningitis, and otitis media. Pneumolysin (Ply) is an important virulence factor of S. pneumoniae and a promising future vaccine target. However, the expansion of clones carrying ply alleles with reduced hemolytic activity has been observed in serotypes associated with outbreaks of invasive disease and includes an allele identified in a highly virulent serotype 1 isolate (ply4496). The virulence of Ply-deficient and ply allelic-replacement derivatives of S. pneumoniae D39 was compared with that of wild-type D39. In addition, the protective immunogenicity of Ply against pneumococci with low versus high hemolytic activity was also investigated. Replacement of D39 ply with ply4496 resulted in a small but statistically significant reduction of virulence. However, both native Ply- and Ply4496-expressing strains were significantly more virulent than a Ply-deficient mutant. While the numbers of both Ply- and Ply4496 expressing isolate cells were higher in the blood than the numbers of Ply deficient mutant cells, the growth of the Ply4496-expressing strain was superior to that of the wild type in the first 15 h postchallenge. Ply immunization provided protection regardless of the hemolytic activity of the challenge strain. In summary, we show that low-hemolytic-activity Ply alleles contribute to systemic virulence and may provide a survival advantage in the blood. Moreover, pneumococci expressing such alleles remain vulnerable to Ply-based vaccines. PMID- 21788390 TI - Cyclic dimeric GMP signaling regulates intracellular aggregation, sessility, and growth of Ehrlichia chaffeensis. AB - Cyclic dimeric GMP (c-di-GMP), a bacterial second messenger, is known to regulate bacterial biofilm and sessility. Replication of an obligatory intracellular pathogen, Ehrlichia chaffeensis, is characterized by formation of bacterial aggregates called morulae inside membrane-bound inclusions. When E. chaffeensis matures into an infectious form, morulae become loose to allow bacteria to exit from host cells to infect adjacent cells. E. chaffeensis expresses a sensor kinase, PleC, and a cognate response regulator, PleD, which can produce c-di-GMP. A hydrophobic c-di-GMP antagonist, 2'-O-di(tert-butyldimethysilyl)-c-di-GMP (CDGA) inhibits E. chaffeensis internalization into host cells by facilitating degradation of some bacterial surface proteins via endogenous serine proteases. In the present study, we found that PleC and PleD were upregulated synchronously during exponential growth of bacteria, concomitant with increased morula size. While CDGA did not affect host cells, when infected cells were treated with CDGA, bacterial proliferation was inhibited, morulae became less compact, and the intracellular movement of bacteria was enhanced. Concurrently, CDGA treatment facilitated the extracellular release of bacteria with lower infectivity than those spontaneously released from sham-treated cells. Addition of CDGA to isolated inclusions induced dispersion of the morulae, degradation of an inclusion matrix protein TRP120, and bacterial intrainclusion movement, all of which were blocked by a serine protease inhibitor. These results suggest that c di-GMP signaling regulates aggregation and sessility of E. chaffeensis within the inclusion through stabilization of matrix proteins by preventing the serine protease activity, which is associated with bacterial intracellular proliferation and maturation. PMID- 21788391 TI - The stringent response is essential for Pseudomonas aeruginosa virulence in the rat lung agar bead and Drosophila melanogaster feeding models of infection. AB - The stringent response is a regulatory system that allows bacteria to sense and adapt to nutrient-poor environments. The central mediator of the stringent response is the molecule guanosine 3',5'-bispyrophosphate (ppGpp), which is synthesized by the enzymes RelA and SpoT and which is also degraded by SpoT. Our laboratory previously demonstrated that a relA mutant of Pseudomonas aeruginosa, the principal cause of lung infections in cystic fibrosis patients, was attenuated in virulence in a Drosophila melanogaster feeding model of infection. In this study, we examined the role of spoT in P. aeruginosa virulence. We generated an insertion mutation in spoT within the previously constructed relA mutant, thereby producing a ppGpp-devoid strain. The relA spoT double mutant was unable to establish a chronic infection in D. melanogaster and was also avirulent in the rat lung agar bead model of infection, a model in which the relA mutant is fully virulent. Synthesis of the virulence determinants pyocyanin, elastase, protease, and siderophores was impaired in the relA spoT double mutant. This mutant was also defective in swarming and twitching, but not in swimming motility. The relA spoT mutant and, to a lesser extent, the relA mutant were less able to withstand stresses such as heat shock and oxidative stress than the wild type strain PAO1, which may partially account for the inability of the relA spoT mutant to successfully colonize the rat lung. Our results indicate that the stringent response, and SpoT in particular, is a crucial regulator of virulence processes in P. aeruginosa. PMID- 21788393 TI - A competitive co-cultivation assay for cancer drug specificity evaluation. AB - The identification of compounds that specifically inhibit or kill cancer cells without affecting cells from healthy tissues is very challenging but very important for reducing the side effects of current cancer therapies. Hence, there is an urgent need for improved assays allowing the selectivity of a given compound to be monitored directly. The authors present an assay system based on the competitive co-cultivation of an excess of cancer cells with a small fraction of noncancer human indicator cells generating a fluorescence signal. In the absence of a specific anticancer compound, the cancer cells outgrow the indicator cells and abolish the fluorescence signal. In contrast, the presence of specific anticancer drugs (such as Tyrphostin-AG1478 or PLX4720) results in the selective growth of the indicator cells, giving rise to a strong fluorescence signal. Furthermore, the authors show that the nonspecific cytotoxic compound sodium azide kills both cancer and noncancer cells, and no fluorescence signal is obtained. Hence, this assay system favors the selection of compounds that specifically target cancer cells and decreases the probability of selecting nonspecific cytotoxic molecules. Z factors of up to 0.85 were obtained, indicating an excellent assay that can be used for high-throughput screening. PMID- 21788392 TI - A high-throughput screening assay for the identification of flavivirus NS5 capping enzyme GTP-binding inhibitors: implications for antiviral drug development. AB - There are no effective antivirals currently available for the treatment of flavivirus infection in humans. As such, the identification and characterization of novel drug target sites are critical to developing new classes of antiviral drugs. The flavivirus NS5 N-terminal capping enzyme (CE) is vital for the formation of the viral RNA cap structure, which directs viral polyprotein translation and stabilizes the 5' end of the viral genome. The structure of the flavivirus CE has been solved, and a detailed understanding of the CE-guanosine triphosphate (GTP) and CE-RNA cap interactions is available. Because of the essential nature of the interaction for viral replication, disrupting CE-GTP binding is an attractive approach for drug development. The authors have previously developed a robust assay for monitoring CE-GTP binding in real time. They adapted this assay for high-throughput screening and performed a pilot screen of 46 323 commercially available compounds. A number of small-molecule inhibitors capable of displacing a fluorescently labeled GTP in vitro were identified, and a second functional assay was developed to identify false positives. The results presented indicate that the flavivirus CE cap-binding site is a valuable new target site for antiviral drug discovery and should be further exploited for broad-spectrum anti-flaviviral drug development. PMID- 21788396 TI - Electrical impedance for assessing muscle. PMID- 21788394 TI - A novel cell-based, high-content assay for phosphorylation of Lats2 by Aurora A. AB - Aurora A kinase is a key regulator of mitosis, which is upregulated in several human cancers, making it a potential target for anticancer therapeutics. Consequently, robust medium- to high-throughput cell-based assays to measure Aurora A kinase activity are critical for the development of small-molecule inhibitors. Here the authors compare measurement of the phosphorylation of two Aurora A substrates previously used in high-content screening Aurora A assays, Aurora A itself and TACC3, with a novel substrate Lats2. Using antibodies directed against phosphorylated forms of Aurora A (pThr288), P-TACC3 (pSer558), and P-Lats2 (pSer83), the authors investigate their suitability in parallel for development of a cell-based assay using several reference Aurora inhibitors: MLN8054, VX680, and AZD1152-HQPA. They validate a combined assay of target specific phosphorylation of Lats2 at the centrosome and an increase in mitotic index as a measure of Aurora A activity. The assay is both sensitive and robust and has acceptable assay performance for high-throughput screening or potency estimation from concentration-response assays. It has the advantage that it can be carried out using a commercially available monoclonal antibody against phospho Lats2 and the widely available Cellomics ArrayScan HCS reader and thus represents a significant addition to the tools available for the identification of Aurora A specific inhibitors. PMID- 21788399 TI - Educators' and parents' perception of what school nurses do: the influence of school nurse/student ratios. AB - The purpose of this qualitative study was to determine how ratios influenced relationships between school nurses and the educators and parents with whom they work; and how the relationships influenced the understanding and value of the school nurse. A purposeful sampling of 33 participants from four states (New Hampshire, Vermont, Michigan, and Utah) was included in the study. The results indicate both educators and parents perceived the primary role of the school nurse to be medication administration and first aid. The value and understanding of the role of the nurse was not based on the school nurse-to-student ratio. It was influenced by the quality of interactions with school nurses; and the extent to which the nurse was a member of the school team. School nurses must understand the culture of education in order to build professional relationships with administrators and be seen as valuable members of the school team. PMID- 21788400 TI - Tumor-specific targeting of pancreatic cancer with Shiga toxin B-subunit. AB - Pancreatic carcinoma is one of the most aggressive tumor entities, and standard chemotherapy provides only modest benefit. Therefore, specific targeting of pancreatic cancer for early diagnosis and therapeutic intervention is of great interest. We have previously shown that the cellular receptor for Shiga toxin B (STxB), the glycosphingolipid globotriaosylceramide (Gb(3) or CD77) is strongly increased in colorectal adenocarcinoma and their metastases. Here, we report an upregulation of Gb(3) in pancreatic adenocarcinoma (21 of 27 cases) as compared with matched normal tissue (n = 27). The mean expression was highly significantly increased from 30 +/- 16 ng Gb(3)/mg tissue in normal pancreas to 61 +/- 41 ng Gb(3)/mg tissue (mean +/- SD, P = 0.0006), as evidenced by thin layer chromatography. Upregulation of Gb(3) levels did not depend on tumor stage or grading and showed no correlation with clinical outcome. Tumor cells and endothelial cells were identified as the source of increased Gb(3) expression by immunocytochemistry. Pancreatic cancer cell lines showed rapid intracellular uptake of STxB to the Golgi apparatus, following the retrograde pathway. The therapeutic application of STxB was tested by specific delivery of covalently coupled SN38, an active metabolite of the topoisomerase I inhibitor irinotecan. The cytotoxic effect of the STxB-SN38 compound in pancreatic cancer cell lines was increased more than 100-fold compared with irinotecan. Moreover, this effect was effectively blocked by competing incubation with nonlabeled STxB, showing the specificity of the targeting. Thus, STxB constitutes a promising new tool for specific targeting of pancreatic cancer. PMID- 21788401 TI - Ethical treatment of school children in research: assuring informed consent. PMID- 21788402 TI - Presidential inaugural address: advocacy, access, and achievement. PMID- 21788403 TI - Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target. AB - Patients with liver metastases from colon carcinoma show highly variable responses to chemotherapy and tumor recurrence is frequently observed. Therapy resistant cancer stem cells have been implicated in drug resistance and tumor recurrence. However, the factors determining therapy resistance and tumor recurrence are poorly understood. The aim of this study was to gain insight into these mechanisms by comparing the proteomes of patient-derived cancer stem cell cultures and their differentiated isogenic offspring. We established colonosphere cultures derived from resection specimens of liver metastases in patients with colon cancer. These colonospheres, enriched for colon cancer stem cells, were used to establish isogenic cultures of stably differentiated nontumorigenic progeny. Proteomics based on one-dimensional gel electrophoresis coupled to nano liquid chromatography tandem MS was used to identify proteome differences between three of these paired cultures. The resulting data were analyzed using Ingenuity Pathway Software. Out of a total data set of 3048 identified proteins, 32 proteins were at least twofold up-regulated in the colon cancer stem cells when compared with the differentiated cells. Pathway analysis showed that "cell death " regulation is strikingly different between the two cell types. Interestingly, one of the top-up-regulated proteins was BIRC6, which belongs to the class of Inhibitor of Apoptosis Proteins. Knockdown of BIRC6 sensitized colon cancer stem cells against the chemotherapeutic drugs oxaliplatin and cisplatin. This study reveals that differentiation of colon cancer stem cells is accompanied by altered regulation of cell death pathways. We identified BIRC6 as an important mediator of cancer stem cell resistance against cisplatin and oxaliplatin. Targeting BIRC6, or other Inhibitors of Apoptosis Proteins, may help eradicating colon cancer stem cells. PMID- 21788405 TI - Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. AB - Antigen-presenting cells in the disease-free brain have been identified primarily by expression of antigens such as CD11b, CD11c, and MHC II, which can be shared by dendritic cells (DCs), microglia, and monocytes. In this study, starting with the criterion of Flt3 (FMS-like receptor tyrosine kinase 3)-dependent development, we characterize the features of authentic DCs within the meninges and choroid plexus in healthy mouse brains. Analyses of morphology, gene expression, and antigen-presenting function established a close relationship between meningeal and choroid plexus DCs (m/chDCs) and spleen DCs. DCs in both sites shared an intrinsic requirement for Flt3 ligand. Microarrays revealed differences in expression of transcripts encoding surface molecules, transcription factors, pattern recognition receptors, and other genes in m/chDCs compared with monocytes and microglia. Migrating pre-DC progenitors from bone marrow gave rise to m/chDCs that had a 5-7-d half-life. In contrast to microglia, DCs actively present self-antigens and stimulate T cells. Therefore, the meninges and choroid plexus of a steady-state brain contain DCs that derive from local precursors and exhibit a differentiation and antigen-presenting program similar to spleen DCs and distinct from microglia. PMID- 21788404 TI - Online nanoflow multidimensional fractionation for high efficiency phosphopeptide analysis. AB - Despite intense, continued interest in global analyses of signaling cascades through mass spectrometry-based studies, the large-scale, systematic production of phosphoproteomics data has been hampered in-part by inefficient fractionation strategies subsequent to phosphopeptide enrichment. Here we explore two novel multidimensional fractionation strategies for analysis of phosphopeptides. In the first technique we utilize aliphatic ion pairing agents to improve retention of phosphopeptides at high pH in the first dimension of a two-dimensional RP-RP. The second approach is based on the addition of strong anion exchange as the second dimension in a three-dimensional reversed phase (RP)-strong anion exchange (SAX) RP configuration. Both techniques provide for automated, online data acquisition, with the 3-D platform providing the highest performance both in terms of separation peak capacity and the number of unique phosphopeptide sequences identified per MUg of cell lysate consumed. Our integrated RP-SAX-RP platform provides several analytical figures of merit, including: (1) orthogonal separation mechanisms in each dimension; (2) high separation peak capacity (3) efficient retention of singly- and multiply-phosphorylated peptides; (4) compatibility with automated, online LC-MS analysis. We demonstrate the reproducibility of RP-SAX-RP and apply it to the analysis of phosphopeptides derived from multiple biological contexts, including an in vitro model of acute myeloid leukemia in addition to primary polyclonal CD8(+) T-cells activated in vivo through bacterial infection and then purified from a single mouse. PMID- 21788406 TI - Chemokine receptor CXCR3 facilitates CD8(+) T cell differentiation into short lived effector cells leading to memory degeneration. AB - Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8(+) T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8(+) T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3(-/-) antigen-specific CD8(+) T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8(+) T cells. Early after infection, CXCR3(-/-) antigen specific CD8(+) T cells fail to cluster at the marginal zone in the spleen where inflammatory cytokines such as IL-12 and IFN-alpha are abundant, thus receiving relatively weak inflammatory stimuli. Consequently, CXCR3(-/-) CD8(+) T cells exhibit transient expression of CD25 and preferentially differentiate into memory precursor effector cells as compared with wild-type CD8(+) T cells. This series of events has important implications for development of vaccination strategies to generate increased numbers of antigen-specific memory CD8(+) T cells via inhibition of CXCR3-mediated T cell migration to inflamed microenvironments. PMID- 21788408 TI - Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3 deficient mice. AB - Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant role, FoxP3-deficient mice sufficient in CD30 but deficient in OX40 signals still eventually develop lethal disease. This result was supported by the observation that blocking antibodies to OX40 and CD30 ligands also abrogated disease mediated by FoxP3-deficient T cells. These observations identify OX40 and CD30 signals as essential for the development of clinically relevant CD4 dependent autoimmunity and suggest that combination therapies that abrogate these signals might be used to treat established human autoimmune diseases. PMID- 21788407 TI - Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. AB - Neutrophil extravasation and the regulation of vascular permeability require dynamic actin rearrangements in the endothelium. In this study, we analyzed in vivo whether these processes require the function of the actin nucleation promoting factor cortactin. Basal vascular permeability for high molecular weight substances was enhanced in cortactin-deficient mice. Despite this leakiness, neutrophil extravasation in the tumor necrosis factor-stimulated cremaster was inhibited by the loss of cortactin. The permeability defect was caused by reduced levels of activated Rap1 (Ras-related protein 1) in endothelial cells and could be rescued by activating Rap1 via the guanosine triphosphatase (GTPase) exchange factor EPAC (exchange protein directly activated by cAMP). The defect in neutrophil extravasation was caused by enhanced rolling velocity and reduced adhesion in postcapillary venules. Impaired rolling interactions were linked to contributions of beta(2)-integrin ligands, and firm adhesion was compromised by reduced ICAM-1 (intercellular adhesion molecule 1) clustering around neutrophils. A signaling process known to be critical for the formation of ICAM-1-enriched contact areas and for transendothelial migration, the ICAM-1-mediated activation of the GTPase RhoG was blocked in cortactin-deficient endothelial cells. Our results represent the first physiological evidence that cortactin is crucial for orchestrating the molecular events leading to proper endothelial barrier function and leukocyte recruitment in vivo. PMID- 21788409 TI - Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection. AB - The development of T cell memory from naive precursors is influenced by molecular cues received during T cell activation and differentiation. In this study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8(+) T cell contraction and memory generation after influenza virus infection. We find that Ccr5(-/-) Cxcr3(-/-) cells show markedly decreased contraction after viral clearance, leading to the establishment of massive numbers of memory CD8(+) T cells. Ccr5(-/-) Cxcr3(-/-) cells show reduced expression of CD69 in the lung during the peak of infection, which coincides with differential localization and the rapid appearance of memory precursor cells. Analysis of single chemokine receptor-deficient cells revealed that CXCR3 is primarily responsible for this phenotype, although there is also a role for CCR5 in the enhancement of T cell memory. The phenotype could be reversed by adding exogenous antigen, resulting in the activation and contraction of Ccr5(-/-) Cxcr3(-/-) cells. Similar results were observed during chronic Mycobacterium tuberculosis infection. Together, the data support a model of memory CD8(+) T cell generation in which the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8(+) T cell activation and differentiation, which ultimately regulates effector versus memory cell fate decisions. PMID- 21788411 TI - A condom in every jail cell. PMID- 21788412 TI - Challenges of family practice: shopping for electronics. PMID- 21788413 TI - Challenges of family practice: using electronic records. PMID- 21788410 TI - Genomic loss of the putative tumor suppressor gene E2A in human lymphoma. AB - The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sezary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity. PMID- 21788415 TI - Europe unveils risk assessment guidance for engineered nanomaterials used in food chain. PMID- 21788416 TI - New Medical College Admissions Test in the works. PMID- 21788417 TI - Recent epidemiologic trends of diabetes mellitus among status Aboriginal adults. AB - BACKGROUND: Little is known about longitudinal trends in diabetes mellitus among Aboriginal people in Canada. We compared the incidence and prevalence of diabetes, and its impact on mortality, among status Aboriginal adults and adults in the general population between 1995 and 2007. METHODS: We examined de identified data from Alberta Health and Wellness administrative databases for status Aboriginal people (First Nations and Inuit people with treaty status) and members of the general public aged 20 years and older who received a diagnosis of diabetes mellitus from Apr. 1, 1995, to Mar. 31, 2007. We calculated the incidence and prevalence of diabetes and mortality rate ratios by sex and ethnicity in 2007. We examined the average relative changes per year for longitudinal trends. RESULTS: The average relative change per year in the prevalence of diabetes showed a smaller increase over time in the Aboriginal population than in the general population (2.39 v. 4.09, p < 0.001). A similar finding was observed for the incidence of diabetes. In the Aboriginal population, we found that the increase in the average relative change per year was greater among men than among women (3.13 v. 1.88 for prevalence, p < 0.001; 2.60 v. 0.02 for incidence, p = 0.001). Mortality among people with diabetes decreased over time to a similar extent in both populations. Among people without diabetes, mortality decreased in the general population but was unchanged in the Aboriginal population (-1.92 v. 0.11, p = 0.04). Overall, mortality was higher in the Aboriginal population than in the general population regardless of diabetes status. INTERPRETATION: The increases in the incidence and prevalence of diabetes over the study period appeared to be slower in the status Aboriginal population than in the general population in Alberta, although the overall rates were higher in the Aboriginal population. Mortality decreased among people with diabetes in both populations but was higher overall in the Aboriginal population regardless of diabetes status. PMID- 21788418 TI - New Delhi metallo-beta-lactamase-1: detection and prevention. PMID- 21788419 TI - Classic Kaposi sarcoma. PMID- 21788420 TI - Idiopathic intracranial hypertension. PMID- 21788422 TI - The responses of Aboriginal Canadians to adjuvanted pandemic (H1N1) 2009 influenza vaccine. AB - BACKGROUND: Because many Aboriginal Canadians had severe cases of pandemic (H1N1) 2009 influenza, they were given priority access to vaccine. However, it was not known if the single recommended dose would adequately protect people at high risk, prompting our study to assess responses to the vaccine among Aboriginal Canadians. METHODS: We enrolled First Nations and Metis adults aged 20-59 years in our prospective cohort study. Participants were given one 0.5-mL dose of ASO3 adjuvanted pandemic (H1N1) 2009 vaccine (Arepanrix, GlaxoSmithKline Canada). Blood samples were taken at baseline and 21-28 days after vaccination. Paired sera were tested for hemagglutination-inhibiting antibodies at a reference laboratory. To assess vaccine safety, we monitored the injection site symptoms of each participant for seven days. We also monitored patients for general symptoms within 7 days of vaccination and any use of the health care system for 21-28 days after vaccination. RESULTS: We enrolled 138 participants in the study (95 First Nations, 43 Metis), 137 of whom provided all safety data and 136 of whom provided both blood samples. First Nations and Metis participants had similar characteristics, including high rates of chronic health conditions (74.4%-76.8%). Pre-existing antibody to the virus was detected in 34.3% of the participants, all of whom boosted strongly with vaccination (seroprotection rate [titre >= 40] 100%, geometric mean titre 531-667). Participants with no pre-existing antibody also responded well. Fifty-eight of 59 (98.3%) First Nations participants showed seroprotection and a geometric mean titre of 353.6; all 30 Metis participants with no pre-existing antibody showed seroprotection and a geometric mean titre of 376.2. Pain at the injection site and general symptoms frequently occurred but were short-lived and generally not severe, although three participants (2.2%) sought medical attention for general symptoms. INTERPRETATION: First Nations and Metis adults responded robustly to ASO3-adjuvanted pandemic (H1N1) 2009 vaccine. Virtually all participants showed protective titres, including those with chronic health conditions. PMID- 21788423 TI - Inhibition of Navbeta4 peptide-mediated resurgent sodium currents in Nav1.7 channels by carbamazepine, riluzole, and anandamide. AB - Paroxysmal extreme pain disorder (PEPD) and inherited erythromelalgia (IEM) are inherited pain syndromes arising from different sets of gain-of-function mutations in the sensory neuronal sodium channel isoform Nav1.7. Mutations associated with PEPD, but not IEM, result in destabilized inactivation of Nav1.7 and enhanced resurgent sodium currents. Resurgent currents arise after relief of ultra-fast open-channel block mediated by an endogenous blocking particle and are thought to influence neuronal excitability. As such, enhancement of resurgent currents may constitute a pathological mechanism contributing to sensory neuron hyperexcitability and pain hypersensitivity associated with PEPD. Furthermore, pain associated with PEPD, but not IEM, is alleviated by the sodium channel inhibitor carbamazepine. We speculated that selective attenuation of PEPD enhanced resurgent currents might contribute to this therapeutic effect. Here we examined whether carbamazepine and two other sodium channel inhibitors, riluzole and anandamide, exhibit differential inhibition of resurgent currents. To gain further insight into the potential mechanism(s) of resurgent currents, we examined whether these inhibitors produced correlative changes in other properties of sodium channel inactivation. Using stably transfected human embryonic kidney 293 cells expressing wild-type Nav1.7 and the PEPD mutants T1464I and M1627K, we examined the effects of the three drugs on Navbeta4 peptide mediated resurgent currents. We observed a correlation between resurgent current inhibition and a drug-mediated increase in the rate of inactivation and inhibition of persistent sodium currents. Furthermore, although carbamazepine did not selectively target resurgent currents, anandamide strongly inhibited resurgent currents with minimal effects on the peak transient current amplitude, demonstrating that resurgent currents can be selectively targeted. PMID- 21788424 TI - 'Idiopathic' partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals? AB - OBJECTIVE: 46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5alpha reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype. SUBJECTS: We investigated 28 newborn/infant males with 46,XY DSD, normal androgen production, and no androgen receptor or steroid-5alphaR type II enzyme (SRD5A2) gene mutations. METHODS: To exclude other genetic defects, we sequenced the steroidogenic factor 1 (SF1) and mastermind-like domain-containing 1 (MAMLD1) genes, which were recently found to be associated with the PAIS-like phenotype. Parents were interviewed about their environmental/occupational exposure to endocrine disrupting chemicals (EDCs) before/during the patients' fetal life. Total estrogenic bioactivity of patient serum was analyzed by ultrasensitive bioassay. RESULTS: All the patients had normal SF1 sequence and one patient showed a double polymorphism of MAMLD1. Eleven (39.3%) of the 28 patients had reported parental fetal exposure to EDCs. The mean estrogenic bioactivity in these 11 patients with fetal EDC exposure (6.65 +/- 8.07 pg/ml) versus 17 cases without contamination (1.27 +/- 0.34 pg/ml) and controls (1.06 +/- 0.44 pg/ml; P<0.05) was elevated. CONCLUSIONS: Our results indicate that the 'idiopathic' PAIS-like phenotype may in some cases be related to EDC contamination during fetal life. PMID- 21788425 TI - Effects of dietary chromium supplementation on performance, carcass characteristics, and meat quality of growing-finishing swine: a meta-analysis. AB - Dietary Cr supplementation has potential to decrease fat and increase lean in carcasses of growing-finishing swine. However, effects of Cr supplementation on performance and economically important carcass and meat quality characteristics varied considerably among studies. Therefore, a meta-analysis was designed to quantitatively describe effects obtained in several independent studies. To accommodate differences in methodology among studies, standardized effect sizes (Hedges's g) were calculated for results from 31 studies, in which Cr was supplemented as complexes of Cr Met chelate, Cr nanocomposite, Cr nicotinate, Cr propionate, Cr tripicolinate, or Cr yeast in diets for growing-finishing swine. Summary statistics were calculated by frequentist fixed and random effects, and hierarchical Bayesian models. With characteristics related to carcass quality, observed heterogeneity (P < 0.10) could not adequately be explained in a meta regression by differences in initial BW and amount of Cr supplemented. Random effects and Bayesian models to summarize effect sizes for these characteristics showed similar results. According to random effects models, dietary Cr supplementation decreased (P < 0.05) 10th-rib fat thickness (mean effect size = 0.479; 95% confidence intervals = -0.680 to -0.279; 24 studies; 59 comparisons), whereas percentage carcass lean (mean effect size = 0.614; 95% confidence intervals = 0.366 to 0.863; 22 studies; 52 comparisons) and LM area (mean effect size = 0.571; 95% confidence intervals = 0.364 to 0.778; 29 studies; 72 comparisons) increased. Average daily gain and G:F, which did not present heterogeneity, were improved by Cr supplementation, whereas no effects were detected in characteristics (CIE color, drip loss, cook loss, shear force) related to meat quality. Some publication, or other small-study bias, was evident in results on growth and feed efficiency. However, directions of mean effect sizes were not changed by application of the trim-and-fill method to correct for bias. PMID- 21788426 TI - DNA fragmentation kinetics and postthaw motility of flow cytometric-sorted white tailed deer sperm. AB - This study examined DNA damage and postthaw motility of white-tailed deer sperm (n = 28) before and after sex selection and conventional sorting using MoFlo XDP SX flow cytometry. Semen samples from the same individuals were treated in 4 different ways: 1) chilled-extended sperm samples (without glycerol); 2) cryopreserved conventional samples, samples directly cryopreserved after the addition of extenders; 3) cryopreserved conventionally sorted samples, sorted samples to remove the dead sperm subpopulation; and 4) cryopreserved sex-sorted samples; sorted samples to remove the dead sperm subpopulation and separation of X- and Y-chromosome-bearing sperm. In all the cases (n = 6), conventional samples showed decreased postthaw motilities (43 +/- 26%) when compared with X-sorted samples (59 +/- 20%; P < 0.05) and Y-sorted samples (54 +/- 20%; P > 0.05). The DNA fragmentation baseline was <5% for frozen-thawed conventional samples, but even less after sex sorting and conventional sorting: 2.4 and 1.7%, respectively. On the other hand, conventional samples showed greater (P < 0.05) DNA fragmentation than the sex-sorted sperm (n = 6) at 96 h (average of 4.8 +/- 4.5% and 5.3 +/- 4%, respectively). Conventionally sorted samples (n = 8) did not have greater (P > 0.05) DNA fragmentation when compared with the sex-sorted samples. Fragmentation of DNA on X-chromosome and Y-chromosome-bearing sorted sperm were not significantly different (n = 10, P > 0.05) after 96 h (2.6 +/- 3.6% and 2.2 +/- 0.5%, respectively). Future research should be implemented for examining the fertilizing potential of sex-sorted white-tailed deer sperm (e.g., AI fertility trials). PMID- 21788427 TI - Protein quality and utilization of timothy, oat-supplemented timothy, and alfalfa at differing harvest maturities in exercised Arabian horses. AB - To evaluate the protein quality and postgut N utilization of full-bloom timothy hay, oat-supplemented timothy-hay diets, and alfalfa hay harvested at different maturities, apparent whole tract N digestibility, urinary N excretion, and serum AA profiles were determined in light to moderately exercised Arabian horses. Six Arabian geldings (16.0 +/- 0.3 yr; 467 +/- 11 kg of BW) were randomly allocated to a 6 * 6 Latin square design. Diets included full-bloom timothy grass hay (G), G + 0.2% BW oat (G1), G + 0.4% BW oat (G2), mid-bloom alfalfa (A1), early-bloom alfalfa (A2), and early-bud alfalfa hay (A3). Forages were fed at 1.6% of the BW of the horse (as-fed). Each period consisted of an 11-d adaptation period followed by total collection of feces and urine for 3 d. Blood samples were taken on d 11 for analysis of serum AA concentrations. During the 3-d collection period, urine and feces were collected every 8 h and measured and weighed, respectively. Approximately 10% of the total urine volume and fecal weight per period was retained for N analyses. Fecal DM output was less (P < 0.05) in A1, A2, or A3 compared with G, G1, or G2. Apparent whole tract N digestibility was greater (P < 0.01) in A1, A2, and A3 compared with G, G1, or G2, and was greater (P < 0.05) in G1 and G2 compared with G. Nitrogen retention was not different from zero, and there were no differences (P > 0.05) in N retention among diets. Urinary N excretion and total N excretion were greater (P < 0.05) in A1, A2, and A3 compared with G, G1, or G2. Plasma concentrations for the majority of AA increased curvilinearly in response to feeding G, A1, A2, and A3 (quadratic, P < 0.05), with values appearing to maximize 2-h postfeeding. Although alfalfa N digestibility increased with decreasing harvest maturity, N retention did not differ and urinary volume and N excretion increased, indicating that postabsorptive N utilization decreased. In contrast, inclusion of oats at either 0.2 or 0.4% of the BW of the horse to timothy hay markedly enhanced N digestibility without increasing N excretion, indicating improvement in postgut N utilization. These findings indicate that feeding oat-supplemented timothy hay is more environmentally sustainable than feeding alfalfa to the horse at maintenance or under light to moderate exercise. PMID- 21788428 TI - Effects of bacterial lipopolysaccharide injection on white blood cell counts, hematological variables, and serum glucose, insulin, and cortisol concentrations in ewes fed low- or high-protein diets. AB - Bacterial lipopolysaccharide endotoxins (LPS) elicit inflammatory responses reflective of acute bacterial infection. We determined if feeding ewes high-CP (15.5%) or low-CP (8.5%) diets for 10 d altered inflammatory responses to an intravenous bolus of 0 (control), 0.75 (L75), or 1.50 (L150) MUg of LPS/kg of BW in a 2 * 3 factorial arrangement of treatments (n = 5/treatment). Rectal temperatures, heart and respiratory rates, blood leukocyte concentrations, and serum cortisol, insulin, and glucose concentrations were measured for 24 h after an LPS bolus (bolus = 0 h). In general, rectal temperatures were greater (P <= 0.05) in control ewes fed high CP, but LPS increased (P <= 0.05) rectal temperatures in a dose-dependent manner at most times between 2 and 24 h after the bolus. Peak rectal temperatures in L75 and L150 occurred 4 h after the bolus. A monophasic, dose-independent increase (P <= 0.023) in serum cortisol occurred from 0.5 to 24 h after the bolus, with peak cortisol at 4 h. Serum insulin was increased (P <= 0.016) by LPS in a dose-dependent manner from 4 to 24 h after the bolus. Insulin did not differ between control ewes fed high- and low-CP diets but was greater (P < 0.001) in L75 ewes fed low CP compared with high CP and in L150 ewes fed high CP compared with low CP. Increased insulin was not preceded by increased serum glucose. Total white blood cell concentrations were not affected (P >= 0.135) by LPS, but the neutrophil and monocyte fractions of white blood cells were increased (P <= 0.047) by LPS at 12 and 24 h and at 24 h after the bolus, respectively, and the lymphocyte fraction was increased (P = 0.037) at 2 h and decreased (P <= 0.006) at 12 and 24 h after the bolus. Red blood cell and hemoglobin concentrations and hematocrit (%) were increased (P <= 0.022) by LPS at 2 and 4 h after the bolus. Rectal temperatures and serum glucose were greater (P <= 0.033) in ewes fed a high-CP diet before LPS injection, but these effects were lost at and within 2.5 h of the bolus, respectively. Feeding high-CP diets for 10 d did not reduce inflammation in ewes during the first 24 h after LPS exposure but may benefit livestock by preventing acute insulin resistance when endotoxin exposure is mild. PMID- 21788429 TI - Bayesian estimation in maternally ancestral animal models for weaning weight of beef cattle. AB - The Bayesian approach was implemented for fitting several maternally ancestral models for weaning weight data of Angus calves. The goal was to evaluate to what extent genetic evaluation models with additive grand maternal effects (G), or with an ancestrally structured covariance matrix for maternal environmental effects (E), or with a sire * year interaction (ISY), or combinations thereof (GE, GSY, ESY, GESY), redistribute the additive variability and reduce the negative magnitude of the additive correlation between direct and maternal effects (r(AoAm)), when compared with the regular maternal animal model (I). All animals with records had known dams and maternal granddams. The sampling scheme induced low autocorrelations among all variables and tended to converge quickly. The signs of the estimates of r(AoAm) were consistently negative for all models fitted. The magnitudes of the estimates of r(AoAm) from models E, G, GE, ESY, and GESY were almost one-third of those from models I and ISY. Inclusion of the sire * year interaction had some effect in reducing the negative magnitude of r(AoAm), but also reduced the size of the estimates of direct (h(0)(2)) and maternal (h(m)(2)) heritabilities. In comparison, models E or G reduced the negative magnitude of r(AoAm) by 0.50 units and produced more favorable estimates of H(0)(2) and h(m)(2) than models I and ISY. The estimate of h(0)(2) from G was similar to the one from I; however, the estimated h(m)(2) was 0.04 units greater, whereas the estimate of r(AoAm) was much less negative (-0.21 vs. -0.71) than the respective estimates from I. The environmental correlation between the weaning weights of dams and their daughters (lambda) was estimated to be -0.28 +/- 0.03 in E and ESY, and -0.21 +/- 0.03 in GE and GESY. Inclusion of the sire * year interaction effect by itself did not have much of an impact in the reduction of the estimated magnitude of r(AoAm). Rank correlations among EBV for direct effects were larger than 0.94 and did not show any appreciable difference among models, whereas the rank correlation among maternal breeding values displayed differences in the ranking between I and the other models. Models E and ESY recovered the largest amount of total additive variability with maternal effects. PMID- 21788430 TI - Exploring breeding opportunities for reduced thermal sensitivity of feed intake in the lactating sow. AB - The aims of this study were, first, to evaluate the effects of climatic variables on daily feed intake of lactating sows and, second, to establish whether the response of sows to variation in temperature on feed intake during lactation was heritable. A total of 82,614 records for daily feed intake during lactation were available for 848 sows with 3,369 litters farrowing from January 2000 to December 2007. Climatic parameters available from the nearest weather station were maximum 24 h outside temperature, day length changes, and humidity. Although ambient room temperature was modified at the animal level in the farrowing shed, these climatic variables still had a significant effect on feed intake during lactation. Regression coefficients temperature and humidity were 0.01385 +/- 0.00300 (temperature) - 0.00031 +/- 0.00009 (temperature(2)) and 0.01443 +/- 0.00620 (humidity) - 0.00009 +/- 0.00004 (humidity(2)). There was an interaction between temperature and humidity, partly due to the climate control in the farrowing shed. At low temperature, feed intake increased considerably with greater humidity, in contrast to a small reduction in feed intake with greater humidity at high temperature. Day length change was modeled with a cosine function. At the start of autumn (September 21), sows ate 0.36 +/- 0.056 kg/d less feed than at the start of spring (March 21). Daily feed intake during lactation was described as a function of days in lactation and as a function of both days in lactation and temperature using random regression models. The average heritability and repeatability summarized over the day in lactation at the mean temperature were 0.21 and 0.69, respectively. Genetic variance of temperature response on feed intake was less than 20% of the day effect. The permanent environmental variance was 2-fold (day) and 4-fold (temperature) greater than the corresponding additive genetic variance. Heritabilities of daily feed intake were greater during the first week of lactation compared with the rest of lactation. The genetic correlation between days decreased as time increased down to about 0.2 between the first and last day in lactation. The genetic correlation between feed intake records at the extreme temperatures decreased to about -0.35. It was concluded that random regression models are useful for research and results may be used to develop simpler models that can be implemented in practical breeding programs. An effect of temperature on lactation feed intake was found even in this climate-controlled environment located in a temperate climate zone. Larger effects are expected in more extreme climatic conditions with less temperature-controlled farrowing sheds. PMID- 21788431 TI - Effects of prepartum supplementation of linoleic and mid-oleic sunflower seed on cow performance, cow reproduction, and calf performance from birth through slaughter, and effects on intake and digestion in steers. AB - Two experiments were conducted to determine the effects of sunflower seed supplements with varying fatty acid profiles on performance, reproduction, intake, and digestion in beef cattle. In Exp. 1, 127 multiparous spring-calving beef cows with free-choice access to bermudagrass hay were individually fed 1 of 3 supplements for an average of 83 d during mid to late gestation. Supplements (DM basis) included 1) 1.23 kg/d of a soybean hull-based supplement (control treatment); 2) 0.68 kg/d of linoleic sunflower seed plus 0.23 kg/d of the control supplement (linoleic treatment); and 3) 0.64 kg/d of mid-oleic sunflower seed plus 0.23 kg/d of the control supplement (oleic treatment). During the first 62 d of supplementation, the BW change was 11, 3, and -3 kg for cows fed the control, linoleic, and oleic supplements, respectively (P < 0.001). No difference in BW change was observed during the subsequent period (-65 kg, P = 0.83) or during the entire 303-d experiment (-31 kg, P = 0.49). During the first 62 d of supplementation, cows fed sunflower supplements tended (P = 0.08) to lose more body condition than cows fed the control diet, but BCS was not different (P > 0.22) for any subsequent measurement. At the beginning of the breeding season, the percentage of cows exhibiting luteal activity was greater for cows fed the control diet (43%; P = 0.02) than for cows fed either linoleic (20%) or oleic (16%) supplementation; however, first-service conception rate (67%; P = 0.22) and pregnancy rate at weaning (92%; P = 0.18) were not different among supplements. No differences were detected in calf birth (P = 0.46) or weaning BW (P = 0.74). In Exp. 2, 8 ruminally cannulated steers were used to determine the effects of sunflower seed supplementation on forage intake and digestion. Treatments (DM basis) included 1) no supplement; 2) a soybean hull-based supplement fed at 0.29% of BW/d; 3) whole linoleic sunflower seed fed at 0.16% of BW/d; and 4) whole high oleic sunflower seed fed at 0.16% of BW/d. Hay intake was not influenced (P = 0.25) by supplement (1.51% of BW/d); however, DMI was greatest (P < 0.01) for steers fed the soybean hull-based supplement (1.93% of BW/d). Sunflower seed supplementation reduced (P < 0.01) NDF and ADF digestibility while increasing (P < 0.01) apparent CP and apparent lipid digestibility. In conclusion, whole sunflower seed supplementation resulted in reduced cow BW gain during mid to late gestation, but this reduction did not influence subsequent cow BW change, pregnancy rate, or calf performance. PMID- 21788432 TI - Visually undetected fever episodes in newly received beef bulls at a fattening operation: occurrence, duration, and impact on performance. AB - Monitoring body temperature of newly received cattle allows for identification of fever episodes not visually detected by feedlot personnel (FENO). Information concerning the occurrence, duration, and impact on performance of these FENO is not available in the literature. Such information is crucial to assess the potential benefit of the identification and treatment of FENO. Therefore, the objectives of this study were to describe the occurrence and duration of FENO and to evaluate their impact on ADG. One hundred twelve beef bulls (initial BW = 346 +/- 36 kg) were studied for 40 d after arrival at 3 French fattening operations. At d 1, each animal was administered orally a reticulo-rumen bolus, which allowed continuous measurement and recording of reticulo-rumen temperature. Animals were weighed on d 1 and 40. Bulls were observed twice daily by personnel for visual signs of apparent disease. Bulls that appeared ill, had a rectal temperature >=39.7 degrees C, and demonstrated symptoms consistent with bovine respiratory disease (BRD) were treated with antibiotics. After d 40, data obtained from the boluses were retrospectively analyzed using a cumulative sum test to detect significant increases in reticulo-rumen temperature considered as fever episodes. Numerous fever episodes (n = 449) were retrospectively detected in 110 bulls. Of these 449 fever episodes, 74% were not associated with any visually detected clinical signs of disease and thus were identified as FENO. These FENO were often transitory (75% lasted less than 47 h). However, 25% lasted from 47 to 263 h. Of the 112 bulls, 88 were treated for BRD with 20 and 7 animals treated, respectively, 2 and 3 times. In treated animals, fever episodes began 4 to 177 h (mean = 50 h) before BRD treatment. The duration of FENO was associated (P = 0.002) with a lesser ADG (d 1 to 40): -33 g/d for daily FENO duration. Our results demonstrated that FENO occurred frequently in bulls during the first weeks after entrance into a fattening operation and can last up to 11 d. The impact of FENO observed on ADG in this study indicated a potential benefit of treating affected animals, specifically those with FENO of long duration. However, further research is needed to determine the medical and economic relevance of such treatment. PMID- 21788433 TI - Effect of shearing on water turnover and thermobiological variables in German Blackhead mutton sheep. AB - Current equations for estimating water requirements in sheep do not differentiate between shorn and unshorn sheep. Furthermore, the effect of shearing on thermoregulative responses in sheep has not been adequately studied under temperate environmental conditions. Therefore, the present study was conducted to investigate the effect of wool coverage on water turnover in relation to thermoregulation in sheep by using the deuterium dilution technique to predict total water intake before and after shearing. Physiological responses, such as water turnover, surface temperature, and rectal temperature, as well as drinking behavior of sheep were also evaluated. Fourteen nonlactating German Blackhead mutton ewes were randomly allocated into 2 groups: a control group (n = 7) that was already shorn, and a treatment group (n = 7) that was left unshorn (wool length: 10.6 +/- 1.2 cm). Individual feed and water intakes were recorded throughout the experiment (d 1 to 71). Two weeks after measurements commenced (d 15), treatment sheep were shorn. Water intake was estimated twice for 2 consecutive weeks by using deuterium dilution techniques (d 1 to 15 and d 57 to 71). Ambient temperature (T(a)), relative humidity, and respiratory rate were measured daily, whereas BW, rectal and animal surface temperatures (using infrared thermography), and wool length were measured weekly. In the first 2 wk, when treatment sheep were unshorn, treatment and control ewes differed (P < 0.05) in DMI (52 +/- 4 vs. 59 +/- 4 g.kg(-0.75).d(-1)), water intake (165 +/- 17 vs. 134 +/- 18 g.kg(-0.75).d(-1)), respiratory rate (66 +/- 5 vs. 31 +/- 4 breath/min), rectal temperature (39.3 +/- 0.2 vs. 38.8 +/- 0.1 degrees C), and surface temperatures (body side: 19.3 +/- 0.3 vs. 24.5 +/- 0.6 degrees C; leg: 25.8 +/- 2.4 vs. 27.4 +/- 1.6 degrees C). However, after shearing, these differences partly disappeared. The same trend in water intake between groups was confirmed using the isotope dilution technique. We found a significant relationship between T(a) and water intake, respiratory rate, and body surface temperatures. Even under temperate conditions (T(a) < 28 degrees C), shearing significantly reduced core body temperature, water intake, and respiratory rate in German Blackhead mutton sheep, thus indicating heat stress in fleeced animals, which should be considered when determining the optimal shearing time in sheep as well as when estimating water requirements. PMID- 21788434 TI - Identification of multipotent stem/progenitor cells in murine sclera. AB - PURPOSE: The sclera forms the fibrous outer coat of the eyeball and acts as a supportive framework. The purpose of this study was to examine whether the sclera contains mesenchymal stem/progenitor cells. METHOD: Scleral tissue from C57BL6/J mice was separated from the retina and choroid and subsequently enzyme digested to release single cells. Proliferation capacity, self-renewal capacity, and ability for multipotent differentiation were analyzed by BrdU labeling, flow cytometry, reverse transcriptase-polymerase chain reaction, immunocytochemistry, and in vivo transplantation. RESULTS: The scleral stem/progenitor cells (SSPCs) possessed clonogenic and high doubling capacities. These cells were positive for the mesenchymal markers Sca-1, CD90.2, CD44, CD105, and CD73 and negative for the hematopoietic markers CD45, CD11b, Flk1, CD34, and CD117. In addition to expressing stem cell genes ABCG2, Six2, Notch1, and Pax6, SSPCs were able to differentiate to adipogenic, chondrogenic, and neurogenic lineages. CONCLUSIONS: This study indicates that the sclera contains multipotent mesenchymal stem cells. Further study of SSPCs may help elucidate the cellular and molecular mechanism of scleral diseases such as scleritis and myopia. PMID- 21788435 TI - Concentrations of IGF-I and IGFBP-3 and brain tumor risk in the European Prospective Investigation into Cancer and Nutrition. AB - BACKGROUND: Insulin-like growth factor-1 (IGF-I) is important in normal brain development but in the adult brain, IGF-I overexpression may be a risk factor for tumor development. METHODS: We examined the association between circulating concentrations of IGF-I and IGFBP-3 in relation to risk of gliomas (74 low-grade, 206 high-grade gliomas), meningiomas (n = 174) and acoustic neuromas (n = 49) by using a case-control design nested in the European Prospective Investigation into Cancer and Nutrition. IGF-I and IGFBP-3 were measured by ELISAs.Conditional logistic regression was used to compute ORs and corresponding 95% CIs. RESULTS: The risk of low-grade gliomas was elevated with increased IGF-I (OR = 3.60, 95% CI: 1.11-11.7; top vs. bottom quartile) and decreased with elevated IGFBP-3 concentrations (OR = 0.28, 95% CI: 0.09-0.84) after mutual adjustment of these two factors; these results became nonsignificant after exclusion of the first year of follow-up. No association was observed for high-grade gliomas or meningiomas. Both high IGF-I and IGFBP-3 concentrations were associated with risk of acoustic neuromas (IGF-I: OR = 6.63, 95% CI: 2.27-19.4, top vs. bottom tertile; IGFBP-3: OR = 7.07, 95% CI: 2.32-21.6), even after excluding the first year of follow-up. CONCLUSION: High concentrations of IGF-I might be positively associated with risk of low-grade gliomas and acoustic neuromas, although we cannot exclude reverse causation, in particular for low-grade gliomas. IMPACT: Factors of the IGF axis might be involved in the etiology of some types of brain tumors. PMID- 21788436 TI - Quality-of-life measures in children with neurological conditions: pediatric Neuro-QOL. AB - BACKGROUND: A comprehensive, reliable, and valid measurement system is needed to monitor changes in children with neurological conditions who experience lifelong functional limitations. OBJECTIVE: This article describes the development and psychometric properties of the pediatric version of the Quality of Life in Neurological Disorders (Neuro-QOL) measurement system. METHODS: The pediatric Neuro-QOL consists of generic and targeted measures. Literature review, focus groups, individual interviews, cognitive interviews of children and consensus meetings were used to identify and finalize relevant domains and item content. Testing was conducted on 1018 children aged 10 to 17 years drawn from the US general population for generic measures and 171 similarly aged children with muscular dystrophy or epilepsy for targeted measures. Dimensionality was evaluated using factor analytic methods. For unidimensional domains, item parameters were estimated using item response theory models. Measures with acceptable fit indices were calibrated as item banks; those without acceptable fit indices were treated as summary scales. RESULTS: Ten measures were developed: 8 generic or targeted banks (anxiety, depression, anger, interaction with peers, fatigue, pain, applied cognition, and stigma) and 2 generic scales (upper and lower extremity function). The banks reliably (r > 0.90) measured 63.2% to 100% of the children tested. CONCLUSIONS: The pediatric Neuro-QOL is a comprehensive measurement system with acceptable psychometric properties that could be used in computerized adaptive testing. The next step is to validate these measures in various clinical populations. PMID- 21788437 TI - Merging developmental and criminal career perspectives: implications for risk assessment and risk prediction of violent/sexual recidivism in adult sexual aggressors of women. AB - Currently, a majority of actuarial risk-assessment tools for sexual recidivism contain static risk factors that measure various aspects of the offender's prior criminal history in adulthood. The goal of the current study was to assess the utility of extending static risk factors, by using developmental and criminal career parameters of offending, in the actuarial assessment of risk of violent/sexual recidivism. The current study was based on a sample of 204 convicted sexual aggressors of women incarcerated in the province of Quebec, Canada between April 1994 and June 2000. Semistructured interviews were used to gather information on the offender's antisocial history prior to adulthood, and police records were used to collect data on the criminal career of these offenders in adulthood. For an average follow-up period of approximately 4 years, the violent/sexual recidivism rate for the sample was 23.7%. The results provided support for the inclusion of both developmental and criminal career indicators for the prediction of violent/sexual recidivism. More specifically, recidivists were characterized by an early onset antisocial trajectory and a pattern of escalation of antisocial behavior between childhood and adolescence. The findings suggest that risk assessors should look beyond broad adult criminal history data to include aspects of antisocial development to improve predictive accuracy. PMID- 21788438 TI - Validation of an adaptation of Levenson's locus of control scale with adult male incarcerated sexual offenders. AB - This article examines the psychometric properties of an adaptation of Levenson's Locus of Control (LoC) measure that is used by the English and Welsh Prison Service as part of the psychometric assessment battery for sexual offenders participating in the Sex Offender Treatment Programme (SOTP). Reliability and validity analyses were conducted on a sample of 2,497 sexual offenders who had completed SOTP. Internal consistency, convergent validity, and relationship to socially desirable responding were investigated. Construct validity was assessed via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Test-retest reliability data were collected from an additional sample of 26 sexual offenders. The scale was found to have excellent internal consistency, good test-retest reliability, and weak to moderate convergent validity with measures of self-esteem, attachment styles, emotional loneliness, and social problem solving. There was a moderate correlation between the scale and socially desirable responding. EFA and CFA suggested that a four-factor solution provided an acceptable fit to the data, with the factors relating to constructs of chance, problem solving, powerful others, and internal control. The findings of the present study suggest that the adapted LoC Scale is a useful tool for assessing sexual offenders' locus of control. PMID- 21788439 TI - Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. AB - IFN-gamma-producing Th1 and IL-17-producing Th17 cells are the key participants in various autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Although both of these T cell subsets are known to be regulated by specific transcription factors and cytokines, the role of microRNAs that control these two inflammatory T cell subsets and whether targeting microRNAs can have therapeutic effects are not known. In this study, we show that microRNA-155 (Mir-155) expression is elevated in CD4(+) T cells during EAE, and Mir-155(-/-) mice had a delayed course and reduced severity of disease and less inflammation in the CNS. The attenuation of EAE in Mir-155(-/-) mice was associated with a decrease in Th1 and Th17 responses in the CNS and peripheral lymphoid organs. The T cell-intrinsic function of Mir 155(-/-) was demonstrated by the resistance of Mir-155(-/-) CD4(+) T cell repleted Rag-1(-/-) mice to EAE. Finally, we found that anti-Mir-155 treatment reduced clinical severity of EAE when given before and after the appearance of clinical symptoms. These findings demonstrate that Mir-155 confers susceptibility to EAE by affecting inflammatory T cell responses and identify Mir-155 as a new target for therapeutic intervention in multiple sclerosis. PMID- 21788440 TI - Immune unresponsiveness to secondary heterologous bacterial infection after sepsis induction is TRAIL dependent. AB - Sepsis is the leading cause of death in most intensive care units, and patients who survive the hyperinflammation that develops early during sepsis later display severely compromised immunity. Not only is there apoptosis of lymphoid and myeloid cells during sepsis that depletes these critical cellular components of the immune system, but also the remaining immune cells show decreased function. Using a cecal-ligation and puncture (CLP) model to induce intra-abdominal polymicrobial peritonitis, we recently established a link between the apoptotic cells generated during sepsis and induction of sepsis-induced suppression of delayed-type hypersensitivity. The present study extends this earlier work to include a secondary heterologous bacterial infection (OVA(257)-expressing Listeria monocytogenes [LM-OVA]) subsequent to sepsis initiation to investigate sepsis-induced alterations in the control of this secondary infection and the associated naive Ag-specific CD8 T cell response. We found that CLP-treated wild type (WT) mice had a reduced ability to control the LM-OVA infection, which was paralleled by suppressed T cell responses, versus sham-treated WT mice. In contrast, CLP-treated Trail(-/-) and Dr5(-/-) mice were better able to control the secondary bacterial infection, and the Ag-specific CD8 T cell response was similar to that seen in sham-treated mice. Importantly, administration of a blocking anti-TRAIL mAb to CLP-treated WT mice was able to restore the ability to control the LM-OVA infection and generate Ag-specific CD8 T cell responses like those seen in sham-treated mice. These data further implicate TRAIL-dependent immune suppression during sepsis and suggest TRAIL neutralization may be a potential therapeutic target to restore cellular immunity in septic patients. PMID- 21788441 TI - FTY720 blocks egress of T cells in part by abrogation of their adhesion on the lymph node sinus. AB - Egress of lymphocytes from lymphoid tissues is a complex process in which Galphai mediated signals play a decisive role. We show here that although FTY720, an agonist of the sphingosine 1-phosphate (S1P)(1) receptor, induces S1P(1) receptor internalization sufficiently in the presence or absence of Galphai2 or Galphai3, the drug blocks egress of wild-type (WT) and Galphai3-deficent T cells, but not Galphai2-deficient T cells, in both WT and Galphai2-deficient hosts. Intravital imaging of lymph nodes revealed that all three groups of T cells approached and engaged cortical sinusoids similarly in the presence or absence of FTY720. The cells also entered and departed the sinus at an almost identical frequency in the absence of the drug. However, after engagement of the sinus, most WT and Galphai3 deficient T cells retracted and migrated back into the parenchyma in FTY720 treated animals, due to a failure of the cells to establish adhesion on the sinus, whereas Galphai2-deficient T cells adhered firmly on the sinus, which prevented their retraction, facilitating their transmigration of the lymphatic endothelial barrier. These data confirm egress of Galphai2(-/-) T cells independent of S1P-mediated chemotaxis and failure of FTY720 to close lymphatic stromal channels and argue for the first time, to our knowledge, that FTY720 induces lymphopenia in part by impairing T cell adhesion to the sinus in a manner dependent on Galphai2. PMID- 21788442 TI - Inhibition of SOCS1-/- lethal autoinflammatory disease correlated to enhanced peripheral Foxp3+ regulatory T cell homeostasis. AB - Suppressor of cytokine signaling 1-deficient (SOCS1(-/-)) mice, which are lymphopenic, die <3 wk after birth of a T cell-mediated autoimmune inflammatory disease characterized by leukocyte infiltration and destruction of vital organs. Notably, Foxp3(+) regulatory T cells (Tregs) have been shown to be particularly potent in inhibiting inflammation-associated autoimmune diseases. We observed that SOCS1(-/-) mice were deficient in peripheral Tregs despite enhanced thymic development. The adoptive transfer of SOCS1-sufficient Tregs, CD4(+) T lymphocytes, or administration of SOCS1 kinase inhibitory region (KIR), a peptide that partially restores SOCS1 function, mediated a statistically significant but short-term survival of SOCS1(-/-) mice. However, the adoptive transfer of SOCS1 sufficient CD4(+) T lymphocytes, combined with the administration of SOCS1-KIR, resulted in a significant increase in the survival of SOCS1(-/-) mice both short and long term, where 100% death occurred by day 18 in the absence of treatment. Moreover, the CD4(+)/SOCS1-KIR combined therapy resulted in decreased leukocytic organ infiltration, reduction of serum IFN-gamma, and enhanced peripheral accumulation of Foxp3(+) Tregs in treated mice. These data show that CD4(+)/SOCS1 KIR combined treatment can synergistically promote the long-term survival of perinatal lethal SOCS1(-/-) mice. In addition, these results strongly suggest that SOCS1 contributes to the stability of the Foxp3(+) Treg peripheral population under conditions of strong proinflammatory environments. PMID- 21788443 TI - Presentation of type B peptide-MHC complexes from hen egg white lysozyme by TLR ligands and type I IFNs independent of H2-DM regulation. AB - In APCs, presentation by MHC II molecules of the chemically dominant peptide from the protein hen egg white lysozyme (HEL) generates different conformational isomers of the peptide-MHC II complexes (pMHC). Type B pMHCs are formed in early endosomes from exogenous peptides in the absence of H2-DM, whereas in contrast, type A pMHC complexes are formed from HEL protein in late vesicles after editing by H2-DM. Thus, H2-DM edits off the more unstable pMHC complexes, which are not presented from HEL. In this study, we show that type B pMHC complexes were presented from HEL protein only after stimulation of dendritic cells (DC) with TLR ligands or type I IFN. Type I IFN contributed to most TLR ligand-induced type B pMHC generation, as presentation decreased in DC lacking the receptor for type I IFNs (IFNAR1(-/-)). In contrast, presentation of type A pMHC from HEL and from peptide was minimally affected by TLR ligands. The relative effectiveness of CD8alpha(+) DC or CD8alpha(-) DC in presenting type B pMHC complexes varied depending on the TLR ligand used. The mechanisms of generation of type B pMHC from HEL protein with TLR stimulation did not involve H2-DM or release of peptides. DC from H2-DM-deficient mice in the presence of TLR ligands presented type B pMHC. Such DC showed a slight enhancement of HEL catabolism, but peptide release was not evident. Thus, TLR ligands and type I IFN alter the pathways of presentation by MHC II molecules of DC such that type B pMHCs are generated from protein Ag. PMID- 21788444 TI - Delta-like ligand 4 regulates central nervous system T cell accumulation during experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated inflammatory demyelinating disease of the CNS that serves as a model for multiple sclerosis. Notch receptor signaling in T lymphocytes has been shown to regulate thymic selection and peripheral differentiation. In the current study, we hypothesized that Notch ligand-receptor interaction affects EAE development by regulating encephalitogenic T cell trafficking. We demonstrate that CNS infiltrating myeloid dendritic cells, macrophages, and resident microglia expressed Delta-like ligand 4 (DLL4) after EAE induction. Treatment of mice with a DLL4-specific blocking Ab significantly inhibited the development of clinical disease induced by active priming. Furthermore, the treatment resulted in decreased CNS accumulation of mononuclear cells in the CNS. Anti-DLL4 treatment did not significantly alter development of effector cytokine expression by Ag specific T cells. In contrast, anti-DLL4 treatment reduced T cell mRNA and functional cell surface expression of the chemokine receptors CCR2 and CCR6. Adoptive transfer of Ag-specific T cells to mice treated with anti-DLL4 resulted in decreased clinical severity and diminished Ag-specific CD4(+) T cell accumulation in the CNS. These results suggest a role for DLL4 regulation of EAE pathogenesis through modulation of T cell chemokine receptor expression and migration to the CNS. PMID- 21788446 TI - Reversible senescence in human CD4+CD45RA+CD27- memory T cells. AB - Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4(+) effector memory (EM) T cells (CD27(-)CD45RA(-)) and also EM T cells that re-express CD45RA (CD27(-)CD45RA(+); EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear gammaH2AX after TCR activation. A paradoxical observation was that although CD4(+) EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM) like (CD27(+)CD45RA(-)) and EM (CD27(-)CD45RA(-)) CD4(+) T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-alpha inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4(+) EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4(+) T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4(+) EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4(+) T cells. In particular, CD4(+) EMRA T cells have features of telomere independent senescence that are regulated by active cell signaling pathways that are reversible. PMID- 21788447 TI - Insomnia and physical activity in adults with prediabetes. AB - This secondary analysis study examines the relationship between physical activity and symptoms of insomnia among adults with prediabetes (N = 958) from the 2005 2006 National Health and Nutrition Examination Survey (NHANES). The sample of participants were generally obese, middle-aged, and racially diverse. NHANES questions included symptoms of insomnia, sleep duration, and sleep latency. Body mass index (BMI) was calculated from measured height and weight; at least 2 days of ActiGraph activity monitor data determined mean steps walked. Men walked more steps than women; however, women had more insomnia symptoms. There were significant associations between insomnia symptoms and increased sleep latency and decreased sleep duration. Multiple regression analysis showed that younger age, lower BMI, higher self-rated health, high school education, and fewer insomnia symptoms were significantly related to increased steps walked. The findings indicate that insomnia in adults with prediabetes may be a barrier to their adapting an active lifestyle. PMID- 21788448 TI - Incidence and cost of serious fall-related injuries in nursing homes. AB - BACKGROUND: Fall-related injuries (FRIs) result in morbidity and mortality for patients, as well as unnecessary expense to health care institutions. OBJECTIVES: (a) Estimate the incidence of falls and FRIs with a nursing home as the source of admission in Veterans Administration (VA) and non-VA facilities. (b) Estimate the cost of hospitalizations for each level of FRI severity. RESEARCH DESIGN: Retrospective analysis of falls and FRI resulting in a hospitalization whose source of admission was a VA nursing home. DATA: Falls and FRIs were obtained from Minimum Data Set (MDS) reports (January 2007-June 2009). Costs were obtained from the VA Decision Support System reports and Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) reports (2000 2006). MEASURES: Incidence of falls, fracture incidence, number of hospitalizations for FRIs, and costs associated with hospitalization for by level of FRI severity. RESULTS: Fall incidence was 10.6% in VA and 13.1% in CMS facilities. Fracture incidence was 0.9% in VHA and 1.65% in CMS facilities. Over a 3-year period, there were 2,400 admissions to VHA hospitals for FRI, with 55.4% hip fractures and10.1% intracranial injuries, with an average cost of US$23,723 per admission. Over a 9-year period, there were 141,308 admissions from nursing homes to non-VA hospitals for FRIs, with 38.8% hip fractures, 35.7% other fractures, and 11.1% intracranial injuries, with an average cost of US$31,507 per admission. CONCLUSIONS: Prevention program emphasis should shift away from a focus on preventing falls as a measure of quality care to decreasing FRIs. These findings support implementation of injury prevention programs for the elderly that reduces risk for injury as the primary outcome. PMID- 21788445 TI - MicroRNA regulation of molecular networks mapped by global microRNA, mRNA, and protein expression in activated T lymphocytes. AB - MicroRNAs (miRNAs) regulate specific immune mechanisms, but their genome-wide regulation of T lymphocyte activation is largely unknown. We performed a multidimensional functional genomics analysis to integrate genome-wide differential mRNA, miRNA, and protein expression as a function of human T lymphocyte activation and time. We surveyed expression of 420 human miRNAs in parallel with genome-wide mRNA expression. We identified a unique signature of 71 differentially expressed miRNAs, 57 of which were previously not known as regulators of immune activation. The majority of miRNAs are upregulated, mRNA expression of these target genes is downregulated, and this is a function of binding multiple miRNAs (combinatorial targeting). Our data reveal that consideration of this complex signature, rather than single miRNAs, is necessary to construct a full picture of miRNA-mediated regulation. Molecular network mapping of miRNA targets revealed the regulation of activation-induced immune signaling. In contrast, pathways populated by genes that are not miRNA targets are enriched for metabolism and biosynthesis. Finally, we specifically validated miR-155 (known) and miR-221 (novel in T lymphocytes) using locked nucleic acid inhibitors. Inhibition of these two highly upregulated miRNAs in CD4(+) T cells was shown to increase proliferation by removing suppression of four target genes linked to proliferation and survival. Thus, multiple lines of evidence link top functional networks directly to T lymphocyte immunity, underlining the value of mapping global gene, protein, and miRNA expression. PMID- 21788449 TI - Motion sickness on tilting trains. AB - Trains that tilt on curves can go faster, but passengers complain of motion sickness. We studied the control signals and tilts to determine why this occurs and how to maintain speed while eliminating motion sickness. Accelerometers and gyros monitored train and passenger yaw and roll, and a survey evaluated motion sickness. The experimental train had 3 control configurations: an untilted mode, a reactive mode that detected curves from sensors on the front wheel set, and a predictive mode that determined curves from the train's position on the tracks. No motion sickness was induced in the untilted mode, but the train ran 21% slower than when it tilted 8 degrees in either the reactive or predictive modes (113 vs. 137 km/h). Roll velocities rose and fell faster in the predictive than the reactive mode when entering and leaving turns (0.4 vs. 0.8 s for a 4 degrees /s roll tilt, P<0.001). Concurrently, motion sickness was greater (P<0.001) in the reactive mode. We conclude that the slower rise in roll velocity during yaw rotations on entering and leaving curves had induced the motion sickness. Adequate synchronization of roll tilt with yaw velocity on curves will reduce motion sickness and improve passenger comfort on tilting trains. PMID- 21788450 TI - Nuclear localization of gamma-tubulin affects E2F transcriptional activity and S phase progression. AB - We show that the centrosome- and microtubule-regulating protein gamma-tubulin interacts with E2 promoter binding factors (E2Fs) to modulate E2F transcriptional activity and thereby control cell cycle progression. gamma-Tubulin contains a C terminal signal that results in its translocation to the nucleus during late G(1) to early S phase. gamma-Tubulin mutants showed that the C terminus interacts with the transcription factor E2F1 and that the E2F1-gamma-tubulin complex is formed during the G(1)/S transition, when E2F1 is transcriptionally active. Furthermore, E2F transcriptional activity is altered by reduced expression of gamma-tubulin or by complex formation between gamma-tubulin and E2F1, E2F2, or E2F3, but not E2F6. In addition, the gamma-tubulin C terminus encodes a DNA-binding domain that interacts with E2F-regulated promoters, resulting in gamma-tubulin-mediated transient activation of E2Fs. Thus, we report a novel mechanism regulating the activity of E2Fs, which can help explain how these proteins affect cell cycle progression in mammalian cells. PMID- 21788452 TI - Immunization of human volunteers with hepatitis C virus envelope glycoproteins elicits antibodies that cross-neutralize heterologous virus strains. PMID- 21788451 TI - The critical need for alternative antiretroviral formulations, and obstacles to their development. PMID- 21788453 TI - Mexican American birthweight and child overweight: unraveling a possible early life course health transition. AB - Mexican American children have a weight distribution that categorizes them as relatively healthy at birth but relatively unhealthy by age 3. This early life course transition in health based on weight raises the question of whether Mexican American children "outgrow" the epidemiologic paradox of favorable birth outcomes despite social disadvantage or whether their birthweight distribution places them on trajectory for overweight in childhood. We address this question using newly available 9-year follow-up data from the Fragile Families and Child Wellbeing birth cohort study linked to pre-natal medical records. We systematically investigate the roles of birthweight, pre-natal factors, and childhood factors in explaining racial/ethnic differences in childhood overweight. Our main finding is that Mexican American children do outgrow the paradox: Their rates of childhood overweight are higher than expected given their birthweight distribution. Observed pre-natal and childhood factors do not explain the elevated rates of overweight among Mexican American children. PMID- 21788454 TI - Intrinsic epidemicity of Streptococcus pneumoniae depends on strain serotype and antibiotic susceptibility pattern. AB - Streptococcus pneumoniae is a major cause of invasive diseases worldwide. It spreads through an interindividual transmission, followed by usually harmless colonization of the host. Possible transmission differences reflecting intrinsic strain features (e.g., serotype and antibiotic susceptibility) have been little studied so far. In this study, we used epidemiological data from an interventional trial of S. pneumoniae carriage among kindergartners and developed a mathematical model to estimate the transmission parameters of the different strains isolated during that study. We found small but significant transmissibility differences between the observed serotypes: serotypes 3, 6A, and 19A were found to be the most epidemic, while serotypes 23F, 9V, and 14 were the least epidemic. Further analysis indicated that, within a serotype, susceptible and resistant strains had different abilities to be transmitted. Susceptible-to resistant transmission rate ratios were computed for five serotypes; susceptible strains were significantly more epidemic than resistant strains for serotypes 6A (mean, 1.02) and 19F (1.05). Serotype 19A resistant strains were not outcompeted by susceptible strains (0.97). Nonsignificant trends were observed for serotypes 6B (1.01) and 15A (0.98). Our results support the existence of heterogeneous abilities of the different serotypes for host-to-host transmission. They also suggest that antibiotic susceptibility within a serotype affects this transmissibility. We conclude that pneumococcal strains should not be considered equally at-risk in terms of transmission. Further quantification of strain specific epidemic potential is needed, especially in a context of extensive use of conjugate vaccines with the aim of preventing pneumococcal infections. PMID- 21788455 TI - The periplasmic protein MppA is not involved in regulation of marA in Escherichia coli. PMID- 21788456 TI - Extended-spectrum AmpC cephalosporinase in Acinetobacter baumannii: ADC-56 confers resistance to cefepime. AB - ADC-56, a novel extended-spectrum AmpC (ESAC) beta-lactamase, was identified in an Acinetobacter baumannii clinical isolate. ADC-56 possessed an R148Q change compared with its putative progenitor, ADC-30, which enabled it to hydrolyze cefepime. Molecular modeling suggested that R148 interacted with Q267, E272, and I291 through a hydrogen bond network which constrained the H-10 helix. This permitted cefepime to undergo conformational changes in the active site, with the carboxyl interacting with R340, likely allowing for better binding and turnover. PMID- 21788457 TI - Characterizing vancomycin-resistant Enterococcus strains with various mechanisms of daptomycin resistance developed in an in vitro pharmacokinetic/pharmacodynamic model. AB - Two daptomycin (DAP) regimens were evaluated in a pharmacokinetic/pharmacodynamic (PK/PD) model, and the mutants recovered were examined for changes in phenotypic characteristics. Three Enterococcus faecium strains (vancomycin-resistant Enterococcus [VRE] ATCC 51559, VRE 12311, and VRE SF 12047) were utilized in a 7 day, 1-compartment in vitro PK/PD model. The simulated dosing regimens were DAP at 6 mg/kg/day (free C(max) [fC(max)] = 7.9 MUg/ml, half-life [t(1/2)] = 8 h) and DAP at 10 mg/kg/day (fC(max) = 13.17 MUg/ml, t(1/2) = 8 h). Samples were plated daily on Mueller-Hinton agar containing DAP at 16 MUg/ml and 50 mg/liter Ca(2+) to assess the emergence of DAP resistance. For each strain, the mutant with the highest DAP MIC was then evaluated for changes in relative surface charge, cell wall thickness, and cytoplasmic membrane depolarization induced by DAP. The initial DAP MICs were 4 MUg/ml for all 3 strains. A dose-dependent response and regrowth were observed for DAP 6 mg/kg/day and DAP 10 mg/kg/day against all 3 strains. Mutants of VRE ATCC 51559 (MIC = 128 and 64 MUg/ml) and VRE 12311 (MIC = 256 and 32 MUg/ml) were recovered from the DAP 6 mg and DAP 10 mg regimen, respectively. For VRE SF 12047, a mutant (MIC = 64 MUg/ml) was recovered from the DAP 6 mg model. All mutants displayed an increase in relative surface charge compared to those of their respective parent strains. The DAP-resistant mutants displayed a 43 to 58% increase in cell wall thickness (P < 0.0001), while DAP membrane depolarization decreased by 53 to 65% compared to that of the susceptible strains. VRE with DAP resistance displayed increased surface charge, increased cell wall thickness, and decreased depolarization induced by DAP, consistent with previous observations in Staphylococcus aureus with reduced DAP susceptibility. Further characterization of DAP-resistant VRE is warranted. PMID- 21788458 TI - In vitro selection of variants resistant to beta-lactams plus beta-lactamase inhibitors in CTX-M beta-lactamases: predicting the in vivo scenario? AB - CTX-M beta-lactamases are the most prevalent group of enzymes within the extended spectrum beta-lactamases (ESBL). The therapeutic options for CTX-M-carrying isolates are scarce, forcing the reexamination of the therapeutic possibilities of beta-lactams plus beta-lactamase inhibitors (BBLIs). Inhibitor-resistant CTX-M beta-lactamases (IR-CTX-M) have not hitherto been described in natural isolates. In this study, 168 cultures of the hypermutagenic Escherichia coli GB20 strain carrying plasmid pBGS18 with different bla(CTX-M) genes were submitted to parallel experimental evolution assays in the presence of increasing concentrations of a combination of amoxicillin and clavulanate. Fourteen CTX-M beta-lactamases belonging to the three most representative clusters (CTX-M-1, -2, and -9) and the two main phenotypes (cefotaxime resistance and cefotaxime ceftazidime resistance) were studied. Three types of IR-CTX-M mutants were detected, having mutations S130G, K234R, and S237G, which are associated with different resistance patterns. The most frequently recovered mutation was S130G, which conferred the highest resistance levels to BBLIs (reaching 12 MUg/ml for amoxicillin-clavulanate and 96 MUg/ml for piperacillin-tazobactam when acquired by CTX-M-1 cluster enzymes). The S130G change also provided a clear antagonistic pleiotropy effect, strongly decreasing the enzyme's activity against all cephalosporins tested. A double mutation, S130G L169S, partially restored the resistance against cephalosporins. A complex pattern observed in CTX-M-58, carrying P167S and S130G or K234R changes, conferred ESBL and IR phenotypes simultaneously. The K234R and S237G changes had a smaller effect in providing inhibitor resistance. In summary, IR-CTX-M enzymes might evolve under exposure to BBLIs, and the probability is higher for enzymes belonging to the CTX-M-1 cluster. However, this process could be delayed by antagonistic pleiotropy. PMID- 21788460 TI - Outcomes of moderate-to-severe Pneumocystis pneumonia treated with adjunctive steroid in non-HIV-infected patients. AB - While it is well-known that adjunctive corticosteroid use improves the outcome of moderate-to-severe Pneumocystis jirovecii pneumonia (PcP) in patients with human immunodeficiency virus (HIV), there are limited data on its efficacy in non-HIV infected patients with PcP. Patients undergoing fiber-optic bronchoscopy with bronchoalveolar lavage for suspected PcP from January 2007 through December 2010 were reviewed retrospectively. We compared demographics, clinical characteristics, and outcomes in 88 non-HIV-infected patients with moderate-to severe PcP with (n = 59) and without (n = 29) adjunctive corticosteroid use. Outcomes of PcP were assessed by respiratory failure and 30-day and 90-day all cause mortality. Survival curves were analyzed by the Kaplan-Meier method and estimated by the log rank test. All-cause mortality of moderate-to-severe PcP at 90 days was lower in the solid-organ transplant recipients than in all other patients (6/26 [23%] versus 34/62 [55%], respectively; P = 0.006), and mortality at 30 days was lower in patients with hematologic malignancies than in all other patients (4/26 [15%] versus 24/62 [39%], respectively; P = 0.03). The outcomes of PcP were not significantly different in moderate-to-severe PcP patients with and without adjunctive corticosteroid use, regardless of recent corticosteroid use. Survival analysis of PcP patients with and without corticosteroid use by the Kaplan-Meier method also did not reveal any difference (log rank test; P = 0.81). There again was no difference within the subgroup of PcP patients with solid organ transplants. Adjunctive corticosteroid use may not improve the outcome of moderate-to-severe PcP in non-HIV-infected patients. PMID- 21788459 TI - F33:A-:B- and F2:A-:B- plasmids mediate dissemination of rmtB-blaCTX-M-9 group genes and rmtB-qepA in Enterobacteriaceae isolates from pets in China. AB - This study investigated the prevalence of 16S rRNA methylase genes in 267 Enterobacteriaceae isolates collected from pets. The rmtB gene was detected in 69 isolates, most of which were clonally unrelated. The coexistence of the rmtB gene with the bla(CTX-M-9) group genes and/or qepA within the same IncFII replicons was commonly detected. The two dominant types of IncF plasmids, F2:A-:B-, carrying rmtB-qepA, and F33:A-:B-, carrying the rmtB-bla(CTX-M-9) group genes (and especially bla(CTX-M-65)), shared restriction patterns within each incompatibility group. PMID- 21788461 TI - Impact of antibiotic exposure patterns on selection of community-associated methicillin-resistant Staphylococcus aureus in hospital settings. AB - Community-associated methicillin-resistant S. aureus (CA-MRSA) is increasingly common in hospitals, with potentially serious consequences. The aim of this study was to assess the impact of antibiotic prescription patterns on the selection of CA-MRSA within hospitals, in a context of competition with other circulating staphylococcal strains, including methicillin-sensitive (MSSA) and hospital associated methicillin-resistant (HA-MRSA) strains. We developed a computerized agent-based model of S. aureus transmission in a hospital ward in which CA-MRSA, MSSA, and HA-MRSA strains may cocirculate. We investigated a wide range of antibiotic prescription patterns in both intensive care units (ICUs) and general wards, and we studied how differences in antibiotic exposure may explain observed variations in the success of CA-MRSA invasion in the hospitals of several European countries and of the United States. Model predictions underlined the influence of antibiotic prescription patterns on CA-MRSA spread in hospitals, especially in the ICU, where the endemic prevalence of CA-MRSA carriage can range from 3% to 20%, depending on the simulated prescription pattern. Large antibiotic exposure with drugs effective against MSSA but not MRSA was found to promote invasion by CA-MRSA. We also found that, should CA-MRSA acquire fluoroquinolone resistance, a major increase in CA-MRSA prevalence could ensue in hospitals worldwide. Controlling the spread of highly community-prevalent CA-MRSA within hospitals is a challenge. This study demonstrates that antibiotic exposure strategies could participate in this control. This is all the more important in wards such as ICUs, which may play the role of incubators, promoting CA-MRSA selection in hospitals. PMID- 21788462 TI - Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis. AB - E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated. PMID- 21788464 TI - Genetic diversity of Tn916-related transposons among drug-resistant Streptococcus pneumoniae isolates colonizing healthy children in Venezuela. AB - Among a collection of 48 multidrug-resistant pneumococcal strains colonizing healthy children in a small municipality of Merida, Venezuela, we identified sequence types (STs) related to a variety of internationally spreading drug resistant clones, as well as ST135, thus far isolated only in Europe. The clones invariably harbored one or more of the Tn916-related transposons Tn3872, Tn5253, Tn6002, Tn2009, and Tn2010. Finally, our data suggest both structural rearrangements in certain transposons and occurrence of novel transposable elements. PMID- 21788463 TI - Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. AB - Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase. PMID- 21788465 TI - PEGylated liposome encapsulation increases the lung tissue concentration of vancomycin. AB - Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) often cannot be cured by vancomycin treatment. Poor lung tissue and intracellular penetration limits the ability to achieve effective bactericidal levels, particularly in alveolar macrophages, where MRSA can evade phagocytic killing. Compared to standard formulations, liposome encapsulation has been shown to enhance vancomycin intracellular killing of MRSA. In this murine pharmacokinetic and biodistribution study, PEGylated liposomal vancomycin, compared to standard and non-PEGylated formulations, significantly prolonged blood circulation time and increased deposition in lung, liver, and spleen and yet reduced accumulation in kidney tissue. As a result of optimizing antimicrobial targeting of infected lung tissue and limiting renal parenchymal exposure, administration of PEGylated liposomal vancomycin may improve the efficacy of treatment of MRSA pneumonia and reduce the risk of nephrotoxicity. PMID- 21788466 TI - Concentrations of tenofovir and emtricitabine in saliva: implications for preexposure prophylaxis of oral HIV acquisition. AB - To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/plasma concentration were 3% (+/-4%) and 86.9% (+/-124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV. PMID- 21788467 TI - Simultaneous determination of 12 beta-lactam antibiotics in human plasma by high performance liquid chromatography with UV detection: application to therapeutic drug monitoring. AB - A rapid and specific high-performance liquid chromatography method with UV detection (HPLC-UV) for the simultaneous determination of 12 beta-lactam antibiotics (amoxicillin, cefepime, cefotaxime, ceftazidime, ceftriaxone, cloxacillin, imipenem, meropenem, oxacillin, penicillin G, piperacillin, and ticarcillin) in small samples of human plasma is described. Extraction consisted of protein precipitation by acetonitrile. An Atlantis T3 analytical column with a linear gradient of acetonitrile and a pH 2 phosphoric acid solution was used for separation. Wavelength photodiode array detection was set either at 210 nm, 230 nm, or 298 nm according to the compound. This method is accurate and reproducible (coefficient of variation [CV] < 8%), allowing quantification of beta-lactam plasma levels from 5 to 250 MUg/ml without interference with other common drugs. This technique is easy to use in routine therapeutic drug monitoring of beta lactam antibiotics. PMID- 21788468 TI - Pharmacokinetics of ethionamide in children. AB - Ethionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration (C(max)), time to C(max) (T(max)), and area under the time-concentration curve from 0 to 6 h (AUC(0-6)) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month (r = 0.50, P = 0.001) and 4 months (r = 0.63, P = 0.001) of therapy. There was no difference in the AUC or C(max) between children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy. PMID- 21788469 TI - Susceptibility of Pneumocystis to echinocandins in suspension and biofilm cultures. AB - The targeted inhibition of cyst but not trophic development by anidulafungin, caspofungin, and micafungin on Pneumocystis murina and Pneumocystis carinii in rodent models of Pneumocystis carinii pneumonia (PCP) was recently reported by us (M. T. Cushion et al., PLoS One 5:e8524, 2010). To better understand the effects of echinocandins on P. carinii, the same three compounds were evaluated in standard suspension and biofilm cultures supplemented with various concentrations of sera using the measurement of ATP as the indicator. In suspension cultures with 1 and 5% serum, anidulafungin was the most active compound but 10 and 20% serum abrogated the efficacy of all three echinocandins. Established biofilm cultures that included both the nonadherent and adherent phases were more resistant to micafungin than caspofungin regardless of serum concentration, while anidulafungin had significant activity at 1 and 5% serum concentrations. Nascent biofilms were mostly affected by anidulafungin in 1 and 5% serum, but none of the compounds showed significant activity in 20% serum. We show for the first time that (i) echinocandins differ in their abilities to deplete the ATP of Pneumocystis in biofilms and in suspension cultures, (ii) this variability mostly reflected the reported efficacies in animal models of infection, and (iii) high serum levels decreased the anti-Pneumocystis activities of the echinocandins in both in vitro systems. PMID- 21788470 TI - Genomic analysis of the multidrug-resistant Acinetobacter baumannii strain MDR ZJ06 widely spread in China. AB - We previously reported that the multidrug-resistant (MDR) Acinetobacter baumannii strain MDR-ZJ06, belonging to European clone II, was widely spread in China. In this study, we report the whole-genome sequence of this clinically important strain. A 38.6-kb AbaR-type genomic resistance island (AbaR22) was identified in MDR-ZJ06. AbaR22 has a structure similar to those of the resistance islands found in A. baumannii strains AYE and AB0057, but it contained only a few antibiotic resistance genes. The region of resistant gene accumulation as previously described was not found in AbaR22. In the chromosome of the strain MDR-ZJ06, we identified the gene bla(oxa-23) in a composite transposon (Tn2009). Tn2009 shared the backbone with other A. baumannii transponsons that harbor bla(oxa-23), but it was bracketed by two ISAba1 elements which were transcribed in the same orientation. MDR-ZJ06 also expressed the armA gene on its plasmid pZJ06, and this gene has the same genetic environment as the armA gene of the Enterobacteriaceae. These results suggest variability of resistance acquisition even in closely related A. baumannii strains. PMID- 21788471 TI - In vitro and in vivo studies of the utility of dimethyl and diethyl carbaporphyrin ketals in treatment of cutaneous leishmaniasis. AB - Carbaporphyrin ketals are porphyrinoid compounds in which a pyrrole ring of a typical porphyrin macrocycle has been replaced by a ketal-substituted indene ring. It was recently demonstrated that these compounds are effective in vitro against Leishmania tarentolae. Their in vitro effectiveness is increased when they are exposed to visible light; they act as photosensitizers capable of mediating the production of reactive oxygen species (ROS). Following on this evidence, the effectiveness and cytotoxicity of the dimethyl and diethyl carbaporphyrin ketals (CKOMe and CKOEt, respectively) were determined in vitro using pathogenic Leishmania species with and without exposure to visible light (2 and 4 h). The effectiveness against various pathogenic Leishmania species was determined to be in a micromolar range. Additionally, the effect of encapsulating the carbaporphyrin ketals in liposome formulations was tested. Liposomal delivery diminished their toxicity, while the effectiveness was enhanced upon exposure to visible light (photodynamic effect). The cytotoxicity levels for human U937 cells and hamster peritoneal macrophages were in the ranges of 0.3 to 9 MUM and 7 to 330 MUM, respectively. When tested in vivo, using a hamster (Mesocricetus auratus) model of cutaneous leishmaniasis, CKOMe was active even in the dark, suggesting that the compound, once metabolized in the animal tissue, produces an active ingredient that does not seem to be photosensitive. Reduction in lesion size, histopathologic analyses, and smears confirmed the in vivo effectiveness of the compound, since the parasitic load was diminished without noticeable toxic effects. PMID- 21788472 TI - CMX001 potentiates the efficacy of acyclovir in herpes simplex virus infections. AB - Although acyclovir (ACV) has proven to be of value in the therapy of certain herpes simplex virus (HSV) infections, there is a need for more effective therapies, particularly for serious infections in neonates and immunocompromised individuals, where resistance to this drug can be problematic. CMX001 is an orally bioavailable lipid conjugate of cidofovir that is substantially less nephrotoxic than the parent drug and has excellent antiviral activity against all the human herpesviruses. This compound retains full antiviral activity against ACV-resistant laboratory and clinical isolates. The combined efficacy of CMX001 and ACV was evaluated in a new real-time PCR combination assay, which demonstrated that the combination synergistically inhibited the replication of HSV in cell culture. This was also confirmed in murine models of HSV infection, where the combined therapy with these two drugs synergistically reduced mortality. These results suggest that CMX001 may be effective in the treatment of ACV-resistant HSV infections and as an adjunct therapy in individuals with suboptimal responses to ACV. PMID- 21788473 TI - OXA-198, an acquired carbapenem-hydrolyzing class D beta-lactamase from Pseudomonas aeruginosa. AB - A carbapenem-resistant Pseudomonas aeruginosa strain (PA41437) susceptible to expanded-spectrum cephalosporins was recovered from several consecutive lower respiratory-tract specimens of a patient who developed a ventilator-associated pneumonia while hospitalized in an intensive care unit. Cloning experiments identified OXA-198, a new class D beta-lactamase which was weakly related (less than 45% amino acid identity) to other class D beta-lactamases. Expression in Escherichia coli TOP10 and in P. aeruginosa PAO1 led to transformants that were resistant to ticarcillin and showed reduced susceptibility to carbapenems and cefepime. The bla(OXA-198) gene was harbored by a class 1 integron carried by a ca. 46-kb nontypeable plasmid. This study describes a novel class D beta lactamase involved in carbapenem resistance in P. aeruginosa. PMID- 21788474 TI - Identification of the thiazolyl peptide GE37468 gene cluster from Streptomyces ATCC 55365 and heterologous expression in Streptomyces lividans. AB - Thiazolyl peptides are bacterial secondary metabolites that potently inhibit protein synthesis in Gram-positive bacteria and malarial parasites. Recently, our laboratory and others reported that this class of trithiazolyl pyridine containing natural products is derived from ribosomally synthesized preproteins that undergo a cascade of posttranslational modifications to produce architecturally complex macrocyclic scaffolds. Here, we report the gene cluster responsible for production of the elongation factor Tu (EF-Tu)-targeting 29 member thiazolyl peptide GE37468 from Streptomyces ATCC 55365 and its heterologous expression in the model host Streptomyces lividans. GE37468 harbors an unusual beta-methyl-delta-hydroxy-proline residue that may increase conformational rigidity of the macrocycle and impart reduced entropic costs of target binding. Isotope feeding and gene knockout were employed in the engineered S. lividans strain to identify the P450 monooxygenase GetJ as the enzyme involved in posttranslational transformation of isoleucine 8 to beta-methyl-delta-hydroxy proline through a predicted tandem double hydroxylation/cyclization mechanism. Loss of Ile8 oxygenative cyclization or mutation of Ile8 to alanine via preprotein gene replacement resulted in a 4-fold and 2-fold drop in antibiotic activity, respectively. This report of genetic manipulation of a 29-member thiazolyl peptide sets the stage for further genetic examination of structure activity relationships in the EF-Tu targeting class of thiazolyl peptides. PMID- 21788475 TI - Electronic properties of the highly ruffled heme bound to the heme degrading enzyme IsdI. AB - IsdI, a heme-degrading protein from Staphylococcus aureus, binds heme in a manner that distorts the normally planar heme prosthetic group to an extent greater than that observed so far for any other heme-binding protein. To understand better the relationship between this distinct structural characteristic and the functional properties of IsdI, spectroscopic, electrochemical, and crystallographic results are reported that provide evidence that this heme ruffling is essential to the catalytic activity of the protein and eliminates the need for the water cluster in the distal heme pocket that is essential for the activity of classical heme oxygenases. The lack of heme orientational disorder in (1)H-NMR spectra of the protein argues that the catalytic formation of beta- and delta-biliverdin in nearly equal yield results from the ability of the protein to attack opposite sides of the heme ring rather than from binding of the heme substrate in two alternative orientations. PMID- 21788476 TI - Engineering hepatocyte growth factor fragments with high stability and activity as Met receptor agonists and antagonists. AB - The Met receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) play an important role in mediating both tumor progression and tissue regeneration. The N-terminal and first Kringle domains (NK1) of HGF comprise a naturally occurring splice variant that retains the ability to activate the Met receptor. However, NK1 is a weak agonist and is relatively unstable, limiting its therapeutic potential. Here, we engineered NK1 mutants with improved biochemical and biophysical properties that function as Met receptor agonists or antagonists. We first engineered NK1 for increased stability and recombinant expression yield using directed evolution. The NK1 variants isolated from our library screens acted as weak Met receptor antagonists due to a mutation at the NK1 homodimerization interface. We introduced point mutations that restored this NK1 homodimerization interface to create an agonistic ligand, or that further disrupted this interface to create more effective antagonists. The rationally engineered antagonists exhibited melting temperatures up to approximately 64 degrees C, a 15 degrees C improvement over antagonists derived from wild-type NK1, and approximately 40-fold improvement in expression yield. Next, we created disulfide-linked NK1 homodimers through introduction of an N-terminal cysteine residue. These covalent dimers exhibited nearly an order of magnitude improved agonistic activity compared to wild-type NK1, approaching the activity of full length HGF. Moreover, covalent NK1 dimers formed from agonistic or antagonistic monomeric subunits elicited similar activity, further signifying that NK1 dimerization mediates agonistic activity. These engineered NK1 proteins are promising candidates for therapeutic development and will be useful tools for further exploring determinants of Met receptor activation. PMID- 21788477 TI - How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH. AB - Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22 A resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe(N)hTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergo pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same alpha-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system. PMID- 21788478 TI - Iron-containing urease in a pathogenic bacterium. AB - Helicobacter mustelae, a gastric pathogen of ferrets, synthesizes a distinct iron dependent urease in addition to its archetypical nickel-containing enzyme. The iron-urease is oxygen-labile, with the inactive protein exhibiting a methemerythrin-like electronic spectrum. Significantly, incubation of the oxidized protein with dithionite under anaerobic conditions leads to restoration of activity and bleaching of the spectrum. Structural analysis of the oxidized species reveals a dinuclear iron metallocenter bridged by a lysine carbamate, closely resembling the traditional nickel-urease active site. Although the iron urease is less active than the nickel-enzyme, its activity allows H. mustelae to survive the carnivore's low-nickel gastric environment. PMID- 21788479 TI - Flexibility of the C-terminal, or CII, ring of KaiC governs the rhythm of the circadian clock of cyanobacteria. AB - In the cyanobacterial circadian oscillator, KaiA and KaiB alternately stimulate autophosphorylation and autodephosphorylation of KaiC with a periodicity of approximately 24 h. KaiA activates autophosphorylation by selectively capturing the A loops of KaiC in their exposed positions. The A loops and sites of phosphorylation, residues S431 and T432, are located in the CII ring of KaiC. We find that the flexibility of the CII ring governs the rhythm of KaiC autophosphorylation and autodephosphorylation and is an example of dynamics driven protein allostery. KaiA-induced autophosphorylation requires flexibility of the CII ring. In contrast, rigidity is required for KaiC-KaiB binding, which induces a conformational change in KaiB that enables it to sequester KaiA by binding to KaiA's linker. Autophosphorylation of the S431 residues around the CII ring stabilizes the CII ring, making it rigid. In contrast, autophosphorylation of the T432 residues offsets phospho-S431-induced rigidity to some extent. In the presence of KaiA and KaiB, the dynamic states of the CII ring of KaiC executes the following circadian rhythm: CII STflexible -> CIISpTflexible -> CIIpSpTrigid > CIIpSTvery-rigid -> CIISTflexible. Apparently, these dynamic states govern the pattern of phosphorylation, ST -> SpT -> pSpT -> pST -> ST. CII-CI ring-on-ring stacking is observed when the CII ring is rigid, suggesting a mechanism through which the ATPase activity of the CI ring is rhythmically controlled. SasA, a circadian clock-output protein, binds to the CI ring. Thus, rhythmic ring stacking may also control clock-output pathways. PMID- 21788480 TI - Structural basis for the function of a small GTPase RsgA on the 30S ribosomal subunit maturation revealed by cryoelectron microscopy. AB - The bacterial RsgA, a circularly permutated GTPase, whose GTPase activity is dependent on the 30S ribosomal subunit, is a late-stage ribosome biogenesis factor involved in the 30S subunit maturation. The role of RsgA is to release another 30S biogenesis factor, RbfA, from the mature 30S subunit in a GTP dependent manner. Using cryoelectron microscopy, we have determined the structure of the 30S subunit bound with RsgA in the presence of GMPPNP at subnanometer resolution. In the structure, RsgA binds to the central part of the 30S subunit, close to the decoding center, in a position that is incompatible with multiple biogenesis factors, all three translation initiation factors, as well as A-, P site tRNAs and the 50S subunit. Further structural analysis not only provides a structural model for the RsgA-dependent release of RbfA from the nascent 30S subunit, but also indicates RsgA's role in the ribosomal protein assembly, to promote some tertiary binding protein incorporation. Moreover, together with available biochemical and genetic data, our results suggest that RsgA might be a general checkpoint protein in the late stage of the 30S subunit biogenesis, whose function is not only to release biogenesis factors (e.g., RbfA) from the nascent 30S subunit, but also to block the association of initiation factors to the premature 30S subunit. PMID- 21788481 TI - Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein. AB - MitoNEET (mNT) is an outer mitochondrial membrane target of the thiazolidinedione diabetes drugs with a unique fold and a labile [2Fe-2S] cluster. The rare 1-His and 3-Cys coordination of mNT's [2Fe-2S] leads to cluster lability that is strongly dependent on the presence of the single histidine ligand (His87). These properties of mNT are similar to known [2Fe-2S] shuttle proteins. Here we investigated whether mNT is capable of cluster transfer to acceptor protein(s). Facile [2Fe-2S] cluster transfer is observed between oxidized mNT and apo ferredoxin (a-Fd) using UV-VIS spectroscopy and native-PAGE, as well as with a mitochondrial iron detection assay in cells. The transfer is unidirectional, proceeds to completion, and occurs with a second-order-reaction rate that is comparable to known iron-sulfur transfer proteins. Mutagenesis of His87 with Cys (H87C) inhibits transfer of the [2Fe-2S] clusters to a-Fd. This inhibition is beyond that expected from increased cluster kinetic stability, as the equivalently stable Lys55 to Glu (K55E) mutation did not inhibit transfer. The H87C mutant also failed to transfer its iron to mitochondria in HEK293 cells. The diabetes drug pioglitazone inhibits iron transfer from WT mNT to mitochondria, indicating that pioglitazone affects a specific property, [2Fe-2S] cluster transfer, in the cellular environment. This finding is interesting in light of the role of iron overload in diabetes. Our findings suggest a likely role for mNT in [2Fe-2S] and/or iron transfer to acceptor proteins and support the idea that pioglitazone's antidiabetic mode of action may, in part, be to inhibit transfer of mNT's [2Fe-2S] cluster. PMID- 21788482 TI - Hyperprolinemic larvae of the drosophilid fly, Chymomyza costata, survive cryopreservation in liquid nitrogen. AB - The larva of the drosophilid fly, Chymomyza costata, is probably the most complex metazoan organism that can survive submergence in liquid nitrogen (-196 degrees C) in a fully hydrated state. We examined the associations between the physiological and biochemical parameters of differently acclimated larvae and their freeze tolerance. Entering diapause is an essential and sufficient prerequisite for attaining high levels of survival in liquid nitrogen (23% survival to adult stage), although cold acclimation further improves this capacity (62% survival). Profiling of 61 different metabolites identified proline as a prominent compound whose concentration increased from 20 to 147 mM during diapause transition and subsequent cold acclimation. This study provides direct evidence for the essential role of proline in high freeze tolerance. We increased the levels of proline in the larval tissues by feeding larvae proline-augmented diets and found that this simple treatment dramatically improved their freeze tolerance. Cell and tissue survival following exposure to liquid nitrogen was evident in proline-fed nondiapause larvae, and survival to adult stage increased from 0% to 36% in proline-fed diapause-destined larvae. A significant statistical correlation was found between the whole-body concentration of proline, either natural or artificial, and survival to the adult stage in liquid nitrogen for diapause larvae. Differential scanning calorimetry analysis suggested that high proline levels, in combination with a relatively low content of osmotically active water and freeze dehydration, increased the propensity of the remaining unfrozen water to undergo a glass-like transition (vitrification) and thus facilitated the prevention of cryoinjury. PMID- 21788483 TI - Transparent lithium-ion batteries. AB - Transparent devices have recently attracted substantial attention. Various applications have been demonstrated, including displays, touch screens, and solar cells; however, transparent batteries, a key component in fully integrated transparent devices, have not yet been reported. As battery electrode materials are not transparent and have to be thick enough to store energy, the traditional approach of using thin films for transparent devices is not suitable. Here we demonstrate a grid-structured electrode to solve this dilemma, which is fabricated by a microfluidics-assisted method. The feature dimension in the electrode is below the resolution limit of human eyes, and, thus, the electrode appears transparent. Moreover, by aligning multiple electrodes together, the amount of energy stored increases readily without sacrificing the transparency. This results in a battery with energy density of 10 Wh/L at a transparency of 60%. The device is also flexible, further broadening their potential applications. The transparent device configuration also allows in situ Raman study of fundamental electrochemical reactions in batteries. PMID- 21788484 TI - PolyU tail of rho-independent terminator of bacterial small RNAs is essential for Hfq action. AB - Major bacterial small RNAs (sRNAs) regulate the translation and stability of target mRNAs through base pairing with the help of the RNA chaperone Hfq. The Hfq dependent sRNAs consist of three basic elements, mRNA base-pairing region, Hfq binding site, and rho-independent terminator. Although the base-pairing region and the terminator are well documented in many sRNAs, the Hfq-binding site is less well-defined except that Hfq binds RNA with a preference for AU-rich sequences. Here, we performed mutational and biochemical studies to define the sRNA site required for Hfq action using SgrS as a model sRNA. We found that shortening terminator polyU tail eliminates the ability of SgrS to bind to Hfq and to silence ptsG mRNA. We also demonstrate that the SgrS terminator can be replaced with any foreign rho-independent terminators possessing a polyU tail longer than 8 without losing the ability to silence ptsG mRNA in an Hfq-dependent manner. Moreover, we found that shortening the terminator polyU tail of several other sRNAs also eliminates the ability to bind to Hfq and to regulate target mRNAs. We conclude that the polyU tail of sRNAs is essential for Hfq action in general. The data also indicate that the terminator polyU tail plays a role in Hfq-dependent stabilization of sRNAs. PMID- 21788485 TI - Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion. AB - The commitment of Plasmodium merozoites to invade red blood cells (RBCs) is marked by the formation of a junction between the merozoite and the RBC and the coordinated induction of the parasitophorous vacuole. Despite its importance, the molecular events underlying the parasite's commitment to invasion are not well understood. Here we show that the interaction of two parasite proteins, RON2 and AMA1, known to be critical for invasion, is essential to trigger junction formation. Using antibodies (Abs) that bind near the hydrophobic pocket of AMA1 and AMA1 mutated in the pocket, we identified RON2's binding site on AMA1. Abs specific for the AMA1 pocket blocked junction formation and the induction of the parasitophorous vacuole. We also identified the critical residues in the RON2 peptide (previously shown to bind AMA1) that are required for binding to the AMA1 pocket, namely, two conserved, disulfide-linked cysteines. The RON2 peptide blocked junction formation but, unlike the AMA1-specific Ab, did not block formation of the parasitophorous vacuole, indicating that formation of the junction and parasitophorous vacuole are molecularly distinct steps in the invasion process. Collectively, these results identify the binding of RON2 to the hydrophobic pocket of AMA1 as the step that commits Plasmodium merozoites to RBC invasion and point to RON2 as a potential vaccine candidate. PMID- 21788486 TI - Crystal structure of human CD1e reveals a groove suited for lipid-exchange processes. AB - CD1e is the only human CD1 protein existing in soluble form in the late endosomes of dendritic cells, where it facilitates the processing of glycolipid antigens that are ultimately recognized by CD1b-restricted T cells. The precise function of CD1e remains undefined, thus impeding efforts to predict the participation of this protein in the presentation of other antigens. To gain insight into its function, we determined the crystal structure of recombinant CD1e expressed in human cells at 2.90-A resolution. The structure revealed a groove less intricate than in other CD1 proteins, with a significantly wider portal characterized by a 2 A-larger spacing between the alpha1 and alpha2 helices. No electron density corresponding to endogenous ligands was detected within the groove, despite the presence of ligands unequivocally established by native mass spectrometry in recombinant CD1e. Our structural data indicate that the water-exposed CD1e groove could ensure the establishment of loose contacts with lipids. In agreement with this possibility, lipid association and dissociation processes were found to be considerably faster with CD1e than with CD1b. Moreover, CD1e was found to mediate in vitro the transfer of lipids to CD1b and the displacement of lipids from stable CD1b-antigen complexes. Altogether, these data support that CD1e could have evolved to mediate lipid-exchange/editing processes with CD1b and point to a pathway whereby the repertoire of lipid antigens presented by human dendritic cells might be expanded. PMID- 21788487 TI - Sperm chemotaxis, fluid shear, and the evolution of sexual reproduction. AB - Chemical communication is fundamental to sexual reproduction, but how sperm search for and find an egg remains enigmatic. For red abalone (Haliotis rufescens), a large marine snail, the relationship between chemical signaling and fluid motion largely determines fertilization success. Egg-derived attractant plumes are dynamic, changing their size and shape in response to unique combinations of physical and chemical environmental features. Attractant plumes that promote sexual reproduction, however, are limited to a precise set of hydrodynamic conditions. Performance-maximizing shears are those that most closely match flows in native spawning habitats. Under conditions in which reproductive success is chronically limited by sperm availability, gametes are under selection for mechanisms that increase sperm-egg encounter. Here, chemoattraction is found to provide a cheap evolutionary alternative for enhancing egg target size without enlarging cytoplasmic and/or cell volume. Because egg signaling and sperm response may be tuned to meet specific fluid dynamic constraints, shear could act as a critical selective pressure that drives gamete evolution and determines fitness. PMID- 21788488 TI - Hyaloperonospora arabidopsidis ATR1 effector is a repeat protein with distributed recognition surfaces. AB - The in planta association of the Hyaloperonospora arabidopsidis effector ATR1 with the cognate Arabidopsis thaliana RPP1 immune receptor activates a disease resistance signaling pathway that inhibits pathogen growth. To define the molecular events specifying effector recognition by RPP1, we determined the crystal structure of ATR1 and assayed in planta the effects of surface polymorphisms that are critical to activating plant immunity. ATR1 adopts an elongated, all-helical, two-domain, seahorse-like structure with an overall architecture unlike any previously described fold. Structural comparisons highlight a tandemly duplicated, five-helix motif in the C-terminal domain that creates a structural framework for rapid diversification. Identification and mapping of critical recognition sites suggest that ATR1 detection by the RPP1 resistance protein is mediated by several distinct protein surfaces that allow the effectors to escape recognition through diverse surface polymorphisms. ATR1 gain-of-recognition mutants demonstrate that multiple amino acid substitutions are necessary for recognition and that surface polymorphisms exert additive effects. These results suggest that ATR1 is a modular repeat protein belonging to an ancient family of oomycete effectors that rapidly evolves to escape host detection and adopt diverse virulence functions. PMID- 21788489 TI - Evolution of direct reciprocity under uncertainty can explain human generosity in one-shot encounters. AB - Are humans too generous? The discovery that subjects choose to incur costs to allocate benefits to others in anonymous, one-shot economic games has posed an unsolved challenge to models of economic and evolutionary rationality. Using agent-based simulations, we show that such generosity is the necessary byproduct of selection on decision systems for regulating dyadic reciprocity under conditions of uncertainty. In deciding whether to engage in dyadic reciprocity, these systems must balance (i) the costs of mistaking a one-shot interaction for a repeated interaction (hence, risking a single chance of being exploited) with (ii) the far greater costs of mistaking a repeated interaction for a one-shot interaction (thereby precluding benefits from multiple future cooperative interactions). This asymmetry builds organisms naturally selected to cooperate even when exposed to cues that they are in one-shot interactions. PMID- 21788490 TI - Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion. AB - Myocardial ischemic disease is the major cause of death worldwide. After myocardial infarction, reperfusion of infracted heart has been an important objective of strategies to improve outcomes. However, cardiac ischemia/reperfusion (I/R) is characterized by inflammation, arrhythmias, cardiomyocyte damage, and, at the cellular level, disturbance in Ca(2+) and redox homeostasis. In this study, we sought to determine how acute inflammatory response contributes to reperfusion injury and Ca(2+) homeostasis disturbance after acute ischemia. Using a rat model of I/R, we show that circulating levels of TNF-alpha and cardiac caspase-8 activity were increased within 6 h of reperfusion, leading to myocardial nitric oxide and mitochondrial ROS production. At 1 and 15 d after reperfusion, caspase-8 activation resulted in S-nitrosylation of the RyR2 and depletion of calstabin2 from the RyR2 complex, resulting in diastolic sarcoplasmic reticulum (SR) Ca(2+) leak. Pharmacological inhibition of caspase-8 before reperfusion with Q-LETD-OPh or prevention of calstabin2 depletion from the RyR2 complex with the Ca(2+) channel stabilizer S107 ("rycal") inhibited the SR Ca(2+) leak, reduced ventricular arrhythmias, infarct size, and left ventricular remodeling after 15 d of reperfusion. TNF-alpha-induced caspase 8 activation leads to leaky RyR2 channels that contribute to myocardial remodeling after I/R. Thus, early prevention of SR Ca(2+) leak trough normalization of RyR2 function is cardioprotective. PMID- 21788491 TI - Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. AB - Astrocytes regulate synaptic connectivity in the CNS through secreted signals. Here we identified two astrocyte-secreted proteins, hevin and SPARC, as regulators of excitatory synaptogenesis in vitro and in vivo. Hevin induces the formation of synapses between cultured rat retinal ganglion cells. SPARC is not synaptogenic, but specifically antagonizes synaptogenic function of hevin. Hevin and SPARC are expressed by astrocytes in the superior colliculus, the synaptic target of retinal ganglion cells, concurrent with the excitatory synaptogenesis. Hevin-null mice had fewer excitatory synapses; conversely, SPARC-null mice had increased synaptic connections in the superior colliculus. Furthermore, we found that hevin is required for the structural maturation of the retinocollicular synapses. These results identify hevin as a positive and SPARC as a negative regulator of synapse formation and signify that, through regulation of relative levels of hevin and SPARC, astrocytes might control the formation, maturation, and plasticity of synapses in vivo. PMID- 21788493 TI - Erionite exposure in North Dakota and Turkish villages with mesothelioma. AB - Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted. PMID- 21788492 TI - Ineffective erythropoiesis with reduced red blood cell survival in serotonin deficient mice. AB - Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5 HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival. PMID- 21788495 TI - Continued warming could transform Greater Yellowstone fire regimes by mid-21st century. AB - Climate change is likely to alter wildfire regimes, but the magnitude and timing of potential climate-driven changes in regional fire regimes are not well understood. We considered how the occurrence, size, and spatial location of large fires might respond to climate projections in the Greater Yellowstone ecosystem (GYE) (Wyoming), a large wildland ecosystem dominated by conifer forests and characterized by infrequent, high-severity fire. We developed a suite of statistical models that related monthly climate data (1972-1999) to the occurrence and size of fires >200 ha in the northern Rocky Mountains; these models were cross-validated and then used with downscaled (~12 km * 12 km) climate projections from three global climate models to predict fire occurrence and area burned in the GYE through 2099. All models predicted substantial increases in fire by midcentury, with fire rotation (the time to burn an area equal to the landscape area) reduced to <30 y from the historical 100-300 y for most of the GYE. Years without large fires were common historically but are expected to become rare as annual area burned and the frequency of regionally synchronous fires increase. Our findings suggest a shift to novel fire-climate vegetation relationships in Greater Yellowstone by midcentury because fire frequency and extent would be inconsistent with persistence of the current suite of conifer species. The predicted new fire regime would transform the flora, fauna, and ecosystem processes in this landscape and may indicate similar changes for other subalpine forests. PMID- 21788494 TI - Comparative genomics of xylose-fermenting fungi for enhanced biofuel production. AB - Cellulosic biomass is an abundant and underused substrate for biofuel production. The inability of many microbes to metabolize the pentose sugars abundant within hemicellulose creates specific challenges for microbial biofuel production from cellulosic material. Although engineered strains of Saccharomyces cerevisiae can use the pentose xylose, the fermentative capacity pales in comparison with glucose, limiting the economic feasibility of industrial fermentations. To better understand xylose utilization for subsequent microbial engineering, we sequenced the genomes of two xylose-fermenting, beetle-associated fungi, Spathaspora passalidarum and Candida tenuis. To identify genes involved in xylose metabolism, we applied a comparative genomic approach across 14 Ascomycete genomes, mapping phenotypes and genotypes onto the fungal phylogeny, and measured genomic expression across five Hemiascomycete species with different xylose-consumption phenotypes. This approach implicated many genes and processes involved in xylose assimilation. Several of these genes significantly improved xylose utilization when engineered into S. cerevisiae, demonstrating the power of comparative methods in rapidly identifying genes for biomass conversion while reflecting on fungal ecology. PMID- 21788496 TI - Craniofacial divergence and ongoing adaptation via the hedgehog pathway. AB - Adaptive variation in craniofacial structure contributes to resource specialization and speciation, but the genetic loci that underlie craniofacial adaptation remain unknown. Here we show that alleles of the hedgehog pathway receptor Patched1 (Ptch1) gene are responsible for adaptive variation in the shape of the lower jaw both within and among genera of Lake Malawi cichlid fish. The evolutionarily derived allele of Ptch1 reduces the length of the retroarticular (RA) process of the lower jaw, a change predicted to increase speed of jaw rotation for improved suction-feeding. The alternate allele is associated with a longer RA and a more robustly mineralized jaw, typical of species that use a biting mode of feeding. Genera with the most divergent feeding morphologies are nearly fixed for different Ptch1 alleles, whereas species with intermediate morphologies still segregate variation at Ptch1. Thus, the same alleles that help to define macroevolutionary divergence among genera also contribute to microevolutionary fine-tuning of adaptive traits within some species. Variability of craniofacial morphology mediated by Ptch1 polymorphism has likely contributed to niche partitioning and ecological speciation of these fishes. PMID- 21788497 TI - Bacterial persistence by RNA endonucleases. AB - Bacteria form persisters, individual cells that are highly tolerant to different types of antibiotics. Persister cells are genetically identical to nontolerant kin but have entered a dormant state in which they are recalcitrant to the killing activity of the antibiotics. The molecular mechanisms underlying bacterial persistence are unknown. Here, we show that the ubiquitous Lon (Long Form Filament) protease and mRNA endonucleases (mRNases) encoded by toxin antitoxin (TA) loci are required for persistence in Escherichia coli. Successive deletion of the 10 mRNase-encoding TA loci of E. coli progressively reduced the level of persisters, showing that persistence is a phenotype common to TA loci. In all cases tested, the antitoxins, which control the activities of the mRNases, are Lon substrates. Consistently, cells lacking lon generated a highly reduced level of persisters. Moreover, Lon overproduction dramatically increased the levels of persisters in wild-type cells but not in cells lacking the 10 mRNases. These results support a simple model according to which mRNases encoded by TA loci are activated in a small fraction of growing cells by Lon-mediated degradation of the antitoxins. Activation of the mRNases, in turn, inhibits global cellular translation, and thereby induces dormancy and persistence. Many pathogenic bacteria known to enter dormant states have a plethora of TA genes. Therefore, in the future, the discoveries described here may lead to a mechanistic understanding of the persistence phenomenon in pathogenic bacteria. PMID- 21788498 TI - Male germ cells express abundant endogenous siRNAs. AB - In mammals, endogenous siRNAs (endo-siRNAs) have only been reported in murine oocytes and embryonic stem cells. Here, we show that murine spermatogenic cells express numerous endo-siRNAs, which are likely to be derived from naturally occurring double-stranded RNA (dsRNA) precursors. The biogenesis of these testicular endo-siRNAs is DROSHA independent, but DICER dependent. These male germ cell endo-siRNAs can potentially target hundreds of transcripts or thousands of DNA regions in the genome. Overall, our work has unveiled another hidden layer of regulation imposed by small noncoding RNAs during male germ cell development. PMID- 21788499 TI - Aging of the cerebral cortex differs between humans and chimpanzees. AB - Several biological changes characterize normal brain aging in humans. Although some of these age-associated neural alterations are also found in other species, overt volumetric decline of particular brain structures, such as the hippocampus and frontal lobe, has only been observed in humans. However, comparable data on the effects of aging on regional brain volumes have not previously been available from our closest living relatives, the chimpanzees. In this study, we used MRI to measure the volume of the whole brain, total neocortical gray matter, total neocortical white matter, frontal lobe gray matter, frontal lobe white matter, and the hippocampus in a cross-sectional sample of 99 chimpanzee brains encompassing the adult lifespan from 10 to 51 y of age. We compared these data to brain structure volumes measured in 87 adult humans from 22 to 88 y of age. In contrast to humans, who showed a decrease in the volume of all brain structures over the lifespan, chimpanzees did not display significant age-related changes. Using an iterative age-range reduction procedure, we found that the significant aging effects in humans were because of the leverage of individuals that were older than the maximum longevity of chimpanzees. Thus, we conclude that the increased magnitude of brain structure shrinkage in human aging is evolutionarily novel and the result of an extended lifespan. PMID- 21788500 TI - Access to DNA establishes a secondary target site bias for the yeast retrotransposon Ty5. AB - Integration sites for many retrotransposons and retroviruses are determined by interactions between retroelement-encoded integrases and specific DNA-bound proteins. The Saccharomyces retrotransposon Ty5 preferentially integrates into heterochromatin because of interactions between Ty5 integrase and the heterochromatin protein silent information regulator 4. We mapped over 14,000 Ty5 insertions onto the S. cerevisiae genome, 76% of which occurred in heterochromatin, which is consistent with the known target site bias of Ty5. Using logistic regression, associations were assessed between Ty5 insertions and various chromosomal features such as genome-wide distributions of nucleosomes and histone modifications. Sites of Ty5 insertion, regardless of whether they occurred in heterochromatin or euchromatin, were strongly associated with DNase hypersensitive, nucleosome-free regions flanking genes. Our data support a model wherein silent information regulator 4 tethers the Ty5 integration machinery to domains of heterochromatin, and then, specific target sites are selected based on DNA access, resulting in a secondary target site bias. For insertions in euchromatin, DNA access is the primary determinant of target site choice. One consequence of the secondary target site bias of Ty5 is that insertions in coding sequences occur infrequently, which may preserve genome integrity. PMID- 21788501 TI - Optogenetic disruption of sleep continuity impairs memory consolidation. AB - Memory consolidation has been proposed as a function of sleep. However, sleep is a complex phenomenon characterized by several features including duration, intensity, and continuity. Sleep continuity is disrupted in different neurological and psychiatric conditions, many of which are accompanied by memory deficits. This finding has raised the question of whether the continuity of sleep is important for memory consolidation. However, current techniques used in sleep research cannot manipulate a single sleep feature while maintaining the others constant. Here, we introduce the use of optogenetics to investigate the role of sleep continuity in memory consolidation. We optogenetically targeted hypocretin/orexin neurons, which play a key role in arousal processes. We used optogenetics to activate these neurons at different intervals in behaving mice and were able to fragment sleep without affecting its overall amount or intensity. Fragmenting sleep after the learning phase of the novel object recognition (NOR) task significantly decreased the performance of mice on the subsequent day, but memory was unaffected if the average duration of sleep episodes was maintained at 62-73% of normal. These findings demonstrate the use of optogenetic activation of arousal-related nuclei as a way to systematically manipulate a specific feature of sleep. We conclude that regardless of the total amount of sleep or sleep intensity, a minimal unit of uninterrupted sleep is crucial for memory consolidation. PMID- 21788502 TI - Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. AB - Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1(+/-) mice and Men1 defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy. PMID- 21788503 TI - Optical measurement of cycle-dependent cell growth. AB - Determining the growth patterns of single cells offers answers to some of the most elusive questions in contemporary cell biology: how cell growth is regulated and how cell size distributions are maintained. For example, a linear growth in time implies that there is no regulation required to maintain homeostasis; an exponential pattern indicates the opposite. Recently, there has been great effort to measure single cells using microelectromechanical systems technology, and several important questions have been explored. However, a unified, easy-to-use methodology to measure the growth rate of individual adherent cells of various sizes has been lacking. Here we demonstrate that a newly developed optical interferometric technique, known as spatial light interference microscopy, can measure the cell dry mass of many individual adherent cells in various conditions, over spatial scales from micrometers to millimeters, temporal scales ranging from seconds to days, and cell types ranging from bacteria to mammalian cells. We found evidence of exponential growth in Escherichia coli, which agrees very well with other recent reports. Perhaps most importantly, combining spatial light interference microscopy with fluorescence imaging provides a unique method for studying cell cycle-dependent growth. Thus, by using a fluorescent reporter for the S phase, we measured single cell growth over each phase of the cell cycle in human osteosarcoma U2OS cells and found that the G2 phase exhibits the highest growth rate, which is mass-dependent and can be approximated by an exponential. PMID- 21788504 TI - Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. AB - The homeostatic control mechanisms regulating human leukocyte numbers are poorly understood. Here, we assessed the role of phagocytes in this process using human immune system (HIS) BALB/c Rag2(-/-)IL-2Rgammac(-/-) mice in which human leukocytes are generated from transplanted hematopoietic progenitor cells. Interactions between signal regulatory protein alpha (SIRPalpha; expressed on phagocytes) and CD47 (expressed on hematopoietic cells) negatively regulate phagocyte activity of macrophages and other phagocytic cells. We previously showed that B cells develop and survive robustly in HIS mice, whereas T and natural killer (NK) cells survive poorly. Because human CD47 does not interact with BALB/c mouse SIRPalpha, we introduced functional CD47/SIRPalpha interactions in HIS mice by transducing mouse CD47 into human progenitor cells. Here, we show that this procedure resulted in a dramatic and selective improvement of progenitor cell engraftment and human T- and NK-cell homeostasis in HIS mouse peripheral lymphoid organs. The amount of engrafted human B cells also increased but much less than that of T and NK cells, and total plasma IgM and IgG concentrations increased 68- and 35-fold, respectively. Whereas T cells exhibit an activated/memory phenotype in the absence of functional CD47/SIRPalpha interactions, human T cells accumulated as CD4(+) or CD8(+) single-positive, naive, resting T cells in the presence of functional CD47/SIRPalpha interactions. Thus, in addition to signals mediated by T cell receptor (TCR)/MHC and/or IL/IL receptor interactions, sensing of cell surface CD47 expression by phagocyte SIRPalpha is a critical determinant of T- and NK-cell homeostasis under steady state conditions in vivo. PMID- 21788505 TI - Architecture, constraints, and behavior. AB - This paper aims to bridge progress in neuroscience involving sophisticated quantitative analysis of behavior, including the use of robust control, with other relevant conceptual and theoretical frameworks from systems engineering, systems biology, and mathematics. Familiar and accessible case studies are used to illustrate concepts of robustness, organization, and architecture (modularity and protocols) that are central to understanding complex networks. These essential organizational features are hidden during normal function of a system but are fundamental for understanding the nature, design, and function of complex biologic and technologic systems. PMID- 21788506 TI - Eco-evolutionary spatial dynamics in the Glanville fritillary butterfly. AB - Demographic population dynamics, gene flow, and local adaptation may influence each other and lead to coupling of ecological and evolutionary dynamics, especially in species inhabiting fragmented heterogeneous environments. Here, I review long-term research on eco-evolutionary spatial dynamics in the Glanville fritillary butterfly inhabiting a large network of approximately 4,000 meadows in Finland. The metapopulation persists in a balance between frequent local extinctions and recolonizations. The genetic spatial structure as defined by neutral markers is much more coarse-grained than the demographic spatial structure determined by the fragmented habitat, yet small-scale spatial structure has important consequences for the dynamics. I discuss three examples of eco evolutionary spatial dynamics. (i) Extinction-colonization metapopulation dynamics influence allele frequency changes in the phosphoglucose isomerase (Pgi) gene, which leads to strong associations between genetic variation in Pgi and dispersal, recolonization, and local population dynamics. (ii) Inbreeding in local populations increases their risk for extinction, whereas reciprocal effects between inbreeding, population size, and emigration represent likely eco evolutionary feedbacks. (iii) Genetically determined female oviposition preference for two host plant species exhibits a cline paralleling a gradient in host plant relative abundances, and host plant preference of dispersing females in relation to the host plant composition of habitat patches influences immigration (gene flow) and recolonization (founder events). Eco-evolutionary spatial dynamics in heterogeneous environments may not lead to directional evolutionary changes unless the environment itself changes, but eco-evolutionary dynamics may contribute to the maintenance of genetic variation attributable to fluctuating selection in space and time. PMID- 21788507 TI - Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. AB - Highly malignant tumors, such as glioblastomas, are characterized by hypoxia, endothelial cell (EC) hyperplasia, and hypercoagulation. However, how these phenomena of the tumor microenvironment may be linked at the molecular level during tumor development remains ill-defined. Here, we provide evidence that hypoxia up-regulates protease-activated receptor 2 (PAR-2), i.e., a G-protein coupled receptor of coagulation-dependent signaling, in ECs. Hypoxic induction of PAR-2 was found to elicit an angiogenic EC phenotype and to specifically up regulate heparin-binding EGF-like growth factor (HB-EGF). Inhibition of HB-EGF by antibody neutralization or heparin treatment efficiently counteracted PAR-2 mediated activation of hypoxic ECs. We show that PAR-2-dependent HB-EGF induction was associated with increased phosphorylation of ERK1/2, and inhibition of ERK1/2 phosphorylation attenuated PAR-2-dependent HB-EGF induction as well as EC activation. Tissue factor (TF), i.e., the major initiator of coagulation dependent PAR signaling, was substantially induced by hypoxia in several types of cancer cells, including glioblastoma; however, TF was undetectable in ECs even at prolonged hypoxia, which precludes cell-autonomous PAR-2 activation through TF. Interestingly, hypoxic cancer cells were shown to release substantial amounts of TF that was mainly associated with secreted microvesicles with exosome-like characteristics. Vesicles derived from glioblastoma cells were found to trigger TF/VIIa-dependent activation of hypoxic ECs in a paracrine manner. We provide evidence of a hypoxia-induced signaling axis that links coagulation activation in cancer cells to PAR-2-mediated activation of ECs. The identified pathway may constitute an interesting target for the development of additional strategies to treat aggressive brain tumors. PMID- 21788508 TI - Network-based prediction for sources of transcriptional dysregulation using latent pathway identification analysis. AB - Understanding the systemic biological pathways and the key cellular mechanisms that dictate disease states, drug response, and altered cellular function poses a significant challenge. Although high-throughput measurement techniques, such as transcriptional profiling, give some insight into the altered state of a cell, they fall far short of providing by themselves a complete picture. Some improvement can be made by using enrichment-based methods to, for example, organize biological data of this sort into collections of dysregulated pathways. However, such methods arguably are still limited to primarily a transcriptional view of the cell. Augmenting these methods still further with networks and additional -omics data has been found to yield pathways that play more fundamental roles. We propose a previously undescribed method for identification of such pathways that takes a more direct approach to the problem than any published to date. Our method, called latent pathway identification analysis (LPIA), looks for statistically significant evidence of dysregulation in a network of pathways constructed in a manner that implicitly links pathways through their common function in the cell. We describe the LPIA methodology and illustrate its effectiveness through analysis of data on (i) metastatic cancer progression, (ii) drug treatment in human lung carcinoma cells, and (iii) diagnosis of type 2 diabetes. With these analyses, we show that LPIA can successfully identify pathways whose perturbations have latent influences on the transcriptionally altered genes. PMID- 21788509 TI - Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c) /- mice improves engraftment of human hematopoietic cells in humanized mice. AB - Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/gamma(c)(-/-) (NSG) and BALB/c Rag2(-/-)gamma(c)(-/-) mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2(-/-)gamma(c)(-/-) mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2(-/ )gamma(c)(-/-) mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated. PMID- 21788510 TI - Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). AB - Store-operated Ca(2+) entry depends critically on physical interactions of the endoplasmic reticulum (ER) Ca(2+) sensor stromal interaction molecule 1 (STIM1) and the Ca(2+) release-activated Ca(2+) (CRAC) channel protein Orai1. Recent studies support a diffusion-trap mechanism in which ER Ca(2+) depletion causes STIM1 to accumulate at ER-plasma membrane (PM) junctions, where it binds to Orai1, trapping and activating mobile CRAC channels in the overlying PM. To determine the stoichiometric requirements for CRAC channel trapping and activation, we expressed mCherry-STIM1 and Orai1-GFP at varying ratios in HEK cells and quantified CRAC current (I(CRAC)) activation and the STIM1:Orai1 ratio at ER-PM junctions after store depletion. By competing for a limited amount of STIM1, high levels of Orai1 reduced the junctional STIM1:Orai1 ratio to a lower limit of 0.3-0.6, indicating that binding of one to two STIM1s is sufficient to immobilize the tetrameric CRAC channel at ER-PM junctions. In cells expressing a constant amount of STIM1, CRAC current was a highly nonlinear bell-shaped function of Orai1 expression and the minimum stoichiometry for channel trapping failed to evoke significant activation. Peak current occurred at a ratio of ~2 STIM1:Orai1, suggesting that maximal CRAC channel activity requires binding of eight STIM1s to each channel. Further increases in Orai1 caused channel activity and fast Ca(2+)-dependent inactivation to decline in parallel. The data are well described by a model in which STIM1 binds to Orai1 with negative cooperativity and channels open with positive cooperativity as a result of stabilization of the open state by STIM1. PMID- 21788511 TI - Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells. AB - Several studies have demonstrated an apparent link between positive selection on hematopoietic cells (HCs) and an "innate" T-cell phenotype. Whereas conventional CD8(+) T cells are primarily selected on thymic epithelial cells (TECs) and certain innate T cells are exclusively selected on HCs, MHC class Ib-restricted CD8(+) T cells appear to be selected on both TECs and HCs. However, whether TEC- and HC-selected T cells represent distinct lineages or whether the same T-cell precursors have the capacity to be selected on either cell type is unknown. Using an M3-restricted T-cell receptor transgenic mouse model, we demonstrate that not only are MHC class Ib-restricted CD8(+) T cells capable of being selected on either cell type but that selecting cell type directly affects the phenotype of the resulting CD8(+) T cells. M3-restricted CD8(+) T cells selected on HCs acquire a more activated phenotype and possess more potent effector functions than those selected on TECs. Additionally, these two developmental pathways are active in the generation of the natural pool of M3-restricted CD8(+) T cells. Our results suggest that these two distinct populations may allow MHC class Ib restricted CD8(+) T cells to occupy different immunological niches playing unique roles in immune responses to infection. PMID- 21788512 TI - Unique structure of iC3b resolved at a resolution of 24 A by 3D-electron microscopy. AB - Activation of C3, deposition of C3b on the target surface, and subsequent amplification by formation of a C3-cleaving enzyme (C3-convertase; C3bBb) triggers the effector functions of complement that result in inflammation and cell lysis. Concurrently, surface-bound C3b is proteolyzed to iC3b by factor I and appropriate cofactors. iC3b then interacts with the complement receptors (CR) of the Ig superfamily, CR2 (CD21), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) on leukocytes, down-modulating inflammation, enhancing B cell-mediated immunity, and targeting pathogens for clearance by phagocytosis. Using EM and small-angle X-ray scattering, we now present a medium-resolution structure of iC3b (24 A). iC3b displays a unique conformation with structural features distinct from any other C3 fragment. The macroglobulin ring in iC3b is similar to that in C3b, whereas the TED (thioester-containing domain) domain and the remnants of the CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain have moved to locations more similar to where they were in native C3. A consequence of this large conformational change is the disruption of the factor B binding site, which renders iC3b unable to assemble a C3-convertase. This structural model also justifies the decreased interaction between iC3b and complement regulators and the recognition of iC3b by the CR of the Ig superfamily, CR2, CR3, and CR4. These data further illustrate the extraordinary conformational versatility of C3 to accommodate a great diversity of functional activities. PMID- 21788514 TI - War and early state formation in the northern Titicaca Basin, Peru. AB - Excavations at the site of Taraco in the northern Titicaca Basin of southern Peru indicate a 2,600-y sequence of human occupation beginning ca. 1100 B.C.E. Previous research has identified several political centers in the region in the latter part of the first millennium B.C.E. The two largest centers were Taraco, located near the northern lake edge, and Pukara, located 50 km to the northwest in the grassland pampas. Our data reveal that a high-status residential section of Taraco was burned in the first century A.D., after which economic activity in the area dramatically declined. Coincident with this massive fire at Taraco, Pukara adopted many of the characteristics of state societies and emerged as an expanding regional polity. We conclude that organized conflict, beginning approximately 500 B.C.E., is a significant factor in the evolution of the archaic state in the northern Titicaca Basin. PMID- 21788513 TI - Extraordinary neoteny of synaptic spines in the human prefrontal cortex. AB - The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders. PMID- 21788515 TI - Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage. AB - Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with growth retardation, mental retardation, and immunodeficiency resulting from a hemizygous deletion of the short arm of chromosome 4, called the WHS critical region (WHSC). The WHSC1 gene is located in this region, and its loss is believed to be responsible for a number of WHS characteristics. We identified WHSC1 in a genetic screen for genes involved in responding to replication stress, linking Wolf Hirschhorn syndrome to the DNA damage response (DDR). Here, we report that the WHSC1 protein is a member of the DDR pathway. WHSC1 localizes to sites of DNA damage and replication stress and is required for resistance to many DNA-damaging and replication stress-inducing agents. Through its SET domain, WHSC1 regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage. We propose that Wolf-Hirschhorn syndrome results from a defect in the DDR. PMID- 21788516 TI - Essential role of Stat3 in PI3K-induced oncogenic transformation. AB - Cells transformed by the p110alpha-H1047R mutant of PI3K show increased tyrosine phosphorylation of Stat3. This activation of Stat3 is important for the transformation process, because a dominant-negative mutant of Stat3 interferes with PI3K-induced oncogenesis. GDC-0941, a specific inhibitor of PI3K reduces the level of Stat3 phosphorylation. The effect of PI3K on Stat3 appears to be mediated by a member of the Tec kinase family. The Tec kinase inhibitor LFM-A13 blocks Stat3 phosphorylation in H1047R-transformed cells. The Janus kinase inhibitor AG490 and the Src kinase inhibitor Src-1, as well as rapamycin, have no effect on Stat3 phosphorylation in H1047R-transformed cells. The H1047R transformed cells also release a factor that induces Stat3 phosphorylation in normal cells with possible effects on the cellular microenvironment. In some human tumor cell lines, the enhanced phosphorylation of Stat3 is inhibited by both PI3K and by Tec kinase inhibitors, suggesting that the link between PI3K and Stat3 is significant in human cancer. PMID- 21788517 TI - Robust averaging during perceptual judgment. AB - An optimal agent will base judgments on the strength and reliability of decision relevant evidence. However, previous investigations of the computational mechanisms of perceptual judgments have focused on integration of the evidence mean (i.e., strength), and overlooked the contribution of evidence variance (i.e., reliability). Here, using a multielement averaging task, we show that human observers process heterogeneous decision-relevant evidence more slowly and less accurately, even when signal strength, signal-to-noise ratio, category uncertainty, and low-level perceptual variability are controlled for. Moreover, observers tend to exclude or downweight extreme samples of perceptual evidence, as a statistician might exclude an outlying data point. These phenomena are captured by a probabilistic optimal model in which observers integrate the log odds of each choice option. Robust averaging may have evolved to mitigate the influence of untrustworthy evidence in perceptual judgments. PMID- 21788518 TI - Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation. AB - Current models of developmental evolution suggest changes in gene regulation underlie the evolution of morphology. Despite the fact that protein complexes regulate gene expression, the evolution of regulatory protein complexes is rarely studied. Here, we investigate the evolution of a protein-protein interaction (PPI) between Homeobox A11 (HoxA11) and Forkhead box 01A (Foxo1a). Using extant and "resurrected" ancestral proteins, we show that the physical interaction between HoxA11 and Foxo1a originated in the mammalian stem lineage. Functional divergence tests and coimmunoprecipitation with heterologous protein pairs indicate that the evolution of interaction was attributable to changes in HoxA11, and deletion studies demonstrate that the interaction interface is located in the homeodomain region of HoxA11. However, there are no changes in amino acid sequence in the homeodomain region during this time period, indicating that the origin of the derived PPI was attributable to changes outside the binding interface. We infer that the amino acid substitutions in HoxA11 altered Foxo1a's access to the conserved binding interface at the HoxA11 homeodomain. We also found an expansion in the number of paired Hox/Fox binding sites in the genomes of mammalian lineage species suggesting the complex has a biological function. Our data indicate that the physical interaction between HoxA11 and Foxo1a evolved through noninterface changes that facilitate the PPI, which prevents inappropriate interactions, rather than through the evolution of a novel binding interface. We speculate that evolutionary changes of intramolecular regulation have limited pleiotropic effects compared with changes to interaction domains themselves. PMID- 21788519 TI - High nitrogen insensitive 9 (HNI9)-mediated systemic repression of root NO3- uptake is associated with changes in histone methylation. AB - In plants, root nitrate uptake systems are under systemic feedback repression by the N satiety of the whole organism, thus adjusting the N acquisition capacity to the N demand for growth; however, the underlying molecular mechanisms are largely unknown. We previously isolated the Arabidopsis high nitrogen-insensitive 9-1 (hni9-1) mutant, impaired in the systemic feedback repression of the root nitrate transporter NRT2.1 by high N supply. Here, we show that HNI9 encodes Arabidopsis INTERACT WITH SPT6 (AtIWS1), an evolutionary conserved component of the RNA polymerase II complex. HNI9/AtIWS1 acts in roots to repress NRT2.1 transcription in response to high N supply. At a genomic level, HNI9/AtIWS1 is shown to play a broader role in N signaling by regulating several hundred N-responsive genes in roots. Repression of NRT2.1 transcription by high N supply is associated with an HNI9/AtIWS1-dependent increase in histone H3 lysine 27 trimethylation at the NRT2.1 locus. Our findings highlight the hypothesis that posttranslational chromatin modifications control nutrient acquisition in plants. PMID- 21788520 TI - A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. AB - The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of mammals, coordinating daily rhythms of behavior and metabolism. Circadian timekeeping in SCN neurons revolves around transcriptional/posttranslational feedback loops, in which Period (Per) and Cryptochrome (Cry) genes are negatively regulated by their protein products. Recent studies have revealed, however, that these "core loops" also rely upon cytosolic and circuit-level properties for sustained oscillation. To characterize interneuronal signals responsible for robust pacemaking in SCN cells and circuits, we have developed a unique coculture technique using wild-type (WT) "graft" SCN to drive pacemaking (reported by PER2::LUCIFERASE bioluminescence) in "host" SCN deficient either in elements of neuropeptidergic signaling or in elements of the core feedback loop. We demonstrate that paracrine signaling is sufficient to restore cellular synchrony and amplitude of pacemaking in SCN circuits lacking vasoactive intestinal peptide (VIP). By using grafts with mutant circadian periods we show that pacemaking in the host SCN is specified by the genotype of the graft, confirming graft-derived factors as determinants of the host rhythm. By combining pharmacological with genetic manipulations, we show that a hierarchy of neuropeptidergic signals underpins this paracrine regulation, with a preeminent role for VIP augmented by contributions from arginine vasopressin (AVP) and gastrin-releasing peptide (GRP). Finally, we show that interneuronal signaling is sufficiently powerful to maintain circadian pacemaking in arrhythmic Cry-null SCN, deficient in essential elements of the transcriptional negative feedback loops. Thus, a hierarchy of paracrine neuropeptidergic signals determines cell- and circuit-level circadian pacemaking in the SCN. PMID- 21788521 TI - Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. AB - Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/beta-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane. PMID- 21788523 TI - Ultra-deep sequencing of foraminiferal microbarcodes unveils hidden richness of early monothalamous lineages in deep-sea sediments. AB - Deep-sea floors represent one of the largest and most complex ecosystems on Earth but remain essentially unexplored. The vastness and remoteness of this ecosystem make deep-sea sampling difficult, hampering traditional taxonomic observations and diversity assessment. This problem is particularly true in the case of the deep-sea meiofauna, which largely comprises small-sized, fragile, and difficult to-identify metazoans and protists. Here, we introduce an ultra-deep sequencing based metagenetic approach to examine the richness of benthic foraminifera, a principal component of deep-sea meiofauna. We used Illumina sequencing technology to assess foraminiferal richness in 31 unsieved deep-sea sediment samples from five distinct oceanic regions. We sequenced an extremely short fragment (36 bases) of the small subunit ribosomal DNA hypervariable region 37f, which has been shown to accurately distinguish foraminiferal species. In total, we obtained 495,978 unique sequences that were grouped into 1,643 operational taxonomic units, of which about half (841) could be reliably assigned to foraminifera. The vast majority of the operational taxonomic units (nearly 90%) were either assigned to early (ancient) lineages of soft-walled, single-chambered (monothalamous) foraminifera or remained undetermined and yet possibly belong to unknown early lineages. Contrasting with the classical view of multichambered taxa dominating foraminiferal assemblages, our work reflects an unexpected diversity of monothalamous lineages that are as yet unknown using conventional micropaleontological observations. Although we can only speculate about their morphology, the immense richness of deep-sea phylotypes revealed by this study suggests that ultra-deep sequencing can improve understanding of deep-sea benthic diversity considered until now as unknowable based on a traditional taxonomic approach. PMID- 21788522 TI - Activation function 2 (AF2) of estrogen receptor-alpha is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. AB - 17beta-Estradiol (E2) regulates estrogen receptor-alpha (ERalpha) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding domain of ERalpha, respectively. We previously reported that ERalpha is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERalphaAF2 in these two major beneficial actions of E2 by electively targeting ERalphaAF2 (named ERalphaAF2(0)). Our results prove four points. (i) Compared with WT ERalpha, the ability of ERalphaAF2(0) to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERalpha. (ii) The uterotrophic action of E2 was totally absent in ERalphaAF2(0) mice, showing the crucial role of ERalphaAF2 in E2-induced uterus hyperplasia. (iii) ERalphaAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERalphaAF2(0) in vivo. (iv) Finally, the atheroprotective effect of E2 was abrogated in ERalphaAF2(0) LDL-r(-/-) mice. Thus, whereas ERalphaAF1 and ERalphaAF2 are both required for the uterotrophic action of E2, we show that only ERalphaAF2 is necessary for its atheroprotective effect. PMID- 21788526 TI - Amnestic mild cognitive impairment: functional MR imaging study of response in posterior cingulate cortex and adjacent precuneus during problem-solving tasks. AB - PURPOSE: To compare the blood oxygen level-dependent (BOLD) response, measured with functional magnetic resonance (MR) imaging, in the posterior cingulate cortex (PCC) and adjacent precuneus regions between healthy control subjects and patients with amnestic mild cognitive impairment (MCI) during problem-solving tasks. MATERIALS AND METHODS: This study was approved by the institutional review board. Each subject provided written informed consent. Thirteen patients with amnestic MCI and 13 age- and sex-matched healthy control subjects participated in the study. The functional magnetic resonance (MR) imaging tasks were simplified 4 * 4-grid number placement puzzles that were divided into a simple task (using the row rule or the column rule to solve the puzzle) and a complex task (using both the row and column rules to solve the puzzle). Behavioral results and functional imaging results between the healthy control group and the amnestic MCI group were analyzed. RESULTS: The accuracy for the complex task in the healthy control group was significantly higher than that in the amnestic MCI group (P < .05). The healthy control group exhibited a deactivated BOLD signal intensity (SI) change in the bilateral PCC and adjacent precuneus regions during the complex task, whereas the amnestic MCI group showed activation. The positive linear correlations between the BOLD SI change in bilateral PCC and adjacent precuneus regions and in bilateral hippocampi in the amnestic MCI group were significant (P < .001), while in the healthy control group, they were not (P >= .23). CONCLUSION: These findings suggest that an altered BOLD response in amnestic MCI patients during complex tasks might be related to a decline in problem-solving ability and to memory impairment and, thus, may indicate a compensatory response to memory impairment. PMID- 21788525 TI - Reproducibility of CT perfusion parameters in liver tumors and normal liver. AB - PURPOSE: To assess the reproducibility of computed tomographic (CT) perfusion measurements in liver tumors and normal liver and effects of motion and data acquisition time on parameters. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this prospective study. The study complied with HIPAA regulations. Two CT perfusion scans were obtained 2 7 days apart in seven patients with liver tumors with two scanning phases (phase 1: 30-second breath-hold cine; phase 2: six intermittent free-breathing cines) spanning 135 seconds. Blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability-surface area product (PS) for tumors and normal liver were calculated from phase 1 with and without rigid registration and, for combined phases 1 and 2, with manually and rigid-registered phase 2 images, by using deconvolution modeling. Variability was assessed with within-patient coefficients of variation (CVs) and Bland-Altman analyses. RESULTS: For tumors, BF, BV, MTT, and PS values and reproducibility varied by analytical method, the former by up to 11%, 23%, 21%, and 138%, respectively. Median PS values doubled with the addition of phase 2 data to phase 1 data. The best overall reproducibility was obtained with rigidly registered phase 1 and phase 2 images, with within-patient CVs for BF, BV, MTT, and PS of 11.2%, 14.4%, 5.5% and 12.1%, respectively. Normal liver evaluations were similar, except with marginally lower variability. CONCLUSION: Absolute values and reproducibility of CT perfusion parameters were markedly influenced by motion and data acquisition time. PS, in particular, probably requires data acquisition beyond a single breath hold, for which motion-correction techniques are likely necessary. PMID- 21788524 TI - Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. AB - PURPOSE: To test the hypothesis-given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)-that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease. MATERIALS AND METHODS: This research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a -950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements. RESULTS: In a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047). CONCLUSION: Greater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes. PMID- 21788527 TI - Virtual elastic sphere processing enables reproducible quantification of vessel stenosis at CT and MR angiography. AB - PURPOSE: To develop and evaluate a user-friendly tool to enable efficient, accurate, and reproducible quantification of blood vessel stenosis in computed tomographic (CT) and magnetic resonance (MR) angiographic data sets. MATERIALS AND METHODS: All clinical experiments were approved by the institutional review board, and informed patient consent was acquired. Animal experiments were approved by the governmental review committee on animal care. A virtual elastic sphere passes through a blood vessel specified by user-provided start and end points, and the adapting diameter over the course of the vessel is recorded. The program was tested in phantoms to determine the accuracy of diameter estimation, and it was applied in micro-CT data sets of mice with induced vessel stenosis. Dual-energy CT angiography and MR angiography were performed in 16 patients with carotid artery stenosis, and reproducibility and required reader time of this automated technique were compared with manual measurements. Additionally, the effect of dual-energy CT-based discrimination between iodine- and calcium-based enhancement was investigated. Differences between carotid artery diameters of mice and between automated and manual measurement durations were assessed with a paired t test. Reproducibility of stenosis scores was evaluated with the Fisher z test. RESULTS: Phantom diameters were determined with an average error of 0.094 mm. Diameters of normal and injured carotid arteries of mice were significantly different (P < .01). For patient data, automated interreader variability was significantly (P < .01) lower than manual intra- and interreader variability, while time efficiency was improved (P < .01). CONCLUSION: The virtual elastic sphere tool is applicable to CT, dual-energy CT, and MR angiography, and it improves reproducibility and efficiency over that achieved with manual stenosis measurements. PMID- 21788528 TI - Small animal Look-Locker inversion recovery (SALLI) for simultaneous generation of cardiac T1 maps and cine and inversion recovery-prepared images at high heart rates: initial experience. AB - PURPOSE: To develop a single magnetic resonance (MR) imaging approach for comprehensive assessment of cardiac function and tissue properties in small animals with high heart rates. MATERIALS AND METHODS: All animal studies were approved by the local animal care committee. Small animal Look-Locker inversion recovery (SALLI) was implemented on a clinical 3.0-T MR unit equipped with a 70 mm solenoid coil. SALLI combines a segmented, electrocardiographically gated, inversion recovery-prepared Look-Locker-type pulse sequence with a multimodal reconstruction framework. Temporal undersampling and radial nonbalanced steady state free precession enabled acceleration of data acquisition and reduction of motion artifacts, respectively. Nine agarose gel phantoms were used to investigate different sequence settings. For in vivo studies, 10 Sprague-Dawley rats were evaluated to establish normal T1 values before and after injection of gadopentetate dimeglumine. Seven rats with surgically induced acute myocardial infarction were examined to test the feasibility of detecting myocardial injury. In vitro T1 behavior was studied with linear regression analysis, and in vivo T1 differences between infarcted and remote areas were tested by using the Wilcoxon signed rank test. RESULTS: Phantom studies demonstrated systematic behavior of the T1 measurements, and T1 error could be reduced to 1.3% +/- 7.4 by using a simple linear correction algorithm. The pre- and postcontrast T1 of myocardium and blood showed narrow normal ranges. In the area of infarction, SALLI demonstrated hypokinesia (on cine images), myocardial edema (on precontrast T1 maps), and myocardial necrosis (on postcontrast T1 maps and late gadolinium enhancement images). CONCLUSION: An MR imaging method enabling simultaneous generation of cardiac T1 maps and cine and inversion recovery-prepared images at high heart rates is presented. SALLI allows for simultaneous and time-efficient assessment of cardiac T1 behavior, function, and late gadolinium enhancement at high heart rates. PMID- 21788529 TI - Effect of transition to digital mammography on clinical outcomes. AB - PURPOSE: To determine the effect of transition to digital screening mammography on clinical outcome measures, including recall rate, cancer detection rate, and positive predictive value (PPV). MATERIALS AND METHODS: Institutional review board approval and the need for informed consent were waived for this HIPAA complaint study. Practice audit data were obtained for three breast imaging radiologists from 2004 to 2009. These data were sorted by time period into the following groups: baseline (2004-2005), digital year 1 (2007), digital year 2 (2008), and digital year 3 (2009). The chi(2) and Fisher exact tests were used to assess differences in proportions among and between years. Clinical outcomes based on lesion type from 2004 to 2008 were also compared. Computer-aided detection was used. RESULTS: The three radiologists interpreted 32 600 screen film mammograms and 33 879 digital mammograms. Recall rates increased from 6.0% at baseline to 7.1% in digital year 1 (P < .0001) and continued to increase in subsequent years to 8.5%. The cancer detection rate increased from 3.3 at baseline to 5.3 in digital year 1 (P = .0061), and it remained higher than that at baseline in subsequent years. PPV after screening mammogaphy (PPV(1)) increased from 5.6% at baseline to 7.5% in digital year 1 and returned to baseline levels in digital year 3. In contrast, PPV after biopsy (PPV(3)) decreased from 44.5% at baseline to 30.3% in digital year 3 (P = .0021). From 2004 to 2008, 3444 patients with 3493 lesions were recalled. The percentage of recalls for calcifications increased from 13.8% at baseline to a peak of 23.9% in digital year 1 and 17.9% in digital year 2. Both PPV(1) and PPV(3) decreased for calcifications after the digital transition. CONCLUSION: Recall rate and cancer detection rate increase for at least 2 years after the transition to digital screening mammography. PPV(3) is significantly reduced after digital transition, primarily in patients with microcalcifications. PMID- 21788530 TI - Evolution of gynoecium morphology in Old World Papaveroideae: a combined phylogenetic/ontogenetic approach. AB - PREMISE OF THE STUDY: The correct assessment of homology is an important prerequisite for reconstructing phylogenetic relationships and character evolution. Old World Papaveroideae (Papaver, Meconopsis, Roemeria, Stylomecon) show substantial diversity in gynoecium and capsule morphology. In particular, capsules can have distinct styles (Meconopsis p.p., Stylomecon) or a sessile stigmatic disc (Papaver). Molecular phylogenetic analyses of Old World Papaveroideae had shown that neither taxa with styles nor those with stigmatic discs represent monophyletic lineages. We here investigate whether either styles or stigmatic discs have arisen repeatedly during the diversification of Old World Papaveroideae. METHODS: We investigated gynoecium ontogeny in Papaver rhoeas, P. californicum, Meconopsis cambrica, and Stylomecon heterophylla by scanning electron microscopy for the first time. Our observations were interpreted on the background of a well-resolved molecular phylogeny of the taxa investigated. KEY RESULTS: Papaver rhoeas and P. californicum share the presence of a developmentally complex garland-like stage in gynoecium ontogeny. The styles of M. cambrica and S. heterophylla result from growth in a ring-like zone beneath the carpel tips. This zone is also present in Papaver. In M. cambrica, traces of a garland-like stage can be seen. Style formation and stigma formation begin more or less simultaneously in M. cambrica, but style formation clearly precedes stigma formation in S. heterophylla. CONCLUSIONS: The styles present in M. cambrica and S. heterophylla are considered to have arisen in parallel from ancestors with a stigmatic disc. We speculate that style formation may have been a means to reduce selfing. PMID- 21788531 TI - Bud production and dynamics of flowering and vegetative tillers in Andropogon gerardii (Poaceae): the role of developmental constraints. AB - PREMISE OF THE STUDY: Perennial grasses maintain aboveground tiller populations through vegetative reproduction via belowground buds and sexual reproduction via seed. The maintenance of a bud bank has important demographic consequences for perennial grasses. A tradeoff between these reproductive modes would be expected for a plant with limited resource availability. However, the ontogeny of the tiller could affect its ability to allocate between these two modes of reproduction. METHODS: Vegetative bud production and dynamics and tiller production were examined biweekly through an annual cycle on vegetative and flowering tillers of Andropogon gerardii. KEY RESULTS: Andropogon gerardii maintains a large reserve of dormant buds. Although vegetative and flowering tillers had similar bud phenology, flowering tillers produced larger numbers of buds of larger size, and transitioned a larger proportion of their buds to tiller, than did vegetative tillers. Therefore, a negative consequence of sexual reproduction on vegetative reproduction was not evident at the tiller level. A size threshold for floral induction likely exists that results in flowering tillers having more buds per tiller than vegetative tillers. The increased bud outgrowth of flowering tillers could be a result of their larger bud size or weaker apical dominance as compared to vegetative tillers. CONCLUSIONS: Plant development can place significant constraints on tradeoffs between the reproductive modes in perennial grasses and could affect their plasticity in plant reproductive allocation. Differences in developmental phenology and bud production between flowering and vegetative tillers may influence grass responses to environmental changes such as altered precipitation regimes or resource availability. PMID- 21788532 TI - Formalizing morphologically cryptic biological entities: new insights from DNA taxonomy, hybridization, and biogeography in the leafy liverwort Porella platyphylla (Jungermanniopsida, Porellales). AB - PREMISE OF THE STUDY: Recognition and formalization of morphologically cryptic species is a major challenge to modern taxonomy. An extreme example in this regard is the Holarctic Porella platyphylla s.l. (P. platyphylla plus P. platyphylloidea). Earlier studies demonstrated the presence of three isozyme groups and two molecular lineages. The present investigation was carried out to elucidate the molecular diversity of P. platyphylla s.l. and the distribution of its main clades, and to evaluate evidence for the presence of one vs. several species. METHODS: We obtained chloroplast (atpB-rbcL, trnL-trnF) and nuclear ribosomal (ITS) DNA sequences from 101 Porella accessions (P. platyphylla s.l., P. * baueri, P. cordaeana, P. bolanderi, plus outgroup species) to estimate the phylogeny using parsimony and likelihood analyses. To facilitate the adoption of Linnean nomenclature for molecular lineages, we chose a DNA voucher as epitype. KEY RESULTS: Phylogenies derived from chloroplast vs. nuclear data were congruent except for P. platyphylla s.l., including a North American lineage that was placed sister to P. cordaeana in the chloroplast DNA phylogeny but sister to the Holarctic P. platyphylla s.str. in the nuclear DNA phylogeny. European and North American accessions of P. cordaeana and P. platyphylla form sister clades. CONCLUSIONS: The genetic structure of P. platyphylla s.l. reflects morphologically cryptic or near cryptic speciation into Holarctic P. platyphylla s.str. and North American P. platyphylloidea. The latter species is possibly an ancient hybrid resulting from crossings of P. cordaeana and P. platyphylla s.str. and comprises several distinct molecular entities. PMID- 21788533 TI - Plant water status and hydraulic conductance during flowering in the southern California coastal sage shrub Salvia mellifera (Lamiaceae). AB - PREMISE OF THE STUDY: Plant water status during flowering is important for plant reproduction, but the physiology of floral water use is not well understood. We investigated plant water status in relation to leaf and floral physiology in naturally occurring individuals of a semiarid shrub, Salvia mellifera E. Greene. METHODS: We measured stomatal (g(s)) and corolla (g(c)) conductance to water vapor, transpiration from leaves (E(leaf)) and corollas (E(corolla)), leaf specific hydraulic conductance (K(H)), bulk shoot water potential (Psi(shoot)), and shoot water content on irrigated and control plants to analyze whether water was limiting to leaf and floral water use. KEY RESULTS: Experimental irrigation caused a 203% increase in soil moisture content, a 20% increase in predawn Psi(shoot), a 29% increase in midday Psi(shoot), and a 92% increase in K(H). Floral and leaf gas exchange did not respond significantly to water addition, indicating that rates were at seasonal maxima and not limited by water availability. Total daily water use by corollas was ~20% of total shoot water use. There were no significant differences in total daily shoot water use with water addition. Mean shoot water content (5.07 g) was close to mean daily shoot water use (6.71 g), indicating that the equivalent of total shoot water content turned over every 0.76 d. CONCLUSIONS: These results demonstrate that although irrigation improved whole-plant hydraulic conductance, gas exchange was not limited by water availability. Additionally, the high water use of flowers in this species might limit future flowering and reproductive success during dry years. PMID- 21788535 TI - Predicting death: an empirical evaluation of predictive tools for mortality. AB - BACKGROUND: The ability to predict death is crucial in medicine, and many relevant prognostic tools have been developed for application in diverse settings. We aimed to evaluate the discriminating performance of predictive tools for death and the variability in this performance across different clinical conditions and studies. METHODS: We used Medline to identify studies published in 2009 that assessed the accuracy (based on the area under the receiver operating characteristic curve [AUC]) of validated tools for predicting all-cause mortality. For tools where accuracy was reported in 4 or more assessments, we calculated summary accuracy measures. Characteristics of studies of the predictive tools were evaluated to determine if they were associated with the reported accuracy of the tool. RESULTS: A total of 94 eligible studies provided data on 240 assessments of 118 predictive tools. The AUC ranged from 0.43 to 0.98 (median [interquartile range], 0.77 [0.71-0.83]), with only 23 of the assessments reporting excellent discrimination (10%) (AUC, >0.90). For 10 tools, accuracy was reported in 4 or more assessments; only 1 tool had a summary AUC exceeding 0.80. Established tools showed large heterogeneity in their performance across different cohorts (I(2) range, 68%-95%). Reported AUC was higher for tools published in journals with lower impact factor (P = .01), with larger sample size (P = .01), and for those that aimed to predict mortality among the highest-risk patients (P = .002) and among children (P < .001). CONCLUSIONS: Most tools designed to predict mortality have only modest accuracy, and there is large variability across various diseases and populations. Most proposed tools do not have documented clinical utility. PMID- 21788534 TI - Risk factor and prediction modeling for sudden cardiac death in women with coronary artery disease. AB - BACKGROUND: To our knowledge, the risk of sudden cardiac death (SCD) and the assessment of risk factors in prediction models have not been evaluated in women with coronary artery disease (CAD). We sought to evaluate the incidence of SCD as well as its risk factors and their predictive accuracy among a population of women with CAD. METHODS: The Heart and Estrogen/progestin Replacement Study evaluated the effects of hormone replacement therapy on cardiovascular events among 2763 postmenopausal women with CAD. Sudden cardiac death was defined as death resulting from a cardiac origin that occurred within 1 hour of symptom onset. The associations between candidate predictor variables and SCD were evaluated in a Cox proportional hazards model. The C-index was used to compare the predictive value of the clinical risk factors with left ventricular ejection fraction (LVEF) alone and in combination. The net reclassification improvement was also computed. RESULTS: Over a mean follow-up of 6.8 years, SCD comprised 136 of the 254 cardiac deaths. The annual SCD event rate was 0.79% (95% confidence interval, 0.67-0.94). The following variables were independently associated with SCD in the multivariate model: myocardial infarction, heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m(2), atrial fibrillation, physical inactivity, and diabetes. The incidences of SCD among women with 0 (n = 683), 1 (n = 1224), 2 (n = 610), and 3 plus (n = 246) risk factors at baseline were 0.3%, 0.5%, 1.2%, and 2.9% per year, respectively. The combination of clinical risk factors and LVEF (C-index, 0.681) were better predictors of SCD than LVEF alone (C-index, 0.600) and resulted in a net reclassification improvement of 0.20 (P < .001). CONCLUSIONS: Sudden cardiac death comprised the majority of cardiac deaths among postmenopausal women with CAD. Independent predictors of SCD, including myocardial infarction, congestive heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m(2), atrial fibrillation, physical inactivity, and diabetes, improved SCD prediction when they were considered in addition to LVEF. PMID- 21788536 TI - Cardiovascular risk stratification, hemoglobin a1c, and the tempo of translation: comment on "Cardiovascular risk prediction in diabetic men and women using hemoglobin A1c vs diabetes as a high-risk equivalent". PMID- 21788537 TI - Sudden cardiac death risk prediction: comment on "Risk factor and prediction modeling for sudden cardiac death in women with coronary artery disease". PMID- 21788539 TI - Interventions to decrease hospital readmission rates: who saves? Who pays? PMID- 21788538 TI - Cardiovascular risk prediction in diabetic men and women using hemoglobin A1c vs diabetes as a high-risk equivalent. AB - BACKGROUND: It is unclear whether models that include hemoglobin A(1c) (HbA(1c)) levels only for diabetic patients improve the ability to predict cardiovascular disease (CVD) risk compared with the currently recommended classification of diabetes as a cardiovascular risk equivalent. METHODS: A total of 24 674 women (including 685 diabetic participants at baseline) and 11 280 men (including 563 diabetic participants at baseline) were followed up prospectively for cardiovascular disease (CVD). One hundred twenty-five CVD events occurred in diabetic women (666 in nondiabetic women), and 170 events occurred in diabetic men (1382 in nondiabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA(1c) levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared with classification of diabetes as a cardiovascular risk equivalent (10-year CVD risk of at least 20%). RESULTS: In women, the models including HbA(1c) levels in diabetic participants improved the C statistic by 0.177 (P < .001) over the risk equivalence model and showed improved reclassification (net reclassification improvement [NRI] of 26.7% [P = .001]). In men, the improvements were more modest but still statistically significant (C statistic change of 0.039 [P = .02]; NRI of 9.2% [P = .04]). Including HbA(1c) levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8% [P = .03]) but not in men. CONCLUSIONS: In both women and men with diabetes at baseline, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA(1c) levels compared with classification of diabetes as a cardiovascular risk equivalent. PMID- 21788540 TI - The care transitions intervention: translating from efficacy to effectiveness. AB - BACKGROUND: Well-executed communication among hospital providers, patients, and receiving providers at the time of hospital discharge contributes to better health outcomes and lower overall health care costs. The Care Transitions Intervention has reduced 30-day hospital readmissions by 30% in a randomized controlled trial in an integrated health system but requires real-world testing to establish effectiveness in other settings. We hypothesized that coaching would reduce 30-day readmission rates for fee-for-service Medicare beneficiaries, even in open, urban health care delivery systems. METHODS: This was a quasi experimental prospective cohort study. From January 1, 2009, through June 30, 2010, coaches recruited a convenience sample of fee-for-service Medicare patients in 6 Rhode Island hospitals to receive the Care Transitions Intervention. We paired coaching data with Medicare claims and enrollment data and used logistic regression to compare the odds of 30-day readmission for the intervention group vs internal and external control groups. RESULTS: Compared with individuals who did not receive any part of the intervention (20.0% readmission rate), 30-day readmissions were fewer for participants who received coaching (12.8%; odds ratio, 0.61; 95% confidence interval, 0.42-0.88). Individuals in the internal control group (declined to participate or were lost to follow-up before completing a home visit) had readmission rates similar to those of the external control group (18.6%; odds ratio, 0.94, 95% confidence interval, 0.77-1.14). CONCLUSIONS: The Care Transitions Intervention appears to be effective in this real-world implementation. This finding underscores the opportunity to improve health outcomes beginning at the time of discharge in open health care settings. PMID- 21788541 TI - Effectiveness and cost of a transitional care program for heart failure: a prospective study with concurrent controls. AB - BACKGROUND: Randomized controlled trials have demonstrated the efficacy of nurse led transitional care programs to reduce readmission rates for patients with heart failure; the effectiveness of these programs in real-world health care systems is less well understood. METHODS: We performed a prospective study with concurrent controls to test an advanced practice nurse-led transitional care program for patients with heart failure who were 65 years or older and were discharged from Baylor Medical Center Garland (BMCG) from August 24, 2009, through April 30, 2010. We compared the effect of the program on 30-day (from discharge) all-cause readmission rate, length of stay, and 60-day (from admission) direct cost for BMCG with that of other hospitals within the Baylor Health Care System. We also performed a budget impact analysis using costs and reimbursement experience from the intervention. RESULTS: The intervention significantly reduced adjusted 30-day readmission rates to BMCG by 48% during the postintervention period, which was better than the secular reductions seen at all other facilities in the system. The intervention had little effect on length of stay or total 60-day direct costs for BMCG. Under the current payment system, the intervention reduced the hospital financial contribution margin on average $227 for each Medicare patient with heart failure. CONCLUSIONS: Preliminary results suggest that transitional care programs reduce 30-day readmission rates for patients with heart failure. This underscores the potential of the intervention to be effective in a real-world setting, but payment reform may be required for the intervention to be financially sustainable by hospitals. PMID- 21788543 TI - Cranberries as antibiotics?: Comment on "Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women". PMID- 21788542 TI - Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. AB - BACKGROUND: The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in cranberries to prevent recurrent urinary tract infections (UTIs). METHODS: In a double-blind, double-dummy noninferiority trial, 221 premenopausal women with recurrent UTIs were randomized to 12-month prophylaxis use of trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily, or cranberry capsules, 500 mg twice daily. Primary end points were the mean number of symptomatic UTIs over 12 months, the proportion of patients with at least 1 symptomatic UTI, the median time to first UTI, and development of antibiotic resistance in indigenous Escherichia coli. RESULTS: After 12 months, the mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; P = .02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to the first symptomatic UTI was 4 months for the cranberry and 8 months for the TMP-SMX group. After 1 month, in the cranberry group, 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant, whereas in the TMP-SMX group, 86.3% of fecal and 90.5% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant. Similarly, we found increased resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month in the TMP-SMX group. After discontinuation of TMP-SMX, resistance reached baseline levels after 3 months. Antibiotic resistance did not increase in the cranberry group. Cranberries and TMP-SMX were equally well tolerated. CONCLUSION: In premenopausal women, TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs, at the expense of emerging antibiotic resistance. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN50717094. PMID- 21788544 TI - Defining health information technology-related errors: new developments since to err is human. AB - Despite the promise of health information technology (HIT), recent literature has revealed possible safety hazards associated with its use. The Office of the National Coordinator for HIT recently sponsored an Institute of Medicine committee to synthesize evidence and experience from the field on how HIT affects patient safety. To lay the groundwork for defining, measuring, and analyzing HIT related safety hazards, we propose that HIT-related error occurs anytime HIT is unavailable for use, malfunctions during use, is used incorrectly by someone, or when HIT interacts with another system component incorrectly, resulting in data being lost or incorrectly entered, displayed, or transmitted. These errors, or the decisions that result from them, significantly increase the risk of adverse events and patient harm. We describe how a sociotechnical approach can be used to understand the complex origins of HIT errors, which may have roots in rapidly evolving technological, professional, organizational, and policy initiatives. PMID- 21788545 TI - The use of dabigatran in elderly patients. AB - Recent approval by the US Food and Drug Administration (FDA) of dabigatran etexilate, an oral direct thrombin inhibitor, for the prevention of stroke in patients with atrial fibrillation will likely extend its administration in elderly patients. The risk of major overdosage of dabigatran etexilate in this population is, however, much increased owing to frequent renal function impairment, low body weight, drug interactions that cannot be detected with a routine coagulation test, and no antagonist available. We report herein 2 clinical cases, including 1 fatal case, illustrating our concern regarding the risk of bleeding events in elderly patients. PMID- 21788546 TI - New anticoagulant drugs among elderly patients is caution necessary?: Comment on "The use of dabigatran in elderly patients". PMID- 21788547 TI - Limitations in the use of qualitative terms to inform diagnoses. PMID- 21788548 TI - Association between physician competence at licensure and the quality of asthma management among patients with out-of-control asthma. PMID- 21788549 TI - Smartphones in clinical practice, medical education, and research. PMID- 21788550 TI - Patients with infectious diseases, overcrowding, and health in hospital staff. PMID- 21788551 TI - In-hospital mobility and length of stay. PMID- 21788552 TI - Achieving co-managment's potential requires system redesign and hospitalist focused training. PMID- 21788553 TI - Interspecialty communication: old problem, new hope? PMID- 21788554 TI - The importance of collaboration among physicians. PMID- 21788555 TI - Marantic endocarditis with cardioembolic strokes mimicking leptomeningeal metastases in breast cancer. PMID- 21788556 TI - Cost-effectiveness of universal hepatitis B virus screening in patients beginning chemotherapy for solid tumors. AB - PURPOSE: Universal screening for chronic hepatitis B virus (HBV) infection before chemotherapy has been recommended. We evaluated the cost-effectiveness of HBV screening before chemotherapy given for nonhematopoietic solid tumors (STs). METHODS: A decision-analytic model was used to compare the cost-effectiveness of universal screening conducted per professional guidelines versus no screening in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non-small-cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. RESULTS: Using an incremental cost-effectiveness ratio threshold of $50,000 (Australian dollars) per life-year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients ($88,224/LY, 13% probability of being cost-effective), palliative patients ($1,344,251/LY, 0%), or pooled (all) patients ($149,857/LY, 1%). Sensitivity analyses found that screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%, $59,445/LY) or HBV reactivation with chemotherapy (41%, $56,537/LY). Cost- effectiveness was also significantly influenced by HBV population prevalence. An alternative screening strategy using hepatitis B surface antigen testing only produced the most economically favorable results, with $30,126/LY (80% probability) for adjuvant patients and $51,201/LY (43%) for the pooled cohort. CONCLUSION: Universal HBV screening conducted per current guidelines is not cost-effective in patients with STs. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy. PMID- 21788557 TI - Ongoing challenge of stage II colon cancer. PMID- 21788558 TI - Chemotherapy, trastuzumab, and pathological complete response: when shall we three meet again? PMID- 21788559 TI - Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. AB - PURPOSE: Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. PATIENTS AND METHODS: Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). RESULTS: The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. CONCLUSION: Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population. PMID- 21788560 TI - Faithful markers of circulating cancer stem cells: is CD133 sufficient for validation in clinics? PMID- 21788562 TI - Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. AB - PURPOSE: Our aim was to determine whether abundance of epidermal growth factor receptor (EGFR) mutations in tumors predicts benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs) for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We detected EGFR mutations in 100 lung cancer samples using direct DNA sequencing and amplification refractory mutation system (ARMS). Mutation-positive tumors by both methods carried high abundance of EGFR mutations. Tumors that were mutation positive by ARMS but mutation negative by direct DNA sequencing harbored low abundance of EGFR mutations. Mutation-negative tumors by both methods carried wild-type EGFR. All patients received gefitinib treatment. The correlation between EGFR mutation abundance and clinical benefit from gefitinib treatment was analyzed. RESULTS: Of 100 samples, 51 and 18 harbored high and low abundances of EGFR mutations, respectively; 31 carried wild type EGFR. Median progression-free survival (PFS) was 11.3 (95% CI, 7.4 to 15.2) and 6.9 months (95% CI, 5.5 to 8.4) in patients with high and low abundances of EGFR mutations, respectively (P = .014). Median PFS of patients with low abundance of EGFR mutations was significantly longer than that of those with wild type tumors (2.1 months; 95% CI, 1.0 to 3.2; P = .010). Objective response rates (ORRs) were 62.7%, 44.4%, and 16.1%, and overall survival (OS) rates were 15.9 (95% CI, 13.4 to 18.3), 10.9 (95% CI, 2.7 to 19.1), and 8.7 months (95% CI, 4.6 to 12.7) for patients with high abundance of EGFR mutations, low abundance of EGFR mutations, and wild-type EGFR, respectively. The difference between patients with high and low abundances of EGFR mutations was not significant regarding ORR and OS. CONCLUSION: The relative EGFR mutation abundance could predict benefit from EGFR-TKI treatment for advanced NSCLC. PMID- 21788561 TI - Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. AB - PURPOSE: Adjuvant chemotherapy is typically considered for patients with stage II colon cancer characterized by poor prognostic features, including obstruction, perforation, emergent admission, T4 stage, resection of fewer than 12 lymph nodes, and poor histology. Despite frequent use, the survival advantage conferred on patients with stage II disease by chemotherapy is yet unproven. We sought to determine the overall survival benefit of chemotherapy among patients with stage II colon cancer having poor prognostic features. PATIENTS AND METHODS: A total of 43,032 Medicare beneficiaries who underwent colectomy for stage II and III primary colon adenocarcinoma diagnosed from 1992 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) -Medicare database. chi(2) and two-way analysis of variance were used to assess differences in patient- and disease-related characteristics. Five-year overall survival was examined using Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting. RESULTS: Of the 24,847 patients with stage II cancer, 75% had one or more poor prognostic features. Adjuvant chemotherapy was received by 20% of patients with stage II disease and 57% of patients with stage III disease. After adjustment, 5-year survival benefit from chemotherapy was observed only for patients with stage III disease (hazard ratio[HR], 0.64; 95% CI, 0.60 to 0.67). No survival benefit was observed for patients with stage II cancer with no poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13). CONCLUSION: Among Medicare patients identified with stage II colon cancer, either with or without poor prognostic features, adjuvant chemotherapy did not substantially improve overall survival. This lack of benefit must be considered in treatment decisions for similar older adults with colon cancer. PMID- 21788563 TI - Validation microsatellite path score in a population-based cohort of patients with colorectal cancer. AB - PURPOSE: Bethesda guidelines are used to recognize patients at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score, based on age, tumor location, and pathologic features, has been developed to effectively predict colorectal cancer with DNA mismatch repair (MMR) deficiencies. However, the MsPath model's performance in an unselected, population-based colorectal cancer (CRC) population is unknown. PATIENTS AND METHODS: We analyzed all patients with CRC regardless of age, personal or family history, and tumor characteristics from the EPICOLON study, an independent, prospective, multicenter, population-based cohort (N = 1,222). All patients underwent tumor microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2, and those with MMR underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. All the pathologic features were centralized and evaluated blinded to the MMR status. RESULTS: MsPath score for prediction of having MSI high, with the recommended MsPath cutoff score >=1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8% (95% CI, 86.9 to 98.3), 64.1% (95% CI, 61.1 to 66.8), and 15.8% (95% CI, 12.2 to 18.6), respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8% (95% CI, 59.0 to 99.8), 60.6% (95% CI, 57.8 to 63.4), and 1.9% (95% CI, 0.7 to 3.1), respectively, for the identification of MLH1/MSH2 gene carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both pathogenic germline MSH2 mutations. CONCLUSION: In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome. PMID- 21788565 TI - Carcinosarcoma derived from nevus sebaceus. PMID- 21788564 TI - Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. AB - PURPOSE: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. PATIENTS AND METHODS: Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. RESULTS: In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. CONCLUSION: mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs. PMID- 21788566 TI - Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2 overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. AB - PURPOSE: To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. PATIENTS AND METHODS: Patients with centrally confirmed HER2-overexpressing breast cancer (>= 2 cm or inflammatory) received four 3-week cycles epirubicin and cyclophosphamide (90/600 mg/m(2)) followed by four 3-week cycles paclitaxel (175 mg/m(2)) and trastuzumab (6 mg/kg) before surgery. Trastuzumab was continued after surgery to complete 1 year of treatment. Primary end point was pathologic complete response (pCR) defined as no residual invasive tumor in breast and lymphatic tissue. RESULTS: Thirty-nine percent of 217 enrolled patients achieved a pCR. Breast conservation was possible in 64% of patients. Three-year disease free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (P = .01). Three-year overall survival (OS) was 96% in patients with pCR compared to 86% in patients without pCR (P = .025). pCR was the only significant prognostic factor for DFS (hazard ratio [HR] 2.5; 95% CI, 1.2 to 5.1; P = .013) and OS (HR, 4.9; 95% CI, 1.4 to 17.4; P = .012) in multivariable analysis. Cardiac toxicity was reported in eight patients (3.7%) of whom six presented with an asymptomatic left ventricular ejection fraction decrease and two with symptomatic chronic heart failure. CONCLUSION: Neoadjuvant combination of trastuzumab and chemotherapy resulted in a high pCR rate in HER2 overexpressing primary breast cancer. Patients with a pCR after neoadjuvant anti HER2 therapy in combination with chemotherapy followed by maintenance trastuzumab have an improved long-term outcome. Patients without a pCR had an increased risk for relapse and death. PMID- 21788567 TI - American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. AB - PURPOSE: To update the American Society of Clinical Oncology (ASCO) Technology Assessment guidelines on chemotherapy sensitivity and resistance assays (CSRAs) published in 2004. METHODS: An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010. MEDLINE and the Cochrane Library were searched. The literature search yielded 11,313 new articles. The limits for "human and English" were used, and then standard ASCO search strings for randomized controlled trials, meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review. Of these, only 21 articles met predefined inclusion criteria and underwent full text review, and five reports of randomized controlled trials were included for data extraction. RESULTS: Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice. RECOMMENDATIONS: The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority. PMID- 21788568 TI - Malignant epithelioid hemangioendothelioma of the liver successfully treated with pegylated liposomal doxorubicin. PMID- 21788569 TI - Art of oncology: new voices wanted. PMID- 21788570 TI - Obesity and survival among black women and white women 35 to 64 years of age at diagnosis with invasive breast cancer. AB - PURPOSE: To evaluate the effect of obesity on survival among black women and white women with invasive breast cancer and to determine whether obesity explains the poorer survival of black women relative to white women. PATIENTS AND METHODS: We observed 4,538 (1,604 black, 2,934 white) women who were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. Multivariate Cox regression models were used to examine the effect of body mass index (BMI, in kilograms per square meter) 5 years before diagnosis on risk of death from any cause and from breast cancer. RESULTS: During a median of 8.6 years of follow-up, 1,053 women died (519 black, 534 white), 828 as a result of breast cancer (412 black, 416 white). Black women were more likely to die than white women (multivariate-adjusted relative risk [RR], 1.33; 95% CI, 1.16 to 1.53). Compared with women with BMI of 20 to 24.9 kg/m(2), those who were obese (BMI >= 30 kg/m(2)) had a greater risk of all-cause mortality (RR, 1.23; 95% CI, 1.04 to 1.47) and breast cancer-specific mortality (RR, 1.20; 95% CI, 0.99 to 1.46). These associations were observed among white women (all-cause RR, 1.54; 95% CI, 1.21 to 1.96; breast cancer RR, 1.46; 95% CI, 1.11 to 1.92), but not among black women (all-cause RR, 1.03; 95% CI, 0.81 to 1.29; breast cancer RR, 1.02; 95% CI, 0.79 to 1.33). CONCLUSION: Obesity may play an important role in mortality among white but not black patients with breast cancer. It is unlikely that differences in obesity distributions between black women and white women account for the poorer survival of black women. PMID- 21788572 TI - Ganglioside GM1 deficiency in effector T cells from NOD mice induces resistance to regulatory T-cell suppression. AB - OBJECTIVE: To detect GM1 deficiency and determine its role in effector T cells (Teffs) from NOD mice in establishing resistance to regulatory T-cell (Treg) suppression. RESEARCH DESIGN AND METHODS: CD4(+) and CD8(+) Teffs were isolated from spleens of prediabetic NOD mice for comparison with similar cells from Balb/c, C57BL/6, and NOR mice. GM1 was quantified with thin-layer chromatography for total cellular GM1 and flow cytometry for cell-surface GM1. Suppression of Teff proliferation was determined by application of GM1 cross-linking agents or coculturing with Tregs. Calcium influx in Teffs was quantified using fura-2. RESULTS: Resting and activated CD4(+) and CD8(+) Teffs of NOD mice contained significantly less GM1 than Teffs from the other three mouse strains tested. After activation, NOD Teffs resisted suppression by Tregs or GM1 cross-linking agents in contrast to robust suppression of Balb/c Teffs; this was reversed by preincubation of NOD Teffs with GM1. NOD Teffs also showed attenuated Ca(2+) influx via transient receptor potential channel 5 (TRPC5) channels induced by GM1 cross-linking, and this, too, was reversed by elevation of Teff GM1. CONCLUSIONS: GM1 deficiency occurs in NOD Teffs and contributes importantly to failed suppression, which is rectified by increasing Teff GM1. Such elevation also reverses subthreshold Ca(2+) influx via TRPC5 channels, an essential aspect of suppression. Our results also support a critical role for galectin-1 as a GM1 cross-linking counter-receptor that fittingly is upregulated and released by Tregs during activation. These findings suggest a novel mechanism by which pathogenic Teffs evade regulatory suppression, thereby leading to autoimmune beta cell destruction and type 1 diabetes. PMID- 21788571 TI - Ghrelin attenuates cAMP-PKA signaling to evoke insulinostatic cascade in islet beta-cells. AB - OBJECTIVE: Ghrelin reportedly restricts insulin release in islet beta-cells via the Galpha(i2) subtype of G-proteins and thereby regulates glucose homeostasis. This study explored whether ghrelin regulates cAMP signaling and whether this regulation induces insulinostatic cascade in islet beta-cells. RESEARCH DESIGN AND METHODS: Insulin release was measured in rat perfused pancreas and isolated islets and cAMP production in isolated islets. Cytosolic cAMP concentrations ([cAMP](i)) were monitored in mouse MIN6 cells using evanescent-wave fluorescence imaging. In rat single beta-cells, cytosolic protein kinase-A activity ([PKA](i)) and Ca(2+) concentration ([Ca(2+)](i)) were measured by DR-II and fura-2 microfluorometry, respectively, and whole cell currents by patch-clamp technique. RESULTS: Ghrelin suppressed glucose (8.3 mmol/L)-induced insulin release in rat perfused pancreas and isolated islets, and these effects of ghrelin were blunted in the presence of cAMP analogs or adenylate cyclase inhibitor. Glucose-induced cAMP production in isolated islets was attenuated by ghrelin and enhanced by ghrelin receptor antagonist and anti-ghrelin antiserum, which counteract endogenous islet-derived ghrelin. Ghrelin inhibited the glucose-induced [cAMP](i) elevation and [PKA](i) activation in MIN6 and rat beta-cells, respectively. Furthermore, ghrelin potentiated voltage-dependent K(+) (Kv) channel currents without altering Ca(2+) channel currents and attenuated glucose-induced [Ca(2+)](i) increases in rat beta-cells in a PKA-dependent manner. CONCLUSIONS: Ghrelin directly interacts with islet beta-cells to attenuate glucose-induced cAMP production and PKA activation, which lead to activation of Kv channels and suppression of glucose-induced [Ca(2+)](i) increase and insulin release. PMID- 21788573 TI - Cyanidin-3-O-beta-glucoside and protocatechuic acid exert insulin-like effects by upregulating PPARgamma activity in human omental adipocytes. AB - OBJECTIVE: Insulin resistance (IR) represents an independent risk factor for metabolic, cardiovascular, and neoplastic disorders. Preventing/attenuating IR is a major objective to be reached to preserve population health. Because many insulin-sensitizing drugs have shown unwanted side effects, active harmless compounds are sought after. Dietary anthocyanins have been demonstrated to ameliorate hyperglycemia and insulin sensitivity. This study aimed at investigating whether cyanidin-3-O-beta-glucoside (C3G) and its metabolite protocatechuic acid (PCA) might have a role in glucose transport activation in human omental adipocytes and 3T3-L1 cells. RESEARCH DESIGN AND METHODS: In cells treated with 50 umol/L C3G and 100 umol/L PCA, [(3)H]-2-deoxyglucose uptake, GLUT4 translocation by immunoblotting, adiponectin secretion, and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation by enzyme-linked immunosorbent assay kits were evaluated. Parallel experiments were carried out in murine adipocyte 3T3-L1. To define the role of PPARgamma in modulating polyphenol effects, small interfering RNA technique and PPARgamma antagonist were used to inhibit transcription factor activity. RESULTS: C3G and PCA increased adipocyte glucose uptake (P < 0.05) and GLUT4 membrane translocation (P < 0.01). Significant increases (P < 0.05) in nuclear PPARgamma activity, as well as in adiponectin and GLUT4 expressions (P < 0.01), were also shown. It is interesting that PPARgamma inhibition counteracted the polyphenol-induced adiponectin and GLUT4 upregulations, suggesting a direct involvement of PPARgamma in this process. CONCLUSIONS: Our study provides evidence that C3G and PCA might exert insulin-like activities by PPARgamma activation, evidencing a causal relationship between this transcription factor and adiponectin and GLUT4 upregulation. Dietary polyphenols could be included in the preventive/therapeutic armory against pathological conditions associated with IR. PMID- 21788574 TI - Does genetic ancestry explain higher values of glycated hemoglobin in African Americans? AB - OBJECTIVE: Glycated hemoglobin (HbA(1c)) values are higher in African Americans than whites, raising the question of whether classification of diabetes status by HbA(1c) should differ for African Americans. We investigated the relative contribution of genetic ancestry and nongenetic factors to HbA(1c) values and the effect of genetic ancestry on diabetes classification by HbA(1c) in African Americans. RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis of data from the community-based Atherosclerosis Risk in Communities (ARIC) Study. We estimated percentage of European genetic ancestry (PEA) for each of the 2,294 African Americans without known diabetes using 1,350 ancestry-informative markers. HbA(1c) was measured from whole-blood samples and categorized using American Diabetes Association diagnostic cut points (<5.7, 5.7-6.4, and >=6.5%). RESULTS: PEA was inversely correlated with HbA(1c) (adjusted r = -0.07; P < 0.001) but explained <1% of its variance. Age and socioeconomic and metabolic factors, including fasting glucose, explained 13.8% of HbA(1c) variability. Eleven percent of participants were classified as having diabetes; adjustment for fasting glucose decreased this to 4.4%. Additional adjustment for PEA did not significantly reclassify diabetes status (net reclassification index = 0.034; P = 0.94) nor did further adjustment for demographic, socioeconomic, and metabolic risk factors. CONCLUSIONS: The relative contribution of demographic and metabolic factors far outweighs the contribution of genetic ancestry to HbA(1c) values in African Americans. Moreover, the impact of adjusting for genetic ancestry when classifying diabetes by HbA(1c) is minimal after taking into account fasting glucose levels, thus supporting the use of currently recommended HbA(1c) categories for diagnosis of diabetes in African Americans. PMID- 21788575 TI - Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation. AB - OBJECTIVE: No previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells. RESEARCH DESIGN AND METHODS: After intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1 day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO(2) <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections. RESULTS: In the native pancreas of nontransplanted animals, ~30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets. CONCLUSIONS: The vascular engraftment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site. PMID- 21788576 TI - Comment on: Ott et al. Reduction in basal nitric oxide activity causes albuminuria. Diabetes 2011;60:572-576. PMID- 21788578 TI - The metabolically benign and malignant fatty liver. PMID- 21788579 TI - Sleeping islets and the relationship between beta-cell mass and function. PMID- 21788580 TI - To B or not to B: (anti)bodies of evidence on the crime scene of type 1 diabetes? PMID- 21788581 TI - A low-oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells. AB - OBJECTIVE: The blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo. RESEARCH DESIGN AND METHODS: The reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas-transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity. RESULTS: In vivo, 20-25% of all islets in normal rats showed low oxygenation (pO(2) <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. CONCLUSIONS: The current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis. PMID- 21788584 TI - Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. AB - BACKGROUND: Experimental studies suggest that low wall shear stress (WSS) promotes plaque development and high WSS is associated with plaque destabilization. We hypothesized that low-WSS segments in patients with coronary artery disease develop plaque progression and high-WSS segments develop necrotic core progression with fibrous tissue regression. METHODS AND RESULTS: Twenty patients with coronary artery disease underwent baseline and 6-month radiofrequency intravascular ultrasound (virtual histology intravascular ultrasound) and computational fluid dynamics modeling for WSS calculation. For each virtual histology intravascular ultrasound segment (n=2249), changes in plaque area, virtual histology intravascular ultrasound-derived plaque composition, and remodeling were compared in low-, intermediate-, and high-WSS categories. Compared with intermediate-WSS segments, low-WSS segments developed progression of plaque area (P=0.027) and necrotic core (P<0.001), whereas high WSS segments had progression of necrotic core (P<0.001) and dense calcium (P<0.001) and regression of fibrous (P<0.001) and fibrofatty (P<0.001) tissue. Compared with intermediate-WSS segments, low-WSS segments demonstrated greater reduction in vessel (P<0.001) and lumen area (P<0.001), and high-WSS segments demonstrated an increase in vessel (P<0.001) and lumen (P<0.001) area. These changes resulted in a trend toward more constrictive remodeling in low- compared with high-WSS segments (73% versus 30%; P=0.06) and more excessive expansive remodeling in high- compared with low-WSS segments (42% versus 15%; P=0.16). CONCLUSIONS: Compared with intermediate-WSS coronary segments, low-WSS segments develop greater plaque and necrotic core progression and constrictive remodeling, and high-WSS segments develop greater necrotic core and calcium progression, regression of fibrous and fibrofatty tissue, and excessive expansive remodeling, suggestive of transformation to a more vulnerable phenotype. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576576. PMID- 21788585 TI - The need for multiple measures of hospital quality: results from the Get with the Guidelines-Heart Failure Registry of the American Heart Association. AB - BACKGROUND: Process and outcome measures are often used to quantify quality of care in hospitals. Whether these quality measures correlate with one another and the degree to which hospital provider rankings shift on the basis of the performance metric is uncertain. METHODS AND RESULTS: Heart failure patients >= 65 years of age hospitalized in the Get With the Guidelines-Heart Failure registry of the American Heart Association were linked to Medicare claims from 2005 to 2006. Hospitals were ranked by (1) composite adherence scores for 5 heart failure process measures, (2) composite adherence scores for emerging quality measures, (3) risk-adjusted 30-day death after admission, and (4) risk-adjusted 30-day readmission after discharge. Hierarchical models using shrinkage estimates were performed to adjust for case mix and hospital volume. There were 19 483 patients hospitalized from 2005 to 2006 from 153 hospitals. The overall median composite adherence rate to heart process measures was 85.8% (25th, 75th percentiles 77.5, 91.4). Median 30-day risk-adjusted mortality was 9.0% (7.9, 10.4). Median risk-adjusted 30-day readmission was 22.9% (22.1, 23.5). The weighted kappa for remaining within the top 20th percentile or bottom 20th percentile was <= 0.15 and the Spearman correlation overall was <= 0.21 between the different measures of quality of care. The average shift in ranks was 33 positions (13, 68) when criteria were changed from 30-day mortality to readmission and 51 positions (22, 76) when ranking metric changed from 30-day mortality to composite process adherence. CONCLUSIONS: Agreement between different methods of ranking hospital-based quality of care and 30-day mortality or readmission rankings was poor. Profiling quality of care will require multidimensional ranking methods and/or additional measures. PMID- 21788582 TI - Anti-islet autoantibodies trigger autoimmune diabetes in the presence of an increased frequency of islet-reactive CD4 T cells. AB - OBJECTIVE: To define cellular mechanisms by which B cells promote type 1 diabetes. RESEARCH DESIGN AND METHODS: The study measured islet-specific CD4 T cell regulation in T-cell receptor transgenic mice with elevated frequencies of CD4 T cells recognizing hen egg lysozyme (HEL) autoantigen expressed in islet beta-cells and thymic epithelium under control of the insulin-gene promoter. The effects of a mutation in Roquin that dysregulates T follicular helper (Tfh) cells to promote B-cell activation and anti-islet autoantibodies were studied, as were the effects of HEL antigen-presenting B cells and passively transferred or maternally transmitted anti-islet HEL antibodies. RESULTS: Mouse anti-islet IgG antibodies-either formed as a consequence of excessive Tfh activity, maternally transmitted, or passively transferred-caused a breakdown of tolerance in islet reactive CD4(+) cells and fast progression to diabetes. Progression to diabetes was ameliorated in the absence of B cells or when the B cells could not secrete islet-specific IgG. Anti-islet antibodies increased the survival of proliferating islet-reactive CD4(+) T cells. FcgammaR blockade delayed and reduced the incidence of autoimmune diabetes. CONCLUSIONS: B cells can promote type 1 diabetes by secreting anti-islet autoantibodies that act in an FcgammaR-mediated manner to enhance the expansion of islet-reactive CD4 T cells and cooperate with inherited defects in thymic and peripheral CD4 T-cell tolerance. Cooperation between inherited variants affecting CD4 T-cell tolerance and anti-islet autoantibodies should be examined in epidemiological studies and in studies examining the efficacy of B-cell depletion. PMID- 21788586 TI - Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. AB - BACKGROUND: Oxidative stress and mitochondrial dysfunction are central mediators of cardiac dysfunction after ischemia/reperfusion. ATP binding cassette mitochondrial erythroid (ABC-me; ABCB10; mABC2) is a mitochondrial transporter highly induced during erythroid differentiation and predominantly expressed in bone marrow, liver, and heart. Until now, ABC-me function in heart was unknown. Several lines of evidence demonstrate that the yeast ortholog of ABC-me protects against increased oxidative stress. Therefore, ABC-me is a potential modulator of the outcome of ischemia/reperfusion in the heart. METHODS AND RESULTS: Mice harboring 1 functional allele of ABC-me (ABC-me(+/-)) were generated by replacing ABC-me exons 2 and 3 with a neomycin resistance cassette. Cardiac function was assessed with Langendorff perfusion and echocardiography. Under basal conditions, ABC-me(+/-) mice had normal heart structure, hemodynamic function, mitochondrial respiration, and oxidative status. However, after ischemia/reperfusion, the recovery of hemodynamic function was reduced by 50% in ABC-me(+/-) hearts as a result of impairments in both systolic and diastolic function. This reduction was associated with impaired mitochondrial bioenergetic function and with oxidative damage to both mitochondrial lipids and sarcoplasmic reticulum calcium ATPase after reperfusion. Treatment of ABC-me(+/-) hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and restored mitochondrial and cardiac function to wild-type levels after reperfusion. CONCLUSIONS: Inactivation of 1 allele of ABC-me increases the susceptibility to oxidative stress induced by ischemia/reperfusion, leading to increased oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and to impaired functional recovery. Thus, ABC-me is a novel gene that determines the ability to tolerate cardiac ischemia/reperfusion. PMID- 21788587 TI - Sports-related sudden death in the general population. AB - BACKGROUND: Although such data are available for young competitive athletes, the prevalence, characteristics, and outcome of sports-related sudden death have not been assessed previously in the general population. METHODS AND RESULTS: A prospective and comprehensive national survey was performed throughout France from 2005 to 2010, involving subjects 10 to 75 years of age. Case detection for sports-related sudden death, including resuscitated cardiac arrest, was undertaken via national ambulance service reporting and Web-based screening of media releases. The overall burden of sports-related sudden death was 4.6 cases per million population per year, with 6% of cases occurring in young competitive athletes. Sensitivity analyses used to address suspected underreporting demonstrated an incidence ranging from 5 to 17 new cases per million population per year. More than 90% of cases occurred in the context of recreational sports. The age of subjects was relatively young (mean +/- SD 46 +/- 15 years), with a predominance of men (95%). Although most cases were witnessed (93%), bystander cardiopulmonary resuscitation was only commenced in 30.7% of cases. Bystander cardiopulmonary resuscitation (odds ratio 3.73, 95% confidence interval 2.19 to 6.39, P<0.0001) and initial use of cardiac defibrillation (odds ratio 3.71, 95% confidence interval 2.07 to 6.64, P<0.0001) were the strongest independent predictors for survival to hospital discharge (15.7%, 95% confidence interval 13.2% to 18.2%). CONCLUSIONS: Sports-related sudden death in the general population is considerably more common than previously suspected. Most cases are witnessed, yet bystander cardiopulmonary resuscitation was only initiated in one third of cases. Given the often predictable setting of sports-related sudden death and that prompt interventions were significantly associated with improved survival, these data have implications for health services planning. PMID- 21788588 TI - Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. AB - BACKGROUND: Mobile thrombi, not routinely recognized on transthoracic echocardiography, are frequently identified on cardiovascular implantable electronic device leads with intracardiac echocardiography (ICE) during ablation procedures. Their incidence, characteristics, and consequences have not yet been defined. METHODS AND RESULTS: We used ICE to examine leads for thrombi and to measure the pulmonary artery systolic pressure in patients with a cardiovascular implantable electronic device presenting for ablation. Patient clinical characteristics, device type, and lead characteristics were correlated with presence of thrombi. Most patients had congestive heart failure (84%), with an average left ventricular ejection fraction of 40%. Thrombi were seen with ICE in 26 of 86 patients (30%) but were seen on transthoracic echocardiography in only 1 of the 26 patients. Thrombi on ICE were mobile, averaged 18 +/- 5.9 mm long by 4.4 +/- 2.3 mm wide, and were more commonly identified in the right atrium (n=25) than in the right ventricle (n=5). Thrombi were associated with higher pulmonary artery systolic pressure: 39 +/- 9 mm Hg with thrombi versus 33 +/- 7 mm Hg without thrombi (odds ratio, 1.11; 95% confidence interval, 1.03 to 1.20; P=0.01). No other characteristic assessed was associated with a significant difference in the presence of lead thrombi. CONCLUSIONS: Mobile thrombi on cardiovascular implantable electronic device leads are present in 30% of patients undergoing ablation and are readily identified with ICE despite being underrecognized with transthoracic echocardiography. Further study is warranted to determine whether lead thrombi are a clinically relevant source of pulmonary emboli in some patients with cardiovascular implantable electronic devices. PMID- 21788589 TI - MicroRNA-24 regulates vascularity after myocardial infarction. AB - BACKGROUND: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. METHODS AND RESULTS: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21 activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. CONCLUSIONS: Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease. PMID- 21788590 TI - NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. AB - BACKGROUND- Reactive oxygen species serve signaling functions in the vasculature, and hypoxia has been associated with increased reactive oxygen species production. NADPH oxidase 4 (Nox4) is a reactive oxygen species-producing enzyme that is highly expressed in the endothelium, yet its specific role is unknown. We sought to determine the role of Nox4 in the endothelial response to hypoxia. METHODS AND RESULTS: Hypoxia induced Nox4 expression both in vitro and in vivo and overexpression of Nox4 was sufficient to promote endothelial proliferation, migration, and tube formation. To determine the in vivo relevance of our observations, we generated transgenic mice with endothelial-specific Nox4 overexpression using the vascular endothelial cadherin promoter (VECad-Nox4 mice). In vivo, the VECad-Nox4 mice had accelerated recovery from hindlimb ischemia and enhanced aortic capillary sprouting. Because endothelial nitric oxide synthase (eNOS) is involved in endothelial angiogenic responses and eNOS is activated by reactive oxygen species, we probed the effect of Nox4 on eNOS. In cultured endothelial cells overexpressing Nox4, we observed a significant increase in eNOS protein expression and activity. To causally address the link between eNOS and Nox4, we crossed our transgenic Nox4 mice with eNOS(-/-) mice. Aortas from these mice did not demonstrate enhanced aortic sprouting, and VECad Nox4 mice on the eNOS(-/-) background did not demonstrate enhanced recovery from hindlimb ischemia. CONCLUSIONS: Collectively, we demonstrate that augmented endothelial Nox4 expression promotes angiogenesis and recovery from hypoxia in an eNOS-dependent manner. PMID- 21788592 TI - Value of primordial and primary prevention for cardiovascular disease: a policy statement from the American Heart Association. AB - The process of atherosclerosis may begin in youth and continue for decades, leading to both nonfatal and fatal cardiovascular events, including myocardial infarction, stroke, and sudden death. With primordial and primary prevention, cardiovascular disease is largely preventable. Clinical trial evidence has shown convincingly that pharmacological treatment of risk factors can prevent events. The data are less definitive but also highly suggestive that appropriate public policy and lifestyle interventions aimed at eliminating tobacco use, limiting salt consumption, encouraging physical exercise, and improving diet can prevent events. There has been concern about whether efforts aimed at primordial and primary prevention provide value (ie, whether such interventions are worth what we pay for them). Although questions about the value of therapeutics for acute disease may be addressed by cost-effectiveness analysis, the long time frames involved in evaluating preventive interventions make cost-effectiveness analysis difficult and necessarily flawed. Nonetheless, cost-effectiveness analyses reviewed in this policy statement largely suggest that public policy, community efforts, and pharmacological intervention are all likely to be cost-effective and often cost saving compared with common benchmarks. The high direct medical care and indirect costs of cardiovascular disease-approaching $450 billion a year in 2010 and projected to rise to over $1 trillion a year by 2030-make this a critical medical and societal issue. Prevention of cardiovascular disease will also provide great value in developing a healthier, more productive society. PMID- 21788591 TI - Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. AB - BACKGROUND: Pediatric dilated cardiomyopathy (DCM) is the leading indication for heart transplantation after 1 year of age. Risk factors by etiology at clinical presentation have not been determined separately for death and transplantation in population-based studies. Competing risks analysis may inform patient prioritization for transplantation listing. METHODS AND RESULTS: The Pediatric Cardiomyopathy Registry enrolled 1731 children diagnosed with DCM from 1990 to 2007. Etiologic, demographic, and echocardiographic data collected at diagnosis were analyzed with competing risks methods stratified by DCM etiology to identify predictors of death and transplantation. For idiopathic DCM (n=1192), diagnosis after 6 years of age, congestive heart failure, and lower left ventricular (LV) fractional shortening z score were independently associated with both death and transplantation equally. In contrast, increased LV end-diastolic dimension z score was associated only with transplantation, whereas lower height-for-age z score was associated only with death. For neuromuscular disease (n=139), lower LV fractional shortening was associated equally with both end points, but increased LV end-diastolic dimension was associated only with transplantation. The risks of death and transplantation were increased equally for older age at diagnosis, congestive heart failure, and increased LV end-diastolic dimension among those with myocarditis (n=272) and for congestive heart failure and decreased LV fractional shortening among those with familial DCM (n=79). CONCLUSIONS: Risk factors for death and transplantation in children varied by DCM etiology. For idiopathic DCM, increased LV end-diastolic dimension was associated with increased transplantation risk but not mortality. Conversely, short stature was significantly related to death but not transplantation. These findings may present an opportunity to improve the transplantation selection algorithm. PMID- 21788593 TI - Re: Comparative effectiveness of prostate cancer treatments: evaluating statistical adjustments for confounding in observational data. PMID- 21788594 TI - Resolution of shock-induced aortic regurgitation with an intraaortic balloon pump. PMID- 21788595 TI - Cardiology patient page. Heart transplantation. PMID- 21788597 TI - Letter by Schindhelm regarding article, "High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndromes: a clinicopathological study". PMID- 21788598 TI - Objective assessment of cardiac risk for noncardiac surgical patients: an up-to date simplified approach. PMID- 21788599 TI - International differences in secular trends in childhood blood pressure: a puzzle to be solved. PMID- 21788600 TI - Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause. PMID- 21788601 TI - Left ventricular assist device-related systolic aortic regurgitation. PMID- 21788602 TI - Differential impacts of blood pressure and lipid lowering on regression of ventricular and arterial mass: the Stop Atherosclerosis in Native Diabetics Trial. AB - The relative impacts of lowering blood pressure versus lowering low-density lipoprotein (LDL) cholesterol on regression of ventricular and arterial mass have not been systematically examined. Changes in left ventricular mass and arterial mass (common carotid artery cross-sectional area) after 36 months of simultaneous lowering of systolic blood pressure and LDL cholesterol were examined in the Stop Atherosclerosis in Native Diabetics Trial of standard versus aggressive LDL cholesterol and blood pressure targets in American Indians with type 2 diabetes mellitus. The 2 treatment groups were combined to examine changes in left ventricular and arterial mass over a spectrum of achieved blood pressure and lipid levels. Among the combined group of 413 Stop Atherosclerosis in Native Diabetics Trials participants, systolic blood pressure, LDL cholesterol, and left ventricular mass were all significantly reduced, whereas arterial mass significantly increased, after 36 months of therapy (P<0.001 for all). In linear regression models, a decrease in arterial mass was significantly related to achieved systolic blood pressure and, to a lesser extent, achieved LDL cholesterol, after adjustment for important covariates. Left ventricular mass progressively decreased with lower achieved levels of systolic blood pressure, independent of baseline levels of left ventricular mass. In conclusion, achieved levels of systolic blood pressure are important determinants of the extent of regression of arterial and ventricular mass during prolonged therapy in diabetic individuals. Achieved levels of LDL cholesterol influence regression of arterial but not ventricular mass. Our findings suggest that there is no threshold of systolic blood pressure below which regression of cardiovascular target organ damage cannot be achieved. PMID- 21788604 TI - Adipocyte-derived factors regulate vascular smooth muscle cells through mineralocorticoid and glucocorticoid receptors. AB - Adipose tissue influences vascular function through adipocyte-derived factors, including components of the renin-angiotensin-aldosterone system. Molecular mechanisms underlying these phenomena are elusive. We investigated the role of adipocyte-derived factors on mitogen-activated protein kinases (MAPKs), proinflammatory status, apoptosis, and mitogenic signaling in vascular smooth muscle cells (VSMCs) and questioned whether these effects involve mineralocorticoid receptor (MR), glucocorticoid receptor (GR), and angiotensin II type 1 receptor (AT(1)R). Cultured mouse VSMCs were exposed to adipocyte conditioned medium (ACM) from differentiated 3T3-L1 adipocytes. ACM induced phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase, p38MAPK, and extracellular signal-regulated kinase 1/2 and increased expression of proinflammatory and proliferative markers in VSMCs. Eplerenone (MR antagonist), mifepristone (GR antagonist), and candesartan (AT(1)R antagonist) inhibited ACM-induced effects on extracellular signal-regulated kinase 1/2, p38MAPK, and proliferating cell nuclear antigen, without influencing apoptosis (Bax, Bcl, and caspase 3). Stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation was inhibited by mifepristone and candesartan but not by eplerenone. ACM-induced increase of fibronectin, vascular cell adhesion molecule 1, and plasminogen activator inhibitor 1 expression was blocked by MR and AT(1)R antagonism but not by GR inhibition. ACM has no effect on GR, MR, and AT(1)R expression. Our data show that adipocyte-derived factors influence MAPK signaling, leading to VSMC proinflammatory and profibrotic responses through distinct pathways. Although ACM stimulates p38MAPK and extracellular signal regulated kinase 1/2 phosphorylation through MR, GR, and AT(1)R, activation of stress-activated protein kinase/c-Jun N-terminal kinase involves GR and AT(1)R. These findings suggest that adipocyte-derived factors regulate VSMC function through specific MAPKs linked to MR, GR, and AT(1)R, a posttranslational phenomenon, because ACM did not influence receptor expression. Such cross-talk between adipocytes and VSMCs may provide a potential molecular mechanism linking renin-angiotensin-aldosterone system, adipocytes, and vascular function. PMID- 21788603 TI - Association of sodium and potassium intake with left ventricular mass: coronary artery risk development in young adults. AB - High salt intake may affect left ventricular mass (LVM). We hypothesized that urinary sodium (UNa) and sodium/potassium ratio (UNa/K) are associated with LVM in a predominantly normotensive cohort of young adults. The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a multicenter cohort of black and white men and women aged 30+/-3.6 years at the time of baseline echocardiographic examination (1990-1991). 2D guided M-mode LVM indexed to body size (grams per meter(2.7)) was calculated, and UNa and potassium excretion assessed (average of three 24-hour urinary samples, n=1042). Linear and logistic regression analysis was used. Participants were 57% women and 55% black. Only 4% were hypertensive. UNa, urinary potassium, and UNa/K ratios were (mean+/-SD) 175.6+/-131.0, 56.4+/ 46.3, and 3.4+/-1.4 mmol/24 h, respectively. Participants in the highest versus the lowest UNa excretion quartile had the greatest LVM (37.5 versus 34.0 g/m(2.7); P<0.001). Adjusted for age, sex, education, and race, LVM averaged 0.945 g/m(2.7) higher per SD of UNa/K (P=0.001). The relationship between UNa/K and LVM persisted among 399 participants with repeat echocardiographic measures 5 years later. In logistic regression analysis adjusted for age, sex, education, and race, each SD higher baseline UNa/K was associated with 23% and 38% greater chances of being in the highest quartile of LVM at baseline (odds ratio: 1.23; P=0.005) and 5 years later (odds ratio: 1.38; P=0.02). A higher sodium/potassium excretion ratio is significantly related to cardiac structure, even among healthy young adults. PMID- 21788606 TI - Functional importance of L- and P/Q-type voltage-gated calcium channels in human renal vasculature. AB - Calcium channel blockers are widely used for treatment of hypertension, because they decrease peripheral vascular resistance through inhibition of voltage-gated calcium channels. Animal studies of renal vasculature have shown expression of several types of calcium channels that are involved in kidney function. It was hypothesized that human renal vascular excitation-contraction coupling involves different subtypes of channels. In human renal artery and dissected intrarenal blood vessels from nephrectomies, PCR analysis showed expression of L-type (Ca(v) 1.2), P/Q-type (Ca(v) 2.1), and T-type subtype (Ca(v) 3.1 and Ca(v) 3.2) voltage gated calcium channels (Ca(v)s), and quantitative PCR showed highest expression of L-type channels in renal arteries and variable expression between patients of subtypes of calcium channels in intrarenal vessels. Immunohistochemical labeling of kidney sections revealed signals for Ca(v) 2.1 and Ca(v) 3.1 associated with smooth muscle cells of preglomerular and postglomerular vessels. In human intrarenal arteries, depolarization with potassium induced a contraction inhibited by the L-type antagonist nifedipine, EC(50) 1.2*10(-8) mol/L. The T type antagonist mibefradil inhibited the potassium-induced constriction with large variations between patients. Interestingly, the P/Q-type antagonist, omega agatoxin IVA, inhibited significantly the contraction with 24% at 10(-9) mol/L. In conclusion L-, P/Q, and T-type channels are expressed in human renal blood vessels, and L- and P/Q-type channels are of functional importance for the depolarization-induced vasoconstriction. The contribution of P/Q-type channels to contraction in the human vasculature is a novel mechanism for the regulation of renal blood flow and suggests that clinical treatment with calcium blockers might affect vascular reactivity also through P/Q-type channel inhibition. PMID- 21788605 TI - Salt sensitivity in blacks: evidence that the initial pressor effect of NaCl involves inhibition of vasodilatation by asymmetrical dimethylarginine. AB - In healthy, mostly normotensive blacks, 19 salt-sensitive (SS) and 18 salt resistant (SR), we tested the hypothesis that, in SS subjects, dietary NaCl loading induces its initial pressor effect by inducing a normal increase of cardiac output, while failing to induce a normal pressor-offsetting vasodilatation, consequent to its inhibition by asymmetrical dimethylarginine that is abnormally increased by NaCl. In SS and SR subjects, dietary NaCl loading, 250 from 30 mmol/d, over a 7-day period, induced similar, immediate increases in external Na(+) balance (by day 2, ~360 mmol), plasma volume (+11%), and cardiac output (+8%). In SR subjects, from day 1, transient decreases occurred in both systemic vascular resistance (nadir: -13%, day 2) and mean arterial pressure (nadir: -5%, day 2). In SS subjects, systemic vascular resistance did not change over days 1 to 3, whereas mean arterial pressure increased progressively after day 1, ultimately by 10 mm Hg. Failure of systemic vascular resistance to normally decrease, while cardiac output normally increased, accounted for salt's initial pressor effect in the SS subjects. In SS subjects, baseline plasma levels of asymmetrical dimethylarginine (0.76 MUmol/L) and symmetrical dimethylarginine (0.60 MUmol/L), which does not affect vasodilatation, approximated those in SR subjects. In SS but not SR subjects, NaCl loading induced increases in asymmetrical dimethylarginine on both days 2 (+38%, median) and 7 (+14%, median). Symmetrical dimethylarginine changed in neither group. For all of the subjects combined, changes in asymmetrical dimethylarginine on day 2 predicted changes in systemic vascular resistance (R=0.751; P<0.001) and mean arterial pressure (R=0.527; P=0.006) on day 2 and similarly on day 7. These observations support the hypothesis tested. PMID- 21788607 TI - Sodium, left ventricular mass, and arterial hypertension: is it time to look for a new paradigm? PMID- 21788608 TI - Redefining our menu: communications and reviews. PMID- 21788609 TI - R1 in the Shaker S4 occupies the gating charge transfer center in the resting state. AB - During voltage-dependent activation in Shaker channels, four arginine residues in the S4 segment (R1-R4) cross the transmembrane electric field. It has been proposed that R1-R4 movement is facilitated by a "gating charge transfer center" comprising a phenylalanine (F290) in S2 plus two acidic residues, one each in S2 and S3. According to this proposal, R1 occupies the charge transfer center in the resting state, defined as the conformation in which S4 is maximally retracted toward the cytoplasm. However, other evidence suggests that R1 is located extracellular to the charge transfer center, near I287 in S2, in the resting state. To investigate the resting position of R1, we mutated I287 to histidine (I287H), paired it with histidine mutations of key voltage sensor residues, and determined the effect of extracellular Zn(2+) on channel activity. In I287H+R1H, Zn(2+) generated a slow component of activation with a maximum amplitude (A(slow,max)) of ~56%, indicating that only a fraction of voltage sensors can bind Zn(2+) at a holding potential of -80 mV. A(slow,max) decreased after applying either depolarizing or hyperpolarizing prepulses from -80 mV. The decline of A(slow,max) after negative prepulses indicates that R1 moves inward to abolish ion binding, going beyond the point where reorientation of the I287H and R1H side chains would reestablish a binding site. These data support the proposal that R1 occupies the charge transfer center upon hyperpolarization. Consistent with this, pairing I287H with A359H in the S3-S4 loop generated a Zn(2+)-binding site. At saturating concentrations, A(slow,max) reached 100%, indicating that Zn(2+) traps the I287H+A359H voltage sensor in an absorbing conformation. Transferring I287H+A359H into a mutant background that stabilizes the resting state significantly enhanced Zn(2+) binding at -80 mV. Our results strongly support the conclusion that R1 occupies the gating charge transfer center in the resting conformation. PMID- 21788610 TI - D4cpv-calsequestrin: a sensitive ratiometric biosensor accurately targeted to the calcium store of skeletal muscle. AB - Current fluorescent monitors of free [Ca(2+)] in the sarcoplasmic reticulum (SR) of skeletal muscle cells are of limited quantitative value. They provide either a nonratio signal that is difficult to calibrate and is not specific or, in the case of Forster resonant energy transfer (FRET) biosensors, a signal of small dynamic range, which may be degraded further by imperfect targeting and interference from endogenous ligands of calsequestrin. We describe a novel tool that uses the cameleon D4cpv, which has a greater dynamic range and lower susceptibility to endogenous ligands than earlier cameleons. D4cpv was targeted to the SR by fusion with the cDNA of calsequestrin 1 or a variant that binds less Ca(2+). "D4cpv-Casq1," expressed in adult mouse at concentrations up to 22 umole/liter of muscle cell, displayed the accurate targeting of calsequestrin and stayed inside cells after permeabilization of surface and t system membranes, which confirmed its strict targeting. FRET ratio changes of D4cpv-Casq1 were calibrated inside cells, with an effective K(D) of 222 uM and a dynamic range [(R(max) - R(min))/R(min)] of 2.5, which are improvements over comparable sensors. Both the maximal ratio, R(max), and its resting value were slightly lower in areas of high expression, a variation that was inversely correlated to distance from the sites of protein synthesis. The average [Ca(2+)](SR) in 74 viable cells at rest was 416 uM. The distribution of individual ratio values was Gaussian, but that of the calculated [Ca(2+)](SR) was skewed, with a tail of very large values, up to 6 mM. Model calculations reproduce this skewness as the consequence of quantifiably small variations in biosensor performance. Local variability, a perceived weakness of biosensors, thus becomes quantifiable. It is demonstrably small in D4cpv. D4cpv-Casq1 therefore provides substantial improvements in sensitivity, specificity, and reproducibility over existing monitors of SR free Ca(2+) concentration. PMID- 21788611 TI - Measurement of RyR permeability reveals a role of calsequestrin in termination of SR Ca(2+) release in skeletal muscle. AB - The mechanisms that terminate Ca(2+) release from the sarcoplasmic reticulum are not fully understood. D4cpv-Casq1 (Sztretye et al. 2011. J. Gen. Physiol. doi:10.1085/jgp.201010591) was used in mouse skeletal muscle cells under voltage clamp to measure free Ca(2+) concentration inside the sarcoplasmic reticulum (SR), [Ca(2+)](SR), simultaneously with that in the cytosol, [Ca(2+)](c), during the response to long-lasting depolarization of the plasma membrane. The ratio of Ca(2+) release flux (derived from [Ca(2+)](c)(t)) over the gradient that drives it (essentially equal to [Ca(2+)](SR)) provided directly, for the first time, a dynamic measure of the permeability to Ca(2+) of the releasing SR membrane. During maximal depolarization, flux rapidly rises to a peak and then decays. Before 0.5 s, [Ca(2+)](SR) stabilized at ~35% of its resting level; depletion was therefore incomplete. By 0.4 s of depolarization, the measured permeability decayed to ~10% of maximum, indicating ryanodine receptor channel closure. Inactivation of the t tubule voltage sensor was immeasurably small by this time and thus not a significant factor in channel closure. In cells of mice null for Casq1, permeability did not decrease in the same way, indicating that calsequestrin (Casq) is essential in the mechanism of channel closure and termination of Ca(2+) release. The absence of this mechanism explains why the total amount of calcium releasable by depolarization is not greatly reduced in Casq-null muscle (Royer et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.201010454). When the fast buffer BAPTA was introduced in the cytosol, release flux became more intense, and the SR emptied earlier. The consequent reduction in permeability accelerated as well, reaching comparable decay at earlier times but comparable levels of depletion. This observation indicates that [Ca(2+)](SR), sensed by Casq and transmitted to the channels presumably via connecting proteins, is determinant to cause the closure that terminates Ca(2+) release. PMID- 21788613 TI - Xenopus laevis oocytes infected with multi-drug-resistant bacteria: implications for electrical recordings. AB - The Xenopus laevis oocyte has been the workhorse for the investigation of ion transport proteins. These large cells have spawned a multitude of novel techniques that are unfathomable in mammalian cells, yet the fickleness of the oocyte has driven many researchers to use other membrane protein expression systems. Here, we show that some colonies of Xenopus laevis are infected with three multi-drug-resistant bacteria: Pseudomonas fluorescens, Pseudomonas putida, and Stenotrophomonas maltophilia. Oocytes extracted from infected frogs quickly (3-4 d) develop multiple black foci on the animal pole, similar to microinjection scars, which render the extracted eggs useless for electrical recordings. Although multi-drug resistant, the bacteria were susceptible to amikacin and ciprofloxacin in growth assays. Supplementing the oocyte storage media with these two antibiotics prevented the appearance of the black foci and afforded oocytes suitable for whole-cell recordings. Given that P. fluorescens associated with X. laevis has become rapidly drug resistant, it is imperative that researchers store the extracted oocytes in the antibiotic cocktail and not treat the animals harboring the multi-drug-resistant bacteria. PMID- 21788612 TI - Thiazolidinedione insulin sensitizers alter lipid bilayer properties and voltage dependent sodium channel function: implications for drug discovery. AB - The thiazolidinediones (TZDs) are used in the treatment of diabetes mellitus type 2. Their canonical effects are mediated by activation of the peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factor. In addition to effects mediated by gene activation, the TZDs cause acute, transcription-independent changes in various membrane transport processes, including glucose transport, and they alter the function of a diverse group of membrane proteins, including ion channels. The basis for these off-target effects is unknown, but the TZDs are hydrophobic/amphiphilic and adsorb to the bilayer water interface, which will alter bilayer properties, meaning that the TZDs may alter membrane protein function by bilayer-mediated mechanisms. We therefore explored whether the TZDs alter lipid bilayer properties sufficiently to be sensed by bilayer-spanning proteins, using gramicidin A (gA) channels as probes. The TZDs altered bilayer elastic properties with potencies that did not correlate with their affinity for PPARgamma. At concentrations where they altered gA channel function, they also altered the function of voltage-dependent sodium channels, producing a prepulse-dependent current inhibition and hyperpolarizing shift in the steady-state inactivation curve. The shifts in the inactivation curve produced by the TZDs and other amphiphiles can be superimposed by plotting them as a function of the changes in gA channel lifetimes. The TZDs' partition coefficients into lipid bilayers were measured using isothermal titration calorimetry. The most potent bilayer modifier, troglitazone, alters bilayer properties at clinically relevant free concentrations; the least potent bilayer modifiers, pioglitazone and rosiglitazone, do not. Unlike other TZDs tested, ciglitazone behaves like a hydrophobic anion and alters the gA monomer-dimer equilibrium by more than one mechanism. Our results provide a possible mechanism for some off-target effects of an important group of drugs, and underscore the importance of exploring bilayer effects of candidate drugs early in drug development. PMID- 21788614 TI - Child neurology: epilepsy of infancy with migrating focal seizures. PMID- 21788615 TI - Teaching NeuroImages: posterior cerebral artery susceptibility vessel sign on T2* weighted gradient echo imaging. PMID- 21788616 TI - Multiple sclerosis and disease-modifying therapies. PMID- 21788619 TI - Slowly progressive Parkinson syndrome due to thalamic butterfly astrocytoma. PMID- 21788620 TI - Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. PMID- 21788621 TI - Quality improvement in neurology: AAN Parkinson disease quality measures. PMID- 21788623 TI - Achieved levels of HbA1c and likelihood of hospital admission in people with type 1 diabetes in the Scottish population: a study from the Scottish Diabetes Research Network Epidemiology Group. AB - OBJECTIVE: People with type 1 diabetes have increased risk of hospital admission compared with those without diabetes. We hypothesized that HbA(1c) would be an important indicator of risk of hospital admission. RESEARCH DESIGN AND METHODS: The Scottish Care Information-Diabetes Collaboration, a dynamic national register of diagnosed cases of diabetes in Scotland, was linked to national data on admissions. We identified 24,750 people with type 1 diabetes during January 2005 to December 2007. We assessed the relationship between deciles of mean HbA(1c) and hospital admissions in people with type 1 diabetes adjusting for patient characteristics. RESULTS: There were 3,229 hospital admissions. Of the admissions, 8.1% of people had mean HbA(1c) <7.0% (53 mmol/mol) and 16.3% had HbA(1c) <7.5% (58 mmol/mol). The lowest odds of admission were associated with HbA(1c) 7.7-8.7% (61-72 mmol/mol). When compared with this decile, a J-shaped relationship existed between HbA(1c) and admission. The highest HbA(1c) decile (10.8-18.4%/95-178 mmol/mol) showed significantly higher odds ratio (95% CI) for any admission (2.80, 2.51-3.12); the lowest HbA(1c) decile (4.4-7.1%/25-54 mmol/mol) showed an increase in odds of admission of 1.29 (1.10-1.51). The highest HbA(1c) decile experienced significantly higher odds of diabetes-related (3.31, 2.94-3.72) and diabetes ketoacidosis admissions (10.18, 7.96-13.01). CONCLUSIONS: People with type 1 diabetes with highest and lowest mean HbA(1c) values were associated with increased odds of admission. People with high HbA(1c) (>10.8%/95 mmol/mol) were at particularly high risk. There is the need to develop effective interventions to reduce this risk. PMID- 21788624 TI - Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the TRANSCEND study. AB - OBJECTIVE: Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS: Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS: During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS: There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes. PMID- 21788625 TI - Novel soy germ pasta improves endothelial function, blood pressure, and oxidative stress in patients with type 2 diabetes. AB - OBJECTIVE: To compare the effects of a novel soy germ-enriched pasta, containing isoflavone aglycons, with conventional pasta on endothelial function and cardiovascular risk markers in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This randomized controlled double-blind crossover study compared one serving/day of soy germ pasta and conventional pasta for 8 weeks for effects on brachial artery flow-mediated vasodilation, blood pressure, plasma lipids, oxidized LDL cholesterol, 8-iso-PGF2alpha, total antioxidant capacity (TAC), glutathione (GSH), and homocysteine. RESULTS: Isoflavone-enriched pasta significantly improved arterial stiffness (P = 0.005) and reduced systolic (P = 0.026) and diastolic (P = 0.017) blood pressures. Plasma TAC increased (P = 0.0002), oxidized LDL cholesterol decreased (P = 0.009), 8-iso-PGF2alpha decreased (P = 0.001), GSH levels increased (P = 0.0003), and homocysteine decreased (P = 0.009) consistent with a reduction in oxidative stress. No significant changes were observed with conventional pasta. CONCLUSIONS: Pasta enriched with biologically active isoflavone aglycons improved endothelial function and had beneficial effects on cardiovascular risk markers in patients with T2D. PMID- 21788626 TI - Cross-sectional and longitudinal changes of glucose effectiveness in relation to glucose tolerance: the insulin resistance atherosclerosis study. AB - OBJECTIVE: Glucose effectiveness (S(G)), the capacity of glucose to enhance its own disposition, is an independent predictor of future diabetes. However, there are data on cross-sectional and longitudinal changes of S(G) and its components, basal insulin effect on S(G) (BIE) and S(G) at zero insulin (GEZI), but the natural course of S(G) has not been described in a large population. RESEARCH DESIGN AND METHODS: S(G) was measured at baseline in 1,265 participants (aged 40 69 years) and at the 5-year examination in 827 participants in the Insulin Resistance Atherosclerosis Study (IRAS) using the frequently sampled intravenous glucose tolerance test. None of these participants were treated with glucose lowering agents. RESULTS: In cross-sectional analyses, S(G), BIE, and GEZI deteriorated with worsening of glucose tolerance (P < 0.001 for all three associations). In longitudinal analyses among subjects with normal glucose tolerance (NGT) at baseline, S(G), BIE, and GEZI declined in those who progressed to impaired glucose tolerance (IGT) or diabetes (P < 0.001 for all three measures). More modest longitudinal changes were demonstrated in individuals with IGT. The transition back to NGT (as opposed to no change) compared with the transition to diabetes was statistically significant for S(G) (P = 0.049) and BIE (P = 0.042) and was not a statistically significant trend for GEZI (P = 0.332). In individuals with diabetes, only BIE had a significant decline (P = 0.003). CONCLUSIONS: S(G), BIE, and GEZI decline in subjects whose glycemic status worsens. S(G) and GEZI deteriorate more in the initial stages of the disease process. PMID- 21788627 TI - Mediterranean diet and type 2 diabetes risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study: the InterAct project. AB - OBJECTIVE: To study the association between adherence to the Mediterranean dietary pattern (MDP) and risk of developing type 2 diabetes, across European countries. RESEARCH DESIGN AND METHODS: We established a case-cohort study including 11,994 incident type 2 diabetic case subjects and a stratified subcohort of 15,798 participants selected from a total cohort of 340,234 participants with 3.99 million person-years of follow-up, from eight European cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The relative Mediterranean diet score (rMED) (score range 0-18) was used to assess adherence to MDP on the basis of reported consumption of nine dietary components characteristic of the Mediterranean diet. Cox proportional hazards regression, modified for the case-cohort design, was used to estimate the association between rMED and risk of type 2 diabetes, adjusting for confounders. RESULTS: The multiple adjusted hazard ratios of type 2 diabetes among individuals with medium (rMED 7-10 points) and high adherence to MDP (rMED 11-18 points) were 0.93 (95% CI 0.86-1.01) and 0.88 (0.79-0.97), respectively, compared with individuals with low adherence to MDP (0-6 points) (P for trend 0.013). The association between rMED and type 2 diabetes was attenuated in people <50 years of age, in obese participants, and when the alcohol, meat, and olive oil components were excluded from the score. CONCLUSIONS: In this large prospective study, adherence to the MDP, as defined by rMED, was associated with a small reduction in the risk of developing type 2 diabetes in this European population. PMID- 21788628 TI - Two-step approach for the prediction of future type 2 diabetes risk. AB - OBJECTIVE: To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG). RESEARCH DESIGN AND METHODS: The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1 h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk. RESULTS: We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study. CONCLUSIONS: A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals. PMID- 21788629 TI - initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria: a post hoc analysis of the IRMA-2 trial. AB - OBJECTIVE: We aimed to investigate the individual impact of initial responses in urinary albumin excretion (UAE) and systolic blood pressure (SBP) to angiotensin II receptor blocker (ARB) treatment on long-term renal outcome in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: In a post hoc analysis of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA)-2 trial we first assessed the individual variability in UAE and SBP response (0-6 months) in 531 subjects. Subsequently, we analyzed the individual effect of both response parameters on renal outcome defined as change in estimated glomerular filtration rate (eGFR) during 2 years of follow-up. RESULTS: The median reductions in UAE and SBP in the population were -18% and -11 mmHg, respectively. In irbesartan-treated patients, 85 (24.4%) had a robust (>median) reduction in UAE but not in SBP (discordant SBP response) and 67 (19.3%) had a robust (>median) reduction in SBP but not in UAE (discordant UAE response). The degree of reduction in UAE was independently associated with the rate of eGFR decline (P = 0.0037). SBP showed a similar trend (P = 0.087). The relation between a larger UAE reduction and a slower rate of renal function decline was present in both cohorts with a SBP change above and below the median. CONCLUSIONS: Within an individual, UAE response to ARB therapy may be discordant from SBP response. The initial change in UAE was independently associated with eGFR slope; the more UAE reduction the less eGFR decline, irrespective of the SBP change. These results suggest that in microalbuminuric patients with type 2 diabetes, UAE should be monitored after initiation of therapy and a separate target for renoprotective therapy. PMID- 21788630 TI - Short form of the Chinese version Diabetes Quality of Life for Youth Scale: a psychometric testing in Taiwanese adolescents with type 1 diabetes. AB - OBJECTIVE: To test the psychometric properties of the short form of the Chinese version Diabetes Quality of Life for Youth scale (C-DQOLY-SF). RESEARCH DESIGN AND METHODS: A 30-item C-DQOLY-SF was administered to 371 adolescents with type 1 diabetes. Exploratory and confirmatory factor analysis, correlation with HbA(1c), internal consistency, and test-retest reliability were used to examine the psychometric characteristics of C-DQOLY-SF. RESULTS: A 25-item questionnaire with three correlated second-order factor structures best fitted data. Scores on the 25-item C-DQOLY-SF significantly correlated with HbA(1c) values. Cronbach's alpha and ICCs of each scale and subscale ranged from 0.77 to 0.90 and from 0.70 to 0.92, respectively. CONCLUSIONS: The C-DQOLY-SF has satisfactory reliability and validity. The C-DQOLY-SF can be conveniently used in clinical settings to assess the quality of life of adolescents with type 1 diabetes. PMID- 21788631 TI - Hemoglobin A1c, fasting glucose, and cardiovascular risk in a population with high prevalence of diabetes: the strong heart study. AB - OBJECTIVE: We compared A1C and fasting plasma glucose (FPG) in predicting cardiovascular disease (CVD) in a population with widespread obesity and diabetes. RESEARCH DESIGN AND METHODS: A total of 4,549 American Indian adults underwent the Strong Heart Study (SHS) baseline examination (1989-1991). Data from 3,850 individuals (60% women) with baseline measurements of FPG and A1C and no prevalent CVD were analyzed; 1,386 had known diabetes. CVD events were ascertained over a median of 15 years. RESULTS: A1C >=6.5% had a 44.3% sensitivity and 98.9% specificity to identify participants with FPG >=126 mg/dL. Increases in A1C were associated with adverse CVD risk factor profiles; individuals with known diabetes had worse profiles. For A1C <5, 5 to <5.5, 5.5 to <6, 6-6.5, or >=6.5% or known diabetes, the multivariate-adjusted hazard ratio (HR) [95% CI] for coronary heart disease (CHD) was significant only for individuals with known diabetes (2.76 [2.17-3.51]). Similarly, the adjusted HRs for total CVD were significant only for individuals with A1C >=6.5% or known diabetes (1.50 [1.10-2.04] and 2.52 [2.06-3.08], respectively). Similar results were observed for FPG. CONCLUSIONS: Individuals with known or newly diagnosed diabetes had increased risk for CVD. Although A1C is more convenient than FPG in diagnosing diabetes, neither test adds to conventional CVD risk factors in predicting CHD or total CVD. PMID- 21788632 TI - Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control. AB - OBJECTIVE: To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient's glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options. RESULTS: The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% (P = 0.001) [corrected] over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P > 0.05). CONCLUSIONS: The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year. PMID- 21788633 TI - Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. AB - OBJECTIVE: To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixteen subjects with type 2 diabetes (age 59.8 +/- 6.8 years, BMI 29.1 +/- 4.8 kg/m(2), HbA(1c) 6.97 +/- 0.61) on oral blood glucose-lowering treatment were included. Participants received vildagliptin 50 mg b.i.d. or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-arterially administered acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator). RESULTS: Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 +/- 0.7, 7.9 +/- 1.1, and 12.6 +/- 1.4 mL ? dL(-1) ? min(-1) in response to three increasing dosages of acetylcholine) than during acarbose (2.0 +/- 0.7, 5.0 +/- 1.2, and 11.7 +/- 1.6 mL ? dL(-1) ? min(-1), respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside. CONCLUSIONS: Four weeks' treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observation might have favorable cardiovascular implications. PMID- 21788634 TI - World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease: part 2. PMID- 21788635 TI - Decreased high molecular weight adiponectin in sera is associated with white matter lesions in Japanese men with type 2 diabetes. PMID- 21788636 TI - Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases. PMID- 21788637 TI - Awaiting autoamputation: a primary management strategy for toe gangrene in diabetic foot disease. PMID- 21788638 TI - Immunosuppression therapy posttransplantation can be associated with a different clinical phenotype for diabetic charcot foot neuroarthropathy. PMID- 21788639 TI - Comment: analyses using time-dependent pioglitazone usage in Cox models may lead to wrong conclusions about its association with cancer. PMID- 21788641 TI - Comment on: Pantalone et al. The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy: a retrospective analysis. Diabetes Care 2010;33:1224-1229. PMID- 21788643 TI - Role of parenting style in achieving metabolic control in adolescents with type 1 diabetes. AB - OBJECTIVE: To examine the role of parenting style in achieving metabolic control and treatment adherence in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Parents of 100 adolescents with type 1 diabetes completed assessments of their parenting style and sense of helplessness. Parents and patients rated patient adherence to the treatment regimen. Glycemic control was evaluated by HbA(1c) values. RESULTS: An authoritative paternal parenting style predicted better glycemic control and adherence in the child; a permissive maternal parenting style predicted poor adherence. A higher sense of helplessness in both parents predicted worse glycemic control and lesser adherence to treatment. Parental sense of helplessness was a significant predictor of diabetes control after correcting for other confounders (patient age, sex, and treatment method). CONCLUSIONS: An authoritative nonhelpless parenting style is associated with better diabetes control in adolescents. Paternal involvement is important in adolescent diabetes management. These results have implications for psychological interventions. PMID- 21788645 TI - Parenting styles and parenting practices in pediatric diabetes. PMID- 21788644 TI - MODY: history, genetics, pathophysiology, and clinical decision making. PMID- 21788647 TI - Challenging the biopsychosocial model in a chronic constipation clinic. AB - In this article we discuss the results of an ethnographic study of professionals' and patients' experiences within a specialist constipation clinic in England. Chronic constipation tends to be poorly understood and inadequately treated. Eleven patients were followed through their illness trajectory during a 5-month fieldwork period, involving 21 home interviews, clinic-based interviews, participant observation, and a focus group. Professionals were likewise observed and interviewed. The clinic could be broadly described as biopsychosocial in its approach. However, professionals expressed uncertainty about how best to provide biopsychosocial care and suggested that some patients were not "open" to psychosocial therapies or to discussing psychosocial aspects of their disease. Patients' concerns were with being taken seriously, receiving treatment, and narrating intersections of life events, emotional well-being, and the bowels. We situate these findings within the discourse of "functional" disorders and discuss why implementing a biopsychosocial approach is problematic in this case. PMID- 21788648 TI - Health literacy as controversy: an online community's discussion of the U.S. Food and Drug Administration acetaminophen recommendations. AB - Adults in the United States increasingly use the Internet for health information, and online discussions can provide insights into public perceptions of health issues. The purpose of this project was to investigate public perceptions of issues related to health literacy, within the context of a conversation about recommendations to the U.S. Food and Drug Administration, driven by concerns about acetaminophen-related liver injuries due in part to health literacy issues. The discussion took place July 2-8, 2009, on a technology/science blog and included 625 comments. Participants debated the risks and benefits of acetaminophen, and most believed responsibility for taking medication safely falls on consumers. Some were implicitly aware of issues related to health literacy and its relationship to patient outcomes; most felt improved education is all that is needed, whereas others acknowledged that health information is confusing--particularly for the elderly and sick. Recommendations for future research into public perceptions of health literacy are discussed. PMID- 21788649 TI - Life stress, emotional health, and mean telomere length in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study. AB - We investigated the association between psychological stress, emotional health, and relative mean telomere length in an ethnically homogeneous population of 4,441 women, aged 41-80 years. Mean telomere length was measured using high throughput quantitative real-time polymerase chain reaction. Social adversity exposure and emotional health were assessed through questionnaire and covariates through direct measurement and questionnaire. This study found evidence that adverse experiences during childhood may be associated with shorter telomere length. This finding remained after covariate adjustment and showed evidence of a dose-response relationship with increasing number of reported childhood difficulties associated with decreasing relative mean telomere length. No associations were observed for any of the other summary measures of social adversity and emotional health considered. These results extend and provide support for some previous findings concerning the association of adverse experience and emotional health histories with shorter telomere length in adulthood. Replication of these findings in longitudinal studies is now essential. PMID- 21788650 TI - Age effects on preattentive and early attentive auditory processing of redundant stimuli: is sensory gating affected by physiological aging? AB - The frontal hypothesis of aging predicts an age-related decline in cognitive functions requiring inhibitory or attentional regulation. In Alzheimer's disease, preattentive gating out of redundant information is impaired. Our study aimed to examine changes associated with physiological aging in both pre- and early attentive inhibition of recurrent acoustic information. Using a passive double click paradigm, we recorded mid-latency (P30-P50) and late-latency (N100 and P200) evoked potentials in healthy young (26 +/- 5 years) and healthy elderly subjects (72 +/- 5 years). Physiological aging did not affect auditory gating in amplitude measures. Both age groups exhibited clear inhibition in preattentive P50 and attention-modulated (N100) components, whereas P30 was not attenuated. Irrespective of age, the magnitude of inhibition differed significantly, being most pronounced for N100 gating. Inhibition of redundant information seems to be preserved with physiological aging. Early attentive N100 gating showed the maximum effect. Further studies are warranted to evaluate sensory gating as a suitable biomarker of underlying neurodegenerative disease. PMID- 21788652 TI - The case for evaluation. PMID- 21788653 TI - Determinants of early child-feeding practices among HIV-infected and noninfected mothers in rural Kenya. AB - Quantitative and qualitative data were collected from mothers with children aged 4 to 24 months to examine the determinants of child-feeding practices among HIV infected and noninfected mothers in the rural parts of Kisumu District in Kenya. More than 40% of children had received other foods or drinks by 3 months of age. Home-based births, perceived small child size at birth, and larger household size were associated with significantly higher risks of premature cessation of exclusive breastfeeding. Maternal HIV infection, overweight/obesity, and having multiple "under-2's" were associated with higher risks of overall breastfeeding cessation. Higher socioeconomic status was associated with significantly lower risks of premature cessation of exclusive breastfeeding. Child-feeding decisions were often made postpartum. Mothers were more likely to discuss feeding methods with their partners only if they were HIV infected. Poverty was identified as a barrier to exclusive breastfeeding in the first 6 months. PMID- 21788654 TI - Initiation and duration of breastfeeding in an aboriginal community in south western Sydney. AB - The Gudaga Study is a prospective, longitudinal birth cohort study of Australian urban Aboriginal children. Mothers of Aboriginal infants were recruited using a survey of all mothers admitted to the maternity ward of an outer urban hospital in Sydney. These data established initiation rates among Gudaga infants and those of non-Aboriginal infants born locally (64.7% and 75.2%, respectively) and factors associated with breastfeeding. Older (relative risk, 1.24; confidence interval, 1.01-1.44), more educated (relative risk, 1.30; confidence interval, 1.11-1.48) mothers who intended to breastfeed (relative risk, 2.22; confidence interval, 2.12-2.3) were more likely to breastfeed. Smokers (relative risk, 0.72) and mothers of Aboriginal infants (relative risk, 0.78) were less likely to initiate breastfeeding. Breastfeeding rates for Gudaga infants dropped rapidly, with 26.3% breastfeeding at 2 months. Local health services providers can benefit from such information as they target relevant prenatal, perinatal, and postnatal services for Aboriginal mothers and their infants. PMID- 21788655 TI - Factors associated with duration of breastfeeding in ireland: potential areas for improvement. AB - There is a need to comprehensively examine why mothers in Ireland discontinue breastfeeding early and to explore the factors influencing duration of breastfeeding during the first 6 months postpartum. Findings from this study provide valuable direction for future strategies and interventions aimed at increasing breastfeeding duration rates in Ireland. PMID- 21788651 TI - Expression of key regulators of mitochondrial biogenesis in growth hormone receptor knockout (GHRKO) mice is enhanced but is not further improved by other potential life-extending interventions. AB - Mitochondrial biogenesis is essential for cell viability. Growth hormone receptor knockout (GHRKO), calorie restriction, and surgical visceral fat removal constitute experimental interventions to delay aging and increase life span. We examined the expression of known regulators of mitochondriogenesis: peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha), adenosine monophosphate (AMP)-activated protein kinase (AMPK), sirtuin-1 (SIRT-1) and sirtuin-3 (SIRT-3), endothelial nitric oxide synthase (eNOS), nuclear respiratory factor-1, mitochondrial transcription factor A (TFAM), and mitofusin-2 (MFN-2) in the skeletal muscles and hearts of control and calorie-restricted female GHRKO mice and in the kidneys of male GHRKOs after visceral fat removal or sham surgery. Expression of PGC-1alpha in skeletal muscles, AMPK, SIRT-1, SIRT-3, eNOS, and MFN-2 in the heart and PGC-1alpha, AMPK, SIRT-3, eNOS, and MFN-2 in kidneys was increased in GHRKO mice but was not affected by calorie restriction or visceral fat removal. GHRKO mice have increased expression of key regulators of mitochondriogenesis, which is not improved further by calorie restriction or visceral fat removal. PMID- 21788656 TI - Relationship between level of education and breastfeeding duration depends on social context: breastfeeding trends over a 40-year period in Spain. AB - This article presents trends of breastfeeding in Spain from the 1960s to the end of the century, analyzing the relationship between level of education and breastfeeding duration. A sample of 666 adult women provided data about breastfeeding practices for children born between 1958 and 2002. Joinpoint regression models for breastfeeding duration for the firstborn child throughout these years show a U-shaped curve, with a sharp decrease at the beginning of the 1970s (-17.2%) and a gradual increase toward the end of the century (1.9%). However, the trend for women with primary studies shows a constant decrease throughout the whole period (-7.4%), while higher education levels relate to a positive trend from the 1970s onward (3.4%). The authors conclude that in the Spanish context, maternal level of education is not associated with breastfeeding duration in the same direction or with the same magnitude across time. Factors related to breastfeeding should be studied, taking into account social context. PMID- 21788657 TI - Serial changes of fatty acids in preterm breast milk of Korean women. AB - Samples of breast milk were collected at postpartum weeks 1, 2, 4, 6, 8, and 12 from 104 Korean mothers who had delivered infants at less than 34 weeks or weighing less than 1.8 kg to investigate changes in fatty acid (FAs). Full-term breast milk (FBM) collected at the end of first week postpartum from 26 Korean women delivering healthy, term infants was used for comparison. Stability in relative FA composition was maintained during the first 3 months of lactation in preterm breast milk (PBM), and the relative composition of polyunsaturated FAs (PUFA), monounsaturated FAs, and saturated FAs remained constant in PBM. However, the omega6/omega3 ratio was significantly higher as lactation progressed owing to lower omega3 PUFA in PBM. The proportions of docosahexaenoic acid (DHA) and arachidonic acid (AA) in PBM gradually decreased over time, but the DHA/AA ratio was kept constant at 1.13, higher than that of Western countries. At the end of the first week, relative proportions of FAs were similar in PBM and FBM, but absolute concentrations of FA were higher in PBM. PMID- 21788659 TI - Bringing your premature or ill breastfeeding baby home. PMID- 21788658 TI - Overcoming barriers to investigating mother-infant interactions in the first two hours of life. AB - As a result of the unexpected delays experienced in a study designed to investigate mother-infant interactions and infant cry patterns in the first 2 hours following delivery, the study was assessed to identify the barriers that the investigators had encountered in its planning and conduct. These barriers can be categorized as issues with (1) institutional review board approval, (2) participant recruitment and retention, (3) requirements for study personnel, (4) instrumentation, (5) potential observer and participant bias, and (6) budgeting. Each barrier is detailed, along with suggested solutions. It is hoped that that these experiences will be of value to other researchers, particularly those working in non-research-intensive institutions, as they gather data to contribute to the understanding of mother-infant interactions in the immediate postpartum period. PMID- 21788660 TI - The Academy of Breastfeeding Medicine. AB - The Academy of Breastfeeding Medicine is a worldwide organization of physicians dedicated to the promotion, protection, and support of breastfeeding and human lactation. In this Physician Focus, we describe the mission and activities of the Academy. We also highlight opportunities for physicians to participate. PMID- 21788662 TI - Breastfeeding, brain imaging, and maternal behavior. PMID- 21788664 TI - Understanding Blind Deconvolution Algorithms. AB - Blind deconvolution is the recovery of a sharp version of a blurred image when the blur kernel is unknown. Recent algorithms have afforded dramatic progress, yet many aspects of the problem remain challenging and hard to understand. The goal of this paper is to analyze and evaluate recent blind deconvolution algorithms both theoretically and experimentally. We explain the previously reported failure of the naive MAP approach by demonstrating that it mostly favors no-blur explanations. We show that, using reasonable image priors, a naive simulations MAP estimation of both latent image and blur kernel is guaranteed to fail even with infinitely large images sampled from the prior. On the other hand, we show that since the kernel size is often smaller than the image size, a MAP estimation of the kernel alone is well constrained and is guaranteed to succeed to recover the true blur. The plethora of recent deconvolution techniques makes an experimental evaluation on ground-truth data important. As a first step toward this experimental evaluation, we have collected blur data with ground truth and compared recent algorithms under equal settings. Additionally, our data demonstrate that the shift-invariant blur assumption made by most algorithms is often violated. PMID- 21788665 TI - Image Signature: Highlighting Sparse Salient Regions. AB - We introduce a simple image descriptor referred to as the image signature. We show, within the theoretical framework of sparse signal mixing, that this quantity spatially approximates the foreground of an image. We experimentally investigate whether this approximate foreground overlaps with visually conspicuous image locations by developing a saliency algorithm based on the image signature. This saliency algorithm predicts human fixation points best among competitors on the Bruce and Tsotsos [1] benchmark data set and does so in much shorter running time. In a related experiment, we demonstrate with a change blindness data set that the distance between images induced by the image signature is closer to human perceptual distance than can be achieved using other saliency algorithms, pixel-wise, or GIST [2] descriptor methods. PMID- 21788663 TI - A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. AB - Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated. PMID- 21788666 TI - Recognizing human actions by learning and matching shape-motion prototype trees. AB - A shape-motion prototype-based approach is introduced for action recognition. The approach represents an action as a sequence of prototypes for efficient and flexible action matching in long video sequences. During training, an action prototype tree is learned in a joint shape and motion space via hierarchical K means clustering and each training sequence is represented as a labeled prototype sequence; then a look-up table of prototype-to-prototype distances is generated. During testing, based on a joint probability model of the actor location and action prototype, the actor is tracked while a frame-to-prototype correspondence is established by maximizing the joint probability, which is efficiently performed by searching the learned prototype tree; then actions are recognized using dynamic prototype sequence matching. Distance measures used for sequence matching are rapidly obtained by look-up table indexing, which is an order of magnitude faster than brute-force computation of frame-to-frame distances. Our approach enables robust action matching in challenging situations (such as moving cameras, dynamic backgrounds) and allows automatic alignment of action sequences. Experimental results demonstrate that our approach achieves recognition rates of 92.86 percent on a large gesture data set (with dynamic backgrounds), 100 percent on the Weizmann action data set, 95.77 percent on the KTH action data set, 88 percent on the UCF sports data set, and 87.27 percent on the CMU action data set. PMID- 21788667 TI - Real-time evaluation and visualization of learner performance in a mixed-reality environment for clinical breast examination. AB - We investigate the efficacy of incorporating real-time feedback of user performance within mixed-reality environments (MREs) for training real-world tasks with tightly coupled cognitive and psychomotor components. This paper presents an approach to providing real-time evaluation and visual feedback of learner performance in an MRE for training clinical breast examination (CBE). In a user study of experienced and novice CBE practitioners (n = 69), novices receiving real-time feedback performed equivalently or better than more experienced practitioners in the completeness and correctness of the exam. A second user study (n = 8) followed novices through repeated practice of CBE in the MRE. Results indicate that skills improvement in the MRE transfers to the real-world task of CBE of human patients. This initial case study demonstrates the efficacy of MREs incorporating real-time feedback for training real-world cognitive-psychomotor tasks. PMID- 21788668 TI - Mesh segmentation with concavity-aware fields. AB - This paper presents a simple and efficient automatic mesh segmentation algorithm that solely exploits the shape concavity information. The method locates concave creases and seams using a set of concavity-sensitive scalar fields. These fields are computed by solving a Laplacian system with a novel concavity-sensitive weighting scheme. Isolines sampled from the concavity-aware fields naturally gather at concave seams, serving as good cutting boundary candidates. In addition, the fields provide sufficient information allowing efficient evaluation of the candidate cuts. We perform a summarization of all field gradient magnitudes to define a score for each isoline and employ a score-based greedy algorithm to select the best cuts. Extensive experiments and quantitative analysis have shown that the quality of our segmentations are better than or comparable with existing state-of-the-art more complex approaches. PMID- 21788669 TI - Coherent time-varying graph drawing with multifocus+context interaction. AB - We present a new approach for time-varying graph drawing that achieves both spatiotemporal coherence and multifocus+context visualization in a single framework. Our approach utilizes existing graph layout algorithms to produce the initial graph layout, and formulates the problem of generating coherent time varying graph visualization with the focus+context capability as a specially tailored deformation optimization problem. We adopt the concept of the super graph to maintain spatiotemporal coherence and further balance the needs for aesthetic quality and dynamic stability when interacting with time-varying graphs through focus+context visualization. Our method is particularly useful for multifocus+context visualization of time-varying graphs where we can preserve the mental map by preventing nodes in the focus from undergoing abrupt changes in size and location in the time sequence. Experiments demonstrate that our method strikes a good balance between maintaining spatiotemporal coherence and accentuating visual foci, thus providing a more engaging viewing experience for the users. PMID- 21788670 TI - Fisheye video correction. AB - Various types of video can be captured with fisheye lenses; their wide field of view is particularly suited to surveillance video. However, fisheye lenses introduce distortion, and this changes as objects in the scene move, making fisheye video difficult to interpret. Current still fisheye image correction methods are either limited to small angles of view, or are strongly content dependent, and therefore unsuitable for processing video streams. We present an efficient and robust scheme for fisheye video correction, which minimizes time varying distortion and preserves salient content in a coherent manner. Our optimization process is controlled by user annotation, and takes into account a wide set of measures addressing different aspects of natural scene appearance. Each is represented as a quadratic term in an energy minimization problem, leading to a closed-form solution via a sparse linear system. We illustrate our method with a range of examples, demonstrating coherent natural-looking video output. The visual quality of individual frames is comparable to those produced by state-of-the-art methods for fisheye still photograph correction. PMID- 21788671 TI - Integrality and separability of multitouch interaction techniques in 3D manipulation tasks. AB - Multitouch displays represent a promising technology for the display and manipulation of data. While the manipulation of 2D data has been widely explored, 3D manipulation with multitouch displays remains largely unexplored. Based on an analysis of the integration and separation of degrees of freedom, we propose a taxonomy for 3D manipulation techniques with multitouch displays. Using that taxonomy, we introduce Depth-Separated Screen-Space (DS3), a new 3D manipulation technique based on the separation of translation and rotation. In a controlled experiment, we compared DS3 with Sticky Tools and Screen-Space. Results show that separating the control of translation and rotation significantly affects performance for 3D manipulation, with DS3 performing faster than the two other techniques. PMID- 21788672 TI - Attention and visual memory in visualization and computer graphics. AB - A fundamental goal of visualization is to produce images of data that support visual analysis, exploration, and discovery of novel insights. An important consideration during visualization design is the role of human visual perception. How we "see" details in an image can directly impact a viewer's efficiency and effectiveness. This paper surveys research on attention and visual perception, with a specific focus on results that have direct relevance to visualization and visual analytics. We discuss theories of low-level visual perception, then show how these findings form a foundation for more recent work on visual memory and visual attention. We conclude with a brief overview of how knowledge of visual attention and visual memory is being applied in visualization and graphics. We also discuss how challenges in visualization are motivating research in psychophysics. PMID- 21788673 TI - Quantum gate circuit model of signal integration in bacterial quorum sensing. AB - Bacteria evolved cell to cell communication processes to gain information about their environment and regulate gene expression. Quorum sensing is such a process in which signaling molecules, called autoinducers, are produced, secreted and detected. In several cases bacteria use more than one autoinducers and integrate the information conveyed by them. It has not yet been explained adequately why bacteria evolved such signal integration circuits and what can learn about their environments using more than one autoinducers since all signaling pathways merge in one. Here quantum information theory, which includes classical information theory as a special case, is used to construct a quantum gate circuit that reproduces recent experimental results. Although the conditions in which biosystems exist do not allow for the appearance of quantum mechanical phenomena, the powerful computation tools of quantum information processing can be carefully used to cope with signal and information processing by these complex systems. A simulation algorithm based on this model has been developed and numerical experiments that analyze the dynamical operation of the quorum sensing circuit were performed for various cases of autoinducer variations, which revealed that these variations contain significant information about the environment in which bacteria exist. PMID- 21788674 TI - Intervention in gene regulatory networks via phenotypically constrained control policies based on long-run behavior. AB - A salient purpose for studying gene regulatory networks is to derive intervention strategies to identify potential drug targets and design gene-based therapeutic intervention. Optimal and approximate intervention strategies based on the transition probability matrix of the underlying Markov chain have been studied extensively for probabilistic Boolean networks. While the key goal of control is to reduce the steady-state probability mass of undesirable network states, in practice it is important to limit collateral damage and this constraint should be taken into account when designing intervention strategies with network models. In this paper, we propose two new phenotypically constrained stationary control policies by directly investigating the effects on the network long-run behavior. They are derived to reduce the risk of visiting undesirable states in conjunction with constraints on the shift of undesirable steady-state mass so that only limited collateral damage can be introduced. We have studied the performance of the new constrained control policies together with the previous greedy control policies to randomly generated probabilistic Boolean networks. A preliminary example for intervening in a metastatic melanoma network is also given to show their potential application in designing genetic therapeutics to reduce the risk of entering both aberrant phenotypes and other ambiguous states corresponding to complications or collateral damage. Experiments on both random network ensembles and the melanoma network demonstrate that, in general, the new proposed control policies exhibit the desired performance. As shown by intervening in the melanoma network, these control policies can potentially serve as future practical gene therapeutic intervention strategies. PMID- 21788675 TI - Smoldyn on graphics processing units: massively parallel Brownian dynamics simulations. AB - Space is a very important aspect in the simulation of biochemical systems; recently, the need for simulation algorithms able to cope with space is becoming more and more compelling. Complex and detailed models of biochemical systems need to deal with the movement of single molecules and particles, taking into consideration localized fluctuations, transportation phenomena, and diffusion. A common drawback of spatial models lies in their complexity: models can become very large, and their simulation could be time consuming, especially if we want to capture the systems behavior in a reliable way using stochastic methods in conjunction with a high spatial resolution. In order to deliver the promise done by systems biology to be able to understand a system as whole, we need to scale up the size of models we are able to simulate, moving from sequential to parallel simulation algorithms. In this paper, we analyze Smoldyn, a widely diffused algorithm for stochastic simulation of chemical reactions with spatial resolution and single molecule detail, and we propose an alternative, innovative implementation that exploits the parallelism of Graphics Processing Units (GPUs). The implementation executes the most computational demanding steps (computation of diffusion, unimolecular, and bimolecular reaction, as well as the most common cases of molecule-surface interaction) on the GPU, computing them in parallel on each molecule of the system. The implementation offers good speed-ups and real time, high quality graphics output PMID- 21788676 TI - The complexity of finding multiple solutions to betweenness and quartet compatibility. AB - We show that two important problems that have applications in computational biology are ASP-complete, which implies that, given a solution to a problem, it is NP-complete to decide if another solution exists. We show first that a variation of BETWEENNESS, which is the underlying problem of questions related to radiation hybrid mapping, is ASP-complete. Subsequently, we use that result to show that QUARTET COMPATIBILITY, a fundamental problem in phylogenetics that asks whether a set of quartets can be represented by a parent tree, is also ASP complete. The latter result shows that Steel's QUARTET CHALLENGE, which asks whether a solution to QUARTET COMPATIBILITY is unique, is coNP-complete. PMID- 21788677 TI - Optimizing phylogenetic networks for circular split systems. AB - We address the problem of realizing a given distance matrix by a planar phylogenetic network with a minimum number of faces. With the help of the popular software SplitsTree4, we start by approximating the distance matrix with a distance metric that is a linear combination of circular splits. The main results of this paper are the necessary and sufficient conditions for the existence of a network with a single face. We show how such a network can be constructed, and we present a heuristic for constructing a network with few faces using the first algorithm as the base case. Experimental results on biological data show that this heuristic algorithm can produce phylogenetic networks with far fewer faces than the ones computed by SplitsTree4, without affecting the approximation of the distance matrix. PMID- 21788678 TI - A sparse regulatory network of copy-number driven gene expression reveals putative breast cancer oncogenes. AB - Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis- versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation. AVAILABILITY: An R package named lol is available from www.markowetzlab.org/software/lol.html. PMID- 21788679 TI - On parameter synthesis by parallel model checking. AB - An important problem in current computational systems biology is to analyze models of biological systems dynamics under parameter uncertainty. This paper presents a novel algorithm for parameter synthesis based on parallel model checking. The algorithm is conceptually universal with respect to the modeling approach employed. We introduce the algorithm, show its scalability, and examine its applicability on several biological models. PMID- 21788680 TI - DBE2 - management of experimental data for the VANTED system. AB - DBE2 is an information system for the management of biological experiment data from different data domains in a unified and simple way. It provides persistent data storage, worldwide accessibility of the data and the opportunity to load, save, modify, and annotate the data. It is seamlessly integrated in the VANTED system as an add-on, thereby extending the VANTED platform towards data management. DBE2 also utilizes controlled vocabulary from the Ontology Lookup Service to allow the management of terms such as substance names, species names, and measurement units, aiming at an eased data integration. PMID- 21788681 TI - Data partitioning enables the use of standard SOAP Web Services in genome-scale workflows. AB - Biological databases and computational biology tools are provided by research groups around the world, and made accessible on the Web. Combining these resources is a common practice in bioinformatics, but integration of heterogeneous and often distributed tools and datasets can be challenging. To date, this challenge has been commonly addressed in a pragmatic way, by tedious and error-prone scripting. Recently however a more reliable technique has been identified and proposed as the platform that would tie together bioinformatics resources, namely Web Services. In the last decade the Web Services have spread wide in bioinformatics, and earned the title of recommended technology. However, in the era of high-throughput experimentation, a major concern regarding Web Services is their ability to handle large-scale data traffic. We propose a stream like communication pattern for standard SOAP Web Services, that enables efficient flow of large data traffic between a workflow orchestrator and Web Services. We evaluated the data-partitioning strategy by comparing it with typical communication patterns on an example pipeline for genomic sequence annotation. The results show that data-partitioning lowers resource demands of services and increases their throughput, which in consequence allows to execute in-silico experiments on genome-scale, using standard SOAP Web Services and workflows. As a proof-of-principle we annotated an RNA-seq dataset using a plain BPEL workflow engine. PMID- 21788682 TI - Mechanisms of molecular beam epitaxy growth in InAs/InP nanowire heterostructures. AB - InAs/InP axial nanowire heterostructures were grown by the Au-assisted vapour liquid-solid method in a gas source molecular beam epitaxy system. The nanowire crystal structure and morphology were investigated by transmission electron microscopy for various growth conditions (temperature, growth rate, V/III flux ratio). Growth mechanisms were inferred from the InAs and InP segment lengths as a function of the nanowire diameter. Short InAs segment lengths were found to grow by depletion of In from the Au particle as well as by direct impingement, while longer segments of InAs and InP grew by diffusive transport of adatoms from the nanowire sidewalls. The present study offers a way to control the lengths of InAs quantum dots embedded in InP barriers. PMID- 21788683 TI - Spin filling of valley-orbit states in a silicon quantum dot. AB - We report the demonstration of a low-disorder silicon metal-oxide-semiconductor (Si MOS) quantum dot containing a tunable number of electrons from zero to N = 27. The observed evolution of addition energies with parallel magnetic field reveals the spin filling of electrons into valley-orbit states. We find a splitting of 0.10 meV between the ground and first excited states, consistent with theory and placing a lower bound on the valley splitting. Our results provide optimism for the realisation in the near future of spin qubits based on silicon quantum dots. PMID- 21788684 TI - Local electrical modification of a conductivity-switching polyimide film formed by molecular layer deposition. AB - The electrical modification of a conductivity-switching polyimide film via molecular layer deposition (MLD) is studied for ultrahigh density data storage based on a scanning probe microscope (SPM). A PMDA-ODA (PMDA = 1, 2, 3, 5 benzenetetracarboxylic anhydride, ODA = 4, 4-oxydianiline) film as a recording medium is uniformly formed from a self-assembled monolayer on a Au surface by MLD. It is demonstrated that the conductivity of the film can be changed by applying a voltage between a SPM probe and the film. This conductivity-switching phenomenon is discussed by the molecular orbital approach and considered to be caused by the charge transfer effect or carrier trapping effect of PMDA-ODA. PMID- 21788685 TI - PEG-detachable and acid-labile cross-linked micelles based on orthoester linked graft copolymer for paclitaxel release. AB - Polyethylene glycol detachable graft copolymer, mPEG-g-p(NAS-co-BMA), was synthesized by grafting 2-(omega-methoxy)PEGyl-1,3-dioxan-5-ylamine onto poly(N (acryloyloxy)succinimide-co-butyl methacrylate). Pseudo in situ cross-linking of the mPEG-g-p(NAS-co-BMA) was performed in dimethylformamide phosphate buffer (v/v = 1/1) by an acid-labile diamine cross-linker bearing two symmetrical cyclic orthoesters. The cross-linked (CL) micelles with different contents of mPEG segments represented different morphologies. The CL micelles containing approximately one mPEG segment exhibited 'echini' morphology whereas the CL micelle with approximately three mPEG segments formed nanowires. The hydrolysis rate of the CL micelles is highly pH-dependent and much more rapid at mild acid than physiological conditions. Hydrolyzates of the CL micelles formed vesicles because new amphiphilic copolymers were formed. Paclitaxel (PTX) was successfully loaded into the CL micelles and a controlled and pH-dependent release behavior was observed. No obvious cytotoxicity was found for the CL micelles at concentration as high as 800 mg l( - 1). PMID- 21788686 TI - Limitations of temperature measurement in the aural canal with an ear mould integrated sensor. AB - Aural canal temperature measurement using an ear mould integrated sensor (T(ac)) might be a method suited for continuous non-invasive core temperature estimation in operational settings. We studied the effect of ambient temperature, wind and high intensity exercise on T(ac) and its ability to predict esophageal (T(es)) and rectal temperatures (T(re)). Seven subjects performed a protocol of rest at 21, 10 and 30 degrees C, followed by exercise and recovery at 30 degrees C. The subjects performed the protocol twice: with and without face-wind from halfway through the 30 degrees C rest period. Extra auricle insulation was applied at one side. Ambient temperature changes affected T(ac) significantly, while T(es) and T(re) remained stable. Insulating the auricle reduced but did not abolish this effect. Wind had an immediate cooling effect on T(ac) independent of auricle insulation. During exercise and recovery in 30 degrees C, T(ac) provided acceptable group predictions of T(re) in trials without wind (bias: -0.66 +/- 0.21 degrees C covered, -1.20 +/- 0.15 degrees C uncovered). Bias was considerably higher with wind, but variability was similar (-1.73 +/- 0.11 degrees C covered, -2.49 +/- 0.04 degrees C uncovered). Individual predictions of T(es) and T(re) showed more variation, especially with wind. We conclude that T(ac) may be used for core temperature assessment of groups in warm and stable conditions. PMID- 21788687 TI - Validity and reliability of temperature measurement by heat flow thermistors, flexible thermocouple probes and thermistors in a stirred water bath. AB - We determined the validity and reliability of heat flow thermistors, flexible thermocouple probes and general purpose thermistors compared with a calibrated reference thermometer in a stirred water bath. Validity (bias) was defined as the difference between the observed and criterion values, and reliability as the repeatability (standard deviation or typical error) of measurement. Data were logged every 5 s for 10 min at water temperatures of 14, 26 and 38 degrees C for ten heat flow thermistors and 24 general purpose thermistors, and at 35, 38 and 41 degrees C for eight flexible thermocouple probes. Statistical analyses were conducted using spreadsheets for validity and reliability, where an acceptable bias was set at +/-0.1 degrees C. None of the heat flow thermistors, 17% of the flexible thermocouple probes and 71% of the general purpose thermistors met the validity criterion for temperature. The inter-probe reliabilities were 0.03 degrees C for heat flow thermistors, 0.04 degrees C for flexible thermocouple probes and 0.09 degrees C for general purpose thermistors. The within trial intra-probe reliability of all three temperature probes was 0.01 degrees C. The results suggest that these temperature sensors should be calibrated individually before use at relevant temperatures and the raw data corrected using individual linear regression equations. PMID- 21788688 TI - Theoretical study of C60 as catalyst for dehydrogenation in LiBH4. AB - Complex light metal hydrides possess many properties which make them attractive as a storage medium for hydrogen, but typically catalysts are required to lower the hydrogen desorption temperature and to facilitate hydrogen uptake in the form of a reversible reaction. The overwhelming focus in the search for catalysing agents has been on compounds containing titanium, but the precise mechanism of their actions remains somewhat obscure. A recent experiment has now shown that fullerenes (C(60)) can also act as catalysts for both hydrogen uptake and release in lithium borohydride (LiBH(4)). In an effort to understand the involved mechanism, we have employed density functional theory to carry out a detailed study of the interaction between this complex metal hydride and the carbon nanomaterial. Considering a stepwise reduction of the hydrogen content in LiBH(4), we find that the presence of C(60) can lead to a substantial reduction of the involved H-removal energies. This effect is explained as a consequence of the interaction between the BH(x)( - ) complex and the C(60) entity. PMID- 21788689 TI - Graphite patterning in a controlled gas environment. AB - Although a number of methods using scanning probe lithography to pattern graphene have already been introduced, the fabrication of real devices still faces limitations. We report graphite patterning using scanning probe lithography with control of the gas environment. Patterning processes using scanning probe lithography of graphite or graphene are normally performed in air because water molecules forming the meniscus between the tip and the sample mediate the etching reaction. This water meniscus, however, may prevent uniform patterning due to its strong surface tension or large contact angle on surfaces. To investigate this side effect of water, our experiment was performed in a chamber where the gas environment was controlled with methyl alcohol, oxygen or isopropanol gases. We found that methyl alcohol facilitates graphite etching, and a line width as narrow as 3 nm was achieved as methyl alcohol also contains an oxygen atom which gives rise to the required oxidation. Due to its low surface tension and highly adsorptive behavior, methyl alcohol has advantages for a narrow line width and high speed etching conditions. PMID- 21788690 TI - A transparent polymeric flexure-hinge nanopositioner, actuated by a piezoelectric stack actuator. AB - Nanopositioning using piezoelectric actuation and a flexure mechanism is one of most common methods for nanometre-scale positioning. Generally, flexure mechanism nanopositioners have been made from metal. Thus, their application to various environments needs careful consideration with regard to corrosion and circumference interference. In this study, we propose the concept of a chip-like polymeric flexure-based nanopositioner equipped with piezoelectric actuation. In its design, motion performance was predicted using finite element analysis of deformation and stress, and injection mouldability was considered through an injection moulding simulation to allow for fabrication by injection moulding. A cyclic olefin copolymer nanopositioner was fabricated using a mesoscale injection moulding process. Experiments demonstrated that the developed nanopositioner had a travel range of 15 um with high linearity and it could be successfully controlled by a proportional-integral-derivative (PID) algorithm including a low pass filter with a root mean square control error of 3 nm. PMID- 21788691 TI - Network single-walled carbon nanotube biosensors for fast and highly sensitive detection of proteins. AB - Detection of proteins is powerfully assayed in the diagnosis of diseases. A strategy for the development of an ultrahigh sensitivity biosensor based on a network single-walled carbon nanotube (SWNT) field-effect transistor (FET) has been demonstrated. Metallic SWNTs (m-SWNTs) in the network nanotube FET were selectively removed or cut via a carefully controlled procedure of electrical break-down (BD), and left non-conducting m-SWNTs which magnified the Schottky barrier (SB) area. This nanotube FET exhibited ultrahigh sensitivity and fast response to biomolecules. The lowest detection limit of 0.5 pM was achieved by exploiting streptavidin (SA) or a biotin/SA pair as the research model, and BD treated nanotube biosensors had a 2 * 10(4)-fold lower minimum detectable concentration than the device without BD treatment. The response time is in the range of 0.3-3 min. PMID- 21788692 TI - Quantum: may be a new-found messenger in biological systems. AB - Current studies on biological communications mainly focus on chemical signals. Since organisms are extremely complex, different kinds of signals may exist in the process of cell communication. The most probable candidate for alternative forms of organism communications is electromagnetic radiation, as many experiments have confirmed that electromagnetic radiation widely exists in cells, tissues, organisms and even between organisms and their surroundings. The well known connection between electromagnetic radiation and quantization of the energy transfer makes us to suggest a bold, but fresh view that quantum can serve as a biological messenger. This view also coincides with the medium of Qi in the human body according to traditional Chinese medicine (TCM). Relating Qi with quantum may further explain a number of phenomena that cannot be explained solely by conventional chemical signaling systems. PMID- 21788693 TI - Affinity of anti-insulin-like growth factor Iota receptor antibody binding to the receptor altered by plant lectins. AB - The binding ability of anti-insulin-like growth factor Iota receptor (IGF-IotaR) single-chain variable fragments (scFvs) to IGF-IR was measured in the presence of plant lectins. Combinations of concanavalin A (Con A), wheat germ agglutinin (WGA), or peanut agglutinin (PNA) and 1H7 or 3B7 anti-IGF-IotaR scFv/phage antibodies that were previously produced and characterized were used. WGA inhibited binding of both scFvs proteins to the receptor. PNA slightly enhanced the binding of 1H7 scFv and phage antibody to the receptor. Con A led to enhancement of 3B7 scFv-binding but had no effect in a test of phage antibodies and determination of kinetic parameters. The effect of lectins differed for scFvs and phage antibodies, implying that affinity altered by lectins is dependent upon the molecular structure of the antibodies. Results indicated that animal lectins may affect the affinity of therapeutic antibodies targeting cell membrane receptors in vivo. PMID- 21788694 TI - No association between Vitamin D receptor gene polymorphisms and nasopharyngeal carcinoma in a Chinese Han population. AB - An abundance of candidate genes have been reported as susceptibility factors for the risk of nasopharyngeal carcinoma (NPC). Vitamin D receptor (VDR) plays an important role in cellular differentiation and the control of proliferation in a variety of cell types. To our knowledge, however, no study has reported the relationship between the VDR and NPC. The purpose of this study is to explore the potential correlation between single-nucleotide polymorphisms of the VDR gene (VDR) Fok I and Bsm I and NPC. A total of 171 patients with NPC and 176 age- and sex-matched controls were involved in this study. Genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. There were no significant differences in the genotype and allele frequencies of VDR Fok I and Bsm I polymorphisms between the group of patients with NPC and the control group in a Chinese Han population (for VDR Fok I: adjusted OR 1.03, 95% CI: 0.76-1.41; for VDR Bsm I: adjusted OR 0.80, 95% CI: 0.48-1.33). Further studies will be needed to explore the complicated gene-gene interaction and gene-environmental interactions in the susceptibility to NPC, especially in ethnically disparate populations in cohort study samples. PMID- 21788695 TI - Study of KAP with regard to taking folic acid supplements and factors affecting the recommendation and prescription of those supplements among obstetricians and specialists in women's health in six provinces of Northern China, 2009. AB - Taking folic acid (FA) supplements reduces the risks of neural tube defects (NTDs) in early pregnancy. Obstetricians and specialists in women's health play important roles in promoting FA intake. However, surveys on their knowledge of, attitudes toward, and behavior regarding giving FA to pregnant women are limited. A cross-sectional study was conducted with 5,860 obstetricians and specialists in women's health using a self-administered questionnaire to collect information on participants' demographic characteristics and their knowledge of and attitudes toward and practices related to taking FA supplements. Chi-square analysis was used for rate comparison while logistic regression analysis was performed to predict influencing factors. For items on knowledge about FA and taking FA supplements the overall correct response rate was 60.3% (24,235/40,173). Questions about related practices and attitudes were correctly answered for the most part (more than 90%), but participants were less likely to follow the practice of prescribing FA tablets to women planning a pregnancy while working (77.2%). Statistical analysis indicated that the "Level of facility where the participant works" and "Rate of correct responses on a test of knowledge" were the main factors affecting participants' recommendation to take FA while "Job title", "Amount of professional work experience", and "Rate of correct responses on a test of knowledge" were the main factors affecting participants' prescription of FA. In conclusion, participants had a good deal of knowledge about NTDs and FA but the lack of some knowledge possibly led to the relatively low rate of correct behaviors. Therefore, educating obstetricians and specialists in women's health in this regard is crucial. PMID- 21788696 TI - The effects of instruction regarding sleep posture on the postural changes and sleep quality among middle-aged and elderly men: a preliminary study. AB - The purpose of this study was to examine whether instruction to sleep in a lateral posture prior to falling asleep could increase the frequency of instructed posture and sleep quality, as evaluated by sleep parameters and a questionnaire for subjective assessment of sleep. The participants were comprised of 8 middle-aged and elderly men who had an awareness of their habitual snoring during sleep. Data were gathered from observations of sleep posture, sleep polysomnography and a subjective sleep quality questionnaire. As a result of the instruction, the frequency of the instructed posture was significantly increased, and there were no significant effects on sleep parameters or the frequency of postural changes. The subjective sleep quality during the instructed sleep showed worse scores than free postural-sleep for all factors. Our findings suggest that the instructed sleep posture could be increased during sleep without substantially worsening the sleep parameters and the frequency of postural changes. Future studies will therefore be required to clarify the mechanism and the long-term effects of such instruction on sleep posture, including the influence on subjective sleep quality. PMID- 21788697 TI - Gonadotropin-releasing hormone-agonist induces apoptosis of human granulosa luteal cells via caspase-8, -9 and -3, and poly-(ADP-ribose)-polymerase cleavage. AB - Gonadotropin-releasing hormone-agonist (GnRH-Ag) used in controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET) has been known to directly affect apoptosis of human ovarian cells, but its mechanism is not clearly understood. Therefore, the purpose of the present study was to investigate whether caspase-8, -9, and -3 activation and poly-(ADP-ribose) polymerase (PARP) cleavage are involved in the mechanism by which GnRH-Ag induces apoptosis in human granulosa-luteal cells. The prospective study was conducted in the research institute and clinical fertility center of university hospital. Human granulosa-luteal cells collected from IVF-ET patients were cultured and treated with 10-6 M GnRH-Ag or saline as a control. To access apoptosis in the cells, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay and DNA fragmentation analysis were preformed 24 h after treatment. Activity of caspase-8, -9, and -3 in the cells was examined using a fluorogenic substrate. Caspase-8, -9, and -3 activation and PARP cleavage were analyzed by Western blot. DNA fragmentation in the cells increased at concentrations over 10-6 M GnRH-Ag. In TUNEL assays, the rate of apoptotic cell formation in GnRH-Ag treatment increased significantly compared with that of saline treatment (p < 0.05). The activity of caspase-8, -9 and, -3 investigated using a fluorogenic substrate increased only in the apoptotic cells. In Western blot analysis, cells treated with GnRH-Ag revealed an increase in active forms of caspase-8, -9, and -3 compared with saline treatment. In addition, cleavage of PARP also increased in cells treated with GnRH-Ag. These results suggest that activation of caspase-8, -9, and -3 and cleavage of PARP might be involved in apoptosis of human granulosa-luteal cells induced by GnRH Ag. PMID- 21788698 TI - Gastrodia elata modulates amyloid precursor protein cleavage and cognitive functions in mice. AB - Gastrodia elata (Tianma) is a traditional Chinese medicine often used for the treatment of headache, convulsions, hypertension, and cardiovascular diseases. The vasodilatory actions of Tianma led us to investigate its specific effects on memory and learning as well as on Alzheimer's disease (AD)-related signaling. We conducted a radial arm water maze analysis and the novel object recognition test to assess the cognitive functions of Tianma-treated mice. Our data show that Tianma enhances cognitive functions in mice. Further investigations revealed that Tianma enhances the alpha-secretase-mediated proteolytic processing of the amyloid precursor protein (App) that precludes the amyloid-beta peptide production and supports the non-amyloidogenic processing of App which is favorable in AD treatment. We hypothesize that Tianma promotes cognitive functions and neuronal survival by inhibiting beta-site App-cleaving enzyme 1 activity and promoting the neuroprotective alpha-secretase activity. PMID- 21788699 TI - Species identification of neglected nontuberculous mycobacteria in a developing country. AB - In developing countries where tuberculosis is still a health challenge, the prevalence of nontuberculous mycobacterial diseases is expected to rise as medical conditions that compromise the immune system become more widespread. In the current study, we aimed to determine the presence and diversity of nontuberculous mycobacteria (NTM) causing infections in Iranian patients. Sixty seven clinical NTM isolates were identified using conventional and molecular methods, including PCR-restriction fragment length polymorphism analysis (PRA) and 16S rRNA sequencing. Out of 67 patients with confirmed mycobacterial infection, 29 had an associated immunosuppressive syndrome, including 9 who were HIV-infected. Forty-nine NTM isolates were identified using PRA, and the remaining 18 isolates were identified using 16S rRNA sequencing. We obtained the following results: Mycobacterium fortuitum, 30 isolates; M. kansasii, 12 isolates; M. gordonae, 8 isolates; M. porcinum, 3 isolates; M. conceptionense, 3 isolates; M. phlei, 2 isolates; and M. austroafricanum, M. avium, M. elephantis, M. intracellulare, M. lentiflavum, M. monacense, M. parascrofulaceum, and M. thermoresistibile, 1 isolate each; and 1 potentially novel mycobacterial species. With regard to the complexity of identification, it is recommended that laboratory diagnosis of NTM diseases be centralized by strengthening or setting up quality national and regional infrastructure. PMID- 21788700 TI - Evaluation of serological tests for diagnosis of brucellosis. AB - The aim of the present study was to compare serological tests (Rose Bengal [RB]; standard agglutination test [SAT]; enzyme immunoassay [EIA] for detection of IgM, IgA, and IgG; and 2-mercaptoethanol [2-ME] test) that are routinely used in patients prediagnosed with different clinical types of brucellosis (acute, subacute, or chronic), and to evaluate the results of the IgG avidity test. Ninety-two patients having titers>=1/160 as measured by SAT were included in the study. The IgG avidity test was performed in 78 patients who had positive EIA-IgG results. RB test results were positive in 88 (95.7%) patients. A statistically significant correlation was found between a positive EIA-IgM result and the diagnosis of acute brucellosis. When compared to the results of the SAT, the 2-ME test showed a lower titer in 55 (59.8%) patients, and the agreement between the 2 ME test and EIA-IgG was calculated as 84.8%. No statistical difference was found between the 40% avidity index used in the IgG avidity test and avidity maturation time (6 months). From our study, we concluded that (i) the RB and SAT tests are appropriate and reliable tests for the serological diagnosis of brucellosis; (ii) IgM can be used as a marker of acute brucellosis; (iii) the 2-ME test, similar to EIA, can be used to determine IgM levels; and (iv) the IgG avidity test should be standardized. PMID- 21788701 TI - Cost-effectiveness analysis of a universal rotavirus immunization program in Japan. AB - In anticipation of the imminent licensure of rotavirus vaccine, we evaluated the cost-effectiveness of rotavirus vaccine in Japan by taking into account the considerable variations in the incidence of rotavirus-associated hospitalizations previously reported in the literature. We assumed that the variation was due to local differences in healthcare utilization practices rather than a true difference in the incidence of severe rotavirus gastroenteritis. Thus, a Markov model was constructed such that the sum of rotavirus-associated hospitalizations and outpatient visits was set a constant value of 129 cases per 1,000 child years. We calculated the direct medical cost, the indirect cost, and the quality adjusted life year (QALY) loss in children aged less than 5 years. For the base case scenario, the incremental cost-effectiveness ratio (ICER) per QALY gained was 9.8 million Japanese yen from the healthcare perspective, but it was 900,000 Japanese yen from the societal perspective, making the program of universal immunization against rotavirus highly cost-effective. Furthermore, the universal immunization program was found to be cost-effective from the societal perspective for any of the previously reported incidence rates of rotavirus-associated hospitalization. Thus, the introduction of the rotavirus vaccine into the childhood immunization schedule and its co-administration with other childhood vaccines will be a cost-effective public health intervention in Japan. PMID- 21788702 TI - Nonstructural protein 1 antibody-based epitope-blocking enzyme-linked immunosorbent assay to differentiate Japanese encephalitis virus from dengue virus infections in humans. AB - Japanese encephalitis virus (JEV) and the four dengue viruses (DENV1-4) are co distributed in Southeast and South Asia. Since JEV is antigenically cross reactive with DENV1-4, the differentiation between these viruses using antibody assays may be difficult. Herein, we describe the development of an epitope blocking enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody specific for the nonstructural protein 1 (NS1) of JEV (JEV-NS1) to differentiate antibodies against JEV from those against DENV1-4. Hyperimmune mouse sera against JEV-NS1 showed >60% inhibition, whereas those against NS1 of DENV1-4 showed <30% inhibition. The present assay could therefore detect antibodies specific for JEV. For testing of human sera, a temporary cutoff value (30.8%) was calculated the average and standard deviation obtained for sera of control humans negative for JEV antibodies. Human sera positive for antibodies to any of DENV1-4 NS1 but negative for antibodies to JEV-NS1 showed a lower percentage inhibition than the cutoff value. On the other hand, sera with JEV-NS1 antibody levels of >=0.400, as determined by the conventional ELISA (medially/strongly positive for JEV-NS1 antibodies), showed percentage inhibition greater than the cutoff. Although this blocking ELISA afforded false-negative results for most sera that were weakly positive for JEV-NS1 antibodies, it may be useful for investigating the seroepidemiology of JEV antibodies in dengue-endemic areas. PMID- 21788703 TI - Synergistic antifungal effect of lactoferrin with azole antifungals against Candida albicans and a proposal for a new treatment method for invasive candidiasis. AB - The combination of lactoferrin with fluconazole has been reported to synergistically enhance the antifungal activity of fluconazole against Candida spp. and inhibit the hyphal formation in fluconazole-resistant strains of Candida albicans. In this study, we investigated the association between the therapeutic effects of this combination and the pharmacological characteristics of fluconazole and itraconazole and the variation in these effects with differences among the strains in terms of the susceptibility and resistance mechanisms. Lactoferrin enhanced the growth-inhibitory activity of fluconazole against two different ergosterol mutants but not againt pump mutants or an azole-susceptible strain; but increased the activity of itraconazole against all the strains tested in this study. Exogenous iron cancelled the synergistic effect, which suggests that the iron-chelating function of lactoferrin may contribute to the synergism. Besides, radiolabeled fluconazole assays revealed that lactoferrin did not affect the intracellular concentrations of fluconazole, thereby indicating that these synergistic effects were not due to the alteration of the intracellular uptake of the drug. The development of new clinical treatments and therapeutic method against resistant Candida will depend on our understanding of the resistance mechanisms and methods to overcome them by the application of suitable drug combinations with synergistic effects. The results of this study might contribute to the improvement of our understand of the mechanisms underlying the resistance of Candida strains. PMID- 21788704 TI - Active surveillance of adverse events following immunization against pandemic influenza A (H1N1) in Korea. AB - Surveillance of vaccine safety is one of the public health interventions used to investigate the causal relationship between vaccines and adverse events. Using active surveillance data, we aimed to compile a detailed summary describing the safety of the pandemic influenza A (H1N1) vaccine. Computer-assisted telephone interview was used to investigate adverse events for 9,000 subjects who had received non-adjuvanted vaccines between November 2009 and January 2010, and for 19,000 adults who received adjuvanted vaccines from January through March 2010. The participants were interviewed to obtain information about local and systemic adverse events. Among subjects who received the non-adjuvanted vaccine, 5.5% (n=492) reported adverse events after vaccination, while 6.7% of those who received the adjuvanted vaccine reported adverse events. In the group receiving the adjuvanted vaccine, the highest reported rate of adverse events was among persons aged 19-49 years (9.1%, 577/6,329), followed by persons aged 50-64 years (7.2%, 485/6,718), and elderly persons aged 65 years and over (3.4%, 204/5,953). The implementation of this active surveillance study demonstrated the safety of both the adjuvanted and non-adjuvanted H1N1 vaccines. PMID- 21788705 TI - Biofilm deficiency in polysaccharide intercellular adhesin-negative variants of Staphylococcus epidermidis selected by subminimal inhibitory concentrations of gentamicin. AB - Staphylococcus epidermidis is a cause of orthopedic device-related infection, and to treat such infection, biofilms should be controlled. Polysaccharide intercellular adhesin (PIA) is associated with the biofilm-forming ability of staphylococcal strains. PIA in biofilm-positive staphylococcal strains can be detected by the Congo red agar (CRA) method. In this study, we used the CRA method to examine the effects of subminimal inhibitory concentrations (sub-MICs) of 11 antibacterial agents on PIA production by S. epidermidis. We found that the PIA-negative variants were selected only by sub-MICs of gentamicin (GM). This PIA negative phenotype was maintained over several generations in the absence of GM. Such selection occurred in six of eight clinical isolates, as well as in the biofilm-positive control strain. No such selection occurred with aminoglycoside antibiotics except for GM. Most of the PIA-negative variants that were selected by GM showed a markedly lower biofilm-forming ability on stainless steel washers than their untreated parent strains. In conclusion, variants with lower biofilm forming ability may be selected by a sub-MIC of GM. Investigation of the reason why variants with reduced biofilm-forming ability can be selected in the presence of sub-MICs of GM may contribute to strategies against biofilm-related infections. PMID- 21788706 TI - Control of a measles outbreak by prohibiting non-vaccinated susceptible students from attending school in Akita Prefecture, Japan. AB - In 2007-2008, a measles outbreak occurred among children above the age of 10 years in Akita Prefecture, northeastern Japan (population, approximately 1,120,000 at the time). Our group controlled the outbreak by (i) implementing a publically financed urgent vaccination program and (ii) prohibiting non vaccinated and non-infected students from attending school as per regulations of the school public health law. We encouraged high-risk students to undergo a vaccination program, which resulted in the successful containment of the outbreak without the development of any severe cases. After the outbreak, the Akita Prefectural Government began an annual"Akita measles elimination month" every April, and no measles case found in Akita Prefecture during 2009-2010 subsequently. Our outbreak response initiative can be applied nationally for the complete elimination of measles throughout Japan. PMID- 21788707 TI - Phage types of Vibrio cholerae O1 and O139 in the past decade in India. AB - Cholera has been a prevalent disease worldwide since the early 19th century. Vibrio cholerae O1 and O139 are the two serogroups that have been mainly implicated in causing cholera. This study reports the results of biotyping, serotyping and phage typing of V. cholerae O1 and O139 (1998-2007) strains received from different parts of India for the identification of the trends in the occurrence and spread of cholera in the country. However, there has been a notable steep decline in the occurrence of V. cholerae O139 strains over the past few years resulting in no strain of V. cholerae O139 being received from any part of India in 2007 and 2008. Of the total strains received, 79.1% were serotyped as Ogawa and the remaining 20.9% were found to be Inaba, which indicates that Ogawa was the predominant serotype. Almost 100% typeability was observed with the new scheme of V. cholerae O1, with type 27 being the dominant phage type and V. cholerae O139 strains were clustered into the predominant phage type T-1. From the phage typing and serotyping results, it can be concluded that V. cholerae O1 (T-27) and O139 (T-1) strains circulate throughout the country at any given time. PMID- 21788708 TI - Assessment of lymph node tuberculosis in two provinces in Turkey. AB - The aim of this study was to evaluate lymph node tuberculosis (LNT) cases in two provinces in Turkey with different demographic and socioeconomic characteristics. A total of 109 LNT cases were reviewed retrospectively. The cases were analyzed and compared for symptoms, findings, age, vaccination status, and diagnostic procedures. Socioeconomic conditions were also assessed for the two provinces. A palpable cervical node was considered a significant predictor for all LNT. Mediastinal lymph node involvement was found to be common in cases of pulmonary manifestation of LNT. Female patients were predominantly from the Van Province, while older patients were found to be from Izmir Province. LNT should be suspected in lymphadenitis patients of all age-groups especially in young adolescents with cervical lymph node enlargements. In the presence of mediastinal lymphadenopathy, pulmonary tuberculosis should be investigated. PMID- 21788709 TI - Prevalence of Schistosoma haematobium infection among schoolchildren in remote areas devoid of sanitation in northwestern Swaziland, Southern Africa. AB - A parasitological survey of Schistosoma haematobium infection among primary schoolchildren in the remote areas of Hhohho and Manzini Provinces in northwestern Swaziland was undertaken. Presence of infection in subjects was confirmed on detection of S. haematobium ova in urine or the presence of hematuria. The intensity of the infection was estimated by calculating the total number of S. haematobium ova present in a 10-ml urine specimen and was expressed in terms of geometric mean intensity (GMI). The prevalence of S. haematobium infection in these populations was 5.3% (21/395) with a GMI of 46.5. Boys had higher prevalence (7.1%, 13/182) and GMI (50.4) than girls (3.8%, 8/213; 40.0) did (P>0.05). Geographically, the prevalence in Manzini schoolchildren (14.6%, 12/82) was significantly higher than that in Hhohho schoolchildren (2.9%, 9/313; P<0.001); however, Hhohho schoolchildren had a higher GMI (70.2) than that observed in Manzini schoolchildren (21.9). Children from schools located in Lowveld had a significantly higher prevalence (11.4%, 19/166) than that in children from schools located in Highveld (0.6%, 1/162) (P<0.0001). PMID- 21788710 TI - Rapid identification of Cardiobacterium hominis by MALDI-TOF mass spectrometry during infective endocarditis. AB - We report a new case of Cardiobacterium hominis endocarditis identified during an acute coronary syndrome. The positivity of the blood cultures was confirmed rapidly (50 h) as a result of improvements to the automated detection system, whereby it is no longer necessary to incubate the vials for long periods of time when Aggregatibacter-Cardiobacterium-Eikenella-Kingella infections is suspected. The phenotype-based VITEK 2 NH identification system is not able to distinguish between the two species of Cardiobacterium, as it does not contain C. valvarum in its library. The method for 16S rRNA gene sequence analysis is able to separate the two species but is not available in all laboratories. We used MALDI-TOF mass spectrometry, as an alternative, to rapidly distinguish between C. hominis and C. valvarum, because both species are contained in the system library. PMID- 21788711 TI - Splenic rupture in dengue hemorrhagic fever: report of a case and review. AB - Dengue is currently the most important arboviral disease in the world, particularly in tropical countries in which the environmental conditions favor the development and proliferation of the mosquito vector. Dengue hemorrhagic fever presents in two phases: an initial phase, which is characterized by sudden onset of fever and a variety of nonspecific signs and symptoms, and a critical phase, which is characterized by the recovery from fever and development of hemorrhagic symptoms and circulatory insufficiency. This report documents a case of splenic rupture in a patient with dengue hemorrhagic fever who developed hypovolemic shock and subsequently died. Although splenic rupture is a known complication of other acute infections, it is a rare complication of dengue; therefore, it may be misdiagnosed. In the case described here, the poor outcome mainly resulted from the sudden onset of complications; the patient died of splenic rupture less than 24 h after admission, and the cause of death was confirmed at necropsy. PMID- 21788712 TI - Detection of Anaplasma phagocytophilum from Wild Boars and Deer in Japan. AB - This study was conducted to determine the prevalence and geographic distribution of Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, in wild deer and boars in Japan. We analyzed the blood samples of the study animals using PCR-targeting the 16S rDNA followed by DNA sequencing. Wild deer infected with Anaplasma spp., including Anaplasma bovis and Anaplasma centrale were detected in the region from Hokkaido to Kyushu. The infection rates of A. phagocytophilum, A. bovis, and A. centrale in deer were 15.6, 21.9, and 37.5%, respectively, and the corresponding infection rates in wild boar were 3.6, 17.9, and 3.6%, respectively. However, p44/msp2 genes specific to A. phagocytophilum were not detected among the 16S rDNA-positive samples on PCR analysis. In addition, the 16S rDNA sequences of A. phagocytophilum were 100% similar to those detected previously in the deer in Japan and 98.6% similar to those of A. phagocytophilum detected in the United States and Europe, and from the tick, Ixodes ovatus and Ixodes persulcatus in Japan. These findings suggested that the A. phagocytophilum-related sequences detected from deer and wild boars in Japan were different from those of typical A. phagocytophilum strains. PMID- 21788713 TI - Antimicrobial susceptibility profiling and genomic diversity of multidrug resistant Acinetobacter baumannii isolates from a teaching hospital in Malaysia. AB - The resistance phenotypes and genomic diversity of 185 Acinetobacter baumannii isolates obtained from the intensive care unit (ICU) of a local teaching hospital in Kuala Lumpur from 2006 to 2009 were determined using antimicrobial susceptibility testing and pulsed-field gel electrophoresis (PFGE). Antibiogram analyses showed that the isolates were fully resistant to beta-lactam antimicrobials and had high resistance rates to the other antimicrobial agents tested. However, the isolates were susceptible to polymyxin B. Resistance to cefoperazone/sulbactam was only detected in strains isolated from 2007 to 2009. Some environmental isolates and an isolate from the hands of a healthcare worker (HCW) had identical resistance profiles and PFGE profiles that were closely related to patient isolates. Cluster analyses based on the PFGE profiles showed there was a persistent clone of endemic isolates in the ICU environment. The transmission route from HCWs to fomites to patients, which caused a long-term infection in the ICU of the University Malaya Medical Centre, was observed in this study. These data provide a better understanding of A. baumannii epidemiology within the hospital and the possible transmission routes. Knowledge of changes in the resistance rates of A. baumannii in our local hospital will improve antimicrobial therapy. PMID- 21788714 TI - Serotyping and multilocus sequence typing of Streptococcus pneumoniae isolates from the blood and posterior nares of Japanese children prior to the introduction of 7-valent pneumococcal conjugate vaccine. AB - In Japan, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. To assess the effects of PCV7 on invasive pneumococcal infection in children, a population-based prospective survey has been conducted in 10 prefectures. As a part of the study, blood and nasopharyngeal isolates from children admitted to the Shibata Hospital, Niigata Prefecture, were analyzed for determining the serotypes, their susceptibilities to antimicrobial agents, and multilocus sequence types. Sixteen blood isolates were obtained from October 2007 to December 2009. Sixty-three nasopharyngeal isolates were obtained from the posterior nares of 118 children with pneumonia from April to September 2008. The coverage rates of the blood and nasopharyngeal isolates for PCV7 were 81.3% and 57.1%, respectively. Although none of these children had received PCV7, serotype 19A isolates were recovered from 12.5% (2/16) of the blood samples and 12.7% (8/63) of the nasopharyngeal samples. The sequence type of a nasopharyngeal isolate of serotype 19A was ST320, and the minimum inhibitory concentration of penicillin G was 4 MUg/mL. In addition to the continuous prospective survey of pneumococcal infection, early introduction of the 13-valent conjugate vaccine, in which the 19A conjugate is included, will be necessary in Japan. PMID- 21788715 TI - Molecular epidemiological study of Bacillus anthracis isolated in Mongolia by multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA-8). AB - The incidence of anthrax, which is caused by Bacillus anthracis, in the human and animal population of Mongolia has increased recently, and control of this infection is a nationwide concern. In this study, 29 isolates obtained from animals and various regions in Mongolia from 2001 to 2007 were analyzed by performing multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA 8) to understand the genetic relationship between the Mongolian B. anthracis isolates. We found that all the Mongolian isolates can be classified into A3 cluster along with the Japanese and the Chinese B. anthracis isolates. Our data revealed that MLVA-8 is useful for studying the molecular epidemiology of the Mongolian B. anthracis isolates and would help characterize B. anthracis infections in Mongolia. PMID- 21788716 TI - HIV epidemic in Japan: different detection patterns between male homosexuals and male heterosexuals. PMID- 21788717 TI - Serotyping and molecular characterization of eae-positive Escherichia coli isolated in a gastroenteritis outbreak. PMID- 21788718 TI - Outbreak of epidemic keratoconjunctivitis caused by adenovirus type 54 in a nursery school in Kobe City, Japan in 2008. PMID- 21788719 TI - Apropos "Evaluation of nonstructural 1 protein rapid test for dengue virus at the Narita Airport Quarantine Station, Japan". PMID- 21788720 TI - [Tinea unguium]. AB - Although onychomycoses are caused by dermatophytes, yeasts or non-dermatophyte molds, tinea unguium describes chronic fungal infections by dermatophytes only. Tinea unguium is a common fungal infection of the nail plate or nail bed with increasing prevalence worldwide. It is not self-limited and shows a higher frequency among the elderly population. In Japan, approximately 10% of the entire population is estimated to have tinea unguium. During the period when only griseofulvin was available for treatment, it was a very difficult disease to treat. Since in the 1990's, however, the introduction of new oral antifungals, itraconazole and terbinafine, initiated a new era in the treatment of tinea unguium. Many excellent textbooks, review articles, and original articles have already been published. This paper considers the circumstances in Japan, epidemiology, causative agents including non-dermatophyte molds, differential diagnosis, diagnostic techniques, the quality of life of the patients with tinea unguium, and then the treatment options are reviewed again. PMID- 21788721 TI - [Aspergillosis]. PMID- 21788722 TI - Recent trend of taxonomy and identification in pathogenic yeasts. PMID- 21788723 TI - Epidemiology of visceral mycoses in autopsy cases in Japan: comparison of the data from 1989, 1993, 1997, 2001, 2005 and 2007 in Annual of Pathological Autopsy Cases in Japan. AB - The data on visceral mycoses reported in the " Annual of Pathological Autopsy Cases in Japan " were analyzed epidemiologically every four years from 1989 to 2005, and in 2007. The frequency rates of visceral mycoses dropped sharply between 1989 (4.5%) and 1994 (3.2%), but by 2001 had risen again and have remained (4.4-4.6%) generally stable since then. The predominant causative agents were Candida and Aspergillus. Although the rate of candidosis showed a gradual decrease, the rate of aspergillosis showed an increase by degrees. Furthermore, the rate of aspergillosis exceeded that of candidosis in 1994, and the difference in the rates between the two conditions apparently further increased until 2001. After 2005, however no changes in this difference were observed. For complicated infections, the incidence of coinfection with Aspergillus and Candida showed a decreasing, and that with Aspergillus and Zygomycetes showed an increasing tendency. Severe infections with Zygomycetes showed a clear increase from 57.4% in 1989 to 88.9% in 2007. Comparing underlying diseases with mycoses in 1989 and 2007, leukemia (including myelodysplastic syndrome) decreased from 26.1% to 18.8% and bacterial infections (including interstitial pneumonia) increased from 11.1% to 22.1%. By age, the highest frequency rate of mycoses was observed in the range of 60-79 years, and the frequency rate of exogenous fungal infections such as aspergillosis, cryptococcosis, zygomycosis and trichosporonosis showed an increasing trend in the less than one-year old group. PMID- 21788724 TI - Microsatellite-based genotyping of Candida albicans isolated from patients with superficial candidiasis. AB - This study aimed to examine the genotype distribution of Candida albicans and the major genotypes involved in superficial candidiasis. The genotypes of C. albicans isolated from the infection sites of patients with superficial candidiasis (referred to as infection isolates) were analyzed by fragment analysis using 4 microsatellite markers (HIS3, CDC3, CAI and CAIII). Genotypes of the infection isolates were compared with those of C. albicans isolated from oral mucosa of non candidiasis patients (referred to as oral isolates). Isolates of C. albicans showed 4 major genotypes for HIS3/CAI (" a " for 148 : 148 / 23 : 23," b " for 148 : 160 / 33 : 41," c " for 148 : 164 / 32 : 41 and " d " for 152 : 152 / 18 : 27). The genotypes " a "," b " and " d " were commonly found in oral (4.7, 8.8 and 7.6%, respectively) and infection (6.6, 9.2 and 15.4%, respectively) isolates. No isolates of genotype " c " were isolated from infection sites. The genotype " a " was found in the isolates from patients with genitalia candidiasis. Genotyping of multiple isolates from an individual patient showed that C. albicans from infection sites was genetically homogenous as compared with that of oral isolates, even in the same patient with candidiasis. PMID- 21788725 TI - [Analysis of 25 cases of microsporum canis infection encountered at a dermatology clinic in Kumamoto during a recent 3-year period]. AB - Twenty-five cases of dermatophytoses caused by Microsporum canis were encountered during a 3-year period (January 2008-December 2010). Their diagnosis was based on detection of fungal elements by direct microscopy and identification of M. canis by fungal culture. There were 17 women and 8 men ; they ranged in age from 4 to 85 years (mean, 34.6). The affected site was the head (n=5), face (n=8), neck (n=5), arm (n=8), leg (n=5), and trunk (n=5) ; exposed sites were those most often affected. A lone eruption was seen in 13 and multiple eruptions in 12 patients. The disease type was tinea corporis in 21 patients, tinea capitis in 5, and a combination of tinea corporis and tinea capitis in one. The disease showed familial onset in 10 patients (5 pairs), including 2 sibling pairs, 2 mother child pairs, and 1 grandmother-granddaughter pair. Twenty-four patients had a history of contact with animals, and animals kept at home may have served as the infection source (cats in 23 patients and a dog in one). Hairbrush culture of the pets was positive in 9 patients. The patients with a lone eruption were treated with topical antifungal agents, while those with multiple eruptions of tinea capitis and tinea corporis were treated with oral itraconazole or terbinafine hydrochloride for 2-14 weeks, combined with topical antifungal therapy. Although reports of dermatophytoses caused by M. canis have been decreasing, our experience indicates the necessity of considering possible transmission of this disease from pets such as cats. PMID- 21788726 TI - Therapeutic effects of cinnamaldehyde and potentiation of its efficacy in combination with methylcellulose on murine oral candidiasis. AB - We examined the therapeutic effects of cinnamaldehyde and the potentiation of those effects with cassia and cinnamaldehyde when combined with the food additive methylcellulose against murine oral candidiasis. When 19.5mg/ml of cinnamaldehyde was administered in the oral cavity of Candida infected mice, the oral symptoms were improved. Furthermore, when either a cassia or a cinnamaldehyde preparation in combination with methylcellulose was administered to oral candidiasis inflicted mice, the therapeutic effects of cassia or cinnamaldehyde potentiated. Methylcellulose itself did not affect the oral symptoms or the viable number of C. albicans cells. GC/MS analysis showed that the dose of cinnamaldehyde remaining in the tongue tissue of mice treated with the cinnamaldehyde methylcellulose mixture was higher than that in mice administered cinnamaldehyde alone, and also showed that cinnamaldehyde was not detected in the blood of any of the tested mice. These findings suggested that the combination of cassia or cinnamaldehyde and methylcellulose may be a useful prophylactic or therapeutic tool against oral candidiasis. PMID- 21788727 TI - Studies on screening, isolation and purification of a fibrinolytic protease from an isolate (VK12) of Ganoderma lucidum and evaluation of its antithrombotic activity. AB - Antithrombotic activity of a protease purified from a medicinal mushroom, Ganoderma lucidum, has been evaluated platelet aggregation in vitro and pulmonary thrombosis in vivo. The purified protease exhibited concentration dependent inhibitory effects on platelet aggregation induced by ADP (adenosine diphosphate), with an IC(50) value of 2.4 mg/mL. The purified protease protected mice against thrombotic death or paralysis induced by collagen and epinephrine in a dose dependent manner when administered orally. It produced a significant inhibition of thrombotic death or paralysis at 60 ug/kg body weight, while aspirin produced a significant inhibition of thrombosis at 10-20 mg/kg body weight. The purified protease also has showed fibrinolytic activity and alters coagulation parameters such as activated partial thromboplastin time (APTT), and thrombin time (TT) in rat platelet. These results suggested that the antithrombotic activity of Ganoderma lucidum protease might be due to antiplatelet activity rather than anticoagulation activity. PMID- 21788728 TI - PrP assemblies: spotting the responsible regions in prion propagation. AB - The "protein only" hypothesis states that the key phenomenon in prion pathogenesis is the conversion of the host protein (PrPC) into a b-sheet enriched polymeric and pathogenic conformer (PrPSc). However the region of PrP bearing the information for structural transfer is still controversial. In a recent report, we highlighted the role of the C terminal part i.e. the helixes H2 and H3, using mutation approaches on recombinant PrP. The H2H3 was shown to be the minimal region necessary to reproduce the oligomerisation pattern of the full-length protein. The oligomers produced from isolated H2H3 domain presented the same structural characteristics as the oligomers formed from the full-length PrP. Combining other groups' results, this paper further discusses the relative, direct or indirect role of different PrP regions in assembly. The H2H3 region represents the core of PrP oligomers and fibrils, whereas the N terminus could explain divergences among different aggregates. Finally this review evocates the possibility to separate the domain involved in prion information transference (i.e. prion replication) from the domain bearing the cytotoxicity properties. PMID- 21788729 TI - Targeting molecular signaling pathways of Schistosoma haemotobium infection in bladder cancer. AB - Since 1911 epidemiological evidence indicates that S. haematobium is associated with squamous cell carcinoma of the bladder. However, the mechanisms of this interaction are not clearly defined. Using normal epithelial cells, S. haematobium parasite extracts were able to induce cancer-like phenotypes such as proliferation, apoptosis, migration, invasion and tumorigenesis. The parasite extracts on normal urothelium also presented carcinogenic and mutagenic ability. To further elucidate the biological effects of this parasite, new estrogenic molecules were identified in its extracts. These estrogens are also present in the sera of Schistosoma-infected patients, and they have the ability to repress ER transcriptional activity both in estrogen-responsive MCF7 cells and normal urothelial HCV29 cells. This review will present some of the recent studies of mass spectrometry of S. haematobium extracts and sequence analysis of bladder tissue treated with the same extracts. Finally the molecular and cellular events that might be responsible for schistosomiasis-related bladder cancer will be discussed. PMID- 21788730 TI - Voriconazole pre-exposure selects for breakthrough mucormycosis in a mixed model of Aspergillus fumigatus-Rhizopus oryzae pulmonary infection. AB - Mucormycosis is an uncommon fungal infection that has been increasingly reported in severely immunocompromised patients receiving Aspergillus-active antifungals. Although clinical studies and pre-clinical animal models have suggested a unique predisposition for breakthrough mucormycoses in patients receiving voriconazole, no study has specifically evaluated the selection dynamics of various Aspergillus -active antifungal classes in vivo. We utilized an Aspergillus fumigatus:Rhizopus oryzae (10:1) model of mixed fungal pneumonia in corticosteroid-immunosuppressed mice to compare the selection dynamics of daily liposomal-amphotericin B (L-AMB), micafungin (MCFG) and voriconazole (VRC) therapy. A. fumigatus and R. oryzae lung fungal burden were serially monitored in parallel using non-cross-amplifying quantitative real-time PCR assays for each fungal genus. Additionally, experiments were performed where the R. oryzae component of the mixed inoculum was serially-passed on VRC-containing agar before animal infection. We found prior exposure to voriconazole in vitro, consistently resulted in a 1.5-2 log 10 increase in R. oryzae fungal burden by day +5 in vivo relative to animals infected with the non-VRC preexposed inoculum, irrespective of the antifungal treatment administered in mice (P <= 0.02 all treatment groups). Mice infected with the VRC-preexposed inoculum and subsequently treated with saline or VRC had the highest mortality rates (82-86%), followed by MCFG (55%) then L-AMB (39%, P = 0.04 vs. control). However, in vivo treatment alone with voriconazole alone did not consistently increase the virulence of non- voriconazole preexposed R. oryzae versus controls. We conclude that exposure of R. oryzae sporangiospores to voriconazole in vitro modulates the subsequent growth rate and/or virulence of the fungus in vivo, which reduces effectiveness of Mucorales-active antifungals. The mechanisms underlying this phenotypic change are unknown. PMID- 21788731 TI - Interplay between Y-box-binding protein 1 (YB-1) and poly(A) binding protein (PABP) in specific regulation of YB-1 mRNA translation. AB - YB-1 is a DNA- and RNA-binding protein that regulates expression of many important genes. Its deficiency or excess may pose threats, including malignant cellular transformation and metastasis, which explains the necessity of strict control over its amount at every level. As we showed previously, the 3' untranslated region (UTR) of YB-1 mRNA contains a regulatory element specifically binding to YB-1 and PABP (PABPC1). Also, we showed that YB-1 selectively inhibits YB-1 mRNA translation, while PABP stimulates it in a poly(A) tail-independent manner. It was suggested that regulation of YB-1 mRNA translation involves competition between PABP and YB-1 for binding to the regulatory element. Here we offer cogent evidence for this model and add novel details to the mechanism of regulation of YB-1 synthesis. In experiments on regulatory element deletion we showed that it is this element that is responsible for a specific effect of YB-1 and PABP on YB-1 mRNA translation. Mutations eliminating only specific YB-1 affinity for this element suppressed the inhibitory effect of YB-1 and concurrently dramatically decreased the PABP stimulating effect. Mutations reducing only specific PABP affinity for this element, as well as spatial separation of the YB-1- and PABP binding sites, did not affect the YB-1 inhibitory action but completely abolished the positive PABP effect. Together, these results unambiguously prove direct inhibitory action of YB-1 on its mRNA translation, while the positive effect of PABP is realized through displacing YB 1 from the regulatory element. PMID- 21788732 TI - Discriminating tastes: physiological contributions of the Hfq-binding small RNA Spot 42 to catabolite repression. AB - Hfq-binding small RNAs (sRNAs) are critical regulators that form limited base pairing interactions with target mRNAs in bacteria. These sRNAs have been linked to diverse environmental responses, yet little is known how Hfq-binding sRNAs participate in the regulatory networks associated with each response. We recently described how the Hfq-binding sRNA Spot 42 in Escherichia coli contributes to catabolite repression, a regulatory phenomenon that allows bacteria to consume some carbon sources over others. Spot 42 base pairs with numerous mRNAs encoding enzymes in central and secondary metabolism, redox balancing, and the uptake and consumption of non-preferred carbon sources. Many of the corresponding genes are transcriptionally activated by the Spot 42-repressor CRP, forming a regulatory circuit called a multi-output feedforward loop. We found that this loop influences both the steady-state levels and dynamics of gene regulation. In this article, we discuss how the CRP-Spot 42 feedforward loop is integrated into encompassing networks and how this loop may benefit enteric bacteria facing uncertain and changing nutrient conditions. PMID- 21788733 TI - Functional dissection of the RNA signal sequence responsible for vegetal localization of XGrip2.1 mRNA in Xenopus oocytes. AB - Grip2.1 is a conserved PDZ-domain protein with a function in the context of primordial germ cell development and migration in Xenopus embryos. Its mRNA is maternally supplied and found to be associated with the germ plasm, located at the tip of the vegetal cortex in Xenopus oocytes. Here, we demonstrate that the 3'-UTR of XGrip2.1 contains a 211 nucleotide RNA signal sequence that promotes localization to the mitochondrial cloud via the early localization pathway upon injection into stage I oocytes. The same element is also capable of using the late transport pathway if injected into stage III/IV oocytes. In vitro protein interaction studies reveal binding to ElrA/B, Vg1RBP and VgRBP60, proteins that have previously been associated with the vegetal localization machinery. Mutational interference with Vg1RBP and VgRBP60 binding severely reduces early and late localization activity. Selective interference with Vg1RBP binding significantly reduces late localization while having only a mild effect on localization to the mitochondrial cloud, indicating that the signal sequences and protein machinery required for early and late pathway localization though overlapping are not identical. PMID- 21788734 TI - Two common SNPs in pri-miR-125a alter the mature miRNA expression and associate with recurrent pregnancy loss in a Han-Chinese population. AB - Although there are plenty of evidence that single-nucleotide polymorphisms (SNPs) that fall within coding sequences of genes are involved in recurrent pregnancy loss (RPL), it is still unknown whether the polymorphisms in microRNAs (miRNAs) are related with RPL. In this study, we established this kind of association by confirming significant differences in genotype distribution of rs41275794 (P= 0.0005) and rs12976445 (P= 0.001) within the pri-miR-125a in 217 Han Chinese patients of RPL compared with 431 controls. Based on this observation, two-locus haplotypes were constructed and the A-T haplotype was found to be associated with an increased risk of RPL (OR=2.84, 95%C.I. 1.98-4.07, P=0.0000000057). Further analysis showed that the levels of pre- and mature- miR-125a were down-regulated in the cells transfected with the A-T haplotype, which was consistent with in vivo detection that the level of mature miR-125a was lower in 30 pregnant women with A-T haplotype than that with G-C haplotype. During in vitro RNA processing assays, we found a similar decrease in the amount of pre-miR-125a and decline in binding capacity of nuclear factors to pri-miR-125a with A-T haplotype. More importantly, the reduction in miR-125a, as a consequence of A-T haplotype, further led to less efficient inhibition of target genes, LIFR and ERBB2, which play important roles in the embryo implantation and decidualization. Thus, our data collectively suggest that two common polymorphisms in pre-miR-125a might contribute to the genetic predisposition to RPL by disrupting the production of miR-125a, which consequently interfered in the expression and function of target genes of miR-125a. PMID- 21788735 TI - Rare codons play a positive role in the expression of the stationary phase sigma factor RpoS (sigma(S)) in Escherichia coli. AB - Rare codons can influence the stability of messenger RNAs, promote regular spacing of ribosomes on a transcript, or modulate stability and proper folding of nascent proteins. The mRNA specifying the stationary phase master regulator RpoS, which belongs to the RpoD family of sigma factors, contains a high number of rare codons, including many codons at positions corresponding to more frequent codons encoding the same amino acids in the homologous RpoD sequence. Substituting these rare codons in rpoS by the more frequent synonymous rpoD codons resulted in decreased transcript and protein levels compared to the natural rare-codon wildtype version of rpoS. The frequent-codon mutant rpoS transcript exhibited faster turnover than the rare-codon wildtype mRNA. Studies with endoribonuclease deficient strains revealed RNase E to be crucial for this accelerated mRNA degradation. Thus, in the case of RpoS expression, "less is obviously more", as our data suggest a model, in which slowing down translational speed by ribosomal pausing at many rare codons along a transcript could reduce ribosome spacing and thereby protect the transcript against ribonucleolytic attack by RNase E. Such a mechanism may be especially important for translationally controlled genes like rpoS where the formation of secondary structure in the translational initiation region competes with (therefore relatively inefficient) ribosome loading. Moreover, strong codon differences in genes encoding isoenzymes expressed in exponential and stationary phase suggest that transcript protection by repetitive ribosome pausing at multiple rare codons in stationary phase-expressed transcripts may be a general principle to save resources under nutrient-limited conditions. PMID- 21788736 TI - Patterning of the Drosophila oocyte by a sequential translation repression program involving the d4EHP and Belle translational repressors. AB - During Drosophila development, translational control plays a crucial role in regulating gene expression, and is particularly important during pre-patterning of the maturing oocyte. A critical step in translation initiation is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the mRNA cap structure, which ultimately leads to recruitment of the ribosome. d4EHP is a translational repressor that prevents translation initiation by out-competing eIF4E on the cap structure for a subset of mRNAs. However, only two examples of mRNAs subject to d4EHP translation repression in Drosophila are known. Here we show that the belle (bel) mRNA is translationally repressed by the d4EHP protein in the Drosophila ovary. Consistent with this regulation, d4EHP overexpression in the ovary phenocopies the bel mutant. We also provide evidence that the Bel protein binds to eIF4E and may itself function as a translation repressor protein, with bruno as a potential target for Bel repression in the oocyte. Bruno is known to repress the mRNA of the key oocyte axis determinant oskar (osk) during oogenesis, and we find that an increase in the level of Bruno protein in bel mutant ovaries is associated with a reduction in Osk protein. Overall, our data suggest that a translational regulatory network exists in which consecutive translational repression events act to correctly pattern the Drosophila oocyte. PMID- 21788737 TI - The role transition of nurses in a university teaching hospital in Pakistan. AB - In a private university teaching hospital in Pakistan, a study using grounded theory design was conducted among new nursing graduates to elicit their transitional experiences from a student to a staff nurse role. Four major themes emerged highlighting the core category of "sailing forward": stepping into the new role, initial adjustment, support systems, and resolution phase. A substantive theory on role transition was the outcome. PMID- 21788738 TI - Understanding the learning needs of the charge nurse: implications for nursing staff development. AB - Charge nurses are part of the nurse manager leadership team, yet they are often appointed to their roles with minimal, if any, leadership training, education, or mentoring. Literature shows that nursing leadership affects staff retention, satisfaction, and patient outcomes. In this study, charge nurses were surveyed about their learning needs, the barriers in functioning as a charge nurse, and their view of helpful resources in performing the role of a charge nurse. Findings point to the need for staff educators to facilitate charge nurse competency through both online training and mentoring. In addition, using a transformational leadership style provides staff educators with a strong framework for ensuring nurse leadership competency. PMID- 21788740 TI - Evaluating orientation preferences of the generation Y new graduate nurse. AB - A literature review was conducted to investigate the characteristics of new graduates and hospital environments that contribute to Generation Y new nurses' susceptibility to role stress and the characteristics of orientation programs that help them successfully overcome the phenomenon. Implications include deliberate preceptor pairings, presence of an advisor/mentor, and focus on professional development. These strategies may help improve retention of the Generation Y new graduate, reduce role stress, and foster empowerment. PMID- 21788742 TI - The effect of a journal club on perceived barriers to the utilization of nursing research in a practice setting. AB - Professional accountability dictates that bedside nurses base their practice on the best available evidence from research findings. However, some staff nurses may be reluctant to read research and scholarly journals, suppressing their practice and self-development. Findings from this study suggest that perceptions of barriers to research utilization in practice may decrease through the use of unit-based journal clubs. The staff development educator can play a pivotal role in nursing practice progression by implementing journal clubs. PMID- 21788743 TI - Caring for nurses: hospital-based study groups for certification. AB - This article describes a hospital-based initiative that provides support for nurses who wish to become certified in a nursing specialty. Because certification becomes increasingly important to individual nurses and acute care organizations, opportunities to support nurses in this endeavor need to be developed. Through the efforts of the director of education and the support of nursing administration, study groups aimed toward assisting nurses to become certified have grown in number throughout this hospital. PMID- 21788744 TI - A customized, integrated approach to cultural competence education. AB - As the racial and ethnic composition of our communities become more diverse, staff educators prepare healthcare workers to recognize the need to adapt their approach to each patient based on their values, beliefs, and lifestyle and to acquire new skills to accomplish this aim. Effective curriculum for cultural competence education customizes the context of the message to align it with the mission, the philosophy, and the strategic goals of the organization and tailors the content of programs to include the specific ethnic groups most frequently encountered in the organization. This article describes a process for developing and implementing a customized, integrated approach to staff cultural competence by the diversity committee of a community hospital in New Hampshire. This approach engages individuals in readiness to learn and supports changes in behavior to promote health equity and cultural proficiency within the framework of the J. Camphina-Bacote (2005) model for cultural competence. Cultural competence education is not an event, but a process. Staff educators can be alert to the need for updated educational programs based on staff and patient outcomes and recommend systems changes that promote cultural competence and support organizational adherence to the Joint Commission standards for culturally and linguistically appropriate care. PMID- 21788745 TI - Effect of student nurse intern position on ease of transition from student nurse to registered nurse. AB - This quantitative study investigated the effect of the student nurse intern position on the ease of transition from student nurse to registered nurse. Results indicated that interns believed the program increased their confidence in performing nursing tasks and in interacting with patients and families and also created opportunities for career advancement. The study results demonstrate that internship programs for nurses can significantly contribute to the success of new graduate nurses and consequently the quality of staff development. PMID- 21788746 TI - Evaluating safety and competency at the bedside. AB - Learning about issues such as national patient safety goals, infection prevention, and documentation can be dry, even for the most enthusiastic learner. However, nurses' knowledge of this information is critical to providing safe and competent patient care. The purpose of this article is to share a fun and effective strategy used to help participants remember and employ what they learned. PMID- 21788747 TI - Peer teaching: using patient-directed information sessions as an active learning strategy. AB - Patient-directed information sessions were implemented on three inpatient surgical units as a method for education delivery. Patient-directed information sessions are brief education sessions that are influenced and planned based on current patient diagnosis, procedures, and treatments. The success of patient directed information sessions has been shown by the more than 300 sessions offered, 2,500 participants, 200 topics, and an average of 8 participants per session over a 1-year period. A patient-directed information session facilitator class was then developed to train bedside nurses to facilitate the sessions during their own shifts. The training of facilitators has provided opportunities for professional development of the staff and increased education offerings on all nursing shifts. PMID- 21788748 TI - Nursing professional development: stories, tips, and techniques. PMID- 21788749 TI - Standards of practice: our accountability. PMID- 21788750 TI - Empathy. PMID- 21788752 TI - Luminal view of an intussusception captured by capsule endoscopy. PMID- 21788754 TI - Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. AB - OBJECTIVES: Eosinophilic esophagitis (EoE) is an immune-mediated chronic inflammatory disorder triggered by food antigen(s). A 6-food elimination diet (SFED) excluding cow's milk, soy, wheat, egg, peanuts/tree nuts, and seafood has been shown to induce remission in a majority of children with EoE. The goal of the present study was to identify specific food antigens responsible for eosinophilic esophageal inflammation in children with EoE who had achieved histological remission with the SFED. PATIENTS AND METHODS: In this analysis, we retrospectively analyzed children with EoE who completed subsequent single-food reintroductions that led to identification of foods causing disease recurrence. Repeat upper endoscopy with biopsies was performed after single-food introductions. Recurrence of esophageal eosinophilia following a food reintroduction identified that food antigen as a cause of EoE. RESULTS: A total of 36/46 (25 M/11F) children who were initially successfully treated with SFED completed this trial; the mean age was 7.6 +/- 4.3 years. The most common foods identified were 25 to cow's milk (74%), 8 to wheat (26%), 4 to eggs (17%), 3 to soy (10%), and 1 to peanut (6%). Milk was 8 times more likely to cause EoE compared with wheat, the next most common food (95% confidence interval 2.41 26.62, P = 0.0007). CONCLUSIONS: Serial single-food reintroductions following induction of histological remission with the SFED can lead to the identification of specific causal food antigen(s) in EoE. Cow's milk was the most common food identified in subjects with EoE treated with SFED. A subset of children with EoE may develop tolerance to their food sensitivities while on the SFED. PMID- 21788753 TI - Epidemiology of inflammatory bowel disease: Is there a shift towards onset at a younger age? AB - OBJECTIVES: Increasing numbers of paediatric and adolescent patients with Crohn disease (CD) and ulcerative colitis (UC) are reported. To determine whether this observation is a consequence of a shift towards onset at a younger age, we analysed retrospective data from patients enrolled in the Swiss IBD Cohort Study (SIBDCS). PATIENTS AND METHODS: The SIBDCS is a disease-based cohort in Switzerland, which collects retrospective and prospective data on a large sample of patients with inflammatory bowel disease (IBD). Patients, diagnosed from 1980, were stratified according to diagnosis of CD and UC. Age at disease onset (age at first symptoms and age at diagnosis) was analysed in relation to calendar year of disease onset. Data were extracted from physician and patient questionnaires. Linear regressions of age at disease onset by calendar year of disease onset adjusted by sex, country of birth, and education were performed. RESULTS: Adjusted regression coefficients for CD and UC were significantly positive, that is, age at disease onset has increased with time. Male sex was associated with an increase in age at disease onset, and birth in Switzerland with a decrease. These associations were statistically significant. CONCLUSIONS: The results from the SIBDCS do not support the hypothesis that disease onset of both CD and UC occur today at a younger age. On the contrary, our results show that there is a significant trend for age at disease onset occurring at an older age today as compared with recent decades. We conclude that the observation of increasing numbers of paediatric and adolescent patients with IBD is not caused by a trend towards disease onset at a younger age, but that this may rather be a consequence of the overall increasing incidence of these conditions. PMID- 21788755 TI - Serum concentrations of VEGF and TGF-beta1 during exclusive enteral nutrition in IBD. AB - BACKGROUND AND AIM: Exclusive enteral nutrition (EEN) is an effective method of treatment in achieving remission in inflammatory bowel disease (IBD); however, its mechanism of action is still poorly understood. The objective of our study was to assess the influence of EEN on serum vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-beta1) in children and adolescents with IBD. PATIENTS AND METHODS: Thirty-nine children and adolescents with IBD (24 with Crohn disease [CD] and 15 with ulcerative colitis [UC]) and 25 healthy controls were enrolled in the study. VEGF and TGF-beta1 were assessed at the baseline and after 2 and 4 weeks of EEN in CD and UC groups and once in controls using enzyme-linked immunosorbent assay immunoassays. RESULTS: At the baseline, we found increased serum VEGF in the CD versus UC group and controls (P < 0.05) and serum TGF-beta1 in the UC versus CD group and controls (P < 0.05). During EEN, VEGF decreased in the UC and CD groups, whereas TGF-beta1 increased in the CD group and decreased in the UC group. The CD group achieved disease remission faster than the UC group, and the weight gain of patients with CD during EEN was higher compared with patients with UC. Additionally, TGF-beta1 concentration correlated with protein and energies daily intake in the CD group (R = 0.95; P < 0.05). CONCLUSIONS: Different effectiveness of EEN in achieving remission in CD and UC may result from a modification of growth factor production. EEN stimulated TGF-beta1 production in CD but not in UC, which possibly resulted in higher effectiveness of EEN in this group of patients. PMID- 21788756 TI - Metoclopramide versus ondansetron for the treatment of vomiting in children with acute gastroenteritis. AB - OBJECTIVE: To compare the efficacy and safety of ondansetron versus less expensive metoclopramide in the treatment of children with persistent vomiting with acute gastroenteritis. MATERIALS AND METHODS: A double-blind trial including consecutive consented patients ages 1 to 14 years was conducted in an urban infirmary setting from June 2008 through December 2008. Children were randomized to receive a single dose of intravenous ondansetron or metoclopramide. The primary efficacy outcome was the proportion of patients with cessation of vomiting shortly after completion of the study medication infusion in each group. Observed adverse effects and diarrhea frequency during admission and in follow-up were recorded to assess safety. RESULTS: One hundred sixty-seven previously healthy children (median age 3 years) diagnosed as having acute gastroenteritis with persistent vomiting completed treatment and observation. Cessation of vomiting was achieved in 68/84 patients (81%) of the ondansetron and 60/83 (72%) of the metoclopramide groups, P = 0.14. Mean time to complete cessation of vomiting was 39 minutes (SD 111) for ondansetron, and 61 minutes (SD 110) for metoclopramide, P = 0.2. The mean length of infirmary stay was 550 minutes (SD 427) for ondansetron and 575 minutes (SD 449) for metoclopramide, P = 0.71. Revisit rate, readmissions rate, and frequency of diarrhea after discharge were similar in the 2 treatment groups. No adverse reaction or other safety concerns were identified. CONCLUSIONS: In the sample size tested, intravenous metoclopramide therapy did not differ from ondansetron in the treatment of persistent vomiting for children with gastroenteritis admitted for intravenous fluid hydration. PMID- 21788758 TI - Prevalence and associated factors of functional gastrointestinal disorders and bowel habits in Chinese adolescents: a school-based study. AB - OBJECTIVES: In the present study, we explored the prevalence rates and association factors of functional gastrointestinal disorders and the most common modes and frequencies of bowel habit among a cohort of Chinese adolescents. PATIENTS AND METHODS: A stratified, randomized study based on cross-sectional data was performed using cluster sampling, which recruited 3671 students in Shanghai, China. All of the students were requested to complete a questionnaire. RESULTS: Overall, 88.05% +/- 0.28% of students had a bowel movement frequency of between 1 of 2 times per day and once every 2 days. Female students were found to have a lower bowel frequency than boys (P < 0.01). The prevalence of irritable bowel syndrome (IBS), functional constipation, and functional diarrhea were 19.89%, 24.93%, and 5.42%, respectively. Certain factors adjusted for age and sex were significantly associated with IBS (P < 0.05), including gastrointestinal tract infection (odds ratio [OR] 2.26), abuse of analgesics (OR 1.25), air swallowing to terminate hiccups (OR 1.28), fatigue (OR 1.15), and depression (OR 1.36). Other factors that were adjusted for age and sex, such as fried food (OR 1.68), air swallowing to terminate hiccups (OR 1.21), anxiety (OR 1.12), and depression (OR 1.57), were significantly associated with the presence of functional constipation (P < 0.05). CONCLUSION: : Our findings suggest that normal bowel frequency among Chinese urban adolescents may be defined as between 1 or 2 bowel movements per day and once every 2 days. IBS, functional constipation, and diarrhea are common disorders among this adolescent group. PMID- 21788757 TI - ORS containing zinc does not reduce duration or stool volume of acute diarrhea in hospitalized children. AB - BACKGROUND AND AIM: The World Health Organization recommends oral zinc (tablets or syrups) as adjunct therapy with oral rehydration solution (ORS) for acute childhood diarrhea. Mixing zinc with ORS can be an attractive approach for simultaneous provision of these 2 effective interventions. This double-masked randomized controlled trial evaluated the efficacy of ORS containing 40 mg/L elemental zinc per liter (zinc-ORS) in reducing stool weight and duration of diarrhea. PATIENTS AND METHODS: Five hundred northern Indian children ages 1 to 35 months with diarrhea <7 days' duration were randomized to zinc-ORS or ORS. The primary outcomes were total stool output and time to recovery. RESULTS: The median total stool output was 2.12 g . kg-1 . h-1 (interquartile range [IQR] 0.9 3.76) in the zinc-ORS group compared with 1.78 g . kg-1 . h-1 (IQR 0.83-3.45) in the ORS group. The time to recovery was also similar in the 2 groups (hazard ratio 1.06 [95% confidence interval 0.88-1.27]). In subjects who received zinc ORS, the median (IQR) zinc intakes were 27 (16-46) mg on day 1, 15 (6-27) mg on day 2, and negligible thereafter. CONCLUSIONS: The World Health Organization recommended daily dose of zinc for diarrhea was not achieved in most children beyond the first day of treatment. This is the likely explanation for the lack of improvement in outcomes from zinc-ORS when compared with ORS alone. Our findings do not support a change from using zinc syrup or dispersible tablets for treatment of acute diarrhea in children. PMID- 21788759 TI - Tolerance, safety, and effect on the faecal microbiota of an enteral formula supplemented with pre- and probiotics in critically ill children. AB - OBJECTIVES: The aim of this study was to demonstrate the tolerance and safety of an enteral formula containing prebiotics/probiotics, and its effect on the faecal microbiota in critically ill children. SUBJECTS AND METHODS: Ninety-four patients between 1 and 3 years old under mechanical ventilation requiring enteral feeding were randomised to receive either a test formula containing a synbiotic blend (composed of 2 probiotic strains [Lactobacillus paracasei NCC 2461 and Bifidobacterium longum NCC 3001], fructooligosaccharides [FOS], inulin, and Acacia gum), or a control formula. Patients remained in the intensive care unit for 7 days and were examined at day 14. Tolerance was assessed by overall caloric intake and time to reach caloric goal. Safety was assessed by abdominal distention, vomiting, and stool frequency. Microbiota was analysed by culture- and molecular-based methods. RESULTS: Overall caloric intake and time to reach caloric goal were similar between groups (noninferiority was shown). Abdominal distention, vomiting, and stool frequency were not affected by the supplementation with pre- and probiotics. Faecal bifidobacteria were higher in the test group at the end of the study. A similar trend was observed for total lactobacilli. L paracasei NCC 2461 and B longum NCC 3001 were detected in 80.4% and 17% of the test group patients, respectively. Enterobacteria levels remained unchanged during hospitalisation in the control group but diminished in the test group. CONCLUSIONS: The enteral formula supplemented with synbiotics was well tolerated by children in intensive care units; it was safe and produced an increase in faecal bacterial groups of previously reported beneficial effects. PMID- 21788760 TI - Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. AB - BACKGROUND: The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established. PATIENTS AND METHODS: The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months. RESULTS: Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 U/L, alanine aminotransferase 727 U/L, alkaline phosphatase 331 U/L, and total bilirubin 3.9 mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury. CONCLUSIONS: Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen. PMID- 21788761 TI - Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD. AB - BACKGROUND AND AIMS: The diagnostic accuracy of hepatic ultrasonography (US) for detection and grading of hepatic steatosis in children with suspected nonalcoholic fatty liver disease (NAFLD) remains poorly characterized. The aim of this study was to prospectively evaluate the clinical utility of ultrasonographic quantification of hepatic steatosis. PATIENTS AND METHODS: Our cohort consisted of 208 consecutive pediatric patients with biopsy-proven NAFLD. Hepatic US was performed within 1 month of the liver biopsy procedure. Steatosis identified by US was scored using a 0 to 3 scale based on echogenicity and visualization of vasculature, parenchyma, and diaphragm, and compared to histological features based on Brunt's classification. RESULTS: The median age at time of first visit was 10.8 years and 64% were boys. Sixty-nine percent had moderate to severe steatosis on histology. Ultrasonographic steatosis score (USS) had an excellent correlation with histological grade of steatosis (with a Spearman's coefficient of 0.80). The area under the receiver operating characteristic curve for ultrasonographic detection of moderate-to-severe steatosis was 0.87. The USS did not correlate significantly with inflammatory activity or fibrosis stage; however, there was significant correlation with the NAFLD activity score (NAS), albeit this was in large part the result of the strong correlation with the steatosis component of NAS. Serum alanine transaminase and aspartate transaminase were not associated with histological grade of steatosis and showed no correlation with USS. CONCLUSIONS: Our results, which represent the largest prospective pediatric study evaluating the role of hepatic US in children with biopsy-proven NAFLD, demonstrate the utility of this technique for noninvasive diagnosis and estimation of hepatic steatosis in children. PMID- 21788762 TI - Factors associated with hepatic steatosis in obese children and adolescents. AB - OBJECTIVES: Obesity is associated with high prevalence of hepatic steatosis. We speculate that determinant factors of susceptibility to hepatic steatosis in obesity could differ between children and adolescents. PATIENTS AND METHODS: Blood biochemical parameters, systemic oxidative stress markers, proinflammatory cytokines, and adipokine levels were determined in 157 obese children and adolescents. The subjects were divided into 2 groups: children and adolescents, identified as such in accordance with Tanner stage and the measured level of dehydroepiandrosterone sulphate. Steatosis was evaluated by ultrasonography in 127 subjects. RESULTS: Steatosis prevalence was 44.8%. In the "children" group, those with hepatic steatosis presented higher levels of erythrocyte oxidised glutathione (GSSG) and resistin, lower levels of high-density lipoprotein (HDL) cholesterol, and lower enzymatic activities of erythrocyte glutathione reductase (GRd) and glutathione oxidase (GPx). In the "adolescents" group, those with hepatic steatosis presented higher values for body mass index z score (BMIz), insulin, peptide C, homeostatic model assessment index (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, GSSG, and leptin. These subjects also presented lower values for soluble leptin receptor, GRd, and GPx. In the "children" group, the only independent factor of steatosis was a decrease in GRd activity (odds ratio [OR] 0.165, 95% CI 0.03 0.84, P = 0.030). Moreover, in the "adolescent" group, the independent factors were higher for GSSG (OR 6.8, 95% CI 1.6-28.7, P = 0.010) and HOMA-IR (OR 1.9, 95% CI 1.17-3.1, P = 0.009). CONCLUSIONS: Factors associated with hepatic steatosis differ between obese children and adolescents. Oxidative stress is seen to be the main process in children, whereas in adolescents oxidative stress and insulin resistance are significant factors for steatosis. PMID- 21788763 TI - Safety of pediatric percutaneous liver biopsy performed by interventional radiologists. AB - OBJECTIVE: National data suggest that pediatric percutaneous liver biopsy is increasingly being performed by interventional radiologists rather than pediatric gastroenterologists. The objective of the present report is to describe the safety and effectiveness of percutaneous liver biopsy performed by interventional radiologists in a large cohort of children and to compare the results with the existing literature on biopsies performed by pediatric gastroenterologists. PATIENTS AND METHODS: The medical records of 249 children undergoing ultrasound guided percutaneous liver biopsy by interventional radiologists were reviewed for adverse events and success of obtaining tissue. Two hundred ninety-four biopsies were reviewed. RESULTS: There were no deaths. There were 2 instances of a 2-g or greater drop in hemoglobin following biopsy, neither of which was associated with clinical signs of hemorrhage. A small, asymptomatic pneumothorax quickly resolved without treatment. One patient developed Klebsiella sepsis 48 hours after biopsy. In all but 1 case, an adequate sample size was obtained. This low incidence of adverse events compares favorably with existing published reports of morbidity and mortality following percutaneous liver biopsy performed by pediatric gastroenterologists. CONCLUSIONS: Ultrasound-guided percutaneous liver biopsy performed by experienced pediatric interventional radiologists in a children's hospital setting is as safe and effective as biopsy performed by pediatric gastroenterologists. PMID- 21788765 TI - Impact of Crohn disease on eosinophilic esophagitis: evidence for an altered T(H)1-T(H)2 immune response. PMID- 21788764 TI - French mothers' milk deficient in DHA contains phospholipid species of potential interest for infant development. AB - OBJECTIVES: An insufficient human milk docosahexaenoic acid (DHA) level was reported worldwide, which leads to the question of the sufficiency of the DHA supply for infant development in the French Mediterranean area. Also, among milk lipids, phospholipids may be of high potential interest for infant brain development, being a specific vector of DHA and providing plasmalogens. We aimed to estimate the consumption of such milk compounds by preterm and term infants. MATERIALS AND METHODS: Milk samples from 22 lactating French women living in a port city, Marseille, were collected in a neonatology department from a single full-breast expression using an electric pump. Amounts of triglycerides, total phospholipids and plasmalogens, and fatty acid profile were determined by gas chromatography, and cholesterol by enzymatic assay. RESULTS: Depending on the infant dietary guidelines we referred to, 46% or 82% of milk samples were below the recommended DHA level (0.4% or 0.7%), and a majority exhibited high linoleic acid/alpha-linolenic acid and n-6/n-3 ratios, probably resulting from high linoleic acid together with low fish and seafood products consumption. DHA carried by phospholipids in a majority of specimens met the requirements for brain development for term but not for premature infants. Milk plasmalogen levels ranged from 3.4 to 39.2 mg/L. CONCLUSIONS: Our results support the recommendation of DHA supplementation to French mothers living in a Mediterranean port city, and of decreased linoleic acid intake, to reach optimal milk composition for infant health. DHA-containing phospholipids including plasmalogen species may represent important bioactive human milk compounds. PMID- 21788766 TI - A child with refractory coeliac disease. PMID- 21788767 TI - Clonidine in cyclic vomiting. PMID- 21788768 TI - Gastric mucosal damage from ingestion of 3 button cell batteries. PMID- 21788769 TI - Neostigmine in the treatment of refractory constipation in critically ill children. AB - Constipation is a common complication in critically ill children and it is occasionally resistant to the drugs typically used in treatment. Neostigmine has been used in some cases of refractory constipation in critically ill adults. There is no reference to its use in critically ill children. We describe 3 cases of refractory constipation in critically ill children treated with intravenous neostigmine by continuous infusion. Two patients responded well. There were no adverse effects. We conclude that continuous intravenous neostigmine can be effective in critically ill children with refractory constipation. Further studies are necessary to determine the dose and safety of the treatment. PMID- 21788770 TI - Summary of "Growth and nutritional status in pediatric Crohn's disease" with a focus on sex differences in statural growth impairment. PMID- 21788771 TI - Transient hypertransaminasemia in pediatric patients with Crohn disease. PMID- 21788772 TI - Reliability of a survey tool for measuring consumer nutrition environment in urban food stores. AB - OBJECTIVE: Despite the increase in the volume and importance of food environment research, there is a general lack of reliable measurement tools. This study presents the development and reliability assessment of a tool for measuring consumer nutrition environment in urban food stores. DESIGN: Cross-sectional design. SETTING: A racially diverse downtown portion (6 ZIP code areas) in Albany, New York. PARTICIPANTS: A sample of 39 food stores was visited by our research team in 2009 to 2010. These stores were randomly selected from 123 eligible food stores identified through multiple government lists and ground truthing. MAIN OUTCOME MEASURES: The Food Retail Outlet Survey Tool was developed to assess the presence of selected food and nonfood items, placement, milk prices, physical characteristics of the store, policy implementation, and advertisements on outside windows. For in-store items, agreement of observations between experienced and lightly trained surveyors was assessed. For window advertisement assessments, inter-method agreement (on-site sketch vs digital photo), and inter-rater agreement (both on-site) among lightly trained surveyors were evaluated. Percent agreement, Kappa, and prevalence-adjusted bias-adjusted kappa were calculated for in-store observations. Interclass correlation coefficients were calculated for window observations. RESULTS: Twenty-seven of the 47 in-store items had 100% agreement. The prevalence-adjusted bias-adjusted kappa indicated excellent agreement (>=0.90) on all items, except aisle width (0.74) and dark-green/orange colored fresh vegetables (0.85). The store type (nonconvenience store), the order of visits (first half), and the time to complete survey (>10 minutes) were associated with lower reliability in these 2 items. Both the inter-method and inter-rater agreements for window advertisements were uniformly high (intraclass correlation coefficient ranged 0.94-1.00), indicating high reliability. CONCLUSIONS: The Food Retail Outlet Survey Tool is a reliable tool for quickly measuring consumer nutrition environment. It can be effectively used by an individual who attended a 30-minute group briefing and practiced with 3 to 4 stores. PMID- 21788774 TI - The relationship of eco-friendly attitudes with walking and biking to work. AB - Active commuting (AC) to work is an effective strategy for integrating regular physical activity (PA) into daily life routines, but limited research exists on influences of AC among adults. Current trends and interests toward environmental consciousness and sustainable forms of travel could impact transportation-related PA. OBJECTIVE: The purpose of this study was to examine the association between eco-friendly attitudes (EFA) and several variables related to AC. DESIGN: A cross sectional study of respondents to an online survey. PARTICIPANTS: Employed adults, physically able to walk or bicycle. MAIN OUTCOME MEASURES: The survey included questions about EFA, AC patterns, motivators and barriers for AC, and demographics. Eco-friendly attitudes were measured using a 9-item scale (eg, "I subscribe to ecological publications"). Participants were divided into quartiles on the basis of their EFA summary score (higher score = more ecologically friendly), and t tests and analyses of variance were used to make comparisons across groups on several variables related to AC. RESULTS: The sample (n = 375) was primarily young to middle-aged adults (mean age 39.4 +/- 12.9 years), female (60.7%), and Caucasian (90.3%), with at least a high school education (94.6% with high school diploma or greater). Participants reported actively commuting an average of 2.4 +/- 4.5 times per week and driving on average 8.4 +/- 3.8 times per week. The mean EFA score was 33.4 +/- 12.1 out of 63. Age was negatively related and education was positively related to EFA. Compared with those in the lower 3 quartiles, individuals in the top quartile of EFA scores were more likely to actively commute and less likely to drive and reported more self-efficacy, fewer barriers, and more motivators for AC. CONCLUSIONS: This study provides insight into potential influences on AC and possible strategies for intervention. Future studies should continue to investigate ecological attitudes as a possible moderator of AC behavior. Public health-based interventions to promote AC may use ecology-themed messages for greater reach and impact. PMID- 21788773 TI - Process evaluation of community care centers providing care, support, and treatment to people living with human immunodeficiency virus in India. AB - CONTEXT: Since 2007, the concept of community care centers (CCC) has evolved to provide care, support, and treatment services to the people living with human immunodeficiency virus in a community-based environment so as to bridge the gap between secondary/tertiary level institutional and home-based care. Monitoring and evaluation, including process evaluation (PE), are integral parts of this scheme. OBJECTIVE: This article presents the design of the "PE" for CCC and the results pertaining to the gaps and constraints in the implementation of the scheme. DESIGN: The CCC PE was conducted in 197 of the 273 CCCs that have been functioning for at least 1 year as on November 30, 2009. Data were collected by structured observations and individual interviews through checklists and semistructured tools. PARTICIPANTS: The targeted population for PE was inpatient/outpatient beneficiaries, caregivers, and service providers of CCCs. RESULTS: The findings revealed that of 197 CCCs evaluated, 55, 57, 52, and 33 were graded as A, B, C, and D, respectively. Of the 33 grade-D CCCs, 22 were from 4 high-prevalence states (Andhra Pradesh, Karnataka, Maharashtra, and Tamil Nadu). There was dearth of good nongovernment organizations in the Northeastern region of the country with more nongovernment organizations in C and D category. The PE indicated some critical constraints in the services, such as shortage of medicines for treatment of opportunistic infections, poor coordination with anti retroviral treatment centers, and transportation for referral cases. In spite of various constraints in the scheme, the majority of the patients were satisfied with the services available at CCC. CONCLUSION: The PE had provided an invaluable base to improve the CCC scheme, which will enhance the quality of service delivery system. The results of our experience may help other researchers and managers plan similar and more improved assessment. PMID- 21788775 TI - Measuring the health of communities--how and why? PMID- 21788776 TI - Health ranking of the largest US counties using the Community Health Status Indicators peer strata and database. AB - OBJECTIVE: Using the structure of the Community Health Status Indicators (CHSI) report, we embarked on analysis of population health data with the aim to validate the CHSI modules as overarching themes and to rank county health within peer strata. DESIGN, SETTING, PARTICIPANTS: Ranking was conducted for the largest (>100 000), nonfrontier counties (county aggregates) (N = 508) in the United States for many aspects of population health. Factor analysis was used to assess CHSI modularity and analyses of variance confirmed peer strata homogeneity. MAIN OUTCOME MEASURES: Ten factors were identified. They were life stage, injury, cancer, adult behaviors, preventive services, environment-food, and health care access. Because they did not contribute to a factor, 4 CHSI summary health measures (all-cause mortality, average life expectancy, health status, and unhealthy days) were also ranked. RESULTS: No single factor emerged as reflecting overall county health. CONCLUSIONS: Further summary of county health will be challenging. We present the ranks for CHSI peer strata #1, local jurisdictions of 1 million or greater population. County factor content and data availability may differ when counties of smaller size are considered. Ranking may be utilized by community leaders for community health assessment and local priority setting, and ultimately incorporated into CHSI Web-based reports. PMID- 21788777 TI - State responses to America's Health Rankings: the search for meaning, utility, and value. AB - CONTEXT: America's Health Rankings (AHR) is a state-level ranking of health determinants and outcomes produced annually by the United Health Foundation. OBJECTIVE: The purpose of this study was to determine how states-particularly state health departments (SHDs)-respond to the annual AHR report. DESIGN: This study utilized a mixed methods approach involving key informant (KI) interviews in selected SHDs and a survey of the 50 state health officials (SHOs). SETTING: Key informants were interviewed at SHD offices in 9 states. The survey was conducted using an online format. PARTICIPANTS: Key informants included the SHO, senior staff in the SHD, and public health partners outside the SHD organization. Survey respondents were the SHO or designee.' MAIN OUTCOME MEASURES: Awareness, use, utility, and value of AHR. RESULTS: Between the interviews and online survey, respondents from at least 40 of the 50 states indicated they were aware of AHR. Fifty-three interview sessions were conducted with 66 different KIs. Of the 37 states providing usable survey information, 20 (54%) reported that AHR was moderately, very, or extremely useful to their agency. Survey respondents indicated that the most common uses of AHR are for problem identification (54%), a source of data (49%), and for grant applications (38%). Regarding overall value of AHR to states, on a scale from 1 to 10, with 1 being no value to 10 being highly valuable, the mean score from survey respondents was 4.7. CONCLUSION: Although there is a wide spectrum of knowledge about AHR and responses to the annual report, the majority of SHDs respond in more positive than negative ways. Although the majority of SHOs are aware of AHR, there is less understanding of the methodology in the rankings at the programmatic level. The strongest call for change related to making the report more actionable, especially by identifying best practices. PMID- 21788778 TI - Estimating the financial resources needed for local public health departments in Minnesota: a multimethod approach. AB - OBJECTIVE: This study presents a model for determining total funding needed for individual local health departments. The aim is to determine the financial resources needed to provide services for statewide local public health departments in Minnesota based on a gaps analysis done to estimate the funding needs. DESIGN: We used a multimethod analysis consisting of 3 approaches to estimate gaps in local public health funding consisting of (1) interviews of selected local public health leaders, (2) a Delphi panel, and (3) a Nominal Group Technique. On the basis of these 3 approaches, a consensus estimate of funding gaps was generated for statewide projections. SETTING: The study includes an analysis of cost, performance, and outcomes from 2005 to 2007 for all 87 local governmental health departments in Minnesota. PARTICIPANTS: For each of the methods, we selected a panel to represent a profile of Minnesota health departments. MAIN OUTCOME MEASURES: The 2 main outcome measures were local-level gaps in financial resources and total resources needed to provide public health services at the local level. RESULTS: The total public health expenditure in Minnesota for local governmental public health departments was $302 million in 2007 ($58.92 per person). The consensus estimate of the financial gaps in local public health departments indicates that an additional $32.5 million (a 10.7% increase or $6.32 per person) is needed to adequately serve public health needs in the local communities. CONCLUSIONS: It is possible to make informed estimates of funding gaps for public health activities on the basis of a combination of quantitative methods. There is a wide variation in public health expenditure at the local levels, and methods are needed to establish minimum baseline expenditure levels to adequately treat a population. The gaps analysis can be used by stakeholders to inform policy makers of the need for improved funding of the public health system. PMID- 21788779 TI - Missed opportunities for tuberculosis prevention in New York City, 2003. AB - BACKGROUND: Proper management and prevention can radically decrease the incidence of tuberculosis (TB). To further decrease TB cases in New York City, every opportunity for prevention must be utilized. This study sought to identify patients whose disease could have been prevented and describe missed opportunities for TB prevention. METHODS: Patients diagnosed with TB from April to July, 2003 were identified using the New York City TB registry. Surveillance data, medical records, and patient interviews were used to determine whether patients missed a prevention opportunity or potential for screening. Preventable TB was defined as inappropriate screening of contacts and immigrants, inappropriate treatment of persons with prior TB diagnoses, or those who tested positive for latent TB infection (LTBI) as contacts, immigration, or in community settings. Potentially preventable TB was defined as occurring when those eligible for LTBI screening in community settings were not screened more than 1 year before TB diagnosis. Patients classified as having preventable or potentially preventable TB were grouped as patients with missed opportunities. We calculated the odds of missing a prevention opportunity using logistic regression. RESULTS: Among the 218 study patients, 22% had preventable TB and 35% had potentially preventable TB. The most common missed opportunity among patients with preventable TB was the failure to initiate LTBI treatment. Birth outside of the United States was not associated with missing a prevention opportunity (odds ratio [OR] = 1.31, confidence interval [CI] = 0.71-2.39); however, extended travel outside of the United States increased the odds (OR = 2.51, CI = 1.19 5.69), particularly among non-US-born patients (OR = 3.01, CI = 1.21-8.59). Missed screening opportunities related to pregnancy, employment, or school attendance were encountered by over half of the study patients. CONCLUSIONS: The majority of New York City TB patients in our cohort experienced at least 1 missed opportunity for prevention. Further study is warranted to determine whether LTBI treatment eligibility should be extended to those who travel for extended periods, particularly among the non-US-born patients. PMID- 21788780 TI - The National Tuberculosis Surveillance System training program to ensure accuracy of tuberculosis data. AB - OBJECTIVES: The Centers for Disease Control and Prevention implemented a national training program for health care workers and surveillance staff to ensure accuracy of data reported to the Centers for Disease Control and Prevention's National Tuberculosis Surveillance System and increase training capacity in tuberculosis surveillance. METHODS: To address the changing epidemiology of tuberculosis and related reporting requirements, a working group of tuberculosis experts revised the Report of Verified Case of Tuberculosis (RVCT), the National Tuberculosis Surveillance System data collection form. The revision prompted a need for training in accurately completing the form. A Centers for Disease Control and Prevention interdisciplinary training team collaborated with key partners in assessing health care worker training needs regarding the RVCT. The team conducted 5 field tests to ensure instructional effectiveness of the training materials. Participants worked through materials, shared experiences, asked questions, and stated concerns about the RVCT. On the basis of these inputs, the team developed an innovative and comprehensive training program. RESULTS: The training materials included instructions for completing each item on the RVCT form, case studies to enable participants to apply the instructions to real-life situations, and visual aids to enhance learning. In both quantitative and qualitative responses, participants indicated that the RVCT training course and self-study materials helped them gain the knowledge needed to accurately complete the RVCT. The team conducted 14 facilitator-led courses and trained 343 health care workers and surveillance staff; 82 of these were training-of-trainers participants. CONCLUSIONS: Collaboration and innovation are essential in implementing an effective national surveillance-training program to ensure the accurate collection and reporting of tuberculosis surveillance data. PMID- 21788781 TI - Community knowledge, risk perception, and preparedness for the 2009 influenza A/H1N1 pandemic. AB - OBJECTIVE: To examine public knowledge, perceptions, and preparedness for the 2009 influenza A/H1N1 pandemic. DESIGN: We conducted a telephone survey of selected households in Arizona during the month of October 2009. RESULTS: Among the 727 households interviewed, one-third (34%) were not aware that the terms swine flu and H1N1 refer to the same virus. Many believed that it is more difficult to contract 2009 H1N1 (27%) than seasonal influenza (14%). About three quarters of respondents perceived the H1N1 situation as urgent (76%), but only about one-third of those surveyed believed a family member would get sick with H1N1 within a year (35%). Approximately half (53%) of those surveyed intended to get the H1N1 influenza vaccine. Family doctors, television news, and local public health officials were the most trusted sources for H1N1 information. CONCLUSIONS: The survey highlighted a number of important misconceptions about H1N1 knowledge, treatment options and transmissibility. Increased efforts should be made to understand how messages are transmitted and received in the community during a pandemic to improve risk communication plans moving forward. PMID- 21788782 TI - Extending the reach: local health department collaboration with community pharmacies in Palm Beach County, Florida for H1N1 influenza pandemic response. AB - OBJECTIVE: Palm Beach County Health Department (PBCHD) in Florida collaborated with pharmacists, community pharmacies, and pharmacy-based retail health clinics to increase access to influenza prevention through a widespread H1N1 influenza vaccination campaign and to disseminate timely and accurate public health recommendations and information using Flu Ready Cards. Selected pharmacy and store managers were surveyed, before and after distribution of H1N1 vaccine regarding issues facing pharmacists and the public in deciding whether or not to recommend or accept influenza vaccinations. PARTICIPANTS: Palm Beach County Health Department collaborated with Walgreens and CVS pharmacies, Publix and Winn Dixie Super Market Pharmacies, and the Palm Beach County Pharmacy Association. OUTCOMES: More than 200000 Flu Ready Cards were distributed in 250 pharmacies between September 2009 and March 2010 as part the county-wide H1N1 influenza pandemic response. Approximately 40000 doses of H1N1 vaccine (12% of the PBCHD allocation) were shipped to local pharmacies and retail health clinics to immunize individuals and families, including those most at risk, vulnerable, or without a medical home. Eighty percent of surveyed store managers and 52% of pharmacists reported the Flu Ready Cards were useful and more than 60% of both groups felt partnership with the local health department was useful during the H1N1 pandemic. CONCLUSIONS: The collaborative relationship proved invaluable for distributing, transferring, and administering the H1N1 influenza vaccine, managing access to antivirals, and serving as a vital link to hospitals and other healthcare providers. Pharmacists can be an integral part of the nation's "first line resource" for health and wellness and can extend the reach for public health initiatives. The public-private collaboration between health departments and community pharmacists could improve individual and family readiness, increase access to trained and trusted professionals and strengthen overall preparedness and community resilience. PMID- 21788783 TI - Development and utilization of best practice operational guidelines for immunization information systems. AB - OBJECTIVE: To describe collaborative efforts to develop best practice operational guidelines for immunization information systems (IIS) and discuss awareness, acceptance, and utilization of the guidelines by the IIS community. DESIGN: Business analysis and facilitation techniques were used to support collaboration among IIS stakeholders who analyzed existing practices, brainstormed new approaches, and developed consensus-based recommendations. The guideline development process and its impact on IIS were evaluated using a postworkshop questionnaire, the IIS Annual Report, and an online survey for one of the guidelines. SETTING: Immunization information systems domain in the United States. PARTICIPANTS: Staff from IIS; federal agencies; state, regional, and county health departments; privately run registries; and vendors/consultants. MAIN OUTCOME MEASURE(S): These included (1) completion of best practice guidelines; (2) degree of satisfaction among the participating IIS stakeholders with the work process and outcomes, interest, and willingness to implement best practice guidelines in their own IIS; (3) awareness and use of, as well as satisfaction with, the guidelines for patient active/inactive immunization status among IIS; and (4) acceptance and implementation of best practice guidelines across the US IIS. RESULTS: Since 2005, operational guidelines (that contain best practice recommendations) have been developed for 5 IIS functional areas: reminder/recall notifications, data quality assurance, vaccination level deduplication, management of patient active/inactive status, and adverse events reporting. Immunization information systems stakeholders who participated in the development of the recommendations expressed a high level of satisfaction with the process and the recommendations. Based on IIS Annual Report data, from 2007 to 2009 use of the guidelines increased from 46% to 80% of IIS. CONCLUSIONS: Best practice recommendations offer practical guidelines on the most challenging operational areas for IIS. Initial evidence indicates adoption of the recommendations and satisfaction with the development process. Additional studies are needed to assess the degree of guidelines use across the IIS community. PMID- 21788784 TI - The San Francisco Community Vital Signs: using web-based tools to facilitate the mobilizing for action through planning and partnerships process. AB - A coalition of local public health system stakeholders in San Francisco developed a community assessment and strategic planning tool, the San Francisco Community Vital Signs (SFCVS). The SFCVS builds on the Mobilizing for Action through Planning and Partnerships (MAPP) model by incorporating Internet-based technology into local public health system evaluation and strengthening. This article describes the overlap between the SFCVS and MAPP processes, the manner in which information technology facilitated the SFCVS process, and a template for infusing a Web-based platform into the MAPP model. Internet-based applications helped to implement many (16 of 41; 39%) of the components of the SFCVS process. Of these 16 process measures, the majority (10; 63%) required the use of Web-based technology. The SFCVS demonstrates that a MAPP-like process can leverage the Internet to augment the functionality of public health activities. PMID- 21788785 TI - Journey to a quality improvement culture. PMID- 21788786 TI - The evolution of a leader. PMID- 21788787 TI - Huddle up! PMID- 21788789 TI - Mentoring smart. PMID- 21788790 TI - Meaningful use 101. PMID- 21788791 TI - Developing a nursing model of care? Try focus groups. PMID- 21788793 TI - Leadership and healthcare disparities. PMID- 21788794 TI - The CNO and the ACO: an alphabet soup of healthcare reform. PMID- 21788795 TI - Taking the pressure off in the ICU. PMID- 21788796 TI - Writing for resolution. PMID- 21788797 TI - Training new nurses; climbing the professional ladder. PMID- 21788798 TI - Rhinoplasty. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Discuss desired preoperative aesthetic and functional assessment of the postsurgical nose with rhinoplasty patients. 2. Identify factors that have the potential to affect procedural outcomes. 3. Develop an operative plan to address aesthetic goals while preserving/improving nasal airway function. 4. Recognize and manage complications following rhinoplasty. SUMMARY: Rhinoplasty is one of the most commonly performed aesthetic surgical procedures in plastic surgery. Over the past 20 years, the trend has shifted away from ablative techniques involving reduction or division of the osseocartilaginous framework to conserving native anatomy with cartilage-sparing suture techniques and augmentation of deficient areas to correct contour deformities and restore structural support. Accurate preoperative systematic nasal analysis and evaluation of the nasal airway, along with identification of both the patient's expectations and the surgeon's goals, form the foundation for success. Intraoperatively, adequate anatomical exposure of the nasal deformity; preservation and restoration of the normal anatomy; correction of the deformity using incremental control, maintenance, and restoration of the nasal airway; and recognition of the dynamic interplays among the composite of maneuvers are required. During postoperative recovery, care and reassurance combined with an ability to recognize and manage complications lead to successful outcomes following rhinoplasty. PMID- 21788799 TI - Restoration of normal eyelid function after resection of orbitotemporal neurofibroma. PMID- 21788800 TI - No association between DNA repair gene (XPD, XRCC1, and XRCC4) polymorphisms and nonsyndromic microtia in Turkish patients. PMID- 21788801 TI - Investigation of Asian adult aging features and the facial aging scoring system of the middle and lower face. PMID- 21788802 TI - The "X-graft" for nasal tip surgery. PMID- 21788803 TI - A novel technique for precise placement and secure fixation of onlay grafts in rhinoplasty: our 4-year experience. PMID- 21788804 TI - Extranasal splint made of a polyethylene container: a distinct fixation method after nasal bone fracture reduction surgery. PMID- 21788805 TI - Acellular porcine dermal collagen implant in saddle nose deformity. PMID- 21788806 TI - Is there any evidence for biofilms in dermal fillers? PMID- 21788807 TI - Mycobacterium abscessus outbreak after rhytidectomies performed in an outpatient surgery center. PMID- 21788808 TI - A novel device for simultaneous dentoalveolar and zygomatic distraction osteogenesis to reconstruct maxillectomy: a preliminary in vitro study. PMID- 21788809 TI - Robotic latissimus dorsi muscle harvest. PMID- 21788810 TI - The use of a barbed self-retaining suture system in the positioning and manipulation of the breast mound during reconstructive and aesthetic breast surgery. PMID- 21788811 TI - Immediate nipple reconstruction using the everted umbilicus. PMID- 21788812 TI - Anatomical versus round implants: discrepancy between what the British public prefers and what British cosmetic clinics offer as standard implants. PMID- 21788813 TI - Hoofbeats. PMID- 21788814 TI - Surgical procedure for transplanting artificial nerve conduits for peripheral nerve regeneration. PMID- 21788815 TI - Brachioplasty incision. PMID- 21788816 TI - Spontaneous resolution of a keloid. PMID- 21788817 TI - A novel minimally invasive technique for components separation. PMID- 21788818 TI - Abdominoplasty with mesh reinforcement ventral herniorrhaphy. PMID- 21788819 TI - Abdominoplasty flap elevation more superficially. PMID- 21788820 TI - Surgical repair of the abdominal bulge using Composix Kugel patch with the intraperitoneal onlay mesh technique. PMID- 21788821 TI - Management of seroma drainage in the community: a further technique for complicated cases. PMID- 21788822 TI - Owning our complications. PMID- 21788823 TI - Publication bias in abstracts presented to the annual scientific meeting of the American Society of Plastic Surgeons. PMID- 21788824 TI - Observational studies and STROBE reporting quality in plastic surgical conference abstracts. PMID- 21788825 TI - Discussion: The oncologic outcome and immediate surgical complications of lipofilling in breast cancer patients: a multicenter study--Milan-Paris-Lyon experience of 646 lipofilling procedures. PMID- 21788826 TI - Autologous fat graft in postmastectomy pain syndrome. AB - BACKGROUND: Mastectomy with axillary dissection is still one of the most common procedures in oncologic surgery. Unfortunately, a condition of neuropathic pain, termed postmastectomy pain syndrome, can appear after mastectomy. Although evidence regarding the epidemiology of postmastectomy pain syndrome is well researched, an effective therapy is still unknown. The aim of this study was to assess the clinical effectiveness of lipoaspirate graft in the treatment of postmastectomy pain syndrome. METHODS: From February of 2006 to August of 2008, a total of 113 patients affected by postmastectomy pain syndrome and severe scar retractions were enrolled for this clinical study. Seventy-two patients were treated with autologous fat grafted in painful scars, and 41 patients did not undergo any further surgical procedure. Pain assessment was performed using a visual analogue scale before and after treatment, with a mean follow-up of 13 months. In addition, antalgic drug intake was recorded in the 34 patients who received a surgical treatment. Results were analyzed using the Wilcoxon rank sum test. RESULTS: A significant decrease in pain according to the visual analogue scale was detected in patients treated with autologous fat graft (3.23-point reduction, p = 0.0005). Twenty-eight of 34 patients stopped their analgesic therapy with a significant follow-up (13 months). CONCLUSIONS: Autologous fat grafting is a safe, relatively noninvasive, and rapid surgical procedure. The authors' results suggest its effectiveness for treatment of postmastectomy pain syndrome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 21788827 TI - Outcome of different timings of radiotherapy in implant-based breast reconstructions. AB - BACKGROUND: The therapeutic role of postmastectomy radiation therapy has been demonstrated both in locally advanced breast cancer and in other high-risk conditions. Implant-based breast reconstruction for irradiated patients can generate higher complication rates. In this study, the authors observed the effects of radiation on temporary expanders and permanent implants. The estimate of the totally failed reconstruction rate was the principal endpoint of this study. Capsular contracture rates and patients' and surgeons' subjective evaluations were the secondary endpoints. METHODS: Two hundred fifty-seven patients were consecutively involved in this study. The population was stratified into two groups: group 1, postmastectomy radiation therapy on permanent implants (n = 109 patients); and group 2, postmastectomy radiation therapy on tissue expanders (n = 50 patients). A nonirradiated control group made up of 98 patients was selected randomly. All patients underwent a two-stage immediate breast reconstruction with subpectoral temporary expanders and permanent implants. RESULTS: The totally failed reconstruction rate was significantly higher in group 2, with 40 percent of unsuccessful reconstructions compared with 6.4 percent in group 1 and 2.3 percent in the control group (p < 0.0001). The capsular contracture rate was significantly higher for groups 1 and 2 compared with the control group. The shape and symmetry assessment and the patients' opinions demonstrated a higher incidence of good results in group 1 in comparison with group 2. The best scores were always obtained by the control group. CONCLUSION: This study demonstrated that radiotherapy during tissue expansion may compromise the outcome of implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 21788828 TI - Discussion: Outcome of different timings of radiotherapy in implant-based breast reconstructions. PMID- 21788830 TI - The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. AB - BACKGROUND: Among hundreds of pathophysiologic factors that impair healing of the diabetic foot, diminished perfusion and neovascularization are critical. This study aimed to show the effect of human adipose-derived stem cells on healing of ischemic wounds in diabetic nude mice and thus to estimate the possibilities of adipose-derived stem cells for diabetic wound care. METHODS: Sixty nude mice were assigned randomly into group Ia (diabetic control, n = 20), group Ib (diabetic experimental, n = 20), or group II (nondiabetic control, n = 20). After creation of an ischemic limb, human adipose-derived stem cells were injected locally. Gross and histologic observations were made after 3, 7, and 25 days, and plasma and tissue levels of vascular endothelial growth factor were quantified. RESULTS: Group Ia animals typically showed gangrene formation with a delayed and sustained inflammatory reaction, which led to a high rate of autoamputation and a lower survival rate. Group Ib animals had a tendency for earlier and abundant neovessel formation and better tissue remodeling rather than fibrotic cicatrization, resulting in lower rate of autoamputation and a survival rate comparable to group II. Surviving stem cells were identified at day 25, but no specific differentiation was observed. Plasma and tissue vascular endothelial growth factor level in group Ib was higher than in group Ia and comparable to that in group II. CONCLUSIONS: This study demonstrated the beneficial effect of human adipose-derived stem cells on healing of ischemic wound in diabetic nude mice. Elevation of vascular endothelial growth factor levels in plasma and tissue suggests the importance of secretory factor, which regulates local angiogenesis and triggers a systemic response. PMID- 21788829 TI - Differences in osteogenic differentiation of adipose-derived stromal cells from murine, canine, and human sources in vitro and in vivo. AB - BACKGROUND: Given the diversity of species from which adipose-derived stromal cells are derived and studied, the authors set out to delineate the differences in the basic cell biology that may exist across species. Briefly, the authors found that significant differences exist with regard to proliferation and osteogenic potentials of adipose-derived stromal cells across species. METHODS: Adipose-derived stromal cells were derived from human, mouse, and canine sources as previously described. Retinoic acid, insulin-like growth factor-1, and bone morphogenetic protein-2 were added to culture medium; proliferation and osteogenic differentiation were assessed by standardized assays. In vivo methods included seeding 150,000 adipose-derived stromal cells on a biomimetic scaffold and analyzing healing by micro-computed tomography and histology. RESULTS: Adipose-derived stromal cells from all species had the capability to undergo osteogenic differentiation. Canine adipose-derived stromal cells were the most proliferative, whereas human adipose-derived stromal cells were the most osteogenic (p < 0.05). Human cells, however, had the most significant osteogenic response to osteogenic media. Retinoic acid stimulated osteogenesis in mouse and canine cells but not in human adipose-derived stromal cells. Insulin-like growth factor-1 enhanced osteogenesis across all species, most notably in human- and canine-derived cells. CONCLUSIONS: Adipose-derived stromal cells derived from human, mouse, and canine all have the capacity to undergo osteogenic differentiation. Canine adipose-derived stromal cells appear to be the most proliferative, whereas human adipose-derived stromal cells appear to be the most osteogenic. Different cytokines and chemicals can be used to modulate this osteogenic response. These results are promising as attempts are made to optimize tissue-engineered bone using adipose-derived stromal cells. PMID- 21788831 TI - Progenitor cell mobilization enhances bone healing by means of improved neovascularization and osteogenesis. AB - BACKGROUND: Although bone repair is a relatively efficient process, a significant portion of patients fail to heal their fractures. Because adequate blood supply is essential to osteogenesis, the authors hypothesize that augmenting neovascularization by increasing the number of circulating progenitor cells will improve bony healing. METHODS: Bilateral full-thickness defects were created in the parietal bones of C57 wild-type mice. Intraperitoneal AMD3100 (n = 33) or sterile saline (n = 33) was administered daily beginning on postoperative day 3 and continuing through day 18. Circulating progenitor cell number was quantified by fluorescence-activated cell sorting. Bone regeneration was assessed with micro computed tomography. Immunofluorescent CD31 and osteocalcin staining was performed to assess for vascularity and osteoblast density. RESULTS: AMD3100 treatment increased circulating progenitor cell levels and significantly improved bone regeneration. Calvarial defects of AMD3100-treated mice demonstrated increased vascularity and osteoblast density. CONCLUSIONS: Improved bone regeneration in this model was associated with elevated circulating progenitor cell number and subsequently improved neovascularization and osteogenesis. These findings highlight the importance of circulating progenitor cells in bone healing and may provide a novel therapy for bone regeneration. PMID- 21788832 TI - Augmenting neovascularization accelerates distraction osteogenesis. AB - BACKGROUND: Distraction osteogenesis has revolutionized the treatment of craniofacial deformities, but it is limited by lengthy consolidation periods and tenuous healing in certain clinical settings, such as irradiated tissue. In this study, the authors aim to investigate whether increasing neovascularization by progenitor cell mobilization accelerates bone formation during distraction. METHODS: Sprague-Dawley rats aged 8 weeks (n = 36) were subjected to unilateral mandibular distraction with 3-day latency, 7-day activation (0.25 mm twice daily), and 21-day consolidation periods. From the beginning of the consolidation period, animals received daily injections of either AMD3100 (bone marrow progenitor cell mobilizing agent) or sterile saline. Animals were euthanized on postoperative day 31; mandibles were harvested; and bone regeneration was assessed using micro-computed tomography, immunohistochemistry, bone morphogenetic protein-2 enzyme-linked immunosorbent assay, and mechanical testing. RESULTS: Immunohistochemistry demonstrated that AMD3100 treatment increased vascular density and bone formation. Micro-computed tomography and dual emission x-ray absorptiometry demonstrated that AMD3100-treated animals had improved bone generation compared with sham-treated controls. Greater force was required on three-point testing to break AMD3100-treated bone. Bone morphogenetic protein-2 expression was up-regulated with AMD3100. Interestingly, the nondistracted contralateral hemimandibles treated with AMD3100 were also stronger than sham-treated counterparts. CONCLUSIONS: Progenitor cell mobilization improves bone regeneration in a rat distraction model. Furthermore, because this effect is seen in healthy bone and in ischemic bone healing during distraction, the mechanism is not merely related to oxygenation, but could be a phenomenon of fluid flow. PMID- 21788833 TI - Dimethyloxalylglycine stabilizes HIF-1alpha in cultured human endothelial cells and increases random-pattern skin flap survival in vivo. AB - BACKGROUND: The goal of this study was to evaluate in vitro and in vivo the effects of up-regulation of the proangiogenic hypoxia inducible factor (HIF) 1alpha induced by dimethyloxalylglycine on endothelial cell cultures and on skin flap survival. METHODS: Human umbilical vein endothelial cell cultures were exposed to hypoxic conditions, to dimethyloxalylglycine, and to cobalt chloride for up to 24 hours. Expression of HIF-1alpha and vascular endothelial growth factor (VEGF) in cell culture media was analyzed. In vivo, 20 male Wistar rats were assigned randomly to either the treatment group (dimethyloxalylglycine intraperitoneal injection, n = 10) or the control group (saline intraperitoneal injection, n = 10). A dorsal skin flap was raised in all animals and sutured back into place. Flap survival was evaluated on postoperative day 7 by laser Doppler and digital planimetry. RESULTS: In vitro treatment of human umbilical vein endothelial cells during a 24-hour period showed a significant elevation of VEGF expression with dimethyloxalylglycine exposure (92 +/- 35 pg/mg total cellular protein) or hypoxia exposure (88 +/- 21 pg/mg total cellular protein) compared with controls (23 +/- 10 pg/mg total cellular protein) (p < 0.05 for both). In vivo experiments showed a significant decrease of flap necrosis in the treatment group animals versus controls (35.95 +/- 5.03 percent versus 44.42 +/- 5.18 percent, p < 0.05). The laser Doppler evaluation revealed significantly increased blood flow in the proximal two-thirds of the flap in the treatment group compared with the control group (p < 0.05). CONCLUSION: Dimethyloxalylglycine treatment significantly increases VEGF and HIF-1alpha expression in endothelial cell cultures and enhances skin flap survival in vivo in a rat model. PMID- 21788834 TI - Comparison of postoperative eyelid position using fibrin sealant versus suture for wound closure in Muller's muscle-conjunctiva resection ptosis repair. AB - BACKGROUND: The purpose of this study was to compare postoperative eyelid position using fibrin sealant versus suture for wound closure in Muller's muscle conjunctiva resection ptosis repair. METHODS: One hundred ninety-six patients (367 eyelids) who underwent Muller's muscle-conjunctiva resection ptosis repair were divided into two groups: wounds closed with suture and those closed with fibrin sealant. Preoperative and postoperative eyelid measurements were compared statistically using appropriate t tests. Complications, eyelid symmetry, and revision rates were analyzed using a two-tailed Fisher's exact test. RESULTS: Suture was used for wound closure on 53 eyelids of 39 patients and fibrin sealant was used on 314 eyelids of 157 patients. There was no statistically significant difference (p = 0.49) when comparing the change from preoperative to postoperative margin-to-reflex distance 1 between the two groups. Postoperative symmetry within 0.5 mm was achieved in 87 percent of patients in the suture group and in 96 percent of patients in the fibrin sealant group (p = 0.06). The percentage of patients requiring additional ptosis adjustment was 2 percent in both groups (p = 1.0). Major complications were more common in the suture group (p = 0.0001). CONCLUSIONS: Muller's muscle-conjunctiva resection ptosis repair using fibrin sealant for wound closure offers equivalent lid position and symmetry as compared with suture wound closure. There is also a reduction in major postoperative complications when using fibrin sealant. PMID- 21788835 TI - Outcomes of surgical excision with pressure therapy using magnets and identification of risk factors for recurrent keloids. AB - BACKGROUND: In a previous study, the authors described an adjuvant pressure therapy using magnets for the management of ear keloids. The purpose of the present study was to build on this previous study by expanding the cohort of patients, evaluating treatment outcomes by means of a prospective study and identifying risk factors for recurrent ear keloids. METHODS: The authors treated 1436 ear keloids in 883 patients with surgical excision followed by pressure therapy using magnets at Kangbuk Samsung Hospital over the 7.25-year period from December of 2002 to February of 2010. Six hundred eighteen of 883 patients (70 percent) had histories of treatment failure at other hospitals. The follow-up period was 18 months. Therapeutic outcomes were evaluated as recurrence or nonrecurrence. Comparisons between the two groups (recurrence versus nonrecurrence) were made using Mann-Whitney tests for continuous variables, the chi-square test and the Fisher's exact test for categorical variables, and multivariate logistic regression for investigating associations between possible risk factors and keloid recurrence. RESULTS: The overall recurrence-free rate was 89.4 percent after a follow-up period of 18 months. Keloid recurrence was significantly associated with the presence of prior treatment history, keloid low growth rate, and high patient body mass index. CONCLUSIONS: The authors' protocol results in excellent outcomes in cases of ear keloids. Patients with prior treatment history, low growth rates of keloids because of longer duration of disease, and high body mass index should be monitored closely for signs of recurrence and managed cautiously during ear keloid treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 21788836 TI - Use of adjuvant techniques improves surgical outcomes of complex vertical rectus abdominis myocutaneous flap reconstructions of pelvic cancer defects. AB - BACKGROUND: Reconstruction of irradiated pelvic defects following oncologic resection requires dead-space obliteration to reduce wound healing complications. Although the vertical rectus abdominis myocutaneous (VRAM) flap is often the best option for pelvic reconstruction following abdominoperineal resection or pelvic exenteration, donor- and recipient-site complications are common. The authors hypothesized that certain adjuvant techniques would improve pelvic VRAM flap outcomes. METHODS: Six technical modifications to improve VRAM flap outcomes were evaluated: fascia-sparing VRAM flap, component separation donor-site closure, inlay mesh abdominal reinforcement, deepithelialized VRAM flap skin paddle, extended VRAM flap, and omental flap plus VRAM flap. Prospectively collected data from consecutive patients with immediate pelvic VRAM flap reconstruction from 2001 to 2009 were analyzed retrospectively. Donor- and recipient-site complications were compared between patients treated with each technical modification and all other study patients. RESULTS: One hundred eighty-five patients were included (mean follow-up, 25.1 months). Fascia-sparing VRAM flaps resulted in significantly fewer hernias (1.5 percent versus 11.5 percent, p < 0.01), with less dehiscence, abdominal bulge, and evisceration. Patients receiving donor-site mesh inlay had fewer postoperative hernias (2.6 percent versus 5.5 percent) but more abdominal laxity/bulge (7.7 percent versus 0 percent, p = 0.01). Minor recipient-site dehiscence was significantly lower with omental plus VRAM flaps (11.1 percent versus 32.5 percent, p < 0.05) and extended VRAM flaps (7.7 percent versus 30.8 percent, p < 0.05). Multivariate logistic regression identified omental plus VRAM flaps as protective against (p < 0.05), and increasing body mass index as predictive for (p = 0.009), perineal skin dehiscence. CONCLUSIONS: Several technical modifications of VRAM flap reconstruction improve pelvic reconstruction outcomes and should be considered. Further prospective studies will be important to elucidate specific indications for each technique. PMID- 21788837 TI - Treatment of hidradenitis suppurativa with intense pulsed light: a prospective study. AB - BACKGROUND: Hidradenitis suppurativa is a chronic skin condition characterized by recurrent inflammation and infection of skin in intertriginous areas containing apocrine glands. Intense pulsed light uses high-energy broad-spectrum light. Current applications include hair removal and the treatment of acne vulgaris, which has a pathogenesis similar to that of hidradenitis suppurativa. The authors conducted a study to determine whether intense pulsed light is an effective treatment for hidradenitis suppurativa. METHODS: Eighteen patients were randomized to treatment of one axilla, groin, or inframammary area with intense pulsed light two times per week for 4 weeks using a Harmony Laser. The contralateral side received no treatment and acted as a control. The response to treatment was assessed using a validated examination and clinical photographs, and by measuring patient satisfaction on a Likert scale. RESULTS: After treatment, there was a significant improvement in the mean examination score that was maintained at 12 months (p < 0.001, logistical regression analysis). The improvement was confirmed by independent assessment of clinical photographs (interrater reliability, 0.79; p < 0.001). Patients reported high levels of satisfaction with the treatment. There was no concurrent improvement on the untreated control side. CONCLUSIONS: This small study suggests that intense pulsed light may be an effective treatment for hidradenitis suppurativa. It could be added to treatments used for this condition, particularly for patients keen on avoiding surgery and those with groin and inframammary disease. Further studies are required to confirm the efficacy and mechanism of action of intense pulsed light in hidradenitis suppurativa. PMID- 21788838 TI - From birth to maturity: a group of patients who have completed their protocol management. Part III. Bilateral cleft lip-cleft palate. AB - BACKGROUND: The optimal management of cleft lip-cleft palate patients presents a formidable challenge to the cleft surgeon. This is especially so in the case of bilateral cleft lip-cleft palate, and the long-term management in a multidisciplinary setting is essential. This study presents the results of the specific management protocol at the Australian Craniofacial Unit for patients with bilateral cleft lip-cleft palate who have completed their protocol treatment under the care of a single surgeon (D.J.D.) during the period 1974 to 2006. METHODS: A retrospective study of the outcomes in relation to facial growth, speech, hearing, and occlusion is presented of patients with bilateral cleft lip cleft palate. RESULTS: Nineteen cases were identified from the departmental database, 12 male patients and seven female patients. Six patients with severe craniofacial deformities who had bilateral cleft lip-cleft palate were excluded. Cephalometric analysis at skeletal maturity identified that a majority of cases had midface hypoplasia requiring midface advancement in 14 cases. Speech and hearing outcomes were worse when compared with other clefting types. CONCLUSION: Overall, these results demonstrate that facial growth is more affected in bilateral cleft lip-cleft palate patients than in either unilateral cleft lip cleft palate or isolated cleft palate patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21788839 TI - Comparison of minimally invasive versus conventional open harvesting techniques for iliac bone graft in secondary alveolar cleft patients. AB - BACKGROUND: Autologous bone grafts, often harvested from the iliac crest, are the criterion standard for secondary alveolar cleft repair. The best technique for harvest remains controversial. Minimally invasive techniques have been used for bone graft harvest in cleft patients, but outcome studies have been limited by small numbers of patients. METHODS: A total of 104 patients undergoing bone grafting for alveolar cleft were reviewed. Fifty-five consecutive patients underwent minimally invasive iliac bone graft harvest using the Acumed power driven trephine system performed by the same surgeon. These patients were compared with 49 control patients undergoing a similar procedure in which the traditional method of open iliac bone harvest with an osteotome was used. RESULTS: Operative time for the bone graft harvest was significantly shorter with the Acumed device when compared with the osteotome (2.37 hours versus 3.26 hours, p < 0.001). Patients who underwent minimally invasive Acumed bone harvest required significantly less postoperative analgesia than did patients who underwent osteotome harvest, for both narcotic (0.31 mg/kg versus 1.64 mg/kg, p < 0.001) and nonnarcotic (15.1 mg/kg versus 27.2 mg/kg, p < 0.01) pain medication. Acumed patients had significantly less pain on discharge (0.26 versus 3.1 pain scores on a scale from 0 to 10, p < 0.001) and left the hospital more quickly (23.3 hours versus 30.1 hours, p < 0.001). CONCLUSION: Minimally invasive bone graft harvest technique using the trephine system offers a superior alternative to the conventional open iliac bone harvest method for patients undergoing secondary alveolar cleft repair, with shorter operative time, decreased requirement for pain medications, less pain on discharge, and a shorter hospital stay. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 21788840 TI - What is the optimal time to start helmet therapy in positional plagiocephaly? AB - BACKGROUND: Although helmet therapy is widely accepted in the treatment of severe positional plagiocephaly, treatment regimens, especially regarding starting age, are controversial. This study investigated the importance of starting age to optimize the management of helmet therapy. METHODS: Sixty-two infants with severe positional plagiocephaly were enrolled in this prospective longitudinal study. Twenty-four started helmet therapy before 6 months of age (group 1) and 38 were older than 6 months (group 2). Cranial diagonal measurements were taken. Resulting differences and Cranial Vault Asymmetry Index values were compared and categorized by age at initiation of therapy. The Mann-Whitney U test was used for statistical analysis. RESULTS: Duration of therapy was significantly shorter in group 1 (14 weeks) compared with group 2 (18 weeks) (p = 0.013), with significantly better outcomes. The Cranial Vault Asymmetry Index in group 1 was reduced to a normal mean value less than 3.5 percent. Infants in group 2 did not achieve normal values (index value, 4.5 percent) (p = 0.021). The relative improvement in asymmetry was significantly better in group 1 (75.3 percent) compared with group 2 (60.6 percent) (p = 0.001). After 4 to 11 weeks of treatment, group 1 already showed a better absolute reduction (p < 0.001) and a better relative reduction (p = 0.002). CONCLUSIONS: Optimal starting age for helmet therapy is months 5 to 6 of life, and early recognition of infants in need is essential. Delaying the onset of treatment significantly deteriorates the outcome. The still often-practiced regimen of starting helmet therapy after physiotherapy should be replaced by a combined therapy in severe cases. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 21788841 TI - Pharmacologic therapies for infantile hemangioma: is there a rational basis? AB - BACKGROUND: Infantile hemangioma is the most common tumor of infancy. The majority of cases are managed conservatively, but intervention is necessary in approximately 10 percent of cases because of the threat to life or function or because of tissue distortion or destruction. The mainstay treatment for these problematic proliferating infantile hemangiomas is pharmacologic therapy, mostly discovered serendipitously. METHODS: This review examines the rational basis of the hitherto empirical pharmacologic therapies for the enigmatic infantile hemangioma, in light of new knowledge regarding its biology, including the critical roles of stem cells and the renin-angiotensin system. RESULTS: Steroids have remained the first-line therapy for problematic infantile hemangioma for over 40 years despite their known side effects and failure rates. Vincristine has emerged as an alternative to interferon for steroid-resistant cases because of interferon's adverse effects, especially neurotoxicity. beta-Blockers are now the preferred first-line therapy for problematic cases. There is increasing evidence that infantile hemangioma is a disorder of aberrant proliferation and differentiation of primitive mesoderm-derived neural crest phenotypic cells. This primitive phenotype that gives rise to a hemogenic endothelium intermediate has the ability to undergo primitive erythropoiesis and terminal mesenchymal differentiation. CONCLUSIONS: The recent discovery of the crucial role of stem cells and the inferred role of the renin-angiotensin system in the biology of infantile hemangioma underscores the possibility of even more targeted therapies, by using modulators of the renin-angiotensin system, on infantile hemangioma. The observation of the potential role of these traditional antihypertensive agents in stem cell biology may lead to better understanding of developmental biology and tumor stem cell growth. PMID- 21788842 TI - High prevalence of body dysmorphic disorder symptoms in patients seeking rhinoplasty. AB - BACKGROUND: Nasal aesthetic deformities may be associated with significant body image dissatisfaction. The only diagnostic category in the current list of psychiatric disorders that directly addresses these concerns is body dysmorphic disorder. This large-scale study determined the prevalence of body dysmorphic disorder and its symptoms in patients seeking rhinoplasty and evaluated the clinical profile of these patients. METHODS: Two hundred twenty-six patients were given questionnaires including demographic characteristics, visual analogue scales for nasal shape, the Yale-Brown Obsessive Compulsive Scale modified for body dysmorphic disorder to assess severity of symptoms, a generic quality-of life questionnaire, and the Derriford Appearance Scale 59, to assess appearance related disruption of everyday living. Independent observers scored the nasal shape. RESULTS: Thirty-three percent of patients showed at least moderate symptoms of body dysmorphic disorder. Aesthetic goals (p < 0.001), revision rhinoplasty (p = 0.003), and psychiatric history (p = 0.031) were associated with more severe symptoms. There was no correlation between the objective and subjective scoring of the nasal shape. Yale-Brown scale modified for body dysmorphic disorder scores correlated inversely with the subjective nasal scoring (n = 210, p < 0.001), without relation to the objective deformity of the nose. Body dysmorphic disorder symptoms significantly reduced the generic quality of life (n = 160, p < 0.001) and led to significant appearance-related disruption of everyday living (n = 161, p < 0.001). CONCLUSIONS: The prevalence of moderate to severe body dysmorphic disorder symptoms in an aesthetic rhinoplasty population is high. Patients undergoing revision rhinoplasty and with psychiatric history are particularly at risk. Body dysmorphic disorder symptoms significantly reduce the quality of life and cause significant appearance-related disruption of everyday living. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 21788843 TI - Discussion: High prevalence of body dysmorphic disorder symptoms in patients seeking rhinoplasty. PMID- 21788844 TI - Changes in quality of life and functional status following abdominal contouring in the massive weight loss population. AB - BACKGROUND: Abdominal contouring surgery is commonly performed following massive weight loss. Outcome data following abdominal contouring have been reported regarding body image and symptoms in general; however, few data exist regarding specific functional improvements. The authors examined functional changes in quality of life following abdominal contouring in the massive weight loss population. METHODS: Fifty-two consecutive patients were reviewed from the authors' prospective database. Outcome measures included body mass indices, comorbidities, resection weight, and 24 functional variables. Outcome measures were assessed by univariate and multivariate analysis. RESULTS: Forty-nine patients completed the survey (94 percent). Average patient age was 45.8 years at the time of surgery (range, 25 to 68 years). Mean maximum body mass index was 56.1 +/- 11.8 kg/m2, mean pre-body contour body mass index was 34.6 +/- 10.1 kg/m2, mean pre-body contour change in body mass index was 21.4 +/- 6.9 kg/m2, mean post-body contour body mass index was 32.4 +/- 9.3 kg/m2, and mean post-body contour change in body mass index was 2.1 +/- 2.9 kg/m2. Statistically significant improvements in all functional outcomes were appreciated, except shoulder pain. Rectus plication did not significantly improve functional outcomes. Higher maximum and pre-body contour body mass index values were significantly related to greater improvement in functional outcomes (p < 0.05); 91.8 percent of patients said they would undergo abdominal contouring again or would recommend it to a friend. CONCLUSIONS: Abdominal contouring surgery improves functional status of massive weight loss patients, especially those with a higher body mass index at the time of surgery. Rectus plication did not influence functional outcomes. Prospective functional assessments may aid in optimizing outcomes in the management of the massive weight loss patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21788845 TI - Discussion: Changes in quality of life and functional status following abdominal contouring in the massive weight loss population. PMID- 21788846 TI - Transversus abdominis plane block anesthesia in abdominoplasties. AB - BACKGROUND: The transversus abdominis plane block is a promising approach to the provision of postoperative analgesia following abdominal incision. This effective method blocks the sensory nerve supply to the anterior abdominal wall. The authors evaluated its analgesic efficacy over the first 12 postoperative hours after abdominoplasty with liposculpture in a randomized, controlled, double-blind clinical trial. METHODS: Twenty-eight women undergoing abdominoplasty by means of a lower abdominal incision were randomized to undergo transversus abdominis plane block (n = 14) in addition to standard care therapy (n = 14). The investigators, who were blinded to the conditions of the study, assessed the patients in the postanesthesia care unit at 4, 6, and 12 hours postoperatively. RESULTS: The transversus abdominis plane block group reported reduced pain scores (F = 12.73, p < 0.001). Morphine requirement was also reduced in the first 12 postoperative hours (chi2 = 19.27; p < 0.005). Transversus abdominis plane block group patients also exhibited early ambulation compared with the control group (F = 65.15, p < 0.001). All of the patients in the transversus abdominis plane block group reported lower levels of pain with their postoperative analgesic regimen, which was demonstrated by their rates of recovery. The Mann-Whitney test was performed on the data, which illustrated that mean ranks consistently corresponded to the trend the authors predicted. CONCLUSIONS: The transversus abdominis plane block seems to hold considerable promise for patients undergoing abdominoplasty by providing effective postoperative analgesia in the first 12 postoperative hours after major abdominoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 21788847 TI - Buttocks fat grafting: 14 years of evolution and experience. AB - BACKGROUND: Fat infiltration for gluteal contour improvement is a procedure that is gaining more advocates. This has caused the application technique and the amount of fat infiltrated to change over time. The authors present their buttocks fat grafting technique evolution that occurred over a 14-year period. METHODS: From April of 1995 to March of 2009, 789 patients underwent liposuction and buttocks fat grafting. Patients were divided into three stages according to chronologic evolution and amount of fat infiltrated. RESULTS: During the first period (April of 1995 to January of 2004), 120 to 320 cc of fat was infiltrated in the upper gluteal area. During the second period (February of 2004 to February of 2006), 210 to 460 cc of fat was infiltrated in the upper and lower gluteal area. In the third period (March of 2006 to March of 2009), 220 to 1160 cc of fat was infiltrated in the aforementioned areas and in the trochanteric and subgluteal areas. Complications such as fat necrosis, gluteal erythema, infection, and fat embolism syndrome were more frequent and serious in the first stage, despite the authors having infiltrated smaller volumes. CONCLUSIONS: Increasing the volume of fat infiltration in the buttocks has resulted in better contour results in the whole area, and distribution of that larger volume in more extensive areas and in different layers has decreased the index and number of complications. Therefore, to obtain better aesthetic results, it is necessary to keep in mind that these larger amounts must be distributed in larger areas and layers to decrease postsurgical morbidity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 21788848 TI - Career evaluation and the decision process for plastic surgery graduates. AB - National experience shows that 50 percent of physicians change positions within the first 2 years of practice. Because of market pressures, medicine in general and plastic surgery in particular are shifting away from solo practice. The authors examine the primary reasons for turnover and discuss job search priorities for recent plastic surgery graduates and established surgeons in job transition, with a current analysis of the different job opportunities available, ranging from government to private practice. The advantages and disadvantages of different positions are compared and income data are presented. Academic income is close to that of private practice at a mean of $366,141 annually but requires more work as measured by an overall higher relative value unit of productivity. The concept of creating a personal inventory before seeking the best job match is introduced. PMID- 21788849 TI - Discussion: career evaluation and the decision process for plastic surgery graduates. PMID- 21788851 TI - Haiti and the road to recovery: surviving the human aftershocks, battles with the cholera epidemic, and the anticipation of a new political era. PMID- 21788850 TI - Certification examination cases of candidates for certification by the American Board of Plastic Surgery: trends in practice profiles spanning a decade (2000 to 2009). AB - BACKGROUND: The purpose of this study was to evaluate the case mix of plastic surgeons in their early years of practice by examining candidate case logs submitted for the oral examination. METHODS: Deidentified data from 2000 to 2009 consisting of case logs submitted by young plastic surgery candidates for the oral examination were analyzed. Data consisted of examination year, Current Procedural Terminology codes and the designation of each code as cosmetic or reconstructive by the candidate, and patient age and sex. Subgroup analyses for comprehensive, cosmetic, craniomaxillofacial, and hand surgery modules were performed by using the Current Procedural Terminology code list designated by the American Board of Plastic Surgery Maintenance of Certification in Plastic Surgery module framework. RESULTS: The authors examined case logs from a yearly average of 261 candidates over 10 years. Wider variations in yearly percentage change in median cosmetic surgery case volumes (-62.5 to 30 percent) were observed when compared with the reconstructive surgery case volumes (-18.0 to 25.7 percent). Compared with cosmetic surgery cases per candidate, which varied significantly from year to year (p < 0.0001), reconstructive surgery cases per candidate did not vary significantly (p = 0.954). Subgroup analyses of proportions of types of surgical procedures based on Maintenance of Certification in Plastic Surgery Current Procedural Terminology code categories revealed hand surgery to be the least performed procedure relative to comprehensive, craniomaxillofacial, and cosmetic surgery procedures. CONCLUSIONS: Graduates of plastic surgery training programs are committed to performing a broad spectrum of reconstructive and cosmetic surgical procedures in their first year of practice. However, hand surgery continues to have a small presence in the practice profiles of young plastic surgeons. PMID- 21788855 TI - Nipple-areola complex evaluation in long pedicled breast reductions with real time fluorescent videoangiography. PMID- 21788858 TI - Accidentally injected formaldehyde during cosmetic blepharoplasty. PMID- 21788859 TI - On the classification of postoncologic midfacial defects. PMID- 21788860 TI - Silhouette thread lift as an ancillary procedure in an unusual case of necrotizing myopathy of the face. PMID- 21788862 TI - Are bilateral TRAM flaps as good as bilateral DIEP flaps? PMID- 21788864 TI - Introducing the septocutaneous gluteal artery perforator flap: a simplified approach to microsurgical breast reconstruction. PMID- 21788865 TI - Clinical considerations regarding the risks and benefits of textured surface implants and double capsule. PMID- 21788866 TI - No differences in aesthetic outcome or patient satisfaction between anatomically shaped and round expandable implants in bilateral breast reconstructions: a randomized study--the role of the sample size calculation. PMID- 21788867 TI - Correction of breast asymmetry does not exist, and the role of three-dimensional imaging remains a question. PMID- 21788868 TI - Evidence-based medicine in breast augmentation: is the goal to promote average or offer the most state-of-the-art treatment for patients? PMID- 21788871 TI - Epinephrine in the digits. PMID- 21788872 TI - Surgical treatment options for unstable mallet fractures. PMID- 21788873 TI - Seroma in lipoabdominoplasty and abdominoplasty: a comparative study using ultrasound--a note about statistics. PMID- 21788875 TI - Management of contour irregularities following superficial liposuction. PMID- 21788878 TI - Minimally invasive reconstructive surgery for complex oncologic foot defects in children. PMID- 21788881 TI - Using data to compare the results of direct closure versus local flaps for treating Mohs defects. PMID- 21788882 TI - Evidence-based approach to seroma. PMID- 21788884 TI - Topical silicone gel versus placebo in promoting the maturation of burn scars: a randomized controlled trial--the pivotal role of statistics. PMID- 21788885 TI - Skin closure with absorbable staples in aesthetic surgery. PMID- 21788886 TI - Microsurgical training model using chicken thigh. PMID- 21788889 TI - Biomarkers in geriatric psychiatry: the promise and the reality. AB - This guest editorial seeks to address the promise and the reality of biomarkers in geriatric psychiatry by tying together the three articles on biomarkers of depression included in this issue of the Journal. They represent different streams of biological research, which have developed over the last 40 years. We will try to put each area of research into context. PMID- 21788890 TI - Travel-associated zoonotic bacterial diseases. AB - PURPOSE OF REVIEW: Bacterial zoonoses are increasingly described in association with travel. Some bacterial zoonoses constitute important causes of post-travel illness. We focus on leptospirosis and rickettsiosis - the most common travel associated bacterial zoonoses. RECENT FINDINGS: Leptospirosis is regarded to be the most common zoonotic disease worldwide. In industrialized countries recreational exposures, both domestic and overseas, are increasingly becoming a major source of infection. Asymptomatic infection is rare among travelers. Rickettsial diseases account for approximately 1.5-3.5% of febrile travelers. In several series of travel-related rickettsioses, the most common travel-related rickettsial disease is Rickettsia africae. Other rickettsioses including Q fever, scrub typhus and murine typhus are considered rare among travelers. Whereas timely diagnosis of both diseases is still based on exposure history, antigen detection tools to aid the diagnosis during the acute illness are under research and far from being available. Due to these constrains, currently, the true incidence of both diseases is probably underestimated. SUMMARY: Both leptospirosis and spotted fever may be rapidly fatal. Empiric doxycycline in severely ill febrile travelers should be considered. There is an urgent need for widely available antigen detection diagnostic tools to improve the detection of leptospirosis and rickettsial infections during the acute illness. PMID- 21788891 TI - Cysticercosis of the central nervous system: how should it be managed? AB - PURPOSE OF REVIEW: Taenia solium neurocysticercosis (NCC) has been long recognized as an important cause of neurological morbidity in most of the world. Unwarranted generalization of diagnostic and treatment recommendations made it difficult to assess individual prognosis and responses for each type of NCC. Understanding of the main clinical presentations (dependent on number, location, size, and stage of parasites, as well as on the immune response of the host) allows a better view of treatment options and expected outcomes. RECENT FINDINGS: Current treatment options are still limited and involve symptomatic agents, antiparasitic agents, or surgery. The importance of adequate symptomatic management, the potential for improved antiparasitic treatment regimes, in particular combination therapy, and the increasingly important role of minimally invasive neurosurgery are also reviewed in this article. SUMMARY: Treatment decisions in NCC should be individualized in relation to the type of NCC. Initial measures should focus on the symptomatic management before considering antiparasitic therapy when appropriate. Appropriate patient categorization, new antiparasitic regimes, and minimally invasive surgery are improving the prognosis of patients with NCC. PMID- 21788892 TI - Health recommendations for international travel: a review of the evidence base of travel medicine. AB - PURPOSE OF REVIEW: International travel is increasing, including travel to countries with emerging economies. Travel may pose health risks for the individual and contribute to the global spread of infectious diseases. The specialty of travel medicine is aimed at minimizing health risks associated with international travel. The field has emerged in the past 25 years, and the evidence base supporting its clinical practice is growing. This review will describe the evidence base underlying travel medicine, highlight recently updated travel medicine guidelines, and outline future research priorities. RECENT FINDINGS: Recommendations for a number of common vaccines for travelers have been updated recently. More sophisticated detection methods are leading to the identification of a wider spectrum of pathogens associated with travelers' diarrhea, and antibiotic resistance is increasingly being identified. New treatment options for malaria are available, and a fifth Plasmodium species causing disease in humans has been identified. SUMMARY: An evidence base for the practice of travel medicine is emerging. Expert opinion and consensus guidelines continue to play an important role in supporting clinical practice. PMID- 21788893 TI - Polypharmacy and medication-related complications in the chronic kidney disease patient. AB - PURPOSE OF REVIEW: Medication-related problems are very common in patients with chronic kidney disease (CKD). Identification, prevention and management of these problems require a comprehensive, interdisciplinary approach. This article reviews the recent literature regarding medication-related problems in CKD and proposes initiatives for addressing these problems through a structured review process and use of patient-centered adherence-promoting strategies. RECENT FINDINGS: Pharmacist-conducted medication review and intervention programs are successful at identifying and resolving medication-related problems in CKD patients. These programs are associated with a reduction in the number of medications and frequency of hospitalization, and are associated with maintenance of quality of life. However, adherence continues to be a major medication-related problem in CKD care. SUMMARY: Structured medication review and assessment of adherence assist in identification and resolution of medication-related problems in CKD. More research is needed on successful methods to improve medication adherence and related health outcomes. PMID- 21788894 TI - Intrarenal urea recycling leads to a higher rate of renal excretion of potassium: an hypothesis with clinical implications. AB - PURPOSE OF REVIEW: This review aims to illustrate why urea recycling may play an important role in potassium (K+) excretion and to emphasize its potential clinical implications. RECENT FINDINGS: A quantitative analysis of the process of intrarenal urea recycling reveals that the amount of urea delivered to the distal convoluted tubule is about two-fold larger than the quantity of urea excreted in the urine. As the number of osmoles delivered to the late cortical distal nephron (CCD) determines its flow rate when aquaporin 2 water channels have been inserted in the luminal membrane of principal cells, urea recycling may play an important role in regulating the rate of excretion of K+ when the distal delivery of electrolytes is not very high. SUMMARY: Urea recycling aids the excretion of K+; this is especially important in patients with disorders or those who are taking drugs that lead to a less lumen-negative voltage in the CCD. As a large quantity of urea is reabsorbed daily in the inner medullary collecting duct, the assumption made in the calculation of the transtubular K concentration gradient that there is no appreciable reabsorption of osmoles downstream CCD is not valid. PMID- 21788896 TI - Challenges for conducting clinical trials for AIDS malignancies in resource limited settings. PMID- 21788897 TI - Technological advances in radiotherapy for cervical cancer. AB - PURPOSE OF REVIEW: To discuss the important technological advances that have taken place in the planning and delivery of both external beam radiotherapy and brachytherapy for patients with locally advanced cervical cancer, and the implications for improved clinical outcomes. RECENT FINDINGS: Technological advances in external beam radiation treatment and brachytherapy for patients with cervical cancer allow more precise targeting of tumour and relative sparing of surrounding normal organs and tissues. Early evidence is emerging to indicate that these advances will translate into improvements in tumour control and reduced side effects. However, there are patient, tumour and treatment-related factors that can detract from these benefits. Foremost among these is complex, unpredictable and sometimes dramatic internal tumour and normal organ motion during treatment. The focus of current research and clinical development is on tracking internal anatomic change in individual patients and adapting treatment plans as required to assure that optimal tumour coverage and normal tissue sparing is maintained at all times. The success of this approach will depend on clear definitions of target volumes, high resolution daily soft tissue imaging, and new software tools for rapid contouring, treatment planning and quality assurance. SUMMARY: Radiation treatment of locally advanced cervical cancer is evolving rapidly, driven by advances in technology, towards more individualized patient care that has the potential to substantially improve clinical outcomes. PMID- 21788895 TI - Bortezomib-induced Epstein-Barr virus and Kaposi sarcoma herpesvirus lytic gene expression: oncolytic strategies. AB - PURPOSE OF REVIEW: Gamma herpesviruses (GHVs) are responsible for a substantial proportion of virus-associated human cancers, particularly in immunocompromised individuals. Methods that employ lytic activation of viruses latently infecting tumors represent a novel strategy of antineoplastic therapy. RECENT FINDINGS: The proteasome inhibitor, bortezomib, has been shown to be a potent activator of GHV lytic cycle and has demonstrated activity in case reports of GHV-related malignancies. Although initial reports implicated the inhibition of the NF-kappaB pathway, more recent studies identify alternative pathways responsible for bortezomib-mediated lytic induction of GHVs and activity against the malignancies that harbor them. SUMMARY: Further exploration of proteasome inhibition as an oncolytic strategy is warranted and will require clinical/translational trials to determine whether lytic induction of GHVs correlates with clinical response to bortezomib, and, if so, to optimize this oncolytic strategy. PMID- 21788898 TI - Exploring the impact of personality dimensions in late-life depression: from group comparisons to individual trajectories. AB - PURPOSE OF REVIEW: In last years, the concept of personality moved from the stability of categorical models over the lifespan to the complex interactions between gene, environment, and clinical expression according to the dimensional approaches. Within this framework, studies start to explore the impact of personality on the evolution and treatment of depression in old age.(Figure is included in full-text article.) RECENT FINDINGS: Empirical evidence from younger patients has repeatedly confirmed that personality traits predict treatment course and outcome of depression. Epigenetic changes may partly determine the individual differences in personality changes facing life stresses. The limited number of studies on late-life depression revealed the differential impact of personality in early-onset versus late-onset depression. In this age group, the standardized assessment of personality traits allows predicting treatment outcome in psychotherapeutic settings for depressive outpatients. Studies on the interaction between genetic background and personality expression in late life are still missing. SUMMARY: Personality traits emerge as a potentially powerful determinant of the clinical outcome in old-age depression. The integration of psychological and molecular genetics findings offers a new perspective into the personality-depression relationship. Its modulation by the accumulation of individual stressful life-events may play a main role in the outcome of late-life depression. PMID- 21788899 TI - Juvenile offenders assessment. AB - PURPOSE OF REVIEW: Evaluation of juveniles is an integral process that includes a broad bio-psycho-social clinical perspective together with the use of auxiliary instruments. The aim of this review is to report relevant issues for this process found in recent publications. RECENT FINDINGS: Several evidences lead to broadening the assessment process of children and youngsters to include family functioning style. Mental health services allow the evaluation of multiple factors associated with antisocial behavior that may lead to devising preventive actions. In the Juvenile Justice System a wide-ranging evaluation must include the exploration of general personality characteristics and psychopathic traits in particular; attention deficit/hyperactivity disorder; intelligence; substance abuse and conduct disorder must be considered. SUMMARY: A number of factors that have an impact on juvenile antisocial behavior have been identified and can be assessed using the appropriate methodology. The exploration of these factors at different developmental stages and in their various manifestations provide guidelines for devising preventive and therapeutic actions as well as for supporting judicial decisions. Though enriching the present state of the art is always a challenge, it is imperative to encourage the governments to utilize this knowledge to improve the care system of children and adolescents. PMID- 21788900 TI - Blau syndrome revisited. AB - PURPOSE OF REVIEW: Blau syndrome is a monogenic disease resulting from mutations in nucleotide oligomerization domain 2 (NOD2) and is phenotypically characterized by granulomatous polyarthritis and uveitis. Not only there has been significant progress in disease characterization but also the biological pathways associated with NOD2 and related proteins of the innate immunity are better understood. RECENT FINDINGS: The phenotype of Blau syndrome has proven to be more complex than initially thought. A discussion on those manifestations will be provided in the clinical sections of this review. As more patients and pedigrees are found new mutations in the NOD2 gene have emerged and we discuss them in some detail. Due to its importance in Crohn's disease NOD2 has become the focus of intense research. A brief review of more recent advances in relevant pathways is presented and published reviews referenced for the interested reader. The granulomatous character of Blau syndrome provides an opportunity to look at possible pathogenic effects of NOD2 'gain of function'. New immunohistochemical data are briefly reviewed as well. SUMMARY: Elucidation of downstream effects of NOD2 mutations could provide valuable clues to mechanisms of arthritis and uveitis in general as well as granulomatous diseases in particular. PMID- 21788901 TI - Clinical care of children with sterile bone inflammation. AB - PURPOSE OF REVIEW: To review the current literature of sterile bone inflammation in childhood and to evaluate the evidence for clinical care including diagnostic methods and treatment. RECENT FINDINGS: Chronic noninfectious osteomyelitis includes several different entities marked by sterile bone inflammation associated with histologic evidence of a predominant neutrophil infiltration in the absence of autoantibodies and autoreactive T cells, some of which are associated with a genetic mutation. Whole body MRI is helpful in detecting asymptomatic lesions. Initial treatment with NSAIDs is usually sufficient to control symptoms as the bone heals. However, if the lesions persist and do not respond to first-line treatment, or involve the spine or hip, treatment with bisphosphonate will usually lead to a resolution of symptoms. Rarely, treatment with anti-TNF agents is required. SUMMARY: This review summarizes recent information on diagnosis, treatment and prognosis of disorders involving sterile bone inflammation in childhood. It also addresses the evolving differential diagnosis for autoinflammatory disorders that include sterile bone inflammation and presents a treatment algorithm for management. PMID- 21788902 TI - Inflammation in osteoarthritis. AB - PURPOSE OF REVIEW: This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage. RECENT FINDINGS: Studies during the past 2 years have uncovered novel pathways that, when activated, cause the normally quiescent articular chondrocytes to become activated and undergo a phenotypic shift, leading to the disruption of homeostasis and ultimately to the aberrant expression of proinflammatory and catabolic genes. Studies in animal models and retrieved human tissues indicate that proinflammatory factors may be produced by the chondrocytes themselves or by the synovium and other surrounding tissues, even in the absence of overt inflammation, and that multiple pathways converge on the upregulation of aggrecanases and collagenases, especially MMP-13. Particular attention has been paid to the contribution of synovitis in posttraumatic joint injury, such as meniscal tears, and the protective role of the pericellular matrix in mediating chondrocyte responses through receptors, such as discoidin domain receptor-2 and syndecan-4. New findings about intracellular signals, including the transcription factors NF-kappaB, C/EBPbeta, ETS, Runx2, and hypoxia-inducible factor-2alpha, and their modulation by inflammatory cytokines, chemokines, adipokines, Toll-like receptor ligands, and receptor for advanced glycation end-products, as well as CpG methylation and microRNAs, are reviewed. SUMMARY: Further work on mediators and pathways that are common across different models and occur in human osteoarthritis and that impact the osteoarthritis disease process at different stages of initiation and progression will inform us about new directions for targeted therapies. PMID- 21788904 TI - The first analysis and clinical evaluation of native breast tissue using differential phase-contrast mammography. AB - OBJECTIVES: Phase-contrast and scattering-based x-ray imaging are known to provide additional and complementary information to conventional, absorption based methods, and therefore have the potential to play a crucial role in medical diagnostics. We report on the first mammographic investigation of 5 native, that is, freshly dissected, breasts carried out with a grating interferometer and a conventional x-ray tube source. Four patients in this study had histopathologically proven invasive breast cancer. One male patient, without the presence of any malignant formations within the resected breast, was included as a control specimen. MATERIALS AND METHODS: We used a Talbot-Lau grating setup installed on a conventional, low-brilliance x-ray source; the interferometer operated at the fifth Talbot distance, at a tube voltage of 40 kVp with mean energy of 28 keV, and at a current of 25 mA. The device simultaneously recorded absorption, differential phase and small-angle scattering signals from the native breast tissue. These quantities were then combined into novel color- and high frequency-enhanced radiographic images. Presurgical images (conventional mammography, ultrasonography, and magnetic resonance imaging) supported the findings and clinical relevance was verified. RESULTS: Our approach yields complementary and otherwise inaccessible information on the electron density distribution and the small-angle scattering power of the sample at the microscopic scale. This information can be used to potentially answer clinically relevant, yet unresolved questions such as unequivocally discerning between malignant and premalignant changes and postoperative scars and distinguishing cancer-invaded regions within healthy tissue. CONCLUSIONS: We present the first ex vivo images of fresh, native breast tissue obtained from mastectomy specimens using grating interferometry. This technique yields improved diagnostic capabilities when compared with conventional mammography, especially when discerning the type of malignant conversions and their breadth within normal breast tissue. These promising results advance us toward the ultimate goal, using grating interferometry in vivo on humans in a clinical setting. PMID- 21788903 TI - Repeat partial nephrectomy: surgical, functional and oncological outcomes. AB - PURPOSE OF REVIEW: The greater utilization of partial nephrectomy and ablative procedures has increased the incidence of patients presenting with local renal recurrence. The choice to either perform a partial or radical nephrectomy in these situations can be a challenging decision. RECENT FINDINGS: Repeat and salvage partial nephrectomy, while challenging and potentially associated with increased complications, offers patients the ability to maintain excellent renal functional outcomes and promising oncologic outcomes at intermediate follow-up. SUMMARY: Surgeons should be familiar with the surgical complications and the functional and oncologic outcomes of reoperative nephron-sparing surgery (NSS). Recent data and outcome analysis support utilization of these procedures in patients presenting with either local recurrence or de-novo lesions in the ipsilateral kidney. PMID- 21788905 TI - Near-infrared imaging of the breast using omocianine as a fluorescent dye: results of a placebo-controlled, clinical, multicenter trial. AB - OBJECTIVES: To evaluate the efficacy of the near-infrared (NIR) dye Omocianine in a placebo-controlled, dose-escalating multicenter trial for the detection of malignant breast lesions by using a NIR imaging system. MATERIALS AND METHODS: The study was approved by the ethical review board of Berlin and Munster,, and all participants provided written informed consent. Fifty-two consecutive patients were examined with NIR imaging before, during, and after intravenous injection of Omocianine. Three-dimensional absorption and fluorescence diffuse optical tomography scans were recorded simultaneously on a prototype NIR imaging unit (Computed Tomography Laser Mammography, Imaging Diagnostic Systems, Inc., Ft. Lauderdale, FL). Two readers assessed the images in consensus and assigned visibility scores to lesions seen on the absorption and absorption-corrected fluorescence diffuse optical tomography mammograms. Imaging results were compared with histopathologic findings. To analyze whether lesion detection rate for malignant lesions depended on the size of the lesion, lesions were dichotomized into those measuring less than 20 mm and those measuring 20 mm or more. Moreover, the shortest diameter between the center of the target lesions and the skin was measured on axial optical mammography data. RESULTS: There were a total of 53 target lesions. Histopathologically, 22 target lesions were diagnosed as benign and 31 target lesions as malignant. In the absorption mode, a detection rate of 11.8% for benign and 44.4% for malignant lesions across all dose groups was found. In the fluorescence mode, a detection rate of 17.6% was revealed for benign and 55.6% for malignant lesions across all dose groups. For dose group 0.1 mg/kg, a detection rate of 100% was found for malignant lesions in the fluorescence mode and 71.4% in the absorption mode. Across all dose groups in the fluorescence mode, detection rate for malignant target lesions in breasts smaller than the median axial breast diameter of 12.8 cm was higher with 69.2% than in median diameters >= 12.8 cm with 46.2%. Omocianine-enhanced fluorescence optical mammography allowed a better detection of more superficially located lesions, with detection rates for a lesion-skin distance <20 mm of 63.6%, for <30 mm of 47.4% and for >= 30 mm of 25%. Malignant target lesions with a diameter >= 20 mm were slightly better detected with 61.5% in contrast to suspicious lesions <20 mm with 53.8%. Optimal imaging time points varied strongly among the different target lesions and Omocianine dose groups, with a mean optimal time point for malignant lesions at 188 +/- 385 minutes. CONCLUSION: Preliminary data suggest that fluorescence imaging after Omocianine administration has the potential to detect malignant breast lesions. As our study showed considerable variations in the detection of breast cancer at different fluorophore concentrations ranging from 20% to 100%, future work needs to be done to assess the suitable dose for NIR imaging. PMID- 21788906 TI - Quantitative perfusion analysis of malignant liver tumors: dynamic computed tomography and contrast-enhanced ultrasound. AB - OBJECTIVE: To prospectively analyze the correlation between quantitative parameters of perfusion derived from dynamic contrast-enhanced CT (DCE-CT) and contrast-enhanced ultrasound (DCE-US) in patients with malignant liver tumors. MATERIALS AND METHODS: Thirty patients (mean age: 59.4 +/- 12.3 years) with primary malignant liver tumors or hepatic metastases of various origin underwent DCE-CT (4D spiral mode, scan range, 14.8 cm; 15 scans; cycle time, 3 seconds) and DCE-US (low mechanical index, <0.1, 2.4 mL microbubbles). DCE-CT and DCE-US images were evaluated by 2 radiologists regarding quantitative perfusion parameters including arterial liver perfusion (ALP), portal-venous perfusion (PVP), and total perfusion (P = ALP + PVP) from DCE-CT, as well as blood inflow velocity (B) and the normalized slope within the calculation range (CVan) from DCE-US. RESULTS: Quantitative assessment was possible with DCE-CT in 12/30 (40%) patients before and in all patients after automated motion correction. With DCE US, quantitative assessment could not be performed in 9/30 (30.0%) patients due to respiratory motion. Interreader agreements for quantitative perfusion analysis were good with DCE-CT (r = 0.640-0.892, each P < 0.001) and DCE-US (r = 0.761 0.909, each P < 0.001). Moderate significant correlations were found between the perfusion parameters from DCE-CT (P, ALP) and DCE-US (B, CVan) (r = 0.446-0.621, each P < 0.05). No significant correlations were found between PVP from CT and perfusion parameters from DCE-US (B, CVan; each P = nonsignificant). CONCLUSIONS: Quantitative evaluation of DCE-CT data was feasible in all patients after automated motion correction, whereas DCE-US data could not be quantitatively evaluated in 30% of patients due to respiratory motion and lack of motion correction software. Quantitative arterial perfusion analysis showed moderate significant correlations for blood flow parameters among modalities. PMID- 21788907 TI - Dual-energy computed tomography imaging of thyroid nodule specimens: comparison with pathologic findings. AB - OBJECTIVE: To quantitatively assess the imaging characteristics of thyroid nodules in dual-energy computed tomography (CT) imaging for differentiation of benign and malignant lesions. MATERIALS AND METHODS: Dual-energy CT imaging was performed on 97 surgically removed thyroid nodule specimens prior to their pathologic examination. Iodine- and water-based material decomposition images and 101 sets of pseudomonochromatic images of each thyroid specimen were reconstructed for quantitative imaging analysis. The iodine concentration and effective atomic number (Zeff) of thyroid nodules and surrounding normal thyroid tissues, HU curve slope (lambdaHU), and mean CT values of nodules were compared between different pathologic categories. RESULTS: In the 97 specimens, a total of 169 nodules were confirmed pathologically, including 108 nodular goiters (group A), 47 follicular adenomas (group B), and 14 papillary carcinomas (group C). Statistical analysis showed a significant difference between benign (A and B) and malignant (C) groups in iodine concentration (P < 0.001), lambdaHU (P < 0.001), and Zeff (P < 0.001). For mean CT values, there existed statistical difference between groups A and C, but no difference between groups B and C. No statistical significance was found at iodine concentrations, the Zeff, or lambdaHU in thyroid tissues surrounding nodules (P > 0.10). Additionally, water content was constant and homogeneous in nodules and adjacent thyroid tissues (P > 0.10). CONCLUSION: Pseudomonochromatic imaging reconstruction and material decomposition-based quantitative dual-energy CT imaging have promising potential for diagnostic differentiation of benign and malignant thyroid nodules. PMID- 21788908 TI - In vivo characterization of changing blood-tumor barrier permeability in a mouse model of breast cancer metastasis: a complementary magnetic resonance imaging approach. AB - OBJECTIVES: The current lack of efficacy for any chemo- or molecular therapeutic in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the blood-brain-barrier (BBB). Little is known about how heterogeneous permeability develops, or how it varies among individual metastases. Understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies. In this article, we developed the first magnetic resonance imaging-based strategy to detect and measure the volumes of BBB permeable and nonpermeable metastases and studied the development of altered BBB permeability in metastases in vivo, over time in a mouse model of breast cancer metastasis to the brain. MATERIALS AND METHODS: Animals bearing human experimental brain metastases of breast cancer (231-BR cells) were imaged, using 3-dimensional balanced steady-state free precession to visualize total metastases, and contrast-enhanced T1-weighted spin echo with gadopentetic acid (Gd-DTPA) to visualize which of these displayed contrast enhancement, as Gd-DTPA leakage is indicative of altered BBB permeability. RESULTS: Metastases detected 20 days after injection showed no Gd-DTPA enhancement. At day 25, 6.1% +/- 6.3% (mean +/- standard deviation) of metastases enhanced, and by day 30, 28.1% +/- 14.2% enhanced (P < 0.05). Enhancing metastases (mid: 0.14 +/- 0.18 mm, late: 0.24 +/- 0.32 mm) had larger volumes than nonenhancing (mid: 0.04 +/- 0.04 mm, late: 0.09 +/- 0.09 mm, P < 0.05); however, there was no significant difference between the growth rates of the 2. CONCLUSIONS: A significant number of brain metastases were uniformly nonpermeable, which highlights the need for developing treatment strategies that can overcome the permeability of the BBB. The model developed herein can provide the basis for in vivo evaluation of both BBB permeable and nonpermeable metastases response to therapy. PMID- 21788909 TI - Optic nerve head drusen in black patients. AB - BACKGROUND: Several studies have suggested racial differences in the prevalence of optic nerve head drusen (ONHD). We aimed to determine the percentage of patients with ONHD who are black and to describe the clinical, ophthalmoscopic, and perimetric findings in these patients. METHODS: We conducted a retrospective chart review of all patients with ONHD seen at our institution between 1989 and 2010. Only black patients with ONHD confirmed on either funduscopy or B-scan ultrasonography were included. Demographic and clinical findings in these patients were recorded and analyzed. RESULTS: Of the 196 patients with confirmed ONHD, 10 (5.1%) were black. This included 7 females and 3 males with ages ranging from 8 to 61 years. Six of the 10 patients had bilateral ONHD. The ONHD were buried in 11 of 16 eyes and exposed in 5 of 16 eyes. Fifteen of 16 eyes with ONHD had small cupless optic nerve heads. Visual fields were normal in 4 of 16 eyes with ONHD. In the remainder, visual field defects included an enlarged blind spot (5 eyes), constricted field (5 eyes), nasal defect (2 eyes), central defect (1 eye), and generalized depression (1 eye). Visual field defects were present in 4 of 5 eyes (80%) with exposed ONHD and 8 of 11 eyes (72.7%) with buried ONHD. None of the patients were related, and none of their examined family members had exposed ONHD on funduscopic examination. CONCLUSIONS: ONHD are rare in blacks, possibly due to the presence of a larger cup-to-disc ratio or a lack of predisposing genetic factors. Visual field defects are common in black patients with both exposed and buried ONHD. PMID- 21788910 TI - Longitudinal changes in bone lead levels: the VA Normative Aging Study. AB - OBJECTIVE: Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population. METHODS: Lead was measured every 3 to 5 years by k-x-ray fluorescence and mixed-effect models with random effects were used to evaluate change over time. RESULTS: A total of 554 participants provided up to four bone lead measurements. Final models predicted a -1.4% annual decline (95% CI: -2.2 to -0.7) for tibia lead and piecewise linear model for patella with an initial decline of 5.1% per year (95% CI: -6.2 to -3.9) during the first 4.6 years but no significant change thereafter (-0.4% [95% CI: -2.4 to 1.7]). CONCLUSIONS: These results suggest that bone lead half-life may be longer than previously reported. PMID- 21788911 TI - Examining the impact of worker and workplace factors on prolonged work absences among Canadian nurses. AB - OBJECTIVE: To evaluate the impact of worker and workplace factors and of their relationships on work absence duration. METHODS: Structural equation modeling of 11,762 female, Canadian nurses from the 2005 National Survey of the Work and Health of Nurses. RESULTS: Worker and workplace factors were associated with prolonged work absence. Key proximal predictors were pain-related work interference, depression, pain severity, and respect and support at work. More distal predictors were multimorbidity, abuse at work, and organizational culture. CONCLUSIONS: Worker health and workplace factors are important in explaining work absence duration. Self-management for pain and mood, adapted to the work context, may be useful for nurses with chronic pain or depression. Policy makers and administrators should focus on creating respect and support at work, and improving organizational culture. PMID- 21788912 TI - Horizontal distribution of the fecal microbiota in adolescents with inflammatory bowel disease. AB - BACKGROUND AND AIMS: The commensal microbiota of the gastrointestinal tract plays an important role in the pathogenesis of inflammatory bowel disease. We examined the horizontal structure of the fecal microbiota in the colon in adolescents with Crohn disease or ulcerative colitis and a control group. PATIENTS AND METHODS: Fecal samples were collected in 3 fractions from patients with Crohn disease (n = 22), ulcerative colitis (n = 12), and controls (n = 24) during preparation for colonoscopy. Additionally, biopsies from colon tissue were taken. Samples were examined using a culture technique and a fluorescent in situ hybridization method. The mucin degradation assay was carried out. RESULTS: Quantitative composition of the microbiota was different in the consecutive 3 fecal fractions and in the colon tissue of the study groups, but in patients from the control group, the composition of microbiota in the consecutive fractions was similar. Statistical analyses showed that the total distribution of the studied bacterial taxons in the contents in all 3 fecal fractions and in the colon tissue in the given disease group, and in the control group was characteristic for the studied patient group. Differences in species distribution among the cohorts studied were highly significant (P < 0.0001). Moreover, it was shown that in the fecal fraction I and in the colon tissue samples, there is no significant difference for any of the analyzed bacterial groups, using the culture methods or fluorescent in situ hybridization, but significant results were demonstrated in the II and III fractions for specific bacterial groups. The bacterial flora attached to the mucus layer in the UC group had significantly more degraded mucus in comparison with the control group (P = 0.045). CONCLUSIONS: Distribution of the microbiota in the colon is layered, which can be called horizontal distribution of the fecal flora. Only in the ulcerative colitis group, the bacterial flora attached to the mucous layer exerts action on the mucin. PMID- 21788913 TI - Transcription factor GATA-4 is abundantly expressed in childhood but not in adult liver tumors. AB - OBJECTIVES: Transcription factor GATA-4 is expressed in early fetal liver and essential for organogenesis. It is also implicated in carcinogenesis in several endoderm-derived organs. Hepatoblastoma (HB), the most common malignant pediatric liver tumor, has features of fetal liver including extramedullary hematopoiesis. We investigated the expression of GATA-4 and its purported target gene erythropoietin (Epo) in liver tumors and the role of GATA-4 in HB pathogenesis. PATIENTS AND METHODS: Immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction were used for liver samples from patients with HB or hepatocellular carcinoma. To further investigate the role of GATA-4 in pediatric liver tumors, we used adenoviral transfections of wild-type or dominant negative GATA-4 constructs in the human HB cell line, HUH6. RESULTS: We found abundant GATA-4 expression in both types of liver tumors in children, whereas it was absent in adult hepatocellular carcinoma. A close family member GATA-6 was expressed in a minority of childhood but not adult liver tumors. Epo, present in the fetal liver, was also expressed in childhood liver tumors. Moreover, cell line HUH6 was GATA-4 positive and produced Epo. We found that altering the amount of functional GATA-4 in HUH6 cells did not significantly affect either proliferation or apoptosis. CONCLUSIONS: GATA-4 is abundant in pediatric liver tumors, but unraveling its exact role in these neoplasms requires further investigation. PMID- 21788914 TI - Circumferential peptic ulceration from Meckel diverticulum by capsule endoscopy. PMID- 21788915 TI - Endoscopic management of gastrointestinal bleeding from multifocal lymphangioendotheliomatosis with thrombocytopenia: limited efficacy and complications. PMID- 21788916 TI - Catecholamine-secreting paraganglioma of the thoracic spinal column: report of an unusual case and review of the literature. AB - BACKGROUND AND IMPORTANCE: Paragangliomas are rare tumors of neuroendocrine origin that arise from paraganglionic tissue of the extrachromaffin cell system. These lesions may be seen at various sites along the neuraxis. Primary thoracic paragangliomas have rarely been reported in the literature, with secretory thoracic lesions being exceedingly rare as only 3 previous cases have been cited. CLINICAL PRESENTATION: A 49-year-old woman presented with episodes of hypertension, palpitations, and diaphoresis. Workup revealed positive urine catecholamines and a thoracic spine mass extending into the thoracic apex. Preoperative alpha-blockade with phenoxybenzamine was used followed by posterior decompression and tumor resection. Arthrodesis from C5 to T4 was subsequently performed, and the patient received postoperative radiation. CONCLUSION: Two years postoperatively, the patient has continued to have regression of her symptoms. We report a rare case of a catecholamine-secreting primary thoracic paraganglioma in a 49-year-old woman. These tumors should be treated carefully by the neurosurgeon with preoperative assistance from endocrinology for alpha blockade, followed by gross total resection and postoperative radiation if residual tumor remains. PMID- 21788917 TI - Method of aneurysm treatment does not affect clot clearance after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Patients undergoing neurosurgical clipping or endovascular coiling of a ruptured aneurysm may differ in their risk of vasospasm. OBJECTIVE: Because clot clearance affects vasospasm, we tested the hypothesis that clot clearance differs in patients depending on method of aneurysm treatment. METHODS: Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). Clot clearance was measured by change in Hijdra score between baseline computed tomography and one performed 24 to 48 hours after aneurysm treatment. Angiographic vasospasm was assessed by the use of catheter angiography 7 to 11 days after SAH, and delayed ischemic neurological deficit (DIND) was determined clinically. Extended Glasgow Outcome Score (GOSE) was assessed 3 months after SAH, and poor outcome was defined as death, vegetative state, or severe disability. Multivariable ordinal and binary logistic regression were used. RESULTS: There was no significant difference in the rate of clot clearance between patients undergoing clipping or coiling (P = .56). Coiling was independently associated with decreased severity of angiographic vasospasm (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.33-0.86), but not with DIND or GOSE. Greater clot clearance decreased the risk of severe angiographic vasospasm (OR 0.86, 95% CI 0.81-0.91), whereas higher baseline Hijdra score predicted increased angiographic vasospasm (OR 1.17, 95% CI 1.11-1.23) and poor GOSE (OR 1.09, 95% CI 1.04-1.14). CONCLUSION: Aneurysm coiling and increased clot clearance were independently associated with decreased severity of angiographic vasospasm in multivariate analysis, although no differences in clot clearance were seen between coiled and clipped patients. PMID- 21788918 TI - Temporary endovascular bypass: rescue technique during mechanical thrombolysis. AB - BACKGROUND: The goal of mechanical thrombolysis is to re-establish blood flow to a completely occluded artery in patients who fail intravenous thrombolytic therapy or who are outside the therapeutic window. OBJECTIVE: We present our single-institution experience with the use of temporary, partial deployment of a self-expanding intracranial stent as a rescue technique for the treatment of acute stroke. The use of the Enterprise stent represents an off-label use of a humanitarian device exemption device. METHODS: We performed a retrospective review of a prospective database of acute stroke patients treated with intra arterial techniques at the Thomas Jefferson University Comprehensive Stroke Center from July 2009 to July 2010. RESULTS: Seven patients were included, and we obtained a 100% recanalization rate to Thrombolysis in Myocardial Infarction grade 2 and 3 with a 28% asymptomatic hemorrhagic transformation. No device related complications were encountered. CONCLUSION: Temporary, partial deployment of a self-expanding intracranial stent as a rescue procedure is feasible, effective, and safe in the setting of endovascular intervention for acute stroke, although our experience is limited. This technique was used only as a rescue procedure when more established procedures failed. PMID- 21788919 TI - Intracranial sebaceous neoplasm: a case report. AB - BACKGROUND AND IMPORTANCE: Sebaceous neoplasms range from hyperplastic hamartomas to malignant tumors and are most commonly cutaneous lesions. We describe the first reported case of an intracranial sebaceous neoplasm, discussing the differential diagnosis and possible pathogenesis in relation to the current literature. CLINICAL PRESENTATION: A 58-year-old man presented with evolving neck stiffness, facial pain, and progressively worsening diplopia. Magnetic resonance imaging identified a moderate-sized lesion intimately related to the left cavernous sinus, which had extended into the posterior fossa. The patient underwent endoscopic, transnasal subtotal resection of the neoplasm with significant improvement. Histologically, the tumor was identified as a sebaceous neoplasm previously unreported intracranially. Follow-up imaging at 6 months revealed no further recurrence. CONCLUSION: This is the first reported case of an intracranial sebaceous neoplasm. Careful follow-up is required to help elucidate the biology of this tumor in an effort to determine the role of adjuvant therapy. PMID- 21788920 TI - A multicenter experience with generic tacrolimus conversion. AB - BACKGROUND: The first generic tacrolimus product gained Food and Drug Administration approval in August 2009. This prospective, observational trial sought to determine the need for dose titrations and measure drug cost savings on conversion to generic tacrolimus. METHODS: Transplant recipients on stable tacrolimus doses were converted from brand to generic tacrolimus on a mg:mg basis. Data were collected at the time of generic conversion (study arm) and at a time point exactly 6 months before conversion (control arm) for all subjects. RESULTS: Seventy conversions from four centers are reported. Subjects were a mean of 70 months after kidney (n=37), liver (n=28), or multiorgan (n=5) transplant. In the study arm, mean tacrolimus doses were 4.4 and 4.5 mg/d and mean tacrolimus trough concentrations were 5.8 and 5.9 ng/mL before and after conversion, respectively. In the control arm, mean tacrolimus doses were 4.6 and 4.6 mg/d and mean tacrolimus trough concentrations were 6.1 and 5.9 ng/mL before and after the control time point, respectively. Dose titrations occurred in five patients (7%) in the control arm and 15 patients (21%) in the study arm (P=0.028). Mean monthly drug costs were $645 for brand, $593 for generic, and $595 for generic after dose titrations. Mean monthly patient copays were $38 for brand and $15 for generic. CONCLUSIONS: These cumulative data show that dose requirements and trough levels are similar between brand and generic tacrolimus and that generic substitution allows for savings. However, postconversion monitoring is prudent as patients may require dose titration. PMID- 21788921 TI - Patterns of alcohol and drug use among depressed older adults seeking outpatient psychiatric services. AB - OBJECTIVE: Alcohol and drug use and related problems may compromise depression treatment, and older adults may be especially at risk for poor outcomes. However, alcohol and drug use among older adults have not been studied in settings in which depression treatment is provided. This study examined the prevalence and clinical and demographic correlates of alcohol and drug use and misuse of prescription drugs among adults with depression seeking outpatient psychiatric care (excluding chemical dependency treatment). METHODS: The sample included 154 older adults (age 60 years and older who scored >=10 on the Beck Depression Inventory-II [BDI-II] at intake). Participants also completed alcohol and drug use questions and the Short Michigan Alcohol Screening Test. RESULTS: Recent alcohol and drug use, heavy episodic drinking, and history of alcohol-related problems were common. Alcohol use in the prior 30 days was reported by 53% of men and 50% of women. Cannabis use in the prior 30 days was reported by 12% of men and 4% of women; and misuse of sedatives in the prior 30 days was reported by 16% of men and 9% of women. In exact logistic regression, higher BDI-II score was associated with cannabis use (odds ratio = 15.8, 95% confidence interval = 2.0 734.0, exactp = 0.003). CONCLUSIONS: Older adults with depression are likely to present for treatment with a range of concurrent alcohol and drug use patterns, including cannabis use and misuse of prescription medication. Clinicians should evaluate depressed patients for substance use and related problems and consider appropriate interventions. PMID- 21788922 TI - Risk of coronary heart disease events over 15 years among older adults with depressive symptoms. AB - OBJECTIVES: To determine whether depression status is associated with an increased risk of coronary heart disease (CHD) events, defined as CHD death or nonfatal acute myocardial infarction (MI). DESIGN: Prospective cohort study. SETTING: An urban primary care practice. PARTICIPANTS: Two thousand seven hundred twenty-eight adults (71.4% women, 65.5% black), age 60 years and older, who were screened for depression between 1991 and 1993. MEASUREMENTS: Depressive symptom severity at baseline was assessed by the Center for Epidemiologic Studies Depression Scale (CES-D). Data regarding baseline demographic and clinical variables, as well as laboratory evidence of acute MI, were obtained from an electronic medical record system. All-cause mortality and CHD death were determined from the National Death Index through 2006. RESULTS: A total of 423 (15.5%) participants reported elevated symptoms of depression (CES-D score >=16). During the 13 to 16 years of follow-up, 1,646 (60.3%) individuals died from any cause, and 727 (26.6%) died from CHD or suffered an acute MI. Cox proportional hazards models revealed that individuals with elevated depressive symptoms were more likely to experience a CHD event, even after adjustment for demographics and comorbid health conditions (relative risk = 1.46, 95% confidence interval: 1.20 1.77). Depression status was also a significant predictor of all-cause mortality in adjusted models. CONCLUSIONS: We report the longest prospective study to date to examine depression status as an independent risk factor for CHD among a cohort of older adults including large numbers of women and underrepresented minorities. The present findings underscore the need to consider depression as a common and modifiable risk factor for CHD events among older adults. PMID- 21788923 TI - Depressive symptoms and change in abdominal obesity in the elderly: positive or negative association? AB - OBJECTIVES: Recent evidence suggests that depression can result in abdominal obesity in the elderly. Few longitudinal studies are available and none has been conducted outside the United States. METHODS: To examine the relationship between depressive symptoms and abdominal obesity, data from 3,998 community-dwelling Chinese elderly men and women age 65 years and older with 4-year follow-up were analyzed. Depression was defined by a Geriatric Depression Scale score of 8 or higher. At baseline and after 4 years, overall obesity measures included body mass index, percentage of body fat, and general adiposity or body fat index (expressed by total body fat mass measured by DEXA (dual-energy x-ray absorptiometry) in kilograms divided by the square of stature in meters). Abdominal obesity measures included waist circumference, waist to hip ratio, and relative truncal fat (ratio of truncal fat mass to total fat mass measured by DEXA). RESULTS: After adjustment for sociodemographics, lifestyle, and medical factors, the presence of clinically relevant depressive symptoms at baseline was associated with significant decrease in waist circumference at follow-up after adjusting for sociodemographic factors, baseline obesity, lifestyle, and medical factors (beta = -1.801, t = -2.93, df = 1564, p = 0.0034), although this relationship disappeared in older age women in further age-stratified analysis. CONCLUSIONS: This study shows that depressive symptoms may result in a decrease in abdominal obesity, suggesting that more research is needed to further explore this relationship. Similar studies conducted in different cultural groups may help to explain these conflicting findings. PMID- 21788924 TI - Association of personality traits with elder self-neglect in a community-dwelling population. AB - OBJECTIVE: Elder self-neglect is an important public health issue. However, little is known about the association between personality traits and risk of elder self-neglect among community-dwelling populations. The objectives of this study are as follows: 1) to examine the association of personality traits with elder self-neglect and 2) to examine the association of personality traits with elder self-neglect severity. METHODS: Population-based study conducted from 1993 to 2005 of community-dwelling older adults (N = 9,056) participating in the Chicago Health Aging Project (CHAP). Subsets of the CHAP participants (N = 1,820) were identified for suspected self-neglect by social services agency, which assessed the severity. Personality traits assessed included neuroticism, extraversion, rigidity, and information processing. Logistic and linear regressions were used to assess these associations. RESULTS: In the bivariate analyses, personality traits (neuroticism, extraversion, information processing, and rigidity) were significantly associated with increased risk of elder self neglect. However, after adjusting for potential confounders, the above associations were no longer statistically significant. In addition, personality traits were not associated with increased risk of greater self-neglect severity. Furthermore, interaction term analyses of personality traits with health and psychosocial factors were not statistically significant with elder self-neglect outcomes. CONCLUSION: Neuroticism, extraversion, rigidity, and information processing were not associated with significantly increased risk of elder self neglect after consideration of potential confounders. PMID- 21788925 TI - Adaptive competence impairment and cognitive deficits in acutely ill schizophrenia patients residing in nursing homes. AB - OBJECTIVES: The loss of long-term inpatient psychiatric hospital beds over the years has caused schizophrenia patients of all ages to be increasingly placed in nursing home environments that were traditionally reserved for elderly patients. Consequently, many nongeriatric patients with chronic schizophrenia are now residing in nursing home settings. The objective of this article is to determine whether many of these nongeriatric patients are placed in nursing homes because of chronicity of illness and severity of impairment, or because of the limited alternative viable housing options. DESIGN: Multiple and stepwise regressions examined predictors of cognitive ability, adaptive competence, social skills and inpatient social and adaptive functioning, and clinical symptomatology. SETTING: Inpatient psychiatric unit in a general hospital. PARTICIPANTS: Fifty acutely ill geriatric and nongeriatric patients with schizophrenia who reside in nursing homes. MEASUREMENTS: Participants' clinical symptoms, cognitive ability, adaptive functioning, social skills, and inpatient social and adaptive functioning were assessed. RESULTS: Findings revealed that patients' cognitive impairment and age of admission to the nursing home, irrespective of patients' current age, were predictors of impaired adaptive competence. CONCLUSIONS: Examination of cognitive and adaptive deficits with assessment of symptom severity, independent of patients' current age, may aide in the determination of appropriate residential placements for individuals with schizophrenia. PMID- 21788926 TI - Synthesis and biological evaluation of novel (99m)Tc-labelled bisphosphonates as superior bone imaging agents. AB - A series of novel zoledronic acid (ZL) derivatives 1-hydroxy-3-(2-methyl-1H imidazol-1-yl)propane-1,1-diyldiphosphonic acid (MIPrDP), 1-hydroxy-4-(2-methyl 1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (MIBDP), and 1-hydroxy-5-(2 methyl-1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (MIPeDP) were prepared and successfully labeled with (99m)Tc in high labeling yields. The in vitro stability and in vivo biodistribution of (99m)Tc-MIPrDP, (99m)Tc-MIBDP and (99m)Tc-MIPeDP were investigated and compared. The biodistribution studies indicate that the radiotracer (99m)Tc-MIPrDP has highly selective uptake in the skeletal system and rapid clearance from soft tissues. The present findings indicate that (99m)Tc-MIPrDP holds great potential for use in bone imaging. PMID- 21788927 TI - Antioxidant activity of papaya seed extracts. AB - The antioxidant activities of the ethanol, petroleum ether, ethyl acetate, n butanol and water extract fractions from the seeds of papaya were evaluated in this study. The ethyl acetate fraction showed the strongest DPPH and hydroxyl free radical-scavenging activities, and its activities were stronger than those of ascorbic acid and sodium benzoate, respectively. The n-butanol fraction demonstrated the greatest ABTS+ radicals scavenging activity. The ethyl acetate fraction and the n-butanol fraction not only showed higher antioxidant activities than the petroleum ether fraction, water fraction and ethanol fraction, but also showed higher superoxide anion and hydrogen peroxide radicals scavenging activities than those of the other extract fractions. The high amount of total phenolics and total flavonoids in the ethyl acetate and n-butanol fractions contributed to their antioxidant activities. The ethyl acetate fraction was subjected to column chromatography, to yield two phenolic compounds, p hydroxybenzoic acid and vanillic acid, which possessed significant antioxidant activities. Therefore, the seeds of papaya and these compounds might be used as natural antioxidants. PMID- 21788928 TI - Preliminary phytochemical screening and in vitro anti-helicobacter pylori activity of extracts of the stem bark of Bridelia micrantha (Hochst., Baill., Euphorbiaceae). AB - Helicobacter pylori is a major risk factor for gastritis, ulcers and gastric cancer. This study was aimed to determine the antimicrobial activity of the stem bark of Bridelia. micrantha on H. pylori isolated in South Africa. Extracts and clarithromycin were tested against 31 clinical strains, including a standard strain (NCTC 11638) of H. pylori, by measuring the diameters of the corresponding inhibition zones, followed by determination of the Minimum Inhibitory Concentration (MIC) (using metronidazole, and amoxicillin as control antibiotics) and the rate of kill. Preliminary phytochemical screening was also done. Inhibition zone diameters which ranged from 0-23 mm were observed for all five of the extracts and 0-35 mm for clarithromycin. Marked susceptibility of strains (100%) was noted for the acetone extract (P < 0.05), followed by ethyl acetate extract (93.5%). The MIC50 values ranged from 0.0048 to 0.156 mg/mL for the ethyl acetate extract and 0.0048 to 0.313 mg/mL for the acetone extract. The MIC90 values ranged from 0.0048 to 2.5 mg/mL for the ethyl acetate extract and 0.078 to > 0.625 mg/mL for the acetone extract, respectively. Insignificant statistical difference in potency was observed when comparing the crude ethyl acetate extract to metronidazole and amoxicillin (P > 0.05). Complete killing of strain PE430C by the ethyl acetate extract was observed at 0.1 mg/mL (2 * MIC) and 0.2 mg/mL (4 * MIC) at 66 and 72 h. For strain PE369C, 100% killing was observed at 0.1 mg/mL (2 * MIC) in 66 and 72 h. The ethyl acetate extract could thus be a potential source of lead molecules for the design of new anti-Helicobacter pylori therapies as this study further confirmed the presence of phytochemicals including alkaloids, flavonoids, steroids, tannins and saponins. PMID- 21788929 TI - New 3',8''-linked biflavonoids from Selaginella uncinata displaying protective effect against anoxia. AB - Seven 3',8''-linked bioflavonoids, including one new compound, (2''S)-2'', 3'' dihydroamentoflavone-4'-methyl ether and six known compounds: (2S)-2,3- dihydroamentoflavone-4'-methyl ether, (2S,2''S)-2,3,2'',3''-tetrahydroamento- flavone-4'-methyl ether, (2S,2''S)-tetrahydroamentoflavone, (2S)-2,3-dihydro- amentoflavone and (2''S)-2'',3''-dihydroamentoflavone (6) and amentoflavone, were isolated from the 60% ethanolic extract of Selaginella uncinata (Desv.) Spring. The structures of these compounds were elucidated mainly by analysis of their 1D and 2D NMR spectroscopic data, and their absolute configurations were determined by circular-dichroism (CD) spectroscopy. All the seven compounds showed protective effect against anoxia in the anoxic PC12 cells assay, in which compound 6 displayed particularly potent activity. PMID- 21788930 TI - The Suzuki reaction in aqueous media promoted by P, N ligands. AB - The synthesis and structure of palladium complexes of trisubstituted PTA derivatives, PTA(R3), are described. Water-soluble phosphine ligands 1,3,5-triaza 7-phosphaadmantane (PTA), tris(aminomethyl)phosphine trihydrobromide, tri(aminomethyl) phosphine, 3,7-dimethyl-1,5,7-triaza-3 phosphabicyclo[3,3,1]nonane (RO-PTA), 3,7-diacetyl-1,3,7-triaza-5 phosphabicyclo[3.3.1]nonane (DAPTA), lithium 1,3,5-triaza-7-phosphaadamantane-6 carboxylate (PTA-CO2Li), 2,4,6-triphenyl-1,3,5-triaza-7-phosphatricyclo [3.3.1.1]decane, and 2,4,6-triphenyl-1,3,5-triaza-7 phosphatricyclo[3.3.1.1]decane were used as ligands for palladium catalyzed Suzuki reactions in aqueous media. RO-PTA in combination with palladium acetate or palladium chloride was the most active catalyst for Suzuki cross coupling of aryl bromides and phenylboronic acid at 80 degrees C in 1:1 water:acetonitrile. The activity of Pd(II) complexes of RO-PTA is comparable to PPh2(m-C6H4SO3Na) (TPPMS) and P(m-C6H4SO3Na)3 (TPPTS) and less active than tri(4,6-dimethyl-3 sulfonatophenyl)phosphine trisodium salt (TXPTS). Activated, deactivated, and sterically hindered aryl bromides were examined, with yields ranging from 50% to 90% in 6 h with 5% palladium precatalyst loading. X-ray crystal structures of (RO PTA)PdCl2, (PTA(R3))2PdCl2 (R = Ph, p-tert-butylC6H5), and PTA(R3) (R = p-tert butylC6H5) are reported. PMID- 21788931 TI - Antiradical, chelating and antioxidant activities of hydroxamic acids and hydroxyureas. AB - Reactive oxygen species, along with reactive nitrogen species, may play an important role in the pathogenesis and progress of many diseases, including cancer, diabetes and sickle cell disease. It has been postulated that hydroxyurea, one of the main treatments in sickle cell disease, achieves its activity partly also through its antioxidant properties. A series of hydroxyurea derivatives of L- and D-amino acid amides and cycloalkyl-N-aryl-hydroxamic acids was synthesized and investigated for their radical scavenging activity, chelating properties and antioxidant activity. All the compounds showed exceptional antiradical activities. For example, free radical scavenging activities of investigated hydroxyureas were higher than the activity of standard antioxidant, butylated hydroxyanisole (BHA). Moreover, most of the investigated hydroxamic acids were stronger Fe2+ ion chelators than quercetin. In addition, the investigated compounds, especially hydroxamic acids, were proven to be excellent antioxidants. They were as effective as BHA in inhibiting beta-carotene-linoleic acid coupled oxidation. It is reasonable to assume that the antioxidant activity of the investigated compounds could contribute to their previously proven biological properties as cytostatic and antiviral agents. PMID- 21788932 TI - Anticancer activity of chamaejasmine: effect on tubulin protein. AB - In this work, the anticancer activity of chamaejasmine was studied by evaluating its in vitro cytotoxicity against several human cancer cell lines (MCF-7, A549, SGC-7901, HCT-8, HO-4980, Hela, HepG2, PC-3, LNCap, Vero and MDCK) using the MTT assay. Results indicated chamaejasmine showed more notable anticancer activity than taxol against PC-3 cells, with IC50 values of 2.28 and 3.98 uM, respectively. Furthermore, Western blot analysis showed that chamaejasmine was able to increase the expression of beta-tubulin, but not alpha-tubulin. In silico simulations indicated that chamaejasmine specifically interacts with the active site which is located at the top of beta-tubulin, thanks to the presence of strong hydrophobic effects between the core templates and the hydrophobic surface of the TB active site. The binding energy (E(inter)) was calculated to be -164.77 kcal.mol-1. Results presented here suggest that chamaejasmine possesses anti cancer properties relating to beta-tubulin depolymerization inhibition, and therefore is a potential source of anticancer leads for the pharmaceutical industry. PMID- 21788933 TI - The inhibitory potential of Thai mango seed kernel extract against methicillin resistant Staphylococcus aureus. AB - Plant extracts are a valuable source of novel antibacterial compounds to combat pathogenic isolates of methicillin-resistant Staphylococcus aureus (MRSA), a global nosocomial infection. In this study, the alcoholic extract from Thai mango (Mangifera indica L. cv. 'Fahlun') seed kernel extract (MSKE) and its phenolic principles (gallic acid, methyl gallate and pentagalloylglucopyranose) demonstrated potent in vitro antibacterial activity against Staphylococcus aureus and 19 clinical MRSA isolates in studies of disc diffusion, broth microdilution and time-kill assays. Electron microscopy studies using scanning electron microscopy and transmission electron microscopy revealed impaired cell division and ultra-structural changes in bacterial cell morphology, including the thickening of cell walls, of microorganisms treated with MSKE; these damaging effects were increased with increasing concentrations of MSKE. MSKE and its phenolic principles enhanced and intensified the antibacterial activity of penicillin G against 19 clinical MRSA isolates by lowering the minimum inhibitory concentration by at least 5-fold. The major phenolic principle, pentagalloylglucopyranose, was demonstrated to be the major contributor to the antibacterial activity of MSKE. These results suggest that MSKE may potentially be useful as an alternative therapeutic agent or an adjunctive therapy along with penicillin G in the treatment of MRSA infections. PMID- 21788935 TI - GABA-activated single-channel and tonic currents in rat brain slices. AB - The GABA(A) channels are present in all neurons and are located both at synapses and outside of synapses where they generate phasic and tonic currents, respectively. The GABA(A) channel is a pentameric GABA-gated chloride channel. The channel subunits are grouped into 8 families (alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, pi and rho). Two alphas, two betas and one 3(rd) subunit form the functional channel. By combining studies of sub-type specific GABA activated single-channel molecules with studies including all populations of GABA(A) channels in the neuron it becomes possible to understand the basic mechanism of neuronal inhibition and how it is modulated by pharmacological agents. We use the patch-clamp technique to study the functional properties of the GABA(A) channels in alive neurons in hippocampal brain slices and record the single-channel and whole-cell currents. We further examine how the channels are affected by different GABA concentrations, other drugs and intra and extracellular factors. For detailed theoretical and practical description of the patch-clamp method please see The Single-Channel Recordings edited by B Sakman and E Neher. PMID- 21788936 TI - A fluorescence microscopy assay for monitoring mitophagy in the yeast Saccharomyces cerevisiae. AB - Autophagy is important for turnover of cellular components under a range of different conditions. It serves an essential homeostatic function as well as a quality control mechanism that can target and selectively degrade cellular material including organelles. For example, damaged or redundant mitochondria (Fig. 1), not disposed of by autophagy, can represent a threat to cellular homeostasis and cell survival. In the yeast, Saccharomyces cerevisiae, nutrient deprivation (e.g., nitrogen starvation) or damage can promote selective turnover of mitochondria by autophagy in a process termed mitophagy. We describe a simple fluorescence microscopy approach to assess autophagy. For clarity we restrict our description here to show how the approach can be used to monitor mitophagy in yeast cells. The assay makes use of a fluorescent reporter, Rosella, which is a dual-emission biosensor comprising a relatively pH-stable red fluorescent protein linked to a pH-sensitive green fluorescent protein. The operation of this reporter relies on differences in pH between the vacuole (pH - 5.0-5.5) and mitochondria (pH - 8.2) in living cells. Under growing conditions, wild type cells exhibit both red and green fluorescence distributed in a manner characteristic of the mitochondria. Fluorescence emission is not associated with the vacuole. When subjected to nitrogen starvation, a condition which induces mitophagy, in addition to red and green fluorescence labeling the mitochondria, cells exhibit the accumulation of red, but not green fluorescence, in the acidic vacuolar lumen representing the delivery of mitochondria to the vacuole. Scoring cells with red, but not green fluorescent vacuoles can be used as a measure of mitophagic activity in cells. PMID- 21788937 TI - Investigating outer hair cell motility with a combination of external alternating electrical field stimulation and high-speed image analysis. AB - OHCs are cylindrical sensorimotor cells located in the Organ of Corti, the auditory organ inside the mammalian inner ear. The name "hair cells" derives from their characteristic apical bundle of stereocilia, a critical element for detection and transduction of sound energy. OHCs are able to change shape elongate, shorten and bend- in response to electrical, mechanical and chemical stimulation, a motor response considered crucial for cochlear amplification of acoustic signals. OHC stimulation induces two different motile responses: i) electromotility, a.k.a fast motility, changes in length in the microsecond range derived from electrically-driven conformational changes in motor proteins densely packed in OHC plasma membrane, and ii) slow motility, shape changes in the millisecond to seconds range involving cytoskeletal reorganization. OHC bending is associated with electromotility, and result either from an asymmetric distribution of motor proteins in the lateral plasma membrane, or asymmetric electrical stimulation of those motor proteins (e.g., with an electrical field perpendicular to the long axis of the cells). Mechanical and chemical stimuli induce essentially slow motile responses, even though changes in the ionic conditions of the cells and/or their environment can also stimulate the plasma membrane-embedded motor proteins. Since OHC motile responses are an essential component of the cochlear amplifier, the qualitative and quantitative analysis of these motile responses at acoustic frequencies (roughly from 20 Hz to 20 kHz in humans) is a very important matter in the field of hearing research. The development of new imaging technology combining high-speed videocameras, LED based illumination systems, and sophisticated image analysis software now provides the ability to perform reliable qualitative and quantitative studies of the motile response of isolated OHCs to an external alternating electrical field (EAEF). This is a simple and non-invasive technique that circumvents most of the limitations of previous approaches. Moreover, the LED-based illumination system provides extreme brightness with insignificant thermal effects on the samples and, because of the use of video microscopy, optical resolution is at least 10 fold higher than with conventional light microscopy techniques. For instance, with the experimental setup described here, changes in cell length of about 20 nm can be routinely and reliably detected at frequencies of 10 kHz, and this resolution can be further improved at lower frequencies. We are confident that this experimental approach will help to extend our understanding of the cellular and molecular mechanisms underlying OHC motility. PMID- 21788938 TI - Visualization of recombinant DNA and protein complexes using atomic force microscopy. AB - Atomic force microscopy (AFM) allows for the visualizing of individual proteins, DNA molecules, protein-protein complexes, and DNA-protein complexes. On the end of the microscope's cantilever is a nano-scale probe, which traverses image areas ranging from nanometers to micrometers, measuring the elevation of macromolecules resting on the substrate surface at any given point. Electrostatic forces cause proteins, lipids, and nucleic acids to loosely attach to the substrate in random orientations and permit imaging. The generated data resemble a topographical map, where the macromolecules resolve as three-dimensional particles of discrete sizes (Figure 1). Tapping mode AFM involves the repeated oscillation of the cantilever, which permits imaging of relatively soft biomaterials such as DNA and proteins. One of the notable benefits of AFM over other nanoscale microscopy techniques is its relative adaptability to visualize individual proteins and macromolecular complexes in aqueous buffers, including near-physiologic buffered conditions, in real-time, and without staining or coating the sample to be imaged. The method presented here describes the imaging of DNA and an immunoadsorbed transcription factor (i.e. the glucocorticoid receptor, GR) in buffered solution (Figure 2). Immunoadsorbed proteins and protein complexes can be separated from the immunoadsorbing antibody-bead pellet by competition with the antibody epitope and then imaged (Figure 2A). This allows for biochemical manipulation of the biomolecules of interest prior to imaging. Once purified, DNA and proteins can be mixed and the resultant interacting complex can be imaged as well. Binding of DNA to mica requires a divalent cation, such as Ni(2+) or Mg(2+), which can be added to sample buffers yet maintain protein activity. Using a similar approach, AFM has been utilized to visualize individual enzymes, including RNA polymerase and a repair enzyme, bound to individual DNA strands. These experiments provide significant insight into the protein-protein and DNA-protein biophysical interactions taking place at the molecular level. Imaging individual macromolecular particles with AFM can be useful for determining particle homogeneity and for identifying the physical arrangement of constituent components of the imaged particles. While the present method was developed for visualization of GR-chaperone protein complexes) and DNA strands to which the GR can bind, it can be applied broadly to imaging DNA and protein samples from a variety of sources. PMID- 21788939 TI - Use of a hanging-weight system for isolated renal artery occlusion. AB - In hospitalized patients, over 50% of cases of acute kidney injury (AKI) are caused by renal ischemia. A recent study of hospitalized patients revealed that only a mild increase in serum creatinine levels (0.3 to 0.4 mg/dl) is associated with a 70% greater risk of death than in persons without any increase. Along these lines, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a renal failure rates of up to 30%. Similarly, AKI after cardiac surgery occurs in over 10% of patients under normal circumstances and is associated with dramatic increases in mortality. AKI are also common complications after liver transplantation. At least 8-17% of patients end up requiring renal replacement therapy. Moreover, delayed graft function due to tubule cell injury during kidney transplantation is frequently related to ischemia-associated AKI. Moreover, AKI occurs in approximately 20% of patients suffering from sepsis. The occurrence of AKI is associated with dramatic increases of morbidity and mortality. Therapeutic approaches are very limited and the majority of interventional trials in AKI have failed in humans. Therefore, additional therapeutic modalities to prevent renal injury from ischemia are urgently needed. To elucidate mechanisms of renal injury due to ischemia and possible therapeutic strategies murine models are intensively required. Mouse models provide the possibility of utilizing different genetic models including gene-targeted mice and tissue specific gene-targeted mice (cre-flox system). However, murine renal ischemia is technically challenging and experimental details significantly influence results. We performed a systematic evaluation of a novel model for isolated renal artery occlusion in mice, which specifically avoids the use of clamping or suturing the renal pedicle. This model requires a nephrectomy of the right kidney since ischemia can be only performed in one kidney due to the experimental setting. In fact, by using a hanging-weight system, the renal artery is only instrumented once throughout the surgical procedure. In addition, no venous or urethral obstruction occurs with this technique. We could demonstrate time-dose-dependent and highly reproducible renal injury with ischemia by measuring serum creatinine. Moreover, when comparing this new model with conventional clamping of the whole pedicle, renal protection by ischemic preconditioning is more profound and more reliable. Therefore his new technique might be useful for other researchers who are working in the field of acute kidney injury. PMID- 21788940 TI - Quantitative autonomic testing. AB - Disorders associated with dysfunction of autonomic nervous system are quite common yet frequently unrecognized. Quantitative autonomic testing can be invaluable tool for evaluation of these disorders, both in clinic and research. There are number of autonomic tests, however, only few were validated clinically or are quantitative. Here, fully quantitative and clinically validated protocol for testing of autonomic functions is presented. As a bare minimum the clinical autonomic laboratory should have a tilt table, ECG monitor, continuous noninvasive blood pressure monitor, respiratory monitor and a mean for evaluation of sudomotor domain. The software for recording and evaluation of autonomic tests is critical for correct evaluation of data. The presented protocol evaluates 3 major autonomic domains: cardiovagal, adrenergic and sudomotor. The tests include deep breathing, Valsalva maneuver, head-up tilt, and quantitative sudomotor axon test (QSART). The severity and distribution of dysautonomia is quantitated using Composite Autonomic Severity Scores (CASS). Detailed protocol is provided highlighting essential aspects of testing with emphasis on proper data acquisition, obtaining the relevant parameters and unbiased evaluation of autonomic signals. The normative data and CASS algorithm for interpretation of results are provided as well. PMID- 21788943 TI - Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. AB - In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with mood and anxiety disorders. The results of such studies could have significant implications for the development of novel treatments for these disorders. A challenge currently facing the field is to assimilate the large and growing corpus of imaging data to inform a systems level model of the neural circuitry underlying the disorders. One prominent theoretical perspective highlights the top-down inhibition of amygdala by ventromedial prefrontal cortex (vmPFC) as a crucial neural mechanism that may be defective in certain mood and anxiety disorders, such as major depression and post-traumatic stress disorder. In this article, we provide a critical review of animal and human data related to this model. In particular, we emphasize the considerable body of research that challenges the veracity (or at least completeness) of the predominant model. We propose a framework for constructing a more comprehensive model of vmPFC function, with the goal of fostering further progress in understanding the neuropathophysiological basis of mood and anxiety disorders. PMID- 21788941 TI - P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis. AB - P-glycoprotein (Pgp), a product of the multi-drug resistance gene MDR1a, is a broad specificity efflux ATP cassette transmembrane transporter that is predominantly expressed in epithelial tissues. Because mdr1a(-/-) mice tend to develop spontaneous colitis in bacteria-dependent manner, Pgp is believed to have a role in protection of the intestinal epithelium from luminal bacteria. Here we demonstrate that levels of Pgp in the small intestine of newborn rodents dramatically increase during breastfeeding, but not during formula feeding (FF). In rats and mice, levels of intestinal Pgp peak on days 3-7 and 1-5 of breastfeeding, respectively. The mdr1a(-/-) neonatal mice subjected to FF, hypoxia, and hypothermia have significantly higher incidence and pathology, as well as significantly earlier onset of necrotizing enterocolitis (NEC) than congenic wild type mice. Breast-fed mdr1a(-/-) neonatal mice are also more susceptible to intestinal damage caused by the opportunistic pathogen Cronobacter sakazakii that has been associated with hospital outbreaks of NEC. Breast milk, but not formula, induces Pgp expression in enterocyte cell lines in a dose- and time-dependent manner. High levels of ectopically expressed Pgp protect epithelial cells in vitro from apoptosis induced by C. sakazakii. Taken together, these results show that breast milk-induced expression of Pgp may have a role in the protection of the neonatal intestinal epithelium from injury associated with nascent bacterial colonization. PMID- 21788945 TI - Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling. AB - Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease. PMID- 21788944 TI - Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. AB - AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use- lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients. PMID- 21788946 TI - The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. AB - Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G(2)/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n=6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies. PMID- 21788947 TI - Coexistence of trisomies of chromosomes 12 and 19 in chronic lymphocytic leukemia occurs exclusively in the rare IgG-positive variant. PMID- 21788948 TI - Mobilization of stem and progenitor cells in cardiovascular diseases. AB - Circulating bone marrow (BM)-derived stem and progenitor cells (SPCs) participate in turnover of vascular endothelium and myocardial repair after acute coronary syndromes. Acute myocardial infarction (MI) produces a generalized inflammatory reaction, including mobilization of SPCs, increased local production of chemoattractants in the ischemic myocardium, as well as neural and humoral signals activating the SPC egress from the BM. Several types of circulating BM cells were identified in the peripheral blood, including hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, circulating angiogenic cells and pluripotent very small embryonic-like cells; however, the contribution of circulating cells to the myocardial and endothelial repair is still unknown. The number and function of these cells is impaired in patients with diabetes and other cardiovascular risk factors, but can be improved by physical exercise and use of statins. The mobilization of SPCs in acute coronary syndromes and stable coronary artery disease seems to predict the clinical outcomes in selected groups of patients. Interpretation of the findings has to incorporate other factors that modulate the process of mobilization, such as coexisting diseases, age and medications. This review discusses the mobilization of SPCs in acute ischemia (MI, stroke), as well as in stable cardiovascular disease, and highlights the possibility of using the SPC as a marker of cardiovascular risk. PMID- 21788949 TI - GSK3 inhibitors enhance retinoic acid receptor activity and induce the differentiation of retinoic acid-sensitive myeloid leukemia cells. PMID- 21788950 TI - Epstein-Barr virus microRNAs repress BCL6 expression in diffuse large B-cell lymphoma. PMID- 21788951 TI - Evaluation of methods to estimate glomerular filtration rate versus actual drug clearance in patients with chronic spinal cord injury. AB - STUDY DESIGN: A retrospective chart review. OBJECTIVES: To evaluate different methods of estimating renal function compared with patient-specific vancomycin and aminoglycoside (AG) clearance (CL(DRUG)) in patients with spinal cord injury (SCI), and to develop a new equation to more accurately estimate glomerular filtration rate (GFR) in SCI patients in order to optimize dosing for vancomycin and AG. SETTING: Veterans Affairs medical center in California, United States of America, tertiary care facility with the largest inpatient SCI center in the VA system. METHODS: Retrospective data collection from patient records. Pharmacokinetic analysis was performed to obtain actual CL(DRUG,) which is compared with different methods of estimating GFR.A total of 310 patients were initially assessed; however, only 141 patients met the inclusion criteria, had a diagnosis of chronic SCI, and received vancomycin or AG with at least one drug level at steady state from January to December of 2008. RESULTS: All four equations evaluated to estimate GFR significantly overestimated CL(DRUG): the Modification of Diet in Renal Disease equation by 141%, Cockcroft-Gault equation by 83%, Chronic Kidney Disease Epidemiology Collaboration equation by 82% and 24 h endogenous creatinine clearance by 71% (P<0.001). The modified Cockcroft-Gault equation (CL(M)) showed improvement, however, still overestimated CL(DRUG) by 39% (P<0.001). Thus, a new equation for SCI (CL(SCI)) was developed which underestimated CL(DRUG) by <5% (P=0.16). CONCLUSION: Compared with different methods of estimating GFR, CL(SCI)=2.3 * x (0.7) (x equals CL(M) in ml min(-1)) more accurately estimates CL(DRUG) in chronic SCI patients. PMID- 21788952 TI - Plasma IL-6 levels during arm exercise in persons with spinal cord injury. AB - STUDY DESIGN: Non-randomized study. OBJECTIVES: Previous studies indicated that at least 2-h leg exercise at more than 60% maximum oxygen consumption (VO(2)max) increased plasma interleukin (IL)-6 in able-bodied (AB) subjects. The purpose of the present study was to compare IL-6 response to arm exercise in AB subjects and persons with spinal cord injury (SCI). SETTING: Wakayama Medical University in Japan. METHODS: Six subjects with SCI between T6 and T10 and seven AB subjects performed 2-h arm crank ergometer exercise at 60%VO(2)max. Plasma catecholamines, IL-6, tumor necrosis factor (TNF)-alpha and high-sensitivity C-reactive protein (hsCRP) were measured before exercise, 60-min exercise, immediately and 2 h after the completion of exercise. RESULTS: Arm exercise increased myoglobin and plasma IL-6 levels in SCI and AB (P<0.01), but there were no differences in them between the two groups throughout the study. Plasma levels creatine kinase, lactate dehydrogenase, TNF-alpha and hsCRP did not change throughout the study in both groups. CONCLUSION: These findings suggest neither significant muscle damage nor inflammatory response during exercise. The increase in plasma IL-6 in SCI was not unexpected, confirming that moderate intensity and relatively long-arm exercise is safe and beneficial for SCI subjects with regard to IL-6 excretion, as in AB subjects. PMID- 21788953 TI - The individual experience of functioning and disability in Switzerland--patient perspective and person-centeredness in spinal cord injury. AB - STUDY DESIGN: Qualitative, multi-center study. OBJECTIVES: The objective of this study is to explore the aspects of functioning and disability that are relevant to individuals with spinal cord injury (SCI), using a comprehensive approach based on the International Classification of Functioning, Disability and Health (ICF). METHODS: Forty-nine people with SCI from early post-acute and long-term rehabilitation settings participated in nine focus groups. Five open-ended questions based on the ICF were used to initiate discussion about relevant Body Functions and Structures, Activities and Participation, Environmental and Personal Factors. The focus groups were audiotaped and the recording was transcribed verbatim. Qualitative analyses included the identification, extraction and coding of meaningful concepts from the transcribed dialogue. Concepts were coded according to established rules using ICF categories and were summarized semi-quantitatively. RESULTS: In the analysis, 1582 different concepts were identified. For coding one concept, an average of 1.4 ICF categories was used. This resulted in 2235 concept-ICF category links, 1068 in the early post acute and 1167 in the long-term context, respectively. For the coding, 274 out of the 1454 categories contained in the ICF were used. CONCLUSION: The ICF coding showed the broad range of relevant aspects in the functioning experience of persons with SCI. Besides body limitations (especially paralysis and pain), the most relevant concepts covered mainly barriers in physical environment, assistive devices and social support, as well as the impact on everyday life regarding leisure and work. The resulting list of ICF categories can be helpful in facilitating person-centered clinical care and research. PMID- 21788954 TI - Consumer preference in ranking walking function utilizing the walking index for spinal cord injury II. AB - STUDY DESIGN: Blinded rank ordering. OBJECTIVE: To determine consumer preference in walking function utilizing the walking Index for spinal cord injury II (WISCI II) in individuals with spinal cord injury (SCI)from the Canada, the Italy and the United States of America. METHOD: In all, 42 consumers with incomplete SCI (25 cervical, 12 thoracic, 5 lumbar) from Canada (12/42), Italy (14/42) and the United States of America (16/42) ranked the 20 levels of the WISCI II scale by their individual preference for walking. Subjects were blinded to the original ranking of the WISCI II scale by clinical scientists. Photographs of each WISCI II level used in a previous pilot study were randomly shuffled and rank ordered. Percentile, conjoint/cluster and graphic analyses were performed. RESULTS: All three analyses illustrated consumer ranking followed a bimodal distribution. Ranking for two levels with physical assistance and two levels with a walker were bimodal with a difference of five to six ranks between consumer subgroups (quartile analysis). The larger cluster (N=20) showed preference for walking with assistance over the smaller cluster (N=12), whose preference was walking without assistance and more devices. In all, 64% (27/42) of consumers ranked WISCI II level with no devices or braces and 1 person assistance higher than multiple levels of the WISCI II requiring no assistance. These results were unexpected, as the hypothesis was that consumers would rank independent walking higher than walking with assistance. CONCLUSION: Consumer preference for walking function should be considered in addition to objective measures in designing SCI trials that use significant improvement in walking function as an outcome measure. PMID- 21788955 TI - Pressure sores significantly increase the risk of developing a Fournier's gangrene in patients with spinal cord injury. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: The aim of our study was to evaluate the mortality rate and further specific risk factors for Fournier's gangrene in patients with spinal cord injury (SCI). SETTING: Division of Spinal Cord Injury, BG-University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Germany. METHODS: All patients with a SCI and a Fournier's gangrene treated in our hospital were enrolled in this study. Following parameters were taken form patients medical records: age, type of SCI, cause of Fournier's gangrene, number of surgical debridements, length of hospital and intensive care unit stay, co morbidity factors and mortality rate. In addition, laboratory parameter including the laboratory risk indicator for necrotizing fasciitis (LRINEC) score and microbiological findings were analyzed. Clinical diagnosis was made via histological examination. RESULTS: A total of 16 male patients (15 paraplegic and one tetraplegic) were included in the study. In 81% of all cases, the origin of Fournier's gangrene was a pressure sore. The median LRINEC score on admission was 6.5. In the vast majority of cases, a polybacterial infection was found. No patient died during the hospital stay. The mean number of surgical debridements before soft tissue closure was 1.9 and after a mean time interval of 39.1 days wound closure was performed in all patients. CONCLUSIONS: Pressure sores significantly increase the risk of developing Fournier's gangrene in patients with SCI. We reported the results of our patients to increase awareness among physicians and training staff working with patients with a SCI in order to expedite the diagnosis. PMID- 21788956 TI - New experimental rabbit animal model for cervical spondylotic myelopathy. AB - STUDY DESIGN: Cervical spondylotic myelopathy (CSM) represents the most commonly acquired cause of spinal cord dysfunction among individuals over 55 years old. The pathophysiology of the disease involves static and dynamic mechanical factors, which are the result of chronic degeneration. The clinical course of the disease remains unpredictable. In the past, many experimental animal models have been developed to study the cellular and molecular mechanisms underlining the pathophysiology of the disease. OBJECTIVES: To create a new animal model of CSM, which will reproduce the temporal course of the disease and the local microenvironment at the site of spinal cord compression. METHODS: We performed posterior laminectomy to New Zealand rabbits at the level of C7, and a thin sheet (5-7 MUm) of aromatic polyether was implanted with microsurgical technique at the epidural space underneath C5-C6 laminae. Motor function evaluation was performed after the operation and once a week thereafter. RESULTS: After 20 weeks, the animals were killed, and the histological evaluation of spinal cord at the site of compression above and below it, using eosin hematoxylin, immonohistochemistry and Kluver-Barrera techniques reveals axonal swelling and demyelination, interstitial edema and myelin sheet fragmentation. Moreover, histological evaluation of C5 and C6 laminae reveals osteophyte formation. CONCLUSION: We believe that this CSM model reproduces the temporal evolution of the disease and creates a local microenvironment at the site of spinal cord compression, which shares the same characteristics with that of human disease. PMID- 21788957 TI - The use of unconventional pressure redistributing cushion in spinal cord injured individuals. AB - STUDY DESIGN: Case report. OBJECTIVES: To report an unconventional pressure redistributing cushion used by spinal cord injured individuals. SETTING: Department of Rehabilitation of Medicine, University Malaya, Kuala Lumpur, Malaysia. METHODS: Description of three cases of persons with spinal cord injury (SCI) using unconventional pressure relieving cushions, and despite high pressure noted on pressure mapping they did not develop pressure ulcer. CONCLUSION: Education and awareness of pressure ulcer prevention is most important in SCI population, as technology is still an adjunct. PMID- 21788958 TI - Iatrogenic spinal cord injury: an observational study. AB - STUDY DESIGN: Retrospective descriptive observational study. OBJECTIVE: The primary objective of this study was to quantify the incidence of iatrogenic spinal cord injury (SCI) at our SCI unit (SCIU). The secondary objective was to discover the surgical and medical procedures that cause iatrogenic SCI and to estimate the incidence with each procedure. SUBJECTS: Patients admitted to or seen at outpatient services of the SCIU at a university hospital. METHODS: Histories were compiled from 1 July 2005 to 30 June 2009. We included patients with SCI caused by any medical or surgical procedure. We collected age, sex, diagnosis leading to medical intervention, predominant clinical manifestations, medical-surgical procedure and level and grade of injury upon admission and discharge. RESULTS: Out of 250 patients admitted to the SCIU, 32 (14.7%) patients presented iatrogenic SCI. Average age was 56.2 (s.d. 17.3), ranging from 0 to 82 years old. The most frequent clinical manifestation was pain. The most common diagnosis was channel stenosis. Lumbar level grade C of American Spine Injury Association (ASIA) was the most frequently observed. CONCLUSION: The rise in the population's life expectancy entails an increase in elderly patients with vascular risk factors, who underwent invasive interventions leading to spinal cord iatrogenia. PMID- 21788959 TI - Heart failure: Nesiritide safe but provides little benefit over existing therapies in acute decompensated heart failure. PMID- 21788960 TI - Hypertension: Salt restriction might lower blood pressure, but are there any beneficial effects on mortality? PMID- 21788962 TI - The role of aspirin for stroke prevention in atrial fibrillation. AB - Atrial fibrillation (AF) is a major cause of stroke and thromboembolism, resulting in substantial morbidity and mortality. For the majority of patients with AF, aspirin has a limited role in stroke prevention, being an inferior strategy and not necessarily safer than the anticoagulant warfarin, especially in the elderly. Novel oral anticoagulant drugs, such as oral direct thrombin inhibitors and oral factor Xa inhibitors, might further diminish the role of aspirin for stroke prevention in AF. Nonetheless, aspirin use should continue in the early stages following presentation of a patient with AF and acute coronary syndrome, and after stenting, in combination with oral anticoagulant drugs and clopidogrel, as appropriate. Notably, aspirin combined with clopidogrel shows only modest benefit in stroke prevention compared with aspirin monotherapy in patients with AF who refuse oral anticoagulant drugs (including warfarin), or in those individuals who have difficulties in anticoagulation monitoring, and can be used where bleeding risk is not excessive. PMID- 21788963 TI - Gene therapy: Can CUPID rescue the broken hearted? PMID- 21788961 TI - Effective communication and ethical consent in decisions related to ICDs. AB - This Review examines recommendations and principles that promote good decision making with regard to the insertion, deactivation, and potential malfunction of implantable cardioverter-defibrillators (ICDs). This guidance is important because ICDs are now used for primary and secondary prevention of arrhythmias in more than 20 diverse clinical populations, which accounts for the exponential increase in insertion rates over the past decade. Current guidelines require clinicians to provide personalized, culturally appropriate, and easy to understand information to patients on the benefits and harms of proposed treatment choices; however, obtaining valid informed consent for insertion and deactivation of ICDs is challenging. Initiating early conversations with patients and continuing this dialogue over time, implementation of localized care protocols, increased collaboration (particularly between cardiac and palliative care teams), and the provision of training for all health professionals involved in the care of these patients, can help to ensure that adequate informed consent is maintained throughout their care. In addition to providing information, health professionals should identify and address high levels of anxiety in patients and their next of kin and promote effective communication throughout decision making. In the future, use of standardized checklists or decision aids based on a clear understanding of the principles underlying key topics could support this process. PMID- 21788964 TI - TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. AB - To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy. PMID- 21788965 TI - Glucocorticoid resistance in Crohn's disease and ulcerative colitis: an association study investigating GR and FKBP5 gene polymorphisms. AB - The aim of this study is to investigate the role of single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) and of the related co chaperone FKBP5 genes in the development of glucocorticoid (GC) resistance in Crohn's disease (CD) and ulcerative colitis (UC) patients. We have developed a high-resolution DNA melting method that allows simultaneous identification of GR (BclI, N363S and ER22/23EK) and FKBP5 (rs3800373, rs1360780 and rs4713916) polymorphisms. Genotype frequencies were determined in 100 consecutive CD and 100 UC patients under GCs therapy (50 responders and 50 resisters). The variation of FKBP5 polymorphism rs4713916 (G/A), in the putative promoter region of FKBP5, is significantly associated with resistance to GC treatment in CD (responder=17% versus resister=35%; P=0.0043). No significant differences were found in UC patients. If these preliminary findings will be confirmed, the combination of GR and FKBP5 mutational analyses could help to identify subgroups of CD patients with higher chances to benefit from GC treatment. PMID- 21788967 TI - Initial combined treatment with anticholinergics and alpha-blockers for men with lower urinary tract symptoms related to BPH and overactive bladder: a prospective, randomized, multi-center, double-blind, placebo-controlled study. AB - We aimed to evaluate the efficacy and safety of combination treatment using anticholinergics with alpha-blocker for initial treatment of both overactive bladder (OAB) and other lower urinary tract symptoms (LUTS), secondary to BPH. A 12-week, randomized, double-blind, placebo-controlled trial was conducted at four urology clinics in Korea, involving men, aged 50 years or older, with LUTS related to BPH and OAB. A total of 176 patients were randomly assigned to receive doxazosin (4 mg) plus placebo or doxazosin (4 mg) plus tolterodine SR (4 mg), once a day for 12 weeks. Changes from baseline in total International Prostate Symptom Score (IPSS), bladder diary variables, patient perception of bladder condition (PPBC), uroflowmetry, postvoid residual volume and IPSS subscores (voiding and storage) were analyzed. Of the 176 enrolled patients, 91 had doxazosin gastrointestinal therapeutic system (GITS) and placebo, and 85 had combined medication with doxazosin GITS and tolterodine SR. Compared with the doxazosin plus placebo group, the doxazosin plus tolterodine group showed significant reductions in IPSS storage subscore and improvement in the quality of life item, urgency episodes, as well as in micturition frequency at weeks 4 and 12. However, it failed to improve PPBC at week 4 as well as at week 12. Earlier intervention with anticholinergics plus alpha-blocker was tolerated well, including the questions about urinary retention (n=1) and dry mouth (n=2). Initial combination treatment of anticholinergics plus alpha-blocker showed positive results for men with LUTS related to BPH and OAB symptoms and did not increase the risk of urinary retention. PMID- 21788966 TI - Quadriplex model enhances urine-based detection of prostate cancer. AB - BACKGROUND: The major advantages of urine-based assays are their non-invasive character and ability to monitor prostate cancer (CaP) with heterogeneous foci. While the test for the prostate cancer antigen 3 (PCA3) is commercially available, the aim of our research was to test other putative urine markers in multiplex settings (AMACR (alpha-methylacyl-CoA racemase), EZH2 (enhancer of zeste homolog 2), GOLM1 (golgi membrane protein 1), MSMB (microseminoprotein, beta), SPINK1 (serine peptidase inhibitor) and TRPM8 (transient receptor potential cation channel, subfamily M, member 8)). METHODS: Expression of the candidate biomarkers was studied in sedimented urine using quantitative reverse transcriptase polymerase chain reaction in two sets of patients with and without restriction on serum PSA levels. RESULTS: We confirmed that PCA3 is an independent predictor of cancer in the patients without restriction of serum PSA values (set 1, n=176, PSA=0.1-587 ng ml(-1)). However, AMACR was the only parameter that differentiated CaP from non-CaP patients with serum PSA between 3 and 15 ng ml(-1) (set 2, n=104). The area under curve (AUC) for this gene was 0.645 with both sensitivity and specificity at 65%. Further improvement was achieved by multivariate logistic regression analysis, which identified novel duplex (TRPM8 and MSMB), triplex (plus AMACR) and quadriplex (plus PCA3) models for the detection of early CaPs (AUC=0.665, 0.726 and 0.741, respectively). CONCLUSIONS: Novel quadriplex test could be implemented as an adjunct to serum PSA or urine PCA3 and this could improve decision making for diagnostics in the case of 'PSA dilemma' patients. PMID- 21788970 TI - Bone: dental radiography and fracture risk. PMID- 21788969 TI - Thyroid cancer stem cells. AB - Thyroid cancer is the most frequently diagnosed endocrine cancer and causes more deaths than all other endocrine cancers combined. Research findings support the concept that a subpopulation of thyroid cancer cells displays properties characteristic of stem cells. These putative cancer-forming entities drive tumorigenesis as a result of their dual ability to undergo self-renewal and to differentiate into various types of cancer cells; they also mediate metastasis and are resistant to the effects of chemotherapy and radiation therapy. This Review discusses the cellular origin of thyroid cancer and the properties of the thyroid cancer stem cell niche. The article critically evaluates the methods used to identify molecular markers expressed by thyroid-cancer-initiating cells and outlines prospective therapeutic strategies to directly target these cells. Stem cell technology offers an unprecedented opportunity to investigate these crucial cancer stem cell populations and to advance understanding of the molecular mechanisms that control disease processes. Such knowledge could potentially lead to the development of more effective and safer treatment regimens for late-stage thyroid cancer than are currently available. PMID- 21788968 TI - The role of homeodomain transcription factors in heritable pituitary disease. AB - The anterior pituitary gland secretes hormones that regulate developmental and physiological processes, including growth, the stress response, metabolic status, reproduction and lactation. During embryogenesis, cellular determination and differentiation events establish specialized hormone-secreting cell types within the anterior pituitary gland. These developmental decisions are mediated in part by the actions of a cascade of transcription factors, many of which belong to the homeodomain class of DNA-binding proteins. The discovery of some of these regulatory proteins has facilitated genetic analyses of patients with hormone deficiencies. The findings of these studies reveal that congenital defects ranging from isolated hormone deficiencies to combined pituitary hormone deficiency syndromes-are sometimes associated with mutations in the genes encoding pituitary-acting developmental transcription factors. The phenotypes of affected individuals and animal models have together provided useful insights into the biology of these transcription factors and have suggested new hypotheses for testing in the basic science laboratory. Here, we summarize the gene regulatory pathways that control anterior pituitary development, with emphasis on the role of the homeodomain transcription factors in normal pituitary organogenesis and heritable pituitary disease. PMID- 21788972 TI - Radiotherapy: Repopulating tumor cells--dying for caspase 3. PMID- 21788971 TI - Bone: reference bone turnover markers-just a fairy tale? PMID- 21788973 TI - Targeted therapies: Improved outcomes for patients with metastatic melanoma. AB - Recently published phase III trials involving interleukin-2, ipilimumab and vemurafenib redefine 'standard-of-care' for metastatic melanoma and demonstrate improved survival compared with dacarbazine. All three therapies are potential first-line options for patients with metastatic melanoma, with optimal treatment strategies evolving based on tumor mutation status, disease burden, performance status and comorbidities. PMID- 21788976 TI - Stroke: Antibody improves stroke outcomes and rtPA therapy. PMID- 21788975 TI - IBD: Intravenous iron in IBD--what's the best preparation? PMID- 21788977 TI - White matter disease: a common target in MS and neonatal hypoxic brain injury. PMID- 21788974 TI - Organ-sparing radiation therapy for head and neck cancer. AB - To improve locoregional tumor control and survival in patients with locally advanced head and neck cancer (HNC), therapy is intensified using altered fractionation radiation therapy or concomitant chemotherapy. However, intensification of therapy has been associated with increased acute and late toxic effects. The application of advanced radiation techniques, such as 3D conformal radiation therapy and intensity-modulated radiation therapy, is expected to improve the therapeutic index of radiation therapy for HNC by limiting the dose to critical organs and possibly increasing locoregional tumor control. To date, Review articles have covered the prevention and treatment of radiation-induced xerostomia and dysphagia, but few articles have discussed the prevention of hearing loss, brain necrosis, cranial nerve palsy and osteoradionecrosis of the mandible, which are all potential complications of radiation therapy for HNC. This Review describes the efforts to prevent therapy related complications by presenting the state of the art evidence regarding advanced radiation therapy technology as an organ-sparing approach. PMID- 21788979 TI - Neurodegenerative disease: the kynurenine pathway--promising new targets and therapies for neurodegenerative disease. PMID- 21788982 TI - Spondyloarthropathies: management of AS-new guidelines in the spotlight. PMID- 21788984 TI - Experimental arthritis: endothelin blockade: a new therapy for inflammatory arthritis? PMID- 21788983 TI - Screening: CyTOF-the next generation of cell detection. PMID- 21788981 TI - Childhood brain tumors: epidemiology, current management and future directions. AB - Brain tumors are the most common solid tumors in children. With the increasingly widespread availability of MRI, the incidence of childhood brain tumors seemed to rise in the 1980s, but has subsequently remained relatively stable. However, management of brain tumors in children has evolved substantially during this time, reflecting refinements in classification of tumors, delineation of risk groups within histological subsets of tumors, and incorporation of molecular techniques to further define tumor subgroups. Although considerable progress has been made in the outcomes of certain tumors, prognosis in other childhood brain tumor types is poor. Among the tumor groups with more-favorable outcomes, attention has been focused on reducing long-term morbidity without sacrificing survival rates. Studies for high-risk groups have examined the use of intensive therapy or novel, molecularly targeted approaches to improve disease control rates. In addition to reviewing the literature and providing an overview of the complexities in diagnosing childhood brain tumors, we will discuss advances in the treatment and categorization of several tumor types in which progress has been most apparent, as well as those in which improvements have been lacking. The latest insights from molecular correlative studies that hold potential for future refinements in therapy will also be discussed. PMID- 21788986 TI - Structural basis for the recognition of Asef by adenomatous polyposis coli. AB - Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (GEF; Asef), which is usually autoinhibited through the binding between its Src homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence and enhanced cell migration. In colorectal cancers, truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis. Here, we report crystal structures of the human APC/Asef complex. We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC-binding region (ABR) of Asef, conformation of which changes dramatically upon binding to APC. Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays. Structural superimposition of the APC/Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef-DH domain and APC, which possibly leads to a conformational change in Asef that stimulates its GEF activity. Our structures thus elucidate the molecular mechanism of Asef recognition by APC, as well as provide a potential target for pharmaceutical intervention against cancers. PMID- 21788985 TI - Plant ubiquitin-proteasome pathway and its role in gibberellin signaling. AB - The ubiquitin-proteasome system (UPS) in plants, like in other eukaryotes, targets numerous intracellular regulators and thus modulates almost every aspect of growth and development. The well-known and best-characterized outcome of ubiquitination is mediating target protein degradation via the 26S proteasome, which represents the major selective protein degradation pathway conserved among eukaryotes. In this review, we will discuss the molecular composition, regulation and function of plant UPS, with a major focus on how DELLA protein degradation acts as a key in gibberellin signal transduction and its implication in the regulation of plant growth. PMID- 21788987 TI - Determining intracellular temperature at single-cell level by a novel thermocouple method. PMID- 21788988 TI - Telomere dynamics in dyskeratosis congenita: the long and the short of iPS. PMID- 21788989 TI - Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. AB - OBJECTIVES: Previous studies have suggested an association between cytomegalovirus (CMV) infection and steroid-refractory inflammatory bowel disease. In this study, the use of CMV DNA load during acute flare-ups of ulcerative colitis (UC) to predict resistance to immunosuppressive therapy was evaluated in intestinal tissue. METHODS: Forty-two consecutive patients (sex ratio M/F: 0.9, mean age: 43.6 years) hospitalized for moderate to severe UC and treated with IV steroids were included prospectively. A colonoscopy was performed for each patient at inclusion; colonic biopsy samples of the pathological tissue, and if possible, of the healthy mucosa, were tested for histological analysis and determination of CMV DNA load by real-time polymerase chain reaction assay. Patients were treated as recommended by the current guidelines. RESULTS: Sixteen patients were found positive for CMV DNA in inflamed intestinal tissue but negative in endoscopically healthy tissue; all of these patients were positive for anti-CMV IgG, three exhibited CMV DNA in blood, and none was positive for intestinal CMV antigen by immunohistochemistry detection. In the 26 remaining patients, no stigmata of recent CMV infection were recorded by any technique. By multivariate analysis, the only factor associated with CMV DNA in inflammatory tissue was the resistance to steroids or to three lines of treatment (risk ratio: 4.7; 95% confidence interval: 1.2-22.5). A CMV DNA load above 250 copies/mg in tissue was predictive of resistance to three successive regimens (likelihood ratio+=4.33; area under the receiver-operating characteristic curve=0.85). Eight UC patients with CMV DNA in inflamed tissue and therapeutic failure received ganciclovir; a clinical remission was observed in seven cases, with a sustained response in five of them. CONCLUSIONS: The CMV DNA load determined in inflamed intestinal tissue predicts resistance to steroid treatment and to three drug regimens in UC. Initiation of an early antiviral treatment in these patients might delay the occurrence of resistance to current treatments. PMID- 21788990 TI - Fecal HMGB1 is a novel marker of intestinal mucosal inflammation in pediatric inflammatory bowel disease. AB - OBJECTIVES: High-mobility group box 1 (HMGB1) is a nuclear protein with functions in the regulation of transcription. In inflammatory conditions, HMGB1 is actively secreted from immune cells in the extracellular matrix, where it behaves as a proinflammatory cytokine. The aim of the present study was to investigate the role of HMGB1 in pediatric inflammatory bowel disease (IBD). METHODS: We analyzed the stools of 19 children with Crohn's disease (CD), 21 with ulcerative colitis (UC), and 13 controls. The gene/protein expression levels of HMGB1 were assessed in bioptic specimens of all children using real-time PCR and western blot assay. Finally, intracellular localization of the protein was analyzed by western blot, after separation of nuclear and cytoplasmic extracts, and by immunohistochemistry. RESULTS: HMGB1 protein levels were significantly increased (P<0.001) in the stools of patients, but were undetectable in the controls; fecal HMGB1 correlated well with fecal calprotectin levels (r: 0.77 in CD, r: 0.70 in UC; P<0.01); and mRNA and protein expression were unchanged in inflamed bioptic tissues compared with controls. However, by separately analyzing the nuclear and cytoplasmic fraction, we detected the cytoplasmic HMGB1 expression to be significantly enhanced (P<0.01) in the inflamed tissues of the patients. In addition, HMGB1 was significantly detected in 16 patients with inactive disease, whose endoscopic scores showed persisting inflammation, suggesting that it may be a sensitive marker of mucosal inflammation, although the disease is clinically inactive. CONCLUSIONS: It was shown for the first time in our study that HMGB1 is secreted by human inflamed intestinal tissues and abundantly found in the stools of IBD patients. Hence, it can be considered as a novel marker for intestinal inflammation. We can also suggest that the presence of HMGB1 in large amounts in the fecal stream of IBD patients is mainly due to active secretion of the protein stored in the nucleus rather than a "de novo" synthesis. PMID- 21788991 TI - Strategies for the prevention of postoperative recurrence in Crohn's disease: results of a decision analysis. AB - OBJECTIVES: Nearly 70% of patients with Crohn's disease (CD) undergo surgical resection, with one-quarter subsequently developing clinical recurrence within 12 months. Several options exist for the prevention of postoperative recurrence in CD, but the comparative cost effectiveness of these competing strategies has not been previously analyzed. METHODS: We developed a decision analytic model comprising five strategies--No Treatment, azathioprine (AZA), antibiotics (ABX), upfront infliximab (IFX), and tailored IFX that consisted of no upfront therapy with initiation of IFX in patients with severe endoscopic recurrence at 6 months. The base-case 1-year clinical recurrence rate was 24% with reduction in recurrence by 41%, 77%, and 99% for AZA, ABX, and IFX, respectively. A 1-year time horizon was used and sensitivity analyses were performed. RESULTS: At the base-case analysis, the ABX (0.82 quality-adjusted life years (QALYs)) and AZA (0.81 QALYs) arms were more effective and less expensive than the No Treatment strategy (0.80 QALYs). The most effective strategy was upfront IFX (0.83 QALYs); however, this was also the most expensive and resulted in a high incremental cost effectiveness ratio (ICER) ($777,732/QALY) compared with no treatment. The tailored IFX arm was less effective than upfront use but had a more acceptable ICER. On increasing the recurrence rate to 78% (high-risk patients), upfront IFX resulted in 0.07 QALYs (ICER $130,580/QALY) gained compared with No Treatment, whereas ABX, AZA, and tailored IFX arms dominated No Treatment. CONCLUSION: Antibiotics are the most cost-effective option for preventing postoperative recurrence, but they have been associated with high rates of intolerance precluding widespread use. Upfront IFX is the most efficacious strategy but is not cost effective even in high-risk patients. Reserving IFX use for high-risk patients with early endoscopic recurrence is more cost effective than upfront use in all patients. PMID- 21788992 TI - Anchoring of a fully covered self-expandable metal stent with a 5F double-pigtail plastic stent to prevent migration in the management of benign biliary strictures. AB - OBJECTIVES: Fully covered self-expandable metal stents (FCSEMSs) can be effectively placed in patients with benign biliary stricture (BBS). However, stent migration is an inherent problem of FCSEMSs. We evaluated the efficacy of anchoring with a 5F double-pigtail plastic stent (anchoring stent) to prevent migration of an FCSEMS in patients with BBS. METHODS: Between January 2007 and December 2009, 33 of 37 consecutive patients with BBS who had experienced treatment failure of at least one plastic stent placement were prospectively enrolled in this study. The patients with BBS were randomly assigned to undergo FCSEMS placement with or without an anchoring stent (anchoring group: 16 patients; non-anchoring group: 17 patients). The main outcome measures were the stent migration rate and success rates. RESULTS: The technical success rate was 100% in both groups. Significantly less stent migration occurred in the anchoring group (6.3%, 1/16) than in the non-anchoring group (41.2%, 7/17; P=0.024). The median indwelling time was significantly longer in the anchoring group (154 days; range, 86-176 days) than in the non-anchoring group (114 days; range, 19-162 days; P=0.010). Improvement or resolution of the BBS was confirmed in 15 of 16 patients (93.8%) in the anchoring group, and in 12 of 17 patients (70.6%) in the non-anchoring group (P=0.101). CONCLUSIONS: The placement of an anchoring stent appears to be a simple and effective method of preventing premature migration of FCSEMSs in patients with BBS. Appropriately powered studies are needed to confirm this finding. PMID- 21788993 TI - Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease. AB - OBJECTIVE The double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease (AD) has been widely used in experimental studies. beta-Amyloid (Abeta) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. METHODS Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Abeta1-40, Abeta1-42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. RESULTS The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Abeta(1-40) and Abeta(1 42) were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Abeta at 6-month age was similar with that at 12-month age. Besides, Abeta(1-40) level in the blood was significantly higher than Abeta(1-42) level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Abeta(1-42) in the brain (160.6 ng/mg protein) was higher than that of Abeta(1-40) (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Abeta(1-40) and Abeta(1-42) varied markedly among different brain regions. Abeta(1-42) level was significantly higher than Abeta(1-40) level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher gamma-secretase activity but was more efficient in producing Abeta(1-42) peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. CONCLUSION These results suggest that this mouse model mimics the early-onset human AD and may represent full blown disease at as early as 6-month age for experimental studies. PMID- 21788994 TI - Bilateral mechanical and thermal hyperalgesia and tactile allodynia after chronic compression of dorsal root ganglion in mice. AB - OBJECTIVE Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion (CCD), in which gene mutation can be applied to facilitate the studies of chronic pain. METHODS Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. RESULTS The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. CONCLUSION This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans. PMID- 21788995 TI - Inhibition of oestrogen biosynthesis induces mild anxiety in C57BL/6J ovariectomized female mice. AB - OBJECTIVE Letrozole, a next-generation aromatase inhibitor, has become a favored drug for the treatment of breast cancer in postmenopausal women. Although letrozole is generally well tolerated, its adverse effects on the central nervous system have been reported. The present study aimed to assess the behavioural outcomes of letrozole administration in mice to determine its side effects. METHODS C57BL/6J female ovariectomized mice received administration of letrozole (2.5 mg/kg per day) or vehicle by gavage for 3 weeks. Behavioural tasks were used to assess anxiety, depression, as well as learning and memory in mice. RESULTS Letrozole-treated mice showed an increased latency to enter the inner area of the chamber on the third day of the open field test, and traveled a shorter distance in the open arms of the elevated plus maze. No significant difference was found in the light-dark box or forced swimming task between letrozole-treated and vehicle-treated mice. Besides, letrozole did not change the spontaneous alternation behaviour of mice in the Y-maze. In the Morris water maze, mice administered with letrozole exhibited an improvement in spatial learning and memory compared with the vehicle-treated mice. CONCLUSION Our results indicate that the inhibition of oestrogen biosynthesis results in mild anxious behaviour, which may be a consideration in the treatment of breast cancer in postmenopausal women using aromatase inhibitors. PMID- 21788996 TI - Diagnostic value of amplitude-integrated electroencephalogram in neonatal seizures. AB - OBJECTIVE To investigate the accuracy of amplitude-integrated electroencephalography (aEEG) in detecting full-term neonatal seizures. METHODS Conventional EEG (cEEG) and aEEG were simultaneously applied to 62 full-term newborns with seizures and results were analyzed with different methods. RESULTS Of 876 seizures confirmed by cEEG, 21% were detected by clinical observation, 44.4% by aEEG and 85.7% by aEEG plus C3/C4 raw EEG. Of 531 seizures with a frequency higher than 5 times/h, 52.5% were detected by aEEG and 96.8% by aEEG plus C3/C4 raw EEG. Of 510 seizures lasting longer than 60 s, 50.6% were diagnosed by aEEG and 84.1% by aEEG plus C3/C4 raw EEG. Of 509 seizures originating in the central region, 57.9% were detected by aEEG and 90.9% by aEEG plus C3/C4 raw EEG. CONCLUSION Combination of aEEG with cEEG offers more accurate diagnosis, especially for detecting high-frequency, long-lasting and central region-generated seizures. PMID- 21788997 TI - A double-blind, placebo-controlled study of traditional Chinese medicine sarsasapogenin added to risperidone in patients with negative symptoms dominated schizophrenia. AB - OBJECTIVE To identify whether sarsasapogenin, a sapogenin from the Chinese medicinal herb Anemarrhena Asphodeloides Bunge, would augment the efficacy of risperidone and significantly improve cognitive functions in patients with negative symptoms dominated schizophrenia. METHODS The trial was a double-blind, placebo-controlled, parallel-group design. The eligible patients were randomized into 2 treatment groups: sarsasapogenin group (sarsasapogenin plus risperidone for 8 weeks, n = 41) and placebo group (risperidone only for 8 weeks, n = 39). At the baseline, as well as at weeks 2, 4 and 8 of treatment, the therapeutic response was measured by using scales including Positive and Negative Symptoms Scale (PANSS), Wechsler Memory Scale (WMS), modified Chinese Wechsler Adult Intelligence Scale (mWAIS), Clinical Global Impression (CGI) and Brief Psychiatry Rating Scale (BPRS). The study period for each subject was 8 weeks and duration of overall trial was 2 years. RESULTS Patients treated with sarsasapogenin plus risperidone demonstrated no statistically significant differences in changes in PANSS, WMS or mWAIS score at the end-point of the trial compared with patients treated with placebo plus risperidone. The incidence of treatment-emergent adverse events in patients treated with sarsasapogenin was not different from that observed in placebo group. CONCLUSION Sarsasapogenin did not augment the efficacy of risperidone in treating negative symptoms dominated schizophrenia. Sarsasapogenin at a dosage of 200 mg per day added to a flexible dosage of risperidone at 2-4 mg per day is safe and well tolerated by patients with negative symptoms dominated schizophrenia. PMID- 21788998 TI - Angiotensin II-derived reactive oxygen species underpinning the processing of the cardiovascular reflexes in the medulla oblongata. AB - The brainstem is a major site in the central nervous system involved in the processing of the cardiovascular reflexes such as the baroreflex and the peripheral chemoreflex. The nucleus tractus solitarius and the rostral ventrolateral medulla are 2 important brainstem nuclei, and they play pivotal roles in autonomic cardiovascular regulation. Angiotensin II is one of the neurotransmitters involved in the processing of the cardiovascular reflexes within the brainstem. It is well-known that one of the mechanisms by which angiotensin II exerts its effect is via the activation of pathways that generate reactive oxygen species (ROS). In the central nervous system, ROS are reported to be involved in several pathological diseases such as hypertension, heart failure and sleep apnea. However, little is known about the role of ROS in the processing of the cardiovascular reflexes within the brainstem. The present review mainly discussed some recent findings documenting a role for ROS in the processing of the baroreflex and the peripheral chemoreflex in the brainstem. PMID- 21789000 TI - Can magnetic resonance image-guided focused ultrasound surgery replace local oncology treatments? A review. AB - Magnetic resonance image-guided focused ultrasound surgery (MRgFUS) is an innovative technology in the new panorama of treatment using ultrasound. It combines two well-known and distinct methodologies: high-intensity focused ultrasound (HIFU) and a magnetic resonance imaging system (MRI). This review on MRgFUS is focused on the technical aspects and the current clinical applications in oncology. More precisely, the advantages/disadvantages of MRgFUS compared to other local approaches such as surgery and radiotherapy are discussed in detail. PMID- 21788999 TI - Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury. AB - Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. Because of the fact that there is still no specific treatment for perinatal brain lesions due to the complexity of neonatal hypoxic-ischemic pathophysiology, the search of new neuroprotective therapies is of great interest. In this regard, therapeutic possibilities of the endocannabinoid system have grown lately. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. Concerning perinatal asphyxia, the neuroprotective role of this endogenous system is emerging these years. The present review mainly focused on the current knowledge of the cannabinoids as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID- 21789002 TI - Second-line chemotherapy with irinotecan, 5-fluorouracil and leucovorin (FOLFIRI) in relapsed or metastatic gastric cancer: lessons from clinical practice. AB - AIMS AND BACKGROUND: Soon after the approval of irinotecan for second-line therapy of advanced gastric cancer, the FOLFIRI regimen represented a possible treatment choice in clinical practice. However, there was still scarce data on the efficacy of irinotecan in this setting. We retrospectively evaluated the efficacy of FOLFIRI as second-line treatment in advanced gastric cancer patients progressing after platinum-based chemotherapy. METHODS: Patients with metastatic gastric cancer progressing after platinum-based chemotherapy who received FOLFIRI as second-line chemotherapy were included in our analysis. RESULTS: Thirty patients were consecutively treated (20 males and 10 females). Median age was 62 years (range, 36-78). All patients had metastatic disease. In 17 cases (56.6%), peritoneal tumor diffusion was present. Six patients (20%) had previously received 5-fluorouracil-based adjuvant chemotherapy. The median number of cycles administered was 4 (range, 1-12). Partial remission was obtained in 1 case (3%) and stable disease in 8 patients (27%). Median progression-free survival and overall survival were 2.7 months and 5.5 months, respectively. The most common toxicities (grade 2-3) observed were neutropenia (13.3%), diarrhea (10%) and vomiting (30%). Ten patients (10%) received 3 or less courses of chemotherapy. In these cases, treatment was stopped before scheduled for accelerated worsening of clinical conditions. CONCLUSIONS: FOLFIRI resulted scarcely active in metastatic gastric cancer patients pre-treated with platinum-based chemotherapy. In this setting, the real benefit of a second-line chemotherapy with the FOLFIRI regimen should be carefully re-considered, especially according to the clinical condition of the patient and possible treatment-related side effects. PMID- 21789001 TI - Use of socio-economic factors and healthcare resources to estimate cancer survival in European countries with partial national cancer registration. AB - BACKGROUND AND AIMS: Cancer is a chronic disease whose clinical history has a strong relationship with socio-economic indicators, and it could be defined as a real "social disease". For this reason, socio-economic factors can be used to project survival rates by means of ecological models. The present study had two main aims: to generalize to all adult patients study of the association between survival and socio-economic and healthcare technologies and related medical resources factors; to provide insights on the possible bias in giving national meaning to survival rates based on pools of regional cancer registries where national coverage is not available. MATERIAL AND METHODS: The EUROCARE 3 Study provided age-standardized survival rates at 5 years from the diagnosis for 10 major cancer sites collected by 52 cancer registries from 21 European countries for the period 1990-1994. For each area and country, socio-economic and health related variables were collected for the period 1993-1995. Multiple linear regression models were used to compute predicted survival rates in countries totally covered by registration, starting from the correlation between socio economic and health-related variables and observed survival rates. For those areas not totally covered by cancer registry activity, a correctional parameter coming from the previous linear regression models was computed in order to estimate survival at a national level also in these countries. RESULTS: Predicted survival rates were very close to the observed rates for countries totally covered by cancer registries. The estimates were also good for nations with partial national cancer registration, with less convergence in results for countries where socio-economic differences between the whole territory and the covered area were relevant. CONCLUSIONS: In the light of these findings, evaluation of the role of socio-economic and health-related factors and the estimation of survival is of utmost importance in order to evaluate healthcare outcomes and to support planners in allocating resources in a more effective and egalitarian way. PMID- 21789003 TI - Concurrent versus sequential administration of CMF chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. AB - AIMS AND BACKGROUND: To compare the outcome of concurrent versus sequential administration of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. METHODS: From February 1992 to January 2002, 156 patients underwent CMF chemotherapy and radiotherapy, either concurrently (CCRT group, 88 patients) or sequentially (SCRT group, 68 patients). There was a predilection of patients with a larger tumor (P = 0.0035), with more frequent nodal involvement (P = 0.0686), and younger age (P = 0.0776) in the CCRT group. RESULTS: The planned radiotherapy was completed in every patient. No grade 3 or 4 late treatment-related toxicity was observed in the CCRT or SCRT group. Compliance to the treatment as well as cosmetic outcome of the two groups were comparable. Despite more adverse factors for local-regional recurrence in the CCRT group, the 5-year local-regional control rate of the CCRT group was similar to that of the SCRT group (97.7% vs 93.8%, respectively, P = 0.1688). On multivariate analysis, concomitant administration of chemotherapy and radiotherapy was associated with improved local-regional control (P = 0.0463). CONCLUSIONS: Concurrent administration of CMF chemotherapy and radiotherapy resulted in improved local-regional control over sequential administration without an increase in significant toxicity. Concurrent CMF chemoradiotherapy may serve as a viable option for patients at high-risk of local-regional relapse not suitable for anthracycline or taxane based chemotherapy. PMID- 21789004 TI - Matrix metalloproteinase-9 decreased after chemotherapy in patients with non small cell lung cancer. AB - AIMS AND BACKGROUND: The aim of the study was to investigate the alteration in serum matrix metalloproteinase-9 (MMP-9) levels after chemotherapy and the association between the changes in serum levels of MMP-9 and response to chemotherapy in patients with advanced stage non-small cell lung cancer. METHODS AND STUDY DESIGN: Twenty-eight consecutive patients with advanced non-small cell lung cancer and 24 healthy controls were enrolled in the study. The patients were treated with cisplatin-based combination chemotherapy. After two cycles, the response was evaluated. Before and after two cycles of chemotherapy, serum samples were collected from the patients. RESULTS: Prechemotherapy MMP-9 (ng/ml) levels were significantly higher in patients with advanced stage non-small cell lung cancer than in controls (7.2 +/- 2.8 vs 4.5 +/- 2.1, P <0.001). Prechemotherapy MMP-9 levels were elevated compared to postchemotherapy levels as well (7.2 +/- 2.8 vs 5.2 +/- 3.3, P = 0.005). Prechemotherapy MMP-9 levels were significantly higher than postchemotherapy MMP-9 levels in patients with partial response (7 patients) (8.2 +/- 1.8 and 3.2 +/- 2.3, respectively; P = 0.018), but the pre- and postchemotherapy MMP-9 levels were no different in patients with stable disease or progressive disease (21 patients) (7 +/- 3.1 and 5.9 +/- 3.3, respectively; P = 0.08). CONCLUSIONS: The difference between pre- and postchemotherapy MMP-9 levels in responders was more prominent than that in nonresponders. Whether the decline in serum MMP-9 levels might be used as a marker of response to chemotherapy should be investigated in larger studies. PMID- 21789006 TI - Larger tumor size predicts nodal involvement in patients with follicular thyroid carcinoma. AB - AIMS AND BACKGROUND: Lymph node metastases are rare in patients with follicular thyroid carcinoma, with an average incidence of 5.5% of all cases reported in the literature. In the present study we focused on the search for risk factors predictive of lymph node involvement in patients with follicular thyroid carcinoma to plan the most appropriate management and follow-up. METHODS AND STUDY DESIGN: We carried out a cross-sectional study among patients with follicular thyroid carcinoma and lymph node metastasis at diagnosis and patients without lymph node involvement. From January 1998 to April 2008, 930 patients underwent thyroidectomy in our surgical department for a variety of thyroid disorders, 420 (45.2%) of them for a differentiated thyroid carcinoma. The medical records of 55 patients with histological diagnosis of follicular thyroid carcinoma were analyzed. RESULTS: Four patients (7.3%) had lymph node metastasis from follicular thyroid carcinoma at presentation in both the lateral and central neck compartments. Mean tumor size was significantly greater for follicular thyroid carcinomas with nodal metastasis (5.1 +/- 1.4 cm) than for those without nodal involvement (3.0 +/- 1.2 cm, P <0.010). Among factors supposed to influence the presence of nodal metastasis at diagnosis (age, gender, tumor size, multifocality, tumor poorly differentiated, tumor widely invasive, vascular invasion, thyroid capsular invasion, and extra thyroid invasion), tumor size larger than 4.0 cm was the only factor retained in the multivariate statistical model. CONCLUSIONS: Lymph node dissection must be planned only in the case of large follicular thyroid carcinomas. Since follicular carcinoma is usually diagnosed postoperatively, more attention should be paid to nodal involvement in the tumor re-staging during follow-up of those patients with tumors larger than 4.0 cm in diameter. PMID- 21789007 TI - Laparoscopic-assisted total gastrectomy for adenocarcinoma in a western country: safety and oncological issues. AB - BACKGROUND: Laparoscopic total gastrectomy for adenocarcinoma is a widely diffused operation in eastern countries, but there are only a few reports from western centers. We assessed a single surgeon's experience at a single, nonacademic, community hospital. METHODS: Short-term outcome of patients undergoing laparoscopic total gastrectomy for adenocarcinoma (June 2005-March 2010) was assessed. RESULTS: Fourteen patients (5 males, 9 females; median age, 66.8 years [interquartile range, 59.7-71.8]) underwent laparoscopic total gastrectomy. The median operative time was 240 min. There were five stage 1 patients, five stage 2, and four stage 3; R0 resection was obtained in all 14 patients, and the median number of lymph nodes retrieved was 38. Mortality and overall morbidity rates were 0% and 35.7%, respectively. CONCLUSIONS: The outcomes of laparoscopic total gastrectomy for adenocarcinoma performed by a well trained laparoscopic surgeon working in a community hospital are good in terms of safety for the patients and response to the oncological criteria used in open surgery. PMID- 21789005 TI - The interaction between antioxidant status and cervical cancer: a case control study. AB - AIMS AND BACKGROUND: To compare the antioxidant status of cervical cancer patients with healthy controls and to assess the antioxidant levels before and after radiotherapy or radiochemotherapy. METHODS AND STUDY DESIGN: Antioxidant levels (glutathione, glutathione peroxidase, superoxide dismutase, and malondialdehyde) were measured in 35 patients with cervical cancer and 35 age matched healthy controls. Blood samples were collected twice (before and after treatment) from cervical cancer patients and once from healthy control subjects. RESULTS: In the patient group, pre-radiotherapy glutathione and glutathione peroxidase levels were significantly lower (P <0.01 and P <0.0001, respectively) than the control group. Pre-radiotherapy levels of superoxide dismutase were significantly higher in cancer patients (P <0.01). In general, no difference was observed between pre- and post-radiotherapy antioxidant levels in cancer patients. However, when post-radiotherapy glutathione levels were analyzed, patients who did not respond to treatment had significantly higher levels than those who did respond (P <0.01). CONCLUSIONS: Levels of antioxidants significantly differed between the patients with cervical cancer and the controls, and no change in antioxidant levels was observed after treatment. Moreover, further studies evaluating the predictive value of glutathione levels on treatment response are warranted. PMID- 21789008 TI - Evaluation of lymphatic compensation by lymphoscintigraphy in the postoperative period of breast cancer surgery with axillary dissection. AB - OBJECTIVE: To evaluate postoperative lymphatic compensation in the upper limb after mastectomy with axillary dissection. SUBJECTS AND METHODS: Twenty-three patients who underwent lymphoscintigraphy before and 60 days after surgery were enrolled from September 2006 to June 2007, in Campinas, Brazil. Protocol examination consisted in static imaging of each upper limb in semi-flexion and thoracic imaging after 10 min and 1 and 2 hr after subcutaneous injection of 1 mCi (37 MBq) of 99mTc dextran into the dorsum of the hand. A comparative analysis was made of hepatic uptake of the radiopharmaceutical, velocity of axillary lymph node visualization (I, visible at 10 min; II, at 1 hr; III, at 2 hr; IV, not visible) and degree (intensity) of uptake (a, marked; b, moderate; c, mild; d, absent) before and 60 days after surgery. RESULTS: In the preoperative period, 3 (13%) patients were considered to have an optimal pattern (Ia) and 2 (9%) showed total involvement (IVd). Compared to velocity in the postoperative period, 9 (39%) patients showed no difference, 5 (22%) improved, 9 (39%) became worse, and one was considerably worse. Regarding the degree, 10 (43%) patients showed no difference, 9 (39%) became worse, and 4 (17%) improved. Regarding classification, 2 (9%) patients had an optimal lymphatic pattern (Ia) and 3 (13%) had total involvement (IVd). No patient presented decreased hepatic uptake after surgical treatment. CONCLUSIONS: The study found relevant changes in preoperative and postoperative lymphoscintigraphy, demonstrating the existence of functional differences in the lymphatic system of the upper limb. Alterations in lymphatic drainage pattern may already be perceived 60 days postoperatively, as can signs of lymphovenous anastomoses. PMID- 21789009 TI - Liver resection for noncolorectal and nonneuroendocrine metastases: results of a study on 56 patients at a single institution. AB - The usefulness of surgical treatment for hepatic metastases of noncolorectal nonneuroendocrine (NCRNNE) tumors is not yet clear due to the natural history of these tumors, their frequent systemic dissemination and their histological heterogeneity. The aim of this study was to evaluate the long-term outcome of patients who underwent liver resection for NCRNNE metastases. For this purpose we retrospectively analyzed 202 patients who underwent liver resection for metastasis between January 1989 and December 2006 at the Department of Surgery of the University Hospital of Udine. Fifty-six patients underwent liver resection because of NCRNNE metastases. The preoperative assessment was based on hepatic ultrasonography and CT scan; PET was used in a few patients. All patients had intraoperative liver ultrasonography to evaluate the lesions and to define the resection. Gender, age, primary tumor site (gastrointestinal or nongastrointestinal), synchronous or metachronous metastasis, unilobar or bilobar localization, number and diameter of the lesion(s), type of resection, margin status, positive lymph nodes in the hepatoduodenal ligament, and time between surgery and diagnosis of liver metastases were evaluated as possible prognostic factors for survival. Univariate analysis showed that the location of the primary tumor and the disease-free interval since the treatment of the primary tumor were positive predictive factors for longer survival. Multivariate analysis showed that the only independent significant factor was gastrointestinal versus nongastrointestinal origin. Demographic data, the synchronous or metachronous appearance of metastases, their unilobar or bilobar location, number and size, the type of resection, the resection margin status and the involvement of lymph nodes did not prove to be prognostic factors. PMID- 21789010 TI - Wall defects after abdominoperineal resection: a modified tension-free technique. AB - BACKGROUND: The treatment of wall defects after abdominoperineal resection has yet to be defined. In this study we report the outcome of a modified prosthetic technique for the treatment of combined large incisional and parastomal hernia performed after abdominoperineal resection. MATERIAL AND METHODS: Between January 2005 and July 2008, 21 consecutive patients who underwent abdominoperineal resection for low rectal cancer received surgical repair for large incisional hernias with a modified mesh technique consisting of a tension-free attachment of the prosthetic material to the posterior sheath of the rectus abdominis muscle. The surgical outcome was assessed mainly as the recurrence rate of abdominal hernia and postoperative complications. RESULTS: Among the 21 patients we reported two minor complications: partial necrosis of the skin flap (4.8%) and a seroma (4.8%). One major complication occurred: extensive necrosis of the skin flap (4.8%). We reported one death due to stroke 20 days after surgery. The mean postoperative hospital stay was 6.1 days (SD, 2.3). CONCLUSIONS: This study encourages the use of a tension-free modified prosthetic technique for the repair of combined wall defects after abdominoperineal resection. The technique does not lead to an increase in the incidence of complications, offering a considerable advantage to the patient. PMID- 21789011 TI - Three-dimensional conformal postoperative radiotherapy in patients with parotid tumors: 10 years' experience at the European Institute of Oncology. AB - AIMS AND BACKGROUND: Salivary gland malignancies are rare. The aim of our study was to investigate radiotherapy-related toxicity and clinical outcome in patients treated at our division with postoperative radiotherapy (pRT) for parotid tumors. METHODS AND STUDY DESIGN: Forty-three consecutive patients (32 with primary parotid tumors, 9 with parotid metastases and 2 with recurrent benign diseases) were retrospectively analyzed. RESULTS: The median follow-up was 28 months. Twenty and 5 patients had a follow-up longer than 2 and 5 years, respectively. Thirty-seven patients were alive and most of them (78%) were free from disease. The local and distant control rates were higher in patients with primary parotid tumors (94% and 87.5%) than in patients with parotid metastases (87.5% and 75%). Grade 3 radiotherapy-related acute toxicity of skin and mucosa was recorded in 20.9% and 28% of patients, respectively. Two patients (4.7%) had grade 4 skin toxicity. Late toxicity data were available for 33 (77%) patients. None of the patients developed severe (grade 3 and 4) late toxicity of soft tissues, skin or temporomandibular joints. CONCLUSIONS: Postoperative radiotherapy is a feasible treatment that was found to be effective mainly in patients with primary parotid tumors. Toxicity was acceptable but could probably be further reduced using more advanced radiotherapy techniques. Longer follow-up is required to achieve definitive results. PMID- 21789012 TI - A retrospective analysis after low-dose-rate prostate brachytherapy with permanent (125)I seed implant: clinical and dosimetric results in 70 patients. AB - AIMS AND BACKGROUND: To evaluate the biochemical disease-free survival (bDFS) rate after (125)I permanent-implant prostate brachytherapy. METHODS: Patients with a diagnosis of prostate adenocarcinoma and adequate PSA follow-up were selected for this retrospective study. Brachytherapy with permanent (125)I seeds was performed as monotherapy, with a prescribed dose of 145 Gy to the prostate. Patients were stratified into recurrence risk groups according to the National Comprehensive Cancer Network (NCCN) guidelines. Biochemical failure was defined using the American Society of Therapeutic Radiology and Oncology (ASTRO) guidelines. The post-implant D90 (defined as the minimum dose covering 90% of the prostate) was obtained for each patient. Two cutoff points were used to test the correlation between D90 and bDFS results: 130 Gy and 140 Gy. bDFS was calculated from the implant date to the date of biochemical recurrence. Univariate and multivariate analysis were performed using the SPSS software and included clinical stage, pretreatment PSA, Gleason score (GS), androgen deprivation therapy, D90, and risk groups. In the univariate analysis we used a cutoff point of 5.89 ng/mL for PSA and 5 for GS. RESULTS: From June 2003 to April 2007, 70 patients were analyzed. The patients' distribution into recurrence risk groups was as follows: 39 patients (56%) in the low-risk group, 23 patients (33%) in the intermediate-risk group, and 8 patients (11%) in the high-risk group. At a median follow-up of 47 months (range, 19-70 months) bDFS was 88.4%, with a global actuarial 5-year bDFS of 86%. Disease-related factors including initial PSA level, GS and risk group were significant predictors of biochemical failure ( P = 0.01, P = 0.01, P = 0.006, respectively). In multivariate analysis, risk group (P = 0.005) and GS (P = 0.03) were statistically significant. CONCLUSION: Our data are in agreement with those in the literature and, despite the short follow-up, confirm the advantage of brachytherapy for patients at low and intermediate risk of recurrence. PMID- 21789013 TI - Impact of delayed radiotherapy on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy. AB - AIM AND BACKGROUND: To evaluate the effect of the surgery-radiotherapy interval (SRI) on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy. METHODS: From February 1992 to January 2002, 171 patients with node-negative breast cancer underwent breast-conserving surgery and adjuvant radiotherapy without chemotherapy. The whole breast was irradiated up to 50.4 Gy in 28 fractions followed by a 10-Gy boost to the tumor bed. Forty-four patients received tamoxifen in addition to radiotherapy. Patients were divided into 2 groups according to the length of SRI: <6 weeks (128 patients) versus >=6 weeks (43 patients). The median follow-up period was 87 months (range, 22-167). RESULTS: The 8-year local control rates of patients with SRI <6 weeks and >=6 weeks were 94.5% and 92.7%, respectively (P = 0.1140). When age, tumor size, resection margin status, combination with hormonal therapy, and SRI were incorporated into the Cox proportional hazards model, SRI <6 weeks and age at diagnosis >=40 years were associated with increased local control (P = 0.0343 and 0.0264, respectively). In the subgroup analysis, SRI <6 weeks was correlated with a higher local control rate for patients aged <40 years (P = 0.0142). Among older patients, however, there was no statistical difference in local control according to SRI (P = 0.6655). Treatment interval had no impact on overall and distant metastasis-free survival. CONCLUSIONS: Early radiotherapy within 6 weeks of breast-conserving surgery is associated with increased local control in patients with node-negative breast cancer not undergoing chemotherapy. PMID- 21789014 TI - Three-dimensional conformal radiation therapy for refractory laryngeal granuloma. AB - AIMS AND BACKGROUND: The etiology of laryngeal granulomas is often multifactorial and the benefit of pharmacological therapy remains unclear. Anti-reflux treatment is only effective in granulomas definitely induced by gastroesophageal reflux. Steroid inhalation has shown favorable results but it is unclear whether it shortens the healing process. Surgical excision is associated with high recurrence rates. The aim of this study was to evaluate the role of 3-dimensional conformal radiation therapy (3DCRT) in the treatment of refractory laryngeal granuloma. METHODS AND STUDY DESIGN: The study was a retrospective review including all patients presenting to the Department of Radiation Oncology at Xijing Hospital from January 2004 to March 2007. We studied a total of 15 cases of refractory laryngeal granuloma that had recurred >=2 times. Patients had previously been managed with voice rest, corticosteroids, antibiotics, antacids, surgery and botulinum toxin. All patients accepted surgical excision and immediate adjuvant 3DCRT at a total dose of 15 Gy over 5 days. RESULTS: All patients were successfully treated with surgery and 3DCRT. There has been no granuloma recurrence in 3 years of follow-up. CONCLUSIONS: 3DCRT is a safe and effective therapy for refractory laryngeal granulomas, especially when other methods have failed. PMID- 21789015 TI - A possible mechanism of impaired NK cytotoxicity in cancer patients: down regulation of DAP10 by TGF-beta1. AB - AIMS AND BACKGROUND: Elevated TGF-BETA1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. However, the molecular mechanism of immunosuppression by TGF-BETA1 is not yet clarified. METHODS: IL-2 activated human NK cells were cultured with TGF-BETA1. Protein levels of NKG2D and DAP10 were examined by FACS or immunoblot analyses. Real-time RTPCR was performed to quantify the transcription levels. MAPK inhibitors were used to investigate intracellular signaling. RESULTS: TGF-BETA1 down-regulated total and surface NKG2D, which was partially dependent on transcriptional regulation. TGF BETA1 treatment of human NK cells resulted in significant changes in both transcriptional and translational levels of DAP10. Moreover, treatment with bafilomycin A1 or folimycin restored total NKG2D levels in TGF-BETA1-treated NK cells. The impaired NKG2D down-modulation by TGF-BETA1 was not associated with activation of the MAPK signaling pathway. CONCLUSIONS: TGF-BETA1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10. PMID- 21789016 TI - Pharmacogenetics of escitalopram and mental adaptation to cancer in palliative care: report of 18 cases. AB - AIMS AND BACKGROUND: In palliative care, few data are available on the diagnosis and treatment of mood disorders and of difficulties of mental adaptation to cancer for patients in the advanced phases of the disease. SSRI antidepressants are the treatment of choice; the 5-HTTLPR genetic polymorphism of the serotonin transporter (SERT) has been shown in psychiatry to significantly determine the therapeutic response and the incidence of adverse effects. The aim of the present investigation has been therefore to examine the effects of the SSRI antidepressant escitalopram, also considering 5-HTTLPR, on depression, anxiety and mental adaptation to cancer in palliative care. METHODS AND STUDY DESIGN: Eighteen consecutive depressed patients with different forms of advanced cancer admitted to the Hospice Ass 6 of S. Vito al Tagliamento (Pordenone, Italy) were genotyped for the "s" and "l" variants of 5-HTTLPR and were treated with escitalopram. Their response after two weeks of treatment was psychometrically evaluated. RESULTS: Treatment with escitalopram significantly decreased anxiety scores on the Hospital Anxiety and Depression Scale (HADS) (P = 0.006) as well as anxious preoccupation (P = 0.007) and hopelessness-helplessness (P = 0.017) scores on the Mini Mental Adjustment to Cancer (Mini-MAC) scale. When patients were stratified by SERT genotype, HADS anxiety was significantly decreased in patients carrying the "s/s" and "s/l" variants (P = 0.024), whereas those with an "l/l" genotype displayed a significant reduction of Mini-MAC anxious preoccupation (P = 0.018). CONCLUSIONS: The results of this study indicate that the use of SSRI antidepressants is effective in the palliative care of cancer patients, and their action affects not only depression but also the patients' mental adaptation to the disease. These results encourage further examination of these drugs in a larger cohort of patients. The significant contribution of pharmacogenetics indicates the possibility of personalized treatment with SSRIs in palliative care. PMID- 21789017 TI - Single-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patients. AB - AIMS AND BACKGROUND: Palonosetron, a unique second-generation 5-HT3 receptor antagonist, has been demonstrated to control emesis related to chemotherapy induced nausea and vomiting (CINV). The aim of this study was to evaluate the efficacy and tolerability of palonosetron followed by a single dose of dexamethasone in patients with breast cancer (BC) or colorectal cancer (CRC) receiving moderate emetogenic chemotherapy (MEC). METHODS AND STUDY DESIGN: Chemotherapy-naive BC and CRC patients were given MEC as adjuvant or first-line treatment. Palonosetron (0.25 mg IV) and dexamethasone (8 mg IV) were administered before chemotherapy on day 1. The primary endpoint was complete response (CR; no vomiting and no use of rescue medication) during the overall study period (days 1-5). The antiemetic response was evaluated during the acute (day 1) and delayed (days 2-5) phases. RESULTS: Sixty-eight patients were enrolled (median age 61 years, 56 females; BC = 40, CRC = 28). CR was observed in 46 of 68 patients (67.6%), while CR during the acute and delayed phases was 75.0% in each cancer group. The antiemetic regimen was well tolerated. CONCLUSIONS: A single administration of palonosetron and dexamethasone on day 1 in BC and CRC patients adequately controls CINV during the entire period of emetic risk. PMID- 21789018 TI - Expectations of survivors, caregivers and healthcare providers for testicular cancer survivorship and quality of life. AB - AIMS AND BACKGROUND: We compared expectations of testicular cancer survivors and their caregivers with those of healthcare providers for testicular cancer survivorship care and quality of life to identify experiences and potential expectations in which there was disagreement. METHODS: In a meeting with testicular cancer survivors, their caregivers, and care providers with an interest in testicular cancer, we distributed a structured questionnaire with 24 questions divided into 3 sections: personal information, information on the quality of life of survivors, information on the role of care providers, general practitioners and health-related internet sources in the expectations of survivors. RESULTS: The overall response rate was 91% (29 of 32) for patients and 100% (14 of 14) for caregivers with all questionnaires evaluable, while among 60 care providers, 42 (70%) responded with 41 (68%) evaluable. Between patients/caregivers and care providers, expectations were most incongruent for the role of primary care physicians in testicular cancer follow-up: important/fundamental for 58% of patients/caregivers and 88% of care providers (P = 0.010). Comparing patients/caregivers with care providers in their views of the experience of testicular cancer survivorship, we found several discrepancies: the fear of recurrence was high/very high for 18 of 43 (42%) patients/caregivers and in the perception of 40 of 41 (98%) care providers (P <0.001), and psychological distress was considered as highly relevant by 35% of patients/caregivers and 93% of care providers (P <0.001). CONCLUSIONS: Patients/caregivers and care providers have different perceptions of survivors' experiences and discordant expectations with respect to the roles of primary care providers in testicular cancer survivorship care. Uncertainties about the roles and responsibilities of physicians can lead to deficiencies in care, supporting the need to make survivorship care planning a standard component in cancer management. PMID- 21789019 TI - Do elderly cancer patients have different care needs compared with younger ones? AB - AIMS AND BACKGROUND: The increasingly older population confronts oncologists with an imposing challenge: older cancer patients have specific healthcare needs both independent of and associated with the diagnosis of cancer. The aim of the present study is to examine whether elderly versus younger cancer patients have different needs with respect to attendance, treatment and information. METHODS AND STUDY DESIGN: This is an observational and cross-sectional study. Cancer patients aged 35 to 82 years were consecutively interviewed. The group was divided into two subgroups aged <=65 and >=66 years old. The Needs Evaluation Questionnaire (NEQ) was used to assess patients' needs and demographic variables were collected. Data analysis was carried out by means of cross-tabulation analyses and the chi-square test. RESULTS: The requests most frequently expressed by the older group concerned financial-insurance information (73.9%), the need to talk to people with the same illness (71.7%), the need to receive more comprehensible information from doctors and nurses (71.7%), and the need for a better dialogue with clinicians (69.6%). Few significant differences between the two age subgroups were found, with the exception of issues such as the need for intimacy and support. CONCLUSIONS: Elderly patients have informational and relational needs similar to those of younger patients. In fact, most of the whole sample flagged up the need for higher levels of satisfaction especially concerning a better dialogue with health staff, along with a new factor: the need to talk to people with the same illness. PMID- 21789020 TI - Expression of AIMP1, 2 and 3, the scaffolds for the multi-tRNA synthetase complex, is downregulated in gastric and colorectal cancer. AB - Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) form a protein complex with aminoacyl-tRNA synthetases. In addition to protein translation, AIMPs play a role in diverse biological processes. Earlier studies suggested that AIMPs may act as tumor suppressors. However, the expression status of the AIMP proteins in human cancer tissues is largely unknown. In this study, we analyzed the expression of AIMP members (AIMP1, AIMP2 and AIMP3) in gastric cancer (GC) and colorectal cancer (CRC) tissues. We analyzed the expression of these proteins in 100 GC and 103 CRC tissues by immunohistochemistry using a tissue microarray method. Normal gastric and colon mucosa expressed AIMP1, AIMP2 and AIMP3 in nearly all of the cases (95-100%). However, the expression of AIMP1, AIMP2 and AIMP3 was significantly decreased in the GC samples (60%, 52% and 70% of the cases, respectively) and in the CRC samples (66%, 53% and 81% of the cases, respectively) ( P <0.01). Expression of AIMP1, AIMP2 or AIMP3 was not associated with clinicopathological parameters including differentiation, depth of invasion and TNM stage. The decreased expression of AIMP1, AIMP2 and AIMP3 in the GC and CRC tissues compared to the corresponding normal tissues suggested that downregulation of these proteins may be related to inactivation of the tumor suppressor functions of AIMP proteins and might play a role in the development of GC and CRC. PMID- 21789021 TI - An investigation into the combined effect of static magnetic fields and different anticancer drugs on K562 cell membranes. AB - AIMS AND BACKGROUND: Cell membranes were shown to be sensitive to and affected by static magnetic fields (SMF). METHODS: Cells were treated with four anticancer drugs followed by treatment with a combination of drugs and SMF. Individual cells were examined using atomic force microscopy (AFM). The drugs were taxol (alkaloid), doxorubicin (anthracycline), cisplatin (platinum compound) and cyclophosphamide (alkylating agent). RESULTS: Holes were observed in cells exposed to SMF but not in control groups. The number, size and shape of the holes were dependent on the drug type, SMF parameters and the duration of exposure. CONCLUSIONS: The results suggest that the application of a SMF could alter membrane permeability, increasing the flow of the anticancer drugs. This may be one of the reasons why SMF can strengthen the effect of anticancer drugs. Observations were also made of the effect of using different anticancer drugs. For example, the effect of SMF combined with taxol or cyclophosphamide on the cells was additive while the effect of SMF combined with cisplatin or doxorubicin was synergistic. The target sites of cisplatin and doxorubicin are nucleic acids; continued research is required into this important area to ascertain the effect of SMF on nucleic acids. PMID- 21789022 TI - Floating cells with stem cell properties in gastric cell line SGC-7901. AB - AIMS: To obtain floating spheres from the adherent gastric cancer cell line SGC 7901 and to analyze the properties of the spheres. METHODS: Serum-free medium was applied to cultured SGC-7901 cells. Limiting dilution assay, tumor formation assay, microarray analysis, and real-time fluorescent quantitative PCR were used to test the stem cell properties of the spheres. RESULTS: A subpopulation of SGC 7901 cells formed floating spheres in serum-free medium. These cells showed enhanced tumorigenic ability and also highly expressed certain stem-cell associated proteins. CONCLUSIONS: We successfully propagated floating spheres with stem cell properties in the SGC-7901 gastric cell line. PMID- 21789023 TI - Low-dose epirubicin inhibits ezrin-mediated metastatic behavior of breast cancer cells. AB - AIMS AND BACKGROUND: Overexpression of ezrin contributes to the progression and invasiveness of several human cancers; however, its role in breast cancer metastasis has not been investigated in detail. METHODS: Ezrin expression in tissue samples from patients with invasive ductal carcinoma of the breast was detected by immunohistochemistry. Ezrin expression in a breast cancer cell line was evaluated using Western blot and RT-PCR. RESULTS: Elevated expression of ezrin was associated with lymph node metastasis and poor prognosis in patients with invasive ductal carcinoma. Ezrin expression was related to the invasiveness of breast cancer cells in vitro. Low-dose epirubicin inhibited the migration of breast cancer cells in a concentration-dependent manner without promoting cytotoxicity in vitro and decreased the expression of ezrin in a concentration dependent manner. CONCLUSIONS: Low-dose epirubicin may be antimetastatic without promoting cytotoxic effects and could serve as a target for the development of therapeutics for breast carcinoma. PMID- 21789024 TI - TomoTherapy stereotactic body radiation therapy (SBRT) for the salvage treatment of locally recurrent esophageal adenocarcinoma following trimodality therapy: a case report. AB - Esophageal cancer patients with local recurrence after chemoradiation and surgery (trimodality therapy) have limited palliative treatment options. We present a case of local recurrence successfully palliated using TomoTherapy stereotactic body radiation therapy (SBRT). The patient was a 58-year-old man with distal esophageal adenocarcinoma initially treated with trimodality therapy. Symptomatic local recurrence developed 4 years later. Using TomoTherapy SBRT successful palliation was achieved with 3500 cGy in 7 fractions given every other weekday. He remained free of local recurrence without requiring further local therapies, eventually succumbing to metastatic disease 11 months after radiation. Presently there are no reported cases of malignant esophageal obstruction treated with SBRT. Radiosurgery is increasingly used in extracranial sites such as the liver, lung and spine. Reirradiation was convenient and well tolerated by our patient and the response durable. Palliation of local recurrence in esophageal cancer initially treated with trimodality therapy can be achieved using SBRT and is a reasonable option in appropriately selected patients. Further studies are needed to clarify its role in this and other body sites. PMID- 21789025 TI - Endometrial metastasis of lung adenocarcinoma: a case report. AB - The female genital tract is an infrequent site of metastasis, in particular from extragenital primary tumors such as non-small cell lung cancer. Ovarian metastases have been described as disseminations of lung adenocarcinoma; rare cases of secondary localizations in adnexa, cervix and vagina were also observed in the literature, but none of these had endometrial involvement. We report the first case, to our knowledge, of non-small cell lung cancer with metastatic spread to the endometrium. PMID- 21789026 TI - Rhabdomyolysis from erlotinib: a case report. PMID- 21789027 TI - What You Feel Influences What You See: The Role of Affective Feelings in Resolving Binocular Rivalry. AB - It seems obvious that what you see influences what you feel, but what if the opposite were also true? What if how you feel can shape your visual experience? In this experiment, we demonstrate that the affective state of a perceiver influences the contents of visual awareness. Participants received positive, negative, and neutral affect inductions and then completed a series of binocular rivalry trials in which a face (smiling, scowling or neutral) was presented to one eye and a house to the other. The percepts "competed" for dominance in visual consciousness. We found, as predicted, that all faces (smiling, scowling, and neutral) were dominant for longer when perceivers experienced unpleasant affect compared to when they were in a neutral state (a social vigilance effect), although scowling faces increased their dominance when perceivers felt unpleasant (a relative negative congruence effect). Relatively speaking, smiling faces increased their dominance more when perceivers were experiencing pleasant affect (a positive congruence effect). These findings illustrate that the affective state of a perceiver serves as a context that influences the contents of consciousness. PMID- 21789028 TI - What cognitive abilities are involved in trail-making performance? AB - The cognitive abilities involved in the Connections (Salthouse, et al., 2000) version of the trail making test were investigated by administering the test, along with a battery of cognitive tests and tests of complex span and updating conceptualizations of working memory, to a sample of over 3,600 adults. The results indicate that this variant of the trail making test largely reflects individual differences in speed and fluid cognitive abilities, with the relative contributions of the two abilities varying according to particular measure of performance considered (e.g., difference, ratio, residual). Relations of age on trail making performance were also examined. Although strong age differences were evident in the Connections and working memory measures, with both sets of variables there was nearly complete overlap of the age differences with individual differences in speed and fluid cognitive abilities. PMID- 21789029 TI - Successful bronchoscopic cryorecanalization in a case of endobronchial lipoma. AB - Endobronchial lipomas are rare benign tumors; less than 150 cases have been reported so far. Bronchial occlusion usually leads to a misdiagnosis of asthma/COPD or malignancy. We report the case of a 67-year-old man with a history of heavy smoking (100 pack years), dyspnea on exertion, cough, and malaise who was treated for pneumonia for three weeks. Due to nonresolving atelectasis of the superior segment of the right lower lobe, a malignant endobronchial tumor was suspected. Rigid bronchoscopy with cryorecanalization led to both the definite histopathological diagnosis of endobronchial lipoma and the reopening of an endoluminal airway obstruction during one procedure. PMID- 21789030 TI - Prevalence of connective tissue diseases in egyptian patients presenting with Fever of unknown origin. AB - OBJECTIVE: To estimate the prevalence of connective tissue diseases in patients presenting with fever of unknown origin (FUO). PATIENTS AND METHODS: In this study thirty patients diagnosed as FUO (Group 1), in 2008, were included in an observational study and diagnostic workup. Additionally, retrospective analysis of seventy patients' files (Group 2), for patients who presented with prolonged unexplained pyrexia to the same hospital in the previous two years, was performed. Patients were subjected to: full clinical assessment including full history taking, thorough clinical examination, laboratory investigations including the basic investigations for patients with prolonged fever, complete blood count, erythrocytes sedimentation rate, urine analysis and culture, blood culture, sputum culture and plain chest X ray. Further diagnostic work up and/or procedures were requested according to the potential diagnostic clues (PDC) present in every patient. RESULTS: Out of 100 FUO patients, 50% were found to have infectious diseases, 24% were found to have connective tissue diseases, 8% miscellaneous causes and 7% neoplastic diseases (P < 0.05). In 11 patients no definite cause for FUO could be identified. Connective tissue patients were: eight systemic lupus patients (33.3%), five patients with familial mediterranean fever (20.8%), four patients with rheumatoid arthritis (16.6%), three patients (12.5%) with Still's disease and Rheumatic fever and one patient with Behcet syndrome/Crohn's disease (4.3%), (P < 0.05). CONCLUSIONS: Despite the advanced technology, FUO remains a challenging medical problem. Infections were the most common cause of FUO in Egypt, confirming the trends found in other parts of the world. There was an increased prevalence of connective tissue patients presented with prolonged unexplained fever. A keen clinical eye, meticulous history taking and repeated physical examination remained the most important diagnostic tools in FUO patients. PMID- 21789031 TI - Identification of Differentially Expressed MicroRNAs in Osteosarcoma. AB - A limited number of reports have investigated the role of microRNAs in osteosarcoma. In this study, we performed miRNA expression profiling of osteosarcoma cell lines, tumor samples, and normal human osteoblasts. Twenty-two differentially expressed microRNAs were identified using high throughput real time PCR analysis, and 4 (miR-135b, miR-150, miR-542-5p, and miR-652) were confirmed and validated in a different group of tumors. Both miR-135b and miR-150 have been previously shown to be important in cancer. We hypothesize that dysregulation of differentially expressed microRNAs may contribute to tumorigenesis. They might also represent molecular biomarkers or targets for drug development in osteosarcoma. PMID- 21789032 TI - Behavioral economics perspectives on public sector pension plans. AB - We describe the pension plan features of the states and the largest cities and counties in the U.S. Unlike in the private sector, defined benefit (DB) pensions are still the norm in the public sector. However, a few jurisdictions have shifted toward defined contribution (DC) plans as their primary savings plan, and fiscal pressures are likely to generate more movement in this direction. Holding fixed a public employee's work and salary history, we show that DB retirement income replacement ratios vary greatly across jurisdictions. This creates large variation in workers' need to save for retirement in other accounts. There is also substantial heterogeneity across jurisdictions in the savings generated in primary DC plans because of differences in the level of mandatory employer and employee contributions. One notable difference between public and private sector DC plans is that public sector primary DC plans are characterized by required employee or employer contributions (or both), whereas private sector plans largely feature voluntary employee contributions that are supplemented by an employer match. We conclude by applying lessons from savings behavior in private sector savings plans to the design of public sector plans. PMID- 21789033 TI - A Kirkwood-Buff Derived Force Field for Aqueous Alkali Halides. AB - A classical nonpolarizable force field is presented for the simulation of aqueous alkali halide solutions (MX), where M = Li(+), Na(+), K(+), Rb(+), Cs(+) and X = F(-), Cl(-), Br(-), I(-), and their interactions with biomolecules. The models are specifically designed to reproduce the experimental Kirkwood-Buff integrals, and thereby the solution salt activities, as a function of salt concentration. Additionally, we demonstrate that these models reasonably reproduce other experimental properties including ion diffusion constants, dielectric decrements, and the excess heats of mixing. The parameters are developed by considering the properties of aqueous NaX and MCl solutions using a previously established model for NaCl. Transferability of the parameters to other salts is then established by the successful simulation of additional aqueous salt solutions, KI and CsBr, not originally included in the parameterization procedure. PMID- 21789034 TI - Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity. AB - The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ~35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionarily conserved. Despite their sequence conservation, there is evidence that the different human BRC repeats have distinct capacities to bind RAD51. A previously published crystal structure reports the structural basis of the interaction between human BRC4 and the catalytic core domain of RAD51. However, no structural information is available regarding the binding of the remaining seven BRC repeats to RAD51, nor is it known why the BRC repeats show marked variation in binding affinity to RAD51 despite only subtle sequence variation. To address these issues, we have performed fluorescence polarisation assays to indirectly measure relative binding affinity, and applied computational simulations to interrogate the behaviour of the eight human BRC-RAD51 complexes, as well as a suite of BRC cancer-associated mutations. Our computational approaches encompass a range of techniques designed to link sequence variation with binding free energy. They include MM-PBSA and thermodynamic integration, which are based on classical force fields, and a recently developed approach to computing binding free energies from large-scale quantum mechanical first principles calculations with the linear-scaling density functional code onetep. Our findings not only reveal how sequence variation in the BRC repeats directly affects affinity with RAD51 and provide significant new insights into the control of RAD51 by human BRCA2, but also exemplify a palette of computational and experimental tools for the analysis of protein-protein interactions for chemical biology and molecular therapeutics. PMID- 21789036 TI - In Situ Porous Structures: A Unique Polymer Erosion Mechanism in Biodegradable Dipeptide-based Polyphosphazene and Polyester Blends Producing Matrices for Regenerative Engineering. AB - Synthetic biodegradable polymers serve as temporary substrates that accommodate cell infiltration and tissue in-growth in regenerative medicine. To allow tissue in-growth and nutrient transport, traditional three-dimensional (3D) scaffolds must be prefabricated with an interconnected porous structure. Here we demonstrated for the first time a unique polymer erosion process through which polymer matrices evolve from a solid coherent film to an assemblage of microspheres with an interconnected 3D porous structure. This polymer system was developed on the highly versatile platform of polyphosphazene-polyester blends. Co-substituting a polyphosphazene backbone with both hydrophilic glycylglycine dipeptide and hydrophobic 4-phenylphenoxy group generated a polymer with strong hydrogen bonding capacity. Rapid hydrolysis of the polyester component permitted the formation of 3D void space filled with self-assembled polyphosphazene spheres. Characterization of such self-assembled porous structures revealed macropores (10-100 MUm) between spheres as well as micro- and nanopores on the sphere surface. A similar degradation pattern was confirmed in vivo using a rat subcutaneous implantation model. 12 weeks of implantation resulted in an interconnected porous structure with 82-87% porosity. Cell infiltration and collagen tissue in-growth between microspheres observed by histology confirmed the formation of an in situ 3D interconnected porous structure. It was determined that the in situ porous structure resulted from unique hydrogen bonding in the blend promoting a three-stage degradation mechanism. The robust tissue in-growth of this dynamic pore forming scaffold attests to the utility of this system as a new strategy in regenerative medicine for developing solid matrices that balance degradation with tissue formation. PMID- 21789037 TI - Dermoscopy and skin cancer. PMID- 21789035 TI - Cornea: Window to Ocular Immunology. AB - The ocular surface is continuously exposed to environmental agents such as allergens, pollutants, and microorganisms, which could provoke inflammation. However, an array of anatomical, physiological, and immunological features of the ocular surface conspire to limit corneal inflammation and endow the eye with immune privilege. A remarkable example of ocular immune privilege is the success of corneal allografts, which unlike all other forms of organ transplantation, survive without the use of systemic immunosuppressive drugs or MHC matching. This review describes the anatomical, physiological, and dynamic immunoregulatory processes that contribute to immune privilege. PMID- 21789039 TI - Toll-like receptor signaling in liver diseases. PMID- 21789038 TI - Z-plasty made simple. AB - A Z-plasty is a critical and reliable technique that is useful for scar revisions and correction of free margin distortion. A Z-plasty can help lengthen a contracted scar, change the direction of a scar so that it is better aligned with the relaxed skin tension lines, or interrupt and break a scar for better camouflage. This article will review the technique of a basic Z-plasty as well as provide case examples of its use in free margin distortion and scar revision. PMID- 21789040 TI - Malnutrition and nutrition-therapy: our neglected responsibility. PMID- 21789041 TI - Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. AB - Introduction. Nephrotoxicity is one of the important side effects of anthracycline antibiotics. The aim of this study was to investigate the effects of nicotinamide (NAD), an antioxidant agent, against nephrotoxicity induced by doxorubicin (DXR). Methods. The rats were divided into control, NAD alone, doxorubicin (20 mg/kg, i.p.) and DXR plus NAD (200 mg/kg, i.p.) groups. At the end of the 10th day, kidney tissues were removed for light microscopy and analysis. The level of tissues' catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), inducible nitric oxide (iNOS) and endothelial nitric oxide (eNOS) activities were determined. Results. The activities of CAT, GPx, and GSH were decreased, and Po was increased in renal tissue of doxorubicin group compared with other groups. The tissue of the doxorubicin group showed some histopathological changes such as glomerular vacuolization and degeneration, adhesion to Bowman's capsule and thickening and untidiness of tubular and glomerular capillary basement membranes. Histopathological examination showed that NAD prevented partly DXR-induced tubular and glomerular damage. Conclusions. Pretreatment with NAD protected renal tissues against DXR-induced nephrotoxicity. Preventive effects of NAD on these renal lesions may be via its antioxidant and anti-inflammatory action. PMID- 21789043 TI - Stents in renal artery bifurcation stenosis: a case report. AB - A 39-year-old patient presented with poorly controlled hypertension, and she was referred to renal angiogram and potential renal angioplasty. Renal angiogram showed a bifurcation lesion of the right renal artery. A guide wire was used to cross the upper branch, while the lower branch was protected by another same-type guide wire through the same introducer. Two thin monorail balloons were used to dilate the two branches; however, despite balloon dilatation, the stenosis of the vessels persisted. The "kissing balloon" technique was then attempted by simultaneously inflating both branches using the same balloons, but more than a 70% residual stenosis persisted in each branch. Two stents were finally placed in a "kissing" way through the main renal artery. The imaging and clinical results were good, without any procedure-related complications. Three years clinical followup was also good, without any reason for further interventional approach. PMID- 21789042 TI - HCV infection and B-cell lymphomagenesis. AB - Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL). Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis. PMID- 21789044 TI - Immune Efficacy of a Genetically Engineered Vaccine against Lymphocystis Disease Virus: Analysis of Different Immunization Strategies. AB - Here, we report the construction of a vaccine against lymphocystis disease virus (LCDV) using nucleic acid vaccination technology. A fragment of the major capsid protein encoding gene from an LCDV isolated from China (LCDV-cn) was cloned into an eukaryotic expression vector pEGFP-N2, yielding a recombinant plasmid pEGFP-N2 LCDV-cn0.6 kb. This plasmid was immediately expressed after liposomal transfer into the Japanese flounder embryo cell line. The recombinant plasmid was inoculated into Japanese flounder via two routes (intramuscular injection and hypodermic injection) at three doses (0.1, 5, and 15 MUg), and then T lymphopoiesis in different tissues and antibodies raised against LCDV were evaluated. The results indicated that this recombinant plasmid induced unique humoral or cell-mediated immune responses depending on the inoculation route and conferred immune protection. Furthermore, the humoral immune responses and protective effects were significantly increased at higher vaccine doses via the two injection routes. Plasmid pEGFP-N2-LCDV0.6 kb is therefore a promising vaccine candidate against LCDV in Japanese flounder. PMID- 21789045 TI - A preliminary study of the microbial resources and their biological activities of the East china sea. AB - East China Sea is one of the four sea areas in China, which possesses peculiar ecological environment and many kinds of living creatures, especially the microorganisms. We established the East China Sea microorganism library (during 2006-2010) for the first time, which stored about 30000 strains that covered most kinds of the species. In this paper, 395 pure strains of East China Sea microorganism library which belong to 33 different genera were mainly introduced. Sulfitobacter, Halomonas, Bacillus, Pseudoalteromonas, and Idiomarina were the most dominant species. On the large-scale biological activity screening of the 395 strains, 100 strains possess different biological activities based on different screening models, of which 11.4% strains have antibacterial activities, 15.9% have cytotoxicity activities, and 6.1% have antioxidation activities. Besides, the secondary metabolites of 6 strains with strong biological activities were studied systematically; diketopiperazines and macrocyclic lactones are the active secondary metabolites. The species and the biological activity of microorganisms diversity, the abundant structure type of the secondary metabolites, and their bioactivities all indicate that East China Sea is a potent marine microorganisms-derived developing resource for drug discovery. PMID- 21789046 TI - Antiamnesic activity of an ayurvedic formulation chyawanprash in mice. AB - Chyawanprash (Chy) is an ayurvedic formulation commonly consumed in Indian households. Chy is a comprehensive herbal tonic, prepared from around 50 herbs employing anwala (Emblica officinalis) as the basic ingredient. The present study was undertaken to explore the beneficial effects of Chy (at the dose of 1 and 2% w/w of diet) administered daily for 15 successive days in mice with memory deficits. A total of 228 mice divided in 38 groups were employed in this study. Morris water maze, Hebb-Williams maze and elevated plus maze served as exteroceptive memory models, whereas scopolamine (Sco)-induced amnesia and alprazolam (Alp)-induced amnesia served as interoceptive memory models. The brain acetylcholinesterase activity, brain thiobarbituric acid reactive substances (TBARS) and reduced glutathione levels (GSH) were also estimated. The administration of Chy for 15 consecutive days significantly protected the animals from developing memory impairment. Furthermore, there was a significant decrease in brain TBARS and increase in GSH levels after administration of Chy (2% w/w), thereby indicating decreased free radical generation and increased scavenging of free radical, respectively. Thus, Chy may prove to be a useful remedy for the management of Alzheimer's disease owing to its antioxidant effect, pro cholinergic action and/or antiamnesic potential. PMID- 21789047 TI - Cardioprotective effects of salvianolic Acid a on myocardial ischemia-reperfusion injury in vivo and in vitro. AB - Salvianolic acid A (SAA), one of the major active components of Danshen that is a traditional Chinese medicine, has been reported to possess protective effect in cardiac diseases and antioxidative activity. This study aims to investigate the cardioprotection of SAA in vivo and in vitro using the model of myocardial ischemia-reperfusion in rat and hydrogen peroxide (H(2)O(2))-induced H9c2 rat cardiomyoblasts apoptosis. It was found that SAA significantly limited infarct size of ischemic myocardium when given immediately prior to reperfusion. SAA also significantly suppressed cellular injury and apoptotic cell death. Additionally, the results of western blot and phospho-specific antibody microarray analysis showed that SAA could up-regulate Bcl-2 expression and increase the phosphorylation of proteins such as Akt, p42/p44 extracellular signal-related kinases (Erk1/2), and their related effectors. The phosphorylation of those points was related to suppress apoptosis. In summary, SAA possesses marked protective effect on myocardial ischemia-reperfusion injury, which is related to its ability to reduce myocardial cell apoptosis and damage induced by oxidative stress. The protection is achieved via up-regulation of Bcl-2 expression and affecting protein phosphorylation. These findings indicate that SAA may be of value in cardioprotection during myocardial ischemia-reperfusion injury, which provide pharmacological evidence for clinical application. PMID- 21789048 TI - Therapeutic Advances in Urology: new crossroads in innovation, research, and clinical practice. PMID- 21789049 TI - Malignancy after gastrointestinal augmentation in childhood. AB - INTRODUCTION: To review the incidence and risks of bladder cancer following gastrointestinal augmentations done for congenial anomalies in childhood. MATERIALS AND METHODS: A literature search using PubMed and Ovid Medline search engines was performed. MeSH terms evaluated were; bladder augmentations, enterocystoplasty, gastrocystoplasty, spina bifida, spinal dysraphism, myelodysplasia, neural tube defects, posterior urethral valves and bladder exstrophy were cross referenced with the terms, bladder cancer and urinary bladder neoplasm. All patients who developed a bladder cancer following a bladder augmentation for a congenital anomaly were reviewed. RESULTS: A total of 20 cases of bladder cancer following augmentations for congential anomalies, were identified, 9 arose following ileal cystoplasty, 3 following colocystolasty and 8 following gastrocystoplasty. The incidence of cancer developing per decade following surgery was 1.5% for ileal/colonic and 2.8% for gastric bladder augmentations. The majority of cancers developing within the augmented bladder are at advanced stages at the time of diagnosis (60%; 12/20 cases were >=T3 at diagnosis). Several of the cases that developed occurred in patients exposed to known carcinogenic stimuli and/or arose in bladders with a known predisposition to carcinoma. CONCLUSION: Patients augmented with ileal or colonic segment for a congenital bladder anomaly have a 7-8 fold and gastric augments a 14-15 fold increased risk for the development of bladder cancer over standard norms. Published data is however unable to determine if gastrointestinal bladder augmentation is an independent risk factor for cancer over the inherent risk of cancer arising from a congenitally abnormal bladder. PMID- 21789051 TI - Second-look nephroscopy after percutaneous nephrolithotomy. AB - Percutaneous nephrolithotomy (PCNL) is the standard of care for the management of large renal stone burdens. Residual stones after PCNL may be cleared with a second-look nephroscopy. Determining whether a patient should undergo a second look procedure is based on both the intraoperative findings and the post operative imaging. Aggressive intraoperative flexible nephroscopy, may reduce the need for routine second-look nephroscopy. Post-operative computed tomograpahy (CT) imaging is the most sensitive method for detecting residual stone fragments. When a clinically significant residual stone burden exists a second-look procedure may be performed in an effort to render the patient stone-free. In most instances the procedure can be performed in an ambulatory facility under conscious intravenous sedation. Future prospective study determining the threshold of fragment size after PCNL that warrants second-look nephroscopy is needed. PMID- 21789050 TI - Use of nomograms for predictions of outcome in patients with advanced bladder cancer. AB - INTRODUCTION: Accurate estimates of risk are essential for physicians if they are to recommend a specific management to patients with bladder cancer. In this review, we discuss the criteria for the evaluation of nomograms and review current available nomograms for advanced bladder cancer. METHODS: A retrospective review of the Pubmed database between 2002 and 2008 was performed using the keywords 'nomogram' and 'bladder'. We limited the articles to advanced bladder cancer. We recorded input variables, prediction form, number of patients used to develop the prediction tools, the outcome being predicted, prediction tool specific features, predictive accuracy, and whether validation was performed. RESULTS: We discuss the characteristics needed to evaluate nomograms such as predictive accuracy, calibration, generalizability, level of complexity, effect of competing risks, conditional probabilities, and head-to-head comparison with other prediction methods. The predictive accuracies of the pre-cystectomy tools (n = 2) range from ~65-75% and that of the post-cystectomy tools (n = 5) range from ~75-80%. While some of these nomograms are well-calibrated and outperform AJCC staging, none has been externally validated. To date, four studies demonstrated a statistically significant improvement in predictive accuracy of nomograms by including biomarkers. CONCLUSIONS: Nomograms provide accurate individualized estimates of outcomes. They currently represent the most accurate and discriminatory decision-making aids tools for predicting outcomes in patients with bladder cancer. Use of current nomograms could improve current selection of patients for standard therapy and investigational trial design by ensuring homogeneous groups. The addition of biological markers to the currently available nomograms using clinical and pathologic data holds the promise of improving prediction and refining management of patients with bladder cancer. PMID- 21789052 TI - TRP family proteins in the lower urinary tract: translating basic science into new clinical prospective. AB - The lower urinary tract (LUT) is densely innervated by capsaicin-sensitive primary afferent neurons, a sub set of sensory nerves, in a number of species including humans. These fibers exhibit both a sensory (afferent) function, including the regulation of the micturition reflex and the perception of pain, and an 'efferent' function, involved in the detrusor smooth muscle contractility and plasma protein extravasation. The discovery of specific binding sites for capsaicin, the pungent ingredient of red chilli, initiated a rush that ended up with the cloning of the 'vanilloid receptor', which belongs to the TRP (transient receptor potential) family. Here we reviewed the knowledge about the presumable functions of TRP family proteins in the LUT as regulators of bladder reflex activity, pain perception and cell differentiation. This review will focus on experimental evidence and promising clinical applications of targeting these proteins for the treatment of detrusor overactivity and bladder pain syndrome. As TRP receptor ligands may promote cellular death, and inhibit the growth of normal and neoplastic cells, the translation of basic science evidence into new clinical prospective for bladder and prostate cancer will be shown. PMID- 21789053 TI - Prostate capsule sparing radical cystectomy: oncologic safety and clinical outcome. AB - OBJECTIVES: Prostate capsule sparing radical cystectomy (PSRC) is a modification of the traditional surgical approach to radical cystectomy and neobladder, which offers the prospect of improved preservation of erectile function and continence. METHODS: This is a review of the literature regarding the oncologic and quality of life outcomes of this approach for transitional cell carcinoma of the bladder, and a comparison of these results to conventional cystoprostatectomy and neobladder. RESULTS: There are a limited number of studies addressing prostate capsule or prostate sparing cystectomy. All are retrospective, non-comparative and not uniform in terms of patient selection and technique. Long-term follow-up is lacking. The incidence of synchronous and or metachronous prostate cancer and TCC of the prostatic urethra is lower than that found in conventional cystoprostatectomy. This is likely due to pre-operative patient selection, restricting the procedure to those with no evidence of prostatic involvement by either disease. The local recurrence rate is 5%, comparable to standard cystoprostatectomy. Recurrence free and overall survival rates are comparable. PMID- 21789054 TI - Methodological quality in medical evidence, quo vadis? AB - Efforts in research quality have led to a diffusion of publication guidelines for high-quality reporting of medical evidence with the aim to instill transparency to its evaluation. The maturity of this process has led to a second stage in which a surplus of scales measuring methodological quality is in place. However, there is no clear consensus as to which of these guidelines should be recommended for usage and how to integrate the methodological quality information into the evidence synthesis process. One major challenge that these scales poses is the fact that slight modifications performed to them in order to adapt to a specific research and/or management question requires revalidation of the scale's properties, a clearly impractical endeavor. This article proposes a potential alternative to this challenge through the formulation of a framework in which quality elements are divided into tiers. This layering aims at separating quality constructs that should be uniformly present across all studies and thus could be validated from constructs that are question-specific and less likely to undergo a formal validation process. An example of this framework applied to the urological literature is presented. PMID- 21789055 TI - PET/CT imaging of clear cell renal cell carcinoma with I labeled chimeric antibody. AB - Clear cell renal cell carcinoma (ccRCC) presents problems for urologists in diagnosis, treatment selection, intraoperative surgical margin analysis, and long term monitoring. In this paper we describe the development of a radiolabeled antibody specific to ccRCC (124I-cG250) and its potential to help urologists manage each of these problems. We believe 124I-cG250, in conjunction with perioperative Positron emission tomography/computed tomography imaging and intraoperative handheld gamma probe use, has the potential to diagnose ccRCC, aid in determining a proper course of treatment (operative or otherwise), confirm complete resection of malignant tissue in real time, and monitor patients post operatively. PMID- 21789057 TI - New techniques for laser prostatectomy: an update. AB - Traditionally, the gold standard for treatment of BPH has been the electrocautery based TransUrethral Resection of the Prostate (TURP). However, the number of laser techniques being performed is rapidly increasing. Potential advantages of laser therapy over traditional TURP include decreased morbidity and shorter hospital stay. There are several techniques for laser prostatectomy that continue to evolve. The main competing techniques are currently the Holmium Laser Enucleation of the Prostate (HoLEP) and the 80W 532nm laser prostatectomy. The HoLEP, using the Holmium:YAG laser, has been shown to have clinical results similar to TURP and is suitable for patients on anticoagulation as well as those with large prostates. Disadvantages of this technique are the high learning curve and requirement of a morcellator. When used to treat BPH, studies have demonstrated that, like the HoLEP, the 80W KTP laser is safe and effective in patients with large prostates and in those taking oral anticoagulation. Several studies have compared these two techniques to TURP. Frequently reported advantages of the HoLEP over the 80W laser prostatectomy are the availability after the procedure of a pathology specimen and ability to remove a higher percentage of prostate tissue during resection. However, the transurethral laser enucleation of the prostate addresses these concerns and has shown to have durable outcomes at 2-year follow-up. Two new laser systems and techniques, the thulium laser and the 980nm laser, have emerged recently. However, clinical data from these procedures are in their infancy and large long-term studies are required. PMID- 21789056 TI - Prospective pharmacologic therapies for the overactive bladder. AB - Lower urinary tract symptoms (LUTS), overactive bladder syndrome (OAB) and detrusor overactivity (DO) are all conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are first-line treatment-they often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium, the spontaneous myocyte activity during bladder filling, and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of LUTS/OAB/DO pathophysiology. There may be several new possibilities to treat LUTS/OAB/DO. beta(3)-AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations (alpha(1) AR antagonist + antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have Randomized controlled trial (RCT) documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established. PMID- 21789059 TI - Laparoscopic retroperitoneal lymph node dissection for stage I and II nonseminomatous germ-cell tumors. AB - OBJECTIVES: Open retroperitoneal lymph node dissection has been traditionally used for the management of patients with nonseminomatous germ-cell tumors (NSGCTs). Over the last decade, laparoscopic retroperitoneal lymph node dissection (LRPLND) has gained popularity in several highly specialized centers. METHODS: We retrospectively reviewed the English-language literature with regard to LRPLND. The perioperative and oncologic outcomes for patients with low stage NSGCTs who underwent LRPLND are summarized in this review with particular emphasis on contemporary studies. RESULTS: Initially only used for staging, LRPLND has evolved to a therapeutic procedure capable of replicating the templates used for open RPLND. Perioperative outcomes including operative time, conversion rates and complications improve with surgeon experience and are acceptable at high volume centers. Oncologic outcomes are promising, but require longer term follow-up and the administration of adjuvant chemotherapy in many studies limits comparison to that of the open technique. CONCLUSION: LRPLND has been demonstrated to be feasible and safe at large volume institutions with experienced laparoscopic surgeons. LRPLND was originally performed as a staging procedure in patients with NSGCTs but has evolved into a therapeutic operation with early reports demonstrating short hospital stays and minimal morbidity. Further studies in larger cohorts of patients with longer term follow up are required to define the exact role of LRPLND. PMID- 21789058 TI - How to improve results with extracorporeal shock wave lithotripsy. AB - OBJECTIVE: Shock wave lithotripsy (SWL) has greatly revolutionized the treatment of patients suffering from stone disease. There are a number of patient- and device-specific factors that can affect treatment outcome. Herein, we review practices that can increase the likelihood of SWL treatment success. METHODS: A systematic literature review was performed to identify studies of SWL treatment parameters. RESULTS: Among the factors affecting the outcome of SWL were patient selection criteria, such as stone burden, stone location, and anatomic features. Additionally, technical aspects of the SWL procedure also can affect outcome; these factors include the acoustic output of the lithotripter, the coupling of the lithotripter to the patient, and the power, total number, and rate of shock wave delivery. CONCLUSIONS: The outcome of SWL can be optimized with close attention to patient selection criteria as well as the manner in which the treatment is performed. PMID- 21789060 TI - The role of the gubernaculum in the descent and undescent of the testis. AB - Testicular descent to the scrotum involves complex anatomical rearrangements and hormonal regulation. The gubernaculum remains the key structure, undergoing the 'swelling reaction' in the transabdominal phase, and actively migrating out of the abdominal wall to the scrotum in the inguinoscrotal phase. Insulin-like hormone 3 (Insl3) is the primary regulator of the first phase, possibly augmented by Mullerian inhibiting substance/anitmullerian hormone (MIS/AMH), and regression of the cranial suspensory ligament by testosterone. The inguinoscrotal phase is controlled by androgens acting both directly on the gubernaculum and indirectly via the genitofemoral nerve, and release of calcitonin gene-related peptide from its sensory fibres. Outgrowth of the gubernaculum and elongation to the scrotum has many similarities to an embryonic limb bud.Cryptorchidism occurs because of both failure of migration congenitally, and failure of elongation of the spermatic cord postnatally. Germ cell development postnatally is disturbed in congenital cryptorchidism, but our current understanding of germ cell biology suggests that early orchidopexy, around 6 months of age, should provide a significant improvement in prognosis compared with a previous generation. Hormone treatment is not currently recommended. Acquired cryptorchid testes may need orchidopexy once they no longer reach the scrotum, although this remains controversial. PMID- 21789061 TI - Endoscopic treatment of vesicoureteral reflux: current practice and the need for multifactorial assessment. AB - Vesicoureteral reflux (VUR) affects around 1% of all children. It carries an increased risk of febrile urinary-tract infections (UTIs) and is associated with impaired renal function. Antibiotic prophylaxis is an established approach to managing the condition, but it does not protect against UTI and encourages bacterial resistance. Ureteral re-implantation (open surgery) is a relatively traumatic procedure typically requiring hospitalization, and there is a risk of significant post-treatment complications. Endoscopic treatment with NASHA/Dx gel (Deflux(r)) is minimally invasive, well tolerated and provides cure rates approaching those of open surgery: 80-90% in several studies. It has also been shown to be effective in a variety of 'complicated' cases. Thus, endoscopic treatment is generally preferable to open surgery and long-term antibiotic prophylaxis. Non-treatment of VUR is being discussed as an alternative option, although this mainly appears suitable for children with low-grade reflux and normal kidneys. A new approach to managing VUR may be considered, with treatment decisions based not only on the grade of reflux but also on factors such as age, sex, renal scarring and bladder dysfunction. Open surgery would be reserved only for use in the 10-15% of children not responding to endoscopic treatment and those with severe ureteral anomalies. PMID- 21789062 TI - Update on ureteral stent technology. AB - Ureteral stents are commonly used in urology but are frequently associated with patient discomfort, stent encrustation and stent-related infection. New biomaterials, coatings and designs have been designed to attempt to reduce these problems. This article reviews coatings to reduce bacterial adhesion and encrustation. In addition, metal ureteral stents, the triclosan and ketorolac drug eluting ureteral stents, and biodegradable ureteral stents are discussed. In summary there is no perfect ureteral stent that avoids all morbidity but there have been significant advances in the last few years in stent technology. PMID- 21789063 TI - Targeted focal therapy for prostate cancer: a review of the literature. AB - Improvements in prostate cancer diagnosis and treatment have resulted in a decreasing age-adjusted death rate. But improved diagnostic tools have not delivered a proportionate decrease in mortality, primarily because physicians now are diagnosing - and treating - more clinically insignificant tumors. Targeted focal therapy (TFT) uses three dimensional (3D) mapping biopsies to guide cryotherapy so that it targets lesions themselves while sparing surrounding healthy tissues, thereby avoiding side effects associated with more invasive treatments. As such, TFT can provide a bridge between active surveillance and more aggressive treatments for patients with low-risk tumors. It is appropriate for men who either do not want or are not good candidates for more aggressive therapies. Identifying patients who are appropriate candidates for TFT is challenging, but the mapping biopsy technique helps identify individuals who have localized disease and could benefit from this treatment. In recent years, improvements in cryotherapy have increased its efficacy while decreasing complications. At the present time using cryotherapy to target and destroy the cancer(s) is appealing. Other approaches to less aggressive therapies are discussed including gland hemi ablation, high intensity ultrasound (HIFU) and others. Going forward, patients will benefit further from development of better imaging technologies and completion of long-term survival studies. PMID- 21789064 TI - The robotic surgery era and the role of laparoscopy training. AB - It has been suggested that the robotic surgery platform is an enabling technology that allows surgeons that are not trained in standard laparoscopy to perform minimally-invasive surgery. This raises the question of whether or not training in laparoscopy is necessary for current and future surgeons. The current status of laparoscopy in urology in the United States is reviewed along with a perspective regarding the potential future role of laparoscopic training as robotic surgery becomes increasingly applied to most major urologic procedures. PMID- 21789065 TI - How close are we to establishing standards of lymphadenectomy for invasive bladder cancer? AB - Radical cystectomy and lymphadenectomy is an accepted standard of care for muscle invasive bladder cancer. Although the absolute limits of lymphadenectomy have not been standardized a growing body of evidence supports an improvement in nodal staging and survival from an extended lymphadenectomy. The benefit has been reported for both node negative and node positive patients. This review focuses on lymph node mapping, factors that influence total lymph node count and the optimal number of lymph nodes that should be removed at lymphadenectomy. PMID- 21789067 TI - Management of the residual post-chemotherapy retroperitoneal mass in germ cell tumors. AB - The management of the residual mass in the retroperitoneum following induction chemotherapy for metastatic testicular cancer has evolved over the past three decades. A multidisciplinary approach involving cisplatin-based chemotherapy and postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) has increased long-term survival rates above 80%. Advances into the appropriate patient selection and timing of surgery have lowered morbidity while improving oncologic outcomes. However, areas of controversy still exist within the field. Management of the small residual mass, predictors of the histology of the residual mass, the extent of PC-RPLND, the role of PC-RPLND in the setting of elevated serum tumor markers, and the role of positron-emission tomography are all topics of ongoing research and debate. We will discuss these issues and review the current guidelines for the management of the residual postchemotherapy retroperitoneal mass in this review. PMID- 21789066 TI - Testosterone and phosphodiesterase type-5 inhibitors: new strategy for preventing endothelial damage in internal and sexual medicine? AB - Normal vascular endothelium is essential for the synthesis and release of substances affecting vascular tone (e.g. nitric oxide; NO), cell adhesion (e.g. endothelins, interleukins), and the homeostasis of clotting and fibrinolysis (e.g. plasminogen inhibitors, von Willebrand factor). The degeneration of endothelial integrity promotes adverse events (AEs) leading to increased atherogenesis and to the development of vascular systemic and penile end-organ disease. Testosterone (T) is an important player in the regulation of vascular tone through non-genomic actions exerted via blockade of extracellular-calcium entry or activation of potassium channels; also, adequate T concentrations are paramount for the regulation of phosphodiesterase type-5 (PDE5) expression and finally, for the actions exerted by hydrogen sulphide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue. It is known that an age-related decline of serum T is reported in approximately 20 to 30% of men whereas T deficiency is reported in up to 50% of men with metabolic syndrome or diabetes. A number of laboratory and human studies have shown the combination of T and other treatments for erectile dysfunction (ED), such as PDE5 inhibitors, to be more beneficial in patients with ED and hypogonadism, who fail monotherapy for sexual disturbances.The aim of this review is to show evidence on the role of T and PDE5 inhibitors, alone or in combination, as potential boosters of endothelial function in internal medicine diseases associated with reduced T or NO bioavailability, i.e. metabolic syndrome, obesity, diabetes, coronary artery disease, hyperhomocysteinemia, that share common risk factors with ED. Furthermore, the possibility of such a strategy to prevent endothelial dysfunction in men at increased cardiovascular risk is discussed. PMID- 21789069 TI - Minimally-invasive correction of ureteropelvic junction obstruction: do retrograde endo-incision techniques still have a role in the era of laparoscopic pyeloplasty? AB - BACKGROUND: This study was designed to review the long-term results and complications of the two techniques of retrograde endopyelotomy; ureteroscopic holmium laser endopyelotomy versus Acucise endopyelotomy. The results were then compared with the laparoscopic pyeloplasty results from a recent publication. PATIENTS AND METHODS: : The study was conducted retrospectively from January 2004 to July 2007. Seventy-two patients with ureteropelvic junction obstruction (UPJO) underwent retrograde endopyelotomy using either ureteroscopic laser endoincision (42 patients) or fluoroscopic guided hot-wire balloon (Acucise) endoincision (30 patients). Preoperative radiological assessment included intravenous pyelogram (IVP), helical computerized tomography and diuretic renography. The follow-up period ranged from 12 to 42 months. Subjective success was guided by the change in the preoperative flank pain while objective success on radiological evaluation was documented by either nonobstructed curve of diuretic renogram and/or T1/2 less than 10 min. RESULTS: The mean patient age was 42.6 +/- 7.5 years for the laser group and 39.2 +/- 15.1 years for the Acucise group (p = 0.24). The operative time was 66.8 +/- 22.2 min in the laser group and 59.8 +/- 20.3 min in the Acucise group (p = 0.84). By objective standards (renal scan), a total of 56 (77.8%) cases were successful (nonobstructed curve). This number included 34 cases in the laser group (80.9%) and 22 cases in the Acucise group (73.3%) (p = 0.2). Overall 16 failure cases were evident clinically within 1 year of the procedure (eight cases in each group). Most of the failure cases (13/16) presented with clinical obstructive symptoms during the early follow-up period (within 3 months postoperatively) and were then confirmed radiologically (six cases in the laser group and seven cases in the Acucise group) while only three patients had failures at 6, 9 and 11 months postoperatively. There was no statistically significant difference as regards intra-operative complications between the two groups (p = 0.4). Intra-operative bleeding was seen in three cases in the Acucise group while postoperatively it was reported in one case. CONCLUSION: The retrograde endopyelotomy approach is safe and effective for the treatment of patients with UPJO. Both ureteroscopic laser and the hot-wire balloon (Acucise) techniques have an important role in the management of UPJO, especially in secondary cases, and they provide comparable long-term objective and subjective outcomes. Laparoscopic pyeloplasty provides far better results but with higher costs, and requires well-equipped centers and involves a long learning curve. PMID- 21789068 TI - Overactive bladder in males. AB - The prevalence of overactive bladder (OAB) symptoms is considerable in both men and women and the impact on quality of life (QOL) is equally substantial. Ironically, despite nearly equal prevalence, OAB symptoms in men are infrequently treated, and often with medical therapies aimed at bladder outlet obstruction (BOO). In this review, we examine the pathophysiology of OAB and its evaluation in the context of benign prostatic hypertrophy and concomitant BOO. We then consider the efficacy and safety of individual therapeutic options for lower urinary tract symptoms in men, focusing on the mainstays of medical therapy: alpha-adrenergic blockers, 5-alpha reductase inhibitors, and antimuscarinic agents. Finally, we aim to comment on new therapeutic strategies and targets that may one day be available for the treatment of male OAB. PMID- 21789070 TI - Non-invasive management of primary phosphodiesterase type 5 inhibitor failure in patients with erectile dysfunction. AB - Phosphodiesterase type 5 inhibitors (PDE5-i) have become first line therapy for the treatment of erectile dysfunction. Most initial prescriptions for PDE5-i are by primary care practitioners. Urologists must now routinely manage the patient who has failed initial therapy with PDE5-i. Lifestyle modifications can be of benefit to patients. Patient education and optimization of the PDE5-i can result in a successful response. Interestingly, there are reports of up to 60% salvage after changing the PDE5-i utilized. Daily PDE5-i have shown benefit, and treatment of hypogonadism can enhance response to PDE5-i. We review the management of PDE5-i failures with emphasis on noninvasive approaches to gaining improved erectile response to these medications. An algorithm based on the reviewed strategies is proposed to guide clinicians in the treatment of erectile dysfunction. PMID- 21789071 TI - Embryology and anatomy of the vesicoureteric junction with special reference to the etiology of vesicoureteral reflux. AB - Concerning the ureterovesical junction - the region most important for the anti reflux mechanism - there is still a lot of misunderstanding and misinterpretation with regard to normal fetal development. Data are scarce on possible causes of primary vesicoureteral reflux and on involved mechanisms of the so-called maturation process of refluxing ureteral endings. The ratio of the intravesical ureteral length to the ureteral diameter is obviously lower than assumed so far, as clearly revealed by some studies. Therefore it can be doubted that the length and course of the intravesical ureter is of sole importance in the prevention of reflux. Additionally refluxing intravesical ureteral endings present with dysplasia, atrophy, and architectural derangement of smooth muscle fibers. Besides, a pathologically increased matrix remodeling combined with deprivation of the intramural nerve supply has been confirmed. Consequently, symmetrical narrowing of the very distal ureteral smooth muscle coat creating the active valve mechanism to defend reflux is not achievable. It is apparent that primary congenital vesicoureteral reflux seems to be the result of an abnormality within the ureterovesical junction with an insufficient muscular wrap. Nature is believed to establish much more sophisticated mechanisms than the so-called passive anti-reflux mechanism. Remodeling processes within the ureterovesical junction of refluxing ureteral endings support that maturation itself is nothing else than wound or defect healing and not a restitution of a morphological normal ureterovesical junction. Lacking the nerve supply a restoration of any muscular structure can not be achieved. PMID- 21789072 TI - Technical advances in robot-assisted laparoscopic radical prostatectomy. AB - Since it was introduced in 1999, the da Vinci Surgical System has become an integral tool in urologic surgery, specifically in the management of localized prostate cancer. The original technique of robot-assisted laparoscopic prostatectomy (RALP) was developed and standardized in 2000 at the Institut Mutualiste Monsouris. Since that time, the technique of RALP has undergone various modifications. The driving force behind the evolution of the RALP technique in the past decade has been based on efforts to improve upon the three main objectives of surgery, namely the 'trifecta' of cancer cure and the preservation of potency and of urinary continence. In this review, we aim to provide an update on the midterm oncologic outcomes of RALP and focus specifically on two technical modifications that have been introduced in an effort to optimize the outcomes of potency and earlier return of urinary continence. PMID- 21789074 TI - Urodynamic studies in the evaluation of the older man with lower urinary tract symptoms: when, which ones, and what to do with the results. AB - Lower urinary tract dysfunction is a major cause of morbidity and decreased quality of life in older men. Most urinary dysfunctions in the elderly are multifactorial in origin and associated with a broad spectrum of mental and physical conditions. In this population, it is essential to have a comprehensive assessment of the lower urinary tract, functional impairments and concurrent medical diseases. A holistic and individualized approach to management is important. Urodynamic studies (UDS) are objective tests which provide a major contribution to our understanding of the pathophysiology of lower urinary tract symptoms (LUTS). Urodynamic findings in older men may include common diagnoses such as bladder outlet obstruction and urinary incontinence. However, coexisting conditions such as detrusor overactivity and impaired detrusor contractility are common in older men. The identification of these conditions is necessary to appropriately counsel patients regarding treatment options. Simple urodynamic tests should be used whenever possible such as uroflowmetry and residual volume estimation. However, in complicated cases more invasive tests such as pressure flow studies are important to help choose the best treatment. PMID- 21789073 TI - Laparoendoscopic single-site surgery in urology. AB - BACKGROUND: Since its introduction, the role of laparoscopic surgery has grown and it has now become the standard approach for many surgical procedures. The benefits of smaller incisions, improved pain and convalescence, and shorter hospital stays have greatly improved patient care and satisfaction. In an effort to further minimize the morbidity of surgery, laparoendoscopic single-site (LESS) or single-incision laparoscopic surgery (SILS) has emerged. We review the collective experience with this novel technique and share our initial observations and early results. METHODS: We performed a literature search to review the published experience with this new technique including the breadth of applications and perioperative outcomes associated with LESS in urology. We also analysed the experience with this emerging technique at our institution. RESULTS: There are numerous variations with regards to nomenclature as well as types of access to the abdominal cavity as it pertains to LESS. Urologic procedures involving single-port access have acceptable operating room time, blood loss, and postoperative pain, which are in line with standard laparoscopic surgical outcomes with the added benefit of improved cosmesis and smaller incisions. CONCLUSIONS: Further studies and larger cohorts are needed to assess the real benefit of LESS procedures. The additional learning curve needed to master these techniques may be a barrier to wider acceptance, although improvements in instrumentation are likely to bridge this gap. PMID- 21789075 TI - Robotic-assisted laparoscopic mesh sacrocolpopexy. AB - The current 'gold standard' surgical repair for apical prolapse is the abdominal mesh sacrocolpopexy. Use of a robotic-assisted laparoscopic surgical approach has been demonstrated to be feasible as a minimally invasive approach and is gaining popularity amongst pelvic floor reconstructive surgeons. Although outcome data for robotic-assisted sacrocolpopexy (RASC) is only just emerging, several small series have demonstrated anatomic and functional outcomes, as well as complication rates, comparable to those reported for open surgery. The primary advantages thus far for RASC over open surgery include decreased blood loss and shorter hospital stay. PMID- 21789076 TI - Chronic orchialgia: evaluation and discussion of treatment options. AB - Virtually all practicing urologists will encounter patients with a complaint of chronic testicular pain. This can be a frustrating process for both patient and physician, as there is no clearly established effective treatment regimen, nor is there a recognized and accepted standard protocol for evaluation. Many of these patients will see multiple physicians during the course of their evaluation, further increasing their frustration and potentially straining the physician/patient relationship. The etiology of testicular pain is varied and is frequently idiopathic. Easily recognized and reversible causes include spermatocele, tumor, infection, varicocele, and torsion. Chronic orchialgia has been defined as at least 3 months of chronic or intermittent pain. Although the diagnosis of chronic orchialgia is frequently given to these patients, it should be recognized that fairly frequently the patient will not have just testicular pain, but may have pain involving the epididymis, vas deferens, or adjacent paratesticular structures. Therefore a more appropriate term would be chronic scrotal content pain. This article reviews the current understanding of chronic scrotal content pain, reviewing the etiology, evaluation, and then a systematic review of the published literature on treatment. It should be recognized that the majority of the published literature are cohort studies with limited numbers of patients, rarely placebo-controlled, and without a uniform standard evaluation. Microdenervation of the spermatic cord is emerging as a reasonable and effective outpatient surgical technique to resolve chronic scrotal content pain, and successful results appear to be predicted by a temporary but complete response to a spermatic cord block. PMID- 21789077 TI - A novel operative technique for concealed penis secondary to penoscrotal web: a case report. AB - Contemporary surgical techniques for concealed penis defined in the literature are sophisticated and, because of this, we decided to perform a simple technique. A child with penoscrotal web was admitted to our Pediatric Surgery Clinic. The patient had recurrent urinary tract infections without urinary tract disease and, therefore, web reconstruction was thought to be useful. A modified unfurling technique and penoscrotal angle reconstruction was used. The main characteristic of our procedure can basically be described as an oblique incision of the outer foreskin leaf which guides the next steps. We report the operative and clinical course of the patient. We demonstrated that the penoscrotal web was treated simply and effectively as an outpatient procedure. In addition, in the follow-up period, we found that the patient had acceptable and cosmetic penile skin. PMID- 21789078 TI - Medical evaluation and management of urolithiasis. AB - Nephrolithiasis is a highly prevalent condition with a high recurrence rate that has a large impact on the quality of life of those affected. It also poses a great financial burden on society. There have been great advancements in the surgical treatment of stone disease over the past several decades. The evolution of surgical technique appears to have overshadowed the importance of prevention of stone disease despite evidence showing medical therapies significantly decreasing stone recurrence rates. Herein we review the metabolic evaluation of stone formers with the use of specific blood and urine tests. We complete our discussion with a review of the medical management of stone formers providing both general recommendations as well as reviewing focused therapies for specific metabolic abnormalities and medical conditions. PMID- 21789079 TI - Advances in renal cell carcinoma treatment. AB - The treatment of advanced renal cell carcinoma has been completely changed by the development of new therapeutic modalities during the past 3 years. In this time period six targeted agents have been approved for the treatment of advanced or metastatic disease. Phase 3 data support the use of sunitinib, bevacizumab plus interferon-alpha and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma. In the pivotal study of temsirolimus a significant longer overall survival compared with interferon-alpha in high-risk disease including non-clear-cell histology was observed. Patients pretreated with cytokines will benefit from sorafenib and pazopanib while everolimus has been shown to increase significantly progression-free survival after previous anti angiogenesis therapy. In addition to these phase 3 data-based recommendations, several other factors have to be considered for treatment selection, for example, side effect profile and patients' comorbidities. Currently, the sequential use of the available targeted drugs and adjuvant treatment are the subject of ongoing clinical trials. However, medical treatment of renal cell carcinoma remains palliative and surgery remains the only curative approach in patients with localized, locally advanced and limited metastatic disease. PMID- 21789081 TI - Penile prostheses. AB - Penile prosthesis implantation is recognized as a valid option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which a pharmacological approach is contraindicated or ineffective. Penile prostheses are subbject to continuous development and they are achieving ever better mechanical reliability and safety. The devices are divided into two general types: semirigid (malleable and mechanical) and inflatables. The AMS(r) (American Medical Systems) and Coloplast Ltd(r) produce the majority of inflatable and semirigid devices.Malleable and mechanical prostheses have the disadvantage that the penis is always erect although it can be orientated in different ways, while the advantages are ease of use and the need for a simpler surgical procedure compared with inflatable prostheses. Three-component prostheses are more sophisticated than semirigid devices. The advantages of these devices are that the prosthesis feels softer than semirigid or two-piece devices when deflated, with a better cosmetic result, and it ensures a more natural erection than others kinds of prosthesis. The disadvantages are the possibility of malfunction and the need for a more complicated surgical technique. Implantation of a penile prosthesis can be performed in a short surgical time under locoregional anaesthesia, and for this reason hospitalization is usually brief and the patient can be discharged 2 days after the operation if complications are not evident. Patient and partner satisfaction reflect the quality and the effectiveness of this treatment. Even though the results are positive in the vast majority of patients, the possibility of several complications makes penile prosthesis implantation a delicate kind of surgery. Complications can happen when the operation is carried out, in the peri-operative and in the postoperative period, and include infections, erosions of the prosthesis and mechanical failure in case of inflatable prosthesis. Penile prostheses available on the market have improved the success of this kind of surgery, thanks to the introduction of new materials and designs. PMID- 21789080 TI - Sperm banking and the cancer patient. AB - The current concepts, recommendations, and principles of sperm banking as it pertains to the comprehensive care of young men of reproductive age with cancer are reviewed. Obstacles to sperm banking are addressed as well as future directions for fertility-preserving technologies. All cancer therapies chemotherapy, radiation, and surgery-are potential threats to a man's reproductive potential. In addition, cancer itself can impair spermatogenesis. Thus, sperm cryopreservation prior to initiating life-saving cancer treatment offers men and their families the best chance to father biologically related children and should be offered to all men with cancer before treatment. Better patient and provider education, as well as deliberate, coordinated strategies at comprehensive cancer care centers are necessary to make fertility preservation for male cancer patients a priority during pretreatment planning. PMID- 21789083 TI - Ablative therapies for renal tumors. AB - Owing to an increased use of diagnostic imaging for evaluating patients with other abdominal conditions, incidentally discovered kidney masses now account for a majority of renal tumors. Renal ablative therapy is assuming a more important role in patients with borderline renal impairment. Renal ablation uses heat or cold to bring about cell death. Radiofrequency ablation and cryoablation are two such procedures, and 5-year results are now emerging from both modalities. Renal biopsy at the time of ablation is extremely important in order to establish tissue diagnosis. Real-time temperature monitoring at the time of radiofrequency ablation is very useful to ensure adequacy of ablation. PMID- 21789084 TI - Current approach to the treatment of penile implant infections. AB - Modern penile implants, introduced to the market almost four decades ago, have provided a predictable and reliable treatment of erectile dysfunction (ED) despite the development of less-invasive therapies. Infection associated with the placement of these devices does occur, and with prophylactic measures and protocols the incidence has decreased fortunately. In the presence of an infection the implant and all foreign material should be removed. A salvage procedure, during which the wound is thoroughly washed with antiseptic solutions after device removal and placement of a new implant during the same procedure, has a high success rate and is becoming a popular approach. The alternative, device removal with return at a later date for placing a new implant, entails a more difficult corporal dilation, and the resulting erection is noticeably shorter. Patient and partner satisfaction with a penile implant is the highest among all of the treatments for ED. PMID- 21789085 TI - The value of prostate-specific antigen in Asia. AB - One of the most important diagnostic tools used to detect prostate cancer is prostate-specific antigen (PSA), yet increased PSA alone does not reflect the presence of prostate cancer. Other pathological prostatic conditions such as prostatitis and benign prostatic hyperplasia (BPH) may also increase the level of PSA. However, unlike in other prostate diseases, PSA has a key role in the diagnosis and management of prostate cancer. The incidence of prostate cancer varies from country to country, with the highest incidence being found in the Western world and the lowest in Asian countries. Owing to the low incidence of prostate cancer, there could be different views regarding the use of PSA in Asian countries, especially for the early detection/screening of prostate cancer. The purpose of this article is to review the use and value of PSA in the diagnosis of prostate diseases (especially prostate cancer) in Asian countries/populations. A literature search was performed in 'MEDLINE' (PubMed) and Google Scholar using main keywords such as 'PSA', 'PSA usage', 'PSA sensitivity and specificity', 'Asia', and various countries in Asia. Articles that provide population/community based PSA data, together with the characteristics, distribution, and indications for PSA testing in the respective countries, were selected. Eleven papers were finally selected for inclusion in this review. Five studies found that PSA, by its 95th percentile value, have an age-referenced tendency in Asian males, similarly to the West. The predictive values of PSA in detecting prostate cancer are also quite similar to those in Western countries. With the exponential growth of the aging population in the world, especially in Asia, the incidence of prostate cancer will follow this upward trend. Therefore, PSA testing for screening or diagnostic purposes would increase with time in Asia. PMID- 21789086 TI - Ureteral stents: new ideas, new designs. AB - Ureteral stents represent a minimally invasive alternative to preserve urinary drainage whenever ureteral patency is deteriorated or is under a significant risk to be occluded due to extrinsic or intrinsic etiologies. The ideal stent that would combine perfect long-term efficacy with no stent-related morbidity is still lacking and stent usage is associated with several adverse effects that limit its value as a tool for long-term urinary drainage. Several new ideas on stent design, composition material and stent coating currently under evaluation, foreseen to eliminate the aforementioned drawbacks of ureteral stent usage. In this article we review the currently applied novel ideas and new designs of ureteral stents. Moreover, we evaluate potential future prospects of ureteral stent development adopted mostly by the pioneering cardiovascular stent industry, focusing, however, on the differences between ureteral and endothelial tissue. PMID- 21789087 TI - Hypogonadism, ADAM, and hormone replacement. AB - Male hypogonadism, or testosterone deficiency syndrome (TDS), results from a failure of the testes to produce adequate androgen. Patients have low circulating testosterone in combination with clinical symptoms such as fatigue, erectile dysfunction, and body composition changes. The cause may be primary (genetic anomaly, Klinefelter's syndrome) or secondary (defect in hypothalamus or pituitary), but often presents with the same symptomatology. In the older patient, androgen deficiency of the aging male (ADAM) is an important cause of secondary hypogonadism because testosterone levels decline progressively after age 40. Hypogonadal patients have alterations not only in sexual function and body composition, but also in cognition and metabolism. Regardless of etiology, hypogonadal patients who are both symptomatic and who have clinically significant alterations in laboratory values are candidates for treatment. The goal of hormone replacement therapy in these men is to restore hormone levels to the normal range and to alleviate symptoms suggestive of hormone deficiency. This can be accomplished in a variety of ways, although most commonly testosterone replacement therapy (TRT) is employed. PMID- 21789090 TI - Computer-assisted robotic renal surgery. AB - Computer-assisted robotic renal surgery (CARRS) is a minimally invasive surgical treatment option for renal tumors. We review the literature regarding techniques and outcomes and the potential advantages of CARRS. We retrospectively reviewed the literature regarding techniques and outcomes of CARRS, with specific analysis on robotic radical nephrectomy (RRN) and robotic partial nephrectomy (RPN). Multiple papers on RRN and RPN were found where the techniques were performed with either a transperitoneal or a retroperitoneal approach. Preliminary outcomes with RRN and RPN were at least comparable to those of a laparoscopic approach, with some parameters of RPN improved over the laparoscopic approach (warm ischemia time, length of hospital stay and estimated blood loss). CARRS is an emerging field with preliminary outcomes at least comparable to the laparoscopic approach. Large prospective, randomized trials are needed to assess the benefit of CARRS compared with current methods. PMID- 21789089 TI - Secondary malignancies following radiotherapy for prostate cancer. AB - Human exposure to sources of radiation as well as the use of radiation-derived therapeutic and diagnostic modalities for medical reasons has been ongoing for the last 60 years or so. The carcinogenetic effect of radiation either due to accidental exposure or use of radiation for the treatment of cancer has been undoubtedly proven during the last decades. The role of radiation therapy in the treatment of patients with prostate cancer is constantly increasing as less invasive treatment modalities are sought for the management of this widely, prevalent disease. Moreover the wide adoption of screening for prostate cancer has led to a decrease in the average age that patients are diagnosed with prostate cancer. Screening has also resulted in the diagnosis of low-grade, less aggressive prostate cancers which would probably never lead to complications or death from the disease. Radiotherapy for prostate cancer has been linked to the late occurrence of second malignancies both in the true pelvis and outside the targeted area due to low-dose radiation scatter. Secondary malignancies following prostate irradiation include predominantly bladder cancer and, to a lesser extent, colon cancer. Those secondary radiation-induced bladder tumors are usually aggressive and sometimes lethal. Care should be given to the long-term follow up of patients under radiation therapy for prostate cancer, while the indications for its use in certain cases should be reconsidered. PMID- 21789088 TI - Androgen receptor molecular biology and potential targets in prostate cancer. AB - The androgen receptor (AR) is a key transcriptional regulator and therapeutic target in prostate cancer. During androgen deprivation therapy to treat metastatic prostate cancer, surviving cells acquire increased AR signaling through a variety of mechanisms, one of which is enhanced interactions with AR coactivators. One recently identified AR-specific coregulator expressed only in human and nonhuman primates is the melanoma antigen gene protein-A11 (MAGE-11). MAGE-11 increases AR transcriptional activity through direct interactions with AR and other coactivators, and its levels increase during prostate cancer progression to castration-recurrent growth. The MAGE-11 gene is located at Xq28 on the human X chromosome as part of an X-linked MAGE gene family of cancer testis antigens. MAGE-11 stabilizes AR when androgen levels are low, and functions in a transcriptional hub to promote AR-mediated gene activation. The evolutionary development and organization of the MAGE-11 gene within the cancer testis antigen family suggests that MAGE-11 provides a gain-of-function to AR among primates in both normal physiology and cancer, and may serve as a therapeutic target in the treatment of advanced prostate cancer. PMID- 21789091 TI - The overactive bladder. AB - Urinary urgency and the associated symptoms which comprise overactive bladder are prevalent amongst the general population and adversely affect quality of life. Disease management consists of a sequential series of options starting with behavioural and lifestyle techniques, pharmacological management (antimuscarinics) and, in severe cases, surgical treatment (urinary diversion, neuromodulation, augmentation cystoplasty and detrusor myectomy). There is increasing recognition of pathophysiological mechanisms in the urothelium, interstitial cells and afferent neurons allowing the importance of peripheral integrative interaction to be identified. The hierarchy of the central nervous system control adds additional complexity to understanding the oflower urinary tract function. Some newer methods of treatment include Botulinum toxin A intramural injections, oral beta-3 adrenergic agonists and rho-kinase inhibitors. The lack of a disease generating hypothesis, the lack of animal models for disease and the subjective nature of the central symptom (urgency) still pose considerable theoretical and scientific hurdles that need to be overcome in the treatment of this condition. PMID- 21789092 TI - The use of fluorescent in situ hybridization in male infertility. AB - Male factors are implicated in up to 50% of couples being evaluated and treated for infertility with advanced assisted reproductive technologies. Genetic abnormalities, including sperm chromosome aneuploidy as well as structural aberrations, are one of the major causes of infertility. The use of chromosome specific DNA probes labeled with fluorochromes, particularly the combination with multiple probes, has been used to indirectly study the sperm chromosome by fluorescent in situ hybridization (FISH). Clinically, this technique is also used to assess the sperm of men recovering from gonadotoxic treatment. Recent advances in this technology facilitate the evaluation of sperm aneuploidy. Sperm FISH is a widely used screening tool to aid in counseling couples with severe male factor infertility, especially in cases of prior repeated in vitro fertilization/intracytoplasmic sperm injection failure or recurrent pregnancy loss. Automation of FISH imaging and analysis, as well as the development of emerging techniques such as comparative genomic hybridization, will all contribute to the promise of future diagnostic approaches aimed at improving the quality, ease, and efficiency of aneuploidy analysis. PMID- 21789093 TI - Hormone therapy in the management of prostate cancer: evidence-based approaches. AB - Hormonal therapy has been the standard for advanced prostate cancer for over 60 years. Recently, the utility of androgen ablation through various means has been demonstrated for earlier stages of disease. In particular, the strongest evidence to date involves the use of hormonal therapy in combination with radiation therapy. In this article we review the basic concepts in hormonal ablation for prostate cancer and review the evidence-based studies that support the use of hormonal therapy in early stage prostate cancer. PMID- 21789095 TI - The role of laparoscopic surgery for renal calculi management. AB - To date, most cases of renal calculi have been managed with extracorporeal shockwave lithotripsy and endoscopic procedures. However, for complex renal stone conditions, these minimally invasive procedures may require multiple operative sessions. Open surgery is usually reserved as a salvage procedure, although it is invasive in nature. Laparoscopic treatment is well accepted in renal surgery. For stone disease, it can duplicate open surgical techniques such as pyelolithotomy, pyeloplasty, anatrophic nephrolithotomy, caliceal diverticulectomy and nephrectomy. Although the laparoscopic techniques for stone treatment are quite challenging, it is both feasible and safe. Laparoscopic treatment is a viable option for large renal stone treatment with an excellent stone-free rate, especially when patients require their stones to be treated within a single session. However, it is more invasive in nature than endourology procedures and so should be reserved as the last resort option for renal stone management in the modern endourology era. PMID- 21789094 TI - The increasing pediatric stone disease problem. AB - While once thought to be relatively rare in developed nations, the prevalence of pediatric urolithiasis appears to be increasing, and a number of factors may be contributing to this increase. Many theories are plausible and such theories include the increasing childhood obesity epidemic, a changing sex predilection, climate change, alterations in dietary habits and improving diagnostic modalities. Yet, unlike adult patients, rigorous epidemiologic studies do not exist in pediatric populations. Thus, in the setting of an increasing prevalence of childhood stone disease, improved research is critical to the development of uniform strategies for pediatric urolithiasis management. PMID- 21789098 TI - The stress of chest pain: a case of tako-tsubo cardiomyopathy. AB - Tako-tsubo cardiomyopathy is an important syndrome whose presentation mimics that of an acute coronary syndrome/myocardial infarction. It is a transient phenomenon characterised by chest pain, electrocardiographic changes, elevation of cardiac enzymes, apical/mid left ventricular ballooning and regional wall motion changes in the absence of significant angiographic coronary artery disease.The present report concerns a case of tako-tsubo cardiomyopathy in a 62-year-old woman admitted following stressful events. The postulated pathogenesis, investigations and treatment of a syndrome whose clinical spectrum of severity ranges from that of stability to cardiogenic shock is discussed.Since its initial description in the 1990s the syndrome has been increasingly diagnosed. Emotional and physical stress is thought to be an important predisposing factor. This syndrome demonstrates the importance of not underestimating the potential organic manifestations of stress as well as the necessity to ensure accurate collection of medical history when assessing patients. PMID- 21789096 TI - Role of inflammation in bladder function and interstitial cystitis. AB - Cystitis, or inflammation of the bladder, has a direct effect on bladder function. Interstitial cystitis is a syndrome characterized by urinary bladder pain and irritative symptoms of more than 6 months duration. It commonly occurs in young to middle-aged women with no known cause and in fact represents a diagnosis of exclusion. Many factors have been suggested, including chronic or subclinical infection, autoimmunity and genetic susceptibility, which could be responsible for initiating the inflammatory response. However, a central role of inflammation has been confirmed in the pathogenesis of interstitial cystitis. Patients with interstitial cystitis are usually managed with multimodal therapy to break the vicious cycle of chronic inflammation at every step. Patients who develop irreversible pathologies such as fibrosis are managed surgically, which is usually reserved for refractory cases. PMID- 21789097 TI - Erectile preservation following radical prostatectomy. AB - Prostate cancer is the most common cancer among men, representing approximately 25% of all new cancer diagnoses in the USA. For clinically localized prostate cancer, the gold standard for therapy remains radical prostatectomy. One of the main adverse effects of this procedure is erectile dysfunction, which can have a significant impact on the patient's quality of life. There are several mechanisms of erectile dysfunction postprostatectomy, including arteriogenic, venogenic and neurogenic types, as well as the potentially heightened risk of postprostatectomy patients to develop Peyronie's disease. The purpose of this review is to explain the various treatment options available, including phosphodiesterase type 5 inhibitors, intracavernosal injections, intraurethral alprostadil suppositories, vacuum erection devices, and penile prostheses. The role of these therapies in an erectile-dysfunction-treatment function, as well as in penile rehabilitation, will be discussed. Finally, a review of research on novel therapies will also be presented. A comprehensive literature review was performed using the PubMed database. Articles were chosen based on topical relevance and assessed for methodology and major findings. There are data to support the use of each of the therapeutic options in both treatment and rehabilitative roles. More study is needed, however, specifically in regard to penile rehabilitation, to confirm its benefits, as well as to determine optimal rehabilitation protocols. PMID- 21789099 TI - A penetrating injury with a cocktail stick resulting in a spreading infection with Streptococcus milleri. AB - This case deals with a penetrating injury with a cocktail stick sustained to the right foot in a 72-year-old woman. Despite being discharged from the Accident and Emergency Department on empirical oral antibiotic therapy, she went on to develop a severe cellulitis, necessitating admission for intravenous antibiotics, multiple debridement procedures under general anaesthesia and eventual split thickness skin grafting to repair areas of necrosis. This case raises a number of important issues, including the potential hazards of apparently so trivial an injury with a common household item, the absence of any benefit of plain radiography in these injuries and the need for exploration and debridement early in the management, in the face of a refractory response to empirical antibiotics. PMID- 21789100 TI - Sudden onset proptosis secondary to cavernous sinus thrombosis from underlying mandibular dental infection. AB - The present report concerns a patient who presented with a 4-day history of left sided facial pain arising from a pre-existing dental infection and progressive shortness of breath. The patient had a previous diagnosis of rheumatoid arthritis and was being treated with methotrexate. The rapid development of a right eye proptosis necessitated urgent decompression with a lateral canthotomy and cantholysis. Imaging revealed a left facial abscess, cavernous sinus thrombosis (CST), bilateral internal jugular thrombosis and multiple lung abscesses. Blood cultures yielded Streptococcus constellatus, a member of the Peptostreptococcus family. The patient was admitted to the intensive care unit (ICU) with respiratory failure and septic shock. She was treated with intravenous meropenem and clindamycin, and anticoagulated. Despite early intervention, the patient developed a middle cerebral artery infarct. Over a 3-week period she was gradually weaned from vasopressor and ventilatory support. PMID- 21789101 TI - Chronotherapy: a smart approach for refractory hypertension. AB - Patients with resistant hypertension are at greater risk for cardiovascular complications. Spreading out medication for the treatment of hypertension is a well known and widely used practice. Chronotherapy, the optimisation of schedules for administering drugs, constitutes a new option in optimising blood pressure control and reducing risk. PMID- 21789102 TI - Atypical early onset of diabetes, deafness and lung cancer in a male patient with mitochondrial mutations in peripheral mononuclear cells. AB - As mitochondria play a major role in the conversion of dietary calories into usable energy, generating reactive oxygen species as a toxic byproduct, mitochondrial dysfunction plays a role in a wide range of age-related disorders and various forms of cancer. The present report concerns a heavy smoker who died of lung cancer at age 40. He also developed progressive diabetes and sensory hearing loss. Mitochondrial DNA sequence analysis revealed four mutations in peripheral mononuclear cells. Three were novel point mutations, including a mutation in ATP synthase F0 subunit 6 (ATP6). Mitochondrial mutations and smoking may have contributed to the development of atypical early onset of senescence related diseases in this case. PMID- 21789103 TI - Turning a blind eye: ocular mucous membrane pemphigoid. PMID- 21789104 TI - Unusually late presentation of lactobezoar leading to necrotising enterocolitis in an extremely low birthweight infant. AB - The present report concerns a case of unusually late presentation of lactobezoar, or inspissated milk curd obstruction, leading to necrotising enterocolitis (NEC) in an extremely low birthweight (ELBW) boy infant, born at 26 weeks gestation with a birth weight of 750 g. He deteriorated acutely on day 84 of postnatal age (corrected age 38 weeks) needing intermittent positive pressure ventilation (IPPV). Over the next 3 days he developed signs of NEC, though a radiograph showed no diagnostic features. In view of increasing abdominal distension, silent abdomen and increasing ventilatory requirements, an emergency exploratory laparotomy was performed. The laparotomy revealed inspissated milk curd obstruction in the terminal ileum. There was also a small area of NEC at the ileocaecal valve. A limited hemicolectomy was performed with creation of an ileostomy and mucous fistula. Following this procedure his clinical status improved. Feeds were reintroduced after 7 days and he was on full enteral feeds by 14 days. PMID- 21789105 TI - Wedding ring in the wrong place: an unusual presentation of penile incarceration in a child with a wedding ring. AB - An unusual case of penile incarceration in a 13-year-old boy is presented, with lessons to be learned for Accident and Emergency Department junior doctors in particular and for all in general. The presentation was misleading and the condition would have gone undiagnosed with fatal consequences without a team effort. The object used was a wedding ring in this case. Penile incarceration is not common in routine practice. The need for development of necessary paediatric history taking and examination techniques among Emergency Department doctors and staff is highlighted. Recalling the basics, this case report emphasises the importance of thorough physical examination. With early diagnosis and treatment, lifelong disabilities can be prevented. PMID- 21789106 TI - Rapid resolution of phlegmonous gastritis using antibiotics alone. PMID- 21789108 TI - Editorial. PMID- 21789107 TI - F-fluorodeoxyglucose positron emission tomography for relapsing polychondritis as a diagnostic approach and evaluation of disease activity. PMID- 21789109 TI - The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer. AB - Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease. PMID- 21789110 TI - Systemic therapy for advanced renal cell carcinoma. AB - Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease. PMID- 21789111 TI - Therapeutic opportunities in noncutaneous melanoma. AB - Recent evidence suggests that the biology of noncutaneous melanoma differs significantly from cutaneous melanoma and may provide therapeutic opportunity. The most frequent sites of origin of noncutaneous melanoma are the eye and mucosal surfaces. Although noncutaneous melanomas are an uncommon group of cancers (representing less than 10% of all melanomas) a greater understanding of their genetic and molecular abnormalites is being translated into novel treatment strategies. These developments are important because there is currently no effective systemic therapy for noncutaneous melanoma. Significant attention has been focused on the role of c-kit (KIT, CD117), a transmembrane receptor with tyrosine kinase activity. In vitro and ex vivo evidence suggests that c-kit is frequently expressed/over expressed/mutated in noncutaneous melanoma. Anti-tumour effects with c-kit inhibitors are seen in pre-clinical models. A variety of multitargeted kinase inhibitors which have activity against c-kit are currently in early phase clinical trials in metastatic ocular, mucosal and acral melanoma. The few case reports of significant clinical activity with targeted therapies provides hope that greater understanding of the biology of noncutaneous melanoma can be translated into effective treatment. PMID- 21789112 TI - Novel agents for advanced bladder cancer. AB - Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced transitional cell carcinoma. Salvage therapy is an unmet need with disappointing outcomes. The emergence of novel biologic agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed. PMID- 21789113 TI - Medical treatment of advanced colorectal cancer in 2009. AB - The treatment options currently available in the medical therapy of advanced colorectal cancer (CRC) appear to be an abundance of riches. The integration of oxaliplatin and irinotecan as conventional cytotoxic agents as well as bevacizumab and the epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, as novel targeted agents into standard medical therapy have improved median overall survival in metastatic CRC beyond 2 years. It cannot be overemphasized that these significant improvements in outcome of patients with CRC are closely linked to the number of active drugs available to treat this disease. The abundance of treatment options, however, comes with specific challenges for the practical management of palliative medical therapy in advanced CRC, in particular with regard to the utilization of targeted agents. In this context, bevacizumab has established itself as the standard component of first line chemotherapy. It is of interest for clinical practice that so far no predictive marker for the activity of bevacizumab in metastatic CRC has been identified. The key questions surrounding the use of bevacizumab in the palliative setting are whether its continuation beyond tumor progression provides clinical benefit, and which patient group is at higher risk for bevacizumab related toxicities. Cetuximab and panitumumab have demonstrated efficacy both in combination with chemotherapy or - in contrast to bevacizumab - as single agent. In unselected patients, the effect of both EGFR antibodies on time-related parameters, progression free survival and overall survival, is moderate at best with emphasis more on the induction of tumor responses in a select group of patients. Therefore, until recently, EGFR antibodies were mainly regarded as salvage therapy options, in particular, since there did not appear to be a loss of activity when used in later lines of therapy. The finding that CRC harboring KRAS (and BRAF) mutations are resistant to EGFR antibodies, has allowed us to enrich the patient population with CRC that have a chance to benefit from cetuximab or panitumumab therapy. Biomarker-based treatment decisions are therefore now an integral part of clinical practice and trial design in CRC. In conclusion, targeted agents have become an integral part of medical therapy for advanced CRC. The challenge for current oncologic practice is to develop a rationale and biomarker-based treatment algorithm utilizing all potentially active agents as individualized therapy. PMID- 21789115 TI - Angiogenesis inhibitors in the treatment of non-small cell lung cancer. AB - A therapeutic plateau seems to have been reached with the standard treatment of cytotoxic chemotherapy alone for advanced stage non-small cell lung cancer (NSCLC) and new treatment options are urgently needed. Recent insight into the molecular biology of cancer has identified angiogenesis as one of the key biological processes. The major player in tumor angiogenesis is the vascular endothelial growth factor (VEGF) pathway. VEGF is expressed in the majority of NSCLC and overexpression is associated with a poor prognosis. The VEGF pathway can be inhibited in two main ways: targeting VEGF directly or inhibiting the VEGF receptors. The development of angiogenesis inhibitors has shown great promise in the treatment of NSCLC. Bevacizumab, an anti-VEGF antibody, has been approved for the treatment of advanced NSCLC and other drugs are undergoing phase III investigation. However, a number of unresolved issues remain. In this review, we discuss the main angiogenesis inhibitors in development for the treatment of NSCLC focusing on the VEGF pathway. PMID- 21789114 TI - Risk stratification in the hormonal treatment of patients with prostate cancer. AB - Prostate cancer (PCa) is the most common type of cancer found in American men, other than skin cancer. The American Cancer Society estimates that there will be 186,320 new cases of prostate cancer in the United States in 2008. About 28,660 men will die of this disease this year and PCa remains the second-leading cause of cancer death in men. One in six men will get PCa during his lifetime and one in 35 will die of the disease. Today, more than 2 million men in the United States who have had PCa are still alive. The death rate for PCa continues to decline, chiefly due to early detection and treatment, and improved salvage therapy such as hormone therapy (HT). HT continues to be a mainstay for primary recurrent PCa and locally-advanced PCa. However, HT is associated with many undesirable side effects including sexual dysfunction, osteoporosis and hot flashes, all of which can lead to decreased quality of life (QOL). These risks are seen in both long- and short-term HT regimens. Additionally, research in recent years has revealed trends related to clinico pathological variables and their predictive ability in HT outcomes. Awareness of the potential adverse effects, the risks associated with HT and the prognostic ability of clinical and pathological variables is important in determining optimal therapy for individual patients. A rigorous evaluation of the current scientific literature associated with HT was conducted with the goal of identifying the most favorable balance of benefits and risks associated with HT. PMID- 21789116 TI - Adjuvant therapy for resected non-small cell lung cancer. AB - Surgery remains the initial treatment for patients with early-stage non-small cell lung cancer (NSCLC). The frequent occurrence of distant metastases and local regional failure after surgical resection would indicate that additional treatment is necessary. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. This was followed by a new generation of randomized phase III trials some of which have reported a benefit for chemotherapy in the adjuvant setting. Based on the results of these trials, platin-based chemotherapy has become the standard of care for resected stages II and IIIA NSCLC. The role of postoperative radiation therapy remains to be defined. In the future, improvement in survival outcomes from adjuvant treatment is likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Gene expression profiles and proteomics are techniques being used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. Increasing the understanding of the molecular makeup of lung cancer will hopefully increase cure rates for patients by maximizing the efficacy of the adjuvant therapy. PMID- 21789118 TI - Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat(r), Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy. PMID- 21789117 TI - Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy? AB - Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy. Several recent clinical trials combining adjuvant endocrine therapy with bisphosphonates have demonstrated efficacy for preventing cancer treatment-induced bone loss in pre- and postmenopausal women with early breast cancer. The largest body of evidence supporting the use of adjuvant bisphosphonates comes from studies with zoledronic acid; however, studies with risedronate, ibandronate, and denosumab (a biologic agent) have also demonstrated efficacy for preventing bone loss. Adding zoledronic acid to endocrine therapy prevents bone loss and improves bone mineral density (BMD). In addition, preclinical studies suggest that bisphosphonates have direct and indirect antitumor activity, such as inducing tumor cell apoptosis, reducing tumor cell adhesion and invasion, reducing angiogenesis, activating immune responses, and synergy with chemotherapy agents, among others. Clinical trials have demonstrated significantly improved disease-free survival in patients receiving adjuvant endocrine therapy plus zoledronic acid compared with endocrine therapy alone. Ongoing studies will further define the role of adjuvant bisphosphonates in maintaining bone health and improving clinical outcomes. The available evidence suggests that pre- and postmenopausal patients may receive clinical benefit from including bisphosphonates as part of their adjuvant treatment regimen for endocrine-responsive early breast cancer. PMID- 21789119 TI - Integration of targeted agents in the neo-adjuvant treatment of gastro-esophageal cancers. AB - Pre- and peri-operative strategies are becoming standard for the management of localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5-10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging and predictive biomarkers. PMID- 21789120 TI - Beyond KRAS: perspectives on new potential markers of intrinsic and acquired resistance to epidermal growth factor receptor inhibitors in metastatic colorectal cancer. AB - The monoclonal antibodies cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), are licensed for the treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Such 'molecular restriction' derived from post-hoc analyses of randomized trials and from other retrospective series all indicate how tumors bearing KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations are resistant to EGFR inhibition. Even if highly sensitive for nonresponse, KRAS testing is not very specific. In fact, a limited but still considerable proportion of KRAS wild-type patients rapidly progress on treatment with an EGFR inhibitor. New potential molecular determinants of benefit from such treatment are under investigation and may further refine the selection of patients. Pharmacogenomic analyses and translational studies are also ongoing for exploring the field of acquired resistance to anti-EGFRs, since all patients eventually progress. New biological data are awaited for optimizing the use of molecular agents in colorectal cancer and for identifying promising targets that could allow to better understand and, potentially, overcome mechanisms of primary or secondary resistance to EGFR inhibitors. PMID- 21789122 TI - Thyroid cancer: emerging role for targeted therapies. AB - The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies. PMID- 21789123 TI - Advanced non-small cell lung cancer: the role of maintenance therapy. AB - Platinum-based chemotherapy has been shown to provide survival benefits in advanced non-small cell lung cancer (NSCLC). Maintenance/consolidation chemotherapy in NSCLC has gained renewed interest with improved tolerability of chemotherapy and the addition of biologic agents. Various studies have evaluated the role of prolonged duration of chemotherapy as well as maintenance/consolidation strategies with both chemotherapy and biologic agents. The available data at this time demonstrates that maintenance or consolidation therapy can improve progression free survival; however this does not result consistently in an improved overall survival. We review the literature with regard to duration of therapy and use of maintenance/consolidation therapy in advanced NSCLC. PMID- 21789121 TI - Targeted therapy in renal cancer. AB - Renal cell cancer (RCC) has an increasing incidence internationally and is a disease for which there have been limited therapeutic options until recently. The last decade has seen a vastly improved understanding of the biological and clinical factors that predict the outcome of this disease. We now understand some of the different molecular underpinnings of renal clear cell carcinoma by mutation or silencing of the von Hippel Lindau (VHL) gene and subsequent deregulated proliferation and angiogenesis. Survival in advanced disease is predicted by factors (performance status, anemia, hypercalcemia, and serum lactate dehydrogenase, time from diagnosis to recurrence) incorporated into the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (also referred to as 'Motzer' criteria). These criteria allow classification of patients with RCC into good, intermediate and poor risk categories with median overall survivals of 22 months, 12 months and 5.4 months, respectively. Predicated upon these advances, six new targeted drugs (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib) have been tested in well-designed phase III trials, selected or stratified for MSKCC risk criteria, with positive results. All of these new drugs act at least in part through vascular endothelial growth factor (VEGF) mediated pathways with other potential therapeutic impact on platelet derived growth factor (PDGF), raf kinase and mammalian target of rapamycin (mTOR) pathways. Importantly, data from each of these trials show a consistent doubling of progression-free survival (PFS) over prior standard of care treatments. In addition, sorafenib, sunitinib and temsirolimus, have demonstrated significant overall survival (OS) benefits as well; further follow-up is required to determine whether the disease control exhibited by everolimus and pazopanib will translate into a survival advantage. These drugs are generally well tolerated, as demonstrated by quality-of-life improvement in clinical trials, and result in clinical benefit for in excess of 70% of patients treated. They have challenged the traditional outcomes of clinical trial design by achieving their benefits with relatively few radiographic responses, but high rates of disease stability. The unique side-effect profile coupled with the chronicity of therapy requires increased vigilance to maximize exposure to the drugs while maintaining quality of life and minimizing toxicity. This review focuses on the background, clinical development and practical use of these new drugs in RCC. PMID- 21789124 TI - Targeted therapies in small cell lung cancer: a review. AB - Small cell lung cancer (SCLC) is an aggressive form of lung cancer that is characterized by a rapid doubling time, early onset of dissemination and high sensitivity to chemotherapy. Despite the potential for cure in patients with limited disease with concurrent chemoradiation and an initial good response to chemotherapy in extensive disease, there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. This review summarizes potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease. PMID- 21789125 TI - Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. AB - An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy. PMID- 21789127 TI - Which patients with renal cancer may benefit from sunitinib therapy? PMID- 21789126 TI - Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. AB - Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies could be radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especially in patients with advanced cancer. The incidence of CID has been reported to be as high as 50-80% of treated patients (>=30% CTC grade 3-5), especially with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation. Despite the number of clinical trials evaluating therapeutic or prophylactic measures in CID, there are just three drugs recommended in current guidelines: loperamide, deodorized tincture of opium and octreotide. Newer strategies and more effective agents are being developed to reduce the morbidity and mortality associated with CID. Recent research focusing on the prophylactic use of antibiotics, budesonide, probiotics or activated charcoal still have to define the role of these drugs in the routine clinical setting. Whereas therapeutic management and clinical work-up of patients presenting with diarrhea after chemotherapy are rather well defined, prediction and prevention of CID is an evolving field. Current research focuses on establishing predictive factors for CID like uridine diphosphate glucuronosyltransferase-1A1 polymorphisms for irinotecan or dihydropyrimidine-dehydrogenase insufficiency for fluoropyrimidines. PMID- 21789128 TI - Renal cell carcinoma bone metastases: clinical advances. AB - Bone is a common site of metastatic spread in patients with advanced renal cell carcinoma (RCC) occurring in around one-third of patients enrolled in clinical trials evaluating modern systemic therapies for this disease. Until recently, limited systemic therapeutic options were available for advanced RCC. Nowadays, a quiver of agents have demonstrated activity, including compounds targeting the vascular endothelial growth factor (VEGF) axis and those targeting the mammalian target of rapamycin (mTOR). Despite a detailed biological understanding of how these drugs work, their effect on bony metastases is less clear. Data suggesting that bisphosphonates (namely zoledronic acid) benefit patients with bone metastases from advanced RCC was gathered prior to the targeted therapy era; therefore, there is some uncertainty about their role in patients on modern RCC therapies. This review summarizes the current targeted therapies registered for use in advanced RCC and postulates how some of them might affect the behavior of bone metastases. It also explores the data available on the role of bisphosphonates for bone metastases from RCC, describes methods of assessing response to therapy for bone metastases and delineates future expectations for the treatment of bone metastases from advanced RCC. PMID- 21789129 TI - Systemic therapy for metastatic pancreatic adenocarcinoma. AB - Systemic treatment of metastatic pancreatic adenocarcinoma achieves only modest benefits, with evidence indicating a survival advantage with 5-fluorouracil (5 FU) over best supportive care alone, and further advantage of single-agent gemcitabine over 5-FU. There are very few regimens better than single-agent gemcitabine despite multiple trials of cytotoxic and targeted agents. The addition of a platinum agent has improved response rate but not survival. The addition of erlotinib has improved survival but only by a small margin. The use of gemcitabine in multidrug regimens containing one or more of: a platinum agent; fluoropyrimidine; anthracycline; and taxane has demonstrated advantages in response rate, progression-free survival and, in one randomized study, overall survival. After gemcitabine failure, second-line therapy with oxaliplatin and 5 FU provides a further survival advantage. Further advances depend upon the current and future clinical trials investigating enhanced delivery of current agents, new agents and novel modalities, improved supportive care, and treatment more tailored to the individual patient and tumour. PMID- 21789131 TI - The way forward in treating pancreatic cancer. PMID- 21789132 TI - Safety and efficacy of weekly 5-fluorouracil/folinic acid/oxaliplatin/irinotecan in the first-line treatment of gastrointestinal cancer. AB - BACKGROUND: Standard chemotherapy for patients with metastatic colorectal cancer (mCRC) or gastric cancer (GC) consists of two-drug, usually fluoropyrimidine based, combinations, with or without the addition of biological agents. Studies of triple-drug regimens combining 5-fluorouracil (5-FU)/folinic acid (FA) with both oxaliplatin and irinotecan have shown promising efficacy in studies of patients with mCRC or GC. However, improved efficacy has often been achieved at the expense of high rates of grade 3 or 4 toxicities such as neutropenia and diarrhoea, occasionally even resulting in toxic deaths. OBJECTIVE/METHODS: We performed a phase II study of previously untreated patients with mCRC or GC to assess the safety and efficacy of our 5-fluorouracil/folinic acid/oxaliplatin/irinotecan (FUFOXIRI) regimen with weekly administration of irinotecan 70 mg/m(2), oxaliplatin 50 mg/m(2), FA 500 mg/m(2) and 5-FU 2000 mg/m(2) on days 1, 8, 15 and 22, repeated from day 36. RESULTS: A total of 22 patients were enrolled, 11 each with mCRC and GC receiving a median of four cycles per patient. The FUFOXIRI regimen was generally well tolerated with no toxic deaths, neutropenic fever or grade 4 toxicities. Most common grade 3 side effects were diarrhoea and neutropenia each affecting 24% of patients. Dose reductions due to toxicity were performed in 48% of all and 60% of patients having received at least two cycles of FUFOXIRI. The overall response rate was 46% (all partial responses), 55% and 36% for patients with mCRC and GC, respectively. Median progression-free survival for all patients, mCRC and GC patients was 9.5, 10.0 and 8.0 months, respectively. The median overall survival for all patients was 16.5, 18.0 and 15.0 months for patients with mCRC and GC, respectively. CONCLUSION: These data show excellent tolerance and efficacy of the FUFOXIRI regimen in both mCRC and GC. Therefore, FUFOXIRI is a promising backbone for future studies incorporating biologic 'targeted' agents for the treatment of gastrointestinal cancers. PMID- 21789133 TI - Practical considerations in ovarian cancer chemotherapy. AB - Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer. PMID- 21789130 TI - Predictive and prognostic molecular markers for cancer medicine. AB - Over the last 10 years there has been an explosion of information about the molecular biology of cancer. A challenge in oncology is to translate this information into advances in patient care. While there are well-formed routes for translating new molecular information into drug therapy, the routes for translating new information into sensitive and specific diagnostic, prognostic and predictive tests are still being developed. Similarly, the science of using tumor molecular profiles to select clinical trial participants or to optimize therapy for individual patients is still in its infancy. This review will summarize the current technologies for predicting treatment response and prognosis in cancer medicine, and outline what the future may hold. It will also highlight the potential importance of methods that can integrate molecular, histopathological and clinical information into a synergistic understanding of tumor progression. While these possibilities are without doubt exciting, significant challenges remain if we are to implement them with a strong evidence base in a widely available and cost-effective manner. PMID- 21789135 TI - Updates on novel therapies for metastatic renal cell carcinoma. AB - Metastatic renal cell carcinoma (RCC) poses one of the great therapeutic challenges in oncology. RCC is predominantly refractory to treatment with traditional cytotoxic chemotherapies, and until recently management options were limited to immunotherapy or palliative care. However, in the past few years we have experienced a sea change in the treatment of advanced RCC with the introduction of targeted therapies that derive their efficacy at least in part through alterations in tumor angiogenesis. The tyrosine kinase inhibitors sunitinib, pazopanib, and sorafenib, the monoclonal antibody bevacizumab (in combination with interferon-alpha), and the rapamycin analogs, temsirolimus and everolimus, are now approved agents in the United States for the treatment of metastatic RCC. Efforts to expand upon these successes include developing novel antiangiogenic agents, optimizing concomitant and sequential regimens, identifying predictors of response to specific treatments, and further dissecting the underlying molecular pathogenesis of RCC to reveal novel therapeutic targets. PMID- 21789136 TI - What is the role of maintenance therapy in the treatment of non-small cell lung cancer? PMID- 21789134 TI - Castration-resistant prostate cancer: new science and therapeutic prospects. AB - There is a growing number of new therapies targeting different pathways that will revolutionize patient management strategies in castration-resistant prostate cancer (CRPC) patients. Today there are more clinical trial options for CRPC treatment than ever before, and there are many promising agents in late-stage clinical testing. The hypothesis that CRPC frequently remains driven by a ligand activated androgen receptor (AR) and that CRPC tissues exhibit substantial residual androgen levels despite gonadotropin-releasing hormone therapy, has led to the evaluation of new oral compounds such as abiraterone and MDV 3100. Their results, coupled with promising recent findings in immunotherapy (eg sipuleucel T) and with agents targeting angiogenesis (while awaiting the final results of the CALGB trial 90401) will most probably impact the management of patients with CRPC in the near future. Other new promising agents need further development. With our increased understanding of the biology of this disease, further trial design should incorporate improved patient selection so that patient populations are those who may be most likely to benefit from treatment. PMID- 21789137 TI - Targeting the Hedgehog pathway in cancer. AB - The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy. PMID- 21789138 TI - Treating advanced non-small cell lung cancer in the elderly. AB - More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70 years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients. PMID- 21789139 TI - Combination therapy in high-risk stage II or stage III colon cancer: current practice and future prospects. AB - Colon cancer represents the second leading cause of cancer-related deaths. For patients who have undergone curative surgery, adjuvant therapy can reduce the risk of recurrence and death from relapsed or metastatic disease. Postoperative chemotherapy with a 5-fluorouracil-based regimen combined with oxaliplatin is the current standard of care for stage III patients. However, there is still controversy in stage II disease about the real impact of adjuvant monotherapy or combined therapy on survival. Better identification of a subgroup of patients with a higher risk of recurrence can select patients who might benefit from adjuvant therapy. For the elderly population, there is a well-established role for postoperative therapy, although the most appropriate regimen remains to be defined. Targeted agents for combined adjuvant therapy in stage II and III colon cancer is a promising area, but to date, there is no evidence supporting its use in this setting. Results from large prospective trials with targeted therapy have been disappointing and new drugs and strategies are needed to define the role of these types of agents in the adjuvant scenario of colon cancer. PMID- 21789141 TI - Highlights of the 2nd European lung cancer conference. PMID- 21789140 TI - Chemotherapy in newly diagnosed primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) accounts for only 3% of brain tumors. It can involve the brain parenchyma, leptomeninges, eyes and the spinal cord. Unlike systemic lymphoma, durable remissions remain uncommon. Although phase III trials in this rare disease are difficult to perform, many phase II trials have attempted to define standards of care. Treatment modalities for patients with newly diagnosed PCNSL include radiation and/or chemotherapy. While the role of radiation therapy for initial management of PCNSL is controversial, clinical trials will attempt to improve the therapeutic index of this modality. Routes of chemotherapy administration include intravenous, intraocular, intraventricular or intra-arterial. Multiple trials have outlined different methotrexate-based chemotherapy regimens and have used local techniques to improve drug delivery. A major challenge in the management of patients with PCNSL remains the delivery of aggressive treatment with preservation of neurocognitive function. Because PCNSL is rare, it is important to perform multicenter clinical trials and to incorporate detailed measurements of long-term toxicities. In this review we focus on different chemotherapeutic approaches for immunocompetent patients with newly diagnosed PCNSL and discuss the role of local drug delivery in addition to systemic therapy. We also address the neurocognitive toxicity of treatment. PMID- 21789142 TI - The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations. AB - Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC. PMID- 21789143 TI - Using bevacizumab with different chemotherapeutic regimens in metastatic colorectal cancer: balancing utility with low toxicity. AB - The addition of bevacizumab to currently available treatment options for metastatic colorectal cancer has changed the traditional chemotherapy-based paradigm. In this review we cover published clinical trials pertaining to the toxicity and efficacy of bevacizumab for metastatic colorectal cancer. Several randomized trials have studied combinations of irinotecan, oxaliplatin, 5 fluorouracil or capecitabine with bevacizumab. Efficacy in terms of progression free survival and overall survival has been improved to varying degrees with the addition of bevacizumab. Bevacizumab's distinctive toxicity profile has been well demonstrated in these trials, and has been shown to be manageable. However, certain patient groups, such as the elderly, may require particular toxicity considerations with bevacizumab. The optimal timing, dose and duration of bevacizumab-containing therapy have yet to be fully determined. Further randomized data, particularly for patients with potentially resectable liver metastases, are required in order to fully define the role of bevacizumab in the increasingly complex management paradigm for this disease. PMID- 21789144 TI - Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer. AB - Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. PMID- 21789145 TI - Bevacizumab in the treatment of patients with advanced breast cancer: where have we landed? AB - Vast preclinical and clinical evidence has made angiogenesis one of the hallmarks of cancer. In many human tumours, vascular endothelial growth factor (VEGF) has been identified as the crucial mediator of this process. Initial studies suggested that angiogenesis, and VEGF in particular, could be inhibited without the risk of major side effects. After the pivotal data in first-line studies in patients with colorectal cancer, numerous clinical trials have been undertaken in patients with breast cancer. This review attempts to update these investigations and define the role of anti-VEGF antibody treatment in advanced breast cancer. PMID- 21789146 TI - Latest therapeutic advances from the ASCO 2010 Annual Meeting. PMID- 21789147 TI - Circulating tumour cells: their utility in cancer management and predicting outcomes. AB - Recent advances in technology now permit robust and reproducible detection of circulating tumour cells (CTCs) from a simple blood test. Standardization in methodology has been instrumental in facilitating multicentre trials with the purpose of evaluating the clinical utility of CTCs. We review the current body of evidence supporting the prognostic value of CTC enumeration in breast, prostate and colorectal cancer, using standardized approaches, and studies evaluating the correlation of CTC number with radiological outcome. The exploitation of CTCs in cancer management, however, is now extending beyond prognostication. As technologies emerge to characterize CTCs at the molecular level, biological information can be obtained in real time, with the promise of serving as a 'surrogate tumour biopsy'. Current studies illuminate the potential of CTCs as pharmacodynamic and predictive biomarkers and potentially their use in revealing drug resistance in real time. Approaches for CTC characterization are summarized and the potential of CTCs in cancer patient management exemplified via the detection of epidermal growth factor receptor mutations from CTCs in patients with non-small cell lung cancer. The opportunity to learn more about the biology of metastasis through CTC analysis is now being realized with the horizon of CTC guided development of novel anticancer therapies. PMID- 21789148 TI - Targeting angiogenesis in melanoma: prospects for the future. AB - Angiogenesis has been identified as a relevant target for melanoma experimental therapeutics, based on preclinical and clinical studies. A variety of angiogenesis inhibitors are currently being tested in both metastatic and adjuvant melanoma clinical trials. To date, the most promising evidence of benefit is based on a statistically nonsignificant trend in survival gain reported in a randomized phase II trial combining bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, with cytotoxic chemotherapy. Larger phase III studies are required to determine the true extent of clinical benefit with this class of agents. Key to these clinical trials is the need to include translational endpoints, since correlation of biological and clinical data will provide the opportunity to identify biomarkers predictive of treatment response. These biological studies will also aid our, as yet, poor understanding of the mechanism of action of angiogenesis inhibitors, as well as drug-related side effects. Finally, if these trials show meaningful clinical benefit, then careful consideration will need to be given when designing second generation trials, in the light of novel gene-directed therapies currently showing promise in melanoma. PMID- 21789149 TI - Choosing chemotherapy in patients with advanced urothelial cell cancer who are unfit to receive cisplatin-based chemotherapy. AB - Transitional cell carcinoma of the urothelial tract is the second most common cancer of the genitourinary system and the fifth most common cancer in Western countries with more than 300,000 new cases per year worldwide. Following the introduction of cisplatin-based chemotherapy, median overall survival in patients with metastatic disease has doubled, demonstrating chemotherapy as an important treatment modality in advanced or metastatic disease. Patients 'unfit' to receive cisplatin-based chemotherapy are characterized by impaired renal function, impaired performance status, and/or comorbidity that preclude the use of cisplatin. In this review we summarize the different chemotherapeutic schemes, focusing on treatment options in cisplatin 'unfit' patients. PMID- 21789151 TI - Latest advances in medical oncology: highlights from Milan ESMO 2010 annual congress. PMID- 21789150 TI - The role of peri-operative treatment in resectable liver metastases of colorectal cancer. AB - Synchronous or metachronous colorectal liver metastases (CLMs), although being the expression of systemic disease, allow a curative approach for about 25-35% of patients. Patients presenting with CLMs should receive a multimodal management in order to increase the number of patients undergoing R0 surgery and to decrease the rate of recurrence. Postoperative and/or pre-operative systemic chemotherapy shows beneficial impact regarding progression-free and overall survival, without increasing postoperative complication rates. Concerning the complex definition of resectability and the number of patients with 'borderline' resectable CLMs, pre operative chemotherapy plays an important role in both the improvement of prognosis and 'conversion' to resectability. Duration of chemotherapy in the peri operative setting should not exceed 6 months. Current data do not recommend the use of locally applied chemotherapy using hepatic artery infusion after resection of CLMs. Liver surgery has made several advances extending resectability to a larger group of patients and decreasing local hepatic recurrence. Moreover, locally ablative procedures such as radiofrequency and selective internal radiation therapy have joined the armamentarium in the case of positive resection margins or unresectable disease. Future research will help in defining treatment regimens and approaches in this setting. PMID- 21789152 TI - Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence. AB - Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity. PMID- 21789153 TI - Neoadjuvant chemoradiotherapy has a potential role in pancreatic carcinoma. AB - Pancreatic cancer has an extremely poor prognosis, only a small minority of patients undergo a resection with curative intent. Chemotherapy and/or radiochemotherapy may improve this by prolonging survival or disease-free interval and improving resectability and the proportion of microscopically complete (R0) resections. With regard to prolonging survival, both in the postoperative adjuvant setting and in locally advanced disease, chemotherapy has a positive but limited effect on survival and may be considered standard. The role of postoperative adjuvant radiochemotherapy remains debatable. For improving resectability/proportion of R0 resections, many studies suggest that the proportion of patients undergoing a resection during exploration and the proportion of R0 resections increase after neoadjuvant radiochemotherapy. This may improve the prognosis of patients with a resectable or borderline resectable pancreatic carcinoma. The effect of neoadjuvant radiochemotherapy, if any, is modest. The search for better combinations, including targeted therapy, must continue. The interpretation of single-arm studies is hampered by (selection) biases. The reporting of pathology and study endpoints should be internationally standardized. To avoid biases in studies of patients with (borderline) resectable tumours, prospective parallel registration of all patients referred for surgery would help. Ultimately, randomized controlled phase III trials should establish the role of neoadjuvant radiochemotherapy. Thus, neoadjuvant radiochemotherapy has a potential benefit in resectable and borderline resectable pancreatic cancer, but better combinations are warranted. PMID- 21789154 TI - Reassessing the need for primary tumor surgery in unresectable metastatic colorectal cancer: overview and perspective. AB - In the absence of symptoms, primary tumor resection in patients who present with unresectable metastatic colorectal cancer is of uncertain benefit. Prophylactic surgery has been traditionally considered in this setting in order to prevent subsequent complications of perforation, obstruction, or bleeding later during the treatment course, which may require urgent surgery associated with higher mortality. However, recent data have called into question the efficacy of this upfront surgical strategy. We provide a brief overview of how current combinations of systemic chemotherapy including fluorouracil, oxaliplatin, irinotecan, and targeted biologic agents have allowed improved local (in addition to distant) tumor control, significantly decreasing the incidence of late primary related complications requiring surgery from roughly 20% in the era of single agent fluoropyrimidine chemotherapy to almost 7% in the era of modern triple-drug chemotherapy. In addition, we attempt to highlight those factors most associated with subsequent primary tumor-related complications in an effort to identify the subset of patients with synchronous metastatic colorectal cancer who might benefit from a surgery-first approach. Finally, we discuss modern nonsurgical options available for palliation of the primary colorectal tumor and review the outcome of patients for which emergent surgery is eventually required to address primary-related symptoms. PMID- 21789155 TI - Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. AB - As the therapeutic options for the treatment of colorectal cancer have expanded over the past 20 years, so has the complexity of decision making. The goals of treatment in the palliative, adjuvant and neoadjuvant settings vary and it is not only the efficacy of drugs that influence treatment decisions. Age, performance status, the presence of significant comorbidities and the different treatment regimens and strategies provide medical oncologists with an array of options to attempt to maximize patients' quality of life and longevity. PMID- 21789156 TI - Health-related quality of life and cancer clinical trials. AB - The measurement of patient-reported outcomes, including health-related quality of life, is a new initiative which has emerged and grown over the past four decades. Following the development of reliable and valid self-report questionnaires, health-related quality of life has been assessed in tens of thousands of patients and a wide variety of cancers. This review is based on a selection of data published in the last decade and is intended primarily for healthcare professionals. The assessments in clinical trials have been particularly useful for elucidating the effects of various cancers and their treatments on patients' lives and have provided additional information that enhances the usual clinical endpoints used for determining the benefits and toxicity of treatment. With growing experience the quality of the health-related quality of studies has improved and, in general, recent studies are more likely to be methodologically robust than those that were performed in earlier decades. Health-related quality of life has become a more accurate predictor of survival than some other clinical parameters, such as performance status. The overall outlook for the routine assessment of patient-reported outcomes in clinical trials is assured and, eventually, it is likely to become a standard part of clinical practice. However, there is still a need for a clear method for determining the clinical meaningfulness of changes in scores. The answer will probably come from the greater use of patient-reported outcomes and the consequent growth of experience that is necessary to make such judgements. PMID- 21789157 TI - Chemotherapy for breast cancer in pregnancy: evidence and guidance for oncologists. AB - It has been estimated that up to 3.8% of breast cancers may be diagnosed in women who are pregnant, with an estimated 1 in 3000-3500 deliveries occurring in women with breast cancer. Owing to the lack of large randomized trials available to guide our clinical practice, our decisions regarding adjuvant systemic management are based on retrospective analyses, case reports and a small number of prospective studies. A tailored approach to treatment is required with careful consideration given at all stages to the needs of the mother and risks to the foetus. Management is critically influenced by the stage of pregnancy, especially the first trimester. Anthracycline-based chemotherapy may be administered during the second and third trimesters, with apparently few short-term implications. Limited data shows the taxanes may also be given with few adverse events at these stages. Weekly fractionation regimens may allow closer monitoring of pregnancy with prompt termination of agents, if necessary. Data concerning the long-term risks of systemic anticancer treatment are limited. All stages of patient management should be discussed within a multidisciplinary team and a clear consensus of treatment options communicated to the mother. Delaying chemotherapy until after delivery may be reasonable in some cases, but where the delay is likely to be prolonged, a decision must be made on the basis of risks versus benefits. PMID- 21789158 TI - Bevacizumab in metastatic breast cancer: when may it be used? AB - Tumor angiogenesis, which is necessary for breast cancer growth, invasion and metastases, is regulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Bevacizumab is a recombinant humanized monoclonal antibody that targets VEGF. The addition of bevacizumab to chemotherapy has improved progression-free survival in the first- and second-line treatment of patients with advanced-stage breast cancer. In this article we review the clinical trials testing the utility of bevacizumab for the treatment of metastatic disease. PMID- 21789159 TI - Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience. AB - Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose-toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose-toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial. PMID- 21789160 TI - Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists. AB - Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Despite the lack of prostate-specific antigen and objective response, a recent phase III randomized trial demonstrated a significant improvement in overall survival in asymptomatic and minimally symptomatic CRPC patients. This review summarizes the clinical development of Sipuleucel-T in CRPC that led to the regulatory approval of this compound in the USA. PMID- 21789162 TI - Peritoneal cavity is dominated by IFNgamma-secreting CXCR3+ Th1 cells. AB - The chemokine receptor CXCR3, which was shown to take part in many inflammatory processes, is considered as a Th1 specific marker. Here, we show in a mouse model that CXCR3 expressing CD4(+) cells preferentially migrate to the peritoneal cavity under steady-state conditions. The peritoneal cavity milieu leads to an up regulated expression of CXCR3. However, blocking of known ligands of this chemokine receptor did not alter the preferential migration. The peritoneal cavity environment also results in an increased percentage of memory cells producing cytokines. Up-regulation of IFNgamma production occurs mostly in CXCR3(+) cells considered as Th1, whereas the up-regulation of IL-4 affects mostly in CXCR3(-) cells which are considered as Th2. We conclude that the peritoneal cavity does not change the Th-lineage of the cells, but that domination of this anatomic niche by Th1 cells rather results from preferential migration to this compartment. PMID- 21789163 TI - Effectiveness of the AS03-adjuvanted vaccine against pandemic influenza virus A/(H1N1) 2009--a comparison of two methods; Germany, 2009/10. AB - During the autumn wave of the pandemic influenza virus A/(H1N1) 2009 (pIV) the German population was offered an AS03-adjuvanted vaccine. The authors compared results of two methods calculating the effectiveness of the vaccine (VE). The test-negative case-control method used data from virologic surveillance including influenza-positive and negative patients. An innovative case-series methodology explored data from all nationally reported laboratory-confirmed influenza cases. The proportion of reported cases occurring in vaccinees during an assumed unprotected phase after vaccination was compared with that occurring in vaccinees during their assumed protected phase. The test-negative case-control method included 1,749 pIV cases and 2,087 influenza test-negative individuals of whom 6 (0.3%) and 36 (1.7%), respectively, were vaccinated. The case series method included data from 73,280 cases. VE in the two methods was 79% (95% confidence interval (CI) = 35-93%; P = 0.007) and 87% (95% CI = 78-92%; P<0.001) for individuals less than 14 years of age and 70% (95% CI = -45%-94%, P = 0.13) and 74% (95% CI = 64-82%; P<0.001) for individuals above the age of 14. Both methods yielded similar VE in both age groups; and VE for the younger age group seemed to be higher. PMID- 21789164 TI - Predicting the tolerated sequences for proteins and protein interfaces using RosettaBackrub flexible backbone design. AB - Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high quality model. The starting structure(s) are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface), interactions between and within parts of the structure (e.g. domains) can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others. PMID- 21789165 TI - A small peptide modeled after the NRAGE repeat domain inhibits XIAP-TAB1-TAK1 signaling for NF-kappaB activation and apoptosis in P19 cells. AB - In normal growth and development, apoptosis is necessary to shape the central nervous system and to eliminate excess neurons which are not required for innervation. In some diseases, however, apoptosis can be either overactive as in some neurodegenerative disorders or severely attenuated as in the spread of certain cancers. Bone morphogenetic proteins (BMPs) transmit signals for regulating cell growth, differentiation, and apoptosis. Responding to BMP receptors stimulated from BMP ligands, neurotrophin receptor-mediated MAGE homolog (NRAGE) binds and functions with the XIAP-TAK1-TAB1 complex to activate p38(MAPK) and induces apoptosis in cortical neural progenitors. NRAGE contains a unique repeat domain that is only found in human, mouse, and rat homologs that we theorize is pivotal in its BMP MAPK role. Previously, we showed that deletion of the repeat domain inhibits apoptosis, p38(MAPK) phosphorylation, and caspase-3 cleavage in P19 neural progenitor cells. We also showed that the XIAP-TAB1-TAK1 complex is dependent on NRAGE for IKK-alpha/beta phosphorylation and NF-kappaB activation. XIAP is a major inhibitor of caspases, the main executioners of apoptosis. Although it has been shown previously that NRAGE binds to the RING domain of XIAP, it has not been determined which NRAGE domain binds to XIAP. Here, we used fluorescence resonance energy transfer (FRET) to determine that there is a strong likelihood of a direct interaction between NRAGE and XIAP occurring at NRAGE's unique repeat domain which we also attribute to be the domain responsible for downstream signaling of NF-kappaB and activating IKK subunits. From these results, we designed a small peptide modeled after the NRAGE repeat domain which we have determined inhibits NF-kappaB activation and apoptosis in P19 cells. These intriguing results illustrate that the paradigm of the NRAGE repeat domain may hold promising therapeutic strategies in developing pharmaceutical solutions for combating harmful diseases involving excessive downstream BMP signaling, including apoptosis. PMID- 21789166 TI - Analysis of rabies in China: transmission dynamics and control. AB - Human rabies is one of the major public-health problems in China. The number of human rabies cases has increased dramatically in the last 15 years, partially due to the poor understanding of the transmission dynamics of rabies and the lack of effective control measures of the disease. In this article, in order to explore effective control and prevention measures we propose a deterministic model to study the transmission dynamics of rabies in China. The model consists of susceptible, exposed, infectious, and recovered subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The model simulations agree with the human rabies data reported by the Chinese Ministry of Health. We estimate that the basic reproduction number R0 = 2 for the rabies transmission in China and predict that the number of the human rabies is decreasing but may reach another peak around 2030. We also perform some sensitivity analysis of R0 in terms of the model parameters and compare the effects of culling and immunization of dogs. Our study demonstrates that (i) reducing dog birth rate and increasing dog immunization coverage rate are the most effective methods for controlling rabies in China; and (ii) large scale culling of susceptible dogs can be replaced by immunization of them. PMID- 21789168 TI - Spheres derived from lung adenocarcinoma pleural effusions: molecular characterization and tumor engraftment. AB - Malignant pleural effusions (MPEs) could represent an excellent source to culture a wide variety of cancer cells from different donors. In this study, we set up culture conditions for cancer cells deriving from MPEs of several patients affected by the most frequent form of lung cancer, namely the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases. AdenoCa malignant pleural effusions gave rise to in vitro cultures both in adherent and/or in spheroid conditions in almost all cases analyzed. We characterized in greater detail two samples which showed the most efficient propagation in vitro. In these samples we also compared gene profiles of spheroid vs adherent cultures and identified a set of differentially expressed genes. Finally we achieved efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells. PMID- 21789167 TI - Long-term persistance of the pathophysiologic response to severe burn injury. AB - BACKGROUND: Main contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury. It is currently unknown how long these conditions persist beyond the acute phase post-injury. The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions. METHODOLOGY/PRINCIPAL FINDINGS: PATIENTS: Nine-hundred seventy-seven severely burned pediatric patients with burns over 30% of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned, non-injured children. Demographics and clinical outcomes, hypermetabolism, body composition, organ function, inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn. Statistical analysis was performed using One-way ANOVA, Student's t-test with Bonferroni correction where appropriate with significance accepted at p<0.05. Resting energy expenditure, body composition, metabolic markers, cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism, p<0.05. Along with increased hypermetabolism, significant elevation of cortisol, catecholamines, cytokines, and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05. CONCLUSIONS: Severe burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown. Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses, we now identified treatment needs for severely burned patients for a much more prolonged time. PMID- 21789169 TI - Expression and function of serotonin 2A and 2B receptors in the mammalian respiratory network. AB - Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs) that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors that are directed towards protein kinase C (PKC). In contrast to 5 HT(2A)Rs, expression and function of 5-HT(2B)Rs within the respiratory network are still unclear. 5-HT(2B)R utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2A)Rs and 5-HT(2B)Rs given intra arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5 HT(2B)R. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation. PMID- 21789170 TI - Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells. AB - Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression. Genomic and proteomic studies have implicated a role for androgen in regulating metabolic processes in prostate cancer. However, there have been no metabolomic profiling studies conducted thus far that have examined androgen-regulated biochemical processes in prostate cancer. Here, we have used unbiased metabolomic profiling coupled with enrichment-based bioprocess mapping to obtain insights into the biochemical alterations mediated by androgen in prostate cancer cell lines. Our findings indicate that androgen exposure results in elevation of amino acid metabolism and alteration of methylation potential in prostate cancer cells. Further, metabolic phenotyping studies confirm higher flux through pathways associated with amino acid metabolism in prostate cancer cells treated with androgen. These findings provide insight into the potential biochemical processes regulated by androgen signaling in prostate cancer. Clinically, if validated, these pathways could be exploited to develop therapeutic strategies that supplement current androgen ablative treatments while the observed androgen-regulated metabolic signatures could be employed as biomarkers that presage the development of castrate-resistant prostate cancer. PMID- 21789171 TI - Demographic processes underlying subtle patterns of population structure in the scalloped hammerhead shark, Sphyrna lewini. AB - Genetic diversity (theta), effective population size (N(e)), and contemporary levels of gene flow are important parameters to estimate for species of conservation concern, such as the globally endangered scalloped hammerhead shark, Sphyrna lewini. Therefore, we have reconstructed the demographic history of S. lewini across its Eastern Pacific (EP) range by applying classical and coalescent population genetic methods to a combination of 15 microsatellite loci and mtDNA control region sequences. In addition to significant population genetic structure and isolation-by-distance among seven coastal sites between central Mexico and Ecuador, the analyses revealed that all populations have experienced a bottleneck and that all current values of theta are at least an order of magnitude smaller than ancestral theta, indicating large decreases in N(e) (theta = 4N(e)MU), where MU is the mutation rate. Application of the isolation-with-migration (IM) model showed modest but significant genetic connectivity between most sampled sites (point estimates of Nm = 0.1-16.7), with divergence times (t) among all populations significantly greater than zero. Using a conservative (i.e., slow) fossil-based taxon-specific phylogenetic calibration for mtDNA mutation rates, posterior probability distributions (PPDs) for the onset of the decline in N(e) predate modern fishing in this region. The cause of decline over the last several thousand years is unknown but is highly atypical as a post-glacial demographic history. Regardless of the cause, our data and analyses suggest that S. lewini was far more abundant throughout the EP in the past than at present. PMID- 21789172 TI - AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. AB - Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (>=24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2 overexpressing cells. PMID- 21789173 TI - Distribution of hyperpolarized xenon in the brain following sensory stimulation: preliminary MRI findings. AB - In hyperpolarized xenon magnetic resonance imaging (HP (129)Xe MRI), the inhaled spin-1/2 isotope of xenon gas is used to generate the MR signal. Because hyperpolarized xenon is an MR signal source with properties very different from those generated from water-protons, HP (129)Xe MRI may yield structural and functional information not detectable by conventional proton-based MRI methods. Here we demonstrate the differential distribution of HP (129)Xe in the cerebral cortex of the rat following a pain stimulus evoked in the animal's forepaw. Areas of higher HP (129)Xe signal corresponded to those areas previously demonstrated by conventional functional MRI (fMRI) methods as being activated by a forepaw pain stimulus. The percent increase in HP (129)Xe signal over baseline was 13 28%, and was detectable with a single set of pre and post stimulus images. Recent innovations in the production of highly polarized (129)Xe should make feasible the emergence of HP (129)Xe MRI as a viable adjunct method to conventional MRI for the study of brain function and disease. PMID- 21789174 TI - LRR conservation mapping to predict functional sites within protein leucine-rich repeat domains. AB - Computational prediction of protein functional sites can be a critical first step for analysis of large or complex proteins. Contemporary methods often require several homologous sequences and/or a known protein structure, but these resources are not available for many proteins. Leucine-rich repeats (LRRs) are ligand interaction domains found in numerous proteins across all taxonomic kingdoms, including immune system receptors in plants and animals. We devised Repeat Conservation Mapping (RCM), a computational method that predicts functional sites of LRR domains. RCM utilizes two or more homologous sequences and a generic representation of the LRR structure to identify conserved or diversified patches of amino acids on the predicted surface of the LRR. RCM was validated using solved LRR+ligand structures from multiple taxa, identifying ligand interaction sites. RCM was then used for de novo dissection of two plant microbe-associated molecular pattern (MAMP) receptors, EF-TU RECEPTOR (EFR) and FLAGELLIN-SENSING 2 (FLS2). In vivo testing of Arabidopsis thaliana EFR and FLS2 receptors mutagenized at sites identified by RCM demonstrated previously unknown functional sites. The RCM predictions for EFR, FLS2 and a third plant LRR protein, PGIP, compared favorably to predictions from ODA (optimal docking area), Consurf, and PAML (positive selection) analyses, but RCM also made valid functional site predictions not available from these other bioinformatic approaches. RCM analyses can be conducted with any LRR-containing proteins at www.plantpath.wisc.edu/RCM, and the approach should be modifiable for use with other types of repeat protein domains. PMID- 21789175 TI - Identification and analysis of intermediate size noncoding RNAs in the human fetal brain. AB - The involvement of noncoding RNAs (ncRNAs) in the development of the human brain remains largely unknown. Applying a cloning strategy for detection of intermediate size (50-500 nt) ncRNAs (is-ncRNAs) we have identified 82 novel transcripts in human fetal brain tissue. Most of the novel is-ncRNAs are not well conserved in vertebrates, and several transcripts were only found in primates. Northern blot and microarray analysis indicated considerable variation in expression across human fetal brain development stages and fetal tissues for both novel and known is-ncRNAs. Expression of several of the novel is-ncRNAs was conspicuously absent in one or two brain cancer cell lines, and transient overexpression of some transcripts in cancer cells significantly inhibited cell proliferation. Overall, our results suggest that is-ncRNAs play important roles in the development and tumorigenesis of human brain. PMID- 21789177 TI - Mink farms predict Aleutian disease exposure in wild American mink. AB - BACKGROUND: Infectious diseases can often be of conservation importance for wildlife. Spillover, when infectious disease is transmitted from a reservoir population to sympatric wildlife, is a particular threat. American mink (Neovison vison) populations across Canada appear to be declining, but factors thus far explored have not fully explained this population trend. Recent research has shown, however, that domestic mink are escaping from mink farms and hybridizing with wild mink. Domestic mink may also be spreading Aleutian disease (AD), a highly pathogenic parvovirus prevalent in mink farms, to wild mink populations. AD could reduce fitness in wild mink by reducing both the productivity of adult females and survivorship of juveniles and adults. METHODS: To assess the seroprevalence and geographic distribution of AD infection in free-ranging mink in relation to the presence of mink farms, we conducted both a large-scale serological survey, across the province of Ontario, and a smaller-scale survey, at the interface between a mink farm and wild mink. CONCLUSIONS/SIGNIFICANCE: Antibodies to AD were detected in 29% of mink (60 of 208 mink sampled); however, seroprevalence was significantly higher in areas closer to mink farms than in areas farther from farms, at both large and small spatial scales. Our results indicate that mink farms act as sources of AD transmission to the wild. As such, it is likely that wild mink across North America may be experiencing increased exposure to AD, via disease transmission from mink farms, which may be affecting wild mink demographics across their range. In light of declining mink populations, high AD seroprevalence within some mink farms, and the large number of mink farms situated across North America, improved biosecurity measures on farms are warranted to prevent continued disease transmission at the interface between mink farms and wild mink populations. PMID- 21789176 TI - A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model. AB - In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. The underlying programming of fetal development was shown to be associated with an increased risk of degenerative diseases in adulthood, including the metabolic syndrome. There are clues that diet-dependent modifications of the metabolism during fetal life can persist until adulthood. This leads to the hypothesis that the offspring's transcriptomes show short-term and long-term changes depending on the maternal diet. To this end pregnant German landrace gilts were fed either a high protein diet (HP, 30% CP) or an adequate protein diet (AP, 12% CP) throughout pregnancy. Hepatic transcriptome profiles of the offspring were analyzed at prenatal (94 dpc) and postnatal stages (1, 28, 188 dpn). Depending on the gestational dietary exposure, mRNA expression levels of genes related to energy metabolism, N-metabolism, growth factor signaling pathways, lipid metabolism, nucleic acid metabolism and stress/immune response were affected either in a short-term or in a long-term manner. Gene expression profiles at fetal stage 94 dpc were almost unchanged between the diets. The gestational HP diet affected the hepatic expression profiles at prenatal and postnatal stages. The effects encompassed a modulation of the genome in terms of an altered responsiveness of energy and nutrient sensing pathways. Differential expression of genes related to energy production and nutrient utilization contribute to the maintenance of development and growth performance within physiological norms, however the modulation of these pathways may be accompanied by a predisposition for metabolic disturbances up to adult stages. PMID- 21789178 TI - Prediction of drought-resistant genes in Arabidopsis thaliana using SVM-RFE. AB - BACKGROUND: Identifying genes with essential roles in resisting environmental stress rates high in agronomic importance. Although massive DNA microarray gene expression data have been generated for plants, current computational approaches underutilize these data for studying genotype-trait relationships. Some advanced gene identification methods have been explored for human diseases, but typically these methods have not been converted into publicly available software tools and cannot be applied to plants for identifying genes with agronomic traits. METHODOLOGY: In this study, we used 22 sets of Arabidopsis thaliana gene expression data from GEO to predict the key genes involved in water tolerance. We applied an SVM-RFE (Support Vector Machine-Recursive Feature Elimination) feature selection method for the prediction. To address small sample sizes, we developed a modified approach for SVM-RFE by using bootstrapping and leave-one-out cross validation. We also expanded our study to predict genes involved in water susceptibility. CONCLUSIONS: We analyzed the top 10 genes predicted to be involved in water tolerance. Seven of them are connected to known biological processes in drought resistance. We also analyzed the top 100 genes in terms of their biological functions. Our study shows that the SVM-RFE method is a highly promising method in analyzing plant microarray data for studying genotype phenotype relationships. The software is freely available with source code at http://ccst.jlu.edu.cn/JCSB/RFET/. PMID- 21789179 TI - Milk lacking alpha-casein leads to permanent reduction in body size in mice. AB - The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate.We have analysed the role of the milk protein alpha-casein by inactivating the corresponding gene in mice. Absence of alpha-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for alpha-casein in the establishment of casein micelles. In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced. The absence of alpha-casein also significantly inhibits transcription of the other casein genes. alpha-Casein deficiency severely delays pup growth during lactation and results in a life-long body size reduction compared to control animals, but has only transient effects on physical and behavioural development of the pups. The data support a critical role for alpha-casein in casein micelle assembly. The results also confirm lactation as a critical window of metabolic programming and suggest milk protein concentration as a decisive factor in determining adult body weight. PMID- 21789180 TI - Spatio-temporal dependence of the signaling response in immune-receptor trafficking networks regulated by cell density: a theoretical model. AB - Cell signaling processes involve receptor trafficking through highly connected networks of interacting components. The binding of surface receptors to their specific ligands is a key factor for the control and triggering of signaling pathways. In most experimental systems, ligand concentration and cell density vary within a wide range of values. Dependence of the signal response on cell density is related with the extracellular volume available per cell. This dependence has previously been studied using non-spatial models which assume that signaling components are well mixed and uniformly distributed in a single compartment. In this paper, a mathematical model that shows the influence exerted by cell density on the spatio-temporal evolution of ligands, cell surface receptors, and intracellular signaling molecules is developed. To this end, partial differential equations were used to model ligand and receptor trafficking dynamics through the different domains of the whole system. This enabled us to analyze several interesting features involved with these systems, namely: a) how the perturbation caused by the signaling response propagates through the system; b) receptor internalization dynamics and how cell density affects the robustness of dose-response curves upon variation of the binding affinity; and c) that enhanced correlations between ligand input and system response are obtained under conditions that result in larger perturbations of the equilibrium ligand + surface receptor [Please see text] ligand - receptor complex. Finally, the results are compared with those obtained by considering that the above components are well mixed in a single compartment. PMID- 21789181 TI - IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. AB - Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22 deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease. PMID- 21789182 TI - REVIGO summarizes and visualizes long lists of gene ontology terms. AB - Outcomes of high-throughput biological experiments are typically interpreted by statistical testing for enriched gene functional categories defined by the Gene Ontology (GO). The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret.REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/. PMID- 21789183 TI - Catalytic and non-catalytic roles for the mono-ADP-ribosyltransferase Arr in the mycobacterial DNA damage response. AB - Recent evidence indicates that the mycobacterial response to DNA double strand breaks (DSBs) differs substantially from previously characterized bacteria. These differences include the use of three DSB repair pathways (HR, NHEJ, SSA), and the CarD pathway, which integrates DNA damage with transcription. Here we identify a role for the mono-ADP-ribosyltransferase Arr in the mycobacterial DNA damage response. Arr is transcriptionally induced following DNA damage and cellular stress. Although Arr is not required for induction of a core set of DNA repair genes, Arr is necessary for suppression of a set of ribosomal protein genes and rRNA during DNA damage, placing Arr in a similar pathway as CarD. Surprisingly, the catalytic activity of Arr is not required for this function, as catalytically inactive Arr was still able to suppress ribosomal protein and rRNA expression during DNA damage. In contrast, Arr substrate binding and catalytic activities were required for regulation of a small subset of other DNA damage responsive genes, indicating that Arr has both catalytic and noncatalytic roles in the DNA damage response. Our findings establish an endogenous cellular function for a mono-ADP-ribosyltransferase apart from its role in mediating Rifampin resistance. PMID- 21789184 TI - A novel inactivated intranasal respiratory syncytial virus vaccine promotes viral clearance without Th2 associated vaccine-enhanced disease. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations. PRINCIPAL FINDINGS: In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsion-adjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSV-specific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines. CONCLUSIONS: These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology. PMID- 21789185 TI - Innate immune responses to bacterial ligands in the peripheral human lung--role of alveolar epithelial TLR expression and signalling. AB - It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFalpha, IL-8 and MCP 1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens. PMID- 21789186 TI - Biphasic oxidation of oxy-hemoglobin in bloodstains. AB - BACKGROUND: In forensic science, age determination of bloodstains can be crucial in reconstructing crimes. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO(2)) to met-hemoglobin (met-Hb) and hemichrome (HC). The fractions of HbO(2), met-Hb and HC in a bloodstain can be used for age determination of bloodstains. In this study, we further analyze the conversion of HbO(2) to met-Hb and HC, and determine the effect of temperature and humidity on the conversion rates. METHODOLOGY: The fractions of HbO(2), met-Hb and HC in a bloodstain, as determined by quantitative analysis of optical reflectance spectra (450-800 nm), were measured as function of age, temperature and humidity. Additionally, Optical Coherence Tomography around 1300 nm was used to confirm quantitative spectral analysis approach. CONCLUSIONS: The oxidation rate of HbO(2) in bloodstains is biphasic. At first, the oxidation of HbO(2) is rapid, but slows down after a few hours. These oxidation rates are strongly temperature dependent. However, the oxidation of HbO(2) seems to be independent of humidity, whereas the transition of met-Hb into HC strongly depends on humidity. Knowledge of these decay rates is indispensable for translating laboratory results into forensic practice, and to enable bloodstain age determination on the crime scene. PMID- 21789187 TI - SNOSite: exploiting maximal dependence decomposition to identify cysteine S nitrosylation with substrate site specificity. AB - S-nitrosylation, the covalent attachment of a nitric oxide to (NO) the sulfur atom of cysteine, is a selective and reversible protein post-translational modification (PTM) that regulates protein activity, localization, and stability. Despite its implication in the regulation of protein functions and cell signaling, the substrate specificity of cysteine S-nitrosylation remains unknown. Based on a total of 586 experimentally identified S-nitrosylation sites from SNAP/L-cysteine-stimulated mouse endothelial cells, this work presents an informatics investigation on S-nitrosylation sites including structural factors such as the flanking amino acids composition, the accessible surface area (ASA) and physicochemical properties, i.e. positive charge and side chain interaction parameter. Due to the difficulty to obtain the conserved motifs by conventional motif analysis, maximal dependence decomposition (MDD) has been applied to obtain statistically significant conserved motifs. Support vector machine (SVM) is applied to generate predictive model for each MDD-clustered motif. According to five-fold cross-validation, the MDD-clustered SVMs could achieve an accuracy of 0.902, and provides a promising performance in an independent test set. The effectiveness of the model was demonstrated on the correct identification of previously reported S-nitrosylation sites of Bos taurus dimethylarginine dimethylaminohydrolase 1 (DDAH1) and human hemoglobin subunit beta (HBB). Finally, the MDD-clustered model was adopted to construct an effective web-based tool, named SNOSite (http://csb.cse.yzu.edu.tw/SNOSite/), for identifying S nitrosylation sites on the uncharacterized protein sequences. PMID- 21789188 TI - Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. AB - BACKGROUND: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. METHODS AND RESULTS: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. CONCLUSIONS: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions. PMID- 21789189 TI - Dysregulated DeltaNp63alpha inhibits expression of Ink4a/arf, blocks senescence, and promotes malignant conversion of keratinocytes. AB - p63 is critical for squamous epithelial development, and elevated levels of the DeltaNp63alpha isoform are seen in squamous cell cancers of various organ sites. However, significant controversy exists regarding the role of p63 isoforms as oncoproteins or tumor suppressors. Here, lentiviruses were developed to drive long-term overexpression of DeltaNp63alpha in primary keratinocytes. Elevated levels of DeltaNp63alpha in vitro promote long-term survival and block both replicative and oncogene-induced senescence in primary keratinocytes, as evidenced by the expression of SA-beta-gal and the presence of nuclear foci of heterochromatin protein 1gamma. The contribution of DeltaNp63alpha to cancer development was assessed using an in vivo grafting model of experimental skin tumorigenesis that allows distinction between benign and malignant tumors. Grafted lenti-DeltaNp63alpha keratinocytes do not form tumors, whereas lenti GFP/v-ras(Ha) keratinocytes develop well-differentiated papillomas. Lenti DeltaNp63alpha/v-ras(Ha) keratinocytes form undifferentiated carcinomas. The average volume of lenti-DeltaNp63alpha/v-ras(Ha) tumors was significantly higher than those in the lenti-GFP/v-ras(Ha) group, consistent with increased BrdU incorporation detected by immunohistochemistry. The block in oncogene-induced senescence corresponds to sustained levels of E2F1 and phosphorylated AKT, and is associated with loss of induction of p16(ink4a)/p19(arf). The relevance of p16(ink4a)/p19(arf) loss was demonstrated in grafting studies of p19(arf)-null keratinocytes, which develop malignant carcinomas in the presence of v-ras(Ha) similar to those arising in wildtype keratinocytes that express lenti DeltaNp63alpha and v-ras(Ha). Our findings establish that DeltaNp63alpha has oncogenic activity and its overexpression in human squamous cell carcinomas contributes to the malignant phenotype, and implicate its ability to regulate p16(ink4a)/p19(arf) in the process. PMID- 21789190 TI - Interleukin-11 drives early lung inflammation during Mycobacterium tuberculosis infection in genetically susceptible mice. AB - IL-11 is multifunctional cytokine whose physiological role in the lungs during pulmonary tuberculosis (TB) is poorly understood. Here, using in vivo administration of specific antibodies against IL-11, we demonstrate for the first time that blocking IL-11 diminishes histopathology and neutrophilic infiltration of the lung tissue in TB-infected genetically susceptible mice. Antibody treatment decreased the pulmonary levels of IL-11 and other key inflammatory cytokines not belonging to the Th1 axis, and down-regulated IL-11 mRNA expression. This suggests the existence of a positive feedback loop at the transcriptional level, which is further supported by up-regulation of IL-11 mRNA expression in the presence of rIL-11 in in vitro cultures of lung cells. These findings imply a pathogenic role for IL-11 during the early phase of Mycobacterium tuberculosis-triggered disease in a genetically susceptible host. PMID- 21789191 TI - Interaction between the triglyceride lipase ATGL and the Arf1 activator GBF1. AB - The Arf1 exchange factor GBF1 (Golgi Brefeldin A resistance factor 1) and its effector COPI are required for delivery of ATGL (adipose triglyceride lipase) to lipid droplets (LDs). Using yeast two hybrid, co-immunoprecipitation in mammalian cells and direct protein binding approaches, we report here that GBF1 and ATGL interact directly and in cells, through multiple contact sites on each protein. The C-terminal region of ATGL interacts with N-terminal domains of GBF1, including the catalytic Sec7 domain, but not with full-length GBF1 or its entire N-terminus. The N-terminal lipase domain of ATGL (called the patatin domain) interacts with two C-terminal domains of GBF1, HDS (Homology downstream of Sec7) 1 and HDS2. These two domains of GBF1 localize to lipid droplets when expressed alone in cells, but not to the Golgi, unlike the full-length GBF1 protein, which localizes to both. We suggest that interaction of GBF1 with ATGL may be involved in the membrane trafficking pathway mediated by GBF1, Arf1 and COPI that contributes to the localization of ATGL to lipid droplets. PMID- 21789192 TI - Using an uncertainty-coding matrix in Bayesian regression models for haplotype specific risk detection in family association studies. AB - Haplotype association studies based on family genotype data can provide more biological information than single marker association studies. Difficulties arise, however, in the inference of haplotype phase determination and in haplotype transmission/non-transmission status. Incorporation of the uncertainty associated with haplotype inference into regression models requires special care. This task can get even more complicated when the genetic region contains a large number of haplotypes. To avoid the curse of dimensionality, we employ a clustering algorithm based on the evolutionary relationship among haplotypes and retain for regression analysis only the ancestral core haplotypes identified by it. To integrate the three sources of variation, phase ambiguity, transmission status and ancestral uncertainty, we propose an uncertainty-coding matrix which combines these three types of variability simultaneously. Next we evaluate haplotype risk with the use of such a matrix in a Bayesian conditional logistic regression model. Simulation studies and one application, a schizophrenia multiplex family study, are presented and the results are compared with those from other family based analysis tools such as FBAT. Our proposed method (Bayesian regression using uncertainty-coding matrix, BRUCM) is shown to perform better and the implementation in R is freely available. PMID- 21789193 TI - Role of plant-specific N-terminal domain of maize CK2beta1 subunit in CK2beta functions and holoenzyme regulation. AB - Protein kinase CK2 is a highly pleiotropic Ser/Thr kinase ubiquituous in eukaryotic organisms. CK2 is organized as a heterotetrameric enzyme composed of two types of subunits: the catalytic (CK2alpha) and the regulatory (CK2beta). The CK2beta subunits enhance the stability, activity and specificity of the holoenzyme, but they can also perform functions independently of the CK2 tetramer. CK2beta regulatory subunits in plants differ from their animal or yeast counterparts, since they present an additional specific N-terminal extension of about 90 aminoacids that shares no homology with any previously characterized functional domain. Sequence analysis of the N-terminal domain of land plant CK2beta subunit sequences reveals its arrangement through short, conserved motifs, some of them including CK2 autophosphorylation sites. By using maize CK2beta1 and a deleted version (DeltaNCK2beta1) lacking the N-terminal domain, we have demonstrated that CK2beta1 is autophosphorylated within the N-terminal domain. Moreover, the holoenzyme composed with CK2alpha1/DeltaNCK2beta1 is able to phosphorylate different substrates more efficiently than CK2alpha1/CK2beta1 or CK2alpha alone. Transient overexpression of CK2beta1 and DeltaNCK2beta1 fused to GFP in different plant systems show that the presence of N-terminal domain enhances aggregation in nuclear speckles and stabilizes the protein against proteasome degradation. Finally, bimolecular fluorescence complementation (BiFC) assays show the nuclear and cytoplasmic location of the plant CK2 holoenzyme, in contrast to the individual CK2alpha/beta subunits mainly observed in the nucleus. All together, our results support the hypothesis that the plant-specific N terminal domain of CK2beta subunits is involved in the down-regulation of the CK2 holoenzyme activity and in the stabilization of CK2beta1 protein. In summary, the whole amount of data shown in this work suggests that this domain was acquired by plants for regulatory purposes. PMID- 21789194 TI - Exploiting mitochondrial dysfunction for effective elimination of imatinib resistant leukemic cells. AB - Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1alpha, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention. PMID- 21789195 TI - alpha-SNAP prevents docking of the acrosome during sperm exocytosis because it sequesters monomeric syntaxin. AB - alpha-SNAP has an essential role in membrane fusion that consists of bridging cis SNARE complexes to NSF. alpha-SNAP stimulates NSF, which releases itself, alpha SNAP, and individual SNAREs that subsequently re-engage in the trans arrays indispensable for fusion. alpha-SNAP also binds monomeric syntaxin and NSF disengages the alpha-SNAP/syntaxin dimer. Here, we examine why recombinant alpha SNAP blocks secretion in permeabilized human sperm despite the fact that the endogenous protein is essential for membrane fusion. The only mammalian organism with a genetically modified alpha-SNAP is the hyh mouse strain, which bears a M105I point mutation; males are subfertile due to defective sperm exocytosis. We report here that recombinant alpha-SNAP-M105I has greater affinity for the cytosolic portion of immunoprecipitated syntaxin than the wild type protein and in consequence NSF is less efficient in releasing the mutant. alpha-SNAP-M105I is a more potent sperm exocytosis blocker than the wild type and requires higher concentrations of NSF to rescue its effect. Unlike other fusion scenarios where SNAREs are subjected to an assembly/disassembly cycle, the fusion machinery in sperm is tuned so that SNAREs progress uni-directionally from a cis configuration in resting cells to monomeric and subsequently trans arrays in cells challenged with exocytosis inducers. By means of functional and indirect immunofluorescense assays, we show that recombinant alpha-SNAPs--wild type and M105I--inhibit exocytosis because they bind monomeric syntaxin and prevent this SNARE from assembling with its cognates in trans. Sequestration of free syntaxin impedes docking of the acrosome to the plasma membrane assessed by transmission electron microscopy. The N-terminal deletion mutant alpha-SNAP-(160-295), unable to bind syntaxin, affects neither docking nor secretion. The implications of this study are twofold: our findings explain the fertility defect of hyh mice and indicate that assembly of SNAREs in trans complexes is essential for docking. PMID- 21789197 TI - Cellular tropism, population dynamics, host range and taxonomic status of an aphid secondary symbiont, SMLS (Sitobion miscanthi L type symbiont). AB - SMLS (Sitobion miscanthi L type symbiont) is a newly reported aphid secondary symbiont. Phylogenetic evidence from molecular markers indicates that SMLS belongs to the Rickettsiaceae and has a sibling relationship with Orientia tsutsugamushi. A comparative analysis of coxA nucleotide sequences further supports recognition of SMLS as a new genus in the Rickettsiaceae. In situ hybridization reveals that SMLS is housed in both sheath cells and secondary bacteriocytes and it is also detected in aphid hemolymph. The population dynamics of SMLS differ from those of Buchnera aphidicola and titer levels of SMLS increase in older aphids. A survey of 13 other aphids reveals that SMLS only occurs in wheat-associated species. PMID- 21789196 TI - Cold-adapted influenza and recombinant adenovirus vaccines induce cross protective immunity against pH1N1 challenge in mice. AB - BACKGROUND: The rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1) highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain matched vaccines became available. Here we test two prototype vaccines for cross protection against the recent pandemic virus. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c and C57BL/6 mice were intranasally immunized with a single dose of cold adapted (ca) influenza viruses from 1977 or recombinant adenoviruses (rAd) expressing 1934 nucleoprotein (NP) and consensus matrix 2 (M2) (NP+M2-rAd). Antibodies against the M2 ectodomain (M2e) were seen in NP+M2-rAd immunized BALB/c but not C57BL/6 mice, and cross-reacted with pH1N1 M2e. The ca-immunized mice did not develop antibodies against M2e. Despite sequence differences between vaccine and challenge virus NP and M2e epitopes, extensive cross-reactivity of lung T cells with pH1N1 peptides was detected following immunization. Both ca and NP+M2-rAd immunization protected BALB/c and C57BL/6 mice against challenge with a mouse-adapted pH1N1 virus. CONCLUSION/SIGNIFICANCE: Cross-protective vaccines such as NP+M2-rAd and ca virus are effective against pH1N1 challenge within 3 weeks of immunization. Protection was not dependent on recognition of the highly variable external viral proteins and could be achieved with a single vaccine dose. The rAd vaccine was superior to the ca vaccine by certain measures, justifying continued investigation of this experimental vaccine even though ca vaccine is already available. This study highlights the potential for cross protective vaccines as a public health option early in an influenza pandemic. PMID- 21789198 TI - Functional modifications of acid-sensing ion channels by ligand-gated chloride channels. AB - Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABA(A) receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABA(A) receptor-mediated currents. Moreover, activation of the GABA(A) receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABA(A) receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABA(A) receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABA(A) receptors, also modified ASICs in spinal neurons. We conclude that GABA(A) receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels. PMID- 21789199 TI - A novel manganese efflux system, YebN, is required for virulence by Xanthomonas oryzae pv. oryzae. AB - Manganese ions (Mn(2+)) play a crucial role in virulence and protection against oxidative stress in bacterial pathogens. Such pathogens appear to have evolved complex mechanisms for regulating Mn(2+) uptake and efflux. Despite numerous studies on Mn(2+) uptake, however, only one efflux system has been identified to date. Here, we report on a novel Mn(2+) export system, YebN, in Xanthomonas oryzae pv. oryzae (Xoo), the causative agent of bacterial leaf blight. Compared with wild-type PXO99, the yebN mutant was highly sensitive to Mn(2+) and accumulated high concentrations of intracellular manganese. In addition, we found that expression of yebN was positively regulated by Mn(2+) and the Mn(2+) dependent transcription regulator, MntR. Interestingly, the yebN mutant was more tolerant to methyl viologen and H(2)O(2) in low Mn(2+) medium than PXO99, but more sensitive in high Mn(2+) medium, implying that YebN plays an important role in Mn(2+) homoeostasis and detoxification of reactive oxygen species (ROS). Notably, deletion of yebN rendered Xoo sensitive to hypo-osmotic shock, suggesting that YebN may protect against such stress. That mutation of yebN substantially reduced the Xoo growth rate and lesion formation in rice implies that YebN could be involved in Xoo fitness in host. Although YebN has two DUF204 domains, it lacks homology to any known metal transporter. Hence, this is the first report of a novel metal export system that plays essential roles in hypo osmotic and oxidative stress, and virulence. Our results lay the foundations for elucidating the complex and fascinating relationship between metal homeostasis and host-pathogen interactions. PMID- 21789200 TI - Acinetobacter baumannii infection inhibits airway eosinophilia and lung pathology in a mouse model of allergic asthma. AB - Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-gamma were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen. PMID- 21789201 TI - Interoperability between biomedical ontologies through relation expansion, upper level ontologies and automatic reasoning. AB - Researchers design ontologies as a means to accurately annotate and integrate experimental data across heterogeneous and disparate data- and knowledge bases. Formal ontologies make the semantics of terms and relations explicit such that automated reasoning can be used to verify the consistency of knowledge. However, many biomedical ontologies do not sufficiently formalize the semantics of their relations and are therefore limited with respect to automated reasoning for large scale data integration and knowledge discovery. We describe a method to improve automated reasoning over biomedical ontologies and identify several thousand contradictory class definitions. Our approach aligns terms in biomedical ontologies with foundational classes in a top-level ontology and formalizes composite relations as class expressions. We describe the semi-automated repair of contradictions and demonstrate expressive queries over interoperable ontologies. Our work forms an important cornerstone for data integration, automatic inference and knowledge discovery based on formal representations of knowledge. Our results and analysis software are available at http://bioonto.de/pmwiki.php/Main/ReasonableOntologies. PMID- 21789202 TI - Generation of germline-competent rat induced pluripotent stem cells. AB - BACKGROUND: Recent progress in rat pluripotent stem cell technology has been remarkable. Particularly salient is the demonstration that embryonic stem cells (ESCs) in the rat (rESCs) can contribute to germline transmission, permitting generation of gene-modified rats as is now done using mouse ESCs (mESCs) or mouse induced pluripotent stem cells (iPSCs; miPSCs). However, determinations of whether rat iPSCs (riPSCs) can contribute to germ cells are not published. Here we report the germline competency of riPSCs. METHODOLOGY/PRINCIPAL FINDINGS: We generated riPSCs by transducing three mouse reprogramming factors (Oct3/4, Klf4, and Sox2) into rat somatic cells, followed by culture in the presence of exogenous rat leukemia inhibitory factor (rLIF) and small molecules that specifically inhibit GSK3, MEK, and FGF receptor tyrosine kinases. We found that, like rESCs, our riPSCs can contribute to germline transmission. Furthermore we found, by immunostaining of testis from mouse-rat interspecific chimeras with antibody against mouse vasa homolog, that riPSCs can contribute to embryonic development with chimera formation in mice (rat-mouse interspecific chimeras) and to interspecific germlines. CONCLUSIONS/SIGNIFICANCE: Our data clearly demonstrate that using only three reprogramming factors (Oct3/4, Klf4, and Sox2) rat somatic cells can be reprogrammed into a ground state. Our generated riPSCs exhibited germline transmission in either rat-rat intraspecific or mouse-rat interspecific chimeras. PMID- 21789203 TI - Cytochrome c-554 from Methylosinus trichosporium OB3b; a protein that belongs to the cytochrome c2 family and exhibits a HALS-Type EPR signal. AB - A small soluble cytochrome c-554 purified from Methylosinus trichosporium OB3b has been purified and analyzed by amino acid sequencing, mass spectrometry, visible, CD and EPR spectroscopies. It is found to be a mono heme protein with a characteristic cytochrome c fold, thus fitting into the class of cytochrome c(2), which is the bacterial homologue of mitochondrial cytochrome c. The heme iron has a Histidine/Methionine axial ligation and exhibits a highly anisotropic/axial low spin (HALS) EPR signal, with a g(max) at 3.40, and ligand field parameters V/xi = 0.99, Delta/xi = 4.57. This gives the rhombicity V/Delta = 0.22. The structural basis for this HALS EPR signal in Histidine/Methionine ligated hemes is not resolved. The ligand field parameters observed for cytochrome c-554 fits the observed pattern for other cytochromes with similar ligation and EPR behaviour. PMID- 21789204 TI - Sea urchins predation facilitates coral invasion in a marine reserve. AB - Macroalgae is the dominant trophic group on Mediterranean infralittoral rocky bottoms, whereas zooxanthellate corals are extremely rare. However, in recent years, the invasive coral Oculina patagonica appears to be increasing its abundance through unknown means. Here we examine the pattern of variation of this species at a marine reserve between 2002 and 2010 and contribute to the understanding of the mechanisms that allow its current increase. Because indirect interactions between species can play a relevant role in the establishment of species, a parallel assessment of the sea urchin Paracentrotus lividus, the main herbivorous invertebrate in this habitat and thus a key species, was conducted. O. patagonica has shown a 3-fold increase in abundance over the last 8 years and has become the most abundant invertebrate in the shallow waters of the marine reserve, matching some dominant erect macroalgae in abundance. High recruitment played an important role in this increasing coral abundance. The results from this study provide compelling evidence that the increase in sea urchin abundance may be one of the main drivers of the observed increase in coral abundance. Sea urchins overgraze macroalgae and create barren patches in the space-limited macroalgal community that subsequently facilitate coral recruitment. This study indicates that trophic interactions contributed to the success of an invasive coral in the Mediterranean because sea urchins grazing activity indirectly facilitated expansion of the coral. Current coral abundance at the marine reserve has ended the monopolization of algae in rocky infralittoral assemblages, an event that could greatly modify both the underwater seascape and the sources of primary production in the ecosystem. PMID- 21789205 TI - Origin and evolution of TRIM proteins: new insights from the complete TRIM repertoire of zebrafish and pufferfish. AB - Tripartite motif proteins (TRIM) constitute a large family of proteins containing a RING-Bbox-Coiled Coil motif followed by different C-terminal domains. Involved in ubiquitination, TRIM proteins participate in many cellular processes including antiviral immunity. The TRIM family is ancient and has been greatly diversified in vertebrates and especially in fish. We analyzed the complete sets of trim genes of the large zebrafish genome and of the compact pufferfish genome. Both contain three large multigene subsets--adding the hsl5/trim35-like genes (hltr) to the ftr and the btr that we previously described--all containing a B30.2 domain that evolved under positive selection. These subsets are conserved among teleosts. By contrast, most human trim genes of the other classes have only one or two orthologues in fish. Loss or gain of C-terminal exons generated proteins with different domain organizations; either by the deletion of the ancestral domain or, remarkably, by the acquisition of a new C-terminal domain. Our survey of fish trim genes in fish identifies subsets with different evolutionary dynamics. trims encoding RBCC-B30.2 proteins show the same evolutionary trends in fish and tetrapods: they evolve fast, often under positive selection, and they duplicate to create multigenic families. We could identify new combinations of domains, which epitomize how new trim classes appear by domain insertion or exon shuffling. Notably, we found that a cyclophilin-A domain replaces the B30.2 domain of a zebrafish fintrim gene, as reported in the macaque and owl monkey antiretroviral TRIM5alpha. Finally, trim genes encoding RBCC-B30.2 proteins are preferentially located in the vicinity of MHC or MHC gene paralogues, which suggests that such trim genes may have been part of the ancestral MHC. PMID- 21789206 TI - A validated model of serum anti-mullerian hormone from conception to menopause. AB - BACKGROUND: Anti-Mullerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. METHODOLOGY/PRINCIPAL FINDINGS: By searching the published literature for AMH concentrations in healthy pre menopausal females, and using our own data (combined n = 3,260) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre pubertal peak. Our model allows us to generate normative data at all ages. CONCLUSIONS/SIGNIFICANCE: These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman. PMID- 21789207 TI - Egg production in a coastal seabird, the glaucous-winged gull (Larus glaucescens), declines during the last century. AB - Seabirds integrate information about oceanic ecosystems across time and space, and are considered sensitive indicators of marine conditions. To assess whether hypothesized long-term foodweb changes such as forage fish declines may be reflected in a consumer's life history traits over time, I used meta-regression to evaluate multi-decadal changes in aspects of egg production in the glaucous winged gull (Larus glaucescens), a common coastal bird. Study data were derived from literature searches of published papers and unpublished historical accounts, museum egg collections, and modern field studies, with inclusion criteria based on data quality and geographic area of the original study. Combined historical and modern data showed that gull egg size declined at an average of 0.04 cc y(-1) from 1902 (108 y), equivalent to a decline of 5% of mean egg volume, while clutch size decreased over 48 y from a mean of 2.82 eggs per clutch in 1962 to 2.25 in 2009. There was a negative relationship between lay date and mean clutch size in a given year, with smaller clutches occurring in years where egg laying commenced later. Lay date itself advanced over time, with commencement of laying presently (2008-2010) 7 d later than in previous studies (1959-1986). This study demonstrates that glaucous-winged gull investment in egg production has declined significantly over the past ~50-100 y, with such changes potentially contributing to recent population declines. Though gulls are generalist feeders that should readily be able to buffer themselves against food web changes, they are likely nutritionally constrained during the early breeding period, when egg production requirements are ideally met by consumption of high-quality prey such as forage fish. This study's results suggest a possible decline in the availability of such prey, and the incremental long-term impoverishment of a coastal marine ecosystem bordering one of North America's rapidly growing urban areas. PMID- 21789208 TI - Copy number variation in CNP267 region may be associated with hip bone size. AB - Osteoporotic hip fracture (HF) is a serious global public health problem associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of key measurable risk factors for HF, independent of bone mineral density (BMD). Hip BS is highly genetically determined, but genetic factors underlying BS variation are still poorly defined. Here, we performed an initial genome-wide copy number variation (CNV) association analysis for hip BS in 1,627 Chinese Han subjects using Affymetrix GeneChip Human Mapping SNP 6.0 Array and a follow-up replicate study in 2,286 unrelated US Caucasians sample. We found that a copy number polymorphism (CNP267) located at chromosome 2q12.2 was significantly associated with hip BS in both initial Chinese and replicate Caucasian samples with p values of 4.73E-03 and 5.66E-03, respectively. An important candidate gene, four and a half LIM domains 2 (FHL2), was detected at the downstream of CNP267, which plays important roles in bone metabolism by binding to several bone formation regulator, such as insulin-like growth factor binding protein 5 (IGFBP-5) and androgen receptor (AR). Our findings suggest that CNP267 region may be associated with hip BS which might influence the FHL2 gene downstream. PMID- 21789209 TI - Characterization of cortical neuronal and glial alterations during culture of organotypic whole brain slices from neonatal and mature mice. AB - BACKGROUND: Organotypic brain slice culturing techniques are extensively used in a wide range of experimental procedures and are particularly useful in providing mechanistic insights into neurological disorders or injury. The cellular and morphological alterations associated with hippocampal brain slice cultures has been well established, however, the neuronal response of mouse cortical neurons to culture is not well documented. METHODS: In the current study, we compared the cell viability, as well as phenotypic and protein expression changes in cortical neurons, in whole brain slice cultures from mouse neonates (P4-6), adolescent animals (P25-28) and mature adults (P50+). Cultures were prepared using the membrane interface method. RESULTS: Propidium iodide labeling of nuclei (due to compromised cell membrane) and AlamarBlueTM (cell respiration) analysis demonstrated that neonatal tissue was significantly less vulnerable to long-term culture in comparison to the more mature brain tissues. Cultures from P6 animals showed a significant increase in the expression of synaptic markers and a decrease in growth-associated proteins over the entire culture period. However, morphological analysis of organotypic brain slices cultured from neonatal tissue demonstrated that there were substantial changes to neuronal and glial organization within the neocortex, with a distinct loss of cytoarchitectural stratification and increased GFAP expression (p<0.05). Additionally, cultures from neonatal tissue had no glial limitans and, after 14 DIV, displayed substantial cellular protrusions from slice edges, including cells that expressed both glial and neuronal markers. CONCLUSION: In summary, we present a substantial evaluation of the viability and morphological changes that occur in the neocortex of whole brain tissue cultures, from different ages, over an extended period of culture. PMID- 21789210 TI - Factors associated with high prevalence of intestinal protozoan infections among patients in Sana'a City, Yemen. AB - BACKGROUND: Intestinal protozoan diseases in Yemen are a significant health problem with prevalence ranging from 18% to 27%. The present study is a cross sectional study aimed at determining the factors associated with the high prevalence of intestinal protozoan infections among patients seeking health care in Sana'a City, the capital of Yemen. METHODOLOGY/PRINCIPAL FINDINGS: Stool samples were collected from 503 patients aged between 1 and 80 years old; 219 were males and 284 females. Biodata were collected via pretested standard questionnaire. Faecal samples were processed and examined for (oo)cysts or ova using a wet mount preparation after formal-ether concentration technique. Cryptosporidium oocysts were detected using the Ziehl-Neelsen staining technique. The overall prevalence of intestinal protozoan infections was 30.9%. Infection rates of Giardia duodenalis, Entamoeba histolytica/dispar and Cryptosporidium were 17.7%, 17.1% and 1%, respectively. Other parasites detected included Ascaris lumbricoides (2.4%), Schistosoma mansoni (0.3%), Hymenolepis nana (1.4%) and Enterobius vermicularis (0.4%). Multivariate analysis using forward stepwise logistic regression based on intestinal protozoan infections showed that contact with animals (OR = 1.748, 95% CI = 1.168-2.617) and taking bath less than twice a week (OR = 1.820, 95% CI = 1.192-2.779) were significant risk factors of protozoan infections. CONCLUSIONS/SIGNIFICANCE: This present study indicated that intestinal protozoan infections are still a public health problem in Yemen, with Giardia and Entamoeba infections being most common. Statistical analysis indicated that low personal hygiene and contact with animals were important predictors for intestinal protozoan infections. As highlighted in this study, in order to effectively reduce these infections, a multi-sectoral effort is needed. Preventive measures should include good hygienic practices, good animal husbandry practices, heightened provision of educational health programs, health services in all governorates including rural areas. Furthermore, it is also essential to find radical solutions to the recent water crises in Yemen. PMID- 21789211 TI - Activation of protein kinase C delta following cerebral ischemia leads to release of cytochrome C from the mitochondria via bad pathway. AB - BACKGROUND: The release of cytochrome c from the mitochondria following cerebral ischemia is a key event leading to cell death. The goal of the present study was to determine the mechanisms involved in post-ischemic activation of protein kinase c delta (deltaPKC) that lead to cytochrome c release. METHODS/FINDINGS: We used a rat model of cardiac arrest as an in vivo model, and an in vitro analog, oxygen glucose deprivation (OGD) in rat hippocampal synaptosomes. Cardiac arrest triggered translocation of deltaPKC to the mitochondrial fraction at 1 h reperfusion. In synaptosomes, the peptide inhibitor of deltaPKC blocked OGD induced translocation to the mitochondria. We tested two potential pathways by which deltaPKC activation could lead to cytochrome c release: phosphorylation of phospholipid scramblase-3 (PLSCR3) and/or protein phosphatase 2A (PP2A). Cardiac arrest increased levels of phosphorlyated PLSCR3; however, inhibition of deltaPKC translocation failed to affect the OGD-induced increase in PLSCR3 in synaptosomal mitochondria suggesting the post-ischemic phosphorylation of PLSCR3 is not mediated by deltaPKC. Inhibition of either deltaPKC or PP2A decreased cytochrome c release from synaptosomal mitochondria. Cardiac arrest results in the dephosphorylation of Bad and Bax, both downstream targets of PP2A promoting apoptosis. Inhibition of deltaPKC or PP2A prevented OGD-induced Bad, but not Bax, dephosphorylation. To complement these studies, we used proteomics to identify novel mitochondrial substrates of deltaPKC. CONCLUSIONS: We conclude that deltaPKC initiates cytochrome c release via phosphorylation of PP2A and subsequent dephosphorylation of Bad and identified deltaPKC, PP2A and additional mitochondrial proteins as potential therapeutic targets for ischemic neuroprotection. PMID- 21789212 TI - Environmental enrichment preceding early adulthood methylphenidate treatment leads to long term increase of corticosterone and testosterone in the rat. AB - Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30-60] rats were reared in EE and were treated with MPH during early adulthood (PND 60-90). Adult (PND 90-92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences. PMID- 21789213 TI - The use of genome-wide eQTL associations in lymphoblastoid cell lines to identify novel genetic pathways involved in complex traits. AB - The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P<0.01) but none significantly replicated in five large consortia of 1,097 16,129 subjects. We also failed to replicate previous reported eQTL associations with body mass index, plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels derived from lymphocytes, adipose and liver tissue. Our results and additional power calculations suggest that proponents may have been overoptimistic in the power of LCLs in eQTL approaches to elucidate regulatory genetic effects on complex traits using the small datasets generated to date. Nevertheless, larger tissue-specific expression data sets relevant to specific traits are becoming available, and should enable the adoption of similar integrated analyses in the near future. PMID- 21789214 TI - Circadian-related sleep disorders and sleep medication use in the New Zealand blind population: an observational prevalence survey. AB - STUDY OBJECTIVES: To determine the prevalence of self-reported circadian-related sleep disorders, sleep medication and melatonin use in the New Zealand blind population. DESIGN: A telephone survey incorporating 62 questions on sleep habits and medication together with validated questionnaires on sleep quality, chronotype and seasonality. PARTICIPANTS: PARTICIPANTS WERE GROUPED INTO: (i) 157 with reduced conscious perception of light (RLP); (ii) 156 visually impaired with no reduction in light perception (LP) matched for age, sex and socioeconomic status, and (iii) 156 matched fully-sighted controls (FS). SLEEP HABITS AND DISTURBANCES: The incidence of sleep disorders, daytime somnolence, insomnia and sleep timing problems was significantly higher in RLP and LP compared to the FS controls (p<0.001). The RLP group had the highest incidence (55%) of sleep timing problems, and 26% showed drifting sleep patterns (vs. 4% FS). Odds ratios for unconventional sleep timing were 2.41 (RLP) and 1.63 (LP) compared to FS controls. For drifting sleep patterns, they were 7.3 (RLP) and 6.0 (LP). MEDICATION USE: Zopiclone was the most frequently prescribed sleep medication. Melatonin was used by only 4% in the RLP group and 2% in the LP group. CONCLUSIONS: Extrapolations from the current study suggest that 3,000 blind and visually impaired New Zealanders may suffer from circadian-related sleep problems, and that of these, fewer than 15% have been prescribed melatonin. This may represent a therapeutic gap in the treatment of circadian-related sleep disorders in New Zealand, findings that may generalize to other countries. PMID- 21789215 TI - Modeling filamentous cyanobacteria reveals the advantages of long and fast trichomes for optimizing light exposure. AB - Cyanobacteria form a very large and diverse phylum of prokaryotes that perform oxygenic photosynthesis. Many species of cyanobacteria live colonially in long trichomes of hundreds to thousands of cells. Of the filamentous species, many are also motile, gliding along their long axis, and display photomovement, by which a trichome modulates its gliding according to the incident light. The latter has been found to play an important role in guiding the trichomes to optimal lighting conditions, which can either inhibit the cells if the incident light is too weak, or damage the cells if too strong. We have developed a computational model for gliding filamentous photophobic cyanobacteria that allows us to perform simulations on the scale of a Petri dish using over 10(5) individual trichomes. Using the model, we quantify the effectiveness of one commonly observed photomovement strategy--photophobic responses--in distributing large populations of trichomes optimally over a light field. The model predicts that the typical observed length and gliding speeds of filamentous cyanobacteria are optimal for the photophobic strategy. Therefore, our results suggest that not just photomovement but also the trichome shape itself improves the ability of the cyanobacteria to optimize their light exposure. PMID- 21789216 TI - CBP/p300 and SIRT1 are involved in transcriptional regulation of S-phase specific histone genes. AB - BACKGROUND: Histones constitute a type of essential nuclear proteins important for chromatin structure and functions. The expression of major histones is strictly confined to the S phase of a cell cycle and tightly coupled to DNA replication. METHODOLOGY/PRINCIPAL FINDINGS: With RT-qPCR and ChIP assays, we investigated transcriptional regulation of the S-phase specific histone genes and found that the acetylation level of histones on core histone gene promoters fluctuated during cell cycle in a pattern similar to RNA polymerase II association. Further, we showed that CBP/p300 and SIRT1 were recruited to histone gene promoters in an NPAT-dependent manner, knockdown of which affected histone acetylation on histone gene promoters and histone gene transcription. SIGNIFICANCE: These observations contribute to further understanding of the mechanism by which the expression of canonical histone genes is regulated, and also implicate a link between histone expression and DNA damage repair and cell metabolism. PMID- 21789217 TI - Accelerating haplotype-based genome-wide association study using perfect phylogeny and phase-known reference data. AB - The genome-wide association study (GWAS) has become a routine approach for mapping disease risk loci with the advent of large-scale genotyping technologies. Multi-allelic haplotype markers can provide superior power compared with single SNP markers in mapping disease loci. However, the application of haplotype-based analysis to GWAS is usually bottlenecked by prohibitive time cost for haplotype inference, also known as phasing. In this study, we developed an efficient approach to haplotype-based analysis in GWAS. By using a reference panel, our method accelerated the phasing process and reduced the potential bias generated by unrealistic assumptions in phasing process. The haplotype-based approach delivers great power and no type I error inflation for association studies. With only a medium-size reference panel, phasing error in our method is comparable to the genotyping error afforded by commercial genotyping solutions. PMID- 21789218 TI - Monitoring fetal electrocortical activity during labour for predicting worsening acidemia: a prospective study in the ovine fetus near term. AB - BACKGROUND: Severe fetal acidemia during labour with arterial pH below 7.00 is associated with increased risk of hypoxic-ischemic brain injury. Electronic fetal heart rate (FHR) monitoring, the mainstay of intrapartum surveillance, has poor specificity for detecting fetal acidemia. We studied brain electrical activity measured with electrocorticogram (ECOG) in the near term ovine fetus subjected to repetitive umbilical cord occlusions (UCO) inducing FHR decelerations, as might be seen in human labour, to delineate the time-course for ECOG changes with worsening acidemia and thereby assess the potential clinical utility of fetal ECOG. METHODOLOGY/PRINCIPAL FINDINGS: Ten chronically catheterized fetal sheep were studied through a series of mild, moderate and severe UCO until the arterial pH was below 7.00. At a pH of 7.24 +/- 0.04, 52 +/- 13 min prior to the pH dropping <7.00, spectral edge frequency (SEF) increased to 23 +/- 2 Hz from 3 +/- 1 Hz during each FHR deceleration (p<0.001) and was correlated to decreases in FHR and in fetal arterial blood pressure during each FHR deceleration (p<0.001). CONCLUSIONS/SIGNIFICANCE: The UCO-related changes in ECOG occurred in advance of the pH decreasing below 7.00. These ECOG changes may be a protective mechanism suppressing non-essential energy needs when oxygen supply to the fetal brain is decreased acutely. By detecting such "adaptive brain shutdown," the need for delivery in high risk pregnant patients may be more accurately predicted than with FHR monitoring alone. Therefore, monitoring fetal electroencephalogram (EEG, the human equivalent of ECOG) during human labour may be a useful adjunct to FHR monitoring. PMID- 21789219 TI - Effects of genetic variants in ADCY5, GIPR, GCKR and VPS13C on early impairment of glucose and insulin metabolism in children. AB - OBJECTIVE: Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of glucose and insulin metabolism in children. RESEARCH DESIGN AND METHODS: We genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305) in 638 Caucasian children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose and insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices) by linear regression analyses adjusted for age, sex, BMI-SDS and pubertal stage. RESULTS: The major allele (C) of rs2877716 (ADCY5) was nominally associated with decreased fasting plasma insulin (P = 0.008), peak insulin (P = 0.009) and increased QUICKI (P = 0.016) and Matsuda insulin sensitivity index (P = 0.013). rs17271305 (VPS13C) was nominally associated with 2 h blood glucose (P = 0.009), but not with any of the insulin or insulin sensitivity parameters. We found no association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated with anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity. CONCLUSIONS: Our data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin metabolism and VPS13C in early impairment of blood glucose homeostasis. PMID- 21789220 TI - Relationships of risk factors for pre-eclampsia with patterns of occurrence of isolated gestational proteinuria during normal term pregnancy. AB - BACKGROUND: Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept. METHODS: Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy. RESULTS: Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (<= 20 weeks gestation), and onset at 21-28 weeks, 29-32 weeks, 33-36 weeks and >= 37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy. CONCLUSIONS: Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of pre-eclampsia. PMID- 21789221 TI - Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. AB - BACKGROUND: Cdc42 and Rac1, members of the Rho family of small GTPases, play critical roles in actin cytoskeleton regulation. We have shown previously that Rac1 is involved in regulation of platelet secretion and aggregation. However, the role of Cdc42 in platelet activation remains controversial. This study was undertaken to better understand the role of Cdc42 in platelet activation. METHODOLOGY/PRINCIPAL FINDINGS: We utilized the Mx-cre;Cdc42(lox/lox) inducible mice with transient Cdc42 deletion to investigate the involvement of Cdc42 in platelet function. The Cdc42-deficient mice exhibited a significantly reduced platelet count than the matching Cdc42(+/+) mice. Platelets isolated from Cdc42( /-), as compared to Cdc42(+/+), mice exhibited (a) diminished phosphorylation of PAK1/2, an effector molecule of Cdc42, (b) inhibition of filopodia formation on immobilized CRP or fibrinogen, (c) inhibition of CRP- or thrombin-induced secretion of ATP and release of P-selectin, (d) inhibition of CRP, collagen or thrombin induced platelet aggregation, and (e) minimal phosphorylation of Akt upon stimulation with CRP or thrombin. The bleeding times were significantly prolonged in Cdc42(-/-) mice compared with Cdc42(+/+) mice. CONCLUSION/SIGNIFICANCE: Our data demonstrate that Cdc42 is required for platelet filopodia formation, secretion and aggregation and therefore plays a critical role in platelet mediated hemostasis and thrombosis. PMID- 21789222 TI - Claudin-7 is frequently overexpressed in ovarian cancer and promotes invasion. AB - BACKGROUND: Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin 7, as well as its possible functions in EOC. METHODOLOGY/PRINCIPAL FINDINGS: A total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression. In real-time RT-PCR analysis, the gene for claudin-7, CLDN7, was found to be upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Small interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in gene expression as measured by microarrays and validated by RT-PCR and immunoblotting. Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions such as cell cycle, cellular growth and proliferation, cell death, development, and cell movement. Through functional experiments in vitro, we found that both migration and invasion were altered in cells where CLDN7 had been knocked down or overexpressed. Interestingly, claudin-7 expression was associated with a net increase in invasion, but also with a decrease in migration. CONCLUSION/SIGNIFICANCE: Our work shows that claudin-7 is significantly upregulated in EOC and that it may be functionally involved in ovarian carcinoma invasion. CLDN7 may therefore represent potential marker for ovarian cancer detection and a target for therapy. PMID- 21789223 TI - Cathelicidin-BF, a snake cathelicidin-derived antimicrobial peptide, could be an excellent therapeutic agent for acne vulgaris. AB - Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules in innate immunity. Cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and it is the first identified cathelicidin antimicrobial peptide in reptiles. In this study, cathelicidin-BF was found exerting strong antibacterial activities against Propionibacterium acnes. Its minimal inhibitory concentration against two strains of P. acnes was 4.7 ug/ml. Cathelicidin-BF also effectively killed other microorganisms including Staphylococcus epidermidis, which was possible pathogen for acne vulgaris. Cathelicidin-BF significantly inhibited pro-inflammatory factors secretion in human monocytic cells and P. acnes-induced O2.- production of human HaCaT keratinocyte cells. Observed by scanning electron microscopy, the surfaces of the treated pathogens underwent obvious morphological changes compared with the untreated controls, suggesting that this antimicrobial peptide exerts its action by disrupting membranes of microorganisms. The efficacy of cathelicidin-BF gel topical administering was evaluated in experimental mice skin colonization model. In vivo anti-inflammatory effects of cathelicidin-BF were confirmed by relieving P. acnes-induced mice ear swelling and granulomatous inflammation. The anti inflammatory effects combined with potent antimicrobial activities and O2.- production inhibition activities of cathelicidin-BF indicate its potential as a novel therapeutic option for acne vulgaris. PMID- 21789224 TI - Who takes precautionary action in the face of the new H1N1 influenza? Prediction of who collects a free hand sanitizer using a health behavior model. AB - BACKGROUND: In order to fight the spread of the novel H1N1 influenza, health authorities worldwide called for a change in hygiene behavior. Within a longitudinal study, we examined who collected a free bottle of hand sanitizer towards the end of the first swine flu pandemic wave in December 2009. METHODS: 629 participants took part in a longitudinal study assessing perceived likelihood and severity of an H1N1 infection, and H1N1 influenza related negative affect (i.e., feelings of threat, concern, and worry) at T1 (October 2009, week 43-44) and T2 (December 2009, week 51-52). Importantly, all participants received a voucher for a bottle of hand sanitizer at T2 which could be redeemed in a university office newly established for this occasion at T3 (ranging between 1-4 days after T2). RESULTS: Both a sequential longitudinal model (M2) as well as a change score model (M3) showed that greater perceived likelihood and severity at T1 (M2) or changes in perceived likelihood and severity between T1 and T2 (M3) did not directly drive protective behavior (T3), but showed a significant indirect impact on behavior through H1N1 influenza related negative affect. Specifically, increases in perceived likelihood (beta = .12), severity (beta = .24) and their interaction (beta = .13) were associated with a more pronounced change in negative affect (M3). The more threatened, concerned and worried people felt (T2), the more likely they were to redeem the voucher at T3 (OR = 1.20). CONCLUSIONS: Affective components need to be considered in health behavior models. Perceived likelihood and severity of an influenza infection represent necessary but not sufficient self-referential knowledge for paving the way for preventive behaviors. PMID- 21789225 TI - Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5' exon usage and splicing. AB - BACKGROUND: Transcription factor 4 (TCF4 alias ITF2, E2-2, ME2 or SEF2) is a ubiquitous class A basic helix-loop-helix protein that binds to E-box DNA sequences (CANNTG). While involved in the development and functioning of many different cell types, recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and TCF4 haploinsufficiency is the cause of the Pitt-Hopkins mental retardation syndrome. However, the structure, expression and coding potential of the human TCF4 gene have not been described in detail. PRINCIPAL FINDINGS: In the present study we used human tissue samples to characterize human TCF4 gene structure and TCF4 expression at mRNA and protein level. We report that although widely expressed, human TCF4 mRNA expression is particularly high in the brain. We demonstrate that usage of numerous 5' exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. In addition, the diversity of isoforms is increased by alternative splicing of several internal exons. For functional characterization of TCF4 isoforms, we overexpressed individual isoforms in cultured human cells. Our analysis revealed that subcellular distribution of TCF4 isoforms is differentially regulated: Some isoforms contain a bipartite nuclear localization signal and are exclusively nuclear, whereas distribution of other isoforms relies on heterodimerization partners. Furthermore, the ability of different TCF4 isoforms to regulate E-box controlled reporter gene transcription is varied depending on whether one or both of the two TCF4 transcription activation domains are present in the protein. Both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination. CONCLUSIONS: Altogether, in this study we have described the inter-tissue variability of TCF4 expression in human and provided evidence about the functional diversity of the alternative TCF4 protein isoforms. PMID- 21789226 TI - JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients. AB - Myeloproliferative neoplasms (MPN) are multiple disease entities characterized by clonal expansion of one or more of the myeloid lineages (i.e. granulocytic, erythroid, megakaryocytic and mast cell). JAK2 mutations, such as the common V617F substitution and the less common exon 12 mutations, are frequently detected in such tumor cells and have been incorporated into the diagnostic criteria published by the World Health Organization since 2008. However, the mechanism by which these mutations contribute to MPN development is poorly understood. We examined gene expression profiles of MPN patients focusing on genes in the JAK STAT signaling pathway using low-density real-time PCR arrays. We identified the following 2 upregulated genes in MPN patients: a known target of the JAK-STAT axis, SOCS3, and a potentially novel target, SPI1, encoding PU.1. Induction of PU.1 expression by JAK2 V617F in JAK2-wildtype K562 cells and its downregulation by JAK2 siRNA transfection in JAK2 V617F-positive HEL cells supported this possibility. We also found that the ABL1 kinase inhibitor imatinib was very effective in suppressing PU.1 expression in BCR-ABL1-positive K562 cells but not in HEL cells. This suggests that PU.1 expression is regulated by both JAK2 and ABL1. The contribution of the two kinases in driving PU.1 expression was dominant for JAK2 and ABL1 in HEL and K562 cells, respectively. Therefore, PU.1 may be a common transcription factor upregulated in MPN. PU.1 is a transcription factor required for myeloid differentiation and is implicated in erythroid leukemia. Therefore, expression of PU.1 downstream of activated JAK2 may explain why JAK2 mutations are frequently observed in MPN patients. PMID- 21789227 TI - Histone deacetylase inhibition enhances self renewal and cardioprotection by human cord blood-derived CD34 cells. AB - BACKGROUND: Use of peripheral blood- or bone marrow-derived progenitors for ischemic heart repair is a feasible option to induce neo-vascularization in ischemic tissues. These cells, named Endothelial Progenitors Cells (EPCs), have been extensively characterized phenotypically and functionally. The clinical efficacy of cardiac repair by EPCs cells remains, however, limited, due to cell autonomous defects as a consequence of risk factors. The devise of "enhancement" strategies has been therefore sought to improve repair ability of these cells and increase the clinical benefit. PRINCIPAL FINDINGS: Pharmacologic inhibition of histone deacetylases (HDACs) is known to enhance hematopoietic stem cells engraftment by improvement of self renewal and inhibition of differentiation in the presence of mitogenic stimuli in vitro. In the present study cord blood derived CD34(+) were pre-conditioned with the HDAC inhibitor Valproic Acid. This treatment affected stem cell growth and gene expression, and improved ischemic myocardium protection in an immunodeficient mouse model of myocardial infarction. CONCLUSIONS: Our results show that HDAC blockade leads to phenotype changes in CD34(+) cells with enhanced self renewal and cardioprotection. PMID- 21789228 TI - Timing actions to avoid refractoriness: a simple solution for streaming sensory signals. AB - Segmenting self- from allo-generated signals is crucial for active sensory processing. We report a dynamic filter used by South American pulse electric fish to distinguish active electro-sensory signals carried by their own electric discharges from other concomitant electrical stimuli (i.e. communication signals). The filter has a sensory component, consisting of an onset type central electro-sensory neuron, and a motor component, consisting of a change in the fish's discharge rate when allo-generated electrical events occur in temporal proximity to the fish's own discharge. We investigated the sensory component of the filter by in vitro mimicking synaptic inputs occurring during behavioral responses to allo-generated interfering signals. We found that active control of the discharge enhances self-generated over allo-generated responses by forcing allo-generated signals into a central refractory period. This hypothesis was confirmed by field potential recordings in freely discharging fish. Similar sensory-motor mechanisms may also contribute to signal segmentation in other sensory systems. PMID- 21789229 TI - Herpes simplex virus type 1 penetrates the basement membrane in human nasal respiratory mucosa. AB - BACKGROUND: Herpes simplex virus infections are highly prevalent in humans. However, the current therapeutics suffer important drawbacks such as limited results in neonates, increasing occurrence of resistance and impeded treatment of stromal infections. Remarkably, interactions of herpesviruses with human mucosa, the locus of infection, remain poorly understood and the underlying mechanisms in stromal infection remain controversial. METHODOLOGY/PRINCIPAL FINDINGS: A human model consisting of nasal respiratory mucosa explants was characterised. Viability and integrity were examined during 96 h of cultivation. HSV1-mucosa interactions were analysed. In particular, we investigated whether HSV1 is able to reach the stroma. Explant viability and integrity remained preserved. HSV1 induced rounding up and loosening of epithelial cells with very few apoptotic and necrotic cells observed. Following 16-24 h of infection, HSV1 penetrated the basement membrane and replicated in the underlying lamina propria. CONCLUSIONS/SIGNIFICANCE: This human explant model can be used to study virus mucosa interactions and viral mucosal invasion mechanisms. Using this model, our results provide a novel insight into the HSV1 stromal invasion mechanism and for the first time directly demonstrate that HSV1 can penetrate the basement membrane. PMID- 21789230 TI - Comparative anatomical analyses of the forearm muscles of Cebus libidinosus (Rylands et al. 2000): manipulatory behavior and tool use. AB - The present study describes the flexor and extensor muscles in Cebus libidinosus' forearm and compares them with those from humans, chimpanzees and baboons. The data is presented in quantitative anatomical indices for similarity. The capuchin forearm muscles showed important similarities with chimpanzees and humans, particularly those that act on thumb motion and allow certain degree of independence from other hand structures, even though their configuration does not enable a true opposable thumb. The characteristics of Cebus' forearm muscles corroborate the evolutionary convergence towards an adaptive behavior (tool use) between Cebus genus and apes. PMID- 21789231 TI - Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. AB - BACKGROUND: Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs. METHODS AND FINDINGS: We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0-12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4 1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9-15.7). CONCLUSIONS: Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded. PMID- 21789232 TI - Exosome-producing follicle associated epithelium is not involved in uptake of PrPd from the gut of sheep (Ovis aries): an ultrastructural study. AB - In natural or experimental oral scrapie infection of sheep, disease associated prion protein (PrP(d)) often first accumulates in Peyer's patch (PP) follicles. The route by which infectivity reaches the follicles is unknown, however, intestinal epithelial cells may participate in intestinal antigenic presentation by delivering exosomes as vehicles of luminal antigens. In a previous study using an intestinal loop model, following inoculation of scrapie brain homogenate, inoculum associated PrP(d) was detected by light microscopy shortly (15 minutes to 3.5 hours) after inoculation in the villous lacteals and sub-mucosal lymphatics. No PrP(d) was located within the follicle-associated epithelium (FAE), sub-FAE domes or the PP follicles. To evaluate this gut loop model and the transportation routes in more detail, we used electron microscopy (EM) to study intestinal tissues exposed to scrapie or control homogenates for 15 minutes to 10 days. In addition, immuno-EM was used to investigate whether exosomes produced in the FAE may possess small amounts of PrP(d) that were not detectable by light microscopy. This study showed that the integrity of the intestinal epithelium was sustained in the intestinal loop model. Despite prominent transcytotic activity and exosome release from the FAE of the ileal PP in sheep, these structures were not associated with transportation of PrP(d) across the mucosa. The study did not determine how infectivity reaches the follicles of PPs. The possibility that the infectious agent is transported across the FAE remains a possibility if it occurs in a form that is undetectable by the methods used in this study. Infectivity may also be transported via lymph to the blood and further to all other lymphoid tissues including the PP follicles, but the early presence of PrP(d) in the PP follicles during scrapie infection argues against such a mechanism. PMID- 21789233 TI - Allele intersection analysis: a novel tool for multi locus sequence assignment in multiply infected hosts. AB - Wolbachia are wide-spread, endogenous alpha-Proteobacteria of arthropods and filarial nematodes. 15-75% of all insect species are infected with these endosymbionts that alter their host's reproduction to facilitate their spread. In recent years, many insect species infected with multiple Wolbachia strains have been identified. As the endosymbionts are not cultivable outside living cells, strain typing relies on molecular methods. A Multi Locus Sequence Typing (MLST) system was established for standardizing Wolbachia strain identification. However, MLST requires hosts to harbour individual and not multiple strains of supergroups without recombination. This study revisits the applicability of the current MLST protocols and introduces Allele Intersection Analysis (AIA) as a novel approach. AIA utilizes natural variations in infection patterns and allows correct strain assignment of MLST alleles in multiply infected host species without the need of artificial strain segregation. AIA identifies pairs of multiply infected individuals that share Wolbachia and differ in only one strain. In such pairs, the shared MLST sequences can be used to assign alleles to distinct strains. Furthermore, AIA is a powerful tool to detect recombination events. The underlying principle of AIA may easily be adopted for MLST approaches in other uncultivable bacterial genera that occur as multiple strain infections and the concept may find application in metagenomic high-throughput parallel sequencing projects. PMID- 21789234 TI - Food web architecture and basal resources interact to determine biomass and stoichiometric cascades along a benthic food web. AB - Understanding the effects of predators and resources on primary producers has been a major focus of interest in ecology. Within this context, the trophic cascade concept especially concerning the pelagic zone of lakes has been the focus of the majority of these studies. However, littoral food webs could be especially interesting because base trophic levels may be strongly regulated by consumers and prone to be light limited. In this study, the availability of nutrients and light and the presence of an omnivorous fish (Hyphessobrycon bifasciatus) were manipulated in enclosures placed in a humic coastal lagoon (Cabiunas Lagoon, Macae - RJ) to evaluate the individual and interactive effects of resource availability (nutrients and light) and food web configuration on the biomass and stoichiometry of periphyton and benthic grazers. Our findings suggest that light and nutrients interact to determine periphyton biomass and stoichiometry, which propagates to the consumer level. We observed a positive effect of the availability of nutrients on periphytic biomass and grazers' biomass, as well as a reduction of periphytic C?N?P ratios and an increase of grazers' N and P content. Low light availability constrained the propagation of nutrient effects on periphyton biomass and induced higher periphytic C?N?P ratios. The effects of fish presence strongly interacted with resource availability. In general, a positive effect of fish presence was observed for the total biomass of periphyton and grazer's biomass, especially with high resource availability, but the opposite was found for periphytic autotrophic biomass. Fish also had a significant effect on periphyton stoichiometry, but no effect was observed on grazers' stoichiometric ratios. In summary, we observed that the indirect effect of fish predation on periphyton biomass might be dependent on multiple resources and periphyton nutrient stoichiometric variation can affect consumers' stoichiometry. PMID- 21789235 TI - An effective method to purify Plasmodium falciparum DNA directly from clinical blood samples for whole genome high-throughput sequencing. AB - Highly parallel sequencing technologies permit cost-effective whole genome sequencing of hundreds of Plasmodium parasites. The ability to sequence clinical Plasmodium samples, extracted directly from patient blood without a culture step, presents a unique opportunity to sample the diversity of "natural" parasite populations in high resolution clinical and epidemiological studies. A major challenge to sequencing clinical Plasmodium samples is the abundance of human DNA, which may substantially reduce the yield of Plasmodium sequence. We tested a range of human white blood cell (WBC) depletion methods on P. falciparum-infected patient samples in search of a method displaying an optimal balance of WBC removal efficacy, cost, simplicity, and applicability to low resource settings. In the first of a two-part study, combinations of three different WBC depletion methods were tested on 43 patient blood samples in Mali. A two-step combination of Lymphoprep plus Plasmodipur best fitted our requirements, although moderate variability was observed in human DNA quantity. This approach was further assessed in a larger sample of 76 patients from Burkina Faso. WBC-removal efficacy remained high (<30% human DNA in >70% samples) and lower variation was observed in human DNA quantities. In order to assess the Plasmodium sequence yield at different human DNA proportions, 59 samples with up to 60% human DNA contamination were sequenced on the Illumina Genome Analyzer platform. An average ~40-fold coverage of the genome was observed per lane for samples with <= 30% human DNA. Even in low resource settings, using a simple two-step combination of Lymphoprep plus Plasmodipur, over 70% of clinical sample preparations should exhibit sufficiently low human DNA quantities to enable ~40-fold sequence coverage of the P. falciparum genome using a single lane on the Illumina Genome Analyzer platform. This approach should greatly facilitate large-scale clinical and epidemiologic studies of P. falciparum. PMID- 21789236 TI - Risk of all-cause mortality in HIV infected patients is associated with clinical, immunologic predictors and the CCR5 Delta32 deletion. AB - OBJECTIVE: Investigation of the interplay between the CCR5 Delta32/wt genotype and demographic, epidemiological, clinical and immunological factors associated with mortality in the cART era. DESIGN: Longitudinal data from 507 HIV-infected patients following the Delta32 allele detection were analyzed. METHODS: Cumulative 15 years mortality was calculated using Kaplan-Meyer methodology. Hazard ratios were estimated using univariate Cox models. Basing on Akakie information criteria and statistical significance multivariate Cox model was constructed and effect plots presenting adjusted hazard ratio time-dependency were drawn. Analysis of the association of all-cause mortality and CCR5 Delta32/wt genotype prior to the antiretroviral treatment (cART) initiation (n = 507) and on the therapy (n = 422) was also performed. RESULTS: A mortality rate of 2.66 (CI 2.57-3.19) per 100 person-years was observed. Univariate analysis factors modifying the risk of death included the CCR5 genotype, gender, history of cART, AIDS diagnosis and also CD4 lymphocyte nadir, zenith, the latest CD4 count and stable levels >500 cells/ul. For multivariate analysis the following predictors were selected: CCR5 genotype (HR for wt/wt 2.53, CI 1.16-5.53, p = 0.02), gender (HR for males 1.91, 95%CI 1.1-3.36, p = 0.023), introduction of combined antiretroviral treatment (HR 4.85, CI 3.0-7.89, if untreated or treated <1 month, p<0.0001) CD4 count of 500 cells/ul for six months or more (HR 4.16, CI 1.95-8.88 if not achieved, p = 0.028), the latest CD4 count (HR 5.44, CI 3.39 8.74 for <100 cells/ul, p<0.0001) and history of AIDS (HR 1.69, CI 1.03-2.79, p = 0.039). Among untreated individuals the Delta32/wt genotype was associated with notably better survival (p = 0.026), while among cART treated individuals the Delta32 mutation did not correlate significantly with higher survival rates (p = 0.23). CONCLUSIONS: The Delta32 CCR5 allele is associated with a reduction of the risk of all-cause mortality in HIV (+) patients alongside clinical and immunologic predictors such as AIDS, history of cART, lymphocyte CD4 cell count and gender. PMID- 21789237 TI - Molecular evolution of phosphoprotein phosphatases in Drosophila. AB - Phosphoprotein phosphatases (PPP), these ancient and important regulatory enzymes are present in all eukaryotic organisms. Based on the genome sequences of 12 Drosophila species we traced the evolution of the PPP catalytic subunits and noted a substantial expansion of the gene family. We concluded that the 18-22 PPP genes of Drosophilidae were generated from a core set of 8 indispensable phosphatases that are present in most of the insects. Retropositons followed by tandem gene duplications extended the phosphatase repertoire, and sporadic gene losses contributed to the species specific variations in the PPP complement. During the course of these studies we identified 5, up till now uncharacterized phosphatase retrogenes: PpY+, PpD5+, PpD6+, Pp4+, and Pp6+ which are found only in some ancient Drosophila. We demonstrated that all of these new PPP genes exhibit a distinct male specific expression. In addition to the changes in gene numbers, the intron-exon structure and the chromosomal localization of several PPP genes was also altered during evolution. The G-C content of the coding regions decreased when a gene moved into the heterochromatic region of chromosome Y. Thus the PPP enzymes exemplify the various types of dynamic rearrangements that accompany the molecular evolution of a gene family in Drosophilidae. PMID- 21789238 TI - Community structure in social networks: applications for epidemiological modelling. AB - During an infectious disease outbreak people will often change their behaviour to reduce their risk of infection. Furthermore, in a given population, the level of perceived risk of infection will vary greatly amongst individuals. The difference in perception could be due to a variety of factors including varying levels of information regarding the pathogen, quality of local healthcare, availability of preventative measures, etc. In this work we argue that we can split a social network, representing a population, into interacting communities with varying levels of awareness of the disease. We construct a theoretical population and study which such communities suffer most of the burden of the disease and how their awareness affects the spread of infection. We aim to gain a better understanding of the effects that community-structured networks and variations in awareness, or risk perception, have on the disease dynamics and to promote more community-resolved modelling in epidemiology. PMID- 21789239 TI - Mechanisms of allergen-antibody interaction of cockroach allergen Bla g 2 with monoclonal antibodies that inhibit IgE antibody binding. AB - BACKGROUND: Cockroach allergy is strongly associated with asthma, and involves the production of IgE antibodies against inhaled allergens. Reports of conformational epitopes on inhaled allergens are limited. The conformational epitopes for two specific monoclonal antibodies (mAb) that interfere with IgE antibody binding were identified by X-ray crystallography on opposite sites of the quasi-symmetrical cockroach allergen Bla g 2. METHODOLOGY/PRINCIPAL FINDINGS: Mutational analysis of selected residues in both epitopes was performed based on the X-ray crystal structures of the allergen with mAb Fab/Fab' fragments, to investigate the structural basis of allergen-antibody interactions. The epitopes of Bla g 2 for the mAb 7C11 or 4C3 were mutated, and the mutants were analyzed by SDS-PAGE, circular dichroism, and/or mass spectrometry. Mutants were tested for mAb and IgE antibody binding by ELISA and fluorescent multiplex array. Single or multiple mutations of five residues from both epitopes resulted in almost complete loss of mAb binding, without affecting the overall folding of the allergen. Preventing glycosylation by mutation N268Q reduced IgE binding, indicating a role of carbohydrates in the interaction. Cation-pi interactions, as well as electrostatic and hydrophobic interactions, were important for mAb and IgE antibody binding. Quantitative differences in the effects of mutations on IgE antibody binding were observed, suggesting heterogeneity in epitope recognition among cockroach allergic patients. CONCLUSIONS/SIGNIFICANCE: Analysis by site directed mutagenesis of epitopes identified by X-ray crystallography revealed an overlap between monoclonal and IgE antibody binding sites and provided insight into the B cell repertoire to Bla g 2 and the mechanisms of allergen-antibody recognition, including involvement of carbohydrates. PMID- 21789240 TI - Production of recombinant human DNA polymerase delta in a Bombyx mori bioreactor. AB - Eukaryotic DNA polymerase delta (pol delta) plays a crucial role in chromosomal DNA replication and various DNA repair processes. It is thought to consist of p125, p66 (p68), p50 and p12 subunits. However, rigorous isolation of mammalian pol delta from natural sources has usually yielded two-subunit preparations containing only p125 and p50 polypeptides. While recombinant pol delta isolated from infected insect cells have some problems of consistency in the quality of the preparations, and the yields are much lower. To address these deficiencies, we have constructed recombinant BmNPV baculoviruses using MultiBac system. This method makes the generation of recombinant forms of pol delta containing mutations in any one of the subunits or combinations thereof extremely facile. From about 350 infected larvae, we obtained as much as 4 mg of pol delta four subunit complex. Highly purified enzyme behaved like the one of native form by rigorous characterization and comparison of its activities on poly(dA)/oligo(dT) template-primer and singly primed M13 DNA, and its homogeneity on FPLC gel filtration. In vitro base excision repair (BER) assays showed that pol delta plays a significant role in uracil-intiated BER and is more likely to mediate LP BER, while the trimer lacking p12 is more likely to mediate SN BER. It seems likely that loss of p12 modulates the rate of SN BER and LP BER during the repair process. Thus, this work provides a simple, fast, reliable and economic way for the large-scale production of human DNA polymerase delta with a high activity and purity, setting up a new platform for our further research on the biochemical properties of pol delta, its regulation and the integration of its functions, and how alterations in pol delta function could contribute to the etiology of human cancer or other diseases that can result from loss of genomic stability. PMID- 21789241 TI - Quantitative analysis and diagnostic significance of methylated SLC19A3 DNA in the plasma of breast and gastric cancer patients. AB - BACKGROUND: Previously, we have examined the methylation status of SLC19A3 (solute carrier family 19, member 3) promoter and found that SLC19A3 was epigenetically down-regulated in gastric cancer. Here, we aim to develop a new biomarker for cancer diagnosis using methylated SLC19A3 DNA in plasma. METHODOLOGY/PRINCIPAL FINDINGS: SLC19A3 gene expression was examined by RT-qPCR. Methylation status of SLC19A3 promoter was evaluated by methylation-specific qPCR. SLC19A3 expression was significantly down-regulated in 80% (12/15) of breast tumors (P<0.005). Breast tumors had significant increase in methylation percentage when compared to adjacent non-tumor tissues (P<0.005). A robust and simple methylation-sensitive restriction enzyme digestion and real-time quantitative PCR (MSRED-qPCR) was developed to quantify SLC19A3 DNA methylation in plasma. We validated this biomarker in an independent validation cohort of 165 case-control plasma including 60 breast cancer, 45 gastric cancer patients and 60 healthy subjects. Plasma SLC19A3 methylated DNA level was effective in differentiating both breast and gastric cancer from healthy subjects. We further validated this biomarker in another independent blinded cohort of 78 plasma including 38 breast cancer, 20 gastric cancer patients and 20 healthy subjects. The positive predictive values for breast and gastric cancer were 90% and 85%, respectively. The negative predictive value of this biomarker was 85%. Elevated level in plasma has been detected not only in advanced stages but also early stages of tumors. The positive predictive value for ductal carcinoma in situ (DCIS) cases was 100%. CONCLUSIONS: These results suggested that aberrant SLC19A3 promoter hypermethylation in plasma may be a novel biomarker for breast and gastric cancer diagnosis. PMID- 21789242 TI - Adaptative potential of the Lactococcus lactis IL594 strain encoded in its 7 plasmids. AB - The extrachromosomal gene pool plays a significant role both in evolution and in the environmental adaptation of bacteria. The L. lactis subsp. lactis IL594 strain contains seven plasmids, named pIL1 to pIL7, and is the parental strain of the plasmid-free L. lactis IL1403, which is one of the best characterized lactococcal strains of LAB. Complete nucleotide sequences of pIL1 (6,382 bp), pIL2 (8,277 bp), pIL3 (19,244 bp), pIL4 (48,979), pIL5 (23,395), pIL6 (28,435 bp) and pIL7 (28,546) were established and deposited in the generally accessible database (GeneBank). Nine highly homologous repB-containing replicons, belonging to the lactococcal theta-type replicons, have been identified on the seven plasmids. Moreover, a putative region involved in conjugative plasmid mobilization was found on four plasmids, through identification of the presence of mob genes and/or oriT sequences. Detailed bioinformatic analysis of the plasmid nucleotide sequences provided new insight into the repertoire of plasmid encoded functions in L. lactis, and indicated that plasmid genes from IL594 strain can be important for L. lactis adaptation to specific environmental conditions (e.g. genes coding for proteins involved in DNA repair or cold shock response) as well as for technological processes (e.g. genes encoding citrate and lactose utilization, oligopeptide transport, restriction-modification system). Moreover, global gene analysis indicated cooperation between plasmid- and chromosome-encoded metabolic pathways. PMID- 21789243 TI - Metabolic versatility and antibacterial metabolite biosynthesis are distinguishing genomic features of the fire blight antagonist Pantoea vagans C9 1. AB - BACKGROUND: Pantoea vagans is a commercialized biological control agent used against the pome fruit bacterial disease fire blight, caused by Erwinia amylovora. Compared to other biocontrol agents, relatively little is currently known regarding Pantoea genetics. Better understanding of antagonist mechanisms of action and ecological fitness is critical to improving efficacy. PRINCIPAL FINDINGS: Genome analysis indicated two major factors Contribute to biocontrol activity: competition for limiting substrates and antibacterial metabolite production. Pathways for utilization of a broad diversity of sugars and acquisition of iron were identified. Metabolism of sorbitol by P. vagans C9-1 may be a major metabolic feature in biocontrol of fire blight. Biosynthetic genes for the antibacterial peptide pantocin A were found on a chromosomal 28-kb genomic island, and for dapdiamide E on the plasmid pPag2. There was no evidence of potential virulence factors that could enable an animal or phytopathogenic lifestyle and no indication of any genetic-based biosafety risk in the antagonist. CONCLUSIONS: Identifying key determinants contributing to disease suppression allows the development of procedures to follow their expression in planta and the genome sequence contributes to rationale risk assessment regarding the use of the biocontrol strain in agricultural systems. PMID- 21789244 TI - A new method to address unmet needs for extracting individual cell migration features from a large number of cells embedded in 3D volumes. AB - BACKGROUND: In vitro cell observation has been widely used by biologists and pharmacologists for screening molecule-induced effects on cancer cells. Computer assisted time-lapse microscopy enables automated live cell imaging in vitro, enabling cell behavior characterization through image analysis, in particular regarding cell migration. In this context, 3D cell assays in transparent matrix gels have been developed to provide more realistic in vitro 3D environments for monitoring cell migration (fundamentally different from cell motility behavior observed in 2D), which is related to the spread of cancer and metastases. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we propose an improved automated tracking method that is designed to robustly and individually follow a large number of unlabeled cells observed under phase-contrast microscopy in 3D gels. The method automatically detects and tracks individual cells across a sequence of acquired volumes, using a template matching filtering method that in turn allows for robust detection and mean-shift tracking. The robustness of the method results from detecting and managing the cases where two cell (mean-shift) trackers converge to the same point. The resulting trajectories quantify cell migration through statistical analysis of 3D trajectory descriptors. We manually validated the method and observed efficient cell detection and a low tracking error rate (6%). We also applied the method in a real biological experiment where the pro-migratory effects of hyaluronic acid (HA) were analyzed on brain cancer cells. Using collagen gels with increased HA proportions, we were able to evidence a dose-response effect on cell migration abilities. CONCLUSIONS/SIGNIFICANCE: The developed method enables biomedical researchers to automatically and robustly quantify the pro- or anti-migratory effects of different experimental conditions on unlabeled cell cultures in a 3D environment. PMID- 21789245 TI - Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors. AB - BACKGROUND: Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls. METHODOLOGY/PRINCIPAL FINDINGS: Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged. CONCLUSION: NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype. PMID- 21789246 TI - An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors. AB - Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers. PMID- 21789247 TI - The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: an example from Pterocarpus (Leguminosae). AB - BACKGROUND: The study of traditional knowledge of medicinal plants has led to discoveries that have helped combat diseases and improve healthcare. However, the development of quantitative measures that can assist our quest for new medicinal plants has not greatly advanced in recent years. Phylogenetic tools have entered many scientific fields in the last two decades to provide explanatory power, but have been overlooked in ethnomedicinal studies. Several studies show that medicinal properties are not randomly distributed in plant phylogenies, suggesting that phylogeny shapes ethnobotanical use. Nevertheless, empirical studies that explicitly combine ethnobotanical and phylogenetic information are scarce. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we borrowed tools from community ecology phylogenetics to quantify significance of phylogenetic signal in medicinal properties in plants and identify nodes on phylogenies with high bioscreening potential. To do this, we produced an ethnomedicinal review from extensive literature research and a multi-locus phylogenetic hypothesis for the pantropical genus Pterocarpus (Leguminosae: Papilionoideae). We demonstrate that species used to treat a certain conditions, such as malaria, are significantly phylogenetically clumped and we highlight nodes in the phylogeny that are significantly overabundant in species used to treat certain conditions. These cross-cultural patterns in ethnomedicinal usage in Pterocarpus are interpreted in the light of phylogenetic relationships. CONCLUSIONS/SIGNIFICANCE: This study provides techniques that enable the application of phylogenies in bioscreening, but also sheds light on the processes that shape cross-cultural ethnomedicinal patterns. This community phylogenetic approach demonstrates that similar ethnobotanical uses can arise in parallel in different areas where related plants are available. With a vast amount of ethnomedicinal and phylogenetic information available, we predict that this field, after further refinement of the techniques, will expand into similar research areas, such as pest management or the search for bioactive plant-based compounds. PMID- 21789248 TI - Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection. AB - RATIONALE: Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability. OBJECTIVES: To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI). METHODS: We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly observed), and isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms. RESULTS: Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen. CONCLUSIONS: Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries. PMID- 21789249 TI - Pre & postsynaptic tuning of action potential timing by spontaneous GABAergic activity. AB - Frequency and timing of action potential discharge are key elements for coding and transfer of information between neurons. The nature and location of the synaptic contacts, the biophysical parameters of the receptor-operated channels and their kinetics of activation are major determinants of the firing behaviour of each individual neuron. Ultimately the intrinsic excitability of each neuron determines the input-output function. Here we evaluate the influence of spontaneous GABAergic synaptic activity on the timing of action potentials in Layer 2/3 pyramidal neurones in acute brain slices from the somatosensory cortex of young rats. Somatic dynamic current injection to mimic synaptic input events was employed, together with a simple computational model that reproduce subthreshold membrane properties. Besides the well-documented control of neuronal excitability, spontaneous background GABAergic activity has a major detrimental effect on spike timing. In fact, GABA(A) receptors tune the relationship between the excitability and fidelity of pyramidal neurons via a postsynaptic (the reversal potential for GABA(A) activity) and a presynaptic (the frequency of spontaneous activity) mechanism. GABAergic activity can decrease or increase the excitability of pyramidal neurones, depending on the difference between the reversal potential for GABA(A) receptors and the threshold for action potential. In contrast, spike time jitter can only be increased proportionally to the difference between these two membrane potentials. Changes in excitability by background GABAergic activity can therefore only be associated with deterioration of the reliability of spike timing. PMID- 21789250 TI - Ensemble place codes in hippocampus: CA1, CA3, and dentate gyrus place cells have multiple place fields in large environments. AB - Previously we reported that the hippocampus place code must be an ensemble code because place cells in the CA1 region of hippocampus have multiple place fields in a more natural, larger-than-standard enclosure with stairs that permitted movements in 3-D. Here, we further investigated the nature of hippocampal place codes by characterizing the spatial firing properties of place cells in the CA1, CA3, and dentate gyrus (DG) hippocampal subdivisions as rats foraged in a standard 76-cm cylinder as well as a larger-than-standard box (1.8 m*1.4 m) that did not have stairs or any internal structure to permit movements in 3-D. The rats were trained to forage continuously for 1 hour using computer-controlled food delivery. We confirmed that most place cells have single place fields in the standard cylinder and that the positional firing pattern remapped between the cylinder and the large enclosure. Importantly, place cells in the CA1, CA3 and DG areas all characteristically had multiple place fields that were irregularly spaced, as we had reported previously for CA1. We conclude that multiple place fields are a fundamental characteristic of hippocampal place cells that simplifies to a single field in sufficiently small spaces. An ensemble place code is compatible with these observations, which contradict any dedicated coding scheme. PMID- 21789252 TI - Evidence of the trade-off between starvation and predation risks in ducks. AB - The theory of trade-off between starvation and predation risks predicts a decrease in body mass in order to improve flight performance when facing high predation risk. To date, this trade-off has mainly been validated in passerines, birds that store limited body reserves for short-term use. In the largest avian species in which the trade-off has been investigated (the mallard, Anas platyrhynchos), the slope of the relationship between mass and flight performance was steeper in proportion to lean body mass than in passerines. In order to verify whether the same case can be applied to other birds with large body reserves, we analyzed the response to this trade-off in two other duck species, the common teal (Anas crecca) and the tufted duck (Aythya fuligula). Predation risk was simulated by disturbing birds. Ducks within disturbed groups were compared to non-disturbed control birds. In disturbed groups, both species showed a much greater decrease in food intake and body mass during the period of simulated high risk than those observed in the control group. This loss of body mass allows reaching a more favourable wing loading and increases power for flight, hence enhancing flight performances and reducing predation risk. Moreover, body mass loss and power margin gain in both species were higher than in passerines, as observed in mallards. Our results suggest that the starvation predation risk trade-off is one of the major life history traits underlying body mass adjustments, and these findings can be generalized to all birds facing predation. Additionally, the response magnitude seems to be influenced by the strategy of body reserve management. PMID- 21789251 TI - Dibucaine mitigates spreading depolarization in human neocortical slices and prevents acute dendritic injury in the ischemic rodent neocortex. AB - BACKGROUND: Spreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury. METHODOLOGY/PRINCIPAL FINDINGS: We have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 uM that preserves synaptic function. Moreover, in vivo two photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model. CONCLUSIONS/SIGNIFICANCE: Dibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations. PMID- 21789253 TI - Visual working memory load-related changes in neural activity and functional connectivity. AB - BACKGROUND: Visual working memory (VWM) helps us store visual information to prepare for subsequent behavior. The neuronal mechanisms for sustaining coherent visual information and the mechanisms for limited VWM capacity have remained uncharacterized. Although numerous studies have utilized behavioral accuracy, neural activity, and connectivity to explore the mechanism of VWM retention, little is known about the load-related changes in functional connectivity for hemi-field VWM retention. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we recorded electroencephalography (EEG) from 14 normal young adults while they performed a bilateral visual field memory task. Subjects had more rapid and accurate responses to the left visual field (LVF) memory condition. The difference in mean amplitude between the ipsilateral and contralateral event related potential (ERP) at parietal-occipital electrodes in retention interval period was obtained with six different memory loads. Functional connectivity between 128 scalp regions was measured by EEG phase synchronization in the theta- (4-8 Hz), alpha- (8-12 Hz), beta- (12-32 Hz), and gamma- (32-40 Hz) frequency bands. The resulting matrices were converted to graphs, and mean degree, clustering coefficient and shortest path length was computed as a function of memory load. The results showed that brain networks of theta-, alpha-, beta-, and gamma- frequency bands were load-dependent and visual-field dependent. The networks of theta- and alpha- bands phase synchrony were most predominant in retention period for right visual field (RVF) WM than for LVF WM. Furthermore, only for RVF memory condition, brain network density of theta-band during the retention interval were linked to the delay of behavior reaction time, and the topological property of alpha-band network was negative correlation with behavior accuracy. CONCLUSIONS/SIGNIFICANCE: We suggest that the differences in theta- and alpha- bands between LVF and RVF conditions in functional connectivity and topological properties during retention period may result in the decline of behavioral performance in RVF task. PMID- 21789254 TI - A technical comparison of digital frequency-lowering algorithms available in two current hearing aids. AB - BACKGROUND: Recently two major manufacturers of hearing aids introduced two distinct frequency-lowering techniques that were designed to compensate in part for the perceptual effects of high-frequency hearing impairments. The Widex "Audibility Extender" is a linear frequency transposition scheme, whereas the Phonak "SoundRecover" scheme employs nonlinear frequency compression. Although these schemes process sound signals in very different ways, studies investigating their use by both adults and children with hearing impairment have reported significant perceptual benefits. However, the modifications that these innovative schemes apply to sound signals have not previously been described or compared in detail. METHODS: The main aim of the present study was to analyze these schemes'technical performance by measuring outputs from each type of hearing aid with the frequency-lowering functions enabled and disabled. The input signals included sinusoids, flute sounds, and speech material. Spectral analyses were carried out on the output signals produced by the hearing aids in each condition. CONCLUSIONS: The results of the analyses confirmed that each scheme was effective at lowering certain high-frequency acoustic signals, although both techniques also distorted some signals. Most importantly, the application of either frequency-lowering scheme would be expected to improve the audibility of many sounds having salient high-frequency components. Nevertheless, considerably different perceptual effects would be expected from these schemes, even when each hearing aid is fitted in accordance with the same audiometric configuration of hearing impairment. In general, these findings reinforce the need for appropriate selection and fitting of sound-processing schemes in modern hearing aids to suit the characteristics and preferences of individual listeners. PMID- 21789255 TI - Overexpression of the lung cancer-prognostic miR-146b microRNAs has a minimal and negative effect on the malignant phenotype of A549 lung cancer cells. AB - INTRODUCTION: Expression levels of miR-146b-5p and -3p microRNAs in human non small cell lung cancer (NSCLC) are associated with recurrence of the disease after surgery. To understand this, the effect of miR-146b overexpression was studied in A549 human lung cancer cells. METHODS: A549 cells, engineered with lentiviruses to overexpress the human pre-miR-146b precursor microRNA, were examined for proliferation, colony formation on plastic surface and in soft agar, migration and invasiveness in cell culture and in vivo in mice, chemosensitivity to cisplatin and doxorubicin, and global gene expression. miR-146b expressions were assessed in microdissected stroma and epithelia of human NSCLC tumors. Association of miR-146b-5p and -3p expression in early stage NSCLC with recurrence was analyzed. PRINCIPAL FINDINGS: A549 pre-miR-146b-overexpressors had 3-8-fold higher levels of both miR-146b microRNAs than control cells. Overexpression did not alter cellular proliferation, chemosensitivity, migration, or invasiveness; affected only 0.3% of the mRNA transcriptome; and, reduced the ability to form colonies in vitro by 25%. In human NSCLC tumors, expression of both miR-146b microRNAs was 7-10-fold higher in stroma than in cancerous epithelia, and higher miR-146b-5p but lower -3p levels were predictive of recurrence. CONCLUSIONS: Only a minimal effect of pre-miR-146b overexpression on the malignant phenotype was seen in A549 cells. This could be because of opposing effects of miR-146b-5p and -3p overexpression as suggested by the conflicting recurrence-predictive values of the two microRNAs, or because miR-146b expression changes in non-cancerous stroma and not cancerous epithelia of tumors are responsible for the prognostic value of miR-146b. PMID- 21789256 TI - Nuclear transport signals control cellular localization and function of androgen receptor cofactor p44/WDR77. AB - The androgen receptor (AR) cofactor p44/WDR77, which regulates expression of a set of androgen target genes, is required for differentiation of prostate epithelium. Aberrant localization of p44/WDR77 in the cytoplasm is associated with prostate tumorigenesis. Here, we describe studies that used the mouse prostate and human prostate cancer cells as model systems to investigate signals that control subcellular localization of p44/WDR77. We observed distinct subcellular location of p44/WDR77 during prostate development. p44/WDR77 localizes in the cytoplasm at the early stage of prostate development, when prostate epithelial cells are rapidly proliferating, and in the nucleus in adult prostate, when epithelial cells are fully differentiated. Subcellular localization assays designed to span the entire open-reading frame of p44/WDR77 protein revealed the presence of two nuclear exclusion signal (NES) and three nuclear localization signal (NLS) sequences in the p44/WDR77 protein. Site directed mutagenesis of critical residues within an NLS led to loss of nuclear localization and transcriptional activity of p44/WDR77, suggesting that nuclear localization of p44/WDR77 is essential for its function as a transcriptional cofactor for AR. Three identified NLS were not functional in AR-positive prostate cancer (LNCaP and 22RV1) cells, which led to localization of p44/WDR77 in cytoplasm. The function of NLS in LNCaP cells could be restored by factor(s) from Cos 7 or PC3 cells. Mass spectrometric (MALDI-TOF/TOF) analysis identified proteins associated with an NLS and an NES in prostate cancer cells. These results provide a basis for understanding subcellular transport of p44/WDR77 during prostate development and tumorigenesis. PMID- 21789257 TI - Large scale comparison of innate responses to viral and bacterial pathogens in mouse and macaque. AB - Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens. PMID- 21789258 TI - Expression of multiple artificial microRNAs from a chicken miRNA126-based lentiviral vector. AB - BACKGROUND: The use of RNAi in both basic and translational research often requires expression of multiple siRNAs from the same vector. METHODS/PRINCIPAL FINDINGS: We have developed a novel chicken miR126-based artificial miRNA expression system that can express one, two or three miRNAs from a single cassette in a lentiviral vector. We show that each of the miRNAs expressed from the same lentiviral vector is capable of potent inhibition of reporter gene expression in transient transfection and stable integration assays in chicken fibroblast DF-1 cells. Transduction of Vero cells with lentivirus expressing two or three different anti-influenza miRNAs leads to inhibition of influenza virus production. In addition, the chicken miR126-based expression system effectively inhibits reporter gene expression in human, monkey, dog and mouse cells. These results demonstrate that the flanking regions of a single primary miRNA can support processing of three different stem-loops in a single vector. CONCLUSIONS/SIGNIFICANCE: This novel design expands the means to express multiple miRNAs from the same vector for potent and effective silencing of target genes and influenza virus. PMID- 21789259 TI - Mortality among patients with cleared hepatitis C virus infection compared to the general population: a Danish nationwide cohort study. AB - BACKGROUND: The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity. METHODOLOGY/PRINCIPAL FINDINGS: Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20-39 years or 40-69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40-69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%-97%), MRR: 1.3 (95% CI: 0.8-2.3)), whereas those aged 20-39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3-14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40-69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1-30.6)). CONCLUSIONS: Mortality in patients aged 40-69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20-39 years without documented substance abuse or comorbidity. PMID- 21789260 TI - Small cofactors may assist protein emergence from RNA world: clues from RNA protein complexes. AB - It is now widely accepted that at an early stage in the evolution of life an RNA world arose, in which RNAs both served as the genetic material and catalyzed diverse biochemical reactions. Then, proteins have gradually replaced RNAs because of their superior catalytic properties in catalysis over time. Therefore, it is important to investigate how primitive functional proteins emerged from RNA world, which can shed light on the evolutionary pathway of life from RNA world to the modern world. In this work, we proposed that the emergence of most primitive functional proteins are assisted by the early primitive nucleotide cofactors, while only a minority are induced directly by RNAs based on the analysis of RNA protein complexes. Furthermore, the present findings have significant implication for exploring the composition of primitive RNA, i.e., adenine base as principal building blocks. PMID- 21789261 TI - Concurrent proinflammatory and apoptotic activity of a Helicobacter pylori protein (HP986) points to its role in chronic persistence. AB - Helicobacter pylori induces cytokine mediated changes in gastroduodenal pathophysiology, wherein, the activated macrophages at the sub-mucosal space play a central role in mounting innate immune response against the antigens. The bacterium gains niche through persistent inflammation and local immune suppression causing peptic ulcer disease or chronic gastritis; the latter being a significant risk factor for the development of gastric adenocarcinoma. What favors persistence of H. pylori in the gastric niches is not clearly understood. We report detailed characterization of a functionally unknown gene (HP986), which was detected in patient isolates associated with peptic ulcer and gastric carcinoma. Expression and purification of recombinant HP986 (rHP986) revealed a novel, ~29 kDa protein in biologically active form which associates with significant levels of humoral immune responses in diseased individuals (p<0.001). Also, it induced significant levels of TNF-alpha and Interleukin-8 in cultured human macrophages concurrent to the translocation of nuclear transcription factor kappaB (NF-kappaB). Further, the rHP986 induced apoptosis of cultured macrophages through a Fas mediated pathway. Dissection of the underlying signaling mechanism revealed that rHP986 induces both TNFR1 and Fas expression to lead to apoptosis. We further demonstrated interaction of HP986 with TNFR1 through computational and experimental approaches. Independent proinflammatory and apoptotic responses triggered by rHP986 as shown in this study point to its role, possibly as a survival strategy to gain niche through inflammation and to counter the activated macrophages to avoid clearance. PMID- 21789262 TI - Recognition of Dual or Multiple Pathology in Skin Biopsies from Patients with HIV/AIDS. AB - A large percentage of patients with HIV/AIDS will develop dermatological complications. Consequently, all practising clinicians and pathologists in regions with a high prevalence of HIV/AIDS must be familiar with the diverse cutaneous manifestations of the disease. This paper highlights the fact that biopsy material in this clinical context may occasionally reveal more than one pathological process. The potential spectrum includes two or more infections in a single skin biopsy (e.g., herpes simplex and cytomegalovirus infection), neoplastic lesions containing infective organisms (Kaposi sarcoma (KS) and cryptococcosis), dermatoses in association with neoplastic lesions (e.g., KS and interface dermatitis), or more than one dermatosis in a given specimen (e.g., papulopruritic eruption and nodular prurigo). Rare biopsies may even demonstrate triple pathology. The importance of careful examination of skin biopsies in this clinical context is emphasised. Failure to recognise an undiagnosed concomitant opportunistic infective pathogen could have potentially disastrous consequences for the patient. PMID- 21789263 TI - Fine-needle aspiration biopsy of hepatocellular carcinoma and related hepatocellular nodular lesions in cirrhosis: controversies, challenges, and expectations. AB - The role of hepatic fine-needle aspiration (FNA) biopsy has evolved. Advances in imaging modalities have obviated the need for tissue confirmation in most hepatocellular carcinomas (HCCs). There is risk of needle-tract seeding. Increasingly, small nodules are being detected on ultrasound surveillance of high risk patients. Diagnostic challenges associated with cirrhosis include distinction of benign hepatocellular nodules, namely, large regenerative nodules and dysplastic nodules, from reactive hepatocytes; and distinction of well differentiated HCCs from benign hepatocellular nodules. This paper will discuss (i) controversies regarding preoperative/pretransplantation FNA diagnosis of HCC, (ii) update of biological evolution, nomenclature, and histopathologic criteria for diagnosis of precancerous nodules and small HCCs, and (iii) algorithmic approach to FNA diagnosis of hepatocellular nodules. Optimal results depend on dedicated radiologist-cytopathologist team, on-site cytology service; combined cytohistologic approach, immunohistochemistry, and clinicopathologic correlation. Hepatic FNA is likely to be incorporated as a point of care as we move towards personalized medicine. PMID- 21789264 TI - Use of fine-needle aspiration in the evaluation of breast lumps. AB - Background. A study was designed to see the role of fine needle aspiration cytology (FNAC) in palpable breast lumps. Materials and Methods. Four hundred and twenty five (425) patients came to the Department of Pathology King Edward Medical University, Lahore in four years for FNAC of their palpable breast masses from June 2006 to June 2010. FNAC diagnosis was compared with histological diagnosis to see the accuracy of fine needle aspiration cytology for neoplastic lesions. Results. There were 271/425 benign, 120/425 malignant, and 32/425 suspicious smears. Inadequate samples were repeated twice or thrice, and the degree of success was improved with consecutive repeating approaches. The frequency of inadequacy declined from 86 to 18, and 2 for first, second and third attempts, respectively. The number of repeats increased the diagnostic accuracy of aspirates which is statistically significant (P = .000). Invasive ductal carcinoma was the most commonly reported lesion with maximum incidence in the 4th, 5th, and 6th decades followed by invasive lobular carcinoma and other malignant lesions. The sensitivity, specificity, accuracy, negative predictive value, and the positive predictive value of FNAC was 98%, 100%, 98%, 100%, and 97%, respectively. Conclusion. FNAC serves as a rapid, economical, and reliable tool for the diagnosis of palpable breast lesions because the cytopathological examination of these lesions before operation or treatment serves as an important diagnostic modality. PMID- 21789265 TI - Human Papillomavirus and Oropharyngeal Squamous Cell Carcinoma: A Case-Control Study regarding Tobacco and Alcohol Consumption. AB - We aimed to determine the role of HPV in the pathogenesis and outcome of oropharyngeal squamous cell carcinoma (OSCC) in lifelong nonsmoking and nondrinking patients. A case-case analysis was performed to compare the presence of HPV-DNA in tumor cells of 16 nonsmoking and nondrinking with 16 matched smoking and drinking patients (matching criteria: age at incidence, gender, tumor sublocation, tumor stage). HPV was detected using 2 PCR tests, FISH analysis, and p16(INK4A) immunostaining. Nonsmoking and nondrinking patients had more HPV positive tumors than smoking and drinking patients (n = 12; 75% versus n = 2; 13%; P < 0.001). All HPV-positive tumors showed p16(INK4A) overexpression, and 1 HPV-negative tumor had p16(INK4A) overexpression, (P < 0.001). Overall survival and disease-specific survival were higher for HPV-positive compared to HPV negative cases (P = 0.027, P = 0.039, resp.). In conclusion, HPV is strongly associated with OSCC of nonsmoking and nondrinking patients. Specific diagnostic and therapeutic actions should be considered for these patients to achieve a better prognosis. PMID- 21789266 TI - Fatal hemothorax caused by pseudomesotheliomatous carcinoma of the lung. AB - We present a case of a poorly differentiated pseudomesotheliomatous carcinoma originating in the lung, which was manifested with the distinctly rare complication of massive true hemothorax and persistent blood loss that proved rapidly fatal in spite of surgery. Pseudomesotheliomatous carcinoma of the lung and neoplasia-associated hemothorax are reviewed and discussed. PMID- 21789267 TI - Antioxidants and the integrity of ocular tissues. AB - Oxygen-derived free radicals are normally generated in many pathways. These radicals can interact with various cellular components and induce cell injury. When free radicals exceed the antioxidant capacity, cell injury causes diverse pathologic changes in the organs. The imbalance between the generation of free radicals and antioxidant defence is known as oxidative stress. The eye can suffer the effect of oxidative damage due to the etiopathogenesis of some pathological changes related to oxidative stress. This paper reviews the role of oxidative stress in the onset and progression of damage in different eye structures, the involvement of the antioxidant network in protecting and maintaining the homeostasis of this organ, and the potential assessment methodologies used in research and in some cases in clinical practice. PMID- 21789268 TI - Atypical Strokes in a Young African American Male: A Case of Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome. AB - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare but important cause of stroke-like symptoms which can often be missed Thambisetty and Newman 2004. We describe a case of a young male presenting with stroke-like episodes, later diagnosed with MELAS in an attempt to improve the understanding about diagnosing MELAS in the appropriate clinical context. PMID- 21789270 TI - Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality. AB - Introduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the influence of the Marburg I polymorphism and the closely linked Marburg II polymorphism (1280G > C) on various cardiovascular outcomes in two large independent study populations. Methods. The two Marburg polymorphisms in the HABP2 gene encoding FSAP were genotyped in a large population of elderly patients at risk for vascular disease (the PROSPER-study, n = 5804) and in a study population treated with a percutaneous coronary intervention (the GENDER-study, n = 3104). Results. In the PROSPER study, the Marburg I polymorphism was associated with an increased risk of clinical stroke (HR: 1.60, 95% CI: 1.13-2.28) and all-cause mortality (HR: 1.33, 95% CI: 1.04 1.71). In the GENDER study carriers of this variant seemed at lower risk of developing restenosis (HR: 0.59, 95% CI: 0.34-1.01). The Marburg II polymorphism showed similar but weaker results. Conclusion. The increase in stroke risk in Marburg I carriers could be due to differential effects on smooth muscle cells and on matrix metalloproteinases, thereby influencing plaque stability. The possible protective effect on restenosis could be the result of reduced activation of zymogens, which are involved in hemostasis and matrix remodeling. PMID- 21789269 TI - Epidemiology and etiology of young stroke. AB - Introduction. Stroke in people under 45 years of age is less frequent than in older populations but has a major impact on the individual and society. In this article we provide an overview of the epidemiology and etiology of young stroke. Methods. This paper is based on a review of population-based studies on stroke incidence that have included subgroup analyses for patients under 45 years of age, as well as smaller community-based studies and case-series specifically examining the incidence of stroke in the young. Trends are discussed along with the relative frequencies of various etiologies. Discussion. Stroke in the young requires a different approach to investigation and management than stroke in the elderly given differences in the relative frequencies of possible underlying causes. It remains the case, however, that atherosclerosis contributes to a large proportion of stroke in young patients, thus, conventional risk factors must be targeted aggressively. PMID- 21789271 TI - Experimental and clinical use of therapeutic hypothermia for ischemic stroke: opportunities and limitations. AB - Stroke remains a disease with a serious impact on quality of life but few effective treatments exist. There is an urgent need to develop and/or improve neuroprotective strategies to combat this. Many drugs proven to be neuroprotective in experimental models fail to improve patient outcome in a clinical setting. An emerging treatment, therapeutic hypothermia (TH), is a promising neuroprotective therapy in stroke management. Several studies with TH in experimental models and small clinical trials have shown beneficial effects. Despite this, implementation into the clinical setting is still lacking due to methodological considerations as well as hypothermia-related complications. This paper discusses the possible opportunities and limitations of the use of TH in animal models and the translation into the clinic. PMID- 21789272 TI - Paediatric Stroke: Review of the Literature and Possible Treatment Options, including Endovascular Approach. AB - Stroke is among the top 10 causes of death in childhood. More than half of the surviving children have long-term neurological sequelae. Ischemic stroke (IS) includes arterial ischemic stroke and cerebral venous thrombosis with venous infarction. Haemorrhagic stroke (HS) includes intracerebral haematoma or subarachnoid haemorrhage. Risk factors for stroke are different in children and in adults. 10-30% of IS have no identified risk factors. However, multiple risk factors are recognizable in the majority of stroke in children; thus, a comprehensive diagnostic evaluation is crucial. Vascular abnormalities, such as arteriovenous malformations, aneurysms, vessel dissection, stenosis, and moyamoya disease, are frequently associated with both IS and HS and lead to high recurrence rates. Endovascular and surgical treatment options are sometimes indicated, performed on the basis of expert opinion, and extrapolated from the adult procedures. In the present paper, we review the recent literature and we discuss the treatment in five cases managed at our institutions. PMID- 21789274 TI - Prevalence and impact of thyroid disorders on maternal outcome in asian-Indian pregnant women. AB - Aims. To establish the prevalence and the effect of thyroid dysfunction on pregnancy outcomes in Asian-Indian population. Subjects and Methods. The study cohort comprised of 483 consecutive pregnant women in the first trimester attending the antenatal clinic of a tertiary center in Mumbai, India. Thyroid hormone levels and thyroid peroxidase antibody were estimated. Patients with thyroid dysfunction were assessed periodically or treated depending on the severity. Subjects were followed until delivery. Results. The prevalence of hypothyroidism, Graves' disease, gestational transient thyrotoxicosis, and thyroid autoimmunity (TAI) was 4.8% (n = 24), 0.6% (n = 3), 6.4 % (n = 31), and 12.4% (n = 60), respectively. Forty percent of the hypothyroid patients did not have any high-risk characteristics. Hypothyroidism and TAI were associated with miscarriage (P = 0.02 and P = 0.001, resp.). Conclusions. The prevalence of hypothyroidism (4.8%) and TAI (12.4%) is high. TAI and hypothyroidism were significantly associated with miscarriage. PMID- 21789273 TI - Infection after acute ischemic stroke: risk factors, biomarkers, and outcome. AB - Background. The activation of inflammatory cascades triggered by ischemic stroke may play a key role in the development of infections. Methods. Patients admitted with ischemic stroke within 24 hours were prospectively enrolled. Biomarkers of infection were measured on days 1, 3, and 5. The patients were continuously monitored for predefined infections. Results. Patients with infection were older (OR 1.06 per year, 95% CI 1.01-1.11) and had a higher National Institute of Health Stroke Scale Score (NIHSS, OR 1.21, 95% CI 1.10-1.34), localization in the insula, and higher stroke volumes on diffusion-weighted imaging. The maximum temperature on days 1 and 3, leukocytes, interleukin-6, lipopolysaccharide binding protein on days 1, 3, and 5, C-reactive protein on days 3 and 5, and procalcitonin on day 5 were higher and HLA-DR-expression on monocytes on days 1, 3, and 5 lower in patients with infection. Age and NIHSS predicted the development of infections. Infection was an independent predictor of poor functional outcome. Conclusions. Severe stroke and increasing age were shown to be early predictors for infections after stroke. PMID- 21789276 TI - Capacity to vote in persons with dementia and the elderly. AB - The capacity to vote in patients with mental illness is increasingly questioned. The objective of this study is to evaluate this capacity in a group of subjects with dementia (Alzheimer's disease) and other elderly subjects without dementia. With a sample of 68 subjects with dementia and 25 controls living in a senior residence, a transversal study was carried out over 4 months. Subjects were evaluated with the Mini-Mental State Examination (MMSE) and the Competence Assessment Tool for voting (CAT-V). The results were more positive for the Doe criteria (as part of the CAT-V), and a correlation was found with the MMSE in subjects with dementia and, to a lesser degree, in the controls. We conclude that the capacity to vote is related to cognitive deterioration and, within that, is more related to understanding and appreciation. PMID- 21789275 TI - Impact of external cue validity on driving performance in Parkinson's disease. AB - This study sought to investigate the impact of external cue validity on simulated driving performance in 19 Parkinson's disease (PD) patients and 19 healthy age matched controls. Braking points and distance between deceleration point and braking point were analysed for red traffic signals preceded either by Valid Cues (correctly predicting signal), Invalid Cues (incorrectly predicting signal), and No Cues. Results showed that PD drivers braked significantly later and travelled significantly further between deceleration and braking points compared with controls for Invalid and No-Cue conditions. No significant group differences were observed for driving performance in response to Valid Cues. The benefit of Valid Cues relative to Invalid Cues and No Cues was significantly greater for PD drivers compared with controls. Trail Making Test (B-A) scores correlated with driving performance for PDs only. These results highlight the importance of external cues and higher cognitive functioning for driving performance in mild to moderate PD. PMID- 21789277 TI - Plasminogen activator inhibitor-type I gene deficient mice show reduced influx of neutrophils in ventilator-induced lung injury. AB - Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LV(T)) or high tidal volumes (HV(T)). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HV(T) as compared to LV(T). In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI. PMID- 21789278 TI - Relationship between Temperament, Depression, Anxiety, and Hopelessness in Adolescents: A Structural Equation Model. AB - The purpose of this study was to test the validity of affective temperaments for predicting psychiatric morbidity and suicide risk, using a two-factor model to explain the relationships between temperament, anxiety, depression, and hopelessness. We investigated 210 high school students, 103 males and 107 females, 18-19 years old, who were administered self-report questionnaires to assess temperament (TEMPS-A), depression (BDI-II), anxiety (STAI) and hopelessness (BHS). The final structural model had a good fit with the data, with two factors significantly correlated, the first labeled unstable cyclothymic temperament including Dysthymic/Cyclothymic/Anxious temperament, Irritable temperament and Depression, and the second labeled Demoralization including Anxiety (State/Trait) and Hopelessness. Depression, anxiety and hopelessness are in a complex relationship partly mediated by temperament. PMID- 21789279 TI - Bipolar Disorder and the TCI: Higher Self-Transcendence in Bipolar Disorder Compared to Major Depression. AB - Personality traits are potential endophenotypes for genetic studies of psychiatric disorders. One personality theory which demonstrates strong heritability is Cloninger's psychobiological model measured using the temperament and character inventory (TCI). 277 individuals who completed the TCI questionnaire as part of the South Island Bipolar Study were also interviewed to assess for lifetime psychiatric diagnoses. Four groups were compared, bipolar disorder (BP), type 1 and 2, MDD (major depressive disorder), and nonaffected relatives of a proband with BP. With correction for mood state, total harm avoidance (HA) was higher than unaffected in both MDD and BP groups, but the mood disorder groups did not differ from each other. However, BP1 individuals had higher self-transcendence (ST) than those with MDD and unaffected relatives. HA may reflect a trait marker of mood disorders whereas high ST may be specific to BP. As ST is heritable, genes that affect ST may be of relevance for vulnerability to BP. PMID- 21789280 TI - Evaluation of Heart Rate Variation Analysis during Rest and Tilting in Patients with Temporal Lobe Epilepsy. AB - Objective. To evaluate spectral heart rate (HR) variation using short-term ECG recordings at rest and during the tilt table test. Methods. The values of spectral components of total power (TP), high-frequency power (HF), low-frequency power (LF) and LF: HF ratio were measured at rest and during the head-up tilt in patients with temporal lobe epilepsy (TLE) and their control subjects. Results. Compared to the control subjects, patients with TLE had lower HF (P < 0.05) and LF : HF ratio (P < 0.05) at rest and lower TP (P < 0.001), HF (P < 0.05), and LF (P < 0.05) during the head-up tilt. Upon changing from supine to standing position TP (P < 0.05) and LF (P < 0.05) were attenuated in patients with TLE compared to the control subjects. Conclusion. These results suggest that spectral analysis of HR variation from ECG recordings of short duration may add value to assessment of autonomic nervous system function using autonomic cardiac tests in patients with TLE. PMID- 21789281 TI - The role of salt in the pathogenesis of fructose-induced hypertension. AB - Metabolic syndrome, as manifested by visceral obesity, hypertension, insulin resistance, and dyslipidemia, is reaching epidemic proportions in the Western World, specifically the United States. Epidemiologic studies suggest that the increased prevalence of metabolic syndrome directly correlates with an increase in the consumption of fructose, mainly in the form of high-fructose corn syrup. This inexpensive alternative to traditional sugar has been increasingly utilized by the food industry as a sweetener since the 1960s. While augmented caloric intake and sedentary lifestyles play important roles in the increasing prevalence of obesity, the pathogenesis of hypertension in metabolic syndrome remains controversial. One intriguing observation points to the role of salt in fructose induced hypertension. Recent studies in rodents demonstrate that increased dietary fructose intake stimulates salt absorption in the small intestine and kidney tubules, resulting in a state of salt overload, thus setting in motion a cascade of events that will lead to hypertension. These studies point to a novel interaction between the fructose-absorbing transporter, Glut5, and the salt transporters, NHE3 and PAT1, in the intestine and kidney proximal tubule. This paper will focus on synergistic roles of fructose and salt in the pathogenesis of hypertension resulting from salt overload. PMID- 21789283 TI - Endometriosis and ovarian cancer: a systematic review. AB - Introduction. Endometriosis is one of the most common benign disorders which affects 10-15% of all women in reproductive age. The association between endometriosis and ovarian cancer has been frequently described in the medical literature. Purpose. To evaluate the literature for evidence of a correlation between endometriosis and ovarian cancer. Method. the English language literature (online MEDLINE and EMBASE database) was searched using the keywords endometriosis combined with cancer, tumour, tumor, carcinoma, or adenocarcinoma. All abstracts between January 1985 and August 2010 were reviewed. Full relevant articles were critically assessed. Reference lists of included studies were checked. Results. Seven out of the eight studies, included in our review, have shown an increased risk of ovarian cancer. However, the effect size is modest (OR, RR, and SIR) ranging between 1.32 and 1.9 (95% CI). A causative relationship between the two incidences cannot be confirmed. There is increasing evidence on the role of genetic mutations in ovarian clear-cell and endometrioid carcinoma developing from endometriosis. Conclusion. More evidence is needed before suggesting any change in the current management of endometriosis. PMID- 21789282 TI - Lipid abnormalities and cardiometabolic risk in patients with overt and subclinical thyroid disease. AB - Dyslipidemia is a common finding in patients with thyroid disease, explained by the adverse effects of thyroid hormones in almost all steps of lipid metabolism. Not only overt but also subclinical hypo- and hyperthyroidism, through different mechanisms, are associated with lipid alterations, mainly concerning total and LDL cholesterol and less often HDL cholesterol, triglycerides, lipoprotein (a), apolipoprotein A1, and apolipoprotein B. In addition to quantitative, qualitative alterations of lipids have been also reported, including atherogenic and oxidized LDL and HDL particles. In thyroid disease, dyslipidemia coexists with various metabolic abnormalities and induce insulin resistance and oxidative stress via a vice-vicious cycle. The above associations in combination with the thyroid hormone induced hemodynamic alterations, might explain the increased risk of coronary artery disease, cerebral ischemia risk, and angina pectoris in older, and possibly ischemic stroke in younger patients with overt or subclinical hyperthyroidism. PMID- 21789284 TI - Assessment of the vitamin B12 status of pregnant women in Nigeria using plasma holotranscobalamin. AB - Maternal vitamin B12 deficiency during pregnancy is an independent risk factor for neural tube defects and other neurological problems in infants. We determined the vitamin B12 status of 143 pregnant women in Nigeria representing all trimesters who presented to an antenatal clinic in Jos, Nigeria, using holotranscobalamin II levels (holoTCII), which is a measure of the vitamin B12 that is available for uptake into tissues. The holoTCII concentration ranged from 13 to 128 pmol/L. Using a cutoff of 40 pmol/L, 36% of the women were classified as vitamin B12-deficient. HoloTCII concentrations correlated negatively with plasma homocysteine levels (r = -0.24, P = 0.003) and positively with red blood cell folate concentrations (r = 0.28, P < 0.001). These data underscore the importance of supplementing pregnant women in Nigeria with vitamin B12 in order to ensure adequate vitamin B12 status and decrease the risk for neural tube defects. PMID- 21789286 TI - Modification of the bidimensional system. AB - In the mid 1970s, Schudy and Schudy developed and described an edgewise bimetric system in which there were brackets with 0.016-inch slots on the incisors and canines and brackets with 0.022-inch slots on the premolars and molars. Modeling after Schudy and Schudy, Gianelly devised a similar, preadjusted system called the bidimensional system, in which the incisor brackets have 0.018-inch slots while the remaining teeth have brackets with 0.022-inch slots. We have further modified the bidimensional system and developed a dual-slot system. Hence, this article compares the bidimensional and dual-slot systems and provides justification for both. The main concerns regarding the bidimensional and dual slot systems are posterior "play" and lack of three-dimensional control. We rationalize both as well as the self-ligating hybrid and dual-slot system. PMID- 21789285 TI - The many forms and functions of long term plasticity at GABAergic synapses. AB - On February 12th 1973, Bliss and Lomo submitted their findings on activity dependent plasticity of glutamatergic synapses. After this groundbreaking discovery, long-term potentiation (LTP) and depression (LTD) gained center stage in the study of learning, memory, and experience-dependent refinement of neural circuits. While LTP and LTD are extensively studied and their relevance to brain function is widely accepted, new experimental and theoretical work recently demonstrates that brain development and function relies on additional forms of plasticity, some of which occur at nonglutamatergic synapses. The strength of GABAergic synapses is modulated by activity, and new functions for inhibitory synaptic plasticity are emerging. Together with excitatory neurons, inhibitory neurons shape the excitability and dynamic range of neural circuits. Thus, the understanding of inhibitory synaptic plasticity is crucial to fully comprehend the physiology of brain circuits. Here, I will review recent findings about plasticity at GABAergic synapses and discuss how it may contribute to circuit function. PMID- 21789287 TI - Posttreatment compliance with removable maxillary retention in a teenage population: a short-term randomized clinical trial. AB - Removable retainer wear is most related to patient comfort and acceptance. Patient compliance is essential for retention and maintenance of the orthodontic treatment results. Even though patients are educated about the need for prolonged retention after active treatment and asked to sign informed consent regarding the risk of noncompliance (relapse) prior to treatment, most orthodontists would estimate that at least half of their teenage patients do not comply at optimal levels. The aim of the present study was to quantify teenage patient compliance with removable maxillary retention and compare actual usage vs prescribed usage between subjects who knew they were being monitored via an implanted microsensor in the retainer and those subjects who were unaware of any monitoring. The final sample consisted of 9 subjects in the test group (5 males and 4 females) and 10 subjects in the control group (4 males and 6 females). The evidence suggests that individuals who were made aware of the orthodontist's ability to monitor compliance wore the device for a significantly larger number of hours per day than those who were unaware of this fact. Patients reporting full usage of the retainer wore the appliance a mean of 4.3 hours more per day than those reporting less than full usage, holding all other variables constant. Patients who misrepresented their retainer use (reported full usage but wore the device less than 19 hours per day) wore the appliance a mean 12.4 hours less than the more honest patients who participated in the study. PMID- 21789288 TI - AUSOM: a 3D placement guide for orthodontic mini-implants. AB - AIM: Anchorage management is an important issue in orthodontic treatment and plays a big role in the success or failure of orthodontic treatment. Using a mini implant system as skeletal anchorage is a suitable solution if maximum or absolute anchorage control is required. Applying mini-implants requires pinpointing their optimal position to prevent damaging adjacent anatomical structures. There are three considerations in locating proper mini-implant position: the point of implant insertion, the angle of implant insertion in the anterior-posterior direction, and the angulation of implant insertion in the vertical plane. Here, we illustrate a new three-dimensional mini-implant guide (Aleppo University Surgical Orthodontic Miniscrew Guide [AUSOM]) developed for determination of ideal mini-implant placement and demonstrate AUSOM's role in mini-implant success. METHODS: After reviewing of articles about mini-implants in orthodontic treatment, we determined the characteristics of an ideal orthodontic implant guide (IOIG). We invented a new instrument, AUSOM, that consists of four components: a horizontal part, a vertical part, a graduation guide, and film holding part. Forty mini-implants were inserted for orthodontic treatment purposes; AUSOM and wire guides were used to insert the mini-implants. CONCLUSION: We found AUSOM to be a practical and accurate device. It works as a radiographic-locating device and a mini-implant surgical placement guide. The failure rate of mini-implants placed by AUSOM was lower than that of those placed by simple metallic guides. Clinical randomized studies must be carried out to prove AUSOM's role in improving the success rate of mini-implant placement. PMID- 21789289 TI - Phantom bite: a survey of US orthodontists. AB - AIM: In 1976, Marbach described the term phantom bite as a patient's perception of an irregular bite when the clinician could identify no evidence of a discrepancy. Typically, the patient presents with a history of bite-altering procedures, hyperawareness of occlusion, and a persistent complaint of an uncomfortable bite, usually with an absence of pain. Patients with phantom bite complaints often undergo lengthy, expensive, irreversible, invasive, and unnecessary treatments in search of a resolution of their symptoms. The objectives of the study were: (1) to gauge orthodontists' awareness of phantom bite and its associated signs and symptoms, (2) to identify the most common types of treatments rendered for this phenomenon, (3) to determine if regional differences or length of practice experience affected the aforementioned factors, and (4) to determine sex characteristics of patients with phantom bite. METHODS: The study consisted of a 14-item survey administered electronically using SurveyMonkey software. Using the American Association of Orthodontists (AAO) directory, 4,124 orthodontists were recruited to participate via email; 337 completed the survey. RESULTS: Approximately 50% of the responding orthodontists were unfamiliar with the term "phantom bite"; however, many reported seeing patients with phantom bite complaints. Demographic differences, such as geographic region of practice or years in practice, did not affect familiarity with this condition or its treatment. CONCLUSION: The results suggest a need for increasing awareness of this condition among orthodontic practitioners to provide patients with appropriate care. PMID- 21789290 TI - A multidisciplinary approach to the treatment of a horizontally impacted mandibular second premolar: 10-year follow-up. AB - This report presents a multidisciplinary approach to the treatment of a rare case of a distally impacted mandibular second premolar indicating a 90-degree tilt of the long axis in a healthy, 15-year-old girl. It also describes the clinical and radiologic findings after a 10-year longitudinal follow-up period. The horizontally impacted mandibular second premolar was positioned behind the roots of the first molar and in close proximity to the root of the second molar, toward the lingual cortex of the mandibular body. Treatment methods required 2 years of cooperation among an orthodontist, an oral and maxillofacial surgeon, a periodontist, and an endodontist to achieve a leveled and aligned position in a properly healed condition. Finally, the horizontally impacted mandibular second premolar was correctly positioned in the arch surrounded by healed periodontal ligament tissue. Root resorption of the adjacent orthodontic anchorage units was recorded. The 10-year postoperative follow-up presented a stable, functional, and symptom-free permanent mandibular second premolar. The multidisciplinary dental team's considerations and cooperation account for the successful repositioning of the compromised mandibular second premolar with minimal damage to the surrounding hard and soft tissue following 10 years of longitudinal follow-up. PMID- 21789291 TI - Orthodontic management of an originally surgically planned treatment of an open bite: a case report. AB - The treatment of open bite malocclusion is generally considered a challenge due to its multifactorial etiology. Many treatment modalities to correct open bites, including orthognathic surgery and dental compensation, have been proposed. Dental compensation (intruding the posterior teeth and uprighting and extruding the anterior teeth with elastics) is a treatment option for borderline patients and those who are reluctant to undergo surgery. This report documents the treatment of a patient with a severe skeletal open bite malocclusion whose treatment plan originally included fixed appliance therapy as well as orthognathic surgery. He was subsequently treated with only fixed appliances. The patient, a male 17 years, 7 months of age, presented with a Class II, Division 1 malocclusion, 5 mm anterior open bite, and an increased anterior facial height. He was treated with extraction of the maxillary and mandibular premolars, full fixed appliances, and anterior vertical elastics. After 30 months of active treatment, a Class I occlusion with improved overjet and overbite was achieved. PMID- 21789292 TI - Dental amalgam corrosion in vacuum-formed retainers. AB - AIM: To report and evaluate the confinement of metal ions released by dental amalgam restorations in vacuum-formed thermoplastic retainers (VFRs). METHODS: VFR samples that contained corrosion tarnish corresponding with dental amalgam restorations were collected from patients, and replacement retainers were fabricated. The stained retainers were tested for trace metals utilizing inductively coupled plasma-atomic emission spectrometry (ICP-AES) and for mercury utilizing cold-vapor atomic absorption (CVAA). The results were compared to a control piece of VRF material from the manufacturer. RESULTS: The tarnished sections of the VFRs contained mercury (61.00 ppm), calcium (205.00 ppm), and zinc (3.05 ppm). The control sample results were below qualitative limits for metal ion and mercury testing and can be considered, for our purposes, to be uncontaminated. CONCLUSION: VFRs that cover surfaces of teeth restored with dental amalgam become tarnished and confine amalgam corrosion products, including mercury and zinc. PMID- 21789293 TI - The dentist as a manager: building effective relationships and networks for personal and professional advancement. PMID- 21789294 TI - Iron-catalyzed aryl- and alkenyllithiation of alkynes and its application to benzosilole synthesis. AB - Phenyl- and vinyllithiums having an alkyl substituent at their ortho- and cis position, respectively, readily added to alkynes in the presence of 5 mol% of Fe(acac)(3). The reaction of o-(trimethylsilyl)phenyllithium with alkynes gave benzosiloles through an addition-cyclization sequence. PMID- 21789295 TI - A photo-induced excited state structure of a hetero-bimetallic ionic pair complex, Nd(DMA)4(H2O)4Fe(CN)6.3H2O, analyzed by single crystal X-ray diffraction. AB - The excited state crystal structure of the ionic complex (Nd(DMA)(4)(H(2)O)(4) Fe(CN)(6).3H(2)O (DMA = dimethylacetamide) has been determined at 15 K upon UV illumination by single crystal X-ray diffraction. Significant structural changes are observed around the Fe site in the excited state. These changes are similar to those observed for a related molecular compound exhibiting photomagnetic properties. PMID- 21789296 TI - The application of DNA and RNA G-quadruplexes to therapeutic medicines. AB - The intriguing structural diversity in folded topologies available to guanine rich nucleic acid repeat sequences have made four-stranded G-quadruplex structures the focus of both basic and applied research, from cancer biology and novel therapeutics through to nanoelectronics. Distributed widely in the human genome as targets for regulating gene expression and chromosomal maintenance, they offer unique avenues for future cancer drug development. In particular, the recent advances in chemical and structural biology have enabled the construction of bespoke selective DNA based aptamers to be used as novel therapeutic agents and access to detailed structural models for structure based drug discovery. In this critical review, we will explore the important underlying characteristics of G-quadruplexes that make them functional, stable, and predictable nanoscaffolds. We will review the current structural database of folding topologies, molecular interfaces and novel interaction surfaces, with a consideration to their future exploitation in drug discovery, molecular biology, supermolecular assembly and aptamer design. In recent years the number of potential applications for G quadruplex motifs has rapidly grown, so in this review we aim to explore the many future challenges and highlight where possible successes may lie. We will highlight the similarities and differences between DNA and RNA folded G quadruplexes in terms of stability, distribution, and exploitability as small molecule targets. Finally, we will provide a detailed review of basic G quadruplex geometry, experimental tools used, and a critical evaluation of the application of high-resolution structural biology and its ability to provide meaningful and valid models for future applications (255 references). PMID- 21789298 TI - Engineering superlyophobic surfaces as the microfluidic platform for droplet manipulation. AB - We propose robust engineering superlyophobic surfaces (SLS) as a universal microfluidic platform for droplet manipulation enabling electric actuation, featured with characteristics of highly nonwetting, low adhesion, and low friction for various liquids including water and oil. To functionalize SLS with embedded electrodes, two configurations with continuous and discrete topologies have been designed and compared. The discrete configuration is found to be superior upon comparison of their fabrication, microstructures and nonwetting performances. We also present new formulation of SLS pressure stability for linear, square and hexagonal pattern layouts, and propose a criterion for three wetting states (the Cassie-Baxter, partial Cassie-Baxter and Wenzel states) by introducing two dimensionless parameters, which are supported by our experimental data. Droplet manipulation experiments including deformation and transport on electrode-embedded SLS were performed, showing that present SLS reduce adhesion and flow resistance of oil droplets respectively by 98% and 73% compared with a smooth hydrophobic surface, and the excellent hydrodynamic performances are applicable for a wide range of droplet velocity. Simulation of an oil droplet electrically actuated on SLS predicts the significantly increased droplet motion for a low solid fraction and a relatively large droplet size. PMID- 21789299 TI - Polyoxometalate-supported ruthenium nanoparticles as bifunctional heterogeneous catalysts for the conversions of cellobiose and cellulose into sorbitol under mild conditions. AB - Ru nanoparticles loaded on a Keggin-type polyoxometalate (Cs(3)PW(12)O(40)), which did not possess strong intrinsic acidity, efficiently catalysed the conversions of cellobiose and cellulose into sorbitol in water medium in H(2) at <=433 K. The Bronsted acid sites generated in situ from H(2) have been demonstrated to play a key role in the formation of sorbitol. PMID- 21789300 TI - AFM investigation of Pseudomonas aeruginosa lectin LecA (PA-IL) filaments induced by multivalent glycoclusters. AB - Atomic force microscopy reveals that Pseudomonas aeruginosa LecA (PA-IL) and a tetra-galactosylated 1,3-alternate calix[4]arene-based glycocluster self-assemble according to an aggregative chelate binding mode to create monodimensional filaments. Lectin oligomers are identified along the filaments and defects in chelate binding generate branches and bifurcations. A molecular model with alternate 90 degrees orientation of LecA tetramers is proposed to describe the organisation of lectins and glycoclusters in the filaments. PMID- 21789301 TI - Structural characterization and DFT study of V(IV)O(acac)2 in imidazolium ionic liquids. AB - We report the structural characterization of vanadyl acetylacetonate in imidazolium room temperature ionic liquids--bbimNTf(2), bmimNTf(2), C(3)OmimNTf(2), bm(2)imNTf(2), bmimPF(6), bmimOTf, bmimBF(4), bmimMeCO(2), bmimMeSO(4), bmimMe(2)PO(4) and bmimN(CN)(2)--and organic solvents. The complex was characterized by visible electronic (Vis) and EPR spectroscopies. VO(acac)(2) shows solvatochromism in the selected ionic liquids and behaves as in organic solvents, evidencing coordination of the ionic liquid anion in the solvents with higher coordinating ability. The Lewis basicity order obtained for the IL anions was: PF(6)(-) < NTf(2)(-) < OTf(-)~ MeCO(2)(-) < MeSO(4)(-) < BF(4)(-)~ N(CN)(2)( ) < Me(2)PO(4)(-). The solvent effect on the spectroscopic data was tentatively examined using linear solvation energy relationships based on the Kamlet-Taft solvent scale (alpha, beta and pi*), however no suitable correlation was found with all data. The EPR characterization showed the presence of two isomers in bmimOTf, bmimMeCO(2) and bmimMe(2)PO(4), suggesting coordination of the ionic liquid anions in both equatorial and axial positions. The full geometry optimization of cis-/trans-VO(acac)(2)(OTf)(-) and cis-/trans VO(acac)(2)(OTf)(mmim) structures was done at the B3P86/6-31G* level of theory. The calculations confirm that the anion OTf(-) is able to coordinate to VO(acac)(2) with the trans isomer being more stable than the cis by 4.8 kcal mol( 1). PMID- 21789302 TI - Spectroscopy of nS, nP, and nD Rydberg series of Cs atoms on helium nanodroplets. AB - The preparation of an artificial superatom consisting of a positive charge inside a superfluid helium nanodroplet and an electron in an orbital surrounding the droplet is of fundamental interest and represents an experimental challenge. In this work, nanodroplets of several thousand helium atoms are doped with single caesium (Cs) atoms. While on the droplet, the Cs valence electron is excited in two steps through an intermediate state into nS, nP, and nD states. The excitation is monitored by laser induced fluorescence or, for high principal quantum numbers, by resonant three-photon-ionization. On-droplet Rydberg excitations are resolved up to about n = 20. The energies are compared with those of free Cs atom Rydberg states and quantum defects as well as the on-droplet ionization threshold are derived. PMID- 21789303 TI - Rotovibrational spectroscopy of hydrogen peroxide embedded in superfluid helium nanodroplets. AB - We report the infrared depletion spectrum of para- and ortho-hydrogen peroxide embedded in superfluid helium nanodroplets in the OH stretching region. Six transitions were observed in the antisymmetric stretching band (v(5)) of H(2)O(2), and three in the weaker symmetric stretching band (v(1)). While rotations about the b- and c-axes are slowed by a factor of ~0.4 relative to the gas phase, rotations about the a-axis are not significantly affected; this relates to the rotational speed about the a-axis being too fast for helium density to adiabatically follow. The trans tunneling splitting does not appear to be considerably affected by the helium droplet environment, and is reduced by only 6% relative to the gas phase, under the assumption that the vibrational shifts of the v(5) and v(1) torsional subbands are the same. The linewidths increase with increasing rotorsional energies, and are significantly narrower for energies which fall within the "phonon gap" of superfluid helium. These narrower lines are asymmetrically broadened, indicative of a dynamical coupling between the H(2)O(2) rotor and surrounding helium density. PMID- 21789304 TI - Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-alpha. AB - 2-Phenylquinoline (1) degraded proteins under photo-irradiation with long wavelength UV light without additives and under neutral conditions. We designed and synthesized a 2-phenylquinoline-estrogen receptor-alpha (ER-alpha) agonist (hybrid 2) and a 2-phenylquinoline-ER-alpha antagonist (hybrid 3) containing estradiol and 4-hydroxytamoxifen moieties, respectively. These 2-phenylquinoline hybrids effectively and selectively photo-degraded the target transcription factor, ER-alpha, which has a high affinity for estradiol and 4-hydroxytamoxifen. Target-selective photo-degradation was examined in both glass vessels and MCF-7 breast cancer cells, which are dependent upon ER-alpha for growth. In addition, 2 phenylquinoline-estradiol hybrid 2 functioned as an agonist of ER-alpha and promoted growth of MCF-7 in the absence of photo-irradiation, while it inhibited the growth of MCF-7 cells upon photo-irradiation due to the photo-degradation of ER-alpha. In contrast, 2-phenylquinoline-4-hydroxytamoxifen hybrid 3 inhibited growth of MCF-7 cells in the absence of photo-irradiation due to the antagonist effect of the 4-hydroxytamoxifen moiety against ER-alpha, and upon photo irradiation significantly inhibited cell growth due to the dual antagonist effect of the 4-hydroxytamoxifen moiety and photo-degradation of ER-alpha. PMID- 21789314 TI - Carotene location in processed food samples measured by cryo In-SEM Raman. AB - Cryo In-SEM Raman has been used for the first time to localise carotene compounds in a food matrix. Raman spectra of lycopene and beta-carotene have been obtained from sampling oil droplets and plant cell structures visualised with cryo-SEM in tomato and carrot based emulsions containing 5% oil. It was possible to identify the carotenoids in both the oil droplets and the cell walls. Furthermore our results gave some indication that the carotenoids were in the non-crystalline state. It has been suggested that a higher amount of carotenes solubilised into the oil phase of the food matrix would lead to a higher bioaccessibility, thus understanding the effect of processing conditions on micronutrients distribution in a food matrix might help the design of plant based food products with a better nutritional quality. This shows improved structural characterisation of the cryo SEM with the molecular sensitivity of Raman spectroscopy as a promising approach for complex biological problems. PMID- 21789315 TI - Collagen I and III and their decorin modified surfaces studied by atomic force microscopy and the elucidation of their affinity toward positive apolipoprotein B 100 residue by quartz crystal microbalance. AB - Collagen, the major component of extracellular matrix (ECM) and the most abundant protein in the human body, is implicated in the development of atherosclerosis. Collagen types I and III were immobilized on fused-silica capillary to investigate their shape, size and structure by atomic force microscopy (AFM). For comparison, collagen was also immobilized on a mica surface. Our studies demonstrated that not only does the adsorption pattern on the substrate vary with the type of collagen, but also the substrate material plays an important role in the fibril formation process. Decorin, which promotes the binding of low-density lipoprotein (LDL) particles with collagen, was investigated for its effect on the fibrillogenesis. On both substrate materials, addition of decorin clearly reduced the fibril diameter of collagen surfaces. Moreover, a quartz crystal microbalance (QCM)-based biosensor approach was applied to clarify and evaluate the affinity of different collagen coatings immobilized on a silicon dioxide sensor chip toward apolipoprotein B-100, the major protein of LDL. The results confirmed the importance of collagen type and their fibrillogenesis on the binding of the positive residues of apolipoprotein B-100 on negatively charged collagen surfaces. PMID- 21789316 TI - Nucleic acid-modulated silver nanoparticles: a new electrochemical platform for sensing chloride ion. AB - Inorganic nanomaterials have generated considerable interest in connection to the design of biosensors. Here we exploit the DNA-induced generation of silver nanoparticles for developing an electrical biosensing protocol for chloride ions. Conjugated with thiol modified oligonucleotide, silver nanoparticles were template-synthesized and immobilized on gold electrode. During cyclic voltammogram (CV) scans, the silver nanoparticles were oxidized at high potential to form a layer of Ag/AgCl complex in the presence of Cl(-), giving off sharp solid state redox signals. Under the optimum condition, the electrode responded to Cl(-) over a dynamic range of 2.0 * 10(-5)-0.01 M, with a detection limit of 5.0 * 10(-6) M. Moreover, the specific solubility product constant-based anion recognition made the electrode applicable at a wide pH range and in complex biological systems. To demonstrate the analytical applications of this sensor in real samples, the Cl(-) concentrations in human urine were measured without any sample pretreatment. Urinary Cl(-) detected by the proposed sensor ranged from 110 to 200 mM, which was comparable to the results obtained by standard silver titration. PMID- 21789317 TI - Self-assembly of polypeptide-based copolymers into diverse aggregates. AB - Recently, increasing attention has been given to the self-assembly behavior of polypeptide-based copolymers. Polypeptides can serve as either shell-forming or core-forming blocks in the formation of various aggregates. The solubility and rigidity of polypeptide blocks have been found to have a profound effect on the self-assembly behavior of polypeptide-based copolymers. Polypeptide graft copolymers combine the advantages of a grafting strategy and the characteristics of polypeptide chains and their self-assembly behavior can be easily adjusted by choosing different polymer chains and copolymer architectures. Fabricating hierarchical structures is one of the attractive topics of self-assembly research of polypeptide copolymers. These hierarchical structures are promising for use in preparing functional materials and, thus, attract increasing attention. Computer simulations have emerged as powerful tools to investigate the self-assembly behavior of polymers, such as polypeptides. These simulations not only support the experimental results, but also provide information that cannot be directly obtained from experiments. In this feature article, recent advances in both experimental and simulation studies for the self-assembly behavior of polypeptide based copolymers are reviewed. PMID- 21789318 TI - Hydrogen bonding mediated enantioselective organocatalysis in brine: significant rate acceleration and enhanced stereoselectivity in enantioselective Michael addition reactions of 1,3-dicarbonyls to beta-nitroolefins. AB - Brine provides remarkable rate acceleration and a higher level of stereoselectivity over organic solvents, due to the hydrophobic hydration effect, in the enantioselective Michael addition reactions of 1,3-dicarbonyls to beta nitroolefins using chiral H-donors as organocatalysts. PMID- 21789319 TI - Thermal annealing of SiC nanoparticles induces SWNT nucleation: evidence for a catalyst-independent VSS mechanism. AB - Density-functional tight-binding molecular dynamics (DFTB/MD) methods were employed to demonstrate single-walled carbon nanotube (SWNT) nucleation resulting from thermal annealing of SiC nanoparticles. SWNT nucleation in this case is preceded by a change of the SiC structure from a crystalline one, to one in which silicon and carbon are segregated. This structural transformation ultimately resulted in the formation of extended polyyne chains on the SiC nanoparticle surface. These polyyne chains subsequently coalesced, forming an extended sp(2) hybridized carbon cap on the SiC nanoparticle. The kinetics of this process were enhanced significantly at higher temperatures (2500 K), compared to lower temperatures (1200 K) and so directly correlated to the surface premelting behavior of the nanoparticle structure. Analysis of the SiC nanoparticle Lindemann index between 1000 and 3000 K indicated that SWNT nucleation at temperatures below 2600 K occurred in the solid, or quasi-solid, phase. Thus, the traditional vapor-liquid-solid mechanism of SWNT growth does not apply in the case of SiC nanoparticles. Instead, we propose that this example of SWNT nucleation constitutes evidence of a vapor-solid-solid process. This conclusion complements our recent observations regarding SWNT nucleation on SiO(2) nanoparticles (A. J. Page, K. R. S. Chandrakumar, S. Irle and K. Morokuma, J. Am. Chem. Soc., 2011, 133, 621-628). In addition, similarities between the atomistic SWNT nucleation mechanisms on SiC and SiO(2) catalysts provide the first evidence of a catalyst-independent SWNT nucleation mechanism with respect to 'non traditional' SWNT catalyst species. PMID- 21789320 TI - Reactions of coordinated hydroxymethylphosphines with NH-functional amines: the phosphorus lone pair is crucial for the phosphorus Mannich reaction. AB - Non-coordinated hydroxymethylphosphines react readily with primary and secondary amines by the phosphorus Mannich reaction. To determine if this reactivity can be used to synthesize phosphine macrocycles, trans-Fe(DHMPE)(2)Cl(2) (DHMPE = 1,2 bis(dihydroxymethylphosphino)ethane) was prepared and reacted with various amines. However, no phosphorus Mannich reactivity was observed. In order to understand why no reactions occurred, the Mannich reactivity of the borane coordinated hydroxymethylphosphines DHMPE.2BH(3) and Ph(2)PCH(2)OH.BH(3) was investigated. These borane-coordinated phosphines also did not undergo the phosphorus Mannich reaction. These results suggest that the lone pair of electrons on the phosphorus atom is essential for the phosphorus Mannich reaction to occur, and therefore it is not possible to use this reaction in a templated synthesis of phosphine macrocycles. It is speculated that the mechanism of the phosphorus Mannich reaction may involve a methylenephosphonium intermediate, analogous to an iminium in the standard Mannich reaction. X-ray crystal structures of trans-Fe(DHMPE)(2)Cl(2) and DHMPE.2BH(3) are also presented. Both crystal structures display an extended hydrogen-bonding network in the solid state. PMID- 21789321 TI - A series of tetranuclear lanthanide complexes comprising two edge-sharing triangular units with field-induced slow magnetic relaxation for Dy4 species. AB - The syntheses, crystal structures and magnetic studies are reported for a series of Ln(4) clusters formulated as Ln(4)(MU(3) OH)(2)(php)(2)(OAc)(6)(H(2)O)(2)].4MeOH.nH(2)O (Ln = Gd (1), Tb (2), Dy (3) (n = 2) and Ho (4) (n = 0); H(2)php = 2,6-(picolinoylhydrazone)pyridine). The overall metal core of each cluster is comprised of two edge-sharing triangular Ln(3) units linked by MU(3)-OH bridges. Direct-current (dc) magnetic susceptibility studies reveal that the Ln(III) ions are very weakly coupled in all four compounds. Alternating-current (ac) magnetic susceptibility studies for 3 indicate that field-induced slow relaxation phenomenon occurs for this compound. PMID- 21789322 TI - Flexible porous coordination polymers constructed from 1,2-bis(4 pyridyl)hydrazine via solvothermal in situ reduction of 4,4'-azopyridine. AB - Solvothermal reactions of Zn(NO(3))(2), 1,4-benzenedicarboxylic acid (H(2)bdc), and 4,4'-azopyridine (azpy) in different conditions yielded [Zn(bdc)(bphy)].DMF.H(2)O (1a, bphy = 1,2-bis(4-pyridyl)hydrazine, DMF = N,N dimethylformamide) and [Zn(bdc)(bphy)].EtOH.H(2)O (1b) with two-fold interpenetrated dmp topology and [Zn(2)(bdc)(2)(bphy)].1.5EtOH.H(2)O (2a) and [Zn(2)(bdc)(2)(bphy)].DMA.1.5H(2)O (2b, DMA = N,N-dimethylacetamide) with two fold interpenetrated pcu topology. The in situ reduction of azpy to bphy was confirmed by single-crystal structures and LC-MS analyses of the acid-digested crystalline samples, as well as controlled solvothermal experiments. Removal of the guest molecules in 1a/1b and 2a/2b converts the materials to guest-free phases [Zn(bdc)(bphy)] (1) and [Zn(2)(bdc)(2)(bphy)] (2), respectively, which were identified by PXRD. CO(2) sorption experiments performed at 195 and 298 K showed low porosity for 1 and gated sorption behavior for 2. At 298 K, 2 exhibits high selectivity for adsorbing CO(2) over CH(4). PMID- 21789323 TI - Isotopic evidence of unaccounted for Fe and Cu erythropoietic pathways. AB - Despite its potential importance for understanding perturbations in the Fe-Cu homeostatic pathways, the natural isotopic variability of these metals in the human body remains unexplored. We measured the Fe, Cu, and Zn isotope compositions of total blood, serum, and red blood cells of ~50 young blood donors by multiple-collector ICP-MS after separation and purification by anion exchange chromatography. Zinc shows much less overall isotopic variability than Fe and Cu, which indicates that isotope fractionation depends more on redox conditions than on ligand coordination. On average, Fe in erythrocytes is isotopically light with respect to serum, whereas Cu is heavy. Iron and Cu isotope compositions clearly separate erythrocytes of men and women. Fe and Cu from B-type men erythrocytes are visibly more fractionated than all the other blood types. Isotope compositions provide an original method for evaluating metal mass balance and homeostasis. Natural isotope variability shows that the current models of Fe and Cu erythropoiesis violate mass balance requirements. It unveils unsuspected major pathways for Fe, with erythropoietic production of isotopically heavy ferritin and hemosiderin, and for Cu, with isotopically light Cu being largely channeled into blood and lymphatic circulation rather than into superoxide dismutase-laden erythrocytes. Iron isotopes provide an intrinsic measuring rod of the erythropoietic yield, while Cu isotopes seem to gauge the relative activity of erythropoiesis and lymphatics. PMID- 21789324 TI - The oxidative stress of zinc deficiency. AB - Zinc is an essential catalytic and structural cofactor for many enzymes and other proteins. While Zn2+ is not redox active under physiological conditions, it has been known for many years that zinc deficiency causes increased oxidative stress and, consequently, increased oxidative damage to DNA, proteins, and lipids. These results have indicated that zinc plays an indirect antioxidant role and that dietary inadequacy may contribute to human diseases such as cancer. Recent studies are helping to identify the primary sources of oxidative stress in low zinc. In addition, through studies of the model eukaryotic cell, Saccharomyces cerevisiae, we are now beginning to understand the strategies cells use to limit this stress and reduce its damage. PMID- 21789325 TI - The development of a silica nanoparticle-based label-free DNA biosensor. AB - A silica nanoparticle-based DNA biosensor capable of detecting Bacillus anthracis bacteria through the use of unlabelled ss-oligonucleotides has been developed. The biosensor makes use of the optical changes that accompany a nanoparticle immobilized cationic conjugated polymer (polythiophene) interacting with single stranded vs. hybridized oligonucleotides, where a fluorescence signal appears only when hybridized DNA is present (i.e. only when the ss-oligonucleotide interacting with the polymer has hybridized with its complement). In order to enhance the sensitivity of the biosensor, two different nanoparticle architectures were developed and used to elucidate how the presence of neighboring fluorophores on the nanoparticle surface affects Forster-resonant energy transfer (FRET) between the polythiophene/oligonucleotide complex (FRET donor) and the fluorophores (FRET acceptors). We demonstrate that the silica nanoparticle-based FRET platform lowers the limit of detection at least 10-fold in comparison to the polythiophene itself, and allows the detection of ~2 * 10( 12) moles of ss-oligonucleotide in a 100 MUL sample with a standard fluorimeter (i.e. has a limit of detection of ~2 nM ssDNA). Such nanoparticle-based biosensor platforms are beneficial because of the robustness and stability inherent to their covalent assembly and they provide a valuable new tool that may allow for the sensitive, label-free detection (the target DNA that produces the fluorescence signal is unlabelled) without the use of polymerase chain reaction. PMID- 21789326 TI - Protonation effects on the resonance Raman properties of a novel (terpyridine)Ru(4H-imidazole) complex: an experimental and theoretical case study. AB - The optically active states in a novel (terpyridine)Ru(4H-imidazole) complex displaying an unusually broad and red-shifted absorption in the visible range are investigated experimentally and theoretically. Since this property renders the complex promising for an application as sensitizer in dye-sensitized solar cells, a detailed knowledge on the correlation between features in the absorption spectrum and structural elements is indispensable in order to develop strategies for spectroscopy/theory-guided design of such molecular components. To this aim, time-dependent density functional theory calculations, including solvent effects, are employed to analyze the experimental UV-vis absorption and resonance Raman (RR) spectra of the unprotonated and protonated forms of the complex. This provides a detailed photophysical picture for a complex belonging to a novel class of Ru-polypyridine black absorbers, which can be tuned by external pH stimuli. The complex presents two absorption maxima in the visible region, which are assigned by the calculations to metal-to-ligand charge transfer (MLCT) and intra-ligand states, respectively. RR simulations are performed in resonance with both bands and are found to correctly reproduce the observed effects of protonation. Finally, the examination of the molecular orbitals and of the RR spectra for the MLCT state shows that protonation favors a charge transfer excitation to the 4H-imidazole ligand. PMID- 21789327 TI - Polycyclic aromatic hydrocarbons with molecular weight 302 in PM 2.5 at two industrial sites in South China. AB - Daytime and nighttime PM(2.5) samples were collected between August 5 and 16, 2009 and between January 24 and February 4, 2010 in an industrial complex site (site A) and an electronic waste recycling site (site B) to determine the seasonal and diurnal variations of 19 individual polycyclic aromatic hydrocarbons (PAHs) with molecular weight 302 (MW302) including four highly carcinogenic dibenzopyrene (DBP) isomers dibenzo[a,l]pyrene (DBalP), dibenzo[a,e]pyrene (DBaeP), dibenzo[a,i]pyrene (DBaiP), and dibenzo[a,h]pyrene (DBahP). This is the first report on DBP isomers in air particles from South China. The total concentration of PAH MW302 isomers ranged from 1.65 to 3.60 ng m(-3) in summer and 3.82 to 9.81 ng m(-3) in winter. The strongest peaks in the chromatograms of the MW302 isomers were naphtha[2,1-a]pyrene (N21aP), dibenzo[j,l]fluoranthene (DBjlF), naphtha[1,2-b]fluoranthene (N12bF), naphtha[1,2-k]fluoranthene (N12kF) and dibenzo[a,e]fluoranthene (DBaeF), constituting 52.0 to 55.4% of the total MW302 isomers. All the MW302 isomers showed notable seasonal variations. Most of the MW302 isomers in site B showed distinctive diurnal variations with higher concentrations occurring in the night. Taking into account both concentration and potency equivalence factors (PEFs), the strongest carcinogen in the analyzed samples was DBaiP, and the ratios of sum carcinogenic potency of four highly carcinogenic DBP isomers to benzo[a]pyrene (BaP) was about 0.94 in winter to 1.89 in summer, indicating the importance of DBP isomers for the risk assessment. Health risk assessment indicated that on average, 1 in 100 000 residents in the two industrial sites may have an increased risk of cancer due to PAH exposure. PMID- 21789328 TI - Unsurpassed cage effect for the photolysis of dibenzyl ketones in water-soluble dendrimers. AB - Amphiphilic water-soluble poly(alkyl aryl ether) dendrimers Gn (n = 1-3) with charge-neutral tetraethylene glycol monomethyl ethers at their periphery were synthesized as microreactors to control the photochemical reactions of dibenzyl ketone derivatives in aqueous solutions. Photophysical studies demonstrated that Gn can encapsulate organic molecules and provide a hydrophobic microenvironment. The product distribution of photolysis of dibenzyl ketone derivatives can be successfully controlled by encapsulating the substrates within dendrimers, and an unsurpassed cage effect of 1.00 is reached in high generation dendrimers, revealing that a thick and compact "shell" was formed at the periphery of the dendrimers. The cage effect is also significantly influenced by the substituent at the para-position of the guest molecules. The higher generation dendrimers exhibit a better confined microenvironment and the aggregates possess more compact cavities to "lock" the guests than the corresponding unimolecular dendrimers. After photolysis, the separation of products can be easily achieved by extracting from the dendrimer solutions and the dendrimers are simply recovered and reused. PMID- 21789329 TI - Synthesis, structures, redox and photophysical properties of benzodifuran functionalised pyrene and anthracene fluorophores. AB - Benzodifuran-functionalised pyrene and anthracene fluorophores 1 and 2 were obtained in reasonable yields. Their single crystal structures, electrochemical, optical absorption, and fluorescence characteristics have been described. They show strong luminescence with high quantum yields of 0.53 for 1 and 0.48 for 2. PMID- 21789330 TI - Synthesis and coordination chemistry of macrocyclic ligands featuring NHC donor groups. AB - Poly-NHC (NHC = N-heterocyclic carbene) ligands emerged almost immediately after the first stable NHCs had been described. Macrocyclic ligands, featuring NHC donor groups and their metal complexes, however, remained rare until recently. This perspective highlights modern developments in the fields of synthesis and coordination chemistry of macrocyclic poly-NHC ligands. These include the synthesis of tetracarbene ligands which were obtained from complexes of beta functionalized isocyanides followed by cyclization of the coordinated iscocyanide ligands to NH,NH-functionalized NHCs and the subsequent metal template controlled bridging alkylation of the NH,NH-NHCs to yield the macrocycle. The template synthesis of ligands featuring a mixed NHC/phosphine donor set like [11]ane P(2)C(NHC) and [16]ane-P(2)C(NHC)(2) by linkage of NH,NH-NHCs to different phosphines is also presented. Finally, methods for the preparation of cyclic polyazolium salts, their deprotonation and metalation and the different modes of coordination of such macrocyclic poly-NHC ligands are discussed. PMID- 21789331 TI - Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon. AB - An easy-to-prepare, reusable and versatile catalyst consisting of oxidised copper nanoparticles on activated carbon has been fully characterised and found to effectively promote the multicomponent synthesis of 1,2,3-triazoles from organic halides, diazonium salts, and aromatic amines in water at a low copper loading. PMID- 21789332 TI - Metal-organic frameworks post-synthetically modified with ferrocenyl groups: framework effects on redox processes and surface conduction. AB - Metal-organic framework (MOF) materials based on zinc(II) and aluminium(III) dicarboxylate frameworks with covalently attached ferrocene functional redox groups were synthesised by post-synthetic modification and investigated by voltammetry in aqueous and non-aqueous media. In the voltammetry experiments, ferrocene oxidation occurs in all cases, but chemically reversible and stable ferrocene oxidation without decay of the voltammetric response requires a "mild" dichloroethane solvent environment. The voltammetric response in this case is identified as "surface-confined" with fast surface-hopping of electrons and without affecting the bulk of MOF microcrystals. In aqueous media a more complex pH-dependent multi-stage redox process is observed associated with chemically irreversible bulk oxidation and disintegration of the MOF framework. A characteristic 30 mV per pH unit dependence of redox potentials is observed attributed to a "framework effect": the hydroxide-driven MOF framework dissolution. PMID- 21789333 TI - Occurrence of PAHs and PCBs in the Alna River, Oslo (Norway). AB - Thirty two polychlorinated biphenyl congeners (PCBs), hexachlorobenzene (HCB) and pentachlorobenzene (PeCB) were analysed in passive sampler extracts from surface water-exposed semipermeable membrane devices (SPMDs) and in bed sediment samples from a small urban watercourse, the River Alna (Oslo, Norway). Performance reference compound-corrected data from the passive samplers deployed at three sites along the river were used to track PCB contamination in the overlying water. SPMDs were able to detect an increase in dissolved PCB concentrations at the site furthest downstream that was corroborated by bed sediment concentrations. In comparison, no major increase in concentration of HCB, PeCB or PAHs could be observed. Comparison of passive sampling-based overlying water concentrations with total concentrations measured in bed sediments supports the possibility of further PCB sources upstream of the study area. Diagnostic PAH ratios (from SPMDs) and PCB congener pattern (from sediments) were used in an attempt to identify possible contaminant sources to the Alna River. Selected PAH diagnostic ratios support a multiple emission source scenario and demonstrate the complexity of identifying specific sources of these compounds to surface waters. PCB congener patterns in sediments from all three sites tend to indicate a source of highly chlorinated PCBs (of the Archlor 1260 type) and either a source of lower chlorinated PCBs or the less-likely occurrence of dechlorination in sediment. Information collected during the present screening study also confirms the Alna River as a continuous source of PCBs to the Oslofjord. PMID- 21789334 TI - Towards understanding the effects of carbon and nitrogen-doped carbon coating on the electrochemical performance of Li4Ti5O12 in lithium ion batteries: a combined experimental and theoretical study. AB - We investigate the effects of carbon coating, with and without nitrogen-dopants, on the electrochemical performance of a promising anode material Li(4)Ti(5)O(12) (LTO) in lithium ion battery applications. The comparative experimental results show that LTO samples coated with nitrogen-doped carbon derived from pyridine and an ionic liquid exhibit significant improvements in rate capability and cycling performance compared with a LTO sample coated by carbon derived from toluene and the pristine LTO sample. For the first time, we construct an atomistic model for the interface between the lithium transition metal oxide and carbon coating layers. Our first-principles calculations based on density functional theory reveal that at this interface there is strong binding between the graphene coating layer and the Ti-terminated LTO surface, which significantly reduces the chemical activity of LTO surfaces and stabilizes the electrode/electrolyte interface, providing a clue to solve the swelling problem for LTO-based batteries. More importantly, electron transfer from the LTO surface to graphene greatly improves the electric conductivity of the interface. Nitrogen-dopants in graphene coatings further increase the interfacial stability and electric conductivity, which is beneficial to the electrochemical performance in energy storage applications. PMID- 21789335 TI - A microfluidic device for performing pressure-driven separations. AB - Microchannels in microfluidic devices are frequently chemically modified to introduce specific functional elements or operational modalities. In this work, we describe a miniaturized hydraulic pump created by coating selective channels in a glass microfluidic manifold with a polyelectrolyte multilayer (PEM) that alters the surface charge of the substrate. Pressure-driven flow is generated due to a mismatch in the electroosmotic flow (EOF) rates induced upon the application of an electric field to a tee channel junction that has one arm coated with a positively charged PEM and the other arm left uncoated in its native state. In this design, the channels that generate the hydraulic pressure are interconnected via the third arm of the tee to a field-free analysis channel for performing pressure-driven separations. We have also shown that modifications in the cross sectional area of the channels in the pumping unit can enhance the hydrodynamic flow through the separation section of the manifold. The integrated device has been demonstrated by separating Coumarin dyes in the field-free analysis channel using open-channel liquid chromatography under pressure-driven flow conditions. PMID- 21789336 TI - Linking molecular feature space and disease terms for the immunosuppressive drug rapamycin. AB - Next to development of novel drugs also drug repositioning appears promising for tackling unmet clinical needs. Here Omics provided the ground for novel analysis strategies for linking drug and disease by integrating profiles on the molecular as well as the clinical data level. We developed a workflow for linking drugs and diseases for identifying repositioning options, and exemplify the procedure for the immunosuppressive drug rapamycin. Our strategy rests on delineating a drug specific molecular profile by combining Omics data reflecting the drug's impact on the cellular status as well as drug-associated molecular features extracted from the scientific literature. For rapamycin the respective profile held 905 unique molecular features reflecting defined molecular processes as identified by molecular pathway and process enrichment analysis. Literature mining identified 419 diseases significantly associated with this rapamycin molecular feature list, and transforming the significance of gene-disease associations into a continuous score allowed us to compute ROC and precision-recall for comparing this disease list with diseases already undergoing clinical trials utilizing rapamycin. The AUC of this assignment was computed as 0.84, indicating excellent recovery of relevant disease terms solely based on the drug molecular feature profile. We verified relevant indications by comparing molecular feature sets characteristic for the identified diseases to the drug molecular feature profile, demonstrating highly significant overlaps. The presented workflow allowed positive identification of diseases associated with rapamycin utilizing the drug-specific molecular feature profile, and may be well applicable to other drugs of interest. PMID- 21789337 TI - Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study. AB - It was the aim of this study to determine the efficacy and safety of vitamin K antagonists (VKAs) and acetylsalicylic acid (ASA) in patients with non-valvular atrial fibrillation (AF), with separate analyses according to predicted thromboembolic and bleeding risk. By individual level-linkage of nationwide registries, we identified all patients discharged with non-valvular AF in Denmark (n=132,372). For every patient, the risk of stroke and bleeding was calculated by CHADS2, CHA2DS2-VASc, and HAS-BLED. During follow-up, treatment with VKA and ASA was determined time-dependently. VKA consistently lowered the risk of thromboembolism compared to ASA and no treatment; the combination of VKA+ASA did not yield any additional benefit. In patients at high thromboembolic risk, hazard ratios (95% confidence interval) for thromboembolism were: 1.81 (1.73-1.90), 1.14 (1.06-1.23), and 1.86 (1.78-1.95) for ASA, VKA+ASA, and no treatment, respectively, compared to VKA. The risk of bleeding was increased with VKA, ASA, and VKA+ASA compared to no treatment, the hazard ratios were: 1.0 (VKA; reference), 0.93 (ASA; 0.89-0.97), 1.64 (VKA+ASA; 1.55-1.74), and 0.84 (no treatment; 0.81-0.88), respectively. There was a neutral or positive net clinical benefit (ischaemic stroke vs. intracranial haemorrhage) with VKA alone in patients with a CHADS2 score of >= 0, and CHA2DS2-VASc score of >= 1. This large cohort study confirms the efficacy of VKA and no effect of ASA treatment on the risk of stroke/thromboembolism. Also, the risk of bleeding was increased with both VKA and ASA treatment, but the net clinical benefit was clearly positive, in favour of VKA in patients with increased risk of stroke/thromboembolism. PMID- 21789338 TI - [German guidelines for brain tumour imaging by PET and SPECT using labelled amino acids]. AB - For the primary diagnosis of brain tumours, morphological imaging by means of magnetic resonance imaging (MRI) is the current method of choice. The complementary use of functional imaging by positron emitting tomography (PET) and single photon emitting computerized tomography (SPECT) with labelled amino acids can provide significant information on some clinically relevant questions, which are beyond the capacity of MRI. These diagnostic issues affect in particular the improvement of biopsy targeting and tumour delineation for surgery and radiotherapy planning. In addition, amino acid labelled PET and SPECT tracers are helpful for the differentiation between tumour recurrence and non-specific post therapeutic tissue changes, in predicting prognosis of low grade gliomas, and for metabolic monitoring of treatment response. The application of dynamic PET examination protocols for the assessment of amino acid kinetics has been shown to enable an improved non-invasive tumour grading. The purpose of this guideline is to provide practical assistance for indication, examination procedure and image analysis of brain PET/SPECT with labelled amino acids in order to allow for a high quality standard of the method. After a short introduction on pathobiochemistry and radiopharmacy of amino acid labelled tracers, concrete and detailed information is given on the several indications, patient preparation and examination protocols as well as on data reconstruction, visual and quantitative image analysis and interpretation. In addition, possible pitfalls are described, and the relevant original publications are listed for further information. PMID- 21789339 TI - (211)At-antiCD33 in NMRI nu/nu mice. Biodistribution, in vivo stability and radiotoxicity. AB - The aim of this study is to verify the in vivo stability, to determine the biodistribution and to estimate the unspecific radiotoxicity of an (211)At labelled CD33-antibody ((211)At-antiCD33) in mice with a view to therapeutic application in treating leukaemia. ANIMALS, METHODS: (211)At was produced via the (209)Bi(a,2n)(211)At reaction and was linked via 3-(211)At-succinimidyl-benzoate to the antiCD33-antibody. The biodistribution and the in vivo stability in serum were determined after i.v.-injection in NMRI nu/nu-mice. For toxicity experiments, mice received either three times 315-650 kBq (211)At-antiCD33 or unlabelled antibody and NaCl-solution respectively. RESULTS: (211)At-antiCD33 showed a characteristic biodistribution complying with the unspecific antibody retention in the reticular endothelial system. The largest proportion of radioactivity remained in blood and blood-rich tissues with a minor accumulation in the thyroid and stomach. After 21 h, >85% of activity in serum still represented intact antibody. Mice showed no difference in unspecific toxicity of (211)At-labelled antibodies over six months compared to those treated with unlabelled antibody and NaCl-solution respectively, with regard to histopathologic lesions, survival time, behaviour and haemograms. CONCLUSION: The radiolabelling method yielded adequate in vivo stability of (211)At-antiCD33. Biodistribution with rapid elimination of free (211)At via kidneys and urine complies with requirements for targeted therapy. Activity doses potentially required for treatment do not elicit radiotoxicity to normal organs in mice. Further development is required to enhance the apparent specific activity and to verify the efficacy in an adequate animal model before phase I clinical studies in leukaemia can be envisaged. PMID- 21789341 TI - Case 3/2011: male, smoker, hypertensive and alcohol consumer, with rapidly progressive heart failure. PMID- 21789340 TI - [Scintigraphically "hot" thyroid nodules mainly go hand in hand with a normal TSH]. AB - AIM: In recent years, various professional societies published guidelines for diagnostic evaluation of thyroid nodules, in which the indication for scintigraphy is restricted to patients with subnormal TSH values. It is seen controversial whether such recommendations should be transferred to Germany, partly because of lower iodine intake in this country and the consequent higher percentage of autonomous thyroid nodules, which are not accompanied by a measurable dysfunction. Since reliable data to this topic are scarce, we analyzed multicentrically the spectrum of scintigraphically "hot" and "warm" nodules under the current epidemiological conditions. PATIENTS, METHODS: In 10 German nuclear medicine out-patient institutions we evaluated the diagnostic data from a total of 514 patients, in whom unequivocally hyperfunctional nodules (focal increased uptake in comparison to perinodular tissue with a sonographically nodular correlative >=1 cm) could be detected by (99m)Tc-pertechnetate scintigraphy. To minimize selection bias, the surveys were not carried out in hospitals.The recorded parameters included the thyroid hormone levels, the global (99m)Tc uptake (TcTU), the size of each nodule and the total autonomous nodular volume (V(aut)). RESULTS: Only 20% of the patients with "hot" nodules had subnormal TSH levels (<0.1 to 0.33 mU / l), the remaining patients had TSH levels from 0.34 to 3.5 mU /l (in one third of the patients TSH levels even exceeded 1.0 mU/l). Moreover, we found no relevant correlation between TSH and TcTU or V(aut). CONCLUSIONS: In Germany, in at far the largest proportion of patients with autonomous thyroid nodules objectified by means of scintigraphy, TSH levels are within the normal range. Since such nodules with maximum safety can be classified as benign, a corresponding scintigraphic finding has a high priority for the patient. These current data support that it is not reasonable to restrict scintigraphy to patients with subnormal TSH values in this country. PMID- 21789342 TI - Pulmonary hypertension in infants linked to horseshoe lung: case report. AB - This is the case report of a young infant with early respiratory distress and pulmonary hypertension, diagnosed as a variant of horseshoe lung and we have reviewed the literature to seek information about this rare pulmonary malformation and its cardiac and hemodynamic repercussions. PMID- 21789343 TI - "Hyper-response" evaluated by 3D echocardiography after cardiac resynchronization therapy. AB - Cardiac resynchronization therapy consists of a promising treatment for patients with severe heart failure, but about 30% of patients do not exhibit clinical improvement with this procedure. However, approximately 10% of patients undergoing this therapy may have hyperresponsiveness, and three-dimensional echocardiography can provide an interesting option for the selection and evaluation of such patients. PMID- 21789344 TI - For patients with acute coronary syndrome, is initial measurement of troponin alone the best we have to offer? PMID- 21789345 TI - I Latin American Guidelines for the diagnosis and treatment of Chagas' heart disease: executive summary. AB - Much has been achieved in one century after Carlos Chagas' discovery. However, there is surely much to be done in the next decades. At present, we are witnessing many remarkable efforts to monitor the epidemiology of the disease, to better understand the biology of the T. cruzi and its interaction with human beings as well as the pathogenesis and pathophysiology of the complications in the chronic phase, and deal more appropriately and effectively with late cardiac and digestive manifestations. Although the vector and transfusion-derived transmission of the disease has been controlled in many countries, there remains a pressing need for sustained surveillance of the measures that led to this achievement. It is also necessary to adopt initiatives that enable appropriate management of social and medical conditions resulting from the migration of infected individuals to countries where the disease formerly did not exist. It's also necessary to standardize the most reliable methods of detection of infection with T. cruzi, not only for diagnosis purposes, but more crucially, as a cure criterion. The etiological treatment of millions of patients in the chronic stage of the disease is also to be unraveled. A renewed interest in this area is observed, including prospects of studies focusing on the association of drugs with benznidazole. We also wait for full evidence of the actual effectiveness of the etiological treatment to impact favorably on the natural history of the disease in its chronic phase. Eventually, cardiologists are primarily responsible for improving the clinical management of their patients with Chagas' disease, judiciously prescribing drugs and interventions that respect, as much as possible, the peculiar pathophysiology of the disease, wasting no plausible therapeutic opportunities. PMID- 21789346 TI - Heart failure with preserved ejection fraction: fighting misconceptions for a new approach. AB - Over the last decades, heart failure with preserved ejection fraction (HFpEF) has received less attention by the medical and scientific communities, which led to the emergence of a number of misconceptions concerning its characteristics, diagnostic and therapeutic approach. In recent years, new studies have changed the concepts traditionally associated with HFpEF, contributing to a new view towards this disease. This review is intended to discuss the latest evidence on HFpEF and to fight the main misconceptions associated with it in order to improve its diagnostic and therapeutic approach. Today we have several data showing that HFpEF is a condition that requires a different clinical approach from that used in systolic heart failure (SHF). HFpEF is no longer seen as a "benign" disease because it is associated with a poor prognosis and high prevalence. Its pathophysiology is complex and not fully clarified. In addition to diastolic dysfunction, we now know that other cardiac and extracardiac factors are also involved in its onset and progression. Using recent consensus guidelines we have objective criteria for its diagnosis, especially by using the new echocardiographic parameters for assessing diastolic function, including the E/e' ratio obtained by tissue Doppler. Finally, treatment of HFpEF remains unknown, because no therapeutic strategy has been shown to improve HFpEF prognosis. Thus, in this review we will also discuss the potentially new therapeutic targets for HFpEF. PMID- 21789347 TI - Acetylsalicylic acid and clopidogrel in the prevention of stent thrombosis. PMID- 21789348 TI - Statin in prevention of atrial fibrillation after cardiac surgery. PMID- 21789349 TI - Beta-blockers and dobutamine in heart failure: a safe combination? PMID- 21789351 TI - Anti-HBs levels among children and adolescents with complete immunization schedule against hepatitis B virus. A cross-sectional study in Blumenau, State of Santa Catarina, Brazil, 2007-2008. AB - INTRODUCTION: Vaccination is the main tool for preventing hepatitis B virus (HBV) infection; however, following the completion of the vaccination series, the concentrations of anti-HBs can decline over the years and reach levels less than 10mIU/mL. The persistence of protection in these individuals is still unknown. The present study aimed to determine the anti-HBs antibody levels among children and adolescents who had received a complete vaccination course for hepatitis B. METHODS: Antibodies against HBV surface antigen (anti-HBs) were tested in 371 individuals aged 10 to 15 years-old. RESULTS: Volunteers who showed undetectable quantities of anti-HBs accounted for 10.2% of the population studied and 39.9% presented antibody titers of less than 10mIU/mL. Anti-HBs >= 10mIU/mL were verified in 49.9%. CONCLUSIONS: These results corroborate other studies indicating levels of anti-HBs below 10mIU/mL in vaccinated individuals. Additional studies are required to assess whether this indicates susceptibility to HBV infection and the need and age for booster doses. PMID- 21789352 TI - Late onset sepsis and intestinal bacterial colonization in very low birth weight infants receiving long-term parenteral nutrition. AB - INTRODUCTION: The purpose of this study was to establish the late onset sepsis (LOS) rate of our service, characterize the intestinal microbiota and evaluate a possible association between gut flora and sepsis in surgical infants who were receiving parenteral nutrition (PN). METHODS: Surveillance cultures of the gut were taken at the start of PN and thereafter once a week. Specimens for blood culture were collected based on clinical criteria established by the medical staff. The central venous catheter (CVC) tip was removed under aseptic conditions. Standard laboratory methods were used to identify the microorganisms that grew on cultures of gut, blood and CVC tip. RESULTS: 74 very low birth weight infants were analyzed. All the infants were receiving PN and antibiotics when the gut culture was started. In total, 21 (28.4%) infants experienced 28 episodes of LOS with no identified source. Coagulase negative staphylococci were the most common bacteria identified, both in the intestine (74.2%) and blood (67.8%). All infections occurred in patients who received PN through a central venous catheter. Six infants experienced episodes of microbial translocation. CONCLUSIONS: In this study, LOS was the most frequent episode in neonates receiving parenteral nutrition who had been submitted to surgery; 28.6% of this infection was probably a gut-derived phenomenon and requires novel strategies for prevention. PMID- 21789353 TI - Molecular detection of Treponema pallidum sp. pallidum in blood samples of VDRL seroreactive women with lethal pregnancy outcomes: a retrospective observational study in northern Brazil. AB - INTRODUCTION: Although control measures of maternal and congenital syphilis are available in Brazil, difficulties exist within the healthcare network in providing a laboratory diagnosis of the infection during the prenatal period. The objective of this study was to confirm the presence of Treponema pallidum by PCR in women with positive VDRL serology and lethal pregnancy outcomes, i.e., abortion, stillbirth and neonatal death. METHODS: A retrospective study was conducted on VDRLseroreactive women with lethal pregnancy outcomes admitted to the Fundacao Santa Casa de Misericordia do Para (FSCM-PA) between January and July 2004. Serum samples and DNA from whole blood were obtained at the time of screening by the VDRL test. These samples were analyzed by IgG ELISA, IgM FTA-Abs and simple PCR (polA). RESULTS: During the study period, 0.7% (36/4,912) of women with lethal pregnancy outcomes presented a positive VDRL test. The polAgene was amplified in 72.7% (24/33) of these women, with 55.6% (20/36) and 94.4% (34/36) presenting IgM and IgG antibodies against T. pallidum, respectively. Comparison of these results showed a significant difference, with agreement between the PCR and IgM FTA-Abs results, suggesting that maternal syphilis was an active infection. No basic cause of death of the conceptus was reported in 97.2% (35/36) of cases. Among women who were submitted to the VDRL test during the prenatal period, only four of the nine seroreactive patients underwent treatment. CONCLUSIONS: The high frequency of syphilis in the group studied indicates the fragility of the service of infection diagnosis, treatment and monitoring, compromising epidemiological control. PMID- 21789354 TI - Dengue: clinical forms and risk groups in a high incidence city in the southeastern region of Brazil. AB - INTRODUCTION: The article describes the epidemiologic profile of dengue cases in Vitoria, the capital of Espirito Santo, Brazil, from 2000 to 2009, aimed at identifying risk groups regarding the incidence and severity of the disease. METHODS: Confirmed cases of dengue among city residents during ten years were classified as dengue fever, dengue hemorrhagic fever, dengue shock syndrome and dengue with complications, and analyzed according to sex, age, race-color and education. RESULTS: The proportion of dengue cases was highest among women aged 20 to 29 years-old and similar between whites and blacks. A gradual decrease occurred in the percentage of dengue cases in the population aged 15 years-old or more, in the historical series of 10 years, and a growing increase in individuals less than 15 years-old, showing statistical significance. The fatality rate ranged from zero to 0.3% for all forms of dengue and from 0.2% to 18.2% for severe forms. CONCLUSIONS: The profile of those affected by the disease in the municipality is similar to those affected in Brazil. The increasing number of cases in individuals under 15 years-old corroborates the results of recent studies in other Brazilian municipalities. PMID- 21789355 TI - Lessons from the epidemiological surveillance program, during the influenza A (H1N1) virus epidemic, in a reference university hospital of Southeastern Brazil. AB - INTRODUCTION: The case definition of influenza-like illness (ILI) is a powerful epidemiological tool during influenza epidemics. METHODS: A prospective cohort study was conducted to evaluate the impact of two definitions used as epidemiological tools, in adults and children, during the influenza A H1N1 epidemic. Patients were included if they had upper respiratory samples tested for influenza by real-time reverse transcriptase polymerase chain reaction during two periods, using the ILI definition (coughing + temperature <= 38oC) in period 1, and the definition of severe acute respiratory infection (ARS) (coughing + temperature <= 38oC and dyspnoea) in period 2. RESULTS: The study included 366 adults and 147 children, covering 243 cases of ILI and 270 cases of ARS. Laboratory confirmed cases of influenza were higher in adults (50%) than in children (21.6%) ( p < 0.0001) and influenza infection was more prevalent in the ILI definition (53%) than ARS (24.4%) (p < 0.0001). Adults reported more chills and myalgia than children (p = 0.0001). Oseltamivir was administered in 58% and 46% of adults and children with influenza A H1N1, respectively. The influenza A H1N1 case fatality rate was 7% in adults and 8.3% in children. The mean time from onset of illness until antiviral administration was 4 days. CONCLUSIONS: The modification of ILI to ARS definition resulted in less accuracy in influenza diagnosis and did not improve the appropriate time and use of antiviral medication. PMID- 21789356 TI - The mission of ABEC regarding the challenges faced by Brazilian periodicals. PMID- 21789357 TI - Electromyographic activity of shoulder muscles during exercises performed with oscillatory and non-oscillatory poles. AB - BACKGROUND: Pain and dysfunction of the shoulder complex are commonly found physiotherapy practice. These musculoskeletal abnormalities are related to instability and inadequate kinematic function, that depend on the integrity of the muscle tissues. Thus, to enhance the results of exercise therapies, and prevent and attenuate pain and dynfunction, the use of oscillatory pole has been implemented in clinical practice. OBJECTIVES: The purpose of this study was to analyze the electromyographic (EMG) activity of shoulder stabilizing muscles during exercises performed with an oscillatory and a non-oscillatory pole. METHODS: Twelve female volunteers, aged 20.4 years+/-1.9, participated in this study. EMG data were collected from upper trapezius (UT), lower trapezius (LT) and middle deltoid (MD) during three different exercises with an oscillatory and a non-oscillatory pole. The EMG signals were analyzed in the time domain through the calculation of Root Mean Square (RMS). The RMS values were normalized by the peak value obtained over all trials for each muscle. Statistical analysis was performed with repeated measures ANOVA and post-hoc of Bonferroni tests. RESULTS: The EMG activity of UT, LT and MD muscles were significantly higher with the oscillatory pole than the non-oscillatory pole (all p<0,001). There were no significant differences in the activation of these muscles between exercises. CONCLUSION: The results of the present study indicated that the oscillatory pole does require higher activation of the shoulder muscles and therefore, may be useful in the training of the shoulder complex. PMID- 21789358 TI - Predictive values at risk of falling in physically active and no active elderly with Berg Balance Scale. AB - BACKGROUND: The consequences of falls are a major cause of autonomy and independence loss among the elderly. In this context, the Berg Balance Scale (BBS) has been widely used to detect the risk of falls in elderly. OBJECTIVE: To evaluate the predictive value of the BBS for fall risk in physically active and inactive elderly subjects. METHODS: The sample included 188 older adults with a mean age of 66 (+/-9) years. Of these, 91 participated in a regular physical activity program and 96 did not. We analyzed the cut-off scores of 45, 47, 49, 51 and 53 in both groups regarding the sensitivity (S), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the test, including the positive likelihood ratio (PLR) and negative likelihood ratio (RVN) for diagnosing the risk of falls. RESULTS: The mean BBS score was 54.7 in physically active subjects and 50.8 in inactive subjects, which was statistically significant (rho=0.001). The best cut-off was a score of 49 for physically inactive subjects, with a sensitivity of 91% and a specificity of 92%. On the other hand, the BBS had low sensitivity (from 0 to 15%) and high specificity (between 83% and 100%) for physically active subjects at the cut-off points analyzed. CONCLUSION: The scale did not achieve sufficient sensitivity to individual differences among physically active older people with higher levels of functional balance ability. PMID- 21789359 TI - Analysis of cardiovascular system responses to forced vital capacity in COPD. AB - BACKGROUND: The forced vital capacity (FVC) test is routinely performed to evaluate pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, the influence of the FVC maneuver on the cardiovascular system of patients with COPD is poorly understood. OBJECTIVES: To analyze the behavior of heart rate (HR), blood pressure (BP) and heart rate variability (HRV) during the FVC test in COPD patients. METHODS: Nineteen men with COPD (72+/-7 years, GOLD stage I=3, II=5, III=7 and IV=4 patients) performed the FVC test while having their HR monitored. HRV was assessed in time (rMSSD) and frequency domains (LF, HF and LF/HF) at rest, before and after the best FVC maneuver. BP was measured at rest, immediately before and at the end of the test, as well as 10 minutes after the end of the test. RESULTS: At the beginning of the FVC maneuver, HR decreased (p<0.001) and then increased gradually until the end of the test (p<0.001). After the end of maneuver, HR continued to increase until it reached a peak (p<0.001), and then it fell quickly to below at-rest values (p<0.001) prior to returning to baseline. The BP and HRV indices did not change during the assessment. CONCLUSION: The FVC test influences the behavior of COPD patient HR without changing autonomic control or BP. PMID- 21789360 TI - Clinical profile, quality of life and depressive symptoms of women with urinary incontince attending a university hospital. AB - OBJECTIVES: To describe the characteristics of urinary incontinence (UI) and to evaluate its impact on health-related quality of life (QOL) and depressive symptoms in women referred for physical therapy at a university hospital. METHODS: A descriptive cross-sectional study with demographic data collection related to UI. All women were evaluated through examination and also through depression and QOL questionnaires. RESULTS: Forty-eight women were evaluated (53.8+/-10.9 years), 47.9% with mixed UI (MUI), 39.6% with stress UI (SUI) and 12.5% with urge UI (UUI). In 50% of the cases the urinary loss lasted between 3.3 and 10 years. There was no significant difference in the pelvic floor muscle strength among the different types of UI (P>0.05). Depressive symptoms were detected in 37% of the women. Changes in the QOL were observed in all three groups of women with UI. According to the King's Health Questionnaire (KHQ), women with MUI presented more compromised health perception and greater physical, social, daily activity and personal relationship limitations (P<0.05). The women with MUI presented a worse health perception (P<0.05) according to the WHOQOL Bref. CONCLUSION: Depressive symptoms were detected in more than a third of the women whose quality of life was adversely affected and the greatest impact was observed in the patients with MUI. PMID- 21789361 TI - Usual gait speed assessment in middle-aged and elderly Brazilian subjects. AB - OBJECTIVES: To evaluate the usual gait speed of asymptomatic adult and elderly Brazilians with a 10-meter walk test and to compare the results with foreign reference values. METHODS: Seventy-nine asymptomatic volunteers >=40 years old of both genders were assessed. After anamnesis, anthropometry and the application of a habitual physical activity questionnaire, the volunteers were submitted to a 10 meter walk test at usual speed by means of which gait speed, the number of steps and length of stride were calculated. RESULTS: Except for age, all study variables were significantly lower in women. Subjects >=70 years old presented a significantly lower gait speed than subjects between 40 and 49 years old and between 50 and 59 in both men (1.09+/-0.18 m/s, 1.35+/-0.11 m/s and 1.34+/-0.22 m/s, respectively) and women (1.02+/-0,10 m/s, 1.27+/-0.20 m/s and 1.27+/-0,15 m/s), respectively). Gait speed showed moderate correlations with age (r=-0.41, p<0.001) and height (r=0.35, p=0.001). After multiple regression analysis, age and gender were selected as relevant attributes of gait speed in that they explained 24.6% of this variable. The gait speed values in this study were significantly lower than foreign reference values (p<0.05). CONCLUSIONS: The gait speed presented age-related decline and values significantly lower than those described for foreign populations. This finding indicates the need for comprehensive investigation of gait speed reference values for the Brazilian population. PMID- 21789362 TI - Total hip arthroplasty in the elderly: impact on functional performance. AB - OBJECTIVES: To compare gait and functional performance parameters in elderly subjects who had or had not total hip arthroplasty (THA). METHODS: Our sample comprised 23 elderly subjects (72+/-6.5 years of age) with a mean of 2.6+/-1.3 years following THA, named the arthroplasty group (AG) and 23 asymptomatic elderly subjects (70.1+/-5.9 years of age), named the control group (CG). Case and control subjects were paired by gender, age, body mass index and level of physical activity. The GAITRite(r) system was used to analyze various gait parameters in four situations: usual speed (US), fast speed (FS), slow speed (SS) and dual task (DT); the Dynamic Gait Index (DGI) and Timed Up and Go test (TUG) methods were used to evaluate functional capacity. The statistical analyses were carried out using the Shapiro-Wilk test, Student's-t-tests for independent samples, chi-square tests, ANOVA for repeated measurements and paired Student's-t tests. RESULTS: The AG had the worst results for gait speed (AG=1.18+/-0.13 and CG=1.39+/-0.09; p=0.012), symmetry index (SI) of step length (AG=3.60+/-1.01 and CG=1.12+/-0.59; p=0.000), SI of step time (AG=-2.65+/-0.92 and CG=0.99+/-0.74; p=0.000), SI of stance phase (AG=-2.55 and CG=-1.04+/-0.50; p=0.005), SI of single support phase (AG=-2.17+/-0.78 and CG=1.21+/-0.51; p=0.003), DGI (AG=20.04+/-1.91 and CG=21.69+/-1.45; p=0.001) and TUG (AG=14.67+/-1.94 and CG=10.08+/-1.49; p=0.001). CONCLUSION: Elderly subjects with a history of THA had changes in gait parameters and lower performance in TUG test even 2.6+/-1,3 years after surgery, which suggests functional impairment. PMID- 21789363 TI - Does the BODE index reflect the level of physical activity in daily life in patients with COPD? AB - OBJECTIVES: To study the relationship between the level of physical activity in daily life and disease severity assessed by the BODE index in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sixty-seven patients with COPD (36 men) with forced expiratory volume in the first second (FEV(1)) of 39 (27-47)% predicted and age of 66 (61-72) years old were evaluated by spirometry, dyspnea levels (measured by the Medical Research Council scale, MRC) and by the 6 minute walking test (6MWT). The BODE index was calculated based on the body mass index (weight/height2), FEV(1), MRC and 6MWT, and then the patients were divided in four quartiles according to their scores (Quartile I: 0 to 2 points, n=15; Quartile II: 3 to 4 points, n=20; Quartile III: 5 to 6 points, n=23; Quartile IV: 7 to 10 points, n=9). Two activity monitors (DynaPort(r) and SenseWear(r)) were used to evaluate the level of physical activity in daily life. The Kruskal-Wallis test (Dunns's post-hoc test), the Mann-Whitney test and the Spearman Correlation Coefficient were used for statistical analysis. RESULTS: There were modest correlation between the BODE index and the time spent walking per day, the total daily energy expenditure and the time spent in moderate and vigorous activities per day (-0.32 <= r <= -0.47; p<=0.01 for all variables). When comparing the pooled quartiles I+II with III+IV, there were significant difference between the time spent walking per day, the total daily energy expenditure and the time spent in moderate activities per day (p<=0.05). CONCLUSION: The level of physical activity in daily life has a modest correlation with the classification of COPD severity assessed by the BODE index, reflecting only differences between patients with classified as mild-moderate and severe-very severe COPD. PMID- 21789364 TI - Relationship between very low birth weight, environmental factors, and motor and cognitive development of children of 5 and 6 years old. AB - OBJECTIVE: To examine the relationships between birth weight, preterm birth, environmental factors and the motor and cognitive development of 5 to 6 year-old children. METHODS: A case control study in which the motor and cognitive performance, as well as the home environment of children aged 5-6 years, born pre term and weighing <1.500 grams, were compared to peers born full-term and with normal weight. The following testes were used: Movement Assessment Battery for Children (MABC), the Developmental Coordination Disorder Questionnaire (DCDQ), the vocabulary and cube tests of the Weschsler Intelligence Test for Children-III (WISC), the Swanson, Nolan and Pelham IV Scale (SNAP IV) and the Home Observation for Measurement of the Environment (HOME). RESULTS: 50.54% of the very low birth weight (VLBW) children died and 15.2% of them demonstrated severe impairments. The scores (+/-SD) of the VLBW and normal birth weight (NBW) groups were: HOME 33.83+/-7.81(VLBW), 39.61+/-8.75(NBW); MABC 8.17+/-7,10(VLBW), 3.06+/-3.80(NBW); DCDQ 54.0+/-11.3(VLBW), 63.0+/-7.5(NBW); WISC Cubes 8.35+/-2.15(VLBW), 10.57+/ 2.25(NBW); WISC Vocabulary 9.61+/-2.62(VLBW), 13.48+/-2.45(NBW); SNAP IV 4.04+/ 4.95(VLBW), 1.57+/-3.27(NBW). Significant differences between the groups were found, with higher scores on all measures for the NBW group. The results of the motor and cognitive tests demonstrated correlations with birth weight (p<0.01) and HOME scores (p<0.05). CONCLUSIONS: The findings reaffirmed the evidences that children born pre-term and with VLBW were more vulnerable to have motor and cognitive impairments, compared to those born full-term. Environmental factors appeared to interfere with development of these children. PMID- 21789365 TI - Functional performance of upper limb and quality of life after sentinel lymph node biopsy of breast cancer. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is commonly used for the treatment of breast cancer with minimal surgical intervention as well as with low morbidity rates of upper limbs. OBJECTIVES: The aim of the present study was to investigate possible impairments and functional performance of the upper limb on activities of daily living (ADL) and health related quality of life (HRQL) among women treated through SLNB in a Brazilian hospital and to study the association among these variables. METHODS: Forty-five women (58.9+/-9.3 years) participated in this descriptive, cross-sectional and correlational study. The visual analogue scale (VAS) was used to quantify pain intensity/discomfort, arm circumference and shoulder range of motion (ROM) measurement were used to measure upper limb impairments. The Disabilites of Arm Shoulder and Hand questionnaire (DASH) was used to quantify functional performance of upper limb during ADL and European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire - Cancer 30 (EORTC-QLQ-C30) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Breast Cancer Module 23 (EORTC-BR23) were used to characterize HRQL. RESULTS: Results revealed a 75% prevalence of symptoms affecting upper limb (pain or discomfort in arm, shoulder) or breast, although the severity of the symptoms was only mild. Only 4.4% exhibited lymphedema and no ROM restriction was observed. There was little limitation in functional performance of the upper limb, which was associated with Arm Symptoms scale (EORTC BR-23). Impairments and functional performance of upper limb did not interfere on HRQL perception, which was considered to be good. CONCLUSION: SLNB caused small impairments and limitation on the functional performance of the upper limb during ADL and did not influence HRQL in our sample. PMID- 21789366 TI - Evaluation of workload among industrial workers with the Need for Recovery Scale. AB - BACKGROUND: Work conditions can overload a worker's capabilities and result in health complaints. The early identification of hazardous work conditions allows the definition of priorities for more efficient ergonomic interventions. OBJECTIVES: To assess the need for recovery among industrial workers under different work conditions using the Need for Recovery Scale (NFR), and to verify the association between the scores and personal factors, occupational factors and daily activities. METHODS: 191 workers (mean age of 34.5+/-8.3 years) from a manufactory industry participated in this study. Workers answered both a questionnaire regarding demographic and occupational factors, and daily activities as well as the NFR. Ergonomic assessment of workplace sectors was carried out based on the Ergonomic Workplace Analysis. The Pearson chi-square test (significance level 5%) was used to verify the association between NFR scores and the variables of interest. RESULTS: The only association was between work sector and NFR score. According to the ergonomic assessment, the work sector with the highest need for recovery also presented the worst environmental and organizational conditions. CONCLUSIONS: The Need for Recovery Scale proved to be a helpful tool for differentiating work sectors presenting different workload demands and contributed to the definition of intervention priorities for preserving worker health. PMID- 21789367 TI - Postoperative chest physical therapy prevents respiratory complications in patients undergoing esophagectomy. AB - BACKGROUND: Esophagectomy presents the highest rate of postoperative pulmonary complications among all types of upper abdominal surgery. The benefits of chest physical therapy in patients undergoing upper abdominal surgery have been shown by many studies; however, its specific effect in patients receiving esophagectomy has been seldom investigated. OBJECTIVES: This study aimed to compare the frequency of respiratory complications in patients undergoing esophagectomy receiving chest physical therapy compared to no treatment. METHODS: 70 consecutive patients were evaluated retrospectively and allocated to two groups: control group (CG=no physical therapy; n=30) and chest physical therapy group (PTG; n=40). Patients received chest physical therapy which includes lung re expansion and airway clearance maneuvers. They were not submitted to either noninvasive ventilation or exercises with devices that generate airways positive pressure. All patients were instructed to early mobilization. Information about pre-operative and respiratory complications were collected. Statistic analysis to compare the frequency of respiratory complications was performed by the Z test. The significance level was set to 5%. RESULTS: Patients in the CG and PTG were similar in terms of age, BMI, smoking and drinking status, malignant diseases, surgical and anesthesia duration and types of esophagectomy (p>0.05). Our results show that patients received chest physical therapy after esophagectomy had a lower frequency of respiratory complications (15% vs. 37%, p<0.05). In addition, the PTG needed a shorter duration of antibiotic treatment and thoracic drainage as well as less re-intubation compared with the control group (p<0.05). CONCLUSIONS: Our results suggest that chest physical therapy treatment reduces respiratory complications and the need for care but does not influence on hospital length of stay. PMID- 21789368 TI - Validity and reliability of clinical tests for assessing passive ankle stiffness. AB - BACKGROUND: The presence of inadequate levels of passive ankle stiffness have been associated with the occurrence of movement disorders, the development of pathological conditions and the reduction in the performance of functional activities such as walking, running and jumping. Therefore, clinical tests to evaluate ankle stiffness may be useful for the physical therapy assessment. OBJECTIVES: To investigate the concurrent validity and the intra- and inter examiner reliability of clinical measures developed to assess passive stiffness of the ankle joint during dorsiflexion movement. METHODS: Fifteen healthy participants underwent to test-retest evaluations of their ankles by two examiners. Two clinical measures were performed: 'position of first detectable resistance' and 'change in passive resistance torque'. The results of these tests were compared to the passive stiffness measured with an isokinetic dynamometer, in which the electromyography activity of specific muscles was monitored to ensure that the test was performed passively (gold standard measure). RESULTS: Pearson correlation coefficients ranged from r=-0.81 to -0.88 (p<0.001) for the correlation between the passive ankle stiffness measured with the isokinetic dynamometer and the results of the clinical measure 'position of the first detectable resistance'. For the measure of 'change in passive resistance torque', these coefficients ranged from r=0.72 to 0.83 (p<0.004). The Intraclass Correlation Coefficients (ICCs) for the intra- and inter-examiner reliability ranged from 0.75 to 0.98. CONCLUSION: The clinical measures presented satisfactory validity and reliability to be used in clinical practice. PMID- 21789369 TI - Sudden unexpected death in people with down syndrome and epilepsy: another piece in this complicated puzzle. PMID- 21789370 TI - Vitamin D status in patients with Behcet's Disease. AB - OBJECTIVES: This study investigated the serum 25-hydroxyvitamin D levels of patients with Behcet's Disease. DESIGN AND METHODS: Thirty-two patients with Behcet's Disease and 31 matched healthy controls were enrolled in this study. The erythrocyte sedimentation rate (ESR) and the levels of C-reactive protein (CRP), serum 25-hydroxyvitamin D, calcium (Ca), phosphate (P), and total alkaline phosphatase (ALP) were measured in both groups. RESULTS: There were no significant differences between the two groups regarding demographic data. The serum 25-hydroxyvitamin D levels of patients and controls were 13.76 (range: 4.00 35.79) and 18.97 (range: 12.05-36.94) ng/ml, respectively. In patients with Behcet's Disease, 25-hydroxyvitamin D values were significantly lower than those of the healthy controls (p<0.001). Serum Ca, P, and ALP levels were similar in both groups. Serum ESR and CRP levels were significantly higher in patients than controls (p<0.05). There was no correlation between 25-hydroxyvitamin D levels and age, body mass index (BMI), disease duration, ESR, or CRP levels. Multivariate regression analysis parameters showed that smoking, alcohol intake, and use of colchicine were the main predictors of 25-hydroxyvitamin D levels. Of the parameters studied, the largest impact was due to colchicine therapy (p<0.001). We did not find a significant relationship between the use of corticosteroids and 25-hydroxyvitamin D levels. CONCLUSION: Our results suggest that serum 25-hydroxyvitamin D levels are decreased in patients with Behcet's Disease. Smoking, alcohol intake, and use of colchicine appear to affect vitamin D levels. PMID- 21789371 TI - Lifetime psychopathology among the offspring of Bipolar I parents. AB - BACKGROUND: Recent studies have demonstrated high rates of psychopathology in the offspring of parents with bipolar disorder. The aim of this study was to identify psychiatric diagnoses in a sample of children of bipolar parents. METHOD: This case series comprised 35 children and adolescents aged 6 to 17 years, with a mean age of 12.5 +/- 2.9 years (20 males and 15 females), who had at least one parent with bipolar disorder type I. The subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime version (K-SADS-PL). Family psychiatric history and demographics were also evaluated. RESULTS: Of the offspring studied, 71.4% had a lifetime diagnosis of at least one psychiatric disorder (28.6% with a mood disorder, 40% with a disruptive behavior disorder and 20% with an anxiety disorder). Pure mood disorders (11.4%) occurred less frequently than mood disorders comorbid with attention deficit hyperactivity disorder (17.1%). Psychopathology was commonly reported in second-degree relatives of the offspring of parents with bipolar disorder (71.4%). CONCLUSIONS: Our results support previous findings of an increased risk for developing psychopathology, predominantly mood and disruptive disorders, in the offspring of bipolar individuals. Prospective studies with larger samples are needed to confirm and expand these results. PMID- 21789372 TI - Translation, cultural adaptation and reproducibility of the Cochin Hand Functional Scale questionnaire for Brazil. AB - OBJECTIVE: To translate, to perform a cultural adaptation of and to test the reproducibility of the Cochin Hand Functional Scale questionnaire for Brazil. METHODS: First, the Cochin Hand Functional Scale questionnaire was translated into Portuguese and was then back-translated into French. These translations were reviewed by a committee to establish a Brazilian version of the questionnaire to be tested. The validity and reproducibility of the Cochin Hand Functional Scale questionnaire was evaluated. Patients of both sexes, who were aged 18 to 60 years and presented with rheumatoid arthritis affecting their hands, were interviewed. The patients were initially interviewed by two observers and were later interviewed by a single rater. First, the Visual Analogue Scale for hand pain, the Arm, Shoulder and Hand Disability questionnaire and the Health Assessment Questionnaire were administered. The third administration of the Cochin Hand Functional Scale was performed fifteen days after the first administration. Ninety patients were assessed in the present study. RESULTS: Two questions were modified as a result of the assessment of cultural equivalence. The Cronbach's alpha value for this assessment was 0.93. The intraclass intraobserver and interobserver correlation coefficients were 0.76 and 0.96, respectively. The Spearman's coefficient indicated that there was a low level of correlation between the Cochin Hand Functional Scale and the Visual Analogue Scale for pain (0.46) and that there was a moderate level of correlation of the Cochin Scale with the Health Assessment Questionnaire (0.66) and with the Disability of the Arm, Shoulder and Hand questionnaire (0.63). The average administration time for the Cochin Scale was three minutes. CONCLUSION: The Brazilian version of the Cochin Hand Functional Scale was successfully translated and adapted, and this version exhibited good internal consistency, reliability and construct validity. PMID- 21789373 TI - Outpatient Quick Diagnosis Units for the evaluation of suspected severe diseases: an observational, descriptive study. AB - BACKGROUND: Hospitals in countries with public health systems have recently adopted organizational changes to improve efficiency and resource allocation, and reducing inappropriate hospitalizations has been established as an important goal. AIMS: Our goal was to describe the functioning of a Quick Diagnosis Unit in a Spanish public university hospital after evaluating 1,000 consecutive patients. We also aimed to ascertain the degree of satisfaction among Quick Diagnosis Unit patients and the costs of the model compared to conventional hospitalization practices. DESIGN: Observational, descriptive study. METHODS: Our sample comprised 1,000 patients evaluated between November 2008 and January 2010 in the Quick Diagnosis Unit of a tertiary university public hospital in Barcelona. Included patients were those who had potentially severe diseases and would normally require hospital admission for diagnosis but whose general condition allowed outpatient treatment. We analyzed several variables, including time to diagnosis, final diagnoses and hospitalizations avoided, and we also investigated the mean cost (as compared to conventional hospitalization) and the patients' satisfaction. RESULTS: In 88% of cases, the reasons for consultation were anemia, anorexia-cachexia syndrome, febrile syndrome, adenopathies, abdominal pain, chronic diarrhea and lung abnormalities. The most frequent diagnoses were cancer (18.8%; mainly colon cancer and lymphoma) and Iron-deficiency anemia (18%). The mean time to diagnosis was 9.2 days (range 1 to 19 days). An estimated 12.5 admissions/day in a one-year period (in the internal medicine department) were avoided. In a subgroup analysis, the mean cost per process (admission-discharge) for a conventional hospitalization was 3,416.13 Euros, while it was 735.65 Euros in the Quick Diagnosis Unit. Patients expressed a high degree of satisfaction with Quick Diagnosis Unit care. CONCLUSIONS: Quick Diagnosis Units represent a useful and cost-saving model for the diagnostic study of patients with potentially severe diseases. Future randomized study designs involving comparisons between controls and intervention groups would help elucidate the usefulness of Quick Diagnosis Units as an alternative to conventional hospitalization. PMID- 21789374 TI - The role of oxidative stress and antioxidants in the pathogenesis of age-related macular degeneration. AB - OBJECTIVE: To investigate the role of oxidant/antioxidant status and protein oxidation in the development of age-related macular degeneration. METHOD: The activities of serum superoxide dismutase and glutathione peroxidase and the levels of serum malondialdehyde, advanced oxidation protein products, glutathione and vitamin C were measured in 25 patients with age-related macular degeneration and 25 control subjects without age-related macular degeneration. RESULT: The malondialdehyde and advanced oxidation protein product levels in the serum were significantly higher in the age-related macular degeneration patient group than in the control group (p<0.05). The superoxide dismutase activity in the serum was significantly lower in the age-related macular degeneration patient group than in the control group (p<0.05). The levels of vitamin C and glutathione and the activity of glutathione peroxidase in the serum were unchanged between groups (p>0.05). CONCLUSION: The results of the present study suggest that decreased effectiveness of the antioxidant defense system and increased oxidative stress may play a role in the pathogenesis of age-related macular degeneration. PMID- 21789375 TI - High cardiorespiratory fitness is more beneficial in pre-diabetic men than women. AB - OBJECTIVES: To investigate gender-specific relationships between cardiorespiratory fitness and factors that predict the development of diabetes and to identify the risk factors that predict fasting plasma glucose and 2-hour plasma glucose levels. INTRODUCTION: Different risk factors (e.g., low cardiorespiratory fitness) may cause elevated plasma glucose levels in men compared to women. Therefore, gender-specific analyses are needed. METHODS: Cardiorespiratory fitness (maximal power output achieved during a standard cycle ergometry test), resting blood pressure, total serum cholesterol, high-density lipoprotein cholesterol and triglyceride levels were measured in 32 pre-diabetic men (mean age: 57.2 +/- 6.8 years; mean body mass index (BMI): 28.5 +/- 3.0 kg/m2) and 40 pre-diabetic women (mean age: 55.0 +/- 7.3 years, mean BMI: 30.4 +/ 5.7 kg/m2). A stepwise regression with backward variable selection was performed to construct models that predict 2-hour and fasting plasma glucose levels. RESULTS: Maximal power output was inversely related to the 2-hour plasma glucose level in the entire group (r= -0.237, p<0.05), but this relationship was significant only for males (r= -0.404, p<0.05). No significant correlation was found between female gender and cardiorespiratory fitness. Age and cardiorespiratory fitness were significant predictors of 2-hour plasma glucose levels in men. High-density lipoprotein cholesterol was predictive of 2-hour plasma glucose levels in women. Triglycerides in women and BMI in men were the only predictors of fasting plasma glucose levels. CONCLUSIONS: These findings may have consequences for the development of gender-specific diabetes prevention programs. Whereas increasing cardiorespiratory fitness should be a key goal for men, improving the lipid profile seems to be more beneficial for women. However, the present results do not negate the positive effects of increasing cardiorespiratory fitness in women. PMID- 21789376 TI - Minichromosome maintenance 2 and 5 expressions are increased in the epithelium of hereditary gingival fibromatosis associated with dental abnormalities. AB - INTRODUCTION: Gingiva fibromatosis is a relatively rare condition characterized by diffuse enlargement of the gingiva, which is caused by expansion and accumulation of the connective tissue. OBJECTIVE: The aim of the present study was to investigate proliferative and apoptotic biomarker expression in normal gingiva and two forms of gingival fibromatosis. METHODS: Archived tissue specimens of hereditary gingival fibromatosis, gingival fibromatosis and dental abnormality syndrome and normal gingiva were subject to morphological analysis and immunohistochemical staining. The results were analyzed statistically. RESULTS: Proteins associated with proliferation were found in the nuclei of epithelial cells from the basal and suprabasal layers, whereas apoptotic proteins were detected in the cytoplasm of the upper layers of the epithelium. Increased expressions of minichromosome maintenance proteins 2 and 5 were observed in the gingival fibromatosis and dental abnormality syndrome samples. In contrast, geminin expression was higher in normal gingiva samples. No difference in the expression of apoptotic proteins was observed among the groups. CONCLUSION: Our findings support a role for augmented proliferation of epithelial cells within the overgrown tissues associated with gingival fibromatosis or dental abnormality syndrome. However, our data suggest that different biological mechanisms may account for the pathogenesis of different types of gingival fibromatosis. PMID- 21789377 TI - Shortening ventilatory support with a protocol based on daily extubation screening and noninvasive ventilation in selected patients. AB - BACKGROUND: Prolonged invasive mechanical ventilation and reintubation are associated with adverse outcomes and increased mortality. Daily screening to identify patients able to breathe without support is recommended to reduce the length of mechanical ventilation. Noninvasive positive-pressure ventilation has been proposed as a technique to shorten the time that patients remain on invasive ventilation. METHODS: We conducted a before-and-after study to evaluate the efficacy of an intervention that combined daily screening with the use of noninvasive ventilation immediately after extubation in selected patients. The population consisted of patients who had been intubated for at least 2 days. RESULTS: The baseline characteristics were similar between the groups. The intervention group had a lower length of invasive ventilation (6 [4;9] vs. 7 [4;11.5] days, p = 0.04) and total (invasive plus noninvasive) ventilator support (7 [4;11] vs. 9 [6;8], p = 0.01). Similar reintubation rates within 72 hours were observed for both groups. In addition, a lower ICU mortality was found in the intervention group (10.8% vs. 24.3%, p = 0.03), with a higher cumulative survival probability at 60 days (p = 0.05). Multivariate analysis showed that the intervention was an independent factor associated with survival (RR: 2.77; CI 1.14-6.65; p = 0.03), whereas the opposite was found for reintubation at 72 hours (RR: 0.27; CI 0.11-0.65; p = 0.01). CONCLUSION: The intervention reduced the length of invasive ventilation and total ventilatory support without increasing the risk of reintubation and was identified as an independent factor associated with survival. PMID- 21789378 TI - A comparison between sphygmomanometer-based and ambulatory blood pressure monitoring in acute salt loading and depletion protocol. AB - INTRODUCTION: Ambulatory blood pressure monitors have been used in salt loading and depletion protocols. However, the agreement between measurements made using ambulatory blood pressure monitors and those made with the sphygmomanometer has not been evaluated. OBJECTIVE: The objective of this study was to compare the concordance of the two methods of blood pressure measurements in protocols of acute salt loading and depletion. METHOD: Systolic blood pressure was measured using a sphygmomanometer at the completion of salt infusion (2 L NaCl 0.9%, 4 h) and salt depletion (furosemide, 120 mg/day, p.o.) in 18 volunteers. Using the Pearson correlation coefficient (rho), these readings were compared with the mean systolic blood pressure measured using the ambulatory blood pressure monitoring device during the following periods: 4 h of saline infusion and 12 h of salt depletion; 4 h of saline infusion and the last 6 h of salt depletion; 12 h of salt loading and the last 6 h of depletion; 12 h of salt loading and 12 h of depletion. Salt sensitivity was defined by a difference in the systolic blood pressure between salt loading and salt depletion greater than 10 mmHg when measured with the sphygmomanometer, and the Kappa analysis of concordance (K) was used with a significance level of P<0.05. RESULTS: Only the blood pressure readings obtained using the ambulatory blood pressure device during 4 h of intravenous NaCl and during 12 h of salt depletion showed a high correlation with the variation in the systolic blood pressure measured by the sphygmomanometer, with a full agreement with the salt sensitivity classification (p = 0.71; P = 0.001 and K=1). CONCLUSION: In acute salt loading and depletion protocols, an ambulatory blood pressure monitoring device should be used to record the blood pressure during the 4-h interval of salt infusion and 12-h interval of salt depletion. PMID- 21789379 TI - C-Reactive protein predicts acute myocardial infarction during high-risk noncardiac and vascular surgery. AB - BACKGROUND: High-sensitivity C-reactive protein predicts cardiovascular events in a wide range of clinical contexts. However, the role of high-sensitivity C reactive protein as a predictive marker for perioperative acute myocardial infarction during noncardiac surgery is not yet clear. The present study investigated high-sensitivity C-reactive protein levels as predictors of acute myocardial infarction risk in patients undergoing high-risk noncardiac surgery. METHODS: This concurrent cohort study included patients aged >= 50 years referred for high-risk noncardiac surgery according to American Heart Association/ACC 2002 criteria. Patients with infections were excluded. Electrocardiograms were performed, and biomarkers (Troponin I or T) and/or total creatine phosphokinase and the MB fraction (CPK-T/MB) were evaluated on the first and fourth days after surgery. Patients were followed until discharge. Baseline high-sensitivity C reactive protein levels were compared between patients with and without acute myocardial infarction. RESULTS: A total of 101 patients undergoing noncardiac surgery, including 33 vascular procedures (17 aortic and 16 peripheral artery revascularizations), were studied. Sixty of the patients were men, and their mean age was 66 years. Baseline levels of high-sensitivity C-reactive protein were higher in the group with perioperative acute myocardial infarction than in the group with non-acute myocardial infarction patients (mean 48.02 vs. 4.50, p = 0.005). All five acute myocardial infarction cases occurred in vascular surgery patients with high CRP levels. CONCLUSIONS: Patients undergoing high-risk noncardiac surgery, especially vascular surgery, and presenting elevated baseline high-sensitivity C-reactive protein levels are at increased risk for perioperative acute myocardial infarction. PMID- 21789380 TI - Statin therapy blunts inflammatory activation and improves prognosis and left ventricular performance assessed by Tissue Doppler Imaging in subjects with chronic ischemic heart failure: results from the Daunia Heart Failure Registry. AB - BACKGROUND: A limited number of studies have used Tissue Doppler Imaging (TDI) to evaluate the effect of statin therapy on left ventricular dysfunction in patients with chronic heart failure. In this work, we aimed to determine whether statin administration influenced prognosis, inflammatory activation and myocardial performance evaluated by Tissue Doppler Imaging in subjects enrolled in the Daunia Heart Failure Registry, a local registry of patients with chronic heart failure. METHODS: This study retrospectively analyzed 353 consecutive outpatients with chronic heart failure (mean follow-up 384 days), based on whether statin therapy was used. In all patients, several Tissue Doppler Imaging parameters were measured; circulating levels of interleukin (IL)-6, IL-10 and C-reactive protein were also assayed. RESULTS: Statin administration in 128 subjects with ischemic heart disease was associated with a lower incidence of adverse events (rehospitalization for HF 15% vs. 46%, p<0.001; ventricular arrhythmias 5% vs. 21%, p<0.01; cardiac death 1% vs. 8%, p<0.05), lower circulating levels of IL-6 (p<0.05) and IL-10 (p<0.01), lower rates of chronic heart failure (p<0.001) and better Tissue Doppler Imaging performance (E/E' ratio 12.82 +/- 5.42 vs. 19.85 +/ 9.14, p<0.001; ET: 260.62 +/- 44.16 vs. 227.11 +/- 37.58 ms, p<0.05; TP: 176.79 +/- 49.93 vs. 136.7 +/- 37.78 ms, p<0.05 and St: 352.35 +/- 43.17 vs. 310.67 +/- 66.46 +/- 37.78 ms, p<0.05). CONCLUSIONS: Chronic ischemic heart failure outpatients undergoing statin treatment had fewer readmissions for adverse events, blunted inflammatory activation and improved left ventricular performance assessed by Tissue Doppler Imaging. PMID- 21789381 TI - Vaginal cone use in passive and active phases in patients with stress urinary incontinence. AB - OBJECTIVE: To evaluate vaginal cone therapy in two phases, passive and active, in women with stress urinary incontinence. METHODS: A prospective study was conducted at the Department of Obstetrics and Gynecology, Sao Paulo University, Brazil. Twenty-four women with a clinical and urodynamic diagnosis of stress urinary incontinence were treated with vaginal cones in a passive phase (without voluntary contractions of the pelvic floor) and an active phase (with voluntary contractions), each of which lasted three months. Clinical complaints, a functional evaluation of the pelvic floor, a pad test, and bladder neck mobility were analyzed before and after each phase. RESULTS: Twenty-one patients completed the treatment. The reduction in absolute risk with the pad test was 0.38 (p<0.034) at the end of the passive phase and 0.67 (p<0.0001) at the end of the active phase. The reduction in absolute risk with the pelvic floor evaluation was 0.62 (p<0.0001) at the end of the passive phase and 0.77 (p<0.0001) at the end of the active phase. The reduction in absolute risk of bladder neck mobility was 0.38 (p<0.0089) at the end of the passive phase and 0.52 (p<0.0005) at the end of the active phase. Complete reversal of symptomatology was observed in 12 (57.1%) patients, and satisfaction was expressed by 19 (90.4%). CONCLUSION: Using vaginal cones in the passive phase, as other researchers did, was effective. Inclusion of the active phase led to additional improvement in all of the study parameters evaluated in women with stress urinary incontinence. Randomized studies are needed, however, to confirm these results. PMID- 21789382 TI - Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes. AB - INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression. PMID- 21789384 TI - Pregnancy after uterine arterial embolization. AB - OBJECTIVE: To evaluate pregnancy outcomes, complications and neonatal outcomes in women who had previously undergone uterine arterial embolization. METHODS: A retrospective study of 187 patients treated with uterine arterial embolization for symptomatic uterine fibroids between 2005-2008 was performed. Uterine arterial embolization was performed using polyvinyl alcohol particles (500-900 mm in diameter). Pregnancies were identified using screening questionnaires and the study database. RESULTS: There were 15 spontaneous pregnancies. Of these, 12.5% were miscarriages (n = 2), and 87.5% were successful live births (n = 14). The gestation time for the pregnancies with successful live births ranged from 36 to 39.2 weeks. The mean time between embolization and conception was 23.8 months (range, 5-54). One of the pregnancies resulted in twins. The newborn weights (n = 14) ranged from 2.260 to 3.605 kg (mean, 3.072 kg). One (7.1%) was considered to have a low birth weight (2.260 kg). There were two cases of placenta accreta (12.5%, treated with hysterectomy in one case [6.3%]), one case of premature rupture of the membranes (PRM) (6.3%), and one case of preeclampsia (6.3%). All of the patients were delivered via Cesarean section. CONCLUSION: In this study, there was an increased risk of Cesarean delivery. There were no other major obstetric risks, suggesting that pregnancy after uterine arterial embolization is possible without significant morbidity or mortality. PMID- 21789383 TI - Low bone mass density is associated with hemolysis in Brazilian patients with sickle cell disease. AB - OBJECTIVES: To determine whether kidney disease and hemolysis are associated with bone mass density in a population of adult Brazilian patients with sickle cell disease. INTRODUCTION: Bone involvement is a frequent clinical manifestation of sickle cell disease, and it has multiple causes; however, there are few consistent clinical associations between bone involvement and sickle cell disease. METHODS: Patients over 20 years of age with sickle cell disease who were regularly followed at the Hematology and Hemotherapy Center of Campinas, Brazil, were sorted into three groups, including those with normal bone mass density, those with osteopenia, and those with osteoporosis, according to the World Health Organization criteria. The clinical data of the patients were compared using statistical analyses. RESULTS: In total, 65 patients were included in this study: 12 (18.5%) with normal bone mass density, 37 (57%) with osteopenia and 16 (24.5%) with osteoporosis. Overall, 53 patients (81.5%) had bone mass densities below normal standards. Osteopenia and osteoporosis patients had increased lactate dehydrogenase levels and reticulocyte counts compared to patients with normal bone mass density (p<0.05). Osteoporosis patients also had decreased hemoglobin levels (p<0.05). Hemolysis was significantly increased in patients with osteoporosis compared with patients with osteopenia, as indicated by increased lactate dehydrogenase levels and reticulocyte counts as well as decreased hemoglobin levels. Osteoporosis patients were older, with lower glomerular filtration rates than patients with osteopenia. There was no significant difference between the groups with regard to gender, body mass index, serum creatinine levels, estimated creatinine clearance, or microalbuminuria. CONCLUSION: A high prevalence of reduced bone mass density that was associated with hemolysis was found in this population, as indicated by the high lactate dehydrogenase levels, increased reticulocyte counts and low hemoglobin levels. PMID- 21789385 TI - A comparison of three different target-controlled remifentanil infusion rates during target-controlled propofol infusion for oocyte retrieval. AB - OBJECTIVE: To evaluate the effects of three different target-controlled remifentanil infusion rates during target-controlled propofol infusion on hemodynamic parameters, pain, sedation, and recovery score during oocyte retrieval. METHODS: Sixty-nine women were scheduled for oocyte retrieval. Target controlled propofol infusion at an effect-site concentration of 1.5 MUg/mL was instituted. The patients were randomly allocated to receive remifentanil at an effect-site concentration of either 1.5 (group I, n = 23), 2 (group II, n = 23) or 2.5 ng/mL (group III, n = 23). Hemodynamic variables, sedation, pain, the Aldrete recovery score, and side effects were recorded. RESULTS: Hemodynamic variables, sedation and pain scores and the number of patients with the maximum Aldrete recovery score 10 min after the procedure were comparable among the groups. The number of patients in group III with the maximum Aldrete recovery score 5 min after the procedure was significantly lower than that in groups I and II. One patient in group II and one patient in group III suffered from nausea. CONCLUSION: Similar pain-free conscious sedation conditions without significant changes in hemodynamic parameters were provided by all three protocols. However, target controlled infusion of remifentanil at 1.5 or 2 ng/mL proved superior at providing early recovery compared to 2.5 ng/mL. PMID- 21789386 TI - Thoracic Injuries in earthquake-related versus non-earthquake-related trauma patients: differentiation via Multi-detector Computed Tomography. AB - PURPOSE: Massive earthquakes are harmful to humankind. This study of a historical cohort aimed to investigate the difference between earthquake-related crush thoracic traumas and thoracic traumas unrelated to earthquakes using a multi detector Computed Tomography (CT). METHODS: We retrospectively compared an earthquake-exposed cohort of 215 thoracic trauma crush victims of the Sichuan earthquake to a cohort of 215 non-earthquake-related thoracic trauma patients, focusing on the lesions and coexisting injuries to the thoracic cage and the pulmonary parenchyma and pleura using a multi-detector CT. RESULTS: The incidence of rib fracture was elevated in the earthquake-exposed cohort (143 vs. 66 patients in the non-earthquake-exposed cohort, Risk Ratio (RR) = 2.2; p<0.001). Among these patients, those with more than 3 fractured ribs (106/143 vs. 41/66 patients, RR=1.2; p<0.05) or flail chest (45/143 vs. 11/66 patients, RR=1.9; p<0.05) were more frequently seen in the earthquake cohort. Earthquake-related crush injuries more frequently resulted in bilateral rib fractures (66/143 vs. 18/66 patients, RR= 1.7; p<0.01). Additionally, the incidence of non-rib fracture was higher in the earthquake cohort (85 vs. 60 patients, RR= 1.4; p<0.01). Pulmonary parenchymal and pleural injuries were more frequently seen in earthquake-related crush injuries (117 vs. 80 patients, RR=1.5 for parenchymal and 146 vs. 74 patients, RR = 2.0 for pleural injuries; p<0.001). Non-rib fractures, pulmonary parenchymal and pleural injuries had significant positive correlation with rib fractures in these two cohorts. CONCLUSIONS: Thoracic crush traumas resulting from the earthquake were life threatening with a high incidence of bony thoracic fractures. The ribs were frequently involved in bilateral and severe types of fractures, which were accompanied by non-rib fractures, pulmonary parenchymal and pleural injuries. PMID- 21789387 TI - Initial respiratory management in preterm infants and bronchopulmonary dysplasia. AB - BACKGROUND: Ventilator injury has been implicated in the pathogenesis of bronchopulmonary dysplasia. Avoiding invasive ventilation could reduce lung injury, and early respiratory management may affect pulmonary outcomes. OBJECTIVE: To analyze the effect of initial respiratory support on survival without bronchopulmonary dysplasia at a gestational age of 36 weeks. DESIGN/METHODS: A prospective 3-year observational study. Preterm infants of <32 weeks gestational age were classified into 4 groups according to the support needed during the first 2 hours of life: room air, nasal continuous positive airway pressure, intubation/surfactant/extubation and prolonged mechanical ventilation (defined as needing mechanical ventilation for more than 2 hours). RESULTS: Of the 329 eligible patients, a total of 49% did not need intubation, and 68.4% did not require prolonged mechanical ventilation. At a gestational age of 26 weeks, there was a significant correlation between survival without bronchopulmonary dysplasia and initial respiratory support. Preterm infants requiring mechanical ventilation showed a higher risk of death and bronchopulmonary dysplasia. After controlling for gestational age, antenatal corticosteroid use, maternal preeclampsia and chorioamnionitis, the survival rate without bronchopulmonary dysplasia remained significantly lower in the mechanically ventilated group. CONCLUSIONS: In our population, the need for more than 2 hours of mechanical ventilation predicted the development of bronchopulmonary dysplasia in preterm infants with a gestational age >26 weeks (sensitivity =89.5% and specificity = 67%). The need for prolonged mechanical ventilation could be an early marker for the development of bronchopulmonary dysplasia. This finding could help identify a target population with a high risk of chronic lung disease. Future research is needed to determine other strategies to prevent bronchopulmonary dysplasia in this high-risk group of patients. PMID- 21789388 TI - The slope of the oxygen pulse curve does not depend on the maximal heart rate in elite soccer players. AB - INTRODUCTION: It is unknown whether an extremely high heart rate can affect oxygen pulse profile during progressive maximal exercise in healthy subjects. OBJECTIVE: Our aim was to compare relative oxygen pulse (adjusted for body weight) curves in athletes at their maximal heart rate during treadmill cardiopulmonary exercise testing. METHODS: A total of 180 elite soccer players were categorized in quartiles according to their maximum heart rate values (n = 45). Oxygen consumption, maximum heart rate and relative oxygen pulse curves in the extreme quartiles, Q1 and Q4, were compared at intervals corresponding to 10% of the total duration of a cardiopulmonary exercise testing. RESULTS: Oxygen consumption was similar among all subjects during cardiopulmonary exercise testing; however subjects in Q1 started to exhibit lower maximum heart rate values when 20% of the test was complete. Conversely, the relative oxygen pulse was higher in this group when cardiopulmonary exercise testing was 40% complete (p<.01). Although the slopes of the lines were similar (p = .25), the regression intercepts differed (p<.01) between Q1 and Q4. During the last two minutes of testing, a flat or decreasing oxygen pulse was identified in 20% of the soccer players, and this trend was similar between subjects in Q1 and Q4. CONCLUSION: Relative oxygen pulse curve slopes, which serve as an indirect and non-invasive surrogate for stroke volume, suggest that the stroke volume is similar in young and aerobically fit subjects regardless of the maximum heart rate reached. PMID- 21789389 TI - An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect. AB - INTRODUCTION AND OBJECTIVE: The heptapeptide angiotensin-(1-7) is a component of the renin-angiotensin system, which promotes many beneficial cardiovascular effects, including antithrombotic activity. We have recently shown that the antithrombotic effect of angiotensin-(1-7) involves receptor Mas-mediated NO release from platelets. Here, we describe an orally active formulation based on angiotensin-(1-7) inclusion in cyclodextrin [Ang-(1-7)- CyD] as an antithrombotic agent. Cyclodextrins are pharmaceutical tools that are used to enhance drug stability, absorption across biological barriers and gastric protection. METHOD: To test the antithrombotic effect of Ang-(1-7)-CyD, thrombus formation was induced in the abdominal vena cava of spontaneously hypertensive rats that were pretreated either acutely or chronically with Ang-(1-7)-CyD. Male Mas-knockout and wild-type mice were used to verify the role of the Mas receptor on the effect of Ang-(1-7)-CyD. RESULTS: Acute or chronic oral treatment with Ang-(1-7)-CyD promoted an antithrombotic effect (measured by thrombus weight; all values are, respectively, untreated vs. treated animals) in spontaneously hypertensive rats (acute: 2.86 +/- 0.43 mg vs. 1.14 +/- 0.40 mg; chronic: 4.27 +/- 1.03 mg vs. 1.39 +/- 0.68 mg). This effect was abolished in Mas-knockout mice (thrombus weight in Mas wild-type: 0.76 +/- 0.10 mg vs. 0.37 +/- 0.02 mg; thrombus weight in Mas knockout: 0.96 +/- 0.11 mg vs. 0.87 +/- 0.14 mg). Furthermore, the antithrombotic effect of Ang-(1-7)-CyD was associated with an increase in the plasma level of Angiotensin-(1-7). CONCLUSION: These results show for the first time that the oral formulation Ang-(1-7)-CyD has biological activity and produces a Mas dependent antithrombotic effect. PMID- 21789390 TI - Chemical composition of the essential oil from kelussia odoratissima Mozaff. and the evaluation of its sedative and anxiolytic effects in mice. AB - OBJECTIVE: The present study aimed to evaluate the sedative and anxiolytic effects of the essential oils and hydroalcoholic extract of Kelussia odoratissima Mozaff. (K. odoratissima) in mice by utilizing an elevated plus maze. The chemical composition of its essential oil was also determined. METHODS: The hydroalcoholic extract or essential oil fraction from this plant were administered intraperitoneally to male mice at various doses 30 min before testing. The anxiolytic and sedative effects were determined by an elevated plus maze and locomotor activity tests, respectively. RESULTS: According to the results, none of the administered doses of hydroalcoholic extract or essential oil fraction of K. odoratissima changed the percentage of the time spent or number of entries into the open arms of the elevated plus maze. In contrast, the cumulative spontaneous locomotor activity of mice treated with the essential oil or hydroalcoholic extract was significantly decreased. Chemical analysis of the essential oil by Gas chromatography-mass spectromentry (GC-MS) showed that 3 butylidene-4,5-dihydrophthalide (85.9%) was the major component. CONCLUSION: These data confirm the sedative properties of K. odoratissima, yet there were no profound anxiolytic effects observed. PMID- 21789391 TI - Histomorphometric changes in the perirenal adipocytes of adrenalectomized rats treated with dexamethasone. AB - INTRODUCTION: Prolonged steroid treatment administered to any patient can cause visceral obesity, which is associated with metabolic disease and Cushing's syndrome. Glucocorticoids have a profound negative effect on adipose tissue mass, giving rise to obesity, which in turn is regulated by the 11beta-hydroxysteroid dehydrogenase type 1 enzyme. Adrenalectomized rats treated with dexamethasone exhibited an increase in visceral fat deposition but not in body weight. OBJECTIVES: The main aim of this study was to determine the effect of dexamethasone on the histomorphometric characteristics of perirenal adipocytes of adrenalectomized, dexamethasone-treated rats (ADR+Dexa) and the association of dexamethasone treatment with the expression and activity of 11 beta hydroxysteroid dehydrogenase type 1 (11 beta-hydroxysteroid dehydrogenase type 1). METHODS: A total of 20 male Sprague Dawley rats were divided into 3 groups: a baseline control group (n = 6), a sham-operated group (n = 7) and an adrenalectomized group (n=7). The adrenalectomized group was given intramuscular dexamethasone (ADR+Dexa) 2 weeks post adrenalectomy, and the rats from the sham operated group were administered intramuscular vehicle (olive oil). RESULTS: Treatment with 120 MUg/kg intramuscular dexamethasone for 8 weeks resulted in a significant decrease in the diameter of the perirenal adipocytes (p<0.05) and a significant increase in the number of perirenal adipocytes (p<0.05). There was minimal weight gain but pronounced fat deposition in the dexamethasone-treated rats. These changes in the perirenal adipocytes were associated with high expression and dehydrogenase activity of 11beta-hydroxysteroid dehydrogenase type 1. CONCLUSIONS: In conclusion, dexamethasone increased the deposition of perirenal fat by hyperplasia, which causes increases in the expression and dehydrogenase activity of 11 beta-hydroxysteroid dehydrogenase type 1 in adrenalectomized rats. PMID- 21789392 TI - Low-Intensity physical activity beneficially alters the ultrastructural renal morphology of spontaneously hypertensive rats. AB - INTRODUCTION AND OBJECTIVE: Kidney disorders can cause essential hypertension, which can subsequently cause renal disease. High blood pressure is also common among those with chronic kidney disease; moreover, it is a well-known risk factor for a more rapid progression to kidney failure. Because hypertension and kidney function are closely linked, the present study aimed to observe the beneficial effects of low-intensity physical activity on structural and ultrastructural renal morphology and blood pressure in normotensive and spontaneously hypertensive rats. METHOD: Male Wistar-Kyoto rats and spontaneously hypertensive rats were randomly allocated into four groups: sedentary or exercised Wistar Kyoto and sedentary or exercised spontaneously hypertensive rats. The exercise lasted 20 weeks and consisted of treadmill training for 1 hour/day, 5 days/week. RESULTS: The exercised, spontaneously hypertensive rats showed a significant blood pressure reduction of 26%. The body masses of the Wistar-Kyoto and spontaneously hypertensive strains were significantly different. There were improvements in some of the renal structures of the animals treated with physical activity: (i) the interdigitations of the proximal and distal convoluted tubules; (ii) the basal membrane of the proximal and distal convoluted tubules; and (iii) in the basal membrane, slit diaphragm and pedicels of the glomerular filtration barrier. The spontaneously hypertensive rats also showed a decreased expression of connexin-43. CONCLUSION: Physical exercise could be a therapeutic tool for improving kidney ultrastructure and, consequently, renal function in hypertensive individuals. PMID- 21789393 TI - Piper sarmentosum enhances fracture healing in ovariectomized osteoporotic rats: a radiological study. AB - INTRODUCTION: Osteoporotic fractures are common during osteoporotic states. Piper sarmentosum extract is known to possess antioxidant and anti-inflammatory properties. OBJECTIVES: To observe the radiological changes in fracture calluses following administration of a Piper sarmentosum extract during an estrogen deficient state. METHODS: A total of 24 female Sprague-Dawley rats (200-250 g) were randomly divided into 4 groups: (i) the sham-operated group; (ii) the ovariectomized-control group; (iii) the ovariectomized + estrogen-replacement therapy (ovariectomized-control + estrogen replacement therapy) group, which was supplemented with estrogen (100 MUg/kg/day); and (iv) the ovariectomized + Piper sarmentosum (ovariectomized + Piper sarmentosum) group, which was supplemented with a water-based Piper sarmentosum extract (125 mg/kg). Six weeks after an ovariectomy, the right femora were fractured at the mid-diaphysis, and a K-wire was inserted. Each group of rats received their respective treatment for 6 weeks. Following sacrifice, the right femora were subjected to radiological assessment. RESULTS: The mean axial callus volume was significantly higher in the ovariectomized-control group (68.2 +/- 11.74 mm3) than in the sham-operated, estrogen-replacement-therapy and Piper sarmentosum groups (20.4 +/- 4.05, 22.4 +/ 4.14 and 17.5 +/- 3.68 mm3, respectively). The median callus scores for the sham operated, estrogen-replacement-therapy and Piper sarmentosum groups had median (range, minimum - maximum value) as 1.0 (0 - 2), 1.0 (1 - 2) and 1.0 (1 - 2), respectively, which were significantly lower than the ovariectomized-control group score of 2.0 (2 - 3). The median fracture scores for the sham-operated, estrogen-replacement-therapy and Piper sarmentosum groups were 3.0 (3 - 4), 3.0 (2 - 3) and 3.0 (2 - 3), respectively, which were significantly higher than the ovariectomized-control group score of 2.0 (1 - 2) (p<0.05). CONCLUSION: The Piper sarmentosum extract improved fracture healing, as assessed by the reduced callus volumes and reduced callus scores. This extract is beneficial for fractures in osteoporotic states. PMID- 21789394 TI - Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice. AB - OBJECTIVE: Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. METHOD: Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n = 16) had access to sugarcane spirit + distilled water, the mice in Group B (n = 15) had access to ethanol + distilled water, and the mice in Group C (control, n = 14) had access to distilled water + distilled water. The ethanol content in the beverages offered to Groups A and B was 2% for the first week, 5% for the second week and 10% for the remaining four weeks. At the end of the experimental period, the mice were evaluated using the elevated-plus maze and the hole-board test to assess their anxiety-related behaviors. We also determined the serum aspartate aminotransferase and alanine aminotransferase levels. RESULTS: In the elevated-plus maze, the time spent in the open arms was increased in the mice exposed to chronic ethanol (32 +/- 8 vs. 7 +/- 2 s, n = 9) or sugarcane spirit (36 +/- 9 vs. 7 +/- 2 s, n = 9) compared to the controls. In the hole-board test, the mice exposed to ethanol or sugarcane spirit displayed increases in their head-dipping frequency (16 +/- 1 for the control group, 27 +/- 2 for the ethanol group, and 31 +/- 3 for the sugarcane spirit group; n = 9 for each group). In addition, the mice exposed to sugarcane spirit displayed an increase in the aspartate aminotransferase / alanine aminotransferase ratio compared to the ethanol group (1.29 +/- 0.17 for the control group and 2.67 +/- 0.17 for the sugarcane spirit group; n = 8 for each group). CONCLUSION: The chronic consumption of sugarcane-spirit produces liver injury and anxiolytic-like effects and the possible liver injury in mice. PMID- 21789395 TI - The effect of Nigella sativa extract on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs. AB - OBJECTIVE: To examine the preventive effect of a hydro-ethanolic extract of Nigella sativa on the tracheal responsiveness and white blood cell count in the lung lavage fluid of sensitized guinea pigs. METHODS: Three groups of guinea pigs sensitized to intraperitoneally injected and inhaled ovalbumin were given drinking water alone (group S), drinking water containing a low concentration of N. sativa extract (group S+LNS) or drinking water containing a high concentration of N. sativa extract (group S+HNS). The tracheal responses of control animals (group C) and the three groups of sensitized guinea pigs (n = 7 for all groups) to methacholine were measured by the assessment of the tracheal smooth muscle response to increasing concentrations of methacholine, and the effective concentration causing 50% of the maximum response (EC50) was determined. Tracheal responses to 0.1% ovalbumin and white blood cell counts in the lung lavage fluid were also examined. RESULTS: The tracheal response of the group S guinea pigs to both methacholine and ovalbumin was significantly higher than the response of the controls (p<0.01 for both cases). The tracheal responses of the S+LNS and S+HNS groups to both methacholine and ovalbumin were significantly decreased compared to those of the S group (p<0.05 to p<0.01). The total white blood cell and eosinophil counts in the lung lavage fluid of group S were significantly higher than those of group C (p<0.01). The white blood cell counts in both treated groups showed significant improvements (p<0.01 for both cases). CONCLUSIONS: These results demonstrate the preventive effect of the N. sativa extract on the tracheal response and lung inflammation in sensitized guinea pigs. PMID- 21789396 TI - Prior exercise training does not prevent acute cardiac alterations after myocardial infarction in female rats. AB - OBJECTIVE: This study aimed to investigate whether previous exercise training could prevent or attenuate acute cardiac alterations after myocardial infarction. METHODS: Female rats were submitted to swim training (1 h/day; 5 days/week) or allowed to remain sedentary for 8 weeks. Afterwards, they were randomly assigned to left coronary artery occlusion or sham surgery. After this procedure, the rats remained sedentary for one week until euthanasia. Cardiac structural and functional analyses were performed using Doppler echocardiography. The rats that had a moderate or large infarct size were included in the evaluations. The data (mean +/- SEM) were analyzed using a two-way ANOVA model followed by Tukey's post hoc test. RESULTS: After the surgery, no significant difference between the exercise and sedentary groups was observed in the left ventricular infarct sizes (34.58 +/- 3.04 vs. 37.59 +/- 3.07). In another group of rats evaluated with Evans blue 1 h after myocardial infarction, no siginificant difference in the area at risk was observed between the exercised and sedentary rats (49.73 +/- 1.52 vs. 45.48 +/- 3.49). The changes in the left ventricular fractional areas for the exercised and sedentary myocardial infarction groups (36 +/- 2% and 39 +/ 3%, respectively) were smaller than those for the exercise sham surgery (ES, 67 +/- 1%) and sedentary sham surgery (SS, 69 +/- 2%) groups. The E/A was higher in the sedentary myocardial infarction (4.4 +/- 0.3) and exercised myocardial infarction (5.5 +/- 0.3) rats than in the SS (2.4 +/- 0.1) and ES (2.2 +/- 0.1) rats. CONCLUSION: Previous swim training of female rats does not attenuate systolic and diastolic function alterations after myocardial infarction induced by left coronary artery occlusion, suggesting that cardioprotection cannot be provided by exercise training in this experimental model. PMID- 21789397 TI - Transforming growth factor-beta in graft vessels: histology and immunohistochemistry. AB - OBJECTIVES: The biological functions of transforming growth factor-beta signaling that involves Smad proteins have not been previously investigated with respect to coronary artery bypass grafts. The aim of the present study was to observe the immunostaining of proteins that are related to this signaling pathway. METHODS: Fifteen remnants of coronary artery bypass grafts, including nine saphenous veins, three radial arteries and three mammary arteries, were collected from 12 patients who were undergoing coronary artery bypass. Hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining of transforming growth factor-beta1, type I receptor of transforming growth factor-beta, Smad2/3, Smad4, and Smad7 were performed. RESULTS: The saphenous veins showed more severe intimal degeneration, more severe smooth muscle cell proliferation and more collagen deposition than the arterial grafts, as evidenced by hematoxylin and eosin and Masson's trichrome stainings. Immunohistochemical assays demonstrated that the majority of the transforming growth factor-beta1 signaling cytokines were primarily localized in the cytoplasm in the medial layers of all three types of grafts, whereas ectopic transforming growth factor-beta1, type I receptor of transforming growth factor-beta, and Smad7 overexpressions in the interstices were observed particularly in the saphenous vein and radial arterial grafts. CONCLUSION: Enhanced transforming growth factor-beta1 signal transduction with medial smooth muscle cell proliferation and ectopic transforming growth factor beta1, the presence of the type I receptor of transforming growth factor-beta, and Smad7 overexpressions in the extracellular matrix may provide primary evidence for early or late graft failure. PMID- 21789398 TI - Heparanase isoform expression and extracellular matrix remodeling in intervertebral disc degenerative disease. AB - OBJECTIVE: To determine the molecules involved in extracellular matrix remodeling and to identify and quantify heparanase isoforms present in herniated and degenerative discs. INTRODUCTION: Heparanase is an endo-beta-glucuronidase that specifically acts upon the heparan sulfate chains of proteoglycans. However, heparanase expression in degenerative intervertebral discs has not yet been evaluated. Notably, previous studies demonstrated a correlation between changes in the heparan sulfate proteoglycan pattern and the degenerative process associated with intervertebral discs. METHODS: Twenty-nine samples of intervertebral degenerative discs, 23 samples of herniated discs and 12 samples of non-degenerative discs were analyzed. The expression of both heparanase isoforms (heparanase-1 and heparanase-2) was evaluated using immunohistochemistry and real-time RT-PCR analysis. RESULTS: Heparanase-1 and heparanase-2 expression levels were significantly higher in the herniated and degenerative discs in comparison to the control tissues, suggesting a possible role of these proteins in the intervertebral degenerative process. CONCLUSION: The overexpression of heparanase isoforms in the degenerative intervertebral discs and the herniated discs suggests a potential role of both proteins in the mediation of inflammatory processes and in extracellular matrix remodeling. The heparanase-2 isoform may be involved in normal metabolic processes, as evidenced by its higher expression in the control intervertebral discs relative to the expression of heparanase-1. PMID- 21789399 TI - The potentially dual-faceted nature of fetuin-A in Helicobacter pylori infection and insulin resistance. PMID- 21789400 TI - Diastolic dysfunction in end-stage renal disease patient: what the ticking clock has told us? PMID- 21789401 TI - Effects of inhaled cigarette smoke on the myo-articular system of female rats with collagen-induced arthritis. PMID- 21789403 TI - Glass-coated kites and cervical injuries: a serious threat to children and adults. PMID- 21789402 TI - The H/R FcgammaRIIA-131 polymorphism and survival in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP: a study in a genetically mixed population. PMID- 21789404 TI - Neuromuscular electrical stimulation in a patient with chronic heart failure due to chagas disease: a case report. PMID- 21789405 TI - Scapular winging in Poland syndrome. PMID- 21789406 TI - Brazilian studies on social determinants of health inequities. PMID- 21789407 TI - Public policy and the social determinants of health: the challenge of the production and use of scientific evidence. AB - This article serves as an introduction to the others published in this thematic issue of the Cadernos de Saude Publica. The author makes a brief historical review of the concepts, approaches and methodologies used to study the relationships between social determinants and health outcomes. By analyzing the current global movement around social determinants of health he emphasizes that the distinctive feature of this movement is the explicit commitment to action through intersectoral public policies that are based on evidence and implemented with the support and participation of broad segments of society. As this special issue of the Cadernos de Saude Publica is dedicated to presenting the results of research related to social determinants of health, the author focuses on an analysis of the difficulties in the production and use of scientific evidence that supports the definition, implementation and evaluation of policies to combat health inequities through action on social determinants of health. To conclude, he presents some recommendations for overcoming these difficulties. PMID- 21789408 TI - Periodontal outcomes and social, racial and gender inequalities in Brazil: a systematic review of the literature between 1999 and 2008. AB - The objective of this study was to review the Brazilian epidemiologic literature on periodontal outcomes and socio-demographic factors, assessing bibliographic and methodological characteristics of this scientific production, as well as the consistency and statistical significance of the examined associations. A systematic review was carried out in six bibliographic sources. The review was limited to the period between 1999 and 2008, without any other type of restriction. Among the 410 papers identified, 29 were included in the review. An increasing number of articles, specifically in the last four years of study, was observed. However, there is a concentration of studies in the South and Southeast regions of Brazil, and many of them are not closely connected to theoretical formulations in the field. In spite of these shortcomings, the review findings corroborate the idea that poor socioeconomic conditions are associated with periodontal outcomes, as demonstrated primarily by income and schooling indicators. PMID- 21789409 TI - Monitoring Millennium Development Goals in Brazilian municipalities: challenges to be met in facing up to iniquities. AB - The Healthy Cities and Agenda 21 programs improve living and health conditions and affect social and economic determinants of health. The Millennium Development Goals (MDG) indicators can be used to assess the impact of social agendas. A data search was carried out for the period 1997 to 2006 to obtain 48 indicators proposed by the United Nations and a further 74 proposed by the technical group for the MDGin Brazil. There is a scarcity of studies concerned with assessing the MDG at the municipal level. Data from Brazilian health information systems are not always consistent or accurate for municipalities. The lack of availability and reliable data led to the substitution of some indicators. The information systems did not always provide annual data; national household surveys could not be disaggregated at the municipal level and there were also modifications on conceptual definitions over time. As a result, the project created an alternative list with 29 indicators. MDG monitoring at the local community can be important to measure the performance of actions toward improvements in quality of life and social iniquities. PMID- 21789410 TI - Social vulnerability and health status: a household survey in the central area of a Brazilian metropolis. AB - The self-rated health in a sample of adults living in the central area of Sao Paulo, Brazil, was studied by comparing a group of residents in census tracts without social vulnerability, identified using an indicator developed by the SEADE Foundation, and a group of residents in census tracts with middle, high or very high social vulnerability. Subject age and sex were used as control variables while family income, education level, degree of happiness, adequacy of income, satisfaction with the neighborhood and sense of discrimination were the intervening variables selected. After adjustment in the hierarchical model the self-rated health status was inversely associated with social vulnerability, age and sense of discrimination, and directly related to income, education level and degree of happiness. Satisfaction with the neighborhood and adequacy of income lose significance after adjustment. The degree of happiness is the variable with the greatest strength of association with health status even after controlling for other variables. PMID- 21789411 TI - Evolution of inequalities in mortality in Salvador, Bahia State, Brazil, 1991/2006. AB - An ecological study was carried out with the aim of analyzing the evolution of inequalities in mortality in Salvador, Bahia State, Brazil, between 1991 and 2006. The city was divided into four social strata from 95 geographic Information Zones. The variables used for social stratification were education level and income of heads of households. Crude and age-standardized mortality rates, age specific mortality rates, proportional Infant mortality and the proportional mortality ratio, were calculated for each zone and social strata. Data was obtained from Death Certificates and the Populational Census. Although differences between strata were smaller in 2000 than in 1991, they persist and are still high, ranging from 28.7% to 65.5%. The differences between Information Zones were as much as 575%. The authors discuss the shortcomings of information systems, recommending that health indicators should be estimated by social classes and pointing out the limits and possibilities of the methodology used here. PMID- 21789412 TI - Avoidable deaths in the first four years of life among children in the 2004 Pelotas (Brazil) birth cohort study. AB - Avoidable deaths have been employed as indicators of health care quality. The aim of this study was to identify factors associated with avoidable deaths from birth to four years of age among children from the 2004 Pelotas (Brazil) birth cohort study. From January 1st, 2004, to December 31st, 2005, deaths were monitored on a daily basis and the causes were investigated and classified according to avoidability. After the first year, deaths were monitored through the Mortality Information System. A total of 94 children died during this period. It was possible to classify 92 deaths, 70 of which were preventable. Low family income, fewer prenatal visits and poor-quality prenatal care, preterm birth, low 5-minute Apgar score, and no breastfeeding in the first 24 hours of life were associated with increased risk of death. Prematurity was present in 39 deaths, but only five of these would have been prevented by measures provided during prenatal care. Although limited, compliance with antenatal care program guidelines is still the most important strategy for preventing avoidable deaths in childhood, particularly among the poorest children. PMID- 21789413 TI - Social inequalities in health among the elderly. AB - The aim of the present study was to assess social inequalities in health status, health behavior and the use of health services based on education level. A population-based cross-sectional study was carried out involving 1,518 elderly residents of Campinas, Sao Paulo State, Brazil. Significant demographic and social differences were found between schooling strata. Elderly individuals with a higher degree of schooling are in greater proportion alcohol drinkers, physically active, have healthier diets and a lower prevalence of hypertension, diabetes, dizziness, headaches, back pain, visual impairment and denture use, and better self-rated health. But, there were no differences in the use of health services in the previous two weeks, in hospitalizations or surgeries in the previous year, nor in medicine intake over the previous three days. Among elderly people with hypertension and diabetes, there were no differences in the regular use of health services and medication. The results demonstrate social inequalities in different health indicators, along with equity in access to some health service components. PMID- 21789414 TI - Socioeconomic development, family income, and psychosocial risk factors: a study of families with children in public elementary school. AB - This article aims to evaluate the effects of Brazil's recent economic growth on the monetary income, consumption patterns, and risk exposures of families with children enrolled in the public elementary school system in Sao Goncalo, Rio de Janeiro State, Brazil. The article analyzes the following information on families of 447 children that participated in two waves in a longitudinal study: social stratum, per capita family income, evolution in income over a three-year period, and psychosocial factors. The findings showed a 74.8% increase in the families' income, accompanied by an increase in the consumption of material assets and access to health services. This increase should not be interpreted as a guarantee of improved living and health conditions, since it was spent on basic products and needs that do not substantially affect the families' form of social inclusion. Psychosocial risk factors were frequent among the families, but decreased during the study period, which may either reflect the improved family situation or result from the later stage in child development. PMID- 21789415 TI - Mortality among Guarani Indians in Southeastern and Southern Brazil. AB - Worldwide, indigenous peoples display a high burden of disease, expressed by profound health inequalities in comparison to non-indigenous populations. This study describes mortality patterns among the Guarani in Southern and Southeastern Brazil, with a focus on health inequalities. The Guarani population structure is indicative of high birth and death rates, low median age and low life expectancy at birth. The crude mortality rate (crude MR = 5.0/1,000) was similar to the Brazilian national rate, but the under-five MR (44.5/1,000) and the infant mortality rate (29.6/1,000) were twice the corresponding MR in the South and Southeast of Brazil. The proportion of post-neonatal infant deaths was 83.3%, 2.4 times higher than general population. The proportions of ill-defined (15.8%) and preventable causes (51.6%) were high. The principal causes of death were respiratory (40.6%) and infectious and parasitic diseases (18.8%), suggesting precarious living conditions and deficient health services. There is a need for greater investment in primary care and interventions in social determinants of health in order to reduce the health inequalities. PMID- 21789416 TI - The relationship between social capital, social support and the adequate use of prenatal care. AB - This study investigated the relationship between social capital and social support and the adequate use of prenatal care. A follow-up study involving 1,485 pregnant women was conducted in two cities in the Rio de Janeiro State, Brazil. Demographic and socioeconomic characteristics, social support and social capital data were collected during the first trimester of pregnancy. The post-partum period included information on levels of prenatal care utilization, social networks, parity, obstetric and gestational risk and prenatal care attendance. Hierarchized multinomial logistic regression was used in the statistical analysis. Prenatal care use above adequate levels was associated with high social capital at the city level (aggregated social capital), socioeconomic status and working during pregnancy. Lower non-aggregated contextual and compositional social capital, gestational risk and pattern of prenatal care were associated with inadequate prenatal care utilization. Contextual social capital and social support were found to be social determinants for the appropriate use of prenatal care. PMID- 21789417 TI - Catastrophic spending on health care in Brazil: private health insurance does not seem to be the solution. AB - The objective of this study was to estimate catastrophic healthcare expenditure in Brazil, using different definitions, and to identify vulnerability indicators. Data from the 2002-2003 Brazilian Household Budget Survey were used to derive total household consumption, health expenditure and household income. Socioeconomic position was defined by quintiles of the National Economic Indicator using reference cut-off points for the country. Analysis was restricted to urban households. Catastrophic health expenditure was defined as expenditure in excess of 10% and 20% of total household consumption, and in excess of 40% of household capacity to pay. Catastrophic health expenditure varied from 2% to 16%, depending on the definition. For most definitions, it was highest among the poorer. The highest proportions of catastrophic health expenditure were found to be in the Central region of Brazil, while the South and the Southeast had the lowest. Presence of an elderly person, health insurance and socioeconomic position were associated with the outcome, and coverage by health insurance did not protect from catastrophic health expenditure. PMID- 21789418 TI - Neonatal and pediatric intensive care in Rio de Janeiro State, Brazil: an analysis of bed distribution, 1997 and 2007. AB - The objective of this study was to describe the characteristics of neonatal and pediatric intensive care units (ICU) and beds in Rio de Janeiro, correlating with population demands in 1997 and 2007. All neonatal and pediatric ICUs were visited, identifying the availability and type of beds. Comparisons were made between: supply and demand using projected need for beds for the population; public and private ICUs; and geographical regions. In 2007, 95 units were included totaling 1,094 beds (74 units and 1,080 beds in 1997): 51% public and 48% private (47% and 52% in 1997); 47% neonatal, 18% pediatric and 35% mixed units. Most units were located in the metropolitan area. The distribution of public and private beds was similar in the metropolitan area in both periods; in the interior, public beds tripled. Access has improved, mainly in the interior, but there is still no equity in the distribution of and accessibility to the available beds, with a shortage in the public sector, an excess in the private sector, and a great concentration in the metropolitan area. PMID- 21789419 TI - Inequalities in access and utilization of dental services: a cross-sectional study in an area covered by the Family Health Strategy. AB - This cross-sectional study aimed to investigate the presence of inequalities in the access and use of dental services for people living in the coverage area of the Family Health Strategy (FHS) in Ponta Grossa, Parana State, Brazil, and to assess individual determinants related to them. The sample consisted of 747 individuals who answered a pre-tested questionnaire. Data analysis was performed by chi-square test and Poisson regression analysis, obtaining explanatory models for recent use and, by limiting the analysis to those who sought dental care, for effective access. Results showed that 41% of the sample had recent dental visits. The lowest visit rates were observed among preschoolers and elderly people. The subjects who most identified the FHS as a regular source of dental care were children. Besides age, better socioeconomic conditions and the presence of a regular source of dental care were positively associated to recent dental visits. We identified inequalities in use and access to dental care, reinforcing the need to promote incentives to improve access for underserved populations. PMID- 21789420 TI - Iniquities in the access to renal transplant for patients with end-stage chronic renal disease in Brazil. AB - The objective of this present study is to analyze individual and contextual factors associated with access to renal transplant in Brazil. An observational, prospective and non-concurrent study was carried out, based on data from the National Database on renal replacement therapies in Brazil. Patients undergoing dialysis between 01/Jan/2000 and 31/Dec/2000 were included and monitored up to the point of transplant, death or until the end of the study period. Variables that were analyzed included: individual variables (age, sex, region of residence, primary renal disease, hospitalizations); and context variables concerning both the dialysis unit (level of complexity, juridical nature, hemodialysis machines and location) and the city (geographic region, location and HDI). Proportional hazard models were adjusted with hierarchical entry to identify factors associated with the risk of transplant. The results point to differentials in access according to socio-demographic, clinical, geographic and social factors, indicating that the organ allocation system has not eliminated avoidable disparities for those who compete for an organ in the nationwide waiting list. PMID- 21789421 TI - Social inequalities and the rise in violent deaths in Salvador, Bahia State, Brazil: 2000-2006. AB - An ecological study was carried out using information zones as units of analysis in order to assess the evolution of socio-spatial inequalities in mortality due to external causes and homicides in Salvador, Bahia State, Brazil, in 2000 and 2006. The Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatistica--IBGE) and the City Health Department (Secretaria Municipal de Saude) provided the data sources, and causes of death were reviewed and reclassified based on reports from the Institute of Legal Medicine (Instituto Medico Legal). The information zones were classified into four social strata according to income and schooling. The ratio between mortality rates (inequality ratio) was calculated and confirmed a rise of 98.5% in the homicide rate. In 2000, the risk of death due to external causes and murders in the stratum with the worst living conditions was respectively 1.40 and 1.94 times greater than in the reference stratum. In 2006 these figures were 2.02 and 2.24. The authors discuss the implications for inter-sectoral public policies, based on evidence from the study's findings. PMID- 21789423 TI - [Professor Heonir Rocha prize]. PMID- 21789422 TI - Social and biological determinants of iron deficiency anemia. AB - This cross-sectional study aimed to identify the social and biological determinants of anemia in children enrolled in the Brazilian Income Transfer Program (PBF). The study evaluated 446 children (69.1% of the total enrolled) ranging from 6 to 84 months of age, of whom 262 were receiving the income transfer (60.2% of the beneficiaries) and 184 were not (87.6% of the non beneficiaries). Testing for anemia was performed with the Hemocue portable hemoglobinometer, and the cutoff points were set at 11.0 and 11.5 g/dL, according to age bracket. The data were analyzed using Poisson hierarchical regression with robust variance for multivariate analysis. There was no difference in the anemia prevalence rates between the beneficiary and non-beneficiary groups. Risk factors for anemia were low paternal schooling, cesarean birth, consumption of untreated water, stunting, and age less than 24 months. Prevalence of anemia in the group of non-beneficiary children under two years of age was significantly higher than in the beneficiary group in the same age bracket, suggesting the importance of the PBF income transfer for preventing anemia in children. PMID- 21789424 TI - Anxiety, depression, and quality of life in patients with familial glomerulonephritis or autosomal dominant polycystic kidney disease. AB - INTRODUCTION: Psychological aspects and quality of life are often evaluated in patients under renal replacement therapy, but studies about anxiety, depression, and quality of life in familial renal diseases are lacking. OBJECTIVES: To evaluate the frequency of anxiety, depression, and quality of life (QOL) and their eventual associations with the main laboratory, clinical, socioeconomic, and cultural parameters in familial glomerulonephritis (GN) or autosomal dominant polycystic kidney disease (ADPKD). METHODS: Ninety adult patients (52 familial GN and 38 ADPKD) completed the questionnaires of State Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and QOL-Short-Form SF-36, and were also submitted to a short interview. RESULTS: Moderate anxiety was detected in both groups. Depression was found in 34.6% of familial GN and 60.5% of ADPKD patients. Anxiety and depression were more associated with female gender in familial GN, and with poorer schooling in ADPKD. Patients of both groups presented two quality of life unfavorable dimensions: emotional role function and general health perception. In addition, quality of life was worse among females, unmarried, and Caucasian subjects, and those individuals with a poorer educational level. CONCLUSION: The use of these instruments allows one to appreciate the frequency and levels of anxiety, depression, and quality of life in patients with familial renal diseases that could affect their compliance to treatment. These findings can contribute to planning a better multidisciplinary assistance to such groups of patients. PMID- 21789425 TI - Quality of life of chronic renal patients on hemodialysis in Marilia, SP, Brazil. AB - INTRODUCTION: Hemodialysis is responsible for significant alterations in the quality of life of chronic renal patients. OBJECTIVE: To compare the quality of life of patients on hemodialysis without depression (A) and those with some level of depression (B). METHODS: This was a transversal and descriptive study in which the Beck Depression Inventory (BDI) and the WHOQOL-bref scale were used. RESULTS: The studied sample consisted of 130 patients, 65.15% in A, and 33.84% in B. The highest levels of depression were related to longer periods of treatment. Quality of life indexes were better for A, and, as certain domain increased, also were the others. More differences were observed in the Psychological (A: 69.40 and B: 49.22) and Physical (A: 62.81 and B: 42.19) Domains; and the Social Relations Domain had a better average between the populations, as well as a better correlation with the other domains. CONCLUSION: Although there was a low prevalence of depression among hemodialysis patients, some investments should be made in the social, psychological and physical support aiming to improve their quality of life. PMID- 21789426 TI - Clinical manifestations and evolution of infection by influenza A (H1N1) in kidney transplant recipients. AB - INTRODUCTION: The emergence of the pandemic outbreak of influenza A (H1N1) in April, 2009, represented a logistic challenge for public health. Although most infected patients presented clinical and evolutionary manifestations which were very similar to seasonal influenza, a significant number of individuals developed pneumonia and severe acute respiratory failure. The impact of influenza A (H1N1) in immunocompromised patients is not well established yet. METHODS: This study aimed to analyze the clinical presentations and evolution of influenza A (H1N1) in 19 kidney transplant recipients. Influenza A (H1N1) infection was confirmed by RT-PCR in all patients. Treatment included antiviral therapy with oseltamivir phosphate and antibiotics. RESULTS: The studied population was compounded mostly of white people (63%), males (79%), at a mean age of 38.6 +/- 17 years and patients with at least one comorbidity (53%). Influenza A (H1N1) infection was identified 41.6 +/- 49.6 months after transplantation. Common symptoms included cough (100%), fever (84%), dyspnea (79%), and myalgia (42%). Acute allograft dysfunction was observed in 42% of the patients. Five patients (26%) were admitted to the Intensive Care Unit, two (10%) required invasive ventilation support, and two (10%) required vasoactive drugs. Mortality rate was 10%. CONCLUSIONS: Acute renal allograft dysfunction was a common finding. Clinical, laboratory, and evolutionary characteristics were comparable to those in the general population. PMID- 21789427 TI - Assessment of social and economic influences on blood pressure of adolescents in public and private schools: an epidemiological study. AB - INTRODUCTION: The high prevalence of hypertension in high school students in Sorocaba, Sao Paulo, Brazil, has already been described. In this study, within a new sample of high school students from public and private schools, we evaluated if socioeconomic and lifestyle influence on blood pressure values. METHODS: This is an epidemiological study, which is part of the activities of a community-based work conducted by medical students. They give speeches to high school students aiming at stimulating a healthy lifestyle and primary prevention of hypertension. In a random sample of 410 students in junior high school (209 from public schools and 201 from private schools), we determined the weight, height, and blood pressure, furthermore, a questionnaire identifying epidemiological and socioeconomic status was applied. RESULTS: No statistical differences were found among students from public and private schools regarding the distribution of gender, body mass index (BMI), systolic and diastolic blood pressure, prevalence of hypertension (16.3%), percentage of smokers (5.9%), regular physical activity, and family history of hypertension. In public schools, there is a higher percentage of African descendents students and a higher percentage of students who also work due to low family income. Men from public and private schools have higher prevalence of hypertension, and their mean blood pressure is higher than in women. BMI has a positive correlation with systolic and diastolic blood pressure. CONCLUSIONS: Hypertension and other cardiovascular risk factors have an early beginning and require educational interventions for primary prevention. Socioeconomic factors do not affect blood pressure in adolescence. PMID- 21789428 TI - Investigation of nephrolithiasis in the West of Parana. AB - INTRODUCTION: Nephrolithiasis is com>mon and has a high rate of recurrence. OBJECTIVES: To assess the prevalence of the main metabolic and anatomical changes and the chemical analysis of stone found in patients with nephrolithiasis in the West region of Parana. METHODS: Retrospective study with 681 adult patients with nephrolithiasis. The laboratory investigation included at least two samples of 24 hour urine test with doses of calcium, uric acid, citrate, oxalate, sodium and creatinine; qualitative cystinuria, urinary pH following 12-hour fast and water restriction, urine culture and chemical analysis, when the stones were available. Renal imaging techniques included at least renal ultrasound and excretory urogram. RESULTS: The metabolic changes most frequently found were: hypercalciuria (51.8%), hyperuricosuria (27.6%), and hypocitraturia (23.5%). Chemical analysis of stones showed calcium oxa late in 85.7% of the cases. The most frequently anatomical changes were renal cyst, duplicated ureter, and ureteropelvic junction obstruction. CONCLUSIONS: This paper served as a base for knowing the characteristics of patients with nephrolithiasis in the West area of Parana. PMID- 21789429 TI - Short-term effects of soy protein diet in patients with proteinuric glomerulopathies. AB - INTRODUCTION: It has been suggested that soy protein can slow renal disease progression by decreasing plasma cholesterol and proteinuria in patients with nephropathies. This study was designed to evaluate the effect of soy protein on proteinuria and dyslipidemia, in patients with proteinuric glomerulopathies. PATIENTS AND METHODS: Patients were divided into three groups: Control Group (n = 9) received diet with 0.8 g/kg/day of animal protein; Study Group 1 (n = 9), 0.8 g/kg/day of soy protein; and Group 2 (n = 9), 0.8 g/kg/day of soy protein plus fibers. The study period corresponded to eight weeks. During the baseline period and by the end of the study, patients were submitted to laboratorial and anthropometric evaluation. RESULTS: There was no statistically significant difference between baseline and post-diet periods among the three groups in anthropometric parameters or body composition, neither in proteinuria levels (Control: 0.7 +/- 0.6 versus 0.8 +/- 0.6; Group 1: 2.0 +/- 1.7 versus 1.9 +/- 1.8; Group 2: 2.0 +/- 1.4 versus 2.1 +/- 2.0). However, a slight decrease in triglycerides (244.8 +/- 275.9 versus 200.5 +/- 34.0), total (234.0 +/- 59.4 versus 181.2 +/- 110.3) and LDL (136.0 +/- 59.1 versus 104.1 +/- 39.4) cholesterol in Group 1 was observed, although not significant. CONCLUSION: We have not observed beneficial effects when using soy protein instead of animal protein with the aim of attenuating proteinuria and hyperlipidemia, but we have shown that soy protein has not caused deleterious changes in body composition, ensuring an adequate nutritional state. PMID- 21789430 TI - Comparison of quality of life between hemodialysis patients waiting and not waiting for kidney transplant from a poor region of Brazil. AB - INTRODUCTION: There are few data about the quality of life (QOL) level among patients undergoing hemodialysis (HD) and not eligible for kidney transplant. OBJECTIVE: The QOL level was compared between HD patients waiting and not waiting for kidney transplant. METHODS: We included 161 end-stage renal disease patients undergoing HD, during April, 2009. All patients were older than 18 years old, had been on HD at least three months, and had no previous transplantation. To measure QOL, the SF-36 was used. We also collected data about death and transplants in the 12 months after April, 2009. QOL scores were compared by analysis of variance with covariates. RESULTS: Patients not awaiting transplantation were older (53.7 versus 36.3 years old; p < 0.001), more often had diabetes (15.8 versus 4.7%; p = 0.032) and hypertension (35.5 versus 12.9%; p < 0.001), and had no lupus (0 versus 4.7%; p = 0.001). They also presented lower creatinine levels (11.5 versus 13.5 mg/dL; p = 0.001) and were submitted to a lower dose of dialysis, estimated by Kt/V (1.6 versus 2.0; p = 0.026). Patients not awaiting transplant died more often in the following 12 months (21.1 versus 5.9%; p = 0.005). Adjusted mean scores were lower among patients not awaiting transplant regarding six dimensions of QOL: functional capacity (42.0 versus 53.4; p = 0.022), physical limitation (29.9 versus 49.2; p = 0.030); pain (45.0 versus 64.0; p = 0.003), social aspects (56.3 versus 75.9; p = 0.003), emotional aspects (45.1 versus 79.0; p = 0.001), and mental health (50.1 versus 64.3; p = 0.004). CONCLUSIONS: Patients undergoing HD and not awaiting transplant are at risk of poor QOL level, mainly regarding role-emotional and role-physical aspects. We recommend psychological approaches and physical rehabilitation for this group of patients. PMID- 21789431 TI - Comparative analysis of lipid and glucose metabolism biomarkers in non-diabetic hemodialysis and peritoneal dialysis patients. AB - OBJECTIVE: To investigate and compare glucose and lipid metabolism biomarkers in non-diabetic peritoneal dialysis and hemodialysis patients. METHODS: The study followed a prospective and cross-sectional design. PARTICIPANTS: Participants included all prevalent end-stage renal disease patients under renal replacement therapy treated in a university-based clinic. INTERVENTIONS: There were no interventions. MAIN OUTCOMES MEASURES: Blood samples were taken after 8 hours of fasting. Insulin serum levels were determined by chemiluminescence. Insulin resistance were assessed by the insulin sensitivity check index (QUICKI) determined as follow: 1/[log(Io) + log(Go)], where Io is the fasting insulin, and Go is the fasting glucose. HOMA index was also measured: (FPG * FPI)/22.5; FPG = fasting plasma glucose (mmol/L); FPI = fasting plasma insulin (mU/mL). The others biochemical exams were measured utilizing the routine tests. RESULTS: We screened 154 patients (80 on hemodialysis and 74 on peritoneal dialysis). Seventy-four diabetic patients were excluded. Of the remaining 80 patients (55% males, mean age 52 +/- 15 years), 35 were on peritoneal dialysis and 45 on hemodialysis. Fasting glucose of peritoneal dialysis patients compared to hemodialysis patients were 5.0 +/- 0.14 versus 4,58 +/- 0.14 mmol/L, p<0.05; glycated hemoglobin 5.9 +/ 0.1 versus 5.5 +/- 0.1%, p < 0.05; total cholesterol 5.06 +/- 0.19 versus 3.39 +/- 0.20 mmol/L, p < 0.01; LDL-c 2.93 +/- 0.17 versus 1.60 +/- 0.17 mmol/L, p < 0.01; and index HOMA 3.27 versus 1,68, p < 0,05. Importantly, all variables were adjusted for age, gender, dialysis vintage, calcium-phosphorus product, albumin and C-reactive protein levels. CONCLUSION: We observed a worst profile of lipid and glucose metabolism biomarkers in peritoneal dialysis patients (lower insulin sensitivity and higher fasting glucose, HbA1c, total cholesterol and LDL-c) when compared to hemodialysis, potentially due to the glucose-based dialysis solutions utilized in the peritoneal dialysis population. PMID- 21789432 TI - Impact of delayed pancreatic graft function in simultaneous pancreas-kidney transplantation. AB - OBJECTIVE: Simultaneous pancreas-kidney transplantation is an effective treatment for patients with type 1 diabetes mellitus and end-stage chronic kidney disease. Delayed pancreatic graft function is a common and multifactor condition with significant impact in short-term outcome of simultaneous pancreas-kidney transplantations. The aim of this study was to analyze the impact of pancreatic delayed pancreatic graft function on simultaneous pancreas-kidney transplantation. METHODS: Donor and recipient's demographic data, percentage of panel reactivity, acute rejection incidence, and patient and grafts survivals were retrospectively analyzed in 180 SPKT performed between 2002 and 2007. RESULTS: The incidence of pancreatic delayed pancreatic graft function was 11%. Donors older than 45 years had significant risk of pancreatic delayed pancreatic graft function (OR 2.26; p < 0,05). Patients with pancreatic delayed pancreatic graft function had higher rates of acute renal rejection (47 versus 24%; p < 0.05), altered fasting plasma glucose (25 versus 5%; p < 0.05) and mean glycated hemoglobin (5.8 versus 5.4%; p < 0.05), than patients without pancreatic delayed pancreatic graft function at the end of the first year of follow up. There were no significant differences between patients with and without pancreatic delayed pancreatic graft function regarding patient survival (95 versus 88.7%; p = 0.38), pancreatic graft survival (90 versus 85.6%; p = 0.59) and renal graft survival (90 versus 87.2%; p = 0.70), respectively at the sample period of time. CONCLUSION: Pancreatic delayed pancreatic graft function had no significant impact in the short-term outcome of simultaneous pancreas-kidney transplantations. Although delayed pancreatic graft function had no impact on 1 year pancreas graft survival, it contributed to early pancreas graft dysfunction, as assessed by enhanced insulin and oral anti-diabetic drugs requirements. PMID- 21789433 TI - [Brazilian Guidelines for bone and mineral disorders in CKD children]. PMID- 21789434 TI - [Guidelines for bone and mineral disorders after kidney transplantation]. PMID- 21789435 TI - [Bone biopsy in chronic kidney disease]. PMID- 21789436 TI - [Parathyroidectomy in CKD]. PMID- 21789437 TI - [Vascular calcification in CKD]. PMID- 21789438 TI - [Aluminium intoxication in chronic kidney disease]. PMID- 21789439 TI - [Adynamic bone disease]. PMID- 21789440 TI - [Dialysate calcium concentration and hypercalcemia in CKD]. PMID- 21789441 TI - [Prevention and treatment of secondary hyperparathyroidism in CKD]. PMID- 21789442 TI - [Management of hyperphosphatemia in CKD]. PMID- 21789443 TI - [Foreword. Brazilian clinical practice guidelines for mineral and bone disorders in chronic renal disease]. PMID- 21789444 TI - [Hyponatremia: basic concepts and practical approach]. AB - Hyponatremia is the most common electrolyte imbalance in hospitalized patients. It is associated with several unfavorable endpoints such as: the need for intensive care, longer hospital stay, higher hospitalization costs, discharge to long-term care facilities, and mortality. It is still not clear if there is a direct causal relationship or if hyponatremia is simply a marker of disease severity. Nevertheless, it is quite clear that improper management of a hyponatremic patient may result in severe neurologic damage or death. This paper addresses the basic pathophysiologic concepts about hyponatremia followed by a practical approach to its diagnosis and management. PMID- 21789445 TI - [Serum cystatin C: a practical alternative for renal function evaluation?]. AB - Glomerular filtration rate is the main marker of renal function in healthy individuals and patients. Despite incontestable advances in medicine, it is still difficult to define precisely this test in clinical practice. Early markers of renal lesion are important, because glomerular filtration rate usually decreases before the first chronic renal failure symptoms or signs appear. Cystatin C has been pointed as an alternative, but it was not tested in many diseases. Advantages and disadvantages of this marker are discussed. Although serum cystatin C determination is increasingly being used in clinical practice worldwide, its limitations as well as the conditions its use is in fact indicated are not adequately established; on the other hand serum creatinine (and creatinine clearance) is an easily available and low cost laboratory marker with well-known limitations that can be used routinely in the assessment of renal function. PMID- 21789446 TI - [Skin diseases in hemodialysis and kidney transplant patients]. AB - Recently, the world is facing an escalate in the incidence of chronic kidney disease (CKD). Databases containing information about patients in end stage renal disease (ESRD), especially in the United States, were the sources of initial information about it. Brazil has the third largest population on dialysis in the world, and there are about 680 dialysis centers, spread across all units of the federation in the present, providing treatment to an estimated population of almost 90,000 patients. Cutaneous involvement in the chronic renal failure is characterized by a number of manifestations, which may be related to three processes: the primary renal disease, the uremic state, or the therapeutic measures used in their handling. The skin changes in these two classes of patients, dialysis and transplant recipients, have been the subject of several studies. n recent years, however, great progress has been achieved in these two therapeutic modalities, which may have changed not only the type of the dermatologic disorders associated with these two conditions, but also their intensity or frequency. This article aims to yield an update as to the topic skin diseases in hemodialysis and kidney transplant patients. PMID- 21789447 TI - [Acute renal failure in patient treated with ATRA and amphotericin B: case report]. AB - This is a report of the case of a patient with acute promyelocytic leukemia treated with all trans-retinoic acid (ATRA), who had suspected all-trans retinoic acid syndrome (ATRA syndrome). The nonspecific febrile leukopenia observed justified the association with antimicrobial and antifungal therapy. Signs and symptoms contributed to the suspicion of ATRA syndrome, and renal function was impaired by the combination with antifungal agents. The decrease in renal function observed initially contributed to the suspicion of ATRA syndrome and was aggravated by antifungals. Thus, the use of ATRA was discontinued. Eight days after the pneumonia characterization, the possibility of ATRA syndrome was dismissed. In this context, ATR's nephrotoxicity and the synergic adverse effect by the use of nephrotoxic antifungal agents were discussed, particularly amphotericin B, as well as the importance of differential diagnosis between ATRA syndrome and infectious diseases. PMID- 21789449 TI - Drinking water quality and fluoride concentration. AB - This paper aimed to analyze the fluoride concentration in drinking water, taking into account the balance between the benefits and risks to health, in order to produce scientific backing for the updating of the Brazilian legislation. Systematic reviews studies, official documents and meteorological data were examined. The temperatures in Brazilian state capitals indicate that fluoride levels should be between 0.6 and 0.9 mg F/l in order to prevent dental caries. Natural fluoride concentration of 1.5 mg F/l is tolerated for consumption in Brazil if there is no technology with an acceptable cost-benefit ratio for adjusting/removing the excess. Daily intake of water with a fluoride concentration > 0.9 mg F/l presents a risk to the dentition among children under the age of eight years, and consumers should be explicitly informed of this risk. In view of the expansion of the Brazilian water fluoridation program to regions with a typically tropical climate, Ordinance 635/75 relating to fluoride added to the public water supply should be revised. PMID- 21789450 TI - [CBC: workshop on surgery research-25 years]. PMID- 21789451 TI - Diagnostic accuracy of frozen section tests for surgical diseases. AB - OBJECTIVE: To evaluate the accuracy of frozen section tests at different anatomical sites performed in an academic department of pathology. METHODS: We conducted a retrospective study from a computerized database of all frozen section tests. These diagnoses were compared to definite paraffin, used as controls. The tests were divided into three groups: inconclusive, consistent and inconsistent, the latter being subdivided into false positives and false negatives. The main indications for examinations and anatomical sites involved with diagnostic disagreements were also analyzed. RESULTS: Four hundred and thirty-three specimens were frozen tested, and the main indication was diagnostic (75.75%). In 404 tests (93.30%) diagnoses of biopsies in paraffin and frozen section were consistent. In 20 cases (4.62%) the results of frozen section biopsy were inconclusive and in 9 (2.08%) they were false negative. There were no false positive results. The most commonly assessed organ was the thyroid (25.64%). In the overall analysis, the body region most related with inconclusive diagnoses was the thyroid (seven cases) and in relation to specific sites it was the lungs/pleura/mediastinum (13.33%). Skin was the organ that showed more discordant diagnoses between frozen biopsies and paraffin. CONCLUSION: The global accuracy of frozen section was 93.30%; for specific anatomical sites, diagnostic accuracy ranged from 86.67% to 100%. PMID- 21789452 TI - Laparoscopic cholecystectomy in 960 elderly patients. AB - OBJECTIVE: To evaluate the operative time, hospital stay, conversion rate, morbidity and mortality in elderly patients undergoing laparoscopic cholecystectomy for gallbladder disease. METHODS: We conducted a descriptive, retrospective study with the chats of 960 patients, aged 60 and 97 years in the period from January 1993 to August 2009. RESULTS: Operative time ranged from nine to 180 minutes. The length of stay ranged from 24 to 120 hours. Conversion occurred in 28 patients (2.92%), of whom 67.9% were women and 28.6% men, a minilaparotomy having been performed in 11 cases (39.3%) and in 17 (60.7%) the conventional open route. The perioperative complications were two ruptures of the gallbladder, one failure in the pneumoperitoneum and one in clipping the cystic duct. Postoperative complications were five umbilical incisional hernias. Systemic complications were: nine arrhythmias, one postoperative jaundice, one acute myocardial infarction and one mesenteric infarction. Mortality occurred in three patients (0.3%), one due to perioperative myocardial infarction, one due to sepsis and one because of mesenteric infarction. CONCLUSION: Elderly patients undergoing laparoscopic cholecystectomy had low hospital stay and low morbimortality. The operative time and hospital stay were short, demonstrating that laparoscopic cholecystectomy is safe and effective in the elderly. PMID- 21789453 TI - Roux-en-Y gastric bypass and inflammatory activity of the adipose tissue. AB - OBJECTIVE: To evaluate the oxidative stress and inflammatory markers in obese patients before and after Roux-en-Y vertical banded gastroplasty. METHODS: We studied 20 class III obese patients undergoing Roux-en-Y vertical banded gastroplasty, seven men and 13 women, mean age 39 years, and 20 non-obese subjects, nine males and 11 females, mean age 38 years. We determined the plasma levels of malondialdehyde, stress an index, total antioxidant capacity, catalase, reduced and oxidized glutathione and inflammatory markers (C reactive protein and a-1 acid glycoprotein). In the obese group, these parameters were determined before and 2, 6 and 12 months after gastroplasty. RESULTS: Preoperatively, the obese group showed elevated levels of inflammatory markers of oxidative stress (malondialdehyde levels and stress index) and lower levels of indicators of antioxidant defense compared to the control group. Weight loss was accompanied by gradual reduction in the levels of malondialdehyde and stress index. We found an increased concentration of reduced glutathione and total antioxidant status and reduced levels of inflammatory markers. CONCLUSION: Weight loss improves the inflammatory state and oxidative stress levels. PMID- 21789454 TI - Biochemical study of dermatan sulfate glycosaminoglycan in adult male patients with Nyhus type II inguinal hernia. AB - OBJECTIVE: To compare the amount of the dermatan sulfate glycosaminoglycan between male patients with Nyhus type II inguinal hernias and subjects without inguinal hernia, aged between 20 and 40 years. METHODS: Two groups were formed: One with 15 male patients with Nyhus type II inguinal hernia and aged between 20 and 40 years with ASA risk I and II, and a control group of ten individuals, also males between 20 and 40, who had died up to 24 h before. We excluded female patients, diabetic patients with connective tissue disease, smokers and surgical risk ASA III and IV. We resected a sample of 1 cm2 of the transversalis fascia in the middle of the inguinal trigone, and 1 cm2 of the anterior sheath of the rectus abdominis muscle in the groin for the quantification of dermatan sulfate glycosaminoglycans by densitometry after agarose gel electrophoresis. RESULTS: The amount of dermatan sulfate showed no statistically significant difference between patients with inguinal hernia and individuals without inguinal hernia in both the transverse fascia (p = 0.108) and anterior sheath of the rectus abdominis muscle (p = 0.292). CONCLUSION: There was no difference in the amount of the dermatan sulfate glycosaminoglycan among patients with Nyhus type II inguinal hernias and subjects without inguinal hernia in adult males. PMID- 21789455 TI - Publication of papers presented in a Brazilian Trauma Congress. AB - OBJECTIVE: To assess the proportion of papers presented at the XXI Panamerican Congress of Trauma, VIII Congress of the Brazilian Society of Integrated Assistance to the Traumatized (SBAIT) and X Brazilian Congress of Trauma Leagues (CoLT) that were published in full. METHODS: In the events cited, based in Campinas in 2008, 347 papers abstracts of were presented and published. To evaluate the proportion of complete published works a retrospective observational study was conducted, reviewing the biomedical databases PubMed and SciELO, with support from Google, from the title of the abstracts and list of authors. RESULTS: Of 347 papers considered, 25 (7.3%) were from foreign services and 322 (92.7%) national. Ten (2.9%) papers were published, of which six (1.7%) of nursing and four (1.2%) medical. Among these, four thesis publications were identified and only one international work has been published. CONCLUSION: Despite a large number of papers presented at trauma conferences in Brazil, the publications in this area are rare. The academy and the societies of surgery need to encourage the submission of scientific papers even before the presentation in Congresses in order for them to be evaluated for publication in indexed journals. PMID- 21789456 TI - Electronic protocol of respiratory physical therapy in patients with idiopathic adolescent scoliosis. AB - OBJECTIVE: To create a clinical database of respiratory function in patients with adolescent idiopathic scoliosis; computerize and store this clinical data through the use of a software; incorporate this electronic protocol to the SINPE(c) (Integrated Electronic Protocols System) and analyze a pilot project with interpretation of results. METHODS: From the literature review a computerized data bank of clinical data of postural deviations was set up (master protocol). Upon completion of the master protocol a specific protocol of respiratory function in patients with adolescent idiopathic scoliosis was designed and a pilot project was conducted to collect and analyze data from ten patients. RESULTS: It was possible to create the master protocol of postural deviations and the specific protocol of respiratory function in patients with adolescent idiopathic scoliosis. The data collected in the pilot project was processed by the SINPE ANALYZER(c), generating charts and statistics. CONCLUSION: The establishment of the clinical database of adolescent idiopathic scoliosis was possible. Computerization and storage of clinical data using the software were viable. The electronic protocol of adolescent idiopathic scoliosis could be incorporated into the SINPE(c) and its use in the pilot project was successful. PMID- 21789458 TI - Dietary galactooligosaccharides increase calcium absorption in normal and gastrectomized rats. AB - OBJECTIVE: To determine whether the galactooligosaccharide stimulates calcium absorption in partially gastrectomized rats. METHODS: Animals were submitted to laparotomy (sham-operated control) and partial gastrectomy (Billroth II) in groups of 20. They were fed a control diet (AIN-93M) without galacto oligosaccharide or a diet containing (galacto-oligosaccharide - 50 g/kg diet) for eight weeks. The animals were divided into four groups: sham-operated and non gastrectomized with galactooligosaccharide, sham-operated and gastrectomized without galactooligosaccharide. On the final day of the study, whole blood was collected for determination of serum calcium concentration. RESULTS: In the group with galactooligosaccharides calcium excretion in feces was significantly lower than the group without prebiotics. The apparent absorption of calcium in gastrectomized and normal rats was higher in groups fed with galactooligosaccharide than in the control diet group. CONCLUSION: The ingestion of galactooligosaccharides prevents osteopenia in partially gastrectomized rats. PMID- 21789457 TI - Morfometric study of arterial branching of the spleen compared to radiological study. AB - OBJECTIVE: To study the distribution of the branches of the splenic artery and relate it to the radiological study of its intraparenchymal distribution, aiming to use this knowledge in partial splenectomy. METHODS: In the macroscopic study, we used 60 human spleens which the splenic artery dissected from its origin to observe the division and the terminal branches directed to the spleen. We measured the distance between the visceral surface of the spleen and the terminal division of the splenic artery and the emergence of the polar branches. In the radiological study, we used 30 human spleens in which contrast was injected in the splenic artery to perform an arteriography and study the terminal division and polar branches. RESULTS: 93.34% of the spleens showed bifurcation and terminal pattern of division and 6.66% trifurcation. We identified secondary and tertiary side branches, having a relative frequency of 10% for type I, 17% for type II and 8.33% for both. The distance between the visceral surface of the spleen and terminal division was on average 2.89 cm and the emergence of type I polar artery was 4.85 cm and 2.39 cm for type II. In the 30 arteriographies we assessed the terminal division and bifurcation was observed in 90% of spleens and trifurcation in 10%, and the presence of polar arteries in 16% type I and type II in 20%. CONCLUSION: The splenic artery deisplays a bifurcation-type terminal division that can be viewed arteriographically. We highlight the existence of independent arterial segmentation in almost all cases (98%), similar in visceral and diaphragmatic surfaces of the spleen. Partial splenectomy is anatomical and the use of radiological methods becomes feasible in conservative treatment of splenic injuries. PMID- 21789459 TI - Current role of imaging methods in the diagnosis of cystic solid pancreas neoplasms: part II. AB - The authors address the value of endoscopic retrograde cholangiopancreatography, ultrasonography, computed tomography, magnetic resonance imaging and endoscopic ultrasound for the diagnosis of cystic and solid neoplasms of the pancreas, demonstrating that each of them is of great importance to undoubtedly increase the diagnostic accuracy of the biliopancreatic system diseases. The best method for each of several tumors is then determined. PMID- 21789460 TI - [Informed consent: what is it real value in medical practice?]. AB - This is an article that talks about the real importance of Informed Consent (IC) in medical practice. This document has been increasingly used as a defensive practice, in order to provide evidence to the defense of any lawsuit of medical responsibility, thus distorting the original idea, which would be to respect patient autonomy and delimit medical liability. The document aims to show that the doctor complied with his duty to inform. Its great value lies in cases where there is a risk of irreversible damage to the patient. We conclude, however, that a well-documented chart, which includes the recording of information that was provided and the degree of participation of patients and their families in treatment decisions, should also have legal and ethical value similar to the IC's. PMID- 21789461 TI - Use en autologous plasma in abdominoplasty: previous note. AB - Autologous plasma began to be studied in the 90's, mainly because its adhesive and angiogenic properties and the presence of growth factors of platelet origin. In fact, plasma can be isolated from autologous manner, from the patient's own blood and obtained in its two parts: a high concentration of platelets (platelet rich plasma - PRP) and one with low concentration of platelets (platelet-poor plasma - PPP). The present study is in development at the Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro (UFRJ-HUCFF) and Marcilio Dias Naval Hospital (HNMD), both in Rio de Janeiro. The objective is to evaluate the properties of platelet-poor plasma, particularly its adhesive action, in patients referred for restorative abdominal dermolipectomy, to reduce postoperative collections, such as hematoma and seroma, two major complications in this type of surgery. PMID- 21789462 TI - [Gastric lipoma case report]. AB - We report a case of gastric lipoma, a rare benign stomach tumor. There are approximately 200 cases previously described in literature. A male, 62-year-old patient with no clinical complaint presented a tumor lesion in the stomach antrum found in a routine upper endoscopy. A surgical resection (subtotal gastrectomy) was done and the histological examination showed submucosal lipoma without signs of malignancy. This report points to the growth of routine examination in the current clinical practice and the dilemma brought by overdiagnosis. PMID- 21789463 TI - [Left paraduodenal hernia]. AB - A left paraduodenal hernia is a protrusion of the small intestine through the paraduodenal fossa, a congenital defect situated to the left of the fourth portion of the duodenum. Imaging studies often play a central role in diagnosing left paraduodenal hernias, as they are not easily identified clinically. Surgery is the treatment of choice. We report a case of left paraduodenal hernia in a 27 year-old female patient. The patient had shown no symptoms until six days before hospitalization. A CT scan suggested the diagnosis of left paraduodenal hernia. After an unsuccessful laparoscopic attempt, a laparotomy was performed. Open surgery consisted in removing adhesions between the hernia and peritoneum, reducing jejunal loops and closing the paraduodenal fossa. The postoperative period was uneventful, and the patient was discharged on the third postoperative day. PMID- 21789464 TI - Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome. AB - Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported. PMID- 21789465 TI - Central chemoreceptors and neural mechanisms of cardiorespiratory control. AB - The arterial partial pressure (P(CO)(2)) of carbon dioxide is virtually constant because of the close match between the metabolic production of this gas and its excretion via breathing. Blood gas homeostasis does not rely solely on changes in lung ventilation, but also to a considerable extent on circulatory adjustments that regulate the transport of CO(2) from its sites of production to the lungs. The neural mechanisms that coordinate circulatory and ventilatory changes to achieve blood gas homeostasis are the subject of this review. Emphasis will be placed on the control of sympathetic outflow by central chemoreceptors. High levels of CO(2) exert an excitatory effect on sympathetic outflow that is mediated by specialized chemoreceptors such as the neurons located in the retrotrapezoid region. In addition, high CO(2) causes an aversive awareness in conscious animals, activating wake-promoting pathways such as the noradrenergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have projections that contribute to the CO(2)-induced rise in breathing and sympathetic outflow. However, since the level of activity of the retrotrapezoid nucleus is regulated by converging inputs from wake-promoting systems, behavior-specific inputs from higher centers and by chemical drive, the main focus of the present manuscript is to review the contribution of central chemoreceptors to the control of autonomic and respiratory mechanisms. PMID- 21789466 TI - Giant cell arteritis presenting as scalp necrosis. AB - The differential of scalp ulceration in older patients should include several causes, such as herpes zoster, irritant contact dermatitis, ulcerated skin tumors, postirradiation ulcers, microbial infections, pyoderma gangrenosum, and giant cell arteritis. Scalp necrosis associated with giant cell arteritis was first described in the 1940s. The presence of this dermatological sign within giant cell arteritis represents a severity marker of this disease, with a higher mean age at diagnosis, an elevated risk of vision loss and tongue gangrene, as well as overall higher mortality rates, in comparison to patients not presenting this manifestation. Even though scalp necrosis due to giant cell arteritis is exceptional, a high level of suspicion must be held for this clinical finding, in order to initiate prompt and proper treatment and avoid blindness. PMID- 21789467 TI - Type B lactic acidosis secondary to malignancy: case report, review of published cases, insights into pathogenesis, and prospects for therapy. AB - Most of the information about type B lactic acidosis associated with cancer is derived from case reports and there are no randomized controlled trials to compare different therapeutic modalities. Previous reviews of cases only refer to hematologic malignancies. We present a patient with non-Hodgkin's lymphoma who developed type B lactic acidosis. We performed a search of the PUBMED database using the MESH terms "neoplasms" AND "acidosis, lactic", limited to the English language, and written between the years 2000 and 2010. A total of 31 cases were retrieved. These cases were identified and reviewed. The possible pathophysiologic mechanisms and treatment options are discussed. Type B lactic acidosis is most commonly seen in patients with lymphoma or leukemia. Although formal prospective trials are lacking, type B lactic acidosis in patients with cancer seems to be a marker of poor prognosis regardless of the treatment offered and may be invariably fatal. Future research should focus on potential therapy based on the pathogenic mechanisms that lead to type B lactic acidosis in cancer patients. PMID- 21789468 TI - Description of a novel murine model for ileocystoplasty and early histologic changes. AB - There is concern that bladder augmentation with bowel segments predisposes toward the development of carcinoma. Additionally, patients with neurogenic bladder and bladder cancer often present with advanced stage and have poor survival. Cellular hyperproliferation at the urointestinal junction (UIJ) has been implicated in this scenario. We aimed to develop a reproducible murine model of ileocystoplasty (ICP). We also performed preliminary analysis of any early histologic changes with focus on cellular proliferation at the UIJ. Fifteen 6- to 8-week-old female C57BL/6 mice underwent ICP, where a 1-cm ileal segment was used for bladder augmentation. Four sham mice underwent cystotomy and closure, and four mice did not undergo surgery. The mice were euthanized at 12 weeks postsurgery, and paraffin sections were stained for hematoxylin and eosin (H&E). Cellular proliferation was investigated using Ki-67. A novel model of ICP in mice was developed and demonstrated to be technically feasible in approximately 60 min under the operating microscope. Twelve-week postsurgical survival rates were 80% (12 of 15). The surviving mice had a similar weight gain as the sham mice. H&E sections showed thickened urothelium (six to 10 cell layers) at the UIJ, but sparse mitotic figures and no dysplastic changes. Ki-67 staining was rare in the urothelium, and showed no differences between the sham and ICP mice in the bladder or at the UIJ. We here demonstrate the first murine model of ICP. Preliminary studies did not show evidence of early hyperproliferation at the UIJ or in the bladder, but further long-term studies as well as studies with transgenic mice are warranted. PMID- 21789469 TI - Antibacterial efficacy of lytic bacteriophages against antibiotic-resistant Klebsiella species. AB - Bacterial resistance to antibiotics is a leading and highly prevalent problem in the treatment of infectious diseases. Bacteriophages (phages) appear to be effective and safe alternatives for the treatment of resistant infections because of their specificity for bacterial species and lack of infectivity in eukaryotic cells. The present study aimed to isolate bacteriophages against Klebsiella spp. and evaluate their efficacy against antibiotic-resistant species. Seventy-two antibiotic-resistant Klebsiella spp. were isolated from samples of patients who referred to the Ghaem Hospital (Mashhad, Iran). Lytic bacteriophages against Klebsiella spp. were isolated from wastewater of the septic tank of the same hospital. Bactericidal activity of phages against resistant Klebsiella spp. was tested in both liquid (tube method; after 1 and 24 h of incubation) and solid (double-layer agar plate method; after 24 h of incubation) phases. In each method, three different concentrations of bacteriophages (low: <10(4) PFU/mL, medium: 10(4)-10(7) PFU/mL, and high: >10(7) PFU/mL) were used. Bacteriophages showed promising bactericidal activity at all assessed concentrations, regardless of the test method and duration of incubation. Overall, bactericidal effects were augmented at higher concentrations. In the tube method, higher activity was observed after 24 h of incubation compared to the 1-h incubation. The bactericidal effects were also higher in the tube method compared to the double layer agar plate method after 24 h of incubation. The findings of the present study suggest that bacteriophages possess effective bactericidal activity against resistant Klebsiella spp. These bactericidal activities are influenced by phage concentration, duration of incubation, and test method. PMID- 21789470 TI - The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. AB - We investigated the potential protective effects of montelukast (MLK) on cecal ligation and puncture (CLP)-induced tissue injury in vital organs - liver, heart, kidneys, and especially lungs - through inhibition of the proinflammatory cytokine response and the generation of reactive oxygen species (ROS) in rats. The rat groups were (1) a 10-mg/kg MLK-treated CLP group; (2) a 20-mg/kg MLK treated CLP group; (3) a 20-mg/kg MLK-treated, sham-operated group; (4) a CLP control group; and (5) a sham-operated control group. MLK treatment significantly decreased proinflammatory (tumor necrosis factor-alpha, interleukin-6) cytokine levels following CLP. The lipid peroxide level increased in the lung, heart, liver, and kidney tissues after CLP-induced sepsis, and myeloperoxidase activity increased in the lung, heart, and liver tissues. MLK attenuated this elevation in all tissues except the kidney, dose dependently. The glutathione levels and superoxide dismutase activity were significantly increased in the lung, liver, and kidney tissues after MLK treatment. MLK treatment after CLP also potentially reduced mortality. The lung and kidney tissues were the most protected by MLK under sepsis conditions. We can suggest that MLK reverses the systemic inflammatory reaction to polymicrobial sepsis and thereby reduces multiple organ failure. PMID- 21789471 TI - Molecular mechanisms regulating hepcidin revealed by hepcidin disorders. AB - Iron is essential for human life, but toxic if present in excess. To avoid iron overload and maintain iron homeostasis, all cells are able to regulate their iron content through the post-transcriptional control of iron genes operated by the cytosolic iron regulatory proteins that interact with iron responsive elements on iron gene mRNA. At the systemic level, iron homeostasis is regulated by the liver peptide hepcidin. Disruption of these regulatory loops leads to genetic diseases characterized by iron deficiency (iron-refractory iron-deficiency anemia) or iron overload (hemochromatosis). Alterations of the same systems are also found in acquired disorders, such as iron-loading anemias characterized by ineffective erythropoiesis and anemia of chronic diseases (ACD) associated with common inflammatory conditions. In ACD, iron is present in the body, but maldistributed, being deficient for erythropoiesis, but sequestered in macrophages. Studies of the hepcidin regulation by iron and inflammatory cytokines are revealing new pathways that might become targets of new therapeutic intervention in iron disorders. PMID- 21789472 TI - Anti-inflammatory properties of dendrimers per se. AB - Dendrimers are polybranched and polyfunctionalized tree-like polymers. Unlike linear polymers, they have perfectly defined structure and molecular weight, due to their iterative step-by-step synthesis. Their multivalent structure and supramolecular properties have made them attractive nanotools for applications, particularly in biology and medicine. Among the different biological and medical properties of dendrimers that have been developed over the past decades, the anti inflammatory properties of several groups of dendrimers are the most recently discovered. Thereof, dendrimers emerge as promising, although heretical, drug candidates for the treatment of still-uncured chronic inflammatory disorders. This mini-review is based on the five main scientific articles giving an overview of what can be the spectrum of anti-inflammatory characteristics displayed by dendrimers. PMID- 21789473 TI - Linear methods for analysis and quality control of relative expression ratios from quantitative real-time polymerase chain reaction experiments. AB - Relative expression quantitative real-time polymerase chain reaction (RT-qPCR) experiments are a common means of estimating transcript abundances across biological groups and experimental treatments. One of the most frequently used expression measures that results from such experiments is the relative expression ratio (RE), which describes expression in experimental samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to one or more experimental or nonbaseline condition) in terms of fold change relative to calibrator samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to a control or baseline condition). Over the past decade, several models of RE have been proposed, and it is now clear that endogenous reference gene stability and amplification efficiency must be assessed in order to ensure that estimates of RE are valid. In this review, we summarize key issues associated with estimating RE from cycle threshold data. In addition, we describe several methods based on linear modeling that enable researchers to estimate model parameters and conduct quality control procedures that assess whether model assumptions have been violated. PMID- 21789474 TI - Reverse genetic strategies in Caenorhabditis elegans: towards controlled manipulation of the genome. AB - Caenorhabditis elegans has a complete annotated genome sequence that is augmented by increasing quantities of data from high-throughput postgenomic analyses. This has led to an increasing need to identify the biological functions of specific genes using reverse genetics, i.e., moving from gene to phenotype. Fundamental to this aim is the ability to alter the structure of particular genes by means that are not accessible to classical genetic strategies. Thus, one dream of C. elegans researchers is to establish a toolkit for the controlled manipulation of any loci within the genome. Although C. elegans is amenable to a wide variety of genetic and molecular manipulations, controlled manipulation of endogenous genes by, for example, gene targeting has proved elusive until relatively recently. In this review, we describe and discuss the different methods available for the inactivation and modification of endogenous loci with a focus on strategies that permit some measure of control in this process. We describe methods that use random mutagenesis to isolate mutations in specific genes. We then focus on techniques that allow controlled manipulation of the genome: gene modification by transposon mobilisation, gene knock-out mediated by zinc-finger nucleases, and gene targeting by biolistic transformation. PMID- 21789475 TI - Challenges of analysing gene-environment interactions in mouse models of schizophrenia. AB - The modelling of neuropsychiatric disease using the mouse has provided a wealth of information regarding the relationship between specific genetic lesions and behavioural endophenotypes. However, it is becoming increasingly apparent that synergy between genetic and nongenetic factors is a key feature of these disorders that must also be taken into account. With the inherent limitations of retrospective human studies, experiments in mice have begun to tackle this complex association, combining well-established behavioural paradigms and quantitative neuropathology with a range of environmental insults. The conclusions from this work have been varied, due in part to a lack of standardised methodology, although most have illustrated that phenotypes related to disorders such as schizophrenia are consistently modified. Far fewer studies, however, have attempted to generate a "two-hit" model, whereby the consequences of a pathogenic mutation are analysed in combination with environmental manipulation such as prenatal stress. This significant, yet relatively new, approach is beginning to produce valuable new models of neuropsychiatric disease. Focussing on prenatal and perinatal stress models of schizophrenia, this review discusses the current progress in this field, and highlights important issues regarding the interpretation and comparative analysis of such complex behavioural data. PMID- 21789476 TI - Relationship of pulmonary artery wedge pressure to left atrial pressure and pulmonary vascular resistance in preoperative Fontan patients. AB - Pulmonary artery wedge pressure (PAWp) as a surrogate for left atrial pressure (LAp) has been validated in patients with fully pulsatile two-ventricle circulations. This study was to validate PAWp as an accurate estimate of LAp for calculating pulmonary vascular resistance in single-ventricle patients after the bidirectional Glenn operation. A prospective study measuring direct branch pulmonary artery pressures, ipsilateral PAWp, and direct LAp to calculate pulmonary and systemic blood flows was conducted. Pulmonary vascular resistance (PVR) was calculated for each patient using the PAWp and compared to the PVR calculated by direct LAp measurements. Twenty-eight patients were enrolled; 27 were eligible for study inclusion. Ages ranged from 21 to 60 months and weights ranged from 9.5 to 20.8 kg. Underlying congenital heart defect diagnoses varied, with all patients either functionally or anatomically univentricular. Left mPAWp measured 4.4 +/- 2.6, statistically different from simultaneous direct mLAp of 2.5 +/- 2.4 mmHg (P < 0.001. Right mPAWp measured 4.3 +/- 3.2 mmHg, statistically different from simultaneous direct mLAp of 2.8 +/- 2.6 mmHg (P < 0.001. The PVR calculated using mPAWp was 1.2 +/- 0.7 W.U., statistically different to 1.8 +/- 0.95 W.U. using mLAp (P < 0.001). The average PVR measurement calculated using mPAWp underestimated the PVR calculated using mLAp by 0.6 W.U. It can be extrapolated that a PVR of 2.3 W.U. calculated using wedge measurements would estimate a PVR of 3 W.U. calculated using direct LA measurements. In this study, the PVR calculated using PAWp as a surrogate for LAp either equaled or underestimated the true PVR, up to 33% different. This difference is important in patients with univentricular physiology who rely on low PVR for cardiac output. Thus, based on this study, a PVR measurement of greater than 2.3 W.U. by the mPAWp method should prompt a direct LA pressure measurement, in order to more appropriately determine true surgical risk. PMID- 21789477 TI - Successful treatment with bosentan for pulmonary hypertension and reduced peripheral circulation in juvenile systemic sclerosis. AB - Pulmonary arterial hypertension (PAH) when associated with systemic sclerosis (SSc) (SSc-PAH) is one of the leading causes of mortality and is found in 10-15% of adult patients with SSc. The ET receptor antagonist bosentan has been shown to be effective in the treatment of adult patients with SSc-PAH. Furthermore, it has been shown that bosentan ameliorates decreased skin perfusion and digital ulceration secondary to SSc. However, the effectiveness and safety of bosentan for treatment of juvenile SSc still remains unclear. We describe a case of juvenile SSc-PAH successfully treated with bosentan. The present case shows that bosentan ameliorated PAH and peripheral circulation as evaluated by cold stress thermography. No bosentan-related adverse events such as liver dysfunction were observed. Prospective randomized trials are required to validate the effectiveness of bosentan for patients with juvenile SSc; however, bosentan might be useful for the management of patients with juvenile SSc. PMID- 21789478 TI - Formation of ventricular aneurysm after endocarditis in a child with methicillin resistant Staphylococcus aureus (MRSA) bacteremia. PMID- 21789479 TI - Effects of fatigue on trunk stability in elite gymnasts. AB - The aim of the present study was to test the hypothesis that fatigue due to exercises performed in training leads to a decrement of trunk stability in elite, female gymnasts. Nine female gymnasts participated in the study. To fatigue trunk muscles, four series of five dump handstands on the uneven bar were performed. Before and after the fatigue protocol, participants performed three trials of a balancing task while sitting on a seat fixed over a hemisphere to create an unstable surface. A force plate tracked the location of the center of pressure (CoP). In addition, nine trials were performed in which the seat was backward inclined over a set angle and suddenly released after which the subject had to regain balance. Sway amplitude and frequency in unperturbed sitting were determined from the CoP time series and averaged over trials. The maximum displacement and rate of recovery of the CoP location after the sudden release were determined and averaged over trials. After the fatigue protocol, sway amplitude in the fore-aft direction was significantly increased (p = 0.03), while sway frequency was decreased (p = 0.005). In addition, the maximum displacement after the sudden release was increased (p = 0.009), while the rate of recovery after the perturbation was decreased (p = 0.05). Fatigue induced by series of exercises representing a realistic training load caused a measurable decrement in dynamic stability of the trunk in elite gymnasts. PMID- 21789481 TI - Gastric acid induces mitochondrial superoxide production and lipid peroxidation in gastric epithelial cells. AB - BACKGROUND: Gastric hydrochloric acid (HCl) has been regarded as an inciting factor in gastric mucosal injuries and has been reported to induce lipid peroxidation in vitro. However, because HCl is not an oxidant per se, the exact mechanism by which the acid induces lipid peroxidation is unknown. We hypothesized that gastric acid may disrupt mitochondrial transmembrane potential and induce the production of superoxide in mitochondria, which subsequently may induce lipid peroxidation and apoptosis in gastric mucosal cells. METHODS: Firstly we treated gastric epithelial RGM1 cells with solutions containing various concentrations of HCl (i.e., of varying pH), and examined cellular injury, lipid peroxidation, and apoptosis with specific fluorescent dyes. Secondly, we performed electron paramagnetic resonance (EPR) spectroscopy of isolated, acid-exposed mitochondria from the cells, using a spin-trapping reagent for superoxide, 5-(2,2-dimethyl-1,3-propoxy cyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO). Finally, we established novel RGM1 cells that overexpressed manganese superoxide dismutase (MnSOD), which removes superoxide from mitochondria, and examined the effect of acid treatment on cellular membrane lipid peroxidation. RESULTS: The results indicated that the exposure to acid indeed induced cellular injury, cellular lipid peroxidation, apoptosis, and the demonstration of the exact superoxide spectra on EPR spectroscopy in gastric epithelial cells, and that overexpression of MnSOD decreased superoxide production and prevented cellular lipid peroxidation. CONCLUSION: These results suggested that gastric acid, like nonsteroidal anti-inflammatory drugs (NSAIDs), induces mitochondrial superoxide production, which induces gastric cellular injury by triggering cellular lipid peroxidation and apoptosis. PMID- 21789482 TI - The building of models as pathway to understand the therapeutic process. AB - The present work highlights the necessity to re-think the paradigmatic, methodological and theoretical assumptions which for a long time have regulated the practices of research in the field of the study of therapeutic processes. Following this suggestion, and commenting on Ribeiro and Goncalves (2011), and Faccio, Centomo and Mininni (2011), I highlight the need to reframe the therapeutic change research in terms of a modelling approach. According to such perspective models arise through focusing on the general rule of the functioning of a change process within the local domain of a particular therapeutic encounter, making it possible both to manage it in line with the specific local aims, and to promote the deepening and the develop of scientific knowledge. This is a step towards a new research perspective able to promote the integration of empirical research and clinical practice. PMID- 21789480 TI - Early activation of interferon-stimulated genes in human liver allografts: relationship with acute rejection and histological outcome. AB - BACKGROUND: Innate immunity mechanisms have been shown to play a paramount role in organ transplantation. Our aim was to investigate the hypothesis that activation of the interferon system may affect clinically relevant outcomes, such as acute rejection and/or early fibrosis progression, after liver transplantation. METHODS: We studied 71 consecutive recipients (57 males; 25 with hepatitis C) who underwent two per protocol graft biopsies: the first, within 60 days after the transplant operation (median 24) and the second, after 1 year. The mRNA expression for five interferon-stimulated genes (Mx1, OAS2, PKR, IRF7A, IFI16) was measured on the first biopsy specimens. The main outcome measures were acute rejection during the first post-transplant year and fibrosis progression at the second biopsy. RESULTS: On multivariate analysis, the independent predictors of gene expression were hepatitis C (Mx1, OAS2, PKR and IFI16), donor age (IFI16) and recipient gender (IRF7A) (P < .05 for all). During the first post-transplant year, 19/71 patients (27%) had acute cellular rejection. At multivariate analysis, acute cellular rejection was independently predicted by high IRF7A mRNA expression. At the end of follow-up, 25 patients had some degree of fibrosis (F2 or higher in seven cases). On multivariate analysis, hepatitis C etiology, recipient age, and OAS2 overexpression were independent predictors of early fibrosis progression. CONCLUSIONS: In the early postoperative period of liver transplantation, interferon-stimulated gene activation is dependent on hepatitis C recurrence (the main factor responsible for early fibrosis progression) and donor age, and is related to the risk of acute cellular rejection. PMID- 21789483 TI - Molecular cloning and expression of gene encoding aromatic amino acid decarboxylase in 'Vidal blanc' grape berries. AB - The pleasantly fruity and floral 2-phenylethanol are a dominant aroma compound in post-ripening 'Vidal blanc' grapes. However, to date little has been reported about its synthetic pathway in grapevine. In the present study, a full-length cDNA of VvAADC (encoding aromatic amino acid decarboxylase) was firstly cloned from the berries of 'Vidal blanc', an interspecific hybrid variety of Vitis vinifera * Vitis riparia. This sequence encodes a complete open reading frame of 482 amino acids with a calculated molecular mass of 54 kDa and isoelectric point value (pI) of 5.73. The amino acid sequence deduced shared about 79% identity with that of aromatic L: -amino acid decarboxylases (AADCs) from tomato. Real time PCR analysis indicated that VvAADC transcript abundance presented a small peak at 110 days after full bloom and then a continuous increase at the berry post-ripening stage, which was consistent with the accumulation of 2 phenylethanol, but did not correspond to the trends of two potential intermediates, phenethylamine and 2-phenylacetaldehyde. Furthermore, phenylalanine still exhibited a continuous increase even in post-ripening period. It is thus suggested that 2-phenylethanol biosynthetic pathway mediated by AADC exists in grape berries, but it has possibly little contribution to a considerable accumulation of 2-phenylethanol in post-ripening 'Vidal blanc' grapes. PMID- 21789484 TI - Cytochrome b gene sequence divergence of seven sisorid species of catfish genus Glyptothorax (siluriformes, sisoridae) from India. AB - Samples of seven Sisorid catfish species of the genus Glyptothorax (G. garhwali, G. dakpathari, G. brevipinnis, G. ngapang, G. granulus, G. ventrolineatus, and G. davissinghi) were collected from the Himalayan region and the Western Ghats of India. They were analyzed for the mitochondrial cytochrome b gene (Cyt b). Out of 1152 nucleotide positions analyzed, 269 (23.3%) were found to be variable and 235 (20.3%) were parsimoniously informative. The sequences showed 111 (9.6%) fourfold degenerate sites. The overall transition/transversion bias was R = 3.457. The average proportion of base substitutions measured as P-distance for all sequences of seven Glyptothorax species and other five species comprising four comparison groups was intraspecies, P = 0.17 +/- 0.05%, intragenus, P = 10.75 +/- 0.48%, intrafamily, P = 20.07 +/- 1.43%, and intraorder, P = 21.10 +/- 0.45%. Within the Glyptothorax genus maximum divergence was obtained among G. brevipinnis sequences, whereas the least divergence was obtained within G. davissinghi. The phylogenetic trees for 193 and 47 sequences of Sisorid catfishes together were developed using the Cyt b gene and four different analytical approaches: Bayesian (BA), neighbour-joining (NJ), maximum parsimony (MP), and maximum likelihood (ML). The analysis revealed a monophyletic origin for the all investigated representatives of the genus Glyptothorax (99, 100, 99, and 73% support level in our BA, NJ, MP, and ML analyses respectively) and with some reservations for Sisoridae, which is the principal family investigated. The monophyletic origin of the two subfamilies of Sisorid catfish defined in the literature was partly also supported by molecular phylogenetic data. PMID- 21789485 TI - Conformational changes during amyloid fibril formation of pancreatic thiol proteinase inhibitor: effect of copper and zinc. AB - Pancreatic thiol proteinase inhibitor (PTPI), a variant of cystatin superfamily of cysteine protease inhibitors, has been isolated from pancreas of Capra hircus. In the present study, we examined the effects of acid denaturation and a co solvent on PTPI with a focus on protein conformational changes and amyloid fibril formation. The results demonstrate that PTPI can form amyloid like fibrils. Acid denaturation as studied by CD and fluorescence spectroscopy showed that PTPI populates three partly unfolded species, a native like state at pH 3.0, a structured molten globule at pH 1.0 and partly unfolded species at pH 2.0, from each of which amyloid like fibrils grow as assessed by Thioflavin T (ThT) spectroscopy. Effect of trifluoroethanol (TFE) on acid induced states of PTPI was analyzed. TFE stabilized each of the three acid-induced intermediates at predenaturational concentrations (10%) and accelerated fibril formation. Morphology of the protein species at the beginning and end of reactions was observed using transmission electron microscopy. Solvent conditions were decisive for final fibril morphology. Biometals, Cu(2+) and Zn(2+) produced a concentration dependent decline in ThT fluorescence suggesting deaggregation of the fibrils. When added prior to amyloid fibril initiation 50 MUM Cu(2+) or 10 MUM Zn(2+) prevented any amyloid aggregation. Implications for therapeutics in view of Cu(2+) and Zn(2+) as essential micronutrients are suggested. PMID- 21789486 TI - The analytical determination of isoprenoid intermediates from the mevalonate pathway. AB - In this article, assays on the analytical determination of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two important isoprenoid intermediates at biochemically relevant branching points in the mevalonate pathway, are summarized and reviewed. There is considerable recent interest in the measurement of these two isoprenoids because of their direct involvement in several diseases, for example, statins lower cholesterol by inhibiting 3-hydroxy 3-methylglutaryl-CoA reductase but equally affect other metabolite biosyntheses. The isoprenoids FPP and GGPP are key intermediates due to their role as CaaX specific substrates for posttranslational modification of proteins (protein prenylation). Disease pathologies and therapeutic efficacy of different treatments (e.g., cholesterol-lowering drugs) may lead to a reduction in isoprenoid levels and an accompanying reduction in prenylation of specific proteins. To understand the exact biochemical role of the isoprenoids FPP and GGPP, we need to know their levels. Several recent studies have shown exact levels of FPP and GGP in plasma and relevant tissues and their modulation following treatment. Furthermore, by directly measuring the extent of protein prenylation and identifying target proteins, further insight into the exact biochemical nature of the pathology and regulatory mechanisms will be possible. This short review aims to highlight the relevant literature on the analytical determination of the free isoprenoids FPP and GGPP in biological tissue as well as techniques for directly measuring prenylated proteins. PMID- 21789487 TI - Kinetic analysis of PI3K reactions with fluorescent PIP2 derivatives. AB - Phosphatidylinositol 3-kinase (PI3K) signaling plays important roles in cell differentiation, proliferation, and migration. Increased mutations and expression levels of PI3K are hallmarks for the development of certain cancers. Pharmacological targeting of PI3K activity has also been actively pursued as a novel cancer therapeutic. Consequently, measurement of PI3K activity in different cell types or patient samples holds the promise as being a novel diagnostic tool. However, the direct measurement of cellular PI3K activity has been a challenging task. We report here the characterization of two fluorescent PIP(2) derivatives as reporters for PI3K enzymatic activity. The reporters are efficiently separated from their corresponding PI3K enzymatic products through either thin layer chromatography (TLC) or capillary electrophoresis (CE), and can be detected with high sensitivity by fluorescence. The biophysical and kinetic properties of the two probes are measured, and their suitability to characterize PI3K inhibitors is explored. Both probes show similar capacity as PI3K substrates for inhibitor characterization, yet also possess distinct properties that may suggest their different applications. These characterizations have laid the groundwork to systematically measure cellular PI3K activity, and have the potential to generate molecular fingerprints for diagnostic and therapeutic applications. PMID- 21789488 TI - Data quality in tissue analysis using desorption electrospray ionization. AB - There has been a recent surge in applications of mass spectrometry (MS) to tissue analysis, particularly lipid-based tissue imaging using ambient ionization techniques. This recent growth highlights the need to examine the effects of sample handling, storage conditions, and experimental protocols on the quality of the data obtained. Variables such as time before freezing after organ removal, storage time at -80 degrees C, time stored at room temperature, heating, and freeze/thaw cycles were investigated for their effect on the data quality obtained in desorption electrospray ionization (DESI)-MS using mouse brain. In addition, analytical variables such as tissue thickness, drying times, and instrumental conditions were also examined for their impact on DESI-MS data. While no immediate changes were noted in the DESI-MS lipid profiles of the mouse brain tissue after spending 1 h at room temperature when compared to being frozen immediately following removal, minor changes were noted between the tissue samples after 7 months of storage at -80 degrees C. In tissue sections stored at room temperature, degradation was noted in 24 h by the appearance of fatty acid dimers, which are indicative of high fatty acid concentrations, while in contrast, those sections stored at -80 degrees C for 7 months showed no significant degradation. Tissue sections were also subjected to up to six freeze/thaw cycles and showed increasing degradation following each cycle. In addition, tissue pieces were subjected to 50 degrees C temperatures and analyzed at specific time points. In as little as 2 h, degradation was observed in the form of increased fatty acid dimer formation, indicating that enzymatic processes forming free fatty acids were still active in the tissue. We have associated these dimers with high concentrations of free fatty acids present in the tissue during DESI-MS experiments. Analytical variables such as tissue thickness and time left to dry under nitrogen were also investigated, with no change in the resulting profiles at thickness from 10 to 25 MUm and with optimal signal obtained after just 20 min in the dessicator. Experimental conditions such as source parameters, spray solvents, and sample surfaces are all shown to impact the quality of the data. Inter-section (relative standard deviation (%RSD), 0.44 7.2%) and intra-sample (%RSD, 4.0-8.0%) reproducibility data show the high quality information DESI-MS provides. Overall, the many variables investigated here showed DESI-MS to be a robust technique, with sample storage conditions having the most effect on the data obtained, and with unacceptable sample degradation occurring during room temperature storage. PMID- 21789489 TI - Clostridium beijerinckii mutant with high inhibitor tolerance obtained by low energy ion implantation. AB - Clostridium beijerinckii mutant strain IB4, which has a high level of inhibitor tolerance, was screened by low-energy ion implantation and used for butanol fermentation from a non-detoxified hemicellulosic hydrolysate of corn fiber treated with dilute sulfuric acid (SAHHC). Evaluation of toxicity showed C. beijerinckii IB4 had a higher level of tolerance than parent strain C. beijerinckii NCIMB 8052 for five out of six phenolic compounds tested (the exception was vanillin). Using glucose as carbon source, C. beijerinckii IB4 produced 9.1 g l(-1) of butanol with an acetone/butanol/ethanol (ABE) yield of 0.41 g g(-1). When non-detoxified SAHHC was used as carbon source, C. beijerinckii NCIMB 8052 grew well but ABE production was inhibited. By contrast, C. beijerinckii IB4 produced 9.5 g l(-1) of ABE with a yield of 0.34 g g(-1), including 2.2 g l(-1) acetone, 6.8 g l(-1) butanol, and 0.5 g l(-1) ethanol. The remarkable fermentation and inhibitor tolerance of C. beijerinckii IB4 appears promising for ABE production from lignocellulosic materials. PMID- 21789490 TI - Hybrid thermochemical processing: fermentation of pyrolysis-derived bio-oil. AB - Thermochemical processing of biomass by fast pyrolysis provides a nonenzymatic route for depolymerization of biomass into sugars that can be used for the biological production of fuels and chemicals. Fermentative utilization of this bio-oil faces two formidable challenges. First is the fact that most bio-oil associated sugars are present in the anhydrous form. Metabolic engineering has enabled utilization of the main anhydrosugar, levoglucosan, in workhorse biocatalysts. The second challenge is the fact that bio-oil is rich in microbial inhibitors. Collection of bio-oil in distinct fractions, detoxification of bio oil prior to fermentation, and increased robustness of the biocatalyst have all proven effective methods for addressing this inhibition. PMID- 21789491 TI - A genomic island provides Acidithiobacillus ferrooxidans ATCC 53993 additional copper resistance: a possible competitive advantage. AB - There is great interest in understanding how extremophilic biomining bacteria adapt to exceptionally high copper concentrations in their environment. Acidithiobacillus ferrooxidans ATCC 53993 genome possesses the same copper resistance determinants as strain ATCC 23270. However, the former strain contains in its genome a 160-kb genomic island (GI), which is absent in ATCC 23270. This GI contains, amongst other genes, several genes coding for an additional putative copper ATPase and a Cus system. A. ferrooxidans ATCC 53993 showed a much higher resistance to CuSO(4) (>100 mM) than that of strain ATCC 23270 (<25 mM). When a similar number of bacteria from each strain were mixed and allowed to grow in the absence of copper, their respective final numbers remained approximately equal. However, in the presence of copper, there was a clear overgrowth of strain ATCC 53993 compared to ATCC 23270. This behavior is most likely explained by the presence of the additional copper-resistance genes in the GI of strain ATCC 53993. As determined by qRT-PCR, it was demonstrated that these genes are upregulated when A. ferrooxidans ATCC 53993 is grown in the presence of copper and were shown to be functional when expressed in copper-sensitive Escherichia coli mutants. Thus, the reason for resistance to copper of two strains of the same acidophilic microorganism could be determined by slight differences in their genomes, which may not only lead to changes in their capacities to adapt to their environment, but may also help to select the more fit microorganisms for industrial biomining operations. PMID- 21789492 TI - Distribution of glyphosate and methylphosphonate catabolism systems in soil bacteria Ochrobactrum anthropi and Achromobacter sp. AB - Bacterial strains capable of utilizing methylphosphonic acid (MP) or glyphosate (GP) as the sole sources of phosphorus were isolated from soils contaminated with these organophosphonates. The strains isolated from MP-contaminated soils grew on MP and failed to grow on GP. One group of the isolates from GP-contaminated soils grew only on MP, while the other one grew on MP and GP. Strains Achromobacter sp. MPS 12 (VKM B-2694), MP degraders group, and Ochrobactrum anthropi GPK 3 (VKM B 2554D), GP degraders group, demonstrated the best degradative capabilities towards MP and GP, respectively, and were studied for the distribution of their organophosphonate catabolism systems. In Achromobacter sp. MPS 12, degradation of MP was catalyzed by C-P lyase incapable of degrading GP (C-P lyase I). Adaptation to growth on GP yielded the strain Achromobacter sp. MPS 12A, which retained its ability to degrade MP via C-P lyase I and was capable of degrading GP with formation of sarcosine, thus suggesting the involvement of a GP-specific C-P lyase II. O. anthropi GPK 3 also degraded MP via C-P lyase I, but degradation of GP in it was initiated by glyphosate oxidoreductase, which was followed by product transformation via the phosphonatase pathway. PMID- 21789493 TI - Synthesis of green note aroma compounds by biotransformation of fatty acids using yeast cells coexpressing lipoxygenase and hydroperoxide lyase. AB - Green notes are substances that characterize the aroma of freshly cut grass, cucumbers, green apples, and foliage. In plants, they are synthesized by conversion of linolenic or linoleic acid via the enzymes lipoxygenase (LOX) and hydroperoxide lyase (HPL) to short-chained aldehydes. Current processes for production of natural green notes rely on plant homogenates as enzyme sources but are limited by low enzyme concentration and low specificity. In an alternative approach, soybean LOX2 and watermelon HPL were overexpressed in Saccharomyces cerevisiae. After optimization of the expression constructs, a yeast strain coexpressing LOX and HPL was applied in whole cell biotransformation experiments. Whereas addition of linolenic acid to growing cultures of this strain yielded no products, we were able to identify high green note concentrations when resting cells were used. The primary biotransformation product was 3(Z)-hexenal, a small amount of which isomerized to 2(E)-hexenal. Furthermore, both aldehydes were reduced to the corresponding green note alcohols by endogenous yeast alcohol dehydrogenase to some extent. As the cosolvent ethanol was the source of reducing equivalents for green note alcohol formation, the hexenal/hexenol ratio could be influenced by the use of alternative cosolvents. Further investigations to identify the underlying mechanism of the rather low biocatalyst stability revealed a high toxicity of linolenic acid to yeast cells. The whole cell catalyst containing LOX and HPL enzyme activity described here can be a promising approach towards a highly efficient microbial green note synthesis process. PMID- 21789494 TI - Characteristic microbial community of a dry thermophilic methanogenic digester: its long-term stability and change with feeding. AB - Thermophilic dry anaerobic digestion of sludge for cellulose methanization was acclimated at 53 degrees C for nearly 5 years using a waste paper-based medium. The stability of the microbial community structure and the microbial community responsible for the cellulose methanization were studied by 16S rRNA gene-based clone library analysis. The microbial community structure remained stable during the long-term acclimation period. Hydrogenotrophic methanogens dominated in methanogens and Methanothermobacter, Methanobacterium, Methanoculleus, and Methanosarcina were responsible for the methane production. Bacteria showed relatively high diversity and distributed mainly in the phyla Firmicutes, Bacteroidetes, and Synergistetes. Ninety percent of operational taxonomic units (OTUs) were affiliated with the phylum Firmicutes, indicating the crucial roles of this phylum in the digestion. Relatives of Clostridium stercorarium, Clostridium thermocellum, and Halocella cellulosilytica were dominant cellulose degraders. The acclimated stable sludge was used to treat garbage stillage discharged from a fuel ethanol production process, and the shift of microbial communities with the change of feed was analyzed. Both archaeal and bacterial communities had obviously changed: Methanoculleus spp. and Methanothermobacter spp. and the protein- and fatty acid-degrading bacteria became dominant. Accumulation of ammonia as well as volatile fatty acids led to the inhibition of microbial activity and finally resulted in the deterioration of methane fermentation of the garbage stillage. PMID- 21789495 TI - Update on the management of ulcerative colitis. AB - The treatment options for inflammatory bowel disease have expanded with the introduction of biological therapies. Recently published controlled clinical trials were searched and those that impact the clinical management of ulcerative colitis (UC) are discussed in this review. In the management of mild to moderate UC, mesalamine still remains the first choice of drug. The newly developed once daily formulations have shown equal efficacy to divided doses and possibly portend better compliance owing to a simplified regimen. In outpatients with moderate to severe UC, recent data indicate that infliximab induced and maintained remission leads to decreased colectomy rates and fewer hospitalizations. An alternative anti-tumor necrosis factor (TNF) agent, adalimumab, was also recently shown to be effective for induction of remission in moderate to severe UC. The use of immunosuppressives, such as azathioprine and mercaptopurine, is associated with decreased colectomy rates and thioguanine was shown to be effective in maintaining clinical remission in those who are intolerant to azathioprine/mercaptopurine. In hospitalized patients with steroid resistant severe UC, infliximab and tacrolimus may be alternatives to cyclosporine in those who are otherwise candidates for colectomy. Adequate long term maintenance therapy with immunosuppressives or anti-TNF therapy is required after rescue therapy for a sustained benefit. Future research is needed to position the available anti-TNF agents and combined immunosuppressive therapy in the treatment of UC to achieve and maintain steroid free remission. PMID- 21789496 TI - The mantra of mucosal healing. PMID- 21789497 TI - Unipolar versus bipolar Exeter hip hemiarthroplasty: a prospective cohort study on 830 consecutive hips in patients with femoral neck fractures. AB - BACKGROUND: Hip replacement using a hemiarthroplasty (HA) is a common surgical procedure in elderly patients with fractures of the femoral neck. Data from the Swedish Hip Arthroplasty Register suggest that there is a higher risk for revision surgery with the bipolar HA compared with the unipolar HA. PURPOSE: In this study we analysed the reoperation and the dislocation rates for Exeter HAs in patients with a displaced femoral neck fracture, comparing the unipolar and bipolar prosthetic designs. Additionally, we compared the outcome for HAs performed as a primary intervention with those performed secondary to failed internal fixation. METHODS: We studied 830 consecutive Exeter HAs (427 unipolar and 403 bipolar) performed either as a primary operation for a displaced fracture of the femoral neck or as a secondary procedure after failed internal fixation of a fracture of the femoral neck. Cox regression analyses were performed to evaluate factors associated with reoperation and prosthetic dislocation. Age, gender, the surgeon's experience, indication for surgery (primary or secondary) and type of HA (unipolar or bipolar) were tested as independent variables in the model. RESULTS: The prosthetic design (uni- or bipolar) had no influence on the risk for reoperation or dislocation, nor had the age, gender or the surgeon's experience. The secondary HAs were associated with a significantly increased risk for reoperation (HR 2.6, CI 1.5-4.5) or dislocation (HR 3.3, CI 1.4-7.3) compared to the primary HAs. We found no difference in the risk for reoperation or dislocation when comparing Exeter unipolar and bipolar HAs, but special attention is called for to reduce the risk of prosthesis dislocation and reoperation after a secondary HA. PMID- 21789498 TI - Position of the prosthesis components in total ankle replacement and the effect on motion at the replaced joint. AB - PURPOSE: In some cases of total ankle replacement, perfect alignment of the prosthetic components is not achieved. This study analyses the extent to which component positioning is critical for the final range of motion. METHODS: Fourteen patients undergoing total ankle replacement were assessed preoperatively and postoperatively at seven and 13 months follow-up. X-ray pictures of the ankle were taken in static double leg stance, i.e. at neutral joint position, and in maximum plantarflexion and dorsiflexion. Measurements were obtained by a specially devised computer program based on anatomical reference points digitised on the radiograms. These allowed calculation of the position and orientation of the components in the sagittal and coronal planes, together with the joint range of motion. RESULTS: The mean range of motion was about 34 degrees at the first follow-up and maintained at the second. Tibial and talar components were more anterior than the mid-tibial shaft in 11 and nine patients, respectively. Mean inclination was about four degrees posterior for the tibial component and nearly one degree anterior for the talar component. A significantly larger range of motion was found in ankles both with the talar component located and inclined more anteriorly than the tibial. CONCLUSIONS: Correlation, though weak, was found between motion at the replaced ankle and possible residual subluxation and inclination of the components. However, a satisfactory range of motion was also achieved in those patients where recommended locations for the components could not be reached because of the size of the original joint deformity. PMID- 21789499 TI - Advances in the diagnosis and management of pediatric osteomyelitis. AB - Acute hematogenous osteomyelitis is a common disease that affects previously healthy children of all age groups. Despite its importance, there are limited data in the current literature to guide many aspects of the diagnosis and therapy of this infection. Over the last decade, our understanding of the etiology of this infection has changed, with increased recognition of Kingella kingae and the dramatic increase in community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. There is a need for the optimization of diagnostic strategies, such as MRI and serum inflammatory markers. Several recent studies have examined treatment strategies, including a rapid transition to oral antimicrobial therapy and a shortened overall course of therapy. Many new therapeutic options are on the horizon that will likely impact the management of this and other childhood bacterial infections. This review summarizes recent investigations into the optimal diagnosis and management of acute hematogenous osteomyelitis in children. PMID- 21789500 TI - NeuroNames: an ontology for the BrainInfo portal to neuroscience on the web. AB - BrainInfo ( http://braininfo.org ) is a growing portal to neuroscientific information on the Web. It is indexed by NeuroNames, an ontology designed to compensate for ambiguities in neuroanatomical nomenclature. The 20-year old ontology continues to evolve toward the ideal of recognizing all names of neuroanatomical entities and accommodating all structural concepts about which neuroscientists communicate, including multiple concepts of entities for which neuroanatomists have yet to determine the best or 'true' conceptualization. To make the definitions of structural concepts unambiguous and terminologically consistent we created a 'default vocabulary' of unique structure names selected from existing terminology. We selected standard names by criteria designed to maximize practicality for use in verbal communication as well as computerized knowledge management. The ontology of NeuroNames accommodates synonyms and homonyms of the standard terms in many languages. It defines complex structures as models composed of primary structures, which are defined in unambiguous operational terms. NeuroNames currently relates more than 16,000 names in eight languages to some 2,500 neuroanatomical concepts. The ontology is maintained in a relational database with three core tables: Names, Concepts and Models. BrainInfo uses NeuroNames to index information by structure, to interpret users' queries and to clarify terminology on remote web pages. NeuroNames is a resource vocabulary of the NLM's Unified Medical Language System (UMLS, 2011) and the basis for the brain regions component of NIFSTD (NeuroLex, 2011). The current version has been downloaded to hundreds of laboratories for indexing data and linking to BrainInfo, which attracts some 400 visitors/day, downloading 2,000 pages/day. PMID- 21789501 TI - New technologies for catheter ablation of atrial fibrillation. AB - OPINION STATEMENT: The past decade of ablation for atrial fibrillation (AF) has seen the adaptation of catheters designed for "focal" tachycardias or single pathways to perform wide encirclement of the pulmonary veins (PV). During the next decade, technologies designed specifically for PV isolation will emerge. Each system has its unique attributes. The cryoballoon system offers rapid PV isolation and the promise of enhanced safety, whereas the success rate is likely to be similar to catheter-based approaches. Although preclinical studies do suggest a very low likelihood of left atria-esophageal fistula using this technology, concerns of phrenic nerve damage and a small incidence of PV stenosis need to be addressed. It is likely that use of the larger 28-mm balloon will mitigate these concerns. The cryoballoon is also the first balloon technology to be approved by the US Food and Drug Administration for clinical use, and this may gain the technology an early foothold in the AF ablation market. The laser balloon ablation system is a more time-consuming and technically demanding procedure, and the risk of thrombus formation if ablation is performed in stagnant blood is a concern. However, early studies suggest a high rate of persistent PV isolation, which hopefully will translate into high single procedure efficacy. The Ablation Frontiers system is the only system currently being developed for more persistent forms of AF. This system offers a rapid approach to PV isolation and left atrial defragmentation. The early results do not demonstrate a success rate better than that described for catheter ablation; however, the results are difficult to compare to standard catheter ablation in this recalcitrant patient group without a prospective randomized study. PMID- 21789502 TI - A new psychological intervention: "512 Psychological Intervention Model" used for military rescuers in Wenchuan Earthquake in China. AB - OBJECTIVE: We sought to compare the efficacy of the "512 Psychological Intervention Model" (that is, "512 PIM", a new psychological intervention) with debriefing on symptoms of post-traumatic stress disorder (PTSD), anxiety and depression of Chinese military rescuers in relation to a control group that had no intervention. METHOD: We conducted a randomized controlled trial with 2,368 military rescuers 1 month after this event and then at follow-up 1, 2 and 4 months later to evaluate changes in symptoms of PTSD, anxiety and depression based on DSM-IV criteria, respectively. RESULTS: Baseline analysis suggested no significant differences between the study groups. Severity of PTSD, anxiety and depression decreased over time in all three groups, with significant differences between the groups in symptoms of PTSD (P < 0.01). Compared with the debriefing and control group, significant lower scores of PTSD and positive efficacy in improving symptoms of re-experiencing, avoidance and hyperarousal were found in the "512 PIM" group. CONCLUSION: "512 PIM" was an effective psychological intervention for military rescuers in reducing symptoms of PTSD, anxiety and depression after a crisis. PMID- 21789503 TI - Paracondylar process, a rare normal variant: the value of MRI in the diagnosis. AB - The paracondylar process is a rare osseous process arising at the cervicooccipital region that belongs to a large and heterogenic group of developmental abnormalities of the craniovertebral junction. We present a rare case of a paracondylar process in an 11-year-old girl, in which the diagnosis was made with the use of MRI, thereby skipping X-ray and CT scan, thus avoiding exposure of the young patient to radiation. To our knowledge, the use of MRI has not previously been reported in the investigation and diagnosis of such an abnormality. We describe the details of this variation emphasizing on awareness of this process, its anatomic relationships and its problems to clinicians, radiologists, surgeons and chiropractors. PMID- 21789504 TI - CD34-positive developing vessels and other structures in human fetuses: an immunohistochemical study. AB - CD34 is a well-known marker of progenitor cells of blood vessels and stromal tissues. Thus, CD34-positive cells have recently been used clinically in the field of vascular and orthopedic biotechnology because of their capacity to assist regeneration of injured tissues. However, to our knowledge, the in situ distribution of CD34-positive cells has not yet been described in the human fetus, with the exception of a few organs. In the present study, we conducted immunohistochemistry for CD34 using 12 human fetuses (9-15 weeks of gestation). CD34-positive structures showed a vessel-like appearance and were regularly arrayed in the viscera, nerves and lymph nodes, whereas in the body wall and extremities, they were distributed diffusely as fibrous tissues, such as the fascia and perimysium. The myocardium was also divided and bundled by CD34 positive fibrous tissues. In striated muscles, limited examples of CD34 expression were found in the tongue and extraocular muscles in which only vessels were positive. Lymphatic vessels were negative for CD34. In addition to their contribution to vascular development in any part of the body, CD34-positive mesenchymal tissues seem to play a critical role in the pattern formation of skeletal muscle, synovial tissue and other muscle/tendon-associated tissues in human fetuses. PMID- 21789505 TI - Human immunodeficiency virus type 1 endocytic trafficking through macrophage bridging conduits facilitates spread of infection. AB - Bridging conduits (BC) sustain communication and homeostasis between distant tethered cells. These are also exploited commonly for direct cell-to-cell transfer of microbial agents. Conduits efficiently spread infection, effectively, at speeds faster than fluid phase exchange while shielding the microbe against otherwise effective humoral immunity. Our laboratory has sought to uncover the mechanism(s) for these events for human immunodeficiency virus type one (HIV-1) infection. Indeed, in our prior works HIV-1 Env and Gag antigen and fluorescent virus tracking were shown sequestered into endoplasmic reticulum-Golgi organelles but the outcomes for spreading viral infection remained poorly defined. Herein, we show that HIV-1 specifically traffics through endocytic compartments contained within BC and directing such macrophage-to-macrophage viral transfers. Following clathrin-dependent viral entry, HIV-1 constituents bypass degradation by differential sorting from early to Rab11(+) recycling endosomes and multivesicular bodies. Virus-containing endocytic viral cargoes propelled by myosin II through BC spread to neighboring uninfected cells. Disruption of endosomal motility with cytochalasin D, nocodasole and blebbistatin diminish intercellular viral spread. These data lead us to propose that HIV-1 hijacks macrophage endocytic and cytoskeletal machineries for high-speed cell-to-cell spread. PMID- 21789506 TI - Delta9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events. AB - Previously, CD8(+) T cells were found to be a sensitive target for suppression by Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in a murine model of influenza infection. To study the effect of Delta(9)-THC on CD8(+) cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)) in Delta(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1) (-/-)CB(2) (-/-)). Delta(9)-THC suppressed CTL function independent of CB(1) and CB(2) as evidenced by reduction of (51)Cr release by CTL generated from CB(1) (-/-)CB(2) (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Delta(9)-THC, independent of CB(1) and CB(2), but no effect of Delta(9)-THC on proliferation was observed, suggesting that Delta(9)-THC decreases the number of T cells initially activated. Delta(9)-THC increased expression of the activation markers, CD69 in CD8(+) cells and CD25 in CD4(+) cells in a concentration dependent manner in cells derived from WT and CB(1) (-/-)CB(2) (-/-) mice. Furthermore, Delta(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Delta(9)-THC increased CD69 expression in CD8(+) cells from CB(1) ( /-)CB(2) (-/-) and WT mice. Overall, these results suggest that CB(1) and CB(2) are dispensable for Delta(9)-THC-mediated suppression and that perturbation of Ca(2+) signals during T cell activation plays an important role in the mechanism by which Delta(9)-THC suppresses CTL function. PMID- 21789508 TI - Characterization of As efflux from the roots of As hyperaccumulator Pteris vittata L. AB - In some plant species, various arsenic (As) species have been reported to efflux from the roots. However, the details of As efflux by the As hyperaccumulator Pteris vittata remain unknown. In this study, root As efflux was investigated for different phosphorus (P) supply conditions during or after a 24-h arsenate uptake experiment under hydroponic growth conditions. During an 8-h arsenate uptake experiment, P-supplied (P+) P. vittata exhibited much greater arsenite efflux relative to arsenate uptake when compared with P-deprived (P-) P. vittata, indicating that arsenite efflux was not proportional to arsenate uptake. In the As efflux experiment following 24 h of arsenate uptake, arsenate efflux was also observed with arsenite efflux in the external solution. All the results showed relatively low rates of arsenate efflux, ranging from 5.4 to 16.1% of the previously absorbed As, indicating that a low rate of arsenate efflux to the external solution is also a characteristic of P. vittata, as was reported with arsenite efflux. In conclusion, after 24 h of arsenate uptake, both P+ and P- P. vittata loaded/effluxed similar amounts of arsenite to the fronds and the external solution, indicating a similar process of xylem loading and efflux for arsenite, with the order of the arsenite concentrations being solution ? roots ? fronds. PMID- 21789509 TI - Single-incision sleeve gastrectomy versus conventional laparoscopic sleeve gastrectomy--a randomised pilot study. AB - BACKGROUND: This is a prospective pilot study done to evaluate the feasibility and to assess the outcomes and complication rates of the single-incision sleeve gastrectomy versus the conventional five-port laparoscopic sleeve gastrectomy. METHODS: A prospective comparative analysis was done of 50 patients in each arm who underwent laparoscopic sleeve gastrectomy and single-incision sleeve gastrectomy from September 2009 until April 2010. Both groups were matched for age, gender and BMI and were then randomly assigned to either group. Postoperative pain scoring was done using the visual analogue scale. Postoperative outcomes in terms of pain scores, excess weight loss, resolution of comorbidities and complication rates were compared in both groups, at the end of 6 months. RESULTS: Operating times in both groups were comparable with experience. Intraoperative blood loss was similar in both groups. VAS scoring revealed lesser postoperative pain after the first 8 h in the single-incision group as compared to the laparoscopy group-P < 0.0001. At 6 months, excess weight loss and resolution of comorbidities were comparable in both groups. There were no major complications or mortalities in either group. CONCLUSIONS: Single incision laparoscopic sleeve gastrectomy is a feasible surgical procedure for morbid obesity in selected individuals. When compared to conventional laparoscopic sleeve gastrectomy, it has equally effective weight loss and resolution of comorbidities. It also has the added benefits of little or no visible scarring and reduced postoperative pain. PMID- 21789510 TI - Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis. AB - Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the anti-proliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC(50) values ranging from 6.9 to 32 MUM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma. PMID- 21789507 TI - Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. AB - Infection rate among intravenous drug users (IDU) is higher than the general public, and is the major cause of morbidity and hospitalization in the IDU population. Epidemiologic studies provide data on increased prevalence of opportunistic bacterial infections such as TB and pneumonia, and viral infections such as HIV-1 and hepatitis in the IDU population. An important component in the intravenous drug abuse population and in patients receiving medically indicated chronic opioid treatment is opioid withdrawal. Data on bacterial virulence in the context of opioid withdrawal suggest that mice undergoing withdrawal had shortened survival and increased bacterial load in response to Salmonella infection. As the body of evidence in support of opioid dependency and its immunosuppressive effects is growing, it is imperative to understand the mechanisms by which opioids exert these effects and identify the populations at risk that would benefit the most from the interventions to counteract opioid immunosuppressive effects. Thus, it is important to refine the existing animal model to closely match human conditions and to cross-validate these findings through carefully controlled human studies. Better understanding of the mechanisms will facilitate the search for new therapeutic modalities to counteract adverse effects including increased infection rates. This review will summarize the effects of morphine on innate and adaptive immunity, identify the role of the mu opioid receptor in these functions and the signal transduction activated in the process. The role of opioid withdrawal in immunosuppression and the clinical relevance of these findings will also be discussed. PMID- 21789512 TI - The impact of Converso Jews on the genomes of modern Latin Americans. AB - Modern day Latin America resulted from the encounter of Europeans with the indigenous peoples of the Americas in 1492, followed by waves of migration from Europe and Africa. As a result, the genomic structure of present day Latin Americans was determined both by the genetic structure of the founding populations and the numbers of migrants from these different populations. Here, we analyzed DNA collected from two well-established communities in Colorado (33 unrelated individuals) and Ecuador (20 unrelated individuals) with a measurable prevalence of the BRCA1 c.185delAG and the GHR c.E180 mutations, respectively, using Affymetrix Genome-wide Human SNP 6.0 arrays to identify their ancestry. These mutations are thought to have been brought to these communities by Sephardic Jewish progenitors. Principal component analysis and clustering methods were employed to determine the genome-wide patterns of continental ancestry within both populations using single nucleotide polymorphisms, complemented by determination of Y-chromosomal and mitochondrial DNA haplotypes. When examining the presumed European component of these two communities, we demonstrate enrichment for Sephardic Jewish ancestry not only for these mutations, but also for other segments as well. Although comparison of both groups to a reference Hispanic/Latino population of Mexicans demonstrated proximity and similarity to other modern day communities derived from a European and Native American two-way admixture, identity-by-descent and Y-chromosome mapping demonstrated signatures of Sephardim in both communities. These findings are consistent with historical accounts of Jewish migration from the realms that comprise modern Spain and Portugal during the Age of Discovery. More importantly, they provide a rationale for the occurrence of mutations typically associated with the Jewish Diaspora in Latin American communities. PMID- 21789513 TI - Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma. AB - Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death. PMID- 21789515 TI - RETRACTED ARTICLE: ShRNA-mediated gene silencing of Heat shock protein 70 inhibits human colon cancer cell growth in vitro and in vivo. PMID- 21789514 TI - New insights into the Orange domain of E(spl)-M8, and the roles of the C-terminal domain in autoinhibition and Groucho recruitment. AB - CK2 is a Ser/Thr protein kinase that regulates the activity of the Drosophila basic-helix-loop-helix (bHLH) repressor M8 encoded by the Enhancer of split Complex (E(spl)C) during neurogenesis. Specifically, phosphorylation appears to elicit a conformational change in an autoinhibited state of M8 to one that is permissive for repression. We describe biochemical and molecular modeling studies that provide new insights into repression by M8. Our studies implicate the phosphorylation domain in autoinhibition, and indicate that binding of the co repressor Groucho (Gro) is context-dependent. Molecular modeling indicates that the Orange domain, proposed to be a specificity-determinant, may instead play a structural role, and that a conformational rearrangement of this domain may be necessary for repression. This model also provides a structural mechanism for the behavior of mutant alleles of the m8 gene. The insights gained from these studies should be applicable to the conserved metazoan bHLH repressors of the Hairy and Enhancer of Split (HES) family that are related to Drosophila M8. PMID- 21789516 TI - HPV L1 capsid protein expression in squamous intraepithelial lesions of cervix uteri and its relevance to disease outcome. AB - PURPOSE: The purpose of this study was to investigate the usefulness of immunocytochemical detection of HPV L1 capsid protein expression in predicting the course of cervical intraepithelial neoplasia. BACKGROUND: It is known that most of the low grade dysplastic lesions of cervix uteri regress spontaneously and only some will progress to high grade dysplastic lesions. HPV L1 capsid protein represents about 90% of the total protein on the surface of the virus and can be detected in mild to moderate dysplasia and rarely in severe dysplasia. METHODS: Pap smears from 65 women, in whom diagnoses of LSIL (n = 43) and HSIL (n = 22) were made on cytology and histology specimens, were immunocytochemically stained using antibody against HPV L1capsid protein. The results of immunocytochemical analysis were correlated with the outcome during the 24-month follow-up. p value <0.05 was considered significant. RESULTS: The immunostaining reaction for L1 capsid protein was positive in 28 cases (65.1%) of LSIL while 15 (34.9%) cases of LSIL and all of the 22 cases of HSIL were negative (p < 0.001). After 24 months of follow-up, among the 28 L1-positive LSIL cases, we found a 60.7% (17/28) spontaneous regression rate, whereas in the 15 L1-negative LSIL patients, the regression rate was 33.3% (5/15). Out of the 22 HSIL cases, 13.6% (3/22) had regression. CONCLUSION: Our data support that immunocytochemical detection of HPV-L1 protein could present prognostic information about the evolution of early dysplastic cervical lesions and can be useful in predicting their biologic potential. PMID- 21789517 TI - Role of serum interleukin-6 in comparing surgical stress after laparoscopic assisted vaginal hysterectomy and non-descent vaginal hysterectomy for large uteri. AB - AIMS AND OBJECTIVES: To compare the perioperative inflammatory response using interleukin-6 (IL-6) in patients of laparoscopic-assisted vaginal hysterectomy (LAVH) and non-descent vaginal hysterectomy (NDVH) for large uteri with benign disease. MATERIALS AND METHODS: Twenty women with benign uterine disease and failed medical management with size of uterus ranging from 300 to 1,500 g (12-24 weeks) were randomized into two equal groups for either technique of hysterectomy, LAVH and NDVH. Venous blood levels of IL-6 were measured preoperatively and 3, 24 and 72 h after beginning of surgery. Statistical analysis was done using SPSS15 software. RESULTS: No statistically significant difference was present in demographic characteristics, operating time, and uterine weight between the two groups. No major complications were encountered. The increase in serum interleukin 6 levels from preoperative value to the value at 3 h postoperatively was found to be significantly higher in LAVH group when compared with NDVH group indicating greater tissue handling and trauma in LAVH group. CONCLUSION: Non-descent vaginal hysterectomy appears to be better than laparoscopic-assisted vaginal hysterectomy for large uteri in terms of inflammatory response. PMID- 21789518 TI - Are teenage pregnancies at high risk? A comparison study in a developing country. AB - OBJECTIVE: The aim of this study was to compare obstetric and perinatal outcome in teenage and non-teenage pregnancies. METHODS: We analyzed retrospective data of 15,498 pregnant patients who delivered from March 2008 to April 2009 in Jawaharlal Institute of Postgraduate Medical Education and Research, a referral tertiary care and teaching hospital in Pondicherry, South India. Girls aged <= 19 years were compared with pregnancy outcomes in women aged > 19 years who delivered in the same hospital during the study period. A total of 620 teenage pregnancies were compared with 14,878 non-teenage women. The obstetric and perinatal outcome was compared in the study and control groups using t test with Yates correction. We calculated Odds ratio (OR), 95% confidence intervals(CI) and p values; p < 0.005 was considered significant. RESULTS: The incidence of teenage pregnancy in the study was 4%. A signicant proportion of teenage mothers were in their first pregnancies and their mean age was 18.04 years. Our study showed a significantly higher incidence of anaemia, past dates, premature rupture of membranes (PROM), normal vaginal delivery, episiotomy, low birth weight, and a significantly lower incidence of caesarean sections/perineal tears in teenage mothers compared to other mothers. In contrast, the incidence of hypertension, intrauterine growth restriction of fetus, pre-term labour and postpartum haemorrhage were similar in both the groups. CONCLUSION: The data in our study should throw more light on the current thinking of the obstetrical problems facing teenage mothers, in which some of our results support and others refute several long held beliefs about the risks in teenage pregnancy. Early booking, adequate antenatal care and delivery by trained people should improve the obstetric and perinatal outcome in teenage pregnancies, which is still an unresolved problem inspite of various government programmes in developing countries. PMID- 21789519 TI - Reward and punishment sensitivity in children with ADHD: validating the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children (SPSRQ-C). AB - This study validates the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children (SPSRQ-C), using a Dutch sample of 1234 children between 6-13 years old. Factor analysis determined that a 4-factor and a 5-factor solution were best fitting, explaining 41% and 50% of the variance respectively. The 4-factor model was highly similar to the original SPSRQ factors found in adults (Punishment Sensitivity, Reward Responsivity, Impulsivity/Fun-Seeking, and Drive). The 5-factor model was similar to the 4-factor model, with the exception of a subdivision of the Punishment Sensitivity factor into a factor with 'social fear' items and a factor with 'anxiety' items. To determine external validity, scores of three groups of children with attention deficit hyperactivity disorder (ADHD) were compared on the EFA models: ADHD-only (n = 34), ADHD and autism spectrum disorder (ADHD+ASD; n = 22), ADHD and oppositional defiant disorder (ADHD+ODD; n = 22). All ADHD groups scored higher than typical controls on Reward Responsivity and on the 'anxiety' factor (n = 75). The ADHD-only and ADHD+ODD group scored higher than other groups on Impulsivity/Fun-Seeking and Drive, while the ADHD+ASD group scored higher on Punishment Sensitivity. The findings emphasize the value of the SPSRQ-C to quickly and reliably assess a child's sensitivity to reinforcement, with the aim to provide individually-tailored behavioral interventions that utilize reward and reprimands. PMID- 21789520 TI - The effects of experimentally induced rumination, positive reappraisal, acceptance, and distancing when thinking about a stressful event on affect states in adolescents. AB - The current study compares the effects of experimentally induced rumination, positive reappraisal, distancing, and acceptance on affect states in adolescents aged 13-18. Participants (N = 160) were instructed to think about a recent stressful event. Next, they received specific instructions on how to think about that event in each condition. Manipulation checks revealed that the manipulations were successful, except for acceptance. The two most reported events were "a fight" and "death of loved one". Results showed that positive reappraisal (i.e., thinking about the benefits and personal growth) caused a significantly larger increase in positive affect and decrease in negative affect compared to rumination, distancing, and acceptance. Current findings implicate that positive reappraisal seems an adequate coping strategy in the short-term, and therefore could be applied in interventions for youth experiencing difficulties managing negative affect. Future research should focus on long-term effects of these cognitive strategies and on more intensive training of acceptance. PMID- 21789521 TI - Do historical changes in parent-child relationships explain increases in youth conduct problems? AB - The coincidence of historical trends in youth antisocial behavior and change in family demographics has led to speculation of a causal link, possibly mediated by declining quality of parenting and parent-child relationships. No study to date has directly assessed whether and how parenting and parent-child relationships have changed. Two national samples of English adolescents aged 16-17 years in 1986 (N = 4,524 adolescents, 7,120 parents) and 2006 (N = 716 adolescents, 734 parents) were compared using identical questionnaire assessments. Youth-reported parental monitoring, expectations, and parent-child quality time increased between 1986 and 2006. Ratings of parental interest did not change. Parenting differences between affluent and disadvantaged families narrowed over time. There was thus little evidence of a decline in quality of parenting for the population as a whole or for disadvantaged subgroups. Parent-reported youth conduct problems showed a modest increase between 1986 and 2006. Findings suggested that the increase in youth conduct problems was largely unrelated to observed change in parent-child relationships. PMID- 21789522 TI - Parental behaviors during family interactions predict changes in depression and anxiety symptoms during adolescence. AB - This study investigated the prospective, longitudinal relations between parental behaviors observed during parent-adolescent interactions, and the development of depression and anxiety symptoms in a community-based sample of 194 adolescents. Positive and negative parental behaviors were examined, with negative behaviors operationalized to distinguish between observed parental expressions of aggression and dysphoria. Results showed that higher levels of parental aggression prospectively predicted higher levels of both depression and anxiety symptoms in adolescents over two-and-a-half years, whereas higher levels of positive parental behaviors prospectively predicted lower levels of depression symptoms only. Parental dysphoric behavior was not related to changes in either symptom dimension. These results suggest that patterns of parental behaviors may be differentially associated with depressive versus anxious outcomes in adolescents, and highlight the potential role for family-focused prevention or treatment interventions aimed at reducing an escalation of depression and anxiety symptoms in adolescence. PMID- 21789523 TI - The association of antimicrobial resistance with cure and quality of life among women with acute uncomplicated cystitis. AB - BACKGROUND: The association of in vitro resistance with bacteriologic, clinical, and health-related quality of life (HRQoL) outcomes for acute uncomplicated cystitis is unclear. METHODS: We conducted a prospective study of women aged 18 40 years with acute uncomplicated cystitis symptoms for <=7 days who subsequently grew an Enterobacteriaceae sp. and initially received trimethoprim/sulfamethoxazole (TMP/SMX) and phenazopyridine. We conducted telephone follow-up evaluating clinical cure at 1-3 days and in-person follow-up evaluating clinical, bacteriologic, and HRQoL outcomes at 3-7 days and 4-6 weeks post-treatment. RESULTS: An Enterobacteriaceae sp. was isolated in 139 (96.5%) patients (25.2% TMP/SMX-resistant). At 1-3 days post-treatment, clinical cure occurred in 56/81 (69.1%) and 14/31 (45.2%) of cases with susceptible and resistant strains, respectively (difference 23.9%; 95% confidence interval [CI], 1.5-46.4%). At 3-7 days post-treatment, bacteriologic cure occurred in 70/73 (95.9%) and 15/25 (60%) of cases with susceptible and resistant strains, respectively (difference 35.9%; 95% CI, 13.5-58.3%). Sustained clinical cure rates at 3-7 days and 4-6 weeks post-treatment were 65.4 and 56.8% with susceptible strains, and 45.2 and 45.2% with resistant strains, respectively. The HRQoL scale assessing role limitations due to physical health problems was lower in TMP/SMX-resistant versus TMP/SMX-susceptible infections, with twice as many hours of missed activities reported (mean, 18.4 vs. 9.1 h). Differences in HRQoL appeared to be largely related to differences in clinical cure rates. CONCLUSIONS: Among women treated for acute uncomplicated cystitis with TMP/SMX, in vitro TMP/SMX resistance was associated with lower bacteriologic and clinical cure rates, and had greater impact on the time lost from daily activities compared to those with TMP/SMX-susceptible infections. PMID- 21789524 TI - Outcomes in patients infected with carbapenem-resistant Acinetobacter baumannii and treated with tigecycline alone or in combination therapy. AB - PURPOSE: Acinetobacter baumannii is a non-fermenting aerobic gram-negative bacteria and one of the important nosocomial pathogens, especially in intensive care units (ICUs). In recent years, multidrug-resistant (MDR) isolates have been an emerging problem, with limited therapeutic options. Tigecycline is a novel antimicrobial, with its in vitro activity against most gram-positive and gram negative pathogens. METHODS: This is a retrospective study that was conducted in a tertiary care hospital with 550 beds in Ankara, Turkey, from January 2009 to July 2010. Thirty-three patients who had carbapenem-resistant Acinetobacter spp. infections and received tigecycline alone or in combination with other antibiotics for at least 3 days were included. RESULTS: The median age of the patients was 62 (18-87) years. All of the patients were diagnosed and treated in the ICU. Clinical responses were observed in 23 patients (69.7%). Ten patients (30%) had clinical failure. There was no significant difference between ventilator-associated pneumonia (VAP) and bloodstream infection (BSI) in terms of clinical or microbiological outcome (p > 0.05). The microbiological response rate was 50%. Superinfection was detected in 13 patients (43.3%) and Pseudomonas aeruginosa was the most frequently isolated pathogen. The 30-day overall mortality rate and attributable mortality rates were 57.6 and 24.2%, respectively. The attributable mortality rate was higher in the group in which microbiological eradication was not provided. CONCLUSIONS: Although it is approved by the Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections, complicated skin and soft tissue infections, and community-acquired bacterial pneumonia, emerged resistance of Acinetobacter spp. and limited therapeutic options left physicians no choice but to use tigecycline for off-label indications. PMID- 21789525 TI - Yersinia pseudotuberculosis bloodstream infection and septic arthritis: case report and review of the literature. AB - Yersinia pseudotuberculosis belongs to the family Enterobacteriaceae and is known to cause enterocolitis, terminal ileitis, pseudoappendicitis, erythema nodosum, reactive polyarthritis, and, occasionally, bloodstream infections. Here, we report the first case of bacteremia and septic arthritis in a patient without obvious risk factors and review all of the published cases of Y. pseudotuberculosis bloodstream infections. PMID- 21789526 TI - Triptolide exhibits anti-inflammatory, anti-catabolic as well as anabolic effects and suppresses TLR expression and MAPK activity in IL-1beta treated human intervertebral disc cells. AB - INTRODUCTION: Increased levels of proinflammatory cytokines seem to play a pivotal role in the development of back pain in a subpopulation of patients with degenerative intervertebral disc (IVD) disease. As current treatment options are mostly limited to surgical interventions or conservative treatment, anti inflammatory substances might offer a novel, more target-orientated therapeutic approach. Triptolide (TPL), a natural substance found in the Chinese medicinal herb Tripterygium wilfordii Hook, has been demonstrated to possess anti inflammatory effects in various cells, but no studies exist so far for the IVD. Therefore, the aim of this study was to determine the effects of TPL on human IVD cells by analyzing changes in gene expression and underlying molecular mechanisms. MATERIALS AND METHODS: In order to investigate the anti-inflammatory, anabolic and anti-catabolic effect of TPL, dose-dependency experiments (n = 5) and time course experiments (n = 5) were performed on IL-1beta prestimulated human IVD cells and changes in gene expression of IL-6/-8, TNF-alpha, PGE2S, MMP1/2/3/13, aggrecan and collagen-I/-II were analyzed by real-time RT-PCR. The molecular mechanisms underlying the effects observed upon TPL treatment were investigated by analyzing involvement of Toll-like receptors TLR2/4 (real-time RT PCR, n = 5), NF-kappaB, MAP kinases p38, ERK and JNK (immunoblotting and immunocytochemistry, n = 4) as well as RNA polymerase II (immunoblotting, n = 3). RESULTS: Results showed that 50 nM TPL exhibited an anti-inflammatory, anti catabolic and anabolic effect on the mRNA level for IL-6/-8, PGE2S, MMP1/2/3/13, aggrecan, collagen-II and TLR2/4, with most pronounced changes after 18 h for proinflammatory cytokines and MMPs or 30 h for TLRs and matrix proteins. However, we also observed an up-regulation of TNF-alpha at higher concentrations. The effects of TPL did not seem to be mediated via an inhibition of NF-kappaB or a decrease of RNA polymerase II levels, but TPL influenced activity of MAP kinases p38 and ERK (but not JNK) and expression of TLR2/4. CONCLUSIONS: In conclusion, TPL may possess promising potential for the treatment of inflammation-related discogenic back pain in vitro, but its analgetic effect will need to be confirmed in an appropriate in vivo animal model. PMID- 21789527 TI - Predictive value of the Acute Low Back Pain Screening Questionnaire and the Orebro Musculoskeletal Pain Screening Questionnaire for persisting problems. AB - INTRODUCTION: A small proportion of individuals with non-specific low back pain (NSLBP) develop persistent problems. Up to 80% of the total costs for NSLBP are owing to chronic NSLBP. Psychosocial factors have been described to be important in the transition from acute to chronic NSLBP. Guidelines recommend the use of the Acute Low Back Pain Screening Questionnaire (ALBPSQ) and the Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) to identify individuals at risk of developing persistent problems, such as long-term absence of work, persistent restriction in function or persistent pain. These instruments can be used with a cutoff value, where patients with values above the threshold are further assessed with a more comprehensive examination. METHODS: We systematically reviewed studies evaluating the accuracy of the ALBPSQ and OMPSQ to predict persistent problems. RESULTS: The 13 included studies used different cutoff values for the screening questionnaires ranging from 68 to 147. The pooled sensitivity was 0.59 (0.43-0.74), while the pooled specificity was 0.77 (0.66 0.86). Heterogeneity (I (2)) was 90.02% for sensitivity and 95.41% for specificity. CONCLUSION: Thus, we do not recommend the use of one cutoff value, but the use of a prediction model with all the individual items. PMID- 21789528 TI - Individualized antibiotic prophylaxis reduces surgical site infections by gram negative bacteria in instrumented spinal surgery. AB - PURPOSE: Surgical site infection (SSI) can be a challenging complication after posterior spinal fusion and instrumentation (PSFI). An increasing rate of SSI by gram-negative bacteria (GNB) has been observed. Current guideline recommendations have not been effective for preventing infection by these microorganisms. METHODS: Retrospective cohort study comparing two consecutive groups of patients undergoing PSFI at a single institution. Cohort A includes 236 patients, operated between January 2006 and March 2007, receiving standard preoperative antibiotic prophylaxis with cefazolin (clindamycin in allergic patients). Cohort B includes 223 patients operated between January and December 2009, receiving individualized antibiotic prophylaxis and treatment based on preoperative urine culture. Cultures were done 3-5 days before surgery in patients meeting one of the following risk criteria for urinary tract colonization: hospitalization longer than 7 days, indwelling catheter, neurogenic bladder, history of urinary incontinence, or history of recurrent urinary tract infection. RESULTS: Twenty two (9.3%) patients in cohort A developed SSI, 68.2% due to GNB. 38 (17%) patients in cohort B were considered at risk for GNB colonization; preoperative urine culture was positive in 14 (36%). After adjusted antibiotic prophylaxis, 15 (6.27%) patients in cohort B developed SSI, 33.4% due to GNB. A statistically significant reduction in GNB SSI was seen in cohort B (Fisher's exact test, p = 0.039). CONCLUSION: Higher preoperative GNB colonization rates were found in patients with neurogenic bladder or indwelling catheters. Preoperative bacteriological screening, treatment for bacteriuria, and individualized antibiotic prophylaxis were effective for reducing GNB SSI. PMID- 21789529 TI - Pregnancy and acromegaly: a review. AB - To review the literature regarding the diagnosis and management of acromegaly during pregnancy. A systematic literature search was performed using MEDLINE including hand-searching reference lists from original articles. The diagnosis of acromegaly during pregnancy is made difficult due to the physiologic changes in pituitary GH secretion and IGF-1 production resulting from placental GH secretion and the inability of commercial assays to discriminate between pituitary and placental GH. Most patients with acromegaly during pregnancy do not have an increase in tumor size, metabolic complications are uncommon, and neonatal outcome is largely unaffected. IGF-1 levels tend to be stable in such patients possibly due to the high estrogen levels causing GH resistance. Dopamine agonists, somatostatin analogues, and a GH receptor antagonist have been reported to be safe during pregnancy. Patients with visual field defects should be considered for surgery, but in most cases this can be safely postponed until after delivery. Overall, pregnancy in acromegaly is uneventful and newborns unaffected. Dopamine agonists and somatostatin analogues have not been associated with major adverse effects to the fetus; however, more data are needed to validate their safety. PMID- 21789530 TI - Interaction frequency and per-interaction effects as predictors of total effects in plant-pollinator mutualisms: a case study with the self-incompatible herb Linaria lilacina. AB - It is widely recognized that pollinators vary in their effectiveness in pollination mutualisms, due both to differences in flower-pollinator morphological fit as well as pollinator behaviour. However, pollination webs typically treat all interactions as equal, and we contend that this method may provide misleading results. Using empirical and theoretical data, we present the case study of a self-incompatible herb in which the number of flowers visited by a pollinator cannot be used as a surrogate for the total effect of a pollinator on a plant due to differences in per-visit effectiveness at producing seeds. In self-incompatible species, the relationship between interaction frequency and per interaction effect may become increasingly negative as more flowers per plant are visited due to geitonogamous pollen transfer. We found that pollinators making longer bouts (i.e. visiting more flowers per plant visit) had an overall higher pollination success per bout. However, per-interaction effects tended to decrease as the bout progressed, particularly for pollinators that cause higher pollen deposition. Since the same interaction frequency may result from different combinations of number of bouts (plant visits) and bout length (flowers visited/bout), pollinators making repeatedly shorter bouts may contribute more to plant reproduction for the same number of flowers visited. Consequently, the magnitude of the differences in number of interactions of different insect types may be overridden by the magnitude of the differences in effectiveness as pollinators, even if the same pollinators consistently interact more frequently. We discuss two predictions regarding the validity of using interaction frequency as a surrogate for plant seed production (as a measure of total effect), depending on the degree of self-compatibility, plant size and floral display. We suggest that the role of interaction frequency must be tested for different species, environments, and across wider scales to validate its use as a surrogate for total effect in plant-pollinator networks. PMID- 21789531 TI - Ultrasound-assisted ionic liquid-based microextraction combined with least squares support vector machines regression for the simultaneous determination of aluminum, gallium, and indium in water and coal samples. AB - A new simple and rapid ultrasound-assisted ionic liquid-based microextraction method was applied to preconcentrate aluminum(III), gallium(III), and indium(III) ions from water samples as a prior step to their simultaneous spectrophotometric determination using least squares support vector machines regression. In the novel procedure, 1-hexyl-3-methylimidazolium hexafluorophosphate [C(6)MIM][PF(6)] was dispersed into the aqueous sample solution as fine droplets by ultrasonication, and the analytes were extracted into the ionic liquid phase after complexation with 1,2,5,8-tetrahydroxy anthraquinone (quinalizarine). After centrifuging, the fine droplets of extractant phase were settled to the bottom of the conical-bottom glass centrifuge tube. The detection limits for Al(III), Ga(III), and In(III) were 1.70, 2.02, and 2.06 ng mL(-1), respectively. The precision of the method, evaluated as the relative standard deviation obtained by analyzing a series of ten replicates, was below 3.2% for all elements. The method was successfully applied for the determination of Al(III), Ga(III), and In(III) in real samples. PMID- 21789532 TI - Hydrochemical analysis to evaluate the seawater ingress in a small coral island of India. AB - The sustainable development of the limited groundwater resources in the tropical island requires a thorough understanding of detail hydrogeological regime including the hydrochemical behavior of groundwater. Detail analysis of chemical data of groundwater helps in assessing the different groundwater zone affected by formation as well as sea water. Groundwater and saline water interaction is better understood using groundwater major ion chemistry over an island aquifer. Multivariate methods to analyze the geochemical data are used to understand geochemical evolution of groundwater. The methods are successfully used to group the data to evaluate influence of various environs in the study area. Various classification methods such as piper, correlation method, and salinity hazard measurements are also employed to critical study of geochemical characteristics of groundwater to identify vulnerable parts of the aquifer. These approaches have been used to successfully evaluate the aquifer zones of a tiny island off the west coast of India. The most part of island is found to be safe for drinking, however some parts of island are identified that are affected by sea water ingress and dissolution of formation minerals. The analysis has successfully leaded to identification of that part of aquifer on the island which needs immediate attention for restoration and avoids further deterioration. PMID- 21789533 TI - Multivariate analysis of mixed contaminants (PAHs and heavy metals) at manufactured gas plant site soils. AB - Principal component analysis (PCA) was used to provide an overview of the distribution pattern of polycyclic aromatic hydrocarbons (PAHs) and heavy metals in former manufactured gas plant (MGP) site soils. PCA is the powerful multivariate method to identify the patterns in data and expressing their similarities and differences. Ten PAHs (naphthalene, acenapthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, chrysene, benzo[a]pyrene) and four toxic heavy metals - lead (Pb), cadmium (Cd), chromium (Cr) and zinc (Zn) - were detected in the site soils. PAH contamination was contributed equally by both low and high molecular weight PAHs. PCA was performed using the varimax rotation method in SPSS, 17.0. Two principal components accounting for 91.7% of the total variance was retained using scree test. Principle component 1 (PC1) substantially explained the dominance of PAH contamination in the MGP site soils. All PAHs, except anthracene, were positively correlated in PC1. There was a common thread in high molecular weight PAHs loadings, where the loadings were inversely proportional to the hydrophobicity and molecular weight of individual PAHs. Anthracene, which was less correlated with other individual PAHs, deviated well from the origin which can be ascribed to its lower toxicity and different origin than its isomer phenanthrene. Among the four major heavy metals studied in MGP sites, Pb, Cd and Cr were negatively correlated in PC1 but showed strong positive correlation in principle component 2 (PC2). Although metals may not have originated directly from gaswork processes, the correlation between PAHs and metals suggests that the materials used in these sites may have contributed to high concentrations of Pb, Cd, Cr and Zn. Thus, multivariate analysis helped to identify the sources of PAHs, heavy metals and their association in MGP site, and thereby better characterise the site risk, which would not be possible if one uses chemical analysis alone. PMID- 21789534 TI - Ground temperature estimations for Bolu, Turkey. AB - The approximation of the soil temperature profile may be considered for many energy, environmental, and agriculture applications. In this study, temperature approximation model of ground in Bolu is developed. Unsteady state one dimensional semi-infinite solid model is used to calculate temperature variation in ground. The results of the temperature equation which are obtained by using analytical method are compared with experimental data obtained from The Turkish State Meteorological Service. Developed model to predict soil temperature variation for Bolu has been solved by using MATLAB computer program. Satisfactory agreement is observed between them. PMID- 21789535 TI - Gas-particle concentration, distribution, and health risk assessment of polycyclic aromatic hydrocarbons at a traffic area of Giza, Egypt. AB - Atmospheric particulate and gaseous polycyclic aromatic hydrocarbons (PAHs) samples were collected from an urban area in Dokki (Giza) during the summer of 2007 and the winter of 2007-2008. The average concentrations of PAHs were 1,429.74 ng/m(3) in the particulate phase, 2,912.56 ng/m(3) in the gaseous phase, and 4,342.30 ng/m(3) in the particulate + gaseous phases during the period of study. Dokki has high level concentrations of PAH compounds compared with many polluted cities in the world. The concentrations of PAH compounds in the particulate and gaseous phases were higher in the winter and lower in the summer. Total concentrations of PAHs in the particulate phase and gaseous phase were 22.58% and 77.42% in summer and 36.97% and 63.03% in winter of the total (particulate + gaseous) concentrations of PAHs, respectively. The gaseous/particulate ratios of PAHs concentration were 3.43 in summer and 1.71 in winter. Significant negative correlation coefficients were found between the ambient temperature and concentrations of the total PAHs in the particulate and gaseous phases. The distribution of individual PAHs and different categories of PAHs based on aromatic ring number in the particulate and gaseous phases during the summer and winter were nearly similar, indicating similar emission sources of PAHs in both two seasons. Benzo(b)fluoranthene in the particulate phase and naphthalene in the gaseous phase were the most abundant compounds. Diagnostic concentration ratios of PAH compounds indicate that these compounds are emitted mainly from pyrogenic sources, mainly local vehicular exhaust emissions. Health risks associated with the inhalation of individual PAHs in particulate and gaseous phases were assessed on the basis of its benzo(a)pyrene equivalent concentration. Dibenzo(a,h)anthracene and benzo(a)pyrene in the particulate phase and benzo(a)pyrene and benzo(a)anthracene in the gaseous phase were the greatest contributors to the total health risks. The relative mean contributions of the total carcinogenic activity (concentrations) of all PAHs to the total concentrations of PAHs were 29.37% and 25.15% in the particulate phase and 0.76% and 0.92% in the gaseous phase during the summer and winter, respectively. These results suggest that PAHs in the particulate phase in the ambient air of Dokki may pose a potential health risk. PMID- 21789536 TI - Atypical and ischemic features of embolized meningiomas. AB - Preoperative embolization (POE) of meningiomas is widely used to facilitate surgical removal and to reduce intraoperative blood loss. The resulting necrosis and enhanced proliferation have been reported to affect subsequent histologic grading. However, there was little concern about ischemic features, for example small cells resembling atypical meningiomas, cytoplasmic vacuoles resembling clear cell meningioma, intercellular discohesion resembling rhabdoid meningioma, and perivascular cuffs resembling papillary meningioma. Therefore, the extent of these ischemic features was scored and Ki-67 staining indices were investigated in a POE group composed of 29 specimens of meningiomas treated with POE and compared with equivalent results for a non-POE group composed of 29 meningiomas that were not treated with POE. Small cells with high N/C ratios, cytoplasmic vacuoles, intercellular discohesion, and perivascular cuffs were significantly increased in the POE group (versus the non-POE group, p < 0.05). There were no significant differences of the Ki-67 index between the POE group (2.2%) and the non-POE group (1.9%) (p = 0.49). Our results suggest that small cell change resulting in necrosis may be followed by POE, and that clear cell-like, rhabdoid cell-like, or pseudopapillary pattern identified in meningiomas may also be induced by POE. Therefore, histological findings and determination of grading should be evaluated cautiously in cases of embolized meningiomas. PMID- 21789537 TI - Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. AB - The oral sphingosine 1-phosphate receptor (S1PR) modulator fingolimod functionally antagonizes S1PR hereby blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation. This results in a reduction in peripheral lymphocyte counts, including potentially encephalitogenic T cells. In patients with relapsing multiple sclerosis fingolimod has been shown to be an effective treatment. In phase 2 and phase 3 studies fingolimod-treated patients had reduced disease activity clinically and in MRI. Although severe infectious complications occurred in single cases treated with fingolimod, the frequency of overall infections was comparable in fingolimod-treated patients and controls. Overall, in clinical studies fingolimod was well tolerated and had a favorable safety profile. In follow-up studies with continuous fingolimod, treatment showed sustained efficacy while being well tolerated. PMID- 21789538 TI - The concept and treatment of locomotive syndrome: its acceptance and spread in Japan. PMID- 21789539 TI - Comorbidities, sphincterotomy, and balloon dilation predict post-ERCP adverse events in PSC patients: operator experience is protective. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease. Interventional ERCP improves survival in PSC patients. AIMS: To describe the frequency and risk factors for post-ERCP adverse events in patients with PSC via multivariate analysis. METHODS: Retrospective cohort study included patients with a diagnosis of PSC who underwent ERCP at academic institutions between February 2000 and October 2009. Demographis, co-morbid conditions, antibiotic use, cannulation method, ERCP maneuvers and 30-day post-ERCP adverse events were collected. Multivariate analysis was performed using logistic regression. RESULTS: A total of 185 procedures were performed on 75 PSC patients (58 M,17 F). Seven endoscopists performed ERCPs. Comorbidies included ulcerative colitis (44%, n = 33), Crohn's disease (12%, n = 9 patients), Cirrhosis (8%, n = 6 patients) and autoimmune hepatitis (2.7%, n = 2). Cannulation was achieved using dye-free guidewire cannulation techniques in 139/185 procedures (76%) and with contrast based techniques in 46/185 procedures (24%). Thirty-day post-ERCP adverse events included post-ERCP pancreatitis (5%, n = 9, cholangitis (1%, n = 2), acute cholecystitis (0.5%, n = 1), stent occlusion (0.5%, n = 1), stent migration (0.5%, n = 1), and bile leak (0.5%, n = 1). In the multivariate analysis, associations with specific endoscopists who performed the procedure (P = 0.01), biliary dilation (P = 0.02), sphincterotomy (P = 0.03), presence of cirrhosis (P = 0.05), Crohn's disease (P < 0.001), and autoimmune hepatitis (P < 0.001) significantly predicted a complication following ERCP. Gender, stenting during procedure, presence of a dominant stricture, and cholangitis were not predictive for post-ERCP adverse events. CONCLUSIONS: Factors predicting 30-day post-ERCP adverse events included certain co-morbid conditions, the endoscopist ERCP volume, maneuvers during ERCP including dilation and sphincterotomy. Stenting was not associated with adverse events. PMID- 21789540 TI - Clinical impact of HAb18G/CD147 expression in esophageal squamous cell carcinoma. AB - BACKGROUND: HAb18G/CD147 expression has been associated with many tumor invasion molecules, which play important roles in recurrence and poor differentiation of esophageal squamous cell carcinoma (ESCC). However, the clinical implications of HAb18G/CD147 in ESCC are still unclear. AIMS: In this study, we clarified the clinical significance of HAb18G/CD147 and characterized the association between HAb18G/CD147 and tumor invasion in ESCC cases. METHODS: Tumor tissues were obtained from 86 ESCC patients who underwent surgical resection between 2002 and 2005. All patients that had received previous therapy were excluded. ESCC tissues were analyzed by IHC using anti HAb18G/CD147 antibody. The expression of HAb18G/CD147 mRNA in esophageal cancer cell lines was analyzed by RT-PCR. RESULTS: HAb18G/CD147 was uniformly expressed in EC109 and EC871214 cell lines, but negatively expressed in EPC2, esophageal normal squamous cell line. HAb18G/CD147 mainly localized to the membrane of tumor cells in 84.9% of ESCC patients (64 out of 86 cases). Furthermore, we also found that higher HAb18G/CD147 expression levels significantly correlated with lymph node metastasis, depth of tumor invasion and differentiation (P < 0.05). But the expression levels of HAb18G/CD147 in lymph node metastatic tissues were almost equal to that in the primary tumor tissues. Furthermore, lymph node metastasis and expression of HAB18G/CD147 were independent prognostic indicators in ESCC. CONCLUSIONS: The expression of HAb18G/CD147 might be involved in the progression and survival of ESCC. Therefore, HAb18G/CD147 could be a clinical marker for the poor prognosis in ESCC patients and may also be a potentially therapeutic target to improve the progression of ESCC. PMID- 21789541 TI - Altered serum selenium and uric acid levels and dyslipidemia in hemodialysis patients could be associated with enhanced cardiovascular risk. AB - In the present study, the first objective was to follow up serum selenium (Se) concentrations in 117 hemodialysis patients (HPs) during a 2-year longitudinal study, relating concentrations to biochemical indexes (n = 6; namely lipoprotein profile, uric acid, and total protein levels). It was also evaluated whether the disease is associated with an enhanced cardiovascular risk. A healthy control group (n = 50) was also studied. Mean serum Se levels were significantly lower in HPs than in the controls (p = 0.002); mean levels significantly increased from the first to third blood sampling (p < 0.001). HPs showed a marked dyslipidemia, with a significant reduction in total cholesterol, low-density lipoprotein, and high-density lipoprotein cholesterol levels and a significant increase in triglyceride levels (p < 0.001). HPs showed a marked hyperuricemia (p < 0.001). Serum selenium levels in HPs were correlated negatively with uric acid levels (inflammation biomarker; p < 0.01). In HPs, serum Se levels are reduced due to their disease (chronic renal failure). Serum Se levels rose until the third blood sampling. The marked dyslipidemia and hyperuricemia found in HPs and the negative correlation between the serum Se and uric acid levels in these patients could imply an enhanced cardiovascular risk. PMID- 21789542 TI - Effect of copper on levels of collagen and alkaline phosphatase activity from chondrocytes in newborn piglets in vitro. AB - The effects of different concentrations of copper on collagen content and alkaline phosphatase (AKP) activity from chondrocytes in newborn piglets were measured. Chondrocytes were cultured in media containing 15% fetal calf serum supplemented with 0, 15.6, 31.2, and 62.5 MUmol/L copper in a 12-well culture plate. Collagen content and AKP activity from the chondrocyte extracellular matrix increased significantly in the culture media with 15.6, 31.2, and 62.5 MUmol/L copper and was the highest at 31.2 MUmol/L copper (P < 0.05). Thus, the results indicated that copper could promote AKP activity and collagen production by chondrocytes. PMID- 21789543 TI - Primary mediastinal DLBCL: evolving biologic understanding and therapeutic strategies. AB - Primary mediastinal diffuse large B-cell lymphoma is a quite rare clinicopathologic entity. Molecular analysis shows it to be distinct from other types of diffuse large B-cell lymphoma, and some retrospective analyses suggests that it may respond better to third-generation chemotherapy regimens than to the more commonly used CHOP. The addition of rituximab could reduce these differences; the role of consolidation with local radiotherapy, which is often used to treat residual mediastinal masses, remains. The real role of FDG-PET scanning requires prospective studies, and it is hoped that this may allow the de escalation of radiation therapy accordingly to yield reliable prognostic information. PMID- 21789544 TI - Beta-actin is a target for transglutaminase activity at synaptic endings in chicken telencephalic cell cultures. AB - Transglutaminases are Ca(2+)-dependent enzymes that catalyse the covalent cross linking of protein-bound glutamine and lysine residues, which can stabilise proteins or protein aggregates. In the brain, elevated expression levels and activity of transglutaminases are known to be linked with several neurodegenerative diseases. However, little is known about the physiological functions of transglutaminases in the central nervous system. In this study, we examined the expression and activity of transglutaminase 1 in chicken telencephalic cell cultures. We observed a cytosolic expression of transglutaminase 1 in telencephalic neurons. However, transglutaminase 1 activity was restricted to synaptic endings. Transglutaminase targets in the cultured cells were characterised via a biotinylation assay and beta-actin was identified as a substrate. Furthermore, we were able to show that beta-actin is a target for the activity of recombinant human transglutaminase 1 in vitro. We propose a mechanism where neuronal transglutaminase 1 is activated by synaptic activity dependent influx of calcium ions and thereupon catalyse the formation of an intramolecular cross-link in beta-actin, thereby stabilising the actin cytoskeleton against depolymerising effects. In this way, transglutaminase 1 could modulate actin-dependent plasticity events at synaptic endings. PMID- 21789546 TI - Some productive characteristics and body measurements of Norduz goats of Turkey. AB - Productive characteristics and body measurements of Norduz goats, a native genetic resource in Turkey, were measured. The animals studied were brought from natural habitats to the farm of the Animal Science Department of Agricultural Faculty, Yuzuncu Yil University. Least squares means of withers height (WH), body length (BL), chest width at back of withers (CWBW), chest depth (CD), chest girth (CG) and leg girth (LG) of Norduz does were 65.9 +/- 1.08, 67.2 +/- 1.08, 21.1 +/ 0.88, 30.8 +/- 0.62, 88.9 +/- 1.78 and 60.4 +/- 1.28 cm, respectively. Least squares means of body weights after parturition of does were 41.3 +/- 2.01 kg. The means of lactation length and lactation milk yield were 226. +/- 7.2 days and 347 +/- 40.1, respectively. Twinning rate, fertility, fecundity, litter size and litter size at weaning were 30%, 98%, 1.27, 1.30 and 1.28, respectively. Means of WH, BL, CWBW, CD, CG, LG and body weights of Norduz bucks were 73.9 +/- 2.61, 75.6 +/- 2.23, 21.4 +/- 0.67, 33.9 +/- 1.15, 95.0 +/- 2.34, 69.8 +/- 2.69 cm and 58.7 +/- 3.91 kg, respectively. PMID- 21789545 TI - Changes in lipid-sensitive two-pore domain potassium channel TREK-1 expression and its involvement in astrogliosis following cerebral ischemia in rats. AB - Astrocytes play an active and important role in the pathophysiology of cerebral ischemia. We have previously shown that mature hipppocampal astrocytes functionally express two-pore domain K(+) channel TREK-1, which significantly contributes to the passive conductance and help to set the negative resting membrane potential essential for the optimal operation of some astrocytic homeostatic functions. However, its expression under ischemic conditions remains to be determined. In this study, we examined the expression of TREK-1 in rat brain under physiological and focal ischemia conditions. The results show that TREK-1 was broadly expressed on astrocytes and neurons in the cortex, CA1 region of hippocampus. After middle cerebral artery occlusion induced focal ischemia, the TREK-1 expression was significantly increased at days 3, 7 and 30 following reperfusion, which correlated with reactive astrogliosis in the cortex and hippocampus. Cultured cortical astrocytes also express TREK-1. TREK-1 inhibitor quinine inhibited the proliferation of astrocytes exposed to hypoxia condition. These data provide evidence showing the astrocytic TREK-1 involvement in ischemia pathology. PMID- 21789547 TI - Bayesian estimates of genetic changes for body weight traits of Moghani sheep using Gibbs sampling. AB - The objective of the present study was to estimate genetic changes of body weight at different ages in Moghani sheep. Traits included were birth weight (BW, n = 4,208), 3-month weight (3MW, n = 4,175), 6-month weight (6MW, n = 3,138), 9-month weight (9MW, n = 2,244), and yearling weight (YW, n = 1,342). Data and pedigree information used in this study were collected at the Breeding Station of Moghani sheep during 1989-2005. The analysis was carried out for five traits, using the MTGSAM program. Breeding values of individual animals were obtained from a multivariate animal model analysis and genetic trends were obtained by regressing the means of predicted breeding values on year of birth for each trait. Direct genetic trends were positive and significant (P < 0.05) for BW, 3MW, 6MW, 9MW, and YW and were 1.63, 69.20, 79.38, 66.83, and 110.22 g/year, respectively. Also, maternal genetic trends for BW, 3MW, 6MW, 9MW, and YW were positive and significant (P < 0.05) and were 2.36, 49.18, 37.33, 17.73, and 9.67 g/year, respectively. The results showed that improvement of body weights of Moghani sheep seems feasible in selection programs. PMID- 21789548 TI - Assessment of cattle welfare at a commercial slaughter plant in the northwest of Mexico. AB - Slaughter plants have been undergoing radical transformations in recent years due to the need to increase efficiency and incorporate new technologies for the improvement of the infrastructure, animal welfare, and product quality. The aim of this study was to assess the cattle welfare status during the unloading, lairage, stunning, bleeding and quantify bruising incidence at a commercial slaughter plant in the northwest of Mexico. We monitored 8,118 cattle during the unloading, lairage, stunning, bleeding, and carcass bruise incidence. Our results showed that in the unloading stage, 2% of the cattle vocalized, 5% were prodded with an electric goad, and 4% either slipped or fell. In the lairage stage, 12% of the animals vocalized, 80% prodded with an electric goad, and 8% of the animals slipped or fell. In the stunning stage, 10% of the animals vocalized, 67% prodded with an electric goad, and 15% of the animals slipped or fell. Ninety five percent of the animals were stunned with a single shot, and 51% of the animals were effectively desensitized. Ninety-two percent of the carcasses had some type of bruise. Although the slaughter plant had adequate infrastructure and stringent operational standards, in all of the stages except unloading handling had an impact on the welfare of the animals being slaughtered. PMID- 21789549 TI - Electrical detection of dsDNA and polymerase chain reaction amplification. AB - Food-borne pathogens and food safety-related outbreaks have come to the forefront over recent years. Estimates on the annual cost of sicknesses, hospitalizations, and deaths run into the billions of dollars. There is a large body of research on detection of food-borne pathogens; however, the widely accepted current systems are limited by costly reagents, lengthy time to completion, and expensive equipment. Our aim is to develop a label-free method for determining a change in DNA concentration after a PCR assay. We first used impedance spectroscopy to characterize the change in concentration of purified DNA in deionized water within a microfluidic biochip. To adequately measure the change in DNA concentration in PCR solution, it was necessary to go through a purification and precipitation step to minimize the effects of primers, PCR reagents, and excess salts. It was then shown that the purification and precipitation of the fully amplified PCR reaction showed results similar to the control tests performed with DNA in deionized water. We believe that this work has brought label free electrical biosensors for PCR amplification one step closer to reality. PMID- 21789550 TI - Attraction of the redbay ambrosia beetle, Xyleborus glabratus, to avocado, lychee, and essential oil Lures. AB - The redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is an exotic wood boring insect that vectors the mycopathogen responsible for laurel wilt, a lethal vascular disease of trees in the Lauraceae. High mortality has occurred in native Persea species in the southeastern U.S., and the vector-pathogen complex poses an imminent threat to the production of commercial avocado, P. americana, in south Florida. There is a critical need for effective attractants to detect, monitor, and control this invasive pest. This study combined field tests and laboratory bioassays to evaluate the response of female X. glabratus to host-based volatiles from wood of avocado (cultivars of West Indian, Guatemalan, and Mexican races); from wood of lychee (Litchi chinensis, a presumed non-host that is high in the sesquiterpene alpha-copaene, a putative attractant); and to commercial lures containing manuka and phoebe oils, two reported attractive baits. Volatile collections and GC-MS analyses were performed to quantify the sesquiterpene content of test substrates. In the field, traps baited with lychee wood captured more beetles than those with wood from avocado cultivars; traps baited with phoebe oil lures captured more beetles than those with manuka oil lures (the current monitoring tool). In field and laboratory tests, X. glabratus did not show a preference among avocado races in either attraction or host acceptance (initiation of boring). In choice tests, lychee was more attractive than avocado initially, but a higher percentage of beetles bored into avocado, suggesting that lychee emits more powerful olfactory/visual cues, but that avocado contains more of the secondary cues necessary for host recognition. Emissions of alpha-copaene, beta-caryophyllene, and alpha-humulene were correlated with field captures, and lychee wood may be a source of additional semiochemicals for X. glabratus. PMID- 21789551 TI - Non-tropical chyluria: CT diagnosis. AB - Chyluria is commonly associated with filariasis, which is prevalent among the population of tropical and subtropical regions. Chyluria is seldom encountered in the United States and other western countries, but may occur if the flow of chyle into the thoracic duct is blocked due to inflammatory, neoplastic, or various other etiologies. We report 10 adult patients, in whom the detection of fat-urine level in their bladder on abdominal CT provided the initial diagnostic clue to the presence of chyluria. This series included 7 men and 3 women, who ranged in age from 25 to 91 years (mean: 62 years). The associated lesions included renal angiomyolipomas (2), lymphangiomas of the kidney and bladder (1), metastatic testicular cancer (1), postoperative status following partial nephrectomy for renal cell carcinoma (4), left radical nephrectomy (1), and segmental cystectomy for carcinomas (1). The clinical and radiological features of this entity are presented along with a brief review of the pertinent literature. PMID- 21789552 TI - Gastric cancer: imaging and staging with MDCT based on the 7th AJCC guidelines. AB - Gastric cancer is a common deadly cancer worldwide. The tumor-node-metastasis (TNM) staging system is one of the most commonly used staging systems, and is accepted and maintained by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). The TNM system is well known to effectively predict the prognosis of gastric cancer patients. The latest revision of TNM staging was presented in the 7th edition of the AJCC in 2009. Multi detector row CT (MDCT) is a powerful test for non-invasive evaluation and can assess metastatic and locoregional staging simultaneously. Current MDCT with isotropic imaging and 3D images has increased the accuracy of T and N staging in patients with gastric cancer. Multi-planar reformatted images permit the radiologist to select the optimal imaging plane to accurately evaluate tumor invasion depth of the gastric wall and perigastric infiltration to identify a fat plane between a tumor and adjacent organs, to avoid partial volume averaging effects, and to differentiate lymph nodes from small perigastric vessels. Thus, MDCT provides a useful all-in-one diagnostic method for the pre-operative evaluation of patients with known, or strongly suspected, gastric cancer according to the 7th AJCC TNM staging system. PMID- 21789553 TI - Cavernous vessels around a patent portal trunk in the liver hilum. AB - OBJECTIVES: Cavernous transformation of the portal vein (CTPV) is considered a sequel to extrahepatic portal vein obstruction. However, we have observed an unusual finding of cavernous vessels around a patent portal trunk in the liver hilum. The aim of our study is to describe the imaging features, clinical profiles, management, and outcome of these patients. MATERIAL AND METHODS: We re evaluated the images of all consecutive non-malignant and non-cirrhotic patients with a diagnosis of CTPV admitted to our department between July 2002 and June 2010. The patients with a patent portal trunk were enrolled in this study. RESULTS: A total of five patients had cavernous vessels around a patent portal trunk. Of them, all presented with abdominal distension, and one with recurrent variceal bleeding. Hepatomegaly and splenomegaly were found in one and four patients, respectively. All but one with previous splenectomy had a decreased platelet count. Three patients had a high level of alkaline phosphatase and/or gamma-glutamyl transferase. Serum bilirubin, albumin, and creatinine were in normal range. Endoscopy demonstrated varices in three patients. Mild ascites was detected in one patient by ultrasound. Conservative therapy was given to two patients with mild abdominal discomfort. Splenectomy or partial spleen embolization was given to two patients with hypersplenism. A transjugular intrahepatic portosystemic shunt insertion was performed in one patient for the prevention of recurrent variceal bleeding. All patients were alive during follow up. CONCLUSIONS: These unusual findings led us to believe that cavernous vessels could develop around a patent portal trunk. Further studies are necessary to explore its pathogenesis. PMID- 21789555 TI - Theory of mind in dogs?: examining method and concept. AB - In line with other research, Udell, Dorey, and Wynne's (in press) finding that dogs and wolves pass on some trials of a putative theory-of-mind test and fail on others is as informative about the methods and concepts of the research as about the subjects. This commentary expands on these points. The intertrial differences in the target article demonstrate how critical the choice of cues is in experimental design; the intersubject-group differences demonstrate how life histories can interact with experimental design. Even the best-designed theory-of mind tests have intractable logical problems. Finally, these and previous research results call for the introduction of an intermediate stage of ability, a rudimentary theory of mind, to describe subjects' performance. PMID- 21789556 TI - Announcement of awards by the Journal of Plant Research. PMID- 21789554 TI - Innate immune cells in breast cancer--from villains to heroes? AB - The innate immune system ensures effective protection against foreign pathogens and plays important roles in tissue remodeling. There are many types of innate immune cells, including monocytes, macrophages, dendritic cells, and granulocytes. Interestingly, these cells accumulate in most solid tumors, including those of the breast. There, they play a tumor-promoting role through secretion of growth and angiogenic factors, as well as immunosuppressive molecules. This is in strong contrast to the tumor-suppressing effects that innate immune cells exert in vitro upon proper activation. Therapeutic approaches have been developed with the aim of achieving similar suppressive activities in vivo. However, multiple factors in the tumor microenvironment, many of which are immunosuppressive, represent a major obstacle to effective treatment. Here, we discuss the potential of combating breast cancer through activation of the innate immune system, including possible strategies to enhance the success of immunotherapy. PMID- 21789557 TI - Fast loading ester fluorescent Ca2+ and pH indicators into pollen of Pyrus pyrifolia. AB - Loading of Ca(2+)-sensitive fluorescent probes into plant cells is an essential step to measure activities of free Ca(2+) ions in cytoplasm with a fluorescent imaging technique. Fluo-3 is one of the most suitable Ca(2+) indicators for CLSM. We loaded pollen with fluo-3/AM at three different temperatures. Fluo-3/AM was successfully loaded into pollen at both low (4 degrees C) and high (37 degrees C) temperatures. However, high loading temperature was best suited for pollen, because germination rate of pollen and growth of pollen tubes were relatively little impaired and loading time was shortened. Moreover, Ca(2+) distribution increased in the three apertures of pollen after hydration and showed a Ca(2+) gradient, similar to the tip of growing pollen tubes. The same protocol can be used with the AM-forms of other fluorescent dyes for effective labeling. When loading BCECF-AM into pollen at high temperature, the pollen did not show a pH gradient after hydration. Ca(2+) activities and fluxes had the same periodicity as pollen germination, but pH did not show the same phase and mostly lagged behind. However, the clear zone was alkaline when pollen tube growth was slowed or stopped and turned acidic when growth recovered. It is likely that apical pH(i) regulated pollen tube growth. PMID- 21789559 TI - Physical and mental health consequences of Katrina on Vietnamese immigrants in New Orleans: a pre- and post-disaster assessment. AB - We assessed the health impacts of a natural disaster upon a major immigrant community by comparing pre- and post-event measures for identical individuals. We collected standard health measures for a population-based sample of working-age Vietnamese-Americans living in New Orleans in 2005, just weeks before Katrina occurred. Near the first- and second-year anniversaries of the event, we located and re-assessed more than two-thirds of this original pre-Katrina cohort. We found statistically significant declines in health status for seven of the eight standard SF-36 subscales and for both the physical and mental health component summaries at the first anniversary of the disaster. By the second anniversary, recovery of the health dimensions assessed by these measures was substantial and significant. Most of the SF-36 mental and physical health subscales returned to their original pre-Katrina levels. Being in middle-age, being engaged in professional or self-employed occupations, being unmarried, being less acculturated, and having extensive post-Katrina property damage have statistically significant negative effects on post-Katrina health status, and several of these factors continued to impede recovery by the second anniversary. Hurricane Katrina had significant negative impacts on the mental and physical health of Vietnamese New Orleanians. Several factors present clear opportunities for targeted interventions. PMID- 21789558 TI - Mobility and HIV in Central America and Mexico: a critical review. AB - Mobility is a key determinant of HIV/sexually transmitted infection (STI) transmission dynamics in Asia and Africa. Scant data exist regarding its dynamic impacts on HIV/STI risk in Central America and Mexico. Our objective was to critically review the epidemiology and social and structural context of HIV/STI risk among mobile populations in Central America and Mexico. Eligible articles were published in English or Spanish between January 1, 2000 and August 31, 2010; conducted in Central America or Mexico; specified the mobile population included; and described primary research. 2045 records were screened, 275 articles reviewed, and 22 studies included. Mobility is associated with increased HIV risk behaviors, though it also may increase preventive behaviors. Among mobile groups in Central America and Mexico, social isolation, the socio-economic impacts of displacement, gender inequalities, and stigma/discrimination shape HIV risk. Epidemiologic research and multi-level interventions that target and engage vulnerable groups in transit stations are recommended. PMID- 21789560 TI - Exploratory study of the occupational health and health-seeking of migrant and seasonal farmworkers on the U.S.-Mexico border. AB - The U.S. migrant and seasonal farmworker (MSFW) workforce is aging. Aging causes functional changes that can affect work performance and increase injury/accident risk. It also has been linked with deferred health-seeking. The exploratory study was conducted to investigate occupational injuries and health-seeking in Hispanic MSFW on the U.S.-Mexico border. Data were collected using an abbreviated Spanish version of the California Agricultural Worker Health Survey. Nearly 60% of the 141 participants were middle-aged or older. Musculoskeletal injuries and those consistent with agrochemical and environmental exposures were common. Farmworkers aged >40 years were 2.5-5 times more likely than younger MSFW to report persistent single and multiple injuries involving the knees, shoulder, feet, and hands. Except for neck and back injuries, few received any medical treatment. Although many self-treated with traditional home remedies, few used CAM practitioners. The study findings highlight the multiple workplace health and health-seeking challenges faced by aging immigrant MSFW. PMID- 21789561 TI - Social support modifies the association between household food insecurity and depression among Latinos with uncontrolled type 2 diabetes. AB - Prevalence of depression is high among individuals with type 2 diabetes (T2D). The objective of the current study was to identify the socio-demographic, psychosocial, cultural, and clinical risk factors that predispose to depression, and resources that protect from depression among low income Latinos with T2D. Participants (N = 211) were interviewed in their homes upon enrollment. Multivariate logistic regression was used to identify factors associated with depressive symptoms based on a score of >=21 on the Center for Epidemiological Studies Depression scale. Lower household income, interference of diabetes with daily activities, and more T2D clinical symptoms were associated with depression risk in the multivariate analyses. At each level of food insecurity the risk of depression was lower the higher the level of social support (P < 0.05). Findings suggest that social support buffers against the negative influence of household food insecurity on depression risk. A comprehensive approach is necessary to address the mental health needs of low income Latinos with T2D. PMID- 21789562 TI - [With or without? The dilemma with protection]. PMID- 21789563 TI - [Anatomy of the liver. What does the radiologist need to know?]. AB - The liver is the largest unpaired parenchymatous organ in the human body and takes part in almost all important metabolic processes. Many patients show alterations of the whole organ due to vascular/cardiac disorders, metabolic or infectious diseases (congestion, fatty liver disease, fibrosis and cirrhosis). However the liver is also a common site for metastatic lesions of malignant tumors. Additionally, benign focal lesions, such as hemangioma or focal nodular hyperplasia (FNH) occur quite frequently. To describe and diagnose these lesions in terms of dignity and location, knowledge of the macroscopic structure and the relative position of the organ in relation to neighbouring organs are important as well as the histology. The microstructure of the liver and its vascular and biliary vessels are determined by the embryonic development and its function as a central metabolic organ. PMID- 21789564 TI - The coconut mite, Aceria guerreronis, in Benin and Tanzania: occurrence, damage and associated acarine fauna. AB - The coconut mite Aceria guerreronis (Eriophyidae) is considered the most important pest of coconut fruits in Africa; however, quantitative knowledge about its distribution and abundance is lacking. We conducted four diagnostic surveys three in Southern Benin and one along the coast of Tanzania-to determine the distribution of A. guerreronis and the severity of its damage to coconut fruits, as well as the diversity and abundance of other associated mites and potential natural enemies. Aceria guerreronis was found in all visited plantations with the percentage of damaged fruits varying considerably among plantations-67-85% in Benin and 43-81% in Tanzania. Overall, 30-40% of the fruit surfaces were damaged by A. guerreronis. Damage severity increased with fruit age and negatively affected fruit weight of 7- to 12-months-old fruits. Aceria guerreronis was by far the most abundant mite on coconut fruits but its abundance depended on fruit age. The highest densities of A. guerreronis were observed on 3- to 4-months-old fruits. Neocypholaelaps sp. (Ameroseiidae) was the most abundant mite on inflorescences. Three species of predatory mites (Phytoseiidae)-Neoseiulus baraki, N. neobaraki and N. paspalivorus-were the most commonly found predatory mites beneath the coconut bracts in association with A. guerreronis. Neoseiulus neobaraki was the prevailing predator in Tanzania while N. paspalivorus was the most frequent predator in Benin. Other mites found beneath the bracts were the herbivore Steneotarsonemus furcatus (Tarsonemidae) and the detritivore and fungivore Tyrophagus putrescentiae (Acaridae). PMID- 21789565 TI - Tyrosine inhibits creatine kinase activity in cerebral cortex of young rats. AB - Tyrosine accumulates in inborn errors of tyrosine catabolism, especially in tyrosinemia type II, where tyrosine levels are highly elevated in tissues and physiological fluids of affected patients. Tyrosinemia type II is a disorder of autosomal recessive inheritance characterized by neurological symptoms similar to those observed in patients with creatine deficiency syndromes. Considering that the mechanisms of brain damage in these disorders are poorly known, in the present study our main objective was to investigate the in vivo and in vitro effects of different concentrations and preincubation times of tyrosine on cytosolic and mitochondrial creatine kinase activities of the cerebral cortex from 14-day-old Wistar rats. The cytosolic CK was reduced by 15% at 1 mM and 32% at 2 mM tyrosine. Similarly, the mitochondrial CK was inhibited by 15% at 1 mM and 22% at 2 mM tyrosine. We observed that the inhibition caused by tyrosine was concentration-dependent and was prevented by reduced glutathione. Results also indicated that mitochondrial, but not cytosolic creatine kinase activity was inhibited by tyrosine in a time-dependent way. Finally, a single injection of L Tyrosine methyl ester administered i.p. decreased cytosolic (31%) and mitochondrial (18%) creatine kinase activities of brain cortex from rats. Considering that creatine kinase is an enzyme dependent of thiol residues for its function and tyrosine induces oxidative stress, the results suggest that the inhibition caused by tyrosine might occur by oxidation of essential sulfhydryl groups of the enzyme. In case this also occurs in patients with tyrosinemia, it is possible that creatine kinase inhibition may contribute to the neurological dysfunction characteristic of tyrosinemia. PMID- 21789566 TI - Effects of oxcarbazepine on monoamines content in hippocampus and head and body shakes and sleep patterns in kainic acid-treated rats. AB - The aim of this work was to analyze the effect of oxcarbazepine (OXC) on sleep patterns, "head and body shakes" and monoamine neurotransmitters level in a model of kainic-induced seizures. Adult Wistar rats were administered kainic acid (KA), OXC or OXC + KA. A polysomnographic study showed that KA induced animals to stay awake for the whole initial 10 h. OXC administration 30 min prior to KA diminished the effect of KA on the sleep parameters. As a measure of the effects of the drug treatments on behavior, head and body shakes were visually recorded for 4 h after administration of KA, OXC + KA or saline. The presence of OXC diminished the shakes frequency. 4 h after drug application, the hippocampus was dissected out, and the content of monoamines was analyzed. The presence of OXC still more increased serotonin, 5-hidroxyindole acetic acid, dopamine, and homovanilic acid, induced by KA. PMID- 21789568 TI - Protective effect of Withania somnifera and Cardiospermum halicacabum extracts against collagenolytic degradation of collagen. AB - The irreversible destruction of extracellular matrix (ECM) such as cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis and osteoarthritis by over-expression of matrix metalloproteinase (MMP) collagenases. We report herein the detailed study on the inhibitory effects of Withania somnifera extract (WSE) and Cardiospermum halicacabum extract (CHE) on Clostridium histolyticum collagenase (ChC) activity against the degradation of the ECM component of bovine Achilles tendon type I collagen by hydroxyproline assay method. Interaction of WSE and CHE with ChC exhibited 71% and 88% inhibition, respectively, to the collagenolytic activity of ChC against collagen degradation, and the inhibition was found to be concentration-dependent. The inhibition kinetics of ChC by both the extracts has been deduced from the extent of hydrolysis of N-[3-(2-furyl) acryloyl]-Leu-Gly-Pro-Ala. Both WSE and CHE are provided competitive and mixed type inhibition on ChC activity, respectively. Circular dichroism studies of ChC on treatment with WSE and CHE revealed changes in the secondary structure of collagenase. These results suggest that the WSE and CHE facilitated collagen stabilization through collagenase inhibition. PMID- 21789567 TI - Evaluation of respiratory chain activity in lymphocytes of patients with Alzheimer disease. AB - Alzheimer disease (AD) is a progressive neurodegenerative disease associated with cognitive impairment in multiple domains, such as memory and executive functions. Studies reveal damage in the electron transport chain of patients with AD, suggesting that this mitochondrial dysfunction plays an important role in the pathophysiology of the disease. Blood samples were taken from patients with AD (n = 20) and older subjects without dementia (n = 40) to evaluate the activity of complexes I, II, II-III, and IV of the mitochondrial respiratory chain in isolated lymphocytes. Results from the patient and control groups were compared. The activity of complexes II and IV was increased among patients compared to the control group. No significant difference was observed between controls who were not using psychotropic medication and patients. Our findings point out a mechanism of cellular compensation in which the mitochondrial respiratory chain requires an increase in electron transport to supply the energy needed for cellular functioning. Additional studies are needed to better clarify the mechanisms involved in the mitochondrial dynamics of AD. PMID- 21789569 TI - High production of beta-glucosidase by Aspergillus niger on corncob. AB - Using low-cost raw material is an effective approach for reducing the cost of cellulolytic enzymes. The farmland waste corncob was found in this study to be the best carbon source for the production of beta-glucosidase by Aspergillus niger. The maximum yield of beta-glucosidase activity was 48.7 IU ml(-1) by using 50 g l(-1) of corncob powder as the substrate. It was found that the water soluble components of the corncob could increase beta-glucosidase production significantly only when mixed with Avicel or wheat bran. The soluble components could not enhance the biomass and beta-glucosidase production when used alone. On the other hand, the water-insoluble components of the corncob still produced high level of beta-glucosidase (30 IU ml(-1)) although lower than that of using whole corncob. The results suggested that the water-insoluble components of corncob were beneficial for beta-glucosidase production. It was further demonstrated that the xylan in the water-insoluble parts of corncob was the important factor in producing beta-glucosidase by A. niger. PMID- 21789570 TI - Management of oculomotor nerve schwannomas in two different locations: surgical nuances and comprehensive review. AB - Rare tumors with anecdotal reportage, oculomotor schwannomas are most often seen in the oculomotor cistern close to the anterior clinoidal region. Adding to the small series of reported cases of this unusual lesion, we report two male patients in their second decade who presented with different degrees of oculomotor palsy. The location of the lesion was caverno-cisternal in one case and orbito-cavernous in the other. Intricate neurovascular relationships of this lesion, especially in non-cavernous locations, are discussed. The risk of damage to nerve rootlets enmeshed within the lesion is high with attempts at near-total excision, rendering the anatomical preservation of the nerve an arduous exercise. The authors review literature pertaining to this unusual lesion and elucidate surgical nuances which may have a bearing on outcome. PMID- 21789572 TI - Aneurysms associated with non-moyamoya collateral arterial networks: report of three cases and review of literature. PMID- 21789571 TI - Bow-hunter's syndrome caused by dynamic vertebral artery stenosis at the cranio cervical junction--a management algorithm based on a systematic review and a clinical series. AB - Bow hunter's syndrome (BHS) is defined as symptomatic, vertebro-basilar insufficiency caused by mechanical occlusion of the vertebral artery (VA) at the atlanto-axial level during head rotation. In the literature, about 40 cases have been reported. However, due to the rarity of this pathology, there are no guidelines for diagnosis and treatment. Conservative, surgical, and endovascular concepts have been proposed. In order to work out an algorithm, we performed a systematic review of the literature and a retrospective analysis of patients, which have been treated in our institutions over the last decade. The clinical series was comprised of five patients. The symptoms ranged from transient vertigo to posterior circulation stroke. Diagnosis was established by dynamic angiography. In all patients, the VA was decompressed; one patient required additional fusion. The clinical and radiological results were good, and the treatment-related morbidity was low. The literature review demonstrated that Bow hunter's syndrome is a rare pathology but associated with a pathognomonic and serious clinical presentation. The gold standard of diagnosis is dynamic angiography, and patients were well managed with tailored vertebral artery decompression. By this management, clinical and radiological results were excellent and the treatment-related morbidity was low. PMID- 21789573 TI - The JUPITER trial: myth or reality? AB - The JUPITER trial is widely hailed as a landmark trial that has the potential to dramatically change the landscape of primary prevention of cardiovascular disease. Like most trials, however, it is not without its limitations. We address some of the common myths and misunderstandings that are underscored by the JUPITER trial. First, by its intentional and ill-advised exclusion of patients with low levels of high-sensitivity C-reactive protein (hsCRP), it is not possible to assess whether baseline hsCRP modifies treatment response to statins or whether it identifies patients most likely to benefit from statin therapy. Second, by stopping the trial early, one cannot rule out the possibility that the treatment benefit was overestimated and risk was underestimated, thereby precluding a reliable estimate of benefit/risk. Finally, as a consequence of early stopping, it is not possible to reliably assess the cost-effectiveness of primary prevention with rosuvastatin. Given these limitations, the attendant societal health policy implications remain largely unknown. PMID- 21789574 TI - Genetics of sudden cardiac death. AB - Advances in genetic testing technology have led to a proliferation of new genetic tests and accelerated developments in the field of cardiovascular genetic medicine. These advances enhance presymptomatic diagnosis and can establish a definitive molecular diagnosis for symptomatic patients at risk for sudden cardiac death. Most importantly, genotype-phenotype correlations can add important information for predicting outcome and selecting treatment for patients with inherited arrhythmic disorders. This paper reviews the current data regarding genotype-phenotype correlations and the role of clinical genetic testing in diagnosis, prognosis, and management of inheritable disorders leading to sudden cardiac death. PMID- 21789575 TI - New paradigms in the prevention of sudden cardiac arrest and heart failure treatment. AB - Congestive heart failure is a very real public health issue not only in the United States, but worldwide. Mortality in patients with congestive heart failure is typically either sudden cardiac death or pump failure. Paradoxically, patients with less severe heart failure are at higher relative risk of sudden cardiac death. Defining which patients are best treated with implantable defibrillators and resynchronization is the purpose of this review. PMID- 21789576 TI - Modified micro-superior percutaneously-assisted total hip: early experiences & case reports. AB - Because of the extensile nature and familiarity of the standard posterior-lateral approach to the hip, a family of "micro-posterior" approaches has been developed. This family includes the Percutaneously-Assisted Total Hip (PATH) approach, the Supercapsular (SuperCap) approach and a newer hybrid approach, the Supercapsular Percutaneously-Assisted Total Hip (SuperPATH) approach. Such approaches should ideally provide a continuum for the surgeon: from a "micro" (external rotator sparing) posterior approach, to a "mini" (external rotator sacrificing) posterior approach, to a standard posterior approach. This could keep a surgeon within his comfort zone during the learning curve of the procedure, while leaving options for complicated reconstructions for the more practiced micro-posterior surgeons. This paper details one author's experiences utilizing this combined approach, as well as permutations of this entire micro-posterior family of approaches as applied to more complex hip reconstructions. PMID- 21789577 TI - Severe asthma with fungal sensitization. AB - A new phenotype of asthma has been described recently, namely severe asthma with fungal sensitization (SAFS). SAFS can be conceptualized as a continuum of fungal sensitization, with asthma at one end and allergic bronchopulmonary aspergillosis at the other. It is diagnosed by the presence of severe asthma, fungal sensitization, and exclusion of allergic bronchopulmonary aspergillosis. Because of the paucity of data and ambiguity in diagnostic criteria, SAFS is currently more of a diagnosis of exclusion than a specific entity. Treatment of SAFS initially should be similar to that of severe asthma, including the use of omalizumab. The potential role of itraconazole as a specific therapy in SAFS requires more evidence before it can be incorporated in routine practice. An urgent need exists for data regarding the prevalence, natural history, and clinical relevance of SAFS so that its exact characterization and importance as a specific subtype of asthma can be clearly defined. This review summarizes the current understanding of the pathogenesis, diagnosis, and management of SAFS. PMID- 21789578 TI - Methamphetamine induces endoplasmic reticulum stress related gene CHOP/Gadd153/ddit3 in dopaminergic cells. AB - We examined the toxicity of methamphetamine and dopamine in CATH.a cells, which were derived from mouse dopamine-producing neural cells in the central nervous system. Use of the quantitative real-time polymerase chain reaction revealed that transcripts of the endoplasmic reticulum stress related gene (CHOP/Gadd153/ddit3) were considerably induced at 24-48 h after methamphetamine administration (but only under apoptotic conditions), whereas dopamine slightly induced CHOP/Gadd153/ddit3 transcripts at an early stage. We also found that dopamine and methamphetamine weakly induced transcripts for the glucose-regulated protein 78 gene (Grp78/Bip) at the early stage. Analysis by immunofluorescence microscopy demonstrated an increase of CHOP/Gadd153/ddit3 and Grp78/Bip proteins at 24 h after methamphetamine administration. Treatment of CATH.a cells with methamphetamine caused a re-distribution of dopamine inside the cells, which mimicked the presynaptic activity of neurons with cell bodies located in the ventral tegmental area or the substantia nigra. Thus, we have demonstrated the existence of endoplasmic reticulum stress in a model of presynaptic dopaminergic neurons for the first time. Together with the recent evidence suggesting the importance of presynaptic toxicity, our findings provide new insights into the mechanisms of dopamine toxicity, which might represent one of the most important mechanisms of methamphetamine toxicity and addiction. PMID- 21789579 TI - Inflammatory phase of bone healing initiates the regenerative healing cascade. AB - Bone healing commences with an inflammatory reaction which initiates the regenerative healing process leading in the end to reconstitution of bone. An unbalanced immune reaction during this early bone healing phase is hypothesized to disturb the healing cascade in a way that delays bone healing and jeopardizes the successful healing outcome. The immune cell composition and expression pattern of angiogenic factors were investigated in a sheep bone osteotomy model and compared to a mechanically-induced impaired/delayed bone healing group. In the impaired/delayed healing group, significantly higher T cell percentages were present in the bone hematoma and the bone marrow adjacent to the osteotomy gap when compared to the normal healing group. This was mirrored in the higher cytotoxic T cell percentage detected under delayed bone healing conditions indicating longer pro-inflammatory processes. The highly activated periosteum adjourning the osteotomy gap showed lower expression of hematopoietic stem cell markers and angiogenic factors such as heme oxygenase and vascular endothelial growth factor. This indicates a deferred revascularization of the injured area due to ongoing pro-inflammatory processes in the delayed healing group. Results from this study suggest that there are unfavorable immune cells and factors participating in the initial healing phase. In conclusion, identifying beneficial aspects may lead to promising therapeutical approaches that might benefit further by eliminating the unfavorable factors. PMID- 21789580 TI - Molecular characterization and expression pattern of an odorant receptor from the myiasis-causing blowfly, Lucilia sericata (Diptera: Calliphoridae). AB - The blowfly Lucilia sericata (Diptera: Calliphoridae) is a facultative ectoparasite that causes myiasis in both man and animals, leading to serious human health problems and economic losses in the livestock industry. Like other insects, olfaction of this species plays an important role in host location and is presumably mediated by a seven transmembrane receptor family. Here, we isolate and characterize LserOR1, which is the first candidate member of the odorant receptor gene family from L. sericata. LserOR1 displayed high amino acid conservation with previously identified Or83b orthologs from different insect species. The transcripts of LserOR1 were detected in the major olfactory organs including the antennae and maxillary palps, as well as in traditionally non olfactory tissues such as the legs and female ovipositors. In developmental studies, a quantitative real-time PCR assay was developed and validated for determining the relative expression levels of LserOR1 during several stages. In contrast to its extremely high expression in the adult stage, LserOR1 expression was at the lowest level during the egg stage, and then increased to a peak through the first two larval stages before declining in the third-instar stage. These results suggest that a broadly expressed LserOR1 receptor is likely to be essential for olfactory sensory processes throughout the lifetime of L. sericata. The present study provides the information that may aid in the development of novel blowfly repellents using olfactory proteins as molecular targets. PMID- 21789581 TI - Ultramorphological characteristics of immature stages of a forensically important fly Parasarcophaga ruficornis (Fabricius) (Diptera: Sarcophagidae). AB - Ultrastructure of all larval instars and puparium of Parasarcophaga ruficornis, a common flesh fly species in India, is presented using light microscopy and scanning electron microscopy for the first time. The principal diagnostic characters, i.e. the cephalopharyngeal apparatus, the cephalic segment, structure and orientation of spines, pupal respiratory horns, the structures of both anterior and posterior spiracles are illustrated and discussed. Information presented herein can be useful during forensic investigations involving this fly species. PMID- 21789582 TI - Phylogenetic characterization of a microsporidium (Endoreticulatus sp. Zhenjiang) isolated from the silkworm, Bombyx mori. AB - This study examined the morphological and molecular characteristics of the microsporidium Endoreticulatus sp. Zhenjiang, isolated from the silkworm (Bombyx mori). The fresh spores were oval, 2.9 +/- 0.2 MUm in length and 1.2 +/- 0.2 MUm in width. The complete rRNA cistron has a length of 4,432 bp (GenBank accession no. FJ772431), including the large subunit rRNA (2,460 bp), the internal transcribed spacer (187 bp), the small subunit rRNA (1,254 bp), the intergenic spacer (276 bp), and the 5S region (115 bp). The organization of the rRNA gene is 5'-LSU-ITS-SSU-IGS-5S-3', which is reverse compared to the organization of most microsporidian rRNA regions. Phylogenetic analysis based on small subunit rRNA sequences showed that this isolate belongs to the genus Endoreticulatus, and is closely related to Glugoides intestinalis. Furthermore, both had a similar reverse arrangement of the rRNA gene. Our study provides another example of a microsporidian species with a novel organization of rRNA genes, demonstrating that the reverse arrangement is exhibited not only by the microsporidian genus Nosema but may also occur in a clade that contains the genera Endoreticulatus and Glugoides. PMID- 21789583 TI - Acaricidal efficacy of synthesized silver nanoparticles using aqueous leaf extract of Ocimum canum against Hyalomma anatolicum anatolicum and Hyalomma marginatum isaaci (Acari: Ixodidae). AB - The use of acaricides had limited efficacy in reducing tick infestations and is often accompanied by serious drawbacks, including the selection of acaricide resistant ticks, contamination of environment, and milk and meat products with drug residues. The present study was based on assessments of the antiparasitic activities to determine the efficacy of synthesized silver nanoparticles (AgNPs) utilizing aqueous leaf extract of Ocimum canum Sims (Labiatae) against the larvae of Hyalomma anatolicum (a.) anatolicum Koch, 1844 and Hyalomma marginatum (m.) isaaci Sharif, 1928 (Acari: Ixodidae). The synthesized AgNPs results were recorded from UV-vis spectrum, X-ray diffraction (XRD) analysis, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) analysis. The production of the AgNPs synthesized from the leaf extract of O. canum was evaluated through UV-visible spectrophotometer in a range of wavelength from 300 to 600 nm. This revealed a peak at 426 nm in leaf extracts of O. canum, indicating the production of AgNPs. The XRD spectrum compared with the standard confirmed spectrum of silver particles formed in the present experiments were in the form of nanocrystals, as evidenced by the peaks at 2theta values of 27.71 degrees , 32.16 degrees , 38.08 degrees , 46.15 degrees , 54.70 degrees and 57.35 degrees . The FTIR spectra of AgNPs exhibited prominent peaks at 818, 1,045, 1,381 and 1,616 in the region 500 3,000 cm(-1). The peaks correspond to the presence of a C-H vibration of the aromatic ring, stretch vibration of C-O, carbonyl groups and flavanones. SEM analyses of the synthesized AgNPs were clearly distinguishable, which measured 25 110 nm in size. It is clear that the rod and cylindrical structures have an average size of 95 nm. The EDX spectra showed the purity of the material and the complete chemical composition of the synthesized AgNPs. Parasite larvae were exposed to varying concentrations of aqueous leaf extract of O. canum and synthesized AgNPs for 24 h. The acaricidal activities of aqueous crude leaf extracts of O. canum against the larvae of H. a. anatolicum and H. m. isaaci have LC(50) and LC(90) values of 15.31 and 13.85 mg/L, and 62.41 and 48.86 mg/L, respectively. The efficacies of 1 mM AgNO(3) solution against H. a. anatolicum and H. m. isaaci were LC(50) = 12.25 and 12.17 mg/L, LC(90) = 49.17 and 46.52 mg/L, respectively, and the maximum efficacy was observed in the synthesized AgNPs against H. a. anatolicum and H. m. isaaci with LC(50) and LC(90) values of 0.78 and 1.00 mg/L, and 1.51 and 1.68 mg/L, respectively. This method is considered as an innovative alternative approach to control parasites. PMID- 21789584 TI - Anthelmintic effect of a methanol extract of leaves of Dregea volubilis on Paramphistomum explanatum. AB - Dregea volubilis (family Asclepediaceae) is widely used as anthelmintic in traditional system of medicine in eastern and southern part of India. The aim of this study was to evaluate the anthelmintic activity of the methanol extract of D. volubilis leaves (MEDV) and to observe its effect through SEM study. Live parasites (trematode Paramphistomum explanatum) were collected from buffalo in 0.9% phosphate-buffered saline (PBS). It was incubated at 37 +/- 1 degrees C in media containing either no extract (control), the test drug, MEDV at four dose levels (10, 25, 50, and 100 mg/ml) or the standard drug, albendazole, at a dose of 10 mg/ml. The effectiveness of the extract was judged on the basis of the loss of spontaneous movement and/or complete destruction or death of the trematodes. After being removed from the experimental medium, trematodes were dipped in PBS at 37 +/- 1 degrees C and on gentle stimulation, the paralyzed parasite showed immobility. Death was confirmed when it completely lost its motility even when vigorously shaken or dipped in warm water (50 degrees C). The trematodes, both drug treated and others, were further processed for SEM study using standard method. The anthelmintic activity was found with all the doses through paralysis and death of the organisms (p < 0.001). Maximum anthelmintic activity was found with a dose of 100 mg/ml. Minor damage was observed with both suckers, but severe distortion was found with tegumental surface of the treated trematodes. The present SEM-based study established the anthelmintic activity of MEDV. PMID- 21789585 TI - Resistance of Trichostrongylus spp. (Nematoda) to benzimidazole in Algerian cattle herds grazed with sheep. AB - Drug resistance in cattle strongyles to anthelmintics is rarely described in Europe and in the Mediterranean areas. The faecal egg counts are usually low in cattle, and detection of resistance may be particularly difficult. We used the method of twice-repeated treatments and used various estimations of efficacies in order to detect cattle strongyle resistance to benzimidazoles. Resistance was found in two farms among eight that were studied. Trichostrongylus axei was the resistant species in one farm whereas Trichostrongylus sp. was found in another farm. In both farms, there were sheep flocks with a history of strongyle benzimidazole resistance and practice of alternate or mixed grazing with cattle. PMID- 21789586 TI - Antitrypanosomal activity of some medicinal plants from Nigerian ethnomedicine. AB - Human African trypanosomiasis is a neglected tropical disease with complex clinical presentation, diagnosis, and difficult treatment. The available drugs for the treatment of trypanosomiasis are old, expensive, and less effective, associated with severe adverse reactions and face the problem of drug resistance. This situation underlines the urgent need for the development of new, effective, cheap, and safe drugs for the treatment of trypanosomiasis. The search for new antitrypanosomal agents in this study is based on ethnomedicine. In vitro antitrypanosomal activity of 36 plant extracts from 10 plant species from Nigerian ethnomedicine was evaluated against bloodstream forms of Trypanosoma brucei rhodesiense STIB 900. Cytotoxic activity was determined against mammalian L6 cells. Alamar blue assay was used to measure the endpoint of both antitrypanosomal and toxicity assays. The ethyl acetate extract of leaves of Ocimum gratissimum Linn. (Labiatae) showed the highest antitrypanosomal activity (IC(50) of 2.08 +/- 0.01 MUg/ml) and a high selective index of 29. Furthermore, the hexane, ethyl acetate, or methanol extracts of Trema orientalis (L.) Blume (Ulmaceae), Pericopsis laxiflora (Benth. ex Baker) Meeuwen, Jatropha curcas Linn. (Euphorbiaceae), Terminalia catappa Linn. (Combretaceae), and Vitex doniana Sweet (Verbenaceae) displayed remarkable antitrypanosomal activity (IC(50) 2.1-17.2 MUg/ml) with high selectivity indices (20-80) for trypanosomes. The antitrypanosomal activity of T. catappa and T. orientalis against T. brucei rhodesiense (STIB 900) is being reported for the first time in Nigerian ethnomedicine, and these plants could be a potential source of antitrypanosomal agents. PMID- 21789587 TI - Physician endorsement alone may not enhance question-asking by advanced cancer patients during consultations about palliative care. AB - PURPOSE: This study aimed to explore the effect of physician endorsement of question-asking on advanced cancer patients' question-asking behaviour during consultations about palliative care and to explore other potential predictors of patient question-asking. METHODS: Data were obtained from 80 control group patients from a randomised controlled trial of standard palliative care (PC) consultation (control group) versus provision of a question prompt list (QPL) before the consultation. Consecutive eligible patients with advanced cancer referred to 15 PC physicians from nine Australian PC centres participated. Baseline measures were obtained from patients; consultations were audiotaped, transcribed and analysed by blinded coders; and physicians estimated the patients' survival. RESULTS: Endorsement of question-asking by the physician was not related to the number of patient questions. Patients with the highest anxiety levels asked 3.5 times as many questions as those with least anxiety (incidence rate ratio (IRR) = 3.54, 95% confidence interval (CI) 1.90-6.59, P = 0.001). After allowing for the effect of anxiety, patients with an estimated survival of >12 weeks asked 76% more questions (IRR = 1.76, 95% CI 1.03-3.00, P = 0.04), whereas age, sex, educational background, occupation, information and involvement preferences and presence of a caregiver were not related to patient question asking behaviour. CONCLUSION: Physician endorsement of question-asking alone does not appear to increase questions by advanced cancer patients during consultations about PC. Additional resources such as QPLs may be needed to facilitate patient question-asking. PMID- 21789588 TI - Surgical treatment of rare cauda equina tumours. AB - BACKGROUND: Cauda equina tumours (CET) are rare and usually benign. Treatment of schwannomas and benign ependymomas, which are the most frequent histopathological types of CET, is now well established. However, management of other presumed histopathological types of CET is still a matter of debate. The aim of this study was to assess the incidence and the surgical treatment of rare CET. METHOD: A retrospective study was carried out on 176 adult patients surgically treated for CET in our two departments from 1994 to 2010. We reviewed pre- and postoperative symptoms, magnetic resonance imaging aspects, surgical findings, outcome including operative neurological morbidity, local recurrence rate and operative mortality, and incidence of rare CET. FINDINGS: Seventeen percent (30 patients) of CETs operated on were neither schwannomas nor benign ependymomas. Half of these cases were benign tumours, with paragangliomas being the most common. Two patients were in poorer clinical condition after surgery, one patient experienced a local recurrence, and one died following surgery, from the progress of his disease (Von Hippel-Lindau disease). The other half were malignant tumours, with metastases being the most common. One third of the patients were worsened by surgery, and the mortality rate was 1/3 at 8 months (1-27 months). CONCLUSIONS: Roughly one in six CET were neither schwannomas nor benign ependymomas. This study demonstrated the efficiency of surgery for rare benign CET with a low local recurrence rate. Surgical treatment of rare malignant CET led to a high rate of increased postoperative neurological deficit in patients with a reduced life expectancy. PMID- 21789589 TI - Sensate composite calcaneal flap in leg amputation: a full terminal weight bearing surface-experience in eight adult patients. AB - Despite modern reconstruction techniques and replantation, the preservation of a severely traumatised limb, or even a limb affected by a congenital malformation, usually gives poorer functional results compared with amputation and prosthetisation. The aim of this study was to describe a hind foot (including the calcaneum and fat pad) sensate flap with a surface that allows full terminal weight bearing in transtibial amputations in adults. Between June 2007 and September 2008, eight patients underwent leg amputations with a sensate composite calcaneal flap reconstruction of the stump. Patients consisted of four men and four women with a mean age of 46.5 (26-66) years. All amputations were unilateral. The mean follow-up was 28.3 (25-42) months. There were no complications. Calcaneum tibial fusion was observed in all patients in a mean time of 3.5 (3-4) months. A below-knee prosthesis was adapted at 16 weeks postoperatively in all cases, and no need for stump revision occurred in this series during the entire follow-up period. A transtibial amputation covered with a sensate plantar flap preserving the calcaneum was proposed. In theory, the anatomic structures spared in this technique provide a strong, full, weight bearing terminal surface of the stump that will last a lifetime. PMID- 21789590 TI - Comparison of two all-in-one adhesives bonded to non-carious cervical lesions- results at 3 years. AB - The aim of this study was to evaluate the clinical performance of S(3) Bond (Kuraray Corp., Japan) and G-Bond (GC Corp., Japan) all-in-one bonding agents, over 3 years in non-carious cervical lesions (NCCLs). Ethics Committee approval was obtained, and 60 restorations were placed in 11 patients aged 45-84 years (mean 60.5 years), using either Clearfil ST resin composite (Kuraray) and S(3) Bond or Gradia resin composite (GC) and G-Bond alternately, without phosphoric acid etch on the uncut enamel margins. Patients were recalled at 6 months, 1 year, 2 years and 3 years, and photographs were taken for assessment of colour match and marginal discoloration. One patient was not available at 3 years, resulting in 54 restorations being available for evaluation. One restoration of S(3)/Clearfil ST was lost at 2 years, giving retention rates of 97% for S(3) and 100% for G-Bond. At 3 years, six restorations for S(3)/Clearfil ST showed slight marginal discoloration and one restoration pronounced marginal staining. For G Bond/Gradia at 3 years, 11 restorations exhibited slight marginal staining and one restoration pronounced marginal staining. Most restorations were bonded to sclerotic dentin. Statistical analysis of marginal staining showed no significant difference between the two restoration groups. The degree of marginal staining was almost identical for both materials and tended to be in larger restorations. Both S(3) and G-Bond all-in-one bonding systems appear to be good adhesives for the restoration of NCCL for the length of the current study. Restoration of NCCLs with the newer all-in-one adhesives appears to be a viable alternative technique to more complicated adhesive materials. PMID- 21789591 TI - Clinical success of implant-supported and tooth-implant-supported double crown retained dentures. AB - The objective of this retrospective study was to compare biological and technical complications of implant-supported and tooth-implant-supported double crown retained dentures (DCRDs) with those of tooth-supported DCRDs. Sixty-three DCRDs were monitored. One study group included 16 prostheses with a combination of implants and natural teeth as double crowns (ti group), whereas in the second study group, 19 dentures were retained exclusively on implants (ii group); a third study group with 28 exclusively tooth-supported dentures served as controls (tt group). Tooth loss, implant failure, and technical complications (loss of retention of primary crown, abutment screw loosening, loss of facing, fracture of resin denture teeth and fracture of saddle resin) were analysed. During the observation period of 24 months, no implants or teeth were lost in the ti group and three technical complications were recorded. In the ii group, two implants were lost, two cases of peri-implantitis occurred and four technical complications were observed. In the tt group, two cases of tooth loss and seven technical complications were observed. At the time of the last examination, all prostheses of the ti group and the ii group were functional. Patients of these two study groups reported high satisfaction with both function and aesthetics with no significant difference between the two groups. Treatment with DCRDs showed comparable results in the three study groups. The 2-year results indicate that double crowns can be recommended for implant and combined tooth-implant retained dentures. PMID- 21789592 TI - Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity. AB - Despite its potent immunostimulatory properties, vaccination with autologous tumor-derived gp96 has relatively modest antitumor effect in a range of clinical trials. Based on our previous study showing a gp96-mediated immune balance between CTL and Tregs, here we investigated possible synergy between gp96 vaccine and systemic Treg depletion on induction of antitumor T-cell immunity and the mechanisms accounting for synergistic efficacy. In gp96-peptide complex immunized BALB/c mice, anti-CD25 mAb treatment significantly increased IFN-gamma-producing CD8(+) and CD4(+) T cells by about 1-2-fold in spleen and 40-50% in lymph node. A significantly higher number of peptide-specific CTL were observed under anti-CD25 mAb treatment compared with no treatment. Moreover, Treg depletion synergistically improved the anticancer activity of tumor-derived gp96 vaccine in the poorly immunogenic and highly tumorigenic B16 melanoma model in C57BL/6 J mice. While gp96 immunization alone led to the modest enhancement of CTL activities in spleen, the combination with Treg depletion dramatically increased tumor-specific CTL responses. In addition, the combination resulted in a significant increase of CD8(+) T-cell infiltration in tumor, which correlated with an enhanced inhibition of tumor growth. Our results provide evidence that targeting Tregs may provide a more efficient strategy to potentiate gp96-mediated T-cell responses and enhance the antitumor efficiency of gp96-based therapeutic vaccine. PMID- 21789594 TI - Lung cancer and Toll-like receptors. AB - Lung carcinoma is one of the leading causes of death worldwide. It is a non immunogenic cancer, resistant to immune surveillance. Toll-like receptors (TLRs) connect the innate to the adaptive immune system. Given that cancerous cells evade the immune system, the activation of TLRs could represent a potential target for cancer therapy. The induction of Th1-like and cytotoxic immunity by TLR signalling could lead to tumour cell death, resulting in tumour regression or arrest. However, basic research and clinical trials revealed that the activation of specific TLRs, such as TLR2, TLR4 and TLR9, do not have any anti-tumour activity in lung carcinoma. Increasing evidence suggests that TLRs are important regulators of tumour biology; however, little is known about their function in lung cancer. Thus, in order to develop new therapeutic approaches, further studies are needed to understand the connection between TLRs and lung cancer progression. This review focuses on the potential mechanisms by which TLR ligands can facilitate or not lung cancer and lung metastases establishment/progression. PMID- 21789593 TI - Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses. AB - Previous studies from our laboratory indicate that intratumoral (i.t.) injections of CpG-ODN are the most effective adjuvant strategy to induce an antitumor immune response in tolerant BALB-neuT mice but insufficient for tumor eradication. We evaluated whether this treatment strategy could be enhanced by the presence of anti-OX40 and anti-4-1BB antibodies. Treatment with anti-4-1BB resulted in a greater antitumor response than anti-OX40. The results indicate that anti-4-1BB but not anti-OX40 inhibited the suppressive function of T regulatory cells (Tregs). Through microarray analysis we evaluated the mechanism by which anti-4 1BB inhibits iTregs using the Foxp3-GFP mice. We observed specific transcriptional differences in over 100 genes in iTregs treated with anti-4-1BB, and selected those genes that remained unaffected by exposure to anti-OX40. Interleukin 9 was transcriptionally down-regulated 28-fold by anti-4-1BB treatment, and this was matched by a significant reduction of IL-9 secretion by iTregs. Furthermore, blockade of the common gamma-chain receptor resulted in the inhibition of iTreg-suppressive function. More importantly, neutralization of IL 9 plus i.t. injections of CpG-ODN induces tumor rejection in BALB-neuT and MUC-1 tolerant transgenic mice. These results indicate that IL-9 plays a role in iTreg biology during the tumor inflammatory process enhancing/promoting the suppressive function of these cells and that the blockade of IL-9 could serve as a novel strategy to modulate the function of Tregs to enhance the antitumor effect of tumor vaccines. PMID- 21789595 TI - Molecular and biochemical characterization of the Mexican axolotl CD3 (CD3epsilon and CD3gamma/delta). AB - In mammals, the T-cell receptor (TCR) complex expressed on mature T-cells consists of alpha/beta or gamma/delta clonotypic heterodimers non-covalently associated with four invariant chains forming the CD3 complex (CD3gamma, CD3delta, CD3epsilon and CD3zeta). The TCR is the unit implicated in the antigenic peptide recognition whereas the CD3 subunits present as three different dimers (delta-epsilon, gamma-epsilon and zeta-zeta) in the receptor complex participate to the signal transduction and are indispensable for the expression of the TCR at the cell surface. We report the cloning, characterization and expression analysis of CD3gamma/delta and CD3epsilon genes in an amphibian urodele, the Mexican axolotl. Amino acid comparisons show that important motifs and residues were preserved between the axolotl CD3 chains and various vertebrate CD3epsilon, CD3gamma, CD3delta and CD3gamma/delta chains. During ontogeny, CD3epsilon transcripts are first detected in the dorsal region of tail-bud embryos before thymus organogenesis. CD3gamma/delta transcripts are first detected in the head of 4-week-old larvae. A cross-reactive polyclonal anti CD3epsilon antibody was used for the co-immunoprecipitation of the two CD3 proteins of 25 and 29 kDa, respectively, associated with the 90-kDa alphabeta TCR heterodimer. PMID- 21789596 TI - Divergent human populations show extensive shared IGK rearrangements in peripheral blood B cells. AB - We have analysed the transcribed immunoglobulin kappa (IGK) repertoire of peripheral blood B cells from four individuals from two genetically distinct populations, Papua New Guinean and Australian, using high-throughput DNA sequencing. The depth of sequencing data for each individual averaged 5,548 high quality IGK reads, and permitted genotyping of the inferred IGKV and IGKJ germline gene segments for each individual. All individuals were homozygous at each IGKJ locus and had highly similar inferred IGKV genotypes. Preferential gene usage was seen at both the IGKV and IGKJ loci, but only IGKV segment usage varied significantly between individuals. Despite the differences in IGKV gene utilisation, the rearranged IGK repertoires showed extensive identity at the amino acid level. Public rearrangements (those shared by two or more individuals) made up 60.2% of the total sequenced IGK rearrangements. The total diversity of IGK rearrangements of each individual was estimated to range from just 340 to 549 unique amino acid sequences. Thus, the repertoire of unique expressed IGK rearrangements is dramatically less than previous theoretical estimates of IGK diversity, and the majority of expressed IGK rearrangements are likely to be extensively shared in individual human beings. PMID- 21789597 TI - Tunicatimonas pelagia gen. nov., sp. nov., a novel representative of the family Flammeovirgaceae isolated from a sea anemone by the differential growth screening method. AB - A Gram-negative, strictly aerobic, reddish-pink pigmented, non-motile, rod-shaped strain designated N5DB8-4(T), was isolated from an orange-striped sea anemone Diadumene lineata by a differential growth screening method. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the family Flammeovirgaceae of the phylum Bacteroidetes and that it showed highest sequence similarity (89.1%) to Porifericola rhodea N5EA6 3A2B(T). The strain could be differentiated phenotypically from recognized members of the family Flammeovirgaceae. The G+C content of the DNA is 52.6 mol%, the major respiratory quinone is menaquinone 7 (MK-7) and iso-C15:0, C16:1omega5c and iso-C15:1 G (the double-bond position indicated by capital letter is unknown) were the major fatty acids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain represents a novel taxon for which the name Tunicatimonas pelagia gen. nov., sp. nov. is proposed. The type strain of Tunicatimonas pelagia is N5DB8-4(T) (=KCTC 23473(T )= NBRC 107804(T)). PMID- 21789598 TI - The neurobiology of mouse models syntenic to human chromosome 15q. AB - Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11-q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11-q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABA(A) subunits as well as huge clusters of non coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11-q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11-q13 and their relationships to autism. PMID- 21789599 TI - Alternative transplantation sites for pancreatic islet grafts. AB - The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being an ideal site because of immunologic, anatomic, and physiologic factors leading to a significant early graft loss. A huge amount of alternative sites have been used for islet transplantation in experimental animal models to provide improved engraftment and long-term survival minimizing surgical complications. The pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis, and thymus have been explored. Site-specific differences exist in term of islet engraftment, but few alternative sites have potential clinical translation and generally the evidence of a post-transplant islet function better than that reached after intraportal infusion is still lacking. This review discusses site specific benefits and drawbacks taking into account immunologic, metabolic, and technical aspects to identify the ideal microenvironment for islet function and survival. PMID- 21789600 TI - Accelerated territorial arterial spin labeling based on shared rotating control acquisition: an observer study for validation. AB - INTRODUCTION: Shared rotating control acquisition can shorten the imaging time of territorial arterial spin labeling (tASL) by 33% compared with the normal control acquisition scheme but potentially results in an inaccurate estimate of vascular territories due to imperfect magnetization transfer compensation. Our purpose was to validate the accuracy of the shared rotating control acquisition method in evaluation of vascular territories. METHODS: Twenty-four patients underwent tASL at a 3.0-T MRI with the conventional normal control acquisition method. Composite vascular territory maps, in which the blood flows from the right and left internal carotid arteries and the posterior circulation were encoded in red-green blue, were generated as a normal averaged control-label scheme and as a simulated shared rotating control scheme. Two observers independently reported the most dominant territorial flow in 26 brain regions corresponding to the arterial segments at three post-labeling time points. Inter-reader and inter-method agreements were analyzed using kappa statistics. RESULTS: Overall inter-reader agreements were excellent for both the normal control and the shared rotating control methods (kappa = 0.98, respectively). Overall inter-method agreement was also excellent (kappa = 0.98), although relatively low agreement was noted in the bilateral posterior cerebral artery territories (kappa = 0.79 to 0.93). CONCLUSION: Our results suggested that tASL using shared rotating control acquisition can provide information on the vascular territories comparable to that obtained using the normal control acquisition while substantially shortening the imaging time. PMID- 21789601 TI - Giant vertebrobasilar aneurysm in a child: a challenging management. PMID- 21789602 TI - Tissue at risk in the deep middle cerebral artery territory is critical to stroke outcome. AB - INTRODUCTION: The clinical efficacy of thrombolysis in stroke patients is explained by the increased rate of recanalization, which limits infarct growth. However, the efficacy could also be explained by the protection of specific sites of the brain. Here, we investigate where is this outcome-related tissue at risk using voxel-based analysis. METHODS: We included 68 acute stroke patients with middle cerebral artery (MCA) occlusion on the admission MRI performed within 6 h of symptoms onset (H6) and 16 controls. MCA recanalization was assessed using the magnetic resonance angiography performed at day 1 (D1). Apparent diffusion coefficient (ADC) changes were analyzed using a voxel-based method between patients vs. controls group at admission (H6) in non-recanalized vs. recanalized and in 3-month poor vs. good outcome patients at D1. RESULTS: Complete or partial MCA recanalization was observed in 52 of 68 patients. Good outcome at 3 months occurred in 40 patients (59%). In non-recanalized patients, ADC was decreased in the deep MCA and watershed arterial territory (the lenticular nucleus, internal capsule, and the overlying periventricular white matter). This decrease was not observed in recanalized patients at D1 or patients at H6. Fiber tracking suggested that the area is crossed by the cortico-spinal, cerebellar, and intra hemispheric association tracts. Finally, this area almost co-localized with the area associated with poor outcome. CONCLUSIONS: A clinically relevant area of tissue at risk may occur in patients with MCA infarcts at the level of deep white matter fiber tracts. These findings suggest that neuroprotection research should be refocused on white matter. PMID- 21789603 TI - High-density fecal Enterococcus faecium colonization in hospitalized patients is associated with the presence of the polyclonal subcluster CC17. AB - Enterococcus faecium belonging to the polyclonal subcluster CC17, with a typical ampicillin-resistant E. faecium (AREfm) phenotype, have become prevalent among nosocomial infections around the world. High-density intestinal AREfm colonization could be one of the factors contributing to the successful spread of these pathogens. We aimed to quantify the enterococcal intestinal colonization densities in stool samples from AREfm-colonized and non-colonized patients using fluorescent in situ hybridization (FISH). Stool samples were collected from AREfm colonized (n = 8) and non-colonized (n = 8) patients. The relative number of Enterococcus faecalis and E. faecium was determined by FISH using specific 16S rRNA probes, while the total amount of bacterial cells was counted by staining the sample with 4',6-diamidino-2-phenylindole (DAPI). The median bacterial cell numbers in fecal samples, counted by DAPI staining, were 7.7 * 10(9) and 4.8 * 10(9) cells/g for AREfm-colonized and non-colonized patients, respectively (p = 0.34). The E. faecium densities in AREfm-colonized patients, accounting for 0.5 7% of all fecal bacterial cells, exceeded E. faecalis levels by over ten-fold. E. faecium was not detected in non-colonized patients. This study demonstrated high E. faecium cell densities in stool samples from patients colonized with AREfm. Increased cell densities may contribute to host-to-host transmission and environmental contamination, facilitating the spread of AREfm in the hospital setting. PMID- 21789604 TI - Self-collected vaginal swabs for the quantitative real-time polymerase chain reaction assay of Atopobium vaginae and Gardnerella vaginalis and the diagnosis of bacterial vaginosis. AB - The aim of this study was to assess the feasibility of using self-collected vaginal specimens for the quantitative real-time polymerase chain reaction (qPCR) assays of bacterial vaginosis (BV)-associated bacteria versus practitioner collected swabs. A cross-sectional study included 190 pregnant women enrolled before 20 weeks' gestation from September 2008 to November 2009. Self- and practitioner-collected swabs were taken during the same prenatal visit for each woman, qPCR assays performed for each, and the results compared. The quantification of the human albumin gene was used as an internal control to ensure sampling quality and accurate comparisons. The level of agreement of the qPCR assays for each microorganism was calculated with the Spearman product moment correlation coefficient and the kappa statistic. In all, 370 vaginal samples (185 self- and 185 practitioner-collected swabs) had a narrow range of values for the number of albumin gene copies and a significant correlation coefficient (Spearman's rho = 0.532; p < 0.001). The agreement between both sampling methods was excellent (Spearman's rho was 0.748 for Atopobium vaginae, 0.918 for Lactobacillus species, 0.940 for Gardnerella vaginalis; p < 0.001), especially for high concentrations of A. vaginae (>=10(8) copies/mL; kappa value = 0.973; p < 0.001) and G. vaginalis (>=10(9) copies/mL; kappa value = 0.903; p < 0.001). This study demonstrates the validity and reliability of self- versus practitioner-collected swabs for the molecular quantification of Lactobacillus species, G. vaginalis, and A. vaginae. PMID- 21789606 TI - Clonal spreading of methicillin-resistant SCCmec Staphylococcus aureus with specific spa and dru types in central Taiwan. AB - The goal of this study was to delineate the molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) in Taiwan. Ninety-six MRSA isolates were collected from the blood cultures of different patients during the period July to December of 2008. The spa typing, staphylococcal chromosomal cassette (SCCmec) typing, mec-associated direct repeat unit (dru) copy numbers, and toxin genes (sea, seb, sec, tst, lukS/F) of each isolate were determined. Thirty-eight, 28, 18, and 12 MRSA isolates were SCCmec type II, SCCmec type III, SCCmec type IV, and SCCmec type V, respectively. Most (31/38, 81.6%) of the SCCmec type II isolates were of spa t002 with four dru repeats. Some of them also carried the sec or tst toxin gene (67.7 and 80.6%, respectively). Of the 28 SCCmec type III MRSA isolates, 15 (53.6%) were of t037 with 14 dru repeats, and all also carried the sea gene. Of the 18 SCCmec type IV MRSA isolates, 13 (72.2%) were of t437 with nine dru repeats, and ten of them also had the seb gene. Among the SCCmec type V MRSA isolates, nine were type V(T). Five (55.6%) of them were of t437 with 11 dru repeats, and all contained the lukS/F gene. The clonal spreading of SCCmec MRSA strains with specific spa and dru types was found. Further longitudinal, multiple-site surveillance is required in order to define the MRSA evolution in Taiwan. PMID- 21789607 TI - Deep cerebellar neurons mirror the spinal cord's gain to implement an inverse controller. AB - Smooth and coordinated motion requires precisely timed muscle activation patterns, which due to biophysical limitations, must be predictive and executed in a feed-forward manner. In a previous study, we tested Kawato's original proposition, that the cerebellum implements an inverse controller, by mapping a multizonal microcomplex's (MZMC) biophysics to a joint's inverse transfer function and showing that inferior olivary neuron may use their intrinsic oscillations to mirror a joint's oscillatory dynamics. Here, to continue to validate our mapping, we propose that climbing fiber input into the deep cerebellar nucleus (DCN) triggers rebounds, primed by Purkinje cell inhibition, implementing gain on IO's signal to mirror the spinal cord reflex's gain thereby achieving inverse control. We used biophysical modeling to show that Purkinje cell inhibition and climbing fiber excitation interact in a multiplicative fashion to set DCN's rebound strength; where the former primes the cell for rebound by deinactivating its T-type Ca2(+) channels and the latter triggers the channels by rapidly depolarizing the cell. We combined this result with our control theory mapping to predict how experimentally injecting current into DCN will affect overall motor output performance, and found that injecting current will proportionally scale the output and unmask the joint's natural response as observed by motor output ringing at the joint's natural frequency. Experimental verification of this prediction will lend support to a MZMC as a joint's inverse controller and the role we assigned underlying biophysical principles that enable it. PMID- 21789605 TI - Molecular characterization of Staphylococcus aureus from outpatients in the Caribbean reveals the presence of pandemic clones. AB - Staphylococcus aureus infections continue to pose a global public health problem. Frequently, this epidemic is driven by the successful spread of single S. aureus clones within a geographic region, but international travel has been recognized as a potential risk factor for S. aureus infections. To study the molecular epidemiology of S. aureus infections in the Caribbean, a major international tourist destination, we collected methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates from community-onset infections in the Dominican Republic (n = 112) and Martinique (n = 143). Isolates were characterized by a combination of pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing (MLST) typing. In Martinique, MRSA infections (n = 56) were mainly caused by t304-ST8 strains (n = 44), whereas MSSA isolates were derived from genetically diverse backgrounds. Among MRSA strains (n = 22) from the Dominican Republic, ST5, ST30, and ST72 predominated, while ST30 t665-PVL+ (30/90) accounted for a substantial number of MSSA infections. Despite epidemiological differences in sample collections from both countries, a considerable number of MSSA infections (~10%) were caused by ST5 and ST398 isolates at each site. Further phylogenetic analysis suggests the presence of lineages shared by the two countries, followed by recent genetic diversification unique to each site. Our findings also imply the frequent import and exchange of international S. aureus strains in the Caribbean. PMID- 21789608 TI - The influence of P. fluorescens cell morphology on the lytic performance and production of phage phiIBB-PF7A. AB - This study aims at assessing the influence of Pseudomonas fluorescence cell morphology on the effectiveness and production of the lytic bacteriophage phiIBB PF7A. P. fluorescens were cultured as rods or as elongated cells by varying the temperature and rotary agitation conditions. Cells presented rod shape when grown at temperatures up to 25 degrees C and also at 30 degrees C under static conditions, and elongated morphology only at 30 degrees C when cultures were grown under agitation. Elongated cells were 0.4 up to 27.9 MUm longer than rod cells. Rod-shaped hosts were best infected by phages at 25 degrees C which resulted in an 82% cell density reduction. Phage infection of elongated cells was successful, and the cell density reductions achieved was statistically similar (P > 0.05) to those obtained at the optimum growth temperature of P. fluorescens. Phage burst size varied with the cell growth conditions and was approximately 58 and 153 PFU per infected rod and elongated cells, grown at 160 rpm, at 25 degrees C (the optimal temperature) and 30 degrees C, respectively. Phage adsorption was faster to elongated cells, most likely due to the longer length of the host. The surface composition of rod and elongated cells is similar in terms of outer membrane proteins and lipopolysaccharide profiles. The results of this study suggest that the change of rod cells to an elongated morphology does not prevent cells from being attacked by phages and also does not impair the phage infection. PMID- 21789609 TI - Proposing a method of regional assessment and a novel outcome measure in rheumatoid arthritis. AB - We proposed a method of regional assessment in patients with rheumatoid arthritis. The utility of this method was demonstrated by assessing drug efficacy in patients who received infliximab (n = 31) or tocilizumab (n = 6). Joints were divided into four regions: upper/large, upper/small, lower/large, and lower/small. The total joint index was calculated as follows: the sum of tender and swollen joint counts divided by the number of evaluable joints in each region. At the baseline, the total joint index of the upper/small region was the lowest and that of the lower/large region was the highest compared with other regions. The change in the total joint index from the baseline to the 30-week point (Delta) did not differ among the four regions. There were significant close relations of Delta between the upper/small and the upper/large region and between the lower/small and the lower/large region. This method allows us to focus on a specific region and to compare and contrast among them. PMID- 21789610 TI - Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. AB - Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis and vasculopathy. A key feature is the presence of T cells in inflammatory lesions. To establish the differences in peripheral blood T helper (Th) subpopulations in diffuse cutaneous (dc) and limited cutaneous (lc) SSc patients, blood samples from 57 dcSSc and 78 lcSSc patients were obtained. Controls were collected from healthy volunteers (n = 16), active systemic lupus erythematosus (aSLE) patients (n = 13), and active rheumatoid arthritis (aRA) patients (n = 12). Mononuclear cells were analyzed by flow cytometry to determine Th1 (CD4+/IFN-gamma+), Th2 (CD4+/IL-4+), Th17 (CD4+/IL-17+), and regulatory T cells (Tregs; CD4+/CD25+/Foxp3+) subsets. Th17 and Th1 subsets were increased in SSc groups versus healthy controls (P < 0.001) and aSLE patients (P < 0.001 for Th17 and P < 0.008 for Th1). Th2 cells were higher in dcSSc patients than in the healthy and aSLE groups (P = 0.03 and P = 0.009, respectively). Tregs were increased in the aRA group when compared with SSc patients and healthy controls (P <= 0.003). Patients with immunosuppressive treatment had lower numbers of Th17 and Th2 cells (P = 0.02). Our results shed further light into the preponderant role of Th17 and Th1 in patients with SSc. However, these findings certainly deserve to be studied in depth. PMID- 21789612 TI - Predictors for neuropsychiatric development in Chinese adolescents with systemic lupus erythematosus. AB - The aim of our study is to investigate the relationship between neuropsychiatric systemic lupus erythematosus (NPSLE) development and clinical factors to elucidate potential predictors at the time of SLE onset as well as during NP flares. Sixty-seven adolescents between the ages of 10 and 18 years with SLE were retrospectively reviewed, and their clinical characteristics and laboratory findings were analyzed. Twenty-four (35.82%) patients with NPSLE were included in the analysis. Renal involvement at the time of SLE onset was significantly less common in patients who developed NP symptoms (P = 0.0038), but renal involvement during the entire follow-up (FU) period was not significantly different between patients with NP and those without NP. Photosensitivity at the time of SLE diagnosis was significantly more common in patients with NP (P = 0.0080). No differences were found in the clinical and laboratory results between the time of SLE onset and NP onset in the same late-onset NP group. Our results suggest that NP development is negatively correlated with renal involvement at the onset of SLE, but not during the entire FU period, and NP development is positively correlated with photosensitivity at the time of SLE onset. We could not identify any factors that might predict the occurrence of NP symptoms during an NP flare. PMID- 21789613 TI - Coexistence of primary aldosteronism and Hashimoto's thyroiditis. AB - In light of research carried out in recent years, it seems that aldosterone may produce a complex proinflammatory effect. Theoretically, excessive aldosterone release may stimulate the development and/or progression of autoimmune disorders. In this article, we report a case of a female in whom primary aldosteronism coexisted with Hashimoto's thyroiditis. Surgical removal of an aldosterone producing tumor improved thyroid function and decreased thyroid autoimmunity. We describe in details diagnostic and treatment strategies applied in our patient and their impact on the course and outcome of thyroiditis. We also present monocyte and lymphocyte cytokine release in the index subjects before and after surgical treatment. We conclude that primary aldosteronism may exacerbate the clinical course of autoimmune thyroiditis and probably also of other autoimmune disorders. PMID- 21789614 TI - Is it safe to use anti-TNF-alpha agents for tuberculosis in children suffering with chronic rheumatic disease? AB - To determine the incidence of latent tuberculosis infection and evaluate the follow-up protocol of the patients diagnosed with juvenile idiopathic arthritis (JIA) and other chronic rheumatologic diseases treated with anti-TNF-alpha treatment (etanercept, infliximab, adalimumab) in Turkey, 144 patients were evaluated retrospectively for the development of tuberculosis. Patients were evaluated every 6 months for tuberculosis using history, physical examination, tuberculin skin test (TST), chest radiographs, and, when required, examination of sputum/early morning gastric aspirates for acid-fast bacilli and chest tomography. A tuberculin skin test over 10 mm induration was interpreted as positive. Patients were diagnosed with JIA (n = 132), enthesitis-related arthritis (ERA; n = 14), juvenile psoriatic arthritis (JPsA; n = 4), chronic idiopathic uveitis (n = 4), and chronic arthritis related to FMF (n = 8). Mean age was 12.25 +/- 3.96 years (4.08-19.41 years), mean duration of illness was 5.86 +/- 3.77 years (0.66-15 years), and the mean duration of anti-TNF-alpha treatment was 2.41 +/- 1.47 years (0.6-7 years). Anti-TNF-alpha agents prescribed were etanercept (n = 133), infliximab (n = 30), and adalimumab (n = 6). When unresponsive to one anti-TNF-alpha therapy, patients were switched to another. There was no history of contact with individuals having tuberculosis. During follow-up, seven patients (4.8%) with positive TST were given INH prophylaxis. One oligoarticular JIA patient (0.69%) diagnosed with secondary uveitis who had been followed for 5 years and had been using infliximab for 2 years, developed a positive Quantiferon-TB test while on INH prophylaxis. He was started on an anti tuberculosis drug regimen. In conclusion, anti-TNF-alpha treatment in children with chronic inflammatory disease is safe. Follow-up every 6 months of children on anti-TNF-alpha treatment with respect to tuberculosis by the pediatric infectious disease department is important to prevent possible complications. PMID- 21789615 TI - Osteoprotegerin expression in bone marrow by treatment with tocilizumab in rheumatoid arthritis. AB - The aim of this study was to investigate histological changes of bone marrow in response to tocilizumab for rheumatoid arthritis (RA). After tocilizumab therapy, bone marrow tissues were extracted from ten RA patients at the time of total knee arthroplasty (TKA). Control samples were obtained from ten RA patients who underwent MTX mono-therapy. Histological examination of structural differences between the tocilizumab and control groups in bone marrow was performed using hematoxylin and eosin (H&E) to evaluate differences. In immunohistochemical examination, the expression of seven molecules including tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), CD68, osteoprotegerin (OPG), receptor activator of nuclear kappa B ligand (RANKL), CD4 and osteopontin (OPN) were compared between two groups. NTx was significantly low at 44.5 +/- 2 nM BCE/mM Cr compared with control at 73.2 +/- 8 nM BCE/mM Cr. Immunohistochemical examination revealed that the bone marrow tissues of the RA patients who underwent tocilizumab therapy demonstrated significant positive OPG as compared with the control. However, immunohistochemical examinations after tocilizumab revealed that TNF-alpha, IL-6, CD68, CD4, OPN and RANKL were not significantly different with control of MTX in bone marrow. Therefore, treatment with tocilizumab increased the expression of OPG as the histological changes with respect to inhibit RANKL-related bone resorption of bone marrow in RA. PMID- 21789616 TI - Osteomalacia caused by tumors in facies cranii mimicking rheumatoid arthritis. AB - Tumor-induced osteomalacia (TIO) is an extremely rare metabolic bone disease and the occult offending tumor arising in facies cranii is even more uncommon. In this report, we described 2 middle-aged females with TIO caused by the tumor in facies cranii, which had ever been misdiagnosed as rheumatoid arthritis. Case 1 was present with diffuse bone pain and muscle weakness for 4 years, as well as esotropia in the right eye for 1 month. Case 2 was present with progressive bone pain in low back and hip for 2 years. Biochemical studies both showed persistent hypophosphatemia and urinary over wasting phosphate. Radiological examinations revealed the infiltrative mass in right apex partis petrosae ossis temporalis in case 1, and the soft mass in left nasal cavity and ethmoid sinuses in case 2, respectively. The offending tumors were resected completely in case 2, however, incompletely in case 1. Pathology examination revealed mixed connective tissue variant phosphaturic mesenchymal tumors. In conclusion, TIO should be presumed in patients presenting with unexplained persistent hypophosphatemia osteomalacia, also a thorough detection for tumor in facies cranii should be performed. PMID- 21789617 TI - Local tolerance of intraarticular administration of lornoxicam into the rabbit knee joint. AB - The local tolerability of lornoxicam (Xefo) after single and repeated intraarticular administration was assessed in the rabbit and compared to established standard therapies (hyaluronic acid--Synvisc and the glucocorticoid triamcinolone--Triam), and the results are discussed in the context of the literature. Two local tolerance studies were performed using five male rabbits per group. Lornoxicam and competitor products were administered into the right knee joint in a volume of 500 MUL. The contralateral left knee joint of the same animal was used as the control and was injected with water for injection. Three out of five animals were killed 72 h after the last administration, whereas the remaining two animals were subjected to a 2- or 6-week recovery period in the first and the second study, respectively. Findings revealed adaptive changes related to the mechanical irritation of the injection and to adaptive responses of the synoviocytes, but no signs of toxicity to bone or chondrotoxicity. Toxicokinetic analysis showed a fast and almost complete absorption of lornoxicam from the joints into the systemic circulation. As a conclusion, repeated intraarticular administration of lornoxicam was well tolerated in rabbits. PMID- 21789618 TI - -383 A/C tumor necrosis factor receptor 1 polymorphism and ankylosing spondylitis in Mexicans: a preliminary study. AB - The objective of this study was to evaluate the differences in allele and genotype frequencies of -383 tumor necrosis factor receptor 1 (TNFR1) polymorphism between ankylosing spondylitis (AS) and controls. Mexican Mestizos with AS were matched by gender, age, and ethnicity with healthy controls and compared in allele and genotype frequencies of the -383 TNFR1 polymorphism. Polymorphisms were genotyped using PCR-RFLP. The AA genotype occurred at a higher frequency in the AS group (92%) compared with controls (79%, P = 0.03). A allele was increased in AS (96% vs. 88%, P = 0.015) and was associated with genetic susceptibility for AS (odds ratio = 3.48, 95% CI = 1.23-10.61). This preliminary study is the first assessing the association of the -383 A/C TNFR1 polymorphism with AS, although it has the limitation of a small sample size. These data are of interest for the genetic epidemiology of AS in the Mexican population, requiring further investigation in other countries. PMID- 21789619 TI - IgG RF and anti-CCP2 antibody can be positive in undifferentiated arthritis due to streptococcal infection, hepatitis B virus, tuberculosis, trauma and hypothyroidism: a preliminary study. AB - Anti-CCP2 antibody and rheumatoid (RF) tests are used for the diagnosis of rheumatoid arthritis (RA). Out of these two, anti-CCP2 antibody is supposed to be more specific for RA. Aim of the study was to present 33 cases of undifferentiated arthritis (UA) in which features of RA were not present, but anti-CCP2 antibody was positive. Out of the 33 cases of UA, 19 had well-known disease like hyperthyroidism, hypothyroidism, tubercular arthritis, traumatic arthritis, pneumonia with arthritis, varicose vein with pain in legs, cervical spondylitis and SSA. The duration of disease was more than one year in 67.86% cases. Majority of the patients were females (63.64%). Knee joint involvement was seen in maximum number (i.e. 20 cases). All 33 cases were positive for anti-CCP2 Ab. Maximum number of cases (78.78%) had involvement of one or two joints. CRP positivity was seen in 23.07% cases. Morning stiffness was present in (36.36%) cases, while swelling of the joint was present in 33.33% cases. In 16 cases, only serum sample was available for further analysis. About 62.5% cases showed IgG RF positivity. Antitubercular IgM and IgG were detected in 18.75% cases; ASO was elevated in 12.5% cases, and HBs Ag was positive in 6.25% cases. None of the controls (30 cases) were positive for these infections, anti-CCP2 antibody or RF. Thus, our study concludes that chronic infections like streptococcus, hepatitis B, tuberculosis and autoimmune thyroid diseases can produce raised levels of anti CCP2 antibody and IgG RF. PMID- 21789620 TI - Allogeneic bone marrow transplantation compared to peripheral blood stem cell transplantation for the treatment of hematologic malignancies: a meta-analysis based on time-to-event data from randomized controlled trials. AB - Controversy remains regarding the transplant outcomes of human leukocyte antigen identical related bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) for the treatment of patients with hematological malignancies. To provide an estimate of the effect of BMT and PBSCT on clinical outcomes in patients with hematological malignancies, we conducted a meta analysis based on time-to-event data from 17 randomized controlled trials. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), from 1972 through July 2010, and conference proceedings through July 2009 and reference lists, without any language restriction, of randomized trials that compared the transplant outcomes after BMT and PBSCT in patients with hematological malignancies were searched for details. Two independent reviewers extracted the data. The outcomes examined were engraftment, graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), leukemia-free survival (LFS), and overall survival (OS). Compared to PBSCT, BMT had lower neutrophil (HR, 2.08; 95% CI, 1.80 to 2.42; p < 0.00001) and platelet (HR, 2.77; 95% CI, 1.78 to 4.30; p < 0.00001) engraftment. BMT was associated with a significant decrease in the development of grades II-IV (HR, 0.75; 95% CI, 0.63 to 0.90; p = 0.002) and III-IV (HR, 0.63; 95% CI, 0.47 to 0.84; p = 0.001) acute GVHD as well as overall (HR, 0.70; 95% CI, 0.59 to 0.83; p < 0.0001) and extensive (HR, 0.60; 95% CI, 0.39 to 0.91; p = 0.002) chronic GVHD. BMT was associated with a higher incidence of relapse (HR, 1.91; 95% CI, 1.34 to 2.74; p = 0.0004). Comparable TRM (1.08; 95% CI, 0.56 to 2.10; p = 0.81), LFS (HR, 1.04; 95% CI, 0.83 to 1.30; p = 0.73), and OS (HR, 1.06; 95% CI, 0.81 to 1.39; p = 0.65) were demonstrated for both treatments. An inverse linear relationship was observed between the acute GVHD difference (PBSCT minus BMT) and the outcome of OS (p = 0.016). Our meta-analysis suggest that BMT leads to slower hematological recovery, increasing rates of relapse, and a lower risk of GVHD, but no significant difference in LFS and OS. A lower incidence of acute GVHD is associated with a superior OS. PMID- 21789621 TI - Sequential vincristine, adriamycin, dexamethasone (VAD) followed by bortezomib, thalidomide, dexamethasone (VTD) as induction, followed by high-dose therapy with autologous stem cell transplant and consolidation therapy with bortezomib for newly diagnosed multiple myeloma: results of a phase II trial. AB - Incorporation of novel agents has resulted in an improved response rate and reduced side effects in multiple myeloma. This has prompted combining novel agents in induction chemotherapy in patients with newly diagnosed multiple myeloma. Our patients received 2 cycles of vincristine, adriamycin, dexamethasone (VAD) and then 2 cycles of bortezomib, thalidomide, dexamethasone (VTD) chemotherapy as an induction treatment. Subsequently, autologous stem cell transplantation was performed, and bortezomib was administered as a consolidation therapy. Seventy-one patients were enrolled, and 65 were evaluable for response. After 2 cycles of VAD, the overall response rate was 69%. After VTD, the response rate improved to 97% with a complete response (CR) and near CR rate of 27%. Importantly, patients with cytogenetics, having poor prognostic features, all responded after VTD. Autologous stem cells were successfully collected in all 58 patients with a median CD34+ cell count of 7.12 * 10(6)/kg (range, 1.94-44.7 * 10(6)/kg), except in 1 patient (2%). After ASCT, 36 patients completed bortezomib maintenance with a combined CR and near CR rate approaching 75%. Median time to response was rapid (1.6 months). With a median follow-up duration of 52.7 months, the median TTP was 29.4 months and median OS was not reached. Toxicities proved manageable. In conclusion, sequential VAD and VTD induction therapy in patients with newly diagnosed multiple myeloma was active with manageable toxicity and excellent stem cell yields. The incorporation of bortezomib as a consolidation therapy improved the clinical outcome with the expense of rather frequent development of peripheral neuropathy. PMID- 21789622 TI - Clinical features and outcomes of Hodgkin's lymphoma in Korea: Consortium for Improving Survival of Lymphoma (CISL). AB - Ethnic and regional differences in the epidemiology and pathological aspects of Hodgkin's lymphoma (HL) between Western and Asian patients may be associated with differences in clinical features and prognosis. We retrospectively analyzed the clinical and histopathological characteristics, therapeutic outcomes, and prognostic factors of 539 HL patients treated at 16 centers in Korea. We found that the incidence of histological subtypes of HL in Korea was similar to that in Western and other Asian countries. However, the incidence peaked between 16 and 30 years of age, unlike the bimodal age distribution seen in Western countries. In patients with stage I-IIA non-bulky disease, the complete response (CR) rate was similar between combined modality therapy and chemotherapy alone (93% vs. 84%, P = 0.44), and there was no difference in relapse-free survival (RFS) and overall survival (OS). Patients with stage I-II disease plus unfavorable factors and those with advanced-stage disease treated with combination chemotherapy regimens had an overall CR rate of 77%, with no difference between doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and non-ABVD regimens (77.2% vs. 76.8%, P = 0.95). Among those patients who achieved final CR, there was no significant difference in RFS or OS between those who achieved interim CR and PR. Only the presence of B symptoms was independently predictive of a shorter RFS. Age > 45 years, Eastern Cooperative Oncology Group 2-4, and B symptoms were independent risk factors for death. Although the incidence of HL was lower in Korea than in Western countries, the distribution of morphological subtypes, treatment outcomes, and patient prognosis were similar. PMID- 21789623 TI - Prevalence and progression of monoclonal gammopathy of undetermined significance and light-chain MGUS in Germany. AB - We determined the prevalence and progression rate of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS (LCMGUS) in Germany utilizing the biobank of the population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4,814 men and women aged 45-75 years. To detect monoclonal proteins, standard serum electrophoresis was combined with parallel screening immunofixation using pentavalent antisera. Additionally, free light chains (FLC) were measured in all samples. Definition of MGUS included M protein concentration, laboratory results, and disease history. LCMGUS was defined as abnormal FLC ratio, increase in FLC causing the abnormal ratio, and lack of intact immunoglobulin. One hundred sixty-five MGUS cases were identified among 4,702 screened samples (prevalence 3.5%, 95% confidence interval (CI) 3.0 4.1; median age 63 years, range 47-75 years; 103 (62%) male; IgG 59%, IgA 17%, IgM 17%, biclonal 4.8%, kappa 56%, and lambda 44%). Five cases progressed (0.6%/year, 95% CI 0.2-1.4). An abnormal FLC ratio was detected in 220 samples. Thirty-nine of these showed intact immunoglobulin. Thirty-four of the remaining met LCMGUS criteria (prevalence 0.7%, 95% CI 0.5-1.0). None of the LCMGUS cases progressed. We demonstrate a MGUS prevalence of 3.5% and a LCMGUS prevalence of 0.7% in the general population aged 45-75 years in Germany using a sensitive screening approach. PMID- 21789624 TI - Local treatment of methicillin-resistant Staphylococcus aureus conjunctivitis with short-term high-concentrated minocycline ointment. PMID- 21789625 TI - Bone marrow mesenchymal cells: how do they contribute to tissue repair and are they really stem cells? AB - Adult stem cells typically generate the cell types of the tissue in which they reside, and thus the range of their differentiation is considered limited. Bone marrow mesenchymal stem cells (MSCs) are different from other somatic stem cells in that they differentiate not only into the same mesodermal-lineage such as bone, cartilage, and adipocytes but also into other lineages of ectodermal and endodermal cells. Thus, MSCs are a unique type of adult stem cells. In addition, MSCs home to damaged sites, differentiate into cells specific to the tissue and contribute to tissue repair. Therefore, application of MSCs in the treatment of various diseases, including liver dysfunction, myocardial infarction, and central nervous system repair, has been initiated. Because MSCs are generally harvested as adherent cells from bone marrow aspirates, however, they comprise heterogeneous cell populations and their wide-ranging differentiation ability and repair functions are not yet clear. Recent evidence suggests that a very small subpopulation of cells that assume a repair function with the ability to differentiate into trilineage cells resides among human MSCs and effective utilization of such cells is expected to improve the repair effect of MSCs. This review summarizes recent advances in the clarification of MSC properties and discusses future perspectives. PMID- 21789626 TI - Transitional B cells: how well are the checkpoints for specificity understood? AB - It is crucial for the immune system to minimise the number of circulating mature self-reactive B cells, in order to reduce the potential for the development of autoantibody-related autoimmune diseases. Studies of animal models have identified two major checkpoints that ensure that such cells do not contribute to the naive B cell repertoire. The first is in the bone marrow as B cells develop and the second is in the spleen; B cells that are released from the bone marrow as transitional B cells go through more stringent selection in the spleen before they develop into mature naive B cells. Transitional B cells and their maturation have mostly been studied in mice. However, recent studies characterised human transitional B cells and found considerable differences to current models. In this review, we will consider these differences alongside known differences in mouse and human splenic function and ask whether human transitional B cells might develop along a different pathway. PMID- 21789628 TI - 1st Joint Meeting of the International Society for Autonomic Neuroscience and the American Autonomic Society (ISAN/AAS 2011), Buzios, Rio de Janeiro, Brazil, September 12-16, 2011. Abstracts. PMID- 21789629 TI - Ischaemia-induced protein ubiquitinylation is differentially accompanied with heat-shock protein 70 expression after naive and preconditioned ischaemia. AB - The aim of this study was to investigate the effect of transient global brain ischaemia, both naive and preconditioned, on accumulation of ubiquitinylated proteins and induction of stress/chaperone proteins specific to cytoplasm and endoplasmic reticulum. In addition, possible correlation between stress response and ischaemia/induced translocation of p53 to mitochondria was investigated. Rats were subjected to 15-min forebrain ischaemia followed by 1, 3, 24 and 72 h of reperfusion. Transient cerebral ischaemia induced a massive increase in protein ubiquitinylation in the hippocampus as well as in both cerebral and cerebellar cortex. Enhanced ubiquitinylation of proteins was paralleled with transcriptional activation of hsp70.1 gene but not hsp70.3 gene. However, HSP70 protein level was significantly elevated 24 and 72 h after ischaemia. Neither ischaemia nor ischaemia followed by reperfusion was associated with significant changes of GRP78, GADD34 and GADD153 levels. Ubiquitinylated protein level was elevated 1 and 48 h after sub-lethal 5 min ischaemia. Preconditioned ischaemia (15 min ischaemia followed 48 h after sub-lethal ischaemia) was associated with even enhanced accumulation of ubiquitinylated proteins of molecular mass higher than 110 kDa. HSP70 protein was significantly elevated 48 h after sub-lethal ischaemia as well as after preconditioned ischaemia and all investigated time intervals of reperfusion. The elevated level of HSP70 might represent plausible explanation of inhibition of both translocation of p53 to mitochondria and ischaemia-induced apoptosis observed after preconditioned ischaemia. PMID- 21789631 TI - Evaluation of mineral content of dentin treated with desensitizing agents and neodymium yttrium-aluminium-garnet (Nd:YAG) laser. AB - The aim of this study was to evaluate the mineral content of dentin prepared using three different desensitizing agents and the Nd:YAG laser. The occlusal third of the crowns of 30 molar teeth were cut with a slow-speed diamond saw sectioning machine under water cooling. Dentin slabs from the 30 teeth were randomly divided into five experimental groups, each comprising six slabs. The five groups were treated as follows: group A, no treatment; group B, treatment with oxalate-containing desensitizing agent (BisBlock); group C, treatment with resin-based desensitizing agent (Admira Protect); group D, treatment with glutaraldehyde-containing desensitizing agent (Systemp); and group E, irradiation with the Nd:YAG laser (DEKATM ) at 0.40 W. The levels of Mg, P, Ca, K, and Na in each slab were measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). Data were analyzed by one-way analysis of variance and the Tukey HSD test. The effect of desensitizing agents and laser irradiation on the dentin surface were evaluated using a scanning electron microscope. There were no significant differences between the groups (p > 0.05). Group E was showed the lowest Ca/P ratio. SEM showed that the resin-based agent occluded the dentinal tubules, the glutaraldehyde-containing agent increased the Ca/P ratio, and Nd:YAG laser irradiation decreased the Ca/P ratio. The mean percentages by weight of Ca, Mg, K, Na and P were not affected by Nd:YAG laser irradiation or any of the desensitizing agents. PMID- 21789630 TI - The striatum and pain modulation. AB - The aim of this review was to give a general aspect of the sensorial function of the striatum related to pain modulation, which was intensively studied in our laboratory. We analyse the effect of electrical and chemical stimulation of the striatum on the orofacial pain, especially that produced by tooth pulp stimulation of the lower incisors. We demonstrated specific sites within the nucleus which electrical or chemical stimulation produced inhibition of the nociceptive jaw opening reflex. This analgesic action of the striatum was mediated by activation of its dopamine D(2) receptors and transmitted through the indirect pathways of the basal ganglia and the medullary dorsal reticular nucleus (RVM) to the sensorial nuclei of the trigeminal nerve. Its mechanism of action was by inhibition of the nociceptive response of the second order neurons of the nucleus caudalis of the V par. PMID- 21789632 TI - Effects of the hydroalcoholic extract of Phyllanthus niruri and its isolated compounds on cyclophosphamide-induced hemorrhagic cystitis in mouse. AB - The effects of Phyllanthus niruri hydroalcoholic extract and the isolated compounds quercetin, rutin, and gallic acid were examined in the mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis (HC). HC was induced by a single CYP injection (300 mg/kg, IP), and the animals were evaluated 4 and 6 h after. Some animals were orally treated with the reference compound 2 mercaptoethane sodium sulfonate (Mesna) 80 mg/kg (30 min before CYP) and 160 mg/kg (2 h after CYP). Other groups were treated with P. niruri extract (30 and 50 mg/kg), or quercetin, rutin, and gallic acid (10 and 20 mg/kg), given orally, at the same intervals described for Mesna. P. niruri extract and its active components produced a significant attenuation of the nociception, edema, and hemorrhage evoked by CYP, which was similar to that seen for Mesna. Gallic acid and rutin displayed greater anti-inflammatory effects, whereas quercetin presented superior antinociceptive activities. Noteworthy is that P. niruri extract and compounds significantly reduced CYP-induced liver lipid peroxidation. Our results shed new light on the beneficial effects of P. niruri extract and its active compounds in attenuating the collateral effects elicited by the chemotherapeutic agent CYP. PMID- 21789633 TI - Sequence analysis of the Meq gene in the predominant Marek's disease virus strains isolated in China during 2006-2008. AB - The main aim of the present study were to investigate sequence diversity in the Meq gene of Marek's disease viruses (MDV) isolated in China and to determine the most prevalent MDV strains. The 19 MDV strains were isolated from dead or diseased chickens from different chicken farms in China during 2006-2008, and the Meq gene was sequenced from each of these strains. Sequence analysis showed that all of the isolates contained an open reading frame of 1020 nucleotides, which encoded a 339 amino acid peptide. Compared with reference MDV strains, 12 of the 19 MDV isolates possessed two amino acid substitutions, (T -> A) at position 139 and (P -> R) at position 176, one isolate shared sequence similarity with the attenuated strain CVI988, and five of the other six isolates exhibited one amino acid change (P -> T) at position 177 or 176. The 19 MDV isolates shared between 99.0 and 100% nucleotide sequence homology, and between 97.7 and 100% amino acid sequence homology. The nucleotide and amino acid sequence identity between the 19 MDV isolates and the 25 reference MDV strains varied from 97.6 to 100% and 94.4 to 100%, respectively. Based on the phylogenetic relationships between Meq gene sequences, Chinese MDV isolates constituted a separate clade to MDV reference strains, demonstrating that a different genotype of MDV was prevalent in China between 2006 and 2008. PMID- 21789634 TI - Porcine kobuvirus from pig stool specimens in Shanghai, China. AB - In this study, a total of 116 stool specimens were collected from pigs of different ages in three pig farms of Shanghai in China during 2010. Forty-five (38.8%) stool specimens were positive for porcine kobuvirus using reverse transcriptase-polymerase chain reaction (RT-PCR). The prevalence rate of porcine kobuvirus in the three pig farms which are located in Minhang District, Qingpu District and Fengxian District was 46.7%(21/45), 35.1%(13/37), and 32.4%(11/34), respectively. We demonstrated that porcine kobuvirus infections are existent in certain domestic pigs in Shanghai and high prevalence of this virus was found in the piglets under the age of 6 weeks and in pigs with diarrhea in Shanghai. Twenty-seven representative strains of porcine kobuvirus detected in this study were randomly selected based on the equal distribution of the sampling date throughout the study and analyzed for their phylogenetic relationships with other kobuvirus reference strains. The phylogenetic analysis suggested the presence of multiple porcine kobuvirus lineages in Shanghai, China. PMID- 21789635 TI - Dehydration and vernalization treatments identify overlapping molecular networks impacting endodormancy maintenance in leafy spurge crown buds. AB - Leafy spurge (Euphorbia esula L.) is a herbaceous perennial weed that reproduces vegetatively from an abundance of underground adventitious buds (UABs), which undergo well-defined phases of seasonal dormancy (para-, endo-, and ecodormancy). In this study, the effects of dehydration stress on vegetative growth and flowering potential from endodormant UABs of leafy spurge was monitored. Further, microarray analysis was used to identify critical signaling pathways of transcriptome profiles associated with endodormancy maintenance in UABs. Surprisingly, only 3-day of dehydration stress is required to break the endodormant phase in UABs; however, the dehydration-stress treatment did not induce flowering. Previous studies have shown that prolonged cold treatment of UABs breaks endodormancy and induces a vernalization response leading to flowering. Thus, in this study, comparing transcriptome data from UABs exposed to short-term dehydration and vernalization provided a unique approach to identify overlapping molecular mechanisms involved in endodormancy maintenance and floral competence. Analysis of transcriptome data associated with breaking endodormancy by both environmental treatments identified LEC1, PHOTOSYSTEM I RC, and brassinosteroids as common central hubs of upregulated genes, while DREB1A, CBF2, GPA1, MYC2, bHLH, BZIP, and flavonoids were identified as common central hubs of downregulated genes. The majority of over-represented gene sets common to breaking endodormancy by dehydration stress and vernalization were downregulated and included pathways involved in hormone signaling, chromatin modification, and circadian rhythm. Additionally, the over-represented gene sets highlighted pathways involved in starch and sugar degradation and biogenesis of carbon skeletons, suggesting a high metabolic activity is necessary during the endodormant phase. The data presented in this study helped to refine our previous model for dormancy regulation. PMID- 21789636 TI - Linked gene networks involved in nitrogen and carbon metabolism and levels of water-soluble carbohydrate accumulation in wheat stems. AB - High levels of water-soluble carbohydrates (WSC) provide an important source of stored assimilate for grain filling in wheat. To better understand the interaction between carbohydrate metabolism and other metabolic processes associated with the WSC trait, a genome-wide expression analysis was performed using eight field-grown lines from the high and low phenotypic tails of a wheat population segregating for WSC and the Affymetrix wheat genome array. The 259 differentially expressed probe sets could be assigned to 26 functional category bins, as defined using MapMan software. There were major differences in the categories to which the differentially expressed probe sets were assigned; for example, probe sets upregulated in high relative to low WSC lines were assigned to category bins such as amino acid metabolism, protein degradation and transport and to be involved in starch synthesis-related processes (carbohydrate metabolism bin), whereas downregulated probe sets were assigned to cell wall-related bins, amino acid synthesis and stress and were involved in sucrose breakdown. Using the set of differentially expressed genes as input, chemical-protein network analyses demonstrated a linkage between starch and N metabolism via pyridoxal phosphate. Twelve C and N metabolism-related genes were selected for analysis of their expression response to varying N and water treatments in the field in the four high and four low WSC progeny lines; the two nitrogen/amino acid metabolism genes demonstrated a consistent negative association between their level of expression and level of WSC. Our results suggest that the assimilation of nitrogen into amino acids is an important factor that influences the levels of WSC in the stems of field-grown wheat. PMID- 21789637 TI - Association between DHEAS and bone loss in postmenopausal women: a 15-year longitudinal population-based study. AB - Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45-68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31-0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21-0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS. PMID- 21789638 TI - Endoscopic and laparoscopic ultrasonography used to predict tumor staging and improve therapeutic decisions for upper gastrointestinal tract cancer. PMID- 21789639 TI - Single-site laparoscopic (SSL) cholecystectomy in human cadavers using a novel percutaneous instrument platform and a magnetic anchoring and guidance system (MAGS): reestablishing the "critical view". AB - INTRODUCTION: SSL introduces ergonomic challenges while establishing the critical view during dissection of the Triangle of Calot (TOC). This study investigates the use of a novel percutaneous instrument platform and MAGS in performing SSL cholecystectomy with a technique that closely mimics four-port cholecystectomy. METHODS: SSL cholecystectomy was performed on four female cadavers via a 15-18-mm incision made at the umbilicus for introduction of these devices and the working port. MAGS comprises an internal effector with a retractable monopolar cautery hook coupled across the abdominal wall to an external magnet held by the surgeon. The novel grasper was introduced percutaneously in the RUQ and comprises a 3-mm transabdominal shaft mated to a 5-mm end effector intracorporeally. Retraction was accomplished using the percutaneous grasper to manipulate the fundus and a standard 5-mm grasper at the umbilicus for the infundibulum. Dissection was performed by using a combination of the MAGS and a standard Maryland dissector. Total procedure time, time from procedure start to obtain a critical view of the TOC and clipping and dividing the cystic duct/artery, time for dissection of the gallbladder from the liver bed, and thickness of the abdominal wall at the umbilicus were measured. RESULTS: The critical view was obtained in each case, and all four procedures were completed successfully. Mean procedure time was 40 (range, 33-51) min; time from procedure start to obtaining the critical view and clipping and dividing the cystic duct/artery was 33 (range, 28-38) min, and time for dissection of the gallbladder from the liver bed was 6.7 (range, 3-13) min. The mean abdominal wall thickness was 1.9 (range, 1.5-2) cm. CONCLUSIONS: The use of a novel graspers and MAGS overcomes the limitations of SSL cholecystectomy and improves surgeon dexterity. Making SSL feel more like traditional laparoscopy will enable a wider adoption of this procedure in the community. PMID- 21789640 TI - Reevaluation of needlescopic surgery. AB - BACKGROUND: Although the use of single-incision laparoscopic surgery (SILS) has spread rapidly, most procedures employ additional needlescopic instruments to ensure safety and shorten the operation time. Therefore, on the basis of results obtained in our department, the present study was conducted to reevaluate the current state of needlescopic surgery (NS) to improve the cosmetic results and postoperative quality of life of patients and to reduce cost and degree of stress on surgeons. METHODS: Between May 1998 and February 2011, we performed NS in 202 patients. The diagnoses included gallbladder diseases in 151 patients, spontaneous pneumothorax in 11, thyroid tumor and axillary lymph node metastases in 10 patients each, splenic cyst and appendicitis in 4 patients each, idiopathic thrombocytopenic purpura and postoperative abdominal wall hernia in 3 patients each, primary aldosteronism and hepatic cyst in 2 patients each, and adhesional bowel obstruction and gastric stromal tumor in 1 patient each. Under general anesthesia, one 12-mm and tow or three 2- or 3-mm ports were introduced into the operative field. The specimen was retrieved via the 12-mm wound using a plastic bag. RESULTS: The operations were completed in all patients without the need to convert to an open procedure. In 8 (5.3%) of the 151 cholecystectomies, a change to 5-mm instruments was required. There were no perioperative complications. Pertinent technical points included avoidance of direct organ mobilization to minimize injury, rotation of the operating table and utilization of organ gravity to create a better operative field, minimum use of needlescope to ensure safe maneuvering, and improvement of the bi-hand technique. CONCLUSIONS: NS is a safe and feasible procedure that allows experienced surgeons to achieve minimally invasive surgery with low morbidity, without the need to convert to a conventional or open procedure. PMID- 21789641 TI - Long-term oncologic outcomes of 714 consecutive laparoscopic gastrectomies for gastric cancer: results from the 7-year experience of a single institute. AB - BACKGROUND: Although many reports have indicated the feasibility of laparoscopic gastrectomy (LG) regarding short-term surgical outcomes, the role of LG remains controversial because studies of long-term outcomes of LG are insufficient. The purpose of this study was to evaluate the long-term oncologic outcomes of patients who have undergone LG. METHODS: Between May 2003 and December 2009, 714 consecutive patients underwent LG for gastric cancer. After excluding operative mortality (n = 4) and a case of Krukenberg tumor that was not identified at the time of surgery (n = 1), a total of 709 patients were analyzed for long-term oncologic outcomes. Gastric cancer cases were analyzed according to the American Joint Committee on Cancer classification (seventh edition). Overall survival and relapse-free survival were estimated by using the Kaplan-Meier method. RESULTS: Median follow-up was 46.2 months. Postoperative recurrence was observed in 26 patients (3.7%). The instances of recurrence were as follows: seven peritoneal, six locoregional, five hematogenous, four distant lymph nodes, and four mixed recurrence. There were neither port-site nor wound site metastases. The 5-year relapse-free survival rates were: 95.8% in stage I, 83.4% in stage II, and 46.4% in stage III. Five-year overall survival rates were: 96.4% in stage I, 83.1% in stage II, and 50.2% in stage III. The independent risk factors for recurrence were T stage and N stage. For survival, age, T stage, and N stage were statistically independent prognostic factors CONCLUSIONS: Our single-center study of a large patient series revealed that LG for gastric cancer had acceptable long term oncologic outcomes comparable to those of conventional open surgery. PMID- 21789642 TI - Self-expanding metallic stent as a bridge to surgery versus emergency surgery for obstructive colorectal cancer: a meta-analysis. AB - BACKGROUND: The use of a colonic stent as a bridge to surgery aims to provide patients with elective one-stage surgical resection while reducing stoma creation and postoperative complications. This study used meta-analytic techniques to compare the outcomes of stent use as a bridge to surgery and emergency surgery in the management of obstructive colorectal cancer. METHODS: A literature search of Medline, Embase, Cochrane controlled trials registry, and the Chinese Biomedical Literature Database was performed on all studies comparing stent as a bridge to surgery and emergency surgery for obstructive colorectal cancer. A meta-analysis of the included studies was carried out to identify the differences in outcomes between the two procedures. RESULTS: Eight studies matched the criteria for inclusion and reported on the outcomes of 601 patients, of whom 232 (38.6%) underwent stent insertion and 369 (61.4%) underwent emergency surgery. Fewer patients in the stent group needed intensive care (risk ratio [RR], 0.42; 95% confidence interval [CI], 0.19-0.93; p = 0.03) and stoma creation (RR, 0.70; 95% CI, 0.50-0.99; p = 0.04). The primary anastomosis rate in the stent group was higher (RR, 1.62; 95% CI, 1.21-2.16; p = 0.001). Overall complications (RR, 0.42; 95% CI, 0.24-0.71; p = 0.001), including anastomotic leakage (RR, 0.31; 95% CI, 0.14-0.69; p = 0.004), were reduced by stent insertion. Stent placement before elective surgery did not adversely affect mortality and long-term survival. CONCLUSIONS: The use of a stent as a bridge to surgery for obstructive left-sided colorectal cancer could increase the chance of primary anastomosis and reduce the need for stoma creation and postprocedural complications. Stent insertion before subsequent surgery has no effect on perioperative mortality and long-term survival. PMID- 21789643 TI - Rapid adaptation of robotic gastrectomy for gastric cancer by experienced laparoscopic surgeons. AB - BACKGROUND: Robotic surgery for gastric cancer patients has been increasing because of its many advantages over conventional laparoscopic surgery. Despite the suggestion that robotic surgery may lessen the learning curve for complex laparoscopic procedures, little is known about the learning curve for robotic gastrectomy. This study aimed to assess the learning curve of robotic gastrectomy for patients with cancer by analyzing the operation time. METHODS: The first 20 consecutive cases of robot-assisted distal gastrectomy with lymphadenectomy for gastric cancer performed by three experienced laparoscopic surgeons' using the da Vinci system were collected and reviewed. A nonlinear least-squares method was developed and used to analyze the learning curves. RESULTS: Overall, the mean operation time was 247.3 +/- 45.7 min, depending on each surgeon's laparoscopic experience and the patient's characteristics. After control was used for confounding factors, the stabilized operation time decreased to 211.8 min. The operation time stabilized at 8.2 cases and was reduced 111.4 min from the first case. A stable operation time was reached in 9.6 cases by surgeon A, in 18.1 cases by surgeon B, and in 6 cases by surgeon C. The stable operation time was 149.2 min for surgeon A, 127.1 min for surgeon B, and 236.8 min for surgeon C, and the reduction in operation time from the first case to stabilization was 233 min for surgeon A, 76.7 min for surgeon B, and 154.6 min for surgeon C. CONCLUSIONS: Surgeons with sufficient experience in laparoscopic gastrectomy can rapidly overcome the learning curve for robotic gastrectomy. In addition, the surgeon's experience with laparoscopic gastrectomy affects the operation time after stabilization and the reduction in operation time. PMID- 21789644 TI - Total laparoendoscopic single-site surgery (LESS) hysterectomy in low-risk early endometrial cancer: a pilot study. AB - BACKGROUND: In the last few years, technical advances have produced a dramatic shift from traditional open surgery toward a minimally invasive approach, even in oncological procedures. We present our initial experience with laparoendoscopic single-site surgery (LESS) in the surgical treatment of early-stage endometrial cancer patients. METHODS: Between July 2009 and May 2010, 20 consecutive low-risk early endometrial cancer patients were enrolled in this single institution prospective cohort trial. RESULTS: The median age of the patients was 57 years (range = 42-68) and median body mass index was 24 kg/m(2) (range = 21-30). Median operative time was 105 min (range = 85-155) and median estimated blood loss was 20 ml (range = 10-180). The larger skin and fascial incision required for the single-port approach was 2.5 cm (median = 2.2 cm; range = 2.0-2.5). No laparoscopic/laparotomic conversion was registered, and no insertion of additional ports was necessary. Median ileus was 16 h (range = 12-20) and median time to discharge was 1 day (range = 1-2). All patients were completely satisfied with the cosmetic results and postoperative pain control. CONCLUSIONS: Laparoendoscopic single-site surgery could represent a surgical option for extra fascial hysterectomy in early-stage endometrial cancer patients, with the potential to further decrease invasiveness of the conventional laparoscopic approach. PMID- 21789645 TI - Postimplant intraperitoneal behavior of collagen-based meshes followed by laparoscopy. AB - BACKGROUND: When repairing an abdominal wall defect, sometimes a prosthetic mesh needs to be placed directly on the parietal peritoneum. Although the standard mesh for this purpose is the laminar implant expanded polytetrafluoroethylene (PTFE), it is gradually being replaced by the laminar collagen-based meshes. This study was designed to assess the intraperitoneal behavior of three of these biomeshes, mainly in terms of their susceptibility to adhesion formation. METHODS: Two 3-cm * 3-cm fragments of prosthetic material were placed on the parietal peritoneum in male New Zealand White rabbits in the following combinations: PTFE and CollaMend((r)), PTFE and Permacol((r)), or PTFE and Surgisis((r)). The meshes were fixed at the four corners with individual 4/0 polypropylene sutures. Adhesion formation was quantified by sequential laparoscopy and image analysis performed at 3, 7, 14, and 90 days postimplant. All animals were killed at 90 days and the mesh specimens were subjected to microscopy and immunohistochemistry. RESULTS: Intensely vascularized adhesions to all the implants were observed, although Surgisis showed the lowest percentage of adhesions at each follow-up time. Adhesions had stabilized by 7-14 days. The PTFE meshes were enveloped by a layer of macrophages and connective tissue, bounded by a monolayer of mesothelial cells. Permacol and CollaMend showed similar histological behavior, including cell ingrowth through their fenestrations with no signs of degradation detected at 90 days. In contrast, the Surgisis mesh at 90 days was practically replaced with neoformed tissue. CONCLUSIONS: No difference in susceptibility to adhesion formation was noted in the crosslinked collagen meshes compared to PTFE meshes. The noncrosslinked collagen mesh Surgisis showed the best behavior in that it induced fewer adhesions. Ninety days after implant, a more intense macrophage response was observed in CollaMend and Permacol than in PTFE or Surgisis. PMID- 21789646 TI - Laparoscopic Dor versus Toupet fundoplication following Heller myotomy for achalasia: results of a multicenter, prospective, randomized-controlled trial. AB - BACKGROUND: The type of fundoplication that should be performed in conjunction with Heller myotomy for esophageal achalasia is controversial. We prospectively compared anterior fundoplication (Dor) with partial posterior fundoplication (Toupet) in patients undergoing laparoscopic Heller myotomy. METHODS: A multicenter, prospective, randomized-controlled trial was initiated to compare Dor versus Toupet fundoplication after laparoscopic Heller myotomy. Outcome measures were symptomatic GERD scores (0-4, five-point Likert scale questionnaire) and 24-h pH testing at 6-12 months after surgery. Data are mean +/ SD. Statistical analysis was by Mann-Whitney U test, Wilcoxon signed rank test, and Freidman's test. RESULTS: Sixty of 85 originally enrolled and randomized patients who underwent 36 Dor and 24 Toupet fundoplications had follow-up data per protocol for analysis. Dor and Toupet groups were similar in age (46.8 vs. 51.7 years) and gender (52.8 vs. 62.5% male). pH studies at 6-12 months in 43 patients (72%: Dor n = 24 and Toupet n = 19) showed total DeMeester scores and % time pH < 4 were not significant between the two groups. Abnormal acid reflux was present in 10 of 24 Dor group patients (41.7%) and in 4 of 19 Toupet patients (21.0%) (p = 0.152). Dysphagia and regurgitation symptom scores improved significantly in both groups compared to preoperative scores. No significant differences in any esophageal symptoms were noted between the two groups preoperatively or at follow-up. SF-36 quality-of-life measures changed significantly from pre- to postoperative for five of ten domains in the Dor group and seven of ten in the Toupet patients (not significant between groups). CONCLUSION: Laparoscopic Heller myotomy provides significant improvement in dysphagia and regurgitation symptoms in achalasia patients regardless of the type of partial fundoplication. Although a higher percentage of patients in the Dor group had abnormal 24-h pH test results compared to those of patients who underwent Toupet, the differences were not statistically significant. PMID- 21789647 TI - Endoscopic submucosal dissection versus local excision for early rectal neoplasms: a comparative study. AB - BACKGROUND: Transanal local excision (LE) is a well-established treatment option for early rectal neoplasms not amenable to complete colonoscopic removal. Endoscopic submucosal dissection (ESD) has been introduced recently as a novel procedure that enables en bloc resection of large rectal neoplasms. To date, no report comparing the two approaches can be found in the literature. This study aimed to compare the short-term clinical outcomes between ESD and LE for early rectal neoplasms. METHODS: Between 2007 and 2010, 14 patients with early rectal neoplasms deemed not feasible for en bloc endoscopic resection using conventional techniques underwent ESD. They were compared with a matched cohort of 30 patients who had early rectal neoplasms and underwent LE between 2000 and 2009. Short-term clinical outcomes including postprocedure recovery and morbidity were compared between the two groups. RESULTS: The mean lesion size was comparable between the ESD and LE groups (2.9 vs 2.6 cm; P = 0.423), but the mean distance of the lesions from the anal verge was greater in the ESD group (8.6 vs 5.0 cm; P = 0.001). En bloc resection was achieved for 12 patients (85.7%) in the ESD group and for all the patients in the LE group. The ESD group exhibited a trend toward a longer operative time (77.5 vs 50.0 min; P = 0.081) but lower morbidity (7.1 vs 33.3%; P = 0.076). The time to full ambulation was shorter in the ESD group (0 vs 1 day; P = 0.005), but the hospital stay was similar in the two groups (2.5 vs 4.0 days; P = 0.129). CONCLUSION: For the treatment of early rectal neoplasms, ESD offers better short-term clinical outcomes in terms of faster recovery and possibly lower morbidity than LE. Further prospective studies with a larger sample are needed to validate the benefits of rectal ESD. PMID- 21789648 TI - Comparison of anterior transgastric access techniques for natural orifice translumenal endoscopic surgery. AB - BACKGROUND: The advancement of natural orifice translumenal endoscopic surgery (NOTES) into clinical practice is dependent on its safety, efficacy, and efficiency. Access is the obligatory first step in NOTES and serves as a surrogate to technical difficulties associated with this novel surgical approach. This study aimed to compare endoscopic transgastric access techniques in terms of safety, reproducibility, and efficiency. METHODS: Seven variations for anterior transgastric NOTES access were evaluated with female domestic swine. After marking of an anterior site, electrocautery was used to create a small gastrotomy, followed by balloon dilation and entry into the peritoneal cavity. Methodologic variations incorporated the use of guidewires, electrocautery and dilation combined within a single device, support tubes, and dilation without electrocautery. Access times were recorded, and tissue injury was evaluated. RESULTS: In 70 access attempts, the most serious complication was bleeding from the gastroepiploic vessel, controlled with electrocautery. High variability in access times was prevalent with almost all the access techniques. CONCLUSIONS: This study supports the presumption that an anterior transgastric access technique for NOTES procedures is safe. The use of a wire to mark the site and another wire to retain the gastrotomy provided safe, efficient, and reproducible transgastric access. Comparison with laparoscopy exposed the disparity in technical challenges facing NOTES, suggesting that new technology and further refinement in methodology are required for NOTES to be clinically relevant. PMID- 21789649 TI - Laparoscopy within a fast-track program enhances the short-term results after elective surgery for resectable colorectal cancer. AB - BACKGROUND: Whether laparoscopic colorectal resection improved recovery within an enhanced recovery program was investigated. METHODS: This study was designed as a query of a prospectively maintained colorectal database to identify 350 patients who underwent elective colorectal resection with primary anastomosis for colorectal cancer between January 1, 2005 and December 31, 2009. Patients were categorized into two groups (laparoscopic and open resection), and demographic, treatment, and outcome variables were independently reviewed for accuracy. A detailed fast-track protocol was prepared and distributed to all patients, department doctors, and nurses to standardize the treatment. RESULTS: A total of 209 patients underwent laparoscopic-assisted colorectal resection, and 141 had open surgery. There was no difference between the two groups in terms of age, sex, BMI, ASA, comorbidity, previous abdominal surgery, preoperative chemoradiotherapy, cancer site, and AJCC 2002 staging. Twenty-three patients in the laparoscopic group required conversion to an open procedure due to hemorrhage, tumor extension, or technical difficulties. Laparoscopic patients had earlier tolerance of diet, bowel movement, flatus and stool canalization, mobilization, suction drain removal, and interruption of analgesic drug administration. Length of postoperative stay was shorter (4 vs. 7 days, p = 0.0004) and fewer postoperative nonsurgical complications (3 vs. 13% p = 0.009) were registered for the laparoscopic group. CONCLUSIONS: This study suggests that within an enhanced recovery program, laparoscopic resection may provide the best short-term clinical outcomes for patients with resectable colorectal cancer. PMID- 21789650 TI - Neurofeedback for insomnia: a pilot study of Z-score SMR and individualized protocols. AB - Insomnia is an epidemic in the US. Neurofeedback (NFB) is a little used, psychophysiological treatment with demonstrated usefulness for treating insomnia. Our objective was to assess whether two distinct Z-Score NFB protocols, a modified sensorimotor (SMR) protocol and a sequential, quantitative EEG (sQEEG) guided, individually designed (IND) protocol, would alleviate sleep and associated daytime dysfunctions of participants with insomnia. Both protocols used instantaneous Z scores to determine reward condition administered when awake. Twelve adults with insomnia, free of other mental and uncontrolled physical illnesses, were randomly assigned to the SMR or IND group. Eight completed this randomized, parallel group, single-blind study. Both groups received fifteen 20-min sessions of Z-Score NFB. Pre-post assessments included sQEEG, mental health, quality of life, and insomnia status. ANOVA yielded significant post-treatment improvement for the combined group on all primary insomnia scores: Insomnia Severity Index (ISI p<.005), Pittsburgh Sleep Quality Inventory (PSQI p<.0001), PSQI Sleep Efficiency (p<.007), and Quality of Life Inventory (p<.02). Binomial tests of baseline EEGs indicated a significant proportion of excessively high levels of Delta and Beta power (p<.001) which were lowered post-treatment (paired z-tests p<.001). Baseline EEGs showed excessive sleepiness and hyperarousal, which improved post-treatment. Both Z-Score NFB groups improved in sleep and daytime functioning. Post-treatment, all participants were normal sleepers. Because there were no significant differences in the findings between the two groups, our future large scale studies will utilize the less burdensome to administer Z-Score SMR protocol. PMID- 21789651 TI - Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. AB - The continuous exposure of the colonic epithelium to high concentrations of bile acids may exert cytotoxic effects and has been related to pathogenesis of colon cancer. A better knowledge of the mechanisms by which bile acids induce toxicity is still required and may be useful for the development of new therapeutic strategies. We have studied the effect of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) treatments in BCS-TC2 human colon adenocarcinoma cells. Both bile acids promote cell death, being this effect higher for CDCA. Apoptosis is detected after 30 min-2 h of treatment, as observed by cell detachment, loss of membrane asymmetry, internucleosomal DNA degradation, appearance of mitochondrial transition permeability (MPT), and caspase and Bax activation. At longer treatment times, apoptosis is followed in vitro by secondary necrosis due to impaired mitochondrial activity and ATP depletion. Bile acid-induced apoptosis is a result of oxidative stress with increased ROS generation mainly by activation of plasma membrane enzymes, such as NAD(P)H oxidases and, to a lower extent, PLA2. These effects lead to a loss of mitochondrial potential and release of pro-apoptotic factors to the cytosol, which is confirmed by activation of caspase-9 and -3, but not caspase-8. This initial apoptotic steps promote cleavage of Bcl-2, allowing Bax activation and formation of additional pores in the mitochondrial membrane that amplify the apoptotic signal. PMID- 21789653 TI - Stenosis of the small intestine after reduction of strangulated Littre hernia in an infant. AB - Herniation and incarceration of a Meckel's diverticulum in a hernial sac-Littre hernia-is a relatively uncommon surgical emergency. Segmental stenosis of small intestine after hernia reduction and consecutive intestinal obstruction is a similarly rare emergency. The combination of both these disorders is extremely uncommon at any age and especially during infancy. The obvious rarity of the condition, its subtle diagnostic features, the potentially ominous course of events and the age of patient indicate early surgery as a life-saving solution. PMID- 21789652 TI - Temperature dependent plasticity of habituation in the crayfish. AB - To determine the effects of thermal preconditioning on a simple form of learning and memory, habituation, we preconditioned crayfish with extreme temperatures and subsequently analysed their effects on mechanosensory input that evokes a response in the lateral giant interneurons, within the normal temperature range of the animal. We found that repetitive stimulation with a 1 s interstimulus interval led to habituation of the response the lateral giant in control animals at 22 degrees C. Neither heat nor cold preconditioning had any effect on the probability of evoking a response in the lateral giant nor on the rate at which habituation occurred. With a 1 min interstimulus interval, however, the rate of habituation of the lateral giant in the heat-preconditioned group was less than either the control or cold-preconditioned animals. The effect of heat or cold pre exposure was specific to the input to the lateral giant at control temperatures. For example, at 22 degrees C prior heat and cold preconditioning had no effect on spontaneous reductor motor neurone activity. They did, however, provide thermoprotection at extreme temperatures, with the probability of spontaneous activity higher in the cold-preconditioned group at low temperatures but higher in the heat-preconditioned group at higher temperatures. PMID- 21789654 TI - Prospective randomized trial comparing sutured with sutureless mesh fixation for Lichtenstein hernia repair: long-term results. AB - BACKGROUND: Following Lichtenstein hernia repair, up to 25% of patients experience prolonged postoperative and chronic pain as well as discomfort in the groin. One of the underlying causes of these complaints are the compression or irritation of nerves by the sutures used to fixate the mesh. We compared the level and rate of chronic pain in patients operated with the classical Lichtenstein technique fixated by sutures to patients with sutureless mesh fixation technique. METHODS: A two-armed randomized trial with 264 male patients was performed. After consent, patients were randomized preoperatively. For the fixation of the mesh we used either sutures with slow-absorbing material (PDS 2.0) (group I, n = 133) or tissue glue (Histoacryl) (group II, n = 131). Follow up examinations were performed after 3, 12 months and after 5 years. RESULTS: Patient characteristics in the two groups were similar. No cross-over between groups was observed. After 5 years, long-term follow-up could be completed for 59% of subjects. After 5 years, 10/85 (11.7%) patients in group I and 3/70 (4.2%) in group II suffered from chronic pain in the groin region (P = 0.108). The operation time was significantly shorter in group II (79 min vs 73 min, P = 0.01). One early recurrence occurred in group II (3 months). The recurrence rate was 0 and 0% after 12 months and 5.9% (5/85) and 10% (7/70) after 5 years in group I and group II, respectively (P = 0.379). CONCLUSION: After 5 years, the two techniques of mesh fixation resulted in similar rates of chronic pain. Whereas recurrence rates were comparable, fixation of the mesh with tissue glue decreased operating room time significantly. Hence, suture less mesh fixation with Histoacryl is a sensible alternative to suture fixation and should be especially considered for patients prone to pain. PMID- 21789655 TI - Long-term quality of life after hernioplasty using a Prolene hernia system in adult inguinal hernia. AB - INTRODUCTION: Most surgeons favour the use of a mesh for open inguinal hernia repair as it has a low recurrence rate. Procedures used most frequently are the Lichtenstein method, mesh plug repair and the Prolene hernia system (PHS). The choice of technique may be influenced by effects on postoperative pain and quality of life. In this retrospective study, results from inguinal hernia repair with the PHS in a regional training hospital were analysed. PATIENTS AND METHODS: Thirty primary inguinal hernias were treated with PHS. The primary endpoint was the recurrence rate. Secondary endpoints were short-term and long-term complications. Pain was evaluated by use of a visual analog scale (VAS, 0-100), and a short-form 36-item questionnaire was used to assess postoperation quality of life. All patients visited the outpatient clinic for a physical examination (100% follow up). RESULTS: After a median follow up of 8 years, one patient was diagnosed with recurrent herniation (3.3%). Three self-limited wound discharge (10%), and one haematoma needing surgical evacuation (3.3%) were diagnosed. Two patients (6.6%) suffered from persistent pain (VAS > 40). Average VAS score was 21 (0-80) 8 years after surgery. CONCLUSION: In a regional training hospital, primary inguinal hernias were treated with low recurrence and few complications by use of the PHS. PMID- 21789656 TI - Pelvic floor muscle function before and after first childbirth. AB - INTRODUCTION AND HYPOTHESIS: Pregnancy and vaginal delivery are considered to be the main risk factors for development of pelvic floor dysfunction. We hypothesize that; 1) pelvic floor muscle (PFM) strength and endurance is significantly reduced by first delivery in general, and 2) changes in PFM strength and endurance are influenced by mode of delivery. METHODS: Prospective repeated measures observational study. Thirty-six women completed the study. PFM function was measured as vaginal squeeze pressure. Paired t-test was used to compare PFM function before and after first childbirth for all participants as a group. One way ANOVA was used to compare changes between different modes of delivery. RESULTS: A significant reduction in PFM strength (p < 0.0001) and endurance (p < 0.0001) was found for all participants after first childbirth. The reduction in strength was 20.1 hPa (CI:16.2; 24.1), 31.4 hPa (CI: 7.4; 55.2) 5.2 hPa (CI: 6.6; 17.0) in the normal vaginal, instrumental vaginal and acute cesarean groups, respectively. The difference was significant between normal vaginal and acute cesarean birth (p = 0.028) and instrumental vaginal and acute cesarean birth (p = 0.003). CONCLUSION: PFM strength is significantly reduced after vaginal delivery, both normal and instrumental, 6 to 12 weeks postpartum. Acute cesarean section resulted in significantly less muscle strength reduction. PMID- 21789657 TI - The IUGA/ICS classification of complications of prosthesis and graft insertion: a comparative experience in incontinence and prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: This is a presentation of case series after the use of alloplasic material in urogynaecology. METHODS: From 2004 to 2010, a total 179 patients with complications have been referred directly after the use of alloplastic material in incontinence and prolapse surgery. Of this total, 125 patients had a previous vaginal sling plasty because of urinary stress incontinence, while 54 patients underwent a prolapse surgery with mesh use. Symptoms and findings are expressed by the recently introduced International Urogynecological Association/International Continence Society (IUGA/ICS) terminology. RESULTS: The most frequent findings after vaginal sling plasty were bladder outlet obstruction, pain and tape exposure. The most frequent findings after prolapse surgery were pain and mesh erosion. The IUGA/ICS classification does not give the possibility to express functional disorders. Most revisions were done more than 2 months after surgery. After incontinence surgery, mostly the vaginal area of suture line was affected; after prolapse surgery, the vagina and the trocar passage were affected. CONCLUSIONS: Mesh complication and affected site after prolapse surgery do differ from those after incontinence surgery. The IUGA/ICS classification of mesh complication facilitates the comparison of mesh complication. PMID- 21789658 TI - Lessons from a patient experience survey in a randomized surgical trial of treatment of stress urinary incontinence in women. AB - INTRODUCTION AND HYPOTHESIS: To understand the patient burden of study procedures/measures at completion of a randomized controlled trial (RCT) requiring extensive testing and follow-up visits. METHODS: A survey sent after completing the 2-year visit of an RCT comparing Burch colposuspension and fascial retropubic sling to treat stress urinary incontinence assessed degree of bother for seven study procedures, eight study-related factors, and possible motivations to participate in the study. RESULTS: A total of 450 study participants (88%) returned the survey. Urodynamic testing was the most bothersome procedure, followed by 24-h pad test and Q-tip test. Self-administered questionnaires were the least bothersome. Main reasons to participate in the study were to help others, obtain better knowledge about the condition, and be guided by a committed team of investigators/study coordinators. CONCLUSIONS: At the end of a large multicenter RCT, we learned from a confidential patient survey that the most burdensome activities involved invasive procedures, frequent visits, and multiple forms to fill out. PMID- 21789659 TI - Genetics of pelvic organ prolapse: crossing the bridge between bench and bedside in urogynecologic research. AB - An increasing number of scientists have studied the molecular and biochemical basis of pelvic organ prolapse (POP). The extracellular matrix content of the pelvic floor is the major focus of those investigations and pointed for potential molecular markers of the dysfunction. The identification of women predisposed to develop POP would help in the patients' management and care. This article includes a critical analysis of the literature up to now; discusses implications for future research and the role of the genetics in POP. PMID- 21789660 TI - The effect of pregnancy and childbirth on pelvic floor muscle function. AB - INTRODUCTION AND HYPOTHESIS: The effect of pregnancy and mode of delivery on pelvic floor muscle function (PFMF) is unclear. Our aim was to prospectively evaluate the effect of pregnancy and childbirth on PFMF. METHODS: Subjective (Oxford scale) and objective (perineometry) assessments of PFMF were performed at 20 and 36 weeks gestation and at 14 weeks and 12 months after delivery. The resting pressure (RP) and the maximum squeeze pressure (MSP) were recorded. RESULTS: Four hundred three women (182 nulliparous and 221 multiparous) were recruited. Two hundred ninety-four (73%) delivered vaginally and 92 (23%) by caesarean section. RP and MSP improved significantly (p < 0.01) during pregnancy. After childbirth, a significant decrease in PFMF was demonstrated, which recovered completely by 1 year in majority of women. CONCLUSIONS: There appears to be a physiological increment in PFMF during pregnancy. The pelvic floor weakens temporarily after childbirth but contractility appears to recover by 1 year irrespective of the mode of delivery. PMID- 21789662 TI - Atypical presentation of abdominal group A streptococcal-necrotizing fasciitis after pessary removal. AB - Group A streptococcal (GAS) necrotizing fasciitis is a potentially life threatening infection. We report on a patient with a history of prolonged pessary use with traumatic removal who developed ascending GAS infection in her gynecologic organs that tracked along the round ligament to her anterior abdominal wall. PMID- 21789661 TI - Double-blinded randomized trial of preoperative antibiotics in midurethral sling procedures and review of the literature. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to determine if prophylactic antibiotic use before midurethral sling procedures reduces infectious complications. METHODS: In this double-blinded randomized trial, we compared infectious complications between women who received cefazolin and placebo before midurethral sling procedures. RESULTS: The study was halted due to low rate of infectious outcomes seen at the first scheduled interim analysis. We enrolled 29 women in the cefazolin group and 30 in the placebo group. Total follow-up was 6 months (3-24 months). The groups were similar at the baseline. There was no statistically significant difference between the cefazolin and placebo groups, respectively, with respect to wound infections [1 (3.3%) and 0 (0%)], mesh exposure [0 (0%) and 1 (3.5%)], and bacteriuria [3 (10%) and 1 (3.5%)]. CONCLUSION: Because infection rates are low in both cefazolin and placebo groups, omitting preoperative antibiotics for midurethral slings may be justified. PMID- 21789663 TI - Maternal depression and child and adolescent depression symptoms: an exploratory test for moderation by CRHR1, FKBP5 and NR3C1 gene variants. AB - This study investigated moderation of the association between recurrent maternal depression and offspring depression symptoms by a selection of biologically relevant gene variants. 271 children/adolescents (aged 9.00 to 16.00 years) whose mothers had experienced at least two episodes of DSM-IV major depression and 165 controls (aged 12.25 to 16.67 years) drawn from a population-based twin register were used. Seven single nucleotide polymorphisms (SNPs) from three genes were genotyped in children. The genes were the Corticotropin Receptor Type 1 gene (CRHR1), the gene coding for the FK506 binding protein 5 (FKBP5) and the Glucocorticoid receptor gene (NR3c1) along with a haplotype formed by the SNPs in CRHR1. A significant association was found between recurrent maternal depression and depression symptoms in offspring. None of the SNPs were associated with offspring depression symptoms and associations did not differ according to the presence of recurrent maternal depression. However, caution is required due to a relatively small sample size. PMID- 21789664 TI - Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto inflammatory condition that mimics multiple classic radiographic findings. AB - Deficiency of interleukin-1-receptor antagonist (DIRA) syndrome is a newly identified inflammatory disease of the skeleton and appendicular soft tissues presenting in early infancy that has yet to be reported in the radiology literature. The radiological manifestations of DIRA syndrome include multifocal osteitis of the ribs and long bones, heterotopic ossification and periarticular soft-tissue swelling. Thus, the pediatric radiologist should be made aware of this novel disease because its radiographic findings can mimic multiple other disease entities. With knowledge of the unique clinical presentation of DIRA syndrome and its multiple radiographic manifestations, the pediatric radiologist may be the first to suggest the correct diagnosis. PMID- 21789665 TI - Residual aganglionosis after pull-through operation for Hirschsprung's disease: a systematic review and meta-analysis. AB - PURPOSE: Most patients with Hirschsprung's disease (HD) have a satisfactory outcome after pull-through (PT) operation. However, some children continue to have persistent bowel symptoms after the initial operation and may require redo PT. Redo PT operation in HD is usually indicated for anastomotic strictures or residual aganglionosis (RA). We designed this meta-analysis to determine the incidence and outcome of RA among patients with HD following PT operation. METHODS: A meta-analysis of redo PT operations for HD reported in the literature between 1985 and 2011 was performed. Detailed information was recorded in patients with RA and transition-zone bowel (TZB), including recurrent bowel problems, histological findings on repeat rectal biopsy, type of redo PT operation and outcome. RESULTS: Twenty-nine articles reported 555 patients with redo PT operations. 193 (34.8%) patients demonstrated abnormal histological findings on rectal biopsy with 144 patients showing RA and 49 patients showing TZB. These 193 patients presented with persistent constipation (n = 135), recurrent enterocolitis (n = 45) and abnormal histology of the pulled-through bowel (n = 13). Mean age at redo PT was 4.4 years (range 4 months-17 years). Redo procedures were Duhamel (n = 57), transanal endorectal PT (n = 40), Soave (n = 35), Swenson (n = 10), posterior sagittal approach (n = 1) and not reported (n = 50). Follow-up information after redo PT was available in 134 (69.4%) patients and not available in 59 patients. Of the 134 patients, 99 (73.9%) patients had normal bowel habits, 19 patients had persistent constipation/soiling and 16 patients had recurrent enterocolitis. CONCLUSION: This meta-analysis reveals that RA and TZB are the underlying causes of persistent bowel symptoms in one-third of all patients with HD requiring redo PT operation. Most patients have a satisfactory outcome after redo operation. Rectal biopsy should be performed in all patients with recurrent bowel problems after PT operation. PMID- 21789666 TI - Ostomy complications in patients with anorectal malformations. AB - PURPOSE: Ostomy is an important step in the treatment of patients with anorectal malformation (ARM). Sometimes this basic surgical procedure may cause a devastating complication. METHODS: The medical reports of the patients with ARM who had ostomy in the past were inspected. How many of them were operated in this center or sent from others, the type of ARM, what type of ostomy performed and which place of the bowel used and the complication type and rate related to ostomy and ostomy closure were evaluated. RESULTS: Nearly, 157 of 230 patients with ARM had ostomy during twenty-two years were evaluated. The prevelent type of ostomy was loop (50.3%) and then separated (36.9%), end (7%), double barrel (4.4%) and window (1.2%). The ostomies were located in the tranverse colon (53.5%), descending colon (24.2%), sigmoid colon (17.8), pouch colon (2.5%) and ileum (1.9). Total complication rate was found to be 15.2% (24/157) (window 100%, double barrel 42.8%, separated 15.5%, loop 11.3%, end 9%). The main complication of loop ostomies was prolapse whereas wound problems, stenosis, intestinal obstruction or perforation were serious problems of separated ostomies. Complication rate in the descending colon and tranverse colon was found to be 7.1 and 28%, respectively (p = 0.001). Any difference for complication rate between loop and separated ostomies was not found. Eighteen of separated ostomies had mucous fistula and six of them (33%) were complicated, this rate was higher than those without mucous fistula (p = 0.012). Two babies with separated ostomy were lost due to surgical complications (1.2%). Complication rate after ostomy closure was 10.7% [wound infection (4.4%), intestinal obstruction (1.7%)]. CONCLUSION: According to this study, ostomy performed in the descending colon carries greater risks for complication regardless of its type. Nevertheless, separated ostomy with mucous fistula should be performed by experienced hands. PMID- 21789667 TI - Medical predictors of psychological anxieties in VATER patients. AB - BACKGROUND/PURPOSE: Following a recent classification of the VATER Association provided by the CURE-Net consortium (submitted), we investigate medical predictors of psychological stress and anxieties in this particular condition. METHODS: We developed a new set of questionnaires measuring psychological adjustment and quality of life outcome in conditions associated with anorectal and/or urogenital malformation (one self- report form to be completed by patients 7-17 years of age, two parent report forms with one relating to patients with an age range of 0-6 years, resp. 7-17 years of age). The questionnaire "Malformation related Stress and Anxieties" comprises 26 items belonging to five subscales (I. Functional and cosmetic impairment, II. Intimacy and relationship, III. Social inclusion, IV. Psychological functioning, V. Family functioning). Every item can be responded to with respect to both actual, present problems already experienced as well as to future anxieties anticipating future development and adjustment (a perspective which especially applies in younger patients). Internal consistencies of the scales are good, resp. very good (Cronbach's alpha = .85 concerning present sources of anxiety scale, resp., .94 concerning future anxieties scale). The items are supplied with a Likert-type 5-point scale. We administered the questionnaire in N = 17 children and adolescents suffering from VATER via parental (proxy) report. RESULTS: As most medical risk factors affected nearly the entire sample, statistical analysis excluded investigation of differential impact on psychological stress experience and anxieties in subjects exposed versus not exposed. Special attention, therefore, was paid to those medical parameters with the best statistical power to differentiate between individuals of high versus low psychological outcome. Medical predictors differentiating between individuals with high versus low adjustment comprise post-operative infections of the urinary tract (t[15] = -3.78, p = .09), wound infections (t[15] = -3.04, p < .01), stoma complications (t[15] = -2.11, p = .08) (e.g., prolapsed (t[13] = -2.37, p = .05), other treatment complications (t[15] = -2.59, p < .05) and presence of a megacolon (t[13] = -2.44, p = .06). DISCUSSION AND CONCLUSIONS: From the perspective of stress psychology, the findings may indicate that particular medical characteristics of a malformation may operate via two different pathways: (a) pathway of severity of a particular medical risk factor: the presence of a megacolon, for example, may restrict quality of life and successful adjustment via multiple and long term functional impairments associated and (b) pathway of subjective predictability and controllability of treatment course. In accordance with theoretical models from stress psychology, the psychological impact of complicating factors such as wound-healing infections is not operating via severity of impairment, but via implicit messages they convey, indicating a low predictability and controllability of course of disease and treatment. As a result, they may increase intensity of worry and anxieties upon further difficulties still to come during future development. As a conclusion, psychological counseling may not only address concrete functional impairments and stressors, but also basic feelings of insecurity, controllability and self-efficacy. PMID- 21789668 TI - Pseudopapillary tumor in pediatric age: clinical and surgical management. AB - BACKGROUND: Solid pseudopapillary tumors of the pancreas are rare exocrine pancreatic tumors. Through a review of pediatric cases in a single Institution, we present the clinical and surgical management of this neoplasm. METHODS: We retrospectively reviewed the clinical charts of patients treated at our unit between 1995 and 2009 for SPT. Clinical and surgical management were analyzed and reported. RESULTS: During the study period 11 patients underwent surgery for pseudopapillary tumor. Five patients were treated with duodenum-preserving pancreatic head resection and six patients with splenopancreasectomy with a Roux en-Y pancreatic jejunostomy. Patients did not show recurrence and are currently disease free. Blood tests, Ultrasound, Computed tomography and Magnetic Resonance Imaging were not useful to preoperatively identify the nature of the pancreatic masses. CONCLUSION: Solid pseudopapillary tumor is a rare condition that should be taken into account for the differential diagnosis of pancreatic masses in pediatric age. Due to its favourable prognosis, surgical removal should be planned and done following the intraoperative findings. PMID- 21789669 TI - A comprehensive review about micronuclei: mechanisms of formation and practical aspects in genotoxicity testing. PMID- 21789670 TI - Sertoli cells proliferate in adult rats with prenatal exposure to 3,3',4,4',5 pentachlorobiphenyl. AB - Sertoli cells play a critical role in spermatogenesis, and in adults, they are terminally differentiated with loss of proliferative activity. This study revealed Sertoli cell proliferation in 17-week-old Sprague-Dawley rats whose dams had been intragastrically administered 250 ng of 3,3',4,4',5 pentachlorobiphenyl/kg on days 13-19 postconception. Immunohistochemical evidence of proliferating cell nuclear antigen (PCNA) expression and electron microscope observation of mitotic figures confirmed the proliferation. Because the serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations were similar to those of vehicle-treated rats, a direct endocrine cause for the observed effects was unlikely. PMID- 21789671 TI - Male faecal incontinence presents as two separate entities with implications for management. AB - AIM: In contrast to females, male faecal incontinence has received little attention. We investigate its pattern and management at a large UK teaching hospital. METHODS: Men presenting with faecal incontinence between January 2006 and December 2008 were identified from a gastrointestinal physiology database and classified into faecal leakage or faecal incontinence on the basis of symptomatology. Demographics, Cleveland Clinic incontinence score (CCIS), aetiological factors, investigations and treatments were collected by case note review and compared to clinical outcomes. RESULTS: Forty-three symptomatic patients were identified with faecal incontinence, in which 33 were classified as having faecal leakage (FL) and ten as faecal incontinence (FI). The mean CCIS was 10.7 (range, 4-14) and 14.2 (8-20) for FL and FI, respectively. The FL group had normal anal sphincter pressures, whilst the FI group had significantly lower mean resting pressure, 45 mmHg (8-90 mmHg), and mean squeeze pressure, 62.1 mmHg (18 110 mmHg). Thirteen out of 33 patients in the FL group and seven out of ten in the FI group had undergone previous anorectal surgery and had demonstrable sphincter defects whilst in the remainder, no definite aetiological factor could be identified. All patients in the FL group improved with lifestyle changes (28/33) or biofeedback (5/33). Six patients in the FI group required surgical intervention (3/6, collagen injection; 1/6, graciloplasty; 1/6, sacral nerve stimulation; 1/6, rectopexy). CONCLUSIONS: Patients presenting with FL characteristically have normal anorectal physiology and respond to non-operative measures, as compared to patients with FI who tend to have weakened anal sphincters, previous history of anorectal surgery, and more often require surgical intervention. PMID- 21789672 TI - ROAD: domestic assistant and rehabilitation robot. AB - This study introduces the concept design and analysis of a robotic system for the assistance and rehabilitation of disabled people. Based on the statistical data of the most common types of disabilities in Spain and other industrialized countries, the different tasks that the device must be able to perform have been determined. In this study, different robots for rehabilitation and assistance previously introduced have been reviewed. This survey is focused on those robots that assist with gait, balance and standing up. The structure of the ROAD robot presents various advantages over these robots, we discuss some of them. The performance of the proposed architecture is analyzed when it performs the sit to stand activity. PMID- 21789673 TI - Acute aquatic toxicity of tire and road wear particles to alga, daphnid, and fish. AB - Previous studies have indicated that tire tread particles are toxic to aquatic species, but few studies have evaluated the toxicity of such particles using sediment, the likely reservoir of tire wear particles in the environment. In this study, the acute toxicity of tire and road wear particles (TRWP) was assessed in Pseudokirchneriella subcapita, Daphnia magna, and Pimephales promelas using a sediment elutriate (100, 500, 1000 or 10000 mg/l TRWP). Under standard test temperature conditions, no concentration response was observed and EC/LC(50) values were greater than 10,000 mg/l. Additional tests using D. magna were performed both with and without sediment in elutriates collected under heated conditions designed to promote the release of chemicals from the rubber matrix to understand what environmental factors may influence the toxicity of TRWP. Toxicity was only observed for elutriates generated from TRWP leached under high temperature conditions and the lowest EC/LC(50) value was 5,000 mg/l. In an effort to identify potential toxic chemical constituent(s) in the heated leachates, toxicity identification evaluation (TIE) studies and chemical analysis of the leachate were conducted. The TIE coupled with chemical analysis (liquid chromatography/mass spectrometry/mass spectrometry [LC/MS/MS] and inductively coupled plasma/mass spectrometry [ICP/MS]) of the leachate identified zinc and aniline as candidate toxicants. However, based on the high EC/LC(50) values and the limited conditions under which toxicity was observed, TRWP should be considered a low risk to aquatic ecosystems under acute exposure scenarios. PMID- 21789674 TI - Effects of injected methylmercury on the hatching of common loon (Gavia immer) eggs. AB - To determine the level of in ovo methylmercury (MeHg) exposure that results in detrimental effects on fitness and survival of loon embryos and hatched chicks, we conducted a field study in which we injected eggs with various doses of MeHg on day 4 of incubation. Eggs were collected following about 23 days of natural incubation and artificially incubated to observe hatching. Reduced embryo survival was evident in eggs injected at a rate of >=1.3 MUg Hg/g wet-mass. When maternally deposited Hg and injected Hg were considered together, the median lethal concentration of Hg (LC(50)) was estimated to be 1.78 MUg Hg/g wet-mass. Organ mass patterns from eggs of chicks injected at a rate of 2.9 MUg Hg/g differed from that of controls and chicks from the 0.5 MUg Hg/g treatment, largely related to a negative relation between yolk sac mass and egg mercury concentration. Chicks from eggs in the 2.9 MUg Hg/g treatment were also less responsive to a frightening stimulus than controls and chicks from the 0.5 MUg Hg/g treatment. We also found that the length of incubation period increased with increasing egg mercury concentration. Tissue Hg concentrations were strongly associated (r(2) >= 0.80) with egg Hg concentration. PMID- 21789675 TI - Multilevel ecotoxicity assessment of polycyclic musk in the earthworm Eisenia fetida using traditional and molecular endpoints. AB - The ecotoxicity assessment of galaxolide (HHCB) and tonalide (AHTN) was investigated in the earthworm Eisenia fetida using traditional and novel molecular endpoints. The median lethal concentration (LC(50)) for 7-day and 14 day exposures was 573.2 and 436.3 MUg g(-1) for AHTN, and 489.0 and 392.4 MUg g( 1) for HHCB, respectively. There was no observed significant effect on the growth rate of E. fetida after a 28-day exposure except that at the highest concentration (100 MUg g(-1)) of AHTN and HHCB, whereas a significant decrease of cocoon production was found in earthworms exposed to 50 and 100 MUg g(-1). To assess molecular-level effect, the expression of encoding antioxidant enzymes and stress protein genes were investigated upon sublethal exposures using the quantitative real time PCR assay. The expression level of SOD, CAT and calreticulin genes was up-regulated significantly, while the level of annetocin (ANN) and Hsp70 gene expression was down-regulated in E. fetida. Importantly, the level of ANN expression had a significant positive correlation with the reproduction rate of earthworms. Furthermore, the lowest observed effect concentration (LOECs) of ANN expression level was 3 MUg g(-1) for AHTN and 10 MUg g(-1) for HHCB, suggesting that ANN gene expression can serve as a more sensitive indicator of exposure to AHTN and HHCB than traditional endpoints such as cocoon production. The transcriptional responses of these genes may provide early warning molecular biomarkers for identifying contaminant exposure, and the data obtained from this study will contribute to better understand the toxicological effect of AHTN and HHCB. PMID- 21789676 TI - Prevalence of bilateral 'mirror-image' lesions in patients with oral potentially malignant epithelial lesions. AB - Early detection of oral potentially malignant epithelial lesions (PMELs) is aimed at improving survival rates as carcinogenesis is a multistep process and prevention is possible if these lesions are detected at an early and reversible stage of the disease. A prospective clinical study aimed at determining the prevalence of bilateral 'mirror-image' oral PMELs was carried out. Sample consisted of 32 (53.3%) Indians, 23 (38.3%) Chinese, 4 (6.7%) Malays and one (1.7%) Nepalese. All had histopathological confirmation of their primary existing PMEL as inclusion criteria. A total of 70 primary lesions were detected. The most common PMEL found was oral lichen planus. Of these, 28 (46.7%) patients exhibited bilateral 'mirror-image' lesions (n = 42) either synchronously (n = 32/42) or metachronously (n = 10/42). The remaining 32 (53.3%) patients had normal-looking contralateral mucosa. Present findings suggest that patients presenting with oral PMELs are at greater risk of developing a second lesion, most probably in the contralateral 'mirror-image' site. PMID- 21789677 TI - Endoscopic treatment of juvenile nasopharyngeal angiofibromas: our experience and review of the literature. AB - The endoscopic resection of juvenile nasopharyngeal angiofibroma (JNA) emerges as an alternative approach to open procedures due to reduced morbidity and comparable recurrence rates. The purpose of this study was to present our experience with the endoscopic management of JNA using retrospective chart review of ten male patients (mean age 15.7 years) with JNA who were treated endoscopically at our institution between the years 2003 and 2010. According to the Radkowski's system, one patient was at stage Ia, two at stage Ib, one at stage IIa, two at stage IIb, two at stage IIc (infratemporal fossa invasion) and two at stage IIIa (clivus erosion). Six patients underwent preoperative embolization. The endoscopic treatment involved total ethmoidectomy, middle meatal antrostomy, sphenoidotomy, clipping of the sphenopalatine artery and its branches and drilling of the pterygoid basis. All patients underwent magnetic resonance imaging 3 months postoperatively and then if indicated clinically. Mean follow-up was 23.7 months (range 3-70). All but one patient were free of macroscopic disease. A patient with stage IIb JNA developed a recurrence after 9 months. The residual tumor was resected endoscopically and the sphenopalatine foramen widened by drilling. The patient is free of disease 25 months postoperatively. The intra-operative blood loss was not excessive (200-800 ml, mean: 444 ml) and no patient required a blood transfusion. Patients were discharged after 4-8 days (mean 5 days). One patient developed postoperative infraorbital nerve hypoesthesia. Results showed that endoscopic treatment of stage I and IIa/b JNA is a valid alternative to external approaches. For select tumors with limited infratemporal fossa invasion and skull base erosion, the endoscopic approach may also be indicated. It is a safe and effective treatment modality due to the lack of external scars, minimal bone resection and blood loss and low recurrence rate. PMID- 21789678 TI - Influence of age and gender in the sensory analysis of balance control. AB - Postural control is achieved through the integration at the central nervous system level of information obtained by the visual, somatosensory and vestibular systems. Computerized dynamic posturography and the Sway Star system are both used to carry out sensory analysis. The purpose of this study was to determine the influence of sex and age on sensory analysis, measured with these two systems, and to compare their results. A prospective trial was conducted with 70 healthy individuals (average age: 44.9 years) uniformly distributed in seven age groups, who underwent postural study with both systems. We used SPSS 16.0 for statistical study: comparison of means test for influence of gender and age and Pearson's correlation test (p < 0.05). Gender variable had no influence. The influence of age in vestibular input was found to be significant with both posturography systems, while visual input was only found to be significant with the Sway Star. The results with the two systems were not comparable. Sensory contribution does not remain stable throughout life. Visual information decreases with age, reaching a minimum at 40-49 years, and may correspond to the deterioration of eyesight with age. Propioceptive information showed no statistically significant changes, and several forms of treatment might correct the deterioration of this system. Vestibular information reaches a maximum in the 40-49 years age group in an attempt to compensate for visual deterioration, and decreases again in subsequent decades. This may be due to aging of the vestibular system and the difficulty in its correction. PMID- 21789679 TI - Harmonic FocusTM versus "knot tying" during total thyroidectomy: a randomized trial. AB - The objective of the study is to compare the outcome of total thyroidectomy (TT) using the Harmonic FocusTM (HF) versus conventional "knot tying" (KT) in terms of operative time, parathyroid function and post-operative complications. This prospective study was designed with a random allocation of subjects using a drawing technique. Eighty-one consecutive patients were submitted to TT in 2010 and randomly divided into two groups: 43 patients operated using HF (HF group) and 38 patients operated using KT (KT group). Parathyroid function was evaluated by parathyroid hormone (PTH) level at 1 h postoperatively and calcium level at first post-operative day. Indications for medical therapy were PTH < 15 pg/ml and/or calcium < 8.0 mg/dl and/or clinical signs or symptoms of hypocalcemia. Main outcomes were operative time, PTH and calcium levels, need for medical therapy and post-operative complications. Mean operative time was significantly lower in HF group compared with KT group (100 +/- 34 vs. 119 +/- 30 min). There were no significant differences concerning transient hypoparathyroidism requiring calcium and/or vitamin D therapy: 17 patients (39.5%) in HF group versus 21 (55.3%) in KT group. Five patients (11.6%) in HF group experienced symptomatic hypocalcemia versus 6 (15.8%) in KT group, without statistically significant difference. No patients experienced recurrent nerve injury. HF is a new ergonomic, reliable device developed for thyroid surgery. According to our results, HF is a safe, time-saving alternative to "knot tying" thyroidectomy, with no influence on parathyroid function, medical therapy and nerve injury. PMID- 21789680 TI - The modernized treatment of hepatocellular cancer: time to think twice! PMID- 21789681 TI - Adenocarcinoma below stapled ileoanal anastomosis after restorative proctocolectomy for ulcerative colitis. AB - A case of adenocarcinoma arising in a 39-year-old patient after restorative proctocolectomy is reported. The patient underwent an ileal pouch-anal anastomosis with double-stapled technique for severe ulcerative colitis 18 years earlier, without evidence of associated neoplasm or dysplasia in operative specimen. After endoscopic diagnosis of adenocarcinoma, the patient was submitted to excision of the pouch and permanent ileostomy, followed by combined radiotherapy and chemotherapy. Pathology showed an AJCC stage III moderately differentiated mucinous adenocarcinoma. The patient died 24 months after the operation, due to cancer progression. There are 50 reported cases in the indexed medical literature of carcinoma arisen after ileal pouch-anal anastomosis for ulcerative colitis. Twenty-five out of these arose after mucosectomy and hand sewn anastomosis, and 25 after stapling technique. Furthermore, in 48% of the patients, dysplasia or cancer was already present at the time of the colectomy. The increase of reported cases suggests a routine long-term endoscopic surveillance in patients with long-standing ileal pouches, especially in presence of dysplasia or cancer in the proctocolectomy specimen. PMID- 21789682 TI - Mapping of CIP/KIP inhibitors, G1 cyclins D1, D3, E and p53 proteins in the rat term placenta. AB - As cell cycle regulation is fundamental to the normal growth and development of the placenta, the aim of the present study was to determine the immunolocalizations of cell cycle related proteins, which have key roles in proliferation, differentiation and apoptosis during the development of the rat placenta. Here immunohistochemistry has been used to localize G1 cyclins (D1, D3, E), which are major determinants of proliferation, CIP/KIP inhibitors (p21, p27, p57), p53 as a master regulator and proliferating cell nuclear antigen in all cell types of the rat term placenta. The proportion of each cell type immunolabeled was counted. Cyclin D1 and cyclin D3 were present mostly in cells of the fetal aspect of the placenta, whereas the G1/S cyclin E was present only in the spongio- and labyrinthine trophoblast populations. Among the CIP/KIP inhibitors, p21 was present only in cells of the fetal aspect whereas p27 and p57 were found in all cell types studied. p53 was only found in a small proportion of cells with no co-localization of p53 and p21. The data suggest that the cells of the fetal side of the rat placenta still have some proliferation potential which is kept in check by expression of the CIP/KIP cell cycle inhibitors, whereas cells of the maternal aspect have lost this potential. Apoptosis is only marginal in the term rat placenta. In conclusion, proliferation and apoptosis in rat placental cells appears controlled mostly by the CIP/KIP inhibitors in late pregnancy. PMID- 21789684 TI - Tropomyosin is in a reduced state in rat cardiac muscle. PMID- 21789683 TI - MGMT promoter gene methylation in pediatric glioblastoma: analysis using MS-MLPA. AB - PURPOSE: Promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene is widely recognized as an important predictive factor in the treatment of glioblastoma (GBM) patients with temozolomide. However, data regarding the methylation status of the MGMT promoter in pediatric GBM are yet to be elucidated. METHODS: Nineteen tissue samples of pediatric GBM were evaluated for the MGMT promoter methylation status using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methylation status was also evaluated using methylation-specific polymerase chain reaction (MSP) for 17 of the 19 patients. The correlation between MGMT promoter methylation and clinical outcome was assessed. RESULTS: Three of the 19 patients (16%) showed methylation of the MGMT promoter, according to MS-MLPA, as did 1 of the 17 (6%), according to MSP. The methylation status did not seem to have a definite effect on clinical outcome. CONCLUSIONS: Pediatric GBMs rarely have methylated MGMT promoters. With a better clinical outcome and lower methylation rate than their adult counterparts, it may be suggested that, for pediatric GBM, MGMT promoter methylation does not play a significant role as a prognostic factor. PMID- 21789685 TI - Balloon kyphoplasty and vertebroplasty in the management of vertebral compression fractures. AB - Vertebral compression fractures (VCFs) are the most prevalent fractures in osteoporotic patients. The classical conservative management of these fractures is through rest, pain medication, bracing and muscle relaxants. The aim of this paper is to review prospective controlled studies comparing the efficacy and safety of minimally invasive techniques for vertebral augmentation, vertebroplasty (VP) and balloon kyphoplasty (BKP), versus non-surgical management (NSM). The Fracture Working Group of the International Osteoporosis Foundation conducted a literature search and developed a review paper on VP and BKP. The results presented for the direct management of osteoporotic VCFs focused on clinical outcomes of these three different procedures, including reduction in pain, improvement of function and mobility, vertebral height restoration and decrease in spinal curvature (kyphosis). Overall, VP and BKP are generally safe procedures that provide quicker pain relief, mobility recovery and in some cases vertebral height restoration than conventional conservative medical treatment, at least in the short term. However, the long-term benefits and safety in terms of risk of subsequent vertebral fractures have not been clearly demonstrated and further prospective randomized studies are needed with standards for reporting. Referral physicians should be aware of VP/BKP and their potential to reduce the health impairment of patients with VCFs. However, VP and BKP are not substitutes for appropriate evaluation and treatment of osteoporosis to reduce the risk of future fractures. PMID- 21789686 TI - Association of cardio-ankle vascular index with physical fitness and cognitive symptoms in aging Finnish firefighters. AB - PURPOSE: Monitoring cardiovascular risk factors is important in health promotion among firefighters. The assessment of arterial stiffness (AS) may help to detect early signs of atherosclerosis. The aim of this study was to analyze associations between aerobic fitness, cognitive symptoms and cardio-ankle vascular index (CAVI) as a measure for AS among Finnish firefighters. METHODS: The data are one part of a large 13-year follow-up study of the health and physical and mental capacity of Finnish professional firefighters. The subjects in this substudy comprised 65 male firefighters of a mean age of 48.0 (42-58) years in 2009. Their maximal oxygen uptake was successfully measured in two cross-sectional studies in 1996 and 2009, and they responded to questionnaires at both sessions, and their CAVI was measured in 2009. CAVI was calculated from the pulse waveform signal and pulse wave velocity. The lifestyle habits and subjective cognitive stress-related symptoms were collected via a standardized questionnaire. Muscular fitness was measured by the routine test battery used for Finnish firefighters. RESULTS: CAVI was related to age. About one-fifth of the firefighters had a CAVI of >8. Aerobic fitness was the main physiological factor correlating with increased CAVI. Interestingly, VO(2)max and the accelerated decrease in VO(2)max during a 13-year follow-up were associated with signs of impaired vascular function. The cognitive symptoms derived from the Profile of Mood States questionnaire (POMS) were mainly associated with stress and sleeping difficulties. No clear association with physical fitness was found in this population of fit firefighters. CONCLUSIONS: Among firefighters, the decrease in aerobic fitness predicts increased arterial stiffness. The speed of the age-related decline in maximal oxygen consumption is as important as absolute level. Against expectations, the cognitive function did not correlate with vascular health parameters. The cognitive symptoms, however, were only mild. PMID- 21789687 TI - Contribution of bone tissue modulus to breast cancer metastasis to bone. AB - Certain tumors, such as breast, frequently metastasize to bone where they can induce bone destruction. Currently, it is well-accepted that the tumor cells are influenced by other cells and growth factors present in the bone microenvironment that lead to tumor-induced bone disease. Over the past 20 years, many groups have studied this process and determined the major contributing factors; however, these results do not fully explain the changes in gene expression and cell behavior that occur when tumor cells metastasize to bone. More recently, groups studying metastasis from soft tissue sites have determined that the rigidity of the microenvironment, which increases during tumor progression in soft tissue, can regulate tumor cell behavior and gene expression. Therefore, we began to investigate the role of the rigid bone extracellular matrix in the regulation of genes that stimulate tumor-induced bone disease. We found that the rigidity of bone specifically regulates parathyroid hormone-related protein (PTHrP) and Gli2 expression in a transforming growth factor beta (TGF-beta) and mechanotransduction-dependent mechanism. In this review, we summarize the mechanotransduction signaling pathway and how this influences TGF-beta signaling and osteolytic gene expression. PMID- 21789688 TI - Oral fludarabine in combination with doxorubicin and dexamethasone as first-line therapy for nodal peripheral T-cell lymphomas: early results of a prospective multicenter study. AB - PURPOSE: Nodal peripheral T-cell lymphomas (PTCLs) have particularly poor prognoses. Few data enabling establishment of an accepted standard treatment modality for PTCLs are available. We hypothesized that fludarabine-based regimens are tolerable and effective in treatment for nodal PTCLs. Therefore, this study was to analyze the toxicity of, response rate for, and outcome of treatment for nodal PTCLs with oral fludarabine, doxorubicin, and dexamethasone (FAD). METHODS: Patients with PTCLs received FAD every 28 days, consisting of oral fludarabine at 40 mg/m(2) on days 1-3, doxorubicin at 50 mg/m(2) on day 1, and oral dexamethasone at 20 mg/day on days 1-5. Patients who did not exhibit disease progression received at least four courses of treatment. RESULTS: Thirty-one of 35 patients with previously untreated nodal PTCLs enrolled in the study from 2007 to 2008 were evaluable. The incidence of grade 3-4 neutropenia was 55%. Nine patients had to have dose reductions of fludarabine and doxorubicin, none of whom had grade 3 or 4 toxic effects at the lower dose. Five of 31 patients had pneumonitis. No treatment-related mortality occurred. The response rate for the entire patient population was 71%, and the complete remission rate was 48%. The PFS and OS rates at 2 years were 54.2 and 77.1%, respectively. Four patients had died of cancer progression at the time of this analysis. The serum lactate dehydrogenase level had a significant effect on PFS and OS. CONCLUSION: The FAD regimen had encouraging efficacy with an acceptable toxicity profile in patients with nodal PTCLs. PMID- 21789689 TI - Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children. AB - PURPOSE: To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data. METHODS: Simulations were performed with PK-Sim((r)) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group. RESULTS: Simulated plasma concentration time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Cl(observed): 0.70 ml/min/kg) versus 0.50 ml/min/kg (Cl(observed): 0.60 ml/min/kg), respectively. Integrated Michaelis Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P glycoprotein inhibitors or nephrotoxic drugs can also be elucidated. CONCLUSIONS: The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children. PMID- 21789691 TI - [New developments in epileptogenesis and therapeutic perspectives]. AB - Epileptogenesis describes the mechanisms of how epilepsies are generated. We have chosen four areas in which significant progress has been achieved in understanding epileptogenesis. Those are (1) inflammatory processes which play an increasingly important role for the generation of temporal lobe epilepsy with hippocampal sclerosis (TLE with HS), (2) disturbances of intrinsic properties of neuronal compartments, in particular acquired defects of ion channels of which those in dendrites are described here for TLE with HS, (3) epigenetic effects, which affect for example the methylation of promoters and secondarily can change the expression of specific genes in TLE with HS, and finally (4) the epileptogenesis of idiopathic epilepsies which are caused by inborn genetic alterations affecting mainly ion channels. Apart from aspects of basic research, we will describe clinical consequences and therapeutic perspectives. PMID- 21789690 TI - Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link. AB - AIMS/HYPOTHESIS: A growing body of research suggests that the prevalence of major depressive disorder (MDD) in children and youth with type 1 diabetes mellitus is significantly higher than that of youth without type 1 diabetes and is associated with increased illness severity. The objective of this article is to review the current literature on the pathophysiology of these two common diseases with respect to potential areas of overlapping biological dysfunction. METHODS: A search of English language articles published between 1966 and 2010 was conducted and augmented with manual review of reference lists from the identified publications. RESULTS: The evidence suggests plausible mechanisms whereby a biological relationship between type 1 diabetes and MDD may exist. These include the effects of circulating cytokines associated with autoimmune diabetes, the direct impact of insulin deficiency on neurogenesis/neurotransmitter metabolism, the effects of the chronic hyperglycaemic state, occurrence of iatrogenic hypoglycaemia and the impact of basal hyperactivity of the hypothalamic-pituitary adrenal axis. CONCLUSIONS/INTERPRETATION: Shared biological vulnerabilities may be implicated in the comorbidity of type 1 diabetes and MDD. Further research is warranted to determine the magnitude of associations and confirm their observation in clinical populations. PMID- 21789693 TI - [The presymptomatic stage of neurodegenerative disorders]. AB - Neurodegenerative disorders, such as Huntington's disease, spinocerebellar ataxias, Parkinson's disease or Alzheimer's disease, manifest in adult age with insidiously developing, slowly progressing symptoms. At this stage, most patients consult a doctor, and a definite diagnosis can be made. It is, however, well established that the manifest disease is preceded by a presymptomatic disease stage that may last for years. A striking example is Parkinson's disease, in which more than half of the dopaminergic neurons of the substantia nigra are lost before motor symptoms appear. Studies of the presymptomatic stage of neurodegenerative disorders are pivotal for an advanced understanding of these disorders and the development of preventive strategies aimed at postponing the clinical onset of these disorders. It is therefore important to identify the earliest and most sensitive clinical signs and biological markers that herald the onset of the illness. Furthermore, studies of presymptomatic disease stages are important because they may help to unravel compensatory mechanisms responsible for apparently normal brain function despite ongoing neurodegeneration. PMID- 21789694 TI - The anti-McCollough effect: the mystery remains. PMID- 21789692 TI - [Difficult decisions in stroke therapy]. AB - In numerous situations stroke physicians face a lack of evidence during their daily practice. In this report the authors address some of the difficult treatment decisions encountered in acute therapy and secondary prevention. Examples include off-label thrombolysis and prevention in high-risk situations. The available data from trials and registries are discussed, and personal views and recommendations are expressed. PMID- 21789695 TI - Two components in IOR: evidence for response bias and perceptual processing delays using the SAT methodology. AB - Inhibition of return (IOR) occurs when reaction times (RTs) are slowed to respond to a target that appears at a previously attended location. We used the speed accuracy trade-off (SAT) procedure to obtain conjoint measures of IOR on sensitivity and processing speed by presenting targets at cued and uncued locations. The results showed that IOR is associated with both delays in processing speed and shifts in response criterion. When the target was briefly presented, the results supported a criterion shift account of IOR. However, when the target was presented until response, the evidence indicated that, in addition to a response bias effect, there was an increase in the minimal time required for information about the target to accumulate above chance level. A hybrid account of IOR is suggested that describes effects on both response bias and perceptual processing. PMID- 21789696 TI - CT-guided percutaneous biopsy of a mass lesion in the upper presacral space: a sacral transneuroforaminal approach. PMID- 21789697 TI - Carotid artery stenting trials: conduct, results, critique, and current recommendations. AB - The carotid stenting trialists have demonstrated persistence and determination in comparing an evolving technique, carotid artery stenting (CAS), against a mature and exacting standard for carotid revascularisation, carotid endarterectomy (CEA). This review focuses on their endeavours. A total of 12 1-on-1 randomised trials comparing CAS and CEA have been reported; 6 of these can be considered major, and 5 of these reflect (in part) current CAS standards of practice and form the basis of this review. At least 18 meta-analyses seeking to compare CAS and CEA exist. These are limited by the quality and heterogeneity of the data informing them (e.g., five trials were stopped prematurely such that they collectively failed to reach recruitment target by >4000 patients). The Carotid Stenting Trialists' Collaboration Publication represents a prespecified meta analysis of European trials that were sufficiently similar to allow valid conclusions to be drawn; these trials and conclusions will be explored. When the rate of myocardial infarction (MI) is rigorously assessed, CAS and CEA are equivalent for the composite end point of stroke/death and MI, with more minor strokes for CAS and more MIs for CEA. These outcomes have a discrepant impact on quality of life and subsequent mortality. The all-stroke death outcomes for patients <70 years old are equivalent, with more minor strokes occurring in the elderly during CAS than CEA. There are significantly more severe haematomas and cranial nerve injuries after CEA. The influence of experience on outcome cannot be underestimated. PMID- 21789698 TI - Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas. AB - Abnormal signaling through the platelet-derived growth factor receptor (PDGFR) has been proposed as a possible mechanism of spinal cord glioma initiation and progression. However, the extent of PDGFR expression in human spinal cord gliomas remains unknown. In this study we perform immunohistochemical analysis of PDGFRalpha expression in a series of 33 primary intramedullary spinal cord gliomas of different types and grades. PDGFRalpha was seen to be expressed in a significant subset of these tumors across all major glioma types including ependymoma, oligodendroglioma, pilocytic astrocytoma, astrocytoma, and glioblastoma. These results support the hypothesis that growth factor signaling through the PDGFR may be important for the development of at least a subset of human spinal cord gliomas. Further studies investigating the prognostic significance of PDGFR expression as well as the role of PDGF signaling on the development of intramedullary spinal cord gliomas are warranted. PMID- 21789699 TI - The toxicity of intrathecal bevacizumab in a rabbit model of leptomeningeal carcinomatosis. AB - Leptomeningeal carcinomatosis (LC) is a devastating complication of cancer. Intrathecal administration of cytotoxic chemotherapy adds little to survival which is measured in weeks. The potential toxicities and efficacy of intrathecally administered anti-angiogenic agents in this setting have not previously been explored. A well-characterized animal model was used to evaluate the neurotoxicity of intraventricularly administered bevacizumab (BCM). Thirty three New Zealand White Rabbits were studied. Subcutaneous reservoirs and ventricular catheters (SRVC) were placed in eight rabbits, which were randomized to receive weekly intraventricular saline with or without BCM for four weeks. These rabbits were euthanized on day 36 and the brains were examined by a blinded neuropathologist. Twenty-five additional rabbits underwent cisternal injection of VX2 carcinoma cells with or without a single dose of BCM and were followed for survival. No clinical manifestations of neurotoxicity were noted in rabbits treated with intraventricular BCM. Similarly, no evidence of BCM neurotoxicity was identified in autopsied animals. The median survival of evaluable rabbits with LC treated with intraventricular saline (N = 13) was 15 days compared to 18 days for the animals receiving VX2 and one dose of BCM (N = 12). CONCLUSION: Intraventricular BCM can be administered to rabbits without clinical or pathologic neurotoxicity. Survival following one dose of BCM in rabbits with LC should be cautiously interpreted given uncertainties regarding the dose, schedule, and limited expected benefit of this non-rabbit antibody. This neurotoxicity study provides safety data to allow phase I/II studies in humans with treatment refractory LC. PMID- 21789700 TI - Critical trial-related criteria in acute schizophrenia studies. AB - The Trial Criteria in Schizophrenia Working Group was convened in November 2007 to define consensus criteria for clinical trials in patients suffering from acute schizophrenia with special focus on placebo-controlled trials and withdrawal conditions. Clinical trials involving patients give rise to ethical and medico legal dilemmas. Essential research of new drugs may potentially expose patients to ineffective treatment regimens or placebo. The complexity of the problem increases when dealing with mentally ill patients. The Working Group's criteria are thought to cover different aspects important in conducting clinical trials namely to ensure the patient's safety, to present criteria that would allow the ethics committees to agree to the proposed criteria and to enable the possibility to reasonably conduct and ensure comparable quality of clinical studies in acutely ill patients with schizophrenia. To furthermore counteract current inconsistencies, these criteria should be evaluated using standardized rating scales applying established cut-off criteria. The developed trial criteria cover inclusion and exclusion criteria as well as withdrawal criteria due to non response or worsening of symptoms. PMID- 21789701 TI - A new modification for safer submental orotracheal intubation. AB - In patients in whom a tracheal tube cannot be inserted through the nostrils due to multiple facial trauma or hypoplasty of the nose, submental orotracheal intubation (SOI) is performed to avoid tracheostomy. We report a new modification for SOI to minimize the risk of apnea. A 20-year-old man was scheduled for sagittal split ramus osteotomy. As the patient had severe hypoplasia of the nose, SOI was planned. Following orotracheal intubation with a spiral tube (first tube), a submental tunnel was surgically created. A second tube that had been confirmed, in advance, to snugly fit into the proximal end of the first tube was passed into the submental tunnel via a polypropylene cylinder and connected between the first tube and the breathing circuit. After careful withdrawal of the second tube through the submental tunnel, the first tube was directly connected to the breathing circuit after removal of the second tube. Although this technique requires additional time, apnea time is minimal even in patients in whom withdrawal of the tracheal tube through the submental tunnel takes time, because the second tube forms a link between the first tube and the breathing circuit, making it possible to ventilate the patient throughout the procedure. PMID- 21789702 TI - Effect of flurbiprofen, metoclopramide and droperidol for nausea and emesis during cesarean section under spinal anesthesia. AB - PURPOSE: Nausea and emesis frequently arise during cesarean section performed under spinal or epidural anesthesia, particularly after delivery. We have evaluated the treatment effects of flurbiprofen, metoclopramide and droperidol on nausea and emesis during cesarean section in patients under combined spinal and epidural anesthesia. METHODS: The patient cohort comprised 361 patients with American Society of Anesthesiologists (ASA) physical status I or II who elected to undergo cesarean section. All patients received combined spinal-epidural anesthesia. After delivery, nausea and emesis was assessed using a 4-point scale as: 1, excellent, with no complaints; 2, mild nausea; 3, severe nausea; 4, emesis. Patients who experienced severe nausea or emesis were randomly assigned to receive one of the following intravenous drugs: Group A, flurbiprofen (50 mg); Group B, metoclopramide (10 mg); Group C, droperidol (1.25 mg). Effects on nausea and emesis were assessed at 5, 10 and 15 min after drug administration using a 4 point scale as: 1, obviously improved; 2, improved; 3, unchanged; 4 worsened. RESULTS: Among the patients, 151 reported nausea or emesis. These patients experienced a longer duration of surgery and anesthesia and lost more blood than patients with no complaints. The frequency of improvement in the flurbiprofen group was significantly higher than that in the metoclopramide group at 5, 10 and 15 min (p < 0.05) after administration, and of that in the droperidol group at 15 min after administration (p < 0.05). CONCLUSION: Intravenous flurbiprofen improves nausea and emesis after delivery by cesarean section more effectively than metoclopramide or droperidol. PMID- 21789703 TI - Treatment outcome of patients with liver-only metastases from breast cancer after mastectomy: a retrospective analysis. AB - PURPOSE: To evaluate the efficiency of combined treatment of transcatheter arterial chemoembolization (TACE) and systemic chemotherapy (SC) for liver-only metastases from breast cancer after mastectomy. METHODS: We compared the outcomes of 44 patients who underwent combined treatment of TACE and systemic chemotherapy (TSC) with those of 43 patients who underwent systemic chemotherapy (SC). RESULTS: The median follow-up from the diagnosis of liver metastases was 29 months (range, 0-89 months). Response rates were 59.1% and 34.9% for TSC group and SC group (P < 0.05), respectively. The 1-, 2- and 3-year survival rates for TSC group were 76.2, 66.7 and 47.6%, and those for SC group were 48.1, 29.6 and 7.4% (P = 0.027), respectively. Estrogen receptor (ER)-negative status of primary tumor, disease-free interval from mastectomy to liver metastases (DFI) less than 24 months and patients who received systemic chemotherapy only were independently associated with poor prognosis (P = 0.009; P = 0.023; P = 0.030). CONCLUSIONS: The combined treatment of TACE and systemic chemotherapy may prolong survival for liver metastases in breast cancer after mastectomy. PMID- 21789704 TI - Expression of cathepsin D and E-cadherin in primary laryngeal cancers correlation with neck lymph node involvement. AB - OBJECTIVE: The aim of this study was to investigate the relation between Cathepsin D (Cath-D) and E-Cadherin (E-Cad) expression levels in tumor tissue and neck lymph node metastasis. This attempt should be made to identify new factors that one could be useful in predicting clinical behavior. STUDY DESIGN: In this study, we investigated rates of dying for E-Cad and Cath-D in paraphin blocks of larynx and neck dissection specimens taken from 56 selected patients. Laryngeal specimens dyed by ECad and Cath-D immunohistochemically. Immunoreactivity classified for E-Cad as positive (75% and above), reduced (25-75%) and negative (below 25%). Immunoreactivity classified for Cath-D:dye absorption rates higher than 50% evaluated positive and absorption rates lower than 50% evaluated negative. We compared the rates of dying for E-Cad and Cath-D groups to with or without neck lymph node metastasis in specimens. RESULTS: Neck metastasis were found in 41% of patients, in 55.6% of patients, if the E-Cad was negative, 40.6% if it was reduced, 33.3% if it was positive in specimens. The neck metastasis was found in 35.4% of patients with Cath-D expression negative, while 75% of patients was found with Cath-D expression positive. CONCLUSION: Neck metastasis was found higher in E-Cad reduced group than positive group. Neck node metastasis was significantly higher in Cath-D positive group than Cath-D negative group. Cath-D and E-Cad essays may useful in identifying neck lymph node involvement. Cath-D expression levels are more in this predictive factor than E-Cad levels for possibility of neck lymph node metastasis in LSCC. PMID- 21789706 TI - Genetic interactions involved in the inhibition of heading by heading date QTL, Hd2 in rice under long-day conditions. AB - Heading date is the one of the most important traits in rice breeding, because it defines where rice can be cultivated and influences the expression of various agronomic traits. To examine the inhibition of heading by Heading date 2 (Hd2), previously detected on the distal end of chromosome 7's long arm by quantitative trait locus (QTL) analysis, we developed backcross inbred lines (BILs) from Koshihikari, a leading Japanese cultivar, and Hayamasari, an extremely early heading cultivar. The BILs were cultivated under natural field conditions in Tsukuba Japan, and under long-day (14.5 h), extremely long-day (18 h), and short day (10 h) conditions. Combinations of several QTLs near Hd1, Hd2, Ghd7, Hd5, and Hd16 were detected under these four conditions. Analysis of advanced backcross progenies revealed genetic interactions between Hd2 and Hd16 and between Hd2 and Ghd7. In the homozygous Koshihikari genetic background at Hd16, inhibition of heading by the Koshihikari allele at Hd2 was smaller than that with the Hayamasari Hd16 allele. Similarly, in the homozygous Koshihikari genetic background at Ghd7, the difference in heading date caused by different alleles at Hd2 was smaller than in plants homozygous for the Hayamasari Ghd7 allele. Based on these results, we conclude that Hd2 and its genetic interactions play an important role in controlling heading under long-day conditions. In addition, QTLs near Hd2, Hd16, and Ghd7, which are involved in inhibition of heading under long-day conditions, function in the same pathway that controls heading date. PMID- 21789707 TI - Specifying the interrelationship between exposure to violence and parental monitoring for younger versus older adolescents: a five year longitudinal test. AB - Five waves of longitudinal data collected from 349 African American youth living in extreme poverty were used to examine the interrelationship between exposure to violence and parenting during adolescence. Semi-parametric group based modeling was used to identify trajectories of parental monitoring and exposure to violence from T1 to T5. Results from these analyses revealed: (1) a trajectory of declining parental monitoring for 48% of youth; and (2) four distinct trajectories of exposure to violence. Multivariate findings were largely consistent with the ecological-transactional model of community violence. Youth with stable and/or increasing trajectories of exposure to violence were more likely than youth with stable-low exposure to violence to have declining parental monitoring, but additional analyses revealed a similar pattern of findings for younger adolescents (age 9-11 T1), but no evidence of linkages between trajectories of exposure to violence and parental monitoring for older adolescents (age 12-16 T1). The theoretical and policy implications of these findings as well as areas for future research are also discussed. PMID- 21789709 TI - Do patients with traumatic recurrent anterior shoulder instability have generalized joint laxity? AB - BACKGROUND: A number of studies suggest a relationship between generalized joint laxity (GJL) and increased risk of some musculoskeletal injuries. However, there are conflicting data on the association between GJL and traumatic recurrent shoulder instability (RSI). QUESTIONS/PURPOSES: We therefore asked whether the incidence of GJL in patients with RSI was greater than that in a control group. METHODS: We preoperatively determined GJL with a Beighton score in 100 male patients arthroscopically treated for RSI. The mean age of the patients was 25 years. We identified a control group of 100 individuals, matched for age and gender, with no known history of instability of the shoulder, knees, or ankles and obtained the same score. Those patients with a Beighton score greater than six points were considered lax (representing GJL). RESULTS: We identified no difference in the rate of GJL in the two groups: 13 of the 100 patients versus nine of the 100 control subjects. CONCLUSION: Our data add to the literature suggesting GJL does not predispose to RSI. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21789710 TI - Residual varus alignment does not compromise results of TKAs in patients with preoperative varus. AB - BACKGROUND: Postoperative varus alignment has been associated with lower IKS scores and increased failure rates. Appropriate positioning of TKA components therefore is a key concern of surgeons. However, obtaining neutral alignment can be challenging in patients with substantial preoperative varus deformity and it is unclear whether residual deformity influences revision rates. QUESTIONS/PURPOSES: We asked: (1) in patients with preoperative varus deformities, does residual postoperative varus limb alignment lead to increased revision rates or lower IKS scores compared with correction to neutral alignment, (2) does placing the tibial component in varus alignment lead to increased revision rates and lower IKS scores, (3) does femoral component alignment affect revision rates and IKS scores, and (4) do these findings change in patients with at least 10 degrees varus alignment preoperatively? PATIENTS AND METHODS: From a prospective database, we identified 553 patients undergoing TKAs for varus osteoarthritis. Patients were divided into those with residual postoperative varus and those with neutral postoperative alignment. Revision rates and International Knee Society (IKS) scores were compared between the two groups and assessed based on postoperative component alignment. Survival analysis was conducted with revision as the endpoint. The analysis was repeated in a subgroup of patients with at least 10 degrees preoperative varus. Minimum followup was 2 years (median, 4.7 years; range, 2-19.8 years). RESULTS: The two groups had similar survival rates to 10 years and similar IKS scores. Varus tibial component alignment and valgus femoral component alignment were associated with lower mean scores. Revision rates and scores were similar in a subgroup of patients with substantial preoperative varus. CONCLUSIONS: Our data suggest residual postoperative varus deformity after TKA does not increase survival rates at medium-term in patients with preoperative varus deformities, providing tibial component varus is avoided. Tibial component varus negatively influences IKS score. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21789715 TI - Infantile orbital abscess caused by community-acquired methicillin-resistant Staphylococcus aureus. AB - An orbital abscess is a severe infectious disease of the eye and carries the risks of visual loss and intracranial complications. Timely treatment in an infant is crucial in order to save sight and can prevent unnecessary morbidity and mortality. We report a case of an orbital abscess in an infant who underwent surgical drainage and medical management. The unique clinical and radiological features are presented in this report. In addition, methicillin-resistant Staphylococcus aureus was isolated from the pus culture. The case reminds us that, before obtaining the result of the pus culture, with the emergence of community-acquired methicillin-resistant S. aureus, physicians should consider empirical antibiotic therapy, which is effective against methicillin-resistant S. aureus. PMID- 21789713 TI - Dual blockade of PKA and NF-kappaB inhibits H2 relaxin-mediated castrate resistant growth of prostate cancer sublines and induces apoptosis. AB - We previously demonstrated that H2 relaxin (RLN2) facilitates castrate-resistant (CR) growth of prostate cancer (CaP) cells through PI3K/Akt/beta-catenin-mediated activation of the androgen receptor (AR) pathway. As inhibition of this pathway caused only ~50% reduction in CR growth, the goal of the current study was to identify additional RLN2-activated pathways that contribute to CR growth. Next generation sequencing-based transcriptome and gene ontology analyses comparing LNCaP stably transfected with RLN2 versus LNCaP-vector identified differential expression of genes associated with cell proliferation (12.7% of differentially expressed genes), including genes associated with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and nuclear factor-kappaB (NF-kappaB) pathways. Subsequent molecular analyses confirmed that the cAMP/PKA and NF-kappaB pathways play a role in facilitating H2 relaxin-mediated CR growth of CaP cells. Inhibition of PKA-attenuated RLN2-mediated AR activity inhibited proliferation and caused a small but significant increase in apoptosis. Combined inhibition of the PKA and NF-kappaB signaling pathways via inhibition of PKA and Akt induced significant apoptosis and dramatically reduced clonogenic potential, outperforming docetaxel, the standard of care treatment for CR CaP. Immunohistochemical analysis of tissue microarrays in combination with multispectral quantitative imaging comparing RLN2 levels in patients with benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia, and CaP determined that RLN2 is significantly upregulated in CaP vs BPH (p = 0.002). The combined data indicate RLN2 overexpression is frequent in CaP patients and provides a growth advantage to CaP cells. A near-complete inhibition of RLN2 induced CR growth can be achieved by simultaneous blockade of both pathways. PMID- 21789714 TI - Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach. AB - Angiogenesis, the sprouting of new blood vessels from the pre-existing vasculature, is a well established target in anti-cancer therapy. It is thought that the Rho GTPase Rac1 is required during vascular endothelial growth factor (VEGF)-mediated angiogenesis. In the present study, we have used a clinically relevant RNA interference approach to silence Rac1 expression. Human umbilical vein endothelial cells were transiently transfected with non-specific control siRNA (siNS) or Rac1 siRNA (siRac1) using electroporation or Lipofectamine 2000. Functional assays with transfected endothelial cells were performed to determine the effect of Rac1 knockdown on angiogenesis in vitro. Silencing of Rac1 inhibited VEGF-mediated tube formation, cell migration, invasion and proliferation. In addition, treatment with Rac1 siRNA inhibited angiogenesis in an in vivo Matrigel plug assay. Intratumoral injections of siRac1 almost completely inhibited the growth of grafted Neuro2a tumors and reduced tumor angiogenesis. Together, these data indicate that Rac1 is an important regulator of VEGF-mediated angiogenesis. Knockdown of Rac1 may represent an attractive approach to inhibit tumor angiogenesis and growth. PMID- 21789716 TI - Evaluation of prosthetic venous valves, fabricated by electrospinning, for percutaneous treatment of chronic venous insufficiency. AB - Chronic venous insufficiency (CVI) remains a major health problem worldwide. Direct venous valve surgical repair and venous segment transplantation are clinical options; however, they are highly invasive procedures. The objectives of this study were to fabricate prosthetic venous valves (PVVs) by electrospinning, for percutaneous treatment of CVI, and evaluate their hydrodynamic characteristics in vitro at the same locations and under the same flow conditions. The PVVs consisted of polyurethane fiber scaffolds attached to a cobalt-chromium stent. PVVs with two different valve-leaflet configurations were compared: biomimetic PVV (bPVV) and open PVV (oPVV). A balloon catheter was used to implant the devices in a poly(vinyl chloride) tube and the column outlet was set at a height of 100 cm above the test valve to simulate the elevation of the heart above a distal vein valve while standing; 50 wt% glycerin solution was used as the test fluid. The devices were evaluated for antegrade flow, effect of ankle flexion, and stagnation zones around the valve leaflets. During sudden hydrostatic backpressure, little leakage and constant peripheral pressure were observed for the devices; under forward pulsatile pressure of 0-4 mmHg, to simulate the effect of breathing, the oPVV had a higher flow rate than the bPVV. With regard to the effect of ankle flexion, the oPVV was functionless. Moreover, the stagnation zone around the oPVV valve leaflets was larger than that around the bPVV valve leaflets. These results suggest that the bPVV would be clinically suitable for percutaneous treatment of CVI. PMID- 21789717 TI - Differential diagnosis generators: an evaluation of currently available computer programs. AB - BACKGROUND: Differential diagnosis (DDX) generators are computer programs that generate a DDX based on various clinical data. OBJECTIVE: We identified evaluation criteria through consensus, applied these criteria to describe the features of DDX generators, and tested performance using cases from the New England Journal of Medicine (NEJM(c)) and the Medical Knowledge Self Assessment Program (MKSAP(c)). METHODS: We first identified evaluation criteria by consensus. Then we performed Google(r) and Pubmed searches to identify DDX generators. To be included, DDX generators had to do the following: generate a list of potential diagnoses rather than text or article references; rank or indicate critical diagnoses that need to be considered or eliminated; accept at least two signs, symptoms or disease characteristics; provide the ability to compare the clinical presentations of diagnoses; and provide diagnoses in general medicine. The evaluation criteria were then applied to the included DDX generators. Lastly, the performance of the DDX generators was tested with findings from 20 test cases. Each case performance was scored one through five, with a score of five indicating presence of the exact diagnosis. Mean scores and confidence intervals were calculated. KEY RESULTS: Twenty three programs were initially identified and four met the inclusion criteria. These four programs were evaluated using the consensus criteria, which included the following: input method; mobile access; filtering and refinement; lab values, medications, and geography as diagnostic factors; evidence based medicine (EBM) content; references; and drug information content source. The mean scores (95% Confidence Interval) from performance testing on a five-point scale were Isabel(c) 3.45 (2.53, 4.37), DxPlain(r) 3.45 (2.63-4.27), Diagnosis Pro(r) 2.65 (1.75-3.55) and PEPIDTM 1.70 (0.71-2.69). The number of exact matches paralleled the mean score finding. CONCLUSIONS: Consensus criteria for DDX generator evaluation were developed. Application of these criteria as well as performance testing supports the use of DxPlain(r) and Isabel(c) over the other currently available DDX generators. PMID- 21789718 TI - Two possible mechanisms of epithelial to mesenchymal transition in invasive ductal breast cancer. AB - Epithelial to mesenchymal transition (EMT) occurs in embryogenesis and normal development. It has been predominantly described in vitro and in animal studies, but EMT is also implicated in the progression of many cancers with proposed roles in invasion, metastasis and resistance to treatment. It is closely associated with loss of epithelial-specific protein expression and up-regulation of mesenchymal proteins, but several pathways are implicated in its execution. We explored what are the expression patterns of EMT proteins in human breast cancer. We interrogated two independent cohorts enriched for high-grade, invasive, ductal breast cancers. We used quantitative immunofluorescence to study the expression of key EMT proteins. Statistical associations to define protein profiles were based on Pearson's correlations. E-cadherin down-regulation in breast cancer was associated with beta-catenin down-regulation, but not with up-regulation of mesenchymal markers. While EMT-related transcription repressors were expressed in some breast cancers, their expression did not negatively correlate with E cadherin. Instead, an additional EMT profile was identified, composing Snail and Slug. In conclusion, EMT occurs in human breast cancer in a manner distinct to that seen in vitro. Certain EMT events are uncoupled from E-cadherin down regulation and may constitute a novel EMT profile, which warrants further exploration. PMID- 21789719 TI - Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met signaling via inhibition of Adam-10. AB - In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease. PMID- 21789720 TI - [Serum and synovial adiponectin, resistin, and visfatin levels in rheumatoid arthritis patients. Relation to disease activity]. AB - BACKGROUND: Recent data provided evidence on the implication of the adipocytokines adiponectin, visfatin, and resistin in inflammation, immune response, and tissue destruction and revealed several links between them and arthritis. AIM OF THE STUDY: The purpose of this study was to assess the levels of adiponectin, visfatin, and resistin in serum and synovial fluid of patients with rheumatoid arthritis (RA) and their relationship with disease activity. SUBJECTS AND METHODS: A total of 70 female patients with RA and 30 age- and sex matched healthy controls were enrolled. The clinical activity of RA patients was assessed according to the 28 joint count Disease Activity Score and patients were classified into two groups: 39 patients with active disease (group A) and 31 patients in remission (group B). Synovial fluid was obtained by arthrocentesis of the affected knee joints from 39 patients with active disease. Serum adiponectin, visfatin, and resistin concentrations were measured in RA patients and controls, while a specific enzyme-linked immunosorbent assay was used to measure the synovial concentrations of adiponectin, visfatin, and resistin in the group of patients with active RA. RESULTS: Serum levels of adiponectin and visfatin were significantly higher in all RA patients and patients with active disease compared to the control group and patients in remission. No significant difference was observed in the resistin level between patients and controls. Serum and synovial adiponectin and visfatin were positively correlated with DAS28-ESR in RA patients with active disease. CONCLUSION: Our data demonstrated that adiponectin and visfatin are related to disease activity in RA patients and might be involved in the progression of RA. The English full-text version of this article is available at SpringerLink (under "Supplemental"). PMID- 21789721 TI - [MEFV gene mutation spectrum in familial Mediterranean fever (FMF) : a single center study in the Aegean region of Turkey]. AB - OBJECTIVES: Familial Mediterranean fever (FMF), an autosomal recessive autoinflammatory disorder, is characterized by recurrent, self-limiting fever and serositis which is frequently seen in Mediterranean populations. In this study, we retrospectively evaluated the MEFV gene mutation distribution of 883 citizens of the Aegean region with preliminary diagnosis of FMF who were referred to the Tepecik Research and Education Hospital's Tissue Typing and Molecular Diagnostic Laboratory (Izmir, Turkey) between 2006 and 2009. METHODS: The FMF Strip Assay(r) (ViennaLab Diagnostics, Vienna, Austria) was used to determine the 12 most common MEFV gene mutations in patients prediagnosed with FMF. FINDINGS: Allelic frequencies of the major mutations in the mutation positive groups, including M694V, E148Q, M680I(G>C), and V726A, accounted for 48.4, 16.5, 13.5, and 9.7%, respectively. CONCLUSION: The M694V mutation was found to be the most common mutation among FMF patients in the Aegean region, which is in accordance with mutation studies reported from other regions of the country and different ethnic populations. An English full-text version of this article is available at SpringerLink as supplemental. PMID- 21789722 TI - Influence of chronic diseases on long-term change in physical health: a consultation-survey linkage cohort study in general practice. AB - PURPOSE: To investigate the influence of disease severity within cardiovascular disease (CVD) and musculoskeletal (MSK) disorder spectrums on physical health change over 3 years. METHODS: Consultation records of 4,672 patients aged 50 years and above from six general practices were linked to their baseline and 3 year Short-Form-12 (SF-12) physical component summary (PCS) scores. Associations between exclusive diagnostic categories and comorbid counts with physical health change over 3 years were examined. RESULTS: There were 1,371 (29.3%) CVD and 1,972 (42.2%) MSK consulters. Adjusted additional change in PCS scores relative to hypertension ranged from -0.43 (95% confidence interval -2.5, 1.7) for atrial fibrillation to -2.09 (-4.2, 0.0) for heart failure. In the MSK spectrum, changes relative to soft tissue disorder ranged from -0.63 (-3.0, 1.8) for soft tissue pain to -1.09 (-4.1, 2.0) for inflammatory polyarthropathy. A trend in association between increasing disease severity and deterioration in physical health was only observed within the CVD spectrum, and this trend was retained in those with CVD and higher levels of comorbidity. CONCLUSIONS: CVD severity with higher levels of comorbidity was associated with greater relative deterioration in long-term physical health. Such findings were not found for the MSK cohorts, suggesting the differing health impact of different chronic diseases. PMID- 21789723 TI - Inheritance pattern and clinical aspects of 93 Iranian patients with chronic granulomatous disease. AB - BACKGROUND: Chronic granulomatous disease (CGD) is a rare immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. We studied CGD inheritance forms (autosomal recessive (AR) or X-linked (XL)) and AR-CGD subtypes in Iran. METHODS: Clinical and functional investigations were conducted in 93 Iranian CGD patients from 75 families. RESULTS: Most of the patients were AR-CGD (87.1%). This was related to consanguineous marriages (p = 0.001). The age of onset of symptoms and diagnosis were lower in XL-CGD compared with AR-CGD (p < 0.0001 for both). Among AR-CGD patients, p47phox defect was the predominant subtype (55.5%). The most common clinical features in patients were lymphadenopathy (65.6%) and pulmonary involvement (57%). XL-CGD patients were affected more frequently with severe infectious manifestations. CONCLUSIONS: Although XL-CGD is the most common type of the disease worldwide, only 12 patients (12.9%) were XL-CGD in our study. The relatively high frequency of AR CGD is probable due to widely common consanguineous marriages in Iran. PMID- 21789724 TI - Progenitor cells confer plasticity to cardiac valve endothelium. AB - The endothelium covering the aortic, pulmonary, mitral, and tricuspid valves looks much like the endothelium throughout the vasculature, in terms of general morphology and expression of many endothelial markers. Closer examination, however, reveals important differences and hints of a unique phenotype that reflects the valvular endothelium's embryonic history, and potentially, its ability to maintain integrity and function over a life span of dynamic mechanical stress. A well-studied property that sets the cardiac valvular endothelium apart is the ability to transition from an endothelial to a mesenchymal phenotype-an event known as epithelial to mesenchymal transition (EMT). EMT is a critical step during embryonic valvulogenesis, it can occur in post-natal valves and has recently been implicated in the adaptive response of mitral valve leaflets exposed to a controlled in vivo setting designed to mimic the leaflet tethering that occurs in ischemic mitral regurgitation. In this review, we will discuss what is known about valvular endothelial cells, with a particular focus on post natal, adult valves. We will put forth the idea that at subset of valvular endothelial cells are progenitor cells, which may serve to replenish valvular cells during normal cellular turnover and in response to injury and disease. PMID- 21789725 TI - Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV infected rhesus macaques. AB - Understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. Using a rhesus lentiviral encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth-associated protein-43 (GAP-43) and ephrin B3. We examined whether the improvement of neuronal metabolism with combined anti retroviral therapy (cART) after simian immunodeficiency virus (SIV) infection in rhesus macaques involved induction of GAP-43, also known as neuromodulin, and ephrin B3, both implicated in axonal pathfinding during neurodevelopment and regulation of synapse formation, neuronal plasticity, and repair in adult brain. We utilized magnetic resonance spectroscopy to demonstrate improved neuronal metabolism in vivo in adult SIV-infected cART animals compared to untreated and uninfected controls. We then assessed levels of GAP-43, ephrin B3, and synaptophysin, a pre-synaptic marker, in three brain regions important for cognitive function, cortex, hippocampus, and putamen, by quantitative real-time RT-PCR and immunohistochemistry. Here we demonstrate that (1) GAP-43 mRNA and protein are induced with SIV infection, (2) GAP-43 protein is higher in the hippocampus outer molecular layer in SIV-infected animals that received cART compared to those that did not, and (3) activated microglia and infiltrating SIV infected macrophages express abundant ephrin B3, an important axonal guidance molecule. We propose a model whereby SIV infection triggers events that lead to induction of GAP-43 and ephrin B3, and that short-term cART results in increased magnitude of repair mechanisms especially in the hippocampus, a region known for high levels of adult plasticity. PMID- 21789726 TI - Tumor environment changed by combretastatin derivative (Cderiv) pretreatment that leads to effective tumor targeting, MRI studies, and antitumor activity of polymeric micelle carrier systems. AB - PURPOSE: To evaluate effect of a vascular disrupting agent, a combretastatin derivative (Cderiv), on tumor targeting for polymeric micelle carrier systems, containing either a diagnostic MRI contrast agent or a therapeutic anticancer drug. METHODS: Cderiv was pre-administered 72 h before polymeric micelle MRI contrast agent injection. Accumulation of the MRI contrast agent in colon 26 murine tumor was evaluated with or without pretreatment of Cderiv by ICP and MRI. RESULTS: Significantly higher accumulation of the MRI contrast agent was found in tumor tissues when Cderiv was administered at 72 h before MRI contrast agent injection. T(1)-weighted images of the tumor exhibited substantial signal enhancement in tumor area at 24 h after the contrast agent injection. In T(1) weighted images, remarkable T(1)-signal enhancements were observed in part of tumor, not in whole tumor. These results indicate that Cderiv pretreatment considerably enhanced the permeability of the tumor blood vessels. Antitumor activity of adriamycin encapsulated polymeric micelles with the Cderiv pretreatment suppressed tumor growth in 44As3 human gastric scirrhous carcinoma bearing nude mice. CONCLUSIONS: Pretreatment of Cderiv enhanced tumor permeability, resulting in higher accumulation of polymeric micelle carrier systems in solid tumors. PMID- 21789728 TI - Comparison of regression methods for phenology. AB - Several methods exist for investigation of the relationship between records and weather data. These can be broadly classified into models that attempt to incorporate information about underlying biological processes, such as those based on the concept of thermal time, and linear regression methods. The latter are less driven by the biology but have the advantages of ease of use and flexibility. Regression can be used where there is no obvious mechanistic model or to suggest the form of a mechanistic or empirical model where there are several to choose from. Stepwise regression is commonly used in phenology. However, it requires aggregation of the weather records, resulting in loss of information. Penalised signal regression (PSR) was recently introduced to overcome this weakness. Here, we introduce a further method to the phenology context called fusion, which is a sparse version of PSR. In this paper, we compare the performance of these three regression methods based on simulations from two types of mechanistic models, the spring warming and sequential models. Given a suitable choice of temperature days as regression covariates, PSR and fusion performed better than stepwise regression for the spring warming model and PSR performed best for the sequential model. However, if a large number of redundant temperature days were included as covariates, the performance of PSR fell off whilst fusion was quite robust to this change. For this reason, it is best to use PSR and fusion methods in tandem, and to vary the number of covariates included. PMID- 21789727 TI - Co-delivery of adenovirus and carmustine by anionic liposomes with synergistic anti-tumor effects. AB - PURPOSE: To improve gene transducibility mediated by adenovirus (Ad) in cancer cells and further enhance anti-tumor effects by co-delivery. METHODS: Calcium induced phase change method was used to prepare the complex of anionic liposomes and adenovirus (AL/Ad5). Gene expression was qualitatively detected by X-gal staining and quantitatively detected by ELISA. Taking adenovirus-mediated stromal cell-derived factor-1alpha (Ad5-SDF1alpha) as therapeutic gene and carmustine (BCNU) as chemotherapeutic agent, a co-delivering system of AL/Ad5-SDF1alpha/BCNU was prepared and administered to tumor-bearing mice by intratumor injection. RESULTS: Enhanced LacZ gene transduction was obtained in B16 and Lewis lung carcinoma cells in vitro and in vivo. Complexes of AL/Ad5-SDF1alpha improved SDF1alpha gene expression and led to accumulation of dendritic cells among the murine B16 melanoma cells in vivo. This co-delivery system of AL/Ad5 SDF1alpha/BCNU could significantly suppress tumor growth and prolong survival of tumor-bearing mice. CONCLUSIONS: Through the co-delivering system, AL/Ad5 SDF1alpha could synergize with BCNU to improve the antitumor effect. It may be a promising strategy for solid tumor therapy. PMID- 21789729 TI - Multi-modal ECG Holter system for sleep-disordered breathing screening: a validation study. AB - BACKGROUND: The high prevalence of sleep disordered breathing (SDB) among heart diseases patients becomes increasingly recognized. A reliable exploring tool of SDB well adapted to cardiologists practice would be very useful for the management of these patients. METHODS: We assessed a novel multi-modal electrocardiogram (ECG) Holter which incorporated both thoracic impedance and pulse oximetry signals. We compared in a home setting, a standard condition for Holter recordings, results from the novel device to a classical ambulatory polygraph in subjects with suspected SDB. The analysis of cardiac arrhythmias in relationship with SDB is also presented. A total of 118 patients clinically suspected of having SDB were evaluated (mean age 57 +/- 14 years, mean body mass index [BMI] 32 +/- 6 kg/m(2)). The new device allows calculating a new index called thoracic impedance (TI) disturbance index (TIDI+) evaluated from TI and SpO(2) signals recorded from a Holter monitor. RESULTS: In the population under study, 93% had more than 70% of usable TI signal and 95% had more than 90% for SpO(2) during sleep time recording. Screening performance results based on automatic analysis is accurate: TIDI + demonstrates a high level of sensitivity (96.8%), specificity (72.3%) as well as positive (82.4%) and negative (94.4%) predictive value for the detection of SDB. Moreover, detection of SDB periods permits us to observe a possible respiratory association of several nocturnal arrhythmias. CONCLUSIONS: The multi-modal Holter should be considered as a valuable evaluating tool for SDB screening and as a case selection technique for facilitating access to a full polysomnography for severe cases. Moreover, it offers a unique opportunity to study arrhythmia consequences with both respiratory and hypoxia disturbances. PMID- 21789731 TI - What is the best and easiest method of preventing counting in different temporal tasks? AB - The aim of the present study was to determine the best and easiest method of suppressing spontaneous counting in a temporal judgment task. Three classic methods used to avoid counting--instructions not to count, articulatory suppression, and administration of an interference task--were tested in temporal generalization, bisection, and reproduction tasks with two duration ranges (1-4 and 2-8 s). All the three no-counting conditions prevented participants from counting, counting leading to estimates that were more accurate and less variable and to violations of the fundamental scalar property of timing. With regard to the differences between the no-counting conditions, the interference task distorted time perception more strongly and increased variability in temporal estimates to a greater extent than did articulatory suppression, as well as the no-counting instructions condition. In addition, articulatory suppression produced more noise in behavioral outcome than did the no-counting instruction condition. In sum, although all methods have disadvantages, the instructions not to count actually constitute the simplest and more efficient method of preventing counting in timing tasks. However, further studies must now concentrate on the role of explicit instructions in our experience of perception. PMID- 21789730 TI - Heat shock protein 10 of Chlamydophila pneumoniae induces proinflammatory cytokines through Toll-like receptor (TLR) 2 and TLR4 in human monocytes THP-1. AB - Inflammatory response is the first line of infection. Previous studies have suggested that Chlamydophila pneumoniae heat shock protein (CHSP) 60 is present in human atheromata, and it plays an important role on the chronic infection elicited by C. pneumoniae. Here, we demonstrated in vitro the impact of heat shock protein 10 (HSP10) of C. pneumoniae on THP-1 cells and the role of Toll like receptors (TLRs) in the procedures of inflammatory response. The production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta were induced by recombinant HSP10 dose dependently, and the proinflammatory activity of HSP10 was greatly reduced by heating and deproteinization treatment. The expression of TLR4 and TLR2 on the cultured cells were determined by reverse transcriptase-polymerase chain reaction and immunofluorescence. Peritoneal macrophages isolated from wild-type (C3H/HeN) and TLR4-deficient mice (C3H/HeJ) were respectively stimulated with endotoxin free proteins. Cytokine responses after stimulation were significantly different, depending on the presence of TLR4. The effect on cytokine expression was blocked by anti-TLR2 or anti-TLR4 MAb partially or dramatically. Thus, HSP10 of C. pneumoniae which could elicit inflammatory reactions in human monocytes may contribute to the inflammatory processes in Chlamydophila infection, and the effects were mediated by TLR4 and, to a lesser extent, TLR2. PMID- 21789732 TI - An Excel sheet for inferring children's number-knower levels from give-N data. AB - Number-knower levels are a series of stages of number concept development in early childhood. A child's number-knower level is typically assessed using the give-N task. Although the task procedure has been highly refined, the standard ways of analyzing give-N data remain somewhat crude. Lee and Sarnecka (Cogn Sci 34:51-67, 2010, in press) have developed a Bayesian model of children's performance on the give-N task that allows knower level to be inferred in a more principled way. However, this model requires considerable expertise and computational effort to implement and apply to data. Here, we present an approximation to the model's inference that can be computed with Microsoft Excel. We demonstrate the accuracy of the approximation and provide instructions for its use. This makes the powerful inferential capabilities of the Bayesian model accessible to developmental researchers interested in estimating knower levels from give-N data. PMID- 21789733 TI - Probing pictorial relief: from experimental design to surface reconstruction. AB - The perception of pictorial surfaces has been studied quantitatively for more than 20 years. During this time, the "gauge figure method" has been shown to be a fast and intuitive method to quantify pictorial relief. In this method, observers have to adjust the attitude of a gauge figure such that it appears to lie flat on a surface in pictorial space. Although the method has received substantial attention in the literature and has become increasingly popular, a clear, step-by step description has not been published yet. In this article, a detailed description of the method is provided: stimulus and sample preparation, performing the experiment, and reconstructing a 3-D surface from the experimental data. Furthermore, software (written in PsychToolbox) based on this description is provided in an online supplement. This report serves three purposes: First, it facilitates experimenters who want to use the gauge figure task but have been unable to design it, due to the lack of information in the literature. Second, the detailed description can facilitate the design of software for various other platforms, possibly Web-based. Third, the method described in this article is extended to objects with holes and inner contours. This class of objects have not yet been investigated with the gauge figure task. PMID- 21789734 TI - A case of acute cerebral gas embolism due to ingestion of hydrogen peroxide. PMID- 21789736 TI - Five-year experience with modified Fogli (Lore's fascia fixation) platysmaplasty. AB - Over a 5-year period, my technique of approaching and modifying the aging neck has changed from direct suturing of the medial platysma bands and strong posterior traction of the platysma to superior elevation of the posterior platysma and strong fixation to the tympanoparotid fascia. When indicated, redundant anterior platysmal bands are resected instead of approximated. Evaluation of these anterior bands preoperatively for thickness and degree of descent allows more precise decision-making regarding the need to resect redundant and excessively thick or long anterior platysmal bands. The added advantage of the strong fixation of the platysma in a vertical fashion to Lore's fascia (the tympanoparotid fascia) leads not only to an improvement in the contour of the jawline and submental area but also to the undervalued aesthetic feature of a defined contour and visually increased length of the sternomastoid muscle. PMID- 21789735 TI - Teachers' assessments of children aged eight predict life satisfaction in adolescence. AB - The objective was to investigate how teachers' assessments of children predict life satisfaction in adolescence. This is a prospective cohort study on the population-based Northern Finland Birth Cohort 1986 (n = 8,959). Information was gathered from parents, teachers and adolescents using questionnaires at the age of 7, 8 and 15. Response rates were 80-90%. Emotional and behavioural problems were assessed with Rutter Children's Behavioural Questionnaires for teachers (RB2) and parents (RA2) during the first grade at age 8. At adolescence, self reported life satisfaction was measured with a question including five response alternatives. According to teachers' assessments, 13.9% of the children had high emotional or behavioural problems (RB2 >=9). These assessments predicted life dissatisfaction in adolescence (OR(crude) = 1.77; 95% CI 1.43-2.20) in several models including also health behaviour and use of psychotropic medicine. However, introducing all the significant variables in the same model, RB2 lost its significance (OR = 1.28; 0.96-1.70), but good school achievement assessed by teachers was still a significant predictor. Life satisfaction in adolescence was associated with a variety of favourable concurrent factors. In conclusion teachers' assessments of children during the first school year predicted life satisfaction in adolescence. In mental health promotion, teachers' early assessments should be utilized for the benefit of children. PMID- 21789737 TI - The role of nuclear medicine in diagnosing complications related to catheter based AF ablation. PMID- 21789738 TI - Anesthesia and the patient with pericardial disease. AB - PURPOSE: Pericardial diseases present unique perioperative considerations for the anesthesiologist. The purpose of this review is to provide a summary of the pertinent issues related to the etiology, diagnosis, pathophysiology, and perioperative management of patients presenting for operative treatment of pericardial disease. SOURCE: A selective search of the anesthesia, cardiology, and cardiothoracic surgical literature was carried out with particular emphasis on acute pericarditis, effusion, tamponade, and constrictive pericarditis. PRINCIPAL FINDINGS: The anesthesiologist needs to be well versed in the etiology (i.e., differential diagnosis), pathophysiology, and diagnostic modalities in order to best prepare the patient for surgery. Diagnosis and guidance of management requires a working knowledge of the specific associated hemodynamic consequences, particularly of the impaired diastolic function that can occur. Echocardiography is essential in the diagnosis and management of these patients. CONCLUSIONS: Patients with acute and chronic pericardial diseases often require the need for surgical intervention. Several unique features of acute tamponade and constrictive pericarditis require careful perioperative consideration. With proper preparation and pre-anesthetic optimization, patients with a variety of pericardial diseases can be safely managed before, during, and after their surgical intervention. PMID- 21789739 TI - Combination of dose escalation with technological advances (intensity-modulated and image-guided radiotherapy) is not associated with increased morbidity for patients with prostate cancer. AB - PURPOSE: The aim was to evaluate treatment-related morbidity after intensity modulated (IMRT) and image-guided (IGRT) radiotherapy with a total dose of 76 Gy in comparison to conventional conformal radiotherapy (3DCRT) up to 70.2-72 Gy for patients with prostate cancer. PATIENTS AND METHODS: All patients were prospectively surveyed prior to, on the last day, as well as after a median time of 2 and 16 months after RT using a validated questionnaire (Expanded Prostate Cancer Index Composite). Criteria for the 78 matched pairs after IMRT vs. 3DCRT were patient age, use of antiandrogens, treatment volume (+/- whole pelvis), prognostic risk group, and urinary/bowel/sexual quality of life (QoL) before treatment. RESULTS: QoL changes after dose-escalated IMRT were found to be similar to QoL changes after 3DCRT in all domains. Only sexual function scores more than 1 year after RT decreased slightly more after 3DCRT in comparison to IMRT (mean 9 vs. 6 points; p = 0.04), with erections firm enough for intercourse in 14% vs. 30% (p = 0.03). Painful bowel movements were reported more frequently after 3DCRT vs. IMRT 2 months after treatment (>= once a day in 10% vs. 1%; p = 0.03), but a tendency for higher rectal bleeding rates was found after IMRT vs. 3DCRT more than 1 year after RT (>= rarely in 20% vs. 9%; p = 0.06). CONCLUSION: Combination of dose escalation with technological advances (IMRT and IGRT) is not associated with increased morbidity for patients with prostate cancer. PMID- 21789740 TI - Monte Carlo simulations applied to conjunctival lymphoma radiotherapy treatment. AB - INTRODUCTION: Small radiation fields are increasingly applied in clinical routine. In particular, they are necessary for the treatment of eye tumors. However, available treatment planning systems do not calculate the absorbed dose with the desired accuracy in the presence of small fields. Absorbed dose estimations obtained with Monte Carlo methods have the required accuracy for clinical applications, but the exceedingly long computation times associated with them hinder their routine use. In this article, a code for automatic Monte Carlo simulation of linacs and an application in the treatment of conjunctival lymphoma are presented. METHODS: Simulations of clinical linear accelerators were performed with the general-purpose radiation transport Monte Carlo code penelope. Accelerator geometry files, in electron mode, were generated with the program AutolinaC. RESULTS: The Monte Carlo simulation of an annular electron 6 MeV field used for the treatment of the conjunctival lymphoma yielded absorbed dose results statistically compatible with experimental measurements. In this simulation, 2% standard statistical uncertainty was reached in the same time employed by a hybrid Monte Carlo commercial code (eMC); however, eMC showed discrepancies of up to 7% on the absorbed dose with respect to experimental data. Results obtained with the analytic algorithm Pencil Beam Convolution differed from experimental data by 10% for this case. CONCLUSION: Owing to the systematic application of variance-reduction techniques, it is possible to accurately estimate the absorbed dose in patient images, using Monte Carlo methods, in times within clinical routine requirements. The program AutolinaC allows systematic use of these variance-reduction techniques within the code penelope. PMID- 21789741 TI - Erlotinib-induced rash spares previously irradiated skin. AB - BACKGROUND: Erlotinib is an epidermal growth factor receptor inhibitor prescribed to patients with locally advanced or metastasized non-small cell lung carcinoma after failure of at least one earlier chemotherapy treatment. Approximately 75% of the patients treated with erlotinib develop acneiform skin rashes. CASE REPORT: A patient treated with erlotinib 3 months after finishing concomitant treatment with chemotherapy and radiotherapy for non-small cell lung cancer is presented. Unexpectedly, the part of the skin that had been included in his previously radiotherapy field was completely spared from the erlotinib-induced acneiform skin rash. CONCLUSION: The exact mechanism of erlotinib-induced rash sparing in previously irradiated skin is unclear. The underlying mechanism of this phenomenon needs to be explored further, because the number of patients being treated with a combination of both therapeutic modalities is increasing. The therapeutic effect of erlotinib in the area of the previously irradiated lesion should be assessed. PMID- 21789742 TI - Salivary cortisol predicts cardiovascular mortality. PMID- 21789743 TI - Overview of penicillin allergy. AB - Allergy to penicillin is the most commonly reported antibiotic allergy. However, most patients who report a positive history of a prior reaction to penicillin are not found to be allergic to penicillin upon skin testing. Often, this history is vague or based on a parent's recollection of an event that occurred in the distant past. Avoidance of penicillin based on self-reported allergic history alone often leads to the use of an alternate antibiotic with greater cost or side effect profile. Patients with a negative skin test to both major and minor determinants may generally be given penicillin, with a statistical risk of developing an allergic reaction similar to that observed in the general population. A more cautious approach in these cases where the degree of suspicion is low, an allergic etiology is unproven, or there is a negative skin test, is to do a graded challenge. If the skin test is positive, an alternate antibiotic should be used. If, however, an alternate antibiotic is not available, then desensitization may be performed, but there are limitations to desensitization as well, and tolerance is not permanent. Avoidance of cephalosporins may be recommended in cases of penicillin allergy, but newer generation cephalosporins have demonstrate less cross-reactivity to penicillin than earlier generation ones. Desensitization protocols for cephalosporins are available but not standardized. The mechanisms of antibiotic sensitization are not clearly understood. PMID- 21789744 TI - NREM sleep staging using WAV(CNS) index. AB - OBJECTIVE: Visual scoring of 30-s epochs of sleep data is not always adequate to show the dynamic structure of sleep in sufficient details. It is also prone to considerable inter- and intra-rater variability. Moreover, it involves considerable training and experience, and is very tedious, time-consuming, labor intensive and costly. Hence, automatic sleep staging is needed to overcome these limitations. Since naturally occurring NREM sleep and anesthesia have been reported to possess various underlying neurophysiological similarities, EEG-based depth-of-anesthesia monitors have started to penetrate into sleep research. This study investigates the ability of WAV(CNS) index (as implemented in NeuroSENSE depth-of-anesthesia monitor) to detect NREM sleep stages and wake state for full overnight PSG data. METHODS: Full overnight PSG sleep data, obtained from 24 adolescents, was scored by a registered PSG technologist for different sleep stages. Retrospective analysis was performed on a single frontal channel using the WAV(CNS) algorithm. Non-parametric descriptive statistics were used to examine the relationship between WAV(CNS) index and sleep stages. RESULTS: A strong correlation (rho = 0.9458) was found between the WAV(CNS) index and NREM sleep stages, with WAV(CNS) index values decreasing with increasing sleep stages. Moreover, there was no significant overlap between different NREM sleep stages as classified by the WAV(CNS) index, which was able to significantly differentiate (P < 0.001) between all pairs of Awake and different NREM stages. CONCLUSIONS: This study demonstrates that changes in the depth of natural NREM sleep are reflected sensitively by changes in the WAV(CNS) index. Hence, WAV(CNS) index may serve as an automatic real-time indicator of depth of natural sleep with high temporal resolution, and can possibly be of great use for automated sleep staging in routine/postoperative somnographic studies. PMID- 21789746 TI - Attention deficit hyperactivity disorder and substance use disorders. AB - During the past two decades, there has been an increased recognition that Attention Deficit Hyperactivity Disorder (ADHD) is overrepresented in treatment and community populations of both adolescents and adults with substance use disorders (SUDs). This chapter explores this relationship, including a review of the prevalence of this comorbidity, ADHD and the risk for the development of SUDs. Possible neurobiological underpinnings of the relationship are also discussed. Because of the salience of the association between smoking (tobacco) and ADHD, this topic is included in the discussion of substance use and SUDs. PMID- 21789747 TI - CT angiography with cardiac MRI: non-invasive functional and anatomical assessment for the etiology in newly diagnosed heart failure. AB - Exclusion of ischemia is important in patients with newly diagnosed systolic heart failure (HF). We prospectively compared standard-of-care invasive catheter angiography (iCA) and echocardiography to a novel non-invasive strategy of both Coronary Computed Tomographic Angiography (CCTA) and Cardiovascular MRI (CMR) to determine the etiology of myocardial dysfunction Prospective data were collected from consecutive patients referred for iCA to investigate echocardiographically confirmed new onset HF. CMR (1.5T GE) and dual source CCTA were performed within 2-7 days of iCA. Results were blinded and separately analyzed by expert readers. 426 coronary segments from 28 prospectively enrolled patients were analyzed by CCTA and quantitative iCA. The per-patient sensitivity and specificity of CCTA was 100% and 90%, respectively, negative predictive value (NPV) 100%, positive predictive value (PPV) 78%. Mean ejection fraction by CMR was 24%. Presence of ischemic-type LGE on CMR conferred a 67% sensitivity, 100% specificity, 90% NPV and 100% PPV. Combining CCTA with CMR conferred 100% specificity, 100% sensitivity, 100% PPV and 100% NPV for detection or exclusion of coronary disease. In patients with negative CCTA all invasive angiograms could have been avoided. In addition, two patients with no ischemic LGE by CMR had severe coronary disease on both CCTA and iCA, indicating global hibernation. This is a noteworthy finding in contrast to previous reports which suggested that absence of LGE rules out significant CAD. CCTA with CMR in newly-diagnosed HF enables non invasive assessment of coronary artery disease, the severity and etiology of myocardial dysfunction and defines suitability for revascularization. Absence of ischemic-type LGE at CMR does not exclude CAD as a cause of LV dysfunction. A first-line strategy of functional and anatomic imaging with CMR and CCTA appears appropriate in newly diagnosed HF. PMID- 21789748 TI - The prevalence and distribution of coronary artery calcium in asymptomatic Korean population. AB - Coronary artery calcium score (CACS) is a strong predictor of coronary heart disease and provides incremental prognostic information beyond traditional risk factors. The difference in prevalence and distribution of CACS in different ethnic groups has been reported with conflicting results. We aimed to investigate the prevalence and distribution of CACS in asymptomatic Korean population. A total of 5,239 asymptomatic patients free of known coronary artery disease who had coronary artery calcium scoring computed tomography during comprehensive medical examinations were included in the analysis. Coronary calcium was present in 33.1% of overall population, 40.5% of males and 19.3% of females. In all age groups, CACS was higher in males. The pattern of increase in CACS appeared in different patterns, with earlier and gradual increase in males. In females, there was a time-lag, behind that observed in males by about 10 years. Multivariate analysis showed that male gender (OR 3.759, 95% CI 3.120-4.529, P < 0.001), older age (OR 1.095, 95% CI 1.085-1.106, P < 0.001), pulse pressure (OR 1.142, 95% CI 1.063-1.227, P < 0.001), HbA1C (OR 1.390, 95% CI 1.255-1.540, P < 0.001), and obesity defined by body mass index (BMI) >= 25 kg/m(2) (OR 1.042, 95% CI 1.011 1.073, P = 0.007) were related to the presence of coronary artery calcification (CACS > 0). This study provides a healthy reference value of coronary artery calcification in Korean subjects, based on sex and age percentiles. Similar age and gender associations and distributions of coronary artery calcification are found, compared to the previous studies in western populations, but median CACS tend to be lower in Koreans. PMID- 21789749 TI - [Which occupational groups in a hospital are particularly stressed?]. AB - BACKGROUND AND OBJECTIVE: Increasing workload in health professionals and resulting health consequences have frequently been reported. We analysed the results from an employee attitude survey within a network of workplace health promotion and compared three occupational groups of a university hospital with two samples of employees of other industries. METHOD: The survey was conducted in the years 2005, 2006 and 2007 using a standardized method, addressing 1748 employees of six companies. In order to compare specific occupational groups, both within the hospital and amongst different companies, five occupational groups were selected (medical profession, nursing service and administration of the hospital, academics of another company and employees of a financial service provider). RESULTS: Some results were specific for an occupational group, such as lower back pain and skin diseases in nurses and exhaustion in clinicians. Regarding several items the responses of employees of the hospital's administration were similar to that of the medical professionals and differed significantly from the responses of administrative and related employees in other companies. Employees of all occupational groups of the hospital were often frustrated and felt their work was not appreciated. Frequent demands included improved work atmosphere, better appreciation of work and better information regarding innovations. CONCLUSIONS: The analysis of standardized survey results specific for companies and occupational groups is an appropriate way to identify targets of health promotion. Constant over three surveys, again a high burden of stress was found in health care workers even affecting the administrative staff, regarding several work-related stress factors. According to our results activities to improve the working conditions in hospitals are urgently needed. PMID- 21789750 TI - [Contrast-enhanced ultrasound of focal fatty sparing]. AB - HISTORY AND CLINICAL FINDINGS: A 52-year-old man went to his family doctor because of nonspecific abdominal complaints. The physical findings were unremarkable. The abdominal ultrasound unexpectedly showed a nonhomogeneous focal fatty sparing around the gallbladder fossa, which was the reason why the patient was referred for contrast-enhanced ultrasonography (CEUS). INVESTIGATIONS: The native ultrasound showed focal fatty sparing around the gallbladder fossa, while the CEUS demonstrated a high-flow hemangioma with subsequent peritumoral fatty sparing caused by arterioportal shunts. MRI of the liver confirmed the hemangioma. CONCLUSION: Focal fatty sparing which is nonspecific and not typical in its localization should be carefully investigated, because it could be a peritumoral fatty sparing. The same is true for nonhomogeneous fatty sparing at a typical position. Special attention should be given to signs of shunting. The CEUS in low-MI mode provides a dynamic real-time examination and is the method of choice in this situation. PMID- 21789751 TI - [Synthetic lethality as a new concept for the treatment of cancer]. AB - Following DNA damage, cells activate a complex DNA-damage-response (DDR) signaling network to arrest the cell cycle, repair DNA and, if the extend of damage is beyond repair capacity, induce apoptosis. DDR genes are among the most commonly mutated genes in human cancer and it is believed that these lesions promote a "MUTATOR-PHENOTYPE" that fuels the runaway proliferation of cancer cells. However, these genetic lesions can also be seen as the "Achilles heel" of cancer. These tumor cell-specific vulnerabilities are of extraordinary clinical interest, since they allow genetically-guided novel therapeutic regimens for the treatment of cancer. Here, we discuss such a novel therapeutic concept - synthetic lethality. We focus on the first successful clinical applications of synthetic lethality for the treatment of different cancer entities. In addition, we give a brief review of recently developed, synthetic lethality-based approaches that are close to clinical testing. PMID- 21789752 TI - [Hypertricglyceridemia: prognostic impact and treatment options]. AB - Elevated Triglyceride levels are associated with increased risk for atherosclerotic disease and additional vascular risk factors such as obesity, hypertension and impaired glucose tolerance. To estimate the individual cardiovascular risk of a patient with elevated triglycerides LDL- and HDL cholesterol levels, concomitant diseases, composition of triglyceride rich lipoproteins and a family history for premature coronary heart disease are important. Primary goals for the management of hypertriglyceridemia are a reduction of cardiovascular risk and prevention of triglyceride associated complications such as the chylomicronemia syndrome. The basis of treatment are lifestyle changes: dietary intervention, alcohol avoidance, regular physical activity, weight loss and smoking cessation to modify risk factors. If triglyceride levels can not be sufficiently reduced by lifestyle intervention pharmacotherapy (nicotinic acid, fibrates and omega-3-acid ethyl esters) is indicated. Beyond reduction of triglyceride levels optimization of non-HDL cholesterol by statin treatment is warranted to reduce vascular risk. PMID- 21789753 TI - [Calling in assistants in an official expert opinion at court]. PMID- 21789754 TI - [Sense of coherence and stress in parents of children with chronic disease and mental health disorders]. AB - QUESTION: The aim of this study was to examine parental sense of coherence (SOC) as a resource for coming to terms with their children's disease. Furthermore we examined the interaction between parental stress experience and SOC while controlling for neuroticism. 3 groups were compared: parents of children with (1) cystic fibrosis (CF, n = 35), (2) juvenile idiopathic arthritis (JIA, n = 31) and (3) mental health disorders (PSY, n = 34). METHODS: Parents were asked to complete the "Heidelberger Sense of Coherence Questionnaire", the "Parenting Stress Index" and the Neuroticism Scale of the "Trierer Integriertes Personlichkeitsinventar". RESULTS: There were no significant differences in SOC and neuroticism. Parents of children with mental health disorders showed significantly higher stress levels (M = 2.60; p = 0.001) than parents of children with CF (M = 2.13) and JIA (M = 1.99). In all groups, significant negative interactions between SOC and stress experience were found (r = - 0.46 to - 0.65). However, this effect decreased when controlling for neuroticism (r = - 0.26 to - 0.31). IMPLICATION: According to our results, the type of the child's disease is not relevant to the parents' SOC. A well developed SOC in parents is likely to be helpful in coping with the stress associated with a child's disease or disorder. PMID- 21789755 TI - [Relationship between family stressors, personal resources of mothers and health related quality of life of their children]. AB - Family stressors and personal resources of mothers are discussed as important risk factors for infant development. At 2 measurement points (beginning and end of mother-child rehabilitation; duration: 3 weeks; N = 564 mother-child-pairs) data of mothers' self-report of stress as well as personal resources and children's self-report of quality of life were examined, using a structural equation model. Family stressors have a direct effect on children's quality of life and an indirect effect mediated by psychological health or maternal self reported competence. Changes in mothers' psychological health and maternal self reported competence show a small but significant correlation with changes in children's quality of life. PMID- 21789756 TI - [Broncho-esophageal fistula after urgent radiation of a patient with superior vena cava syndrome]. PMID- 21789757 TI - [Gastric cancer: current status of multimodality treatment]. AB - BACKGROUND: The overall prognosis of gastric cancer with an overall 5-year survival of 25% is still poor despite improvements of the surgical and perioperative procedures. To improve the surgical treatment results other therapeutic options as chemo- and/or radiotherapy have been investigated for more than 20 years. METHODS: After a literature review, the results of actual trials of multimodality treatment were analysed and described. RESULTS: Adjuvant treatment was less effective compared with neoadjuvant or perioperative chemotherapy performed in advanced tumour categories T3/4. Actual trials could show that the rate of curative (R0) resection can be augmented resulting in an increase of the overall 5-year survival rate of more than 10 %. CONCLUSION: To confirm this trend, further studies with high pathological and surgical quality control are necessary as well as a more exact definition of prediction and evaluation of the response following chemotherapy. PMID- 21789758 TI - Pattern and predictors of false positive lymph node involvement on positron emission tomography in patients with non-small cell lung cancer. AB - Objectives The aim of this study was to elucidate the optimal parameters for diagnosing false positive (FP) lymph nodes (LNs) in patients with non-small cell lung cancer.Methods We reviewed 292 patients with non-small cell lung cancer (NSCLC). Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging was performed at 1 hour (early) post-FDG injection and repeated 2 hours (delayed) after injection. We analyzed the relationship between the pathology of LNs and the results of PET, and the percent change in the standardized uptake value (%DeltaSUV) between the two time-points.Results Eighteen of 46 cases (39.1%) in the FP group showed higher SUVs for their LNs compared with those for primary tumor, whereas 13.2% in the true positive group (p = 0.032) had higher SUVs for their LNs. Thirty-four of 36 cases in the true positive group had %DeltaSUV ranging from 0% to 61.5% compared with only 13 of 33 in the FP group. Twenty out of 22 cases (90.9%) where %DeltaSUV was over 61.5% or under 0% were considered as FP.Conclusions Patients with higher SUVs for LNs than for primary tumors and patients with extremely high or low %DeltaSUVs tended to have FP LNs. PMID- 21789759 TI - Effects of human amniotic fluid on costal cartilage regeneration (an experimental study). AB - OBJECTIVE: After surgical correction of thoracic wall deformities, promoting neochondrogenesis in the perichondrial bed is very important for obtaining a flexible chest wall. In this experimental study, we aimed to investigate the effects of human amniotic fluid on cartilage regeneration in the costal perichondrial bed in a rabbit model. METHODS: Fifty-four adult New Zealand rabbits were divided into three groups, with 18 rabbits in each group. The third and fifth costal cartilages were excised totally on the right side and partially excised on the left side in all groups. Group 1 served as controls. All rabbits in group 1 underwent closure of the perichondrium of the third costal cartilage and closure of the perichondrium of the fifth costal cartilage with reimplantation of reshaped cartilage into the fifth costal perichondrial bed. Rabbits in group 2 underwent closure of the perichondrium of the third and fifth costal cartilages after the administration of human amniotic fluid into the perichondrial bed. Group 3 rabbits received both human amniotic fluid and underwent cartilage reimplantation. The third and fifth costal perichondriums in group 3 rabbits were closed after the administration of human amniotic fluid and the reimplantation of reshaped cartilages. Rabbits were sacrificed at two, eight and 12 weeks after operation. RESULTS: Numerical scores for the right perichondrial bed were significantly higher for group 2 compared to group 1 ( P < 0.05). But the difference was not significant for the left perichondrial bed ( P > 0.05). The diameter of chondrogenesis also did not differ significantly between left and right perichondrial bed for all groups. CONCLUSION: Our study shows that administration of human amniotic fluid into the perichondrial bed increases chondrogenesis in adult rabbits, an important finding which may contribute to improving chest wall flexibility after the surgical correction of pectus excavatum. PMID- 21789760 TI - Endurance and performance of two different concepts for left ventricular stimulation with bipolar epicardial leads in long-term follow-up. AB - BACKGROUND: Epicardial left ventricular (LV) leads represent an alternative for CRT therapy if transvenous lead implantation fails. Data on endurance, performance, the impact of the surgical approach (lateral minithoracotomy vs. median sternotomy simultaneously with other cardiac surgery), and the optimal technical concept (screw-in vs. suture-on) is limited. METHODS: Over a period of 48 months we evaluated 130 consecutive patients with comparable characteristics. A total of 54 screw-in (MyoDexTM 1084T, SJM) and 76 suture-on (Capture Epi 4968, Medtronic) bipolar epicardial steroid-eluting LV leads were implanted either via a left lateral or a median thoracotomy. Sensing, pacing threshold, impedance and NYHA class were recorded at defined time points. RESULTS: No surgery-related death or major complication was observed. At the time of implantation, the pacing threshold, sensing and NYHA class did not differ significantly between the two groups. The impedances of screw-in leads were significantly lower compared to those of suture-on leads. Suture-on leads showed a moderate initial drop in their pacing threshold but afterwards remained stable. Screw-in leads were characterized by a moderate but significant increase in the pacing threshold in the first year followed by a continuous decrease thereafter. Twenty-four months post-implantation no differences between both lead types could be detected. Sensing and NYHA class improved in both groups. The surgical approach had no significant impact on lead functionality. CONCLUSION: Our study showed that the implantation of epicardial leads was safe with very low complication rates. There was no superior technical epicardial lead concept (screw-in vs. suture-on leads) and all epicardial leads demonstrated an excellent long-term performance and durability. Therefore, it seems that epicardial leads represent a good alternative to transvenous leads and surgeons should be encouraged to implant epicardial leads during concomitant cardiac surgery when the indications for CRT are present. PMID- 21789761 TI - Hemolysis at different vacuum levels during vacuum-assisted venous drainage: a prospective randomized clinical trial. AB - BACKGROUND: There are several reports on the application of variable degrees of vacuum pressure to hardshell venous reservoirs. The aim of the current study was to compare the hemolytic effects of vacuum-assisted venous drainage (VAVD) at two different vacuum levels with the classical gravity siphon method. METHODS: A prospective, equally randomized (1: 1: 1), parallel group study was performed in elective coronary artery bypass grafting (CABG) operations. PATIENTS: (n = 162) were divided into three groups: gravity siphon (group 1, n = 55), VAVD at -40 mmHg (group 2, n = 55) and VAVD at -80 mmHg (group 3, n = 52). Hemolysis tests were performed at 2, 24 and 48 h following the operations. RESULTS: There were no deaths in this study. Plasma-free hemoglobin (PfHb) levels showed a difference at 2 h (p < 0.001) compared to 24 h (p = 0.02) between the groups. Haptoglobin (Hp) levels also revealed hemolysis in groups 2 and 3 at all sampling times. CONCLUSIONS: Constant negative suction at -80 mmHg during elective coronary bypass operations caused more hemolysis. We do not recommend a constant suction of -80 mmHg for VAVD. PMID- 21789762 TI - Hybrid approach combining off-pump CABG with transapical aortic valve implantation via median sternotomy. AB - We report the case of a 75-year-old patient diagnosed with severe aortic stenosis and two-vessel coronary artery disease. Due to multiple comorbidities including chronic renal insufficiency, stroke and pulmonary hypertension (EuroSCORE: 34%; STS mortality risk: 14.9%), he was not a candidate for conventional aortic valve surgery. He underwent a novel hybrid treatment approach combining off-pump CABG and transapical aortic valve implantation via a median sternotomy. Extracorporeal circulation could be entirely avoided. PMID- 21789763 TI - [How family carers of people with dementia experienced their stay on an acute care facility and their own collaboration with professionals: a qualitative study]. AB - About one third of geriatric patients admitted to an acute care setting suffer from dementia as second diagnosis. For those patients, a hospital stay can negatively influence health outcomes and cause additional burden for families, because structure and organisation of acute care settings are often not adapted to dementia care. The purpose of this qualitative study was to explore the experiences of family members of people with dementia who were admitted to an acute geriatric care facility. Data were collected through interviews with 12 family members and a qualitative content analysis was carried out. Findings showed that, regardless of patients' signs of dementia, family members worried: Will she manage? Will her needs be met? Family members felt a special responsibility. They appreciated the rehabilitative and nursing care; most could subsequently relinquish responsibility and felt temporary relief. Collaboration with professionals was experienced in different ways: Family members were relieved and appreciative when involved, but disillusioned or disappointed when they thought that they were not understood and neglected. For some family members, quality of care and collaboration was related to the practice of individual professionals. It is recommended to reinforce interventions that are experienced positively by family members and to develop a team culture of active relationship building and collaboration with the families of patients with dementia. PMID- 21789765 TI - [Mindfulness and the development of professional health competence in nursing]. AB - Health competence is not only a requirement for personal health action; it is also a condition for professionalisation of health promotion. Health promotion has meanwhile become a well recognised part of nursing. This is the reason why in this study the term "health competence", which is actually very much discussed in health sciences, is presented. This concept is knowledge based (health literacy). It is focused on the ability to read, understand and work with health information to be able to do decisions in daily life which are positive for the health. An experienced-based understanding, which focuses on the ability to feel and to perceive and which is regarded as a precondition of self care, is added to this knowledge-based understanding of "health competence". The concept for this interpretation is the "Leibkonzept" which has already been discussed as a fruitful concept in nursing science in other publications. PMID- 21789764 TI - [Necessities and needs of intervention for workplace health promotion in residential elderly care?]. AB - The current demographic change coincides with an increasing demand for elderly care nursing services as well as a decrease of available nursing personnel. Against this background, efforts should be made to sustain the health and work motivation of the current workforce. In order to adequately design interventions, one needs an appropriate overview of subjective stress and health-related experiences of target groups as well as insight into influencing factors and organisational conditions. The study at hand analyses corresponding relations on the basis of a scientific survey conducted in six residential nursing homes and one institution for assisted accommodation. Survey results show that burnout is the most meaningful health indicator, while the strongest predictor for burnout turned out to be a conflicting relation between work and private life. There were significant differences between groups of staff concerning subjective perceptions of health. Based on these results, the authors argue for an organisational concept of health promotion. PMID- 21789766 TI - [Recognizing and defining dying. Analysis of end-of-life coverage in German nursing textbooks]. AB - Text books play an important role in basic education in nursing. This study aimed at capturing the extent and content of end-of-life issues in nursing text books in German language. For that reason, a quantitative and a qualitative analysis of relevant content in a comprehensive sample of nursing text books available (n = 65) were conducted. Whereas 29.2 % of the books do not cover the issue at all, 44.5 % dedicate a separate chapter to the issue of dying, which accounts for 1.34 % of all pages on average. Of all specialties, both surgery and internal medicine feature the lowest, and paediatrics and oncology the highest share of coverage. 41.53 % of all text books studied contain a definition of the term dying which is based on a great variety of approaches. 23 books list criteria that define the recognition of dying, 21 of which draw attention to symptoms of impending death. 84 % of the books refer to the work of Elisabeth Kubler-Ross. Overall, the amount of coverage of the issue of dying in nursing text books can be considered marginal by international comparison. What is problematic is the conceptual reduction to physiological signs of impending death and the lack of references to existing theoretical work. Integration of knowledge from the area of palliative care in all specialties is strongly needed. Additionally, there is a need for a stronger conceptual debate in order to avoid problems in communication about death and dying in nursing education and practice. PMID- 21789767 TI - [Institutional family systems and the role of the housemother 1945-1995. A hermeneutic-interpretive study of the restrospective experiences of the former housemothers in homes for "the sick and needy" in a diaconical institution - methodologically informed by the principles of grounded theory]. PMID- 21789768 TI - [Referee report and point by point processing protocol]. PMID- 21789769 TI - Aggregation in protein-based biotherapeutics: computational studies and tools to identify aggregation-prone regions. AB - Because of their large, complex, and conformationally heterogeneous structures, biotherapeutics are vulnerable to several physicochemical stresses faced during the various processing steps from production to administration. In particular, formation of protein aggregates is a major concern. The greatest risk with aggregates arises from their potential to give rise to immunogenic reactions. Hence, it is desirable to bring forward biotherapeutic drug candidates that show low propensity for aggregation and, thus, improved developability. Here, we present a comprehensive review of computational studies into the sequence and structural factors that underpin protein and peptide aggregation. A number of computational approaches have been applied including coarse grain models, atomistic molecular simulations, and bioinformatic approaches. These studies have focused on both the mechanism of aggregation and the identification of potential aggregation-prone sequence and structural motifs. We also survey the computational tools available to predict aggregation in therapeutic proteins. The findings communicated here provide insights that could be potentially useful in the rational design of therapeutic candidates with not only high potency and specificity but also improved stability and solubility. These sequence-structure based approaches can be applied to both novel as well as follow-on biotherapeutics. PMID- 21789770 TI - A high-throughput UPLC method for the characterization of chemical modifications in monoclonal antibody molecules. AB - Development of high-throughput release and characterization assays is critical for the effective support of the rapidly growing biologics pipeline for biotherapeutics. Clipping of polypeptide chains is commonly monitored during process optimization, formulation development, and stability studies. A reduced capillary electrophoresis-sodium dodecyl sulfate (rCE -SDS) method is often used as a purity release assay for monitoring clips in monoclonal antibodies (mAbs); however, it has a cycle time of approximately 40 min, which is not suited for high-throughput screening. Additionally, the characterization of clips and variants from electropherograms is not straightforward and takes significant time. Reduced reversed-phase (RP) chromatography has been a popular assay for the characterization and identification of clips and variants because it can be directly coupled with online mass spectrometric analysis. However, the high column temperature and low pH required for RP assays can induce on-column cleavage and therefore skew the results. To minimize on-column degradation, we have developed a high-throughput method with a significantly shorter cycle time of 5 min. The short cycle time was achieved using an ultra-high-pressure liquid chromatography (UPLC) system with a 1.7 MUm phenyl column. This UPLC method allowed quantitation of hinge clipping in an IgG1 molecule and acid induced aspartic acid/proline (D/P) clip in an IgG2 molecule. The results from the UPLC method were comparable to those obtained with rCE-SDS. Additionally, the phenyl column offered partial resolution of oxidation and other chemical modifications, making this technique an attractive assay for high-throughput process characterization and formulation screens. PMID- 21789771 TI - Biopharmaceutical characterization of ciprofloxacin HCl-ferrous sulfate interaction. AB - The ciprofloxacin-iron interaction, resulting in a lower bioavailability, is well documented in vivo; however, a mechanistic explanation supported by experimental data of this interaction is missing. In the present study, ciprofloxacin hydrochloride (HCl) and ferrous sulfate interaction was simulated in vitro by performing solubility and dissolution studies in the reactive media containing ferrous sulfate. Characterization of the precipitate formed indicated its probable chemical structure as Fe(SO(4) (2-) )(2) (Cl(-) )(2) (ciprofloxacin)(2) * (H(2) O)(n) , where n is up to 12 molecules of water. The solubility of this complex in water was estimated to be approximately 2 mg/mL, being about 20-fold lower than the solubility of ciprofloxacin HCl. The solubility of the complex was used as input parameter for an in silico modeling by GastroPlusTM and the resulting predicted plasma time curves were in good agreement with the in vivo data. These results strongly indicate that ciprofloxacin-iron interaction in vivo is caused by the formation of a low soluble complex. This interaction was also simulated by in vitro dissolution, in which a mini scale apparatus provided more biorelevant results than the standard dissolution apparatus, probably because the drug concentrations in the mini apparatus were higher and, thus, closer to the conditions encountered in vivo. PMID- 21789772 TI - High-throughput assessment of thermal and colloidal stability parameters for monoclonal antibody formulations. AB - Design of experiment and statistical analyses were applied to evaluate the effects of several formulation components on the thermal and colloidal stability for a series of monoclonal antibody (mAb) formulations. The high-throughput assessment of the protein stability was performed by measuring the temperature of hydrophobic exposure (T(h) , thermal stability) and the diffusion interaction parameter (k(D) , colloidal stability). To correlate the measured parameters with protein stability, the propensity to aggregate was tested by exposing the mAb samples to two types of stress: mechanical stress caused by shaking agitation and thermal stress. Mechanical stress led to increased formation of large particles, whereas temperature stress resulted in an increase in oligomers. The data obtained from the stress studies were used to determine the critical values for the stability parameters. The optimal formulation compositions were determined based on the statistical models and the predication tests. This approach of high throughput thermal and colloidal stability screening can be applied to the characterization and prediction of protein formulation properties. PMID- 21789773 TI - Sonographic thymic measurements in Down syndrome fetuses. AB - OBJECTIVE: Children with Down syndrome (DS) can have hypoplastic thymuses with an impaired capacity to liberate newly generated T cells. We sought to determine if the size of the thymus in DS fetuses is different from control fetuses. METHODS: We performed comprehensive prenatal sonographic evaluation that included measurements of the thymus in 874 control fetuses and in 12 DS fetuses. We used graphic comparisons between thymic measurements obtained from the two groups of fetuses and a nested case-control validation study in which DS fetuses were matched for gestational age with control fetuses using a 2-to-1 ratio to make group comparisons. RESULTS: The plot analysis showed that more than two-thirds of DS fetuses had sonographic signs of thymic hypoplasia. The nested case-control study confirmed that the thymus of DS fetuses was statistically smaller than the thymus of control fetuses [DS transverse diameter 12.3 mm, interquartile range (IQR) 6.2 vs. control 18.1 mm, IQR 4.4; p < 0.001 and, DS perimeter 30.9 mm, IQR 20.1 vs. control 48.6 mm, IQR 20.4; p < 0.01]. CONCLUSIONS: Our findings suggest that the majority of DS fetuses have smaller thymuses than control. Prenatal measurements of the thymus may be clinically useful in the management of DS pregnancies. PMID- 21789774 TI - Comparisons of outcomes after cordocentesis at mid-pregnancy between singleton and twin pregnancies. AB - OBJECTIVE: To compare the outcomes after mid-pregnancy cordocentesis between singleton and twin pregnancies. METHODS: We compared immediate complications and pregnancy outcomes between a cohort of twin pregnancies undergoing mid-pregnancy diagnostic cordocentesis between the years 1989 and 2010, and a control group of singleton pregnancies matched based on maternal age and years of the procedure with a ratio of 1:3. RESULTS: Among 6147 pregnancies undergoing cordocentesis during the study period, 122 twin fetuses met the study criteria and were matched with 336 singleton controls. Success rate of sampling was slightly higher in singleton than in twin gestations (98.8% vs 97.3%), and time required for the procedure was significantly longer in the twin group (8.1 vs 6.3 min, p = 0.02). Immediate complications, such as fetal bradycardia and transient bleeding from the puncture site, were significantly higher in twins (13% vs 6.0%, p = 0.001; and 34.8% vs 26.1%, p = 0.03, respectively). However, fetal loss rate within 2 weeks of cordocentesis was not different (1.4% and 1.1%, p = 0.42). CONCLUSION: Immediate complications following cordocentesis are significantly higher in twin pregnancies, but fetal loss rate within 2 weeks of the procedure is comparable. PMID- 21789775 TI - Gender differences in the assessment, stability, and correlates to bullying roles in middle school children. AB - The current study investigated bullying behaviors in 284 school children in the fourth through seventh grades at the time of the initial assessment. Peer ratings of bullying behavior were obtained at the end of the spring semester of one school year and at the end of the fall semester of the next school year. Importantly, peer ratings were obtained by assessing not only the level at which participants actually bully other students but also whether participants help bullies to hurt the victim (assister), encourage bullies (reinforce), or help the victim of bullying (defender). Our results did not support the utility of differentiating between bullies, assisters, or reinforcers. Specifically, these bullying roles were highly intercorrelated, both concurrently and across school years, and they showed similar correlations with aggression and several characteristics often associated with aggression (i.e., conduct problems, callous unemotional traits, and positive expectancies about aggression). In contrast, ratings of defending designated a particularly prosocial group of students. Finally, whereas bullying appeared to be very similar in boys and girls, it was somewhat more stable across school years and was related to lower levels of prosocial behavior in boys, both of which could suggest that bullying may be somewhat more related to social group dynamics in girls. PMID- 21789776 TI - Three-dimensional photonic crystal intermediate reflectors for enhanced light trapping in tandem solar cells. PMID- 21789777 TI - Laser-induced control of TiO2 porosity for enhanced photovoltaic behavior. PMID- 21789778 TI - Coloured semi-reflective thin films for biomass-hydrolyzing enzyme detection. AB - A new enzymatic activity detection assay based on colour change of the semi reflective films is presented. The method is based on the preparation of multilayered thin films of controlled thickness obtained by sequential deposition of cellulose nanocrystals and xyloglucan. The hydrolysis of the films leads to a decrease in layer thickness that enables to detect enzyme activity, to the naked eye, from the resulting colour changes in a span of few minutes. The method allows direct, fast, highly sensitive, and easy-to-use characterization of enzymatic activities. PMID- 21789779 TI - Disgust sensitivity and anorexia nervosa. AB - BACKGROUND: Previous studies found inconsistent differences in disgust sensitivity between patients with a variety of eating disorders and normal controls. AIM: The objective of this study was to compare disgust sensitivity between a larger and more specific sample of anorexia nervosa (AN) patients and control subjects. METHOD: We compared the scores on the 'disgust sensitivity scale' of AN patients (N = 62) and control subjects (N = 62) using a multivariate analysis of variance. All subjects were women. RESULTS: AN patients scored consistently higher on all domains of disgust sensitivity. This difference was significant for six of eight disgust domains. The largest significant difference between the groups was on the domains food and magical thinking. CONCLUSION: Our findings elaborate on previous findings and are in line with recent neurological findings suggesting that disgust and insular impairments are associated with AN. Clinical implications of our findings are discussed. PMID- 21789780 TI - Prediction of biological protein-protein interactions using atom-type and amino acid properties. AB - Identification and analysis of types of biological protein-protein interactions and their interfaces to predict obligate and non-obligate complexes is a problem that has drawn the attention of the research community in the past few years. In this paper, we propose a prediction approach to predict these two types of complexes. We use desolvation energies - amino acid and atom type - of the residues present in the interface. The prediction is performed via two state-of the-art classification techniques, namely linear dimensionality reduction (LDR) and support vector machines (SVM). The results on a newly compiled data set, namely BPPI, which is a joint and modified version of two well-known data sets consisting of 213 obligate and 303 non-obligate complexes, show that the best prediction is achieved with SVM (76.94% accuracy) when using desolvation energies of atom-type features. Also, the proposed approach outperforms the previous solvent accessible area-based approaches using SVM (75% accuracy) and LDR (73.06% accuracy). Moreover, a visual analysis of desolvation energies in obligate and non-obligate complexes shows that a few atom-type pairs are good descriptors for these types of complexes. PMID- 21789781 TI - Antidepressant may help ease hot flashes. PMID- 21789782 TI - An unusual cause of skull and cervical spine masses. Multiple myeloma. PMID- 21789783 TI - Headache, collapse and coma. Deep cerebral venous sinus thrombosis. PMID- 21789784 TI - Mycoplasmas and human prostate cancer: an exciting but cautionary note. PMID- 21789785 TI - Debt crisis strains Greece's ailing health system. PMID- 21789786 TI - Uncertainty clouds China's road-traffic fatality data. PMID- 21789787 TI - Netrin-1 overexpression is predictive of ovarian malignancies. AB - Netrin-1 (NTN1) is functionally important for the development of the nervous system.Interestingly, few recent studies showed that NTN1 may also promote cancer by increasing survival and resistance of lung and breast cancer cells to apoptosis. Our purpose was to investigate whether NTN1 and its receptor DCC may be involved in ovarian cancer. The NTN1 and DCC mRNAs were quantified by real time RTPCR in normal (10), benign (8) and cancer (17) ovarian tissues. ALAS1 and TBP housekeeping genes were used for normalization. NTN1 was found overexpressed in 76% of ovarian cancer specimens (13/17) as compared to normal (0/10, p<0.004)and benign (1/8, p<0.008) samples. Increased NTN1 mRNA levels correlated with advanced tumor stage (stage III, n=8, 100%) and grade (grade 3, n=7, 100%). In contrast, DCC was found downregulated in 59% (10/17) of ovarian tumors tested but correlation was not significant when compared to normal or benign specimens. Here,we demonstrated that NTN1 may be involved in ovarian cancer as the expression of NTN1 mRNA is strongly upregulated in ovarian malignant tumors but not in benign tumors. The fact that increased NTN1 is specifically observed in cancerous tissues indicates that NTN1 may represent a novel candidate biomarker for ovarian cancer. PMID- 21789788 TI - Dr Jenner's House: the birthplace of vaccination. PMID- 21789789 TI - Time to mandate influenza vaccination in health-care workers. PMID- 21789790 TI - No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. AB - The Warburg effect describes the circumstance that tumor cells preferentially use glycolysis rather than oxidative phosphorylation for energy production. It has been reported that this metabolic reconfiguration originates from a switch in the expression of alternative splice forms (PKM1 and PKM2) of the glycolytic enzyme pyruvate kinase (PK), which is also important for malignant transformation.However, analytical evidence for this assumption was still lacking. Using mass spectrometry, we performed an absolute quantification of PKM1 and PKM2 splice isoforms in 25 human malignant cancers, 6 benign oncocytomas, tissue matched controls, and several cell lines. PKM2 was the prominent isoform in all analyzed cancer samples and cell lines. However, this PKM2 dominance was not a result of a change in isoform expression, since PKM2 was also the predominant PKM isoform in matched control tissues. In unaffected kidney, lung, liver, and thyroid, PKM2 accounted for a minimum of 93% of total PKM, for 80% - 96% of PKM in colon,and 55% - 61% of PKM in bladder. Similar results were obtained for a panel of tumor and non-transformed cell lines, where PKM2 was the predominant form.Thus, our results reveal that an exchange in PKM1 to PKM2 isoform expression during cancer formation is not occurring, nor do these results support conclusions that PKM2 is specific for proliferating, and PKM1 for non proliferating tissue. PMID- 21789791 TI - Novel insights into the synergistic interaction of Bortezomib and TRAIL: tBid provides the link. AB - The proteasome inhibitor Bortezomib has been identified as a potent enhancer of TRAIL-induced apoptosis in several human cancers. However, the identification of the underlying molecular mechanisms of this synergistic cell death induction has been ongoing over the last years. A recent study identifies a new mechanism of action for the synergism of TRAIL and Bortezomib. PMID- 21789792 TI - c-JUN prevents methylation of p16(INK4a) (and Cdk6): the villain turned bodyguard. AB - A novel way by which the AP-1 factor c-JUN interferes with tumorigenesis has recently been elucidated [1]. In a model of murine leukemia, c-JUN prevents the epigenetic silencing of the cell cycle kinase CDK6. In the absence of c-JUN, CDK6 is down-regulated and the 5'region of the gene is methylated. Down-regulation of CDK6 results in significantly delayed leukemia formation. Here we show that c-JUN is also involved in protecting the promoter region of the tumor suppressor p16(INK4a), which is consistently methylated over time in c-JUN deficient cells. In cells expressing c-JUN, p16(INK4a) promoter methylation is a less frequent event. Our study unravels a novel mechanism by which the AP-1 factor c-JUN acts as a "bodyguard",and preventing methylation of a distinct set of genes after oncogenic transformation. PMID- 21789794 TI - Piracetam-induced immune thrombocytopenia. PMID- 21789793 TI - Addendum to "Strain-to-strain difference of V protein of measles virus affects MDA5-mediated IFN-beta-inducing potential" [Mol. Immunol. 48(4) (2011) 497-504]. AB - Measles virus (MV) V protein blocks type I IFN signaling in MV-infected cells. Previous studies suggested that some MV strains could release the V protein mediated type I IFN suppression in affected cells by two distinct modes: V protein mutation and production of DI RNA. These two modes of type I interferon regulation involves the IPS-1 (MAVS, Cardif, VISA) pathway (Takaki et al., 2011. Mol. Immunol. 48(4), 497-504). We add the comment to this previous issue that the release of the V protein-mediated suppression of type I IFN occurs only by a laboratory-adapted strain of Edmonston. PMID- 21789795 TI - [Contribution of D I Ivanovsky Research Institute of Virology to monitoring influenza viruses during epidemics and 2009 pandemic in Russia]. AB - The data on monitoring influenza viruses in Russia are presented based on the research underway at Ivanovsky Research Institute of Virology since 1959. The Institute's priority in isolation and identification of influenza viruses during epidemics and 2009 pandemic is confirmed. Results of assessment of influenza vaccines and etiotropic preparations, development and introduction of new methods for diagnostics of influenza are discussed. PMID- 21789796 TI - [Children's health protection in the state political system]. AB - The system of children's health protection in this country still lacks an adequate legal basis. Its improvement should be considered as a function of the state realized through legal regulation of public relations for the benefit of each child based on the legislatively fixed government policy in the sphere of children's health care. Such an approach may strengthen the role of this sphere in the intersectoral relations and implies the extension of pediatrics toward interaction with the spheres of politics and law. It reflects the understanding that physiological processes behind regulation of the functioning of the child's organism in the course of its development need an adequate support from the outside through regulation of public relations on behalf of children. The definition of state policy in the sphere of children's health care is proposed and its basic principles are considered. PMID- 21789798 TI - [Molecular markers for the diagnosis of non-muscle-invasive bladder cancer]. AB - The diagnostic efficiency of oncomarkers, such as cytokeratins 8, 18 (TPA, TPS, UBC) and vascular endothelial growth factor, was evaluated to diagnose non-muscle invasive bladder cancer. The serum and urinary levels of the markers were studied using enzyme immunoassay; their diagnostic properties were assessed by the ROC analysis. Comparison of the groups of apparently healthy individuals, patients with chronic cystitis, and those with noninvasive bladder cancer showed that the oncomarkers might potentially serve as screening parameters of the early diagnosis of bladder cancer and, in a number of cases, permit the differential diagnosis with chronic cystitis. PMID- 21789797 TI - [Advances and challenges in immunoprophylaxis]. AB - A significant progress in the management of controllable infections achieved by the early XXI century made it possible eliminate poliomyelitis across the nation, and practically eliminate measeles by vaccinating 96-99% of the children without raising the complication rate. The list of counterindications was shortened significantly, the Calendar of immunoprophylaxis was supplemented by inoculations against hepatitis B, rubella, flu, and type b Haemophilis influenzae infections. Morbidity of controllable infections in Russia decreased substantially compared with that in the 1990s. Nevertheless, the public health services are faced with the necessity of speedy application of new vaccines (including combined ones) allowing the inoculation impact on the child to be reduced. A rationale for the use of vaccines against pneumococcal and meningococcal infections, hepatitis A, varicella and for scaling up anti-pertussis vaccination coverage is proposed. Equally important is more extensive vaccination against papillomavirus infection as a means of cervical cancer prevention and introduction of the rotavirus vaccine to control most viral diarrheas. PMID- 21789799 TI - [Malonaldehyde and tumor necrosis factor-alpha as indicators of intoxication syndrome in erysipelatous inflammation]. AB - The aim of the investigation was to study the implication of infectious endotoxicosis in the pathogenesis of erysipelas, by measuring the level of malondialdehyde and the proinflammatory cytokine tumor necrosis factor-a (TNF-a) depending on the stage, severity, pattern of the disease, and possible complications. Fifty-six patients with erysipelas were followed up. Their blood level of malondialdehyde and TNF-a was determined at the height of the disease and during the reduction of clinical symptoms, and early convalescence. There was an increase in the study indicators, which depended on the period and severity of the disease and the presence of comorbidity and complications. The changes found in the study indicators characterize the development of intoxication syndrome in erysipelas and make possible their use to evaluate the severity of the diseases, the presence of complications, and the completeness of recovery. PMID- 21789800 TI - [Analysis of single nucleotide polymorphism rs415430 in the WNT3 gene in the Russian population with the Parkinson disease]. AB - The Parkinson disease (PD) is the second most common progressive neurodegenerative disorder that arises due to degeneration of dopaminergic neurons. The causes of this disease are still unknown, but a number of genes involved in pathogenesis of familial and sporadic forms of PD has been identified. According to recent data of genome wide association studies (GWAS), single nucleotide polymorphisms (SNPs) in these genes (including MAPT locus) may play an important role in the development of PD. Therefore, we analyzed distribution of genotype frequencies of SNP rs415430 in the WNT3 gene in the Russian patients with sporadic PD and in the Russian population controls (OR = 0.84, Confidence Interval (95% CI) 0.58-1.23, p = 0.39). It was concluded that SNP rs415430 in the WNT3 gene was not associated with the risk of development of PD. PMID- 21789801 TI - [Preparation and characterization of the recombinant protein containing immunomimetic peptide of benzo[a]pyrene]. AB - Two recombinant plasmids were constructed. The first plasmid contained the hybrid gene composed of immunomimetic peptide of benzo[a]pyrene, of the protein pIII of bacteriophage M13 and of cellulose binding domain encoding sequences. The second plasmid contained the hybrid gene composed of the signal peptide of the protein pIII of bacteriophage M13, of immunomimetic peptide of benzo[a]pyrene, of the protein pill of bacteriophage M13 and of cellulose binding domain sequences. The obtained recombinant plasmids were used in expression of chimeric protein containing immunomimetic peptide ofbenzo[a]pyrene based on strain E. coli M15. The lack of the recombinant protein expression using first plasmid was demonstrated. In the same time, it was shown that accumulation of recombinant protein contained immunomimetic peptide with signal peptide of the protein pIIIl of bacteriophage was present. This chimeric protein was produced in "mature" (without signal peptide) and "unprocessing" (with signal peptide) forms. Using the Western-blot analysis, it was shown that the "mature" form only specifically bound to the B2 monoclonal antibody against benzo[a]pyrene. Thus, we expressed, purified, and characterized the recombinant protein containing immunomimetic peptide of benzo[a]pyrene. PMID- 21789802 TI - [Specifying national program on elimination of asbestos-related diseases]. PMID- 21789803 TI - [Clinical and epidemiologic aspects of tuberculosis in asbestosis patients in connection with dust load]. AB - The article covers results of "case-control" study concerning clinical and epidemiologic aspects of tuberculosis in asbestosis patients, in connection with dust load. Findings are that the patients having asbestosis complicated with tuberculosis demonstrated total dust load (both in general dust weight and overall accumulated dose of respirable fibers of chrysotile asbestos) decreased with statistical significance, and therefore prevalence of tuberculosis among asbestosis patients decreased 5 times, in spite of growing prevalence of tuberculosis in Russia. Now the disease shows no progressive forms, light and medium course, lower prevalence of bacterioexcretion, longer survival of the patients. Trend of morbidity among the patients having asbestosis complicated with tuberculosis supports epidemiologic situation of tuberculosis in the country. Some workplaces remain with increased concentrations of chrysotile containing dust, thus in future the patients having asbestosis complicated with tuberculosis could get occupational malignancies. PMID- 21789804 TI - [Improving system of prevention and rehabilitation for asbestos-related broncho pulmonary diseases in workers]. AB - To improve a system of prevention and rehabilitation for broncho-pulmonary diseases among workers engaged into extraction and utilization of chrysotile asbestos, the authors specified major criteria for diagnosis of asbestos-related pulmonary diseases and signs of exposure to asbestos-containing dust, with definition of risk groups for broncho-pulmonary diseases. The authors formulated main concepts of prevention and rehabilitation for asbestos-related pulmonary diseases in workers engaged into asbestos industry. Special attention was paid to harmonization of all medical and technical measures aimed to prevention and liquidation of asbestos-related diseases. PMID- 21789805 TI - [Ecologic and hygienic evaluation of chrysotile asbestos fibers elimination in cargo handling and transportation on railways]. AB - Studies proved that plastic bags with chrysotile asbestos put in rows and piled packs covered by shrinkable film, when stored and cargo handling, are not sources of chrysotile asbestos fibers release into the air of workplace. Transporting mass consignment of chrysotile asbestos on railways in covered waggons, irrespective of package, does not result in higher asbestos load for railway workers, passengers and residents of area near railways. PMID- 21789807 TI - Active euthanasia--potential abuse in South Africa. PMID- 21789806 TI - Termination of pregnancy and children. PMID- 21789808 TI - Heart-failure patients may benefit from bypass surgery. Landmark clinical trial answers longstanding question about appropriate treatment for these patients. PMID- 21789809 TI - Two studies show benefits of lifestyle changes on diabetes. Structured exercise and better sleep patterns may help patients control blood sugar levels. PMID- 21789810 TI - Prostate cancer progression and obesity are linked. Men who are overweight or obese who have prostate cancer have an elevated risk of cancer progression compared to normal-weight men. PMID- 21789811 TI - The biology of food addiction. Neural activity in certain regions of the brain indicates that food addiction can be as strong as drug or alcohol dependence. PMID- 21789812 TI - Yes, there is a "happiness" gene...but it's not that simple...The 5-HTT gene that transports serotonin in the brain can lead to feelings of satisfaction in life. PMID- 21789813 TI - What is the real story on taking calcium supplements? On the one hand, we're urged to get 1,200 mg of calcium daily for bone health, and on the other, we're told that calcium supplements appear to raise risk of heart attack and other cardiovascular events. Which is correct? PMID- 21789814 TI - Point man. Interview by Jeff Berry. PMID- 21789815 TI - [Case of pulmonary aspergillosis complicated with intractable nasal-type extranodal NK/T cell lymphoma]. PMID- 21789816 TI - [Picture of the month: endocarditis]. PMID- 21789817 TI - Advances in cancer care-cost and value. Abstracts of the Medical Oncology Group of Australia Incorporated Annual Scientific Meeting. August 10-12, 2011. Adelaide, SA, Australia. PMID- 21789818 TI - Takayuki Kuroda and Vincent G. Kokich elected to receive WFO honorary membership. PMID- 21789819 TI - Contours of coffee trade in India in the eighteenth century. PMID- 21789820 TI - Sport and anti-Communism: Danish gymnastics' encounter with Stalinism in its formative years. PMID- 21789821 TI - The tubs of pleasure: Tudor and Stuart spas. PMID- 21789822 TI - New voluntary self-assessment system for European orthodontists takes off. PMID- 21789823 TI - WFO participates in the Graduate Orthodontic Residents Program to encourage membership among orthodontic residents. PMID- 21789824 TI - WFO offers Guidelines for Postgraduate Orthodontic Education. PMID- 21789825 TI - Supermanism and culture of the body in Italy: the case of futurism. PMID- 21789826 TI - Climate and causation in African history. PMID- 21789827 TI - Where physical and ideological landscapes meet: landscape use and ecological knowledge in Iraqw, northern Tanzania, 1920s-1950s. PMID- 21789828 TI - The problem with normal orthodontic shear bond strength values. PMID- 21789829 TI - Prof Athanasiou on WFO past accomplishments and expectations for the future. PMID- 21789830 TI - WFO Executive Committee elects Dr Allan Thom as vice-president in March. PMID- 21789831 TI - WFO Council convenes, elects new Executive Committee. PMID- 21789832 TI - Symposium on Orthodontic Certifying Boards ignites interest in board certification. PMID- 21789833 TI - World Village Day provides global exposure to participating WFO affiliate organizations. PMID- 21789834 TI - AAO offers support to WFO Executive Committee, strengthens connections with WFO affiliates. PMID- 21789835 TI - Fooling the central governor: the tragic story of Tom Simpson. PMID- 21789837 TI - Mapping character types onto space: the urban-rural distinction in early statistical writings. AB - This article investigates the construction of urban/rural binary distinctions in 18th- and 19th-century social scientific literature, and in particular in the writings of the statistical societies in England. The 18th-century writers were primarily concerned with the spread of luxury, vice, and effeminacy among the upper social strata in large cities. Later on, statisticians began to focus on moral hazards among the urban working poor. These writings are significant in several respects: they contributed to the spatial mapping of moral character, played a role in the development of quantitative social scientific techniques, and foreshadowed later sociological debates over the nature and consequences of social evolution from simpler to more complex societies. PMID- 21789839 TI - [Strengthen the etiology study of viral acute respiratory tract infection in children]. PMID- 21789838 TI - Urine trouble: a social history of bedwetting and its regulation. AB - Bedwetting has confounded the presumed boundaries of the human body, existing in a fluid space, between the normal and pathological, its treatment has demanded the application of a wide array of different technologies, each based on a distinct conception of the relationship between the body and personality, human organs and personal conduct. In tracing the social history of bedwetting and its regulation, this article examines the ontological assumptions underpinning the treatment of bedwetting and how they have changed over the past two centuries. Through the analysis of medical journals, newspaper articles and magazine advertisements, different topologies are identified which redefine the boundaries of the human body and its capacities. From 16th-century naturalism, in which the human body is subordinated to a cosmic totality, to the circumscribed space of 19th-century paediatrics and the expansive circuits of behavioural psychology and modern psychoanalysis, the body has become multiplied, differently enacted through the application of diverse technologies. It was be shown how coordinating the messy and divergent conceptions of the human body has posed an endemic problem for the human sciences, and how the enduring tension between object enactment and subject constitution is an expression of modern "baroque" subjectivity. PMID- 21789840 TI - [Detection and clinical study on coronavirus HKU1 with acute lower respiratory tract infections of hospitalized children in Changsha]. AB - OBJECTIVE: In order to understand the epidemiological and virologic characteristics of coronavirus HKU1 infection in hospitalized children with acute respiratory tract infection (ARTI) in Changsha. METHODS: 1165 nasopharyngeal aspirates (NPA) specimens were collected from hospitalized children with ARTI between September 2007 and August 2008 in Changsha. Specimens were screened for pol gene of coronavirus HKU1 by polymerase chain reaction. All positive amplification products were confirmed by sequencing and compared with those in GenBank. RESULTS: Coronavirus HKU1 were detected in 12 patients (1.03%) out of the 1165 children. The patients were from 8 days to 3 years. The most common clinical diagnosis was bronchopneumonia(83.33%). Similarity of coronavirus HKU1 with those published in the GenBank at nucleotide levels was 98.18% - 100%. CONCLUSION: Coronavirus HKU1 may be important pathogens in children with acute lower respiratory tract infection. Coronavirus HKU1 infections are common in children under 3 years old. There is no significant difference in the infectious rate between the boys and the girls. The peak of its prevalence is in spring and winter. A single genetic lineage of Coronavirus HKU1 was revealed in human subjects in Changsha. PMID- 21789841 TI - [Detection and clinical characteristics analysis of human bocavirus 1-3 in children for acute respiratory infection in Lanzhou area]. AB - OBJECTIVE: To study the clinical and molecular epidemiology characteristics of human Bocavirus 1-3 (HBoV1-3) in children for acute respiratory infection in Lanzhou area. METHODS: Nasopharyngeal aspiration samples and throat swabs were collected from 524 children with ARTI at the First Hospital of Lanzhou University, Gansu Province, China, between December 2009 and November 2010. Nested PCR was employed to screening HBoV1-3, which amplified a 518-bp fragment of the partial NS1 gene. Furthermore, a standard reverse transcription-PCR was used to screen for other common respiratory viruses. RESULTS: The overall frequency of HBoV was 8.2% (43/524), lining up behind human rhinovirus, RSV, parainfluenza virus 3. Thirty of the HBoV-postive children(69.8%) were co infected with other respiratory viruses. The prevalence of HBoV1 in ALRTI was obviously higher than that in AURI. The 2 HBoV2 NS1 sequences shared 99% and 100% nucleotide sequence identity with HBoV2 strain CU47TH respectively. Two cases of HBoV2 postive children appears gastrointestinal symptoms. The one HBoV3 NS1 sequences shared 99% nucleotide sequence identity with HBoV3 isolate 46-BJ07. CONCLUSION: The HBoV3 was detected at the first time in lanzhou area. HBoV1-3 infection exists in children with acute respiratory tract infections in Lanzhou region, HBoV1 were dominant. The mixed infection rate was higher. PMID- 21789842 TI - [The research of saffold virus in children with lower respiratory tract infection in Changsha]. AB - OBJECTIVE: To investigate prevalence of Saffold virus (SAFV) in Changsha area of hospitalized children with respiratory tract infection, and to discuss whether this virus is related to respiratory tract infection of children. METHODS: 643 nasopharyngeal aspirates samples were collected from hospitalized children with respiratory tract infection of the first affiliated hospital of Hunan nomal university during Nov. 2007 to Oct. 2008. Real-time fluorescent quanti-tative PCR(FQ-PCR) performed to screen the 5'UTR gene. And then analyze clinical data. RESULTS: SAFV were detected in 67 patients (10.42%) out of the 643 children, it was not detected over 5 years of age. The virus were detected in 8 patients (25.81%) out of the 31 children with persistent pneumonia and chronic pneumonia, there was statistically significant. CONCLUSION: There existed SAFV infection in hospitalized children with lower respiratory infection in Changsha area; SAFV maybe related to disease onset with lower respiratory tract infection of children. PMID- 21789843 TI - [Molecular epideiological and clinical feature of human metapneumovirus in children with acute respiratory tract infection in Nanjing City]. AB - OBJECTIVE: To investigate the molecular epideiological and clinical feature of human metapneumovirus in children with acute respiratory tract infection in Nanjing city, China. METHOD: Nasopharyngeal aspirates and nasopharyngeal swab were taken from 642 outpatients or hospitalized pediatric patients with acute at the Children Hospital of Nanjing, Jiangsu Province, China, between August 2009 and July 2010. Respiratory speciments were tested for the M gene of hMPV by reverse-transcription polymerase chain reaction (RT-PCR). All RT-PCR positive products were sequenced and phlogenetic analysis was conducted. RESULT: hMPV was detected in 35 (5.5%) of the 642 children. Phylogenetic analysis revealed that 51.4% of the hMPV were B1, 31.4% were A2b. The peak of the positive rate was in April. The majority of the hMPV-positive patients(71.4%) were 0-1 years old. Of the 35 hMPV-positive patients, 15 (42.8%) were co-infected with other respiratory viruses, and human rhinovirus (HRV) were the most common additional respiratory virus. The most common clinical diagnosis was pneumonia (48.6%). CONCLUSION: Human metapneumovirus is an important pathogen of acute respiratory tract infection in children in Nanjing city. The subtype B1 was the predominating lineage in 2009-2010 in Nanjing city. No significant differences were found for clinical characteristics between genotype A and genotype B human metapneumovirus infection in children in Nanjing. PMID- 21789844 TI - [The verification of a new DNA double-detection diagnostic kit for identifying novel influenza A (H1N1)]. AB - OBJECTIVE: To verify a new kit of "universal and novel influenza A (H1N1) virus nucleic acid double-detection methods (PCR-fluorescence probe)". METHODS: 150 cases of throat swab specimens were collected consecutively. After RNA was extracted, the specimens were detected by the verified kit. At the same time, the same specimens were detected by Real-time PCR diagnostic kit from Beijing CDC as the control. The data were analysed by the Kappa in agreement and by McNemar chi2 in difference test. RESULTS: The consistency rate of the verified kit and the Beijing CDC kit was universal primer M 97.33%, H1N1 98.67% respectively. The Kappa test and McNemar chi2 test showed that two methods had a higher consistency. Compared to the CDC kit, the "false negative rate" and "false positive rate"of double-check kit were lower. CONCLUSION: The kit of "universal and novel influenza A (H1N1) virus nucleic acid double-detection methods (PCR fluorescence probe)" from Shanghai Kehua Bio-Engineering Co., Ltd can be used to detect influenza A and novel influenza A (H1N1). PMID- 21789845 TI - [Serological survey of pandemic influenza A (H1N1) virus infection among population in Hunan Province]. AB - OBJECTIVE: To understand the infection condition and analytical methods of Influenza A (H1N1) virus in the population of Hunan Province during different periods. METHODS: Quick surveys on the positive rate of Influenza A (H1N1) virus hemagglutination inhibition (HI) test have been conducted for 5 times successively from November 2009 to March 2010 in 14 medical and health institutions of Changsha city, whose results were then compared with those from the sampling surveys of whole Hunan province. RESULTS: 2131 subjects were involved in this study; the total population standardized rates of antibody positive investigated for 5 times were 9.32% , 14.62%, 31.08%, 28.43% and 22.80% respectively; the population of 6-17-years-old has the highest rate of antibody positive; only 9.84% of the antibody positive subjects attributed to vaccine inoculation; there was no significant difference in the standardized positive rates between the quick serological surveys and the corresponding sampling survey of Hunan province (P > 0.05). CONCLUSION: The positive rate of A (H1N1) virus antibody reached the peak in late January 2010; quick investigations in small region could be used to evaluate the infection prevalence during pandemic of infectious diseases. PMID- 21789846 TI - [Analysis on the etiological surveillance of influenza/novel influenza A (H1N1) from 2009-2010 in Shanxi Province]. AB - OBJECTIVE: To study the epidemical characteristics of influenza/novel influenza A (H1N1) in Shanxi province from 2009 to 2010, and to provide scientific foundations for predicting and controlling the pandemic outbreak of influenza/novel influenza A (H1N1) effectively. METHODS: All samples were collected from cases that resemble influenza cases in sentinel hospital and influenza outbreak. The influenza were detected by PCR and isolated by MDCK cell culture method. Finally, Shanxi province surveillance data from May, 2009 to April, 2010 of influenza like illness (ILI) cases and pathogen detections were analyzed. RESULTS: In Shanxi province, influenza viruses kept activation in whole year. The predominant pandemic strain in 2009 was novel influenza A (H1N1) virus. The strong peak was around November, 2009 [positive rate: 58.1%, novel influenza A ( H1N1) of the total: 88.1%]. As well, the people infected influenza caused by novel influenza A (H1N1) were mainly under 59-year-old, and the higher positive rates were concentrated in the people from 5-year-old to 24-year-old. In 2010, influenza B (Victoria) viruses were mainly detected from clinical specimens and became the dominant strain. CONCLUSION: Surveillance of Influenza liue illnes, (ILI) and etiology, which can promptly reflect the influenza epidemic situation, play a significant role for understanding epidemic rule of influenza/novel influenza A (H1N1). PMID- 21789847 TI - [Variants and quasispecies of reverse transcriptase region in polymerase gene of hepatitis B virus during lamivudine treatment]. AB - OBJECTIVE: To investigate the variants and quasispecies of reverse transcriptase region in polymerase gene of hepatitis B virus (HBV) during lamivudine treatment and their relationship with genotypes and viral loads. METHODS: HBV DNA of 117 chronic hepatitis B patients treated with lamivudine were amplified by using PCR. The PCR products including the YMDD motif were sequenced by DNA sequencer, of which, HBV DNA viral loads of 99 patients were determined by real-time PCR and 64 samples were sequenced by Pyrosequencing. RESULTS: In HBV YMDD variant group and no variant group, the HBV genotypes were 79.6% and 86.7% of type C, 18.5% and 12.7% of type B, 1.9% of A/B recombinant type and 2.6% of type D, respectively. The viral loads (log 10) were 6.5699 and 6.6165, respectively. There was no significant difference in HBV genotypes and viral loads between these two groups. The rtL180M variant was found in association with the rtM204I/V variant, HBV variants and wild-type in YMDD motif all existed together in these two groups. CONCLUSIONS: HBV variants (quasispecies) in YMDD motif could be quantified by pyrosequencing, which would be a feasible measure during nucleoside or nucleotide analogue therapy against chronic HBV infection. PMID- 21789848 TI - [The relationship of serum HBsAg, HBeAg concentration and HBV-DNA load in chronic hepatitis B during IFN treatment]. AB - OBJECTIVE: To investigate the relation of serum HBsAg, HBeAg contents and HBV-DNA load changes in HBeAg-positive chronic hepatitis B during IFN-alpha treatment. METHODS: After enrolled, the patients were treated with 3MU-5MU IFN subcutaneous injection every two days, and their serum was collected before treatment and every 3 months during the treatment course. The serum HBV-DNA load was determined by real-time fluorescence quantitative PCR method kit (lower detection limit 500 copies/ml, Piji company, Shenzhen city, China,) according to production instruction, and HBeAg and HBsAg contents were detected by ARCHITECH I 2000.chemiluminescent kit. The relation of serum HBV-DNA, HBeAg and HBsAg content was analyzed by SPSS statistic software. RESULTS: There were 228 patients enrolled into this group, male 162 cases, female 66 cases, aged 14-60 years, average 30.94 years old. After IFN treatment the HBV-DNA, HBeAg and HBsAg levels were all gradually decreased. But there was no relation of HBsAg content to HBV DNA and HBeAg content before and during treatment course(P > 0.05). However the serum HBeAg content was related to HBV-DNA content significantly (P < 0.05) and their changes was correspondence. CONCLUSION: Before and during treatment of interferon, HBeAg and HBV-DNA content changes are closely related, while there is no significant correlation between HBsAg and HBeAg and HBV-DNA content. During interferon therapy, HBsAg, HBeAg, HBV-DNA contents should be detected together. PMID- 21789849 TI - [The cytotoxic effect of CD8+ T subsets plays an important role in the chronic hepatitis B]. AB - OBJECTIVE: The aim of this study is to explore the cytotoxic effect of CD8+ T subsets in peripheral blood with chronic hepatitis B subjects who are at immune tolerance phase and immune clearance phase (before and after three months' treatment with interferon-alpha), further to investigate their impact in the pathogenesis of chronic hepatitis B and antiviral therapy. METHODS: The subjects of chronic hepatitis B, including 20 subjects of immune tolerance phase and 20 subjects of immune clearance phase, are enrolled in the study. And we use flow cytometry to detect Lysosome-associated membrane protein-1 (LAMP-1, CD107a) and Granzyme B (GrB) expression of CD8(high) and CD8(low) T cells in peripheral blood with chronic hepatitis B subjects. RESULTS: (1) At immune clearance phase, the CD8+ T subsets expressing GrB and CD107a are higher than counterpart of immune tolerance phase. (2) At immune tolerance phase and immune clearance phase in HBV infection, the CD8(low) T cells expressing GrB and CD107a are higher than that of CD8(high) T cells. (3) After three months' treatment with interferon-a, except for GrB+ CD107a+ CD8(high) T cells, CD8(high) T cells expressing GrB and CD107a present a tendency of ascensus at the same time with that of CD8(low) T cells a tendency of descensus except for GrB(-)CD107a+ CD8(low) T cells. (4) The CD8+ T cell expressing GrB and CD107a, correlate positively with HBV DNA load at immune tolerance phase, but correlated negatively at immune clearance phase. CONCLUSIONS: (1) GrB and CD107a molecule expressed by different CD8+ T cell subsets play an important role in disease evolution and antivirus therapy of chronic hepatitis B, the cytotoxic effect of CD8(high) T cell subset became more and more stronger during the treatment of IFN-alpha, and the cytotoxic effect of CD8(low) T cell subset couldn't be neglected before antivirus therapy. (2) To some degree, the correlation between HBV-DNA load and the expression of GrB and CD107a at different CD8+ T cell subsets, could hint the relationship between virus and immune response. PMID- 21789850 TI - [The study on frequency distribution of regulatory T cells and its functional markers in peripheral blood of chronic hepatitis B]. AB - OBJECTIVE: To explore the role of treg cells and its functional markers in pathogenesis of chronic hepatitis B, and the correlation with disease progression. METHODS: 20 cases of healthy control people,53 cases of chronic hepatitis B patients and 24 cases of liver cirrhosis patients were enrolled into the groups. Detecting the frequencies of CD4+ CD25+ Fox3+ cells, CD4+ CD25+ CD127(low) cells, CD39+ treg cells and CTLA-4+ treg cells in treg cells by flow cytometry. Clinical parameters were investigated in the same time. RESULTS: The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significant different among healthy control group, CHB group and LC group (P < 0.01). The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significantly different in moderate-severe CHB group compared with mild CHB group (P < 0.05, P < 0.05, P < 0.01). In CHB group the frequencies of CD4+ CD25+ Foxp3+ cells were positively correlated with ALT (r = 0. 289, P < 0.05) and AST (r = 0.302, P < 0.05), the frequencies of CD4+ CD25+ Foxp3+ cells had a significant positive correlation with the frequencies of CD4+ CD25+ CD127(low) cells (r = 0.478, P < 0.01). CONCLUSION: The frequencies of treg cells and its functional markers probably had a dynamic tendency in the process of chronic hepatitis B and were closely related with the change of liver function parameters. CD39+ treg cells may be a group of functional treg cells, which indicated that CD39 be a sensitive marker to react treg cells function. In some sense, CD4+ CD25+ CD127(low) cells frequency could represent treg cell frequency. PMID- 21789851 TI - [Molecular and epidemiological study on viral diarrhea among infants in Lanzhou]. AB - OBJECTIVE: To study the epidemiologic characteristics of viral diarrhea in children under 5 years old in Lanzhou, understand the four major virus in children of distribution. METHODS: In the first hospital of Lanzhou university from Jul 2009 to Jun 2010,we collected 290 stool specimens from children with diarrhea and 114 asymptomatic controls. Rotavirus was detected by ELISA,further strain characterization was carried out by nested PCR. The human calicivirus, astrovirus, adenovirus were detected by RT-multiplex PCR and PCR. RESULTS: At least one of the four viral agents was found in 60% of the specimens. Rotavirus, human calicivirus, adenovirus, and astrovirus were identified in 39.31%, 11.38%, 10.69%, and 4.83% in 290 specimens respectively. Rotavirus G3 was the most prevailing serotype, P [8] was the most common genotype. In the 114 control samples, 7 sample was positived for calicivirus, 5 samples were positived for human adenovirus and 1 sample was positived for astrovirus. CONCLUSION: The results indicated clearly the impact of viral agents causing diarrhea and the importance of long-term systematic surveillance. PMID- 21789852 TI - [Study of human papillomavirus in biopsy tissue specimens of esophageal carcinomas in Linzhou city]. AB - OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV), particularly of high-risk HPV in biopsy tissue specimens of esophageal carcinomas in Linzhou city. METHODS: General nested primer sets were used to detected the whole HPV genotypes, following by HPV16 and 18 type specific PCR for the HPV16 and 18 detection respectively. RESULTS: All 18 biopsy samples were HPV positive, and HPV 16 was detected in 13 of the 18 samples, HPV 18 was detected in 4 of the 18 samples. CONCLUSION: The high rate of HPV in the esophageal carcinoma samples suggested that HPV infection may be an important etiologic factor in the development of esophageal cancer in Linzhou city. PMID- 21789853 TI - [Ananlysis on the molecular characteristics of CVA9 virus in Tibet]. AB - OBJECTIVE: To study the molecular characterization of CVA9 virus in Tibet. METHODS: To isolate the enteroviruses from stool specimens of AFP cases and other children in Tibet in 1999-2002, and identify them by neutralization test using the RIVM antiserum; then determine the complete nucleotide sequence of VP1 region of CVA9 viruses, and analyze the results. RESULTS: A total of 10 strains of CVA9 virus were isolated from the stool specimens and identified. The complete nucleotide sequence of VP1 region of these CVA9 viruses were 906nt coding 302 amino acids. To compare with the sequences of the 10 strains of Tibet, the homogeneity of nucleotide sequence were 79.0% - 99.9%; while they were 75.7% - 78.7% compared with Griggs. The phylogenetic tree of CVA9 viruses showed 2 groups, and the isolates from Tibet belong to 1, 2 groups. CONCLUSION: The deduction is that the 10 strains are proposed 2 different groups, the strains epidemic in 1999 belong to group 2,while strains in 2000 belong to group 1. PMID- 21789854 TI - [Detection and molecular characterization of human parechovirus (HPeV) in children with acute gastroenteritis]. AB - OBJECTIVE: To study HPeV from stool samples of children with acute gastroenteritis under 5 years old. METHODS: We conducted a real-time PCR to detect HPeV from stool samples and to amply VP1 sequence by nested RT-PCR to identify HPeV type. RESULTS: The results showed that 27 of 306 (8.82%) children with acute gastroenteritis were infected HPeV. 11 strains were typed. 9 strains HPeV1, both HPeV2 and HPeV4 was 1 strain. HPeV was mostly identified in autumn season with a peak in July. HPeV seemed relevant in children >2 years old. The range of nucleotide identity between all isolated strains with reference strains was 79%-92%. CONCLUSION: Epidemiology characteristic of HPeV in Jilin was concordance with that of reports. HPeV3 wasnt detected. It's significant to conduct the large scale and long-term surveillance of HPeV. PMID- 21789855 TI - [Enterovirus 71 induces apoptosis in a Bax dependent manner]. AB - OBJECTIVE: To explore the molecular mechanism of apoptosis induced by enterovirus 71 (EV71) infection. METHODS: The effects of EV71 on Rhabdomyosarcoma (RD) cell viability were detected by CCK8 assay. EV71-induced apoptosis on RD cells were detected by Hoechst 33342 staining and Western blot targeting Caspase 3, 8 and PARP. Bax conformational change was detected by immunoprecipitation with Bax 6A7 antibody. RESULTS: EV71 decreased the viability of RD cells and induces the activation of Caspase 3, 8 and PARP. Bax expression increases in RD cells after EV71 infection, and Bax conformational change also can be detected after EV71 infection. CONCLUSION: Our study reveals that EV71 induces Caspase-dependent apoptosis by Bax conformational change. PMID- 21789856 TI - [The genetical evolution of the full length genes of 5 EV 71 strains from 5 Shenzhen patients with hand-food-mouth disease associated with EV71 infection]. AB - OBJECTIVE: To investigate the characteristics of molecular epidemiology and molecular evolution of 5 EV 71 (enterovirus 71, EV71) strains from 5 Shenzhen patients with hand-food-mouth disease associated with EV 71 infection. METHODS: 5 EV 71 strains were isolated, and sequenced to analyzed the full length gene sequences in order to compare nucleotide and amino acid homology with other EV71 strains from other regions and countries as well as previous strains across the world through bioinformatics software. RESULTS: 5 strains of EV 71 belonged to sub-genotype C4 by analysis of nucleotide sequences of VP1 and VP4 of EV 71. The differences of nucleotide and amino acid sequences were much small with nucleotide homology of 93% and amino acid homology of 98% among these 5 strains. A phylogenetic tree analysis indicated that 2008 Shenzhen epidemic strains were the most close to 2004 Shenzhen circulating strains, and also much close to 1998 Shenzhen epidemic strains and 2008 Fuyang Anhui strains. The dead strain was very close to 2008 Fuyang Anhui epidemic strains. CONCLUSION: It can be speculated that this epidemic strains of EV 71 probably originate from the same ancient strain in the history, may from 1998 Shenzhen strain. PMID- 21789857 TI - [The effects of human cytomegalovirus infection on college students' neurobehaviors]. AB - OBJECTIVE: To explore relevant between human cytomegalovirus (HCMV) infection and college students' neurobehaviors. METHODS: 87 college students were enlisted. They were tested with Bole. Neurobehavioral evaluation system (B. NES), and HCMV IgG antibody was detected after separation of serum. We analyzed the test results of B. NES by SPSS software. RESULTS: 76 college students were infected by HCMV in the past and 11 college students were not infected. The infected group scored 8.89 +/- 6.60 in depression aspect of emotion state test, while control group got 15.73 +/- 9.00. There was Significant difference between infection group and control (P < 0.05). There were no significant differences in other aspects of emotion states, study and memory, perception and mental movement (P > 0.05). CONCLUSION: HCMV infection is associated with depression status. PMID- 21789858 TI - [Identification A novel protein TRIM38 that activate NF-kappaB signaling pathways]. AB - OBJECTIVE: The tripartite motif (TRIM) proteins are a family of more than 70 human members, however only a few of them have been well studied. It has been shown that TRIM proteins are involved in various cellular processes such as cell proliferation, differentiation, apoptosis and antiviral defense. The functions of TRIM38 are largely unknown. In this study we explore the effect of TRIM38 on NF kappaB signaling pathway. METHODS: 293T cells were transfected with NF-kappaB-Luc and plasmids expressing TRIM38 and its mutants fused to Flag. 24 h after transfection, cells were harvested and luciferase activities were measured. Data are representative of three independent experiments with triplicate samples. The expression of proteins was analyzed by Western Blot. RESULTS: TRIM38 could activate NF-kappaB signaling pathway. The mutants of TRIM38 affected the function of TRIM38. Only the mutant of SPRY domain deletion had no obviously influence of the function of TRIM38. CONCLUSION: Our study reveals that NF-kappaB is activated in response to TRIM38. PMID- 21789859 TI - [Study of human papillomavirus in small cell neuroendocrine carcinoma of the uterine cervix]. AB - OBJECTIVE: To observe the infection of the high risk human papillomavirus (HPV) in the specimen of the small cell neuroendocrine carcinoma of the uterine cervix (SCNEC). METHODS: We extracted the nucleic acids in the formalin-fixed and paraffin-embedded specimen from a 33-year-old patient diagnosed as small cell neuroendocrine carcinoma of uterine cervix and detected the HPV genotype with the nested PCR. RESULTS: We identified HPV18, a high-risk genotype, in the specimen. CONCLUSION: The HPV detection with the nested PCR was available for identification of the HPV genotype(s) in the paraffin-embedded specimens of small cell neuroendocrine carcinoma of the uterine cervix with a high accuracy and sensitivity. PMID- 21789860 TI - [Compare real-time RT-PCR with two culture methods for influenza virus detection]. AB - OBJECTIVE: Real-time RT-PCR, cell culture and embryonated eggs culture for influenza detection were compared by analyzing the data of influenza surveillance in Shenzhen in second half of 2009. METHODS: 1092 clinical samples (throat swabs) collected during second half of 2009 were tested by real-time RT-PCR, cell culture and embryonated eggs culture, and the results were analyzed by statistical methods. RESULTS: The positive rate were 54.21%, 27.11% and 16.21% using real-time RT-PCR, cell culture and embryonated eggs culture, and the sensitive were 100%, 50% and 29.9%. The lowest dilutions of virus detected by real-time RT-PCR were 10(-2) TCID50/ml. CONCLUSION: The sensitive of real-time RT PCR was higher than culture and the specificity was also very high. It was more suitable for emergency detect. The sensitive of cell culture for H3N2 subtype was higher, and sensitive of embryonated eggs culture for type B was higher. PMID- 21789861 TI - [Detection and typing of human papillomavirus by a GeXP based multiplex PCR assay]. AB - OBJECTIVE: To establish a new and rapid GeXP based multiplex PCR assay for the detection and typing of human papillomavirus 6, 11, 31, 33 and 52. METHODS: Nucleotide sequences of HPV6, HPV11, HPV31, HPV33 and HPV52 from NCBI were obtained and compared. Genotype-specific primers were then designed and the sensitivity and specificity of multiple PCR assay was evaluated. Optimized assay was further validated with 30 clinical specimens collected from the cervical secretions of patients. RESULTS: A GeXP based multiplex PCR was developed for sensitive detection and reliable differentiation of five HPV genotypes (HPV6, 11, 31, 33 and 52), CONCLUSION: A GeXP based multiplex PCR assay is demonstrated to be a new and rapid technique for simultaneous detection and typing of 5 different human papillomaviruses. PMID- 21789862 TI - [Comparison between recombinant virus assay and live virus assay on evaluating anti-HIV-1 drugs]. AB - OBJECTIVE: To compaire results of recombinant virus assay and live virus assay on evaluateing anti-HIV-1 drugs. METHODS: The pseudoviruse was generated by cotransfection of the plasmid B01 containing gp160 genes and pSG3 delta env plasmid. After co-incubation of pseudovirus with serially diluted drug, the EC50 and ED50 were calculated according to RLU(relative light unit) for each drug. After co-incubation of live virus with serially diluted drug, the EC50 was calculated according to cytopathic effect. RESULTS: EC50 of IDV measured by the recombinant virus assay and live virus assay was 88.9 nmol/L, 89.5 nmol/L, respectively, while EC50 of NVP measured by the recombinant virus assay and live virus assay was 0.36 micromol/L, 0.23 micromol/L, respectively. The recombinant virus assay showed good reproducibility with coefficient variation of 0, however coefficient variation of live virus assay reached to 60%. ED50 of IDV and NVP measured by the recombinant virus assay were 70.6 nmol/L and 0.62 micromol/L, respectively. Coefficient variations for IDV and NVP were 14.3% and 9.7%, respectively. CONCLUSION: The pseudoviruses could be used in evaluating anti-HIV 1 drugs. The recombinant virus assay showed good reproducibility and could calculate not only the EC50 but also the ED50 of drugs. PMID- 21789863 TI - High density lipoprotein--quality and function. PMID- 21789864 TI - The knowledge and attitude of primary school teachers in Sri Lanka towards childhood attention deficit hyperactivity disorder. AB - OBJECTIVE: To assess the knowledge and attitudes towards attention deficit hyperactivity disorder (ADHD) among primary school teachers in the Gampaha District. METHODS: A descriptive cross sectional study was conducted in randomly selected schools of Gampaha district using a stratified sampling method. The knowledge and attitudes on ADHD were assessed by a self-administered questionnaire distributed among all the consenting primary school teachers in the selected schools. RESULTS: Total of 202 completed questionnaires of 210 distributed were returned. The majority showed good understanding about ill effects ofADHD, teachers' role in management and counterproductive effects of punishment. Three-fourths had a positive attitude towards behavioural therapy. However, only a minority had adequate knowledge about the presentation of ADHD and its treatment with medication. More than 80% of teachers believed that the parents were to be blamed for the child's ADHD. The majority of participating teachers also believed that behavioural disturbances caused by ADHD children were deliberate and malicious. Teachers who had training in child psychology recorded a significantly higher knowledge and had a more favourable attitude. CONCLUSIONS: The knowledge of ADHD and its treatment among primary school teachers needs to be improved. Particular focus should be on improving attitudes and disseminating the message that timely interventions can make a difference in the educational and social development of the child. PMID- 21789865 TI - Nutritional assessment of a jackfruit (Artocarpus heterophyllus) meal. AB - OBJECTIVES: The mature jackfruit (Artocarpus heterophyllus) is consumed in Sri Lanka either as a main meal or a meal accompaniment. However, there is no scientific data on the nutrient compositions of cooked jackfruit meals. Thus, the objective of the study was to carry out a nutritional assessment of a composite jackfruit breakfast meal comprising seeds and flesh. DESIGN: A jackfruit meal comprising of flesh (80% available carbohydrate) and seeds (20% available carbohydrate) was included in the study. The study was carried out in a random cross over design. Setting University of Sri Jayewardenepura. Study participants Healthy individuals (n=10, age: 20-30 yrs). MEASUREMENTS: The macronutrient contents, rapidly and slowly available glucose (SAG) contents, water solubility index of the jackfruit meal were determined according to standard methods. The GI of the meal was calculated according to FAO/WHO guidelines. RESULTS: The moisture content of the boiled jackfruit flesh was high (82% FW). Jack seeds contained 4.7% protein (FW), 11.1% total dietary fibre (FW) and 8% resistant starch (FW). Jackfruit meal elicited a GI of 75. The Glycaemic Load (GL) of the normal serving size of the meal is medium. The slowly available glucose (SAG) percentage of jackfruit meal (30%) was twice that of the standard. The boiled jackfruit flesh contained disintegrated starch granules while seeds contained intact swollen and disintegrated granules. CONCLUSIONS: The jackfruit seeds are a good source of starch (22%) and dietary fibre. The meal is categorized as a low GI meal. The low GI could be dueto the collective contributions from dietary fibre, slowly available glucose and un-gelatinised (intact) starch granules in the seeds. PMID- 21789866 TI - Assessment of the psychological status of children with growth hormone deficiency and their parents. AB - INTRODUCTION: Children with growth hormone deficiency may have psychological ramifications due to their disease condition. Having a child with growth hormone deficiency may affect the parents' psychological health. OBJECTIVES: To assess the psychological health of children with GHD and their parents. METHODS: A descriptive cross sectional study was done over four years from July 2006 on children with growth hormone deficiency. The self-administered, culturally validated Personality Assessment Questionnaire (PAQ) was given to children above 8 years of age. By considering seven personality dimensions, the PAQ assesses whether a child is psychologically maladjusted. A score > or = 89 indicates such maladjustment. The parents were given the self-administered General Health Questionnaire-30 (GHQ-30). A score > or = 4 is indicative of mental health difficulties in the respondent. RESULTS: Fourty of 56 children with GHD were more than 8 years of age and there were 33 boys. According to the PAQ, 24 children (60%: 19 boys) appeared to be psychologically maladjusted. Of the 74 parents (47 mothers) who answered the GHQ-30, forty (54%) were deemed to have mental health difficulties, a majority of them were mothers. CONCLUSIONS: Psychological maladjustment was observed in a majority of children in the study and most of their mothers had mental health difficulties. PMID- 21789867 TI - Mental health research trends in Sri Lanka. AB - OBJECTIVE: To review the number of research publications in the field of mental health in Sri Lanka from 1900 to 2009. METHODS: A search of all publications in psychiatry and mental health from Sri Lanka was conducted using Pubmed, all medical journals published in Sri Lanka and researchers. The identified papers were reviewed for their content and categorised as research in psychiatry and mental health, based on strict inclusion and exclusion criteria. RESULTS: A total of 207 papers were identified. The first mental health research publication from Sri Lanka is in 1964. The last decade (2000-2009) accounted for 62% of the publications with the majority of the papers being published in indexed journals. The Ceylon Medical Journal carried the most number of papers and the topic on which most of the research was conducted was suicide and deliberate self harm. CONCLUSIONS: There is an increasing trend towards research in to psychiatry and mental health in Sri Lanka. PMID- 21789868 TI - Uses of a familial adenomatous polyposis registry. AB - OBJECTIVES: To improve the prognosis of patients with familial adenomatous polyposis (FAP) by early diagnosis and prophylactic treatment through a coordinated FAP register. DESIGN: The establishment and descriptive analysis of the prospective database of the FAP registry. SETTING: University surgical unit, Colombo North Teaching Hospital Ragama, Sri Lanka. PATIENTS: Probands were identified by tracing all diagnosed FAP patients from 1996 to 2010 and their family members at risk. INTERVENTIONS: The establishment of a polyposis register included the following stages: ascertainment of probands (first contact symptomatic FAP patients), construction of pedigrees, counselling relatives and prophylactic screening of family members at risk, treatment and follow up. RESULTS: Twenty seven enrolled probands (12 male and 15 female, age 11-52 years, median age 34 years) were investigated. Pedigree analyses showed 206 relatives at risk. Twenty four family members at risk were screened of a total of 51 registered individuals. The rate of spontaneous mutations was 41%. Thirty five were diagnosed with FAP. Eight were screen detected (median age - 32 years) and 27 symptomatic (median age - 34 years). Concomitant colorectal cancer was detected in 17 (63%) symptomatic individuals and in 1 (13%) screen detected individual. Colectomy was performed in 27 (77%) patients while 8 (23%) are on chemoprophylaxis. Congenital hypertrophic retinal pigment epithelium was detected in 15. Desmoids tumours (6%) and other extraintestinal manifestations including osteomas, sebacious cysts and dental abnormalities (34%) were also detected. A thyroid gland malignancy was screen detected while retinoblastoma, hepatoblastoma and cerebral tumours were seen in pedigrees. CONCLUSIONS: A polyposis register may improve prognosis of FAP by early detection. It will help coordinate, optimise and streamline clinical management of patients with FAP and their relatives at risk. PMID- 21789869 TI - Pre-treatment human chorionic gonadotrophin (hCG) ratio in the management of non tubal ectopic pregnancy. PMID- 21789870 TI - Pseudohypoaldosteronism type 1 in an infant. PMID- 21789872 TI - An unusual manifestation of amiodarone toxicity: lung mass mimicking a lung carcinoma. PMID- 21789871 TI - A parapharyngeal meningioma presenting as a neck mass and multiple cranial nerve palsies. PMID- 21789873 TI - Treatment and prevention of childhood obesity. PMID- 21789874 TI - The first successful liver transplant in Sri Lanka. PMID- 21789875 TI - Ultrasonographic visualisation of live Wuchereria bancrofti adult worms in situ. PMID- 21789876 TI - Nerve tube in peripheral nerve repair. PMID- 21789877 TI - Optochin-resistant Streptococcus pneumoniae. PMID- 21789878 TI - 'Kuppi' classes versus the assessed curriculum. PMID- 21789879 TI - Rapid shallow breathing index and its predictive accuracy measured under five different ventilatory strategies in the same patient group. AB - The rapid shallow breathing index (RSBI) is commonly used clinically for predicting the outcome of weaning from mechanical ventilation. We compared the RSBI and its predictive accuracies measured under 5 ventilatory strategies before weaning trials. Ninety-eight patients were included and divided into successful (n=71) and failed (n=27) groups based on their weaning outcomes. The RSBI was randomly measured when patients spontaneously breathed 21% O2 with no ventilator support (the control strategy) or were connected to ventilator breathing with 21% or 40% O2 and 0 or 5 cm H2O of continuous positive airway pressure (CPAP). We found that the RSBI values did not exhibit significant differences among the 4 ventilator strategies, but all were higher than that of the control; this remained valid in the non-chronic obstructive pulmonary disease (COPD) subgroup, but not in the COPD subgroup. Values of the area under the receiver operating characteristic curve of the RSBI for the 5 strategies were 0.51-0.62 with no significant difference between any 2 strategies. The incidences of adverse reactions (respiratory rate > or =35 breaths/min or oxygen saturation < or =89% for > or =1 min) were relatively high for the 21% O2-0 and 5 cm H2O CPAP groups (20 patients each) and low for the 40% O(2)-5 cmH2O CPAP group (2 patients). We concluded that RSBI values increased with the use of a ventilator, but not with additional applications of 40% 02 and/or 5 cm H2O CPAP. Their accuracies for predicting weaning outcome were unaltered by any of these interventions, but the incidence of adverse reactions increased with the use of the ventilator and decreased with additional 40% O2 supplementation. PMID- 21789880 TI - Identification of an autoantibody against the proliferating cell nuclear antigen from a patient with systemic lupus erythematosus. AB - Antibodies against the proliferating cell nuclear antigen (PCNA) was first discovered in the sera of systemic lupus erythematosus (SLE) patients. However, the reactivity and specificity of anti-PCNA autoantibodies are still unclear. To investigate the property of anti-PCNA autoantibodies, we conducted an ELISA screening of the anti-PCNA autoantibodies in sera of SLE patients. Eighteen out of 191 SLE sera were found to be positive for anti-PCNA antibodies giving a frequency of nearly 10%. Among the positive sera, a sample with the highest titer of anti-PCNA autoantibody preferentially recognizes the wild-type PCNA as compared to the Y114A mutation which contains a single amino acid substitution at 114 and fails to form the toroidal structure. Moreover, the autoantibody purified from this serum identifies only the free PCNA in crude mammalian cell extracts but not other associated cellular components. This finding raises a possibility that immunostaining with the human anti-PCNA autoantibodies in previous studies might have only partially PCNAs in tissues. PMID- 21789881 TI - Effects of short-term dehydroepiandrosterone supplementation on body composition in young athletes. AB - Dehydroepiandrosterone (DHEA) is often promoted as a slimming and weight/fat loss agent and ingestion of DHEA may have hypolipidemic and anti-obesity properties. The main aim of this study was to examine the effects of acute DHEA intake on body composition and serum steroid hormones in young athletes. Twenty young (19 to 22 years) male soccer players were allocated into two randomly assigned trials in double-blind design by ingesting 100-mg daily oral DHEA or as placebo (PLA) for 28 days. Body mass was not affected by 4 weeks of DHEA supplementation (P > 0.05). No significant changes in body mass index (BMI), waist-to-hip ratio (WHR) and body fat or total muscle mass for the two groups were detected at the end of the trial (P > 0.05). There was no within- or between-group difference in arm fat index (AFI) and corrected mid-upper-arm muscle area (cAMA) (P > 0.05). Treatment with DHEA resulted in a significant increase of total testosterone, estradiol and DHEA-S levels in treated subjects versus the placebo group (P < 0.05). Results of this study suggest that DHEA supplementation has no beneficial effects on body composition in young competitive athletes. PMID- 21789882 TI - Effect of lithium on secretory factors and growth stimulation by bombesin in rat pancreas and salivary glands. AB - Lithium, a drug of choice in bipolar affective disorders, also affects the metabolism and cell proliferation in a diverse array of organisms. In this study, we investigated the effect of lithium on bombesin-mediated function in excretion and growth of the pancreas and the salivary glands. The weight, protein content, amylase concentration and salivary flow rate of the pancreas, parotid and the submandibular glands were determined in male Wistar rats after consumption of either water or lithium chloride (600 mg/l) for 14 days and each group received s.c. injection of either saline or bombesin (10 microg/kg) during the last 4 days of experiment. Our results revealed that administration of bombesin in lithium treated group not only suppressed pancreas and parotid weight augmentation due to bombesin, but also significantly decreased pancreas growth. Chronic lithium consumption significantly inhibited the protein content augmentation due to bombesin in the salivary glands. Getting bombesin, as well as saline in lithium treated group, resulted in notable decrease in salivary protein content. Protein content of pancreatic gland increased considerably in the bombesin-injected groups either treated with saline or lithium. In conclusion, the stimulatory effect of bombesin on the growth and protein content of the pancreas and the salivary gland was inhibited by lithium. Lithium seems to be a potent inhibitor of growth factors induced by bombesin probably through inhibiting phosphatidylinositol 4,5,bisphosphate hydrolysis. PMID- 21789883 TI - Attenuation of pulmonary arterial smooth muscle cell proliferation following hypoxic pulmonary hypertension by the Na+/H+ exchange inhibitor amiloride. AB - Chronic hypoxia results in pulmonary hypertension. To investigate the role of Na+/H+ exchange in this process, we determined the effect of amiloride, a Na+/H+ exchange inhibitor, on hypoxic pulmonary hypertension and pulmonary arterial smooth muscle cell proliferation, both in vivo and in vitro. Sprague-Dawley rats were placed either in a hypobaric, hypoxic chamber (10.5% 02) or under normal 21% O2 atmosphere for 8 h each day for 3 weeks. Rats under hypoxic conditions received 1, 3, or 10 mg/kg/d amiloride or the vehicle alone. Hematologic indices, including red blood cells, hemoglobin, hematocrit and mean corpuscular hemoglobin increased in hypoxic rats, but these changes were prevented by treatment with amiloride. In the hypoxic rats, the right ventricular systolic pressure and right ventricular hypertension index (weight ratio of right ventricular to left and septum together) were increased by 88% and 129%, respectively. Arteriolar wall thickness and area in the hypoxia-treated animals increased 3- and 2-fold, respectively, over normoxic controls; the increase in each of these indices was attenuated by amiloride in a dose-dependent manner. In cultured pulmonary arterial smooth muscle cells, hypoxia greatly increased cellular proliferation, and this similarly showed a dose-dependent attenuation in the presence of amiloride. Amiloride did not affect blood pressure in vivo or cause cell damage in vitro. These data suggest that the Na+/H+ exchange inhibitor amiloride may represent an effective adjunctive therapy in pulmonary hypertension induced by chronic hypoxia. PMID- 21789884 TI - Reduction of superior mesenteric hemodynamic responsiveness to [Sar1, Thr8] angiotensin II and bradykinin, but not sodium nitroprusside, in the presence of homocysteine infusion. AB - Hyperhomocysteinemia (HHcy) has been shown to be an independent risk factor for cardiovascular diseases, superior mesenteric thrombosis and inflammatory bowel disease. Superior mesenteric artery (SMA) supplies the intestine and reduced SMA blood flow results in intestinal ischemia. Although in vitro studies have shown that endothelium-dependent vasorelaxation of SMA is reduced in the presence of homocysteine incubation, it is not confirmed with in vivo studies. In this work, we evaluated responsiveness of SMA to endothelium-dependent or -independent vasodilators and a vasoconstrictor in the absence and presence of acute HHcy in vivo to clarify effect of HHcy on superior mesenteric vascular function. Sodium nitroprusside (SNP), bradykinin (BK), and [Sar1,Thr8]angiotensin II ([Sar1,Thr8] ANG II) were intravenously administrated in sequence in male Sprague-Dawley rats with or without D,L-homocysteine infusion (6 mg/kg/min) through femoral vein. Agonists-induced changes in carotid artery blood pressure, superior mesenteric blood flow and vascular resistance were measured in the present study. We found that acute HHcy infusion had little effects on SNP-induced hemodynamic changes; however, BK-induced changes in blood pressure, blood flow and vascular resistance were significantly reduced in the presence of HHcy infusion. Additionally, HHcy also markedly decreased [Sar1,Thr8]-ANG II-induced superior mesenteric hemodynamic changes. These results demonstrated that responsiveness of SMA to vasoconstrictor, endothelium-dependent, but not endothelium-independent vasodilator, was inhibited in the presence of Hcy infusion. This HHcy-associated vascular hyporesponsiveness to vasoconstrictors and endothelium-dependent vasodilators may partially contribute to circulatory dysfunctions. PMID- 21789885 TI - Differences in the pattern of ventricular activation in small rodents determined by morphological organization of the cardiac ventricular conduction system. AB - Ventricular activation of the mouse heart differs significantly compared to activation in larger mammals. Knowledge of structural and functional characteristics of laboratory animals is essential for evaluation of results obtained from experiments. The present study was performed to evaluate whether the different pattern of activation is common to small rodents or unique for mice. Hearts of adult Wistar rats were isolated and Langendorff perfused. After removing the right and left ventricular free wall, extracellular activity of the septum and bundle branches (BB) was determined using a multi-terminal electrode harboring 247 terminals. Immunolabeling on cryosections was performed to assess expression and distribution of the gap junction proteins Connexin40 (Cx40), Cx43, Cx45, contractile (Desmin, alpha-actinin) and intercalated disk-related (N cadherin, beta-catenin) proteins. Collagen distribution was assessed by Sirius Red staining. Reconstruction of the left and right bundle branch (LBB and RBB) using immuno-labeling revealed that the LBB spreads all over the septal surface. The RBB too is broad, albeit to a lesser extend than LBB. A sheet of connective tissue electrically separates the common bundle and proximal BB from the septal working myocardium. Immunolabeling revealed clear differences between the conduction system and the working myocardium with respect to expression level and distribution of the different proteins analyzed. The morphological organization of the area resulted in an electrical activation pattern of the septum comparable to what is common in larger mammals: earliest activation at the midseptum via the bundle branches. From our data we conclude that the pattern of ventricular activation in the rat heart and the structure of the conduction system fit to data described for larger mammals and differ from the different pattern previously found in mouse heart. PMID- 21789886 TI - Effect of mild intermittent hypoxia on glucose tolerance, muscle morphology and AMPK-PGC-1alpha signaling. AB - The main goal of this study was to investigate the long-term effect of daily 8 hour mild intermittent hypoxia (14-15% O2) on glucose tolerance and muscle morphology of Sprague-Dawley rats. The involvement of AMPK-PGC-1alpha-VEGF signaling pathways in the skeletal muscle was also determined during the first 8 hours of hypoxia. We found that mRNA levels of VEGF and PGC-1alpha were significantly increased above control after 8-h mild hypoxia without a change in AMPK phosphorylation. After 8 weeks of mild intermittent hypoxia treatment, plasma glucose and insulin levels in oral glucose tolerance test (OGTT), epididymal fat mass, and body weight were significantly lower compared to the control group. While soleus muscle weight was not changed, capillary and fiber densities in the hypoxia group were 33% and 35% above the control suggesting reorganization of muscle fibers. In conclusion, our data provide strong evidence that long-term mild intermittent hypoxia decreases the diffusion distance of glucose and insulin across muscle fibers, and decreases adiposity in rats. These changes may account for the improved glucose tolerance observed following the 8 week hypoxia treatment, and provides grounds for investigating the development of a mild non-pharmacological intervention in the treatment of obesity and type 2 diabetes. PMID- 21789887 TI - Effects of BCAA, arginine and carbohydrate combined drink on post-exercise biochemical response and psychological condition. AB - This study investigated the effects of BCAA, arginine and carbohydrate combined beverage (BCAA Drink) on biochemical responses and psychological conditions during recovery after a single bout of exhaustive exercise. Fourteen healthy males were assigned to drink either BCAA Drink (BA trial) or placebo (PL trial) on two sessions separated by 2 weeks. Blood samples of each subject were collected before exercise, 0, 10, 20, 40, 60, 120 min and 24 h after exercise. No significant differences in the levels of lactate, ammonia, creatine kinase and glycerol between the two groups were observed at any of the time points. However, the levels of glucose and insulin were significantly higher in the BA trial as compared to those in the PL trial at the 40 and 60 min recovery points. Furthermore, the testosterone-to-cortisol ratio at the 120 min recovery point was significantly higher in the BA trial as compared to that in the PL trial. The results indicate the occurrence of anabolic response during the recovery period. The benefit of BCAA Drink was also performed by Profile of Mood States to assess the psychological condition. Fatigue score increased immediately at exhaustion in both groups, but the decrease in the fatigue score at 120 min recovery point was significant only in BA trial. These data indicate that a single bout of exhaustive exercise enhanced the feeling of fatigue. The detrimental consequence was reduced by an ingestion of BCAA Drink. PMID- 21789888 TI - Nephro-protective effects of a ginger extract on cytosolic and mitochondrial enzymes against streptozotocin (STZ)-induced diabetic complications in rats. AB - Diabetes is characterized by elevated blood glucose levels and disturbed homeostasis of metabolic enzymes in whole-body. This study aimed to investigate the effect of ginger administration on altered blood glucose levels, intra- and extra-mitochondrial enzymes and tissue injuries in streptozotocin (STZ)-induced diabetic rats. Wistar strain rats (n = 30) were equally divided into 5 groups: normal control (NC), ginger treated (Gt, 200 mg/kg b.w. orally/30 days), diabetic control (DC, 50 mg/kg b.w.), diabetic plus ginger treated (D + Gt) and diabetic plus glibenclamide treated (D + Gli) groups. We found highly elevated blood glucose levels in the diabetic group, and the glucose levels were significantly (P < 0.001) lowered by ginger administration. Activities of intra- and extra mitochondrial enzymes such as glucose-6-phosphate dehydrogenase (G6PD), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and glutamate dehydrogenase (GDH) were significantly (P < 0.01) decreased in the kidneys of the diabetic rats, while this was significantly reversed by 30 days of ginger treatment. We also observed consistent renal tissue damages in the diabetic rats; however, these injuries recovered in the ginger-treated diabetic rats as shown in histopathological studies. In this study, we demonstrated that an ethanolic extract of ginger could lower the blood glucose levels as well as improve activities of intra- and extra-mitochondrial enzymes in diabetic rats. Our results suggest that ginger extracts could be used as a nephro-protective supplement particularly to reverse diabetic-induced complications. PMID- 21789889 TI - Enhancement of vasorelaxation in hypertension following high-intensity exercise. AB - Exercise can ameliorate vascular dysfunction in hypertension, but its underlying mechanism has not been explored thoroughly. We aimed to investigate whether the high-intensity exercise could enhance vasorelaxation mediated by insulin and insulin-like growth factor-1 (IGF-1) in hypertension. Sixteen-week-old spontaneously hypertensive rats were randomly divided into non-exercise sedentary (SHR) and high-intensity exercise (SHR+Ex) groups conducted by treadmill running at a speed of 30 m/ min until exhaustion. Age-matched Wistar-Kyoto rats (WKY) were used as the normotensive control group. Immediately after exercise, the agonist-induced vasorelaxation of aortas was evaluated in organ baths with or without endothelial denudation. Selective inhibitors were used to examine the roles of nitric oxide synthase (NOS) and phosphatidylinositol-3 kinase (PI3K) in the vasorelaxation. By adding superoxide dismutase (SOD), a superoxide scavenger, the role of superoxide production in the vasorelaxation was also clarified. We found that, the high-intensity exercise significantly (P < 0.05) induced higher vasorelaxant responses to insulin and IGF-1 in the SHR+Ex group than that in the SHR group; after endothelial denudation and pre-treatment of the PI3K inhibitor, NOS inhibitor, or SOD, vasorelaxant responses to insulin and IGF-1 became similar among three groups; the protein expression of insulin receptor, IGF-1 receptor, and endothelial NOS (eNOS) was significantly (P < 0.05) increased in the SHR+Ex group compared with the SHR group;] the relaxation to sodium nitroprusside, a NO donor, was not different among three groups. Our findings suggested that the high intensity exercise ameliorated the insulin- and IGF-1-mediated vasorelaxation through the endothelium-dependent pathway, which was associated with the reduced level of superoxide production. PMID- 21789891 TI - Ultra short-term heart rate recovery after maximal exercise: relations to aerobic power in sportsmen. AB - The main aim of the study was to investigate whether different levels of aerobic power influence heart rate (HR) responses during the first minute of recovery following maximal exercise in athletes. Thirty-two young male soccer players were recruited for the study during the final week of their training prior to [corrected] the competition. Following the maximal exercise on treadmill the participants were placed supine for 60 s of HR recording. The time between exercise cessation and the recovery HR measurement was kept as short as possible. At the end of exercise (i.e., the start of recovery), HRs were [corrected] was similar in both trials. At both 10 s and 20 s of recovery period, the players characterized by high aerobic power (> 60 ml/kg/ min) revealed significantly lower HR as compared to their sub-elite counterparts (< 50 ml/kg/min; P < 0.05). No differences between the groups were found at later stages of the analyzed post exercise HR. The data suggest that the athletes characterized by high aerobic capacity could be better adapted to maximal exercise with faster recovery HR immediately following an exercise test. These results generally suggest that the aerobic power along with autonomic modulation might have played a role in the ultra short-term cardiovascular responses to all-out exercise. PMID- 21789890 TI - Effects of chronic, systemic treatment with the dopamine receptor agonist R apomorphine in partially lesioned rat model of Parkinson's disease: an electrophysiological study of substantia nigra dopamine neurons. AB - Previous studies have suggested that R-apomorphine (R-APO), a non-selective dopamine (DA) receptor agonist, has neuroprotective effects in the experimental models of Parkinson's disease (PD). In this study, we investigated the effects of chronic, systemic treatment with R-APO in the firing activity of substantia nigra pars compacta (SNc) DA neurons in 6-hydroxydopamine (6-OHDA) partially lesioned rats. In the 6-OHDA-lesioned rats treated with vehicle, injection of 6-OHDA (20.1 microg) into the striatum produced a partial lesion causing 41% loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNc. In the partially lesioned rats, chronic, systemic treatment of R-APO (10 mg/kg/day, s.c., 11 days) attenuated loss of TH-ir neurons in the SNc. The partial lesion of the nigrostriatal pathway and R-APO treatment did not change the firing rate and firing pattern of DA neurons in the SNc of rats. In contrast, the R-APO treatment increased the number of spontaneously active DA neurons of the SNc in the partially lesioned rats, while the lesion decreased the number of spontaneously active DA neurons. In addition, the chronic R-APO treatment decreased the responsiveness of the DA neurons to intravenously administrated R-APO in the partially lesioned rats. These results indicate that chronic, systemic R-APO treatment has the neuroprotective effect, and reverses the decrease in the number of spontaneously active DA neurons in the SNc whereas the treatment induces a reduction in the sensitivity of DA receptors in the SNc to R-APO stimulation in this model. PMID- 21789892 TI - Tea polyphenol-induced neuron-like differentiation of mouse mesenchymal stem cells. AB - Bone marrow mesenchymal stem cells (BMSCs) can be induced to differentiate into neuron-like cells under appropriate conditions often involving toxic reagents that are not applicable for clinical transplantation. The present study investigated whether tea polyphenol (TP), a native nontoxic antioxidant, could induce mouse neuron-like cell differentiation of BMSCs in vitro. BMSCs, dissected from mouse femur bone marrow, were amplified in culture and treated with TP or beta-mercaptoethanol (BME, control). Morphological changes were observed under light microscopy. After 12 h treatment with 50 microg/ml TP or 5 mM BME, most cells differentiated into neuron-like cells exhibiting neuronal morphological characteristics, cellular shrinkage and neurite growth. Immunocytochemistry and reverse transcription (RT)-PCR results demonstrated neuronal marker expression in the induced cells with no glial fibrillary acidic protein expression. Taken together, TP induced mouse BMSCs to differentiate into neuron-like cells in vitro. These findings provide a potential source for the treatment of various neurological diseases. PMID- 21789893 TI - Effect of delta-opioid receptor over-expression on cortical expression of GABAA receptor alpha1-subunit in hypoxia. AB - Recent studies show that both delta-opioid receptors (DOR) and GABA receptors play a neuroprotective role in the mature cortex. Since we have observed that DOR over-expression renders the cortex more tolerant to hypoxic stress, we asked whether DOR over-expression affects GABA receptors expression in the cortex under hypoxia. As the first step, we investigated the expression of GABAA receptor alpha1-subunit (GABAA Ralpha1, the most abundant alpha-subunit of GABA receptors in the adult brain) in the mouse cortex with transgenic DOR over-expression after hypoxia. The results showed that GABAA Ralpha1 expression was lower in the transgenic than wild-type cortex, suggesting that DOR overexpression induces an inhibitory effect on GABAA receptor expression. Hypoxia for 1-3 days significantly increased GABAA Ralpha1 expression in the wild-type cortex, which may be an adaptive strategy for protecting the cortex against hypoxic stress. Interestingly, such increase was not found in the transgenic cortex with DOR over expression. This may represent an interactive regulation in the transgenic cortex to efficiently balance energy production and consumption for better adaptation to hypoxic environment. Since DOR over-expression increases cortical tolerance to hypoxia, an increase in GABA receptors expression (an energy-costing process) may not be necessary in the cortex with DOR over-expression. PMID- 21789894 TI - Interference of the apoptotic signaling pathway in RGC stress response by SP600125 in moderate ocular hypertensive rats. AB - The aim of the present study was to investigate the effect of SP600125 (1,9 pyrazoloanthrone), an inhibitor of JNK, on apoptosis of retinal ganglion cells (RGCs) induced by moderate elevation of intraocular pressure (IOP) in male rats. IOP was elevated by suture-pulley compression on eyeballs. Cell apoptosis, expression of phosphorylated JNK (p-JNK) and cleaved caspase-3 in retina were studied by TUNEL staining and immunohistochemistry. The expression of c-Jun in retina was assayed by Western blot. Following IOP elevation (about 45 mmHg) for 6 h, the number of TUNEL, p-JNK and cleaved caspase-3 positive cells and the amount of c-Jun expression in retina were significantly increased. All these changes were reversed by SP600125 treatment. The immune positive cells for TUNEL, p-JNK and cleaved caspase-3 following IOP elevation were localized at the RGC layer. We conclude that moderate elevation of IOP for 6 h induced apoptosis of RGCs, and SP600125 treatment attenuated this process by suppressing c-Jun expression. PMID- 21789895 TI - Differences in sarcoplasmic reticulum Ca2+ leak characteristics between systolic and diastolic heart failure rabbit models. AB - Diastolic heart failure (DHF) and systolic heart failure (SHF) are two clinical subsets of chronic heart failure (CHF). Sarcoplasmic reticulum (SR) Ca2+ leak has been measured in SHF and might contribute to contractile dysfunction and arrhythmogenesis. However, no study has investigated a similar phenomenon in DHF. Thus, we established DHF and SHF rabbit models and compared the differences in Ca2+ leak between these models. New Zealand white rabbits were randomly divided into three groups (n = 8 in each group): sham operation (SO) group, DHF group and SHF group. Cardiac functions were determined by echocardiography and hemodynamic assays. The SR Ca2+ leak was measured with a calcium-imaging device and the expression and activities of related proteins were evaluated with Western blots and autophosphorylation. In the DHF group, there was significantly increased ventricular wall thickness and stiffness, reduced diastolic function, and total amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of protein kinase A (PKA) and phosphorylation site (P2809) in the ryanodine receptor (RyR2), but no prominent Ca2+ leak. In the SHF group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca2+ leak, reduced total amount of FKBP12.6 and FKBP12.6-RyR2 association, increased expression and activity of PKA and Ca2+/calmodulin dependent protein kinase II (CaMKII) and their RyR2 phosphorylation sites with unchanged P2030. Our results suggest that a prominent SR Ca2+ leak was not observed in the DHF model, which may provide a new idea for the reasons in preserved systolic function, and CaMKII possibly plays a more important role in SR Ca2+ leak. PMID- 21789896 TI - Effects of hot and cold foods on signals of heart rate variability and nail fold microcirculation of healthy young humans: a pilot study. AB - In traditional Chinese medicine, hot- and cold-attribute of food ingredients are a major part of dietary therapy. The aim of this study was to establish a suitable scientific methodology to define the attributes of food ingredients by investigating the relationship between food attributes and the physiological signals produced in healthy young subjects with different constitutions. Thirty subjects were grouped into hot and cold constitutions by Chinese medical doctors. Every subject took water, aged ginger tea and coconut water, which are well recognized as having neutral-, hot- and cold-attribute, respectively, on different visits. The different physiological signals induced by the samples were observed using skin and axillary temperature sensors, a heart rate variability analyzer and a laser Doppler anemometer. We found that the capillary red blood cell (RBC) velocity in nail fold microcirculation (NFM) of the subjects with hot constitution accelerated significantly after taking the hot-attribute aged ginger tea, which might be the result of elevated vagal activity leading to arteriole dilation in these subjects. In contrast, in subjects with cold constitution, capillary RBC velocity decelerated significantly and skin temperature decreased markedly after taking the cold-attribute coconut water, which might have been induced by sympathetic nerve activation causing the arteriole to be constricted. Accordingly, the use of capillary RBC velocity of NFM measured by laser Doppler anemometer may be a promising way to classify attributes of food ingredients commonly used in Chinese medicine dietary therapy in accordance with different personal constitutions. PMID- 21789897 TI - Significant association of caveolin-1 genotypes with bladder cancer susceptibility in Taiwan. AB - Many articles have reported the caveolin-1 gene to be down-regulated thus suggesting that it might be a candidate tumor suppressor gene in many tumors. However, its involvement in bladder cancer is not clear and may be depending on pathological grade. In this case-control study, the association of Cav-1 polymorphisms with bladder cancer risk in a central Taiwanese population was investigated. Three hundred and seventy-five patients with bladder cancer and the same number of age- and gender-matched healthy controls were genotyped. There were significant differences between bladder cancer and control groups in the distributions of their genotypes (P = 1.0 x 10(-12) and 0.299) and allelic frequencies (P = 1.4 x 10(-14) and 6.2 x 10(-3)) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. As for haplotype analysis, subjects who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a decreased risk of bladder cancer compared to subjects with GG/TT, while those of any other combinations were of increased risk. There were joint effects of Cav-1 G14713A and T29107A genotypes with smoking status on individual bladder cancer susceptibility. This is the first report providing evidence that Cav-1 was involved in bladder cancer in that the A allele of the Cav-1 G14713A is risky, the A allele of the Cav-1 T29107A is protective, and AA/TT on these two polymorphisms may be the most risky haplotype for the development of bladder cancer and may be novel useful genomic markers for early detection of bladder cancer. PMID- 21789898 TI - Expression of LGR8 and related biomarkers in hepatocellular carcinoma: correlation with clinicopathological parameters. AB - This study aimed to evaluate the relationship between expression of LGR8, VEGF, MMP-2, MMP-9, fascin-1 and cortactin with clinicopathological parameters in hepatocellular carcinoma (HCC). The six biomarkers were investigated immunohistochemically using tissue microarrays of 93 HCC specimens. The tumor cells showed significant expression of LGR8, VEGF, MMP-9, fascin-1 and cortactin, but not of MMP-2. In addition, higher immunostaining scores for LGR8 in HCC showed negative correlation with T and AJCC clinical stages and upregulation of MMP-9, but no correlation with poorer survival rate; cortactin expression is correlated with poorer tumor differentiation in HCC. Thus, our data suggest that higher expression of LGR8 may facilitate tumor invasiveness in the early clinical stage of hepatocellular carcinoma, and synergic effects of cortactin also play a crucial role in the intrahepatic metastasis. Although tumor biological evidence implicates the relaxin-like hormone family as endocrine mediators of critical cellular action in cancer, characterization of target molecules and signaling pathways specific for LGR8 in defined tumor entities and crosstalk of the relaxin receptors with other receptor systems relevant to carcinogenesis will be of significant clinical relevance and may contribute to novel therapeutic strategies against hepatocellular carcinoma. PMID- 21789899 TI - Protection of bone marrow-derived CD45+/CD34-/lin- stromal cells with immunosuppressant activity against ischemia/reperfusion injury in rats. AB - Non-hematopoietic CD45+ precursor cells are not known to differentiate into cardiomyocytes. We found that CD45+/CD34-/lin- stromal cells isolated from mouse bone marrow (BMSCs) potentially differentiated into cardiomyocyte-like cells in vitro. Therefore, we hypothesized that the CD45+/CD34-/ lin- BMSCs might protect rat hearts against ischemia/reperfusion (IR) injury following xeno transplantation. In the present study, BMSCs were isolated by immunoselection and their cellular phenotype and biochemical properties were characterized. The immunological inertness of BMSCs was examined by the allogeneic and xenogeneic mixed lymphocyte reaction (MLR). The potential role of BMSCs for cardioprotection was evaluated by intravenous introduction of 1 x 10(6) cells into rat IR hearts, induced by left coronary ligation for 45 min and released for 72 h. Changes in cardiac contractility and the degree of myocardial injury were assessed. Our findings indicated that BMSCs expressed the muscle-cell marker alpha-actinin after 5-azacytidine treatment. CD45+/CD34-/lin- stromal cells were characterized as mesenchymal progenitor cells based on the expression of Sca-1 and Rex-1. The MLR assay revealed an immunosuppression of BMSCs on mouse and rat lymphocytes. After xeno-transplantation, the BMSCs engrafted into the infarct area and attenuated IR injury. However, increases in intracardial TGF-beta and IFN-gamma contents of IR hearts were not affected by BMSC treatment. Interestingly, ex vivo evidence indicated that CXCR4, SDF-1 and TGFbeta-1 receptors were up-regulated after the cells were exposed to tissue extracts prepared from rat post-IR hearts. In addition, IFN-gamma treatment also markedly increased Sca-1 expression in BMSCs. Mechanistically, these results indicated that CXCR4/SDF-1 and TGF-beta signals potentially enhanced the interaction of BMSCs with the damaged myocardium, and increased IFN-gamma in post-ischemic hearts might cause BMSC to behave more like stem cells in cardioprotection. These data show that CD45+/CD34 /lin- BMSCs possess cardioprotective capacity. Evidently, the accurate production of soluble factors TGF-beta and IFN-gamma in parallel with increased expression of both TGF-beta and Sca-1 receptors may favor BMSCs to achieve a more efficient protective capacity. PMID- 21789900 TI - Astringinin-mediated attenuation of the hepatic injury following trauma hemorrhage. AB - Although astringinin administration under adverse circulatory conditions is known to be protective, the mechanism by which astringinin produces the salutary effects remains unknown. We hypothesize that astringinin administration in males following trauma-hemorrhage decreases cytokine production and protects against hepatic injury. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure: 40 mmHg for 90 min, then resuscitation). Different doses of astringinin (0.01, 0.03, 0.1, 0.3 mg/kg of body weight) or vehicle were administered intravenously during resuscitation. Concentrations of plasma aspartate aminotransferase (AST) with alanine aminotransferase (ALT) and various hepatic parameters were measured (n = 8 rats/group) at 24 h after resuscitation. One-way ANOVA and Tukey testing were used for statistical analysis. Trauma-hemorrhage significantly increased plasma AST and ALT levels at 24 h postresuscitation; there was a dose-related benefit when astringinin was administered at doses of 0.01 to 0.3 mg/kg. In astringinin-treated (0.3 mg/kg) rats subjected to trauma hemorrhage, there were significant improvements in liver myeloperoxidase (MPO) activity (237.80 +/- 45.89 vs. 495.95 +/- 70.64 U/mg protein, P < 0.05), interleukin-6 (IL-6) levels (218.54 +/- 34.52 vs. 478.60 +/- 76.21 pg/mg protein, P < 0.05), cytokine-induced neutrophil chemoattractant (CINC)-1 (88.32 +/- 20.33 vs. 200.70 +/- 32.68 pg/mg protein, P < 0.05), CINC-3 (110.83 +/- 26.63 vs. 290.14 +/- 76.82 pg/mg protein, P < 0.05) and intercellular adhesion molecule (ICAM)-1 concentrations (1,868.5 +/- 211.5 vs. 3,645.0 +/- 709.2 pg/mg protein, P < 0.05), as well as in histology. Results show that astringinin significantly attenuates proinflammatory responses and hepatic injury after trauma-hemorrhage. In conclusion, the salutary effects of astringinin administration on attenuation of hepatic injury following trauma-hemorrhage are likely due to reduction of pro inflammatory mediator levels. PMID- 21789901 TI - Involvement of synaptic NR2B-containing NMDA receptors in long-term depression induction in the young rat visual cortex in vitro. AB - Activation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in the induction of long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of the young rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A- and NR2B-containing NMDARs in the induction of LTD in visual cortical slices from 12- to 15-day old rats. We found that LTD was readily induced in layer II/III pyramidal neurons of the rat visual cortex with 10-min 1-Hz stimulation paired with postsynaptic depolarization. D-APV, a selective NMDAR antagonist, blocked the induction of LTD. Moreover, the selective NR2B-containing NMDAR antagonists (Ro 25-6981 and ifenprodil) also prevented the induction of LTD. However, Zn2+, a voltage-independent NR2A-containing NMDAR antagonist, displayed no influence on the induction of LTD. These results suggest that the induction of LTD in layer II/III pyramidal neurons of the young rat visual cortex is NMDAR-dependent and requires NR2B-containing NMDARs, not NR2A-containing NMDARs. PMID- 21789902 TI - Potential role of CCND1 G870A genotype as a predictor for urothelial carcinoma susceptibility and muscle-invasiveness in Taiwan. AB - The cell cycle regulator cyclin D1 (CCND1) is thought to play a major role in the transition of cell cycle from G1 to S phase. It is known that a common CCND1 G870A genotype is associated with bladder cancer in Japan and China, but not in the Western World. There is neither a report about its role in Taiwan's population, nor its genetic role of CCND1 G870A in another worldwide urothelial cancer, upper tract urothelial cancer (UTUC). Therefore, we aimed at investigating the role of CCND1 G870A in both bladder cancer and UTUC in Taiwanese cohorts. The CCND1 G870A genotypes of 171 (101 bladder cancer and 70 UTUC) patients and 243 control subjects were determined by PCR-RFLP and their correlation with clinical and histopathological data was evaluated. The genotype analysis results showed that CCND1 GG genotype was associated with a lower risk overall in urothelial (P = 0.008, OR = 0.44, 95% CI = 0.24-0.81) and bladder cancer patients (P = 0.008, OR = 0.34, 95% CI = 0.15-0.76) than those of the AA genotype. In addition, patients carrying the AG genotype had a 0.29-fold lower odds ratio of muscle-invasive cancer procession (95% CI = 0.12-0.70) compared with those carrying the AA genotype in bladder cancer patients. Surprisingly, the GG genotype had a 5.88-fold higher odds ratio of muscle-invasive cancer procession (95% CI = 1.08-32.01) compared with those carrying the AA genotype in UTUC. No association between any CCND1 G870A genotype and higher-grade risk was found. Our results suggest that the G allele of the CCND1 G870A polymorphism may be a potential predictive and prognostic biomarker to distinguish between bladder cancer and UTUC in Taiwan. PMID- 21789903 TI - ED case managers are crucial to help maximize reimbursement. AB - As payers tighten their belts and recoup payments for inappropriate care and regulators increase penalties for fraud and abuse, hospitals need to ensure all admissions are appropriate and patient are placed in the right level of care. Hospitals are likely to have to return reimbursement for patients who don't meet inpatient criteria. Improper admissions can exacerbate capacity problems and result in hospital-acquired conditions. Correcting inappropriate admissions retrospectively can be a red flag to auditors. ED case managers can impact length of stay by ensuring that care starts in the emergency department. PMID- 21789904 TI - ED case managers save $4.5 million. AB - Emergency department case managers at Lee Memorial Health System in Fort Myers, FL saved more than $4.5 million by ensuring that patients were in the right status and transferring patients who did not meet admission criteria to a more appropriate level of care. Case managers and social workers cover the emergency department at peak hours, seven days a week. Case managers screen patients for admission criteria and make sure admission orders are complete and correct. Case managers and social workers coordinate community services and placement for patients who don't meet admission criteria. Social workers intervene when there are concerns about abuse and neglect, and they facilitate placement to other acute care facilities. PMID- 21789905 TI - Case management insider. Every day, the case management department faces multiple dilemmas over ethics. PMID- 21789906 TI - Case management insider. Solution: committees on organizational ethics. PMID- 21789907 TI - Use data to justify adding staff in the ED. PMID- 21789908 TI - Pilot project to improve discharge process. AB - The care management department at Saddleback Memorial Hospital in Laguna Hills, CA, is piloting a standardized work flow process for discharging patients. Process identifies who is responsible for what after discharge orders are written. Discharge process is tracked on an electronic board. Process eliminates duplications and omissions. PMID- 21789909 TI - RNs failed to follow Dr.'s orders, inform Dr. or chart failure. Poteet v. National Healthcare of Cleveland, Inc., E2009-01978-COA (4/19/2011)-TN. PMID- 21789910 TI - Wound-care nurse not targeted in death from infection. CASE ON POINT: Stokes v. Schindler Elevator Corp., 1D10-1748 FLCA (4/7/2011)-FL. PMID- 21789911 TI - PA: cell phone use results in termination: denial of unemployment benefits affirmed. Chapman v. Unemployment Compensation Board of Review, 1583 C.D. 210 (4/25/2011)-PA. PMID- 21789912 TI - OB/GYN nurse botched care - palsy resulted. CASE ON POINT: Reilly v. Ninia, 2011 01451 NYAPP2 (2/22/2011)-NY. PMID- 21789913 TI - Sustainable development, urban environment and population health. PMID- 21789914 TI - [Effects of calcium antagonists on brain ischemia]. AB - INTRODUCTION: Stroke is the second leading cause of death in the world and the leading cause of serious, long-term disability in adults; about half of those who survive become dependent on others in performing personal activities of daily living. Ischemia disturbs calcium cellular homeostasis, whereas calcium channel blockers re-establish it. This study was aimed at assessing benefits of calcium channel blockers on the outcome of rehabilitation of the patients afflicted by ischemic stroke. MATERIAL AND METHODS: The functional independence was measured by the Barthel index in 90 patients subjected to rehabilitative therapeutic treatment. The functional recovery of patients treated with calcium channel blockers and with other drugs (control) was compared and tested. RESULTS: The analysis of variance (ANOVA) for the 0.5 confidence interval showed that the increases of the Barthel index values were significantly higher in the patients treated with calcium antagonists (p < 0.5). DISCUSSION: According to the literature, such an outcome is the result of improved brain blood flow auto regulation, increased brain perfusion as well as of neuroprotective, antioxidative, platelet anti-aggregatory effects of investigated drugs. CONCLUSION: The calcium channel blockers improved the outcome of rehabilitative therapeutic treatment significantly in the patients afflicted by ischemic stroke. PMID- 21789915 TI - [Conflict styles observed in doctors and nurses in health care organization]. AB - INTRODUCTION: Health care workers often come into conflict situations while performing their daily activities. People behave differently when they come into conflicts and they are usually not aware of their own reactions. The aim of this paper was to establish the presence of conflict styles among health workers and the differences in relation to demographic characteristics (education, working experience, managerial position). MATERIAL AND METHODS: The research was done as a cross-sectional study and through surveys. The conflict handling questionnaire was used as the research instrument. The questionnaire contained 30 statements arranged in five dimensions of conflict styles. The sample included one hundred nurses and fifty-five doctors. RESULTS: The research showed that accommodating was the most often used conflict style. There was no significant difference in styles of managerial and non-managerial staff, but there was a significant difference in the styles adopted by doctors and nurses. It should be noted that nurses used avoiding and accommodating conflict styles much more often. CONCLUSION: It is important to increase the awareness of conflict existence and the possibility of solving the problem constructively in order to achieve more efficient duty performance. PMID- 21789916 TI - [Cerebrovascular disease morbidity on the territory of the municipality of Doljevac]. AB - INTRODUCTION: Cerebrovascular diseases have drawn great public attention recently due to a high death rate and an even higher disability rate. The aim of the research was to determine the basic descriptive-epidemic characteristics of patients with cerebrovascular diseases, to assess the incidence rate according to the gender and age, as well as mortality and the disease prognosis after one-year follow up period. MATERIAL AND METHODS: A prospective survey was conducted, and the study included all registered patients with cerebrovascular diseases from the municipality of Doljevac in the period from 2005-2007, who were monitored for 1 year since the onset of the disease. RESULTS: During the period monitored, there were a total of 230 patients suffering from this disease. The average standardised incidence rate in both genders was 274.67. Ischemic brain stroke occurred in 146 (63.4%) subjects, the intracerebral haemorrhage in 39 (17%) and the subarachnoid haemorrhage occurred in 9 (3.9%). The 90-day lethality was 14.8%; 1-year lethality was 21.7%. Out of 123 patients (53.4%), who were recorded to have various degree of disability, 44 (35.8%) were independent in everyday activities, 41 (33.3%) needed assistance while walking and maintaining personal hygiene, whereas 38 (30.9) were bedridden. After a year of monitoring, 30 (13.1%) patients suffered a recurrent brain stroke. CONCLUSION: Cerebrovascular disease morbidity rate was found to be increasing. However, there were no statistically significant differences in morbidity by diagnosis and the disease outcome between genders. PMID- 21789917 TI - Myocardial revascularization without extracorporeal circulation in patients at high operative risk. AB - It is considered that over 25% of surgical patients with coronary artery disease are treated without extracorporeal circulation, i.e. off-pump coronary artery bypass. The aim of the study was to evaluate results of surgical myocardium revascularization in patients at high operative risk. During the period 2005 2008, 148 patients were operated without the use of extracorporeal ciruculation. According to the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) stratification, 28 patients (19%) were designated as the high risk patients. The average age of these high risk patients was 72 years (55-86). The group consisted of 23 men (82.1%) and 5 women (17.8%). The postoperative mortality in the whole group of patients was 0.68% (1/148), whereas it was 0% in the high risk group. The average number of coronary anastomoses was 2.4. Eight patients (28.6%) had some sort of postoperative complications. Our results demonstrate safety and efficacy of surgical revascularization without cardiopulmonary bypass in patients at high operative risk. PMID- 21789918 TI - [Influence of air pollution on pregnant women's health and pregnancy outcomes]. AB - Outdoor and indoor air pollution pollutants can be a potential cause to a lot of negative effects on the health of pregnant women and outcome of pregnancy. The objective of this paper was to estimate the influence of outdoor and indoor air pollution on the health of pregnant women and outcome of pregnancy. MATERIAL AND METHODS: The study subjects were the pregnant women, non-smokers, who were not professionally exposed to air pollution. They were divided into the exposed group (n = 189) and control group (n = 178) during the exposure to outdoor air pollution. The data on exposure to sources of indoor air pollution (smoke produced by burning fossil fuels and passive smoking) during pregnancy were obtained from the questionnaire. Data on health condition and outcome of pregnancy were obtained from medical records of tested pregnant women. RESULTS: The research results have shown that the frequency of anemia (OR = 6.76; 95% CI = 1.28-7.72), upper respiratory symptoms (OR = 9.53; 95% CI = 1.32-3.8) and bleeding (OR = 20.5; 95% CI = 2.03-6.97) was significantly higher in pregnant women exposed to outdoor air pollution as compared with the control group. The occurrence of upper respiratory symptoms (OR = 40.42; 95% CI = 2.96-8.91) and bleeding (OR = 53.21; 95% CI = 4.3-15.73) was significantly higher in pregnant women who had been exposed to fossil fuel smoke. Exposure to passive smoking had significant influence on the development of upper respiratory symptoms (OR = 34.58; 95% CI = 3.05-11.66). PMID- 21789919 TI - [Counterfeit drugs as a gobal threat to health]. AB - According to the World Health Organisation, counterfeit medicines are medicines that are mislabelled deliberately and fraudulently regarding their identity and/or source. All kinds of medicines have been counterfeited, both branded and generic ones. Counterfeit medicines may include products containing correct or wrong ingredients; without active or with insufficiently or over-active ingredients, or with fake packaging. Many sources of information have been explored, including reports from the national medicine regulatory authorities, pharmaceutical companies and literature data. Since the time counterfeit drugs first appeared, they have become more sophisticated and more difficult to be detected. The World Health Organisation estimate is that up to 1% of medicines available in the developed world are likely to be counterfeit. This figure rises to 10% globally, although in some developing countries it is 50%. The World Health Organisation estimate is that 50% of medicines available via the internet are counterfeit. The knowledge about counterfeit drugs should be used to educate students of pharmacy and medicine, health professionals and patients. The most important players in campaign against counterfeit medicines are health professionals. Pharmacists and doctors should stay vigilant and report suspicious products, and consider counterfeits as a possible cause of adverse reactions or therapeutic failure. Patients should inform their pharmacists and doctors if they suspect any irregularity concerning their medication, if they experience side effects or a decrease in beneficial effect. The crucial step in the prevention of counterfeit medicines is to get supplied from reliable sources, i.e. licensed pharmacies. PMID- 21789920 TI - [Prevention of sudden cardiac death by the implantable cardioverter defibrilator]. AB - INTRODUCTION; Sudden cardiac death or, as it is also called, a modern man's killer occurs a few hours after the beginning of the disease. Sudden death is the one that happens within an hour from the onset of the subjective discomforts regardless of the existence of any previous disease. According to modern statistics, 450.000 people die suddenly in the USA and 150,000 in Germany. CAUSES OF SUDDEN DEATH: The most frequent causes of sudden death are cardiologic or, in other words, a heart rhythm disorder such as ventricular tachycardia, ventricular fibrillation and bradycardiac rhythm disorder. All these reasons can be efficiently prevented by the implantation of the cardioverter defibrillators. IMPLANTABLE CARDIOVERTER DEFIBRILLATOR: In comparison with the already known medications, the defibrillator seems to be the most efficient in prevention of sudden cardiac death. This fact has been confirmed by large multicentre studies. The implantation itself is a routine procedure. It lasts about an hour and it often passes without any complications. The patient leaves the hospital a few days after the procedure. About 150 of these procedures are performed per year at the Institute of Cardiovascular Diseases Vojvodina. The Social Insurance Fund bears medical costs and the patient only pays the participation fee, which is symbolical if compared to the value and use of the device. Owing to this fact, this device is available to every patient thus making the efficient sudden cardiac death prevention possible. PMID- 21789921 TI - [Juvenile myasthenia]. AB - INTRODUCTION: Juvenile myasthenia is a chronic autoimmune neuromuscular disease characterized by varying degrees of fluctuating, painless muscle weakness and rapid fatigue of any muscles under voluntary control. Juvenile myasthenia is a form of myasthenia appearing in adolescent age, representing 10% to 15% of all cases of myasthenia gravis. Juvenile myasthenia is presented by a defect in the transmission of nerve impulses to muscles, resulting from a breakdown in the normal communication between nerves and muscles. In myasthenia, antibodies produced by the body's own immune system block, alter, or destroy the receptors for acetylcholine. Juvenile myasthenia is neither directly inherited nor is it contagious. SIGNS AND SYMPTOMS: The first noticeable symptoms may be eye muscle weakness, difficulty in swallowing, or slurred speech. Juvenile myasthenia usually affects muscles innervated by the cranial nerves (face, lips, tongue, neck and throat), but it can affect any muscle group. Symptoms vary in type and severity with typical periods of exacerbation interspersed with periods of remission. When the muscles necessary for breathing are affected, a patient is said to be in a myasthenic crisis, which is a life-threatening situation. DISEASE OUTCOME AND TREATMENT: Juvenile myasthenia produces sporadic but progressive weakness and abnormal fatigability of striated (skeletal) muscles, exacerbated by exercise and repeated movement, but improved by rest and anticholinesterase drugs. Juvenile myasthenia follows an unpredictable course of recurring exacerbations and periodic remissions. With current therapies, however, most cases of juvenile myasthenia are not as serious as the name implies. Although there is no known cure, drug treatment has improved prognosis and allows patients to lead relatively normal lives, except during exacerbations. PMID- 21789922 TI - [Effects of functional electrical therapy on upper extremity functional motor recovery in patients after stroke--our experience and future directions]. AB - INTRODUCTION: New neurorehabilitation together with conventional techniques provide methods and technologies for maximizing what is preserved from the sensory motor system after cerebrovascular insult. The rehabilitation technique named functional electrical therapy was investigated in more than 60 patients in acute, subacute and chronic phase after cerebrovascular insult. The functional sensory information generated by functional electrical therapy was hypothesized to result in the intensive functional brain training of the activities performed. FUNCTIONAL ELECTRICAL THERAPY: Functional electrical therapy is a combination of functional exercise and electrical therapy. The functional electrical therapy protocol comprises voluntary movement of the paretic arm in synchrony with the electrically assisted hand functions in order to perform typical daily activities. The daily treatment of 30 minutes lasts three weeks. The outcome measures include several tests for the evaluation of arm/hand functionality: upper extremity function test, drawing test, modified Aschworth scale, motor activity log and passive range of movement. RESULTS OF FUNCTIONAL ELECTRICAL THERAPY STUDIES: Results from our several clinical studies showed that functional electrical therapy, if applied in acute and subacute stroke patients, leads to faster and greater improvement of functioning of the hemiplegic arm/hand compared to the control group. The outcomes were significantly superior at all times after the treatment for the higher functioning group. DISCUSSION: Additional well planned clinical studies are needed to determine the adequate dose of treatment (timing, duration, intensity) with functional electrical therapy regarding the patient's status. A combination with other techniques should be further investigated. PMID- 21789923 TI - [Analysis of suspected adverse reactions following immunization against pandemic influenza]. AB - INTRODUCTION: The surveillance on adverse reaction following immunization was aimed at recording all adverse events possibly related with vaccines. During the implementation of immunization strategy against pandemic influenza A(H1N1) in 2009. the post-marketing comprehensive surveillance was suggested to be conducted due to limited clinical experience in applying this particular vaccine and because of the fact that some vaccines had been licensed only on the basis of the data regarding their quality. MATERIAL AND METHODS: The passive surveillance on adverse events following immunization was conducted simultaneously with immunization campaign against pandemic influenza in the Autonomous Province of Vojvodina. Reporting of adverse events was conducted by health care service through a specially designed questionnaire. RESULTS: In the period from December 17th 2009 to February 7th 2010, of the total number of 55720 people who were vaccinated, 50433 received one dose and 5287 received two doses of vaccine. The total number of doses administered was 61007. During the observed period, some adverse reactions were recorded in 37 people, the rate of occurrence of adverse reactions being 6.6 per 10.000 vaccinated. Since the majority of patients had several symptoms and signs, the number of recorded clinical manifestations was much higher (140) than the number of patients with reactions. The dominant symptoms and signs were fever (51.4%), weakness/fatigue (48.6%), headache (40.5%) and myalgia (31.5%). The reactions in the majority of patients were mild and transient. Only two patients sought medical care and one was hospitalised. Since the immunization coverage was very small, it was not possible to record rare adverse events, whose expected incidence is, anyway, very low. CONCLUSION: Surveillance on adverse reaction following immunization represents an important component of immunization program, especially when new vaccines are introduced. Therefore, this form of surveillance in our country needs further improvement in order to provide more complete information on occurrence and characteristics of adverse reactions following immunization. PMID- 21789924 TI - [Adjunctive therapy with brinzolamide in patients on travoprost treatment]. AB - INTRODUCTION: This study was aimed at evaluating the safety and efficacy of brinzolamide 1% suspension (Azopt 1%) and travoprost 0.004% (Travatan) combined therapy in patients with open-angle glaucoma or ocular hypertension who are in need of additional intraocular pressure lowering. MATERIAL AND METHODS: This is a prospective, three-month, open-label, clinical study. Forty patients (80 eyes) with primary open-angle glaucoma or ocular hypertension on Travatan treatment and with unsatisfactory results in lowering intraocular pressure were included in the study. The qualifying intraocular pressure on previous treatment with Travatan (at least 6 weeks) was 22-36 mmHg in at least one eye at 8 a.m. intraocular pressure measurements at three eligibility visits. The patients received brinzolamide 1% twice a day in addition to travoprost 0.004% given once a day in the evening for 3 months. The follow-up examinations assessing the safety and efficacy of combined therapy of brinzolamide 1% and travoprost 0.004% were performed after 1 and 3 months. RESULTS: Adjunctive therapy with brinzolamide resulted in statistically significant reductions in intraocular pressure from the travoprost baseline at all visits. Treatment with brinzolamide/travoprost caused statistically significant sustained reduction in intraocular pressure with the reduction of 17.39% (p < 0.001) after 4 weeks and 20.08% (p < 0.001) after 12 weeks. The intraocular pressure change from the baseline ranged from -3.9 mmHg after 4 weeks to -4.48 mmHg after 12 weeks. The most frequently related adverse effect was abnormal taste and blurred vision. CONCLUSION: Brinzolamide 1% (b.i.d) used adjunctively with travoprost 0.004% (q.d.) lowers intraocular pressure significantly compared to travoprost alone. Both drugs were well tolerated and safe in the studied patients. PMID- 21789925 TI - Dysplastic nevus--a risk factor of developing skin melanoma clinical and epidemiological study with retrospective review of literature. AB - Dysplastic nevus is a risk factor for developing skin melanoma. The aim was to analyze patients with both skin melanoma and dysplastic nevi. A 10-year retrospective analysis (1999-2009) was conducted at the Department for Plastic and Reconstructive Surgery, Clinical Centre Vojvodina. During the observed time interval, of 482 patients treated for skin melanoma, 165 (34.2%) had also dysplastic nevi. Melanoma developed more often de novo (67.9%) and 32.1% by malignant alteration. The most dominant type of melanoma was nodular one (70.3%), the most frequent depth being 3.1-4mm (40.6%). The highest incidence of melanoma (32.1%) was in patients aged from 51 to 60 years. The 5- and 10-year survival rates were 72.7% and 50.3%, respectively. Our results correspond to those found in literature except for the fact that the majority of diagnosed melanomas were of nodular type with worse prognosis. PMID- 21789926 TI - [Prophylaxis of infective endocarditis]. AB - INTRODUCTION: Infective endocarditis is defined as an infection of the endothelial surface of the heart and heart valves, above all. It is a great challenge for doctors to diagnose infective endocarditis especially in primary health care, because this is a disease in evolution, bearing in mind changes in epidemiological and clinical characteristics, which developed in the last decades. Even today this is a very severe and insidious disease, with poor prognosis and high mortality. PREVENTION OF INFECTIVE ENDOCARDITIS: Although previous guidelines proposed a limitation to prophylaxis in patients at increased risk of adverse outcome of infective endocarditis, new guidelines recommend the principles of antibiotic prophylaxis when performing procedures at risk of infective endocarditis in patients with predisposing cardiac conditions, and limit its indication to patients at the highest risk of infective endocarditis undergoing the highest risk procedures. CONCLUSION: Despite the fact that previous guidelines for diagnostics and treatment of infective endocarditis were published only several years ago, the Task Force on Prevention, Diagnosis and Treatment of Infective Endocarditis of the European Society of Cardiology identify infective endocarditis as a clearly evolving disease, with changes in its microbiological profile and higher incidence of health care associated cases which has brought about a need for new recommendations to help health care providers in making clinical decisions including preventive measures and antibiotic prophylaxis. As a novelty, a group of patients at the highest risk of infective endocarditis was defined as well as the type of procedures at risk divided into four categories. PMID- 21789927 TI - Adenomyomatosis of the gallbladder--case report. AB - Adenomyomatosis of the gallbladder is a benign, mostly asymptomatic condition of an unknown aetiology. Hyperplastic changes in the gallbladder wall cause an overgrowth of the mucosa, thickening of the muscular wall, and formation of intramural diverticula or sinus tracts termed Rokitansky-Aschoff sinuses. Adenomyomatosis is divided on general, segmental and localised. Ultrasound examination, computerized tomography and magnetic resonance are used in diagnostic procedure. The importance of the disease lies in the fact that it can cause recurrent right upper quadrant pain so it must be concerned in resolving pain cause. This paper was aimed at explaining the aetiology of the disease, its clinical manifestation, making diagnosis and therapy in order to make its diagnosis and treatment possible. PMID- 21789928 TI - [Cavernous hemangioma of the lung]. AB - INTRODUCTION: Cavernous hemangiomas are benign vascular tumours rarely described in the lungs. Symptoms include respiratory distress, cardiac failure and massive haemoptysis, but they are mostly asymptomatic. CASE REPORT: A 67-year-old woman was referred to our institute and treated for pneumonia. A computed tomography scan of the thorax showed an infiltrative mass about 46mm in its greatest dimension in the right upper lobe. The mass was in contact with the mediastinal pleura. Since bronchial biopsy and FNAC did not reveal the aetiology of the lesion, the video-assisted thoracic surgery with right anterolateral thoracotomy and enucleation was performed. The intraoperative and postoperative pathohistological study showed cavernous hemangioma and this diagnosis was confirmed on immunohistochemical staining. CONCLUSION: In spite of its benign behaviour and mostly asymptomatic clinical course it is necessary to consider cavernous hemangioma in the differential diagnosis of other pulmonary lesions. The definitive diagnosis can be made only by histopathological and immunohistochemical examination. PMID- 21789929 TI - [The most frequent causes of ischemic stroke in young adults]. AB - INTRODUCTION: Pathogenesis of ischemic stroke in young adults is heterogeneous, thus making differential diagnosis very broad. MATERIAL AND METHODS: The study comprised 60 ischemic stroke patients of both sexes aged 15-45 years who were treated at the Department of Neurology of the Clinical Centre of Vojvodina. Information about sex and age, detailed history, risk factors for ischemic stroke were obtained for all patients who underwent neurological examination as well. Diagnostic procedures applied in all patients included brain computed tomography and/or magnetic resonance imaging, routine laboratory tests, Doppler imaging of extra and endocranial blood vessels and coagulation tests. Contrast and/ or transesophageal echocardiography, immunological blood assays, magnetic resonance angiography and/or computed tomography angiography and/or conventional angiography, immunological tests, assessment of levels of natural coagulation inhibitors, toxicological examination, etc. were performed in selected patients. RESULTS: Causes of ischemic stroke were determined according to the Trial of ORG 10172 in Acute Stroke Treatment criteria. The most frequent were the so called other causes of ischemic stroke, which were found in 26.7% patients. The second most frequent cause was cardiac embolisation, found in 25%. The cause of ischemic stroke remained undetermined in 21.7% of all patients. CONCLUSION: Aetiology of ischemic stroke in young adults is diverse and demands thorough diagnostic evaluation. PMID- 21789930 TI - [Oral health assessment of Hungarian adult population based on epidemiologic examination]. AB - A representative national survey by the dentists of the Department of Prosthodontics, Semmelweis University was performed to assess oral health conditions of Hungarian adult population before joining the European Union. The aim of this study was to evaluate periodontal conditions of the population from data collected in the survey and to investigate the associations between gender, age and demographic regions and the prevalence of periodontal problems. The 2 years long nationwide investigation followed the WHO criteria (World Health Organization, 1997) and assessed 4606 person throughout all regions of the country. Periodontal conditions and treatment needs of 4153 person were assessed in intraoral examinations by Community Periodontal Index (CPI) method. Age, gender, demographic regions were recorded on questionnaires. According to our findings CPI 2 was the most frequent finding in all age groups which primarily reflected poor oral hygiene. When we consider gender differences, CPI 3 and CPI 4 were more frequent among males while women had CPI 0 and CPI 2 with higher frequency. Our findings reflect regional differences of periodontal health conditions as 16% of the population of the capitol and its surroundings had healthy periodontal condition however we could find CPI 0 only in 5-8% of Middle and South-Danubium population. Findings of our epidemiologic survey call attention on poor oral hygene of the population. There is a need in Hungary for better oral health education of the population, more preventive programs and action plans to promote regular dental office attendance. PMID- 21789931 TI - [Effect of decontaminating solutions on titanium surface: an in vitro study of human epithelial cell culture]. AB - INTRODUCTION: The effects of three different decontaminating solutions in clinical use for peri-implantitis therapy on the chemical structure and surface roughness of commercially pure (CP) Ti were investigated. A further aim was to survey the response of the biological environment to these changes, by examining the attachment and proliferation of human epithelial cells after treatment of the Ti surfaces with these solutions. MATERIALS AND METHODS: CP (grade 4) machined titanium discs (CAMLOG Biotechnologies AG, Switzerland) were treated with 3% H2O2 (5 min), saturated citric acid (pH = 1; 1 min) or chlorhexidine gel (CHX, 5 min). The surface properties were followed through the use of X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The epithelial cell attachment and proliferation was examined by means of 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) and bicinchoninic acid (BCA) protein content assays. RESULTS: XPS showed an intact TiO2 layer on each sample and CHX was adsorbed by the surface, as C-O and/or C=O bond formation was revealed. AFM results gave no significant changes in the roughness after treating the surfaces with the cleaning solutions. While MTT and BCA assays did not show significant differences in epithelial cell attachments, the cell proliferation was significantly increased after H2O2 treatment as compared to CHX (not shown by BCA assays). CONCLUSIONS: The applied decontaminating agents do not damage the Ti surface. H2O2 can be used effectively in decontaminating the implants affected by peri-implantitis, as the human epithelial cell growth was improved, in contrast with CHX. PMID- 21789932 TI - [The management of a single Miller-I type gingival recession at the maxillar incisor with single tunnel technique combined with enamel matrix derivative and connective tissue graft. A case report]. AB - Gingival recession defect in the dentition are routinely encountered in periodontal practice and presents a challenge for a periodontist. Mucogingival surgical procedures aim to restore both gingival function and aesthetics. Recently as the population is getting to be more concerned about aesthetics the aesthetical indications are more relevant. In the presented case a coronally advanced flap prepared by single tunnel technique and combined with subepithelial connective tissue graft and enamel matrix derivatives (EMD) has been employed for root coverage in a Miller's class I recession. The combined technique used resulted in approximately 100% root coverage in the treated site after 6 months. Treatment outcomes met the patient's aesthetic demands and also eliminated her root sensitivity. PMID- 21789933 TI - [The specific panoramic radiographic signs and their relation with inferior alveolar nerve injuries after mandibular third molar surgery]. AB - The aim of the authors was to describe the classic specific panoramic signs (indicating a close spatial relationship between dental canal and third molar's root) on panoramic radiographic images and determine their role in the risk assessment, predicting inferior alveolar nerve (IAN) paresthesia after lower third molar removal. The authors represented an informative case, where the IAN was visible during the surgery. The exact knowledge of classic panoramic radiographic signs should help the determination of "high risk" cases predicting IAN paresthesia after mandibular third molar removal. The authors keep panoramic radiography rather a routine than the most superior diagnostic tool in third molar surgery. PMID- 21789934 TI - [Risk assessment of periodontal disease in Hungary]. AB - In this study, risk determinants were assessed for periodontal disease in the oral health survey of a representative Hungarian adult population sample. 4153 individuals participated in the study after formal consent. Participants were questionned on level of education, dental office attendance, smoking habits, oral hygiene habits and general health conditions. Quality of fixed partial dentures (FPD) were evaluated. Periodontal health status was assessed with the CPI method according to WHO criteria. When the prevalence of CPI scores was assessed by educational level, significant differences were found between groups. With increasing levels of education, a significantly higher percentage of subjects visited the dental office regularly. Higher prevalence of CPI 0 was found among those with higher level of education but there was also high prevalence of CPI 2, representing bad oral hygiene in the highly educated group. Findings of our study showed high percentage (66%) of the population attending the dental office only in case of emergency. The investigation revealed destructive effect of unsatisfactory construction of FPD on the periodontium. Healthy periodontium (CPI 0) was found among 16% of those wearing no FPD and 9% among FPD-wearers. The prevalence of deep periodontal pockets (CPI 4) was 1,6 times higher among smokers as non-smokers. Oral health statistics play an important role in planning for improvement of dental health care. Hungary needs effective prevention programs and emphasize on regular dental office attendance of individuals to improve the nation's oral health status. PMID- 21789935 TI - [Replacement of extracted tooth by means of implant-supported direct abutment. A case report]. AB - Abutment manipulation, namely repeated screwing and unscrewing may have an affect on the final marginal bone level, consequently, soft tissue position around endosseous implants. In order to maintain the crestal bone level constant and avoid the apical recession of gingiva final abutment (Direct Abutment, Astra Tech) has been connected to submerged OsseoSpeed 4.5 dental implant (Astra Tech) in position of tooth 14, immediately after second surgical exposure. Following a healing period of three weeks, impression was taken using closed tray system and plastic impression pic-up for laboratory manufacturing of zirconium crown restoration. The functional and aesthetic result of the reconstruction was highly met patient is the satisfaction. The maintenance of marginal bone level and the excellent health of the peri-implant tissues, as registered at 6-month recall, may support the benefit of the idea of final abutment insertion immediately after one-, or two-stage surgery. PMID- 21789936 TI - [Possibilities of clinical testing of osseointegration in oral implants]. AB - The osseointegration of oral implants is of utmost importance as far as the success of implant prosthetics is concerned. In clinical practice osseointegration can only be tested indirectly. The loading of implants is usually linked to osseointegration as a condition. Under some circumstances implants can be loaded before osseointegration is completed. The present study reviews the various methods of testing osseointegration and the conditions of immediate loading. In the present study the changes in the stability of 59 implants restored with screw-retained superstructures and partly immediately loaded, were observed over a period of several years, with the help of the Periotest method. Based on the statistical evaluation of the results, a significant correlation was found between implant insertion torque and primary stability. A difference was found between the stability of implants in the upper and lower jaws. A typical curve in the temporal changes of implant stability was described. PMID- 21789937 TI - Craig Richmond driving best-in-class revenue cycle improvement. PMID- 21789938 TI - Medicare spending-again in the spotlight. PMID- 21789939 TI - Culture clash the impact of culture on physician-hospital integration. AB - Hospitals and physicians that are undertaking a merger should take five key steps to avoid a culture clash that could derail the integration initiative: Clearly identify who the physician and hospital leaders will be. Form a small, agile work team to manage the transition. Communicate with staff every step of the way. Be sensitive to feelings of uncertainty that staff may experience as a result of the change. Implement a clear ongoing process to promote cultural alignment. PMID- 21789941 TI - HFMA examines value in health care. PMID- 21789940 TI - Budget planning under payment reform. AB - Healthcare reform makes budgeting topline reimbursement, volume, payer mix, and collections more difficult than in the past. Finance should take the lead at educating physicians and operators on what reform will mean to unit reimbursement, collections, volume, and payer mix. The team should analyze future scenarios for each variable before finalizing the budget, rather than assuming revenue cycle or managed care will come through with a last-second rate increase as they have in the past. PMID- 21789942 TI - Delivering during a time of need. PMID- 21789943 TI - Managing the risks of accountable care. AB - Hospitals and health systems should assess the risks of participation in Medicare's Shared Savings Program before deciding whether to participate: Start up costs will likely be prohibitive. The ACO will lack key tools needed to drive down unnecessary medical costs. Participating providers would have to accept significant downside risk for costs over which they have no control. ACOs generating significant savings in a program year would still face numerous preconditions to-and limitations on-payment. PMID- 21789944 TI - The value of shared services. AB - A multisite shared services organization, combined with a robust business continuity plan, provides infrastructure and redundancies that mitigate risk for hospital CFOs. These structures can position providers to do the following: move essential operations out of a disaster impact zone, if necessary. Allow resources to focus on immediate patient care needs. Take advantage of economies of scale in temporary staffing. Leverage technology. Share in investments in disaster preparedness and business continuity solutions PMID- 21789945 TI - Understanding hospital professional liability claim costs. AB - Managing the total cost of professional liability should be a top priority for health systems as professional liability costs will increase in coming years. The frequency of hospital professional liability claims has entered a period of modest growth. The severity of claims continues to grow, with claim severity projected to increase 4 percent in 2011. The combined effect of frequency and severity indicates HPL loss rates are expected to increase 5 percent in 2011. PMID- 21789946 TI - Tax-exempt bank loans still an option for providers. AB - In evaluating the potential for tax-exempt bank financing, healthcare organizations should carefully consider: Pricing. Loan structure. Security requirements (such as financial covenants and default remedies). PMID- 21789947 TI - 5 things you should know about co-management arrangements. AB - Key factors that a hospital finance leader should focus on when considering a potential co-management agreement with physicians, in which the physicians are compensated at fair market value, include: Fee structure of the agreement. The quality metrics that will be used. Benchmarking to set appropriate targets for metrics. Historical performance against the metrics. Legal guidelines regarding such agreements. PMID- 21789948 TI - Physician compensation 5 mistakes, 1 solution. AB - Compensation models for employed physicians should be based on productivity and adhere to four key principles: Focus on factors physicians can control. Include productivity-based risk and reward. Allow physicians to control personal income. Tie reward/consequence to behavior in a timely manner. PMID- 21789949 TI - Capital efficiency and integrated health system designs. AB - Community health system design plays a role in capital efficiency, including returns on invested capital. This role becomes important in a future healthcare world of pressured payments, increased consolidation, constrained resources, and stretched community service missions and budgets. PMID- 21789950 TI - Overcoming barriers to EHR adoption. AB - Implementing an electronic health record (EHR) system that links medical facilities in three states taught PeaceHealth these valuable lessons: Establish clinical standards. Talk to clinicians early on. Look for an EHR with clinical decision support capabilities. PMID- 21789951 TI - Leaders need to say "no". PMID- 21789952 TI - HFMA recognizes future financial leaders. PMID- 21789953 TI - The transformative role of healthcare IT in accountable care. PMID- 21789954 TI - What would have happened if Darwin had known Mendel (or Mendel's work)? AB - The question posed by the title is usually answered by saying that the "synthesis" between the theory of evolution by natural selection and classical genetics, which took place in 1930s-40s, would have taken place much earlier if Darwin had been aware of Mendel and his work. What is more, it nearly happened: it would have been enough if Darwin had cut the pages of the offprint of Mendel's work that was in his library and read them! Or, if Mendel had come across Darwin in London or paid him a visit at his house in the outskirts! (on occasion of Mendel's trip in 1862 to that city). The aim of the present paper is to provide elements for quite a different answer, based on further historical evidence, especially on Mendel's works, some of which mention Darwins's studies. PMID- 21789955 TI - Darwin's "beloved barnacles": tough lessons in variation. AB - In 1846, burdened by insecurity and self-doubt, and having been convinced that he needed to study some group of organisms closely, Darwin embarked on an eight-year odyssey in the protean and perplexing world of barnacles. At the time, he was searching for evidence in support of his theory of evolution by natural selection. In the course of his long study of barnacles, however, he was not just validating his preexisting theoretical system, but was also modifying his views on such fundamental aspects as the universality of individual variation, which is the focus of this paper. According to this notion, the members of any population of living things are expected to exhibit sufficient differences from one another for natural selection to operate. By emphasizing the theoretical value of the barnacle project, my analysis contributes to the historiographic tradition which highlights the significance of the period between the first comprehensive formulation of the theory of evolution by natural selection in 1844 and its urgent publication in the late 1850s. In the course of these years, Darwin's theory was not just accumulating empirical laurels, but was also expected to adapt to a changing conceptual landscape. PMID- 21789956 TI - From metaphor to practices: The introduction of "information engineers" into the first DNA sequence database. AB - This paper explores the introduction of professional systems engineers and information management practices into the first centralized DNA sequence database, developed at the European Molecular Biology Laboratory (EMBL) during the 1980s. In so doing, it complements the literature on the emergence of an information discourse after World War II and its subsequent influence in biological research. By the careers of the database creators and the computer algorithms they designed, analyzing, from the mid-1960s onwards information in biology gradually shifted from a pervasive metaphor to be embodied in practices and professionals such as those incorporated at the EMBL. I then investigate the reception of these database professionals by the EMBL biological staff, which evolved from initial disregard to necessary collaboration as the relationship between DNA, genes, and proteins turned out to be more complex than expected. The trajectories of the database professionals at the EMBL suggest that the initial subject matter of the historiography of genomics should be the long-standing practices that emerged after World War II and to a large extent originated outside biomedicine and academia. Only after addressing these practices, historians may turn to their further disciplinary assemblage in fields such as bioinformatics or biotechnology. PMID- 21789957 TI - The chemical characterization of the gene: vicissitudes of evidential assessment. AB - The chemical characterization of the substance responsible for the phenomenon of "transformation" of pneumococci was presented in the now famous 1944 paper by Avery, MacLeod, and McCarty. Reception of this work was mixed. Although interpreting their results as evidence that deoxyribonucleic acid (DNA) is the molecule responsible for genetic changes was, at the time, controversial, this paper has been retrospectively celebrated as providing such evidence. The mixed and changing assessment of the evidence presented in the paper was due to the work's interpretive flexibility--the evidence was interpreted in various ways, and such interpretations were justified given the neophytic state of molecular biology and methodological limitations of Avery's transformation studies. I argue that the changing context in which the evidence presented by Avery's group was interpreted partly explains the vicissitudes of the assessments of the evidence. Two less compelling explanations of the reception are a myth-making account and an appeal to the wartime historical context of its publication. PMID- 21789958 TI - Clarifying creationism: five common myths. PMID- 21789959 TI - Tooth regeneration: a revolution in stomatology and evolution in regenerative medicine. AB - A tooth is a complex biological organ and consists of multiple tissues including the enamel, dentin, cementum and pulp. Tooth loss is the most common organ failure. Can a tooth be regenerated? Can adult stem cells be orchestrated to regenerate tooth structures such as the enamel, dentin, cementum and dental pulp, or even an entire tooth? If not, what are the therapeutically viable sources of stem cells for tooth regeneration? Do stem cells necessarily need to be taken out of the body, and manipulated ex vivo before they are transplanted for tooth regeneration? How can regenerated teeth be economically competitive with dental implants? Would it be possible to make regenerated teeth affordable by a large segment of the population worldwide? This review article explores existing and visionary approaches that address some of the above-mentioned questions. Tooth regeneration represents a revolution in stomatology as a shift in the paradigm from repair to regeneration: repair is by metal or artificial materials whereas regeneration is by biological restoration. Tooth regeneration is an extension of the concepts in the broad field of regenerative medicine to restore a tissue defect to its original form and function by biological substitutes. PMID- 21789960 TI - Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues. AB - When adipose-derived stem cells (ASCs) are retrieved from the stromal vascular portion of adipose tissue, a large amount of mature adipocytes are often discarded. However, by modified ceiling culture technique based on their buoyancy, mature adipocytes can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and undertake multipotent capacities. Compared with ASCs and other adult stem cells, DFAT cells showed unique advantages in their abundance, isolation and homogeneity. In this concise review, the establishment and culture methods of DFAT cells are introduced and the current profiles of their cellular nature are summarized. Under proper induction culture in vitro or environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic and myogenic potentials. In angiogenic conditions, DFAT cells could exhibit perivascular characteristics and elicit neovascularization. Our preliminary findings also suggested the pericyte phenotype underlying such cell lineage, which supported a novel interpretation about the common origin of mesenchymal stem cells and tissue specific stem cells within blood vessel walls. Current research on DFAT cells indicated that this alternative source of adult multipotent cells has great potential in tissue engineering and regenerative medicine. PMID- 21789961 TI - Comparison of microRNA profiles of human periodontal diseased and healthy gingival tissues. AB - MicroRNAs (miRNAs) have been demonstrated to play an important role in regulation of the immunoinflammatory response; however, the function of miRNAs in periodontal inflammation has not been investigated. The objective of this study was to explore the properties of miRNAs in periodontal inflammation by comparing miRNA profiles of inflamed and healthy gingival tissues. Gingival tissues were obtained from 10 periodontitis patients and 10 healthy subjects. After RNA extraction, miRNA profiles were analyzed by microarray, and expression levels of selected miRNAs were confirmed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Analyses using two computational methods, Targetscan and MicroRNA.org, were combined to identify common targets of these miRNAs. Finally, the individual miRNA expression levels of three toll-like receptor (TLR)-related miRNAs from inflamed and healthy gingival tissues were evaluated by RT-PCR. Ninety-one miRNAs were found to be upregulated and thirty four downregulated over two-fold in inflamed gingival tissue compared with those in healthy gingival tissue. Twelve selected inflammatory-related miRNAs, hsa-miR 126*, hsa-miR-20a, hsa-miR-142-3p, hsa-miR-19a, hsa-let-7f, hsa-miR-203, hsa-miR 17, hsa-miR-223, hsa-miR-146b, hsa-miR-146a, hsa-miR-155, and hsa-miR-205 showed comparable expression levels by microarray and real-time quantitative RT-PCR analyses. In addition, the putative inflammation targets of these miRNAs were predicted, and three that were tested (hsa-miRNA-146a, hsa-miRNA-146b, and hsa miRNA-155), showed significant differences between inflamed and healthy gingiva. This remarkable difference in miRNA profiles between periodontal diseased and healthy gingiva implicates a probable close relationship between miRNAs and periodontal inflammation. The data also suggest that the regulation of TLRs in periodontal inflammation may involve miRNA pathways. PMID- 21789962 TI - Tooth anatomy risk factors influencing root canal working length accessibility. AB - The aim of this study was to analyze the specific influence of root canal anatomy on the accessibility of working length during root canal therapy. Four hundred seventy-six root canal therapy cases (amounting to a total of 1 005 root canals) were examined. The anatomy risk factors assessed in each case included: tooth type (tooth location), root canal curvature, and root canal calcification, as well as endodontic retreatment. The investigation examined the correlation between each of these anatomic factors and the working length, with statistical analysis consisting of Chi-square tests and multiple logistic regression analysis. In an independent factor analysis, tooth type (tooth location), root canal curvature, canal calcification, and endodontic retreatment were determined to be the primary risk factors. In a multiple-factor regression model, root curvature and canal calcification were found to most significantly influence root canal working length accessibility (P<0.05). Root canal anatomy increases the difficulty of root canal preparation. Appropriate consideration of tooth anatomy will assist in accurate determination of preparation difficulty before instrumentation. This study alerts clinical therapists to anatomical factors influencing the working length accessibility, and allows for a direct estimate of success rate given in situ measurements of tooth factors during the root canal treatment procedure. PMID- 21789963 TI - Primary tumor prevalence has an impact on the constituent ratio of metastases to the jaw but not on metastatic sites. AB - This article provides an overview of metastases to jaws (MJ), mainly concerning the differences between American and Chinese patients, and exploring the relationship between the primary tumors' prevalence (PTP) and constituent ratio of MJ. Information concerning of 399 MJ cases in 215 papers, including one new case in our hospital, was subjected to statistic analysis. The main clinical features of MJ, such as constituent ratio of PTP and that of MJ, metastatic sites, treatments, and prognosis were summarized. Breast, lung, kidney, prostate and thyroid (in descending order) were the leading primary sites of MJ. Furthermore, the constituent ratio of MJ was found to be correlated with that of PTP in all subjects including American and Chinese subjects in our study. As to metastatic sites in the mandible, a specific "M" shaped pattern appeared regardless of the tumor type or constituent ratios of MJ were in all subjects. Almost all subjects received traditionally palliative treatments, and the prognosis was quite poor. The PTP had a significant impact on the constituent ratio of MJ. However, it was the properties of the microenvironment rather than characteristics or constituent ratios of tumor cells, that decided the metastatic sites in various tumor subjects. PMID- 21789964 TI - Six cases report of differential diagnosis of periapical diseases. AB - The distinction of some particular forms of periapical area, involving diseases from regular periapical disease, is a matter of considerable importance when choosing a correct treatment. The aim of this study is to describe the differential diagnosis of periapical diseases from six rare cases in clinical practice. The six rare cases are examples of situations where it is difficult to make a differential diagnosis in clinical practice. By retrospective surveys on the clinical examination, radiographs and pathological results, six patients referred to endodontic treatment in our department were analyzed for the accuracy of diagnosis and therapy. The pathoses of the six cases included two atypical radical cysts, periapical cemental dysplasia, cemento-ossifying fibroma, thymus cancer metastasis in the periapical site and tuberculosis. This report indicates that endodontists should be cognizant of a few particular circumstances when clinically treating periapical diseases. PMID- 21789965 TI - Changes in oral trace gas concentrations following orthognathic surgery and intermaxillary fixation: a case study using selected ion flow tube mass spectrometry. AB - Orthognathic surgery is frequently accompanied by intermaxillary fixation. Intermaxillary fixation impedes the maintenance of effective oral hygiene and prolonged fixation can result in periodontal disease. A potential shorter term effect is the generation of oral malodour. It is unclear, however, as to how the production of malodorous compounds in the oral cavity is altered post-surgery. Oral air concentration of sulphur containing compounds, short chain organic acids, ammonia, isoprene and acetone were measured using selected ion flow tube mass spectrometry in a patient who had undergone orthognathic surgery with subsequent intermaxillary fixation. Total sulphide levels rose approximately 5 fold during fixation with metal ties, with smaller increases recorded for the other compounds measured with the exception of isoprene which remained close to baseline levels. Organic acid levels declined markedly once elastic ties had replaced metal ties, with a lesser reduction being observed in sulphide levels, with both declining further after the commencement of a chlorhexidine-containing mouthwash. These data suggest that bacterial generation of a variety of malodorous compounds increases markedly following intermaxillary fixation. This single case also suggests that the use of elastic ties and effective oral hygiene techniques, including the use of chlorhexidine mouthwash, may help ameliorate such post-surgical effects. PMID- 21789966 TI - Is the strange case of mugwort sensitivity in ragweed-allergic subjects coming eventually to a solution? PMID- 21789967 TI - Has allergenic pollen an impact on non-allergic diseases? AB - Recent observations suggest that pollen do not only interacts with the human immune system to elicit an allergic response in susceptible individuals. It would have a much broader impact on human health. This applies more especially, yet not exclusively, to three groups of diseases: non-allergic respiratory conditions, cardio- and cerebrovascular accidents, and psychiatric disorders including suicide and suicide attempt. At present, the reasons for these unexpected connections are only hypothetical, and require further exploration in larger samples, but there is perhaps a multitude of them. One must therefore favour a holistic approach of pollen and its impact on human health. PMID- 21789968 TI - Analysis of hypersensitivity to oleaceae pollen in an olive-free and ash-free area by commercial pollen extracts and recombinant allergens. AB - BACKGROUND: Olive pollen sensitization is surprisingly frequent in Milan, an area that is virtually both olive- and ash-free. OBJECTIVE: To establish the prevalence of olive pollen sensitization north of Milan, and to investigate the allergens involved. METHODS: 300 pollen-allergic patients living in this area were randomly selected. Based on SPT results, olive pollen reactors were classified as multi-sensitized, oligo-sensitized, or mono-sensitized. IgE to markers of primary sensitization to olive pollen (Ole e 1), as well as to pollen pan-allergens such as profilin (Phl p 12) or polcalcin (Phl p 7) were measured. Further, the putative cross-reactivity between grass group XI allergen and Ole e 1 was investigated. RESULTS: 107 (36%) patients were sensitized to olive pollen; 67 (63%) were multi-sensitized, while only 4 (4%) were mono-sensitized. Specific IgE to Ole e 1 were found in 32/46 (70%) cases; 22 of them (69%) co-recognized pollen pan-allergens, as shown by IgE reactivity to Phlp 7 and/or Phlp 12. Sera from 14 (30%)patients did not react to Ole e 1; of these, 10 (71%) were pan allergens reactors. No correlation was found between IgE levels to Phl p 11 and Ole e 1. CONCLUSIONS: A majority of olive pollen-sensitized subjects seen in the surroundings of Milan are truly allergic to Oleaceae. In the absence of both olive and ash trees exposure to privet pollen might represent the source of this kind of sensitization. PMID- 21789969 TI - Is high prevalence of vitamin D deficiency evidence for asthma and allergy risks? AB - BACKGROUND: Studies suggest a link between vitamin D deficiency and development of asthma and allergic diseases. AIM: To determine a) the association between vitamin D and asthma among children, b) difference in level of vitamin D in asthmatic children and control, and c) effect of vitamin D on atopy markers. SETTING: Case-control study done, between October 2009 to July 2010, on asthmatics and controls (< 15 years) at Pediatric Allergy-Immunology Clinics and Primary Health care Clinics (PHC), Qatar. METHODS & SUBJECTS: A total of 483 cases and 483 controls matched by age, gender and ethnicity. Sociodemographic & clinical data was collected through physician diagnosis and questionnaire. Their health status was assessed by past or present clinical manifestations, family history, physical examination, BMI, and serum 25(OH) vitamin D, calcium, and phosphorus. RESULTS: 44.8% of asthmatic and 50.0% of controls were males, and 55.2% of asthmatic and 50% of controls were females. The mean age (+/- SD, in years)for asthmatic versus controls was 7.0 +/- 3.8 vs. 8.4 +/- 3.6. Vitamin D deficiency was more prevalent in asthmatics than controls. The mean value of Vitamin D in asthmatics was much lower than the normal value, and there was a significant difference found in the mean values of vitamin D between asthmatics (17.5 +/- 11.0) and the controls (20.8 +/- 10.0). Furthermore, there were statistically significant differences between asthmatic subjects and controls with respect to serum level of vitamin D (p < 0.001). Lower Vitamin D levels were associated with more allergic disease and elevated serum IgE. CONCLUSION: Serum vitamin D levels were lower in asthmatic than control. Vitamin D deficiency was higher among children with asthma, allergic rhinitis, atopic dermatitis, acute urticaria, and food allergy. In addition, vitamin D deficiency was associated with IgE atopy markers in asthmatic children more than controls. PMID- 21789970 TI - When allergology meets psychiatry: delusional parasitosis (Ekbom's syndrome). AB - Delusional parasitosis (DP) or Ekbom's syndrome is uncommon psychiatric disorder that may represent a challenge for the allergist. DP is characterized by the fixed belief to be infested with parasites or small living creatures, although there is no medical evidence for this. The management of this condition is difficult, as patients with this paranoid disorder reject psychiatric diagnosis and treatment and often consult many specialists (dermatologists, internists or allergists). The patients may also share the delusional disease with other people living in close emotional relationship. We report herein a delusion of parasitosis simultaneously occurring in two spouses, and discuss the clinical features of the disease. PMID- 21789971 TI - Omega-5 gliadin anaphylaxis: an integrated diagnostic approach. AB - We report the case of a 62-year old man who presented a wheat-dependent, exercise induced anaphylaxis (WDEIA). The case illustrates the usefulness of skin prick test not only with wheat extract, but also with native gliadin extract. Moreover we confirm the value of recombinant IgE dosage with rTri a 19 omega-5 gliadin in the diagnostic pathway of this condition. PMID- 21789973 TI - Brain-numbing complexities: in healthcare, as in neuroscience, the issues are always multi-faceted. PMID- 21789972 TI - Rheumatoid nodules: the importance of a correct differential diagnosis. AB - Knuckle pads is a syndrome characterized by the presence of multiple nodules located on the extensor side of the interphalangeal or metacarpophalangeal joints. Several conditions can be confused with Knuckle pads. We describe a case of a 47-years-old man who developed multiple bilateral roundish nodules located in the skin over the dorsal and lateral interphalangeal joints in both hands. PMID- 21789974 TI - Balancing act: Can CMIOs and CIOs make physician documentation work for everyone? AB - Physician documentation in the patient record has long served multiple purposes, from core clinician-to-clinician communication, to billing requirements, to data analysis tasks. Now with the advancing progress of the meaningful use process under the federal Health Information Technology for Economic and Clinical Health (HITECH) Act, even more elements are being added to the demands on M.D. documentation. What kinds of strategies are the leaders of pioneering organizations coming up with that might serve as models for their peers across the industry? PMID- 21789975 TI - Health IT: the glue for accountable care organizations. Four big systems show how they're using EHRs, connectivity, and data warehouses to drive ACOs. AB - Healthcare organizations moving into the uncharted territory of accountable care organizations (ACOs) face technological and organizational challenges that could stop their fledgling attempts in their tracks. Many have embraced health IT as the key to establishing successful ACO models. PMID- 21789976 TI - Secure messaging via the cloud and mobile devices: data security issues emerge with new technologies. AB - The secure messaging space is alive with new innovations that are moving the industry forward. Key in this space is the push toward moving secure messaging to the cloud and pushing it out to mobile devices. Among the examples are solutions that allow physicians to receive encrypted email on mobile devices, as well as ones that allow doctors to securely text-message each other to coordinate care. However, the security issues around these emerging technologies in this very active space must be further explored. PMID- 21789977 TI - Mastering revenue cycle management: two strategies for tightening up the revenue stream. AB - Having a good understanding of the billing process, whether through internal workflow audits or employing a software solution to make sure a hospital is being reimbursed for every service it provides, is crucial to maximizing revenue streams. PMID- 21789978 TI - Keys to EHR success: how two rural health providers are meeting the challenges of meaningful use. PMID- 21789979 TI - Patients learn to see the value in EHRs. Interview by Kayt Sukel. PMID- 21789980 TI - Using EHRs to improve patient outcomes. Interview by Kayt Sukel. PMID- 21789981 TI - Put your best foot forward: tips for making sure that your interview produces the best outcome. PMID- 21789982 TI - Diabetes and depression are a lethal combination in women. PMID- 21789983 TI - Improving lower urinary tract symptoms in BPH. AB - Benign prostatic hyperplasia (BPH) is one of the most common diseases to affect older men. Histological disease is present in more than 60% of men beyond their sixties, and more than 40% of men in this age group have lower urinary tract symptoms (LUTS). The prevalence increases with age. About one-fifth of patients with symptomatic disease who present to a doctor will eventually be treated surgically. The remainder will often be managed initially by active surveillance. The majority of these men suffer gradual progression of symptoms and increasingly require treatment. BPH is characterised by a spectrum of obstructive and irritative symptoms, known collectively as LUTS. Poor urinary flow and the sensation of incomplete bladder emptying are the two symptoms that correlate most closely with the eventual need for prostate surgery. Untreated, a significant number of men with BPH will eventually develop acute urinary retention. In addition tosymptom assessment, digital rectal examination can provide an estimate of prostate volume and exclude a palpable nodule suggestive of prostate cancer. PSA testing provides additional information about the risk of prostate cancer being present. Medical management of BPH is suitable for most patients with moderate symptoms. The two main evidence-based approaches are treatment with alpha1-blockers and 5alpha-reductase inhibitors (5-ARLs). Severely symptomatic patients may also respond to these drugs. Mild symptoms should usually be managed by active surveillance. Combination therapy with an alpha1-blocker and a 5-ARI is more effective than monotherapy in terms of symptom relief and prevention of progression. PMID- 21789984 TI - Managing patients with acute urinary retention. AB - Acute urinary retention (AUR) is more than ten times more common in men than women. In men it tends to occur in the elderly; the risk of AUR is higher in men > 70 years. The causes in men can be divided into precipitated or occurring spontaneously. These can be further divided according to the mechanism i.e. obstructive, neurological and myogenic. Spontaneous AUR, caused by progression of BPH leading to a mechanical obstruction of the bladder outlet, is the most common cause of AUR. The typical presentation of AUR is a patient complaining of a sudden inability to urinate associated with progressive abdominal distension which is usually painful. The pain increases in intensity with increasing distension of the bladder. An abdominal examination should reveal a distended bladder which can be confirmed by a dull percussion note. A digital rectal examination is vital to gain information on prostatic enlargement (benign or malignant), faecal load in rectum, anal tone and presence of other masses. Urinalysis and culture should be carried out on a sample obtained after catheterisation to rule out infection. Renal function should be assessed to see if there has been damage to the upper tracts. It is better not to perform a PSA test in this situation as it will invariably be raised due to distension of the bladder and catheter insertion. If catheter insertion fails then a urological consultation is required for insertion of a suprapubic catheter. Admission is essential if the patient is: unwell with urosepsis; has abnormal renal function needing investigation and fluid monitoring; has acute neurological problems; or cannot take care of the catheter. Trial without catheter needs to be planned and the ideal time to do this is within 2-3 days so that the patient can pass urine naturally. PMID- 21789985 TI - Training of athletes. 1911. PMID- 21789986 TI - Increasing uptake of HIV tests in men who have sex with men. AB - In 2010, just under half of new HIV diagnoses in the UK were in men who have sex with men (MSM). This group are most at risk of acquiring and transmitting HIV in the UK. In March 2011, NICE published guidance specifically aimed at increasing uptake of HIV testing in MSM, because of the high levels of infection, high levels of recent acquisition of HIV infection and continued high-risk behaviour in this group. Delayed diagnosis of HIV confers a poor prognosis: 73% of the 516 patients with HIV who died in 2009 had been diagnosed late. An estimated 39% of MSM in 2009 were diagnosed when their immune system was below the threshold at which antiretroviral treatment should be commenced. Many of these men had seen their own GP with signs and symptoms of HIV and the opportunity to make the diagnosis had been missed. One of the most important indicators is primary HIV infection. This seroconversion illness presents with a flu-like illness often lasting more than two weeks with a rash, sore throat and lymphadenopathy. An HIV test should be performed straightaway on all MSM presenting with these features. The benefits of increased testing and early diagnosis include reduced mortality and morbidity related to HIV and the potential to reduce onward transmission. NICE recommends that MSM have HIV tests at least annually as part of routine care, and additionally if the patient: has a new sexual partner has high-risk sexual intercourse; is diagnosed with another STI; requests a sexual health screen; or presents with an HIV indicator disease. PMID- 21789987 TI - Pigmentation disorders. PMID- 21789988 TI - Patients keep us anchored in the real world. PMID- 21789989 TI - [Annual scientific-practical conference with international participation. "Actual Problems of Clinical Surgery" Abstracts]. PMID- 21789990 TI - [Application of intradermal sutures on the skin]. AB - There were analyzed the results of treatment of 87 patients, in whom intradermal sutures were applied while doing the cutaneous wounds closure: continuous removable suture, adjusted according to Holsted method, continuous nonremovable Hoisted suture, separate nonremovable vertical suture of Abudy, separate cutaneous horizontal nonremovable suture. Peculiarities of postoperative cicatrix formation, its aesthetic qualities were studied up. While adjusting separate nonremovable intradermal sutures, using biodegrading thread made of polydyoxanone, the qualitative, minimally wide cicatrix is formed, promoting reduction of the patients treatment duration due to absence of necessity to remove cutaneous sutures, preventing screwing of the wound edges and possibility of kelloid cicatrix formation due to minimal trauma occurrence of the skin layers. PMID- 21789991 TI - [Observation of Pfeiffer-Weber-Christian syndrome, simulating sepsis]. PMID- 21789992 TI - [An acute respiratory distress syndrome of adults in injured person with polytrauma]. PMID- 21789993 TI - [Genetic diversity and phylogenetic relationships of the Manchurian zokor Myospalax psilurus (Rodentia, Muridae) according to RAPD-PCR analysis]. AB - The population structuring and low genetic diversity of the Manchurian zokor Myospalax psilurus Milne-Edwards, 1874, an East Asian endemic included in the Red List of Russia, were demonstrated. Two separate geographical groups differing in the level of their genetic diversity were found on the territory of the Primorskii krai. The subpopulation located closest to the main area of this species was determined as ancestral. A subspecies differentiation of the Primorskii krai and Transbaikal M. psilurus populations was shown, as was the monophyletic origin of M. psilurus and its high divergence from M. aspalax. The animals from northern localities are recommended for reintroduction in nature under species recovery programs in Primorskii krai. PMID- 21789994 TI - [Temporal dynamics of morphologic diversity of the Japanese scallop Mizuhopecten Yessoensis (Jay, 1856)]. AB - The temporal diversity of 11 morphological features of both shell valves in eight cultivated samples of the Japanese scallop M. yessoensis from Alexeev Bay (Popov Island, Sea ofJapan) at different ages and from different generations was analyzed. The sample diversity with respect to each investigated feature was observed. The sample differences in the studied features as well as shell valve variability within the sample were demonstrated to be determined by both mollusk age and sample generation. This phenomenon is considered to be the result of differences in the environmental influence on each mollusk generation under constant technological conditions. PMID- 21789995 TI - [Selection of foraging tactics in leaf Warblers (phylloscopus)]. AB - Aviary observations revealed particularities of foraging behavior in seven species of leaf warblers of the genus Phylloscopus, which sympatrically inhabit the middle-taiga Yenisei. The differences consist in the ratio of the tactics of each type, including the flight, frequency of using them, and selectivity with respect to maneuvers. The obtained results are discussed from the point of view of particularities of the external morphology of the species. PMID- 21789996 TI - [Similarities and differences in the effect of cocaine on alpha-adrenergic and muscarinic response]. AB - Similarities and differences in the effect of cocaine on alpha-adrenergic and muscarinic receptors were shown in three experimental models. The postsynaptic stimulating effect of cocaine through activation of alpha-adrenergic receptors was found in a chicken embryo without innervation and in an innervated rat vas deferens. Cocaine caused an increase of the amount of activated alpha-adrenergic receptors and the appearance of an additional receptor pool and changed their dimerization level. Cocaine acts as an antagonist on muscarinic receptors of the chicken embryo. The inhibition of muscarinic receptors in the rat brain by cocaine leads to a decrease in the number of receptors and their partial monomerization. Thus, cocaine influences both the alpha-adrenergic response and the muscarinic response by its influence on receptors. Experiments on various objects have shown that cocaine activates the alpha-adrenergic response and inhibits the muscarinic response. PMID- 21789997 TI - [Microbiological characteristic of anthills of Lasius niger]. AB - The characteristics of microbial communities of the anthills of Lasius niger compared to the soil beyond the area of the strong effect of ants is given. PMID- 21789998 TI - [Isotopic signature (15N/14N and 13C/12C) confirms similarity of trophic niches of millipedes (Myriapoda, Diplopoda) in a temperate deciduous forest]. AB - The species composition, abundance, and isotopic signature of millipedes (Myriapoda, Diplopoda) were investigated in seven biotopes of Kaluzhskie Zaseki State Nature Reserve. Nine Diplopoda species were found in total, and the local species diversity (within a sampling plot) reached seven species. The Diplopoda tissues were similar to the plant litter in the isotopic composition of nitrogen (delta15N was by 0.4% per hundred higher, on average), but were more strongly enriched in heavy carbon (delta13C was by 4% per hundred higher, on average). Removal of mineral carbon from the cuticle reduced delta13C of Diplopoda by about 1.4% per hundred on average. Differences in the delta15N and delta13C values between the species did not exceed 2.5 per hundred. Differences in the isotopic compositions of the considered species are insignificant, and thus, it is impossible to distinguish particular trophic guilds in the Diplopoda community. Analysis of the published data confirmed that isotopic differentiation of millipedes was much less pronounced than in other investigated groups of soil animals. Hence, millipedes of the deciduous forest form a uniform trophic group. PMID- 21789999 TI - [The expression of genes encoding the voltage-dependent L-type Ca2+ channels in proliferating and differentiating C2C12 myoblasts of mice]. AB - Votage-dependent L-type Ca+ channels of the C2C12 line myoblasts of mice have been studied at the stage of proliferation and 24 h after the beginning of differentiation. The expression of genes Cacna1s, Cacna1S, Cacna1d, and Cacna1f, which encode channel forming subunits alpha1S, alpha1C, alph1D, and alpha1F, respectively, has been assessed. The expression of genes Cacna2d and Cacn1g, which encode the alpha2, delta, and gamma regulatory subunits, has been studied as well. For the first time, the expression of Cacnald, which is typical for nerve cells, units, has been revealed in proliferating myoblasts, whereas in differentiating mononuclear myoblasts the expression of this gene was significantly decreased. On the contrary, the low level of expression of Cacnal IS, which encodes the specific alpha1S channel forming subunit of skeletal muscles, has been observed in proliferating myoblasts, whereas in differentiating mononuclear myoblasts it has been shown to increase multifold. No considerable changes in expression of Cacna2d and Cacn 1g have been revealed in proliferating and differentiating myoblasts. No traces of expression of Cacna1c and Cacna1f have been revealed in myoblasts. PMID- 21790000 TI - [The different effects of carbon dioxide on the toxicity of silver ions for prokaryotic and eukaryotic microorganisms]. AB - The effect of carbon dioxide on survivability of bacteria Escherichia coli and the germination ability ofconidia of the fungus Neurospora crassa in the presence of silver nitrate was studied. It was shown that carbon dioxide increased the toxic effect of silver ions on prokaryotic cells of E. coli but did not change the survivability of spores of the eukaryote N. crassa. PMID- 21790001 TI - [Activity of the hypothalamo-pituitary-adrenals axis in the Siberian tiger (Panthera tigris altaica) in captivity and in the wild, and their dynamics throughout the year]. AB - A noninvasive evaluation method of hypothalamo-pituitary-adrenals axis (HPA) activity in the Siberian tiger was verified. Comparison of the activity level of HPA in Siberian tigers in the wild and in captivity, and their alterations over the year was carried out. Significant seasonal deviations between activity levels of HPA in tigers in captivity were not found. In the wild, this level was significantly higher, reaching the maximum from November to January, which can be related with an unfavorable influence on tigers in low temperatures and deep snow cover. PMID- 21790002 TI - [Macrokinetics of vital manifestations in microbes]. AB - An equation for the complete dynamics of the growth and die-off indices of microbes has been obtained in the framework of the macrokinetic approach. The equation allows differentiation of intervals with different values of kinetic characteristics. Analytical expressions were found for coefficients of the model and interval boundaries with the kinetics of growth and die-off of microbes. The adequacy of the equation was confirmed in the cases of experimental dynamics: the growth of Candida albicans culture in a Sabouraud liquid medium, the number of viable cells of Brochothrix thermosphacta in meat extract, and trimethylbutanol secretion by these organisms. PMID- 21790003 TI - [Regulation of bacterial transcription elongation]. AB - The elongation complex, which involves RNA polymerase, DNA template and nascent RNA, is a central intermediate in transcription cycle. It is elongation complex that represents the main target for the action of different regulatory factors. Over the past several years, many structural and biochemical data have been obtained that shed light upon the molecular details of RNA polymerase function. Cooperation between RNA polymerase elongation complex and translating ribosome was established recently. Here we discuss the mechanisms of the regulation of bacterial transcription elongation. PMID- 21790004 TI - [Melanoma: surface markers as the first point of targeted delivery of therapeutic genes in multilevel gene therapy]. AB - Melanoma is one of the most malignant tumors, aggressively metastasizing by lymphatic and hematogenous routes. Due to the resistance of melanoma cells to many types of chemotherapy, this disease causes high mortality rate. High hopes are pinned on gene therapeutic approaches to melanoma treatment. At present, one of the main problems of the efficient use of the post-genomic generation therapeutic means is the lack of optimal techniques of delivery of foreign genetic material to the patient's target cells. Surface specific markers of melanoma cells can be considered as promising therapeutic targets. This review describes currently known melanoma specific receptors and its stem cells, as well as contains data on melanoma antigens presented on the cell surface by major histocompatibility complex proteins. The ability of surface proteins to internalize might be successfully used for the development of methods of targeted delivery of gene therapeutic constructs. In conclusion, a concept of multilevel gene therapy and the possible role therein of surface determinants as targets of gene systems delivery to the tumor are discussed. PMID- 21790005 TI - The complete mitochondrial genome of the marbled rockfish Sebastiscus marmoratus (Scorpaeniformes, Scorpaenidae): genome characterization and phylogenetic considerations. AB - The complete mitochondrial genome sequence of the marbled rockfish Sebastiscus marmoratus (Scorpaeniformes, Scorpaenidae) was determined and phylogenetic analysis was conducted to elucidate the evolutionary relationship of the marbled rockfish with other Sebastinae species. This mitochondrial genome, consisting of 17301 bp, is highly similar to that of most other vertebrates, containing the same gene order and an identical number of genes or regions, including 13 protein coding genes, two ribosomal RNAs, 22 transfer RNAs, and one putative control region. Most of the genes are encoded on the H-strand, while the ND6 and seven tRNA genes (for Gln, Ala, Asn, Tyr, Ser (UCA), Glu, and Pro) are encoded on the L strand. The reading frame of two pairs of genes overlapped on the same strand (the ATPase 8 and 6 genes overlapped by ten nucleotides; ND4L and ND4 genes overlapped by seven nucleotides). The possibly nonfunctional light-strand replication origin folded into a typical stem-loop secondary structure and a conserved motif (5'-GCCGG-3') was found at the base of the stem within the tRNA(Cys) gene. An extent termination-associated sequence (ETAS) and conserved sequence blocks (CSB) were identified in the control region, except for CSB-1; unusual long tandem repeats were found at the 3' end of the control region. Phylogenetic analyses supported the view that Sebastinae comprises four genera (Sebates, Hozukius, Helicolenus, and Sebasticus). PMID- 21790006 TI - [Genetic diversity of Khakassian gene pool: subethnic differensiation and the structure of Y-chromosome haplogroups,]. AB - The structure of Khakass gene pool has been investigated: compositions and frequencies of Y-chromosome haplogroups were described in seven population samples of two basic subethnic groups--Sagays and Kachins from three territorially distanced regions of Khakassia Republic. Eight haplogroups: C3, E, N*, N1b, N1c, R1a1a and R1b1b1 have been determined in Khakass gene pool. Significant differences between Sagays and Kachins were shown in haplogroup spectra and a level of genetic diversity in haplogroups and YSTR-haplotypes. Kachin samples are characterized by a low value of gene diversity, whereas the level of Sagay diversity is similar to that of other South-Siberian ethnoses. Sagay samples from Askizsky region are very similar to each other just as two Kachin samples from Shirinsky region, while Sagay samples from Tashtypsky region greatly differ from each other. A great portion of intergroup differences was determined among different ethnic groups, which testifies to significant genetic differentiation of native populations in Khakassia. Khakass gene pool is greatly differentiated both in haplogroup frequencies and in YSTR-haplotypes within N1b haplogroup. Frequencies and molecular phylogenesis of YSTR-haplotypes were revealed within N1b, N1c and R1a1 haplogroups of Y-chromosome. We carried out comparative analysis of the data obtained. The results of factor, cluster and dispersion analyses are evidence of structuredness of Khakass gene pool according to territorial-subethnic principle. PMID- 21790007 TI - [Expression of GSK3B gene in peripheral blood in patient with Parkinson's disease]. AB - Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Detecting changes in gene expression in untreated de novo patients with PD is important for understanding disease pathogenesis and for identifying biomarkers for preclinical stage of PD. In this study we investigate expression of gene of Glycogen synthase kinase-3 beta (GSK3B) in the peripheral blood of different groups of patients with neurological diseases using reverse transcription reaction and real-time polymerase chain reaction (PCR). Our results suggest that the expression levels of GSK3B can't serve as a biomarker for early stages of PD. PMID- 21790008 TI - [Genome-wide association study of allergic diseases in Russians of Western Siberia]. AB - Genome-wide association studies are currently considered as one of the most powerful tools to establishing the genetic basis of complex diseases. A number of such studies were carried out for allergic diseases; however, in Russian population this analysis has not been performed so far. For the first time, we performed genome-wide association study of allergic diseases in Russian inhabitants of Western Siberia. Two new loci associated with childhood bronchial asthma were identified (20q13.12, rs2425656, P = 1.99 x 10(-7); 1q32.1, rs3817222, rs12734001, P = 2.18 x 10(-7) and 2.79 x 10(-7), respectively) as well as one locus, associated with allergic rhinitis (2q36.1, rs1597167, P = 3.69 x 10(-7)). Genes located in the loci, YWHAB and PPP1R12B for asthma and KCNE4 for allergic rhinitis, are new genes for these diseases. It was found that BAT1 (6p21.33), MAGI2 (7q21.11) and ACPL2 (3q23) genes are, likely, common (syntropic) genes of allergic disease and a topic sensitisation. It was shown that RIT2 (18q12.3) and (5q31.1) genes can be involved in the control of lung function. The results of the study enlarge the body of data on genetic factors of allergy and expand the list of genes underlying these diseases. PMID- 21790009 TI - [Namesakes or relatives? Approaches to investigating the relationship between Y chromosomal haplogroups and surnames]. AB - Population genetics successfully applies surnames as quasi-genetic markers when estimating similarity between populations and calculating a measure of random inbreeding. These calculations are based on an isonomy coefficient which assumes that every surname is monophyletic: that it originated from single common ancestor and all namesakes are therefore relatives. On the other hand, there is a general opinion that a typical Russian surname is polyphyletic: it originated multiple times and most namesakes are therefore not related to each other. Combined studies of Y chromosomes and surnames now allow us to address this issue. In this study, we discuss approaches for statistical evaluation of Y chromosomal haplogroup frequencies in groups of people bearing the same surname (namesakes). We propose an 'Index of Accumulated Haplogroup Frequency', which allows for errors due to random (artifactual) effects increasing a haplogroup frequency in a group of namesakes by subtracting the population frequency of this haplogroup. This population frequency is calculated as the weighted average of the frequencies of this haplogroup in the populations that the carriers of this surname come from. Fom the total sample (comprising 1244 persons from 13 populations of the historical Russian area) we chose 123 persons carrying 14 surnames which were the most frequent in the total sample. Haplogroup frequencies in these 14 "surname" groups were compared with the respective 14 "population" control groups compiled from the total sample as described above. We found that even these widespread surnames exhibit non-random accumulation of specific Y chromosomal haplogroups. More detailed analyses of the relationships between namesakes could be carried out using Y-STR haplotypes rather than Y-SNP haplogroups, and will be the subject of a future study. PMID- 21790010 TI - [Novel bidirectional promoter from human genome]. AB - In human and other mammalian genomes a number of closely linked gene pairs transcribed in opposite directions are found. According to bioinformatic analysis up to 10% of human genes are arranged in this way. In present work the fragment of human genome was cloned that separates genes localized at 2p13.1 and oriented "head-to-head", coding for hypothetical proteins with unknown functions--CCDC (Coiled Coil Domain Containing) 142 and TTC (TetraTricopeptide repeat Containing) 31. Intergenic CCDC142-TTC31 region overlaps with CpG-island and contains a number of potential binding sites for transcription factors. This fragment functions as bidirectional promoter in the system ofluciferase reporter gene expression upon transfection of human embryonic kidney (HEK293) cells. The vectors containing genes of two fluorescent proteins--green (EGFP) and red (DsRed2) in opposite orientations separated by the fragment of CCDC142-TTC31 intergenic region were constructed. In HEK293 cells transfected with these vectors simultaneous expression of two fluorescent proteins is observed. Truncated versions of intergenic region were obtained and their promoter activity measured. Minimal promoter fragment contains elements Inr, BRE, DPE characteristic for TATA-less promoters. Thus, from the human genome the novel bidirectional promoter was cloned that can be used for simultaneous constitutive expression of two genes in human cells. PMID- 21790011 TI - The novel protein TSR2 inhibits the transcriptional activity of nuclear factor kappaB and induces apoptosis. AB - The nuclear factor-kappaB (NF-kappaB) pathway is involved in a variety of cellular functions, including cell proliferation, differentiation, development, oncogenesis, and apoptosis. In this study, we report on cloning and characterization of the human TSR2 (also known as 20S rRNA accumulation homolog), a protein containing a WGG motif, which has no known specific function, although this protein is conserved during evolution across different species. The cDNA sequence contains a 576 bp open reading frame, encoding a 191 amino acid protein with a predicted molecular mass of 20.9 kDa. Northern blot analysis revealed broad TSR2 mRNA expression in human tissues. Overexpression of TSR2 in human epidermal HEp-2 cells inhibited the transcriptional activity of NF-kappaB, with or without tumor necrosis factor a stimulus, and induced HEp-2 cell apoptosis. This data for the first time suggests that TSR2 is involved in the NF-kappaB signaling pathway and may regulate apoptosis. PMID- 21790012 TI - Expression patterns of two Arabidopsis endo-beta-1,4-glucanase genes (At3g43860, At4g39000) in reproductive development. AB - Endo-beta-1,4-D-glucanases (EGases) are a widespread and vital group of glycosyl hydrolases that generally break the beta-1,4-glucosyl linkages. Studies of plant EGases have mainly been concentrated on vegetative growth, while little is currently known about their role in reproductive processes. Using the GUS reporter aided analysis of promoter activities, we identified the expression patterns of two putative Arabidopsis EGases genes (At3g43860 and At4g39000) whose promoters conferred specific localization of the GUS activity in reproductive organs. We found that At3g43860, which is similar to KOR in its protein structural organization, is expressed in mature pollen and the pollen tube, implying that it may have a role in pollen and pollen tube growth. At4g39000 was found to be activated in the developing ovules and seeds, especially at the micropylar end of the inner integuments and nucellus in a proximal-distal pattern. Our results suggested that the two EGases play specific roles in Arabidopsis sexual reproduction. PMID- 21790013 TI - [Designing of hybrid human interferon alfa-2 strain-producers and the use of enteropeptidase for obtaining N-terminal methionine-free interferons]. AB - A system for production of human interferon-alpha2a (IFN-alpha2a) and IFN-alpha2b lacking N-terminal methionine has been developed. Plasmids containing genes of hybrid IFN-alpha2 under the control of different promoters were constructed; a sequence encoding the enteropeptidase hydrolysis site being introduced in proximal part of the genes. As the result, 4 strains of Escherichia coli producing hybrid IFN-alpha2 have been obtained. The methodology for IFN-alpha2 renaturation, hydrolysis of its N-terminal part, chromatographic purification of N-terminal methionine-free IFN-alpha2 has been developed. PMID- 21790014 TI - [The structural protein Gag of the gypsy retrovirus forms virus-like particles in the bacterial cell]. AB - The amino acid sequence of the drosophila retrovirus MDG4 (gypsy) structural protein Gag does not contain a canonical motif known for the majority of vertebrate retroviruses. Moreover, the protein translation can theoretically begin with two separated initiation codons located within its unique open reading frame. We designed constructs for expression of two theoretically possible variants of Gag polypeptide and investigated an ability of the each product to form virus-like particles in the bacterial cell, i.e. in the absence of eukaryotic cell factors. The results obtained showed that the both variants of the gypsy protein Gag form globular particles in the bacterial cell. PMID- 21790015 TI - [Effects of the IbpAB AND ClpA chaperones on DnaKJE-dependent refolding of bacterial luciferases in Escherichia coli cells]. AB - The rate and level of DnaKJE-dependent refolding of the thermoinactivated Aliivibrio fischeri luciferase are considerably lower in Escherichia coli ibpA and ibpB mutants than in wild type cells. The rate and level of refolding are lower in E. coli ibpB::kan than in ibpA::kan cells. The decline of refoldings level in E. coli clpA::kan makes progress only with the increase of thermoinactivation time of luciferase. Plasmids with the genes ibpAB don't compensate clpA mutation. It is supposed that small chaperones IbpAB and chaperone ClpA operate independently in a process of DnaKJE-dependent refolding of proteins at the different stages. PMID- 21790016 TI - [Critical amino acids of ornitin decarboxylase degron: the presence and C terminal arrangement is insufficient for alfa-fetoprotein degradation]. AB - Mouse ornithine decarboxylase (ODC) degrades in proteasome in an ubiquitin independent manner with an averagehalf-life of 2 h. The 37 amino acid long C terminal fragment known as a degradation signal (degron) is responsible for the effective degradation of ODC. Recently, amino acids being critical for degradation in the ODC-degron have been mapped. Mutations of Cys441 and Ala442 led to protein stabilization, while a substitution of other amino acids composing ODC-degron had almost no effect on the protein turnover; whereas insertions or deletions in region between Ala442 and ODC C-terminus diminished greatly rate of protein degradation, e.g. positioning of the key amino acids from the C-terminus was shown to be crucial. Using these data we introduced both key amino acids into the alfa-fetoprotein with truncated exportation signal (deltaAFP), at the same distance from the C-terminus as they being in the ODC (deltaAFPCAG and deltaAFPLCAG). Removal of N-terminal exportation signal prevented secretion of modified proteins. Using in silico approach we demonstrated no significant difference in hydrophobicity or secondary structure between C-terminus of deltaAFP and mutated proteins. The degradation kinetics of deltaAFP, deltaAFPCAG, deltaAFPLCAG in cyloheximide-chase and proteasome inhibition assay (using MG132) was identical. Obtained results suggest that introduced substitutions are insufficient for effective recognition of mutated deltaAFP by26S proteasome. We assume thatadditional amino aci ds composing ODC-degron or their combine action could also affect degradation. Besides that, one cannot exclude that conformation of the mutated deltaAFP limits its C-terminus accessibility to proteasome. PMID- 21790017 TI - [DNA methylation profile in human placental tissues]. AB - For the first time using genome-wide Infinium HumanMethylation27 BeadChip Array (Illumina, USA) DNA methylation pattern was determined in the human cytotrophoblast and extraembryonic mesoderm. These tissues are the derivatives of trophectoderm and inner cell mass of blastocyst and have substantial differences in dynamics of epigenetic genome reprogramming during early stages of differentiation. The genome of the extraembryonic mesoderm cells has been shown to be more methylated compared to the cytotrophoblast similarly to other mammalian species. Differences in methylation pattern of single CpG-dinucleotides and dinucleotides localized within promoter CpG-islands have been found. It has been shown that the majority of single CpG-dinucleotides in both tissues were methylated whereas promoter CpG-island sites were not. Comparative analysis revealed 202 differentially methylated genes in extraembryonic mesoderm and 40 genes in cytotrophoblast. These genes are responsible for diverse biological processes. However, in the extraembryonic mesoderm the main functional groups included genes responsible for DNA binding and transcriptional factors' activity whereas in the cytotrophoblast--for transport and protein and cytokine secretion. PMID- 21790018 TI - [Changing of filamentation dynamics of RecA protein, induced by D112R amino acid substitution or ATP to dATP replacement, results in filament steadiness TO THE RecX protein action]. AB - It is known that RecX is a negative regulator of RecA protein. We found that the mutant RecA D112R protein exhibits increased resistance to RecX protein comparatively to wild-type RecA protein in vitro and in vivo. Using molecular modeling we showed, that amino acid located in position 112 can not approach RecX closer than 25-28 angstroms. Thus, direct contact between amino acid and RecX is impossible. RecA D112R protein more actively competes with SSB protein for the binding sites on ssDNA and, therefore, differs from the wild-type RecA protein by dynamics of filamentation on ssDNA. On the other hand, after the replacement of ATP by dATP, the wild-type RecA protein, changing the dynamics of filamentation on ssDNA, also becomes more resistant to RecX. Based on these data it is concluded that the dynamics of filamentation has a great, if not dominant role in the stability of RecA filament to RecX relative to the role of RecA-RecX protein protein interactions discussed earlier. We also propose an improved model of regulation of RecA by RecX protein, where RecA filament elongation along ssDNA is blocked by RecX protein on the ssDNA region, located outside the filament. PMID- 21790019 TI - [Structural and thermodynamic features of intergenic and intronic human primary microRNAs]. AB - MicroRNAs are small non-coding RNAs involved in the regulation of gene expression in eukaryotes. Being transcribed in the nucleus in the form of a long primary precursor a primary microRNA undergoes multistep biogenesis that leads to the formation of a mature microRNA. One of the critical biogenesis steps is the recognition and processing of primary microRNAs by microprocessor complex. A primary microRNA secondary structure is considered to play a key role during this biogenesis step, but specific structural motives have not been identified yet. In the result of the study on structural and thermodynamic features of intergenic and intronic microRNAs we have demonstrated that the two main classes of human microRNAs have no statistically significant difference in respect of these parameters. The conclusion maybe a base for combining the two class microRNA sequences in a common set for the search for new microRNAs. Specific structural and thermodynamic features in human primary microRNA transcript hairpins have been found; the data may be used for search of new microRNA candidates in human genome and for a design of artificial microRNA sequences for gene therapy and functional genomics purposes. PMID- 21790020 TI - [Improved procedure of the search for poly(ADP-ribose) polymerase-1 potential inhibitors with use of molecular docking approach]. AB - A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been done. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 database chemicals 9 PARP1 inhibitors were revealed; the most active ones, namely: STK031481, STK056130, and STK265022,--displayed biological effect at a micro molar concentration (IC50 = 2.0 microM, 1.0 microM and 2.6 microM, respectively). PMID- 21790021 TI - [NtcA- and NtcB-regulons in cyanobacteria and Rhodophyta chloroplasts]. PMID- 21790022 TI - [Wound repair in plant tissues (Review)]. AB - Signaling systems responsible for repair processes in plants and manifestation of defensive effects in plant tissues were analyzed. Special attention was given to jasmonic acid, a mobile systemic repair signal, as well as to jasmonate biosynthesis and signal transport to the areas where protective responses of plants are induced. The main defense responses of potato tubers induced by wounding were considered. PMID- 21790023 TI - [Identification of catalytically active groups of pea (Pisum sativum L.) beta glucosidase]. AB - Functional groups ofcytoplasmic pea beta-glucosidase pretreated to an electrophoretically homogeneous state were identified. Data on the pH dependence of the enzyme activity, calculated heat of ionization, photoinactivation of the enzyme in the presence of methylene blue, and inactivation of the enzyme with diethyl pyrocarbonate suggest that the catalytic site of beta-glucosidase contains the carboxyl group of glutamic or aspartic acids and the imidazole group of histidine. PMID- 21790024 TI - [Chymotrypsin and trypsin inhibitor isolated from potato tubers]. AB - Potato Kunitz-type chymotrypsin inhibitor (PKCI-23) was isolated from potato tubers (Solanum tuberosum L., Zhukov's Jubilee breed) and purified to a homogenous state. The protein was purified by gel-filtration chromatography and ion-exchange chromatography using Sephadex G-75 and CM-Sepharose CL-6B, respectively. PKCI-23 protein has been shown to inhibit both chymotrypsin and trypsin with equal efficacy, forming equimolar complexes with these enzymes. However, much weaker inhibitory effect of PKCI-23 has been observed for Carlsberg subtilisin. The N-terminal 20 amino acid sequence of PKCI-23 has been sequenced. PKCI-23 has been shown to suppress, with different efficacy, the growth and development of pathogenic microorganisms Fusarium culmorum (Wm. G. Sm.) Sacc. and Phytophtora infestans (Mont.) de Bary that infect potato. PMID- 21790025 TI - [Purification of extracellular proteinases from B. subtilis SKB 256 by biospecific chromatography]. AB - Abstract-A simple and efficient method of preparing highly purified extracellular proteinases of B. subtilis B-1 (SKB 256) has been developed. A sorbent based on sorsilen impregnated with hemoglobin or cytochrome c has been synthesized for this purpose. A significant difference between the efficiency of hemoglobin and cytochrome c as biospecific ligands has been observed: the enzyme yield amounted to 40.6 and 65.6% of the total amount of enzyme adsorbed, respectively. The culture was shown to contain two major proteinase forms with different molecular masses that could be separated by chromatography on a Sephadex G-50 but gave only one band with MW 27 kDa upon denaturing electrophoresis in 12.5% PAG in the presence of 0.1% SDS. The influence of eluent pH, ionic strength and ethanol concentration on the sorption of the proteinases on the biospecific sorbent, as well as on the desorption from it, has been investigated. Positive influence of 20% ethanol on proteinase desorption has been demonstrated. PMID- 21790026 TI - Purification and characterization of an endoxylanase from the culture broth of Bacillus cereus BSA1. AB - An extracellular xylanase from the fermented broth of Bacillus cereus BSA1 was purified and characterized. The enzyme was purified to 3.43 fold through ammonium sulphate precipitation, DEAE-cellulose chromatography and followed by gel filtration through Sephadex G-100 column. The molecular mass of the purified xylanse was about 33 kDa. The enzyme was an endoxylanase as it initially degraded xylan to xylooligomers. The purified enzyme showed optimum activity at 55 degrees C and at pH 7.0 and remained reasonably stable in a wide range ofpH (5.0-8.0) and temperature (40-65 degrees C). The Km and Vmax values were found to be 8.2 mg/ml and 181.8 micromol/(min mg), respectively. The enzyme had no apparent requirement ofcofactors, and its activity was strongly inhibited by Cu++, Hg++. It was also a salt tolerant enzyme and stable upto 2.5 M of NaCl and retained its 85% activity at 3.0 M. For stability and substrate binding, the enzyme needed hydrophobic interaction that revealed when most surfactants inhihited xylanase activity. Since the enzyme was active over wide range ofpH, temperature and remained active in higher salt concentration, it could find potential uses in biobleaching process in paper industries. PMID- 21790027 TI - Rapid differentiation of bacterial species by high resolution melting curve analysis. AB - Molecular based differentiation of various bacterial species is important in phylogenetic studies, diagnostics and epidemiological surveillance, particularly where unusual phenotype makes the classical phenotypic identification of bacteria difficult. Molecular approach based on the sequence of 16S ribosomal RNA gene analysis can achieve fast and reliable identification ofbacteria. High resolution melting (HRM) curve analysis has been developed as an attractive novel technique for DNA sequence discrimination but it's application for bacteria differentiation has not been well studied yet. W have developed HRM assay for differentiation of sixteen pathogenic or opportunistic bacterial species. Amplified partial 16S ribosomal RNA gene region between 968 and 1401 positions (E. coli reference numbering) was subsequently used in high resolution melting curve analysis of PCR products for bacterial species differentiation. Sixteen bacterial species were simultaneously discerned by difference plot of normalized and temperatures shifted melting curves, without need for spiking of DNA, hetero-duplexing experiments or application of several primer pairs. High resolution melting curve analysis of duplex DNA is simple, fast and reliable tool for bacterial species differentiation and may efficiently complement phenotypic identification ofbacteria. PMID- 21790028 TI - [Antistress cross-protection of UV irradiated yeast cells with participation of extracellular peptide factors]. AB - Antistress effect of extracellular peptides on UV irradiated yeast of different phylogenetic groups was studied. Yeast from different ecotopes and taxonomic groups exposed to UV radiation of a lethal intensity showed a protective effect and reactivating effect with participation of extracellular peptides. The highest protective activity was found in peptide reactivation factors (RFs) of bakery yeast-Saccharomyces cerevisiae, Kluyveromyces fragilis, and Candida utilis; the highest reactivating activity was exhibited by factors of the above-mentioned cultures and Debariomyces hansenii. Cross-protective and reactivating effects of RFs of yeast belonging to different taxonomic groups were demonstrated. Cross protection increased two to three times after preexposure of reactivation factors to UV light (activation) in contrast to their reactivating effect. PMID- 21790029 TI - [Conversion of soybean sterols into 3,17-diketosteroids using actinobacteria Mycobacterium neoaurum, Pimelobacter simplex, and Rhodococcus erythropolis]. AB - Abstract-Soybean sterols were converted into androst-4-ene-3,17-dione (AD) and 9alpha-hydroxyandrost-4-ene-3,17-dione (9-OH-AD) using three actinobacterium strains. The transformation of a microcrystallic substrate (particle size 5-15 nm) or the transformation in the presence of randomly methylated beta cyclodextrin (MCD) were carried out by Mycobacterium neoaurum with a phytosterol load of 30 g/l over 144 h with an AD content of 14.5 and 15.2 g/l, respectively. AD obtained in the presence of MCD was transformed into ADD (13.5 g/l) by Pimelobacter simplex cells over 3 h and into 9-OH-AD by Rhodococcus erythropolis cells after 22 h without the isolation of AD from the cultural liquid. The technical product ADD was obtained in 75% yield, based on phytosterol. It contained as impurity 1.25% of AD and 1.5% of 1,2-dehydrotestosterone. In a control experiment-the process of 1,2-dehydrogenation of 20 g/l AD in the water solution of MCD-no by products were isolated. Thus, it is more expedient to introduce the 1,2-double bond into pure AD, whereas R. erythropolis strain with low destructive activity towards steroid nucleus can be used in the mixed culture with M. neoaurum. The crystal product contained, according to HPLC, 80% of 9-OH AD, and 1.5 AD was combined. The yield of 9-OH-AD (m.p. 218-220 degrees C) based on transformed phytosterol was 56%. PMID- 21790030 TI - [Effect of phytohormones synthesized by rhizosphere bacteria on plants]. AB - New strains of rhizosphere microorganisms Azotobacter chroococcum Az d10, Bacillus megaterium P1-04, and Bacillus mucilaginosus B-1574 were found to be able to synthesize cytokinins (CKs) and indolylacetic acid (IAA). Three forms of CKs-dihydrozeatin riboside, isopentenyl adenosine, and trans-zeatin riboside-were identified, whose ratio was different in the three bacterial cultures. Inoculation of cucumber (Cucumis sativus L.) plants increased the content of CKs and IAA in them by 35.6 and 21.3%, respectively, and also stimulated seed germination and increased the growth rate, the biomass of shoots, the number of lateral roots, and the root hair area, which ensured better plant nutrition. The IAA/CKs ratio shifted during bacterization towards CKs due to increase in the content of riboside forms, which apparently caused growth stimulation. PMID- 21790031 TI - [Creation of a heterologous gene expression system on the basis of Aspergillus awamori recombinant strain]. AB - A heterologous gene expression system was created in a domestic Aspergillus awamori Co-6804 strain, which is a producer of the glucoamylase gene. Vector pGa was prepared using promoter and terminator areas of the glucoamylase gene, and A. niger phytase, Trichoderma reesei endoglucanase, and Penicillium canescens xylanase genes were then cloned into pGa vector. Separation of enzyme samples using FPLC showed the amount of the recombinant proteins to be within the 0.6-14% range of total protein. PMID- 21790033 TI - [Effect of organic and inorganic toxic compounds on luminescence of luminous fungi]. AB - The possibility of the development of the solid phase bioluminescent biotest using aerial mycelium of the luminous fungi was investigated. Effect of organic and inorganic toxic compounds (TC) at concentrations from 10(-6) to 1 mg/ml on luminescence of aerial mycelia of four species of luminous fungi-Armillaria borealis (Culture Collection of the Institute of Forest, Siberian Branch, Russian Academy of Sciences), A. mellea, A. gallica, and Lampteromyces japonicus (Fungi Collection of the Botanical Institute, Russian Academy of Sciences)--has been studied. Culture of A. mellea was shown to be most sensitive to solutions of the model TC. It was demonstrated that the sensitivity of the luminous fungi is comparable with the sensitivity of the bacteria that are used for environmental monitoring. Use of the aerial mycelium of the luminous fungi on the solid support as a test object is a promising approach in biotesting for the development of continuous biosensors for air monitoring. PMID- 21790032 TI - [New producers of biologically active compounds--fungal strains of the genus Penicillium isolated from permafrost]. AB - Screening of producers of secondary metabolites was carried out among 25 fungal strains of Penicillium genus isolated from permafrost in Arctic and Antarctic regions and Kamchatka. Nearly 50% of the investigated strains synthesize biologically active substances of alkaloid nature: ergot alkaloids, diketopiperazines, and quinoline derivatives. A large group of the identified metabolites belongs to mycotoxins. A strain of Penicillium waksmanii was found producing epoxiagroclavine-I and quinocitrinins. The main physiological and biochemical characteristics of this producer were investigated. PMID- 21790034 TI - [Melanin of Laetiporus sulphureus (Bull.: Fr.) Murr sterile form]. AB - Melanin complex was isolated from mycelium of the basidiomycete Laetiporus sulphumreus (Bull.: Fr.) Murr (with a yield of 2.49% of the fresh weight). UV and IR spectroscopies, gel chromatography, and alkaline cleavage assay demonstrated that the isolated melanin was heterogeneous and belonged to the dihydronaphthalene type. 13C-NMR data suggested that aromatic fragments were dominant in the melanin structure. In vitro study of the antioxidant action demonstrated that the L. sulphureus melanin displayed a radical-scavenging activity and the ability to inactivate hydrogen peroxide and nitrogen(II) oxide molecules and to chelate iron(II) ions. PMID- 21790035 TI - [Bioengineering of symbiotic systems: creation of new associative symbiosis with the use of lectins on the example of tobacco and colza]. AB - "Barbate roots" in tobacco and colza transgenic on lectin gene were obtained with the use of a wild strain of Agrobacterium rhizogenes 15834 transformed with pCAMBIA1305.1 plasmid containing the full-size lectin gene (psl) from the Pisum sativum. Influence of expression oflectin gene on colonization oftransgenic roots with symbiont of pea (Rhizobium leguminosarum) was investigated. The number of adhered bacteria onto the roots transformed with lectin gene was 14-fold and 37 fold higher in comparison with the control; this confirms the interaction of R. leguminosarum with pea lectin at the surface of the transformed roots of tobacco and colza. The developed experimental approach, based on the simulation of recognition processes and early symbiotic interactions with lectins of pea plants, may, in perspective, be used for obtaining stable associations of economically valuable, nonsymbiotrophic plant species with rhizobia. PMID- 21790036 TI - [Biopolymer of alginate nature with a predominance of L-guluronic acid]. AB - Highly viscous polysaccharide (250-350 kDa) of an alginate nature with a predominance of alpha-L-guluronic acid (M/G = 0.22) was obtained from Azotobacter vinelandi. The yield ofpolysaccharide was 20.5 +/- 0.5 g/l when cultured in a medium containing molasses at a viscosity of the cultural liquid of over 30000 cSt. The biopolymer is stable at pH 4.0-9.0 in a wide temperature range and well soluble in highly mineralized water; it retains a high viscosity level and can be used in the petroleum industry for enhanced oil recovery. PMID- 21790037 TI - [Effect of soybean lipoxygenae on baking properties of wheat flour]. AB - Changes in bread-baking properties of wheat flour caused by soybean lipoxygenase and polyunsaturated fatty acids were studied. A positive effect of soybean flour added during dough kneading in an amount of 2% was demonstrated. A method for dough fermentation increasing the loaf volume and improving organoleptic characteristics and total bread-baking estimate is recommended. PMID- 21790038 TI - [Development and application of indirect competitive enzyme immunoassay for detection of neomycin in milk]. AB - As a result of immunization of rabbits with neomycin B (N M) conjugated to periodate-oxidized transferrin, polyclonal antibodies were generated and used to develop an indirect competitive enzyme-linked immunosorbent assay (ELISA) of NM. Several heterologous conjugates, namely, glutaraldehyde (GA)-polymerized NM, gelatin-ribostamycin (sp), and gelatin-NM (ga) were used as coating antigens in different ELISA variants for quantification of NM in milk. These variants were characterized by different dynamic ranges and detection limits of 1.0, 0.1, and 0.01 ng/ml, respectively. Maximum residue level (MRL) of this antibiotic in milk accepted in the EU can be detected without any special pretreatment at a 100-fold sample dilution in the least sensitive assay variant. The mean recovery rate from NM-spiked milk containing 1.5-10% fat was 111.7% and ranged from 84 to 125.2%. We found that 57 of 106 tested milk samples contained NM at concentrations higher than 100 ng/ml. In ten percent of cases (11/1 06), the residual level of this antibiotic was greater than 500 ng/ml. In one case, the M RL was exceeded (1690 ng/ml). The assay developed in this study is specific shows no cross-reactivity with other veterinary aminoglycosides, has a good sensitivity reserve, and can serve as an effective tool to monitor the NM content in milk stuff. PMID- 21790039 TI - Hydrolyzed Al(III) clusters: speciation stability of nano-Al13. AB - Pure nano-Al13 and aggregates at various concentrations were prepared to examine the particle size effect of coagulation with inorganic polymer flocculant. The property and stability of various species formed were characterized using Infrared, 27Al-NMR, photo correlation spectroscopy (PCS), and Ferron assay. Results showed that concentration and temperature exhibited different roles on the stability of Al13. The quantity of Alb species analyzed by ferron assay in the initial aging period corresponded well with that of Al13, which has been confirmed in a dimension range of 1-2 nm by PCS. Al13 solutions at high concentrations (0.5-2.11 mol/L) were observed to undergo further aggregation with aging. The aggregates with a wide particle size distribution would contribute to the disappeared/decreased Al13 basis on the 27Al-NMR spectrum, whereas a part of Al13 would still remain as Alb. At low concentrations, Al13 solution was quite stable at normal temperature, but lost its stability quickly when heating to 90 degrees C. PMID- 21790040 TI - Removal of airborne microorganisms emitted from a wastewater treatment oxidation ditch by adsorption on activated carbon. AB - Bioaerosol emissions from wastewater and wastewater treatment processes are a significant subgroup of atmospheric aerosols. Most previous work has focused on the evaluation of their biological risks. In this study, however, the adsorption method was applied to reduce airborne microorganisms generated from a pilot scale wastewater treatment facility with oxidation ditch. Results showed adsorption on granule activated carbon (GAC) was an efficient method for the purification of airborne microorganisms. The GAC itself had a maximum adsorption capacity of 2217 CFU/g for airborne bacteria and 225 CFU/g for fungi with a flow rate of 1.50 m3/hr. Over 85% of airborne bacteria and fungi emitted from the oxidation ditch were adsorbed within 80 hr of continuous operation mode. Most of them had a particle size of 0.65-4.7 microm. Those airborne microorganisms with small particle size were apt to be adsorbed. The SEM/EDAX, BET and Boehm's titration methods were applied to analyse the physicochemical characteristics of the GAC. Relationships between GAC surface characteristics and its adsorption performance demonstrated that porous structure, large surface area, and hydrophobicity rendered GAC an effective absorber of airborne microorganisms. Two regenerate methods, ultraviolet irradiation and high pressure vapor, were compared for the regeneration of used activated carbon. High pressure vapor was an effective technique as it totally destroyed the microorganisms adhered to the activated carbon. Microscopic observation was also carried out to investigate original and used adsorbents. PMID- 21790041 TI - Material conversion from paper sludge ash in NaOH solution to synthesize adsorbent for removal of Pb2+, NH4+ and PO4(3-) from aqueous solution. AB - Material conversion from paper sludge ash (PSA) in NaOH solution was attempted to synthesize the adsorbent for removal of inorganic pollutants, such as Pb2+, NH4+ and PO4(3-) from aqueous solution. PSA of 0.5 g was added into 10 mL of 3 mol/L NaOH solution, and then heated at 80, 120, and 160 degrees C for 6-48 hr to obtain the product. PSA mainly composed of two crystalline phases, gehlenite (Ca2Al2SiO7) and anorthite (CaAl2Si2O8), and amorphous phase. Hydroxysodalite (Na6Al6Si6O24 8H2O) was formed at 80 degrees C, and anorthite dissolved, whereas gehlenite remained unaffected. Katoite (Ca3Al2SiO4(OH)8) was formed over 120 degrees C, and hydroxycancrinite (Na8(OH)2Al6Si6O24 2H2O) was formed at 160 degrees C, due to the dissolution of both gehlenite and anorthite. Specific surface areas of the products were almost same and were higher than that of raw ash. Cation exchange capacities (CECs) of the products were also higher than that of raw ash, and CEC obtained at lower temperature was higher. Removal abilities of products for Pb2+, NH4+, and PO4(3-) were higher than that of raw ash. With increasing reaction temperature, the removal efficiencies of Pb2+ and NH4+ decreased due to the decrease of CEC of the product, while removal efficiency for PO4(3-) was almost same. The concentrations of Si and Al in the solution and the crystalline phases in the solid during the reaction explain the formation of the product phases at each temperature. PMID- 21790042 TI - Pretreatment of heterocyclic pesticide wastewater using ultrasonic/ozone combined process. AB - Ultrasonic/O3 combined process was employed to pretreat heterocyclic pesticide wastewater for increasing biodegradability and reducing biological toxicity. Influences of ultrasonic frequency, ultrasonic power, probe diameter, initial pH and O3 dosage on the COD removal were studied. The results showed that the ultrasonic/O3 process significantly improved the biodegradability and reduced the biological toxicity of the wastewater. The ratio of BOD5/COD was increased from 0.03 to 0.55 and the EC50 increased from 11% to 52% under ultrasonic/O3 treatment. Low ultrasonic frequency brought better COD removal. Initial pH was found to have a high influence on the COD removal and alkaline conditions were more favorable. The influences of ultrasonic power and probe diameter were small. With an increase in O3 dosage, COD removal was effectively improved. The optimal operational parameters for the combined process on COD removal were ultrasonic frequency 20 kHz, initial pH 9.00, ultrasonic power 300 W and dosage of O3 454.8 mg/(L min), under which the efficiency of COD removal reached 67.2%. PMID- 21790043 TI - Effects of humic acid on recoverability and fractal structure of alum-kaolin flocs. AB - Particle surface characteristics, floc recoverability and fractal structure of alum-kaolin flocs were investigated using in situ particle image velocimetry (PIV) and microbalance with or without humic acid. Experimental results indicated that the zeta potential of kaolin particle surface after adsorption of humic acid was related with humic acid concentration and its acid-base buffering capacity. Adsorption of humic acid resulted in more negative electrophoresis on the particle surface. Coagulant dosages for particles to form flocs would increase with increasing humic concentration. PIV was used to evaluate floc structural fragmentation, floc surface erosion as well as recoverability after high shear. It was found that the floc size during the steady phase of growth was small, while the regrowing capability decreased in the presence of humic acid. The recoverability was closely related with floc breakage modes including floc structural fragmentation and floc surface erosion. The fractal dimensions of alum kaolin flocs by mass-size method based on microbalance would decrease with increasing humic concentration. This study proved that humic acid had adverse influences on the performance of coagulation process. PMID- 21790044 TI - Efficiency of active barriers attaching biofilm as sediment capping to eliminate the internal nitrogen in eutrophic lake and canal. AB - Three active barrier materials (zeolite, ceramicite and light porous media) were applied for preventing nitrogen (N) release from eutrophic lake sediments. Long term experiment of two different lake sediments were carried out and the effect of zeolite dose was evaluated. The results indicated that about 90%-100% of total N in overlying water was eliminated by using zeolite. While the N removal efficiency by ceramic was lower than that by zeolite, and light porous media present the lowest efficiency of 59%. Long term sediment incubation experiments indicated that two eutrophic sediments were both effective in preventing N release in spite of different release characteristics. Bio-zeolite capping technology was able to effectively inhibit the release of N from the sediment, and the zeolite dose was independently from N removal. PMID- 21790045 TI - Production and contribution of hydroxyl radicals between the DSA anode and water interface. AB - Hydroxyl radicals play the key role during electrochemical oxidation and photoelectrochemical oxidation. The production and effect of hydroxyl radicals on the interface between DSA anode and water was investigated by examining the quenching effect of iso-propanol on Orange II decolorization. We observed that with an increase in electrode potential from 4 to 12 V across electrodes at pH 7.0, the contribution percentage of hydroxyl radicals increased dramatically. More OH radicals were produced in acidic and alkaline conditions than at neutral conditions. At electrode potential of 4 V, the contribution percentage of hydroxyl radicals was obviously higher at near neutral pH conditions, while removal efficiency of Orange II achieved was the lowest concurrently. Finally, for photocatalytic oxidation, electrochemical oxidation, and photoelectrochemical oxidation using the same DSA electrode, the effect of hydroxyl radicals proved to be dominant in photocatalytic oxidation but the contribution of hydroxyl radicals was not dominant in electrochemical oxidation, which implies the necessity of UV irradiation for electrochemical oxidation during water treatment. PMID- 21790046 TI - Speciation characterization and coagulation of poly-silica-ferric-chloride: the role of hydrolyzed Fe(III) and silica interaction. AB - The highly efficient inorganic polymer flocculants (IPFs) of the ferric-silica system is a new and promising coagulant. Interactions between ferric species and silica play a large part in the coagulation of suspensions. These effects are quite distinct from those associated with polymeric or colloid silica. However, although these species are key to coagulation efficiency, they have not been comprehensively discussed. A new type of coagulant, poly-silica-ferric-chloride (PFSC), was synthesized by co-polymerization and characterized by time complexation spectroscopy and photon correlation spectroscopy. Compared with traditional ferric salt, the results indicated that PFSC had a higher molecular weight, lesser positive charge, lower Fe(b) and higher Fe(c). The higher the Si/Fe ratio, the higher the silica and lower the silica(c) found. The PFSC with appropriate polysilica acid not only obtained better coagulation/flocculation efficiency in turbidity removal, enhanced the flocculation index (FI) and provided less residual ferric, it also lowered water treatment costs compared to traditional ferric salt. Results showed that PFSC could remove colloid particles in water by charge neutralization and sweeping, adsorption bridging mechanism. PMID- 21790047 TI - Transport and fate of mercury under different hydrologic regimes in polluted stream in mining area. AB - Seepage from Hg mine wastes and calcines contains high concentrations of mercury (Hg). Hg pollution is a major environmental problem in areas with abandoned mercury mines and retorting units. This study evaluates factors, especially the hydrological and sedimentary variables, governing temporal and spatial variation in levels and state of mercury in streams impacted by Hg contaminated runoff. Samples were taken during different flow regimes in the Wanshan Hg mining area in Guizhou Province, China. In its headwaters the sampled streams/rivers pass by several mine wastes and calcines with high concentration of Hg. Seepage causes serious Hg contamination to the downstream area. Concentrations of Hg in water samples showed significant seasonal variations. Periods of higher flow showed high concentrations of total Hg (THg) in water due to more particles being re suspended and transported. The concentrations of major anions (e.g., Cl-, F-, NO3 and SO4(2-)) were lower during higher flow due to dilution. Due to both sedimentation of particles and dilution from tributaries the concentration of THg decreased from 2100 ng/L to background levels (< 50 ng/L) within 10 km distance downstream. Sedimentation is the main reason for the fast decrease of the concentration, it accounts for 69% and 60% for higher flow and lower flow regimes respectively in the upper part of the stream. Speciation calculation of the dissolved Hg fraction (DHg) (using Visual MINTEQ) showed that Hg(OH)2 associated with dissolved organic matter is the main form of Hg in dissolved phase in surface waters in Wanshan (over 95%). PMID- 21790048 TI - Effect of ferric and bromide ions on the formation and speciation of disinfection byproducts during chlorination. AB - The effects of ferric ion, pH, and bromide on the formation and distribution of disinfection byproducts (DBPs) during chlorination were studied. Two raw water samples from Huangpu River and Yangtze River, two typical drinking water sources of Shanghai, were used for the investigation. Compared with the samples from Huangpu River, the raw water samples from Yangtze River had lower content of total organic carbon (TOC) and ferric ions, but higher bromide concentrations. Under controlled chlorination conditions, four trihalomethanes (THMs), nine haloacetic acids (HAAs), total organic halogen (TOX) and its halogen species fractions, including total organic chlorine (TOC1) and total organic bromide (TOBr), were determined. The results showed that co-existent ferric and bromide ions significantly promoted the formation of total THMs and HAAs for both raw water samples. Higher concentration of bromide ions significantly changed the speciation of the formed THMs and HAAs. There was an obvious shift to brominated species, which might result in a more adverse influence on the safety of drinking water. The results also indicated that high levels of bromide ions in raw water samples produced higher percentages of unknown TOBr. PMID- 21790049 TI - Effects of Cu(II) and humic acid on atrazine photodegradation. AB - This work was designed to explore the characteristics of photodegradation of herbicides in the copper-polluted water body. The results showed that Cu(II) alone could induce a photo Fenton-like reaction to enhance the degradation of atrazine, in which hydroxyl radical (*OH) was a main active species. Humic acids restrained atrazine degradation, nevertheless, when introducing Cu(II), the photodegradation was accelerated, in which singlet oxygen (1O2) replaced *OH acting as the prevailing species. A feasible mechanism for the photochemical process was also proposed, which is helpful for better understanding the environmental photochemistry of atrazine in the copper-polluted water. PMID- 21790050 TI - Chelation of heavy metals by potassium butyl dithiophosphate. AB - Potassium butyl dithiophosphate (PBD) was developed and introduced as a new chelating agent for heavy metal removal. The synthesized PBD were characterized by IR and NMR. The effects of pH, chelating agent dosage, and other heavy metal ions on the performance of PBD in Cd2+ removal from water are investigated. Experimental results showed that the chelating agent could be used to treat acidic heavy metal wastewater. The Cd2+ removal was not affected by solution pH value within the range of 2 to 6. The Cd2+ removal rate could reach over 99%. Therefore, the deficiency of the precipitation process using hydroxide under alkaline condition can be overcome. Without the need for pH adjustment, the method could save on costs. If Cd2+ co-exists with Pb2+ and Cu2+, the affinity of the chelating agent with these three heavy metal ions was in the order of: Cu2+ > Pb2+ > Cd2+. Through PBD chelating precipitation, all the contents of Pb2+, Cd2+, and Cu2+ in wastewater met the standard levels through a one-step treatment. The one-step treatment process was superior to the process (sectional treatment is required) of precipitation with hydroxide. When the pH was between 3 and 11, the amount of leached chelated Cd2+ was much lower than that obtained by precipitation with hydroxide. Therefore, the risk of environmental pollution could be further reduced. PMID- 21790051 TI - Carbonyl sulfide and dimethyl sulfide fluxes in an urban lawn and adjacent bare soil in Guangzhou, China. AB - Carbonyl sulfide (COS) and dimethyl sulfide (DMS) fluxes from an urban Cynodon dactylon lawn and adjacent bare soil were measured during April-July 2005 in Guangzhou, China. Both the lawn and bare soil acted as sinks for COS and sources for DMS. The mean fluxes of COS and DMS in the lawn (-19.27 and 18.16 pmol/(m2 sec), respectively) were significantly higher than those in the bare soil (-9.89 and 9.35 pmol/(m2 sec), respectively). Fluxes of COS and DMS in mowed lawn were also higher than those in bare soils. Both COS and DMS fluxes showed diurnal variation with detectable but much lower values in the nighttime than in the daytime. COS fluxes were related significantly to temperature and the optimal temperature for COS uptake was 29 degrees C. While positive linear correlations were found between DMS fluxes and temperature. COS fluxes increased linearly with ambient COS mixing ratios, and had a compensation point of 336 ppt. PMID- 21790052 TI - Applying model simulation and photochemical indicators to evaluate ozone sensitivity in southern Taiwan. AB - Ozone sensitivity was investigated using CAMx simulations and photochemical indicator ratios at three sites (Pingtung City, Chao-Chou Town, and Kenting Town) in Pingtung County in southern Taiwan during 2003 and 2004. The CAMx simulations compared fairly well with the hourly concentrations of ozone. Simulation results also showed that Pingtung City was mainly a volatile organic compounds (VOC) sensitive regime, while Chao-Chou Town was either a VOC-sensitive or a NOx sensitive regime, depending on the seasons. Measurements of three photochemical indicators (H2O2, HNO3, and NOy) were conducted, and simulated three transition ranges of H2O2/HNO3 (0.5-0.8), O3/HNO3 (10.3-16.2) and O3/NOy (5.7-10.8) were adopted to assess the ozone sensitive regime at the three sites. The results indicated that the three transition ranges yield consistent results with CAMx simulations at most times at Pingtung City. However, both VOC-sensitive and NOx sensitive regimes were important at the rural site Chao-Chou Town. Kenting Town, a touring site at the southern end of Taiwan, was predominated by a NOx-sensitive regime in four seasons. PMID- 21790053 TI - Effects of continuously regenerating diesel particulate filters on regulated emissions and number-size distribution of particles emitted from a diesel engine. AB - The effects of continuously regenerating diesel particulate filter (CRDPF) systems on regulated gaseous emissions, and number-size distribution and mass of particles emanated from a diesel engine have been investigated in this study. Two CRDPF units (CRDPF-1 and CRDPF-2) with different specifications were separately retrofitted to the engine running with European steady-state cycle (ESC). An electrical low pressure impactor (ELPI) was used for particle number-size distribution measurement and mass estimation. The conversion/reduction rate (R(CR)) of hydrocarbons (HC) and carbon monoxide (CO) across CRDPF-1 was 83% and 96.3%, respectively. Similarly, the R(CR) of HC and CO and across CRDPF-2 was 91.8% and 99.1%, respectively. The number concentration of particles and their concentration peaks; nuclei mode, accumulation mode and total particles; and particle mass were highly reduced with the CRDPF units. The nuclei mode particles at downstream of CRDPF-1 and CRDPF-2 decreased by 99.9% to 100% and 97.8% to 99.8% respectively; and the particle mass reduced by 73% to 92.2% and 35.3% to 72.4%, respectively, depending on the engine conditions. In addition, nuclei mode particles increased with the increasing of engine speed due to the heterogeneous nucleation initiated by the higher exhaust temperature, while accumulation mode particles were higher at higher loads due to the decrease in the air-to-fuel ratio (A/F) at higher loads. PMID- 21790054 TI - Passive air sampling of organochlorine pesticides in a northeastern state of India, Manipur. AB - Thirty-six polyurethane foam disk passive air samplers (PUF-PAS) were deployed over a year during January to December, 2009 at three locations, i.e., Imphal (urban site), Thoubal (rural site) and Waithou (alpine site) of Manipur, to assess the seasonal local atmospheric emission of selected organochlorine pesticides (OCPs). The average concentration of HCHs monitored at mountain site during hot season (Mar, Apr, and May) and rainy seasons (Jun, Jul, Aug, and Sep) were 403 and 349 pg/m3, respectively. DDTs had a high concentration with 384 pg/m3 at rural site and 379 pg/m3 at urban site during hot seasons. Endosulfans and chlordane were found high in concentration during hot seasons (260 pg/m3) and low during retreating monsoon seasons (44 pg/m3) at rural site. Most of the OCPs concentrations were high during cultivation period. The OCP concentrations of rainy season were highly correlated (p < 0.01) with OCPs of hot seasons. Further, positive correlation (p < 0.05) was also obtained between cold seasons and retreating monsoon. Principal component analysis showed a significant correlation among the four seasons and distribution pattern of OCPs in air. Back trajectory analysis by using HYPSLIT model showed a long range air transport of OCPs to the present study area. Present OCP levels at Manipur is an outcome of both local emission and also movement of air mass by long range atmospheric transport. PMID- 21790055 TI - Biodegradation of geosmin in drinking water by novel bacteria isolated from biologically active carbon. AB - Three strains of Gram-negative bacteria capable of removing geosmin from drinking water were isolated from biologically active carbon and identified to be Chryseobacterium sp., Sinorhizobium sp. and Stenotrophomonas sp. based on physio biochemistry analysis and 16S rRNA gene sequence analysis. Removal efficiencies of 2 mg/L geosmin in mineral salts medium were 84.0%, 80.2% and 74.4% for Chryseobacterium sp., Sinorhizobium sp. and Stenotrophomonas sp., respectively, while removal efficiencies of 560 ng/L geosmin in filter influent were 84.8%, 82.3% and 82.5%, respectively. The biodegradation of geosmin was determined to be a pseudo first-order reaction, with rate constants at 2 mg/L and 560 ng/L being 0.097 and 0.086 day(-1), 0.089 and 0.084 day(-1), 0.074 and 0.098 day(-1) for the above mentioned degraders, respectively. The biomass of culture in the presence of geosmin was much higher than that in the absence of geosmin. PMID- 21790056 TI - Tolerance and biosorption of copper (Cu) and lead (Pb) by filamentous fungi isolated from a freshwater ecosystem. AB - Filamentous fungi are able to accumulate significant amount of metals from their environment. The potential of fungal biomass as agents for biosorption of heavy metals from contaminated sediments is currently receiving attention. In the present study, a total of 41 isolates of filamentous fungi obtained from the sediment of the Langat River, Selangor, Malaysia were screened for their tolerance and uptake capability of copper (Cu) and lead (Pb). The isolates were identified as Aspergillus niger, A. fumigatus, Trichoderma asperellum, Penicillium simplicissimum and P. janthinellum. A. niger and P. simplicissimum, were able to survive at 1000 mg/L of Cu(II) concentration on Potato Dextrose Agar (PDA) while for Pb, only A. niger survived at 5000 mg/L concentration. The results showed that A. niger, P. simplicissimum and T. asperellum have a better uptake capacity for Pb compared to Cu and the findings indicated promising biosorption of Cu and Pb by these filamentous fungi from aqueous solution. The present study was also determined the maximum removal of Cu(II) and Pb(II) that was performed by A. niger. The metal removal which occurred at Cu(II) 200 mg/L was (20.910 +/- 0.581) mg/g and at 250 mg/L of Pb(II) was (54.046 +/- 0.328) mg/g. PMID- 21790057 TI - Application of enriched stable isotope technique to the study of copper bioavailability in Daphnia magna. AB - The biokinetics of Cu in Daphnia magna, including dissolved uptake, assimilation and efflux, has been determined using a gamma 67Cu radiotracer methodology. However, this gamma emitting radioisotope is not readily available due to its very short half-life. In the present study, we employed a stable isotope tracer (65Cu) to determine the Cu biokinetics and compared our results to those determined using 67CU. The dissolved uptake rate constant of 65Cu was 3.36 L/(g day), which is higher than that of 67Cu (1.32 L/(g day)). With increasing food concentrations from 2 x 10(4) to 1 x 10(5) cells/mL, the Cu assimilation efficiency (AE) decreased from 46% to 11%, compared to a decrease from 27% to 16% when determined using 67Cu. The efflux of Cu from Daphnia magna was quantified following both dissolved and dietary uptake. The efflux of waterborne Cu was comparable to that of dietborne Cu and the efflux rate constant (0.32-0.52 day( 1)) was higher than that determined by 67Cu (0.19-0.20 day(-1)). By considering different water properties and handling procedure between the two experiments, we believe that these differences are reasonable. Overall, this study demonstrated that the enriched stable isotope tracer technique is a powerful tool to investigate metal bioavailability and maybe a good alternative to radioactive measurements. PMID- 21790058 TI - Interactions of zinc and cadmium toxicity in their effects on growth and in antioxidative systems in tomato plants (Solanum lycopersicum). AB - The interaction between zinc and cadmium was investigated in tomato plants (Solanum lycopersicum). Ten-day-old seedlings were treated with 10 micromol/L CdCl2 associated to different concentrations of ZnCl2 (10, 50, 100, and 150 micromol/L). Zn supply clearly reduced Cd accumulation in leaves and simultaneously increased Zn concentration. Cd induced oxidative stress in leaves as indicated by an increase in thiobarbituric acid-reactive substances (TBARS) level and chlorophyll breakdown. Furthermore, compared with control, Cd-treated plants had significantly higher activities of superoxide dismutase (SOD, EC 1.15.1.1), whereas, catalase (CAT, EC 1.111.1.6), ascorbate peroxidase (APX, EC 1.11.1.11), and glutathione reductase (GR, EC 1.6.4.2) activities were significantly suppressed by Cd addition. Zn supplementation, at low level, restored and enhanced the functional activity of these enzymes (SOD, CAT, APX and GR) as compared to Cd-alone-treated plants. The beneficial effect of adequate Zn level on Cd toxicity was confirmed by a significant decrease in TBARS level and restoration of chlorophyll content. However, when Zn was added at high level in combination with Cd there was an accumulation of oxidative stress, which was higher than that for Cd or excess Zn alone treatments. These results suggested that higher Zn concentrations and Cd are synergistic in their effect on plant growth parameters and oxidative stress. PMID- 21790059 TI - Eco-toxicity of petroleum hydrocarbon contaminated soil. AB - Total petroleum hydrocarbons (TPH) contaminated soil samples were collected from Shengli Oilfield of China. Toxicity analysis was carried out based on earthworm acute toxicity, plant growth experiment and luminescent bacteria test. The soil was contaminated by-petroleum hydrogcarbons with TPH concentration of 10.57%. With lethal and sub-lethal rate as endpoint, earthworm test showed that the LD50 (lethal dose 50%) values in 4 and 7 days were 1.45% and 1.37% respectively, and the inhibition rate of earthworm body weight increased with higher oil concentration. TPH pollution in the soil inhibited seed germination in both wheat and maize experiment when the concentration of petroleum was higher than 0.1%. The EC50 (effective concentration 50%) for germination is 3.04% and 2.86% in maize and wheat, respectively. While lower value of EC50 for root elongation was to be 1.11% and 1.64% in maize and wheat, respectively, suggesting higher sensitivity of root elongation on petroleum contamination in the soil. The EC50 value in luminescent bacteria test was 0.47% for petroleum in the contaminated soil. From the experiment result, it was concluded that TPH content of 1.5% is considered to be a critical value for plant growth and living of earthworm and 0.5% will affect the activity of luminescent bacteria. PMID- 21790060 TI - Hormetic response of cholinesterase from Daphnia magna in chronic exposure to triazophos and chlorpyrifos. AB - In vivo activity of cholinesterase (ChE) in Daphnia magna was measured at different time points during 21-day exposure to triazophos and chlorpyrifos ranging from 0.05 to 2.50 microg/L and 0.01 to 2.00 microg/L, respectively. For exposure to triazophos, ChE was induced up to 176.5% at 1.5 microg/L and day 10 when measured by acetylthiocholine (ATCh), whereas it was induced up to 174.2% at 0.5 microg/L and day 10 when measured by butyrylthiocholine (BTCh). For exposure to chlorpyrifos, ChE was induced up to 134.0% and 160.5% when measured by ATCh and BTCh, respectively, with both maximal inductions detected at 0.1 microg/L and day 8. Obvious induction in terms of ChE activity was also detected in daphnia removed from exposures 24 hr after their birth and kept in a recovery culture for 21 days. Results indicated that the enzyme displayed symptoms of hormesis, a characteristic featured by conversion from low-dose stimulation to high-dose inhibition. In spite of that, no promotion in terms of reproduction rate and body size was detected at any tested concentrations regardless of whether the daphnia were collected at end of the 21-day exposure or at end of a 21-day recovery culture. This suggested that induction of ChE caused by anticholinesterases had nothing to do with the prosperity of the daphnia population. PMID- 21790061 TI - TiO2 nanotubes as solid-phase extraction adsorbent for the determination of polycyclic aromatic hydrocarbons in environmental water samples. AB - An analytical method based on TiO2 nanotubes solid-phase extraction (SPE) combined with gas chromatography (GC) was established for the analysis of seven polycyclic aromatic hydrocarbons (PAHs): acenaphtylene, acenaphthene, anthracene, fluorene, phenanthrene, fluoranthene and pyrene. Factors affecting the extraction efficiency including the eluent type and its volume, adsorbent amount, sample volume, sample pH and sample flow rate were optimized. The characteristic data of analytical performance were determined to investigate the sensitivity and precision of the method. Under the optimized extraction conditions, the method showed good linearity in the range of 0.01-0.8 microg/mL, repeatability of the extraction (RSD were between 6.7% and 13.5%, n = 5) and satisfactory detection limits (0.017-0.059 ng/mL). The developed method was successfully applied to the analysis of surface water (tap, river and dam) samples. The recoveries of PAHs spiked in environmental water samples ranged from 90% to 100%. All the results indicated the potential application of titanate nanotubes as solid-phase extraction adsorbents to pre-treat water samples. PMID- 21790062 TI - Methanotrophic community structure of aged refuse and its capability for methane bio-oxidation. AB - Aged refuse from waste landfills closed for eight years was examined and found to contain rich methanotrophs capable of biooxidation for methane. Specially, community structure and methane oxidation capability of methanotrophs in the aged refuse were studied. The amount of methanotrophs ranged 61.97 x 10(3)-632.91 x 10(3) cells/g (in dry basis) in aged refuse from Shanghai Laogang Landfill. Type I and II methanotrophs were found in the aged refuse in the presence of sterilized sewage sludge and only Type I methanotrophs were detected in the presence of nitrate minimal salt medium (NMS). The clone sequences of the pmoA gene obtained from the aged refuse were similar to the pmoA gene of Methylobacter Methylocaldum, and Methylocystis, and two clones were distinct with known genera of Type I methanotrophs according to phylogenetic analysis. Aged refuse enriched with NMS was used for methane biological oxidation and over 93% conversions were obtained. PMID- 21790063 TI - Moisture distribution in sludges based on different testing methods. AB - Moisture distributions in municipal sewage sludge, printing and dyeing sludge and paper mill sludge were experimentally studied based on four different methods, i.e., drying test, thermogravimetric-differential thermal analysis (TG-DTA) test, thermogravimetric-differential scanning calorimetry (TG-DSC) test and water activity test. The results indicated that the moistures in the mechanically dewatered sludges were interstitial water, surface water and bound water. The interstitial water accounted for more than 50% wet basis (wb) of the total moisture content. The bond strength of sludge moisture increased with decreasing moisture content, especially when the moisture content was lower than 50% wb. Furthermore, the comparison among the four different testing methods was presented. The drying test was advantaged by its ability to quantify free water, interstitial water, surface water and bound water; while TG-DSC test, TG-DTA test and water activity test were capable of determining the bond strength of moisture in sludge. It was found that the results from TG-DSC and TG-DTA test are more persuasive than water activity test. PMID- 21790064 TI - Replication and persistence of VHSV IVb in freshwater turtles. AB - With the emergence of viral hemorrhagic septicemia virus (VHSV) strain IVb in the Great Lakes of North America, hatchery managers have become concerned that this important pathogen could be transmitted by animals other than fish. Turtles are likely candidates because they are poikilotherms that feed on dead fish, but there are very few reports of rhabdovirus infections in reptiles and no reports of the fish rhabdoviruses in animals other than teleosts. We injected common snapping turtles Chelydra serpentine and red-eared sliders Trachemys scripta elegans intraperitoneally with 10(4) median tissue culture infectious dose (TCID50) of VHSV-IVb and 21 d later were able to detect the virus by quantitative real-time reverse transcriptase PCR (qrt-RTPCR) in pools of kidney, liver, and spleen. In a second experiment, snapping turtles, red-eared sliders, yellow bellied sliders T. scripta scripta, and northern map turtles Grapetemys geographica at 14 degrees C were allowed to feed on tissues from bluegill dying of VHSV IVb disease. Turtle kidney, spleen, and brain pools were not positive by qrt-RTPCR on Day 3 post feeding, but were positive on Days 10 and 20. Map turtles on Day 20 post-feeding were positive by both qrt-RTPCR and by cell culture. Our work shows that turtles that consume infected fish are a possible vector for VHSV IVb, and that the fish rhabdoviruses may have a broader host range than previously suspected. PMID- 21790066 TI - Tenacibaculum sp. associated with winter ulcers in sea-reared Atlantic salmon Salmo salar. AB - Coldwater-associated ulcers, i.e. winter ulcers, in seawater-reared Atlantic salmon Salmo salar L. have been reported in Norway since the late 1980s, and Moritella viscosa has been established as an important factor in the pathogenesis of this condition. As routine histopathological examination of winter ulcer cases in our laboratory revealed frequent presence in ulcers of long, slender rods clearly different from M. viscosa, a closer study focusing on these bacteria was conducted. Field cases of winter ulcers during 2 sampling periods, 1996 and 2004 2005, were investigated and long, slender rods were observed by histopathological examination in 70 and 62.5% of the ulcers examined, respectively, whereas cultivation on marine agar resulted in the isolation of yellow-pigmented colonies with long rods from 3 and 13% of the ulcers only. The isolates could be separated into 2 groups, both identified as belonging to the genus Tenacibaculum based on phenotypic characterization and 16S rRNA sequencing. Bath challenge for 7 h confirmed the ability of Group 1 bacterium to produce skin and cornea ulcers. In fish already suffering from M. viscosa-induced ulcers, co-infection with the Group 1 bacterium was established within 1 h. Ulcers from field cases of winter ulcers and from the transmission experiments tested positive by immunohistochemistry with polyclonal antiserum against the Group 1 bacterium but not the Group 2 bacterium. Our results strongly indicate the importance of the Group 1 bacterium in the pathogenesis of winter ulcers in Norway. The bacterium is difficult to isolate and is therefore likely to be underdiagnosed based on cultivation only. PMID- 21790065 TI - Ultrastructural and sequence characterization of Penaeus vannamei nodavirus (PvNV) from Belize. AB - The Penaeus vannamei nodavirus (PvNV), which causes muscle necrosis in Penaeus vannamei from Belize, was identified in 2005. Infected shrimp show clinical signs of white, opaque lesions in the tail muscle. Under transmission electron microscopy, the infected cells exhibit increases in various organelles, including mitochondria, Golgi stacks, and rough endoplasmic reticulum. Cytoplasmic inclusions containing para-crystalline arrays of virions were visualized. The viral particle is spherical in shape and 19 to 27 nm in diameter. A cDNA library was constructed from total RNA extracted from infected shrimp. Through nucleotide sequencing from the cDNA clones and northern blot hybridization, the PvNV genome was shown to consist of 2 segments: RNA1 (3111 bp) and RNA2 (1183 bp). RNA1 contains 2 overlapped open reading frames (ORF A and B), which may encode a RNA dependent RNA polymerase (RdRp) and a B2 protein, respectively. RNA2 contains a single ORF that may encode the viral capsid protein. Sequence analyses showed the presence of 4 RdRp characteristic motifs and 2 conserved domains (RNA-binding B2 protein and viral coat protein) in the PvNV genome. Phylogenetic analysis based on the translated amino acid sequence of the RdRp reveals that PvNV is a member of the genus Alphanodavirus and closely related to Macrobrachium rosenbergii nodavirus (MrNV). In a study investigating potential PvNV vectors, we monitored the presence of PvNV by RT-PCR in seabird feces and various aquatic organisms collected around a shrimp farm in Belize. PvNV was detected in mosquitofish, seabird feces, barnacles, and zooplankton, suggesting that PvNV can be spread via these carriers. PMID- 21790067 TI - Anisakis simplex (s.s.) larvae in wild Alaska salmon: no indication of post mortem migration from viscera into flesh. AB - The prevalence, mean intensity and distribution of Anisakis nematode third-stage larvae (L3) in the muscle and viscera of wild-caught chum salmon Oncorhynchus keta, pink salmon O. gorbuscha and sockeye salmon O. nerka were compared immediately after catch. Salmon were collected during the fishing season in July 2007 in Bristol Bay and Prince William Sound close to Cordova, Alaska (USA). All fish were infected, and more than 90% of the nematode larvae were found in the edible muscle meat. The isolated anisakid L3 were genetically identified as A. simplex (s.s.). The distribution of nematodes in the muscle meat of fresh-caught salmon was examined in 49 O. keta, 50 O. nerka and 12 O. gorbuscha from Cordova. Most of the larvae were detected in the muscle parts around the body cavity, but nematodes were also found in the tail meat and epaxial muscle (loins). The mean intensity of Anisakis larvae in the edible part was 21 individuals for O. gorbuscha, 62 individuals for O. keta and 63 individuals for O. nerka. No difference in the intensity of Anisakis larvae in the hypaxial muscle was found between fresh-caught and immediately gutted salmon and individuals stored ungutted for 24 h either on ice or in refrigerated sea water. PMID- 21790068 TI - Characterisation of two vitellogenins in the salmon louse Lepeophtheirus salmonis: molecular, functional and evolutional analysis. AB - The salmon louse Lepeophtheirus salmonis Kroyer affects a variety of wild salmonoid hosts, but is also an important pest in aquaculture, which is a globally important and rapidly growing industry. Salmon lice have large reproductive outputs, and knowledge of reproductive processes may be crucial for the control of this parasite. Here, we report on the characterisation of 2 vitellogenins (LsVit1 and LsVit2), which are the precursors of salmon-louse egg yolk glycoprotein. The structure of LsVit1 and LsVit2 was examined and compared to that in other oviparous animals. Phylogenetic analysis of LsVit1 and LsVit2 confirmed the view that crustaceans are a polyphyletic group. Transcriptional and translational analysis demonstrated production of LsVit1 and LsVit2 in the subcuticular tissue of the adult female lice. LsVit1 and LsVit2 could also be found in maturing oocytes and developing embryos and early larval stages. LsVit2 was found to be processed into 2 smaller fragments, whereas LsVit1 was found to be full length when deposited into the oocytes. Degradation of LsVit1 and LsVit2 was characterised through embryogenesis and the early non-feeding larval stages. Finally, protein content and the level of free amino acids were analysed in embryos and larval stages and their role in nutrition and osmoregulation discussed. In conclusion, our results confirm the role of vitellogenins in reproduction as providers of embryonic and larval nutrition. PMID- 21790069 TI - Dental pathology in dolphins (Cetacea: Delphinidae) from the southern coast of Brazil. AB - Pathological processes observed in the stomatognathic systems of mammalian species are a useful source of information about the habits, evolution and general health of such animals. Studies of pathological conditions on teeth are common in humans and other primates, but rare in wild animals in general and marine mammals in particular. For cetaceans, previous studies provided scanty records of dental anomalies in a few species. This is the first broad and systematic inventory of dental pathology in dolphins. Specimens stored at scientific collections from the southern coast of Brazil were visually inspected under a stereoscopic microscope using a dental explorer. Diagnosis of lesions and anomalies followed literature descriptions. Abnormalities such as caries-like lesions, mineralized calculus deposits, dental erosion, enamel anomalies (hypoplasia and exogenous pigmentation), root resorption, germination and other shape anomalies, were diagnosed in the delphinids Sotalia guianensis, Delphinus capensis, Stenella frontalis, Stenella coeruleoalba, Lagenodelphis hosei, Pseudorca crassidens, Orcinus orca, Steno bredanensis and Tursiops truncatus. Endogenous causes may be related to the occurrence of certain conditions, but the aetiology of caries-like lesions and calculus accumulation is still unknown for cetaceans. The diagnosis of alveolar anomalies and other bone lesions in specimens with dental pathology lead us to believe these lesions modify the integrity of the periodontal ligament and bony tissues, adding to the burden of morbidity of affected animals. PMID- 21790070 TI - Elevated temperature as a treatment for Batrachochytrium dendrobatidis infection in captive frogs. AB - The amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in amphibian declines worldwide. In vitro laboratory studies and those done on wild populations indicate that Bd grows best at cool temperatures between 17 and 25 degrees C. In the present study, we tested whether moderately elevating the ambient temperature to 30 degrees C could be an effective treatment for frogs infected with Bd. We acquired 35 bullfrogs Rana catesbeiana from breeding facilities and 36 northern cricket frogs Acris crepitans from the wild and acclimated them to either 23 or 26 degrees C for 1 mo. Following the acclimation period, frogs were tested for the presence of Bd using qPCR TaqMan assays. The 12 R. catesbeiana and 16 A. crepitans that tested positive for Bd were subjected to 30 degrees C for 10 consecutive days before returning frogs to their starting temperatures. Post-treatment testing revealed that 27 of the 28 frogs that had tested positive were no longer infected with Bd; only a single A. crepitans remained infected following treatment. This result indicates that elevating ambient temperature to a moderate 30 degrees C can be effective as a treatment for Bd infection in captive amphibians, and suggests that heat may be a superior alternative to antifungal drugs. PMID- 21790071 TI - Viral basophilic inclusions in the digestive gland of razor clams Ensis arcuatus (Pharidae) in Galicia (NW Spain). AB - During a histological survey of razor clam Ensis arcuatus (Jeffreys, 1865) from Galicia (NW Spain), basophilic inclusion bodies were observed in epithelial cells of the digestive gland. Transmission electron microscopy revealed the intranuclear position of these inclusions containing viral particles with icosahedral symmetry. Size and symmetry of these unenveloped virus particles suggest similarities to the families Papillomaviridae and Polyomaviridae which have been described as causing a viral gametocytic hypertrophy in oysters Crassostrea virginica and C. gigas. This is the first report of viral particles in E. arcuatus. PMID- 21790072 TI - Isolation of a novel adenovirus from California sea lions Zalophus californianus. AB - Viral hepatitis associated with adenoviral infection has been reported in California sea lions Zalophus californianus admitted to rehabilitation centers along the California coast since the 1970s. Canine adenovirus 1 (CAdV-1) causes viral hepatitis in dogs and infects a number of wildlife species. Attempts to isolate the virus from previous sea lion hepatitis cases were unsuccessful, but as the hepatitis had morphologic features resembling canine infectious hepatitis, and since the virus has a wide host range, it was thought that perhaps the etiologic agent was CAdV-1. Here, we identify a novel adenovirus in 2 stranded California sea lions and associate the infection with viral hepatitis and endothelial cell infection. Phylogenetic analysis confirmed the classification of the sea lion adenovirus in the Mastadenovirus genus with the most similarity to tree shrew adenovirus 1 (TSAdV-1, 77%). However, as the sea lion adenovirus appeared to be equally distant from the other Mastadenovirus species based on phylogenetic analysis, results indicate that it represents an independent lineage and species. Although sequences from this novel virus, otarine adenovirus 1 (OtAdV-1), show some similarity to CAdV-1 and 2, it is clearly distinct and likely the cause of the viral hepatitis in the stranded California sea lions. PMID- 21790073 TI - Molecular identification and virulence of three Aeromonas hydrophila isolates cultured from infected channel catfish during a disease outbreak in west Alabama (USA) in 2009. AB - Three isolates (AL09-71, AL09-72, and AL09-73) of Aeromonas hydrophila were cultured from infected channel catfish Ictalurus punctatus during a disease outbreak in west Alabama, USA, in August 2009. Sequence analysis of the 16S-23S rDNA intergenic spacer region (ISR), cpn60, gyrB, and rpoD genes of the 3 strains revealed that the 3 strains were closely related to each other, sharing 97 to 99% nucleotide sequence similarities. However, ISR sequences of the 3 isolates from 2009 shared only 64% nucleotide sequences with AL98-C1B, a 1998 isolate of A. hydrophila cultured from diseased fish in Alabama. Sequences of cpn60, gyrB, and rpoD from the 3 isolates from 2009 shared 91 to 95% homologies with AL98-C1B. Based on both LD50 and LD95 values of intraperitoneal injection assays, the virulences of the 3 isolates from 2009 were not significantly different from each other, but were at least 200-fold more virulent than AL98-C1B, indicating that the 3 west Alabama isolates of A. hydrophila from 2009 were highly virulent to channel catfish. PMID- 21790074 TI - Welfare of aquatic organisms: is there some faith-based HARKing going on here? AB - Much of the literature on aquatic animal welfare is flawed by 4 non-mutually exclusive (and often inter-related) biases: under-reporting/ignoring of negative results, faith-based research and/or interpretations, Hypothesizing After the Results are Known (HARKing), and inflating the science boundary. These biases have an insidious impact on the credibility of the 'science' surrounding aquatic animal welfare. While concerns about the welfare of aquatic organisms are valid, research on this topic should be grounded in the scientific method, embrace negative results, avoid faith-based interpretations of experimental results and/or HARKing, and strictly respect the science boundary. PMID- 21790075 TI - Influence of seasonal variability of lower Mississippi River discharge, temperature, suspended sediments, and salinity on oil-mineral aggregate formation. AB - Under certain conditions, oil droplets that have separated from the main oil slick may become coated by suspended sediments forming oil-mineral aggregates (OMAs). The formation of these aggregates depends on suspended particulate characteristics, temperature, salinity, mixing energy, droplet size and number, and oil properties. The OMAs do not re-coalesce with the slick and tend not to adhere to surfaces, potentially evading surface cleanup measures, enhancing opportunity for biodegradation and reducing shoreline oiling. Potential OMA formation was quantified during four distinct states of the Lower Mississippi River during a typical year using empirical relationships from laboratory and field studies for three common oils and different combinations of discharge, temperature, suspended sediments, and salinity. The largest potential OMA formation for the two lighter oils, up to 36% of the total release volume, was in the winter and spring, when high sediment availability promotes formation. For the denser, high-viscosity oil, the peak potential OMA formation, 9% of the release volume, occurred in the summer, when the salinity was higher. These results provide some evidence that, depending on environmental and spill characteristics, the formation of OMAs could be an important, but unaccounted for, process in the fate and transport of oils released in the Lower Mississippi River and should be included in oil spill dispersion models and post-spill site assessment and remediation actions. PMID- 21790076 TI - Decomposition of acetone by hydrogen peroxide/ozone process in a rotating packed contactor. AB - The direct use of ozone (O3) in water and wastewater treatment processes is found to be inefficient, incomplete, and limited by the ozone transfer between the gas liquid interface because of its low solubility and instability in aqueous solutions. Therefore, rotating packed contactors were introduced to improve the transfer of ozone from the gaseous phase to the solution phase, and the effect of several reaction parameters were investigated on the temporal variations of acetone concentration in aqueous solution. The decomposition rate constant of acetone was enhanced by increasing the rotor speed from 450 to 1800 rpm. Increasing the hydrogen peroxide (H2O2)/O3 molar ratios accelerated the decomposition rate until a certain optimum H2O2/O3 molar ratio was reached; further addition of H2O2 inhibited the decomposition of acetone, possibly because excessive amounts of H2O2 added might serve as a scavenger to deplete hydroxyl free radicals. PMID- 21790077 TI - Biological phosphorus removal performance and relevant microorganism characteristics of activated sludge in municipal wastewater treatment plants, China. AB - Municipal wastewater discharge is threatening the ecological security of the local water environment. This study investigated the field process performance and microorganism characteristics of enhanced biological phosphorus removal (EBPR) in municipal wastewater treatment plants (WWTPs) in China. The results showed that three WWTPs met the required criteria of phosphorus for discharge (< or = 1 mg/L), but with a low level of Accumulibacter (6.4 to 3.8%, on average) and a relatively high level of Competibacter (3.2 to 9.1%) in sludge. The phosphorus release and uptake rates were varied from 0.224 to 7.770 mg/gVSS x h and 0.386 to 7.901 mg/gVSSh, respectively. Denitrifying polyphosphate accumulating organisms were estimated to be 28.2% of the polyphosphate accumulating organisms. Sludge characteristics (phosphorus release and uptake rates) were positively correlated with the abundance of Accumulibacter and negatively correlated with the proportion of Competibacter. Moreover, the lower the ratio of anaerobic phosphorus/acetate (e.g., 0.496) is, the more abundant the Competibacter would be. Further discussion on an improvement strategy for these WWTPs for EBPR should be comprehensively based on the data of periodic investigations on field operation, sludge activities, and microbial populations. PMID- 21790078 TI - Groundwater remediation using an enricher reactor-permeable reactive biobarrier for periodically absent contaminants. AB - A combined enricher reactor (ER)-permeable reactive biobarrier (PRBB) system was developed to treat groundwater with contaminants that appear in batches. An enricher reactor is an offline reactor used to enrich contaminant degraders by supplying necessary growth materials, and the enriched degraders are used to augment PRBB to increase its performance after a period of contaminant absence. Bench-scale experiments on PRBBs with and without bacterial supply from the enricher reactor were conducted to evaluate PRBB removal performances for benzene, which was used as a model contaminant. Benzene absence periods of 10 and 25 days were tested in the presence and absence of ethanol. The PRBBs without the bioaugmentation from the enricher reactor experienced a decrease in performance from approximately 65% to 30% after benzene reappeared. The presence of ethanol accelerated the benzene removal performance recovery of PRBBs. The 25-day benzene absence period caused greater changes in the bacterial community structure, regardless of the ethanol availability. PMID- 21790079 TI - Effects of potassium and magnesium in the enhanced biological phosphorus removal process using a membrane bioreactor. AB - This study assessed the role of potassium (K+), magnesium (Mg2+), and calcium (Ca2+) ions in the enhanced biological phosphorus removal (EBPR) from wastewaters using a membrane bioreactor (MBR). A linear relationship in the anaerobic and aerobic/ anoxic phases for P(uptake) versus P(release) was obtained using the known equation deltaP(uptake) = a x deltaP(release)+ b, where the constants "a" and "b" were found to be 0.44 and 8.40, respectively. Both potassium and magnesium were soluble with phosphate in the anaerobic phase, but they accumulated again during the successive aerobic/anoxic phase. The linear correlation coefficients (R2) of K+/PO4-P and Mg2/PO4-P were calculated as 0.6682 and 0.8884, respectively. The molar ratio of C(K/P) during anaerobic phosphorus release was observed to be 0.20 mol/mol, whereas C(Mg/P) was 0.21 mol/mol. Furthermore, unlike potassium and magnesium, calcium was not co-transported with phosphorus during the release and uptake processes. PMID- 21790080 TI - Inhibition of nitrification by low oxygen concentrations in an aerated treatment pond system with biofilm promoting mats. AB - Inhibition of nitrification in the presence of low oxygen concentrations (below 1.2 mg/L) and temperature dependency at oxygen saturation levels were observed in an aerated treatment pond system with biofilm promoting mats in two parallel ponds for remediation of ammonium, methyl tertiary butyl ether (MTBE), and benzene-contaminated groundwater. Within the first 18 months, at an average oxygen concentration of 0.7 +/- 0.5 mg/L along the ponds, no significant decrease of ammonium or significant formation of nitrification products were observed. After increasing the aeration to oxygen saturation levels, the ammonium removal increased up to a maximum of 27%, with concomitant formation of nitrite and nitrate (up to 26 and 0.6 mM). The subsequent reduction of aeration in one pond to the previous level resulted in a definitive stop of nitrification, while, in the other pond, nitrification was well-correlated with the water temperature, reaching up to 45% ammonium removal. PMID- 21790081 TI - Comparison of conventional and integrated fixed-film activated sludge systems: attached- and suspended-growth functions and quantitative polymerase chain reaction measurements. AB - Pilot-scale integrated fixed-film activated sludge (IFAS) and non-IFAS control systems were compared, with respect to overall performance and functional behaviors and microbial population composition in the attached and suspended phases. The suspended phases of the control and IFAS systems exhibited similar rates of ammonia consumption; the attached phase in the second aerobic IFAS reactor had significantly higher rates of ammonia consumption and nitrate production than any other biomass source, and the attached biomass from the first aerobic reactor had the lowest ammonia consumption rates. Quantitative polymerase chain reaction (qPCR) indicated the presence of the ammonia-oxidizing bacteria Nitrosomonas oligotropha and the nitrite-oxidizing bacteria Nitrospira spp. and Nitrobacter spp. Mathematical modeling and qPCR both indicated greater concentrations of nitrifiers in the attached phases of a downstream aerobic reactor relative to the upstream reactor, possibly because of increased competition from heterotrophs for space in the attached phase of the upstream aerobic reactor. PMID- 21790082 TI - Optimization of operating parameters of intermittent aeration-type activated sludge process for nitrogen removal: a simulation-based approach. AB - Biological nitrogen removal is becoming a proven approach to reducing the total nitrogen discharged from wastewater treatment facilities. Simulation performed with intermittent aeration-type activated sludge process using Activated Sludge Model No. 1 predicted that up to 90% total nitrogen removal could be attained when the total cycle time and its anoxic phase were balanced adequately. This control limits electron donor and acceptor levels--ammonia-nitrogen (NH4(+)-N) in the aerobic phase and nitrate-nitrogen (NO3(-)-N) in the anoxic phase. Specifically, maximum nitrogen removal appears to be achieved with a 2- to 3-hour cycle time, during which, anoxic conditions were present for 40 to 50% of the time. A 10- to 16-hour hydraulic retention time appears adequate to achieve these results. The solids retention time studied was between 15 and 25 days, as this range was deemed sufficient to establish the nitrifying organism population in most applications. Predictions indicate that the conventional activated sludge system can be retrofitted for better nitrogen management at the treatment plants. PMID- 21790083 TI - Effect of feeding strategy on the performance of sequencing batch reactor with dual anoxic feedings for swine wastewater treatment. AB - Two feeding ratios, 3:1 (RUN I) and 2:1 (RUN II), were experimented to investigate their effect on removal of nitrogen, phosphorus, organic matter, and on the trends of oxidization-reduction potential (ORP) and pH in sequencing batch reactors (SBR) with dual anoxic feedings of swine wastewater. Results showed for both runs, the feeding ratio had a more significant effect on the removal of phosphorus and nitrogen than on COD in the operating cycle. As compared to RUN I, the removal of nitrogen and phosphorus was enhanced in RUN II. In addition, the optimal feeding ratio greater than 1:1 for SBR with dual anoxic feedings can be determined with reference to the decreasing range of ORP following the primary feeding, and the denitrification-associated ORP bending point in the second non aeration phase. PMID- 21790084 TI - Treatment of wastewaters containing bisphenol A: state of the science review. AB - The presence of microconstituents in effluents from municipal wastewater treatment plants (WWTPs) and their receiving waters has attracted considerable recent attention. This review summarizes the state of the science on the removal of bisphenol A (BPA) by WWTPs and presents evidence that the compound should be effectively removed in well-operated activated sludge systems. The biological treatment of BPA has been extensively studied in laboratory, pilot, and full scale municipal WWTPs. Although removal efficiencies varied, the average of the reported removal efficiencies for BPA in full-scale facilities was 84%. Mass balance studies conducted in the laboratory with 14C-labeled BPA and studies of full-scale facilities show that biodegradation is the dominant removal process, consistent with the fact that BPA is readily degradable and able to support microbial growth. Many of the plants were able to reduce BPA concentrations in the wastewater effluent to significantly less than 1 microg/L. This review examines operating parameters important for optimizing and sustaining the performance of wastewater treatment systems including solids residence time (SRT), which proved to be the most critical. The weight of evidence suggests the optimum SRT needs to be approximately 10 days to ensure high treatment efficiencies. Other optimum operating conditions include maintaining dissolved oxygen concentrations of greater than or equal to 2.0 mg/L, elevating the SRT during periods of low temperature, and implementing step-feed control during storm-induced high flow conditions to avoid the washout of biomass. PMID- 21790085 TI - Comparative investigation of parameters for determining the dewaterability of activated sludge. AB - This paper compared four parameters evaluating the dewaterability of sludge- capillary suction time (CST), specific resistance to filtration (SRF), bound water content, and dry solids content in the centrifuged sludge cake of the different sludge flocs from seven full-scale wastewater treatment plants. The dry solids content correlated with the normalized CST (R2 = 0.7112, p = 0.003), SRF (R2 = 0.6043, p = 0.011), and the bound water content (R2 = 0.8106, p = 0.001). The normalized CST was correlated significantly with SRF (R2 = 0.9450, p = 0.000) and correlated with the bound water (R2 = 0.5110, p = 0.0417). However, SRF correlated very weakly with the bound water (R2 = 0.3929, p = 0.0448). It is not necessary to use both CST and SRF at the same time to estimate the sludge dewaterability. The normalized CST is feasible because of its affordability, simple equipment, and measurement procedure. However, another parameter indicating the dewatering extent, such as dry solids content in sludge cake, should be applied together to evaluate the dewatering efficiency of the activated sludge. PMID- 21790086 TI - Don't stifle IT innovation. PMID- 21790087 TI - Disaster response. 'You can't teach that kind of character'. PMID- 21790088 TI - Aligning forces to improve quality, equity of care. Interview by Bob Kehoe. PMID- 21790089 TI - Payment. Hospitals partner with Blue Cross Blue Shield on value-based purchasing. PMID- 21790090 TI - Technology. Telehealth programs spreading like 'wildfire'. PMID- 21790091 TI - Legislation. Gaps in equipment sterilization lead to calls for worker certification. PMID- 21790092 TI - 'From hell and back'. PMID- 21790093 TI - Patient safety. Hospital system sets sights on reducing infections, mortality. PMID- 21790094 TI - Going their way. PMID- 21790095 TI - The most difficult budget year. AB - With most states facing severe budget shortfalls, community health centers and Medicaid programs could be in for major funding cuts, threatening the health care safety net and putting hospital emergency departments on the line to fill the gap. "Hospitals and community health centers are going to have to work a lot more closely together in the future," says Craig Becker, president of the Tennessee Hospital Association. PMID- 21790096 TI - No rest for the weary. PMID- 21790097 TI - Integrate your revenue cycle. AB - Payment and collection functions no longer can be confined to the financial silo. Clinical input is critical to building a successful process. PMID- 21790098 TI - Pioneering hospitals are reinventing intensive care units. PMID- 21790099 TI - A faster track for data exchange. PMID- 21790100 TI - Animosity, antagonism, and avatars: teaching conflict management in second life. AB - Conflict exists in all health care organizations and may take many forms, including lateral or horizontal violence. The Essentials of Baccalaureate Nursing Education identified the development of conflict resolution strategies as core knowledge required of the bachelor's of science in nursing generalist. However, learning the art of conflict management takes both time and practice. With competition for clinical space increasing, class time in short supply, and traditional clinical opportunities for teaching conflict management lacking, a virtual approach to teaching conflict resolution was explored through the use of Second Life(r). The project presented here explored students' perceptions of this unique approach to learning conflict management and sought to examine the effectiveness of this teaching method. PMID- 21790101 TI - Student-centered outcomes evaluation of the Clinical Immersion Program: five years later. AB - Curricular innovation is an ever-present element of nursing education. It is incumbent for nurse educators to evaluate their curricula and its outcomes to ensure quality nursing education. This article describes a comprehensive student centered outcome evaluation of the Clinical Immersion Model. This model and the foundational components unique to the curricular design and the senior clinical immersion are described. Several methods of evaluation, including National Council Licensure Examination for Registered Nurses pass rates, exit surveys, alumni surveys, and a senior nursing student focus group, are presented. Implications of this evaluation and future directions are explored to inform potential implementation and adaptation of this effective curriculum by other schools of nursing. PMID- 21790102 TI - Nursing students' preconceptions of the community health clinical experience: implications for nursing education. AB - It is essential that nurse educators identify and attempt to understand students' preconceptions related to upcoming clinical experiences to develop strategies that are effective in preparing the students for entry into new and unique settings. This qualitative study described nursing students' preconceptions as they entered the community health clinical rotation. Six major themes emerged: feeling insecure and unprepared for the community health clinical experience; contemplating risks to personal and client safety in the community; anticipating a change of pace; sensing a loss of control; envisioning isolation; and interpreting the value of community health nursing. Findings from this study provide nurse educators and preceptors with insight into understanding students' needs as they enter the community setting. Facilitating a positive transition for students supports efforts to improve the image of and create favorable attitudes toward community health nursing practice. PMID- 21790103 TI - Making a case for the case study method. PMID- 21790104 TI - Who do you bring to practice? Making plaster of paris masks. PMID- 21790105 TI - Occupational health assessment: a tool for nursing faculty. PMID- 21790106 TI - Photoacoustic ophthalmoscopy for in vivo retinal imaging: current status and prospects. AB - Photoacoustic ophthalmoscopy (PAOM) is a new retinal imaging technology that offers the unique capability to measure optical absorption in the retina. Because PAOM is compatible with optical coherence tomography, scanning laser ophthalmoscopy, and autofluorescence imaging, registered multimodal images can be acquired from a single device at comparable resolution for comprehensive anatomic and functional retinal characterizations. Therefore, PAOM is anticipated to have applications in both research and clinical diagnosis of many blinding diseases. The authors explain the basic principles of the photoacoustic effect and imaging. Then, different types of photoacoustic microscopy are introduced and compared. Finally, the current status of photoacoustic imaging in animal eyes is presented and the prospects of future development of PAOM are suggested. PMID- 21790107 TI - Volumetric three-dimensional reconstruction and segmentation of spectral-domain OCT. AB - Despite advances in optical coherence tomography (OCT), three-dimensional (3D) renderings of OCT images remain limited to scanning consecutive two-dimensional (2D) OCT slices. The authors describe a method of reconstructing 2D OCT data for 3D retinal analysis and visualization in a Computer Assisted Virtual Environment (CAVE). Using customized signal processing software, raw data from 2D slice-based spectral-domain OCT images were rendered into high-resolution 3D images for segmentation and quantification analysis. Reconstructed OCT images were projected onto a four-walled space and viewed through stereoscopic glasses, resulting in a virtual reality perception of the retina. These 3D retinal renderings offer a novel method for segmentation and isolation of volumetric images. The ability to manipulate the images in a virtual reality environment allows visualization of complex spatial relationships that may aid our understanding of retinal pathology. More importantly, these 3D retinal renderings can be viewed, manipulated, and analyzed on traditional 2D monitors independent of the CAVE. PMID- 21790108 TI - Ultra-high resolution optical coherence tomography for imaging the anterior segment of the eye. AB - Developments in optical coherence tomography (OCT) have expanded its clinical applications for ultra-high resolution imaging of the anterior segment of the human eye. This review presents the latest advances for imaging the anterior segment of the eye using ultra-high resolution OCT (UHR-OCT). Unique applications of UHR-OCT technology in clinical and basic scientific laboratory research are discussed and a summary of the results is provided. The authors focused on the use of UHR-OCT for imaging of tear dynamics, contact lens interactions with the corneal surface, and in vivo histological diagnosis of disorders of the cornea, as well as the future direction in this field. PMID- 21790109 TI - Optical coherence tomography in the diagnosis and management of optic neuritis and multiple sclerosis. AB - Optic neuritis (ON) is an inflammatory optic nerve injury, which is strongly associated with multiple sclerosis (MS). Optical coherence tomography (OCT) has the potential to provide a reliable means of capturing axonal deficits, which can be paired to tests of visual function to provide a structural-functional paradigm of brain injury. In this respect, the eye provides a unique view into the effects of central nervous system inflammation, which may enhance the understanding of disease mechanisms that contribute to neurological disability in MS. This review addresses the published experience with OCT in the diagnosis and treatment of patients with ON and MS, and discusses the applications of OCT in ongoing clinical trials. The potential gains and limitations of spectral-domain OCT as an evolving technology and surrogate marker of axonal brain injury are also discussed. PMID- 21790110 TI - Optical coherence tomography in the diagnosis and management of diabetic macular edema: time-domain versus spectral-domain. AB - Optical coherence tomography (OCT) is an important imaging modality in the setting of diabetic macular edema (DME). Its use allows more precise evaluation of retinal pathology in DME, including retinal thickness and edema, vitreomacular interface abnormalities, subretinal fluid, and foveal microstructural changes. Additional advantages include its ability to quantitatively monitor response to treatment of DME by laser, intravitreal pharmacotherapies, and vitreoretinal surgery. OCT measurements are now used in all major clinical studies of DME treatment as critical endpoints. This article presents a review of both time domain and spectral-domain OCT in the diagnosis and management of DME. The authors discuss the various parameters evaluated by the OCT systems and provide an evidence-based evaluation of their accuracy, significance, reliability, and limitations. As the capability of OCT continues to advance, it appears that its use will play an increasingly important role in the understanding, evaluation, and treatment of DME. PMID- 21790111 TI - OCT: a bright future. PMID- 21790112 TI - The role of spectral-domain OCT in the diagnosis and management of neovascular age-related macular degeneration. AB - Spectral-domain optical coherence tomography (SD-OCT) has emerged as the ancillary examination of choice to assist the diagnosis and management of neovascular age-related macular degeneration (AMD). SD-OCT provides more detailed images of intraretinal, subretinal, and subretinal pigment epithelium fluid when compared to time-domain technology, leading to higher and earlier detection rates of neovascular AMD activity. Improvements in image analysis and acquisition speed make it important for decision-making in the diagnosis and treatment of this disease. However, this new technology needs to be validated for its role in the improvement of visual outcomes in the context of anti-angiogenic therapy. PMID- 21790114 TI - Clinical applications of long-wavelength (1,000-nm) optical coherence tomography. AB - Commercial optical coherence tomography (OCT) instruments generally use light sources in the range of 800 to 860 nm. Although imaging with these light sources provides excellent visualization of the retinal architecture, details of structures and abnormalities below the retinal pigment epithelium are often limited. At the same time, the optimal light source wavelength for clinical OCT imaging is unknown. OCT imaging using longer wavelength light (1,050 nm) has several potential advantages, including less scattering with media opacity and deeper penetration. This article reviews the current state-of-the-art of long wavelength OCT imaging and explores potential clinical applications. PMID- 21790113 TI - Clinical use of OCT in assessing glaucoma progression. AB - Detection of disease progression is an important and challenging component of glaucoma management. Optical coherence tomography (OCT) has proved to be valuable in the detection of glaucomatous damage. With its high resolution and proven measurement reproducibility, OCT has the potential to become an important tool for glaucoma progression detection. This manuscript presents the capabilities of the OCT technology pertinent for detection of progressive glaucomatous damage and provides a review of the current knowledge on the device's clinical performance. PMID- 21790115 TI - Enhanced depth imaging optical coherence tomography. AB - Imaging the choroid with conventional commercial spectral-domain optical coherence tomography (SD-OCT) has been difficult, mainly because of difficulty in signal transmission beyond the retinal pigment epithelium. A recent modification to the standard technique, termed enhanced depth imaging optical coherence tomography (EDI-OCT), was able to image the choroid with reasonable clarity using commercial SD-OCTs. The aim of this article was to review the technique, principle, recent findings, and possible future developments regarding EDI-OCT. A MEDLINE search on all published articles on EDI-OCT was performed up to December 2010. The principle behind EDI-OCT was discussed. Modification to the conventional technique in image acquisition was described and illustrated with figures. EDI-OCT findings in various retinal and choroidal diseases were discussed. Advantages and disadvantages were also discussed. EDI-OCT has proved to be a promising novel technique in imaging the choroid. PMID- 21790117 TI - Binocular optical coherence tomography. AB - The use of optical coherence tomography (OCT) in the field of ophthalmology has increased rapidly in recent years and may continue on this trajectory as more indications for OCT imaging are described. Recent pressures on the healthcare system, such as rising costs, increasing demand, and decreasing reimbursements, suggest that continued growth in OCT use may be unsustainable unless cheaper and more efficient methods are developed. Binocular OCT has the potential to decrease the cost, increase the quality, and improve the efficiency not just of OCT imaging, but of eye care as a whole. Binocular OCT devices should be cheaper to build and operate than conventional OCT instruments. They may be able to replace labor-intensive, qualitative tests with patient-operated, quantitative examinations. They could also usher in a new era of comprehensive, remote eye care and eye disease screening that has the potential to reengineer the practice of ophthalmology. PMID- 21790116 TI - The use of optical coherence tomography in intraoperative ophthalmic imaging. AB - Optical coherence tomography (OCT) has transformed diagnostic ophthalmic imaging but until recently has been limited to the clinic setting. The development of spectral-domain OCT (SD-OCT), with its improved speed and resolution, along with the development of a handheld OCT scanner, enabled portable imaging of patients unable to sit in a conventional tabletop scanner. This handheld SD-OCT unit has proven useful in examinations under anesthesia and, more recently, in intraoperative imaging of preoperative and postoperative manipulations. Recently, several groups have pioneered the development of novel OCT modalities, such as microscope-mounted OCT systems. Although still immature, the development of these systems is directed toward real-time imaging of surgical maneuvers in the intraoperative setting. This article reviews intraoperative imaging of the posterior and anterior segment using the handheld SD-OCT and recent advances toward real-time microscope-mounted intrasurgical imaging. PMID- 21790118 TI - Efficient light-harvesting antenna with a multi-porphyrin cascade. AB - A light-harvesting antenna 1 comprising three varieties of porphyrins, each having a different number of ethynyl groups at its meso positions, was designed and synthesized. Antenna 1 exhibits intense absorption throughout the visible region up to 700 nm. Steady-state and time-resolved fluorescence studies showed that singlet-excited-state energy transfer occurs from the peripheral porphyrins to the central porphyrin with >90% efficiency and rate constants on the order of 10(10) s(-1). PMID- 21790119 TI - Ergopeptines bromocriptine and ergovaline and the dopamine type-2 receptor inhibitor domperidone inhibit bovine equilibrative nucleoside transporter 1-like activity. AB - Neotyphodium coenophialum-infected tall fescue contains ergopeptines. Except for interactions with biogenic amine receptors (e.g., dopamine type-2 receptor, D2R), little is known about how ergopeptines affect animal metabolism. The effect of ergopeptines on bovine nucleoside transporters (NT) was evaluated using Madin Darby bovine kidney (MDBK) cells. Equilibrative NT1 (ENT1)-like activity accounted for 94% of total NT activity. Inhibitory competition (IC(50)) experiments found that this activity was inhibited by both bromocriptine (a synthetic model ergopeptine and D2R agonist) and ergovaline (a predominant ergopeptine of tall fescue). Kinetic inhibition analysis indicated that bromocriptine inhibited ENT1-like activity through a competitive and noncompetitive mechanism. Domperidone (a D2R antagonist) inhibited ENT1 activity more in the presence than in the absence of bromocriptine and displayed an IC(50) value lower than that of bromocriptine or ergovaline, suggesting that inhibition was not through D2R-mediated events. These novel mechanistic findings imply that cattle consuming endophyte-infected tall fescue have reduced ENT1 activity and, thus, impaired nucleoside metabolism. PMID- 21790120 TI - Protection-free one-pot synthesis of 2'-deoxynucleoside 5'-triphosphates and DNA polymerization. AB - By differentiating the functional groups on nucleosides, we have designed and developed a one-pot synthesis of deoxyribonucleoside 5'-triphosphates without any protection on the nucleosides. A facile synthesis is achieved by generating an in situ phosphitylating reagent that reacts selectively with the 5'-hydroxyl groups of the unprotected nucleosides. The synthesized triphosphates are of high quality and can be effectively incorporated into DNAs by DNA polymerase. This novel approach is straightforward and cost-effective for triphosphate synthesis. PMID- 21790121 TI - Highly chromic, proton-responsive phenyl pyrimidones. AB - Aryl pyrimidones are pharmacologically relevant compounds whose optical properties have only been partially explored. We report the synthesis and optical characterization of a series of aryl- and diaryl-2(1H)-pyrimidones. The electronic transitions of these chromophores are modulated by the extent of conjugation between the pendant phenyl ring and the pyrimidone core as well as the presence of electron-donating auxochromes. Monoprotonation of the pyrimidone ring results in large hyperchromic and bathochromic shifts as well as switching of fluorescence making these phenyl pyrimidones of interest as sensory materials. PMID- 21790122 TI - Discovery and process synthesis of novel 2,7-pyrrolo[2,1-f][1,2,4]triazines. AB - The synthesis of a new kinase inhibitor template 2-anilino-7-aryl-pyrrolo[2,1 f][1,2,4]triazine is described which includes a late stage orthogonally reactive key intermediate amenable to rapid diversification as well an optimized in situ triflate displacement to install the C2-aniline. Furthermore, an efficient scalable process approach will be highlighted which begins with tert-butyl carbazate to provide the key N-N bond and generates the pyrrolotriazine core through a stable bromoaldehyde intermediate followed by condensation with ammonium carbonate. PMID- 21790123 TI - Palladium-catalyzed direct ethynylation of C(sp3)-H bonds in aliphatic carboxylic acid derivatives. AB - The first catalytic alkynylation of unactivated C(sp(3))-H bonds has been accomplished. The method allows for the straightforward introduction of an ethynyl group into aliphatic acid derivatives under palladium catalysis. This new reaction can be applied to the rapid elaboration of complex aliphatic acids, for example, via azide/alkyne cycloaddition. PMID- 21790124 TI - Palladium-catalyzed approach to primary amides using nongaseous precursors. AB - A simple protocol is reported for the preparation of primary aryl amides under Pd catalyzed carbonylation chemistry applying a two-chamber system with crystalline and nontransition metal based sources of carbon monoxide and ammonia. The method is suitable for the synthesis of a number of primary amides with good functional group tolerance. Incorporation of (13)CO into the primary amide group was also found to be effective making this approach useful for accessing carbon isotope labeled derivatives. PMID- 21790125 TI - Gold nanoparticles grown on star-shaped block copolymer monolayers. AB - We report on the growth of gold nanoparticles in polystyrene/poly(2-vinyl pyridine) (PS/P2VP) star-shaped block copolymer monolayers. These amphiphilic PS(n)P2VP(n) heteroarm star copolymers differ in molecular weight (149,000 and 529,000 Da) and the number of arms (9 and 28). Langmuir-Blodgett (LB) deposition was utilized to control the spatial arrangement of P2VP arms and their ability to reduce gold nanoparticles. The PS(n)P2VP(n) monolayer acted as a template for gold nanoparticle growth because of the monolayer's high micellar stability at the liquid-solid interface, uniform domain morphology, and ability to adsorb Au ions from the water subphase. UV-vis spectra and AFM and TEM images confirmed the formation of individual gold nanoparticles with an average size of 6 +/- 1 nm in the P2VP-rich outer phase. This facile strategy is critical to the formation of ultrathin polymer-gold nanocomposite layers over large surface areas with confined, one-sided positioning of gold nanoparticles in an outer P2VP phase at polymer-silicon interfaces. PMID- 21790126 TI - Synthesis and evaluation of novel carbon-11 labeled oxopurine analogues for positron emission tomography imaging of translocator protein (18 kDa) in peripheral organs. AB - To develop a PET ligand for imaging TSPO in peripheral organs, we designed three novel oxopurine analogues [(11)C]3a-c (LogD: 1.81-2.17) by introducing a pyridine ring in place of a benzene ring in the lead compound [(11)C]2 (LogD: 3.48). The desmethyl precursors 10 for radiosynthesis were synthesized by reacting glycine 7 with picolylamines 4, followed by hydrolysis and by Curtius rearrangement with diphenylphosphoryl azide. Methylation of 10a-c with methyl iodide produced unlabeled compounds 3a-c. The radiosynthesis of [(11)C]3a-c was performed by reacting 10a-c with [(11)C]methyl iodide. Compounds 3a-c displayed high or moderate in vitro binding affinities (K(i): 5-40 nM) for TSPO. PET with [(11)C]3a c in rats showed high uptake in the lung, heart, and kidney, which are organs with high TSPO expression. Metabolite analysis with [(11)C]3a showed that radioactivity in these organs mainly corresponded with unchanged [(11)C]3a. PET with [(11)C]3a using a rat model of lung inflammation showed a significant signal in the lipopolysaccharide-treated lung. PMID- 21790127 TI - One-dimensionally extended paddlewheel dirhodium complexes from metal-metal bonds with diplatinum complexes. AB - We have succeeded in obtaining unique one-dimensional (1D) chain complexes (1, 2, and 3) comprised of two types of metal species: rhodium and platinum. These compounds are constructed from a dinuclear rhodium complex (i.e., [Rh(2)]) and a pivalamidate-bridged platinum complex (i.e., [Pt(2)]), forming an attractive quasi-1D infinite chain, expressed as -{[Rh(2)]-[Pt(2)]-[Pt(2)]}(n)-. Interestingly, the bridging ligands of [Rh(2)] can be varied with trifluoroacetate, acetate, and acetamidate groups, indicating the possibility of electronic structure modulation in the 1D chain. PMID- 21790128 TI - Self-assembly of tissue transglutaminase into amyloid-like fibrils using physiological concentration of Ca2+. AB - Tissue transglutaminase (tTG or TG2) is a member of the transglutaminase family that catalyzes calcium dependent formation of isopeptide bonds. It has been shown that the expression of TG2 is elevated in neurodegenerative diseases such as Parkinson's, Huntington's, and Alzheimer's. We have investigated the self assembly of TG2 in vitro. First, using software, hot spots, which are prone for aggregation, were identified in domain 2 of the enzyme. Next we expressed and purified recombinant TG2 and its truncated version that contains only the catalytic domain, and examined their amyloidogenic behavior in various conditions including different temperatures and pHs, in the presence of metal ions and Guanosine triphosphate (GTP). To analyze various stages leading to TG2 fibrillation, we employed various techniques including Thioflavin T (ThT) binding assay, Congo-Red, birefringence, Circular Dichroism (CD), 8-anilino-1-naphthalene sulfonic acid (ANS) binding, Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM). Our results indicated that using low concentrations of Ca(2+), TG2 self-assembled into amyloid-like fibrils; this self-assembly occurred at the physiological temperature (37 degrees C) and at a higher temperature (57 degrees C). The truncated version of TG2 (domain 2) also forms amyloid-like fibrils only in the presence of Ca(2+). Because amyloid formation has occurred with domain 2 alone where no enzymatic activity was shown, self-cross-linking by the enzyme was ruled out as a mechanism of amyloid induction. The self-assembly of TG2 was not significant with magnesium and zinc ions, indicating specificity of the self-assembly for calcium ions. The calcium role in self-assembly of TG2 into amyloid may be extended to other proteins with similar biophysical properties to produce novel biomaterials. PMID- 21790131 TI - Vibrational properties of CaAlH5 and alpha-AlH3 with different AlH6 networks studied by inelastic neutron scattering. AB - We performed a combined study using inelastic neutron scattering (INS) and first principles calculations of the vibrational properties of CaAlH(5) and alpha AlH(3) with different AlH(6) networks, a zigzag one-dimensional AlH(6) network for CaAlH(5), and a three-dimensional AlH(6) network for alpha-AlH(3). Both materials showed qualitatively similar INS spectra, in which CaAlH(5)/alpha AlH(3) was mainly divided into three regions: (i) the translational modes (318/316 cm(-1)), (ii) the librational modes of the octahedral AlH(6) units (external molecular motion) in the lower frequency range and H-Al-H bond-bending modes (intra molecular motion) at a higher frequency (420-1157/513-1038 cm(-1)), and (iii) the Al-H bond-stretching modes (1238-1750/1486-1942 cm(-1)). In region ii, the appearance of both librational and bond-bending modes was determined by the networked nature of the octahedral AlH(6) units. In addition, the librational modes of AlH(6) on alpha-AlH(3) exhibit higher frequencies than CaAlH(5) due to the tighter bonding between the octahedral AlH(6) units. With regard to average frequencies for the Al-H, omega(S), bond-stretching modes, and average Al-H bond distances on the aluminum-based hydrides including CaAlH(5) and alpha-AlH(3), omega(S) showed lower frequencies that correlate with lengthening of the Al-H bond distances. PMID- 21790129 TI - Characterization of interactions of 4-nitrophenylpropyl-N-alkylamine with sigma receptors. AB - Sigma receptors are small membrane proteins implicated in a number of pathophysiological conditions, including drug addiction, psychosis, and cancer; thus, small molecule inhibitors of sigma receptors have been proposed as potential pharmacotherapeutics for these diseases. We previously discovered that endogenous monochain N-alkyl sphingolipids, including d-erythro-sphingosine, sphinganine, and N,N-dimethylsphingosine, bind to the sigma-1 receptor at physiologically relevant concentrations [Ramachandran, S., et al. (2009) Eur. J. Pharmacol. 609, 19-26]. Here, we investigated several N-alkylamines of varying chain lengths as sigma receptor ligands. Although the K(I) values for N alkylamines were found to be in the micromolar range, when N-3-phenylpropyl and N 3-(4-nitrophenyl)propyl derivatives of butylamine (1a and 1b, respectively), heptylamine (2a and 2b, respectively), dodecylamine (3a and 3b, respectively), and octadecylamine (4a and 4b, respectively) were evaluated as sigma receptor ligands, we found that these compounds exhibited nanomolar affinities with both sigma-1 and sigma-2 receptors. A screen of high-affinity ligands 2a, 2b, 3a, and 3b against a variety of other receptors and/or transporters confirmed these four compounds to be highly selective mixed sigma-1 and sigma-2 ligands. Additionally, in HEK-293 cells reconstituted with K(v)1.4 potassium channel and the sigma-1 receptor, these derivatives were able to inhibit the outward current from the channel, consistent with sigma receptor modulation. Finally, cytotoxicity assays showed that 2a, 2b, 3a, and 3b were highly potent against a number of cancer cell lines, demonstrating their potential utility as mixed sigma-1 and sigma-2 receptor anticancer agents. PMID- 21790130 TI - Predicting phospholipidosis: a fluorescence noncell based in vitro assay for the determination of drug-phospholipid complex formation in early drug discovery. AB - This paper describes for the first time, a high-throughput fluorescence noncell based assay to screen for the drug-phospholipid interaction, which correlates to phospholipidosis. Anionic amphiphilic phospholipids can form complexes in aqueous solution, and its critical micelle concentration (CMC) can be determined using the fluorescence probe N,N-dimethyl-6-propionyl-2-naphthylamine (Prodan). Upon interaction with drug candidates, this CMC may shift to a lower value due to the association between lipids and drug candidates, the stronger the interaction, the greater the shift. Metabolism of a drug can change the degree of phospholipidosis depending on the rate of metabolism and the nature of the metabolite(s). Our data from 45 drugs and metabolites of 10 drugs using this fluorescence approach demonstrate a good correlation with phospholipidosis as reported with human studies, in vivo testing, and cellular assays. This assay therefore offers a fast, reliable, and cost-effective screening tool for early prediction of the phospholipidosis-inducing potential of drug candidates. PMID- 21790132 TI - Amine-promoted beta-elimination of a beta-aryloxy aldehyde for fluorogenic chemodosimeters. AB - We previously reported a fluorescent chemodosimeter for ozone. The beta elimination step after the ozonolysis of the chemodosimeter was too slow to be practical for real-time monitoring of ozone. We examined primary, secondary, and tertiary amines at various pHs. It was found that pyrrolidine in pH 9 buffer could accelerate the elimination to generate a fluorescence signal. The elimination step is now sufficiently rapid to monitor ozone exposure in real time. We also discovered that azetidine was distinctly effective for the same elimination reaction in a pH 6 buffer. PMID- 21790133 TI - Nanoparticle flotation collectors: mechanisms behind a new technology. AB - This is the first report describing a new technology where hydrophobic nanoparticles adsorb onto much larger, hydrophilic mineral particle surfaces to facilitate attachment to air bubbles in flotation. The adsorption of 46 nm cationic polystyrene nanoparticles onto 43 MUm diameter glass beads, a mineral model, facilitates virtually complete removal of the beads by flotation. As little as 5% coverage of the bead surfaces with nanoparticles promotes high flotation efficiencies. The maximum force required to pull a glass bead from an air bubble interface into the aqueous phase was measured by micromechanics. The pull-off force was 1.9 MUN for glass beads coated with nanoparticles, compared to 0.0086 MUN for clean beads. The pull-off forces were modeled using Scheludko's classical expression. We propose that the bubble/bead contact area may not be dry (completely dewetted). Instead, for hydrophobic nanoparticles sitting on a hydrophilic surface, it is possible that only the nanoparticles penetrate the air/water interface to form a three-phase contact line. We present a new model for pull-off forces for such a wet contact patch between the bead and the air bubble. Contact angle measurements of both nanoparticle coated glass and smooth films from dissolved nanoparticles were performed to support the modeling. PMID- 21790134 TI - Hydrolysis influence on phytochemical composition, antioxidant activity, plasma concentration, and tissue distribution of hydroethanolic Ilex paraguariensis extract components. AB - The infusion of aerial parts of Ilex paraguariensis is widely consumed. Its antioxidant activity suggests an important role of this plant in the treatment/prevention of oxidative stress related diseases. Plant extract active compounds are frequently found in esterified form that may be poorly absorbed. Hydrolysis of the extract is a possible approach to increase its bioavailability. The aim of this study was to perform a phytochemical analysis and evaluate in rats the plasma concentration and tissue distribution of antioxidant compounds in the hydroethanolic extract of Ilex paraguariensis, before and after enzymatic hydrolysis. Both extracts presented high antioxidant activity and phenolic content. Rats given single or repeated doses of the hydrolyzed extract showed increased plasma antioxidant activity and higher plasma levels of caffeic acid. However, no changes of endogenous antioxidants were observed. In conclusion, hydrolysis of the extract of Ilex paraguariensis is a strategy to improve its bioavailability and in vivo antioxidant activity. PMID- 21790135 TI - Unusual metal ion selectivities of the highly preorganized tetradentrate ligand 1,10-phenanthroline-2,9-dicarboxamide: a thermodynamic and fluorescence study. AB - Some metal ion complexing properties of the ligand PDAM (1,10-phenanthroline-2,9 dicarboxamide) in aqueous solution are reported. Using UV-visible spectroscopy to follow the intense pi-pi* transitions of PDAM as a function of metal ion concentration, log K(1) values in 0.1 M NaClO(4) and at 25 degrees C are, for Cu(II), 3.56(5); Ni(II), 3.06(5); Zn(II), 3.77(5); Co(II), 3.8(1); Mg(II), 0.1(1); Ca(II), 1.94(4); and Ba(II), 0.7(1). For more strongly bound metal ions, competition reactions between PDAM and EDTA (ethylenedinitrilo-tetraacetic acid) or tetren (1,4,7,10,13-pentaazatridecane), monitored following the UV spectrum of PDAM, gave the following log K(1) values in 0.1 M NaClO(4) and at 25 degrees C: Cd(II), 7.1(1); Pb(II), 5.82(5); In(III), 9.4(1); and Bi(III), 9.4(1). The very low log K(1)(PDAM) values for small metal ions such as Cu(II) or Zn(II) are unprecedented for a phen-based ligand (phen = 1,10-phenanthroline), which is rationalized in terms of the low basicity of the N donors of the ligand (pK(a) = 0.6) and the fact that PDAM has a best-fit size corresponding to large metal ions of ionic radius ~1.0 A. Large metal ions with ionic radius >=1.0 A show large increases in log K(1) relative to their phen complexes, which in turn produces unparalleled selectivities, such as a 3.5 log units greater log K(1)(PDAM) for Cd(II) than for Cu(II). PDAM shows strong fluorescence in aqueous solution, suggesting that its carboxamide groups do not produce a fluorescence-quenching photon-induced electron transfer (PET) effect. Only Ca(II) produces a weak CHEF (chelation enhanced fluorescence) effect with PDAM, while all other metal ions tested produce a decrease in fluorescence, a CHEQ (chelation enhanced quenching effect). The production of the CHEQ effect is rationalized in terms of the idea that coordination of metal ions to PDAM stabilizes a canonical form of the carboxamide groups that promotes a PET effect. PMID- 21790136 TI - Structural characterization of chitin and chitosan obtained by biological and chemical methods. AB - Chitin production was biologically achieved by lactic acid fermentation (LAF) of shrimp waste (Litopenaeus vannameii) in a packed bed column reactor with maximal percentages of demineralization (D(MIN)) and deproteinization (D(PROT)) after 96 h of 92 and 94%, respectively. This procedure also afforded high free astaxanthin recovery with up to 2400 MUg per gram of silage. Chitin product was also obtained from the shrimp waste by a chemical method using acid and alkali for comparison. The biologically obtained chitin (BIO-C) showed higher M(w) (1200 kDa) and crystallinity index (I(CR)) (86%) than the chemically extracted chitin (CH-C). A multistep freeze-pump-thaw (FPT) methodology was applied to obtain medium M(w) chitosan (400 kDa) with degree of acetylation (DA) ca. 10% from BIO-C, which was higher than that from CH-C. Additionally, I(CR) values showed the preservation of crystalline chitin structure in BIO-C derivatives at low DA (40-25%). Moreover, the FPT deacetylation of the attained BIO-C produced chitosans with bloc copolymer structure inherited from a coarse chitin crystalline morphology. Therefore, our LAF method combined with FPT proved to be an affective biological method to avoid excessive depolymerization and loss of crystallinity during chitosan production, which offers new perspective applications for this material. PMID- 21790137 TI - Effect of hydrophilic organic seed aerosols on secondary organic aerosol formation from ozonolysis of alpha-pinene. AB - Gas-particle partitioning theory is widely used in atmospheric models to predict organic aerosol loadings. This theory predicts that secondary organic aerosol (SOA) yield of an oxidized volatile organic compound product will increase as the mass loading of preexisting organic aerosol increases. In a previous work, we showed that the presence of model hydrophobic primary organic aerosol (POA) had no detectable effect on the SOA yields from ozonolysis of alpha-pinene, suggesting that the condensing SOA compounds form a separate phase from the preexisting POA. However, a substantial faction of atmospheric aerosol is composed of polar, hydrophilic organic compounds. In this work, we investigate the effects of model hydrophilic organic aerosol (OA) species such as fulvic acid, adipic acid, and citric acid on the gas-particle partitioning of SOA from alpha-pinene ozonolysis. The results show that only citric acid seed significantly enhances the absorption of alpha-pinene SOA into the particle phase. The other two seed particles have a negligible effect on the alpha-pinene SOA yields, suggesting that alpha-pinene SOA forms a well-mixed organic aerosol phase with citric acid and a separate phase with adipic acid and fulvic acid. This finding highlights the need to improve the thermodynamics treatment of organics in current aerosol models that simply lump all hydrophilic organic species into a single phase, thereby potentially introducing an erroneous sensitivity of SOA mass to emitted OA species. PMID- 21790138 TI - Effect of self-assembled monolayers on charge injection and transport in poly(3 hexylthiophene)-based field-effect transistors at different channel length scales. AB - Charge injection and transport in bottom-contact regioregular-poly(3 hexylthiophene) (rr-P3HT) based field-effect transistors (FETs), wherein the Au source and drain contacts are modified by self-assembled monolayers (SAMs), is reported at different channel length scales. Ultraviolet photoelectron spectroscopy is used to measure the change in metal work function upon treatment with four SAMs consisting of thiol-adsorbates of different chemical composition. Treatment of FETs with electron-poor (electron-rich) SAMs resulted in an increase (decrease) in contact metal work function because of the electron-withdrawing ( donating) tendency of the polar molecules. The change in metal work function affects charge injection and is reflected in the form of the modulation of the contact resistance, R(C). For example, R(C) decreased to 0.18 MOmega in the case of the (electron-poor) 3,5-bis-trifluoromethylbenzenethiol treated contacts from the value of 0.61 MOmega measured in the case of clean Au-contacts, whereas it increased to 0.97 MOmega in the case of the (electron-rich) 3-thiomethylthiophene treated contacts. Field-effect mobility values are observed to be affected in short-channel devices (<20 MUm) but not in long-channel devices. This channel length-dependent behavior of mobility is attributed to grain-boundary limited charge transport at longer channel lengths in these devices. PMID- 21790139 TI - Synthesis and properties of a blue bipolar indenofluorene emitter based on a D-pi A design. AB - Through a rational design, a novel Donor-Acceptor pi-conjugated (D-pi-A) blue fluorescent indenofluorene dye, DA-DSF-IF, has been synthesized for application in single-layer Small Molecule Organic Light Emitting Diodes (SMOLEDs). This new blue emitter possesses bipolar properties as well as good morphological and emission color stabilities and has been successfully used in a blue emitting single-layer SMOLED, with performances impressively magnified compared to a nonbipolar indenofluorene emitter. PMID- 21790140 TI - Oligomerization state of photosynthetic core complexes is correlated with the dimerization affinity of a transmembrane helix. AB - In the Rhodobacter (Rba.) species of photosynthetic purple bacteria, a single transmembrane alpha-helix, PufX, is found within the core complex, an essential photosynthetic macromolecular assembly that performs the absorption and the initial processing of light energy. Despite its structural simplicity, many unresolved questions surround PufX, the most important of which is its location within the photosynthetic core complex. One proposed placement of PufX is at the center of a core complex dimer, where two PufX helices associate in the membrane and form a homodimer. Inability for PufX of certain Rba. species to form a homodimer is thought to lead to monomeric core complexes. In the present study, we employ a combination of computational and experimental techniques to test the hypothesized homodimerization of PufX. We carry out a systematic investigation to measure the dimerization affinity of PufX from four Rba. species, Rba. blasticus , Rba. capsulatus , Rba. sphaeroides , and Rba. veldkampii , using a molecular dynamics-based free-energy method, as well as experimental TOXCAT assays. We found that the four PufX helices have substantially different dimerization affinities. Both computational and experimental techniques demonstrate that species with dimeric core complexes have PufX that can potentially form a homodimer, whereas the one species with monomeric core complexes has a PufX with little to no dimerization propensity. Our analysis of the helix-helix interface revealed a number of positions that may be important for PufX dimerization and the formation of a hydrogen-bond network between these GxxxG-containing helices. Our results suggest that the different oligomerization states of core complexes in various Rba. species can be attributed, among other factors, to the different propensity of its PufX helix to homodimerize. PMID- 21790141 TI - Characterization of the unfolding process of the tetrameric and dimeric forms of Cratylia mollis seed lectin (CRAMOLL 1): effects of natural fragmentation on protein stability. AB - pCRAMOLL 1 is a major, non-glycosylated isolectin found in seeds of Cratylia mollis, which belongs to the Leguminosae family and the Diocleinae subtribe. The lectin (~25 kDa) consists of 236 amino acids, sharing 82% identity and virtually identical topological architecture with concanavalin A. Both lectins also share the same pH-dependent dimer-tetramer equilibrium and the ability to recognize Glc/Man moieties. Intricate post-translational events occurring in Diocleinae seed cotyledons result in a mixture of intact and fragmented monomers within the oligomeric assemblies of pCRAMOLL 1. In an earlier report, we demonstrated the production, purification, and characterization of the bacterially expressed form of CRAMOLL 1 (rCRAMOLL 1). The recombinant lectin retained sugar-binding activity and several other biophysical properties of pCRAMOLL 1, but its tetramers, which are composed of intact monomers only, show little enhancement in stability when probed with acidification, high temperatures, or hydrostatic pressure. Here we examined the urea-induced unfolding of the nonfragmented tetramers and dimers of rCRAMOLL 1 and compared this behavior with that of the mixed plant lectin counterparts. Using fluorescence, circular dichroism, size-exclusion chromatography, and chemical cross-linking experiments, we posited that the absence of fragmentation lent greater firmness to tetramers, but not to dimers. Dimeric and tetrameric pCRAMOLL 1 unfolded via a compact monomeric intermediate. In contrast, dimers of rCRAMOLL 1 behaved similarly to the plant dimer counterpart, but its tetrameric form remarkably showed no evidence of such partially unfolded monomers. By analyzing the crystal structure of pCRAMOLL 1, we were able to dissect the importance of the fragmentation to lectin stability. PMID- 21790142 TI - Synchrotron FTIR microspectroscopy of single natural silk fibers. AB - Synchrotron FTIR (S-FTIR) microspectroscopy was used to monitor the silk protein conformation in a range of single natural silk fibers (domestic and wild silkworm and spider dragline silk). With the selection of suitable aperture size, we obtained high-resolution S-FTIR spectra capable of semiquantitative analysis of protein secondary structures. For the first time, we have determined from S-FTIR the beta-sheet content in a range of natural single silk fibers, 28 +/- 4, 23 +/- 2, and 17 +/- 4% in Bombyx mori, Antheraea pernyi, and Nephila edulis silks, respectively. The trend of beta-sheet content in different silk fibers from the current study accords quite well with published data determined by XRD, Raman, and (13)C NMR. Our results indicate that the S-FTIR microspectroscopy method has considerable potential for the study of single natural silk fibers. PMID- 21790143 TI - Stretchable, transparent graphene interconnects for arrays of microscale inorganic light emitting diodes on rubber substrates. AB - This paper describes the fabrication and design principles for using transparent graphene interconnects in stretchable arrays of microscale inorganic light emitting diodes (LEDs) on rubber substrates. We demonstrate several appealing properties of graphene for this purpose, including its ability to spontaneously conform to significant surface topography, in a manner that yields effective contacts even to deep, recessed device regions. Mechanics modeling reveals the fundamental aspects of this process, as well as the use of the same layers of graphene for interconnects designed to accommodate strains of 100% or more, in a completely reversible fashion. These attributes are compatible with conventional thin film processing and can yield high-performance devices in transparent layouts. Graphene interconnects possess attractive features for both existing and emerging applications of LEDs in information display, biomedical systems, and other environments. PMID- 21790144 TI - Softness of atherogenic lipoproteins: a comparison of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) using elastic incoherent neutron scattering (EINS). AB - Apolipoprotein B100 (apoB100)-containing plasma lipoproteins (LDL and VLDL) supply tissues and cells with cholesterol and fat. During lipolytic conversion from VLDL to LDL the size and chemical composition of the particles change, but the apoB100 molecule remains bound to the lipids and regulates the receptor mediated uptake. The molecular physical parameters which control lipoprotein remodeling and enable particle stabilization by apoB100 are largely unknown. Here, we have compared the molecular dynamics and elasticities of VLDL and LDL derived by elastic neutron scattering temperature scans. We have determined thermal motions, dynamical transitions, and molecular fluctuations, which reflect the temperature-dependent motional coupling between lipid and protein. Our results revealed that lipoprotein particles are extremely soft and flexible. We found substantial differences in the molecular resiliences of lipoproteins, especially at higher temperatures. These discrepancies not only can be explained in terms of lipid composition and mobility but also suggest that apoB100 displays different dynamics dependent on the lipoprotein it is bound to. Hence, we suppose that the inherent conformational flexibility of apoB100 permits particle stabilization upon lipid exchange, whereas the dynamic coupling between protein and lipids might be a key determinant for lipoprotein conversion and atherogenicity. PMID- 21790145 TI - Secondary organic aerosol: a comparison between foggy and nonfoggy days. AB - Carbonaceous species, meteorological parameters, trace gases, and fogwater chemistry were measured during winter in the Indian city of Kanpur to study secondary organic aerosol (SOA) during foggy and clear (nonfoggy) days. Enhanced SOA production was observed during fog episodes. It is hypothesized that aqueous phase chemistry in fog drops is responsible for increasing SOA production. SOA concentrations on foggy days exceeded those on clear days at all times of day; peak foggy day SOA concentrations were observed in the evening vs peak clear day SOA concentrations which occurred in the afternoon. Changes in biomass burning emissions on foggy days were examined because of their potential to confound estimates of SOA production based on analysis of organic to elemental carbon (OC/EC) ratios. No evidence of biomass burning influence on SOA during foggy days was found. Enhanced oxidation of SO(2) to sulfate during foggy days was observed, possibly causing the regional aerosol to become more acidic. No evidence was found in this study, either, for effects of temperature or relative humidity on SOA production. In addition to SOA production, fogs can also play an important role in cleaning the atmosphere of carbonaceous aerosols. Preferential scavenging of water-soluble organic carbon (WSOC) by fog droplets was observed. OC was found to be enriched in smaller droplets, limiting the rate of OC deposition by droplet sedimentation. Lower EC concentrations were observed on foggy days, despite greater stagnation and lower mixing heights, suggesting fog scavenging and removal of EC was active as well. PMID- 21790146 TI - Fluorescent single-walled carbon nanotube aerogels in surfactant-free environments. AB - A general challenge in generating functional materials from nanoscale components is integrating them into useful composites that retain or enhance their properties of interest. Development of single walled carbon nanotube (SWNT) materials for optoelectronics and sensing has been especially challenging in that SWNT optical and electronic properties are highly sensitive to environmental interactions, which can be particularly severe in composite matrices. Percolation of SWNTs into aqueous silica gels shows promise as an important route for exploiting their properties, but retention of the aqueous and surfactant environment still impacts and limits optical response, while also limiting the range of conditions in which these materials may be applied. Here, we present for the first time an innovative approach to obtain highly fluorescent solution-free SWNT-silica aerogels, which provides access to novel photophysical properties. Strongly blue-shifted spectral features, revelation of new diameter-dependent gas phase adsorption phenomena, and significant increase (approximately three times that at room temperature) in photoluminescence intensities at cryogenic temperatures all indicate greatly reduced SWNT-matrix interactions consistent with the SWNTs experiencing a surfactant-free environment. The results demonstrate that this solid-state nanomaterial will play an important role in further revealing the true intrinsic SWNT chemical and photophysical behaviors and represent for the first time a promising new solution- and surfactant-free material for advancing SWNT applications in sensing, photonics, and optoelectronics. PMID- 21790147 TI - Enantiospecific synthesis of pyridinones as versatile intermediates toward asymmetric piperidines. AB - The enantiospecific syntheses of pyridinones from amino acids via a gold catalyzed strategy are reported. Excellent stereocontrol was observed during the cyclization. This approach provides a straightforward tool for further synthetic applications toward piperidines. PMID- 21790148 TI - How to understand and interpret current flow in nanopore/electrode devices. AB - Nanopore-based single-molecule sensors have become an important class of analytical devices that have in some cases already reached the market place. Traditionally operated in a two-electrode configuration, devices with three or more electrodes have emerged recently, for example with a view on switching the transport properties of the nanopore or even tunneling-based detection of analytes with the ultimate goal of inexpensive and ultrafast DNA sequencing. How do these additional electrodes affect the current distribution in the cell and hence the sensor performance? This is significantly less clear and thus in focus here. We use impedance modeling of a prototypical three-electrode nanopore sensor and show that, depending on the conditions, standard experimental device characterization is severely affected by the presence of the third electrode. On the other hand, the simulations also provide guidelines on how to avoid such complications, identify "safe" operating conditions, and design criteria for optimized nanopore sensors. PMID- 21790149 TI - Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. AB - The development of small molecule drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclinical profiling that have improved compound triaging and altered the underlying reasons for compound attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochemical properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by molecules with increased molecular weight and higher overall lipophilicity. The preponderance of molecules expressing these properties is frequently a function of increased aromatic ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochemical properties associated with marketed drugs, guidelines for drug design have been developed that are based largely on calculated parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochemical properties of a molecule that are consistent with the potential for good oral absorption were initially defined by Lipinski, with additional insights allowing further refinement, while deeper analyses have explored the correlation with metabolic stability and toxicity. These insights have been augmented by careful analyses of physicochemical aspects of drug-target interactions, with thermodynamic profiling indicating that the signature of best-in-class drugs is a dependence on enthalpy to drive binding energetics rather than entropy, which is dependent on lipophilicity. Optimization of the entropic contribution to the binding energy of a ligand to its target is generally much easier than refining the enthalpic element. Consequently, in the absence of a fundamental understanding of the thermodynamic complexion of an interaction, the design of molecules with increased lipophilicity becomes almost inevitable. The application of ligand efficiency, a measure of affinity per heavy atom, group efficiency, which assesses affinity in the context of structural changes, and lipophilic ligand efficiency, which relates potency to lipophilicity, offer less sophisticated but practically useful analytical algorithms to assess the quality of drug-target interactions. These parameters are readily calculated and can be applied to lead optimization programs in a fashion that helps to maximize potency while minimizing the kind of lipophilic burden that has been dubbed "molecular obesity". Several recently described lead optimization campaigns provide illustrative, informative, and productive examples of the effect of paying close attention to carefully controlling physicochemical properties by monitoring ligand efficiency and lipophilic ligand efficiency. However, to be successful during the lead optimization phase, drug candidate identification programs will need to adopt a holistic approach that integrates multiple parameters, many of which will have unique dependencies on both the drug target and the specific chemotype under prosecution. Nevertheless, there are many important drug targets that necessitate working in space beyond that which has been defined by the retrospective analyses of marketed drugs and which will require adaptation of some of the guideposts that are useful in directing lead optimization. PMID- 21790150 TI - New chiral cyclooctatriene-based polycyclic architectures. AB - The synthesis and properties of new chiral polycyclic architectures that display both helicity and a saddle-type shape are described. The enantiomers have been separated, and their absolute configuration was determined by VCD and ECD. The unprecedented molecular architecture is based on a cyclooctatriene core surrounded by an association of benzo[c]fluorene and ortho-phenylene units. PMID- 21790151 TI - Maleimide-dimethylfuran exo adducts: effective maleimide protection in the synthesis of oligonucleotide conjugates. AB - The reaction of maleimide-containing compounds with 2,5-dimethylfuran gives a mixture of exo and endo isomers from which the exo cycloadduct can be easily isolated taking advantage of its stability in concentrated aqueous ammonia. Bifunctional compounds incorporating a dimethylfuran-protected maleimide (exo adduct) have been attached to resin-linked oligonucleotide chains. Removal of protecting groups masking oligonucleotide functionalities followed by retro-Diels Alder maleimide deprotection affords maleimido-oligonucleotides suitable for conjugation, as assessed by their reaction with different thiols. PMID- 21790152 TI - Reductive electrosynthesis of crystalline metal-organic frameworks. AB - Electroreduction of oxoanions affords hydroxide equivalents that induce selective deposition of crystalline metal-organic frameworks (MOFs) on conductive surfaces. The method is illustrated by cathodic electrodeposition of Zn(4)O(BDC)(3) (MOF-5; BDC = 1,4-benzenedicarboxylate), which is deposited at room temperature in only 15 min under cathodic potential. Although many crystalline phases are known in the Zn(2+)/BDC(2-) system, MOF-5 is the only observed crystalline MOF phase under these conditions. This fast and mild method of synthesizing MOFs is amenable to direct surface functionalization and could impact applications requiring conformal coatings of microporous MOFs, such as gas separation membranes and electrochemical sensors. PMID- 21790154 TI - Efficient synthesis of dissymmetric malonic acid S,O-esters via monoalcoholysis of symmetric dithiomalonates under neutral conditions. AB - A novel method for the highly selective synthesis of dissymmetric S,O-malonates starting from symmetric diphenyl dithiomalonates under neutral conditions is described. The key step is the thermal formation of an acylketene, the stability of which would contribute to the selectivity. The synthetic utility of the dissymmetric S,O-malonates is also shown. PMID- 21790153 TI - Water-soluble superparamagnetic magnetite nanoparticles with biocompatible coating for enhanced magnetic resonance imaging. AB - Ultrasmall superparamagnetic Fe(3)O(4) nanoparticles (USIRONs) were synthesized by a novel, easily scalable chemical reduction of colloidal iron hydroxide under hydrothermal conditions. The average crystallite size (5.1 +/- 0.5 nm) and good crystallinity of the samples were supported by HR-TEM analysis and the saturation magnetization value (47 emu g(-1)). Vitamin C, used as a chemical reducing agent, also served as a capping agent in the oxidized form (dehydroascorbic acid, DHAA) to impart nanoparticles with exceptional solubility and stability in water, PBS buffer, and cell culture medium. Detailed physicochemical analysis of the USIRON suspensions provided insight into the magnetic ordering phenomena within the colloid, arising from the formation of uniform clusters displaying a hydrodynamic size of 41 nm. Phantom experiments on the contrast agent (clinical 3 T MRI scanner) revealed an enhanced r(2)/r(1) ratio of 36.4 (r(1)= 5 s(-1) mM(-1) and r(2)= 182 s(-1) mM(-1)) when compared to the clinically approved agents. The potential of the DHAA-Fe(3)O(4) nanoparticles as negative contrast agents for MRI with optimal hydrodynamic size for extended blood circulation times was confirmed by strong contrast observed in T(2)- and T(2)*-weighted images. The cell tests performed with primary human immune-competent cells confirmed the excellent biocompatibility of USIRONs. PMID- 21790155 TI - Experimental evidence of icosahedral and decahedral packing in one-dimensional nanostructures. AB - The packing of spheres is a subject that has drawn the attention of mathematicians and philosophers for centuries and that currently attracts the interest of the scientific community in several fields. At the nanoscale, the packing of atoms affects the chemical and structural properties of the material and, hence, its potential applications. This report describes the experimental formation of 5-fold nanostructures by the packing of interpenetrated icosahedral and decahedral units. These nanowires, formed by the reaction of a mixture of metal salts (Au and Ag) in the presence of oleylamine, are obtained when the chemical composition is specifically Ag/Au = 3:1. The experimental images of the icosahedral nanowires have a high likelihood with simulated electron micrographs of structures formed by two or three Boerdijk-Coxeter-Bernal helices roped on a single structure, whereas for the decahedral wires, simulations using a model of adjacent decahedra match the experimental structures. To our knowledge, this is the first report of the synthesis of nanowires formed by the packing of structures with 5-fold symmetry. These icosahedral nanowire structures are similar to those of quasicrystals, which can only be formed if at least two atomic species are present and in which icosahedral and decahedral packing has been found for bulk crystals. PMID- 21790156 TI - Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. AB - Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 A-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors. PMID- 21790158 TI - Evolution of the structure and chemical state of Pd nanoparticles during the in situ catalytic reduction of NO with H2. AB - An in-depth understanding of the fundamental structure of catalysts during operation is indispensable for tailoring future efficient and selective catalysts. We report the evolution of the structure and oxidation state of ZrO(2) supported Pd nanocatalysts (~5 nm) during the in situ reduction of NO with H(2) using X-ray absorption fine-structure spectroscopy and X-ray photoelectron spectroscopy. Prior to the onset of the reaction (<=120 degrees C), a NO-induced redispersion of our initial metallic Pd nanoparticles over the ZrO(2) support was observed, and Pd(delta+) species were detected. This process parallels the high production of N(2)O observed at the onset of the reaction (>120 degrees C), while at higher temperatures (>=150 degrees C) the selectivity shifts mainly toward N(2) (~80%). Concomitant with the onset of N(2) production, the Pd atoms aggregate again into large (6.5 nm) metallic Pd nanoparticles, which were found to constitute the active phase for the H(2)-reduction of NO. Throughout the entire reaction cycle, the formation and stabilization of PdO(x) was not detected. Our results highlight the importance of in situ reactivity studies to unravel the microscopic processes governing catalytic reactivity. PMID- 21790157 TI - Bypass of aflatoxin B1 adducts by the Sulfolobus solfataricus DNA polymerase IV. AB - Aflatoxin B(1) (AFB(1)) is oxidized to an epoxide in vivo, which forms an N7-dG DNA adduct (AFB(1)-N7-dG). The AFB(1)-N7-dG can rearrange to a formamidopyrimidine (AFB(1)-FAPY) derivative. Both AFB(1)-N7-dG and the beta anomer of the AFB(1)-FAPY adduct yield G->T transversions in Escherichia coli, but the latter is more mutagenic. We show that the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) bypasses AFB(1)-N7-dG in an error-free manner but conducts error-prone replication past the AFB(1)-FAPY adduct, including misinsertion of dATP, consistent with the G->T mutations observed in E. coli. Three ternary (Dpo4 DNA-dNTP) structures with AFB(1)-N7-dG adducted template:primers have been solved. These demonstrate insertion of dCTP opposite the AFB(1)-N7-dG adduct, and correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB(1)-N7-dG:dC pair. The insertion of dTTP reveals hydrogen bonding between the template N3 imino proton and the O(2) oxygen of dTTP, and between the template T O(4) oxygen and the N3 imino proton of dTTP, perhaps explaining why this polymerase does not efficiently catalyze phosphodiester bond formation from this mispair. The AFB(1)-N7-dG maintains the 5'-intercalation of the AFB(1) moiety observed in DNA. The bond between N7-dG and C8 of the AFB(1) moiety remains in plane with the alkylated guanine, creating a 16 degrees inclination of the AFB(1) moiety with respect to the guanine. A binary (Dpo4-DNA) structure with an AFB(1)-FAPY adducted template:primer also maintains 5' intercalation of the AFB(1) moiety. The beta-deoxyribose anomer is observed. Rotation about the FAPY C5-N(5) bond orients the bond between N(5) and C8 of the AFB(1) moiety out of plane in the 5'-direction, with respect to the FAPY base. The formamide group extends in the 3'-direction. This improves stacking of the AFB(1) moiety above the 5'-face of the FAPY base, as compared to the AFB(1)-N7-dG adduct. Ternary structures with AFB(1)-beta-FAPY adducted template:primers show correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB(1)-beta-FAPY:dC pair. For dATP, the oxygen atom of the FAPY formamide group participates in a water-mediated hydrogen bond with Arg332. The insertion of dTTP yields a structure similar to that observed for the AFB(1)-N7 dG adduct. The differential accommodation of these AFB(1) adducts within the active site may, in part, modulate lesion bypass. PMID- 21790159 TI - Solid-state thermochromism and phase transitions of charge transfer 1,3-diamino 4,6-dinitrobenzene dyes. AB - The lower 1,3-bis(hydroxyalkylamino) homologues of the strong intramolecular X type charge transfer (CT) system 1,3-diamino-4,6-dinitrobenzene (DADNB) exhibit reversible color change in the solid state from yellow at room temperature (RT) to orange and red at high temperature (HT). To investigate the structural prerequisites for occurrence of this phenomenon, we prepared 10 new derivatives of DADNB where the hydroxyalkyl arms at the amino groups were replaced with substituents having different electronic and steric profiles. Two of the new materials exhibit sharp and reversible thermochromic change in the solid state: when heated, the bis(aminoethyl) derivative (DADNB-1) undergoes color change from orange-red to brown, while one of the three polymorphs of the bisphenyl product (DADNB-2) changes its color from red to yellow. The physicochemical analysis and the crystal structures of seven of these compounds, one of which is trimorphic, confirmed that both phenomena are due to solid-solid phase transitions. The brown high-temperature phase of DADNB-1 presents the first example where the absorption is shifted beyond the red region. Form C of DADNB-2 is the first material of this group that exhibits "negative" thermochromism, where the high-temperature phase absorbs at lower wavelength than the low-temperature one. The results demonstrate the potentials of these simple and easily accessible organic molecular materials for thermal switching of the optical properties by utility of intermolecular interactions to modulate the intramolecular CT. PMID- 21790160 TI - Metal anion-alkyl ammonium complexes as direct write precursors to produce nanopatterns of metals, nitrides, oxides, sulfides, and alloys. AB - The study explores the possibility of using metal anions complexed with tetraoctylammonium bromide (ToABr) as single-source direct write precursors in e beam and soft lithography processes to obtain micro- and nanoscale patterns of various metals, i.e., Au, Pd, Pt, Ag, Pb and Cu, as well as of their alloys (AuCu), oxides (Co(3)O(4), ZnO), nitrides (CoN, InN, GaN), and sulfides (Ag(2)S). The extraction efficiency of ToABr for different metal anions is found to be varied (40-90%), but the obtained precursors are easily processable as they have reasonable solubility in common solvents and are obtainable as smooth films, both being important for high-resolution patterning. The e-resist action of the precursors originates from the extreme e-beam sensitivity of the hydrocarbon chain present in ToABr, while direct micromolding has been possible due to easy flow of the precursor solutions in capillaries. The interaction of the anion and ToABr being mainly electrostatic enables easy removal of the hydrocarbon from patterned regions by thermolysis on a hot plate in the ambient or in controlled atmosphere to form the desired product. This method can be easily generalized. PMID- 21790161 TI - Inheritance and physiological basis for 2,4-D resistance in prickly lettuce (Lactuca serriola L.). AB - Experiments were conducted to determine the inheritance and physiological basis for resistance to the synthetic auxinic herbicide (2,4-dichlorophenoxy)acetic acid (2,4-D) in a prickly lettuce biotype. Inheritance of 2,4-D resistance in prickly lettuce is governed by a single codominant gene. Absorption and translocation were conducted using (14)C-2,4-D applied to 2,4-D-resistant and susceptible biotypes. At 96 h after treatment (HAT), the resistant biotype absorbed less applied 2,4-D and retained more 2,4-D in the treated portion of the leaf compared to the susceptible biotype. The resistant biotype translocated less applied 2,4-D to leaves above the treated leaf and crown at 96 HAT compared to the susceptible biotype. No difference in the rate of metabolism of 2,4-D was observed between the two biotypes. Resistance to 2,4-D appears to originate from a reduced growth deregulatory and overstimulation response compared to the susceptible biotype, resulting in lower translocation of 2,4-D in the resistant prickly lettuce biotype. PMID- 21790164 TI - Sensitivity limit of rapidly swept continuous wave cavity ring-down spectroscopy. AB - The averaged transmitted intensity of a cavity excited by a linearly frequency swept laser with finite line width is derived and presented as a sum over passes, analytical integrals (where the sum of passes is converted to a continuous time variable), and an approximate but computationally more stable stationary phase approximation expression. The transmitted waveform is used to derive the bias in extraction of the cavity decay rate from such a cavity transient for three different fitting models. Numerical simulation of cavity excitation gives statistical fluctuations in the transmitted intensity that leads to noise in the cavity decay rate. For a range of parameters spanning those likely to be encountered in real experiments, numerical results are presented. These demonstrate that the theoretical signal-to-noise ratio and thus sensitivity of swept cavity (or equivalently, frequency) CRDS is substantially below that for CRDS where one attenuates the laser either with current modulation or with an external modulator. PMID- 21790162 TI - Remediation of fungicide residues on fresh produce by use of gaseous ozone. AB - Ozone fumigation was explored as a means for degrading organic fungicide residues on fresh produce. Fungicides sorbed onto model abiotic glass surfaces or onto grape berries were fumigated separately in a flow-through chamber. Gaseous ozone at a constant concentration of 150 +/- 10 ppmv (MUL.L(-1)) selectively oxidized fungicides sorbed to model surfaces. Over 140 min, boscalid and iprodione levels did not change significantly based on a single-factor analysis of variance (ANOVA) at the 95% level of confidence (p = 0.05); however, pseudo-first-order losses resulted in observable rate constants of ozonolysis, k(ozonolysis) (min( 1)), of 0.0233 +/- 0.0029 (t(1/2) ~ 29.7 min), 0.0168 +/- 0.0028 (t(1/2) ~ 41.3 min), and 0.0127 +/- 0.0010 (t(1/2) ~ 54.6 min) for fenhexamid, cyprodinil, and pyrimethanil, respectively. The relative degradation of fungicides on berries at gaseous ozone concentrations of 900 +/- 12 ppmv (MUL.L(-1)) over 2 h was similar to that on glass; decreases in residue concentration were observed for only fenhexamid (~ 64%), cyprodinil (~ 38%), and pyrimethanil (~ 35%) with corresponding k(ozonolysis) (min(-1)) of 0.0085 +/- 0.0021 (t(1/2) ~ 81.5 min), 0.0039 +/- 0.0008 (t(1/2) ~ 177.7 min), and 0.0036 +/- 0.0007 (t(1/2) ~ 192.5 min). Heterogeneous rate constants of gaseous ozone reacting with a sorbed fungicide, k(O(3)) (M(-1).min(-1)), were calculated for both surfaces and indicate losses proceed ~ 15-fold slower on grapes. The kinetics and mechanism of fungicide removal, supported by gas chromatography- and liquid chromatography mass spectrometry product analyses, is discussed in the context of facilitating compliance with maximum residue level (MRL) tolerances for fresh produce. PMID- 21790165 TI - Basis set dependence of coupled cluster optical rotation computations. AB - Specific rotations for five notoriously difficult molecules, (S)-methyloxirane, (S)-methythiirane, (S)-2-chloropropionitrile, (1S,4S)-norbornenone, and (1R,5R) beta-pinene, have been computed using coupled cluster (CC) and density functional theory (DFT). The performance of the recently developed LPol basis sets compared to the correlation-consistent sets of Dunning and co-workers has been examined at four wavelengths: 355, 436, 589, and 633 nm. We find that the LPol basis sets are an efficient choice, often outperforming the more commonly used correlation consistent basis sets of comparable size. The smallest of the four, LPol-ds, performs nearly as well as the rest of the series and often yields results closer to the basis set limit than appreciably larger basis sets. While the performance of the LPol bases is admirable, they still do not alleviate the need for high levels of electron correlation, vibrational corrections, and the inclusion of solvent effects to accurately reproduce experimental rotations. In particular in the case of beta-pinene we find that they do not produce agreement between DFT and experiment as was previously suggested. PMID- 21790166 TI - Modulation of prototropic activity and rotational relaxation dynamics of a cationic biological photosensitizer within the motionally constrained bio environment of a protein. AB - The present work describes the interaction of a promising cancer cell photosensitizer, harmane (HM), with a model transport protein, Bovine Serum Albumin (BSA). The studied molecule of interest (HM) belongs to the family of naturally occurring fluorescent drug-binding alkaloids, the beta-carbolines. A combined use of steady-state and time-resolved fluorescence techniques is applied to follow and characterize the binding interaction. The polarity-dependent prototropic activity of HM is found to be responsible for the commendable sensitivity of the probe to the protein environments and is distinctly reflected on the emission profile. Steady-state fluorescence anisotropy study reveals the impartation of a considerable degree of motional restriction on the drug molecule as a result of binding to the protein. Contrary to the single-exponential nature of fluorescence anisotropy decay of HM in aqueous buffer, they are found to be biexponential in the protein environment. The rotational relaxation dynamics of HM within the protein has been interpreted on the lexicon of the Two-Step and Wobbling-in-Cone model. The probable binding location for the cationic drug is found to be the hydrophilic binding zone of BSA, i.e., domain I (characterized by a net negative charge). The AutoDock-based blind docking simulation has been explored for evaluating an unbiased result of the probable interaction site of HM in the protein. To unfold the effect of binding of the drug on the secondary structural content of the protein, circular dichroism (CD) spectroscopy has been exploited to see that binding of the drug accompanies some decrease in alpha helical content of BSA, and the effect gradually saturates toward a higher drug/protein molar ratio. PMID- 21790167 TI - Biophysical characterization of complexes of DNA with mixtures of the neutral lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-hexanoylamine or 1,2 dioleoyl-sn-glycero-3-phosphoethanolamine-N-dodecanoylamine and 1,2-dioleoyl-sn glycero-3-phosphocholine in the presence of bivalent metal cations for DNA transfection. AB - Neutral lipids have received up to now a little attention as genetic material carriers, despite some valuable features, such as the absence of toxicity and the high stability in serum of their complexes with DNA. We have prepared two quaternary complexes of DNA and mixtures of 1, 2-dioleoyl-sn-glycero-3 phosphoethanolamine-N-hexanoylamine (6PE) or 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine-N-dodecanoylamine (12PE) with DOPC in aqueous dispersions of bivalent metal cations (PE/DOPC-DNA-M(2+)). The aim was to evaluate the effect of the amide moiety on the transfection efficiency. These complexes form in a self assembled manner, the DNA condensation being promoted by the metal cations. Synchrotron X-ray diffraction analysis was used to determine the structure of the complexes, which exhibit the lamellar symmetry of the L(alpha)(c) phase. The size and surface charge of the complexes have also been measured, and promising results of DNA transfections in vitro have been reported. PMID- 21790168 TI - Three-component reaction of N'-(2-alkynylbenzylidene)hydrazide, alkyne, with sulfonyl azide via a multicatalytic process: a novel and concise approach to 2 amino-H-pyrazolo[5,1-a]isoquinolines. AB - A novel and efficient route for the synthesis of 2-amino-H-pyrazolo[5,1 a]isoquinolines via a three-component reaction of N'-(2 alkynylbenzylidene)hydrazide, alkyne, and sulfonyl azide is described. This transformation, co-catalyzed by silver triflate and copper(I) bromide under mild conditions, proceeds efficiently to generate the 2-amino-H-pyrazolo[5,1 a]isoquinolines in good to excellent yields. PMID- 21790169 TI - NSAIDs interactions with membranes: a biophysical approach. AB - This work focuses on the interaction of four representative NSAIDs (nimesulide, indomethacin, meloxicam, and piroxicam) with different membrane models (liposomes, monolayers, and supported lipid bilayers), at different pH values, that mimic the pH conditions of normal (pH 7.4) and inflamed cells (pH 5.0). All models are composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) which is a representative phospholipid of most cellular membranes. Several biophysical techniques were employed: Fluorescence steady-state anisotropy to study the effects of NSAIDs in membrane microviscosity and thus to assess the main phase transition of DPPC, surface pressure-area isotherms to evaluate the adsorption and penetration of NSAIDs into the membrane, IRRAS to acquire structural information of DPPC monolayers upon interaction with the drugs, and AFM to study the changes in surface topography of the lipid bilayers caused by the interaction with NSAIDs. The NSAIDs show pronounced interactions with the lipid membranes at both physiological and inflammatory conditions. Liposomes, monolayers, and supported lipid bilayers experiments allow the conclusion that the pH of the medium is an essential parameter when evaluating drug-membrane interactions, because it conditions the structure of the membrane and the ionization state of NSAIDs, thereby influencing the interactions between these drugs and the lipid membranes. The applied models and techniques provided detailed information about different aspects of the drug-membrane interaction offering valuable information to understand the effect of these drugs on their target membrane-associated enzymes and their side effects at the gastrointestinal level. PMID- 21790170 TI - Rationalizing the effect of halogenation on the molecular structure of simple cyclobutene derivatives by topological real-space analysis of their electron density. AB - The accurate gas-phase equilibrium structures on the ground-state potential energy surface of the complete series of fluorinated and chlorinated cyclobutene derivatives with C(2v) symmetry have been evaluated at DFT PBE0/6-311++G(d,p) theory level. The optimized geometries have been compared with all the available experimental data reported in the literature, as obtained by microwave spectroscopy (MW) and gas-phase electron diffraction (GED) techniques. For hexafluorocyclobutene and 1,2-dichloro-3,3',4,4'-tetrafluorocyclobut-1-ene, the results of accurate low-temperature single-crystal X-ray diffraction experiments have also been considered. Structural changes within the cyclobutene ring, as induced by fluorination and chlorination at allylic and vinylic positions, have been correlated with changes in the corresponding theoretical charge densities. To this aim, several local and nonlocal topological descriptors provided by the quantum theory of atoms in molecules, QTAIM, have been employed, with particular emphasis on the delocalization indices and integrated source function decomposition schemes. Key factors for the resulting molecular structures are the chemical nature and the steric hindrance of the substituents, as well as quantum mechanical effects, such as delocalization and partial conjugation. When fluorine atoms replace hydrogens at allylic or vinylic positions, the corresponding Csp(3) Csp(3) or Csp(2)?Csp(2) bonds between the substituted carbons undergo a significant strengthening, while chlorination has just the opposite effect. In the latter case the steric hindrance between bulky chlorine atoms occupying vicinal positions is crucial in determining the single Csp(3)-Csp(3) bond length. These findings are discussed in the context of the reactivity of chemically related chlorofluorocarbon compounds. PMID- 21790171 TI - Toward stereoselective lactide polymerization catalysts: cationic zinc complexes supported by a chiral phosphinimine scaffold. AB - The P-stereogenic phosphinimine ligands (dbf)MePhP?NAr (7: Ar = Dipp; 8: Ar = Mes; dbf = dibenzofuran, Dipp = 2,6-diisopropylphenyl, Mes = 2,4,6 trimethylphenyl) were synthesized as racemates via reactions of the parent phosphines (rac)-(dbf)MePhP (6) with organoazides. The ligands 7 and 8 were protonated by Bronsted acids to afford the aminophosphonium borate salts [(7) H][BAr(4)] (9: Ar = C(6)F(5); 11: Ar = Ph) and [(8)-H][BAr(4)] (10: Ar = C(6)F(5); 12: Ar = Ph). The protonated ligands 9 and 10 were active toward alkane elimination reactions with diethylzinc and ethyl-[methyl-(S)-lactate]zinc to give the heteroleptic complexes [{(dbf)MePhP?NAr}ZnR][B(C(6)F(5))(4)] (Ar = Dipp, 13: R = Et; 15: R = methyl-(S)-lactate; Ar = Mes, 14: R = Et; 16: R = methyl-(S) lactate). By contrast, reaction of the tetraphenylborate derivative 11 with diethylzinc yielded a phenyl transfer product, [(dbf)MePhP?NDipp]ZnPh(2) (17). Complex 15 was found to catalyze the ring-opening polymerization of rac-lactide. PMID- 21790172 TI - Thermo-, photo-, and chemo-responsive shape-memory properties from photo-cross linked metallo-supramolecular polymers. AB - Films exhibiting multiresponsive shape-memory properties have been accessed using covalently cross-linked metallo-supramolecular polymers. Low molecular weight poly(butadiene) was end-capped with 4-oxy-2,6-bis(N-methylbenzimidazolyl)pyridine (-OMebip) ligands that upon addition of metal salts spontaneously formed high molecular weight metallo-supramolecular polymers. The addition of a tetra functional thiol along with a photoinitiator results in mechanically stable films via solution-casting. These films consist of a soft poly(butadiene) phase and a hard metal-ligand phase. Photo-cross-linking of the poly(butadiene) soft phase, via the thiol-ene reaction, upon exposure to relatively low intensity light, allows access to a diverse range of permanent shapes. Investigations into the temporary shape fixing and recovery of these materials were undertaken to determine the effects of cross-link density and the nature of the metal salts. The key component in fixing and releasing the temporary shape is the metal-ligand hard phase, and as such any stimulus that can disrupt this phase (light, heat, or chemicals) can be used to create the temporary shape and induce its recovery back to the permanent shape. PMID- 21790173 TI - Photobehavior of mixed npi*/pipi* triplets: simultaneous detection of the two transients, solvent-dependent hydrogen abstraction, and reequilibration upon protein binding. AB - In the present work, a systematic study on hydrogen abstraction by the excited triplet states of 4-methoxybenzophenone (1) and 4,4'-dimethoxybenzophenone (2) from 1,4-cyclohexadiene (3), 4-methylphenol (4), 1,2,3,4-tetrahydroquinoline (5), and 1-methyl-1,2,3,4-tetrahydroquinoline (6) in different media has been undertaken. Laser flash photolysis (LFP) revealed that in nonpolar solvents, 1 and 2 triplets have a npi* configuration with the typical benzophenone-like T-T absorption spectrum (lambda(max) ca. 525 nm). Conversely, in aqueous solution, transient absorption spectra with maxima at 450 and 680 nm, attributed to the pipi* triplet, were obtained. Quenching of 1 or 2 triplet by 3 led to ketyl radical formation with rate constants in the range of 10(6)-10(8) M(-1) s(-1), being one order of magnitude higher in acetonitrile than in aqueous media. The rate constants of quenching by 4 and 5 were similar in both polar and nonpolar solvents; the highest value was found for 6 in acetonitrile ((6.3 to 6.9) * 10(9) M(-1) s(-1)). For mechanistic insight, LFP of 1 or 2 in the presence of dimethoxybenzene as electron donor was performed. The results showed that in this case, triplet quenching is favored in aqueous solution. In addition, 2 included in human serum albumin (HSA) was submitted to LFP. The decay kinetics, monitored at 430 nm, fitted well with three lifetimes of 0.45, 1.4, and 14.4 MUs assignable to 2 in bulk solution and in site II or in site I of HSA, respectively. This assignment was confirmed by using oleic acid and ibuprofen as selective displacement probes. PMID- 21790174 TI - Synthesis of thermosensitive microgels with a tunable magnetic core. AB - In this work, we describe a new methodology for the preparation of monodisperse and thermosensitive microgels with magnetic core. In order to produce such a material, hydrophobic magnetic Fe(3)O(4) nanoparticles were prepared by two methods: thermal decomposition and coprecipitation. The surface of these nanoparticles was modified by addition of 3-butenoic acid, and after that these nanoparticles were dispersed in water and submitted to free radical polymerization at 70 degrees C in the presence of N-isopropylacrylamide (NIPAM) and bisacrylamide. The result of this reaction was monodisperse microgels with a magnetic core. By varying the amount of 3-butenoic acid, it was possible to obtain hybrid microgels with different magnetic core sizes and different architectures. PMID- 21790175 TI - Electro-functional octupolar pi-conjugated columnar liquid crystals. AB - A series of propeller-shaped pi-conjugated molecules based on 2,4,6 tris(thiophene-2-yl)-1,3,5-triazines has been designed and synthesized to obtain ambipolar charge-transporting liquid-crystalline materials. The 3-fold electron donating aromatic units are attached to the electron-accepting triazine core, which forms electro-functional octupolar pi-conjugated structures. These octupolar molecules self-organize into one-dimensional columnar nanostructures and exhibit ambipolar carrier transport behavior, which has been revealed by time of-flight measurements. In this approach, electron-donor and acceptor electro active segments are assembled individually in each column to give one-dimensional nanostructured materials with precisely tuned electronic properties. Their desirable electronic structures responsible for both hole and electron conductions have also been examined by cyclic voltammetry and theoretical calculations. The present results provide a new guideline and versatile approach to the design of ambipolar conductive nanostructured liquid-crystalline materials. PMID- 21790176 TI - Photomechanical degrafting of azo-functionalized poly(methacrylic acid) (PMAA) brushes. AB - We report on the preparation and characterization of photosensitive polymer brushes. The brushes are synthesized through polymer analogous attachment of azo benzene groups to surface-attached poly(methacrylic acid) (PMAA) chains. The topography of the photosensitive brushes shows a strong reaction upon irradiation with UV light. While homogeneous illumination leaves the polymer topography unchanged, irradiation of the samples with interference patterns with periodically varying light intensity leads to the formation of surface relief gratings (SRG). The height of the stripes of the grating can be controlled by adjusting the irradiation time. The SRG pattern can be erased through solvent treatment when the periodicity of the stripe pattern is less than the length of the fully stretched polymer chains. In the opposite case, photomechanical scission of receding polymer chains is observed during SRG formation, and the inscribed patterns are permanent. PMID- 21790177 TI - Photodeposition of Ag or Pt onto TiO2 nanoparticles decorated on step edges of HOPG. AB - Ordered linear arrays of titanium dioxide nanoparticles were fabricated on highly oriented pyrolytic graphite utilizing a step edge decoration method. Ag- or Pt based nanoparticles were then photodeposited onto the titanium dioxide nanoparticles (~18 nm) to simultaneously verify photocatalytic activity and to demonstrate a viable route to load the titanium dioxide nanoparticles with metals. Scanning electron microscopy and atomic force microscopy determined the morphology, size, and distribution of the particles. X-ray photoelectron spectroscopy confirmed the identity of the titanium dioxide nanoparticles, and transmission electron microscopy showed that some of the particles were rutile single crystals. Energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy determined the chemical composition of the metal-based nanoparticles selectively loaded on the linear arrays of titanium dioxide nanoparticles. PMID- 21790180 TI - Using self-assembled monolayers to understand alpha8beta1-mediated cell adhesion to RGD and FEI motifs in nephronectin. AB - Nephronectin is an extracellular matrix protein that interacts with the alpha8beta1 integrin receptor and plays a role in tissue and organ development, though the motifs that mediate adhesion to the receptor remain unclear. This paper describes the use of self-assembled monolayers to study the adhesion of alpha8beta1-presenting cells to the RGD and DLFEIFEIER ligands in nephronectin and found that both ligands can independently mediate cell adhesion through nonoverlapping binding sites on the integrin. Peptide truncation experiments showed FEI to be the minimal binding sequence within the DLFEIFEIER sequence, and adhesion experiments with peptides that include both the RGD and FEI sequences demonstrate that the two peptides bind synergistically to the receptor. Finally, a peptide array was used to establish a strict requirement for the glutamate residue of FEI and tolerance of other aromatic and hydrophobic residues in the first and third positions, respectively. This work provides an enhanced understanding of the binding of nephronectin with alpha8beta1 and identifies a peptide ligand that can be used for targeting the alpha8beta1 integrin. PMID- 21790179 TI - Ligation of D1-His332 and D1-Asp170 to the manganese cluster of photosystem II from Synechocystis assessed by multifrequency pulse EPR spectroscopy. AB - Multifrequency electron spin-echo envelope modulation (ESEEM) spectroscopy is used to ascertain the nature of the bonding interactions of various active site amino acids with the Mn ions that compose the oxygen-evolving cluster (OEC) in photosystem II (PSII) from the cyanobacterium Synechocystis sp. PCC 6803 poised in the S(2) state. Spectra of natural isotopic abundance PSII ((14)N-PSII), uniformly (15)N-labeled PSII ((15)N-PSII), and (15)N-PSII containing (14)N histidine ((14)N-His/(15)N-PSII) are compared. These complementary data sets allow for a precise determination of the spin Hamiltonian parameters of the postulated histidine nitrogen interaction with the Mn ions of the OEC. These results are compared to those from a similar study on PSII isolated from spinach. Upon mutation of His332 of the D1 polypeptide to a glutamate residue, all isotopically sensitive spectral features vanish. Additional K(a)- and Q-band ESEEM experiments on the D1-D170H site-directed mutant give no indication of new (14)N-based interactions. PMID- 21790181 TI - Experimental and computational investigations of oxygen reactivity in a heme and tyrosyl radical-containing fatty acid alpha-(di)oxygenase. AB - Rice alpha-(di)oxygenase mediates the regio- and stereospecific oxidation of fatty acids using a persistent catalytic tyrosyl radical. Experiments conducted in the physiological O(2) concentration range, where initial hydrogen atom abstraction from the fatty acid occurs in a kinetically reversible manner, are described. Our findings indicate that O(2)-trapping of an alpha-carbon radical is likely to reversibly precede reduction of a 2-(R)-peroxyl radical intermediate in the first irreversible step. A mechanism of concerted proton-coupled electron transfer is proposed on the basis of natural abundance oxygen-18 kinetic isotope effects, deuterium kinetic isotope effects, and calculations at the density functional level of theory, which predict a polarized transition state in which electron transfer is advanced to a greater extent than proton transfer. The approach outlined should be useful for identifying mechanisms of concerted proton coupled electron transfer in a variety of oxygen-utilizing enzymes. PMID- 21790182 TI - Retraction. Pharmacokinetics and tissue depletion of cyadox and its two metabolites in pigs and broilers. PMID- 21790184 TI - Controlling the transmission of stereochemical information through space in terphenyl-edged Fe4L6 cages. AB - A series of terphenyl-edged Fe(4)L(6) cages were synthesized from substituted 4,4''-diamino-p-terphenyls, 2-formylpyridine, and iron(II). For the parent diaminoterphenyl, all three possible diastereomers, with T, S(4), and C(3) point symmetries, were formed in nearly equal amounts, as determined by (1)H and (13)C NMR. When 2,2"-dimethylterphenylenediamine was used, the T-symmetry diastereomer was observed to predominate. The use of 2',3',5',6' tetramethylterphenylenediamine generated predominantly the S(4) cage diastereomer, whereas 2',5'-dimethylterphenylenediamine produced the C(3) symmetric cage to a greater degree than the other two diastereomers. The factors contributing to the transfer of chiral information between metal vertices were analyzed, and the general principles underlying the delicately balanced thermodynamics were determined. PMID- 21790183 TI - Fluoroalkyl and alkyl chains have similar hydrophobicities in binding to the "hydrophobic wall" of carbonic anhydrase. AB - The hydrophobic effect, the free-energetically favorable association of nonpolar solutes in water, makes a dominant contribution to binding of many systems of ligands and proteins. The objective of this study was to examine the hydrophobic effect in biomolecular recognition using two chemically different but structurally similar hydrophobic groups, aliphatic hydrocarbons and aliphatic fluorocarbons, and to determine whether the hydrophobicity of the two groups could be distinguished by thermodynamic and biostructural analysis. This paper uses isothermal titration calorimetry (ITC) to examine the thermodynamics of binding of benzenesulfonamides substituted in the para position with alkyl and fluoroalkyl chains (H(2)NSO(2)C(6)H(4)-CONHCH(2)(CX(2))(n)CX(3), n = 0-4, X = H, F) to human carbonic anhydrase II (HCA II). Both alkyl and fluoroalkyl substituents contribute favorably to the enthalpy and the entropy of binding; these contributions increase as the length of chain of the hydrophobic substituent increases. Crystallography of the protein-ligand complexes indicates that the benzenesulfonamide groups of all ligands examined bind with similar geometry, that the tail groups associate with the hydrophobic wall of HCA II (which is made up of the side chains of residues Phe131, Val135, Pro202, and Leu204), and that the structure of the protein is indistinguishable for all but one of the complexes (the longest member of the fluoroalkyl series). Analysis of the thermodynamics of binding as a function of structure is compatible with the hypothesis that hydrophobic binding of both alkyl and fluoroalkyl chains to hydrophobic surface of carbonic anhydrase is due primarily to the release of nonoptimally hydrogen-bonded water molecules that hydrate the binding cavity (including the hydrophobic wall) of HCA II and to the release of water molecules that surround the hydrophobic chain of the ligands. This study defines the balance of enthalpic and entropic contributions to the hydrophobic effect in this representative system of protein and ligand: hydrophobic interactions, here, seem to comprise approximately equal contributions from enthalpy (plausibly from strengthening networks of hydrogen bonds among molecules of water) and entropy (from release of water from configurationally restricted positions). PMID- 21790185 TI - HER2 expression in breast cancer cells is downregulated upon active targeting by antibody-engineered multifunctional nanoparticles in mice. AB - Subcellular destiny of targeted nanoparticles in cancer cells within living organisms is still an open matter of debate. By in vivo and ex vivo experiments on tumor-bearing mice treated with antibody-engineered magnetofluorescent nanocrystals, in which we combined fluorescence imaging, magnetic relaxation, and trasmission electron microscopy approaches, we provide evidence that nanoparticles are effectively delivered to the tumor by active targeting. These nanocrystals were demonstrated to enable contrast enhancement of the tumor in magnetic resonance imaging. In addition, we were able to discriminate between the fate of the organic corona and the metallic core upon cell internalization. Accurate immunohistochemical analysis confirmed that hybrid nanoparticle endocytosis is mediated by the complex formation with HER2 receptor, leading to a substantial downregulation of HER2 protein expression on the cell surface. These results provide a direct insight into the pathway of internalization and degradation of targeted hybrid nanoparticles in cancer cells in vivo and suggest a potential application of this immunotheranostic nanoagent in neoadjuvant therapy of cancer. PMID- 21790186 TI - Elucidation of the thermal deterioration mechanism of bio-oil pyrolyzed from rice husk using Fourier transform infrared spectroscopy. AB - In this study, the rationale for exploring the thermal deterioration mechanism of the bio-oil pyrolyzed from rice husk is established. This is based on identification of the unstable intermediates in the thermal deterioration process. Fourier transform infrared (FTIR) spectroscopy was used to monitor such a thermal deterioration process of bio-oil samples in thermal treatment and/or during long-term storage at ambient temperatures of 20-30 degrees C. Terminal olefins, as a key intermediate, so-called "signature", were identified qualitatively by using FTIR spectroscopy. A band shift observed at 880 cm(-1), which was assigned to the C-H out-of-plane deformation vibration of terminal olefins, indicates the start-up of the bio-oil thermal deterioration. A two-step pathway was proposed to describe the thermal deterioration process of bio-oil. This study suggests that the status of bio-oil could be rapidly monitored by the FTIR method. PMID- 21790187 TI - Electrothermal dynamics of semiconductor nanowires under local carrier modulation. AB - Charge transfer, surface/interface, defect states, and internal fields strongly influence carrier statics and dynamics in semiconductor nanowires. These effects are usually probed using spatially resolved scanning current techniques, where charge carriers are driven to move by diffusion force due to a density gradient, drift force due to internal fields, and thermoelectric force due to a temperature gradient. However, in the analysis of experimental data, analytical formulas are usually used which are based on the assumption that a single component of these forces dominates the carrier dynamics. In this work we show that this simplification is generally not justified even in the simplest configurations, and the scanning microscopy data need to be analyzed with caution. We performed a comprehensive numerical modeling of the electrothermal dynamics of free charge carriers in the scanning photocurrent microscopy configuration. The simulation allows us to reveal and predict important, surprising effects that are previously not recognized, and assess the limitation as well as potential of these scanning current techniques in nanowire characterization. PMID- 21790188 TI - How good can monolayer MoS2 transistors be? AB - Monolayer molybdenum disulfide (MoS(2)), unlike its bulk form, is a direct band gap semiconductor with a band gap of 1.8 eV. Recently, field-effect transistors have been demonstrated experimentally using a mechanically exfoliated MoS(2) monolayer, showing promising potential for next generation electronics. Here we project the ultimate performance limit of MoS(2) transistors by using nonequilibrium Green's function based quantum transport simulations. Our simulation results show that the strength of MoS(2) transistors lies in large ON OFF current ratio (>10(10)), immunity to short channel effects (drain-induced barrier lowering ~10 mV/V), and abrupt switching (subthreshold swing as low as 60 mV/decade). Our comparison of monolayer MoS(2) transistors to the state-of-the art III-V materials based transistors, reveals that while MoS(2) transistors may not be ideal for high-performance applications due to heavier electron effective mass (m = 0.45 m(0)) and a lower mobility, they can be an attractive alternative for low power applications thanks to the large band gap and the excellent electrostatic integrity inherent in a two-dimensional system. PMID- 21790189 TI - Quantum point contact microscopy. AB - We introduce quantum point contact microscopy (QPCM) as a novel method for surface characterization, where the conductance through a quantum point contact formed by a metal atom between the tip of a scanning tunneling microscope and the surface is mapped across the surface. Application of QPCM to copper and gold (111) shows reproducibly atomic resolution, on gold (111) the alternating atomic stacking of the surface reconstruction is observed in real space. The perspectives for chemical sensitivity in QPCM images are demonstrated for an iron platinum surface alloy where we observe local variations of the transport current due to changes in the chemical environment of the point contact. PMID- 21790190 TI - Methyl salicylate-induced arginine catabolism is associated with up-regulation of polyamine and nitric oxide levels and improves chilling tolerance in cherry tomato fruit. AB - The effects of methyl salicylate (MeSA) on chilling injury (CI) and gene expression levels, enzyme activities, and metabolites related to arginine catabolism in cherry tomato fruit were investigated. Freshly harvested fruits were treated with 0.05 mM MeSA vapor at 20 degrees C for 12 h and then stored at 2 degrees C for up to 28 days. MeSA reduced CI and enhanced the accumulation of putrescine, spermidine, and spermine, which was associated with increased gene expression levels and activities of arginase, arginine decarboxylase, and ornithine decarboxylase at most sampling times. MeSA also increased nitric oxide synthase activity, which at least partly contributed to the increased nitric oxide content. The results indicate that MeSA activates the different pathways of arginine catabolism in cold-stored fruit and that the reduction in CI by MeSA may be due to the coordinated metabolism of arginine and the increase in polyamines and nitric oxide levels. PMID- 21790191 TI - Functional characterization of copA gene encoding multicopper oxidase in Xanthomonas campestris pv. campestris. AB - The gram-negative plant pathogenic Xanthomonas campestris pv. campestris (Xcc) is the causative agent of black rot in crucifers, a disease causing tremendous loss in agriculture. Copper-containing bactericides have been widely used to control this disease for many years, possibly leading to the development of copper resistance in Xcc. Homologues of copper resistance genes copLAB are present in the Xcc genome, but none has been characterized. In this study, mutations in copL, copA, and copB decreased Xcc copper tolerance. Among them, the copA mutant displayed the most significant reduction. The copA mutant also resulted in a reduction in virulence on the host cabbage. Sequence and mutational analysis demonstrated that copA encodes a multicopper oxidase and that CopA is able to catalyze the oxidation of 2,6-dimethoxyphenol. Alanine substitutions in each of the putative copper binding residues (H538, H583, C584, and H585) of CopA caused a loss of function including copper tolerance and oxidase activity. Furthermore, reporter assays showed that copA transcription is inducible in the presence of copper, subject to catabolite repression, and repressed under conditions of high osmolarity, nitrogen starvation, or oxygen limitation. This is the first time that multicopper oxidase has been characterized in the crucifer pathogen Xcc. PMID- 21790192 TI - Hexameric supramolecular scaffold orients carbohydrates to sense bacteria. AB - Carbohydrates are integral to biological signaling networks and cell-cell interactions, yet the detection of discrete carbohydrate-lectin interactions remains difficult since binding is generally weak. A strategy to overcome this problem is to create multivalent sensors, where the avidity rather than the affinity of the interaction is important. Here we describe the development of a series of multivalent sensors that self-assemble via hydrophobic supramolecular interactions. The multivalent sensors are comprised of a fluorescent ruthenium(II) core surrounded by a heptamannosylated beta-cyclodextrin scaffold. Two additional series of complexes were synthesized as proof-of-principle for supramolecular self-assembly, the fluorescent core alone and the core plus beta cyclodextrin. Spectroscopic analyses confirmed that the three mannosylated sensors displayed 14, 28, and 42 sugar units, respectively. Each complex adopted original and unique spatial arrangements. The sensors were used to investigate the influence of carbohydrate spatial arrangement and clustering on the mechanistic and qualitative properties of lectin binding. Simple visualization of binding between a fluorescent, multivalent mannose complex and the Escherichia coli strain ORN178 that possesses mannose-specific receptor sites illustrates the potential for these complexes as biosensors. PMID- 21790193 TI - Xenon hydrate dissociation measurements with model protein systems. AB - Effective long-term storage remains a significant challenge to the use and development of protein pharmaceuticals. We have investigated the interactions between clathrate hydrates and model protein solutions to determine the effects on hydrate formation. Here, the dissociation curve and equilibrium conditions for xenon clathrate hydrate with model lysozyme and lactate dehydrogenase (LDH) protein solutions have been studied using calorimetry measurements at pressures ranging from 3 to 20 bar. Sucrose in solution was shown to exhibit small inhibition effects on xenon hydrate formation, shifting the dissociation curve and decreasing the conversion of water to hydrate by 15-26%. The addition of l histidine buffer and lysozyme at low concentrations did not substantially inhibit hydrate formation. However, small shifts in the dissociation curve were demonstrated for solutions containing LDH. The presence of lysozyme and LDH in solution did not significantly alter the conversion of water to hydrate, indicating that these and similar proteins do not substantially affect the extent of xenon gas hydrate formation. Preliminary experiments were performed for LDH solutions to assess the impact of xenon hydrate formation and dissociation on enzymatic activity, with samples stored in hydrate systems showing small decreases in activity. PMID- 21790194 TI - Electronic structure, bonding, spectra, and linear and nonlinear electric properties of Ti@C28. AB - The potential energy surface (PES) of Ti@C(28) has been revisited, and the stationary points have been carefully characterized. In particular, the C(2v) symmetry structure considered previously turns out to be a transition state lying 2.3 kcal/mol above the ground state of C(3v) symmetry at the MP2/6-31G(d) level. A large binding energy of 181.3 kcal/mol is found at the ROMP2/6-31G(d) level. Topological analysis of the generalized Ti@C(28) density reveals four bond paths between Ti and carbon atoms of the host. The character of all four contacts corresponds to a partially covalent closed shell interaction. UV-vis, IR, and Raman spectra are calculated and compared with C(28)H(4). The dipole moment and the static electronic and double harmonic vibrational (hyper)polarizabilities have been obtained. Distortion of the fullerene cage due to encapsulation leads to nonzero diagonal components of the electronic first hyperpolarizability beta, and to an increase in the diagonal components of the electronic polarizability alpha and second hyperpolarizability gamma. However, introduction of the Ti atom causes a comparable or larger reduction in most cases due to localized bonding interactions. At the double harmonic level, the average vibrational beta is much larger than its electronic counterpart, but the opposite is true for alpha and for the contribution to gamma that has been calculated. There is also a very large anharmonic (nuclear relaxation) contribution to beta which results from a shallow PES with four minima separated by very low barriers. Thus, the vibrational gamma (and alpha) may, likewise, become much larger when anharmonicity is taken into account. PMID- 21790195 TI - Continuous synthesis process of hexagonal nanoplates of P6m ordered mesoporous silica. AB - Hexagonally ordered mesoporous silica coined COK-12 was synthesized in a continuous process by combining streams of sodium silicate and citric acid/sodium citrate buffered solution of (ethylene oxide)(20)-(propylene oxide)(70)-(ethylene oxide)(20) triblock copolymer (Pluronic P123) from separate reservoirs. COK-12 precipitated spontaneously upon combining both streams at nearly neutral pH and ambient temperature. Stable intermediates of the COK-12 formation process could be prepared by limiting sodium silicate addition. Investigation of these intermediates using small-angle X-ray scattering revealed COK-12 formed via an assembly process departing from spherical uncharged core-shell P123-silica micelles. The sterical stabilization of these micelles decreased upon accumulation of silicate oligomers in their shell. Aggregation of the spherical micelles led to cylindrical micelles, which aligned and adopted the final hexagonal organization. This unprecedentedly fast formation of P6m ordered mesoporous silica was caused by two factors in the synthesis medium: the neutral pH favoring uncharged silicate oligomers and the high salt concentration promoting hydrophobic interactions with surfactant micelles leading to silica accumulation in the PEO shell. The easy continuous synthesis process is convenient for large-scale production. The platelet particle morphology with short and identical internal channels will be advantageous for many applications such as pore replication, nanotube or fiber growth, catalytic functionalization, drug delivery, film and sensor development, and in nano dyes as well as for investigation of pore diffusion phenomena. PMID- 21790196 TI - Metal-catalyzed rearrangement of cyclopropenes to allenes. AB - A novel transition-metal-catalyzed rearrangement of silylated cyclopropenes to the corresponding allenes is described. The presence of both the trimethylsilyl group on the cyclopropene and the platinum catalyst are crucial for this rearrangement. PMID- 21790197 TI - Reaction of O2 with [(-)-sparteine]Pd(H)Cl: evidence for an intramolecular [H-L]+ "reductive elimination" pathway. AB - (Sp)PdCl(2) [Sp = (-)-sparteine] catalyzes a number of different aerobic oxidation reactions, and reaction of O(2) with a Pd(II)-hydride intermediate, (Sp)Pd(H)Cl (1), is a key step in the proposed catalytic mechanism. Previous computational studies suggest that O(2) inserts into the Pd(II)-H bond, initiated by abstraction of the hydrogen atom by O(2). Experimental and computational results obtained in the present study challenge this conclusion. Oxygenation of in-situ-generated (Sp)Pd(H)Cl exhibits a zero-order dependence on [O(2)]. This result is inconsistent with a bimolecular H-atom-abstraction pathway, and DFT computational studies identify a novel "reductive elimination" mechanism, in which the chelating nitrogen ligand undergoes intramolecular deprotonation of the Pd(II)-hydride. The relevance of this mechanism to other Pd(II) oxidation catalysts with chelating nitrogen ligands is evaluated. PMID- 21790198 TI - Extraction and enrichment of n-3 polyunsaturated fatty acids and ethyl esters through reversible pi-pi complexation with aromatic rings containing ionic liquids. AB - The present study investigated the potentials of ionic liquids (ILs) containing aromatic rings in extracting and enriching n-3 polyunsaturated compounds. The relationship between extraction efficiency, selectivity, and structure of ILs was studied and elucidated. Ionic liquids containing aromatic rings such as the N,N' dialkylimidazolium and N-alkylpyridinium are found to selectively extract and enrich n-3 polyunsaturated compounds. The IL extraction process reached equilibrium relatively quickly (<30 min), and the extraction efficiency can be further enhanced by increasing the volume ratio of IL to solvent, addition of silver tetrafluoroborate, and usage of double bond containing solvents such as 1 hexene as stripping solvent. At optimal conditions, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF(6) and 1-butyl-3-methylpyridinium dicyanamide [BuMePyr]DCN had increased extraction capabilities of n-3 polyunsaturated fatty acids (PUFA) (16.19%) and n-3 polyunsaturated fatty acid ethyl esters (PUFAEE) (144.54%), respectively. Multiple-step reverse extraction whereby n-3 PUFAs were first enriched through IL/hexane extraction followed by addition of fresh hexane repeatedly up to three times to the IL phase to desorb the saturated FAs resulted in a higher purity of n-3 PUFAs. Following this reverse extraction operation, the purity of n-3 PUFA and n-3 PUFAEE in the IL phase increased from the initial 15.88 to 38% (step 1) and further to 45% (step 3) and from the initial 72.56 to 82% (step 1) and further to 89% (step 3), respectively. The results from this study strongly suggested the correlation of n-3 PUFA extraction with aromatic/delocalized cation structure of ILs, which provides the basis for future research in designing novel ILs task-specified for efficient long-chain PUFA concentration. PMID- 21790199 TI - Effect of the surface topography of electrospun poly(epsilon-caprolactone)/poly(3 hydroxybuterate-co-3-hydroxyvalerate) fibrous substrates on cultured bone cell behavior. AB - The use of electrospun fibrous matrices as substrates for cell/tissue culture has usually been confined to those consisting of smooth fibers. Here, we demonstrated that in vitro responses of mouse-calvaria-derived preosteoblastic cells (MC3T3 E1) that had been cultured on electrospun fibrous substrates made from blend solutions of 50/50 w/w poly(epsilon-caprolactone) (PCL) and poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) of varying concentrations, ranging from 4 to 14 wt %, depended strongly on the topography of the individual fibers. As the concentration of the blend solutions increased from 4 to 14 wt %, the topography of the individual fibers changed from discrete beads/smooth fibers to beaded fibers/smooth fibers and finally to smooth fibers, and the average diameter of the individual, smooth fibers increased from ~0.4 to ~1.8 MUm. The results clearly showed that MC3T3-E1 preferred the smooth hydrophilic surface of the fibrous substrate from 10 wt % PCL/PHBV solution because the cells appeared to attach, proliferate, and differentiate on the surface of this substrate particularly well. PMID- 21790200 TI - Unraveling persistent host cell infection with Coxiella burnetii by quantitative proteomics. AB - The interaction between the immune system and invading bacteria is sufficient to eradicate microorganisms for the majority of bacterial infections, but suppression of the microbicidal response leads to reactivation or chronic evolution of infections and to bacterial persistence. To identify the cellular pathways affected by bacterial persistence, we applied the MS-driven combined fractional diagonal chromatography (COFRADIC) proteomics technique for a comparative study of protein expression in the C. burnetii strains Nine Mile (NM) and its respective strain (NMper) isolated from 18 months persistently infected cell cultures. In total, three different proteome comparisons were performed with the total bacterial proteome, potentially secreted bacterial proteins, and the eukaryotic infected proteome being assessed. Our results revealed that among the 547 identified bacterial proteins, 53 had significantly altered levels of expression and indicated potential metabolic differences between the two strains. Regarding differences in the secreted proteins between both strains and different modulation of the host cell, machineries reflect at least large rearrangements of both bacterial and eukaryotic proteomes during the persistent model of infection when compared to the acute one, which emphasizes that C. burnetii orchestrates a vast number of different bacterial and eukaryotic host cell processes to persist within its host. PMID- 21790201 TI - Composite geochemical database for coalbed methane produced water quality in the Rocky Mountain region. AB - Coalbed methane (CBM) or coalbed natural gas (CBNG) is an unconventional natural gas resource with large reserves in the United States (US) and worldwide. Production is limited by challenges in the management of large volumes of produced water. Due to salinity of CBM produced water, it is commonly reinjected into the subsurface for disposal. Utilization of this nontraditional water source is hindered by limited knowledge of water quality. A composite geochemical database was created with 3255 CBM wellhead entries, covering four basins in the Rocky Mountain region, and resulting in information on 64 parameters and constituents. Database water composition is dominated by sodium bicarbonate and sodium chloride type waters with total dissolved solids concentrations of 150 to 39,260 mg/L. Constituents commonly exceeding standards for drinking, livestock, and irrigation water applications were total dissolved solids (TDS), sodium adsorption ratio (SAR), temperature, iron, and fluoride. Chemical trends in the basins are linked to the type of coal deposits, the rank of the coal deposits, and the proximity of the well to fresh water recharge. These water composition trends based on basin geology, hydrogeology, and methane generation pathway are relevant to predicting water quality compositions for beneficial use applications in CBM-producing basins worldwide. PMID- 21790202 TI - Characteristic chain-end racemization behavior during photolysis of poly(L-lactic acid). AB - Photolysis of poly(L-lactic acid) (PLLA) has many unclear points, such as the degradation mechanism, kinetics, products, and racemization mechanism. To clarify these features of PLLA photolysis, we examined the relationship between photolysis and racemization. The hexad stereosequential analysis of photodegraded PLLA was investigated to specify the racemized positions within a chain in comparison with hydrolysis and thermal degradation. Results from (13)C NMR spectra of UV-irradiated PLLA samples indicated that the samples have racemized d lactate units at chain ends. From the comparison of racemization behavior among photolysis, hydrolysis, and thermal degradation, it was confirmed that the preferential racemization behavior of each of these three degradation processes is characteristic and distinct, being identified as chain-end racemization, poor racemization, or internal-unit racemization, respectively. The characteristic chain-end racemization behavior of photolysis was first confirmed in this study. PMID- 21790203 TI - Re-formation of fibrils from hydrolysates of beta-lactoglobulin fibrils during in vitro gastric digestion. AB - In this study, in vitro digestion of beta-lactoglobulin (beta-Lg) fibrils and the re-formation of fibril-like structures after prolonged enzymatic hydrolysis (up to 48 h) were investigated using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), thioflavin T fluorescence photometry, and transmission electron microscopy (TEM). Pure beta-Lg fibrils that had been formed by heat treatment at pH 2.0 were rapidly hydrolyzed by pepsin in the simulated gastric fluid (pH 1.2), and some new peptides that were suitable for further fibril formation were produced. TEM showed that the new fibrils were long and straight but thinner than the original fibrils, and both TEM and MALDI-MS indicated that the peptides in the new fibrils were shorter/smaller than the peptides in the original fibrils. The formation of new fibrils was found to be affected more by pH than by enzyme activity or temperature. PMID- 21790204 TI - Role of upper triplet states on the photophysics of nitrated polyaromatic compounds: S(1) lifetimes of singly nitrated pyrenes. AB - The photophysics of most nitrated polycyclic aromatic compounds is dominated by an ultrafast intersystem crossing channel, which makes their first singlet excited states decay with rates on the order of 10(12) to 10(13) s(-1). Some questions, however, remain about the nature of the receiver triplet states, which have been in principle assigned to specific triplets of a different electronic configuration from T(1). In particular, it could be suggested that even a small degree of n-pi* character of the T(1) state may be enough to allow the S(1) state to couple to upper vibronic states of the lowest energy triplet, without the requirement for specific upper triplet states. In this report, we show that there are, in fact, nitroaromatic compounds that do not show the ultrafast intersystem crossing channel but instead have S(1) states that are two to three orders of magnitude longer lived. Our studies focused on the time resolution of the emission from singly nitrated pyrenes, which show a strong photophysical dependence on the position of the NO(2) group: Whereas S(1) in 1-nitropyrene is short-lived (up to 3 ps), in 4-nitropyrene and 2-nitropyrene this state has 0.41 and 1.2 ns lifetimes, respectively, in acetonitrile solution. Computational work at the TD-DFT level of theory indicates that such remarkable increase in the first excited singlet lifetime can indeed be explained by a loss of the energy coincidence between the S(1) state with specific upper triplet states formed from transitions that involve the nonbonding orbitals at the oxygen atoms. These results are in strong support of the previous descriptions about the requirement for intermediacy of specific triplet states in the ultrafast decay of the fluorescent state present in most nitroaromatics. The implications for the photochemistry of this group of toxic atmospheric pollutants, including the channel that redounds in the dissociation of the NO. fragment, are discussed in view of the present results. PMID- 21790205 TI - Microwave and UV excitation spectra of 4-fluorobenzyl alcohol at high resolution. S0 and S1 structures and tunneling motions along the low frequency -CH2OH torsional coordinate in both electronic states. AB - Rotationally resolved electronic spectra of several low frequency vibrational bands that appear in the S(1) <- S(0) transition of 4-fluorobenzyl alcohol (4FBA) in the collision-free environment of a molecular beam have been observed and assigned. Each transition is split into two or more components by the tunneling motion of the attached -CH(2)OH group. A similar splitting is observed in the microwave spectrum of 4FBA. Analyses of these data show that 4FBA has a gauche structure in both electronic states, but that the ground state C(1)C(2)-C(7)O dihedral angle of ~60 degrees changes by ~30 degrees when the photon is absorbed. The barriers to the torsional motion of the attached -CH(2)OH group are also quite different in the two electronic states; V(2) ~ 300 cm(-1) high and ~60 degrees wide in the S(0) state, and V(2) ~ 300 cm(-1) high and ~120 degrees wide (or V(2) ~ 1200 cm(-1) high and ~60 degrees wide) in the S(1) state. Possible reasons for these behaviors are discussed. PMID- 21790206 TI - Quantification of bovine milk oligosaccharides using liquid chromatography selected reaction monitoring-mass spectrometry. AB - Oligosaccharides are important components of milk with bioefficacy as prebiotics, anti-infectives, and immune system modulators and as a possible source of sialic acid for neural function. Bovine milk oligosaccharides are lower in concentration and lack the diversity of human milk oligosaccharides but could be a commercial source of milk oligosaccharides for pediatric foods. For this development, an ability to quantify the oligosaccharides is required. This study validated a hydrophilic interaction chromatography high-performance liquid chromatography high-resolution selected reaction monitoring-mass spectrometry (HILIC HPLC-HRSRM MS) method for measuring six different oligosaccharides in bovine milk, bovine colostrum, and infant formulas. The extraction resulted in a high recovery (90 103%) with a repeatability coefficient of variation ranging from 2 to 9% for the two dominant oligosaccharides, 3'-sialyllactose and 6'-sialyllactose, and ranging from 1 to 17% for the much lower concentration oligosaccharides, 6' sialyllactosamine, disialyllactose, and N-acetylgalactosaminyllactose. The sixth oligosaccharide, 3'-sialyllactosamine, was not detected in any of the samples. PMID- 21790207 TI - Vitamin D, cognitive dysfunction and dementia in older adults. AB - The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D(3), is a fat-soluble steroid hormone with a well established role in skeletal health. A growing body of evidence suggests low vitamin D levels also play a role in the pathogenesis of a wide range of non-skeletal, age-associated diseases including cancer, heart disease, type 2 diabetes mellitus and stroke. Low levels of serum 25-hydroxyvitamin D [25(OH)D], a stable marker of vitamin D status, are also associated with increased odds of prevalent cognitive dysfunction, Alzheimer's disease and all-cause dementia in a number of studies, raising the possibility that vitamin D plays a role in the aetiology of cognitive dysfunction and dementia. To date, the majority of human studies reporting associations between vitamin D and cognition or dementia have been cross-sectional or case-control designs that do not permit us to exclude the possibility that such associations are a result of disease progression rather than being causal. Animal and in vitro experiments have identified a number of neuroprotective mechanisms that might link vitamin D status to cognitive dysfunction and dementia, including vasoprotection and amyloid phagocytosis and clearance, but the clinical relevance of these mechanisms in humans is not currently clear. Two recent, large, prospective studies go some way to establish the temporal relationship with cognitive decline. The relative risk of cognitive decline was 60% higher (relative risk = 1.6, 95% CI 1.2, 2.0) in elderly Italian adults with severely deficient 25(OH)D levels (<25 nmol/L) when compared with those with sufficient levels (>=75 nmol/L). Similarly, the odds of cognitive decline were 41% higher (odds ratio = 1.4, 95% CI 0.9, 2.2) when elderly US men in the lowest quartile (<=49.7 nmol/L) were compared with those in the highest quartile (>=74.4 nmol/L). To our knowledge, no prospective studies have examined the association between 25(OH)D levels and incident dementia or neuroimaging abnormalities. The possible therapeutic benefits of vitamin D have attracted considerable interest as over 1 billion people worldwide are thought to have insufficient 25(OH)D levels and these levels can be increased using inexpensive and well tolerated dietary supplements. However, no large randomized controlled trials have yet examined the effect of vitamin D supplements on cognitive decline or incident dementia. Further studies are urgently needed to establish which mechanisms have clinical relevance in human populations and whether vitamin D supplements are effective at minimizing cognitive decline or preventing dementia. PMID- 21790209 TI - Antipsychotic pharmacotherapy and orthostatic hypotension: identification and management. AB - Orthostatic hypotension is a common adverse effect of antipsychotics that may delay or prevent titration to a dose necessary to control psychotic symptoms. Complications of orthostatic hypotension include syncope, transient ischaemic attack, stroke, myocardial infarction and death. The risk of orthostatic hypotension associated with antipsychotic therapy is increased in patients with disorders of the autonomic nervous system, fluid imbalance and those taking concomitant drug therapy that affects haemodynamic tone. Prospective monitoring for changes in postural blood pressure is important because patients with psychotic disorders often do not articulate symptoms of orthostasis and the subjective report of dizziness does not correlate well with orthostatic blood pressure changes. Nonpharmacological strategies and patient education, most notably, slowly rising from the supine position, are crucial first steps in the prevention and treatment of both symptomatic and asymptomatic orthostatic hypotension. Pharmacological treatment is only recommended when symptomatic orthostatic hypotension persists despite proper nonpharmacological therapy and there is a compelling indication for antipsychotic treatment. Fludrocortisone is a reasonable first choice for symptomatic orthostatic hypotension. Other agents including desmopressin and midodrine may be considered in patients who do not respond favourably to a trial of fludrocortisone, but safety concerns and lack of evidence limit the utility of these agents. PMID- 21790210 TI - Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis. AB - Oral fingolimod (GilenyaTM), a sphingosine 1-phosphate (S1P) receptor agonist, is the first oral agent and the first in a novel class of disease-modifying therapies (DMTs) to be approved for use in the US for the treatment of relapsing forms of multiple sclerosis (MS). In the EU, fingolimod is approved for use as a single-agent DMT in selected patients with highly-active, relapsing-remitting (RR) MS. This article reviews the pharmacological properties and clinical use of the drug in patients with RRMS. Fingolimod is rapidly converted in vivo to the active moiety S-fingolimod-phosphate, which binds with high affinity to S1P receptors, thereby sequestering lymphocytes in the lymph nodes and preventing their egress into the peripheral circulation. As a consequence, there is a reduction in the infiltration of autoaggressive lymphocytes into the CNS. Fingolimod-phosphate also acts as a functional antagonist, as its binding to S1P receptors results in their internalization and degradation, thereby downregulating S1P receptors on the lymphocyte cell surface. Since fingolimod crosses the blood : brain barrier, it also potentially acts at S1P receptors on neural cells in the CNS to mitigate neuropathological processes associated with MS. In large multinational trials in adult patients with RRMS, oral fingolimod 0.5 mg/day was more effective than oral placebo (FREEDOMS) and recommended dosages of intramuscular interferon-beta (IFNbeta)-1a (TRANSFORMS) in reducing the annualized relapse rate and was also generally more effective at slowing progression of neurological disability and at reducing the burden and activity of disease. Fingolimod was generally well tolerated in these trials of up to 2 years' duration, with most adverse events being manageable and of mild to moderate severity; there were two deaths from opportunistic infections, albeit these occurred with fingolimod 1.25 mg/day (higher than the recommended dosage). Limited long-term data indicated that no new safety concerns had arisen after 5 years of fingolimod treatment. However, further clinical experience is required to fully determine the long-term safety profile of fingolimod, particularly with regard to any potentially serious or life-threatening adverse events. In the absence of robust pharmacoeconomic studies and of head-to-head trials comparing fingolimod with other formulations of IFNbeta and glatiramer acetate, the relative position of fingolimod with respect to other DMTs remains to be fully determined. In the meantime, given its convenient once-daily oral treatment regimen and better efficacy than intramuscular IFNbeta-1a, fingolimod is a valuable emerging option for the treatment of adult patients with relapsing forms of MS. PMID- 21790211 TI - Rotigotine transdermal patch: a review of its use in the treatment of Parkinson's disease. AB - A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro(r)) is indicated as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine transdermal patch (referred to here as rotigotine) provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In six large, well designed clinical trials, rotigotine was an efficacious treatment for Parkinson's disease. In early Parkinson's disease, rotigotine initiated without levodopa produced significantly greater improvements than placebo in the Unified Parkinson's Disease Rating Scale (UPDRS) summed motor and activities of daily living (ADL) scores, as well as significantly higher response rates. In a comparison with oral ropinirole, rotigotine did not meet a prespecified response rate noninferiority criterion, although this may reflect the dosages used, which may not have been directly comparable. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time and improved motor functioning and ADL significantly more than levodopa plus placebo. Rotigotine was noninferior to oral pramipexole in reducing 'off' time, although it did not meet a response-rate noninferiority criterion. A recent trial focused on both motor and non-motor endpoints in patients with inadequate early morning motor control despite antiparkinsonian treatment (most received levodopa). Rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. Rotigotine was generally well tolerated across the trials and in longer-term extension studies, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. Application-site reactions were generally mild to moderate in severity; where reported, up to 3% of patients had severe skin reactions. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease. PMID- 21790208 TI - Implications of gliotransmission for the pharmacotherapy of CNS disorders. AB - The seminal discovery that glial cells, particularly astrocytes, can release a number of gliotransmitters that serve as signalling molecules for the cross-talk with neighbouring cellular populations has recently changed our perception of brain functioning, as well as our view of the pathogenesis of several disorders of the CNS. Since glutamate was one of the first gliotransmitters to be identified and characterized, we tackle the mechanisms that underlie its release from astrocytes, including the Ca2+ signals underlying its efflux from astroglia, and we discuss the involvement of these events in a number of relevant physiological processes, from the modulatory control of neighbouring synapses to the regulation of blood supply to cerebral tissues. The relevance of these mechanisms strongly indicates that the contribution of glial cells and gliotransmission to the activities of the brain cannot be overlooked, and any study of CNS physiopathology needs to consider glial biology to have a comprehensive overview of brain function and dysfunction. Abnormalites in the signalling that controls the astrocytic release of glutamate are described in several experimental models of neurological disorders, for example, AIDS dementia complex, Alzheimer's disease and cerebral ischaemia. While the modalities of glutamate release from astrocytes remain poorly understood, and this represents a major impediment to the definition of novel therapeutic strategies targeting this process at the molecular level, some key mediators deputed to the control of the glial release of this excitatory amino acid have been identified. Among these, we can mention, for instance, proinflammatory cytokines, such as tumour necrosis factor-alpha, and prostaglandins. Agents that are able to block the major steps of tumour necrosis factor-alpha and prostaglandin production and/or signalling can be proposed as novel therapeutic targets for the treatment of these disorders. PMID- 21790212 TI - MicroRNAs might be promising biomarkers of human gliomas. AB - Recently, altered expression levels of several microRNAs have been observed in gliomas, the most frequent primary brain tumor in adults. To review whether microRNAs might be promising biomarkers of human gliomas, we comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to 2010 with the language limitation of English. We found that further understanding of the functions of miRNAs in specific cellular events is needed; the continuous technological advances in accurate and cost-effective miRNAs detection provide the prospect of a very promising role for miRNAs as novel diagnostic biomarkers of gliomas. PMID- 21790213 TI - Taxanes: promising anti-cancer drugs. AB - Taxanes are amongst the most promising antitumor agents available at hand today, of increasing importance in Asia given that cancer is now one of the major public health problems which needs to be dealt urgently for the benefit of affected patients. Several ongoing experimental and clinical trials have supported the fact that even with their side effects and poor solubilities, taxanes are still the first lines of treatment chosen for breast, ovary, lung and other metastatic cancers. Prolonging the life of cancer patients is the main aim of all researchers, scientists, pharmaceutical companies and clinicians; therefore this review emphasizes the mechanisms of action of taxanes and how they can play an important role in palliative treatment if not applied for curative purposes, hence being considered a boon for cancer management. PMID- 21790214 TI - Human papilloma virus prevalence, genotype distribution, and pattern of infection in Thai women. AB - BACKGROUND: The pattern of infection in cervical lesions with respect to HPV subtype has not been systematically studied in Thai women. The aim here was to determine HPV prevalence, genotype, and infection pattern in cervical lesions and to estimate the potential efficacy of an HPV prophylactic vaccine. DESIGN: Formalin-fixed paraffin-embedded cervical tissue blocks of 410 Thai patients from 8 institutes in 4 regions of Thailand (northern, southern, north-eastern, and central) were studied. The samples included 169 low grade squamous intraepithelial lesions (LSILs), 121 high grade squamous intraepithelial lesions (HSILs), and 120 squamous cell carcinomas (SCCs). HPV-DNA was amplified by PCR using consensus primers GP5+ and GP6+. The HPV genotype was then determined by reverse linear blot assay that included 37 HPV-specific 5'-amino-linked oligonucleotide probes. Patterns of infection were classified as single infection (one HPV type), double infection (two HPV types), and multiple infection (three or more HPV types). RESULTS: The mean age of the subjects was 42 years. The prevalence of HPV infection was 88.8%. The highest HPV prevalence was found in the southern region (97.1%) and the lowest in the central region (78.6%). HPV-DNA was detected in 84.6% of LSILs, 90.1% of HSILs, and 93.3% of SCCs. A total of 20 HPV genotypes were identified. The five most common high risk HPV were HPV16 (83.2%), HPV18 (59.3%), HPV58 (9.3%), HPV52 (4.1%), and HPV45 (3.8%). In double and multiple infection patterns, the most common genotypes were HPV16/18 (27.8%) and HPV11/16/18 (54.9%). HPV6 was found only in LSIL and never in combination with other subtypes. HPV11 was most common in LSIL. CONCLUSION: There is no difference of HPV type distribution in women from 4 regions of Thailand with prominent HPV16 and HPV18 in all cases. The bivalent and quadrivalent vaccines have the potential to prevent 48.6 % and 74.5% of cervical cancers in Thai women. The potential of cancer prevention would rise to 87.6% if other frequent HR-HPV types (HPV58, 52, and 45) were also targeted by an HPV vaccine. PMID- 21790215 TI - Synchronous primary cancers of the female reproductive tract in Turkish women. AB - OBJECTIVES: To evaluate the synchronous gynecologic cancers in Turkish women. MATERIALS AND METHODS: A population-based longitudinal cohort study was conducted using Izmir Cancer Registry (ICR) data on gynecologic cancer patients diagnosed in the period 1993 to 2005. The registry covers the 3.7 million population of Izmir and has been collecting data on cancer incidence and survival of cancer patients' since 1992. The ICR collects data on all new cases of cancer from all the hospitals (n = 22) in the city. RESULTS: A total of 4,185 women were identified with gynecologic cancer between 1993 and 2005, 1,526 with endometrial, 1,206 with cervical, 1,198 with ovarian, 115 with vulvar, 67 with other uterine ( sarcoma etc.), 33 with vaginal and 40 with other gynecologic cancers ( tuba uterina etc.). Fifty-five (1.3%) patients with invasive synchronous primary cancers were identified, 43 of these tumor pairs being endometrium-ovaries (81%), 66 of all lesions being endometrioid adenocarcinomas. CONCLUSIONS: Independent primary tumors of the endometrium and ovary are the most commonly encountered synchronous tumors of the female genital tractus with endometrioid adenocarcinoma as the most frequent component. PMID- 21790216 TI - World gynecologic oncology publications and the Turkish contribution to the literature between 2000 and 2007. AB - AIM: To investigate the number of publications and the contribution from top ranking countries, institutions, and authors in 3 gynecologic oncology journals (Gynecologic Oncology [GO], International Journal of Gynecological Cancer [IJGC], and European Journal of Gynaecological Oncology [EJGO]),as well as the degree of Turkish contribution between 2000 and 2007. METHOD: Articles published between 2000 and 2007 in 3 gynecologic oncology journals indexed by the Science Citation Index were accessed via the ISI-Thomson website. Additionally, PubMed, Sciencedirect, and Blackwell-Synergy databases were used to identify the originating countries and institutions of the published articles. The types of articles, originating countries, and names of the institutions and authors were determined. Furthermore, the number of articles affiliated with Turkish institutions and the publication year were also determined. RESULTS: We located 6,851 articles published in the 3 journals. During this period 36.1%, 7.7%, 7.2%, 5.8% and 4.8% of the papers originated from the USA, Japan, Italy, Turkey, and England, respectively. The 5 most productive institutions were the University of Texas, Memorial Sloan-Kettering Cancer Center, Roswell Park Cancer Institute, University of Alabama, and University of Athens. The 5 most productive authors were Markman (USA), Chi (USA), Ayhan (Turkey), Barakat (USA), and Vergote (Belgium), respectively. In all, 36.1% of the papers originated from the USA, while 44% originated from 17 European countries. The USA was the first-ranked country of origin in GO and IJGC, while Turkey was the first-ranked country of origin in EJGO. Overall, 399 (5.8%) papers originated from Turkish institutions. CONCLUSION: Most of the gynecologic oncology publications originated from the USA and Western European countries, where gynecologic oncology training is available and surgical and research traditions are well established. On the other hand, Turkish researchers made an important contribution to gynecologic oncology research during the selected period of time; publications originating from Turkey exceeded in number all European countries, except those originating from Italy. PMID- 21790217 TI - An upstream estrogen response element linked to exogenous p53 tumor suppressor gene expression differentiates effects of the codon 72 polymorphism. AB - The objective of this study was to assess the effects of an upstream estrogen response element (ERE) on exogenous p53 tumor suppressor gene with a codon 72 polymorphism about which there have been controversial reports in relation to cancer risk. The p53 gene (bases 166-1143 from start codon) with the codon 72 polymorphism, inserted into the pIRES-hrGFP II plasmid with or without upstream ERE, were transfected into HHUA endometrial cancer cells expressing the estrogen receptor. The ERE-linked p53 gene with the proline variant at codon 72 showed lower transfection rates than the gene without ERE or with the arginine variant at codon 72. p21 expression was significantly higher in HHUA cells transfected with the proline variant gene than in those transfected with the arginine variant gene. We consider that the presence of an upstream ERE promotes the transcriptional effects of the exogenous p53 gene with the proline variant, which strengthens the expression of p21, and results in lower transfection rates through cell cycle inhibition. PMID- 21790218 TI - Audience segmentation to promote lifestyle for cancer prevention in the Korean community. AB - OBJECTIVES: This study was designed to segment the audience group of '10 lifestyle for cancer prevention' based on demographic characteristics and the level of knowledge about each guideline for cancer prevention among the community in South Korea. METHODS: Participants were chosen through stratified random sampling according to the age and gender distribution of Gangwon province in South Korea. A telephone survey was conducted from 6 to 15 calls among 2,025 persons on October 2008. A total of 1,687 persons completed the survey (response rate: 83.3%). Survey items were composed of socio-demographic characteristics such as age, gender, income, education, and residence area and the knowledge level of '10 guidelines for cancer prevention', developed by 'Korean Ministry of Health and Welfare' and covering smoking cessation, appropriate drinking, condom use, and regular physical activity and so on. We selected the priority needed to promote awareness and segmented the audience group based on the demographic characteristics, homogeneous with respect to the knowledge level using Answer Tree 3.0 with CHAID as a data mining algorithm. RESULTS: The results of analysis showed that each guideline of ' 10 lifestyle for cancer prevention' had its own segmented subgroup characterized by each demographic. Especially, residence area, city or county, and ages were the first split on the perceived level of knowledge and these findings suggested that segmentation of audiences for targeting is needed to deliver more effective education of patients and community people. In developing the strategy for effective education, the method of social marketing using the decision tree analysis could be a useful and appropriate tool. CONCLUSION: The study findings demonstrate the potential value of using more sophisticated strategies of designing and providing health information based on audience segmentation. PMID- 21790219 TI - An alternative approach to study the changes in the cancer pattern of men in India (1988-2005). AB - BACKGROUND: Changes in cancer pattern are often studied with regard to rank of leading sites, variation in age adjusted rates of sites over the time or with the help of time trends. However, these methods do not quantify the changes in relation to overall changes that occurred in the total cancer cases over the period of time. An alternative approach is therefore necessary, particularly to identify emerging new cancers. METHODS: The cancer incidence data of various sites for men, over the periods 1988-90 and 2003-05 in India, for five urban registries namely Bangalore, Bhopal, Chennai, Delhi and Mumbai, functioning under the network of National Cancer Registry Programme (ICMR), formed the sources of data for the present analysis. Changes in incidence cases by various cancer sites for men are assessed by calculating the differences in incidence cases over the two period of time. Based on the contribution of each site to total change, the ten most leading sites are identified separately for each registry. The relative changes in the sites with time are taken to identify the most emerging new cancer cases over the period of time. RESULTS: The pooled cancer cases for men among five urban registries increased from 30042 cases in 1988-90 to 46946 cases in 2003-05 registering an increase of about 55.8%. The lowest percentage of increase is observed in the registry of Mumbai (25.6%) and the maximum in Bhopal (96.4%). Based on the pooled figures of five urban registries, the lung cancer contributed the maximum % change (9.7%), followed by cancer of prostate (9.2%), mouth (7.5%), tongue (5.9%) and NHL (5.9%). Based on the pooled figures and the relative changes, the emerging new cancers are prostate (140%), liver (112%) and mouth (95%). The % change by sites and the emerging new cancers varied between the registries. PMID- 21790220 TI - Comparison of trends in cancer incidence and mortality in Osaka, Japan, using an age-period-cohort model. AB - BACKGROUND: We aimed to estimate the effects of age, period and birth cohort on trends in cancer incidence and death for all sites and selected sites of cancer in Osaka using an age-period-cohort model. METHODS: Cancer incidence data during 1968-2003 were obtained from the Osaka Cancer Registry, and cancer mortality with population data in Osaka during 1968-2007 were obtained from vital statistics departments. We estimated age, period and birth cohort effects for incidence and mortality using Nakamura's Bayesian Poisson age-period-cohort model. RESULTS: For most sites of cancer, linear ageing effects were observed, the exceptions being breast and cervix which levelled-off at around 40 years old, while period effects were small. Decreasing cohort effects were observed in stomach and liver cancer. Cohort effects peaked at the generation born in the early 1950s for colorectal, lung, breast cancers. For most sites of cancer, incidence and mortality showed similar trends, but in the late cohorts for cervical cancer, cohort effects decreased in mortality, while increasing in incidence. CONCLUSION: Period effects reflecting immediate effects to cancer incidence and mortality, such as development of the effective treatment and screening programme were stable in most sites of cancer. Cohort effects influenced by long-term risk factors were prominently observed for every site, decrease in stomach and liver cancer cases being related to reduction in risk factor prevalence. Cancer control activities could be evaluated through the results, indicating utility for future cancer control planning. PMID- 21790221 TI - Role of human papilloma virus in oral tongue squamous cell carcinoma. AB - BACKGROUND: Human papilloma virus (HPV) is an important risk factor for head and neck cancer, specifically oropharyngeal cancer, but its association with oral tongue squamous cell carcinoma (SCC) is uncertain. The objectives were to determine the HPV16 prevalence in oral tongue SCCs, its integration status and to correlate the expression of oncogenic proteins with targets. METHODS: In this case-control study with oral tongue SCC cases (n=60) and normal oral mucosa (n=46), HPV positivity was determined by polymerase chain reaction (PCR) using consensus and HPV 16 type specific primers and p16 immunohistochemistry (IHC). The viral integration status was determined with primers specific to the E2 gene and in situ hybridization (ISH). Immunohistochemical analysis of HPV oncogenic proteins (E6, E7) and their target proteins (p53, pRb, cyclinD1, p16, Notch-1, EGFR) proteins was carried out in HPV positive cases. The data was analyzed with SPSS software (v 11.0). Survival analysis was carried out by the Kaplan-Meier method. RESULTS: HPV16 was detected in 48% (n=29) of the cases and none of the controls by PCR assay (p<0.001) while p16 IHC, as a surrogate HPV marker, detected 33% (n=18) of the cases; 18% (n=10) were detected by both the methods. Integration was observed in 83% (n=24) by E2-PCR and 67% (n=18) by ISH. The E6 p53 pathway was active in 33% of the cases; E7-pRb in 52% and both in 11%. HPV positivity was associated with well-differentiated cancers (p=0.041) and low recurrence rate (p=0.014). CONCLUSION: Our study confirms a positive correlation of HPV infection with oral tongue cancer. PMID- 21790222 TI - Is there any association between Helicobacter Pylori infection and laryngeal carcinoma? AB - OBJECTIVE: To investigate the possible role of Helicobacter pylori as a cause of squamous cell carcinoma of larynx in a case-control study in an otolaryngology ward at an academic university. SUBJECTS AND METHODS: A total of 65 patients with laryngeal cancer and 65 matched cancer-free controls underwent esophagogastroduodenoscopy and biopsy of antral and body regions of the stomach for evaluation of Helicobacter pylori infection. RESULTS: The proportion of subjects with a positive rapid urease test for gastric infection was similar between the two groups (49.2 % in cases vs. 40% in controls). However, a positive rapid urease test for body was less frequently seen in patients with laryngeal cancer whereas a positive rapid urease test for antrum was significantly higher (P=0.04). CONCLUSION: Our study failed to show Helicobacter pylori as one of the etiologies of laryngeal cancer. However, it supported the hypothesis that colonization of Helicobacter pylori only in the gastric body might have a protective effect against laryngeal cancer with decreasing gastric acid while antral Helicobacter pylori, increasing gastric acid due to G cell hyperplasia, may be a predisposing factor for laryngeal cancer, with acid reflux as a possible underlying etiology. PMID- 21790223 TI - Multivariate analysis of prognostic factors in gastric cancer patients using additive hazards regression models. AB - BACKGROUND AND OBJECTIVES: Gastric cancer is the second leading cause of cancer death worldwide and is the most common type of cancer in Iran. The objective of this research was to apply additive hazards models to the study of survival of patients with gastric cancer and to compare with results obtained using the Cox model. METHODS: We retrospectively studied 213 patients with gastric cancer who were registered in one referral cancer registry center in Tehran, Iran. Age at diagnosis, sex, presence of metastasis, tumor size, histology type, lymph node metastasis, and pathologic stages were entered into analysis using the Cox model and additive hazard models. To visualize a covariate effect over time, the estimated cumulative regression function by the Aalen's model was examined. RESULTS: The five-year survival rate and the median life expectancy in the studied patients were 14.6% and 29.6 months, respectively. Multivariate Cox and Additive hazards models analysis identified age at diagnosis, tumor size and pathologic stage as independent prognostic factors for the survival of patients with gastric cancer. Moreover, pathologic stage had a late or delayed effect according to the Aalen's plot. Other clinicopathological characteristics were not statistically significant. CONCLUSION: Since Cox and Aalen models give different aspects of the association between risk factors and the study outcome, it seems desirable to use then together to give a more comprehensive understanding of data. Our results also suggest that early detection of patients at younger age and in primary stages is important to increase survival of patients with gastric cancer. PMID- 21790224 TI - Preoperative prediction of neurovascular bundle involvement of localized prostate cancer by combined T2 and diffusion-weighted imaging of magnetic resonance imaging, number of positive biopsy cores, and Gleason score. AB - Because recovery of erectile function and avoidance of positive surgical margins are important but competing outcomes with prostate cancer therapy, the decision to preserve or resect a neurovascular bundle (NVB) during laparoscopic radical prostatectomy (LRP) should be firmly based on information concerning the presence and location of extracapsular extension. In the current retrospective study, the propriety of actual decisions was assessed using preoperative magnetic resonance imaging (MRI), combining T2-weighted imaging (T2WI) with diffusion-weighted imaging (DWI), the apparent diffusion coefficient (ADC), numbers of positive biopsy cores, tumor volume and the Gleason score. MRI before prostate biopsy was performed in 35 patients who underwent LRP for clinically localized prostate cancer. A single radiologist retrospectively assessed whether the tumor localization, capsular penetration, seminal vesicle invasion, NVB involvement, and MRI findings correlated with the postoperative histological results. With the postoperative specimens, 83 lesions demonstrated a Gleason score of 6 or more. Using T2WI with and without DWI and ADC, 39 and 27 of 54 lesions were correctly identified, respectively, the difference being significant. For cancers in the transitional zone, using a threshold Gleason score of 3 or greater, sensitivity was also significantly higher for T2+DWI+ADC than for T2WI alone. Of 35 patients, using all available clinical information (biopsy results including Gleason score, tumor location, percentage of positive biopsy cores, and the percentage of tumor involved core tissue), we found that the preoperative and postoperative staging were concordant in 25 cases. There is no universal consensus for nerve-sparing LRP; therefore, we performed an additional analysis using simplified clinically defined selection criteria (PSA level >15ng/mL, cT2, less than two positive biopsy scores in the unilateral lobe and less than 30% tumor volume, and a Gleason score of 6). Using this criteria, we selected 12 of 35 patients, and the detection rate of NVB involvement by MRI combined T2WI + DWI + ADC maps was 100% in their 30 lesions, and therefore we consider it safe to perform nerve-sparing LRP using our criteria. Our findings suggest that NVB can be safely preserved in patients with low-grade tumors using simplified clinically defined selection criteria to determine margin involvement. PMID- 21790226 TI - Inadequate knowledge levels of Turkish male university students about testicular self-examination. AB - INTRODUCTION: Testicular cancer occurs in men aged between 15-35, accounting for 1% of all male cancers. The most common symptom is a painless swelling in the early period, so it is important for individuals to be conscious about and perform testicular self-examination. The aim of this study was to determine the knowledge and performance of testicular self-examination (TSE) in male university students. METHODS: The target population of the study consisted of 275 male university students aged between 20-25. Data were collected using a 27 item questionnaire developed by the investigators consisting of 3 sections: 1) socio demographic characteristics; 2) risk factors for testicular cancer; 3) practices related to TSE. The data obtained were analyzed using frequency distribution and percentages. RESULTS: 88% of the students (n=242) reported having no knowledge of TSE, whereas 36% (n=12) of the remaining 12% (n=33) reported having performed TSE. With regard to the reasons for non-performance, 88% (n=242) of the participants said they did not know about TSE, 6% (n=17) said they did not attach importance to TSE and 4% (n=11) were afraid. CONCLUSION: The results of our study demonstrated that adolescent males should be educated by nurses about testicular tumors and their symptoms as well as TSE performance. PMID- 21790225 TI - Psychometric properties of the Malay Version of the hospital anxiety and depression scale: a study of husbands of breast cancer patients in Kuala Lumpur, Malaysia. AB - The main objective of this paper is to examine the psychometric properties of the Malay Version of the Hospital Anxiety and Depression Scale (HADS), tested on 67 husbands of the women who were diagnosed with breast cancer. The eligible husbands were retrieved from the Clinical Oncology Clinic at three hospitals in Kuala Lumpur, Malaysia. Data was collected at three weeks and ten weeks following surgery for breast cancer of their wives. The psychometric properties of the HADS were reported based on Cronbach' alpha, Intraclass Correlation Coefficients (ICC), Effect Size Index (ESI), sensitivity and discriminity of the scale. Internal consistency of the scale is excellent, with Cronbach's alpha of 0.88 for Anxiety subscale and 0.79 for Depression subscale. Test-retest Intraclass Correlation Coefficient (ICC) is 0.35 and 0.42 for Anxiety and Depression Subscale, respectively. Small mean differences were observed at test-retest measurement with ESI of 0.21 for Anxiety and 0.19 for Depression. Non-significant result was revealed for the discriminant validity (mastectomy vs lumpectomy). The Malay Version of the HADS is appropriate to measure the anxiety and depression among the husbands of the women with breast cancer in Malaysia. PMID- 21790227 TI - Cervical cancer risk levels in Turkey and compliance to the national cervical cancer screening standard. AB - Cervical cancer screening with Pap smear test is a cost-effective method. The Ministry of Health in Turkey recommends that it be performed once every five years after age 35. The purpose of this study was to determine the cervical cancer risk levels of women between 35 and 69, and the intervals they have the Pap smear test, and to investigate the relation between the two. This study was performed on 227 women aged between 35 and 69 living in Balcova District of Izmir province. Using the cervical cancer risk index program of Harvard School of Public Health, the cervical cancer risk level of 70% of the women was found below average, 22.1% average, and 7.9% above average. Only 52% of the women have had Pap smear test at least once in their lives. The percentage screening regularly in conformity with the national screening standard was 39.2%. Women in the 40-49 age group, were married, conformed significantly more (p<0.05) to the national screening standard. Compliance also increased with the level of education and decreased with the cervical cancer risk level (p<0.05). A logistic regression model was constructed including age, education level, menstruation state of the women and the economic level of the family. Not having the Pap smear test in conformity with the national cervical cancer screening standard in 35-39 age group was 2.52 times more than 40-49 age group, while it was 3.26 times more in 60-69 age group (p< 0.05). Not having Pap smear test in 35-39 age group more than other groups might result from lack of information on the cervical cancer national screening standard and the necessity of having Pap smear test. As for 60 69 age group, the low education level might cause not having Pap smear test. Under these circumstances, the cervical cancer risk levels should be determined and the individuals should be informed. Providing Pap smear test screening service to individuals in the target group of national screening standard, as a public service may resolve the inequalities due to age and educational differences. PMID- 21790228 TI - Expression of miR-143 reduces growth and migration of human bladder carcinoma cells by targeting cyclooxygenase-2. AB - Systemic chemotherapy is the only current modality that provides the potential for long-term survival in bladder carcinoma patients with metastatic disease. Overexpression of cyclooxygenase-2 COX-2 induces expression of immune- and cell proliferation-related genes and is associated with the grade, prognosis and recurrence of transitional cell carcinoma of the bladder. There is abundant evidence that aberrant expression of microRNAs (miRNAs) is implicated in numerous disease states and miRNAs have the potential to be used for cancer therapeutics. Here, we found expression of miR-143 to be low in a series of human bladder carcinomas as compared to background tissue. In addition, restoration of miR-143 by cell transfection in T24 cancer cells led to decreased COX-2 expression, reduced proliferation and mobility. Our findings will help to further understand the functions of miRNAs in cancer cells and point to a specific potential of miR 143 may be employed as a therapeutic agent for bladder carcinoma. The results provide insights into the development of novel tumor markers or new therapeutic strategies. PMID- 21790229 TI - Promising fusion protein design to target the U87 MG glioma cell line. AB - Gliomas, with a poor clinical course, account for 30% to 40% of all intracranial tumors. Immunotherapy with monoclonal antibodies has emerged as a promising area of investigation and recently it has been shown that antibodies utilize complementarity-determining regions (CDRs) of their variable domains to bind to antigens with high affinity and specificity. Here, we designed an antibody mimetic fused with diphtheria toxin to target the U87 MG glioma cell line. VHCDR1 and VLCDR3, together with 5 amino acid residues on both side of the CDRs, through a cognate framework region (VHFR2) yielded a mimetic of BT32/A6 (United States Patent number: 5639863). We fused the mimetic with the first 388 amino acid residues of diphtheria toxin and E. coli strain BL21 (ED3) was used to express the soluble immunotoxin DT-MG. The immunotoxin DT-MG alone did not kill Raji up to the maximal concentration tested (10-6M) in vitro. By contrast, concentrations >= 10-9M, of the fused DT-MG killed more than 95% of U-87 MG cells. It is suggested that the mimetic maintained the synergic interactions and high-affinity associated with the parent antibody. This construct holds promise for targeting specific cancer epitopes and may be useful when incorporated into diagnostic and therapeutic regimens. PMID- 21790230 TI - "Initial clinical response" to neoadjuvant chemotherapy: an in-vivo chemosensitivity test for efficacy in patients with advanced breast cancer. AB - Neoadjuvant chemotherapy (NACT) is well established as the standard of care and initial management of choice for patients with advanced breast cancer (ABC). The response is however not uniform. The present study was an endeavor to develop a clinically applicable tool based on the available clinico-pathological data in the routine clinical setting to predict response to chemotherapy in breast cancer in a developing country. From 1st June 2005 to 30th June 2007, 149 patients registered at INMOL hospital with ABC at initial diagnosis having tumor size 5 cm or more and treated with FAC as NACT were prospectively included in the study to analyze association of response after first cycle of chemotherapy (initial clinical response) with that after the third cycle. Tumor measurements were done at base line (before starting chemotherapy), three weeks after the first course of chemotherapy and three weeks after the third course. Percentage change was calculated for the latter two stages. Clinical response was assessed according to WHO/UICC criteria. Pathological complete response (pCR) was based on the histopathology of the operative specimen after NACT. 67.1% patients (cCR 7.4%+cPR 59.7%) responded to chemotherapy while 32.9% (cSD 23.5%+cPD 9.4%) did not. pCR rate was 4%. No patient had initial clinical complete response while 23% had icPR, 74% had icSD and 3% had icPD. All patients with icPR responded to NACT (cCR 29%+cPR 71%) while 60% of icSD responded to chemotherapy (cCR 1%+cPR 59%) and 40% of icSD failed to respond (cSD 31%+cPD 9%). All patients with icPD developed cPD. The high sensitivity of initial clinical response for prediction of cCR and 100% specificity of icPD for prediction of cPD favors its incorporation in clinical practice, as an early predictor of response to NACT in ABC patients. PMID- 21790231 TI - Increased expression of the PRL-3 gene in human oral squamous cell carcinoma and dysplasia tissues. AB - Phosphatase of regenerating liver (PRL) belongs to a class of the protein tyrosine phosphatase family, which is known so far to consist of 3 members, PRL 1, PRL-2, and PRL-3. The aim of this study was to uncover the role of PRL genes in development of oral malignancy. We analyzed expression levels of the 3 PRL genes in 50 human oral squamous cell carcinomas (OSCCs), 11 dysplasia and 12 normal mucosa tissues by a real-time RT-PCR method. PRL-3 but not PRL-1 or PRL-2 expressions were significantly higher in OSCC and dysplasia than in normal mucosa tissues. Additionally, PRL-3 expressions were significantly higher in OSCC tissues harboring dominant-negative p53 or recessive p53 mutation than in those harboring wild-type p53. These results suggest that PRL-3 plays a role in oral cancer development and can be useful as a marker of pre-malignant and malignant lesion of oral mucosa. PMID- 21790232 TI - Morphology, TNM staging and survival with Pancreatico-duodenectomy specimens received at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan. AB - BACKGROUND: Whipple specimens consists of duodenum from the pylorus to the ligament of Treitz, the head of the pancreas and distal extrahepatic biliary tract, sometimes with most distal portion of the stomach. Adequate gross handling of the specimen and assessment of histological variables is of prognostic importance. METHODS: At the Pathology Department of Shaukat Khanum Memorial Cancer Hospital and Research Centre, we here evaluated survival with a total of 65 pancreaticoduodenectomy specimens from 2006 to 2010 with reference to histological parameters like tumour type, site, size, grade, pT, pN, margin status and perineural invasion, and compared our results with international data. Patients were followed up and P-values were calculated regarding association between survival and prognostic factors, Kaplan-meier survival curves also being plotted. RESULTS: Most of the patients were males (60%), with a mean age of 50 yrs. The most frequent site was periampullary region (43.2%), with adenocarcinoma, NOS accounting for 72.4%. G2 was the most common grade (58.5%) and the most frequent pT was pT2 (52.4%), nearly half presenting with lymph node metastasis (47.7%). Significant associations (p<0.05) were noted for survival with grade, pT, pN, margins, tumor size and perineural invasion, but not tumor site, tumor type and age. Kaplan-Meier curve revealed that at end of 1 month, 70% of the patients were alive, this decreasing to 40%, 15% and 5% and at the end of 6 months, 1 year and 2 years. CONCLUSION: Tumor size, type, pathologic T and N staging, margins and perineural invasion are directly related to survival with pancreatico-duodenal lesions. PMID- 21790233 TI - Hepatitis B knowledge and practices among Cambodian Americans. AB - BACKGROUND: Liver cancer occurs more frequently among Americans of Southeast Asian descent than any other group. This health disparity can be attributed to high rates of hepatitis B virus (HBV) infection. We examined HBV awareness, knowledge about HBV transmission, HBV testing levels, and HBV vaccination levels among Cambodian Americans. METHODS: A population-based survey was conducted in metropolitan Seattle during 2010. The study sample included 667 individuals. We created a composite knowledge score (0-9) by summing the number of correct answers to survey items addressing HBV transmission. Data were analyzed using Generalized Estimating Equations. RESULTS: Seventy-eight percent of the study group had heard of HBV (before it was described to them). The proportions who knew that HBV cannot be spread by eating food prepared by an infected person, can be spread during childbirth, and can be spread during sexual intercourse were only 33%, 69%, and 72%, respectively. The mean knowledge score was 5.5 (standard deviation 1.7). Fifty percent of the survey respondents had been tested and 52% had been vaccinated. HBV awareness, higher knowledge scores, and vaccination were all associated (p<0.05) with younger age, higher educational level, younger age at immigration, and greater English proficiency. DISCUSSION: Our study findings confirm the need for Khmer language HBV programs for less acculturated and educated members of the Cambodian community. Such programs should aim to increase HBV testing rates, HBV vaccination rates among individuals who remain susceptible to infection, and levels of knowledge about routes of hepatitis B transmission. PMID- 21790234 TI - Genetic risk of DNA repair gene polymorphisms (XRCC1 and XRCC3) for high risk human papillomavirus negative cervical cancer in Northeast Thailand. AB - To identify risk factors other than high risk human papillomavirus infection for the development of cervical cancer, functional polymorphisms of DNA repair genes, XRCC1 Arg399Gln and Arg194Trp and XRCC3 Thr241Met, were studied among Northeastern Thai women. Cases (n=111) were defined as squamous cell cervical cancer and controls (n=118) were recruited from healthy women without cervical abnormalities. The XRCC1 194Trp/Trp genotype significantly increased the risk for cervical cancer (OR=5.52; 95%CI=1.14-26.64; p=0.03). Among the HPV infection negative group, significantly higher risks for cervical cancer were visualized for XRCC1 399Arg/Gln (adjusted OR=3.69; 95%CI=1.04-13.06; p=0.04) and XRCC1 194Arg/Trp (adjusted OR=4.13; 95%CI=1.13-15.12; p=0.03). This study indicates that variant types of DNA repair genes play partial roles in modifying individual susceptibility to cervical cancer. Since cervical cancer is a multi-factorial disease, the contribution of DNA repair enzymes to the development of cervical cancer, if it exists may be concealed by HPV infection. PMID- 21790235 TI - Adjuvant modified FOLFOX-4 in patients with stage III rectum adenocarcinoma. AB - PURPOSE: The aim of this study was to investigate efficacy and toxicity of a modified 5-fluorouracil (5-FU), folinic acid, oxaliplatin (mFOLFOX-4) regimen followed by infusional 5-FU concomitant with radiotherapy for curatively resected stage III rectum adenocarcinoma patients. PATIENTS AND METHODS: Between April 2005 and July 2009, 55 operated stage III rectum cancer patients were evaluated retrospectively. mFOLFOX-4 regimen (oxaliplatin 85 mg/m2 1st day, folinic acid 200 mg/m2 1st day, 5-FU 400 mg/m2 iv bolus 1st day, 5-FU 1600 mg/m2 46 hours continuous infusion) was applied every 2 weeks. After four courses of mFOLFOX-4, 50.4 Gy (1.8 Gy in 28 fractions) radiotherapy with continuous 5-FU 200 mg/m(2)/day by infusion pump were given. On completion of chemoradiation four more mFOLFOX-4 courses were given. RESULTS: Median age of the patients was 54 years (range 23-73 years). Low anterior resection was performed in 37 (67.3%) and abdominoperineal resection in 16 (29.1%) . Ten (18.2%) patients were at stage IIIA, 24 (43.6%) at stage IIIB and 21 (38.2%) at stage IIIC. Planned chemotherapy cycles were completed in 92.7% of patients. Grades 3-4 toxicity included neutropenia (9.1%), febrile neutropenia (3.6%), anemia (3.6%), diarrhea (21.8%), neuropathy (9.1%), renal toxicity (3.6%), hepatotoxicity (5.5%). Median follow-up time was 30 (9-57) months. Local recurrence and distant metastasis was observed in 3 (5.5%) and 10 (18.2%) patients, respectively. Ten (18.2%) patients died during follow-up. Three years disease free survival and overall survival were 67.5% and 77.3%, respectively. CONCLUSION: mFOLFOX-4 following chemoradiotherapy with continuous 5- FU infusion is an effective and well tolerated adjuvant treatment for stage III rectal carcinoma patients. PMID- 21790236 TI - Pentoxifylline therapy in the management of oral submucous fibrosis. AB - OBJECTIVES: Oral submucous fibrosis is a common premalignant condition in the Indian subcontinent and is caused by chewing areca nut and other irritants in various forms. Its medical treatment is not yet fully standardized. In this study we compared the efficacy of Pentoxifylline as compared to placebo. MATERIALS AND METHODS: 75 patients suffering from oral submucous fibrosis were randomly divided into two groups A and B. Group A patients received placebo, while Group B patients received 400 mg. Pentoxifylline for a period of 7 months. Treatment outcome was evaluated on the basis of improvement in symptom and sign scores. Student's t test was applied for comparing the results. RESULTS: The improvement in total (i.e. symptoms + sign) score was 25% in group A and 49.15% in group B. This difference was found to be statistically significant. (p < 0.05) CONCLUSION: Treatment regimen of group B was more effective. No significant side effects were seen. A follow up study is required to assess long term outcome of this therapy. PMID- 21790237 TI - Knowledge, facilitators and perceived barriers for early detection of breast cancer among elderly Turkish women. AB - This article deals with elderly Turkish women's experiences with breast self examination, clinical breast examination and mammography screening, as well as perceived barriers and facilitators in the theoretical framework of the Health Belief Model and the Health Promotion Model. This is a qualitative study performed on 46 elderly women aged 60-75 years. Data were collected with focus group interviews and analyzed systematically with qualitative analysis techniques to determine themes concerning knowledge and facilitators of and perceived barriers to early detection of breast cancer among elderly women. Barriers to screening were insufficient knowledge, fear, neglect/postponement, embarrassment/religious beliefs, inability to make an appointment, lack of a physician's recommendation and health professionals' attitudes. Facilitating factors were being informed about screening, fear, awareness of cancer screening, familial history of breast cancer and social support, making an appointment, health professionals' communication and physicians' recommendations. Public health nurses and health professionals from other health disciplines should be aware of elderly women's need for knowledge about screening, understand elderly women's fear and worries about their health and know barriers to and facilitators of screening. PMID- 21790238 TI - Ubenimex capsule improves general performance and chemotherapy related toxicity in advanced gastric cancer cases. AB - OBJECTIVE: To evaluate the effect of ubenimex capsule on general performance and chemotherapy related toxicity in patients with advanced gastric cancer undergoing chemotherapy. METHODS: Patients with advanced gastric cancer were randomly divided into two groups: with or without ubenimex. All received the following regimen for 2 cycles: docetaxel 40mg/m(2) intravenous infusion on days 1 and 8, cisplatin 15mg/m(2) and tegafur 600mg/m(2) intravenous infusion from days 1 to 5. Oral ubenimex capsule at 30mg daily was continued for 8 weeks from the start of chemotherapy. Study targets included Karnofsky performance status (KPS), body weight, leukocytes, hemoglobin, variation of several immunologic index prior,during and after chemotherapy. RESULTS: Sixty-three patients were recruited into this study, 32 randomly entered into the ubenimex capsule and 31 into the control group. KPS score and body weight after chemotherapy were more stable in the treatment group (P <0.05), and myelosuppression, including reduction of leukocytes, hemoglobin and platelets, was milder (P <0.05). T lymphocytes (CD3 +), T assisted- induced lymphocytes (CD3 +, CD4 +), T suppressor and NK cells (CD16 +, CD56 +) all increased after ubenimex capsule intake, while decreasing in the control group (P <0.05). CONCLUSION: Ubenimex capsule could improve general performance and reduce chemotherapy related toxicity in patients with advanced gastric cancer. PMID- 21790239 TI - Comparison between direct sequencing and INNO-LiPA methods for HPV detection and genotyping in Thai Women. AB - Human papillomaviruses (HPVs) have been recognized as etiologic factors in cervical carcinoma and several other anogenital cancers in females and males. HPV are classified as low risk (LR), probable high risk and high risk (HR) on the basis of their oncogenic potential. HPV genotypes, which are crucial for diagnosis and relationship with carcinogenesis, have been determined by several genotyping methods. In this study, two genotyping methods were compared: direct sequencing and INNO-LiPA. In total, 2,494 cervical specimens were tested and 27.2 % of these were found to be HPV DNA positive with 24.5% showing normal cytology. Specimens were divided into four groups according to their pathological cytology as normal, LSIL, HSIL and cancer and 134 specimens were selected for HPV genotyping by both methods. HPV genotyping results showed 87.5% positive correlation. With 17 specimens, the results were discordant, 12 specimens showed different genotypes. Others had genotypes that could not be typed by the INNO LiPA method. Neither did direct sequencing in 3 different regions yield unequivocal results. Both genotyping methods have advantages and disadvantages. Consequently, the method most suitable for the study objective, budget and predominance of HPV genotype in any given area should be selected. PMID- 21790240 TI - Perceptions and opinions towards skin cancer prevention in Malaysia: a qualitative approach. AB - INTRODUCTION: Malignant melanoma in particular is one of the few remaining cancers with an increasing incidence. OBJECTIVES: The objective of this study is to explore the perceptions and opinions of young Malaysians towards skin cancer prevention. METHODOLOGY: Focus group discussions were conducted among 33 medical science students from Management and Science University (MSU), Shah Alam, Malaysia, using convenience sampling. Students were divided into 4 focus groups consisting of 8, 8, 9 and 8 students respectively. The facilitator wrote down the conversations and data obtained were classified into various categories and analyzed manually. RESULTS: The majority of the participants mentioned that overexposure to ultraviolet light is the commonest cause of skin cancer but also that the most benefit we get from sun ight is vitamin D synthesis. The majority mentioned that the best prevention measure for skin cancer is using a sunscreen, followed by limit exposure to the sun. CONCLUSION: The present study demonstrated there is a lack of knowledge regarding screening methods and prevention measures of skin cancer. Therefore, there is a need to establish health education unit in all universities to educate all university students regarding various health problems including skin cancer prevention. PMID- 21790241 TI - Colorectal cancer in young Cambodians. AB - AIM: Colorectal cancer (CRC) is a common disease in the older population, but it has become increasingly evident that it is also not infrequent in the young. The aim of this study was to describe the epidemiological, clinical and pathological characteristics of CRC in young Cambodians. METHODS: We examined clinical and pathological data from all CRC cases registered in the two reference centres for gastrointestinal tumours in Cambodia between 2005-2010. Age-specific CRC incidence rates were computed using the national population census 2008 data from the National Institute of Statistics. We compared differences in distribution of tumour location, histology, differentiation and UICC/TNM stage in two age groups, namely < 40 and >= 40. RESULTS: During this period, there were 356 new CRC cases, of which 29.8% affected patients younger than 40. This proportion is the second highest in the world, with a higher proportion only reported in Egyptian population. The crude incidence was 2.82 and 2.36 per 100,000 in females and males, respectively. Adenocarcinoma was the most common histologic type, and >50% of all tumours occurred in the colon, with no appreciable variation between the two age groups. Mucin-producing and advanced-grade tumours were twice more frequent in the young. CONCLUSION: The unusually high CRC proportion in the young in our study could be due to referral bias. Nevertheless, together with the continuous exposure to hazardous environmental agents and the prevalent consanguinity in Cambodia, this question warrants further research to advance our understanding of CRC risk factors and perhaps genetic-environmental interactions in CRC epidemiology in young adults. PMID- 21790242 TI - Colorectal cancer screening amongst first degree relatives of colon cancer cases in Jordan. AB - OBJECTIVES: Early detection and screening for colorectal cancer is important among first degree relatives (FDR) of colon cancer cases. METHODS: Our target population comprised all such FDR, above 40 years of age, registered during the years 2003-2007, Jordan. Detailed information about cancer cases was collected from Jordan Cancer Registry. The screening study was conducted through two stages, where all FDR were examined at their homes for any suggestive related symptoms of colorectal cancer, then those who were suspected to have cancer were referred to hospital for confirmatory colonoscopy. RESULTS: First degree relatives amounted to 3,574 subjects, 153 (4.3%) were complaining of signs and/or symptoms suggestive of CRC. Of them 58 (37.9%) did not accept colonoscopy. The confirmation colonoscopy results for the remaining 95 (62.1%) indicated two confirmed CRC cases. Seventy three percent of the suspected cases complained mainly from change in bowel habit and about one fifth felt cramping. CONCLUSION: This study raised the question of cost effectiveness and cost benefits of running a nationwide screening program for such cancer in a developing country. On the other hand it highlights the importance of early detection activities in Jordan as it was the first study to be conducted among a community dwelling high risk population in the country. PMID- 21790243 TI - Cost of care for lung cancer in the first year after diagnosis in Iran. AB - OBJECTIVE: The aim of this study was to estimate the cost of lung cancer treatment in the first year after diagnosis in Iran. MATERIALS AND METHODS: Patients from two referral hospitals providing all lines of treatment to cancer patients in Tehran were sampled. The direct cost included the costs that patients and other payer' s (insurance, NGO's, or other source of payment services) paid for the services received since their first confirmed diagnosis of cancer for the duration of one year. Nine items of services were evaluated for each case with exact costs abstracted from patient's files. Using incidence of lung cancer and population figure of the country, total number of lung cancer was estimated. The total and itemized costs were estimated using an average per patients for each service. RESULTS: The average age at diagnosis was around 56 years and majority of cases were male. All patients were insured by major insurance companies. A total of 5,829 cases of lung cancer were estimated to occur in 2010. The average+/-standard deviation (sd) of duration of hospital stay was 11.9+/-9.7 days. Not all the patients received all lines of services: 86% received surgery, 36% radiotherapy; and 45% chemotherapy in the first year. Some 14% of cases utilized physiotherapy and 11.5% needed pre-treatment counseling. The grand total cost of treatment for the first year of services since diagnosis was estimated at 11,262,386 US dollars for the whole population of Iran in the year 2010. Among different services provided to the patients, surgery with annual cost of 3,178,725 US dollars constitute 28% of the total cost; radiotherapy and cost of paid for medication with an annual cost of 4,242,244 US dollars accounted for 38% of total costs. With 7.8% of Iranian GDP being consumed in health expenditure, the direct cost of lung cancer for the first year after diagnosis amounted to 4% of this figure. CONCLUSION: Our study, the first to estimate the direct cost of lung cancer in Iran, indicate how costly lung cancer is to the country. More comprehensive studies are needed to validate our results plus to assess other cost including indirect costs. PMID- 21790244 TI - p53 Expression as a marker of microinvasion in oral squamous cell carcinoma. AB - INTRODUCTION: Oral squamous cell carcinoma (OSCC) has high local recurrence, partly caused by the lack of clear margin identification on surgical removal of cancerous tissues. Direct visualization by immunostaining and fluorescent in situ hybridization (FISH) in tissue sections gives more definite information about genetic damage at margins with appropriately selected biomarkers. AIMS: To determine the usefulness of immunohistochemical techniques and FISH of the tumour suppressor TP 53 gene to identify microinvasion in marginal tissue sections and to relate the possible correlation between protein expression and genetic aberrations in OSCC cases in Malaysia. METHODS: Immunohistochemistry and FISH of TP 53 genes were applied on 26 OSCC formalin fixed paraffin embed (FFEP) blocks selected from two oral cancer referral centers in Malaysia. RESULTS: For p53 protein immunohistochemistry, 96% of the 26 OSCC studied showed positive immunostaining at the excision margins. In FISH assay, 48.9+/-9.7% of the cancerous cells were monoploid for p53 probe signals, 41.0+/-9.5 % were diploid, and 10.2+/-7.8 % were polyploid. A correlation between p53 immunostaining and TP53 gene aberrations was noted (p< 0.05). CONCLUSIONS: Immunohistochemical analysis of p53 protein expression and FISH of TP53 gene could be applied as screening tool for microinvasion of OSCC. PMID- 21790245 TI - Prevalence of vitamin-mineral supplements use and associated factors among young Malaysians. AB - The objective of this study is to determine the prevalence and associated factors of vitamin-mineral supplements use among Management and Science University students. The cross-sectional study protocol was approved by the Ethics and Research Committee and questionnaires were distributed randomly using simple random sampling to students from all faculties and consent was obtained. The data were analyzed using the SPSS version 13. Total number of the participants in this study is 105. More than half of them were female, older than 20 years of age and Malay (58.1%, 61.9 and 61.9% respectively). The prevalence of vitamin-mineral supplement use was 43%, the main reasons being 'to maintain good health' 80%, followed by 'to ensure adequate nutrition' (10.5%). There was a significant positive association with monthly household income and BMI (P=0.039; P=0.048), with significant dependence on race and knowledge about vitamin-mineral supplements (P=0.002). There was a significant difference between medical and health sciences as compared to non-medical and health science faculties (p =0.05). The conclusion is that although the prevalence of vitamin-mineral supplement use among university students is relatively high, many of them do not have accurate information about supplements. Therefore, there is a need to provide them with education and access to scientific and unbiased information. PMID- 21790246 TI - Her2 amplification status in Iranian breast cancer patients: comparison of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). AB - INTRODUCTION: Her2/neu is a biomarker which is amplified and/or overexpressed in a subset of breast cancer patients who are eligible to receive trastuzumab. Her-2 gene amplification analysed by fluorescence in situ hybridisation (FISH) and/or protein over-expression detected by immunohistochemistry (IHC) are the two main methods used to detect Her-2 status in clinical practice. The concordance rate between the two techniques is controversial. METHODS: FISH analysis were performed on 104 tumoural samples from breast cancer patients with known IHC results to determine the Her2 gene status. The FISH/IHC analyses results were then compared and the concordance rate was determined. RESULTS: Her2 gene amplification was detected in 0 of IHC score 1+, 24/86 (27.91%) 2+, and 8/13 (61.54%) 3+. The IHC and FISH results concordance rates were 100%, 27.9%, and 61.5% for IHC scores of 1+, 2+, and 3+ respectively. CONCLUSION: The results of this study suggest that IHC 1+ should be considered as negative while IHC 2+ results need further confirmative analysis by FISH. Further quality control and standardization of IHC technique are required to improve the concordance rate between the two methods. PMID- 21790247 TI - Relation between IRF-1 gene and acute myelocytic leukemia in Kashmiri population. AB - The IRF-1 protein, a mammalian transcriptional factor encoded by a gene located in 5q23-q31, has antioncogenic properties. Involved in regulation of differentiation and proliferation, IRF-1 acts as a tumor suppressor gene and is inactivated by deletion of its one or more exons (exon skipping) in many hematological malignancies, including acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS). DNA samples, extracted from peripheral blood, taken from 50 Kashmiri AML subjects, were analysed using the polymerase chain reaction and compared with examples of age and gender matched healthy controls from the same population. Three different exon regions (2, 3 and 4) of the IRF-1 gene that were previously shown to be prone to deletion were selected for amplification and analysis. Deletion was observed in 31(62%) out of 50 AML patients (p=0.016). Exon 3 was most frequently deleted (58%), followed by exon 2 (28%), while exon 4 was least affected (12%), providing insights into critical roles in leukemogenesis. The number of deleted exons was variable, but single exon deletions were more frequent (30%). Of interest, IRF-1 gene deletions were not observed in 19 (38%) patients. In our study, the frequency of deletions of these three exons was slightly higher than in an Indian population (52%), but lower than in Sweden in Europe (95%). This study also explored the prevalence and clinical profile of IRF-1 deletions in AML patients. Adults had a significantly higher incidence than children (p=0.0168) and IRF-1 deletions were associated with low Hb (p< 0.0001), high TLC (p=0.0033) and a low platelet count (p=0.0076). PMID- 21790248 TI - Biomonitoring of genotoxic effects among shielded manual metal arc welders. AB - Hexavalent chromium Cr (VI) used in shielded metal arc welding is widely recognized to act as a carcinogen, mutagen and teratogen. The carcinogenic potential of metals is a major issue in defining human health risk from exposure. Hence in the present investigation, 66 welders and 60 control subjects with similar mean ages, smoking prevalences and alcohol consumption were enrolled for DNA damage analysis of buccal cells by micronucleus (MN) and comet assay. Welders showed a significant increase in micronucleated cells compared to controls and a larger mean comet tail length. The current study thus suggested that chronic occupational exposure to Cr (VI) during welding could lead to increased level of DNA damage. Understanding the complexity of the relationships between exposure, basal DNA damage and MN frequencies requires larger scale studies and application of complementary biomarkers. PMID- 21790249 TI - Extended full-thickness transanal local excision to treat ultra-low rectal cancer: an initial clinical exploration. AB - OBJECTIVE: To investigate the feasibility of extended full-thickness transanal local excision for rectal cancers invading anorectal junction. METHODS: Four patients with small (size <=3cm) unfixed rectal cancer, which extended into the upper anal canal, were submitted to transanal local excision with a dissection plane extended to the striated muscle layer around the upper anal canal, so that a portion of striated muscle beneath or around the tumor was excised en bloc with the anorectal wall. The defect in the anorectal wall was laid open to granulate and epithelize. RESULTS: The mean operative time was 28+/-6 min, with no related mortality. Postoperative pathological examination confirmed clear resection and revealed 1, T2, 2, T1, and 1 Tis carcinomas. The median follow-up was 3.2 months (range, 1.5-13.0 months). Minor soiling with flatus incontinence was common during the first postoperative month. Two patients with a follow-up longer than 3 months had perfect anal continence. No local recurrence was observed. CONCLUSION: Extended full-thickness transanal local excision for rectal tumors lying at the anorectal junction is safe and simple. Patients with partial excision of striated muscle around the upper anal canal may still enjoy good anal continence. Further studies on extended full-thickness transanal excision are worthwhile. PMID- 21790250 TI - Long-term high-dose proton pump inhibitor administration to Helicobacter pylori infected Mongolian gerbils enhances neuroendocrine tumor development in the glandular stomach. AB - Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model. PMID- 21790251 TI - Irinotecan as a second-line monotherapy for small cell lung cancer. AB - OBJECTIVES: The present study was designed to investigate the efficacy of irinotecan monotherapy as a second-line treatment for small cell lung cancers (SCLCs). METHODS: Irinotecan monotherapy was administered to 46 SCLC patients who were previously undergone cisplatin based chemotherapy protocols. Response to treatment, time to progression (TTP), overall survival rates and adverse events associated with irinotecan monotherapy (300mg/m2; total 153 cycles; mean 3.78 ? 1.98) were determined, retrospectively. RESULTS: Limited stage disease was diagnosed in 19.6% of patients (n=9) while 80.4% (n=37) were diagnosed with extensive stage cancer preceeding the irinotecan monotherapy. None of the patients had complete response to irinotecan. Partial response and stable disease were achieved among 17.5% of patients. Mean time to tumor progression (TTP) was determined to be 11.3+/-5.94 weeks while overall survival was 13.3+/-6.83 months. Considering adverse events, grade 3 and 4 toxicity was encountered in 8.9% and 4.5% of patients, respectively. Irinotecan monotherapy in brain metastasized tumors was found to be associated with significantly higher survival times compared with tumors lacking brain metastasis (15.0+/-5.95 vs 10.7+/-4.82 months; p< 0.05). CONCLUSIONS: Irinotecan as a monotherapy in the second-line treatment of SCLC seems to have an acceptable level of toxicity and significant palliative effects. The prominent survival step-up effect particularly in brain metastasis patients appears worthy of note. PMID- 21790252 TI - Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. AB - AIM/HYPOTHESIS: Diabetes and breast cancer are both serious life-threatening diseases across the world. Some studies shows that diabetes is associated with many kinds of tumor, but links with breast cancer remain controversial. The aim of this study was to assess the association the available evidence. SUBJECTS AND METHODS: A meta-analysis was conducted including 16 studies published between 2000 and 2010 and summary relative risks(RRs) with 95% CIs were calculated using random-effects model. RESULTS: The combined evidence supports that diabetes was associated with a statistically significant 23% increased risk of breast cancer, especially in postmenopausal women (RR=1.25 95%CI 1.20-1.29). The correlation between diabetes and breast cancer was the most obvious in Europe (RR=1.88,95%CI:1.56-2.25), followed by America (RR=1.16, 95%CI:1.12-1.20). In Asia the result was not significant (RR=1.01, 95%CI=0.84-1.21). Diabetes also increased mortality from breast cancer overall (RR=1.44, 95%CI:1.31-1.58). CONCLUSIONS/INTERPRETATION: This meta-analysis indicated that diabetes can be considered as a risk factor for breast cancer. In addition, menstruation status as well as geographical distribution can affect the relationship. PMID- 21790254 TI - Colorectal cancer in Central Tunisia: increasing incidence trends over a 15-year period. AB - INTRODUCTION: Significant variation in colorectal cancer incidence rates and trends has been observed across countries. Data from Tunisia are sparse. In this paper, we analyzed trends in incidence rates of the colorectal cancer over a 15 year period, 1993-2007, in Central Tunisia. DESIGN: Five-year age-specific rates, crude incidence rates, world age-standardized rates, and annual percent change were calculated using annual data on population size and its estimated age structure. RESULTS: A total of 1,443 incident cases of colorectal cancer were registered, with a male to-female sex ratio of 1.1:1. The world age-standardized rate was 10.0 per 100,000 among females and 11.7 among males. Over time, there were significant increasing trends by +2.6% (95% CI: 0.1%, 5.1%) and +5.3% (95% CI: 2.7%, 7.9%) for females and males, respectively. CONCLUSION: The absence of a screening program for colorectal cancer could explain the increasing trends observed among males and females in Central Tunisia. Our findings point the need to plan and develop effective programs aimed at the control and prevention of the spread of colorectal cancer in Tunisia. PMID- 21790253 TI - Association of the hOGG1 Ser326Cys polymorphism with increased lung cancer susceptibility in Asians: a meta-analysis of 18 studies including 7592 cases and 8129 controls. AB - OBJECTIVE: To understand the influence of the hOGG1 Ser326Cys polymorphism on lung cancer susceptibility, an updated meta-analysis was performed. METHODS: A total of 7,592 patients and 8,129 controls from 18 studies, identified by searching ISI Web of Knowledge, PubMed, EMBase and CNKI database up to January 2011, were included. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Overall, the hOGG1 Ser326Cys polymorphisms were associated with the risk of lung cancer. In the subgroup analyses by ethnicity, histological type, smoking status, significant association with lung cancer risk in Asians was found either in the dominant (crude OR, 1.19; 95% CI, 1.07-1.33 for Cys/Cys+Ser/Cys versus Ser/Ser) or recessive (crude OR, 1.21; 95% CI, 1.08-1.35 for Cys/Cys versus Ser/Cys+Ser/Ser) model. An increased risk with statistical significance was found in recessive model for squamous carcinoma (adjusted OR, 1.91; 95% CI, 1.30-2.80) and adenocarcinoma (adjusted OR, 1.52; 95% CI, 1.23-1.87). Significant association with lung cancer risk among heavy smokers was found in the recessive model (crude OR, 1.67; 95% CI, 1.26-2.21). CONCLUSIONS: The results indicated that the hOGG1 Ser326Cys polymorphism might contribute to the risk of non-small cell lung cancer in the Asian population. PMID- 21790255 TI - Comparison of Helicobacter pylori antibody detection in stool with other diagnostic tests for infection. AB - For detection of Helicobacter pylori, bacterial culture and histopathological examination are invasive in nature, whereas the fast urease test and urea breath test are non-invasive and indirect methods of detection. Stool antibody tests and polymerase chain reaction (PCR) to detect genomic DNA are serological methods, which are preferred to invasive examinations. Our aim was to assess diagnostic specifity and sensitivity of stool antibody tests, with histopathological examination as the golden standard and to compare results with fast urease test findings. Biopsy samples of patients in the study were evaluated as examples of invasive methods, and also stool antibody screening were made (HpSA). When urease and HpSA test results were compared with histopathological results, sensitivity and specificity of urease test were 62.2% and 100%, respectively, and 68.9% and 100% for the HpSA test. General accuracy was 80% and 81%, respectively , positive predictive value 100% with each and negative predictive values 66.1% and 67.2% . The differences were not statistically significant, and the confidence intervals were approximately in the same range. Thus results obtained with biopsy urease and HpSA tests were generally similar to those obtained by histopathological examination. A review of national and international literature showed similar findings. PMID- 21790256 TI - Socioeconomic status and lung cancer risk in Nepal. AB - BACKGROUND: Lung cancer is the most common cancer among men and the third most common cancer among women in Nepal. Socioeconomic disparities in lung cancer have not been studied in the Nepalese population. METHODS: We conducted a lung cancer case-control study, including 209 cases and 313 controls at the main cancer hospital in Nepal, the B.P. Koirala Memorial Cancer Hospital (BPKMCH). RESULTS: We observed differences in lung cancer risk by ethnicity; the Rai, Limbu and Magar groups had a higher risk of lung cancer than Brahmin (OR=3.11, 95%CI=1.55 6.23). An inverse association was observed between education and lung cancer risk (p for trend=0.0008). We also observed greater lung cancer risk among unmarried individuals (OR=2.25, 95%CI=1.12-4.53), and lower risk in individuals who lived in the Central region compared to the West (OR=0.47, 95%CI=0.26-0.85). There were greater proportions of late stage cancers among women compared to men, in the Rai/Limbu/Magar ethnic groups, in individuals with lower education and in older age groups. CONCLUSIONS: Disparities in lung cancer risk were observed by race/ethnicity, education, marital status, and by region of residence. Further research on socioeconomic influence on lung cancer in Nepal is warranted to develop better prevention efforts against the disease. PMID- 21790257 TI - Mate consumption and risk of cancer: a multi-site case-control study in Uruguay. AB - In the time period 1990-2004 we conducted a multisite case-control study in order to examine the relationship of mate consumption and risk of 13 cancer sites in Montevideo, Uruguay. The study included 13,201 participants (8,875 cases and 4,326 controls) drawn from the four major public hospitals in the city of Montevideo. Newly diagnosed and microscopically confirmed cases of cancers of the mouth, pharynx, esophagus, stomach, colon, rectum, larynx, lung, female breast, cervix uteri, prostate, bladder and kidney were included in the study. Controls were drawn from the same hospitals and in the same time period and were afflicted by non-neoplastic conditions not related with tobacco smoking or alcohol drinking and without recent changes in their diets. Odds ratios for mate consumption was directly associated with cancers of the upper aerodigestive tract (UADT), esophagus, stomach, larynx, lung, cervix uteri, prostate, bladder, and kidney. In conclusion these results suggest that chemicals, like benzo[a]pyrene, could be responsible of the carcinogenic effect of mate in the above mentioned cancer sites. PMID- 21790258 TI - HPV vaccination in Hong Kong: implications for medical education. AB - OBJECTIVE: To explore the experience and attitudes of physicians in clinics, and to facilitate physicians' promotion of HPV vaccination. DATA SOURCES: Primary data collected from conducting semi-structural in-depth interviews from May to June 2010 with 12 physicians in one district in Hong Kong to understand their experience of providing HPV vaccines, the difficulties in promoting HPV vaccines, and their attitudes towards HPV vaccination. STUDY DESIGN: Physicians identified 4 categories of factors related to their experiences of and attitudes to providing HPV vaccination: (a) background information on HPV vaccination provided by physicians, (b) factors influencing women to receive vaccination, (c) physicians' recommendations to the public on HPV vaccines, and (d) physicians' perspectives on HPV vaccine promotion. CONCLUSIONS: Our findings show that public knowledge on HPV and cervical cancer is insufficient and the role of government in vaccine promotion is unclear. Promotion strategies such as physicians' recommendation, financial assistance and health education provided by the government will influence HPV vaccination and its promotion. PMID- 21790259 TI - Outcomes of children with relapsed acute lymphoblastic leukemia in India. PMID- 21790260 TI - Successful management of bevacizumab-associated surgical bleeding with an Ankaferd blood stopper. PMID- 21790261 TI - Bone health in survivors of lymphoma, treated with high dose steroids - is there a need for clearer guidelines on bone care? PMID- 21790262 TI - Idaho rural family physician workforce study: the Community Apgar Questionnaire. AB - CONTEXT: Community factors of varied importance help determine the success of achieving and maintaining a physician workforce. The purpose of this study was to develop an evaluation instrument (Community Apgar Questioinnaire) useful to rural Idaho communities' in their assessment of the assets and capabilities related to physician recruitment and retention. METHODS: A quantitative scoring interview instrument was developed based on a literature review, site visits and discussions with rural physicians and hospital administrators. A total of 11 rural Idaho communities differing in geography and other known variables were selected, some identified historically to have more success in recruitment and retention (alpha communities) and some historically noted to have more challenges (beta comunities). In each community, the administrator of the hospital and the physician with recruiting responsibilities participated individually in a structured interview. RESULTS: A total of 11 physicians and 11 CEOs participated in the study. Differences were found across and within classes of factors associated with success in physician recruitment and retention where alpha communities scored higher on Community Apgar Questionnaire metrics. Some differences were noted by respondent class. Cumulative mean Community Apgar scores are higher in communities that have historically better track records in recruitment and retention. CONCLUSION: The Community Apgar Questionnaire seems to discriminate between communities with differing assets and capabilities, based on historical community-specific workforce trends. This assessment may allow for identification of both modifiable and non-modifiable factors and also may suggest which factors are most important for a community with limited available resources to address. PMID- 21790263 TI - Emotional/behavioral difficulties and adolescent obesity: effect of sex and Hispanic origin/race. AB - This study examines the relationship between emotional/behavioral difficulties and obesity among US adolescents aged 12-17 using parent-reported data for 11,042 adolescents in the National Health Interview Survey. Obesity was defined as body mass index (BMI) >=sex/age-specific 95th percentile BMI cut-points from the 2000 CDC Growth Charts. Types of emotional/behavioral difficulties were identified using the Strengths and Difficulties Questionnaire. Among females, emotional/behavioral difficulties were associated with obesity among non-Hispanic (NH) white and Hispanic adolescents (both those with interviews in English and interviews in Spanish). Among males, emotional/behavioral difficulties were associated with obesity among NH white adolescents and Hispanic males with interviews in English. No association between any difficulties and obesity was found among NH black adolescents, either male or female, or Hispanic males with interviews in Spanish. Awareness of the differing association between emotional/behavioral difficulties and obesity among subgroups of adolescents may aid in the development of targeted obesity interventions. PMID- 21790266 TI - Reconceptualizing medication adherence: six phases of dynamic adherence. AB - Nonadherence is the Achilles' heel of effective psychiatric treatment. It affects the resolution of mental health symptoms and interferes with the assessment of treatment response. The meaning of the term adherence has evolved over time and is now associated with a variety of definitions and measurement methods. The result has been a poorly operationalized and nonstandardized term that is often interpreted differently by providers and patients. Drawing extensively from the literature, this article aims to (1) describe changes in the concept of adherence, drawing from the mental health treatment literature, (2) present a more comprehensive definition of adherence that recognizes the role of patient provider transactions, (3) introduce dynamic adherence, a six-phase model, which incorporates the role of transactional processes and other factors that influence patients' adherence decisions, and (4) provide recommendations for providers to improve adherence as well as their relationships with patients. PMID- 21790267 TI - A perspective on psychosis in late life and deficits in social cognition. AB - The etiology of new psychotic symptoms in late life, including subtle changes in cognition, is a controversial emerging area of study. The development of psychotic symptoms, particularly paranoia, is a common occurrence in late life, and the symptoms of cognitive dysfunction and psychosis are often prominent in dementia, schizophrenia, and mood disorders. This intermixing of symptoms has inescapably led to diagnostic confusion with regard to elderly patients with new onset psychosis. The complex relationship among different domains of psychopathology makes it difficult to tease apart disorders of affect from psychosis, affect from cognition, and psychosis from cognition. It is therefore potentially useful to modify and expand our approach to how we conceptualize these patients. Emerging evidence suggests that those with dementia, psychotic disorders, and mood disorders suffer from growing cognitive deficits. The article suggests that deficits in social cognition, in particular, may be the unifying deficit that helps to explain why heterogeneous patients may develop paranoia and psychotic symptoms in late life. PMID- 21790268 TI - "There's something in my body that shouldn't be there": using cognitive behavioral therapy in treating psychosis and HIV. PMID- 21790269 TI - The relevance of Caenorhabditis elegans genetics for understanding human psychiatric disease. PMID- 21790270 TI - Teledermatology via a social networking web site: a pilot study between a general hospital and a rural clinic. AB - Teledermatology via a free public social networking Web site is a practical tool to provide attention to patients who do not have access to dermatologic care. In this pilot study, a general practitioner sent consults to a dermatology department at a general hospital via Facebook((r)). Forty-four patients were seen and treatment was installed. We identified both simple-to-treat, common skin diseases and rare congenital diseases that require genetic counseling and more complex treatment. The majority of patients (75%) benefited with the diagnoses and treatments offered, thus avoiding unnecessary expenses or transportation to urban areas. PMID- 21790271 TI - A blueprint for telerehabilitation guidelines--October 2010. PMID- 21790272 TI - Effect of LED red and IR Photobiomodulation in tongue mast cells in Wistar rats: histological study. AB - OBJECTIVE: This article aimed to study the effect of LED Phototherapy (LED-PHT) (?630?nm or ?850?nm) on mast cells on the dorsum of the tongue of rodents. BACKGROUND DATA: Vasodilatation is one of the reported effects of laser light on tissues. Laser light is able to induce the release of mediators responsible for vasodilatation, such as those produced by mast cells. Mast cells are also related to some diseases such as hay fever. METHODS: Sixty Wistar rats were divided into three groups: I, Control; II, IR-LED (?850?nm, 21.9?J/cm(2), 73 sec; and III, red LED (?630?nm, 21.9?J/cm(2), 73?sec). The specimens were taken after, 20, 45, and 60?min following irradiation. The specimens were routinely processed; stained with toluidine blue; and then total, degranulated, and non-degranulated mast cells were counted and statistical analysis performed. RESULTS: Both LED irradiated subjects showed significant difference when compared to the control subjects on the total number mast cells (p<0.001, ANOVA), degranulated mast cells (p<0.001, ANOVA), and non-degranulated mast cells (p<0.001, ANOVA). Comparing the two groups of LED irradiated subjects, significant difference was observed regarding the total number of cells (p<0.001, paired t-test) and degranulated mast cells (p<0.001, paired t-test) with a greater number of these cells noted in the IR-LED group. On the other hand, Red-LED irradiated subjects showed a significantly greater number of non-degranulated mast cells (p=0.001, paired t test). CONCLUSIONS: Our results lead us to conclude that both red and IR-LED light caused increased mast cell degranulation and that IR-LED light resulted in a greater number of mast cells. PMID- 21790273 TI - Evaluation of the safety and effectiveness of nevirapine plus coformulated tenofovir/emtricitabine as first-line therapy in routine clinical practice. AB - Despite having demonstrated noninferior efficacy against atazanavir/ritonavir plus coformulated tenofovir/emtricitabine (cTDF/FTC), the combination of nevirapine plus cTDF/FTC is not included among preferred regimens in some international guidelines. This combination is frequently used in Spain. We analyzed its effectiveness and safety as first-line therapy in a routine clinical practice. A retrospective, multicenter study was performed in treatment-naive HIV 1-infected subjects who started nevirapine plus cTDF/FTC as first-line therapy according to the nevirapine CD4(+) cell count threshold. The primary endpoint was the proportion of subjects with plasma HIV-1 RNA <50 copies/ml at week 48. We included 123 subjects starting the regimen from 2005 to 2008. The median age was 41.0 years, the median baseline CD4(+) cell count was 215 cells/MUl, the median plasma viral load (VL) was 4.83 log(10) copies/ml, and 22% had hepatitis C coinfection. At week 48, 96 subjects (78%; 95% CI: 69.9-84.4) had a VL <50 copies/ml in an ITT analysis, and the median rise in the CD4(+) cell count was 118 cells/MUl. Virological failure was observed in 6.5% (8/123) of subjects, all them before week 24 and related to poor adherence. There was no relationship between virological failure and baseline CD4(+) cell count or VL. Ten percent (13/123) of the subjects discontinued the treatment due to adverse events. There was a significant decrease in total/HDL-cholesterol ratio (p=0.03) with an increase in HDL-cholesterol (p=0.01) over 48 weeks. The combination of nevirapine plus cTDF/FTC showed a high virological efficacy without unexpected toxicities as a first-line treatment in a routine clinical practice. PMID- 21790274 TI - Facebook tells me so: applying the theory of planned behavior to understand partner-monitoring behavior on Facebook. AB - The social networking site (SNS) Facebook is becoming increasingly recognized as a medium through which individuals can investigate and monitor others' activities. However, little is known about whether Facebook monitoring behavior occurs within romantic relationships and, accordingly, the psychological predictors of this behavior. The present study employed an extended theory of planned behavior (TPB) framework including self-esteem, partner trust, and demographic characteristics, to predict frequent Facebook partner-monitoring. Facebook users (N=244) in romantic relationships completed measures assessing the standard TPB constructs (attitude, subjective norm, and perceived behavioral control), additional predictor variables (self-esteem and partner trust), and demographic characteristics (age, gender, relationship length, daily Facebook logins, and time spent per login). One week later, participants reported their level of Facebook partner-monitoring during the previous week. Regression analyses supported the standard TPB constructs of attitude and subjective norm in predicting intentions to engage in frequent Facebook partner-monitoring, with intention, in turn, predicting behavior. Partner trust, but not self-esteem, significantly predicted frequent Facebook partner-monitoring intentions. Of the demographic characteristics, daily Facebook logins significantly predicted both intention and behavior and, unexpectedly, relationship length directly affected behavior. Overall, the current study revealed that frequent Facebook partner monitoring is influenced by attitudinal, normative, and relational factors and, potentially, increased visits to Facebook. These findings provide a new understanding of an individual's use of the world's leading SNS to monitor their partner's activities and provide a foundation for future studies to investigate the potential negative implications this activity may have for those in romantic relationships. PMID- 21790275 TI - The effectiveness of personalized e-mail newsletters and the role of personal characteristics. AB - Personalizing communication means creating persuasive messages that refer to aspects of a person's self. Although the use of personalization is increasing, research on its effectiveness is limited and the results are mixed. This study examined the persuasiveness of personalized e-mail newsletters in terms of increased attention, cognitive activity, evaluation, attitude, intention, and behavior by means of an experiment (n=109). Participants randomly received either a personalized or a generic newsletter advertising a sports center. Personalization triggered a more positive evaluation of the message; however, it did not influence the other effect variables. The effects were moderated by consumers' need for uniqueness, trust, and privacy concerns, suggesting that personalization is a good strategy to increase message evaluation only among individuals who have a high need for uniqueness. PMID- 21790276 TI - An outbreak of Salmonella typhimurium 108/170 at a privately catered barbeque at a Sydney sports club. AB - An outbreak of gastrointestinal illness was identified among attendees at a large community barbeque at a Sydney sports club on 30 January 2009. A retrospective cohort study was initiated, and attendees were identified through hospital emergency department gastroenteritis presentations, snowball recruitment through known cases, responders to linguistically specific press, and those returning to the venue the next week. A symptom and food history was collected from attendees, and stool samples were provided for microbiological investigation. An environmental investigation and trace back of implicated foods was also undertaken. Attendance estimates at the barbeque ranged from 100 to 180, and the food was prepared by a family that was not registered as a food business. Seventy one of the 87 attendees identified met the case definition. Thirty attendees (42%) had laboratory confirmed Salmonella Typhimurium phage-type 108/170, all with the same multilocus variable number of tandem repeat analysis typing. Burden of illness was high with 76% of cases seeking medical attention and 18% admitted to hospital. Microbiological evidence confirmed that a number of food items were contaminated with Salmonella Typhimurium 108/170, with the raw egg mayonnaise used in a Russian salad being the most likely primary food vehicle (adjusted odds ratio=10.3 [95% confidence interval 1.79-59.5]). Further, having Russian salad on the plate even if it was not consumed increased the relative risk of illness, thus suggesting that other food items may have been contaminated when they came into contact with it on the plate. This Salmonella outbreak highlighted the risks associated with the improper handling of food in private residences, which are then sold at a large public event. PMID- 21790277 TI - Novel insights in the pathogenesis of systemic sclerosis. PMID- 21790278 TI - Models for prediction of death in systemic sclerosis: current perspectives and future directions. PMID- 21790279 TI - Evaluating microangiopathy in systemic sclerosis: what have we learnt and what is left to discover? PMID- 21790280 TI - Disease-modifying drugs for systemic sclerosis: why have we not found them yet? PMID- 21790281 TI - The pleomorphism of systemic sclerosis: are we ready for 'personalized medicine' in scleroderma? PMID- 21790284 TI - Budesonide in the treatment of inflammatory bowel disease. AB - Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, features recurrent episodes of inflammation of the GI tract. The treatment of inflammatory bowel disease is aimed at breaking the cycle of relapsing and remitting inflammation by inducing and maintaining remission. Systemically active conventional corticosteroids have long played a role in the induction of remission in both Crohn's disease and ulcerative colitis, however, their long term use can lead to adverse systemic effects. Budesonide, a synthetic steroid, has potent local anti-inflammatory effects and limited systemic bioavailability making it an appealing therapeutic option. Ulcerative colitis with predominantly distal disease may be treated with topical budesonide, however, novel oral controlled-release formulations have also been developed to allow for treatment of the entire colon. This article summarizes the use of budesonide in the management of inflammatory bowel disease. PMID- 21790283 TI - Mepolizumab in eosinophilic disorders. AB - Mepolizumab (Bosatria((r)), GlaxoSmithKline) is a biologic agent developed to treat asthma. It represents a humanized monoclonal antibody of IgG1 kappa type, which targets human IL-5 and thus prevents its interaction with the alpha-chain of the IL-5 receptor. To date, it has not been approved for use in any eosinophil related disorder; however, several studies have suggested some therapeutic benefit across a spectrum of eosinophil-related disorders. This article evaluates the currently available preclinical and clinical studies, and the impact of mepolizumab against a variety of eosinophilic disorders. PMID- 21790285 TI - Hepatitis B immunoglobulin for prevention of hepatitis B virus infection and recurrence after liver transplantation. AB - Intravenous hepatitis B immunoglobulin (HBIG) is a human plasma-derived purified gammaglobulin (IgG) that has proven efficacy and dose-dependent response in the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. It is also indicated for postexposure prophylaxis after contact with blood or body fluids of serum hepatitis B surface antigen (HBsAg)-positive carriers and in prevention of mother-to-child (vertical) transmission. The exact mechanism of passive immunization is unknown; HBIG may block HBV entry and binding to hepatocytes, neutralize circulating HBV and target HBV-infected cells through an antibody-mediated immune response. The drug is well tolerated and common side effects include fever, chills and arthralgias that are usually mild and transient. This article summarizes the main indications and the recommendations for use of intravenous HBIG, as well as the usage of intramuscular HBIG in the liver transplant setting. PMID- 21790286 TI - Oralair(r): sublingual immunotherapy for the treatment of grass pollen allergic rhinoconjunctivitis. AB - Oralair((r)) is a sublingual grass pollen immunotherapy tablet that was authorized for use in Europe on 26 November 2009 and is currently in Phase III clinical trials in the USA. It is indicated for the management of grass pollen allergic rhinitis with or without conjunctivitis in adults, adolescents and children (above the age of 5) with clinically relevant symptoms, confirmed by a positive cutaneous test and/or a positive titer of the specific IgE to the grass pollen. Treatment is composed of an initiation phase (3-day dose escalation: 100 IR [index of reactivity] on day 1, 200 IR on day 2 and 300 IR on day 3) and a continuation phase at a dosage of 300 IR/day. Treatment is scheduled to start approximately 4 months before the actual start of the pollen season and should be continued throughout the season. The treatment should be prescribed and initiated by an experienced allergy specialist. PMID- 21790287 TI - Targeting STAT4 in systemic sclerosis: a promising new direction. AB - Evaluation of: Avouac J, Furnrohr BG, Tomcik M et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum. 63(3), 800-809 (2011). STAT4 has been identified as a genetic risk factor for the development of autoimmune diseases including systemic sclerosis. STAT4 regulates Th1 cell development and cell-mediated immunity, but it is not known how it may regulate the development of dermal fibrosis. Using the bleomycin-induced dermal fibrosis model, it has now been demonstrated that STAT4-deficient mice have reduced dermal fibrosis in part via STAT4-dependent alterations in T-cell proliferation and cytokine production. These data stress the importance of STAT4 in autoimmune diseases such as systemic sclerosis and provide an important direction for future research to improve our understanding of systemic sclerosis pathogenesis. PMID- 21790288 TI - Deciphering the genetic background of systemic sclerosis. AB - Systemic sclerosis (SSc) is a severe autoimmune connective tissue disease. Over the years, evidence for a genetic background of SSc susceptibility has clearly accumulated. This article aims to provide an extensive overview of genetics in SSc research. We discuss indicators for a genetic component present in SSc, family studies, chromosomal aberrances, the involvement of the HLA region and multiple candidate genes and, finally, genome-wide association studies. PMID- 21790290 TI - Epigenetic modifications: novel therapeutic strategies for systemic sclerosis? AB - Epigenetic modifications of gene expression comprise modifications of DNA by DNA methylation and modifications of the histone proteins by acetylation, methylation, SUMOylation or phosphorylation. DNA methylation in the promoter region of genes represses gene transcription. Histone modifications influence the structure of DNA and regulate gene expression by changing the availability of DNA for the transcriptional machinery or DNA-binding proteins. Histone modifications are mediated by enzymes and induce or repress gene expression. Aberrant expression of single enzymes disturb the normal balance of these modifiers leading to cancer or autoimmune diseases. We show in this article that epigenetic modifications contribute to the massive production of extracellular matrix proteins in systemic sclerosis skin fibroblasts. Both DNA methylation and histone modifications contribute to the activated phenotype of systemic sclerosis fibroblasts. In vitro and in vivo experiments demonstrate that the use of epigenetic-based drugs on these cells is able to reverse their activated phenotype. PMID- 21790289 TI - Capturing the heterogeneity in systemic sclerosis with genome-wide expression profiling. AB - Heterogeneity in the clinical presentation and basic science findings of systemic sclerosis (SSc) has hindered the understanding of pathogenesis and development of effective treatments. Genome-wide profiling of SSc has measured this heterogeneity. Gene expression studies of diffuse SSc skin have shown reproducible, disease-specific gene expression signatures when compared with healthy controls and, surprisingly, disease-specific gene expression was found in both lesional and non-lesional skin. SSc-specific gene expression in peripheral blood cells and the lungs has also been demonstrated. Hypothesis-driven approaches that assess the contribution of individual pathways provide insight into the etiology of gene expression subsets. PMID- 21790291 TI - Novel insights on the role of the innate immune system in systemic sclerosis. AB - Over the last several years the involvement of the innate immune system in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) has become well established. As systemic sclerosis (SSc; scleroderma) shares clinical features and autoantibodies with SLE, investigation has recently focused on the role of innate immunity in SSc. This has been supported by recent genetic studies. However, unlike SLE and other related autoimmune diseases, SSc patients suffer from pathologic fibrosis of skin and internal organs. The fibrotic component of SSc shares several features with syndromes following environmental exposures to agents such as organic solvents, silica dust and bleomycin. Recent work in SSc and these related fibrotic diseases have identified several areas in which innate immunity can stimulate inflammation as well as fibrosis. This article will focus on the recent discoveries identifying a prominent role of cells of the innate immune system, pattern recognition receptors, and activation of dendritic cells in the pathogenesis of SSc. PMID- 21790292 TI - Fibroblast abnormalities in the pathogenesis of systemic sclerosis. AB - Systemic sclerosis (SSc) is a chronic systemic disease characterized by autoimmunity, vascular lesions and progressive fibrosis. The fibrotic component is dominant in SSc compared with other vascular or autoimmune diseases and determines its prognosis and therapeutic refractoriness. Fibroblasts are responsible for abnormal extracellular matrix accumulation. Studies in cultured SSc skin fibroblasts have facilitated the identification of potential pathways involved in their profibrotic phenotype. Profibrotic fibroblasts characterized by abnormal growth and extracellular matrix synthesis may differentiate or expand from normal resident fibroblasts. Recruitment of bone marrow-derived progenitors and transdifferentiation of different cell lineages might also be involved. Multiple factors and signaling pathways appear to be involved in the development or persistence of the SSc fibroblast phenotype. Although their relative relevance and interplay are unclear, aberrant TGF-beta signaling seems pivotal and constitutes the best characterized therapeutic target. PMID- 21790293 TI - CD4+CD25+ regulatory T cells in systemic sclerosis and other rheumatic diseases. AB - Systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities, leading to a progressive thickening and fibrosis of the skin and other organs, such as the lungs, GI tract, heart and kidneys. SSc is thought to be an autoimmune disease owing to the presence of high affinity antibodies and possible clinical overlap with other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Autoimmune diseases arise because of a breakdown in immunological self tolerance. Self tolerance is maintained via multiple regulatory mechanisms within the immune system, including the thymic deletion of self-reactive T cells and mechanisms of peripheral tolerance. In recent years, the presence of CD4(+)CD25(+)FOXP3(+) Tregs has been identified as a major mechanism of peripheral tolerance, and accumulating evidence indicates that alterations in Treg frequencies and/or function may contribute to autoimmune diseases. Here, we will review recent data on the percentage, function and phenotype of CD4(+)CD25(+) Tregs in rheumatic disease, and discuss how recent developments may guide research in this area in SSc. PMID- 21790294 TI - Relevance of rituximab therapy in pemphigus vulgaris: analysis of current data and the immunologic basis for its observed responses. AB - Treatment of pemphigus vulgaris (PV) patients with rituximab therapy has not been critically evaluated. This article will provide in significant detail the available data to date, in order to provide a clinical and immunologic basis for clinicians to decide how best to treat recalcitrant PV patients with rituximab. PV is an autoimmune blistering disorder that affects the skin and mucous membranes. The immunopathology is well characterized, including the target antigens. PV patients have traditionally been treated with systemic corticosteroids and adjuvant immunosuppressive therapies. Clinical remission has been achieved in roughly 30% of patients. However, many patients experience severe side effects from this immunosuppression, including death. B-cell depletion therapy with rituximab therapy has been used to treat several autoimmune diseases including PV. In this article, we examined the data on 153 patients with PV who have been treated with rituximab. Our focus is on the clinical response of the patients with emphasis on adjuvant therapies, dosing regimens, potential adverse events and mechanism of action related to B-cell modulation during therapy. Importantly, the use of rituximab has increased clinical remission rates to 65% including many patients who were able to discontinue all systemic medications. Finally, an expert commentary is provided, which includes suggestions for optimizing current therapy and recommends the future direction of the field. The authors strongly endorse the use of rituximab in treatment of PV patients, particularly those nonresponsive to or who develop serious side effects to conventional therapy. Proper monitoring of patients including peripheral B-cell counts and overt signs of infection are warranted, given the potential for prolonged B-cell depletion. PMID- 21790295 TI - Development of diabetes mellitus in living pancreas donors and recipients. AB - Previously, recurrence of insulin-dependent diabetes mellitus after pancreas transplants was only sporadically reported. Newer data, however, indicate recurrence rates as high as 5%. After identical-twin pancreas transplants, diabetes recurs in the absence of immunosuppressive therapy - strong evidence that it is an autoimmune disease. After deceased donor pancreas transplants, immunologic markers (autoantibodies, autoreactive T cells) herald recurrence. Selective destruction of beta cells, still relatively uncommon, is not restricted to MHC compatibility. The development of diabetes in living pancreas donors is rare; it can be largely avoided by meticulous metabolic evaluation before donation and prevention of obesity after donation. PMID- 21790298 TI - Comparison of the efficacy of two different modified release methylphenidate preparations for children and adolescents with attention-deficit/hyperactivity disorder in a natural setting: comparison of the efficacy of Medikinet((r)) retard and Concerta((r))--a randomized, controlled, double-blind multicenter clinical crossover trial. AB - OBJECTIVE: The comparison of the efficacy of Medikinet((r)) retard and Concerta((r)) trial was a multisite, randomized, double-blind, crossover trial that aimed at comparing the effects of two different modified release methylphenidate preparations (Medikinet retard: 50% immediate release (IR); Concerta: 22% IR) in a natural setting across the day in 113 randomized children and adolescents with attention-deficit/hyperactivity disorder (age range 6-16 years). The duration of the study per patient was 3 weeks. METHODS: The primary outcome variable was the German version of the "Swanson, Kotkin, Agler, M-Flynn, and Pelham scale" in the first 3 hours of school as assessed by teachers. RESULTS: Medikinet retard with a higher IR component than Concerta (and an equivalent daily dose) was superior to Concerta (p=0.0009), and Medikinet retard with similar IR components in the morning as Concerta (but a lower daily dose) was noninferior to Concerta with regard to the primary outcome. Further, exploratory analyses on teacher and parent ratings on attention deficit/hyperactivity disorder and on externalizing symptoms during the day revealed no evidence for the superiority of Concerta over Medikinet retard in an equivalent daily dosage throughout the day. CONCLUSION: Children and adolescents may be treated with a lower daily dose of Medikinet retard (which has a similar IR component as Concerta) without resulting in a clinically relevant worse effect during school time. PMID- 21790300 TI - Age-related macular degeneration and association of CFH Y402H and LOC387715 A69S polymorphisms in a Turkish population. AB - Age-related macular degeneration (AMD) is a disease with multifactorial etiology characterized by irreversible loss of central visual acuity. The discovery of susceptive single-nucleotide polymorphisms (SNPs) has progressed our understanding of AMD. Complement factor H (CFH) gene Y402H polymorphism and high temperature requirement A-1 (HTRA1) LOC387715 gene A69S polymorphisms are the most important SNPs reported in the literature. Determination of genetic risk factors and genotype-phenotype relationship in AMD may result in rapid and cost effective therapeutic applications for young and old population. In this study, we hypothesized a potential association between CFH gene Y402H and HTRA1 LOC387715 gene A69S polymorphism in Turkish AMD patients. In blood samples from a total of 252 individuals, 147 clinically diagnosed as AMD and the others control, polymorphic sites in CFH, Y402H (Tsp509I T/C), and HTRA1, LOC387715 A69S (FnuHI G/T), were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. There was significant difference between CFH genotypes in the AMD group, TT 21.8%, TC 48.3%, and CC 29.9%, and in the control subjects, TT 45% (p=0.003), TC 41% (p=0.0001), and CC 14% (p=0.0001). Further, the A69S polymorphism of LOC387715 was investigated and found to be significantly associated with AMD. LOC387715 genotypes in the AMD group were GG 30.6%, GT 38.1%, and TT 31.3% and in the control subjects were GG 59% (p=0.027), GT 39% (p=0.0001), and TT 2% (p=0.0001), respectively. We also found that Y402H C and A69S T allele were associated with AMD. This is the first study showing that Y402H and LOC387715 are associated with AMD in Turkish population. PMID- 21790301 TI - Efficacy and safety of switching from topical latanoprost to bimatoprost in patients with normal-tension glaucoma. AB - PURPOSE: The aim of this study was to evaluate the efficacy and safety of bimatoprost in Japanese patients with normal-tension glaucoma (NTG) who showed insufficient response to latanoprost. METHODS: A prospective, nonrandomized study was conducted in patients with NTG, with <=20% intraocular pressure (IOP) decrease from pretreatment baseline with latanoprost monotherapy who had been switched to bimatoprost. The IOP was measured at 4, 8, and 12 weeks after the switch to bimatoprost. In 12 weeks after the switch to bimatoprost, efficacy and safety were evaluated. RESULTS: Postswitch to bimatoprost, IOP was significantly reduced at every visit. Bimatoprost produced significantly greater mean% IOP reduction rate from pretreatment than that of latanoprost at week 12 (P<0.01). There was a significant correlation between% IOP reduction of bimatoprost and that of latanoprost (Pearson r(2)=0.374; P=0.007). No significant difference was observed in the mean scores of conjunctival hyperemia and corneal epithelial disorder between bimatoprost-treated eyes and latanoprost-treated eyes. CONCLUSIONS: Significant additional IOP lowering was achieved by switching to bimatoprost in Japanese patients with NTG with insufficient response to latanoprost. Bimatoprost treatment was safe and well tolerated. PMID- 21790302 TI - Nanostructured natural-based polyelectrolyte multilayers to agglomerate chitosan particles into scaffolds for tissue engineering. AB - The layer-by-layer (LbL) deposition technique is a self-assembly process that allows the coating of material's surface with nanostructured layers of polyelectrolytes, allowing to control several surface properties. This technique presents some advantages when compared with other thin film assembly techniques, like having the possibility to coat surfaces with complex geometries in mild conditions or to incorporate active compounds. Tissue engineering (TE) involves typically the use of porous biodegradable scaffolds for the temporary support of cells. Such structures can be produced by agglomeration of microspheres that needs to be fixed into a three-dimensional (3D) structure. In this work we suggest the use of LbL to promote such mechanical fixation in free-formed microspheres assemblies and simultaneously to control the properties of its surface. For the proof of concept the biological performance of chitosan/alginate multilayers is first investigated in two-dimensional (2D) models in which the attachment and proliferation of L929 and ATDC5 cells are studied in function of the number of layers and the nature of the final layer. Scaffolds prepared by agglomeration of chitosan particles using the same multilayered system were processed and characterized; it was found that they could support the attachment and proliferation of ATDC5 cells. This study suggests that LbL can be used as a versatile methodology to prepare scaffolds by particle agglomeration that could be suitable for TE applications. PMID- 21790304 TI - Effects of different treatments on soil-borne DDT and HCH dynamics and plant uptake. AB - Pot experiments were conducted to examine the effects of various fertilizers, as well as soil dilution treatments on the dynamics of soil-borne DDTs [sum of dichlorodiphenyltrichloroethane (DDT), chlorodiphenyldichloroethylene (DDE) and di- chlorodiphenyldichloroethane (DDD)] and hexachlorocyclohexanes (HCHs, sum of alpha-HCH, beta-HCH, gamma-HCH and delta-HCH) and their subsequent impacts on the uptake of DDTs and HCHs by a test plant. The results show that the soil residual DDTs and HCHs concentrations in the iron-rich fertilizer-treated soil were significantly lower than those in other fertilizer-treated soils. There was a close relationship between the soil residual DDTs and the plant tissue DDTs. This suggests that the uptake rate of DDTs by the plant was dependent on the concentration of soil-borne DDTs. A less close relationship between soil residual HCHs and plant tissue HCHs was also observed. Dilution of pesticide-contaminated soil with the non-contaminated soil not only physically reduced the concentration of pesticides in the soil but also enhanced the loss of soil-borne pesticides, possibly through the improvement of soil conditions for microbial degradation. Soil dilution had a better effect on promoting the loss of soil-borne HCHs, relative to soil-borne-DDTs. The research findings obtained from this study have implications for management of heavily contaminated soils with DDTs and HCHs. Remediation of DDTs and HCHs-contaminated soils in a cost-effective way can be achieved by incorporating treatment techniques into conventional agricultural practices. Applications of iron-rich fertilizer and soil dilution treatments could cost-effectively reduce soil-borne DDTs and HCHs, and subsequently the uptake of these organochlorine pesticides by vegetables. PMID- 21790305 TI - Hair as a marker for pesticides exposure. AB - Rats were orally treated with mixtures of chlorinated pesticides. Hair was collected and analyzed for pesticide residues over a period of up to four weeks. Quantitative and qualitative analysis of the recovered pesticides in hair were determined using gas chromatography with electron capture detector. Results suggest that hair can be used as a biomarker for the monitoring of organochlorinated pesticide residues at low parts per billion levels. Chlorinated pesticides were also detected in human hair of environmentally exposed and occupationally exposed individuals, which indicates that hair can be used for monitoring pesticides exposure. PMID- 21790303 TI - The interplay between cell adhesion cues and curvature of cell adherent alginate microgels in multipotent stem cell culture. AB - Cell-adherent microcarriers are increasingly used to expand multipotent stem cells on a large scale for therapeutic applications. However, the role of the microcarrier properties and geometry on the phenotypic activities of multipotent cells has not been well studied. This study presents a significant interplay of the number of cell adhesion sites and the curvature of the microcarrier in regulating cell growth and differentiation by culturing mesenchymal stem cells on alginate microgels chemically linked with oligopeptides containing the Arg-Gly Asp (RGD) sequence. Interestingly, the cell growth rate and osteogenic differentiation level were increased with the RGD peptide density. At a given RGD peptide density, the cell growth rate was inversely related to the microgel diameter, whereas the osteogenic differentiation level was minimally influenced. The dependency of the cell growth rate on the microgel diameter was related to changes in shear stresses acting on cells according to simulation. Overall, this study identifies material variables key to regulating cellular activities on microcarriers, and these findings will be useful to designing a broad array of bioactive microcarriers. PMID- 21790306 TI - Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials. AB - BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. MATERIAL AND METHODS: Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range. RESULTS: A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. CONCLUSION: Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival. PMID- 21790307 TI - Effects of fluoride on expression of bone-specific genes in developing Xenopus laevis larvae. AB - The effect of fluoride treatment on the expression of a panel of osteogenic and stress markers in Stage 55 premetamorphic Xenopus larvae was examined at the precise onset of replacement of the larval cartilaginous skeleton with bone. A dosing regimen of 10 mmol/L sodium fluoride over 8 days was followed, during which time larvae developed to Stage 58, when the process of progressive ossification takes place in the vertebral column and membranous bones of the skull, pelvic, and pectoral girdles and portions of the appendicular skeleton. Markers of bone formation, including COL1A1, the transcription factors Osterix, RUNX2-II, and matrix metalloproteinases MMP1 and MMP13, decreased relative to age matched controls, though the osteoblast marker BGLAP was not significantly altered. Expression of the pro-osteoclastogenic factor RANKL decreased, whereas expression of the anti-osteoclastogenic factor osteoprotegerin increased. Altered expression of oxidative stress markers, with the exception of superoxide dismutase, was generally not observed. These data demonstrate the potent effects of fluoride on the expression of factors required for osteoblast and osteoclast differentiation, as well as on the expression of osteoblast products, including MMP1 and collagen. Importantly, these effects were observed in the absence of significant changes in the expression of oxidative stress markers. The results provide the first molecular insights into the mechanisms underlying skeletal fluorosis in a whole organism developmental model. PMID- 21790308 TI - Human telomerase expression regulation. AB - Since telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells, it has become a very promising target for anti-cancer therapy. A correlation between short telomere length and increased mortality was revealed in many studies. The telomerase expression/activity appears to be one of the most crucial factors to study to improve cancer therapy and prevention. However, this multisubunit enzymatic complex can be regulated at various levels. Thus, several strategies have been proposed to control telomerase in cancer cells such as anti-sense technology against TR and TERT, ribozymes against TERT, anti estrogens, progesterone, vitamin D, retinoic acid, quadruplex stabilizers, telomere and telomerase targeting agents, modulation of interaction with other proteins involved in the regulation of telomerase and telomeres, etc. However, the transcription control of key telomerase subunits seems to play the crucial role in whole complexes activity and cancer cells immortality. Thus, the research of telomerase regulation can bring significant insight into the knowledge concerning stem cells metabolism but also ageing. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms at the transcription level in human that might become attractive anti-cancer therapy targets. PMID- 21790309 TI - Characterization of extrahepatic distribution of Tc-99m macroaggregated albumin in hepatic perfusion imaging studies prior to yttrium-90 microsphere therapy. AB - Tc-99m macroaggregated albumin (MAA) hepatic perfusion study and hepatic angiography are routinely performed prior to yttrium-90 (Y-90) microsphere therapy for patients with hepatocellular carcinoma (HCC) or metastatic cancers to the liver. The purpose of this study was to examine the incidence of altered Tc 99m MAA distribution in these patients and to identify factors that are associated with these changes. A total of 176 Tc-99m MAA hepatic perfusion studies in 159 patients performed in preparation for Y-90 microsphere therapy were retrospectively reviewed. Abnormal findings were identified and correlated with diagnosis, infusion site, tumor volume, and tumor uptake by using bivariate statistical analysis. Abnormal Tc-99m MAA distribution on the hepatic perfusion imaging studies include excessive hepatopulmonary shunting with an elevated shunting fraction (>10%; n=23, 13%) and abnormal intra-abdominal visceral deposition in the GI tract, pancreas, spleen, and umbilical vein (n=19; 11%). Patients with a diagnosis of HCC showed higher incidence of abnormal hepatopulmonary shunting compared with other types of tumors (p<0.05). The incidence of abnormal intra-abdominal visceral deposition is higher with infusion into the left hepatic artery or proper hepatic artery/common hepatic artery compared with infusion into right hepatic artery (p<0.001). In 9 of 12 cases with abnormal deposition in the stomach, duodenum, or pancreas, the cause was identified upon reviewing angiography retrospectively and was subsequently corrected. In conclusion, the hepatic perfusion imaging study is an important imaging modality in preparation and guidance of Y-90 microsphere treatment. PMID- 21790310 TI - Beta androstenediol mitigates the damage of 1 GeV/n Fe ion particle radiation to the hematopoietic system. AB - Space exploration is associated with exposure to 1-3 Gy solar particle radiation and galactic cosmic radiation that could increase cancer rates. Effective nontoxic countermeasures to high linear energy transfer (LET) radiation exposure are highly desirable but currently not available. The aim was to determine whether a single subcutaneous injection of androstenediol (Delta(5) androsten 3beta, 17beta-diol [AED]) could mitigate and restore the mouse hematopoetic system from the radiation-mediated injury of 3 Gy whole-body high LET (56)Fe(26+) exposure. The findings show that postradiation AED treatment has an overall positive and significant beneficial effect to restore the levels of hematopoeitic elements (p<0.001). Androstenediol treatment significantly increased monocyte levels at days 4, 7, and 14 and, similarly, increased red blood cell, hemoglobin, and platelet counts. Flow cytometry analysis 14 days after radiation and AED treatment demonstrated an increase (p<0.05) in bone marrow cells counts. Ex vivo osteoclastogenesis studies show that AED treatment is necessary and advantageous for the development and restoration of osteoclastogenesis after radiation exposure. These findings clearly show that androstenediol functions as a countermeasure to remedy hematopoeitic injury mediated by high LET iron ion radiation. Presently, no other agent has been shown to have such properties. PMID- 21790311 TI - Neuroendocrine disruption: the emerging concept. PMID- 21790313 TI - Stem cell-derived in vitro models for investigating the effects of endocrine disruptors on developing neurons and neuroendocrine cells. AB - Neuroendocrine cells are a set of specialized hormone-releasing neurons that control most vital functions in humans and wildlife, such as growth, reproduction, metabolism, and stress responses. Increasing evidence points to neuroendocrine cells as the primary neuronal target of endocrine disruptors. Endocrine disruption appears to be most significant during prenatal and early postnatal development. However, limitations with traditional cell culture models of neuronal development led to a lack of understanding regarding the mechanisms by which endocrine disruptors affect neurodevelopment. In recent years, Stem Cell derived neuronal models have become available and may offer distinct advantages over other in vitro model systems for investigating the effects of endocrine disruptors on the developing brain. Further, recently new models of Stem Cell derived neuroendocrine cells that may provide more effective ways for studying the effects of endocrine disruptors directly on developing neuroendocrine cells in vitro were developed. This constitutes a review of currently available cell models of developing neurons that have been used to investigate in vitro effects of endocrine disruptors on developing brain. The review also presents recently developed models of Stem Cell-derived neuroendocrine cells that might be used to investigate in vitro effects of endocrine disruptors and their mechanisms of action directly on the developing neuroendocrine cells. PMID- 21790312 TI - Neuroendocrine disruption: more than hormones are upset. AB - Only a small proportion of the published research on endocrine-disrupting chemicals (EDC) directly examined effects on neuroendocrine processes. There is an expanding body of evidence that anthropogenic chemicals exert effects on neuroendocrine systems and that these changes might impact peripheral organ systems and physiological processes. Neuroendocrine disruption extends the concept of endocrine disruption to include the full breadth of integrative physiology (i.e., more than hormones are upset). Pollutants may also disrupt numerous other neurochemical pathways to affect an animal's capacity to reproduce, develop and grow, or deal with stress and other challenges. Several examples are presented in this review, from both vertebrates and invertebrates, illustrating that diverse environmental pollutants including pharmaceuticals, organochlorine pesticides, and industrial contaminants have the potential to disrupt neuroendocrine control mechanisms. While most investigations on EDC are carried out with vertebrate models, an attempt is also made to highlight the importance of research on invertebrate neuroendocrine disruption. The neurophysiology of many invertebrates is well described and many of their neurotransmitters are similar or identical to those in vertebrates; therefore, lessons learned from one group of organisms may help us understand potential adverse effects in others. This review argues for the adoption of systems biology and integrative physiology to address the effects of EDC. Effects of pulp and paper mill effluents on fish reproduction are a good example of where relatively narrow hypothesis testing strategies (e.g., whether or not pollutants are sex steroid mimics) have only partially solved a major problem in environmental biology. It is clear that a global, integrative physiological approach, including improved understanding of neuroendocrine control mechanisms, is warranted to fully understand the impacts of pulp and paper mill effluents. Neuroendocrine disruptors are defined as pollutants in the environment that are capable of acting as agonists/antagonists or modulators of the synthesis and/or metabolism of neuropeptides, neurotransmitters, or neurohormones, which subsequently alter diverse physiological, behavioral, or hormonal processes to affect an animal's capacity to reproduce, develop and grow, or deal with stress and other challenges. By adopting a definition of neuroendocrine disruption that encompasses both direct physiological targets and their indirect downstream effects, from the level of the individual to the ecosystem, a more comprehensive picture of the consequences of environmentally relevant EDC exposure may emerge. PMID- 21790314 TI - Effects of estrogens and endocrine-disrupting chemicals on cell differentiation survival-proliferation in brain: contributions of neuronal cell lines. AB - Estrogens and estrogen receptors (ER) are key actors in the control of differentiation and survival and act on extrareproductive tissues such as brain. Thus, estrogens may display neuritogenic effects during development and neuroprotective effects in the pathophysiological context of brain ischemia and neurodegenerative pathologies like Alzheimer's disease or Parkinson's disease. Some of these effects require classical transcriptional "genomic" mechanisms through ER, whereas other effects appear to rely clearly on "membrane-initiated mechanisms" through cytoplasmic signal transduction pathways. Disturbances of these mechanisms by endocrine-disrupting chemicals (EDC) may exert adverse effects on brain. Some EDC may act via ER-independent mechanisms but might cross react with endogenous estrogen. Other EDC may act through ER-dependent mechanisms and display agonistic/antagonistic estrogenic properties. Because of these potential effects of EDC, it is necessary to establish sensitive cell-based assays to determine EDC effects on brain. In the present review, some effects of estrogens and EDC are described with focus on ER-mediated effects in neuronal cells. Particular attention is given to PC12 cells, an interesting model to study the mechanisms underlying ER-mediated differentiating and neuroprotective effects of estrogens. PMID- 21790316 TI - Neurotoxicity of endocrine disruptors: possible involvement in brain development and neurodegeneration. AB - Environmental chemicals that act as endocrine disruptors do not appear to pose a risk to human reproduction; however, their effects on the central nervous systems are less well understood. Animal studies suggested that maternal exposure to endocrine-disrupting chemicals (EDC) produced changes in rearing behavior, locomotion, anxiety, and learning/memory in offspring, as well as neuronal abnormalities. Some investigations suggested that EDC exert effects on central monoaminergic neurons, especially dopaminergic neurons. Our data demonstrated that EDC attenuate the development of dopaminergic neurons, which might be involved in developmental disorders. Perinatal exposure to EDC might affect neuronal plasticity in the hippocampus, thereby potentially modulating neuronal development, leading to impaired cognitive and memory functions. Endocrine disruptors also attenuate gender differences in brain development. For example, the locus ceruleus is larger in female rats than in males, but treatments with bisphenol-A (BPA) enlarge this region in males. Some reports indicated that EDC induce hypothyroidism, which might be evidenced as abnormal brain development. Endocrine disruptors might also affect mature neurons, resulting in neurodegenerative disorders such as Parkinson's disease. The current review focused on alterations in the brain induced by EDC, specifically on the possible involvement of EDC in brain development and neurodegeneration. PMID- 21790317 TI - Neuroendocrine effects of endocrine disruptors in teleost fish. AB - Because a large proportion of potential endocrine disruptors (EDC) end up in surface waters, aquatic species are particularly vulnerable to their potential adverse effects. Recent studies identified a number of brain targets for EDC commonly present in environmentally relevant concentrations in surface waters. Among those neuronal systems disrupted by EDC are the gonadotropin-releasing hormone (GnRH) neurons, the dopaminergic and serotoninergic circuits, and more recently the Kiss/GPR54 system, which regulates gonadotropin release. However, one of the most striking effects of EDC, notably estrogen mimics, is their impact on the cyp19a1b gene that encodes the brain aromatase isoform in fish. Moreover, this is the only example in which the molecular basis of endocrine disruption is fully understood. The aims of this review were to (1) synthesize the most recent discoveries concerning the EDC effects upon neuroendocrine systems of fish and (2) provide, when possible, the underlying molecular basis of disruption for each system concerned. The potential adverse effects of EDC on neurogenesis, puberty, and brain sexualization are also described. It is important to point out the future environmental, social, and economical issues arising from endocrine disruption studies in the context of risk assessment. PMID- 21790315 TI - Early developmental actions of endocrine disruptors on the hypothalamus, hippocampus, and cerebral cortex. AB - Sex steroids and thyroid hormones play a key role in the development of the central nervous system. The critical role of these hormonal systems may explain the sensitivity of the hypothalamus, the cerebral cortex, and the hippocampus to endocrine-disrupting chemicals (EDC). This review examines the evidence for endocrine disruption of glial-neuronal functions in the hypothalamus, hippocampus, and cerebral cortex. Focus was placed on two well-studied EDC, the insecticide dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCB). DDT is involved in neuroendocrine disruption of the reproductive axis, whereas polychlorinated biphenyls (PCB) interact with both the thyroid hormone- and sex steroid-dependent systems and disturb the neuroendocrine control of reproduction and development of hippocampus and cortex. These results highlight the impact of EDC on the developing nervous system and the need for more research in this area. PMID- 21790318 TI - Pharmaceuticals as neuroendocrine disruptors: lessons learned from fish on Prozac. AB - Pharmaceuticals are increasingly detected in a variety of aquatic systems. One of the most prevalent environmental pharmaceuticals in North America and Europe is the antidepressant fluoxetine, a selective serotonin reuptake inhibitor (SSRI) and the active ingredient of Prozac. Usually detected in the range below 1 MUg/L, fluoxetine and its active metabolite norfluoxetine are found to bioaccumulate in wild-caught fish, particularly in the brain. This has raised concerns over potential disruptive effects of neuroendocrine function in teleost fish, because of the known role of serotonin (5-HT) in the modulation of diverse physiological processes such as reproduction, food intake and growth, stress and multiple behaviors. This review describes the evolutionary conservation of the 5-HT transporter (the therapeutic target of SSRIs) and reviews the disruptive effects of fluoxetine on several physiological endpoints, including involvement of neuroendocrine mechanisms. Studies on the goldfish, Carassius auratus, whose neuroendocrine regulation of reproduction and food intake are well characterized, are described and represent a reliable model to study neuroendocrine disruption. In addition, fish studies investigating the effects of fluoxetine, not only on reproduction and food intake, but also on stress and behavior, are discussed to complement the emerging picture of neuroendocrine disruption of physiological systems in fish exposed to fluoxetine. Environmental relevance and key lessons learned from the effects of the antidepressant fluoxetine on fish are highlighted and may be helpful in designing targeted approaches for future risk assessments of pharmaceuticals disrupting the neuroendocrine system in general. PMID- 21790319 TI - Neuroendocrine impacts of endocrine-disrupting chemicals in birds: life stage and species sensitivities. AB - Assessing potential risk associated with exposure to endocrine-disrupting chemicals (EDC) has been difficult due to species specific variation in vulnerability and to both short- and long-term effects produced by EDC. In precocial birds, embryonic exposure to EDC impacts sexual differentiation of neuroendocrine systems and behavior. Often, detectable nonlethal effects of EDC diminish as the organism matures such that the chronic impact of EDC may appear relatively innocuous by the time an individual is sexually mature. In addition, studies have not addressed lifetime effects of EDC exposure on birds. Consequently, it is difficult to assess chronic effects of nonlethal exposure on the fitness of an individual and whether there is a potential risk to a wild population. Assessing behavioral and neuroendocrine consequences of exposure is complicated by individual and species variation in sensitivity as well as exposure to complex mixtures. Our studies are designed to examine effects of individual EDC administered to the embryo as well as in a multigenerational dietary study in which birds received low doses of the pesticide methoxychlor (MXC). The influence of dietary MXC exposure was also compared between Japanese quail and northern bobwhite quail. The effects of dietary exposures to 0.5, 5, or 10 ppm that are relatively environmentally low were determined. The selection of these doses was to mimic levels that might be encountered in the field and higher doses that might potentially reveal effects of exposure at relatively low exposures. These doses were also based on the regulations by the U.S. Environmental Protection Agency that mandate a limit 0.04 ppm MXC in drinking water, with a limit of no more than 0.05 ppm in water that children drink. Further there is a limit of 1-100 ppm for crops and other food for human and livestock consumption; bottled water has a 0.1 ppm limit for MXC content. Our data are discussed in the context of applicability of toxicological yardsticks, including the toxic equivalent (TEQ) and neurotoxic equivalent (NEQ) as predictive indices for short- and long-term outcomes to nonlethal concentrations of EDC. Other approaches have been developed to address inconsistencies in effects and incorporate diverse data into potency estimates. Perhaps it is time to develop a more inclusive estimation method for endocrine and neuroendocrine effects. An endocrine disruption index (EDI) would (1) complement other indices, (2) focus on endocrine disruption, and (3) include effects beyond those mediated by the aryl hydrocarbon receptor (AhR) for a comparative assessment of nonlethal EDC effects. PMID- 21790320 TI - The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. AB - The obesogen concept proposes that environmental contaminants may be contributing to the epidemic of obesity and its related pathology, metabolic disorder. The first references to such a notion appeared at the beginning of the current decade, with the hypothesis that the correlation between increasing incidence of obesity and enhanced industrial chemical production was not simply coincidental, but potentially causally related. The next event was the introduction of the term "obesogen" as representing an environmental pollutant that adversely affects various aspects of adipose tissue functions. More recently, the concept was extended to include substances that may modify metabolic balance at the central, hypothalamic level. The actions of two prime candidate obesogens, tributyltin (TBT) and tetrabromobisphenol A (TBBPA), acting at the central level are the main focus of this review. Having discussed the evidence for contaminant accumulation in the environment and in human tissues and the potential mechanisms of action, data are provided showing that these two widespread pollutants modify hypothalamic gene regulations. Our studies are based on maternal exposure and measurement of effects in the progeny, mainly based on in vivo gene reporter assays. Such models are obviously pertinent to testing current hypotheses that propose that early exposure might exert effects on later development and physiological functions. The potential molecular mechanisms involved are discussed, as are the broader physiological consequences of these hypothalamic dysregulations. PMID- 21790321 TI - Neuropeptides and enzymes are targets for the action of endocrine disrupting chemicals in the vertebrate brain. AB - Endocrine-disrupting chemicals (EDC) are molecules that interfere with endocrine signaling pathways and produce adverse consequences on animal and human physiology, such as infertility or behavioral alterations. Some EDC act through binding to androgen or/and estrogen receptors primarily operating through a genomic mechanism regulating gene expression. This mechanism of action may induce profound developmental adverse effects, and the major targets of the EDC action are the gene products, i.e., mRNAs inducing the synthesis of various peptidic molecules, which include neuropeptides and enzymes related to neurotransmitters syntheses. Available immunohistochemical data on some of the systems that are affected by EDC in lower and higher vertebrates are detailed in this review. PMID- 21790322 TI - Tryptophan hydroxylase: a target for neuroendocrine disruption. AB - Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) synthesis, performs an essential role in the maintenance of serotonergic functions in the central nervous system (CNS), including regulation of the neuroendocrine system controlling reproduction. The results of recent studies in a teleost model of neuroendocrine disruption, Atlantic croaker, indicated that hypothalamic TPH is a major site of interference of hypothalamic-pituitary gonadal function by environmental stressors. The effects of exposure to two different types of environmental stressors, low dissolved oxygen (hypoxia) and a polychlorinated biphenyl mixture (Aroclor 1254), on the stimulatory brain serotonergic system controlling reproductive neuroendocrine function in Atlantic croaker are reviewed. Exposure to both stressors produced decreases in TPH activity, which were accompanied by a fall in hypothalamic 5-HT and gonadotropin releasing hormone (GnRH I) content in the preoptic-anterior hypothalamic area and were associated with reduction in luteinizing hormone (LH) secretion and gonadal development. Pharmacological restoration of hypothalamic 5-HT levels after exposure to both stressors also restored neuroendocrine and reproductive functions, indicating that the serotonergic system is an important site for hypoxia- and Aroclor 1254-induced inhibition of reproductive neuroendocrine functions. The mechanisms underlying downregulation of TPH activity by these stressors remain unclear but may involve alterations in hypothalamic antioxidant status. In support of this hypothesis, treatment with an antioxidant, vitamin E, was found to reverse the inhibitory effects of Aroclor 1254 on TPH activity. The results suggest that TPH is a major target for neuroendocrine disruption by diverse environmental stressors. PMID- 21790323 TI - Nitric oxide signaling as a common target of organohalogens and other neuroendocrine disruptors. AB - Organohalogen compounds such as polychlorinated biphenyls (PCB) and polybrominated diphenyl ethers (PBDE) are global environmental pollutants and highly persistent, bioaccumulative chemicals that produce adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination is a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. Toxicological studies on organohalogen pollutants primarily focused on sex steroid and thyroid hormone actions, and findings have largely shaped the way one envisions their disruptive effects occurring. Organohalogens exert additional effects on other systems including other complex endocrine systems that may be disregulated at various levels of organization. Over the last 20 years evidence has mounted in favor of a critical role of nitric oxide (NO) in numerous functions ranging from neuroendocrine functions to learning and memory. With its participation in multiple systems and action at several levels of integration, NO signaling has a pervasive influence on nervous and endocrine functions. Like blockers of NO synthesis, PCBs and PBDEs produce multifaceted effects on physiological systems. Based on this unique set of converging information it is proposed that organohalogen actions occur, in part, by hijacking processes associated with this ubiquitous bioactive molecule. The current review examines the emerging evidence for NO involvement in selected organohalogen actions and includes recent progress from our laboratory that adds to our current understanding of the actions of organohalogens within hypothalamic neuroendocrine circuits. The thyroid, vasopressin, and reproductive systems as well as processes associated with long-term potentiation were selected as sample targets of organohalogens that rely on regulation by NO. Information is provided about other toxicants with demonstrated interference of NO signaling. Our focus on the convergence between NO system and organohalogen toxicity offers a novel approach to understanding endocrine and neuroendocrine disruption that is particularly problematic for developing organisms. This new working model is proposed as a way to encourage future study in elucidating common mechanisms of action that are selected with a better operational understanding of the systems affected. PMID- 21790324 TI - Analysis of carbonaceous biomarkers with the Mars Organic Analyzer microchip capillary electrophoresis system: carboxylic acids. AB - The oxidizing surface chemistry on Mars argues that any comprehensive search for organic compounds indicative of life requires methods to analyze higher oxidation states of carbon with very low limits of detection. To address this goal, microchip capillary electrophoresis (MUCE) methods were developed for analysis of carboxylic acids with the Mars Organic Analyzer (MOA). Fluorescent derivatization was achieved by activation with the water soluble 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC) followed by reaction with Cascade Blue hydrazide in 30 mM borate, pH 3. A standard containing 12 carboxylic acids found in terrestrial life was successfully labeled and separated in 30 mM borate at pH 9.5, 20 degrees C by using the MOA CE system. Limits of detection were 5-10 nM for aliphatic monoacids, 20 nM for malic acid (diacid), and 230 nM for citric acid (triacid). Polyacid benzene derivatives containing 2, 3, 4, and 6 carboxyl groups were also analyzed. In particular, mellitic acid was successfully labeled and analyzed with a limit of detection of 300 nM (5 ppb). Analyses of carboxylic acids sampled from a lava tube cave and a hydrothermal area demonstrated the versatility and robustness of our method. This work establishes that the MOA can be used for sensitive analyses of a wide range of carboxylic acids in the search for extraterrestrial organic molecules. PMID- 21790325 TI - Protective effects of hydrogen saline on diabetic retinopathy in a streptozotocin induced diabetic rat model. AB - PURPOSE: Diabetic retinopathy is the leading cause of blindness in the working population of the developed countries and also a significant cause of blindness in the elderly. This study aimed at examining the protective effect of H(2) saline on diabetic retinopathy in a streptozotocin-induced diabetic rat model. METHODS: Sprague-Dawley male rats were divided into 3 groups as follows: (1) nondiabetic control group (non-DM control); (2) diabetic control group (DM control); and (3) diabetic rats receiving H(2) saline therapy (DM H(2) saline). Rats in DM H(2) saline group were intraperitoneally injected with H(2) saturated saline (5 mL/kg) every day for 4 weeks. Retinal vascular permeability was assessed by measuring Evans blue leakage into the retina. Retinal apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and measuring caspase-3 activity. Retinal thickness was observed by hematoxylin and eosin staining. RESULTS: Our results showed that H(2) saline treatment could depress the caspase activity, reduce the retinal apoptosis, and vascular permeability. The H(2) saline could also prominently attenuate the retinal parenchyma thickening that resulted from diabetic retinopathy. CONCLUSIONS: Our preliminary studies indicated that H(2) saline may have potentials in the clinical treatment of diabetic retinopathy. PMID- 21790326 TI - Long-term outcomes of prostaglandin analog versus timolol maleate in ocular hypertensive or primary open-angle glaucoma patients in Europe. AB - PURPOSE: To determine the direct costs of therapy over 5 years of a European monotherapy cohort begun on a prostaglandin (PTG) versus timolol in patients with primary open-angle glaucoma or ocular hypertension. METHODS: A retrospective, multicenter, active-controlled, observational study. Data were abstracted for European patients treated as initial monotherapy in 1996 or afterward, with 5 years of available records. RESULTS: This study included 271 patients (166 on a PTG and 105 on timolol at baseline). The average cost/month/patient over 5 years was $45.47+/-12.61 for PTG and $31.50+/-15.47 for timolol (P<0.001, based on German prices). After 5 years, although there was no difference in number of glaucoma medicines prescribed between groups (1.0 PTGs and 1.1 timolol, P=0.41), the timolol group demonstrated a higher intraocular pressure (17.7+/-2.9 vs. 16.5+/-3.0 mm Hg, P<0.001), more medication changes (P=0.01), greater incidence of glaucomatous progression (P=0.04), and less patients persistent on original monotherapy (P<0.001) than the PTG cohort. CONCLUSIONS: Patients originally on timolol monotherapy have a lower cost of care over 5 years than those started on a PTG. However, timolol patients during follow-up may demonstrate a higher intraocular pressure, more progression, more medication changes, and lower persistency of the original monotherapy. PMID- 21790327 TI - Behavioral responses to combinations of timed light, food availability, and ultradian rhythms in the common vole (Microtus arvalis). AB - Light is the main entraining signal of the central circadian clock, which drives circadian organization of activity. When food is made available during only certain parts of the day, it can entrain the clock in the liver without changing the phase of the central circadian clock. Although a hallmark of food entrainment is a behavioral anticipation of food availability, the extent of behavioral alterations in response to food availability has not been fully characterized. The authors have investigated interactions between light and temporal food availability in the timing of activity in the common vole. Temporally restricted food availability enhanced or attenuated re-entrainment to a phase advance in light entrainment when it was shifted together with the light or remained at the same time of day, respectively. When light-entrained behavior was challenged with temporal food availability cycles with a different period, two distinct activity components were observed. More so, the present data indicate that in the presence of cycles of different period length of food and light, an activity component emerged that appeared to be driven by a free-running (light-entrainable) clock. Because the authors have previously shown that in the common vole altering activity through running-wheel availability can alter the effectiveness of food availability to entrain the clock in the liver, the authors included running wheel availability as a parameter that alters the circadian/ultradian balance in activity. In the current protocols, running-wheel availability enhanced the entraining potential of both light and food availability in a differential way. The data presented here show that in the vole activity is a complex of individually driven components and that this activity is, itself, an important modulator of the effectiveness of entraining signals such as light and food. PMID- 21790328 TI - Time-of-day effect on cardiac responses to progressive exercise. AB - This study was designed to examine time-of-day effects on markers of cardiac functional capacity during a standard progressive cycle exercise test. Fourteen healthy, untrained young males (mean +/- SD: 17.9 +/- 0.7 yrs of age) performed identical maximal cycle tests in the morning (08:00-11:00 h) and late afternoon (16:00-19:00 h) in random order. Cardiac variables were measured at rest, submaximal exercise, and maximal exercise by standard echocardiographic techniques. No differences in morning and afternoon testing values at rest or during exercise were observed for oxygen uptake, heart rate, cardiac output, or markers of systolic and diastolic myocardial function. Values at peak exercise for Vo(2) at morning and afternoon testing were 3.20 +/- 0.49 and 3.24 +/- 0.55 L min(-1), respectively, for heart rate 190 +/- 11 and 188 +/- 15 bpm, and for cardiac output 19.5 +/- 2.8 and 19.8 +/- 3.5 L min(-1). Coefficients of variation for morning and afternoon values for these variables were similar to those previously published for test-retest reproducibility. This study failed to demonstrate evidence for significant time-of-day variation in Vo(2)max or cardiac function during standard progressive exercise testing in adolescent males. PMID- 21790329 TI - Novel ophthalmic timolol meleate liposomal-hydrogel and its improved local glaucomatous therapeutic effect in vivo. AB - To overcome the limitations of common eye drops, the study developed a novel timolol mealate (TM) liposomal-hydrogel to enhance drug permeability and prolong residence time in the precorneal region, which achieved more effective local glaucomatous therapeutic effect. Firstly, TM liposome was prepared by an ammonium sulfate gradient-pH regulation method, which its entrapment efficiency reached up to 94% and its averaged particle size is 187 nm with narrow distribution. The corneal permeability through isolated rabbit cornea was measured by modified Franz-type diffusion cells. The results of trans-corneal penetration exhibited that the apparent permeability coefficients (P(app)) and the flow rates of steady state (J(ss)) of TM liposome was 1.50-fold higher than that of the commercialized eye drop, while TM liposome with 0.02% transcutol P was 2.19 times. In order to increase the retention time and improve the stability of liposome, we further developed a TM liposomal-hydrogel formulation by adding 1.0% HPMC K4M in TM liposome. The results showed an stability during a 120 days storage period than TM liposome. Precorneal retention study in vivo indicated that the optimal liposomal-hydrogel formulation had improved bioavailability and its retention time on rabbit corneal surface were significantly longer than that of pure liposomes or eye-drops. No obvious irritations to rabbit eyes were observed by histopathology microscopy after 7 days exposure.. Comparing to the eye drops, the TM liposomal-gel displayed prolonged therapeutic effect in cornea and greatly lowered the intraocular pressure IOP on the eyes of normal and glaucomatous pigmented rabbits. PMID- 21790330 TI - Can oral bacteria cause pregnancy complications? PMID- 21790331 TI - Does tobacco smoke cause breast cancer? PMID- 21790333 TI - Cigarette smoking and breast cancer risk. AB - Luo et al. have had the advantage of assessing active and passive smoking effects on breast cancer in 40 clinical centers in the USA involving 79,990 women aged 50 79 years, who were enrolled in the Women's Health Initiative Observational Study from 1993 to 1998. This is the possibly the largest cohort that has demonstrated the hazards of cigarette smoking and its impact on carcinoma of the breast in women. PMID- 21790334 TI - Omitting axilla lymphadenectomy even by positive sentinel lymph node: a change in breast cancer treatment practice. AB - Sentinel lymph node biopsy (SLNB) has been a reliable technique to accurately predict the axilla node status in women with breast cancer with clinically negative lymph nodes. Based on predictive accuracy evidence from large-scale clinical trials, SLNB has become the current standard of care in breast cancer, preventing unnecessary axilla lymph node dissection and its related adverse events in patients who test negative with SLNB. Now a Phase III randomized trial provides evidence that avoiding axilla lymphadenectomy in patients with positive SLNB does not increase locoregional recurrence or mortality. In this article the benefits, risks and selection criteria to safely prevent axilla lymphadenectomy even by positive SLNB are discussed. Moreover, limitations of this practice changing trial are described with emphasis on caution in patient selection. PMID- 21790335 TI - Vitamin D and cardiovascular disease and cancer: not too much and not too little? The need for clinical trials. AB - Low vitamin D levels are more common in women than in men. Low vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus and cancers. In this article we review recent evidence regarding associations between low vitamin D levels and cancers and cardiovascular disease. We also review evidence regarding associations between high vitamin D levels and vascular calcifications and pancreatic cancer. It appears that there is probably an optimal level of vitamin D that is neither too high nor too low that is required to maximize health. On going clinical trials should aid in elucidating the optimal levels of 25-hydroxyvitamin D for numerous health outcomes. PMID- 21790336 TI - Low-molecular-weight heparin in women with repeated implantation failure. AB - Implantation failure is common in assisted reproduction techniques (ART). The role of low-molecular-weight heparin (LMWH) is a matter of debate as a potential factor to improve implantation. AIM: To evaluate the pregnancy rate in patients with or without heparin administration. MATERIALS & METHODS: We performed a retrospective observational analysis of patients with at least two IVF/intracytoplasmic sperm injection cycles with implantation failure, screened for inherited thrombophilia and submitted to further ART cycles with or without administration of LMWH. A total of 265 patients fulfilled the enrollment criteria. Of these 149 (56%) were primary infertile and 116 (44%) were secondary infertile. Their mean age was 36.3 +/- 3.6 years. We analyzed basal FSH, smoking habit, gene variants for inherited thrombophilia (i.e., MTHFR C677T, prothrombin G202A10G and Factor V Leiden). The patients underwent 569 new ART cycles: 512 (90%) without and 57 (10%) with LMWH. RESULTS: In total 105 clinical pregnancies were observed in 569 cycles (18.8%). The pregnancy rate was 17.19% (88/512) in patients not treated with LMWH and 29.52% (17/57) in the LMWH-treated group (p = 0.006). In women over 36 years of age the pregnancy rate was 15.53% (50/322) in nontreated versus 35.71% (10/28) in treated cycles (p = 0.007), while no difference was found in younger women. No statistical difference was found between the presence of inherited thrombophilia and pregnancy rate in treated and untreated cycles. DISCUSSION: significantly higher pregnancy rate in patients with previous ART implantation failures was observed with LMWH. Our results confirm no relation among inherited thrombophilia and pregnancy rate in patients with previous IVF implantation failures. These findings should be confirmed by randomized controlled trials before use of LMWH for ART cycles is recommended. PMID- 21790337 TI - How to stay heart healthy in 2011: considerations for the primary prevention of cardiovascular disease in women. AB - More women die of cardiovascular disease than any other cause. Effective primary prevention depends on accurate assessment of risk status. While most risk factors are similar for men and women, risk factors may differ in magnitude between the sexes, and recognition of gender-specific risk factors such as gestational diabetes, hypertensive syndromes of pregnancy and polycystic ovarian syndrome provides opportunities for early intervention and prevention. Obesity, hypertension and hyperlipidemia affect both genders; however, women often postpone addressing these risk factors until later in life. The American Heart Association emphasizes that all women are at cardiovascular risk and should maintain a healthy lifestyle and avoid smoking. Blood pressure, hyperlipidemia and diabetes should be aggressively treated. Current available data regarding proposed preventive drug therapies including daily aspirin, HRT, vitamin D and omega-3 fatty acid supplements will be reviewed. PMID- 21790338 TI - No time to 'weight': the link between obesity and stroke in women. AB - The obesity epidemic in the USA threatens the gains that have been made in the prevention and treatment of stroke. Both obesity and stroke disproportionately affect women more than men. Understanding the effect of obesity on stroke risk in women may be a useful stepping stone to reducing the burden of stroke in this vulnerable population. This article reviews the association between stroke and general obesity, abdominal obesity and metabolic syndrome in women. All three factors have been shown to independently increase stroke risk in women. PMID- 21790339 TI - Sex differences in antiplatelet response in ischemic stroke. AB - Sex differences exist in the occurrence, treatment and outcome of ischemic stroke. Compared with men, women have more stroke events and are less likely to fully recover from a stroke. Given the rapidly aging population, stroke incidence and mortality among women are projected to substantially rise by 2050. This has important public health consequences. Mitigating the burden of stroke among women will require a fundamental understanding of sex differences and sex-specific issues including cerebrovascular disease pathophysiology, treatment and outcome. An aspect of stroke treatment receiving increasing but insufficient attention involves possible interactions between estrogen levels, antiplatelet drugs and stroke outcome. Emerging evidence suggests that antiplatelet therapy may provide primary stroke protection but not primary myocardial infarction prevention in women, while the opposite may be true among men. Understanding sex-specific issues related to women who experience stroke is critical to clinicians who treat women with antiplatelet medications as part of a secondary stroke prevention regimen; however, the ideal antiplatelet medication, and dose, in women requires further research. In this article we present a conceptual framework for sex differences in antiplatelet treatment response in ischemic stroke, thrombus formation and the mediating role of estrogen, sex differences in antiplatelet treatment response in clinical trials, and sex differences in antiplatelet treatment use in ischemic stroke. PMID- 21790340 TI - Individualizing hormone therapy to minimize risk: accurate assessment of risks and benefits. AB - Contrary to the exaggerated risks associated with HRT that developed after the initial press reports held by the Women's Health Initiative (WHI) writing group, the recent approach to hormone therapy is more balanced and evidence based. A review of over 40 years of scientific studies demonstrates that estrogen is a medication that can decrease mortality, cardiovascular disease, osteoporosis fracture, urogenital atrophy and dementia. When timing of administration, dose of therapy and route of administration are considered, estrogen is associated with low risks and substantial benefits. The decision of whether or not to take HRT for either short symptom relief or for long-term therapy, should be based on an accurate risk-benefit analysis. Adjusting the dose of therapy and considering a transdermal approach, particularly in high-risk patients, are important considerations. PMID- 21790341 TI - Functional imaging for assessing tumor response in cancer of the cervix. AB - Treatment options for carcinoma of the cervix are guided by tumor stage, and include radical surgery, in cases where the tumor is confined to the cervix, or concurrent chemotherapy and radiotherapy. In those cases treated with chemoradiation, the ability to monitor the response to treatment in order to adapt the management plan during its course may be beneficial. This approach has the potential to offer an individualized treatment plan, allowing for differences in behavior between tumors to be addressed early, rather than a 'one size fits all' treatment approach. This article aims to review the use of evolving functional imaging techniques including diffusion-weighted MRI, dynamic contrast enhanced MRI, and PET as tools for the evaluation of response to treatment of uterine cervical carcinoma. PMID- 21790344 TI - Sex differences of salivary cortisol secretion in patients with major depression. AB - Depression is associated with increased cortisol secretion and occurs more often in women than in men. Thus, it has been hypothesized that differences in cortisol secretion might, in part, be responsible for the greater risk of developing depression in women. However, only few studies have examined sex differences in baseline cortisol secretion in depressed patients and healthy controls. We examined sex effects on cortisol secretion in 52 medication-free patients with major depression (37 women, 15 men, mean +/- SD age 35 +/- 11 years, Hamilton Depression Scale mean score 27 +/- 5) and 50 healthy age- and sex-matched control subjects. Salivary cortisol concentrations were measured at 8:00, 12:00, 16:00, and 22:00 h. Repeated measures analysis of covariance revealed a group * sex interaction (p = 0.05). Post hoc tests revealed higher cortisol concentrations in depressed compared to healthy men [F(1;29) = 7.5, p = 0.01]. No differences were found between depressed and non-depressed women. Our results do not support the hypothesis that differences in cortisol secretion between depressed and non depressed subjects are more pronounced in women than in men. Study characteristics and methods as well as sex-specific confounding variables such as menstrual cycle, menopause and the use of oral contraceptives may account for inconclusive results across studies. PMID- 21790343 TI - Behaviorally inhibited temperament is associated with severity of post-traumatic stress disorder symptoms and faster eyeblink conditioning in veterans. AB - Prior studies have sometimes demonstrated facilitated acquisition of classically conditioned responses and/or resistance to extinction in post-traumatic stress disorder (PTSD). However, it is unclear whether these behaviors are acquired as a result of PTSD or exposure to trauma, or reflect preexisting risk factors that confer vulnerability for PTSD. Here, we examined classical eyeblink conditioning and extinction in veterans self-assessed for current PTSD symptoms, exposure to combat, and the personality trait of behavioral inhibition (BI), a risk factor for PTSD. A total of 128 veterans were recruited (mean age 51.2 years; 13.3% female); 126 completed self-assessment, with 25.4% reporting a history of exposure to combat and 30.9% reporting current, severe PTSD symptoms (PTSS). The severity of PTSS was correlated with current BI (R(2) = 0.497) and PTSS status could be predicted based on current BI and combat history (80.2% correct classification). A subset of the veterans (n = 87) also completed the eyeblink conditioning study. Among veterans without PTSS, childhood BI was associated with faster acquisition; veterans with PTSS showed delayed extinction, under some conditions. These data demonstrate a relationship between current BI and PTSS, and indicate that the facilitated conditioning sometimes observed in patients with PTSD may partially reflect personality traits such as childhood BI that pre date and contribute to vulnerability for PTSD. PMID- 21790345 TI - Differences between diurnal patterns of salivary cortisol and dehydroepiandrosterone in healthy female adolescents. AB - The adrenal hormones cortisol and dehydroepiandrosterone (DHEA) share a common secretagogue: adrenocorticotropic hormone; however, secretion of these hormones can be dissociated suggesting subtle individual regulation at the level of the adrenal gland. We examined differences in the diurnal patterns of cortisol and DHEA secretion in healthy adolescent girls, with the aim of informing the possibility of exploiting these differences to aid interpretation of data from clinical populations in which these patterns can become dysregulated. Fifty-six healthy females aged 10-18 years provided saliva samples at 0 and 30 min (morning samples) and 12 h post-awakening on 2 consecutive weekdays. For morning salivary cortisol in relation to morning DHEA concentrations, correlational analysis revealed only a trend (p = 0.054). Similarly, the association between evening cortisol and DHEA was characterised as a trend (p = 0.084). Mean morning DHEA concentrations showed more day-to-day consistency than equivalent cortisol samples (r = 0.829 for DHEA and 0.468 for cortisol; z = 3.487, p < 0.0005). Unlike the cortisol pattern, characterised by a marked awakening response (cortisol awakening response, CAR), a significant rise in DHEA concentration post awakening was not evident. Finally, there was a strong association between morning and evening concentrations of DHEA, not found for cortisol. The study shows differences in cortisol and DHEA secretion in the post-awakening period and informs work that seeks to examine correlates of dysregulated hypothalamic pituitary-adrenal axis function. Parallel examination of both hormones enables enhanced interpretation of aberrant patterns of the CAR, i.e. an exploration of whether dysregulation affects both hormones (reflecting overall steroidogenic capacity) or cortisol alone (CAR-specific mechanisms). PMID- 21790347 TI - The endocrine heart: 30 years later (23rd Meeting for the International Society of Hypertension). PMID- 21790346 TI - Ileal inducible nitric oxide synthase mRNA expression in response to stress is modified in Sprague-Dawley rats exposed to a previous intestinal inflammation. AB - The ability of stress to initiate or reactivate an inflammatory process seems to depend on an individual's susceptibility to stressful stimuli. The aim of this study was to establish whether previous inflammation alters the response to stress in Sprague-Dawley rats, a strain not especially susceptible to stressful stimuli. Stress exposure was performed in rats treated with indomethacin, to induce cyclic intestinal inflammation, during the inactive phase of inflammation. Both control and indomethacin-treated rats submitted to stress showed a decrease in body weight gain and blood leukocyte levels, as well as an increase in fecal pellet output. The increase in intestinal mucosal mast cell count induced by stress was similar in both groups of animals. Moreover, no differences were observed between control and indomethacin-treated rats in the degree of bacterial translocation and myeloperoxidase levels after stress exposure. Despite these similarities, differences between groups were observed in inducible nitric oxide synthase (iNOS) mRNA expression. Although ileal iNOS mRNA expression was inhibited in healthy rats submitted to stress, stress failed to modify this parameter in indomethacin-treated rats. As iNOS is another inflammatory marker, our results may allow the possibility that a previous intestinal inflammation could change the intestinal susceptibility to stress. Whether these differences in ileal iNOS expression can be indicative of a possible change in the predisposition to develop an intestinal inflammatory reaction in response to stress in Sprague-Dawley rats remains to be elucidated. PMID- 21790366 TI - Presence of Plasmodium and Haemoproteus in breeding prothonotary warblers (Protonotaria citrea: Parulidae): temporal and spatial trends in infection prevalence. AB - Prothonotary warbler (Protonotaria citrea) has shown a long-term decline in abundance in the United States. As a long-range migrant, these warblers are exposed to parasites in both tropical and temperate regions. The focus of this study was to use molecular techniques to examine the temporal prevalence patterns of heamosopridian parasites Plasmodium and Haemoproteus in breeding prothonotary warblers. The prevalence (presence or absence) of Plasmodium and Haemoproteus species was assayed using primer sets for the cytochrome b gene of the mitochondrial DNA. Blood samples were obtained from 187 adult prothonotary warblers collected at 3 central Virginia, U.S.A., breeding sites. The relationship between haemosporidian parasite infections and reproductive success also was examined. We found that 71% of captured prothonotary warblers were infected with haemosporidian parasites, specifically, with 36% prevalence for Haemoproteus spp. and 44% prevalence for Plasmodium spp., during the 2008 breeding season; for both parasites, prevalence increased throughout the season. We found significant variation in haemosporidian parasite prevalence across the breeding season that was strongly site specific. Conversely, we found no significant effects of haemosporidian parasite infections on the reproductive success of prothonotary warblers. This is in sharp contrast to recent reports suggesting considerable effects of these parasites on the reproductive success of wild birds. PMID- 21790367 TI - A survey of Neospora caninum and Toxoplasma gondii infection in urban rodents from Brazil. AB - Toxoplasma gondii is a protozoan parasite that infects humans and other warm blooded animals; it uses feral and domestic cats as the definitive hosts. Neospora caninum is a protozoan parasite of animals whose life cycle is very similar to T. gondii but uses canids as definitive hosts. Small rodents play an important role in the life cycle of T. gondii , and a few findings indicated that they may be natural intermediate hosts for N. caninum . The present study was aimed at identifying infections by T. gondii and N. caninum in urban rodents. Infections by T. gondii were quantified using isolation of the parasite by bioassay in mice; molecular methods were also used for both parasites. Overall, 217 rodents were captured. Brain and heart tissues of all rodents were bioassayed in mice for the detection of T. gondii infection. Brain and heart tissues of 121 rodents had the DNA extracted for molecular analysis. Toxoplasma gondii was isolated by bioassay from a single rodent. From the 121 rodents tested for the presence of T. gondii DNA, 2 animals were positive. In contrast, DNA of N. caninum was not detected in any of the samples. In conclusion, the surveys of N. caninum and T. gondii infection in Rattus rattus , Rattus norvegicus , and Mus musculus captured in urban areas of Sao Paulo reveal a striking low frequency of occurrence of these infections. PMID- 21790368 TI - Stress induces glucocorticoid-mediated apoptosis of rat Leydig cells in vivo. AB - Stress can disrupt endocrine signalling in the male reproductive axis through high concentrations of glucocorticoids, the hallmark of stress. Our previous work revealed that a stress level of exogenous glucocorticoids could induce apoptosis of rat Leydig cells, which are the primary source of testosterone. The aim of this study was to investigate whether stress can induce apoptosis in rat Leydig cells in vivo and, if so, whether the process is the result of a direct effect of glucocorticoids. In a chronically stressed rat model, serum corticosterone concentration was increased significantly whereas serum testosterone was decreased. The frequency of apoptotic Leydig cells in stressed rats was also increased. Adrenalectomised rats subjected to chronic stress showed an elevated serum testosterone, while the apoptotic frequency of Leydig cells was not increased. It was established that glucocorticoid-induced Leydig cell apoptosis is mediated by glucocorticoid receptors (GRs), which translocate from cytoplasm to nucleus. Adenovirus microRNA-induced downregulation of GR expression in vitro alleviated the corticosterone-induced increase in apoptosis of Leydig cells. These results indicate that the stress-induced increase in corticosterone secretion resulted in apoptosis in rat Leydig cells in vivo, and thereby decreased testosterone synthesis. PMID- 21790446 TI - Effects of dehydroepiandrosterone supplementation during stressful military training: a randomized, controlled, double-blind field study. AB - Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are anabolic prehormones involved in the synthesis of testosterone. Both have been shown to exert neuroprotective effects during stress. In this randomized, controlled, double blind field study, we examined the effects of a 12-day DHEA regimen on stress indices in military men undergoing survival training. Forty-eight men were randomized to either a DHEA treatment group or placebo control group. The treatment group received 50 mg of oral DHEA supplementation daily for 5 days during classroom training followed by 7 days of 75 mg during stressful field operations. Control subjects received identical placebo pills. Salivary assays (DHEA[S], testosterone, and cortisol) were conducted at four time points: distal pre-stress (T1), proximal pre-stress (T2), mock-captivity stress (T3), and 24 h recovery (T4). Subjective distress was also assessed at T1, T3, and T4. As expected, DHEA treatment resulted in higher salivary concentrations of DHEA and DHEAS during daily living, mock-captivity stress, and recovery. Similar patterns were observed for salivary markers of anabolic balance: DHEA/cortisol, DHEAS/cortisol, and testosterone/cortisol concentration ratios. Despite notable time effects, no group differences emerged for subjective distress. A brief, low dose DHEA regimen yielded large increases in salivary DHEA(S) concentrations and enhanced anabolic balance throughout sustained military stress. These physiological changes did not extrapolate to subjective distress. PMID- 21790452 TI - Sex-dependent changes induced by prenatal stress in cortical and hippocampal morphology and behaviour in rats: an update. AB - Recent prospective studies have shown that gestational stress in humans is more likely to cause cognitive and emotional problems in the offspring if it occurs during weeks 12-20 of pregnancy. There are also suggestions that such problems may be gender dependent. This review describes recent studies that found sex differences in the behaviour and brain morphology of rats stressed prenatally during the equivalent period of neuronal development in humans. Learning deficits are more prevalent in males and anxious behaviour in females but their appearance depends also on the timing and intensity of the stress and the age when the offspring were tested. Cognitive deficits and anxiety are linked to a sex dependent reduction in neurogenesis and in measures of dendritic morphology in the prefrontal cortex and hippocampal formation. Maternal adrenalectomy prior to the stress prevents the anxiety in both sexes and learning deficits in males. Corticosterone administration to the dam to mimic levels induced by stress reinstates only the anxiety, indicating that it arises from foetal exposure to corticosterone from the maternal circulation. Learning deficits in males may result from a combination of a reduction in testosterone and in aromatase activity, together with the action of other adrenal hormones. PMID- 21790467 TI - Influence of brain-derived neurotrophic factor and catechol O-methyl transferase polymorphisms on effects of meditation on plasma catecholamines and stress. AB - Meditation may show differential effects on stress and plasma catecholamines based on genetic polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol O-methyl transferase (COMT). Eighty adults (40 men, 40 women; mean age 26 years) who practiced meditation regularly and 57 healthy control adults (35 men, 22 women; mean age 26 years) participated. Plasma catecholamines (norepinephrine (NE), epinephrine (E), and dopamine (DA)) concentrations were measured, and a modified form of the Stress Response Inventory was administered. The results were analyzed using two-way analysis of covariance (ANCOVA) with control and meditation subjects, gene polymorphism as factors, and meditation duration as the covariate. Two-way ANCOVA showed a significant interaction between control and meditation subjects, and BDNF Val66Met polymorphism on DA/NE+DA/E (p = 0.042) and NE/E+NE/DA (p = 0.046) ratios. A significant interaction was found for control and meditation subjects with COMT Val158Met polymorphism and plasma NE concentrations (p = 0.009). Post hoc ANCOVA in the meditation group, adjusted for meditation duration, showed significantly higher plasma NE concentrations for COMT Met carriers than COMT Val/Val subjects (p = 0.025). Significant differences of stress levels were found between the control and meditation subjects in BDNF Val/Met (p < 0.001) and BDNF Met/Met (p = 0.003), whereas stress levels in the BDNF Val/Val genotype did not differ between the control and meditation groups. This is the first evidence that meditation produces different effects on plasma catecholamines according to BDNF or COMT polymorphisms. PMID- 21790468 TI - Prenatal maternal anxiety and early childhood temperament. AB - The consequences of exposure to prenatal maternal anxiety for the development of child temperament were examined in a sample of 120 healthy, 2-year-old children. Prenatal maternal state and pregnancy-specific anxiety (PSA) were measured five times during pregnancy, and maternal state anxiety was measured again at 2 years post partum. Child temperament was measured at 2 years using the Early Childhood Behavior Questionnaire. The relationship between the trajectory of maternal anxiety across gestation and negative affectivity was evaluated using hierarchical linear growth curve modeling. Higher maternal PSA between 13 and 17 weeks of gestation was associated with increased negative temperament in the children. This association could not be explained by postnatal maternal anxiety, demographic, or obstetric factors. Prenatal maternal state anxiety was not associated with child temperament. These findings demonstrate that PSA early in gestation has a distinctive influence on the developing fetus. PMID- 21790469 TI - The impact of a multidisciplinary educational intervention to reduce PEG tube placement in patients with terminal-stage dementia: a translation of research into practice. AB - The purpose of this translation of research into practice (TRIP) project was to to determine the impact of a multidisciplinary education-consultation intervention to reduce percutaneous endoscopic gastrostomy (PEG) tube placement in patients with terminal-stage dementia at a single urban hospital in a city characterized by numerous health care transitions. We attempted a "just-in-time" approach to educate busy clinicians through explicit recommendations offered during routine and requested consultation. The project results showed that the intervention had a modest positive clinical impact. PMID- 21790470 TI - Development of the Palliative Care Parental Self-Efficacy Measure. AB - Caring for a child with a potentially fatal medical condition is a challenge for parents or caregivers. The ability to measure parental self-efficacy in pediatric palliative care may be an important component of targeting supportive services that address individual needs of families. Therefore, the goal was to develop a Pediatric Palliative Care Parental Self-Efficacy Measure (PCPEM). First, a list of questions were generated that asked parents their level of confidence in carrying out tasks involved in caring for a child with a potentially fatal medical condition in 6 palliative care domains: 1) medical discussion/decisions; 2) symptom management/medication; 3) daily activities; 4) feelings/concerns; 5) spirituality; and 6) end-of-life care. The PCPEM was narrowed to 58 questions after expert reviews. Then, 16 caregivers of children receiving palliative care services and 9 bereaved caregivers participated in individual focus interviews conducted by a psychologist to obtain feedback about the content and clarity of the PCPEM. Results indicated that 53 of the 58 questions were rated as "comfortable being asked," and 55 of the 58 questions were rated as "important" by the majority (>80%) of the 25 caregivers. This suggests that it is feasible and valuable to ask caregivers difficult questions related to end-of-life care if done in a supportive and sensitive manner. Pilot testing of the PCPEM will be conducted to determine preliminary psychometric properties. PMID- 21790471 TI - HIV type 1 molecular epidemiology in pol and gp41 genes among naive patients from Mato Grosso do Sul State, central western Brazil. AB - Antiretroviral naive patients (n=49) were recruited in central western Brazil (Campo Grande City/Mato Grosso do Sul State, located across the Bolivia and Paraguay borders). HIV-1 protease (PR), reverse transcriptase (RT), and env gp41 HR1 fragments were sequenced. Genetic diversity was analyzed by REGA/phylogenetic analyses. Intersubtype recombinants were identified by SimPlot/phylogenetic trees. PR/RT resistance was analyzed by Calibrated Population Resistance/Stanford databases. T-20 resistance in gp41 was assessed by Stanford, Los Alamos, and other sources. Of HIV-1 subtypes 65.3% were B(PR)B(RT), 10.2% were C(PR)C(RT), and 8.2% were F1(PR)F1(RT). Intersubtype recombinants were 16.3%: four B/F1 and four B/C (two were "CRF31_BC-like"). The Pol-RT V75M mutation was detected in two homosexual partners; one patient had the T215S revertant mutation. T-20/gp41 resistance mutations were L44M (n=2) and V38A (n=1). The high percentage of non-B isolates (~35%) highlights the importance of molecular surveillance studies in settings distant from the origin of the epidemic. Our data help elaborate the molecular epidemiological map of HIV-1 in Brazil. PMID- 21790472 TI - IL28B polymorphism associated with spontaneous clearance of hepatitis C infection in a Southern Brazilian HIV type 1 population. AB - About one-third of people infected with human immunodeficiency virus-1 (HIV-1) are coinfected with hepatitis C virus (HCV) because of shared transmission routes. Studies report that HIV-1 complicates hepatitis C infection by increasing HCV viral load and reducing spontaneous clearance. Single nucleotide polymorphisms (SNPs) upstream of the IL28B gene have been associated with spontaneous and treatment-induced clearance of HCV infection. The aim of this study was to evaluate the association between the SNP rs12979860 of the IL28B gene and spontaneous clearance of HCV infection in a Brazilian HIV-1 population. The SNP was analyzed by polymerase chain reaction (PCR) followed by restriction digestion in 138 anti-HCV-positive patients. Spontaneous clearance was observed in 34 subjects (24.6%). Genotype distribution was significantly different between spontaneous clearance and HCV chronic patients. The CT/TT genotypes conferred a nearly 3-fold increased odds to chronic HCV infection relative to the CC genotype (odds ratio, 2.78; 95% confidence interval, 1.16-6.64; p=0.011). In conclusion, the rs12979860 polymorphism is associated with spontaneous clearance of HCV in HIV-1 Brazilian infected patients. PMID- 21790473 TI - Transmission of two distinct HIV type 1 strains to an individual that were harbored for many years by another. AB - The concept of transmission bottlenecks in HIV-1 infection is well established. Coinfections and superinfections have been increasingly documented and provide a founding cause for the expansion of viral diversity through recombination. It is still relatively unclear how HIV-1 will propagate and evolve in individuals infected with more than one viral strain. Here we report on the parallel transmission of genetically distant viral strains cocirculating in one individual over many years to a single recipient. PMID- 21790474 TI - Short communication routine HIV testing in the emergency department: assessment of patient perceptions. AB - The CDC released revised HIV testing guidelines in 2006 recommending routine, opt out HIV testing in acute care settings including emergency departments (ED). Patient attitudes have been cited as a barrier to implementation of routine HIV testing in the ED. We assessed patients' perceptions of HIV testing in the ED through a contextual qualitative approach. The study was conducted during a 72-h period. All adults presenting to the ED without life-threatening trauma or psychiatric crisis completed a standardized questionnaire. The questionnaire explored HIV testing history, knowledge of testing resources, and qualitative items addressing participant perceptions about advantages and disadvantages to ED testing. After completion of the interview, participants were offered a free, confidential, rapid HIV test. Among 329 eligible individuals approached, 288 (87.5%) completed the initial interview. Participants overwhelmingly (n=247, 85.8%) reported support for testing and identified increased knowledge (41%), prevention (12.5%), convenience (11.8%), and treatment (4.9%) among the advantages. Fear and denial about one's HIV status, reported by <5% of patients, were identified as the most significant barriers to ED testing. Bivariate analysis determined race and ethnicity differences between individuals completing the interview and those who refused (p<0.05). Among individuals consenting for testing (n=186, 64.6%), no positives were detected. Most patients support HIV testing in the ED, noting knowledge of status, prevention, convenience, and linkage to early treatment as distinct advantages. These data are of particular benefit to decision makers considering the addition of routine HIV testing in EDs. PMID- 21790475 TI - Percutaneous nephrolithotomy among patients with renal anomalies: patient characteristics and outcomes; a subgroup analysis of the clinical research office of the endourological society global percutaneous nephrolithotomy study. AB - PURPOSE: This study compared the characteristics and outcomes of percutaneous nephrolithotomy (PCNL) in patients with and without renal malformations using the Clinical Research Office of the Endourological Society (CROES) PCNL Global Study database. PATIENTS AND METHODS: The CROES PCNL Global Study collected prospective data for consecutive patients who were treated with PCNL at centers around the world during 1 year. Patient characteristics, operative data, and outcomes of PCNL in patients with renal anomalies and those with normal kidneys were compared. RESULTS: Of 5542 patients whose renal anatomy was recorded, 202 (3.6%) patients had a renal malformation. The most frequent anomalies were horseshoe kidneys (1.8%) and malrotated kidneys (1.3%). The prone position was the most frequently used position for patients with renal anomalies as was upper pole puncture. PCNL achieved stone-free rates of 76.6% in patients with anomalous kidneys and 76.2% in those with normal kidneys. The frequency of complications was similar in the two groups. Median operative time was significantly longer (87 min vs 75 min, P=0.037), and access for PCNL was unsuccessful in significantly more patients (5% vs 1.7%, P=0.001) in whom renal anomalies were present. CONCLUSION: In patients undergoing PCNL, the presence of renal malformation is likely to extend operative time. Stone-free rates as well as incidence of complications after PCNL are similar irrespective of the presence of renal anomalies. PMID- 21790476 TI - Effects of motherless rearing on basal and stress-induced corticosterone secretion in rat pups. AB - Rearing of rat pups without a mother, artificial rearing (AR), produces substantial changes in the pups' behavior in later life. These changes are similar to those produced by the stress of repeated mother-pup separations. The predominant interpretation is that the long-term effects of disruptions to the mother-pup relationship are mediated by exposure to elevated levels of corticosterone which affect the development of neurobiological systems underlying cognition and behavior. Indeed, repeated separation of pups from the mother sensitizes the pups' corticosterone response to stress. This study examined basal and stress-induced corticosterone release in AR pups. Corticosterone levels were increased immediately following implantation of feeding cannulae. One day after the start of AR, circulating concentrations of corticosterone were not increased unless AR pups were challenged with an additional stressor (injection). Corticosterone levels were lowest when cannulation and AR started on postnatal day (PND) 5 compared with earlier PNDs. On PND 12, there was no evidence of increased corticosterone levels in AR pups at baseline or in response to stress, indicating that AR did not result in persistent sensitization of corticosterone release. The long-term effects of motherless rearing on rat behavior are mediated by mechanisms that are independent of sustained early corticosterone exposure. PMID- 21790477 TI - Relationship between interstitial and blood glucose during hypoglycemia in subjects with type 2 diabetes. AB - BACKGROUND: Continuous glucose monitoring devices measure interstitial glucose and are commonly used to investigate hypoglycemia. The relationship between interstitial glucose and blood glucose is not completely understood, particularly at low blood glucose concentrations. Interstitial glucose during hypoglycemia is generally lower than blood glucose in young subjects without diabetes and those with type 1 diabetes, but the effect of insulin resistance and obesity in type 2 diabetes on this relationship has not been examined previously. We studied the relationship between blood and interstitial glucose during experimental hypoglycemia in subjects with type 2 diabetes treated with insulin or sulfonylureas and matched controls without diabetes. METHODS: Twenty subjects with type 2 diabetes (10 sulfonylurea-treated and 10 insulin-treated) and 10 controls without diabetes of similar age and weight underwent stepped hyperinsulinemic hypoglycemic clamps. We compared blood and interstitial glucose at different levels of hypoglycemia using random effects modeling. RESULTS: Interstitial glucose was significantly higher than blood glucose at all levels of hypoglycemia (P<0.001), and this difference increased as glucose fell. For every 1 mmol/L drop in blood glucose, the difference increased by 0.32 mmol/L (P<0.001). This difference was not affected by presence of type 2 diabetes or by modality of treatment (P=0.10). CONCLUSIONS: In older subjects with or without type 2 diabetes, interstitial glucose is significantly higher than blood glucose, and this difference increases with increasing severity of hypoglycemia. Continuous glucose monitors may underestimate hypoglycemia in this group, and this should be taken into account when interpreting results obtained using this technology. PMID- 21790478 TI - Beta-blockade prevents hematopoietic progenitor cell suppression after hemorrhagic shock. AB - BACKGROUND: Severe injury is accompanied by sympathetic stimulation that induces bone marrow (BM) dysfunction by both suppression of hematopoietic progenitor cell (HPC) growth and loss of cells via HPC mobilization to the peripheral circulation and sites of injury. Previous work demonstrated that beta-blockade (BB) given prior to tissue injury both reduces HPC mobilization and restores HPC colony growth within the BM. This study examined the effect and timing of BB on BM function in a hemorrhagic shock (HS) model. METHODS: Male Sprague-Dawley rats underwent HS via blood withdrawal, maintaining the mean arterial blood pressure at 30-40 mm Hg for 45 min, after which the extracted blood was reinfused. Propranolol (10 mg/kg) was given either prior to or immediately after HS. Blood pressure, heart rate, BM cellularity, and death were recorded. Bone marrow HPC growth was assessed by counting colony-forming unit-granulocyte-, erythrocyte-, monocyte-, megakaryocyte (CFU-GEMM), burst-forming unit-erythroid (BFU-E), and colony-forming unit-erythroid (CFU-E) cells. RESULTS: Administration of BB prior to injury restored HPC growth to that of naive animals (CFU-GEMM 59 +/- 11 vs. 61 +/- 4, BFU-E 68 +/- 9 vs. 73 +/- 3, and CFU-E 81 +/- 35 vs. 78 +/- 14 colonies/plate). Beta-blockade given after HS increased the growth of CFU-GEMM, BFU-E, and CFU-E significantly and improved BM cellularity compared with HS alone. The mortality rate was not increased in the groups receiving BB. CONCLUSION: Administration of propranolol either prior to injury or immediately after resuscitation significantly reduced post-shock BM suppression. After HS, BB may improve BM cellularity by decreasing HPC mobilization. Therefore, the early use of BB post-injury may play an important role in attenuating the BM dysfunction accompanying HS. PMID- 21790479 TI - Antibiotic regimen and the timing of prophylaxis are important for reducing surgical site infection after elective abdominal colorectal surgery. AB - BACKGROUND: Surgical site infections (SSIs) cause morbidity after elective colorectal surgery, and antibiotic prophylaxis can decrease SSIs. The aim of this study was to determine compliance with an antibiotic administration protocol, including regimen, initial dose timing, and re-dosing, and determine the risk of SSI associated with each. We hypothesized that appropriate antibiotic administration reduces the risk of SSI. METHODS: Retrospective review from a prospective database of a random sample of patients undergoing elective abdominal colorectal procedures with anastomosis. Antibiotic regimens, initial dose timing (IDT), and re-dosing were evaluated. Appropriate regimens covered gram-positive cocci, gram-negative bacilli, and anaerobes. The IDT was considered proper if completed within 30 min prior to incision; re-dosing parameters were determined pharmacokinetically for each agent. The main outcome was SSI. Sequential logistic models were generated: Model 1 assessed antibiotic administration factors, whereas Model 2 controlled for patient and clinical factors, including disease process, patient characteristics, intra-operative factors, and post-operative factors. RESULTS: Six hundred five patients (mean age 59.7 [standard deviation 17.8] years, 42.8% male) were included. The most common diagnoses were cancer (38.8%) and inflammatory bowel disease (22.0%). Seventy-six patients (12.6%) had superficial or deep incisional SSI, and 54 (8.9%) had organ/space SSI. Regimens included cefazolin + metronidazole for 219 patients (36.2%), cefoxitin for 214 (35.4%), and levofloxacin + metronidazole for 48 (7.9%). One hundred fourteen patients (18.8%) received other/nonstandard regimens, and ten had no documented antibiotic prophylaxis. Fifty-five patients (9.1%) received insufficient coverage, whereas 361 patients (59.7%) had proper IDT, and 401 regimens (66.3%) were re-dosed properly. In Model 1, the use of other/nonstandard regimens (odds ratio [OR] 2.069; 95% confidence interval [CI] 1.078-1.868) and early administration of the initial prophylaxis dose (OR 1.725; 95% CI 1.147-2.596) were associated with greater odds of SSI. After adding clinical factors in Model 2, both of these factors remained significant (OR 2.505; 95% CI 1.066-5.886 and OR 1.733; 95% CI 1.017-2.954, respectively). CONCLUSIONS: Appropriate antibiotic selection and timing of administration for prophylaxis are crucial to reduce the likelihood of SSI after elective colorectal surgery with intestinal anastomosis. PMID- 21790480 TI - Contemporary predictors of conversion from laparoscopic to open appendectomy. AB - BACKGROUND: We defined the contemporary conversion rate from laparoscopic appendectomy (LA) to open appendectomy and identified pre-operative factors associated with conversion. METHODS: Retrospective review of 941 consecutive LAs performed for suspected acute appendicitis in a single urban university hospital between 2000 and 2007. Patient characteristics, clinical features, physical examination findings, laboratory values, computed tomography (CT) findings, surgeon identity, operative findings, and pathologic results were assessed. Categorical variables were compared in patients undergoing LA and those in whom conversion was necessary using the Fisher exact test; the Student t-test was used to compare continuous variables. Multivariable analysis was performed with binomial logistic regression. Statistical significance was established at alpha = 0.05. RESULTS: The overall conversion rate was 4.1% and did not change significantly over the course of the study. By univariable analysis, conversion was significantly associated with older age, male gender, American Society of Anesthesiologists (ASA) score >2 points, longer duration of symptoms, rigidity on physical examination, increased percentage of neutrophils on admission white blood cell differential count, extraluminal air on CT, inexperience of the attending surgeon with LA, retrocecal location of the appendix, gross necrosis or perforation, murky or purulent ascites, and microscopic evidence of perforation. By multivariable analysis, advanced age (hazard ratio [HR] 1.02 per year; 95% confidence interval [CI] 1.01-1.04, p = 0.02), ASA score >2 points (HR 11.2; 95% CI 5.6-24.4; p < 0.001), CT inflammation grade >= 4 (HR 4.8; 95% CI 1.9-12.3; p = 0.001), and attending surgeon inexperience (HR 7.4; 95% CI 2.6-20.8; p < 0.001) were independent predictors of conversion. CONCLUSION: The conversion rate during laparoscopic appendectomy has not changed significantly over the past seven years and remains ~4%. Independent pre-operative predictors of conversion are advanced age, ASA score >2 points, attending surgeon inexperience, and extensive inflammation observed on pre-operative CT scan. Proceeding directly with open appendectomy under these circumstances may reduce operative time, expense, and morbidity. PMID- 21790482 TI - The neurobiology of the stress-resistant brain. AB - The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences of acute, repeated, and chronic stressor exposure on health and disease. Session IV entitled "The neurobiology of the stress-resistant brain" explored how we can intervene to promote stress resistance and stress resilience. Four scientists, who explore this topic from unique and convergent perspectives, presented their experimental results derived from studies in rat (Fleshner and Maier), non-human primates (Lyons), and human (Raskind). Summaries of each presentation, supporting publications, and overall take-home messages from the session are presented. PMID- 21790483 TI - Effectiveness of photodynamic therapy against Enterococcus faecalis, with and without the use of an intracanal optical fiber: an in vitro study. AB - BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a new technique introduced in endodontics that combines the action of a photosensitizer (dye) and a low intensity light source. Currently, there are no PDT studies evaluating the microbial disinfection of root canals in order to compare the effects of light delivery systems in the photosensitizer activation. The aim of this study was to evaluate the PDT effectiveness in reducing Enterococcus faecalis, with and without the aid of an intracanal optical fiber. METHODS: Extracted single-rooted teeth were selected, instrumented, inoculated with E. faecalis and divided into six groups: one control group (untreated), one conventionally-treated group (1% NaOCl irrigation) and four PDT-treated groups. Irradiation (diode laser) was performed with (OF) or without an intracanal optical fiber (NOF) using two different irradiation times: 1 min and 30 sec (IT(90)) or 3 min (IT(180)). Samples were collected before and after testing procedures and CFU/mL was determined. RESULTS: The greatest reduction of E. faecalis (99.99%) was achieved with irrigation with 1% NaOCl. PDT also significantly reduced E. faecalis in the following decreasing order: OF/IT(180), NOF/IT(180), OF/IT(90) and NOF/IT(90), with no significant statistical difference among the groups. CONCLUSIONS: These results suggest that PDT was effective against E. faecalis, regardless of the use of an intracanal optical fiber. PMID- 21790481 TI - Stress modulation of cognitive and affective processes. AB - This review summarizes the major discussion points of a symposium on stress modulation of cognitive and affective processes, which was held during the 2010 workshop on the neurobiology of stress (Boulder, CO, USA). The four discussants addressed a number of specific cognitive and affective factors that are modulated by exposure to acute or repeated stress. Dr David Morilak discussed the effects of various repeated stress situations on cognitive flexibility, as assessed with a rodent model of attentional set-shifting task, and how performance on slightly different aspects of this test is modulated by different prefrontal regions through monoaminergic neurotransmission. Dr Serge Campeau summarized the findings of several studies exploring a number of factors and brain regions that regulate habituation of various autonomic and neuroendocrine responses to repeated audiogenic stress exposures. Dr Kerry Ressler discussed a body of work exploring the modulation and extinction of fear memories in rodents and humans, especially focusing on the role of key neurotransmitter systems including excitatory amino acids and brain-derived neurotrophic factor. Dr Israel Liberzon presented recent results on human decision-making processes in response to exogenous glucocorticoid hormone administration. Overall, these discussions are casting a wider framework on the cognitive/affective processes that are distinctly regulated by the experience of stress and some of the brain regions and neurotransmitter systems associated with these effects. PMID- 21790485 TI - Role of the sympathetic nervous system in cerebrovascular responses to air-jet stress in rats. AB - This study examined the role of sympathetic nerves in the control of cerebral hemodynamics during air-jet stress. In adult male Sprague-Dawley rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after excision of one superior cervical ganglion. Blood pressure (BP) and carotid blood flows (CBFs) were simultaneously recorded during exposure to air-jet stress. In 5 out of 13 rats, stress was applied after beta(2)-adrenoceptor blockade with ICI 118551 (0.4 mg/kg, then 0.2 mg/kg/h, i.v). Stress evoked an immediate rise in BP, CBFs, and vascular conductances. Vasodilatation was much larger on the denervated side than on the intact side (mean +/- SEM: 78 +/- 7 versus 19 +/- 4%; P < 0.02) and lasted about 10 s. Thereafter, blood flows returned to or near normal and showed parallel variations while BP remained elevated. There was, therefore, a net vasoconstriction on both sides. In ICI 118551-treated rats, the initial vasodilatation was not significantly reduced on the denervated side (64 +/- 4%), but the subsequent vasoconstriction was enhanced (P < 0.05) on both sides. In conclusion, air-jet stress evokes an immediate, short-lasting vasodilatation through a mechanism unrelated to beta(2) adrenoceptor stimulation. Sympathetic nerves powerfully limit this phenomenon, and thus contribute to protect the cerebral circulation from stress-induced BP surges. PMID- 21790484 TI - Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer's disease caregivers. AB - The stress associated with providing care for a spouse diagnosed with Alzheimer's disease can have adverse effects on cardiovascular health. One potential explanation is that chronic caregiving stress may contribute to the development of atherosclerosis. The purpose of this study was to determine whether the duration that one has provided care is associated with the degree of atherosclerotic burden, as measured by carotid artery intima-media thickness (IMT). One hundred and ten Alzheimer caregivers [mean age 74 +/- 8 (SD) years, 69% female] underwent in-home assessment of carotid artery IMT via B-mode ultrasonography. Data regarding medical history, blood pressure, and multiple indicators of caregiving stress were also collected. Multiple regression indicated that duration of care was positively associated with IMT measured in the internal/bifurcation segments of the carotid artery (beta = 0.202, p = 0.044) independent of risk factors such as age, gender, body mass index, smoking history, sleep quality, hypertension status, and caregiving stressors. Duration of care was positively associated with IMT in the common carotid artery, but the relationship was not significant. These findings provide more evidence of the link between chronic caregiving stress and cardiovascular disease and indicate that enduring the experience of caregiving over a period of years might be associated with atherosclerotic burden. PMID- 21790486 TI - Dealing with dissonance: responding to an incongruent test result in a new media environment. AB - In a new media environment replete with opportunities to test and express political identity, this study examines how people respond when confronted with a political test result that contradicts their partisan affiliation. An incongruent test result should produce motivated processing, but only when individuals do not dismiss the incongruent result will they experience dissonance and alter their social identification. Using a series of experiments, the results of this study supported these hypotheses. Implications of these findings for political psychology and message response are discussed. PMID- 21790487 TI - Usage pattern of synthetic food colours in different states of India and exposure assessment through commodities preferentially consumed by children. AB - Exposure studies in children are emphasized nowadays given children's higher consumption vulnerability. The present study generated national-level data covering 16 major states of India on the usage pattern of colours and it identified food commodities through which a particular colour has the scope to exceed ADI limits. Out of the total analysed samples, 87.8% contained permitted colours, of which only 48% adhered to the prescribed limit of 100 mg kg(-1). The majority of candyfloss, sugar toys, beverages, mouth fresheners, ice candy and bakery product samples exceeded the prescribed limit. Non-permitted colours were mostly prevalent in candyfloss and sugar toy samples. Though sunset yellow FCF (SSYFCF) and tartrazine were the two most popular colours, many samples used a blend of two or more colours. The blend of SSYFCF and tartrazine exceeded the prescribed limit by a factor of 37 in one sample, and the median and 95th percentile levels of this blend were 4.5- and 25.7-fold, respectively. The exposure assessment showed that the intake of erythrosine exceeded the ADI limits by two to six times at average levels of detected colours, whereas at the 95th percentile level both SSYFCF and erythrosine exceeded the respective ADI limits by three- to 12-fold in all five age groups. Thus, the uniform prescribed limit of synthetic colours at 100 mg kg(-1) under Indian rules needs to be reviewed and should be governed by consumption profiles of the food commodities to check the unnecessary exposure of excessive colours to those vulnerable in the population that may pose a health risk. PMID- 21790488 TI - Occurrence of toxigenic fungi in ochratoxin A contaminated liquorice root. AB - Fungi associated with ochratoxin A (OTA)-contaminated liquorice root and their capabilities for OTA production were investigated. Medicinal materials of mouldy liquorice root were collected from herbal markets located in Jiangxi, Zhejiang, Henan provinces and Beijing, China, respectively. Sixteen fungal species belonging to Penicillium, Aspergillus, Eurotium, Fusarium, Mucor and Scopulariopsis were isolated; the fungal composition was different in each liquorice root sample. Penicillium polonicum was predominant, comprising 54% of the total isolates in the liquorice root sample from Jiangxi province, which was contaminated with OTA at the highest level. In other samples with lower OTA contents, species of Aspergillus and Eurotium were predominant. OTA production of representative strains on rice media was detected by LC-MS/MS; all Penicillium polonicum isolates and a P. chrysogenum were ochratoxigenic; OTA concentrations ranged from 6.94 to 217.37 ng g(-1). This is the first study to report P. polonicum as an OTA-producing fungus. OTA contamination of mouldy liquorice root constitutes a major health hazard in consumption. This situation demands urgent and undivided attention. PMID- 21790489 TI - Determination of silver in nano-plastic food packaging by microwave digestion coupled with inductively coupled plasma atomic emission spectrometry or inductively coupled plasma mass spectrometry. AB - The detection of silver in nano-plastic food packaging by microwave digestion coupled with either inductively coupled plasma atomic emission spectrometry (ICP AES) or inductively coupled plasma mass spectrometry (ICP-MS) was investigated. Microwave digestion was optimised by trialling different acid mixtures. Both ICP AES and ICP-MS showed good reproducibility, repeatability and recovery. For ICP AES the limit of detection of the method (LODm) was 25.0 ug g(-1), the limit of detection of the instrument (LODi) was 30.0 ng ml(-1), the linear range was 0.10 10.0 ug ml(-1). The average recoveries for blank samples spiked with silver at 100, 250 and 500 ug g(-1) ranged from 82.53% to 87.60%, and the relative standard deviations (RSDs) were from 1.79% to 8.30%. For ICP-MS analysis the LODm was 0.75 ug g(-1), the LODi was 0.04 ng ml(-1), the linear range was 0.20-500.0 ng ml(-1), the RSDs were 2.26-4.79%, and the recoveries were 78.09-92.72% (spiked concentrations of 2.5, 5.0 and 10.0 ug g(-1)). These results indicate that the proposed method could be employed to analyse silver in nano-plastic food packaging. PMID- 21790490 TI - Effect of A-HRS on blood pressure and metabolic alterations in fructose-induced hypertensive rats. AB - Fructose feeding induces a rise in blood pressure in normal rats that is associated with insulin resistance, hyperinsulinemia, hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia. We have examined the effect of chronic administration of A-HRS (100 and 300 mg kg-1; p.o.) isolated from Hibiscus rosa sinensis (Malvaceae) on systolic blood pressure (SBP), vascular reactivity, serum glucose, triglycerides, cholesterol, uric acid and insulin in fructose-induced hypertension model. A-HRS treatment (100 and 300 mg kg-1, p.o. for 6 weeks) reduced SBP, vascular reactivity changes to catecholamines and reversed the metabolic alterations induced by fructose (10%) treatment for 6 weeks. The cumulative concentration response curve (CCRC) of angiotensin II (Ang II) was shifted towards the right in rats treated with A-HRS using an isolated strip of ascending colon. The results suggest that A-HRS could prevent the development of high-blood pressure induced by a diet rich in fructose, probably by reversing the metabolic alterations induced by fructose. In conclusion, A-HRS has an antihypertensive action in a fructose model. PMID- 21790491 TI - Two oleananes from Ammannia auriculata Willd. AB - Two new compounds: 3-beta,15-alpha,23,28-tetrahydroxyolean-12-en-3-O arabinopyaranoside and 3-beta,23,28-trihydroxy-olean-12-en-3-O-beta-D glucopyranoside were isolated from the aerial parts of Ammania auriculata along with the known compounds kaempferol, beta-sitosterol-3-O-beta- D-glucoside, 2 alpha,3-beta,23-trihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranoside, quercetin, kaempferol-3-O-alpha-L-arabinofuranoside, kaempferol-3-O-beta-D xylopyranoside and ellagic acid. Structures of these compounds were elucidated on the basis of their spectroscopic data (NMR, UV, MS and IR spectra). The antioxidant activities of the total extract, the fractions CH(2)Cl(2), EtOAc and the remaining aqueous together with the compounds 1, 6 and 9 were comparable with that of the standard antioxidant, ascorbic acid. PMID- 21790492 TI - Liriodenine alkaloid in Annona diversifolia during early development. AB - Plants of the Annonaceae family produce a series of alkaloids, including liriodenine oxoaporphine. Its distribution in these primitive angiosperms suggests that it plays an important role, but very little is known about which plant organs it accumulates in, or in which developmental stages it is synthesised. Accordingly, liriodenine production was studied during the early stages of germination and seedling development in Annona diversifolia Saff. Liriodenine samples were obtained from the roots and were characterised on the basis of spectroscopic data. Quantification was done by HPLC in the organs and tissues of newly collected seeds, seeds following 1-, 2-, 5- and 10-day imbibitions, upon emergence of the radicle and at the seedling stage. According to our results, liriodenine could not have originated from the parent plant, nor during embryogenesis because it appears for the first time in the endosperm approximately 5 days after the start of imbibition. Therefore, its synthesis does not depend directly on photosynthesis. During the seedling stage it is found in the root and the stem but it is absent from the cotyledonary leaves and the first true leaves. Liriodenine biosynthesis begins during the early stages of development in the endosperm and seed radicles. PMID- 21790493 TI - Phenolic compounds from Scorzonera latifolia (Fisch. & Mey.) DC. AB - A new 3-benzylphthalide, scorzoveratrin 4'-O-beta-glucoside (1), together with the known 3-benzylphthalides, scorzoveratrin (2) and scorzoveratrozit (3), the caffeoyl derivatives, chlorogenic acid methyl ester (4), 4,5-dicaffeoylquinic acid (5), 4,5-dicaffeoylquinic acid methyl ester (6), 3,5-dicaffeoylquinic acid (7) and caffeic acid (8) were isolated from the subaerial parts of Scorzonera latifolia (Fisch. & Mey.) DC. All secondary metabolites were assigned using physicochemical and spectroscopic data. The known compounds 2-8 were isolated for the first time from this species. PMID- 21790494 TI - What's in a mask? Information masking with forward and backward visual masks. AB - Three experiments tested how the physical format and information content of forward and backward masks affected the extent of visual pattern masking. This involved using different types of forward and backward masks with target discrimination measured by percentage correct in the first experiment (with a fixed target duration) and by an adaptive threshold procedure in the last two. The rationale behind the manipulation of the content of the masks stemmed from masking theories emphasizing attentional and/or conceptual factors rather than visual ones. Experiment 1 used word masks and showed that masking was reduced (a masking reduction effect) when the forward and backward masks were the same word (although in different case) compared to when the masks were different words. Experiment 2 tested the extent to which a reduction in masking might occur due to the physical similarity between the forward and backward masks by comparing the effect of the same content of the masks in the same versus different case. The result showed a significant reduction in masking for same content masks but no significant effect of case. The last experiment examined whether the reduction in masking effect would be observed with nonword masks--that is, having no high level representation. No reduction in masking was found from same compared to different nonword masks (Experiment 3). These results support the view that the conscious perception of a rapidly displayed target stimulus is in part determined by high-level perceptual/cognitive factors concerned with masking stimulus grouping and attention. PMID- 21790495 TI - Toxicity and influences of the alkaloids from Cynanchum komarovii AL. Iljinski (Asclepiadaceae) on growth and cuticle components of Spodoptera litura Fabricius (Noctuidae) larvae. AB - The acute lethal toxicity of the extracted and purified gross alkaloids from Cynanchum komarovii has been demonstrated on the insect pest, Spodoptera litura. The toxic regression equation of the gross alkaloids for S. litura larvae was Y = -2.69701 + 0.78711X and the LC(50) value 2669.88 mg L(-1). The growth disruptions of S. litura caused by the alkaloids from C. komarovii were also evaluated. The rates of growth inhibition, malformation, developmental duration (from third instar to pupation), pupation and emergence inhibition of S. litura caused by the gross alkaloids at dose rates between 50 and 800 mg L(-1) were 30.13-91.71%, 0.00 20.00%, 12-72 h, 16.66-36.66% and 16.66-50.00%, respectively. The alkaloids caused the modification of the cuticular components of S. litura. The relative contents of cuticular lipids, proteins and chitins showed a 3.02-17.11% rise before exposure, followed by 2.29-12.96% and 0.75-4.13% declines 72 h after treatment with gross alkaloids with concentrations between 50 and 800 mg L(-1). Initial studies on the insecticidal properties of C. komarovii gross alkaloids indicate these to be very potent insect growth inhibitors. PMID- 21790496 TI - Effect of ethanol extract of Sphaeranthus indicus on cisplatin-induced nephrotoxicity in rats. AB - Cisplatin is an anticancer drug extensively used against a variety of cancers. Cisplatin chemotherapy is found to manifest dose-dependent nephrotoxicity. Depletion of the renal antioxidant defence system has been suggested to be the main cause of cisplatin-induced nephrotoxicity. The purpose of this study is to investigate whether the ethanol extract of entire plant of Sphaeranthus indicus could reduce the intensity of toxicity in albino rats. Nephrotoxicity was assessed by determining the serum creatinine and urea levels and renal antioxidant status in rats after cisplatin administration (12 mg kg(-1) body weight, i.p.). The ethanol extract of S. indicus (150 and 300 mg kg(-1) body weight) was administered orally from the sixth day onwards for 10 days after cisplatin administration. The extract significantly reduced the elevated serum creatinine and urea levels. Renal antioxidant defence systems, such as superoxide dismutase, catalase, glutathione peroxidase activities and reduced glutathione level that are depleted by cisplatin therapy were restored to normal by treatment with the extract. Cisplatin-induced lipid peroxidation was also found to be markedly reduced by treatment with the extract. These results suggest that S. indicus has protective effect against cisplatin-induced nephrotoxicity, which may be attributed to its antioxidant potential. PMID- 21790497 TI - A new iridoid compound from Patrinia rupestris (Pall.) Juss. AB - Extraction of roots of Patrinia rupestris (Pall.) Juss. gave a new iridoid compound, 1beta,3alpha-diethyloxy-7-hydromethyl-4-(3-methyl-butyryloxymethyl) cyclopenta-4(4a),7(7a)-diene[c]pyran-6-one (1), together with a known compound, (1alpha,4aalpha, 6alpha,7beta,7aalpha)-[4a,5,6,7,7a-hexahydro-6,7-dihydroxy-1-(3 methyl-1-oxobutoxy) cyclopenta[c]pyran-4,7-diyl]bis(methylene) 3-methyl-butanoic acid ester (2). The structure of 1 was characterised by HRESIMS, IR, UV, 1-D NMR and 2-D NMR methods. Compound 2 was isolated from this genus for the first time. PMID- 21790498 TI - Anti-inflammatory and analgesic activity of Alkanna bracteosa and Alkanna tricophila. AB - Alkanna bracteosa and Alkanna tricophila, Boraginaceae, have been reported to be useful for their anti-inflammatory and wound-healing effects in traditional medicine. Methanol extracts of A. bracteosa and A. tricophila were evaluated for their potential analgesic and anti-inflammatory properties. Alkanna bracteosa was observed to produce a maximum of 42% reduction of hind paw licking in acute as well as 68% alleviation in inflammatory phase of formalin test in mice and about 30% declination of carrageenan-induced rats paw swelling at doses 100-400 mg kg-1 in comparison to negative control; on the other hand, A. tricophila required at least 200 mg kg-1 to exhibit a significant reduction in paw licking or oedemas at the early phase of formalin test and the late phase of carrageenan test, respectively. Our results suggest that the extracts may be of use for their analgesic and anti-inflammatory effects. PMID- 21790499 TI - Chemical modification and anticancer effect of prenylated flavanones from Taiwanese propolis. AB - Our previous studies demonstrated that eight prenylated flavanones (1-8), isolated from Taiwanese propolis, were capable of a broad spectrum of biological activities. Among them, nymphaeol A (3), nymphaeol B (4) and nymphaeol C (7), abundant in Taiwanese propolis, exhibited cytotoxicity against cancer cell lines. It therefore seemed interesting to improve their activity via a semi-synthetic strategy. In this study, 12 novel prenylated flavanones were synthesised in our laboratory and their activities were assessed for two human prostate cancer cell lines, PC-3 and DU-145, and a human hepatoma cell line, Hep-3B. Of these compounds, 10c, 11 and 12 showed more potent cytotoxicity against the PC-3 cell line than 5-Fu. Using cytometric analysis followed by double staining with annexin V-FITC and propidium iodide, it was observed that these compounds induced apoptosis as well. This suggests that prenylated flavanones 10c, 11 and 12 may have anticancer potential for further development. PMID- 21790500 TI - 6-O-methylkrigeine, a new amaryllidaceae alkaloid from Nerine huttoniae Schonland. AB - A novel Amaryllidaceae alkaloid, 6-O-methylkrigeine, has been isolated from Nerine huttoniae and the configuration was elucidated by 1-D and 2-D (1)H-NMR, (13)C-NMR, HRMS and optical rotation. PMID- 21790501 TI - Moving beyond behaviour: advancing HIV risk prevention epistemologies and interventions (A report on the state of the literature). AB - This paper is based on an extensive literature review of academic, policy and 'grey' literatures on the intersections of culture and the global HIV/AIDS pandemic commissioned by UNESCO. It highlights that the review exposed a dominant conceptual perspective that poorly captures structures of vulnerability, particularly structures that expose entire populations to risk in relatively uniform ways. Stemming from this, the review revealed a series of specific topical areas in need of further research including masculinities, transactional sex, infrastructural deficits in health and education, fragile states and global governance. For each of these topical areas the authors demonstrate the relationship to the conceptual limitation, summarise relevant research in this area, and provide evidence of applicability to public health interventions. In pursuit of more effective interventions, this paper draws attention to some of the conceptual limitations of current approaches to understanding the pandemic, and calls for interventions that move beyond individual behaviours to address structures that shape individual behaviour and make entire populations more vulnerable to HIV. PMID- 21790502 TI - A review of the impacts of tobacco industry privatisation: Implications for policy. AB - State-owned tobacco companies, which still account for 40% of global cigarette production, face continued pressure from, among others, the International Monetary Fund (IMF), to be privatised. This review of available literature on tobacco industry privatisation suggests that any economic benefits of privatisation may be lower than supposed, because private owners avoid competitive tenders (thus underpaying for assets), negotiate lengthy tax holidays and are complicit in the smuggling of cigarettes to avoid import and excise duties. It outlines how privatisation leads to increased marketing, more effective distribution and lower prices, creating additional demand for cigarettes among new and existing smokers, leading to increased cigarette consumption, higher smoking prevalence and lower age of smoking initiation. Privatisation also weakens tobacco control because private owners, in their drive for profits, lobby aggressively against effective policies and ignore or overturn existing policies. This evidence suggests that further tobacco industry privatisation is likely to increase smoking and that instead of transferring assets from state to private ownership, alternative models of supply should be explored. PMID- 21790503 TI - Effect of rotigotine on sleep and quality of life in Parkinson's disease patients: post hoc analysis of RECOVER patients who were symptomatic at baseline. AB - OBJECTIVE: The aim of this research is to characterize further the potential motor and non-motor benefits of rotigotine reported in the double-blind, placebo controlled RECOVER trial primary publication, by performing a post hoc exploratory analysis of patient status (symptom improvement/worsening). METHODS: Full RECOVER trial methodological details have already been reported. The post hoc analyses presented here are done on individual items of the PDSS-2 and PDQ-8 for all patients and two subgroups (baseline symptomatic and highly symptomatic patients). RESULTS: Ten PDSS-2 and five PDQ-8 items show significant mean treatment difference versus placebo. In the overall population, items that most favor rotigotine in percentage of patients with improvement are 'limb pain causes waking' and 'uncomfortable in bed due to immobility' for PDSS-2; for PDQ-8, rotigotine is most favored in 'difficulty dressing', 'felt depressed' and 'difficulty getting around in public'. Among symptomatic and highly symptomatic patients, the PDSS-2 items that most favor rotigotine are both indicators of pain. On the PDQ-8, the two items most favored in symptomatic patients are 'difficulty dressing' and 'embarrassed in public due to PD', and in the highly symptomatic subgroup 'difficulty dressing' and 'difficulty getting around in public'. CONCLUSION: Though this trial was not powered for statistical subgroup analysis, these post hoc results indicate that treatment with rotigotine may benefit patients with sleep, pain, mood and quality-of-life issues. PMID- 21790504 TI - Peripartum care of the parturient with Tourette's syndrome: more questions than answers. PMID- 21790505 TI - Prenatal screening for trisomy 21: recent advances and guidelines. AB - The performance of prenatal screening tests for the identification of trisomy 21 (Down syndrome) has markedly improved since the 1970s and early 1980s when maternal age was the sole mode of screening the general pregnant population. With the discovery of second trimester serum markers in the 1980s and 1990s and implementation of double, triple, and quad marker testing; the discovery of first trimester serum and ultrasound markers in the 1990s and implementation of the combined test; and the development of the integrated test and sequential screening strategies over the past decade, the performance of screening has improved to a detection rate of 90%-95% at a false positive rate of 2%-5%. In this review, I will describe the advances in prenatal screening for trisomy 21, present current screening strategies, and discuss guidelines published by professional societies and regulatory bodies, with a focus on current prenatal screening practice in the USA. PMID- 21790506 TI - Canine olfactory detection of cancer versus laboratory testing: myth or opportunity? AB - According to the most recent global cancer statistics, the burden of malignancies continues to increase worldwide, so that there is a compelling need to reinforce the screening strategies and implement novel diagnostic approaches for early detection. Canines are widely used by police forces and civilian services for detecting explosives and drugs due to their superior olfactive apparatus, which is characterized by a detection threshold as low as parts per trillion. There is mounting evidence that dogs might be effectively trained to detect patients with various form of cancers due to the presence of a characteristic "odor signature". In particular, preliminary studies reported that appropriately trained dogs exhibit an extraordinary ability to detect melanoma as well as prostate, breast, ovary and lung cancers by recognizing a characteristic "odor signature" in body, urines, sweat, breath and even blood. The most problematic issue that has emerged so far is the large heterogeneity of performance across the different studies as well as within the same study, which might be dependent upon genetic characteristics or training methodology. This article is aimed to provide an overview of the available data on cancer sniffer dogs, highlighting the appealing perspectives and the potential drawbacks. PMID- 21790507 TI - Cognitive mechanisms underlying relapse to nicotine. AB - Much of the addictive power of nicotine in humans may be attributable to learned contextual associations, such that these secondary cues become potent predictive incentives for both maintaining and driving relapse to drug use, even after long periods of abstinence. Here, I review the evidence that chronic nicotine in vivo can induce persistent neuronal changes in excitability within the hippocampal circuitry, with a specific emphasis on the dentate gyrus as an initiator of drug use. The relevance of these early homeostatic (can be fully reversed by acute application of nicotine) neuroadaptations on withdrawal from nicotine is then related to known cognitive deficits also produced following chronic nicotine. I briefly discuss how the hippocampus may influence other parts of the reward circuitry to affect chronic drug use and how periods of drug cessation and/or withdrawal may convert these short-term changes into permanent alterations within the brain that may drive craving and/or relapse many years of abstinence. PMID- 21790508 TI - Pharmacokinetics of triamcinolone acetonide for the treatment of macular edema. AB - INTRODUCTION: The use of intravitreal triamcinolone acetonide (TA) for the treatment of various types of macular edema has been widespread, particularly for the last decade. Currently, there is a scant amount of evidence-based literature evaluating the pharmacokinetic profile of TA despite clinical data showing the efficacy of intravitreal TA for multiple forms of macular edema. AREAS COVERED: This paper is an extensive review of human and experimental studies published on the pharmacokinetics of TA for the treatment of macular edema. The literature search was conducted via OVID, TRIP Database and EMBASE, up to April 2011. EXPERT OPINION: The pharmacokinetic profile of TA is unpredictable and the agent has a time-limited therapeutic action due to its relatively short half-life. This has led to the need for repeated injections. Future research should investigate the pharmacokinetic profiles of TA when administered intravitreally, as well as through alternate routes in more robust studies. PMID- 21790509 TI - Male sexual disorders following stroke: an overview. AB - Stroke is one of the leading causes of death and disability throughout the world. Although physical and cognitive impairments after stroke have been well studied, little information is known about one of the crucial aspect of the quality of life of stroke patients, namely, sexual functioning and satisfaction. Poststroke sexual dysfunctions seem to be very common since in men affected by stroke, a decline in libido and poor or tailed erection and ejaculation are frequently observed. Sexual disorders after stroke are thought to be due to multiple etiologies, including both organic (i.e., lesion localization, premorbid medical conditions, and medications) and psychosocial (i.e., fear of recurrences, loss of self-esteem, role changes, anxiety, and depression). Thus, exploration in sexual dysfunctions and sexual counseling by trained professionals should be a part of stroke rehabilitation. The aim of this review is to evaluate the burden of stroke on sexual function taking into account the complex interaction between neurological, psychological, and relational factors. PMID- 21790510 TI - The translation of product concept to bone products: a partnership of therapeutic effectiveness and commercialization. AB - The fields of tissue engineering and regenerative medicine have the capacity to substantially impact clinical care through the introduction of new products that can address unmet clinical needs, or significantly improve on present therapies. These products will be developed through the demonstration of therapeutic effectiveness, adequate safety, and meeting regulatory requirements. The technology used in the product will dictate the product development and manufacturing costs; the regulatory pathway; and the time taken to complete clinical trials, gain regulatory approval, and become commercialized. A comparison of the required investment of time and funds, with the potential revenue generated, allows for a determination of the likely commercialization opportunity. Ultimately, the long-term success of a product will be dependent on its clinical effectiveness and commercial viability. PMID- 21790511 TI - Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects. AB - INTRODUCTION: Over the past few decades, the domain of drug formulations has metamorphosed from the conventional tablets and capsules to advanced and intricate drug delivery systems (DDS), both temporal and spatial. Formulation development of the oral DDS, accordingly, cannot be adequately accomplished using the traditional 'trial and error' approaches of one variable at a time. This calls for the adoption of rational, systematized, efficient and cost-efficient strategies using 'design of experiments (DoE)'. The recent regulatory guidelines issued by the key federal agencies to practice 'quality by design (QbD)' paradigms have coerced researchers in industrial milieu, in particular, to use experimental designs during drug product development. AREAS COVERED: This review article describes these principles of DoE and QbD as applicable to drug delivery development using a more apt expression, that is, 'formulation by design (FbD)'. The manuscript describes the overall FbD methodology along with a summary of various experimental designs and their application in formulating oral DDS. The article also acts as a ready reckoner for FbD terminologies and methodologies. Select literature and an extensive FbD case study have been included to provide the reader with a comprehensive portrayal of the FbD precept. EXPERT OPINION: FbD is a holistic concept of formulation development aiming to design more efficacious, safe, economical and patient-compliant DDS. With the recent regulatory quality initiatives, implementation of FbD has now become an integral part of drug industry and academic research. PMID- 21790512 TI - Ultrasonic imaging technologies in perspective. AB - Ultrasonic imaging is a mature and widely used medical diagnostic technology but it is also a field of intense research activity. Innovations are viewed with differing perspectives by the stakeholders- users, industrialists, regulators, and researchers and research funders. The more important recent developments include advances in transducers, scanning schemes, coded excitation, three dimensional, high-resolution and high-speed imaging, contrast agents, harmonic, elasticity and strain imaging, point-of-care devices, computed tomography, thermoacoustic, photoacoustic, acousto-optic and Hall effect imaging. Viewed from diverse perspectives, the assessment of ultrasonic imaging technologies is intellectually challenging. This is a general problem, which demands a multidisciplinary approach. An emerging, integrated, context for such assessment is presented. Given the straitened economies around the world, the need to articulate value for each and all stakeholders is becoming increasingly important. PMID- 21790513 TI - Identification of a novel HLA-A allele, A*29:28, in an East African population. AB - The new allele is identical to A*29:01:01:01 in exons 2 and 3, except for a single-nucleotide substitution (TTG to TGG) at codon 156. PMID- 21790514 TI - Identification of a novel HLA-B*40 allele, B*40:162, in a Chinese individual. AB - The allele was identified in a Chinese individual by sequence-based typing. HLA B*40:162 differs from B*40: 06:01 by a single nucleotide at position 272 C->T in exon 2. PMID- 21790515 TI - Blockade of the axillary nerve. PMID- 21790516 TI - Absence of clinical and dermoscopic differences between congenital and noncongenital melanocytic naevi in a cohort of 2-year-old children. AB - BACKGROUND: Congenital melanocytic naevi (CMN) are present at birth. Some naevi, tardive congenital naevi (TCN), become clinically apparent only after birth, during the first years of life. The number of naevi continues to increase due to the appearance of acquired melanocytic naevi (AMN). When AMN begin to appear has not been well defined. OBJECTIVES: To investigate the clinical and dermoscopic features of the melanocytic naevi present in 2-year-old children and to search for and highlight any differences between CMN present at birth (BPN) and naevi appearing after birth during the first 2 years of life (FLN). METHODS: A nonrandomized observational study was performed. A total of 133 melanocytic naevi in 103 children aged 21-26 months were analysed by clinical and dermoscopic examination. RESULTS: Of the subjects, 76% of children had one naevus, 20% had two naevi, 3% had three naevi and 1% had four naevi. Of the naevi, 76 were BPN and 57 were FLN. The naevi with the largest diameters were significantly associated with BPN (P = 0.025). Polycyclic edges (P = 0.0378) were observed with a higher frequency in BPN than in FLN. The predominant dermoscopic patterns were globular (BPN 51%; FLN 58%) and reticular (BPN 28%; FLN 14%). CONCLUSIONS: The number of naevi present in the first 2 years of life is small, and over half have already appeared at birth. They are distributed widely over the skin. BPN are larger than FLN, but most naevi are small. There was no significant difference in the dermoscopic features between the 133 BPN and FLN. The predominant patterns were globular and reticular. We could not identify defined criteria that allowed us to diagnose CMN with certainty and distinguish them from TCN and AMN. PMID- 21790517 TI - Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1. AB - BACKGROUND: Psoriasis is a chronic, inflammatory skin disease associated with abnormal plasma lipid metabolism and with a high frequency of cardiovascular events. Modifications of plasma lipids and an increase in the levels of biochemical markers of lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, lipoproteins and oxidative damage. OBJECTIVES: To investigate further the relationship between lipoproteins and oxidative stress in psoriasis. METHOD: The levels of plasma lipids, lipoprotein(a) [Lp(a)] and markers of lipid peroxidation were evaluated in subjects with psoriasis (n=23) and in controls (n=25). In the same subjects, the activity of paraoxonase-1 (PON1), an antioxidant and an anti-inflammatory enzyme associated with high-density lipoproteins, was investigated. RESULTS: The results showed higher levels of Lp(a) in the serum of patients with psoriasis compared with controls (P<0.001). Higher levels of lipid hydroperoxides (P<0.001) and lower PON1 activity were observed in the serum of patients compared with healthy subjects, confirming that psoriasis is associated with oxidative stress. The imbalance between oxidative stress and antioxidant enzymes, and the increase of Lp(a) serum levels was related to the extent and severity of psoriasis. Finally, our results demonstrated that Lp(a) levels were positively correlated with markers of lipid peroxidation and negatively related to PON1 activity, suggesting that subjects with higher levels of Lp(a) are more exposed to oxidative damage. CONCLUSIONS: Our results provide further evidence that oxidative stress and impairment of the antioxidant system in the plasma of patients may play a role in pathogenesis and progression of psoriasis and related complications. PMID- 21790518 TI - A comparison of pudendal block vs dorsal penile nerve block for circumcision in children: a randomised controlled trial. AB - We compared the analgesic and anaesthetic efficacy of pudendal nerve block with that of dorsal penile nerve block in male patients aged 3-5 years of age, undergoing elective circumcision. Thirty patients had a nerve stimulator-guided pudendal nerve block with two separate injection points 1.5-2 cm from the centre of the anus, and thirty patients received a dorsal penile nerve block. The same total anaesthetic volume of 0.3 ml.kg(-1) was used in both groups. The pudendal nerve group showed significantly lower postoperative pain scores than the dorsal group (SD) (p < 0.05), and significantly fewer patients consumed analgesics in the pudendal group than the dorsal group: 0 vs 5 (17%) at 0 and 6 h, respectively. This study demonstrates the effectiveness of pudendal nerve block in comparison to the dorsal nerve block, with improved postoperative outcomes in children undergoing circumcision. PMID- 21790519 TI - Acute epidural haematoma following epidural steroid injection in a patient with spinal stenosis. AB - Extradural haematoma is a rare but known complication of neuraxial procedures. Although the literature quotes an incidence of 1:150,000 and 1:220,000 after epidural and spinal procedures, respectively, there is only a limited number of case reports described in pain practice. This case report describes an unusual occurrence of thoracic extradural haematoma following a lumbar epidural steroid injection. An entirely unique feature was its occurrence at a level distant to the site of injection, which has not been reported previously unless associated with catheterisation. We would like to highlight this report as it raises several pertinent and challenging questions; both for regional anaesthesia and pain practice. PMID- 21790520 TI - The prevalence and association with transfusion, intensive care unit stay and mortality of pre-operative anaemia in a cohort of cardiac surgery patients. AB - Anaemia is increasingly prevalent in the United Kingdom. Despite recommendations to the contrary, many patients undergo cardiac surgery with undiagnosed and untreated anaemia. According to the World Health Organization definition, 1463/2688 (54.4%) patients undergoing cardiac surgery between 2008 and 2009 in our institution were anaemic. Compared with non-anaemic patients, anaemia was significantly associated with transfusion (791 (54.1%) vs 275 (22.4%), p < 0.001, OR (95% CI) 3.4 (2.8-4.1)), death (45 (3.1%) vs 13 (1.1%), p = 0.0005, OR 2.4 (1.2-4.5)), and prolonged ICU stay (287 (19.6%) vs 168 (13.7%) p < 0.001, OR 1.3 (1.0-1.6)). The prevalence of anaemia in this cohort is much greater than that previously reported. The cause of this excess is not clear. Pre-operative anaemia is a strong predictor of increased transfusion requirement, risk of ICU stay and death during cardiac surgery. The effect of increasing haemoglobin concentration therapeutically is not yet clear. PMID- 21790521 TI - Critical incident reports concerning anaesthetic equipment: analysis of the UK National Reporting and Learning System (NRLS) data from 2006-2008*. AB - Anaesthetic equipment plays a central role in anaesthetic practice but brings the potential for malfunction or misuse. We aimed to explore the national picture by reviewing patient safety incidents relating to anaesthetic equipment from the National Reporting and Learning System for England and Wales between 2006 and 2008. We searched the database using the system's own classification and by scrutinising the free text of relevant incidents. There were 1029 relevant incidents. Of these, 410 (39.8%) concerned patient monitoring, most commonly screen failure during anaesthesia, failure of one modality or failure to transfer data automatically from anaesthetic room to operating theatre. Problems relating to ventilators made up 185 (17.9%) of the reports. Sudden failures during anaesthesia accounted for 142 (13.8%) of these, with a further 10 cases (0.9%) where malfunction caused a sustained or increasing positive pressure in the patient's airway. Leaks made up 99 (9.6%) of incidents and 53 (5.2%) of incidents arose from the use of infusion pumps. Most (89%) of the incidents caused no patient harm; only 30 (2.9%) were judged to have led to moderate or severe harm. Although equipment was often faulty, user error or unfamiliarity also played a part. A large variety of causes led to a relatively small number of clinical scenarios, that anaesthetists should be ready, both individually and organisationally, to manage even when the cause is not apparent. We make recommendations for enhancing patient safety with respect to equipment. You can respond to this article at http://www.anaesthesiacorrespondence.com. PMID- 21790522 TI - Evaluation of pre-procedure ultrasound examination as a screening tool for difficult spinal anaesthesia*. AB - We performed a pre-procedure ultrasound examination of the spine on 60 patients undergoing lower extremity orthopaedic surgery under spinal anaesthesia. We hypothesised that the inability to identify the posterior longitudinal ligament or vertebral body easily with ultrasound would be associated with difficulty placing a spinal anaesthetic. Clinicians blinded to the ultrasound scan performed the injections using the traditional landmark technique. The spinal procedure was videotaped and subsequently reviewed by independent investigators. We defined procedure difficulty by total procedure time (> 400 s) and number of needle passes (>= 10) required to achieve return of cerebrospinal fluid, or abandonment of the procedure due to unsuccessful dural puncture. When images of the posterior longitudinal ligament were poor (low score group), the mean (SD) number of passes was 21.2 (30.6), compared with 4.8 (7.5) with good ultrasound images (high score group) (p < 0.01). The mean (SD) time for placement was 420 (300) s in the low score group vs 176 (176) s in the high score group (p < 0.01). You can respond to this article at http://www.anaesthesiacorrespondence.com. PMID- 21790523 TI - Transgrediens pachyonychia congenita (PC): case series of a nonclassical PC presentation. AB - BACKGROUND: Pachyonychia congenita (PC) is a rare keratin disorder that typically presents with nail dystrophy and focal plantar keratoderma. We present seven cases of PC with transgrediens involvement of the dorsal feet. OBJECTIVES: To document the extension of their disease to the dorsum of the feet in patients with mutation-confirmed PC, to report the natural history of PC with such transgrediens involvement, to generate hypotheses regarding aetiology, and to suggest prevention and treatment modalities. METHODS: Genetically confirmed cases of PC with transgrediens foot involvement were verified through the International Pachyonychia Congenita Research Registry (IPCRR) and characterized via telephone survey and photography. RESULTS: Seven patients with PC in the IPCRR were confirmed to have transgrediens lesions on the dorsal feet (six KRT6A mutations; one KRT16 mutation). Six cases had pre-existing nontransgrediens keratoderma and all cases reported standing, wearing shoes, foot moisture, and/or infection as exacerbating or predisposing factors. Improvement, reported in six cases, was attributed to use of antibiotics or gentian violet, or improved footwear. CONCLUSIONS: Transgrediens involvement of the dorsal feet is a rare manifestation of mutation-confirmed PC and may be more common in patients who carry a KRT6A mutation. Trauma, friction, infection and wound healing may exacerbate or predispose toward transgrediens lesions. It remains to be proven whether transgrediens-associated infection is causal or represents a primary or secondary process. Patients with PC who develop transgrediens lesions may benefit from fungal and bacterial cultures, followed by appropriate antimicrobial treatments. Efforts to decrease skin friction and moisture may also improve and/or prevent transgrediens spread. PMID- 21790524 TI - Genetic variants and monoallelic expression of surfactant protein-D in inflammatory bowel disease. AB - Surfactant protein-D (SP-D) is expressed on mucosal surfaces and functions in the innate immune response to microorganisms. We studied the genetic association of the two nonsynonymous SP-D single nucleotide polymorphisms (SNPs) rs721917 and rs2243639 in 256 inflammatory bowel disease (IBD) cases (123 CD and 133 UC) and 376 unrelated healthy individuals from an IBD population from Central Pennsylvania. Case-control analysis revealed a significant association of rs2243639 with susceptibility to Crohn's disease (CD) (p= 0.0036), but not ulcerative colitis (UC) (p= 0.883), and no association of rs721917 with CD (p= 0.328) or UC (p= 0.218). Using intestinal tissues from 19 individuals heterozygous for each SNP, we compared allelic expression of these two SNPs between diseased and matched normal tissues. rs2243639 exhibited balanced biallelic (BB) expression; while rs721917 exhibited differential allelic expression (BB 37%, imbalanced biallelic [IB] 45%, and dominant monoallelic [DM] 18%). Comparison of allelic expression pattern between diseased and matched normal tissues, 13 of 19 individuals (14 UC, 5 CD) showed a similar pattern. The six patients exhibiting a different pattern were all UC patients. The results suggest that differential allelic expression may affect penetrance of the SNP rs721917 disease-susceptibility allele in IBD. The potential impact of SP-D monoallelic expression on incomplete penetrance is discussed. PMID- 21790525 TI - Repigmentation of leucotrichia in vitiligo with noncultured cellular grafting. AB - BACKGROUND: Vitiligo in hair-bearing areas is often associated with leucotrichia. Repigmentation of leucotrichia has been reported mainly with tissue and follicular hair grafts. OBJECTIVES: To evaluate the repigmentation response of leucotrichia after noncultured cellular grafting. METHODS: We retrospectively reviewed patients with stable generalized and segmental vitiligo who underwent noncultured cellular grafting from March 2008 to November 2010 in areas with leucotrichia. The percentage repigmentation of white hairs was based on clinical assessment and standardized digital photography, and was graded 'poor', 'fair', 'good' or 'excellent', corresponding to a scale of 0-100% repigmentation with respective intervals of 25%. RESULTS: Eighty-four patients with vitiligo underwent cellular grafting; of these, 13 had grafting in areas with leucotrichia. Twelve patients (92%) had poor repigmentation of leucotrichia 3 months after transplant. One patient defaulted follow-up after this period. At 6months, fair repigmentation was achieved in eight out of the 12 remaining patients (67%). After 9-12months, however, 91% (10 out of 11) of the patients achieved good or excellent repigmentation. One patient did not reach the 9-month follow-up period at the time of data analysis. Leucotrichia of eyebrows yielded excellent repigmentation in eight out of nine patients, whereas hairs on the limbs and scalp showed good repigmentation in two out of two patients at 9-12 months. CONCLUSIONS: Good to excellent repigmentation of leucotrichia can be achieved with noncultured cellular grafting, obviating the need for hair transplantation. PMID- 21790526 TI - Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis. AB - BACKGROUND: Loss-of-function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients' susceptibility to recurrent skin infection. OBJECTIVES: To investigate the association between FLG-null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. METHODS: This study included 228 Singaporean Chinese patients with AD with at least 1year of follow up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG-null mutations. RESULTS: Compared with those without the FLG-null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6.74; 95% confidence interval 2.29 19.79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. CONCLUSION: This study highlights a novel association between FLG-null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD. PMID- 21790527 TI - Guidelines for the laboratory investigation of heritable disorders of platelet function. AB - The guideline writing group was selected to be representative of UK-based medical experts. MEDLINE was systematically searched for publications in English up to the Summer of 2010 using key words platelet, platelet function testing and platelet aggregometry. Relevant references generated from initial papers and published guidelines/reviews were also examined. Meeting abstracts were not included. The writing group produced the draft guideline, which was subsequently revised and agreed by consensus. Further comment was made by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 40 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in appendix 7 of the Procedure for Guidelines Commissioned by the BCSH [http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMME DATION/43_GRADE.html]. The objective of this guideline is to provide healthcare professionals with clear guidance on platelet function testing in patients with suspected bleeding disorders. The guidance may not be appropriate to patients receiving antiplatelet therapy and in all cases individual patient circumstances may dictate an alternative approach. PMID- 21790528 TI - Array-based DNA methylation profiling in acute myeloid leukaemia. AB - Methylation in the promoter region of many genes is involved in regulating gene expression patterns. Using the Illumina GoldenGate(c) methylation assay, we examined the methylation status of 1505 CpG-sites from 807 genes in 32 samples from patients with acute myeloid leukaemia (AML) at diagnosis, nine at relapse and 15 normal controls and performed additional pyrosequencing and semiquantitative methylation specific polymerase chain reaction (MSP) of the GNMT promoter in 113 diagnostic AML samples. We found a gain of overall methylation in AML samples with a further increase at relapse. Regional hypermethylation as assessed by array analysis could be confirmed by both MSP and pyrosequencing. Additionally, large-scale methylation analysis identified interesting candidate genes. Cluster analysis indicated that cytogenetic subgroups seemed to be characterized by additional distinct epigenetic modifications and that basic DNA methylation patterns remain at relapse. Therefore, promoter hypermethylation is a frequent event in AML and is accentuated at relapse. Array-based methylation analysis determined distinct methylation profiles for non-malignant controls and AML samples with specific chromosomal aberrations and can identify target genes for further evaluation. PMID- 21790529 TI - Visceral leishmaniasis after alemtuzumab in a patient with chronic lymphocytic leukaemia. PMID- 21790530 TI - BIOMED-2 PCR assays for IGK gene rearrangements are essential for B-cell clonality analysis in follicular lymphoma. AB - B-cell clonality analysis is commonly performed by polymerase chain reaction (PCR) targeting the IGH genes although a high false-negative rate is recognized for germinal centre/post-germinal centre B-cell malignancies, especially follicular lymphoma. We assessed the diagnostic value of BIOMED-2 IGK assays and investigated the cause of IGH PCR failure in 77 patients with follicular lymphoma. Using the full set of BIOMED-2 reactions, clonal immunoglobulin gene rearrangements were detected in 74 (96%) cases. The clonality detection rate was 86% by two IGK reactions but only 68% by five IGH reactions (P < 0.001). Sequencing of the clonal PCR products showed significantly fewer somatic mutations in the rearranged IGKV (9/27 cases, 33%, mean mutation rate 0.5%) than IGHV (17/17 cases, 100%, rate 11.0%) (P < 0.01). All IGHV-IGHJ PCR failures occurred in cases with at least one mutation at the corresponding IGHV primer binding sites. t(14:18)(q32:q21)/IGH-BCL2 was detected in 50 of 71 (70%) cases and the presence of the translocation was not associated with the poor performance of IGH assays. Our results showed that BIOMED-2 IGK assays are significantly more sensitive than IGH assays in follicular lymphoma due to the fact that the rearranged IGKV is less frequently targeted by somatic hypermutation than IGHV, and therefore, are essential in routine clonality analysis of these lymphomas. PMID- 21790531 TI - Imaging--the interface with pharmacology: looking to the future. AB - Basic research is constantly adopting novel, innovative and powerful approaches to enable a deeper interrogation of the specific subject matter. A clear example of this strategy is the development of multiple imaging modalities, both in vitro and in vivo based, that have revolutionized medical research, drug discovery, diagnosis and clinical monitoring. In this themed section of the British Journal of Pharmacology, we highlight a number of imaging platforms which are discussed in relation to their applicability for pharmacological experiments, including longitudinal studies. As such, the authors endeavour to describe the technology, its limitations and how these approaches can complement pharmacological research. In addition, there is discussion of the role of pharmacological imaging from a clinical perspective. PMID- 21790532 TI - Acute alcohol intoxication reduces mortality, inflammatory responses and hepatic injury after haemorrhage and resuscitation in vivo. AB - BACKGROUND AND PURPOSE: Haemorrhagic shock and resuscitation (H/R) induces hepatic injury, strong inflammatory changes and death. Alcohol intoxication is assumed to worsen pathophysiological derangements after H/R. Here, we studied the effects of acute alcohol intoxication on survival, liver injury and inflammation after H/R, in rats. EXPERIMENTAL APPROACH: Rats were given a single oral dose of ethanol (5 g.kg(-1) , 30%) or saline (control), 12 h before they were haemorrhaged for 60 min and resuscitated (H/R). Sham groups received the same procedures without H/R. Measurements were made 2, 24 and 72 h after resuscitation. Survival was assessed 72 h after H/R. KEY RESULTS: Ethanol increased survival after H/R three-fold and also induced fatty changes in the liver. H/R-induced liver injury was amplified by ethanol at 2 h but inhibited 24 h after H/R. Elevated serum IL-6 levels as well as hepatic IL-6 and TNF-alpha gene expression 2 h after H/R were reduced by ethanol. Ethanol enhanced serum IL 1beta at 2 h, but did not affect increased hepatic IL-1beta expression at 72 h after H/R. Local inflammatory markers, hepatic infiltration with polymorphonuclear leukocytes and intercellular adhesion molecule 1 expression decreased after ethanol compared with saline, following H/R. Ethanol reduced H/R induced IkappaBalpha activation 2 h after H/R, and NF-kappaB-dependent gene expression of MMP9. CONCLUSIONS AND IMPLICATIONS: Ethanol reduced H/R-induced mortality at 72 h, accompanied by a suppression of proinflammatory changes after H/R in ethanol-treated animals. Binge-like ethanol exposure modulated the inflammatory response after H/R, an effect that was associated with NF-kappaB activity. PMID- 21790534 TI - Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword? AB - Statins are best-selling medications in the management of high cholesterol and associated cardiovascular complications. They inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase in order to prevent disproportionate cholesterol synthesis. Statins slow the progression of atherosclerosis, prevent the secondary cardiovascular events and improve the cardiovascular outcomes in patients with elevated cholesterol levels. The underlying mechanisms pertaining to the cardioprotective role of statins are linked with numerous pleiotropic actions including inhibition of inflammatory events and improvement of endothelial function, besides an effective cholesterol-lowering ability. Intriguingly, recent studies suggest possible interplay between statins and nuclear transcription factors like PPARs, which should also be taken into consideration while analysing the potential of statins in the management of cardiovascular complications. It could be suggested that statins have two major roles: (i) a well-established cholesterol-lowering effect through inhibition of HMG-CoA-reductase; (ii) a newly explored PPAR-activating property, which could mediate most of cardiovascular protective pleiotropic effects of statins including anti-inflammatory, antioxidant and anti-fibrotic properties. The present review addressed the underlying principles pertaining to the modulatory role of statins on PPARs. PMID- 21790533 TI - Pharmacological characterization of native alpha7 nicotinic ACh receptors and their contribution to depolarization-elicited exocytosis in human chromaffin cells. AB - BACKGROUND AND PURPOSE: Expression of alpha7 nicotinic acetylcholine receptors (nAChRs) and their role in exocytosis have not yet been examined in human chromaffin cells. EXPERIMENTAL APPROACH: To characterize these receptors and investigate their function, patch-clamp experiments were performed in human chromaffin cells from organ donors. KEY RESULTS: The nicotinic current provoked by 300uM ACh in voltage-clamped cells was blocked by the nicotinic receptor antagonists alpha-bungarotoxin (alpha-Bgtx; 1uM; 6 +/- 1.7%) or methyllycaconitine (MLA; 10nM; 7 +/- 1.6%), respectively, in an irreversible and reversible manner, without affecting exocytosis. Choline (10mM) pulses induced a biphasic current with an initial quickly activated (5.5 +/- 0.4ms rise time) and inactivated component (8.5 +/- 0.4ms time constant) (termed alpha7), which was blocked by alpha-Bgtx or MLA, followed by a slower component (non-alpha7). alpha7 nAChR currents were dissected by blocking the non-alpha7 nAChR current component of the ACh and choline response with the alpha6* nAChR blocker alpha-conotoxin (alpha-Ctx) MII[S4A, E11A, L15A]. PNU-282987, an alpha7 nAChR-specific agonist, elicited rapidly activated and rapidly inactivated currents. alpha7 nAChR positive allosteric modulators, such as 5-hydroxyindole (1mM) and PNU-120596 (10uM), potentiated responses that were blocked by alpha-Bgtx or MLA. Exocytosis was evoked by depolarization-elicited alpha7 nAChR currents, using choline in the presence of alpha-Ctx MII[MS4A, E11A, L15A] or PNU-282987 as agonists. CONCLUSIONS AND IMPLICATIONS: Our electrophysiological recordings of pure alpha7 nAChR currents elicited by rapid application of agonists demonstrated that functional alpha7 nAChRs are expressed and contribute to depolarization-elicited exocytosis in human chromaffin cells. PMID- 21790535 TI - The intestinal anti-inflammatory effect of dersalazine sodium is related to a down-regulation in IL-17 production in experimental models of rodent colitis. AB - BACKGROUND AND PURPOSE: Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR-12715) with 5-aminosalicylic acid (5-ASA). DS has been demonstrated to have anti-inflammatory effects on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti-inflammatory effects of DS. EXPERIMENTAL APPROACH: Effect of DS (10 or 30 mg.kg(-1) b.i.d.) on TNBS-induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti-inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)-induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL-17. KEY RESULTS: DS, when administered for 7 days, showed intestinal anti-inflammatory effects in TNBS-induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL-1beta, IL-6 and IL-17). Although the 2 day treatment with DS did not induce intestinal anti-inflammatory effects, it was sufficient to reduce the enhanced IL-17 expression. DS showed beneficial effects on DSS-induced colitis in C57BL/6 mice and reduced colonic pro-inflammatory cytokines IL-1beta, IL-6 and IL 17. In contrast, it did not exert intestinal anti-inflammatory effects on DSS induced colitis in BALB/c mice. CONCLUSIONS AND IMPLICATIONS: DS exerts intestinal anti-inflammatory activity in different rodent models of colitis through down-regulation of IL-17 expression. PMID- 21790536 TI - Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence. AB - BACKGROUND AND PURPOSE: Oxidative stress plays a critical role in liver fibrogenesis. Reactive oxygen species (ROS) stimulate hepatic stellate cells (HSCs), and ROS-mediated increases in calcium influx further increase ROS production. Azelnidipine is a calcium blocker that has been shown to have antioxidant effects in endothelial cells and cardiomyocytes. Therefore, we evaluated the anti-fibrotic and antioxidative effects of azelnidipine on liver fibrosis. EXPERIMENTAL APPROACH: We used TGF-beta1-activated LX-2 cells (a human HSC line) and mouse models of fibrosis induced by treatment with either carbon tetrachloride (CCl(4) ) or thioacetamide (TAA). KEY RESULTS: Azelnidipine inhibited TGF-beta1 and angiotensin II (Ang II)-activated alpha1(I) collagen mRNA expression in HSCs. Furthermore, TGF-beta1- and Ang II-induced oxidative stress and TGF-beta1-induced p38 and JNK phosphorylation were reduced in HSCs treated with azelnidipine. Azelnidipine significantly decreased inflammatory cell infiltration, pro-fibrotic gene expressions, HSC activation, lipid peroxidation, oxidative DNA damage and fibrosis in the livers of CCl(4) - or TAA-treated mice. Finally, azelnidipine prevented a decrease in the expression of some antioxidant enzymes and accelerated regression of liver fibrosis in CCl(4) -treated mice. CONCLUSIONS AND IMPLICATIONS: Azelnidipine inhibited TGF-beta1- and Ang II induced HSC activation in vitro and attenuated CCl(4) - and TAA-induced liver fibrosis, and it accelerated regression of CCl(4) -induced liver fibrosis in mice. The anti-fibrotic mechanism of azelnidipine against CCl(4) -induced liver fibrosis in mice may have been due an increased level of antioxidant defence. As azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti-fibrotic therapy. PMID- 21790538 TI - Preschoolers' use of morphosyntactic cues to identify generic sentences: indefinite singular noun phrases, tense, and aspect. AB - Generic sentences (e.g., "Birds lay eggs") convey generalizations about entire categories and may thus be an important source of knowledge for children. However, these sentences cannot be identified by a simple rule, requiring instead the integration of multiple cues. The present studies focused on 3- to 5-year olds' (N = 91) use of morphosyntactic cues--in particular, on whether children can (a) interpret indefinite singular noun phrases (e.g., "a strawberry") as generic and (b) use a verb's tense and aspect (e.g., "A bat sleeps/slept/is sleeping upside down") to determine whether its subject noun phrase is generic. Children demonstrated sensitivity to both cues. Thus, solving the in-principle problem of identifying generics may not be beyond the reach of young children's comprehension skills. PMID- 21790537 TI - Molecular and functional characterization of the human platelet Na(+) /Ca(2+) exchangers. AB - BACKGROUND AND PURPOSE The Na(+) /Ca(2+) exchanger is a bi-directional transporter that plays an important role in maintaining the concentration of cytosolic Ca(2+) ([Ca(2+) ](i) ) of quiescent platelets and increasing it during activation with some, but not all, agonists. There are two classes of Na(+) /Ca(2+) exchangers: K(+) -independent Na(+) /Ca(2+) exchanger (NCX) and K(+) dependent Na(+) /Ca(2+) exchanger (NCKX). Platelets have previously been shown to express NCKX1. However, initial studies from our laboratory suggest that NCX may also play a role in platelet activation. The objective of this study was to determine if the human platelet expresses functional NCXs. EXPERIMENTAL APPROACH RT-PCR, DNA sequencing and Western blot analysis were utilized to characterize the human platelet Na(+) /Ca(2+) exchangers. Their function during quiescence and collagen-induced activation was determined by measuring [Ca(2+) ](i) with calcium-green/fura-red in response to: changes in the Na(+) and K(+) gradient, NCX pharmacological inhibitors (CBDMB, KB-R7943 and SEA0400) and antibodies specific to extracellular epitopes of the exchangers. KEY RESULTS Human platelets express NCX1.3, NCX3.2 and NCX3.4. The NCXs operate in the Ca(2+) efflux mode in resting platelets and also during their activation with thrombin but not collagen. Collagen-induced increase in [Ca(2+) ](i) was reduced with the pharmacological inhibitors of NCX (CBDMB, KB-R7943 or SEA0400), anti-NCX1 and anti-NCX3. In contrast, anti-NCKX1 enhanced the collagen-induced increase in [Ca(2+) ](i) . CONCLUSIONS AND IMPLICATIONS Human platelets express K(+) independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. During collagen activation, NCX1 and NCX3 transiently reverse to promote Ca(2+) influx, whereas NCKX1 continues to operate in the Ca(2+) efflux mode to reduce [Ca(2+) ](i) . PMID- 21790539 TI - Shyness-sensitivity and unsociability in rural Chinese children: relations with social, school, and psychological adjustment. AB - The purpose of this study was to examine how shyness-sensitivity and unsociability were associated with social, school, and psychological adjustment in rural Chinese children. Participants were third- to fifth-grade students (N = 820; M age = 10 years) in rural schools in P. R. China. Data on shyness sensitivity, unsociability, and adjustment were obtained from multiple sources including peer assessments, sociometric nominations, teacher ratings, self reports, and school records. It was found that unsociability was associated with social, school, and psychological problems, whereas shyness was generally associated with indexes of adjustment such as social status, teacher-rated competence, and academic achievement. The results indicate that rural Chinese context may play an important role in defining the functional meanings of children's social behaviors. PMID- 21790540 TI - Wherein lies children's intergroup bias? Egocentrism, social understanding, and social projection. AB - Does children's bias toward their own groups reflect egocentrism or social understanding? After being categorized as belonging to 1 of 2 fictitious groups, 157 six- to ten-year-olds evaluated group members and expressed preferences among neutral items. Children who expected the in-group to share their item preferences (egocentric social projection) showed intergroup bias. However, most bias was expressed by children who expected their in-group to share, but the out-group to oppose, their own evaluations of members. These oppositional expectations were associated with better social perspective taking, and better understanding that groups expect loyalty from their members. Consistent with the developmental model of subjective group dynamics (D. Abrams, A. Rutland, J. Pelletier, & J. M. Ferrell, 2009), social understanding, rather than egocentrism, provides a more parsimonious explanation of children's intergroup bias. PMID- 21790541 TI - Characterizing children's expectations about expertise and incompetence: halo or pitchfork effects? AB - Do children expect an expert in one domain to also be an expert in an unrelated domain? In Study 1, 32 three- and four-year-olds learned that one informant was an expert about dogs relative to another informant. When presented with pictures of new dogs or of artifacts, children who could remember which informant was the dog expert preferred her over the novice as an informant about the names of dogs, but they had no preference when the informants presented artifact labels. In Study 2, 32 children learned that one informant was incompetent about dogs whereas another was neutral. In this case, children preferred the neutral speaker over the incompetent one about both dogs and artifacts. Taken together, these results suggest that for children, expertise is not subject to a "halo effect," but incompetence may be subject to a "pitchfork effect." PMID- 21790542 TI - Can children with autism spectrum disorders "hear" a speaking face? AB - This study used eye-tracking methodology to assess audiovisual speech perception in 26 children ranging in age from 5 to 15 years, half with autism spectrum disorders (ASD) and half with typical development. Given the characteristic reduction in gaze to the faces of others in children with ASD, it was hypothesized that they would show reduced influence of visual information on heard speech. Responses were compared on a set of auditory, visual, and audiovisual speech perception tasks. Even when fixated on the face of the speaker, children with ASD were less visually influenced than typical development controls. This indicates fundamental differences in the processing of audiovisual speech in children with ASD, which may contribute to their language and communication impairments. PMID- 21790544 TI - Lichen striatus and nail involvement: truly rare or question of time? PMID- 21790543 TI - Examining the Black-White achievement gap among low-income children using the NICHD study of early child care and youth development. AB - The Black-White achievement gap in children's reading and mathematics school performance from 41/2 years of age through fifth grade was examined in a sample of 314 lower income American youth followed from birth. Differences in family, child care, and schooling experiences largely explained Black-White differences in achievement, and instructional quality was a stronger predictor for Black than White children. In addition, the achievement gap was detected as young as 3 years of age. Taken together, the findings suggest that reducing the Black-White achievement gap may require early intervention to reduce race gaps in home and school experiences during the infant and toddler years as well as during the preschool and school years. PMID- 21790545 TI - Morris-Coole Epilepsia Prize - 2010. PMID- 21790546 TI - Seizure outcome and its predictors after temporal lobe epilepsy surgery in patients with normal MRI. AB - PURPOSE: To characterize seizure outcomes following temporal lobe epilepsy (TLE) surgery in patients with normal preoperative brain magnetic resonance imaging (MRI). METHODS: We reviewed adult patients with pharmacoresistant epilepsy and normal MRI who underwent TLE surgery (1996-2009). Seizure outcomes were analyzed using survival and multivariate regression with Cox proportional hazard modeling. Two analyses were performed using two favorable outcome definitions: complete seizure freedom and Engel classification. KEY FINDINGS: Sixty-four patients were analyzed (mean follow-up 4.1 years; range 1-14.5 years). Most had a standard anterior temporal lobectomy (84%) and unremarkable pathology (45%). At 1 year, the chance of complete seizure freedom was 76% [95% confidence interval (CI) 71 81%] comparable to an 81% (95% CI 76-86%) chance of Engel score of 1. With longer follow-up, a progressively broadening significant discrepancy between the two outcome measures was observed. The chance of complete seizure freedom was 66% (95% CI 61-71%) at 2 years, and 47% (95% CI 40-54%) at 7 years and beyond, whereas the respective chances of achieving an Engel 1 classification were 76% (95% CI 70-82%), and 69% (95% CI 63-75%) at similar time points. Seizure outcome as defined by either measure was worse in patients with higher baseline seizure frequency (adjusted risk-ratio 2.7 when >12 seizures/month; p = 0.01) and with preoperative generalized tonic-clonic seizures (adjusted risk ratio 10.8; p = 0.0006). Memory measures declined with dominant hippocampus resections. SIGNIFICANCE: A normal MRI should not prevent presurgical evaluations in patients with suspected TLE, as favorable long-term postoperative seizure outcomes are possible. Proposed mechanisms of epileptogenicity and seizure recurrence in this group are discussed. PMID- 21790548 TI - A case of cutaneous type pemphigus vulgaris. PMID- 21790547 TI - Breakthrough disseminated fusariosis in an immunocompromised patient on voriconazole therapy. PMID- 21790549 TI - Brucellosis presenting as septal panniculitis with vasculitis. PMID- 21790551 TI - Eosinophilic pustular folliculitis (Ofuji's disease) without macroscopic pustules. AB - BACKGROUND: Eosinophilic pustular folliculitis (EPF), first described by Ofuji et al. in 1970, is a rare dermatosis characterized by pruritic papules and pustules on circinate erythematous plaques with eosinophilic infiltration in and around the hair follicle. METHODS AND RESULTS: We report three cases of EPF that showed no macroscopic pustules during the total observation period. Histopathological examination revealed eosinophilic infiltration in and around the hair follicle in the lower dermis and subcutis. CONCLUSIONS: EPF consists of clinical variants, one of which lacks obvious pustules. PMID- 21790550 TI - The antiproliferative function of violacein-like purple violet pigment (PVP) from an Antarctic Janthinobacterium sp. Ant5-2 in UV-induced 2237 fibrosarcoma. AB - BACKGROUND: In this study, we have investigated the chemotherapeutic potential of a purple violet pigment (PVP), which was isolated from a previously undescribed Antarctic Janthinobacterium sp. (Ant5-2), against murine UV-induced 2237 fibrosarcoma and B16F10 melanoma cells. METHODS: The 2237, B16F10, C50, and NIH3T3 cells were treated with PVP at different doses and for different times, and their proliferation and viability were detected by 3-[4,5-dimethylthiazol-2 yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle arrest induced by PVP in 2237 fibrosarcoma cells was assessed by flow cytometry and expression analysis of cell cycle regulatory proteins were done by Western blot. Apoptosis induced by PVP in 2237 cells was observed by annexin-V/propidium iodide double staining flow cytometry assay and fluorescence microscopy. To further determine the molecular mechanism of apoptosis induced by PVP, the changes in expression of Bcl-2, Bax and cytochrome c were detected by Western blot. The loss of mitochondrial membrane potential in PVP treated 2237 cells was assessed by staining with JC-1 dye following flow cytometry. Caspase-3, Caspase-9 and PARP cleavage were analyzed by Western blot and Caspase-3 and -9 activities were measured by colorimetric assays. RESULTS: In vitro treatment of murine 2237 cells with the PVP resulted in decreased cell viability (13-79%) in a time (24-72 h) and dose (0.1-1 MUM)-dependent manner. The PVP-induced growth inhibition in 2237 cells was associated with both G0/G1 and G2/M phase arrest accompanied with decrease in the expression of cyclin dependent kinases (Cdks) and simultaneous increase in the expression of cyclin dependent kinase inhibitors (Cdki) - Cip1/p21 and Kip1/p27. Further, we observed a significant increase in the apoptosis of the 2237 fibrosarcoma cells which was associated with an increased expression of pro apoptotic protein Bax, decreased expression of anti-apoptotic proteins Bcl-2, disruption of mitochondrial membrane potential, cytochrome c release, activation of caspase-3, caspase-9 and poly-ADP-ribose-polymerase (PARP) cleavage. CONCLUSIONS: We describe the anti-cancer mechanism of the PVP for the first time from an Antarctic bacterium and suggest that the PVP could be used as a potent chemotherapeutic agent against nonmelanoma skin cancers. PMID- 21790552 TI - Nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. AB - BACKGROUND: Renal transplantation is associated with an increased incidence of nonmela-noma skin cancer (NMSC) caused by immunosuppression. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the two major histological types of NMSC, exhibit more aggressive biological and clinical courses in renal transplant recipients (RTRs), with higher rates of recurrence and mortality than in the general population. METHODS: We retrospectively analyzed our experience of NMSC in 1736 renal transplantations performed over a 25-year period. All cases of skin cancer after renal transplantation were included except those of skin cancer resulting from melanoma and mesenchymal skin tumors. RESULTS: In our series, the overall incidence of NMSC after transplantation was 2.2% (n = 39), and SCC represented the most frequent skin malignancy (64.1%), followed by BCC (17.9%), Bowen's disease (10.2%), basosquamous carcinoma (5.1%), and a rare case of invasive sebaceous carcinoma (2.6%). A shift to newer immunosuppressive regimens after the initial diagnosis of NMSC had been implemented in eight cases (20.5%). The recurrence rate after initial treatment was 41% (n = 16), and distant metastatic disease was diagnosed in 15.4% (n = 6) of NMSC patients. The NMSC specific mortality rate was 25.6% (n = 10). CONCLUSIONS: Nonmelanoma skin cancer remains a significant source of morbidity and mortality in RTRs, and post transplant surveillance should be increased. PMID- 21790553 TI - Anti-laminin 5 pemphigoid: a case report of a benign cutaneous confined non cicatricial variant. PMID- 21790554 TI - A case of mucosal leishmaniasis of the tongue in a kidney transplant recipient. PMID- 21790555 TI - Lyngbya dermatitis (toxic seaweed dermatitis). AB - Lyngbya dermatitis is an irritant contact dermatitis caused by the blue-green alga (or cyanobacterium), Lyngbya majuscula, commonly found in tropical and temperate waters worldwide. Lesions generally appear in a bathing suit distribution minutes to hours after exposure, initially with itching or burning, evolving into a blistering eruption which eventually desquamates leaving bright red, tender erosions that resolve spontaneously in about a week. Our case is of a 13-year-old female that presented with haphazard clusters of reddish-brown vesicles and papules on her abdomen one day after swimming in rough surf conditions on the shores of Oahu, Hawaii. Histopathological examination revealed an acute irritant contact dermatitis consistent with Lyngbya dermatitis. L. majuscule, with its wealth of biologically active compounds, should be a consideration in any patient presenting with an acute irritant contact dermatitis following temperate saltwater exposure. PMID- 21790556 TI - Negative modulation of bone morphogenetic protein signaling by Dullard during wing vein formation in Drosophila. AB - Studies in Xenopus have shown that the C-terminal domain phosphatase-like domain (CPD) phosphatase Dullard is essential for proper neural development via inhibition of bone morphogenetic protein (BMP) signaling receptors. In contrast, the orthologous budding yeast Nem1 and human Dullard have been shown to dephosphorylate the phosphatidate phosphatases yeast Smp2/Pah1 and human Lipin, and the relationship between phospholipid metabolism and BMP signaling remain unsolved. Here we report evidence that the Dullard-Lipin phosphatase cascade in Drosophila can regulate BMP signaling, most likely by affecting the function of the nuclear envelope. Manipulating expression levels of either the Drosophila Dullard gene, d-dullard (ddd) or the Lipin gene, DmLpin affected wing vein formation in a manner suggesting a negative effect on BMP signaling. Furthermore, both genes exhibit genetic interaction with BMP signaling pathway components, and can affect the levels of phosphorylated-Mothers against dpp (p-Mad). Although changing ddd expression levels did not have an obvious effect on overall nuclear envelope morphology as has been shown for yeast nem1, the nuclear import machinery components Importin-beta and RanGAP were mislocalized and membrane lipid staining was altered in cells overexpressing ddd. Considering the known genetic interaction between Nup84 complex nucleoporins and nem1 in yeast, and the recently reported requirement for components from the orthologous nucleoporin complex in the nuclear translocation of Drosophila Mad (Chen & Xu 2010), it is likely that the role of Drosophila Dullard in regulating membrane lipid homeostasis is conserved and is critical for normal BMP signaling. PMID- 21790557 TI - Coordination of fingertip forces in object transport during gait in children with hemiplegic cerebral palsy. PMID- 21790559 TI - Introduction: Transitioning care for adults with Lennox-Gastaut syndrome: challenges and promises. PMID- 21790560 TI - Definition and natural history of Lennox-Gastaut syndrome. AB - Lennox-Gastaut syndrome (LGS) is a rare epileptic encephalopathy with a peak age of onset of 3-5 years of age. Reported prevalence rates for LGS vary widely from 1-10% of all childhood epilepsies. Incidence rates are much lower. LGS is characterized by intractable, multiple, generalized seizure types and an interictal electroencephalogram showing bursts of slow spike-and-wave, paroxysmal bursts of generalized polyspikes, and a slow background. All patients have tonic seizures during sleep that may be subtle, and nearly all have treatment resistant, lifelong epilepsy. Cognitive stagnation and behavioral problems are seen in almost all patients and lead to a life of dependency. The differential diagnosis includes other symptomatic generalized epilepsies and pseudo-Lennox syndrome. Misdiagnosis is common. Children and adults with LGS have an enormous impact on their families, and efforts to improve the quality of life for these patients are complex. PMID- 21790561 TI - Rational approach to treatment options for Lennox-Gastaut syndrome. AB - Lennox-Gastaut syndrome (LGS) is an intractable childhood-onset epileptic encephalopathy. Seizure freedom is rare in LGS. One of the hallmarks of LGS is medical intractability, with generally poor response to antiepileptic drugs (AEDs). Nevertheless, several treatment options are available that can mitigate the severity of seizures and curtail their frequency. New AEDs have been validated in randomized, controlled trials for the treatment of seizures in LGS. In some cases, nonpharmacologic options may be effective, although more data are needed to confirm efficacy outcomes. Comprehensive patient assessments are critical to achieve an optimal AED treatment regimen and minimize the potential for adverse effects. PMID- 21790562 TI - Strategies for transitioning to adult care for youth with Lennox-Gastaut syndrome and related disorders. AB - Transition is the process of preparing children with chronic illness and their families for the adult health care system. In patients with Lennox-Gastaut syndrome (LGS) and related disorders, the process of transition is complicated by the presence of intellectual handicap, treatment-resistant epilepsy, and behavioral issues. Patients who are not successfully transitioned to adult care may end up without specialty care, may not receive satisfactory adult services, may lack adequate follow-up and access to newer therapies, and may lack appropriate management of comorbid conditions. Several family related and clinician-related barriers can inhibit the transition process. Transition strategies that maximize each patient's ability to achieve his or her potential and optimize self-sufficiency may lead to better social outcomes. Adolescent clinics that include members of the pediatric and adult neurology teams may help ensure a smooth transition to adult care, although studies are needed to objectively establish the best model. Results are reported from a survey of 133 symposium attendees on the topic of practice characteristics and issues related to transitioning care. Results suggested a great deal of dissatisfaction about the process of transition, especially for patients with intellectual handicap. We provide suggestions for developing a transition program, including identifying a willing adult service, adapting a multidisciplinary approach, addressing legal and psychosocial issues, and celebrating rites of passage. PMID- 21790563 TI - Conclusions: Long-term management of Lennox-Gastaut syndrome: future directions. PMID- 21790564 TI - Some inconvenient truths about sex chromosome dosage compensation and the potential role of sexual conflict. AB - Sex chromosome dosage compensation was once thought to be required to balance gene expression levels between sex-linked and autosomal genes in the heterogametic sex. Recent evidence from a range of animals has indicated that although sex chromosome dosage compensation exists in some clades, it is far from a necessary companion to sex chromosome evolution, and is in fact rather rare in animals. This raises questions about why complex dosage compensation mechanisms arise in some clades when they are not strictly needed, and suggests that the role of sex-specific selection in sex chromosome gene regulation should be reassessed. We show there exists a tremendous diversity in the mechanisms that regulate gene dosage and argue that sexual conflict may be an overlooked agent responsible for some of the variation seen in sex chromosome gene dose regulation. PMID- 21790565 TI - Sex-dependent selection differentially shapes genetic variation on and off the guppy Y chromosome. AB - Because selection is often sex-dependent, alleles can have positive effects on fitness in one sex and negative effects in the other, resulting in intralocus sexual conflict. Evolutionary theory predicts that intralocus sexual conflict can drive the evolution of sex limitation, sex-linkage, and sex chromosome differentiation. However, evidence that sex-dependent selection results in sex linkage is limited. Here, we formally partition the contribution of Y-linked and non-Y-linked quantitative genetic variation in coloration, tail, and body size of male guppies (Poecilia reticulata)-traits previously implicated as sexually antagonistic. We show that these traits are strongly genetically correlated, both on and off the Y chromosome, but that these correlations differ in sign and magnitude between both parts of the genome. As predicted, variation in attractiveness was found to be associated with the Y-linked, rather than with the non-Y-linked component of genetic variation in male ornamentation. These findings show how the evolution of Y-linkage may be able to resolve sexual conflict. More generally, they provide unique insight into how sex-specific selection has the potential to differentially shape the genetic architecture of fitness traits across different parts of the genome. PMID- 21790566 TI - Adaptive chromosomal divergence driven by mixed geographic mode of evolution. AB - Chromosomal inversions are ubiquitous in nature and of great significance for understanding adaptation and speciation. Inversions were the first markers used to investigate the genetic structure of natural populations, leading to the concept of coadapted gene complexes and theories concerning founder effects and genetic drift in small populations. However, we still lack elements of a general theory accounting for the origins and distribution of inversions in nature. Here, we use computer simulations to show that a "mixed geographic mode" of evolution involving allopatric separation of populations followed by secondary contact and gene flow generates chromosomal divergence by natural selection under wider conditions than previous hypotheses. This occurs because inversions arising in allopatry contain a full complement of locally adapted genes. Once gene flow ensues, reduced recombination within inversions keeps these favorable genotypic combinations intact, resulting in inverted genomic regions being favored over collinear regions. This process allows inversions to establish to high frequencies. Our model can account for several classic patterns in the geographic distribution of inversions and highlights how selection on standing genetic variation allows rapid chromosomal evolution without the waiting time for new mutations. As inversion differences often separate closely related taxa, mixed modes of divergence could be common. PMID- 21790567 TI - Evolution of male and female genitalia following release from sexual selection. AB - Despite the key functions of the genitalia in sexual interactions and fertilization, the role of sexual selection and conflict in shaping genital traits remains poorly understood. Seed beetle (Callosobruchus maculatus) males possess spines on the intromittent organ, and females possess a thickened reproductive tract wall that also bears spines. We investigated the role of sexual selection and conflict by imposing monogamous mating on eight replicate populations of this naturally polygamous insect, while maintaining eight other populations under polygamy. To establish whether responses to mating system manipulation were robust to ecological context, we simultaneously manipulated life-history selection (early/late reproduction). Over 18-21 generations, male genital spines evolved relatively reduced length in large males (i.e., shallower static allometry) in monogamous populations. Two nonintromittent male genital appendages also evolved in response to the interaction of mating system and ecology. In contrast, no detectable evolution occurred in female genitalia, consistent with the expectation of a delayed response in defensive traits. Our results support a sexually antagonistic role for the male genital spines, and demonstrate the evolution of static allometry in response to variation in sexual selection opportunity. We argue that further advances in the study of genital coevolution will require a much more detailed understanding of the functions of male and female genital traits. PMID- 21790568 TI - Coevolution of male mating signal and female preference during early lineage divergence of the Hawaiian cricket, Laupala cerasina. AB - Sexual selection is a powerful evolutionary force shaping mate choice phenotypes, initiating phenotypic shifts resulting in (or reinforcing) population divergence and speciation when such shifts reduce mating probabilities among divergent populations. In the Hawaiian cricket genus Laupala, pulse rate of male calling song, a conspicuous mating signal, differs among species, potentially behaving as a speciation phenotype. Populations of the widespread species Laupala cerasina show variation in pulse rate. We document the degree of population differentiation in three features of calling song: pulse rate, pulse duration, and carrier frequency. All show significant population differentiation, with pulse rate showing the greatest heterogeneity. A Mantel test found no relationship between geographic distance and pulse rate divergence, indicating that a simple model of greater divergence with increasing distance cannot explain the observed pattern of differentiation. We demonstrate that female preference functions for pulse rate are unimodal, and that preference means show significant differentiation among populations. Furthermore, estimates of pulse rate preference correlate significantly with mean pulse rates across populations, indicating song and preference coevolve in a stepwise manner. This correlated divergence between signal and preference suggests that sexual selection facilitates the establishment of sexual isolation, reduced gene flow, and population differentiation, prerequisites for speciation. PMID- 21790569 TI - Trophic novelty is linked to exceptional rates of morphological diversification in two adaptive radiations of Cyprinodon pupfish. AB - Adaptive radiations are known for rapid morphological and species diversification in response to ecological opportunity, but it remains unclear if distinct mechanisms drive this pattern. Here, we show that rapid rates of morphological diversification are linked to the evolution of novel ecological niches in two independent Cyprinodon radiations nested within a wide-ranging group repeatedly isolated in extreme environments. We constructed a molecular phylogeny for the Cyprinodontidae, measured 16 functional traits across this group, and compared the likelihoods of single or multiple rates of morphological diversification. We found that rates of morphological diversification within two sympatric Cyprinodon clades containing unique trophic specialists are not part of an adaptive continuum with other clades, but are instead extreme outliers with rates up to 131 times faster than other Cyprinodontidae. High rates were not explained by clade age, but were instead linked to unique trophic niches within Cyprinodon, including scale-eating, zooplanktivory, and piscivory. Furthermore, although both radiations occur in similar environments and have similar sister species, they each evolved unique trophic specialists and high rates of morphological diversification in different sets of traits. We propose that the invasion of novel ecological niches may be a key mechanism driving many classic examples of adaptive radiation. PMID- 21790570 TI - Evolution in extreme environments: replicated phenotypic differentiation in livebearing fish inhabiting sulfidic springs. AB - We investigated replicated ecological speciation in the livebearing fish Poecilia mexicana and P. sulphuraria (Poeciliidae), which inhabit freshwater habitats and have also colonized multiple sulfidic springs in southern Mexico. These springs exhibit extreme hypoxia and high concentrations of hydrogen sulfide, which is lethal to most metazoans. We used phylogenetic analyses to test whether springs were independently colonized, performed phenotypic assessments of body and gill morphology variation to identify convergent patterns of trait differentiation, and conducted an eco-toxicological experiment to detect differences in sulfide tolerances among ecotypes. Our results indicate that sulfidic springs were colonized by three different lineages, two within P. mexicana and one representing P. sulphuraria. Colonization occurred earlier in P. sulphuraria, whereas invasion of sulfidic springs in P. mexicana was more recent, such that each population is more closely related to neighboring populations from adjacent nonsulfidic habitats. Sulfide spring fish also show divergence from nonsulfidic phenotypes and a phenotypic convergence toward larger heads, larger gills, and increased tolerance to H(2) S. Together with previous studies that indicated significant reproductive isolation between fish from sulfidic and nonsulfidic habitats, this study provides evidence for repeated ecological speciation in the independent sulfide spring populations of P. mexicana and P. sulphuraria. PMID- 21790571 TI - Pumping ions: rapid parallel evolution of ionic regulation following habitat invasions. AB - Marine to freshwater colonizations constitute among the most dramatic evolutionary transitions in the history of life. This study examined evolution of ionic regulation following saline-to-freshwater transitions in an invasive species. In recent years, the copepod Eurytemora affinis has invaded freshwater habitats multiple times independently. We found parallel evolutionary shifts in ion-motive enzyme activity (V-type H(+) ATPase, Na(+) /K(+) -ATPase) across independent invasions and in replicate laboratory selection experiments. Freshwater populations exhibited increased V-type H(+) ATPase activity in fresh water (0 PSU) and declines at higher salinity (15 PSU) relative to saline populations. This shift represented marked evolutionary increases in plasticity. In contrast, freshwater populations displayed reduced Na(+) /K(+) -ATPase activity across all salinities. Most notably, modifying salinity alone during laboratory selection experiments recapitulated the evolutionary shifts in V-type H(+) ATPase activity observed in nature. Maternal and embryonic acclimation could not account for the observed shifts in enzyme activity. V-type H(+) ATPase function has been hypothesized to be critical for freshwater and terrestrial adaptations, but evolution of this enzyme function had not been previously demonstrated in the context of habitat transitions. Moreover, the speed of these evolutionary shifts was remarkable, within a few generations in the laboratory and a few decades in the wild. PMID- 21790572 TI - Phylogenetic versus functional signals in the evolution of form-function relationships in terrestrial vision. AB - Phylogeny is deeply pertinent to evolutionary studies. Traits that perform a body function are expected to be strongly influenced by physical "requirements" of the function. We investigated if such traits exhibit phylogenetic signals, and, if so, how phylogenetic noises bias quantification of form-function relationships. A form-function system that is strongly influenced by physics, namely the relationship between eye morphology and visual optics in amniotes, was used. We quantified the correlation between form (i.e., eye morphology) and function (i.e., ocular optics) while varying the level of phylogenetic bias removal through adjusting Pagel's lambda. Ocular soft-tissue dimensions exhibited the highest correlation with ocular optics when 1% of phylogenetic bias expected from Brownian motion was removed (i.e., lambda= 0.01); the value for hard-tissue data were 8%. A small degree of phylogenetic bias therefore exists in morphology despite of the stringent functional constraints. We also devised a phylogenetically informed discriminant analysis and recorded the effects of phylogenetic bias on this method using the same data. Use of proper lambda values during phylogenetic bias removal improved misidentification rates in resulting classifications when prior probabilities were assumed to be equal. Even a small degree of phylogenetic bias affected the classification resulting from phylogenetically informed discriminant analysis. PMID- 21790573 TI - Exploring possible human influences on the evolution of Darwin's finches. AB - Humans are an increasingly common influence on the evolution of natural populations. Potential arenas of influence include altered evolutionary trajectories within populations and modifications of the process of divergence among populations. We consider this second arena in the medium ground finch (Geospiza fortis) on Santa Cruz Island, Galapagos, Ecuador. Our study compared the G. fortis population at a relatively undisturbed site, El Garrapatero, to the population at a severely disturbed site, Academy Bay, which is immediately adjacent to the town of Puerto Ayora. The El Garrapatero population currently shows beak size bimodality that is tied to assortative mating and disruptive selection, whereas the Academy Bay population was historically bimodal but has lost this property in conjunction with a dramatic increase in local human population density. We here evaluate potential ecological-adaptive drivers of the differences in modality by quantifying relationships between morphology (beak and head dimensions), functional performance (bite force), and environmental characteristics (diet). Our main finding is that associations among these variables are generally weaker at Academy Bay than at El Garrapatero, possibly because novel foods are used at the former site irrespective of individual morphology and performance. These results are consistent with the hypothesis that the rugged adaptive landscapes promoting and maintaining diversification in nature can be smoothed by human activities, thus hindering ongoing adaptive radiation. PMID- 21790574 TI - The evolutionary genetics of acquisition and allocation in the wing dimorphic cricket, Gryllus firmus. AB - The evolutionary trajectories of trade-offs are ultimately governed by the evolution of the underlying physiological processes of the acquisition and subsequent allocation of resources. In this study, we focused directly on acquisition and allocation as traits and estimated their genetic architecture in the trade-off between flight capability and reproduction in the cricket, Gryllus firmus. To determine the evolutionary genetics of acquisition and allocation both within and between resource environments, we performed a large-scale quantitative genetic breeding experiment in which families were split over several resource levels. Our findings were fourfold: (1) there was substantial genetic variance in acquisition and allocation, (2) contrary to the assumption of independence between acquisition and allocation, there was a significant genetic correlation between them, (3) the genetic covariance between acquisition and allocation was significantly different in the different food environments, (4) the trade-off, as measured by the genetic correlation between flight muscle mass and ovary mass, was only significant in the food restriction environments. However, when measured directly as the genetic correlation between reproductive allocation and flight allocation, we found a consistent strong negative genetic correlation, demonstrating that when allocation is measured independently of acquisition we find evidence for the trade-off. PMID- 21790575 TI - Exploitation of the same trophic link favors convergence of larval life-history strategies in complex life cycle helminths. AB - Switching from one host to the next is a critical life-history transition in parasites with complex life cycles. Growth and mortality rates are thought to influence the optimal time and size at transmission, but these rates are difficult to measure in parasites. The parasite life cycle, in particular the trophic link along which transmission occurs, may be a reasonable proxy for these rates, leading to the hypothesis that life cycle should shape life-history strategy. We compiled data on the size and age at infectivity for trophically transmitted helminths (i.e., acanthocephalans, cestodes, and nematodes), and then categorized species into trophic links (e.g., planktonic crustaceans to fish, insects to terrestrial vertebrates, etc.). Comparative analyses that explicitly included stabilizing selection within trophic links fit the data significantly better than random walk models, indicating that parasites with different life cycles have different optimal times/sizes for host switching. The major helminth groups have often independently evolved similar life cycles, and we show that this has frequently led to convergent and/or parallel evolution of size and age at infectivity. This suggests that for particular life cycles there are universal optimal transmission strategies, applicable to widely divergent taxa, although the cases of parallelism might indicate that lineage-specific constraints sometimes prevent evolution to a single adaptive peak. PMID- 21790576 TI - Stochasticity in reproductive opportunity and the evolution of egg limitation in insects. AB - Is reproduction by adult female insects limited by the finite time available to locate hosts (time limitation) or by the finite supply of eggs (egg limitation)? An influential model predicted that stochasticity in reproductive opportunity favors elevated fecundity, rendering egg limitation sufficiently rare that its importance would be greatly diminished. Here, I use models to explore how stochasticity shapes fecundity, the likelihood of egg limitation, and the ecological importance of egg limitation. The models make three predictions. First, whereas spatially stochastic environments favor increased fecundity, temporally stochastic environments favor increases, decreases, or intermediate maxima in fecundity, depending on egg costs. Second, even when spatially or temporally stochastic environments favor life histories with less-frequent egg limitation, stochasticity still increases the proportion of all eggs laid in the population that is laid by females destined to become egg limited. This counterintuitive result is explained by noting that stochasticity concentrates reproduction in the hands of a few females that are likely to become egg limited. Third, spatially or temporally stochastic environments amplify the constraints imposed by time and eggs on total reproduction by the population. I conclude that both egg and time constraints are fundamental in shaping insect reproductive behavior and population dynamics in stochastic environments. PMID- 21790577 TI - Altitudinal divergence in maternal thermoregulatory behaviour may be driven by differences in selection on offspring survival in a viviparous lizard. AB - Plastic responses to temperature during embryonic development are common in ectotherms, but their evolutionary relevance is poorly understood. Using a combination of field and laboratory approaches, we demonstrate altitudinal divergence in the strength of effects of maternal thermal opportunity on offspring birth date and body mass in a live-bearing lizard (Niveoscincus ocellatus). Poor thermal opportunity decreased birth weight at low altitudes where selection on body mass was negligible. In contrast, there was no effect of maternal thermal opportunity on body mass at high altitudes where natural selection favored heavy offspring. The weaker effect of poor maternal thermal opportunity on offspring development at high altitude was accompanied by a more active thermoregulation and higher body temperature in highland females. This may suggest that passive effects of temperature on embryonic development have resulted in evolution of adaptive behavioral compensation for poor thermal opportunity at high altitudes, but that direct effects of maternal thermal environment are maintained at low altitudes because they are not selected against. More generally, we suggest that phenotypic effects of maternal thermal opportunity or incubation temperature in reptiles will most commonly reflect weak selection for canalization or selection on maternal strategies rather than adaptive plasticity to match postnatal environments. PMID- 21790578 TI - Natural genetic variation in social environment choice: context-dependent gene environment correlation in Drosophila melanogaster. AB - Gene-environment correlation (rGE) occurs when an individual's genotype determines its choice of environment, generating a correlation between environment and genotype frequency. In particular, social rGE, caused by genetic variation in social environment choice, can critically determine both individual development and the course of social selection. Despite its foundational role in social evolution and developmental psychology theory, natural genetic variation in social environment choice has scarcely been examined empirically. Drosophila melanogaster provides an ideal system for investigating social rGE. Flies live socially in nature and have many opportunities to make social decisions; and natural, heterozygous genotypes may be replicated, enabling comparisons between genotypes across environments. Using this approach, I show that all aspects of social environment choice vary among natural genotypes, demonstrating pervasive social rGE. Surprisingly, genetic variation in group-size preference was density dependent, indicating that the behavioral and evolutionary consequences of rGE may depend on the context in which social decisions are made. These results provide the first detailed investigation of social rGE, and illustrate that that genetic variation may influence organismal performance by specifying the environment in which traits are expressed. PMID- 21790579 TI - Fitness recovery and compensatory evolution in natural mutant lines of C. elegans. AB - Deleterious mutation accumulation plays a central role in evolutionary genetics, conservation biology, human health, and evolutionary medicine (e.g., methods of viral attenuation for live vaccines). It is therefore important to understand whether and how quickly populations with accumulated deleterious mutational loads can recover fitness through adaptive evolution. We used laboratory experimental evolution with four long-term mutation-accumulation (MA) lines of Caenorhabditis elegans nematodes to study the dynamics of such fitness evolution. We previously showed that when homozygous mutant populations are evolved in large population sizes, they can rapidly achieve wild-type fitness through the accumulation of new beneficial or compensatory epistatic mutations. Here, we expand this approach to demonstrate that when replicate lineages are initiated from the same mutant genotype, phenotypic evolution is only sometimes repeatable. MA genotypes that recovered ancestral fitness in the previous experiment did not always do so here. Further, the pattern of adaptive evolution in independently evolved replicates was contingent upon the MA genotype and varied among fitness-related traits. Our findings suggest that new beneficial mutations can drive rapid fitness evolution, but that the adaptive process is rendered somewhat unpredictable by its susceptibility to chance events and sensitivity to the evolutionary history of the starting population. PMID- 21790580 TI - Spatial environmental variation can select for evolvability. AB - Previous studies have shown that temporally fluctuating environments can create indirect selection for modifiers of evolvability. Here, we use a simple computational model to investigate whether spatially varying environments (multiple demes with limited migration among them, and a different, static selective optimum in each) can also create indirect selection for increased evolvability. The answer is surprisingly complicated. Spatial variation in the environment can sharply reduce the survival rate of migrants, because migrants may be maladapted to their new deme, relative to incumbents. The incumbent advantage can be removed by occasional extinctions in single demes. After all incumbents in a particular deme die, incoming migrants from other demes will, on average, be similarly maladapted to the new environment. This sets off a race to adapt rapidly. Over many extinction events, and the subsequent invasions by maladapted immigrants into a new environment, indirect selection for the ability to adapt rapidly, also known as high evolvability, may result. PMID- 21790581 TI - Migration rates, frequency-dependent selection and the self-incompatibility locus in Leavenworthia (brassicaceae). AB - Loci subject to negative frequency-dependent selection are expected to exhibit higher effective migration rates compared to reference loci. Although the number of gene copies transferred between populations by migration is the same for all genes, those subject to negative frequency-dependent selection are more likely to be retained in the immigrant population because rare alleles are selectively favored. So far, evidence for this prediction has been indirect, based on summary statistics rather than on migration rate estimates. Here, we introduce an approximate Bayesian procedure to jointly estimate migration rates at two predefined sets of loci between two populations. We applied the procedure to compare migration rate estimates at the self-incompatibility locus (S-locus) with that at 10 reference loci in two plant species, Leavenworthia alabamica and L. crassa (Brassicaceae). The maximum likelihood estimate for the proportion of migrants (m) was four times higher at the S-locus than at reference loci, but the difference was not statistically significant. Lack of significance might be due to insufficient data, but perhaps also to the recent divergence of the two species (311 ka), because we also show using simulations that the effective migration rate at the S-locus is expected to increase with increasing divergence time. These findings aid in understanding the evolutionary dynamics of negative frequency-dependent selection and they suggest that divergence time should be accounted for when employing migration rates to help detect negative frequency dependent selection. PMID- 21790582 TI - Epistasis buffers the fitness effects of rifampicin- resistance mutations in Pseudomonas aeruginosa. AB - Epistatic interactions between resistance mutations in antibiotic-free environments potentially play a crucial role in the spread of resistance in pathogen populations by determining the fitness cost associated with resistance. We used an experimental evolution approach to test for epistatic interactions between 14 different pairs of rifampicin mutations in the pathogenic bacterium Pseudomonas aeruginosa in 42 different rifampicin-free environments. First, we show that epistasis between rifampicin-resistance mutations tends to be antagonistic: the fitness effect of having two mutations is generally smaller than that predicted from the effects of individual mutations on the wild-type. Second, we show that sign epistasis between resistance mutations is both common and strong; most notably, pairs of deleterious resistance mutations often partially or completely compensate for each others' costs, revealing a novel mechanism for compensatory adaptation. These results suggest that antagonistic epistasis between intragenic resistance mutations may be a key determinant of the cost of antibiotic resistance and compensatory adaptation in pathogen populations. PMID- 21790583 TI - Computational prediction of MHC II-antigen binding supports divergent allele advantage and explains trans-species polymorphism. AB - The major histocompatibility complex (MHC), coding for antigen presenting molecules of the adaptive immune system, represents one of the most polymorphic regions in the vertebrate genome. The exceptional polymorphism, which is potentially maintained by balancing selection under host-parasite coevolution, comprises excessive sequence divergence among alleles as well as ancient allelic lineages that predate species divergence (trans-species polymorphism). Here, the mechanisms that are proposed to maintain such sequence divergence and ancient lineages are investigated. Established computational antigen-binding prediction algorithms, which are based on empirical databases, are employed to determine the overlap in bound antigens among individual MHC class IIB alleles. The results show that genetically more divergent allele pairs experience less overlap and thus present a broader range of potential antigens. These findings support the divergent allele advantage hypothesis and furthermore suggest an evolutionary advantage explaining the maintenance of divergent allelic lineages, that is, trans-species polymorphism. In addressing a quantitative rather than qualitative aspect of MHC alleles, these insights highlight a new direction for future research on MHC evolution. PMID- 21790585 TI - Internal selection against the evolution of left-right reversal. AB - Among metazoan species, left-right reversals in primary asymmetry have rarely gone to fixation. This suggests that a general mechanism suppresses the evolution of polarity reversal. Most metazoans appear externally symmetric and reproduce by external fertilization or copulation with genitalia located in the midline. Thus, reversal should generate little exogenous disadvantage when interacting with the external environment or in mating with the common wild-type. Accordingly, an endogenously caused fitness reduction may be responsible for the general absence of reversed species. However, how this selection operates is little understood. Phenotypic changes associated with reversal are usually inseparable from zygotic pleiotropy. By exploiting hermaphroditism and the maternal inheritance of left right polarity, we generated dextral and sinistral snails that share the same zygotic genotype. Before hatching, these sinistrals developed lethal morphological anomalies more frequently than dextrals. Their shell shape at maturity differed from the mirror image of the dextral shell. These interchiral differences demonstrate pleiotropy in maternal effects of the polarity or linked genes. Variation in interchiral differences between parental crosses suggests the presence of epistatic variation in relative performance of sinistrals. Our results show that internal selection operates against polarity reversal, and we suggest that this is due to changes in blastomere configuration. PMID- 21790584 TI - A slowly evolving host moves first in symbiotic interactions. AB - Symbiotic relationships, both parasitic and mutualistic, are ubiquitous in nature. Understanding how these symbioses evolve, from bacteria and their phages to humans and our gut microflora, is crucial in understanding how life operates. Often, symbioses consist of a slowly evolving host species with each host only interacting with its own subpopulation of symbionts. The Red Queen hypothesis describes coevolutionary relationships as constant arms races with each species rushing to evolve an advantage over the other, suggesting that faster evolution is favored. Here, we use a simple game theoretic model of host-symbiont coevolution that includes population structure to show that if the symbionts evolve much faster than the host, the equilibrium distribution is the same as it would be if it were a sequential game where the host moves first against its symbionts. For the slowly evolving host, this will prove to be advantageous in mutualisms and a handicap in antagonisms. The result follows from rapid symbiont adaptation to its host and is robust to changes in the parameters, even generalizing to continuous and multiplayer games. Our findings provide insight into a wide range of symbiotic phenomena and help to unify the field of coevolutionary theory. PMID- 21790586 TI - The relationship between physician compensation strategies and the intensity of care delivered to Medicare beneficiaries. AB - OBJECTIVE: To examine the relationship between primary care physicians' (PCPs) payment arrangements and the total costs and intensity of care for specific episodes of care for Medicare beneficiaries. DATA SOURCES/STUDY SETTING: We combined data from the 2004 to 2005 Community Tracking Study Physician Survey on PCP compensation methods with administrative data from the Medicare program for beneficiaries to whom these physicians provided services over the time period 2004-2006. STUDY DESIGN: Cross-sectional analysis of physician survey data linked to Medicare claims. PRINCIPAL FINDINGS: The 2,211 PCP respondents included 937 internists and 1,274 family or general physicians who were linked to more than 250,000 Medicare enrollees. Most physicians (62 percent) had been in practice for 11 or more years and 87 percent were board certified. The total spending models show that for both employed physicians and owners, those in highly capitated practice environments had the lowest risk adjusted spending per beneficiary, whereas those receiving just productivity payments had the highest spending. These physicians also had lower intensity of care for episodes of care. CONCLUSIONS: Physicians in highly capitated practices had the lowest total costs and intensity of care, suggesting that these physicians develop an overall approach to care that also applies to their FFS patients. PMID- 21790587 TI - Hospital standardized mortality ratios: sensitivity analyses on the impact of coding. AB - INTRODUCTION: Hospital standardized mortality ratios (HSMRs) are derived from administrative databases and cover 80 percent of in-hospital deaths with adjustment for available case mix variables. They have been criticized for being sensitive to issues such as clinical coding but on the basis of limited quantitative evidence. METHODS: In a set of sensitivity analyses, we compared regular HSMRs with HSMRs resulting from a variety of changes, such as a patient based measure, not adjusting for comorbidity, not adjusting for palliative care, excluding unplanned zero-day stays ending in live discharge, and using more or fewer diagnoses. RESULTS: Overall, regular and variant HSMRs were highly correlated (rho>0.8), but differences of up to 10 points were common. Two hospitals were particularly affected when palliative care was excluded from the risk models. Excluding unplanned stays ending in same-day live discharge had the least impact despite their high frequency. The largest impacts were seen when capturing postdischarge deaths and using just five high-mortality diagnosis groups. CONCLUSIONS: HSMRs in most hospitals changed by only small amounts from the various adjustment methods tried here, though small-to-medium changes were not uncommon. However, the position relative to funnel plot control limits could move in a significant minority even with modest changes in the HSMR. PMID- 21790588 TI - Abandonment of high-dose chemotherapy/hematopoietic cell transplants for breast cancer following negative trial results. AB - OBJECTIVE: In 1999, three randomized controlled trials concluded that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDC/HCT) is no better than conventional chemotherapy for women with breast cancer. This study documents the impact of the trials on use of HDC/HCT and describes how hospitals reacted to the trials. DATA SOURCE: We used patient-level data on 15,847 HDC/HCTs reported to the Center for International Blood and Marrow Transplant Research between 1994 and 2005. STUDY DESIGN: We report trends in total HDC/HCT procedure volume, compare the time to hospitals' exit from the HDC/HCT market between research and nonresearch hospitals, and document trends in hospital-specific volumes in the 2 years before exit. PRINCIPAL FINDINGS: HDC/HCT volume declined from 3,108 in 1998 to 1,363 the year after trial results were released. In 2002, only 76 procedures were performed. Teaching hospitals and the hospitals that participated in the trials were no slower to discontinue the procedure compared with nonteaching, nonparticipating hospitals. At the hospital level, volume declined steadily in the months before abandonment. CONCLUSION: The results suggest that comparative effectiveness research studies that report negative results can reduce spending, but specialists may be reluctant to relinquish cutting-edge technologies. PMID- 21790589 TI - Assessment of a novel hybrid Delphi and Nominal Groups technique to evaluate quality indicators. AB - OBJECTIVE: To test the implementation of a novel structured panel process in the evaluation of quality indicators. DATA SOURCE: National panel of 64 clinicians rating usefulness of indicator applications in 2008-2009. STUDY DESIGN: Hybrid panel combined Delphi Group and Nominal Group (NG) techniques to evaluate 81 indicator applications. PRINCIPAL FINDINGS: The Delphi Group and NG rated 56 percent of indicator applications similarly. Group assignment (Delphi versus Nominal) was not significantly associated with mean ratings, but specialty and research interests of panelists, and indicator factors such as denominator level and proposed use were. Rating distributions narrowed significantly in 20.8 percent of applications between review rounds. CONCLUSIONS: The hybrid panel process facilitated information exchange and tightened rating distributions. Future assessments of this method might include a control panel. PMID- 21790591 TI - Differences in relative fitness among alternative mating tactics might be more apparent than real. AB - Two theoretical frameworks guide research on multiple male phenotypes within natural populations. Each scheme recognizes that male polymorphisms vary in the degree to which genotype and environment influence trait expression. Consensus remains elusive, however, on whether average fitnesses must be equivalent and whether genetic differences need exist for polymorphism to persist over time. Schradin and Lindholm address these hypotheses in African four-striped mice with detailed parentage and body size data. Their results and interpretation call each framework's predictions into question, but reveal a common truth. Debate might be resolved if researchers agreed on which parameters to measure and compare. PMID- 21790590 TI - Does information matter? Competition, quality, and the impact of nursing home report cards. AB - OBJECTIVE: We evaluate the effects of the Nursing Home Quality Initiative (NHQI), which introduced quality measures to the Centers for Medicare and Medicaid Services' Nursing Home Compare website, on facility performance and consumer demand for services. DATA SOURCES: The nursing home Minimum Data Set facility reports from 1999 to 2005 merged with facility-level data from the On-Line Survey, Certification, and Reporting System. STUDY DESIGN: We rely on the staggered rollout of the report cards across pilot and nonpilot states to examine the effect of report cards on market share and quality of care. We also exploit differences in nursing home market competition at baseline to identify the impacts of the new information on nursing home quality. RESULTS: The introduction of the NHQI was generally unrelated to facility quality and consumer demand. However, nursing homes facing greater competition improved their quality more than facilities in less competitive markets. CONCLUSIONS: The lack of competition in many nursing home markets may help to explain why the NHQI report card effort had a minimal effect on nursing home quality. With the introduction of market based reforms such as report cards, this result suggests policy makers must also consider market structure in efforts to improve nursing home performance. PMID- 21790592 TI - Fuel, fasting, fear: routine metabolic rate and food deprivation exert synergistic effects on risk-taking in individual juvenile European sea bass. AB - 1. Individuals of the same species often exhibit consistent differences in metabolic rate, but the effects of such differences on ecologically important behaviours remain largely unknown. In particular, it is unclear whether there is a cause-and-effect relationship between metabolic rate and the tendency to take risks while foraging. Individuals with higher metabolic rates may need to take greater risks while foraging to obtain the additional food required to satisfy their energy requirements. Such a relationship could be exacerbated by food deprivation if a higher metabolic demand also causes greater mass loss and hunger. 2. We investigated relationships among metabolic rate, risk-taking and tolerance of food deprivation in juvenile European sea bass. Individual fish were tested for risk-taking behaviours following a simulated predator attack, both before and after a 7-day period of food deprivation. The results were then related to their routine metabolic rate (RMR), which was measured throughout the period of food deprivation. 3. The amount of risk displayed by individual fish before food deprivation showed no relationship with RMR. After food deprivation, however, the amount of risk among individuals was positively correlated with RMR. In general, most fish showed an increase in risk-taking after food deprivation, and the magnitude of the increase in risk-taking was correlated with the rate of individual mass loss during food deprivation, which was itself strongly correlated with RMR. 4. The observation that RMR was related to risk-taking behaviour after food deprivation, but not before, suggests that although RMR can influence risk-taking, the strength of the relationship is flexible and context dependent. The effects of RMR on risk-taking may be subtle or non-existent in regularly feeding animals, but may lead to variability in risk-taking among individuals when food is scarce or supply is unpredictable. This synergistic relationship between RMR and food deprivation could lead to an increased likelihood of being predated for individuals with a relatively high intrinsic energy demand during times when food is scarce. PMID- 21790593 TI - Fatality involving complications of bupivacaine toxicity and hypersensitivity reaction. AB - This case represents unusual findings of elevated bupivacaine and tryptase concentrations following local anesthetic, bupivacaine, administered as a scalene nerve block for elective rotator cuff repair surgery. Following bupivacaine injection, the patient exhibited almost immediate seizure activity, bradycardia, and cardiac arrest. Resuscitative efforts including cardiopulmonary bypass restored a cardiac rhythm. However, the clinical medical status of the patient progressively declined and he died 7 h following administration of the local anesthetic. Autopsy revealed several abnormalities of the heart including cardiomegaly, myocardial bridging, and lipomatous hypertrophy of the intraatrial septum, which may have contributed to bradycardia and arrhythmia. Postmortem toxicology results revealed elevated bupivacaine and tryptase concentrations. Elevated postmortem bupivacaine concentrations 7 h following administration and abrupt onset of seizures indicate unintentional intravascular injection instead of nerve and tissue infiltration. An elevated postmortem tryptase concentration points to the possibility of a hypersensitivity reaction to bupivacaine. PMID- 21790594 TI - Sleeping accidents in the elderly. AB - Two cases of dangerous sleeping environments in the elderly are reported to demonstrate similarities and differences of these "sleeping accidents" to similar episodes that occur in infants and children. CASE REPORTS: An 87-year-old wheelchair-bound man with a history of dementia was found in his nursing home room hanging off the side of the bed from a vertical metal bar, and an 87-year old woman with epilepsy, ischemic heart disease, and insulin-dependent diabetes mellitus was found in hospital wedged between an inflatable mattress and the bars of her bed. These cases demonstrate that, as in the very young, relatively poor coordination and strength in the elderly often with limited comprehension and ability to deal with dangerous environments may predispose to sleeping accidents. Significant underlying organic disease may, however, make determination of the precise lethal mechanisms difficult. Modification of beds should only be undertaken when safety issues have been carefully evaluated. PMID- 21790595 TI - The "coffin fly"Conicera tibialis (Diptera: Phoridae) breeding on buried human remains after a postmortem interval of 18 years. AB - The "coffin fly,"Conicera tibialis Schmitz (Order: Diptera, Family: Phoridae), is well known for its frequent occurrence on buried corpses, in some cases after postmortem intervals of even 3-5 years. The present report describes the presence of a large amount of individuals of C. tibialis inside the coffin of a buried human corpse exhumed 18 years after death in central Spain. Adults, some of them newly emerged, and empty puparia were found in connection with the remains. Such postmortem interval is significantly longer than previously known for this species and raises the question on the current state of knowledge about the use of insects for estimating the postmortem interval in old, buried remains. PMID- 21790597 TI - Improving the point of origin determination in bloodstain pattern analysis. AB - In bloodstain pattern analysis, it is important to know the point of origin (PO) of an impact pattern. This point can be estimated by means of the stringing method, the tangent method, or by commercially available computer programs. In this study, the accuracy of two computer programs was investigated under different conditions. Impact patterns were created by means of a modified mouse trap, and subsequently the PO was calculated. By examining the characteristics of single bloodstains, the influence on the deviation could be determined. To improve the estimation of the PO, it is important to select bloodstains that lie close to the presumable location of the blood source, that are large (width >1.5 mm) and that show an elliptical form. If possible, bloodstains from different walls should be taken into account. Our recommendations may improve the PO determination of impact patterns. PMID- 21790596 TI - Cluster hanging suicides in the young in South Australia. AB - Retrospective review of hanging suicides in individuals aged <= 17 years was undertaken at Forensic Science South Australia, Australia, over two 5-year periods: 1995-1999 and 2005-2009. Seven cases of hanging suicides were identified from 1995 to 1999, with a further 14 cases from 2005 to 2009, an increase of 100% (p < 0.001). Hanging accounted for 33.3% of all suicides in this age group (7/21) from 1995 to 1999, compared with 93.3% of the total number of suicides (14/15) in the second 5-year period. In contrast, Australian national data from 1998 and 2008 showed a 30% decrease in hanging suicides in the young, from one case/100,000 population in 1998 to 0.7 in 2008. Cluster suicides occur in the young and are often initiated by direct communication. As it is possible that Internet-based social sites may facilitate this phenomenon, investigations should include an evaluation of the victim's Internet access given the potential risk of similar actions by peers. PMID- 21790598 TI - Rapid screening for the detection and differentiation of gamma-hydroxybutyrate using ion chromatography. AB - The analysis of gamma-hydroxybutyric acid (GHB) is problematic because it is hygroscopic, it lacks a good UV chromophore, and it undergoes heat-induced cyclization. This paper presents a new method utilizing ion-exchange chromatography (IC) with conductivity detection. The simple sample preparation, rapid analysis time, and inorganic anion detection capabilities are all advantages over the current methods. The detection of inorganic salts (formed during GHB synthesis) gives insight into the synthetic route utilized and can aid in drug seizure comparison. The developed method has a detection limit for GHB anions of 0.57 mg/L and chloride of 0.22 mg/L. A comparison of this technique with a current gas chromatography-mass spectrometry technique is presented, and a t-test found that the two methods' results are not statistically different at the 99.9% confidence level demonstrating the merits of this fast, simple, and informative IC method as a routine screening tool. PMID- 21790599 TI - Use of styryl 11 and STaR 11 for the luminescence enhancement of cyanoacrylate developed fingermarks in the visible and near-infrared regions. AB - In current casework, most post-cyanoacrylate stains rely on luminescence emission in the visible region (400-700 nm). While traditional stains such as rhodamine 6G work well under most circumstances, some surfaces may generate background luminescence under the same conditions. Detection in the near-infrared region (NIR > 700 nm) has shown to be effective in minimizing the interferences from such surfaces. The laser dye styryl 11 generated strongly luminescent fingermarks when applied after cyanoacrylate fuming on all surfaces tested. When compared to rhodamine 6G, the dye was superior only when viewed in the NIR. Styryl 11 was subsequently combined with rhodamine 6G, and the mixed stain formulation (named StaR 11 by the authors) induced stronger luminescence compared with styryl 11 alone with an ability to visualize in both the visible and NIR regions. Reliable and consistent results were obtained when using either styryl 11 alone or the STaR 11 mixture. The enhancement achieved did not otherwise vary depending on the source of the fingermark secretions. With visualization possible in both the visible and NIR regions, the styryl 11/rhodamine 6G mixture showed significant potential as a post-cyanoacrylate stain. PMID- 21790600 TI - An investigation into the use of a portable cyanoacrylate fuming system (SUPERfume(r)) and aluminum powder for the development of latent fingermarks. AB - Few techniques offer "in situ" methods of friction ridge skin mark development. "In situ" development reduces mark transportation, degradation, and often cost. The effectiveness of cyanoacrylate fuming using the SUPERfume((r)) and dusting with aluminum powder for latent fingermark development on several nonporous surfaces, stored in various temperature environments for time periods up to 52 weeks, was investigated. Five thousand and four hundred latent fingermarks were deposited under controlled conditions and graded. The results suggested that cyanoacrylate fuming (SUPERfume((r)), Foster and Freeman, U.K.) was more effective at developing latent fingermarks on textured and smooth plastic surfaces and for marks stored in temperatures of 37 degrees C, whereas aluminum powder was more effective on glass, enameled metal paint, and varnished wood, and for storage temperatures below 20 degrees C. There were no significant benefits to using either technique for marks older than 24 h, but it was possible to develop fingermarks following 52 weeks of storage using both techniques. PMID- 21790601 TI - Development of microwave-assisted extraction procedure for organic impurity profiling of seized 3,4-methylenedioxymethamphetamine (MDMA). AB - Organic impurity profiling of seized 3,4-methylenedioxymethamphetamine (MDMA) tablets aims to link tablets to common production sources. Conventionally, organic impurities are extracted from tablets using a liquid-liquid extraction (LLE) procedure prior to analysis by gas chromatography-mass spectrometry (GC MS). In this research, the development of an alternative microwave-assisted extraction/headspace solid-phase microextraction (MAE/HS-SPME) procedure is described. The optimal procedure used phosphate buffer (1 M, pH 8), with an HS SPME extraction temperature of 70 degrees C for 40 min, using a divinylbenzene/CarboxenTM/polydimethylsiloxane (DVB/CAR/PDMS) fiber. Impurities were extracted from seized MDMA exhibits using the MAE/HS-SPME procedure, as well as HS-SPME alone, and a conventional LLE procedure. The HS-SPME procedure was deemed to be the most practical because of the affordability and need for less analyst involvement. Although the LLE was limited in the number of impurities extracted, the procedure is still useful for the extraction of less volatile impurities that are not extracted by HS-SPME. PMID- 21790602 TI - Occurrence of contamination by controlled substances in Euro banknotes from the Spanish archipelago of the Canary Islands. AB - The social problems of drug abuse are a matter of increasing global problem. Nowadays, international agencies need fresh methods to monitor trends of the use of illicit drugs. In this sense, small amounts of drugs are transferred to banknotes and they could be detected and quantified. An analytical procedure based upon extraction with organic solvent, liquid chromatography separation, and mass spectrometric detection allowed the identification of 21 drugs and metabolites in 120 used Euro banknotes collected in the Canary Islands (Spain). Most of the banknotes analyzed showed detectable drug residues (92.5%). Cocaine was the most frequently detected drug, present in approximately 90% of the samples. In addition, 75%, 35%, and 15% of the banknotes showed residues of amphetamine derivatives, opiates, and benzodiazepines, respectively. An average of three drug residues per banknote was detected. In summary, the presence of drug residues in banknotes could be useful as tracer for drugs prevalence. PMID- 21790604 TI - Substitutions of amino acids in the pore domain of homomeric alpha7 nicotinic receptors for analogous residues present in heteromeric receptors modify gating, rectification and binding properties. AB - We have studied the role of different amino acids in the M2 transmembrane domain of the alpha7 neuronal nicotinic receptor by mutating residues that differ from the ones located at the same positions in other alpha (alpha2-alpha10) or beta (beta2-beta4) subunits. Our aim was to investigate the contribution of these amino acids to the peculiar kinetic and inward rectification properties that differentiate the homomeric alpha7 receptor from other nicotinic receptors. Mutations of several residues strongly modified receptor function. We found that Thr245 had the most profound effect when mutated to serine, an amino acid present in all heteromeric receptors composed of alpha and beta subunits, by dramatically increasing the maximal current, decreasing the decaying rate of the currents and decreasing receptor rectification. Some mutants also showed altered agonist binding properties as revealed by shifts in the dose-response curves for acetylcholine. We conclude that residues in the M2 segment and flanking regions contribute to the unusual properties of the alpha7 receptor, especially to its characteristic fast kinetic behavior and strong inward rectification and furthermore to the potency of agonists. PMID- 21790603 TI - Melatonin synthesis in retina: cAMP-dependent transcriptional regulation of chicken arylalkylamine N-acetyltransferase by a CRE-like sequence and a TTATT repeat motif in the proximal promoter. AB - Arylalkylamine N-acetyltransferase (AANAT) is the key regulatory enzyme controlling the daily rhythm of melatonin biosynthesis. In chicken retinal photoreceptor cells, Aanat transcription and AANAT activity are regulated in part by cAMP-dependent mechanisms. The purpose of this study was to identify regulatory elements within the chicken Aanat promoter responsible for cAMP dependent induction. Photoreceptor-enriched retinal cell cultures were transfected with a luciferase reporter construct containing up to 4 kb of 5' flanking region and the first exon of Aanat. Forskolin treatment stimulated luciferase activity driven by the ~4 kb promoter construct and by all 5'-deletion constructs except the smallest, Aanat (-217 to +120)luc. Maximal basal and forskolin-stimulated expression levels were generated by the Aanat (-484 to +120)luc construct. This construct lacks a canonical cyclic AMP-response element (CRE), but contains two other potentially important elements in its sequence: an eight times TTATT repeat (TTATT8) and a CRE-like sequence. Electrophoretic mobility shift assays, luciferase reporter assays, chromatin immunoprecipitation, and siRNA experiments provide evidence that these elements bind c-Fos, JunD, and CREB to enhance basal and forskolin-stimulated Aanat transcription. We propose that the CRE-like sequence and TTATT8 elements in the 484 bp proximal promoter interact to mediate cAMP-dependent transcriptional regulation of Aanat. PMID- 21790605 TI - Biochemical and strain properties of CJD prions: complexity versus simplicity. AB - Prions, the agents responsible for transmissible spongiform encephalopathies, are infectious proteins consisting primarily of scrapie prion protein (PrP(Sc)), a misfolded, beta-sheet enriched and aggregated form of the host-encoded cellular prion protein (PrP(C)). Their propagation is based on an autocatalytic PrP conversion process. Despite the lack of a nucleic acid genome, different prion strains have been isolated from animal diseases. Increasing evidence supports the view that strain-specific properties may be enciphered within conformational variations of PrP(Sc). In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent form of prion diseases and has demonstrated a wide phenotypic and molecular spectrum. In contrast, variant Creutzfeldt-Jakob disease (vCJD), which results from oral exposure to the agent of bovine spongiform encephalopathy, is a highly stereotyped disease, that, until now, has only occurred in patients who are methionine homozygous at codon 129 of the PrP gene. Recent research has provided consistent evidence of strain diversity in sCJD and also, unexpectedly enough, in vCJD. Here, we discuss the puzzling biochemical/pathological diversity of human prion disorders and the relationship of that diversity to the biological properties of the agent as demonstrated by strain typing in experimental models. PMID- 21790606 TI - Propofol post-conditioning induced long-term neuroprotection and reduced internalization of AMPAR GluR2 subunit in a rat model of focal cerebral ischemia/reperfusion. AB - We previously reported that propofol (20 mg/kg/h) post-conditioning provided acute (up to 24 h) neuroprotection in rats with transient middle cerebral artery occlusion. In this study, we extend these data by examining long-term protection and exploring underlying mechanisms involving AMPA receptor GluR2 subunit internalization. Rats were treated with propofol 20 mg/kg/h after 60 min of occlusion (beginning of reperfusion for 4 h). Propofol post-conditioning reduced infarct volume and improved spatial memory deficiencies (up to 28 days) induced by ischemia/reperfusion injury. Additionally, Propofol post-conditioning promoted neurogenesis in the dentate gyrus of hippocampus, as measured by bromodeoxyuridine and neuron-specific nuclear protein immunofluorescence-double staining at day 28 after reperfusion. Finally, propofol post-conditioning increased the surface expression of AMPA receptor GluR2 subunit, thus inhibited the internalization of this part until 28 days after stroke. In conclusion, our data suggest that propofol post-conditioning provides long-term protection against focal cerebral ischemia/reperfusion injury in rats. Furthermore, we found that the inhibition of AMPA receptor GluR2 subunit internalization may contributed to this long-term neuroprotection. PMID- 21790607 TI - Glycine release provoked by disturbed Na+, Na+ and Ca2+ homeostasis in cerebellar nerve endings: roles of Ca2+ channels, Na+/Ca2+ exchangers and GlyT2 transporter reversal. AB - Glycine release provoked by ion dysregulations typical of some neuropathological conditions was analyzed in cerebellar synaptosomes selectively pre-labelled with [3H]glycine through GlyT2 transporters and exposed in superfusion to KCl, 4 aminopyridine (4-AP) or veratridine. The overflows caused by relatively low concentrations of the releasers were largely external Ca2+-dependent. Higher concentrations of KCl (50 mM) or veratridine (10 MUM), but not of 4-AP (1 mM), involved also external Ca2+-independent mechanisms. GlyT1-mediated release could not be observed; only the external Ca2+-independent veratridine-evoked overflow occurred significantly by GlyT2 reversal. None of the three depolarizing agents activated store-operated or transient receptor potential or L-type Ca2+ channels. The overflows caused by KCl or 4-AP occurred in part by N- and P/Q-type voltage sensitive calcium channel-dependent exocytosis. Significant portions of the external Ca2+-dependent overflow evoked by KCl or 4-AP (and all that caused by veratridine) were mediated by reverse plasmalemmal Na+/Ca2+ exchangers. Significant contribution to the overflows evoked by KCl or veratridine came from Ca2+ originated through mitochondrial Na+/Ca2+ exchangers. Ca2+-induced Ca2+ release (CICR) mediated by inositoltrisphosphate receptors (InsP3Rs) represents the final trigger of the glycine release evoked by high KCl. The overflows evoked by 4-AP or, less so, by veratridine also involved InsP3R-mediated CICR and, in part, CICR mediated by ryanodine receptors. To conclude, ionic dysregulations typical of ischemia and epilepsy caused glycine release in cerebellum by multiple differential mechanisms that may represent potential therapeutic targets. PMID- 21790608 TI - The Pisum sativum psp54 gene requires ABI3 and a chromatin remodeller to switch from a poised to a transcriptionally active state. AB - Aspects of transcriptional regulation in plants, such as the order in which transcriptional factors and the preinitiation complex are assembled, are obscure because studies carried out under conditions in which native chromatin structure is preserved are still few in comparison with those carried out under other conditions. In vivo chromatin immunoprecipitation (ChIP) experiments were used here to study the regulation of Pisum sativum psp54, which codes for the precursor of a chromatin-associated protein in dry seeds. Antibodies against PsSNF5, a component of the SWI/SNF remodelling complex, and against the transcriptional factor Pisum sativum abscisic acid insensitive 3 (PsABI3) were raised and used for ChIP experiments, which showed that both factors are bound to the psp54 promoter only when the gene is actively expressed during seed maturation and germination. However, RNA polymerase II appeared to be bound to the inactive promoter, which was poised for transcription, before the assembly of factors. Micrococcal nuclease protection assays showed that chromatin conformation at the proximal psp54 promoter changes in shifting from the active to inactive state. The changes in the promoter chromatin of psp54 are discussed. Stalled polymerase is described for the first time at the promoter of a non-heat shock plant gene. PMID- 21790609 TI - Silencing of 4-coumarate:coenzyme A ligase in switchgrass leads to reduced lignin content and improved fermentable sugar yields for biofuel production. AB - * The lignin content of feedstock has been proposed as one key agronomic trait impacting biofuel production from lignocellulosic biomass. 4-Coumarate:coenzyme A ligase (4CL) is one of the key enzymes involved in the monolignol biosynthethic pathway. * Two homologous 4CL genes, Pv4CL1 and Pv4CL2, were identified in switchgrass (Panicum virgatum) through phylogenetic analysis. Gene expression patterns and enzymatic activity assays suggested that Pv4CL1 is involved in monolignol biosynthesis. Stable transgenic plants were obtained with Pv4CL1 down regulated. * RNA interference of Pv4CL1 reduced extractable 4CL activity by 80%, leading to a reduction in lignin content with decreased guaiacyl unit composition. Altered lignification patterns in the stems of RNAi transgenic plants were observed with phloroglucinol-HCl staining. The transgenic plants also had uncompromised biomass yields. After dilute acid pretreatment, the low lignin transgenic biomass had significantly increased cellulose hydrolysis (saccharification) efficiency. * The results demonstrate that Pv4CL1, but not Pv4CL2, is the key 4CL isozyme involved in lignin biosynthesis, and reducing lignin content in switchgrass biomass by silencing Pv4CL1 can remarkably increase the efficiency of fermentable sugar release for biofuel production. PMID- 21790610 TI - Alcohol consumption and body weight: a systematic review. AB - Based on the fact that energy content in 1 gram of alcohol is 29 kJ or 7.1 kcal, alcohol consumption can lead to weight gain. The present review was conducted to analyze the effects of alcohol consumption on body weight. A search of the Medline database for the period 1984 to March 2010 was conducted to identify cross-sectional, prospective cohort studies and intervention trials investigating the relationship between alcohol consumption and the risk of weight gain. Thirty one publications were selected on the basis of relevance and quality of design and methods. The findings from large cross-sectional studies as well as from well powered, prospective, cohort studies with long periods of follow-up were contradictory. Findings from short-term experimental trials also did not show a clear trend. The overall results do not conclusively confirm a positive association between alcohol consumption and weight gain; however, positive findings between alcohol intake and weight gain have been reported, mainly from studies with data on higher levels of drinking. It is, therefore, possible that heavy drinkers may experience such an effect more commonly than light drinkers. Moreover, light-to-moderate alcohol intake, especially wine intake, may be more likely to protect against weight gain, whereas consumption of spirits has been positively associated with weight gain. Further research should be directed towards assessing the specific roles of different types of alcoholic beverages. Studies should also take the effect of consumption patterns into account. In addition, a potential effect modifier that has not been evaluated before but might be important to consider is the subjects' previous tendency to gain weight. PMID- 21790611 TI - Emerging evidence of the health benefits of S-equol, an estrogen receptor beta agonist. AB - Many clinical studies have been carried out to determine the health benefits of soy protein and the isoflavones contained in soy. S-equol is not present in soybeans but is produced naturally in the gut of certain individuals, particularly Asians, by the bacterial biotransformation of daidzein, a soy isoflavone. In those intervention studies in which plasma S-equol levels were determined, a concentration of >5-10 ng/mL has been associated with a positive outcome for vasomotor symptoms, osteoporosis (as measured by an increase in bone mineral density), prostate cancer, and the cardiovascular risk biomarkers low density lipoprotein cholesterol and C-reactive protein. These studies suggest that S-equol may provide therapeutic benefits for a number of medical needs. PMID- 21790612 TI - Characterizing whole diets of young children from developed countries and the association between diet and health: a systematic review. AB - Early childhood is an important nutritional period that involves the transition from a milk-based diet to ordinary foods. A systematic review was conducted of studies that applied whole-of-diet analysis of children aged 1-5 years to examine associations between diet and nutrition, health, and development. Literature searches identified 40 articles using dietary indices, principal component analysis, or cluster analysis. Reports that applied indices (n = 23, 18 indices) were cross-sectional, and most measured diet quality or variety. Articles reporting principal component or cluster analyses (n =17) described between two and six dietary patterns, and most identified healthy, unhealthy, and traditional patterns. In cross-sectional analyses, mixed associations were found between index or pattern scores and nutrient intake (n = 10), nutritional biomarkers (n = 1), and anthropometry (n = 10). Five reports from two birth cohorts showed healthier dietary patterns were associated with better lean mass, cognition, and behavior, but not with bone mass or body mass index at later ages. Few studies have characterized the diets of children under 5 years of age and linked diet with health. Given the limited evidence, research establishing the predictive validity of whole-of-diet methods in childhood is needed. PMID- 21790613 TI - Vitamin D deficiency and disease risk among aboriginal Arctic populations. AB - Aboriginal populations living above the Arctic Circle are at particularly high risk of vitamin D deficiency due to limited ultraviolet B exposure (related to geographic latitude) and inadequate dietary intake (recently related to decreased traditional food consumption). Major changes in diet and lifestyle over the past 50 years in these populations have coincided with increased prevalence rates of rickets, cancer, diabetes, and obesity, each of which may be associated with vitamin D inadequacy. This review examines the risk factors for vitamin D inadequacy, the associations between vitamin D and disease risk at high geographic latitudes, and the recommendations for improving vitamin D status particularly among aboriginal Arctic populations. Traditional foods, such as fatty fish and marine mammals, are rich sources of vitamin D and should continue to be promoted to improve dietary vitamin D intake. Supplementation protocols may also be necessary to ensure adequate vitamin D status in the Arctic. PMID- 21790614 TI - Incorporation of whole, ancient grains into a modern Asian Indian diet to reduce the burden of chronic disease. AB - Refined carbohydrates, such as white rice and white flour, are the mainstay of the modern Asian Indian diet, and may contribute to the rising incidence of type 2 diabetes and cardiovascular disease in this population. Prior to the 1950s, whole grains such as amaranth, barley, brown rice, millet, and sorghum were more commonly used in Asian Indian cooking. These grains and other non-Indian grains such as couscous, quinoa, and spelt are nutritionally advantageous and may be culturally acceptable carbohydrate substitutes for Asian Indians. This review focuses on practical recommendations for culturally sensitive carbohydrate modification in a modern Asian Indian diet to reduce type 2 diabetes and cardiovascular disease in this population. PMID- 21790616 TI - A hand-held fiber-optic implement for the site-specific delivery of photosensitizer and singlet oxygen. AB - We have constructed a fiber optic device that internally flows triplet oxygen and externally produces singlet oxygen, causing a reaction at the (Z)-1,2 dialkoxyethene spacer group, freeing a pheophorbide sensitizer upon the fragmentation of a reactive dioxetane intermediate. The device can be operated and sensitizer photorelease observed using absorption and fluorescence spectroscopy. We demonstrate the preference of sensitizer photorelease when the probe tip is in contact with octanol or lipophilic media. A first-order photocleavage rate constant of 1.13 h(-1) was measured in octanol where dye desorption was not accompanied by readsorption. When the probe tip contacts aqueous solution, the photorelease was inefficient because most of the dye adsorbed on the probe tip, even after the covalent ethene spacer bonds have been broken. The observed stability of the free sensitizer in lipophilic media is reasonable even though it is a pyropheophorbide-a derivative that carries a p formylbenzylic alcohol substituent at the carboxylic acid group. In octanol or lipid systems, we found that the dye was not susceptible to hydrolysis to pyropheophorbide-a, otherwise a pH effect was observed in a binary methanol-water system (9:1) at pH below 2 or above 8. PMID- 21790617 TI - Effects of photoactivated titanium dioxide nanopowders and coating on planktonic and biofilm growth of Pseudomonas aeruginosa. AB - We exploited the ability of photocatalytic titanium dioxide (TiO(2)) as an agent for the biofilm control. Two photocatalytic systems were investigated: a 3 g L( 1) suspension of TiO(2) nanopowder in demineralized water and glass slides coated with a TiO(2) thin film, achieved by sol-gel deposition. A running protocol for the photoactivation of TiO(2) was set up using the dye rhodamine B. The microorganisms studied were Pseudomonas stutzeri, Pseudomonas aeruginosa and a Bacillus cereus-group as planktonic cells. P. aeruginosa biofilms were also studied at both the solid-liquid and the solid-air interface. The TiO(2) nanopowder produced 1-log reduction of Bacillus sp. planktonic cells in 24 h, 2 log reduction of P. stutzeri planktonic cells in 30 min and 1-log reduction of P. aeruginosa planktonic cells in 2 h compared with non-photo-activated TiO(2). TiO(2) thin film produced almost a complete eradication of P. aeruginosa planktonic cells (initial concentration 10(8) cells mL(-1)) in 24 h compared to a 3-log reduction caused by UV-A light alone. In contrast, neither the photocatalytic treatment with TiO(2) film nor that with TiO(2) nanopowder had any effect on P. aeruginosa biofilms at all the interfaces investigated. Possible explanations for these findings, and for the discrepancy between this work and literature data, are discussed. PMID- 21790618 TI - Design of a coupled bioluminescent assay for a recombinant pyruvate kinase from a thermophilic Geobacillus. AB - A simple and rapid method using coupled bioluminescent assay was developed to determine level of ADP. ADP is involved in many biological reactions and ADP assay can be used for assaying some reactions universally by monitoring ADP formation or depletion. ADP analysis involves incubation of ADP or extracts containing ADP with pyruvate kinase (PK) and PEP. The ATP formed by this reaction is determined by measuring the intensity of the initial light flash produced when luciferin-luciferase preparation injected into the reaction mixture. In regard to the main role of the PK in this assay, the gene of PK from a Geobacillus species has been cloned in expression vector pET28a (+), sequenced and overexpressed in Escherichia coli. Recombinant protein was purified using Ni-NTA column and then the purified PK was used in a coupled bioluminescent assay for ADP measurement. Kinetic properties of PK are determined according to a bioluminescent assay using firefly luciferase. PMID- 21790619 TI - He-Ne laser-induced improvement in biochemical, physiological, growth and yield characteristics in sunflower (Helianthus annuus L.). AB - The water-soaked seeds of sunflower were exposed to low power continuous wave He Ne laser irradiation of energies 0, 100, 300 and 500 mJ to evaluate the effect on various biochemical, physiological, growth and yield parameters of sunflower. The experiments which consisted of four replicates arranged in a completely randomized design (CRD) were carried out under the greenhouse conditions. The physiological attributes like, photosynthetic rate (A), transpiration rate (E), intrinsic CO(2) concentration (C(i) ), stomatal conductance (g(s)), chlorophyll a and b contents, relative membrane permeability and leaf water (psi(w)), osmotic (psi(s)) and turgor (psi(p)) potentials, relative water contents and leaf area increased significantly as compared to control due to He-Ne treatment of seeds. The activities of superoxide dismutase, peroxidase and catalases and contents of total soluble proteins, malondialdehyde, proline and leaf total phenolic also increased due to laser treatment. Significant increase in growth parameters of sunflower like shoot fresh and dry masses, root fresh and dry masses, root and shoot lengths, number of leaves per plant and stem diameter has also been observed. The contents of K, Ca and Mg in shoot and root were also increased and an overall increase of up to 28.12% was observed due to laser treatment. PMID- 21790620 TI - A self-help book is better than sleep hygiene advice for insomnia: a randomized controlled comparative study. AB - The objective was to compare the effects of two types of written material for insomnia in a randomized trial with follow-up after three months. Insomniacs were recruited through newspaper advertisements to a web-based survey with validated questionnaires about sleep, anxiety, depression, and use of sleep medications. A self-help book focusing on cognitive behavioral therapy for insomnia was compared to standard sleep hygiene advice; 77 and 78 participants were randomized to self help book or sleep hygiene advice, respectively. The response rate was 81.9%. The self-help book gave significantly better scores on the sleep questionnaires compared to sleep hygiene advice. The proportion using sleep medications was reduced in the self-help book group, whereas it was increased in the sleep hygiene group. Compared to pre-treatment, the self-help book improved scores on the sleep (effect sizes 0.61-0.62) and depression (effect size 0.18) scales, whereas the sleep hygiene advice improved scores on some sleep scales (effect sizes 0.24-0.28), but worsened another (effect size -0.36). In addition, sleep hygiene advice increased the number of days per week where they took sleep medications (effect size -0.50). To conclude, in this randomized controlled trial, the self-help book improved sleep and reduced the proportion using sleep medications compared to sleep hygiene advice. The self-help book is an efficient low-threshold intervention, which is cheap and easily available for patients suffering from insomnia. Sleep hygiene advice also improved sleep at follow-up, but increased sleep medication use. Thus, caution is warranted when sleep hygiene advice are given as a single treatment. PMID- 21790621 TI - A randomized controlled pilot study of adherence to transfusion strategies in cardiac surgery. AB - BACKGROUND: It is important to determine the optimal hemoglobin (Hb) concentration for red blood cell (RBC) transfusion for patients undergoing cardiac surgery because increased mortality has been associated with the severity of anemia and exposure to RBCs. Because a definitive trial will require thousands of patients, and because there is variability in transfusion practices, a pilot study was undertaken to determine adherence to proposed strategies. STUDY DESIGN AND METHODS: A single-center parallel randomized controlled pilot trial was conducted in high-risk cardiac patients to assess adherence to two transfusion strategies. Fifty patients were randomly assigned either to a "restrictive" transfusion strategy (RBCs if their Hb concentration was 70 g/L or less intraoperatively during cardiopulmonary bypass [CPB] and 75 g/L or less postoperatively) or a "liberal" transfusion strategy (RBCs if their Hb concentration was 95 g/L or less during CPB and less than 100 g/L postoperatively). RESULTS: The percentage of adherence overall was 84% in the restrictive arm and 41% in the liberal arm. Twenty-two (88%) patients were transfused 99 units of RBCs in the liberal group compared to 13 patients who were transfused 50 units in the restrictive group (p<0.01). There were no significant differences in individual adverse outcomes; however, more adverse events occurred in the restrictive group (38 vs. 15, p<0.01). CONCLUSION: Adherence to the evaluated interventions is vital to all randomized controlled trials as it has the potential to affect outcomes. Further pilot studies are required to optimize enrollment and transfusion adherence before a definitive study is conducted. PMID- 21790622 TI - Red blood cell products: consideration of the discrepant temperature ranges permitted for storage versus transport. AB - The focus of this study was to determine if there is significant data to prohibit short-term storage of red blood cells (RBCs; i.e., <24 hr) at 1 to 10 degrees C rather than 1 to 6 degrees C, which occurs not uncommonly when RBCs are stored in a cooler for a patient during surgery. This document will describe the evidence in the literature to date regarding the potential impact of having RBCs temporarily in the 1 to 10 degrees C range versus in the 1 to 6 degrees C range, if any, on key measures of the quality of RBC storage: potassium, adenosine triphosphate, 2,3-diphosphoglycerate, posttransfusion survival, and bacterial contamination. PMID- 21790623 TI - Inactivation of hepatitis A variants during heat treatment (pasteurization) of human serum albumin. AB - BACKGROUND: Pasteurization of human serum albumin (HSA) is detailed in the US and European Pharmacopoeial monographs and therefore a process that allows for little variation in physiochemical variables. Nevertheless, differences of up to 3.9 log in hepatitis A virus (HAV) inactivation by pasteurization have been reported. Here, the hypothesis that the choice of HAV variant used in the pasteurization might contribute to this inactivation variability is evaluated experimentally. STUDY DESIGN AND METHODS: The identity of four widely used cytopathic variants of the original HAV HM175 strain was determined by partial sequencing. These variants were used in pasteurization studies conducted under the principles of good laboratory practice, for which HAV-spiked HSA of 5 or 25% protein content was kept at 58+/-1 degrees C for 600+/-10 minutes, and the virus inactivation was assessed. In addition, data from previous pasteurization studies were included in the analysis. RESULTS: The four HAV variants could be divided into two subgroups, with significantly different (p<=0.0001) virus inactivation by pasteurization (4.7 and 4.8 log vs. 2.3 and 2.6 log, respectively). Also, the protein concentration of the HSA solution used for pasteurization had a significant effect on the achieved HAV inactivation, with reduction factors obtained in 5% HSA significantly lower than in 25% HSA (p<0.002). CONCLUSION: HAV variant and protein concentration of the HSA solution affect the overall HAV inactivation that is achieved during pasteurization. As the HAV inactivation capacity should not be overestimated, an HAV variant more resistant to heat inactivation should be used for studies investigating the viral safety profiles of plasma derivatives. PMID- 21790624 TI - In vitro variables of apheresis platelets are stably maintained for 7 days with 5% residual plasma in a glucose and bicarbonate salt solution, PAS-5. AB - BACKGROUND: Platelet additive solutions (PASs) facilitate improved recovery of plasma and may reduce the severity and/or frequency of plasma-associated transfusion reactions. Current apheresis platelet (PLT) PAS products contain approximately 30 to 40% residual plasma. In an effort to further decrease the residual plasma, two in vitro studies were conducted with PLTs suspended in 5% plasma and a reformulated PAS-3, named PAS-5, that contains additional salts, glucose, and bicarbonate. STUDY DESIGN AND METHODS: In Study 1, PLTs suspended in 5% plasma/95% PAS-5 were prepared directly on a separator (Amicus, Fenwal, Inc.) without additional centrifugation or washing. In Study 2, a double unit of hyperconcentrated Amicus PLTs in plasma was collected, divided, and centrifuged to prepare a control unit in 100% plasma and a paired test unit in 5% plasma/95% PAS-5. The in vitro properties of PLTs were assessed in both studies during 7-day storage at 20 to 24 degrees C with continuous agitation. RESULTS: In Study 1, PLT concentration, pH, mean PLT volume (MPV), HCO(3)(-), pCO(2), pO(2), lactate dehydrogenase, and hypotonic shock response (HSR) did not significantly change during storage. By Day 7, glucose levels and morphology scores modestly decreased (17.6 and 14.4%, respectively) and lactate levels modestly increased (to 7.2 mmol/L). In Study 2, MPV, pH, glucose, pO(2), HSR, and morphology were comparable in control and test PLTs during 7-day storage. Glucose consumption and lactate production were significantly less in test versus control PLTs (p<=0.0015). Extent of shape change and %CD62P-positive test PLTs were less than those of controls (p<0.001). CONCLUSION: Apheresis PLTs suspended in 5% plasma/95% PAS-5 maintained in vitro properties during 7-day storage. PMID- 21790625 TI - African American adult apheresis donors respond to granulocyte-colony-stimulating factor with neutrophil and progenitor cell yields comparable to those of Caucasian and Hispanic donors. AB - BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) are the most common source of cells used for hematopoietic transplantation. Benign ethnic neutropenia has been found in persons of African descent, affecting circulating white blood cells (WBCs), but not WBC production within marrow. Persons of African descent have reduced neutrophil mobilization after steroid administration, and newborns have fewer nucleated and progenitor cells in their cord blood. STUDY DESIGN AND METHODS: Twenty-two African American (AA) and 12 Hispanic PBPC donors were age, sex, and weight matched with 34 Caucasian donors. Groups were compared based on WBC and neutrophil counts after mobilization and numbers of CD34+ cells collected on Day 5 of G-CSF mobilization. RESULTS: AA donors had significantly lower baseline WBC (6.1+/-1.1 vs. 7.1+/-1.7, p=0.04) and neutrophil (3.4+/-1.1 vs. 4.5+/-1.3, p=0.01) counts compared to matched Caucasian donors. G-CSF-stimulated AAs had a significantly greater increase in WBC and neutrophil counts compared to matched Caucasians (889+/-293% vs. 665+/-230% neutrophils, p=0.02). There was no significant difference in product cell counts when comparing total nucleated, CD3+, CD34+, and mononuclear cells or colony-forming units (CFUs) between Caucasians and Hispanics or AAs and trends to greater numbers of neutrophils in products from AA donors. CONCLUSION: When stimulated by G-CSF, AAs are able to increase WBC and neutrophil counts to a higher degree than Caucasians, achieving similar numbers of neutrophil and progenitor cells in apheresis products despite starting from lower baseline blood counts. PMID- 21790626 TI - Autoimmune hemolytic anemia in pediatric liver or combined liver and small bowel transplant patients: a case series and review of the literature. AB - BACKGROUND: Autoimmune hemolytic anemia (AIHA) occurring after solid organ transplantation is an infrequently reported entity. We describe in this report six cases of AIHA in pediatric liver or combined liver and small bowel transplant patients. STUDY DESIGN AND METHODS: We retrospectively identified and reviewed the records of pediatric liver or combined liver and small bowel transplant patients with both serologic and clinical evidence of AIHA. We also performed an English language literature review for prior publications of AIHA occurring after solid organ transplantation. RESULTS: We identified six patients presenting with severe hemolysis 9 months to 14 years after transplantation. All six developed warm AIHA, and two had concomitant cold agglutinins. All except one patient received various therapeutic combinations including steroids, intravenous immune globulin, rituximab, plasmapheresis, splenectomy, and vincristine. Five patients achieved remission 2 weeks to 3 months after presentation. Although tacrolimus has been speculated to play a causative role in the development of AIHA after organ transplantation, our case series demonstrated slightly better outcomes despite continuing tacrolimus compared to published cases where most patients either received significantly reduced doses of tacrolimus or were switched to a different immunosuppressant (83% vs. 76% cumulative literature remission rate). CONCLUSION: AIHA may occur in solid organ transplant patients at a much higher frequency than previously believed. Hemolysis is often severe and resistant to steroid treatment alone. Thus early diagnosis and institution of aggressive multimodality treatment, including the use of rituximab, may be needed to achieve remission. PMID- 21790628 TI - European regulations on cord blood banking: an overview. PMID- 21790627 TI - Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease. AB - BACKGROUND: Increased rates of red blood cell (RBC) alloimmunization in patients with sickle cell disease may be due to transfusion frequency, genetic predisposition, or immune dysregulation. To test the hypothesis that sickle cell pathophysiology influences RBC alloimmunization, we utilized two transgenic mouse models of sickle cell disease. STUDY DESIGN AND METHODS: Transgenic sickle mice, which express human alpha and beta(S) globin, were transfused with fresh or 14 day-stored RBCs containing the HOD (hen egg lysozyme, ovalbumin, and human Duffy(b) ) antigen; some recipients were inflamed with poly(I : C) before transfusion. Anti-HOD alloantibody responses were subsequently measured by enzyme linked immunosorbent assay and flow crossmatch; a cohort of recipients had posttransfusion serum cytokines measured by bead array. RESULTS: Both Berkeley and Townes homozygous (SS) and heterozygous (AS) mice had similar rates and magnitude of anti-HOD RBC alloimmunization after fresh HOD RBC transfusion compared with control animals; under no tested condition did homozygous SS recipients make higher levels of alloantibodies than control animals. Unexpectedly, homozygous SS recipients had blunted cytokine responses and lower levels of anti-HOD alloantibodies after transfusion of 14-day stored RBCs, compared with control animals. CONCLUSIONS: In sum, homozygous beta(S) expression and the ensuing disease state are not alone sufficient to enhance RBC alloimmunization to transfused HOD RBCs in two distinct humanized murine models of sickle cell disease under the conditions examined. These data suggest that other factors may contribute to the high rates of RBC alloimmunization observed in humans with sickle cell disease. PMID- 21790630 TI - Flow cytometric analyses of CD34+ cells with inclusion of internal positive controls. AB - BACKGROUND: Flow cytometric measurement of CD34+ events is used to ensure the quality of human progenitor cell grafts. This study was conducted to evaluate whether the spiking of routine samples from peripheral blood and apheresis products with CD34+ positive controls is feasible. STUDY DESIGN AND METHODS: A total of 42 samples from 32 patients and one healthy donor were stained in duplicate for CD34+ cells. Before flow cytometric analysis, one tube was spiked with stabilized CD34+ cells at a defined concentration. RESULTS: Median numbers of viable CD34+ cells/uL did not differ between unspiked and spiked tubes (median 37, range 0-714; and median 34, range 0-719, respectively). The 95% confidence interval (CI) of the mean showed a broad overlap between these samples (41.9 119.1 and 41.4-119.3, respectively). In addition, the 95% CI of the mean for CD45+ cells/uL overlapped broadly and median numbers did not differ. Median viability of all CD45+ cells was significantly lower in the spiked tubes (96.75, range 64-98.8 vs. 99.25, range 97.5-99.8) with no overlap of the 95% CI of the mean viability. CONCLUSION: The results of this study show that spiking of routine samples with internal positive controls does not affect CD34+ cell analyses, but does support the reliability of important clinical data. The inclusion of positive controls is expedient for laboratories that perform analyses with low CD34+ numbers and laboratories that use different flow cytometric analyzers and may also become a requirement to meet statutory regulations. PMID- 21790629 TI - Red blood cell preservation by droplet freezing with polyvinylpyrrolidone or sucrose-dextrose and by bulk freezing with glycerol. AB - BACKGROUND: Red blood cell (RBC) preservation is essential to transfusion medicine. Many blood group reference laboratories need a method to preserve rare blood samples for serologic testing at a later date. This study offers a comparison of three common cryoprotective agents and protocols used today: bulk preservation with glycerol and droplet freezing with sucrose-dextrose (S+D) or polyvinylpyrrolidone (PVP). STUDY DESIGN AND METHODS: Human blood from 14 volunteers was collected and frozen at set intervals over 2 weeks with PVP, S+D, or glycerol. The frozen RBCs were later thawed and the percentage of surviving RBCs was determined. Detailed protocols and an instructional video are supplied. RESULTS: Over a 2-week period, RBCs preserved with glycerol and thawed with a widely used protocol showed a recovery of 41 +/- 16% (mean +/- standard deviation) while those thawed with a modified glycerol protocol showed a recovery of 76 +/- 8%. RBCs preserved by droplet freezing with S+D showed a recovery of 56 +/- 11% while those preserved by droplet freezing with PVP showed a recovery of 85 +/- 6%. Recovery values were similar with ethylenediaminetetraacetic acid or heparin anticoagulants, differing freezing rates, and varying droplet volumes. CONCLUSION: Droplet freezing with PVP offered the greatest recovery. While bulk freezing with glycerol can also be effective, droplet freezing may be a more convenient method overall. It requires less effort to thaw, needs much less storage room, and allows blood group laboratories to be frugal with thawing rare samples. PMID- 21790631 TI - Reinvestigations of six unusual paternity cases by typing of autosomal single nucleotide polymorphisms. AB - BACKGROUND: In some relationship cases, the initial investigations of autosomal short tandem repeats (STRs) lead to an ambiguous conclusion and supplementary investigations become necessary. STUDY DESIGN AND METHODS: Six unusual paternity cases were previously investigated by other researchers and published as case work examples in forensic journals. Here, the cases were reinvestigated by typing the samples for 49 autosomal single-nucleotide polymorphisms (SNPs) using the SNPforID multiplex assay. RESULTS: Three cases were solved by the SNP investigation without the need for any additional testing. In two cases, the SNP results supported the conclusions based on STRs. In the last case, the SNP results spoke in favor of paternity, and the combined paternity index based on autosomal STRs and SNPs was 12.3 billion. Nevertheless, the alleged father was excluded by X-chromosome typing. CONCLUSION: The case work examples underline the importance of performing supplementary investigations, and they advocate for the implementation of several panels that may be used in the highly unusual cases. Panels with SNPs or other markers with low mutation probabilities are preferable as supplementary markers, because the risk of detecting (additional) mutations is very low. PMID- 21790632 TI - A flow cytometric method for platelet counting in platelet concentrates. AB - BACKGROUND: The platelets (PLTs) in PLT concentrates are counted with hematology analyzers, but varying results among different hematology analyzers are observed, making comparisons very difficult. Due to the absence of red blood cells in PLT concentrates, the International Council for Standardization in Hematology (ICSH) reference method was modified to be used for PLT concentrates and validated in an international comparative study. STUDY DESIGN AND METHODS: Five PLT samples were shipped to eight participating centers of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative and counted on the same day. PLTs were stained with fluorescein isothiocyanate-labeled anti-CD41a in tubes (TruCount, BD Biosciences), measured on a flow cytometer, and analyzed with a uniform template. These samples were also counted on 15 hematology analyzers. RESULTS: The ICSH method and newly developed BEST method yielded PLT counting results with less than 1% difference (not significant). The intercenter coefficient of variation (CV) of the BEST method was on average 6.3% versus 7.6% on average for hematology analyzers. The CV of individual hematology analyzers was on average 0.9%, which was considerably lower than for the flow cytometers with a mean of 3.7%. CONCLUSION: The BEST flow cytometric method has a smaller intercenter CV and a smaller center-to-center deviation from the group mean compared to hematology analyzers. Conversely, individual hematology analyzers are more precise than the flow cytometric method. Thus, the flow cytometric method provides a calibration tool to allow comparisons between centers, but there is no need to replace routine counting with hematology analyzers. PMID- 21790633 TI - Increased numbers of total nucleated and CD34+ cells in blood group O cord blood: an analysis of neonatal innate factors in the Korean population. AB - BACKGROUND: We analyzed neonatal factors that could affect hematopoietic variables of cord blood (CB) donated from Korean neonates. STUDY DESIGN AND METHODS: The numbers of total nucleated cells (TNCs), CD34+ cells, and CD34+ cells/TNCs of CB in neonates were compared according to sex, gestational age, birth weight, birth weight centile for gestational age, and ABO blood group. RESULTS: With 11,098 CB units analyzed, blood group O CB showed an increased number of TNCs, CD34+ cells, and CD34+ cells/TNCs compared with other blood groups. Although TNC counts were lower in males, no difference in the number of CD34+ cells was demonstrated because the number of CD34+ cells/TNCs was higher in males. An increase in the gestational age resulted in an increase in the number of TNCs and decreases in the number of CD34+ cells and CD34+ cells/TNCs. The numbers of TNCs, CD34+ cells, and CD34+ cells/TNCs increased according to increased birth weight centile as well as birth weight. CONCLUSION: CB with blood group O has unique hematologic variables in this large-scale analysis of Korean neonates, although the impact on the storage policies of CB banks or the clinical outcome of transplantation remains to be determined. PMID- 21790634 TI - Splanchnic-cerebral oxygenation ratio as a marker of preterm infant blood transfusion needs. AB - BACKGROUND: Premature neonates often receive red blood cell (RBC) transfusions to improve tissue perfusion and oxygen delivery. Clinical and laboratory indicators used to guide transfusion therapy are inadequate to determine physiologic need with high predictability and transfusions frequently do not result in clinical improvement. The splanchnic-cerebral oxygenation ratio (SCOR) provides insight into overall tissue oxygen sufficiency and can be determined using near-infrared spectroscopy (NIRS). Our aim was to assess the usefulness of SCOR as a marker for transfusion need in preterm infants. STUDY DESIGN AND METHODS: This study was a prospective observational pilot study utilizing NIRS to analyze the SCOR in symptomatic anemic premature neonates receiving RBC transfusions and nontransfused asymptomatic premature neonates with similarly low hemoglobin (Hb) levels. Subject clinical status was determined based on frequency of apnea, bradycardia, pulse-oximetry desaturation events, heart rate, respiratory support, and feeding tolerance. We then assessed for any difference between baseline (pretransfusion) SCOR of 1) symptomatic subjects who improved after transfusion, 2) symptomatic subjects who did not improve, and 3) asymptomatic subjects. RESULTS: The study included 52 subjects (34 transfused, 18 asymptomatic): mean birth weight was 1164 g, mean gestational age was 28.6 weeks, and mean Hb level was 9.0 g/dL. Of 34 transfused subjects, 19 improved (56%). Mean baseline SCOR values were lower in neonates who improved with transfusion, 0.61 +/- 0.22, when compared to those without improvement, 0.75 +/- 0.17, and asymptomatic neonates, 0.77 +/- 0.16 (p = 0.03). Infants with a low baseline SCOR (<= 0.73) were more likely to improve after transfusion (likelihood ratio, 2.8; 95% confidence interval, 1.1-6.7). CONCLUSION: SCOR may help identify premature infants who will benefit from RBC transfusion. PMID- 21790635 TI - Initial experiences with point-of-care rapid thrombelastography for management of life-threatening postinjury coagulopathy. AB - BACKGROUND: Massive transfusion (MTP) protocol design is hindered by lack of accurate assessment of coagulation. Rapid thrombelastography (r-TEG) provides point-of-care (POC) analysis of clot formation. We designed a prospective study to test the hypothesis that integrating TEG into our MTP would facilitate goal directed therapy and provide equivalent outcomes compared to conventional coagulation testing. STUDY DESIGN AND METHODS: Thiry-four patients who received more than 6 units of red blood cells (RBCs)/6 hours who were admitted to our Level 1 trauma center after r-TEG implementation (TEG) were compared to 34 patients admitted prior to TEG implementation (Pre-TEG). Data are presented as mean+/-SEM. RESULTS: Emergency department pre-TEG versus TEG shock, and coagulation indices, were not different: systolic blood pressure (94 mmHg vs. 101 mmHg), temperature (35.3 degrees C vs. 35.9 degrees C), pH (7.16 vs. 7.11), base deficit (-13.0 vs. -14.7), lactate (6.5 vs. 8.1), international normalized ratio (INR; 1.59 vs. 1.83), and partial thromboplastin time (48.3 vs. 57.9). Although not significant, patients with Injury Severity Score range 26 to 35 were more frequent in the pre-TEG group. Fresh-frozen plasma (FFP):RBCs, platelets:RBCs, and cryoprecipitate (cryo):RBC ratios were not significantly different at 6 or 12 hours. INR at 6 hours did not discriminate between survivors and nonsurvivors (p=0.10), whereas r-TEG "G" value was significantly associated with survival (p=0.03), as was the maximum rate of thrombin generation (MRTG; mm/min) and total thrombin generation (TG; area under the curve) (p=0.03 for both). Patients with MRTG of more than 9.2 received significantly less components of RBCs, FFP, and cryo (p=0.048, p=0.03, and p=0.04, respectively). CONCLUSION: Goal-directed resuscitation via r-TEG appears useful for management of trauma-induced coagulopathy. Further experience with POC monitoring could result in more efficient management leading to a reduction of transfusion requirements. PMID- 21790636 TI - Partial D phenotypes and genotypes in the Chinese population. AB - BACKGROUND: The D variant phenotypes are often categorized into weak D types and partial D types. Although the molecular basis underlying the partial D phenotype has been investigated in several races, data from Chinese populations are rare. STUDY DESIGN AND METHODS: We collected partial D samples from 1,274,540 blood donors, as well as from sporadic patients in the Chinese population, over a 4 year period. Samples with partial D phenotype were determined by commercial monoclonal anti-D panels and molecular methods. Blood samples with discrepant results of serologic and molecular methods were further investigated by polymerase chain reaction (PCR) with sequence-specific primers and nucleotide sequencing of RHD exons. The detection of antibodies was performed. RESULTS: A total of 44 samples with partial D phenotypes were confirmed. Molecular typing revealed five different known aberrant alleles as well as four new RHD alleles. As described previously, DVI represented the most frequent partial D type in China with a total of 36 samples. However, discrepant results were observed in four DVI samples with serotyping and genotyping (i.e., DVI category identified by D-screen test and grossly intact RHD gene identified by multiplex PCR). We also found four novel alleles, termed DFR-4, DCS-3, DCC, and DLX. CONCLUSION: To date, this study presents the most comprehensive report on partial D in China. The distribution of partial D types in China was found to be complicated and polymorphic, whereas RhD genotyping of DVI-variant samples might give inaccurate results due to a relatively high incidence of RHD(1227G>A) in the Chinese population. PMID- 21790637 TI - The healthy donor effect: a matter of selection bias and confounding. PMID- 21790638 TI - The Three 'R's'. PMID- 21790639 TI - Letters to the editor. PMID- 21790640 TI - The Barthel Index and ADL Evaluation in Stroke Rehabilitation in Australia, Japan, the UK and the USA. AB - At present many of the activities of daily living indices used in Australia lack essential characteristics of an index yielding desirable results. This study argues that the Barthel Index as modified by Shah, Vanclay and Cooper (1989a) is robust and has the required biometric and psychometric qualities. It presents evidence in support of the use of the Barthel Index as a preferred measure of the activities of daily living function to report therapeutically meaningful and valid information of patient care and stroke rehabilitation outcomes in Australia. It also presents the functional performance on the modified Barthel Index and the outcome of all 258 first stroke patients admitted for inpatient rehabilitation in Brisbane, Australia. Using the Barthel Index as a measure of activities of daily living functions, the study then compares the performances and outcomes of stroke patients between Australia, Japan, the United Kingdom and the United States of America. PMID- 21790641 TI - Awareness of deficit after traumatic brain injury: a literature review. AB - Much of the research literature on long term psychosocial adjustment to traumatic brain injury (TBI) suggests that persons with TBI do not adequately perceive their deficits of higher cortical functioning and, as a consequence, they may adopt maladaptive responses to their social environment. This issue poses a major challenge for occupational therapists and other rehabilitation professionals involved in the social and vocational rehabilitation of persons with TBI. However, the literature is characterised by disagreement concerning the nature and extent of unawareness of deficits in this group. In addressing this issue, several factors are considered: severity of injury, time since injury, prevailing neuropsychological and psychosocial perspectives, and access to intensive rehabilitation programmes. Implications for occupational therapists as practitioners and researchers are discussed. PMID- 21790642 TI - Improving handwriting through kinaesthetic sensitivity practice. AB - Children in their first two years of formal education (kindergarten and year one) were assessed for handwriting performance. Those with poor handwriting were given practice on one of three tasks: kinaesthetic acuity, kinaesthetic memory and perception or a handwriting task. Both forms of kinaesthetic sensitivity practice produced significant improvement in handwriting performance by the year one children, while handwriting practice did not. The younger children did not demonstrate as clear cut gains as the older. These results support the findings of previous research which indicates the importance of kinaesthetic ability for performance of complex motor tasks. PMID- 21790643 TI - "Give me a fish and I eat today: teach me to fish and I eat for a lifetime". The Newcastle Programme. AB - The development of a new occupational therapy course at the University of Newcastle has proved an exciting challenge to the authors. A common core year with other health professionals introduces students to the concepts of holistic health. Students develop problem solving skills and an attitude to therapy which encourages them to focus on each client as an individual, living and working within their specific environment. The reductionist view of intervention does not seem to be compatible with the self directed, problem based approach to learning. New patterns of fieldwork to support and consolidate theoretical input have been developed. Staff have learnt a new approach to education which is satisfying and rewarding. We believe students will graduate with skills which will allow them to meet the challenge of a new century. PMID- 21790644 TI - Isometric joystick: a study of control by adolescents and young adults with cerebral palsy. AB - This research was undertaken to determine the best wheelchair driving method for clients with cerebral palsy who were experiencing difficulties using displacement joysticks. The hypothesis was that adolescents with cerebral palsy would perform better in a tracking task using an isometric joystick (which has no moving parts) than a displacement joystick of the type used in commercial wheelchair controllers. A series of single subject case studies was performed in which the activating force of the isometric joystick was individualised for each subject. Comparative evaluation of the isometric joystick and a displacement joystick was then carried out. Results indicate that performance using the displacement joystick was superior to performance with the isometric joystick for the able bodied subject and four of the five subjects with cerebral palsy. One of the subjects showed significantly better performance on the displacement joystick using his hand, and no significant difference between joysticks using his foot. The remaining subject, who used his foot, showed no significant difference between joysticks. These findings suggest that subjects with cerebral palsy with prior experience using a displacement joystick do not appear to benefit by the use of an isometric joystick compared to a displacement joystick. No difference in the use of the two joysticks was found for subjects with cerebral palsy who had no prior experience using a joystick. This suggests that an isometric joystick is an option for people beginning to learn to drive an electric wheelchair. PMID- 21790645 TI - The AAOT Research Awards, 1991. PMID- 21790646 TI - A fold up walker tray. PMID- 21790647 TI - Colloquium on Development of Occupational Therapy as an Academic Discipline through Postgraduate Education. PMID- 21790648 TI - Sensitization to furry animals in an urban atopic population living in Naples, Italy. PMID- 21790649 TI - Proceedings of the 7th Copenhagen Workshop on Testicular Carcinoma in situ and Germ Cell Cancer, 13-15 October 2010. PMID- 21790650 TI - A pathologist's view on the testis biopsy. AB - Aspects of the biopsy of the testis from the pathologist's point of view are discussed. Direct enzyme-histochemical staining for alkaline phosphatase (dAP) on frozen sections of biopsies taken during operation is a useful diagnostic tool to aid surgeons in testis-sparing surgery. Biopsy of the contralateral testis for the diagnosis of carcinoma in situ (CIS) in patients with a testicular germ cell tumour is not standard of care in most countries because of the high rate of negative biopsies. Based on risk factors for germ cell tumours, i.p. microlithiasis, a patient population is defined in which the rate of CIS in the contralateral biopsy is about 25%. It is reiterated that the diagnosis of CIS in testicular biopsies requires expertise, and should not be carried out without immunohistochemistry for markers for CIS. As OCT3/4 is increasingly used as marker, it is important to be aware that it may be false-negative in biopsies fixed in Bouin's or Stieve's fixative. Preliminary results are presented on a series of biopsies from cryptorchid testes in infants and children allowing the definition of morphological and immunohistochemical criteria for delayed maturation of gonocytes and pre-CIS. PMID- 21790651 TI - Pathogenesis of testicular carcinoma in situ and germ cell cancer: still more questions than answers. PMID- 21790652 TI - Treatment of patients with relapsed and/or cisplatin-refractory metastatic germ cell tumours: an update. AB - Since the introduction of cisplatin-based therapy in the late 1970s, germ cell tumours (GCT) have been one of the successes in oncology with high cure rates even in patients presenting with metastatic disease. For patients with relapse after cisplatin-based therapy, treatment is still curative in approximately 50% of the cases. Management options for these patients include surgery, radiotherapy and use of conventional dose or high-dose chemotherapy (HDCT). Therefore, treatment of relapsed or refractory patients is complex and there is no uniformly accepted approach available. Data comparing conventional dose and HDCT in the first salvage therapy is limited to one randomized trial which was not able to ultimately define optimal treatment. More recently, a large retrospective analysis of nearly 1600 patients not only identified prognostic factors in relapse, but retrospectively suggested a 10-15% benefit regarding overall survival for patients receiving HDCT plus autologous stem cell transplantation over patients receiving conventional-dose chemotherapy. Prognosis in multiply relapsed and primary cisplatin-refractory patients is generally poor. Currently, a number of mechanisms of cisplatin resistance and potential drug targets like global methylation and BRAF mutation status are under investigation in refractory GCT. PMID- 21790654 TI - Effects of endogenous FSH on normal human spermatogenesis in adults. AB - Unilateral orchiectomy (UO) in adult bonnet monkeys and boars elicits a compensatory increase in size and sperm production of the remaining testis. The objective of this study was to investigate whether a similar effect is evident also in humans. We prospectively studied 50 patients from October 2003 to December 2005 who underwent UO for seminomatous tumour, with sperm concentration >20 * 10(6) /mL or total sperm count >40 * 10(6) at diagnosis and without elevation of serum tumour markers. Patients were followed-up with surveillance and they were studied at the time of diagnosis of testicular cancer (T(-1) ), 1 month after unilateral orchiectomy (T(0) ) and yearly for 3 years (T(1) , T(2) , T(3) ) with semen analysis, measurement of plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, total testosterone, and oestradiol and ultrasonographic scanning of the remaining testis. A decline in circulating inhibin B and an increase in FSH levels were evident 1 month after UO. The elevation of FSH was maintained up to 3 years and was associated with a significant increase in testicular volume of 19 and 30%, 2 and 3 years after UO respectively. Although patients had normozoospermia at the time of diagnosis of testicular cancer, they showed a statistically significant increase in total sperm count at T(2) and T(3) with respect to T(-1) and T(0.) In conclusion, we showed that in humans, the testes are not normally operating at their maximal potential in terms of spermatogenesis. Therefore, in physiological situations, FSH secretion is insufficient to stimulate spermatogenesis to its ceiling. A sustained endogenous increase in FSH secretion might drive human testes towards their maximal function. PMID- 21790653 TI - Human spermatogonial stem cells: a possible origin for spermatocytic seminoma. AB - In mammals, spermatogenesis is maintained throughout life by a small subpopulation of type A spermatogonia called spermatogonial stem cells (SSCs). In rodents, SSCs, or Asingle spermatogonia, form the self-renewing population. SSCs can also divide into Apaired (Apr) spermatogonia that are predestined to differentiate. Apaired spermatogonia produce chains of Aaligned (Aal) spermatogonia that divide to form A1 to A4, then type B spermatogonia. Type B spermatogonia will divide into primary spermatocytes that undergo meiosis. In human, there are only two different types of A spermatogonia, the Adark and Apale spermatogonia. The Adark spermatogonia are considered reserve stem cells, whereas the Apale spermatogonia are the self-renewing stem cells. There is only one generation of type B spermatogonia before differentiation into spermatocytes, which makes human spermatogenesis less efficient than in rodents. Although the biology of human SSCs is not well known, a panel of phenotypic markers has recently emerged that is remarkably similar to the list of markers expressed in mice. One such marker, the orphan receptor GPR125, is a plasma membrane protein that can be used to isolate human SSCs. Human SSCs proliferate in culture in response to growth factors such as GDNF, which is essential for SSC self-renewal in mice and triggers the same signalling pathways in both species. Therefore, despite differences in the spermatogonial differentiation scheme, both species use the same genes and proteins to maintain the pool of self-renewing SSCs within their niche. Spermatocytic seminomas are mainly found in the testes of older men, and they rarely metastasize. It is believed that these tumours originate from a post-natal germ cell. Because these lesions can express markers specific for meiotic prophase, they might originate from a primary spermatocyte. However, morphological appearance and overall immunohistochemical profile of these tumours indicate that the cell of origin could also be a spermatogonial stem cell. PMID- 21790655 TI - Should human papillomavirus testing be performed in men participating in protocols of assisted reproduction? PMID- 21790656 TI - Con A-binding protein Zn-alpha2-glycoprotein on human sperm membrane is related to acrosome reaction and sperm fertility. AB - Fertilization, the recognition and fusion between spermatozoa and oocyte, involves various molecules on the spermatozoa and oocyte membranes. Concanavalin A (ConA)-binding proteins may be one of the molecules involved in mammal spermatozoa fertilization; however, their structure and function remain largely unknown. Here, we initially identified a ConA-binding protein, Zn-alpha2 glycoprotein (ZAG), involved in regulating the acrosome reaction (AR) of human spermatozoa. ZAG is localized on the pre-equatorial region covering the acrosome, neck and tail (some parts of middle piece and principal piece respectively) regions of the acrosome intact human spermatozoa, and disappears in the acrosomal region of the acrosome-reacted spermatozoa. Polyclonal antibodies against human recombinant ZAG significantly reduced the AR and sperm capability binding to human zona pellucida or penetration into zona-free hamster oocytes. Furthermore, assessment of the signaling pathways regulated by ZAG revealed that ZAG affects sperm AR through both the cAMP/PKA and PKC pathways. These results indicate that ZAG, which is present on the human sperm membrane, plays a critical role in the AR and subsequently, may be involved in sperm fertility. PMID- 21790657 TI - Erectile response to type 5 phosphodiesterase inhibitor could be preserved with the addition of simvastatin to conventional insulin treatment in rat model of diabetes. AB - Enhanced RhoA/Rho-kinase pathway plays anti-erectile role and is associated with reduced response to type 5 phosphodiesterase inhibitor (PDE5I) in diabetic animals. We tested whether adjunctive simvastatin to conventional insulin treatment would restore PDE5I-induced as well as basal erectile response in diabetic rat model of erectile dysfunction. Forty 8-week-old male Sprague-Dawley rats were equally divided into four groups, (n=10) i.e. the diabetic group (D), age-matched control (C), conventional insulin treatment (I) and adjunctive simvastatin to conventional insulin treatment (S). Following 10weeks of intraperitoneal injection of streptozotocin (STZ, 35mg/kg), the group I and S received insulin (10U NPH/day) for 4weeks. Concurrently, group S received simvastatin (20mg/kg/day). Following 14weeks of diabetes induction, basal and PDE5I (intravenous mirodenafil 1mg/kg)-elicited erectile response were assessed during cavernous nerve electrostimulation. Then, penile tissues were processed for molecular assessment. Although group I failed to restore basal and PDE5I induced erectile response, group S showed normalized erectile responses. Furthermore, group I showed improvement of only eNOS-related pathway, whereas group S effectively controlled both eNOS-related and RhoA/Rho-kinase pathway. Conclusively, adjunctive use of simvastatin to conventional insulin treatment showed more effectiveness in restoring erectile responses of diabetic rats by controlling the RhoA/Rho-kinase pathway than conventional insulin treatment alone. PMID- 21790658 TI - 7alpha-methyl-19-nortestosterone vs. testosterone implants for hypogonadal osteoporosis: a preclinical study in the aged male orchidectomized rat model. AB - Overt male hypogonadism induces not only osteoporosis but also unfavourable changes in body composition, which can be prevented by testosterone (T) replacement. In this preclinical study, the potential of synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) as alternative treatment for male hypogonadism was evaluated in comparison with T. Eleven-month-old male rats were orchidectomized (orch) and left untreated for 2-months. Subsequently, the effects of 4-month MENT (12 MUg/day) and T (72 MUg/day) treatment on bone, muscle and fat were analysed using microcomputed tomography, dual-energy X-ray absorptiometry, dynamic bone histomorphometry and muscle fibre typing. At the onset of treatment, orch rats were clearly hypogonadal. This was evidenced by significant reductions of androgen-sensitive organ weight, lean mass, cortical thickness and trabecular bone volume compared with sham-operated aged-matched controls (sham). MENT and T restored weight of androgen-sensitive organs to a similar extent, with a superior anabolic action of MENT on levator ani muscle. Both androgens not only fully rescued hypogonadal loss of lean mass but also restored muscle fibre type composition and trabecular bone volume. Cortical bone loss was similarly prevented by MENT and T, but without full recovery to sham. Both androgens stimulated periosteal bone formation, but with a stronger effect of T. By contrast, MENT more strongly suppressed endocortical bone formation and bone turnover rate and reduced fat mass and serum leptin to a greater extent than T. MENT and T are both effective replacement therapies to stimulate bone and muscle in hypogonadal rats, with stronger lipolytic action of MENT. PMID- 21790659 TI - Associations between hazard indices of di-n-butylphthalate and di-2 ethylhexylphthalate exposure and serum reproductive hormone levels among occupationally exposed and unexposed Chinese men. AB - The knowledge on the dose-response relationships between cumulative phthalate exposure and reproductive hormones in human are lacking. To assess the characteristics of the associations between hazard index (HI) of cumulative di-n butylphthalate (DBP) and di-2-ethylhexylphthalate (DEHP) exposures and serum concentrations of free testosterone (fT), estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), we used restricted cubic spline function to characterize the dose-response curves between the HI values and reproductive hormones for 74 male workers occupationally exposed to high levels of DBP and DEHP, and 63 male construction workers as comparison group matched for age and smoking status. The median of HI value was 5.30 for exposed workers, 53.0-fold that of unexposed workers (0.10). 89.2% of exposed workers and 1.6% of unexposed workers have HI over 1.00. We observed a borderline significantly negative association between HI and fT in exposed workers (r=-0.195, p=0.096), but not in unexposed workers. The exposed workers showed inverted long-tailed J-shaped fT and FSH curves, and small changes in the LH curve, whereas unexposed workers had inverted and flattened-S-shaped fT and mirror-S-shaped LH and FSH curves. Both T production and hypothalamo-pituitary-testis (HPT) axis function were damaged in workers with high HI of phthalate exposures. HPT feedback function was activated in workers with both high and low HI, and plays an important role in preventing fT level from further decreasing with a rise in HI. PMID- 21790660 TI - External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long-chain triglyceride emulsion propofol in beagle dogs. AB - This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PK-PD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.6-20.5), 1.9%/h, 7.3% (5.4-9.3), and -0.5% (-2.6 to 1.6), 8.7% (7.3-10.1), 2.5%/h, 6.0% (4.1-7.2) for microemulsion propofol, and -9.3% ( 11.6 to -6.9), 20.1% (18.2-22.0), 5.1%/h, 7.6% (6.1-9.1) and 5.6% (4.1-7.1), 8.0% (6.9-9.3), 4.7%/h, 4.1% (3.1-5.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PK-PD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration. PMID- 21790661 TI - Molecular basis of human body odour formation: insights deduced from corynebacterial genome sequences. AB - During the past few decades, there has been an increased interest in the essential role of commensal skin bacteria in human body odour formation. It is now generally accepted that skin bacteria cause body odour by biotransformation of sweat components secreted in the human axillae. Especially, aerobic corynebacteria have been shown to contribute strongly to axillary malodour, whereas other human skin residents seem to have little influence. Analysis of odoriferous sweat components has shown that the major odour-causing substances in human sweat include steroid derivatives, short volatile branched-chain fatty acids and sulphanylalkanols. In this mini-review, we describe the molecular basis of the four most extensively studied routes of human body odour formation, while focusing on the underlying enzymatic processes. Considering the previously reported role of beta-oxidation in odour formation, we analysed the genetic repertoire of eight Corynebacterium species concerning fatty acid metabolism. We particularly focused on the metabolic abilities of the lipophilic axillary isolate Corynebacterium jeikeium K411. PMID- 21790662 TI - In vitro human skin permeation and cutaneous metabolism of catechins from green tea extract and green tea extract-loaded chitosan microparticles. AB - Catechins are major antioxidants in green tea (Camellia sinensis or Camellia assamica), but because they do not permeate the skin well, the application of green tea in cosmetic products has so far been limited. This study aims to evaluate the cutaneous absorption of catechins from an extract of green tea and from a green tea extract-loaded chitosan microparticle. The catechin skin metabolism was also examined. The results suggest that chitosan microparticles significantly improve the ability of catechins to permeate skin. The cutaneous metabolism of the catechins significantly affected their permeation profiles. Epicatechin (EC) and epigallocatechin (EGC) penetrated the skin more than epigallocatechin gallate (EGCG) and epicatechin gallate (ECG). The galloyl groups in EGCG and ECG were enzymatically hydrolysed to EGC and EC, respectively. Dehydroxylation of catechins was also observed. Chitosan microparticles effectively prevented enzymatic changes of the catechins; therefore, chitosan microparticles are here found to be the promising carriers for enhancing the skin permeation. PMID- 21790663 TI - Effect of compression load and temperature on thermomechanical tests for gutta percha and Resilon(r). AB - AIM: To analyse a method used to evaluate the thermomechanical properties of gutta-percha and Resilon((r)) at different temperatures and compression loads. METHODOLOGY: Two hundred and seventy specimens measuring 10 mm in diameter and 1.5 mm in height were made from the following materials: conventional gutta percha (GCO), thermoplastic gutta-percha (GTP) and Resilon((r)) cones (RE). After 24 h, the specimens were placed in water at 50 degrees C, 60 degrees C or 70 degrees C for 60 s. After that, specimens were placed between two glass slabs, and loads weighing 1.0, 3.0 or 5.0 kg were applied. Images of the specimens were digitized before and after the test and analysed using imaging software to determine their initial and final areas. The thermomechanical property of each material was determined by the difference between the initial and final areas of the specimens. Data were subjected to anova and SNK tests at 5% significance. To verify a possible correlation between the results of the materials, linear regression coefficients (r) were calculated. RESULTS: Data showed higher flow area values for RE under all compression loads at 70 degrees C and under the 5.0 kg load at 60 degrees C (P < 0.05). Regarding gutta-percha, GTP showed higher flow under loads weighing 3.0 and 5.0 kg, at 60 and 70 degrees C (P < 0.05). GCO presented higher flow at 70 degrees C with a load of 5.0 kg. Regression analyses showed a poor linear correlation amongst the results of the materials under the different experimental conditions. CONCLUSION: Gutta-percha and Resilon((r)) cones require different compression loads and temperatures for evaluation of their thermomechanical properties. For all materials, the greatest flow occurred at 70 degrees C under a load of 5.0 kg; therefore, these parameters may be adopted when evaluating endodontic filling materials. PMID- 21790664 TI - Diagnostic yield of conventional radiographic and cone-beam computed tomographic images in patients with atypical odontalgia. AB - AIM: To investigate whether the additional diagnostic yield of a cone-beam computed tomography (CBCT) examination over conventional radiographs in patients primarily suspected of having atypical odontalgia (AO) improves differentiation between AO and symptomatic apical periodontitis (SAP) in patients with severe chronic intraoral pain. METHODOLOGY: In this clinical study, 25 patients (mean age 54 +/- 11 years, range 34-72) participated; 20 were diagnosed with AO and 5 with SAP. All patients were recruited from the clinics of the Faculty of Odontology, Malmo University. AO inclusion criteria were chronic pain (>6 months) in a region where a tooth had been endodontically or surgically treated, with no pathological cause detectable in clinical or radiologic examinations. SAP inclusion criteria were recurrent pain from a tooth diagnosed with apical periodontitis in clinical and radiographic examinations. Assessments comprised a self-report questionnaire on pain characteristics, a comprehensive clinical examination and a radiographic examination including panoramic and intraoral radiographs and CBCT images. The main outcome measure was periapical bone destruction. RESULTS: Sixty per cent of patients with AO had no periapical bone destructions detectable with any radiographic method. Overall, CBCT rendered 17% more periapical bone destructions than conventional radiography. Average pain intensity in patients with AO was 5.6 (+/- 1.8) on a 0-10 numerical rating scale, and average pain duration was 4.3 (+/- 5.2) years. CONCLUSION: Cone-beam computed tomography improves identification of patients without periapical bone destruction, which may facilitate differentiation between AO and SAP. PMID- 21790665 TI - A note on epistemics and discourse analysis. AB - Discursive Psychology has the great merit of having introduced discourse analysis (DA) to social psychology and to have contributed to DA itself by its study of the expression of 'psychological' notions in text and talk. Within this perspective, this paper presents some elements of a proposal to study the expression of knowledge in discourse. Beginning with a brief summary of our multidisciplinary approach to knowledge, followed by a summary of discourse structures that express knowledge, the main argument of the paper is that we not only need to take discourse seriously in the study of knowledge, but cannot ignore their cognitive underlying structures if we want to describe and explain many properties of discourse, such as all implicit or presupposed knowledge, as well as the interactional and contextual management of old and new knowledge in text and talk. PMID- 21790666 TI - Discursive social psychology now. AB - This paper reviews the progress of discourse-analytic approaches in social psychology from the late 1980s to the present day, with a particular focus on the way conceptual and methodological contributions from within the Discourse and Rhetoric Group at Loughborough University have negotiated a positive role for innovative studies of language in the discipline of psychology. Social psychology has become a key site for the accumulation of a series of empirical studies that have seen the flourishing of a distinctive form of 'discursive social psychology' that has succeeded in moving from the margins of the discipline to a more accepted position. The paper traces this trajectory of discourse analysis from the limits to the centre of social psychology attending to five features that now characterise its contribution to psychology; an emphasis on everyday conversation, a concern with interpersonal interaction, explication of formal sequences; an insistence on empirical claims; and fidelity to the ethos of its host discipline. The paper concludes with some comments on the wider context of this new approach inside psychology today. PMID- 21790667 TI - Diffusion tensor imaging of the cerebellum and eyeblink conditioning in fetal alcohol spectrum disorder. AB - BACKGROUND: Prenatal alcohol exposure is related to a wide range of neurocognitive effects. Eyeblink conditioning (EBC), which involves temporal pairing of a conditioned with an unconditioned stimulus, has been shown to be a potential biomarker of fetal alcohol exposure. A growing body of evidence suggests that white matter may be a specific target of alcohol teratogenesis, and the neural circuitry underlying EBC is known to involve the cerebellar peduncles. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that has proven useful for assessing central nervous system white matter integrity. This study used DTI to examine the degree to which the fetal alcohol related deficit in EBC may be mediated by structural impairment in the cerebellar peduncles. METHODS: Thirteen children with fetal alcohol spectrum disorder (FASD) and 12 matched controls were scanned using DTI and structural MRI sequences. The DTI data were processed using a voxelwise technique, and the structural data were used for volumetric analyses. Prenatal alcohol exposure group and EBC performance were examined in relation to brain volumes and outputs from the DTI analysis. RESULTS: Fractional anisotropy (FA) and perpendicular diffusivity group differences between alcohol-exposed and nonexposed children were identified in the left middle cerebellar peduncle. Alcohol exposure correlated with lower FA and greater perpendicular diffusivity in this region, and these correlations remained significant even after controlling for total brain and cerebellar volumes. Conversely, trace conditioning performance was related to higher FA and lower perpendicular diffusivity in the left middle peduncle. The effect of prenatal alcohol exposure on trace conditioning was partially mediated by lower FA in this region. CONCLUSIONS: This study extends recent findings that have used DTI to reveal microstructural deficits in white matter in children with FASD. This is the first DTI study to demonstrate mediation of a fetal alcohol-related effect on neuropsychological function by deficits in white matter integrity. PMID- 21790668 TI - Alcohol induces liver neoplasia in a novel alcohol-preferring rat model. AB - BACKGROUND: Alcohol is a significant risk factor for the development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated the formation of hepatic neoplasia in the setting of chronic alcohol consumption alone. METHODS: We investigated whether rats selectively bred for high alcohol preference (P rats), allowed free access to water, or water and 10% (v/v) alcohol, for 6, 12, or 18 months, develop hepatic neoplasia. RESULTS: At necropsy, liver tumor incidence and multiplicity were significantly increased in 18-month alcohol-consuming versus water-consuming P rats. These data were confirmed histologically by glutathione-S-transferase pi-class (GSTp) staining. Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK) staining was also increased in the sinusoidal lining cells within livers of alcohol-consuming versus water only P rats. In addition, cytochrome p450IIE1 (CYP2E1) mRNA, protein expression/activity, and intrahepatic oxidative stress were significantly increased in alcohol-consuming P rat livers versus water only. In contrast, acetaldehyde dehydrogenase expression decreased in alcohol-consuming versus water only P rats. No significant difference in alcohol dehydrogenase expression was detected. CONCLUSIONS: These data demonstrate that chronic alcohol consumption is associated with hepatic neoplasia, MAPK/ERK activation, increased CYP2E1 activity, and intrahepatic oxidative stress in P rats. As these rats are well characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or "alcoholism"-induced liver neoplasia. PMID- 21790669 TI - Limited therapeutic effect of N-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis. AB - BACKGROUND: Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver. METHODS: Adult male Sprague Dawley rats were fed for 130 days with liquid diets containing 0 or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow-fed controls were studied in parallel. Liver tissues were used for histopathology, cytokine activation, and insulin/IGF-1 signaling assays. RESULTS: We observed significant positive trends of increasing severity of steatohepatitis (p = 0.016) with accumulation of neutral lipid (p = 0.0002) and triglycerides (p = 0.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol-fed rats, NAC reduced inflammation, converted the steatosis from a predominantly microvesicular to a mainly macrovesicular histological pattern, reduced pro-inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF-1 receptor and IGF-2 in liver. However, NAC did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3beta, or p70S6K, nor did it significantly reduce pro-ceramide or GM3 ganglioside gene expression in liver. CONCLUSIONS: Antioxidant treatments reduce the severity of chronic alcohol related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin/IGF-1 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance. PMID- 21790670 TI - Does variance in drinking motives explain the genetic overlap between personality and alcohol use disorder symptoms? A twin study of young women. AB - BACKGROUND: Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Although drinking motives have been posited as important mediators of the alcohol personality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e., abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear. METHODS: Using data from 2,904 young adult female twins, the phenotypic and genetic associations between personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen A, 1982 unpublished data], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa and McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested. RESULTS: Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant. CONCLUSIONS: Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms. PMID- 21790671 TI - Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following alcohol binge in chronically ethanol-fed rats. AB - BACKGROUND: Binge drinking after chronic ethanol consumption is one of the important factors contributing to the progression of steatosis to steatohepatitis. The molecular mechanisms of this effect remain poorly understood. We have therefore examined in rats the effect of single and repeat ethanol binge superimposed on chronic ethanol intake on liver injury, activation of mitogen-activated protein kinases (MAPKs), and gene expression. METHODS: Rats were chronically treated with ethanol in liquid diet for 4 weeks followed by single ethanol binge (5 gm/kg body weight) or 3 similar repeated doses of ethanol. Serum alcohol and alanine amino transferase (ALT) levels were determined by enzymatic methods. Steatosis was assessed by histology and hepatic triglycerides. Activation of MAPK, 90S ribosomal kinase (RSK), and caspase 3 were evaluated by Western blot. Levels of mRNA for tumor necrosis factor alpha (TNFalpha), early growth response-1 (egr-1), and plasminogen activator inhibitor 1 (PAI-1) were measured by real-time qRT-PCR. RESULTS: Chronic ethanol treatment resulted in mild steatosis and necrosis, whereas chronic ethanol followed by binge group exhibited marked steatosis and significant increase in necrosis. Chronic binge group also showed significant increase (compared with chronic ethanol alone) in the phosphorylation of extracellular regulated kinase 1 (ERK1), ERK2, and RSK. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK did not increase by the binge. Ethanol binge, after chronic ethanol intake, caused increase in mRNA for egr-1 and PAI-1, but not TNFalpha. CONCLUSIONS: Chronic ethanol exposure increases the susceptibility of rat liver to increased injury by 1 or 3 repeat binge. Among other alterations, the activated levels of ERK1, and more so ERK2, were remarkably amplified by binge suggesting a role of these isotypes in the binge amplification of the injury. In contrast, p38 MAPK and JNK1/2 activities were not amplified. These binge-induced changes were also reflected in the increases in the RNA levels for egr-1 and PAI-1. This study offers chronic followed by repeat binge as a model for the study of progression of liver injury by ethanol and highlights the involvement of ERK1 and ERK2 isotypes in the amplification of liver injury by binge ethanol. PMID- 21790672 TI - The genetic effect of copy number variations on the risk of alcoholism in a Korean population. AB - BACKGROUND: Alcoholism, a chronic behavioral disorder characterized by excessive alcohol consumption, has been a leading cause of morbidity and premature death. This condition is believed to be influenced by genetic factors. As copy number variation (CNV) has been recently discovered in human genome, genomic diversity of human genome is more frequent than previously thought. Many studies have reported evidences that CNV is associated with the development of complex diseases. In this study, we hypothesized that CNV can predict the risk of alcoholism. METHODS: Using the Illumina HumanHap660W-Quad BeadChip (~660 k markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 116 alcoholic cases and 1,022 healthy controls (total n = 1,138) in a Korean population. To identify alcoholism-associated CNV regions, we performed a genome-wide association analysis, using multivariate logistic regression model controlling for age and gender. RESULTS: We identified a total of 255,732 individual CNVs and 3,261 CNV regions (1,067 common CNV regions, frequency > 1%) in this study. Results from multivariate logistic regression showed that the chr20:61195302-61195978 regions were significantly associated with the risk of alcoholism after multiple corrections (p = 5.02E-05, p(corr) = 0.04). Most of the identified variations in this study overlapped with the previously reported CNVs in the Database of Genomic Variants (95.3%). The identified CNVs, which encompassed 3,226 functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the cell part, in developmental processes, in cell communication, in neurological system process, in sensory perception of smell and chemical stimulus, and in olfactory receptor activity. CONCLUSIONS: This is the first genome-wide association study to investigate the relationship between common CNV and alcoholism. Our results suggest that the newly identified CNV regions may contribute to the development of alcoholism. PMID- 21790673 TI - Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. AB - BACKGROUND: Rapid tolerance to the anxiolytic effects of ethanol appears to be an important factor in the development of alcoholism. Here, we investigated the involvement of amygdaloid histone deacetylases (HDAC)-induced epigenetic changes in rapid ethanol tolerance (RET). METHODS: RET in rats was induced by 2 ethanol injections administered 24 hours apart. Both ethanol-tolerant and control rats were treated with the HDAC inhibitor, trichostatin A (TSA), and anxiety-like behaviors were measured. HDAC activity, histone (H3 and H4) acetylation, and neuropeptide Y (NPY) expression in the amygdala of these rats were also measured. RESULTS: A single ethanol exposure was able to produce an anxiolytic response, inhibit amygdaloid HDAC activity, and increase both histone acetylation and NPY expression (mRNA and protein levels) in the central nucleus of amygdala (CeA) and medial nucleus of amygdala (MeA) of rats. In contrast, 2 exposures of the same dose of ethanol (24 hours apart) neither elicited a similar anxiolytic response nor modulated HDAC activity, histone acetylation, or NPY expression in the amygdala. However, exposure to a higher dose of ethanol on the second day was able to produce an anxiolytic response and also inhibit amygdaloid HDAC activity. TSA treatment caused the reversal of RET by inhibiting HDAC activity, thereby increasing histone acetylation and NPY expression in the CeA and MeA. CONCLUSIONS: Cellular tolerance to the initial acute ethanol-induced inhibition of HDAC activity and the subsequent upregulation of histone acetylation and NPY expression in the amygdala may be involved in the mechanisms underlying rapid tolerance to the anxiolytic effects of ethanol. PMID- 21790674 TI - Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes. AB - BACKGROUND: Many alcoholic patients have serum protein deficiency that contributes to their systemic problems. The unfolded protein response (UPR) is induced in response to disequilibrium in the protein folding capability of the endoplasmic reticulum (ER) and is implicated in hepatocyte lipid accumulation and apoptosis, which are associated with alcoholic liver disease (ALD). We investigated whether alcohol affects ER structure, function, and UPR activation in hepatocytes in vitro and in vivo. METHODS: HepG2 cells expressing human cytochrome P450 2E1 and mouse alcohol dehydrogenase (VL-17A) were treated for up to 48 hours with 50 and 100 mM ethanol. Zebrafish larvae at 4 days postfertilization were exposed to 350 mM ethanol for 32 hours. ER morphology was visualized by fluorescence in cells and transmission electron microscopy in zebrafish. UPR target gene activation was assessed using quantitative PCR, in situ hybridization, and Western blotting. Mobility of the major ER chaperone, BIP, was monitored in cells by fluorescence recovery after photobleaching (FRAP). RESULTS: VL-17A cells metabolized alcohol yet only had slight activation of some UPR target genes following ethanol treatment. However, ER fragmentation, crowding, and accumulation of unfolded proteins as detected by immunofluorescence and FRAP demonstrate that alcohol induced some ER dysfunction despite the lack of UPR activation. Zebrafish treated with alcohol, however, showed modest ER dilation, and several UPR targets were significantly induced. CONCLUSIONS: Ethanol metabolism directly impairs ER structure and function in hepatocytes. Zebrafish are a novel in vivo system for studying ALD. PMID- 21790675 TI - A novel strategy to engineer small-diameter vascular grafts from marrow-derived mesenchymal stem cells. AB - Tissue-engineered blood vessels have mainly relied on endothelial cells (ECs), smooth muscle cells (SMCs), and biocompatible materials. However, long-term results have revealed several material-related failures, such as stenosis, thromboembolization, and the risk of infection. Furthermore, SMCs from elderly persons have reduced capacity in proliferation and collagen production. Mesenchymal stem cells (MSCs) have the ability to differentiate into multiple cell lineages, including osteoblasts, chondrocytes, ECs, and SMCs. In the current experiment, rabbit MSCs were cultured to form a cell sheet. A tissue-engineered vascular graft (TEVG) was fabricated by rolling the MSC sheet around a mandrel. The TEVG was implanted into a defect of the common carotid artery after it was examined macroscopically and microscopically. Hematoxylin and eosin staining showed that cell sheet was composed of five to seven layers of cells with the thickness of 40-50 um. Results from the adhesion assay revealed that MSCs had similar antiplatelet adhesion property to ECs. Histological analysis of TEVGs showed that the layers of the cell sheet had fully fused in vitro. After implantation, TEVGs had excellent patency and integrated well with the native vessel. The structure of the TEVGs was similar to that of the native artery 4 weeks after implantation. Electron microscopy showed that the implanted TEVGs endothelialized. These results indicated that a completely biological TEVG could be assembled with autologous MSCs. These TEVGs are useful for revascularization in humans, which would reduce the occurrence of complications caused by foreign materials. PMID- 21790676 TI - Myocardial contractility and relaxation after deep hypothermic circulatory arrest in a neonatal piglet model. AB - Cooling before circulatory arrest or ischemic arrest has been reported to influence myocardial performance in isolated neonatal hearts. The aim of the present study was to analyze indices of myocardial contractility and relaxation in an in vivo neonatal model after deep hypothermic circulatory arrest (DHCA). DHCA (18 degrees C; DHCA group; n = 8) or mild hypothermic cardiopulmonary bypass ([MH-CPB] 32 degrees C; MH-CPB group; n = 10) was applied in newborn piglets. After reperfusion (60 and 120 min), left ventricular dP/dt(max) increased in DHCA and MH-CPB, while-dP/dt(max) decreased slightly in DHCA and increased in MH-CPB. Nevertheless, the differences between the two groups did not reach statistical significance. In conclusion, left ventricular contractility remained stable after reperfusion following DHCA, to some degree at the expense of the diastolic function. PMID- 21790677 TI - Experience of sternal secondary closure by means of a titanium fixation system after transverse thoracosternotomy. AB - Sternal dehiscence is a common complication after transverse thoracosternotomy in patients undergoing bilateral sequential lung transplantation (BSLT). These patients can be treated with conservative therapy, but severe dehiscence requires surgical reapproximation and secondary closure of the sternum. Seventy-one cases of patients who underwent BSLT between January 2007 and May 2009 were reviewed retrospectively. Out of 71 patients, the sternum was intact in two cases due to the use of bilateral anterolateral thoracotomy, and a clamshell incision had been utilized in 69 patients. Four patients (6.8%) presented with persistent chest pain with severe sternal dehiscence diagnosed by chest X-ray and/or chest computed tomography, and underwent sternal reapproximation using the Synthes Titanium Sternal Fixation System for longitudinal sternal plating. All four patients had successful sternal realignment and resolution of their preoperative clinical symptoms. No perioperative or postoperative complications were observed. The Synthes Titanium Sternal Fixation System is an appropriate and effective method for internal fixation of the sternum when used for symptomatic severe sternal dehiscence after sequential BSLT via transverse thoracosternotomy. PMID- 21790678 TI - Effect of liposome-encapsulated hemoglobin on antigen-presenting cells in mice. AB - Liposome-encapsulated hemoglobin (LEH) is removed from the circulation and degraded in the reticuloendothelial system, including dendritic cells (DCs) and macrophages. Therefore, LEH at a large dose may overload the system, cause a competitive inhibition in antigen-presenting activity, and impair the immune response of the host. Changes in cellularity of immunocompetent cells were monitored serially up to 4 weeks by flow cytometry in wild-type mice receiving 20 mL/kg of LEH, syngeneic red blood cells (RBCs), or saline. DCs were collected from the host spleen 1, 7, and 28 days after receiving the solution and were cocultured with naive cluster of differentiation 4 T cells from T-cell receptor transgenic mice in the absence or presence of third-party antigens. After LEH administration, the cellularity of DCs and macrophages in the recipient spleen remained unchanged from control mice receiving RBCs or saline. While subset populations and costimulatory molecule expressions were different, DCs from LEH administered mice expressed high levels of interleukin-2 production and helper T cell activation in response to a third-party antigen and superantigens, as did the DCs from control mice receiving RBCs or saline. The results suggest that 20 mL/kg of LEH does not greatly alter antigen-presenting activity to third-party antigens. PMID- 21790679 TI - Dose-response time modelling for highly pathogenic avian influenza A (H5N1) virus infection. AB - AIMS: To develop time-dependent dose-response models for highly pathogenic avian influenza A (HPAI) of the H5N1 subtype virus. METHODS AND RESULTS: A total of four candidate time-dependent dose-response models were fitted to four survival data sets for animals (mice or ferrets) exposed to graded doses of HPAI H5N1 virus using the maximum-likelihood estimation. A beta-Poisson dose-response model with the N(50) parameter modified by an exponential-inverse-power time dependency or an exponential dose-response model with the k parameter modified by an exponential-inverse time dependency provided a statistically adequate fit to the observed survival data. CONCLUSIONS: We have successfully developed the time dependent dose-response models to describe the mortality of animals exposed to an HPAI H5N1 virus. The developed model describes the mortality over time and represents observed experimental responses accurately. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study describing time-dependent dose-response models for HPAI H5N1 virus. The developed models will be a useful tool for estimating the mortality of HPAI H5N1 virus, which may depend on time postexposure, for the preparation of a future influenza pandemic caused by this lethal virus. PMID- 21790680 TI - Randomised clinical trial: preventive treatment with topical rectal beclomethasone dipropionate reduces post-radiation risk of bleeding in patients irradiated for prostate cancer. AB - BACKGROUND: Radiotherapy is an established treatment modality for prostate cancer; however, up to a third of patients develops a radiation-induced proctopathy. AIM: To assess the effect of topical beclomethasone dipropionate (BDP) in the prevention of radiation-induced proctopathy in patients undergoing radiotherapy for prostate cancer through a double-blind, placebo-controlled, randomised trial. METHODS: Patients were randomised either to BDP or to placebo (PL). Patients received daily a 3mg BDP enema or identical-looking PL during radiotherapy and, subsequently, two 3mg BDP suppositories or PL for 4 more weeks. Clinical and endoscopic evaluations before, 3 and 12months after the end of radiotherapy were assessed with the RTOG/EORTC toxicity scales, the modified Simple Clinical Colitis Activity Index (SCCAI), the modified Inflammatory Bowel disease Quality of Life Index (IBDQ) and the Vienna Rectoscopy Score (VRS). RESULTS: From June 2007 to October 2008, 120 patients were randomised to the BDP (n=60) and PL (n=60) arms and were followed up for 12months. The overall assessment of rectal side effects did not show significant differences between the two groups of treatment. However, when only rectal bleeding was considered, a significantly reduced risk was observed in patients on BDP (OR 0.38; 95% CI 0.17 0.86; P=0.02; NNT=5). Patients on BDP had also significantly lower VRS scores (P=0.028) and significantly higher IBDQ scores (P=0.034). CONCLUSIONS: Preventive treatment with topical rectal BDP during radiotherapy for prostate cancer significantly reduces the risk of rectal bleeding and radiation-induced mucosal changes and improves patient's quality of life, but does not influence other radiation-induced symptoms. PMID- 21790681 TI - Diverticular disease and the risk of colon cancer - a population-based case control study. AB - BACKGROUND: Colon cancer and diverticular disease are most common in the Western world and their incidences tend to increase with advancing age. The association between the diseases remains unclear. AIM: To analyse the risk of colon cancer after hospitalisation for diverticular disease. METHODS: Nationwide case-control study. A total of 41,037 patients with colon cancer during 1992-2006, identified from the Swedish Cancer Register were included. Each case was matched with two control subjects. From the Swedish Inpatient Register, cases and control subjects hospitalised for diverticular disease were identified. Odds ratios (OR) and confidence intervals for receiving a diagnosis of colon cancer after hospital discharge for diverticular disease were calculated. Colon cancer mortality was compared between patients with or without diverticular disease. RESULTS: Within 6months after an admission due to diverticular disease, OR of having a colon cancer diagnosis were up to 31.49 (19.00-52.21). After 12 months, there was no increased risk. The number of discharges for diverticular disease did not affect the risk. Colon cancer mortality did not differ between patients with and without diverticular disease. CONCLUSIONS: Diverticular disease does not increase the risk of colon cancer in the long term, and a history of diverticular disease does not affect colon cancer mortality. The increased risk of colon cancer within the first 12months after diagnosing diverticular disease is most likely due to surveillance and misclassification. Examination of the colon should be recommended after a primary episode of symptomatic diverticular disease. PMID- 21790682 TI - Systematic review: the pathophysiology and management of polycystic liver disease. AB - BACKGROUND: Polycystic liver diseases (PCLD) represent a group of genetic disorders in which cysts occur solely in the liver, or together with renal cysts. Most of the patients with PCLD are asymptomatic, however, in some patients, expansion of liver cysts causes invalidating abdominal symptoms. AIM: To provide a systemic review on the pathophysiology and management of PCLD. METHODS: A PubMed search was undertaken to identify relevant literature using search terms including polycystic liver disease, pathophysiology, surgical and medical management. RESULTS: The most common complication in patients with PCLD is extensive hepatomegaly, which may lead to malnutrition and can be lethal. Conservative surgical approaches are only partially effective and do not change the natural course of the disease. Liver transplantation has been successfully performed in PCLD, however, in an era of organ shortage, medical management needs to be evaluated. A better understanding of the pathophysiology and the availability of animal models have already identified promising drugs. Abnormalities in cholangiocyte proliferation/apoptosis and enhanced fluid secretion are key factors in the pathophysiology. It has been demonstrated in rodents and in humans that somatostatin analogues diminish liver volume. The role of the inhibitors of the mammalian target of rapamycin (mTOR) in the management of PCLD is still under investigation. CONCLUSIONS: The exact pathophysiology of polycystic liver disease still remains unclear. In symptomatic patients, none of the currently available surgical options except liver transplantation have been shown to change the natural course of the disease. The use of somatostatin analogues has been shown to diminish liver volume. PMID- 21790683 TI - Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study. AB - BACKGROUND: Aspirin has detrimental effects on the gastrointestinal tract mucosa and may play a role in the aetiology of inflammatory bowel disease. AIM: To investigate if the regular use of aspirin is associated with the development of Crohn's disease (CD) and ulcerative colitis (UC) using, for the first time, a prospective cohort study design. METHODS: A total of 135,780 men and women in Europe, aged 30-74years, were recruited into the European Prospective Investigation into Cancer and Nutrition study. Participants completed questionnaires at baseline detailing their regular aspirin use and were then followed up to identify those who developed either incident CD or UC. Each case was matched with four controls and odds ratios (OR) were calculated, adjusting for cigarette smoking. Potential interactions between aspirin and smoking were assessed. RESULTS: A total of 35 participants developed CD and a further 84 were diagnosed with UC. Regular aspirin intake was positively associated with the risk of developing CD (OR=6.14, 95% CI=1.76-21.35). In those who took aspirin and smoked there was no detectable increased risk of CD (OR=0.30, 95% CI=0.03-3.08). No association was found between regular aspirin use and UC (OR=1.29, 95% CI=0.67 2.46). CONCLUSIONS: A strong positive association between regular aspirin use and CD, but not UC, was observed. The data suggest that regular aspirin use should be measured in epidemiological work on CD. If such findings are consistent in other work then aspirin may affect the development of CD in a middle-aged to elderly population. PMID- 21790684 TI - The association of coeliac disease in childhood with functional gastrointestinal disorders: a prospective study in patients fulfilling Rome III criteria. AB - BACKGROUND: An association between coeliac disease (CD) and functional gastrointestinal disorders (FGIDs) has at present only been demonstrated in adults. AIMS: To assess the prevalence of FGIDs at 1 year and the role of psychological aspects on the development of FGIDs in CD children. METHODS: One hundred consecutive CD children (36M and 64F) were followed up for 1 year. Fifty six children (25M and 31F) represented the control group. All children and/or their parents completed validated questionnaires for GI symptoms, depression, and anxiety. GI symptoms at diagnosis and after 1 year of gluten-free diet (GFD) were compared. RESULTS: Twenty-three/82 (28%) CD patients followed up prospectively, on GFD from at least 1 year, fulfilled the Rome III criteria for FGIDs compared with 5/56 (8.9%) controls (P = 0.008; chi2 = 6.8; OR: 3.97; 95% CI: 1.40-11.21). Children complaining with GI symptoms alone [21/52 (40.3%)] more likely fulfilled Rome III criteria for FGIDs after 1 year of GFD than children with extra intestinal symptoms (P = 0.045). CD children with FGDIs presented significantly higher anxiety and depression compared to CD children without FGIDs and controls (P = 0.02). CONCLUSIONS: This study demonstrates that children with CD on a GFD for a year have a much higher prevalence of functional GI symptoms than do controls. Whether the risk is due to the residua of a chronic inflammatory process, and/or due to psychological factors remains to be further tested. PMID- 21790685 TI - Hyperuricemia is associated with histological liver damage in patients with non alcoholic fatty liver disease. AB - BACKGROUND: Hyperuricemia has been associated with metabolic disorders. In this line recent studies observed an independent link between higher uric acid serum levels and clinical diagnosis of non-alcoholic fatty liver disease (NAFLD). AIMS: We aimed to assess the potential association between uric acid serum levels and histological liver damage in a homogeneous cohort of biopsy-proven NAFLD patients. METHODS: Consecutive NAFLD patients (n = 166), assessed by liver biopsy (Kleiner score), anthropometric, biochemical and metabolic features, were included. Enzymatic colorimetric test was used for serum uric acid assays (Roche Diagnostics GmbH, Mannheim, Germany). Hyperuricemia was diagnosed when uric acid serum levels were > 7 mg/dL in men, and > 6 mg/dL in women. RESULTS: Mean uric acid serum level was 5.75 mg/dL, and about 20% of patients had hyperuricemia, that was independently associated with younger age (OR 0.951, 95% CI 0.918-0.984, P = 0.004), lobular inflammation (OR 2.144, 95% CI 1.055-4.357, P = 0.03) and steatosis grade (OR 1.859, 95% CI 1.078-3.205, P = 0.02), by multivariate logistic regression analysis. Female gender (OR 2.656, 95% CI 1.190-5.928, P = 0.01), higher HOMA index (OR 1.219, 95% CI 1.043-1.426, P = 0.01), and hyperuricemia (OR 4.906, 95% CI 1.683-14.296, P = 0.004) were linked to NAFLD activity score (NAS) >= 5 by multiple logistic regression analysis. Conversely, higher HOMA index (OR 1.140, 95% CI 1.001-1.229, P = 0.04), and NAS (OR1.954, 95% CI 1.442-2.649, P < 0.001) were independently associated with significant fibrosis by logistic regression analysis. CONCLUSIONS: In NAFLD patients, hyperuricemia is independently associated with the severity of liver damage, representing, in this setting of patients, together with insulin resistance, a potential new therapeutic target in future intervention trials. PMID- 21790686 TI - The mosquito Aedes (Aedimorphus) vexans arabiensis as a probable vector bridging the West Nile virus between birds and horses in Barkedji (Ferlo, Senegal). AB - Active catches of adult females of Aedes vexans arabiensis Patton, (Diptera: Culicidae) Patton by nets or aspirator, were conducted in 2003 and 2004 in the vegetation at the edge of temporary ponds in Barkedji, Senegalese Ferlo area. Two hundred and forty-one engorged females were captured, dissected and the gut content adsorbed on a Whatman filter paper and analysed using the enzyme-linked immunosorbent assay (ELISA) technique to determinate the bloodmeal origin. Results indicated that Ae v. arabiensis fed primarily on mammals, including horses (35.7% of the bloodmeals), but also on birds (10%). Moreover, associations between horses and birds accounted for 42% of the mixed bloodmeals. These results show an opportunistic feeding behaviour and suggest that Ae v. arabiensis is a probable vector bridging the West Nile virus between horses and birds hosts in the Ferlo area. PMID- 21790687 TI - Development of a classification system for drug-related problems in the hospital setting (APS-Doc) and assessment of the inter-rater reliability. AB - WHAT IS KNOWN AND OBJECTIVE: Identifying, preventing and resolving drug-related problems (DRP) is an important issue in the pharmaceutical care process. Because DRPs have been detected in a more systematic way, the need for a classification system to document, classify and evaluate the collected data has become necessary. The objective was to develop a classification system for DRPs within the hospital setting, to evaluate the practicality and to assess the inter-rater reliability. METHODS: All DRPs defined in PI-Doc and PCNE, which are relevant in the hospital setting, were included. Further relevant DRPs identified in other projects in a hospital setting as well as DRPs from the daily work on the ward were collected, and a short description of each DRP was written. A prospective study was conducted at Klinikum Fulda, Germany, in both a non-surgical and a surgical setting to explore whether the new classification system is suitable to classify DRPs in clinics with different specifications. For assessing the inter rater reliability, 24 standardized case reports were provided. All participants classified them independently. The inter-rater reliability was analysed using Kappa coefficient. RESULTS AND DISCUSSION: A classification system for DRPs in the hospital setting (APS-Doc) was established with 10 main categories and 48 subcategories. Practicality was assessed in 250 patients in a non-surgical ward as well as in 100 patients in a surgical ward. The inter-rater agreement was 0.68 (95% CI, 0.66-0.69) for main categories, which comprises substantial agreement. Moderate agreement (kappa = 0.58; 95% CI, 0.58-0.59) was demonstrated for the subcategories. WHAT IS NEW AND CONCLUSION: A new hierarchical classification system for DRPs in the hospital setting has been developed. APS-Doc seems suitable for various parts of the medication process such as medication reconciliation and drug therapy within both non-surgical and surgical wards. Inter-rater reliability was found to be substantial in the main categories and moderate in the subcategories. PMID- 21790688 TI - The practical importance of theory in clinical ethics support services. PMID- 21790689 TI - Theory and practice of clinical ethics support services: narrative and hermeneutical perspectives. AB - In this paper we introduce narrative and hermeneutical perspectives to clinical ethics support services (CESS). We propose a threefold consideration of 'theory' and show how it is interwoven with 'practice' as we go along. First, we look at theory in its foundational role: in our case 'narrative ethics' and 'philosophical hermeneutics' provide a theoretical base for clinical ethics by focusing on human identities entangled in stories and on moral understanding as a dialogical process. Second, we consider the role of theoretical notions in helping practitioners to understand their situation in clinical ethics practice, by using notions like 'story', 'responsibility', or 'vulnerability' to make explicit and explain their practical experience. Such theoretical notions help us to interpret clinical situations from an ethical perspective and to foster moral awareness of practitioners. And, thirdly, we examine how new theoretical concepts are developed by interpreting practice, using practice to form and improve our ethical theory. In this paper, we discuss this threefold use of theory in clinical ethics support services by reflecting on our own theoretical assumptions, methodological steps and practical experiences as ethicists, and by providing examples from our daily work. In doing so, we illustrate that theory and practice are interwoven, as theoretical understanding is dependent upon practical experience, and vice-versa. PMID- 21790690 TI - Monological versus dialogical consciousness: two epistemological views on the use of theory in clinical ethical practice. AB - In this article, we argue that a critical examination of epistemological and anthropological presuppositions might lead to a more fruitful use of theory in clinical-ethical practice. We differentiate between two views of conceptualizing ethics, referring to Charles Taylors' two epistemological models: 'monological' versus 'dialogical consciousness'. We show that the conception of ethics in the model of 'dialogical consciousness' is radically different from the classical understanding of ethics in the model of 'monological consciousness'. To reach accountable moral judgments, ethics cannot be conceptualized as an individual enterprise, but has to be seen as a practical endeavor embedded in social interactions within which moral understandings are being negotiated. This view has specific implications for the nature and the role of ethical theory. Theory is not created in the individual mind of the ethicist; the use of theory is part of a joint learning process and embedded in a cultural context and social history. Theory is based upon practice, and serves practical purposes. Thus, clinical ethics support is both practical and theoretical. PMID- 21790691 TI - Who are we when we are doing what we are doing?: the case for mindful embodiment in ethics case consultation. AB - This paper explores the theory and practice of embodied epistemology or mindful embodiment in ethics case consultation. I argue that not only is this epistemology an ethical imperative to safeguard the integrity of this emerging profession, but that it has the potential to improve the quality of ethics consultation (EC). It also has implications for how ethics consultants are trained and how consultation services are organized. My viewpoint is informed by ethnographic research and by my experimental application of mindful embodiment to the development of an ethics consultation service. My argument proceeds in four phases. First I explore the notion of 'situatedness' in the bioethics literature, identifying gaps in the field's theories as they apply to EC. I then describe my theoretical approach to embodiment grounded in critical-interpretive medical anthropology and autoethnography. I use embodiment to refer to a moral epistemology grounded in the body, comprised of the interplay of physical, symbolic, intersubjective and political elements. Third, I describe how mindful embodiment can inform the role of the ethics consultant and the development of effective training techniques, vocabularies and processes for EC. I also discuss the benefits of this orientation, and the potential harms of ignoring the embodied dimensions of EC. My goals are to expose the fallacy of the 'theory practice gap', to demonstrate how my own EC practice is deeply informed by this theoretical orientation, and to argue for a wider definition of what 'counts' as relevant theory for ethics consultation. PMID- 21790692 TI - The role of emotions in moral case deliberation: theory, practice, and methodology. AB - In clinical moral decision making, emotions often play an important role. However, many clinical ethicists are ignorant, suspicious or even critical of the role of emotions in making moral decisions and in reflecting on them. This raises practical and theoretical questions about the understanding and use of emotions in clinical ethics support services. This paper presents an Aristotelian view on emotions and describes its application in the practice of moral case deliberation. According to Aristotle, emotions are an original and integral part of (virtue) ethics. Emotions are an inherent part of our moral reasoning and being, and therefore they should be an inherent part of any moral deliberation. Based on Aristotle's view, we examine five specific aspects of emotions: the description of emotions, the attitude towards emotions, the thoughts present in emotions, the reliability of emotions, and the reasonable principle that guides an emotion. We then discuss three ways of dealing with emotions in the process of moral case deliberation. Finally, we present an Aristotelian conversation method, and present practical experiences using this method. PMID- 21790693 TI - Mapping out structural features in clinical care calling for ethical sensitivity: a theoretical approach to promote ethical competence in healthcare personnel and clinical ethical support services (CESS). AB - Clinical ethical support services (CESS) represent a multifaceted field of aims, consultancy models, and methodologies. Nevertheless, the overall aim of CESS can be summed up as contributing to healthcare of high ethical standards by improving ethically competent decision-making in clinical healthcare. In order to support clinical care adequately, CESS must pay systematic attention to all real-life ethical issues, including those which do not fall within the 'favourite' ethical issues of the day. In this paper we attempt to capture a comprehensive overview of categories of ethical tensions in clinical care. We present an analytical exposition of ethical structural features in judgement-based clinical care predicated on the assumption of the moral equality of human beings and the assessment of where healthcare contexts pose a challenge to achieving moral equality. The account and the emerging overview is worked out so that it can be easily contextualized with regards to national healthcare systems and specific branches of healthcare, as well as local healthcare institutions. By considering how the account and the overview can be applied to i) improve the ethical competence of healthcare personnel and consultants by broadening their sensitivity to ethical tensions, ii) identify neglected areas for ethical research, and iii) clarify the ethical responsibility of healthcare institutions' leadership, as well as specifying required institutionalized administration, we conclude that the proposed account should be considered useful for CESS. PMID- 21790694 TI - Evidence - competence - discourse: the theoretical framework of the multi-centre clinical ethics support project METAP. AB - In this paper we assume that 'theory' is important for Clinical Ethics Support Services (CESS). We will argue that the underlying implicit theory should be reflected. Moreover, we suggest that the theoretical components on which any clinical ethics support (CES) relies should be explicitly articulated in order to enhance the quality of CES. A theoretical framework appropriate for CES will be necessarily complex and should include ethical (both descriptive and normative), metaethical and organizational components. The various forms of CES that exist in North-America and in Europe show their underlying theory more or less explicitly, with most of them referring to some kind of theoretical components including 'how to' questions (methodology), organizational issues (implementation), problem analysis (phenomenology or typology of problems), and related ethical issues such as end-of-life decisions (major ethical topics). In order to illustrate and explain the theoretical framework that we are suggesting for our own CES project METAP, we will outline this project which has been established in a multi-centre context in several healthcare institutions. We conceptualize three 'pillars' as the major components of our theoretical framework: (1) evidence, (2) competence, and (3) discourse. As a whole, the framework is aimed at developing a foundation of our CES project METAP. We conclude that this specific integration of theoretical components is a promising model for the fruitful further development of CES. PMID- 21790695 TI - Responsibility after the apparent end: 'following-up' in clinical ethics consultation. AB - Clinical ethics literature typically presents ethics consultations as having clear beginnings and clear ends. Experience in actual clinical ethics practice, however, reflects a different characterization, particularly when the moral experiences of ethics consultants are included in the discussion. In response, this article emphasizes listening and learning about moral experience as core activities associated with clinical ethics consultation. This focus reveals that responsibility in actual clinical ethics practice is generated within the moral scope of an ethics consultant's activities as she or he encounters the unique and specific features that emerge from interactions with a specific patient, or family, or practitioner within a given situation and over time. A long-form narrative about an ethics consultant's interactions is interwoven with a more didactic discussion to highlight the theme of responsibility and to probe questions that arise regarding follow-up within the practice of clinical ethics consultation. PMID- 21790696 TI - Plasma biochemical reference values in clinically healthy captive bearded dragons (Pogona vitticeps) and the effects of sex and season. AB - BACKGROUND: Bearded dragons are one of the most popular pet lizard species, and biochemical reference values are useful for health management of these reptiles. OBJECTIVES: The objectives of this study were to measure plasma biochemical values in healthy captive bearded dragons, determine reference values, and evaluate the effects of sex and season on the results. METHODS: Blood samples were collected from 100 captive healthy bearded dragons in Tokyo during the summer and winter. Plasma biochemical measurements were performed using a dry slide automated biochemical analyzer. The data were then compared based on sex and season using 2-way ANOVA. RESULTS: Globulin, cholesterol, and calcium concentrations of females were higher in both summer and winter compared with the values obtained for males. Both males and females had higher uric acid concentrations in winter than in summer. When compared with males, females had a higher chloride concentration in summer and a higher total protein concentration and aspartate aminotransferase activity in winter. Potassium concentration in males was lower in winter than in summer, whereas in females cholesterol concentration was lower in winter than in summer. CONCLUSIONS: Biochemical values that differed based on sex and season in bearded dragons were similar to those in other lizards. These differences reflect physiologic differences in reproductive status in females and seasonal changes in temperature and hydration status. Plasma biochemical values established for bearded dragons in this study will be useful in the diagnostic assessment of captive animals. PMID- 21790697 TI - Serum biochemical reference intervals for wild dwarf ornate wobbegong sharks (Orectolobus ornatus). AB - BACKGROUND: Sharks are important to sport and commercial fishing, public aquaria, and research institutions. However, serum biochemical reference values have been established for few species. OBJECTIVE: The aim of this study was to establish serum biochemical reference intervals for wild-caught dwarf ornate wobbegong sharks (Orectolobus ornatus). METHODS: Fifty wobbegongs were caught, and their health status, sex, length, and weight were evaluated and recorded. Following collection of blood, serum biochemical analytes were measured and analyzed using standard analytical and statistical methods. Combined samples generated means, medians, and reference intervals. RESULTS: For the measured analytes, means (reference intervals) were as follows: sodium 287 (284-289) mmol/L, chloride 277 (274-280) mmol/L, potassium 5.2 (5.0-5.3) mmol/L, total calcium 4.6 (4.5-4.7) mmol/L, magnesium 1.9 (1.7-2.0) mmol/L, inorganic phosphate 1.8 (1.7-1.9) mmol/L, glucose 2.6 (2.4-2.8) mmol/L, total protein 46 (45-47) g/L, urea 396 (392-401) mmol/L, creatinine <= 0.02 mmol/L, total bilirubin 2.0 (1.9-2.1) MUmol/L, cholesterol 1.3 (1.2-1.4) mmol/L, triglyceride 0.5 (0.4-0.6) mmol/L, alkaline phosphatase 24 (21-28) U/L, alanine aminotransferase 3 U/L, aspartate aminotransferase 28 (25-31) U/L, creatine kinase 49 (38-59) U/L, and osmolarity 1104 (1094-1114) mmol/L. Serum values were not affected by sex, length, or weight. CONCLUSIONS: Established reference values will assist with clinical evaluation and treatment of dwarf ornate wobbegongs in aquaria, research institutions, and the wild. PMID- 21790698 TI - Serum alkaline phosphatase activity is not a marker for neoplastic transformation of esophageal nodules in canine spirocercosis. AB - BACKGROUND: Spirocerca lupi is a nematode of Canidae that matures within the esophageal wall to form fibroblastic nodules with potential for malignant transformation. Diagnosis is based on histopathologic examination, but false negative results may be obtained from samples collected by endoscopy. Serum alkaline phosphatase (ALP) activity, frequently increased in hepatobiliary disease, is also increased in a variety of neoplastic conditions in dogs, including appendicular osteosarcoma, and has also been reported to be increased in dogs with spirocercosis. OBJECTIVE: The aim of this study was to evaluate serum ALP activity as a marker for malignant transformation of esophageal nodules in S. lupi-infected dogs. METHODS: In this retrospective study, medical records of dogs diagnosed with spirocercosis from 1991 to 2008 were reviewed, and serum ALP activity determined at presentation was compared between dogs with nonneoplastic and neoplastic nodules. Owing to use of multiple analyzers, ratios of ALP activity to the upper reference interval for ALP were calculated and compared. RESULTS: Median ALP activity ratios were 0.65 (0.07-4.00) and 0.86 (0.10-3.40) for dogs with nonneoplastic (n=88) and neoplastic (n=32) nodules, respectively, with no significant difference (P=.18) and substantial overlap between groups. Tumors included osteosarcoma (15 dogs), fibrosarcoma (15 dogs), and anaplastic sarcoma (2 dogs); there was no difference in ALP activity between the dogs with osteosarcoma and fibrosarcoma. CONCLUSION: ALP is a poor marker of malignant transformation in canine spirocercosis. PMID- 21790699 TI - Babesia canis rossi infection in a Texas dog. AB - A 5-month-old intact male Boerboel dog, imported from South Africa 1 week previously, was presented to a Texas veterinarian for lethargy, anorexia, and labored breathing. The dog was febrile, anemic, leukopenic, thrombocytopenic, and slightly azotemic. Results of the IDEXX SNAP-4Dx enzyme immunoassay were negative for Dirofilaria immitis antigen and antibodies against Ehrlichia canis, Borrelia burgdorferi, and Anaplasma phagocytophilum. An EDTA blood sample analyzed at Oklahoma State University Center for Veterinary Health Sciences revealed nonregenerative anemia, neutropenia, and large protozoal piroplasms in 0.7% of the RBCs. Piroplasms were 2-5MUm long and varied in shape from round to oval to piriform; extracellular merozoites were also observed. Nested PCR was performed on DNA extracted from blood using primers that amplify the 18s rRNA gene from all known Babesia species, and the product was sequenced. Basic Local Alignment Search Tool analysis of the 437 base sequence revealed 99-100% similarity to Babesia canis rossi, 92-93% similarity to Babesia canis canis, and 92% similarity to Babesia canis vogeli. The dog responded well to treatment with imidocarb. PCR analysis of a second blood sample 2 weeks later was negative for Babesia spp. DNA. This case represents the first diagnosis of B. canis rossi infection in the United States. PMID- 21790700 TI - Identification of the first germline HRPT2 whole-gene deletion in a patient with primary hyperparathyroidism. AB - OBJECTIVE: Germline mutations in the HRPT2 gene are associated with the hereditary hyperparathyroidism-jaw tumour syndrome (HPT-JT) and a subset of familial isolated hyperparathyroidism (FIHP). Somatic HRPT2 mutations are detected in sporadic parathyroid carcinomas and less frequently in cystic adenomas. The purpose of this study was to investigate the underlying HRPT2 defect in a young patient with symptomatic hyperparathyroidism due to an apparently sporadic parathyroid adenoma with cystic features. DESIGN AND METHODS: HRPT2 mutations in the patient's genomic and parathyroid tumour DNA were screened by PCR-based sequencing. Tumour loss of heterozygosity (LOH) at the HRPT2 locus was assessed with microsatellite markers. A large germline HRPT2 deletion was investigated by real-time quantitative PCR analysis (qPCR). Genomic DNA losses were also appraised by chromosomal comparative genomic hybridization (cCGH). RESULTS: No germline HRPT2 point mutation was detected by direct sequencing. A novel hemizygous HRPT2 somatic mutation (c.32delA) was identified in the tumour. Apparent constitutional homozygosity for HRPT2 flanking microsatellite markers, and absence of LOH at a distal marker, suggested a large germline deletion. Gene dose mapping by qPCR unveiled a de novo deletion of the whole HRPT2 gene and adjacent loci (<9.3 Mb in size). cCGH confirmed germline DNA loss involving the HRPT2 locus. CONCLUSIONS: We report the first large germline deletion of the HRPT2 gene, which was not detectable by conventional PCR-based sequencing methods. This finding emphasizes that qPCR should be implemented in HRPT2 molecular analysis, which may improve genetic assessment and clinical management of patients with FIHP and HPT-JT. PMID- 21790701 TI - Assessment of gonadotrophin suppression in girls treated with GnRH analogue for central precocious puberty; validity of single luteinizing hormone measurement after leuprolide acetate injection. AB - OBJECTIVE: Intravenous GnRH stimulation test has often been used as gold standard test for the evaluation of hypothalamic-pituitary-gonadal axis in the diagnosis of central precocious puberty (CPP) and in the assessment of pubertal suppression. However, this test is time-consuming, costly and uncomfortable for the patients. We aimed to analyse the validity of single LH sample 90 min after GnRH analogue (GnRHa) administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut-off level for LH indicating adequate suppression. DESIGN: Prospective study. PATIENTS AND METHODS: One hundred and forty-two patients with CPP were included in this study. Peak LH level during iv GnRH stimulation test after the third dose of GnRHa was compared with LH level 90 min after injection of the 3rd dose of GnRHa. RESULTS: There was a positive correlation between LH level following a GnRHa injection and peak LH during standard iv GnRH stimulation test (r = 0.83; P < 0.0001). A LH value of 2.5 mIU/ml or less 90 min after GnRHa injection was considered to be the cut-off for the determination of pubertal suppression (sensitivity and specificity was 100% and 88%, respectively). In 117 patients, gonadotrophin suppression was existed according to both GnRHa and iv GnRH tests. In 25 patients, gonadotrophin suppression was not found in the GnRHa test. However, 16 of them were suppressed according to the iv GnRH test. CONCLUSION: Single LH determination 90 min after GnRHa administration using a cut-off level of 2.5 mIU/ml reflects pubertal suppression with a high sensitivity and specificity. However, this test may fail to show pubertal suppression in some cases. Those patients who appear to be inadequately suppressed should be reassessed using standard iv GnRH stimulation test for optimal dose adjustment. PMID- 21790702 TI - Ipr1 gene mediates RAW 264.7 macrophage cell line resistance to Mycobacterium bovis. AB - Tuberculosis caused by Mycobacterium bovis (M. bovis) seriously affects efficiency of animal production with impacts on public health as well. Effective programmes of prevention and eradication of M. bovis infection therefore are urgently needed. Intracellular pathogen resistance gene 1 (Ipr1) is well known to mediate innate immunity to Mycobacterium tuberculosis (MTB), but there are no reports as to whether Ipr1 can enhance the phagocytic ability of macrophage against M. bovis. In this investigation, RAW 264.7 macrophage was transduced with lentiviral vector carrying Ipr1 (named Lenti-Ipr1); transgenic cells were identified by RT-PCR and western blotting. Transgenic positive cells (R-Ipr1) were then infected with an M. bovis virulent strain, with non-transduced cells used as control. When cell proliferation, viability and apoptosis of the two groups were investigated, it was found that infected RAW 264.7 died by necrosis whereas R-Ipr1 underwent apoptosis. Furthermore, the numbers of intracellular bacteria in R-Ipr1 were lower than those in control cells (P < 0.05). To identify the role of Ipr1, we measured the genes of Casp3, Mcl-1 and NOS2A which associated with macrophage activation and apoptosis by real-time quantitative PCR. The results demonstrated that Ipr1 gene expression can enhance anti-M. bovis infection of macrophage. This establishes a basis for the future production of Ipr1-transgenic cattle to strengthen the tuberculosis resistance. PMID- 21790703 TI - Elevated serum BAFF levels in patients with autoimmunity and lymphoproliferation. PMID- 21790704 TI - Aspergillus oryzae lectin induces anaphylactoid oedema and mast cell activation through its interaction with fucose of mast cell-bound non-specific IgE. AB - We investigated whether Aspergillus oryzae lectin (AOL), a fucose-specific lectin, induces anaphylactoid reactions and mast cell activation. The injection of AOL into footpads of mice produced a dose-related acute paw oedema. The AOL induced oedema was attenuated by predose of histamine H1 receptor blocker or pretreatment of the lectin with fucose before injection and was not observed in SCID and mast cell-deficient WBB6F1-W/Wv mice. These results suggested that the AOL-induced anaphylactoid reaction was mediated by histamine released from mast cells. In addition, the activation of mast cells was seemed to be induced by the crosslinking of IgE on the cell surface following the binding of AOL to fucose residues in IgE. Consistent with the in vivo results, AOL induced the degranulation of the rat mast cell line RBL2H3 sensitized with monoclonal IgE. As AOL induced the increase in intracellular Ca(2+) concentration of IgE-sensitized RBL2H3 cells as well as antigen stimulation, AOL could input signals from FcepsilonRI. The degranulation of IgE-sensitized RBL2H3 cells by AOL was diminished by pretreatment of AOL with fucose. Defucosylated IgE did not induce degranulation of RBL2H3 cells in response to AOL stimulation, in spite of its ability to induce degranulation by antigen stimulation as intact IgE. These results indicated that AOL bound to fucose residue of IgE causing antigen independent IgE-mediated mast cell activation and anaphylactoid reactions in vitro and in vivo, respectively. AOL bound to human IgE as well as to mouse IgE, suggesting the possible implication of AOL in the allergic response to Aspergillus oryzae in humans. PMID- 21790705 TI - The polymorphisms of C-reactive protein gene modify the association between central obesity and lung function in taiwan asthmatics. AB - High-sensitivity C-reactive protein (hs-CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = -7.54%, 95% CI = -13.82 to 1.25%). Waist-to-hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene. PMID- 21790706 TI - The isotype of autoantibodies influences the phagocytosis of antibody-coated platelets in autoimmune thrombocytopenic purpura. AB - Autoimmune thrombocytopenic purpura (AITP) is an acquired autoimmune bleeding disorder, characterized by isolated thrombocytopenia because of destruction of auto-antibody-coated platelets by Fc-receptor-mediated phagocytosis. The destruction of autoantibody-sensitized platelets by FcgammaR-bearing phagocytic cells and the following antigen presentation are considered to play a key role for the pathophysiology of AITP. Although different isotypes of AITP-mediating autoantibodies, e.g. IgG, IgM and IgA, are frequently found in AITP patients, their role in the pathophysiology of AITP remains unclear. Using a flow cytometric monocyte-based phagocytosis assay, we investigated the impact of disease-associated autoantibody isotype in antibody-mediated phagocytosis of platelets. Platelets, labelled with 5-chloromethyl fluorescein diacetate (CMFDA), were incubated with AITP patients' serum characterized by pure IgG or IgM antiplatelet autoantibodies. Labelled platelets were incubated with monocytes. Phagocytosis was defined as the product of percentage of CMFDA-positive monocytes and mean fluorescence intensity of CMFDA. Adherence of platelets to monocytes was quantified by anti-CD61-PerCp in a CMFDA(+) CD14(+) gate. IgG-coated platelets showed a significantly higher phagocytic index than IgM-coated platelets (mean 796 +/- 157 versus 539 +/- 78, P < 0.01). There were no significant differences regarding platelet adherence to monocytes. The isotype of autoantibodies influences the quantity of in vitro phagocytosis of autologous platelets by monocytes. Therefore, the AITP-mediating autoantibody isotype should be considered more carefully in pathophysiologic models and furthermore in diagnostic, therapeutic and prognostic approaches in AITP. PMID- 21790707 TI - Tumour necrosis factor gene polymorphism and disease prevalence. AB - Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases. PMID- 21790708 TI - Dysfunction of the endothelial-platelet pathway in patients with erectile dysfunction before and after daily treatment with tadalafil. AB - Platelet activation results from the exposure of receptors on the surface of the platelet to specific structures on the vessel wall. The aim of this study was to assess the serum concentrations of apoptotic endothelial microparticles (EMPa) and the vitronectin receptor (VR) in patients with erectile dysfunction (ED) before and after treatment with tadalafil. This study included 50 patients with arterial ED. EMPa and VR levels were measured by using flow cytometry. The CD45(neg)-CD144(pos)-annexin V(Pos) events were defined as EMPa, and the CD51(pos)-CD61(pos) events were defined as VR. Patients with ED were evaluated before and after daily treatment with 5 mg tadalafil for 90 days. Patients with arterial ED had serum concentrations of EMPa and VR significantly higher than the control group at baseline. After tadalafil, the serum concentrations of EMPa and VR of the patients with arterial ED were significantly lower than before treatment, but significantly higher than controls. Patients with arterial ED expressed higher levels of both EMPa that are associated with dysfunction of the arterial endothelial pathway and VR-expressing platelet-endothelial elements. Chronic treatment with tadalafil reduced endothelial apoptosis in these patients and also reduced VR expression. PMID- 21790709 TI - Sensitivity and specificity of serum FSH and testis size in predicting the existence of spermatogenesis in azoospermic infertile men. AB - The objective of research was to determine the sensitivity, specificity and positive predictive value of serum follicle stimulating hormone and testis size in predicting spermatogenesis in infertile men with azoospermia. In a prospective study, azoospermic men were studied. Serum follicle stimulating hormone measurement and scrotal sac ultrasonography were performed. Bilateral testis biopsy was performed for all of these patients. The sensitivity and specificity of follicle stimulating hormone and testis size were determined to predict the existence of different cellular steps of spermatogenesis. Of eighty infertile men who recruited into the study, 53 patients did not represent any different cellular steps of spermatogenesis, while 27 of them had various steps of such differentiation. Among the 53 patients without cellular steps of spermatogenesis in the biopsy, 41 were predicted to be azoospermic based on their serum follicle stimulating hormone levels (77.3% sensitivity), and of 27 patients with various cellular steps of spermatogenesis in the biopsy, 23 were predicted to have spermatozoa according to the follicle stimulating hormone level (85.2%) specificity. It is suggested that combination of these two indicators can substitute the invasive testis biopsy for predicting the existence of spermatozoa in infertile men with azoospermia. PMID- 21790710 TI - Angiosarcoma with tingible body macrophages. PMID- 21790712 TI - A golden time. PMID- 21790713 TI - New or unusual dermatopathology tumors: a review. AB - As experience is acquired, there is a constant evolution in both terminology and understanding of various relatively newly described tumors in the realm of dermatopathology. Several mesenchymal tumors of the lower extremity have undergone various changes in nomenclature, molecular discoveries, and histologic grading. Examples include hemosiderotic fibrohistiocytic lipomatous lesion/pleomorphic hyalinizing angiectatic tumor; superficial acral fibromyxoma; and myxoinflammatory fibroblastic sarcoma. Primary cutaneous myoepithelioma is also a relatively newly described entity for which grading and classification continue to evolve. Finally, even our understanding of the classic granular cell tumor has expanded to include a non-neural variant. This article reviews the current nomenclature, emerging concepts, and differential diagnosis of these evolving entities. PMID- 21790715 TI - Asymmetric lip-closing forces in children with repaired unilateral cleft lip and/or palate. AB - The objectives of this study were to estimate the effects of cleft lip and/or palate (CLP) repair on the multidirectional lip-closing forces (LCF) produced during maximum voluntary pursing-like lip-closing movement in children. Thirty Japanese children were divided into the control group and repaired unilateral CLP (RUCL) group, which was subdivided into the unilateral cleft lip and/or alveolus (UCLA) and the unilateral cleft lip and cleft palate (UCLP) groups. The maximum voluntary LCF were recorded in eight directions. No significant differences in any of the directional LCF (DLCF) or total LCF were observed between RUCL and control groups. Symmetrical DLCF were seen in the oblique directions on both sides of the upper lip in the control group, while the oblique DLCF on the non cleft side was significantly greater than that on the cleft side in RUCL group. Furthermore, symmetrical vertical DLCF were observed in the upper and lower directions in control and UCLA groups, while the vertical DLCF obtained from the lower direction was significantly greater than that obtained from the upper direction in UCLP group. These results indicate that children with repaired CLP display impaired directional specificity, which may cause secondary deformities. These findings aid our understanding of the pathology of secondary deformities in CLP patients after primary surgery for cleft lip or palate. We propose that quantitative assessments of lip-closing function based on the directional specificity of the multidirectional LCF produced during maximum voluntary pursing like lip-closing movement are useful for assessing the nature of lip-closing dysfunctions. PMID- 21790716 TI - Sleep disturbances in a community sample from preschool to school age. AB - OBJECTIVE: To study the prevalence of various sleep problems at school age in a Finnish community sample and to evaluate the persistence of the sleep problems from the preschool age to school age in a 4-year follow-up. METHODS: Parents completed the Sleep Disturbance Scale for Children questionnaire on their child's sleep during the preschool years (3-6 years) and again during the school years (7 11 years). At follow-up the parents also completed a questionnaire on family structure and socio-economic status. RESULTS: The parents of 481 children completed the questionnaires during both the first study and the follow-up (girls 49%, boys 51%; mean age 9, range 7-11). At the population level, sleep problems slightly declined from preschool to school age (P < 0.05). However, sleep problems at preschool age showed a strong persistence to school age. At the follow-up, 35% of the children who were considered to have a sleep disorder at preschool age still suffered from it at school age. At the community level, this equates to 9% of the children. The children with no sleep problems at preschool age rarely developed sleep problems at school age. CONCLUSIONS: This study showed that various types of sleep problems are common at school age. Sleep problems persisted from preschool to school age at the individual level. It is important to recognize all types of sleep problems, especially persistent ones. Persistent sleep problems in children may cause and exacerbate other somatic, cognitive and psychiatric problems. Therefore, more attention should be focused on sleep problems in paediatric health care with interventions aimed particularly at children with prolonged sleep problems. PMID- 21790718 TI - How can we tell if frogs jump further? PMID- 21790719 TI - Comparison of the organization of T-tubules, sarcoplasmic reticulum and ryanodine receptors in rat and human ventricular myocardium. AB - 1. It is apparent from the literature that there are significant differences in excitation-contraction coupling between species, particularly in the density of calcium transporting proteins in the t-system and sarcoplasmic reticulum (SR) Ca(2+) release channels. Unfortunately, there is a lack of information as to how the principal structures that link electrical excitation to the activation of calcium-induced calcium release (CICR) are different between human and animal models (particularly rat). 2. Comparison of wheat germ agglutinin and caveolin-3 labelling revealed a non-uniform distribution of surface membrane glycosylation in the rat, rabbit and human, and that the rat t-system appeared more complex in geometry than the latter species. Analysis of the t-system skeleton showed that the t-system was highly branched in the rat compared with that of the human (0.8 +/- 0.08 and 0.2 +/- 0.07 branch points per MUm(2) , respectively; P < 0.001). 3. We also compared the distribution of contractile machinery, sodium-calcium exchange, SR and ryanodine receptors (RyR) in rat and human. F-Actin and RyR labelling was used to estimate the area of contractile apparatus supplied by each RyR cluster. In the rat, each RyR cluster supplied an average cross-sectional area of contractile machinery of 0.36 +/- 0.03MUm(2) compared with 0.49 +/- 0.04 MUm(2) in human (P = 0.048). Sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) labelling showed that the SR formed a tight network of loops surrounding contractile fibrils that were denser than the t-tubule network, but otherwise appeared similar in both species. 4. In general, the results show a higher density in structures involved in CICR in the rat compared with human. PMID- 21790720 TI - C-C chemokine receptor type 3 expression in lymphomatoid papulosis, but not in mycosis fungoides lesions from the same patient. PMID- 21790721 TI - Lymphomatoid papulosis: is a second lymphoma commoner among East Asians? AB - BACKGROUND: Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Around 10-20% of LyP cases are associated with a second lymphoma. AIM: To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. METHODS: Patients were identified through the NSC clinical and histological databases. RESULTS: During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow-up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large-cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T-cell lymphoma. CONCLUSIONS: LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP. PMID- 21790722 TI - Peroxisome proliferator activated receptor-alpha agonists suppress transforming growth factor-alpha-induced matrix metalloproteinase-9 expression in human keratinocytes. AB - The peroxisome proliferator-activated receptors (PPARs), PPARalpha, PPARdelta, and PPARgamma, are nuclear ligand-activated transcription factors that are best known as regulators of glucose and lipid metabolism. PPARalpha agonists have been shown to have profound anti-inflammatory and antiproliferative effects on human keratinocytes, and are important for maintaining homeostasis of the skin. To better characterize the mechanisms underlying these phenomena, we analysed the effects of PPARalpha agonists on transforming growth factor (TGF)-alpha-induced expression of matrix metalloproteinase (MMP)-9. MMP-9 expression in keratinocytes has previously been linked to inflammatory skin diseases, regenerative skin mechanisms, and tumour development and metastasis. We found that PPARalpha agonists effectively inhibited TGF-alpha-induced MMP-9 expression in human keratinocytes via a post-transcriptional mechanism, revealing a novel and important aspect of the anti-inflammatory and anticarcinogenic action of these compounds. PMID- 21790723 TI - Participation, satisfaction and knowledge level of patients with cutaneous psoriasis or psoriatic arthritis. AB - There have been few studies about the participation in health care and the satisfaction of patients with psoriasis and with psoriatic arthritis. The objective of this study was to examine the attitudes of and satisfaction with decision-making of patients with psoriasis. The study was based on a self completed questionnaire, given after a routine medical visit to a consecutive sample of 240 patients with psoriasis [207 with cutaneous psoriasis (CP) and 33 with psoriatic arthritis (PA)]. Of the patients with CP and PA, only about a third (27.3% and 28.1%, respectively) preferred to leave decisions entirely to their doctor, whereas the majority (72.7% and 71.9%, respectively) wanted to be involved in decision-making. However, the level of knowledge about the disease was not as high, with 17.0% and 21.4% of patient with CP and PA, respectively, having a good level of knowledge about psoriasis treatment. Participation, knowledge and overall satisfaction were not significantly different between patients with CP and those with PA. Information on treatment side-effects (OR = 5.11; 95% CI 2.5-15.0; P < 0.001) and information on treatment options (OR = 3.15; 95% CI 1.4-7.1; P = 0.006) were significantly associated with overall patient satisfaction. PMID- 21790724 TI - Study of Blastocystis hominis isolates in urticaria: a case-control study. AB - Blastocystis hominis is a common intestinal parasite, with a prevalence in developing countries of up to 50%. The aim of this study was to investigate the association of this parasite with urticaria by determining the genotypic isotypes in the Egyptian population. In total, 54 patients with urticaria and 50 controls were enrolled in the study. Stool samples were examined and assessed by PCR. The parasite was detected in a significantly higher number (P < 0.001) of the patient group than the control group. There was no significant difference between the patients with acute and those with chronic urticaria (P = 0.2). The amoeboid form was found in 60.6% of Blastocystis-positive patients with urticaria, but in none of the healthy controls. Subtype 3 was the only isolate found in both the patient and control groups. We recommend treatment for Blastocystis-positive patients with urticaria in developing countries. The prevalence is much lower (around 10%) in developed countries, where treatment should only be considered in the absence of other possible causes of urticaria. PMID- 21790725 TI - Specific cutaneous lesions in patients with systemic sarcoidosis: relationship to severity and chronicity of disease. AB - BACKGROUND: Specific (granulomatous) cutaneous lesions are seen in 9-37% of cases of systemic sarcoidosis, and are usually classified into maculopapules, plaques, lupus pernio (LP), scar sarcoidosis, and subcutaneous sarcoidosis. Their prognostic significance has not been fully established. AIM: To analyse the relationship between the clinical type of granulomatous cutaneous lesions and the systemic features and prognosis of systemic sarcoidosis. METHODS: The clinical charts of 86 patients (19 men, 67 women, mean age 46.82 years) with systemic sarcoidosis and granulomatous cutaneous involvement followed up for > 2 years at Bellvitge University Hospital were reviewed. RESULTS: Cutaneous lesions developed before or at the time of diagnosis of systemic sarcoidosis in 80.23% of patients. The main cutaneous lesions were classified as maculopapules (28 patients), plaques (31), LP (6), scar sarcoidosis (7) and subcutaneous sarcoidosis (14). Erythema nodosum (EN) was seen in 30 patients. Radiological stage was 0 for 8 patients, I for 48, II for 24, III for 5 and IV for 1. Systemic sarcoidosis activity persisted for > 2 years in 47 patients, and 42 received systemic corticosteroid treatment for their disease. Maculopapular and subcutaneous sarcoidosis were mainly seen in patients with EN and radiological stage I. Plaques and LP were associated with chronic disease and requirement for systemic corticosteroids. CONCLUSIONS: Cutaneous granulomatous lesions are usually present at the diagnosis of systemic sarcoidosis, and the type of cutaneous involvement may have prognostic significance. PMID- 21790726 TI - A diagnostic challenge: acute generalized exanthematous pustulosis or pustular psoriasis due to terbinafine. AB - A 72-year-old man developed a generalized erythematous pustular eruption 11 weeks after commencing terbinafine. Clinically and histologically, the appearance was that of acute generalized exanthematous pustulosis (AGEP), and the disease was managed with topical preparations. Initial improvement was marred by relapse of acute pustulosis, now more in keeping with terbinafine-induced pustular psoriasis (PP), which was successfully treated with acitretin. This case highlights the difficulty of differentiating between AGEP and PP. PMID- 21790727 TI - A distinctive flexural eruption implicating Pseudomonas aeruginosa. PMID- 21790729 TI - Reduced dermatology hospital bed numbers in Scotland: where do patients go? PMID- 21790728 TI - The role of inflammatory markers in assessing disease severity and response to treatment in patients with psoriasis treated with etanercept. AB - BACKGROUND: Psoriasis is a chronic, systemic, inflammatory disease. Inflammatory markers are used in clinical practice to detect acute inflammation, and as markers of treatment response. Etanercept blocks tumour necrosis factor (TNF) alpha, which plays a central role in the psoriatic inflammation process. AIM: To reveal any possible association between disease severity [measured by Psoriasis Area and Severity Index (PASI)] and the inflammatory burden (measured by a group of inflammatory markers), before and after etanercept treatment. METHODS: In total, 41 patients with psoriasis vulgaris, eligible for biological treatment with etanercept, were enrolled in the study. A set of inflammatory markers was measured, including levels of white blood cells and neutrophils, fibrinogen, ferritin, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), haptoglobin, ceruloplasmin and alpha1-antitrypsin, before and after 12 weeks of etanercept 50 mg twice weekly. RESULTS: All markers were reduced after treatment (P < 0.001). PASI correlated with fibrinogen and hs-CRP. Of the 41 patients, 19 (46.3%) achieved reduction of 75% in PASI (PASI75). An increase in hs-CRP and ESR difference (values before minus values after treatment) was related to higher likelihood of achieving PASI75. CONCLUSIONS: Inflammatory markers, particularly hs-CRP and to a lesser extent, fibrinogen and ESR, can be used to assist in assessing disease severity and response to treatment in patients with psoriasis. A combination of selected inflammatory factors (which we term the Index of Psoriasis Inflammation) in combination with PASI might reflect inflammatory status in psoriasis more accurately than each one separately. PMID- 21790730 TI - Severe acute generalized exanthematous pustulosis with blistering, mimicking toxic epidermal necrolysis. PMID- 21790731 TI - Verrucous epidermal naevus and naevus spilus associated with lower limb asymmetry and right bundle-branch block: a case of phacomatosis pigmentokeratotica? PMID- 21790732 TI - Pathomechanisms of nephrogenic systemic fibrosis: new insights. AB - Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is a generalized fibrotic disorder occurring in people with renal failure, following exposure to gadolinium-based contrast agents used to enhance MRI. The cellular elements involved in pathology of NSF include bone-marrow derived collagen-producing fibrocytes, myofibroblasts and activated macrophages. Mechanisms that have been hypothesized to play a role in the pathogenesis of NSF include upregulation of osteopontin, imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinase 1, and presence of transforming growth factor-beta, nuclear factor kappaB, decorin and metallothioneins. Gadolinium (both free and chelated) is thought to be a bioactive trigger for NSF. Elucidation of these potential pathomechanisms would be useful for development of targeted therapies for NSF. PMID- 21790733 TI - Molecular evidence for the role of X-chromosome inactivation in linear presentation of X-linked hypohidrotic ectodermal dysplasia. PMID- 21790734 TI - Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare, noninfectious form of skin ulceration, typically accompanied by neutrophilic infiltration. Several familial cases have been reported, suggesting the involvement of genetic factors in the aetiology of PG. Two mutations (A230T and E250Q) in the PSTPIP1 gene, encoding proline-serine-threonine phosphatase-interacting protein (PSTPIP)1 have been identified in patients with PAPA (pyogenic sterile arthritis with PG and acne) syndrome, a rare autoinflammatory disorder with autosomal dominant inheritance. AIM: The aim of this study was to sequence PSTPIP1 complementary cDNA and genomic DNA for mutations, and to identify genetic polymorphisms in the promoter region of PSTPIP1 in patients with PG. METHODS: The genomic region and cDNA of the PSTPIP1 gene were sequenced from peripheral blood leucocytes of 14 patients with PG and 20 healthy controls. RESULTS: One patient (PG1) had aberrant splicing variants of the PSTPIP1 transcript with deletions of exons 9, 11 and 12 and of exons 9-12 together, and all other patients with PG carried deletions of exon 11 and of 11-12. We also identified a novel mutation (G258A) in patient PG3, and novel polymorphisms [(CCTG)(6) and (CCTG)(8) tandem repeats] in the promoter region of the PSTPIP1 gene. CONCLUSION: All combinations of aberrant splicing variants had frame shifts and premature stop codons leading to truncated proteins and loss of function of PSTPIP1. The (CCTG)(n) tandem repeats in the promoter region of PSTPIP1 had no association with PG. The mutations G258A and R52Q are predicted by the improved prediction algorithm to have a possibly damaging effect on PSTPIP1 function. PMID- 21790735 TI - A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema. AB - C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient. PMID- 21790736 TI - The shifting nature of women's experiences and perceptions of ductal carcinoma in situ. AB - AIM: This paper is a report of a descriptive qualitative study of the evolution of women's perceptions and experiences of ductal carcinoma in situ from the period near to diagnosis to 1 year later. BACKGROUND: Ductal carcinoma in situ is a non-invasive breast condition where cancer cells are detected but confined to the ducts of the breast. With treatment, the condition has a positive prognosis but ironically patients undergo treatment similar to that for invasive breast cancer. There is a lack of longitudinal qualitative research studying women's experiences of ductal carcinoma in situ, especially among newly diagnosed patients, and how experiences change over time. METHODS: Forty-five women took part in an initial interview following a diagnosis of ductal carcinoma in situ and 27 took part in a follow-up interview 9-13 months later. Data were collected between January 2007 and October 2008. Transcripts were analysed using a hybrid approach to thematic analysis. FINDINGS: Women's early perceptions of ductal carcinoma in situ merged and sometimes conflicted with their lay beliefs of breast cancer. Perceptions and experiences of the condition shifted over time. These overriding aspects were evident in four themes identified across the interviews: (i) perceptions of ductal carcinoma in situ vs. breast cancer, (ii) from paradox to acceptance, (iii) personal impact, and (iv) support and interactions with others. CONCLUSION: This study represents one of the few longitudinal qualitative studies with newly diagnosed patients, capturing women's initial and shifting experiences and perceptions of the condition. The issues identified need to be recognized in clinical practice and supported appropriately. PMID- 21790737 TI - The theory-practice relationship: reflective skills and theoretical knowledge as key factors in bridging the gap between theory and practice in initial nursing education. AB - AIM: This paper is a report of a correlational study of the relations of nursing students' acquired reflective skills, practical skills and theoretical knowledge on their perception of coherence between theory and practice. BACKGROUND: Reflection is considered a key factor in bridging the gap between theory and practice. However, it is not evident whether reflective skills are primarily generic in nature or whether they develop from a theoretical knowledge base or the acquisition of practical skills. METHOD: This study is a secondary analysis of existing data. The data are part of a student survey that was conducted among third-year nursing students in Norway during the spring of 2007. A total of 446 nursing students participated in this study and the response rate was 71%. Structural equation modelling analyses were performed. FINDINGS: The results indicate that students' perception of coherence between theory and practice during initial nursing education is directly influenced by reflective skills and theoretical knowledge. The results also reveal that reflective skills have mediating effects and that practical skills have a fully mediated and theoretical knowledge a partially mediated influence on students' perception of coherence. CONCLUSION: The findings imply that helping students perceive coherence between theory and practice in nursing education, developing students' reflective skills and strengthening the theoretical components of the initial nursing education programme might be beneficial. The results suggest that reflective thinking is not merely a generic skill but rather a skill that depends on the acquisition of relevant professional knowledge and experience. PMID- 21790738 TI - Time to clarify--the value of advanced practice nursing roles in health care. AB - AIM: This article presents a discussion of the importance of providing meaningful advanced practice nursing role definition and clarity to improve international standards of nursing titles and scopes of practice. BACKGROUND: A plethora of international literature exists discussing advanced practice nursing roles and their contribution to healthcare delivery in various countries. However, lack of consistency around title, role definition and scope of practice remains. DATA SOURCES: CINAHL and Medline databases were searched using 'nurse practitioner', 'nurse practitioner role', 'nurse practitioner practice', 'nurse practitioner in public health', 'advanced practice nursing roles' and 'development of new nursing roles' with articles limited to years 1995-2010. Citations used in those articles were also explored. All cited articles were in the English language. DISCUSSION: This article supports the need to strengthen the Nurse Practitioner role in health care and professional clarity is identified as a strategy to enhance this. Themes around role clarity, professional identity, ability to enhance healthcare provision and inter-professional issues are examined. The need to more clearly articulate advanced nursing roles in light of the evolution of the Nurse Practitioner role is highlighted. Much work has already occurred in this domain and a means of adapting and broadening these developments for a wider, more global audience whilst maintaining local context is discussed. CONCLUSION: Although evidence exists that advanced practice nursing roles are increasing internationally, uncertainty around role clarity remains. This is problematic because the valuable contribution of nursing roles is lost, if the ability to clearly express their function does not exist. PMID- 21790739 TI - The effectiveness of the Omaha System intervention on the women's health promotion lifestyle profile and quality of life. AB - AIM: This article is a report of a quasi-experimental study of the effectiveness of the Omaha System intervention on the women's health promotion lifestyle profile and the quality of life. BACKGROUND: The Omaha System is a model for organizing, documenting and evaluating the outcomes of comprehensive, community based, client-centred care. Therefore, the Omaha System is important for public health nurses whose aim is to protect and promote health. However, few studies addressed the influence of the Omaha System on health promotion activities or quality of life in adult population. METHODS: The design of the study was one group pre-test and post-test. The study took place in Turkey in 2007; the sample comprised 76 women from an urban primary healthcare centre. The women completed questionnaires consisting of demographical characteristics, the health promotion lifestyle profile scale developed by Walker and colleagues and the quality of life scale developed by Burckhardt and colleagues. The researcher then visited selected women in their home weekly or biweekly for a 4-month period. At the end of intervention, the scales were applied to the women as the post-test. FINDINGS: The mean scores of self-actualization, health responsibility, interpersonal support, stress management subscales of the health promotion lifestyle profile and the total score increased in post-test, except for nutrition subscale. There were statistically significant differences between pre- and post-test scores. CONCLUSIONS: This study demonstrated that the Omaha System intervention increases health promotion lifestyle profile of the women. It is recommended as a nursing care to health promotion. PMID- 21790740 TI - The mediating role of the nurse-patient dyad bonding in bringing about patient satisfaction. AB - AIM: This article is a report on a Synergy Model-guided correlational study of the direct and indirect relations of nurse-characteristics and patient characteristics to patient satisfaction, as mediated by nurse-patient dyad bonding. BACKGROUND: Findings from previous studies have revealed that interventions alone do not fully account for patient outcomes, and that the effect of interventions on outcomes is mediated by factors such as interpersonal communication. The characteristics of the nurse and the patient synergize during their interaction, forming nurse-patient dyad bonding that affects patient satisfaction. Patient satisfaction is regarded as a critical part of the quality outcomes in healthcare. METHOD: A total of 210 nurse-patient dyadic interactions were observed using the Nurse-Patient Bonding Instrument. Nurse characteristics and patient characteristics were gathered through observation, interview and chart review. Data were collected in 2008 from four hospitals in the Philippines. RESULTS: Path analysis revealed that the patient characteristic of predictability had both direct effect and indirect effects on patient satisfaction, and that the nurse characteristic of facilitation of learning had an indirect effect on patient satisfaction. Nurse-patient dyad bonding mediated the relations between patient predictability and patient satisfaction, and nurse facilitation of learning and patient satisfaction. CONCLUSION: The nurse and the patient both have a role to play in forming a therapeutic dyadic relationship that brings about the desired outcome. Further research on the formation and development of nurse-patient dyads in other settings and with other patient outcomes is recommended. PMID- 21790741 TI - Effects of maternal confidence and competence on maternal parenting stress in newborn care. AB - AIM: This paper is a report of a correlational study of the relations of maternal confidence and maternal competence to maternal parenting stress during newborn care. BACKGROUND: Maternal role development is a cognitive and social process influenced by cultural and family contexts and mother and child characteristics. Most knowledge about maternal role development comes from western society. However, perceptions of the maternal role in contemporary Taiwanese society may be affected by contextual and environmental factors. METHODS: A prospective correlational design was used to recruit 372 postpartum Taiwanese women and their infants from well-child clinics at 16 health centres in central Taiwan. Inclusion criteria for mothers were gestational age >37 weeks, >=18 years old, and healthy, with infants <4 months old. Data were collected between August 2007 and January 2008 using a self-report questionnaire on mothers' and infants' demographic variables, maternal confidence, maternal competence and self-perceived maternal parenting stress. RESULTS: After controlling for maternal parity and infant temperament, high maternal confidence and competence were associated with low maternal parenting stress. Maternal confidence influenced maternal parenting stress both directly and indirectly via maternal competence. CONCLUSION: To assist postpartum women in infant care programmes achieve positive outcomes, nurses should evaluate and bolster mothers' belief in their own abilities. Likewise, nurses should not only consider mothers' infant care skills, but also mothers' parity and infant temperament. Finally, it is crucial for nurses and researchers to recognize that infant care programmes should be tailored to mothers' specific maternal characteristics. PMID- 21790742 TI - Ultrasonographic and macroscopic anatomy of the enucleated eyes of the buffalo (Bos bubalis) and the one-humped camel (Camelus dromedarius) of different ages. AB - The ultrasonographic appearance and measurements of the normal buffalo and camel eye globes were described in 60 buffaloes (Bos bubalis) aged 1 year (28 eyes) and 10 years (32 eyes), and in 51 humped camels (Camelus dromedarius) aged 1 year (26 eyes) and 10 years (24 eyes). Ocular measurements were recorded by A- and B-scan ultrasonographic examination of 40 buffalo eyes (18 young and 22 adult eyes) and 34 camel eyes (14 young and 20 adult eyes) using a KANGH ultrasound scanner equipped with 10 MHz probe. For gross measurements, 20 buffalo and 16 camel eye globes were frozen and dissected and the same measurements were made using fine callipers macroscopically. The aqueous and vitreous humour of the buffalo and camel eyes appeared anechoic. The cornea, anterior and posterior lens capsule and iris appeared hyperechoic. The ocular measurements for the axial length, vitreous chamber depth (VCD), corneal thickness, lens thickness and scleroretinal rim thickness increase with the advance of age in both buffaloes and camels. Except for the anterior chamber depth, VCD and lens thickness, which were larger in adult camels than in adult buffaloes, no other differences between ocular dimensions were observed in both species. The results of this study are valuable for comparative ocular anatomy and will be useful for ultrasonographic evaluation of ocular diseases in buffaloes and camels. PMID- 21790743 TI - Patterns of moral judgment derive from nonmoral psychological representations. AB - Ordinary people often make moral judgments that are consistent with philosophical principles and legal distinctions. For example, they judge killing as worse than letting die, and harm caused as a necessary means to a greater good as worse than harm caused as a side-effect (Cushman, Young, & Hauser, 2006). Are these patterns of judgment produced by mechanisms specific to the moral domain, or do they derive from other psychological domains? We show that the action/omission and means/side-effect distinctions affect nonmoral representations and provide evidence that their role in moral judgment is mediated by these nonmoral psychological representations. Specifically, the action/omission distinction affects moral judgment primarily via causal attribution, while the means/side effect distinction affects moral judgment via intentional attribution. We suggest that many of the specific patterns evident in our moral judgments in fact derive from nonmoral psychological mechanisms, and especially from the processes of causal and intentional attribution. PMID- 21790744 TI - Conscious vision for action versus unconscious vision for action? AB - David Milner and Melvyn Goodale's dissociation hypothesis is commonly taken to state that there are two functionally specialized cortical streams of visual processing originating in striate (V1) cortex: a dorsal, action-related "unconscious" stream and a ventral, perception-related "conscious" stream. As Milner and Goodale acknowledge, findings from blindsight studies suggest a more sophisticated picture that replaces the distinction between unconscious vision for action and conscious vision for perception with a tripartite division between unconscious vision for action, conscious vision for perception, and unconscious vision for perception. The combination excluded by the tripartite division is the possibility of conscious vision for action. But are there good grounds for concluding that there is no conscious vision for action? There is now overwhelming evidence that illusions and perceived size can have a significant effect on action (Bruno & Franz, 2009; Dassonville & Bala, 2004; Franz & Gegenfurtner, 2008; McIntosh & Lashley, 2008). There is also suggestive evidence that any sophisticated visual behavior requires collaboration between the two visual streams at every stage of the process (Schenk & McIntosh, 2010). I nonetheless want to make a case for the tripartite division between unconscious vision for action, conscious vision for perception, and unconscious vision for perception. My aim here is not to refute the evidence showing that conscious vision can affect action but rather to argue (a) that we cannot gain cognitive access to action-guiding dorsal stream representations, and (b) that these representations do not correlate with phenomenal consciousness. This vindicates the semi-conservative view that the dissociation hypothesis is best understood as a tripartite division. PMID- 21790745 TI - Influence of bilateral motor behaviors on flexible functioning: an embodied perspective. AB - To examine the influence of bilateral motor behaviors on flexibility performance, two studies were conducted. Previous research has shown that when performing unilateral motor behavior that activates the affective and motivational systems of approach versus avoidance (arm flexion vs. extension), it is the congruence between laterality and motor activation that determines flexibility-rigidity functioning (Cretenet & Dru, 2009). When bilateral motor behaviors were performed, a mechanism of embodiment was revealed. It showed that the flexibility scores were determined by the match between the respective qualities of congruence of each of the unilateral motor behaviors performed. These results bring to light an overall embodied mechanism associated with the compatibility of the cognitive impact(s) of each motor behavior performed. PMID- 21790746 TI - "Frequent frames" in German child-directed speech: a limited cue to grammatical categories. AB - Mintz (2003) found that in English child-directed speech, frequently occurring frames formed by linking the preceding (A) and succeeding (B) word (A_x_B) could accurately predict the syntactic category of the intervening word (x). This has been successfully extended to French (Chemla, Mintz, Bernal, & Christophe, 2009). In this paper, we show that, as for Dutch (Erkelens, 2009), frequent frames in German do not enable such accurate lexical categorization. This can be explained by the characteristics of German including a less restricted word order compared to English or French and the frequent use of some forms as both determiner and pronoun in colloquial German. Finally, we explore the relationship between the accuracy of frames and their potential utility and find that even some of those frames showing high token-based accuracy are of limited value because they are in fact set phrases with little or no variability in the slot position. PMID- 21790747 TI - Dedication to Professor G. Barrie Edwards. PMID- 21790748 TI - Influence of mechanical manipulations on the local inflammatory reaction in the equine colon. AB - REASONS FOR PERFORMING STUDY: Large intestinal diseases in horses are characterised by inflammation, which could arise from the disease process with some contribution from intestinal manipulation. The effects of the latter are unknown but important to surgeons and could contribute to post operative complications. OBJECTIVES: To characterise type and degree of intestinal inflammation induced by various mechanical stimuli in the equine ascending colon. METHODS: Laparotomy was performed in 12 horses, the left dorsal colon exteriorised and 3 segments randomly exposed to different mechanical manipulations: 1) enterotomy, 2) enterotomy and mucosal irritation and 3) serosal irritation. Intestinal biopsies were harvested before, immediately after and 30 min after each manipulation for histological evaluation. Eosinophils were detected with Luna's stain and neutrophils identified by immunohistochemical staining for calprotectin. Additionally, left dorsal colon samples from 14 horses from a jejunal ischaemia-reperfusion study were collected immediately after laparotomy (7 horses) and at the end of the experiment without previous manipulation of the colon (7 horses). Horses were subjected to euthanasia at the end of both studies. RESULTS: Redistribution of mucosal neutrophils and eosinophils towards the luminal surface and increased neutrophilic infiltration of the submucosa were demonstrated after serosal and mucosal irritation. All manipulations resulted in serosal infiltration with neutrophils. Laparotomy and small intestinal manipulation increased mucosal eosinophilic infiltration. CONCLUSIONS AND POTENTIAL RELEVANCE: Mechanical intestinal manipulation caused a rapid local inflammatory reaction in the mucosa, submucosa and serosa including a mucosal eosinophilic response. These changes could exacerbate existing inflammation in horses with large colon disease. Colic surgery can lead to intestinal inflammation in nonmanipulated intestine and this could contribute to a higher morbidity rate in horses after prolonged colic surgery. An intestinal biopsy should be collected at the beginning of surgery to avoid false interpretations. PMID- 21790749 TI - Ultrastructural changes in the equine colonic mucosa after ischaemia and reperfusion. AB - REASON FOR PERFORMING STUDY: Ultrastructural changes in the epithelium can provide information on early changes in barrier properties, repair and inflammation in equine colon after ischaemia and reperfusion (I/R). OBJECTIVES: To describe the morphology and ultrastructure of the epithelium in equine large colonic mucosa after I/R, and the response of inflammatory cells to injury. METHODS: Ischaemia was induced for 1 h followed by 4 h of reperfusion in a 40 cm segment of the pelvic flexure in 6 horses. Mucosal biopsies before and after ischaemia, and after 1, 2 and 4 h of reperfusion were fixed in glutaraldehyde/paraformaldehyde and osmium tetroxide, and embedded in epon. Morphological and ultrastructural changes were evaluated in toluidine blue stained semithin sections by light microscopy and in thin sections stained with uranyl acetate/lead citrate by transmission electron microscopy. RESULTS: Ischaemia caused swelling of epithelial cells and their organelles, opening of tight junctions, detachment from the basement membrane, early apoptosis and single cell necrosis. Autophagy was a prominent feature in epithelial cells after ischaemia. Reperfusion was characterised by apoptosis, epithelial regeneration and restoration of apical cell junctions. Phagocytic-like vacuoles containing cellular debris and bacteria were evident in epithelial cells after reperfusion. Paracellular and subepithelial clefts formed, accompanied by infiltration of neutrophils, lymphocytes and eosinophils into the epithelium. Subepithelial macrophages and luminal neutrophils had increased phagocytic activity. CONCLUSIONS: Ischaemia caused ultrastructural damage to the colonic epithelium, but epithelial cells recovered during reperfusion. POTENTIAL RELEVANCE: Transmission electron microscopy can demonstrate subtle ultrastructural damage to epithelial cells and evidence of recovery after I/R in equine colon. PMID- 21790750 TI - Mucosal injury and inflammatory cells in response to brief ischaemia and reperfusion in the equine large colon. AB - REASON FOR PERFORMING STUDY: Intestinal ischaemia and reperfusion (I/R) can activate inflammatory cells in the equine colon, although effects on different types of inflammatory cells have received little attention. OBJECTIVES: To assess early mucosal injury, the reaction of mucosal neutrophils, eosinophils, mast cells and macrophages, and cyclooxygenase (COX)-1 and -2 expression in response to I/R in the equine large colon. METHODS: Large colon ischaemia was induced for 1 h (1hI) followed by 4 h of reperfusion in 6 horses, and mucosal biopsies were sampled before and after ischaemia, and after 1, 2 and 4 h of reperfusion. Semithin sections (500 nm) of epon-embedded biopsies were stained with toluidine blue for histomorphometric evaluation. The number and distribution of mucosal macrophages (CD163), neutrophils (calprotectin), eosinophils (LUNA) and mast cells (toluidine blue) were determined, and mucosal COX-1 and -2 expression was identified. RESULTS: Ischaemia caused epithelial cell and nuclear swelling (mean +/- s.e. nuclear width; control: 2.7 +/- 0.2 um vs. 1hI: 4.2 +/- 0.2 um; P<0.01), subepithelial oedema (control: 0.2 +/- 0.1 um vs. 1hI: 3.2 +/- 0.2 um; P<0.01) and increased epithelial apoptosis (control: 14.3 +/- 4.1 apoptotic cells/mm mucosa vs. 1hI: 60.4 +/- 14.0 apoptotic cells/mm mucosa; P<0.01). COX-2 expression (P<0.01) was evident after ischaemia. Reperfusion caused paracellular fluid accumulation (control: 0.9 +/- 0.1 um vs. 1hI: 0.6 +/- 0.6 um vs. 1hI + 4hR: 1.6 +/- 0.2 um; P<0.05). Epithelial repair started at 1 h of reperfusion (P<0.001), followed by migration of neutrophils into the mucosa after 2 h (control: 72.3 +/- 18.4 cells/mm(2) mucosa vs. 1hI + 2hR: 1149.9 +/- 220.6 cells/mm(2) mucosa; P<0.01). Mucosal eosinophils, mast cells and macrophages did not increase in numbers but were activated. CONCLUSIONS: Epithelial injury and COX-2 expression caused by short-term hypoxia were followed by intense inflammation associated with epithelial repair during reperfusion. POTENTIAL RELEVANCE: Equine colonic mucosa subjected to a brief period of ischaemia can repair during reperfusion, despite increased mucosal inflammation. PMID- 21790751 TI - Adipose tissue-derived adiponectin expression is significantly associated with increased post operative mortality in horses undergoing emergency abdominal surgery. AB - REASONS FOR PERFORMING STUDY: Adipose tissue is an important source of inflammatory cytokines (adipokines) and adiposity has been identified as having a significant effect on human morbidity and mortality. Obesity is also an emerging welfare problem in the UK horse population, but the role that it plays in secondary diseases is unclear. OBJECTIVES: To examine the expression of inflammation-related adipokine genes in retroperitoneal adipose tissue of horses undergoing emergency abdominal surgery and to explore associations with adiposity and post operative survival. METHODS: Retroperitoneal adipose tissue samples were obtained from 76 horses undergoing emergency abdominal surgery. Real-time PCR was used to measure gene expression for leptin, adiponectin, tumour necrosis factor alpha, macrophage chemoattractant protein-1, macrophage inhibitory factor, serum amyloid A, haptoglobin and interleukin-1. Multivariate patterns of adipokine expression were explored with principal component analysis (PCA), whilst univariable associations with post operative survival were tested in a Cox proportional hazards model. RESULTS: Leptin gene expression was higher in overweight and obese horses than in lean animals. Expression of mRNA encoding adiponectin mRNA in visceral adipose tissue was positively associated with increased post operative mortality (hazard ratio 1.31, 95% CI 1.05-1.65). However, PCA did not demonstrate multivariable patterns of adipokine gene expression from visceral adipose tissue associated with body mass index or with survival. CONCLUSIONS: In horses presented with acute intestinal disease, increased adiponectin gene expression from retroperitoneal adipose tissue is associated with an increased risk of mortality. Obesity assessed by BMI had no association with increased post operative mortality in horses with primary gastrointestinal disease. POTENTIAL RELEVANCE: Further study is warranted on the expression and effects of adipokines, particularly adiponectin, and correlation with postoperative outcome. PMID- 21790752 TI - Implications of urine F2-isoprostane metabolite concentration in horses with colic and its potential use as a predictor for surgical intervention. AB - REASONS FOR PERFORMING STUDY: F2-isoprostanes have been used extensively to quantify lipid peroxidation in association with risk factors in various diseases. Horses with colic may have intestinal ischaemia and/or inflammation characterised by oxidative stress and increased production of isoprostanes. OBJECTIVES: To gather preliminary data regarding the feasibility of using urine F2-isoprostanes and isoprostane metabolites as early screening tools for the presence of gastrointestinal disease requiring surgical intervention in horses and ultimately develop a stall-side test capable of identifying these horses as early as possible for timely referral. METHODS: Concentrations of urine isoprostane and isoprostane metabolite were determined by mass spectroscopy and normalised to urine creatinine (Cr) concentrations in urine samples from 42 healthy control horses and 43 horses with gastrointestinal pain or colic. RESULTS: Horses with colic were treated medically (n = 21) or surgically (n = 22). Mean +/- s.d. concentrations of urine isoprostane and isoprostane metabolite were significantly higher in horses with colic (2.94 +/- 1.69 and 0.31 +/- 0.22 ng/mg Cr, respectively), compared to control horses (1.89 +/- 1.39 and 0.22 +/- 0.08 ng/mg Cr, respectively). Mean urine isoprostane metabolite concentrations were significantly higher in horses undergoing surgery (0.38 +/- 0.28 ng/mg Cr) compared to controls and medical colics (0.26 +/- 0.11 ng/mg Cr). Nonsurvivors had significantly higher mean urine isoprostane metabolite concentrations (0.47 +/- 0.39 ng/mg Cr) than control or surviving colic horses (0.29 +/- 0.24 ng/mg Cr). CONCLUSIONS: Measurement of urine isoprostane metabolite concentration may be a useful prognostic indicator in equine colic. POTENTIAL RELEVANCE: Urine isoprostane metabolites may aid in early recognition of surgical colic. Isoprostanes are a potential therapeutic target to prevent further systemic and gastrointestinal tissue injury in horses with colic. PMID- 21790753 TI - In vitro validation of the lactose 13C-ureide breath test for equine orocaecal transit time measurement. AB - REASONS FOR PERFORMING STUDY: Validation of a reliable, noninvasive clinical test for quantification of equine orocaecal transit time (OCTT) is required. This would facilitate an evidence-based approach to investigation and treatment of equine small intestinal disorders. OBJECTIVES: 1) Comparison of the lactose (13) C-ureide breath test (LUBT) with the hydrogen breath test (H(2) BT) for OCTT measurement. 2) Identification of the characteristics of gastrointestinal microbial glycosylureide hydrolase activity in vitro. 3) Production of an optimised protocol for the LUBT for in vivo measurement of equine OCTT. HYPOTHESIS: Significant lactose (13) C-ureide ((13) C-LU) hydrolase activity is restricted to the large bowel. The rate of expiratory (13) CO(2) production after ingestion of the isotope will provide an indirect quantifiable measure of orocaecal transit rate. Requisite bacterial activity may be enhanced by a primer dose of unlabelled substrate as shown in Man. METHODS: Combined LUBT and H(2) BT were performed in 8 healthy individuals. Analysis of sequential end expiratory breath samples was used to calculate OCTT and results compared. Digestion of (13) C-LU was investigated in vitro using fresh faecal material or intestinal aliquots collected post mortem. Isotopic fermentation rate was measured by rate of appearance of (13) CO(2) . RESULTS: Peaks in expiratory (13) CO(2) occurred in all individuals after ingestion of the labelled test meal, whereas H(2) expiration was variable. Both faecal and intestinal microbial digestion of (13) C LU were maximised by prior exposure to (12) C-LU. Induced bacterial glucoseureide hydrolase activity was significantly greater in the caecum than in the small intestine (n = 10, P<0.05). CONCLUSIONS: Significant (13) C-LU digestion is restricted to the equine large intestine under normal conditions, and is enhanced by prior exposure to (12) C-LU, making (13) C-LU a suitable noninvasive marker of equine OCTT. The LUBT is more reliable than the H(2) BT for measurement of equine OCTT. PMID- 21790754 TI - Application of the lactose 13C-ureide breath test for measurement of equine orocaecal transit time. AB - REASONS FOR PERFORMING STUDY: Application of the lactose (13) C-ureide breath test (LUBT) for measurement of equine orocaecal transit time (OCTT) has not been reported previously. The ability to assess OCTT noninvasively, and to investigate its relationship to gastric emptying rate and small intestinal transit, would be of both clinical and research value. OBJECTIVES: 1) Assessment of the LUBT in healthy horses, with comparison of induced versus noninduced test protocols. 2) Application of a new dual stable isotope breath test (lactose (13) C-ureide and (13) C-octanoic acid) for gastrointestinal transit measurement. HYPOTHESIS: The LUBT will allow quantification of equine OCTT, and test efficacy will be enhanced by prior administration of lactose (12) C-ureide as shown in vitro. The dual tracer breath test will permit simultaneous measurement of gastric emptying, OCTT and small bowel transit times. METHODS: Induced and noninduced LUBTs were performed in 3 healthy mature horses in randomised order using a standard test meal and protocol. Combined LUBT and (13) C-octanoic acid breath tests ((13) C OABT) were performed in 4 individuals on 4 occasions at weekly intervals. Expiratory isotopic recovery was modelled to allow generation of gastric emptying data, small bowel transit times and caecal transit parameters. RESULTS: The induction protocol for the LUBT increased the rate and magnitude of expiratory (13) CO(2) significantly. Mean +/- s.d. values for OCTT, caecal lag phase (t(lag) ) and caecal t(1/2) using the induced LUBT were 3.24 +/- 0.65 h, 5.62 +/- 1.22 h and 6.31 +/- 1.21 h, respectively. Dual stable isotope tests resulted in the production of 2 discrete peaks in expiratory (13) CO(2) in 15/16 tests from which gastric t(1/2), OCTT and small bowel transit (SBT) parameters could be calculated. CONCLUSIONS: The induced LUBT provides a reliable noninvasive measure of equine OCTT and can be paired with the (13) C-OABT to provide further information about small intestinal motility. PMID- 21790755 TI - Factors associated with survival of epiploic foramen entrapment colic: a multicentre, international study. AB - REASONS FOR PERFORMING STUDY: Epiploic foramen entrapment (EFE) has been associated with reduced post operative survival compared to other types of colic but specific factors associated with reduced long-term survival of these cases have not been evaluated in a large number of horses using survival analysis. OBJECTIVE: To describe post operative survival of EFE cases and to identify factors associated with long-term survival. METHODS: A prospective, multicentre, international study was conducted using clinical data and long-term follow-up information for 126 horses diagnosed with EFE during exploratory laparotomy at 15 clinics in the UK, Ireland and USA. Descriptive data were generated and survival analysis performed to identify factors associated with reduced post operative survival. RESULTS: For the EFE cohort that recovered following anaesthesia, survival to hospital discharge was 78.5%. Survival to 1 and 2 years post operatively was 50.6 and 34.3%, respectively. The median survival time of EFE cases undergoing surgery was 397 days. Increased packed cell volume (PCV) and increased length of small intestine (SI) resected were significantly associated with increased likelihood of mortality when multivariable analysis of pre- and intraoperative variables were analysed. When all pre-, intra- and post operative variables were analysed separately, only horses that developed post operative ileus (POI) were shown to be at increased likelihood of mortality. CONCLUSIONS: Increased PCV, increased length of SI resected and POI are all associated with increased likelihood of mortality of EFE cases. This emphasises the importance of early diagnosis and treatment and the need for improved strategies in the management of POI in order to reduce post operative mortality in these cases. POTENTIAL RELEVANCE: The present study provides evidence-based information to clinicians and owners of horses undergoing surgery for EFE about long-term survival. These results are applicable to university and large private clinics over a wide geographical area. PMID- 21790756 TI - Nephrosplenic entrapment of the large colon in 142 horses (2000-2009): analysis of factors associated with decision of treatment and short-term survival. AB - REASONS FOR PERFORMING STUDY: Previous studies indicate similar overall survival of horses with nephrosplenic entrapment of the large colon (NSE), regardless of treatment strategy. Short-term survival of a primarily conservative treatment strategy without rolling under general anaesthesia (GA) and a low proportion of surgical intervention as well as indicators of short-term nonsurvival has not been documented. OBJECTIVES: To document short-term survival of horses with NSE treated in a university referral hospital with a low rate of surgical interventions and to determine factors associated with the decision of treatment and short-term nonsurvival. METHODS: A retrospective review of medical records of 142 horses diagnosed with NSE between January 2000 and October 2009 was undertaken. Case details and clinical parameters from the initial examination, treatment and outcome were recorded. Factors associated with decision of treatment and short-term survival were identified by multiple logistic regression analysis. RESULTS: Warmblood breeds were over-represented in comparison to the general colic population. Overall short-term survival was 91.5% (130/142) which is similar to previous studies. Three horses considered to be in need of surgery were subjected to euthanasia for economical reasons before treatment. Of 114 conservatively treated horses, 110 (96.5%) survived, as did 20/25 (80%) of surgically treated horses. Nine conservatively managed horses were treated with phenylephrine. Gastric reflux (P = 0.0077), pain (P = 0.024) and abdominal distension (P = 0.05) were associated with the decision to treat surgically. Increased heart rate (P<0.001), and surgery (P = 0.032) were associated with reduced likelihood of short-term survival. CONCLUSIONS AND POTENTIAL RELEVANCE: Overall short-term survival was similar to that reported in previous studies with higher proportions of surgically managed cases. Consequently, horses with NSE should be managed by a primarily conservative treatment strategy, with the decision to treat surgically based on specific evidence based criteria. PMID- 21790757 TI - Comparison of primary closure of incisional hernias in horses with and without the use of prosthetic mesh support. AB - REASONS FOR PERFORMING STUDY: Repair of incisional hernias in horses has been described previously; however, this report describes the outcome of primary closure of incisional hernias in a large number of horses and compares these results with those of mesh implantation. OBJECTIVE: To report the perioperative care, complications and long-term outcome of primary closure of incisional hernias in horses and to compare these results with a second population of horses in which prosthetic mesh was used. METHODS: Medical records of horses undergoing an incisional herniorrhaphy between 1998 and 2009 were reviewed. Information obtained included case details, factors from the initial surgery that contributed to the hernia formation, method of hernia repair and outcome. Comparisons between horses with and without mesh were made using logistic regression. RESULTS: Thirty eight horses with primary closure and 9 horses with mesh implantation met inclusion criteria. Long-term follow-up for cases in which a mesh was not used was available for 25 cases; of these, 21 horses (84%) had a normal cosmetic appearance and 4 (16%) had a visible defect. There was no significant difference between the 2 repair methods in terms of age, sex, breed, weight, size of the hernia, number of defects, timing of the repair or cosmetic outcome. Horses in which a mesh was used had significantly longer duration of surgery and hospitalisation, and were significantly more likely to develop post operative complications while having a longer duration of convalescence prior to return to use. CONCLUSIONS: Primary apposition of incisional hernias in horses without the use of mesh support appears to result in a good cosmetic outcome while avoiding the complications associated with mesh implantation in this population of horses. POTENTIAL RELEVANCE: Surgical time, duration of hospitalisation, and post operative complications may be reduced by using this technique of primary repair and avoiding mesh implantation. PMID- 21790758 TI - Ex vivo comparison of three hand sewn end-to-end anastomoses in normal equine jejunum. AB - REASONS FOR PERFORMING STUDY: Although single layer techniques are preferred in man and small animals for small intestinal end-to-end anastomoses, double layer techniques are more popular in equine surgery. This study was undertaken to evaluate the ex vivo characteristics of 2 single layer anastomoses in comparison to the traditionally performed double layer anastomosis in equine jejunum. OBJECTIVES: To compare ex vivo: 1) construction time; 2) bursting pressure; and 3) lumen size reduction of 3 suture patterns (double layer simple continuous/Cushing pattern [2C]; single layer Lembert pattern [1L]; and single layer Cushing pattern [1C]) for end-to-end equine jejunojejunostomies. METHODS: End-to-end jejunojejunostomies were constructed using 2C (n = 7), 1L (n = 7) and 1C (n = 7) in harvested equine jejunum and construction times were recorded. Anastomosed and control segments were distended with gas until failure. Intraluminal pressure at failure and mode of failure were recorded. Lumen size reduction was calculated as a percentage decrease from control jejunum. Results were compared using an ANOVA and P<0.05 was considered significant. RESULTS: The 1C anastomoses were faster to construct than the 1L anastomoses, which were faster to construct than the 2C anastomoses. There were no differences in bursting pressures between the different anastomoses and control jejunum. All anastomoses decreased lumen size from control values but there were no differences in lumen reduction between types of anastomoses. CONCLUSIONS: Single layer anastomoses are faster to construct than double layer anastomoses, with the 1C being fastest. Single layer anastomoses are as strong and result in comparable lumen size reduction as traditional 2C anastomoses. POTENTIAL RELEVANCE: As the 1C anastomosis results in less exposed potentially adhesiogenic suture material than the 1L while providing adequate strength and similar luminal size reduction, the 1C may be better for equine small intestine anastomosis and further in vivo studies are warranted. PMID- 21790759 TI - Recurrent colic in the horse: incidence and risk factors for recurrence in the general practice population. AB - REASONS FOR PERFORMING STUDY: The frequency of recurrent colic in the UK equine general practice population is previously unreported. Elucidating risk factors for recurrent colic could provide a basis for clinical decision making and interventions. OBJECTIVES: To determine the incidence rate of and risk factors for recurrent colic. HYPOTHESES: Horse management, prophylactic health care and innate behaviour contribute to the risk of recurrent colic. METHODS: A cohort of 127 horses was enrolled at the point of a veterinary-diagnosed medical colic episode. Participating owners completed a baseline and 3 follow-up telephone questionnaires over one year. Clinical details of each colic episode were collected with data on management, behaviour and preventive healthcare. Incidence was calculated using time at risk data; non-time varying covariates were assessed for association with recurrent colic using multivariable logistic regression. RESULTS: The recurrence rate was 50 colic events/100 horse years at risk (HYAR). Including only veterinary attended recurrent colic episodes the incidence was 35 colic events per 100 HYAR. A multivariable logistic regression model was built to explore non-time varying risk factors for recurrence collected from baseline data. The model showed that horses that have a known dental problem (OR 5.5, 95% CI 1.3, 23.1) or crib-bite/windsuck (OR 12.1, 95% CI 1.4, 108.1) were at increased risk of recurrence during the year following a colic event. CONCLUSIONS AND POTENTIAL RELEVANCE: The incidence of recurrence in horses following a medical episode of colic is high in this population and represents a welfare concern. The incidence rate can be used to compare intervention efficacy in similar populations. Identified risk factors could provide the basis for management interventions or highlight at risk individuals. PMID- 21790760 TI - Strongyle egg counts in Standardbred trotters: are they associated with race performance? AB - REASONS FOR PERFORMING STUDY: Strongyle worm burdens are assumed to subclinically affect equine performance. This assumption appears to be particularly pronounced in the equine racing industry. HYPOTHESIS: Race results of Standardbred trotters are negatively affected by high strongyle faecal egg count levels. METHODS: Faecal samples were obtained from 213 racing Standardbred trotters, aged >= 2 years, and stabled at training facilities of 21 professional trainers with license at racecourses in Denmark. Strongyle egg counts were generated using a McMaster technique. Race results were recorded as the finishing position of the horse (position 1-3 vs. finishing lower) and winning purse. The effect of strongyle egg counts on performance was assessed using regression analyses. RESULTS: Strongyle egg counts ranged from 0-3500 with a mean of 319 and a median of 150 eggs/g. Finishing in positions 1-3 was significantly associated with higher egg counts. CONCLUSIONS: Race performance of the population of professionally trained Danish Standardbred trotters was not negatively affected by higher strongyle faecal egg count levels. POTENTIAL RELEVANCE: The traditional frequent anthelmintic treatments of racehorses may be inordinate. PMID- 21790761 TI - Investigation of the effect of pasture and stable management on large intestinal motility in the horse, measured using transcutaneous ultrasonography. AB - REASON FOR PERFORMING STUDY: Management regimes have been identified as risk factors for equine intestinal motility disorders. However, it is not known how management factors affect gastrointestinal motility. HYPOTHESIS: Large intestinal motility was similar in horses on a stabled and a pastured management regime. OBJECTIVE: To investigate the effect of 2 different management regimes on large intestinal motility assessed with ultrasonography. METHODS: A within-subjects crossover design was used to compare large intestinal motility between a stabled and a pastured regime in 16 working horses. Group A was managed under a standardised stabled regime throughout the study. Group B was maintained at pasture for the first monitoring phase and then transferred to the stabled regime for the second monitoring phase. Motility of the caecum, sternal flexure and aboral left ventral colon (contractions/min) was measured twice daily for 2 consecutive days using transcutaneous ultrasonography. Mean values for each management regime were pooled for analysis using multilevel statistical modelling. RESULTS: Significant variables identified by the model included: time of day, region of intestine, management regime, and combination of region of intestine and management regime. Motility assessed by ultrasound was significantly lower in stabled horses compared to pasture-kept horses. Intestinal motility for caecum was 1.7 +/- 0.3 contractions/min (pastured = 2.0, stabled = 1.4), sternal flexure was 1.6 +/- 0.2 contractions/min (mean (pastured = 1.7, stabled = 1.5), and left ventral colon was 0.8 +/- 0.3 contractions/min (pastured = 1.0, stabled = 0.7). CONCLUSIONS: The null hypothesis was disproven. Large intestinal motility assessed by ultrasound was significantly reduced in stabled horses compared to pastured horses. This effect was most marked in the aboral left ventral colon. POTENTIAL RELEVANCE: This study has demonstrated a possible mechanism for the increased risk of large intestinal impactions in stabled horses. PMID- 21790762 TI - Is there a statistical correlation between ultrasonographic findings and definitive diagnosis in horses with acute abdominal pain? AB - REASON FOR PERFORMING STUDY: Abdominal ultrasonography has become a part of the diagnostic investigation for the acute abdomen in many equine clinics. There is limited information on the correlation between abnormalities detected on abdominal ultrasonography and the specific category of small intestine (SI) and large intestine (LI) diseases. OBJECTIVES: To investigate the relationship between abdominal ultrasonographic findings and disease categories that cause abdominal pain requiring surgery. METHODS: Medical records were reviewed for horses undergoing surgery or post mortem examination for colic. The ultrasound examination was performed to assess free peritoneal fluid, the left kidney, stomach, appearance and motility of the duodenum, identification, appearance, motility and thickness of small intestine loops, and the appearance and motility of the colon. Logistic regression analysis was used to identify associations between disease categories and ultrasonographic findings; a Chi-squared test was used to test for associations between each variable and disease categories. RESULTS: The study included 158 horses. Distended and nonmotile SI loops were associated with strangulated obstruction (n = 45); increased free peritoneal fluid, completely distended SI loops with abnormal motility and thickened loops were associated with definitive diagnosis involving SI (n = 58). Failure to visualise the left kidney was associated with renosplenic entrapment (n = 16); thickened large colon (LC) was associated with LC strangulating volvulus (n = 9). CONCLUSION: The use of abdominal ultrasonography can be used for the accurate definitive diagnosis involving SI and LI diseases. POTENTIAL RELEVANCE: This retrospective study may be used as a basis for prospective studies to assess the ultrasonographic findings in horses with medical colic and to compare these with surgical findings. PMID- 21790763 TI - The effects of a novel anti-inflammatory compound (AHI-805) on cyclooxygenase enzymes and the recovery of ischaemia injured equine jejunum ex vivo. AB - REASONS FOR PERFORMING STUDY: Flunixin meglumine is used for treatment of equine colic despite evidence of inhibited recovery of mucosal barrier function following small intestinal ischaemic injury. This study aimed to characterise an alternative treatment (AHI-805) for abdominal pain in the horse. OBJECTIVE: To determine the effect of AHI-805, an aza-thia-benzoazulene derivative, on the cyclooxygenase enzymes and the recovery of mucosal barrier function following ischaemic injury. METHODS: Effect of AHI-805 on in vitro COX-1 and COX-2 activity was determined by measuring coagulation-induced thromboxane B(2) (TXB(2)) and lipopolysaccharide-stimulated prostaglandin E(2) concentrations in equine whole blood. Horses (n = 6) were anaesthetised and jejunum subjected to ischaemia for 2 h. Control and ischaemia injured mucosa was placed in Ussing chambers and treated with Ringer's solution containing control treatment (DMSO), flunixin meglumine (27 umol/l), or AHI-805 (27 umol/l). Transepithelial electrical resistance (TER), mucosal-to-serosal flux of (3) H-mannitol, and bathing solution TXB(2) and prostaglandin E metabolites (PGEM) were measured over a 4 h recovery period. RESULTS: Treatment with AHI-805 had no significant effect on TXB(2) production but significantly inhibited production of PGE(2) at a concentration of 1 umol/l or greater. TER of flunixin or AHI-805 treated ischaemia-injured jejunum was significantly lower than control treated injured tissue over the recovery period. Mannitol flux and grade of histological damage were significantly increased by ischaemic injury only. There was a significant increase in PGEM and TXB(2) in control tissues over the 240 min recovery period, but not in flunixin or AHI-805 treated tissues. CONCLUSIONS: Flunixin meglumine and AHI-805 inhibit recovery of barrier function in ischaemic-injured equine jejunum in vitro through inhibition of the COX enzymes. POTENTIAL RELEVANCE: The novel compound AHI-805 may not be suitable for the treatment of equine colic associated with ischaemic injury. PMID- 21790764 TI - Effects of flunixin meglumine on the recovery of ischaemic equine colonic mucosa in vitro. AB - REASONS FOR PERFORMING STUDY: The effects of prostaglandins and nonsteroidal anti inflammatory drugs (NSAIDs) on repair of equine intestinal mucosa are important since most horses with gastrointestinal diseases are routinely treated with NSAIDs, such as flunixin meglumine (FM), and these drugs can be toxic to equine gastrointestinal mucosa. HYPOTHESIS: Flunixin meglumine would not affect recovery of equine colonic mucosa in vitro, 18 h after a reversible ischaemic injury. METHODS: In 14 anaesthetised horses, a segment of pelvic flexure was subjected to 2 h of ischaemia and the horses were allowed to recover for 18 h. Seven horses received normal saline and 7 received FM, 1.1 mg/kg bwt i.v., at the end of ischaemia and 12 h later. Colonic mucosa was harvested during a second anaesthesia, 18 h after recovery from ischaemia and then horses were subjected to euthanasia. Transepithelial electrical resistance (TER) and transepithelial flux of tritiated mannitol were used to measure mucosal permeability during 4 h of incubation in Ussing chambers, with the following in vitro treatments: 1) no addition, 2) FM 14 umol/l as powder, 3) FM 14 umol/l in injectable form and 4) diluent for injectable FM. Histomorphological changes were assessed by light microscopy. RESULTS: There were no significant differences in any of the measurements between saline and FM treated horses. The mucosal height of the ischaemic FM tissues incubated in diluent was significantly decreased compared to the nonischaemic tissues. CONCLUSIONS: Flunixin meglumine did not adversely affect barrier integrity in ischaemic equine colonic mucosa. PMID- 21790765 TI - Cardiovascular effects of N-butylscopolammonium bromide and xylazine in horses. AB - REASONS FOR PERFORMING STUDY: N-butylscopolammonium bromide (NBB) and xylazine are commonly used medications for the treatment of spasmodic colic and other forms of abdominal pain in horses. Both NBB and xylazine exert significant effects on the cardiovascular system and other vital systems of horses. OBJECTIVE: To evaluate the effects of i.v. administration of NBB, xylazine, and the combination of NBB and xylazine on heart rate, other commonly measured physiological parameters, cardiac rhythm and blood pressure. METHODS: Six mature horses of mixed breed were used. In a random cross-over design, each horse was given 0.3 mg/kg bwt of NBB i.v., 0.25 mg/kg bwt xylazine i.v., and a combination of 0.3 mg/kg bwt NBB and 0.25 mg/kg bwt xylazine. Heart rate, physiological parameters, cardiac rhythm and indirect blood pressure were recorded at timed intervals before and 60 min following administration. RESULTS: Heart rate and blood pressure were significantly elevated immediately following administration of NBB or NBB with xylazine. Administration of NBB with xylazine resulted in significantly greater initial and peak blood pressure values than with NBB alone. Administration of xylazine resulted in a decrease in heart rate, with an initial increase in blood pressure followed by a decrease in blood pressure. Sinus tachycardia was seen with NBB, and NBB and xylazine administration. First and second degree atrioventricular block was identified with xylazine administration. Ventricular tachycardia was identified in one horse following NBB and xylazine administration. CONCLUSIONS: Results of this study suggest that the effects of administration of NBB alone or in combination with xylazine to horses with colic, especially to those with systemic cardiovascular compromise, should be considered carefully to assess condition and predict prognosis accurately, and to avoid potential adverse effects. PMID- 21790766 TI - Surgical drainage and post operative lavage of large abdominal abscesses in six mature horses. AB - Six mature horses with large abdominal abscesses (defined as an abscess >15-20 cm in at least one dimension) were treated by surgical drainage and post operative lavage. The abscess was associated with previous intestinal surgery in one horse, and with Streptococcus equi spp. equi infection in the other 5. A Foley catheter was used to drain and lavage the abscess in all cases. The abscess was accessed by a ventral midline laparotomy in 5 cases and by standing flank laparoscopy in one. Two horses were subjected to euthanasia within 7 days due to persistent or recurrent colic. The other 4 horses survived. Lavage of the abscess was continued for a median time of 19 days. Antibacterial therapy was continued until the plasma fibrinogen concentration was normal (median 47 days). Follow-up information was obtained at a median of 1.8 years. All 4 horses were alive at the time of follow-up; 2 horses had suffered one or more bouts of colic that had responded to medical treatment. PMID- 21790767 TI - Multiple small intestinal pseudodiverticula associated with lymphoma in three horses. AB - Three mature horses presented with progressive weight loss, inappetence, ventral abdominal oedema and lethargy. Two of the animals had intermittent signs of low grade abdominal pain. At presentation, all 3 had hypoalbuminaemia; 2 had hyperfibrinogenaemia and the other had neutrophilia. An oral glucose tolerance test was performed in 2 cases, both of which demonstrated impaired glucose absorption. One pony treated with corticosteroids failed to improve and developed peritonitis and was subjected to euthanasia after 2 weeks. One pony had small intestinal biopsies obtained via a standing flank laparotomy, which revealed a mainly mononuclear cell infiltrate of the mucosa. It failed to respond to treatment with antibiotics and corticosteroids and, after 2 months, developed sternal oedema in addition to the ventral abdominal oedema and peritonitis and was subjected to euthanasia. The remaining pony deteriorated despite symptomatic therapy and was subjected to euthanasia after one week. At post mortem examination, all 3 animals had multifocal lesions of small intestinal wall thickening, mucosal ulceration, pseudodiverticula and enlarged mesenteric lymph nodes. One pony also had a multinodular mass at the root of the mesentery, a mediastinal mass and a lung mass. Histological examination confirmed the presence of lymphoma of the intestinal wall at post mortem examination in each case and immunohistochemistry (including retrospective evaluation of the intestinal biopsies obtained from the pony that underwent a flank laparotomy) indicated that the lymphomas were of T cell origin. PMID- 21790768 TI - An update on cyathostomins: anthelmintic resistance and diagnostic tools. AB - Cyathostomins represent a potential cause of equine morbidity and have become the main focus of endoparasite control in managed horses. All grazing horses are at risk of infection with cyathostomins; therefore, the application of appropriate management measures is essential. Anthelmintics currently comprise the main method of control for equine nematodes and the ready availability of these products in some countries has resulted in their use becoming dissociated from veterinary involvement. This is concerning given the levels of anthelmintic resistance that have been recorded in cyathostomin populations. It is important that veterinarians re-establish control over the implementation of parasite control programmes, a major objective of which should be the preservation of anthelmintic efficacy. This article details the principles of cyathostomin control in horses with particular reference to anthelmintic resistance, and the use and interpretation of diagnostic tests for detecting cyathostomins and identifying anthelmintic resistance. PMID- 21790769 TI - The effect of nonsteroidal anti-inflammatory drugs on the equine intestine. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management of pain and endotoxaemia associated with colic in the horse. While NSAIDs effectively treat the symptoms of colic, there is evidence to suggest that their administration is associated with adverse gastrointestinal effects including right dorsal colitis and inhibition of mucosal barrier healing. Several studies have examined the pathophysiology of NSAID associated effects on the large and small intestine in an effort to avoid these complications and identify effective alternative medications. Differences in the response of the large and small intestines to injury and NSAID treatment have been identified. Flunixin meglumine has been shown in the small intestine to inhibit barrier function recovery and increase permeability to lipopolysaccharide (LPS). A range of NSAIDs has been examined in the small intestine and experimental evidence suggests that those NSAIDs with cyclooxygenase independent anti-inflammatory effects or a COX-2 selective mode of action may offer significant advantages over traditional NSAIDs. PMID- 21790770 TI - In vitro electrical activity of the equine pelvic flexure. AB - REASONS FOR PERFORMING STUDY: The generation and maintenance of intestinal motility patterns involve the complex interactions of several components including the gastrointestinal pacemaker cells (interstitial cells of Cajal, ICC). Central to ICC function is the generation of rhythmic pacemaker currents, namely slow waves, which represent the rate limiting step for intestinal smooth muscle contractions. Currently, intracellular slow wave activity has not been demonstrated in the equine colon. OBJECTIVES: To characterise the in vitro myoelectrical activity of the equine pelvic flexure using intracellular recording techniques. METHODS: Intestinal samples were collected immediately following euthanasia from 14 normal horses. One millimetre thick tissue sections were pinned and superfused with warmed, oxygenated Krebs solution. Intracellular recordings were made from smooth muscle cells close to the submucosal border of the circular muscle layer. The L-type Ca(2+) channel blocker nifedipine was added to the superfusion fluid in 9 experiments while the Na(+) channel blocker tetrodotoxin was added to the superfusion fluid in 4 experiments. The data were recorded and stored using an acquisition system and a software package used to analyse the recordings. RESULTS: In 10 of the 14 horses, electrical events consistent with slow wave patterns were recorded from individual smooth muscle cells. Surprisingly, adding nifedipine to the superfusion fluid abolished all electrical activity. In contrast, tetrodotoxin had no apparent effect on the electrical activity. CONCLUSIONS: Assuming that the electrical events were slow waves, the blockade by nifedipine suggests significant and potentially important differences in the ionic mechanisms responsible for slow waves in the different regions of the equine intestinal tract, which deserve further evaluation. PMID- 21790771 TI - The effect of sedation on D(+)-xylose absorption tests in 6 normal horses. AB - REASONS FOR PERFORMING STUDY: D(+)-xylose absorption tests are commonly performed when investigating suspected small intestinal malabsorption in the horse. The test involves the administration of a D(+)-xylose solution via a nasogastric tube followed by serial blood sampling to determine its rate of absorption. In some horses, nasogastric intubation cannot be safely performed without prior administration of a sedative. Due to its short duration of action, the alpha(2) agonist xylazine is commonly used for this purpose. However, alpha(2) agonists have also been reported to influence the rate of gastric emptying as well as small intestinal motility patterns. OBJECTIVE: To evaluate if prior sedation with xylazine would influence the rate of absorption of D(+)-xylose in 6 normal Standardbred horses in a randomised cross-over study. METHODS: D(+)-xylose was administered by nasogastric intubation at a dose rate of 0.5 g/kg bwt given as a 10% solution with water while xylazine was administered iv at a dose rate of 0.5 mg/kg bwt. A heparinised blood sample was collected prior to administration of D(+)-xylose (and xylazine when used) and then at 30, 45, 60, 75, 90, 120, 150, 180 and 240 min following administration. Samples were immediately analysed using a modified colorimetric micro method. The cumulative amount of D(+)-xylose absorbed at each time point with and without prior sedation were. The significance rate was set at P<0.05. RESULTS: The study failed to demonstrate a statistically significant difference in the amount of D(+)-xylose absorbed between sedated and unsedated animals, although there was a tendency for a less rapid initial uptake with prior sedation. CONCLUSION: This study suggests that prior sedation with xylazine will not significantly affect the result of a D(+) xylose absorption test in the normal horse. PMID- 21790772 TI - Ultrasonographic evidence of colonic mesenteric vessels as an indicator of right dorsal displacement of the large colon in 13 horses. AB - This report describes the use of ultrasound to diagnose right dorsal displacement of the large colon (RDDLC) in 13 horses prior to surgery. Horses had ultrasonographic examinations performed of the right lateroventral aspect of the abdomen upon admission to the hospital with a 2-5 MHz broadband curvilinear sector scanning transducer after alcohol was used to wet the hair. First, the caecal vessels were identified in the right flank and followed medially and cranially. Next, each intercostal space, from caudal to cranial, was scanned from dorsal to ventral evaluating for abnormally-located mesenteric vessels associated with the large colon. Abnormally-located mesenteric vessels associated with the large colon, distinct from the caecal vessels, were identified in 13 of 23 horses with a diagnosis of RDDLC obtained at exploratory laparotomy. In horses, ultrasonographic visualisation of mesenteric vessels along the right lateral abdomen, dorsal to the costochondral junction in at least 2 intercostal spaces, distinct from the caecal vessels, is consistent with a surgical diagnosis of RDDLC. PMID- 21790773 TI - Predictive value of HbA1c for incident diabetes among subjects with impaired glucose tolerance--analysis of the Indian Diabetes Prevention Programmes. AB - AIMS: The objectives of the study were to assess the predictive value of baseline HbA(1c) for incident diabetes among the participants with impaired glucose tolerance in the Indian Diabetes Prevention Programmes 1 and 2. METHODS: Data at baseline and at 3-year follow-up were analysed in combined cohorts of the Indian Diabetes Prevention Programmes 1 and 2. Within the 3 years, 324 of the 845 participants developed diabetes (World Health Organization criteria). The predictive value of baseline HbA(1c) for incident diabetes was determined by logistic regression analysis. RESULTS: Baseline HbA(1c) values had heterogenous distribution. The distribution was similar in isolated impaired glucose tolerance or in impaired glucose tolerance in combination with impaired fasting glucose. A progressive increase in diabetes occurred with increasing HbA(1c). HbA(1c) showed the strongest association with incident diabetes in the multiple logistic regression analysis (odds ratio 3.548, P < 0.0001). The cut-off HbA(1c) of 43 mmol/mol (6.05%) had 67% sensitivity and 60% specificity to predict future diabetes. The diagnostic sensitivity of HbA(1c) of >= 48 mmol/mol (>= 6.5%) was only 51%, with a specificity of 87%, when compared with the oral glucose tolerance glucose values. CONCLUSIONS: Baseline HbA(1c) was highly predictive of future diabetes in Asian Indian subjects with impaired glucose tolerance and nearly 60% of the incidence occurred with values >= 42 mmol/mol (>= 6.0). Diagnostic sensitivity of HbA(1c) >= 48 mmol/mol (>= 6.5%) for new diabetes was only 51% using the oral glucose tolerance test as the standard for comparison. PMID- 21790774 TI - Diabetes in care homes: current care standards and residents' experience. AB - AIMS: The Diabetes UK good clinical practice guidelines for care home residents were revised in 2010. In this study, we examined current care against these standards and sought the views of residents on their diabetes. METHODS: Mixed methods (qualitative and quantitative), including interviews with residents, carers and staff, participant record reviews and focus group discussions were used to gather data in care homes in Newcastle upon Tyne. RESULTS: Thirty-one residents from seven care homes participated. Eighty-seven per cent of residents had probable dementia (based on abbreviated mental test score or clock-drawing test). Weight, body mass index and blood pressure were satisfactorily monitored. Glucose monitoring took place in all residents who received insulin, but was monitored unnecessarily in those with diet-controlled diabetes (63%). The majority of residents (90%) had seen a chiropodist and had received eye screening (> 80%) recently. Only one of the care homes had staff that had diabetes training. Residents reported little knowledge of diabetes management. However, when asked what they knew about diabetes, comments included 'It's a common thing... like cancer'; '[I would have liked a] plain language explanation of diabetes' and 'They told me they could control it by diet, and then it was tablets, then insulin. They didn't explain why.' CONCLUSIONS: In Newcastle upon Tyne care homes there is good care provided but also evidence of inadequacies. Despite high levels of dementia, many patients have strong and valid opinions about their disease and the care they receive. Despite the challenges, we believe that residents must be included in discussions about service development. PMID- 21790775 TI - Lung spirometry parameters and diffusion capacity are decreased in patients with Type 2 diabetes. AB - AIMS: In cohort studies, Type 2 diabetes mellitus has been associated with decreased forced 1 s expiratory volume and forced vital capacity. We examined if forced vital capacity, forced 1 s expiratory volume and diffusion lung capacity correlate with diabetes mellitus across different races in a clinical setting. METHODS: We examined the medical records of 19,882 adults 18-97 years of age in our centre from 1 January 2000 to 1 May 2009. After excluding patients with diseases causing abnormal lung function, 4164 subjects were available for analysis. We used multiple linear regressions to examine cross-sectional differences in forced vital capacity, forced 1 s expiratory volume and carbon monoxide diffusing capacity between patients with and without diabetes mellitus, after adjustment for age, sex, race, height, smoking, BMI and heart failure. RESULTS: Patients with diabetes (n = 560) were older (62 +/- 12 vs. 55 +/- 16 years), more likely to be men (56 vs. 43%), overweight (BMI 31.7 +/- 8.5 vs. 27.3 +/- 6.7 kg/m2 ), have heart failure (33 vs. 14%) and less likely to be Caucasians (65 vs. 76%) and never smokers (66 vs. 72%) compared with patients without diabetes (n = 3604). The mean unadjusted values in patients with diabetes vs. those without were: forced vital capacity 2.78 +/- 0.91 vs. 3.19 +/- 1.03 l; forced 1 s expiratory volume 2.17 +/- 0.74 vs. 2.49 +/- 0.0.83; and carbon monoxide diffusing capacity 16.67 +/- 5.53 vs. 19.18 +/- 6.72 ml(-1) min(-1) mmHg, all P < 0.0001. These differences remained significant after adjustment for covariates. After race stratification, only Caucasians with diabetes had a significant decrease in all lung function measures. CONCLUSIONS: Patients with diabetes have decreased lung function compared with those without diabetes. Caucasians with diabetes have more global lung function impairment compared with African-Americans and Hispanics. PMID- 21790776 TI - Melatonin attenuates decrease of protein phosphatase 2A subunit B in ischemic brain injury. AB - Melatonin is an antioxidant that has neuroprotective functions in ischemic brain injury. Protein phosphatase 2A (PP2A) is a serine and threonine phosphatase that modulates cell metabolism and cell survival. This study investigated whether melatonin modulates PP2A subunit B in focal cerebral ischemia and glutamate toxicity-induced neuronal cell death in a rat model. Middle cerebral artery occlusion (MCAO) was performed to induce permanent cerebral ischemic injury. Adult male rats were treated with vehicle or melatonin (5 mg/kg) prior to MCAO, and cerebral cortex tissues were collected 24 hr after MCAO. A proteomic approach elucidated the decrease in PP2A subunit B in MCAO-operated animals. Melatonin treatment attenuated injury-induced reductions in PP2A subunit B levels. Western blot analyses indicated that melatonin prevents injury-induced decrease in PP2A subunit B levels. In neuronal cells, glutamate toxicity induced a lowering of PP2A subunit B, while melatonin treatment attenuated the glutamate exposure induced decreases in PP2A subunit B. These results suggest that the maintenance of PP2A subunit B by melatonin in ischemic injury is critical to the neuroprotective function of melatonin during neuronal cell damage. PMID- 21790777 TI - Melatonin restores muscle regeneration and enhances muscle function after crush injury in rats. AB - The goal of this study was to provide evidence that melatonin improves muscle healing following blunt skeletal muscle injury. For this purpose, we used 56 rats and induced an open muscle injury. After injury, all animals received either daily melatonin or vehicle solution intraperitoneally. Subsequent observations were performed at day 1, 4, 7, and 14 after injury. After assessment of fast twitch and tetanic muscle force, we analyzed leukocyte infiltration, satellite cell number, and cell apoptosis. We further quantified the expression of the melatonin receptor and the activation of extracellular-signal-regulated kinase (ERK). Chronic treatment with melatonin significantly increased the twitch and tetanic force of the injured muscle at day 4, 7, and 14. At day 1, melatonin significantly reduced the leukocyte infiltration and significantly increased the number of satellite cells when compared to the control group. Consistent with this observation, melatonin significantly reduced the number of apoptotic cells at day 4. Furthermore, phosphorylation of ERK reached maximal values in the melatonin group at day 1 after injury. Additionally, we detected the MT1a receptor in the injured muscle and showed a significant up-regulation of the MT1a mRNA in the melatonin group at day 4. These data support the hypothesis that melatonin supports muscle restoration after muscle injury, inhibits apoptosis via modulation of apoptosis-associated signaling pathways, increases the number of satellite cells, and reduces inflammation. PMID- 21790778 TI - Melatonin attenuates cognitive dysfunction and reduces neural oxidative stress induced by phosphamidon. AB - Melatonin is an important modulator of nervous system functioning and important neural antioxidant. Organophosphate pesticides like phosphamidon (PHOS) have been shown to adversely affect memory and induce oxidative stress on both acute and chronic exposure. This study was designed to explore the modulation of the effects of PHOS on cognitive function by melatonin (MEL). Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. Oxidative stress was assessed by examining the levels of malondialdehyde (MDA) and nonprotein thiols (NP-SH) in isolated homogenized whole brain samples. The results showed a significant reduction in SDL and prolongation of TL in the PHOS (1.74 mg/kg/day; p.o.) treated group at weeks 6 and 8 as compared to the control group. Two-week treatment with MEL (5 mg/kg/day; i.p.) antagonized the effect of PHOS on SDL as well as TL. PHOS alone produced a significant increase in the brain MDA levels and decrease in the brain NP-SH levels. Treatment with MEL attenuated the effect of PHOS on oxidative stress. Together the results showed that MEL attenuated the cognitive dysfunction and decreased oxidative stress induced by PHOS in the brain. PMID- 21790779 TI - Systemic activity of inhaled beclomethasone dipropionate: a double-blind comparison of volume spacers. AB - BACKGROUND: To which extent volume spacers may influence systemic activity of inhaled beclomethasone dipropionate (BDP) has not been evaluated. AIM: To assess whether the AeroChamber PlusTM spacer is equivalent to the VolumaticTM spacer for administration of inhaled hydroflouroalkane 134a propelled BDP in terms of lower leg growth rate (LLGR). PATIENTS AND METHODS: Prepubertal children with mild asthma (n = 26, aged 6-14 years) were included in a 3-time periods of 2 weeks duration randomized double-blind cross-over study with a single-blind placebo run in and two washout periods. LLGR was measured with the knemometer. Interventions were inhaled BDP hydroflouroalkane 134a pressurized metered dose inhaler 100 MUg and 200 MUg b.i.d. with the AeroChamber Plus and 200 MUg b.i.d. with the Volumatic spacer. RESULTS: Beclomethasone dipropionate 200 MUg b.i.d. from the AeroChamber Plus was non-inferior to BDP 200 b.i.d. from the Volumatic spacer as the lower margin of confidence interval of the difference between treatments ( 0.18 to 0.13 mm/week) was greater than the prespecified lower limit for non inferiority (-0.20 mm/week). UFC/creatinine data showed no statistically significant variations. CONCLUSION: The systemic activity of BDP, via the VolumaticTM, and AeroChamber PlusTM spacers is similar. The AeroChamber Plus spacer may be used in children without risk of increasing systemic activity of BDP. PMID- 21790780 TI - Incidence of diabetic retinopathy in a Hong Kong Chinese population. AB - BACKGROUND: The aim was to examine the progression and regression of diabetic retinopathy within a four-year period in a Chinese population with type 2 diabetes mellitus in a community optometry clinic in Hong Kong. METHODS: During the period May 2005 to November 2009, 5,160 patients with type 2 diabetes mellitus who had attended at least two diabetic retinopathy screening sessions at a community optometry clinic were included as subjects in this study. All had retinal photographs taken of both eyes, which were of sufficiently good quality for grading. For the purpose of this study, diabetic retinopathy grading was based on the results of the worst eye. The main outcomes were the within four year incidence of diabetic retinopathy and the incidence of progression and regression of diabetic retinopathy. RESULTS: Of the 5,160 subjects in this study, 3,647 had no diabetic retinopathy, while 1,513 had diabetic retinopathy at the baseline visit. Of those 3,647 subjects with no diabetic retinopathy, the within four-year cumulative incidence of any diabetic retinopathy, mild or moderate non proliferative diabetic retinopathy and sight-threatening diabetic retinopathy was 15.16 per cent, 14.45 per cent, 0.69 per cent and 0.03 per cent, respectively. Of those 1,513 subjects with diabetic retinopathy at baseline, the within four-year progression incidence of diabetic retinopathy was 6.61 per cent and the regression incidence of diabetic retinopathy was 45.54 per cent. CONCLUSION: The high regression incidence of diabetic retinopathy suggests that it might not be necessary for all patients with diabetes to be screened annually. Other methods to determine the screening frequency for an individual patient should be explored. PMID- 21790781 TI - Aortic valve replacement in a patient with a retrosternal gastric tube. AB - A 65-year-old male with a history of a total thoracic esophagectomy with a retrosternal gastric tube reconstruction required aortic valve replacement for aortic valve stenosis due to a bicuspid aortic valve. Preoperative multidetector computed tomography demonstrated that the gastric tube occupied the retrosternal space and the gastroepiploic artery was located on the left side of the gastric tube. Aortic valve replacement was performed through a median sternotomy approach. Blunt dissection on the anterior and right side of the gastric tube was performed without injury, and we could then perform cardiac surgery with the standard surgical view. PMID- 21790782 TI - Pseudoaneurysm at the aortic anastomosis following heart transplantation. PMID- 21790783 TI - A critical assessment of the use of surrogate species in conservation planning in the Sacramento-San Joaquin Delta, California (U.S.A.). AB - Conservation biology has provided wildlife managers with a wealth of concepts and tools for use in conservation planning; among them is the surrogate species concept. Over the past 20 years, a growing body of empirical literature has demonstrated the limited effectiveness of surrogates as management tools, unless it is first established that the target species and surrogate will respond similarly to a given set of environmental conditions. Wildlife managers and policy makers have adopted the surrogate species concept, reflecting the limited information available on most species at risk of extirpation or extinction and constraints on resources available to support conservation efforts. We examined the use of surrogate species, in the form of cross-taxon response-indicator species (that is, one species from which data are used to guide management planning for another, distinct species) in the Sacramento-San Joaquin Delta, California (U.S.A.). In that system there has been increasing reliance on surrogates in conservation planning for species listed under federal or state endangered species acts, although the agencies applying the surrogate species concept did not first validate that the surrogate and target species respond similarly to relevant environmental conditions. During the same period, conservation biologists demonstrated that the surrogate concept is generally unsupported by ecological theory and empirical evidence. Recently developed validation procedures may allow for the productive use of surrogates in conservation planning, but, used without validation, the surrogate species concept is not a reliable planning tool. PMID- 21790784 TI - How research-prioritization exercises affect conservation policy. AB - Conservation scientists are concerned about the apparent lack of impact their research is having on policy. By better aligning research with policy needs, conservation science might become more relevant to policy and increase its real world salience in the conservation of biological diversity. Consequently, some conservation scientists have embarked on a variety of exercises to identify research questions that, if answered, would provide the evidence base with which to develop and implement effective conservation policies. I synthesized two existing approaches to conceptualizing research impacts. One widely used approach classifies the impacts of research as conceptual, instrumental, and symbolic. Conceptual impacts occur when policy makers are sensitized to new issues and change their beliefs or thinking. Instrumental impacts arise when scientific research has a direct effect on policy decisions. The use of scientific research results to support established policy positions are symbolic impacts. The second approach classifies research issues according to whether scientific knowledge is developed fully and whether the policy issue has been articulated clearly. I believe exercises to identify important research questions have objectives of increasing the clarity of policy issues while strengthening science-policy interactions. This may facilitate the transmission of scientific knowledge to policy makers and, potentially, accelerate the development and implementation of effective conservation policy. Other, similar types of exercises might also be useful. For example, identification of visionary science questions independent of current policy needs, prioritization of best practices for transferring scientific knowledge to policy makers, and identification of questions about human values and their role in political processes could all help advance real world conservation science. It is crucial for conservation scientists to understand the wide variety of ways in which their research can affect policy and be improved systematically. PMID- 21790785 TI - Effects of economic downturns on mortality of wild African elephants. AB - Declines in economic activity and associated changes in human livelihood strategies can increase threats of species overexploitation. This is exemplified by the effects of economic crises, which often drive intensification of subsistence poaching and greater reliance on natural resources. Whereas development theory links natural resource use to social-economic conditions, few empirical studies of the effect of economic downturns on wild animal species have been conducted. I assessed the relations between African elephant (Loxodonta africana) mortality and human-caused wounds in Samburu, Kenya and (1) livestock and maize prices (measures of local economic conditions), (2) change in national and regional gross domestic product (GDP) (measures of macroeconomic conditions), and (3) the normalized difference vegetation index (NDVI) (a correlate of primary productivity). In addition, I analyzed household survey data to determine the attitudes of local people toward protected areas and wild animals in the area. When cattle prices in the pastoralist study region were low, human-caused wounds to and adult mortality of elephants increased. The NDVI was negatively correlated with juvenile mortality, but not correlated with adult mortality. Changes in Kenyan and East Asian (primary market for ivory) GDP did not explain significant variation in mortality. Increased human wounding of elephants and elephant mortality during periods of low livestock prices (local economic downturns) likely reflect an economically driven increase in ivory poaching. Local but not macroeconomic indices explained significant variation in mortality, likely due to the dominance of the subsistence economy in the study area and its political and economic isolation. My results suggest economic metrics can serve as effective indicators of changes in human use of and resulting effects on natural resources. Such information can help focus management approaches (e.g., antipoaching effort or proffering of alternative occupational opportunities) that address variation in local activities that threaten plant and animal populations. PMID- 21790786 TI - Invasive species research to meet the needs of resource management and planning. AB - As zebra mussels (Dreissena polymorpha) continue to spread among inland lakes of the United States and Canada, there is growing interest from professionals, citizens, and other stakeholders to know which lakes are likely to be colonized by zebra mussels. Thus, we developed a classification of lake suitability for zebra mussels on the basis of measured or estimated concentrations of dissolved calcium in lake water and applied the classification to >11,500 lakes in Wisconsin and the Upper Peninsula of Michigan. The majority of lakes (58%) were classified as unsuitable (<10 mg/L Ca) for survival and reproduction of zebra mussels, 27% were identified as suitable (>=21 mg/L Ca), and 15% were classified as borderline suitable (>=10 and <21 mg/L Ca). Of the 77 inland lakes with confirmed zebra mussel records for which data on dissolved calcium were available, our method classified 74 as suitable and 3 as borderline suitable. To communicate this lake-specific suitability information and to help prioritize regional efforts to monitor and prevent the expansion of zebra mussels and other invasive species, we developed a web-based interface (available from http://www.aissmartprevention.wisc.edu/). Although we are still uncertain of how access to suitability information ultimately affects decision making, we believe this is a useful case study of building communication channels among researchers, practitioners, and the public. PMID- 21790787 TI - Homage to an avant-garde conservation leader, Navjot Sodhi. PMID- 21790788 TI - Low-dose versus high-dose aspirin after percutaneous coronary intervention: analysis from the guthrie health off-label StenT (GHOST) registry. AB - BACKGROUND: The optimal dose of aspirin therapy after percutaneous coronary intervention (PCI) remains unclear. We sought to compare the effectiveness and safety of low and high doses of aspirin in preventing adverse outcomes after PCI. METHODS: We studied 2,820 consecutive patients who underwent coronary stenting for stable or unstable coronary artery disease (excluding cardiogenic shock) discharged alive without any complications between 2001 and 2007. Patients were categorized based on the discharge aspirin dose into low-dose (81 mg/day, N = 313) or high-dose (162-325 mg/day, N = 2,507) groups. The primary end-points (adjusted using Cox Proportional Hazard and propensity scores) were major adverse cardiovascular events (MACE; a composite of death, myocardial infarction [MI], stent thrombosis [ST], or target vessel revascularization) and net adverse clinical events (NACE; a composite of MACE and thrombolysis in myocardial infarction [TIMI][major or minor] bleeding) at 1 year. RESULTS: In the low-dose versus high-dose groups, MACE occurred in 8.6 versus 9.2% (log rank P = 0.71) and NACE in 11 versus 10% (log rank P = 0.58). In multivariable analysis, low-dose aspirin was not associated with worse outcomes (adjusted HR [95% CI] 0.74 [0.49 1.14] for MACE; 1.03 [0.71-1.50] for NACE). CONCLUSION: Low-dose aspirin, as prescribed in this study of routine practice, was not associated with worse outcomes compared to high-dose aspirin. (J Interven Cardiol 2011;24:307-314). PMID- 21790789 TI - AML associated with extensive erythrophagocytosis and tetraploidy. PMID- 21790791 TI - Prognostic models for renal cell carcinoma recurrence: external validation in a Japanese population. AB - The aim of the present study was to compare the accuracy of three prognostic models in predicting recurrence-free survival among Japanese patients who underwent nephrectomy for non-metastatic renal cell carcinoma (RCC). Patients originated from two centers: Chiba University Hospital (n = 152) and Chiba Cancer Center (n = 65). The following data were collected: age, sex, clinical presentation, Eastern Cooperative Oncology Group performance status, surgical technique, 1997 tumor-node-metastasis stage, clinical and pathological tumor size, histological subtype, disease recurrence, and progression. Three western models, including Yaycioglu's model, Cindolo's model and Kattan's nomogram, were used to predict recurrence-free survival. Predictive accuracy of these models were validated by using Harrell's concordance-index. Concordance-indexes were 0.795 and 0.745 for Kattan's nomogram, 0.700 and 0.634 for Yaycioglu's model, and 0.700 and 0.634 for Cindolo's model, respectively. Furthermore, the constructed calibration plots of Kattan's nomogram overestimated the predicted probability of recurrence-free survival after 5 years compared with the actual probability. Our findings suggest that despite working better than other predictive tools, Kattan's nomogram needs be used with caution when applied to Japanese patients who have undergone nephrectomy for non-metastatic RCC. PMID- 21790792 TI - Prostate cancer detection by prebiopsy 3.0-Tesla magnetic resonance imaging. AB - OBJECTIVES: The diagnostic value of 3.0-Tesla magnetic resonance imaging (MRI) for prostate cancer remains to be determined. The aim of the present study was to assess the features of prostate cancer detectable by prebiopsy 3.0-Tesla MRI. METHODS: From January 2007 through to December 2008, 116 patients who were examined by prebiopsy 3.0-Tesla MRI underwent radical prostatectomy for localized prostate cancer. Prostate specimens were examined to see whether the largest cancer area was the same as the area indicated on the MRI. Univariate and multivariate logistic regression analyses were conducted to identify variables predictive of agreement between MRI and histopathological findings. RESULTS: Sixty-six (56.9%) patients were suspected of having prostate cancer on the basis of MRI findings. In 49 of these patients (74.2%), it was considered that there was agreement between the abnormal area on the MRI and the index tumor. Univariate analysis revealed that there were significant differences in abnormal digital rectal examination, capsular penetration, the diameter of the index tumor of the radical prostatectomy specimen, and the Gleason scores of the biopsy and radical prostatectomy specimens. Multivariate analysis revealed that the Gleason score of the radical prostatectomy specimen was associated with the accurate detection of the prostate cancer by MRI (P = 0.0177). CONCLUSIONS: In conclusion, 3.0-Tesla MRI tends to accurately diagnose prostate cancer with high tumor burden and aggressiveness. Multimodal examination (T2-weighted imaging, dynamic contrast enhanced imaging, and diffusion-weighted imaging) is recommended for the diagnosis of prostate cancer using 3.0-Tesla MRI. PMID- 21790793 TI - Randomized, double-blind, split-side comparison study of moisturizer containing licochalcone vs. 1% hydrocortisone in the treatment of infantile seborrhoeic dermatitis. AB - BACKGROUND: Infantile seborrhoeic dermatitis (ISD) is a common skin lesion in infants. There may be differences in recommendation for treatment of ISD. OBJECTIVE: To compare the efficacy of moisturizer containing licochalcone vs. 1% hydrocortisone for the treatment of ISD. METHODS: This was a randomized, prospective, split-side, double-blind study that was conducted in 75 infants between the age of 2 weeks and 1 year. Patients with a clinical diagnosis of ISD were treated twice daily, simultaneously with either moisturizer containing 0.025% licochalcone or 1% hydrocortisone on opposite sides of the lesion. The scoring system was used to assess the severity of the rash by the presence of erythema, scale and crusts. The lesions on each side were evaluated on day 0, 3 4, 6-7 and 14. RESULTS: A total of 72 patients completed the study. The moisturizer containing licochalcone group had a higher clearing rate (42%) compared to 1% hydrocortisone group (32%) (P=0.03) on day 3-4. Both products were equally effective in the treatment at day 6-7 and 14 (P=0.45 and 1, respectively). By the end of the second week, the cure rate of the moisturizer containing 0.025% licochalcone and 1% hydrocortisone group was 90% and 92%, respectively. LIMITATIONS: The small sample size was a study limitation. CONCLUSION: Moisturizer containing 0.025% licochalcone had higher cure rate compared to 1% hydrocortisone for the treatment of ISD at day 3-4. However, by the end of the first week, this difference was no longer significant. PMID- 21790794 TI - Cantharidin-podophylotoxin-salicylic acid versus cryotherapy in the treatment of plantar warts: a randomized prospective study. AB - BACKGROUND: Plantar warts are refractory to any form of treatment. High cure rates have been reported with a topical proprietary formulation consisting of 1% cantharidin, 5% podophyllotoxin and 30% salicylic acid (CPS). However, no data exists comparing the efficacy of this formulation with another treatment. Cryotherapy is a method that is also widely used in the treatment of plantar warts. Likewise, there is no evidence that it is more effective than any topical treatment. OBJECTIVE: We aim to compare the efficacy of topical CPS and cryotherapy in the treatment of plantar warts. METHODS: Patients with plantar warts were consecutively treated with either cryotherapy or topical CPS. Both treatments were performed every 2 weeks for up to five sessions. In patients without complete clearance, the therapy was switched to the other treatment option. RESULTS: Twenty-six patients with a total of 134 warts were included. Fourteen patients were completely cleared of their warts with topical CPS, whereas only in five of 12 patients (41.7%) warts were completely cleared with cryotherapy (P=0.001). In seven patients without complete clearance, the therapy was switched to CPS. Four of these patients missed the follow-up. While the two of the remaining three patients were cleared of their warts, one patient's warts still failed to clear. CONCLUSION: Topical CPS is more effective than cryotherapy in the treatment of plantar warts. PMID- 21790796 TI - NB-UVB (311-312 nm)-induced lentigines in patients with mycosis fungoides: a new adverse effect of phototherapy. AB - BACKGROUND: Lentigines are a common pigmentary disorder in adults and in patients treated by psoralen and ultraviolet A (PUVA) radiation. Their appearance following treatment with narrow-band ultraviolet B (NB-UVB) radiation has been reported in only two patients. OBJECTIVE: To describe the clinical and histological features of NB-UVB-induced lentigines their relation to dosimetry and the course of the eruption in patients with mycosis fungoides (MF). METHODS: The files of all patients with MF treated in our department in 2003-2010 were searched to identify those in whom lentigines appeared following monotherapy with NB-UVB radiation. RESULTS: Of the 73 patients with early stage MF identified, 10 met the study criteria. Lentigines were detected in skin previously involved by MF in seven patients, and in both involved and uninvolved skin in three patients. They appeared during therapy in three patients, after a mean of 56 exposures (range 50-61), and several months (mean 7.8) following completion of treatment in seven patients, after a mean of 69 exposures (range 32-157). Histopathological study of lesions from five patients revealed basal hyperpigmentation relative to adjacent normal-looking skin. Two lesions had a slight increased number of normal looking melanocytes on immunohistochemical staining with melanoma cocktail. One lesion had elongated rete ridges. The lesions persisted throughout follow-up (mean 26.7 months) in 8 patients. CONCLUSIONS: Patients with MF treated with NB UVB may acquire lentigines. As opposed to PUVA-induced lentigines which are a known common side-effect of long-term treatment, NB-UVB-induced lentigines are uncommon but appear earlier, even after a few months of treatment. PMID- 21790795 TI - Dermoscopy of scalp tumours: a multi-centre study conducted by the international dermoscopy society. AB - BACKGROUND: Little is known about the dermoscopic features of scalp tumours. Objective To determine the dermoscopic features of scalp tumours. METHODS: Retrospective analysis of dermoscopic images of histopathologically diagnosed scalp tumours from International Dermoscopy Society members. RESULTS: A total of 323 tumours of the scalp from 315 patients (mean age: 52 years; range 3-88 years) were analysed. Scalp nevi were significantly associated with young age (<30 years) and exhibited a globular or network pattern with central or perifollicular hypopigmentation. Melanoma and non-melanoma skin cancer were associated with male gender, androgenetic alopecia, age >65 years and sun damage. Atypical network and regression were predictive for thin (<=1 mm) melanomas, whereas advanced melanomas (tumour thickness > 1 mm) revealed blue white veil, unspecific patterns and irregular black blotches or dots. CONCLUSIONS: The data collected provide a new knowledge regarding the clinical and dermoscopy features of pigmented scalp tumours. PMID- 21790797 TI - A study on the prognostic value of clinical and surgical features of dermatofibrosarcoma protuberans in Korean patients. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare spindle cell tumour with locally aggressive characteristics. Only few studies on the epidemiology of DFSP in Asians have been reported. OBJECTIVES: : The purpose of the study was to evaluate the epidemiological and clinical characteristics of DFSP in Korean patients and determine the prognostic factors that affect disease-free survival. METHODS: We conducted a retrospective review of patients diagnosed with primary or recurrent DFSP between 2000 and 2009 at three Seoul National University Hospitals. Patient, tumour and treatment factors were analysed for local recurrence-free survival. RESULTS: We analysed data for 65 patients, of whom 36 (55.4%) were female. The mean age at disease onset was 34.4 years with 50% aged between 20 and 40 years. Involved sites were most often on the trunk (66.1%). Among the 65 patients, 60 patients underwent wide excision; seven patients (10.8%) experienced local recurrence during 3.6 years of follow-up. The recurrence-free survival was significantly related to the microscopic resection margins (P = 0.005), clinical presentation (P = 0.002) and frequency of recurrence (P = 0.014) in the univariate analysis. There were three cases with metastasis, two of whom died because of progression of the disease despite continuous chemotherapy with imatinib mesylate. CONCLUSIONS: We report the epidemiologic and clinical characteristics of DFSP in Korea. Patients with recurrent disease at presentation and frequent recurrence have a high risk of recurrence and metastasis, and therefore close observation is needed in these patients. PMID- 21790798 TI - Multilocus enzyme electrophoresis analysis and exoenzymatic activity of Candida albicans strains isolated from women with vaginal candidiasis. AB - Twenty-eight Candida albicans strains obtained from women with vaginal candidiasis were tested for phospholipase and proteinase production and clustered by multilocus enzyme electrophoresis (MLEE). The proteolytic and phospholipidic activity were considered moderate (0.56 +/- 0.12 mm and 0.53 +/- 0.09 mm, respectively) for all isolates. The isoenzymes malate dehydrogenase (MDH) and sorbitol dehydrogenase (SDH) showed strong intra-specific discriminatory power. The numerical and genetic interpretation of the bands produced by the isoenzymes tested presented similar discriminatory power. The genetic diversity of the isolates was measured by allelic and genic frequency, perceptual index of polymorphic loci (P = 87.5%), average number of alleles per locus, average number of alleles per polymorphic locus, average heterozygosity observed and average heterozygosity expected. We verified that three isoenzymatic loci (Adh, Gdh and Sdh-2) were not in Hardy-Weinberg equilibrium. A dendrogram constructed based on the genetic distance matrix of Nei showed seven clusters; 57.15% (16) of the isolates were considered highly related or indistinguishable, and 42.85% were considered moderately related or unrelated. We did not find a relationship between the clusters and the exoenzymes production. PMID- 21790799 TI - Pharmacoeconomic analysis of voriconazole vs. caspofungin in the empirical antifungal therapy of febrile neutropenia in Australia. AB - In two major clinical trials, voriconazole and caspofungin were recommended as alternatives to liposomal amphotericin B for empirical use in febrile neutropenia. This study investigated the health economic impact of using voriconazole vs. caspofungin in patients with febrile neutropenia. A decision analytic model was developed to measure downstream consequences of empirical antifungal therapy. Clinical outcomes measured were success, breakthrough infection, persistent base-line infection, persistent fever, premature discontinuation and death. Treatment transition probabilities and patterns were directly derived from data in two relevant randomised controlled trials. Resource use was estimated using an expert clinical panel. Cost inputs were obtained from latest Australian sources. The analysis adopted the perspective of the Australian hospital system. The use of caspofungin led to a lower expected mean cost per patient than voriconazole (AU$40,558 vs. AU$41,356), with a net cost saving of AU$798 (1.9%) per patient. Results were most sensitive to the duration of therapy and the alternative therapy used post-discontinuation. In uncertainty analysis, the cost associated with caspofungin is less than that with voriconazole in 65.5% of cases. This is the first economic evaluation of voriconazole vs. caspofungin for empirical therapy. Caspofungin appears to have a higher probability of having cost-savings than voriconazole for empirical therapy. The difference between the two medications does not seem to be statistically significant however. PMID- 21790800 TI - Protective effects of melatonin against oxidative stress in flow cytometry-sorted buffalo sperm. AB - Previous reports of the ability of melatonin to scavenge a variety of toxic oxygen and nitrogen-based reactants suggest that melatonin could be an effective antioxidant for protecting sperm. In this study, flow cytometry and laser tweezers Raman spectroscopy were used to evaluate the effect of melatonin on buffalo sperm quality to optimize sperm sex-sorting procedures. In fresh sperm incubated in the presence or absence of melatonin (10(-4) m) for 1, 24, 48 h or 72 h at 27 degrees C, the mitochondrial activity was significantly higher than in a non-melatonin control (p < 0.05). Also, during the flow-sorting process, sperm in melatonin-supplemented groups had higher (p < 0.05) mitochondrial activity than the control. The intensity of Raman spectra from sperm frozen in media supplemented with melatonin was significantly weaker than that for non-melatonin treated groups, except for a band at 1302 per cm. Thus, melatonin helps to protect buffalo sperm from reactive oxygen species induced by staining, sorting and freezing and increases semen quality after the freezing-thawing processes. Furthermore, the results indicate the high potential of the laser tweezers Raman spectroscopy technique for rapid, effective and non-invasive assessment of the quality of sperm cells. PMID- 21790801 TI - Role of ginger against the reproductive toxicity of aluminium chloride in albino male rats. AB - The aim of the current study was to evaluate reproductive disorders concomitant with aluminium chloride (AlCl(3) ) toxicity in Albino male rats. Attention was also directed to study the protective influence of ginger against this toxicity. Forty-five mature Albino Wistar male rats were equally divided into three groups; the first group was served as control group while those of the second group (AlCl(3) ) were daily treated with 34 mg/kg bw. AlCl(3) orally. The third group (AlCl(3) + ginger) was treated daily with AlCl(3) as in group 2 in combination with ginger (40 mg/kg bw), which started 2 weeks prior to AlCl(3) . Five animals from each group were sacrificed on days 30, 45 and 60 of treatment. AlCl(3) administration significantly decreased serum testosterone levels, increased testicular homogenate malondialdehyde and deteriorated semen picture with increased testicular DNA fragmentation. Histopathological examination revealed degenerative changes of the seminiferous tubules with focal areas of necrosed spermatogenic cells, marked degeneration and desquamation of the lining epithelial cells of epididymis as well as multiple calcified material in prostate gland following 60 days of aluminium treatment. Ginger treatment started to improve significantly all studied parameters after 60 days as compared with AlCl(3) -treated group. In the current study, it was concluded that AlCl(3) had a destructive effect on all the studied reproductive parameters. Treatment with ginger has an ameliorating effect against AlCl(3) toxicity after 60 days post treatment. PMID- 21790802 TI - Heritability estimate and genetic correlations of reproductive features in Nellore bulls, offspring of super precocious, precocious and normal cows under extensive farming conditions. AB - The present work aimed to estimate heritability and genetic correlations of reproductive features of Nellore bulls, offspring of mothers classified as superprecocious (M1), precocious (M2) and normal (M3). Twenty one thousand hundred and eighty-six animals with average age of 21.29 months were used, evaluated through the breeding soundness evaluation from 1999 to 2008. The breeding soundness features included physical semen evaluation (progressive sperm motility and sperm vigour), semen morphology (major, minor and total sperm defects), scrotal circumference (SC), testicular volume (TV) and SC at 18 months of age (SC18). The components of variance, heritability and genetic correlations for and between the features were estimated simultaneously by restricted maximum likelihood, with the use of the vce software system vs 6. The heritability estimates were high for SC18, SC and TV (0.43, 0.63 and 0.54; 0.45, 0.45 and 0.44; 0.42, 0.45 and 0.41, respectively for the categories of mothers M1, M2 and M3) and low for physical and morphological semen aspects. The genetic correlations between SC18 and SC were high, as well as between these variables with TV. High and positive genetic correlations were recorded among SC18, SC and TV with the physical aspects of the semen, although no favourable association was verified with the morphological aspects, for the three categories of mothers. It can be concluded that the mother's sexual precocity did not affect the heritability of their offspring reproduction features. PMID- 21790803 TI - A larger transcript is required for the synthesis of the smaller isoform of ferredoxin:NADP oxidoreductase. AB - Ferredoxin:NADP oxidoreductases (FNRs) constitute a family of flavoenzymes that catalyse the exchange of electrons between ferredoxin and NADP(H). In cyanobacteria FNR provides NADPH for photoautotrophic metabolism, but the enzyme is also capable of oxidizing NADPH providing reduced ferredoxin. In the cyanobacterium Synechocystis sp. strain PCC6803, the unique petH gene has two translation products depending on growth conditions. As a consequence two isoforms of the FNR accumulate - FNR(L) and FNR(S) . In the present work, analysis of petH expression reveals that different transcriptional start points (tsp) are responsible for this differential translation initiation. Under standard conditions (where FNR(L) accumulates), two tsps were found at -52 and 34 relative to the first translation start site. Under nitrogen-starvation conditions (where FNR(S) accumulates) a tsp was mapped at -126 relative to the first translation start site. Therefore, the transcript responsible for FNR(S) translation is longer than that producing FNR(L) . In addition, expression of the short or long transcript in E. coli resulted in the accumulation of FNR(L) or FNR(S) respectively. This result demonstrates that translation can initiate at two different sites, 336-bases apart (ATG-1 to ATG-113), depending only on the 5'UTR structure. PMID- 21790804 TI - Stage-specific requirement for Isa1 and Isa2 proteins in the mitochondrion of Trypanosoma brucei and heterologous rescue by human and Blastocystis orthologues. AB - IscA/Isa proteins function as alternative scaffolds for the assembly of Fe-S clusters and/or provide iron for their assembly in prokaryotes and eukaryotes. Isa are usually non-essential and in most organisms are confined to the mitochondrion. We have studied the function of TbIsa1 and TbIsa2 in Trypanosoma brucei, where the requirement for both of them to sustain cell growth depends on the life cycle stage. The TbIsa proteins are abundant in the procyclic form, which contains an active organelle. Both proteins are indispensable for growth, as they are required for the assembly of Fe-S clusters in mitochondrial aconitase, fumarase and succinate dehydrogenase. Reactive oxygen species but not iron accumulate in the procyclic mitochondrion upon ablation of the TbIsa proteins, but their depletion does not influence the assembly of Fe-S clusters in cytosolic proteins. In the bloodstream form, which has a downregulated mitochondrion, the TbIsa proteins are non-essential. The Isa2 orthologue of the anaerobic protist Blastocystis partially rescued the growth and enzymatic activities of TbIsa1/2 knock-down. Rescues of single knock-downs as well as heterologous rescues with human Isa orthologues partially recovered the activities of aconitase and fumarase. These results show that the Isa1 and Isa2 proteins of diverse eukaryotes have overlapping functions. PMID- 21790805 TI - The cell wall binding domain of Listeria bacteriophage endolysin PlyP35 recognizes terminal GlcNAc residues in cell wall teichoic acid. AB - The cell wall binding domains (CBD) of bacteriophage endolysins target the enzymes to their substrate in the bacterial peptidoglycan with extraordinary specificity. Despite strong interest in these enzymes as novel antimicrobials, little is known regarding their interaction with the bacterial wall and their binding ligands. We investigated the interaction of Listeria phage endolysin PlyP35 with carbohydrate residues present in the teichoic acid polymers on the peptidoglycan. Biochemical and genetic analyses revealed that CBD of PlyP35 specifically recognizes the N-acetylglucosamine (GlcNAc) residue at position C4 of the polyribitol-phosphate subunits. Binding of CBDP35 could be prevented by removal of wall teichoic acid (WTA) polymers from cell walls, and inhibited by addition of purified WTAs or acetylated saccharides. We show that Listeria monocytogenes genes lmo2549 and lmo2550 are required for decoration of WTAs with GlcNAc. Inactivation of either gene resulted in a lack of GlcNAc glycosylation, and the mutants failed to bind CBDP35. We also report that the GlcNAc-deficient phenotype of L. monocytogenes strain WSLC 1442 is due to a small deletion in lmo2550, resulting in synthesis of a truncated gene product responsible for the glycosylation defect. Complementation with lmo2550 completely restored display of characteristic serovar 1/2 specific WTA and the wild-type phenotype. PMID- 21790807 TI - Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity. AB - Bifrontal transcranial direct current stimulation (tDCS), with the anodal electrode overlying the right and the cathodal electrode overlying the left dorsolateral prefrontal cortex, has been shown to suppress tinnitus significantly in 30% of patients. The source localized resting-state electrical activity is recorded before and after bifrontal tDCS in patients who respond to tDCS to unravel the mechanism by which tDCS suppresses tinnitus. The present electroencephalography study (N = 12) provides support for the ability of bifrontal tDCS to suppress tinnitus intensity and tinnitus-related distress by modulation of the pregenual anterior cingulate cortex, parahippocampal area and right primary auditory cortex in resting-state spontaneous brain activity. These findings provide direct support for tDCS having an impact not only directly on the underlying dorsolateral prefrontal cortex but also indirectly on functionally connected brain areas relevant for tinnitus distress and tinnitus intensity, respectively. PMID- 21790806 TI - The Vibrio cholerae VctPDGC system transports catechol siderophores and a siderophore-free iron ligand. AB - Vibrio cholerae, the causative agent of cholera, has an absolute requirement for iron. It transports the catechol siderophores vibriobactin, which it synthesizes and secretes, and enterobactin. These siderophores are transported across the inner membrane by one of two periplasmic binding protein-dependent ABC transporters, VctPDGC or ViuPDGC. We show here that one of these inner membrane transport systems, VctPDGC, also promotes iron acquisition in the absence of siderophores. Plasmids carrying the vctPDGC genes stimulated growth in both rich and minimal media of a Shigella flexneri mutant that produces no siderophores. vctPDGC also stimulated the growth of an Escherichia coli enterobactin biosynthetic mutant in low iron medium, and this effect did not require feoB, tonB or aroB. A tyrosine to phenylalanine substitution in the periplasmic binding protein VctP did not alter enterobactin transport, but eliminated growth stimulation in the absence of a siderophore. These data suggest that the VctPDGC system has the capacity to transport both catechol siderophores and a siderophore free iron ligand. We also show that VctPDGC is the previously unidentified siderophore-independent iron transporter in V. cholerae, and this appears to complete the list of iron transport systems in V. cholerae. PMID- 21790808 TI - Regulation of choline acetyltransferase expression by 17 beta-oestradiol in NSC 34 cells and in the spinal cord. AB - Motoneurones located in the ventral horn of the spinal cord conciliate cholinergic innervation of skeletal muscles. These neurones appear to be exceedingly affected in neurodegenerative diseases such as amyotrophic lateral sclerosis. The dysfunction of motoneurones is typically accompanied by alterations of cholinergic metabolism and signalling, as demonstrated by a decrease in choline acetyltransferase (ChAT) expression. 17 beta-Oestradiol (E(2)) is generally accepted as neuroprotective factor in the brain under acute toxic and neurodegenerative conditions and also appears to exert a protective role for motoneurones. In the present study, we attempted to analyse the role of E(2) signalling on ChAT expression in the motoneurone-like cell line NSC-34 and in vivo. In a first step, we demonstrated the presence of oestrogen receptor alpha and beta in NSC-34 cells, as well as in the cervical and lumbar parts, of the male mouse spinal cord. Subsequently, we investigated the effect of E(2) treatment on ChAT expression. The application of E(2) significantly increased the transcription of ChAT in NSC-34 cells and in the cervical but not lumbar part of the spinal cord. Our results indicate that E(2) can influence the cholinergic system by increasing ChAT expression in the mouse spinal cord. This mechanism might support motoneurones, in addition to survival-promoting mechanisms, in the temporal balance toxic or neurodegenerative challenges. PMID- 21790809 TI - Oestrogen receptors and signalling pathways: implications for neuroprotective effects of sex steroids in Parkinson's disease. AB - Parkinson's disease (PD) is an age-related neurodegenerative disorder with a higher incidence in the male population. In the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of PD, 17beta-oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors (ER)alpha and beta distinctly contribute to neuroprotection against MPTP toxicity, as revealed by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hyroxylase in ER wild-type (WT) and knockout (ERKO) C57Bl/6 male mice. Intact ERKObeta mice had lower levels of striatal DAT and VMAT2, whereas ERKOalpha mice were the most sensitive to MPTP toxicity compared to WT and ERKObeta mice and had the highest levels of plasma androgens. In both ERKO mice groups, treatment with 17beta-oestradiol did not provide neuroprotection against MPTP, despite elevated plasma 17beta-oestradiol levels. Next, the recently described membrane G protein-coupled oestrogen receptor (GPER1) was examined in female Macaca fascicularis monkeys and mice. GPER1 levels were increased in the caudate nucleus and the putamen of MPTP monkeys and in the male mouse striatum lesioned with methamphetamine or MPTP. Moreover, neuroprotective mechanisms in response to oestrogens transmit via Akt/glycogen synthase kinase-3 (GSK3) signalling. The intact and lesioned striata of 17beta-oestradiol treated monkeys, similar to that of mice, had increased levels of pAkt (Ser 473)/betaIII-tubulin, pGSK3 (Ser 9)/betaIII-tubulin and Akt/betaIII-tubulin. Hence, ERalpha, ERbeta and GPER1 activation by oestrogens is imperative in the modulation of ER signalling and serves as a basis for evaluating nigrostriatal neuroprotection. PMID- 21790810 TI - Why the maternal brain? AB - In the rat, the change from a virgin/nulliparous female to the maternal animal takes place at many levels. A subtle developmental wave washes over the female nervous system and transforms her from largely self-centred to offspring directed, from personal care and protection to care of genetically-related offspring, from indifference to ardour. Such change is preceded by substantial and apparently permanent neural alterations, the depth of which results in the maternal brain, and is the basis of the present review. The neuroplasticity of pregnancy, inherent to the female brain and, we believe, representative of the full expression of the female nervous system's capacity, is a result of significant hormonal and other neurochemical actions. It results in the striking brain changes that are associated with, and necessary for, successful reproduction. We discuss some of these changes and their ramifications. Collectively, they represent the culmination of mammalian evolution and have led to the development of the social brain characteristic of higher orders of mammal, including the human. We also examine different facets of the maternal brain, beginning with a review of the genes involved in maternal behaviour, and in the subsequent 'expression' of the maternal brain. We next discuss olfaction and the manner in which this major sense draws from the rich sensory milieu of the mother to regulate and support maternal behaviour. Last, we discuss the 'whys' of maternal behaviour, a theoretical foray into the reasons for such substantial maternal brain alterations. We focus on the male's potential role as the raison d'etre for the manifest alterations in his mate's brain. In the end, it is clear that the female brain undergoes a significant reorganisation en route to motherhood, the results of which are deep and enduring. PMID- 21790811 TI - Transepidermal water loss in healthy and atopic dogs, treated and untreated: a comparative preliminary study. AB - An impaired skin barrier function is thought to be crucial for allergic sensitization. In humans, the skin barrier is assessed by noninvasive methods, such as the measurement of transepidermal water loss (TEWL). Although limitations have been reported, measurement of TEWL has been demonstrated to be a suitable method to assess barrier function indirectly in dogs. The purposes of this prospective clinical study were twofold. The first aim was to evaluate and compare TEWL in healthy and atopic dogs. The second aim was to evaluate TEWL in a population of atopic dogs and to assess TEWL in dogs whose disease was in remission after successful therapy and compare it with dogs whose disease was not controlled or receiving treatment. One hundred and fifty dogs were selected and divided into the following three groups: 50 atopic dogs before specific treatment (group A); 50 in remission (group B); and 50 control dogs (group C). The mean values for TEWL for each group were 22.47 (g/m(2) h) (group A; 95% confidence interval 20.85-24.09), 12.57 (g/m(2) h) (group B; 95% confidence interval 11.43 13.7) and 8.81 (g/m(2) h) (group C; 95% confidence interval 8.09-9.52); P-value was 0.0001 for TEWL (groups A, B and C). This study showed a significant difference of TEWL between healthy control dogs and dogs with atopic dermatitis. Additionally, TEWL was lower in atopic dogs whose disease was in remission due to treatment. These results were consistent with reports in human medicine about TEWL. PMID- 21790812 TI - Characterization of Linaria KNOX genes suggests a role in petal-spur development. AB - Spurs are tubular outgrowths of perianth organs that have evolved iteratively among angiosperms. They typically contain nectar and often strongly influence pollinator specificity, potentially mediating reproductive isolation. The identification of Antirrhinum majus mutants with ectopic petal spurs suggested that petal-spur development is dependent on the expression of KNOTTED 1-like homeobox (KNOX) genes, which are better known for their role in maintaining the shoot apical meristem. Here, we tested the role of KNOX genes in petal-spur development by isolating orthologs of the A. majus KNOX genes Hirzina (AmHirz) and Invaginata (AmIna) from Linaria vulgaris, a related species that differs from A. majus in possessing long, narrow petal spurs. We name these genes LvHirz and LvIna, respectively. Using quantitative reverse-transcription PCR, we show that LvHirz is expressed at high levels in the developing petals and demonstrate that the expression of petal-associated KNOX genes is sufficient to induce sac-like outgrowths on petals in a heterologous host. We propose a model in which KNOX gene expression during early petal-spur development promotes and maintains further morphogenetic potential of the petal, as previously described for KNOX gene function in compound leaf development. These data indicate that petal spurs could have evolved by changes in regulatory gene expression that cause rapid and potentially saltational phenotypic modifications. Given the morphological similarity of spur ontogeny in distantly related taxa, changes in KNOX gene expression patterns could be a shared feature of spur development in angiosperms. PMID- 21790813 TI - Combined activity of LACS1 and LACS4 is required for proper pollen coat formation in Arabidopsis. AB - Very long chain lipids are important components of the plant cuticle that establishes the boundary surface of aerial organs. In addition, these lipids were detected in the extracellular pollen coat (tryphine), where they play a crucial role in appropriate pollen-stigma communication. As such they are involved in the early interaction of pollen with the stigma. A substantial reduction in tryphine lipids was shown to compromise pollen germination and, consequently, resulted in male sterility. We investigated the role of two long-chain acyl-CoA synthetases (LACSs) in Arabidopsis with respect to their contribution to the production of tryphine lipids. LACS was shown to provide CoA-activated very long chain fatty acids (VLCFA-CoAs) to the pathways of wax biosynthesis. The allocation of sufficient quantities of VLCFA-CoA precursors should therefore be relevant to the generation of tryphine lipids. Here, we report on the identification of lacs1 lacs4 double knock-out mutant lines that were conditionally sterile and showed significant reductions in pollen coat lipids. Whereas the contributions of both LACS proteins to surface wax levels were roughly additive, their co-operation in tryphine lipid biosynthesis was clearly more complex. The inactivation of LACS4 resulted in increased levels of tryphine lipids accompanied by morphological anomalies of the pollen grains. The additional inactivation of LACS1 neutralized the morphological defects, decreased the tryphine lipids far below wild-type levels and resulted in conditionally sterile pollen. PMID- 21790814 TI - Arabidopsis MAP kinase phosphatase 1 and its target MAP kinases 3 and 6 antagonistically determine UV-B stress tolerance, independent of the UVR8 photoreceptor pathway. AB - Plants perceive UV-B radiation as an informational signal by a pathway involving UVR8 as UV-B photoreceptor, activating photomorphogenic and acclimation responses. In contrast, the response to UV-B as an environmental stress involves mitogen-activated protein kinase (MAPK) signalling cascades. Whereas the perception pathway is plant specific, the UV-B stress pathway is more broadly conserved. Knowledge of the UV-B stress-activated MAPK signalling pathway in plants is limited, and its potential interplay with the UVR8-mediated pathway has not been defined. Here, we show that loss of MAP kinase phosphatase 1 in the mutant mkp1 results in hypersensitivity to acute UV-B stress, but without impairing UV-B acclimation. The MKP1-interacting proteins MPK3 and MPK6 are activated by UV-B stress and are hyperactivated in mkp1. Moreover, mutants mpk3 and mpk6 exhibit elevated UV-B tolerance and partially suppress the UV-B hypersensitivity of mkp1. We show further that the MKP1-regulated stress-response MAPK pathway is independent of the UVR8 photoreceptor, but that MKP1 also contributes to survival under simulated sunlight. We conclude that, whereas UVR8 mediated acclimation in plants promotes UV-B-induced defence measures, MKP1 regulated stress signalling results when UV-B protection and repair are insufficient and damage occurs. The combined activity of these two mechanisms is crucial to UV-B tolerance in plants. PMID- 21790815 TI - Arabidopsis RUGOSA2 encodes an mTERF family member required for mitochondrion, chloroplast and leaf development. AB - Little is known about the mechanisms that control transcription of the mitochondrial and chloroplastic genomes, and their interplay within plant cells. Here, we describe the positional cloning of the Arabidopsis RUG2 gene, which encodes a protein that is dual-targeted to mitochondria and chloroplasts, and is homologous with the metazoan mitochondrial transcription termination factors (mTERFs). In the loss-of-function rug2 mutants, most organs were pale and showed reduced growth, and the leaves exhibited both green and pale sectors, with the latter containing sparsely packed mesophyll cells. Chloroplast and mitochondrion development were strongly perturbed in the rug2-1 mutant, particularly in pale leaf sectors, in which chloroplasts were abnormally shaped and reduced in number, thereby impairing photoautotrophic growth. As expected from the pleiotropic phenotypes caused by its loss-of-function alleles, the RUG2 gene was ubiquitously expressed. In a microarray analysis of the mitochondrial and chloroplastic genomes, 56 genes were differentially expressed between rug2-1 and the wild type: most mitochondrial genes were downregulated, whereas the majority of the chloroplastic genes were upregulated. Quantitative RT-PCR analyses showed that the rug2-1 mutation specifically increases expression of the RpoTp nuclear gene, which encodes chloroplastic RNA polymerase. Therefore, the RUG2 nuclear gene seems to be crucial for the maintenance of the correct levels of transcripts in the mitochondria and chloroplasts, which is essential for optimized functions of these organelles and proper plant development. Our results highlight the complexity of the functional interaction between these two organelles and the nucleus. PMID- 21790816 TI - Chitinase III in pomegranate seeds (Punica granatum Linn.): a high-capacity calcium-binding protein in amyloplasts. AB - Chitinases are a class of ubiquitous proteins that are widely distributed in plants. Defense is the major natural role for chitinases, primarily against fungal pathogens. Little is known regarding their non-defensive roles in seeds. In this study, a new class III chitinase from pomegranate seeds (pomegranate seed chitinase, PSC) was isolated and purified to homogeneity. The native state of PSC is a monomer with a molecular weight of approximately 30 kDa. This chitinase naturally binds calcium ions with high capacity and low affinity, suggesting that PSC is a calcium storage protein. Consistent with this idea, its amino acid sequence (inferred from cDNA) is rich in acidic amino acid residues, especially Asp, similar to reported calcium storage proteins. The presence of calcium considerably improves the stability of the protein but has little effect on its enzymatic activity. Transmission electron microscopy analyses indicate that, similar to phytoferritin, this enzyme is widely distributed in the stroma of amyloplasts of the embryonic cells, suggesting that amyloplasts in seeds could serve as an alternative plastid for calcium storage. Indeed, the transmission electron microscopy results showed that, within the embryonic cells, calcium ions are mainly distributed in the stroma of the amyloplasts, consistent with a role for PSC in calcium storage. Thus, the plant appears to have evolved a new plastid for calcium storage in seeds. During seed germination, the content of this enzyme decreases with time, suggesting that it is involved in the germination process. PMID- 21790817 TI - David versus Goliath. Branding, intellectual property rights and the 'nanny state': why Australia has to win its trial of strength against the tobacco giants. PMID- 21790818 TI - Temporal variation in genetic diversity and effective population size of Mediterranean and subalpine Arabidopsis thaliana populations. AB - Currently, there exists a limited knowledge on the extent of temporal variation in population genetic parameters of natural populations. Here, we study the extent of temporal variation in population genetics by genotyping 151 genome-wide SNP markers polymorphic in 466 individuals collected from nine populations of the annual plant Arabidopsis thaliana during 4 years. Populations are located along an altitudinal climatic gradient from Mediterranean to subalpine environments in NE Spain, which has been shown to influence key demographic attributes and life cycle adaptations. Genetically, A. thaliana populations were more variable across space than over time. Common multilocus genotypes were detected several years in the same population, whereas low-frequency multilocus genotypes appeared only 1 year. High-elevation populations were genetically poorer and more variable over time than low-elevation populations, which might be caused by a higher overall demographic instability at higher altitudes. Estimated effective population sizes were low but also showed a significant decreasing trend with increasing altitude, suggesting a deeper impact of genetic drift at high-elevation populations. In comparison with single-year samplings, repeated genotyping over time captured substantially higher amount of genetic variation contained in A. thaliana populations. Furthermore, repeated genotyping of populations provided novel information on the genetic properties of A. thaliana populations and allowed hypothesizing on their underlying mechanisms. Therefore, including temporal genotyping programmes into traditional population genetic studies can significantly increase our understanding of the dynamics of natural populations. PMID- 21790819 TI - Intraspecific support for the polygyny-vs.-polyandry hypothesis in the bulldog ant Myrmecia brevinoda. AB - The number of queens per colony and the number of matings per queen are the most important determinants of the genetic structure of ant colonies, and understanding their interrelationship is essential to the study of social evolution. The polygyny-vs.-polyandry hypothesis argues that polygyny and polyandry should be negatively associated because both can result in increased intracolonial genetic variability and have costs. However, evidence for this long debated hypothesis has been lacking at the intraspecific level. Here, we investigated the colony genetic structure in the Australian bulldog ant Myrmecia brevinoda. The numbers of queens per colony varied from 1 to 6. Nestmate queens within polygynous colonies were on average related (r(qq) = 0.171 +/- 0.019), but the overall relatedness between queens and their mates was indistinguishable from zero (r(qm) = 0.037 +/- 0.030). Queens were inferred to mate with 1-10 males. A lack of genetic isolation by distance among nests indicated the prevalence of independent colony foundation. In accordance with the polygyny-vs.-polyandry hypothesis, the number of queens per colony was significantly negatively associated with the estimated number of matings (Spearman rank correlation R = 0.490, P = 0.028). This study thus provides the rare intraspecific evidence for the polygyny-vs.-polyandry hypothesis. We suggest that the high costs of multiple matings and the strong effect of multiple mating on intracolonial genetic diversity may be essential to the negative association between polygyny and polyandry and that any attempt to empirically test this hypothesis should place emphasis upon these two key underlying aspects. PMID- 21790820 TI - Temporal genetic stability and high effective population size despite fisheries induced life-history trait evolution in the North Sea sole. AB - Heavy fishing and other anthropogenic influences can have profound impact on a species' resilience to harvesting. Besides the decrease in the census and effective population size, strong declines in mature adults and recruiting individuals may lead to almost irreversible genetic changes in life-history traits. Here, we investigated the evolution of genetic diversity and effective population size in the heavily exploited sole (Solea solea), through the analysis of historical DNA from a collection of 1379 sole otoliths dating back from 1957. Despite documented shifts in life-history traits, neutral genetic diversity inferred from 11 microsatellite markers showed a remarkable stability over a period of 50 years of heavy fishing. Using simulations and corrections for fisheries induced demographic variation, both single-sample estimates and temporal estimates of effective population size (N(e) ) were always higher than 1000, suggesting that despite the severe census size decrease over a 50-year period of harvesting, genetic drift is probably not strong enough to significantly decrease the neutral diversity of this species in the North Sea. However, the inferred ratio of effective population size to the census size (N(e) /N(c) ) appears very small (10(-5) ), suggesting that overall only a low proportion of adults contribute to the next generation. The high N(e) level together with the low N(e) /N(c) ratio is probably caused by a combination of an equalized reproductive output of younger cohorts, a decrease in generation time and a large variance in reproductive success typical for marine species. Because strong evolutionary changes in age and size at first maturation have been observed for sole, changes in adaptive genetic variation should be further monitored to detect the evolutionary consequences of human-induced selection. PMID- 21790821 TI - No evidence for host specialization or host-race formation in the European bitterling (Rhodeus amarus), a fish that parasitizes freshwater mussels. AB - Coevolutionary relationships between parasites and hosts can elevate the rate of evolutionary changes owing to reciprocal adaptations between coevolving partners. Such relationships can result in the evolution of host specificity. Recent methodological advances have permitted the recognition of cryptic lineages, with important consequences for our understanding of biological diversity. We used the European bitterling (Rhodeus amarus), a freshwater fish that parasitizes unionid mussels, to investigate host specialization across regions of recent and ancient sympatry between coevolving partners. We combined genetic data (12 microsatellite and 2 mitochondrial markers) from five populations with experimental data for possible mechanisms of host species recognition (imprinting and conditioning). We found no strong evidence for the existence of cryptic lineages in R. amarus, though a small proportion of variation among individuals in an area of recent bitterling-mussel association was statistically significant in explaining host specificity. No other measures supported the existence of host-specific lineages. Behavioural data revealed a weak effect of conditioning that biased behavioural preferences towards specific host species. Host imprinting had no effect on oviposition behaviour. Overall, we established that populations of R. amarus show limited potential for specialization, manifested as weak effects of host conditioning and genetic within-population structure. Rhodeus amarus is the only species of mussel-parasitizing fish in Europe, which contrasts with the species rich communities of bitterling in eastern Asia where several host-specific bitterling occur. We discuss costs and constraints on the evolution of host specific lineages in our study system and more generally. PMID- 21790822 TI - Risk-taking and other effects of sleep loss on brain function and behaviour. AB - The sleep-deprivation paradigm remains a powerful approach in the study of the functions of sleep. When combined with the assessment of novel dependent measures or integration of multiple standard variables new insights may be obtained. This issue of the Journal of Sleep Research contains several studies that shed some new light on the effects of sleep deprivation and sleepiness. In addition, several papers emphasize the need to better characterize and understand the consequences of insomnia. PMID- 21790823 TI - The housing and support needs of people with an intellectual disability into older age. AB - BACKGROUND: People with intellectual disabilities (IDs) are growing older as a population cohort. Many live at home with family members who are their carers but who are also becoming older and less able to provide care. The housing and support preferences of people with IDs and their carers into older age are poorly characterised in the literature. METHODS: Focus groups and individual interviews were conducted with 15 people with IDs who work in supported employment and with 10 family members who care for adults with IDs. Data were thematically analysed independently by two researchers. RESULTS: The major themes that emerged were as follows: (1) living arrangements; (2) housing preferences; (3) ageing in place; and (4) transition from informal to formal housing and support services. CONCLUSIONS: Participants with an ID and their carers want housing and support that enable people with an ID to maintain and enhance their social networks with their peers as they grow older and require transition to formal housing and support services, and to be able to 'age in place'. A preference was expressed for models of housing that provide the opportunity for people with an ID to live in close proximity to their peers and in large groups in the community rather than in small, dispersed community housing. PMID- 21790824 TI - Development and behaviour in Marshall-Smith syndrome: an exploratory study of cognition, phenotype and autism. AB - BACKGROUND: Marshall-Smith syndrome (MSS) is an infrequently described entity characterised by failure to thrive, developmental delay, abnormal bone maturation and a characteristic face. In studying the physical features of a group of patients, we noticed unusual behavioural traits. This urged us to study cognition, behavioural phenotype and autism in six patients. METHODS: Information on development, behavioural characteristics, autism symptoms, and adaptive and psychological functioning of six MSS children was collected through in-person examinations, questionnaires, semi-structured interviews of parents and neuropsychological assessments. RESULTS: Participants showed moderate to severe delays in mental age, motor development and adaptive functioning, with several similarities in communication, social interactions and behaviour. There was severe delay of speech and motor milestones, a friendly or happy demeanour and enjoyment of social interactions with familiar others. They exhibited minimal maladaptive behaviours. Deficits in communication and social interactions, lack of reciprocal social communication skills, limited imaginary play and the occurrence of stereotyped, repetitive behaviours were noted during assessments. CONCLUSIONS: Systematic collection of developmental and behavioural data in very rare entities such as MSS allows recognition of specific patterns in these qualities. Clinical recognition of physical,developmental and behavioural features is important not only for diagnosis, prognosis and counselling of families, but also increases our understanding of the biological basis of the human physical and behavioural phenotype. PMID- 21790825 TI - Comparison of conditioning impairments in children with Down syndrome, autistic spectrum disorders and mental age-matched controls. AB - BACKGROUND: This study investigated the relative ease of learning across four tasks suggested by an adaptation of Thomas's hierarchy of learning in children with Down syndrome, autism spectrum disorders and mental age-matched controls. METHODS: Learning trials were carried out to investigate observational learning, instrumental learning, reversal learning and conditional discrimination. RESULTS: The sample with autism spectrum disorders performed worse than the other two groups on the observational learning and conditional discrimination tasks, while the Down syndrome sample performed worse on the instrumental learning task. CONCLUSIONS: These findings are discussed in terms of there implications for reward-based educational intervention programmes. PMID- 21790826 TI - Good intentions, increased inequities: developing social care services in Emergency Departments in the UK. AB - Addressing the quality of services provided in Emergency Departments (EDs) has been a central area of development for UK government policy since 1997. Amongst other aspects of this concern has been the recognition that EDs constitute a critical boundary between the community and the hospital and a key point for the identification of social care needs. Consequently, EDs have become the focus for a variety of service developments which combine the provision of acute medical and nursing assessment and care with a range of activities in which social care is a prominent feature. One approach to this has been the establishment of multidisciplinary teams aiming to prevent re-attendance or admission, re-direct patients to other services, or speed patients through EDs with the aim of providing improved quality of care. This study, carried out between September 2007 and April 2008, was the first UK national survey of social care initiatives based in EDs and aimed to determine the objectives, organisation, extent, functions, funding and evidence on outcomes of such interventions. Eighty-three per cent of UK Type I and II EDs responded to the survey. Approximately, one third of EDs had embedded social care teams, with two-thirds relying on referrals to external social care services. These teams varied in their focus, size and composition, leadership, availability, funding and permanence. As a result, the unintended effect has been to increase inequities in access to social care services through EDs. Three further conclusions are drawn about policy led, locally-based service development. This survey adds to international evidence pointing to the potential benefits of a variety of social care interventions being based in EDs and justifies the establishment of a research programme which can provide answers to key outstanding questions. PMID- 21790827 TI - Exploring the potential of refugees and asylum seekers for social care work in England: a qualitative study. AB - Literature highlights the potential for refugees to contribute to the labour force of receiving countries. Such a contribution may be welcomed in sectors, such as social care, where demand for labour is increasing and high vacancy rates exist. This article reports on empirical data examining the potential of refugee communities to work in social care in England. The analysis is based primarily on 20 interviews with refugees and asylum seekers and five representatives of refugee support groups, conducted in 2008-2009. The findings of this sub-study are set within results obtained from other interviews as part of a multi-methods study examining the contribution of migrants to the English care sector. In-depth interviews were analysed thematically, guided by a theoretical framework linking employment, migration and the nature of care work. The findings highlight a general willingness of refugee participants to join the care workforce. Individual and structural barriers to increased employability were identified, as well as possible strategies to overcome them. Although the findings and discussions presented are based on data collected in England and are specific to the care sector, most are more generalisable and may inform strategies aiming at maximising refugees' employability in other sectors and in other developed states. PMID- 21790828 TI - Human glioblastoma stem-like cells are more sensitive to allogeneic NK and T cell mediated killing compared with serum-cultured glioblastoma cells. AB - Glioblastoma multiforme (GBM) is the most dramatic primary brain cancer with a very poor prognosis because of inevitable disease recurrence. The median overall survival is less than 1 year after diagnosis. Cancer stem cells have recently been disclosed in GBM. GBM stem-like cells (GSCs) exhibit resistance to radio/chemotherapeutic treatments and are therefore considered to play an important role in disease recurrence. GSCs are thus appealing targets for new treatments for GBM patients. In this study, we show that GBM cells with stem cell characteristics are resistant to lysis mediated by resting natural killer (NK) cells because of the expression of MHC class I molecules. However, GSCs are killed by lectin-activated NK cells. Furthermore, in experiments using the therapeutic antibody CetuximAb, we show that GSCs are sensitive to antibody mediated cytotoxicity. We confirm the sensitivity of GSC to cytotoxicity carried out by IL2-activated NK cells and tumor-specific T cells. More importantly, we show that GSCs are more sensitive to NK and T cell-mediated lysis relatively to their corresponding serum-cultured GBM cells obtained from the same initial tumor specimen. Altogether, these results demonstrate the sensitivity of GSC to immune cell cytotoxicity and, therefore, strongly suggest that GSCs are suitable target cells for immunotherapy of GBM patients. PMID- 21790829 TI - The PKR activator PACT is induced by Abeta: involvement in Alzheimer's disease. AB - The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques made of Abeta peptide, neurofibrillary tangles containing hyperphosphorylated tau protein and neuronal loss. The pro-apoptotic kinase PKR can be activated by Abeta and can phosphorylate tau protein via GSK3beta kinase activation. The activated form of PKR (pPKR) accumulates in affected neurons and could participate in neuronal degeneration in AD. The mechanism of abnormal PKR activation in AD is not elucidated but could be linked to the PKR activator PACT. PACT stainings, and levels were assessed in the brains of AD patients and in APP/PS1 knock-in transgenic mice and in cell cultures exposed to stresses. We showed that PACT and pPKR colocalizations are enhanced in AD brains. Their levels are increased and correlated in AD and APP/PS1 knock-in mice brains. In human neuroblastoma cells exposed to Abeta, tunicamycin or H2O2, PACT and pPKR concentrations are increased. PACT then PKR inhibitions indicate that PACT is upstream of PKR activation. Our findings demonstrate that PACT levels are enhanced in AD brains and could partly be caused by the action of Abeta. In addition, PACT participates in PKR activation. The PACT-PKR pathway represents a potential link between Abeta accumulation, PKR activation and tau phosphorylation. PMID- 21790830 TI - Diagnosis in developmental-behavioural paediatrics: the art of diagnostic formulation. AB - This paper considers diagnostic frameworks in developmental-behavioural paediatrics. The purpose of a diagnostic assessment is reviewed, and the use of categorical diagnoses is explored. A multi-level process of diagnostic formulation is outlined, highlighting the importance of a comprehensive focus on presenting symptoms, neuropsychological constructs, biological factors and environmental influences. The axis of time, developmental benchmarks and the enhancement of resilience are discussed as part of the diagnostic formulation framework. Limitations imposed on diagnostic practice by systemic and personal factors are reviewed. Implications for training and practice are discussed. PMID- 21790831 TI - Providing adequate directions for medication use in pregnant women and nursing mothers: an overview of pregnancy labeling. PMID- 21790832 TI - Early onset scoliosis: what the primary care provider needs to know and implications for practice. AB - PURPOSE: The purpose of this article is to discuss the role of the primary care provider in the detection of and referral for early onset scoliosis. An overview of scoliosis including etiology, natural history, guidelines for physical examination, current practice for scoliosis screening, and available treatments will be discussed. DATA SOURCES: PubMed, OVID Medline, Psychinfo. Search terms: juvenile scoliosis, childhood onset scoliosis, early onset scoliosis, idiopathic scoliosis, and infantile scoliosis. CONCLUSIONS: Scoliosis is classified depending on the magnitude, location, direction, and cause of the curve, and can lead to a variety of health effects if not treated. The greater the scoliosis curve and the earlier it presents, the more likely it may affect thoracic growth, inhibit cardiopulmonary function, and cause psychosocial distress. IMPLICATIONS FOR PRACTICE: Routine scoliosis screening should be incorporated into each healthcare maintenance visit beginning in infancy and continue into adolescence until the child reaches skeletal maturity. Curves with a scoliometer reading greater than 5 degrees should be referred, and conservative treatment should be considered for curves that surpass 20 degrees . If scoliosis is detected early, it may be possible to stabilize the curve from progressing and even prevent thoracic deformity and secondary complications from occurring. PMID- 21790833 TI - Developing a selection method for graduate nursing students. AB - PURPOSE: The student selection process is an important faculty responsibility that impacts student success in individual courses, retention, and ultimately graduation rates. The purpose of this article is to review the existing research on graduate student selection and describe one university's newly developed selection process. DATA SOURCES: Existing literature and research and one university's selection data. CONCLUSIONS: There is limited existing research on graduate student selection to assist faculty in selecting students. One university's process is described in detail for possible replication by others to improve the process. IMPLICATIONS FOR PRACTICE: The process highlighted in this article may be useful to other faculty as a model for improvement of student selection processes. PMID- 21790834 TI - Role of the nurse practitioner in the management of patients with chronic hepatitis C. AB - PURPOSE: To inform nurse practitioners (NPs) of the vital role they play in recognizing patients who may have hepatitis C. DATA SOURCES: Selected review of scientific literature. CONCLUSIONS: NPs involved in the management of patients with chronic hepatitis C are well positioned to provide supportive care and contribute to the development of effective treatment strategies that maximize the opportunity for successful treatment outcomes. Although peginterferon alfa plus ribavirin therapy is associated with a well-described series of side effects, effective measures are available for the management of these events that permit the continuation of treatment and enhance the likelihood of attaining sustained virologic response. NPs can play a pivotal role in ensuring that these measures are in place in a preemptive manner. For example, growth factor supplementation represents an alternative to dose reduction or treatment discontinuation in selected patients with neutropenia or anemia and may help to improve treatment adherence. IMPLICATIONS FOR PRACTICE: Hepatitis C is a widespread problem; approximately 3% of the global population is chronically infected with the virus. Awareness of risk factors for hepatitis C will help the NP to recognize at-risk patients, who should then be screened for the virus and referred for treatment based on specific criteria. PMID- 21790835 TI - A literature review on breathing retraining as a self-management strategy operationalized through Rosswurm and Larrabee's evidence-based practice model. AB - PURPOSE: The purpose of this article is to critically appraise and synthesize the literature on breathing retraining as a self-management strategy for individuals with chronic obstructive pulmonary disease (COPD) guided by Rosswurm and Larrabee's evidence-based practice model. DATA SOURCES: Scientific literature review, grey literature review, and hand searching. CONCLUSIONS: An exhaustive review of the literature revealed evidence that regularly practiced pursed lip breathing is an effective self-management strategy for individuals with COPD to improve their dyspnea. IMPLICATIONS FOR PRACTICE: It is expected that implementation of this non-pharmacological self-management intervention will improve perception of dyspnea, functional performance, and self-efficacy in individuals with COPD. PMID- 21790836 TI - Acute coronary syndromes in deployed military personnel. AB - PURPOSE: The purpose of this study was to describe the cardiovascular (CV) risk profile of deployed military men who experience acute coronary syndrome (ACS). DATA SOURCES: A retrospective record review of deployed military men who experienced ACS while deployed and were treated at an overseas military medical center between 2001 and 2007 was conducted to obtain the information for this descriptive study (N= 100). CONCLUSIONS: Acute myocardial infarction was diagnosed in 82% of the sample, and 18% experienced unstable angina. Subjects' mean age was 44.7 years (SD+/- 7.6; range 29-60) and most were enlisted and reservists. Risk factors included a family history of premature coronary artery disease (41%) and smoking (47%) as well as a history of hyperlipidemia (48%), hypertension (28%), and glucose abnormalities (6%). The group was overweight (BMI 27.77 kg/m(2) +/- 3.2) and low risk for CV events (Framingham risk score 7.8%[+/- 4.4]). IMPLICATIONS FOR PRACTICE: Young military men are regarded as the epitome of health and fitness; however, findings from this study suggest that this generally low-risk group do indeed have multiple CV risk factors and experience ACS. Early risk factor assessment and modification, including smoking cessation, weight management, and improving dyslipidemia, is essential. PMID- 21790837 TI - The treatment of osteopenia in Asian women: a new approach. AB - PURPOSE: Compare dual energy x-ray absorptiometry (DEXA) scan results to the World Health Organization FRAXTM tool 10-year projected hip fracture risk of immigrant Vietnamese women at antiresorptive medication therapy initiation and to identify whether the current and/or future treatment of patients with osteopenia would change based on the FRAX tool results. DATA SOURCE: Retrospective study involving a convenience sample of 57 postmenopausal,Vietnamese women concerning the variables age, height, weight, smoking, alcohol use, glucocorticoid use, personal and family fracture history, presence of secondary osteoporosis, and recent DEXA-scan T score. The data were then entered into FRAX and 10-year fracture risk for hip calculated. CONCLUSIONS: Of the 18 subjects deemed osteopenic by DEXA scan and previously started on an antiresorptive agent, nine would not have been initiated had the FRAX tool been available at the time. IMPLICATIONS FOR PRACTICE: The FRAX tool was easy to use and applicable in day-to day care of patients and significantly increases the clinician's ability to make evidence-based decisions. PMID- 21790838 TI - Assessment of smokeless tobacco use in the history and physical examination by primary healthcare providers. AB - PURPOSE: Following a simple descriptive research design, we examined how and to what extent primary healthcare providers in rural southern regions of the United States ask patients about the use of smokeless tobacco as indicated in the document used for the patient history. DATA SOURCES: Copies of blank history and physical forms used in offices of primary care providers in Alabama, Georgia, South Carolina, and Tennessee were examined to identify items related specifically to tobacco use. CONCLUSIONS: Twenty-nine providers returned history and physical forms, which revealed 24% showed no item related to tobacco use. Others included questions related to smoking, but only 7% mentioned any sort of smokeless tobacco use. IMPLICATIONS FOR PRACTICE: Although a few studies have suggested the use of smokeless tobacco to be less harmful than smoking, all forms of smokeless tobacco are recognized carcinogens and dangerous for health. It is not sufficient to simply ask patients about smoking behaviors. Primary care providers, especially nurse practitioners, have the unique opportunity to assess use of smokeless tobacco and to offer treatment and counsel to help patients to stop the behavior. PMID- 21790839 TI - International emergency medicine: a review of the literature from 2010. AB - The International Emergency Medicine (IEM) Literature Review aims to highlight and disseminate high-quality global EM research in the fields of EM development, disaster and humanitarian response, and emergency care in resource-limited settings. For this review, we conducted a Medline search for articles published between January 1 and December 31, 2010, using a set of international and EM search terms and a manual search of journals that have produced large numbers of IEM articles for past reviews. This search produced 6,936 articles, which were divided among 20 reviewers who screened them using established inclusion and exclusion criteria to select articles relevant to the field of IEM. Two-hundred articles were selected by at least one reviewer and approved by an editor for scoring. Two independent reviewers using a standardized and predetermined set of criteria then scored each of the 200 articles. The 27 top-scoring articles were chosen for full review. The articles this year trended toward evidence-based research for treatment and care options in resource-limited settings, with an emphasis on childhood illness and obstetric care. These articles represent examples of high-quality international emergency research that is currently ongoing in high-, middle-, and low-income countries alike. This article is not intended to serve as a systematic review or clinical guideline but is instead meant to be a selection of current high-quality IEM literature, with the hope that it will foster further growth in the field, highlight evidence-based practice, and encourage discourse. PMID- 21790840 TI - Intravital microscopy of the murine urinary bladder microcirculation. AB - OBJECTIVE: To establish an in vivo mouse model of the urinary bladder microcirculation, and characterize the molecular mechanisms of endotoxin-induced leukocyte recruitment. METHODS: The murine model was adapted from a technique previously reported for the rat. Mouse bladder microcirculation was observed using intravital microscopy, four hours after intravesical challenge with lipopolysaccharide (LPS) and leukocyte-endothelial interactions were examined. Molecular mechanisms of leukocyte recruitment were identified using antibodies to adhesion molecules and chemokines. RESULTS: LPS from Escherichia coli administered intravesically resulted in a significant increase in leukocyte adhesion and rolling at four hours post stimulation. LPS from Pseudomonas aeruginosa administered at similar doses resulted in a significant, but lower increase in leukocyte adhesion after four hours compared with E. coli LPS. Leukocyte adhesion within the bladder microcirculation was dependent on alpha(4) integrins and ICAM-1, whereas leukocyte rolling was P-selectin dependent, but alpha(4) -integrin independent. Blockade of MIP-2 and KC did not alter leukocyte endothelial interactions. The bladder endothelium expressed P-selectin, ICAM-1, VCAM-1, MIP-2, and MCP-1. Only VCAM-1 endothelial expression was significantly increased after LPS stimulation. CONCLUSION: The mouse model of the urinary bladder microcirculation is suitable for the study of inflammatory responses during urinary tract infection (UTI) in vivo. PMID- 21790841 TI - Adenoid cystic breast carcinoma: is axillary staging necessary in all cases? Results from the California Cancer Registry. AB - Adenoid cystic carcinoma (ACC) is an uncommon type of breast cancer. There are limited data about its epidemiology, tumor characteristics, and outcomes. Using a large, population-based data base, this study aimed to identify specific characteristics of patients with adenoid cystic breast cancer, investigate its natural history, and determine its long-term prognosis. The California Cancer Registry, a population-based registry, was reviewed from the years 1988 to 2006. The data were analyzed with relation to patient age, tumor size and stage, and overall survival. Relative cumulative actuarial survival was determined using the Berkson-Gage life table method. A total of 244 cases of invasive adenoid cystic cancer were identified in women during this time period. The patients' median age was 61.9 years. Most cases were diagnosed in non-Hispanic White women (82%, n = 200), followed by African American (6%, n = 15), Asian/Pacific-Islander (5.7%, n = 14) and Hispanic women (4.4%, n = 12). The remainder of the patients was of unknown or other ethnicity. Tumors were between 1 and 140 mm in size. At the time of diagnosis, 92% (n = 225) of patients had localized disease, 5% (n = 12) of patients had regional disease, and even fewer (n = 7) had either distant or unknown staged disease. Lymph node involvement was not present in any tumors smaller than 1.4 cm. The relative cumulative survival of patients with adenoid cystic breast carcinoma was 95.6% at 5 years and 94.9% at 10 years. ACC of the breast is a rare disease with an overall good prognosis. Knowing that this cancer usually presents as localized disease, with lymph node involvement seen only with larger tumors, can help clinicians plan the operative management of these tumors. PMID- 21790843 TI - Reducing disparities in breast cancer survival--the effect of large-scale screening of the uninsured. PMID- 21790842 TI - ACR Appropriateness Criteria(r) conservative surgery and radiation--stage I and II breast carcinoma: expert panel on radiation oncology: breast. AB - Breast conservation is a safe and effective alternative to mastectomy for the majority of women with early-stage breast cancer. Adjuvant radiation therapy lowers the risk of recurrence within the breast and also confers a survival benefit. Although acute side effects of radiation therapy are generally well tolerated; efforts are ongoing to minimize the long-term side effects of radiation, most prominently atherosclerotic heart disease. Efforts to minimize radiation therapy are also underway. They include omitting treatment altogether in the elderly and using accelerated, hypofractionated whole-breast irradiation, and accelerated partial-breast irradiation. Several randomized studies are ongoing to determine the efficacy, safety, and appropriate patients for these shorter treatments. PMID- 21790844 TI - Improving survival of the paramedian forehead flap in patients with excessive tobacco use: the vascular delay. PMID- 21790845 TI - A retrospective study of q-switched alexandrite laser in treating nevus of ota. AB - BACKGROUND: The Q-switched alexandrite laser (QSAL) has been clinically proven to be effective in treating nevus of Ota, but a large-scale retrospective study with long-term follow-up has never been performed. OBJECTIVE: To evaluate the efficacy of the QSAL in treating nevus of Ota, the laser's long-term side effects, complications associated with the treatments, and the recurrence rate. MATERIALS AND METHODS: Eight hundred six patients (651 female, 155 male) with a diagnosis of nevus of Ota who had received a series of QSAL (wavelength 755 nm) treatments were recruited. The typical settings were fluences of 3.8 to 4.8 J/cm(2) and a spot size of 3 mm. Follow-ups were conducted via questionnaire with 590 patients who had completed the treatment at least 3 years earlier. RESULTS: Overall, 93.9% of patients achieved complete clearance after an average of 5.2 sessions. All recurrences (0.8%) appeared beyond the previously treated sites. No long-term adverse effects, including hypopigmentation, hyperpigmentation, textural changes, and malignant transformation, were observed. CONCLUSION: The QSAL is a safe and effective modality for treating nevus of Ota. Recurrence was rare and appeared beyond the previously treated sites. The authors have indicated no significant interest with commercial supporters. PMID- 21790846 TI - Scleroderma and raynaud's phenomenon improve with high-peak power laser therapy: a case report. PMID- 21790847 TI - Reflectance confocal microscopy for recurrent lentigo maligna. PMID- 21790848 TI - Polidocanol concentration and time affect the properties of foam used for sclerotherapy. AB - BACKGROUND: How foam is created for sclerotherapy varies and is not standardized. Moreover, the effect of several factors on the quality of the foam is not well studied. OBJECTIVE: To investigate the effects of different parameters on foam stability and bubble size. METHODS: As a measure of foam stability, foam half time (FHT) and bubble size distribution were determined for various parameters (polidocanol (POL) concentration, freshness of the POL, syringe size, liquid-to air ratio, number of pump cycles, and needle size) in the foam creation process. RESULTS: FHT was 115 to 157 seconds for POL 1% and 143 to 192 seconds for POL 3%. The other parameters had a limited effect on FHT. POL foam 1% (t=0 seconds) had a mean bubble size of 71 +/- 9 MUm that increased when the foam was maintained horizontally in the syringe: 102 +/- 12 MUm) at 30 seconds and 121 +/- 20 MUm at 60 seconds. The other parameters had no significant influence on bubble size distribution. CONCLUSIONS: Higher concentration of POL and rapid injection optimize foam stability and bubble size distribution, but other important foam characteristics are largely independent of differences in the generation and injection of foam. The authors have indicated no significant interest with commercial supporters. PMID- 21790849 TI - A decade of melanomas: identification of factors associated with delayed detection in an academic group practice. AB - BACKGROUND: Melanoma incidence is increasing, but the effect of various clinical factors on tumor stage is unclear. OBJECTIVE: To review histologic and clinical features of melanomas diagnosed in our group over a 10-year period to determine trends in diagnosis and lesion derivation, predictive value of clinical lesion size, and effect of physician and patient concerns before biopsy. METHOD: Relevant pathology reports and physician clinic notes were reviewed for 572 melanomas. RESULT: From 1999 to 2008, melanoma biopsies increased significantly more than nevus biopsies and patient visits. Melanomas predominantly (81%) arose de novo, with remaining lesions as likely to arise from common as dysplastic nevi. Melanomas were detected at twice the rate, and at earlier stage, in established as in new patients. Clinical size of invasive melanomas was related to lesion depth. For 64% of melanomas, patient and physician concern drove the decision to biopsy, whereas 1.4% of melanomas were biopsied only for patient concern. CONCLUSION: The increase in melanoma diagnoses was largely due to increases in cases of lentigo maligna on the head and neck. Delayed detection was associated with location on trunk and extremities, new patient status, patient concern before biopsy, and physician suspicion of nonmelanoma skin cancer. PMID- 21790850 TI - Diagnostic challenges of cutaneous draining sinus tracts of odontogenic origin: a case report. PMID- 21790851 TI - Does endovenous laser ablation induce endothelial damage at the saphenofemoral junction? AB - BACKGROUND AND OBJECTIVE: One of the possible complications of endovenous laser ablation (EVLA) is thrombus progression into the common femoral vein or popliteal vein with the potential risk of pulmonary embolism or stroke. We set out to investigate the effect of laser energy applied under standardized treatment conditions on biomarkers of platelet and endothelial activation and on the hemostatic system. METHODS: Twenty patients with incompetence of the great saphenous vein were included in this prospective study. Blood samples of the iliofemoral and anticubital veins were collected before, during, and after EVLA. Plasma levels of soluble (s) P-selectin, soluble thrombomodulin (sTM), prothrombin fragment F1+2 (F1+2), and d-dimer were measured. (s) P-selectin and sTM were analyzed as surrogate markers of endothelial and platelet activation. F1+2 and d-dimer were monitored to quantify the degree of surgical trauma. RESULTS: Whereas there was no immediate rise of (s) P-selectin and sTM plasma concentrations in iliofemoral or anticubital blood, plasma levels of F1+2 and d dimer increased significantly after EVLA. CONCLUSION: Pulsed mode laser ablation with an 810-nm fiber does not induce measurable platelet and endothelium activation in the iliofemoral or systemic blood. Furthermore, the immediate surgical trauma associated with EVLA appears to be modest. The authors have indicated no significant interest with commercial supporters. PMID- 21790852 TI - Botulinum toxin for the treatment of menopausal hot flushes: a pilot study. PMID- 21790853 TI - Malignant peripheral nerve sheath tumor of the scalp: case report and review of the literature. PMID- 21790854 TI - Modification of the running suture to avoid wound edge protrusion. PMID- 21790855 TI - Desmoplastic melanoma presenting after laser treatment: a case report and tale of caution. PMID- 21790856 TI - Ultrasound-guided fascia iliaca compartment block in pediatric patients using a long-axis, in-plane needle technique: a report of three cases. AB - Ultrasound guided fascia iliaca compartment block (FICB) has not been previously described in pediatric patients. Reported here is an ultrasound guided long axis, in-plane needle technique used to perform FICB in three pediatric patients undergoing hip or femur surgery. Postoperative assessment revealed nerve blockade of the lateral femoral cutaneous, femoral, and obturator nerves or no requirement for narcotics in the PACU. FICB using this ultrasound guided technique was easy to perform and provided postoperative analgesia for hip and femur surgical procedures within the presumed distribution of the lateral femoral cutaneous, femoral, and obturator nerves. PMID- 21790857 TI - Pandemic influenza A(H1N1) virus infection in solid organ transplant recipients: impact of viral and non-viral co-infection. AB - Solid organ transplant recipients (SOTR) are at risk of serious influenza-related complications. The impact of respiratory co-infection in SOTR with 2009 pandemic influenza A(H1N1) is unknown. A multicentre prospective study of consecutive cases of pandemic influenza A(H1N1) in SOTR was carried out to assess the clinical characteristics and outcome and the risk factors for co-infection. Overall, 51 patients were included. Median time from transplant was 3.7 years, 5.9% of the cases occurred perioperatively and 7.8% were hospital-acquired. Pneumonia was diagnosed in 15 (29.4%) patients. Ten cases were severe (19.6%): 13.7% were admitted to intensive care units, 5.9% suffered septic shock, 5.9% developed acute graft rejection and 7.8% died. Co-infection was detected in 15 patients (29.4%): eight viral, six bacterial and one fungal. Viral co-infection did not affect the outcome. Patients with non-viral co-infection had a worse outcome: longer hospital stay (26.2 +/- 20.7 vs. 5.5 +/- 10.2) and higher rate of severe diseases (85.7% vs. 2.3%) and mortality (42.8% vs. 2.3%). Independent risk factors for non-viral co-infection were: diabetes mellitus and septic shock. Other factors associated with severe influenza were: delayed antiviral therapy, diabetes mellitus, time since transplantation <90 days and pneumonia. In conclusion, pandemic influenza A can cause significant direct and indirect effects in SOTR, especially in the early post-transplant period, and should be treated early. Clinicians should be aware of the possibility of non-viral co infection, mainly in diabetic patients and severe cases. An effort should be made to prevent influenza with immunization of the patient and the environment. PMID- 21790858 TI - Histology-directed matrix-assisted laser desorption/ionization analysis reveals tissue origin and p53 status of primary liver cancers. AB - To date, protein profiles for hepatocellular carcinomas and cholangiocarcinomas have not been systematically evaluated and compared with each other in an unbiased way. Thirty-six hepatocellular carcinomas and adjacent normal tissue samples were analyzed using histology-directed, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Four cholangiocarcinomas and adjacent normal tissue samples were also evaluated. Tissue samples were sectioned at 10 um, with 1-3 sections thaw-mounted on a conductive indium tin oxide-coated glass slide. Sinapinic acid was manually deposited on areas of each tissue section enriched by epithelial cells, either tumor or normal, and mass spectra were acquired using a MALDI-time of flight instrument. According to class prediction analysis, average prediction accuracy in test sets (composed of 18 hepatocellular carcinoma-normal pairs) ranged from 93.0 to 95.8%. Cholangiocarcinomas and hepatocellular carcinomas had different protein profiles, as evidenced by average prediction accuracy of >95% in the test set for all classifiers. Permutation P-values for 0.632 + bootstrap cross validated misclassification rates (at feature selection P < 0.001) were less than 0.05 for predicting p53 immunostaining status. We conclude that MALDI MS profiles may be useful in assisting with the diagnosis and the differential diagnosis of primary liver cancers. PMID- 21790859 TI - Association between the expression pattern of p16, pRb and p53 and the response to intravesical bacillus Calmette-Guerin therapy in patients with urothelial carcinoma in situ of the urinary bladder. AB - There is limited data regarding the association between the expression of cell cycle-regulating molecules and the response of patients with urothelial carcinoma in situ (CIS) to bacillus Calmette-Guerin (BCG) therapy. To examine the relationship between p16, pRb and p53 expression in bladder CIS and patient response to initial BCG therapy, we performed immunohistochemical studies for 27 patients with bladder CIS. Overexpression of p16, pRb, and p53 was observed in 37%, 41%, and 48% of patients, respectively. Initial BCG therapy was effective in 21 patients (78%). Coexistence of papillary urothelial carcinoma, depth (pTa or pT1) and grade of coexisting papillary carcinoma did not affect the response to BCG therapy. pRb overexpression had a significant relationship to poor response to BCG therapy (P= 0.027). The results of this study indicate that overexpression of pRb in bladder CIS predicts poor response of intravesical BCG instillation and status of p16 and p53 may not be predictive of initial BCG failure. PMID- 21790860 TI - Establishment and characterization of a novel dedifferentiated liposarcoma cell line, NDDLS-1. AB - We established a dedifferentiated liposarcoma cell line (NDDLS-1) that produces interleukin-6 (IL-6) and granulocyte-colony stimulating factor (G-CSF). The parental tumor showed high leukemoid reactions. The NDDLS-1 cell line was established from a pleural effusion associated with a lung metastasis. Pleomorphic tumor cells arranged in a haphazard growth pattern were seen in xenograft tumors. Numerous inflammatory cells including neutrophils or eosinophils were present throughout the tumor cells. This finding resembled the dedifferentiated area of the parental tumor. The mice bearing NDDLS-1 showed marked leukocytosis. In addition, the NDDLS-1 cells expressed IL-6 and G-CSF at both the mRNA and protein levels, while the NDDLS-1 cells produced near normal levels of tumor necrosis factor alpha (TNF-alpha). In the cytogenetic analysis, both the parental tumor and the NDDLS-1 cells showed a ring or giant marker chromosomes. The NDDLS-1 cell line demonstrated the amplification and expression of both MDM2 and CDK4 by fluorescence in situ hybridization and immunohistochemical analysis. The NDDLS-1 cell line is consistent with the parental dedifferentiated liposarcoma, and it should therefore be useful for further investigations of human dedifferentiated liposarcomas. PMID- 21790861 TI - Biochemical, cytological and histopathological examination of sudden unexpected death in infancy. AB - To evaluate the pathophysiological mechanisms underlying sudden infant death syndrome (SIDS), four sudden unexpected death in infancy (SUDI) and four sudden deaths in children over 1 year of age were examined. In the SUDI cases, increased numbers of scavenger receptor A positive (SRA(+) ) cells (4/4), numerous platelet aggregates (3/4), and tumor necrosis factor (TNF)-alpha(+) cells (4/4) were observed in the peripheral blood (PB) smear preparations. Macrophage colony stimulating factor, interleukin (IL)-6, IL-8, TNF-alpha and IL-1beta all exceeded the normal levels. Minute foci of inflammatory lung injury (4/4), numerous platelet emboli in lungs and among cardiac myocytes (3/4) and appreciable contraction band necrosis (1/4) were observed. And neutrophils accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these findings, cytokine abnormality induced by SRA(+) cells in PB was considered to play an important role in the development of tissue injury, and platelet emboli or contraction band necrosis might have been the leading cause of death in our SUDI cases. Patients with characteristics thought to be similar to our SUDI cases were included in the SIDS group; cytokine abnormality was considered to be one of the underlying mechanisms in SIDS. PMID- 21790862 TI - Papillary adenoma of the lung with a peculiar raw macroscopic feature. AB - We report a case of papillary adenoma of the lung with a peculiar raw macroscopic feature at intraoperative consultation. A 52-year-old man was admitted to our hospital for the evaluation of a solitary peripheral nodule in the left lower lobe which was detected with chest CT. When we took staples off from the stump of the partially resected lung in order to make a frozen section diagnosis, granular fragments leaked out from the stump. On the cut surface, the dark reddish and granular tumor grew expansively; however, hemorrhage and necrosis were absent. Histologically, granular fragments were mainly composed of papillary structures, which consisted of a single layer of cuboidal to low columnar cells with round to oval nuclei lining the surface of the fibrovascular cores. Characteristically, papillary structures lacked elastic fibers in the stroma and were packed within an elastic fiber framework derived from pre-existing alveolar structures. We considered that high intratumoral pressure might have made the granular fragments leak out of the stump as soon as we removed staples and that peculiar macroscopic findings before fixation may be a diagnostic clue for papillary adenoma. PMID- 21790863 TI - Autoimmune pancreatitis and biliary intraepithelial neoplasia of the common bile duct: a case with diagnostically challenging but pathogenetically significant association. AB - Autoimmune pancreatitis (AIP) (also called IgG4-related sclerosing pancreatitis (IgG4-SP)) and IgG4-related sclerosing cholangitis (IgG4-SC) are frequently associated with each other. It is generally believed that association of these diseases with pancreatobiliary malignancy is, however, rare. Here, we report on the case of a patient with AIP whose biliary cytology revealed severely atypical cells. Surgically resected specimens from this patient showed typical AIP with IgG4-SC, as well as a mildly elevated lesion in the common bile duct with varying degrees of cellular atypia. In addition, the atypical cells tested positive for the mucin-core protein, MUC5AC and p53 overexpression. These findings led us to diagnose the common bile duct lesion as biliary intraepithelial neoplasia (BilIN, mainly BilIN-1/2). Recently, associations between K-ras mutations and pancreatobiliary carcinoma have been reported in patients with AIP. This case, therefore, provides important new insight into the potential association of AIP and/or IgG4-SC with malignancy (or precursor lesions) of the pancreatobiliary system. PMID- 21790864 TI - Case of polycythemia vera with unusual organizing pneumonia mimicking the clinical features of military tuberculosis and possibly caused by the involvement of neoplastic megakaryocytes. AB - Polycythemia vera (PV) is a clonal myeloproliferative neoplasm (MPN) of hematopoietic stem cells. Although the management of MPN patients generally focuses on the prevention of thromboembolic events caused by hypercoagulability, it is true that the patients with hematological malignancy often suffer from pulmonary diseases with atypical radiological patterns. We present here a 56-year old woman with PV harboring a JAK2(V617F) mutation that had a diffuse reticulonodular pattern on chest radiography and was initially suspected of having military tuberculosis. Pathological assessment of a video-assisted thoracoscopic surgery lung biopsy revealed that the lesions were in fact organizing pneumonia (OP). Interestingly, pulmonary extramedullary hematopoiesis with a diffuse plugging of the alveolar blood capillaries by numerous atypical megakaryocytes was also observed around the granulation components. The histological findings of our case of unusual OP suggest that local activated neoplastic megakaryocytes and platelets played an important role in the development of spreading fibrotic lesions. JAK2 mutation or the preleukemic phase of MPN may accelerate the activation of megakaryocytes and result in the proliferative process of fibrosis. PMID- 21790865 TI - High serum level of alpha-fetoprotein in focal nodular hyperplasia of the liver. AB - Serum alpha-fetoprotein (AFP), the main serum marker of hepatocellular carcinoma, may increase in some benign conditions involving the liver but is usually within normal values in focal nodular hyperplasia (FNH) in adults. We present a case of a FNH associated with serum AFP increase, and in which both the lesion and the non-lesional adjacent liver showed AFP-positive immunostained areas. Moreover, only one case of FNH with AFP-positive immunostaining has been previously reported. In addition, our case of FNH is remarkable as it displayed some morphological and immunophenotypical features of progenitor cells. The serum AFP levels rose after liver resection and progressively returned to the preoperative high values. These findings are concordant with the hypothesis that FNH is a regenerative process, and suggest that regenerative areas in the liver might be the source of AFP production. PMID- 21790866 TI - Leiomyoma of the kidney parenchyma. PMID- 21790867 TI - Extramammary Paget's disease arising in a mature cystic teratoma of the ovary: immunohistochemical expression of androgen receptor. PMID- 21790868 TI - A post-deferential society? PMID- 21790869 TI - Economic crisis, austerity discourses and caregiving: how to remain relevant through engagement and social justice. PMID- 21790870 TI - Constructing mentally ill inmates: nurses' discursive practices in corrections. AB - The concepts of discourse, subjectivity and power allow for innovative explorations in nursing research. Discourse take many different forms and may be maintained, transmitted, even imposed, in various ways. Nursing practice makes possible many discursive spaces where discourses intersect. Using a Foucauldian perspective, were explored the ways in which forensic psychiatric nurses construct the subjectivity of mentally ill inmates. Progress notes and individual interviews constitute discursive spaces within which nurses construct patients' subjectivities. Progress notes provide a written (and permanent) form of discourse, while interviews set the space for a more fluid and contextual form of discourse. We identified five types of subjectivities - the (in)visible patient, the patient as risk, the deviant patient, the disturbed patient and the disciplined patient. These subjectivities were rooted in various types of discourses circulating in the selected setting. Despite the multiple discursive dimensions of forensic psychiatric nursing, progress notes remain the main formal source of information regarding nursing care even though it is not representative of the care provided nor is it representative of nurses' complex discursive practices in corrections. PMID- 21790871 TI - Globalisation, localisation and implications of a transforming nursing workforce in New Zealand: opportunities and challenges. AB - Severe staff and skill shortages within the health systems of developed countries have contributed to increased migration by health professionals. New Zealand stands out among countries in the Organisation for Economic Co-operation and Development in terms of the high level of movements in and out of the country of skilled professionals, including nurses. In New Zealand, much attention has been given to increasing the number of Maori and Pacific nurses as one mechanism for improving Maori and Pacific health. Against a backdrop of the changing characteristics of the New Zealand nursing workforce, this study demonstrates that the globalisation of the nursing workforce is increasing at a faster rate than its localisation (as measured by the growth of the Maori and New Zealand born Pacific workforces in New Zealand). This challenges the implementation of culturally appropriate nursing programmes based on the matching of nurse and client ethnicities. PMID- 21790872 TI - Why older persons seek nursing care: towards a conceptual model. AB - Despite similar health problems, older persons show different care seeking behaviours for a variety of reasons. The aim of this study was to identify motives underlying the attitudes of older persons to seek nursing care and to develop a theoretical rationale which allows viewing their mutual interaction. Theory development according to Walker and Avant was used as a method to derive a model from the reviewed literature. Six categories were identified that may influence seeking of nursing care: perceived threat, disposition, external options & barriers, current coping abilities, influence of significant others, and outcome value. Findings do not allow determination of factors that may predict care seeking attitude but provide a loosely structured conceptual model for culture specific investigations. Qualitative studies guided by the model should be conducted in order to develop testable theories of care seeking for different cultures and settings. PMID- 21790873 TI - Managing the burden: nursing older people in England, 1955-1980. AB - This article is a historical exploration of the work undertaken, by both nurses in training and qualified ward level nurses, on older adult wards of the National Health Service hospitals in England between 1955 and 1980. It focuses particularly on the personal care given to older patients, including pressure area care, the importance of meal times for the patients and the central role of the ward sister in the administration of food, and the training of the student nurses. These key practice themes will be examined in turn and related to the realities that the nurses faced in terms of the shortages of equipment, expertise, training, and also the low status accorded to the care of older people. It will be demonstrated that the care received by the elderly patients was often uncaring, routine and regimented. However, the blame for this treatment cannot be laid solely at the feet of the nurses themselves, but the system which conspired against them and their patients - a system, based on a prevailing attitude in which the older adult population was considered to be a 'burden', or the 'cuckoos in the nest of the acute general hospital' (Grimley Evans 1997, 1076). It is hoped that this article will contribute to the emerging and important area of the history of nursing work. PMID- 21790874 TI - Intensive care patient diaries in Scandinavia: a comparative study of emergence and evolution. AB - Critical illness and intensive care therapy are often followed by psychological problems such as nightmares, hallucinations, delusions, anxiety, depression, and symptoms of posttraumatic stress. Intensive care patient diaries have been kept by nurses and the patients' family since the early 1990s in the Scandinavian countries to help critically ill patients come to terms with their illness after hospital discharge. The aim of the study was to describe and compare the emergence and evolution of intensive care patient diaries in Denmark, Norway, and Sweden. The study had a comparative international design using secondary analysis of qualitative data generated by key-informant telephone interviews with intensive care nurses (n=114). The study showed that diaries were introduced concurrently in the three Scandinavian countries as a grass-roots initiative by mutual cross-national inspiration. The concept has evolved from a pragmatic practice to an evidence-based domain of inquiry propelled by academically prepared nurses. Several schools of thought were identified in our study: diaries as (i) a therapeutic instrument, (ii) an act of caring, (iii) an expression of empathy, and (iv) a hybrid of the above. Diaries have the potential to fulfill the existential needs of patients who struggle to make sense of their experiences and construct their own illness narrative. PMID- 21790875 TI - Technological intimacy in haemodialysis nursing. AB - BENNETT PN. Nursing Inquiry 2011; 18: 247-252 Technological intimacy in haemodialysis nursing Technology plays a major role in nursing care. Among the challenges for nurses is being able to maintain a patient focus while surrounded by highly complex technology. The provision of high quality nursing care in technologically complex environments is particularly challenging when nurses develop relationships with their patients over an extended period of time. In these environments the potential for intimate relationships can increase. This potential for intimacy is evident in the haemodialysis context where dialysis technology, nurses and patients interface. As nurses and patients can spend up to 20 hours per week together intimate relationships can develop. This paper identifies the challenges these dialysis nurses face and introduces the concept of technological intimacy. Technological intimacy can be defined as physical touching and self disclosure, associated with closeness and knowing, that is undertaken in the full view of others in a healthcare environment dominated by technology. In the haemodialysis context technological intimacy has been scarcely acknowledged and rarely researched. Further research will assist in guiding haemodialysis nursing practice. PMID- 21790876 TI - Problems and consequences in the use of professional interpreters: qualitative analysis of incidents from primary healthcare. AB - The aim of this study was to explore what problems are reported by healthcare professionals in primary healthcare concerning the use of interpreters and what the problems lead to. The study involved a single case in a real-life situation with qualitative content analysis of 60 incident reports written by different healthcare professionals. The main problems documented were related to language, such as lack of the interpreters with proficiency in a particular language, and to organisational routines, with difficulties in the availability of interpreters and access to the interpreter agency. The problems reported led to incorrect use of time and resources, which increased the workload and thus delayed treatment. Other consequences were limited possibilities to communicate and thus consultation was carried out without a professional interpreter, using family members instead. The results highlight the importance of developing good co operation between the interpreter agency and the primary healthcare centre in order to fulfil the existing policy of using professional interpreters to provide the right interpreter at the right time and guarantee high-quality care. PMID- 21790877 TI - Beyond greener pastures: exploring contexts surrounding Filipino nurse migration in Canada through oral history. AB - The history of immigrant Filipino nurses in Canada has received little attention, yet Canada is a major receiving country of a growing number of Filipino migrants and incorporates Filipino immigrant nurses into its healthcare workforce at a steady rate. This study aims to look beyond the traditional economic and policy analysis perspectives of global migration and beyond the push and pull factors commonly discussed in the migration literature. Through oral history, this study explores biographical histories of nine Filipino immigrant nurses currently working in British Columbia and Alberta, Canada. Narratives reveal the instrumental role of the deeply embedded culture of migration in the Philippines in influencing Filipino nurses to migrate. Additionally, the stories illustrate the weight of cultural pressures and societal constructs these nurses faced that first colored their decision to pursue a career in nursing and ultimately to pursue emigration. Oral history is a powerful tool for examining migration history and sheds light on nuances of experience that might otherwise be neglected. This study explores the complex connections between various factors motivating Filipino nurse migration, the decision-making process, and other pre migration experiences. PMID- 21790880 TI - Beyond talc pleurodesis: do we really need new methods? PMID- 21790881 TI - Evaluation of serological tests for diagnosis of Bordetella pertussis infection in adolescents and adults. AB - BACKGROUND AND OBJECTIVE: Bacterial agglutination antibodies against Bordetella pertussis, Yamaguchi and Tohama strains, are frequently measured for serodiagnosis of pertussis infection in Japan. To determine the serological criteria, the comparative titres of bacterial agglutination antibody and anti pertussis toxin (PT) antibody were evaluated. METHODS: Antibody titres were analysed in 36 definitive (fourfold increase in agglutination antibody) and 137 presumptive (high titre of single-antibody) cases of B. pertussis infection among adolescents and adults, and in a control group of 318 healthy volunteers. RESULTS: When a single Yamaguchi agglutinin titre of >= 1:1280 (> three SD above the geometric mean for the control group) was taken as diagnostic, the sensitivity and specificity at 4-5 weeks after onset of cough were 58% and 98%, respectively. Using this criterion, the clinical findings in presumptive cases were almost identical to those in definitive cases. When the two tests were compared using 318 control sera, there was no association between the Tohama agglutinin titre and the anti-PT antibody titre, whereas a weak association between the Yamaguchi agglutinin titre and the anti-PT antibody titre was observed. When the numbers of pertussis cases with high antibody titres in the two tests were compared, 60% of cases with a Yamaguchi agglutinin titre of >=1:1280 showed an anti-PT antibody titre of >=100 EU/mL. CONCLUSIONS: These results indicate that the bacterial agglutination test is a method with low sensitivity and specificity for the diagnosis of B. pertussis infection. Therefore, to yield an accurate diagnosis, anti-PT antibody levels should be measured instead of bacterial agglutination antibody. PMID- 21790882 TI - Risk factors for fractured clavicle in the newborn. AB - AIM: To disclose potential risk factors for sustaining a fractured clavicle in the newborn. METHOD: A retrospective case-control analysis of women who gave birth to an infant with a fractured clavicle during a four-year period (2003 2006) was performed. A control group of newborns who did not sustain a fractured clavicle was formed (2:1) matched for maternal age, parity and gestational age at delivery. RESULTS: The rate of fractured clavicle was 0.35%. Heavier newborns' birth weight (3632.9 +/- 376.1 g vs. 3429.5 +/- 513.0 g, P < 0.05) and the use of oxytocin (91.3% vs. 69.5%, P < 0.05) were associated with the occurrence of fractured clavicle during birth. Fractured clavicle was not well correlated with maternal height, maternal pregestational body mass index, maternal body mass index at delivery, maternal weight gain during pregnancy, induction of labor, duration of the second stage of labor, instrumental delivery or newborn birth weight of more than 4000 g. CONCLUSION: We could not identify significant risk factors that could be dealt with in order to avoid a fractured clavicle being sustained during birth. Most fractured clavicles occur in normal newborns following normal labor and delivery. PMID- 21790883 TI - Effects of combined estrogen and progesterone replacement treatment on detrusor contractility and histology in oophorectomized rats. AB - AIM: The aim of this study was to investigate the effects of estrogen plus progesterone treatment administered after surgical menopause on morphological and muscarinic receptor sensitivity in detrusor muscle bands of rats. MATERIALS AND METHODS: A total of 40 female Albino-Wistar rats were assigned into two groups to undergo surgical menopause with sham operation (n = 10) and bilateral oophorectomy (n = 30). Thirty oophorectomized rats were assigned into three groups for different treatments administered for 8 weeks beginning from the 7th postoperative day. At the end of the 8th postoperative week, laparotomy was performed in all of them and the urinary bladders were excised and investigated with light microscope. All statistical analysis and graphs were performed using GraphPad Prism version 4. P < 0.05 was considered to be statistically significant. RESULTS: It was determined that average bodyweights were increased to some extent in oophorectomized and sham groups after treatment and while it was more marked in the group receiving estrogen therapy, bodyweights were decreased in the group receiving estrogen plus progesterone therapy. However, this was not statistically significant. No statistically significant difference was determined between the sham, placebo and 17-beta estradiol treatment groups regarding contractile response of urinary bladder tapes to carbachol (P > 0.05). Contractile responses of urinary bladder tapes of the estrogen plus progesterone treatment group were found to be statistically lower than the placebo group (P < 0.05). CONCLUSION: Our in vitro findings demonstrate that treatment with estrogen plus progesterone decreases muscarinic activity in oophorectomized rats, whereas estrogen-only treatment does not. Our study establishes the basis for further studies to answer whether combination of estrogen and progesterone treatment can restore detrusor overactivity associated with sex hormone defects seen at menopause. PMID- 21790884 TI - Clinical outcome of stage Ia1 squamous cell carcinoma of the uterine cervix and pathological findings of initial conization. AB - AIM: The present study investigated the clinical outcome of stage Ia1 squamous cell carcinoma (SCC) of the uterine cervix at a single institute. MATERIALS AND METHODS: Subjects were 84 patients with cervical SCC, International Federation of Gynecology and Obstetrics stage Ia1 diagnosed according to conization findings between January 2000 and June 2009. Correlations between clinical outcome and pathological findings on initial conization were investigated. RESULTS: Of 65 hysterectomy (without pelvic lymphadenectomy) patients, two (3.1%) showed metastasis to the vaginal wall, and two (3.1%) to the pelvic lymph nodes. Five patients (6.0%) showed lymphovascular invasion, and three (3.6%) showed confluent patterns of stromal invasion (confluent invasion) on initial conization findings. All of these five patients were included in the hysterectomy group. Of 19 patients with conization alone, two showed vaginal metastasis. Of four patients with vaginal metastasis, two showed lymphovascular invasion and one showed confluent invasion despite negative conization margin. In patients with nodal metastasis, stromal invasion of 3.0 mm and 2.8 mm, and horizontal spread of 6.8 mm and 6.9 mm were observed on conization, respectively. All patients are currently alive due to adequa?e therapy including chemo-radiation for six patients with recurrent disease. CONCLUSIONS: In patients showing stromal invasion of nearly 3.0 mm and horizontal spread of nearly 7.0 mm in stage Ia1 cervical SCC, pelvic lymphadenectomy may be considered. Even for patients showing a negative conization margin, careful follow up is necessary, because vaginal metastasis sometimes occurs. PMID- 21790885 TI - Chronic myelocytic leukemia in pregnancy: a case report describing successful treatment using multimodal therapy. AB - Leukemia during pregnancy is rare, posing a complex series of questions, including appropriate therapy and maternal counseling. Management of chronic myelocytic leukemia (CML) during pregnancy is limited. Our patient presented at 30 weeks' gestation with anemia, leukocytosis, and a non-productive cough. Polymerase chain reaction performed on a peripheral blood sample confirmed presence of the breakpoint cluster region-Abl1 chromosomal translocation and the diagnosis of CML. Therapy included acute leukocytapheresis, followed by alpha interferon and imatinib mesylate. The patient responded to treatment and delivered a viable female infant at term weighing 2613 g. Continued imatinib mesylate chemotherapy post-delivery resulted in complete clinical remission. Successful antepartum management of newly diagnosed CML is possible utilizing leukocytapheresis, alpha-interferon and, more recently, imatinib mesylate. Definitive treatment should not be delayed due to pregnancy. PMID- 21790886 TI - Spontaneous spinal epidural hematoma during pregnancy: three case reports. AB - We present three extremely rare cases of spontaneous spinal epidural hematoma occurring in pregnancy. The patients developed progressive paralysis of the upper and lower limbs and the diagnoses were confirmed by magnetic resonance imaging. Urgent decompression is required to prevent neurological sequelae. The pregnancy may either be continued or delivered depending on the gestational age and severity of the disorder. Pregnancy-induced structural changes of the vascular walls and hemodynamic changes may play a role in the pathogenesis of spontaneous spinal epidural hematoma. PMID- 21790887 TI - Small cell carcinoma of the endometrium: a report of two cases. AB - Primary small cell carcinoma of the endometrium is rare and has an extremely poor prognosis. This report describes two cases of small cell carcinoma of the endometrium diagnosed as stage III. Case 1 was diagnosed as stage IIIc. She underwent surgery and chemotherapy. For a locally recurrent tumor, she received radiotherapy. She has been well with no evidence of disease for 4 years. Case 2 was diagnosed as stage IIIa. She underwent surgery. The tumor recurred soon after the surgery, and she died 33 days after the surgery. In the literature, the median survival reported for patients with stage III and IV is only 5 months. Case 1 is the 4th case showing long-term survival with advanced-stage disease. The optimal treatment for this rare tumor has not been established. Considering its rarity and variability, it is difficult to establish an evidence-based therapeutic regimen. PMID- 21790888 TI - Prenatal diagnosis of autosomal recessive polycystic kidney disease by molecular genetic analysis. AB - A 27-year-old primigravida was referred for evaluation of severe oligohydramnios at 22 weeks of gestation. For a more accurate diagnosis and detection of other fetal anomalies, complementary fetal magnetic resonance imaging (MRI) was performed. Findings of fetal MRI evaluation were consistent with autosomal recessive polycystic kidney disease (ARPKD). Parental mutation analysis in the PKHD1 gene was performed. By PKHD1 mutation analysis, we were able to identify a heterozygous missense mutation in exon 20 (K626R) in the father. Molecular genetic analysis can be helpful for an early and reliable prenatal diagnosis of ARPKD. Herein, we present a case of ARPKD that was diagnosed at 22 weeks of gestation by ultrasonographic examination and MRI and verified by PKHD1 mutation analysis and array-based genetic deletion analysis. PMID- 21790889 TI - Three-dimensional volume-rendered imaging of normal and abnormal fetal fluid filled structures using inversion mode. AB - A total of six normal and eight abnormal fetuses at 16-38 weeks of gestation were studied using transabdominal three-dimensional sonography with an inversion mode. In normal fetuses, the stomach, gallbladder and bladder could be depicted. In particular, peristalsis of the stomach was noted. In the case of holoprosencephaly, fused hemispheres were evident. In the case of hydrocephalus, the enlargement of ventricular cavities was noted. In the case of bilateral pleural effusion, the spatial relationship and size of the effusions were depicted. In the case of meconium peritonitis, the spatial relationship between the dilated intestines and ascites was depicted. In two cases of hydronephrosis, the dilated renal pelvis and calyces were clearly shown. In the case of multicystic dysplastic kidney, the number and size of cysts were clearly identified. In the case of left ovarian cyst, the anatomical relationships among the ovarian cyst, kidney, stomach and bladder could be easily understood. PMID- 21790890 TI - Thermal balloon ablation versus laparoscopic supracervical hysterectomy for the surgical treatment of heavy menstrual bleeding: a randomized study. AB - AIM: To compare postoperative outcomes and effects on quality of life following thermal balloon ablation (TBA) or laparoscopic supracervical hysterectomy (LSH) in women with heavy menstrual bleeding (HMB). MATERIAL AND METHODS: Sixty-eight women requiring surgical treatment for HMB were randomly allocated into two treatment arms: TBA (n = 34) and LSH (n = 34). The randomization procedure was based on a computer-generated list. The primary outcome was a comparison of the effects on menstrual bleeding (Pictorial Blood Loss Assessment Chart [PBAC]) between the two procedures. The secondary outcome measures were quality of life, improvement of bleeding patterns, intensity of postoperative pain, and early postoperative complications. Continuous outcome variables were analyzed using Student's t-test. Discrete variables were analyzed with the chi2 test or Fisher's exact test. P < 0.05 was considered statistically significant. RESULTS: The PBAC score was significantly reduced in both treatment groups. After LSH all women had amenorrhea. After TBA there was a significant improvement of bleeding frequency and length. The postoperative pain intensity at 24 h was significantly minor in women treated with TBA rather than with LSH. The Medical Outcomes Survey Short Form 36 (SF-36) score improved in both groups. However, LSH showed a negative impact on the emotional state. No intraoperative complications occurred, and no case was returned to the theatre in either group. CONCLUSION: The effectiveness of TBA as a possible treatment of HMB is confirmed. However, LSH showed a definitive improvement of the symptoms, and a better life quality profile. Further controlled prospective studies are required for identifying the best surgical approach in women with HMB. PMID- 21790891 TI - Rare case of spina bifida in both twins with possible genetic basis. AB - Neural tube defects (NTD) are a group of congenital malformations of the brain and spine, the etiology of which is still debated. Although presumed to be the consequence of interactions between genetic and environmental factors, so far, it is not known which genes are involved in the pathogenesis of these malformations. NTD affecting both fetuses in a twin gestation is a rare event. In view of this rarity, we present a case of dichorionic diamniotic twin pregnancy with spina bifida in both fetuses concordantly. This gestation was preceeded by another dichorionic diamniotic twin pregnancy that was complicated by placental abruption. PMID- 21790892 TI - Massive postpartum hemorrhage after chemotherapy in a patient with acute promyelocytic leukemia. AB - A pregnant woman was diagnosed with acute promyelocytic leukemia at 38 weeks of gestation. Induction of labor was successful, and the patient delivered a healthy male baby. Soon after delivery, she was treated with chemotherapy using all-trans retinoic acid (ATRA). The number of white blood cells was increased on the fifth postpartum day and retinoic acid syndrome (RAS) was considered a concern. On the sixth postpartum day, remission induction chemotherapy with idarubicin and cytosine arabinoside was started. On the seventh postpartum day, massive uterine bleeding of more than 1300 mL suddenly occurred. As administration of cytotoxic agents may induce disseminated intravascular coagulation, we should take care to avoid uterine bleeding after chemotherapy in acute promyelocytic leukemia cases treated soon after delivery. PMID- 21790893 TI - Acquisition of anti-Diego b antibodies possibly resulting from feto-maternal hemorrhage during pregnancy. AB - Anti-Diego b (Di(b) ) antibodies, rare antibodies against red blood cell antigens, can cause severe hemolysis. We report a patient who most likely acquired anti-Di(b) antibodies during pregnancy. The patient was a 39-year-old Japanese woman who delivered by cesarean section at 38 weeks of gestation. She required a second operation to treat re-bleeding of the surgical scar, but it was difficult to schedule this surgery because we could not obtain enough blood for transfusion due to the presence of anti-Di(b) antibodies. These antibodies were likely acquired during pregnancy; she did not have irregular antibodies at 11 weeks of gestation. We speculate that she became sensitized to fetal blood due to feto-maternal hemorrhage. The infant had no hemolytic conditions. Testing for the presence of irregular antibodies should be performed during late stages of pregnancy as well as early stages. PMID- 21790894 TI - Advances in therapies for acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor alpha (RARalpha) and the promyelocytic leukemia (PML) gene. The resultant PML-RARalpha fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARalpha fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients. PMID- 21790895 TI - Cyclin D2 is overexpressed in proliferation centers of chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-kappaB, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-kappaB expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-kappaB-related pathways are also involved, because NF-kappaB upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-kappaB-related pathways. PMID- 21790896 TI - Genetic and environmental predictors, endogenous hormones and growth factors, and risk of estrogen receptor-positive breast cancer in Japanese women. AB - The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We have recently shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype. It is necessary to establish risk factors capable of predicting the risk of ER-positive breast cancer that will enable the efficient selection of candidates for preventive therapy. We analyzed genetic factors, including 14 single nucleotide polymorphisms (SNPs), environmental risk factors (body mass index, age at menarche, pregnancy, age at first birth, breastfeeding, family history of breast cancer, age at menopause, use of hormone replacement therapy, alcohol intake, and smoking), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 [IGF1] and IGF binding protein 3 [IGFBP3]), and mammographic density in 913 women with breast cancer and 278 disease-free controls. To identify important risk factors, risk prediction models for ER positive breast cancer in both pre- and postmenopausal women were created by logistic regression analysis. In premenopausal women, one SNP (CYP19A1-rs10046), age, pregnancy, breastfeeding, alcohol intake, serum levels of prolactin, testosterone, and IGFBP3 were considered to be risk predictors. In postmenopausal women, one SNP (TP53-rs1042522), age, body mass index, age at menopause, serum levels of testosterone, and IGF1 were identified as risk predictors. Risk factors may differ between women of different menopausal status, and inclusion of common genetic variants and serum hormone measurements as well as environmental factors might improve risk assessment models. Further validation studies will clarify appropriate risk groups for preventive therapy. PMID- 21790897 TI - Joint health and functional ability in children with haemophilia who receive intensive replacement therapy. AB - Joint physical examination is an important outcome in haemophilia; however its relationship with functional ability is not well established in children with intensive replacement therapy. Boys aged 4-16 years were recruited from two European and three North American treatment centres. Joint physical structure and function was measured with the Haemophilia Joint Health Score (HJHS) while functional ability was measured with the revised Childhood Health Assessment Questionnaire (CHAQ38. Two haemophilia-specific domains were created by selecting items of the CHAQ38 that cover haemophilia-specific problems. Associations between CHAQ, HJHS, cumulative number of haemarthroses and age were assessed. A total of 226 subjects - mean 10.8 years old (SD 3.8) - participated; the majority (68%) had severe haemophilia. Most severe patients (91%) were on prophylactic treatment. Lifetime number of haemarthroses [median=5; interquartile range (IQR)=1-12] and total HJHS (median = 5; IQR=1-12) correlated strongly (rho = 0.51). Total HJHS did not correlate with age and only weakly (rho=-0.19) with functional ability scores (median=0; IQR=-0.06-0). Overall, haemarthroses were reported most frequently in the ankles. Detailed analysis of ankle joint health scores revealed moderate associations (rho=0.3-0.5) of strength, gait and atrophy with lower extremity tasks (e.g. stair climbing). In this population, HJHS summating six joints did not perform as well as individual joint scores, however, certain elements of ankle impairment, specifically muscle strength, atrophy and gait associated significantly with functional loss in lower extremity activities. Mild abnormalities in ankle assessment by HJHS may lead to functional loss. Therefore, ankle joints may warrant special attention in the follow up of these children. PMID- 21790898 TI - Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. AB - Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine-stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild-type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R [GHR-R ((-/-) )] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R ((-/-) ) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R ((-/-) ) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood-brain barrier and interacts with GHR-Rs located on ventral tegmental dopamine neurons. PMID- 21790901 TI - The mGluR5 antagonist MPEP elevates accumbal dopamine and glycine levels; interaction with strychnine-sensitive glycine receptors. AB - Studies have indicated that the metabotropic glutamate receptor 5 (mGluR5) antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) decreases ethanol self administration, and the same receptor type was also suggested to be involved in the mechanism of action of the anti-craving substance acamprosate. Our previous research suggested that glycine receptors (GlyRs) in the nucleus accumbens (nAc) play a major part in mediating the dopamine-elevating properties of ethanol and are highly involved in the ethanol intake-reducing effect of acamprosate. The aim of this study was to examine if modulation of nAc dopamine via mGluR5 antagonism or GlyR agonism is a linked or separated phenomena. The extracellular levels of dopamine as well as of the GlyR ligands, glycine, taurine and beta-alanine were measured in the nAc by means of microdialysis after local perfusion of MPEP (100 or 500 uM) with or without pre-treatment with strychnine. MPEP increased dopamine levels, an effect that was blocked by pre-treatment with strychnine. In addition, the higher MPEP concentration increased glycine output, whereas no alterations of taurine or beta-alanine were observed. These results indicate a relationship between the glutamatergic and glycinergic transmitter systems in regulating dopamine output, possibly via alteration of extracellular glycine levels. Taken together with our previous data demonstrating the importance of accumbal GlyRs both in ethanol-induced elevation of nAc dopamine and in ethanol consumption, it is plausible that the effects of MPEP treatment, on dopamine output and on ethanol intake, may be mediated via interaction with the same neuronal circuitry that previously has been demonstrated for ethanol, taurine and acamprosate. PMID- 21790900 TI - Addictive potential of modafinil and cross-sensitization with cocaine: a pre clinical study. AB - Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine. PMID- 21790903 TI - Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis. AB - Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide insights for effective treatment. As endocannabinoid signaling and dopamine neurotransmission have been shown to be involved in drug reward, genes related to these systems are plausible candidates for susceptibility to CD. The cannabinoid receptor 1 protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been associated previously with substance dependence. In this study, we attempt to replicate findings associating CNR1 with CD in African Americans. Cocaine-addicted individuals (n=860) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in CNR1 (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (P<=0.042). A meta-analysis was also performed combining our data with that of Zuo et al. who also studied these polymorphisms in African American cocaine addicts (total n=1253 cases versus 543 controls). When our data were combined, rs6454674 increased in significance to P=0.027; however, rs806368 was no longer significant. This study confirms the association between rs6454674 and CD. However, because there is considerable co-morbidity of CD with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction. Furthermore, as this population consists of American individuals of African descent, the possibility of population stratification should not be excluded. PMID- 21790904 TI - The role of context in the processing of alcohol-relevant cues. AB - In line with learning theories of drug addiction, drug-related cues may be viewed as important motivators of continued drug use. They may be differentially effective depending on the context and motivational significance. The present study aimed to test the significance of different contexts in modulating alcohol related cue reactivity. Pictures depicting alcohol intake or its paraphernalia and pictures without any relation to alcohol intake were varied to depict physical and social contexts or different consumptive contexts associated with full/half-full/empty alcohol beverage containers. We obtained ratings of craving, valence and arousal of the cues as well as skin conductance responses (SCRs) and startle reflex modulation measures from 21 abstinent alcohol-dependent patients, recruited from an addiction treatment center, and 21 matched healthy controls. Social scenes and full glasses or bottles were rated as more pleasant and arousing compared with neutral drinking situations and empty glasses or bottles in patients. Furthermore, we found a decreased startle reflex magnitude to social compared with neutral drinking situations, and both higher SCRs and decreased startle reflex magnitude to full compared with empty glasses or bottles in patients versus controls. These results show that both physical and social and consumptive contexts differentially influence cue reactivity in abstinent alcohol dependent patients with both social and pub-related physical contexts, and the initial consumptive context eliciting the most appetitive and arousing responses. These data have not only important implications for our understanding of the role of learning in drug dependence but also for treatment, which needs to take these factors into account. PMID- 21790902 TI - (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) and 3-[(2 methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) similarly attenuate stress induced reinstatement of cocaine seeking. AB - Metabotropic glutamate receptors (mGluRs) have been implicated in the regulation of anxiety, stress responses and the neurobehavioral effects of psychostimulants. The present study was designed to examine whether antagonizing mGluR5 or activating mGluR2/3 prevents stress-induced reinstatement of cocaine seeking. Male Wistar rats were trained to self-administer cocaine and then subjected to daily extinction training for 2 weeks. Subsequent exposure to 15 minutes of intermittent footshock elicited robust reinstatement of responding at the previously active lever. Both the selective mGluR5 antagonist 3-[(2-methyl-1,3 thiazol-4-yl)ethynyl]piperidine (MTEP) (0-3 mg/kg, intraperitoneally) and the selective mGluR2/3 agonist (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) (0-3 mg/kg, subcutaneously) prevented cocaine seeking induced by footshock stress following the same dose-response function. The data show that although mGluR2/3 and mGluR5 are differentially located on synaptic compartments, both LY379268 and MTEP produced the same behavioral effects in reducing stress induced reinstatement. These results are important because they demonstrate that a reduction in glutamate-mediated neural excitability (albeit via different mechanisms of action) reverses footshock-induced reinstatement and suggest that pharmacological manipulations of mGluR2/3 and mGluR5 can prevent the effects of stress, a major precipitating factor for relapse. These findings further confirm that mGluR2/3 or mGluR5 are promising targets for relapse prevention. PMID- 21790899 TI - Neural correlates of craving and resisting craving for tobacco in nicotine dependent smokers. AB - Craving is a significant factor which can lead to relapse during smoking quit attempts. Attempts to resist urges to smoke during cue-elicited craving have been shown to activate regions in the brain associated with decision-making, anxiety regulation and visual processing. In this study, 32 treatment-seeking, nicotine dependent smokers viewed blocks of smoking and neutral cues alternating with rest periods during magnetic resonance imaging scanning in a 3T Siemens scanner (Siemens AG, Erlangen, Bavaria, Germany). While viewing cues or control images, participants were instructed either to 'allow yourself to crave' or 'resist craving.' Data were analyzed with FSL 4.1.5, focused on the smoking cues versus neutral cues contrast, using cluster thresholding (Z > 2.3 and corrected cluster threshold of P = 0.05) at the individual and group levels. During the Crave condition, activation was seen on the left anterior cingulated cortex (LACC), medial prefrontal cortex, left middle cingulate gyrus, bilateral posterior cingulated gyrus and bilateral precuneus, areas associated with attention, decision-making and episodic memory. The LACC and areas of the prefrontal cortex associated with higher executive functioning were activated during the Resist condition. No clear distinctions between group crave and resist analyses as a whole were seen without taking into account specific strategies used to resist the urge to smoke, supporting the idea that craving is associated with some degree of resisting the urge to smoke, and trying to resist is almost always accompanied by some degree of craving. Different strategies for resisting, such as distraction, activated different regions. Understanding the underlying neurobiology of resisting craving to smoke may identify new foci for treatments. PMID- 21790906 TI - Ethanol inhibits excitatory neurotransmission in the nucleus accumbens of adolescent mice through GABAA and GABAB receptors. AB - Age-related differences in various acute physiological and behavioral effects of alcohol have been demonstrated in humans and in other species. Adolescents are more sensitive to positive reinforcing properties of alcohol than adults, but the cellular mechanisms that underlie such a difference are not clearly established. We, therefore, assessed age differences in the ability of ethanol to modulate glutamatergic synaptic transmission in the mouse nucleus accumbens (NAc), a brain region importantly involved in reward mechanisms. We measured field excitatory postsynaptic potentials/population spikes (fEPSP/PS) in NAc slices from adolescent (22-30 days old) and adult (5-8 months old) male mice. We found that 50mM ethanol applied in the perfusion solution inhibits glutamatergic neurotransmission in the NAc of adolescent, but not adult, mice. This effect is blocked by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline and by the GABAB receptor antagonist CGP 55845. Furthermore, bicuculline applied alone produces a stronger increase in the fEPSP/PS amplitude in adult mice than in adolescent mice. Activation of GABAA receptors with muscimol produces a stronger and longer lasting depression of neurotransmission in adolescent mice as compared with adult mice. Activation of GABAB receptors with SKF 97541 also depresses neurotransmission more strongly in adolescent than in adult mice. These results demonstrate that an increased GABA receptor function associated with a reduced inhibitory tone underlies the depressant action of ethanol on glutamatergic neurotransmission in the NAc of adolescent mice. PMID- 21790908 TI - Improved cognitive flexibility in serotonin transporter knockout rats is unchanged following chronic cocaine self-administration. AB - Cocaine dependence is associated with orbitofrontal cortex (OFC)-dependent cognitive inflexibility in both humans and laboratory animals. A critical question is whether cocaine self-administration affects pre-existing individual differences in cognitive flexibility. Serotonin transporter knockout (5-HTT(-/-) ) mice show improved cognitive flexibility in a visual reversal learning task, whereas 5-HTT(-/-) rats self-administer increased amounts of cocaine. Here we assessed: (1) whether 5-HTT(-/-) rats also show improved cognitive flexibility (next to mice); and (2) whether this is affected by cocaine self-administration, which is increased in these animals. Results confirmed that naive 5-HTT(-/-) rats (n = 8) exhibit improved cognitive flexibility, as measured in a sucrose reinforced reversal learning task. A separate group of rats was subsequently trained to intravenously self-administer cocaine (0.5 mg/kg/infusion), and we observed that the 5-HTT(-/-) rats (n = 10) self-administered twice as much cocaine [632.7 mg/kg (+/-26.3)] compared with 5-HTT(+/+) rats (n = 6) [352.3 mg/kg (+/-62.0)] over 50 1-hour sessions. Five weeks into withdrawal the cocaine exposed animals were tested in the sucrose-reinforced reversal learning paradigm. Interestingly, like the naive 5-HTT(-/-) rats, the cocaine exposed 5-HTT(-/-) rats displayed improved cognitive flexibility. In conclusion, we show that improved reversal learning in 5-HTT(-/-) rats reflects a pre-existing trait that is preserved during cocaine-withdrawal. As 5-HTT(-/-) rodents model the low activity s-allele of the human serotonin transporter-linked polymorphic region, these findings may have heuristic value in the treatment of s-allele cocaine addicts. PMID- 21790905 TI - CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. AB - Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose-response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP2D6. The CYP2B6*6 allele [single nucleotide polymorphisms (SNPs) 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13 and 260mg (mean 140+/-52mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96mg, respectively) were significantly lower than those of the heterozygotes (133, 129mg, respectively) and the non-carriers (150, 151mg, respectively) (nominal P=0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), which was previously shown to be associated with high methadone dose requirement in this population (P=0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations. PMID- 21790909 TI - Efficient expression and purification of human replication fork-stabilizing factor, Claspin, from mammalian cells: DNA-binding activity and novel protein interactions. AB - Purification of recombinant proteins of a large size often poses problems of instability or low expression in bacterial or insect cells. Here, we established a method for a high-level expression of large-sized recombinant proteins in mammalian cells and subsequent purification of the full-length proteins. We applied this method to express human Claspin and Tim-Tipin complex, which play important roles in replication checkpoint responses as fork-stabilizing factors, and successfully purified them in functional forms in amount sufficient for enzymatic characterization. Purified Claspin behaves as a monomer and binds preferentially to fork-like DNA. Over-expression of tagged Claspin in mammalian cells facilitated the detection of its interacting factors. Claspin interacts with many factors involved in checkpoint regulation and replication fork machinery, including ATR, ATM, Chk1, Tim, MCM4, MCM10, Cdc45, DNA polymerases alpha, delta, epsilon and Cdc7 kinase. We will discuss the potential implication of these findings in architecture of replication fork. We will also discuss the advantage of this system for purification and characterization of those proteins that are large and have been difficult to deal with. PMID- 21790907 TI - Validating incentive salience with functional magnetic resonance imaging: association between mesolimbic cue reactivity and attentional bias in alcohol dependent patients. AB - Alcohol-associated cues are able to elicit brain activations in mesocorticolimbic networks that are related to the rewarding properties of the drug. Some authors hypothesize that the activation of the mesocorticolimbic reward system triggers an attention allocation to alcohol-associated cues. Yet, no functional magnetic resonance imaging (fMRI) studies examining this proposition are available. In this fMRI study we investigate the association between attentional bias and neural cue reactivity. Thirty-eight recently abstinent alcohol-dependent patients were examined. fMRI was used to study cue reactivity during the presentation of alcohol-related pictures. A modified visual dot-probe task was used to assess attentional bias. Alcohol-dependent patients showed an attentional bias to alcohol-associated cues as well as cue-induced fMRI activation in response to alcohol-related stimuli in limbic and reward-related brain regions and visual areas. We found a positive correlation between cue-induced brain activation and attentional bias score in a network including frontal, temporal and subcortical regions. This study is the first demonstrating that, in line with previous suggestions, cue induced activation of the mesocorticolimbic reward system triggers focusing attention to substance-associated cues. However, this association could also be bidirectional with the attentional bias enhancing cue induced neural activity. PMID- 21790910 TI - Translational repression stabilizes messenger RNA of autophagy-related genes. AB - In response to amino acid starvation, autophagy mediates the lysosome-dependent turnover of cytosolic components via autophagosome formation. Despite advances in understanding the molecular basis of autophagy process, the regulatory mechanism remains unclear. Here, we show that repression of protein synthesis stabilizes the messenger RNAs of specific autophagy-related (ATG) genes, increasing their respective half-lives. Further analysis indicated that the stabilization process is attributable to the coding region of the mRNAs. The results suggest a novel mechanism of autophagy regulation by post-transcriptional mRNA stabilization, in which repression of protein synthesis plays a direct role to sustain the autophagy process. PMID- 21790911 TI - Distinct roles of Rab11 and Arf6 in the regulation of Rab11-FIP3/arfophilin-1 localization in mitotic cells. AB - Rab11 family interacting protein 3/arfophilin-1 is a dual effector of Rab11 and Arf6 and exhibits Rab11-dependent localization to recycling endosomes in interphase. Furthermore, FIP3 undergoes dynamic redistribution to the intercellular bridge during cytokinesis. However, regulation of FIP3 redistribution and its local function by Rab11 and Arf6 has remained controversial. In this study, we developed a procedure for detecting endogenous FIP3, Arf6, and Rab11 and determined that FIP3 is localized near the intercellular bridge during cytokinesis, and to the Flemming body (the midbody) immediately before abscission; Rab11 is localized near the intercellular bridge, but not to the Flemming body; and Arf6 is localized to the Flemming body. Time lapse analyses showed that FIP3 is transported to the intercellular bridge during cytokinesis, together with Rab11; before abscission, FIP3 becomes localized to the Flemming body, where Arf6 is already present. After abscission, FIP3 and Arf6 are incorporated into one of the daughter cells as a Flemming body remnant. Based on these observations, we propose that FIP3 localization to recycling endosomes in interphase and their transport to the intercellular bridge during cytokinesis depend on Rab11, and targeting of FIP3-positive endosomal vesicles to the Flemming body in the abscission phase depends on Arf6. PMID- 21790912 TI - Economic implications of three strategies for the control of taeniasis. AB - OBJECTIVE: To evaluate the cost-effectiveness of three strategies for the control of taeniasis in a community, in terms of cost per case treated. METHODS: A study was conducted in South India to determine the prevalence of taeniasis by screening stool samples from 653 randomly chosen subjects, for coproantigens. The costs incurred in the project were used to estimate the cost per case screened and treated. A one-way sensitivity analysis was carried out for varying rates of taeniasis, different screening strategies and mass therapy. Further sensitivity analysis was carried out with different manpower and test costs. RESULTS: The rate of taeniasis as detected by ELISA for coproantigen was 3 per 1000 (2 of 653 samples). Our study showed that mass therapy without screening for taeniasis would be the most economical strategy in terms of cost per case treated if field workers are employed exclusively for either mass therapy or screening. For each strategy, costs per case treated are higher at low prevalence of taeniasis, with a sharp rise below 15%. CONCLUSIONS: In places that are endemic for taeniasis and neurocysticercosis, mass therapy or screening for taeniasis should be considered. Screening by stool microscopy is not cost-effective in terms of cost per case of taeniasis treated owing to its low sensitivity. Although the cost per case of taeniasis treated is high at low prevalence of taeniasis for all options, incorporating mass therapy into existing mass drug distribution programmes might prove to be the most cost-effective control strategy. PMID- 21790913 TI - Effects of ozone on membrane permeability and ultrastructure in Pseudomonas aeruginosa. AB - AIMS: To examine the mechanism of ozone-induced damage to cytoplasmic membrane and cell ultrastructure of Pseudomonas aeruginosa ATCC27853. METHODS AND RESULTS: Cell suspensions of Ps. aeruginosa ATCC27853 were treated with ozonated water. The leakages of cellular potassium (K+), magnesium (Mg2+) and adenosine triphosphate (ATP), determined by inductively coupled plasma/mass spectrometry (ICP/MS) and a commercial bioluminescence assay kit, were to assess ozone-induced damage to the cytoplasmic membrane. Maximum leakages of K+ and Mg2+ were attained, respectively, at 0.53 mg l-1 ozone after 0.5 and 2 min with > 99% inactivation of culturable bacteria, while that of ATP was achieved at 0.67 mg l 1 ozone after 1 min. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed that treated cells retained intact shapes and cytoplasm agglutinations and vacuoles occurred. CONCLUSIONS: Ozone inactivates Ps. aeruginosa ATCC27853 by the combined results of increased cytoplasmic membrane permeability and cytoplasm coagulation, rather than by severe membrane disruption and cell lysis. SIGNIFICANCE AND IMPACT OF THE STUDY: Pseudomonas aeruginosa is a common water-related pathogen. These insights into the leakage of cytoplasmic components and ultrastructural changes provide evidence for the mechanisms of ozone-mediated inactivation. PMID- 21790914 TI - A rapid and simple PCR method for identifying isolates of the genus Azospirillum within populations of rhizosphere bacteria. AB - AIMS: To develop a rapid and simple genus-specific polymerase chain reaction (PCR) method for detecting and identifying isolates of the genus Azospirillum which is well-recognized as plant growth-promoting rhizobacterium. METHODS AND RESULTS: Nine pairs of PCR primers were designed based on the Azospirillum 16S rRNA, ipdC, nifA and nifH genes to assess their genus specificity by testing against 12 Azospirillum (from seven species) and 15 non-Azospirillum reference strains, as compared with the fAZO/rAZO pair reported by Baudoin et al. (J Appl Microbiol, 108, 2010, 25). Among the primer pairs assessed, the Az16S-A pair designed on the 16S rRNA gene sequence showed the highest genus specificity: it successfully yielded a single amplicon of the expected size in all the 12 Azospirillum strains and for a close relative, Rhodocista centenaria. The PCR with the Az16S-A primers generated a detectable amount of the amplicon from >=103 CFU ml-1 of Azospirillum cell suspensions even in the presence of contaminants and accurately discriminated Azospirillum and non-Azospirillum species in both 35 Azospirillum-like and 70 unknown isolates from plant roots and rhizosphere soils. CONCLUSIONS: We developed a rapid and simple PCR method for detecting and identifying Azospirillum isolates within populations of rhizosphere bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The method developed would serve as a useful tool for isolating a variety of indigenous Azospirillum bacteria from agricultural samples. PMID- 21790915 TI - Species identification of Aspergillus section Flavi isolates from Portuguese almonds using phenotypic, including MALDI-TOF ICMS, and molecular approaches. AB - AIMS: Section Flavi is one of the most significant sections in the genus Aspergillus. Taxonomy of this section currently depends on multivariate approaches, entailing phenotypic and molecular traits. This work aimed to identify isolates from section Flavi by combining various classic phenotypic and genotypic methods as well as the novel approach based on spectral analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF ICMS) and to evaluate the discriminatory power of the various approaches in species identification. METHODS AND RESULTS: Aspergillus section Flavi isolates obtained from Portuguese almonds were characterized in terms of macro- and micromorphology, mycotoxin pattern, calmodulin gene sequence and MALDI TOF protein fingerprint spectra. For each approach, dendrograms were created and results were compared. All data sets divided the isolates into three groups, corresponding to taxa closely related to Aspergillus flavus, Aspergillus parasiticus and Aspergillus tamarii. In the A. flavus clade, molecular and spectral analyses were not able to resolve between aflatoxigenic and nonaflatoxigenic isolates. In the A. parasiticus cluster, two well-resolved clades corresponded to unidentified taxa, corresponding to those isolates with mycotoxin profile different from that expected for A. parasiticus. PMID- 21790916 TI - Factors predicting persistent thrombocytopenia after living donor liver transplantation in pediatric patients. AB - Thrombocytopenia is common after LT for pediatric end-stage liver diseases. Seventy-six pediatric patients (<=15 yr old) who underwent LDLT were evaluated for the incidence and predictive factors of post-transplant thrombocytopenia (PLT <100, 000/mm(3) ). The prevalence of thrombocytopenia at two wk and at 12 months post-transplant was 22/76 (28.9%) and 11/62 (17.7%), respectively. Thrombocytopenia at two wk after LDLT was significantly associated with age at transplant, preoperative PLT, GRWR, acute rejection, and CMV infection in univariate analysis. Moreover, preoperative PLT, GRWR, and acute rejection had a strong correlation in multivariate analysis. Thrombocytopenia at 12 months after LDLT was associated only with preoperative PLT. We also demonstrated that vascular complications caused thrombocytopenia and that successful treatment recovered the PLT. These results showed that, in addition to considering the preoperative PLT, post-operative monitoring of platelets is very helpful for the early detection of adverse events related to the graft liver in pediatric liver transplant patients. PMID- 21790918 TI - Hepatobiliary scintigraphy for the assessment of biliary stricture after pediatric living donor liver transplantation for hepaticojejunostomy reconstruction: the value of the excretion rate at 60 min. AB - HBS is performed to determine the presence of biliary stricture after liver transplantation. We focused on the Ex-60 after an intravenous injection of tracer during HBS. The aim of this study was to review the cutoff values for the diagnosis of biliary stricture by HBS after pediatric LDLT. We analyzed 114 HBS studies using (99m) Tc-PMT in 80 cases after pediatric LDLT. HBS was performed three months after LDLT on a routine basis and/or was performed when ultrasonography and blood test findings indicated biliary stricture. A ROC curve analysis was performed to identify the cutoff value for the correlation between Ex-60 and biliary stricture. The Ex-60 (mean +/- s.d.) in the cases diagnosed as having biliary stricture and in normal subjects were 49.1 +/- 20.2% vs. 78.0 +/- 9.7% (p < 0.01), respectively. As a result of an ROC curve analysis of the Ex-60, the recommended cutoff value to diagnose biliary stricture was set at 69.2% (sensitivity 87.0%, specificity 81.8%). In cases where the Ex-60 by (99m) Tc-PMT HBS is <69.2%, it is recommended that further treatment for biliary stricture should be provided. PMID- 21790917 TI - Segmental ABO-incompatible liver graft from a donor after cardiac death in neonatal acute liver failure. AB - Segmental liver grafts from DCD in pediatric LT have been safely used even in acute liver failure situations. Furthermore, despite the risk of antibody mediated acute rejection, some studies have also demonstrated the safety of ABO incompatible LT in infants. The use of such grafts can be beneficial by reducing the time on the transplant waiting list but they are more susceptible to initial dysfunction and there is a lack of enthusiasm to consider their use especially for an emergency LT as a life-saving procedure. In this short article, we describe the use and successful outcome in a neonate with fulminant acute liver failure secondary to neonatal hemochromatosis who received an ABO-incompatible reduced-size DCD graft. PMID- 21790920 TI - Cerebral effects of severe hypoglycemia in young people with type 1 diabetes. PMID- 21790919 TI - Racial differences in arterial stiffness among adolescents and young adults with type 2 diabetes. AB - BACKGROUND: African-American adults demonstrate a higher prevalence of cardiovascular complications including myocardial infarction and stroke. Whether similar racial disparities are present to suggest African-Americans adolescents are at higher risk to develop cardiovascular disease is not known. Thus, we compared arterial stiffness, an early marker of cardiovascular disease, in African-American and Caucasian adolescents and young adults with type 2 diabetes. METHODS: Demographic, anthropometric, laboratory data, and arterial stiffness measures including pulse wave velocity (PWV) and augmentation index (AIx) were collected in a cross-sectional study of 215 adolescents (average age 18 yr) with type 2 diabetes (55% African-American and 65% female). RESULTS: Compared to Caucasians, African-Americans had increased PWV (6.21 +/- 0.87 vs. 6.96 +/- 1.30, p < .01) and AIx (4.44 +/- 11.17 vs. 7.64 +/- 12.02, p = 0.05). Regression modeling demonstrated age, lipids, blood pressure, and duration of diabetes were differently associated with arterial stiffness in each race group (p < 0.05). CONCLUSIONS: African-American adolescents and young adults with type 2 diabetes have increased vascular stiffness than age-matched Caucasians. This process is mediated by different cardiovascular risk factors. These results suggest race specific risk factor modification may be helpful to prevent early cardiovascular disease in this high risk population. PMID- 21790921 TI - Risk factors for 30-day readmission in general medical patients admitted from the emergency department: a single centre study. AB - BACKGROUND: Overcrowding in emergency departments (ED) around the world is an increasingly serious problem with an adverse impact on both patient flow and patient outcomes. A significant contributing factor to ED overcrowding is possibly due to readmission. Risk factors for readmission in patients admitted from ED are rarely studied, particularly in Asian countries where the length of stay is reportedly longer. METHODS: A retrospective study of patients admitted to general medical wards from the ED of a referral centre in northern Taiwan from November 2009 to April 2010 was conducted. The primary outcome was 30-day hospital readmission and clinical characteristics were analysed for predictors of readmission. RESULTS: Of the recruited 2698 patients, 451 (16.7%) were readmitted within 30 days after discharge. Age, gender, marital status and the activities of daily living (Barthel's score) were not associated with 30-day readmission. Higher Charlson score ((score 2-4) hazard ratio (HR): 1.42, 95% confidence interval (CI): 1.07-1.89; (score >4) HR: 1.93, 95% CI: 1.37-2.73), longer hospital stay ((8-14 days) HR: 1.51, 95% CI: 1.17-1.95; (15-28 days) HR: 1.64, 95% CI: 1.22-2.19; (>28 days) HR: 1.97, 95% CI: 1.43-2.71), and presence of underlying active malignancy (HR: 1.66, 95% CI: 1.27-2.16) and anaemia (HR: 1.26, 95% CI: 1.02-1.55) were independently associated with readmission. CONCLUSION: Medical patients admitted from the ED of a referral centre have a 30-day readmission rate of 16.7%. Post-discharge care should focus on patients with higher Charlson score, longer hospitalisation, anaemia and underlying active malignancy, which are independent predictive factors for 30-day readmission. PMID- 21790922 TI - Investigating the adverse respiratory effects of beta-blocker treatment: six years of prospective longitudinal data in a cohort with cardiac disease. AB - BACKGROUND: Globally, cardiovascular disease (CVD) is the leading cause of death. Beta-blocker medications have well-established survival benefit for myocardial infarction and heart failure. However, CVD frequently coexists with chronic obstructive airways disease (COPD), a disease in which beta-blockers are traditionally avoided. AIM: We sought to investigate the adverse respiratory effects associated with long-term beta-blocker treatment in patients with cardiac disease, and presumed high risk of COPD. METHODS: In this prospective cohort study, patients admitted with acute cardiac disease were recruited from the cardiology unit of a tertiary referral hospital. The treating cardiologist determined beta-blocker treatment, independent of the study. Repeated measures of spirometry and respiratory symptom scores were assessed over 12 months. Respiratory exacerbations, cardiac events and survival were recorded over 6 years. Outcomes were compared according to beta-blocker exposure. RESULTS: Sixty four subjects participated, 30 of whom received beta-blockers. Beta-blockers did not adversely affect spirometry, respiratory symptoms or survival. However, considering two categories of respiratory exacerbations (symptom-based vs treated), subjects taking beta-blockers accumulated increased annual risk (relative risk (RR) 1.30, 95% confidence interval (CI) 1.11-1.53, P= 0.001 and RR 1.37, 95% CI 1.09-1.72, P= 0.008) and concluded with overall increased risk (RR 3.67, 95% CI 1.65-8.18, P= 0.001 and RR 4.03, 95% CI 1.26-12.9, P= 0.019), when compared with the group not taking beta-blockers. CONCLUSION: Long-term beta blocker treatment did not adversely affect lung function, respiratory symptom scores or survival, but was associated with increased risk of respiratory exacerbations. PMID- 21790923 TI - Low positive predictive value of the ABCD2 score in emergency department transient ischaemic attack diagnoses: the South Western Sydney transient ischaemic attack study. AB - BACKGROUND: The ABCD(2) stroke risk score is recommended in national guidelines for stratifying care in transient ischaemic attack (TIA) patients, based on its prediction of early stroke risk. We had become concerned about the score accuracy and its clinical value in modern TIA cohorts. METHODS: We identified emergency department-diagnosed TIA at two hospitals over 3 years (2004-2006). Cases were followed for stroke occurrence and ABCD(2) scores were determined from expert record review. Sensitivity, specificity and positive predictive values (PPV) of moderate-high ABCD(2) scores were determined. RESULTS: There were 827 indexed TIA diagnoses and record review was possible in 95.4%. Admitted patients had lower 30 day stroke risk (n = 0) than discharged patients (n = 7; 3.1%) (P < 0.0001). There was no significant difference in proportion of strokes between those with a low or moderate-high ABCD(2) score at 30 (1.2 vs 0.8%), 90 (2.0 vs 1.9%) and 365 days (2.4 vs 2.4%) respectively. At 30 days the sensitivity, specificity and PPV of a moderate-high score were 57% (95% confidence interval (CI) 25.0-84.2), 32.2% (95% CI 29.1-35.6) and 0.75% (95% CI 0.29-1.91) respectively. CONCLUSIONS: Early stroke risk was low after an emergency diagnosis of TIA and significantly lower in admitted patients. Moderate-high ABCD(2) scores did not predict early stroke risk. We suggest local validation of ABCD(2) before its clinical use and a review of its place in national guidelines. PMID- 21790924 TI - Can we predict sputum eosinophilia from clinical assessment in patients referred to an adult asthma clinic? AB - BACKGROUND: There is overwhelming evidence that asthma guidelines aimed at reducing airway inflammation are superior to those based on clinical symptoms alone. This involves targeting eosinophilic inflammation with inhaled corticosteroids. AIM: Because induced sputum is not readily available, our study set out to investigate whether the collective or singular use of routine asthma investigations can predict sputum eosinophilia. METHODS: Eighty patients underwent skin prick testing, blood tests (IgE, full blood count), spirometry, exhaled fraction nitric oxide (FeNO), PD15 to hypertonic saline, and induced sputum testing at first assessment. A predictive model for sputum eosinophilia (defined as >=3% eosinophils) was sought using routinely available tests. RESULTS: Fifty-four subjects underwent both induced sputum and FeNO testing. Seventeen (30%) revealed eosinophilic inflammation, nine (16%) neutrophilic, four (7%) mixed granulocytic and 26 (46%) paucigranulocytic. Positive predictors for sputum eosinophilia included low forced expiratory volume in 1 s (FEV(1))% predicted, raised serum eosinophil, positive smoking history, Polynesian ethnicity and negative asthma family history. There was a non-statistically significant trend for FeNO predicting sputum eosinophilia. The best combination of predictors was low FEV(1)% predicted, raised serum eosinophil, positive smoking history and negative family history of asthma. CONCLUSION: This study demonstrates that the serum eosinophil count and FEV(1) combined with aspects of a clinical history may provide a simple and practical alternative to assessment of airway (sputum) eosinophilia in the clinical setting. A full blood count can be performed at a substantially lesser cost and with greater accessibility than induced sputum. We feel the time has come for the clinical utility of the serum eosinophil count to be revisited. PMID- 21790925 TI - Anaemia is highly prevalent among unselected internal medicine inpatients and is associated with increased mortality, earlier readmission and more prolonged hospital stay: an observational retrospective cohort study. AB - BACKGROUND: Anaemia is associated with adverse outcomes in elderly community dwelling individuals, but this problem is less well characterised in the inpatient setting. AIMS: To determine the prevalence of anaemia and its associations in a well-defined cohort of internal medicine inpatients. METHODS: A retrospective cohort study of non-elective admissions under internal medicine at Palmerston North Hospital, New Zealand, was conducted for 4 months of 2008 with outcome analysis on 1 March 2010. RESULTS: At admission, 497 of 1491 (33.3%) patients were anaemic by World Health Organization criteria (haemoglobin <130 g/L for males; <120 g/L for females). Anaemia was more prevalent in males (38.1%) than females (28.2%), P < 0.001, in patients aged 65 years or older (41%) than in those under 65 (21.3%), P < 0.001, in New Zealand Europeans (34.3%) than in Maori and people from the Pacific Islands (26.4%), P= 0.04, and in patients admitted primarily because of malignancy, endocrine/metabolic disease, infection, and acute coronary syndrome/congestive heart failure (P < 0.001). Anaemia was independently associated with increased length of hospital stay (7.3 days vs 5.1 days in non-anaemic patients; P < 0.001), with mortality (P < 0.001) and unplanned hospital readmission (P < 0.001) during the follow-up period. Anaemia was infrequently acknowledged or investigated. Secondary analysis using a haemoglobin threshold of 110 g/L showed similar results. CONCLUSIONS: Anaemia is highly prevalent among medical inpatients with variation because of gender, age, race and reason for admission. Anaemia independently predicts for prolonged hospital stay, increased mortality and shorter time to readmission, but is usually not documented or investigated in this setting. PMID- 21790927 TI - Use of biological disease-modifying anti-rheumatic drugs in patients with concurrent rheumatic disease and hepatitis B. AB - BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the management of inflammatory arthritides. Reactivation of hepatitis B virus (HBV) is a potential adverse outcome in patients treated with bDMARDs. There is currently no consensus on the approach to identifying and treating these patients with underlying HBV infection. AIM: The aims of this study were to assess the risk of HBV reactivation in patients treated with bDMARDs, and to determine whether HBV screening should be carried out in all patients prior to commencing bDMARDs. METHODS: A literature search was undertaken to identify all reports of patients with inflammatory arthritides and concurrent HBV infection being treated with bDMARDs. RESULTS: Forty-three patients with HBV infection were identified, of whom eight patients developed HBV reactivation after exposure to bDMARDs. Of the patients who experienced reactivation, two had unknown infection that surfaced during bDMARD therapy. Patients who experienced reactivation were promptly treated with antiviral therapy and saw clinical improvement. There are no long-term data on these patients. CONCLUSIONS: HBV reactivation may result in serious consequences, including death. Tuberculosis screening prior to bDMARD treatment is already standard practice, as is HBV screening for patients undergoing cancer chemotherapy. Implementing HBV screening for all patients prior to bDMARD treatment can identify patients with chronic HBV who may require antiviral therapy. PMID- 21790928 TI - Prevalence of paraproteinaemia in older Australians. AB - BACKGROUND: Estimates of the prevalence of paraproteinaemia vary, from 1% in persons aged over 25 years to 10% in those aged over 80 years, although there are limited data from well-defined populations. We sought to determine the prevalence of paraproteinaemia in Australians aged 50 years and over, and to determine risks factors for its presence. METHODS: We performed a population-based, cross sectional study using data and serum collected in the Blue Mountains Eye Study. Serum samples from 2933 patients were analysed by capillary zone electrophoresis and, where indicated, immunosubtraction, which allowed for both quantitation and isotype detection. RESULTS: A paraprotein was detected in 134 of the 2933 samples, giving an overall prevalence of 4.6% (95% confidence interval, 3.8 5.3%). The presence of a paraprotein was strongly age-related (P(trend) = 0.001), with a prevalence of 2.8% in persons aged 50-59 years, rising steadily to 9.1% in those aged 80 years and over. The prevalence was significantly higher in men (5.9%) compared with women (4.0%) (P= 0.03). CONCLUSION: We conclude that approximately one in 20 Australians aged 50 years or over harbours a paraprotein, a prevalence that appears higher than from similar cohorts in other countries. PMID- 21790926 TI - Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status? AB - AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol. PMID- 21790929 TI - Voice hearing: a secondary analysis of talk by people who hear voices. AB - Unitary explanations of mental illness symptoms appear to be inadequate when faced with everyday experiences of living with these conditions. In particular, the experience of voice hearing is not sufficiently accounted for by biomedical explanations. This paper revisits data collected from a sample of people who hear voices to perform a secondary analysis with the aim of examining the explanatory devices deployed by individuals in their accounts of voice hearing. Secondary analysis is the use of existing data, collected for a previous study, in order to explore a research question distinct from the original inquiry. In this study, we subjected these data to a thematic analysis. People who hear voices make use of standard psychiatric explanations about the experience in their accounts. However, the accounts paint a more complex picture and show that people also impute personal meaning to the experience. This in turn implicates both personal and social identity; that is, how the person is known to themselves and to others. We suggest that this knowledge can inform a more thoughtful engagement with the experiences of voice hearing by mental health nurses. PMID- 21790930 TI - Do edge responses cascade up or down a multi-trophic food web? AB - Despite nearly 100 years of edge studies, there has been little effort to document how edge responses 'cascade' to impact multi-trophic food webs. We examined changes within two, four-tiered food webs located on opposite sides of a habitat edge. Based on a 'bottom-up' resource-based model, we predicted plant resources would decline near edges, causing similar declines in specialist herbivores and their associated predators, while a generalist predator was predicted to increase due to complementary resource use. As predicted, we found declines in both specialist herbivores and predators near edges, but, contrary to expectations, this was not driven by gradients in plant resources. Instead, the increase in generalist predators near edges offers one alternative explanation for the observed declines. Furthermore, our results suggest how recent advances in food web theory could improve resource-based edge models, and vice versa. PMID- 21790932 TI - A framework for studying transient dynamics of population projection matrix models. AB - Empirical models are central to effective conservation and population management, and should be predictive of real-world dynamics. Available modelling methods are diverse, but analysis usually focuses on long-term dynamics that are unable to describe the complicated short-term time series that can arise even from simple models following ecological disturbances or perturbations. Recent interest in such transient dynamics has led to diverse methodologies for their quantification in density-independent, time-invariant population projection matrix (PPM) models, but the fragmented nature of this literature has stifled the widespread analysis of transients. We review the literature on transient analyses of linear PPM models and synthesise a coherent framework. We promote the use of standardised indices, and categorise indices according to their focus on either convergence times or transient population density, and on either transient bounds or case specific transient dynamics. We use a large database of empirical PPM models to explore relationships between indices of transient dynamics. This analysis promotes the use of population inertia as a simple, versatile and informative predictor of transient population density, but criticises the utility of established indices of convergence times. Our findings should guide further development of analyses of transient population dynamics using PPMs or other empirical modelling techniques. PMID- 21790931 TI - Predicting trait values and measuring selection in complex life histories: reproductive allocation decisions in Soay sheep. AB - Accurate prediction of life history phenomena and characterisation of selection in free-living animal populations are fundamental goals in evolutionary ecology. In density regulated, structured populations, where individual state influences fate, simple and widely used approaches based on individual lifetime measures of fitness are difficult to justify. We combine recently developed structured population modelling tools with ideas from modern evolutionary game theory (adaptive dynamics) to understand selection on allocation of female reproductive effort to singletons or twins in a size-structured population of feral sheep. In marked contrast to the classical selection analyses, our model-based approach predicts that the female allocation strategy is under negligible directional selection. These differences arise because classical selection analysis ignores components of offspring fitness and fails to consider selection over the complete life cycle. PMID- 21790933 TI - The ecological causes of individual specialisation. AB - Many generalist populations are composed of specialised individuals, whose niches are small subsets of the population niche. This 'individual specialisation' is a widespread phenomenon in natural populations, but until recently few studies quantified the magnitude of individual specialisation and how this magnitude varies among populations or contexts. Such quantitative approaches are necessary for us to understand how ecological interactions influence the amount of among individual variation, and how the amount of variation might affect ecological dynamics. Herein, we review recent studies of individual specialisation, emphasising the novel insights arising from quantitative measures of diet variation. Experimental and comparative studies have confirmed long-standing theoretical expectations that the magnitude of among-individual diet variation depends on the level of intra and interspecific competition, ecological opportunity and predation. In contrast, there is little empirical information as to how individual specialisation affects community dynamics. We discuss some emerging methodological issues as guidelines for researchers studying individual specialisation, and make specific recommendations regarding avenues for future research. PMID- 21790935 TI - Response to technical comment on 'meta-analysis reveals negative yet variable effects of ocean acidification on marine organisms'. AB - It has been proposed that crustaceans should be excluded from a comparison of biological responses to ocean acidification among organisms with different calcium carbonate (CaCO3 ) forms in their calcified structures. We re-analysed our data without crustaceans and found high variation in organismal responses within CaCO3 categories. We conclude that the CaCO3 polymorph alone does not predict sensitivity, and a consideration of functional differences among organisms is necessary for predicting variation in response to acidification. PMID- 21790936 TI - Belowground biodiversity effects of plant symbionts support aboveground productivity. AB - Soil microbes play key roles in ecosystems, yet the impact of their diversity on plant communities is still poorly understood. Here we demonstrate that the diversity of belowground plant-associated soil fungi promotes plant productivity and plant coexistence. Using additive partitioning of biodiversity effects developed in plant biodiversity studies, we demonstrate that this positive relationship can be driven by complementarity effects among soil fungi in one soil type and by a selection effect resulting from the fungal species that stimulated plant productivity the most in another soil type. Selection and complementarity effects among fungal species contributed to improving plant productivity up to 82% and 85%, respectively, above the average of the respective fungal species monocultures depending on the soil in which they were grown. These results also indicate that belowground diversity may act as insurance for maintaining plant productivity under differing environmental conditions. PMID- 21790934 TI - Community assembly: alternative stable states or alternative transient states? AB - The concept of alternative stable states has long been a dominant framework for studying the influence of historical contingency in community assembly. This concept focuses on stable states, yet many real communities are kept in a transient state by disturbance, and the utility of predictions for stable states in explaining transient states remains unclear. Using a simple model of plant community assembly, we show that the conditions under which historical contingency affects community assembly can differ greatly for stable versus transient states. Differences arise because the contribution of such factors as mortality rate, environmental heterogeneity and plant-soil feedback to historical contingency changes as community assembly proceeds. We also show that transient states can last for a long time relative to immigration rate and generation time. These results argue for a conceptual shift of focus from alternative stable states to alternative transient states for understanding historical contingency in community assembly. PMID- 21790938 TI - The two-component sensor kinase KdpD is required for Salmonella typhimurium colonization of Caenorhabditis elegans and survival in macrophages. AB - The ability of enteric pathogens to perceive and adapt to distinct environments within the metazoan intestinal tract is critical for pathogenesis; however, the preponderance of interactions between microbe- and host-derived factors remain to be fully understood. Salmonella enterica serovar Typhimurium is a medically important enteric bacterium that colonizes, proliferates and persists in the intestinal lumen of the nematode Caenorhabditis elegans. Several Salmonella virulence factors important in murine and tissue culture models also contribute to worm mortality and intestinal persistence. For example, PhoP and the virulence plasmid pSLT are virulence factors required for resistance to the C. elegans antimicrobial peptide SPP-1. To uncover additional determinants required for Salmonella typhimurium pathogenesis in vivo, we devised a genetic screen to identify bacterial mutants defective in establishing a persistent infection in the intestine of C. elegans. Here we report on identification of 14 loci required for persistence in the C. elegans intestine and characterization of KdpD, a sensor kinase of a two-component system in S. typhimurium pathogenesis. We show that kdpD mutants are profoundly attenuated in intestinal persistence in the nematode and in macrophage survival. These findings may be attributed to the essential role KdpD plays in promoting resistance to osmotic, oxidative and antimicrobial stresses. PMID- 21790937 TI - Cathelicidin is involved in the intracellular killing of mycobacteria in macrophages. AB - Macrophages have been shown to kill Mycobacterium tuberculosis through the action of the antimicrobial peptide cathelicidin (CAMP), whose expression was shown to be induced by 1,25-dihydroxyvitamin D3 (1,25D3). Here, we investigated in detail the antimycobacterial effect of murine and human cathelicidin against Mycobacterium smegmatis and M. bovis BCG infections. We have synthesized novel LL 37 peptide variants that exhibited potent in vitro bactericidal activity against M. smegmatis, M. bovis BCG and M. tuberculosis H37Rv, as compared with parental peptide. We show that the exogenous addition of LL-37 or endogenous overexpression of cathelicidin in macrophages significantly reduced the intracellular survival of mycobacteria relative to control cells. An upregulation of cathelicidin mRNA expression was observed that correlated with known M. smegmatis killing phases in J774 macrophages. Moreover, RNAi-based Camp knock down macrophages and Camp(-/-) bone marrow derived mouse macrophages were significantly impaired in their ability to kill mycobacteria. M. smegmatis killing in Camp(-/-) macrophages was less extensive than in Camp(+/+) cells following activation with FSL-1, an inducer of cathelicidin expression. Finally we show that LL-37 and 1,25D3 treatment results in increase in colocalization of BCG-containing phagosomes with lysosomes. Altogether, these data demonstrate that cathelicidin plays an important role in controlling intracellular survival of mycobacteria. PMID- 21790940 TI - Lipid raft-dependent adhesion of Giardia intestinalis trophozoites to a cultured human enterocyte-like Caco-2/TC7 cell monolayer leads to cytoskeleton-dependent functional injuries. AB - Gardia intestinalis, the aetiological agent of giardiasis, one of the most common intestinal diseases in both developing and developed countries, induces a loss of epithelial barrier function and functional injuries of the enterocyte by mechanisms that remain unknown. Three possible mechanisms have been proposed: (i) Giardia may directly alter the epithelial barrier after a close interaction between the trophozoite and polarized intestinal cells, (ii) intestinal functions may be altered by factors secreted by Giardia including an 'enterotoxin', proteinases and lectins, and (iii) based on mouse studies, a mechanism involving the intervention of activated T lymphocytes. We used fully differentiated cultured human intestinal Caco-2/TC7 cells forming a monolayer and expressing several polarized functions of enterocytes of small intestine to investigate the mechanisms by which G. intestinalis induces structural and functional alterations in the host intestinal epithelium. We first report that adhesion of G. intestinalis at the brush border of enterocyte-like cells involves the lipid raft membrane microdomains of the trophozoite. We report an adhesion-dependent disorganization of the apical F-actin cytoskeleton that, in turn, results in a dramatic loss of distribution of functional brush border-associated proteins, including sucrase-isomaltase (SI), dipeptidylpeptidase IV (DPP IV) and fructose transporter, GLUT5, and a decrease in sucrose enzyme activity in G. intestinalis infected enterocyte-like cells. We observed that the G. intestinalis trophozoite promotes an adhesion-dependent decrease in transepithelial electrical resistance (TER) accompanied by a rearrangement of functional tight junction (TJ)-associated occludin, and delocalization of claudin-1. Finally, we found that whereas the occludin rearrangement induced by G. intestinalis was related to apical F-actin disorganization, the delocalization of claudin-1 was not. PMID- 21790941 TI - Complement receptor 1 and malaria. AB - Plasmodium falciparum malaria is an intracellular parasite that is transmitted by Anopheles mosquitoes. It is responsible for approximately 1 million deaths per year. Most deaths occur as a result of complications such as severe anaemia or cerebral malaria (coma). The complement receptor 1 is a key complement regulator found on the surface of red cells and most leucocytes. A growing body of evidence suggests that this molecule plays a critical role in the pathogenesis of P. falciparum malaria. Initial reports showed that CR1 enables the binding of infected red cells to uninfected red cells to form rosettes, which can potentially obstruct small capillaries. However, further evidence suggests that CR1 is also important in the control of complement activation and immune complex formation during malaria infection. Most recently, CR1 has also been shown to be a receptor for the invasion of red cells by the parasite. Its polymorphic nature almost certainly has allowed the selection of variants that have helped humankind survive the scurge of malaria. The finding of conflicting reports about the exact role of these variants in severe disease underlies the complexity of the parasite host interactions and highlights the need for further studies. PMID- 21790943 TI - Regulation of cyclooxygenase-2 expression in human bladder epithelial cells infected with type I fimbriated uropathogenic E. coli. AB - The type 1 fimbriae of uropathogenic Escherichia coli (UPEC) have been described as important for the establishment of bladder infections and urinary tract infections (UTI). Urinary prostaglandin (PG) levels and cyclooxygenase (COX)-2 expression in urine particulates may increase with infectious and inflammatory processes, including UTIs. We investigated the mechanisms underlying the modulation of COX-2 expression through the invasion of type 1 fimbriated UPEC strain J96 (J96-1) in human bladder 5637 cells. Bladder 5637 cells infected with J96-1 induced increases in the expression of COX-2 and secretion of PGE(2) . By using specific inhibitors and short hairpin RNA (shRNA), we have demonstrated that the activation of extracellular signal-related kinase (ERK), c-Jun-NH(2) terminal kinase (JNK) and p38 MAPK pathways is critical for J96-1-induced COX-2 expression. Luciferase reporters and chromatin immunoprecipitation assays suggest that J96-1 invasion increases NF-kappaB- and AP-1-DNA-binding activities in 5637 cells. Inhibition of NF-kappaB and AP-1 activations blocked the J96-1-induced COX 2 promoter activity and expression. The effect of J96-1 on 5637 cell signalling and COX-2 expression is mediated by Toll-like receptor (TLR)-4. In summary, our findings provide the molecular pathways underlying type 1 fimbriated J96 dependent COX-2 expression in 5637 cells, providing insight into the function of UPEC invasion in bladder epithelial cells. PMID- 21790939 TI - Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice. AB - Defence mechanisms against intracellular bacterial pathogens are incompletely understood. Our study characterizes a type I IFN-dependent cell-autonomous defence pathway directed against Legionella pneumophila, an intracellular model organism and frequent cause of pneumonia. We show that macrophages infected with L. pneumophila produced IFNbeta in a STING- and IRF3- dependent manner. Paracrine type I IFNs stimulated upregulation of IFN-stimulated genes and a cell-autonomous defence pathway acting on replicating and non-replicating Legionella within their specialized vacuole. Our infection experiments in mice lacking receptors for type I and/or II IFNs show that type I IFNs contribute to expression of IFN-stimulated genes and to bacterial clearance as well as resistance in L. pneumophila pneumonia in addition to type II IFN. Overall, our study shows that paracrine type I IFNs mediate defence against L. pneumophila, and demonstrates a protective role of type I IFNs in in vivo infections with intracellular bacteria. PMID- 21790946 TI - Class II enveloped viruses. AB - A number of viruses transport their genomic material from cell to cell enclosed within a lipid bilayer that is in turn encased within a symmetric protein shell. This review focuses in a group of RNA viruses that have this type of virions. This group includes several of important human pathogenic viruses, such as the hepatitis C virus, dengue virus, chikungunya virus, rubella virus and the bunyaviruses. The best studied are the flaviviruses and the alphaviruses, which have a beta-sheet rich class II viral fusion protein used for entry into susceptible cells. We extend here the class II concept to encompass symmetric viruses in which the envelope proteins are derived from a precursor polyprotein containing two transmembrane glycoproteins arranged in tandem. The first glycoprotein acts as chaperone for the folding of the second one, which carries the membrane fusion function. Since the bunyaviruses, included here, are very similar to the class I arenaviruses in other respects, this analysis highlights the patchwork nature of the various viral functional modules acting at different stages of the virus cycle, which appear assembled from genes of different origins. PMID- 21790942 TI - Innate immune control of West Nile virus infection. AB - West Nile virus (WNV), from the Flaviviridae family, is a re-emerging zoonotic pathogen of medical importance. In humans, WNV infection may cause life threatening meningoencephalitis or long-term neurologic sequelae. WNV is transmitted by Culex spp. mosquitoes and both the arthropod vector and the mammalian host are equipped with antiviral innate immune mechanisms sharing a common phylogeny. As far as the current evidence is able to demonstrate, mosquitoes primarily rely on RNA interference, Toll, Imd and JAK-STAT signalling pathways for limiting viral infection, while mammals are provided with these and other more complex antiviral mechanisms involving antiviral effectors, inflammatory mediators, and cellular responses triggered by highly specialized pathogen detection mechanisms that often resemble their invertebrate ancestry. This mini-review summarizes our current understanding of how the innate immune systems of the vector and the mammalian host react to WNV infection and shape its pathogenesis. PMID- 21790945 TI - Critical role for a stage-specific actin in male exflagellation of the malaria parasite. AB - Male gametogenesis occurs directly after uptake of malaria parasites by the mosquito vector and leads to the release of eight nucleated flagellar gametes. Here, we report that one of the two parasite actin isoforms, named actin II, is essential for this process. Disruption of actin II in Plasmodium berghei resulted in viable asexual blood stages, but male gametogenesis was specifically inhibited. Upon activation, male gametocyte DNA was replicated normally and axonemes assembled, but egress from the host cell was inhibited, and axoneme motility abolished. The major actin isoform, actin I, displayed dual localization to the cytoplasm and the nucleus in male gametocytes. After activation actin I was found to be restricted to the cytoplasm. In actII(-) mutant parasites, this re-localization was abolished and actin I remained in both cellular compartments. These findings reveal vital and pleiotropic functions for the actin II isoform in male gametogenesis of the malaria parasite. PMID- 21790944 TI - Bacterial subversion of host actin dynamics at the plasma membrane. AB - Invasion of non-phagocytic cells by a number of bacterial pathogens involves the subversion of the actin cytoskeletal remodelling machinery to produce actin-rich cell surface projections designed to engulf the bacteria. The signalling that occurs to induce these actin-rich structures has considerable overlap among a diverse group of bacteria. The molecular organization within these structures act in concert to internalize the invading pathogen. This dynamic process could be subdivided into three acts - actin recruitment, engulfment, and finally, actin disassembly/internalization. This review will present the current state of knowledge of the molecular processes involved in each stage of bacterial invasion, and provide a perspective that highlights the temporal and spatial control of actin remodelling that occurs during bacterial invasion. PMID- 21790949 TI - Delayed plumage maturation and delayed reproductive investment in birds. AB - Delayed plumage maturation is the delayed acquisition of a definitive colour and pattern of plumage until after the first potential breeding period in birds. Here we provide a comprehensive overview of the numerous studies of delayed plumage maturation and a revised theoretical framework for understanding the function of delayed plumage maturation in all birds. We first distinguish between hypotheses that delayed plumage maturation is attributable to a moult constraint with no adaptive function and hypotheses that propose that delayed plumage maturation is a component of an adaptive life-history strategy associated with delayed reproductive investment. We then recognize three potential benefits of delayed plumage maturation: crypsis, mimicry and status signaling. Evidence suggests that delayed plumage maturation is not a consequence of developmental constraints and instead represents a strategy to maximize reproductive success in circumstances where young adults cannot effectively compete with older adults for limited resources, particularly breeding opportunities. A multi-factorial explanation that takes into account lifespan and the degree of competition for limited breeding resources and that combines the benefits of an inconspicuous appearance with the benefits of honest signaling of reduced competitiveness provides a general explanation for the function of delayed plumage maturation in most bird species. Delayed plumage maturation should be viewed as a component of alternative reproductive strategies that can include delay in both plumage and sexual development. Such strategies are frequently facultative, with individuals breeding prior to the acquisition of definitive plumages when conditions are favourable. Presumably, the benefits of delayed plumage maturation ultimately enhance lifetime reproductive success, and studying delayed plumage maturation within the context of lifetime reproductive success should be a goal of future studies. PMID- 21790947 TI - Double anchorage to the membrane and intact inter-chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons. AB - Tetanus and botulinum neurotoxins are di-chain proteins that cause paralysis by inhibiting neuroexocytosis. These neurotoxins enter into nerve terminals via endocytosis inside synaptic vesicles, whose acidic pH induces a structural change of the neurotoxin molecule that becomes capable of translocating its L chain into the cytosol, via a transmembrane protein-conducting channel made by the H chain. This is the least understood step of the intoxication process primarily because it takes place inside vesicles within the cytosol. In the present study, we describe how this passage was made accessible to investigation by making it to occur at the surface of neurons. The neurotoxin, bound to the plasma membrane in the cold, was exposed to a warm low pH extracellular medium and the entry of the L chain was monitored by measuring its specific metalloprotease activity with a ratiometric method. We found that the neurotoxin has to be bound to the membrane via at least two anchorage sites in order for a productive low-pH induced structural change to take place. In addition, this process can only occur if the single inter-chain disulfide bond is intact. The pH dependence of the conformational change of tetanus neurotoxin and botulinum neurotoxin B, C and D is similar and take places in the same slightly acidic range, which comprises that present inside synaptic vesicles. Based on these and previous findings, we propose a stepwise sequence of molecular events that lead from toxin binding to membrane insertion. PMID- 21790950 TI - Pregnancy incidence and outcome among patients with cervical intraepithelial neoplasia: a retrospective cohort study. AB - OBJECTIVE: To investigate the effect of cervical intraepithelial neoplasia (CIN) treatment on incidence of pregnancy and pregnancy outcome. DESIGN: Retrospective cohort study. SETTING: Helsinki University Central Hospital, Finland, the sole reference centre in the Helsinki-Uusimaa region for women referred for colposcopy. POPULATION: A cohort of 6179 women treated for CIN between 1974 and 2001, and a randomly selected, age- and municipality-matched, reference population of 30,436 women. METHODS: Based on nationwide registers, all women were followed-up for pregnancy outcomes until death, emigration, sterilization, or until the end of 2004. MAIN OUTCOME MEASURES: Incidence of any pregnancy, livebirths, miscarriages, extrauterine pregnancies, molar pregnancies, and terminations of pregnancies (TOPs) before and after CIN treatment, estimated by calculating hazard ratios (HRs) with stratified Cox regression and Poisson regression. RESULTS: After CIN treatment, both incidence of pregnancy (HR 1.20; 95% CI 1.15-1.26; P < 0.001) and incidence of livebirths (HR 1.12; 95% CI 1.06 1.18; P < 0.001) were higher among the treated women than among the reference population. Before treatment, only incidence of pregnancy had been elevated among those treated (HR 1.06; 95% CI 1.04-1.09; P < 0.001). The incidence of extrauterine pregnancies and of TOPs was significantly elevated among those treated both before and after CIN treatment. CONCLUSIONS: No clear evidence emerged of adverse effects resulting from the CIN treatment itself, because the women treated had more pregnancies and more children than their reference population. TOPs and extrauterine pregnancies were more common among the treated women already before the CIN treatment. PMID- 21790951 TI - Birth outcomes following treatment for precancerous changes to the cervix: a population-based record linkage study. AB - OBJECTIVE: To examine whether treatments for precancerous changes to the cervix are associated with adverse birth outcomes in subsequent pregnancies. DESIGN: Population-based retrospective cohort study using electronic linkage of data from the Welsh cervical screening programme and a national routine child health database. SETTING: Wales. POPULATION: A total of 174,325 women aged 20-39 years who received cervical screening between April 2001 and March 2004. METHODS: Logistic regression was used to compare the odds of each birth outcome between women who had negative cervical smears and women who received either colposcopy +/- punch biopsy only or colposcopy and excisional or ablative treatments, adjusted for confounding factors (e.g. age, social deprivation and smoking). MAIN OUTCOME MEASURES: Preterm birth (before 37, 32 and 28 weeks of gestation), and low birthweight (<2500 g). RESULTS: Compared with women who had negative cervical smears, the odds ratio for preterm birth (<37 weeks) was significantly increased in women who had colposcopy only (adjusted odds ratio 1.54, 95% CI 1.32-1.80) and single excisional treatment (adjusted odds ratio 1.77, 95% CI 1.47-2.13). Similar results were observed for preterm birth at <32 weeks of gestation. There was no increased risk of preterm birth or low birthweight for women who had treatment compared with women who had colposcopy only. CONCLUSION: Women who were referred for colposcopy had an increased risk of preterm births regardless of whether or not they received treatment to the cervix. This increased risk could be the result of common risk factors for abnormal smears and preterm birth. PMID- 21790952 TI - The measurement properties of the menorrhagia multi-attribute quality-of-life scale: a psychometric analysis. AB - Menorrhagia, or heavy menstrual bleeding (HMB), is a common gynaecological condition. As the aim of treatment is to improve women's wellbeing and quality of life (QoL), it is necessary to have effective ways to measure this. This study investigated the reliability and validity of the menorrhagia multi-attribute scale (MMAS), a menorrhagia-specific QoL instrument. Participants (n = 431) completed the MMAS and a battery of other tests as part of the baseline assessment of the ECLIPSE (Effectiveness and Cost-effectiveness of Levonorgestrel containing Intrauterine system in Primary care against Standard trEatment for menorrhagia) trial. Analyses of their responses suggest that the MMAS has good measurement properties and is therefore an appropriate condition-specific instrument to measure the outcome of treatment for HMB. PMID- 21790954 TI - In vitro myometrial contractility reflects indication for caesarean section. AB - OBJECTIVE: To assess the extent to which in vitro measurements of myometrial contractility reflect the clinical indication for caesarean section. DESIGN: A prospective, observational hypothesis-generating study. SETTING: Women were recruited from Liverpool Women's NHS Foundation Trust and experiments were performed in the Physiology Department at the University of Liverpool. POPULATION: Myometrial samples were taken from women undergoing a caesarean section during labour (n = 50) or from women having a repeat nonlabouring caesarean section (n = 70). METHODS: The demographic characteristics of the women and indications for current and previous caesarean sections were recorded. The force, frequency and duration of spontaneous contractions of myometrial strips, and changes in the intracellular calcium concentration of the strips, were measured. Kruskall-Wallis and post hoc tests were used to assess the significance of differences between groups. RESULTS: Samples from women whose caesarean section was for fetal distress/acidosis (scalp pH <7.2) contracted with more force than those from women whose caesarean section was for delay in the first stage of labour (P < 0.001). For repeat, nonlabouring caesarean sections, samples from women whose first caesarean section was for fetal distress/acidosis also contracted with more force than did samples from women whose first caesarean section was for delay in the first stage of labour (P = 0.03). CONCLUSIONS: These findings suggest that the myometrium contracts with greater force in women who have a caesarean section for fetal distress. PMID- 21790959 TI - Visual bioethics. PMID- 21790955 TI - Shift work and pregnancy outcomes: a systematic review with meta-analysis of currently available epidemiological studies. AB - BACKGROUND: Varying work schedules are suspected of increasing risks to pregnant women and to fetal wellbeing. In particular, maternal hormonal disturbance arising from sleep deprivation or circadian rhythm disruption might impair fetal growth or lead to complications of pregnancy. Two independent meta-analyses (from 2000 to 2007) reported a small adverse effect of shift work on the risk of preterm delivery (PTD). However, these reviews were based on few high-quality studies. OBJECTIVES: To provide an updated review of the associations of shift work with PTD, low birthweight (LBW), small-for-gestational-age (SGA) infants and pre-eclampsia. SEARCH STRATEGY AND SELECTION CRITERIA: We conducted a systematic search of MEDLINE using combinations of keywords and MeSH terms. DATA COLLECTION AND ANALYSIS: For each relevant paper we abstracted standard details, used to summarise design features and rate methodological quality. We calculated pooled estimates of relative risk (RR) in random-effect meta-analyses. MAIN RESULTS: We retrieved 23 relevant studies. The pooled estimate of RR for PTD was 1.16 (95% CI 1.00-1.33, 16 studies), but when five reports of poorer methodological quality were excluded, the estimated RR decreased to 1.03 (95% CI 0.93-1.14). We also observed increased RRs for LBW (RR 1.27, 95% CI 0.93-1.74) and for SGA (RR 1.12, 95% CI 1.03-1.22), which varied little by study quality. Little evidence was found on pre-eclampsia. CONCLUSIONS: These findings suggest that overall, any risk of PTD, LBW, or SGA arising from shift work in pregnancy is small. PMID- 21790956 TI - Fetal growth and birthweight standards as screening tools: methods for evaluating performance. AB - OBJECTIVE: To discuss different methods for evaluating fetal growth and population-based birthweight standards relevant to different uses: either in antenatal care or in epidemiology. DESIGN: Population-based cohort study. SETTING: Routinely collected data in Scotland. POPULATION: A total of 540,849 singletons born after 24 weeks between 1980 and 2003. METHODS: The performance of a fetal growth standard and a population-based birthweight standard are compared in two ways. First, we consider the accuracy of estimated risks of stillbirth at any point during the remaining pregnancy, a measure that is relevant in antenatal care. Second, the rates of stillbirth at each gestation, which are measures relevant in epidemiology, are compared with the actual rates. MAIN OUTCOME MEASURES: Standard measures of screening and diagnostic performance: sensitivity, specificity, and positive and negative predictive values. RESULTS: In clinical care, the evidence points towards using fetal growth standards: sensitivity at term is about 30%, increasing to 43% for preterm births (24-31 weeks of gestation), compared with about 29% across all ages under the birthweight standard. Positive predictive values are about 1% across gestations. For epidemiology, the evidence is not so clear-cut: preterm, the population birthweight standard has higher sensitivity and specificity, but this is not the case in the full-term weeks. CONCLUSIONS: The performance of fetal growth and birthweight standards should be evaluated in different ways, depending on whether they are intended for use in antenatal care or in epidemiological investigations. PMID- 21790960 TI - International service learning programs: ethical issues and recommendations. AB - Inequities in global health are increasingly of interest to health care providers in developed countries. In response, many academic healthcare programs have begun to offer international service learning programs. Participants in these programs are motivated by ethical principles, but this type of work presents significant ethical challenges, and no formalized ethical guidelines for these activities exist. In this paper the ethical issues presented by international service learning programs are described and recommendations are made for how academic healthcare programs can carry out international service learning programs in a way that minimizes ethical conflicts and maximizes benefits for all stakeholders. Issues related to project sustainability and community involvement are emphasized. PMID- 21790953 TI - Metastatic choriocarcinoma presenting and treated during viable pregnancy: a case report. PMID- 21790961 TI - Costa Rica's 'White legend': how racial narratives undermine its health care system. AB - A dominant cultural narrative within Costa Rica describes Costa Ricans not only as different from their Central American neighbours, but it also exalts them as better: specifically, as more white, peaceful, egalitarian and democratic. This notion of Costa Rican exceptionalism played a key role in the creation of their health care system, which is based on the four core principles of equity, universality, solidarity and obligation. While the political justification and design of the current health care system does, in part, realize this ideal, we argue that the narrative of Costa Rican exceptionalism prevents the full actualization of these principles by marginalizing and excluding disadvantaged groups, especially indigenous and black citizens and the substantial Nicaraguan minority. We offer three suggestions to mitigate the self-undermining effects of the dominant national narrative: 1) encouragement and development of counternarratives; 2) support of an emerging field of Costa Rican bioethics; and 3) decoupling health and national successes. PMID- 21790958 TI - The contribution of psychiatric illness on perinatal outcomes. PMID- 21790962 TI - What's wrong with the brain drain (?). AB - One of the characteristics of the relationship between the developed and developing worlds is the 'brain drain'- the phenomenon by which expertise moves towards richer countries, thereby condemning poorer countries to continued comparative and absolute poverty. It is tempting to see the phenomenon as a moral problem in its own right, such that there is a moral imperative to end it, that is separate from (and additional to) any moral imperative to relieve the burden of poverty. However, it is not clear why this should be so - why, that is, there is a moral reason to stem the flow of expertise in addition to seeking to improve welfare. In this paper, I examine three explanations of the putative moral aspect of the brain drain. PMID- 21790957 TI - Post-traumatic stress disorder, child abuse history, birthweight and gestational age: a prospective cohort study. AB - OBJECTIVE: To determine the extent to which prenatal post-traumatic stress disorder (PTSD) is associated with lower birthweight and shorter gestation, and to explore the effects of childhood maltreatment as the antecedent trauma exposure. DESIGN: Prospective three-cohort study. SETTING: Ann Arbor and Detroit, Michigan, United States. SAMPLE: In all, 839 diverse nulliparas in PTSD-positive (n = 255), trauma-exposed, resilient (n = 307) and non-exposed to trauma (n = 277) cohorts. METHODS: Standardised telephone interview before 28 weeks of gestation to ascertain trauma history, PTSD, depression, substance use, mental health treatment history and sociodemographics, with chart abstraction to obtain chronic condition history, antepartum complications and prenatal care data, as well as outcomes. MAIN OUTCOME MEASURES: Infant birthweight and gestational age per delivery record. RESULTS: Infants born to women with PTSD during pregnancy had a mean birthweight 283 g less than infants of trauma-exposed, resilient women and 221 g less than infants of non-exposed women (F(3,835) = 5.4, P = 0.001). PTSD was also associated with shorter gestation in multivariate models that took childhood abuse history into account. Stratified models indicated that PTSD subsequent to child abuse trauma exposure was most strongly associated with adverse outcomes. PTSD was a stronger predictor than African American race of shorter gestation and a nearly equal predictor of birthweight. Prenatal care was not associated with better outcomes among women abused in childhood. CONCLUSIONS: Abuse-related PTSD may be an additional or alternative explanation for adverse perinatal outcomes associated with low socio-economic status and African American race in the USA. Biological and interventions research is warranted along with replication studies in other nations. PMID- 21790963 TI - HIV testing of pregnant women: an ethical analysis. AB - Recent global advances in available technology to prevent mother-to-child HIV transmission necessitate a rethinking of contemporary and previous ethical debates on HIV testing as a means to preventing vertical transmission. In this paper, we will provide an ethical analysis of HIV-testing strategies of pregnant women. First, we argue that provider-initiated opt-out HIV testing seems to be the most effective HIV test strategy. The flip-side of an opt-out strategy is that it may end up as involuntary testing in a clinical setting. We analyse this ethical puzzle from a novel perspective, taking into account the moral importance of certain hypothetical preferences of the child, as well as the moral importance of certain actual preferences of the mother. Finally, we balance the conflicting concerns and try to arrive at an ethically sound solution to this dilemma. Our aim is to introduce a novel perspective from which to analyse testing strategies, and to explore the implications and possible benefits of our proposal. The conclusion from our analysis is that policies that recommend provider-initiated opt-out HIV testing of pregnant mothers, with a risk of becoming involuntary testing in a clinical setting, are acceptable. The rationale behind this is that the increased availability of very effective and inexpensive life-saving drugs makes the ethical problems raised by the possible intrusiveness of HIV testing less important than the child's hypothetical preferences to be born healthy. Health care providers, therefore, have a duty to offer both opt-out HIV testing and available PMTCT (preventing mother-to-child transmission) interventions. PMID- 21790964 TI - Congestive Heart Failure special issue on advanced heart failure. PMID- 21790967 TI - Cognitive impairment in patients with advanced heart failure and its implications on decision-making capacity. AB - Cognitive impairment (CI) is a multifaceted entity that entails more than just memory loss. Deficits in other domains, most importantly executive function, can have profound effects on health outcomes in afflicted patients. The prevalence of CI among the heart failure population is exceedingly high, and even higher so among patients with advanced heart failure (AHF). These patients display consistent declines in memory, attention, psychomotor abilities, and executive function. Such deficits interfere with patients' abilities to recognize worsening symptoms, adhere to complex medication regimens, and make sound decisions pertaining to medical care. Regular evaluation of cognitive status using instruments such as the Montreal Cognitive Assessment is a fast, reliable method that allows physicians who treat patients with AHF to anticipate these obstacles to treatment and act accordingly. Referral for more comprehensive neuropsychological evaluation should be considered for patients with unexplained declines from baseline, legal determination of competence, and for heart transplant or ventricular assist device placement candidates. PMID- 21790966 TI - Biomarkers in advanced heart failure: diagnostic and therapeutic insights. AB - Publications regarding the potential clinical utility of biomarker testing in the management of heart failure have been exponentially increasing over the last decade. The majority of non-cardiac biomarkers are commonly used to identify end organ dysfunction or comorbidities. The diagnostic utility of natriuretic peptide testing has been well-established. Despite consistently demonstrating their prognostic values and some promising initial results, treatment guided by natriuretic peptide testing is still debated. Although cardiac troponins have been extensively used in diagnosis of myocardial injury, their primary use of biomarkers in advanced heart failure is prognostication and risk stratification. Congest Heart Fail. Congest Heart Fail. 2011;17:169-174. (c) 2011 Wiley Periodicals, Inc. PMID- 21790968 TI - Renal function in advanced heart failure. AB - Despite recent advances with neurohormonal antagonists and devices, the prognosis of patients with advanced heart failure (HF) remains grave. Renal dysfunction is a common comorbid condition in HF and is associated with adverse outcomes. Current evidence indicates that intrinsic renal disease and inflammation in HF makes the kidney susceptible to hemodynamic compromise and congestion and contributes to a great extent to the development of renal dysfunction. Relief of congestion requires combination treatment with diuretics, neurohormonal antagonists, and occasionally vasodilators as well as inotropes. However, high doses of diuretics may accelerate the development of renal dysfunction by increasing neurohumoral activity and inducing renal structural and functional changes. Ultrafiltration should be reserved for patients with true diuretic resistance. Finally, early identification of the "patient at risk" remains a challenging issue and is limited by the currently used conventional parameters of renal function. However, novel biomarkers of acute kidney ischemia and/or injury are emerging and promise to become a diagnostic option for this patient population. PMID- 21790976 TI - Management of a 9-year-old boy experiencing severe dental injury--a 21-year follow-up of three autotransplants: a case report. AB - The replacement of missing anterior teeth is a particular challenge in children and adolescents. This report describes the management of a 9-year-old boy suffering a severe dental injury. The treatment included three autotransplantations and orthodontic space closure to replace four maxillary teeth. A follow-up period of 21 years demonstrated a successful outcome. Autotransplantation of premolars in growing individuals is a predictable method for replacement of missing teeth and for re-establishment of the alveolar process after traumatic bone loss. This case report shows that a multidisciplinary approach is essential for the management and outcome of severe dental injuries in children. PMID- 21790970 TI - Nutritional assessment in heart failure patients. AB - Heart failure (HF) is a growing epidemic worldwide with a particularly large presence in the United States. Nutritional assessment and supplementation is an area that can be studied to potentially improve the outcomes of these chronically ill patients. There have been many studies reporting the effect of various nutrients on HF patients, often with mixed results. Amino acids such as taurine, which is involved in calcium exchange, has been reported to improve heart function. Coenzyme Q10, a key component in the electron transport chain, is vital for energy production. l-carnitine, an amino acid derivative, is responsible for transport of fatty acids into the mitochondria along with modulating glucose metabolism. Thiamine and the other B vitamins, which serve as vital cofactors, can often be deficient in HF patients. Omega-3 fatty acid supplementation has been demonstrated to benefit HF patients potentially through anti-arrhythmic and anti-inflammatory mechanisms. Vitamin D supplementation can potentially benefit HF patients by way of modulating the renin-angiotensin system, smooth muscle proliferation, inflammation, and calcium homeostasis. Although supplementation of all of the above nutrients has the potential to benefit patients with HF, more studies are needed to solidify these recommendations. PMID- 21790974 TI - Characteristics of avulsed permanent teeth treated at Beijing Stomatological Hospital. AB - Prevention of dental injury is considered to be more important than its treatment. A study was established to reduce the prevalence and the complications of tooth avulsion. AIM: The aim of this study was to investigate the characteristics of tooth avulsion of permanent teeth among patients that visited the Emergency Department of Beijing Stomatological Hospital in China. MATERIALS AND METHODS: A retrospective analysis was performed of the dental records of 88 patients with 120 avulsed permanent teeth between 7 and 75 years old who had attended the Emergency Department of Beijing Stomatological Hospital in China during the period 1 July 2008 until 30 June 2009. RESULTS: In 88 examined patients, the number of avulsed permanent teeth was 120. In 63 (71.6%) patients, in total 85 avulsed teeth were treated with replantation. In 18 (28.6%) patients, the avulsed teeth were stored in dry media. In only eight cases (12.7%), the avulsed teeth were replanted within 30 min. In approximately half of the cases (49.2%), the replanted teeth were fixed with stainless steel splint and a composite resin. CONCLUSIONS: It was evident from this study that there were delayed tooth replantations in many tooth avulsion cases. Thus, educational programs should be conducted to create awareness about the importance of immediate replantation, which will entail better prognosis of traumatic avulsed permanent tooth. PMID- 21790971 TI - Cardiac shock wave therapy: assessment of safety and new insights into mechanisms of tissue regeneration. AB - Although low-energy extracorporeal cardiac shock wave (ECSW) therapy represents an attractive non-invasive treatment option for ischaemic heart disease, the precise mechanisms of its action and influence on the cardiac tissue remain obscure. The goal of this study was to evaluate the effects of SW application on cardiac function and structure. Four-month-old Fisher 344 rats were subjected to ECSW therapy. Echocardiographic measurements of cardiac function were performed at baseline and at 1 and 3 months after treatment. Signs of inflammation, apoptosis and fibrosis were evaluated by immunohistochemistry in the control and treated hearts. ECSW application did not provoke arrhythmia or increase the troponin-I level. At all time points, the left ventricular ejection fraction and fractional shortening remained stable. Histological analysis revealed neither differences in the extracellular matrix collagen content nor the presence of fibrosis; similarly, there were no signs of inflammation. Moreover, a population of cardiac cells that responded eagerly to ECSW application in the adult heart was identified; c-kit-positive, Ki67-positive, orthochromatic cells, corresponding to cardiac primitive cells, were 2.65-fold more numerous in the treated myocardium. In conclusion, non-invasive ECSW therapy is a safe and effective way of activating cardiac stem cells and myocardial regeneration. Because many factors influence cellular turnover in the ischaemic myocardium during the course of ischaemic heart disease, cardiac remodelling, and heart failure progression, studies to identify the optimal treatment time are warranted. PMID- 21790965 TI - Who has advanced heart failure?: definition and epidemiology. AB - Summarizing current guidelines and advanced heart failure (AHF) clinical trials/registries, this review focuses on the current definition of AHF and emphasizes the secular trends in this definition over the last two decades. Further, clinical, imaging, hemodynamic, functional capacity and biomarker parameters that may aid clinicians to better recognize patients with AHF are reviewed. Finally, we review the limited data concerning the epidemiology of AHF which to date has been poorly characterized. PMID- 21790977 TI - [Comment on the article "HPV73 and HPV82 positive anal carcinoma with secondary ulcerating herpes simplex type 2 infection" (Kreuter, Potthoff, Brockmeyer, Stuckland, KompNet HIV/AIDS)]. PMID- 21790972 TI - Activators and inhibitors of the plasminogen system in Alzheimer's disease. AB - Accumulation and deposition of Abeta is one of the main neuropathological hallmarks of Alzheimer's disease (AD) and impaired Abeta degradation may be one mechanism of accumulation. Plasmin is the key protease of the plasminogen system and can cleave Abeta. Plasmin is activated from plasminogen by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The activators are regulated by inhibitors which include plasminogen activator inhibitor-1 (PAI 1) and neuroserpin. Plasmin is also regulated by inhibitors including alpha2 antiplasmin and alpha2-macroglobulin. Here, we investigate the mRNA levels of the activators and inhibitors of the plasminogen system and the protein levels of tPA, neuroserpin and alpha2-antiplasmin in post-mortem AD and control brain tissue. Distribution of the activators and inhibitors in human brain sections was assessed by immunoperoxidase staining. mRNA measurements were made in 20 AD and 20 control brains by real-time PCR. In an expanded cohort of 38 AD and 38 control brains tPA, neuroserpin and alpha2-antiplasmin protein levels were measured by ELISA. The activators and inhibitors were present mainly in neurons and alpha2 antiplasmin was also associated with Abeta plaques in AD brain tissue. tPA, uPA, PAI-1 and alpha2-antiplasmin mRNA were all significantly increased in AD compared to controls, as were tPA and alpha2-antiplasmin protein, whereas neuroserpin mRNA and protein were significantly reduced. alpha2-macroglobulin mRNA was not significantly altered in AD. The increases in tPA, uPA, PAI-1 and alpha2 antiplasmin may counteract each other so that plasmin activity is not significantly altered in AD, but increased tPA may also affect synaptic plasticity, excitotoxic neuronal death and apoptosis. PMID- 21790969 TI - Pulmonary hypertension and right ventricular function in advanced heart failure. AB - Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequently encountered in patients with advanced heart failure (HF). Both conditions aggravate prognosis and influence clinical decisions. Echocardiography is the screening tool of choice for pulmonary pressures and RV function, although invasive assessment of PH is necessary when advanced therapies are considered. Reversibility of PH in response to short-term pharmacologic treatment or even to long-term unloading after left ventricular assist device (LVAD) implantation is a favorable prognostic sign for both medically treated patients and heart transplant candidates. Although patients with severe PH secondary to HF have not derived benefit from pulmonary arterial hypertension therapies thus far, agents that modulate the cyclic guanosine monophosphate pathway, including phosphodiesterase 5A inhibitors, hold promise and are being actively investigated in advanced HF. Therapies that lead to reduction in left-sided pressures, including cardiac resynchronization and LVAD placement, also have a favorable effect on pulmonary pressures and RV function. However, no specific medical treatment for RV dysfunction exists to date, highlighting an important gap in the management of patients with advanced HF. PMID- 21790984 TI - [Papules, plaques and nodules on hands and elbow]. PMID- 21790981 TI - In vivo monitoring of epidermal absorption of hazardous substances by confocal Raman micro-spectroscopy. AB - BACKGROUND: Presently, percutaneous absorption of potentially hazardous chemicals in humans can only be assessed in animal experiments, in vitro, or predicted mathematically. Our aim was to demonstrate the proof-of-principle of a novel quantitative in vivo assay for percutaneous absorption: confocal Raman micro spectroscopy (CRS). The advantages and limitations of CRS for health risk assessments are discussed. PATIENTS AND METHODS: 2-butoxyethanol, toluene, and pyrene were applied in pure form, diluted in water, or in ethanol on the skin of three healthy volunteers. CRS measurements were done following application for 15 min and 3 hours. The concentrations of the three substances as a function of distance to the skin surface were calculated and further analyzed with regard to mass transport into the stratum corneum (MUg/cm(2)) and the flux through the stratum corneum (MUg/cm(2)h). The results were compared with the available data from literature. RESULTS: Considering the preliminary nature of these data, good accordance with data from the literature was observed. In addition, we observed that 2-butoxyethanol penetrates markedly faster when dissolved in water as compared to ethanol. This observation is also in agreement with previous results. CONCLUSIONS: CRS has the potential to provide fast, accurate and reliable results for advanced studies of in vivo percutaneous absorption kinetics of hazardous substances in human skin. This will require further research with other substances and under differing conditions. PMID- 21790975 TI - Non-accidental collision followed by dental trauma: associated factors. AB - The aim of the present cross-sectional survey was to assess factors associated with non-accidental collision followed by dental trauma among adolescents in the city of Diamantina, Brazil. A total of 387 students from 12 to 15 years of age (mean = 14 SD = 0.9) were randomly selected. The study was carried out in two stages. Firstly, data were collected through dental examinations of permanent incisors. Secondly, a thorough interview was held with 85 adolescents who exhibited dental trauma in the dental examinations. The interview consisted of a detailed description of the incident and physical environment in which it occurred. Descriptive analysis and the chi-square test (P < 0.05) were performed. The prevalence of dental injury was 22% (n = 85). Dental trauma was more prevalent in boys (P = 0.001) and individuals with overjet >3 mm (P = 0.007) and inadequate lip coverage (P = 0.013). Analysis of the event revealed that 22.3% of the cases of dental trauma occurred because of non-accidental collision. Non accidental collision followed by injury occurred mainly at school (P < 0.001) and in an environment with a concrete, tiled or ceramic floor (P = 0.001). No statistically significant associations were found between non-accidental collision and gender, age or mother's schooling. It was concluded that the non accidental collisions happened especially at school and in indoor environments with a concrete, tiled or ceramic floor. PMID- 21790987 TI - Influence of wire extension and type on splint rigidity--evaluation by a dynamic and a static measuring method. AB - OBJECTIVES: To evaluate the influence of wire dimension and wire length on the splint rigidity of wire-composite splints in vitro. MATERIALS AND METHODS: A custom-made artificial model was used. The central incisors simulated 'injured' teeth with increased mobility, and the lateral incisors and canines served as 'uninjured' teeth with physiological mobility. To assess horizontal and vertical tooth mobility before and after splinting, the Periotest and Zwick methods were applied. Teeth 13-23 were splinted using wire-composite splint 1 (WCS1; Dentaflex 0.45 mm) and wire-composite splint 2 (WCS2; Strengtheners 0.8 * 1.8 mm). Splint length was varied by successively shortening the wire. The influence of wire dimension was tested using t-test and Wilcoxon-Mann-Whitney test with the Bonferroni-Holm procedure (alpha = 0.05). To test the influence of wire length, anova and Kruskal-Wallis tests as well as Tukey range and Wilcoxon test with Bonferroni-Holm procedure were applied (alpha = 0.05). RESULTS: Wire dimension significantly influenced splint rigidity (P < 0.05). The wire length significantly influenced the splint rigidity of WCS1 in the horizontal dimension and WCS2 in the horizontal and vertical dimensions (P < 0.05). Splint rigidity was significantly reduced when splinting only 'injured' teeth compared with splints including 'uninjured' adjacent teeth (P < 0.05). No differences were found between splints including one or two 'uninjured' teeth on each side (P > 0.05). CONCLUSION: WCS1 is flexible compared with the more rigid WCS2. The wire length influences the rigidity. To ensure adequate fixation and reduce the risk of enamel damage during splint removal, the splint should include only one 'uninjured' tooth bilaterally. PMID- 21790989 TI - 3-D imaging in post-traumatic malformation and eruptive disturbance in permanent incisors: a case report. AB - Injury to the primary dentition is one of the common problems of childhood. Disturbances during crown development of the permanent teeth result in morphologic alterations. This case report highlights the role of 3-D imaging when conventional dental radiographs are not enough to answer our clinical questions regarding future eruptive disturbances. 3-D imaging can many times give us a definitive diagnosis and improve the treatment planning after early injuries in the deciduous dentition. The current status of multislice computed tomography (CT) and cone beam CT (CBCT) as diagnostic tools in pediatric dental population is also discussed briefly. PMID- 21790990 TI - Spontaneous re-eruption of a permanent maxillary central incisor after 15 years of ankylosis--a case report. AB - Intrusion injuries are considered among the most severe forms of dental trauma, potentially leading to ankylosis as a late consequence. In 1991, a 7-year-old boy suffered a traumatic intrusion leading to an infraposition of tooth 21 along with its immobility. Based on the clinical findings, including bright-sounding percussion testing, disappearance of the periodontal space and a failed attempt at orthodontic movement, a diagnosis of ankylosis was made. Following prosthetic restoration of the infrapositioned tooth, spontaneous re-eruption occurred 15 years later. With the help of a partial multibracket appliance, the tooth could be adjusted to occlusal level and was then restored to the patient's satisfaction. Radiographically, it was demonstrated that extrusion of the tooth had been accompanied by a significant gain in local alveolar bone volume. While a wait-and-see strategy cannot be recommended as a treatment option following ankylosis, considering that spontaneous re-eruption after several years is an extremely rare finding, elucidating the mechanisms at work in spontaneous re eruption at a cellular level might create an opportunity for iatrogenic triggering of re-eruption, thus paving the way to new forms of therapy. PMID- 21790986 TI - Rigidity evaluation of quartz-fiber splints compared with wire-composite splints. AB - AIM: To evaluate the influence of reinforcement material on in vitro dental splint rigidity. MATERIALS AND METHODS: A custom-made artificial model was used. The central incisors simulated 'injured' teeth with increased mobility, and the lateral incisors served as 'uninjured' teeth with physiologic mobility. The Periotest and Zwick methods were used to assess horizontal and vertical tooth mobility before and after splinting, and relative splint effect (SpErel) was calculated. Teeth 12-22 were splinted using two wire-composite splints (WCS), WCS1 (Dentaflex 0.45mm), and WCS2 (Strengtheners 0.8*1.8mm) as well as four quartz-fiber splints, QS1 (Quartz Splint UD 1.5mm), QS2 (Quartz Splint Rope 1.5mm), QS3 (Quartz Splint Woven 2.5mm), and QS4 (dry fibers 667 tex). The influence of the splint type was evaluated using anova, Tukey range, and the Dunnett-T3 test (alpha=0.05). To test the influence of initial tooth mobility, the t-test was applied (alpha=0.05). RESULTS: Reinforcement materials significantly influenced splint rigidity (P<0.05). The horizontal and vertical SpErel of WCS1 compared with WCS2 and QFSs1-4 was statistically significant (P<0.05). Significant differences were found when comparing the horizontal SpErel of WCS2 with WCS1 and QSs1-4 (P<0.05). SpErels of the 'injured' and 'uninjured' teeth showed significant differences (P<0.05). CONCLUSION: WCS1 is flexible compared with the more rigid WCS2 and QSs1-4. Initial tooth mobility influences SpErel. The flexible WCS1 can be recommended for splinting dislocation injuries whereas the semi-rigid/rigid WCS2 and QS1-4 can be used for horizontal root fractures and alveolar process fractures. The QS1-4 provide good esthetic outcome. PMID- 21790988 TI - In vitro splint rigidity evaluation--comparison of a dynamic and a static measuring method. AB - OBJECTIVES: The aim of this in vitro study was to investigate a dynamic and static tooth mobility assessment method in terms of reproducibility and correlation. MATERIALS AND METHODS: A custom-made artificial model was used. The central incisors simulated 'injured' teeth with increased mobility, and the lateral incisors served as 'uninjured' teeth with physiological mobility. To assess tooth mobility, three consecutively repeated measurements were taken, in the vertical and horizontal dimensions before and after splinting, using the Periotest method as well as the Zwick universal testing machine. Reproducibility of the measurements was tested using anova and the Bonferroni post hoc test (alpha = 0.05). Correlation was analysed using Spearman's rank correlation (alpha = 0.05). RESULTS: No significant differences were found when comparing the three consecutively taken Periotest values and the vertical Zwick values (P > 0.05). In the horizontal dimension, the first Zwick values differed from the second and third values (P < 0.05). Only a few random correlations (P < 0.05) were found when comparing the two assessment methods. Horizontal and vertical measurements within one method did not correlate (P > 0.05). CONCLUSIONS: The Periotest and vertical Zwick values are highly reproducible. The measurements of the two methods do not correlate; therefore, a conversion of Periotest values into metric displacement data is not feasible. The two methods provide different valuable information about tooth mobility. The Periotest method describes the damping characteristics of the periodontal ligament while the Zwick method reveals quantitative metric values. PMID- 21790991 TI - Knowledge level of primary school teachers regarding traumatic dental injuries and their emergency management before and after receiving an informative leaflet. AB - AIM: The aim of this study was to evaluate via a questionnaire the knowledge level of primary school teachers in Ankara, Turkey, regarding dental trauma; to inform them on the subject through a leaflet; and to evaluate the effectiveness of the leaflet by reapplying the questionnaire. MATERIALS AND METHODS: A questionnaire was distributed to 500 teachers in seven randomly selected primary schools. The questionnaire consisted of four different scenarios presented with photographs and a total of eight questions on crown fracture, lateral luxation, root fracture, and avulsion. After responding to the questionnaire, teachers were given a leaflet containing information about traumatic dental injuries and their emergency management. After 1 month, the same questionnaire was distributed, and the responses collected. RESULTS: A total of 450 of 500 teachers responded to the questionnaire. Initial responses indicated the knowledge level of teachers to be quite low. Following the distribution of the information leaflet, the rate of correct answers increased for each of the individual questions, and the total scores for the questionnaire increased significantly (P = 0.0001). CONCLUSION: There is a clear need to inform teachers about traumatic dental injuries. The use of educational leaflets can be a successful and appropriate means of providing teachers with information. PMID- 21790992 TI - Assessment of nose protector for sport activities: finite element analysis. AB - There has been a significant increase in the number of facial fractures stemming from sport activities in recent years, with the nasal bone one of the most affected structures. Researchers recommend the use of a nose protector, but there is no standardization regarding the material employed. Clinical experience has demonstrated that a combination of a flexible and rigid layer of ethylene vinyl acetate (EVA) offers both comfort and safety to practitioners of sports. The aim of the present study was the investigation into the stresses generated by the impact of a rigid body on the nasal bone on models with and without an EVA protector. For such, finite element analysis was employed. A craniofacial model was constructed from images obtained through computed tomography. The nose protector was modeled with two layers of EVA (1 mm of rigid EVA over 2 mm of flexible EVA), following the geometry of the soft tissue. Finite element analysis was performed using the LS Dyna program. The bone and rigid EVA were represented as elastic linear material, whereas the soft tissues and flexible EVA were represented as hyperelastic material. The impact from a rigid sphere on the frontal region of the face was simulated with a constant velocity of 20 m s(-1) for 9.1 MUs. The model without the protector served as the control. The distribution of maximal stress of the facial bones was recorded. The maximal stress on the nasal bone surpassed the breaking limit of 0.13-0.34 MPa on the model without a protector, while remaining below this limit on the model with the protector. Thus, the nose protector made from both flexible and rigid EVA proved effective at protecting the nasal bones under high-impact conditions. PMID- 21790994 TI - Hepatic hemangioma and hemochromatosis misdiagnosed by MRI as metastatic melanoma. PMID- 21790995 TI - Tinea incognita due to Trichophyton mentagrophytes. PMID- 21790973 TI - Orais and STIMs: physiological mechanisms and disease. AB - The stromal interaction molecules STIM1 and STIM2 are Ca(2+) sensors, mostly located in the endoplasmic reticulum, that detect changes in the intraluminal Ca(2+) concentration and communicate this information to plasma membrane store operated channels, including members of the Orai family, thus mediating store operated Ca(2+) entry (SOCE). Orai and STIM proteins are almost ubiquitously expressed in human cells, where SOCE has been reported to play a relevant functional role. The phenotype of patients bearing mutations in STIM and Orai proteins, together with models of STIM or Orai deficiency in mice, as well as other organisms such as Drosophila melanogaster, have provided compelling evidence on the relevant role of these proteins in cellular physiology and pathology. Orai1-deficient patients suffer from severe immunodeficiency, congenital myopathy, chronic pulmonary disease, anhydrotic ectodermal dysplasia and defective dental enamel calcification. STIM1-deficient patients showed similar abnormalities, as well as autoimmune disorders. This review summarizes the current evidence that identifies and explains diseases induced by disturbances in SOCE due to deficiencies or mutations in Orai and STIM proteins. PMID- 21790993 TI - Microscopic evaluation of induced tooth movement in traumatized teeth: an experimental study in rats. AB - The clinical management of orthodontic patients with dental trauma before or during the treatment is mainly founded on clinical experience, expert opinions, and individual case reports. It is proposed in the literature that teeth sustaining mild trauma with minor damage to the periodontium (e.g. subluxation) should be followed for a period of time before being subjected to orthodontic forces. A minimum period of 3 months has been proposed. In this study, we used an animal model to investigate whether shorter observation periods could be established in case of mild trauma. The periradicular region of rat molars was examined microscopically to determine the biological events of tooth movement started 15 and 30 days after intentional subluxation using an experimental method to induce dentoalveolar trauma. Thirty adult male Wistar rats were assigned to 6 groups (n = 5): Group 1 (control - no trauma/orthodontic movement); Group 2: the animals received an orthodontic device and were sacrificed after 7 days; Groups 3 and 4: dentoalveolar trauma (subluxation) was experimentally induced by the application of an axial force of 900 cN on the occlusal surface of the maxillary right first molar, and the animals were sacrificed after 22 and 37 days, respectively; and Groups 5 and 6: 15 and 30 days, respectively, after force application, an orthodontic device was installed and the rats were sacrificed 7 days later. In G5 and G6, the periodontal ligament and pulp tissue were rich in cellular elements and blood vessels, the alveolar bone was preserved, and the root surface presented only very small areas of surface resorption (cementum), maintaining the characteristics of normality. In conclusion, the microscopic alterations in the gingival and periodontal tissues in response to an experimentally induced mild dentoalveolar trauma simulating subluxation were not sufficient to contraindicate starting the orthodontic movement 15 and 30 days after trauma. PMID- 21790997 TI - Plasmids containing NRSE/RE1 sites enhance neurite outgrowth of retinal ganglion cells via sequestration of REST independent of NRSE dsRNA expression. AB - Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor of neuron-specific genes that binds to a conserved DNA element, the neuron restrictive silencer element (NRSE/RE1). Interestingly, increased REST activity is found in several neurological diseases like Huntington's disease and cerebral ischemia. Recently, it was shown that NRSE dsRNA, a double-stranded non coding RNA can bind to REST during a defined period of neuronal differentiation, and thereby changes REST from a transcriptional repressor to an activator of neuron-specific genes. Here, we analyzed the effects of NRSE dsRNA expression in primary retinal ganglion cells. We found that NRSE dsRNA expression vectors significantly enhance neurite outgrowth even when axonal degeneration is induced by neurotrophin deprivation. Transfection of HEK cells with NRSE dsRNA-expressing vectors altered their morphology leading to the formation of thin processes and induced the expression of neurofilament-68. Surprisingly, control vectors containing REST-binding sites, but not expressing NRSE dsRNA, resulted in the same effects, also in the retinal ganglion cell model. Reporter assays and retention of REST in the cytoplasm with a labeled NRSE/RE1-containing plasmid incapable of entering the nucleus suggest that sequestration of REST in the cytoplasm is the reason for the observed effects. No evidence for a biological function of NRSE dsRNA could be found in these models. We conclude that sequestration of REST leads to enhanced neurite outgrowth in retinal ganglion cells and that an increased activity of REST, as it is found in several neurodegenerative diseases, can be effectively modulated by sequestration of REST with plasmids containing NRSE/RE1 sites. PMID- 21790996 TI - Intramolecular electron transfer in laccases. AB - Rate constants and activation parameters have been determined for the internal electron transfer from type 1 (T1) to type 3 (T3) copper ions in laccase from both the fungus Trametes hirsuta and the lacquer tree Rhus vernicifera, using the pulse radiolysis method. The rate constant at 298 K and the enthalpy and entropy of activation were 25 +/- 1 s(-1), 39.7 +/- 5.0 kJ.mol(-1) and -87 +/- 9 J.mol( 1) .K(-1) for the fungal enzyme and 1.1 +/- 0.1 s(-1), 9.8 +/- 0.2 kJ.mol(-1) and -211 +/- 3 J.mol(-1) .K(-1) for the tree enzyme. The initial reduction of the T1 site by pulse radiolytically produced radicals was direct in the case of T. hirsuta laccase, but occured indirectly via a disulfide radical in R. vernicifera. The equilibrium constant that characterizes the electron transfer from T1 to T3 copper ions was 0.4 for T. hirsuta laccase and 1.5 for R. vernicifera laccase, leading to full reduction of the T1 site occurring at 2.9 +/ 0.2 electron equivalents for T. hirsuta and 4 electron equivalents for R. vernicifera laccase. These results were compared with each other and with those for the same process in other multicopper oxidases, ascorbate oxidase and Streptomyces coelicolor laccase, using available structural information and electron transfer theory. PMID- 21790998 TI - A reinvestigation of the lipopolysaccharide structure of Helicobacter pylori strain Sydney (SS1). AB - In this study, we describe a reinvestigation of the lipopolysaccharide (LPS) structure of Helicobacter pylori strain Sydney (SS1) based on the NMR analysis of oligosaccharides obtained through the use of various degradations of the LPS as well as capillary electrophoresis-MS data. The results of the analysis indicated that the core region of a major H. pylori SS1 LPS glycoform consists of a backbone core oligosaccharide substituted at the D-glycero-D-manno-heptose (DD Hep) residue by a linear chain composed of a trisaccharide fragment alpha-ddHep-3 alpha-L-Fuc-3-beta-GlcNAc, as previously demonstrated for H. pylori strain 26695, further elongated by consecutively added alpha-Glc and beta-Gal residues, and terminating in a novel linear chain consisting of 1,2-linked beta-ribofuranosyl residues, where the last beta-ribofuranosyl residue provides a point of attachment for the O-chain polysaccharide: [Formula: see text] where [2-beta-Ribf ](n) is a short (three to five residues) oligomer of 1,2-linked beta-ribofuranose (riban), and PS is a polysaccharide chain consisting of N-acetyllactosamine, substituted with alpha-Fuc to form Lewis (Le)-type structures. In addition to the previously identified LacNAc, Le(y) and Le(x) components, the O-chain polysaccharide of H. pylori SS1 LPS was found to contain a novel LacNAc unit carrying a phosphoethanolamine substituent at the O-6 position of beta-GlcNAc residues. PMID- 21791000 TI - Mutations in 16S rRNA that suppress cold-sensitive initiation factor 1 affect ribosomal subunit association. AB - A mutation in the infA gene encoding initiation factor 1 (IF1) gives rise to a cold-sensitive phenotype. An Escherichia coli strain with this mutation was used as a tool to select for second-site suppressors that compensate for the cold sensitivity and map specifically to rRNA. Several suppressor mutants with altered 16S rRNA that partially restore growth of an IF1 mutant strain in the cold were isolated and characterized. Suppressor mutations were found in helix (h)18, h32, h34 and h41 in 16S rRNA. These mutations are not clustered to any particular region in 16S rRNA and none overlap previously reported sites of interaction with IF1. While the isolated suppressors are structurally diverse, they are functionally related because all affect ribosomal subunit association in vivo. Furthermore, in vitro subunit-association experiments indicate that most of the suppressor mutations directly influence ribosomal subunit association even though none of these are confined to any of the known intersubunit bridges. These results are consistent with the model that IF1 is an rRNA chaperone that induces large-scale conformational changes in the small ribosomal subunit, and as a consequence modulates initiation of translation by affecting subunit association. PMID- 21791001 TI - Sexual health for all? PMID- 21790999 TI - Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by sorafenib--the role of extracellular signal-regulated kinase counteraction. AB - A multikinase inhibitor of the Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, sorafenib, is increasingly being used in the management of hepatocellular carcinoma, and its combination with conventional chemotherapeutics has stimulated particular interest. Although the combination of sorafenib with doxorubicin (DOX) is presently being investigated in a phase III randomized trial, little is known about the molecular mechanisms of their interaction. Because DOX causes cell death through upregulation of the MEK/ERK pathway, and sorafenib has an opposite influence on the same cascade, we hypothesized that co-treatment with these drugs may lead to an antagonistic effect. DOX treatment arrested proliferation and induced autophagic cell death in Hep3B cells, whereas apoptotic changes were not conspicuous. Sorafenib alone affected viability and caused massive mitochondrial degradation. However, when added together with DOX, sorafenib facilitated cell cycle progression, increased survival, and reduced autophagy. To evaluate the molecular mechanisms of this phenomenon, we examined the expression of ERK1/2, protein kinase B (Akt), and cyclin D1, as well as the members of Bcl-2 family. ERK1/2 activation induced by DOX was suppressed by sorafenib. Similarly, ERK targeting with the selective inhibitor U0126 impaired DOX-induced toxicity. Treatment with sorafenib, either alone or in combination with DOX, resulted in Akt activation. The role of sorafenib-induced degradation of cyclin D1 in the suppression of DOX efficiency is discussed. In conclusion, MEK/ERK counteraction, stimulation of survival via Akt and dysregulation of cyclin D1 could contribute to the escape from DOX-induced autophagy and thus promote cancer cell survival. The use of MEK/ERK inhibitors in combination with chemotherapeutics, intended to enhance anticancer efficacy, requires the consideration of possible antagonistic effects. PMID- 21791002 TI - Sexual function: diagnosis and management of sexual dysfunction. PMID- 21791007 TI - Penile rehabilitation. PMID- 21791006 TI - The controversial role of phosphodiesterase type 5 inhibitors in the treatment of premature ejaculation. AB - INTRODUCTION: It is controversial whether or not the most frequent male sexual dysfunctions, premature ejaculation (PE) and erectile dysfunction (ED), share pathogenetic mechanisms and treatments. METHODS: Three scientists (C.McM., J.C., and A.A.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of PE, present different perspectives on the use of phosphodiesterase type 5 inhibitors (PDE5is) in PE. The psychological point of view is discussed by an expert in sexology (M.P.). MAIN OUTCOME MEASURE: Outcome measures used are expert opinions supported by the critical review of the currently available literature. RESULTS: This Controversy examines the role of nitric oxide (NO) as a neurotransmitter involved in the central and peripheral control of ejaculation, the adherence of methodology to the contemporary consensus of ideal PE drug trial design, the impact of methodology on treatment outcomes, and the role of PDE5i drugs (sildenafil, tadalafil, and vardenafil) in the treatment of PE. CONCLUSIONS: While it is evident that PDE5is are the first choice in patients with comorbid ED and PE (where one may be secondary to the other), well-designed studies on the possible use of PDE5is in PE patients without ED are still limited. The issue will be less controversial when further evidence on the role of NO and PDE5 in the mechanism of ejaculation is available. PMID- 21791003 TI - Management of erectile dysfunction in patients with sickle cell disease. PMID- 21791011 TI - Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study. AB - Amyloids are protein fibrils of nanometer size resulting from protein self assembly. They have been shown to be associated with a wide variety of diseases such as Alzheimer's and Parkinson's and may contribute to various other pathological conditions, known as amyloidoses. Insulin is prone to form amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds. In this study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin-T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds. PMID- 21791008 TI - Practical synthesis and biological evaluation of bergenin analogs. AB - Here, we describe the practical synthesis and biological properties of bergenin and its structural analogs. Synthetic bergenin compounds were prepared by acylation of bergenin. These compounds were then evaluated for suppression of lipopolysaccharide-induced nitric oxide (NO) generation in cultured cells and anti-narcotic effects on morphine-dependent mice. We found that bergenin derivatives showed potent anti-inflammatory activity (suppression of NO generation) at concentrations ranging from 20 to 30 MUmin vitro, and bergenin derivatives (10-20 mg/kg) exhibited significant anti-narcotic effects on morphine dependence in mice. These results suggest the potential utility of bergenin and its analogs as anti-narcotic agents and the design of more potent anti inflammatory compounds. PMID- 21791009 TI - Study on the anticancer activity of coumarin derivatives by molecular modeling. AB - Protein kinase 2 (CK2) is a potential target, and the coumarins were identified as the attractive CK2 inhibitors. In this study, two models (CoMFA and CoMSIA) were established, and their reliabilities were supported by statistical parameters. From the CoMFA and CoMSIA models, the hydrophobic and hydrogen bonds play very important roles in the interactions between inhibitors and CK2, which were confirmed sufficiently by molecular docking. Furthermore, the binding mode of the inhibitors at the active sites of CK2 was also investigated by docking study. The hydroxyl at the position R(5) is more important for coumarins inhibitors because it forms hydrogen bonds not only with Lys68 as hydrogen acceptor but also with H(2) O as hydrogen donor. In addition, hydroxyl can make electrostatic interactions with electropositive Lys68 residue. The large group at the R(6) position is not conducive to inhibitor dock into the groove of the binding site of CK2. When there is nitro group, the electrostatic interaction between ligand and receptor is enhanced significantly, and the nitro oxygen can form hydrogen bonds with the backbone NH of Lys68 and Asp175 simultaneously. The results obtained from molecular modeling techniques not only provide the models to predict the activity of inhibitors but also lead to a better understanding of the interactions between inhibitors and CK2, which will be very helpful for drug design. PMID- 21791010 TI - Synthesis, saccharide-binding and anti-cancer cell proliferation properties of arylboronic acid derivatives of indoquinolines. AB - A facile synthesis of a series of saccharide-binding arylboronic acid derivatives of indoloquinoline was described. The key synthetic steps were polyphosphoric acid-mediated cyclization, chlorinative aromatization, and amidation. Mass spectrometry experiments revealed these synthetic arylboronic acid derivatives of indoquinolines could bind to biologically important carbohydrates (sialic acid, fucose, glucose, and galactose) by forming boronate di-esters in alkaline aqueous solution. Most of the arylboronic acid derivatives of indoquinolines inhibited human breast cancer cell (MDA-231) proliferation at a concentration of 5 MUm, whereas the compound 17 exhibited highest percentages (76.74%) of the cancer cell proliferation inhibition. PMID- 21791012 TI - Synthesis and anti-hypercholesterolemic evaluations of calcium salts of 4 substituted quinoline-based mevalonic acid. AB - A series of calcium (3R,5S,6E)-7-[4,6,7,8-substituted-quinoline-3-yl]-3,5 dihydroxy-hept-6-enoates was synthesized from the lactones, and the anti hypercholesterolemic evaluation in quails was presented in this report. It was found that most of the compounds significantly decreased levels of total cholesterol and low-density lipoprotein. 2e showed better hypolipidemic effect than atorvastatin, and 2d and 2j exhibited comparable efficacy to atorvastatin. These three compounds were selected as the hypocholesterolemic candidates for further evaluation. PMID- 21791013 TI - A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors. AB - Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid-furanyl derivative that inhibits ephrin-A5 binding to EphA4 with an IC(50) of 3 MUm in ELISAs. This compound, which appears to bind to the ephrin-binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid-furanyl derivative inhibits EphA2 phosphorylation in response to TNFalpha and capillary-like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin-A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors. PMID- 21791015 TI - Attenuated relationship between cardiac output and oxygen uptake during high intensity exercise. AB - AIM: Recent findings have challenged the belief that the cardiac output (CO) and oxygen consumption (VO(2) ) relationship is linear from rest to maximal exercise. The purpose of this study was to determine the CO and stroke volume (SV) response to a range of exercise intensities, 40-100% of VO(2max), during cycling. METHODS: Ten well-trained cyclists performed a series of discontinuous exercise bouts to determine the CO and SV vs. VO(2) responses. RESULTS: The rate of increase in CO, relative to VO(2) , during exercise from 40 to 70% of VO(2max) was 4.4 +/- 1.4 L L(-1). During exercise at 70-100% of VO(2max) , the rate of increase in CO was reduced to 2.1 +/- 0.9 L L(-1) (P = 0.01). Stroke volume during exercise at 80 100% of VO(2max) was reduced by 7% when compared to exercise at 50-70% of VO(2max) (134 +/- 5 vs. 143 +/- 5 mL per beat, P = 0.02). Whole body arterial venous O(2) difference increased significantly as intensity increased. CONCLUSION: The observation that the rate of increase in CO is reduced as exercise intensity increases suggests that cardiovascular performance displays signs of compromised function before maximal VO(2) is reached. PMID- 21791014 TI - Membrane cycling after the excess retrieval mode of rapid endocytosis in mouse chromaffin cells. AB - AIM: After exocytosis, neuroendocrine cells and neurones keep constant the plasma membrane and the releasable vesicle pools by performing endocytosis and vesicular cycling. Patch-clamp capacitance measurements on chromaffin cells showed that strong Ca(+2) entry activates excess retrieval: a rapid endocytosis process that retrieves more membrane than the one fused by preceding exocytosis. The main purpose of the present experiments was to study the recycling pathway that follows excess retrieval, which is unknown. METHODS: Membrane recycling after exocytosis-endocytosis can be studied by fluorescence imaging assays with FM1-43 (Perez Bay et al. Am J Physiol Cell Physiol 2007; 293, C1509). In this work, we used this assay in combination with fluorescent dextrans and specific organelle targeted antibodies to study the membrane recycling after excess retrieval in mouse chromaffin cells. RESULTS: Excess retrieval was observed after the application of high-K(+) or cholinergic agonists during 15 or 30 s in the presence of FM1-43. We found that the excess retrieval membrane pool (defined as endocytosis-exocytosis) was associated with the generation of a non-releasable fraction of membrane (up to 30% of plasma membrane surface) colocalizing with the lysosomal compartment. The excess retrieval membrane pool followed a saturable cytosolic Ca(2+) dependency, and it was suppressed by inhibitors of L-type Ca(2+) channels, endoplasmic reticulum Ca(2+) release and PKC. CONCLUSION: Excess retrieval is not associated with the cycling of releasable vesicles, but it is related to the formation of non-releasable endosomes. This process is activated by a concerted contribution of Ca(2+) entry through L-channels and Ca(2+) release from endoplasmic reticulum. PMID- 21791016 TI - Increased steady-state VO2 and larger O2 deficit with CO2 inhalation during exercise. AB - AIM: To examine whether inhalation of CO(2) -enriched gas would increase steady state VO(2) during exercise and enlarge O(2) deficit. METHODS: Ten physically active men (VO(2) 53.7 +/- 3.6 mL min(-1) kg(-1) ; x +/- SD) performed transitions from low-load cycling (baseline; 40 W) to work rates representing light (~ 45% VO(2); 122 +/- 15 W) and heavy (~ 80% VO(2); 253 +/- 29 W) exercise while inhaling normal air (air) or a CO(2) mixture (4.2% CO(2) , 21% O(2) , balance N(2) ). Gas exchange was measured with Douglas bag technique at baseline and at min 0-2, 2-3 and 5-6. RESULTS: Inhalation of CO(2) -enriched air consistently induced respiratory acidosis with increases in PCO(2) and decreases in capillary blood pH (P < 0.01). Hypercapnic steady-state VO(2) was on average about 6% greater (P < 0.01) than with air in both light and heavy exercise, presumably because of increased cost of breathing (DeltaVE 40-50 L min(-1) ; P < 0.01), and a substrate shift towards increased lipid oxidation (decline in R 0.12; P < 0.01). VO(2) during the first 2 min of exercise were not significantly different whereas the increase in VO(2) from min 2-3 to min 5-6 in heavy exercise was larger with CO(2) than with air suggesting a greater VO(2) slow component. As a result, O(2) deficit was greater with hypercapnia in heavy exercise (2.24 +/- 0.51 L vs. 1.91 +/- 0.45 L; P < 0.05) but not in light (0.64 +/- 0.21 L vs. 0.54 +/- 0.20 L; ns). CONCLUSION: Inhalation of CO(2)-enriched air and the ensuing respiratory acidosis increase steady-state VO(2) in both light and heavy exercise and enlarges O(2) deficit in heavy exercise. PMID- 21791017 TI - Endoscopic submucosal dissection for colonic lesions: why and how should we do it? AB - Endoscopic submucosal dissection (ESD) is a safe and effective alternative to surgery for large non-polypoid colonic lesions and early colorectal carcinoma. In this article, we discuss the development, efficacy and safety of ESD. As the incidence of colorectal cancer is rapidly increasing in Asia, we advocate standardization of ESD program, including patient selection, hardware prerequisites, and training of operators. PMID- 21791018 TI - Meta-analysis: circulating adiponectin levels and risk of colorectal cancer and adenoma. AB - OBJECTIVE: To provide a systematic review with a meta-analysis for addressing the association between circulating adiponectin levels and the risk of colorectal cancer and adenoma. METHODS: Multiple electronic sources including MEDLINE, EMBASE and the Science Citation Index Expanded databases were searched to identify relevant studies for this systematic review. All existing observational studies that examined the relationship between circulating adiponectin and colorectal cancer or adenoma were included. Weighted mean difference and 95% confidence intervals (CI) were estimated and pooled using meta-analysis methods. RESULTS: Overall 13 case control or nested case control studies met the inclusion criteria. A total of 6175 participants and 3015 cases of colorectal cancer and adenoma were included in this meta-analysis. The weighted mean difference (95% CI) were -1.084 ug/mL (-1.836, -0.331), P = 0.005 in colorectal cancer and -1.43 ug/mL (-2.231, -0.628), P = 0.000 in adenoma. In men, a 2% decreased risk of colorectal neoplasm for a 1 ug/mL increment in adiponectin levels was observed (OR = 0.98, 95% CI 0.96-0.99) whereas among women there is no evidence of such a trend (OR = 0.99, 95% CI 0.97-1.01). CONCLUSIONS: Patients with colorectal cancer and adenoma demonstrated markedly lower adiponectin values than controls, yet there was significant heterogeneity among studies. A negative dose response relationship between levels of adiponectin and the risk of colorectal neoplasm was observed in men. PMID- 21791019 TI - Hepatobiliary disorders and complications of inflammatory bowel disease. AB - One of typical examples of liver-gut cross talk is the interaction and impact of inflammatory bowel disease (IBD) and hepatobiliary (HB) abnormalities on each other's disease course. There are several layers of association between IBD and HB diseases: (i) HB diseases and IBD share pathogenetic mechanisms; (ii) HB diseases parallel structural and pathophysiological changes seen with IBD; and (iii) hepatic toxicity is associated with medical therapy for IBD. Interdisciplinary approach, involving gastroenterologists, hepatologists and, in advanced cases, general, colorectal, and liver transplant surgeons, is advocated. PMID- 21791020 TI - The effect of fundoplication on proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease: 4-year follow-up study. AB - OBJECTIVE: The capacity of fundoplication to prevent esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti apoptosis, for which little data exist as to their response to fundoplication. Therefore, we wanted to clarify the effect of fundoplication on the magnitude of Ki-67 and B-cell lymphoma 2 (Bcl-2) during 48 months of follow up. METHODS: Ki-67 and Bcl-2 were assessed quantitatively from biopsies of the esophagogastric junction (EGJ) and from the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication. An upper gastrointestinal endoscopy was performed preoperatively and postoperatively at 6 months for 20 patients and 48 months for 16 patients, respectively. Ki-67 and Bcl 2 were compared to those of 7 controls. RESULTS: Compared to the preoperative level, Ki-67 was elevated in the distal (P = 0.012) and proximal (P = 0.007) esophagus at 48 months. Compared to control values, Ki-67 was lower at 6 months in the EGJ (P = 0.037) and the proximal esophagus (P = 0.003) and higher at 48 months in the distal esophagus (P = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (P = 0.038). Correlations between Ki-67 and Bcl-2 were positive in the EGJ (P > 0.001) and in the distal (P = 0.001) and proximal esophagus (P = 0.013). CONCLUSION: Proliferative activity after fundoplication increased during long-term follow up in the distal esophagus despite a normal fundic wrap and objective healing of GERD. PMID- 21791021 TI - Comparison of intestinal metaplasia in gastric cardia and Barrett's esophagus. AB - OBJECTIVE: To evaluate and compare the pathological features and immunostaining pattern (cytokeratin 7 (CK-7), mucin core peptide 1 (Muc-1)) in Barrett's esophagus (BE) and cardiac intestinal metaplasia (CIM). METHODS: According to endoscopic diagnosis, patients with gastric cardiac inflammation and BE were selected from March 2008 to February 2009 in Renji Hospital, Shanghai Jiaotong University School of Medicine. Those patients who had histological findings of intestinal metaplasia (82 cases of CIM and 64 special type BE) were enrolled in our study. Hematoxylin-eosin, periodic acid-Schiff and Alcian blue staining and an immunohistochemical examination (CK-7, Muc-1) were undertaken in all of them. RESULTS: Squamous mucosa overlying the columnar crypts with intestinal metaplasia, also called buried metaplasia, was often found in the BE group (56.2%), mainly as an incomplete type (85.9%). Inflammation in the gastric antrum was more severe in the CIM group (45.1% vs 26.6%), in contrast, esophagitis was more severe in the BE group (53.1% vs 35.4%). CK-7 was highly expressed in the BE group (84.4%) in contrast to the CIM group (37.8%). There was no difference in the expression of Muc-1 in these two kinds of intestinal metaplasia (14.1% vs 19.5%). CONCLUSIONS: Buried intestinal metaplasia, mainly as an incomplete type, is the major predominant type of BE. The degree of inflammation in the gastric antrum and esophagus can differentiate BE from CIM to some extent. CK-7 immunohistochemical staining can help identify BE and CIM but Muc-1 cannot. PMID- 21791022 TI - The intrinsic fluorescence spectrum of dilute gastric juice as a novel diagnostic tool for gastric cancer. AB - OBJECTIVE: To investigate the intrinsic fluorescence spectrum of gastric juice as a diagnostic method for gastric cancer. METHODS: We collected gastric juice by gastroscopy in 1,870 patients from May 2001 to March 2006, of whom 202 were involved in a preliminary test, 162 in experimental optimization and 1,506 in clinical verification. The best dilution and pH value were chosen in the experimental optimization phase. Clinical verification was based on optimized samples. Intrinsic fluorescence spectra were measured in all samples with a fluorescence spectrophotometer using an excitation wavelength of 288 nm. RESULTS: The first peak of fluorescence intensity (P(1) FI) of the intrinsic fluorescence spectrum was significantly higher in gastric juice from patients with gastric cancer than from those with benign lesions. There was no significant difference in the P(1) FI differences between patients with benign and malignant lesions with samples diluted by 20-fold to 80-fold and from pH 9 to pH 11. Clinical verification in 1,506 patients showed that P(1) FI >= 76.5 was the optimal cut off on the receiver operating characteristic curve for diagnosing gastric cancers: sensitivity was 83.2%, specificity 80.7% and accuracy 82.0%. CONCLUSIONS: P(1) FI of the intrinsic fluorescence at 288 nm is significantly higher in patients with gastric cancers than in individuals with benign lesions. As a clinical indicator of gastric cancer, its sensitivity, specificity and accuracy were high. PMID- 21791023 TI - Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease. AB - OBJECTIVE: Forkhead box P3 (FOXP3) plays an important role in the development and function of CD4(+) regulatory T (Treg) cells. In this study the percentage of CD4(+) FOXP3(+) Treg cells in peripheral blood mononuclear cells (PBMC) and the frequency of Treg cells in the colonic mucosa of patients with inflammatory bowel disease (IBD) were investigated. METHODS: The percentage of CD4(+) FOXP3(+) Treg cells in PBMC was analyzed by flow cytometry. Immunohistochemistry was used to examine the FOXP3(+) cells in the inflamed mucosa. Real-time polymerase chain reaction and Western blot were used to detect the expressions of FOXP3 mRNA and protein in PBMC and mucosal biopsy specimens of IBD patients, respectively. RESULTS: Together with the decrease of percentage of Treg cells in PBMC, we found that the frequency of Treg cells increased significantly in inflamed mucosa of active or inactive Crohn's disease (CD) and ulcerative colitis (UC). The expressions of FOXP3 mRNA and protein increased in inflamed mucosa when compared with those in healthy controls, especially the FOXP3 mRNA in patients with active CD or UC. Interestingly, the expression of FOXP3 protein in active UC was higher than that in active CD. CONCLUSIONS: There was a decrease of CD4(+) FOXP3(+) Treg cells in peripheral blood and an accumulation of Treg cells in inflamed mucosa. These data suggested that the suppressive function of Treg cells may be partially inhibited and this could be an important factor in the recurrence of disease, especially in UC. PMID- 21791024 TI - Preliminary experimental research on the mechanism of liver bile secretion stimulated by peppermint oil. AB - OBJECTIVE: To investigate the choleretic effect and molecular mechanisms of action of peppermint oil (PO), the main component of Danshu capsules (Sichuan Jishengtang Pharmaceutical Co., Ltd., Pengzhou, Sichuan Province, China). METHODS: Bile secretion was measured by biliary drainage in rats. Total bile acids, total cholesterol and bilirubin in bile were determined. Cholesterol 7alpha-hydroxylase (CYP7A1), and farnesoid X receptor (FXR) messenger ribonucleic acid (mRNA) levels were assessed in HepG2 cells (a human hepatocellular carcinoma cell line) by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: PO significantly promoted bile and bile acid secretion in rats. It also increased bile acid efflux and decreased cholesterol levels (P < 0.01) in bile. In HepG2 cells the mRNA levels of CYP7A1 and FXR were significantly upregulated after treatment with PO. CONCLUSIONS: PO stimulates bile fluid secretion and thus has a choleretic effect. PO might play a role in upregulating CYP7A1 and FXR mRNA levels, suggesting that the molecular mechanisms are related to gene expression involved in bile acid synthesis. PMID- 21791025 TI - Circulating interleukin-27 levels in Helicobacter pylori-infected patients with gastric or duodenal ulcers, independent of the bacterial cytotoxin-associated gene A virulence factor. AB - OBJECTIVE: The aim was to evaluate the interleukin (IL)-27 levels in Helicobacter pylori (H. pylori)-infected patients with gastric ulcer (GU) or duodenal ulcer (DU) and to determine its association with H. pylori virulence factor cytotoxin associated gene A (CagA). METHODS: In all, 127 H. pylori infected patients (including 96 DU patients, of whom 61 were anti-CagA(+) and 35 were anti-CagA(-)) and 31 GU patients (of whom 15 were anti-CagA(+) and 16 were anti-CagA(-)), 60 asymptomatic (AS) carriers (of whom 30 were anti-CagA(+) and 30 were anti-CagA( )) and 30 healthy H. pylori-negative participants (as a control) were enrolled in the study. Serum concentrations of IL-27 were measured by the enzyme-linked immunosorbent assay method. RESULTS: The mean levels of IL-27 in the GU (44.26 +/ 7.12 pg/mL) and DU patients (40.84 +/- 3.90 pg/mL) was significantly higher than those observed in the AS carriers (22.06 +/- 1.90 pg/mL, P < 0.001) and the control group (18.12 +/- 1.68 pg/mL, P < 0.001 and P < 0.002, respectively). In the GU, DU and AS groups the levels of IL-27 in anti-CagA(+) participants were not significantly differ from that in the anti-CagA(-) participants. CONCLUSIONS: These results showed that the mean concentration of IL-27 in H. pylori-infected peptic ulcer (PU) patients was higher than in AS carriers and the healthy control group. The serum concentrations of IL-27 were not affected by the CagA factor. PMID- 21791026 TI - Isolated jejunal stricture formation two years after corrosive ingestion: case report and review of literature. PMID- 21791027 TI - Diagnosis and treatment of portal hypertension secondary to myeloproliferative disorders: a report of three cases. PMID- 21791028 TI - Prevention of depressive disorders: towards a further reduction of the disease burden of mental disorders. PMID- 21791029 TI - Molecular and physiological properties of bacteriophages from North America and Germany affecting the fire blight pathogen Erwinia amylovora. AB - For possible control of fire blight affecting apple and pear trees, we characterized Erwinia amylovora phages from North America and Germany. The genome size determined by electron microscopy (EM) was confirmed by sequence data and major coat proteins were identified from gel bands by mass spectroscopy. By their morphology from EM data, phiEa1h and phiEa100 were assigned to the Podoviridae and phiEa104 and phiEa116 to the Myoviridae. Host ranges were essentially confined to E. amylovora, strains of the species Erwinia pyrifoliae, E. billingiae and even Pantoea stewartii were partially sensitive. The phages phiEa1h and phiEa100 were dependent on the amylovoran capsule of E. amylovora, phiEa104 and phiEa116 were not. The Myoviridae efficiently lysed their hosts and protected apple flowers significantly better than the Podoviridae against E. amylovora and should be preferred in biocontrol experiments. We have also isolated and partially characterized E. amylovora phages from apple orchards in Germany. They belong to the Podoviridae or Myoviridae with a host range similar to the phages isolated in North America. In EM measurements, the genome sizes of the Podoviridae were smaller than the genomes of the Myoviridae from North America and from Germany, which differed from each other in corresponding nucleotide sequences. PMID- 21791030 TI - Laccase-catalysed oxidations of naturally occurring phenols: from in vivo biosynthetic pathways to green synthetic applications. AB - Laccases are oxidases that contain several copper atoms, and catalyse single electron oxidations of phenolic compounds with concomitant reduction of oxygen to water. The enzymes are particularly widespread in ligninolytic basidiomycetes, but also occur in certain prokaryotes, insects and plants. Depending on the species, laccases are involved in various biosynthetic processes contributing to carbon recycling in land ecosystems and the morphogenesis of biomatrices, wherein low-molecular-weight naturally occurring phenols serve as key enzyme substrates. Studies of these in vivo synthetic pathways have afforded new insights into fungal laccase applicability in green synthetic chemistry. Thus, we here review fungal laccase-catalysed oxidations of naturally occurring phenols that are particularly relevant to the synthesis of fine organic chemicals, and we discuss how the discovered synthetic strategies mimic laccase-involved in vivo pathways, thus enhancing the green nature of such reactions. Laccase-catalysed in vivo processes yield several types of biopolymers, including those of cuticles, lignin, polyflavonoids, humus and the melanin pigments, using natural mono- or poly-phenols as building blocks. The in vivo synthetic pathways involve either phenoxyl radical-mediated coupling or cross-linking reactions, and can be adapted to the design of in vitro oxidative processes involving fungal laccases in organic synthesis; the laccase substrates and the synthetic mechanisms reflect in vivo processes. Notably, such in vitro synthetic pathways can also reproduce physicochemical properties (e.g. those of chromophores, and radical-scavenging, hydration and antimicrobial activities) found in natural biomaterials. Careful study of laccase-associated in vivo metabolic pathways has been rewarded by the discovery of novel green applications for fungal laccases. This review comprehensively summarizes the available data on laccase-catalysed biosynthetic pathways and associated applications in fine chemical syntheses. PMID- 21791031 TI - Detection of parasitizing coccidia and determination of host crane species, sex and genotype by faecal DNA analysis. AB - In Japan, the three main crane species are the endangered red-crowned crane (Grus japonensis) inhabiting Hokkaido, the northernmost island of Japan; the vulnerable hooded crane (Grus monacha); and the vulnerable white-naped crane (Grus vipio). Both the hooded and white-naped cranes migrate in winter to Izumi in Kyushu, the southern island of Japan. In this study, we investigated the cranes and their coccidian parasites, through a targeted molecular approach using faecal DNA to develop a noninvasive method for infectious disease research. To determine the origin of noninvasively collected faecal samples, host species were identified by sequencing a region of approximately 470 bp of the mitochondrial 16S ribosomal RNA gene in the faecal DNA. Furthermore, to avoid sample redundancy, individual determination was performed by fragment analysis using microsatellite and sex linked markers. For microsatellite genotyping, previously reported markers and markers isolated in this study were examined, and seven loci for red-crowned cranes, eight for hooded cranes and six for white-naped cranes displayed polymorphisms. A low error rate was demonstrated by comparing microsatellite data generated from faecal DNA samples with that generated from feather DNA samples, indicating a high reliability. Polymerase chain reaction-based capillary electrophoresis (PCR-CE), employing genetic markers in the second internal transcribed spacer (ITS2) of nuclear ribosomal DNA, was employed to detect crane coccidia. The sensitivity of detection of PCR-CE using faecal DNA was inferior to that with traditional microscopy; however, our results suggest that PCR-CE can depict crane coccidia diversity with higher resolution and it is a useful tool to characterize community composition of coccidia in detail. PMID- 21791032 TI - Hit or miss in phylogeographic analyses: the case of the cryptic NUMTs. AB - Phylogeographic studies call for attention as nuclear copies of mitochondrial DNA (NUMT) may generate erroneous results. Here, we report the presence of NUMTs differing only by 1-3 bp from authentic mitochondrial haplotypes, consequently named cryptic NUMTs. In contrast to traditional NUMTs, for which reliable tools for detection are established, cryptic NUMTs question the validity of phylogeographic analyses based solely on mitochondrial DNA, like the one presented here on the European bark beetle Ips typographus. Caution is called as cryptic NUMTs might be responsible for haplotype richness found in several species, and the necessity of refined methods for NUMT detection is highlighted. PMID- 21791033 TI - Museum genomics: low-cost and high-accuracy genetic data from historical specimens. AB - Natural history collections are unparalleled repositories of geographical and temporal variation in faunal conditions. Molecular studies offer an opportunity to uncover much of this variation; however, genetic studies of historical museum specimens typically rely on extracting highly degraded and chemically modified DNA samples from skins, skulls or other dried samples. Despite this limitation, obtaining short fragments of DNA sequences using traditional PCR amplification of DNA has been the primary method for genetic study of historical specimens. Few laboratories have succeeded in obtaining genome-scale sequences from historical specimens and then only with considerable effort and cost. Here, we describe a low-cost approach using high-throughput next-generation sequencing to obtain reliable genome-scale sequence data from a traditionally preserved mammal skin and skull using a simple extraction protocol. We show that single-nucleotide polymorphisms (SNPs) from the genome sequences obtained independently from the skin and from the skull are highly repeatable compared to a reference genome. PMID- 21791034 TI - Improvement in smallholder farmer knowledge of cattle production, health and biosecurity in Southern Cambodia between 2008 and 2010. AB - Farmer knowledge surveys were conducted in 2008 and 2010 in Cambodia to evaluate the impact of a research project studying interventions that can improve cattle production and health, including biosecurity and practices relating to risks of transmission of transboundary diseases. The project hypothesis is that by increasing the value of smallholder-owned large ruminants through nutritional interventions and improved marketing, knowledge-based interventions including risk management for infectious diseases such as foot-and-mouth disease (FMD) can be implemented into a more sustainable pathway for rural development. Between 2008 and 2010, significant improvements in farmer knowledge and attitudes were recorded in three villages in three provinces of southern Cambodia. This was achieved through participatory 'applied field research', 'on the job' training plus 'formal' training programmes. No cases of FMD were recorded during the study period in the 'high-intervention' (HI) villages despite the common occurrence of the disease in a nearby 'low-intervention' and many other villages in the three provinces. Whilst it is likely that protection of these villages from FMD infection was from increasing the herd immunity by vaccination, it could also have been partly because of a decrease in risk behaviours by farmers as a result of their increasing knowledge of biosecurity. The research indicates that smallholder farmers are motivated by nutritional interventions that improve the value of their cattle 'bank' and offer better marketing opportunities. This provides a more receptive environment for introduction of disease risk management for infectious and other production limiting diseases, best implemented for smallholder farmers in Cambodia by intensive training programmes. In lieu of a widespread public awareness programme to deliver mass education of smallholder farmers in disease prevention and biosecurity, livestock development projects in South-East Asia should be encouraged to include training in disease risk management as an important intervention if the current momentum for trade in large ruminant livestock and large ruminant meat is to continue to progress and contribute to addressing global food security concerns. PMID- 21791035 TI - Cross-national epidemiology of DSM-IV major depressive episode. AB - BACKGROUND: Major depression is one of the leading causes of disability worldwide, yet epidemiologic data are not available for many countries, particularly low- to middle-income countries. In this paper, we present data on the prevalence, impairment and demographic correlates of depression from 18 high and low- to middle-income countries in the World Mental Health Survey Initiative. METHODS: Major depressive episodes (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DMS-IV) were evaluated in face-to-face interviews using the World Health Organization Composite International Diagnostic Interview (CIDI). Data from 18 countries were analyzed in this report (n = 89,037). All countries surveyed representative, population based samples of adults. RESULTS: The average lifetime and 12-month prevalence estimates of DSM-IV MDE were 14.6% and 5.5% in the ten high-income and 11.1% and 5.9% in the eight low- to middle-income countries. The average age of onset ascertained retrospectively was 25.7 in the high-income and 24.0 in low- to middle-income countries. Functional impairment was associated with recency of MDE. The female: male ratio was about 2:1. In high-income countries, younger age was associated with higher 12-month prevalence; by contrast, in several low- to middle-income countries, older age was associated with greater likelihood of MDE. The strongest demographic correlate in high-income countries was being separated from a partner, and in low- to middle-income countries, was being divorced or widowed. CONCLUSIONS: MDE is a significant public-health concern across all regions of the world and is strongly linked to social conditions. Future research is needed to investigate the combination of demographic risk factors that are most strongly associated with MDE in the specific countries included in the WMH. PMID- 21791036 TI - Scaling analysis for the investigation of slip mechanisms in nanofluids. AB - The primary objective of this study is to investigate the effect of slip mechanisms in nanofluids through scaling analysis. The role of nanoparticle slip mechanisms in both water- and ethylene glycol-based nanofluids is analyzed by considering shape, size, concentration, and temperature of the nanoparticles. From the scaling analysis, it is found that all of the slip mechanisms are dominant in particles of cylindrical shape as compared to that of spherical and sheet particles. The magnitudes of slip mechanisms are found to be higher for particles of size between 10 and 80 nm. The Brownian force is found to dominate in smaller particles below 10 nm and also at smaller volume fraction. However, the drag force is found to dominate in smaller particles below 10 nm and at higher volume fraction. The effect of thermophoresis and Magnus forces is found to increase with the particle size and concentration. In terms of time scales, the Brownian and gravity forces act considerably over a longer duration than the other forces. For copper-water-based nanofluid, the effective contribution of slip mechanisms leads to a heat transfer augmentation which is approximately 36% over that of the base fluid. The drag and gravity forces tend to reduce the Nusselt number of the nanofluid while the other forces tend to enhance it. PMID- 21791037 TI - Global proteomic analysis of plasma from mice infected with Plasmodium berghei ANKA using two dimensional gel electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry. AB - BACKGROUND: A global proteomic strategy was used to identify proteins, which are differentially expressed in the murine model of severe malaria in the hope of facilitating future development of novel diagnostic, disease monitoring and treatment strategies. METHODS: Mice (4-week-old CD1 male mice) were infected with Plasmodium berghei ANKA strain, and infection allowed to establish until a parasitaemia of 30% was attained. Total plasma and albumin depleted plasma samples from infected and control (non-infected) mice were separated by two dimensional gel electrophoresis (2-DE). After staining, the gels were imaged and differential protein expression patterns were interrogated using image analysis software. Spots of interest were then digested using trypsin and the proteins identified using matrix-assisted laser desorption and ionization-time of flight (MALDI-TOF) mass spectrometry (MS) and peptide mass fingerprinting software. RESULTS: Master gels of control and infected mice, and the corresponding albumin depleted fractions exhibited distinctly different 2D patterns comparing control and infected plasma, respectively. A wide range of proteins demonstrated altered expression including; acute inflammatory proteins, transporters, binding proteins, protease inhibitors, enzymes, cytokines, hormones, and channel/receptor derived proteins. CONCLUSIONS: Malaria-infection in mice results in a wide perturbation of the host serum proteome involving a range of proteins and functions. Of particular interest is the increased secretion of anti-inflammatory and anti apoptotic proteins. PMID- 21791038 TI - Islands beneath islands: phylogeography of a groundwater amphipod crustacean in the Balearic archipelago. AB - BACKGROUND: Metacrangonyctidae (Amphipoda, Crustacea) is an enigmatic continental subterranean water family of marine origin (thalassoid). One of the species in the genus, Metacrangonyx longipes, is endemic to the Balearic islands of Mallorca and Menorca (W Mediterranean). It has been suggested that the origin and distribution of thalassoid crustaceans could be explained by one of two alternative hypotheses: (1) active colonization of inland freshwater aquifers by a marine ancestor, followed by an adaptative shift; or (2) passive colonization by stranding of ancestral marine populations in coastal aquifers during marine regressions. A comparison of phylogenies, phylogeographic patterns and age estimations of clades should discriminate in favour of one of these two proposals. RESULTS: Phylogenetic relationships within M. longipes based on three mitochondrial DNA (mtDNA) and one nuclear marker revealed five genetically divergent and geographically structured clades. Analyses of cytochrome oxidase subunit 1 (cox1) mtDNA data showed the occurrence of a high geographic population subdivision in both islands, with current gene flow occurring exclusively between sites located in close proximity. Molecular-clock estimations dated the origin of M. longipes previous to about 6 Ma, whereas major cladogenetic events within the species took place between 4.2 and 2.0 Ma. CONCLUSIONS: M. longipes displayed a surprisingly old and highly fragmented population structure, with major episodes of cladogenesis within the species roughly correlating with some of the major marine transgression-regression episodes that affected the region during the last 6 Ma. Eustatic changes (vicariant events) -not active range expansion of marine littoral ancestors colonizing desalinated habitats-explain the phylogeographic pattern observed in M. longipes. PMID- 21791039 TI - Comparative high-throughput transcriptome sequencing and development of SiESTa, the Silene EST annotation database. AB - BACKGROUND: The genus Silene is widely used as a model system for addressing ecological and evolutionary questions in plants, but advances in using the genus as a model system are impeded by the lack of available resources for studying its genome. Massively parallel sequencing cDNA has recently developed into an efficient method for characterizing the transcriptomes of non-model organisms, generating massive amounts of data that enable the study of multiple species in a comparative framework. The sequences generated provide an excellent resource for identifying expressed genes, characterizing functional variation and developing molecular markers, thereby laying the foundations for future studies on gene sequence and gene expression divergence. Here, we report the results of a comparative transcriptome sequencing study of eight individuals representing four Silene and one Dianthus species as outgroup. All sequences and annotations have been deposited in a newly developed and publicly available database called SiESTa, the Silene EST annotation database. RESULTS: A total of 1,041,122 EST reads were generated in two runs on a Roche GS-FLX 454 pyrosequencing platform. EST reads were analyzed separately for all eight individuals sequenced and were assembled into contigs using TGICL. These were annotated with results from BLASTX searches and Gene Ontology (GO) terms, and thousands of single-nucleotide polymorphisms (SNPs) were characterized. Unassembled reads were kept as singletons and together with the contigs contributed to the unigenes characterized in each individual. The high quality of unigenes is evidenced by the proportion (49%) that have significant hits in similarity searches with the A. thaliana proteome. The SiESTa database is accessible at http://www.siesta.ethz.ch. CONCLUSION: The sequence collections established in the present study provide an important genomic resource for four Silene and one Dianthus species and will help to further develop Silene as a plant model system. The genes characterized will be useful for future research not only in the species included in the present study, but also in related species for which no genomic resources are yet available. Our results demonstrate the efficiency of massively parallel transcriptome sequencing in a comparative framework as an approach for developing genomic resources in diverse groups of non-model organisms. PMID- 21791040 TI - Comparison of quantitative real time PCR with Sequencing and ribosomal RNA-FISH for the identification of fungi in formalin fixed, paraffin-embedded tissue specimens. AB - BACKGROUND: Identification of the causative agents of invasive fungal infections (IFI) is critical for guiding antifungal therapy. Cultures remain negative in a substantial number of IFI cases. Accordingly, species identification from formalin fixed, paraffin embedded (FFPE) tissue specimens by molecular methods such as fluorescence in situ hybridisation (FISH) and PCR provides an appealing approach to improve management of patients. METHODS: We designed FISH probes targeting the 28S rRNA of Aspergillus and Candida and evaluated them with type strains. Fluorescence microscopy (FM), using FISH probes and quantitative broad range fungal PCR targeting the rRNA gene were applied to FFPE tissue specimens from patients with proven IFI in order to explore benefits and limitations of each approach. RESULTS: PCR followed by sequencing identified a broad spectrum of pathogenic fungi in 28 of 40 evaluable samples (70%). Hybridisation of FISH probes to fungal rRNA was documented in 19 of 40 tissue samples (47.5%), including 3 PCR negative samples with low fungal burden. The use of FISH was highly sensitive in invasive yeast infections, but less sensitive for moulds. In samples with hyphal elements, the evaluation of hybridisation was impaired due to autofluorescence of hyphae and necrotic tissue background. CONCLUSIONS: While PCR appears to be more sensitive in identifying the causative agents of IFI, some PCR negative and FISH positive samples suggest that FISH has some potential in the rapid identification of fungi from FFPE tissue samples. PMID- 21791041 TI - Exercise therapy for stress-related mental disorder, a randomised controlled trial in primary care. AB - BACKGROUND: to investigate whether a structured physical exercise programme (PEP) improves the recovery of general health in patients suffering from Stress-related Mental Disorder (SMD). METHOD: STUDY DESIGN: randomised open trial in general practice. Patients from two regions in the Netherlands were included between September 2003 and December 2005, and followed up for 12 weeks. INTERVENTION: the patients were referred to a physical therapist for instruction in and monitoring of physical exercise of an intermediate intensity. Following the Dutch Guidelines for Healthy Physical Exercise, the patients were instructed to exercise at least five times a week, for at least 30 minutes per day. CONTROL GROUP: usual care from the GP OUTCOME: Primary: improvement of general health after 6 weeks according to the 'general health' dimension of the Short-Form 36.Secondary: total days off work, percentage that resumed work after 6 and 12 weeks, change in distress score and change in remaining SF36 dimensions after 6 and 12 weeks. RESULTS: out of 102 randomised patients (mean age 43, 60 (59%) female), 70 (68%) completed the trial, of whom 31 were in the intervention group. After 6 weeks, the mean (SD) general health score was 54.6 (22.1) for the intervention group and 57.5 (19.2) for the controls. The corresponding effect size (Cohen's d with 95% confidence interval) from analysis of covariance was -0.06 (-0.41, 0.30) indicating no effect on general health. No significant effects of the intervention were detected for any secondary outcome parameter either. CONCLUSION: Notwithstanding the relatively high drop-out rate, our results suggest that referral to a physical therapist for structured physical exercise is not likely to be very effective in improving recovery from SMD. TRIAL REGISTRY: Current Controlled Trials ISRCTN15609105. PMID- 21791042 TI - Non-specific symptoms as clues to changes in emotional well-being. AB - BACKGROUND: Somatic symptoms are a common reason for visits to the family physician. The aim of this study was to examine the relation between non-specific symptoms and changes in emotional well-being and the degree to which the physician considers the possibility of mental distress when faced with such patients. METHODS: Patients who complained of two or more symptoms including headache, dizziness, fatigue or weakness, palpitations and sleep disorders over one year were identified from the medical records of a random sample of 45 primary care physicians. A control group matched for gender and age was selected from the same population. Emotional well-being was assessed using the MOS-SF 36 in both groups. RESULTS: The study group and the control group each contained 110 patients. Completed MOS questionnaires were obtained from 92 patients, 48 patients with somatic symptoms and 44 controls. Sixty percent of the patients with somatic symptoms experienced decreased emotional well being compared to 25% in the control group (p = 0.00005). Symptoms of dizziness, fatigue and sleep disturbances were significantly linked with mental health impairments. Primary care physicians identified only 6 of 29 patients (21%) whose responses revealed functional limitations due to emotional problems as suffering from an emotional disorder and only 6 of 23 patients (26%) with a lack of emotional well being were diagnosed with an emotional disorder. CONCLUSIONS: Non-specific somatic symptoms may be clues to changes in emotional well-being. Improved recognition and recording of mental distress among patients who complain of these symptoms may enable better follow up and treatment. PMID- 21791043 TI - T cell activity in successful treatment of chronic urticaria with omalizumab. AB - Omalizumab, a humanized monoclonal anti-IgE antibody has the potential to alter allergen processing. Recently, it has been postulated the assessment of PHA stimulated adenosine triphosphate (ATP) activity as maker of CD4+ T cells activity in peripheral blood cells. We present the case report of a 35-year-old woman with a history of chronic idiopathic urticaria and angioedema of 8 years of development with poor response to treatment. The patient was partially controlled with cyclosporine at doses of 100 mg/12 h. However, she was still developing hives daily. Finally treatment with omalizumab was started at dose of 300 mg every 2 weeks. The patient experienced a decrease in urticarial lesions 2 days after starting therapy. We also evaluated the effects of omalizumab therapy on the activity of peripheral blood CD4+ T cells from the patient, in order to determine the potential modification of anti-IgE therapy on the process of antigen presentation-recognition. Activity of CD4+ cells by ATP release was clearly increased demonstrating an enlarged CD4 activity. Omalizumab may be useful in the treatment of severe chronic urticaria. ATP activity of peripheral blood CD4+ T cells might be a non-subjective method to assess Omalizumab activity. PMID- 21791044 TI - PaCO2 and alveolar dead space are more relevant than PaO2/FiO2 ratio in monitoring the respiratory response to prone position in ARDS patients: a physiological study. AB - INTRODUCTION: Our aims in this study were to report changes in the ratio of alveolar dead space to tidal volume (VDalv/VT) in the prone position (PP) and to test whether changes in partial pressure of arterial CO2 (PaCO2) may be more relevant than changes in the ratio of partial pressure of arterial O2 to fraction of inspired O2 (PaO2/FiO2) in defining the respiratory response to PP. We also aimed to validate a recently proposed method of estimation of the physiological dead space (VDphysiol/VT) without measurement of expired CO2. METHODS: Thirteen patients with a PaO2/FiO2 ratio < 100 mmHg were included in the study. Plateau pressure (Pplat), positive end-expiratory pressure (PEEP), blood gas analysis and expiratory CO2 were recorded with patients in the supine position and after 3, 6, 9, 12 and 15 hours in the PP. Responders to PP were defined after 15 hours of PP either by an increase in PaO2/FiO2 ratio > 20 mmHg or by a decrease in PaCO2 > 2 mmHg. Estimated and measured VDphysiol/VT ratios were compared. RESULTS: PP induced a decrease in Pplat, PaCO2 and VDalv/VT ratio and increases in PaO2/FiO2 ratios and compliance of the respiratory system (Crs). Maximal changes were observed after six to nine hours. Changes in VDalv/VT were correlated with changes in Crs, but not with changes in PaO2/FiO2 ratios. When the response was defined by PaO2/FiO2 ratio, no significant differences in Pplat, PaCO2 or VDalv/VT alterations between responders (n = 7) and nonresponders (n = 6) were observed. When the response was defined by PaCO2, four patients were differently classified, and responders (n = 7) had a greater decrease in VDalv/VT ratio and in Pplat and a greater increase in PaO2/FiO2 ratio and in Crs than nonresponders (n = 6). Estimated VDphysiol/VT ratios significantly underestimated measured VDphysiol/VT ratios (concordance correlation coefficient 0.19 (interquartile ranges 0.091 to 0.28)), whereas changes during PP were more reliable (concordance correlation coefficient 0.51 (0.32 to 0.66)). CONCLUSIONS: PP induced a decrease in VDalv/VT ratio and an improvement in respiratory mechanics. The respiratory response to PP appeared more relevant when PaCO2 rather than the PaO2/FiO2 ratio was used. Estimated VDphysiol/VT ratios systematically underestimated measured VDphysiol/VT ratios. PMID- 21791045 TI - Biobanking after robotic-assisted radical prostatectomy: a quality assessment of providing prostate tissue for RNA studies. AB - BACKGROUND: RNA quality is believed to decrease with ischaemia time, and therefore open radical prostatectomy has been advantageous in allowing the retrieval of the prostate immediately after its devascularization. In contrast, robotic-assisted laparoscopic radical prostatectomies (RALP) require the completion of several operative steps before the devascularized prostate can be extirpated, casting doubt on the validity of this technique as a source for obtaining prostatic tissue. We seek to establish the integrity of our biobanking process by measuring the RNA quality of specimens derived from robotic-assisted laparoscopic radical prostatectomy. METHODS: We describe our biobanking process and report the RNA quality of prostate specimens using advanced electrophoretic techniques (RNA Integrity Numbers, RIN). Using multivariate regression analysis we consider the impact of various clinicopathological correlates on RNA integrity. RESULTS: Our biobanking process has been used to acquire 1709 prostates, and allows us to retain approximately 40% of the prostate specimen, without compromising the histopathological evaluation of patients. We collected 186 samples from 142 biobanked prostates, and demonstrated a mean RIN of 7.25 (standard deviation 1.64) in 139 non-stromal samples, 73% of which had a RIN >= 7. Multivariate regression analysis revealed cell type--stromal/epithelial and benign/malignant--and prostate volume to be significant predictors of RIN, with unstandardized coefficients of 0.867(p = 0.001), 1.738(p < 0.001) and -0.690(p = 0.009) respectively. A mean warm ischaemia time of 120 min (standard deviation 30 min) was recorded, but multivariate regression analysis did not demonstrate a relationship with RIN within the timeframe of the RALP procedure. CONCLUSIONS: We demonstrate the robustness of our protocol--representing the concerted efforts of dedicated urology and pathology departments--in generating RNA of sufficient concentration and quality, without compromising the histopathological evaluation and diagnosis of patients. The ischaemia time associated with our prostatectomy technique using a robotic platform does not negatively impact on biobanking for RNA studies. PMID- 21791047 TI - Immune reconstitution inflammatory syndrome associated with acquired immunodeficiency syndrome-related gastrointestinal limited Kaposi's sarcoma presenting as acute intestinal obstruction: a case report. AB - INTRODUCTION: Immune reconstitution inflammatory syndrome during anti-retroviral treatment of acquired immunodeficiency syndrome (AIDS) -associated gastrointestinal Kaposi's sarcoma has rarely been reported. CASE PRESENTATION: A 36-year-old Asian Indian male, newly diagnosed with AIDS and treatment naive, was started on highly active antiretroviral therapy (HAART). He developed acute intestinal obstruction after four weeks of therapy. A laparotomy was done with excision and adhesiolysis leading to relief of symptoms. A histology report revealed the lesion to be Kaposi's sarcoma. Our patient was diagnosed to be having immune reconstitution inflammatory syndrome associated with AIDS associated gastrointestinal limited Kaposi's sarcoma, which presented as acute intestinal obstruction. Our patient was treated with paclitaxel post-operatively and HAART was continued. Our patient responded to therapy. CONCLUSION: Immune reconstitution inflammatory syndrome involving Kaposi's sarcoma may occur in HAART-naive individuals with AIDS-related Kaposi's sarcoma. Gastrointestinal Kaposi's sarcoma may present with sudden increase in size or inflammation leading to acute intestinal obstruction. This does not indicate failure of HAART or a need for changes in anti-retroviral regimen. PMID- 21791046 TI - Is antipsychotic polypharmacy associated with metabolic syndrome even after adjustment for lifestyle effects?: a cross-sectional study. AB - BACKGROUND: Although the validity and safety of antipsychotic polypharmacy remains unclear, it is commonplace in the treatment of schizophrenia. This study aimed to investigate the degree that antipsychotic polypharmacy contributed to metabolic syndrome in outpatients with schizophrenia, after adjustment for the effects of lifestyle. METHODS: A cross-sectional survey was carried out between April 2007 and October 2007 at Yamanashi Prefectural KITA hospital in Japan. 334 patients consented to this cross-sectional study. We measured the components consisting metabolic syndrome, and interviewed the participants about their lifestyle. We classified metabolic syndrome into four groups according to the severity of metabolic disturbance: the metabolic syndrome; the pre-metabolic syndrome; the visceral fat obesity; and the normal group. We used multinomial logistic regression models to assess the association of metabolic syndrome with antipsychotic polypharmacy, adjusting for lifestyle. RESULTS: Seventy-four (22.2%) patients were in the metabolic syndrome group, 61 (18.3%) patients were in the pre-metabolic syndrome group, and 41 (12.3%) patients were in visceral fat obesity group. Antipsychotic polypharmacy was present in 167 (50.0%) patients. In multinomial logistic regression analyses, antipsychotic polypharmacy was significantly associated with the pre-metabolic syndrome group (adjusted odds ratio [AOR], 2.348; 95% confidence interval [CI], 1.181-4.668), but not with the metabolic syndrome group (AOR, 1.269; 95%CI, 0.679-2.371). CONCLUSIONS: These results suggest that antipsychotic polypharmacy, compared with monotherapy, may be independently associated with an increased risk of having pre-metabolic syndrome, even after adjusting for patients' lifestyle characteristics. As metabolic syndrome is associated with an increased risk of cardiovascular mortality, further studies are needed to clarify the validity and safety of antipsychotic polypharmacy. PMID- 21791048 TI - From PALSA PLUS to PALM PLUS: adapting and developing a South African guideline and training intervention to better integrate HIV/AIDS care with primary care in rural health centers in Malawi. AB - BACKGROUND: Only about one-third of eligible HIV/AIDS patients receive anti retroviral treatment (ART). Decentralizing treatment is crucial to wider and more equitable access, but key obstacles are a shortage of trained healthcare workers (HCW) and challenges integrating HIV/AIDS care with other primary care. This report describes the development of a guideline and training program (PALM PLUS) designed to integrate HIV/AIDS care with other primary care in Malawi. PALM PLUS was adapted from PALSA PLUS, developed in South Africa, and targets middle-cadre HCWs (clinical officers, nurses, and medical assistants). We adapted it to align with Malawi's national treatment protocols, more varied healthcare workforce, and weaker health system infrastructure. METHODS/DESIGN: The international research team included the developers of the PALSA PLUS program, key Malawi-based team members and personnel from national and district level Ministry of Health (MoH), professional associations, and an international non-governmental organization. The PALSA PLUS guideline was extensively revised based on Malawi national disease specific guidelines. Advice and input was sought from local clinical experts, including middle-cadre personnel, as well as Malawi MoH personnel and representatives of Malawian professional associations. RESULTS: An integrated guideline adapted to Malawian protocols for adults with respiratory conditions, HIV/AIDS, tuberculosis, and other primary care conditions was developed. The training program was adapted to Malawi's health system and district-level supervision structure. PALM PLUS is currently being piloted in a cluster randomized trial in health centers in Malawi (ISRCTN47805230). DISCUSSION: The PALM PLUS guideline and training intervention targets primary care middle-cadre HCWs with the objective of improving HCW satisfaction and retention, and the quality of patient care. Successful adaptations are feasible, even across health systems as different as those of South Africa and Malawi. PMID- 21791049 TI - Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study. AB - INTRODUCTION: Vitamin D has been postulated to be involved in cancer prognosis. Thus far, only two studies reported on its association with recurrence and survival after breast cancer diagnosis yielding inconsistent results. Therefore, the aim of our study was to assess the effect of post-diagnostic serum 25 hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease free survival. METHODS: We conducted a prospective cohort study in Germany including 1,295 incident postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2002 and 2005 and median follow-up was 5.8 years. Cox proportional hazards models were stratified by age at diagnosis and season of blood collection and adjusted for other prognostic factors. Fractional polynomials were used to assess the true dose-response relation for 25(OH)D. RESULTS: Lower concentrations of 25(OH)D were linearly associated with higher risk of death (hazard ratio (HR) = 1.08 per 10 nmol/L decrement; 95% confidence interval (CI), 1.00 to 1.17) and significantly higher risk of distant recurrence (HR = 1.14 per 10 nmol/L decrement; 95%CI, 1.05 to 1.24). Compared with the highest tertile (>= 55 nmol/L), patients within the lowest tertile (< 35 nmol/L) of 25(OH)D had a HR for overall survival of 1.55 (95%CI, 1.00 to 2.39) and a HR for distant disease-free survival of 2.09 (95%CI, 1.29 to 3.41). In addition, the association with overall survival was found to be statistically significant only for 25(OH)D levels of blood samples collected before start of chemotherapy but not for those of samples taken after start of chemotherapy (P for interaction = 0.06). CONCLUSIONS: In conclusion, lower serum 25(OH)D concentrations may be associated with poorer overall survival and distant disease-free survival in postmenopausal breast cancer patients. PMID- 21791050 TI - Limited redundancy in genes regulated by Cyclin T2 and Cyclin T1. AB - BACKGROUND: The elongation phase, like other steps of transcription by RNA Polymerase II, is subject to regulation. The positive transcription elongation factor b (P-TEFb) complex allows for the transition of mRNA synthesis to the productive elongation phase. P-TEFb contains Cdk9 (Cyclin-dependent kinase 9) as its catalytic subunit and is regulated by its Cyclin partners, Cyclin T1 and Cyclin T2. The HIV-1 Tat transactivator protein enhances viral gene expression by exclusively recruiting the Cdk9-Cyclin T1 P-TEFb complex to a RNA element in nascent viral transcripts called TAR. The expression patterns of Cyclin T1 and Cyclin T2 in primary monocytes and CD4+ T cells suggests that Cyclin T2 may be generally involved in expression of constitutively expressed genes in quiescent cells, while Cyclin T1 may be involved in expression of genes up-regulated during macrophage differentiation, T cell activation, and conditions of increased metabolic activity To investigate this issue, we wished to identify the sets of genes whose levels are regulated by either Cyclin T2 or Cyclin T1. FINDINGS: We used shRNA lentiviral vectors to stably deplete either Cyclin T2 or Cyclin T1 in HeLa cells. Total RNA extracted from these cells was subjected to cDNA microarray analysis. We found that 292 genes were down- regulated by depletion of Cyclin T2 and 631 genes were down-regulated by depletion of Cyclin T1 compared to cells transduced with a control lentivirus. Expression of 100 genes was commonly reduced in either knockdown. Additionally, 111 and 287 genes were up-regulated when either Cyclin T2 or Cyclin T1 was depleted, respectively, with 45 genes in common. CONCLUSIONS: These results suggest that there is limited redundancy in genes regulated by Cyclin T1 or Cyclin T2. PMID- 21791051 TI - An integrative approach to inferring biologically meaningful gene modules. AB - BACKGROUND: The ability to construct biologically meaningful gene networks and modules is critical for contemporary systems biology. Though recent studies have demonstrated the power of using gene modules to shed light on the functioning of complex biological systems, most modules in these networks have shown little association with meaningful biological function. We have devised a method which directly incorporates gene ontology (GO) annotation in construction of gene modules in order to gain better functional association. RESULTS: We have devised a method, Semantic Similarity-Integrated approach for Modularization (SSIM) that integrates various gene-gene pairwise similarity values, including information obtained from gene expression, protein-protein interactions and GO annotations, in the construction of modules using affinity propagation clustering. We demonstrated the performance of the proposed method using data from two complex biological responses: 1. the osmotic shock response in Saccharomyces cerevisiae, and 2. the prion-induced pathogenic mouse model. In comparison with two previously reported algorithms, modules identified by SSIM showed significantly stronger association with biological functions. CONCLUSIONS: The incorporation of semantic similarity based on GO annotation with gene expression and protein protein interaction data can greatly enhance the functional relevance of inferred gene modules. In addition, the SSIM approach can also reveal the hierarchical structure of gene modules to gain a broader functional view of the biological system. Hence, the proposed method can facilitate comprehensive and in-depth analysis of high throughput experimental data at the gene network level. PMID- 21791052 TI - Is it time to recast the principles of antimicrobial prophylaxis? AB - Perioperative antimicrobial prophylaxis has been a time-honored principle in the prevention of surgical site infection. Its effectiveness has recently been questioned. Potential reasons for the lack of demonstrable efficacy and suggestions for re-examination of this concept are presented. PMID- 21791053 TI - Synthesis and crystal structures of 5'-phenylspiro[indoline-3, 2'-pyrrolidin]-2 one derivatives. AB - BACKGROUND: The spiro- indole-pyrrolidine ring system is a frequently encountered structural motif in many biologically important and pharmacologically relevant alkaloids. The derivatives of spirooxindole ring systems are used as antimicrobial, antitumour agents and as inhibitors of the human NKI receptor besides being found in a number of alkaloids like horsifiline, spirotryprostatin and (+) elacomine. The recently discovered small-molecule MDM2 inhibitor MI-219 and its analogues are in advanced preclinical development as cancer therapeutics. RESULTS: In the crystal structures of the two organic compounds, 4'-Nitro-3',5' diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro 5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one, N-H...O hydrogen bonds make the R22 (8) ring motif. Further, the structures are stabilized by intermolecular hydrogen bonds. CONCLUSION: The crystal structures of 4'-Nitro-3',5' diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro 5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one have been investigated in detail. In both the compounds, the R22(8) motif is present. Due to the substitution of methoxyphenyl instead of phenyl ring, the entire configuration is inverted with respect to the 2-oxyindole ring. PMID- 21791054 TI - Web GIS in practice X: a Microsoft Kinect natural user interface for Google Earth navigation. AB - This paper covers the use of depth sensors such as Microsoft Kinect and ASUS Xtion to provide a natural user interface (NUI) for controlling 3-D (three dimensional) virtual globes such as Google Earth (including its Street View mode), Bing Maps 3D, and NASA World Wind. The paper introduces the Microsoft Kinect device, briefly describing how it works (the underlying technology by PrimeSense), as well as its market uptake and application potential beyond its original intended purpose as a home entertainment and video game controller. The different software drivers available for connecting the Kinect device to a PC (Personal Computer) are also covered, and their comparative pros and cons briefly discussed. We survey a number of approaches and application examples for controlling 3-D virtual globes using the Kinect sensor, then describe Kinoogle, a Kinect interface for natural interaction with Google Earth, developed by students at Texas A&M University. Readers interested in trying out the application on their own hardware can download a Zip archive (included with the manuscript as additional files 1, 2, &3) that contains a 'Kinnogle installation package for Windows PCs'. Finally, we discuss some usability aspects of Kinoogle and similar NUIs for controlling 3-D virtual globes (including possible future improvements), and propose a number of unique, practical 'use scenarios' where such NUIs could prove useful in navigating a 3-D virtual globe, compared to conventional mouse/3 D mouse and keyboard-based interfaces. PMID- 21791055 TI - The cross-pathway control system regulates production of the secondary metabolite toxin, sirodesmin PL, in the ascomycete, Leptosphaeria maculans. AB - BACKGROUND: Sirodesmin PL is a secondary metabolite toxin made by the ascomycetous plant pathogen, Leptosphaeria maculans. The sirodesmin biosynthetic genes are clustered in the genome. The key genes are a non-ribosomal peptide synthetase, sirP, and a pathway-specific transcription factor, sirZ. Little is known about regulation of sirodesmin production. RESULTS: Genes involved in regulation of sirodesmin PL in L. maculans have been identified. Two hundred random insertional T-DNA mutants were screened with an antibacterial assay for ones producing low levels of sirodesmin PL. Three such mutants were isolated and each transcribed sirZ at very low levels. One of the affected genes had high sequence similarity to Aspergillus fumigatus cpcA, which regulates the cross pathway control system in response to amino acid availability. This gene was silenced in L. maculans and the resultant mutant characterised. When amino acid starvation was artificially-induced by addition of 3-aminotriazole for 5 h, transcript levels of sirP and sirZ did not change in the wild type. In contrast, levels of sirP and sirZ transcripts increased in the silenced cpcA mutant. After prolonged amino acid starvation the silenced cpcA mutant produced much higher amounts of sirodesmin PL than the wild type. CONCLUSIONS: Production of sirodesmin PL in L. maculans is regulated by the cross pathway control gene, cpcA, either directly or indirectly via the pathway-specific transcription factor, sirZ. PMID- 21791056 TI - Molecular analysis of lipoid proteinosis: identification of a novel nonsense mutation in the ECM1 gene in a Pakistani family. AB - Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood that is caused by homozygous or compound heterozygous mutations in the ECM1 gene located on chromosome 1q21. The aim of the study was to investigate the molecular genetic defect underlying lipoid proteinosis in a consanguineous Pakistani family. METHODS: Genotyping of seven members of the family was performed by amplifying microsatellite markers, tightly linked to the ECM1 gene. To screen for mutations in the ECM1 gene, all of its exons and splice junctions were PCR amplified from genomic DNA and analyzed by SSCP and sequenced directly in an ABI 3130 genetic analyzer. RESULTS: The results revealed linkage of the LP family to the ECM1 locus. Sequence analysis of the coding exons and splice junctions of the ECM1 gene revealed a novel homozygous mutation (c.616C > T) in exon 6, predicted to replace glutamine with stop codon (p.Q206X) at amino acid position 206. CONCLUSIONS: The finding of a novel mutation in Pakistani family extends the body of evidence that supports the importance of ECM1 gene for the development of lipoid proteinosis. PMID- 21791057 TI - Clostridium difficile and methicillin-resistant Staphylococcus aureus shedding by slaughter-age pigs. AB - BACKGROUND: Clostridium difficile and methicillin-resistant Staphylococcus aureus are critical human pathogens and of increasing concern in food animals. Because of the apparent impact of age on prevalence of these organisms, studies of slaughter age pigs are important when considering the potential for contamination of food. This study evaluated C. difficile and MRSA shedding by slaughter age pigs from farms across Canada. RESULTS: Clostridium difficile was isolated from 30/436 (6.9%) samples from 15/45 (33%) farms. After adjusting for clustering at the herd level, the prevalence was 3.4%. Ribotype 078 (toxinotype V, North American Pulsotype 7) was the most common strain, accounting for 67% of isolates. MRSA was isolated from 21/460 (4.6%) pigs from 5/46 (11%) farms. The prevalence in pigs after adjusting for clustering at the herd level was 0.2%. Seven different spa types were identified, with 3 related spa types (t011, t034, new) accounting for 16 (76%) consistent with ST398 predominating. Both MRSA and C. difficile samples were collected from 45 farms. Both MRSA and C. difficile were detected on 2 (4.4%), with C. difficile only on 13 (29%), MRSA only on 3 (6.7%) and neither on 27 (60%). CONCLUSIONS: The prevalence of C. difficile and MRSA in slaughter age pigs was relatively low, particularly in comparison with studies involving younger pigs. The predominance of C. difficile ribotype 078 and MRSA ST398 was not surprising, but there was diversity in strain types and the majority of isolates of both organisms were strains that can be found in humans. While the prevalence of C. difficile and MRSA in slaughter age pigs was relatively low, there is clearly potential for contamination of meat from healthy pigs carrying this pathogen into slaughterhouses. PMID- 21791058 TI - Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study. AB - BACKGROUND: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. METHODS: Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). RESULTS: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. CONCLUSIONS: Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01235416. PMID- 21791060 TI - Rational design of the gram-scale synthesis of nearly monodisperse semiconductor nanocrystals. AB - We address two aspects of general interest for the chemical synthesis of colloidal semiconductor nanocrystals: (1) the rational design of the synthesis protocol aiming at the optimization of the reaction parameters in a minimum number of experiments; (2) the transfer of the procedure to the gram scale, while maintaining a low size distribution and maximizing the reaction yield. Concerning the first point, the design-of-experiment (DOE) method has been applied to the synthesis of colloidal CdSe nanocrystals. We demonstrate that 16 experiments, analyzed by means of a Taguchi L16 table, are sufficient to optimize the reaction parameters for controlling the mean size of the nanocrystals in a large range while keeping the size distribution narrow (5-10%). The DOE method strongly reduces the number of experiments necessary for the optimization as compared to trial-and-error approaches. Furthermore, the Taguchi table analysis reveals the degree of influence of each reaction parameter investigated (e.g., the nature and concentration of reagents, the solvent, the reaction temperature) and indicates the interactions between them. On the basis of these results, the synthesis has been scaled up by a factor of 20. Using a 2-L batch reactor combined with a high throughput peristaltic pump, different-sized samples of CdSe nanocrystals with yields of 2-3 g per synthesis have been produced without sacrificing the narrow size distribution. In a similar setup, the gram-scale synthesis of CdSe/CdS/ZnS core/shell/shell nanocrystals exhibiting a fluorescence quantum yield of 81% and excellent resistance of the photoluminescence in presence of a fluorescent quencher (aromatic thiol) has been achieved.PACS: 81.20.Ka, 81.07.Bc, 78.67.Bf. PMID- 21791059 TI - Dexamethasone restrains ongoing expression of interleukin-23p19 in peripheral blood-derived human macrophages. AB - BACKGROUND: Since its recent discovery, interleukin-23 has been shown to be involved in the pathogenesis of autoimmune diseases favoring the development of a T cell subset referred to as T helper 17. Glucocorticoids are widely employed in inflammatory and autoimmune diseases as they inhibit pro-inflammatory signaling and prevent production of inflammation mediators. Very limited information is available about the efficacy of synthetic glucocorticoids in containing the expression of interleukin-23 under cell activation. RESULTS: We demonstrate here that the glucocorticoid analogue dexamethasone administered to human monocyte derived macrophages is indeed able to restrain the expression of interleukin-23 once it has been triggered by a pro-inflammatory stimulus. This effect of dexamethasone is here demonstrated being secondary to suppression of p38 MAPK activity, and involving a protein phosphatase--likely MAPK phosphatase-1 (MKP-1). CONCLUSIONS: Results reported in this paper show that a 10 nanomolar dose of dexamethasone not only prevents inflammatory activation but is also efficacious in confining active inflammation. This effect is here demonstrated not to occur through "canonical" inhibition of the NF-kappaB transcription factor but through a distinct cascade of down-modulation, that underlines the importance of the transactivating activity of glucocorticoid receptor in the context of its anti inflammatory action. PMID- 21791061 TI - Evaluation of sexual history-based screening of anatomic sites for chlamydia trachomatis and neisseria gonorrhoeae infection in men having sex with men in routine practice. AB - BACKGROUND: Sexually transmitted infection (STI) screening programmes are implemented in many countries to decrease burden of STI and to improve sexual health. Screening for Chlamydia trachomatis and Neisseria gonorrhoeae has a prominent role in these protocols. Most of the screening programmes concerning men having sex with men (MSM) are based on opportunistic urethral testing. In The Netherlands, a history-based approach is used. The aim of this study is to evaluate the protocol of screening anatomic sites for C. trachomatis and N. gonorrhoeae infection based on sexual history in MSM in routine practice in The Netherlands. METHODS: All MSM visiting the clinic for STI in The Hague are routinely asked about their sexual practice during consulting. As per protocol, tests for urogenital, oropharyngeal and anorectal infection are obtained based on reported site(s) of sexual contact. All consultations are entered into a database as part of the national STI monitoring system. Data of an 18 months period were retrieved from this database and analysed. RESULTS: A total of 1455 consultations in MSM were registered during the study period. The prevalence of C. trachomatis and N. gonorrhoeae per anatomic site was: urethral infection 4.0% respectively and 2.8%, oropharynx 1.5% and 4.2%, and anorectum 8.2% and 6.0%. The majority of chlamydia cases (72%) involved a single anatomic site, which was especially manifest for anorectal infections (79%), while 42% of gonorrhoea cases were single site. Twenty-six percent of MSM with anorectal chlamydia and 17% with anorectal gonorrhoea reported symptoms of proctitis; none of the oropharyngeal infections were symptomatic. Most cases of anorectal infection (83%) and oropharyngeal infection (100%) would have remained undiagnosed with a symptom based protocol. CONCLUSIONS: The current strategy of sexual-history based screening of multiple anatomic sites for chlamydia and gonorrhoea in MSM is a useful and valid guideline which is to be preferred over a symptom-based screening protocol. PMID- 21791062 TI - Validation of the Turkish version of the Centre for Epidemiologic Studies Depression Scale (CES-D) in patients with type 2 diabetes mellitus. AB - BACKGROUND: Depression is a common co-morbid health problem in patients with diabetes that is underrecognised. Current international guidelines recommend screening for depression in patients with diabetes. Yet, few depression screening instruments have been validated for use in this particular group of patients. Aim of the present study was to investigate the psychometric properties of the Turkish version of the Centre for Epidemiologic Studies Depression Scale (CES-D) in patients with type 2 diabetes. METHODS: A sample of 151 Turkish outpatients with type 2 diabetes completed the CES-D, the World Health Organization-Five Well Being Index (WHO-5), and the Problem Areas in Diabetes scale (PAID). Explanatory factor analyses, various correlations and Cronbach's alpha were investigated to test the validity and reliability of the CES-D in Turkish diabetes outpatients. RESULTS: The original four-factor structure proposed by Radloff was not confirmed. Explanatory factor analyses revealed a two-factor structure representing two subscales: (1) depressed mood combined with somatic symptoms of depression and (2) positive affect. However, one item showed insufficient factor loadings. Cronbach's alpha of the total score was high (0.88), as were split-half coefficients (0.77-0.90). The correlation of the CES-D with the WHO-5 was the strongest (r = -0.70), and supported concurrent validity. CONCLUSION: The CES-D appears to be a valid measure for the assessment of depression in Turkish diabetes patients. Future studies should investigate its sensitivity and specificity as well as test-retest reliability. PMID- 21791063 TI - Safety of liver resection and effect on quality of life in patients with benign hepatic disease: single center experience. AB - BACKGROUND: Although liver resection has long been established for selected patients with benign hepatic disease, the success of surgical treatment of these patients cannot be evaluated exclusively through postoperative morbidity and mortality. Therefore, the aim of the study was to prove the safety of liver resection in the treatment of benign liver tumors and to evaluate the effect of surgical treatment on the patients' quality of life. METHODS: A total of 146 patients who underwent liver resection because of benign liver tumors were included in this study. Postoperative outcome was assessed and patients evaluated their quality of life before surgery and at the present time using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ C-30). RESULTS: The rate of serious (> grade 2) complications was 4.1% with no postoperative death. The quality of life assessment revealed an overall improvement of general health status after resection (0.7 vs. 0.56, p < 0.001) and additionally a significant reduction of 6 out of 9 symptoms. Furthermore, compelling benefits in the patients' social and emotional coping could be detected after surgery. CONCLUSIONS: Liver resection for benign liver disease is a safe procedure and leads to a significant improvement of quality of life in selected patients. PMID- 21791064 TI - Who is the research subject in cluster randomized trials in health research? AB - This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met. PMID- 21791065 TI - High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality. AB - INTRODUCTION: Current guidelines recommend maintaining central venous oxygen saturation (ScvO2) higher than 70% in patients with severe sepsis and septic shock. As high levels of ScvO2 may reflect an inadequate use of oxygen, our aim was to evaluate the relation between maximal ScvO2 levels (ScvO2max) and survival among intensive care unit (ICU) patients with septic shock. METHODS: We retrospectively analyzed data from all admissions to our ICU between January 2008 and December 2009. All septic shock patients in whom the ScvO2 was measured were included. The measures of ScvO2max within the first 72 hours after the onset of shock were collected. RESULTS: A total of 1,976 patients were screened and 152 (7.7%) patients met the inclusion criteria. The level of ScvO2max was 85% (78 to 89) in the non-survivors, compared with 79% (72 to 87) in the survivors (P = 0.009). CONCLUSIONS: Our findings raise concerns about high levels of ScvO2 in patients with septic shock. This may reflect the severity of the shock with an impaired oxygen use. Future strategies may target an optimization of tissue perfusion in this specific subgroup of patients. PMID- 21791066 TI - Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas. AB - BACKGROUND: Mammographic density (MD) and malignant-appearing microcalcifications (MAMCs) represent the earliest mammographic findings of non-palpable breast carcinomas. Matrix proteoglycans versican and decorin are frequently over expressed in various malignancies and are differently involved in the progression of cancer. In the present study, we have evaluated the expression of versican and decorin in non-palpable breast carcinomas and their association with high risk mammographic findings and tumor characteristics. METHODS: Three hundred and ten patients with non-palpable suspicious breast lesions, detected during screening mammography, were studied. Histological examination was carried out and the expression of decorin, versican, estrogen receptor alpha (ERalpha), progesterone receptor (PR) and c-erbB2 (HER-2/neu) was assessed by immunohistochemistry. RESULTS: Histological examination showed 83 out of 310 (26.8%) carcinomas of various subtypes. Immunohistochemistry was carried out in 62/83 carcinomas. Decorin was accumulated in breast tissues with MD and MAMCs independently of the presence of malignancy. In contrast, versican was significantly increased only in carcinomas with MAMCs (median +/- SE: 42.0 +/- 9.1) and MD (22.5 +/- 10.1) as compared to normal breast tissue with MAMCs (14.0 +/- 5.8), MD (11.0 +/- 4.4) and normal breast tissue without mammographic findings (10.0 +/- 2.0). Elevated levels of versican were correlated with higher tumor grade and invasiveness in carcinomas with MD and MAMCs, whereas increased amounts of decorin were associated with in situ carcinomas in MAMCs. Stromal deposition of both proteoglycans was related to higher expression of ERalpha and PR in tumor cells only in MAMCs. CONCLUSIONS: The specific accumulation of versican in breast tissue with high MD and MAMCs only in the presence of malignant transformation and its association with the aggressiveness of the tumor suggests its possible use as molecular marker in non-palpable breast carcinomas. PMID- 21791067 TI - Systematic discovery of unannotated genes in 11 yeast species using a database of orthologous genomic segments. AB - BACKGROUND: In standard BLAST searches, no information other than the sequences of the query and the database entries is considered. However, in situations where two genes from different species have only borderline similarity in a BLAST search, the discovery that the genes are located within a region of conserved gene order (synteny) can provide additional evidence that they are orthologs. Thus, for interpreting borderline search results, it would be useful to know whether the syntenic context of a database hit is similar to that of the query. This principle has often been used in investigations of particular genes or genomic regions, but to our knowledge it has never been implemented systematically. RESULTS: We made use of the synteny information contained in the Yeast Gene Order Browser database for 11 yeast species to carry out a systematic search for protein-coding genes that were overlooked in the original annotations of one or more yeast genomes but which are syntenic with their orthologs. Such genes tend to have been overlooked because they are short, highly divergent, or contain introns. The key features of our software - called SearchDOGS - are that the database entries are classified into sets of genomic segments that are already known to be orthologous, and that very weak BLAST hits are retained for further analysis if their genomic location is similar to that of the query. Using SearchDOGS we identified 595 additional protein-coding genes among the 11 yeast species, including two new genes in Saccharomyces cerevisiae. We found additional genes for the mating pheromone a-factor in six species including Kluyveromyces lactis. CONCLUSIONS: SearchDOGS has proven highly successful for identifying overlooked genes in the yeast genomes. We anticipate that our approach can be adapted for study of further groups of species, such as bacterial genomes. More generally, the concept of doing sequence similarity searches against databases to which external information has been added may prove useful in other settings. PMID- 21791068 TI - miRTar: an integrated system for identifying miRNA-target interactions in human. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that are ~22-nt long sequences capable of suppressing protein synthesis. Previous research has suggested that miRNAs regulate 30% or more of the human protein-coding genes. The aim of this work is to consider various analyzing scenarios in the identification of miRNA-target interactions, as well as to provide an integrated system that will aid in facilitating investigation on the influence of miRNA targets by alternative splicing and the biological function of miRNAs in biological pathways. RESULTS: This work presents an integrated system, miRTar, which adopts various analyzing scenarios to identify putative miRNA target sites of the gene transcripts and elucidates the biological functions of miRNAs toward their targets in biological pathways. The system has three major features. First, the prediction system is able to consider various analyzing scenarios (1 miRNA:1 gene, 1:N, N:1, N:M, all miRNAs:N genes, and N miRNAs: genes involved in a pathway) to easily identify the regulatory relationships between interesting miRNAs and their targets, in 3'UTR, 5'UTR and coding regions. Second, miRTar can analyze and highlight a group of miRNA-regulated genes that participate in particular KEGG pathways to elucidate the biological roles of miRNAs in biological pathways. Third, miRTar can provide further information for elucidating the miRNA regulation, i.e., miRNA-target interactions, affected by alternative splicing. CONCLUSIONS: In this work, we developed an integrated resource, miRTar, to enable biologists to easily identify the biological functions and regulatory relationships between a group of known/putative miRNAs and protein coding genes. miRTar is now available at http://miRTar.mbc.nctu.edu.tw/. PMID- 21791069 TI - Rapid progress or lengthy process? Electronic personal health records in mental health. AB - A major objective of many healthcare providers is to increase patients' participation in their own care. The introduction of electronic personal health records (ePHRs) may help to achieve this. An ePHR is an electronic database of an individual's health information, accessible to and maintained by the patient. ePHRs are very much in vogue, with an increasing number of studies reporting their potential utility as well as cost. However, the vast majority of these studies focus on general healthcare. Little attempt has been made to document the specific problems which might occur throughout the implementation of ePHRs in mental health. This review identifies such concerns through an electronic search of the literature. Several potential difficulties are highlighted and addressed, including access to information technology, identifying relevant populations and the handling of sensitive information. Special attention is paid to the concept of 'empowerment' and what this means in relation to ePHRs. PMID- 21791070 TI - Collaborative planning approach to inform the implementation of a healthcare manager intervention for Hispanics with serious mental illness: a study protocol. AB - BACKGROUND: This study describes a collaborative planning approach that blends principles of community-based participatory research (CBPR) and intervention mapping to modify a healthcare manager intervention to a new patient population and provider group and to assess the feasibility and acceptability of this modified intervention to improve the physical health of Hispanics with serious mental illness (SMI) and at risk for cardiovascular disease (CVD). METHODS: The proposed study uses a multiphase approach that applies CBPR principles and intervention-mapping steps--an intervention-planning approach--to move from intervention planning to pilot testing. In phase I, a community advisory board composed of researchers and stakeholders will be assembled to learn and review the intervention and make initial modifications. Phase II uses a combination of qualitative methods--patient focus groups and stakeholder interviews--to ensure that the modifications are acceptable to all stakeholders. Phase III uses results from phase II to further modify the intervention, develop an implementation plan, and train two care managers on the modified intervention. Phase IV consists of a 12-month open pilot study (N = 30) to assess the feasibility and acceptability of the modified intervention and explore its initial effects. Lastly, phase V consists of analysis of pilot study data and preparation for future funding to develop a more rigorous evaluation of the modified intervention. DISCUSSION: The proposed study is one of the few projects to date to focus on improving the physical health of Hispanics with SMI and at risk for CVD by using a collaborative planning approach to enhance the transportability and use of a promising healthcare manager intervention. This study illustrates how blending health-disparities research and implementation science can help reduce the disproportionate burden of medical illness in a vulnerable population. PMID- 21791071 TI - Herpes simplex virus type 1 UL14 tegument protein regulates intracellular compartmentalization of major tegument protein VP16. AB - BACKGROUND: Herpes simplex virus type 1 (HSV-1) has a complicated life-cycle, and its genome encodes many components that can modify the cellular environment to facilitate efficient viral replication. The protein UL14 is likely involved in viral maturation and egress (Cunningham C. et al), and it facilitates the nuclear translocation of viral capsids and the tegument protein VP16 during the immediate early phase of infection (Yamauchi Y. et al, 2008). UL14 of herpes simplex virus type 2 exhibits multiple functions (Yamauchi Y. et al, 2001, 2002, 2003). METHODS: To better understand the function(s) of UL14, we generated VP16-GFP incorporated UL14-mutant viruses with either single (K51M) or triple (R60A, R64A, E68D) amino acid substitutions in the heat shock protein (HSP)-like sequence of UL14. We observed the morphology of cells infected with UL14-null virus and amino acid-substituted UL14-mutant viruses at different time points after infection. RESULTS: UL14(3P)-VP16GFP and UL14D-VP16GFP (UL14-null) viruses caused similar defects with respect to growth kinetics, compartmentalization of tegument proteins, and cellular morphology in the late phase. Both the UL14D-VP16GFP and UL14(3P)-VP16GFP viruses led to the formation of an aggresome that incorporated some tegument proteins but did not include nuclear-egressed viral capsids. CONCLUSIONS: Our findings suggest that a cluster of charged residues within the HSP-like sequence of UL14 is important for the molecular chaperone-like functions of UL14, and this activity is required for the acquisition of functionality of VP16 and UL46. In addition, UL14 likely contributes to maintaining cellular homeostasis following infection, including cytoskeletal organization. However, direct interactions between UL14 and VP16, UL46, or other cellular or viral proteins remain unclear. PMID- 21791072 TI - Adjuvant chemoradiotherapy for locoregionally advanced and high-risk salivary gland malignancies. AB - BACKGROUND: To report the outcomes of patients with locoregionally advanced and high- risk salivary gland malignancies treated with surgery followed by adjuvant chemoradiotherapy. METHODS: From 09/1991 - 06/2007, 24 high-risk salivary gland cancer patients were treated with surgery, followed by adjuvant chemoradiotherapy for high-risk pathologic features including, perineural involvement, nodal involvement, positive margins, or T3/T4 tumors. Chemoradiotherapy was delivered for 4-6 alternating week cycles: the most common regimen, TFHX, consisted of 5 days paclitaxel (100 mg/m2 on d1), infusional 5-fluorouracil (600 mg/m2/d * 5d), hydroxyurea (500 mg PO BID), and 1.5 Gy twice daily irradiation followed by a 9 day break without treatment. RESULTS: Median follow-up was 42 months. The parotid gland was more frequently involved (n = 17) than minor (n = 4) or submandibular (n = 3) glands. The median radiation dose was 65 Gy (range 55-68 Gy). Acute treatment related toxicity included 46% grade 3 mucositis and 33% grade 3 hematologic toxicity. Six patients required feeding tubes during treatment. One patient progressed locally, 8 patients progressed distantly, and none progressed regionally. Five-year locoregional progression free survival was 96%. The 3 and 5 year overall survival was 79% and 59%, respectively. Long-term complications included persistent xerostomia (n = 5), esophageal stricture requiring dilatation (n = 1), and tempromandibular joint syndrome (n = 1). CONCLUSIONS: Surgical resection followed by adjuvant chemoradiotherapy results in promising locoregional control for high-risk salivary malignancy patients. PMID- 21791073 TI - Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study. AB - BACKGROUND: While the factors for poor adherence for treatment with statins have been highlighted, the impact of their combination on adherence is not clear. AIMS: To estimate adherence for statins and whether it differs according to the number of cardiovascular risk factors. METHODS: A cohort study was conducted using data from the main French national health insurance system reimbursement database. Newly treated patients with statins between September 1 and December 31, 2004 were included. Patients were followed up 15 months. The cohort was split into three groups according to their number of additional cardiovascular risk factors that included age and gender, diabetes mellitus and cardiovascular disease (using co-medications as a proxy). Adherence was assessed for each group by using four parameters: (i) proportion of days covered by statins, (ii) regularity of the treatment over time, (iii) persistence, and (iv) the refill delay. RESULTS: 16,397 newly treated patients were identified. Of these statin users, 21.7% did not have additional cardiovascular risk factors. Thirty-one percent had two cardiovascular risk factors and 47% had at least three risk factors. All the parameters showed a sub-optimal adherence whatever the group: days covered ranged from 56% to 72%, regularity ranged from 23% to 33% and persistence ranged from 44% to 59%, but adherence was better for those with a higher number of cardiovascular risk factors. CONCLUSIONS: The results confirm that long-term drug treatments are a difficult challenge, particularly in patients at lower risk and invite to the development of therapeutic education. PMID- 21791074 TI - Change in serum KL-6 level from baseline is useful for predicting life threatening EGFR-TKIs induced interstitial lung disease. AB - BACKGROUND: A high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting. METHODS: We retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD. RESULTS: Among the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005). CONCLUSIONS: The results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD. PMID- 21791075 TI - The wider determinants of inequalities in health: a decomposition analysis. AB - BACKGROUND: The common starting point of many studies scrutinizing the factors underlying health inequalities is that material, cultural-behavioural, and psycho social factors affect the distribution of health systematically through income, education, occupation, wealth or similar indicators of socioeconomic structure. However, little is known regarding if and to what extent these factors can assert systematic influence on the distribution of health of a population independent of the effects channelled through income, education, or wealth. METHODS: Using representative data from the German Socioeconomic Panel, we apply Fields' regression based decomposition techniques to decompose variations in health into its sources. Controlling for income, education, occupation, and wealth, we assess the relative importance of the explanatory factors over and above their effect on the variation in health channelled through the commonly applied measures of socioeconomic status. RESULTS: The analysis suggests that three main factors persistently contribute to variance in health: the capability score, cultural behavioural variables and to a lower extent, the materialist approach. Of the three, the capability score illustrates the explanatory power of interaction and compound effects as it captures the individual's socioeconomic, social, and psychological resources in relation to his/her exposure to life challenges. CONCLUSION: Models that take a reductionist perspective and do not allow for the possibility that health inequalities are generated by factors over and above their effect on the variation in health channelled through one of the socioeconomic measures are underspecified and may fail to capture the determinants of health inequalities. PMID- 21791076 TI - Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells. AB - BACKGROUND: 209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel VHL regulated genes. FINDINGS: NMU (Neuromedin U) is a neuropeptide that has been implicated in energy homeostasis and tumour progression. Here we show for the first time that VHL loss-of-function results in dramatic upregulation of NMU expression in renal cancer cells. The effect of VHL inactivation was found to be mediated via activation of Hypoxia Inducible Factor (HIF). Exposure of VHL expressing RCC cells to either hypoxia or dimethyloxalylglycine resulted in HIF activation and increased NMU expression. Conversely, suppression of HIF in VHL defective RCC cells via siRNA of HIF-alpha subunits or expression of Type 2C mutant VHLs reduced NMU expression levels. We also show that renal cancer cells express a functional NMU receptor (NMUR1), and that NMU stimulates migration of renal cancer cells. CONCLUSIONS: These findings suggest that NMU may act in an autocrine fashion, promoting progression of kidney cancer. Hypoxia and HIF expression are frequently observed in many non-renal cancers and are associated with a poor prognosis. Our study raises the possibility that HIF may also drive NMU expression in non-renal tumours. PMID- 21791077 TI - Lung function in asbestos-exposed workers, a systematic review and meta-analysis. AB - BACKGROUND: A continuing controversy exists about whether, asbestos exposure is associated with significant lung function impairments when major radiological abnormalities are lacking. We conducted a systematic review and meta-analysis in order to assess whether asbestos exposure is related to impairment of lung function parameters independently of the radiological findings. METHODS: MEDLINE was searched from its inception up to April 2010. We included studies that assessed lung function parameters in asbestos exposed workers and stratified subjects according to radiological findings. Estimates of VC, FEV1 and FEV1/VC with their dispersion measures were extracted and pooled. RESULTS: Our meta analysis with data from 9,921 workers exposed to asbestos demonstrates a statistically significant reduction in VC, FEV1 and FEV1/VC, even in those workers without radiological changes. Less severe lung function impairments are detected if the diagnoses are based on (high resolution) computed tomography rather than the less sensitive X-ray images. The degree of lung function impairment was partly related to the proportion of smokers included in the studies. CONCLUSIONS: Asbestos exposure is related to restrictive and obstructive lung function impairment. Even in the absence of radiological evidence of parenchymal or pleural diseases there is a trend for functional impairment. PMID- 21791078 TI - Native low density lipoprotein induces pancreatic beta cell apoptosis through generating excess reactive oxygen species. AB - BACKGROUND: The growing evidences demonstrated hyperlipidemia in obesity and type 2 diabetes is characterized by high levels of free fatty acids, low-density lipoprotein (LDL), triglyceride, and cholesterol. METHOD AND RESULTS: We investigated the effect of LDL particles (LDLs) loading on MIN6 cells derived from pancreatic beta cells. Exposure of MIN6 cells to LDLs induced apoptosis in dose and time-dependent manner, demonstrated by the TUNEL in situ apoptotic assay. The immunocytochemical analysis and Western blotting revealed that the LDLs-induced apoptosis is associated with the activation of caspase 3 and upregulation of p53. The intracellular concentration of Reactive Oxygen Species (ROS) measured by use of DCFHDA was significantly increased after loading LDLs, demonstrating the induced apoptosis by LDLs loading was mediated through oxidative stress. Addition of reduced form of Glutathione (GSH) in the medium rescued MIN6 cells from apoptosis. The Cellular cholesterol level was increased significantly after LDLs loading, suggesting that the excess cholesterol induced by LDLs loading might contribute to the apoptosis in MIN6s. Agarose electrophoresis demonstrated that the LDLs added to the medium were not oxidized. CONCLUSION: Taken together, these results demonstrate that the LDLs loading can induce apoptosis of MIN6 cells mediated by the excess cellular cholesterol and generation of oxidative stress. PMID- 21791079 TI - Proteomic analysis of pregnancy-related proteins from pig uterus endometrium during pregnancy. AB - Many important molecular events associated with implantation and development occur within the female reproductive tract, especially within the uterus endometrium, during pregnancy periods. The endometrium includes the mucosal lining of the uterus, which provides a suitable site for implantation and development of a fertilized egg and fetus. To date, the molecular cascades in the uterus endometrium during pregnancy periods in pigs have not been elucidated fully. In this study, we compared the functional regulated proteins in the endometrium during pregnancy periods with those in non-pregnant conditions and investigated changes in expression patterns during pregnancy (days 40, 70, and 93) using two-dimensional gel electrophoresis (2-DE) and western blotting. The functional regulated proteins were identified and discovered from differentially expressed proteins in the uterus endometrium during pregnancy. We discovered 820 protein spots in a proteomic analysis of uterus endometrium tissues with 2-DE gels. We identified 63 of the 98 proteins regulated differentially among non pregnant and pregnant tissues (matched and unmatched spots). Interestingly, 10 of these 63 proteins are development-, cytoskeleton- and chaperon-related proteins such as transferrin, protein DJ-1, transgelin, galectin-1, septin 2, stathmin 1, cofilin 1, fascin 1, heat shock protein (HSP) 90beta and HSP 27. The specific expression patterns of these proteins in the endometrium during pregnancy were confirmed by western blotting. Our results suggest that the expressions of these genes involved in endometrium function and endometrium development from early to late gestation are associated with the regulation of endometrium development for maintaining pregnancy. PMID- 21791080 TI - E-learning interventions are comparable to user's manual in a randomized trial of training strategies for the AGREE II. AB - BACKGROUND: Practice guidelines (PGs) are systematically developed statements intended to assist in patient and practitioner decisions. The AGREE II is the revised tool for PG development, reporting, and evaluation, comprised of 23 items, two global rating scores, and a new User's Manual. In this study, we sought to develop, execute, and evaluate the impact of two internet interventions designed to accelerate the capacity of stakeholders to use the AGREE II. METHODS: Participants were randomized to one of three training conditions. 'Tutorial'- participants proceeded through the online tutorial with a virtual coach and reviewed a PDF copy of the AGREE II. 'Tutorial + Practice Exercise'--in addition to the Tutorial, participants also appraised a 'practice' PG. For the practice PG appraisal, participants received feedback on how their scores compared to expert norms and formative feedback if scores fell outside the predefined range. 'AGREE II User's Manual PDF (control condition)'--participants reviewed a PDF copy of the AGREE II only. All participants evaluated a test PG using the AGREE II. Outcomes of interest were learners' performance, satisfaction, self-efficacy, mental effort, time-on-task, and perceptions of AGREE II. RESULTS: No differences emerged between training conditions on any of the outcome measures. CONCLUSIONS: We believe these results can be explained by better than anticipated performance of the AGREE II PDF materials (control condition) or the participants' level of health methodology and PG experience rather than the failure of the online training interventions. Some data suggest the online tools may be useful for trainees new to this field; however, this requires further study. PMID- 21791081 TI - Isolation and characterization of a novel podovirus which infects burkholderia pseudomallei. AB - Burkholderia pseudomallei is a saprophytic soil bacterium and the etiological agent that causes melioidosis. It is naturally resistant to many antibiotics and therefore is difficult to treat. Bacteriophages may provide an alternative source of treatment. We have isolated and characterised the bacteriophage PhiBp-AMP1. The phage is a member of the Podoviridae family and has a genome size of ~ 45 Kb. Molecular data based on the gene which encodes for the phage tail tubular protein suggests that the phage is distinct from known phages but related to phages which infect B. thailandensis and Ralstonia spp. The phage PhiBp-AMP1 is the first B. pseudomallei podovirus to be isolated from the environment rather than being induced from a bacterial culture. It has a broad host range within B. pseudomallei and can infect all 11 strains that we tested it on but not related Burkholderia species. It is heat stable for 8 h at 50 degrees C but not stable at 60 degrees C. It may potentially be a useful tool to treat or diagnose B. pseudomallei infections as it can lyse several strains of clinical relevance. PMID- 21791082 TI - Proteolytic cleavage of stingray phospholipase A2: isolation and biochemical characterization of an active N-terminal form. AB - BACKGROUND: Mammalian GIB-PLA2 are well characterized. In contrast, much less is known about aquatic ones. The aquatic world contains a wide variety of living species and, hence represents a great potential for discovering new lipolytic enzymes. The aim of this study was to check some biochemical and structural properties of a marine stingray phospholipase A2 (SPLA2). RESULTS: The effect of some proteolytic enzymes on SPLA2 was checked. Chymotrypsin and trypsin were able to hydrolyze SPLA2 in different ways. In both cases, only N-terminal fragments were accumulated during the hydrolysis, whereas no C-terminal fragment was obtained in either case. Tryptic and chymotryptic attack generated 13 kDa and 12 kDa forms of SPLA2, respectively. Interestingly, the SPLA2 13 kDa form was inactive, whereas the SPLA2 12 kDa form conserved almost its full phospholipase activity. In the absence of bile slats both native and 12 kDa SPLA2 failed to catalyse the hydrolysis of PC emulsion. When bile salts were pre-incubated with the substrate, the native kinetic protein remained linear for more than 25 min, whereas the 12 kDa form activity was found to decrease rapidly. Furthermore, The SPLA2 activity was dependent on Ca2+; other cations (Mg2+, Mn2+, Cd2+ and Zn2+) reduced the enzymatic activity notably, suggesting that the arrangement of the catalytic site presents an exclusive structure for Ca2+. CONCLUSIONS: Although marine and mammal pancreatic PLA2 share a high amino acid sequence homology, polyclonal antibodies directed against SPLA2 failed to recognize mammal PLA2 like the dromedary pancreatic one. Further investigations are needed to identify key residues involved in substrate recognition responsible for biochemical differences between the 2 classes of phospholipases. PMID- 21791083 TI - A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes. AB - BACKGROUND: Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM. METHODS: Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets. RESULTS: In the overall analysis, the most significant association was found to rs10743465, downstream of the SOX5 gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in beta coefficients), located upstream of TMTC1. Twelve additional SNPs in or near 6 genes had p < 0.001. CONCLUSIONS: The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. SOX5 may play an important role in the regulation of LVM. An interaction of TMTC1 with abdominal obesity may contribute to phenotypic variation of LVM. PMID- 21791084 TI - High-level inhibition of mitochondrial complexes III and IV is required to increase glutamate release from the nerve terminal. AB - BACKGROUND: The activities of mitochondrial complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) and complex IV (cytochrome c oxidase EC 1.9.3.1) are reduced by 30-70% in Huntington's disease and Alzheimer's disease, respectively, and are associated with excitotoxic cell death in these disorders. In this study, we investigated the control that complexes III and complex IV exert on glutamate release from the isolated nerve terminal. RESULTS: Inhibition of complex III activity by 60-90% was necessary for a major increase in the rate of Ca2+ independent glutamate release to occur from isolated nerve terminals (synaptosomes) depolarized with 4-aminopyridine or KCl. Similarly, an 85-90% inhibition of complex IV activity was required before a major increase in the rate of Ca2+-independent glutamate release from depolarized synaptosomes was observed. Inhibition of complex III and IV activities by ~ 60% and above was required before rates of glutamate efflux from polarized synaptosomes were increased. CONCLUSIONS: These results suggest that nerve terminal mitochondria possess high reserves of complex III and IV activity and that high inhibition thresholds must be reached before excess glutamate is released from the nerve terminal. The implications of the results in the context of the relationship between electron transport chain enzyme deficiencies and excitotoxicity in neurodegenerative disorders are discussed. PMID- 21791086 TI - Letter to the editors: the potential role for prehospital thrombolysis and time critical stroke transfers in the northern Norway aeromedical retrieval system; In response to: Norum J, Elsbak TM: Air ambulance services in the Arctic: a Norwegian study. Int J Emerg Med 2011, 4:1. AB - The role for prehospital thrombolysis for ST-elevation acute myocardial infarction and time-critical stroke transfers in the northern Norway aeromedical retrieval system as well as the aero-evacuation impact of increased Arctic expedition tourism could benefit from further discussion by Norum and Elsbak. Close ECG surveillance for ST elevation and retrieval thrombolysis en route to the accepting hospital could be of benefit for acute coronary syndrome patients in northern Norway who require prolonged aeromedical transfer. For patients who remain within a reasonable time frame for stroke thrombolysis (up to 4.5 h after symptom onset), expedited transfer for neuroimaging to determine eligibility is recommended. PMID- 21791085 TI - Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. AB - BACKGROUND: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. METHODS: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. RESULTS: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3 hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. CONCLUSION: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways. PMID- 21791087 TI - Association of HCV with diabetes mellitus: an Egyptian case-control study. AB - BACKGROUND: The highest Hepatitis C Virus (HCV) prevalence in the world occurs in Egypt. Several studies from different parts of the world have found that 13% to 33% of patients with chronic HCV have associated diabetes, mostly type II Diabetes Mellitus (DM). In Egypt the prevalence of DM is 25.4% among HCV patients. Therefore, it is important to identify the magnitude of the problem of diabetes in order to optimize the treatment of chronic hepatitis C. METHODS: The objective of this case-control study was to evaluate the prevalence of DM and other extrahepatic (EH) manifestations among patients with different HCV morbidity stages including asymptomatic, chronic hepatic and cirrhotic patients. In this study, 289 HCV patients older than 18 were selected as cases. Also, 289 healthy controls were included. Laboratory investigations including Liver Function tests (LFT) and blood glucose level were done. Also serological assays including cryoglobulin profile, rheumatoid factor, antinuclear antibody, HCV-PCR were performed. RESULTS: Out of 289 HCV cases, 40 (13.84%) were diabetic. Out of 289 healthy controls, 12 (4.15%) were diabetic. It was found that the diabetic HCV group mean age was [48.1 (+/- 9.2)]. Males and urbanians represented 72.5% and 85% respectively. Lower level of education was manifested in 52.5% and 87.5% were married. In the nondiabetic HCV group mean age was [40.7 (+/- 10.4)]. Males and urbanians represented 71.5% and 655% respectively. secondary and higher level of education was attained in 55.4% and 76.7% were married. Comparing between the diabetic HCV group and the non diabetic HCV group, age, residence and alcohol drinking were the only significant factors affecting the incidence of diabetes between the two groups. There was no significant difference regarding sonar findings although cirrhosis was more prevalent among diabetic HCV cases and the fibrosis score was higher in diabetic HCV patients than among the non diabetic HCV cases. CONCLUSION: The diabetic patients in the HCV group were older, more likely to have a history of alcohol drinking than the non diabetic HCV cases. Age and alcohol drinking are factors that could potentially contribute to the development of type 2 diabetes. Logistic regression analyses showed that age and residence in urban regions were the predictive variables that could be associated with the presence of diabetes. Alcohol consumption was not a significant predictive factor. PMID- 21791088 TI - Deterministic and stochastic population-level simulations of an artificial lac operon genetic network. AB - BACKGROUND: The lac operon genetic switch is considered as a paradigm of genetic regulation. This system has a positive feedback loop due to the LacY permease boosting its own production by the facilitated transport of inducer into the cell and the subsequent de-repression of the lac operon genes. Previously, we have investigated the effect of stochasticity in an artificial lac operon network at the single cell level by comparing corresponding deterministic and stochastic kinetic models. RESULTS: This work focuses on the dynamics of cell populations by incorporating the above kinetic scheme into two Monte Carlo (MC) simulation frameworks. The first MC framework assumes stochastic reaction occurrence, accounts for stochastic DNA duplication, division and partitioning and tracks all daughter cells to obtain the statistics of the entire cell population. In order to better understand how stochastic effects shape cell population distributions, we develop a second framework that assumes deterministic reaction dynamics. By comparing the predictions of the two frameworks, we conclude that stochasticity can create or destroy bimodality, and may enhance phenotypic heterogeneity. CONCLUSIONS: Our results show how various sources of stochasticity act in synergy with the positive feedback architecture, thereby shaping the behavior at the cell population level. Further, the insights obtained from the present study allow us to construct simpler and less computationally intensive models that can closely approximate the dynamics of heterogeneous cell populations. PMID- 21791089 TI - Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib. AB - BACKGROUND: Targeted therapies for metastatic renal cell carcinoma (RCC), including mammalian target of rapamycin (mTOR) inhibitors and small-molecule multikinase inhibitors, have produced clinical effects. However, most patients acquire resistance over time. Thus, new therapeutic strategies need to be developed. Here, we evaluated the effect of the dual PI3K/mTOR inhibitor NVP BEZ235, in combination with the multikinase inhibitor sorafenib on renal cancer cell proliferation and survival in vitro as well as on tumor growth in vivo. METHODS: The renal carcinoma cell lines 786-0 and Caki-1 were treated with NVP BEZ235 or sorafenib, either alone or in combination. Tumor cell proliferation and apoptosis were investigated in vitro. The anticancer efficacy of NVP-BEZ235 alone, or in combination with sorafenib, was also evaluated on RCC xenografts in nude mice. RESULTS: Treatment of 786-0 and Caki-1 cells with NVP-BEZ235 or sorafenib resulted in reduced tumor cell proliferation and increased tumor cell apoptosis in vitro. The combination of NVP-BEZ235 and sorafenib was more effective than each compound alone. Similarly, in vivo, NVP-BEZ235 or sorafenib reduced the growth of xenografts generated from 786-0 or Caki-1 cells. The antitumor efficacy of NVP-BEZ235 in combination with sorafenib was superior to NVP-BEZ235 or sorafenib alone. CONCLUSIONS: Our findings indicate that the simultaneous use of NVP-BEZ235 and sorafenib has greater antitumor benefit compared to either drug alone and thus provides a treatment strategy in RCC. PMID- 21791090 TI - High mixed venous oxygen saturation levels do not exclude fluid responsiveness in critically ill septic patients. AB - INTRODUCTION: The aim of this study was to determine whether the degree of fluid responsiveness in critically ill septic patients is related to baseline mixed venous oxygen saturation (SvO2) levels. We also sought to define whether fluid responsiveness would be less likely in the presence of a high SvO2 (>70%). METHODS: This observational study was conducted in a 32-bed university hospital medicosurgical ICU. The hemodynamic response to a fluid challenge was evaluated in 65 critically ill patients with severe sepsis. Patients were divided into two groups (responders and nonresponders) according to their cardiac index (CI) response to the challenge (>10% or <10%). RESULTS: Of the 65 patients, 34 (52%) were fluid responders. Baseline SvO2, CI, heart rate (HR) and mean arterial pressure (MAP) were not statistically different between groups. The responders had lower pulmonary artery occlusion pressure (PAOP) and central venous pressure (CVP) at baseline than the nonresponders. After the fluid challenge, there were no differences between the two groups in MAP, CVP, PAOP or HR. There was no correlation between changes in CI or stroke volume index and baseline SvO2. Receiver operating characteristic analysis showed that SvO2 was not a predictor of fluid responsiveness. CONCLUSIONS: The response of septic patients to a fluid challenge is independent of baseline SvO2. The presence of a high SvO2 does not necessarily exclude the need for further fluid administration. PMID- 21791092 TI - Evaluating syndromic surveillance systems at institutions of higher education (IHEs): a retrospective analysis of the 2009 H1N1 influenza pandemic at two universities. AB - BACKGROUND: Syndromic surveillance has been widely adopted as a real-time monitoring tool for timely response to disease outbreaks. During the second wave of the pH1N1 pandemic in Fall 2009, two major universities in Washington, DC collected data that were potentially indicative of influenza-like illness (ILI) cases in students and staff. In this study, our objectives were three-fold. The primary goal of this study was to characterize the impact of pH1N1 on the campuses as clearly as possible given the data available and their likely biases. In addition, we sought to evaluate the strengths and weaknesses of the data series themselves, in order to inform these two universities and other institutions of higher education (IHEs) about real-time surveillance systems that are likely to provide the most utility in future outbreaks (at least to the extent that it is possible to generalize from this analysis). METHODS: We collected a wide variety of data that covered both student ILI cases reported to medical and non-medical staff, employee absenteeism, and hygiene supply distribution records (from University A only). Communication data were retrieved from university broadcasts, university preparedness websites, and H1N1-related on campus media reports. Regional data based on the Centers for Disease Control and Prevention Outpatient Influenza-like Illness Surveillance Network (CDC ILINet) surveillance network, American College Health Association (ACHA) pandemic influenza surveillance data, and local Google Flu Trends were used as external data sets. We employed a "triangulation" approach for data analysis in which multiple contemporary data sources are compared to identify time patterns that are likely to reflect biases as well as those that are more likely to be indicative of actual infection rates. RESULTS: Medical personnel observed an early peak at both universities immediately after school began in early September and a second peak in early November; only the second peak corresponded to patterns in the community at large. Self-reported illness to university deans' offices was also relatively increased during mid-term exam weeks. The overall volume of pH1N1-related communication messages similarly peaked twice, corresponding to the two peaks of student ILI cases. CONCLUSIONS: During the 2009 H1N1 pandemic, both University A and B experienced a peak number of ILI cases at the beginning of the Fall term. This pattern, seen in surveillance systems at these universities and to a lesser extent in data from other IHEs, most likely resulted from students bringing the virus back to campus from their home states coupled with a sudden increase in population density in dormitories and lecture halls. Through comparison of data from different syndromic surveillance data streams, paying attention to the likely biases in each over time, we have determined, at least in the case of the pH1N1 pandemic, that student health center data more accurately depicted disease transmission on campus at both universities during the Fall 2009 pandemic than other available data sources. PMID- 21791091 TI - Heparin based prophylaxis to prevent venous thromboembolic events and death in patients with cancer - a subgroup analysis of CERTIFY. AB - BACKGROUND: Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer. METHODS: Acutely-ill, non-surgical patients >= 70 years with (n = 274) or without cancer (n = 2,965) received certoparin 3,000 UaXa o.d. or UFH 5,000 IU t.i.d. for 8-20 days. RESULTS: 1) Thromboembolic events in cancer patients (proximal DVT, symptomatic non-fatal PE and VTE-related death) occurred at 4.50% with certoparin and 6.03% with UFH (OR 0.73; 95% CI 0.23 2.39). Major bleeding was comparable and minor bleedings (0.75 vs. 5.67%) were nominally less frequent. 7.5% of certoparin and 12.8% of UFH treated patients experienced serious adverse events. 2) Thromboembolic event rates were comparable in patients with or without cancer (5.29 vs. 4.13%) as were bleeding complications. All cause death was increased in cancer (OR 2.68; 95%CI 1.22 5.86). 10.2% of patients with and 5.81% of those without cancer experienced serious adverse events (OR 1.85; 95% CI 1.21-2.81). CONCLUSIONS: Certoparin 3,000 UaXa o.d. and 5,000 IU UFH t.i.d. were equally effective and safe with respect to bleeding complications in patients with cancer. There were no statistically significant differences in the risk of thromboembolic events in patients with or without cancer receiving adequate anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov, NCT00451412. PMID- 21791094 TI - Bayesian semi-supervised classification of bacterial samples using MLST databases. AB - BACKGROUND: Worldwide effort on sampling and characterization of molecular variation within a large number of human and animal pathogens has lead to the emergence of multi-locus sequence typing (MLST) databases as an important tool for studying the epidemiology and evolution of pathogens. Many of these databases are currently harboring several thousands of multi-locus DNA sequence types (STs) enriched with metadata over traits such as serotype, antibiotic resistance, host organism etc of the isolates. Curators of the databases have thus the possibility of dividing the pathogen populations into subsets representing different evolutionary lineages, geographically associated groups, or other subpopulations, which are defined in terms of molecular similarities and dissimilarities residing within a database. When combined with the existing metadata, such subsets may provide invaluable information for assessing the position of a new set of isolates in relation to the whole pathogen population. RESULTS: To enable users of MLST schemes to query the databases with sets of new bacterial isolates and to automatically analyze their relation to existing curated sequences, we introduce here a Bayesian model-based method for semi-supervised classification of MLST data. Our method can use an MLST database as a training set and assign simultaneously any set of query sequences into the earlier discovered lineages/populations, while also allowing some or all of these sequences to form previously undiscovered genetically distinct groups. This tool provides probabilistic quantification of the classification uncertainty and is highly efficient computationally, thus enabling rapid analyses of large databases and sets of query sequences. The latter feature is a necessary prerequisite for an automated access through the MLST web interface. We demonstrate the versatility of our approach by anayzing both real and synthesized data from MLST databases. The introduced method for semi-supervised classification of sets of query STs is freely available for Windows, Mac OS X and Linux operative systems in BAPS 5.4 software which is downloadable at http://web.abo.fi/fak/mnf/mate/jc/software/baps.html. The query functionality is also directly available for the Staphylococcus aureus database at http://www.mlst.net and shortly will be available for other species databases hosted at this web portal. CONCLUSIONS: We have introduced a model-based tool for automated semi-supervised classification of new pathogen samples that can be integrated into the web interface of the MLST databases. In particular, when combined with the existing metadata, the semi-supervised labeling may provide invaluable information for assessing the position of a new set of query strains in relation to the particular pathogen population represented by the curated database.Such information will be useful both for clinical and basic research purposes. PMID- 21791093 TI - Client satisfaction among participants in a randomized trial comparing oral methadone and injectable diacetylmorphine for long-term opioid-dependency. AB - BACKGROUND: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Patient satisfaction with treatment has been associated with improved addiction treatment outcomes. However, there is a paucity of studies evaluating patients' satisfaction with Opioid Substitution Treatment (OST). In the present study, participants' satisfaction with OST was evaluated at 3 and 12 months. We sought to test the relationship between satisfaction and patients' characteristics, the treatment modality received and treatment outcomes. METHODS: Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone vs. injectable diacetylmorphine over 12 months. A small sub-group of patients received injectable hydromorphone on a double blind basis with diacetylmorphine. The Client Satisfaction Questionnaire (CSQ-8) was used to measure satisfaction with treatment. CSQ-8 scores, as well as retention and response to treatment, did not differ between those receiving hydromorphone and diacetylmorphine at 3 or 12 months assessments; therefore, these two groups were analyzed together as the 'injectable' treatment group. RESULTS: A total of 232 (92%) and 237 (94%) participants completed the CSQ-8 at 3 and 12 months, respectively. Participants in both groups were highly satisfied with treatment. Independent of treatment group, participants satisfied with treatment at 3 months were more likely to be retained at 12 months. Multivariate analysis indicated that satisfaction was greater among those randomized to the injection group after controlling for treatment effectiveness. Participants who were retained, responded to treatment, and had fewer psychological symptoms were more satisfied with treatment. Finally, open-ended comments were made by 149 (60.3%) participants; concerns about the randomization process and the study ending were most commonly reported by participants receiving the oral and injectable medications, respectively. CONCLUSIONS: The higher satisfaction among those receiving medically prescribed injectable diacetylmorphine (or hydromorphone) supports current evidence regarding the attractiveness of this treatment for long-term, opioid-dependent individuals not benefiting sufficiently from other treatments. In addition, the measurement of treatment satisfaction provides valuable information about participants at risk of relapse and in need of additional services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00175357. PMID- 21791096 TI - Improved functionality, health related quality of life and decreased burden of disease in patients with ADHD treated with OROS(r) MPH: is treatment response different between children and adolescents? AB - BACKGROUND: To compare clinical and health-related quality of life (HRQoL) outcomes between children and adolescents with ADHD treated with OROS(r) MPH, using data from two large similarly-designed multicenter, prospective, open label, single-arm, non-interventional studies. METHODS: Pooled analysis (42603ATT4037, 42603 - ATT - 4001) including patients (6 to 18 years) with a confirmed diagnosis of ADHD. Patients were treated with OROS(r) MPH for 12 weeks; ADHD symptoms, functioning, HRQoL, safety and tolerability parameters were assessed. RESULTS: 822 patients (583 children [6-12 years], 239 adolescents [13 18 years]) were included in the pooled analysis. Mean daily OROS(r) MPH starting doses in the child and adolescent subgroups were 29.0 +/- 11.7 and 37.6 +/- 15.6 mg, respectively (p < 0.001). At study end (week 12), the overall mean daily dose was 35.5 +/- 14.0 mg, with children and adolescents receiving 32.8 +/- 12.7 and 42.0 +/- 15.1 mg/day, respectively (p < 0.001). Significant (p < 0.0001: overall population, children, adolescents) symptomatic, functional and HRQoL improvements were observed from baseline to study end using the Conners' Parents Rating Scale (overall: 29.2 +/- 10.7 [baseline] to 19.3 +/- 11.3 [endpoint]), Children's Global Assessment Scale (overall: 58.5 +/- 14.5 [baseline] to 69.6 +/- 16.1 [endpoint]), and ILC-LQ0-28. At week 12, between-age group differences were seen in the individual ILC-LQ0-28 parameters: school performance (p = 0.001 [parents' assessment], p = 0.032 [childrens' assessment]), global QoL (p = 0.012 [parents']) and interests and hobbies (p = 0.023 [childrens']). Treating physician's planned continued use of OROS(r) MPH in 76.9%, 86.0% and 79.3% of children, adolescents and the total population, respectively, at study end (p = 0.029 between-age subgroups). 195 of 822 patients (23.7%) experienced at least one treatment-emergent adverse event; most commonly reported AEs in the total group (>=4%) were insomnia (7.2%), anorexia (4.3%) and involuntary muscle contractions (4.1%). No clinically relevant changes in body weight or vital signs were observed. CONCLUSIONS: Clinically relevant differences between children and adolescents with ADHD are present. Adolescents appeared to have a lower health related quality of life and functioning compared to children at baseline, however, they were able to reach comparable ratings at endpoint for most items. Similarly, burden of disease decreased in patients and their carers. OROS MPH was generally safe and well tolerated. PMID- 21791095 TI - Immunovirological response to combined antiretroviral therapy and drug resistance patterns in children: 1- and 2-year outcomes in rural Uganda. AB - BACKGROUND: Children living with HIV continue to be in urgent need of combined antiretroviral therapy (ART). Strategies to scale up and improve pediatric HIV care in resource-poor regions, especially in sub-Saharan Africa, require further research from these settings. We describe treatment outcomes in children treated in rural Uganda after 1 and 2 years of ART start. METHODS: Cross-sectional assessment of all children treated with ART for 12 (M12) and 24 (M24) months was performed. CD4 counts, HIV RNA levels, antiretroviral resistance patterns, and non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations were determined. Patient adherence and antiretroviral-related toxicity were assessed. RESULTS: Cohort probabilities of retention in care were 0.86 at both M12 and M24. At survey, 71 (83%, M12) and 32 (78%, M24) children remained on therapy, and 84% participated in the survey. At ART start, 39 (45%) were female; median age was 5 years. Median initial CD4 percent was 11% [IQR 9-15] in children < 5 years old (n = 12); CD4 count was 151 cells/mm(3) [IQR 38-188] in those >= 5 years old (n = 26). At M12, median CD4 gains were 11% [IQR 10-14] in patients < 5 years old, and 206 cells/mm(3) [IQR 98-348] in >= 5 years old. At M24, median CD4 gains were 11% [IQR 5-17] and 132 cells/mm(3) [IQR 87-443], respectively. Viral suppression (< 400 copies/mL) was achieved in 59% (M12) and 33% (M24) of children. Antiretroviral resistance was found in 25% (M12) and 62% (M24) of children. Overall, 29% of patients had subtherapeutic NNRTI plasma concentrations. CONCLUSIONS: After one year of therapy, satisfactory survival and immunological responses were observed, but nearly 1 in 4 children developed viral resistance and/or subtherapeutic plasma antiretroviral drug levels. Regular weight adjustment dosing and strategies to reinforce and maintain ART adherence are essential to maximize duration of first-line therapy in children in resource limited countries. PMID- 21791097 TI - Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. AB - INTRODUCTION: The aim of this study was to examine the serum levels of S100 proteins and to evaluate their role in patients with recent-onset rheumatoid arthritis (RA). METHODS: Serum levels of S100A8/9 and S100A12 were analysed in 43 patients with recent-onset RA, both before and three months after the initiation of conventional treatment, as well as in 32 healthy individuals. Disease activity was assessed based on serum levels of C-reactive protein (CRP), the Disease Activity Score for 28 joints (DAS28) and the total number of swollen joints count for 66 joints (SJC). RESULTS: The levels of serum S100A8/9 and S100A12 were significantly higher in patients with recent-onset RA compared to the levels in healthy individuals (P < 0.0001) and normalised after three months of treatment. Using age- and sex-adjusted analysis, S100A8/9 levels were correlated with CRP (r = 0.439, P < 0.01), DAS28 (r = 0.501, P = 0.002) and SJC (r = 0.443, P = 0.007), while S100A12 was less significantly correlated with these parameters. Higher levels of S100A8/9 at baseline predicted improvement in the levels of CRP and SJC over time. Moreover, decreases in serum S100A8/9 were associated with decreased serum levels of CRP (r = 0.459, P = 0.005) and improvements in SJC (r = 0.459, P = 0.005). In multiple linear regression analyses, decreases in S100A8/9 but not CRP were significant predictors for improvements in SJC (P = 0.001). CONCLUSIONS: This study is the first to show normalisation of elevated S100 proteins in patients with recent-onset RA after the initiation of conventional treatment. Therefore, S100A8/9 might potentially be a predictive marker for improvement in the total number of swollen joints in patients in the early phase of RA. PMID- 21791098 TI - A brachialis muscle rupture diagnosed by ultrasound; case report. AB - Trauma to the elbow caused by lifting heavy objects frequently involves rupture of the tendon of the biceps brachii muscle. Less frequently a rupture of the brachialis muscle occurs. To our knowledge, only five cases involving traumatic rupture of the brachialis muscle were described in the past 20 years. We will briefly report these cases.To demonstrate and evaluate muscle injuries, magnetic resonance imaging (MRI) is considered the most sensitive and specific method of choice. We report an isolated brachialis muscle rupture caused by resisted flexion and pronation of the lower arm. Physical examination combined with ultrasound evaluation confirmed the diagnosis of ruptured brachialis muscle. Treatment was non-operative with full restoration of function. PMID- 21791099 TI - Development of a proxy-reported pulmonary outcome scale for preterm infants with bronchopulmonary dysplasia. AB - BACKGROUND: To develop an accurate, proxy-reported bedside measurement tool for assessment of the severity of bronchopulmonary dysplasia (also called chronic lung disease) in preterm infants to supplement providers' current biometric measurements of the disease. METHODS: We adapted Patient-Reported Outcomes Measurement Information System (PROMIS) methodology to develop the Proxy-Reported Pulmonary Outcomes Scale (PRPOS). A multidisciplinary group of registered nurses, nurse practitioners, neonatologists, developmental specialists, and feeding specialists at five academic medical centers participated in the PRPOS development, which included five phases: (1) identification of domains, items, and responses; (2) item classification and selection using a modified Delphi process; (3) focus group exploration of items and response options; (4) cognitive interviews on a preliminary scale; and (5) final revision before field testing. RESULTS: Each phase of the process helped us to identify, classify, review, and revise possible domains, questions, and response options. The final items for field testing include 26 questions or observations that a nurse assesses before, during, and after routine care time and feeding. CONCLUSIONS: We successfully created a prototype scale using modified PROMIS methodology. This process can serve as a model for the development of proxy-reported outcomes scales in other pediatric populations. PMID- 21791100 TI - Prototype semantic infrastructure for automated small molecule classification and annotation in lipidomics. AB - BACKGROUND: The development of high-throughput experimentation has led to astronomical growth in biologically relevant lipids and lipid derivatives identified, screened, and deposited in numerous online databases. Unfortunately, efforts to annotate, classify, and analyze these chemical entities have largely remained in the hands of human curators using manual or semi-automated protocols, leaving many novel entities unclassified. Since chemical function is often closely linked to structure, accurate structure-based classification and annotation of chemical entities is imperative to understanding their functionality. RESULTS: As part of an exploratory study, we have investigated the utility of semantic web technologies in automated chemical classification and annotation of lipids. Our prototype framework consists of two components: an ontology and a set of federated web services that operate upon it. The formal lipid ontology we use here extends a part of the LiPrO ontology and draws on the lipid hierarchy in the LIPID MAPS database, as well as literature-derived knowledge. The federated semantic web services that operate upon this ontology are deployed within the Semantic Annotation, Discovery, and Integration (SADI) framework. Structure-based lipid classification is enacted by two core services. Firstly, a structural annotation service detects and enumerates relevant functional groups for a specified chemical structure. A second service reasons over lipid ontology class descriptions using the attributes obtained from the annotation service and identifies the appropriate lipid classification. We extend the utility of these core services by combining them with additional SADI services that retrieve associations between lipids and proteins and identify publications related to specified lipid types. We analyze the performance of SADI enabled eicosanoid classification relative to the LIPID MAPS classification and reflect on the contribution of our integrative methodology in the context of high throughput lipidomics. CONCLUSIONS: Our prototype framework is capable of accurate automated classification of lipids and facile integration of lipid class information with additional data obtained with SADI web services. The potential of programming-free integration of external web services through the SADI framework offers an opportunity for development of powerful novel applications in lipidomics. We conclude that semantic web technologies can provide an accurate and versatile means of classification and annotation of lipids. PMID- 21791101 TI - A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing. AB - BACKGROUND: KRAB-ZFPs (Kruppel-associated box domain-zinc finger proteins) are vertebrate-restricted transcriptional repressors encoded in the hundreds by the mouse and human genomes. They act via an essential cofactor, KAP1, which recruits effectors responsible for the formation of facultative heterochromatin. We have recently shown that KRAB/KAP1 can mediate long-range transcriptional repression through heterochromatin spreading, but also demonstrated that this process is at times countered by endogenous influences. METHOD: To investigate this issue further we used an ectopic KRAB-based repressor. This system allowed us to tether KRAB/KAP1 to hundreds of euchromatic sites within genes, and to record its impact on gene expression. We then correlated this KRAB/KAP1-mediated transcriptional effect to pre-existing genomic and chromatin structures to identify specific characteristics making a gene susceptible to repression. RESULTS: We found that genes that were susceptible to KRAB/KAP1-mediated silencing carried higher levels of repressive histone marks both at the promoter and over the transcribed region than genes that were insensitive. In parallel, we found a high enrichment in euchromatic marks within both the close and more distant environment of these genes. CONCLUSION: Together, these data indicate that high levels of gene activity in the genomic environment and the pre-deposition of repressive histone marks within a gene increase its susceptibility to KRAB/KAP1-mediated repression. PMID- 21791102 TI - Applications of the pipeline environment for visual informatics and genomics computations. AB - BACKGROUND: Contemporary informatics and genomics research require efficient, flexible and robust management of large heterogeneous data, advanced computational tools, powerful visualization, reliable hardware infrastructure, interoperability of computational resources, and detailed data and analysis protocol provenance. The Pipeline is a client-server distributed computational environment that facilitates the visual graphical construction, execution, monitoring, validation and dissemination of advanced data analysis protocols. RESULTS: This paper reports on the applications of the LONI Pipeline environment to address two informatics challenges - graphical management of diverse genomics tools, and the interoperability of informatics software. Specifically, this manuscript presents the concrete details of deploying general informatics suites and individual software tools to new hardware infrastructures, the design, validation and execution of new visual analysis protocols via the Pipeline graphical interface, and integration of diverse informatics tools via the Pipeline eXtensible Markup Language syntax. We demonstrate each of these processes using several established informatics packages (e.g., miBLAST, EMBOSS, mrFAST, GWASS, MAQ, SAMtools, Bowtie) for basic local sequence alignment and search, molecular biology data analysis, and genome-wide association studies. These examples demonstrate the power of the Pipeline graphical workflow environment to enable integration of bioinformatics resources which provide a well-defined syntax for dynamic specification of the input/output parameters and the run-time execution controls. CONCLUSIONS: The LONI Pipeline environment http://pipeline.loni.ucla.edu provides a flexible graphical infrastructure for efficient biomedical computing and distributed informatics research. The interactive Pipeline resource manager enables the utilization and interoperability of diverse types of informatics resources. The Pipeline client server model provides computational power to a broad spectrum of informatics investigators--experienced developers and novice users, user with or without access to advanced computational-resources (e.g., Grid, data), as well as basic and translational scientists. The open development, validation and dissemination of computational networks (pipeline workflows) facilitates the sharing of knowledge, tools, protocols and best practices, and enables the unbiased validation and replication of scientific findings by the entire community. PMID- 21791103 TI - Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy. AB - BACKGROUND AND PURPOSE: Most information on the dose-response of radiation induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. MATERIALS AND METHODS: For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. RESULTS: The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. CONCLUSIONS: In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (alpha and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three-dimensional inhomogenous dose distribution, cancer risk can be compared by computing OED using the coefficients obtained in this work. PMID- 21791105 TI - Social support and leisure-time physical activity: longitudinal evidence from the Brazilian Pro-Saude cohort study. AB - BACKGROUND: Although social support has been observed to exert a beneficial influence on leisure-time physical activity (LTPA), multidimensional approaches examining social support and prospective evidence of its importance are scarce. The purpose of this study was to investigate how four dimensions of social support affect LTPA engagement, maintenance, type, and time spent by adults during a two-year follow-up. METHODS: This paper reports on a longitudinal study of 3,253 non-faculty public employees at a university in Rio de Janeiro (the Pro Saude study). LTPA was evaluated using a dichotomous question with a two-week reference period, and further questions concerning LTPA type (individual or group) and time spent on the activity. Social support was measured by the Medical Outcomes Study Social Support Scale (MOS-SSS). To assess the association between social support and LTPA, two different statistical models were used: binary and multinomial logistic regression models for dichotomous and polytomous outcomes, respectively. Models were adjusted separately for those who began LTPA in the middle of the follow up (engagement group) and for those who had maintained LTPA since the beginning of the follow up (maintenance group). RESULTS: After adjusting for confounders, statistically significant associations (p < 0.05) between dimensions of social support and group LTPA were found in the engagement group. Also, the emotional/information dimension was associated with time spent on LTPA (OR = 2.01; 95% CI 1.2-3.9). In the maintenance group, material support was associated with group LTPA (OR = 1.80; 95% CI; 1.1-3.1) and the positive social interaction dimension was associated with time spent on LTPA (OR = 1.65; 95% CI; 1.1-2.7). CONCLUSIONS: All dimensions of social support influenced LTPA type or the time spent on the activity. However, our findings suggest that social support is more important in engagement than in maintenance. This finding is important, because it suggests that maintenance of LTPA must be associated with other factors beyond the individual's level of social support, such as a suitable environment and social/health policies directed towards the practice of LTPA. PMID- 21791104 TI - The ColRS system is essential for the hunger response of glucose-growing Pseudomonas putida. AB - BACKGROUND: The survival of bacteria largely depends on signaling systems that coordinate cell responses to environmental cues. Previous studies on the two component ColRS signal system in Pseudomonas putida revealed a peculiar subpopulation lysis phenotype of colR mutant that grows on solid glucose medium. Here, we aimed to clarify the reasons for the lysis of bacteria. RESULTS: We present evidence that the lysis defect of P. putida colR mutant is linked to hunger response. A subpopulation prone to lysis was located in the periphery of bacterial cultures growing on solid medium. Cell lysis was observed in glucose limiting, but not in glucose-rich conditions. Furthermore, lysis was also alleviated by exhaustion of glucose from the medium which was evidenced by a lower lysis of central cells compared to peripheral ones. Thus, lysis takes place at a certain glucose concentration range that most probably provides bacteria a hunger signal. An analysis of membrane protein pattern revealed several hunger induced changes in the bacterial outer membrane: at glucose limitation the amount of OprB1 channel protein was significantly increased whereas that of OprE was decreased. Hunger-induced up-regulation of OprB1 correlated in space and time with the lysis of the colR mutant, indicating that hunger response is detrimental to the colR-deficient bacteria. The amount of OprB1 is controlled post transcriptionally and derepression of OprB1 in glucose-limiting medium depends at least partly on the carbon catabolite regulator protein Crc. The essentiality of ColR in hunger response can be bypassed by reducing the amount of certain outer membrane proteins. In addition to depletion of OprB1, the lysis defect of colR mutant can be suppressed by the down-regulation of OprF levels and the hindering of SecB-dependent protein secretion. CONCLUSIONS: We show that Pseudomonas putida growing on solid glucose medium adapts to glucose limitation through up regulation of the sugar channel protein OprB1 that probably allows enhanced acquisition of a limiting nutrient. However, to survive such hunger response bacteria need signalling by the ColRS system. Hence, the ColRS system should be considered a safety factor in hunger response that ensures the welfare of the cell membrane during the increased expression of certain membrane proteins. PMID- 21791106 TI - Medication knowledge, certainty, and risk of errors in health care: a cross sectional study. AB - BACKGROUND: Medication errors are often involved in reported adverse events. Drug therapy, prescribed by physicians, is mostly carried out by nurses, who are expected to master all aspects of medication. Research has revealed the need for improved knowledge in drug dose calculation, and medication knowledge as a whole is poorly investigated. The purpose of this survey was to study registered nurses' medication knowledge, certainty and estimated risk of errors, and to explore factors associated with good results. METHODS: Nurses from hospitals and primary health care establishments were invited to carry out a multiple-choice test in pharmacology, drug management and drug dose calculations (score range 0 14). Self-estimated certainty in each answer was recorded, graded from 0 = very uncertain to 3 = very certain. Background characteristics and sense of coping were recorded. Risk of error was estimated by combining knowledge and certainty scores. The results are presented as mean (+/-SD). RESULTS: Two-hundred and three registered nurses participated (including 16 males), aged 42.0 (9.3) years with a working experience of 12.4 (9.2) years. Knowledge scores in pharmacology, drug management and drug dose calculations were 10.3 (1.6), 7.5 (1.6), and 11.2 (2.0), respectively, and certainty scores were 1.8 (0.4), 1.9 (0.5), and 2.0 (0.6), respectively. Fifteen percent of the total answers showed a high risk of error, with 25% in drug management. Independent factors associated with high medication knowledge were working in hospitals (p < 0.001), postgraduate specialization (p = 0.01) and completion of courses in drug management (p < 0.01). CONCLUSIONS: Medication knowledge was found to be unsatisfactory among practicing nurses, with a significant risk for medication errors. The study revealed a need to improve the nurses' basic knowledge, especially when referring to drug management. PMID- 21791107 TI - Structural and biomechanical alterations in rabbit thoracic aortas are associated with the progression of atherosclerosis. AB - BACKGROUND: Atherosclerosis is a diffuse and highly variable disease of arteries that alters the mechanical properties of the vessel wall through highly variable changes in its cellular composition and histological structure. We have analyzed the effects of acute atherosclerotic changes on the mechanical properties of the descending thoracic aorta of rabbits fed a 4% cholesterol diet. METHODS: Two groups of eight male New Zealand White rabbits were randomly selected and fed for 8 weeks either an atherogenic diet (4% cholesterol plus regular rabbit chow), or regular chow. Animals were sacrificed after 8 weeks, and the descending thoracic aortas were excised for pressure-diameter tests and histological evaluation to examine the relationship between aortic elastic properties and atherosclerotic lesions. RESULTS: All rabbits fed the high-cholesterol diet developed either intermediate or advanced atherosclerotic lesions, particularly American Heart Association-type III and IV, which were fatty and contained abundant lipid-filled foam cells (RAM 11-positive cells) and fewer SMCs with solid-like actin staining (HHF-35-positive cells). In contrast, rabbits fed a normal diet had no visible atherosclerotic changes. The atherosclerotic lesions correlated with a statistically significant decrease in mean vessel wall stiffness in the cholesterol-fed rabbits (51.52 +/- 8.76 kPa) compared to the control animals (68.98 +/- 11.98 kPa), especially in rabbits with more progressive disease. CONCLUSIONS: Notably, stiffness appears to decrease with the progression of atherosclerosis after the 8-week period. PMID- 21791108 TI - Thelazia callipaeda: infection in dogs: a new parasite for Spain. AB - BACKGROUND: Thelazia callipaeda (Spirurida, Thelaziidae), eyeworms, are known as the causative agents of thelaziosis, initially described in Asia and, later on, over the last decade, also in some European countries (e.g., Italy, France, Germany and Switzerland). In June 2010, the first case of canine thelaziosis was observed in central western Spain (La Vera region, Caceres) and subsequent epidemiological investigation is reported in the present study. RESULTS: This study describes the first autochthonous cases of infection by T. callipaeda in dogs from central western Spain where the first case of eyeworm infection was reported.A total of 456 dogs was examined in this geographical area. Thelazia callipaeda eyeworms were observed in 182 (39.9%) animals, of which 28 showed apparent clinical signs (i.e., conjunctivitis, oedema, epiphora and petechiae). A total of 762 adult nematodes (214 males, 548 females; mean infection rate of 4.18; SD 4.74) were collected with cotton swabs or by flushing of the conjunctival sac of infected animals using physiological saline solution. Nematodes were identified as T. callipaeda according to the morphological keys and molecular analysis of sequences of a portion of the mitochondrial cytochrome c oxidase subunit 1 (cox 1) gene. The sequences were identical to those representing T. callipaeda haplotype 1, previously reported in Europe. CONCLUSIONS: The high infection rate of canine thelaziosis herein reported suggests that practitioners should include this eye infection amongst differential diagnoses of ocular diseases in dogs from this area of Spain or those moving across this area of Spain. Based on the high infection prevalence recorded, the potential public health risk to humans from this region is also discussed. PMID- 21791109 TI - Living with prostate cancer: randomised controlled trial of a multimodal supportive care intervention for men with prostate cancer. AB - BACKGROUND: Prostate cancer is the most common male cancer in developed countries and diagnosis and treatment carries with it substantial morbidity and related unmet supportive care needs. These difficulties may be amplified by physical inactivity and obesity. We propose to apply a multimodal intervention approach that targets both unmet supportive care needs and physical activity. METHODS/DESIGN: A two arm randomised controlled trial will compare usual care to a multimodal supportive care intervention "Living with Prostate Cancer" that will combine self-management with tele-based group peer support. A series of previously validated and reliable self-report measures will be administered to men at four time points: baseline/recruitment (when men are approximately 3-6 months post-diagnosis) and at 3, 6, and 12 months after recruitment and intervention commencement. Social constraints, social support, self-efficacy, group cohesion and therapeutic alliance will be included as potential moderators/mediators of intervention effect. Primary outcomes are unmet supportive care needs and physical activity levels. Secondary outcomes are domain specific and health-related quality of life (QoL); psychological distress; benefit finding; body mass index and waist circumference. Disease variables (e.g. cancer grade, stage) will be assessed through medical and cancer registry records. An economic evaluation will be conducted alongside the randomised trial. DISCUSSION: This study will address a critical but as yet unanswered research question: to identify a population-based way to reduce unmet supportive care needs; promote regular physical activity; and improve disease-specific and health related QoL for prostate cancer survivors. The study will also determine the cost effectiveness of the intervention. TRIAL REGISTRATION: ACTRN12611000392965. PMID- 21791110 TI - The ultrastructure of book lung development in the bark scorpion Centruroides gracilis (Scorpiones: Buthidae). AB - BACKGROUND: Near the end of the nineteenth century the hypothesis was presented for the homology of book lungs in arachnids and book gills in the horseshoe crab. Early studies with the light microscope showed that book gill lamellae are formed by outgrowth and possibly some invagination (infolding) of hypodermis (epithelium) from the posterior surface of opisthosomal limb buds. Scorpion book lungs are formed near the bilateral sites of earlier limb buds. Hypodermal invaginations in the ventral opisthosoma result in spiracles and sac-like cavities (atria). In early histological sections of embryo book lungs, widening of the atrial entrance of some lamellae (air channels, air sacs, saccules) was interpreted as an indication of invagination as hypothesized for book gill lamellae. The hypodermal infolding was thought to produce the many rows of lamellar precursor cells anterior to the atrium. The ultrastructure of scorpion book lung development is compared herein with earlier investigations of book gill formation. RESULTS: In scorpion embryos, there is ingression (inward migration) of atrial hypodermal cells rather than invagination or infolding of the atrial hypodermal layer. The ingressing cells proliferate and align in rows anterior to the atrium. Their apical-basal polarity results in primordial air channels among double rows of cells. The cuticular walls of the air channels are produced by secretion from the apical surfaces of the aligned cells. Since the precursor cells are in rows, their secreted product is also in rows (i.e., primordial air channels, saccules). For each double row of cells, their opposed basal surfaces are gradually separated by a hemolymph channel of increasing width. CONCLUSIONS: The results from this and earlier studies show there are differences and similarities in the formation of book lung and book gill lamellae. The homology hypothesis for these respiratory organs is thus supported or not supported depending on which developmental features are emphasized. For both organs, when the epithelial cells are in position, their apical-basal polarity results in alternate page-like channels of hemolymph and air or water with outward directed hemolymph saccules for book gills and inward directed air saccules for book lungs. PMID- 21791111 TI - Use and perceived helpfulness of smoking cessation methods: results from a population survey of recent quitters. AB - BACKGROUND: Increasing rates of smoking cessation is one of the most effective measures available to improve population health. To advance the goal of increasing successful cessation at the population level, it is imperative that we understand more about smokers' use of cessation methods, as well as the helpfulness of those methods in real-world experiences of quitting. In this survey of recent quitters, we simultaneously examined rates of use and perceived helpfulness of various cessation methods. METHODS: Recent quitters (within 12 months; n = 1097) completed a telephone survey including questions relating to 13 cessation methods. Indices of use and perceived helpfulness for each method were plotted in a quadrant analysis. Socio-demographic differences were explored using bivariate and multivariate analyses. RESULTS: From the quadrant analysis, cold turkey, NRT and gradual reduction before quitting had high use and helpfulness; GP advice had high use and lower helpfulness. Prescribed medication and online programs had low use but high helpfulness. Remaining methods had low use and helpfulness. Younger quitters were more likely to use unassisted methods such as cold turkey; older or less educated quitters were more likely to use assisted methods such as prescribed medication or advice from a general practitioner. CONCLUSIONS: The majority of recent quitters quit cold turkey or cut down before quitting, and reported that these methods were helpful. Efforts to influence population smoking prevalence should attempt to provide support and motivation for smokers choosing these methods, in addition to assessing the effectiveness and accessibility of other methods for smokers who need or choose them. PMID- 21791112 TI - Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients. AB - BACKGROUND: To examine the expression of SMAD4 at gene and protein levels in glioma samples with different WHO grades and its association with survival. METHODS: Two hundreds fifty-two glioma specimens and 42 normal control tissues were collected. Immunochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of SMAD4. Kaplan Meier method and Cox's proportional hazards model were used in survival analysis. RESULTS: Immunohistochemistry showed that SMAD4 expression was decreased in glioma. SMAD4 mRNA and protein levels were both lower in glioma compared to control on real-time PCR and Western blot analysis (both P < 0.001). In addition, its expression levels decrease from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry analysis and Western blot. Moreover, the survival rate of SMAD4-positive patients was higher than that of SMAD4-negative patients. We further confirmed that the loss of SMAD4 was a significant and independent prognostic indicator in glioma by multivariate analysis. CONCLUSIONS: Our data provides convincing evidence for the first time that the reduced expression of SMAD4 at gene and protein levels is correlated with poor outcome in patients with glioma. SMAD4 may play an inhibitive role during the development of glioma and may be a potential prognosis predictor of glioma. PMID- 21791113 TI - Expression of EBV encoded viral RNA 1, 2 and anti-inflammatory cytokine (interleukin-10) in FFPE lymphoma specimens: a preliminary study for diagnostic implication in Pakistan. AB - BACKGROUND: Epstein Barr Virus (EBV) plays a significant role as a cofactor in the process of tumorigenesis and has consistently been associated with a variety of malignancies. EBV encoded RNAs (EBER1 and EBER2) are the most abundant viral transcripts in latently EBV-infected cells and their role in viral infection is still unclear. Formalin fixed paraffin embedded (FFPE) tissues of surgically removed carcinoma biopsies are widely available form but have never been exploited for expressional studies previously in Pakistan. Immunohistochemistry (IHC) and in situ hybridization (ISH) in FFPE biopsy tissues remains the gold standard for proving EBV relationship in a histopathological lesion but their reagents associated limitations confines their reliability in some applications. Recently introduced targeted drug delivery systems induce viral lytic gene expression and therefore require more sensitive method to quantify viral as well as cellular gene expression. METHODS: Eight (8) lymphoma samples were screened to detect the EBV genome. Qualitative and quantitative expression of EBV Encoded RNAs (EBER1, EBER2) and anti-inflammatory cytokine (interleukin-10) in FFPE EBV positive lymphoma tissue samples were then analysed by using reverse transcriptase polymerase chain reaction (RT-PCR) and real time polymerase chain reaction (qRT-PCR), respectively. RESULTS: In this study we have successfully quantified elevated expressional levels of both cellular and viral transcripts, namely EBER1, EBER2 and anti-inflammatory cytokine (IL-10) in the FFPE Burkitt's lymphoma (BL) specimens of Pakistani origin. CONCLUSIONS: These results indicate that FFPE samples may retain viral as well as cellular RNA expression information at detectable level. To our knowledge, this is first study which represents elevated expressional levels of EBER1, EBER2 and IL-10 in FFPE tissue samples of Burkitt's lymphoma in Pakistan. These observations will potentially improve current lacunas in clinical as well as diagnostic practices in Pakistan and can be further exploited to develop new strategies for studying cellular and/or viral gene expression. PMID- 21791114 TI - ZEB1 limits adenoviral infectability by transcriptionally repressing the coxsackie virus and adenovirus receptor. AB - BACKGROUND: We have previously reported that RAS-MEK (Cancer Res. 2003 May 1;63(9):2088-95) and TGF-beta (Cancer Res. 2006 Feb 1;66(3):1648-57) signaling negatively regulate coxsackie virus and adenovirus receptor (CAR) cell-surface expression and adenovirus uptake. In the case of TGF-beta, down-regulation of CAR occurred in context of epithelial-to-mesenchymal transition (EMT), a process associated with transcriptional repression of E-cadherin by, for instance, the E2 box-binding factors Snail, Slug, SIP1 or ZEB1. While EMT is crucial in embryonic development, it has been proposed to contribute to the formation of invasive and metastatic carcinomas by reducing cell-cell contacts and increasing cell migration. RESULTS: Here, we show that ZEB1 represses CAR expression in both PANC 1 (pancreatic) and MDA-MB-231 (breast) human cancer cells. We demonstrate that ZEB1 physically associates with at least one of two closely spaced and conserved E2 boxes within the minimal CAR promoter here defined as genomic region -291 to 1 relative to the translational start ATG. In agreement with ZEB1's established role as a negative regulator of the epithelial phenotype, silencing its expression in MDA-MB-231 cells induced a partial Mesenchymal-to-Epithelial Transition (MET) characterized by increased levels of E-cadherin and CAR, and decreased expression of fibronectin. Conversely, knockdown of ZEB1 in PANC-1 cells antagonized both the TGF-beta-induced down-regulation of E-cadherin and CAR and the reduction of adenovirus uptake. Interestingly, even though ZEB1 clearly contributes to the TGF-beta-induced mesenchymal phenotype of PANC-1 cells, TGF beta did not seem to affect ZEB1's protein levels or subcellular localization. These findings suggest that TGF-beta may inhibit CAR expression by regulating factor(s) that cooperate with ZEB1 to repress the CAR promoter, rather than by regulating ZEB1 expression levels. In addition to the negative E2 box-mediated regulation the minimal CAR promoter is positively regulated through conserved ETS and CRE elements. CONCLUSIONS: This report provides evidence that inhibition of ZEB1 may improve adenovirus uptake of cancer cells that have undergone EMT and for which ZEB1 is necessary to maintain the mesenchymal phenotype. Targeting of ZEB1 may reverse some aspects of EMT including the down-regulation of CAR. PMID- 21791116 TI - Tobacco retailer density surrounding schools and youth smoking behaviour: a multi level analysis. AB - BACKGROUND: Youth smoking prevention should be a public health priority. It is not only vital to prevent youth from smoking but also to prevent non-smoking youth from becoming susceptible to smoking. Past research has examined factors associated with youth's susceptibility to become a future smoker, but research has yet to examine tobacco retailer density and susceptibility to smoking among never smokers. The objectives of this study are to examine how tobacco retailer density surrounding schools and social smoking influences are associated with smoking susceptibility among youth of never smokers, and occasional and daily smoking among youth of current smokers. METHODS: Data were collected in 2005-2006 from grade 9 to 12 students attending 76 secondary schools in Ontario, Canada, as part of the SHAPES-On study. A series of multi-level logistic regression analyses were performed to understand how student- and school-level factors are associated with three smoking behaviour outcomes: smoking susceptibility among never smokers, occasional smoking, and daily smoking. RESULTS: The number of tobacco retailers surrounding a school was found to be associated with the likelihood of a never smoker being susceptible to future smoking (OR 1.03, 95CI% 1.01, 1.05). We also identified that being surrounded by smoking social influences, specifically family and close friends, can substantially increase the likelihood that never smokers are at risk for future smoking or that youth are already occasional or daily smokers. CONCLUSIONS: We identified that the number of tobacco retailers surrounding a school was associated with an increased odds of being susceptible to future smoking among male never smokers. Smoking social models surrounding youth also appears to have an important impact on their smoking behaviour regardless of their smoking status. It is important for youth smoking prevention programs to begin early, interrupt youths' susceptibility to future smoking, and focus on subgroups that are at higher risk of smoking. The government should consider the impact of tobacco retailer density on youth smoking behaviour, and be cautious when granting licenses for establishments to sell tobacco products. PMID- 21791115 TI - An overview of triple infection with hepatitis B, C and D viruses. AB - Viral hepatitis is one of the major health problems worldwide, particularly in South East Asian countries including Pakistan where hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are highly endemic. Hepatitis delta virus (HDV) is also not uncommon world-wide. HCV, HBV, and HDV share parallel routes of transmission due to which dual or triple viral infection can occur in a proportion of patients at the same time. HBV and HCV are important factors in the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In addition to LC and HCC, chronic HDV infection also plays an important role in liver damage with oncogenic potential.The current article reviews the available literature about the epidemiology, pathogenesis, transmission, symptoms, diagnosis, replication, disease outcome, treatment and preventive measures of triple hepatitis infection by using key words; epidemiology of triple infection, risk factors, awareness status, treatment and replication cycle in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. Total data from 74 different studies published from 1983 to 2010 on triple hepatitis infections were reviewed and included in this study. The present article briefly describes triple infection with HCV, HBV and HDV. PMID- 21791117 TI - Single and dual task gait training in people with Parkinson's disease: a protocol for a randomised controlled trial. AB - BACKGROUND: Difficulty performing more than one task at a time (dual tasking) is a common and disabling problem experienced by people with Parkinson disease (PD). If asked to perform another task when walking, people with PD often take shorter steps or walk more slowly. Currently there is uncertainty about whether clinicians should teach people with PD to avoid dual tasking or whether they should encourage them to practice dual tasking with the hope that practice will lead to enhanced performance. This study will address this issue by comparing single to dual task gait training. METHODS AND DESIGN: A prospective randomised clinical trial is being conducted. Sixty participants with idiopathic PD will be recruited, provided they score I-IV on the modified Hoehn and Yahr (1967) scale, and fulfil other inclusion criteria. Participants will be randomly allocated to either a single or dual task gait training group. Both groups will receive 12 hours of walking training over 4 weeks. The single task group will undertake gait training with cueing strategies to increase step length. The dual task group will train to improve step length when walking and performing a variety of added tasks. Both groups will receive a tailored home program for 6 months. Blinded assessors will conduct four assessments: two baseline assessments, one post intervention and one at 6 months follow-up. The primary outcome measure will be step length when dual tasking over 8 m. Secondary outcome measures include: spatiotemporal gait parameters when walking under single and dual task conditions, measures of executive function, the timed up and go test, measures of community mobility, and quality of life. All analyses will be based on intention to treat principle. DISCUSSION: This trial will examine the immediate and longer term effect of dual task walking training as compared to single task training in people with idiopathic PD, at the impairment, activity, and participation levels. It has the potential to identify a new intervention that may improve and maintain walking beyond the laboratory. The results of this trial will provide guidance for clinicians in the development of walking training programs for people with PD. TRIAL REGISTRATION: ACTRN12609000791235. PMID- 21791118 TI - Complex genotype by environment interactions and changing genetic architectures across thermal environments in the Australian field cricket, Teleogryllus oceanicus. AB - BACKGROUND: Biologists studying adaptation under sexual selection have spent considerable effort assessing the relative importance of two groups of models, which hinge on the idea that females gain indirect benefits via mate discrimination. These are the good genes and genetic compatibility models. Quantitative genetic studies have advanced our understanding of these models by enabling assessment of whether the genetic architectures underlying focal phenotypes are congruent with either model. In this context, good genes models require underlying additive genetic variance, while compatibility models require non-additive variance. Currently, we know very little about how the expression of genotypes comprised of distinct parental haplotypes, or how levels and types of genetic variance underlying key phenotypes, change across environments. Such knowledge is important, however, because genotype-environment interactions can have major implications on the potential for evolutionary responses to selection. RESULTS: We used a full diallel breeding design to screen for complex genotype environment interactions, and genetic architectures underlying key morphological traits, across two thermal environments (the lab standard 27 degrees C, and the cooler 23 degrees C) in the Australian field cricket, Teleogryllus oceanicus. In males, complex three-way interactions between sire and dam parental haplotypes and the rearing environment accounted for up to 23 per cent of the scaled phenotypic variance in the traits we measured (body mass, pronotum width and testes mass), and each trait harboured significant additive genetic variance in the standard temperature (27 degrees C) only. In females, these three-way interactions were less important, with interactions between the paternal haplotype and rearing environment accounting for about ten per cent of the phenotypic variance (in body mass, pronotum width and ovary mass). Of the female traits measured, only ovary mass for crickets reared at the cooler temperature (23 degrees C), exhibited significant levels of additive genetic variance. CONCLUSIONS: Our results show that the genetics underlying phenotypic expression can be complex, context-dependent and different in each of the sexes. We discuss the implications of these results, particularly in terms of the evolutionary processes that hinge on good and compatible genes models. PMID- 21791119 TI - Electron States and light absorption in strongly oblate and strongly prolate ellipsoidal quantum dots in presence of electrical and magnetic fields. AB - In framework of the adiabatic approximation the energy states of electron as well as direct light absorption are investigated in strongly oblate and strongly prolate ellipsoidal quantum dots (QDs) at presence of electric and magnetic fields. Analytical expressions for particle energy spectrum are obtained. The dependence of energy levels' configuration on QD geometrical parameters and field intensities is analytically obtained. The energy levels of electrons are shown to be equidistant both for strongly oblate and prolate QDs. The effect of the external fields on direct light absorption of a QD was investigated. The dependence of the absorption edge on geometrical parameters of QDs and intensities of the electric and magnetic fields is obtained. Selection rules are obtained at presence as well as absence of external electric and magnetic fields. In particular, it is shown that the presence of the electric field cancels the quantum numbers selection rules at the field direction, whereas in radial direction the selection rules are preserved. Perspectives of practical applications for device manufacturing based on ellipsoidal quantum dots are outlined. PMID- 21791123 TI - Cervical cancer. AB - INTRODUCTION: Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5-15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microinvasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib), radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of hysterectomy versus each other for treating early-stage and bulky early stage cervical cancer. PMID- 21791127 TI - [A woman with 'strange bumps' on her feet]. AB - A 57-year-old woman came to the dermatologist because of 'strange bumps' on her feet. The bumps were not painful. On physical examination bumps were seen on the medial parts of her left foot, near the sole. They had the same colour as the skin and decreased in size while sitting. The diagnosis was: 'piezogenic papules'. PMID- 21791124 TI - Gastroenteritis in children. AB - INTRODUCTION: Acute gastroenteritis results from infection of the gastrointestinal tract, most commonly with a virus. It is characterised by rapid onset of diarrhoea with or without vomiting, nausea, fever, and abdominal pain. Diarrhoea is defined as the frequent passage of unformed, liquid stools. Regardless of the cause, the mainstay of management of acute gastroenteritis is provision of adequate fluids to prevent and treat dehydration. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute gastroenteritis in children? What are the effects of treatments for acute gastroenteritis in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 42 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of: rotavirus vaccines for the prevention of gastroenteritis; enteral rehydration solutions (oral or gastric), lactose-free feeds, loperamide, probiotics, and zinc for the treatment of gastroenteritis; and ondansetron for the treatment of vomiting. PMID- 21791125 TI - Brain metastases. AB - INTRODUCTION: Metastases to the central nervous system may occur with tumours of any primary origin. Brain (cerebral) metastases may be either single or multiple, with or without disseminated disease elsewhere. Brain metastases may present with focal or generalised symptoms, although up to one third of people may be asymptomatic. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for managing brain metastases in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We identified 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: corticosteroids, surgery, radiosurgery, whole-brain radiotherapy (external beam), cytotoxic chemotherapy (systemic), surgery plus radiosurgery, surgery plus whole-brain radiotherapy (external beam), whole-brain radiotherapy plus radiosurgery, surgery plus radiosurgery plus whole brain radiotherapy (external beam), and whole-brain radiotherapy (external beam) plus radiation sensitisers. PMID- 21791128 TI - [Cost effectiveness of biologicals: high costs are the other face of success]. AB - Where health care is concerned, the introduction of biologicals has greatly improved the treatment of chronic inflammatory disorders. This class of drugs is not only noticeably effective, but is also well tolerated. The cost effectiveness of these drugs means that there are limits to their use. This is the other face of success. The Dutch Ministry of Health, Welfare and Sport recently announced measures intended to limit the growth of costs while at the same time requiring that savings should be made on the current budget. Recently the Canadian Agency for Drugs and Technologies in Health (CADTH) produced a report on the effects and costs of biologicals for adults with rheumatoid arthritis (www.cadth.ca). Here we discuss their findings. Organizations for medical specialists should be societal aware and be able to deal with these drugs in a cost-conscious manner, including the development of dynamic guidelines and quality visitations. PMID- 21791130 TI - [Sudden severe headache not always harmless: thunderclap headache as a result of reversible cerebral vasoconstriction]. AB - BACKGROUND: Thunderclap headache may be a symptom of a severe underlying disorder. CASE DESCRIPTION: A 41-year-old man had recurrent episodes of thunderclap headache triggered by Valsalva-like manoeuvres. His medical history reported cannabis exposure. Angiography showed segmental vasoconstriction of cerebral arteries. He stopped using cannabis and tried to avoid intracranial pressure increasing activities. 3 months later he was no longer experiencing any symptoms and the vascular anomalies had clearly improved. We concluded that reversible cerebral vasoconstriction syndrome (RCVS) was the underlying cause of the thunderclap headache. CONCLUSION: In contrast with primary thunderclap headache and primary headache due to sex, cough and exertion, RCVS is not harmless, since the characteristic cerebral vasoconstriction can lead to life threatening neurologic complications. The increasing quality of diagnostic imaging techniques will probably lead to such primary headaches being diagnosed less frequently and, more specifically, to more frequent diagnosis of severe underlying pathology. Because of the differences in prognosis and treatment, proper diagnostic imaging should be performed in all patients with thunderclap headache. PMID- 21791132 TI - [Neurological complications caused by desmopressin in adults with nocturia]. AB - Desmopressin is occasionally used to reduce the frequency of nocturnal toilet visits. We describe an 86-year-old woman with nocturnal incontinence due to a urinary tract infection, and a 49-year-old man with frequent toilet visits in the night, known to consume excessive amounts of alcohol. They were admitted to hospital with neurological symptoms due to severe hyponatraemia, 114 and 102 mmol/l respectively, while using desmopressin. After the desmopressin had been discontinued and the fluid balance restored, they recovered completely. Hyponatraemia is inherent to the mechanism of action of desmopressin. Desmopressin should be prescribed only on sound indication, and risk factors for developing severe hyponatraemia should always be taken into consideration. Proper instruction and follow-up are important to prevent severe complications. PMID- 21791133 TI - [Fractures of the hamate bone and metacarpal bone: a rare combination]. AB - BACKGROUND: Fractures of the hamate bone are rare, but are being seen more frequently due to the increasing popularity of racket sports and golf. CASE DESCRIPTION: A 43-year-old man presented at our emergency department with a swollen, painful left hand after hitting a concrete wall with his fist. X-rays and CT scans revealed comminuted fracture of the hamate bone and the base of the fourth metacarpal bone. Open reduction and internal fixation, using screws and Kirschner wires, were performed. The postoperative course was uneventful. At one year follow-up the patient had regained full use of his hand. CONCLUSION: On conventional X-rays, 60% of wrist fractures are missed. If the clinical picture indicates a fracture of the hamate bone but conventional X-rays reveal no abnormalities then a supplementary CT-scan is advisable. Non-displaced fractures, or fractures with little displacement, can be treated conservatively, but surgical treatment is preferred in the case of displacement or non-union. PMID- 21791135 TI - [Determining cardiovascular risk in patients with rheumatoid arthritis: waiting for trial outcomes is not recommended]. AB - Cardiovascular risk management is clearly indicated in patients with rheumatoid arthritis (RA) today because this risk is comparable to patients with diabetes. Although formal evidence of cardiovascular endpoint trials with statins and/or antihypertensives is lacking in patients with RA, there are no indications that these drugs will have limited effect. In contrast, there is accumulating evidence as to the efficacy of the use of these drugs in RA that is at least comparable to their effects in the general population. All patients with RA should therefore receive cardiovascular risk-management therapy aimed at powerful suppression of the chronic inflammatory process as well as treatment with statins and/or antihypertensives, if indicated. Obviously, monitoring in the clinical setting is necessary to document if such therapy does indeed reduce cardiovascular disease in patients with RA. PMID- 21791136 TI - [Participation of patients in medical research]. AB - Physicians and patients often have a different perspective on disease. This perspective is traditionally determined by anamnesis, physical examination, and objective measurements such a laboratory investigation and X-ray imaging. However, patient reported outcome parameters such as fatigue or sleep quality have been found to be as informative for assessment of the illness status, improvement during interventions or prediction of long-term outcome. The experience skills of patients are a valuable supplement to the skills of research workers and physicians. In scientific research in the area of rheumatology there is considerable experience with patient participation, for example in the international network 'Outcome measures in Rheumatology Clinical Trials' (OMERACT). One of the preconditions for optimal patient participation is avoidance of jargon. Patients and research workers should also realise that the relationship between physician and patient differs basically from the relationship between patient and research worker. PMID- 21791137 TI - [Early treatment of rheumatoid arthritis is useful. Emphasizing the importance of early referral to patients and doctors]. AB - It is becoming clearer that early treatment of rheumatoid arthritis (RA) is useful. Recently, Dutch investigators observed a difference between RA referred early (within 12 weeks) and RA referred later (after 12 weeks). Patients who were referred earlier had a better prognosis, less damage on radiology, and a higher chance of going into remission. We discuss that these data support the importance of the early recognition of RA. Educating the public and establishing early arthritis clinics could help to prevent delay for both patient and doctor. PMID- 21791139 TI - ['Don't fence me in'. Portrayal in novels and TV dramas of illnesses that impose a limitation of movement]. AB - Diseases that lead to a limitation of movement play a role in many novels, autobiographies and TV dramas. The cause of such diseases may lie centrally, in the central nervous system, or peripherally, in bones or muscles. They have great symbolic significance due to the loss of freedom imposed. Patients' reactions may vary from acceptance to denial. Denial is best seen in Anna Enquist's novel The secret, but above all in The Singing Detective by Dennis Potter. PMID- 21791140 TI - [Determining cardiovascular risk in patients with rheumatoid arthritis: prove the efficacy of interventions first]. AB - In the multidisciplinary Dutch guideline on Cardiovascular Risk Management (revision 2011) the recommendation for preventive treatment of elevated risks of cardiovascular disease in patients with arthritis lacks a trial-based justification. This section should therefore be removed. Introduction of clinical guidelines with recommendations justified by evidence of an unacceptably low grade is a growing international tendency that should be stopped. PMID- 21791141 TI - SNP may modify the effect of vitamin A supplementation at birth on cytokine production in a whole blood culture assay. AB - Within a neonatal vitamin A supplementation (VAS) trial, we investigated the effect of VAS on TNF-alpha, IL-10, IL-5 and IL-13 production after lipopolysaccharide, purified protein derivative (PPD) of Mycobacterium tuberculosis and phytohaemagglutinin stimulation using a whole blood culture protocol. We found that VAS recipients had lower unstimulated TNF-alpha concentrations than placebo recipients. In the present paper, we investigated whether the SNP TNF-alpha - 308, TNF-alpha - 238, IL-10 - 592, IL-10 - 1082 and toll-like receptor 4 (TLR4)+896 modified the effect of VAS on cytokine production. DNA and cytokine concentrations were available from 291 children. We found a significant interaction between TNF-alpha - 308 genotype and VAS for the unstimulated TNF-alpha production (Pinteraction = 0.04); among G homozygotes, TNF alpha concentrations were significantly lower after VAS compared with placebo, whereas for A carriers, VAS did not appear to have any effect. For TNF-alpha - 238, there was a tendency towards an increase in PPD-stimulated TNF-alpha production after VAS for the G homozygotes, but the opposite tendency for A allele carriers (Pinteraction = 0.07). Stratification by sex revealed a significant VAS-genotype interaction for boys for TNF-alpha - 238. There was a borderline-significant three-way interaction (P = 0.05) between sex, VAS and TLR4+896 genotype. Although the present study had very limited representation of the genetic variation with potential for modification of the response to VAS, it adds to the efforts of untangling the diverse effects and impact of VAS. PMID- 21791142 TI - Marine n-3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients. AB - Patients treated with haemodialysis are at high risk of sudden cardiac death (SCD) often caused by arrhythmias. Atrial fibrillation (AF) is frequent among haemodialysis patients and is associated with increased mortality. Prolonged QTc is a risk marker of ventricular arrhythmia and is thereby associated with SCD. Studies have suggested that n-3 PUFA may have an antiarrhythmic effect, but the exact mechanism is not clear. The aim of this study was to examine whether AF was associated with n-3 PUFA in plasma phospholipids and whether supplementation with n-3 PUFA would shorten the QTc interval in haemodialysis patients compared to placebo. In a double-blinded randomised, placebo-controlled intervention trial 206 haemodialysis patients with CVD were treated with 1.7 g n-3 PUFA or placebo (olive oil) daily for 3 months. Blood samples and electrocardiogram evaluations were carried out at baseline and after 3 months. The QT interval, PQ interval and heart rate were measured in all patients with sinus rhythm (SR). At baseline 13 % of patients had AF. The content of the n-3 PUFA, DHA, was significantly lower (P < 0.05) in serum of patients with AF compared with patients with SR. Thus, the DHA content was independently negatively associated with AF. Supplementation with n-3 PUFA did not shorten the QT interval significantly compared to the placebo group (P = 0.42), although subgroup analysis within the n-3 PUFA group revealed a shortening effects on QTc (P = 0.01). In conclusion, an inverse association was found between the presence of AF and the plasma DHA in haemodialysis patients. Intervention with n-3 PUFA did not shorten the QTc interval compared to placebo. PMID- 21791143 TI - Within-plant distribution of cotton aphids, Aphis gossypii Glover (Hemiptera: Aphididae), in Bt and non-Bt cotton fields. AB - Knowledge of the vertical and horizontal distribution of Aphis gossypii Glover (Hemiptera: Aphididae) on genetically modified cotton plants over time could help optimize decision-making in integrated cotton aphid management programs. Therefore, the aim of the present study was to determine the vertical and horizontal distribution of A. gossypii in non-transgenic Bt cotton and transgenic Bt-cotton over time during two cotton seasons by examining plants throughout the seasons. There was no significant interaction between years and cotton cultivar treatments for apterous or alate aphids. Considering year-to-year data, analyses on season-long averages of apterous or alate aphids showed that aphid densities per plant did not differ among years. The number of apterous aphids found per plant for the Bt transgenic cultivar (2427 apterous aphids per plant) was lower than for its isoline (3335 apterous aphids per plant). The number of alate aphids found per plant on the Bt transgenic cultivar (12.28 alate aphids per plant) was lower than for the isoline (140.56 alate aphids per plant). With regard to the vertical distribution of apterous aphids or alate aphids, there were interactions between cotton cultivar, plant age and plant region. We conclude that in comparison to non-Bt cotton (DP 4049), Bt cotton (DP 404 BG (Bollgard)) has significant effects on the vertical, horizontal, spatial and temporal distribution patterns of A. gossypii, showing changes in its distribution behaviour inside the plant as the cotton crop develops. The results of our study are relevant for understanding the vertical and horizontal distribution of A. gossypii on Bt cotton cultivar (DP 404 BG (Bollgard)) and on its isoline (DP 4049), and could be useful in decision-making, implementing controls and determining the timing of population peaks of this insect. PMID- 21791144 TI - Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells. AB - In the present study, we examined the effect of repeated and long-term treatment with resveratrol on NO production in endothelial cells as a model of routine wine consumption. Repeated treatment with resveratrol for 5 d resulted in an increase in endothelial NO synthase (eNOS) protein content and NO production in human umbilical vein endothelial cell (HUVEC) in a concentration-dependent manner. A significant increase in functional eNOS protein content was observed with resveratrol, even at 50 nm. In contrast, eNOS phosphorylation was not stimulated and inducible NO synthase (iNOS) was not detected after resveratrol treatment. Both eNOS protein and mRNA expression were promoted by 50 nm-resveratrol in a time-dependent manner. Increased eNOS mRNA expression in response to resveratrol was not decreased by an oestrogen receptor (ER) antagonist ICI182780, a PPARalpha inhibitor MK886 or a sirtuin inhibitor Salermide. However, a combination of ICI182780 and MK886 significantly inhibited resveratrol-induced eNOS mRNA expression. Salermide had no effect even in the presence of ICI182780 or MK886. These results demonstrate that resveratrol within the physiological range increases eNOS mRNA and protein expression through ER and PPARalpha activation, thereby promoting NO production in endothelial cells. eNOS induction might result from the accumulative effect of nanomolar concentrations of resveratrol. The present study results can account in part for the observation that cardiovascular benefits of red wine are experienced with routine consumption, but not with acute consumption. PMID- 21791145 TI - Dietary reporting errors on 24 h recalls and dietary questionnaires are associated with BMI across six European countries as evaluated with recovery biomarkers for protein and potassium intake. AB - Whether there are differences between countries in the validity of self-reported diet in relation to BMI, as evaluated using recovery biomarkers, is not well understood. We aimed to evaluate BMI-related reporting errors on 24 h dietary recalls (24-HDR) and on dietary questionnaires (DQ) using biomarkers for protein and K intake and whether the BMI effect differs between six European countries. Between 1995 and 1999, 1086 men and women participating in the European Prospective Investigation into Cancer and Nutrition completed a single 24-HDR, a DQ and one 24 h urine collection. In regression analysis, controlling for age, sex, education and country, each unit (1 kg/m2) increase in BMI predicted an approximately 1.7 and 1.3 % increase in protein under-reporting on 24-HDR and DQ, respectively (both P < 0.0001). Exclusion of individuals who probably misreported energy intake attenuated BMI-related bias on both instruments. The BMI effect on protein under-reporting did not differ for men and women and neither between countries on both instruments as tested by interaction (all P>0.15). In women, but not in men, the DQ yielded higher mean intakes of protein that were closer to the biomarker-based measurements across BMI groups when compared with 24-HDR. Results for K were similar to those of protein, although BMI-related under reporting of K was of a smaller magnitude, suggesting differential misreporting of foods. Under-reporting of protein and K appears to be predicted by BMI, but this effect may be driven by 'low-energy reporters'. The BMI effect on under reporting seems to be the same across countries. PMID- 21791146 TI - DNA methylation and cognitive functioning in healthy older adults. AB - Long-term supplementation with folic acid may improve cognitive performance in older individuals. The relationship between folate status and cognitive performance might be mediated by changes in methylation capacity, as methylation reactions are important for normal functioning of the brain. Although aberrant DNA methylation has been implicated in neurodevelopmental disorders, the relationship between DNA methylation status and non-pathological cognitive functioning in human subjects has not yet been investigated. The present study investigated the associations between global DNA methylation and key domains of cognitive functioning in healthy older adults. Global DNA methylation, defined as the percentage of methylated cytosine to total cytosine, was measured in leucocytes by liquid chromatography-MS/MS, in 215 men and women, aged 50-70 years, who participated in the Folic Acid and Carotid Intima-Media Thickness (FACIT) study (clinical trial registration number NCT00110604). Cognitive performance was assessed by means of the Visual Verbal Word Learning Task, the Stroop Colour-Word Interference Test, the Concept Shifting Test, the Letter-Digit Substitution Test and the Verbal Fluency Test. Using hierarchical linear regression analyses adjusted for age, sex, level of education, alcohol consumption, smoking status, physical activity, erythrocyte folate concentration and 5,10-methylenetetrahydrofolate reductase 677 C -> T genotype, we found that global DNA methylation was not related to cognitive performance on any of the domains measured. The present study results do not support the hypothesis that global DNA methylation, as measured in leucocytes, might be associated with cognitive functioning in healthy older individuals. PMID- 21791147 TI - Mycoplasmas in the urine of HIV-1 infected men. AB - The aim of this study was determine the prevalence of Mycoplasma hominis, M. genitalium, M. fermentans, M. pirum, M. penetrans and Ureaplasma urealyticum in HIV-infected patients. Culture and PCR were used to detect six species of Mycoplasma in first-void urine of HIV-1 infected men. A total of 497 HIV/AIDS patients (age range 5-75 years, mean 37 years) were screened in the study. All presented positive for at least one kind of mycoplasma, especially U. urealyticum and M. hominis. Six mycoplasmas were significant in the homosexual contact and heterosexual contact groups. The distribution of M. hominis, M. penetrans, and M. pirum were significantly different in this four-transmission category. CD4+ cell count levels were lower in the AIDS-associated Mycoplasma-positive group than in the Mycoplasma-negative group (P<0.01). This study indicates that U. urealyticum, M. hominis and M. fermentans are prevalent in HIV-1-infected male patients. This may be an indication of whether mycoplasmas are co-factors in the progression of HIV disease. PMID- 21791148 TI - Prevalence of haemorrhagic fever with renal syndrome in mainland China: analysis of National Surveillance Data, 2004-2009. AB - The monthly and annual incidence of haemorrhagic fever with renal syndrome (HFRS) in China for 2004-2009 was analysed in conjunction with associated geographical and demographic data. We applied the seasonal autoregressive integrated moving average (SARIMA) model to fit and forecast monthly HFRS incidence in China. HFRS was endemic in most regions of China except Hainan Province. There was a high risk of infection for male farmers aged 30-50 years. The fitted SARIMA(0,1,1)(0,1,1)12 model had a root-mean-square-error criterion of 0.0133 that indicated accurate forecasts were possible. These findings have practical applications for more effective HFRS control and prevention. The conducted SARIMA model may have applications as a decision support tool in HFRS control and risk management planning programmes. PMID- 21791149 TI - Seroepidemiological study of livestock brucellosis in a pastoral region. AB - A seroepidemiological study of Brucella infections in multiple livestock species in the Borana pastoral system of Ethiopia was performed between December 2007 and October 2008. A cross-sectional multi-stage sampling technique was employed to select 575 cattle, 1073 camels and 1248 goats from the target populations. Sera were collected from the animals, and serially tested using Rose Bengal test and complement fixation test. Overall prevalence and prevalence with respect to explanatory variables were established, and potential risk factors for seropositivity were analysed using a multivariable logistic regression. The results showed that 8.0% (95% CI 6.0-10.6), 1.8% (95% CI 1.1-2.8) and 1.6% (95% CI 1.0-2.5) of the tested cattle, camels and goats, respectively, had antibodies to Brucella antigen. Positive reactors were found in 93.8% of the villages with more frequent detection of positive cattle (93.3%) than camels (56.3%) and goats (37.5%). Risk factors identified for cattle were: keeping more livestock species at household level (OR 4.1, 95% CI 1.9-8.9), increasing age of the animal (OR 2.8, 95% CI 1.3-6.0) and wet season (OR 3.3, 95% CI 1.6-6.9). Increase in household-level species composition (OR 4.1, 95% CI 1.2-14.2) and wet season (OR 3.7, 95% CI 1.5-9.1) were found to be risk factors for seropositivity in camels and goats, respectively. Existence of more than one seroreactor animal species in most villages and association of increased livestock species composition with seropositivity may add more credence to the possibility of cross-species transmission of Brucella infections. Although no attempt to isolate Brucella spp. was made, our results suggest that cattle are more likely maintenance hosts of Brucella abortus which has spread to goats and camels. This should be substantiated by further isolation and identification of Brucella organisms to trace the source of infection and transmission dynamics in various hosts kept under mixed conditions. In conclusion, the present study suggests the need for investigating a feasible control intervention and raising public awareness on prevention methods of human exposure to brucellosis. PMID- 21791150 TI - Cyclospora cayetanensis: a description of clinical aspects of an outbreak in Quebec, Canada. AB - Cyclospora cayetanensis is an emerging infectious agent. The aim of this study was to describe an outbreak that occurred in 250 adults exposed to contaminated food, focusing on the duration and relapses of symptoms, complications and evidence of local transmission. This outbreak affected workers who ate in a restaurant in June 2005. Cyclospora sp. was observed in the stools of 20 cases and 122 probable cases were identified. The attack rate was estimated at 89%. Main symptoms were diarrhoea (96%), nausea (88%), fatigue (87%), abdominal cramps (85%), fever (52%) and headaches (45%). Contaminated fresh basil originating from a Mexican farm, used to prepare an uncooked appetizer, was identified as the source. In this non-endemic population of immunocompetent adults, Cyclospora infection presents with watery diarrhoea lasting from 4 to 18 days and fatigue lasting from 11 to 42 days. For a small proportion of affected persons, recovery can be delayed. PMID- 21791151 TI - Proteinase and phospholipase activities and development at different temperatures of yeasts isolated from bovine milk. AB - The presence of yeasts in milk may cause physical and chemical changes limiting the durability and compromising the quality of the product. Moreover, milk and dairy products contaminated by yeasts may be a potential means of transmission of these microorganisms to man and animals causing several kinds of infections. This study aimed to determine whether different species of yeasts isolated from bovine raw milk had the ability to develop at 37 degrees C and/or under refrigeration temperature. Proteinase and phospholipase activities resulting from these yeasts were also monitored at different temperatures. Five genera of yeasts (Aureobasidium sp., Candida spp., Geotrichum spp., Trichosporon spp. and Rhodotorula spp.) isolated from bovine raw milk samples were evaluated. All strains showed one or a combination of characteristics: growth at 37 degrees C (99.09% of the strains), psychrotrophic behaviour (50.9%), proteinase production (16.81% of the strains at 37 degrees C and 4.09% under refrigeration) and phospholipase production (36.36% of the isolates at 37 degrees C and 10.9% under refrigeration), and all these factors may compromise the quality of the product. Proteinase production was similar for strains incubated at 37 degrees C (16.81% of the isolates) and room temperature (17.27%) but there was less amount of phospholipase-producing strains at room temperature (15.45% of the isolates were positive) when compared with incubation at 37 degrees C (36.36%). Enzymes production at 37 degrees C by yeasts isolated from milk confirmed their pathogenic potential. The refrigeration temperature was found to be most efficient to inhibit enzymes production and consequently ensure better quality of milk. The viability of yeasts and the activity of their enzymes at different temperatures are worrying because this can compromise the quality of dairy products at all stages of production and/or storage, and represent a risk to the consumer. PMID- 21791153 TI - Restrictions on addition: children's interpretation of the focus particles auch 'also' and nur 'only' in German. AB - Children up to school age have been reported to perform poorly when interpreting sentences containing restrictive and additive focus particles by treating sentences with a focus particle in the same way as sentences without it. Careful comparisons between results of previous studies indicate that this phenomenon is less pronounced for restrictive than for additive particles. We argue that this asymmetry is an effect of the presuppositional status of the proposition triggered by the additive particle. We tested this in two experiments with German learning three- and four-year-olds using a method that made the exploitation of the information provided by the particles highly relevant for completing the task. Three-year-olds already performed remarkably well with sentences both with auch 'also' and with nur 'only'. Thus, children can consider the presuppositional contribution of the additive particle in their sentence interpretation and can exploit the restrictive particle as a marker of exhaustivity. PMID- 21791152 TI - Children's interpretation of disjunction in the scope of 'before': a comparison of English and Mandarin. AB - This study investigates three- to five-year-old children's interpretation of disjunction in sentences like 'The dog reached the finish line before the turtle or the bunny'. English disjunction has a conjunctive interpretation in such sentences ('The dog reached the finish line before the turtle and before the bunny'). This interpretation conforms with classical logic. Mandarin disjunction ('huozhe') can take scope over 'before' ('zai ... zhiqian'), so the same sentence can mean 'The dog reached the finish line before the turtle or before the bunny (I don't know which)'. If children are guided by adult input in the acquisition of sentence meanings, English- and Mandarin-speaking children should assign different interpretations to such sentences. If children are guided by logical principles, then children acquiring either language should initially assign the conjunctive interpretation of disjunction. A truth-value judgment task was used to test this prediction and English- and Mandarin-speaking children were found to behave similarly. PMID- 21791154 TI - Clarification of the systematic position of Cercariaeum crassum Wesenberg-Lund, 1934 (Digenea), based on karyological analysis and DNA sequences. AB - Chromosome set and rDNA sequences of the larval digenean Cercariaeum crassum were analysed in order to clarify its systematic position and possible adult form. Parasites were obtained from the sphaeriid bivalve Pisidium amnicum, collected in Lithuanian and Finnish rivers. The karyotype is shown to consist of five pairs (2n = 10) of large, up to 14 MUm, chromosomes. Complement, composed of a low diploid number of exclusively bi-armed elements, presumably arose through Robertsonian fusions of acrocentric chromosomes. Consistent with a Robertsonian derived karyotype, one or two small, metacentric, mitotically stable B chromosomes were detected in the cells of parthenitae isolated from some host individuals. A phylogenetic analysis using rDNA internal transcribed spacer 2 (ITS2) and 28S sequences corroborates the allocation of C. crassum to the family Allocreadiidae. In neighbour-joining and maximum parsimony phylogenetic trees C. crassum clusters into one clade with Allocreadium spp., and is the closest sister group in relation to A. isoporum; the level of rDNA sequence divergence between them (2.67% for ITS2 and 1.16% for 28S) is consistent with the level expected for intrageneric variation. The present study adds significant information to a database for establishing species-specific characters for confident characterization of different developmental stages of allocreadiid species, clarification of their life cycles and evaluation of intra- and interspecific variability. PMID- 21791155 TI - Infection dynamics of Cichlidogyrus tilapiae and C. sclerosus (Monogenea, Ancyrocephalinae) in Nile tilapia (Oreochromis niloticus L.) from Uganda. AB - The infection dynamics of the gill monogeneans Cichlidogyrus tilapiae and C. sclerosus on Oreochromis niloticus with respect to habitat type (reservoir, stream, ponds and cages), host sex, size and seasons was determined between January and November 2008. During the study period, 45.2% of the 650 fish examined were infected with Cichlidogyrus spp. The infected hosts harboured an average of 8.6 +/- 3.4 parasites/fish. Across habitat types, the proportion of infected fish was not statistically different. In contrast, the number of parasites recorded on infected fish from different habitat types differed significantly. The highest parasite number was recorded in reservoir-dwelling fish and lowest in stream-dwelling hosts. Concerning sex, more female O. niloticus were infected and harboured a high number of parasites than male and sexually undifferentiated fish. A weak negative relationship was found between rainfall and monthly parasite infections. However, a higher number of parasites and proportion of infected hosts were found during dry than in wet seasons, except in ponds. Results of this study show that differential exposure due to changes in fish behaviour associated with habitat modification and sex may account for the infection difference across the sampled sites. Meanwhile, rainfall and the associated hydrological events are important factors regulating monogenean infections in tropical aquatic environments. The continuous presence of Cichlidogyrus spp. in fish provides evidence of possible parasite outbreaks, indicating the application of biosecurity measures as crucial for the success of intensive fish farming. PMID- 21791156 TI - Negative predictive value of normal nasal endoscopy for sinus disease as a cause of isolated facial pain. AB - OBJECTIVE: To determine the negative predictive value of normal nasal endoscopy in assessing paranasal sinus disease as the cause of isolated facial pain in the sinus regions. SUBJECTS AND METHODS: The study group comprised 42 consecutive adult patients presenting with the isolated symptom of facial pain, and a negative nasal endoscopy. Patients underwent sinus computed tomography to determine whether radiographic findings indicated a sinugenic aetiology. RESULTS: Patients comprised 27 women and 15 men, with a median age of 38 years. Twenty patients had unilateral pain, 33 per cent had sinus radiographic findings that might explain their facial pain, and 10 per cent had imaging demonstrating mucosal disease in one or more sinuses correlating with the location of the facial pain. Thirty-one per cent had anatomical radiographic findings that could potentially obstruct the osteomeatal unit. CONCLUSION: Normal nasal endoscopy had a negative predictive value of 67 per cent in excluding a sinugenic cause of isolated facial pain, if radiographically determined anatomical factors and mucosal disease were both included as positive findings; this rose to more than 90 per cent if only those patients with mucosal sinus disease were considered as true positive patients. PMID- 21791157 TI - An unusual cause of nasal airway obstruction in a neonate: trans-sellar, trans sphenoidal cephalocoele. AB - INTRODUCTION: Neonates are obligate nasal breathers, and nasal obstruction may have serious implications. We present an extremely rare cause of neonatal nasal obstruction, and its management. CASE REPORT: An eight-day-old neonate was referred for upper airway obstruction. Initial investigations had identified no obvious cause. Rigid airway endoscopy revealed a large, cystic lesion appearing to arise from the roof of the posterior nasal space. Computed tomography and magnetic resonance imaging indicated a basal cephalocoele projecting inferiorly into the oropharynx, with an intracranial connection to the pituitary fossa. Histology showed fibrovascular tissue lined on one aspect by respiratory type epithelium, with mucous glands present. The tissue contained multiple cystic spaces lined by choroid plexus epithelium, with glial tissue present in the walls of the mass. A transpalatal excision of the nasopharyngeal cephalocoele, with closure of the intracranial connection, palatal repair and lumbar drain placement was undertaken. Post-operative recovery was uneventful, with no evidence of cerebrospinal fluid leakage or palatal dysfunction. CONCLUSION: This surgical approach gave excellent access whilst avoiding the obvious morbidity associated with an intracranial approach. Nasal masses should be considered in the differential diagnosis of neonatal respiratory distress due to nasal obstruction. PMID- 21791158 TI - Comparison of nasal cytology and symptom scores in patients with seasonal allergic rhinitis, before and after treatment. AB - OBJECTIVE: To evaluate symptom scores and nasal smear cytology findings in seasonal allergic rhinitis patients, before and after treatment. METHODS: Twenty nine consecutive adult patients with seasonal allergic rhinitis were evaluated prospectively. They received mometasone furoate nasal spray and cetirizine for 21 days. Nasal and ocular symptom scores were recorded before and after treatment. Nasal cytology was also assessed as a means of determining treatment. RESULTS: The combined use of an intranasal corticosteroid and an oral antihistamine caused a significant improvement in nasal and ocular symptom scores. Cytological evaluation revealed significant reduction in nasal eosinophil, neutrophil and goblet cell counts after three weeks' treatment. CONCLUSION: Symptom scoring systems are widely used for the evaluation of drug efficacy in allergic rhinitis treatment. When investigating the disease and evaluating treatment efficacy, objective as well as subjective methods are needed. Nasal cytological assessment is a simple, objective method which provides valuable information about the nasal mucosa. PMID- 21791159 TI - Vitamin B12 deficiency: an unusual cause of vocal fold palsy. AB - OBJECTIVE: We report an extremely rare case of vocal fold palsy secondary to vitamin B12 deficiency. METHOD: Case report and English-Language review of the world literature concerning vitamin B12 deficiency and its neurological manifestations. We discuss the physiological role of vitamin B and its specific relationship to the presented patient's symptoms. RESULTS: We describe a rare instance of a patient presenting with bilateral lower limb weakness and unilateral vocal fold palsy, as a manifestation of vitamin B12 deficiency. Quick recognition and treatment resulted in a full recovery. DISCUSSION: To our knowledge, this is the first reported case of unilateral vocal fold palsy secondary to vitamin B12 deficiency. Central and peripheral neuropathies have been described; however, other than the optic nerve, the cranial nerves are very rarely affected. It is important to consider vitamin B12 deficiency as a cause, as speedy identification and treatment can help prevent permanent neurological damage. PMID- 21791160 TI - Nicotinamide-N-methyltransferase (NNMT) in schizophrenia: genetic association and decreased frontal cortex mRNA levels. AB - Emerging evidence suggests impaired one-carbon metabolism in schizophrenia. Homocysteine is one of the key components of one-carbon metabolism. Elevated plasma homocysteine levels were reported in schizophrenia. A linkage study found that nicotinamide-N-methyltransferase (NNMT), an enzyme involved in one-carbon metabolism, is a determinant of plasma homocysteine levels. In an association study the rs694539 NNMT single nucleotide polymorphism (SNP) was found significantly associated with hyperhomocysteinaemia. Aiming to assess the possible involvement of NNMT in the aetiology of schizophrenia we (1) performed an association study of eight NNMT tagged SNPs in 202 families sharing the same ethnic origin including healthy parents and a schizophrenia proband; (2) assessed NNMT mRNA levels in post-mortem frontal cortex of schizophrenia patients. Genotyping was performed using the ABI SNaPshot and the HRM methods. Individual SNPs and haplotypes were analysed for association using the family-based association test (UNPHASED software). NNMT mRNA levels were measured using RT real-time PCR. In the single SNP analysis, rs694539, previously reported to be associated with hyperhomocysteinaemia, and rs1941404 were significantly associated with schizophrenia (p<0.004 and p=0.033, respectively, following permutation test adjustment). Several haplotypes were also significantly associated with schizophrenia (global p values <0.05 following permutation test adjustment). This is the first study demonstrating an association of NNMT with schizophrenia. Post-mortem frontal cortex NNMT mRNA levels were ~35% lower in schizophrenia patients vs. control subjects. Our study favours the notion that NNMT is involved in the aetiology of schizophrenia. PMID- 21791161 TI - Premeiotic transformation of germ plasm-related structures during the sea urchin spermatogenesis. AB - The germ plasm-related structures (GPRS) and the transformation that occurs to them during the spermatogenesis of the sea urchin Anthocidaris crassispina were studied by electron microscopy and morphometry. The GPRS were observed in spermatogonia and spermatocytes, but not in spermatids and sperm, which suggests an important role for these structures during the onset of meiosis. It was proposed that the germinal granules are fragmented into the compact electron dense nuage, and fragments of the latter penetrate into the periphery of the compact electron-lucent nuage. The process of nuage integration is completed with the formation of the combined nuage, which aggregates some mitochondria into clusters. Once formed, the mitochondrial clusters undergo dissemination and assume the appearance of the dispersed nuage with mitochondrial derivatives, which in turn develops into the scattered nuage. The scattered nuage, which presumably presents the composite mixture saturated with mitochondrial matrix, terminates the GPRS transformation. PMID- 21791162 TI - Developmental competence of porcine oocytes after in vitro maturation and in vitro culture under different oxygen concentrations. AB - In this study, we investigated the effect of two oxygen concentrations (5 and 20%) during in vitro maturation (IVM) and during in vitro culture (IVC) on porcine embryo development and analysed differences in gene expression between cumulus-oocyte complexes matured under 5 or 20% oxygen and the resulting blastocysts cultured under 5% or 20% oxygen following parthenogenetic activation. There was no significant difference in oocyte maturation rate. However, the numbers of resulting blastocysts were significantly increased in the 5% IVC group compared with the 20% IVC group. Moreover, the M20C5 treatment group (23.01%) supported greater blastocyst development compared with the M5C5 (14.32%), M5C20 (10.30%), and M20C20 (17.88%) groups. However, total cell numbers were not significantly different among groups. According to mRNA abundance data of multiple genes, each treatment altered the expression of genes in different patterns. GLUT1, G6PD and LDHA were up-regulated in cumulus cells that had been matured in low oxygen, suggesting a higher glucose uptake and an increase in anaerobic glycolysis, whereas cyclin B1 (CCNB) and MnSOD (Mn-superoxide dismutase) were upregulated in cumulus cells that had been matured in high oxygen, which suggests a higher activity of mitosis-promoting factor and antioxidant response. In spite of these differential effects on cumulus cells, oocytes could mature normally regardless of different oxygen concentrations. Therefore, it can be concluded that high oxygen concentration during in vitro maturation and low oxygen during in vitro culture may alter the expression of multiple genes related to oocyte competence and significantly improves embryo development (p < 0.05) but not blastocyst quality. PMID- 21791163 TI - Effect of bovine age on the proliferative activity, global DNA methylation, relative telomere length and telomerase activity of granulosa cells. AB - Granulosa cells influence the growth and acquisition of the developmental competence of oocytes. We investigated the effects of ageing on the proliferative activity, global genomic DNA methylation, relative telomere length and telomerase activity of bovine granulosa cells. The proliferative activity of cells was examined by bromodeoxyuridine (BrdU) assay, genomic DNA methylation was examined by enzyme-linked immunosorbent assay (ELISA), and relative telomere length and telomerase activity were examined by real-time polymerase chain reaction. We first compared the proliferative activity of the granulosa cells of the medium follicles between in dominant phase ovaries and growth phase ovaries. We observed that the proliferative activity of the granulosa cells of dominant phase ovaries was significantly lower than those of growth phase ovaries. In addition, the proliferative activity of granulosa cells was inversely associated with follicular size. Based on the results, we used granulosa cells harvested from the medium follicles (3-5 mm in diameter) on the surfaces of the dominant phase ovaries collected from cows at a slaughterhouse. The proliferative activity of the granulosa cells harvested from the ovaries of old cows (N = 8; average age 165.1 months) was lower than that of the cells from young cows (N = 8; average age 30.9 months). Global loss of cytosine methylation was detected in the granulosa cells of old cows (N = 12; average age 141.0 months) compared with young cows (N = 15; average age 27.4 months). Although the relative telomere lengths of cumulus cells were similar in the two age groups, the relative telomere lengths and telomerase activity of the granulosa cells from old cows (N = 17 and 9; average age, 164.6 and 151.3 months, respectively) tended to be shorter than those of the cells from young cows (N = 17 and 10; average age 30.6 and 28.1 months, respectively); however, this difference was not significant p = 0.09 and 0.053, respectively). In conclusion, the proliferative activity and genomic global DNA methylation significantly decreased, and the relative telomere lengths and telomerase activity of granulosa cells tended to be shorter with the age of donor cows. PMID- 21791164 TI - Selection of bovine oocytes by brilliant cresyl blue staining: effect on meiosis progression, organelle distribution and embryo development. AB - The selection of competent oocytes for in vitro maturation is still a major problem during bovine in vitro embryo production. Markers for in vitro cytoplasmic maturation, based on the organization of cortical granule and mitochondria, are lacking. We examined the pre-selection of immature bovine oocytes by brilliant cresyl blue stain (BCB test) based on glucose-6-phosphate dehydrogenase (G6PDH) activity during oocyte development. Oocytes were recovered from ovarian follicles exposed to 26 MUM BCB stain and classified according to the aspect of their cytoplasm: BCB(+) (oocytes with blue cytoplasm) and BCB(-) (unstained cytoplasm) and then in vitro matured into a conventional in vitro maturation (IVM) medium and standard procedure. In Experiment 1, nuclear maturation was determined by polar body identification, while cytoplasmic maturation was based on cortical granule (CG) migration (peripheral) and mitochondria distribution (central). Evidence of polar body, cortical granule migration and of centrally located mitochondria was significantly (p < 0.05) higher in BCB(+) oocytes than in BCB(-) (polar body present: 65% vs 20%; peripheral CG: 72% vs. 14%; and central mitochondria: 85% vs. 19%, respectively). In Experiment 2, the efficiency pre-selection of bovine oocytes by BCB on embryo development in vitro was assessed. Cleavage rates were similar (75%) among control, BCB(+) and BCB(-) groups, while blastocyst rates on D7 were (p < 0.05) higher (35%) in BCB(+) vs BCB(-) (10%) or control (28%). We showed that the BCB test is efficient to identify competent immature bovine oocytes to undergo synchronous nuclear and cytoplasmic in vitro maturation thus yielding higher in vitro embryo development to blastocyst stage. PMID- 21791165 TI - Cat fertilization by mouse sperm injection. AB - Interspecies intracytoplasmic sperm injection has been carried out to understand species-specific differences in oocyte environments and sperm components during fertilization. While sperm aster organization during cat fertilization requires a paternally derived centriole, mouse and hamster fertilization occur within the maternal centrosomal components. To address the questions of where sperm aster assembly occurs and whether complete fertilization is achieved in cat oocytes by interspecies sperm, we studied the fertilization processes of cat oocytes following the injection of cat, mouse, or hamster sperm. Male and female pronuclear formations were not different in the cat oocytes at 6 h following cat, mouse or hamster sperm injection. Microtubule asters were seen in all oocytes following intracytoplasmic injection of cat, mouse or hamster sperm. Immunocytochemical staining with a histone H3-m2K9 antibody revealed that mouse sperm chromatin is incorporated normally with cat egg chromatin, and that the cat eggs fertilized with mouse sperm enter metaphase and become normal 2-cell stage embryos. These results suggest that sperm aster formation is maternally dependent, and that fertilization processes and cleavage occur in a non-species specific manner in cat oocytes. PMID- 21791166 TI - Effects of linseed consumption for a short period of time on lipid profile and atherosclerotic lesions in rabbits fed a hypercholesterolaemic diet. AB - Linseed contains biologically active substances, such as lignans, fibres and linoleic acid, which are believed to provide cardioprotective effects. The objective of the present study was to assess the potential hypolipaemic, anti atherogenic and anti-inflammatory effects of linseed consumption using an experimental animal model, with rabbits fed a hypercholesterolaemic diet (1 % cholesterol extracted from lyophilised egg). A total of twenty white male rabbits were selected and divided into two groups: group I (GI), control group, ten rabbits; group II (GII), ten rabbits. The animals were fed a hypercholesterolaemic diet for 56 d. For the GII diet, ground linseed was added from day 29 through to day 56. Animals underwent aortic arch and descending aorta dissection on day 56 for histological, morphometric and immunohistochemical analysis. At the end of the experiment, GII animals presented with lower levels of total cholesterol (TC, 10 068.3 v. 16 767.0 mg/l; P < 0.05) and lower levels of LDL-cholesterol (LDL-C; 10 743.2 v. 15 961.2 mg/l; P < 0.05) when compared with the GI control group. There was no significant difference in serum HDL cholesterol and TAG between the two groups. Almost all animals exhibited type III atherosclerotic lesions in the descending aorta. There was no statistically significant difference between the intima area and the intima:media layer area ratio in both groups. There was no difference between the positive areas for vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 molecules between the groups. Linseed consumption showed hypolipaemic action by reducing LDL-C and TC levels; however, this cholesterol-lowering effect did not reduce the atherosclerotic lesions induced by a hypercholesterolaemic diet (1 % cholesterol) for a short period of time. PMID- 21791167 TI - Effect of oocyte-secreted factors on porcine in vitro maturation, cumulus expansion and developmental competence of parthenotes. AB - The oocyte is known from recent studies in the mouse, cow, sheep and human to be a central regulator of follicular cell function. However, in the pig, little information is known about the regulation of cumulus expansion by oocyte-secreted factors and oocyte quality. We investigated the possible effects of oocyte secreted factors during in vitro maturation on cumulus expansion and on porcine oocytes as judged by subsequent embryonic development after parthenogenetic activation. Cumulus-oocyte complexes (COC) from antral follicles of pig ovaries collected from a local abattoir were divided into control and treatment groups and were cultured in tissue culture medium 199 supplemented with follicle stimulating hormone. Treatment groups consisted of increasing numbers of denuded oocytes (DO) co-cultured with COC (at ratios of COC to DO of 1:1, 1:2, 1:3, 1:4 and 1:5). After incubation for 44 h, cumulus expansion and maturation rates were assessed and oocytes were activated parthenogenetically. Cumulus expansion in the 1 COC:4 DO and 1 COC:5 DO groups was low and altered because full dispersion of the outer layer did not occur. Cell viability was not affected, as measured by the automated cell counter, but scanning electron microscopy revealed only a scanty extracellular matrix. Blastocyst rate was significantly higher in the 1 COC:4 DO (34.4%) and in the 1 COC:5 DO (34.9%) groups (p < 0.05) when compared with other groups. Maturation rate, cleavage rate and total cell number showed no significant difference between control and treatment groups. Amplification by reverse transcription polymerase chain reaction (RT-PCR) showed up-regulation of growth differentiation factor 9 (GDF9) in the cumulus cells in the 1 COC:4 DO group at 44 h. We conclude that denuded porcine oocytes could improve the maturation of COC as evidenced by increased blastocyst development in the 1 COC:4 DO, even though cumulus expansion was poor. This improvement could be a result of the GDF9 up-regulation. PMID- 21791168 TI - Selection of Rattus norvegicus oocytes for in vitro maturation by brilliant cresyl blue staining. AB - The objective of this work was to evaluate the rate of meiosis resumption and nuclear maturation of rat (Rattus norvegicus) oocytes selected for in vitro maturation (IVM) after staining of cumulus-oocyte complexes (COCs) with blue cresyl brilliant (BCB) using different protocols: exposure for 30, 60 or 90 min at 26 MUM BCB (Experiment 1), and exposure for 60 min at 13, 20 or 26 MUM BCB (Experiment 2). In Experiment 1, the selection of oocytes exposed to BCB for 60 min was found to be the most suitable, as meiosis resumption rates in the BCB(+) group (n = 35/61; 57.37%) were the closest to the observed in the control (not exposed) group (n = 70/90; 77.77%) and statistically higher than the values observed for the BCB(-) group (n = 3/41; 7.32%). Additionally, the more effective evaluation of diagnostic tests (sensitivity and negative predictive value 100%) was observed in COCs exposed for 60 min. In Experiment 2, the 13 MUM BCB(+) group presented rates of meiosis resumption (n = 57/72; 72.22%) similar to the control group (n = 87/105; 82.86%) and higher than other concentration groups. However, this results of the analysis between BCB(-) oocytes was also higher in the 13 MUM BCB group (n = 28/91; 30.78%) when compared with BCB(-) COCs exposed to 20 MUM (n = 3/62; 4.84%) or 26 MUM (n = 3/61; 4.92%) BCB. The nuclear maturation rate in the 13 MUM BCB group was similar between BCB(+) or BCB(-) oocytes. The 20 MUM BCB group had a lower rate of nuclear maturation of BCB(-) oocytes than other groups. Thus, our best results in the selection of Rattus norvegicus oocytes by staining with BCB were obtained using the concentration of 13 MUM and 20 MUM, and an incubation period of 60 min. PMID- 21791170 TI - Relation between alpha-isoform and phosphatase activity of Na+,K+-ATPase in rat skeletal muscle fiber types. AB - In skeletal muscle the relationship between Na+,K+-ATPase activity and isoform content remains controversial (9,6). It could be due to the fiber-type content, membrane isolation and analytical methods. We investigated the distribution of subunit alpha1 and alpha2 Na+,K+-ATPase catalytic isoforms and the Na+,K+-ATPase activity in isolated membranes from white ( type I and glycolitic fibers) and red (type II and oxidative fibers) skeletal muscles. Red Gastrocnemius and White Gastrocnemius muscles were sampled from 8 week-old female Wistar rats and crude membranes were performed. The Na+,K+-ATPase activity and membrane distribution of Na+,K+-ATPase alpha1 and alpha2 isoforms were assessed by ouabain sensitive K phosphatase (Kpase) measurements and Western Blot respectively. The Na+,K+-ATPase activity was 6 fold lower in White Gastrocnemius membranes than in Red Gastrocnemius membranes. The alpha1 and alpha2-isoform levels are higher in RG than in White Gastrocnemius. The alpha1 and alpha2-subunit Red Gastrocnemius content was significantly higher than in WG. The correlation between crude membrane Kpase activity and both catalytic alpha-subunit of the Na+,K+-ATPase exist.These data suggest that the Na+,K+-ATPase phosphatase activity correlates with the alpha1 and alpha2 isoforms levels in Red Gastrocnemius and White Gastrocnemius and confirms the fiber-specific Na+,K+-ATPase catalytic alpha subunits and alpha2-isoform as the major catalytic isoform in rat skeletal muscle. PMID- 21791169 TI - Dysconnectivity of multiple resting-state networks in patients with schizophrenia who have persistent auditory verbal hallucinations. AB - BACKGROUND: Functional neuroimaging studies on schizophrenia have suggested abnormal task-related functional connectivity in patients with schizophrenia who have auditory verbal hallucinations (AVHs). However, little is known about intrinsic functional connectivity in these patients. METHODS: Between January 2009 and February 2010, we studied patients with schizophrenia who had persistent and treatment-refractory AVHs in comparison with healthy controls. Using functional magnetic resonance imaging, we studied the functional connectivity of multiple resting state networks (RSNs) and their relation to symptom severity. We analyzed the data using a spatial group independent component analysis, and we used random-effects t tests to compare spatial components between groups. RESULTS: There were 10 patients and 14 controls enrolled in this study. In total, 16 RSNs were identified, from which we selected 4 networks of interest for further analyses. Within a speech-related network, patients showed increased connectivity in bilateral temporal regions and decreased connectivity in the cingulate cortex. Within 2 additional RSNs associated with attention and executive control, respectively, patients exhibited abnormal connectivity in the precuneus and right lateral prefrontal areas. We found correlations between measures of AVH severity and functional connectivity of the left anterior cingulate, left superior temporal gyrus and right lateral prefrontal cortex. LIMITATIONS: The relatively small sample size, the patients' use of antipsychotic medication and the lack of a clinical control group have to be considered as potential limitations. CONCLUSION: Our findings indicate that disrupted intrinsic connectivity of a speech-related network could underlie persistent AVHs in patients with schizophrenia. In addition, the occurrence of hallucinatory symptoms seems to modulate RSNs associated with attention and executive control. PMID- 21791171 TI - Generation of dopaminergic neurons by fusion of neural stem cells and midbrain neurons. AB - Neural stem cells (NSCs) are multipotent and self-renewing that can potentially generate various neurons for clinical purposes. However, the mechanism of regulating differentiation from NSCs to neurons is not well understood. In this report, we established a new method to obtain specific neurons from NSCs by cell fusion. NSCs were fused with midbrain neurons, resulting in hybrid cells that express an antigen pattern characteristic of dopaminergic neurons. Analysis of the marker enzyme tyrosine hydroxylase (TH) showed that hybrid cells were reprogrammed to somatic cells. This report represents a new significant contribution toward revealing the directional differentiation of NSCs and eventually providing the application in clinical transplantation therapy. PMID- 21791172 TI - Calpain cleaved-55kDa N-terminal huntingtin delocalizes from neurons to astrocytes after ischemic injury. AB - The huntingtin (htt) mutation causes a polyglutamine expansion in the N-terminal region of protein. Mutant N-htt proteolytic fragments aggregate and cause cell death in Huntington's disease (HD). The normal huntingtin also can be cleaved by calpain and produce N-terminal htt fragments following ischemic injury, but the fate of cleaved fragment in dead neurons in the brain are unclear. To determine the localization of huntingtin following proteolysis, we examined htt expression after transient ischemic injury. Huntingtin immunoreactivity in mixed cultures of neuronal and astrocytes-derived clonal cells showed alteration of immunoreactivity from neurons into astrocytes. In the brain, both focal and global ischemia induced reactive astrocytes that were co-immunoreactive for huntingtin with elevated GFAP expression. The immunoreactive huntingtin was 55kDa calpain-cleaved N-terminal fragment, which appeared initially in the process, and extended into the cytoplasm of astrocytes. The results showed, after ischemic injury, huntingtin accumulated in astrocytes indicating that astrocytes may play a role in uptake of cleaved N-htt fragments. PMID- 21791173 TI - Toxicity of alpha-ketoglutarate following 14-days repeated oral administration in Wistar rats. AB - Oral treatment of alpha-ketoglutarate (A-KG) is known to antagonise experimental cyanide poisoning in rodents. Maximum protective efficacy of A-KG has been observed at a dose of 2.0 g kg-1 body weight but no acute toxicity has been observed at this dose level. As a pre-clinical regulatory requirement, sub-acute toxicity of A-KG has to be determined in two different animal species, following repeated exposure by the intended route of use. The present study reports the toxicity and No Observed Adverse Effect Level (NOAEL) of A-KG following 14 days repeated oral administration at low (1.0 g kg-1), middle (2.0 g kg-1) and high (4.0 g kg-1) doses of A-KG in Wistar rats. After termination of the exposure, animals were further observed for 7 days to assess the recovery pattern and residual effects. Clinical signs included diarrhoea at 4.0 g kg-1 in both the sexes and decrease in mean body weight in males. This dose also caused anaemia in females which resolved after withdrawal of treatment. In males, significant increase in absolute and relative weights of organs (adrenal, liver and kidneys) and haematological changes were observed at the end of recovery period, suggesting delayed toxic manifestations at 2.0 and 4.0 g kg-1 dose. However, these observations were not accompanied by any histological changes to suggest any toxicity of A-KG of clinical significance. The NOAEL of A-KG was determined as 1.0 g kg-1 body weight. Although A-KG is intended to treat acute cyanide poisoning, caution on dosage should be observed during its repeated administration. PMID- 21791174 TI - Laminar shear stress promotes endothelial cell migration and inhibits cell apoptosis in the presence of hydroxyurea. AB - Cell migration plays important roles in both physiological and pathological processes. Recent studies have shown that hydroxyurea, which is an anti proliferative inhibitor, can affect cell morphology and specific gene expression of endothelial cells (ECs). In vivo, the functions of ECs are modulated by shear stress. It is well known that shear stress can have effects on EC migration by affecting cell morphology, cytoskeletal arrangement and cell-cell junction, and activating mechanosensors, inducing the changes of signaling pathways, and then increasing or decreasing the expression of gene and protein. However, the influences of hydroxyurea on EC function under shear stress are still unclear. In present study, we investigated the effects of hydroxyurea on EC proliferation, apoptosis and migration under laminar shear stress. The results showed that hydroxyurea prevented growth of ECs in a dose-dependent manner. Hydroxyurea at 2 mM completely inhibited the proliferation of ECs. The results also demonstrated that hydroxyurea induced EC apoptosis, but it was inhibited by 15.27 dyn/cm2 laminar shear stress. Furthermore, shear stress induced cell migration in the presence of hydroxyurea. Therefore, 2 mM hydroxyurea, which completely inhibited the proliferation of HUVECs, could be used to eliminate any confounding effect of shear stress on proliferation in shear stress-induced cell migration. These results also do confirm that shear stress plays important roles in achieving and maintaining the stabilization of ECs. PMID- 21791175 TI - Evaluation of the uterine environment early in pregnancy establishment to characterise cows with a potentially superior ability to support conceptus survival. AB - During previous investigations, the capacity of the cow to secrete prostaglandin in response to oxytocin has been linked with pregnancy outcome. The objective of the present study was to evaluate the predictive value of prostaglandin release to identify groups of cows as potentially superior (SR, low prostaglandin release) or inferior (IR, high prostaglandin release) for pregnancy outcome and to utilise these cows to investigate factors that contribute to optimum uterine conditions for early pregnancy. Animals were synchronised and received an in vitro-derived blastocyst on Day 7 post-oestrus. Tissues (trophoblast and endometrial) and uterine luminal fluid (ULF) were recovered 10 days later. Pregnancy rates were 94 and 78% for SR and IR cows, respectively. Of the pregnant SR cows, 69% had larged conceptuses (>24 cm) in contrast to 43% IR of cows. IR cows with small conceptuses (<12 cm) had significantly lower mean Day 3 and 5 post-oestrous progesterone concentrations than cows with large conceptuses. The expression of factors involved in the prostaglandin pathway, pregnancy and conceptus development were analysed via quantitative RT-PCR and Western blot analysis. Investigation of 16 endometrial gene transcripts indicated no differences between IR and SR cows except for osteopontin expression which, in uteri with large conceptuses, was 2-fold greater in SR than IR cows (P=0.02). There was greater expression of CTGF, OXTR, PGES, PGHS2 and UTMP mRNA in uteri of SR and IR cows that had large compared with small conceptuses (P<0.05). More IFNT protein was recovered in SR compared with IR ULF (P<0.03). SR cows with large conceptuses had less TIMP2 and legumain protein in their gravid, compared with their non-gravid horns (P<=0.02) whereas IR cows did not. The predictive value of prostaglandin release in response to oxytocin challenge does not appear to be an effective indicator of subsequent pregnancy rates in cows. Differences between the two groups appear to be associated with subtle differences in progesterone and uterine protein concentrations that may be related to differences in conceptus size. PMID- 21791176 TI - Transforming growth factor-beta (TGFbeta) in porcine seminal plasma. AB - Bioactive factors in seminal plasma induce cellular and molecular changes in the female reproductive tract after coitus. An active constituent of seminal plasma in mice and humans is the potent immune-modulating cytokine transforming growth factor-beta (TGFbeta). To investigate whether TGFbeta is present in boar seminal plasma, TGFbeta(1) and TGFbeta(2) were measured by immunoassay. High levels of TGFbeta(1) and TGFbeta(2) were detected in 100% of seminal fluid samples from 73 boars. Both were predominantly in the active, not latent form. Interferon-gamma (IFNgamma) and lipopolysaccharide (LPS), agents that interact with TGFbeta signalling, were detectable in 5% and 100% of samples, respectively. TGFbeta(1) and TGFbeta(2) concentrations varied widely between boars, but correlated with each other and with sperm density, and remained relatively constant within individual boars over a 6-month period. Frequent semen collection substantially diminished the concentration of both TGFbeta isoforms. Using retrospective breeding data for 44 boars, no correlation between TGFbeta content and boar reproductive performance by artificial insemination (AI) with diluted semen was found. It is concluded that TGFbeta is abundant in boar seminal plasma, leading to the speculation that, in pigs, TGFbeta may be a male-female signalling agent involved in immune changes in the female reproductive tract elicited by seminal fluid. PMID- 21791177 TI - Acute fasting before conception affects metabolic and endocrine status without impacting follicle and oocyte development and embryo gene expression in the rabbit. AB - Food deprivation affects female reproduction. The goal of the present study was to elucidate in the rabbit model the effects of acute energy restriction on ovarian function (follicle development, atresia rate and in vitro oocyte maturation) and embryonic development and gene expression of some candidate genes. Serum metabolic parameters (non-esterified fatty acids (NEFA), triglycerides, glucose, insulin and leptin concentrations) and endocrine markers (oestradiol-17beta and progesterone concentrations) were also studied. A control group of nulliparous does fed ad libitum and a 72-h fasted group were used. At the end of the nutritional treatment, the ovaries of half of the animals were retrieved while the other animals were re-fed and artificially inseminated to recover embryos at 84 h after insemination, during the luteal phase. At the end of fasting, increased serum NEFA and decreased leptin concentrations were observed in the fasted group, but no differences appeared in serum steroid concentrations, follicle population and atresia rate or nuclear and cytoplasmic oocyte maturation. In the luteal phase, insulin concentrations increased notably in the fasted group. The number of recovered embryos per female and the speed of embryo development were reduced in the food-deprived group. Acute fasting altered both metabolic and endocrine markers and embryo development, but follicle and oocyte development and embryo gene expression were not affected. PMID- 21791178 TI - Sperm genome cloning used in biparental bovine embryo reconstruction. AB - The generation of androgenetic haploid embryos enables several haploid blastomeres to be obtained as identical copies of a single spermatozoon genome. In the present study, we compared the developmental ability of bovine androgenetic haploid embryos constructed by different methods, namely IVF and intracytoplasmic sperm injection (ICSI) before and after oocyte enucleation. Once obtained, the blastomeres of these androgenetic haploid embryos were used as male genome donors to reconstruct biparental embryos by fusion with matured oocytes. To verify the cytoplasmic contribution of androgenetic haploid blastomeres, we used spermatozoa incubated previously with exogenous DNA that coded for a green fluorescent protein gene (pCX-EGFP) and the enhanced green fluorescent protein (EGFP)-positive androgenetic haploid blastomeres generated were fused with mature oocytes. Of the reconstructed embryos reaching the cleavage and blastocyst stages, 85.1% and 9.0%, respectively, expressed EGFP (P>0.05). EGFP expression was observed in 100% of reconstructed embryos, with 91.2% exhibiting homogenic expression. To confirm sperm genome incorporation, androgenetic haploid blastomeres generated by ICSI prior to enucleation and using Y chromosome sexed spermatozoa were used for biparental embryo reconstruction. Incorporation of the Y chromosome was confirmed by polymerase chain reaction and fluorescence in situ hybridisation analysis. In conclusion, the results of the present study prove that it is possible to use sperm genome replicates to reconstruct biparental bovine embryos and that it is a highly efficient technique to generate homogeneous transgene-expressing embryos. PMID- 21791179 TI - Effects of corticotropin-releasing hormone and its antagonist on the gene expression of gonadotrophin-releasing hormone (GnRH) and GnRH receptor in the hypothalamus and anterior pituitary gland of follicular phase ewes. AB - There is no information in the literature regarding the effect of corticotropin releasing hormone (CRH) on genes encoding gonadotrophin-releasing hormone (GnRH) and the GnRH receptor (GnRHR) in the hypothalamus or on GnRHR gene expression in the pituitary gland in vivo. Thus, the aim of the present study was to investigate, in follicular phase ewes, the effects of prolonged, intermittent infusion of small doses of CRH or its antagonist (alpha-helical CRH 9-41; CRH-A) into the third cerebral ventricle on GnRH mRNA and GnRHR mRNA levels in the hypothalamo-pituitary unit and on LH secretion. Stimulation or inhibition of CRH receptors significantly decreased or increased GnRH gene expression in the hypothalamus, respectively, and led to different responses in GnRHR gene expression in discrete hypothalamic areas. For example, CRH increased GnRHR gene expression in the preoptic area, but decreased it in the hypothalamus/stalk median eminence and in the anterior pituitary gland. In addition, CRH decreased LH secretion. Blockade of CRH receptors had the opposite effect on GnRHR gene expression. The results suggest that activation of CRH receptors in the hypothalamus of follicular phase ewes can modulate the biosynthesis and release of GnRH through complex changes in the expression of GnRH and GnRHR genes in the hypothalamo-anterior pituitary unit. PMID- 21791180 TI - Immunisation against inhibin enhances follicular development, oocyte maturation and superovulatory response in water buffaloes. AB - This study was carried out to test the feasibility of enhancing embryo production in vivo and in vitro by immunoneutralisation against inhibin or follistatin. In Experiment 1, multi-parity buffaloes were assigned into three groups: High group (n=8), which received one primary (2mg) and two booster (1mg) vaccinations (28 day intervals) with a recombinant inhibin alpha subunit in 1 mL of white oil adjuvant; Low group (n=8), which received half that dose; and Control group (n=7), which received only adjuvant. Immunisation against inhibin stimulated development of ovarian follicles. Following superovulation and artificial insemination, inhibin-immunised buffaloes had more developing follicles than the Control buffaloes. The average number of embryos and unfertilised ova (4.5+/-0.6, n=6) in the High group was higher (P<0.05) than in the Control group (2.8+/-0.6, n=5) and was intermediate (4.1+/-0.7, n=7) in the Low group. The pooled number of transferable embryos of the High and Low groups (3.2+/-0.5, n=13) was also higher (P<0.05) than that (1.6+/-0.7, n=5) of the controls. The immunised groups also had higher plasma concentrations of activin, oestradiol and progesterone. In Experiment 2, the addition of anti-inhibin or anti-follistatin antibodies into buffalo oocyte IVM maturation medium significantly improved oocyte maturation and cleavage rates following parthenogenic activation. Treatment with anti follistatin antibody also doubled the blastocyst yield from activated embryos. These results demonstrated that immunisation against inhibin stimulated follicular development, enhanced oocyte quality and maturation competence, yielded more and better embryos both in vivo and in vitro. PMID- 21791181 TI - Characterisation of mouse interferon-induced transmembrane protein-1 gene expression in the mouse uterus during the oestrous cycle and pregnancy. AB - During the oestrous cycle, pregnancy and parturition, the uterus undergoes marked morphological, physiological and functional changes. Amid these changes, the Wnt/beta-catenin signalling pathway has been identified as having a crucial role in regulating associated biological events. Recently, based on results from a mouse embryo study, interferon-induced transmembrane protein 1 (Ifitm1) was reported as a downstream molecule of the Wnt/beta-catenin signalling pathway. Differential expression patterns of the Ifitm1 gene during the oestrous cycle, pregnancy and parturition were identified in the present study. Quantitative real time polymerase chain reaction data from uterine samples of mice induced start the oestrous cycle by injection of human chorionic gonadotropin (hCG) and revealed that Ifitm1 mRNA expression increased from late pro-oestrus to metoestrus, and decreased during dioestrus and early pro-oestrus. During pregnancy, Ifitm1 gene expression was minimal until parturition, but increased markedly 2 days after parturition. This significant elevation in Ifitm1 gene expression at post partum stage was identical to Ifitm1 expression after the induction of abortion by injection of prostaglandin F(2alpha). Interestingly, pregnant mare serum gonadotropin (PMSG) and oestrogen are also facilitates changes in Ifitm1 gene expression in an ovariectomised (OVX) mouse model. Expression of Ifitm1 mRNA was higher in response to PMSG than other hormones investigated. These results suggest that Ifitm1 may be involved in uteri physiology, although the mechanisms involved in the regulation of this gene expression and function in the uterus remain unknown. In the present study, differential expression patterns of the Ifitm1 gene were identified in the uteri of mice and the correlation between the patterns of Ifitm1 gene expression and Wnt/beta-catenin signalling discussed. PMID- 21791183 TI - Prolonged storage of epididymal spermatozoa does not affect their capacity to fertilise in vitro-matured domestic cat (Felis catus) oocytes when using ICSI. AB - The impact of different storage conditions of epididymal spermatozoa (including prolonged storage, cryopreservation and freeze-drying) on their fertilisation capacity was tested using intracytoplasmic sperm injection (ICSI). This kind of information is urgently needed when applying assisted reproductive technology to endangered felids in zoos. In particular, the utilisation of epididymal spermatozoa of castrated or deceased felids often requires time-consuming transportation and is therefore susceptible to loss of gamete quality. Sperm cells were stored at 4 degrees C for up to 72 h followed by cryopreservation or freeze-drying. Thawed motile and immotile spermatozoa were used for ICSI and the embryo cleavage rate was assessed 36 h after injection. A significant impact on the fertilisation rate of oocytes could only be detected when using immotile thawed or rehydrated spermatozoa. Cryopreservation or storage at 4 degrees C showed no influence. The simulation of transport conditions using domestic cat spermatozoa revealed that in vitro production of felid embryos with gametes from euthanised individuals is possible if testes are stored cool and arrive at the laboratory within 72 h. An essential prerequisite is the application of ICSI to achieve fertilisation even with single motile spermatozoa. Additional cryopreservation of spermatozoa after transportation is possible and will allow the establishment of a sperm bank for felids. PMID- 21791182 TI - High hydrostatic pressure treatment improves the quality of in vitro-produced ovine blastocysts. AB - Exposure to sub-lethal hydrostatic pressure (HP) treatment is emerging as an approach to improve the general resistance of gametes and embryos to in vitro conditions. The present study was aimed to evaluate the effect of HP treatment on in vitro-produced ovine blastocysts. Experiment 1 was aimed to define optimal treatment parameters: two different HP treatments were applied to blastocysts and embryo survival was evaluated. In Experiment 2, HP parameters (40 MPa, 70 min, 38 degrees C) selected in Experiment 1 were used to treat blastocysts. Embryo quality was assessed and compared with untreated controls by counting total cell number, the inner cell mass (ICM) and trophectoderm (TE) cells and by evaluating nuclear picnosis. HP-treated blastocysts were processed for gene expression analysis (AQP3, ATP1A1, BAX, CDH1, HSP90beta, NANOG, OCT4 and TP53) 1, 5h after the end of HP exposure. Results showed that the hatching rate of embryos treated at 40 MPa was significantly higher than that of the 60 MPa-treated group (P<0.01) and similar to untreated embryos. Blastocysts exposed at 40 MPa showed higher ICM (P<0.05) and TE (P<0.01) cell number and a lower percentage of picnotic nuclei (P<0.05) compared with the control group. Significantly lower abundance for BAX (P<0.01) and OCT4 (P<0.05) transcripts were observed in HP embryos than in the control group. In conclusion, treatment with HP improved the quality of in vitro produced ovine blastocysts by increasing their cell number and reducing the proportion of nuclear picnosis. PMID- 21791184 TI - Inactivated Sendai-virus-mediated fusion improves early development of cloned bovine embryos by avoiding endoplasmic-reticulum-stress-associated apoptosis. AB - Somatic cell nuclear transfer (SCNT) is a powerful tool, not only for producing cloned animals, but also in revealing various early developmental events. However, relatively little is known regarding the biological events and underlying mechanism(s) directly associated with early development of SCNT embryos. Here, we show that production of high-quality bovine SCNT blastocysts is dependent on the method used for fusion and the associated reduction in endoplasmic reticulum (ER) stress. During fusion between the donor cell and the enucleated oocyte, electrofusion triggers spontaneous oocyte activation, accompanied by an increase in intracellular Ca(2+) and improper nuclear remodelling. These events can be greatly reduced by the use of Sendai virus (SV) mediated fusion. Moreover, SV-SCNT improves the blastulation rate and blastocyst quality, defined by the number and ratio of inner cell mass and trophectoderm cells in each blastocyst, in comparison with electrofusion-mediated SCNT (E SCNT). Interestingly, expression of ER-stress-associated genes and blastomere apoptosis were significantly increased in E-SCNT embryos. These increases could be reversed by inhibition of ER stress or by using the SV-mediated fusion method. Collectively, these results indicate that SV-mediated fusion improves the developmental competence and quality of SCNT blastocysts, by reducing ER-stress associated apoptosis. PMID- 21791185 TI - Tools of the trade. PMID- 21791186 TI - Bloody tears: historical review and report of a new case. PMID- 21791187 TI - Tear lipocalin: structure and function. AB - Lipocalins are a family of diverse low molecular weight proteins that act extracellularly. They use multiple recognition properties that include 1) ligand binding to small hydrophobic molecules, 2) macromolecular complexation with other soluble macromolecules, and 3) binding to specific cell surface receptors to deliver cargo. Tear lipocalin (TLC) is a major protein in tears and has a large ligand-binding cavity that allows the lipocalin to bind an extensive and diverse set of lipophilic molecules. TLC can also bind to macromolecules, including the tear proteins lactoferin and lysozyme. The receptor to which TLC binds is termed tear lipocalin-interacting membrane receptor (LIMR). LIMR appears to work by endocytosis. TLC has a variety of suggested functions in tears, including regulation of tear viscosity, binding and release of lipids, endonuclease inactivation of viral DNA, binding of microbial siderophores (iron chelators used to deliver essential iron to bacteria), serving as a biomarker for dry eye, and possessing anti-inflammatory activity. Additional research is warranted to determine the actual functions of TLC in tears and the presence of its receptor on the ocular surface. PMID- 21791188 TI - BAK to basics. PMID- 21791189 TI - Preservative use in topical glaucoma medications. AB - Benzalkonium chloride (BAK) is the principal preservative employed in topical ocular hypotensive medications, although alternative compounds recently have begun to be employed or examined. Individual clinical trials have shown that exposure to BAK concentrations contained in ophthalmic solutions does not produce adverse sequelae in the majority of glaucoma patients, but concerns continue with regard to its long-term use. These concerns have resulted from an extensive research effort, including preclinical studies with in vitro and in vivo models, as well as recent clinical investigations dedicated specifically to this issue. The aim of this systematic literature review of both preclinical and clinical data was to determine the relevance of these findings to clinical practice. Most preclinical studies reported negative effects of BAK exposure, but with few exceptions, BAK concentrations and exposure times greatly exceeded those likely to be experienced by patients, given the normal physiological dilution by the tear film. In addition, consistent evidence of BAK-related toxicity did not emerge from our review of dedicated clinical investigations. Thus, taken together, current evidence supports the safety of BAK for most glaucoma patients, although subpopulations with abnormal tearing may benefit from alternative preservative compounds or preservative-free formulations. Further studies to identify these populations are needed. PMID- 21791190 TI - Benzalkonium chloride in glaucoma medications. AB - Benzalkonium chloride (BAK) is the preservative used most commonly in eye drops. Although it is effective as an antimicrobial and antifungal agent, both in vitro and in vivo studies have demonstrated adverse effects on surface epithelial cell populations. This is of particular concern with regard to topical medications used over long periods for chronic conditions, such as glaucoma. Newer non-BAK containing drops are becoming increasingly available, providing an alternative for patients needing long-term eye drop therapy. PMID- 21791191 TI - Sulfur mustard-induced ocular surface disorders. AB - Sulfur mustard is a vesicant agent with severe irritating effects on living tissues, including skin, mucous membranes, eyes, and respiratory tract. The eyes are the most susceptible tissue to mustard gas effects, and varying degrees of ocular involvement are seen in 75% to 90% of exposed individuals. Most cases resolve uneventfully; however, a minority of exposed patients will have a continuous process, which manifests clinically either as a persistent smoldering inflammation (chronic form) or late-onset lesions appearing many years after a variable "silent" period (delayed form). Distinctive features common to most cases with chronic involvement include chronic blepharitis, meibomian gland dysfunction, dry eye, limbal ischemia, limbal stem cell deficiency, aberrant conjunctival vessels, corneal neovascularization, and secondary degenerative changes, including lipid and amyloid deposition and corneal irregularity, thinning and scarring. Most cases can be managed with conservative measures, eg, preservative-free artificial tears, lubricants, and topical steroids. Punctal plugs or punctal cauterization is helpful in moderate and severe forms of injury. Surgical modalities, including lateral or medial tarsorrhaphies, amniotic membrane transplantation, lamellar or penetrating keratoplasty, and stem cell transplantation have been used. PMID- 21791192 TI - Personal profile. Carlos Belmonte, MD, PhD. PMID- 21791193 TI - Drop size: an issue wrapped in a non-issue wrapped in an issue. PMID- 21791194 TI - Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma. AB - We evaluated the safety and efficacy of plerixafor, subsequent to disease specific chemotherapy followed by granulocyte-colony stimulating factor (G-CSF), in 37 multiple myeloma (MM) or lymphoma patients, who were candidates for autologous stem cell transplantation (ASCT) predicted as poor mobilizers (PMs). Patients were identified as predicted PMs according to the history of a previously failed mobilization attempt or the presence of >=1 factors predicting an unsuccessful harvest, such as advanced disease, prior extensive radiotherapy, or prolonged treatment, with stem cell poisons, advanced age, or extensive bone marrow involvement. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to 3 consecutive days while continuing G-CSF for 9 to 11 hours before the planned apheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a median 4-fold increase (range: 1.4-32) in the number of circulating CD34(+) cells following plerixafor compared with baseline CD34(+) cell concentration (from a median of 5 cells/MUL, range: 1-32, to a median of 32 cells/MUL, range: 6-201). Twenty-seven of the 37 patients (14 of 17 with MM and 13 of 20 with lymphoma) had >=2*10(6) CD34(+) cells/kg collected in 1 3 apheretic procedures. Of the 27 patients rescued with plerixafor, 24 (13 MM, 11 lymphoma) have been transplanted with plerixafor-mobilized peripheral blood stem cells, showing a rapid and durable hematologic recovery. Our results suggest that the addition of plerixafor to G-CSF after disease-oriented chemotherapy is safe and allows for a satisfactory harvest in order to perform a safe ASCT, in a relevant proportion of lymphoma and MM patients considered to be PMs. PMID- 21791195 TI - Symptom indexes in refractory gastroesophageal reflux disease: overrated or misunderstood? PMID- 21791196 TI - The control of hookworm disease in Commonwealth Caribbean countries. AB - Like other countries around the globe where conditions existed for the parasites causing hookworm disease to thrive, this disease was a serious problem to settlers in countries of the Commonwealth Caribbean, i.e. those countries that were formerly part of the British Empire. Early in the 20th century, the Rockefeller Foundation (RF) assisted the southern United States in controlling this disease. Soon other countries requested assistance and the Rockefeller Foundation responded by creating their International Health Commission to target the problem. Guyana (then British Guiana) was the first country where work was started. Through a system of chemotherapy, sanitation with the provision of latrines and health education the RF assisted the Commonwealth Caribbean countries during the period 1914-1925 in controlling the disease. Most countries continued the programmes started by the Rockefeller Foundation and this paper provides evidence through a series of surveys to show that hookworm disease is no longer a public health problem. PMID- 21791197 TI - Photochemical characterization of a novel fungal rhodopsin from Phaeosphaeria nodorum. AB - Eukaryotic microbial rhodopsins are widespread bacteriorhodopsin-like proteins found in many lower eukaryotic groups including fungi. Many fungi contain multiple rhodopsins, some significantly diverged from the original bacteriorhodopsin template. Although few fungal rhodopsins have been studied biophysically, both fast-cycling light-driven proton pumps and slow-cycling photosensors have been found. The purpose of this study was to characterize photochemically a new subgroup of fungal rhodopsins, the so-called auxiliary group. The study used the two known rhodopsin genes from the fungal wheat pathogen, Phaeosphaeria nodorum. One of the genes is a member of the auxiliary group while the other is highly similar to previously characterized proton pumping Leptosphaeria rhodopsin. Auxiliary rhodopsin genes from a range of species form a distinct group with a unique primary structure and are located in carotenoid biosynthesis gene cluster. Amino acid conservation pattern suggests that auxiliary rhodopsins retain the transmembrane core of bacteriorhodopsins, including all residues important for proton transport, but have unique polar intramembrane residues. Spectroscopic characterization of the two yeast-expressed Phaeosphaeria rhodopsins showed many similarities: absorption spectra, conformation of the retinal chromophore, fast photocycling, and carboxylic acid protonation changes. It is likely that both Phaeosphaeria rhodopsins are proton pumping, at least in vitro. We suggest that auxiliary rhodopsins have separated from their ancestors fairly recently and have acquired the ability to interact with as yet unidentified transducers, performing a photosensory function without changing their spectral properties and basic photochemistry. PMID- 21791198 TI - Oxidative stress increases angiotensin receptor type I responsiveness by increasing receptor degree of aggregation using image correlation spectroscopy. AB - Oxidative stress and hyper-functioning of angiotensin II receptor type I (AT(1)R) are commonly observed in hypertensive patients but the relationship between oxidative stress and AT(1)R function is still unclear. We investigated the effects of H(2)O(2) treatment on AT(1)R-mediated intracellular calcium [Ca(2+)](i) signaling and its cell surface distribution pattern in HEK cells stably expressing EGFP-tagged rat AT(1)R using image correlation spectroscopy (ICS). Following H(2)O(2) treatment (50-800MUM), [Ca(2+)](i) was significantly increased upon angiotensin II stimulation. Similarly ICS revealed a significant increase in degree of AT(1)R aggregation in H(2)O(2) treated group during Ang II activation but no difference in cluster density compared with untreated control cells or those with N-acetyl cysteine pretreatment. Thus, oxidative stress induced AT(1)R hyper-responsiveness can be attributed by an increase in cell surface receptor aggregation state, possibly stemming in part from oxidant related increase receptor-receptor interactions. PMID- 21791199 TI - Comparative NMR analysis of an 80-residue G protein-coupled receptor fragment in two membrane mimetic environments. AB - Fragments of integral membrane proteins have been used to study the physical chemical properties of regions of transporters and receptors. Ste2p(G31-T110) is an 80-residue polypeptide which contains a portion of the N-terminal domain, transmembrane domain 1 (TM1), intracellular loop 1, TM2 and part of extracellular loop 1 of the alpha-factor receptor (Ste2p) from Saccharomyces cerevisiae. The structure of this peptide was previously determined to form a helical hairpin in lyso-palmitoylphosphatidyl-glycerol micelles (LPPG) [1]. Herein, we perform a systematic comparison of the structure of this protein fragment in micelles and trifluoroethanol (TFE):water in order to understand whether spectra recorded in organic:aqueous medium can facilitate the structure determination in a micellar environment. Using uniformly labeled peptide and peptide selectively protonated on Ile, Val and Leu methyl groups in a perdeuterated background and a broad set of 3D NMR experiments we assigned 89% of the observable atoms. NOEs and chemical shift analysis were used to define the helical regions of the fragment. Together with constraints from paramagnetic spin labeling, NOEs were used to calculate a transiently folded helical hairpin structure for this peptide in TFE:water. Correlation of chemical shifts was insufficient to transfer assignments from TFE:water to LPPG spectra in the absence of further information. PMID- 21791200 TI - Multi-Tox: application of the ToxR-transcriptional reporter assay to the study of multi-pass protein transmembrane domain oligomerization. AB - ToxR-based transcriptional reporter assays allow the strength of transmembrane helix interactions in biological membranes to be measured. Previously, these assays have only been used to study single-pass transmembrane systems. To facilitate investigation of polytopic transmembrane domain (TMD) oligomerization, we applied the ToxR methodology to the study of multi-pass TMD oligomerization to give 'Multi-Tox'. Association propensities of the viral oncoprotein, latent membrane protein-1 (LMP-1), and the E. coli membrane-integral diacylglycerol kinase (DAGK) were studied by Multi-Tox, highlighting residues of particular mechanistic importance. Both homo- and hetero-oligomerizations were studied. PMID- 21791201 TI - Protective action of L-carnitine on cardiac mitochondrial function and structure against fatty acid stress. AB - Cardiovascular risks are frequently accompanied by high serum fatty acid levels. Although recent studies have shown that fatty acids affect mitochondrial function and induce cell apoptosis, L-carnitine is essential for the uptake of fatty acids by mitochondria, and may attenuate the mitochondrial dysfunction and apoptosis of cardiocytes. This study aimed to elucidate the activity of L-carnitine in the prevention on fatty acid-induced mitochondrial membrane permeability transition and cytochrome c release using isolated cardiac mitochondria from rats. Palmitoyl CoA-induced mitochondrial respiration that was observed with L-carnitine was inhibited with oligomycin. The palmitoyl-CoA-induced mitochondrial membrane depolarization and swelling were greatly inhibited by the presence of L carnitine. In ultrastructural observations, terminally swollen and ruptured mitochondria with little or no distinguishable cristae structures were induced by treatment with palmitoyl-CoA. However, the severe morphological damage in cardiac mitochondria was dramatically inhibited by pretreatment with L-carnitine. Treatment with L-carnitine also attenuated 4-hydroxy-L-phenylglycine- and rotenone-induced mitochondrial swelling even when the L-carnitine could not protect against the decrease in oxygen consumption associated with these inhibitors. Furthermore, L-carnitine completely inhibited palmitoyl-CoA-induced cytochrome c release. We concluded that L-carnitine is essential for cardiac mitochondria to attenuate the membrane permeability transition, and to maintain the ultrastructure and membrane stabilization, in the presence of high fatty acid beta-oxidation. Consequently, the cells may be protected against apoptosis by L carnitine through inhibition of the fatty acid-induced cytochrome c release. PMID- 21791202 TI - Drosophila adducin regulates Dlg phosphorylation and targeting of Dlg to the synapse and epithelial membrane. AB - Adducin is a cytoskeletal protein having regulatory roles that involve actin filaments, functions that are inhibited by phosphorylation of adducin by protein kinase C. Adducin is hyperphosphorylated in nervous system tissue in patients with the neurodegenerative disease amyotrophic lateral sclerosis, and mice lacking beta-adducin have impaired synaptic plasticity and learning. We have found that Drosophila adducin, encoded by hu-li tai shao (hts), is localized to the post-synaptic larval neuromuscular junction (NMJ) in a complex with the scaffolding protein Discs large (Dlg), a regulator of synaptic plasticity during growth of the NMJ. hts mutant NMJs are underdeveloped, whereas over-expression of Hts promotes Dlg phosphorylation, delocalizes Dlg away from the NMJ, and causes NMJ overgrowth. Dlg is a component of septate junctions at the lateral membrane of epithelial cells, and we show that Hts regulates Dlg localization in the amnioserosa, an embryonic epithelium, and that embryos doubly mutant for hts and dlg exhibit defects in epithelial morphogenesis. The phosphorylation of Dlg by the kinases PAR-1 and CaMKII has been shown to disrupt Dlg targeting to the NMJ and we present evidence that Hts regulates Dlg targeting to the NMJ in muscle and the lateral membrane of epithelial cells by controlling the protein levels of PAR 1 and CaMKII, and consequently the extent of Dlg phosphorylation. PMID- 21791203 TI - G-protein coupled receptor-associated sorting protein 1 (GASP-1), a potential biomarker in breast cancer. AB - An innovative "2-D high performance liquid electrophoresis" (2-D HPLE) technology was used to identify serum biomarkers associated with the early stage of breast cancer in addition to other more advanced stages. 2-D HPLE is a newly developed electrophoretic technology that separates 100s of serum albumin complexes on a polyvinyl membrane based on their surface charges. Association of cancer proteins or their fragments (biomarkers) with pre-existing albumin complexes in the blood of cancer patients results in altered mobility on the membrane. Using 2-D HPLE we identified that a specific fragment of G-protein coupled receptor-associated sorting protein 1 (GASP-1) was present in the sera of patients with early stage disease but absent in sera of normal patients. GASP-1 has been shown to modulate lysosomal sorting and functional down-regulation of a variety of G-protein coupled receptors in neuronal cells. However, no reports have linked GASP-1 to breast cancer pathogenesis. GASP-1 was detected in tumor extracts of 7 cases of Stage 2 and Stage 3 breast cancers, but not in adjacent normal tissue as revealed by western blot analysis using an antibody developed against a GASP-1 peptide identified by our 2-D HPLE technology. Using this antibody, we immunohistochemically detected over-expression of GASP-1 in all of 107 cases of archived ductal breast carcinoma tumor samples, while normal adjacent breast tissue from 12 cases of ductal carcinoma showed little or no staining. Additionally, all 10 cases of metastatic breast carcinoma present in lymph nodes were positive. Strong positive GASP-1 staining was observed in all tumor tissue including ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. Additionally, we observed a wide spectrum of enhanced staining of premalignant ductal epithelial cells present in benign ducts and those found in atypical ductal hyperplasia (ADH). These studies identify GASP-1 as a potential new serum and tumor biomarker for breast cancer and suggest that GASP-1 may be a novel target for the development of breast cancer therapeutics. PMID- 21791204 TI - MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis. AB - Adiponectin protects from inflammation and fibrosis in metabolic liver disease. In the present study we analyzed whether this adipokine may directly affect the activity of matrix metalloproteinases (MMPs), central regulators of fibrinolysis, in hepatocytes. Global gene expression analysis indicated upregulation of MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in primary human hepatocytes (PHH) in response to stimulation with adiponectin, and these results were confirmed by real-time RT-PCR. Furthermore, gelatin zymography revealed that MMP-9 activity was significantly induced in supernatants of adiponectin stimulated PHHs. In a murine model of hepatic steatosis and in human steatotic liver samples hepatic MMP-9 activity was not significantly altered. However, in two different murine models of non-alcoholic steatohepatitis (NASH) MMP-9 activity was significantly elevated compared to chow fed control mice. Of note, MMP-9 activity did not or even negatively, respectively, correlate with adiponectin serum levels in these models. The current data indicate that in NASH hepatic inflammation and fibrosis but not hepatic steatosis induce liver MMP-9 activity, and this induction seems to be related to the anti-inflammatory activity of adiponectin rather than its effect on hepatocellular MMP-9 expression. PMID- 21791205 TI - Immunoregulatory effects of alpha-GalCer in a murine model of autoimmune myocarditis. AB - This study was designed to investigate the role of alpha-galactosylceramide (alpha-GalCer) on experimental autoimmune myocarditis (EAM), and to explore the underlying mechanisms. Balb/c mice were immunized with porcine cardiac myosin to establish the EAM model. All the immunized mice were divided into two groups, the alpha-GalCer group and the EAM group. alpha-GalCer or vehicle was given intraperitoneally at the time of immunization. Then alpha-GalCer or PBS was injected on alternate days for 6 weeks. Myocardial inflammation was evaluated by H & E staining and the expression levels of C/EBPbeta and alpha-SMA were determined by immunohistochemistry. CD4(+)CD25(+)Foxp3(+) Tregs and iNKT cells were analyzed and sorted by flow cytometry. Western blot analysis was performed to detect MMP-2 and MMP-9 protein expression. Following alpha-GalCer treatment for 6 weeks, myocardial inflammation improved significantly in the alpha-GalCer treated group compared to the EAM group. The proportions of CD4(+)CD25(+)Foxp3(+) regulatory T cells and NK1.1(+) iNKT cells were statistically increased in the alpha-GalCer treated group compared to the EAM and normal control groups. In contrast to the EAM group, alpha-GalCer treatment significantly increased myocardial MMP-2 and MMP-9 expression. Expression of C/EBPbeta increased significantly in the EAM group compared to the other two groups. In contrast, the expression of alpha-SMA did not differ significantly among the three groups. This study demonstrated that alpha-GalCer alleviates EAM. Thus, alpha-GalCer represents a potential therapeutic target for autoimmune-inflammation mediated cardiac damage. alpha-GalCer protects EAM through upregulation of the proportion of iNKT and Tregs and increased expression of myocardial MMP-2 and MMP-9. PMID- 21791206 TI - Neuroprotective effects of prostaglandin analogues on retinal ganglion cell death independent of intraocular pressure reduction. AB - Prostaglandin (PG) analogues may have an additional effect to protect neurons independent of IOP reduction. Only a few reports indicated that some PG analogues had neuroprotective effects or increased blood flow in in vivo and in vitro models. However, there is no comparative study using all clinically available PG analogues and also using primary culture of retinal ganglion cell (RGC). Our purpose of study is to investigate the direct neuroprotective effect of PG analogues on glutamate- and hypoxia-induced RGC death using rat purified primary RGC culture with latanoprost acid, travoprost acid, bimatoprost acid, bimatoprost, tafluprost acid, unoprostone, and PGF2alpha. Purified RGCs cultures were obtained from retinas of 6 days old Wistar rats, following a two-step immuno panning procedure. After 72 h of cultivation, the neuroprotective effect of PG analogues (1 nM, 10 nM and 100 nM) was investigated by culturing the RGCs in 25 MUM glutamate for a further 72 h or 5% O2 hypoxic condition for 24 h. The RGC viability under each condition normalized to that under normal condition without stress was evaluated as live cell percentage based on a total of 15 repeated experiments. As a result, 100 nM of latanoprost acid, tafluprost acid, bimatoprost acid, and bimatoprost significantly increased RGC survival rate by suppressing apoptosis. PG analogues indicated IOP independent neuroprotective effect on glutamate- or hypoxia-induced RGC death using rat primary RGC culture at clinically available intracameral concentration. Since those profiles were different from clinical efficacy in IOP reduction, the mechanism of neuroprotection may be not related to FP receptor stimulation. PMID- 21791207 TI - Model systems for hepatitis C research: the cup half empty? PMID- 21791208 TI - Unlocking the gates to inflammatory bowel disease: the role of Enterococcus faecalis gelatinase. PMID- 21791209 TI - T-Helping Colitis. PMID- 21791210 TI - Nonalcoholic steatohepatitis treatment. PMID- 21791211 TI - MAPing the role of Kras mutations in hyperplastic polyps. PMID- 21791212 TI - Bariatric surgery: metabolic benefits beyond weight loss. PMID- 21791213 TI - Hepatic abscess and colonic stenosis: two complications of an unlikely cause. PMID- 21791214 TI - Unusual cause of GI obstruction. PMID- 21791216 TI - Abdominal pain after consumption of a Bavarian Beef Roulade in a 45-year-old patient. PMID- 21791218 TI - Interaction of bupropion and zinc with neuronal nicotinic acetylcholine receptors. AB - Zinc is known to exert antidepressant-like actions and to make the effects of some antidepressants more efficient in animal models of depression. Both zinc and bupropion interact with nicotinic acetylcholine receptors (nAChRs) which are related with depression. Here we examined the effects of bupropion, in the absence and presence of zinc, on the ion current elicited by acetylcholine (ACh current) in Xenopus oocytes expressing neuronal alpha4beta4 nAChRs. We found that bupropion-inhibited ACh-currents depending on ACh and bupropion concentrations. Thus, the IC(50) of bupropion was lower with a higher ACh concentration: 3.51 and 2.27 MUM for the current elicited with 0.5 and 2 MUM ACh, respectively. The inhibitory effect of bupropion was more potent in the presence of zinc, e.g. the IC(50) was 0.81 MUM in the presence of 100 MUM zinc and 2 MUM ACh. Furthermore, the zinc-potentiated ACh-current decreased with increasing bupropion concentration. Thus, zinc potentiation was 5.05 and 1.25 fold of the ACh-current inhibited by 10 nM and 5 MUM bupropion, respectively. The ACh-current inhibited by 3 MUM bupropion was voltage-independent, decreasing to 0.48 of the ACh-current at all voltages. Zinc potentiation of the bupropion-inhibited ACh-current was slight and voltage-independent. In addition, the zinc-potentiated ACh-current was slightly voltage-dependent: 1.8 fold of the ACh-current at -120 mV and 2.3 at -40 mV. Bupropion inhibition of the zinc-potentiated ACh-current was strong and voltage-independent, decreasing to 0.15 of the zinc-potentiated ACh-current at all voltages. Accordingly, zinc may interact within the ion channel, whereas bupropion, and bupropion in the presence of zinc (which causes greater inhibition) interact in an external region of the receptor-channel complex. These results suggest that bupropion interacts with alpha4beta4 nAChRs in a non competitive manner, that zinc increases the sensitivity of nAChRs to bupropion, and that bupropion decreases the sensitivity of nAChRs to zinc. PMID- 21791219 TI - Comparative analysis of the neurophysiological profile of group II metabotropic glutamate receptor activators and diazepam: effects on hippocampal and cortical EEG patterns in rats. AB - Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2 ((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3-4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABA(A) PAMs. This article is part of a Special Issue entitled 'Anxiety and Depression'. PMID- 21791217 TI - Endothelial-cardiomyocyte crosstalk enhances pharmacological cardioprotection. AB - Endothelial cells (EC) serve a paracrine function to enhance signaling in cardiomyocytes (CM), and conversely, CM secrete factors that impact EC function. Understanding how EC interact with CM may be critically important in the context of ischemia-reperfusion injury, where EC might promote CM survival. We used isoflurane as a pharmacological stimulus to enhance EC protection of CM against hypoxia and reoxygenation injury. Triggering of intracellular signal transduction pathways culminating in the enhanced production of nitric oxide (NO) appears to be a central component of pharmacologically induced cardioprotection. Although the endothelium is well recognized as a regulator for vascular tone, little attention has been given to its potential importance in mediating cardioprotection. In the current investigation, EC-CM in co-culture were used to test the hypothesis that EC contribute to isoflurane-enhanced protection of CM against hypoxia and reoxygenation injury and that this protection depends on hypoxia-inducible factor (HIF1alpha) and NO. CM were protected against cell injury [lactate dehydrogenase (LDH) release] to a greater extent in the presence vs. absence of isoflurane-stimulated EC (1.7 +/- 0.2 vs. 4.58 +/- 0.8 fold change LDH release), and this protection was NO-dependent. Isoflurane enhanced release of NO in EC (1103 +/- 58 vs. 702 +/- 92 pmol/mg protein) and EC-CM in co-culture sustained NO release during reoxygenation. In contrast, lentiviral mediated HIF1alpha knockdown in EC decreased basal and isoflurane stimulated NO release in an eNOS dependent manner (517 +/- 32 vs. 493 +/- 38 pmol/mg protein) and prevented the sustained increase in NO during reoxygenation when co-cultured. Opening of mitochondrial permeability transition pore (mPTP), an index of mitochondrial integrity, was delayed in the presence vs. absence of EC (141 +/- 2 vs. 128 +/- 2.5 arbitrary mPTP opening time). Isoflurane stimulated an increase in HIF1alpha in EC but not in CM under normal oxygen tension (3.5 +/- 0.1 vs. 0.79 +/- 0.15 fold change density) and this action was blocked by pretreatment with the Mitogen-activated Protein/Extracellular Signal-regulated Kinase inhibitor U0126. Expression and nuclear translocation of HIF1alpha were confirmed by Western blot and immunofluorescence. Taken together, these data support the concept that EC are stimulated by isoflurane to produce important cardioprotective factors that may contribute to protection of myocardium during ischemia and reperfusion injury. PMID- 21791220 TI - Frequent biphasic cellular responses of permanent fish cell cultures to deoxynivalenol (DON). AB - Contamination of animal feed with mycotoxins is a major problem for fish feed mainly due to usage of contaminated ingredients for production and inappropriate storage of feed. The use of cereals for fish food production further increases the risk of a potential contamination. Potential contaminants include the mycotoxin deoxynivalenol (DON) which is synthesized by globally distributed fungi of the genus Fusarium. The toxicity of DON is well recognized in mammals. In this study, we confirm cytotoxic effects of DON in established permanent fish cell lines. We demonstrate that DON is capable of influencing the metabolic activity and cell viability in fish cells as determined by different assays to indicate possible cellular targets of this toxin. Evaluation of cell viability by measurement of membrane integrity, mitochondrial activity and lysosomal function after 24 h of exposure of fish cell lines to DON at a concentration range of 0 3000 ng ml(-1) shows a biphasic effect on cells although differences in sensitivity occur. The cell lines derived from rainbow trout are particularly sensitive to DON. The focus of this study lies, furthermore, on the effects of DON at different concentrations on production of reactive oxygen species (ROS) in the different fish cell lines. The results show that DON mainly reduces ROS production in all cell lines that were used. Thus, our comparative investigations reveal that the fish cell lines show distinct species-related endpoint sensitivities that also depend on the type of tissue from which the cells were derived and the severity of exposure. PMID- 21791221 TI - Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects. AB - This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents. PMID- 21791223 TI - Targeting sphingosine kinase 1 in cancer. PMID- 21791222 TI - Aroclor 1254, a developmental neurotoxicant, alters energy metabolism- and intracellular signaling-associated protein networks in rat cerebellum and hippocampus. AB - The vast literature on the mode of action of polychlorinated biphenyls (PCBs) indicates that PCBs are a unique model for understanding the mechanisms of toxicity of environmental mixtures of persistent chemicals. PCBs have been shown to adversely affect psychomotor function and learning and memory in humans. Although the molecular mechanisms for PCB effects are unclear, several studies indicate that the disruption of Ca(2+)-mediated signal transduction plays significant roles in PCB-induced developmental neurotoxicity. Culminating events in signal transduction pathways include the regulation of gene and protein expression, which affects the growth and function of the nervous system. Our previous studies showed changes in gene expression related to signal transduction and neuronal growth. In this study, protein expression following developmental exposure to PCB is examined. Pregnant rats (Long Evans) were dosed with 0.0 or 6.0mg/kg/day of Aroclor-1254 from gestation day 6 through postnatal day (PND) 21, and the cerebellum and hippocampus from PND14 animals were analyzed to determine Aroclor 1254-induced differential protein expression. Two proteins were found to be differentially expressed in the cerebellum following PCB exposure while 18 proteins were differentially expressed in the hippocampus. These proteins are related to energy metabolism in mitochondria (ATP synthase, sub unit beta (ATP5B), creatine kinase, and malate dehydrogenase), calcium signaling (voltage dependent anion-selective channel protein 1 (VDAC1) and ryanodine receptor type II (RyR2)), and growth of the nervous system (dihydropyrimidinase-related protein 4 (DPYSL4), valosin-containing protein (VCP)). Results suggest that Aroclor 1254 like persistent chemicals may alter energy metabolism and intracellular signaling, which might result in developmental neurotoxicity. PMID- 21791224 TI - Torsion of the human left ventricle: experimental analysis and computational modeling. AB - We set a twofold investigation: we assess left ventricular (LV) rotation and twist in the human heart through 3D-echocardiographic speckle tracking, and use representative experimental data as benchmark with respect to numerical results obtained by solving our mechanical model of the LV. We aim at new insight into the relationships between myocardial contraction patterns and the overall behavior at the scale of the whole organ. It is concluded that torsional rotation is sensitive to transmural gradients of contractility which is assumed linearly related to action potential duration (APD). Pressure-volume loops and other basic strain measures are not affected by these gradients. Therefore, realistic torsional behavior of human LV may indeed correspond to the electrophysiological and functional differences between endocardial and epicardial cells recently observed in non-failing hearts. Future investigations need now to integrate the mechanical model proposed here with minimal models of human ventricular APD to drive excitation-contraction coupling transmurally. PMID- 21791225 TI - Inter-model consistency and complementarity: learning from ex-vivo imaging and electrophysiological data towards an integrated understanding of cardiac physiology. AB - Computational models of the heart at various scales and levels of complexity have been independently developed, parameterised and validated using a wide range of experimental data for over four decades. However, despite remarkable progress, the lack of coordinated efforts to compare and combine these computational models has limited their impact on the numerous open questions in cardiac physiology. To address this issue, a comprehensive dataset has previously been made available to the community that contains the cardiac anatomy and fibre orientations from magnetic resonance imaging as well as epicardial transmembrane potentials from optical mapping measured on a perfused ex-vivo porcine heart. This data was used to develop and customize four models of cardiac electrophysiology with different level of details, including a personalized fast conduction Purkinje system, a maximum a posteriori estimation of the 3D distribution of transmembrane potential, the personalization of a simplified reaction-diffusion model, and a detailed biophysical model with generic conduction parameters. This study proposes the integration of these four models into a single modelling and simulation pipeline, after analyzing their common features and discrepancies. The proposed integrated pipeline demonstrates an increase prediction power of depolarization isochrones in different pacing conditions. PMID- 21791226 TI - Two cases illustrating successful adjunctive interferon-gamma immunotherapy in refractory disseminated coccidioidomycosis. AB - Protective immunity and host resistance to coccidioidomycosis require a robust cell-mediated immunity with adequate production of Th1 cytokines including interleukin-12, and IFN-gamma and appropriate regulation and coordinated functionality of Th1/Th2 responses and IL-12/IFN-gamma cytokine axes. IFN-gamma augments the anti-fungal activity of effector immune cells against a variety of fungi. Numerous animal models have demonstrated the potential efficacy of adjunctive IFN-gamma in treatment of invasive mycoses. Yet, despite these promising data, a paucity of literature documents efficacious adjunctive IFN gamma administration in refractory coccidioidomycosis. We present two cases of refractory disease occurring at our institution who responded to adjunctive IFN gamma. PMID- 21791227 TI - Simple and tunable Forster resonance energy transfer-based bioprobes for high throughput monitoring of caspase-3 activation in living cells by using flow cytometry. AB - Sensing systems based on Forster resonance energy transfer (FRET) can be used to monitor enzymatic reactions, protein-protein interactions, changes in conformation, and Ca2+ oscillations in studies on cellular dynamics. We developed a series of FRET-based chimeric bioprobes, each consisting of fluorescent protein attached to a fluorescent dye. Green and red fluorescent proteins were used as donors and a series of Alexa Fluor dyes was used as acceptors. The basic fluorescent proteins were substituted with appropriate amino acids for recognition of the target (caspase-3) and subjected to site-directed modification with a fluorescent dye. Variants that retained similar emission profiles to the parent proteins were readily derived for use as FRET-based bioprobes with various fluorescent patterns by incorporating various fluorescent proteins and dyes, the nature of which could be adjusted to experimental requirements. All the constructs prepared functioned as bioprobes for quantitative measurement of caspase-3 activity in vitro. Introduction of the bioprobes into cells was so simple and efficient that activation of caspase-3 upon apoptosis could be monitored by means of cytometric analysis. FRET-based bioprobes are valuable tool for high-throughput flow-cytometric analysis of many cellular events when used in conjunction with other fluorescent labels or markers. Statistical dynamic studies on living cells could provide indications of paracrine signaling. PMID- 21791228 TI - Development of multiplex PCR assay for rapid detection of Riemerella anatipestifer, Escherichia coli, and Salmonella enterica simultaneously from ducks. AB - Three pathogens, Riemerella anatipestifer, Escherichia coli, and Salmonella enterica, are leading causes of bacterial fibrinous pericarditis and perihepatitis in ducks in China and worldwide. It is difficult to differentiate these pathogens when obtaining a diagnosis on clinical signs and pathological changes. The aim of this research was to develop a multiplex polymerase chain reaction (m-PCR) that could discriminate R. anatipestifer, E. coli, and S. enterica rapidly in field isolates, or detect the three bacteria in clinical samples from diseased ducks. We selected the DnaB helicase (dnaB) gene of R. anatipestifer, alkaline phosphatase (phoA) gene of E. coli and invasion protein (invA) gene of S. enterica as target genes. In optimized conditions, the limitation of detection was approximately 10(3) colony forming units (CFU) of each of these three bacterial pathogens per PCR reaction tube. The m-PCR method showed specific amplification of respective genes from R. anatipestifer, E. coli, and S. enterica. Using the m-PCR system, bacterial strains isolated from diseased ducks in our laboratory were categorized successfully, and the pathogens could also be detected in clinical samples from diseased ducks. Therefore, the m-PCR system could distinguish the three pathogens simultaneously, for identification, routine molecular diagnosis and epidemiology, in a single reaction. PMID- 21791229 TI - Effect of stabilization on biomass activity. AB - The study aimed to compare aerobic and aerobic/anoxic stabilization processes in terms of organic matter and the biomass removal efficiencies using a municipal sludge sample. The efficiency of stabilization process was assessed monitoring suspended solids (SS), volatile suspended solids (VSS), total and dissolved organic carbon (TOC, DOC), nitrate, nitrite, and phosphate parameters. The oxygen uptake rate (OUR) measurements were conducted to determine active biomass concentration. On the 30th day of the aerobic stabilization, the SS, VSS and TOC removal efficiencies were 22%, 28% and 55%, respectively. Under aerobic/anoxic conditions, removal efficiencies for SS, VSS and TOC were 25%, 27% and 67%. On the 17th day of the stabilization, SS and VSS removal rates were 60 mg SS/L day and 47 mg VSS/L day for aerobic and 102 mg SS/L day and 63 mg VSS/L day for aerobic/anoxic conditions, respectively. These findings reflected the higher stabilization performance of the aerobic/anoxic conditions. Based on respirometric results, the ratios of the active biomass were decreased to 30% and 24% for the 17th and 30th day of the aerobic stabilization, respectively. Such results have significant implications relative to the activity decrease quantification of the biomass as well as its further application potentials after aerobic or aerobic/anoxic sludge stabilization. PMID- 21791230 TI - Novel C1q assay reveals a clinically relevant subset of human leukocyte antigen antibodies independent of immunoglobulin G strength on single antigen beads. AB - It has been known for 40 years that cytotoxic human leukocyte antigen (HLA) antibodies are associated with graft rejection. However, the complement-dependent cytotoxicity assay (CDC) used to define these clinically deleterious antibodies suffers from a lack of sensitivity and specificity. Recently, methods exploiting immunoglobulin G (IgG) antibody binding to HLA single antigen beads (SAB) have overcome sensitivity and specificity drawbacks but introduced a new dilemma: which of the much broader set of antibodies defined by these methods are clinically relevant. To address this, we developed a complement-fixing C1q assay on the HLA SAB that combines sensitivity, specificity, and functional potential into one assay. We compared the CDC, IgG, and C1q assays on 96 sera having 2,118 defined antibodies and determined that CDC detects only 19% of complement-fixing antibodies detected by C1q, whereas C1q detects only 47% of antibodies detected by IgG. In the same patient, there is no predictability by IgG mean fluorescence intensity (MFI) as to which of the antibodies will bind C1q because fixation is independent of MFI values. In 3 clinical studies, C1q(+) antibodies appear to be more highly correlated than those detected by IgG alone for antibody-mediated rejection in hearts as well as for kidney transplant glomerulopathy and graft failure. PMID- 21791231 TI - A stable plasmid system for heterologous antigen expression in attenuated Vibrio anguillarum. AB - To stably synthesize heterologous protein in an attenuated Vibrio anguillarum strain (MVAV6203) for potential multivalent live vaccine application, plasmids with different replicons were used to construct protein expression systems in this work. The gfp fragment under control of a strict low-iron-regulated promoter P(viua) was inserted into seven plasmids with varied replicons derived from pAT153, pACYC184, pBBR1, pEC, pMW118, pRK2, and pSC101, to generate seven corresponding plasmids. Our results revealed that the plasmid pUTat with the replicon from pAT153 was retained by 100% of the host cells and mediated stable expression of heterologous protein in antibiotic-free medium within 250 generations. Further analyses in animal model (zebrafish larvae) demonstrated that the constructed plasmid pUTat was well retained by bacteria and continuously expressed GFP in vivo in zebrafish. The gapA40 gene, encoding Glyceraldehyde-3 phosphate dehydrogenase from the fish pathogen Edwardsiella tarda, was introduced into the pUTat-based protein expression system, and transformed into V. anguillarum MVAV6203. The resultant recombinant vector vaccine 6203/pUTatgap was evaluated in turbot (Scophtalmus maximus). After 30 days post vaccination, the fish showed an increased survival ratio by 80% and 67% under the challenge of wild V. anguillarum and E. tarda, respectively. Our results suggested that the pUTat-based antigen expression system had great potential with its efficiency and stability in the design of bacterial vector vaccine. PMID- 21791232 TI - Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection Workshop in dendritic cell-based vaccine clinical trials in HIV-1. AB - Therapeutic immunization has been proposed as an approach that might help limit the need for lifelong combined antiretroviral therapy (cART). One approach for therapeutic vaccination which has been explored during the last few years is the administration of autologous monocyte-derived DCs (MD-DCs) loaded ex vivo with a variety of antigens. It has been shown in experimental murine models as well as in cancer patients and in patients with chronic infections that this approach can induce and potentiate antigen-specific T-cell response (and to induce a potent protective immunity). Contrary to the wide experience with this strategy in cancer, in HIV-1 infection the experience is limited and the design of the clinical trials varies greatly between groups. This variability affects all the steps of the process, from preparation of immunogen and DCs to clinical trial design and immune monitoring. Although both the study designs and the DC preparation (the maturation stimuli and the identity and source of HIV-1 antigens used to pulse DCs) varied in most of the studies that were published so far, overall the results indicate that DC immunotherapy elicits some degree of immunological response. To address this situation and to allow comparison between trials a panel of experts working in DC-based clinical trials in HIV-1 infection met in Barcelona at the end of 2010. During this meeting, the participants shared the data of their current research activities in this field in order to unify criteria for the future. This report summarizes the present situation of the field and the discussions and conclusions of this meeting. PMID- 21791233 TI - An in silico DNA vaccine against Listeria monocytogenes. AB - Listeria monocytogenes causes listeriosis with mortality rate >20%. Listeriolysin O (LLO), a pore-forming hemolysin, belongs to the family of cholesterol-dependent toxins (CDTX) and plays roles in the pathogenicity. In this study bioinformatic analyses were carried out on LLO sequence as a major immunodominant listerial antigen toward designing a DNA vaccine stimulating cytotoxic T-lymphocytes (CTLs). Mouse and human constructs were designed based on predicted T cell epitopes and MHC class I binders, which were then tandemly fused together. LLO derived construct codons and a variety of critical gene expression efficiency parameters were optimized. Post-translational modifications such as glycosylation, phosphorylation were analysed. The constructs corresponded to LLO sequences of L. monocytogenes in BLAST search. Neither human nor mouse construct was allergen. Secretory pathway was location of the human construct that enhances immune induction and contribute to the efficacy of the vaccine candidate. mRNAs from optimized DNA sequences of both human and mouse constructs are more stable than the native and are suitable for initiation of translation. The constructs contain several sites for phosphorylation that could improve its degradation and subsequent entry into the MHC class I pathway. Addition of GPI anchor, myristoylation and ubiquitin signals or proline (P), glutamic acid (E), serine (S), threonine (T) (PEST)-like motifs at the N-terminal of constructs increase efficacy of the DNA vaccine. Close physical contact between the favorable immunogen and the suitable CpG oligodeoxynucleotides (CpG ODN) promotes immune response. Vectors for checking the expression of constructs in mammalian cells and for harboring the foreign genes as DNA vaccine are suggested. PMID- 21791235 TI - HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease. AB - Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (chi2)=6.446, p=0.040 for genotypic distribution; chi2=5.762, p=0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population. PMID- 21791234 TI - LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats. AB - Depressed patients with increased inflammatory cytokines in peripheral blood have been reported to be more likely to exhibit treatment resistance. However, it is unknown whether the inflammation influences the action of antidepressant drugs. Here, we investigated the influence of lipopolysaccharide (LPS) on the antidepressant action of fluoxetine in depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, we first modified the CUMS paradigm by administration of LPS daily before the stressor, and then investigated the influence of inflammation on the antidepressant action of fluoxetine. The effects of stress exposure and antidepressant treatment were assessed by behavioral testing (sucrose preference test, forced swimming test, novelty suppressed feeding test) and hippocampal BrdU labeling. The CUMS-induced behavioral changes can be reversed by 4-week fluoxetine treatment. Fluoxetine also increased the hippocampal neurogenesis in the depressive rats. Pretreatment with LPS, to mimic inflammation, had no significant effect on depressive behavior but attenuated the antidepressant action of fluoxetine significantly. Thus, our results suggest that the inflammation might play a certain role in the pathophysiology of antidepressant treatment resistance. PMID- 21791236 TI - Systems biology of microorganisms. Preface. PMID- 21791237 TI - Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli. AB - BACKGROUND: Fosfomycin is widely used to treat urinary tract and pediatric gastrointestinal infections of bacteria. It is supposed that this antibiotic enters cells via two transport systems, including the bacterial Glycerol-3 phosphate Transporter (GlpT). Impaired function of GlpT is one mechanism for fosfomycin resistance. METHODS: The interaction of fosfomycin with the recombinant and purified GlpT of Escherichia coli reconstituted in liposomes has been studied. IC(50) and the half-saturation constant of the transporter for external fosfomycin (K(i)) were determined by transport assay of [(14)C]glycerol 3-phosphate catalyzed by recombinant GlpT. Efficacy of fosfomycin on growth rates of GlpT defective bacteria strains transformed with recombinant GlpT was measured. RESULTS: Fosfomycin, externally added to the proteoliposomes, poorly inhibited the glycerol-3-phosphate/glycerol-3-phosphate antiport catalyzed by the reconstituted transporter with an IC(50) of 6.4mM. A kinetic analysis revealed that the inhibition was completely competitive, that is, fosfomycin interacted with the substrate-binding site and the K(i) measured was 1.65mM. Transport assays performed with proteoliposomes containing internal fosfomycin indicate that it was not very well transported by GlpT. Complementation study, performed with GlpT defective bacteria strains, indicated that the fosfomycin resistance, beside deficiency in antibiotic transporter, could be due to other gene defects. CONCLUSIONS: The poor transport observed in a reconstituted system together with the high value of K(i) and the results of complementation study well explain the usual high dosage of this drug for the treatment of the urinary tract infections. GENERAL SIGNIFICANCE: This is the first report regarding functional analysis of interaction between fosfomycin and GlpT. PMID- 21791238 TI - Advances in carcinogenesis: a historical perspective from observational studies to tumor genome sequencing and TP53 mutation spectrum analysis. AB - Tumor sequencing projects have been initiated over the last decade with the promising goal of identifying novel cancer genes and potential therapeutic targets. One of the unexpected findings of these projects was the discovery that cancer genomes contain thousands of passenger mutations that are irrelevant to tumor development and are coselected by a small number of driver mutations that constitute the true selection power in cancer progression. Although often discarded and considered to be irrelevant, the value of passenger mutations should not be underestimated, as they are the most important markers of the exposure to various carcinogens and are essential to assess the etiology of individual tumors. Over the last century, the history of cancer epidemiology evolved in different stages and concepts from occupational observational studies beginning in the 18th century, in vitro and in vivo experimental analyses and cancer gene analyses, such as Ha-ras or TP53. Mutation spectra of passenger mutations from various types of cancers not only confirm the findings of molecular epidemiology analysis, but also reveal novel profiles that will extend this knowledge to single tumors in all types of cancer. PMID- 21791239 TI - Ferulic acid-induced anti-depression and prokinetics similar to Chaihu-Shugan-San via polypharmacology. AB - Selective serotonin reuptake inhibitors (SSRIs), one of popular antidepressants as "one-compound-one-target" paradigm, cannot but discontinue because of inhibiting gut movement. Traditional Chinese medicine (TCM) Chaihu-Sugan-San (CSS) can simultaneously exert anti-depression and prokinetics. From this thread, we aimed to find a new antidepressant with polypharmacological mechanisms. In vivo antidepressive and prokinetic comparisons between CSS and its absorbed compound ferulic acid (FA) were made. And FA's action mechanisms involved in monoaminergic systems, HPA axis and gastrointestinal peptide ghrelin was then studied in forced swimming test (FST) of rat. Lastly, the jejunal contraction activity evoked by FA was measured in vitro. Compared with vehicle, FA reduced immobility time, increased locomotor activity, accelerated gastric emptying and intestinal transit similar to CSS whose absorbable component FA was identified in hippocampus and jejunum. FA's prokinetics in vivo was further supported by its jejunal contraction in vitro. FA-induced anti-immobility was prevented by pretreated with PCPA, WAY-100635, ketanserin, sulpiride, SCH233390, haloperidol and yohimbine, respectively. CRH, ACTH and 5-HT were significantly decreased, but ghrelin was apparently increased compared with vehicle. In summary, FA induced anti-depression and prokinetics similar to CSS via inhibiting serotonin, norepinephrine and dopamine reuptakes, regulating HPA axis, increasing ghrelin and stimulating jejunal contraction simultaneously. PMID- 21791240 TI - Enhancement of wound healing by topical application of Scorzonera species: determination of the constituents by HPLC with new validated reverse phase method. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Scorzonera species are mainly used against arteriosclerosis, kidney diseases, hypertension, diabetes mellitus and rheumatism, as well as for pain relief and wound healing in Turkish folk medicine. In the current study, aerial parts and roots of Scorzonera cinerea, Scorzonera incisa, Scorzonera latifolia, Scorzonera mollis ssp. szowitsii, Scorzonera parviflora, and Scorzonera tomentosa collected from different regions of Anatolia and yaki sakizi which is prepared by drying the latex is obtained from the roots of Scorzonera latifolia were evaluated for their wound healing and anti-inflammatory effects. MATERIALS AND METHODS: In vivo wound healing activity of the plants was evaluated by linear incision and circular excision wound models. Hydroxyproline content of the treated tissues was also assessed. Acetic acid-induced capillary permeability test was used for anti-inflammatory activity. For the determination of the active constituents, a new high performance liquid chromatographic method was developed. Precision of the developed method was performed by the evaluation of intra-day and inter-day variations of the each standard at limits of quantification (LOQ) levels. RESULTS: The aqueous methanolic extracts of Scorzonera latifolia, Scorzonera mollis ssp. szowitsii demonstrated the highest activities. The main compound was detected as chlorogenic acid both in roots and aerial parts of the most Scorzonera species and hyperoside or rutin was determined as one of the main component of the aerial parts. CONCLUSION: The experimental study revealed that methanol-water extracts from aerial parts of Scorzonera latifolia and Scorzonera mollis ssp. szowitsii were found to have better activity on the wound healing compared to the other extracts and control groups. This might be due to the combined effect of the constituents present in the extracts. PMID- 21791241 TI - Heat shock protein 60 from Klebsiella pneumoniae protects mononuclear cells from apoptotic cell death induced by dexamethasone. AB - AIMS: Bacterial heat shock proteins can have anti-apoptotic effects on human cells. We investigated whether enterobacterial HSP60 can protect peripheral blood mononuclear cells (PBMC) from DXM-induced apoptosis and if this effect requires cytoskeleton participation. MAIN METHODS: Anti-apoptotic effect from enterobacterial HSP60 was analyzed by adding these proteins to peripheral mononuclear cells cultures before DXM induction. Percentage of apoptotic cells was determined by SubG0 peak and TUNEL techniques in a flow cytometer. KEY FINDINGS: Our results showed significant protective effect of HSP60 Klebsiella pneumoniae and E. coli, in the DXM-induced apoptosis in PBMC. Similar results were obtained with recombinant human HSP60. The same protective effect of proteins was observed in CD4+ and CD8 + T cell subpopulations. To analyze if enterobacterial HSP60 need internalization to have the anti-apoptotic effect, we used cytoskeleton inhibitors such as: nocodazole, cytochalasin D and amiloride, the three inhibitors significantly affected the protective role of HSP60 in apoptosis induced with DXM. Results suggest that the protective effect of HSP60 K. pneumoniae and E. coli requires the participation of contractile structures for the internalization of this protein by the cells, we suggest that the internalization of enterobacterial HSP60 could be carry out by macropinocytosis. SIGNIFICANCE: We report for the first time that K. pneumoniae and E. coli HSP60 have protective effect in the apoptosis induced with DXM in PBMC from healthy subjects and that this effect requires the internalization of the protein with active participation of the cytoskeleton. PMID- 21791242 TI - Lethal factor is not required for Bacillus anthracis virulence in guinea pigs and rabbits. AB - The major virulence factor of Bacillus anthracis is the tripartite anthrax toxin, comprising the protective antigen (PA), lethal factor (LF) and edema factor (EF). The LF of B. anthracis is a metalloprotease that has been shown to play an important role in pathogenicity. Deletion of this gene (lef) in the Sterne strain was reported to dramatically reduce the pathogenicity of this strain in mice, and was reported to be as dramatic as the deletion of PA. We evaluated the effect on pathogenicity of the lef deletion in the fully virulent Vollum strain in guinea pigs and NZW rabbits by either subcutaneous injection or intranasal instillation. In guinea pigs, no major differences between the mutant strain and the wild type could be detected in the LD(50) or mean time to death values. On the other hand, the lef deletion caused death of 50-70% of all rabbits infected with the mutant spores at doses equivalent or higher than the wild type LD(50). The surviving rabbits, which were infected with spore doses higher than the wild type LD(50), developed a protective immune response that conferred resistance to challenge with the wild type strain. These findings may indicate that the mutant lacking the LF is capable of host colonization which causes death in 50-70% of the animals and a protective immune response in the others. These results indicate that unlike the data obtained in mice, the LF mutation does not abolish B. anthracis pathogenicity. PMID- 21791243 TI - Roles of superoxide and myeloperoxidase in ascorbate oxidation in stimulated neutrophils and H2O2-treated HL60 cells. AB - Ascorbate is present at high concentrations in neutrophils and becomes oxidized when the cells are stimulated. We have investigated the mechanism of oxidation by studying cultured HL60 cells and isolated neutrophils. Addition of H(2)O(2) to ascorbate-loaded HL60 cells resulted in substantial oxidation of intracellular ascorbate. Oxidation was myeloperoxidase-dependent, but not attributable to hypochlorous acid, and can be explained by myeloperoxidase (MPO) exhibiting direct ascorbate peroxidase activity. When neutrophils were stimulated with phorbol myristate acetate, about 40% of their intracellular ascorbate was oxidized over 20 min. Ascorbate loss required NADPH oxidase activity but in contrast to the HL60 cells did not involve myeloperoxidase. It did not occur when exogenous H(2)O(2) was added, was not inhibited by myeloperoxidase inhibitors, and was the same for normal and myeloperoxidase-deficient cells. Neutrophil ascorbate loss was enhanced when endogenous superoxide dismutase was inhibited by cyanide or diethyldithiocarbamate and appears to be due to oxidation by superoxide. We propose that in HL60 cells, MPO-dependent ascorbate oxidation occurs because cellular ascorbate can access newly synthesized MPO before it becomes packaged in granules: a mechanism not possible in neutrophils. In neutrophils, we estimate that ascorbate is capable of competing with superoxide dismutase for a small fraction of the superoxide they generate and propose that the superoxide responsible is likely to come from previously identified sites of intracellular NADPH oxidase activity. We speculate that ascorbate might protect the neutrophil against intracellular effects of superoxide generated at these sites. PMID- 21791244 TI - Molecular recruitment as a basis for negative dominant inheritance? propagation of misfolding in oligomers of IMPDH1, the mutated enzyme in the RP10 form of retinitis pigmentosa. AB - Retinitis pigmentosa, causing progressive blindness, is genetically heterogeneous. RP10, due to a defect in inosine monophosphate dehydrogenase 1 (IMPDH1), shows autosomal dominant inheritance. Recombinantly expressed clinical mutants show unaltered kinetic behaviour. It is unclear why reportedly impaired DNA binding is important and how it would explain negative dominance. An alternative view relates to the mutant proteins' tendency to aggregate. Regarding negative dominance, a key question is whether the defective protein can subvert the function of its normal counterpart in the same cell. Potentially, the homotetrameric structure of IMPDH1 might offer a vehicle for such an effect. We have established a reliable protocol for reproducible refolding of recombinantly expressed IMPDH1 in vitro. Clinical mutants R224P and D226N both show impaired folding. For equimolar mixtures of normal and mutant enzymes, independent refolding would predict activity regain midway between pure mutant and pure normal. Under various conditions regain is close to the mutant figure, suggesting that, in hybrid tetramers, mutant subunits impose their faulty conformation on normal partners. The observed molecular recruitment is a negative counterpart of the intra-allelic complementation, also mediated via oligomeric structure and postulated many years ago by Fincham. These findings appear potentially to account for the negative dominant inheritance. This interpretation must be provisional at present, as the predominant transcript in retina is an alternatively spliced version not fully identical to that used in our study. The results nevertheless have a general significance in pointing to a mechanism for negative dominance that could be widespread. PMID- 21791245 TI - IL-1beta inhibits axonal growth of developing sympathetic neurons. AB - Several secreted proteins facilitate the growth and guidance of sympathetic axons to their target organs during development. Here we show that IL-1beta, a key regulator of inflammation in the immune system, inhibits axonal growth and branching from cultured sympathetic neurons at a stage in development when their axons are ramifying within their targets in vivo. IL-1beta is synthesised in sympathetic ganglia and its targets at this stage, and IL-1beta protein is detectable in the axons and perikarya of the innervating neurons. It acts directly on developing axons to inhibit their growth via NF-kappaB signalling. These findings show that IL-1beta is a novel locally, and target-derived factor that can regulate the extent of sympathetic axon growth during the late embryonic and early postnatal period in developing rat sympathetic neurons. PMID- 21791246 TI - Temperature effects on immune response and hematological parameters of channel catfish Ictalurus punctatus vaccinated with live theronts of Ichthyophthirius multifiliis. AB - This study evaluated the influence of temperature on the immune responses and hematological parameters in channel catfish Ictalurus punctatus immunized via intraperitoneal injection with live theronts of Ichthyophthirius multifiliis. Fish were distributed in 18 aquaria and received 9 treatments: 4 groups of fish were vaccinated with live theronts and maintained at constant temperature 15 degrees C, 20 degrees C, 25 degrees C and 30 degrees C; 3 groups of fish vaccinated and subjected to cycling temperature regime from 15-25 degrees C, 20 25 degrees C and 20-30 degrees C, changed 5 degrees C each day; 2 groups of fish were not vaccinated and served as controls at 25 degrees C, one with Ich challenge and the other without challenge. Non vaccinated fish and those vaccinated at 15 degrees C or 15-25 degrees C did not show anti-Ich antibodies in the serum 14 and 21 days post-immunization. The antibody levels were significantly higher from fish vaccinated at 25 degrees C, 30 degrees C, 20-25 degrees C and 20-30 degrees C compared to fish at 15 degrees C, 20 degrees C and 15-25 degrees C both 14 and 21 days post-immunization. At constant water temperature, fish vaccinated at 15 degrees C showed significantly higher mortality rate (67.8%, P < 0.05) than those vaccinated at 20 degrees C, 25 degrees C, and 30 degrees C (0-10.7% mortalities). At cycling water temperature, fish vaccinated at 15-25 degrees C showed significantly higher mortality rate (67.8%) than those vaccinated at 20-25 degrees C and 20-30 degrees C (P < 0.05). Twenty days after immunization fish vaccinated at 30 degrees C and 20-30 degrees C showed significant increase in the red blood cells, white blood cells, thrombocytes and monocytes. Six days after challenge with I. multifiliis theronts the fish showed decreased white blood cells, thrombocytes and monocytes. This study suggests that vaccinated catfish were severely impacted by low temperature, either at 15 degrees C constant temperature or at 15-25 degrees C cycling temperature. The fish showed no anti-Ich antibodies and suffered high mortality similar to non vaccinated control fish. PMID- 21791247 TI - Brain microstructural correlates of visuospatial choice reaction time in children. AB - The corticospinal tracts and the basal ganglia continue to develop during childhood and adolescence, and indices of their maturation can be obtained using diffusion-weighted imaging. Here we show that a simple measure of visuomotor function is correlated with diffusion parameters in the corticospinal tracts and neostriatum. In a cohort of 75 typically-developing children aged 7 to 13years, mean 5-choice reaction times (RTs) were assessed. We hypothesised that children with faster choice RTs would show lower mean diffusivity (MD) in the corticospinal tracts and neostriatum and higher fractional anisotropy (FA) in the corticospinal tracts, after controlling for age, gender, and handedness. Mean MD and/or FA were extracted from the right and left corticospinal tracts, putamen, and caudate nuclei. As predicted, faster 5-choice RTs were associated with lower MD in the corticospinal tracts, putamen, and caudate. MD effects on RT were bilateral in the corticospinal tracts and putamen, whilst right caudate MD was more strongly related to performance than was left caudate MD. Our results suggest a link between motor performance variability in children and diffusivity in the motor system, which may be related to: individual differences in the phase of fibre tract and neostriatal maturation in children of similar age, individual differences in motor experience during childhood (i.e., use-dependent plasticity), and/or more stable individual differences in the architecture of the motor system. PMID- 21791248 TI - Social exclusion and punishment of excluders: neural correlates and developmental trajectories. AB - Social exclusion is a distressing experience and can result in a reduction of prosocial behavior. In this fMRI study we examined the neural networks involved in social exclusion and subsequent fairness considerations across adolescent development. Participants from 3 age groups (10-12, 14-16 and 19-21 year olds) participated in the study and performed two tasks; first, participants played Cyberball to induce feelings of social inclusion and exclusion, followed by a Dictator game in which participants were asked to divide coins between themselves and the players who previously included or excluded them. Results revealed a network of regions associated with social exclusion, which involve the medial prefrontal cortex (mPFC)/ventral anterior cingulate cortex (vACC), subgenual ACC and the lateral PFC, as well as the insula and the dorsal ACC. Although social exclusion generated strong distress for all age groups, 10-12 year olds showed increased activity in the subgenual ACC in the exclusion game, which has been associated in previous studies with negative affective processing. Results of the Dictator game revealed that all age groups selectively punished the excluders by making lower offers. These offers were associated with activation in the temporoparietal junction (TPJ), superior temporal sulcus (STS) and the lateral PFC. Age comparisons revealed that adults showed additional activity in the insula and dorsal ACC when making offers to the excluders. The results are discussed in the light of recent findings on neural networks involved in social exclusion and the development of social brain regions. PMID- 21791249 TI - Identification of octopine dehydrogenase from Mytilus galloprovincialis. AB - A cDNA encoding the putative octopine dehydrogenase (OcDH) from the mussel Mytilus galloprovincialis was cloned and sequenced. The complete coding region was expressed in the bacteria Escherichia coli and the recombinant protein was purified. The M. galloprovincialis OcDH appears to have the highest affinity for the amino acid substrate L-arginine (88.22%), compared to L-alanine (9.04%) and glycine (2.74%). This enzyme showed no activity when taurine or beta-alanine was used as substrate. These data strongly support that this recombinant enzyme is octopine dehydrogenase and not another opine dehydrogenase such as alanopine or strombine dehydrogenases. The superimposition of the theoretical three dimensional model of the M. galloprovincialis OcDH and the crystal structure of its homologous counterpart from the great scallop Pecten maximus showed interesting changes in the amino acid binding site which could explain the differences found in the substrate affinity between the two molluscs. A phylogenetic analysis was performed comparing M. galloprovincialis OcDH and annotated sequences representing the five opine dehydrogenase (OpDH) protein family members. The phylogenetic tree which was obtained clustered the OpDH enzymes according to the evolutionary relationships of the species and not to the biochemical reaction catalysed. Octopine dehydrogenase has been identified in the Mytilidae family for the first time, having previously only been established in one other marine invertebrate (P. maximus). PMID- 21791250 TI - Purification and characterization of luteinizing hormone from pituitary glands of rockfish, Sebastes schlegeli. AB - To acquire greater knowledge of the reproductive function of luteinizing hormone (LH) in the viviparous rockfish Sebastes schlegeli, LH from the pituitary glands of mature rockfish was isolated, purified, and localized and its biological activity was characterized. The molecular mass of purified LH was estimated to be approximately 33 kDa, similar to that of known LH. When rockfish LH was purified by reverse-phase high-performance liquid chromatography, its N-terminal amino acid sequences were found to coincide with those of predicted cDNA sequences of rockfish gonadotropin alpha (ssGTHalpha) and ssLHbeta mature peptides. Immunocytochemical analysis using antisera against ssGTHalpha (molecular weight [MW], ~14.5 kDa) and ssLHbeta (MW, ~18.5 kDa) indicated that the LH-producing cells are mainly distributed throughout the proximal pars distalis and along the periphery of the pars intermedia. Further, in vitro ovarian follicle analysis demonstrated that purified intact rockfish LH significantly enhances E(2) secretion in a dose-dependent manner. This is the first report on the purification and characterization of LH from a viviparous teleost, and these results will enable future research and increase our understanding of the mechanisms underlying the maturation of such fish. PMID- 21791251 TI - Distribution of repetitive DNA sequences in chromosomes of five opisthorchid species (Trematoda, Opisthorchiidae). AB - Genomes of opisthorchid species are characterized by small size, suggesting a reduced amount of repetitive DNA in their genomes. Distribution of repetitive DNA sequences in the chromosomes of five species of the family Opisthorchiidae (Opisthorchis felineus 2n = 14 (Rivolta, 1884), Opisthorchis viverrini 2n = 12 (Poirier, 1886), Metorchis xanthosomus 2n = 14 (Creplin, 1846), Metorchis bilis 2n = 14 (Braun, 1890), Clonorchis sinensis 2n = 14 (Cobbold, 1875)) was studied with C- and AgNOR-banding, generation of microdissected DNA probes from individual chromosomes and fluorescent in situ hybridization on mitotic and meiotic chromosomes. Small-sized C-bands were discovered in pericentric regions of chromosomes. Ag-NOR staining of opisthorchid chromosomes and FISH with ribosomal DNA probe showed that karyotypes of all studied species were characterized by the only nucleolus organizer region in one of small chromosomes. The generation of DNA probes from chromosomes 1 and 2 of O. felineus and M. xanthosomus was performed with chromosome microdissection followed by DOP-PCR. FISH of obtained microdissected DNA probes on chromosomes of these species revealed chromosome specific DNA repeats in pericentric C-bands. It was also shown that microdissected DNA probes generated from chromosomes could be used as the Whole Chromosome Painting Probes without suppression of repetitive DNA hybridization. Chromosome painting using microdissected chromosome specific DNA probes showed the overall repeat distribution in opisthorchid chromosomes. PMID- 21791253 TI - Biophysical characterization of alpha-amylase inhibitor Parvulustat (Z-2685) and comparison with Tendamistat (HOE-467). AB - Parvulustat is a small, highly active proteinaceous alpha-amylase inhibitor whose high-resolution NMR structure was recently solved in Frankfurt. Here, we present its biochemical and biophysical characterization. Several spectroscopic methods such as UV, fluorescence and CD were utilized to extract conformational changes upon modification of pH, temperature and chemical denaturant. Parvulustat revealed native like behavior over a wide range of denaturizing agents as reflected in terms of activity and thermodynamic data. In addition, spectroscopic and thermodynamic properties of Parvulustat were compared to the well characterized Tendamistat. Despite the overall structural similarity, the thermodynamic stability of the two proteins is different. Our analysis led to the conclusion that Parvulustat is even more stable than Tendamistat. Furthermore, investigations on three C-terminally truncated Parvulustat derivatives indicate that the higher stability is caused by the long flexible C-terminus. PMID- 21791252 TI - The expression of Foxp3 and ROR gamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients. AB - Foxp3- and ROR gamma t-expressing cells are involved in acquired immune responses. The change in Foxp3 and ROR gamma t expression in lung tissue and their role in emphysema has not been studied for COPD patients and normal smokers. In the present study, Foxp3 and ROR gamma t were assessed using real time quantitative polymerase chain reaction and western blotting, and the expression and distribution of Foxp3, IL-17, IL-23R and CCR6 were measured by immunohistochemistry in peripheral lung tissue (10 smokers with COPD, 10 smokers and 10 nonsmokers with normal lung function). Foxp3 expression was lower and ROR gamma t expression was higher in COPD patients when compared with smokers and nonsmokers (all P values were less than 0.001). The ratios of Foxp3/ROR gamma t mRNA and protein were positively correlated to FEV1%pred and negatively correlated to the mean alveoli area. Foxp3(+) cell numbers were decreased, while the number of IL-17(+) cells, IL-23R(+) cells and CCR6(+) cells were increased in the lung alveolar walls of COPD patients compared with normal smokers and nonsmokers (all P values were less than 0.001). The IL-17(+) cell numbers were positively correlated to both CCR6(+) and IL-23R(+) cells. Our data show a decreased Foxp3 expression and an increased ROR gamma t expression in COPD patients and normal smokers that parallels the aggravation of the disease. The IL 17(+)-cell-related cytokines receptors CCR6 and IL-23R had an association with the mechanism of IL-17(+) cell number increasing, which will provide a new immuno therapeutic target for COPD. PMID- 21791254 TI - Fabrication of a model continuously graded co-electrospun mesh for regeneration of the ligament-bone interface. AB - Current scaffolds for the regeneration of anterior cruciate ligament injuries are unable to capture intricate mechanical and chemical gradients present in the natural ligament-bone interface. As a result, stress concentrations can develop at the scaffold-bone interface, leading to poor osseointegration. Hence, scaffolds that possess appropriate mechano-chemical gradients would help establish normal loading properties at the interface, while promoting scaffold integration with bone. With the long-term goal of investigating regeneration of the ligament-bone interface, this feasibility study aimed to fabricate a continuously graded mesh. Specifically, graded meshes were fabricated by co electrospinning nanohydroxyapatite/polycaprolactone (nHAP-PCL) and poly(ester urethane) urea elastomer solutions from offset spinnerets. Next, mineral crystallites were selectively deposited on the nHAP-PCL fibers by treatment with a 5* simulated body fluid (5* SBF). X-ray diffraction and energy-dispersive spectroscopy indicated calcium-deficient hydroxyapatite-like mineral crystallites with an average Ca/P ratio of 1.48. Tensile testing demonstrated the presence of a mechanical gradient, which became more pronounced upon treatment with 5* SBF. Finally, biocompatibility of the graded meshes was verified using an MC3T3-E1 osteoprogenitor cell line. The study demonstrates that graded meshes, for potential application in interfacial tissue engineering, can be fabricated by co electrospinning. PMID- 21791255 TI - LMNA mutation in progeroid syndrome in association with strokes. AB - Hutchinson-Gilford progeria syndrome is a very rare but well-characterized genetic disorder that causes premature ageing. Clinical features affect growth, skeleton, body fat, skin, hair and the cardiovascular system. It is caused by mutations in LMNA gene, the most frequent being p.Gly608Gly (c.1824C > T) in exon 11. Here we present a four-year-old HGPS patient who presented several severe strokes and carried a heterozygous LMNA missense mutation in exon 2: p.Glu138Lys. This mutation is located far from the C-terminal region implicated in the posttranslational processing of prelamin A, but it lies within the rod domain of lamin A/C that represents a highly conserved domain specific to nuclear lamins. We hypothesize that this region could be involved in early and severe strokes in HGPS, such as those presented by our patient. PMID- 21791256 TI - Evidence for neurodegeneration and neuroplasticity as part of the neurobiology of suicide. PMID- 21791257 TI - Depression and the hippocampus: cause or effect? PMID- 21791258 TI - Ruminating on rumination. PMID- 21791259 TI - Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder. AB - BACKGROUND: Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is known about alterations of the topological organization of whole-brain networks in MDD patients. METHODS: Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics. RESULTS: Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity. CONCLUSIONS: These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients. PMID- 21791260 TI - Patient education. Preface. PMID- 21791261 TI - The evaluation of chronic disease self-management support across settings: the international experience of the health education impact questionnaire quality monitoring system. AB - Chronic disease self-management is a growing field yet few systematic measures of its impact exist. The Health Education Impact Questionnaire (heiQ)-rigorously developed in partnership with key stakeholders-is a panel of eight highly relevant questionnaires that has been tested and applied in many settings. Wide uptake across diseases has occurred because it resonates with patient concerns, helps researchers and practitioners develop quality services, and assists policy makers to appreciate the value of self-management support interventions. The heiQ continues to be adapted for new uses and applications creating a web of knowledge of the value and impact of health education programs. PMID- 21791262 TI - Improving medication adherence: moving from intention and motivation to a personal systems approach. AB - Medication nonadherence is a challenging and prevalent problem in older adults. Effective medication management involves successfully completing a complex group of behaviors. Meta-analyses and narrative review findings support limited benefits to medication adherence with interventions preoccupied with personal characteristics, intention, and motivation. Evidence supports a paradigm shift toward changing personal systems in which the person lives to improve and maintain medication adherence behavior. Personal-systems change systematically improves individual systems through collaboratively shaping routines, involving supportive-others in routines, and using medication self-monitoring to improve and maintain behavior. Other advances that support personal systems change are also presented. PMID- 21791263 TI - Ethics of patient education and how do we make it everyone's ethics. AB - Patient education has long been central to nursing's philosophy of practice, and, because of this commitment, nurses in all practice settings have been deeply distressed with the careless and generally incomplete manner in which it is practiced in the health care system. This article examines the ethical underpinning of this distress and of this neglect in patient education and what actions nurses can take to correct this situation. PMID- 21791264 TI - Using a competency-based approach to patient education: achieving congruence among learning, teaching and evaluation. AB - Millions of Americans are living with, and managing, their chronic health problems. Patient education plays an essential role in promoting safe self management practice. To ensure that patients attain the required abilities, patient education needs to be competency-based. When developing and applying a competency-based patient education lesson/program, each nurse must answer questions concerning essential competencies, optimal teaching methods, best method to evaluate patient achievement, and documentation of evidence. This article describes how the authors used these questions as a guide to achieve congruence among intended learning, instruction, and evaluation to design and implement a patient education program, Managing Heart Failure, at a local hospital. PMID- 21791265 TI - Creating educational objectives for patient education using the new Bloom's Taxonomy. AB - Whenever the nurse encounters a patient or a patient's family, there is a transfer of information that is expected to be incorporated into the patient's overall outcome. Objectives help guide the transfer of knowledge and provide a basis by which to evaluate the extent of the patient's understanding. Bloom's Taxonomy has been a cornerstone for the development of objectives in academe for over half of a century. The Revised Bloom's Taxonomy is a tool that can be used by nurses who educate patients to ensure the education session is focused, clear, has standards for evaluation, and is well documented. PMID- 21791266 TI - Assessing learning styles: practical tips for patient education. AB - Nurses must facilitate and support patient and family decision-making and improvement in health outcomes using instructional skills. Complex patient needs and nursing responsibilities necessitate thoughtful consideration for maximizing the effectiveness of patient teaching encounters. This article reviews assessment of patient learning styles in combination with context for an individualized approach, as well as motivation for adult learners as a framework for organization of patient teaching. Methods and modes of patient teaching are discussed as well as tips for overcoming barriers to planning and implementing patient teaching. PMID- 21791267 TI - Promoting health literacy: a nursing imperative. AB - It is imperative that nursing responds to the call of creating a health literate society by taking an active role in health literacy research, education, and promotion. Nurses have a professional and ethical obligation to communicate in a clear, purposeful way that addresses the unique information needs of each patient. Evidence-based strategies that promote health literacy must be incorporated in every patient's plan of care and become part of the routine practice of nursing. The goal of all patient interactions should be to empower the patient to obtain, understand, and act on information that is needed for optimal health. This article explores the concept of health literacy and its relationship to patient education and communication. Practical strategies that the nurse can use to assess, communicate with, and evaluate comprehension in patients with low literacy skills are provided. PMID- 21791268 TI - Cultural sensitivity in patient health education. AB - Changes in demographics, economic, and political factors have affected health care delivery, while the patient population and the health care providers have continued to increase in diversity. Cultural sensitivity is a necessary component in development of comprehensive patient, family, or community health education plans. Consideration of the ACCESS Model can facilitate the development of successful interactions in providing culturally sensitive patient education programs. PMID- 21791269 TI - Educating the patient: challenges and opportunities with current technology. AB - Patients using the Internet are inundated with abundant information on health care that may be correct and may be incorrect. It is becoming the role of clinicians to enable patients to educate themselves by providing information about accurate and reliable Web sites, and to answer questions from literature that patients encounter. In addition, there is a myriad of technological advances to help patients and clinicians access, retrieve, and file information, and numerous communication tools to foster the patient-clinician dialog. This article provides an overview and some recommendations for clinicians to help patients better use information to achieve better outcomes. PMID- 21791270 TI - Creating a tool to evaluate patient performance. AB - Patient education is a nursing responsibility that is often impromptu, spontaneous, and poorly documented. In many cases the patient's ability to perform a skill or task in the management of an illness or disease process affects the patient's outcome. A tool designed to evaluate patient performance guides the teaching process, promotes communication between the patient and nurse, and promotes communication among health care providers as it relates to patient performance. Nurses are in key positions to develop patient performance tools to ensure that the patient, or a patient's family member, can manage the health care requisites. PMID- 21791271 TI - Patient-driven education materials: low-literate adults increase understanding of health messages and improve compliance. AB - Providing educational materials for low-literate patients is an enormous challenge for nursing professionals given that 90 million adults in the health care setting have limited literacy skills. Through the use of a 5-step process, patient educational materials can be created to increase patient understanding of health messages and improve patient compliance. PMID- 21791274 TI - Carotid intima media thickness. PMID- 21791277 TI - Noradrenaline enhances signal-to-noise ratio of inhibitory inputs in the dorsal cochlear nucleus. AB - What are the mechanisms that enhance the response to behaviorally relevant external stimuli? In this issue of Neuron, Kuo and Trussell show that in the dorsal cochlear nucleus, noradrenaline functions to simultaneously reduce spontaneous inhibitory inputs while increasing evoked inhibition. PMID- 21791278 TI - How glutamate receptor subunits mix and match: details uncovered. AB - Until now, the atomic details explaining why certain subunits prefer to coassemble has been lacking in our understanding of glutamate receptor biogenesis. In this issue, Kumar et al. describe the structural basis by which preferential subunit assembly occurs for homomeric and heteromeric kainate-type glutamate receptors. PMID- 21791279 TI - A prestabilized harmony. AB - The appearance of discontinuous network events and their transformation into continuous oscillatory activity are fundamental milestones in cortical circuit development. In this issue, Brockmann et al. demonstrate a protracted development of activity patterns in the prefrontal cortex in neonatal rats and a possible role for hippocampal theta bursts in the maturation of PFC connectivity. PMID- 21791280 TI - How to perfect a chocolate souffle and other important problems. AB - When learning to achieve a goal through a complex series of actions, humans often group several actions into a subroutine and evaluate whether the subroutine achieved a specific subgoal. A new study reports brain responses consistent with such "hierarchical reinforcement learning." PMID- 21791281 TI - Cognitive and perceptual functions of the visual thalamus. AB - The thalamus is classically viewed as passively relaying information to the cortex. However, there is growing evidence that the thalamus actively regulates information transmission to the cortex and between cortical areas using a variety of mechanisms, including the modulation of response magnitude, firing mode, and synchrony of neurons according to behavioral demands. We discuss how the visual thalamus contributes to attention, awareness, and visually guided actions, to present a general role for the thalamus in perception and cognition. PMID- 21791283 TI - Pathway-specific genetic attenuation of glutamate release alters select features of competition-based visual circuit refinement. AB - A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections by competitive activity-dependent processes. In the developing visual system retinal ganglion cell (RGC) axons from the two eyes undergo activity-dependent competition for territory in the dorsal lateral geniculate nucleus (dLGN). The direct contributions of synaptic transmission to this process, however, remain unclear. We used a genetic approach to reduce glutamate release selectively from ipsilateral-projecting RGCs and found that their release-deficient axons failed to exclude competing axons from the ipsilateral eye territory in the dLGN. Nevertheless, the release-deficient axons consolidated and maintained their normal amount of dLGN territory, even in the face of fully active competing axons. These results show that during visual circuit refinement glutamatergic transmission plays a direct role in excluding competing axons from inappropriate target regions, but they argue that consolidation and maintenance of axonal territory are largely insensitive to alterations in synaptic activity levels. PMID- 21791282 TI - Consolidation and reconsolidation: two lives of memories? AB - Most studies on memory consolidation consider the new information as if it were imposed on a tabula rasa, but considerable evidence indicates that new memories must be interleaved within a large network of relevant pre-existing knowledge. Early studies on reconsolidation highlighted that a newly consolidated memory could be erased after reactivation, but new evidence has shown that an effective reactivation experience must also involve memory reorganization to incorporate new learning. The combination of these observations on consolidation and reconsolidation highlights the fundamental similarities of both phenomena as the integration of new information and old, and it suggests reconsolidation = consolidation as a neverending process of schema modification. PMID- 21791284 TI - Differences between neural activity in prefrontal cortex and striatum during learning of novel abstract categories. AB - Learning to classify diverse experiences into meaningful groups, like categories, is fundamental to normal cognition. To understand its neural basis, we simultaneously recorded from multiple electrodes in lateral prefrontal cortex and dorsal striatum, two interconnected brain structures critical for learning. Each day, monkeys learned to associate novel abstract, dot-based categories with a right versus left saccade. Early on, when they could acquire specific stimulus response associations, striatum activity was an earlier predictor of the corresponding saccade. However, as the number of exemplars increased and monkeys had to learn to classify them, PFC activity began to predict the saccade associated with each category before the striatum. While monkeys were categorizing novel exemplars at a high rate, PFC activity was a strong predictor of their corresponding saccade early in the trial before the striatal neurons. These results suggest that striatum plays a greater role in stimulus-response association and PFC in abstraction of categories. PMID- 21791285 TI - Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity. AB - Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs. PMID- 21791286 TI - Anatomical coupling of sensory and motor nerve trajectory via axon tracking. AB - It is a long-standing question how developing motor and sensory neuron projections cooperatively form a common principal grid of peripheral nerve pathways relaying behavioral outputs and somatosensory inputs. Here, we explored this issue through targeted cell lineage and gene manipulation in mouse, combined with in vitro live axon imaging. In the absence of motor projections, dorsal (epaxial) and ventral (hypaxial) sensory projections form in a randomized manner, while removal of EphA3/4 receptor tyrosine kinases expressed by epaxial motor axons triggers selective failure to form epaxial sensory projections. EphA3/4 act non-cell-autonomously by inducing sensory axons to track along preformed epaxial motor projections. This involves cognate ephrin-A proteins on sensory axons but is independent from EphA3/4 signaling in motor axons proper. Assembly of peripheral nerve pathways thus involves motor axon subtype-specific signals that couple sensory projections to discrete motor pathways. PMID- 21791287 TI - Endocytosis promotes rapid dopaminergic signaling. AB - D(1) dopamine receptors are primary mediators of dopaminergic signaling in the CNS. These receptors internalize rapidly following agonist-induced activation, but the functional significance of this process is unknown. We investigated D(1) receptor endocytosis and signaling in HEK293 cells and cultured striatal neurons using real-time fluorescence imaging and cAMP biosensor technology. Agonist induced activation of D(1) receptors promoted endocytosis of receptors with a time course overlapping that of acute cAMP accumulation. Inhibiting receptor endocytosis blunted acute D(1) receptor-mediated signaling in both dissociated cells and striatal slice preparations. Although endocytic inhibition markedly attenuated acute cAMP accumulation, inhibiting the subsequent recycling of receptors had no effect. Further, D(1) receptors localized in close proximity to endomembrane-associated trimeric G protein and adenylyl cyclase immediately after endocytosis. Together, these results suggest a previously unanticipated role of endocytosis, and the early endocytic pathway, in supporting rapid dopaminergic neurotransmission. PMID- 21791288 TI - Nitric oxide is an activity-dependent regulator of target neuron intrinsic excitability. AB - Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. PMID- 21791289 TI - Spontaneous spiking and synaptic depression underlie noradrenergic control of feed-forward inhibition. AB - Inhibitory interneurons across diverse brain regions commonly exhibit spontaneous spiking activity, even in the absence of external stimuli. It is not well understood how stimulus-evoked inhibition can be distinguished from background inhibition arising from spontaneous firing. We found that noradrenaline simultaneously reduced spontaneous inhibitory inputs and enhanced evoked inhibitory currents recorded from principal neurons of the mouse dorsal cochlear nucleus (DCN). Together, these effects produced a large increase in signal-to noise ratio for stimulus-evoked inhibition. Surprisingly, the opposing effects on background and evoked currents could both be attributed to noradrenergic silencing of spontaneous spiking in glycinergic interneurons. During spontaneous firing, glycine release was decreased due to strong short-term depression. Elimination of background spiking relieved inhibitory synapses from depression and thereby enhanced stimulus-evoked inhibition. Our findings illustrate a simple yet powerful neuromodulatory mechanism to shift the balance between background and stimulus-evoked signals. PMID- 21791291 TI - Coupled oscillations mediate directed interactions between prefrontal cortex and hippocampus of the neonatal rat. AB - The coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and maturation of functional units underlying information storage at adulthood. PMID- 21791292 TI - The Y cell visual pathway implements a demodulating nonlinearity. AB - Neural encoding of sensory signals involves both linear and nonlinear processes. Determining which nonlinear operations are implemented by neural systems is crucial to understanding sensory processing. Here, we ask if demodulation, the process used to decode AM radio signals, describes how Y cells in the cat LGN nonlinearly encode the visual scene. In response to visual AM signals across a wide range of carrier frequencies, Y cells were found to transmit a demodulated signal, with the firing rate of single-units fluctuating at the envelope frequency but not the carrier frequency. A comparison of temporal frequency tuning properties between LGN Y cells and neurons in two primary cortical areas suggests that Y cells initiate a distinct pathway that carries a demodulated representation of the visual scene to cortex. The nonlinear signal processing carried out by the Y cell pathway simplifies the neural representation of complex visual features and allows high spatiotemporal frequencies to drive cortical responses. PMID- 21791290 TI - Structure and assembly mechanism for heteromeric kainate receptors. AB - Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors. PMID- 21791293 TI - Binocular rivalry requires visual attention. AB - An interocular conflict arises when different images are presented to each eye at the same spatial location. The visual system resolves this conflict through binocular rivalry: observers consciously perceive spontaneous alternations between the two images. Visual attention is generally important for resolving competition between neural representations. However, given the seemingly spontaneous and automatic nature of binocular rivalry, the role of attention in resolving interocular competition remains unclear. Here we test whether visual attention is necessary to produce rivalry. Using an EEG frequency-tagging method to track cortical representations of the conflicting images, we show that when attention was diverted away, rivalry stopped. The EEG data further suggested that the neural representations of the dichoptic images combined without attention. Thus, attention is necessary for dichoptic images to be engaged in sustained rivalry and may be generally required for resolving conflicting, potentially ambiguous input and giving a single interpretation access to consciousness. PMID- 21791295 TI - Traditional Chinese medicines and Alzheimer's disease. AB - Traditional Chinese medicines have been widely investigated for the treatment of Alzheimer's disease (AD) because none of the current therapies-either the cholinesterase inhibitors or antagonist of N-methyl-d-aspartate receptors-has profound effects on halting the progression of AD. In recent years, scientists have isolated many active compounds from herbs, which can alleviate dementia and neurodegenerative syndrome with fewer side effects than conventional drugs and, thus, are regarded as promising drug candidates for AD therapy. In this review, we summarize the latest research progress on six herbs for AD therapy-Huperzia serrata, Amaryllidaceae family, Ginkgo biloba, Uncaria rhynchophylla, Polygala tenuifolia, and Salvia officinalis-and focus on the analysis of their active components and possible mechanisms of pharmacological actions on AD. PMID- 21791294 TI - A neural signature of hierarchical reinforcement learning. AB - Human behavior displays hierarchical structure: simple actions cohere into subtask sequences, which work together to accomplish overall task goals. Although the neural substrates of such hierarchy have been the target of increasing research, they remain poorly understood. We propose that the computations supporting hierarchical behavior may relate to those in hierarchical reinforcement learning (HRL), a machine-learning framework that extends reinforcement-learning mechanisms into hierarchical domains. To test this, we leveraged a distinctive prediction arising from HRL. In ordinary reinforcement learning, reward prediction errors are computed when there is an unanticipated change in the prospects for accomplishing overall task goals. HRL entails that prediction errors should also occur in relation to task subgoals. In three neuroimaging studies we observed neural responses consistent with such subgoal related reward prediction errors, within structures previously implicated in reinforcement learning. The results reported support the relevance of HRL to the neural processes underlying hierarchical behavior. PMID- 21791296 TI - Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study. AB - OBJECTIVE: This retrospective study aimed to investigate the use of an oxytocin antagonist in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure (RIF). MATERIALS AND METHODS: A total of 150 infertile couples with RIF undergoing IVF-ET were divided into three groups. Patients who did not receive atosiban were used as controls (Group 1; n=80). Forty patients received a single bolus dose (6.75mg, 0.9mL/vial) of atosiban before ET (Group 2), and 30 patients received a bolus dose of 6.75mg atosiban followed by infusion at 18mg/hr for 3 hours immediately after ET (Group 3). RESULTS: A significantly higher implantation rate (30.21%) was noted in Group 2 compared with Groups 1 and 3 (11.8% and 15.9%, respectively; p=0.0006). The clinical pregnancy rate of Group 2 (37.5%) was significantly higher than that of Groups 1 (12.5%) and 3 (20%) (p=0.0057). The live birth rate was significantly higher in Group 2 (35%) than in Groups 1 and 3 (10% and 16.67%, respectively; p=0.0031). CONCLUSION: These results suggest that IVF-ET using lower dosage of atosiban may improve pregnancy outcomes of patients with RIF. PMID- 21791297 TI - Primary fallopian tube carcinoma: clinicopathological analysis of 12 cases. AB - OBJECTIVE: Primary fallopian tube carcinoma is one of the least common gynecological cancers and is difficult to diagnose preoperatively. We aimed to analyze the clinicopathological characteristics of this rare disease and to identify the prognostic factors predicting prognosis. MATERIALS AND METHODS: Twelve cases of primary fallopian tube carcinoma that had been diagnosed and treated in Kaohsiung Chang Gung Memorial Hospital between July 1986 and December 2005 were retrospectively reviewed. Factors, including age, gravidity, parity, stage, surgical intervention, pathological findings, relapse, and survival, were analyzed. RESULTS: The median age of the 12 cases was 54 years (range, 32-67 years), whereas the median follow-up time was 38 months. None of the 12 cases were diagnosed preoperatively. Preoperative diagnoses were adnexal mass of unknown nature in six (50%), tubo-ovarian abscess in three (25%), ovarian carcinoma in two (16.7%), and endometrioma in one (8.3%) cases. Two patients (16.7%) had experienced the typical symptom of watery vaginal discharge. Three patients (25%) were in Stage I, three (25%) in Stage II, four (33.3%) in Stage III, and two (16.7%) were unstaged. Nine patients had received postoperative platinum-based adjuvant chemotherapy. The 5-year disease-free survival rate was 64%. On evaluating the correlation between clinicopathological parameters and survival, only the Federation of Gynecology and Obstetrics stage (p=0.017) was a significant prognostic factor. CONCLUSION: Although preoperative diagnosis of fallopian tube carcinoma is difficult, still 16.7% of our patients experienced the typical symptom suggestive of tubal carcinoma. Prognostic factors associated with fallopian tube cancer were similar to those of epithelial ovarian cancer. PMID- 21791298 TI - Etiologies and contributing factors of perinatal mortality: a report from southeast of Iran. AB - OBJECTIVE: The aim of this study was to investigate the etiology and risk factors of perinatal mortality in Rafsanjan, Iran. MATERIALS AND METHODS: This case control prospective study was conducted on 321 perinatal deaths (as case group) and 321 live births who were alive until 28 days after birth (as control group) during a 2-year period. Data about demographic characteristics of mother, fetus, and newborn and also mother's obstetrics and clinical status was recorded in a questionnaire. RESULTS: The most important causes of newborn death were prematurity (63.24%), cardiac arrest (11.49%), and septicemia (5.75%) as well as premature rupture of membrane, pregnancy-induced hypertension, placenta decolman, and congenital abnormality for stillbirth. A significant association was found among the fetal weight, gestational age, and amniotic fluid volume with stillbirth. CONCLUSION: Prematurity, cardiac arrest, and septicemia were the most important causes of neonatal mortality. It is concluded that attention to the following points is very important: adopting program for pregnancy care improvement, finding and removing risk factors of premature birth, control of infection in mother's and newborn's wards, examining of personnel skill about correct newborn resuscitation methods, and arrangement of training courses. PMID- 21791299 TI - Maternal serum leptin concentration in gestational diabetes. AB - OBJECTIVE: The aim of this study was to evaluate fasting serum leptin concentration and its relation to insulin resistance in women with gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (IGT). MATERIALS AND METHODS: This case-control study, at 28 weeks of gestation, measured serum concentration of fasting leptin, insulin, and homeostatic model assessment index in three groups, GDM, IGT, and normal control, and compared them with each other. RESULTS: The serum leptin level was significantly higher in women with GDM than in the two other groups (p=0.03). In women with GDM and IGT, leptin was significantly positively related with insulin and homeostatic model assessment index (r=0.221, p=0.03) and (r=0.246, p=0.03), respectively. In all of the participants, there was a significant correlation between leptin and body mass index before pregnancy (r=0.416, p=0.001). CONCLUSION: Our data showed that serum leptin level was higher in GDM and had a positive correlation with insulin resistance. Our findings suggest that high leptin levels might be a risk factor for GDM and IGT in pregnant women. PMID- 21791300 TI - Psychological responses of women infected with cervical human papillomavirus: a qualitative study in Taiwan. AB - OBJECTIVE: To determine the psychological response of cervical human papillomavirus (HPV) infected women. MATERIALS AND METHODS: Twenty oncogenic or high-risk HPV infected cases were collected by purposive sampling, and a 2-hour in-depth interview was carried out with 20 women at a tertiary referring medical center. The interview content was analyzed using the qualitative method. Psychological responses included cognition, emotions, and behavior. RESULTS: Differences in psychological responses arose more from individual cognition and personality than from whether or not one was single or married. After learning of their infection, most patients searched the Internet for HPV information and for a reputable doctor. They cared about privacy in the outpatient clinic. Most patients had all kinds of negative feelings, principally involving fear, worry, and suspicion. The better a couple's relationship, the less these patients struggled to tell the truth (HPV infection). Patients often urged partners to check-up and advised friends for Pap smear tests. CONCLUSIONS: Most HPV infected women have many kinds of negative feelings. Psychological help for these women is necessary. PMID- 21791301 TI - The factors affecting the outcome of frozen-thawed embryo transfer cycle. AB - OBJECTIVE: To determine the impact of the clinical and embryological factors on the pregnancy outcome of frozen-thawed embryo transfer. MATERIALS AND METHODS: The data of 247 frozen-thawed embryo transfer cycles were assessed at Royan Institute from March 2006 to March 2008. Appropriate statistical analysis was performed using Student t test and Chi-square or Fisher exact test. Forward logistic regression was done to predict the individual impact of factors on the success of frozen embryo transfer. RESULTS: According to our results, 1,523 frozen embryos were thawed with a survival rate of 79.8%. The overall chemical and clinical pregnancy rates per embryo transfer cycle were 28.1% and 26.3%, respectively. A total of 71 gestational sacs were implanted (7.9%). The pregnancy outcome was higher in women who were stimulated with the gonadotrophin releasing hormone agonist long protocol, treated by a combination of follicle stimulating hormone and luteinizing hormone, who had endometrial thickness greater than or equal to 8mm on the embryo transfer day, and who had positive fresh-cycle pregnancy test. CONCLUSION: Protocol type, gonadotrophin preparations, fresh cycle outcome, endometrial thickness and the numbers of obtained oocytes, embryos, and high-quality thawed embryos transferred are the factors affecting pregnancy outcome of frozen-thawed embryo transfer. PMID- 21791302 TI - Low-dose LBH589 increases the sensitivity of cisplatin to cisplatin-resistant ovarian cancer cells. AB - OBJECTIVE: There is a need to develop alternative therapeutic strategies to overcome cisplatin-associated resistance in patients with ovarian cancer. Histone deacetylation (HDAC) associated with inactivation of genes has been implicated in the epigenetic silencing of tumor suppressor genes affecting critical biological activities in cancer cells and may be an important factor in acquired cisplatin associated resistance. In this report, we tested a combination of cisplatin and LBH589 (histone deacetylation inhibitor) in cisplatin-resistant ovarian cancer cells to explore the reversal effect of cisplatin resistance and changes of gene expression. MATERIALS AND METHODS: To detect the synergistic effects of antiproliferation between cisplatin and LBH589 in ovarian cancer cells, we performed a cell viability assay and a clonogenic assay. To investigate the differences of gene expression between cells treated by cisplatin alone and cotreated with cisplatin and LBH589, a microarray mRNA analysis was performed. RESULTS: In the presence of low-dose LBH589, the inhibition concentration value of cisplatin for A2780-cp70 cells was much lower than with cisplatin treatment alone. Gene expression profiles identified that a total of 354 genes had been significantly upregulated and a total of 63 genes been downregulated with LBH589 cotreatment. CONCLUSION: We hypothesized that combination of cisplatin and LBH589 can override cisplatin-associated resistance in ovarian cancer cells. These results provide initial evidence for testing this combination in clinical use. PMID- 21791304 TI - Hayman uterine compression stitch for arresting atonic postpartum hemorrhage: 5 years experience. AB - OBJECTIVES: The present study was planned to access the efficacy of Hayman uterine compression stitch which is easy, can be applied faster and avoids the performance of a lower segment hysterotomy in patients with atonic postpartum hemorrhage. MATERIALS AND METHODS: It is a study carried out from January 2004 to December 2008 at a tertiary care center and included 48 women who had intractable atonic PPH not managed with medical treatment and who were wishing to preserve their fertility. Hayman stitch which is a simplified approach to uterine compression sutures was performed by tying two parallel vertical sutures from just above the bladder reflection to the fundus of the uterus. RESULTS: With Hayman stitch hysterectomy was avoided in 93.75% (45 out of the 48) patients with PPH. The postoperative course was uncomplicated, six women conceived spontaneously within 12 month after uterine compression suturing. Four delivered vaginally and two underwent cesarean section in view of fetal distress. The uterine cavity was found to be normal during caesarean section. CONCLUSION: Two parallel vertical compression sutures (Hayman stitch) placed in the uterus controls bleeding effectively. The technique is easy, rapid and requires less skill and this simple procedure be tried first before other complex measures like uterine artery ligation are undertaken particularly for those obstetricians who lack sufficient training and skill. PMID- 21791303 TI - Sectional anatomy of the fetal brain in uterus at term on the sagittal plane. AB - OBJECTIVE: To provide sectional anatomic data for the precise localization of developmental malformation of fetal brain in sagittal magnetic resonance imaging (MRI). METHOD: After abdominal and pelvic MRI scanning, the gravid specimen was cut into serial sagittal slices in correspondence with MRI in a low temperature laboratory to demonstrate the structures of fetal brain. RESULT: (1) Directional determination of the sloping and rotating fetal head. From the serial sagittal sections of pregnant cadaver at term, we concluded that, the longitudinal lying and cephalic presentation fetal had run into maternal pelvis, and rotated and sloped to right. Anteroposterior position and median sagittal plane of the fetal was in correspondence with his mother's. (2) Seven serial sagittal sections of the fetal brain were obtained through lateral surface of the right cerebral hemisphere, lateral sulcus, internal capsule, median sagittal plane, middle cerebellar peduncle, brainstem, and lateral surface of the left cerebral hemisphere. CONCLUSION: Through the comparison study between sagittal sections and corresponding MRI of fetal brain at term, we could obtain morphological anatomic structures and MRI of fetal brain, providing morphological demonstration of the intrauterine development of fetal brain and auxiliary diagnosis of ultrasound and MRI in pregnant woman. PMID- 21791305 TI - Prenatal diagnosis and molecular cytogenetic characterization of a derivative chromosome der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3) presenting as apparent isochromosome 18q in a fetus with holoprosencephaly. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of a derivative chromosome der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3). MATERIALS, METHODS, AND RESULTS: A 32-year-old woman was referred for genetic counseling of prenatally detected isochromosome 18q [i(18q)]. She had undergone amniocentesis at 19 gestational weeks because of a trisomy 18 risk of 1/39 derived from abnormally low levels of maternal serum unconjugated estriol, inhibin A, alpha fetoprotein, and total beta-human chorionic gonadotropin. Amniocentesis revealed a karyotype of 46,XX,i(18)(q10). Parental karyotypes were normal. Prenatal ultrasound showed alobar holoprosencephaly. Repeated amniocentesis was requested and performed at 21 gestational weeks. Array-comparative genomic hybridization analyses revealed a 14-Mb deletion of 18p11.32-p11.21, a 37.8-Mb duplication of 18q12.1-q22.1, and a 6.9-Mb duplication of 18q22.3-q23. Metaphase fluorescence in situ hybridization study showed the absence of an 18q12.1-specific probe signal in one arm and the absence of an 18q22.2-specific probe signal in the other arm of the derivative chromosome. Quantitative fluorescent polymerase chain reaction analysis determined a paternal origin of the derivative chromosome. The cytogenetic result was 46,XX,der(18;18)(q10;q10)del(18)(q11.1q12.1)del(18)(q22.1q22.3). The fetus postnatally manifested cebocephaly. CONCLUSION: Concomitant monosomy 18p and trisomy 18q can be associated with holoprosencephaly and abnormal maternal serum screening results. Array-comparative genomic hybridization, fluorescence in situ hybridization, and quantitative fluorescent polymerase chain reaction are useful in genetic counseling of prenatally detected isochromosomes by providing information on the origin and genetic components of the isochromosome. PMID- 21791306 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from ring chromosome 4. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from ring chromosome, or r(4) by spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH). MATERIALS, METHODS, AND RESULTS: A 37-year-old, primigravid woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in 16 of 31 amniocyte colonies. The parental karyotypes were normal. Level II ultrasound findings were unremarkable. Repeated amniocentesis revealed a karyotype of 47,XX,+mar[17]/46,XX[19]. The sSMC was characterized by SKY and FISH, which showed a chromosome 4 origin of the sSMC. aCGH demonstrated a 21.7-Mb gain in the gene dosage encompassing the region of 4p12->q13.2. The sSMC was r(4)(p12q13.2). The fetal karyotype was 47,XX,+r(4)(p12q13.2)[17]/46,XX[19]. The pregnancy was subsequently terminated. The fetus postnatally manifested hypertelorism, epicanthic folds, a prominent nose, a triangular face, low-set ears, clinodactyly of the fingers, and small big toes. Postnatal cytogenetic analyses of fetal and extraembryonic tissues revealed the karyotypes of 47,XX,+r(4)[18]/46,XX[21] in cord blood, 47,XX,+r(4)[20]/48,XX,+r(4),+r(4)[1]/46,XX[9] in umbilical cord, 47,XX,+r(4)[14]/47,XX,+dic r(4)[1]/46,XX[25] in skin, 47,XX,+r(4)[15]/46,XX[25] in amnion, and 47,XX,+r(4)[12]/47,XX,+dic r(4)[1]/46,XX[2] in placenta. CONCLUSION: SKY, FISH, and aCGH are helpful in genetic counseling of prenatally detected sSMCs by providing the immediate and thorough information on the origin and genetic component of the sSMC. PMID- 21791307 TI - Meigs' syndrome with elevated serum cancer antigen 125 levels in a case of ovarian sclerosing stromal tumor. AB - OBJECTIVE: Meigs' syndrome presenting as an ovarian tumor with elevated serum cancer antigen 125 (CA 125) levels is unusual. Only 37 cases have been reported, including three cases of ovarian sclerosing stromal tumor (SCT). Many reports have suggested that the presence of ascites is the major factor inducing mesothelial expression of CA 125. CASE REPORT: An 18-year-old woman presented with massive ascites, elevated serum CA 125 levels, and radiographic evidence of ovarian tumor. The histological and immunohistochemical examinations revealed a benign SCT. CONCLUSION: SCT is a benign ovarian tumor and complete excision is curative. We also review all 37 cases and discuss possible mechanisms of Meigs' syndrome and elevated serum CA 125 level. PMID- 21791308 TI - Coexistence of borderline ovarian epithelial tumor, primary pelvic hydatid cyst, and lymphoepithelioma-like gastric carcinoma. AB - OBJECTIVES: Borderline ovarian tumors (BOTs) represent a heterogeneous group of ovarian epithelial neoplasms. Despite a favorable prognosis, 10-20% of BOTs exhibit progressively worsening clinic. Primary involvement of pelvic organs with echinococcus is very rare. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach. CASE REPORT: A 58-year-old woman referred with abdominal swelling and gastric complaints. Imaging studies revealed a huge cystic mass with multiple septations and solid component, another cystic mass with an appearance of cyst hydatid in the pelvis, and thickening of the small curvature of stomach. Gastroscopy revealed an ulcer with a suspicious malignant appearance, and histology of the endoscopic specimen showed severe chronic inflammation and lymphocytic infiltration. No other involvement of hydatid cyst was detected. In the exploration, there was a 25cm cystic lesion with solid components arising from right ovary, another 6cm cyst over the former, 7cm cystic lesion arising from left ovary, and 10cm mass near the small curvature of the stomach. Excision of the masses; total gastrectomy with esophagojejunal anastomosis; total abdominal hysterectomy; bilateral salpingo-oophorectomy; omentectomy; appendectomy; splenectomy; and pelvic, paraaortic, and coeliac lympadenectomy were performed. Final pathology revealed lymphoepithelioma-like gastric carcinoma, bilateral serous BOT, and hydatid cyst. DISCUSSION: Hydatid cyst should always be considered in the differential diagnosis of abdominopelvic masses in endemic regions of the world. Preoperative diagnosis of primary pelvic hydatid disease is difficult and awareness of its possibility is very important especially in patients residing in or coming from endemic areas. PMID- 21791309 TI - Partial monosomy 13q (13q21.32--->qter) and partial trisomy 8p (8p1--->pter) presenting with anencephaly and increased nuchal translucency: array comparative genomic hybridization characterization. AB - OBJECTIVE: To present array comparative genomic hybridization (aCGH) characterization of partial monosomy 13q (13q21.32->qter) and partial trisomy 8p (8p12->pter) presenting with anencephaly and increased nuchal translucency (NT). CASE REPORT: A 34-year-old primigravid woman was referred to the hospital at 12 weeks of gestation for termination of the pregnancy because of major structural abnormalities of the fetus. Prenatal ultrasound revealed a malformed fetus with anencephaly and an increased NT thickness of 5mm at 12 weeks of gestation. Cytogenetic analysis of the fetus revealed a derivative chromosome 13. The mother was subsequently found to carry a balanced reciprocal translocation between 8p12 and 13q21. Bacterial artificial chromosome-based aCGH using fetal DNA demonstrated partial trisomy 8p and partial monosomy 13q [arr cgh 8p23.3p12 (RP11 1150M5->RP11-1145H12)*3, 13q21.32q34 (RP11-326B4->RP11-450H16)*1]. Oligonucleotide-based aCGH showed a 36.7-Mb duplication of distal 8p and a 48.4 Mb deletion of distal 13q. The fetal karyotype was 46,XY,der(13) t(8;13)(p12;q21.32)mat. The maternal karyotype was 46,XX,t(8;13)(p12;q21.32). CONCLUSION: The 13q deletion syndrome can be associated with neural tube defects and increased NT in the first trimester. Prenatal sonographic detection of neural tube defects should alert chromosomal abnormalities and prompt cytogenetic investigation, which may lead to the identification of an unexpected parental translocation involving chromosomal segments associated with neural tube development. PMID- 21791310 TI - Galloway-Mowat syndrome: prenatal ultrasound and perinatal magnetic resonance imaging findings. AB - OBJECTIVE: To present prenatal ultrasound and perinatal magnetic resonance imaging (MRI) findings of Galloway-Mowat syndrome. CASE REPORT: A 31-year-old woman, gravida 3, para 2, was referred for genetic counseling at 29 weeks of gestation because of abnormal ultrasound findings and a previous child with Galloway-Mowat syndrome. During this pregnancy, microcephaly, intrauterine growth restriction (IUGR), and oligohydramnios were first noted at 27 weeks of gestation. Repeated ultrasounds showed microcephaly, IUGR, and oligohydramnios. MRI performed at 32 weeks of gestation showed reduced sulcation of the brain, pachygyria, poor myelination of the white matter, and cerebellar atrophy. A diagnosis of recurrent Galloway-Mowat syndrome was made. At 40 weeks of gestation, a 2,496-g female baby was delivered with microcephaly, a narrow slopping forehead, epicanthic folds, microphthalmos, a highly arched palate, a small midface, a beaked nose, thin lips, large low-set floppy ears, clenched hands, and arachnodactyly. Postnatal MRI findings were consistent with the prenatal diagnosis. Renal ultrasound showed enlarged bilateral kidneys with increased echogenicity. At the age of 2 weeks, the infant became edematous and developed nephrotic syndrome. CONCLUSION: Microcephaly, IUGR, and oligohydramnios are significant ultrasound triad of fetal Galloway-Mowat syndrome. Prenatal ultrasound diagnosis of microcephaly, IUGR, and oligohydramnios in late second trimester or in early third trimester should alert clinicians to the possibility of Galloway-Mowat syndrome and prompt a detailed search of abnormal sulcation, cortical gyral maldevelopment, and cerebellar atrophy by fetal ultrafast MRI. PMID- 21791311 TI - Ovarian hyperstimulation syndrome associated with von Willebrand's disease. PMID- 21791312 TI - Oxytocin antagonist successfully prevents from threatened abortion in 15 weeks' gestation. PMID- 21791313 TI - Secondary amenorrhea associated with 46,X,der(X)t(X;X)(p22;p22). PMID- 21791314 TI - Cost utility analysis of human papilloma virus vaccination for females in three different age groups: a medical economics analysis. PMID- 21791315 TI - Management of severe immune thrombocytopenic purpura in a pregnant woman with inevitable preterm forceps breech delivery. PMID- 21791316 TI - Cytomegalovirus infection and fetal death in one monozygotic twin. PMID- 21791317 TI - Puerperal breast abscess caused by oxacillin-resistant Staphylococcus aureus successfully treated by aspiration and antimicrobial therapy. PMID- 21791318 TI - Disseminated granulosa cell tumor of pelvis. PMID- 21791319 TI - Rectal abscess during pregnancy. PMID- 21791320 TI - Prenatal diagnosis and follow-up of giant sacrococcygeal teratoma. PMID- 21791321 TI - Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic isochromosome 20q detected at amniocentesis. PMID- 21791322 TI - Prenatal diagnosis and array comparative genomic hybridization characterization of a de novo interstitial deletion of chromosome 20p. PMID- 21791323 TI - Prenatal diagnosis and molecular cytogenetic characterization of a small marker chromosome derived from Y chromosome. PMID- 21791324 TI - Prenatal ultrasound demonstration of limb-body wall complex with megacystis. PMID- 21791325 TI - Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). AB - Red blood cell transfusion is common in patients with acute myocardial infarction (AMI). However, observational data suggest that this practice may be associated with worse clinical outcomes and data from clinical trials are lacking in this population. We conducted a prospective multicenter randomized pilot trial in which 45 patients with AMI and a hematocrit level <=30% were randomized to a liberal (transfuse when hematocrit <30% to maintain 30% to 33%) or a conservative (transfuse when hematocrit <24% to maintain 24% to 27%) transfusion strategy. Baseline hematocrit was similar in those in the liberal and conservative arms (26.9% vs 27.5%, p = 0.4). Average daily hematocrits were 30.6% in the liberal arm and 27.9% in the conservative arm, a difference of 2.7% (p <0.001). More patients in the liberal arm than in the conservative arm were transfused (100% vs 54%, p <0.001) and the average number of units transfused per patient tended to be higher in the liberal arm than in the conservative arm (2.5 vs 1.6, p = 0.07). The primary clinical safety measurement of in-hospital death, recurrent MI, or new or worsening congestive heart failure occurred in 8 patients in the liberal arm and 3 in the conservative arm (38% vs 13%, p = 0.046). In conclusion, compared to a conservative transfusion strategy, treating anemic patients with AMI according to a liberal transfusion strategy results in more patients receiving transfusions and higher hematocrit levels. However, this may be associated with worse clinical outcomes. A large-scale definitive trial addressing this issue is urgently required. PMID- 21791326 TI - Long-term prognosis of first myocardial infarction according to the electrocardiographic pattern (ST elevation myocardial infarction, non-ST elevation myocardial infarction and non-classified myocardial infarction) and revascularization procedures. AB - The aim of this study was to describe differences in the characteristics and short- and long-term prognoses of patients with first acute myocardial infarction (MI) according to the presence of ST-segment elevation or non-ST-segment elevation. From 2001 and 2003, 2,048 patients with first MI were consecutively admitted to 6 participating Spanish hospitals and categorized as having ST segment elevation MI (STEMI), non-ST-segment elevation MI (NSTEMI), or unclassified MI (pacemaker or left bundle branch block) according to electrocardiographic results at admission. The proportions of female gender, hypercholesterolemia, hypertension, and diabetes were higher among NSTEMI patients than in the STEMI group. NSTEMI 28-day case fatality was lower (2.99% vs 5.26%, p = 0.02). On multivariate analysis, the odds ratio of 28-day case fatality was 2.23 for STEMI patients compared to NSTEMI patients (95% confidence interval 1.29 to 3.83, p = 0.004). The multivariate adjusted 7-year mortality for 28-day survivors was higher in NSTEMI than in STEMI patients (hazard ratio 1.31, 95% confidence interval 1.02 to 1.68, p = 0.035). However, patients with unclassified MI presented the highest short- and long-term mortality (11.8% and 35.4%, respectively). The excess of short-term mortality in unclassified and STEMI patients was mainly observed in those patients not treated with revascularization procedures. In conclusion, patients with first NSTEMI were older and showed a higher proportion of previous coronary risk factors than STEMI patients. NSTEMI patients had lower 28-day case fatality but a worse 7-year mortality rate than STEMI patients. Unclassified MI presented the worst short- and long-term prognosis. These results support the invasive management of patients with acute coronary syndromes to reduce short-term case fatality. PMID- 21791327 TI - Associations of patient demographic characteristics and regional physician density with early physician follow-up among medicare beneficiaries hospitalized with heart failure. AB - Early physician follow-up after a heart failure (HF) hospitalization is associated with lower risk of readmission. However, factors associated with early physician follow-up are not well understood. We identified 30,136 patients with HF >=65 years at 225 hospitals participating in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE) registry or the Get With The Guidelines-Heart Failure (GWTG-HF) registry from January 1, 2003 through December 31, 2006. We linked these clinical data to Medicare claims data for longitudinal follow-up. Using logistic regression models with site-level random effects, we identified predictors of physician follow-up within 7 days of hospital discharge. Overall 11,420 patients (37.9%) had early physician follow-up. Patients residing in hospital referral regions with higher physician concentration were significantly more likely to have early follow-up (odds ratio 1.29, 95% confidence interval 1.12 to 1.48, for highest vs lowest quartile). Patients in rural areas (0.84, 0.78 to 0.91) and patients with lower socioeconomic status (0.79, 0.74 to 0.85) were less likely to have early follow up. Women (0.87, 0.83 to 0.91) and black patients (0.84, 0.77 to 0.92) were less likely to receive early follow-up. Patients with greater co-morbidity were less likely to receive early follow-up. In conclusion, physician follow-up within 7 days after discharge from a HF hospitalization varied according to regional physician density, rural location, socioeconomic status, gender, race, and co morbid conditions. Strategies are needed to ensure access among vulnerable populations to this supply-sensitive resource. PMID- 21791328 TI - Twenty-five year experience with balloon aortic valvuloplasty for congenital aortic stenosis. AB - Balloon aortic valvuloplasty (BAV) is the primary therapy for congenital aortic stenosis (AS). Few reports describe long-term outcomes. In this study, a retrospective single-institution review was performed of patients who underwent BAV for congenital AS. The following end points were evaluated: moderate or severe aortic insufficiency (AI) by echocardiography, aortic valve replacement, repeat BAV, surgical aortic valvotomy, and transplantation or death. From 1985 to 2009, 272 patients who underwent BAV at ages 1 day to 30.5 years were followed for 5.8 +/- 6.7 years. Transplantation or death occurred in 24 patients (9%) and was associated with depressed baseline left ventricular shortening fraction (LVSF) (p = 0.04). Aortic valve replacement occurred in 42 patients (15%) at a median of 3.5 years (interquartile range 75 days to 5.9 years) after BAV and was associated with post-BAV gradient >=25 mm Hg (p = 0.02), the presence of post-BAV AI (p = 0.03), and below-average baseline LVSF (p = 0.04). AI was found in 83 patients (31%) at a median of 4.8 years (interquartile range 1.4 to 8.7) and was inversely related to post-BAV gradient >=25 mm Hg (p <0.04). AI was associated with depressed baseline LVSF (p = 0.02). Repeat valvuloplasty (balloon or surgical) occurred in 37 patients (15%) at a median of 0.51 years (interquartile range 0.10 to 5.15) and was associated with neonatal BAV (p <0.01), post-BAV gradient >=25 mm Hg (p = 0.03), and depressed baseline LVSF (p = 0.05). In conclusion, BAV confers long-term benefits to most patients with congenital AS. Neonates, patients with post-BAV gradients >=25 mm Hg, and patients with lower baseline LVSF experienced worse outcomes. PMID- 21791329 TI - Differentiating ST-elevation myocardial infarction from nonischemic ST-elevation in patients with chest pain. AB - Current guidelines state that patients with compatible symptoms and ST-segment elevation (STE) in >=2 contiguous electrocardiographic leads should undergo immediate reperfusion therapy. Aggressive attempts at decreasing door-to-balloon times have led to more frequent activation of primary percutaneous coronary intervention (pPCI) protocols. However, it remains crucial to correctly differentiate STE myocardial infarction (STEMI) from nonischemic STE (NISTE). We assessed the ability of experienced interventional cardiologists in determining whether STE represents acute STEMI or NISTE. Seven readers studied electrocardiograms of consecutive patients showing STE. Patients with left bundle branch block or ventricular rhythms were excluded. Readers decided if, based on electrocardiographic results, they would have activated the pPCI protocol. If NISTE was chosen, readers selected from 12 possible explanations as to why STE was present. Of 84 patients, 40 (48%) had adjudicated STEMI. The percentage for which readers recommended pPCI varied (33% to 75%). Readers' sensitivity and specificity ranged from 55% to 83% (average 71%) and 32% to 86% (average 63%), respectively. Positive and negative predictive values ranged from 52% to 79% (average 66%) and 67% to 79% (average 71%), respectively. Broad inconsistencies existed among readers as to the chosen reasons for NISTE classification. In conclusion, we found wide variations in experienced interventional cardiologists in differentiating STEMI with a need for pPCI from NISTE. PMID- 21791330 TI - Relation of plasma levels of adiponectin to left ventricular diastolic dysfunction in patients undergoing cardiac catheterization for coronary artery disease. AB - In the present study, we hypothesized that hypoadiponectinemia and hyperleptinemia might be associated with left ventricular (LV) diastolic dysfunction. To test the hypothesis, we examined the relation of the plasma levels of adiponectin and leptin with the indexes of LV diastolic and systolic function (relaxation time constant, end-diastolic pressure, and ejection fraction) in 193 consecutive patients undergoing cardiac catheterization for coronary artery disease (age 69 +/- 9 years, 74% men; ejection fraction 68.4 +/- 9.9%). Regardless of gender, the adiponectin levels correlated negatively with the relaxation time constant and end-diastolic pressure, and the correlations remained significant after adjustment for potential confounders, including age, body mass index, heart rate, blood pressure, and coronary artery disease severity. Adiponectin levels did not significantly correlate with the ejection fraction in either men or women. The leptin levels did not significantly correlate with the indexes of LV diastolic or systolic function in either men or women. In conclusion, we found that decreased adiponectin levels were associated with LV diastolic dysfunction in patients with known or suspected coronary artery disease. PMID- 21791331 TI - Comparison of one-year outcome of patients aged <75 years versus >=75 years undergoing "rescue" percutaneous coronary intervention. AB - The influence of age on the clinical results after rescue angioplasty (percutaneous coronary intervention [PCI]) has been poorly investigated. In the present study, we evaluated the outcome of 514 consecutive patients undergoing rescue PCI who were divided into 2 groups according to age: <75 years (n = 469) and >=75 years (n = 45). The primary end point of the study was the incidence of death at 1 year of follow-up. The secondary end point was the 1-year incidence of major cardiac adverse events (MACE) defined as a composite of death, recurrent acute myocardial infarction, and target vessel revascularization. The predictors of death and MACE at 1 year were also investigated. At 1 year of follow-up, the <75-year-old group had a significantly lower incidence of death (7% vs 24%, p = 0.0001) and MACE (14% vs 28%, p = 0.01) compared to the >=75-year-old group. The Cox proportional hazards model identified age (adjusted hazard ratio 0.2665, 95% confidence interval 0.1285 to 0.5524, p = 0.0004), cardiogenic shock (hazard ratio 0.1057, 95% confidence interval 0.0528 to 0.2117, p <0.000001), Thrombolysis In Myocardial Infarction flow grade 2 to 3 after PCI versus 0 to 1 (hazard ratio 3.8380, 95% confidence interval 1.7781 to 8.2843, p = 0.0006), multi- versus single-vessel disease (hazard ratio 0.3716, 95% confidence interval 0.1896 to 0.7284, p = 0.0039) as independent predictors of survival at 1 year of follow-up. In conclusion, at 1 year of follow-up after rescue PCI, the patients aged >=75 years had a greater incidence of death and MACE compared to patients aged <75 years. Age, cardiogenic shock, Thrombolysis In Myocardial Infarction flow grade 0-1 after PCI, and multivessel coronary disease were predictors of survival and freedom from MACE at 1 year of follow-up. PMID- 21791332 TI - Comparison of long-term clinical and angiographic outcomes following implantation of bare metal stents and drug-eluting stents in aorto-ostial lesions. AB - Percutaneous coronary intervention (PCI) to aorto-ostial (AO) lesions is technically demanding and associated with high revascularization rates. The aim of this study was to assess outcomes after bare metal stent (BMS) compared to drug-eluting stent (DES) implantation after PCI to AO lesions. A retrospective cohort analysis was conducted of all consecutive patients who underwent PCI to AO lesions at 2 centers. Angiographic and clinical outcomes in 230 patients with DES from September 2000 to December 2009 were compared to a historical control group of 116 patients with BMS. Comparison of the baseline demographics showed more diabetics (32% vs 16%, p = 0.001), lower ejection fractions (52.3 +/- 9.7% vs 55.0 +/- 11.5%, p = 0.022), longer stents (17.55 +/- 7.76 vs 14.37 +/- 5.60 mm, p <0.001), and smaller final stent minimum luminal diameters (3.43 +/- 0.53 vs 3.66 +/- 0.63 mm, p = 0.001) in the DES versus BMS group. Angiographic follow-up (DES 68%, BMS 66%) showed lower restenosis rates with DES (20% vs 47%, p <0.001). At clinical follow-up, target lesion revascularization rates were lowest with DES (12% vs 27%, p = 0.001). Cox regression analysis with propensity score adjustment for baseline differences suggested that DES were associated with a reduction in target lesion revascularization (hazard ratios 0.28, 95% confidence interval 0.15 to 0.52, p <0.001) and major adverse cardiac events (hazard ratio 0.50, 95% confidence interval 0.32 to 0.79, p = 0.003). There was a nonsignificantly higher incidence of Academic Research Consortium definite and probable stent thrombosis with DES (n = 9 [4%] vs n = 1 [1%], p = 0.131). In conclusion, despite differences in baseline characteristics favoring the BMS group, PCI with DES in AO lesions was associated with improved outcomes, with lower restenosis, revascularization, and major adverse cardiac event rates. PMID- 21791333 TI - Prevalence, electrophysiological properties, and clinical implications of dissociated pulmonary vein activity following pulmonary vein antrum isolation. AB - The objective of this study was to investigate the prevalence, electrophysiologic properties, and clinical implications of dissociated pulmonary vein (PV) activity after PV antrum isolation (PVAI) in patients with paroxysmal atrial fibrillation (AF). One hundred seventy-three consecutive patients (61 +/-10 years old, 141 men) with drug-refractory paroxysmal AF who underwent AF ablation were analyzed. After identification of arrhythmogenic foci, PVAI was performed in all patients. Of the total 346 isolated ipsilateral PVs, 97 (28.0%) were silent, 35 (10.1%) demonstrated isolated ectopic beats, 209 (60.4%) demonstrated a regular ectopic rhythm, and 5 (1.4%) demonstrated fibrillatory activity. The culprit thoracic vein was identified in 77 patients (44.5%). After isolation of ipsilateral PVs, venous activity was observed in 68 (79.1%) and 178 (68.5%) PVs among the 86 PVs with AF triggers and 260 PVs without AF triggers, respectively (p = 0.06). There was no significant difference in the incidence of acute PV reconnections exposed by adenosine triphosphate between the 97 silent ipsilateral PVs and 209 ipsilateral PVs with dissociated PV activity after the PVAI (20.6% vs 19.1%, p = 0.78). After a mean follow-up of 48.7 +/- 7.9 months there was no significant difference in rates of freedom from atrial tachyarrhythmias after a single procedure between patients with and those without dissociated activity (62.1% vs 63.3%, p = 0.74, log-rank test). In conclusion, although dissociated PV activity appearing after PV isolation is an important electrophysiologic finding to prove bidirectional conduction block between the left atrium and the PV during the procedure, the clinical implications might be limited. PMID- 21791334 TI - Natural history, clinical consequences, and morphologic features of coronary arterial aneurysms in adults. AB - Clinical and morphologic features are described in 20 adults (15 men) aged 17 to 85 years (mean 56) who at necropsy were found to have >=1 aneurysm in >=1 of their 3 major (right, left anterior descending, and left circumflex) epicardial coronary arteries. Of the 34 coronary aneurysms in the 20 patients (single in 10 patients, >=2 in 10 patients), 27 (79%) contained intra-aneurysmal thrombi, and in each, the thrombus severely narrowed the lumen. Additionally, atherosclerotic plaque was present in the aneurysmal wall in all 27 aneurysms containing thrombi and also in the major coronary arteries uninvolved by aneurysm. The causes of the aneurysms in the 16 patients with intra-aneurysmal thrombi were therefore considered atherosclerotic. In the other 4 patients, with 7 aneurysms, none contained intra-aneurysmal thrombus or atherosclerotic plaque, and the aneurysms were considered congenital. Clinical diagnosis of coronary aneurysm was not made in any of the 20 patients, but none had proper imaging studies during life. Despite the coronary aneurysms and the associated luminal narrowing, only 8 patients (40%) had left ventricular wall scarring or necrosis or clinical evidence of myocardial ischemia. Proper therapy remains ill defined. PMID- 21791335 TI - Relation of homocysteinemia to contrast-induced nephropathy in patients undergoing percutaneous coronary intervention. AB - Hyperhomocysteinemia induces oxidative stress and endothelial dysfunction, which share the proposed pathophysiologic mechanisms of contrast-induced nephropathy (CIN). However, no study has investigated the relation between hyperhomocysteinemia and CIN. The aim of the present study was to evaluate the effects of hyperhomocysteinemia on CIN in patients undergoing percutaneous coronary intervention. This was an observational cohort study that included 572 patients who underwent percutaneous coronary intervention. CIN was defined as an absolute >=0.5 mg/dl or a relative >=25% increase in the serum creatinine level at 48 hours after the procedure. The incidence of CIN was significantly greater in patients in the third homocysteine tertile (from lowest to highest, 4.7%, 7.3%, and 24.2%, p <0.001). Furthermore, the homocysteine levels were significantly greater in patients with CIN than in those without CIN (16.9 +/- 4.9 vs 13.5 +/- 4.2 MUmol/L, p <0.001). In multiple logistic regression models, hyperhomocysteinemia was an independent risk factor for CIN (per the SD change in the plasma homocysteine level [4.44 MUmol/L], odds ratio 1.70, 95% confidence interval 1.07 to 2.71, p = 0.025) after adjusting for major risk factors such as age, diabetes, and baseline cardiac and renal function. In subgroup analyses according to diabetes, acute coronary syndrome, or baseline estimated glomerular filtration rate, significant, graded associations were found between the homocysteine level and the incidence of CIN. In conclusion, hyperhomocysteinemia is independently associated with a greater risk of CIN in patients undergoing percutaneous coronary intervention. PMID- 21791336 TI - Heterosexual pedophilia in a frontotemporal dementia patient with a mutation in the progranulin gene. PMID- 21791338 TI - Metabolic study of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone to the enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in vitro in human bronchial epithelial cells using chiral capillary electrophoresis. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) with one chiral center at the carbinol is a major metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK). As tobacco specific N-nitrosamines (TSNAs), NNK and NNAL are the most pulmonary carcinogens in tobacco products and smoke. In this paper, a chiral CE method modified with highly sulfated beta-cyclodextrin (S-beta-CD) was developed to investigate the stereoselective formation of NNAL from NNK in vitro in normal human bronchial epithelial (NHBE) cells. Combined with solid phase extraction (SPE) of the cell samples, NNK and NNAL enantiomers were baseline separated under the proposed CE conditions, with satisfactory recoveries (72.5 113% for NNK and (+/-)-NNAL) and low limits of detection (LOD, 2.5-3 MUg/mL for NNK and (+/-)-NNAL). The cytotoxicity of NNK in NHBE cells was investigated through the cell counting kit (CCK) assay and proved to be highly dependent on the NNK's concentration. The metabolic results obtained from CE analysis demonstrated that NNK was preferentially metabolized to (+)-NNAL through carbonyl reduction. Meanwhile, the ratio of [(+)-NNAL]/[(-)-NNAL] was independent of NHBE cells' incubation time with NNK, but could be changed according to the original incubation concentration of NNK. This chiral CE method could be useful for the study on toxicology and metabolic transformations of related TSNAs. PMID- 21791337 TI - Proteomics and metabolomics analysis of a trait anxiety mouse model reveals divergent mitochondrial pathways. AB - BACKGROUND: Although anxiety disorders are the most prevalent psychiatric disorders, no molecular biomarkers exist for their premorbid diagnosis, accurate patient subcategorization, or treatment efficacy prediction. To unravel the neurobiological underpinnings and identify candidate biomarkers and affected pathways for anxiety disorders, we interrogated the mouse model of high anxiety related behavior (HAB), normal anxiety-related behavior (NAB), and low anxiety related behavior (LAB) employing a quantitative proteomics and metabolomics discovery approach. METHODS: We compared the cingulate cortex synaptosome proteomes of HAB and LAB mice by in vivo (15)N metabolic labeling and mass spectrometry and quantified the cingulate cortex metabolomes of HAB/NAB/LAB mice. The combined data sets were used to identify divergent protein and metabolite networks by in silico pathway analysis. Selected differentially expressed proteins and affected pathways were validated with immunochemical and enzymatic assays. RESULTS: Altered levels of up to 300 proteins and metabolites were found between HAB and LAB mice. Our data reveal alterations in energy metabolism, mitochondrial import and transport, oxidative stress, and neurotransmission, implicating a previously nonhighlighted role of mitochondria in modulating anxiety-related behavior. CONCLUSIONS: Our results offer insights toward a molecular network of anxiety pathophysiology with a focus on mitochondrial contribution and provide the basis for pinpointing affected pathways in anxiety related behavior. PMID- 21791339 TI - Chiral separation of basic compounds on a cellulose 3,5-dimethylphenylcarbamate coated zirconia monolithin basic eluents by capillary electrochromatography. AB - Porous zirconia monolith (ZM) modified with cellulose 3,5-dimethylphenylcarbamate (CDMPC) was used as chiral stationary phase to separate basic chiral compounds in capillary electrochromatography. The electroosmotic flow behavior of bare and CDMPC-modified zirconia monolithic (CDMPC-ZM) column was studied in ACN/phosphate buffer eluents of pH ranging from 2 to 12. The CDMPC-ZM column was evaluated by investigating the influences of pH, the type and composition of organic modifier of the eluent on enantioseparation. CEC separations at pH 9 provided the best resolutions for the analytes studied, which are better than those observed on CDMPC-modified silica monolithic columns under similar chromatographic conditions. No appreciable decline in retention and resolution factors after over 200 injections, and run-to-run and day-to-day repeatabilities of the column of less than 3% indicate the stability of the zirconia monolithic column in basic media. PMID- 21791340 TI - Simultaneous determination of perfluoroalkyl phosphonates, carboxylates, and sulfonates in drinking water. AB - A trace analytical method based on high performance liquid chromatography coupled to quadrupole time-of-flight high resolution mass spectrometry was developed for simultaneous determination of perfluoroalkyl phosphonates (PFPAs, carbon chain lengths C6,8,10), perfluoroalkyl carboxylates (PFCAs, C5-12), and perfluoroalkyl sulfonates (PFSAs, C4,6,8,10) in drinking water (tap water). Analytes were enriched on a mixed mode co-polymeric sorbent (C8+quaternary amine) using solid phase extraction. Chromatographic separation was achieved on a Zorbax Extend C18 reversed phase column using a mobile phase gradient consisting of water, methanol, and acetonitrile containing 2mM ammonium acetate and 5 mM 1-methyl piperidine. The mass spectrometer was operated in electrospray negative ion mode. Use of 1-methyl piperidine in the mobile phase resulted in a significant increase in instrument sensitivity for PFPAs through improved chromatographic resolution, background suppression, and increased ionization efficiency. Method detection limits for extraction of 500 mL tap water were in the ranges of 0.095-0.17 ng/L, 0.027-0.17 ng/L, and 0.014-0.052 ng/L for PFPAs, PFCAs, and PFSAs, respectively. Whole method recoveries at a spiking level of 0.5 ng/L to 500 mL HPLC grade water were 40-56%, 56-97%, and 55-77% for PFPAs, PFCAs, and PFSAs, respectively. A matrix effect (signal enhancement) was observed in the detection of PFPAs in tap water extracts, leading to calculated recoveries of 249-297% at a 0.5 ng/L spiking level. This effect resulted in an additional improvement of method sensitivity for PFPAs. To compensate for the matrix effect, PFPAs in tap water were quantified using matrix-matched and extracted calibration standards. The method was successfully applied to the analysis of drinking water collected from six European countries. PFPAs were not detected except for perfluorooctyl phosphonate (PFOPA) at close to the detection limit of 0.095 ng/L in two water samples from Amsterdam, the Netherlands. Highest levels were found for perfluorobutane sulfonate (PFBS, 18.8 ng/L) and perfluorooctanoate (PFOA, 8.6 ng/L) in samples from Amsterdam as well as for perfluorooctane sulfonate (PFOS, 8.8 ng/L) in tap water from Stockholm, Sweden. PMID- 21791341 TI - Simultaneous determination of thirteen polycyclic aromatic hydrocarbons and twelve aldehydes in cooked food by an automated on-line solid phase extraction ultra high performance liquid chromatography tandem mass spectrometry. AB - An on-line solid phase extraction (SPE) ultra high performance liquid chromatography tandem mass spectrometry method has been developed for the simultaneous identification and determination of thirteen polycyclic aromatic hydrocarbons (PAHs) and twelve aldehydes (derivatized with 2,4 dinitrophenylhydrazine). The chromatographic conditions have been optimized to obtain the maximum of sensitivity and resolution taking into account the different retention interactions and the different ionization conditions of PAHs and derivatized aldehydes. LOD values ranging from 0.028 to 0.768 MUg L(-1) for PAHs and from 0.002 to 0.125 MUg L(-1) for aldehydes were obtained. The resolution permitted the separation of four couples of PAH isomers. Sample pre treatment and SPE were optimized in order to apply the whole methodology to the analysis of different food matrices as salmon, frankfurter, steak, and pork chop, subjected to different cooking modes (smoked, grilled, cooked in oil or in butter). Particular attention was devoted to the evaluation of matrix effect that was significantly reduced through the on-line SPE treatment. For each food matrix the method detection limits, the method quantitation limits, and the recovery R were evaluated. R was shown not to depend on analyte concentration in the explored concentration range (LOQ - 50.000 MUg L(-1)): the average R percent ranges from 70.6% to 120.0%. PMID- 21791342 TI - A phase II clinical trial of neoadjuvant ketoconazole and docetaxel chemotherapy before radical prostatectomy in high risk patients. AB - PURPOSE: Patients with high risk prostate cancer (prostate specific antigen greater than 20 ng/ml, Gleason score greater than 7, or clinical stage T2b or greater) have been shown to have a 30% to 40% biochemical recurrence rate after definitive local therapy. Looking for improvement on these outcomes, we conducted a phase II clinical trial examining the combination of ketoconazole and docetaxel in the neoadjuvant setting before radical prostatectomy. MATERIALS AND METHODS: A total of 22 patients with clinically localized, high risk prostate cancer were enrolled in the study. For 12 weeks they were treated with neoadjuvant docetaxel and ketoconazole, with dosing based on phase I data. Patients were monitored for tolerance of therapy and dosing adjustments were made for significant toxicities. Radical prostatectomy with extended lymph node dissection was subsequently performed and patients were followed postoperatively for biochemical recurrence. RESULTS: At a median followup of 18 months 8 patients remained biochemically free of recurrence after surgery alone. An additional 6 patients received salvage therapy and had an undetectable prostate specific antigen. Of the 22 patients 16 experienced National Cancer Institute grade 3 or 4 toxicity at some point during the therapy. However, 16 patients completed all 4 cycles of chemotherapy. CONCLUSIONS: Neoadjuvant ketoconazole combined with docetaxel has appreciable but acceptable toxicity with 73% of the patients completing all 4 courses of therapy. Of those who underwent radical prostatectomy 36% remained continuously biochemically free of recurrence at a median followup of 18 months. PMID- 21791344 TI - Urinating in the standing position: a feasible alternative for elderly women with knee osteoarthritis. AB - PURPOSE: Urinating while standing is a possible alternative for elderly women with knee osteoarthritis when a sitting toilet is unavailable. We evaluated uroflowmetric characteristics and post-void residual urine volume in elderly women with knee osteoarthritis who urinated while standing. MATERIALS AND METHODS: We recruited 21 women with a mean+/-SD age of 65.0+/-4.6 years who had a knee osteoarthritis Lequesne index score of at least 6 points and were unable to maintain or found it difficult to stand up from a squat or crouch. Participants used a homemade auxiliary appliance to collect urine and drain it forward while stand voiding. Uroflowmetric data, including voided volume, and maximal and average flow rates, were recorded. Post-void residual urine volume was detected using an ultrasound bladder scanner. Participants completed a questionnaire to evaluate their attitude toward stand voiding and using the auxiliary device. RESULTS: Maximal and average flow rates, and voided and post-void residual urine volumes were not statistically different while sitting and standing. No learning curve was noted for stand voiding. Uroflowmetry patterns while standing were smooth. Of the 21 participants 17 (81%) experienced no difficulty while stand voiding. All expressed willingness to urinate while standing position if they did not have access to a satisfactorily clean toilet seat. CONCLUSIONS: Urinating while standing is a feasible option for elderly women with knee osteoarthritis who have difficulty crouching or squatting to void in public restrooms. PMID- 21791345 TI - Selective arterial embolization of angiomyolipomas: a comparison of smaller and larger embolic agents. AB - PURPOSE: Selective transarterial embolization for renal angiomyolipomas is effective in preventing or limiting hemorrhage and preserving normal parenchyma. Data are insufficient regarding the safety and efficacy of embolic agents. We compared transarterial embolization of angiomyolipomas using embolic agents of different sizes. MATERIALS AND METHODS: We performed a retrospective review of all transarterial angiomyolipoma embolizations from 1999 to 2010, and evaluated demographics, procedural data, embolization response and outcomes comparing smaller (less than 150 microns) and larger (more than 150 microns) embolic agents. RESULTS: Overall 48 patients underwent 66 embolization procedures for 72 angiomyolipomas. Smaller agents were used more commonly (58%). Age, gender, indications, pre-embolization angiomyolipoma size and prevalence of tuberous sclerosis were similar between the groups. Angiomyolipomas decreased a mean+/-SD 25%+/-18% after embolization with no differences between the groups (p=0.24). There were 10 angiomyolipomas that required 14 repeat embolizations (median 14 months). Repeat embolization of the same mass was almost sixfold more likely in those embolized with smaller agents (OR 5.88, 95% CI 1.64-20.8, p=0.002). Complications were similar between the groups, although 2 of 3 patients with acute respiratory distress underwent embolization with smaller agents. Patients with tuberous sclerosis had similar angiomyolipoma size, decrease in angiomyolipoma size, followup, complications and need for repeat embolization. Practice patterns changed regarding embolization agent size during the study period. CONCLUSIONS: Angioembolization with larger embolic agents is associated with higher long-term efficacy compared to smaller agents. Due to concerns for serious pulmonary complications, we no longer use agents smaller than 150 microns. Prospective studies are necessary to evaluate the optimal embolization technique to achieve durable outcomes without increasing patient morbidity. PMID- 21791346 TI - Methods of developing UWIN, the modified American Urological Association symptom score. AB - PURPOSE: The American Urological Association symptom score instrument is widely used to assess lower urinary tract symptom severity in men. We describe the methods used to develop a shorter form of the American Urological Association symptom score that may provide symptom score assessment with minimal compromise in accuracy. MATERIALS AND METHODS: Complete American Urological Association symptom score data were collected on 8,731 men who attended Prostate Cancer Awareness Week in 2003 or 2004. Correlation analysis and area under the ROCs were used to determine the best reduced index and cutoff points in scores for the severity categories of mild, moderate and severe. RESULTS: The number of responses in the original 7 American Urological Association symptom score items was lowered from 6 to 4 and for the bothersome index it was lowered from 7 to 3. Four of the original 7 items were retained. Cronbach's alpha was 0.851 for the symptom score items in our data. The combination of items with the best joint correlation to the American Urological Association symptom score and bothersome score was UWIN (urgency, weak stream, incomplete emptying and nocturia). The correlation of UWIN with the American Urological Association symptom score was 0.938. The correlation of UWIN bother to the American Urological Association bothersome score was 0.638. The ROC for the mild, moderate and severe UWIN categories compared to the categorized American Urological Association symptom score was 0.96, 0.97 and 0.99, respectively. CONCLUSIONS: The UWIN instrument may potentially be a valuable tool to assess American Urological Association symptom score severity and bother. Clinical validation of this instrument is indicated in a prospective comparative study. PMID- 21791347 TI - 1-stage repair of obliterative distal urethral strictures with buccal graft urethral plate reconstruction and simultaneous onlay penile skin flap. AB - PURPOSE: When penile skin is available, onlay flap reconstruction is an excellent choice for 1-stage repair of complex hypospadias and strictures involving the glans, fossa navicularis and penile urethra. When the urethra is deficient circumferentially, tube flaps are an option but there is a high failure rate. We report our 8-year experience with 1-stage reconstruction using a dorsal buccal mucosa graft to reconstruct the deficient urethral plate with repair completed using an onlay penile skin flap. MATERIALS AND METHODS: A total of 12 patients with a mean age of 42.8 years (range 16 to 77) underwent dorsal buccal grafting with ventral skin flap repair. Buccal mucosa was quilted to the penile ventral corpora to reconstruct the dorsal urethral aspect. Most surgeries included buccal graft reconstruction of the glans and fossa navicularis. Onlay penile skin flap repair was then performed to complete the reconstruction. RESULTS: All 12 patients were free of disabling chordee or urethral stricture disease at a mean 39-month followup (range 7 to 96). In 1 patient a small urethrocutaneous fistula developed, which was repaired. In another patient a fistula and medium caliber fossa navicularis narrowing developed with associated chordee, which were successfully repaired. CONCLUSIONS: Dorsal buccal grafting with ventral flap reconstruction appears to be an excellent option to repair circumferential urethral deficiency when penile skin is available, especially when chordee correction with distal urethral plate reconstruction is required. PMID- 21791348 TI - Illinois statewide dual kidney transplantation experience--are we appropriately selecting kidneys? AB - PURPOSE: Dual kidney transplantation is a technique that some transplant centers have adopted to increase organ use. We investigated whether kidneys that were recovered and discarded were similar to those kidneys used for dual kidney transplantation. MATERIALS AND METHODS: We reviewed all kidneys recovered, biopsied and placed on machine perfusion in the state of Illinois from January 2002 to October 2009. We selected those kidneys used in dual kidney transplant, and compared their characteristics to those of kidneys that were recovered and biopsied but ultimately discarded. The immediate and 1-year outcomes of the dual kidney transplant recipients were analyzed. RESULTS: During the study period 60 dual transplants were performed while 94 kidney pairs were discarded. Overall donors from the used group had a lower mean creatinine clearance, older mean patient age, lower percentage of glomerulosclerosis, higher final flow rate and lower resistance. However, the comparison between those kidneys used successfully with 1-year graft survival and those discarded demonstrated only 3 less favorable parameters among the discarded group, namely a higher percentage of glomerulosclerosis (18.5% vs 13.9%, p=0.024), a higher degree of interstitial fibrosis and a higher final resistance (0.39 vs 0.31, p<0.001). CONCLUSIONS: The considerable overlap in demographics, histology and perfusion parameters between used and discarded kidneys suggests that many kidneys that were recovered and discarded could have been used in dual kidney transplantation with acceptable outcomes. This highlights the need for further study of how kidneys are selected and used. PMID- 21791349 TI - Editorial comment. PMID- 21791350 TI - Outcomes and complications after 532 nm laser prostatectomy in anticoagulated patients with benign prostatic hyperplasia. AB - PURPOSE: Patients on anticoagulation are at high risk for bleeding after electrocautery transurethral resection of the prostate or open prostatectomy and they are often denied surgery for symptomatic benign prostatic hyperplasia. Using photoselective vaporization of the prostate, patients at high risk may safely undergo surgery. We explored outcomes and complications after photoselective vaporization of the prostate in an anticoagulated, high risk cohort. MATERIALS AND METHODS: Between 2002 and 2008, 162 men on systemic anticoagulation underwent photoselective vaporization of the prostate. Data were collected on demographics, comorbidities, complications, serum sodium, hematocrit, maximum flow rate, post void residual urine, International Prostate Symptom Score and complications. RESULTS: Mean+/-SD age was 72+/-8 years, mean baseline prostate volume was 91+/ 49 gm and mean prostate specific antigen was 4.1+/-5 ng/ml. Of the patients 31 (19%) were on warfarin, 101 (62%) were on acetylsalicylic acid, 19 (12%) were on clopidogrel and 11 (7%) were on 2 or more anticoagulants. Median American Society of Anesthesiologists class was 3 and mean Charlson comorbidity index was 5. Median operative time was 105 minutes and mean energy use was 280+/-168 kJ. The immediate mean hematocrit decrease was 1.94%+/-2.42%. One patient who received excessive intravenous fluids experienced heart failure. Complications within 30 days included urinary tract infection in 4 patients (2.5%) and delayed bleeding in 6 (4%). Three of these patients (50%) required blood transfusion and 1 (17%) required reoperation. In 2 years of followup 3 patients (2%) required repeat photoselective vaporization of the prostate. No incontinence or urethral stricture developed. Significant improvements occurred in International Prostate Symptom Score, maximum flow rate and post-void residual urine. CONCLUSIONS: Results support using 532 nm photoselective vaporization of the prostate in patients at high risk on systemic anticoagulation, even those on 2 or more anticoagulation agents and with a large prostate requiring longer operative time. Few complications developed and significant durable clinical improvement was seen. PMID- 21791351 TI - Botulinum toxin type A in patients with Parkinson's disease and refractory overactive bladder. AB - PURPOSE: In this 6-month followup study we investigated the effect of intradetrusor injection of 100 U botulinum toxin type A in patients with Parkinson's disease and refractory detrusor overactivity. MATERIALS AND METHODS: Eight patients with Parkinson's disease and detrusor overactivity refractory to anticholinergics were injected with 100 U botulinum toxin type A. Daytime and nighttime urinary frequency, and urinary incontinence episodes were recorded. Patients also completed a standardized quality of life questionnaire on incontinence and a visual analog scale on the impact of bladder problems on daily life activities, and underwent urodynamic assessment, including pressure flow studies. Clinical and urodynamic assessment was performed before, and 1, 3 and 6 months after injection. RESULTS: In all patients 100 U botulinum toxin type A induced decreased daytime and nighttime urinary frequency, a decreased number of urinary incontinence episodes, increased quality of life scores and, as shown by increased maximum cystometric capacity, improved urodynamic findings. In 2 patients with Parkinson's disease post-void residual urine volume developed. CONCLUSIONS: Intradetrusor injection of 100 U botulinum toxin type A induced clinical and urodynamic improvement in overactive bladder symptoms that lasted at least 6 months in patients with Parkinson's disease. PMID- 21791352 TI - Benign prostatic hyperplasia evaluation and management by urologists and primary care physicians: practice patterns from the observational BPH registry. AB - PURPOSE: We examined the evaluation of and management for lower urinary tract symptoms/benign prostatic hyperplasia by physician specialty (urologist vs primary care physician). MATERIALS AND METHODS: The BPH Registry and Patient Survey is a longitudinal, observational, disease registry cohort of patients enrolled from January 2004 to February 2005 in the United States. The survey examines patient outcomes and physician practice patterns in the management of lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. It includes 402 urologist and primary care physician practices throughout the United States. Included in this study were 6,924 men with lower urinary tract symptoms/benign prostatic hyperplasia managed by watchful waiting or medical therapy. Data were collected on demographics, clinical characteristics and lower urinary tract symptoms/benign prostatic hyperplasia management using physician and patient completed forms. Multivariate analysis was done by physician specialty. RESULTS: Based on multivariate analysis urologists were more likely than primary care physicians to perform urinalysis (OR 3.9), serum prostate specific antigen (OR 1.2) and post-void residual urine (OR 18.9) measurement, uroflowmetry (OR 17.3), prostate ultrasound (OR 7.7) and biopsy (OR 3.5), renal ultrasound (OR 4.0) and cystoscopy (OR 4.6) but less likely to measure creatinine (OR 0.1). Men seeing urologists were twice as likely as men seeing primary care physicians to be treated with benign prostatic hyperplasia medical therapy vs watchful waiting. Significant differences by physician specialty were also observed for specific benign prostatic hyperplasia medical therapies. CONCLUSIONS: Significant differences in practice patterns were observed between primary care physicians and urologists in the evaluation of and management for lower urinary tract symptoms/benign prostatic hyperplasia. These data establish valuable benchmarks and identify possible interventions that may improve the standard of care. PMID- 21791353 TI - The incidence of urolithiasis among commercial aviation pilots. AB - PURPOSE: A kidney stone event in a commercial aviation pilot has significant vocational implications since the Federal Aviation Administration specifically prohibits medical certification in the setting of recent or recurrent stone disease. Given these serious concerns, an understanding of the burden of stone disease on the commercial aviation community is important. Thus, we performed a study in partnership with the Federal Aviation Administration to better characterize the epidemiology of this condition. MATERIALS AND METHODS: We reviewed the Federal Aviation Administration Aerospace Medical Certification database for 2000 through 2007. Pilots with a class I certificate (scheduled commercial aviation) were selected for further review. All medical certificates submitted with a pathology code of 573 (urolithiasis) were identified for analysis. RESULTS: From 2000 through 2007 between 3.7% and 4.6% of scheduled commercial aviation pilots were diagnosed with urolithiasis. However, during the study period there was a significant decrease in the proportion of pilots diagnosed with urolithiasis. CONCLUSIONS: A meaningful number of commercial aviation pilots are affected by urolithiasis each year. Our analysis detected a significant decrease in the proportion of affected pilots, although the reason for this trend is not well understood. It may be that changes in the occupational environment that could affect risk factors for stone formation are responsible. Further efforts to characterize stone risk in this unique population are welcome, given the larger vocational and societal consequences of a stone event in the setting of airline transport. PMID- 21791354 TI - Greater endothelial dysfunction and arterial stiffness in men with chronic prostatitis/chronic pelvic pain syndrome--a possible link to cardiovascular disease. AB - PURPOSE: Men with chronic prostatitis/chronic pelvic pain syndrome have higher self-reported rates of cardiac disease than controls. Peripheral arterial tone abnormalities correlate with cardiac disease and mortality. We studied vascular dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome and controls. MATERIALS AND METHODS: A total of 21 men with chronic prostatitis/chronic pelvic pain syndrome and 14 asymptomatic controls were tested with an Endo-PAT(r)2000 machine which assessed the augmentation index, a measure of arterial stiffness, and reactive hyperemia index, a measure of endothelial vasodilation. Symptoms were measured with the National Institutes of Health Chronic Prostatitis Symptom Index and patient phenotype was characterized by the UPOINT (Urinary, Psychosocial, Organ Specific, Infection, Neurologic/Systemic, Tenderness of Skeletal Muscles) system. Statistical significance was set at p<0.05. RESULTS: Age was similar in the chronic prostatitis/chronic pelvic pain syndrome group (range 22 to 63 years, median 40) and controls (range 19 to 57, median 40). Patients had median symptom duration of 24 months (range 3 to 440), a mean Chronic Prostatitis Symptom Index score of 24.7+/-5.1 and mean UPOINT domains of 2.9+/-1.1 (range 1 to 5). The augmentation index was significantly higher (greater arterial stiffness) in patients with chronic pelvic pain syndrome vs controls (5.0%+/-2.3 vs -6.0%+/-3.0, p=0.006). The reactive hyperemia index was significantly lower (more endothelial dysfunction) in patients with chronic pelvic pain syndrome (1.76+/-1.2 vs 2.21+/-1.7, p=0.03). There was no correlation between symptom duration, severity or phenotype (number or type of UPOINT domains) and reactive hyperemia index or augmentation index. CONCLUSIONS: Men with chronic prostatitis/chronic pelvic pain syndrome have evidence of increased arterial stiffness and vascular endothelial dysfunction. This is the first mechanistic correlation found that links the higher incidence of self-reported cardiac disease in these patients. Noninvasive Endo-PAT testing may allow stratification of cases of chronic prostatitis/chronic pelvic pain syndrome by vascular dysfunction, which may require specific treatment or at least further assessment of cardiac risk. PMID- 21791355 TI - Sacral neuromodulation as treatment for refractory idiopathic urge urinary incontinence: 5-year results of a longitudinal study in 60 women. AB - PURPOSE: We evaluated the results of sacral neuromodulation after 5-year followup in women with refractory idiopathic urge urinary incontinence. MATERIALS AND METHODS: A neuromodulation system with an original (nontined) lead was implanted by open surgery after a positive percutaneous nerve evaluation in 60 women from 1990 to 2004. Voiding incontinence diary parameters were used to evaluate efficacy. Success was defined as at least a 50% decrease in the number of incontinence episodes or pads used daily. Safety was also evaluated. RESULTS: The success rate gradually decreased from 52 patients (87%) at 1 month to 37 (62%) at 5 years. Complete continence persisted in 15% of patients. The system was still used by 80% of patients at 5 years. In 32 patients a total of 57 adverse events occurred, which were not severe (Clavien grade I and IIIb in 61% and 39%, respectively). CONCLUSIONS: Sacral neuromodulation appears to be a safe technique for refractory idiopathic urge urinary incontinence in women. The success rate gradually decreased to 62% after 5 years with 15% of patients completely continent. PMID- 21791357 TI - Validation of the modified American Urological Association symptom score. AB - PURPOSE: We created a shorter version of the American Urological Association symptom score, called UWIN (urgency, weak stream, incomplete emptying and nocturia). MATERIALS AND METHODS: Participants in Prostate Cancer Awareness Week from 2006 and 2007 were administered the regular American Urological Association symptom score and UWIN. A total of 278 participants completed each questionnaire. Total scores of each participant for the American Urological Association symptom score (range 0 to 35) and UWIN (range 0 to 12) were evaluated using Spearman's correlation coefficients and Bland-Altman plots to determine the level of agreement between the 2 questionnaires. RESULTS: The correlation between the total American Urological Association symptom score (range 0 to 35) and the total UWIN score (range 0 to 12) was 0.913 (p<0.0001). The correlation between the quality of life question on the American Urological Association symptom score and UWIN was 0.821 using the Spearman correlation coefficient (p<0.0001). A second analysis performed using Bland-Altman plots showed good agreement between the American Urological Association symptom score and UWIN. Overall, respondents tended to have slightly higher UWIN total scores than their American Urological Association symptom scores. CONCLUSIONS: This study validates that the UWIN questionnaire can be used in place of the American Urological Association symptom score. The UWIN questionnaire will lessen the burden on the respondent, broaden the applicability of the instrument and make collecting data as efficient and effective as possible. PMID- 21791356 TI - Effects of 100 and 300 units of onabotulinum toxin A on lower urinary tract symptoms of benign prostatic hyperplasia: a phase II randomized clinical trial. AB - PURPOSE: We conducted a 2-stage, multicenter, double-blind, randomized phase II clinical trial of 100 and 300 unit doses of onabotulinum toxin A to treat the lower urinary tract symptoms of benign prostatic hyperplasia. MATERIALS AND METHODS: Men 50 years old or older with clinically diagnosed benign prostatic hyperplasia, American Urological Association symptom index 8 or greater, maximum urinary flow rate less than 15 ml per second, voided volume 125 ml or greater, and post-void residual 350 ml or less were randomized to prostatic transrectal injection of 100 or 300 units of onabotulinum toxin A. The primary outcome was at least 30% improvement from baseline to 3 months in American Urological Association symptom index and/or maximum urinary flow rate and safety. The men were followed for 12 months. RESULTS: A total of 134 men were randomized and treated (68 with 100 units, 66 with 300 units), with 131 assessed at 3 months and 108 assessed at 12 months. Each dose met the 3-month primary outcome criteria. In the 100 unit arm the mean baseline American Urological Association symptom index of 18.8 decreased by 7.1 and 6.9 at 3 and 12 months, respectively. In the 300 unit arm the baseline of 19.5 decreased by 8.9 and 7.1, respectively. In the 100 unit arm the mean baseline maximum urinary flow rate of 10.0 ml per second increased by 2.5 and 2.2, respectively, and in the 300 unit arm the baseline of 9.6 increased by 2.6 and 2.3, respectively. CONCLUSIONS: The intraprostatic injection of 100 or 300 units of onabotulinum toxin A passed predetermined criteria for treatment efficacy and safety, and a randomized trial with either dose is warranted. The 100 unit dose may be preferable due to similar efficacy with reduced costs and adverse effects. PMID- 21791358 TI - Post-prostatectomy incontinence during sexual activity: a single center prevalence study. AB - PURPOSE: The prevalence and mechanism of incontinence during sexual activity after radical prostatectomy has not been well described. We determined the prevalence and severity of incontinence during sexual activity with time and the relationship between incontinence during sexual activity and stress urinary incontinence in the absence of sexual activity. MATERIALS AND METHODS: A total of 1,459 men with prostate cancer underwent radical prostatectomy between October 2000 and December 2007, as performed by 1 surgeon. Patients completed UCLA-PCI preoperatively, and 3, 6, 12 and 24 months postoperatively. We analyzed the frequency distribution of incontinence during sexual activity and stress urinary incontinence with time. We also examined the relationship between incontinence during sexual activity and stress urinary incontinence by chi-square analysis. RESULTS: The percent of patients who reported any bother from incontinence during sexual activity was 44.4% at 3 months, which decreased to 36.1% at 24 months. The percent of patients reporting major bother from incontinence during sexual activity was 22.4% and 12.1% at 3 and 24 months, respectively. Bother from incontinence during sexual activity and from stress urinary incontinence were strongly associated at all times (p<0.001). More than half of the men with major bother due to incontinence during sexual activity also reported bother from stress urinary incontinence. However, more than 10% of those with no stress urinary incontinence problem reported major bother from incontinence during sexual activity. CONCLUSIONS: Incontinence during sexual activity is a persistent problem for some men after radical prostatectomy. Significant incontinence during sexual activity may occur in the absence of stress urinary incontinence during nonsexual activities. Effective management of this problem requires further investigation. PMID- 21791359 TI - Is there a role for alpha-blockers in ureteral stent related symptoms? A systematic review and meta-analysis. AB - PURPOSE: We evaluated the efficacy of alpha-blockers to improve ureteral stent related morbidity and quality of life. MATERIALS AND METHODS: We performed a search of MEDLINE(r), EmbaseTM and The Cochrane Library plus a hand search of conference proceedings from January 2000 to October 2010 to identify randomized, controlled trials comparing treatment for ureteral stent symptoms with alpha blockers. Two reviewers independently screened studies and extracted data. Trial methodological quality was assessed by The Cochrane Collaboration quality assessment tool. Placebo randomized, controlled trials with the ureteral stent symptom questionnaire as the outcome were eligible for meta-analysis. Meta analysis was done using the mean difference to determine the aggregate effect size. RESULTS: A total of 12 randomized, controlled trials including 2 alpha blockers in a total of 946 patients were eligible, including 4 (33%) presented only as an abstract at a urological meeting and 4 (33%) eligible for meta analysis. Meta-analysis using a random effects model showed that alpha-blockers were associated with a significant decrease in urinary symptoms (MD -6.76, 95% CI -11.52 to -2.00, p=0.005), a significant decrease in pain (MD -3.55, 95% CI -5.51 to -1.60, p=0.0004) and significant improvement in general health (MD -1.90, 95% CI -3.05 to -0.75, p=0.001). However, they were not associated with a benefit in work (MD 2.41, 95% CI -1.62 to 6.44, p=0.24) or sexual matters (MD 0.20, 95% CI 1.06 to 1.45, p=0.33). Eight studies were not included in the meta-analysis, of which 7 showed a significant clinical decrease in urinary symptoms and pain. CONCLUSIONS: Existing evidence from randomized, controlled trials shows that alpha-blockers are associated with improvement in ureteral stent symptoms and supports their use in routine clinical practice. PMID- 21791360 TI - Human papillomavirus type 16 E6 inhibits p21(WAF1) transcription independently of p53 by inactivating p150(Sal2). AB - HPV16 E6 deregulates G1/S cell cycle progression through p53 degradation preventing transcription of the CDK inhibitor p21(WAF1). However, additional mechanisms independent of p53 inactivation appear to exist. Here, we report that HPV16 E6 targets the cellular factor p150(Sal2), which positively regulates p21(WAF1) transcription. HPV16 E6 associates with p150(Sal2), inducing its functional inhibition by preventing its binding to cis elements on the p21(WAF1) promoter. A HPV16 E6 mutant, L110Q, which was unable to bind p150(Sal2), did not affect the ability of the cellular protein to bind p21(WAF1) promoter, underlining the linkage between these events. These data describe a novel mechanism by which HPV16 E6 induces cell cycle deregulation with a p53 independent pathway. The viral oncoprotein targets p150(Sal2), a positive transcription regulator of p21(WAF1) gene, preventing G1/S arrest and allowing cellular proliferation and efficient viral DNA replication. PMID- 21791361 TI - Prostate specific antigen velocity per prostate volume: a novel tool for prostate biopsy prediction. AB - OBJECTIVE: To investigate whether altered prostate specific antigen (PSA) levels due to individual prostate growth may affect the PSA velocity (PSAV). MATERIALS AND METHODS: Between January 2000 and December 2009, a total of 159 men with at least 2 transrectal ultrasonography (TRUS) procedures and concurrent PSA measurements underwent prostate biopsy because of suspicion of prostate cancer. We measured PSAV, prostate volume velocity (PVV), PSA density (PSAD), PSAD velocity (PSADV), and PSAV per initial volume. We then classified the total group into a prostate cancer (PC) group and non-PC group, and compared the 2 groups. We investigated which variables were exact to predict prostate biopsy using univariate and multivariate analyses, and assessed the diagnostic performance using the receiver operating characteristic (ROC) curve. RESULTS: PVV showed a positive correlation with initial prostate volume in the total and non-PC group; PVV showed a positive correlation with PSAV, and initial prostate volume correlated with PSAV in the non-PC group. The PC group showed smaller prostate volumes, higher PSAD, higher PSADV, higher PSAV per initial volume, and longer follow-up periods. After adjusting for confounding factors, the odds ratios of prostate cancer across the quartile of PSAVD were 1, 1.889, 3.226, and 7.125 (P for trend = .007), and PSAV per initial volume were 1, 2.924, 2.937, and 7.536 (P for trend = .031). On the ROC curve, the areas under the curves (AUC) of PSAV per initial volume were higher than for PSAV and PSADV. CONCLUSION: Altered PSA levels due to individual prostate growth may affect the use of PSAV to predict prostate biopsy outcomes in follow-up. PMID- 21791362 TI - Executive functions and neurocognitive aging: dissociable patterns of brain activity. AB - Studies of neurocognitive aging report altered patterns of brain activity in older versus younger adults performing executive function tasks. We review the extant literature, using activation likelihood estimation meta-analytic methods, to compare age-related differences in the pattern of brain activity across studies examining 2 categories of tasks associated with executive control processing: working memory and inhibition. In a direct contrast of young and older adult activations, older adults engaged bilateral regions of dorsolateral prefrontal cortex as well as supplementary motor cortex and left inferior parietal lobule during working memory. In contrast, age-related changes during inhibitory control were observed in right inferior frontal gyrus and presupplementary motor area. Additionally, when we examined task-related differences within each age group we observed the predicted pattern of differentiated neural response in the younger subjects: lateral prefrontal cortex activity associated with working memory versus right anterior insula/frontal opercular activity associated with inhibition. This separation was largely maintained in older subjects. These data provide the first quantitative meta analytic evidence that age-related patterns of functional brain change during executive functioning depend on the specific control process being challenged. PMID- 21791363 TI - Evaluation of resynchronization therapy for heart failure in patients with a QRS duration greater than 120 ms (GREATER-EARTH) trial: rationale, design, and baseline characteristics. AB - BACKGROUND: Heart failure is considered an epidemic of the modern era. In selected candidates on optimal medical therapy, cardiac resynchronization therapy (CRT) has emerged as a valuable adjunctive treatment. Despite its demonstrated salutary effects on clinical evolution, left ventricular (LV) function, and overall survival, at least 30% of patients fail to respond to CRT. METHODS: The Greater Evaluation of Resychronization Therapy for Heart Failure (GREATER-EARTH) (ClinicalTrials.gov Identifier NCT00901212) is a randomized, double-blind, multicentre study involving 11 centres across Canada and compares LV CRT with biventricular CRT in patients with severe LV dysfunction and a QRS duration>120 ms. RESULTS: This article describes the rationale and design of the study and presents the baseline characteristics of all randomized patients. The primary outcome consists of the effects of CRT on submaximal exercise tolerance (treadmill test), and secondary outcomes explore mechanisms of asynchrony and effects of CRT on asynchrony and LV function. CONCLUSION: The study was initiated in November 2003, with the last patient randomized on February 12, 2009. As expected, follow-up was in February 2010 and the results are presently being analyzed in March 2010. PMID- 21791364 TI - The relationship between kidney function and angiographically-derived SYNTAX score. AB - BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in patients with coronary artery disease (CAD) and is an independent risk factor for adverse cardiovascular disease (CVD) and all-cause mortality in patients with acute coronary syndromes. SYNTAX score (SXscore) can predict the outcomes of patients undergoing percutaneous coronary intervention. However, the association between kidney function and SXscore has not been previously reported. METHODS: The estimated glomerular filtration rate (eGFR) and SXscore were retrospectively collected in 2262 patients with established CAD undergoing coronary angiography at Peking University Third Hospital from March 2005 to September 2010. Ordinal logistic regression and Pearson and partial correlation were used to analyze the association between eGFR and SXscore. RESULTS: Patients with renal dysfunction were older, more likely to be female, and have a history of hypertension and diabetes. The unadjusted correlation coefficient of eGFR and SXscore was -0.125 (P<0.001).This remained significant after adjustment for age, sex, hypertension, diabetes, hyperlipidemia, or current smoking (r=-0.075, P=0.019). Ordinal logistic regression showed that age, gender, diabetes, and eGFR exerted independent influences on SXscore. CONCLUSIONS: Kidney function was an independent predictor of SXscore in patients with established CAD. This helps explain the increased risk of cardiovascular disease events and mortality in patients with renal dysfunction. Further prospective multicentre studies are needed to confirm this finding. PMID- 21791366 TI - Hypofractionated radiotherapy of the breast may be safer for the heart. PMID- 21791365 TI - Prasugrel as an alternative for clopidogrel-associated neutropenia. AB - Clopidogrel has mostly replaced the use of ticlopidine due to its more favourable hematologic adverse event profile. Prasugrel is the newest thienopyridine approved for use in Canada. This case describes a patient who was diagnosed with an acute coronary syndrome and treated with bare metal stenting of his coronary artery. He was discharged home on clopidogrel therapy. Two weeks later he presented with severe neutropenia. Clopidogrel was discontinued and prasugrel was initiated. Neutrophil count gradually increased and returned to normal. In patients with neutropenia associated with clopidogrel therapy, prasugrel may be considered as an alternative. PMID- 21791367 TI - Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, orotate phosphoribosyltransferase mRNA expression in lung cancer metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration: a pilot study. AB - INTRODUCTION/BACKGROUND: Pyrimidine antimetabolites' target molecules thymidylate synthase (TS) and flopropyrimidine-metabolising enzymes such as dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT) are known as biomarkers of 5-fluorouracil (5-FU) treatment. The purpose of this study was to evaluate the feasibility of mRNA expression analysis for TS, DPD, TP, and OPRT using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Metastatic lymph nodes from 20 patients with NSCLC diagnosed by EBUS TBNA were analyzed. After pathological diagnosis, additional sections were made and confirmed the existence of tumor cells by hematoxylin and eosin staining. Tumor cells were extracted using laser-captured microdissection and the mRNA levels were measured by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for each marker. RESULTS: There were 17 mediastinal and 3 hilar lymph nodes. The histology included 13 cases of adenocarcinoma and 7 cases of squamous cell carcinoma. DPD and TP could be successfully analyzed in all samples and TS and OPRT could be measured in 18 samples. The median values of the relative TS, DPD, TP, and OPRT mRNA expression levels were 10.68, 6.23, 18.32, and 1.77, respectively. CONCLUSION: TS, DPD, TP, and OPRT mRNA expression levels could be analyzed using metastatic lymph node samples obtained by EBUS-TBNA. The result of this pilot study may be applicable for further translational research for the treatment of locally advanced NSCLC. PMID- 21791369 TI - Keratin film made of human hair as a nail plate model for studying drug permeation. AB - The limited source of human nail plate for studying drug permeation inspired us to develop a nail plate model made of human hair keratin. The manufacturing process consisted of keratin extraction, dialysis, molding, solvent evaporation, and curing, producing a water-resistant film. The permeability of the film was examined using three markers: sodium fluorescein, rhodamine B, and fluorescein isothiocyanate-dextran as water-soluble, lipid-soluble, and large molecule models, respectively. Bovine hoof was used for comparison. First investigation showed that keratin films (thickness 120 MUm) resembled hooves (thickness 100 MUm) except that these films were more permeable to rhodamine B compared with hooves (1.8-fold, p<0.01). Subsequent investigations using ungual penetration enhancers (urea, thioglycolic acid, and papain) showed that keratin films were generally more susceptible than hooves. This study revealed that the produced keratin film offers a possibility as a human nail plate substitute. However, inclusion of the penetration enhancer must be carefully interpreted. PMID- 21791370 TI - Cell metabolic changes of porphyrins and superoxide anions by anthracene and benzo(a)pyrene. AB - The aim of this work was to evaluate the induction of protoporphyrins IX (PpIX) activity and superoxide anions (SO) in human leukocytes exposed to anthracene (ANT) and benzo(a)pyrene (B(a)P). The leukocyte LC(50)s for both hydrocarbons and the PpIX accumulation and SO overproduction were measured. The LC(50)s were 0.35 and 3.23MUM for ANT and B(a)P, respectively. A linear relationship (r=0.97, p<0.01) between PpIX and ANT concentration was obtained. The induced accumulation of PpIX was proportional (r=0.63, p<0.01) to B(a)P concentration. SO overproduction showed a linear relationship (r=0.83, p<0.05) with ANT concentrations. The linear regression analysis of the effect of B(a)P on the superoxide anion overproduction showed a good coefficient (r=0.97, p<0.01), showed that ANT and B(a)P exposure induces PpIX accumulation, probably by disruption of the haem biosynthesis. ANT and B(a)P induce SO overproduction, perhaps through a process of redox cycling. PMID- 21791371 TI - Protective effect of potato peel extract against carbon tetrachloride-induced liver injury in rats. AB - Our earlier studies have shown that extracts derived from potato peel (PPE) are rich in polyphenols and possess strong antioxidant activity both in vitro and in vivo. The objective of the present study was to investigate its potential to offer protection against acute liver injury in rats. Rats pretreated with PPE (oral, 100mg/kgb.w./day for 7 days) were administered a single oral dose carbon tetrachloride (CCl(4), 3ml/kg b.w., 1:1 in groundnut oil) and sacrificed 8h of post-treatment. Hepatic damage was assessed by employing biochemical parameters (transaminase enzyme levels in plasma and liver [AST-aspartate transaminase; ALT alanine transaminase, LDH-lactate dehydrogenase]). Further, markers of hepatic oxidative damage were measured in terms of malondialdehyde (MDA), enzymic antioxidants (CAT, SOT, GST, GPX) and GSH (reduced glutathione) levels. In addition, the CCl(4)-induced pathological changes in liver were evaluated by histopathological studies. Our results demonstrated that pretreatment of rats with PPE significantly prevented the increased activities of AST and ALT in serum, prevented the elevation of hepatic MDA formation as well as protected the liver from GSH depletion. PPE pretreatment also restored CCl(4)-induced altered antioxidant enzyme activities to control levels. The protective effect of PPE was further evident through the decreased histological alterations in liver. Our findings provide evidences to demonstrate that PPE pretreatment significantly offsets CCl(4)-induced liver injury in rats, which may be attributable to its strong antioxidant propensity. PMID- 21791372 TI - Protective effects of mecamylamine and atropine against alpha(4)beta(2) nicotinic receptor expression and functional toxicity in paraoxon-treated rats. AB - Chronic and acute exposure to organophosphate pesticides or related nerve agents may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. In the present study, the effects of mecamylamine (2mg/kg), or atropine (10mg/kg) alone, or in combination, on the expression of nicotinic acetylcholine receptors (nAChRs) subunits, functional signs of toxicity and lethality in paraoxon-treated rats were investigated. Surviving animals were sacrificed after 48h of paraoxon administration. Paraoxon, at dosage of 1* LD50, significantly reduced expression of alpha(4) and beta(2) nAChR subunits mRNA and protein in rat brain homogenates. Mecamylamine, efficiently prevented reduction of the alpha(4) and beta(2) nAChR mRNA and protein in paraoxon exposed rat brains, but atropine was not efficient. Concurrent treatment with mecamylamine and atropine restored nAChRs mRNA and protein level and prevented lethality and severe involuntary movements induced by paraoxon. Nicotinic receptors antagonists may be included in the cocktail of therapeutic agents targeting the various mechanisms for neuronal injury by organophosphates. PMID- 21791373 TI - Heavy metals: Implications associated to fish consumption. AB - Metals are being utilized of ways in industries and agriculture; particularly heavy metals such as mercury, cadmium, lead and arsenic constitute a significant potential threat to human health because they are associated to many adverse effects on health. The consumption of fish is recommended because it is a good source of omega-3 fatty acids, which have been associated with health benefits due to its cardio-protective effects. However, the content of heavy metals discovered in some fish makes it difficult to establish clearly the role of fish consumption on a healthy diet. Therefore the present mini-review accounts for the recent evidence of the effect of these toxic metals on the human health and their possible implications in fish consumption. PMID- 21791374 TI - Excretion of enrofloxacin in pigs and its effect on ecological environment. AB - The concentration of enrofloxacin and its metabolite, ciprofloxacin, in feces and urines were investigated in healthy pigs after oral administration (p.o.) of a single dose of 5.0mg/kgbw and an indoor soil model was set to study the effects of enrofloxacin and ciprofloxacin through biological and chemical metrics including changes to edaphon, edaphic ammonification and nitrification and the soil bacterial community. The results showed that the concentrations of entofloxacin and ciprofloxacin in feces and urines fluctuated, the maximum concentrations of enrofloxacin and ciprofloxacin in the urine were 22.74 and 48.04MUg/ml, respectively, 24.68 and 30.98MUg/g in the feces, respectively. The effect of enrofloxacin and ciprofloxacin on edaphon, edaphic ammonification and nitrification and the soil bacterial community differed at different time points. And the model can be used to evaluate environmental safety of enrofloxacin and develop possible procedures for the safe handling and utilization of animal excrement. PMID- 21791375 TI - Chemopreventive efficacy of mangiferin against benzo(a)pyrene induced lung carcinogenesis in experimental animals. AB - Chemoprevention has emerged as a very effective preventive measure against carcinogenesis. Several bioactive compounds present in fruits and vegetables have revealed their cancer curative potential on carcinogenesis. Tumor markers correlate strongly with prognosis on tumor burden. Glycoprotein and membrane ATPases play an important role in carcinogenesis. Hence this study was launched to evaluate the effect of mangiferin on the changes in glycoprotein components, ATPases and membrane lipid peroxidation in control and lung carcinoma bearing mice. A significant increase in the levels of glycoproteins, membrane ATPases and membrane lipid peroxidation were observed in animals with lung carcinoma. On administration of mangiferin, these changes were reverted back to near normal levels. The increased levels of glycoprotein components found in lung carcinoma were also significantly decreased in mangiferin treated. Overall, the above data shows that the anticancer effect of mangiferin is more pronounced when used as an chemopreventive agent rather than as a chemotherapeutic agent against B(a)P induced lung carcinogenesis. PMID- 21791376 TI - Efficacy and dosing of antidotes applied to Daphnia intoxicated by nerve agent tabun. AB - A new assay with Daphnia, which can be used as a time, cost, and human effort saving tool in the development of effective antidotes against organophosphate intoxications, is presented. Five concentrations of atropine (antimuscarinic anticholinergics) as well as a reactivator (trimedoxime) were tested to define the optimal dosage. Various reactivators (trimedoxime, obidoxime) were used to examine difference in effectivity of treatments. The most effective dose of trimedoxime corresponded to the 75% of its EC(50)(24) value, i.e. 77.85mgl(-1). The most effective dose of atropine corresponded to the 25% of its EC(50)(24) value, i.e. 104.70mgl(-1). The most effective treatment was a combined atropine obidoxime treatment, followed by the combined atropine-trimedoxime treatment, the atropine only and the obidoxime only treatments. The efficacy of the trimedoxime only treatment was doubtful. The surprisingly high efficacy of obidoxime in the obidoxime only treatment indicates that some oximes might act in daphnids not just as reactivators but also by some other mechanisms. PMID- 21791377 TI - Further preliminary assessment of three human glioma cell lines as models of human astrocytic toxicity in vitro. AB - Three human astroglioma lines U251-MG, U373-MG and CCF-STTG1 have been evaluated further as possible models for astrocytotoxicity (GFAP and IL-6 release). The effects of bacterial lipopolysaccharide, chloroquine diphosphate and acrylamide were studied on GFAP expression and LPS, chloroquine diphosphate, ethanol, trimethyltin chloride (TMTC) and acrylamide were examined on interleukin-6 (IL-6) release in the U373-MG line only. At 4-h LPS elevated GFAP (17.0+/-5.0% P<0.05) above control in the U251-MG cell line only. Chloroquine diphosphate over 4h in the U251-MG line resulted in an increase in GFAP-IR to 20.3+/-4.2% and 21.1+/ 4.1% above control levels 0.1MUM (P<0.05) and 1MUM (P<0.05) respectively. CQD was associated with decreases in MTT turnover, particularly after 24h incubation. With the U373-MG line, LPS (0.5MUg/ml) increased IL-6 expression 640% above control (P<0.001), whilst chloroquine diphosphate (100MUM), ethanol (10mM) and TMTC chloride (1MUM) also increased IL-6. It is possible that batteries of astrocytic human glioma cell lines may be applicable to the sensitive evaluation of toxicants on astrogliotic expression markers such as GFAP and IL-6. PMID- 21791378 TI - Reversal of ionoregulatory disruptions in occupational lead exposure by vitamin C. AB - In order to investigate the toxic effects of lead during occupational exposure to this metal and the antidotal efficacy of ascorbic acid directed against these toxic effects, various artisans in Abeokuta, Nigeria, who have been shown to be occupationally exposed to lead were supplemented daily with 500mg ascorbic acid for 2 weeks. Ca(2+)-Mg(2+)-ATPase activity in erythrocyte membrane, as well as calcium and magnesium concentrations in plasma, erythrocytes, erythrocyte membrane and urine of the artisans were determined before and after ascorbic acid supplementation. The 2-week ascorbic acid administration resulted in the reversal of lead-induced accumulation of calcium and magnesium in the erythrocyte membranes of the artisans. Ascorbic acid also reversed lead-induced inhibition of erythrocyte membrane Ca(2+)-Mg(2+)-ATPase. Urinary excretion of calcium and magnesium was not affected by ascorbic acid. There may be some scope in introducing ascorbic acid as an intervention strategy for the prevention and therapy of lead intoxication, especially in cases where the subjects cannot be removed from the source of lead exposure. PMID- 21791379 TI - Influence of experimentally induced fever on the disposition of cefpirome in buffalo calves. AB - The influence of Escherichia coli endotoxin-induced fever on the disposition of cefpirome was investigated in five male buffalo calves following a single intravenous dose of 10mgkg(-1). Blood samples were collected from 1min to 24h of drug administration. The drug concentration in plasma was estimated by microbiological assay using E. coli as a test organism. The disposition of cefpirome followed two-compartment open model and the drug was detected above the minimum inhibitory concentration in plasma up to 12h. The Vd(area) and AUC were 0.75+/-0.01Lkg(-1) and 35.1+/-0.46MUgml(-1)h, respectively. The elimination half life of 1.81+/-0.009h and Cl(B) of 0.29+/-0.004Lkg(-1)h(-1) reflected rapid elimination and body clearance of cefpirome in febrile buffalo calves. Based on the results, a satisfactory dosage regimen of cefpirome in febrile buffalo calves was calculated to be 6mgkg(-1) to be repeated at 8h intervals. PMID- 21791380 TI - Cytotoxicity of HC Orange NO. 1 to L929 fibroblast cells. AB - HC Orange No. 1 (HCO1, 2-nitro-4'-hydroxydiphenylamine) (CAS No. 54381-08-7) is used as a colorant in commercial hair dyes. The cytotoxicity of HCO1 to L929 mouse connective tissue fibroblast cells was determined by use of a battery of endpoints that included electron transport activity determined by the MTT assay and fluorescence microscopy with Hoechst 33258, DNA agarose gel electrophoresis detected by ethidium bromide and flow cytometry. Cytotoxicity of HCO1 was found to be concentration- and time-dependent with EC(50) values of 28.0 and 12.0mg/L after 24h or 48h exposure, respectively. The mechanism of toxicity of HCO1 was more characteristic of necrosis than apoptosis. These results can be used to evaluate the relative in vitro toxicity of other dyes and to elucidate their mechanisms of toxicity so that accurate assessment of risks to humans can be made, especially from dermal exposure. PMID- 21791381 TI - Effects of decabrominated diphenyl ether (DBDE) on developmental immunotoxicity in offspring mice. AB - Decabrominated diphenyl ether (DBDE), a representative brominated flame retardant ubiquitous in the environment, is suspected of being hazardous to humans. We evaluated the developmental immunotoxicity of DBDE by an assay system using respiratory syncytial virus (RSV) infection in offspring mice. Pregnant mice were continuously exposed to DBDE (10, 100, 1000, or 10,000ppm) in the diet from gestation day 10 to weaning on postnatal day 21. Offspring mice born to these dams were intranasally infected with RSV. Virus titers in the lungs of RSV infected offspring exposed perinatally to DBDE increased dose-dependently compared with the control. The level of interferon-gamma in the bronchoalveolar lavage fluids and gene expression of the chemokine RANTES in the lungs were also significantly elevated in offspring mice exposed to DBDE. Histopathological analysis revealed that pneumonia in the lungs of offspring mice exposed to 10,000ppm of DBDE was exacerbated compared with the control. These results indicate that DBDE is a developmental immunotoxic agent. PMID- 21791382 TI - Anti-oxidative and anti-proliferative character of glycoprotein isolated from geranium sibiricum linne in Chang liver cells. AB - Geranium sibiricum Linne (GSL) has been used to treat intestinal inflammation in traditional Korean folk medicine. We examined its anti-oxidative and anti proliferative activity in the Chang liver cells. We determined that GSL glycoprotein isolated from GSL has a molecular weight of 18kDa and consists of a carbohydrate (10.45%) and protein moiety (89.55%). After confirmation of anti oxidative activity, we investigated the changes in the production of intracellular reactive oxygen radicals (iROS) and nitric oxide in glucose oxidase stimulated Chang liver cells, because they play a critical role for the cell proliferation as a signal mediator. The results in this study showed that GSL glycoprotein significantly reduced iROS production at 5MUg/mL and increased NO production at 20MUg/mL in the G/GO system (100mU/mL). Also, our finding indicated that the GSL glycoprotein ((50MUg/mL) in the presence of Concanavalin A (Con A, 10MUg/mL) resulted in inhibition of proliferating cell nuclear antigen (PCNA, cell proliferation marker). Taken together, GSL glycoprotein inhibits cell proliferation through modulation of intracellular ROS (iROS) and NO in the Chang liver cells. Therefore, we speculate that GSL glycoprotein has an anti-oxidative and anti-proliferative character. PMID- 21791383 TI - Protective function of cis-mulberroside A and oxyresveratrol from Ramulus mori against ethanol-induced hepatic damage. AB - The aim of the study was to investigate the protective effects of oxyresveratrol and cis-mulberroside A isolated from Ramulus mori on the liver of mice intoxicated with ethanol. Animals were pretreated with different doses (30 and 60mg/kg of body weight) of oxyresveratrol and cis-mulberroside A prior to the ethanol (9g/kg of body weight) orally for 7 days. Ethanol treatment induced the decrease of reduced glutathione level and antioxidant enzymes activities, the elevation of the lipid peroxidation and cytochrome P450 2E1 activity accompanied with the increase of iron concentration and mitochondrial permeability transition. Pretreatment with oxyresveratrol and cis-mulberroside A restored the changes in the above parameters up to the basal level. The protective effects of the two active compounds were further supported by attenuation of the degree of tissue damage and the regulation of the expression of TNF-alpha. It could be concluded that oxyresveratrol and cis-mulberroside A from R. mori could protect mice against ethanol-induced hepatic damage. PMID- 21791384 TI - Protection of S-adenosyl methionine against the toxicity of clivorine on hepatocytes. AB - In this study, we investigated the protective effects of S-adenosyl-l-methionine (SAM), which is a precursor of cellular reduced glutathione (GSH), against the hepatotoxicity of pyrrolizidine alkaloid clivorine. MTT assay showed that SAM (5MUM) prevented the cytotoxicity of clivorine on human normal liver L-02 cells. DNA fragmentation assay showed that SAM (5MUM) improved clivorine-induced L-02 cell apoptosis, and the results of Western blot showed that SAM (5MUM) decreased clivorine-induced caspase-3 activation. Cellular GSH analysis showed that when L 02 cells were exposed to different concentrations (0, 3, 10, 30, 50 and 100MUM) of clivorine for 48h, cellular GSH was decreased in a concentration-dependent manner, while SAM (5MUM) enhanced 50MUM clivorine decreased cellular GSH. Further MTT assay showed that 5mM GSH and 5mM N-acetyl-l-cysteine (NAC) both had protective effects against clivorine-induced hepatotoxicity. Our results suggest that SAM has protective effects against the hepatotoxicity of clivorine possibly by enhancing cellular GSH level and increasing cellular defensive ability against clivorine-induced cytotoxicity. PMID- 21791385 TI - Effects of an aqueous extract of Croton bonplandianum Baill in rats. AB - We have investigated the cytotoxic and biochemical effects of injecting aqueous phytoextract of Croton bonplandianum (Baill) leaves in male rats. Subchronic dosages of 3.25, 4.65 and 6.97mgphytoextractg(-1)b.wt.week(-1) were administered to rats. To test ameliorative effects, rats were injected with phytoextract mixed with 0.2mgg(-1)b.wt. of cyclophosphamide. Positive controls received only cyclophosphamide, while negative control groups were kept on normal diet and water. Our results demonstrate that phytoextract did not induce micronuclei formation in rats and shows insignificant amelioration (P<0.05). However, differences in serum LDH isoenzymes, ALP, SGOT, SGPT activities and bilirubin were remarkable and displayed dose as well as duration dependent variations. The most outstanding observation of this study was the release of cardiac TnI in sera of rats injected with 6.97mgg(-1)b.wt. of phytoextract for 21 days. Our findings suggest that at the highest concentrations used here phytoextract of C. bonplandianum is not clastogenic; instead it is cardio- and hepatotoxic. PMID- 21791386 TI - Boron compounds reduce vanadium tetraoxide genotoxicity in human lymphocytes. AB - Vanadium has potential medical and pharmacological uses although it may also show genotoxic effects. Biological effects of boron are defined, but its interaction with vanadium is not known for therapeutic uses. The objective of present study was especially to determine whether boron compounds (boric acid and borax) conferred the protection against vanadium(IV) tetraoxide genotoxicity. After the application of vanadium (5, 10 and 20mg/l) and boron compounds (5 and 10mg/l), blood cultures were assessed by genetic endpoints and total antioxidant capacity (TAC). According to our results, vanadium(IV) tetraoxide induced a reduction in proliferation index (PI). Besides, the frequencies of sister-chromatid exchanges (SCEs), micronuclei (MN) rates and chromosomal aberrations (CAs) in peripheral lymphocytes were significantly increased by vanadium(IV) tetraoxide (10 and 20mg/l) compared to controls. On the other hand, boric acid and borax did not show cytotoxic and genotoxic effects at the concentrations tested. Moreover, these compounds elevated TAC in erythrocytes. The order of anti-genotoxicity efficacy against vanadium was boric acid and borax, respectively. In conclusion, boron compounds have been shown to protect vanadium-induced DNA damage in vitro for the first time. PMID- 21791387 TI - Proteasome affects the expression of aryl hydrocarbon receptor-regulated proteins. AB - The effect of proteasome inhibition with N-acetyl-leucyl-leucyl-norleucinal (ALLN) on the protein expression regulated by aryl hydrocarbon receptor (AhR) was studied in T47D breast tumor cells. The luciferase reporter gene assay using a construct which has the xenobiotic responsive element showed that the inducible expression of the reporter with AhR ligands was significantly reduced by co treatment with ALLN. The same suppressive effect by ALLN was observed for ethoxyresorufin O-deethylase (EROD) activity induced by an AhR ligand, 3 methylcholanthrene (3MC). Despite the above effects, the induced expression of CYP1A1 and CYP1B1 mRNAs was unaffected by ALLN. While lactacystin, another proteasome inhibitor, exhibited the same effect as ALLN on EROD activity induced by 3MC, leupeptin, which is one of the cysteine protease inhibitors, had no such effect. Based on the evidence obtained, it appears that proteasome inhibition results in a reduction in the expression of AhR-regulated proteins. PMID- 21791388 TI - Dichlorvos-induced hepatotoxicity in rats and the protective effects of vitamins C and E. AB - Dichlorvos is an organophosphate insecticide that is widely used in pest control. Vitamin C (200mg/kg)+vitamin E (200mg/kg), dichlorvos (1.6mg/kg), or a combination of vitamin C (200mg/kg)+vitamin E (200mg/kg)+dichlorvos (1.6mg/kg) was given to rats via oral gavage for 7 weeks. When rats of the dichlorvos treated group and the vitamins+dichlorvos-treated group were compared with the control group, body weights were decreased and liver weights were increased significantly at the end of the 4th and 7th week. Serum total protein, albumin, triglyceride, low density lipoprotein-cholesterol (VLDL-cholesterol) levels were decreased, and serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase (GGT), lactate dehydrogenase (LDH), and total cholesterol levels were increased significantly at the end of the 4th and 7th week in the dichlorvos- and vitamins+dichlorvos treated rats. There was a statistically significant difference for all biochemical parameters when the vitamins+dichlorvos-treated group was compared with the dichlorvos-treated group at the end of the 4th and 7th week. In an electron microscopic investigation, swelling of mitochondria and dilatation of endoplasmic reticulum were observed in liver cells of the dichlorvos- and vitamins+dichlorvos-treated rats at the end of the 4th and 7th week. As a result, vitamins C and E reduced dichlorvos hepatotoxicity, but vitamins C and E did not confer complete protection. PMID- 21791389 TI - Induced gene expression in oyster Crassostrea gigas exposed to sewage. AB - Pacific oysters, Crassostrea gigas, were exposed to untreated sewage diluted in seawater. After 48h of exposure, the expression of genes associated to biotransformation pathways (CYP356A1, GSTO, MDR, FABP and ALAS) were analyzed in gills through semi-quantitative RT-PCR. A significant induction in all genes analyzed in the sewage-exposed oysters was observed. These genes are related to phase I (CYP356A1), phase II (GSTO) and phase III (MDR) biotransformation systems, to the uptake and transport of hydrophobic ligands (FABP) and to the synthesis of prosthetic group heme (ALAS). The organisms were able to survive in contaminated conditions since protective mechanisms have been properly stimulated. PMID- 21791390 TI - Investigation of chronic toxicity of (14)C-fenitrothion and its degradation products on stored soybeans. AB - Grains of soybeans were treated with the recommended dose of fenitrothion insecticide, 5mg/kg, and double that dose, before storage for 30 weeks under ambient local conditions. During the storage period, the penetration and distribution of insecticide residues were studied. The amount of surface residues on stored soybeans, internal extractable and bound residues were determined. Surface residues were found to decrease with the increase in time of storage, whereas internal residues showed a gradual increase with time to reach 56%, 54% of applied doses after 30 weeks. The amount of bound residues inside the matrix showed a slow increase with time. Toxicity of the total internal residues of fenitrothion in stored soybeans was studied in mice through a sub-chronic feeding experiment for 3 months. The maximum inhibition in plasma and erythrocyte cholinesterase activity was 37% and 13% after the first month, respectively. Treated mice suffered from deterioration of hepatic and renal functions as indicated by the increase level of blood serum esterase's and blood urea nitrogen. Percentage increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was reached to about 62% and 55%, respectively as compared with control animals with the end of feeding period. PMID- 21791391 TI - Selenium toxicosis assessment (in vivo and in vitro) and the protective role of vitamin B12 in male quail (Coturnix Coturnix). AB - The present study was undertaken to elucidate the toxicity induced by sodium selenite in male quail through in vivo and in vitro studies and the role played by vitamin B12 in alleviating selenium toxicity. Administration of selenite orally for 1 month induced hepatic oxidative damage. Selenite decreased body weight gain and increased relative liver weight. Selenite reduced hemoglobin and iron concentrations and elevated total bilirubin concentration. Serum transaminases and alkaline phosphatase activities were increased in selenium intoxicated quails. Total protein concentration was decreased associated with the appearance of prealbumin fraction, an increased gamma-globulin and a decreased alpha- and beta-globulins. The highest level of selenium was found in liver followed by kidney, testis, faeces and blood. Supplementation of vitamin B12 orally for 1 month simultaneously with selenite caused less marked biological alteration in the investigated parameters. In vitro study using isolated quail hepatocytes incubated with sodium selenite showed a dose-dependent response for toxicity markers. These results suggest that selenosis can be reduced by vitamin B12 supplementation. PMID- 21791392 TI - Reversal of acetaminophen induced subchronic hepatorenal injury by propolis extract in rats. AB - The ethanolic extract of propolis (200mg/kg, p.o.) was evaluated against acetaminophen (APAP; 20mg/kg, p.o.) induced subchronic hepatorenal injury in rats. Administration of APAP significantly increased the release of serum transaminases, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin and serum proteins, whereas concomitantly decreased hemoglobin, blood sugar and albumin. Hepatorenal reduced glutathione and activities of superoxide dismutase and catalase, hepatic CYPs i.e., aniline hydroxylase and amidopyrine-N-demethylase were significantly decreased after APAP intoxication. Lipid peroxidation showed significant elevation in both organs significantly after APAP assault. Total proteins, glycogen contents and the activities of certain metabolic enzymes i.e., adenosine triphosphatase, alkaline phosphatase and acid phosphatase were altered after APAP administration. Propolis extract exhibited curative effects by reversing APAP induced alterations in blood biochemical variables, CYP enzymes and markers of oxidative stress. Histopathological analysis of liver and kidney was consistent with the biochemical findings and led us to conclude the curative potential of propolis against APAP induced hepatorenal injury. PMID- 21791393 TI - Length of treatment and dose as determinants of mutagenicity in sickle cell disease patients treated with hydroxyurea. AB - Hydroxyurea (HU) is an antineoplastic drug widely used in the clinical management of patients with sickle cell disease (SCD), and many questions related with its use remain unresolved. Given the severity of SCD, HU benefits, although not thoroughly confirmed, seem to outweigh its potential carcinogenicity. This study aimed to assess the genotoxicity associated with HU dose and treatment length by evaluating mutagenicity in patients with SCD treated with HU (SCHU) using the cytokinesis-block micronucleus assay (CBMN) in white cells. The study was conducted with 35 individuals in the SCHU group and 34 controls matched according to age, sex and smoking habit. CBMN results showed an increase (p=0.032) in the number of micronuclei (MN), but not of nucleoplasmic bridges (NPB) or nuclear buds (NBUD) in the SCHU group. The increased frequency of MN in the SCHU group was significantly correlated with treatment length and final HU dose, which confirms that patients with SCD treated with HU should be carefully monitored to reduce the risk of carcinogenicity. PMID- 21791394 TI - Glutathione and malondialdehyde levels in common carp after exposure to simazine. AB - Several water contamination incidents with simazine have occurred in the province of Badajoz (Spain). Simazine residues were also detected in drinking water, increasing public health concern. Since little information was found concerning the effects of sublethal concentrations of simazine on aquatic organisms, we investigated some oxidative stress biomarkers in tissues of carps from contaminated waters. Results confirmed an increase in tissue reduced glutathione and malondialdehyde levels in carps inhabiting one of the contaminated ponds. To assess the biological significance of this finding, a laboratory study in which carps were exposed to simazine at 45MUgL(-1) (10-fold that of the natural water levels) for 90 days was developed. The results obtained in the field study were not confirmed in the laboratory exposure, where no differences were seen between the control and the exposure groups. Therefore, carps did not suffer oxidative stress phenomena by the presence of the simazine, at concentrations found in both studies. PMID- 21791395 TI - Does light-stick content pose any threat to marine organisms? AB - Light-stick is a light attractor used in longline fishing which is often dumped or lost into the ocean after used, becoming a potential pollutant to marine organisms. In the present study, toxicity was evaluated by exposing Artemia to light-stick contents. The effects were observed on the survival of nauplii and hatchability of cysts. The LC(50) was 0.063mLL(-1) after 24h of exposure, whilst hatchability was 100% reduced after 48h of exposure to 0.8mLL(-1). The results showed that its content can be toxic to marine organisms, especially under low dilution conditions or direct contact. PMID- 21791396 TI - Wanted/found. PMID- 21791397 TI - Boston research takes center stage. Interview by Pamela Reynolds. PMID- 21791398 TI - The MGH/HST Athinoula A. Martinos Center. PMID- 21791399 TI - The Wyss Institute at Harvard University. PMID- 21791400 TI - Neuroscience at MIT. PMID- 21791401 TI - Northeastern University. PMID- 21791402 TI - From bench to bedside. PMID- 21791403 TI - The Center for Integration of Medicine and Innovative Technologies. PMID- 21791404 TI - Global Health Technology 2.0. PMID- 21791405 TI - Harvard-MIT Division of Health Sciences and Technology. PMID- 21791406 TI - Biomedical engineering continues to make the future. AB - Biomedical engineering (BME) continues to make the future, not just respond to the present, by anticipating the needs of interface engineering and clinical medicine. In many respects, BME is the educational mode of the future, fostering collaboration among disciplines at its core by building on basic concepts in engineering and biology. We strive to educate where the needs, opportunities, and jobs are and will be in the future. The bridge between engineering, biology, and medicine is a growing link, and there is no sign that this interface will slow. With an aging population, dynamic changes in health care, as well as global economies and related themes upon us, we are only at the very beginning of the impact that BME will have on medicine and the quality of life. Those of us in BME are excited to be setting this agenda and welcome your participation. In part, this is why we have designed our BME major to cover both the depth and breadth, always a challenge, but one that we are committed to. The depth of the design projects, research experience, coursework, study abroad options, and internships all convenes to establish a solid foundation for our students as they embark on their career paths. PMID- 21791407 TI - Fast multiscale modeling of cardiac electrophysiology including Purkinje system. AB - In this paper, we present a modeling methodology to couple the cardiac conduction system to cardiac myocytes through a model of Purkinje-ventricular junctions to yield fast and realistic electrical activation of the ventricles. A patient specific biventricular geometry is obtained from processing computed tomography scan data. A one-manifold implementation of the fast marching method based on Eikonal-type equations is used for modeling heart electrophysiology, which facilitates the multiscale 1-D-3-D coupling at very low computational costs. The method is illustrated in in-silico experiments where we analyze and compare alternative pacing strategies on the same patient-specific anatomy. We also show very good agreement between the results from the proposed approach and more detailed and comprehensive biophysical models for modeling cardiac electrophysiology. The effect of atrioventricular delay on the distribution of activation time in myocardium is studied with two experiments. Given the reasonable computational times and realistic activation sequences provided by our method, it can have an important clinical impact on the selection of optimal implantation sites of pacing leads or placement of ablation catheter's tip in the context of cardiac rhythm management therapies. PMID- 21791408 TI - Generative-discriminative basis learning for medical imaging. AB - This paper presents a novel dimensionality reduction method for classification in medical imaging. The goal is to transform very high-dimensional input (typically, millions of voxels) to a low-dimensional representation (small number of constructed features) that preserves discriminative signal and is clinically interpretable. We formulate the task as a constrained optimization problem that combines generative and discriminative objectives and show how to extend it to the semi-supervised learning (SSL) setting. We propose a novel large-scale algorithm to solve the resulting optimization problem. In the fully supervised case, we demonstrate accuracy rates that are better than or comparable to state of-the-art algorithms on several datasets while producing a representation of the group difference that is consistent with prior clinical reports. Effectiveness of the proposed algorithm for SSL is evaluated with both benchmark and medical imaging datasets. In the benchmark datasets, the results are better than or comparable to the state-of-the-art methods for SSL. For evaluation of the SSL setting in medical datasets, we use images of subjects with mild cognitive impairment (MCI), which is believed to be a precursor to Alzheimer's disease (AD), as unlabeled data. AD subjects and normal control (NC) subjects are used as labeled data, and we try to predict conversion from MCI to AD on follow-up. The semi-supervised extension of this method not only improves the generalization accuracy for the labeled data (AD/NC) slightly but is also able to predict subjects which are likely to converge to AD. PMID- 21791409 TI - Source separation and clustering of phase-locked subspaces. AB - It has been proven that there are synchrony (or phase-locking) phenomena present in multiple oscillating systems such as electrical circuits, lasers, chemical reactions, and human neurons. If the measurements of these systems cannot detect the individual oscillators but rather a superposition of them, as in brain electrophysiological signals (electro- and magneoencephalogram), spurious phase locking will be detected. Current source-extraction techniques attempt to undo this superposition by assuming properties on the data, which are not valid when underlying sources are phase-locked. Statistical independence of the sources is one such invalid assumption, as phase-locked sources are dependent. In this paper, we introduce methods for source separation and clustering which make adequate assumptions for data where synchrony is present, and show with simulated data that they perform well even in cases where independent component analysis and other well-known source-separation methods fail. The results in this paper provide a proof of concept that synchrony-based techniques are useful for low noise applications. PMID- 21791410 TI - Stochastic uncertainty models for the luminance consistency assumption. AB - In this paper, a stochastic formulation of the brightness consistency used in many computer vision problems involving dynamic scenes (for instance, motion estimation or point tracking) is proposed. Usually, this model, which assumes that the luminance of a point is constant along its trajectory, is expressed in a differential form through the total derivative of the luminance function. This differential equation linearly links the point velocity to the spatial and temporal gradients of the luminance function. However, when dealing with images, the available information only holds at discrete time and on a discrete grid. In this paper, we formalize the image luminance as a continuous function transported by a flow known only up to some uncertainties related to such a discretization process. Relying on stochastic calculus, we define a formulation of the luminance function preservation in which these uncertainties are taken into account. From such a framework, it can be shown that the usual deterministic optical flow constraint equation corresponds to our stochastic evolution under some strong constraints. These constraints can be relaxed by imposing a weaker temporal assumption on the luminance function and also in introducing anisotropic intensity-based uncertainties. We also show that these uncertainties can be computed at each point of the image grid from the image data and hence provide meaningful information on the reliability of the motion estimates. To demonstrate the benefit of such a stochastic formulation of the brightness consistency assumption, we have considered a local least-squares motion estimator relying on this new constraint. This new motion estimator significantly improves the quality of the results. PMID- 21791411 TI - Integrating segmentation information for improved MRF-based elastic image registration. AB - In this paper, we propose a method to exploit segmentation information for elastic image registration using a Markov-random-field (MRF)-based objective function. MRFs are suitable for discrete labeling problems, and the labels are defined as the joint occurrence of displacement fields (for registration) and segmentation class probability. The data penalty is a combination of the image intensity (or gradient information) and the mutual dependence of registration and segmentation information. The smoothness is a function of the interaction between the defined labels. Since both terms are a function of registration and segmentation labels, the overall objective function captures their mutual dependence. A multiscale graph-cut approach is used to achieve subpixel registration and reduce the computation time. The user defines the object to be registered in the floating image, which is rigidly registered before applying our method. We test our method on synthetic image data sets with known levels of added noise and simulated deformations, and also on natural and medical images. Compared with other registration methods not using segmentation information, our proposed method exhibits greater robustness to noise and improved registration accuracy. PMID- 21791412 TI - On convergence of differential evolution over a class of continuous functions with unique global optimum. AB - Differential evolution (DE) is arguably one of the most powerful stochastic real parameter optimization algorithms of current interest. Since its inception in the mid 1990s, DE has been finding many successful applications in real-world optimization problems from diverse domains of science and engineering. This paper takes a first significant step toward the convergence analysis of a canonical DE (DE/rand/1/bin) algorithm. It first deduces a time-recursive relationship for the probability density function (PDF) of the trial solutions, taking into consideration the DE-type mutation, crossover, and selection mechanisms. Then, by applying the concepts of Lyapunov stability theorems, it shows that as time approaches infinity, the PDF of the trial solutions concentrates narrowly around the global optimum of the objective function, assuming the shape of a Dirac delta distribution. Asymptotic convergence behavior of the population PDF is established by constructing a Lyapunov functional based on the PDF and showing that it monotonically decreases with time. The analysis is applicable to a class of continuous and real-valued objective functions that possesses a unique global optimum (but may have multiple local optima). Theoretical results have been substantiated with relevant computer simulations. PMID- 21791413 TI - Identification of Flt3+CD150- myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential. AB - Common myeloid progenitors (CMPs) were first identified as progenitors that were restricted to myeloid and erythroid lineages. However, it was recently demonstrated that expression of both lymphoid- and myeloid-related genes could be detected in myeloid progenitors. Furthermore, these progenitors were able to give rise to T and B lymphocytes, in addition to myeloid cells. Yet, it was not known whether these progenitors were multipotent at the clonogenic level or there existed heterogeneity within these progenitors with different lineage potential. Here we report that previously defined CMPs possess T-lineage potential, and that this is exclusively found in the Flt3(+)CD150(-) subset of CMPs at the clonal level. In contrast, we did not detect B-lineage potential in CMP subsets. Therefore, these Flt3(+)CD150(-) myeloid progenitors were T/myeloid potent. Yet, Flt3(+)CD150(-) myeloid progenitors are not likely to efficiently traffic to the thymus and contribute to thymopoiesis under normal conditions because of the lack of CCR7 and CCR9 expression. Interestingly, both Flt3(+)CD150(-) and Flt3( )CD150(-) myeloid progenitors are susceptible to Notch1-mediated T-cell acute lymphoblastic leukemia (T-ALL). Hence, gain-of-function Notch1 mutations occurring in developing myeloid progenitors, in addition to known T-lineage progenitors, could lead to T-ALL oncogenesis. PMID- 21791414 TI - Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. AB - Paratarg-7, a frequent autoantigenic target, and all other autoantigenic targets of human paraproteins molecularly defined to date are hyperphosphorylated in the respective patients compared with healthy controls, suggesting that hyperphosphorylation of autoantigenic paraprotein targets is a general mechanism underlying the pathogenesis of these paraproteins. We now show that hyperphosphorylation of paratarg-7 occurs because of an additional phosphorylation of Ser17, which is located within the paraprotein-binding epitope. Coimmunoprecipitation identified phosphokinase C zeta (PKCzeta) as the kinase responsible for the phosphorylation of most, and phosphatase 2A (PP2A) as the phosphatase responsible for the dephosphorylation of all hyperphosphorylated autoantigenic targets of paraproteins. Single-nucleotide polymorphisms (SNPs) or mutations of PKCzeta and PP2A were excluded. However, PP2A was inactivated by phosphorylation of its catalytic subunit at Y307. Stimulation of T cells from healthy carriers of wild-type paratarg-7 induced a partial and transient hyperphosphorylation between days 4 and 18, which was maintained by incubation with inhibitors of PP2A, again indicating that an inactivation of PP2A is responsible for the hyperphosphorylation of autoantigenic paraprotein targets. We conclude that the genetic defect underlying the dominantly inherited hyperphosphorylation of autoantigenic paraprotein targets is not in the PP2A itself, but in genes or proteins controlling PP2A activity by phosphorylation of its catalytic subunit. PMID- 21791415 TI - Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease. AB - Chronic GVHD is one of the most severe complications of allogeneic HSCT. The sclerotic skin manifestations of cGVHD (ScGVHD) result from inflammation and fibrosis of the dermis, subcutaneous tissue, or fascia, leading to significant functional disability. Risk factors and clinical markers associated with ScGVHD remain largely unexamined. By using a single-visit, cross-sectional design, we evaluated 206 patients with cGVHD at the National Institutes of Health. Most patients manifested severe (ie, 63% National Institutes of Health score "severe"), refractory disease (median treatments = 4). ScGVHD was detected in 109 (52.9%) patients. ScGVHD was associated with greater platelet count (P < .001) and C3 (P < .001), and decreased forced vital capacity (P = .013). Total body irradiation (TBI) was associated with development of ScGVHD (P = .002). TBI administered in reduced-intensity conditioning was most strongly associated with ScGVHD (14/15 patients, P < .0001). Patients with ScGVHD had significant impairments of joint range of motion and grip strength (P < .001). Greater body surface area involvement was associated with poorer survival (P = .015). We conclude that TBI, particularly in reduced-intensity regimens, may be an important risk factor for ScGVHD. Widespread skin involvement is associated with significant functional impairment, distressing symptoms, and diminished survival. This trial is registered at http://www.clinicaltrials.gov as NCT00331968. PMID- 21791416 TI - Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T-cell reservoirs in mice. AB - Memory T cells (T(M)s) have been detected in many tissues but their quantitative distribution remains largely undefined. We show that in mice there is a remarkably biased accumulation of long-term CD4 T(M)s into mucosal sites (mainly gut, especially Peyer patches), and CD8 T(M)s into lymph nodes and spleen (in particular, peripheral lymph nodes [PLNs]). This distinction correlates with their differentiated expression of PLN- and gut-homing markers. CD8 and CD4 T(M)s selectively require the expression of PLN-homing marker CCR7 or gut-homing marker alpha4beta7 for maintenance. PLNs and gut supply CD8 and CD4 T(M)s with their individually favored homeostatic cytokine, IL-15, or IL-7. Cytokine stimulation in turn regulates the different gut-homing marker expression on CD4 and CD8 T(M)s. IL-15 plays a major role in vivo regulating CD8 T(M)s homing to PLNs. Thus, the reservoir segregation of CD4 and CD8 T(M)s meets their individual needs for homeostatic cytokines and is under feedback control of cytokine stimulation. PMID- 21791417 TI - Surface-retained tPA is essential for effective fibrinolysis on vascular endothelial cells. AB - In a previous study, we demonstrated unique secretory dynamics of tissue plasminogen activator (tPA) in which tPA was retained on the cell surface in a heavy chain-dependent manner after exocytosis from secretory granules in vascular endothelial cells. Here, we examined how retained tPA expresses its enzymatic activity. Retained tPA effectively increased the lysine binding site-dependent binding of plasminogen on the cell surface and pericellular area; this was abolished by inhibition of enzymatic activity of either tPA or plasmin, which suggests that de novo generation of carboxyl-terminal lysine as a consequence of degradation of surface/pericellular proteins by plasmin is essential. Retained tPA initiated zonal clot lysis of a fibrin network that had been formed on vascular endothelial cells, which was preceded by the binding of plasminogen to the lysis front. Our results provide evidence that secreted and retained tPA is essential for maintaining both high fibrinolytic activity and effective clot lysis on the vascular endothelial cell surface. PMID- 21791418 TI - Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression. AB - Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for <= 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 * 10-8) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 * 10-27) and in an independent sample of 2755 persons of European descent (P = 1.64 * 10-5). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 * 10-6) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype. PMID- 21791419 TI - In vivo distribution of beta2 glycoprotein I under various pathophysiologic conditions. AB - In vitro studies have documented beta2 glycoprotein I (beta2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of beta2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled beta2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The beta2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar beta2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after beta2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that beta2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes. PMID- 21791420 TI - Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. AB - The hereditary stomatocytoses are a series of dominantly inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glucose transporter 1 (glut1) deficiency syndromes (glut1DSs) result from mutations in SLC2A1, encoding glut1. Glut1 is the main glucose transporter in the mammalian blood-brain barrier, and glut1DSs are manifested by an array of neurologic symptoms. We have previously reported 2 cases of stomatin-deficient cryohydrocytosis (sdCHC), a rare form of stomatocytosis associated with a cold induced cation leak, hemolytic anemia, and hepatosplenomegaly but also with cataracts, seizures, mental retardation, and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. On the basis of a 3-dimensional model of glut1, we propose potential mechanisms underlying the phenotypes of the 2 mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia, and sdCHC phenotypes are compared and discussed. PMID- 21791421 TI - Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection. AB - Natural killer (NK) cells are classically viewed as effector cells that kill virus-infected and neoplastic cells, but recent studies have identified a rare mucosal NK- cell subpopulation secreting the TH17 cytokine IL-22. Here, we report identification of 2 distinct lineages of mucosal NK cells characterized as NKG2A(+)NFIL3(+)RORC(-) and NKp44(+)NFIL3(+)RORC(+). NKG2A(+) NK cells were systemically distributed, cytotoxic, and secreted IFN-gamma, whereas NKp44(+) NK cells were mucosae-restricted, noncytotoxic, and produced IL-22 and IL-17. During SIV infection, NKp44(+) NK cells became apoptotic, were depleted, and had an altered functional profile characterized by decreased IL-17 secretion; increased IFN-gamma secretion; and, surprisingly, increased potential for cytotoxicity. NKp44(+) NK cells showed no evidence of direct SIV infection; rather, depletion and altered function were associated with SIV-induced up-regulation of inflammatory mediators in the gut, including indoleamine 2,3-dioxygenase 1. Furthermore, treatment of NKp44(+) NK cells with indoleamine 2,3-dioxygenase 1 catabolites in vitro ablated IL-17 production in a dose-dependent manner, whereas other NK-cell functions were unaffected. Thus lentiviral infection both depletes and modifies the functional repertoire of mucosal NK cells involved in the maintenance of gut integrity, a finding that highlights the plasticity of this rare mucosal NK-cell population. PMID- 21791422 TI - Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. AB - We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3 21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. PMID- 21791423 TI - Mouse embryonic stem cell-derived thymic epithelial cell progenitors enhance T cell reconstitution after allogeneic bone marrow transplantation. AB - We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to differentiate into thymic epithelial cell progenitors (TEPs). When placed in vivo, these mESC-derived TEPs differentiate into cortical and medullary thymic epithelial cells, reconstitute the normal thymic architecture, and enhance thymocyte regeneration after syngeneic BM transplantation (BMT). Here, we show that transplantation of mESC-derived TEPs results in the efficient establishment of thymocyte chimerism and subsequent generation of naive T cells in both young and old recipients of allo-geneic BM transplant. GVHD was not induced, whereas graft-versus-tumor activity was significantly enhanced. Importantly, the reconstituted immune system was tolerant to host, mESC, and BM transplant donor antigens. Therefore, ESC-derived TEPs may offer a new approach for the rapid and durable correction of T-cell immune deficiency after BMT, and the induction of tolerance to ESC-derived tissue and organ transplants. In addition, ESC-derived TEPs may also have use as a means to reverse age-dependent thymic involution, thereby enhancing immune function and decreasing infection rates in the elderly. PMID- 21791424 TI - Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. AB - In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2 year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689. PMID- 21791425 TI - Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. AB - Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56(+)CD3(-) natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor-ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 * 10(6)/Kg. T cells were < 10(5)/Kg. No NK cell-related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus recipient alloreactive NK cells were shown in vivo by the detection of donor derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799. PMID- 21791426 TI - Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. AB - Sustained undetectable molecular residual disease (UMRD) is obtained in a minority of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. It remains unclear whether these patients are definitively cured of their leukemia or whether leukemic stem cells (LSCs) persist in their BM. We have evaluated the presence of BCR-ABL-expressing marrow LSCs in 6 patients with chronic myeloid leukemia with sustained UMRD induced by IFN-alpha (n = 3), imatinib mesylate after IFN-alpha failure (n = 2), and dasatinib after imatinib intolerance (n = 1). Purified CD34(+) cells were used for clonogenic and long term culture-initiating cell assays performed on classic or HOXB4-expressing MS-5 feeders. Using this strategy, we identified BCR-ABL-expressing LSCs in all patients. Interestingly, long-term culture-initiating cell assays with MS-5/HOXB4 stromal feeders increased detected numbers of LSCs in 3 patients. The relation between LSC persistency and a potential risk of disease relapse for patients with durable UMRD (on or off tyrosine kinase inhibitor therapy) warrants further investigation. PMID- 21791427 TI - Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161(hi) CD8alpha+ semi-invariant T cells. AB - Type 17 programmed CD161(hi)CD8alpha(+) T cells contribute to mucosal immunity to bacteria and yeast. In early life, microbial colonization induces proliferation of CD161(hi) cells that is dependent on their expression of a semi-invariant Valpha7.2(+) TCR. Although prevalent in adults, CD161(hi)CD8alpha(+) cells exhibit weak proliferative and cytokine responses to TCR ligation. The mechanisms responsible for the dichotomous response of neonatal and adult CD161(hi) cells, and the signals that enable their effector function, have not been established. We describe acquired regulation of TCR signaling in adult memory CD161(hi)CD8alpha(+) T cells that is absent in cord CD161(hi) cells and adult CD161(lo) cells. Regulated TCR signaling in CD161(hi) cells was due to profound alterations in TCR signaling pathway gene expression and could be overcome by costimulation through CD28 or innate cytokine receptors, which dictated the fate of their progeny. Costimulation with IL-1beta during TCR ligation markedly increased proinflammatory IL-17 production, while IL-12-induced Tc1-like function and restored the response to TCR ligation without costimulation. CD161(hi) cells from umbilical cord blood and granulocyte colony stimulating factor-mobilized leukaphereses differed in frequency and function, suggesting future evaluation of the contribution of CD161(hi) cells in hematopoietic stem cell grafts to transplant outcomes is warranted. PMID- 21791428 TI - Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis. AB - Although several transcription factors have been shown to be critical for the induction and maintenance of IL-17 expression by CD4 Th cells, less is known about the role of nontranscriptional mechanisms. Here we show that the p38 MAPK signaling pathway is essential for in vitro and in vivo IL-17 production by regulating IL-17 synthesis in CD4 T cells through the activation of the eukaryotic translation initiation factor 4E/MAPK-interacting kinase (eIF-4E/MNK) pathway. We also show that p38 MAPK activation is required for the development and progression of both chronic and relapsing-remitting forms of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis. Furthermore, we show that regulation of p38 MAPK activity specifically in T cells is sufficient to modulate EAE severity. Thus, mechanisms other than the regulation of gene expression also contribute to Th17 cell effector functions and, potentially, to the pathogenesis of other Th17 cell-mediated diseases. PMID- 21791429 TI - IRF4 mutations in chronic lymphocytic leukemia. AB - Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory factor family of transcription factors and has been shown to have critical functions at several stages of B-cell development. Genome-wide association study identified a polymorphism in the 3' untranslated region of IRF4 as a chronic lymphocytic leukemia risk locus. In this study, we report a recurrent heterozygous somatic mutation in the DNA-binding domain of IRF4 detected in 7 of 457 chronic lymphocytic leukemia patients (1.5%). Patients with IRF4 mutation have a good prognosis, and 4 of 6 have a trisomy 12. We also found that IRF4 mRNA expression is higher in the patients with the mutation. PMID- 21791431 TI - The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor. AB - Mast cell maturation is poorly understood. We show that enhanced PI3K activation results in accelerated maturation of mast cells by inducing the expression of microphthalmia transcription factor (Mitf). Conversely, loss of PI3K activation reduces the maturation of mast cells by inhibiting the activation of AKT, leading to reduced Mitf but enhanced Gata-2 expression and accumulation of Gr1(+)Mac1(+) myeloid cells as opposed to mast cells. Consistently, overexpression of Mitf accelerates the maturation of mast cells, whereas Gata-2 overexpression mimics the loss of the PI3K phenotype. Expressing the full-length or the src homology 3- or BCR homology domain-deleted or shorter splice variant of the p85alpha regulatory subunit of PI3K or activated AKT or Mitf in p85alpha-deficient cells restores the maturation but not growth. Although deficiency of both SHIP and p85alpha rescues the maturation of SHIP(-/-) and p85alpha(-/-) mast cells and expression of Mitf; in vivo, mast cells are rescued in some, but not all tissues, due in part to defective KIT signaling, which is dependent on an intact src homology 3 and BCR homology domain of p85alpha. Thus, p85alpha-induced maturation, and growth and survival signals, in mast cells can be uncoupled. PMID- 21791430 TI - Approach to the treatment of multiple myeloma: a clash of philosophies. AB - In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice. PMID- 21791432 TI - The miR-144/451eGFP allele, a novel tool for resolving the erythroid potential of hematopoietic precursors. AB - A long outstanding problem is the resolution of the full potential of hematopoietic precursors. The commonly used allotypic marker Ly5 permits the tracing of lymphoid and granulocyte-macrophage (GM) output. Here we present a novel eGFP allele that allows the quantitative analysis of red blood cell (RBC) origin at the single-cell level. The miR-144/451 locus is required for erythroid development and homeostasis. Taking advantage of the fact that miR-451 is specifically and highly expressed in the erythroid lineage, we inserted an eGFP expression cassette into the miR-144/451 locus. In miR-144/451(+/eGFP) animals, accumulation of eGFP is exclusively observed during terminal erythroid differentiation. Expression of miR-144/451(eGFP) ignites immediately before the CFU-E stage and results in strong and complete labeling of all mature RBCs in circulation. Using competitive reconstitution experiments in the Ly5 transplant model, we show that eGFP linearly correlates with Ly5 expression. Thus, the miR 144/451(eGFP) allele represents a novel tool for the resolution of erythroid potential. PMID- 21791433 TI - Efficient differentiation and function of human macrophages in humanized CSF-1 mice. AB - Humanized mouse models are useful tools to understand pathophysiology and to develop therapies for human diseases. While significant progress has been made in generating immunocompromised mice with a human hematopoietic system, there are still several shortcomings, one of which is poor human myelopoiesis. Here, we report that human CSF-1 knockin mice show augmented frequencies and functions of human myeloid cells. Insertion of human CSF1 into the corresponding mouse locus of Balb/c Rag2(-/-) gammac(-/-) mice through VELOCIGENE technology resulted in faithful expression of human CSF-1 in these mice both qualitatively and quantitatively. Intra-hepatic transfer of human fetal liver derived hematopoietic stem and progenitor cells (CD34(+)) in humanized CSF-1 (CSF1(h/h)) newborn mice resulted in more efficient differentiation and enhanced frequencies of human monocytes/macrophages in the bone marrow, spleens, peripheral blood, lungs, liver and peritoneal cavity. Human monocytes/macrophages obtained from the humanized CSF-1 mice show augmented functional properties including migration, phagocytosis, activation and responses to LPS. Thus, humanized mice engineered to express human cytokines will significantly help to overcome the current technical challenges in the field. In addition, humanized CSF-1 mice will be a valuable experimental model to study human myeloid cell biology. PMID- 21791434 TI - Stromal pleiotrophin regulates repopulation behavior of hematopoietic stem cells. AB - Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (Ptn(KD)) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn(+/+)) HSCs into Ptn(-/-) mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin(-)Kit(+)Sca1(+) function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPalpha (Cepba), but reduced of PPARgamma. The known HSC regulator beta-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through beta-catenin-independent regulation of Ccnd1 and Cebpa. PMID- 21791435 TI - Differential expression of the microRNAs in superior and inferior spikelets in rice (Oryza sativa). AB - MicroRNAs (miRNAs) play a critical role in post-transcriptional gene regulation and have been shown to control many genes involved in various biological and metabolic processes. This work investigated miRNAs in rice (Oryza sativa), an important food crop. High-throughput sequencing technology was used to reveal expression differences in miRNAs between superior and inferior spikelets in rice (japonica cultivar Xinfeng 2) at 18 d after fertilization. Totals of 351 and 312 known miRNAs were obtained from the superior and inferior spikelets, respectively. Analysis of the expression profiles of these miRNAs showed that 189 miRNAs were differentially expressed between superior spikelets and inferior spikelets. In addition, 43 novel miRNAs were identified mostly by the accumulation of miRNA*s expressed differentially between the superior and inferior spikelets. Further analysis with bioinformatics software and comparison with existing databases showed that these differentially expressed miRNAs may individually participate in regulating hormone metabolism, carbohydrate metabolic pathways, and cell division during rice grain development. The results indicate that the slow grain-filling and low grain weight of rice inferior spikelets are attributed partly to differences in expression and function between superior and inferior spikelet miRNAs. PMID- 21791436 TI - Impact of down-regulation of starch branching enzyme IIb in rice by artificial microRNA- and hairpin RNA-mediated RNA silencing. AB - The inactivation of starch branching IIb (SBEIIb) in rice is traditionally associated with elevated apparent amylose content, increased peak gelatinization temperature, and a decreased proportion of short amylopectin branches. To elucidate further the structural and functional role of this enzyme, the phenotypic effects of down-regulating SBEIIb expression in rice endosperm were characterized by artificial microRNA (amiRNA) and hairpin RNA (hp-RNA) gene silencing. The results showed that RNA silencing of SBEIIb expression in rice grains did not affect the expression of other major isoforms of starch branching enzymes or starch synthases. Structural analyses of debranched starch showed that the doubling of apparent amylose content was not due to an increase in the relative proportion of amylose chains but instead was due to significantly elevated levels of long amylopectin and intermediate chains. Rices altered by the amiRNA technique produced a more extreme starch phenotype than those modified using the hp-RNA technique, with a greater increase in the proportion of long amylopectin and intermediate chains. The more pronounced starch structural modifications produced in the amiRNA lines led to more severe alterations in starch granule morphology and crystallinity as well as digestibility of freshly cooked grains. The potential role of attenuating SBEIIb expression in generating starch with elevated levels of resistant starch and lower glycaemic index is discussed. PMID- 21791437 TI - Mast cell tryptase stimulates production of decorin by human testicular peritubular cells: possible role of decorin in male infertility by interfering with growth factor signaling. AB - BACKGROUND: Myofibroblastic, peritubular cells in the walls of seminiferous tubules produce low levels of the extracellular matrix (ECM) protein decorin (DCN), which has the ability to interfere with growth factor (GF) signaling. In men with impaired spermatogenesis, fibrotic remodeling of these walls and accumulation of tryptase-positive mast cells (MCs) occur. METHODS: Human testicular biopsies with normal and focally impaired spermatogenesis (mixed atrophy) were subjected to immunohistochemistry and laser micro-dissection followed by RT-PCR. Primary human testicular peritubular cells (HTPCs), which originate from normal and fibrotically altered testes (HTPC-Fs), were studied by qRT-PCR, western blotting, enzyme-linked immunosorbent assay measurements and Ca(2+) imaging. Phosphorylation and viability/proliferation assays were performed. RESULTS: Immunohistochemistry revealed DCN deposits in the walls of tubules with impaired spermatogenesis. Mirroring the situation in vivo, HTPC-Fs secreted more DCN than HTPCs (P < 0.05). In contrast to HTPCs, HTPC-Fs also responded to the main MC product, tryptase, and to a tryptase receptor (PAR-2) agonist by further increased production of DCN (P < 0.05). Several GF receptors (GFRs) are expressed by HTPCs and HTPC-Fs. DCN acutely increased intracellular Ca(2+)-levels and phosphorylated epidermal GF (EGFR) within minutes. Platelet derived GF (PDGF) and EGF induced strong mitogenic responses in HTPC/-Fs, actions that were blocked by DCN, suggesting that DCN in the ECM interferes with GF/GFRs signaling of peritubular cells of the human testis. CONCLUSIONS: The data indicate that the increase in testicular DCN found in male infertility is a consequence of actions of MC-derived tryptase. We propose that the increases in DCN may consequently imbalance the paracrine signaling pathways in human testis. PMID- 21791438 TI - Lymphangiogenesis in deep infiltrating endometriosis. AB - BACKGROUND: In patients diagnosed with deep infiltrating endometriosis (DIE), foci of endometriosis are detected in mesorectal lymph nodes (LNs) after segmental bowel resection and in pelvic sentinel LNs. Lymph vessels (LVs) seem to be the possible routes for the dissemination of endometriotic cells from DIE lesions to LN. Therefore, we conducted a study to investigate the occurrence and density of LV and lymphangiogenic growth factors in DIE. METHODS: Included in this study were 38 premenopausal women who underwent surgery due to symptomatic rectovaginal DIE. In order to identify LV, immunohistochemical analysis with anti Podoplanin (D2-40), LYVE-1 and Prox-1 was performed. Furthermore, the expression of VEGF-C and VEGF-D in endometriotic tissue was investigated. RESULTS: LV density (LVD) of DIE lesions was significantly higher compared with healthy corresponding tissue. All LV makers could be detected, and the density of LYVE-1- or Prox-1-positive LV was significantly higher than that of D2-40-positive LV. Endometriotic epithelial cells and stromal cells showed a moderate to strong VEGF C and VEDF-D expression. CONCLUSIONS: DIE lesions have lymphangiogenic properties, probably leading to endometriosis-like cells in lymphatic vessels and LNs featuring a loco-regional disease. PMID- 21791439 TI - Impact of a multipronged education strategy on antibiotic prescribing in Quebec, Canada. AB - BACKGROUND: Antibiotic overuse and resistance have become a major threat in the last 2 decades. Many programs tried to optimize antibiotic consumption in the inpatient setting, but the outpatient environment that represents the bulk of antibiotic use has been challenging. Following a significant rise of Clostridium difficile infections, all the health care stakeholders in the province of Quebec, Canada initiated a global education program targeting physicians and pharmacists. METHODS: A bundle approach was used; 11 user-friendly guidelines were produced by a group of experts and sent to all physicians and pharmacists in Quebec in January 2005. Downloadable versions of guidelines were posted on a dedicated Web site. They were promoted by professional organizations, universities, and experts during educational events, and there was strong acceptance by the pharmaceutical industry with a willingness to follow the recommendations in their marketing. The Intercontinental Medical Statistics (IMS) database was used to analyze and compare Quebec's total outpatient prescriptions per 1000 inhabitants with those in the other Canadian provinces for 2 time periods: preintervention (January 2003 to December 2004), and postintervention (February 2005 to December 2007). RESULTS: In 2004, antibiotic consumption per capita was 23.3% higher in Canada generally than in Quebec. After the guidelines dissemination, the gap between Quebec and the other Canadian provinces increased by 4.1 prescriptions/1000 inhabitants (P = .0002), and the trend persisted 36 months later. Antibiotic costs fell $134.5/1000 inhabitants in Quebec compared with the rest of Canada (P = .054). CONCLUSIONS: The implementation of guidelines significantly reduced antibiotic prescriptions in Quebec compared with the rest of the country, and there was a strong trend toward significant cost reduction. PMID- 21791440 TI - Quality of published case reports on adverse drug reactions in children. PMID- 21791441 TI - Efficacy of increasing dosages of clarithromycin for treatment of experimental Mycoplasma pneumoniae pneumonia. AB - OBJECTIVES: Mycoplasma pneumoniae respiratory infection is a common cause of acute respiratory infection in children and adults. We evaluated the efficacy of increasing dosages of clarithromycin for the optimized therapy of M. pneumoniae respiratory infection in a mouse model. METHODS: BALB/c mice were intranasally inoculated once with M. pneumoniae or SP4 broth (control). Groups of mice were treated with increasing dosages of clarithromycin (10, 25 or 75 mg/kg/day) or placebo subcutaneously daily. Groups of mice were evaluated after 1, 2, 3, 6 and 12 days of therapy. Outcome variables included quantitative M. pneumoniae culture, histopathological score of the lungs, bronchoalveolar lavage (BAL) cytokine/chemokine/growth factor concentrations and plethysmography after aerosolized methacholine to assess airway hyperresponsiveness. RESULTS: Elevated dosages of clarithromycin resulted in greater antimicrobial efficacy with significantly reduced M. pneumoniae quantitative cultures (P < 0.05), as well as greater improvement in markers of disease severity with significantly reduced lung histopathology scores, BAL cytokine concentrations and airway hyperresponsiveness (P < 0.05). CONCLUSIONS: Escalated dosing of clarithromycin resulted in significantly greater therapeutic efficacy in the treatment of experimental M. pneumoniae respiratory infection. PMID- 21791442 TI - Impaired fitness of Mycobacterium tuberculosis resistant isolates in a cell culture model of murine macrophages. AB - OBJECTIVES: We analysed the ability of Mycobacterium tuberculosis clinical isolates to penetrate and grow inside murine macrophages as a surrogate of fitness. METHODS: Thirty-five drug-resistant and 10 drug-susceptible M. tuberculosis isolates were studied in a murine macrophage model from the J774.2 cell line in a 6 day protocol, performing semi-quantitative counts in Middlebrook 7H11 medium. The mycobacterial penetration index (MPI) after infection and the mycobacterial growth ratio (MGR) inside the macrophages were determined to evaluate the fitness of isolates. RESULTS: Isolates with the katG S315T mutation and multidrug-resistant (MDR) isolates had a significantly lower MGR compared with drug-susceptible isolates. The MPI of the isolates with the katG S315T mutation showed a significant decrease compared with the MPI of those without this mutation. A trend to significantly lower values was also observed on comparing the MPI of the MDR isolates with that of the drug-susceptible isolates and the isolates resistant to isoniazid. CONCLUSIONS: The isoniazid-resistant and MDR isolates with mutations in the katG gene showed decreased multiplication inside murine macrophages, suggesting a lower fitness of M. tuberculosis with these resistance patterns. PMID- 21791443 TI - Pharmacokinetics of oral voriconazole in patients with cystic fibrosis. PMID- 21791444 TI - Enterococci increase the morbidity and mortality associated with severe intra abdominal infections in elderly patients hospitalized in the intensive care unit. AB - OBJECTIVES: Enterococci may increase morbidity and mortality in elderly patients with intra-abdominal infections (IAIs) hospitalized in the intensive care unit (ICU). PATIENTS AND METHODS: A single-centre, retrospective evaluation of an ICU database (1997-2007) of elderly ICU patients (>=75 years) with a severe IAI was performed. Demographics, severity scores, underlying diseases, microbiology and outcomes were recorded. Patients with enterococci isolated in peritoneal fluid (E+ group) were compared with those lacking enterococci in peritoneal fluid (E- group). Stepwise multivariate logistic regression was used to identify independent factors associated with mortality. RESULTS: One hundred and sixty patients were included (mean +/- SD age 82 +/- 5 years; n = 72 in the E+ group). The E+ group was more severely ill than the E- group, with higher Simplified Acute Physiologic Score 2 (61 +/- 20 versus 48 +/- 16, P = 0.0001) and Sequential Organ Failure Assessment scores (8 +/- 3 versus 5 +/- 3, P = 0.0001), a greater postoperative infection rate (58.3% versus 34.1%, P = 0.01), a higher incidence of inappropriate empirical antimicrobial therapies (33.3% versus 19.3%, P = 0.04), a longer duration of mechanical ventilation (11.8 +/- 10.9 versus 7.8 +/- 10.2 days, P = 0.02) and greater vasopressor use (7.2 +/- 7.1 versus 3.3 +/- 4.1 days, P = 0.001). ICU mortality was higher in the E+ group than in the E- group (54.2% versus 38.6%, P = 0.05). In the multivariate analysis, E+ status was independently associated with mortality (odds ratio 2.24; 95% confidence interval 1.06-4.75; P = 0.03). CONCLUSIONS: In severely ill, elderly patients in the ICU for an IAI, the isolation of enterococci was associated with increased disease severity and morbidity and was an independent risk factor for mortality. PMID- 21791445 TI - Alpha 1 antitrypsin phenotypes and obstructive airway disease in subjects over 65 years of age: QUID R cohort. PMID- 21791446 TI - Consensus on core outcome measures of function are needed to progress our knowledge of 'best practice' exercise components for older people. PMID- 21791447 TI - Correlates of frailty in Alzheimer's disease and mild cognitive impairment. PMID- 21791449 TI - Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? AB - OBJECTIVE: To examine the risk of serious infection conveyed by tumour necrosis factor alpha (TNFalpha) inhibitors in the treatment of rheumatoid arthritis (RA). METHODS: Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR(adj)) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. RESULTS: Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRR(adj) 2.1 (95% CI 1.4 to 3.2); >= 15 mg/day, IRR(adj) 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFalpha inhibitors (IRR(adj) 1.8 (95% CI 1.2 to 2.7)). CONCLUSION: Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles. PMID- 21791448 TI - Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. AB - OBJECTIVE: To evaluate if two different measures of synovial activation, baseline Hoffa synovitis and effusion synovitis, assessed by MRI, predict cartilage loss in the tibiofemoral joint at 30 months follow-up in subjects with neither cartilage damage nor tibiofemoral radiographic osteoarthritis of the knee. METHODS: Non-contrast-enhanced MRI was performed using proton density-weighted fat-suppressed sequences in the axial and sagittal planes and a short tau inversion recovery sequence in the coronal plane. Hoffa synovitis, effusion synovitis and cartilage status were assessed semiquantitatively according to the WORMS scoring system. Included were knees that had neither radiographic osteoarthritis nor MRI-detected tibiofemoral cartilage damage at the baseline visit. The presence of Hoffa synovitis was defined as any grade >= 2 (range 0-3) and effusion synovitis as any grade >= 2 (range 0-3). Logistic regression was performed to examine the relation of the presence of either measure to the risk of cartilage loss at 30 months adjusting for other potential confounders. RESULTS: Of 514 knees included in the analysis, the prevalence of Hoffa synovitis and effusion synovitis at the baseline visit was 8.4% and 10.3%, respectively. In the multivariable analysis, baseline effusion synovitis was associated with an increased risk of cartilage loss. No such association was observed for baseline Hoffa synovitis. CONCLUSIONS: Baseline effusion synovitis, but not Hoffa synovitis, predicted cartilage loss. The findings suggest that effusion synovitis, a reflection of inflammatory activity including joint effusion and synovitic thickening, may play a role in the future development of cartilage lesions in knees without osteoarthritis. PMID- 21791450 TI - Measuring participation in people with spondyloarthritis using the social role participation questionnaire. AB - OBJECTIVES: People with spondyloarthritis (SpA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) have identified the importance of understanding how their disease and its treatment impacts on their social roles. This requires a reliable and valid standardised measure, and this study evaluates these measurement properties of the Social Role Participation Questionnaire (SRPQ). METHODS: 109 participants (44 with AS, 65 with PsA) completed questionnaires on demographics, participation measures (SRPQ, Keele Assessment of Participation (KAP), Late Life Disability Instrument (LLDI)), disease severity (physician global) and activity (pain, fatigue, Bath Ankylosing Spondylitis Disease Activity Index), psychological measures (depressive symptoms (Hospital Anxiety and Depression Scale), Illness Intrusiveness)) and function (Health Assessment Questionnaire, Bath Ankylosing Spondylitis Functional Index). After testing scaling properties, test-retest reliability of the SRPQ was evaluated using intraclass correlation coefficients (ICC) and hypotheses of construct validity were evaluated using correlation coefficients. RESULTS: Patients with AS had a mean age of 40 years and 65% were male, whereas patients with PsA had a mean age of 53 years and 63% were male. Although there were some differences between AS and PsA participants in their social role participation, scaling properties were good for both groups. ICCs were >0.90 for the satisfaction subscales of the SRPQ. For construct validity, SRPQ satisfaction subscales were moderately correlated with the KAP and LLDI (0.64-0.78), and less satisfaction was associated with higher disease severity and activity, more depressive symptoms, more illness intrusiveness and more disability (coefficients -0.67 to -0.88). CONCLUSION: Social role participation is an important concept for people with SpA, and the SRPQ is a reliable and valid measure for use with people with AS and PsA. PMID- 21791451 TI - MRI synovitis and bone lesions are common in acute gouty arthritis of the wrist even during the first attack. PMID- 21791452 TI - Psychosocial determinants of outcomes in knee replacement. AB - OBJECTIVE: To identify potential psychosocial and educational barriers to clinical success following knee replacement. PATIENTS AND METHODS: The authors evaluated 241 patients undergoing total knee replacement, preoperatively and 6 months after surgery. Outcomes included the Western Ontario McMaster (WOMAC) scale and the Knee Society rating system (KSRS). Independent variables included: the medical outcome study-social support scale; depression, anxiety and stress scale; brief COPE inventory; health locus of control; arthritis self-efficacy scale and the life orientation test-revised. Multiple regression models evaluated associations of baseline demographic and psychosocial variables with outcomes at 6 months, controlling for body mass index, comorbidities and baseline outcome scores. RESULTS: Patients' mean age was 65 +/- 9 years; 65% were women. Most patients improved outcomes after surgery. Several psychosocial variables were associated with outcomes. Regression analyses indicated lower education, less tangible support, depression, less problem-solving coping, more dysfunctional coping, lower internal locus of control were associated with worse WOMAC scores (R(2) contribution of psychosocial variables for pain 0.07; for function, 0.14). Older age, lower education, depression and less problem-solving coping were associated with poorer total KSRS scores (R(2) contribution of psychosocial variables to total KSRS model 0.09). Psychosocial variables as a set contributed from 25% to 74% of total explained variance across the models tested. CONCLUSION: Patients' level of education, tangible support, depression, problem-solving coping, dysfunctional coping and internal locus of control were associated with pain and functional outcomes after knee replacement. The findings suggest that, in addition to medical management, perioperative psychosocial evaluation and intervention are crucial in enhancing knee replacement outcomes. PMID- 21791453 TI - A stratified model for health outcomes in ankylosing spondylitis. AB - OBJECTIVE: To investigate the relationships between several health outcomes in ankylosing spondylitis (AS). METHODS: Baseline pretreatment data from 214 patients with AS participating in the AS Study for the Evaluation of Recombinant Infliximab Therapy were analysed. Measures of health-related quality of life (HRQoL) and physical function were used as dependent variables in linear regression analysis. Associations between HRQoL (36-Item Short Form (SF-36)), physical function, clinical disease activity, spinal mobility, structural damage, MRI inflammation, disease duration, age, gender, body mass index and HLA-B27 were explored. Univariate associations were retested in multivariate models. The robustness of the models was evaluated by sensitivity analyses. RESULTS: The physical component of SF-36 was independently associated with measures of physical function and disease activity (adjusted R(2) (adjR(2))=0.39-0.40). The mental component of SF-36 was independently associated with physical function (adjR(2)=0.07). Physical function was independently associated with measures of spinal mobility and disease activity (adjR(2)=0.39-0.45). Spinal mobility was hierarchically shown to be an intermediate variable between structural damage and physical function, while physical function was shown to be intermediate between spinal mobility and the physical component of SF-36. CONCLUSION: According to the proposed stratified model for health outcomes in AS, HRQoL is determined by physical function and disease activity, physical function is determined by spinal mobility and disease activity, and spinal mobility is determined by structural damage and inflammation of the spine. As more is learnt about how to measure AS, knowledge about the disease improves and better decisions can be made on the assessment and treatment of this disease. PMID- 21791454 TI - Effectiveness of intra-articular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first metatarsophalangeal joint osteoarthritis: a randomised placebo controlled trial. AB - OBJECTIVES: To evaluate the effectiveness of a single intra-articular injection of hylan G-F 20 (Synvisc) for symptomatic first metatarsophalangeal joint (MTPJ) osteoarthritis (OA). METHODS: Participants (n = 151) with symptomatic first MTPJ OA were randomly allocated to receive up to 1 ml intra-articular injection of either hylan G-F 20 or placebo (saline). Participants and assessors were blinded. Outcomes were evaluated at 1, 3 and 6 months after injection. The primary outcome measurement was the foot pain domain of the Foot Health Status Questionnaire (FHSQ) at 3 months. Secondary outcome measurements were foot function assessed via the FHSQ, first MTPJ pain and stiffness, magnitude of symptom change, global satisfaction, health-related quality of life (assessed using the Short-Form-36 version two), first MTPJ dorsiflexion range of motion, hallux plantar flexion strength, use of pain-relieving medication or co-interventions and changes in plantar pressures. RESULTS: No statistically significant differences in foot pain were found between the groups at 3 months. There were few statistically significant differences in the secondary outcome measures. Overall, the incidence of adverse effects was not significantly different between groups. CONCLUSIONS: An intra-articular injection of hylan G-F 20 is no more effective than a placebo in reducing symptoms in people with symptomatic first MTPJ OA.Australian New Zealand Clinical Trials Registry: number ACTRN12607000654459. PMID- 21791455 TI - Factors responsible for deep-sowing tolerance in wheat seedlings: varietal differences in cell proliferation and the co-ordinated synchronization of epidermal cell expansion and cortical cell division for the gibberellin-mediated elongation of first internodes. AB - BACKGROUND AND AIMS: A wheat cultivar, Triticum aestivum 'Hong Mang Mai', shows tolerance to deep-sowing conditions by extreme elongation of the first internode, likely mediated by the gibberellin (GA) response. To understand factors involved in the response of this deep-sowing-tolerant cultivar, cell expansion and division that confer elongation on the first internodes of wheat seedlings were investigated. METHODS: The lengths and numbers of epidermal and cortical cells of the first internodes in three wheat cultivars were measured. These parameters were compared in wheat seedlings treated with gibberellin A(3) (GA(3)) or an inhibitor of GA biosynthesis, uniconazole. KEY RESULTS: The varietal differences in the elongation of the first internodes were due to differences in cell numbers resulting from the different abilities of cell division, but not cell expansion. In seedlings treated with GA(3), the first internode of 'Hong Mang Mai' was 2 fold longer than the control. The GA-stimulated elongation of the first internodes was attributed to 2-fold increases in the number of cortical cells and length of epidermal cells. The different GA-responses observed in these two tissues were also detected in other cultivars, although the response was much lower than that noted in 'Hong Mang Mai'. The seedlings treated with uniconazole exhibited reduced numbers of cortical cells and reduced lengths of epidermal cells, with both of these effects being more pronounced in 'Hong Mang Mai'. CONCLUSIONS: The deep-sowing-tolerant cultivar 'Hong Mang Mai' is able to elongate the first internode to a greater degree due to enhanced cell division and a heightened response to GA. In addition, cell expansion in the epidermis and cell division in the cortex are synchronized for the elongation of the first internodes. In response to GA, this well-co-ordinated synchronization yields the rapid elongation of the first internodes in wheat seedlings. PMID- 21791456 TI - Physical activity and cardiovascular risk factors in children. AB - BACKGROUND: A number of recent systematic reviews have resulted in changes in international recommendations for children's participation in physical activity (PA) for health. The World Health Authority (WHO) has recently released new recommendations. The WHO still recommends 60 min of moderate to vigorous physical activity (MVPA), but also emphasises that these minutes should be on top of everyday physical activities. Everyday physical activities total around 30 min of MVPA in the quintile of the least active children, which means that the new recommendations constitute more activity in total compared with earlier recommendations. OBJECTIVE: To summarise evidence justifying new PA recommendation for cardiovascular health in children. METHODS: The results of recent systematic reviews are discussed and supplemented with relevant literature not included in these reviews. PubMed was searched for the years 2006-2011 for additional topics not sufficiently covered by the reviews. RESULTS: PA was associated with lower blood pressure and a healthier lipid blood profile in children. The association was stronger when a composite risk factor score was analysed, and the associations between physical fitness and cardiovascular disease (CVD) risk factors were even stronger. Muscle strength and endurance exercise each had an effect on blood lipids and insulin sensitivity even if the effect was smaller for muscle strength than for aerobic exercise. New evidence suggests possible effects of PA on C-reactive protein. CONCLUSION: There is accumulating evidence that PA can have beneficial effects on the risk factors of CVD in children. Public health policy to promote PA in children, especially the most sedentary children, may be a key element to prevent the onset of CVD later in the children's lives. PMID- 21791457 TI - Resistance training in musculoskeletal rehabilitation: a systematic review. AB - OBJECTIVE: To review the efficacy of resistance training (RT) as a therapeutic modality in various musculoskeletal conditions. DESIGN: Systematic review. SUBJECTS: Data from 1545 rehabilitation patients who had participated in structured RT programmes were included into the review. The total number of patients was composed of separate musculoskeletal conditions-chronic low back pain (CLBP) (549), tendinopathy (299), knee osteoarthritis (433), anterior cruciate ligament reconstruction (189) and hip replacement surgery (75). RESULTS: Evidence suggests that RT can increase muscle strength, reduce pain and improve functional ability in patients suffering from CLBP, knee osteoarthritis, and chronic tendinopathy and those under recovery after hip replacement surgery. CONCLUSION: RT can be used successfully as a therapeutic modality in several musculoskeletal conditions, especially those of a chronic variety. Although the exact application of training intensity and volume for maximal therapeutic effects is still unclear, it appears that RT guidelines, which have proven effective in a healthy population, can also be successfully applied in a rehabilitation context. PMID- 21791458 TI - Structural cardiac disease diagnosed by echocardiography in asymptomatic young male soccer players: implications for pre-participation screening. AB - PURPOSE: To evaluate the prevalence of structural cardiac lesions using echocardiography in apparently healthy boys referred for pre-participation screening (PPS). SUBJECTS AND METHODS: 3100 male soccer players were evaluated by echocardiography in addition to the standard PPS. RESULTS: In 56 subjects (1.8%), a structural cardiac lesion with potential future complication was detected. Specifically, hypertrophic cardiomyopathy (HCM) was found in two boys; bicuspid aortic valve (BAV) in 24; mitral valve prolapse in 10 and atrial septal defects (ASDs) in 20. Resting physical examination (PE) failed to identify any abnormalities in the majority of the subjects. All the boys presented an uncomplicated echocardiography, except two boys with HCM, one with BAV associated with aortic dilatation and one with a large ASD. CONCLUSION: Asymptomatic young athletes may have a structural cardiac alteration with the potential of present or future haemodynamic and arrhythmic consequences. A majority of mild cardiac lesions are difficult to diagnose or suspect by the current screening based on medical history, PE and ECG. Transthoracic echocardiography significantly improves the diagnostic power of screening in the detection of both mild and serious cardiac conditions in the athletic population. PMID- 21791459 TI - Is activation of transversus abdominis and obliquus internus abdominis associated with long-term changes in chronic low back pain? A prospective study with 1-year follow-up. AB - OBJECTIVE: To investigate associations between deep abdominal muscle activation and long-term pain outcome in chronic non-specific low back pain (LBP). METHODS: Recruitment of transversus abdominis and obliquus internus abdominis during the abdominal drawing-in manoeuvre was recorded by B-mode ultrasound and anticipatory onset of deep abdominal muscle activity with M-mode ultrasound. Recordings were done before and after 8 weeks with guided exercises for 109 patients with chronic non-specific LBP. Pain was assessed with a numeric rating scale (0-10) before and 1 year after intervention. Associations between muscle activation and long-term pain were examined by multiple linear and logistic regression methods. RESULTS: Participants with a combination of low baseline lateral slide in transversus abdominis and increased slide after intervention had better odds for long-term clinically important pain reduction (>=2 points on the numeric rating scale) compared with participants with small baseline slide and no improvement in slide (OR 14.70, 95% CI 2.41 to 89.56). There were no associations between contraction thickness ratios in transversus abdominis or obliquus internus abdominis and pain at 1-year follow-up. Transversus abdominis lateral slide before intervention was marginally associated with a lower OR for clinically important improvement in pain at 1-year follow-up (OR 0.76, 95% CI 0.62 to 0.93). Delayed onset of the abdominal muscles after the intervention period was weakly associated with higher long-term pain. CONCLUSION: Improved transversus abdominis lateral slide among participants with low baseline slide was associated with clinically important long-term pain reduction. High baseline slide and delayed onset of abdominal muscles after the intervention period were weakly associated with higher pain at 1-year follow-up. Clinical Trial Registration number The study was preregistered in ClinicalTrials.gov with identifier NCT00201513. PMID- 21791460 TI - Conceptualization and measurement of criminal thinking: initial validation of the Criminogenic Thinking Profile. AB - This article describes two studies concerning the development of a new measure of criminal thinking, the CriminogenicThinking Profile (CTP), influenced by the construct of psychopathy, and traditional models of cognitive-behavioral therapy (CBT). An experimental item pool based on verbalizations from offenders served as the pilot version of the instrument. Principal components analysis of the items resulted in a 62-item, eight-factor scale that was internally consistent. In terms of content, six of the resulting factors were conceptually related to psychopathy, one to CBT, and one to neutralization theory. The factor structure and internal reliability was supported by a subsequent confirmatory factor analysis. Initial support for the CTP's convergent validity was indicated by its positive correlations with psychopathy and personality disorders associated with criminal, aggressive, and impulsive behaviors. The CTP's divergent validity was supported by its inverse correlations with indices of healthy personality functioning. The CTP offers a somewhat different constellation of thinking patterns than those found on previously published criminal thinking instruments. The utility of the CTP to identify relevant cognitive targets for offender treatment is a recommended area of future research. PMID- 21791461 TI - Under the surface: the dynamic interpersonal and affective world of psychopathic high-security and detention prisoners. AB - The present study yields an in-depth examination of the interpersonal and affective world of high-security and detention prisoners with possible (Psychopathy Checklist: Screening Version [PCL:SV] >= 13) and strong (PCL:SV >= 18) indications of psychopathy. A group of male inmates (n = 16) was compared with noncriminal and non-personality disordered controls (n = 35) on measures of self and other (Young Schema Questionnaire-Short Form [YSQ-SF], Inventory of Interpersonal Problems-Circumplex Scales [IIP-C]), and the experience and regulation of affect (Positive and Negative Affect Schedule [PANAS], Emotion Control Questionnaire 2 [ECQ2]). Results confirm the established grandiose, dominant, and callous characteristics of the psychopath (PCL:SV, Structured Clinical Interview for DSM-IV Axis II Disorders [SCID-II], DSM-IV and ICD-10 Personality Questionnaire [DIP-Q], IIP-C), while demonstrating personal distress and important nuances and variations in psychopathic offenders' interpersonal and affective functioning (YSQ-SF, PANAS, ECQ2, SCID-II, DIP-Q). These preliminary findings support, expand, and challenge the ordinary portrayal of the psychopath and, if replicated in larger samples, point to a need for an expansion or reformulation of the concept, measurement, and treatment of psychopathy. PMID- 21791462 TI - Envisioning life "on the outs": exit narratives of incarcerated male youth. AB - In this article, the author explores the significance of "exits" for juvenile male offenders who are preparing to leave correctional institutions. The analysis focuses on practical and cognitive exit strategies, anticipated challenges, and future visions based on qualitative interviews with 20 juvenile males (ages 15-17 years) from two correctional facilities in the upper Midwest region of the United States. At the juncture of exit, all of the youth were involved in practical preparation for reentry and shared an emphasis on the theme of "individual responsibility" for their futures. However, the cognitive strategies they used to prepare for exit were strongly differentiated by level of motivation or expressed "openness" to change. Youth who had little motivation to change tended to deny the potential challenges associated with their return to the community, whereas those who expressed a greater openness to change were contemplating how to achieve an alternative, law-abiding future while realistically considering the potential pitfalls of crime temptations. Ambivalence about change was the most common pattern, expressed as a desire to move toward desistance but lacking the internal confidence or sense of social support to achieve such change. From these findings, implications for theory and practice are proposed. PMID- 21791463 TI - Not so fast! Sick sinus syndrome is a complex and incompletely understood disease that might prove hard to model in animals. PMID- 21791465 TI - The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality. AB - BACKGROUND: The 2005 National Institutes of Health Consensus Development Conference on chronic graft-versus-host disease proposed major changes in the classification and grading of severity of chronic graft-versus-host disease. DESIGN AND METHODS: We aimed to study the association of the proposed chronic graft-versus-host disease classification and global severity with transplantation outcomes among a consecutive series of patients who received pharmacokinetically targeted doses of intravenous busulfan and fludarabine conditioning followed by transplantation of allogeneic peripheral blood stem cells. RESULTS: From a total cohort (n = 242) of patients surviving more than 100 days after hematopoietic stem cell transplantation, 181 (75% of those at risk) had some manifestations of graft-versus-host disease after day 100. Of these, at onset 13 (7%) had late acute graft-versus-host disease, 62 (34%) had classic chronic graft-versus-host disease, and 106 (59%) had the overlap subtype of chronic graft-versus-host disease. The global severity of the chronic graft-versus-host disease was mild in 25% of cases, moderate in 46%, and severe in 29%. Multivariable modeling demonstrated the independent association of global severity of chronic graft versus-host disease with overall survival (moderate/severe versus mild; HR 2.9, 95% CI 1.8-4.7, P < 0.0001) and non-relapse mortality (moderate versus mild; HR 3.86, 95% CI 1.17-12.73, P = 0.03, and severe versus mild (HR 10.06, 95% CI 3.07 32.97, P < 0.001). The type of onset of progressive chronic graft-versus-host disease and the platelet count at the time of diagnosis of the disease were significantly associated with overall survival. The occurrence and severity of chronic graft-versus-host disease was also significantly associated with primary disease relapse. CONCLUSIONS: Patients with moderate to severe chronic graft versus-host disease, as determined by National Institutes of Health Consensus criteria, have an inferior overall survival and worse non-relapse mortality. Clinical and research advances are needed to improve the outcomes of affected patients. PMID- 21791466 TI - Variants in genetic modifiers of beta-thalassemia can help to predict the major or intermedia type of the disease. AB - A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) beta-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb alpha-thal deletion; (iv) the tag SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia Intermedia phenotype associated with the different combinations of alleles. The presence or absence of the favorable alleles could accurately predict the type of thalassemia in 83.2% of the cases. The percentage of correct predictions made from the beta-thalassemia mutations and the XmnI SNP alone were significantly improved by the adjustment with the 3 other modifiers; from 73.6% to 83.2% (P<0.001). In this study, we showed that predictions based on genetic modifiers can foresee the Major or Intermedia type of beta-thalassemia, even in cohorts of patients with various beta-globin genotypes. PMID- 21791467 TI - The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia. AB - BACKGROUND: Prognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. DESIGN AND METHODS: Janus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. RESULTS: The morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P = 0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P = 0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P = 0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P = 0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P = 0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P = 0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P = 0.024) and overall survival (P = 0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. CONCLUSIONS: Janus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype. PMID- 21791468 TI - Invasive aspergillosis in patients with hematologic malignancies: incidence and description of 127 cases enrolled in a single institution prospective survey from 2004 to 2009. AB - BACKGROUND: The study objectives were: 1) to report on invasive aspergillosis patients in a hematology department; and 2) to estimate its incidence according to the hematologic diagnosis. DESIGN AND METHODS: A prospective survey of invasive aspergillosis cases was undertaken between January 2004 and December 2009 in the hematology department of a university hospital. Meetings with clinicians, mycologists and infection control practitioners were organized monthly to confirm suspected aspergillosis cases. Demographic characteristics, clinical and complementary examination results were recorded prospectively. Information on hospitalization was extracted from administrative databases. Invasive aspergillosis diagnosis followed the European Organization for Research and Treatment of Cancer criteria, and proven and probable IA cases were retained. A descriptive analysis was conducted with temporal trends of invasive aspergillosis incidence assessed by adjusted Poisson regression. RESULTS: Overall, 4,073 hospitalized patients (78,360 patient-days) were included in the study. In total, 127 (3.1%) patients presented invasive aspergillosis. The overall incidence was 1.6 per 1,000 patient-days (95% confidence interval: 1.4, 1.9) with a decrease of 16% per year (-1%, -28%). The incidence was 1.9 per 1,000 patient-days (1.5, 2.3) in acute myeloid leukemia patients with a decrease of 20% per year (-6%, -36%). Serum Aspergillus antigen was detected in 89 (71%) patients; 29 (23%) had positive cultures, and 118 (93%), abnormal lung CT scans. One-month mortality was 13%; 3-month mortality was 42%. Mortality tended to decrease between 2004 and 2009. CONCLUSIONS: Invasive aspergillosis incidence and mortality declined between 2004 and 2009. Knowledge of invasive aspergillosis characteristics and its clinical course should help to improve the management of these patients with severe disease. PMID- 21791469 TI - Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients. AB - Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n = 238) and a validation set (HOVON65/GMMG HD4 and a Czech dataset; n = 231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1. (IFM 2005-01 clinicaltrials.gov identifier: NCT00200681; HOVON-65/GMMG-HD4 isrctn.org identifier: ISRCTN64455289). PMID- 21791470 TI - Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy. AB - BACKGROUND: In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis. DESIGN AND METHODS: Evaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n = 320) and in relapse cases (APEX, SUMMIT, CREST trials; n = 264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail. RESULTS: Tissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 17 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival. CONCLUSIONS: Relapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients. The HOVON 65/GMMG-HD4 trial is registered under Dutch trial register n. NTR-213. CREST, SUMMIT and APEX trials were registered under ns. M34100-024, M34100-025 and NCT00049478/NCT00048230, respectively. PMID- 21791471 TI - Elevated liver iron concentration is a marker of increased morbidity in patients with beta thalassemia intermedia. AB - BACKGROUND: Patients with beta thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with beta thalassemia intermedia is associated with morbidity. DESIGN AND METHODS: This was a cross-sectional study of 168 patients with beta thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity. RESULTS: The mean age of the patients was 35.2 +/- 12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4 +/- 6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease. CONCLUSIONS: Elevated liver iron concentration in patients with beta thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease. PMID- 21791472 TI - Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. AB - BACKGROUND: Several studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort. DESIGN AND METHODS: We studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt Munster Study Group and Dutch Childhood Oncology Group treatment protocols. RESULTS: Genetic aberrations were associated with specific clinical characteristics, e.g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e.g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1- and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a 'favorable karyotype', i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22+/-14%) and 5-year event-free survival (20+/-13%), although it was not an independent factor in multivariate analysis. CONCLUSIONS: Integrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies. PMID- 21791474 TI - High CD33 expression levels in acute myeloid leukemia cells carrying the nucleophosmin (NPM1) mutation. AB - The CD33 antigen is expressed on the blast cells of most cases of acute myeloid leukemia and represents a suitable tumor-associated target antigen for antibody based therapies. The aim of this study was to investigate the relationship between the CD33 levels quantified by mean fluorescence intensity and antibody binding capacity, and the presence/absence of NPM1 and FLT3 gene mutations in 99 newly diagnosed acute myeloid leukemia cases. The CD33 intensity evaluated as mean fluorescence intensity and antibody binding capacity was significantly higher in the NPM1-mutated acute myeloid leukemia cases compared to the NPM1 unmutated cases (P=0.0001 and P=0.0088, respectively). On the contrary, FLT3 gene mutations did not influence the levels of CD33 expression on the leukemic cells. These results establish a rational basis for the therapeutic use of anti-CD33 antibodies in NPM1-mutated acute myeloid leukemia patients. PMID- 21791473 TI - A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. AB - Deferiprone was shown to reverse iron deposition in Friedreich's ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation. (Clinicaltrials.gov Identifier: NTC00907283). PMID- 21791476 TI - Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T cell non-Hodgkin's lymphoma. AB - We recently reported deletion of the protein tyrosine phosphatase gene PTPN2 in T cell acute lymphoblastic leukemia. Functional analyses confirmed that PTPN2 acts as classical tumor suppressor repressing the proliferation of T cells, in part through inhibition of JAK/STAT signaling. We investigated the expression of PTPN2 in leukemia as well as lymphoma cell lines. We identified bi-allelic inactivation of PTPN2 in the Hodgkin's lymphoma cell line SUP-HD1 which was associated with activation of the JAK/STAT pathway. Subsequent sequence analysis of Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma identified bi-allelic inactivation of PTPN2 in 2 out of 39 cases of peripheral T-cell lymphoma not otherwise specified, but not in Hodgkin's lymphoma. These results, together with our own data on T cell acute lymphoblastic leukemia, demonstrate that PTPN2 is a tumor suppressor gene in T-cell malignancies. PMID- 21791475 TI - Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia. AB - BACKGROUND: In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. DESIGN AND METHODS: Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. RESULTS: Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17 aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. CONCLUSIONS: Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423). PMID- 21791477 TI - Learning biomarkers of pluripotent stem cells in mouse. AB - Pluripotent stem cells are able to self-renew, and to differentiate into all adult cell types. Many studies report data describing these cells, and characterize them in molecular terms. Machine learning yields classifiers that can accurately identify pluripotent stem cells, but there is a lack of studies yielding minimal sets of best biomarkers (genes/features). We assembled gene expression data of pluripotent stem cells and non-pluripotent cells from the mouse. After normalization and filtering, we applied machine learning, classifying samples into pluripotent and non-pluripotent with high cross validated accuracy. Furthermore, to identify minimal sets of best biomarkers, we used three methods: information gain, random forests and a wrapper of genetic algorithm and support vector machine (GA/SVM). We demonstrate that the GA/SVM biomarkers work best in combination with each other; pathway and enrichment analyses show that they cover the widest variety of processes implicated in pluripotency. The GA/SVM wrapper yields best biomarkers, no matter which classification method is used. The consensus best biomarker based on the three methods is Tet1, implicated in pluripotency just recently. The best biomarker based on the GA/SVM wrapper approach alone is Fam134b, possibly a missing link between pluripotency and some standard surface markers of unknown function processed by the Golgi apparatus. PMID- 21791478 TI - The lifestyle of the segmented filamentous bacterium: a non-culturable gut associated immunostimulating microbe inferred by whole-genome sequencing. AB - Numerous microbes inhabit the mammalian intestinal track and strongly impact host physiology; however, our understanding of this ecosystem remains limited owing to the high complexity of the microbial community and the presence of numerous non culturable microbes. Segmented filamentous bacteria (SFBs), which are clostridia related Gram-positive bacteria, are among such non-culturable populations and are well known for their unique morphology and tight attachment to intestinal epithelial cells. Recent studies have revealed that SFBs play crucial roles in the post-natal maturation of gut immune function, especially the induction of Th17 lymphocytes. Here, we report the complete genome sequence of mouse SFBs. The genome, which comprises a single circular chromosome of 1 620 005 bp, lacks genes for the biosynthesis of almost all amino acids, vitamins/cofactors and nucleotides, but contains a full set of genes for sporulation/germination and, unexpectedly, for chemotaxis/flagella-based motility. These findings suggest a triphasic lifestyle of the SFB, which comprises two types of vegetative (swimming and epicellular parasitic) phases and a dormant (spore) phase. Furthermore, SFBs encode four types of flagellin, three of which are recognized by Toll-like receptor 5 and could elicit the innate immune response. Our results reveal the non-culturability, lifestyle and immunostimulation mechanisms of SFBs and provide a genetic basis for the future development of the SFB cultivation and gene manipulation techniques. PMID- 21791479 TI - Detection of high serological prevalence and comparison of different tests for Salmonella in pigs in Northern Ireland. AB - Thirty-one farrow-to-finish pig units with a Zoonoses National Control Programme (ZNCP) for Salmonella above the UK target of 10 per cent during the previous 12 months were selected for the study. Pooled faecal samples were collected from different groups of pigs. Furthermore, mice, rat and bird faeces and carcases were collected, if found on the unit. In total, 937 samples were collected on farm and analysed for Salmonella. The four carcases selected monthly per producer by the slaughterhouse for the British Pig Executive ZNCP Salmonella Programme were tested for antibodies to groups B and C with a mix-ELISA test. The same four carcases were swabbed externally and internally, mesenteric lymph nodes (MLNs) were collected and colonic contents were swabbed. A wide variety of Salmonella serovars was isolated from the samples. Most of the isolates were detected in the rearing herd (on-farm) and in the MLNs (slaughterhouse). There was no correlation between ELISA results from the meat juice and bacteriological isolations using Spearman correlation analyses. Furthermore, no significant association was found between positive results of ELISA and positive results from the bacteriological samples taken. PMID- 21791480 TI - Suspected side effects of doxycycline use in dogs - a retrospective study of 386 cases. AB - This study investigated doxycycline-related side effects in a large population of dogs. Data from 386 dogs that had received doxycycline for the treatment of various infectious diseases were analysed retrospectively. Potential side effects that developed during treatment were documented, and correlations with signalment, dose, duration of treatment, frequency of application, doxycycline preparation and use of additional drugs were investigated. Vomiting was reported in 18.3 per cent of dogs, 7.0 per cent developed diarrhoea and 2.5 per cent developed anorexia. While being treated with doxycycline, 39.4 per cent of dogs showed an increase in alanine aminotransferase (ALT) activity and 36.4 per cent showed an increase in alkaline phosphatase (ALP) activity. There was a dose related risk of an increase in ALP activity (P=0.011, odds ratio [OR]=1.27, 95 per cent confidence interval [CI] 1.06 to 1.53), and older dogs treated with doxycycline were more likely to develop an increase in ALT activity (P=0.038, OR=1.23, 95 per cent CI 1.01 to 1.50) and vomiting (P=0.017, OR=1.11, 95 per cent CI 1.02 to 1.21). PMID- 21791481 TI - Cavernous hemangioma of the proximal femur. PMID- 21791482 TI - The use of the Bethesda terminology in thyroid fine-needle aspiration results in a lower rate of surgery for nonmalignant nodules: a report from a reference center in Turkey. AB - The Bethesda system (BS) for reporting thyroid fine-needle aspiration (FNA), which classifies nodules as nondiagnostic (ND), benign (B), atypia/follicular lesion of undetermined significance (AUS/FLUS), suspicious for follicular neoplasm (SFN/FN), suspicious for malignancy (SFM), or malignant (M), uses clinically valuable management guidelines. The authors employed a similar in house classification system (IS) for thyroid FNAs, using the categories of ND, B, suspicious follicular cells (SFC), follicular lesion/neoplasm (FL/FN), SFM, and M. The authors compared IS and BS, and assessed the utility of BS in clinical practice. A total of 581 nodules with cytological/histological follow-up were examined and indeterminate lesions by BS were reclassified. The sensitivity and specificity for malignancy using IS were similar to that of BS (77% vs 99%). However, when SFN/FN and SFM were both considered positive, the results for IS and BS were as follows: sensitivity, 85% versus 85%; specificity, 87% versus 94%; and diagnostic accuracy, 86% versus 90%, respectively. Discrepancies between cytological and histological data were evident in 35 cases among all categories of BS except AUS/FLUS. The rate of surgery for nonmalignant nodules was lesser (20% vs 9%) by BS. Among 34 AUS/FLUS cases with follow-up data, hypocellularity was the case in 11 (46%) nonneoplastic and 10 (100%) neoplastic nodules. The use of BS results in a lower rate of surgery for nonmalignant nodules even though patients with borderline cytopathologic features are still encountered. AUS/FLUS category can be separated into subgroups according to the factors causing difficulties in the interpretation. There is a need of accumulation of AUS/FLUS cases to do further evaluations and studies. PMID- 21791483 TI - Uterine adenosarcoma with bowel metastasis. PMID- 21791484 TI - Two out of three required: a case of incomplete Carney triad. AB - A 48-year-old woman presented with chest symptoms. Multiple lesions seen on chest imaging were found to be pulmonary chondromas following surgical resection. Whole body magnetic resonance scan performed to investigate the possibility of Carney triad demonstrated a gastric lesion. This was resected and found to be a gastrointestinal stromal tumor. No evidence of paragangliomata was found on imaging. A diagnosis of incomplete Carney triad was made. Carney triad is a rare multiple neoplastic association of pulmonary chondroma, gastrointestinal stromal tumor, and paraganglioma. At least 2 tumors are required for diagnosis. Most patients are young women. No genetic cause has been identified. Management involves surgical resection of tumors and follow-up for recurrence and investigation for other elements of the triad. PMID- 21791485 TI - Rhabdoid carcinoma of the colon: a distinct entity with a very aggressive behavior: a case report associated with a polyposis coli and review of the literature. AB - Rhabdoid colon tumors (RCTs) are rare lesions whose existence as an independent distinct entity remains controversial. To date, 6 RCTs have been reported. This study reports a novel case associated with polyposis coli in a 73-year-old woman. Histologically, the neoplasia was heterogeneous consisting of an adenocarcinoma associated with rhabdoid features. In rhabdoid component, an intense expression of MSH2 was noted but MLH1 was negative. A BRAF V600E mutation and no KRAS mutations were identified. The promoter regions of subset of genes highly specific to characterize the CIMP status (NEUROG1, IGF2, RUNX3, SOCS1, including MLH1) were hypermethylated, suggesting the presence of CIMP+ and MSI high tumor. In conclusion, all RCTs have similar clinical features. The presence of polyposis and adenocarcinoma component as well as the expression of mesenchymal marker suggests a sarcomatous dedifferentiation. It is argued that RCT could be a very aggressive entity of colon, which could benefit from new biological colonic treatments. PMID- 21791486 TI - Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status. AB - INTRODUCTION: The relationship between tumor budding, epithelial-mesenchymal transition (EMT) protein expression, and survival has not been closely examined in stage II colorectal cancer (CRC). This study aimed to assess proteins implicated in EMT and to correlate their expression with tumor budding, microsatellite status, and survival. METHODS: A total of 258 stage II CRCs were identified (tumor budding characterized in 122 cases). Immunohistochemistry for LAMC2, E cadherin, cathepsin L, and beta catenin using tissue microarrays was performed. EMT and mismatch repair (MMR) protein expression were correlated with tumor budding and survival. RESULTS: LAMC2 positivity (P < .001) and low membranous beta catenin (P = .056) were associated with tumor budding. In a univariate survival analysis, tumor budding (P < .001), LAMC2 positivity (P < .03), and stromal cytoplasmic cathepsin L (P = .025) predicted poorer prognosis. Multivariate analysis showed tumor budding to be the only variable independently associated with survival: hazard ratio = 7.9 (95% confidence interval = 3-21); P < .001. Tumor budding was more frequent in microsatellite-stable (MSS) versus microsatellite-instable (MSI) tumors: 48% versus 26%, respectively; P = .087. MSS cases exhibited reduced membranous beta catenin (P = .002) and increased cytoplasmic and nuclear beta catenin (P < .001) compared with MSI cases. CONCLUSION: Epithelial mesenchymal protein expression plays a key role in tumor budding and prognosis in early-stage colorectal cancer and requires further evaluation. PMID- 21791487 TI - Incidental prostatic paraganglia in radical prostatectomy specimens: a diagnostic pitfall. AB - Paraganglia are an uncommon but previously reported finding in the genitourinary system. Recognition of this entity in the prostate is important in distinguishing it from prostatic adenocarcinoma. In this series, 1230 radical prostectomy specimens were examined for the presence of paraganglia, and a total of 57 cases (4.5%) were found to contain paraganglia. The majority of paraganglia were extraprostatic and could easily mimic extension of prostatic adenocarcinoma into extraprostatic tissue. It is important to recognize paraganglia, particularly when they are extraprostatic and could confer a falsely higher tumor stage to the patient. The paraganglia demonstrated characteristic histology, and immunohistochemistry was supportive when enough tissue was available. No association between patient age and frequency of paraganglia was found. PMID- 21791488 TI - Mucin-producing urothelial-type adenocarcinoma of the prostate as a mimicker of colonic adenocarcinoma: a case report and review of the literature. AB - A 59-year-old man presented with persistent urinary obstructive symptoms, gross hematuria, and mucusuria. Subsequently, a prostate-specific antigen (PSA) negative mucin-producing urothelial type adenocarcinoma of prostate was found. The serum PSA level was within the normal limit. Colonoscopy, positron emission tomography, and other tumor surveys showed this to be the only prostate lesion. Microscopically, there was an adenocarcinoma with copious mucin production, with the formation of mucin pools. The neoplastic glands were variously arranged in cribriform, glandular, and villous adenoma-like patterns. This is a very rare tumor, of which there are only 20 cases reported in the literature in the English language. It is critical to distinguish it from mucinous acinar adenocarcinoma of the prostate and from metastatic adenocarcinoma of either the bladder or colon. This is mainly because mucin-producing urothelial type adenocarcinoma of the prostate has a different clinical behavior, and hence, the treatment plan is different from that for conventional prostatic adenocarcinoma. Specifically, it has a more aggressive clinical course and is unresponsive to hormone therapy. PMID- 21791489 TI - Renal-cell carcinomas in end-stage kidneys: a clinicopathological study with emphasis on clear-cell papillary renal-cell carcinoma and acquired cystic kidney disease-associated carcinoma. AB - Clear-cell papillary renal-cell carcinoma (CCPC) and acquired cystic kidney disease-associated carcinoma (ACDAC) are neoplasms with distinct morphological characteristics that behave less aggressively than conventional renal-cell carcinomas. End-stage kidney specimens from 61 patients (47 males and 14 females) with 109 renal-cell carcinomas were selected. Papillary renal-cell carcinoma was the most common malignancy (61/109, 56%), followed by CCPC (20/109, 18%). The CCPC showed a papillary or tubular/solid architecture, clear cytoplasm, low nuclear grade, and a distinct immunohistochemical profile (RCC-, vimentin+, CK7+, p504S-). ACDAC displayed a variety of architectural patterns, eosinophilic cytoplasm, high nuclear grade, intratumoral calcium oxalate deposits, and an immunohistochemical profile similar to type 2 papillary renal-cell carcinoma (RCC+, vimentin+, CK7-/+, p504S+). Less than 5% (3/69) of pathologically staged renal-cell carcinomas in end-stage kidneys presented with lymphogenous and/or hematogenous metastases. PMID- 21791490 TI - How should we define health? PMID- 21791492 TI - Sexual dysfunction in cardiovascular disease. PMID- 21791491 TI - Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial. AB - OBJECTIVE: To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. DESIGN: Multicentre crossover randomised controlled trial. SETTING: Outpatient clinics in the Netherlands. PARTICIPANTS: 52 patients with non diabetic nephropathy. INTERVENTIONS: All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. MAIN OUTCOME MEASURES: The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. RESULTS: Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition. CONCLUSIONS: Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675. PMID- 21791493 TI - Breathlessness and plethora. PMID- 21791495 TI - Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. AB - OBJECTIVE: To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes. DESIGN: Meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane database of systematic reviews. STUDY SELECTION: Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (>= 18 years) with type 2 diabetes. DATA EXTRACTION: Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events. Synthesis of results Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with chi(2), tau(2), and I(2) statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score. RESULTS: 13 studies were included. Of 34,533 patients, 18,315 received intensive glucose lowering treatment and 16,218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001). CONCLUSIONS: The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomised controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes. PMID- 21791496 TI - Intensive glucose lowering treatment in type 2 diabetes. PMID- 21791497 TI - Changes in energy content of lunchtime purchases from fast food restaurants after introduction of calorie labelling: cross sectional customer surveys. AB - OBJECTIVE: To assess the impact of fast food restaurants adding calorie labelling to menu items on the energy content of individual purchases. DESIGN: Cross sectional surveys in spring 2007 and spring 2009 (one year before and nine months after full implementation of regulation requiring chain restaurants' menus to contain details of the energy content of all menu items). Setting 168 randomly selected locations of the top 11 fast food chains in New York City during lunchtime hours. PARTICIPANTS: 7309 adult customers interviewed in 2007 and 8489 in 2009. MAIN OUTCOME MEASURES: Energy content of individual purchases, based on customers' register receipts and on calorie information provided for all items in menus. RESULTS: For the full sample, mean calories purchased did not change from before to after regulation (828 v 846 kcal, P = 0.22), though a modest decrease was shown in a regression model adjusted for restaurant chain, poverty level for the store location, sex of customers, type of purchase, and inflation adjusted cost (847 v 827 kcal, P = 0.01). Three major chains, which accounted for 42% of customers surveyed, showed significant reductions in mean energy per purchase (McDonald's 829 v 785 kcal, P = 0.02; Au Bon Pain 555 v 475 kcal, P<0.001; KFC 927 v 868 kcal, P<0.01), while mean energy content increased for one chain (Subway 749 v 882 kcal, P<0.001). In the 2009 survey, 15% (1288/8489) of customers reported using the calorie information, and these customers purchased 106 fewer kilocalories than customers who did not see or use the calorie information (757 v 863 kcal, P<0.001). CONCLUSION: Although no overall decline in calories purchased was observed for the full sample, several major chains saw significant reductions. After regulation, one in six lunchtime customers used the calorie information provided, and these customers made lower calorie choices. PMID- 21791499 TI - Calorie labelling on the high street. PMID- 21791498 TI - Effect of pregnancy planning and fertility treatment on cognitive outcomes in children at ages 3 and 5: longitudinal cohort study. AB - OBJECTIVE: To investigate how pregnancy planning, time to conception, and infertility treatment influence cognitive development at ages 3 and 5. DESIGN: Prospective population based cohort study. SETTING: Millennium Cohort Study in the United Kingdom. PARTICIPANTS: 18,818 children recruited at 9 months and followed up at 3 and 5 years. 11,790 singletons with available data on pregnancy, cognitive outcomes, and confounders were included in analyses at age 3 and 12,136 at age 5. Exposure measures Mothers reported whether the pregnancy was planned, and their feelings when first pregnant; those in whom the pregnancy was planned provided time to conception, and details of any assisted reproductive technologies. The population was divided into "unplanned" (unplanned and unhappy), "mistimed" (unplanned but happy), "planned" (planned, time to conception <12 months), "subfertile" (planned, time to conception >= 12 months), "induced ovulation" (received clomiphene citrate), and "assisted reproduction" (in vitro fertilisation or intracytoplasmic sperm injection). The "planned" group was the comparison group in all analyses. OUTCOME MEASURES: Three components of the British Ability Scales (BAS II). Naming vocabulary assessed verbal ability at age 3; this test was repeated at age 5 with the picture similarities and pattern construction subscales, which measure non-verbal and spatial abilities. RESULTS: In unadjusted analyses, the scores on all scales in children from unplanned pregnancies were significantly lower than in those from planned pregnancies-for example, the difference in mean verbal ability score at age 3 was -4.8 (95% confidence interval -6.0 to -3.7; P<0.05), equivalent to an average delay of four months. After adjustment for sociodemographic factors these differences were attenuated: -0.3 (-1.3 to 0.7), equivalent to no delay. Children born after assisted reproduction performed consistently better in verbal ability tests (3.8 (-0.2 to 7.9) at age 3 and 3.5 (0.2 to 6.8) at age 5), which suggests that on average these children are three to four months ahead; this difference did not completely disappear with adjustment for confounders. Children born after infertility treatment had lower mean scores in non-verbal tests (-1.2 (-4.1 to 1.6) after assisted reproduction and -1.5 (-3.5 to 0.4) after induced ovulation) and in spatial ability tests (-2.7 (-6.9 to 1.6) after assisted reproduction), though the differences were not significant. CONCLUSIONS: Pregnancy planning, subfertility, or assisted reproduction do not adversely affect children's cognitive development at age 3 or 5. The differences observed in the unadjusted analyses are almost entirely explained by marked inequalities in socioeconomic circumstances between the groups. PMID- 21791501 TI - Consultant surgeon is suspended by GMC for botching operations and lying to coroner. PMID- 21791503 TI - Acute and subacute dual energy CT findings of pulmonary embolism in rabbits: correlation with histopathology. AB - OBJECTIVE: The purpose of this study was to describe quantitative dual energy CT (DECT) findings and their accuracy in the detection of acute and subacute pulmonary embolism (PE) in rabbits. METHODS: Pulmonary emboli were created in 24 rabbits by gelatin sponge femoral vein injection. Conventional CT pulmonary angiography (CTPA) and DECT were obtained at either 2 h, 1 day, 3 days or 7 days after embolisation (n=6 rabbits for each time point). The location and number of PEs in the different stages were recorded at CTPA and iodine maps from DECT on a per-lobe basis. With histopathology as the reference standard, sensitivity and specificity of CTPA and DECT were calculated. CT and iodine map overlay values of the embolic and non-embolic areas were measured for each scan. RESULTS: With histopathology as the reference standard, the overall sensitivity and specificity of CTPA were 98% and 100% and those of iodine maps were 100% and 95%, respectively. Conventional CT and iodine map values of the embolised and non embolised areas were significantly different between 2 h and 1 day (p<0.001), but not between 3 days and 7 days (p>0.05). A statistical difference was found for overlay values measured in the embolic and non-embolic regions for four groups. CONCLUSION: Iodine maps derived from DECT show alterations in lung perfusion for acute and subacute PE in an experimental rabbit model and show comparable sensitivity for PE detection and conventional CTPA. PMID- 21791504 TI - Diagnostic performance of multidetector CT for acute cholangitis: evaluation of a CT scoring method. AB - OBJECTIVE: The aim of this study was to retrospectively assess the diagnostic performance of multidetector CT (MDCT) for the diagnosis of acute cholangitis using a new scoring method. METHODS: Of 80 patients with suspected biliary disease who underwent biphasic CT and endoscopic retrograde cholangiography, 39 were diagnosed as having acute cholangitis (Group 1) and 41 patients were classified as suspected biliary disease (Group 2). 100 age-matched patients without evidence of biliary disease were selected randomly as a control group (Group 3). Each patient's axial scan was scored by two independent radiologists for the extent of transient hepatic attenuation difference, the presence of biliary dilatation and identification of a biliary obstructive lesion. The difference in the scores among the three groups was evaluated and the optimal cut off score for the diagnosis of acute cholangitis was determined. Interobserver agreement was also evaluated. RESULTS: The total scores (mean +/- standard deviation) for Groups 1, 2 and 3 were 7.0 +/- 2.0, 4.4 +/- 2.4 and 0.9 +/- 1.2, respectively, for Reviewer 1 and 7.2 +/- 2.7 and 0.7 +/- 1.1, respectively, for Reviewer 2. Significant differences were found for the subscores and the total scores among the three groups (p < 0.001). Using a cut-off score of >= 5, the sensitivity and specificity for diagnosing acute cholangitis were 84.6% and 83.7%, respectively, for Reviewer 1 and 89.7% and 83.7%, respectively, for Reviewer 2. Agreement for the subscores between readers was good to excellent (kappa = 0.74-0.86). CONCLUSION: Based on dynamic MDCT and the described CT scoring method, the diagnosis of acute choangitis can be made with high sensitivity and specificity. PMID- 21791505 TI - Transthoracic needle biopsy using a C-arm cone-beam CT system: diagnostic accuracy and safety. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy and safety of performing transthoracic needle biopsy (TNB) under combined fluoroscopy and CT guidance using a C-arm cone-beam CT (CBCT) system. METHODS: We evaluated the diagnostic accuracy and safety of performing TNB using a C-arm CBCT system. We retrospectively evaluated 99 TNB cases performed in 98 patients using a C-arm CBCT system with an 18-gauge automated cutting needle. We reviewed the diagnostic accuracy according to the size and depth of the lesion, incidence of complications, additional treatment for complications, procedure time, number of needle passes per biopsy and radiation dose. RESULTS: The final diagnoses revealed 72 malignant and 27 benign lesions. The overall malignancy sensitivity, malignancy specificity and diagnostic accuracy were 95.8%, 100% and 97.0%, respectively, and those for small pulmonary nodules <20 mm in size were 94.1%, 100% and 96.6%, respectively. There was no significant difference in the correct diagnosis of malignancy according to lesion size (p = 0.634) or depth (p = 0.542). For benign lesions, a specific diagnosis was obtained in 14 cases (51.9%). TNB induced complications in 19 out of 99 procedures (19.2%), including pneumothorax (16.2%), immediate haemoptysis (2.0%) and subcutaneous emphysema (1.0%). Among these, four patients with pneumothorax required chest tube insertion (2.0%) or pig-tail catheter drainage (2.0%). The mean procedure time, number of needle passes and radiation doses were 11.9 +/- 4.0 min, 1.2 +/- 0.5 times and 170.0 +/- 67.2 mGy, respectively. CONCLUSION: TNB using a C-arm CBCT system provides high diagnostic accuracy with a low complication rate and a short procedure time, particularly for small pulmonary nodules. PMID- 21791506 TI - Post-fundoplication contrast studies: is there room for improvement? AB - OBJECTIVE: Since the mid-1990s, laparoscopic fundoplication for gastro oesophageal reflux disease has become the surgical procedure of choice. Several surgical groups perform routine post-operative contrast studies to exclude any (asymptomatic) anatomical abnormality and to expedite discharge from hospital. The purpose of this study was to determine the accuracy and interobserver reliability for surgeons and radiologists in contrast study interpretation. METHODS: 11 surgeons and 13 radiologists (all blinded to outcome) retrospectively reviewed the contrast studies of 20 patients who had undergone a laparoscopic fundoplication. Each observer reported on fundal wrap position, leak or extravasation of contrast and contrast hold-up at the gastro-oesophageal junction (on a scale of 0-4). A kappa coefficient was used to evaluate interobserver reliability. RESULTS: Surgeons were more accurate than radiologists in identifying normal studies (specificity = 91.6% vs 78.9%), whereas both groups had similar accuracy in identifying abnormal studies (sensitivity = 82.3% vs 85.2%). There was higher agreement amongst surgeons than amongst radiologists when determining wrap position (kappa = 0.65 vs 0.54). Both groups had low agreement when classifying a wrap migration as partial or total (kappa = 0.33 vs 0.06). Radiologists were more likely to interpret the position of the wrap as abnormal (relative risk = 1.25) while surgeons reported a greater degree of hold up of contrast at the gastro-oesophageal junction (mean score = 1.17 vs 0.86). CONCLUSION: Radiologists would benefit from more information about the technical details of laparoscopic anti-reflux surgery. Standardised protocols for performing post-fundoplication contrast studies are needed. PMID- 21791507 TI - Artisan iris-claw lenses for the correction of aphakia in children following lensectomy for ectopia lentis. AB - PURPOSE: To describe the results of Artisan iris-claw lens implants in children with aphakia following lensectomy for ectopia lentis. METHOD: We measured visual acuity, refractive error and endothelial cell counts and recorded complications in a group of children after insertion of Artisan iris-claw implants. RESULTS: Artisan implants were implanted in eight eyes of five children. Mean follow-up was 28 months (range: 4-58 months). The mean preoperative LogMAR best-corrected visual acuity was 0.21 +/- 0.2, and postoperatively, mean LogMAR uncorrected visual acuity was 0.04 +/- 0.09 (p=0.04). Mean endothelial cell count was 3312 +/ 277 cells preoperatively and 2913 +/- 268 cells postoperatively, representing a mean cell loss of 14.2% (p<0.001). Mean defocus equivalent was 11.38 +/- 1.04 preoperatively and 2.34 +/- 0.66 postoperatively. We encountered no postoperative complications in any of the eyes. CONCLUSION: Artisan iris-claw implants are safe and effective in the correction of aphakia in children following lensectomy for ectopia lentis, enabling good spectacle-free distance vision in 75% of eyes with no postoperative complications. PMID- 21791508 TI - Glaucoma in indigenous Australians. PMID- 21791509 TI - Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. AB - AIMS: To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularisation (CNV). METHODS: The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subretinal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). RESULTS: 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. CONCLUSIONS: Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies. PMID- 21791510 TI - Current situation and future challenges of tobacco control policy in Thailand. AB - In Thailand, the prevalence of smoking has steadily declined over the past 20 years, suggesting an effective tobacco control policy. However, the prevalence has recently stabilised and youth smoking now appears to be on the rise. Tobacco use is the third highest risk factor contributing to the burden of disease in the country. This is an issue of concern and led to the present review of tobacco control measures in Thailand. The present evidence-based review shows that Thailand's tobacco control measures are relatively strong and comply well with the WHO Framework Convention on Tobacco Control in terms of taxation, advertisement through popular media, and warning labels on cigarettes and other tobacco product packages. However, challenges remain in dealing with highly prevalent roll-your-own cigarettes, strict prohibition of tobacco sale to underage youths, household smoking, illicit trade of tobacco products, viable tobacco crop diversification for domestic tobacco growers and liability. If these challenges are met, the prevalence of tobacco consumption could possibly be further reduced. PMID- 21791511 TI - CD8 T cell deficiency impairs control of Epstein--Barr virus and worsens with age in multiple sclerosis. PMID- 21791512 TI - Myocardial pathology in pulmonary thromboembolism. AB - OBJECTIVE: To assess the nature of necroinflammatory changes identified in postmortem histological sections of the right ventricular myocardium in cases of fatal pulmonary thromboembolism (PTE). DESIGN/SETTING: A retrospective study examining coronial autopsy cases (n = 28, age 58 +/- 21 years, 9 men/19 women) of PTE in which isolated right ventricular myocardial pathology was encountered. Detailed immunohistological analysis was undertaken on sections of myocardium, and comparison was made to age- and sex-matched controls (n=28, age 57 +/- 21 years, 9 men/19 women) without significant cardiorespiratory disease. RESULTS: The PTE was considered extensive in 86% of cases, and histological features of organisation were observed in 68%. PTE cases had similar body mass indices to controls (32 +/- 2 kg/m(2) vs 28 +/- 2 kg/m(2), p = 0.13) but greater heart weights (414 +/- 17 g vs 358 +/- 18 g, p = 0.02) and, where documented, thicker right ventricular walls (4.8 +/- 0.3 mm (n = 18) vs 3.4 +/- 0.2 mm (n = 15), p = 0.0008). The inflammatory infiltrate in PTE cases comprised predominantly macrophages and T cells, though neutrophilic inflammation was a frequent accompaniment. Myocyte necrosis was identified in association with the inflammatory foci in 64%. There was a 6.6-fold greater amount of diffuse macrophage recruitment within the right ventricle in cases of PTE compared to controls (p<0.0001), and there was a 6.1-fold increase in right ventricular fibrosis (p = 0.01). Right ventricular fatty replacement was similar between the two groups (p = 0.46). CONCLUSIONS: We conclude that PTE may result in right ventricular myocardial inflammation and necrosis, distinct from that seen in typical myocardial infarction due to atherosclerotic coronary artery disease, or myocarditis. This observation may be explained, in part, by local stretch and strain of the right ventricle due to increased afterload, possibly compounded by diminished diastolic blood flow to the right ventricular myocardium and the effects of global myocardial hypoxia. PMID- 21791513 TI - Non-cardiac surgery in patients with coronary stents: the RECO study. AB - CONTEXT: Interruption or maintenance of oral antiplatelet therapy (OAT) during an invasive procedure may result in ischaemic and/or haemorrhagic complications. There is currently a lack of clear guidance regarding the issue of treatment interruption during surgical procedures. OBJECTIVE: To evaluate the rate of major adverse cardiac and cerebrovascular events (MACCEs) and major or minor bleeding complications and their associated independent correlates in coronary stented patients undergoing urgent or planned non-cardiac surgery. DESIGN, SETTING, AND PATIENTS: Prospective, multicentre, observational cohort study of 1134 consecutive patients with coronary stents. MAIN OUTCOME MEASURES: The co-primary endpoints consisted of the incidence of MACCE and major bleeding within the first 30 days of an invasive procedure. RESULTS: MACCE and haemorrhagic complications were observed in 124 (10.9%) and 108 (9.5%) patients, respectively, within an average time delay from invasive procedure to event of 3.3+/-3.9 and 5.3+/-5.3 days. Independent preoperative correlates for MACCE were complete OAT interruption for more than 5 days prior to surgery, preoperative haemoglobin <10 g/dl, creatinine clearance of <30 ml/min and emergency or high-risk surgery. Independent factors for haemorrhagic complications were preoperative haemoglobin <10 g/dl, creatinine clearance between 30 and 60 ml/min, a delay from stent implantation to surgery <3 months and high-risk surgery according to the Lee classification. CONCLUSIONS: Patients with coronary stents undergoing an invasive procedure are at high risk of perioperative myocardial infarction including stent thrombosis irrespective of the stent type and major bleeding. Interruption of OAT more than 5 days prior to an invasive procedure is a key player for MACCE. CLINICAL TRIAL REGISTRATION: NCT01045850. PMID- 21791514 TI - Genetic determinants of coronary heart disease: new discoveries and insights from genome-wide association studies. AB - With the advent of the Human Genome Project and the genomic era, new tools and methodologies have revitalised genetic research into coronary heart disease (CHD). Unprecedented collaborative efforts are discovering novel risk variants for CHD, with most in hitherto unknown molecular pathways. These findings have stimulated a plethora of follow-up of functional and risk prediction studies to mine this wealth of new data. This review will explore the current state of knowledge of the genetic basis of CHD, with an emphasis on recent genomic studies and how these may eventually lead to the promised goals of new therapeutics and personalised medicine. PMID- 21791515 TI - Improving prediction of long-term success of ablation for atrial fibrillation. PMID- 21791516 TI - Successfully treated descending necrotizing mediastinitis through thoracotomy using a pedicled muscular serratus anterior flap. AB - Descending necrotizing mediastinitis (DNM) is rare and aggressive. A 68-year-old female with no medical history, was admitted to our institution for cervical cellulitis. After a conventional medical treatment, multiple abscesses of the upper mediastinum appeared on computed tomography (CT) findings. Although two cervicotomies were performed, a new necrotic abscess appeared in the anterior upper and middle mediastinum. An extensive debridement of cellulitis and abscess extended to the pericardium was made by thoracotomy. Middle mediastinum and pericardium were covered and reconstructed by a right pedicled serratus anterior flap. After radical surgery, follow-up was uneventful. Early extensive and complete debridement of cervical and mediastinal collections and irrigation with broad-spectrum intravenous antibiotics is essential. Combined surgery is the best approach in DNM. The use of a pedicled muscular flap helps control the sepsis. In such cases, serratus anterior flap is a flap of choice because it is reliable and always available even in a skinny patient, contrary to omentum. In this life threatening disease, an early aggressive combined surgery with debridement of all necrotic tissues extended to the pericardium if necessary associated with a pedicled flap is mandatory. PMID- 21791517 TI - Neonatal repair of right interrupted aortic arch with cerebro-myocardial perfusion technique. AB - Right interrupted aortic arch and descending aorta is exceedingly rare and most likely cause respiratory presentation, since patent ductus arteriosus (PDA) courses over the right mainstem bronchus. We report a case of successful neonatal biventricular repair of a right interrupted aortic arch (type B), with an aberrant right subclavian artery ventricular septal defect (VSD) in a 2.7 kg term neonate with DiGeorge syndrome. Patient presented in severe respiratory distress and acidosis at one day old. Two-dimensional (2D) echocardiography revealed aortic arch interruption beyond the common carotid arteries with large perimembranous outlet VSD. Aortic annulus diameter was 4.8 mm and there was no left ventricle (LV) outflow tract obstruction. Three-dimensional (3D) CT-scan confirmed these findings and identified a right-sided ductal arch that continued over the right mainstem bronchus into a right-sided descending aorta and aberrant right subclavian artery. Brachiocephalic perfusion and ductal perfusion was employed for cooling during cardiopulmonary bypass. Under deep hypothermia (27 degrees C rectal temperature), selective cerebro-myocardial perfusion was used for successful aortic arch repair without sacrificing the aberrant right subclavian artery. A direct tension-free anastomosis was attained. Her postoperative course was uneventful and her respiratory symptoms disappeared postoperatively. Early surgical correction is mandatory for these patients with unique anatomy and presentation. PMID- 21791518 TI - Coexistence of a pulmonary adenocarcinoma with a focal organizing pneumonia. AB - We report a case of a pulmonary adenocarcinoma in coexistence with an organizing pneumonia. A 73-year-old male presented with an abnormal shadow on a chest X-ray. The pathological diagnosis, made via a partial resection, was a focal organizing pneumonia with reactive proliferation of the bronchial epithelium. Three years later, two tumors adjacent to the staple line were revealed by computed tomography. A left lower lobectomy was performed and both tumors were diagnosed as an adenocarcinoma. Because the histological findings for the atypical epithelial areas of the previous tumor were similar to the two new lesions in this patient, we regarded these tumors as a marginal recurrence. PMID- 21791519 TI - The 'packing of the groin' technique: an innovative approach for groin lymphocele. AB - Groin lymphocele is a serious complication of vascular and cardiac surgery as well as of interventional procedures that cannulate the femoral vessels, whose treatment lacks standardization because of high risk of failure. The aim of the technique we describe is the sealing of open lymphatic channels thanks to prolonged external compression of the groin by application of prolene or silk stitches tied upon plastic pledgets. We have used our technique, called 'packing of the groin', as first treatment in 10 patients affected by lymphocele of the groin: nine patients had complete resolution of the lymph leakage, followed by normal healing of the wound whereas one patient had infective complication with treatment failure. Our technique is simple and safe with appreciable results in terms of success and it does not require immobilization with positive effects on patient's management. PMID- 21791520 TI - Does prophylactic inhaled nitric oxide reduce morbidity and mortality after lung transplantation? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was does prophylactic inhaled nitric oxide (NO) reduce morbidity and mortality after lung transplantation? Altogether 232 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. Primary graft dysfunction and failure are serious complications in the first few days following lung transplantation. These phenomena are characterised by bilateral infiltrates on chest radiographs, reduced lung compliance and increased FiO(2) requirements and alveolar-arterial gradients; thus necessitating prolonged mechanical ventilation and often leading to significant mortality. The process known as ischaemic-reperfusion injury is thought to underlie primary graft failure. The studies conducted examining the role of inhaled NO in preventing morbidity and mortality after orthotropic lung transplant tend to focus on potential reductions in the incidence of ischaemic reperfusion injury as the determinant of clinical outcomes. The majority of these are unfortunately non-randomised and/or uncontrolled studies. All the studies discussed, including the two prospective randomised controlled trials, suffer from small sample sizes. Nonetheless, despite their limitations, there are currently, no randomised controlled studies that demonstrate a reduction in morbidity [time to extubation, length of intensive care unit (ICU) or hospital stay] or mortality. As such it is difficult to currently, recommend the routine use of prophylactic inhaled NO in lung transplant surgery. Further studies may outline a benefit in certain types of surgeries, e.g. single-lung transplants or double-lung requiring cardiopulmonary bypass. PMID- 21791521 TI - Long-term results of endovascular aortic repair for thoracic pseudoaneurysms after previous surgical coarctation repair. AB - OBJECTIVES: Late aneurysm formation has been reported after every type of surgical coarctation repair in up to 10%, with rupture of such aneurysms being responsible for approximately 7% of all deaths. Secondary surgical repair carries a significant mortality (up to 15%) and morbidity rate (recurrent laryngeal nerve paralysis ~20%, phrenic nerve injury ~5%). According to the positive experience with endovascular therapy of atherosclerotic thoracic aortic aneurysms, it is worthwhile to evaluate the concept of minimally invasive endovascular stent grafting for secondary repair of postsurgical aneurysms. METHODS: Data were collected prospectively on consecutive patients who presented with postcoarctation false aneurysms. RESULTS: Since 1999, in a cohort of 210 endovascularly treated patients with thoracic and thoracoabdominal aortic pathologies, four patients with postcoarctation false aneurysms underwent endoluminal stent-graft placement. All of these procedures were technically successful without 30-day or one-year procedure-related mortality. After a follow up of 71 months in median (range, 7-93 months; mean, 60.5 months), all aneurysms remain excluded without any endoleak. CONCLUSIONS: According to the current limited experience of small series, the endoluminal repair seems to be a promising alternative to redo open operations for postsurgical thoracic aneurysms associated with coarctation repair. Long-term follow-up of our small cohort confirmed the durability of the stent-graft treatment. PMID- 21791522 TI - How effective is cryoablation for atrial fibrillation during concomitant cardiac surgery? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether performing cryoablative procedures during concomitant cardiac surgical procedures is effective for the treatment of atrial fibrillation (AF). Altogether 291 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All studies showed that cryoablation during concomitant surgery had a significant effect on return to sinus rhythm (SR) conversion rate. One study showed that cryoablation was significantly more effective than mitral valve surgery alone at a 12-month follow-up (73.3% vs. 42.9%, respectively, P=0.013). The use of a concomitant cryoablative procedure has also been shown to be far superior to subsequent catheter based cryoablation in returning patients to SR at a 12-month follow-up (82% and 55.2%, respectively, P<0.001). Another study showed a significant return to AF over a three-year period (91.8% and 84.1% at discharge and three years, respectively). Return to SR was significantly decreased in those patients suffering from permanent rather than paroxysmal AF (47% vs. 85%, P<0.001). Paucity of level 1 evidence was a major limitation to this analysis. All nine papers were either small randomised controlled trials or retrospective studies with small sample sizes (57-521) and varied follow-up regimens. Six of nine studies suggested that cryoablation is most successful in patients suffering from paroxysmal rather than permanent AF. A lack of 24-h monitoring in seven of nine studies prevented effective elucidation of the rate of paroxysmal AF following cryoablation. Only one study suggested an increased complication rate from cryoablation, however, none suggested any negative impact on mortality or morbidity. We conclude that cryoablation during concomitant surgery is a safe and acceptable intervention for the treatment of AF with an SR conversion rate of between 60% and 82% at 12-months postsurgery. PMID- 21791523 TI - The development of a new measure of social-emotional functioning for young adolescents. AB - Social and emotional impairments are frequently reported following acquired brain injury, including an inability to adopt another's perspective, empathize, and display guilt, and inappropriate social conduct. Case studies suggest that these problems are particularly apparent when the injury is sustained in childhood, with deficits increasing with age and persisting throughout adulthood. In addition to these deficits, individuals may have limited insight into their cognitive or social-emotional deficits, which in turn may also affect social functioning and have implications for the success of rehabilitation. Despite the frequency of these problems, there is a dearth of suitable measures for detecting them in children or adolescents. The purpose of the current study was to develop one such measure from a measure initially intended for adults. Normative data were collected from 109 typically-developing 11- to 14-year-olds and their parent/guardian on the Social-Emotional Questionnaire for Children (SEQ-C). Factor and reliability analyses were conducted and the subscales were then explored in association with key demographic information. Social-emotional development showed a fluctuating course across early adolescence, alongside some gender differences. This measure, with its normative data, will be of value to neuropsychologists wishing to explore such functioning in their clinical practice. PMID- 21791524 TI - Test of time: Anna Freud's Normality and Pathology in Childhood (1965). PMID- 21791525 TI - An interview with Magdalena Gotz. PMID- 21791527 TI - Fgf signaling controls pharyngeal taste bud formation through miR-200 and Delta Notch activity. AB - Taste buds, the taste sensory organs, are conserved in vertebrates and composed of distinct cell types, including taste receptor, basal/presynaptic and support cells. Here, we characterize zebrafish taste bud development and show that compromised Fgf signaling in the larva results in taste bud reduction and disorganization. We determine that Fgf activity is required within pharyngeal endoderm for formation of Calb2b(+) cells and reveal miR-200 and Delta-Notch signaling as key factors in this process. miR-200 knock down shows that miR-200 activity is required for taste bud formation and in particular for Calb2b(+) cell formation. Compromised delta activity in mib(-/-) dramatically reduces the number of Calb2b(+) cells and increases the number of 5HT(+) cells. Conversely, larvae with increased Notch activity and ascl1a(-/-) mutants are devoid of 5HT(+) cells, but have maintained and increased Calb2b(+) cells, respectively. These results show that Delta-Notch signaling is required for intact taste bud organ formation. Consistent with this, Notch activity restores Calb2b(+) cell formation in pharyngeal endoderm with compromised Fgf signaling, but fails to restore the formation of these cells after miR-200 knock down. Altogether, this study provides genetic evidence that supports a novel model where Fgf regulates Delta Notch signaling, and subsequently miR-200 activity, in order to promote taste bud cell type differentiation. PMID- 21791526 TI - An emerging role for TOR signaling in mammalian tissue and stem cell physiology. AB - The mammalian target of rapamycin (mTOR) is a kinase that responds to a myriad of signals, ranging from nutrient availability and energy status, to cellular stressors, oxygen sensors and growth factors. The finely tuned response of mTOR to these stimuli results in alterations to cell metabolism and cell growth. Recent studies of conditional knockouts of mTOR pathway components in mice have affirmed the role of mTOR signaling in energy balance, both at the cell and whole organism levels. Such studies have also highlighted a role for mTOR in stem cell homeostasis and lifespan determination. Here, we discuss the molecular mechanisms of TOR signaling and review recent in vitro and in vivo studies of mTOR tissue specific activities in mammals. PMID- 21791529 TI - The web of science subject category 'primary health care'. PMID- 21791528 TI - Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development. AB - Goblet cell metaplasia and mucus overproduction contribute to the pathogenesis of chronic lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notch signaling regulates cell fate decisions and is crucial in controlling goblet cell differentiation in the gut epithelium. Little is known, however, about how endogenous Notch signaling influences the goblet cell differentiation program that takes place in the postnatal lung. Using a combination of genetic and in vitro approaches here we provide evidence of a novel role for Notch in restricting goblet cell differentiation in the airway epithelium during the postnatal period. Conditional inactivation of the essential Notch pathway component Pofut1 (protein O-fucosyltransferase1) in Tgfb3-Cre expressing mice resulted in an aberrant postnatal airway phenotype characterized by marked goblet cell metaplasia, decreased Clara cell number and increase in ciliated cells. The presence of the same phenotype in mice in which the Notch transcriptional effector Rbpjk was deleted indicated the involvement of the canonical Notch pathway. Lineage study in vivo suggested that goblet cells originated from a subpopulation of Clara cells largely present in proximal airways in which Notch was disrupted. The phenotype was confirmed by a panel of goblet cell markers, showed no changes in cell proliferation or altered expression of proinflammatory cytokines and was associated with significant downregulation of the bHLH transcriptional repressor Hes5. Luciferase reporter analysis suggested that Notch directly repressed MUC5AC transcription in lung epithelial cells. The data suggested that during postnatal life Notch is required to prevent Clara cells from differentiating into goblet cells. PMID- 21791530 TI - The use of electronic databases in primary care research. PMID- 21791531 TI - Role of HIV-1 RNA and protein determinants for the selective packaging of spliced and unspliced viral RNA and host U6 and 7SL RNA in virus particles. AB - HIV-1 particles contain RNA species other than the unspliced viral RNA genome. For instance, viral spliced RNAs and host 7SL and U6 RNAs are natural components that are non-randomly incorporated. To understand the mechanism of packaging selectivity, we analyzed the content of a large panel of HIV-1 variants mutated either in the 5'UTR structures of the viral RNA or in the Gag-nucleocapsid protein (GagNC). In parallel, we determined whether the selection of host 7SL and U6 RNAs is dependent or not on viral RNA and/or GagNC. Our results reveal that the polyA hairpin in the 5'UTR is a major packaging determinant for both spliced and unspliced viral RNAs. In contrast, 5'UTR RNA structures have little influence on the U6 and 7SL RNAs, indicating that packaging of these host RNAs is independent of viral RNA packaging. Experiments with GagNC mutants indicated that the two zinc-fingers and N-terminal basic residues restrict the incorporation of the spliced RNAs, while favoring unspliced RNA packaging. GagNC through the zinc finger motifs also restricts the packaging of 7SL and U6 RNAs. Thus, GagNC is a major contributor to the packaging selectivity. Altogether our results provide new molecular insight on how HIV selects distinct RNA species for incorporation into particles. PMID- 21791532 TI - Alignment of distantly related protein structures: algorithm, bound and implications to homology modeling. AB - MOTIVATION: Building an accurate alignment of a large set of distantly related protein structures is still very challenging. RESULTS: This article presents a novel method 3DCOMB that can generate a multiple structure alignment (MSA) with not only as many conserved cores as possible, but also high-quality pairwise alignments. 3DCOMB is unique in that it makes use of both local and global structure environments, combined by a statistical learning method, to accurately identify highly similar fragment blocks (HSFBs) among all proteins to be aligned. By extending the alignments of these HSFBs, 3DCOMB can quickly generate an accurate MSA without using progressive alignment. 3DCOMB significantly excels others in aligning distantly related proteins. 3DCOMB can also generate correct alignments for functionally similar regions among proteins of very different structures while many other MSA tools fail. 3DCOMB is useful for many real-world applications. In particular, it enables us to find out that there is still large improvement room for multiple template homology modeling while several other MSA tools fail to do so. AVAILABILITY: 3DCOMB is available at http://ttic.uchicago.edu/~jinbo/software.htm. CONTACT: jinboxu@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21791533 TI - VISTA Region Viewer (RViewer)--a computational system for prioritizing genomic intervals for biomedical studies. AB - SUMMARY: Current genome browsers are designed for linear browsing of individual genomic regions, but the high-throughput nature of experiments aiming to elucidate the genetic component of human disease makes it very important to develop user-friendly tools for comparing several genomic regions in parallel and prioritizing them based on their functional content. We introduce VISTA Region Viewer (RViewer), an interactive online tool that allows for efficient screening and prioritization of regions of the human genome for follow-up studies. The tool takes as input genetic variation data from different biomedical studies, determines a number of various functional parameters for both coding and non coding sequences in each region and allows for sorting and searching the results of the analysis in multiple ways. AVAILABILITY AND IMPLEMENTATION: The tool is implemented as a web application and is freely accessible on the Web at http://rviewer.lbl.gov CONTACT: rviewer@lbl.gov; ildubchak@lbl.gov. PMID- 21791534 TI - A dynamic programming algorithm for identification of triplex-forming sequences. AB - MOTIVATION: Current methods for identification of potential triplex-forming sequences in genomes and similar sequence sets rely primarily on detecting homopurine and homopyrimidine tracts. Procedures capable of detecting sequences supporting imperfect, but structurally feasible intramolecular triplex structures are needed for better sequence analysis. RESULTS: We modified an algorithm for detection of approximate palindromes, so as to account for the special nature of triplex DNA structures. From available literature, we conclude that approximate triplexes tolerate two classes of errors. One, analogical to mismatches in duplex DNA, involves nucleotides in triplets that do not readily form Hoogsteen bonds. The other class involves geometrically incompatible neighboring triplets hindering proper alignment of strands for optimal hydrogen bonding and stacking. We tested the statistical properties of the algorithm, as well as its correctness when confronted with known triplex sequences. The proposed algorithm satisfactorily detects sequences with intramolecular triplex-forming potential. Its complexity is directly comparable to palindrome searching. AVAILABILITY: Our implementation of the algorithm is available at http://www.fi.muni.cz/lexa/triplex as source code and a web-based search tool. The source code compiles into a library providing searching capability to other programs, as well as into a stand-alone command-line application based on this library. CONTACT: lexa@fi.muni.cz SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21791535 TI - ReplacementMatrix: a web server for maximum-likelihood estimation of amino acid replacement rate matrices. AB - SUMMARY: Amino acid replacement rate matrices are an essential basis of protein studies (e.g. in phylogenetics and alignment). A number of general purpose matrices have been proposed (e.g. JTT, WAG, LG) since the seminal work of Margaret Dayhoff and co-workers. However, it has been shown that matrices specific to certain protein groups (e.g. mitochondrial) or life domains (e.g. viruses) differ significantly from general average matrices, and thus perform better when applied to the data to which they are dedicated. This Web server implements the maximum-likelihood estimation procedure that was used to estimate LG, and provides a number of tools and facilities. Users upload a set of multiple protein alignments from their domain of interest and receive the resulting matrix by email, along with statistics and comparisons with other matrices. A non parametric bootstrap is performed optionally to assess the variability of replacement rate estimates. Maximum-likelihood trees, inferred using the estimated rate matrix, are also computed optionally for each input alignment. Finely tuned procedures and up-to-date ML software (PhyML 3.0, XRATE) are combined to perform all these heavy calculations on our clusters. AVAILABILITY: http://www.atgc-montpellier.fr/ReplacementMatrix/ CONTACT: olivier.gascuel@lirmm.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at http://www.atgc-montpellier.fr/ReplacementMatrix/ PMID- 21791536 TI - Baseline left ventricular dP/dtmax rather than the acute improvement in dP/dtmax predicts clinical outcome in patients with cardiac resynchronization therapy. AB - AIMS: The maximum rate of left ventricular (LV) pressure rise (dP/dt(max)) has been used to assess the acute haemodynamic effect of cardiac resynchronization therapy (CRT). We tested the hypothesis that LV dP/dt(max) predicts long-term clinical outcome after initiation of CRT. METHODS AND RESULTS: This was a retrospective observational multicentre study in 285 patients in whom dP/dt(max) was measured invasively following implantation of a CRT device. The minimum required follow-up was 1 year. We analysed the relationship between dP/dt(max) and time to the composite endpoint, consisting of all-cause mortality, heart transplantation (HTX), or LV assist device (LVAD) implantation within the first year of CRT. Thirty-four events occurred after a mean follow-up of 160 days (range 21-359). Patients with an event had lower dP/dt(max) than patients without an event both at baseline (705 +/- 194 vs. 800 +/- 222 mmHg/s, P= 0.018) and during CRT (894 +/- 224 vs. 985 +/- 244 mmHg/s, P= 0.033), but the acute increase in dP/dt(max) was similar in patients with and without an event (190 +/- 133 vs. 185 +/- 115 mmHg/s, P= n.s.). Left ventricular dP/dt(max)-level at baseline and during CRT both predicted the clinical outcome after adjustment for gender, aetiology and New York Heart Association class: hazard ratio (HR) 0.791 [95% confidence interval (CI) 0.658-0.950, P= 0.012] and HR 0.846 (95% CI 0.723-0.991, P= 0.038), respectively. CONCLUSION: Left ventricular dP/dt(max) measured at baseline and during CRT are predictors of 1-year survival free from all-cause mortality, HTX, or LVAD implantation, but the acute improvement in dP/dt(max) is not correlated to clinical outcome. PMID- 21791537 TI - Revisiting the cardio-renal hypothesis: the pivotal role of the kidney in congestive heart failure. PMID- 21791538 TI - Home care in heart failure: towards an integrated care model. PMID- 21791539 TI - Measuring shortness of breath in heart failure (SOB-HF): development and validation of a new dyspnoea assessment tool. AB - AIM: To validate a previously developed instrument for measurement of breathlessness in patients with acute heart failure (HF). METHODS AND RESULTS: We tested descriptors of breathlessness among 190 patients seeking care at the emergency department (ED) for acute shortness of breath. Out of 115 patients with confirmed HF, 107 (94%) had dyspnoea as their main symptom. There were no significant differences between those patients with HF and those who were not diagnosed as heart failure (NHF) (n = 75) in the descriptors of breathlessness, although patients with HF scored significantly (P = 0.03) higher on a visual analogue scale (VAS). In addition, they had significantly (P = 0.03) higher breathing frequency than NHF patients and they were significantly (P < 0.001) more likely to be treated with >40 mg furosemide. CONCLUSION: Assessment of acute dyspnoea using a VAS is useful in distinguishing HF from NHF, and may be a more valid approach as compared with using descriptors of intensity of breathlessness in the acute setting. PMID- 21791540 TI - Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. AB - AIMS: Neutrophil gelatinase-associated lipocalin (NGAL) is a measure of acute kidney injury. Renal dysfunction portends significant risk after discharge from acute heart failure (AHF). Thus, a sensitive marker of renal injury might also help to risk stratify HF patients. METHODS AND RESULTS: GALLANT [NGAL EvaLuation Along with B-type NaTriuretic Peptide (BNP) in acutely Decompensated Heart Failure] was a multicentre, prospective study to assess the utility of plasma NGAL, alone and in combination with BNP, as an early risk marker of adverse outcomes. We studied 186 patients (61% male). There were 29 events (AHF readmissions and all-cause mortality) at 30 days (16%). Patients with events had higher levels of NGAL than those without (134 vs. 84 ng/mL, P < 0.001). The area under the receiver operating characteristic curve was higher for NGAL (0.72) than BNP (0.65), serum creatinine (0.57), or estimated glomerular filtration rate (eGFR; 0.55). In multivariable analyses, NGAL predicted events (P= 0.001), BNP approached significance (P= 0.052 and 0.070 without creatinine and GFR, respectively) while neither serum creatinine nor eGFR were significant. The addition of discharge NGAL over BNP alone improved classification by a net 10.3% in those with events and 19.5% in those without events, for a net reclassification improvement of 29.8% (P= 0.010). Subjects with both BNP and NGAL elevated were at significant risk [hazard ratio (HR) = 16.85, P= 0.006], as were subjects with low BNP and high NGAL (HR = 9.95, P= 0.036). CONCLUSIONS: Plasma NGAL is a measure of kidney injury that at the time of discharge is a strong prognostic indicator of 30 days outcomes in patients admitted for AHF. CLINICAL TRIAL REGISTRATION NUMBER: NCT 00693745. PMID- 21791541 TI - Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients. AB - AIMS: Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. METHODS AND RESULTS: This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0-4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5-3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. CONCLUSION: Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies. PMID- 21791542 TI - Are beta2-agonists responsible for increased mortality in heart failure? AB - AIMS: Previous large-scale, retrospective studies have shown increased mortality in heart failure (HF) patients using beta2-agonists (B2As). We further examined the relationship between B2A use and mortality in a well-characterized population by adjusting for natriuretic peptide levels as a measure of HF severity. METHODS AND RESULTS: This was a retrospective cohort study of patients attending an HF Disease Management Programme with mean follow-up of 2.9 +/- 2.4 years. Chart review confirmed B2A use, dose and duration of use, and documented pulmonary function evaluation. The primary endpoint was the effect of B2A use compared with no B2A use on mortality using unadjusted and adjusted Kaplan-Meier survival curves. Data were available for 1294 patients (age 70.6 +/- 11.5 years) of whom 64% were male and 22.2% were taking B2As. beta2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma, and less likely to take beta-blockers. Multivariable associates of mortality included: B-type natriuretic peptide (BNP), coronary artery disease, age, and beta-blocker use. Unadjusted mortality rates for B2A users were found to be significantly higher than non-B2A users [hazard ratio (HR) 1.304, 95% confidence interval (CI) 1.030-1.652, P= 0.028]. However, when adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771 1.412), P= 0.783]. CONCLUSION: Unlike previous reports, this retrospective evaluation of B2A therapy in HF patients shows no relationship with long-term mortality when adjusted for population differences including BNP. Large, prospective studies are required to define the risk/benefit ratio of B2As in patients with heart failure. PMID- 21791543 TI - The Heart failure and Optimal Outcomes from Pharmacy Study (HOOPS): rationale, design, and baseline characteristics. AB - AIMS: The effect on mortality and morbidity of pharmacist-led intervention to optimize pharmacological therapy in patients with systolic heart failure (HF) has not been tested in a large-scale, long-term, clinical trial. METHODS: We describe the rationale and design of a UK, primary care-based, prospective cluster randomized controlled trial of a pharmacist-led intervention in HF and report baseline characteristics of the patients randomized. Eighty-seven practices (1092 patients) were assigned to the intervention arm and 87 practices (1077 patients) to usual care. The average age of patients at baseline was 71 years, 70% were male, 86% were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and 62% with a beta-blocker. Data for the primary outcome of death from any cause or hospitalization for HF will be available up to 31 December 2010, giving a mean follow-up of 5 years. More than 750 patients would have experienced the primary outcome during this period. The first secondary outcome is death from any cause or hospitalization for a cardiovascular reason. Deaths and hospitalizations are being identified using the Scottish National Health Service electronic patient record-linkage system (hence the delay between the end of follow-up and database lock). CONCLUSION: This trial is powered to provide a robust evaluation of the effect of pharmacist-led treatment optimization in patients with systolic HF in primary care. PMID- 21791544 TI - RPT2a, a 26S proteasome AAA-ATPase, is directly involved in Arabidopsis CC-NBS LRR protein uni-1D-induced signaling pathways. AB - Arabidopsis semi-dominant uni-1D shows both constitutive defense responses and diverse morphological defects. In particular, uni-1D homozygote (uni-1D) mutants exhibit severe phenotypes including not only highly up-regulated pathogenesis related-1(PR-1) gene expression, but also lethality in the early stage of true leaf formation after germination. The gene responsible for the mutant encodes a coiled-coil-nucleotide-binding site-leucine-rich repeat (CC-NBS-LRR)-type R protein that functions in the recognition of pathogen and the triggering of defense responses. However, the molecular basis of how uni-1D can induce these phenotypes was unknown. In this study, we isolated the regulatory particle triple ATPase (RPT) subunits 2a and 2b, base components of the 19S regulatory particle in the 26S proteasome, as uni-1D-interacting proteins using yeast two-hybrid screening. Genetic studies showed that crossing with the rpt2a mutant reduces the level of uni-1D-induced PR-1 gene expression and suppresses the lethality of uni 1D, by leading to restoration of lost expression of the WUSCHEL gene, which functions to maintain meristem activity, in the shoot apical mersitem of uni-1D. These results suggest that RPT2a is a major interacting partner of uni-1D/UNI, and that the interaction between uni-1D and RPT2a is responsible for activating both morphology and defense signals. PMID- 21791545 TI - Research on orchid biology and biotechnology. AB - Orchidaceae constitute one of the largest families of angiosperms. They are one of the most ecological and evolutionary significant plants and have successfully colonized almost every habitat on earth. Because of the significance of plant biology, market needs and the current level of breeding technologies, basic research into orchid biology and the application of biotechnology in the orchid industry are continually endearing scientists to orchids in Taiwan. In this introductory review, we give an overview of the research activities in orchid biology and biotechnology, including the status of genomics, transformation technology, flowering regulation, molecular regulatory mechanisms of floral development, scent production and color presentation. This information will provide a broad scope for study of orchid biology and serve as a starting point for uncovering the mysteries of orchid evolution. PMID- 21791546 TI - Number and phenotype of rheumatoid arthritis patients' CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept. AB - OBJECTIVE: To analyse the therapeutic effects of etanercept (ETA) or adalimumab (ADA) on the numbers and phenotypes of CD4+CD25hi Tregs in RA patients. METHODS: RA patients received ADA (n = 28) or ETA (n = 20) and stable-dose MTX or LEF. Therapeutic responses were assessed with the 28-joint DAS (DAS-28) criteria after 12 weeks of treatment. Treg numbers and phenotypes, determined by flow cytometry using different gating strategies, were compared between responders and non responders before and after 6 and 12 weeks of treatment. RESULTS: The percentages of good, moderate and non-responders among patients given ADA or ETA, respectively, were 46.5, 35.7 and 17.8% or 30, 20 and 50%, with respective mean (s.d.) pre-treatment CD4+CD25hi Treg percentages of 5.5 (0.04)% or 4.95 (0.02)%. Overall, for patients with active RA given ADA or ETA, neither TNF-alpha-blocking agent had an effect on Tregs percentage and absolute number. Moreover, CD4+CD25hi Treg counts remained unaffected in RA responders to ADA or ETA, compared with RA non-responders. Furthermore, the CD4+CD25hiCD45RA+, CD4+CD25hiCD45RO+ and CD4+CD25hiCD62L+ cell populations were unchanged by TNF-alpha-blocking agents. CONCLUSION: Neither ADA nor ETA modified the percentages or absolute numbers of circulating CD4+CD25hi Tregs and their phenotypes after being administered for 6 and 12 weeks to RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00234234. PMID- 21791547 TI - Effects of genetic polymorphisms of programmed cell death 1 and its ligands on the development of ankylosing spondylitis. AB - OBJECTIVES: There is a known association of imbalanced peripheral tolerance and autoimmune diseases. The binding of programmed cell death 1 (PD-1) with its ligands 1 and 2 (PD-L1 and PD-L2) inhibits T-cell proliferation through a negative signal via recruitment of src homology 2-domain-containing tyrosine phosphatase 2. Therefore we evaluated the effect of the PD-1, PD-L1 and PD-L2 genotypes on the occurrence of AS in a population of Taiwanese patients. METHODS: Genetic polymorphisms of PD-1 G-536A, PD-L1 A8923C and PD-L2 C47103T were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 330 AS patients and 330 healthy controls who were matched by age and gender. RESULTS: Subjects with the PD-1 GG genotype [matched relative risk (RR(m)) 1.78; 95% CI 1.13, 2.81] and the GA genotype (RR(m) 1.59; 95% CI 1.09, 2.31) had significantly greater risk for AS than those with the AA genotype. Subjects with the PD-L2 CT genotype had lower risk for AS than those with the CC genotype (RR(m) 0.01; 95% CI 0.001, 0.06). Interestingly, the combined genotypes of PD-1 G-536A, PD-L1 A8923C and PD-L2 C47103T also appear to be associated with AS development. CONCLUSIONS: Our results suggest that PD-1 G-536A, PD-L1 A8923C and PD-L2 C47103T polymorphisms are associated with the presence of AS. PMID- 21791548 TI - The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. AB - Sirtuin 2 (SIRT2) is one of seven known mammalian protein deacetylases homologous to the yeast master lifespan regulator Sir2. In recent years, the sirtuin protein deacetylases have emerged as candidate therapeutic targets for many human diseases, including metabolic and age-dependent neurological disorders. In non neuronal cells, SIRT2 has been shown to function as a tubulin deacetylase and a key regulator of cell division and differentiation. However, the distribution and function of the SIRT2 microtubule (MT) deacetylase in differentiated, postmitotic neurons remain largely unknown. Here, we show abundant and preferential expression of specific isoforms of SIRT2 in the mammalian central nervous system and find that a previously uncharacterized form, SIRT2.3, exhibits age-dependent accumulation in the mouse brain and spinal cord. Further, our studies reveal that focal areas of endogenous SIRT2 expression correlate with reduced alpha-tubulin acetylation in primary mouse cortical neurons and suggest that the brain-enriched species of SIRT2 may function as the predominant MT deacetylases in mature neurons. Recent reports have demonstrated an association between impaired tubulin acetyltransferase activity and neurodegenerative disease; viewed in this light, our results showing age-dependent accumulation of the SIRT2 neuronal MT deacetylase in wild-type mice suggest a functional link between tubulin acetylation patterns and the aging brain. PMID- 21791549 TI - Allele-specific distribution of RNA polymerase II on female X chromosomes. AB - While the distribution of RNA polymerase II (PolII) in a variety of complex genomes is correlated with gene expression, the presence of PolII at a gene does not necessarily indicate active expression. Various patterns of PolII binding have been described genome wide; however, whether or not PolII binds at transcriptionally inactive sites remains uncertain. The two X chromosomes in female cells in mammals present an opportunity to examine each of the two alleles of a given locus in both active and inactive states, depending on which X chromosome is silenced by X chromosome inactivation. Here, we investigated PolII occupancy and expression of the associated genes across the active (Xa) and inactive (Xi) X chromosomes in human female cells to elucidate the relationship of gene expression and PolII binding. We find that, while PolII in the pseudoautosomal region occupies both chromosomes at similar levels, it is significantly biased toward the Xa throughout the rest of the chromosome. The general paucity of PolII on the Xi notwithstanding, detectable (albeit significantly reduced) binding can be observed, especially on the evolutionarily younger short arm of the X. PolII levels at genes that escape inactivation correlate with the levels of their expression; however, additional PolII sites can be found at apparently silenced regions, suggesting the possibility of a subset of genes on the Xi that are poised for expression. Consistent with this hypothesis, we show that a high proportion of genes associated with PolII accessible sites, while silenced in GM12878, are expressed in other female cell lines. PMID- 21791551 TI - Dietary kakrol (Momordica dioica Roxb.) flesh inhibits triacylglycerol absorption and lowers the risk for development of fatty liver in rats. AB - Kakrol (Momordica dioica Roxb.) is a cucurbitaceous vegetable native to India and Bangladesh. Bitter gourd (Momordica charantia Linn.), a species related to kakrol, has been shown to have pharmacological properties including antidiabetic and antisteatotic effects. In this study, we investigated the effect of dietary kakrol on lipid metabolism in rats. Sprague-Dawley rats were fed AIN-76 formula diets containing 3% freeze-dried powders of whole kakrol or bitter gourd for two weeks. Results showed significantly lowered liver cholesterol and triacylglycerol levels in rats fed on both diets. Fecal lipid excretion increased in rats fed the kakrol diet, and lymphatic transport of triacylglycerol and phospholipids decreased in rats fed the kakrol diet after permanent lymph cannulation. Furthermore, n-butanol extract from kakrol caused a significant concentration dependent decrease in the pancreatic lipase activity in vitro. These results indicate that the mechanisms of action on lipid metabolism in kakrol and bitter gourd are different and that dietary kakrol reduces liver lipids by inhibiting lipid absorption. PMID- 21791550 TI - Common variants at VRK2 and TCF4 conferring risk of schizophrenia. AB - Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 * 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 * 10(-9)). PMID- 21791552 TI - Effect of moderate-to-severe chronic kidney disease on flow-mediated dilation and progenitor cells. AB - A reduction in progenitor cell populations that help preserve vascular continuity and induce vascularization may accentuate endothelial cell apoptosis and dysfunction, ultimately contributing to organ failure and increased cardiovascular disease in chronic kidney disease (CKD). We hypothesized that CD45+ myeloid and CD34+ hematopoietic circulating progenitor cell (CPC) subpopulations would be reduced, peripheral blood mononuclear cell (PBMNC) colony forming units (CFU) would be impaired, and flow-mediated dilation (FMD) would be impaired in patients with moderate-to-severe CKD as compared with healthy controls. Eleven moderate-to-severe CKD patients (mean estimated glomerular filtration rate [eGFR]: 36 +/- 5) and 14 healthy controls were studied; blood was drawn and FMD was assessed by brachial artery FMD. CPCs were quantified via flow cytometry, and isolated PBMNCs were cultured for the colony-forming assay. CKD patients had significantly impaired FMD; lower CD34+, CD34+/KDR+, CD34+/CD45- and CD34+/KDR+/CD45- hematopoietic CPCs; lower CD45+, CD45+/KDR+, CD34+/CD45+ and CD34+/KDR+/CD45+ myeloid CPCs; and impaired CFUs as compared with healthy controls. Regression analysis revealed that CD34+, CD34+/KDR+ and CD34+/CD45- hematopoietic CPCs were associated positively with eGFR and negatively with blood urea nitrogen and serum creatinine. The CD45+/KDR+ myeloid CPCs also were associated positively with eGFR and negatively with serum creatinine. CD34+ hematopoietic CPCs and CD45+/KDR+ as well as CD34+/CD45+ myeloid CPCs were associated positively with FMD. In conclusion, myeloid and hematopoietic CPCs are reduced and associated with renal function as well as FMD in CKD. Therefore, reductions in CPCs may be a potential mechanism by which vascular integrity is compromised, increasing cardiovascular disease risk and contributing to renal disease progression in CKD. PMID- 21791553 TI - Transplantation of induced bone marrow mesenchymal stem cells improves the cardiac function of rabbits with dilated cardiomyopathy via upregulation of vascular endothelial growth factor and its receptors. AB - Bone marrow mesenchymal stem cells (BMMSCs) have shown promise in repairing injured myocardium. However, few studies have explored the potential of BMMSC transplantation for dilated cardiomyopathy (DCM). In this study we aimed to examine whether BMMSC transplantation improves the cardiac function of dilated cardiomyopathy and investigate the underlying mechanism. We established a DCM model in rabbit, then transplanted BMMSCs induced by 5-azacytidine into the rabbit, and determined the left ventricular pressure and the expression of vascular endothelial growth factor (VEGF) and its receptors. Immunohistochemistry, ultrastructural and reverse transcription polymerase chain reaction (RT-PCR) analysis proved that 5-azacytidine induced the differentiation of BMMSCs into cardiomyocyte-like cells. Upon transplantation of the induced BMMSCs into a DCM model, significantly higher maximum rates of rise and decline (+/-dp/dt) of left ventricular pressure and left ventricular systolic pressure, as well as much lower left ventricular diastolic pressure, were observed compared with the control group (P < 0.05). After four weeks, deposition of collagen fibers in the myocardium of transplantation group was reduced, accompanied by increased expression of VEGF and its receptors as detected by RT-PCR. Taken together, our results suggest that BMMSC transplantation could alleviate DCM through angiogenesis via the upregulation of VEGF and its receptors. PMID- 21791554 TI - A guide to using RNAi and other nucleotide-based technologies. PMID- 21791555 TI - RNA interference in mammals: behind the screen. AB - The discovery of RNA interference (RNAi) and the development of technologies exploiting its biology have enabled scientists to rapidly examine the consequences of depleting a particular gene product in a cell or an animal. The availability of genome-wide RNAi libraries targeting the mouse and human genomes has made it possible to carry out large scale, phenotype-based screens, which have yielded seminal information on diverse cellular processes ranging from virology to cancer biology. Today, several strategies are available to perform RNAi screens, each with their own technical and monetary considerations. Special care and budgeting must be taken into account during the design of these screens in order to obtain reliable results. In this review, we discuss a number of critical aspects to consider when planning an effective RNAi screening strategy, including selecting the right biological system, designing an appropriate selection scheme, optimizing technical aspects of the screen, and validating and verifying the hits. Similar to an artistic production, what happens behind the screen has a direct impact on its success. PMID- 21791556 TI - Inducible brown adipogenesis of supraclavicular fat in adult humans. AB - Brown adipose tissue (BAT) plays key roles in thermogenesis and energy homeostasis in rodents. Metabolic imaging using positron emission tomography (PET)-computer tomography has identified significant depots of BAT in the supraclavicular fossa of adult humans. Whether supraclavicular fat contains precursor brown adipocytes is unknown. The aim of the present study was to determine the adipogenic potential of precursor cells in human supraclavicular fat. We obtained fat biopsies from the supraclavicular fossa of six individuals, as guided by PET-computer tomography, with paired sc fat biopsies as negative controls. Each piece of fat tissue was divided and processed for histology, gene analysis, and primary culture. Cells were examined for morphological changes in culture and harvested for RNA and protein upon full differentiation for analysis of UCP1 level. Histological/molecular analysis of supraclavicular fat revealed higher abundance of BAT in PET-positive than PET-negative individuals. In all subjects, fibroblast-like cells isolated from supraclavicular fat differentiated in vitro and uniformly into adipocytes containing multilobulated lipid droplets, expressing high level of UCP1. The total duration required from inoculation to emergence of fibroblast-like cells was 32-34 and 40-42 d for PET-positive- and PET-negative-derived samples, respectively, whereas the time required to achieve full differentiation was 7 d, regardless of PET status. Precursor cells from sc fat failed to proliferate or express UCP1. In summary, preadipocytes isolated from supraclavicular fat are capable of differentiating into brown adipocytes in vitro, regardless of PET status. This study provides the first evidence of inducible brown adipogenesis in the supraclavicular region in adult humans. PMID- 21791557 TI - Gonadotropin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood-brain barrier. AB - GnRH neurons project axons to the median eminence to control pituitary release of gonadotropins and, as such, represent the principal output neurons of the neuronal network controlling fertility. It is well established that the GnRH neurons exhibit a simple bipolar morphology with one or two long dendrites. Using adult GnRH-green fluorescent protein transgenic mice and juxtacellular cell filling, we report here that a subpopulation of GnRH neurons located in the rostral preoptic area exhibit extremely complex branching dendritic trees that fill the organum vasculosum of the lamina terminalis (OVLT). The dendritic nature of these processes was demonstrated at both light and electron microscopic levels by the presence of spines, dendritic ultrastructure, and synapses. Further, electrophysiological recordings showed that GnRH neurons were excited by glutamate as well as kisspeptin puffed onto their dendrites located within the OVLT. Using iv injection of horseradish peroxidase, a molecule unable to penetrate the blood-brain barrier (BBB), we show that GnRH neuron cell bodies and dendrites within 100 MUm of the OVLT reside outside the BBB. Approximately 85% of GnRH neurons in this area express c-Fos at the time of the GnRH surge. These observations demonstrate that GnRH neurons extend complex, highly branched dendritic trees beyond the BBB into the OVLT, where they will be able to sense directly molecules circulating in the bloodstream. This indicates a new mechanism for the modulation of GnRH neurons that extends considerably the range of factors that are integrated by these neurons for the control of fertility. PMID- 21791558 TI - Systematic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. AB - Protease genes were identified that exhibited increased mRNA levels before and immediately after rupture of the naturally selected, dominant follicle of rhesus macaques at specific intervals after an ovulatory stimulus. Quantitative real time PCR validation revealed increased mRNA levels for matrix metalloproteinase (MMP1, MMP9, MMP10, and MMP19) and a disintegrin and metalloproteinase with thrombospondin-like repeats (ADAMTS1, ADAMTS4, ADAMTS9, and ADAMTS15) family members, the cysteine protease cathepsin L (CTSL), the serine protease urokinase type plasminogen activator (PLAU), and the aspartic acid protease pepsinogen 5 (PGA5). With the exception of MMP9, ADAMTS1, and PGA5, mRNA levels for all other up-regulated proteases increased significantly (P < 0.05) 12 h after an ovulatory human chorionic gonadotropin (hCG) bolus. MMP1, -10, and -19; ADAMTS1, -4, and 9; CTSL; PLAU; and PGA5 also exhibited a secondary increase in mRNA levels in 36 h postovulatory follicles. To further determine metalloproteinase involvement in ovulation, vehicle (n = 4) or metalloproteinase inhibitor (GM6001, 0.5 MUg/follicle, n = 8) was injected into the preovulatory follicle at the time of hCG administration. Of the eight GM6001-injected follicles, none displayed typical stigmata indicative of ovulation at 72 h after hCG; whereas all four vehicle-injected follicles ovulated. No significant differences in mean luteal progesterone levels or luteal phase length occurred between the two groups. Subsequent histological analysis revealed that vehicle-injected follicles ruptured, whereas GM6001-injected follicles did not, as evidenced by an intact stroma and trapped oocytes (n = 3). These findings demonstrate metalloproteinases are critical for follicle rupture in primates, and blocking their activity would serve as a novel, nonhormonal means to achieve contraception. PMID- 21791559 TI - Identification and regulation of bone morphogenetic protein antagonists associated with preantral follicle development in the ovary. AB - The TGFbeta superfamily comprises several bone morphogenetic proteins (BMP) capable of exerting gonadotropin-independent effects on the development of small preantral follicles. In embryonic tissues, BMP concentration gradients, partly formed by antagonistic factors, are essential for establishing phenotypic fate. By examining the expression of candidate genes whose protein products are known to interact with BMP ligands, we set out to determine which antagonists would most likely contribute toward regulation of paracrine signaling during early follicle development. Juvenile mouse ovaries of 4, 8, 12, and 21 d of age enriched with follicles at successive developmental stages were used to assess changes in candidate gene transcripts by quantitative RT-PCR. Although some antagonists were found to be positively associated with the emergence of developing follicles (Nog, Htra1, Fst, Bmper, Vwc2), two (Sostdc1, Chrd) showed a corresponding reduction in expression. At each age, twisted gastrulation homolog 1 (Twsg1), Htra1, Nbl1, and Fst were consistently highly expressed and localization of these genes by in situ hybridization, and immunohistochemistry further highlighted a clear pattern of expression in granulosa cells of developing follicles. Moreover, with the exception of Nbl1, levels of these antagonists did not change in preantral follicles exposed to FSH in vitro, suggesting regulation by local factors. The presence of multiple antagonists in the juvenile ovary and their high level of expression in follicles imply the actions of certain growth factors are subject to local modulation and further highlights another important level of intraovarian regulation of follicle development. PMID- 21791560 TI - Differential effects of growth hormone versus insulin-like growth factor-I on the mouse plasma proteome. AB - The GH/IGF-I axis has both pre- and postpubertal metabolic effects. However, the differential effects of GH and/or IGF-I on animal physiology or the plasma proteome are still being unraveled. In this report, we analyzed several physiological effects along with the plasma proteome after treatment of mice with recombinant bovine GH or recombinant human IGF-I. GH and IGF-I showed similar effects in increasing body length, body weight, lean and fluid masses, and organ weights including muscle, kidney, and spleen. However, GH significantly increased serum total cholesterol, whereas IGF-I had no effect on it. Both acute and longer term effects on the plasma proteome were determined. Proteins found to be significantly changed by recombinant bovine GH and/or recombinant human IGF-I injections were identified by mass spectrometry (MS) and MS/MS. The identities of these proteins were further confirmed by Western blotting analysis. Isoforms of apolipoprotein A4, apolipoprotein E, serum amyloid protein A-1, clusterin, transthyretin, and several albumin fragments were found to be differentially regulated by GH vs. IGF-I in mouse plasma. Thus, we have identified several plasma protein biomarkers that respond specifically and differentially to GH or IGF-I and may represent new physiological targets of these hormones. These findings may lead to better understanding of the independent biological effects of GH vs. IGF-I. In addition, these novel biomarkers may be useful for the development of tests to detect illicit use of GH or IGF-I. PMID- 21791561 TI - Male hypogonadism and germ cell loss caused by a mutation in Polo-like kinase 4. AB - The genetic etiologies of male infertility remain largely unknown. To identify genes potentially involved in spermatogenesis and male infertility, we performed genome-wide mutagenesis in mice with N-ethyl-N-nitrosourea and identified a line with dominant hypogonadism and patchy germ cell loss. Genomic mapping and DNA sequence analysis identified a novel heterozygous missense mutation in the kinase domain of Polo-like kinase 4 (Plk4), altering an isoleucine to asparagine at residue 242 (I242N). Genetic complementation studies using a gene trap line with disruption in the Plk4 locus confirmed that the putative Plk4 missense mutation was causative. Plk4 is known to be involved in centriole formation and cell cycle progression. However, a specific role in mammalian spermatogenesis has not been examined. PLK4 was highly expressed in the testes both pre- and postnatally. In the adult, PLK4 expression was first detected in stage VIII pachytene spermatocytes and was present through step 16 elongated spermatids. Because the homozygous Plk4(I242N/I242N) mutation was embryonic lethal, all analyses were performed using the heterozygous Plk4(+/I242N) mice. Testis size was reduced by 17%, and histology revealed discrete regions of germ cell loss, leaving only Sertoli cells in these defective tubules. Testis cord formation (embryonic day 13.5) was normal. Testis histology was also normal at postnatal day (P)1, but germ cell loss was detected at P10 and subsequent ages. We conclude that the I242N heterozygous mutation in PLK4 is causative for patchy germ cell loss beginning at P10, suggesting a role for PLK4 during the initiation of spermatogenesis. PMID- 21791562 TI - Transcriptomic analysis of the osmotic and reproductive remodeling of the female rat supraoptic nucleus. AB - The supraoptic nucleus (SON) of the hypothalamus is an important integrative brain structure that coordinates responses to perturbations in water balance and regulates maternal physiology through the release of the neuropeptide hormones vasopressin and oxytocin into the circulation. Both dehydration and lactation evoke a dramatic morphological remodeling of the SON, a process known as function related plasticity. We hypothesize that some of the changes seen in SON remodeling are mediated by differential gene expression, and have thus used microarrays to document global changes in transcript abundance that accompany chronic dehydration in female rats, and in lactation. In situ hybridization analysis has confirmed the differential expression of three of these genes, namely TNF-induced protein 6, gonadotropin-inducible transcription factor 1, and ornithine decarboxylase antizyme inhibitor 1. Comparison of differential gene expression patterns in male and female rats subjected to dehydration and in lactating rats has enabled the identification of common elements that are significantly enriched in gene classes with particular functions. Two of these are related to the requirement for increased protein synthesis and hormone delivery in the physiologically stimulated SON (translation initiation factor activity and endoplasmic reticulum-Golgi intermediate compartment, respectively), whereas others are consistent with the concept of SON morphological plasticity (collagen fibril organization, extracellular matrix organization and biogenesis, extracellular structure organization and biogenesis, and homophilic cell adhesion). We suggest that the genes coordinately regulated in the SON as a consequence of dehydration and lactation form a network that mediates the plastic processes operational in the physiologically activated SON. PMID- 21791564 TI - Deficiency in interferon-gamma results in reduced body weight and better glucose tolerance in mice. AB - Obesity is a chronic low-grade inflammatory disease caused by increased energy intake and reduced energy expenditure. Studies using animal models with deletion of inflammatory cytokines have produced conflicting results with some showing increased weight gain and others showing no effect or even reduced body weights. Clearly, more work is necessary to understand the role of cytokines on body weight control. The aim of this study was to determine the effect of interferon gamma deletion (IFNgamma(-/-)) on body weight regulation and glucose metabolism. Male IFNgamma(-/-) and wild-type C57BL/6 mice were fed a low-fat chow diet, and body weight, food intake, and energy expenditure were monitored over 20 wk. At the end of the study, ip glucose tolerance test, insulin tolerance test, basal glucose turnover, and hyperinsulinemic/euglycemic clamps were performed. Expression levels of arcuate nucleus neuropeptide Y, Agouti-related peptide, and proopiomelanocortin mRNA as well as circulating leptin levels were also determined. IFNgamma(-/-) mice had improved glucose tolerance with reduced rate of glucose appearance and increased insulin sensitivity due to greater suppression of endogenous glucose output, which was associated with decreased hepatic glucose-6-phosphatase activity. In addition, we also observed reduced body weight associated with decreased food intake and increased physical activity. Neuropeptide Y and Agouti-related peptide mRNA expression was reduced, whereas proopiomelanocortin mRNA expression was increased, as were plasma leptin levels. Global deletion of IFNgamma in mice resulted in reduced body weight associated with negative energy balance, improved glucose tolerance, and hepatic insulin sensitivity. Our findings demonstrate that IFNgamma plays a critical role in the regulation of body weight and glucose metabolism. PMID- 21791563 TI - PPARgamma-independent increase in glucose uptake and adiponectin abundance in fat cells. AB - Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)gamma induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARgamma or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARgamma, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARgamma and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2 infected cell types under the following conditions: 1) undifferentiated human adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARgamma inhibitor, 4) NIH/3T3 that have impaired PPARgamma expression, and 5) PPARgamma-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARgamma served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARgamma, Ad36 significantly enhanced glucose uptake and PPARgamma, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARgamma. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARgamma induction associated with TZD actions. PMID- 21791565 TI - Postlesion estradiol treatment increases cortical cholinergic innervations via estrogen receptor-alpha dependent nonclassical estrogen signaling in vivo. AB - 17beta-Estradiol (E2) treatment exerts rapid, nonclassical actions via intracellular signal transduction system in basal forebrain cholinergic (BFC) neurons in vivo. Here we examined the effect of E2 treatment on lesioned BFC neurons in ovariectomized mice and the role of E2-induced nonclassical action in this treatment. Mice given an N-methyl-d-aspartic acid (NMDA) injection into the substantia innominata-nucleus basalis magnocellularis complex (SI-NBM) exhibited cholinergic cell loss in the SI-NBM and ipsilateral cholinergic fiber loss in the cortex. A single injection of E2 after NMDA lesion did not have an effect on cholinergic cell loss in the SI-NBM, but it restored the ipsilateral cholinergic fiber density in the cortex in a time- and dose-dependent manner. The most effective cholinergic fiber restoration was observed with 33 ng/g E2 treatment at 1 h after NMDA lesion. The E2-induced cholinergic fiber restoration was absent in neuron-specific estrogen receptor-alpha knockout mice in vivo. Selective activation of nonclassical estrogen signaling in vivo by estren induced E2-like restorative actions. Selective blockade of the MAPK or protein kinase A pathway in vivo prevented E2's ability to restore cholinergic fiber loss. Finally, studies in intact female mice revealed an E2-induced restorative effect that was similar to that of E2-treated ovariectomized mice. These observations demonstrate that a single E2 treatment restores the BFC fiber loss in the cortex, regardless of endogenous E2 levels. They also reveal the critical role of nonclassical estrogen signaling via estrogen receptor-alpha and protein kinase A-MAPK pathways in E2-induced restorative action in the cholinergic system in vivo. PMID- 21791566 TI - Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice. AB - BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders. PMID- 21791567 TI - Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. AB - Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression. PMID- 21791568 TI - Polyamines on the reproductive landscape. AB - The polyamines are ubiquitous polycationic compounds. Over the past 40 yr, investigation has shown that some of these, namely spermine, spermidine, and putrescine, are essential to male and female reproductive processes and to embryo/fetal development. Indeed, their absence is characterized by infertility and arrest in embryogenesis. Mammals synthesize polyamines de novo from amino acids or import these compounds from the diet. Information collected recently has shown that polyamines are essential regulators of cell growth and gene expression, and they have been implicated in both mitosis and meiosis. In male reproduction, polyamine expression correlates with stages of spermatogenesis, and polyamines appear to function in promoting sperm motility. There is evidence for polyamine involvement in ovarian follicle development and ovulation in female mammals, and polyamine synthesis is required for steroidogenesis in the ovary. Studies of the embryo indicate a polyamine requirement that can be met from maternal sources before implantation, whereas elimination of polyamine synthesis abrogates embryo development at gastrulation. Polyamines play roles in embryo implantation, in decidualization, and in placental formation and function, and polyamine privation during gestation results in intrauterine growth retardation. Emerging information implicates dietary arginine and dietary polyamines as nutritional regulators of fertility. The mechanisms by which polyamines regulate these multiple and diverse processes are not yet well explored; thus, there is fertile ground for further productive investigation. PMID- 21791569 TI - Frequency of rearrangements in Lynch syndrome cases associated with MSH2: characterization of a new deletion involving both EPCAM and the 5' part of MSH2. AB - Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3' end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation-dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3' end region of EPCAM to the 5' initial sequences of the MSH2 (c.859-1860_MSH2:646 254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome. PMID- 21791570 TI - Lapatinib, a preventive/therapeutic agent against mammary cancer, suppresses RTK mediated signaling through multiple signaling pathways. AB - Activation of receptor tyrosine kinases (RTK) plays a key role in the prognosis of mammary cancer. Lapatinib is a small molecule dual RTK inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats were given methylnitrosourea (MNU) by intravenous injection resulting in the development of multiple estrogen receptor-positive tumors. Treatment with lapatinib beginning 5 days after MNU was highly effective in preventing cancer development. In addition, we treated rats with palpable mammary tumors with lapatinib daily. In these tumor-bearing animals, treatment continued for 42 days and therapeutic results were obtained. Some rats bearing cancers were treated for 5 days, and the resulting lesions were examined for biomarker modulation. Lapatinib effectively suppressed the abundance of HER2, phosphorylated HER2 (Tyr1221/1222), and phosphorylated EGFR (Tyr1173, Tyr1110) compared with tumors from untreated rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and proteins associated with apoptosis. These results combined with immunoreactivity data indicated that, in addition to EGFR and HER2, lapatinib treatment was associated with changes in a number of other signaling molecules, including IGF-1R, Akt, and downstream targets such as GSK3, p27, p53, and cyclin D1 presumably leading to impaired proliferation, apoptosis, or cell cycle arrest. PMID- 21791571 TI - Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases. AB - Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic beta emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach. PMID- 21791572 TI - A novel chemo-radiotherapy with low-dose daily cisplatin, 5-fluorouracil and doxorubicin for anaplastic thyroid carcinoma: a preliminary report. AB - OBJECTIVE: Although anaplastic thyroid carcinoma has a dismal prognosis, some patients show favorable survival following multimodal treatment with surgery, external irradiation and chemotherapy. However, no regimen has yet been established. We reviewed outcomes for patients who underwent a unique chemoradiotherapy regimen between 1998 and 2007. METHODS: The regimen consists of external irradiation (40 Gy at 2 Gy/day) combined with concurrent low-dose cisplatin at 5 mg/m(2) on Days 1-5, 8-12, 15-19 and 22-26, 5-fluorouracil at 200 mg/m(2) on Days 1-26 and doxorubicin at 20 mg/m(2) on Days 1 and 15. This regimen was performed on 21 patients (13 men, 8 women) with anaplastic thyroid carcinoma. Median age at the time of treatment was 66 years (range, 54-81 years). RESULTS: The treatment regimen was completed in 19 patients (90%) and was interrupted in 2 (10%) due to progressive distant metastases. After excluding 10 patients who underwent complete resection before chemoradiotherapy, 1 patient (11%) showed partial response, 7 (78%) showed stable disease and 1 (11%) had progressive disease on the basis of Response Evaluation Criteria in Solid Tumors. Overall, 6 month survival rate for patients treated with chemoradiotherapy was 57%. With this novel chemoradiotherapy, death from loco-regional disease was seen in only two patients (11%). Grade 3-4 toxicities were observed in 12 patients (63%), but no treatment-related deaths were encountered. CONCLUSIONS: Our new chemoradiotherapy is effective for loco-regional control of anaplastic thyroid carcinoma, particularly when combined with radical surgery. This regimen could not prevent distant metastases, but offers acceptable toxicity while maintaining patient quality of life. PMID- 21791574 TI - Identification of cysteines involved in the effects of methanethiosulfonate reagents on human equilibrative nucleoside transporter 1. AB - Inhibitor and substrate interactions with equilibrative nucleoside transporter 1 (ENT1; SLC29A1) are known to be affected by cysteine-modifying reagents. Given that selective ENT1 inhibitors, such as nitrobenzylmercaptopurine riboside (NBMPR), bind to the N-terminal half of the ENT1 protein, we hypothesized that one or more of the four cysteine residues in this region were contributing to the effects of the sulfhydryl modifiers. Recombinant human ENT1 (hENT1), and the four cysteine-serine ENT1 mutants, were expressed in nucleoside transport-deficient PK15 cells and probed with a series of methanethiosulfonate (MTS) sulfhydryl modifying reagents. Transporter function was assessed by the binding of [(3)H]NBMPR and the cellular uptake of [(3)H]2-chloroadenosine. The membrane permeable reagent methyl methanethiosulfonate (MMTS) enhanced [(3)H]NBMPR binding in a pH-dependent manner, but decreased [(3)H]2-chloroadenosine uptake. [2 (Trimethylammonium)ethyl] methane-thiosulfonate (MTSET) (positively charged, membrane-impermeable), but not sodium (2-sulfonatoethyl)-methanethiosulfonate (MTSES) (negatively charged), inhibited [(3)H]NBMPR binding and enhanced [(3)H]2 chloroadenosine uptake. Mutation of Cys222 in transmembrane (TM) 6 eliminated the effect of MMTS on NBMPR binding. Mutation of Cys193 in TM5 enhanced the ability of MMTS to increase [(3)H]NBMPR binding and attenuated the effects of MMTS and MTSET on [(3)H]2-chloroadenosine uptake. Taken together, these data suggest that Cys222 contributes to the effects of MTS reagents on [(3)H]NBMPR binding, and Cys193 is involved in the effects of these reagents on [(3)H]2-chloroadenosine transport. The results of this study also indicate that the hENT1-C193S mutant may be useful as a MTSET/MTSES-insensitive transporter for future cysteine substitution studies to define the extracellular domains contributing to the binding of substrates and inhibitors to this critical membrane transporter. PMID- 21791575 TI - Long-term alpha1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. AB - The role of alpha(1)-adrenergic receptors (alpha(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. alpha(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term alpha(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the alpha(1A)AR. CAM-alpha(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the alpha(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-alpha(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the alpha(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-alpha(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-alpha(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term alpha(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders. PMID- 21791573 TI - Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference. AB - While management of atrial fibrillation (AF) patients is improved by guideline conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF. PMID- 21791576 TI - Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration. AB - The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the Per-ARNT-Sim family of proteins. These proteins sense molecules and stimuli from the cellular/tissue environment and initiate signaling cascades to elicit appropriate cellular responses. Recent literature reports suggest an important function of AhR in hematopoietic stem cell (HSC) biology. However, the molecular mechanisms by which AhR signaling regulates HSC functions are unknown. In previous studies, we and others reported that treatment of mice with the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compromises the competitive reconstitution of bone marrow (BM) cells into irradiated host animals. Additional studies indicated a requirement for AhR in hematopoietic cells and not marrow microenvironment cells. In this study, we tested the hypothesis that TCDD mediated phenotypic and functional changes of HSCs are a result of changes in gene expression that disrupt stem cell numbers and/or their migration. TCDD treatment to mice increased the numbers of phenotypically defined HSCs in BM. These cells showed compromised migration to the BM in vivo and to the chemokine CXCL12 in vitro, as well as increased expression of the leukemia-associated receptors CD184 (CXCR4) and CD44. Gene expression profiles at 6 and 12 h after exposure were consistent with the phenotypic and functional changes observed. The expressions of Scin, Nqo1, Flnb, Mmp8, Ilf9, and Slamf7 were consistently altered. TCDD also disrupted expression of other genes involved in hematological system development and function including Fos, JunB, Egr1, Ptgs2 (Cox2), and Cxcl2. These data support a molecular mechanism for an AhR ligand to disrupt the homeostatic cell signaling of HSCs that may promote altered HSC function. PMID- 21791577 TI - Identifying population-level indicators to measure the quality of cancer care for women. AB - OBJECTIVE: Although there is interest in measuring the quality of cancer care, there has been limited effort to evaluate quality for specific subpopulations such as women or to examine differences in performance among women associated with sociodemographic characteristics. The objective of this study was to identify a comprehensive set of quality indicators for evaluation of the quality of cancer care received by women using administrative data. DESIGN: A conceptual measurement framework developed by the study investigators was used to guide literature review to identify existing quality indicators. The list of potential indicators from the literature was first reviewed by the study investigators with respect to importance and feasibility to determine a set of indicators to present to an expert panel who used a modified Delphi process to select indicators for inclusion using predetermined explicit criteria. SETTING: The Project for an Ontario Women's Health Evidence-Based Report Card. PARTICIPANTS: A multidisciplinary expert panel consisting of clinicians, researchers and administrators with expertise in cancer, quality of care and/or health services research. MAIN OUTCOME MEASURE: Set of quality indicators evaluable from administrative data. RESULTS: The initial literature search identified 427 indicators, of which 46 were rated as important and feasible by the study investigators. Following two rounds of ratings and an in-person meeting, the expert panel recommended 31 indicators for inclusion in the final set spanning the following areas: general indicators (three indicators), cancer screening (six), colorectal cancer (four), lung cancer (three), breast cancer (five), gynecologic cancers (five), and end-of-life care (five). CONCLUSIONS: A comprehensive set of 31 indicators was identified to evaluate the quality of cancer care received by women that also allows assessment of gender and socioeconomic disparities in cancer care. PMID- 21791578 TI - Direct saliva transcriptome analysis. AB - BACKGROUND: Current standard operating procedures for salivary transcriptomic analysis require low temperatures and lengthy mRNA isolation, which substantially hamper its use in the clinic. We developed a streamlined, ambient-temperature processing, stabilization, and storage protocol for clinical analysis of salivary RNA. METHODS: The direct saliva transcriptome analysis (DSTA) used cell-free saliva supernatant instead of isolated mRNA for saliva transcriptomic detection, and all procedures, including processing, stabilization, and storage of saliva samples, were performed at ambient temperature without a stabilizing reagent. We evaluated this streamlined protocol by comparing the mRNA expression levels of 3 saliva internal reference genes [glyceraldehyde-3-phosphate dehydrogenase (GAPDH); actin, beta (ACTB); and ribosomal protein S9 (RPS9)] to levels measured with standard procedures, and detecting the variation of their expression levels under long-term ambient temperature storage. The clinical utility of DSTA was assessed by use of 7 oral cancer salivary mRNA biomarkers in a clinical study. RESULTS: Each saliva internal reference gene mRNA showed similar expression levels when assayed by the DSTA or standard procedures, and remained stable under ambient temperature storage for at least 10 weeks without significant degradation (P = 0.918, 0.288, and 0.242 for GAPDH, ACTB, and RPS9, respectively). Compared with standard procedures, the performance characteristics of oral cancer salivary transcriptomic markers were retained as assayed by DSTA after 10 weeks of storage at ambient temperature. These results indicate that the DSTA is a suitable alternative method for saliva transcriptomic analysis and is feasible for use in clinical cancer research applications. CONCLUSIONS: The streamlined DSTA protocol can impact the saliva-handling method and improve the standard operating procedures for clinical saliva transcriptomic diagnostics. PMID- 21791579 TI - Stress alters rates and types of loss of heterozygosity in Candida albicans. AB - Genetic diversity is often generated during adaptation to stress, and in eukaryotes some of this diversity is thought to arise via recombination and reassortment of alleles during meiosis. Candida albicans, the most prevalent pathogen of humans, has no known meiotic cycle, and yet it is a heterozygous diploid that undergoes mitotic recombination during somatic growth. It has been shown that clinical isolates as well as strains passaged once through a mammalian host undergo increased levels of recombination. Here, we tested the hypothesis that stress conditions increase rates of mitotic recombination in C. albicans, which is measured as loss of heterozygosity (LOH) at specific loci. We show that LOH rates are elevated during in vitro exposure to oxidative stress, heat stress, and antifungal drugs. In addition, an increase in stress severity correlated well with increased LOH rates. LOH events can arise through local recombination, through homozygosis of longer tracts of chromosome arms, or by whole-chromosome homozygosis. Chromosome arm homozygosis was most prevalent in cultures grown under conventional lab conditions. Importantly, exposure to different stress conditions affected the levels of different types of LOH events, with oxidative stress causing increased recombination, while fluconazole and high temperature caused increases in events involving whole chromosomes. Thus, C. albicans generates increased amounts and different types of genetic diversity in response to a range of stress conditions, a process that we term "stress-induced LOH" that arises either by elevating rates of recombination and/or by increasing rates of chromosome missegregation. IMPORTANCE: Stress-induced mutagenesis fuels the evolution of bacterial pathogens and is mainly driven by genetic changes via mitotic recombination. Little is known about this process in other organisms. Candida albicans, an opportunistic fungal pathogen, causes infections that require adaptation to different host environmental niches. We measured the rates of LOH and the types of LOH events that appeared in the absence and in the presence of physiologically relevant stresses and found that stress causes a significant increase in the rates of LOH and that this increase is proportional to the degree of stress. Furthermore, the types of LOH events that arose differed in a stress-dependent manner, indicating that eukaryotic cells generate increased genetic diversity in response to a range of stress conditions. We propose that this "stress-induced LOH" facilitates the rapid adaptation of C. albicans, which does not undergo meiosis, to changing environments within the host. PMID- 21791580 TI - Physiological differentiation within a single-species biofilm fueled by serpentinization. AB - Carbonate chimneys at the Lost City hydrothermal field are coated in biofilms dominated by a single phylotype of archaea known as Lost City Methanosarcinales. In this study, we have detected surprising physiological complexity in single species biofilms, which is typically indicative of multispecies biofilm communities. Multiple cell morphologies were visible within the biofilms by transmission electron microscopy, and some cells contained intracellular membranes that may facilitate methane oxidation. Both methane production and oxidation were detected at 70 to 80 degrees C and pH 9 to 10 in samples containing the single-species biofilms. Both processes were stimulated by the presence of hydrogen (H(2)), indicating that methane production and oxidation are part of a syntrophic interaction. Metagenomic data included a sequence encoding AMP-forming acetyl coenzyme A synthetase, indicating that acetate may play a role in the methane-cycling syntrophy. A wide range of nitrogen fixation genes were also identified, many of which were likely acquired via lateral gene transfer (LGT). Our results indicate that cells within these single-species biofilms may have differentiated into multiple physiological roles to form multicellular communities linked by metabolic interactions and LGT. Communities similar to these Lost City biofilms are likely to have existed early in the evolution of life, and we discuss how the multicellular characteristics of ancient hydrogen fueled biofilm communities could have stimulated ecological diversification, as well as unity of biochemistry, during the earliest stages of cellular evolution. IMPORTANCE: Our previous work at the Lost City hydrothermal field has shown that its carbonate chimneys host microbial biofilms dominated by a single uncultivated "species" of archaea. In this paper, we integrate evidence from these previous studies with new data on the metabolic activity and cellular morphology of these archaeal biofilms. We conclude that the archaeal biofilm must contain cells that are physiologically and possibly genetically differentiated with respect to each other. These results are especially interesting considering the possibility that the first cells originated and evolved in hydrothermal systems similar to Lost City. PMID- 21791581 TI - Phylogenetic molecular ecological network of soil microbial communities in response to elevated CO2. AB - Understanding the interactions among different species and their responses to environmental changes, such as elevated atmospheric concentrations of CO(2), is a central goal in ecology but is poorly understood in microbial ecology. Here we describe a novel random matrix theory (RMT)-based conceptual framework to discern phylogenetic molecular ecological networks using metagenomic sequencing data of 16S rRNA genes from grassland soil microbial communities, which were sampled from a long-term free-air CO(2) enrichment experimental facility at the Cedar Creek Ecosystem Science Reserve in Minnesota. Our experimental results demonstrated that an RMT-based network approach is very useful in delineating phylogenetic molecular ecological networks of microbial communities based on high-throughput metagenomic sequencing data. The structure of the identified networks under ambient and elevated CO(2) levels was substantially different in terms of overall network topology, network composition, node overlap, module preservation, module based higher-order organization, topological roles of individual nodes, and network hubs, suggesting that the network interactions among different phylogenetic groups/populations were markedly changed. Also, the changes in network structure were significantly correlated with soil carbon and nitrogen contents, indicating the potential importance of network interactions in ecosystem functioning. In addition, based on network topology, microbial populations potentially most important to community structure and ecosystem functioning can be discerned. The novel approach described in this study is important not only for research on biodiversity, microbial ecology, and systems microbiology but also for microbial community studies in human health, global change, and environmental management. IMPORTANCE: The interactions among different microbial populations in a community play critical roles in determining ecosystem functioning, but very little is known about the network interactions in a microbial community, owing to the lack of appropriate experimental data and computational analytic tools. High-throughput metagenomic technologies can rapidly produce a massive amount of data, but one of the greatest difficulties is deciding how to extract, analyze, synthesize, and transform such a vast amount of information into biological knowledge. This study provides a novel conceptual framework to identify microbial interactions and key populations based on high throughput metagenomic sequencing data. This study is among the first to document that the network interactions among different phylogenetic populations in soil microbial communities were substantially changed by a global change such as an elevated CO(2) level. The framework developed will allow microbiologists to address research questions which could not be approached previously, and hence, it could represent a new direction in microbial ecology research. PMID- 21791582 TI - ChePep controls Helicobacter pylori Infection of the gastric glands and chemotaxis in the Epsilonproteobacteria. AB - Microbes use directed motility to colonize harsh and dynamic environments. We discovered that Helicobacter pylori strains establish bacterial colonies deep in the gastric glands and identified a novel protein, ChePep, necessary to colonize this niche. ChePep is preferentially localized to the flagellar pole. Although mutants lacking ChePep have normal flagellar ultrastructure and are motile, they have a slight defect in swarming ability. By tracking the movement of single bacteria, we found that DeltaChePep mutants cannot control the rotation of their flagella and swim with abnormally frequent reversals. These mutants even sustain bursts of movement backwards with the flagella pulling the bacteria. Genetic analysis of the chemotaxis signaling pathway shows that ChePep regulates flagellar rotation through the chemotaxis system. By examining H. pylori within a microscopic pH gradient, we determined that ChePep is critical for regulating chemotactic behavior. The chePep gene is unique to the Epsilonproteobacteria but is found throughout this diverse group. We expressed ChePep from other members of the Epsilonproteobacteria, including the zoonotic pathogen Campylobacter jejuni and the deep sea hydrothermal vent inhabitant Caminibacter mediatlanticus, in H. pylori and found that ChePep is functionally conserved across this class. ChePep represents a new family of chemotaxis regulators unique to the Epsilonproteobacteria and illustrates the different strategies that microbes have evolved to control motility. IMPORTANCE: Helicobacter pylori strains infect half of all humans worldwide and contribute to the development of peptic ulcers and gastric cancer. H. pylori cannot survive within the acidic lumen of the stomach and uses flagella to actively swim to and colonize the protective mucus and epithelium. The chemotaxis system allows H. pylori to navigate by regulating the rotation of its flagella. We identified a new protein, ChePep, which controls chemotaxis in H. pylori. ChePep mutants fail to colonize the gastric glands of mice and are completely outcompeted by normal H. pylori. Genes encoding ChePep are found only in the class Epsilonproteobacteria, which includes the human pathogen Campylobacter jejuni and environmental microbes like the deep-sea hydrothermal vent colonizer Caminibacter mediatlanticus, and we show that ChePep function is conserved in this class. Our study identifies a new colonization factor in H. pylori and also provides insight into the control and evolution of bacterial chemotaxis. PMID- 21791583 TI - Prevalence of corneal dystrophies in the United States: estimates from claims data. AB - PURPOSE: To estimate the prevalence of corneal dystrophies. METHODS: Records of almost 8 million enrollees in a national managed-care network throughout the United States who had an eye care visit in 2001 to 2009 were searched for a recording of corneal dystrophy on a claim submitted by an ophthalmologist or optometrist from January 1, 2001, through December 31, 2007. RESULTS: Unique individuals (n = 27,372) received two or more diagnoses of any type of corneal dystrophy, for an overall corneal dystrophy prevalence rate of 897 per million (106) covered lives. Endothelial and anterior corneal dystrophies accounted for most of the reported dystrophies, and granular corneal dystrophy was the least common, being reported in 167 enrollees. Age, sex, and race variations among the various corneal dystrophies were observed. The mean age of those with macular corneal dystrophy (47.3 years) was 15 years younger than the age of those with endothelial dystrophy (62.9 years), and females were most highly represented (68.5%) among those with lattice corneal dystrophy. Hispanics and blacks were underrepresented relative to enrollees undergoing eye care for reasons other than corneal dystrophy. Keratoplasty was most frequently coded among those with lattice dystrophy. CONCLUSIONS: Although caveats must be considered in using claims data to estimate prevalence in a population, these data provide an indication of corneal dystrophy's prevalence within insured subjects across the United States. Variations in age, sex, and race, within and between the different types of corneal dystrophies, raise questions that warrant further study. PMID- 21791584 TI - Fetal check ligament connected between the conjunctiva and the medial and lateral recti. AB - PURPOSE: There seems to be little or no information about the morphology of the fetal eye check ligament. METHODS: The authors examined longitudinal and cross histologic sections from the large collection of human fetuses at Universidad Complutense, Madrid. RESULTS: In longitudinal sections from 20 fetuses (four at each of 12, 15, 20, 25, and 30 weeks of gestation), a distinct connective tissue band was found connecting the medial and lateral recti and the limbus of the conjunctiva (sites at and around the lateral and medial angles of the conjunctival space). Silver impregnation revealed that the muscle endomysium (type 4 collagen dominant) was connected with composite fibers of the band (type 1 collagen). The cross-sections from three fetuses (20 weeks) exhibited a site dependent difference in the rectus sheaths: the orbital-sided sheath suddenly increased in thickness when it tightly attached to the muscle bundles. The attaching orbital-sided muscle bundles reached 14% to 15% (or 18%-20%) in the cross-sectional area of the MR (or the LR). CONCLUSIONS: Taken together, the distinct connective tissue band extending to the conjunctiva was "originated from" the MR and LR rather than from a part of the muscles inserting into the connective tissue band. This band was most likely a primitive form of the check ligament. The authors hypothesize that the primitive check ligament conducts muscle tension to the conjunctiva to coordinate growth patterns between the anterior and posterior sides of the eyeball. This hypothesis may support en bloc recession for infantile esotropia. PMID- 21791585 TI - Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis. AB - PURPOSE: To investigate the relationship between size of demyelinated lesion, extent of axonal loss, and degree of latency delay of visual evoked potentials (VEPs) in a rat model of experimental demyelination. METHODS: Lysolecithin 1% (0.4 or 0.8 MUL) was microinjected into an optic nerve of each of 14 rats 2 mm posterior to the globe. Standard flash VEPs were recorded with skull-implanted electrodes before and 2, 4, and 6 days after the microinjection. The optic nerves were stained with Luxol-fast blue and Bielschowsky's silver to assess demyelination and axonal pathology, respectively. Demyelinated areas were measured on serial sections, and lesion volumes were deduced by three-dimensional reconstruction. RESULTS: Focal lesions of demyelination and variable axonal loss were observed. The mean volume of the lesion was 3.2 +/- 1.1 * 10-2 mm3. The injected eye showed a significant latency delay and amplitude decrease. Regression analysis demonstrated a strong correlation between N1 latency delay and lesion volume (r = 0.863, P < 0.0001), which remained significant after adjustment for axonal loss (r = 0.829, P < 0.001). N1 latency delay also showed a correlation with axonal loss (r = 0.552, P = 0.041), but the correlation became nonsignificant when controlling for demyelination (r = 0.387, P = 0.191). A linear association between N1-P2 amplitude decrease and axonal loss (r = 0.681, P = 0.007) was also observed. CONCLUSIONS: The latency of the VEP accurately reflected the amount of demyelination in the visual pathway, whereas the amplitude correlated with axonal damage. This study supports the concept that the VEP provides a highly sensitive tool with which to measure demyelination in optic neuritis. PMID- 21791586 TI - 24-hour IOP telemetry in the nonhuman primate: implant system performance and initial characterization of IOP at multiple timescales. AB - PURPOSE: IOP is the most common independent risk factor for development and progression of glaucoma, but very little is known about IOP dynamics. Continuous IOP telemetry was used in three nonhuman primates to characterize IOP dynamics at multiple time scales for multiple 24-hour periods. METHODS: An existing implantable telemetric pressure transducer system was adapted to monitoring anterior chamber IOP. The system records 500 IOP, ECG, and body temperature measurements per second and compensates for barometric pressure in real time. The continuous IOP signal was digitally filtered for noise and dropout and reported using time-window averaging for 19, 18, and 4 24-hour periods in three animals, respectively. Those data were analyzed for a nycthemeral pattern within each animal. RESULTS: Ten-minute time-window averaging for multiple 24-hour periods showed that IOP fluctuated from 7 to 14 mm Hg during the day, and those changes occurred frequently and quickly. Two-hour time-window averages of IOP for multiple 24-hour periods in three animals showed a weak nycthemeral trend, but IOP was not repeatable from day-to-day within animals. CONCLUSIONS: The measured IOP was successfully measured continuously by using a new, fully implantable IOP telemetry system. IOP fluctuates as much as 10 mm Hg from day to day and hour to hour in unrestrained nonhuman primates, which indicates that snapshot IOP measurements may be inadequate to capture the true dynamic character of IOP. The distributions, magnitudes, and patterns of IOP are not reproducible from day to day within animals, but IOP tends to be slightly higher at night when IOP data are averaged across multiple 24-hour periods within animals. PMID- 21791587 TI - Hypodense regions (holes) in the retinal nerve fiber layer in frequency-domain OCT scans of glaucoma patients and suspects. AB - PURPOSE: To better understand hypodense regions (holes) that appear in the retinal nerve fiber layer (RNFL) of frequency-domain optical coherence tomography (fdOCT) scans of patients with glaucoma and glaucoma suspects. METHODS: Peripapillary circle (1.7-mm radius) and cube optic disc fdOCT scans were obtained on 208 eyes from 110 patients (57.4 +/- 13.2 years) with glaucomatous optic neuropathy (GON) and 45 eyes of 45 controls (48.0 +/- 12.6 years) with normal results of fundus examination. Holes in the RNFL were identified independently by two observers on the circle scans. RESULTS: Holes were found in 33 (16%) eyes of 28 (25%) patients; they were not found in any of the control eyes. Twenty-four eyes had more than one hole. Although some holes were relatively large, others were small. In general, the holes were located adjacent to blood vessels; only three eyes had isolated holes that were not adjacent to a vessel. The holes tended to be in the regions that are thickest in healthy controls and were associated with arcuate defects in patients. Holes were not seen in the center of the temporal disc region. They were more common in the superior (25 eyes) than in the inferior (15 eyes) disc. Of the 30 eyes with holes with reliable visual fields, seven were glaucoma suspect eyes with normal visual fields. CONCLUSIONS: The holes in the RNFL seen in patients with GON were probably due to a local loss of RNFL fibers and can occur in the eyes of glaucoma suspects with normal visual fields. PMID- 21791588 TI - The effect of vasopressin on choroidal blood flow, intraocular pressure, and orbital venous pressure in rabbits. AB - PURPOSE: To investigate the effects of arginine-vasopressin (AVP) on intraocular pressure (IOP), orbital venous pressure (OVP), and choroidal blood flow (ChorBF) regulation in anesthetized rabbits. METHODS: Mean arterial pressure (MAP), IOP, and OVP were measured by direct cannulation of the central ear artery, the vitreous, and the orbital venous sinus, respectively. Laser Doppler flowmetry was used to record ChorBF. To change the perfusion pressure (PP), MAP was manipulated mechanically with occluders around the aorta and vena cava. In the first group of animals (n = 11) the dose-response relationship was measured. In the second group of animals (n = 8) pressure-flow relationships were determined at baseline and in response to intravenous application of a low (0.08 ng/kg/min) and a high (1.33 ng/kg/min) infusion rate of AVP. RESULTS: AVP caused a dose-dependent increase of MAP and choroidal vascular resistance (ChorR), whereas IOP, OVP, ChorBF, and heart rate (HR) were decreased. In contrast to the high infusion rate, the low infusion rate of AVP had no effect on baseline ChorBF. However, the pressure-flow relationship was shifted downward significantly by both infusion rates at PP below baseline. CONCLUSIONS: AVP reduces IOP and OVP significantly and is a potent vasoconstrictor in the choroidal vascular bed. In the choroid, the effect of AVP is not only dose-dependent, but also PP-dependent, which is indicated by the reduced perfusion relative to control with low-dosed AVP at low PP. PMID- 21791589 TI - Ocular biometry in an urban Indian population: the Singapore Indian Eye Study (SINDI). AB - PURPOSE. To describe the distribution and determinants of ocular biometric parameters in adult Singapore Indians. METHODS. A population-based, cross sectional study was conducted on 3400 Indians aged 40 to 83 years residing in Singapore. Ocular components including axial length (AL), anterior chamber depth (ACD), and corneal radius (CR) were measured by partial coherence interferometry. Refraction was recorded in spherical equivalent (SE). RESULTS. After 502 individuals with previous cataract surgery were excluded, ocular biometric data on 2785 adults were analyzed. The mean AL, ACD, and CR were 23.45 +/- 1.10, 3.15 +/- 0.36, and 7.61 +/- 0.26 mm, respectively. The mean AL/CR ratio was 3.08 +/- 0.13. The mean AL was 23.53, 23.49, 23.35, and 23.25 mm in 40- to 49-, 50- to 59 , 60- to 69-, and 700 to 83-year age groups, respectively (P < 0.001). Men had significantly longer ALs than women (23.68 mm versus 23.23 mm, P < 0.001). In multivariate linear regression models, AL was found to be longer in adults who were taller (P < 0.001), better educated (University, P < 0.001), and more apt to spend time reading (P < 0.001). Increasing CR was associated with increasing height (P = 0.008). AL was the strongest determinant for refraction in all age groups, whereas lens nuclear opacity was a predictor in adults aged 60 to 83 years. CONCLUSIONS. The AL in Indians living in Singapore was similar to that of Malays in Singapore, but longer than that of Indians living in India. Time spent reading, height, and educational level were the strongest determinants of AL. AL was the strongest predictor of SE in all age groups. PMID- 21791590 TI - Intravitreal concentrations of a near-infrared fluorescence-labeled biotherapeutic determined in situ using confocal scanning laser ophthalmoscopy. AB - PURPOSE: The pharmacokinetics of ophthalmic biotherapeutics are difficult to determine in human vitreous humor. Because of the high transparency of living tissue to near-infrared (NIR) light, the temporal changes in vitreous concentrations of a biomolecule labeled with an NIR fluorescent probe can be monitored in situ with a scanning laser ophthalmoscope (SLO). METHODS: A humanized IgG was labeled with the NIR probe IRDye800CW (CVX-4164). Rabbits were given CVX-4164 intravitreally, and NIR fluorescence intensity was measured in the central plane of the vitreous humor with an SLO. Fluorescence intensities were converted to concentrations by using standard curves. RESULTS: Little background fluorescence was detected, and the minimum detectable concentration of CVX-4164 was <10 nM. Vitreal concentrations of CVX-4164 determined in situ declined with time, with C(max) ~ 1 MUM and t1/2 = 145 hours (112-MUg dose). The t1/2 of CVX 4164 was approximately three times greater than that of the IRDye800CW alone, whereas the vitreal clearance (CL) and volume of distribution (V(ss)) of the native dye were approximately 2000- and 550-fold greater than that of the conjugate. CVX-4164 concentrations determined in situ were 2.6 to 4.4 times higher than those determined by ex vivo NIR fluorescence or ELISA in homogenized vitreous humor, reflecting the greater spatial resolution of in situ imaging. Moreover, vitreal concentrations determined in situ were >3 orders of magnitude greater than plasma concentrations of CVX-4164, as determined by ELISA, and had a different kinetic profile. CONCLUSIONS: This study demonstrates the feasibility of determining the pharmacokinetics of intraocular biotherapeutics labeled with NIR fluorescent probes by in situ monitoring. PMID- 21791591 TI - Quality and reproducibility of retinal thickness measurements in two spectral domain optical coherence tomography machines. AB - PURPOSE: To evaluate the accuracy and reproducibility of retinal thickness measurements in exudative age-related macular degeneration (AMD) by the Spectralis (Heidelberg Engineering, Heidelberg, Germany) and the Cirrus (Carl Zeiss Meditec, Dublin, CA) optical coherence tomography (OCT) systems. METHODS: Eyes with exudative age-related macular degeneration were randomly assigned to one of eight groups, each different in the sequence of examiner and OCT system. The 512 * 128 cube program of the Cirrus and the 30 degrees * 25 degrees volume scan containing 32 lines of the Spectralis were performed twice. The correlation between the examinations was expressed by the interclass correlation coefficient (ICC). RESULTS: Enrolled in the study were 112 patients and 112 eyes (mean age, 76.5 +/- 7.9 years; range 51-89), with 14 patients in each group. The mean error scores per line were 0.53 and 0.52 in the Cirrus, significantly (P < 0.001) lower than in the Spectralis (0.83 and 0.98). For automatic central retinal thickness (CRT), the ICC for Cirrus (all examinations calculated) was 0.61 for groups 1 to 4 (the same examiner) and 0.65 for groups 5 to 8 (two different examiners); for Spectralis (13.4% not calculated) the ICC was 0.93 for groups 1 to 4 and 0.86 for groups 5 to 8. After error correction, the Cirrus ICC improved to 1.0 and 0.99 and the Spectralis ICC to 1.0 in both groups. CONCLUSIONS: Considerable differences were found between the two systems, both of which incorporate the spectral-domain technology. Different positioning of segmentation lines, control of localization, density of included scan lines, and number of available maps explain the differences in segmentation quality and reproducibility. Manual correction of segmentation and centralization improves the reproducibility. PMID- 21791592 TI - Increased Toll-like receptor-2 expression on nonclassic CD16+ monocytes from patients with inflammatory stage of Eales' disease. AB - PURPOSE: To identify the distribution, differential Toll-like receptor (TLR) expression, and functional contribution of monocyte subpopulations in the inflammatory stage of Eales' disease (ED). METHODS: Peripheral blood mononuclear cells were isolated from nine patients during the inflammatory stage of ED and nine age- and sex-matched healthy controls. The expression of CD14, CD16, TLR-2, and TLR-4 on monocytes was measured by flow cytometry. The CD14+, CD16-, and CD16+ monocyte populations were sorted on the basis of magnetic-activated cell sorting methodology, and levels of cytokines were measured by ELISA. RESULTS: In ED patients, the number of circulating monocytes was significantly expanded compared with that in controls (P = 0.01), with a marked increase in the nonclassic CD16+ subset, which showed an activated phenotype in patients that correlated with levels of serum proinflammatory cytokines and clinical progression. A higher expression of cell surface TLR-2 (P = 0.02), but not TLR-4, was found in monocytes of patients with ED. Furthermore, TLR-2 was expressed at higher levels on CD16+ monocytes than on CD16- monocytes in patients, whereas no significant variation was found in TLR-4 expression on different monocyte subsets. Peptidoglycan-induced TNF-alpha expression correlated with TLR-2 expression in monocytes isolated from controls (r = 0.85, P = 0.0061), but not in monocytes isolated from ED patients (r = 0.553, P = 0.1328). CONCLUSIONS: These results indicate that in the pathogenesis of ED, TLR activation and increased numbers of nonclassic CD16+ monocytes are crucial regulators, along with the secretion of proinflammatory cytokines that perpetuate the inflammatory process in the retina. PMID- 21791593 TI - Retinal nerve fiber layer defect and cerebral small vessel disease. AB - PURPOSE: To determine whether retinal nerve fiber layer defect (RNFLD) is associated with cerebral small vessel diseases (SVDs) and to identify risk factors for RNFLD. METHODS: A total of 4421 Korean subjects who underwent health checkups including brain magnetic resonance imaging (MRI) and fundus photography between January 2008 and October 2009 were included in this study. Co-morbid systemic diseases including hypertension, diabetes mellitus, and stroke or ocular diseases were evaluated using detailed questionnaires and medical records. Two experienced ophthalmologists assessed RNFLD on fundus photographs, according to the definition that describes the condition as marked thinning or absence of retinal nerve fiber layer bundles. RESULTS: RNFLD was detected in 238 of 4395 eligible subjects, and the estimated prevalence was 5.4%. Multivariate regression analysis results showed the prevalence of RNFLD to be significantly higher in hypertensive subjects (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.28 2.34), in those with cerebral SVD based on MRI (OR, 1.58; 95% CI, 1.17-2.12), and in male (OR, 1.47; 95% CI, 1.10-1.96) and older subjects (OR, 1.02; 95% CI, 1.00 1.03). Among the cases of cerebral SVD, white matter lesions (WMLs) were associated with RNFLD, whereas lacunar infarctions were not significantly associated with it. CONCLUSIONS: The results indicate that RNFLD may be related to the presence of cerebral SVD, particularly WMLs. Furthermore, being older and male and having hypertension increase the risk of RNFLD. PMID- 21791594 TI - In vivo ocular fluorophotometry: delivery of fluoresceinated dextrans via transscleral diffusion in rabbits. AB - PURPOSE: To evaluate the transscleral delivery of fluoresceinated dextrans (FITC D) with molecular mass up to 70 kDa to the rabbit posterior segment using sub Tenon injections. METHODS: Eighteen NZW rabbits received a unilateral 200-MUL injection of 2 mg/mL sodium fluorescein (NaF), 25 mg/mL 40-kDa FITC-D, or 25 mg/mL 70-kDa FITC-D, with (n = 9) or without (n = 9) immediate euthanatization. In live animals, fluorescence was measured in the retina/choroid and mid-vitreous by fluorophotometry, immediately after injection and after 4, 24, 48, and 72 hours. Euthanatized animals were examined hourly through 5 or 6 hours. RESULTS: In live animals, the average peak NaF concentration in the retina/choroid was 310.2 ng/mL, measured 3 hours after injection. Average 40- and 70-kDa FITC-D concentrations in the retina/choroid peaked at 5409.6 and 2375.6 ng/mL, respectively, 24 hours after injection. Fluorescence returned to baseline levels 6 hours after NaF injection, and 48 and 72 hours after 40- and 70-kDa FITC-D injections, respectively. Rabbits that received NaF followed by euthanatization exhibited a continuous increase in retina/choroid and mid-vitreous fluorescence, beginning 1 hour after injection, whereas FITC-D-injected eyes did not show elevated retina/choroid or mid-vitreous fluorescence through 6 hours. CONCLUSIONS: FITC-D weighing up to 70-kDa, as well as NaF, reached the posterior retina/choroid after sub-Tenon injections in live rabbits. NaF and 40-kDa FITC-D reached higher peak concentrations and were cleared from the eye more rapidly than was 70-kDa FITC-D. There was minimal penetration of NaF and FITC-D into the mid-vitreous in the in vivo experiments. PMID- 21791595 TI - Contribution of mucoviscosity-associated gene A (magA) to virulence in experimental Klebsiella pneumoniae endophthalmitis. AB - PURPOSE: Endogenous endophthalmitis secondary to Klebsiella pneumoniae liver abscess is a blinding infection that is being reported more frequently in the literature. The K1 capsule and magA contribute to virulence of systemic infection in mice; however, little is known about the role of magA in secondary ocular infections. METHODS: To assess the role of K. pneumoniae capsule in endophthalmitis, the authors induced experimental endophthalmitis by direct inoculation of 100 colony-forming unit wild-type, magA-deficient, or magA complemented K. pneumoniae into the posterior segments of mouse eyes. Eyes were analyzed by quantitation of viable bacteria, retinal function, and inflammatory cell influx as well as by histology. RESULTS: Wild-type K1 K. pneumoniae caused significant ocular disease. At the end point of 24 hours postinfection, eyes infected with wild-type K. pneumoniae retained significantly less retinal A-wave function than eyes infected with an isogenic magA-mutant strain. B-wave function retention was also greater in eyes infected with the magA mutant than with wild type K. pneumoniae. Additionally, intraocular growth of the magA-deficient strain was less than it was in the wild-type strain. The amount of myeloperoxidase elicited was also significantly higher for wild-type-infected eyes at 24 hours. CONCLUSIONS: These results indicate that in the eye, the K1 capsule of invasive K. pneumoniae significantly contributes to the ability of the bacteria to disrupt retinal function, to grow to high density, and to persist despite immune cell recruitment. PMID- 21791596 TI - Long-term changes of the anterior corneal topography after photorefractive keratectomy for myopia and myopic astigmatism. AB - PURPOSE: To analyze the anterior corneal topography changes after 8 years after photorefractive keratectomy (PRK) for the correction of myopia and myopic astigmatism. METHODS: Sixty-six eyes (33 patients) underwent PRK using an excimer laser platform. Patients were subdivided into three groups: the low myopia (13 patients; range, -1.25 to -4.40 diopters [D]), the high myopia (13 patients; 4.50 to -9.00 D), and astigmatism (7 patients; cylinder component between -2.00 and -5.00 D) groups. The preoperative and 1-, 2-, 4-, 6-, and 8-year postoperative average corneal maps were computed for each study group. Changes inside and outside the optical zone, which was 6.00 mm in diameter for all eyes, during follow-up were further investigated. RESULTS: The topographic central region, 2.00-mm diameter, was almost stable in all study groups, with changes < 0.39 D between 1 and 8 years. The postoperative variations at the peripheral region, 6.00- to 8.00-mm diameter, were related to the type and amount of refractive correction: a higher flattening (P < 0.05) has been assessed in the high-myopia group (-0.85 D) in comparison with the low-myopia group (-0.42 D) between 1 and 8 years. On the contrary, corneal periphery steepened (+2.22 D; P < 0.05) in the astigmatism group during follow-up, mainly at the superior and inferior emimeridians. CONCLUSIONS: The anterior corneal topography continues to change configuration even long term after PRK. Changes are confined outside the functional optical zone of the cornea. PRK for the correction of myopia was shown not to influence the mechanical stability of the corneal tissue at 8 years after surgery. PMID- 21791598 TI - Protein disulfide isomerase redox-dependent association with p47(phox): evidence for an organizer role in leukocyte NADPH oxidase activation. AB - Mechanisms of leukocyte NADPH oxidase regulation remain actively investigated. We showed previously that vascular and macrophage oxidase complexes are regulated by the associated redox chaperone PDI. Here, we investigated the occurrence and possible underlying mechanisms of PDI-mediated regulation of neutrophil NADPH oxidase. In a semirecombinant cell-free system, PDI inhibitors scrRNase (100 MUg/mL) or bacitracin (1 mM) near totally suppressed superoxide generation. Exogenously incubated, oxidized PDI increased (by ~40%), whereas PDIred diminished (by ~60%) superoxide generation. No change occurred after incubation with PDI serine-mutated in all four redox cysteines. Moreover, a mimetic CxxC PDI inhibited superoxide production by ~70%. Thus, oxidized PDI supports, whereas reduced PDI down-regulates, intrinsic membrane NADPH oxidase complex activity. In whole neutrophils, immunoprecipitation and colocalization experiments demonstrated PDI association with membrane complex subunits and prominent thiol mediated interaction with p47(phox) in the cytosol fraction. Upon PMA stimulation, PDI was mobilized from azurophilic granules to cytosol but did not further accumulate in membranes, contrarily to p47(phox). PDI-p47(phox) association in cytosol increased concomitantly to opposite redox switches of both proteins; there was marked reductive shift of cytosol PDI and maintainance of predominantly oxidized PDI in the membrane. Pulldown assays further indicated predominant association between PDIred and p47(phox) in cytosol. Incubation of purified PDI (>80% reduced) and p47(phox) in vitro promoted their arachidonate dependent association. Such PDI behavior is consistent with a novel cytosolic regulatory loop for oxidase complex (re)cycling. Altogether, PDI seems to exhibit a supportive effect on NADPH oxidase activity by acting as a redox-dependent enzyme complex organizer. PMID- 21791597 TI - TLR2-dependent modulation of dendritic cells by LT-IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin. AB - A host of human pathogens invades the body at mucosal surfaces. Yet, strong, protective mucosal immune responses directed against those pathogens routinely cannot be induced without the use of adjuvants. Although the strongest mucosal adjuvants are members of the family of HLTs, the inherent toxicities of HLT holotoxins preclude their clinical use. Herein, it is shown that LT-IIa-B(5) enhances mucosal immune responses by modulating activities of DCs. i.n. immunization of mice with OVA in the presence of LT-IIa-B(5) recruited DCs to the NALT and significantly increased uptake of OVA by those DCs. Furthermore, LT-IIa B(5) increased expression of CCR7 by DCs, which mediated enhanced migration of the cells from the NALT to the draining CLNs. LT-IIa-B(5) also enhanced maturation of DCs, as revealed by increased surface expression of CD40, CD80, and CD86. Ag-specific CD4(+) T cell proliferation was augmented in the CLNs of mice that had received i.n. LT-IIa-B(5). Finally, when used as an i.n. adjuvant, LT IIa-B(5) dramatically increased the levels of OVA-specific salivary IgA and OVA specific serum IgG. Strikingly, each of the activities induced by LT-IIa-B(5) was strictly TLR2-dependent. The data strongly suggest that the immunomodulatory properties of LT-IIa-B(5) depend on the productive modulation of mucosal DCs. Notably, this is the first report for any HLT to demonstrate in vivo the elicitation of strong, TLR2-dependent modulatory effects on DCs with respect to adjuvanticity. PMID- 21791599 TI - Role of alloreactive KIR2DS1(+) NK cells in haploidentical hematopoietic stem cell transplantation. AB - In allo-HSCT, donor-derived, "alloreactive" NK cells have been shown to play a crucial role in the treatment of acute leukemia, contributing to eradication of leukemic blasts (GvL effect) and to clearance of residual recipient DCs and T lymphocytes (thus, preventing GvHD and graft rejection, respectively). Such alloreactive NK cells do not express CD94/NKG2A but express inhibitory KIRs, specific for HLA class I allotypes, present in the donor but lacking in the recipient. This review is focused on the role of the activating KIR2DS1 receptor (specific for the C2-epitope of HLA-C) in haplo-HSCT. Recent data indicate that KIR2DS1 expression in HSC donors may represent a remarkable advantage in alloreactive NK responses. This is a result of a substantial increase in the NK mediated capability to kill, not only recipients' leukemic cells but also DCs and T cell blasts. The beneficial effects mediated by alloreactive KIR2DS1(+) NK cells may occur after de novo expression of CCR7 upon interaction with allogeneic, KIR ligand-mismatched CCR7(+) cells. As a consequence, they can be redirected to LNs, where they can prevent priming of donor T cells and induction of GvHD. Finally, KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of "not alloreactive" NK cells into potent alloreactive cells. PMID- 21791600 TI - Biphasic gene expression changes elicited by Phakopsora pachyrhizi in soybean correlate with fungal penetration and haustoria formation. AB - Inoculation of soybean (Glycine max) plants with Phakopsora pachyrhizi, the causal organism of Asian soybean rust, elicits a biphasic response characterized by a burst of differential gene expression in the first 12 h. A quiescent period occurs from 24 to 48 h after inoculation, in which P. pachyrhizi continues to develop but does not elicit strong host responses, followed by a second phase of intense gene expression. To correlate soybean responses with P. pachyrhizi growth and development, we inoculated the soybean cultivar Ankur (accession PI462312), which carries the Rpp3 resistance gene, with avirulent and virulent isolates of P. pachyrhizi. The avirulent isolate Hawaii 94-1 elicits hypersensitive cell death that limits fungal growth on Ankur and results in an incompatible response, while the virulent isolate Taiwan 80-2 grows extensively, sporulates profusely, and produces a compatible reaction. Inoculated leaves were collected over a 288-h time course for microarray analysis of soybean gene expression and microscopic analysis of P. pachyrhizi growth and development. The first burst in gene expression correlated with appressorium formation and penetration of epidermal cells, while the second burst of gene expression changes followed the onset of haustoria formation in both compatible and incompatible interactions. The proliferation of haustoria coincided with the inhibition of P. pachyrhizi growth in the incompatible interaction or the beginning of accelerated growth in the compatible interaction. The temporal relationships between P. pachyrhizi growth and host responses provide an important context in which to view interacting gene networks that mediate the outcomes of their interactions. PMID- 21791601 TI - Essential role of tissue-specific proline synthesis and catabolism in growth and redox balance at low water potential. AB - To better define the still unclear role of proline (Pro) metabolism in drought resistance, we analyzed Arabidopsis (Arabidopsis thaliana) Delta(1)-pyrroline-5 carboxylate synthetase1 (p5cs1) mutants deficient in stress-induced Pro synthesis as well as proline dehydrogenase (pdh1) mutants blocked in Pro catabolism and found that both Pro synthesis and catabolism were required for optimal growth at low water potential (psi(w)). The abscisic acid (ABA)-deficient mutant aba2-1 had similar reduction in root elongation as p5cs1 and p5cs1/aba2-1 double mutants. However, the reduced growth of aba2-1 but not p5cs1/aba2-1 could be complemented by exogenous ABA, indicating that Pro metabolism was required for ABA-mediated growth protection at low psi(w). PDH1 maintained high expression in the root apex and shoot meristem at low psi(w) rather than being repressed, as in the bulk of the shoot tissue. This, plus a reduced oxygen consumption and buildup of Pro in the root apex of pdh1-2, indicated that active Pro catabolism was needed to sustain growth at low psi(w). Conversely, P5CS1 expression was most highly induced in shoot tissue. Both p5cs1-4 and pdh1-2 had a more reduced NADP/NADPH ratio than the wild type at low psi(w). These results indicate a new model of Pro metabolism at low psi(w) whereby Pro synthesis in the photosynthetic tissue regenerates NADP while Pro catabolism in meristematic and expanding cells is needed to sustain growth. Tissue-specific differences in Pro metabolism and function in maintaining a favorable NADP/NADPH ratio are relevant to understanding metabolic adaptations to drought and efforts to enhance drought resistance. PMID- 21791602 TI - Balanced interactions between Lyn, the p85alpha regulatory subunit of class I(A) phosphatidylinositol-3-kinase, and SHIP are essential for mast cell growth and maturation. AB - The growth and maturation of bone marrow-derived mast cells (BMMCs) from precursors are regulated by coordinated signals from multiple cytokine receptors, including KIT. While studies conducted using mutant forms of these receptors lacking the binding sites for Src family kinases (SFKs) and phosphatidylinositol 3-kinase (PI3K) suggest a role for these signaling molecules in regulating growth and survival, how complete loss of these molecules in early BMMC progenitors (MCps) impacts maturation and growth during all phases of mast cell development is not fully understood. We show that the Lyn SFK and the p85alpha subunit of class I(A) PI3K play opposing roles in regulating the growth and maturation of BMMCs in part by regulating the level of PI3K. Loss of Lyn in BMMCs results in elevated PI3K activity and hyperactivation of AKT, which accelerates the rate of BMMC maturation due in part to impaired binding and phosphorylation of SHIP via Lyn's unique domain. In the absence of Lyn's unique domain, BMMCs behave in a manner similar to that of Lyn- or SHIP-deficient BMMCs. Importantly, loss of p85alpha in Lyn-deficient BMMCs not only represses the hyperproliferation associated with the loss of Lyn but also represses their accelerated maturation. The accelerated maturation of BMMCs due to loss of Lyn is associated with increased expression of microphthalmia-associated transcription factor (Mitf), which is repressed in MCps deficient in the expression of both Lyn and p85alpha relative to controls. Our results demonstrate a crucial interplay of Lyn, SHIP, and p85alpha in regulating the normal growth and maturation of BMMCs, in part by regulating the activation of AKT and the expression of Mitf. PMID- 21791603 TI - Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. AB - Polymerase eta (PolH) is necessary for translesion DNA synthesis, and PolH deficiency predisposes xeroderma pigmentosum variant (XPV) patients to cancer. Due to the critical role of PolH in translesion DNA synthesis, the activity of PolH is tightly controlled and subjected to multiple regulations, especially posttranslational modifications. Here, we show that PolH-dependent lesion bypass and intracellular translocation are regulated by Pirh2 E3 ubiquitin ligase through monoubiquitination. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues. We also show that monoubiquitination of PolH inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions, leading to decreased viability of UV-damaged cells. Moreover, we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions. Considering that Pirh2 is known to be overexpressed in various cancers, we postulate that in addition to mutation of PolH in XPV patients, inactivation of PolH by Pirh2 via monoubiquitination is one of the mechanisms by which PolH function is controlled, which might be responsible for the development and progression of some spontaneous tumors wherein PolH is not found to be mutated. PMID- 21791604 TI - Analysis of human syndromes with disordered chromatin reveals the impact of heterochromatin on the efficacy of ATM-dependent G2/M checkpoint arrest. AB - Heterochromatin (HC) poses a barrier to gammaH2AX focus expansion and DNA double strand break (DSB) repair, the latter being relieved by ATM-dependent KAP-1 phosphorylation. Using high-resolution imaging, we show here that the HC superstructure markedly restricts ATM signaling to cell cycle checkpoint proteins. The impact of HC is greater than anticipated from the percentage of HC DNA and, in distinction to DSB repair, ATM only partly overcomes the constraints posed by HC. Importantly, we examine ATM signaling in human syndromes with disordered HC. After depletion of MeCP2 and DNMT3B, proteins defective in the Rett and immunodeficiency with centromere instability and facial anomalies (ICF) syndromes, respectively, we demonstrate enhanced gammaH2AX signal expansion at HC chromocenters in mouse NIH 3T3 cells, which have visible HC-chromocenters. Previous studies have shown that the G(2)/M checkpoint is inefficient requiring multiple DSBs to initiate arrest. MeCP2 and DNMT3B depletion leads to hypersensitive radiation-induced G(2)/M checkpoint arrest despite normal DSB repair. Cell lines from Rett, ICF, and Hutchinson-Guildford progeria syndrome patients similarly showed hyperactivated ATM signaling and hypersensitive and prolonged G(2)/M checkpoint arrest. Collectively, these findings reveal that heterochromatin contributes to the previously described inefficient G(2)/M checkpoint arrest and demonstrate how the signaling response can be uncoupled from DSB repair. PMID- 21791605 TI - Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics. AB - Histone deacetylase inhibitors (HDACi) are promising antitumor drugs acting through reactivation of silenced tumor suppressor genes. Several HDACi are currently in clinical trials both for hematological and solid tissue malignancies. Cooperative action of HDACi and DNA methylation inhibitors (DNMTi) has been reported, making combined treatment an attractive choice for cancer therapy. There is some evidence that synergistic effects of HDACi and DNMTi are achieved by their action on common targets, including DNA methyltransferase 1 (DNMT1). To further analyze this interaction, we investigated the effect of the HDACi trichostatin A on global and gene-specific DNA methylation and applied methods with single molecule sensitivity, confocal laser scanning microscopy with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), to study its effect on the nuclear dynamics of DNMT1 in live cells. Our data show that trichostatin A treatment reduces global DNA methylation and the DNMT1 protein level and alters DNMT1 nuclear dynamics and interactions with chromatin. The mechanisms underlying these effects are apparently distinct from the mechanisms of action of the DNMT inhibitor 5-azacytidine. Our study sheds light on the molecular mechanisms underlying the synergistic action of HDACi and DNMTi and may also help to define improved policies for cancer treatment. PMID- 21791606 TI - Vital role of the calpain-calpastatin system for placental-integrity-dependent embryonic survival. AB - Although the calpain-calpastatin system has been implicated in a number of pathological conditions, its normal physiological role remains largely unknown. To investigate the functions of this system, we generated conventional and conditional calpain-2 knockout mice. The conventional calpain-2 knockout embryos died around embryonic day 15, preceded by cell death associated with caspase activation and DNA fragmentation in placental trophoblasts. In contrast, conditional knockout mice in which calpain-2 is expressed in the placenta but not in the fetus were spared. These results suggest that calpain-2 contributes to trophoblast survival via suppression of caspase activation. Double-knockout mice also deficient in calpain-1 and calpastatin resulted in accelerated and rescued embryonic lethality, respectively, suggesting that calpain-1 and -2 at least in part share similar in vivo functions under the control of calpastatin. Triple knockout mice exhibited early embryonic lethality, a finding consistent with the notion that this protease system is vital for embryonic survival. PMID- 21791607 TI - Phosphorylated Grb14 is an endogenous inhibitor of retinal protein tyrosine phosphatase 1B, and light-dependent activation of Src phosphorylates Grb14. AB - Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14(-/-) studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling in a tissue-specific manner. In this study, we made a novel finding that Grb14 inhibits the activity of PTP1B, the major negative regulator of insulin receptor (IR) signaling, in a phosphorylation-regulated manner. Phosphorylation of Tyr-347 in the BPS domain of Grb14 is critical for interaction with PTP1B, resulting in the competitive inhibition of PTP1B activity. We also found that rhodopsin regulated Src kinase activation in retina leads to the phosphorylation of Grb14. Further, ablation of Grb14 resulted in significantly elevated retinal PTP1B activity in vivo. PTP1B is known to be regulated by oxidation, glutathionylation, phosphorylation, and SUMOlyation, and our study for the first time demonstrates the inhibition of PTP1B activity in vivo by protein molecule Grb14 in a tissue specific manner. PMID- 21791608 TI - Checkpoint kinase 1 prevents cell cycle exit linked to terminal cell differentiation. AB - Trophoblast stem (TS) cells proliferate in the presence of fibroblast growth factor 4, but in its absence, they differentiate into polyploid trophoblast giant (TG) cells that remain viable but nonproliferative. Differentiation is coincident with expression of the cyclin-dependent kinase (CDK)-specific inhibitors p21 and p57, of which p57 is essential for switching from mitotic cell cycles to endocycles. Here, we show that, in the absence of induced DNA damage, checkpoint kinase-1 (CHK1), an enzyme essential for preventing mitosis in response to DNA damage, functions as a mitogen-dependent protein kinase that prevents premature differentiation of TS cells into TG cells by suppressing expression of p21 and p57, but not p27, the CDK inhibitor that regulates mitotic cell cycles. CHK1 phosphorylates p21 and p57 proteins at specific sites, thereby targeting them for degradation by the 26S proteasome. TG cells lack CHK1, and restoring CHK1 activity in TG cells suppresses expression of p57 and restores mitosis. Thus, CHK1 is part of a "G2 restriction point" that prevents premature cell cycle exit in cells programmed for terminal differentiation, a role that CHK2 cannot play. PMID- 21791609 TI - Casein kinase 2 sends extracellular signal-regulated kinase nuclear. PMID- 21791610 TI - Bioluminescence imaging captures the expression and dynamics of endogenous p21 promoter activity in living mice and intact cells. AB - To interrogate endogenous p21(WAF1/CIP1) (p21) promoter activity under basal conditions and in response to various forms of stress, knock-in imaging reporter mice in which expression of firefly luciferase (FLuc) was placed under the control of the endogenous p21 promoter within the Cdkn1a gene locus were generated. Bioluminescence imaging (BLI) of p21 promoter activity was performed noninvasively and repetitively in mice and in cells derived from these mice. We demonstrated that expression of FLuc accurately reported endogenous p21 expression at baseline and under conditions of genotoxic stress and that photon flux correlated with mRNA abundance and, therefore, bioluminescence provided a direct readout of p21 promoter activity in vivo. BLI confirmed that p53 was required for activation of the p21 promoter in vivo in response to ionizing radiation. Interestingly, imaging of reporter cells demonstrated that p53 prevents the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway from activating p21 expression when quiescent cells are stimulated with serum to reenter the cell cycle. In addition, low-light BLI identified p21 expression in specific regions of individual organs that had not been observed previously. This inducible p21(FLuc) knock-in reporter strain will facilitate imaging studies of p53-dependent and -independent stress responses within the physiological context of the whole animal. PMID- 21791611 TI - TSC-22 promotes transforming growth factor beta-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity. AB - Transforming growth factor beta (TGF-beta) plays a critical role in tissue fibrosis. The duration and intensity of TGF-beta signaling are tightly regulated. Here we report that TSC-22 (TGF-beta-stimulated clone 22) facilitates TGF-beta signaling by antagonizing Smad7 activity to increase receptor stability. TSC-22 enhances TGF-beta-induced Smad2/3 phosphorylation and transcriptional responsiveness. The stimulatory effect of TSC-22 is dependent on Smad7, as silencing Smad7 expression abolishes it. TSC-22 interacts with TGF-beta type I receptor TbetaRI and Smad7 in mutually exclusive ways and disrupts the association of Smad7/Smurfs with TbetaRI, thereby preventing ubiquitination and degradation of the receptor. We also found that TSC-22 can promote the differentiation of cardiac myofibroblasts by increasing expression of the fibrotic genes for alpha-smooth muscle actin (alpha-SMA), PAI-1, fibronectin, and collagen I, which is consistent with upregulation of TSC-22, phospho-Smad2/3, and the fibrotic genes in isoproterenol-induced rat myocardial fibrotic hearts. Taken together with the notion that TGF-beta induces TSC-22 expression, our findings suggest that TSC-22 regulates TGF-beta signaling via a positive-feedback mechanism and may contribute to myocardial fibrosis. PMID- 21791612 TI - Key functional regions in the histone variant H2A.Z C-terminal docking domain. AB - The incorporation of histone variants into nucleosomes represents one way of altering the chromatin structure to accommodate diverse functions. Histone variant H2A.Z has specific roles in gene regulation, heterochromatin boundary formation, and genomic integrity. The precise features required for H2A.Z to function and specify an identity different from canonical H2A remain to be fully explored. Analysis of the C-terminal docking domain of H2A.Z in Saccharomyces cerevisiae using epistatic miniarray profile (E-MAP) uncovered nuanced requirements of the H2A.Z C-terminal region for cell growth when additional genes were compromised. Moreover, the H2A.Z(1-114) truncation, lacking the last 20 amino acids of the protein, did not support regular H2A.Z functions, such as resistance to genotoxic stress, restriction of heterochromatin in its native context, GAL1 gene activation, and chromatin anchoring. The corresponding region of H2A could fully rescue the strong defects caused by loss of this functionally essential region in the C terminus of H2A.Z. Despite the dramatic reduction in function, the H2A.Z(1-114) truncation still bound the H2A.Z deposition complex SWR1-C, the histone chaperone Chz1, and histone H2B. These data are consistent with a model in which retaining the variant in chromatin after its deposition by SWR1-C is a crucial determinant of its function. PMID- 21791613 TI - The midblastula transition defines the onset of Y RNA-dependent DNA replication in Xenopus laevis. AB - Noncoding Y RNAs are essential for the initiation of chromosomal DNA replication in mammalian cell extracts, but their role in this process during early vertebrate development is unknown. Here, we use antisense morpholino nucleotides (MOs) to investigate Y RNA function in Xenopus laevis and zebrafish embryos. We show that embryos in which Y RNA function is inhibited by MOs develop normally until the midblastula transition (MBT) but then fail to replicate their DNA and die before gastrulation. Consistent with this observation, Y RNA function is not required for DNA replication in Xenopus egg extracts but is required for replication in a post-MBT cell line. Y RNAs do not bind chromatin in karyomeres before MBT, but they associate with interphase nuclei after MBT in an origin recognition complex (ORC)-dependent manner. Y RNA-specific MOs inhibit the association of Y RNAs with ORC, Cdt1, and HMGA1a proteins, suggesting that these molecular associations are essential for Y RNA function in DNA replication. The MBT is thus a transition point between Y RNA-independent and Y RNA-dependent control of vertebrate DNA replication. Our data suggest that in vertebrates Y RNAs function as a developmentally regulated layer of control over the evolutionarily conserved eukaryotic DNA replication machinery. PMID- 21791614 TI - p300-Dependent ATF5 acetylation is essential for Egr-1 gene activation and cell proliferation and survival. AB - ATF5 has been shown to be a critical regulator of cell proliferation and survival; however, the underlying mechanism remains largely unknown. We demonstrate here that ATF5 interacts with the transcriptional coactivator p300, which acetylates ATF5 at lysine-29 (K29), which in turn enhances the interaction between ATF5 and p300 and binding of the ATF5/p300 complex to the ATF5 response element (ARE) region of the Egr-1 promoter. ARE-bound ATF5/p300 acetylates lysine 14 (K14) of nucleosomal histone H3 at both the ARE and serum response element (SRE) of the Egr-1 promoter, which facilitates binding of extracellular signal regulated kinase (ERK)-phosphorylated Elk-1 to the SRE, activating the Egr-1 promoter. Interference of p300-dependent acetylation of ATF5 or nucleosomal histone H3 or blockade of ERK-dependent Elk-1 phosphorylation abrogates ATF5 dependent Egr-1 activation and cell proliferation and survival. These findings assign a central role for the ATF5/p300 complex in ATF5 function and suggest that coordinated actions by ATF5, p300, Elk-1, and ERK/mitogen-activated protein kinase (MAPK) are essential for ATF5-dependent Egr-1 activation and cell proliferation and survival. PMID- 21791615 TI - A novel cyclic AMP/Epac1/CaMKI signaling cascade promotes GCM1 desumoylation and placental cell fusion. AB - Cyclic AMP (cAMP) signaling and the placental transcription factor glial cell missing 1 (GCM1) regulate expression of syncytin-1 and -2 fusogenic proteins, which are critical for syncytiotrophoblast formation by trophoblast fusion. We recently revealed a cAMP/protein kinase A (PKA)/CBP signaling pathway that activates GCM1 by coordinating GCM1 phosphorylation and acetylation. In contrast, GCM1 activity is downregulated by sumoylation of Lys156. How GCM1 sumoylation is regulated was unknown. Here, we identify a novel PKA-independent cAMP signaling pathway as the critical regulator of GCM1 sumoylation. We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. Using RNA interference (RNAi), we further demonstrate that 8-(4-chlorophenylthio)-2'-O-Me cAMP-AM (8-CPT-AM), an Epac activator, stimulates syncytin-1 and -2 gene expression and cell fusion of placental BeWo cells in a GCM1-dependent manner. Importantly, the cell fusion defect in GCM1-knockdown BeWo cells can be reversed and enhanced by the RNAi-resistant phosphomimetic GCM1(S47D) mutant. Our study has identified a novel cAMP/Epac1/CaMKI/GCM1 signaling cascade that stimulates trophoblast fusion through promoting GCM1 phosphorylation and desumoylation. PMID- 21791616 TI - Human cancer-associated mutations in the Aalpha subunit of protein phosphatase 2A increase lung cancer incidence in Aalpha knock-in and knockout mice. AB - Strong evidence has indicated that protein phosphatase 2A (PP2A) is a tumor suppressor, but a mouse model for testing the tumor suppressor activity was missing. The most abundant forms of trimeric PP2A holoenzyme consist of the scaffolding Aalpha subunit, one of several regulatory B subunits, and the catalytic Calpha subunit. Aalpha mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant Aalpha subunits are defective in binding the B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated Aalpha point mutants defective in binding B' subunits, one knockout mouse expressing truncated Aalpha defective in B and C subunit binding, and a floxed mouse for generating conditional Aalpha knockouts. We found that the cancer-associated Aalpha mutations increased the incidence of cancer by 50 to 60% in lungs of FVB mice treated with benzopyrene, demonstrating that PP2A acts as a tumor suppressor. We show that the effect of Aalpha mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that the Aalpha mutation E64D, which was detected in a human lung carcinoma, increases the lung cancer incidence in mice suggests that this mutation also played a role in the development of the carcinoma in which it was discovered. PMID- 21791618 TI - Hormonal factors and the risk of papillary thyroid cancer in the California Teachers Study cohort. AB - BACKGROUND: Despite the increasing incidence of thyroid cancer, there is limited information on its etiology. The strikingly higher rates in young women, compared with men, suggest that sex steroid hormones may be involved in the development of this disease. METHODS: We investigated the effects of menstrual, reproductive, and other hormonal factors on papillary thyroid cancer risk in the prospective California Teachers Study cohort. Among 117,646 women, 233 were diagnosed with invasive histologically confirmed papillary thyroid cancer after cohort enrollment and before January 1, 2008. Relative risks (RR) and 95% CIs were estimated by using Cox proportional hazards regression models. RESULTS: Among younger women (age <45 years at baseline; approximately one-third of the cohort), but not older women, later age at menarche (age >=14 years) was associated with increased risk (RR = 1.88, 95% CI: 1.13-3.13; p(interaction) by age = 0.06). Risk was also increased among young women who had longer (>30 days) adolescent menstrual cycles (RR = 1.78, 95% CI: 1.01-3.14) and whose last pregnancy had ended within five years of cohort enrollment (RR = 2.21, 95% CI: 1.13-4.34). Among older women (age >=45 years at baseline), ever use of estrogen-only therapy was associated with a statistically nonsignificant increase in risk (RR = 1.69, 95% CI: 0.95-2.98). CONCLUSIONS: The findings from this prospective analysis suggest that several factors related to delayed pubertal development and the transient effects of pregnancy may be particularly important in influencing risk in young women. IMPACT: These results suggest the importance of future research into the role of progesterone and the estrogen-to-progesterone ratio. PMID- 21791617 TI - DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. AB - The cytoplasmic viral RNA sensors RIG-I and MDA5 are important for the production of type I interferon and other inflammatory cytokines. DDX60 is an uncharacterized DEXD/H box RNA helicase similar to Saccharomyces cerevisiae Ski2, a cofactor of RNA exosome, which is a protein complex required for the integrity of cytoplasmic RNA. Expression of DDX60 increases after viral infection, and the protein localizes at the cytoplasmic region. After viral infection, the DDX60 protein binds to endogenous RIG-I protein. The protein also binds to MDA5 and LGP2 but not to the downstream factors IPS-1 and IkappaB kinase epsilon (IKK epsilon). Knockdown analysis shows that DDX60 is required for RIG-I- or MDA5 dependent type I interferon and interferon-inducible gene expression in response to viral infection. However, DDX60 is dispensable for TLR3-mediated signaling. Purified DDX60 helicase domains possess the activity to bind to viral RNA and DNA. Expression of DDX60 promotes the binding of RIG-I to double-stranded RNA. Taken together, our analyses indicate that DDX60 is a novel antiviral helicase promoting RIG-I-like receptor-mediated signaling. PMID- 21791619 TI - Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats. AB - The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting. PMID- 21791621 TI - Impact of maternal dietary n-3 and n-6 fatty acids on milk medium-chain fatty acids and the implications for neonatal liver metabolism. AB - Levels of n-6, n-3, and medium-chain fatty acids (MCFA) in milk are highly variable. Higher carbohydrate intakes are associated with increased mammary gland MCFA synthesis, but the role of unsaturated fatty acids for milk MCFA secretion is unclear. This study addressed whether n-6 and n-3 fatty acids, which are known to inhibit hepatic fatty acid synthesis, influence MCFA in rat and human milk and the implications of varying MCFA, n-6, and n-3 fatty acids in rat milk for metabolic regulation in the neonatal liver. Rats were fed a low-fat diet or one of six higher-fat diets, varying in 16:0, 18:1n-9, 18:2n-6, 18:3n-3, and long chain (LC) n-3 fatty acids. Higher maternal dietary 18:2n-6 or 18:3n-3 did not influence milk MCFA, but lower maternal plasma triglycerides, due to either a low fat or a high-fat high-LC n-3 diet led to higher milk MCFA. MCFA levels were inversely associated with 18:1n-9, 18:2n-6, and 18:3n-3 in human milk, likely reflecting the association between dietary total fat and unsaturated fatty acids. High LC n-3 fatty acid in rat milk was associated with lower hepatic Pklr, Acly, Fasn, and Scd1 and higher Hmgcs2 in the milk-fed rat neonate, with no effect of milk 18:1n-9, 18:2n-6, or MCFA. These studies show that the dietary fatty acid composition does not impact MCFA secretion in milk, but the fatty acid composition of milk, particularly the LC n-3 fatty acid, is relevant to hepatic metabolic regulation in the milk-fed neonate. PMID- 21791622 TI - Simultaneous measurement of glucose transport and utilization in the human brain. AB - Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K(M)(t) and V(max)(t), in humans have so far been obtained by measuring steady-state brain glucose levels by proton ((1)H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMR(glc)) obtained from other tracer studies, such as (13)C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state (1)H NMR data with a reversible, non-steady state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ~17 mmol/l for ~2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMR(glc), this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain. PMID- 21791620 TI - Leptin in human physiology and pathophysiology. AB - Leptin, discovered through positional cloning 15 years ago, is an adipocyte secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics. PMID- 21791624 TI - Resveratrol ameliorates metabolic disorders and muscle wasting in streptozotocin induced diabetic rats. AB - Diabetes mellitus (DM) is characterized by dysregulated energy metabolism. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in diabetic animals. However, its overall in vivo effects on energy metabolism and the underlying mechanism require further investigation. In the present study, electrospray ionization-tandem mass spectrometry was employed to characterize the urine and plasma metabolomes of control, streptozotocin-induced DM and RSV treated DM rats. Using principal component analysis (PCA) and heat map analysis, we discovered significant differences among control and experimental groups. RSV treatment significantly reduced the metabolic abnormalities in DM rats. Compared with the age-matched control rats, the level of carnitine was lower, and the levels of acetylcarnitine and butyrylcarnitine were higher in the urine and plasma of DM rats. RSV treatment ameliorated the deranged carnitine metabolism in DM rats. In addition, RSV treatment attenuated the diabetic ketoacidosis and muscle protein degradation, as evidenced from the attenuation of elevated urinary methyl-histidine and plasma branched-chain amino acids levels in DM rats. The beneficial effects of RSV in DM rats were correlated with activation of hepatic AMP-activated protein kinase and SIRT1 expression, increase of hepatic and muscular mitochondrial biogenesis and inhibition of muscle NF-kappaB activities. We concluded that RSV possesses multiple beneficial metabolic effects in insulin deficient DM rats, particularly in improving energy metabolism and reducing protein wasting. PMID- 21791623 TI - Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle. AB - Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERalpha and ERbeta, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens. PMID- 21791625 TI - 1,25-Dihydroxyvitamin D3 contributes to regulating mammary calcium transport and modulates neonatal skeletal growth and turnover cooperatively with calcium. AB - To assess the interaction of 1,25(OH)(2)D(3) and dietary calcium on mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate, female lactating 1alpha(OH)ase(+/-) or 1alpha(OH)ase(-/-) mice were fed either a high-calcium diet containing 1.5% calcium in the drinking water or a "rescue diet." Dietary effects on the expression of molecules mediating mammary calcium transport were determined in the dams, and the effects of milk calcium content were assessed on skeletal growth and turnover in 2-wk-old 1,25(OH)(2)D(3) deficient pups. Results showed that the reduction of milk calcium levels in the 1alpha(OH)ase(-/-) dams and the elevation of milk calcium levels in dams fed the rescue diet were associated with the down- or upregulation of calbindin D(9k) and plasma membrane Ca(2+) ATPase isoform 2b expression, respectively, in mammary epithelial cells. The action of ambient calcium in stimulating skeletal growth in the neonates appeared to supercede the direct action of 1,25(OH)(2)D(3), and the response of chondrocytes in the neonates to elevated calcium was more sensitive in hypocalcemic animals. Osteopenia was more apparent in pups nursed by dams with lower milk calcium than in 1,25(OH)(2)D(3)-deficient pups nursed by dams with higher milk calcium. Bone formation parameters were increased significantly in all pups fed by dams on the rescue diet but were still lower in 1alpha(OH)ase(-/ ) pups than in 1alpha(OH)ase(+/-) pups. Consequently, there is an important contributory role of calcium in conjunction with 1,25(OH)(2)D(3) to mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate. PMID- 21791626 TI - Comparison of clinical results of anatomic posterolateral corner reconstruction for posterolateral rotatory instability of the knee with or without popliteal tendon reconstruction. AB - BACKGROUND: It is unknown whether popliteal tendon reconstruction is necessary in anatomic posterolateral corner reconstruction, although the tendon has function in the varus and rotatory stability of the knee joint. HYPOTHESIS: Anatomic reconstructions of the posterolateral corner with the popliteal tendon reconstructed will present better clinical and radiographic results than cases with the popliteal tendon not reconstructed. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The authors retrospectively analyzed 32 cases of anatomic posterolateral corner reconstruction with a minimum 2-year follow-up. There were 17 cases of anatomic reconstruction with popliteal tendon reconstruction and 15 cases without popliteal tendon reconstruction. The authors compared preoperative and postoperative range of motion, varus instability by varus stress test, lateral joint opening on varus stress radiographs, posterolateral rotatory instability by dial test, Tegner activity score, Lysholm score, and International Knee Documentation Committee (IKDC) subjective knee evaluation form and knee examination form between the 2 groups. They also compared posterior translation on posterior stress radiographs in cases with posterior cruciate ligament reconstruction. RESULTS: There was no difference in range of motion, varus stress test, dial test, Tegner score, Lysholm score, or the score by IKDC subjective knee evaluation form. The side-to-side difference in lateral joint opening on the varus stress radiographs significantly improved after anatomic reconstruction in both groups (P < .001, P = .001), but there was no preoperative or postoperative differences between the groups. No difference was found in the grade distribution on the IKDC examination form. In the cases with posterior cruciate ligament reconstruction, there was also no difference in posterior translation between the groups on posterior stress radiographs at the last follow-up. CONCLUSION: No effect of popliteal tendon reconstruction was found in anatomic posterolateral corner reconstruction on the stability and clinical results. PMID- 21791628 TI - AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase. AB - N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl) 2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1beta. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases. PMID- 21791629 TI - ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. AB - PURPOSE: About 50% of prostate cancers have TMPRSS2-ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes. EXPERIMENTAL DESIGN: A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines. RESULTS: ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity. CONCLUSIONS: The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials. PMID- 21791630 TI - Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C18-ceramide as a novel biomarker for monitoring response. AB - PURPOSE: Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C(18)-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed. EXPERIMENTAL DESIGN: Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements. RESULTS: We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4-4.2) with a median survival of 5.6 months (95% CI: 3.8-18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment. CONCLUSIONS: Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response. PMID- 21791631 TI - Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. AB - PURPOSE: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy. EXPERIMENTAL DESIGN: A total of 132 patients treated with first line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR). RESULTS: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1alpha rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003). CONCLUSION: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy. PMID- 21791634 TI - Introducing CCR perspectives in drug approval. PMID- 21791632 TI - MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. AB - PURPOSE: The presence of tumor-associated macrophages (TAM) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, noninvasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonanceI and clinically applicable iron oxide nanoparticles. EXPERIMENTAL DESIGN: F4/80 negative mammary carcinoma cells and F4/80-positive TAMs were incubated with iron oxide nanoparticles and were compared with respect to magnetic resonance signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced magnetic resonance imaging (MRI) up to 1 hour and 24 hours after injection. The tumor enhancement on MRIs was correlated with the presence and location of TAMs and nanoparticles by confocal microscopy. RESULTS: In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs but not by malignant tumor cells. In vivo, all tumors showed an initial contrast agent perfusion on immediate postcontrast MRIs with gradual transendothelial leakage into the tumor interstitium. Twenty-four hours after injection, all tumors showed a persistent signal decline on MRIs. TAM depletion via alphaCSF1 monoclonal antibodies led to significant inhibition of tumor nanoparticle enhancement. Detection of iron using 3,3'-diaminobenzidine-enhanced Prussian Blue staining, combined with immunodetection of CD68, localized iron oxide nanoparticles to TAMs, showing that the signal effects on delayed MRIs were largely due to TAM-mediated uptake of contrast agent. CONCLUSION: These data indicate that tumor enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions, and the evaluation of new immune-targeted therapies. PMID- 21791635 TI - Exploring breast cancer estrogen disposition: the basis for endocrine manipulation. AB - Although normal breast tissue and breast cancer estrogens are known to be elevated compared with plasma estrogen levels, the mechanism behind this phenomenon has been an issue of debate for 2 decades. If local estrogen aromatization were to be confirmed as the main estrogen source in breast cancer tissue, tissue-specific inhibition of estrogen production, avoiding systemic side effects, would become a potentially attractive option for breast cancer treatment and prevention. Based on recent results from our groups exploring tissue estrogens, together with estrogen-synthesizing and estrogen-regulated gene expression levels, we propose a new model to explain elevated breast tissue estrogen levels. Although local estrogen production may be important, the local contribution is overruled by rapid plasma-to-tissue equilibration, including active uptake of circulating estrogens or enhanced tissue binding. As for breast cancer tissue levels, elevated levels of estradiol may be explained to a large extent by estrogen receptor binding and local conversion of estrone into estradiol. This model indicates that effective suppression of benign and malignant tissue estrogens as a treatment for ER+ breast cancer requires systemic suppression and will not be markedly affected by local enzyme targeting. PMID- 21791633 TI - Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance. AB - PURPOSE: Acquired resistance to cetuximab, a chimeric epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance. EXPERIMENTAL DESIGN: We generated cetuximab resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab, followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo. RESULTS: We generated a novel model of cetuximab resistance, and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a C-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. CONCLUSIONS: These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study conducted in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality. PMID- 21791636 TI - The National Institute for Health and Clinical Excellence and its role in assessing the value of new cancer treatments in England and Wales. AB - The boundaries of medical science in the treatment of cancer are constantly extending. Developments of existing treatments, innovative approaches, new discoveries, and more targeted therapeutic options are translating into practice. With advances come increasing costs, often of a magnitude that stretches finite financial resources. When decisions about funding are made on behalf of a population, standardized processes and methods are needed in order to produce robust guidance in a fair, consistent, and transparent way. The challenges of making these difficult decisions are brought into particularly stark relief when potentially life-extending treatments for patients with a short life expectancy are appraised. The National Institute for Health and Clinical Excellence (NICE) produces guidance on the clinical- and cost-effectiveness of medicines compared with current standard practice. Approximately 40% of the technologies appraised by NICE are indicated for cancer, and the majority of these are pharmaceuticals, mostly biological agents. This article provides an overview of the current role of NICE in making new technologies for cancer available in England and Wales. This includes a summary of experiences with end-of-life treatments and the supplementary advice regarding such treatments that was issued by NICE to its decision-making committees in 2009. PMID- 21791637 TI - HER2-affitoxin: a potent therapeutic agent for the treatment of HER2 overexpressing tumors. AB - PURPOSE: Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific Affibody and modified Pseudomonas aeruginosa exotoxin A (PE 38), which, after binding to HER2, is internalized and delivered to the cytosol of the tumor cell, where it blocks protein synthesis by ADP ribosylation of eEF-2. EXPERIMENTAL DESIGN: The effect of the Affitoxin on cell viability was assessed using CellTiter-Glo (Promega). To assess HER2-specific efficacy, athymic nude mice bearing BT-474 breast cancer, SK OV-3 ovarian cancer, and NCI-N87 gastric carcinoma xenografts were treated with the Affitoxin (HER2- or Tag-specific), which was injected every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays. RESULTS: In vitro experiments proved that HER2-Affitoxin is a potent agent that eliminates HER2 overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation (T(1/2) < 10 minutes) and was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose. CONCLUSIONS: Our findings showed that HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies. PMID- 21791638 TI - Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3. AB - To characterize the endothelial dysfunction associated with Type II diabetes, we surveyed transcriptional responses in the vascular endothelia of mice receiving a diabetogenic, high-fat diet. Tie2-GFP mice were fed a diet containing 60% fat calories (HFD); controls were littermates fed normal chow. Following 4, 6, and 8 wk, aortic and leg muscle tissues were enzymatically dispersed, and endothelial cells were obtained by fluorescence-activated cell sorting. Relative mRNA abundance in HFD vs. control endothelia was measured with long-oligo microarrays; highly dysregulated genes were confirmed by real-time PCR and protein quantification. HFD mice were hyperglycemic by 2 wk and displayed vascular insulin resistance and decreased glucose tolerance by 5 and 6 wk, respectively. Endothelial transcripts upregulated by HFD included galectin-3 (Lgals3), 5 lipoxygenase-activating protein, and chemokine ligands 8 and 9. Increased LGALS3 protein was detected in muscle endothelium by immunohistology accompanied by elevated LGALS3 in the serum of HFD mice. Our comprehensive analysis of the endothelial transcriptional response in a model of Type II diabetes reveals novel regulation of transcripts with roles in inflammation, insulin sensitivity, oxidative stress, and atherosclerosis. Increased endothelial expression and elevated humoral levels of LGALS3 supports a role for this molecule in the vascular response to diabetes, and its potential as a direct biomarker for the inflammatory state in diabetes. PMID- 21791639 TI - Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy. AB - Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions. We used genome-wide expression profiling analyses and quantitative PCR to identify the molecular changes that occur in two clinically relevant mouse models of muscle atrophy: hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7, and 14 days after casting or injury. The total amount of muscle loss, as measured by wet weight and muscle fiber size, was equivalent between models on day 14, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tenotomy resulted in the regulation of significantly more mRNA transcripts then did casting. Analysis of the regulated genes and pathways suggest that the mechanisms of atrophy are distinct between these models. The degradation following casting was ubiquitin-proteasome mediated, while degradation following tenotomy was lysosomal and matrix-metalloproteinase mediated, suggesting a possible role for autophagy. These data suggest that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat atrophy resulting from different conditions. PMID- 21791641 TI - A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. AB - Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684) sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684 resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients. PMID- 21791642 TI - MicroRNA expression and outcome in resected NSCLC--letter. PMID- 21791648 TI - Antiretroviral use during pregnancy and risk of preterm delivery: more questions than answers. PMID- 21791649 TI - Viral kinetics of genital herpes: a molecular probe into host-viral interactions. PMID- 21791650 TI - At what cost echinocandin resistance? PMID- 21791651 TI - Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. AB - BACKGROUND: Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. METHODS: HIV-infected, HAART-naive pregnant women with CD4+ counts >=200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. RESULTS: Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. CONCLUSIONS: PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study. PMID- 21791652 TI - Antiretroviral drug resistance in HIV-1-infected patients experiencing persistent low-level viremia during first-line therapy. AB - Population sequencing was performed for persons identified with persistent low level viremia in 2 clinical trials. Persistent low-level viremia (defined as plasma HIV-1 RNA level >50 and <1000 copies/mL in at least 2 determinations over a 24-week period, after at least 24 weeks of antiretroviral therapy) was observed in 65 (5.6%) of 1158 patients at risk. New resistance mutations were detected during persistent low-level viremia in 37% of the 54 evaluable cases. The most common mutations were M184I/V (14 cases), K103N (9), and M230L (3). Detection of new mutations was associated with higher HIV-1 RNA levels during persistent low level viremia. PMID- 21791653 TI - The impact of fasting on the interpretation of triglyceride levels for predicting myocardial infarction risk in HIV-positive individuals: the D:A:D study. AB - We assessed whether fasting modifies the prognostic value of these measurements for the risk of myocardial infarction (MI). Analyses used mixed effect models and Poisson regression. After confounders were controlled for, fasting triglyceride levels were, on average, 0.122 mmol/L lower than nonfasting levels. Each 2-fold increase in the latest triglyceride level was associated with a 38% increase in MI risk (relative rate, 1.38; 95% confidence interval, 1.26-1.51); fasting status did not modify this association. Our results suggest that it may not be necessary to restrict analyses to fasting measurements when considering MI risk. PMID- 21791655 TI - Deteriorating pneumococcal-specific B-cell memory in minimally symptomatic African children with HIV infection. AB - Invasive pneumococcal disease is a leading cause of human immunodeficiency virus (HIV)-associated mortality in sub-Saharan African children. Defective T-cell mediated immunity partially explains this high disease burden, but there is an increased risk of invasive pneumococcal disease even in the context of a relatively preserved percentage of CD4 cells. We hypothesized that impaired B cell immunity to this pathogen further amplifies the immune defect. We report a shift in the B-cell compartment toward an apoptosis-prone phenotype evident early in HIV disease progression. We show that, although healthy HIV-uninfected and minimally symptomatic HIV-infected children have similar numbers of isotype switched memory B cells, numbers of pneumococcal protein antigen-specific memory B cells were lower in HIV-infected than in HIV-uninfected children. Our data implicate defective naturally acquired B-cell pneumococcal immunity in invasive pneumococcal disease causation in HIV-infected children and highlight the need to study the functionality and duration of immune memory to novel pneumococcal protein vaccine candidates in order to optimize their effectiveness in this population. PMID- 21791654 TI - Identifying the early post-HIV antibody seroconversion period. AB - BACKGROUND: Identifying persons with recent human immunodeficiency virus (HIV) antibody seroconversion is useful for treatment, research, and prevention, but the sensitivity and specificity of tests for this purpose are uncertain. METHODS: We used longitudinal specimens panels from 155 persons identified prior to HIV seroconversion to assess antibody-based methods for classifying persons as within 30, 60, or 90 days of seroconversion, including 2 incidence assays, a less sensitive (LS) enzyme immunoassay (EIA), and the BED assay. RESULTS: Sensitivity and specificity, respectively, for identifying persons within 30 days of seroconversion were: 34%-57% and 98%-100% for 2 standard EIAs (employing a signal to-cutoff <=4.0; >=1.0 defines HIV positive), 84% and 73% for the LS-EIA (<=0.2 cutoff), 88% and 72% for the BED (<=0.2 cutoff), and 43%-58% and 98% (<=3 bands) for 2 Western blot (WB) assays. By area under the receiver operator curves, the best test for identifying persons within 30 days of seroconversion was the number of bands on the Bio-Rad WB (0.90); within 60 days, the LS-EIA and BED (both 0.85); and for persons within 90 days the BED (0.86). CONCLUSIONS: Standard EIAs, Western blots, and HIV incidence assays provide useful information for identifying persons 30 to 90 days after seroconversion. PMID- 21791656 TI - Alveolar and blood T lymphocyte profiles in Pneumocystis jirovecii-positive patients: effects of HIV status. AB - BACKGROUND: There are substantial differences in the risk evaluation, clinical presentation, and outcome of Pneumocystis pneumonia between human immunodeficiency virus (HIV)-positive and HIV-negative immunocompromised patients. To compare the host immune defenses against Pneumocystis jirovecii, the blood and alveolar lymphocyte profile was explored in these 2 populations. METHODS: The total, CD3(+), CD4(+), and CD8(+) T-lymphocyte counts were measured in the blood and alveoli of immunocompromised patients with a P. jirovecii DNA detected in their bronchoalveolar lavage samples, according to their HIV status. RESULTS: In blood and alveoli, the CD4(+) and CD8(+) T-lymphocyte counts were higher and lower, respectively, in the HIV-negative group. The threshold for initiating prophylaxis in HIV-positive persons, 200 CD4(+) T cells/MUL, was not pertinent for HIV-negative patients. The P. jirovecii burden correlated with the blood CD4(+) T-cell counts in the HIV-positive but not in the HIV-negative group. Nevertheless, whatever the HIV status, a correlation was observed between alveolar CD4(+) T cells and the P. jirovecii burden. CONCLUSIONS: The T lymphocyte profile was different between HIV-positive and HIV-negative patients with P. jirovecii, suggesting a distinct pathogenesis. Alveolar CD4(+) T cells could be critical to explain the development of Pneumocystis pneumonia but may also be important for evaluation of disease risk, mostly among HIV-negative immunocompromised patients. PMID- 21791657 TI - The kinetics of mucosal herpes simplex virus-2 infection in humans: evidence for rapid viral-host interactions. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) reactivations in the genital tract are responsible for mucocutaneous lesions and transmission and manifest as discrete shedding episodes. METHODS: We analyzed duration, peak copy number, and expansion and decay rates of 1020 shedding episodes in 531 immunocompetent HSV-2 seropositive persons from whom daily swabs of genital secretions were collected. RESULTS: Viral quantity varied by as much as a multiple of 10 million in a single person over time. Peak episode copy number was distributed approximately evenly from 10(3) through 10(8) HSV DNA copies/mL. Median rate of increase was 10(7.6) HSV DNA copies/day during the first 12 hours of an episode and 10(5) copies/d from episode initiation to peak. These values depended only moderately on episode duration. Median decay rate was -10(6.2) HSV DNA copies/d during the final 12 hours of an episode and -10(3.6) copies/d from peak to termination. Episodes lasted a median of 3 days (interquartile range, 1-8 days). Prolonged (>5 days) episodes were associated with nonmonotonic decay. CONCLUSIONS: HSV-2 shedding episodes are notable for rapid expansion and decay and extreme heterogeneity of duration and viral production. The net effect of these dynamic episodes is frequent shedding at high copy numbers. PMID- 21791658 TI - Human papillomavirus (HPV) 6, 11, 16, and 18 prevalence among females in the United States--National Health And Nutrition Examination Survey, 2003-2006: opportunity to measure HPV vaccine impact? AB - The 2003-2006 National Health and Nutrition Examination Surveys were used to assess human papillomavirus (HPV) types 6, 11, 16, and 18 DNA detection from females aged 14-59 years who self-collected cervicovaginal swab specimens. Prevalence was 8.8% (95% confidence interval [CI], 7.8%-10.0%) and was highest among women aged 20-24 years (18.5%; 95% CI, 14.9%-22.8%). Age group, education, marital status, and sexual behavior were associated with detection. These data provide baseline information before HPV vaccine introduction. Early impact of vaccine in the United States may be determined by a reduction in the prevalence of HPV 6, 11, 16, and 18 infection among young women. PMID- 21791659 TI - Prevalence of genital human papillomavirus among females in the United States, the National Health And Nutrition Examination Survey, 2003-2006. AB - BACKGROUND: Genital human papillomaviruses (HPV) include >40 sexually transmitted viruses. Most HPV infections do not progress to disease, but infection with certain types of HPV can cause cervical and other anogenital and oropharyngeal cancer, and other types of HPV are associated with anogenital warts. HPV vaccines prevent infection with HPV 16 and 18, which account for 70% of cases of cervical cancer, and HPV 6 and 11, which cause 90% of the cases of anogenital warts. METHODS: Using data and self-collected cervicovaginal specimens from 4150 females, 14-59 years of age, from consecutive National Health and Nutrition Examination Surveys (2003-2006), we estimated the prevalence of type-specific HPV DNA and examined sociodemographic and sexual determinants. RESULTS: The overall prevalence of HPV was 42.5% in females 14-59 years of age and varied significantly by age, race or ethnicity, and number of sex partners. Individual type prevalence was less than 7%, ranging from <0.5% through 6.5%. The most common type was nononcogenic HPV 62 (found in 6.5% of subjects), followed by HPV 53 and HPV 16 (4.7%), both of which are oncogenic types. The most prevalent species was nononcogenic alpha3. CONCLUSIONS: HPV infection is common among US females, with the highest burden of infection found in young females 20-24 years of age. Monitoring trends in HPV type distribution will contribute to our understanding of the early impact of HPV vaccines. PMID- 21791660 TI - Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults. AB - BACKGROUND: Accelerated immunization schedules may help gain early control of influenza pandemics. We investigated different schedules of an AS03(A)-adjuvanted H5N1 vaccine. METHODS: This phase II, open-label, 6-month study randomized participants (aged 18-64 years) to 2 vaccine doses administered 21 (standard schedule), 14, or 7 days apart, or on the same day. Coprimary end points were that the lower limit of the 98.75% confidence interval 14 days after the last dose must be (1) >40% for seroconversion rate (SCR) (Center for Biologics Evaluation and Research [CBER] criterion) and (2) >50% for seroprotection rate (SPR) (attainment rate for reciprocal hemagglutination inhibition titers >=40, protocol-defined criterion) for the vaccine homologous strain (A/Indonesia/5/2005). European Committee for Human Medicinal Products (CHMP) immunogenicity criteria were also evaluated. RESULTS: Coprimary end points were achieved (lower 98.75% confidence intervals exceeded defined values). Titers were highest with the standard schedule. Nevertheless, CBER SCR, protocol-defined SPR, and CHMP criteria were met with all schedules for the A/Indonesia/5/2005 strain. There were no significant differences between age groups (18-40 vs 41-64 years). Immune response was robust against drift variants A/turkey/Turkey/1/2005 and A/Vietnam/1194/2004. CONCLUSIONS: The AS03(A)-adjuvanted H5N1 vaccine in accelerated schedules offers a robust immune response against vaccine homologous and drift variant strains, allowing consideration of compressed vaccination intervals. CLINICAL TRIALS REGISTRATION: NCT00695669. PMID- 21791661 TI - Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection. AB - BACKGROUND: Excessive inflammatory host response increases morbidity and mortality associated with seasonal respiratory influenza, and highly pathogenic virus strains are characterized by massive infiltration of monocytes and/or macrophages that produce a storm of injurious cytokines. METHODS: Here, we examined the role in respiratory influenza of serpinB1, an endogenous inhibitor of the serine proteases elastase, cathepsin G, and proteinase-3, increasingly recognized as regulators of inflammation. RESULTS: After challenge with high-dose surfactant protein-D (SP-D)-sensitive influenza A/Philadelphia/82 (H3N2), serpinB1(-/-) mice died earlier and in greater numbers than did wild-type mice. Sublethally infected animals suffered increased morbidity, delayed resolution of epithelial injury, and increased immune cell death. Viral clearance and SP-D/SP-A upregulation were unimpaired and so were early virus-induced cytokine and chemokine burst and influx of large numbers of neutrophils and monocytes. Whereas initial cytokines and chemokines rapidly cleared in wild-type mice, TNF-alpha, IL 6, KC/CXCL1, G-CSF, IL-17A, and MCP-1/CCL2 remained elevated in serpinB1(-/-) mice. Monocyte-derived cells were the dominant immune cells in influenza-infected lungs, and those from serpinB1(-/-) mice produced excessive IL-6 and TNF-alpha when tested ex vivo. Pulmonary gammadelta T-cells that produced IL-17A were also increased. CONCLUSIONS: Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection. PMID- 21791662 TI - Antiviral activity of danoprevir (ITMN-191/RG7227) in combination with pegylated interferon alpha-2a and ribavirin in patients with hepatitis C. AB - BACKGROUND: Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease. METHODS: The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon alpha-2a (180 MUg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily). RESULTS: Danoprevir in combination with pegylated interferon alpha-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was 5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and 2.0 log(10) IU/mL (with 3 times daily regimen). CONCLUSIONS: Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon alpha-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted. PMID- 21791663 TI - Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase. AB - BACKGROUND: Hepatitis C virus (HCV) chronically infects >170 million persons worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. The identification of more effective and better-tolerated agents for treating HCV is a high priority. We have reported elsewhere the discovery of the anti-HCV compound ceestatin using a high-throughput screen of a small molecule library. METHODS: To identify host or viral protein targets in an unbiased fashion, we performed affinity chromatography, using tandem liquid chromatography/mass spectrometry to identify specific potential targets. RESULTS. Ceestatin binds to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase and irreversibly inhibits HMG-CoA synthase in a dose-dependent manner. Ceestatin's anti-HCV effects are reversed by addition of HMG-CoA, mevalonic acid, or geranylgeraniol. Treatment with small interfering RNA against HMG-CoA synthase led to a substantial reduction in HCV replication, further validating HMG-CoA synthase as an enzyme essential for HCV replication. CONCLUSIONS: Ceestatin therefore exerts its anti-HCV effects through inhibition of HMG-CoA synthase. It may prove useful as an antiviral agent, as a probe to study HCV replication, and as a cholesterol lowering agent. The logical stepwise process employed to discover the mechanism of action of ceestatin can serve as a general experimental strategy to uncover the targets on which novel uncharacterized anti-HCV compounds act. PMID- 21791664 TI - Mucosal immunization of rhesus macaques with Rift Valley Fever MP-12 vaccine. AB - Rhesus macaques given 5 * 10(4) or 1 * 10(5) plaque-forming units (pfu) of Rift Valley fever (RVF) MP-12 vaccine by oral, intranasal drops, or small particle aerosol showed no adverse effects up to 56 days after administration. All monkeys given the vaccine by aerosol or intranasal drops developed 80% plaque reduction neutralization titers of >= 1:40 by day 21 after inoculation. Only 2 of 4 monkeys given the vaccine by oral instillation developed detectable neutralizing antibodies. All monkeys vaccinated by mucosal routes that developed detectable neutralizing antibodies were protected against viremia when challenged with 1 * 10(5) pfu of virulent RVF virus delivered by a small particle aerosol at 56 days after vaccination. A single inoculation of the RVF MP-12 live attenuated vaccine by the aerosol or intranasal route may provide an alternative route of protective immunization to RVFV in addition to conventional intramuscular injection. PMID- 21791665 TI - Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. AB - The identification of FKS1 mutations in Candida albicans associated with echinocandin resistance has raised concerns over the spread of drug-resistant strains. We studied the impact of fks1 mutations on C. albicans virulence and fitness. Compared with wild-type strains for FKS1, echinocandin-resistant C. albicans strains with homozygous fks1 hot-spot mutations had reduced maximum catalytic capacity of their glucan synthase complexes and thicker cell walls attributable to increased cell wall chitin content. The fks1 mutants with the highest chitin contents had reduced growth rates and impaired filamentation capacities. Fks1 mutants were hypovirulent in fly and mouse models of candidiasis, and this phenotype correlated with the cell wall chitin content. In addition, we observed reduced fitness of echinocandin-resistant C. albicans in competitive mixed infection models. We conclude that fks1 mutations that confer echinocandin resistance come at fitness and virulence costs, which may limit their epidemiological and clinical impact. PMID- 21791666 TI - Combining vaccination and postexposure CpG therapy provides optimal protection against lethal sepsis in a biodefense model of human melioidosis. AB - The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a major cause of lethal sepsis and morbidity in endemic areas of Southeast Asia and a potential bioterrorism threat. We have used susceptible BALB/c mice to evaluate the potential of targeting vaccination and generic immunotherapy to the lung for optimal protection against respiratory challenge. Intranasal vaccination with live attenuated B. pseudomallei increased survival and induced interferon-gamma-secreting T cells in the lung. Intranasal delivery of CpG oligodeoxynucleotides also provided significant protection; however, combining preexposure vaccination with CpG treatment at the time of infection or up to 18 hours after infection, provided significantly greater protection than either treatment alone. This combination prolonged survival, decreased bacterial loads by >1000-fold, and delayed the onset of sepsis. This novel approach may be applicable to other potential biodefense agents for which existing countermeasures are not fully effective. PMID- 21791667 TI - Reduced memory CD4+ T-cell generation in the circulation of young children may contribute to the otitis-prone condition. AB - BACKGROUND: An explanation for the immunologic dysfunction that causes children to be prone to repeated episodes of acute otitis media (AOM) has long been sought. Poor antibody response has been associated with the otitis-prone condition; however, there is no precise mechanistic explanation for this condition. METHODS: Non-otitis-prone and otitis-prone children with AOM or nasopharyngeal (NP) colonization caused by either Streptococcus pneumoniae or Haemophilus influenzae were compared for pathogen-specific CD4(+) T-helper memory responses by stimulating peripheral blood mononuclear cells using 6 vaccine candidate S. pneumoniae and 3 H. influenzae protein antigens. Samples were analyzed by multi-parameter flow cytometry. RESULTS: Significantly reduced percentages of functional CD45RA(Low) memory CD4(+) T cells producing specific cytokines (interferon gamma, interleukin [IL]-2, IL-4 and IL-17a) were observed in otitis-prone children following AOM and NP colonization with either S. pneumoniae or H. influenzae. Immunoglobulin (Ig) G responses to the studied protein antigens were reduced, which suggests that antigen-specific B-cell function may be compromised as a result of poor T-cell help. Staphylococcal enterotoxin B stimulated similar cytokine patterns in memory CD4(+)T cells in both groups of children. CONCLUSIONS: Otitis-prone children have suboptimal circulating functional T-helper memory and reduced IgG responses to S. pneumoniae or H. influenzae after colonization and after AOM; this immune dysfunction causes susceptibility to recurrent AOM infections. PMID- 21791668 TI - Chlamydia psittaci genetic variants differ in virulence by modulation of host immunity. AB - BACKGROUND: Psittacosis is a zoonosis caused by Chlamydia psittaci and is characterized by severe pneumonia and systemic infection. We sought to determine the basis of the 1000-fold difference in lethal dose of 2 C. psittaci 6BC strains in mice. METHODS: Genomes of the strains were sequenced. Mice were infected intraperitoneally and the growth kinetics, immune responses, and pathology were compared. RESULTS: The 2 strains differed by the presence of a 7.5-kb plasmid in the attenuated strain and 7 nonsynonomous single-nucleotide polymorphisms between the chromosomes, including a serine/threonine protein kinase gene pkn5. The plasmid was cured from the attenuated strain, but it remained nonlethal. Strains did not differ in growth kinetics in vitro or in vivo. Infection with the attenuated strain led to influx of activated macrophages with relatively minor organ damage. In contrast, the virulent strain caused an influx of nonactivated macrophages, neutrophils, and significant end organ damage. Mice infected with the virulent strain survived challenge when coinfected with either the plasmid positive or plasmid-negative attenuated strain, indicating that an active process elicited by the attenuated strain reduces inflammation and disease. CONCLUSIONS: C. psittaci modulates virulence by alteration of host immunity, which is conferred by small differences in the chromosome. PMID- 21791670 TI - Impact of coronary plaque morphology assessed by optical coherence tomography on cardiac troponin elevation in patients with elective stent implantation. AB - BACKGROUND: Mild elevations of cardiac troponin frequently occur after percutaneous coronary intervention (PCI), and patients with elevated post-PCI biomarkers have a worse prognosis. We used optical coherence tomography (OCT) to study the relationship between pre-PCI plaque morphology and post-PCI cardiac troponin I elevations. METHODS AND RESULTS: One hundred thirty-one patients with normal pre-PCI cardiac troponin I levels underwent OCT before nonemergency stent implantation. Clinical and OCT findings were compared between patients with (n=31, 23.7%) and without (n=100, 76.3%) post-PCI cardiac troponin I of >3 * upper reference limit (post-PCI myocardial infarction [MI]). After PCI, long-term follow-up data were collected. Post-PCI MI was associated with angiographic lesion length, type B2/C lesions, presence of thin-cap fibroatheroma, and fibrous cap thickness. In multivariable analysis, presence of thin-cap fibroatheroma (odds ratio, 10.47; 95% confidence interval, 3.74 to 29.28; P<0.001) and type B2/C lesions (odds ratio, 3.74; 95% confidence interval, 1.41 to 9.92; P=0.008) were predictors of post-PCI MI. At a median follow-up of 12 months, cardiac event free survival was significantly worse in patients with post-PCI MI (log-rank test chi(2)=8.9; P=0.003). Cox proportional hazards analysis showed that post-PCI MI (hazard ratio, 3.67; 95% confidence interval, 1.39 to 9.65; P=0.009) and ejection fraction (hazard ratio, 0.96; 95% confidence interval, 0.92 to 0.99; P=0.029) were independent predictors of adverse cardiovascular events during follow-up. CONCLUSIONS: Type B2/C lesions and the presence of OCT-defined thin-cap fibroatheroma can predict post-PCI MI in patients treated with elective stent implantation, who may require adjunctive therapy after otherwise successful PCI. PMID- 21791671 TI - Everolimus-eluting versus sirolimus-eluting stents: a meta-analysis of randomized trials. AB - BACKGROUND: The aim of the study was to compare the outcomes after placement of the everolimus-eluting stent (EES; Xience V) and the sirolimus-eluting stent (SES; Cypher) in patients with coronary artery disease. The second-generation EES is currently one of the most commonly used drug-eluting stents in clinical practice. Although it has clearly been shown superior to paclitaxel-eluting stents, its relative merits against SES have been less extensively assessed. METHODS AND RESULTS: We identified 5 eligible randomized trials comparing EES with SES in 7370 patients. The primary end point was major adverse cardiac events. Secondary end points were cardiac death, myocardial infarction, repeat revascularization, and the composite of definite and probable stent thrombosis. Overall hazard ratios (HR) and 95% confidence intervals (CI) were calculated for EES versus SES for each of the end points. No heterogeneity across the trials was observed regarding the primary and secondary end points. The risk of major adverse cardiac events (HR, 0.91 [95% CI, 0.77 to 1.08]; P=0.28), cardiac death (HR, 1.02 [95% CI, 0.73 to 1.41]; P=0.92), myocardial infarction (HR, 0.97 [95% CI, 0.66 to 1.35]; P=0.76), repeat revascularization (HR, 0.85 [95% CI, 0.68 to 1.07]; P=0.16), and composite of definite and probable stent thrombosis (HR, 0.79 [95% CI, 0.49 to 1.27], P=0.33) were not significantly different between EES and SES. CONCLUSIONS: This meta-analysis did not show significant differences between EES and SES in terms of clinical efficacy and safety. Future studies with longer follow-up are needed to better define the relative merits of these drug-eluting stents. PMID- 21791672 TI - Percutaneous closure of left ventricular pseudoaneurysm. AB - BACKGROUND: Left ventricular pseudoaneurysm is a rare but serious complication from myocardial infarction and cardiac surgery. Although standard treatment is surgical intervention, percutaneous closure of left ventricular pseudoaneurysm has become an option for high-risk surgical candidates. Experience with percutaneous treatment is limited to a few single case reports. This is the first series of percutaneous treatment of the left ventricular pseudoaneurysms. METHODS AND RESULTS: This is a retrospective analysis of 9 procedures of percutaneous repair of left ventricular pseudoaneurysm in 7 consecutive patients (ages 51 to 83 years, 6 men) completed in our Structural Heart Disease center from June 2008 to December 2010. All patients were considered as a high risk for surgery because of multiple comorbidities. Multiple imaging modalities were used before, during, and after the procedures to improve success and efficacy. The left ventricular pseudoaneurysms of all 7 patients were successfully repaired. Fluoroscopy time on average was 36.5+/-24.0 minutes (range, 12.4 to 75.7 minutes). All patients were followed up for a period ranging from 3 to 32 months after the procedure. Each patient improved by at least 1 New York Heart Association functional class, and 4 patients improved by 2 classes. CONCLUSIONS: Transcatheter closure of the left ventricular pseudoaneurysm is a feasible alternative for high-risk surgical candidates. The use of multiple imaging modalities is required for a detail planning and execution of the procedure. PMID- 21791673 TI - Percutaneous repair of paravalvular prosthetic regurgitation: acute and 30-day outcomes in 115 patients. AB - BACKGROUND: Percutaneous repair has emerged as a potential therapy for patients with prosthetic paravalvular regurgitation. However, there is a relative paucity of data on the feasibility and outcome of this procedure. METHODS AND RESULTS: All patients in whom percutaneous paravalvular regurgitation closure was attempted at our hospital were identified and included. Under echocardiographic and fluoroscopic guidance, patients underwent implantation of >=1 an Amplatzer Septal Occluder, Duct Occluder, Muscular Ventricular Septal Defect Occluder, or Vascular Plug II. Percutaneous repair of 141 paravalvular defects was attempted in 115 patients (age, 67+/-12 years; men, 53%) with heart failure, hemolytic anemia, or both and who were at high risk of open surgery (mean estimated Society of Thoracic Surgeons mortality, 6.9%). Devices were implanted in 125 defects (89% of total defects), including in 19 patients with multiple defects. Because of the complexity of the procedures, wire exteriorization was required in 29 patients. Overall, successful percutaneous closure (defined as <=1+ residual regurgitation) was achieved in 88 (77%) patients. Procedural time decreased with increasing case experience for percutaneous repair of both perimitral and periaortic defects. Overall, the 30-day complication rate was 8.7% (sudden and unexplained death, 1.7%; stroke, 2.6%; emergency surgery, 0.9%; bleeding, 5.2%). Two devices embolized during the procedure and were retrieved without sequelae. No procedural deaths occurred, but 2 (1.7%) patients died by 30 days. CONCLUSIONS: Percutaneous repair of paravalvular prosthetic regurgitation can be performed with a reasonable rate of procedural success and may be an initial therapeutic option, particularly in patients at significant risk for open surgery. Increased case experience is associated with shorter procedural time. PMID- 21791675 TI - Empirical evaluation of gene and environment interactions: methods and potential. PMID- 21791674 TI - Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. AB - BACKGROUND: Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. METHODS: To assess interactions between single nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35 rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7 rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 * 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. RESULTS: We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 * 10(-3) -3.96 * 10(-19)). Three SNPs (LSP1 rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). CONCLUSION: This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer. PMID- 21791676 TI - The cover. The incense burner. PMID- 21791678 TI - New tool to gauge depression remission focuses on good feelings, not bad ones. PMID- 21791677 TI - A piece of my mind. Throwback. PMID- 21791679 TI - Strategies sought for reducing cost, improving efficiency of clinical research. PMID- 21791680 TI - Opioid overdose-related deaths. PMID- 21791681 TI - Opioid overdose-related deaths. PMID- 21791682 TI - Opioid overdose-related deaths. PMID- 21791683 TI - Reducing opioid abuse and diversion. PMID- 21791684 TI - Reducing opioid abuse and diversion. PMID- 21791685 TI - Reducing opioid abuse and diversion. PMID- 21791686 TI - Clinical inertia and uncertainty in medicine. PMID- 21791687 TI - Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. AB - CONTEXT: Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. OBJECTIVE: To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. DESIGN, SETTING, AND PATIENTS: From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. INTERVENTIONS: All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. MAIN OUTCOME MEASURES: Overall survival (primary end point) and disease-free survival (a secondary end point). RESULTS: Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. CONCLUSION: Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003854. PMID- 21791688 TI - Change in prevalence of chronic conditions between childhood and adolescence among extremely low-birth-weight children. AB - CONTEXT: Extremely low-birth-weight (ELBW) children have high rates of chronic conditions during childhood. Information on their trajectory of health during adolescence is needed for health care planning. OBJECTIVE: To examine changes in the rates of chronic conditions between the ages of 8 and 14 years among ELBW children compared with normal-birth-weight (NBW) controls. DESIGN, SETTING, AND PARTICIPANTS: Cohort study conducted from 2004 through 2009 of 181 ELBW children (weight < 1 kg) and 115 NBW controls of similar sociodemographic status born from 1992 through 1995 in Cleveland, Ohio. MAIN OUTCOME MEASURES: Rates of chronic conditions overall (measured with the revised Questionnaire for Identifying Children With Chronic Conditions) and rates of asthma and obesity. RESULTS: The overall rates of chronic conditions did not change significantly between the ages of 8 and 14 years among ELBW children (75% at age 8 years vs 74% at age 14 years) or NBW controls (37% at age 8 years vs 47% at age 14 years). In generalized estimating equations logistic regression adjusting for sociodemographic status, sex, and race, ELBW children continued to have a higher rate of chronic conditions than NBW controls at age 14 years (74% vs 47%, respectively, adjusted odds ratio [AOR], 2.8 [95% confidence interval {CI}, 1.7 to 4.6]). Rates of asthma requiring medication did not change between the ages of 8 and 14 years among ELBW children (23% at both ages) but increased among NBW controls from 8% at age 8 years to 17% at age 14 years (P = .002). Differences in rates of asthma between ELBW and NBW children were no longer significant at the age of 14 years (23% vs 17%, respectively; AOR, 1.5 [95% CI, 0.8 to 2.8]). Mean z scores for body mass index increased in ELBW children from 0.06 at age 8 years to 0.38 at age 14 years (P <.001) and rates of obesity increased from 12% at age 8 years to 19% at age 14 years (P = .02). However, the scores and rates did not change among NBW controls such that at the age of 14 years the differences between ELBW and NBW children in mean z scores for body mass index (0.38 vs 0.56, respectively; adjusted mean difference -0.2 [95% CI, -0.5 to 0.1]) or rates of obesity (19% vs 20%, respectively; AOR, 1.1 [95% CI, 0.6 to 2.0]) were not significant. CONCLUSIONS: Among ELBW children, rates of overall chronic conditions and asthma did not change between the ages of 8 and 14 years but the rate of obesity increased. Compared with NBW controls, the rates of chronic conditions were higher but there were no significant differences in the rates of asthma or obesity. PMID- 21791689 TI - Implementation of Medicare Part D and nondrug medical spending for elderly adults with limited prior drug coverage. AB - CONTEXT: Implementation of Medicare Part D was followed by increased use of prescription medications, reduced out-of-pocket costs, and improved medication adherence. Its effects on nondrug medical spending remain unclear. OBJECTIVE: To assess differential changes in nondrug medical spending following the implementation of Part D for traditional Medicare beneficiaries with limited prior drug coverage. DESIGN, SETTING, AND PARTICIPANTS: Nationally representative longitudinal survey data and linked Medicare claims from 2004-2007 were used to compare nondrug medical spending before and after the implementation of Part D by self-reported generosity of prescription drug coverage before 2006. Participants included 6001 elderly Medicare beneficiaries from the Health and Retirement Study, including 2538 with generous and 3463 with limited drug coverage before 2006. Comparisons were adjusted for sociodemographic and health characteristics and checked for residual confounding by conducting similar comparisons for a control cohort from 2002-2005. MAIN OUTCOME MEASURE: Nondrug medical spending assessed from claims, in total and by type of service (inpatient and skilled nursing facility vs physician services). RESULTS: Total nondrug medical spending was differentially reduced after January 1, 2006, for beneficiaries with limited prior drug coverage (-$306/quarter [95% confidence interval {CI}, -$586 to -$51]; P = .02), relative to beneficiaries with generous prior drug coverage. This differential reduction was explained mostly by differential changes in spending on inpatient and skilled nursing facility care (-$204/quarter [95% CI, -$447 to $2]; P = .05). Differential reductions in spending on physician services ( $67/quarter [95% CI, -$134 to -$5]; P = .03) were not associated with differential changes in outpatient visits (-0.06 visits/quarter [95% CI, -0.21 to 0.08]; P = .37), suggesting reduced spending on inpatient physician services for beneficiaries with limited prior drug coverage. In contrast, nondrug medical spending in the control cohort did not differentially change after January 1, 2004, for beneficiaries with limited prior drug coverage in 2002 ($14/quarter [95% CI, -$338 to $324]; P = .93), relative to beneficiaries with generous prior coverage. CONCLUSION: Implementation of Part D was associated with significant differential reductions in nondrug medical spending for Medicare beneficiaries with limited prior drug coverage. PMID- 21791691 TI - Does this patient have medical decision-making capacity? AB - CONTEXT: Evaluation of the capacity of a patient to make medical decisions should occur in the context of specific medical decisions when incapacity is considered. OBJECTIVE: To determine the prevalence of incapacity and assessment accuracy in adult medicine patients without severe mental illnesses. DATA SOURCES: MEDLINE and EMBASE (from their inception through April 2011) and bibliographies of retrieved articles. STUDY SELECTION: We included high-quality prospective studies (n = 43) of instruments that evaluated medical decision-making capacity for treatment decisions. DATA EXTRACTION: Two authors independently appraised study quality, extracted relevant data, and resolved disagreements by consensus. DATA SYNTHESIS: Incapacity was uncommon in healthy elderly control participants (2.8%; 95% confidence interval [CI], 1.7%-3.9%) compared with medicine inpatients (26%; 95% CI, 18%-35%). Clinicians accurately diagnosed incapacity (positive likelihood ratio [LR+] of 7.9; 95% CI, 2.7-13), although they recognized it in only 42% (95% CI, 30%-53%) of affected patients. Although not designed to assess incapacity, Mini-Mental State Examination (MMSE) scores less than 20 increased the likelihood of incapacity (LR, 6.3; 95% CI, 3.7-11), scores of 20 to 24 had no effect (LR, 0.87; 95% CI, 0.53-1.2), and scores greater than 24 significantly lowered the likelihood of incapacity (LR, 0.14; 95% CI, 0.06-0.34). Of 9 instruments compared with a gold standard, only 3 are easily performed and have useful test characteristics: the Aid to Capacity Evaluation (ACE) (LR+, 8.5; 95% CI, 3.9-19; negative LR [LR-], 0.21; 95% CI, 0.11-0.41), the Hopkins Competency Assessment Test (LR+, 54; 95% CI, 3.5-846; LR-, 0; 95% CI, 0.0-0.52), and the Understanding Treatment Disclosure (LR+, 6.0; 95% CI, 2.1-17; LR-, 0.16; 95% CI, 0.06-0.41). The ACE was validated in the largest study; it is freely available online and includes a training module. CONCLUSIONS: Incapacity is common and often not recognized. The MMSE is useful only at extreme scores. The ACE is the best available instrument to assist physicians in making assessments of medical decision-making capacity. PMID- 21791690 TI - Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. AB - CONTEXT: Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development. OBJECTIVE: To identify risk alleles or mutated genes associated with BE/EAC. DESIGN, SETTING, AND PATIENTS: Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010). MAIN OUTCOME MEASURES: Identification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene. RESULTS: Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P < .001). In addition, 13 patients (11.2%) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030-0.130; P < .001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P = .09). MSR1 mutation resulted in CCND1 up regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1. CONCLUSION: MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases. PMID- 21791692 TI - Physician stewardship of health care in an era of finite resources. PMID- 21791693 TI - Facts, facts, facts: what is a physician to do? PMID- 21791694 TI - Regulation of organ transplantation in China: difficult exploration and slow advance. PMID- 21791695 TI - Evidence-based medicine in surgery: the importance of both experimental and observational study designs. PMID- 21791696 TI - JAMA patient page. Tension-type headache. PMID- 21791698 TI - Store-operated calcium channels: new perspectives on mechanism and function. AB - Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca(2+) entry pathway stimulated by numerous cell surface receptors via the reduction of Ca(2+) concentration in the ER. The discovery of STIM proteins as ER Ca(2+) sensors and Orai proteins as structural components of the Ca(2+) release-activated Ca(2+) (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca(2+) entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field. PMID- 21791700 TI - Relative familial clustering of cerebral versus coronary ischemic events. AB - BACKGROUND: Few population-based studies have ascertained both cerebral and coronary events or considered their relative heritability. Differences in heritability of transient ischemic attack and ischemic stroke versus acute coronary syndromes (ACS) may inform risk prediction, genetic studies, and understanding of disease mechanisms. METHODS AND RESULTS: In a population-based study of all acute vascular events, irrespective of age, we studied family history of myocardial infarction (MI), stroke, and related risk factors in first degree relatives. To allow for differences in rates of affected first-degree relatives caused by differences in disease incidence, we looked at the extent to which parental history was associated with affected siblings within disease category. Nine hundred six probands (604 men; mean age, 70 years) with ACS and 1015 (484 men; mean age, 73 years) with cerebral events had complete family history data. In ACS probands, parental MI was associated with MI in >=1 sibling (1 parent with MI: odds ratio, 1.48; 1.04 to 2.10; P=0.03; both parents with MI: odds ratio, 5.97; 3.23 to 11.03; P<0.0001). In probands with cerebral events, however, parental stroke was not associated with sibling stroke. The overall frequency of >=2 siblings with the same condition was also greater in probands with ACS than in those with cerebral events (odds ratio, 5.43; 3.03 to 9.76; P<0.00001), despite similar overall incidence of MI and stroke in our study population. One hundred forty-two (15.7%) cases of ACS occurred in families with >=2 affected first-degree relatives compared with 56 (5.1%) transient ischemic attack/strokes. All results were similar when analyses were confined to probands with MI only versus stroke only, and independent of smoking. CONCLUSIONS: Heritability of coronary events was greater than that of cerebral events, such that MI was more likely to cluster in families than was stroke. PMID- 21791701 TI - Stem cell proliferation in the skin: alpha-catenin takes over the hippo pathway. AB - Epithelial tissues in the human body undergo constant renewal. For example, the skin is regenerated continuously through the periodic proliferation of normally quiescent stem cells in the basal compartment of the skin. Proper balance between stem cell quiescence and proliferation is maintained over the lifetime of the organism to preserve pools of stem cells required to maintain and repair tissues. However, mechanisms controlling the rate of stem cell renewal are poorly understood. Additionally, whether deregulation of these mechanisms within epidermal stem cells leads to skin cancer is not known. The adherens junction component alpha-catenin has been identified as a regulator of epidermal stem cell proliferation and as a suppressor of skin cancer through its inhibition of Yap, a transcriptional effector of the Hippo growth control pathway. Understanding the pathways that regulate the proliferation of stem cells in the skin holds promise for reversing the aging process and tumor development. PMID- 21791697 TI - Calcium signaling in synapse-to-nucleus communication. AB - Changes in the intracellular concentration of calcium ions in neurons are involved in neurite growth, development, and remodeling, regulation of neuronal excitability, increases and decreases in the strength of synaptic connections, and the activation of survival and programmed cell death pathways. An important aspect of the signals that trigger these processes is that they are frequently initiated in the form of glutamatergic neurotransmission within dendritic trees, while their completion involves specific changes in the patterns of genes expressed within neuronal nuclei. Accordingly, two prominent aims of research concerned with calcium signaling in neurons are determination of the mechanisms governing information conveyance between synapse and nucleus, and discovery of the rules dictating translation of specific patterns of inputs into appropriate and specific transcriptional responses. In this article, we present an overview of the avenues by which glutamatergic excitation of dendrites may be communicated to the neuronal nucleus and the primary calcium-dependent signaling pathways by which synaptic activity can invoke changes in neuronal gene expression programs. PMID- 21791699 TI - Germline stem cells. AB - Sperm and egg production requires a robust stem cell system that balances self renewal with differentiation. Self-renewal at the expense of differentiation can cause tumorigenesis, whereas differentiation at the expense of self-renewal can cause germ cell depletion and infertility. In most organisms, and sometimes in both sexes, germline stem cells (GSCs) often reside in a defined anatomical niche. Factors within the niche regulate a balance between GSC self-renewal and differentiation. Asymmetric division of the germline stem cell to form daughter cells with alternative fates is common. The exception to both these tendencies is the mammalian testis where there does not appear to be an obvious anatomical niche and where GSC homeostasis is likely accomplished by a stochastic balance of self-renewal and differentiation and not by regulated asymmetric cell division. Despite these apparent differences, GSCs in all organisms share many common mechanisms, although not necessarily molecules, to guarantee survival of the germline. PMID- 21791702 TI - Proteome-wide mapping of the Drosophila acetylome demonstrates a high degree of conservation of lysine acetylation. AB - Posttranslational modification of proteins by acetylation and phosphorylation regulates most cellular processes in living organisms. Surprisingly, the evolutionary conservation of phosphorylated serine and threonine residues is only marginally higher than that of unmodified serines and threonines. With high resolution mass spectrometry, we identified 1981 lysine acetylation sites in the proteome of Drosophila melanogaster. We used data sets of experimentally identified acetylation and phosphorylation sites in Drosophila and humans to analyze the evolutionary conservation of these modification sites between flies and humans. Site-level conservation analysis revealed that acetylation sites are highly conserved, significantly more so than phosphorylation sites. Furthermore, comparison of lysine conservation in Drosophila and humans with that in nematodes and zebrafish revealed that acetylated lysines were significantly more conserved than were nonacetylated lysines. Bioinformatics analysis using Gene Ontology terms suggested that the proteins with conserved acetylation control cellular processes such as protein translation, protein folding, DNA packaging, and mitochondrial metabolism. We found that acetylation of ubiquitin-conjugating E2 enzymes was evolutionarily conserved, and mutation of a conserved acetylation site impaired the function of the human E2 enzyme UBE2D3. This systems-level analysis of comparative posttranslational modification showed that acetylation is an anciently conserved modification and suggests that phosphorylation sites may have evolved faster than acetylation sites. PMID- 21791704 TI - Sleep medicine clinical and surgical training during otolaryngology residency: a national survey of otolaryngology residency programs. AB - OBJECTIVE: The authors sought to assess the otolaryngology residency training experiences in adult sleep medicine and sleep surgery in the United States. STUDY DESIGN: Internet survey. SETTING: US academic otolaryngology residency programs. SUBJECTS AND METHODS: This Internet survey was emailed to the program directors of 103 US Accreditation Council for Graduate Medical Education (ACGME)-approved otolaryngology residency programs in 2010. RESULTS: A total of 47 program directors responded, representing 46% of programs surveyed. In 59% of these programs, there was at least 1 faculty member with clinical practice dedicated to adult medicine. Most commonly, these clinicians spent less than 50% of their clinical time on adult sleep medicine. While most otolaryngology residents were reported being well trained in commonly performed procedures such as septoplasty and uvulopalatopharyngoplasty (UPPP), the training on hypopharyngeal or multilevel surgeries, such as partial glossectomy, tongue base resection, hyoid or tongue suspension, or geniotubercle advancement, was considered less frequent. The overall exposure to education regarding the interpretation of original data of laboratory-based sleep studies or portable home monitoring devices was infrequent. A significant portion of respondents indicated that they would like to expand their residents' exposure to adult sleep medicine and sleep surgery. CONCLUSION: This survey provides a starting point to further assess the rigor of sleep medicine/sleep surgery training in US residency programs. Continued assessment and strengthening of the current curriculum are crucial to keep residents up to date with this evolving field. This result calls attention to the importance of bolstering sleep medicine and surgery curriculum to meet the academic requirements of otolaryngology training. PMID- 21791703 TI - A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion. AB - Acquisition of invasive cell behavior underlies tumor progression and metastasis. To further define the molecular mechanisms underlying invasive behavior, we developed a high-throughput screening strategy to quantitate invadopodia, which are actin-rich membrane protrusions of cancer cells that contribute to tissue invasion and matrix remodeling. We tested the LOPAC 1280 collection of pharmacologically active agents in a high-content, image-based assay and identified compounds that inhibited invadopodium formation without overt toxicity, as well as compounds that increased invadopodia number. The chemotherapeutic agent paclitaxel increased both the number of invadopodia and the invasive behavior of various human cancer cell lines, effects that have potential clinical implications for its use before surgical removal of a primary tumor (neoadjuvant therapy) or in patients with chemoresistant tumors. Several compounds that inhibited invasion have been characterized as cyclin-dependent kinase (Cdk) inhibitors, and loss-of-function experiments determined that Cdk5 was the relevant target. We further determined that Cdk5 promoted both invadopodium formation and cancer cell invasion by phosphorylating and thus decreasing the abundance of the actin regulatory protein caldesmon. PMID- 21791705 TI - Quality of voice evaluation in patients treated by supracricoid laryngectomy and modified supracricoid laryngectomy. AB - OBJECTIVE: To compare quality of voice in patients treated by supracricoid laryngectomy and patients treated by modified supracricoid laryngectomy using the sternohyoid muscle for neoglottis reconstruction. STUDY DESIGN: Case series. Setting. Teaching hospital. SUBJECTS AND METHODS: This study was performed between 2004 and 2008 on 28 consecutive patients affected by T1b-T2 laryngeal carcinoma. Eleven patients were treated by supracricoid laryngectomy, and 17 patients were treated by modified supracricoid laryngectomy. For each patient, postoperative parameters such as decannulation time, nasogastric feeding tube, and length of hospitalization were noted. Vocal function, Voice Handicap Index scores, and perceptual voice analysis scores on intelligibility, noise, fluency, and voice scale were evaluated. RESULTS: The postoperative course of the patients treated by modified supracricoid laryngectomy was similar to patients treated by supracricoid laryngectomy. No delay in the length of hospitalization was detected in patients undergoing surgery with the new technique. A significant difference was detected in the nasogastric tube removal time and decannulation time. The data from intelligibility, noise, fluency, and voice scale analyses revealed a better quality of voice in patients treated by modified supracricoid partial laryngectomy with a significant difference in intelligibility, fluency, and voicing. The Voice Handicap Index mean value of physical, functional, and emotional subscales confirmed patients' perceptions of a minor voice handicap in patients treated by modified supracricoid laryngectomy, with a significant difference on the physical subscale. CONCLUSION: Modified supracricoid laryngectomy seems to be a good way to improve quality of voice and quality of life in patients with early laryngeal cancer. PMID- 21791706 TI - Contemporary role of lymphoscintigraphy: we can no longer afford to ignore! PMID- 21791707 TI - Missing data. PMID- 21791709 TI - In vitro primary human lymphocyte flow cytometry based micronucleus assay: simultaneous assessment of cell proliferation, apoptosis and MN frequency. AB - In order to minimise the number of positive in vitro cytogenetic results which are not confirmed in rodent carcinogenicity tests, biological systems that are p53 and DNA repair proficient should be recommended. Moreover, an appropriate cytotoxicity parameter for top dose selection should be considered. Recent International Conference on Harmonisation draft S2 and Organisation for Economic Co-operation and Development (OECD) 487 guideline accepted the in vitro micronucleus test (MNT) as a valid alternative method for in vitro chromosome aberration test within the in vitro cytogenetic test battery. Since mitosis is a prerequisite for expression of the micronuclei, it is compulsory to demonstrate that cell division occurred, and if possible, to identify the cells that completed mitosis. The OECD guideline recommends the use of a cytokinesis block for the assessment of proliferation in primary T-lymphocytes. The work presented in this manuscript was initiated to develop a novel flow cytometry-based primary human lymphocyte MNT method. This new assay is based on a three-step staining procedure: carboxyfluorescein succinimidyl ester as a proliferation marker, ethidium monoazide for chromatin of necrotic and late apoptotic cells discrimination and 4,6-diaminodino-2-phenylindole as a DNA marker. The proof of principle of the method was performed using genotoxic and non-genotoxic compounds: methyl methanesulfonate, mitomycin C, vinblastine sulphate, cyclophosphamide, sodium chloride and dexamethasone. It has been shown that the new flow cytometry-based primary human lymphocyte MNT method is at least equally reliable method as the standard Cytochalasin B MNT. However, further validation of the assay using a wide selection of compounds with a variety of mechanisms of action is required, before it can be used for regulatory purposes. Moreover, a miniaturisation of the technology may provide an additional advantage for early drug development. PMID- 21791710 TI - Associations of cigarette smoking and alcohol consumption with advanced or multiple colorectal adenoma risks: a colonoscopy-based case-control study in Korea. AB - The associations between alcohol consumption and cigarette smoking habits and the risk for colorectal adenomatous polyps according to the detailed clinical information about polyps were assessed in a large colonoscopy-based study. The study enrolled participants who visited the National Cancer Center of the Republic of Korea for cancer screening between April 2007 and April 2009. In 1,242 newly diagnosed colorectal adenoma patients and 3,019 polyp-free controls, past smokers (odds ratio (OR) = 1.31, 95% confidence interval (CI): 1.04, 1.65) and current smokers (OR = 1.70, 95% CI: 1.37, 2.11) had increased risks for adenomas compared with nonsmokers. Cigarette smoking conferred an even higher risk for advanced adenomas and 3 or more adenomas than for low-risk adenomas or a single adenoma. Dose-response relations were observed among the daily number of cigarettes smoked, the duration of smoking, the pack-years of smoking, and the risk for adenomas. A longer duration of alcohol consumption was associated with a higher risk for advanced adenomas (for >28 years of consumption: OR = 2.0, 95% CI: 1.10, 3.64) and 3 or more adenomas (OR = 2.19, 95% CI: 1.27, 3.76). In conclusion, cigarette smoking and alcohol consumption play roles in colorectal carcinogenesis, and the association differs by the clinical features of the adenomas. PMID- 21791711 TI - Aesthetic nickel titanium wires--how much do they deliver? AB - The purpose of this study was to evaluate and compare the force levels of aesthetic Ni-Ti wires to regular Ni-Ti wires of the same dimension and evaluate their mechanical properties. Aesthetic and regular maxillary superelastic Ni-Ti wires (0.016 * 0.022) from four different manufacturers (G&H Wire Company, TP Orthodontics, GAC International, and Ortho Organizers) were selected and grouped I-IV. The loading and unloading values were compared using a three-point bending test. The unloading end values were also recorded to evaluate the recovery of archwires after each deflection. The unloading values were recorded at 0.5, 1.5, and 2.5 mm after loading deflections of 1, 2, and 3 mm, respectively. Cross sectional scanning electron microscopy was used to assess the coating thickness of aesthetic wires. The results, statistically analysed, showed a significant decrease in force values for the aesthetic wires in groups I, III, and IV (P < 0.001) as compared to regular Ni-Ti wires of the same dimension from the same manufacturer. There was no significant difference in force values for group II wires. A statistically significant decrease in force values of epoxy-coated wires was observed in groups I, III, and IV only. This is of obvious clinical significance during wire selection. The group II coated wires, however, exhibited forces comparable to their regular Ni-ti wires with a difference that was statistically insignificant. The end values of aesthetic wires showed almost complete recovery for groups I, II, and III after 2 and 3 mm deflections. PMID- 21791712 TI - The effect of increased overjet on the magnitude and reproducibility of smiling in adult females. AB - The objective of this study was to determine if increased overjet (greater than 6 mm) influences the magnitude and reproducibility of natural smile and maximal smile in Caucasian adult females. Twenty adult females with an increased overjet (6-10 mm) and 20 control adult females (overjet 2-4 mm) with no history of orthodontic treatment volunteered to participate. The mean age in the control group was 30.1 +/- 6.4 years and the mean age in the test group was 31.9 +/- 10.8 years. Three-dimensional stereophotogrammetric images were captured of each subject for three expressions: at rest, natural smile, and maximal smile. The images were recorded twice on two separate occasions, 6 weeks apart. Images were landmarked and a partial ordinary Procrustes superimposition was used to adjust for the differences in head posture between the same expressions. The magnitude of movement relative to the rest position, averaged over all the landmarks, was calculated and compared between the groups using analysis of variance (linear mixed-effects model); the intra- and inter-session reproducibility of both expressions was assessed. There was greater mean movement, averaged over all the landmarks, in the control group than in the increased overjet group for both natural smile and maximal smile (P = 0.0068). For these expressions, there were no statistically significant differences in reproducibility within sessions (P = 0.5403) or between sessions (P = 0.3665). Increased overjet had a statistically significant effect on the magnitude of smiling but did not influence the reproducibility of natural or maximal smile relative to controls. PMID- 21791713 TI - Ribonucleotide reductase as a target to control apicomplexan diseases. AB - Malaria is caused by species in the apicomplexan genus Plasmodium, which infect hundreds of millions of people each year and kill close to one million. While malaria is the most notorious of the apicomplexan-caused diseases, other members of eukaryotic phylum Apicomplexa are responsible for additional, albeit less well known, diseases in humans, economically important livestock, and a variety of other vertebrates. Diseases such as babesiosis (hemolytic anemia), theileriosis and East Coast Fever, cryptosporidiosis, and toxoplasmosis are caused by the apicomplexans Babesia, Theileria, Cryptosporidium and Toxoplasma, respectively. In addition to the loss of human life, these diseases are responsible for losses of billions of dollars annually. Hence, the research into new drug targets remains a high priority. Ribonucleotide reductase (RNR) is an essential enzyme found in all domains of life. It is the only means by which de novo synthesis of deoxyribonucleotides occurs, without which DNA replication and repair cannot proceed. RNR has long been the target of antiviral, antibacterial and anti-cancer therapeutics. Herein, we review the chemotherapeutic methods used to inhibit RNR, with particular emphasis on the role of RNR inhibition in Apicomplexa, and in light of the novel RNR R2_e2 subunit recently identified in apicomplexan parasites. PMID- 21791714 TI - Complications in laparoscopic renal surgery. Five year experience. AB - OBJECTIVES: Retroperitoneal laparoscopic surgery has been applied in many centers as the first therapeutic option in an ever increasing number of cases. We analyze the complications seen in our 5 years of experience in laparoscopic renal surgery. METHODS: We retrospectively analyze intraoperative and postoperative complications that occurred in the laparoscopic renal procedures carried out between June 2004 and November 2009. We also study several demographic factors that may play a role in the cause of the complications. RESULTS: A total of 404 laparoscopic procedures that meet these characteristics were performed with a total of 98 medical and surgical complications (24.2%). Death rate was 0.6, conversion to open surgery occurred in 8 patients (1.9%) and postoperative surgical revision was required on 4 patients (0.99%). The most common intraoperative complication was bleeding (6.4%) and the most common postoperative complication was deterioration of renal function (6.4%). Nephroureterectomy was the procedure with the highest complication rate. CONCLUSIONS: Analysis of the complications of a surgical technique is fundamental and a consensus on the definition of such complications must be reached in order for the study to be as complete and critical as possible. PMID- 21791716 TI - Transrectal high-intensity focused ultrasound for local treatment of prostate cancer: current role. AB - Attractivity of robotic high intensity focused ultrasound (HIFU) is based largely on the non-invasive, extremely precise nature of this high-tech robotic therapy as well as its clean, radiation free, surgical, but nevertheless, bloodless character. Today, in urological oncology, HIFU is used clinically as a therapeutic tool for the treatment of prostate cancer. Experimentally it is investigated for therapeutic use in kidney and breast cancer. Transrectal treatment of localized prostate cancer with HIFU has been under investigation since the 1990s and it is meanwhile an actively used therapy for the disease in many urological departments worldwide. Since 2000 HIFU is mostly used in combination with transurethral resection of the prostate in order to reduce prostate gland size, to facilitate effective tissue destruction and to avoid side effects. Palliative and salvage indications as well as focal therapy of prostate cancer are under investigation to extend the spectrum of HIFU indications for non invasive prostate cancer therapy. PMID- 21791717 TI - Hypebaric oxygen treatment in urology. AB - OBJECTIVES: Hyperbaric oxygen therapy (HBO) has been successfully used in several disorders derived from tissue hypoxia, due to the extra oxygen supply to the tissues it enables. In this manuscript we performed a systematic review including all the existing data published until 2010 about HBO in urologic disorders. METHODS: We performed a Medline search using the terms "hyperbaric oxygen", "radical cystitis", "interstitial cystitis", "hemorrhagic cystitis", "urological/pelvic fistula"and "Fournier's gangrene". The search was restricted to human clinical trials published in any language. RESULTS: We found 56 papers: 1 randomized controlled trial, 7 reviews and 48 case reports; only one of them was a prospective study. A total of 695 patients were included. Just one study used tissue oxygen measurement to define hypoxia. The number of hyperbaric oxygen therapy sessions ranged from 4 to 44 (mean 19.2 sessions/patient). CONCLUSIONS: The level of evidence from most reviewed papers is low because most of them are case series. Nevertheless, results of most of those studies regarding patient management are good or very good. So it seems that HBO can be very useful in urological diseases related to tissue hypoxia. PMID- 21791718 TI - Experience in the treatment of rectourethral fistulae after radical prostatectomy. AB - OBJECTIVES: To report the clinical characteristics of rectourethral fistula (RUF) after radical prostatectomy (RP) as well as our experience managing them. METHODS: We present our experience in the treatment of RUF based on their clinical characteristics and the presence of associated complexity factors. After medical history and physical examination, the diagnostic work up was completed in all cases with urethrograms, cystoscopy and barium enema. From January 2000 to July 2010 we treated 12 patients with RUF. Mean age was 64 years(range 56-74 years). The etiology was open surgery in two cases and laparoscopic surgery in ten. Clinical presentation varied from 4 to 60 days after surgery. RESULTS: In our experience, endoscopic and radiological findings were well correlated. Two fistulae were small-less than 5 mm- on the urethral side of the anastomosis allowing spontaneous closure after conservative treatment. Ten patients had larger fistulas on the bladder side of the anastomosis and/or were associated with complexity factors that required a posterior transsphincteric York-Mason approach for resolution, with good recovery of urinary and fecal continence. CONCLUSION: The RUF is a significant complication after RP and it is difficult to solve. We propose early reconstructive surgery in large or complex RUF. The posterior transsphincteric York-Mason approach has allowed the repair in all cases. PMID- 21791719 TI - Predictive factors for recurrence in clinically localized squamous cell carcinoma of the penis. Analisys of our case series. AB - OBJECTIVE: To evaluate the predictive factors for relapse in clinically localized squamous cell carcinoma of the penis undergoing surgical treatment. METHODS: Forty-nine patients were diagnosed with cancer of the penis in our Service between 1999 and 2009. In the present study we excluded 18 subjects: 9 due to the presence of palpable adenopathies, 6 due to histological characteristics other than squamous cell carcinoma, two lost to follow-up, and one due to death at the time of diagnosis. Diagnosis was based on physical examination and biopsy findings. The primary lesion was treated by circumcision, partial surgery or total penectomy. Disease relapse was defined by lymph node or metastatic involvement after three months from surgery. Univariate and multivariate analysis were carried out using the chi-squared test and logistic regression to identify the factors involved in tumor relapse. RESULTS: Thirty-one patients were included in the study. Mean follow-up was 36 months (median 29). The histopathological study yielded the following profile: 55% pT1 cases, 32% pT2 cases and 13% pT3 tumors. Regarding histological grade, the distribution was G1: 29%, G2: 32%, G3: 39%. Recurrence and mortality rates were 38.7% and 35.5%, respectively. In the univariate analysis, location of the lesion (p=0.004), type of surgery (p=0.008), tumor stage (p=0.003) and cellular grade (p<0.001)were significantly correlated to disease relapse. In the multivariate analysis, only cellular grade proved statistically significant (p=0.01). CONCLUSION: In our series, only histological grade could be regarded as an independent predictor of tumor relapse. PMID- 21791720 TI - Scrotal carcinoma. AB - OBJECTIVE: We report a rare clinical case of scrotum carcinoma and evaluate its treatment and prognosis. METHODS: We describe the case of a 62 year old man who presented an ulcerated-bleeding lesion on the right side of the scrotum. The diagnostic tests found carcinoma of the scrotum. We performed surgical radical treatment preserving the left scrotum. RESULTS: Histological examination showed lesions of well differentiated squamous cell tumor. CONCLUSIONS: After literature review we conclude that scrotal carcinoma is currently a rare tumor, and even more in cases with industrial exposure to carcinogens. Its incidence has declined greatly and advanced cases requiring radical surgery are rare. PMID- 21791721 TI - Bladder metastasis of gastric adenocarcinoma. Report of 2 cases and bibliographic review. AB - OBJECTIVE: Metastases to the urinary bladder are rare, representing less than 2% of bladder tumors. We report two cases of bladder involvement by primary gastric adenocarcinoma and perform a bibliographic review of the literature on this subject. METHODS: A search for published data was performed in the PubMed database using the key words "bladder", "secondary malignant tumors" and "metastatic gastric carcinoma". We reviewed the two cases of secondary bladder involvement by primary gastric adenocarcinoma managed at our institution. RESULTS: Case 1: 62 year old female presenting with irritative LUTS, hypogastric pain and constitutional symptoms, with bilateral hydronephrosis. After bilateral nephrostomy, bladder wall biopsies revealed poorly differentiated metastatic gastric carcinoma. Case 2: 41 year old male with gastric adenocarcinoma diagnosed by endoscopic biopsy with pancreatic involvement, under neoadjuvant chemotherapy regimen, with sporadic macroscopic hematuria. Cistoscopy revealed a protuberant bladder mass with biopsies conclusive for secondary bladder involvement by gastric carcinoma. CONCLUSION: Bladder metastasis from primary gastric adenocarcinoma usually means advanced disease with multiple metastatic involvement and peritoneal dissemination. The overall prognosis is very poor. PMID- 21791722 TI - Hematuria secondary to congenital arteriovenous fistula treated with embolization. AB - OBJECTIVE: To report a rare case of hematuria caused by an arteriovenous fistula which may be a urological emergency. METHODS: We describe the medical history, physical examination, complementary tests performed and their results, as well as the treatment applied in an adolescent with hematuria. RESULTS: Congenital arteriovenous fistula was diagnosed and treated by percutaneous embolization with immediate stop of hematuria. CONCLUSION: Non-traumatic renal arteriovenous fistulae are rare, even more if they present with gross hematuria. We present a case of a life-threatening emergency caused by one of them the treatment of which was possible by embolization, avoiding surgery. PMID- 21791723 TI - Pelvic venous congestion syndrome: case report. AB - OBJECTIVE: To remind the existence of pelvic venous congestion syndrome as a diagnostic possibility in women with chronic or relapsing abdominal pain that simulates repetitive renal colic, in which common diagnostic tests do not show any positive finding. METHODS: We present the case of a 36-year-old woman with a picture of unilateral relapsing abdominal pain that, after many visits to the emergency room is sent for study with the diagnosis of renal colic. Ultrasound, intravenous urogram and ureteroscopy did not demonstrate any pathological finding. RESULTS: Contrast enhanced CT scan demonstrated the severe dilatation of the gonadal venous system as unique finding. She was diagnosed of pelvic venous congestion syndrome and sent to the Gynecology Department for specific treatment. CONCLUSIONS: The pelvic venous congestion syndrome is a clinical entity to keep in mind in patients with chronic or relapsing abdominal pain in whom we do not find evidence of urinary lithiasic disease. Generally, patients present an anxiety or depression state that is secondary to the problems caused by chronic pain and the absence of diagnosis, despite of the many diagnostic tests performed. Reaching a diagnosis that allows adequate treatment will also solve this picture. Contrast enhanced CT scan must be the first step for diagnosis, leaving venography for special situations. PMID- 21791724 TI - Penile lesions secondary to indwelling catheter decubitus. PMID- 21791725 TI - Orchyoepididymitis secondary to massive deferential duct reflux after retropubic adenomectomy. PMID- 21791726 TI - Taking directions: the role of microtubule-bound nucleation in the self organization of the plant cortical array. AB - The highly aligned cortical microtubule array of interphase plant cells is a key regulator of anisotropic cell expansion. Recent computational and analytical work has shown that the non-equilibrium self-organization of this structure can be understood on the basis of experimentally observed collisional interactions between dynamic microtubules attached to the plasma membrane. Most of these approaches assumed that new microtubules are homogeneously and isotropically nucleated on the cortical surface. Experimental evidence, however, shows that nucleation mostly occurs from other microtubules and under specific relative angles. Here, we investigate the impact of directed microtubule-bound nucleations on the alignment process using computer simulations. The results show that microtubule-bound nucleations can increase the degree of alignment achieved, decrease the timescale of the ordering process and widen the regime of dynamic parameters for which the system can self-organize. We establish that the major determinant of this effect is the degree of co-alignment of the nucleations with the parent microtubule. The specific role of sideways branching nucleations appears to allow stronger alignment while maintaining a measure of overall spatial homogeneity. Finally, we investigate the suggestion that observed persistent rotation of microtubule domains can be explained through a handedness bias in microtubule-bound nucleations, showing that this is possible only for an extreme bias and over a limited range of parameters. PMID- 21791727 TI - The elastic network model reveals a consistent picture on intrinsic functional dynamics of type II restriction endonucleases. AB - The vibrational dynamics of various type II restriction endonucleases, in complex with cognate/non-cognate DNA and in the apo form, are investigated with the elastic network model in order to reveal common functional mechanisms in this enzyme family. Scissor-like and tong-like motions observed in the slowest modes of all enzymes and their complexes point to common DNA recognition and cleavage mechanisms. Normal mode analysis further points out that the scissor-like motion has an important role in differentiating between cognate and non-cognate sequences at the recognition site, thus implying its catalytic relevance. Flexible regions observed around the DNA-binding site of the enzyme usually concentrate on the highly conserved beta-strands, especially after DNA binding. These beta-strands may have a structurally stabilizing role in functional dynamics for target site recognition and cleavage. In addition, hot spot residues based on high-frequency modes reveal possible communication pathways between the two distant cleavage sites in the enzyme family. Some of these hot spots also exist on the shortest path between the catalytic sites and are highly conserved. PMID- 21791728 TI - Expanded modeling of temperature-dependent dielectric properties for microwave thermal ablation. AB - Microwaves are a promising source for thermal tumor ablation due to their ability to rapidly heat dispersive biological tissues, often to temperatures in excess of 100 degrees C. At these high temperatures, tissue dielectric properties change rapidly and, thus, so do the characteristics of energy delivery. Precise knowledge of how tissue dielectric properties change during microwave heating promises to facilitate more accurate simulation of device performance and helps optimize device geometry and energy delivery parameters. In this study, we measured the dielectric properties of liver tissue during high-temperature microwave heating. The resulting data were compiled into either a sigmoidal function of temperature or an integration of the time-temperature curve for both relative permittivity and effective conductivity. Coupled electromagnetic-thermal simulations of heating produced by a single monopole antenna using the new models were then compared to simulations with existing linear and static models, and experimental temperatures in liver tissue. The new sigmoidal temperature dependent model more accurately predicted experimental temperatures when compared to temperature-time integrated or existing models. The mean percent differences between simulated and experimental temperatures over all times were 4.2% for sigmoidal, 10.1% for temperature-time integration, 27.0% for linear and 32.8% for static models at the antenna input power of 50 W. Correcting for tissue contraction improved agreement for powers up to 75 W. The sigmoidal model also predicted substantial changes in heating pattern due to dehydration. We can conclude from these studies that a sigmoidal model of tissue dielectric properties improves prediction of experimental results. More work is needed to refine and generalize this model. PMID- 21791729 TI - Detection of a coronary artery vessel wall: performance of 0.3 mm fine-cell detector computed tomography--a phantom study. AB - The purpose of this study was to evaluate whether experimental fine-cell detector computed tomography with a 0.3125 mm cell (0.3 mm cell CT) can improve the detection of coronary vessel walls compared with conventional 64-slice computed tomography with a 0.625 mm cell (0.6 mm cell CT). A coronary vessel wall phantom was scanned using 0.6 mm cell CT and 0.3 mm cell CT. The data for 0.3 mm cell CT were obtained using four protocols: a radiation dose equal, double, triple or quadruple that were used in the 0.6 mm cell CT protocol. The detectable size of the vessel wall was assessed based on the first and second derivative functions, and the minimum measurable values were compared using a paired t-test. As a result, the minimum detectable wall thickness of 0.6 mm cell CT (1.5 mm) was significantly larger than that of 0.3 mm cell CT performed using the triple- and quadruple-dose protocols (0.9 mm) and the double-dose protocol (1.1 mm). The difference in the minimum detectable vessel wall thickness measured using 0.6 mm cell CT (1.5 +/- 0.1 mm) and 0.3 mm cell CT (0.9 +/- 0.1 mm, 1.1 +/- 0.2 mm) was significant (p < 0.01). We concluded that 0.3 mm cell CT improved the detection of coronary vessel walls when a more than double-dose protocol was used compared with 0.6 mm cell CT. PMID- 21791730 TI - Effects of injected dose, BMI and scanner type on NECR and image noise in PET imaging. AB - Noise equivalent count rate (NECR) and image noise are two different but related metrics that have been used to predict and assess image quality, respectively. The aim of this study is to investigate, using patient studies, the relationships between injected dose (ID), body mass index (BMI) and scanner type on NECR and image noise measurements in PET imaging. Two groups of 90 patients each were imaged on a GE DSTE and a DRX PET/CT scanner, respectively. The patients in each group were divided into nine subgroups according to three BMI (20-24.9, 25-29.9, 30-45 kg m(-2)) and three ID (296-444, 444-555, 555-740 MBq) ranges, resulting in ten patients/subgroup. All PET data were acquired in 3D mode and reconstructed using the VuePoint HD(r) fully 3D OSEM algorithm (2 iterations, 21(DRX) or 20 (DSTE) subsets). NECR and image noise measurements for bed positions covering the liver were calculated for each patient. NECR was calculated from the trues, randoms and scatter events recorded in the DICOM header of each patient study, while image noise was determined as the standard deviation of 50 non-neighboring voxels in the liver of each patient. A t-test compared the NECR and image noise for different scanners but with the same BMI and ID. An ANOVA test on the other hand was used to compare the results of patients with different BMI but the same ID and scanner type as well as different ID but the same BMI and scanner type. As expected the t-test showed a significant difference in NECR between the two scanners for all BMI and ID subgroups. However, contrary to what is expected no such findings were observed for image noise measurement. The ANOVA results showed a statistically significant difference in both NECR and image noise among the different BMI for each ID and scanner subgroup. However, there was no statistically significant difference in NECR and image noise across different ID for each BMI and scanner subgroup. Although the GE DRX PET/CT scanner has better count rate performance than the GE DSTE PET/CT scanner, this improvement does not translate to a lower image noise when using OSEM reconstruction. Our results show that patients with larger BMI consistently generate poorer image quality. Dose reduction from >555 to 296-444 MBq has minimal impact on image quality independent of the scanner used. A reduction in ID decreases patient and technologist exposure and can potentially reduce the overall cost of the study. PMID- 21791731 TI - A Monte Carlo pencil beam scanning model for proton treatment plan simulation using GATE/GEANT4. AB - This work proposes a generic method for modeling scanned ion beam delivery systems, without simulation of the treatment nozzle and based exclusively on beam data library (BDL) measurements required for treatment planning systems (TPS). To this aim, new tools dedicated to treatment plan simulation were implemented in the Gate Monte Carlo platform. The method was applied to a dedicated nozzle from IBA for proton pencil beam scanning delivery. Optical and energy parameters of the system were modeled using a set of proton depth-dose profiles and spot sizes measured at 27 therapeutic energies. For further validation of the beam model, specific 2D and 3D plans were produced and then measured with appropriate dosimetric tools. Dose contributions from secondary particles produced by nuclear interactions were also investigated using field size factor experiments. Pristine Bragg peaks were reproduced with 0.7 mm range and 0.2 mm spot size accuracy. A 32 cm range spread-out Bragg peak with 10 cm modulation was reproduced with 0.8 mm range accuracy and a maximum point-to-point dose difference of less than 2%. A 2D test pattern consisting of a combination of homogeneous and high-gradient dose regions passed a 2%/2 mm gamma index comparison for 97% of the points. In conclusion, the generic modeling method proposed for scanned ion beam delivery systems was applicable to an IBA proton therapy system. The key advantage of the method is that it only requires BDL measurements of the system. The validation tests performed so far demonstrated that the beam model achieves clinical performance, paving the way for further studies toward TPS benchmarking. The method involves new sources that are available in the new Gate release V6.1 and could be further applied to other particle therapy systems delivering protons or other types of ions like carbon. PMID- 21791732 TI - Maximum likelihood estimation-based denoising of magnetic resonance images using restricted local neighborhoods. AB - In this paper, we propose a method to denoise magnitude magnetic resonance (MR) images, which are Rician distributed. Conventionally, maximum likelihood methods incorporate the Rice distribution to estimate the true, underlying signal from a local neighborhood within which the signal is assumed to be constant. However, if this assumption is not met, such filtering will lead to blurred edges and loss of fine structures. As a solution to this problem, we put forward the concept of restricted local neighborhoods where the true intensity for each noisy pixel is estimated from a set of preselected neighboring pixels. To this end, a reference image is created from the noisy image using a recently proposed nonlocal means algorithm. This reference image is used as a prior for further noise reduction. A scheme is developed to locally select an appropriate subset of pixels from which the underlying signal is estimated. Experimental results based on the peak signal to noise ratio, structural similarity index matrix, Bhattacharyya coefficient and mean absolute difference from synthetic and real MR images demonstrate the superior performance of the proposed method over other state-of-the-art methods. PMID- 21791733 TI - Investigation of voxel warping and energy mapping approaches for fast 4D Monte Carlo dose calculations in deformed geometries using VMC++. AB - A new deformable geometry class for the VMC++ Monte Carlo code was implemented based on the voxel warping method. Alternative geometries which use tetrahedral sub-elements were implemented and efficiency improvements investigated. A new energy mapping method, based on calculating the volume overlap between deformed reference dose grid and the target dose grid, was also developed. Dose calculations using both the voxel warping and energy mapping methods were compared in simple phantoms as well as a patient geometry. The new deformed geometry implementation in VMC++ increased calculation times by approximately a factor of 6 compared to standard VMC++ calculations in rectilinear geometries. However, the tetrahedron-based geometries were found to improve computational efficiency, relative to the dodecahedron-based geometry, by a factor of 2. When an exact transformation between the reference and target geometries was provided, the voxel and energy warping methods produced identical results. However, when the transformation is not exact, there were discrepancies in the energy deposited on the target geometry which lead to significant differences in the dose calculated by the two methods. Preliminary investigations indicate that these energy differences may correlate with registration errors; however, further work is needed to determine the usefulness of this metric for quantifying registration accuracy. PMID- 21791734 TI - Imaging the 3D structure of secondary osteons in human cortical bone using phase retrieval tomography. AB - By applying a phase-retrieval step before carrying out standard filtered back projection reconstructions in tomographic imaging, we were able to resolve structures with small differences in density within a densely absorbing sample. This phase-retrieval tomography is particularly suited for the three-dimensional segmentation of secondary osteons (roughly cylindrical structures) which are superimposed upon an existing cortical bone structure through the process of turnover known as remodelling. The resulting images make possible the analysis of the secondary osteon structure and the relationship between an osteon and the surrounding tissue. Our observations have revealed many different and complex 3D structures of osteons that could not be studied using previous methods. This work was carried out using a laboratory-based x-ray source, which makes obtaining these sorts of images readily accessible. PMID- 21791735 TI - Editorial introduction. PMID- 21791736 TI - Intrathecal baclofen in cerebral palsy: A decade of treatment outcomes. AB - Continuous intrathecal baclofen (CITB) is considered a standard treatment for spasticity in patients with cerebral palsy (CP). This review summarizes the recent literature and assesses the evidence for the efficacy of ITB for spasticity and its related sequelae in patients with CP. The literature was searched using electronic databases and reference lists from March 2000 through April 2007. Studies included report treatment effects of ITB in patients with CP. The outcomes reported in the 29 studies identified are classified using the International Classification of Functioning, Disability and Health model. The studies are graded for their level and, when appropriate, quality of evidence. The majority of the studies are case series which receive a Level IV grade of evidence. One study provides Level II evidence for the reduction of spasticity after administration of a bolus test dose of ITB as documented by changes in neurophysiologic reflexes. Longer term studies support the effectiveness of CITB for maintenance of muscle tone reduction as documented by clinical scales. Multiple studies suggest a linkage of CITB with improvements in function, ease of care, and quality of life. The evidence for improvements in dystonia and musculoskeletal problems is equivocal. Limitations of the research in this area and recommendations for improving its quality are discussed. PMID- 21791737 TI - Child Life in pediatric healthcare. PMID- 21791738 TI - Qualifications of a pediatric dentist. PMID- 21791739 TI - The role of pediatric Physical Medicine and Rehabilitation in the national Leadership Education in Neurodevelopmental Disabilities (LEND) program: The Virginia experience. AB - This article describes the role of pediatric Physical Medicine and Rehabilitation (pediatric PM&R) in the Leadership Education in Neurodevelopmental Disabilities (LEND) program. It provides an overview of the LEND program and the field of pediatric rehabilitation, details the scope and resources of the national LEND network, and describes the role of pediatric PM&R within the Virginia LEND (Va LEND) program. Emphasis is placed on the natural fit of pediatric rehabilitation within the LEND program in order to encourage others in the field to become involved in their own state or regional LEND program. PMID- 21791740 TI - Training in pediatric neurosurgery. AB - Pediatric neurosurgery is now a well-established subspecialty within neurosurgery with distinct training requirements and its own certification process. Currently there are over 180 diplomates of the American Board of Pediatric Neurological Surgery (ABPNS). Neurosurgeons in training get a limited and variable experience in pediatric neurosurgery over the course of their residency program. For those who decide to specialize in pediatric neurosurgery, a one year clinical fellowship following the completion of a general neurosurgical residency is recommended. The American Board of Pediatric Neurological Surgeons oversees the certification process for pediatric neurosurgeons. Board certification extends for 10 years, after which time recertification is required. The Board is not under the auspices of the Accreditation Council of Graduate Medical Education (ACGME) but is widely recognized as the pediatric neurosurgery accrediting group. PMID- 21791742 TI - Pediatric orthopaedics and rehabilitation. PMID- 21791741 TI - Pediatric rehabilitation nursing: Education and certification. AB - Pediatric rehabilitation nurses specialize in providing care and services to children and adolescents with disabilities. Although few formal education experiences exist, there are a myriad of opportunities to gain the knowledge, skills, and expertise to provide the care that yields the most benefit to this population. Certification recognizes the nurse's proficiency and excellence in a specialty practice area. Examples of certification options for pediatric rehabilitation nurses include Certified Rehabilitation Registered Nurse (CRRN), Registered Nurse Certification in Developmental Disabilities (CDDN), Certified Pediatric Nurse (CPN), Clinical Nurse Specialist (CNS), and Certified Pediatric Nurse Practitioner (CPNP). PMID- 21791743 TI - Pediatric residency and sub-specialty training. PMID- 21791744 TI - Training requirements and scope of practice in rehabilitation psychology and neuropsychology. AB - The purpose of this article is to educate the reader regarding the training requirements and scope of practice for rehabilitation psychology and neuropsychology. As discussed below, subspeciality training in pediatric rehabilitation psychology and pediatric neuropsychology is not yet formalized. While the clinical services of rehabilitation psychologists largely involve providing treatment, most clinical neuropsychologists primarily are involved in diagnostic assessment [19,20]. In rehabilitation settings, it is not unusual for psychologists to draw upon both rehabilitation psychology and neuropsychology expertise. PMID- 21791745 TI - Educational and clinical qualifications of speech-language pathologists treating children with disabilities. AB - The ability to communicate is arguably the most critical and fundamental human behavior. From the moment of birth through adolescence children proceed through a development process during which they master the intricacies of human communication. When this process is altered due to neurological or physical trauma, referral to a speech-language pathologist (SLP) is warranted. Speech language pathologists are uniquely qualified to work with children exhibiting a variety of communicative disabilities. The Certificate of Clinical Competence in Speech-Language Pathology is awarded upon completion of a graduate degree, passing a national examination and completion of a Clinical Fellowship. This rigorous process prepares SLPs to serve children with a variety of disorders across all practice settings. PMID- 21791746 TI - Training pediatric surgeons to care for children with special health care needs. PMID- 21791747 TI - Integrated preservice pediatric team education: The Transteam experience. AB - The need for interdisciplinary preservice educational programs for professionals serving infants and young children has been well-established. Physical and occupational therapy education, however, provides entry-level education to prepare clinicians for practice as generalists. Requirements of accrediting agencies and focus on licensure examination pass rates as evidence of program efficacy support this generalist focus, in spite of the fact that significant numbers of both disciplines practice in pediatric settings. In addition, education to develop skills as a member of a professional team is lacking from most curricula.This paper describes an interdisciplinary preservice education program funded by the Department of Education. Professions included were nursing, early childhood education, early childhood special education, and occupational and physical therapy. The program consisted of a two semester course sequence plus fieldwork experiences in team-based settings for children. The curriculum was based on competencies in early intervention and inclusive education practices, transdisciplinary team skills, and evidence-based practice. Outcome asssessment demonstrated significant changes in students' knowledge related to program objectives from the start of the program to the end. Such programs demonstrate it is feasible to integrate specialty knowledge into the entry level curriculum for occupational and physical therapists. PMID- 21791748 TI - Case scenarios for training in Pediatric Rehabilitation Medicine. PMID- 21791750 TI - CME Section. PMID- 21791751 TI - Editorial. PMID- 21791752 TI - Participation of the child with cerebral palsy in the home, school, and community: A review of the literature. AB - Improving participation of children with cerebral palsy is an important outcome in the practice of pediatric rehabilitation. Current knowledge of how a child's interactions with various environments influence participation can affect care provision to children with cerebral palsy. The literature was searched using electronic databases and reference lists from 1991 to 2008. Studies included reports on one or more factors influencing a child's participation. Using the International Classification of Function, Disability, and Health (ICF) as a framework, factors that influence participation are summarized. PMID- 21791753 TI - Neurodevelopmental disabilities in pediatrics and child neurology: Child development training for the future. PMID- 21791754 TI - Bone health in children with cerebral palsy. AB - Low bone mass and subsequent increased risk of fractures is a common finding in children with cerebral palsy. The available literature on this topic has increased over the last decade. The following is a review of the prevalence of fractures in this population, a description of the factors that are associated with reduced bone mineral density, and a summary of the interventions that have been reported to improve osteopenia and osteoporosis in children with cerebral palsy. PMID- 21791755 TI - Management of neurogenic bladder in patients with cerebral palsy. AB - Cerebral palsy (CP) is a non-progressive injury of the brain that affects muscle movement and coordination secondary to anoxia that occurred during the perinatal period. Babies who are premature, low birth weight, and those who sustained perinatal infection, seizure, or intracranial hemorrhage are at an increase risk of being affected. The injury mainly involves the motor control center of the brain; therefore, presents clinically with variable physical impairments, ranging from delayed gross or fine motor development to altered muscle tone and gait. With public awareness and research, the full spectrum of intelligence and capabilities of these children is now being appreciated. Studies have shown that with supportive caretakers, many of these children go on to enjoy near-normal adult lives. Therefore, it is imperative that their physical disabilities are identified and managed properly. In this review, we will focus primarily on urologic evaluation and management of patients with CP, with a brief review of normal bladder physiology and voiding pattern. PMID- 21791756 TI - Identifying barriers to occupational and physical therapy services for children with cerebral palsy. AB - Project Export/Cerebral Palsy Project was a three-year study funded by the National Institute of Health (1R24 MD000509-01) to investigate barriers to adequate and appropriate therapy services for children and adults with Cerebral Palsy who are living in the south metropolitan region of Chicago. This study examined barriers individuals with Cerebral Palsy (CP) and their families encounter when accessing Occupational Therapy (OT) and Physical Therapy (PT) services in the region. The study utilized a 3-tiered investigation system (survey, educational forum, and focus groups) that provided families and community therapists opportunities to identify barriers that impact access to evaluations and ongoing therapy services for individuals with Cerebral Palsy.The findings revealed a multitude of barriers identified by family and therapist participants. These barriers included, but are not limited to, financial resources, availability of therapists, convenient appointment times, and transportation issues. The educational forum and focus groups were effective in identifying knowledge gaps regarding Cerebral Palsy and strategies for accessing therapy in the region. Future plans include continuing collaborative initiatives for families and therapy providers. These include community educational forums that are accessible and provide relevant information, opportunities for networking, and advocacy information. The findings of the study will also be utilized to help occupational and physical therapists develop and implement alternative models of service delivery that provide greater access to therapy services for individuals with Cerebral Palsy. PMID- 21791757 TI - Bronchoscopy findings in children and young adults with tracheostomy due to congenital anomalies and neurological impairment. AB - The aim of this study was to examine bronchoscopy findings for children and young adults with long-term tracheostomies due to congenital anomalies and neurological impairment and identify characteristics associated with abnormal bronchoscopic findings. We conducted a retrospective study of 128 bronchoscopy cases (81 children) at a pediatric rehabilitation center. Thirty-eight cases (30%) had normal findings and 14 children (17% of all children) were decannulated following bronchoscopy. Ninety cases (70% of cases) had abnormal findings (e.g. granulomas, airway inflammation, fixed obstruction). An acute indication for bronchoscopy was the strongest predictor of an abnormal finding, while age (younger) and diagnosis (multiple congenital anomalies (MCA)) also were associated with abnormalities. For a subsample of children undergoing bronchoscopy for routine surveillance (n= 90), underlying diagnosis (MCA) was the strongest predictor of an abnormal finding, while younger age contributed slightly. These findings add to the limited literature describing bronchoscopic findings in children and youth with tracheostomies due to congenital anomalies or neurological impairment. These findings may be useful for rehabilitation clinicians in determining care needs for children with long-term tracheostomy. PMID- 21791758 TI - Intensity, perception, and descriptive characteristics of chronic pain in children with cerebral palsy. AB - OBJECTIVES: Children with cerebral palsy (CP) experience bodily pain, leading to functional impairment and decreased quality of life. The purpose of this study is to characterize subjective descriptors of chronic pain in children with CP. METHODS: One hundred fifty-seven children were invited to participate in a quantitative pilot survey. Parents were mailed the Varni-Thompson Pediatric Pain Questionnaire, designed to assess three dimensions of pain: sensory (physical aspects), affective (emotional response), and evaluative (the combined intensity of the emotional and physical responses). Parents assessed their child's pain using non-verbal and verbal cues. RESULTS: Fifty-two families responded (33% return rate). Thirty-eight children ages 6-8 years with CP and Gross Motor Function Classification System (GMFCS) levels I-V were included. Ninety percent of families reported that their child was experiencing some pain at the time of the survey. At the time of assessment the children's pain was mild. Their pain, at its worst, was in the distressing range. The two largest GMFCS groups of children, levels I and IV, were compared in both severity and intensity of pain experienced. Increasing intensity of pain was reported in children in the level IV group compared to children classified as level I. Pain severity in all dimensions was reported as increasing in Level IV children compared to Level I. DISCUSSION: Children with CP experience frequent pain, which increases with worsening impairment. Descriptive qualifiers of pain help to elucidate the etiology of various types of pain which would lead to the development of more effective approaches to pain management and treatment. PMID- 21791759 TI - Adapted recreational and sports programs for children with disabilities: A decade of experience. AB - OBJECTIVE: To identify and describe community based adapted sports and recreational programs (SARPs) for children with physically disabilities, documenting program types, benefits, challenges, growth and/or decline, and lessons they have learned over a 10-year period. METHODS: In 1996, a total of 277 children's hospitals and freestanding rehabilitation hospitals stating that they provided pediatric rehabilitation services were contacted and asked to provide information regarding adapted recreational and sports programs in their region. Seventy-nine SARPs were identified, contacted, and survyed about programming, benefits and challenges they faced. They were then re-surveyed in 2006 for comparison data. RESULTS: Ten years ago, the average SARP served 25 or fewer clients and was led by a therapeutic recreation specialist with assistance from volunteers. Most programs had been in place for 5 years or more, met weekly for 2 3 hours, and were recreational in orientation. Activities varied, with basketball, aquatics, horseback riding and snow skiing being most common. Fund raisers and grants supported most programs, and securing funding was their greatest challenge. Participant benefits noted by programs included improved socialization, enhanced physical fitness, increased self esteem, improved therapeutic skills (ADL's, transfers, etc.), enhanced cognition, expanded client independence, improved community relations, and enhanced leisure skills. Ten years later, the majority of SARPs noted similar benefits, and reported an increase in number of participants despite continued challenges with funding and staffing. Leadership and mentorship by those with disabilities was still very low, but community awareness of the abilities of those with disabilities had increased. CONCLUSIONS: Adapted sports and recreation programs surveyed in 1996 and again in 2006, report overall that their health is good, and many have retained the same programming, financial support mechanisms, leadership and participant mix over the years. Many have increased athlete participation despite financial challenges being a predominant concern. They report that their staying power is dependent on many factors, including leadership, participant referrals, an ample supply of volunteers, and consistent community and financial support. They feel that their success is important to the physical and psychological well being of individuals with disabilities and that an increased focus on corporate sponsorship, participation and mentorship by those with disabilities may assist with future growth. Increased school involvement, development of more competitive vs. recreational programs, and improved research documenting the physical and psychological benefits of adapted sports programs were also recommended to improve future SARP stability. PMID- 21791760 TI - The contribution of tone to resting energy expenditure in children with moderate to severe cerebral palsy: Evaluation utilizing intrathecal baclofen injection. AB - The extent to which high muscle tone contributes to the caloric needs of children with cerebral palsy (CP) is debated. Understanding its contribution is important in predicting calorie needs in this population which frequently experiences under nutrition. Intrathecal baclofen is an innovative therapy now used for treatment of excessive tone. We prospectively studied the changes in resting energy expenditure (REE) observed in 12 children with CP undergoing intrathecal baclofen injection. REE was measured in the fasting state before intrathecal injection of 50 micrograms of baclofen. Patients remained fasting and REE measures were repeated four hours later. Tone changes were assessed using the Modified Ashworth Scale at the same time points. One child was excluded from study because he became increasingly agitated over the observation period and one child demonstrated no tone reduction after the baclofen injection. In the remaining 10 patients, the average REE prior to injection was 101 +/- 17% of predicted and decreased to 84 +/- 24% of predicted after injection (p<0.004). This study suggests that tone contributes substantially to the caloric needs of children with CP and must be carefully considered when providing nutritional recommendations. PMID- 21791761 TI - Approaches to therapy for children in India with cerebral palsy. AB - This article describes the approach to intervention programs for children with cerebral palsy in India. It provides an overview of services available in particular in the fields of physiotherapy, speech therapy and AAC. PMID- 21791762 TI - Injected contrast study fails to demonstrate catheter-pump connector tear. AB - SETTING: Regional children's specialty hospital. PATIENT: 11 year old boy with a history of quadriparetic cerebral palsy (CP), shunted hydrocephalus, and continuous infusion of intrathecal baclofen (ITB) to treat hypertonicity. CASE DESCRIPTION: The patient presented for a second opinion after experiencing three weeks of increased tone treated by shunt revision three times after two studies injecting contrast into the ITB pump catheter via the catheter access port did not demonstrate any extravasation of contrast material. Parents report that there was little change in his lower extremity tightness. His speech showed increased dysarthria during this time, and he had unusual difficulty with handling food. On evaluation, the patient had severely increased muscle tone. He also was noted to have palpable fluid in his pump pocket. Review of the X-rays that accompanied the patient revealed findings that caused us to be suspicious of a tear of the sleeve that is part of the mechanism that connects the intrathecal catheter to the pump. A 100 microgram bolus of ITB was administered, which did result in some relaxation.Assessment/Results: PATIENT underwent surgery at which time a torn pump-catheter connector was confirmed and replaced with a different type of connector. His symptoms resolved and he required a lower dose of ITB than on admission for significantly better tone control. DISCUSSION: Individuals typically reach a stable dose of ITB and if they develop a need for increasing dose later, most frequently a catheter problem exists. Also, if there is fluid in the pump pocket, we have a high index of suspicion for this type of catheter/pump connector tear. CONCLUSION: In this case, careful evaluation of plain radiographs coupled with careful history taking, including the individual's response to interventions, was all that was necessary to make an accurate diagnosis. PMID- 21791765 TI - Abprm. PMID- 21791763 TI - Cerebral palsy masking spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive anterior horn cell disease that results in progressive muscular weakness and atrophy without sensory involvement. A wide clinical spectrum that ranges from early death to essentially normal adult live exists. We describe a case of two 12 years olds, who represent two of three surviving non-identical quadruplets, born at 25 weeks gestational age. A diagnosis of hypotonic cerebral palsy (CP) was made in early childhood and early intervention services were initiated. At 3 years of age, MRI's showed white matter changes. Both briefly attained Gross Motor Functional Classification Scale (GMFCS) 3 status, but by 12 years of age their ambulatory abilities had decreased to Level 4. Physical Medicine and Rehabilitation (PM&R) physicians were consulted. On exam, distal lower extremities atrophy, hypotonia, hyporeflexia, and muscle weakness were noted. Neither child had upper motor neuron signs or spasticity. Cognition was normal. Neuromuscular disorder was suspected and genetic testing confirmed spinal muscular atrophy in both patients. While prior MRI/CT demonstrated static encephalopathy, recognition of symptoms and signs consistent with neuromuscular disease should have led to a secondary diagnosis. Therapeutic and surgical treatment decisions may have differed. Fragmentation of care and lack of a comprehensive team approach also contributed to the delay in recognition of their dual diagnosis. PMID- 21791766 TI - CME Section. PMID- 21791767 TI - Twenty-one years later: Twenty-first century rehabilitation. PMID- 21791768 TI - Forty years neuromuscular experience. PMID- 21791769 TI - Cognition in neuromuscular disease. AB - Although neuromuscular diseases primarily affect an individual's physical functioning, the cognitive and psychosocial effects of these conditions can be quite significant. This paper provides an overview of a subset of neuromuscular diseases and their associated neurocognitive risks. It provides a heuristic for thinking about the associated neuropsychological differences in children and adolescents with neuromuscular disorder. Areas for further research are identified and practical guidelines for optimizing functioning within the school setting are provided. PMID- 21791770 TI - Cardiac involvement in the dystrophinopathies. AB - The dystrophinopathies are a group of disorders that are characterized by absence or deficiency of functional dystrophin, a large cytoskeletal protein of striated muscle that is closely associated with transmembrane glycoprotein complexes. The most severe dystrophinopathy is Duchenne Muscular Dystrophy (DMD), a progressive disorder of all striated muscle that leads to death via cardiorespiratory failure in the second to third decades of life. Other dystrophinopathies include the similar but somewhat milder Becker Muscular Dystrophy (BMD) and X-linked dilated cardiomyopathy (XLDCM) where the cardiac manifestations predominate. While this review will focus specifically on the cardiac aspects of the dystrophinopathies, the principal elements of screening and monitoring cardiac status are applicable to patients with a broad range of myopathies and muscular dystrophies. PMID- 21791771 TI - Wheelchair seating for children with Duchenne Muscular Dystrophy. AB - Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder which features progressive muscle wasting and weakness. Despite advances in treatment, the weakness of DMD will eventually necessitate a wheelchair for almost all children. The goal of wheelchair use is to maximize function and mobility while minimizing discomfort and postural abnormalities. Because of the large variation of patient symptoms and functional deficits, no single wheelchair would adequately serve the needs of all children with DMD. Unfortunately, little information to guide selection of equipment for children with DMD is available. This article discusses the decision-making processes regarding appropriate time to provide equipment, the evaluation of DMD clients, and reviews the numerous options in order to help prescribers, caregivers and clients design an appropriate wheelchair system. PMID- 21791772 TI - Physical function for children and youth with cerebral palsy: Item bank development for computer adaptive testing. AB - The purposes of this paper are to: 1) present a conceptual framework that supports development of a computer adaptive test (CAT) outcome measure of physical functioning for children with cerebral palsy; 2) illustrate the development and refinement of an item bank for use in the CAT; and 3) describe the intended application of these newly developed items in a CAT platform. Improvement in physical functioning is one of the most important developmental and rehabilitative outcomes for children with cerebral palsy (CP). Computer adaptive testing technology provides means to improve outcome measures. We adopted a conceptual framework appropriate to support a CAT of physical functioning consisting of 4 sub-domains: lower extremity skills, upper extremity skills, physical activity, and global physical health. Review of existing tests and measures of physical function, expert clinician review, and cognitive testing were used to identify, develop and refine sets of items (item banks) that reflect the breadth of each sub-domain. These item banks will be used to develop contemporary parent-report instruments by application of Item Response Theory (IRT) analyses, leading to a CAT outcome measure. Such CAT approaches can efficiently assess broad areas of physical functioning across a wide age-range and levels of severity of children with CP. PMID- 21791773 TI - The outcome of intrathecal baclofen treatment on spastic diplegia: Preliminary results with a minimum of two year follow-up. AB - The purpose of this study is to report the short-term outcome of intrathecal baclofen therapy on the function of individuals with diplegic cerebral palsy (CP) and the health-related quality of life (HRQL) of their caregivers. Eight pediatric patients with spastic diplegia were treated with ITB following failed oral spasticity management and were followed for a minimum of 2 years. Physical and functional outcomes were assessed using Ashworth Scores (AS), Physician Rating Scale (PRS), and a subset of the Functional Independence Measure for children (WeeFIM). HRQL was assessed using SF-36, CES-D short form, Impact on Family Scale, Life Orientation Test, Rand Social Support Scale, and Social Desirability Scale. At final follow-up, AS was significantly reduced (all p ? 0.03). The PRS scale showed statistically significant improvement in four out of six subscales: median gait pattern (p = 0.05), median hind foot strike (p = 0.03), median knee position (p = 0.03) and median hind foot gait (p = 0.05). The WeeFIM score improved significantly with a mean increase of 32% (p = 0.03). ITB therapy significantly reduced spasticity and improved the function of these eight children with diplegic CP. HRQL of the parents or the caregivers remained stable despite the surgical intervention and follow-up visits required for pump refills. PMID- 21791775 TI - Certification in neuromuscular medicine. PMID- 21791774 TI - Use of intrathecal baclofen in a pediatric cerebral palsy patient with refractory hemiplegia to maintain orthopaedic surgery gains. AB - Spasticity, a common symptom accompanying cerebral palsy (CP), can severely affect patients' function and cause disability in childhood. Intrathecal baclofen (ITB) therapy is a widely used treatment to reduce spasticity in quadriparetic CP patients. Likewise, adults sustaining strokes and subsequent spastic hemiplegic have proven excellent candidates as well from ITB therapy. However, data on ITB treatment in pediatric patients with hemiplegic CP are lacking. This is the first report to present such a case. A nine-year old girl with spastic hemiplegic CP failed chemical denervation and serial casting of lower extremity spasticity and an associated equinovarus contracture. An ITB bolus test revealed an improvement in her Ashworth score from a mean of 2.8 to 1.2 on the involved side, whereas the unaffected side stayed constant from a mean of 1.3 to 1.2. The patient was subsequently treated with continuous ITB with improvement of Ashworth scores from a mean of 2.8 at baseline to 1.1 at 17 months after implantation of the ITB pump. Subsequent surgery was performed to correct the residual ankle deformity resulting in improvements in passive range of motion, gait function and brace tolerance. Hemiplegic CP pediatric patients can be successfully treated with ITB to reduce spasticity, improve function, and retain postoperative surgical correction without affecting the normal side. PMID- 21791776 TI - Competency based objectives for pediatric physical medicine and rehabilitation residency rotations. PMID- 21791777 TI - CME Section. PMID- 21791779 TI - Guest editorial. PMID- 21791780 TI - Commentary. PMID- 21791781 TI - Development of a bladder management protocol as part of a comprehensive care program for spina bifida in Kenya. AB - Most children with spina bifida have neurogenic bladders. Prior to the use of clean intermittent catheterization (CIC) in 1972, approximately 30% of children with spina bifida died of renal failure. In developing countries where CIC is not done, even more children with spina bifida continue to die from renal failure. This article presents data from Kenya collected from a nurse run comprehensive spina bifida program which evaluates bladder function with leak point pressure (LPP) and begins CIC in those children with LPP >30 cm water. 371 children were seen for surgical closure. Urodynamic studies were done in 249 and of these 167 were started on CIC because of high LPP or need for social continence. 99/371 were lost to follow-up. 72 have died. To date, only 3 deaths were from renal complications. Of 59 children age 5 or older, 45 have achieved social continence. We conclude that a nurse run bladder management program including CIC for children with spina bifida can be done in a developing country with good results on renal function and continence. PMID- 21791782 TI - Adolescent development and family functioning in youth with spina bifida. AB - The purpose of this article is to review research concerning adolescent development and family functioning among youth with spina bifida myelomeningocele (SBM). Adolescence is a developmental period characterized by substantial changes in biological, psychological, and social functioning, as well as transformation and reorganization within the family system. A biopsychosocial-contextual model of development was utilized to describe the interface between normative adolescent development and the experience of a chronic health condition among youth with SBM. Major empirical findings relevant to family functioning in adolescents with SBM are presented, including the family environment, parenting behaviors, and marital and parental functioning. There is variability with regards to the influence of SBM on the family system and research identifies both disruption and resilience in families. Current research suggests that families of youth with SBM may have higher levels of family stress, difficulties with family roles, lower levels of cohesion, less adaptive parental control and overprotection, and a greater risk for child and parental psychosocial adjustment difficulties. The review concludes with a discussion of the clinical implications of these findings for the care of youth with SBM and directions for future research. PMID- 21791783 TI - Barriers to community participation: Teens and young adults with spina bifida. AB - This study identified the baseline participation rates for 101 teens and young adults ages 10-32 years old with a diagnosis of spina or lipomenigocele bifida in various domains: school, employment, community activities, physical activity and peer social relationships. The goal of the study was also to identify barriers to community participation. Our findings demonstrate that overall participation is low in several domains. Community participation is low with only 30% partaking in an organized community activity at least once a week. Multiple individual, family, and environmental barriers were identified by participants and their family. The most frequent barriers identified were low motivation (38%), lack of information (25%) and time constraints (21%). Barriers need to be addressed on an individualized basis as well as addressing the community as a whole. Future plans are to intervene based on the barriers and reassess participation at 6 months and a year with the goal of increased long term participation, employment, quality of life and social relationships. PMID- 21791784 TI - Neurogenic bowel and continence programs for the individual with spina bifida. AB - The neurogenic bowel in the person with spina bifida has been difficult to manage. Current literature reveals very little research conducted on the outcome of continence programs in the person with spina bifida. It has different characteristics than the neurogenic bowel seen with spinal cord injury because it occurs during fetal development. Management of the neurogenic bowel to achieve continence is based upon thirteen assessment items that include stool form, individual physiologic parameters, family patterns, diet and medications. Programs are developmentally related to appropriately support the child's involvement. Continence strategies include the use of oral medication early in the day and timed sitting, suppositories or enemas later in the day at a time convenient to the family. The timing of the medications and evacuation is very important to the success. An interdisciplinary team is important in supporting the family as the child with spina bifida grows into an independent adult. The dietician and occupational therapist have invaluable insight into diet, fluids, adaptive aids and techniques that contribute to positive outcomes of the continence program. PMID- 21791785 TI - Primary care providers and medical homes for individuals with spina bifida. AB - The contributions of primary care providers to the successful care of children with spina bifida cannot be underestimated. Overcoming systemic barriers to their integration into a comprehensive care system is essential. By providing routine and disability specific care through the structure of a Medical Home, they are often the first line resource and support for individuals and their families. The Medical Home model encourages primary care providers to facilitate discussions on topics as varied as education and employment. Knowledge of specific medical issues unique to this population allows the primary care provider to complement the efforts of other specialty clinics and providers in often neglected areas such as sexual health, obesity and latex sensitization. As individuals with spina bifida live into adulthood, and access to traditional multidisciplinary care models evolves, these skills will take on increasing importance within the scope of providing comprehensive and coordinated care. PMID- 21791788 TI - CME Section. PMID- 21791789 TI - Guest editorial. PMID- 21791790 TI - Medical care of adults with spina bifida. AB - Survival into adulthood for individuals with spina bifida has significantly improved over the last 40 years. Health services research suggests the majority of patients with spina bifida are now over 18 years old. Adults with spina bifida have ongoing increased medical needs compared to the general population, including spina bifida-specific care, age-related secondary disabilities, and general adult medical needs. Unlike pediatric-aged patients, adults may not have access to multi-disciplinary spina bifida clinics and must often coordinate their own care with adult providers less familiar with spina bifida and the associated monitoring and treatment issues. This article will provide an overview of the medical issues of adults with spina bifida, highlighting areas that are different than pediatric care. PMID- 21791791 TI - Rehabilitation of pediatric spinal cord injury: From acute medical care to rehabilitation and beyond. AB - OBJECTIVE: Spinal Cord Injury (SCI) in the pediatric population is an uncommon but potentially devastating entity that may be unfamiliar to many practitioners. Because its treatment requires a long-term, well-planned, integrated approach, understanding the natural history, treatment, and common comorbidities of pediatric SCI is crucial for all physicians caring for these children. We present a review of the current literature on this topic to discuss the current standard of medical and rehabilitation care of pediatric SCI patients. DATA SOURCES: Studies for this review article were obtained by a thorough PubMed search, including but not limited to the terms "spinal cord injury," "SCI," "spinal rehabilitation," and "pediatric spinal injury." Frequently referenced articles of particular prominence in the field were also reviewed. STUDY SELECTION: Studies were included primarily to illustrate specific clinical situations in this overview article. DATA EXTRACTION: Studies were reviewed by the authors (JG and HK) and clinically important details were incorporated into the review. DATA SYNTHESIS: Not applicable. CONCLUSIONS: Pediatric SCI, while relatively uncommon, is a life-changing event for affected children and their families, physically, medically, and economically. Providing multidisciplinary care, as well as early and extensive rehabilitation, translates into superior outcomes. However, more research remains necessary to identify tactics for better community integration and increased educational, financial, and social success. PMID- 21791792 TI - Secondary tethered cord syndrome in patients with myelomeningocele. AB - Myelomeningocele is associated with other neurological abnormalities, including hydrocephalus, Chiari II malformations, syringomyelia, and secondary tethered cord syndrome. Tethered cord syndrome occurs because of abnormal attachment of the spinal cord to the caudal dural sac, causing cord ischemia. Occasionally, symptoms of progressive neurological deterioration may occur and can significantly affect the long-term outcome of these patients. Proper management of patients with myelomeningocele requires long-term follow-up and evaluation of signs of neurological deterioration that suggest secondary tethered cord syndrome. Treatment of these patients may target symptoms, such as urological intervention for bladder dysfunction, or it may target the tethered cord itself. Recently, many studies have shown that tethered cord release can significantly improve symptoms in these patients. PMID- 21791793 TI - Risky business: Preventing skin breakdown in children with spina bifida. AB - The purpose of this article is to provide an overview of skin issues in children with spina bifida. Included in the discussion below is a review of the etiology of pressure ulcers and the updated 2007 pressure ulcer definition and pressure ulcer staging system as defined by the National Pressure Ulcer Advisory Panel (NPUAP). Pediatric risk factors for skin breakdown are presented including risk factors unique to children with spina bifida. Pediatric pressure ulcer risk assessment scales are described. The 5 Million Lives Kids' Campaign which has a focus on preventing hospital-acquired pressure ulcers in children is also reviewed along with evidence based prevention strategies. The key to preventing skin breakdown and pressure ulcers in children with spina bifida is early identification of the child's individual risk factors so that a prevention protocol can be implemented in all settings: hospital, home and the community. Options for wound management, dressing selection and pain management are included. PMID- 21791794 TI - Urologic issues of the pediatric spina bifida patient: A review of the genitourinary concerns and urologic care during childhood and adolescence. AB - Myelodysplasia is a complex patient problem that continues to present challenges for multidisciplinary care teams. The spectrum of bladder and bowel dysfunction created by this neurologic lesion is broad and requires long-term surveillance of these organ systems. This review outlines the diagnosis and management of urologic issues of the spina bifida patient throughout infancy, childhood and adolescence. Specifically, examining different approaches to care of these patients (proactive vs reactive), quality of life issues and medical and surgical management options and decision-making at each phase of life. PMID- 21791795 TI - The role of the Malone antegrade continence enema (MACE) in the management of myelodeysplatic patients. AB - Myelodysplasia is a congenital neural tube defect commonly affecting bladder and bowel function. Management of fecal incontinence is paramount to achieve patient independence and self-confidence. When conservative measures fail alternative invasive methods can be successfully applied. The Malone antegrade continence enema (MACE) was introduced in the late 1980's to treat spina bifida patients with fecal incontinence refractory to conservative management. Since its introduction, multiple successful variations have been described and its role has expanded. Indeed, the MACE has revolutionized the care of myelodysplastic patients, their bowel function, and ultimately their self image. PMID- 21791796 TI - Apolipoprotein E and functional motor severity in cerebral palsy. AB - Cerebral palsy is attributed to non-progressive disturbances in the developing fetal or infant brain. The APOE epsilon4 allele has been associated with poor outcome after brain injury in adults but may be protective among very young children. We conducted this study to explore the hypothesis that the APOE epsilon4 is associated with lowered severity of cerebral palsy. 158 individuals with CP and their parents were genotyped for APOE. Mean age was 9.1 years; 54% were males. 61% were preterm at birth; 34% less than 30 weeks gestation. 30% of the CP subjects had at least one epsilon4 allele. There was a trend towards significance for subjects with at least one epsilon4 allele assigned to the low severity group (p = 0.11). The greater number of epsilon4 alleles, the more likely an individual was in the low severity CP group (p = 0.12). Individuals with brain injury in the perinatal period were almost 5 times more likely to be in the low severity group (p < 0.01). Family analysis via the TDT supported a protective effect of APOE epsilon4. Further study is needed to confirm that, in contrast to adults, the APOE epsilon4 allele appears to confer protection and/or facilitate recovery after brain injury in the fetus or newborn, particularly when that injury occurs around term. PMID- 21791798 TI - CME Section. PMID- 21791797 TI - An intensive motor skills treatment program for children with cerebral palsy. AB - This article describes the development and efficacy of the Intensive Motor Skills Program conducted at Primary Children's Medical Center. The program was designed for children with cerebral palsy who have undergone a medical procedure and were determined to need a "jumpstart" to gain functional skills. Data was collected from parent interviews that determine desired outcomes during the two-week program. Parent ratings of performance and satisfaction were then analyzed to determine parents' perceptions of the program. Information was also collected and analyzed from therapists' short-term objectives and parent satisfaction surveys. The results indicated that parents perceived positive changes in their children's performance on goals addressed during the program. Positive changes in parents' satisfaction with how their child performed on the defined goals were also noted. Therapists documented that children in the program required decreasing levels of assistance on short-term objectives as the program progressed. PMID- 21791799 TI - Care for children with special health care needs in disasters. PMID- 21791800 TI - Psychological and neuropsychological issues in the care of children with disabilities. AB - Pediatric specialists are faced with many challenges when confronted with young patients diagnosed with acquired or congenital disabilities. In addition to the myriad of presenting medical issues, team members also need to acknowledge and address contributing psychological, social and environmental factors when working with medically involved children. Specifically, the understanding of developmental, cognitive, familial, and emotional considerations is essential for tailoring more successful individual treatment plans. The purpose of this article is to address the multidimensional aspects associated with the treatment of children presenting with physical or neurological impairments. Specifically, psychological and neuropsychological perspectives will be discussed and case examples will be presented in an effort to propose a comprehensive approach for the promotion of better outcomes in pediatric patient care. PMID- 21791801 TI - Urgent surgical issues in children with special health care needs: A brief report. PMID- 21791802 TI - Evaluation of ventriculoperitoneal shunt emergencies. PMID- 21791803 TI - Respiratory surveillance of patients with Duchenne and Becker muscular dystrophy. AB - Duchenne muscular dystrophy is is the most common form of the childhood muscular dystrophies. It follows a predictable clinical course marked by progressive skeletal muscle weakness, lost of ambulation before teen-age and death in early adulthood secondary to respiratory or cardiac failure. Becker muscular dystrophy is less common and has a milder clinical course but also results in respiratory and cardiac failure.Altough recent advances in respiratory care and new technologies have improved the outlook many patients already received only a traditional non-interventional approach. The aims of this work are: to analyse the pathophysiology and natural history of respiratory function in these diseases, to descript their clinical manifestations, to present the diagnostics tools and to provide recommendations for an adequated respiratory care in this particular population based on the updated literature referenced. PMID- 21791804 TI - Communication during times of natural or man-made emergencies. AB - During man-made or natural emergencies, communication is essential. However, for millions of individuals worldwide who have significant communication disabilities, spoken language may not be effective or efficient. As a result, emergencies can quickly turn into life-threatening situations. Alternatives to spoken language or augmentative and alternative communication (AAC) may be necessary to ensure effective and efficient communication. The purpose of this study was to identify needed vocabulary for communication during times of emergency. In order to identify needed vocabulary, two online focus groups generated and prioritized this vocabulary. Based on the 209 words that were identified, we used 50 priority words to develop downloadable communication aids for use during times of natural or man-made emergencies. PMID- 21791805 TI - CME Section. PMID- 21791807 TI - Pediatric limb deficiency. PMID- 21791808 TI - Factors to be considered in prosthetic prescription for the pediatric limb deficient or amputee patient. PMID- 21791809 TI - Rehabilitation of the child with lower limb loss. AB - Care for the child with limb deficiency or amputation is optimized when provided by an interdisciplinary team. A center specializing in the care of children with limb loss is typically the best choice and has the most experience in providing up to date, evidence based practice. The child and his/her family must be integral members of the team and optimal functional outcome requires recognizing and addressing their expectations and goals. We present an overview of rehabilitation strategies, including prosthetic management, for children with lower extremity limb loss. PMID- 21791810 TI - Reconstruction of congenital hand anomalies to provide stable pinch and/or grasp: Case pictorial series. AB - Congenital hand anomalies can cause substantial functional problems. There are multiple situations where there is lack of stable pinch and/or grasp that can be improved by surgical intervention. An example of reconstructive surgical intervention in each of three specific congenital hand anomalies is presented: hypoplastic thumb, absence of the fingers, and insufficient length and stability of the digits. Focus is on the approach to the patient, surgical treatment and the goals achieved. It is important to mention that other techniques may be preferred by other surgeons, and may also yield excellent results. PMID- 21791811 TI - Adaptive upper extremity prostheses for recreation and play. AB - Children of all ages, regardless of any limb loss, need to play. Sports and recreation needs vary from person to person and by age. Adapting upper extremity prostheses for play, sport, and recreation is an option. The decision making process regarding the use of adaptive prostheses should involve a team-oriented approach which places the patient at the center of the team. When an individual chooses to adapt his/her prosthesis, the treating prosthetist is invaluable. The type of adaptation depends on the particular activity. As technology continues to improve, the barriers that exist for an individual with a limb deficiency will continue to be challenged. There are a number of resources and groups dedicated to helping limb deficient individuals achieve a greater level of independence by allowing them to interact with their peers through both recreation and competitive sports. PMID- 21791812 TI - Prenatal evaluation of the fetus with limb deficiency/hypoplasia - A case report and review of common congenital limb anomalies. AB - Congenital limb deficiencies/hypoplasias are a heterogeneous group of anomalies that range from mild abnormalities of little long-term clinical significance to the severe limb-reduction defects spectrum associated with fetal thalidomide exposure. This article reviews the approach to the prenatal evaluation of congenital limb deficiency/hypoplasia and provides an overview of selected limb reduction defects along with a discussion of etiology and genetic aspects. A case report detailing the prenatal evaluation of a fetus with a skeletal dysplasia illustrates the importance of a comprehensive, multidisciplinary and dysmorphology-based approach. PMID- 21791813 TI - Comprehensive care for the child with upper extremity limb deficiency. AB - Children with limb deficiencies/amputations are best managed by a multidisciplinary team comprised of physicians specializing in their care, prosthetists, and therapists. For a successful functional outcome, the rehabilitation team will need to consider the goals of the child and parents as they select appropriate components that will aid and not overwhelm the child. The prosthesis will need to accommodate growth and development and withstand the rigors of use during play. The child will benefit from a team approach to introduce, train, and problem-solve the process of prosthetic restoration. We examine strategies for decision making for children with upper extremity limb deletions that will allow appropriate component selection to ensure the prosthesis will be accepted and improve function for the child. PMID- 21791814 TI - Care Coordination and the prosthetic clinic: A clinical outcomes and program evaluation project. AB - INTRODUCTION: Care Coordination is the health care delivery model that has been implemented in the prosthetic clinic at the Shriners Hospital for Children - Canada. In delivering comprehensive, family-centered services, it is important to evaluate the extent to which patients and families perceive coordinated care to occur. AIM: To evaluate the delivery of Care Coordination services to our patients and families in the prosthetic clinic, and to identify strengths and areas for improvement. The time required to provide coordinated care was also evaluated. METHODS: The MPOC-20 was administered to the parents of 23 lower extremity deficiency or amputee patients seen in the prosthetic clinic over a 14 month period. RESULTS: Providing coordinated and comprehensive care related to involving families as part of the team was the most frequently reported strength of the prosthetic clinic Care Coordination. Providing information to families about their child's progress and having information and resources available were areas identified as needing improvement by approximately 30% of respondents. Those with complex health needs required five times the amount of Care Coordination devoted time than the average patient. CONCLUSIONS: The MPOC-20 proved to be a useful tool to highlight areas for improvement in the prosthetic clinic and to validate aspects of care coordination that were appreciated by families. PMID- 21791815 TI - The consequences for children of explosive remnants of war: Land mines, unexploded ordnance, improvised explosive devices, and cluster bombs. AB - Land mines are particularly a problem for children. The deaths and loss of body parts have been publicized, but the secondary effects - the loss or maiming of parents, the loss of physical and social space the loss of access to education, and the loss of cultivatable land with the resultant malnutrition and sickness, are less frequently considered. "Explosive Remnants of War" (ERW) is becoming the generic term to refer to land mines, unexploded ordnance, improvised explosive devices and cluster bombs. The United Nations estimates that there are currently as many as 100 million unexploded landmines with an equal number stockpiled around the world waiting to be planted. Mines are designed to be difficult to locate and their clearance is costly. Children in at least 80 countries are at risk due to ERW. The type of mine, the proximity of the child to the explosion, and location of the mine in relation to the child's body are the important determinants of the nature and severity of the injury. Children are especially susceptible to picking up explosive remnants thinking they are toys. The result is commonly loss of the hands, facial injuries, blindness and deafness. Rehabilitation for these children is extremely difficult due to remoteness and the limited resources available. PMID- 21791816 TI - The fitting of a unilateral shoulder disarticulation prosthesis after electrical burn injury: A case report. PMID- 21791819 TI - CME Section. PMID- 21791817 TI - Bony overgrowth in children after amputation. PMID- 21791820 TI - Pediatric traumatic brain injury - are we making progress toward evaluating rehabilitation efficacy? PMID- 21791821 TI - Social information processing skills in adolescents with traumatic brain injury: Relationship with social competence and behavior problems. AB - OBJECTIVE: To examine social information processing (SIP) skills, behavior problems, and social competence following adolescent TBI and to determine whether SIP skills were predictive of behavior problems and social competence. DESIGN: Cross-sectional analyses of adolescents with TBI recruited and enrolled in a behavioral treatment study currently in progress. SETTING: Two tertiary care children's hospitals with Level 1 trauma centers. PARTICIPANTS: Adolescents aged 11 to 18 years with severe TBI (n=19) and moderate TBI (n=24) who were injured up to 24 months prior to recruitment. ASSESSMENT OF RISK FACTORS: TBI severity, race, maternal education, and age at testing. MAIN OUTCOME MEASUREMENTS: a measure of SIP skills, Child Behavior Checklist (CBCL), Youth Self Report (YSR), and Home and Community Social Behavior Scale (HCSBS). RESULTS: The severe TBI group did not obtain significantly lower scores on the SIP measures than the moderate TBI group. In comparison to adolescents with moderate TBI, those with severe TBI had significantly more parent-reported externalizing behaviors and self-reported weaknesses in social competence. SIP skills were strong predictors of problems and social competence in adolescents with TBI. More specifically, an aggressive SIP style predicted externalizing problems and a passive SIP style predicted internalizing problems. Both passive and aggressive SIP skills were related to social competence and social problems. CONCLUSIONS: Adolescents with TBI are at risk for deficits in social and behavioral outcomes. SIP skills are strongly related to behavior problems and social competence in adolescents with TBI. SIP skills, social competence, and behavior problems are important targets for intervention that may be amenable to change and lead to improved functional outcomes following TBI. PMID- 21791824 TI - CME Section. PMID- 21791825 TI - Promoting Bone Health in MPS VI (Maroteaux-Lamy syndrome): Framing New Therapies, Part 1. PMID- 21791826 TI - An overview of intra-articular therapy for mucopolysaccharidosis VI. PMID- 21791822 TI - Acute brain injury and therapeutic hypothermia in the PICU: A rehabilitation perspective. AB - Acquired brain injury from traumatic brain injury, cardiac arrest (CA), stroke, and central nervous system infection is a leading cause of morbidity and mortality in the pediatric population and reason for admission to inpatient rehabilitation. Therapeutic hypothermia is the only intervention shown to have efficacy from bench to bedside in improving neurological outcome after birth asphyxia and adult arrhythmia-induced CA, thought to be due to its multiple mechanisms of action. Research to determine if therapeutic hypothermia should be applied to other causes of brain injury and how to best apply it is underway in children and adults. Changes in clinical practice in the hospitalized brain injured child may have effects on rehabilitation referral practices, goals and strategies of therapies offered, and may increase the degree of complex medical problems seen in children referred to inpatient rehabilitation. PMID- 21791827 TI - Intrathecal enzyme replacement therapy to treat spinal cord compression in mucopolysaccharidosis: Overview and rationale. PMID- 21791828 TI - Evaluation of disease severity in mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders characterized by a wide variation in symptoms and progression rates. Each of the MPS types is caused by a deficiency in one of the enzymes involved in the catabolic pathway of glycosaminoglycans. MPS are usually suspected on the basis of the concomitant presence of several typical features of the disease, such as short stature, coarse facial features, loss of hearing, bone deformities, joint stiffness, organomegaly, respiratory and cardiovascular complications, and, in some cases, developmental delay. Very reduced or absent enzyme activity is required to confirm an MPS diagnosis. In the past, treatment of MPS was limited to the management of individual symptoms of the diseases. Currently, specific therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy have improved the outlook for many MPS patients. To monitor disease progression and the impact of therapy in these patients, there is need for a validated scoring system for evaluating disease severity in MPS. A scoring system should take into account all aspects of MPS, particularly quality of life and functioning of arms, hands and legs and related mobility, endurance, self care and social functioning. This paper discusses several of the available scoring systems for bone/skeletal disorders and their potential usefulness in patients with MPS. PMID- 21791829 TI - Orthopedic management of mucopolysaccharide disease. AB - With advances in the treatment of the mucopolysaccharidosis (MPS) disorders, musculoskeletal problems are increasingly becoming a focus of care for these patients. This review discusses the current understanding of the pathophysiology of musculoskeletal disease in MPS and its orthopedic management. Deformities of the spine, hips and extremities are common and often functionally limiting. Carpal tunnel syndrome and flexor tendon triggering are common. Surgical intervention is often required to optimize long-term function. PMID- 21791830 TI - Clinical assessment and treatment of carpal tunnel syndrome in the mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) are a common cause of carpal tunnel syndrome (CTS) in children and adolescents. As the MPS diseases are progressive in nature, it is essential that CTS in these children is readily diagnosed and treated, before damage to the median nerve becomes irreversible. Currently, no standards for diagnosing and treating CTS associated with MPS exist. Proper diagnosis of CTS generally involves the assessment of clinical signs and symptoms, in combination with nerve conduction studies. As the clinical signs and symptoms of CTS described for adults are often absent in children with MPS, early diagnosis of CTS in these children requires recognition of subtle findings such as decreased sweating, nocturnal waking, gnawing of hands, and manual clumsiness. Sensory tests could also be useful for detecting early CTS when the integrity of the nerve is still relatively intact. Nerve conduction velocities, which are the gold standard for diagnosing CTS, can be difficult to perform in patients with MPS and should be adapted to the patients' clinical characteristics such as their abnormally small hands and young age. Ongoing monitoring for CTS is indicated for all MPS patients, including those treated with hematopoietic stem cell transplantation or enzyme replacement therapy. PMID- 21791831 TI - Skeletal complications in mucopolysaccharidosis VI patients: Case reports. AB - Mucopolysaccharidosis (MPS) VI is an inheritable lysosomal storage disorder that is often associated with severe orthopedic problems such as hip dysplasia, spinal deformities, and deformities in the skull, knees and hands. We describe the progression and management of three MPS VI cases with focus on their orthopedic problems. PMID- 21791833 TI - CME Section. PMID- 21791832 TI - Difficulties in diagnosing slowly progressive mucopolysaccharidosis VI: A case series. AB - An Erratum for this article can be found here: http://iospress.metapress.com/content/e16437020701m0u5/?p=df8dd6709cf44367a0c0e5d 17aaeddf&pi=11We describe the cases of two adult sisters recently diagnosed with the attenuated form of mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). MPS VI is a rare, clinically heterogeneous lysosomal storage disorder that is characterized by a deficiency in the glycosaminoglycan-degrading enzyme arylsulfatase B. Both cases had been misdiagnosed for over 30 years despite the presence of several characteristics of the disease, including short stature (mild), coarse facial features, skeletal dysmorphisms, carpal tunnel syndrome, heart valve disease, and spinal cord compression, which together are suggestive of a lysosomal storage disease. Awareness about the clinical features of MPS VI should be communicated amongst treating neurologists, rheumatologists and other specialists who are involved in the healthcare decisions of these patients with presenting symptoms, so they can refer them to specialized centers for proper diagnosis and treatment. PMID- 21791835 TI - Promoting Bone Health in MPS VI (Maroteaux-Lamy syndrome): Framing New Therapies, Part 2. PMID- 21791836 TI - Cartilage and chondrocyte pathology in the mucopolysaccharidoses: The role of glycosaminoglycan-mediated inflammation. PMID- 21791837 TI - Musculoskeletal health in Hunter disease (MPS II): ERT improves functional outcomes. AB - Musculoskeletal disease is a significant burden for children with Mucopolysaccharide (MPS) disorders. The Pediatric Outcomes Data Collection Instrument (PODCI) is a validated, functional measure of musculoskeletal health in children with disabilities. The goal of this study is to describe the musculoskeletal manifestations of children with MPS II (Hunter syndrome), and their functional response to intravenous enzyme replacement therapy (ERT). Patients with MPS II were prospectively entered into an IRB approved registry. Chart review of physical findings including, shoulder, elbow, hip, knee and ankle range of motion, and need for carpal tunnel release was performed. Radiographs of the spine and pelvis were evaluated in all patients. Serial PODCI exams were administered to all patients. Seven patients, 5 receiving ERT, were included. Four patients had spinal deformities, seven had modest hip disease, and two required carpal tunnel release. PODCI scores were abnormally low in all domains, but significant improvements in PODCI scores were documented with enzyme replacement therapy. Spine and hip deformity are ubiquitous in MPS II, none of which have required surgical intervention, but require long term monitoring. Patients with MPS II should be monitored for carpal tunnel syndrome. Functional improvements are seen, as documented by the PODCI, in children with MPS II on ERT. PMID- 21791838 TI - Radiologic and neuroradiologic findings in the mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) represent a group of inheritable, clinically heterogeneous lysosomal storage disorders, in which progressive accumulation of glycosaminoglycans (GAGs) can affect organs and tissues all over the body. The current paper discusses the skeletal X-ray and neuroimaging findings in MPS patients, and the imaging techniques that can be used for diagnosing and monitoring abnormalities in the skeleton and central nervous system. Most MPS types show a typical radiologic expression, called dysostosis multiplex, which manifests as malformations of the skeletal system involving bones in the skull, thorax, spine, pelvis, long bones, and hands. Abnormalities of the spine and GAG deposits in the meninges surrounding the spinal cord can result in spinal cord compression, which, if untreated, can lead to compressive myelopathy. Magnetic resonance imaging (MRI) is the most powerful imaging technique for detecting spinal cord compression, but also radiography and computed tomography are useful. GAG deposits in the brain and surrounding tissues can result in brain anomalies, i.e. white matter lesions, brain atrophy, and hydrocephalus, which can be detected using MRI. Skeletal X-ray and neuroimaging findings can play an important role in diagnosis, follow-up, surgical or medical planning, and assessment of treatment response in MPS patients. There is a need for standardized procedures in evaluating and monitoring neurologic complications in these patients. PMID- 21791840 TI - CME Section. PMID- 21791839 TI - Clinical utility of endurance measures for evaluation of treatment in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). AB - Increased functional capacity of major organ systems improves the quality of life and contributes to reductions in the morbidity associated with chronic debilitating diseases. Routine endurance tests can be used to gauge the progression of disease and the impact of therapeutic modalities in disorders with multiple organ system involvement such as with Mucopolysaccharidosis type VI (MPS VI). MPS VI is a progressive disorder affecting multiple organs and tissues due to the deficient activity of N-acetylgalactosamine-4-sulfatase leading to the accumulation of glycosaminoglycan (GAG) dermatan sulfate. Since 2005, enzyme replacement therapy (ERT) with human recombinant N-acetylgalactosamine-4 sulfatase (galsulfase) has been an available treatment option for MPS VI. These patients are routinely evaluated for extent of disability, disease progression and the impact of ERT. Evaluations are made by a combination of urinary GAG measurement and submaximal intensity endurance tests such as the 3-minute stair climb (3-MSC), and the 6- and 12-minute walk tests (6-MWT and 12-MWT). This review highlights the clinical validity of endurance measures as inexpensive diagnostic tools for diseases affecting multiple organ systems and evaluating the impact of therapeutic modalities, such as ERT for MPS VI. PMID- 21791843 TI - Erratum. AB - The original article can be found here: http://iospress.metapress.com/content/a7354504104m28t0/?p=a902fc8ed5764a7ea8f97bb b5e3d33a&pi=9. PMID- 21791845 TI - Editor's Corner. PMID- 21791844 TI - Erratum. AB - The original article can be found here: http://iospress.metapress.com/content/a8621160n2130837/?p=a902fc8ed5764a7ea8f97bb b5e3d33a&pi=3. PMID- 21791846 TI - Discrepancies in health care funding for individuals with special needs. PMID- 21791847 TI - Effect of ankle-foot orthoses on gait in typically developing children: Developmental trend in segmental coordination. AB - OBJECTIVE: As orthoses, and particularly ankle-foot orthoses, are widely used in the management of children with motor disorders, including cerebral palsy, we aimed to study their effect in normal children in order to add to normative gait data, which are essential for diagnosing, understanding and treating abnormal gait patterns. DESIGN: We analyzed the effect of ankle-foot orthoses on classical gait parameters and lower limb segments coordination patterns in typically developing children in two age groups reflecting different neuromaturational/developmental situations. We recorded 3D kinematic gait patterns in 9 children (4-5 years) and 11 children (9-10 years) walking barefoot or wearing bilateral solid ankle-foot orthoses maintaining the ankle joint angle at a neutral position. RESULTS: Ankle-foot orthoses induced little change in cadence, step length, step width or walking velocity in younger children, though they altered intralimb coordination through the gait cycle. In older children, walking velocity was reduced, shank elevation amplitude increased, while lower limb coordination changed less significantly. In this age group, ankle-foot orthoses significantly reduced the variability of coordinative strategies. CONCLUSION: Ankle-foot orthoses affect the gait pattern in children with a typical development at different levels in younger and older subjects, but the resulting changes are minimal. PMID- 21791848 TI - Gross motor outcomes in children with hemiparesis involved in a modified constraint-induced therapy program. AB - OBJECTIVE: Constraint-Induced Therapy (CIT) has been used in pediatric rehabilitation and targets upper extremity (UE) outcomes. The purpose of this study was to measure concurrent gross motor and lower extremity functional changes using the Gross Motor Function Measure (GMFM) before and after a modified UE CIT program. The Assisting Hand Assessment (AHA) was used to evaluate upper extremity outcomes. DESIGN: Before-after trial design of a 19-day outpatient CIT program at Seattle Children's Hospital in Seattle, WA, USA of six ambulatory children with spastic hemiparesis between the ages of 5 and 11 years with GMFCS scores of 1. GMFM Section D (Standing) and E (Walking, Running, Jumping) and AHA scores were obtained before and after a modified CIT program. RESULTS: Significant differences were found between pre and post-CIT AHA and GMFM section D and E scores (p < 0.05). All children improved from baseline, yet the child with the lowest initial scores revealed the greatest improvements. CONCLUSIONS: Improvements in GMFM and AHA scores were noted after a modified CIT program. Such data suggests that CIT may also influence rehabilitation outcomes not only specific to the upper extremity and warrants further investigation. PMID- 21791849 TI - Outpatient medical conditions among children and adults with spina bifida in the United States: Frequency and expenditures. AB - OBJECTIVE: To describe the most prevalent conditions and their associated expenditures for the outpatient care of individuals with spina bifida (SB) of varying ages. DESIGN: From a large health insurance claims database of people with private insurance, we examined records on outpatient health care received during 2005-2006 for individuals with SB and a matched comparison group. Chronic conditions from the most frequently recorded 4-digit ICD-9-CM codes for individuals with SB were grouped into four categories: cardiovascular disease risk factors, SB secondary conditions, pain, and other symptoms. RESULTS: Diseases affecting the nervous, genitourinary, and musculoskeletal systems and miscellaneous symptoms (e.g., headache, fever) account for about 70% of outpatient expenditures, excluding those associated with perinatal and congenital conditions. The most common and costly conditions by age group were diseases of the nervous system for children and adults younger than age 30 years and diseases of the musculoskeletal system for adults aged 30-64 years. Individuals with SB had significantly elevated risks for essential hypertension, urinary tract infection, and constipation at young ages and headache, sleep disturbance, and fever throughout the life span. CONCLUSIONS: The frequency of health conditions associated with SB varies across the life span. These conditions should be a priority for further investigations to identify risk factors, treatment and prevention strategies for individuals with SB. PMID- 21791850 TI - Clinical implications of design characteristics, flow rates, and suction pressure attributes in commercially available training cups. AB - OBJECTIVE: Transitioning from a bottle to open cup drinking can be a lengthy process in typical development. Children are often introduced to training cups during this period. Due to a lack of standardization in commercially available training cups, differences in design and performance characteristics may potentially create medical complications in developmentally delayed individuals. Our purpose is to report commercially available training cup design characteristics, residual fluid, flow rates, and suction pressures and discuss the potential clinical implications. DESIGN: A testing apparatus was developed to determine suction pressure and flow rate. Nine commercially available training cups were tested by two independent research teams. Experimental data were filtered and then fit with a linear approximation determined by a least squares method. RESULTS: Commercially available cups exhibited extensive variability in design parameters, suction pressure, rate of flow, and residual fluid. CONCLUSION: The extensive variability of design and function within current commercially available cups has clinical implications for children with development delays such as the ingestion of air and aspiration. Studying the variability of existing training cup performance identifies characteristics that impact cup function which can influence future cup design. PMID- 21791851 TI - A systematic review of supported standing programs. AB - OBJECTIVE: The routine clinical use of supported standing in hospitals, schools and homes currently exists. Questions arise as to the nature of the evidence used to justify this practice. This systematic review investigated the available evidence underlying supported standing use based on the Center for Evidence-Based Medicine (CEBM) Levels of Evidence framework. DESIGN: The database search included MEDLINE, CINAHL, GoogleScholar, HighWire Press, PEDro, Cochrane Library databases, and APTAs Hooked on Evidence from January 1980 to October 2009 for studies that included supported standing devices for individuals of all ages, with a neuromuscular diagnosis. We identified 112 unique studies from which 39 met the inclusion criteria, 29 with adult and 10 with pediatric participants. In each group of studies were user and therapist survey responses in addition to results of clinical interventions. RESULTS: The results are organized and reported by The International Classification of Function (ICF) framework in the following categories: b4: Functions of the cardiovascular, haematological, immunological, and respiratory systems; b5: Functions of the digestive, metabolic, and endocrine systems; b7: Neuromusculoskeletal and movement related functions; Combination of d4: Mobility, d8: Major life areas and Other activity and participation. The peer review journal studies mainly explored using supported standers for improving bone mineral density (BMD), cardiopulmonary function, muscle strength/function, and range of motion (ROM). The data were moderately strong for the use of supported standing for BMD increase, showed some support for decreasing hypertonicity (including spasticity) and improving ROM, and were inconclusive for other benefits of using supported standers for children and adults with neuromuscular disorders. The addition of whole body vibration (WBV) to supported standing activities appeared a promising trend but empirical data were inconclusive. The survey data from physical therapists (PTs) and participant users attributed numerous improved outcomes to supported standing: ROM, bowel/bladder, psychological, hypertonicity and pressure relief/bedsores. BMD was not a reported benefit according to the user group. CONCLUSION: There exists a need for empirical mechanistic evidence to guide clinical supported standing programs across practice settings and with various-aged participants, particularly when considering a life-span approach to practice. PMID- 21791852 TI - A perspective on early mobilization for adult patients with respiratory failure: Lessons for the pediatric population. AB - OBJECTIVE: To summarize the evidence for early mobilization programs in critically ill pediatric and adult patients with respiratory failure. This paper describes our review of the literature and outlines the morbidities associated with immobility, mechanical ventilation and sedation.The clinical management of acutely ill pediatric patients with respiratory failure traditionally consists of mechanical ventilation, sedation and prolonged immobilization. Although the most severely ill patients require these therapies for survival, each therapy comes with adverse consequences. Early mobilization may reduce complications and confer benefit for children with respiratory failure or those who require prolonged mechanical ventilator support. DESIGN: Systematic review of the literature pertaining to early mobilization in pediatric and adult patients with respiratory failure. We searched Medline, PubMed, CINAHL and Cochrane database of controlled trials. Randomized controlled trials (RCTs), observational cohort studies, case control studies and population-based analysis were considered for inclusion. Two reviewers (MM and EH) independently selected pertinent studies. RESULTS: No studies of early mobilization in pediatric populations were found. Five adult studies were identified for review; two randomized controlled trials and three observational studies. All studies suggested an improvement in morbidity and economic benefit with implementation of early mobilization. CONCLUSIONS: Early mobilization in critically ill adult patients with respiratory failure is associated with a decrease in duration of sedatives, ventilator dependant days, ICU and hospital length of stay. The paucity of studies of early mobilization suggest that implementation of early mobilization is not widely practiced. Studies of early mobilization therapy in the adult patient requiring prolonged mechanical ventilator support are reviewed, and the physiologic rational and observed obstacles to integration of an early mobilization program are discussed. The adult data and scientific evidence are combined to support an opinion about the possible benefits of early mobilization programs. The generalizability of the findings and the feasibility of implementing early mobilization in critically ill children who require prolonged mechanical ventilator support are also considered. PMID- 21791853 TI - Caffeine as a neurostimulant: Two pediatric acquired brain injury cases. AB - OBJECTIVE: This report describes two pediatric patients undergoing acute inpatient rehabilitation for acquired brain injury. DESIGN: The first patient was a 16-year-old African American female with an acquired brain injury from multiple intracranial hemorrhages secondary to an arteriovenous malformation. The second patient was a 16 year-old African American male who sustained a traumatic brain injury due to assault. In both cases, the patients had difficulty participating in therapy due to significant attention/arousal impairments. RESULTS: Both patients demonstrated functional improvements after the initiation of caffeine 80 mg daily. The first patient's function improved from being unable to communicate to being able to signal yes/no with thumb movements. The functional independence measurement (FIM) scores of the second patient improved dramatically after caffeine was initiated. His function improved from being totally dependent in ambulation, wheelchair ambulation, and communication to only requiring moderate assistance with ambulation and supervision with wheelchair ambulation and communication after 3 weeks of treatment. The second patient's attention/arousal and FIM scores declined when caffeine was stopped for 3 days and improved once administration of caffeine resumed. There were no adverse events reported for either patient. CONCLUSION: Caffeine is a safe and inexpensive neurostimulant that may be used to treat attention/arousal impairments. Additional research is warranted to determine criteria of use, optimal timing, duration, and dosing of caffeine administration and to investigate whether caffeine improves chronic functional outcomes after ABI in pediatric acquired brain injury patients. PMID- 21791854 TI - CME Section. PMID- 21791856 TI - Author information section. PMID- 21791857 TI - Editor's Corner. PMID- 21791858 TI - Communication access for children: the role of augmentative and alternative communication technologies and strategies in pediatric rehabilitation. PMID- 21791859 TI - Linguistic difficulties in children and adolescents after acquired brain injury: A retrospective study. AB - OBJECTIVE: The purpose of this study was to focus on two linguistic abilities, word retrieval (expressive language) and comprehension of vocabulary and grammar (receptive language), as well as to investigate to what extent long-term problems exist in these areas in children following traumatic brain injury. METHODS: Two groups of children were studied retrospectively: twenty-four children with traumatic brain injury (TBI) and twenty-one children diagnosed with brain tumour. All children had been referred to the rehabilitation team for assessment. The children were between four and seventeen years old when assessed, with the assessments performed at least one year after the injury or brain tumour diagnosis. An established set of tests regarding word retrieval and comprehension of vocabulary and grammar was used, and the results were compared with normative test data. RESULTS: In both clinical groups, significantly more children scored lower than the designated "normal" score than in the normative sample on tests measuring confrontation naming and phonological word retrieval. In addition, in the brain tumour group, more children demonstrated significantly lower results than normal performance on a test for semantic word retrieval. In the TBI group, significantly more children scored below the normal value on tests of word and grammatical comprehension when compared to the normative sample. CONCLUSIONS: This study confirms that word retrieval is an area of deficit in many children with acquired brain injuries one year or more after the injury occurred. The study also indicates that children with TBI may have persistent deficits in comprehension of both vocabulary and grammar. PMID- 21791860 TI - Medical equipment use in children with disabilities: A descriptive survey. AB - OBJECTIVE: To investigate the use of medical equipment by children with disabilities, the reasons for use, and prescribers of equipment. METHODS: A convenience sample. SETTING: Referral clinic for children with developmental conditions. PARTICIPANTS: Caregivers of children with motor disabilities completed an interview survey for children 0-21 years. RESULTS: 108 parents/caregivers reported 467 (mean=4.3 per patient) pieces of owned equipment. The mean age of children was 7.1 years (+/- 5.0), and 49% were female. The most common diagnoses were cerebral palsy (45%), 'Other' diagnoses including intellectual disability (19%), genetic abnormality (13%), spina bifida (13%), and neuromuscular diseases (7%). Survey participants described use of the following types of equipment: orthotics (82%), bath chair (37%), seating device (34%), stander (19%), augmentative communication devices (17%), walker (14%), and gait trainer (10%). Reasons for "non-use" of equipment included: outgrown (19%), not useful (14%), and child refusal (15%). Physicians were the sole prescriber for 15% of families, whereas physical or occupational therapists most commonly recommended new equipment (76%). CONCLUSION: Based on parental report, children with neuromuscular disabilities use most equipment that is medically recommended. The majority of equipment needs are identified by therapists. Pediatricians can benefit from additional expertise in the provision of medical equipment for children. PMID- 21791861 TI - Augmentative and alternative communication intervention in children with traumatic brain injury and spinal cord injury. AB - Children and youth who sustain a traumatic brain injury (TBI) and/or spinal cord injury (SCI) may have temporary or permanent disabilities that affect their speech, language and communication abilities. Having a way to communicate can help reduce children's confusion and anxiety, as well as enable them to participate more actively in the rehabilitation process and thus, recover from their injuries. In addition, effective communication with family, care staff, peers, teachers and friends is essential to long-term recovery and positive outcomes for children with TBI and SCI as they are integrated back into their communities. This article describes how rehabilitation teams can use augmentative and alternative communication (AAC) and assistive technologies (AT) to support the communication of children recovering from TBI and SCI over time. PMID- 21791862 TI - Communication supports in pediatric rehabilitation. AB - This article introduces the roles of parents and rehabilitation professionals in the provision of communication supports for children who cannot meet their communication needs through natural speech alone, also referred to as individuals with complex communication needs (CCN). The authors present a personnel framework, introduce intervention models of augmentative and alternative communication (AAC) services, and address issues parents face in preparing to provide communication supports to children with CCN using AAC and assistive technology (AT). PMID- 21791863 TI - Communication vulnerable patients in the pediatric ICU: Enhancing care through augmentative and alternative communication. AB - Children in pediatric intensive care units (PICUs) may experience a broad range of motor, sensory, cognitive, and linguistic difficulties that make it difficult for them to communicate effectively. Being unable to communicate is emotionally frightening for children and can lead to an increase in sentinel events, medical errors and extended lengths of stay. Implementation of augmentative and alternative communication (AAC) tools and strategies can address the communication needs of children in the PICU by enabling them to communicate their wants, needs and feelings to healthcare providers and family members and participate in their own care more productively. Hospitals around the world are increasingly recognizing and addressing patients' needs for communication access and have begun to implement communication screenings and assessments and interventions at admission and throughout the hospital stay. New standards for all American hospitals, in fact, mandate efforts to improve patient communication. When patient-provider communication improves, treatment success goes up, hospital-caused errors decrease and patient and family satisfaction improve. This article describes three phases of intervention for communication vulnerable children in the PICU and provides examples of treatment approaches that ensure communication access as their medical condition changes. PMID- 21791864 TI - Effects of AAC interventions on communication and language for young children with complex communication needs. AB - Children with complex communication needs (CCN) who require augmentative and alternative communication (AAC) are at considerable risk in many aspects of their development: (a) functional communication skills, (b) speech development, (c) language development, (d) cognitive/conceptual development, (e) literacy development, (f) social participation, (g) access to education, and (h) overall quality of life. Early intervention is critical to address these areas and provide successful and functional outcomes. AAC offers the potential to enhance communication, language, and learning for children with significant communication disabilities. This paper provides an overview of the effects of AAC interventions on communication, behavior, language, and speech outcomes for young children with CCN for pediatricians and other medical and rehabilitation professionals. Future research directions to maximize the communication development of young children with CCN are also discussed. PMID- 21791865 TI - Health transitions for youth with complex communication needs: The importance of health literacy and communication strategies. AB - Pediatric rehabilitation specialists have key roles to play in preparing young people with complex communication needs (CCN) to participate in the adult health care system. As adults, individuals with CCN are responsible for describing their health needs, scheduling services, and self-advocating with health care specialists so they can access habilitation and rehabilitation services and technologies and have their health concerns addressed. Pediatric rehabilitation specialists can help adolescents with CCN (and their support teams) acquire both an understanding of how adult services are organized, as well as the health literacy, communication, and collaboration skills they will need to ensure successful health outcomes. PMID- 21791866 TI - Communication Matrix: A clinical and research assessment tool targeting children with severe communication disorders. AB - The Communication Matrix [20] is an assessment instrument that is designed to evaluate the expressive communication skills of children with severe and multiple disabilities. It accommodates any type of communicative behavior, including forms of augmentative and alternative communication (AAC) such as picture systems, electronic devices, sign language and 3-dimensional symbols; pre-symbolic communication such as gestures, body movements, sounds, eye gaze and facial expressions; as well as the typical forms of communication such as speech and writing. It covers seven levels of communication observed in typically developing infants during the first two years of life. The instrument, which is widely used to assess children with severe acquired and congenital disorders in community and school settings, is appropriate for both inpatient and outpatient pediatric rehabilitation. Data from an associated database demonstrating the value of this tool for clinical service and research are presented. PMID- 21791868 TI - Natriuretic Peptide-guided therapy for heart failure. AB - Chronic heart failure (HF) remains a major medical problem in the developed world, with rapidly rising prevalence, substantial morbidity, and high costs. The concept of titrating chronic HF therapies using physiologic markers, so called "biomarker guided therapy (BGT)", has become an area of substantial interest in HF given the underutilization of evidence-based medications and suboptimal outcomes with current management strategies. Several recent trials of BGT have had mixed results, with some demonstrating improved outcomes and others showing no benefit. The heterogeneity of patient populations compounded by the lack of standardized BGT algorithms and trial endpoints has complicated interpretation of these results. This article reviews the rationale, accumulated data, and unanswered questions for BGT in chronic HF. PMID- 21791870 TI - Depression and outcomes in hospitalized Japanese patients with cardiovascular disease. - Prospective single-center observational study-. AB - BACKGROUND: Several studies have suggested that depression poses a risk in cardiovascular patients. The aim of the present study was to evaluate the prevalence of depression and its effect on cardiovascular events and mortality in Japanese inpatients with cardiovascular disease. METHODS AND RESULTS: A total of 505 patients hospitalized with cardiovascular disease (28% female; mean age, 61 +/- 14 years; 31% ischemic heart disease; 47% New York Heart Association [NYHA] class II-IV; 25% implantation of pacing devices) were enrolled in the present prospective observational study. The Zung Self-Rating Depression Scale (SDS) was used to screen for depression. The primary outcome was the time to death or cardiovascular event, and the secondary outcome was death. In total, 109 patients (22%) were diagnosed with depression (Zung SDS index score >= 60). NYHA class III/IV, defibrillator implantation, and being unmarried were independently associated with depression. During an average follow-up period of 38 +/- 15 months, 92 patients (18%) reached the primary outcome. There was a higher incidence of the primary outcome in patients with depression than in those who were not depressed (P<0.01). Depressed patients had a significantly higher rate of mortality than non-depressed patients (P<0.01). Depression was an independent predictor of the primary outcome (hazard ratio, 2.25; 95% confidence interval: 1.30-3.92, P<0.01). CONCLUSIONS: Depression was not uncommon in Japanese inpatients with cardiovascular disease and was associated with cardiovascular outcomes. PMID- 21791871 TI - Inhibition of cytochrome P450 2C8-mediated drug metabolism by the flavonoid diosmetin. AB - The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6alpha-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6alpha-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC(50) values 4.25 +/- 0.02 and 68.5 +/- 3.3 uM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (K(i)) being 3.13 +/- 0.11 uM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the V(max) (maximum velocity) and increased the K(m) value (substrate concentration yielding 50% of V(max)) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP. PMID- 21791872 TI - Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan. AB - Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1 *10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15 0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied. PMID- 21791873 TI - Pathophysiological role of autophagy: lesson from autophagy-deficient mouse models. AB - Autophagy is a cellular degradation system in which cytoplasmic components including organelles are sequestered by double membrane structures called autophagosomes and sequestered materials are degraded by lysosomal hydrolases for supply of amino acids and for cellular homeostasis. The autophagy induced in response to nutrient deprivation is executed in a nonselective fashion, and adaptation to nutrient-poor conditions is the main purpose of autophagy. On the other hand, recent studies have shed light on another indispensable role for starvation-independent or constitutive autophagy in cellular homeostasis, which is mediated by selective degradation of a specific substrate(s). Herein, we introduce pathophysiological roles of starvation-induced, constitutive, and selective autophagy (in particular, selective turnover of p62 through autophagy) disclosed by autophagy-deficient mouse models. PMID- 21791874 TI - A new twist on behavioral genetics by incorporating wild-derived mouse strains. AB - Behavior has been proven to be extremely variable among human individuals. One of the most important factors for such variations of behavior is genetic diversity. A variety of mouse strains are reportedly suitable animal models for investigating the genetic basis of large individual differences in behavior. Laboratory strains have been shown to exhibit different behavioral traits due to variations in their genetic background. However, they show low-level genetic polymorphism because the original colony used for establishing the strains comprises a relatively small number of mice. Furthermore, because the laboratory strains were derived from fancy mice, they have lost the original behavioral phenotype of wild mice. Therefore, incorporation of inbred strains derived from wild mice of different mouse subspecies for behavioral studies is a marked advantage. In the long-term process of establishing a variety of wild-derived inbred strains from wild mice captured all over the world, a number of strains have been established. We previously identified a marked variety in behavioral traits using a Mishima battery. This review reports on the usefulness of wild derived strains for genetic analyses of behavioral phenotypes in mice. PMID- 21791869 TI - Determinants of warfarin use and international normalized ratio levels in atrial fibrillation patients in Japan. - Subanalysis of the J-RHYTHM Registry-. AB - BACKGROUND: Determinants of warfarin use and anticoagulation levels in atrial fibrillation (AF) patients have not been clarified thoroughly. METHODS AND RESULTS: A total of 6,324 patients with non-valvular AF and congestive heart failure, hypertension, age, diabetes, prior stroke (CHADS2) score >= 1 were used to investigate determinants of warfarin use, and 6,932 patients with AF receiving warfarin were used to investigate determinants of international normalized ratio (INR) of prothrombin time. Target INR levels for non-valvular AF patients were 1.6-2.6 for patients aged >= 70 years and 2-3 for patients aged < 70 years. Those for patients with valvular AF were 2-3. Patients with non-valvular AF and CHADS2 score >= 1 receiving warfarin (n = 5,614) more frequently had permanent AF, congestive heart failure, and stroke or transient ischemic attack (TIA), and had higher CHADS2 scores than those not receiving warfarin. Determinants of warfarin use were age (>= 60 years), AF type (persistent and permanent), and comorbidities (congestive heart failure, diabetes mellitus, and prior stroke or TIA). Use of antiplatelet drugs was a negative determinant of warfarin use. Only 53% of patients met the target INR levels. Determinants for the meeting of the target INR level (vs. lower INR level) were age (>= 60 years), permanent AF, hypertension, and prior stroke or TIA. Use of antiplatelet drugs was a negative determinant of the INR level. CONCLUSIONS: Currently in Japan, adherence to the guidelines regarding anticoagulation therapy is limited (UMIN Clinical Trials Registry UMIN000001569). PMID- 21791875 TI - Bcl11b heterozygosity leads to age-related hearing loss and degeneration of outer hair cells of the mouse cochlea. AB - BCL11B/CTIP2 zinc-finger transcription factor is expressed in various types of cells in many different tissues. This study showed that BCL11B is expressed in the nucleus of the outer hair cells of the mouse cochlea, degeneration of which is known to cause deafness and presbycusis or age-related hearing loss (AHL). We tested whether or not Bcl11b heterozygosity would affect AHL in mice. Analysis of auditory brainstem responses revealed AHL in Bcl11b (+/-) heterozygous, but not wild-type, mice, which was evident as early as 3 months after birth. Histological abnormalities were observed in the outer hair cells of the Bcl11b (+/-) mice at 6 months of age with hearing loss. These results suggest that the AHL observed in Bcl11b (+/-) mice is the result of impairment of the outer hair cells and that BCL11B activity is required for the maintenance of outer hair cells and normal hearing. PMID- 21791876 TI - Effects of levonorgestrel on reproductive hormone levels and their receptor expression in Mongolian gerbils (Meriones unguiculatus). AB - The effects of levonorgestrel (LNG) on serum levels of reproductive hormones and their receptor mRNA expression in the ovary and uterus of Mongolian gerbils were examined. The results show that serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased, whereas serum estradiol (E2) and progesterone (P4) decreased profoundly after LNG treatment. LNG down-regulated the mRNA expression of follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), estrogen receptor (ER) beta and progesterone receptor (PR) in the ovary, and ERalpha and PR in the uterus of Mongolian gerbils. The down-regulated effects were time-dependent and dose-dependent. LNG had no obvious effects on ERalpha mRNA expression in the ovary. The findings suggest that LNG impairs reproductive hormone receptor expression at the molecular level in Mongolian gerbils. Also, the two ER subtypes may play different roles in the ovary, and ERbeta may not be the predominant ER subtype in the uterus of Mongolian gerbils. The ovary and uterus may be the important sites of action of LNG through its direct progesterone-like effects in Mongolian gerbils. PMID- 21791877 TI - Usefulness of rat skin as a substitute for human skin in the in vitro skin permeation study. AB - Sprague-Dawley (SD) rats are broadly used in preclinical studies for drug development, so a lot of information for the rats can be obtained especially from pharmacokinetic, pharmacological and toxicological studies. The purpose of this study was to clarify whether SD rat skin can be used to predict human skin permeability. In vitro permeation studies of the three model drugs, nicorandil, isosorbide dinitrate, and flurbiprofen, through human skin and SD rat skin were performed using Franz-type diffusion cells. The permeation rates of the three model drugs through human skin and SD rat skin were determined, and their variations were evaluated. The inter-individual variations in SD rat skin permeability of the three model drugs were much lower than that in human skin permeability, although the permeation rates of the three model drugs through the SD rat skin were about twice those through human skin. In addition, no difference in the skin permeability coefficients of the three model drugs was obtained between fresh SD rat skin and frozen SD rat skin. The markedly smaller variation in the permeability through SD rat skin compared with that through human skin indicated that in vitro permeation studies using SD rat skin would be especially useful for evaluating differences in the skin permeability of the three model drugs as well as for predicting human skin permeability. PMID- 21791878 TI - Low intensity pulsed ultrasound accelerates delayed healing process by reducing the time required for the completion of endochondral ossification in the aged mouse femur fracture model. AB - The aim of this study is to clarify the effect of low intensity pulsed ultrasound (LIPUS) on shortening of the fracture healing period and endochondral ossification during the fracture healing process. We first established a model of aging-related delayed union fractures consisting of aged mouse (C57BL/6J; 40 weeks old) with closed femur fractures. We compared the healing process of 40 week-old mice to the healing process of 8-week-old (young) mice using radiological and histological analysis. In aged mice, some cartilage formation was observed 10 days after the fracture; however, endochondral ossification and hard callus bridging were observed 21 and 28 days after the fracture, respectively, whereas cartilage remained in the callus on day 28, suggesting delayed endochondral ossification following bone remodeling. Meanwhile, in aged mice with LIPUS treatment, cartilage formation was similar to that in aged mice without LIPUS; however, hard callus bridging and bone remodeling were observed 21 and 28 days after fracture, respectively, suggesting that LIPUS shortened the healing period due to promotion of endochondral ossification. Immunohistochemical analysis showed marked expression of vascular endothelial growth factor and neovascularization in the fibrous tissue comprising the periosteum that surrounded the whole callus. A cell migration test involving primary cultured human endothelial cells also showed promotion of cell migration by LIPUS. These results suggested that endothelial cell migration and neovascularization, which were observed around fracture sites, played a part in the mechanism of promotion of endochondral ossification by LIPUS. PMID- 21791879 TI - Nuclear but not mitochondrial DNA involvement in respiratory complex I defects found in senescence-accelerated mouse strain, SAMP8. AB - This study determined pathogenicity of an A11181G mtDNA mutation found in a senescence-accelerated mouse strain, SAMP8. The mutation was at a highly conserved site of the mt-Nd4 gene, which encodes one of the respiratory complex I subunits. The young SAMP8 expressed reduced complex I activity, which is controlled by both nuclear and mitochondrial DNA (mtDNA). To exclude the nuclear effects, we isolated transmitochondrial cybrids that share the same nuclear background, but possess mtDNA with or without the mutation. The cybrids showed normal respiratory function irrespective of whether their mtDNA possessed the mutation or not, suggesting that the A11181G mutation is not responsible for respiration defects found in SAMP8. PMID- 21791880 TI - Quantitative trait loci analysis for peripheral blood parameters in a (BALB/cW * C57BL/6J-Mpl (hlb219)/J) F(2) mice. AB - The genetic basis of the peripheral blood cell parameters is not fully elucidated. Thus, it is essential to research the correlation between blood cell counts levels and the genome in laboratory animals and subsequently in humans. In the present study, we examined 288 F(2) mice from a cross between BALB/cW and C57BL/6J-Mpl(hlb219)/J. The C57BL/6J-Mpl (hlb219)/J strain is a mouse model of thrombocytopenia. We found very strong correlations for PLT counts and revealed some highly significant correlations for RBC counts. On the basis of the obtained results, we presume that genetic control of erythrocyte parameters is divided into two pathways: first, the morphological determinants responsible for the red blood cell count (RBC), hematocrit (HCT), and mean corpuscular volume (MCV), and second, the functional pathway determining the hemoglobin content (HGB). The locus on Chromosome 4 is the only detected quantitative trait locus (QTL) influencing the analyzed platelets parameters. We also detected highly significant correlations for erythrocyte parameters on Chromosome 1 (RBC, MCV, MCH), Chr 7 (HGB), Chr 9 (MCHC), Chr 11 (RBC), and Chr 17 (MCH). Finally, with regards to the given correlations, using the Mouse Genome Database resource, we proposed candidate genes with possible meaning for the level of these parameters: cytokine receptor genes (e.g., Mpl), transcription factor genes (e.g., Xbp1, Ikzf1), hemoglobin chain genes (e.g., Hbb-b1, Hbb-ar), and many others localized in the confidence intervals of found QTLs. PMID- 21791881 TI - Sex identification using the ZFX and ZFY genes in common marmosets (Callithrix jacchus). AB - We investigated sex determination via the ZFX and ZFY genes using PCR-RFLP in the common marmoset. We designed a novel primer set to detect ZFX and ZFY. A 483-bp band from the ZFX gene and a 471-bp band from the ZFY gene were amplified. Sequencing data of the products amplified from ZFX and ZFY showed the recognition sites of two restriction enzymes, DdeI and MseI, respectively. After digestion of the products using each enzyme, we found that the band patterns between females and males were different. PCR-based sex identification might provide a tool for further breeding studies and experimental embryological studies using marmosets. PMID- 21791882 TI - Five-item version of the international index of erectile function correlated with albuminuria and subclinical atherosclerosis in men with type 2 diabetes. AB - AIM: There is increasing evidence of a strong link between erectile dysfunction and atherosclerosis. The aim of this study was to evaluate the relationships between the 5-item version of the International Index of Erectile Function (IIEF 5) score and albuminuria as well as markers of subclinical atherosclerosis in men with type 2 diabetes. METHODS: We evaluated the relationship of the IIEF-5 score with the degree of urinary albumin excretion, pulse wave velocity, ankle-brachial index or toe-brachial index (n = 125) as well as with major cardiovascular risk factors, including age, blood pressure, serum lipid concentration and hemoglobin A1c, body mass index, severity of diabetic retinopathy or nephropathy, and presence of neuropathy or cardiovascular disease in 197 men with type 2 diabetes. RESULTS: The mean IIEF-5 score was 10.0 +/- 6.9. The IIEF-5 score was inversely correlated with age or duration of diabetes, and positively correlated with diastolic blood pressure or serum total cholesterol concentration. The IIEF-5 score inversely correlated with log (urinary albumin excretion; r =-0.190, p =0.0078) or pulse wave velocity (r =-0.255, p =0.0003), and positively correlated with the toe-brachial index (r = 0.379, p < 0.0001). The IIEF-5 score was lower in patients with proliferative diabetic retinopathy than in patients with no diabetic retinopathy, and in patients with macroalbuminuria than in patients with normoalbuminuria. The IIEF-5 score was also lower in patients with neuropathy or cardiovascular disease than without. CONCLUSIONS: The IIEF-5 score correlated with diabetic micro- and macroangiopathy in men with type 2 diabetes. PMID- 21791883 TI - Efficacy of predicting thrombotic events with combination of dual point-of-care testing (POCT) after drug-eluting stent implantation for coronary heart disease: results from the CILON-T randomized trial POCT substudy. AB - AIM: Previous studies regarding on-treatment platelet reactivity have focused on response variability to individual antiplatelet agents. There are limited data on [1] response variability to both of these anti-platelet drugs, [2] efficacy of combining two point-of-care tests (POCT) simultaneously and [3] how it predicts the clinical outcome after percutaneous coronary intervention (PCI). METHODS: We analyzed 716 patients, enrolled in the CILON-T prospective randomized controlled trial, with both VerifyNow P2Y12 (PRU) and Aspirin (ARU) data at discharge. Patients were classified according to the tertile of PRU, ARU and the sum of the tertiles of PRU and ARU. The primary endpoint was the composite of cardiac death, nonfatal myocardial infarction (MI) and ischemic stroke at 6 months post-PCI. RESULTS: Ten patients reached the primary endpoint, four of which were nonfatal MI and six ischemic stroke. When analyzed for the primary endpoint, tertiles of ARU and PRU were not able to discriminate patients with future thrombotic events from the remainder (p= 0.197 for ARU and 0.058 for PRU with the log-rank test, respectively), whereas combining the tertiles of ARU and PRU was significantly effective (p= 0.019 for ARU+PRU with the log-rank test). Multivariate analysis showed that the highest tertile of the sum of ARU and PRU tertiles was the only significant predictor of future thrombotic events after PCI (HR 6.34, 95% confidence interval 1.32-30.47, p= 0.021). CONCLUSIONS: In this post-hoc analysis of the CILON-T trial, combining the results of ARU and PRU simultaneously had a significant role in discriminating patients at highest risk of future thrombotic events after PCI compared with either assay alone. PMID- 21791884 TI - Oxidative stress induced in microorganisms by zero-valent iron nanoparticles. AB - Nanoscale zero-valent iron particles (nZVI), with sizes smaller than 100 nm, are promising for environmental remediation of polluted water, soil and sediments. nZVI particles have high potential for migration in the environment and are likely to interact not only with pollutant chemicals but also with living organisms. For these reasons, an environmental concern is rising with respect to unintended effects that need to be weighed against the benefits of remediation. The nZVI particles have a tendency to release electrons and Fe(2+). The Fe(2+) can convert less reactive hydrogen peroxide to more reactive oxygen species, particularly hydroxyl radicals, via the Fenton reaction. Hydroxyl radicals show strong biochemical activity and can react directly with membrane lipids, proteins and DNA. Reactive oxygen species are normally scavenged by antioxidants and various enzymes; however, elevated concentrations of ROS in microbial cells can result in oxidative stress. Cells under severe oxidative stress show various dysfunctions of membrane lipids, proteins and DNA. This review focuses on the processes resulting in oxidative stress and on up-to-date studies of nZVI-induced intracellular changes leading to such stress in microorganisms. PMID- 21791885 TI - Seasonal variations in the community structure of actively growing bacteria in neritic waters of Hiroshima Bay, western Japan. AB - Using bromodeoxyuridine (BrdU) magnetic beads immunocapture and a PCR-denaturing gradient gel electrophoresis (DGGE) technique (BUMP-DGGE), we determined seasonal variations in the community structures of actively growing bacteria in the neritic waters of Hiroshima Bay, western Japan. The community structures of actively growing bacteria were separated into two clusters, corresponding to the timing of phytoplankton blooms in the autumn-winter and spring-summer seasons. The trigger for changes in bacterial community structure was related to organic matter supply from phytoplankton blooms. We identified 23 phylotypes of actively growing bacteria, belonging to Alphaproteobacteria (Roseobacter group, 9 phylotypes), Gammaproteobacteria (2 phylotypes), Bacteroidetes (8 phylotypes), and Actinobacteria (4 phylotypes). The Roseobacter group and Bacteroidetes were dominant in actively growing bacterial communities every month, and together accounted for more than 70% of the total DGGE bands. We revealed that community structures of actively growing bacteria shifted markedly in the wake of phytoplankton blooms in the neritic waters of Hiroshima Bay. PMID- 21791886 TI - Evaluation of the aflatoxin biosynthetic genes for identification of the Aspergillus section Flavi. AB - Several fungi in the Aspergillus section Flavi have been widely used for fermentative food production, while some related species in the section are known to produce mycotoxin(s) that causes mycotic diseases. Common evolutionary markers, such as rRNA gene sequences and their internal transcribed spacers, cannot differentiate these non-aflatoxin-producing species from aflatoxin producers. Multilocus sequence analysis (MLSA) based on four aflatoxin biosynthetic genes encoding aflR, aflT, norA, and vbs, which are more variable nucleotide sequences than rRNA genes, can distinguish safe koji molds, A. oryzae and A. sojae, from aflatoxin-producing strains, A. flavus, A. toxicarius and A. parasiticus. PMID- 21791887 TI - Bartonella species in wild rodents and fleas from them in Japan. AB - The purpose of this study was to assess the role of fleas for transmission of Bartonella species among wild rodents in Japan. Flea samples were collected from wild rodents and examined genetically for Bartonella infection. Bartonella DNA was detected from 16 of 40 (40.0%) flea samples. Sequence analysis demonstrated that 3 of 16 (18.8%) of the Bartonella-positive animals were infested with fleas from which the closely related Bartonella DNA sequence was detected, indicating that the fleas acquired Bartonella from the infested rodents. The DNA was detected in hemolymph, the midgut and the ovary (only in female), indicating that Bartonella might be colonized through the midgut and distributed into the body. PMID- 21791888 TI - Clinical evaluation of total intravenous anesthesia using a combination of propofol and medetomidine following anesthesia induction with medetomidine, guaifenesin and propofol for castration in Thoroughbred horses. AB - Seven Thoroughbred horses were castrated under total intravenous anesthesia (TIVA) using propofol and medetomidine. After premedication with medetomidine (5.0 ug/kg, intravenously), anesthesia was induced with guaifenesin (100 mg/kg, intravenously) and propofol (3.0 mg/kg, intravenously) and maintained with constant rate infusions of medetomidine (0.05 ug/kg/min) and propofol (0.1 mg/kg/min). Quality of induction was judged excellent to good. Three horses showed insufficient anesthesia and received additional anesthetic. Arterial blood pressure changed within an acceptable range in all horses. Decreases in respiratory rate and hypercapnia were observed in all horses. Three horses showed apnea within a short period of time. Recovery from anesthesia was calm and smooth in all horses. The TIVA-regimen used in this study provides clinically effective anesthesia for castration in horses. However, assisted ventilation should be considered to minimize respiratory depression. PMID- 21791889 TI - Association of women's birth weight with their blood pressure during pregnancy and with the body size of their babies. AB - The women's own intrauterine environment may influence their own pregnancy and their babies. The aim of our study was to investigate how a woman's birth weight affects the course of her pregnancy later in life as well as the body size of her babies; this study was based on the developmental origins of health and disease (DOHaD) concept. We collected Maternal and Child Health handbooks from 414 women and their biological mothers. They were classified into 3 categories based on the Fetal growth curve of Japan: light-for-date (LFD), which means birth weight is less than the -1.5SD; appropriate-for-date (AFD), which means it lies between the -1.5SD and +1.5SD; and heavy-for-date (HFD), which means it is in the +1.5SD, or higher. In the first trimester, systolic blood pressures (SBPs) were 117.6 (14.4 mmHg), 111.6 (12.4 mmHg), and 105.0 (11.6 mmHg), and diastolic blood pressures (DBP) were 71.0 (8.5 mmHg), 65.7 (9.4 mmHg), and 62.1 (8.7 mmHg) in women born LFD, AFD, and HFD, respectively (SBP: p for trend = 0.018, DBP: p for trend = 0.027). In the second and third trimesters, both SBP and DBP were higher for women born LFD than for those of the other 2 groups. Birth weights of the babies of women born LFD, AFD, and HFD were 2,791.1 (483.0 g), 3,043.4 (361.0 g), and 3,248.0 (431.5 g), respectively (p for trend < 0.01). Our findings support the DOHaD concept and suggest that intrauterine environment in fetal life may be passed down from generation to generation. PMID- 21791890 TI - A complete pathological response to treatment in a young patient with locally advanced minimal deviation adenocarcinoma of the uterine cervix undergoing chemoradiation followed by radical surgery. AB - Minimal deviation adenocarcinoma (MDA) is a very rare variant of cervical adenocarcinoma, this pathological entity is composed of mucinous very-well differentiated glands deeply invading cervical stroma, and often surrounded by a desmoplastic reaction. Despite its benign histological appearance, MDA is typically characterized by aggressive clinical behavior and by relevant difficulties in achieving a final diagnosis. Moreover, the intrinsic chemotherapy resistance, as well as the frequent failure of radiotherapy approaches has raised the need to investigate the efficacy of multimodal strategies for the treatment of MDA patients. Here, we report a case of locally advanced MDA of the uterine cervix in a very young woman, who was successfully treated with concomitant chemoradiation followed by radical surgery. PMID- 21791892 TI - Normal tempo of bone formation in Turner syndrome despite signs of accelerated bone resorption. AB - AIMS: To evaluate area bone mineral density (aBMD) and volumetric BMD (vBMD) by dual-energy X-ray absorptiometry, and relations to bone markers and hormones in adolescent women with Turner syndrome (TS). METHODS: Cross-sectional study in TS patients (n = 37, 16.7 +/- 3.4 years) and control group (n = 49), assessed by dual-energy X-ray absorptiometry, bone markers and hormones. TS patients were divided into a young group receiving ('ongoing') GH (n = 15) and an older group previously receiving ('previous') GH (n = 22). RESULTS: vBMD(spine) was similar in 'ongoing GH' TS, but higher in 'previous GH' TS, compared to controls. vBMD(hip) was lower in 'ongoing GH' TS, but similar in 'previous GH'. z scores for aBMD were uniformly reduced in 'ongoing TS', but near-normalized in 'previous GH' TS. Bone formation and resorption markers were increased in 'ongoing GH' TS, while 'previous GH' TS had elevated bone resorption markers. CONCLUSION: BMD increased in parallel with age in TS patients receiving optimal estradiol replacement therapy and GH according to consensus guidelines, and in controls. Young TS undergoing pubertal induction and still receiving GH have lower z score BMD than older TS patients receiving hormonal replacement therapy, where a near normalization of BMD was achieved. TS patients previously receiving GH showed signs of increased bone resorption. PMID- 21791891 TI - Magnitude of [(11)C]PK11195 binding is related to severity of motor deficits in a rabbit model of cerebral palsy induced by intrauterine endotoxin exposure. AB - Intrauterine inflammation is known to be a risk factor for the development of periventricular leukomalacia (PVL) and cerebral palsy. In recent years, activated microglial cells have been implicated in the pathogenesis of PVL and in the development of white matter injury. Clinical studies have shown the increased presence of activated microglial cells diffusely throughout the white matter in brains of patients with PVL. In vitro studies have reported that activated microglial cells induce oligodendrocyte damage and white matter injury by release of inflammatory cytokines, reactive nitrogen and oxygen species and the production of excitotoxic metabolites. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1 methylpropyl)-3-isoquinoline carboxamide] is a ligand that is selective for the 18-kDa translocator protein expressed on the outer mitochondrial membrane of activated microglia and macrophages. When labeled with carbon-11, [(11)C]PK11195 can effectively be used as a ligand in positron emission tomography (PET) studies for the detection of activated microglial cells in various neuroinflammatory and neurodegenerative conditions. In this study, we hypothesized that the magnitude of [(11)C]-(R)-PK11195 uptake in the newborn rabbit brain, as measured using a small-animal PET scanner, would match the severity of motor deficits resulting from intrauterine inflammation-induced perinatal brain injury. Pregnant New Zealand white rabbits were intrauterinely injected with endotoxin or saline at 28 days of gestation. Kits were born spontaneously at 31 days and underwent neurobehavioral testing and PET imaging following intravenous injection of the tracer [(11)C]-(R)-PK11195 on the day of birth. The neurobehavioral scores were compared with the change in [(11)C]PK11195 uptake over the time of scanning, for each of the kits. Upon analysis using receiver operating characteristic curves, an optimal combined sensitivity and specificity for detecting abnormal neurobehavioral scores suggestive of cerebral palsy in the neonatal rabbit was noted for a positive change in [(11)C]PK11195 uptake in the brain over time on PET imaging (sensitivity of 100% and area under the curve of >0.82 for all parameters tested). The strongest agreements were noted between a positive uptake slope - indicating increased [(11)C]PK11195 uptake over time - and worsening scores for measures of locomotion (indicated by hindlimb movement, forelimb movement, circular motion and straight- line motion; Cohen's kappa >0.75 for each) and feeding (indicated by ability to suck and swallow and turn the head during feeding; Cohen's kappa >0.85 for each). This was also associated with increased numbers of activated microglia (mean ratio +/- SD of activated to total microglia: 0.96 +/- 0.16 in the endotoxin group vs. 0.13 +/- 0.08 in controls; p < 0.001) in the internal capsule and corona radiata. Our findings indicate that the magnitude of [(11)C]PK11195 binding measured in vivo by PET imaging matches the severity of motor deficits in the neonatal rabbit. Molecular imaging of ongoing neuroinflammation in the neonatal period may be helpful as a screening biomarker for detecting patients at risk of developing cerebral palsy due to a perinatal insult. PMID- 21791893 TI - Binocular vision and ipsilateral retinal projections in relation to eye and forelimb coordination. AB - It is commonly proposed that the number of fibers that do not cross in the optic chiasm (OC) is proportional to the size of the binocular visual field, and that the major advantage of binocular vision is acute depth perception. I present an alternative, an 'eye-forelimb' (EF) hypothesis, suggesting that alterations in the OC influence the length of neural pathways that transmit visual information to motor nuclei and somatosensory areas involved in forelimb coordination. Evolutionary processes resulting in increased ipsilateral retinal projections (IRP) are of adaptive value in animals that regularly use the forelimbs in a frontal position, while evolutionary change towards reduced IRP is of value for animals that mainly use the forelimbs in lateral positions. Primates and cats, to a large extent, use visually guided forelimb maneuvers, and both groups have high proportions of IRP. The fact that vertebrates' IRP arise exclusively from the temporal retina supports the hypothesis, since IRP from the nasal retina would increase the length of neural pathways involved in forelimb coordination. The EF hypothesis offers new perspectives on why a high proportion of IRP among early limbless vertebrates became reduced during the evolution of laterally situated limbs, and why reptiles that lost their limbs (snakes) evolved more IRP. Anatomical, neurophysiological, phylogenetic, ontogenetic and ecological data suggest that mutations changing the proportions of ipsilateral visual connections in the OC may have selective value for EF coordination. PMID- 21791894 TI - Ebstein's anomaly of the tricuspid valve in association with tetralogy of fallot and absent pulmonary valve syndrome. AB - Ebstein's anomaly and absent pulmonary valve syndrome belong to the rarest congenital heart defects. Their association has never been reported so far. We present the unusual case of a fetus at 23 weeks of gestation with Ebstein's anomaly, tetralogy of Fallot, absent pulmonary valve and agenesis of the arterial duct. The main diagnostic features were apical displacement of the septal leaflet of the tricuspid valve with an offset from the mitral valve of 8 mm, a pronounced atrialization of the right ventricle, a large malalignment ventricular septal defect with overriding aorta in combination with absence of the pulmonary valve leaflets, to and fro flow pattern over the stenotic pulmonary valve annulus, turbulent flow in the pulmonary trunk, massive dilatation of the pulmonary trunk plus the pulmonary arteries and a right aortic arch with retroesophageal course of an aberrant left subclavian artery. The arterial duct and the thymus were absent. The remaining fetal anatomy was unremarkable. Amniocentesis revealed a normal male karyotype; 22q11 microdeletion was ruled out. After being counseled on the unfavorable prognosis, the parents opted for termination of pregnancy. The prenatal cardiac findings were confirmed at autopsy; however, a severely hypoplastic thymus was found instead of the suspected aplasia. PMID- 21791895 TI - Does smoking have a significant impact on early irritant hand dermatitis in metal workers? AB - BACKGROUND: Although they know the long-term complications of smoking, many smokers require additional motivation for entering a smoking cessation programme. At the same time, smoking is considered a possible promoting factor for various skin diseases. OBJECTIVE: The present study assesses the impact of smoking on occupational hand dermatitis in a high-risk population. MATERIAL AND METHODS: 1,355 metal workers, 97.3% of them shift workers, took part in a standardized interview and a dermatological examination of their hands. A subgroup of 1,020 males was willing to be followed-up for 1 year. Of those, 78.3% could be included in the final assessment. RESULTS: Compared to the general German adult population the percentage of smokers was increased (41.7% at baseline). Probably due to self selection bias and to a higher drop-out rate, the proportion of smokers was significantly lower at follow-up. Compared to nonsmokers, smokers had significantly higher score values for both erythematous lesions and vesicles. CONCLUSION: The present data might give additional support for occupational physicians or dermatologists to convince workers to quit smoking. PMID- 21791896 TI - Optical coherence tomography: a new tool to assess nail disease in psoriasis? AB - BACKGROUND: Nail disease is a characteristic manifestation of the psoriatic disease spectrum but is poorly understood. OBJECTIVE: Given the intrinsically high spatial resolution imaging capabilities of optical coherence tomography (OCT), we assessed its value in psoriatic nail disease compared to high resolution ultrasonography (US). METHODS: All fingernails in a psoriatic arthritis patient with nail changes were scanned with OCT, and findings were compared with high-resolution US. RESULTS: US showed loss of trilaminar appearance in all nails, resulting in the nail plate being visualized as a single hyperechoic layer with inhomogeneous thickness. The OCT images showed much higher resolution changes with prominent thickening in the ventral plate at the nail bed which was grossly inhomogeneous, 'eroded' and irregularly fused with the underlying epidermis, which correlated with the clinical observation of subungal hyperakeratosis. CONCLUSION: OCT has considerable potential for the evaluation of psoriatic nail disease and may be superior to US. PMID- 21791897 TI - 'A man paints with his brains and not with his hands' (Michelangelo). AB - The goals of a post-stroke rehabilitation plan are very specific to each patient. The side of the body affected by hemiplegia can influence the rehabilitation plan, as people with right-sided hemiplegia may also have difficulties with speech and language (aphasia). Because of the aphasia, drawing may remain a crucial instrument of creative expression and the clinical case presented highlights how this goal may also be successfully achieved in the elderly by using the left hand. PMID- 21791898 TI - Screening for the prevention of cervical cancer in the era of human papillomavirus vaccination: an Australian perspective. AB - Australia has a unique and highly successful screening program for cervical cancer which is based on the conventional Pap smear. Since its introduction in 1991 there has been a decline in both the incidence of and mortality from this disease. Part of the success of this program has been the introduction of Pap test registers and strict quality assurance measures for cervical cytology, including compulsory key performance indicators for laboratories. Using these measures, nationwide calculations give cervical cytology in Australia a sensitivity of 78% for high-grade lesions and a positive predictive value (PPV) of 78%. Australia was the first country to introduce a widespread government funded human papillomavirus (HPV) vaccination program in 2007. Because of the high accuracy of Australian cytology, HPV testing alone, given its low PPV and high cost, is unlikely to be a viable alternative to cytology for primary screening in this country. Australia therefore faces unique issues and choices in integrating its extensive vaccination program with a successful cervical screening program. PMID- 21791899 TI - Metaplastic carcinoma of the breast: cytological diagnosis and diagnostic pitfalls. AB - OBJECTIVE: Metaplastic carcinoma of the breast is a rare malignant neoplasm comprised of ductal, squamous and/or mesenchymal elements in various proportions. Fine needle aspiration diagnosis of this entity is problematic because of its pathological heterogeneity. In this study, we have described the cytomorphological features of histologically confirmed metaplastic carcinomas and also discussed the diagnostic limitations along with a brief review of the literature. STUDY DESIGN: In this observational study, the histology and cytology files of all cases identified as metaplastic carcinomas during the study period (2004-2009) were retrieved. The slides were reviewed for the presence of various elements. RESULTS: Ten cases were identified as metaplastic carcinomas during the study period. All cases were diagnosed as malignant on cytology. Three cases showed presence of squamous carcinoma cells, 4 showed presence of atypical spindle cells, 2 showed presence of mesenchymal fragments and 1 showed presence of osteoclastic giant cells. CONCLUSION: The presence of biphasic tumor cells, atypical spindle cells admixed with poorly differentiated carcinoma cells, squamous carcinoma cells, osteoclastic giant cells and matrix may provide clues for the fine needle aspiration diagnosis of metaplastic carcinomas. However, cytological diagnosis may not be possible in all the cases because of selective sampling of various pathological elements. PMID- 21791900 TI - Cytological analysis of atypical squamous epithelial cells of undetermined significance using the world wide web. AB - OBJECTIVE: The low-level consistency of the cytodiagnosis of uterine cervical atypical squamous epithelial cells of undetermined significance (ASC-US) employing the Bethesda System has been reported, suggesting the necessity of a wide survey. We presented cases judged as ASC-US on the Web and analyzed the voting results to investigate ASC-US cytologically. STUDY DESIGN: Cytology samples from 129 patients diagnosed with ASC-US were used. Images of several atypical cells observed in these cases were presented on the Web. The study, based on the voting results, was presented and opinions were exchanged at the meeting of the Japanese Society of Clinical Cytology. RESULTS: The final diagnosis of ASC-US was benign lesions in 76 cases and low- and high-grade squamous intraepithelial lesions in 44, but no definite diagnosis could be made for the remaining 9. The total number of votes was 17,884 with a 36.5% consistency of cases judged as ASC-US. Benign cases were divided into 6 categories. Four categories not corresponding to the features of koilocytosis and small abnormal keratinized cells were judged as negative for an intraepithelial lesion or malignancy at a high rate. CONCLUSION: A Web-based survey would be useful which could be viewed at any time and thereby facilitate the sharing of cases to increase consistency. PMID- 21791901 TI - Endometrial cells in liquid-based cervical cytology: a diagnostic pitfall solved by preparing cytohistology from the residual thin layer sample. AB - OBJECTIVE: It was our aim to assess the usefulness of cytohistology in cervical thin layer brush samples with problems in the differential diagnosis of endometrial cells. STUDY DESIGN: This study reveals the cytological, cytohistological and immunohistochemistry findings of 8 cases suspicious of adenocarcinoma in situ (AIS)/adenocarcinoma (AC) in cervical liquid-based cytology (LBC) preparations that turned out to be normal endometrial cells. RESULTS: All 8 cervical LBCs featured endometrial and atypical endocervical-like columnar cells with frequent ragged 'feathered' edge appearance and rosette formations. Overlapping atypical glandular cell groups were present on 2 ThinPrep slides as well. In cytohistology of 7 cases, the recognition of endometrial stroma with endometrial glands easily allowed the diagnosis of normal endometrium. In 1 case with very small loose tissue fragments without glands, the diagnosis could be established by positivity for CD10 marker (endometrial stroma) and without proliferative activity in the Ki-67 immunostaining. CONCLUSION: In cervical LBC preparations, nuclear hyperchromasia, pleomorphism and nucleoli in normal endometrial cells are more obvious than in conventional smears, and their arrangement is sometimes suggestive of AIS or AC. In the 8 cases presented, we could avoid a false-positive diagnosis of AIS or AC through cytohistology/immunohistochemistry, and in consequence, unnecessary colposcopical/histological examination. PMID- 21791902 TI - A prospective randomized study of two reminding strategies: telephone versus mail in the screening of cervical cancer in women who did not initially respond. AB - OBJECTIVE: To compare the efficacy and cost-effectiveness of two reminding strategies addressed to women who did not respond to a first invitation to undergo cervical cancer screening. STUDY DESIGN: A randomized study was carried out by a programme created in Alsace to organize cervical cancer screening. In total, 10,662 women who did not have a smear test 1 year after a first notice was sent, were randomly allocated to receive either a new letter with a reply coupon or a telephone call. The uptake of screening was measured using routine data. Efficacy and direct costs of the two methods were compared. RESULTS: Uptake at 8 months was 6.3% [95% confidence interval (CI) 5.6-7.0%] for telephone calls and 5.8% (95% CI 5.2-6.4%) for letters. The difference was not significant. More information was collected through telephone calls than by letters, but with less reliability. Furthermore, telephone calls were more costly. CONCLUSIONS: We found that in our region, a mail reminder was as effective as, and less expensive than, a telephone call; moreover, it was applicable to the whole population, including patients without a telephone. PMID- 21791903 TI - Performance of the New INNO-LiPA HPV extra to genotype human papillomavirus in cervical cell specimens. AB - OBJECTIVE: It was our aim to compare the INNO-LiPA HPV Genotyping Extra (LiPA; Innogenetics) versus the Linear Array test (LA; Roche) in cervical samples. STUDY DESIGN: One hundred cervical samples were selected, obtained from a cancer prevention center. All samples were human papillomavirus (HPV) DNA positive by Hybrid Capture 2 HPV test and genotyped by LA HPV genotyping test. All data were analyzed using Cohen's kappa tests. kappa values ranged from poor, fair, moderate and good to very good agreement strength. RESULTS: Detection of multiple infection and HPV genotypes per sample was higher by LA than by LiPA (61.5 vs. 52.1 and 2.2 vs. 1.7%, respectively). There were concordant results in 65 samples and compatible results in 33 samples. Only 2 samples were considered as discordant. In 21 samples, additional types were detected by LA, and in 13 samples, additional types were detected by LiPA. Analyzing the kappa values, we have found very good agreement for 14 genotypes (6, 16, 26, 31, 33, 35, 45, 51, 52, 53, 58, 66, 68 and 70). CONCLUSIONS: We considered that the new LiPA is highly comparable with other methods and suitable for clinical and epidemiological studies. PMID- 21791904 TI - Evaluation of the frequency of micronuclei in exfoliated cells from oral lesions previously identified by toluidine blue. AB - OBJECTIVE: Patients using a removable prosthesis are susceptible to a variety of oral lesions that may progress to cancer. Toluidine blue (TB) staining is used to identify premalignant lesions, but the results are still controversial. Since micronuclei (MN) are a biomarker of genetic instability, the objective of this study was to determine the frequency of MN in white lesions of the oral mucosa and to compare the results with those of the TB test. STUDY DESIGN: The study included 20 removable prosthesis users with white lesions that were previously classified as toluidine positive or negative. The frequency of MN was evaluated in exfoliated cells from lesions and normal mucosa. Nuclear anomalies were also registered. RESULTS: A significant increase (p < 0.05) in the frequency of MN was observed in exfoliated cells from lesions compared to normal mucosal cells, and no relationship was seen with TB staining. Lifestyle factors or gender did not influence the results. CONCLUSIONS: The frequency of MN is a sensitive biomarker and can be used to predict genomic instability in white oral lesions. The MN assay may serve as a good parameter in the battery of tests used to identify high risk individuals, contributing to the identification of the biological conditions of oral lesions. PMID- 21791905 TI - Three-dimensional nuclear luminance analysis in well-differentiated adenocarcinoma of the lung. AB - OBJECTIVE: Well-differentiated papillary adenocarcinoma of the lung (G1 cancer cells) is difficult to distinguish from benign bronchial columnar epithelial cells with reactive atypia (benign cells) in many cases because nuclear atypia is mild. We focused on the 3-dimensional presence of nuclei in cell smears. Several images focused on the nucleus were acquired, and the nuclear luminance was measured and analyzed. STUDY DESIGN: One hundred G1 cancer cells and benign cells (nuclei), respectively, were selected from those on a bronchial brushing preparation for cytology. Images of 41 layers were acquired at 0.25-MUm intervals in each cell, and the nuclear luminance was measured (a total of 8,400 images). RESULTS: There were more focus positions in the G1 cancer cell nuclei, showing a 3-dimensional nucleus, compared to benign cells, and the 3-dimensional variation in the coefficient of variation (CV) of nuclear luminance at the focus position was smaller in G1 cancer than in benign cells, showing a significant difference. CONCLUSION: The G1 cancer cells' nuclear structure was more 3-dimensional, and the chromatin distribution was homogeneous. The three-dimensional variation in the nuclear luminance CV could be numerically presented, which might be an objective index for cancer diagnosis. PMID- 21791906 TI - Simultaneous detection of T lymphocyte-related antigens (CD4/CD8, CD57, TCRbeta) with nuclei by fluorescence-based immunohistochemistry in paraffin-embedded human lymph node, liver cancer and stomach cancer. AB - OBJECTIVE: To develop a method for immunohistochemical staining of three different T lymphocyte antigens (CD4 or CD8, CD57 and TCRbeta) on the same tissue section and to determine whether tissues have been infiltrated with T lymphocytes expressing these markers. STUDY DESIGN: Commercially available antibodies were tested for immunohistochemical usefulness in a dye-based conventional single immunostaining method after antigen retrieval on paraffin-embedded human lymph nodes. We searched for the combination of antibodies that could detect T lymphocyte antigens on the same section without any cross-reactivity and that have fluorescent signals robust enough to overcome paraffin autofluorescence. RESULTS: Application of the antigen retrieval technique and the Sudan black B quenching technique enabled staining of paraffin-embedded tissue sections with fluorescent-labeled secondary antibodies. The combination of primary and secondary antibodies that could simultaneously detect the T lymphocyte antigens CD4 or CD8, CD57 and TCRbeta in histochemical analysis of a paraffin-embedded human lymph node section was established, and was successfully applied to a human tissue section infiltrated with T lymphocytes that express these markers. CONCLUSION: The antibodies listed here would be helpful for histopathologists who wish to investigate T lymphocytes in the paraffin-embedded sections that have accumulated in pathology labs throughout the world. PMID- 21791907 TI - A comparison of dacron versus Flocked nylon swabs for anal cytology specimen collection. AB - OBJECTIVES: We compared the performance of commonly used Dacron versus flocked nylon swabs for anal cytology. STUDY DESIGN: From 23 HIV-positive men screened at Kaiser Permanente San Francisco (San Francisco, Calif., USA), 2 anal specimens were collected, 1 with each swab in random order, and placed into liquid cytology medium. Specimens were tested for cellularity by quantifying a genomic DNA (erv 3). The number of cells was assessed from prepared slides by automated image analysis. Performance was compared between swabs using 2-sample t tests and standard crossover trial analysis methods accounting for period effect. RESULTS: Flocked swabs collected slightly more erv-3 cells than Dacron for the first sample although not significantly (p = 0.18) and a similar number of erv-3 cells for the second sample (p = 0.85). Flocked swabs collected slightly more cells per slide than the Dacron swabs at both time periods although this was only significant in the second time period (p = 0.42 and 0.03 for first and second periods, respectively). In crossover trial analysis, flocked swabs outperformed Dacron for cell count per slide based on slide imaging (p = 0.03), but Dacron and flocked swabs performed similarly based on erv-3 quantification (p = 0.14). CONCLUSIONS: Further studies should determine whether flocked swabs increase the representation of diagnostically important cells compared to Dacron. PMID- 21791908 TI - Uterine cervical sarcoidosis identified on pap test: cytomorphologic findings and differential diagnosis. AB - BACKGROUND: Sarcoidosis is a multisystem inflammatory disease of uncertain etiology that is histopathologically characterized by non-necrotizing granulomas. It typically involves the lungs and lymph nodes, but has been reported in many other organ systems as well. Sarcoidosis involving the female genital tract, the uterus in particular, is a rare event with isolated accounts in the medical literature. CASE: We present a rare occurrence of cervical sarcoidosis in a Pap test of a 31-year-old woman with a history of biopsy-proven mediastinal lymph node sarcoidosis and mediastinal pleomorphic liposarcoma with status post chemotherapy. The Surepath smear showed crowded cellular groups with abundant epithelioid histiocytes and lymphocytes consistent with granulomatous inflammation. No granular necrotic debris or polarizable foreign body material was identified. There were no microorganisms present. The cytomorphologic features and differential diagnoses are discussed. CONCLUSION: Uterine cervical sarcoidosis, although rare, can be an overlooked cause of non-necrotizing granulomatous inflammation in a cervical Pap test. Sarcoidosis should be a diagnosis of exclusion; other common conditions with similar morphologic presentation such as non-necrotizing tuberculosis, foreign body-related granulomatous inflammation, and neoplastic/chemotherapy-related sarcomatoid reaction need to be excluded in conjunction with the patient's clinical history. PMID- 21791909 TI - Case report of renal cell carcinoma diagnosed in voided urine confirmed by CD10 immunocytochemistry. AB - BACKGROUND: Preoperative diagnosis of renal cell carcinoma (RCC) by exfoliative urine cytology is difficult, as infiltration of RCC into the pelvicalyceal system is uncommon. The exfoliation of RCC cells in urine is a rare phenomenon and when it does occur, it is likely to be missed. Cytologic examination of the urine coupled with ancillary immunocytochemistry can clinch the diagnosis leading to appropriate clinical management. CASE: A 50-year-old man presented with complaints of hematuria and abdominal pain of 6 months' duration. Ultrasonographic examination of the abdomen and pelvis showed a well-defined mass lesion in the upper pole of the left kidney, suggestive of neoplastic etiology. In the given clinical context of renal mass, urine cytology was suggestive of RCC and biopsy confirmation was suggested. One cytology smear subjected to immunocytochemistry with anti-CD10 antibody which showed strong diffuse cytoplasmic positivity in these cells confirmed the diagnosis of RCC. Subsequently, fine needle aspiration cytology of the kidney mass was reported as RCC. CONCLUSIONS: RCC has distinct cytologic features that facilitate a diagnosis in urine in an appropriate clinical and radiological context. Their recognition in the urine smear is important to avoid costly and invasive modalities like image-guided needle biopsy. PMID- 21791910 TI - Negative image of blastomyces on diff-quik stain. AB - BACKGROUND: Blastomycosis is caused by a dimorphic fungus that can be difficult to diagnose in certain situations. The disease is sometimes serious and can be deadly. Diagnosis by fungal serology and urinary antigens is not easy to establish and unreliable. Culture is also time-consuming and is not easy to perform. Thus, documentation of such an organism on cytology offers a quick and cost-effective alternative. This report describes for the first time identification of the 'negative image' of Blastomyces budding yeast. CASE: A 79 year-old man presented with a left lung nodule associated with mediastinal and hilar lymphadenopathy. Fine needle aspiration was performed, and a 'negative image' of a yeast with wide base budding was noted on Diff-Quik (DQ)-stained smears. Blastomyces species were confirmed with periodic acid-Schiff fungal stain. Additionally, the fungal capsule contained focally polarizable material on Congo red stain and lacked mucin with mucicarmine stain. CONCLUSION: Blastomyces yeast forms can be easily identified with DQ staining by their 'negative image'. This feature can be utilized as a quick and cost-effective cytological characteristic to further triage these specimens for confirmation. The information can be of great value to clinicians in making appropriate clinical decisions. PMID- 21791912 TI - Successful thyroid aspiration biopsies: additional suggestions. PMID- 21791911 TI - Cytologic, immunocytologic, histopathologic and immunohistologic diagnosis of the poorly differentiated sertoli-leydig cell tumor. AB - BACKGROUND: Sertoli-Leydig cell tumors (SLCTs), also known as arrhenoblastomas, are tumors of the sex cord-stromal group of ovary and testis cancers. They comprise <1% of all ovarian tumors. They are divided into 6 categories based on the degree of differentiation and the presence of heterologous elements. However, <15% of these tumors are poorly differentiated. CASE: A 23-year-old unmarried female presented with an 8-month history of irregular menstrual cycle and abdominal pain. There were no clinical features suggesting virilization. The left salpingo-oophorectomy specimen revealed an oval ovarian mass of 11 * 7 * 4 cm in dimension. Grossly, the cut surface of the mass was yellowish white in color and solid in consistency and touch preparation was made. By applying cytology and immunocytochemistry techniques, a preliminary diagnosis suggestive of poorly differentiated SLCT was made. The tumor was confirmed as a poorly differentiated SLCT. CONCLUSION: Cytology and immunocytochemistry by WT-1, melan A, vimentin and calretinin are helpful in the diagnosis of poorly differentiated SLCTs. PMID- 21791913 TI - JAK2 mutation-negative secondary erythrocytosis in smoldering plasma cell myeloma: a case study and review of the literature. PMID- 21791914 TI - Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-beta(1) induced fibroblast activation. AB - BACKGROUND: Novel therapeutic agents are urgently needed to combat renal fibrosis. The purpose of this study was to assess, using complete unilateral ureteral obstruction (UUO) in rats, whether fluorofenidone (AKF-PD) [1-(3 fluorophenyl)-5-methyl-2-(1H)-pyridone] inhibits renal fibrosis, and to determine whether it exerts its inhibitory function on renal fibroblast activation. METHODS: Sprague-Dawley rats were randomly divided into 3 groups: sham operation, UUO and UUO/AKF-PD (500 mg/kg/day). Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF beta(1), collagen III, alpha-SMA, p-Smad2, p-Smad3, p-ERK1/2, p-JNK and p-p38 were measured. In addition, the expressions of alpha-SMA, fibronectin, CTGF, p Smad2/3, p-ERK1/2, p-p38 and p-JNK were measured in TGF-beta(1)-stimulated normal rat renal fibroblasts (NRK-49F). RESULTS: AKF-PD treatment significantly attenuated tubulointerstitium damage, ECM deposition, the expressions of TGF beta(1), collagen III, alpha-SMA, p-ERK1/2, p-p38 and p-JNK in vivo. In vitro, AKF-PD dose-dependently inhibited expressions of alpha-SMA, fibronectin and CTGF. Furthermore, AKF-PD did not inhibit Smad2/3 phosphorylation or nuclear accumulation, but rather attenuated ERK, p38 and JNK activation. CONCLUSION: AKF PD treatment inhibits the progression of renal interstitial fibrosis in obstructed kidneys; this is potentially achieved by suppressing fibroblast activation. Therefore, AKF-PD is a special candidate for the treatment of renal fibrosis. PMID- 21791915 TI - The role of statins in chronic kidney disease. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality not only amongst the general population, but also in patients with chronic kidney disease (CKD). Persons with CKD are much more likely to die of CVD than to experience kidney failure. Clinical trials have demonstrated that statins are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD. In CKD patients the role of statins in primary prevention of CVD remains to be clarified. The absolute benefit of treatment with a statin seems to be greater among nondialysis dependent-CKD patients. Studies in end-stage renal disease patients on dialysis did not confirm these results. Recently, however, the Study of Heart and Renal Protection (SHARP) has suggested that statins with ezetimibe may be beneficial even in dialysis patients. Clinical studies with statins on proteinuria reduction and renal disease progression have yielded conflicting results. Some studies have shown a prominent reduction in proteinuria, while other studies have shown that statins had no effect or may cause proteinuria at high doses. This review examines the clinical evidence of the observed benefits of kidney function with the use of this drug category in CKD patients. PMID- 21791916 TI - C-reactive protein and the risk of contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: The relationship between preprocedural C-reactive protein (CRP) levels and the incidence of contrast-induced acute kidney injury (CI-AKI) is unknown. METHODS: Documents of 7,310 consecutive patients undergoing percutaneous coronary intervention (PCI) were screened. Patients with acute myocardial infarction, cardiogenic shock, concomitant inflammatory conditions or undergoing CABG within 48 h were excluded due to potential confounding effects. RESULTS: A total of 4,522 patients were valid for analysis. The median follow-up was 26 months (interquartile range 20-33 months). According to preprocedural CRP values, patients were divided into 3 groups: group 1: CRP <1.0 mg/l (n = 1,523); group 2: 1.0 mg/l <= CRP <= 3.0 mg/l (n = 1,626); group 3: CRP >3.0 mg/l (n = 1,373). Patients with higher preprocedural CRP levels were associated with a significantly increased rate of CI-AKI (10.6 vs. 14.9 vs. 23.5%, p < 0.0001). After adjustment for baseline covariates, CRP level was still an independent predictor for the incidence of CI-AKI, either as a continuous variable or a categorical variable. Patients with higher CRP values had a significantly higher rate of all-cause mortality and myocardial infarction during follow-up. CONCLUSION: Elevated preprocedural CRP is associated with an increased risk for CI-AKI in patients undergoing PCI. Preprocedural risk stratification with CRP as an adjunct to established clinical risk factors might be useful. PMID- 21791917 TI - Activation of arterial matrix metalloproteinases leads to vascular calcification in chronic kidney disease. AB - BACKGROUND: The objective of the current study was to determine if altered regulation of matrix metalloproteinases (MMPs) may predispose to extracellular matrix degradation, facilitating arterial calcification in chronic kidney disease (CKD) using a progressive model of CKD-MBD, the Cy/+ rat. METHODS: Sera were collected from normal or CKD rats at various times and MMP-2 and MMP-9 levels determined by ELISA or zymography. Aorta tissue was harvested at sacrifice for RT PCR and immunostaining. Calcification of aorta rings was assessed with MMP inhibitors. RESULTS: There was an increase in MMP-2, MMP-9, TIMP-1, and RUNX-2 expression in the aorta with progressive CKD, and increased MMP-2 activity in the serum. Immunostaining revealed increased expression of MMP-2 and MMP-9 in areas of aorta calcification. There was also an upregulation of MMP-2 and MMP-9 in vascular smooth muscle cells (VSMC) from CKD rats. MMP inhibitors decreased calcification of aorta rings from normal and CKD rats. High phosphorus increased MMP-2 and MMP-9 expressions in VSMC from normal rats but not from CKD rats. CONCLUSION: MMP-2 and MMP-9 expression and activity are increased with progressive CKD, and blockade of MMP activity can inhibit arterial calcification. These data suggest degradation of the extracellular matrix is a critical step in the pathogenesis of arterial calcification in CKD. PMID- 21791918 TI - Repeat renal biopsy in lupus nephritis: a change in histological pattern is common. AB - BACKGROUND: The role of longitudinal change in sequential renal biopsies of lupus nephritis (LN) patient remains elusive. METHODS: Clinical and pathological documents of 156 LN patients with repeat renal biopsies (412 times) were collected from a database. RESULTS: The percent of transformation of the biopsy class from reference biopsies to repeat biopsies was 75%. For the reference biopsies that showed pure proliferative, pure membranous, and mixed nephritis, the histological pattern in the repeat biopsies changed in 57.8, 50.0, and 60.4%, respectively. As compared to reference biopsy, repeat biopsy had a higher degree of tubulointerstitial scarring (p < 0.001), chronicity index (p < 0.001) and serum creatinine (p < 0.001). In addition, baseline serum creatinine was significantly lower (p = 0.004), and the time lapse between the two biopsies was significantly longer (p < 0.001) amongst patients who had a change in the histological pattern upon repeat renal biopsy than those whose histological pattern remained the same. CONCLUSION: The present study suggests that a change in the histological class of LN is common in systemic lupus erythematosus patients with lupus flare, and the histology during disease flare could not be predicted by baseline clinical, biochemical, or pathological parameters. Our results indicate that when there is lupus flare with renal involvement, repeat renal biopsy is often necessary to guide the treatment. PMID- 21791919 TI - Reduction in protein-bound solutes unacceptable as marker of dialysis efficacy during alternate-night nocturnal hemodialysis. AB - BACKGROUND: The uremic retention solutes indoxyl sulfate and p-cresyl sulfate are linked to cardiovascular disease and overall survival. Dialytic clearances are limited, which is principally attributed to tight protein binding. Extending dialysis duration would be expected to substantially increase protein-bound uremic solute removal. The aim of the current study was to study protein-bound uremic retention solute clearances and kinetics during longer-hours nocturnal hemodialysis. METHODS: In a prospective cohort study of 32 maintenance alternate night nocturnal hemodialysis patients, we followed serum concentrations, solute removals and solute clearances of p-cresyl sulfate and indoxyl sulfate. Spent dialysate sampling was fractionated to compare solute removals between the first 4 h and next 4 h of nocturnal dialysis. Single-compartment variable volume kinetics were calculated. RESULTS: Dialytic clearances of protein-bound uremic retention solutes are maintained during nocturnal (longer-hours) dialysis. Clearances of indoxyl sulfate exceed those of p-cresyl sulfate, presumably due to less tight protein-binding. Apparent distribution volumes increase substantially during nocturnal dialysis, indicative of multi-compartmental behavior of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. CONCLUSIONS: During nocturnal hemodialysis, serum concentrations of protein-bound solute concentrations are reduced less than predicted. Reduction ratios are not a valid tool to estimate total solute removal of protein-bound uremic retention solutes. PMID- 21791920 TI - Mutation in the tight-junction gene claudin 19 (CLDN19) and familial hypomagnesemia, hypercalciuria, nephrocalcinosis (FHHNC) and severe ocular disease. AB - BACKGROUND/AIMS: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare renal tubular disorder complicated by progressive renal failure during childhood or adolescence. Recently, causative mutations in the CLDN19 gene have been identified in FHHNC patients presenting with severe ocular involvement. The aim of the study was to investigate the molecular genetic defect underlying FHHNC in a consanguineous Pakistani family. METHODS: Clinical and biochemical parameters of the proband were studied during the follow-up period over 5 years. Genotyping of 7 members of the family was performed by amplifying microsatellite markers, tightly linked to the CLDN16 and CLDN19 genes. The two genes were sequenced directly in an automated sequencer. PCR-RFLP assay and bioinformatic analysis were performed to verify the identified mutation. RESULTS: Genotyping revealed that the proband was homozygous for the marker loci tightly linked to the CLDN19 gene. Sequence analysis in the proband revealed homozygosity for a novel missense mutation in exon 3 of the CLDN19 gene (389G>A) resulting in G130D amino acid substitution. Bioinformatic analysis supported the pathogenicity of the identified mutation. Family screening revealed nephrolithiasis in 3 of 6 (50%) heterozygous carriers of the pathogenic mutation. CONCLUSION: This study supports the fundamental role of claudin 19 for magnesium homeostasis, normal tubular structures in the kidney, and undisturbed organization and development of the retina. PMID- 21791921 TI - Association of adiponectin with carotid arteriosclerosis in predialysis chronic kidney disease. AB - BACKGROUND/AIMS: Adiponectin is an adipocyte-derived protein with antiatherogenic properties. Chronic kidney disease (CKD) is one of the risk factors for cardiovascular disease. We investigated the potential association between adiponectin and carotid arteriosclerosis in patients with predialysis CKD. METHODS: We enrolled 95 CKD patients without dialysis and 81 non-CKD patients. Intima-media thickness (IMT) and plaque score (PS) in the common carotid artery were measured using an ultrasound system. Carotid arteriosclerosis was defined as IMT >1.2 mm and/or PS >5.0 mm. RESULTS: The prevalence of CKD was independently associated with carotid arteriosclerosis after adjustment for other risk factors. Higher adiponectin levels were observed in CKD patients compared with non-CKD patients. Adiponectin levels were not independently correlated with the presence of carotid arteriosclerosis in all subjects. To evaluate the association between adiponectin and carotid arteriosclerosis among a CKD population, we divided the CKD patients into 2 groups according to a cutoff level of adiponectin determined by ROC analysis. The prevalence of carotid arteriosclerosis was significantly higher in the low-adiponectin group than in the high-adiponectin group among CKD patients. After adjusting for other risk factors, low levels of adiponectin were independently correlated with carotid arteriosclerosis in CKD patients. CONCLUSION: Our data document that adiponectin is associated with increased risk of carotid atherosclerosis in a predialysis CKD population. PMID- 21791922 TI - Effects of calcimimetic combined with an angiotensin-converting enzyme inhibitor on uremic cardiomyopathy progression. AB - BACKGROUND/AIMS: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. METHODS: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R 568). A group of normal rats served as controls (NC). RESULTS: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-beta1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. CONCLUSIONS: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade. PMID- 21791923 TI - Vascular risk factors and dementia: 40-year follow-up of a population-based cohort. AB - AIMS: Our aim was to evaluate the longitudinal associations of individual and multiple vascular risk factors with the subsequent development of dementia and Alzheimer's disease (AD). METHODS: The Uppsala Longitudinal Study of Adult Men started in 1970 when the 2,268 participants were 50 years old. Baseline investigations included determinations of blood pressure, fasting glucose, cholesterol, BMI and smoking status. Over a maximum follow-up of 40 years, 349 participants were diagnosed with dementia, out of which 127 had AD. Analyses were repeated using a re-examination of the cohort at 70 years of age as a baseline. RESULTS: No associations between vascular risk factors and AD were found. For all type dementia, the association between high systolic blood pressure and dementia was the most consistent. High fasting glucose was associated with increased risk of all-type dementia only when measured at 70 years. Individuals with both an APOE epsilon4 allele and vascular risk factors had the greatest dementia risk. CONCLUSION: Vascular risk factors influence the future risk of dementia, in particular vascular and mixed-type rather than AD. The impact of vascular risk factors on dementia in a longitudinal study depends on the age at baseline and the length of follow-up. PMID- 21791924 TI - Sexually transmitted infections and sexual practices among injecting drug users in harm reduction centers in Catalonia. AB - BACKGROUND: The objectives of the study were to estimate the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae and sexual risk practices, and to identify factors associated with infection by C. trachomatis/N. gonorrhoeae. METHODS: Injecting drug users were interviewed at harm reduction centers and biological samples were collected to estimate the prevalence of C. trachomatis and N. gonorrhoeae. RESULTS: The prevalence of C. trachomatis was 2.3%, and this was higher among immigrants (3.6%); the prevalence of N. gonorrhoeae was 0.7% (no differences between Spanish-born and immigrants). Respondents aged <=25 years had a higher risk of sexually transmitted infections (STIs) (OR 3.39), as did women (OR 3.08). Also associated with having an STI were not having registered employment (OR 4.70), injecting drugs daily (OR 4.21), and having unprotected sex with a stable partner (OR 3.37). CONCLUSION: Although the prevalence of STIs observed is low, scant condom use makes it necessary for prevention programs to include messages related to sexual risk practices, especially among young people and women. PMID- 21791925 TI - Use of online conductivity monitoring to study sodium mass balance in chronic haemodialysis patients: prospects for treatment individualisation. AB - BACKGROUND: Failure to achieve isonatric haemodialysis (HD) drives an expansion of extracellular volume leading to increased interdialytic weight gain (IDWG). This may be a causative factor in the development of HD-induced cardiac injury. We examined total and diffusive sodium mass balance during HD. METHODS: 24 chronic HD patients using a fixed 140 mmol/l sodium concentration were studied over 4 weeks. Dialysate and plasma conductivity and ionic mass balance (IMB) were recorded. IMB estimates total ionic transfer across the HD membrane. RESULTS: Mean total IMB was 338 mmol indicating net sodium removal. Intrapatient variability was less than interpatient variability (coefficient of variation = 42 vs. 26%, respectively). The diffusive component of ionic mass balance (IMB(diff)) was 97 +/- 18 mmol approximating 29% (+/-22-36) of total sodium removal. IMB(diff) also correlated with both plasma conductivity and predialysis plasma sodium (r(2) = 0.82 and 0.6, respectively; p < 0.0001) as well as the reduction in plasma conductivity and plasma sodium during HD (r(2) = 0.7 and 0.5, respectively; p < 0.0001). CONCLUSION: HD against a fixed dialysate sodium concentration of 140 mmol/l results in a wide range of sodium removal with a mean of 29% removed by diffusion. Online conductivity monitoring can be utilized as part of a variety of strategies to enable the delivery of individualised and isonatric HD. Further study is required to explore the utility of such strategies which may be crucial in reducing IDWG and HD-induced cardiac injury. PMID- 21791926 TI - Functional dilatation and medial remodeling of the renal artery in response to chronic increased blood flow. AB - BACKGROUND/AIMS: Renal blood flow (RBF) is tightly regulated by several intrinsic pathways in maintaining optimal kidney blood supply. Using a rat model of aortocaval (AC) fistula, we investigated remodeling of the renal artery following prolonged increased blood flow. METHODS: An AC fistula was created in the infrarenal aorta of anesthetized rats, and changes of blood flow in the renal artery were assessed using an ultrasonic flow probe. Morphological changes and expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 in the remodeled renal artery were analyzed. RESULTS: Blood flow in the renal artery increased immediately after creation of AC fistula, but normal RBF was restored 8 weeks later. The renal artery dilated significantly 8 weeks after operation. Expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 was upregulated shortly after blood flow increase, and returned to baseline levels after 3 weeks. Histological sections showed luminal dilatation with medial thickening and endothelial cell-to-smooth muscle cell attachments in the remodeled renal artery. CONCLUSION: Increased RBF was accommodated by functional dilatation and remodeling in the medial layer of the renal artery in order to restore normal blood flow. Our results provide important mechanistic insight into the intrinsic regulation of the renal artery in response to increased RBF. PMID- 21791927 TI - Longitudinal manganese-enhanced magnetic resonance imaging of delayed brain damage after hypoxic-ischemic injury in the neonatal rat. AB - BACKGROUND: Hypoxia-ischemia (HI) in the neonatal brain results in a prolonged injury process. Longitudinal studies using noninvasive methods can help elucidate the mechanisms behind this process. We have recently demonstrated that manganese enhanced magnetic resonance imaging (MRI) can depict areas with activated microglia and astrogliosis 7 days after hypoxic-ischemic brain injury. OBJECTIVE: The current study aimed to follow brain injury after HI in rats longitudinally and compare manganese enhancement of brain areas to the development of injury and presence of reactive astrocytes and microglia. METHODS: The Vannucci model for hypoxic-ischemic injury in the neonatal rat was used. Pups were injected with either MnCl(2) or saline after 6 h and again on day 41 after HI. Longitudinal MRI (T(1) weighted) was performed 1, 3, 7 and 42 days after HI. The brains were prepared for immunohistochemistry after the final MRI. RESULTS: There was severe loss of cerebral tissue from day 7 to day 42 after HI. Most manganese-enhanced areas in the hippocampus, thalamus and basal ganglia at day 7 were liquefied after 42 days. Manganese-enhancement on day 42 corresponded to areas of activated microglia and reactive astrocytes in the remaining cortex, hippocampus and amygdala. However, the main area of enhancement was in the remaining thalamus in a calcified area surrounded by activated microglia and reactive astrocytes. CONCLUSION: Manganese-enhanced MRI can be a useful tool for in vivo identification of cerebral tissue undergoing delayed cell death and liquefaction after HI. Manganese enhancement at a late stage seems to be related to the accumulation of manganese in calcifications and gliotic tissue. PMID- 21791928 TI - Does admission hypothermia predispose to intraventricular hemorrhage in very-low birth-weight infants? AB - BACKGROUND: The etiology of intraventricular hemorrhage (IVH) in very-low-birth weight (VLBW) infants is multifactorial and is associated with low gestational age (GA) and severity of neonatal respiratory disease. The role of admission hypothermia (AHT) in the pathogenesis of IVH in VLBW infants has not yet been elucidated. We searched risk factors for IVH in VLBW infants while focusing on AHT. PATIENTS AND METHODS: VLBW infants <=33 weeks' gestation from three participating medical centers were included. From patients' medical charts we collected variables known to be associated with IVH, focusing on AHT. AHT was defined as rectal temperature <=35.5 degrees C at admission to the NICU. Head ultrasound was performed at 2-5 and 6-10 days of age and before discharge. RESULTS: 271 VLBW infants were studied. Univariate analysis showed that AHT at <=35.5 degrees C was not significantly associated with IVH (all grades; p = 0.16), but associated with IVH grade 3-4 (p = 0.034), while AHT at <=35 degrees C was significantly associated with IVH (p = 0.036) and with IVH grade 3-4 (p = 0.003). Multivariate logistic regression analysis showed that AHT (at <=35.5 and at <=35 degrees C) were not associated with IVH. Only four variables were independently significantly associated with IVH: GA, use of nitric oxide, hypocarbia and base deficit >10. Four variables were strongly associated with severe IVH (grades 3-4): GA, hypotension, base deficit >10 and hyponatremia. CONCLUSIONS: In VLBW infants, AHT at <=35.5 and at <=35.0 degrees C were not significantly associated with IVH. GA, use of nitric oxide, hypocarbia and base deficit >10 were strongly associated with IVH. PMID- 21791929 TI - Low birth weight is associated with reduced nephron number and increased blood pressure in adulthood in a novel spontaneous intrauterine growth-restricted model in Yucatan miniature Swine. AB - BACKGROUND: Impaired fetal growth and rapid postnatal growth are associated with programming of hypertension and metabolic syndrome in adulthood. OBJECTIVES: This study evaluated this phenomenon in a novel spontaneous intrauterine growth restricted (IUGR) model in Yucatan miniature pigs. METHODS: IUGR piglets (n = 6, 3 days old, 0.73 +/- 0.11 kg) were paired with a normal weight (NW) same-sex littermate (n = 6, 1.11 +/- 0.13 kg), fed milk replacer for 4 weeks followed by a standard diet ad libitum for 5 h/day. At 9 months of age, arterial blood pressure (BP) telemeters were implanted to assess BP before (0.5% NaCl) and after (4.5% NaCl) a 7-day salt-loading period. At 10 months of age, nephron numbers were determined. RESULTS: Prior to sexual maturity, IUGR pigs showed greater (p < 0.05) relative feed intake and experienced significant catch-up growth. Adult IUGR pigs also had higher BP (diastolic BP: 93.8 +/- 5.5 vs. 90.0 +/- 8.7 mm Hg, p < 0.05) and 43% fewer nephrons per kidney (p < 0.05). Nephron number was positively associated with birth weight and negatively correlated with BP (p < 0.05). Acute salt loading increased BP in both groups (p < 0.05); however, the degree of salt sensitivity was similar between groups (p > 0.05). CONCLUSIONS: In conclusion, IUGR piglets have reduced nephron endowment associated with a modest BP increase in early adulthood. This new model can be used to conduct longitudinal mechanistic studies on the early programming phenomenon. PMID- 21791930 TI - Early transient hypoglycemia is associated with increased albumin nitration in the preterm infant. AB - BACKGROUND: The clinical significance of early transient hypoglycemia (ETH), a frequent event in preterm newborns, is a highly controversial issue. In experimental models, hypoglycemia has been reported to cause oxidative stress. Among the reactive species, early generated peroxynitrite is responsible for protein nitration and lipid peroxidation, a process referred to as nitrative stress. OBJECTIVES: The aim of the present study is to investigate whether ETH is associated with protein nitration in the preterm newborn. METHODS: Using a novel highly sensitive ELISA, we quantified plasma nitroalbumin (PNA) as a marker of peroxynitrite generation in 72 preterm newborns (28-36 weeks), among which 25 had a glycemia level of <2.5 mmol/l during the first hour of life (H1). RESULTS: PNA was significantly higher in ETH than in normoglycemic infants at H1 [median = 6.3 (3.8-8.8) vs. 3.4 ng/ml (2.1-5.1), p = 0.027] and at day 1 [median = 6.6 (5.6 15.3) vs. 3.9 ng/ml (2.3-4.6), p = 0.014]. PNA was inversely correlated with glycemia at H1 (r = -0.30, p = 0.01) and at day 1 (r = -0.63, p = 0.001). In ETH infants, lactatemia was inversely correlated with PNA. At day 1, PNA was higher in ETH infants treated by gavage than in those treated with intravenous dextrose [median = 8.9 ng/ml (7.1-10.4) vs. 4.4 ng/ml (2.6-5.7), p = 0.008]. CONCLUSIONS: These results indicate that ETH is associated with increased peroxynitrite generation resulting in systemic protein nitration in premature newborns. Treatment of ETH with intravenous dextrose is associated with lower PNA levels than gavage. PMID- 21791932 TI - Cow's milk and the emergence of group B streptococcal disease in newborn babies. AB - BACKGROUND: Group B streptococcus (GBS), the most significant cause of neonatal bacterial sepsis, is thought to have emerged in the 1960s. GBS also causes mastitis in cows, and there is indirect evidence that human GBS is derived from a bovine ancestor. OBJECTIVE: A major change in the collection of milk from farms, using bulk tanks rather than churns, occurred in the 1960s. We sought to define the temporal relationship between this change in farming and the emergence of GBS neonatal disease. METHODS: We searched PubMed for reports of GBS disease from 1930 until 1980 to more exactly determine the time of emergence of neonatal infection and supported this data with UK hospital admission statistics for GBS infections. We identified the dates of the change from churns to bulk tanks by searching the internet and books for information on the history of milk transportation, farming and milk collection in the UK. RESULTS: There are no PubMed reports of neonatal GBS disease between 1930 and 1950, and reports from the UK only emerged in the mid-1960s, confirming the notion that GBS neonatal infection was a newly emergent disease in the 1960s. No national data on hospital admissions are available around this time, but the Oxford Record Linkage Study, with admission data available for Oxford from 1968, showed no cases of neonatal disease until 1974. Cow's milk collection in the UK switched to bulk tank between 1960 and 1979, and publications relating to GBS disease emerged soon after. CONCLUSIONS: There is a temporal relationship between the emergence of neonatal GBS disease reports in the UK in the 1960s and a change in cow's milk collection. This finding may be a temporal coincidence or may add support to the notion that human GBS was historically derived from a bovine ancestor. PMID- 21791931 TI - Birthweight centile charts for South Asian infants born in the UK. AB - BACKGROUND: UK-born infants of South Asian ethnic origin are known to have lower birthweights than their White British counterparts. When plotted on currently used birthweight charts they can be misclassified as small for gestational age. Similarly, large for gestational age infants can be missed. This has important clinical implications in their management. OBJECTIVE: To create birthweight centile charts for the UK-born South Asian infants to identify true small and large for gestational age infants. METHODS: A retrospective cross-sectional analysis of infants born 1 January 2003 to 31 December 2006 was undertaken. The birthweights of the South Asian and White British infants were compared. The LMS method was used to construct centile charts for the South Asian infants. RESULTS: 24,274 White British and 7,190 South Asian infants were included in the analysis. Overall, the South Asian males were 9-15% lighter than the White British males and the South Asian females were 9-13% lighter than the White British females. At term, the median birthweight for South Asian males was 329 g lower than that for White British males and for South Asian females 295 g less than the White British females. CONCLUSION: There are significant differences in the birthweights of White British and UK-born South Asian infants. Hence the standard birthweight centile charts which were designed using the birthweight data of White British infants appear to misclassify a proportion of South Asian infants. Use of ethnic specific birthweight charts would allow better detection of truly growth restricted and macrosomic South Asian infants. PMID- 21791933 TI - Biomarkers in neonatal posthemorrhagic hydrocephalus. AB - Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH. PMID- 21791934 TI - Advanced clinical medicine requires advanced clinical ethics. AB - Many advances have occurred in clinical medicine in the last decades. Solid organ transplants, corrective surgery for congenital malformations, improved cytostatic regimes for children with cancer, and respiratory care for premature infants are but a few examples of the changing face of medical practice. Such changes have added years to life. But along the way many patients have paid a price, both in terms of loss of life and of added suffering. Even today, some survivors are faced with a life of impairment and suffering. Follow-up studies of extremely low birth-weight infants show that the smallest infants have a high rate of severe sequelae. Some argue that such suffering should be sufficient reason to make us desist from further attempts to advance the frontiers of therapy. This paper seeks to reflect on the character of advanced medicine and on how we relate to patients and their kin in our quest for further improvements in therapy. The price for continued advances will inevitably be paid by some patients who will not profit from them. Therefore, patients who are asked to participate in such a quest must receive honest and transparent information, including a discussion about where and how they would draw the limits. Clinical competency is a core concept in advanced medicine, but a caring comportment also demands that our relationship to the patient be characterized by honesty, integrity, and decency. In dialogue with parents, finding the right balance between parental exercise of autonomy and safe-guarding the best interest of the child remains a challenge. PMID- 21791935 TI - Discrepancies between arterial oxygen saturation and functional oxygen saturation measured with pulse oximetry in very preterm infants. AB - BACKGROUND: Discrepancies between pulse oximetry saturation (SpO(2)) and arterial saturation (SaO(2)) at low blood oxygenation values have been previously reported with significant variations among instruments and studies. Whether pulse oximeters that attenuate motion artifact are less prone to such discrepancies is not well known. OBJECTIVE: To prospectively assess the agreement of the Masimo V4 pulse oximeter within the critical 85-95% SpO(2) target range. PATIENTS AND METHODS: For all consecutive babies with gestational age <33 weeks, postnatal age <7 days, and an umbilical arterial line, SpO(2) was measured continuously and SaO(2) analyzed on an as-needed basis. Bland-Altman techniques provided estimates of the difference (D = SaO(2) - SpO(2)), standard deviation (SD), and 95% limits of agreement (D +/- 2*SD). RESULTS: There were 1,032 measurements (114 babies) with SpO(2) between 85 and 95%. The 95% limits of agreement were -2.0 +/- 5.8, 2.4 +/- 9.2, and -1.9 +/- 5.3 in the SpO(2) categories 85-95, 85-89, and 91-95%, respectively. For the SpO(2) categories 85-89% and 91-95%, only 52% (53/101) and 59% (523/886) of SpO(2) values, respectively, corresponded to the analogous SaO(2) categories. In the 85-89% SpO(2) category, SaO(2) was lower than 85% in 39 of the 101 (39%) measurements. CONCLUSION: SaO(2) was lower on average than SpO(2) with an increased bias at lower saturation. The -2.4 +/- 9.2 95% limits of agreement for SaO(2) - SpO(2) in the 85-89% SpO(2) category suggest that SpO(2) and SaO(2) are not interchangeable and intermittent SaO(2) assessments are warranted when the targeted SpO(2) is within this range. PMID- 21791936 TI - Indomethacin impairs coronary perfusion in infants with hemodynamically significant ductus arteriosus. AB - BACKGROUND: A haemodynamically significant ductus arteriosus (HSDA) is commonly associated with morbidity in preterm infants. AIM: To study the effect of the first dose of indomethacin on coronary blood flow in preterm neonates diagnosed with an HSDA. METHOD: A prospective observational echocardiographic study was performed on preterm infants. A single study dose of intravenous indomethacin (0.1 mg/kg) was administered over 1 h. Serial echocardiography was performed before and after indomethacin treatment to study the effect on coronary artery perfusion and cardiovascular performance. RESULTS: Eighteen infants born at a median gestation of 25.8 (24.2, 28.1) weeks and a birth weight of 773 g (704, 1,002) were evaluated. The median age at indomethacin administration was 7.5 days (4, 17). There was no significant change in arterial pressure or ventilatory indices. Left anterior descending artery diastolic velocity and time integral declined from 0.3 +/- 0.1 and 3.19 +/- 1.2 m/s to 0.22 +/- 0.08 and 2.01 +/- 0.9 m/s, respectively, within 10 min of completion of infusion. These indices showed partial recovery when reassessed after 60 min. There were no changes in left ventricular output or transductal flow. CONCLUSIONS: Intravenous indomethacin was followed by a decline in coronary arterial diastolic blood flow. PMID- 21791937 TI - Effect of a phosphodiesterase 5 inhibitor on pulmonary and cerebral arteries of newborn piglets with chronic hypoxia-induced pulmonary hypertension. AB - BACKGROUND: The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations. OBJECTIVES: To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA. METHODS: Two day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined. RESULTS: Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure diameter relationships (autoregulation) did not differ between the groups. CONCLUSIONS: Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia. PMID- 21791938 TI - Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. AB - BACKGROUND: Despite the potential importance of pulmonary artery hypertension (PAH) in preterm infants with bronchopulmonary dysplasia (BPD), little is known about the risk factors for PAH. OBJECTIVES: To investigate the risk factors for PAH in preterm infants with BPD. METHODS: Infants diagnosed with BPD were assigned to the PAH group or non-PAH group except for infants with mild BPD who had no PAH. PAH was diagnosed on the basis of echocardiograms demonstrating elevated right ventricle pressure beyond the postnatal age of 2 months. Logistic regression analysis was done for the multivariate assessment of the risk factors for PAH in preterm infants with moderate or severe BPD. RESULTS: A total of 98 infants among 145 infants with BPD were divided into a PAH group (n = 25) or non PAH group (n = 73), while the remaining 47 infants had mild BPD with no PAH. Among the study patients, survival rate of the PAH group was significantly lower than that of the non-PAH group. Infants with PAH had more severe cases of BPD and underwent longer durations of oxygen therapy, conventional or high-frequency ventilation, and hospitalization compared to those without PAH. Low 5-min Apgar scores (<=6; relative risk (RR) 6.2; 95% confidence interval (CI) 1.4-28.0; p = 0.017) and oligohydramnios (RR 7.7; 95% CI 2.0-29.6; p = 0.030) were found to be significant risk factors for PAH according to multivariate analysis. CONCLUSIONS: The present study shows that oligohydramnios is a specific risk factor for PAH in preterm infants with moderate or severe BPD. PMID- 21791939 TI - Activation of the renin-angiotensin system in hyperoxia-induced lung fibrosis in neonatal rats. AB - BACKGROUND: Oxygen toxicity plays an important role in lung injury and may lead to bronchopulmonary dysplasia. We previously demonstrated that hyperoxia activated the renin-angiotensin system (RAS) in cultured human fetal lung fibroblasts. OBJECTIVE: To examine whether the upregulation of RAS components is associated with hyperoxia-induced lung fibrosis in neonatal Sprague-Dawley rats. METHODS: Experimental rat pups were exposed to 1 week of >95% O(2) and a further 2 weeks of 60% O(2). Control pups were exposed to room air over the same periods. Lung tissues were taken for biochemical and histochemical assays on postnatal days 7 and 21. RESULTS: Hyperoxia significantly increased total collagen content and the expression of type I collagen and alpha smooth muscle actin when compared to control rats. RAS components including angiotensinogen, angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor were significantly upregulated by hyperoxia. The results also demonstrated that only the extracellular signal-regulated kinase (ERK) signaling pathway was activated by hyperoxia exposure. p38 mitogen-activated protein kinase and c-Jun N-terminal kinase were not activated. CONCLUSIONS: Local RAS activation is involved in the pathogenesis of hyperoxia-induced lung fibrosis in neonatal rats. ERK phosphorylation might mediate angiotensin II type 1 receptor activation. PMID- 21791940 TI - Optimal techniques for mRNA extraction from neonatal salivary supernatant. AB - BACKGROUND: Gene expression profiling of the salivary supernatant is emerging as a new and important source of real-time, systemic, biological information. However, existing technologies prevent RNA extraction of small quantities found in neonatal salivary supernatant. OBJECTIVE: The aim of this study was to develop techniques to enhance extraction of cell-free RNA from neonatal salivary supernatant. METHODS: Two saliva samples (10-100 MUl) were serially collected from newborns (36-41 weeks' gestation) (n = 13) and stabilized. Total RNA was extracted from salivary supernatant with the use of two modified extraction techniques: Qiagen RNAprotect(r) Saliva Mini Kit (method 1) and the QIAamp Viral RNA Mini Kit (method 2). Quantitative RT-PCR amplification for GAPDH was performed on extracted salivary samples. Statistical analyses were performed on mean threshold cycle (Ct) levels to compare RNA yield from each protocol. Paired microarray analyses were made between neonatal whole saliva and supernatant (n = 3) to discern gene expression differences between these biolayers. RESULTS: mRNA was successfully extracted and amplified from all salivary supernatant samples. Extraction with method 2 yielded more RNA than with method 1 (p = 0.008). There was a 7.5% discordance between paired gene expression analyses for whole saliva and supernatant. Genes that were statistically significantly upregulated in supernatant highlighted 16 distinct biological functions not seen in whole saliva. Conversely, only two biological functions were unique to whole saliva. CONCLUSION: Neonatal cell-free salivary supernatant mRNA may be readily extracted and utilized on downstream applications. These technical enhancements allow for further exploration of the diagnostic potential of the neonatal salivary transcriptome. PMID- 21791941 TI - Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors. AB - OBJECTIVE: Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. METHODS: 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. RESULTS: All patients demonstrated (177)Lu DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. CONCLUSIONS: SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc EDDA/HYNIC-TOC. PMID- 21791942 TI - Ifosfamide, carboplatin and etoposide in recurrent malignant glioma. AB - After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse. PMID- 21791943 TI - The diagnostic value of cytokeratin 5/6, 14, 17, and 18 expression in human non small cell lung cancer. AB - OBJECTIVES: The expression patterns of cytokeratin (CK) filaments in human epithelial neoplasms are complex and distinctive. The aims of this study were to analyze CK expression and to evaluate the diagnostic application of CKs in human non-small cell lung cancer (NSCLC). METHODS: mRNA expression of CK5, CK6, CK14, CK15, CK17, and CK19 was analyzed by Northern blotting. Protein expression of CK5/6, CK7, CK14, CK17, and CK18 was evaluated by immunohistochemistry on tissue microarrays. RESULTS: Northern blotting showed that CKs were highly expressed in human bronchial epithelial cells and/or small airway epithelial cells. In NSCLC cell lines, the expression pattern of CKs was heterogeneous. Regarding protein expression of CKs in 95 primary lung tumors, expression of CK5/6, CK14, and CK17 proteins was increased in squamous cell carcinomas compared to adenocarcinomas (ADC; p = 0.001, p = 0.030, and p = 0.001, respectively), and higher expression was significantly associated with lower grading (p = 0.006, p = 0.002, and p = 0.001, respectively), while increased expression of CK7 and CK18 was observed in ADC (p = 0.001, respectively). CONCLUSIONS: Our data suggest that CK5/6, CK7, CK14, CK17, and CK18 have diagnostic value in the subclassification of NSCLC. PMID- 21791944 TI - Molecular class as a predictor of locoregional and distant recurrence in the neoadjuvant setting for breast cancer. AB - BACKGROUND: The molecular subtype by hormone receptor status predicts recurrence in the adjuvant setting. Here, we report recurrence patterns by molecular subtype following neoadjuvant chemotherapy (NACT) to identify subgroups prone to recurrence. MATERIALS AND METHODS: We retrospectively analyzed 331 patients receiving NACT plus lumpectomy and whole breast radiation therapy (RT) (n = 155), or mastectomy with (n = 122) or without (n = 50) adjuvant RT. Tumors were classified by immunohistochemical (IHC) surrogate markers into luminal A (strong ER+/PR+; HER2-), luminal B (weak-to-moderate ER+/PR+; HER2-), HER2 (HER2+), and triple-negative/basal subtypes. RESULTS: The median follow-up was 43 months (range 10-104). The 5-year disease-free survival (DFS) was 71.4, 70.1, 70.4, and 62.1% for luminal A, luminal B, HER2, and basal subtypes, respectively. The 5 year distant recurrence rates were 25.8, 28.7, 28.7, and 35.2%. The 5-year locoregional recurrence rates were 3.8, 1.6, 1.3, and 4.2%. Molecular class (p = 0.003) and pathologic complete response (pCR; p = 0.004) predicted distant recurrence, DFS, and overall survival (OS). Only the omission of adjuvant RT following mastectomy (p = 0.006) predicted locoregional recurrence. CONCLUSIONS: IHC subclassification and pCR predict distant failure, DFS, and OS in the neoadjuvant setting. While not predictive of locoregional recurrence, the total number of events were small. More work is needed to define if molecular class can predict patients at risk for locoregional recurrence. PMID- 21791945 TI - Bevacizumab in the treatment of advanced, non-squamous non-small cell lung cancer: an evidence-based approach. AB - BACKGROUND: To assess the efficacy and safety of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous non-small cell lung cancer (NSCLC) on the basis of the two registrative trials [ECOG E4599 trial and BO17704 (AVAiL) trial]. METHODS: A pooled analysis of the two trials was performed using a random effect model, and the results were summarized as number needed-to-treat (NNT) and number-needed-to-harm (NNH). A 2-step analysis was performed. The primary analysis included only the patients treated with bevacizumab 15 mg/kg in the experimental arm, whereas the secondary analysis (with descriptive aim) included the patients treated with bevacizumab 15 mg/kg or those treated with bevacizumab 7.5 mg/kg in the experimental arm. The 1-year survival and 6-month progression-free rates were assumed as indexes of efficacy, and grade III-IV side effects were assumed as index of safety in both analyses. RESULTS: 1,921 patients were potentially eligible for the pooled analysis and were included in the secondary analysis, whereas 1,576 patients were included in the primary analysis. A large heterogeneity was documented for both 6-month progression-free interval (I(2) = 88.164%, p = 0.004) and overall survival (I(2) = 73.541, p = 0.052). The absolute risk reduction of 1-year death and 6-month progression were 3.3% (95% CI = -6.5 to 13.2%, p = 0.507), with a NNT = 30; and 15.2% (95% CI = 0.07-29.6%, p = 0.04), with a NNT = 6 (both in favor of the bevacizumab-containing regimens), respectively. The absolute risk of treatment related death was 2.4% (95% CI = 0.8-3.9%, p = 0.003), with a NNH = 41 against the bevacizumab-containing regimens; that of bleeding was 3.3% (95% CI = 1.6 4.9%, p < 0.001), with a NNH = 30; that of hypertension was 6.6% (95% CI = 4.6 8.6%, p < 0.001), with a NNH = 15; that of proteinuria was 2.1% (95% CI = 0.3 3.8%, p = 0.024), with a NNH = 47; that of neutropenia was 7.3% (95% CI = 3.2 11.4%, p < 0.001), with a NNH = 13; that of thrombocytopenia was 1.5% (95% CI = 0.2-2.7%, p = 0.021), with a NNH = 66. No significant differences were observed in the efficacy and the safety analysis when all the patients treated with bevacizumab 7.5 mg/kg and 15 mg/kg were included into the pooled analysis. CONCLUSION: Adding bevacizumab to standard chemotherapy in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC seems to favor a modest improvement in the main outcomes, with a significant worsening of the safety profile. These data suggest caution in the generalized use of bevacizumab containing regimens in the treatment of advanced, chemotherapy-naive, non squamous NSCLC. PMID- 21791946 TI - Circulating sex hormones modulate vascular contractions and acute response to 17beta-estradiol in rat mesenteric arteries. AB - AIMS: We investigated how modification of levels of the sex hormones 17beta estradiol and testosterone affects vascular contraction and nongenomic vascular effects of 17beta-estradiol. METHODS: Male and female rats were treated with vehicle, 17beta-estradiol (25 MUg/kg/day) or testosterone (1 mg/kg/day) for 14 consecutive days after sham gonadectomy or gonadectomy was performed. Isometric tensions were then measured from mesenteric arteries of each group of rats. RESULTS: Contraction to phenylephrine was increased in mesenteric arteries from rats with or without gonadectomy treated with testosterone for 14 days compared to their intact controls. Contraction to phenylephrine was reduced in mesenteric arteries of rats with or without gonadectomy treated with 17beta-estradiol for 14 days compared to their intact controls. Incubation of mesenteric arteries with 17beta-estradiol (1 nmol/l) for 30 min reduced contraction to phenylephrine in mesenteric arteries of rats that were treated with testosterone for 14 days. This acute incubation of 17beta-estradiol had no effect on arteries from rats that were treated with 17beta-estradiol for 14 days. The acute effect of 17beta estradiol (1 nmol/l) is preserved in arteries without endothelium. CONCLUSION: Our results suggest that 14 days' testosterone treatment enhances while 14 days' 17beta-estradiol treatment suppresses contraction as well as the nongenomic effects of 17beta-estradiol in the vascular smooth muscles. PMID- 21791947 TI - Subcutaneous peripheral neurostimulation for the treatment of severe chronic poststernotomy neuralgia. AB - OBJECTIVE: Poststernotomy pain frequently develops after sternotomy in thoracic and cardiovascular surgery, and may affect patients' quality of life. In some cases of severe poststernotomy neuralgia, pharmacologic therapy does not provide adequate relief. CASE REPORT: We report on a 42- year-old woman who underwent sternotomy for aortic and mitral valve replacement. She developed severe chronic poststernotomy neuralgia that was refractory to medical treatment. After local anesthesia markedly but only transiently alleviated pain, we considered the option of subcutaneous peripheral neurostimulation (SPNS). Plate electrodes were implanted bilaterally in the parasternal region at the site of maximal pain. After a period of test stimulation, the electrodes were connected to a dual channel implantable pulse generator. SPNS induced paresthesias in the painful area. Revision surgery was necessary twice because of electrode migration. Chronic SPNS markedly alleviated pain (visual-analog scale, VAS, 9/10 preoperatively, 2/10 postoperatively) and allodynia (VAS 9/10 preoperatively, 2/10 postoperatively) at the last available follow-up, 15 months postoperatively. CONCLUSIONS: SPNS may be a viable treatment option in patients with severe chronic poststernotomy neuralgia. PMID- 21791948 TI - Can the clinical outcome of deep brain stimulation be predicted? PMID- 21791950 TI - Conditional knockout of Lgr4 leads to impaired ductal elongation and branching morphogenesis in mouse mammary glands. AB - We have analyzed the function of LGR4 in the development of various mouse epithelial tissues. Here we first report the retarded invasion of mammary ducts into the fat pad observed in Lgr4(K5 KO) mice at 4 weeks, compared with that of age-matched Lgr4(K5 ctrl). Furthermore, we demonstrate a significant decrease in mammary ductal branching in Lgr4(K5 KO) at several stages (4, 6 and 8 weeks). On the other hand, immunohistochemical analysis of the mammary gland of Lgr4(K5 KO) using anti-alphaSMA, anti-K18 and anti-laminin antibodies showed structures similar to those of Lgr4(K5 ctrl) mammary glands. In addition, we did not detect significant differences in the expression of ERalpha, which was suggested to be a downstream molecule of LGR4, and Lgr4(K5 KO) showed no retarded invasion in the response to 17beta-estradiol administration. Furthermore, the phosphorylated form of Smad1/5/8 was normally detected in the mammary gland of Lgr4(K5 KO). PMID- 21791949 TI - Gonadal development and tumor formation at the crossroads of male and female sex determination. AB - Malignant germ cell tumor (GCT) formation is a well-known complication in the management of patients with a disorder of sex development (DSD). DSDs are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD patients in whom the karyotype - at least at the gonadal level - contains (a part of) the Y chromosome are at increased risk for neoplastic transformation of germ cells, leading to the development of the so called 'type II germ cell tumors'. However, tumor risk in the various forms of DSD varies considerably between the different diagnostic groups. This contribution integrates our actual knowledge on the pathophysiology of tumor development in DSDs, recent findings on gonadal (mal)development in DSD patients, and possible correlations between the patient's phenotype and his/her risk for germ cell tumor development. PMID- 21791951 TI - A new esterase, belonging to hormone-sensitive lipase family, cloned from Rheinheimera sp. isolated from industrial effluent. AB - The gene for esterase (rEst1) was isolated from a new species of genus Rheinheimera by functional screening of E. coli cells transformed with the pSMART/HaeIII genomic library. E. coli cells harboring the esterase gene insert could grow and produce clear halo zones on tributyrin agar. The rEst1 ORF consisted of 1,029 bp, corresponding to 342 amino acid residues with a molecular mass of 37 kDa. The signal P program 3.0 revealed the presence of a signal peptide of 25 amino acids. Esterase activity, however, was associated with a homotrimeric form of molecular mass 95 kDa and not with the monomeric form. The deduced amino acid sequence showed only 54% sequence identity with the closest lipase from Cellvibrio japonicus strain Ueda 107. Conserved domain search and multiple sequence alignment revealed the presence of an esterase/ lipase conserved domain consisting of a GXSXG motif, HGGG motif (oxyanion hole) and HGF motif, typical of the class IV hormone sensitive lipase family. On the basis of the sequence comparison with known esterases/ lipases, REst1 represents a new esterase belonging to class IV family. The purified enzyme worked optimally at 50 degrees C and pH 8, utilized pNP esters of short chain lengths, and showed best catalytic activity with p-nitrophenyl butyrate (C4), indicating that it was an esterase. The enzyme was completely inhibited by PMSF and DEPC and showed moderate organotolerance. PMID- 21791952 TI - Improvement of transformation efficiency by strategic circumvention of restriction barriers in Streptomyces griseus. AB - DNA methylation in Streptomyces griseus IFO 13350 was analyzed by high performance liquid chromatographic analysis and bisulfite-based analysis to reveal two methylation sites, 5'-GC5mCGGC-3' and 5'-GAG5mCTC-3'. The methylation was reconstituted in Escherichia coli by simultaneous expression of S. griseus SGR4675 and S. achromogenes M.SacI. The E. coli cells produced plasmids that mimicked the methylation profile of S. griseus DNA, which was readily introduced into S. griseus. The results of this study raise the possibility of a promising approach to establish efficient transformation in several streptomycetes. PMID- 21791953 TI - Homologous expression and quantitative analysis of T3SS-dependent secretion of TAP-tagged XoAvrBs2 in Xanthomonas oryzae pv. oryzae induced by rice leaf extract. AB - Xanthomonas oryzae pv. oryzae (Xoo) produces a putative effector, XoAvrBs2. We expressed XoAvrBs2 homologously in Xoo with a TAP-tag at the C-terminus to enable quantitative analysis of protein expression and secretion. Addition of rice leaf extracts from both Xoo-sensitive and Xoo-resistant rice cultivars to the Xoo cells induced expression of the XoAvrBs2 gene at the transcriptional and translational levels, and also stimulated a remarkable amount of XoAvrBs2 secretion into the medium. In a T3SS-defective Xoo mutant strain, secretion of the TAPtagged XoAvrBs2 was blocked. Thus, we elucidated the transcriptional and translational expressions of the XoAvrBs2 gene in Xoo was induced in vitro by the interaction with rice and the induced secretion of XoAvrBs2 was T3SSdependent. It is the first report to measure the homologous expression and secretion of XoAvrBs2 in vitro by rice leaf extract. Our system for the quantitative analysis of effector protein expression and secretion could be generally used for the study of host-pathogen interactions. PMID- 21791954 TI - The plant growth-promoting fungus Aspergillus ustus promotes growth and induces resistance against different lifestyle pathogens in Arabidopsis thaliana. AB - To deal with pathogens, plants have evolved sophisticated mechanisms including constitutive and induced defense mechanisms. Phytohormones play important roles in plant growth and development, as well as in the systemic response induced by beneficial and pathogen microorganisms. In this work, we identified an Aspergillus ustus isolate that promotes growth and induces developmental changes in Solanum tuberosum and Arabidopsis thaliana. A. ustus inoculation on A. thaliana and S. tuberosum roots induced an increase in shoot and root growth, and lateral root and root hair numbers. Assays performed on Arabidopsis lines to measure reporter gene expression of auxin-induced/ repressed or cell cycle controlled genes (DR5 and CycB1, respectively) showed enhanced GUS activity, when compared with mock-inoculated seedlings. To determine the contribution of phytohormone signaling pathways in the effect elicited by A. ustus, we evaluated the response of a collection of hormone mutants of Arabidopsis defective in auxin, ethylene, cytokinin, or abscisic acid signaling to the inoculation with this fungus. All mutant lines inoculated with A. ustus showed increased biomass production, suggesting that these genes are not required to respond to this fungus. Moreover, we demonstrated that A. ustus synthesizes auxins and gibberellins in liquid cultures. In addition, A. ustus induced systemic resistance against the necrotrophic fungus Botrytis cinerea and the hemibiotrophic bacterium Pseudomonas syringae DC3000, probably through the induction of the expression of salicylic acid, jasmonic acid/ethylene, and camalexin defense-related genes in Arabidopsis. PMID- 21791955 TI - Isolation and characterization of a mesophilic Arthrospira maxima strain capable of producing docosahexaenoic acid. AB - A strain of the cyanobacterium Arthrospira was isolated from Lake Chahannaoer in northern China and was characterized according to microscopic morphology, photosynthetic oxygen-evolving activity, growth rate, and nutritional profile. Compared with thermophilic Arthrospira species occurring naturally in tropical and subtropical lakes, this isolate is mesophilic and grows optimally at ~20 degreesC. The total protein, fatty acid, phycocyanin, carotenoid, and chlorophyll a contents were 67.6, 6.1, 4.32, 0.29, and 0.76 grams per 100 grams of dry weight, respectively. The strain is rich in polyunsaturated fatty acids (PUFAs). An essential omega-3 fatty acid, docosahexaenoic acid (DHA), was detected, and gamma-linolenic acid (GLA) and DHA accounted for 28.3% of the total fatty acid content. These features of this newly isolated strain make it potentially useful in commercial mass culture in local areas or as a biofuel feedstock. It is also an alternative resource for studying the metabolic PUFA pathways and mechanisms of cold stress tolerance in cyanobacteria. PMID- 21791956 TI - Simultaneous saccharification and fermentation of ground corn stover for the production of fuel ethanol using Phanerochaete chrysosporium, Gloeophyllum trabeum, Saccharomyces cerevisiae, and Escherichia coli K011. AB - Enzymatic saccharification of corn stover using Phanerochaete chrysosporium and Gloeophyllum trabeum and subsequent fermentation of the saccharification products to ethanol by Saccharomyces cerevisiae and Escherichia coli K011 were achieved. Prior to simultaneous saccharification and fermentation (SSF) for ethanol production, solid-state fermentation was performed for four days on ground corn stover using either P. chrysosporium or G. trabeum to induce in situ cellulase production. During SSF with S. cerevisiae or E. coli, ethanol production was the highest on day 4 for all samples. For corn stover treated with P. chrysosporium, the conversion to ethanol was 2.29 g/100 g corn stover with S. cerevisiae as the fermenting organism, whereas for the sample inoculated with E. coli K011, the ethanol production was 4.14 g/100 g corn stover. Corn stover treated with G. trabeum showed a conversion 1.90 and 4.79 g/100 g corn stover with S. cerevisiae and E. coli K011 as the fermenting organisms, respectively. Other fermentation co products, such as acetic acid and lactic acid, were also monitored. Acetic acid production ranged between 0.45 and 0.78 g/100 g corn stover, while no lactic acid production was detected throughout the 5 days of SSF. The results of our experiment suggest that it is possible to perform SSF of corn stover using P. chrysosporium, G. trabeum, S. cerevisiae and E. coli K011 for the production of fuel ethanol. PMID- 21791957 TI - Characterization of cellobiohydrolase from a newly isolated strain of Agaricus arvencis. AB - A highly efficient cellobiohydrolase (CBH)-secreting basidiomycetous fungus, Agaricus arvensis KMJ623, was isolated and identified based on its morphological features and sequence analysis of internal transcribed spacer rDNA. An extracellular CBH was purified to homogeneity from A. arvencis culture supernatant using sequential chromatography. The relative molecular mass of A. arvencis CBH was determined to be 65 kDa by SDSPAGE and 130 kDa by size-exclusion chromatography, indicating that the enzyme is a dimer. A. arvencis CBH showed a catalytic efficiency (kcat/Km) of 31.8 mM-1 s-1 for p-nitrophenyl-beta-D cellobioside, the highest level seen for CBH-producing microorganisms. Its internal amino acid sequences showed significant homology with CBHs from glycoside hydrolase family 7. Although CBHs have been purified and characterized from other sources, A. arvencis CBH is distinguished from other CBHs by its high catalytic efficiency. PMID- 21791958 TI - Effect of adjuvants on antibody titer of synthetic recombinant light chain of botulinum neurotoxin type B and its diagnostic potential for botulism. AB - Botulism is a neuroparalytic disease caused by Clostridium botulinum, which produces seven (A-G) antigenically diverse neurotoxins (BoNTs). BoNTs are the most poisonous substances known to humans, with a median lethal dose (LD50) of approximately 1 ng/kg of body weight. Owing to their extreme potency and lethality, they have the potential to be used as a bioterrorism agent. The mouse bioassay is the gold standard for the detection of botulinum neurotoxins; however, it requires at least 3-4 days for completion. Attempts have been made to develop an ELISA-based detection system, which is potentially an easier and more rapid method of botulinum neurotoxin detection. The present study was designed using a synthetic gene approach. The synthetic gene encoding the catalytic domain of BoNT serotype B from amino acids 1-450 was constructed with PCR overlapping primers (BoNT/B LC), cloned in a pQE30 UA vector, and expressed in an E. coli M15 host system. Recombinant protein production was optimized at 0.5 mM IPTG final concentration, 4 h post induction, resulting in a maximum yield of recombinant proteins. The immunogenic nature of the recombinant BoNT/B LC protein was evaluated by ELISA. Antibodies were raised in BALB/c mice using various adjuvants. A significant rise in antibody titer (p<0.05) was observed in the Alum group, followed by the Titermax Classic group, Freund's adjuvant, and the Titermax Gold group. These developed high-titer antibodies may prove useful for the detection of botulinum neurotoxins in food and clinical samples. PMID- 21791959 TI - Endophytic fungi as a source of biofuel precursors. AB - Endophytic fungi, isolated from a number of different species of tropical plants, were investigated for lipid biodiesel precursor production. The extracts produced from liquid cultures of these fungi were subjected to acidcatalyzed transesterification reactions with methanol producing methyl esters and then analyzed through chromatographic (GC-FID) and spectrometric techniques (MS, NMR 1H). The European Standard Method, EN 14103, was used for the quantification of methyl esters extracted from the fungi of the species and genera studied. Xylariaceous fungi exhibited the highest concentrations of methyl esters (91%), and hence may be a promising source for biofuel. PMID- 21791960 TI - Purification of capsular polysaccharide produced by Streptococcus pneumoniae serotype 19A. AB - Streptococcus pneumoniae is a major cause of invasive infection in young infants and older adults. There are currently 90 capsular serotypes identified and 23 serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F) are responsible for about 90% of invasive disease. Among the more than 90 different S. pneumoniae serotypes, serotype 19A is globally very prevalent. A simplified purification procedure including adjustment of cell lysate pH to 4.5, fractionation with 50- 80% ethanol, and dialysis rendered capsular polysaccharide (CPS) in a yield of 31.32 +/- 3.11 mg from 1 l culture (75% recovery after lyses). The product contained only 69.6 microng of protein (99.78% purity) and 0.8 mg (sum of the precipitants from 50~60%, 60~70%, and 70~80%) of nucleic acid (97.45% purity). The purified CPS was conjugated with bovine serum albumin; the product size ranged from 100 to 180 kDa. PMID- 21791961 TI - Statistical optimization of medium composition for bacterial cellulose production by Gluconacetobacter hansenii UAC09 using coffee cherry husk extract--an agro industry waste. AB - During the production of grape wine, the formation of thick leathery pellicle/bacterial cellulose (BC) at the airliquid interface was due to the bacterium, which was isolated and identified as Gluconacetobacter hansenii UAC09. Cultural conditions for bacterial cellulose production from G. hansenii UAC09 were optimized by central composite rotatable experimental design. To economize the BC production, coffee cherry husk (CCH) extract and corn steep liquor (CSL) were used as less expensive sources of carbon and nitrogen, respectively. CCH and CSL are byproducts from the coffee processing and starch processing industry, respectively. The interactions between pH (4.5- 8.5), CSL (2-10%), alcohol (0.5 2%), acetic acid (0.5- 2%), and water dilution rate to CCH ratio (1:1 to 1:5) were studied using response surface methodology. The optimum conditions for maximum BC production were pH (6.64), CSL (10%), alcohol (0.5%), acetic acid (1.13%), and water to CCH ratio (1:1). After 2 weeks of fermentation, the amount of BC produced was 6.24 g/l. This yield was comparable to the predicted value of 6.09 g/l. This is the first report on the optimization of the fermentation medium by RSM using CCH extract as the carbon source for BC production by G. hansenii UAC09. PMID- 21791962 TI - Enhancing the anaerobic digestion of corn stalks using composite microbial pretreatment. AB - A composite microbial system (XDC-2) was used to pretreat and hydrolyze corn stalk to enhance anaerobic digestion. The results of pretreatment indicated that sCOD concentrations of hydrolysate were highest (8,233 mg/l) at the fifth day. XDC-2 efficiently degraded the corn stalk by nearly 45%, decreasing the cellulose content by 22.7% and the hemicellulose content by 74.1%. Total levels of volatile products peaked on the fifth day. The six major compounds present were ethanol (0.29 g/l), acetic acid (0.55 g/l), 1,2-ethanediol (0.49 g/l), propionic acid (0.15 g/l), butyric acid (0.22 g/l), and glycerine (2.48 g/l). The results of anaerobic digestion showed that corn stalks treated by XDC-2 produced 68.3% more total biogas and 87.9% more total methane than untreated controls. The technical digestion time for the treated corn stalks was 35.7% shorter than without treatment. The composite microbial system pretreatment could be a cost-effective and environmentally friendly microbial method for efficient biological conversion of corn stalk into bioenergy. PMID- 21791963 TI - Characterization of methane oxidation by a methanotroph isolated from a landfill cover soil, South Korea. AB - A methane-oxidizing bacterium was isolated from the enriched culture of a landfill cover soil. The closest relative of the isolate, designated M6, is Methylocystis sp. Based on a kinetic analysis, the maximum specific methane oxidation rate and saturation constant were 4.93 mmol.g--dry cell weight--1.h-1 and 23 microM, respectively. This was the first time a kinetic analysis was performed using pure methanotrophic culture. The methane oxidation by M6 was investigated in the presence of aromatic (m- and p-xylene and ethylbenzene) or sulfur (hydrogen sulfide, dimethyl sulfide, methanthiol) compounds. The methane oxidation was inhibited by the presence of aromatic or sulfur compounds. PMID- 21791964 TI - Wild ginseng attenuates repeated morphine-induced behavioral sensitization in rats. AB - Many studies have suggested that the behavioral and reinforcing effects of morphine are induced by hyperactivation of the mesolimbic dopaminergic system, which results in increases in locomotor activity, c-Fos expression in the nucleus accumbens (NAc), and tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). In order to investigate the effect of wild ginseng (WG) on treating morphine addiction, we examined the behavioral sensitization of locomotor activity and c-Fos and TH expression in the rat brain using immunohistochemistry. Intraperitioneal injection of WG (100 and 200 mg/kg), 30 min before administration of a daily injection of morphine (40 mg/kg, s.c.), significantly inhibited morphine-induced increases in c-Fos expression in NAc and TH expression in VTA as well as in locomotor activity, as compared with Panax ginseng. It was demonstrated that the inhibitory effect of WG on the behavioral sensitization after repeated exposure to morphine was closely associated with the reduction of dopamine biosynthesis and postsynaptic neuronal activity. It suggests that WG extract may be effective for inhibiting the behavioral effects of morphine by possibly modulating the central dopaminergic system and that WG might be a useful resource to develop an agent for preventing and treating morphine addiction. PMID- 21791965 TI - High molecular weight poly-gamma-glutamic acid regulates lipid metabolism in rats fed a high-fat diet and humans. AB - We investigated the effect of high molecular weight polygamma- glutamic acid (hm gamma-PGA) on adiposity and lipid metabolism of rats in the presence of an obesity-inducing diet. Thirty-two Sprague-Dawley rats were fed either a normal fat (11.4% kcal fat, NFC) or high-fat (51% kcal fat, HFC) diet. After 5 weeks, half of each diet-fed group was treated with hm gamma-PGA (NFP or HFP) for 4 weeks. The HFC group had significantly higher body weight, visceral fat mass, fasting serum levels of total cholesterol, LDL cholesterol, and leptin, and lower serum HDL cholesterol level compared with those of the NFC group (p < 0.05). Treatment with hm gamma-PGA decreased body weight gain and perirenal fat mass (p<0.05), fasting serum total cholesterol, and mRNA expression of glucose-6- phosphate dehydrogenase (G6PD), regardless of dietary fat contents (p < 0.01). However, hm gamma-PGA increased serum HDL cholesterol in the HFC group (p < 0.05). In vitro, 3-hydroxy-3-methylglutaryl coenzyme-A (HMGCoA) reductase activity was suppressed by the addition of hm gamma-PGA. In agreement with observations in animal study, the supplementation of hm gamma-PGA (150 mg/day) to 20 female subjects in an 8-week double-blind, placebocontrolled study resulted in a tendency to decrease total cholesterol and LDL cholesterol concentrations. We thus conclude that dietary supplementation of hm gamma-PGA may act as a hypocholestrolemic agent, secondary to its inhibitor effect on HMG-CoA reductase, and decrease abdominal adiposity by decreasing hepatic lipogenesis. The present study is an important first step in establishing the effect of hm gamma-PGA on cholesterol levels in rats and humans. PMID- 21791966 TI - Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome. AB - The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA IR>=2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS. PMID- 21791967 TI - Rosiglitazone protects diabetic rats from liver destruction. AB - AIMS: To investigate whether rosiglitazone (ROS) protects diabetic rats from destructive changes in the liver. METHODS: Twenty-four Sprague Dawley rats were randomly divided into 3 groups: control (NC) group (no.=8), streptozocin (STZ) treated diabetic (DM) group (no.=8), and STZ+ROStreated diabetic (RSG) group (no.=8). After 8 weeks, the liver structure was observed by light microscopy and transmission electron microscopy. Apoptosis was detected by TUNEL, and apoptosis index was calculated. The Fas ligand (FasL) mRNA expression of apoptosis promoting gene and cyclooxygenase- 2 (COX-2) mRNA in the liver were detected by RTPCR. COX-2 protein in the liver was tested via immunohistochemical staining. RESULTS: Compared to NC group, DM group showed a visible fatty degeneration and inflammatory cell infiltration in the liver under microscopy. Obvious hepatocyte swelling with atrophic mitochondria was observed, and the central zone of cholangiole was severely outstretched. Meanwhile, in RSG group, the hepatocyte steatosis and inflammatory cell infiltration decreased, and the hepatic ultra structure was markedly improved. Hepatocyte apoptosis (p<0.05) and the expression levels for hepatic COX-2 mRNA (p<0.05), FasL mRNA (p<0.01), and COX-2 protein (p<0.05) were higher in DM group compared to the NC group, while the expression level of hepatic COX-2 mRNA (p<0.05), FasL mRNA (p<0.01), COX-2 protein (p<0.05), and hepatocyte apoptosis (p<0.05) in RSG group were decreased compared to DM group. CONCLUSION: Diabetes causes severe liver injury and ROS can protect diabetic rats from liver destruction, which may be related to inhibition of the expression of COX-2 and the hepatocyte apoptosis induced by FasL gene over expression. PMID- 21791968 TI - Serum levels of the adipokine zinc-alpha2-glycoprotein are increased in preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is associated with facets of the metabolic syndrome and an increased future metabolic and cardiovascular risk for mother and newborn. Recently, zinc-alpha2-glycoprotein (ZAG) has been proposed as a new adipokine involved in the pathogenesis of obesity. AIM: In the current study, we investigated ZAG serum levels in PE patients as compared to healthy gestational age-matched controls. SUBJECTS AND METHODS: We quantified serum concentrations of ZAG in patients with PE (no.=37) as compared to healthy gestational age-matched controls (no.=37) by enzyme-linked immunosorbent assay. Furthermore, association of this adipokine with renal function, glucose and lipid metabolism, as well as inflammation was studied. RESULTS: Median serum ZAG levels were 1.4-fold higher in PE patients (58.8 mg/l) as compared to controls (41.9 mg/l) (p<0.01). Furthermore, circulating ZAG was positively correlated to systolic and diastolic blood pressure, creatinine, triglycerides, and leptin in univariate analyses. In multiple regression analysis, creatinine remained independently associated with ZAG. CONCLUSIONS: We demonstrate that maternal ZAG serum concentrations are significantly increased in PE. Furthermore, renal function is an independent predictor of circulating ZAG. PMID- 21791969 TI - Peripheral bone mineral density in correlation to disease-related predisposing conditions in patients with multiple endocrine neoplasia type 1. AB - BACKGROUND AND AIM: Patients with multiple endocrine neoplasia type 1 (MEN1) often have low bone mineral density (BMD) attributed to primary hyperparathyroidism (pHPT). However, in MEN1 patients, other endocrine dysfunctions and conditions such as hypercortisolism, hypogonadism, and GH deficiency due to pituitary manifestation, and surgery on the upper gastrointestinal tract may affect BMD. SUBJECTS AND METHODS: In 23 patients with MEN1 (10 females, 13 males; 46+/-12 yr), BMD was determined by quantitative computed tomography at the forearm (pqCT), compared to a reference population and related to different conditions suspected to affect bone metabolism in MEN1. RESULTS: In this cohort, Z-score for trabecular BMD was -0.85+/-1.18 and for total BMD -1.16+/-1.04. There was a similar trend towards lower BMD in uncontrolled hyperparathyroidism, hypercortisolism, hypogonadism/GH deficiency and the state after surgery at the upper gastrointestinal tract. CONCLUSIONS: These data while confirming previous observations on reduced BMD in patients with MEN1, however, challenge its only or even predominant association with pHPT. Other conditions such as hypercortisolism, somatotrophic/ gonadotrophic pituitary insufficiency, and previous upper gastrointestinal surgery seem to be factors contributing to the risk of developing osteoporosis. PMID- 21791970 TI - Glucagon test in insulinoma: Is it useful? AB - Diagnosis of endogenous hyperinsulinism caused by insulinoma is based on confirmation of hypoglycemia during the symptoms associated to elevated insulin levels. Patients with insulinoma may demonstrate an excessive insulin response and subsequent hypoglycemia after 1 mg of glucagon iv injection. Glucagon test was performed in 11 patients with insulinoma before therapy and in 4 after therapy. Our study suggests that the presence of plasma glucose levels less than 55 mg/dl and below baseline at time 120 min of glucagon test strongly reinforce the diagnosis of insulinoma. PMID- 21791972 TI - Should the chickenpox vaccine be included in the National Immunization Schedule in India? AB - Varicella (chickenpox) is an acute, highly contagious viral disease with worldwide distribution. The highest prevalence occurs in the 4-10 year age group but tends to be more severe in adults. It may be fatal in neonates, immunocompromised persons, and normal adults, especially smokers. Varicella is usually a benign childhood disease, and rarely rated as an important public health problem, but this can be severe and even fatal in otherwise healthy children (< 1 out of every 10,000 cases). Chickenpox can cause pneumonia (23 out of every 10,000 cases), and is an important risk factor for developing severe invasive "strep" (group A streptococcal disease). Complications of varicella include bacterial infections (up to 5% of cases), decreased platelets, arthritis, hepatitis, pneumonia (more commonly in adults) or encephalitis (1 in 10,000 cases), which may cause a failure of muscular coordination, sometimes resulting in persistent sequelae or death. Varicella is the leading cause of vaccine preventable death in children. Universal vaccination can cause a dramatic reduction in the incidence of varicella, associated complications, hospitalizations and fatality rates. In India, due to the high cost of the vaccine, it would be difficult to vaccinate a large percentage of the children. The government of India should consider the inclusion of varicella vaccine in the National Immunization Schedule with the help of International agencies. PMID- 21791971 TI - The Ran importin system in cilia trafficking. AB - Cilia are microtubule-based organelles that arise from the centrosome and project from the surface of many cells. Defects in cilia-localized proteins are felt to lead to polycystic kidney disease as well as ciliopathies with multiple organ involvement. Movement of proteins along mammalian cilia is a specialized process that is highly related to the intraflagellar movement of proteins in lower organisms. Entry of proteins into the cilia appears to be a tightly regulated process. Several cilia-targeting sequences have been identified that appear to mediate the movement of proteins into cilia, although the molecular basis through which these sequences operate is still being elucidated. Entry of proteins into cilia appears to be regulated at the base of the cilia at a region known as the transition zone. It has been proposed that a ciliary pore exists in this zone that controls entry of proteins into the cilia, similar to the nuclear pore that controls entry of proteins into the nucleus. Our group at the University of Michigan has found that proteins important in nuclear import appear to function similarly in cilia entry. In particular, we have identified roles for the small GTPase, Ran and its binding partners, the importins, in regulating cilia entry of specific proteins. PMID- 21791973 TI - New generation typhoid vaccines: an effective preventive strategy to control typhoid fever in developing countries. AB - Typhoid fever is a serious systemic infection, caused by the enteric pathogen Salmonella enterica serovar Typhi, a highly virulent and invasive enteric bacterium. This disease occurs in all parts of world where water supplies and sanitation are substandard. These pathogens then travel to food, drinks and water through house-flies and other vectors. Globally, an estimated 12-33 million cases of enteric fever occur with 216,00-600,000 deaths per year, almost exclusively in the developing countries. Health surveys conducted by the Health Ministry of India in the community development areas indicated a morbidity rate varying from 102-2219/100,000 population in different parts of the country. A limited study in an urban slum showed 1% of children up to 17 years of age suffer from typhoid fever annually. The continued high burden of typhoid fever and the alarming spread of antibiotic resistant strains led the World Health Organization (WHO), almost ten years ago, to recommend immunization using the two new-generation vaccines in school- aged children in areas where typhoid fever posed a significant problem and where antibiotic resistant strains were prevalent. Morbidity and mortality due to high incidence of typhoid fever favors the introduction of typhoid vaccine in routine immunization in India. This vaccine should be given at the age of 2 years with Vi antigen vaccine and at least one more dose be given at 5 years of age. PMID- 21791974 TI - Enhanced survival of pluripotent stem cells under stressful conditions. PMID- 21791975 TI - The first Chinese case of Creutzfeldt-Jakob disease patient with R208H mutation in PRNP. AB - A case of Creutzfeldt-Jakob disease (CJD) with a rare mutation of the prion protein (PrP) gene (PRNP) at codon 208 (R208H), while the codon 129 was a methionine homozygous genotype is reported. The patient initial displayed hand tremor, dizziness and progressive cognitive dysfunction. Subsequently, other symptoms gradually appeared, including cerebellar ataxia and mental disorder. No periodic activity was recorded at electroencephalography (EEG) and 14-3-3 protein in cerebrospinal fluid was negative. Total clinical course was about 4 months. Retrospective investigation of this family across seven generations did not figure out clear family history. However, genetic analyses revealed six first degree family members with the R208H allele. PMID- 21791976 TI - A trial of production of the plant-derived high-value protein in a plant factory: photosynthetic photon fluxes affect the accumulation of recombinant miraculin in transgenic tomato fruits. AB - One of the ultimate goals of plant science is to test a hypothesis obtained by basic science and to apply it to agriculture and industry. A plant factory is one of the ideal systems for this trial. Environmental factors affect both plant yield and the accumulation of recombinant proteins for industrial applications within transgenic plants. However, there have been few reports studying plant productivity for recombinant protein in closed cultivation systems called plant factories. To investigate the effects of photosynthetic photon flux (PPF) on tomato fruit yield and the accumulation of recombinant miraculin, a taste modifying glycoprotein, in transgenic tomato fruits, plants were cultivated at various PPFs from 100 to 400 (umol m(-2) s(-)1) in a plant factory. Miraculin production per unit of energy used was highest at PPF100, although miraculin production per unit area was highest at PPF300. The commercial productivity of recombinant miraculin in transgenic tomato fruits largely depended on light conditions in the plant factory. Our trial will be useful to consider the trade offs between the profits from production of high-value materials in plants and the costs of electricity. PMID- 21791977 TI - DCL3 and DCL4 are likely involved in the light intensity-RNA silencing cross talk in Nicotiana benthamiana. AB - Plants have substantially invested in RNA silencing as the central defense mechanism to combat nucleotide 'invaders' such as viruses, trasposable elements and transgenes. The quantity and quality of light perceived by a plant is a constant environmental stimulus refining cell homeostasis and RNA silencing mechanism seems not to be an exception In our recent paper in BMC Plant Biology we documented that light intensity, in physiological ranges, positively affects silencing initiation and spread. (1) Here, we show that virus induced gene silecing under high light conditions results in more frequent systemic silencing events of a transgene and is acompanied by elevated DCL3 and DCL4 mRNA levels. In addition, our results show that DCL3 holds a vital role in systemic silencing spread and the positive effect of light intensity on RNA silencing requires DCL4 function. PMID- 21791978 TI - Plants, like mammals, but unlike Saccharomyces, do not regulate nuclear cytoplasmic tRNA trafficking in response to nutrient stress. AB - Cells respond to nutrient stress by regulating gene transcription and various key metabolic processes, including ribosome biogenesis and protein synthesis. Several studies have shown that yeasts and mammalian cells also regulate export of tRNAs from the nucleus to the cytosol in response to nutrient stress. However, nuclear export of tRNA in mammalian cells during nutrient stress is controversial, as it has been recently shown that nuclear-cytoplasmic transport of tRNAs in several mammalian cell lines is not affected by nutrient deprivation. Furthermore, contrary to previous studies, data reported recently indicate that nuclear export of mature tRNAs derived from intron-containing precursor tRNAs, but not tRNAs made from intronless precursors, is affected by nutrient availability in several Saccharomyces species, although not in Kluyveromyces lactis and Schizosaccharomyces pombe. Here, we report that plants, like mammals and some yeasts, but unlike Saccharomyces, do not directly regulate nuclear export of tRNA in response to nutrient stress, indicating that this process is not entirely conserved among evolutionarily diverse organisms. PMID- 21791979 TI - The use of FTIR spectroscopy to monitor modifications in plant cell wall architecture caused by cellulose biosynthesis inhibitors. AB - Fourier Transform InfraRed (FTIR) spectroscopy is a powerful and rapid technique for analysing cell wall components and putative cross-links, which is able to non destructively recognize polymers and functional groups and provide abundant information about their in muro organization. FTIR spectroscopy has been reported to be a useful tool for monitoring cell wall changes occurring in muro as a result of various factors, such as growth and development processes, mutations or biotic and abiotic stresses. This mini-review examines the use of FTIR spectroscopy in conjunction with multivariate analyses to monitor cell wall changes related to (1) the exposure of diverse plant materials to cellulose biosynthesis inhibitors (CBIs), and (2) the habituation/dehabituation of plant cell cultures to this kind of herbicides. The spectra analyses show differences not only regarding the inhibitor, but also regarding how long cells have been growing in its presence. PMID- 21791981 TI - Multiple nails in the brain: an unusual suicidal attempt. AB - We describe dangerous multiple self-inflicted brain-penetrating injuries caused by a nail gun device after a suicidal attempt for the first time in Iran. At the first forensic visit, we could not explain the manner of injuries. The authors reviewed the literature on the topics, and clinical presentation, radiographic findings, and forensic medical records are discussed. PMID- 21791980 TI - Sugarcane glycoproteins may act as signals for the production of xanthan in the plant-associated bacterium Xanthomonas albilineans. AB - Visual symptoms of leaf scald necrosis in sugarcane (Saccharum officinarum) leaves develop in parallel to the accumulation of a fibrous material invading exocellular spaces and both xylem and phloem. These fibers are produced and secreted by the plant-associated bacterium Xanthomonas albilineans. Electron microscopy and specific staining methods for polysaccharides reveal the polysaccharidic nature of this material. These polysaccharides are not present in healthy leaves or in those from diseased plants without visual symptoms of leaf scald. Bacteria in several leaf tissues have been detected by immunogold labelling. The bacterial polysaccharide is not produced in axenic culture but it is actively synthesized when the microbes invade the host plant. This finding may be due to the production of plant glycoproteins after bacteria infection, which inhibit microbial proteases. In summary, our data are consistent with the existence of a positive feedback loop in which plant-produced glycoproteins act as a cell-to-bacteria signal that promotes xanthan production, by protecting some enzymes of xanthan biosynthesis against from bacterial proteolytic degradation. PMID- 21791982 TI - Comparison of cardiac rehabilitation and acute care nurses perceptions of providing sexual counseling for cardiac patients. AB - PURPOSE: : The purpose of this study was to examine the differences between outpatient cardiac rehabilitation (CR) and acute care nurses perceived barriers and clinical practices of providing sexual counseling for myocardial infarction patients. METHODS: : A nonexperimental descriptive, comparative research design with convenience sampling was used to survey CR and acute care nurses using the Survey of Sexuality Related Nursing Practice-Myocardial Infarction questionnaire. RESULTS: : A total of 320 nurses (81 CR nurses, 239 acute care nurses), in midwestern states completed the survey. Using ANCOVA analyses with age, work status, and education level as covariates, findings demonstrated CR nurses had significantly higher levels of role responsibility (F[4, 315] = 5.4, P < .05) and implementation of sexual counseling in clinical practice (F[4, 315] = 9.1, P < .0001). CONCLUSIONS: : Findings from this study further elucidate the influence of practice settings on the actual implementation of patient education and counseling of cardiac patients regarding sexual functioning. Outpatient CR nurses reported fewer barriers and reported higher rates of implementing sexual counseling into their practice. These findings support the importance of CR referral to provide both physical and psychosocial rehabilitation after a cardiac event. Findings bring to light the need to address the gap in practice to meet the perceived unmet needs of patients regarding their concerns of sexual functioning while hospitalized and for those patients who may not enroll in CR after hospital discharge. PMID- 21791985 TI - Increased recurrences using IMRT in the postoperative setting? PMID- 21791984 TI - Phase II study of biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin as first-line chemotherapy in patients with advanced gastric cancer. AB - PURPOSE: This study was conducted to evaluate the efficacy and safety of combination chemotherapy with biweekly paclitaxel plus infusional 5-fluorouracil (5-FU) and leucovorin as first-line treatment for patients with advanced gastric cancer. METHODS: Eligible patients with histologically confirmed advanced or metastatic gastric cancer were enrolled. The chemotherapeutic regimen consisted of paclitaxel (100 mg/m(2) on day 1) as a 3-hour intravenous infusion, followed sequentially by leucovorin (400 mg/m(2) on day 1) as a 2-hour intravenous infusion, bolus 5-FU (400 mg/m(2) on day 1), and then continuous infusion 5-FU (3000 mg/m(2) on day 1) over 46 hours. Cycles were repeated every 2 weeks. RESULTS: Sixty patients were enrolled (median age, 52.5 years old). Of these, 65% patients had Eastern Cooperative Oncology Group performance status of grade 2. A median of 8 cycles was administered (range, 4-12). Fifty-five patients were evaluable for response. Two patients achieved a complete response and 28 patients achieved a partial response, producing an overall response rate of 50% by intent to-treat analysis. The median duration of response was 6.4 months (95% CI, 5.14 7.60 months). Median progression-free survival and median overall survival were 7.7 months (95% CI, 6.5-8.9 months) and 14.3 months (95% CI, 9.4-19.1 months), respectively. Hematologic toxicity was mild; grade 3 neutropenia was noted in only 6.7% of patients. Alopecia was the most common nonhematologic toxicity in 51 patients (71.4%). Grade 3 alopecia occurred in 11 patients (18.3%). CONCLUSION: Combination chemotherapy of biweekly paclitaxel followed sequentially by infusion leucovorin, bolus 5-FU, and continuous infusion 5-FU over 46 hours is effective and well tolerated in patients with advanced gastric cancer, especially in patients with poor performance status who cannot tolerate aggressive chemotherapy regimens. PMID- 21791988 TI - Siker's Mapleson-modified Boyle apparatus for halothane. PMID- 21791989 TI - An advertising card for peruvian syrup. PMID- 21791990 TI - An airway pastel by Chevalier Jackson. PMID- 21791991 TI - Ivan the terrible anesthetist. PMID- 21791992 TI - Preparation of modern anesthesia workstations for malignant hyperthermia susceptible patients: when are they really clean? PMID- 21791993 TI - New device simplifies workstation preparation for malignant hyperthermia susceptible patients. PMID- 21791995 TI - Hypoxemia during one-lung ventilation: looking the other way. PMID- 21791997 TI - Just who is burning out ... Chairpersons or program directors? PMID- 21791998 TI - "Life-threatening" Hypoxemia in One-lung Ventilation. PMID- 21792001 TI - Management of unanticipated difficult airway in the prehospital emergency setting. PMID- 21792000 TI - Pharmacological Treatment of Hypoxemia during One-lung Ventilation. PMID- 21792002 TI - A modified difficult airway management algorithm incorporating video devices in routine anesthesia practice. PMID- 21792004 TI - Questioning succinylcholine usage in grade IV (difficult) mask ventilation. PMID- 21792006 TI - Difficult tracheal intubation of in-hospital emergent patients. PMID- 21792008 TI - Reasons for diagnostic delay in gynecological malignancies. AB - INTRODUCTION: To describe the different delay types in women with gynecological cancer and to analyze the relationship between diagnostic delay and a number of characteristics for patients, cancers, and the health care system. METHOD: Data were obtained from 4 different questionnaires, the Electronic Patient Journal (EPJ), and the Danish Gynecological Cancer Database (DGCD). A total of 161 women with ovarian cancer (63), endometrial cancer (50), cervical cancer (34), and vulvar cancer (14) were included. Outcome measures were different delay types counted in days and 4 clinically important variables' impact on the diagnostic delay: presence of alarm symptoms, age (divided into 2 groups: <=60 or >60 years), performance of gynecological examination by the general practitioner (GP), and notification of cancer suspicion on first referral from GP. RESULTS: Across cancer types, median total delay was 101 days. Some 10% of women experienced the longest delay with a total delay of 436 days or more. Vulva cancer had the longest delay, whereas women with ovarian cancer had the shortest delay. More than one third (39%) of the women consulted their GP for reasons other than the predefined alarm symptoms. Gynecological examination by the GP was less likely to be performed if the woman did not present with vaginal bleeding. The length of the delay was shortened by performance of a gynecological examination by the GP and a primary referral from the GP raising the receiver's suspicion of cancer. CONCLUSION: Reducing diagnostic delays should be achievable, particularly for those most delayed, and interventions aimed at reducing delays need to be developed. Creation of new valid instruments for measuring delay is essential in future research. PMID- 21792009 TI - CHFR suppression by hypermethylation sensitizes endometrial cancer cells to paclitaxel. AB - OBJECTIVE: Impairment of a cell cycle checkpoint is often associated with sensitivity to chemotherapeutic drugs. Here, we studied the correlations between the checkpoint with forkhead-associated and ring finger (CHFR) gene expression and responses to paclitaxel in endometrial cancer cells. METHODS: We cultured 6 endometrial cancer cell lines exposed to paclitaxel, studied the cell cytotoxicity, cell cycle distribution, CHFR expression, and methylation status before and after a demethylation agent (5-aza) treatment. CHFR was silenced by small interfering RNA (siRNA). Then we examined tumor growth and CHFR expression with paclitaxel alone or combined with 5-aza pretreatment in vivo. RESULTS: We found that HEC-1B, RL-952, and AN3CA cells were sensitive to paclitaxel. Moreover, CHFR was weakly expressed in these cells, whereas paclitaxel-resistant cells (ISH, HEC-1A, and KLE) had high CHFR expression. Then we found that restored expression of CHFR by demethylation decreased the sensitivity to paclitaxel in AN3CA cells. In addition, cells with CHFR demethylation resulted in G2/M phase arrest that induced to paclitaxel resistance. These results were confirmed again in small interfering RNA-transfected HEC-1A cells. Furthermore, in nude mice model, restored expression of CHFR by demethylation inhibited tumor growth and decreased sensitivity to paclitaxel. CONCLUSION: Our data suggest that CHFR suppression regulated by hypermethylation may sensitize endometrial cancer cells to paclitaxel, and CHFR may be a promising marker to predict the response of endometrial cancer to paclitaxel. PMID- 21792010 TI - Expression of macrophage migration inhibitory factor and CD74 in cervical squamous cell carcinoma. AB - OBJECTIVE: Macrophage migration inhibitory factor (MIF) and CD74 emerge as important players in pathogenesis and angiogenesis of several types of malignant tumors. The purpose of this study was to evaluate the expression of MIF and CD74 in cervical squamous cell carcinoma and explore the potential roles they play in cervical tumor angiogenesis. METHODS: Macrophage migration inhibitory factor and CD74 expression was assessed by immunohistochemistry in 209 cases with various degrees of cervical epithelial lesions, including 40 normal cervical epithelia, 43 mild cervical intraepithelial neoplasia 1 (CIN 1), 41 moderate-severe cervical intraepithelial neoplasia (CIN 2 to 3), and 85 cervical squamous cell carcinomas (SCCs). CD34 staining was used for counting microvessel density. Semiquantitative reverse transcription polymerase chain reaction and Western blot were used to detect messenger RNA and protein levels of MIF and CD74 in normal and malignant cervical tissues and cervical cancer cell lines SiHa and C-33A. The concentration of vascular endothelial growth factor (VEGF) in the conditioned media of cervical cancer cells was analyzed by enzyme-linked immunosorbent assay. RESULTS: Immunohistochemical analysis showed that MIF and CD74 expression was significantly higher in CIN than in the normal samples and higher in SCC than in CIN. The overexpression of MIF was correlated with deep stromal infiltration but not with the other clinicopathologic features of SCC. Correlation analyses revealed that MIF was positively related to CD74, and both protein levels were associated with microvessel density. Exogenous MIF induced VEGF secretion in SiHa and C-33A cells in a dose-dependent manner, which can be inhibited by MIF specific inhibitor (ISO-1) or anti-CD74 antibody. CONCLUSION: Overexpression of MIF and CD74 in SCC and its precancerous lesions and the up-regulation of VEGF secretion in cervical cancer cells indicate that MIF and CD74 may play critical roles in the pathogenesis and angiogenesis of cervical cancer. PMID- 21792011 TI - Possible use of CA-125 level normalization after the third chemotherapy cycle in deciding on chemotherapy regimen in patients with epithelial ovarian cancer: brief report. AB - BACKGROUND: Cancer antigen (CA)-125 is a biomarker widely used in the monitoring of response to chemotherapy in patients with epithelial ovarian cancer (EOC). We hypothesize that normalization of the CA-125 after the third cycle of chemotherapy is an independent prognostic indicator of prolonged progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective analysis of patients with a diagnosis of advanced-stage (III-IV) EOC who were treated with cytoreductive surgery and adjuvant platinum-based chemotherapy from January 1999 to June 2009 was conducted. Patient demographics and the prognostic significance of CA-125 level above the discrimination value of 35 U/mL were assessed by univariate and multivariate analyses. RESULTS: A total of 124 women met the study inclusion criteria. The median PFS for all patients with a CA-125 level of less than 35 U/mL (n = 72) after the third chemotherapy cycle was 18 months versus that of the patients with a CA-125 level of 35 U/mL or greater (n = 52) was 9 months (P < 0.0001). The median OS was 42 and 22 months, respectively (P < 0.0001). Optimal microscopically debulked patients with normalization of CA-125 after the third cycle did significantly better than those who did not normalize (PFS, 48 vs 8.3 months; OS, 59 vs 23.8 months; P < 0.0001). When patients with macroscopic disease and normalization of CA-125 after the third cycle were compared with those with CA-125 of 35 U/mL or greater, a significant difference in OS was seen between the 2 groups (47 vs 29 months, respectively; P < 0.0001). On multivariate analysis, only 2 variables were associated with poor prognosis: (1) the failure of CA-125 level to normalize after the third chemotherapy cycle (hazard ratio, 2.5; confidence interval, 1.3-4.6) and (2) the grade of the tumor (hazard ratio, 7.7; confidence interval, 1.6-37.6). CONCLUSIONS: Although hypothesis generating at this point, normalization of CA-125 level after the third chemotherapy cycle is an independent predictor of survival for patients with advanced EOC regardless of debulking status. We would propose future trials that consider switching regimens in patients who do not normalize their CA-125 after the third cycle to see if such a switch can improve PFS and OS. PMID- 21792012 TI - Prognostic impact of concomitant p53 and PTEN on outcome in early stage (FIGO I II) epithelial ovarian cancer. AB - INTRODUCTION: The objective of the study was to evaluate the prognostic effect of p53, PTEN, and concomitant p53 PTEN status on clinicopathologic features, recurrent disease, and disease-free survival (DFS) of 131 patients in FIGO stages I to II with epithelial ovarian cancer. METHODS: The technique of tissue microarray and immunohistochemistry was used for the detection of positivity of the biologic markers p53 and PTEN. RESULTS: In the complete series, the 5-year DFS rate was 68%, and the overall survival rate was 71%. Positive staining for p53 and PTEN was detected in 25% and 22% of cases, respectively. Positivity of p53 was associated with tumor grade in the total series but not in the subgroup of serous tumors. In survival analysis, there was worse survival (P = 0.003) in the group of patients with p53-positive tumors compared with the group of patients with p53-negative tumors with DFS of 62% and 82%, respectively. Furthermore, DFS was 15% for the subgroup of patients with concomitant p53 positivity and PTEN-negativity of tumors compared with DFS of 62% for others in 1 group (p53+PTEN+, p53-PTEN+, p53-PTEN-) at 100 months. The difference was highly significant (P = 0.006). FIGO stage (odds ratio = 8.0) and p53 PTEN status (odds ratio = 0.6) were predictive factors for tumor recurrences in a logistic regression and prognostic factors with hazard ratios (HRs) of 4.0 and 0.6, respectively, in a multivariate Cox regression analysis. In a separate Cox regression analysis, FIGO stage (HR = 3.6) and p53 status (HR = 2.0) were prognostic factors for DFS. For serous tumors (n = 51) recurrent disease was associated with FIGO stage (P = 0.013), and p53 loss (P = 0.029) but not with FIGO grade (P = 0.169). CONCLUSIONS: p53 status divides ovarian carcinomas into 2 subgroups after prognosis, also in serous tumors. Presence of PTEN in p53 positive tumors seems to protect from bad prognosis and absence of PTEN seems to worsen prognosis in early stages. PMID- 21792013 TI - Expression of ERCC1, p53, and class III beta-tubulin do not reveal chemoresistance in endometrial cancer: results from an immunohistochemical study. AB - BACKGROUND: In non-small cell lung cancer, expression of excision repair cross complementation group 1 (ERCC1) and p53 correlates with platinum resistance and class III beta-tubulin with resistance to taxanes. The potential to personalize treatment in endometrial cancer remains uninvestigated. METHODS: Patients received platinum-based chemotherapy, with or without paclitaxel. Patients were divided into 2 groups: group A (n = 33) consisted of patients with early-stage endometrial cancer treated with adjuvant chemotherapy. Group B (n = 116) included cases with primary advanced or recurrent disease. Immunohistochemistry was performed to analyze the expression of ERCC1 and p53, for all cases, and class III beta-tubulin for cases treated with paclitaxel. The findings were correlated with response according to Response Criteria in Solid Tumors; recurrence-free, disease-specific survival; and established prognostic markers. RESULTS: The mean age of 149 patients was 64 years (range, 31-84 years). Distribution of histopathologic subtypes was as follows: 44 endometrioid (30%), 92 serous/clear cell (62%), and 13 carcinosarcomas (8%).In group A, 11 (33%) and 19 patients (58%) showed expression for ERCC1 and p53, respectively. Seven (78%) of nine patients receiving paclitaxel were positive for class III beta-tubulin. There was no correlation between expression of ERCC1, p53, or class III beta-tubulin and recurrence or survival. In group B, 25 (22%) and 61 patients (64%) were positive for ERCC1 and p53, respectively. Fifty-two (74%) of seventy patients receiving paclitaxel were positive for class III beta-tubulin. Only p53 expression correlated with survival (P = 0.01). CONCLUSIONS: In contrast to theoretical assumptions, the current study did not reveal evidence that the expression of ERCC1 and class III beta-tubulin predicts response to cytotoxic treatment and patient outcome in endometrial cancer. PMID- 21792015 TI - 18F-fluoro-2-deoxy-D-glucose positron emission tomography standard uptake value ratio as an indicator of cervical cancer chemoradiation therapeutic response. AB - HYPOTHESIS: A ratio of 3 months of posttherapy to pretherapy 2-[F]fluoro-2-deoxy d-glucose positron emission tomography with computed tomography (F-FDG PET/CT) standard uptake values (SUVs) predicts progression-free survival after chemoradiation in patients with stages IB2 to IVA cervical cancer. METHODS: This retrospective review included 51 patients who received treatments of daily pelvic radiation and once-weekly cisplatin chemotherapy followed by brachytherapy. Posttherapy confirmatory surgical or cytologic pathology was done a median of 7 days after 3-month F-FDG PET/CT. RESULTS: All 51 patients receiving chemoradiation achieved at least a partial metabolic response (ie, >25% decrease in F-FDG PET/CT SUV) in the expected region of the cervix. A ratio of less than 0.33 for posttherapy to pretherapy F-FDG PET/CT SUVs of the expected area of the cervix was associated with a 35% improvement in 6-month progression-free survival. CONCLUSIONS: In patients with cervical cancer, the 3-month posttherapy F-FDG PET/CT value is an indicator of therapeutic response to chemoradiation and needs further validation in clinical trials. PMID- 21792014 TI - YY1 is a novel potential therapeutic target for the treatment of HPV infection induced cervical cancer by arsenic trioxide. AB - OBJECTIVE: YY1 is a zinc finger transcription factor involved in the regulation of cell growth, development, and differentiation. Although YY1 can regulate human papillomavirus-type (HPV) viral oncogenes E6 and E7, it remains unknown if YY1 plays a key role in carcinoma progression of HPV-infected cells. Here we sought to determine whether YY1 is upregulated in the cervical cancer tissues and YY1 inhibition contributes to apoptosis of cervical cancer cells, which is at least partly p53 dependent. Therefore, YY1 can be a potential therapeutic target for cervical cancer treatment by arsenic trioxide (As2O3). MATERIALS AND METHODS: The expression level of YY1 was examined and analyzed by Western blot in pathologically confirmed primary cervical cancer samples, in the adjacent normal samples, as well as in normal cervix samples. The effects of YY1 inhibition by specific small interfering RNA in HeLa cells were determined by Western blot analysis of p53 level, cell growth curve, colony formation assay, and apoptosis. The contribution of YY1 to As2O3-induced p53 activation and apoptosis was also examined by Western blot and cell cycle analysis. RESULTS: Here we report that the expression level of YY1 is significantly elevated in the primary cancer tissues. In HPV-positive HeLa cells, small interfering RNA-mediated YY1 inhibition induced apoptosis and increased the expression of p53. Treatment of HeLa cells with As2O3, a known anti-cervical cancer agent, reduced both protein and mRNA levels of YY1 in HeLa cells. YY1 knockdown significantly further enhanced As2O3-induced apoptosis. CONCLUSIONS: These results demonstrated that the expression of YY1 is upregulated in cervical carcinomas and that YY1 plays a critical role in the progression of HPV-positive cervical cancer. In addition, YY1 inhibition induces p53 activation and apoptosis in HPV-infected HeLa cells. Thus, YY1 is an As2O3 target and could serve as a potential drug sensitizer for anti-cervical cancer therapy. PMID- 21792016 TI - Double prophylaxis for deep venous thrombosis in patients with gynecologic oncology who are undergoing laparotomy: does preoperative anticoagulation matter? AB - OBJECTIVE: Double prophylaxis for deep venous thrombosis (DVT) with thromboprophylaxis plus sequential compression devices (SCDs) is recommended for high-risk surgical patients with gynecologic oncology. Despite the use of preoperative thromboprophylaxis in clinical trials, the schedule of perioperative low molecular-weight heparin varies widely. We sought to determine the effectiveness and adverse effects of a preoperative dose of anticoagulation in patients with gynecologic oncology. METHODS: A multi-institutional chart review from January 2006 to July 2008 was performed. Patients with gynecologic oncology who received double prophylaxis for laparotomy were eligible. The patients were grouped according to whether they received preoperative anticoagulation (YES PREOP vs NO PREOP). All patients received postoperative low molecular-weight heparin for thromboprophylaxis and SCDs until discharge. Demographic, surgicopathologic, and complication data were collected. RESULTS: A total of 239 patients were identified: YES PREOP (n = 101) and NO PREOP (n = 138). Groups were similar with respect to demographics, diagnosis, and length of hospital stay. There were 2 DVTs in the YES PREOP group compared with 11 in the NO PREOP group (P = 0.04; relative risk, 0.77). There were also fewer DVT-attributable deaths in the YES PREOP group (0 vs 2; P < 0.001). Postoperative hematocrit (30.2% vs 31.4%; P = 0.42) and number of transfusions (26 vs 14; P = 0.31) were similar. CONCLUSION: The use of preoperative anticoagulation seems to significantly decrease the risk of DVT in this patient population, and complication rates are not increased. Patients receiving double prophylaxis should receive a preoperative dose of anticoagulation for maximum benefit. PMID- 21792017 TI - Clinical study on the efficacy of fluvoxamine for psychological distress in gynecologic cancer patients. AB - BACKGROUND: Diagnosis of cancer causes psychological distress. The present study investigated the safety and efficacy of fluvoxamine therapy in gynecologic cancer patients with either adjustment disorder or major depression after cancer was diagnosed. METHODS: Screening with the Hospital Anxiety and Depression Scale (HADS) was conducted at least 2 weeks after notification of the diagnosis of cancer in 214 gynecologic cancer patients hospitalized between January 2007 and December 2008. The HADS cutoff score was set at 11 points or greater. Informed consent to the study was obtained from 10 patients, and fluvoxamine was administered for 8 weeks. As primary end points, the safety and efficacy of fluvoxamine were evaluated using the HADS and the SF-36. As a secondary end point, the Clinical Global Impression was determined. RESULTS: The total HADS score, the anxiety score, and the depression score were significantly reduced after 6, 4, and 6 weeks of treatment, respectively. The SF-36 revealed significant improvement in vitality, mental health, and role (emotional) after 8 weeks of treatment. In the 5 patients with adjustment disorder, only the HADS anxiety score was significantly reduced after 4 weeks. In the 5 patients with major depression, the total HADS score, the anxiety score, and the depression score were significantly reduced after 6, 8, and 6 weeks, respectively. According to the SF-36, the adjustment-disorder groups showed significant improvement in mental health after 8 weeks of treatment, whereas the major-depression group showed significant improvement in vitality and role (emotional) after 8 weeks. No adverse events occurred in any subject. Assessment of the Clinical Global Impression suggested that fluvoxamine improved psychological distress in all 10 subjects. CONCLUSIONS: The present findings suggest that fluvoxamine is useful for alleviating psychological distress, including adjustment disorder and major depression, in gynecologic cancer patients. Management of psychological distress after diagnosis of cancer is important. PMID- 21792019 TI - Management of cancer during pregnancy: obstetric and neonatal outcomes. AB - OBJECTIVE: This study aimed to assess the management and the obstetric and neonatal outcomes of pregnancies complicated by cancer. METHODS: A retrospective analysis of patients with cancer during pregnancy who were treated at King Hussein Cancer Center and King Abdullah University Hospital in Jordan between January 2002 and December 2009 was conducted. The medical records of patients with invasive cancer diagnosed during pregnancy and their newborns were reviewed to retrieve information on treatment and obstetric and neonatal outcomes. Numerical data were tested for normal distribution using Kolmogorov-Smirnov. Statistical analyses were conducted using SPSS 18.0. RESULTS: A total of 46 patients with a diagnosis of cancer in pregnancy were treated. The most common tumor types were breast cancer, hematologic malignancies, and gastrointestinal malignancies. In 17 patients, a miscarriage or a termination of pregnancy occurred in the first trimester. In 25 of 46 patients, a single or a combination of treatment modalities was commenced. The distribution of therapies was as follows: chemotherapy alone, n = 5; surgery alone, n = 7; surgery and chemotherapy, n = 6; surgery and radiation therapy, n = 1; surgery with chemotherapy and radiation therapy, n = 3; chemotherapy and radiation therapy, n = 1; interferon, n = 1; and hormonal therapy, n = 1. The mean (SD) gestational age at delivery was 35.7 (2.7) weeks. The mean birth weight was 2580 (870) g. Preterm delivery occurred in 17 patients. There were 4 neonatal deaths, 2 of them delivered at 33 weeks, 1 delivered at 34 weeks, and 1 delivered at 35 weeks gestation. There were no congenital malformations. CONCLUSIONS: The remarkable finding is a high rate of iatrogenic preterm delivery with a high rate of neonatal mortality. Delivery should be postponed preferably until after a gestational age of 35 weeks. PMID- 21792018 TI - Prevalence of human papillomavirus infection in women in Portugal: the CLEOPATRE Portugal study. AB - OBJECTIVE: Human papillomavirus (HPV) is responsible for a range of diseases, including cervical cancer. The primary objectives of the CLEOPATRE Portugal study were to estimate the overall and age-stratified prevalence of cervical HPV infection and to assess HPV prevalence and type-specific distribution by cytological results among women aged 18 to 64 years, who reside in mainland Portugal. MATERIALS AND METHODS: This cross-sectional population-based study recruited women aged 18 to 64 years, according to an age-stratified sampling strategy, who attended gynecology/obstetrics or sexually transmitted disease clinics across the 5 regional health administrations in mainland Portugal between 2008 and 2009. Liquid-based cytology samples were collected and analyzed centrally for HPV genotyping (clinical array HPV 2 assay) and cytology. Prevalence estimates were adjusted for age using 2007 Portuguese census data. RESULTS: A total of 2326 women were included in the study. The overall prevalence of HPV infection in the study was 19.4% (95% confidence interval, 17.8%-21.0%), with the highest prevalence in women aged 18 to 24 years. High-risk HPV types were detected in 76.5% of infections, of which 36.6% involved multiple types. The commonest high-risk type was HPV-16. At least 1 of the HPV types 6/11/16/18 was detected in 32.6% of infections. The HPV prevalence in normal cytology samples was 16.5%. There was a statistically significant association between high-risk infection and cytological abnormalities (P < 0.001). CONCLUSIONS: This is the first population-based study to quantify and describe cervical HPV infection in mainland Portugal. This study provides baseline data for future assessment of the impact of HPV vaccination programs. PMID- 21792021 TI - An endogenous brake on the sympathetic nervous system: the emerging role of catestatin in hypertension. PMID- 21792022 TI - Predicting mortality and hospital admission in patients with COPD: significance of NT pro-BNP, clinical and echocardiographic assessment. AB - AIMS: To quantify the ability of N-terminal pro-brain natriuretic peptide (NT pro BNP) to predict mortality and hospitalization in patients with chronic obstructive airways disease (COPD). METHODS: Prospective single-centre observational study of 140 consecutive patients aged at least 18 years with COPD between 27 March 2004 and 28 February 2008 (median follow-up 3.9 years). RESULTS: Sixty-five (46%) men, 26 (19%) O2 therapy, 115 (82%) smokers, 38 (27%) patients receiving diuretics, 15 (11%) left-ventricular ejection fraction less than 45%. Median [interquartile range (IQR)] NT pro-BNP concentration 16.2 (25.4) pmol/l. NT pro-BNP was higher in those with a dilated left atrium (P<0.001), aortic stenosis (P=0.02), left-ventricular systolic dysfunction (P=0.027), right ventricular impairment (P=0.011), atrial fibrillation (P<0.001), patients receiving diuretics (P=0.010) and angiotensin-converting enzyme (ACE) inhibitors (P=0.006). One-year mortality and hospitalization rates were 2.9 and 25.4%. The median (IQR) time to hospitalization and length of first hospital stay: 383.5 (605) and 4.0 (7.0) days. NT pro-BNP was an excellent discriminator of right ventricular impairment (C statistic=0.90) and predicted survival (highest quartile versus lowest quartile relative risk=3.02, P=0.001), but not hospital admission. After adjustment this association was not significant. CONCLUSION: NT pro-BNP predicts survival, but not hospital admission in patients with COPD. The ability of NT pro-BNP to independently predict death or hospitalization is superseded by the presence of a dilated left atrium, aortic stenosis and left ventricular systolic dysfunction. PMID- 21792024 TI - A complex coronary artery fistula with aberrant mediastinic and abdominal feeding arteries and pulmonary artery drainage. AB - Coronary artery fistulas are rare congenital malformations that can originate from anywhere in the coronary artery system and terminate in any of the cardiac chambers, great veins or pulmonary arteries. We illustrate the unique case of a multidetector computed tomography coronary angiography scan of a young man, showing a complex coronary fistula between the left anterior descending coronary artery and a branch of the left pulmonary artery (with drainage function) with adjunctive mediastinic and abdominal aberrant feeding arteries arising, respectively, from the left internal mammary artery and the celiac trunk. PMID- 21792023 TI - Association between right ventricular two-dimensional strain and exercise capacity in patients with either idiopathic or ischemic dilated cardiomyopathy. AB - OBJECTIVES: To detect right ventricular myocardial function in dilated cardiomyopathy (DCM) using two-dimensional strain echocardiography (2DSE) and to evaluate the relationship between right ventricular dysfunction and response to cardiopulmonary exercise test (CPET). METHODS: Seventy-five DCM patients (44 idiopathic and 31 ischemic) without clinical signs of right ventricular failure underwent standard echo, 2DSE analysis of right ventricle and bicycle CPET. RESULTS: The two groups were comparable for clinical and standard two-dimensional echocardiographic and Doppler variables, except for right ventricular diameters that were mildly increased in patients with idiopathic DCM. Right ventricular global longitudinal strain (RV GLS) and regional peak myocardial right ventricular strain were significantly impaired in patients with idiopathic DCM compared with ischemic DCM (both P<0.001). A significant correlation was detectable among RV GLS and VO2 peak percentage (r= -0.65, P<0.0001), VE/VCO2 slope (r=0.35, P<0.01), maximum work rate percentage (r= -0.55, P<0.001) and peak circulatory power (r=0.53, P<0.001). These correlations with RV GLS remained significant even in multivariate analysis. CONCLUSION: 2DSE represents a promising noninvasive technique to assess right ventricular myocardial function in patients with DCM. Reduced right ventricular myocardial deformation is related to decreased ability to perform aerobic exercise and work rate, and to impaired ventilatory response. PMID- 21792025 TI - Giant right coronary artery aneurysm. AB - Coronary artery aneurysm (CAA) is defined as dilatation of the coronary artery that is more than 1.5 times the diameter of normal adjacent segments. A coronary artery with a diameter more than 2 cm is termed as 'giant aneurysm' and only a few cases have been described in the literature. In adults, CAA is predominantly atherosclerotic in origin; however, other causes include Kawasaki disease, autoimmune disease, trauma, infection, dissection, congenital malformation and angioplasty. Clinical presentation, prognosis and management of a giant CAA are not well defined due to limited experience. We present the case of a patient with giant aneurysm of the proximal segment of the right coronary artery. PMID- 21792026 TI - No significant interaction between diabetes and clinical presentation in the outcome of percutaneous coronary intervention: have we considered silent ischemia? PMID- 21792027 TI - Effect and safety of granulocyte transfusions in pediatric patients with febrile neutropenia or defective granulocyte functions. AB - BACKGROUND: Despite the introduction of new broad-spectrum antibiotics and antifungal therapies over the past decade, infections remains the most frequent cause of death in patients with neutropenia. The aim of this study is to assess the effect and safety of granulocyte transfusions (GTX) for the treatment of severe life-threatening infections in pediatric patients with febrile neutropenia or defective granulocyte functions. METHODS: In this study, 35 pediatric patients with high-risk febrile neutropenia or defective granulocyte functions, who received 111 GTX, were included. GTX were used for 3 consecutive days during infections not responding to antimicrobial therapy. RESULTS: The mean granulocyte content per concentrate was 27.4*109 (min: 4.2*109 to max: 68.4*109) depending on donor's white blood cell count before harvest. GTX were well tolerated in all patients. The infection-related survival rate was 82.4% and overall survival rate was 77.1% at day 30. The overall survival rate was 65.7% and 52% at 3 and 48 months, respectively. CONCLUSIONS: GTX is safe and effective in controlling the life-threatening infections. Further randomized controlled studies with long-term follow-up are needed to assess the exact role of GTX in the outcome of patients with neutropenia and patients with defective granulocyte functions. PMID- 21792028 TI - Survival and long-term outcomes in children with hepatoblastoma treated with continuous infusion of cisplatin and doxorubicin. AB - Despite high survival rates, many survivors of hepatoblastoma develop late effects including ototoxicity and cardiomyopathy. With the goal of minimizing long-term toxicities, our institution treated hepatoblastoma with continuous infusion of doxorubicin and cisplatinum (PLADO), rather than short infusion or bolus dosing as used in other treatment protocols. This retrospective cohort study includes consecutive patients diagnosed between 1985 and 2007. Patients were scheduled for treatment with 6 cycles of continuous infusion of PLADO with resection after the third or fourth cycle. Audiograms and echocardiograms were obtained at baseline, after every 2 chemotherapy cycles and yearly after the completion of therapy. Fifty-five patients were treated (34 localized; 21 metastatic). Fifty-one patients received at least 1 cycle of PLADO. Median follow up was 7.0 years (range, 0.11 to 17.8 y). Event-free and overall survival for these 51 patients were 72.2% (standard error 6.3%) and 75.6% (standard error 6.2%) respectively. Of the 38 survivors treated with cisplatin who had an audiogram during follow-up, 4 (11%) demonstrated severe (Brock grade 3/4) and 13 (34%) mild (Brock grade 1/2) hearing loss. At a median of 10.0 years (range, 5.0 to 13.0 y) after therapy, 2 of 41 (5%) patients who were still alive had evidence of cardiac dysfunction. Overall, continuous infusion of PLADO therapy resulted in survival rates consistent with those observed in intergroup studies, but rates of chronic cardiac and ototoxicity did not differ sufficiently from those observed after shorter infusion of PLADO therapy to warrant the use of continuous infusions. PMID- 21792029 TI - Effects of growth hormone therapy on bone mass, metabolic balance, and well-being in young adult survivors of childhood acute lymphoblastic leukemia. AB - Growth hormone deficiency (GHD), mostly after cranial radiotherapy (CRT), may lead to several negative effects. Young adult survivors of acute lymphoblastic leukemia (ALL) could benefit from GH therapy in different ways. Twenty ALL survivors (17.1 +/- 4.3 y after diagnosis) with low bone mineral densities and/or low insulin-like growth factor-1 were included. Two of the 3 patients who only received chemotherapy had GHD. Of the 20 patients, 17 started with GH therapy and 14 completed the 2-year study period. At several time points, bone mineral density (BMD) was measured. Psychological functioning was assessed. At the start of the study, standard deviation scores of height, insulin-like growth factor-1, lumbar spine, and femoral neck BMD were all below -1. After 2 years of GH therapy, total body BMD and lean mass were significantly higher (P < 0.01 and P < 0.001, respectively), whereas the percentage fat was significantly lower (P < 0.02). Several psychological measures improved significantly after 2 years. In conclusion, GH therapy during 2 years in young adult survivors of childhood ALL did have a number of benefits, such as improvement of total body bone density and body composition. Results also suggest improvement of psychological well being. Furthermore, it also became clear that patients after chemotherapy alone should be tested for GHD. PMID- 21792030 TI - Osteomyelitis and pyomyositis due to Pseudomonas aeruginosa in a child with sickle beta0-thalassemia. AB - Sickle cell osteomyelitis is usually due to Salmonella or Staphylococcal etiology. Pseudomonas as a cause of sickle cell osteomyelitis is rare. Similarly, pyomyositis is a rare complication in children with sickle cell disease and few cases have been reported, predominantly due to Staphylococcus. We describe an 8 year-old boy who presented with high-grade fever and tender, swollen left thigh. There was a history of intramuscular injections in the left thigh. He also had severe anemia, hepatosplenomegaly, and laboratory evidence of hemolysis. Hemoglobin electrophoresis showed sickle beta-thalassemia. Magnetic resonance imaging of the left thigh showed evidence of osteomyelitis with pyomyositis. Surgical drainage of the pus was done and Pseudomonas aeruginosa was isolated. He was treated with intravenous antibiotics for 8 weeks. The child had a protracted course of illness with development of pathologic fracture of the femur. Clinicians need to be aware of Pseudomonas infection as a complication in children with sickle cell disease, as this affects therapeutic decisions, including the choice of antibiotics. PMID- 21792031 TI - Phenylketonuria with acute myeloblastic leukemia in a 9-year-old boy: reporting a rare case. AB - Phenylketonuria is a genetic metabolic disorder resulting in phenylalanine accumulation in blood. Phenylacetate, which is an abnormal phenylalanine metabolities, was hypothesized to have anticancer activity. Two-years-old boy was diagnosed with classical phenylketonuria because of mental motor retardation. When the patient was 9-year-old, he developed acute myeloblastic leukemia. Here, we present the case with phenylketonuria and acute myeloblastic leukemia because of its extreme rarity. PMID- 21792032 TI - Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant. AB - A 6-week-old boy presented with fever, pallor, and hepatomegaly. Ultrasound showed a huge midline abdominal mass. beta-human chorionic gonadotropin was markedly elevated, suggesting a diagnosis of infantile choriocarcinoma of the liver. A biopsy confirmed the diagnosis. The patient received 6 cycles of bleomycin, cisplatin, and etoposide with significant decrease in tumor size. However, the tumor remained unresectable. A donor liver became available, and the infant underwent successful liver transplantation. He received 2 posttransplant cycles of moderate dose of methotrexate. This case shows the use of liver transplantation in cases of infantile choriocarcinoma of the liver where the tumor remains unresectable despite chemotherapy. PMID- 21792033 TI - James B. Nachman, 1948 to 2011: a remembrance. PMID- 21792034 TI - Reducing the risk for adrenal insufficiency in those treated for all: tapering glucocorticoids before abrupt discontinuation. PMID- 21792035 TI - Alloimmunization and erythrocyte autoimmunization in transfusion-dependent Egyptian thalassemic patients. AB - BACKGROUND: Alloimmunization to red blood cells' (RBCs) antigens and formation of autoantibodies against RBCs is a frequent complication among immunocompetent transfusion-dependent patients. Autoantibodies can result in clinical hemolysis and difficulty in cross-matching blood. The objective of this study was to evaluate the presence of alloantibodies and autoantibodies in regularly transfused beta-thalassemic patients and the factors influencing the development of alloantibodies. MATERIALS AND METHODS: The clinical and transfusion records of 95 Egyptian beta-thalassemic patients, with a mean age of 17.07 years, presenting to the National Blood Transfusion Centre for regular blood transfusion were evaluated for alloimmunization and antibody formation. RESULTS: Alloantibodies were encountered in 27 patients (28.4%). The most frequent alloantibodies encountered were anti-Kell (23.6%) and anti-E (23.6%). Patients with blood group O were the highest in developing antibodies (37.9%). Patients with blood phenotypes R2r Kell negative developed more alloantibodies. Autoantibodies were encountered in only 1 patient. CONCLUSIONS: Alloimmunization to RBCs' antigens is a frequent finding among Egyptian transfusion-dependent thalassemic patients, with the majority of patients being transfused with blood matched for ABO and D antigens only. Absence of phenotypically matched donors, except for a limited number of patients, may have contributed to this problem. PMID- 21792036 TI - The use of incentive spirometry in pediatric patients with sickle cell disease to reduce the incidence of acute chest syndrome. AB - INTRODUCTION: To determine if incentive spirometry (IS) in pediatric patients admitted with sickle cell disease for nonrespiratory complaints will decrease acute chest syndrome (ACS). METHODS: This was an Institutional Review Board approved before-after 2-year retrospective cohort study evaluating an evidence based guideline (EBG) initiating mandatory IS in admitted pediatric sickle cell patients from a tertiary children's emergency center. Student t testing and chi2 analysis were performed. RESULTS: There were 1551 patient visits. About 258 visits were enrolled in the pre-EBG year, and 230 in the EBG year. Between year characteristics were similar. The EBG year reported higher use of hydroxyurea (P<0.01), analgesics (P=0.02), and chest pain (P=0.03). Sixty-seven patients (25.9%) in the pre-EBG year received transfusions versus 51 (22.5%) in the EBG year (NS). Twenty-five (9.6%) of the pre-EBG patients received blood for ACS versus 14 (6.1%) in the EBG group (absolute risk reduction: 3.5%, 95% confidence interval: -1-8.4%). Subgroup analysis revealed that patients who presented with back pain experienced a significant decrease in the development of ACS in the EBG year (P=0.04, absolute risk reduction: 14%, 95% confidence interval: 1-28%, number needed to treat: 8). CONCLUSION: Mandatory IS for sickle cell disease patients admitted without respiratory complaints reduces transfusions and ACS, particularly for those presenting with back pain. PMID- 21792037 TI - Risk factors for acute chest syndrome in patients from low socioeconomic background: a cohort study from Sergipe, Brazil. AB - A prospective cohort study to assess the risk factors for acute chest syndrome (ACS) in individuals with sickle cell disease was carried out in a referral center from Sergipe, Brazil. A total of 168 SS homozygotic individuals (ages between 12 wk and 26 y) were followed for 12 months. There were 134 admissions of 81 patients. There were 50 events of ACS, which was the second most frequent cause of hospital admission (after pain crisis). One patient died of ischemic stroke during follow up. In bivariate analysis, the following variables showed statistically significant associations with the occurrence of ACS: age less than 5 years, living in rural area, history of previous hospital admission; white blood cell count greater than 10,000/dL; hemoglobin concentration less than 7 g/dL and oxygen saturation <= 95% on admission. After controlling for confounding in multivariate logistic regression, only a history of previous admission remained as an independent predictor of ACS (relative risk=4.20; 95% confidence interval: 1.79-9.87; P=0.001). Patients with a positive history of hospital admission are under increased risk and should be monitored closely for prevention and early detection of ACS. PMID- 21792038 TI - Expression of Ikaros isoform 6 in chinese children with acute lymphoblastic leukemia. AB - Ikaros is a zinc-finger transcription factor that plays an important role in the differentiation and proliferation of lymphocytes. Dominant-negative Ikaros isoform 6 (Ik6), one of its common subtypes, is overexpressed in leukemia patients and is associated with unfavorable prognosis in childhood B-cell progenitor acute lymphoblastic leukemia (ALL). This study was to identify specific isoforms, especially Ik6, in Chinese pediatric patients with ALL. The mRNA expression of Ikaros was detected in 88 children with previously untreated ALL by nested reverse transcription-polymerase chain reaction (RT-PCR). Sequencing of the PCR products was performed to identify specific isoforms. The expression of fusion genes was determined by using multiplex RT-PCR. The functional isoforms Ik1, Ik2/3, and dominant negative isoforms Ik4, 6, 8, 9, 10 identified by nested RT-PCR were further confirmed by sequence analysis. In the 88 cases, the Ik6 was found to be overexpressed in 8 of 70 cases of B-lineage ALL and in 1 of 18 cases of T-lineage ALL patients. Among Ik6 B-lineage ALL patients, 3 had expression of BCR/ABL fusion gene and 1 had HOX11 expression. Ik6 overexpression was independent of age, white blood cell count at diagnosis, risk group, and expression of the fusion genes currently measured in China except BCR/ABL (P<0.01). And it was strongly associated with elevated levels of minimal residual disease at day 28 (P<0.01). Ik6 can be included as a high-risk factor at diagnosis. In developing countries with limited resources, it can be economically detected by nested RT-PCR. PMID- 21792039 TI - Immunophenotypic, cytogenetic, and clinical features of 207 cases of childhood acute lymphoblastic leukemia in china. AB - OBJECTIVE: In this study, we investigated the immunophenotypic subtype profiles of 207 Chinese children with acute lymphoblastic leukemia (ALL) and its association with cytogenetics and clinical features. METHODS: A total of 207 children with ALL were immunophenotyped by 4-color flow cytometry using a panel of monoclonal antibodies. Among the 207 patients enrolled in this study, 146 cases were also subjected to karyotype analysis by R-banding technology. RESULTS: Of the 207 children with ALL, 11.6% were identified as T-ALL and 88.4% as B-ALL. Among B-ALL, 6.6% were identified as Pro-B ALL, 67.2% as Com-B ALL, 24.0% as Pre B ALL, and 2.2% as mature-B ALL. Myeloid antigen (MyAg) expression was documented in 42.5% of the 207 cases analyzed and CD13 was the most commonly expressed MyAg (31.4%). No difference was observed in the expression of MyAg between the groups of patients with T-ALL (41.7%) and B-ALL (42.6%). Abnormal karyotypes were detected in 84 of 146 (57.5%) children. The clinical and biological characteristics of ALL patients between the MyAg+ and MyAg- groups showed that a higher percentage of patients with high WBC count (>50*109/L) and higher CD34 positivity were found to be correlated with MyAg+ ALL. CONCLUSIONS: Our results indicate that the distribution of ALL in Chinese children was similar to the general distribution pattern in other countries. Unlike previous studies, we found that the expression of MyAg in children with T-ALL and B-ALL was comparable, and the percentage of patients with a high WBC count (>50*109/L) and CD34 positivity in MyAg+ was higher than that in MyAg- ALL types, but no differences were found with regard to other clinical features. PMID- 21792040 TI - Duration of adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia. AB - Children with acute lymphoblastic leukemia (ALL) recive high doses of glucocorticosteroid as part of their treatment. This may lead to suppression of the hypothalamic-pituitary-adrenal axis, acute adrenal insufficiency, and ultimately to life-threatening conditions. This study explores the adrenal function in 96 children with ALL treated according to common protocols. After cessation of induction glucocorticosteroid therapy, they received hydrocortisone substitution therapy (10 mg/m/24 h) until an adrenocorticotropic hormone test (250 MUg tetracosatide) showed a sufficient adrenal response [plasma (p)-cortisol >=500 nM]. At the first adrenocorticotropic hormone test, 67% of the patients had adrenal insufficiency. When including these patients in a multivariate model, not adjusting for risk factors, the mean elapsed time between end of induction therapy and adrenal sufficiency was 8.5 months (95% confidence interval: 6.3;10.7). Low 0-minute p-cortisol (P=0.02) and low rise in p-cortisol (P<0.0001) at first test caused a longer time of adrenal insufficiency. In addition, patients with B-cell precursor leukemia reached adrenal sufficiency later than those with T-cell leukemia (P=0.067). As adrenal insufficiency is frequent in children treated for ALL and as they often experience infections and other stressors, the adrenal response should be determined and hydrocortisone substitution therapy should be considered during such episodes in patients with adrenal insufficiency. PMID- 21792041 TI - Polycythemia and adrenal cortex tumor in children: a case report and literature review. AB - Brazil has the world's highest incidence of adrenal cortex tumor in childhood, mainly in Parana and Sao Paulo states. The diagnosis in children is done by the signs and symptoms secondary to the production of adrenal cortex hormones. The occurrence of polycythemia in patients with adrenal cancer is very rare, especially in children. The authors describe a case of adrenal cortex tumor in a child diagnosed during investigation of polycythemia. In the case described, the polycythemia was justified by increased production of erythropoietin. PMID- 21792042 TI - Pulmonary glial heterotopia in a child diagnosed with fanconi anemia and epilepsy. AB - BACKGROUND: Pulmonary glial heterotopia is rare and its pathogenesis is still obscure as for Fanconi anemia (FA). OBSERVATION: This study describes a very rare case of an incidental finding of pulmonary glial heterotopia in a girl diagnosed with FA, epilepsy, and mental retardation. Before this report, the association of pulmonary glial heterotopia and FA had not been described. CONCLUSIONS: The unique finding in this patient could be a link between FA and abnormal cell migration, but it certainly teaches us that there is still much to be learnt of the molecular mechanisms underlying the clinical manifestations in FA. PMID- 21792043 TI - Autoimmune thrombocytopenic purpura in partial DiGeorge syndrome: case presentation. AB - The absence of an appropriate central tolerance in primary immunodeficiencies favors proliferation of autoreactive lymphocyte clones, causing a greater incidence of autoimmunity. Del 22q11.2 syndrome presents an increased incidence of allergic and autoimmune diseases. One of the most relevant and frequent immune manifestations is autoimmune thrombocytopenia. We present the case of a pediatric patient with autoimmune thrombocytopenia due to the immunological dysregulation observed in partial DiGeorge syndrome. PMID- 21792044 TI - Normal hemoglobin at the age of 1 year does not protect infants from developing iron deficiency anemia in the second year of life. AB - BACKGROUND: Iron deficiency anemia (IDA) is the most common hematologic disorder worldwide. Measures to prevent IDA in infants have been successful with questionable sustainability. AIM: To evaluate the incidence of developing IDA in the second year of life, in infants who were nonanemic at the age of 1 year on routine blood test. METHODS: Blood samples were obtained from 193, 24-month-old toddlers, from 2 large clinics of both main sectors in Southern Israel, comparable for lower economic status. IDA was defined as hemoglobin < 11 gr% and microcytosis as mean corpuscular volume < 70 fL. RESULTS: IDA was detected in 8 of 118 Bedouins (5 males) and in 10 of 75 Jewish (6 males) infants (P < 0.01). The probability of a nonanemic child to develop IDA in the second year of life for the whole study population was 9.3% (18 of 193 infants) and significantly higher in the Jewish population (13.3.0% vs. 6.8%, P < 0.01). CONCLUSIONS: Given the difficulty of toddlers to maintain a non-IDA status, and the very low probability of iron overload, our results clearly support the need to continue iron supplementation into the second year. PMID- 21792045 TI - Survival outcome of childhood acute lymphoblastic leukemia in India: a resource limited perspective of more than 40 years. AB - The outcome of childhood acute lymphoblastic leukemia in India has been inferior to more than 80% cure rates in developed nations. This study was done to analyze the outcome of acute lymphoblastic leukemia in India over 4 decades. There has been a gradual improvement in survival rates of up to >70% in some centers along with a decline in relapse and mortality. However, these results cannot be generalized to the entire nation. There is a crying need to address treatment abandonment, take quality improvement, educational and financial initiatives; cooperative research into risk factors and disease biology, and the implementation of risk stratification along with the assessment of response to therapy. PMID- 21792046 TI - Polytetrafluoroethylene membrane (Gore Preclude Vessel Guard) for vessel protection during anterior lumbar surgery: a preliminary study in pigs. AB - STUDY DESIGN: The effects of implanting a polytetrafluoroethylene (PTFE) membrane (Gore Preclude Vessel Guard, WL Gore and Associates, Flagstaff, AZ) during anterior lumbar surgery were studied in a pig model. OBJECTIVE: We investigated whether placement of a PTFE membrane between the great vessels and anterior surface of the lumbar spine would minimize adhesions. SUMMARY OF BACKGROUND DATA: Anterior lumbar procedures continue to increase, as do revision operations. Anterior approaches remain challenging, however, because of the considerable risk of vascular injury. The risk is especially high with revision procedures because of the presence of adhesions that can hinder visualization and mobilization of vessels. Use of an anti-adhesion barrier may decrease the rate of vascular complications associated with revision surgery. METHODS: Three spinal levels in 3 pigs were subjected to either discectomy, creation of a hole in the disc, or disc exposure only. In 5 of the 9 levels, a PTFE membrane was then implanted over the disc; the other 4 levels were controls. Spine segments were obtained 12 weeks later, and the tenacity of adhesions (scale of 0 to 4) and percentage of disc space covered by adhesions were assessed. The specimens were also studied histologically. RESULTS: Mean values for adhesion tenacity were 2.75 for control spinal levels and 0.4 for levels with a PTFE membrane (P=0.008). Mean values for adhesion coverage were 81% for control disc spaces and 15% for spaces with a PTFE membrane (P=0.008). Histologic studies showed minimal adhesions, lack of an inflammatory reaction, and vascularized connective tissue between PTFE membranes and the vena cava. CONCLUSIONS: In a pig model, implantation of a PTFE membrane during anterior lumbar surgery decreased the tenacity and amount of adhesions observed at necropsy. Studies of the efficacy and safety of the PTFE membrane in clinical anterior lumbar surgery are warranted. PMID- 21792047 TI - First successful double lung transplantation from brain death donor in China. PMID- 21792048 TI - Gout and transplantation: new treatment option-same old drug interaction. PMID- 21792049 TI - Lower malignancy rates in renal allograft recipients converted to sirolimus based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. AB - BACKGROUND: Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI) free regimen. METHODS: This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person years of follow-up). RESULTS: At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). CONCLUSION: In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance. PMID- 21792050 TI - Perioperative point-of-care ultrasonography: the past and the future are in anesthesiologists' hands. PMID- 21792051 TI - Intraoperative pneumothorax identified with transthoracic ultrasound. PMID- 21792052 TI - Steroids to ameliorate postoperative pain. PMID- 21792053 TI - MyD88 and Trif signaling play distinct roles in cardiac dysfunction and mortality during endotoxin shock and polymicrobial sepsis. AB - BACKGROUND: Toll-like receptors (TLRs) such as TLR2, TLR4, and TLR9 contribute to the pathogenesis of polymicrobial sepsis. These TLRs signal via the common myeloid differentiation factor 88 (MyD88)-dependent pathways. TLR4 also signals through MyD88-independent but TIR domain-containing adaptor inducing interferon beta-mediated transcription factor (Trif)-dependent pathway. The role of the two signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock is unknown. METHODS: Sepsis was generated by cecum ligation and puncture. Mice were divided into sham and cecum ligation and puncture groups or subjected to saline or endotoxin. Left ventricular function was assessed in a Langendorff apparatus or by echocardiography. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. RESULTS: In comparison with wild-type mice, MyD88( /-) but not Trif(-/-) mice had markedly improved cardiac function and survival after cecum ligation and puncture. In comparison, both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock. Septic MyD88(-/-) but not Trif(-/-) mice had diminished cytokine production in serum and in peritoneal space in comparison with wild-type mice after cecum ligation and puncture. In contrast, both MyD88(-/-) and Trif(-/-) mice had attenuated serum cytokines in comparison with wild-type mice after endotoxin challenge. Neither MyD88(-/-) nor Trif(-/-) signaling had any effect on neutrophil phagocytic function or bacterial clearance at 24 h of polymicrobial sepsis. CONCLUSIONS: These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis. Both MyD88 and Trif are essential for cardiac depression and mortality during endotoxin shock. PMID- 21792055 TI - "Let's give some fluid and see what happens" versus the "mini-fluid challenge". PMID- 21792054 TI - Reducing noninfectious risks of blood transfusion. AB - As screening for transfusion-associated infections has improved, noninfectious complications of transfusion now cause the majority of morbidity and mortality associated with transfusion in the United States. For example, transfusion related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion-reactions are the first, second, and third leading causes of death from transfusion, respectively. These complications and others are reviewed, and several controversial methods for prevention of noninfectious complications of transfusion are discussed, including universal leukoreduction of erythrocyte units, use of male-only plasma, and restriction of erythrocyte storage age. PMID- 21792057 TI - Effects of topical cyclosporine a plus artificial tears versus artificial tears treatment on conjunctival goblet cell density in dysfunctional tear syndrome. AB - OBJECTIVES: The aim was to compare the effects of topical cyclosporine A and artificial tears combination with artificial tears alone in patients with dysfunctional tear syndrome (DTS). METHODS: Forty-two eyes of 42 patients with DTS were enrolled in the study. The inclusion criteria for the study were Schirmer I (without anesthesia) scores below 10 mm/5 min and tear film break-up time (BUT) below 10 sec. The patients were randomly divided into two groups. The study group (22 patients) underwent 0.05% cyclosporine A treatment twice a day and preservative-free artificial tears for four times a day for 4 months. The control group (20 patients) was administered only preservative-free artificial tears four times a day for 4 months. The BUT, Schirmer test scores, corneal fluorescein staining, conjunctival lissamine green staining, and goblet cell density derived by impression cytology were recorded before and after treatment in each group. RESULTS: In the study group, all parameters improved statistically significantly after treatment at the 4-month follow-up compared with the pretreatment values (P<0.001 for all). In the control group, corneal fluorescein staining (P<0.001) and conjunctival lissamine green staining (P=0.014) improved, but BUT and Schirmer scores did not change significantly after treatment. At the end of the 4-month follow-up, the study group demonstrated statistically significantly better BUT (P=0.020), Schirmer scores (P=0.002), goblet cell density (P=0.006), corneal fluorescein staining (P=0.003), and conjunctival lissamine green staining (P=0.017) scores than did the control group. CONCLUSIONS: Topical cyclosporine A and artificial tears treatment significantly increases goblet cell density, decreases the signs of DTS, and improves ocular surface health. PMID- 21792056 TI - An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. AB - BACKGROUND: Predicting fluid responsiveness remains a difficult question in hemodynamically unstable patients. The author's objective was to test whether noninvasive assessment by transthoracic echocardiography of subaortic velocity time index (VTI) variation after a low volume of fluid infusion (100 ml hydroxyethyl starch) can predict fluid responsiveness. METHODS: Thirty-nine critically ill ventilated and sedated patients with acute circulatory failure were prospectively studied. Subaortic VTI was measured by transthoracic echocardiography before fluid infusion (baseline), after 100 ml hydroxyethyl starch infusion over 1 min, and after an additional infusion of 400 ml hydroxyethyl starch over 14 min. The authors measured the variation of VTI after 100 ml fluid (DeltaVTI 100) for each patient. Receiver operating characteristic curves were generated for (DeltaVTI 100). When available, receiver operating characteristic curves also were generated for pulse pressure variation and central venous pressure. RESULTS: After 500 ml volume expansion, VTI increased >= 15% in 21 patients (54%) defined as responders. DeltaVTI 100 >= 10% predicted fluid responsiveness with a sensitivity and specificity of 95% and 78%, respectively. The area under the receiver operating characteristic curves of DeltaVTI 100 was 0.92 (95% CI: 0.78-0.98). In 29 patients, pulse pressure variation and central venous pressure also were available. In this subgroup of patients, the area under the receiver operating characteristic curves for DeltaVTI 100, pulse pressure variation, and central venous pressure were 0.90 (95% CI: 0.74-0.98, P < 0.05), 0.55 (95% CI: 0.35-0.73, NS), and 0.61 (95% CI: 0.41-0.79, NS), respectively. CONCLUSION: In patients with low volume mechanical ventilation and acute circulatory failure, DeltaVTI 100 accurately predicts fluid responsiveness. PMID- 21792058 TI - Contact lens characteristics and contrast sensitivity of patients with keratoconus. AB - OBJECTIVES: The aim was to describe the contact lens characteristics and contrast sensitivity of patients with keratoconus managed conservatively with contacts lenses at a tertiary eye center in Singapore. METHODS: A prospective cross sectional study of 116 patients with clinically evident or suspected keratoconus (on videokeratography) recruited over 11 months. Demographic and medical details, visual acuity (VA) and refraction, corneal topography and contact lens characteristics were documented. Contrast sensitivity with contact lenses was performed with the Vision Contrast Test System 6500 under standardized conditions. RESULTS: Overall, 67% of the study patients were wearing contact lenses. Of the 129 eligible eyes analyzed, there were 108 eyes with keratoconus and 21 eyes with keratoconus suspect, and 94% were fitted with rigid gas permeable (RGP) lenses. Proprietary keratoconus design lenses were fitted in 74.9% of keratoconus eyes and 30.0% of suspect eyes. With contact lens wear, 83.3% of keratoconus eyes and 100% of suspect eyes achieved 0.3 vision. Mean contrast sensitivity curves of eyes with keratoconus and keratoconus suspect were found to be within normal, although contrast sensitivity in the keratoconus group was consistently lower. CONCLUSIONS: Most of our patients were managed conservatively with contact lenses, and keratoconus design RGP lenses were the most common type fitted. Good VA can be achieved, but patients with keratoconus may still experience a reduction in contrast sensitivity. PMID- 21792059 TI - Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. AB - PURPOSE: : Recently, molecular cytogenetic techniques have identified novel copy number variants in individuals with schizophrenia. However, no large-scale prospective studies have been performed to characterize the broader spectrum of phenotypes associated with such copy number variants in individuals with unexplained physical and intellectual disabilities encountered in a diagnostic setting. METHODS: : We analyzed 38,779 individuals referred to our diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. We also analyzed the indications for study for individuals with copy number variants overlapping those found in six individuals referred for schizophrenia. RESULTS: : After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), we identified 1113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the six individuals referred to our laboratory for schizophrenia. Of these, 1035 had a copy number variant of one of six recurrent loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. The indications for study for these 1150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. CONCLUSION: : The results from our study, the largest genotype-first analysis of schizophrenia susceptibility loci to date, suggest that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions. PMID- 21792060 TI - Factors affecting the value of professional association affiliation. AB - BACKGROUND: The resource-based view of the firm suggests that organizations must obtain valuable resources from external sources to obtain lasting benefits. Professional associations today exist in every industry and offer resources to assist their affiliates' organizations and individual members. Today, there are more than 23,000 national and 64,000 state, local, and regional professional associations that claim to significantly benefit their affiliates. The value of these benefits and what organizational and individual factors that may affect their value have not been explored. PURPOSE: This article explores the influence of organizational and individual factors on the value of resources offered by a prominent health care professional association. METHODOLOGY/APPROACH: Data from a national survey of hospital CEOs were combined with American Hospital Association data for descriptive statistics and regression analyses to examine the organizational and individual characteristics influencing the value of professional association affiliation. FINDINGS: Our research suggests that most hospital CEOs perceived value in the resources provided by their primary professional organization. In addition, both organizational and individual factors contributed to the perceived value of professional association affiliation. Significant organizational influences included hospital ownership and system membership, which were related to less importance and value from affiliation. Positive and significant individual characteristics included certification as an association fellow and CEOs who have a high value for coaching. Interestingly, men perceived less organizational value from affiliation and older CEOs saw less individual value. PRACTICAL IMPLICATIONS: Executives considering affiliating with a professional association can better understand how existing affiliates perceive and value the associations' benefits. In addition, executives and professional associations can be more informed how professional association affiliation is significantly influenced by organizational and individual characteristics. Individuals, organizations, and professional associations should be aware of the perceptions and differences among those who do and could avail themselves of professional association resources. PMID- 21792061 TI - HIV infection and progression of carotid and coronary atherosclerosis: the CARE study. AB - BACKGROUND: Progression of carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) are increasingly used as surrogates for vascular risk. We assessed the predictors of c-IMT and CAC progression in a large longitudinal cohort of HIV-infected adults. METHODS: c-IMT, CAC scores, and vascular and HIV risk factors were evaluated at baseline and at 3-year follow-up in 255 HIV infected adults. Multivariate regression was used to determine the predictors of atherosclerotic progression. RESULTS: The mean change in c-IMT per year of follow up was 0.016 mm for the common and 0.020 mm for the internal. Significant predictors of yearly progression were age, systolic blood pressure, triglycerides, and insulin for common c-IMT and triglycerides >=150 mg/dL, glucose >126 mg/dL, use of glucose-lowering medications, quantitative insulin sensitivity check index, high waist circumference, and current smoking for internal c-IMT. Twenty-eight percent had CAC progression. Of those with zero CAC at baseline, 32% had detectable scores at follow-up. Of those with detectable CAC at baseline, 26% had progression at follow-up. For CAC score, quantitative insulin sensitivity check index, apolipoprotein B, and triglycerides predicted progression. Those with abnormal surrogate markers at baseline were more likely to have the metabolic syndrome reversed and be started on antihypertensive medications over the 3-year follow-up period than those who had no abnormalities at baseline. CONCLUSIONS: Although c-IMT and CAC progression rates in HIV infected patients appear higher than expected for this age and risk groups, traditional cardiovascular risk factors remain the strongest determinants of carotid and coronary atherosclerotic disease progression in HIV-infected patients. Aggressive cardiovascular risk reduction is effective at slowing the atherosclerotic progression in those with preexisting disease. PMID- 21792062 TI - Highly active antiretroviral therapy versus zidovudine for prevention of mother to-child transmission in a programmatic setting, Botswana. AB - Few studies have compared the programmatic effectiveness of the recommended strategies of antenatal highly active antiretroviral therapy (HAART) and zidovudine for prevention of mother-to-child transmission. We prospectively followed infants (93% formula fed) whose mothers who took either HAART (258 infants) or zidovudine (170 infants) during pregnancy in the Botswana national program. Overall, 10 infants (2.5%) acquired HIV--9 infants in the zidovudine group (5.5%, 95% confidence interval: 2.6% to 10.2%) and 1 infant in the HAART group (0.4%, 95% confidence interval: 0.0% to 2.2%). Maternal HAART was associated with decreased prevention of mother-to-child transmission (P = 0.001) and improved HIV-free survival (P = 0.040) compared with zidovudine (with or without single-dose nevirapine) in a programmatic setting. PMID- 21792063 TI - European mitochondrial DNA haplogroups and metabolic disorders in HIV/HCV coinfected patients on highly active antiretroviral therapy. AB - BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups play an important role in susceptibility to metabolic disorders and cardiovascular disease. METHODS: We carried out a cross-sectional study in 248 HIV/hepatitis C virus-coinfected patients on highly active antiretroviral therapy to investigate whether mtDNA haplogroups had any influence on metabolic disorders. mtDNA genotyping was performed using the Sequenom MassARRAY platform. Insulin resistance (IR) was estimated using the homeostatic model assessment (HOMA) (HOMA >= 3.8), which was calculated as fasting plasma glucose (mmol/L) times fasting serum insulin (mU/L) divided by 22.5. A high atherogenic risk was assessed when the atherogenic index (AI) was >=3.5. AI was calculated as total cholesterol (mg/dL) divided by HDL (mg/dL). RESULTS: The major haplogroup HV and haplogroup H had reduced odds ratios of IR (HOMA >= 3.8) [0.45 (95% CI: 0.24 to 0.85) and 0.36 (95% CI: 0.18 to 0.69), respectively], and high AI (AI >= 3.5) [0.44 (95% CI: 0.22 to 0.87) and 0.40 (95% CI: 0.19 to 0.80), respectively]. The major haplogroup U had increased odds of IR [2.66 (95% CI: 1.39 to 5.8)]. The major haplogroup JT and haplogroup T had increased odds of high AI [2.86 (95% CI: 1.29 to 6.33) and 4.01 (95%CI: 1.59 to 10.03), respectively]. Additionally, we found that patients belonging to the major haplogroup HV had lower values of serum hepatic growth factor and nerve growth factor, and higher values of adiponectin than patients belonging to the major haplogroup JT (P < 0.05). CONCLUSIONS: mtDNA haplogroups were associated with IR and atherogenic dyslipidemia; suggesting that mitochondrial genomics may play a significant role in metabolic disorders and cardiovascular diseases in HIV/hepatitis C virus-coinfected patients on highly active antiretroviral therapy. PMID- 21792065 TI - Disease-modifying therapeutic concepts for HIV in the era of highly active antiretroviral therapy. AB - Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials. PMID- 21792064 TI - The interrelated transmission of HIV-1 and cytomegalovirus during gestation and delivery in the offspring of HIV-infected mothers. AB - Our objective was to analyze, in formula-fed infants, correlates of HIV mother-to child transmission, including cytomegalovirus (CMV) infection. HIV-infected infants were matched with HIV uninfected by maternal HIV RNA in a case-control design. Infant CMV infection was determined by CMV IgG at 18 months and timed by earlier CMV IgM or CMV DNA. Correlations were assessed using logistic regression. In utero HIV infection was independently associated with congenital CMV infection (P = 0.01), intrapartum HIV infection with congenital-plus-intrapartum/neonatal CMV infection (P = 0.01), and overall HIV with overall CMV infection (P = 0.001), and prematurity (P = 0.004). Congenital and acquired CMV infections are strong independent correlates of mother-to-child HIV transmission. PMID- 21792067 TI - Activation of NK cells by ADCC antibodies and HIV disease progression. AB - Antibody-dependent cellular cytotoxicity (ADCC) is of considerable interest as an immune response that may facilitate the control of HIV infection. We studied ADCC responses prospectively in a cohort of 79 HIV-positive subjects followed up for a mean of 2.3 years without antiretroviral therapy. We used a novel assay of the ability of ADCC to activate natural killer (NK) cells, either from the same HIV positive subject or from a healthy blood donor. We found that ADCC responses to either gp140 Env protein or HIV peptide pools were common in HIV-positive subjects when NK cells from the HIV-positive subject were used but did not correlate with markers of HIV disease progression. In contrast, ADCC responses to whole gp140 Env protein were strongly associated with a slower decline in CD4 T cell loss when healthy donor NK cells were used as effectors. Our data had implications for induction of the most effective ADCC responses by HIV vaccines. PMID- 21792068 TI - Emerging gram-negative infections in burn wounds. AB - Gram-negative infection remains a major contributor to morbidity, mortality, and cost of care. In the absence of comparative multinational epidemiological studies specific to burn patients, we sought to review literature trends in emerging Gram negative burn wound infections within the past 60 years. Mapping trends in these organisms, although in a minority compared with the six "ESKAPE" pathogens currently being targeted by the Infectious Diseases Society of North America, would identify pathogens of increasing concern to burn physicians in the near future and develop patient profiles that may predict susceptibility to infection. Aeromonas hydrophila infection was identified as the emerging pathogen of note, constituting 76% of the identified publications. A. hydrophila constituted 96% of Aeromonas spp. isolates (mortality 10.7%). The following patient profile indicated predisposition to Aeromonas infection: mean age (mean 33.7 years, range 17 <= R <= 80, SD = 15.6); TBSA (mean 41.1%, range 8% <= R <= 80%, SD = 15.2); full-thickness skin burns (mean 27.7%, range 3% <= R <= 60%, SD = 16.6); and a male predominance (81.3%). Other pathogens included Stenotrophomonas maltophilia Vibrio spp., Chryseobacterium spp., Alcaligenes xylosoxidans, and Cedecia lapigei. Arresting the thermal injury by untreated water was the common predisposing factor. These emerging infections clearly constitute a minority of Gram-negative bacterial infections in burn patients at present. However, these are the infections most likely to pose significant clinical challenge because of the high prevalence of multidrug resistance, rapid acquisition of multidrug resistance, high mortality, and ubiquity in the natural environment. This article therefore presents a rationale for understanding and recognizing the role of these emerging infections in burn patients. PMID- 21792066 TI - Mitochondrial genomics and CD4 T-cell count recovery after antiretroviral therapy initiation in AIDS clinical trials group study 384. AB - BACKGROUND: Mitochondrial DNA (mtDNA) variation has been associated with time to progression to AIDS and adverse effects from antiretroviral therapy (ART). In this study, full mitochondrial DNA (mtDNA) sequence data from US-based adult participants in the AIDS Clinical Trials Group study 384 was used to assess associations between mtDNA variants and CD4 T-cell recovery with ART. METHODS: Full mtDNA sequence was determined using chip-based array sequencing. Sequence and CD4 cell count data was available at baseline and after ART initiation for 423 subjects with HIV RNA levels <400 copies per milliliter plasma. The primary outcome was change in CD4 count of >=100 cells per cubic millimeter from baseline. Analyses were adjusted for baseline age, CD4 cell count, HIV RNA, and naive:memory CD4 cell ratio. RESULTS: Race-stratified analysis of mtDNA variants with a minor allele frequency >1% revealed multiple mtDNA variants marginally associated (P < 0.05 before Bonferroni correction) with CD4 cell recovery. The most significant single nucleotide polymorphism associations were those tagging the African L2 haplogroup, which was associated with a decreased likelihood of >=100 cells per cubic millimeter CD4 count increase at week 48 in non-Hispanic blacks (adjusted odds ratio = 0.17; 95% confidence interval = 0.06 to 0.53; P = 0.002). CONCLUSIONS: An African mtDNA haplogroup was associated with CD4 cell recovery after ART in this clinical trial population. These initial findings warrant replication and further investigation to confirm the role of mtDNA variation in CD4 cell recovery during ART. PMID- 21792069 TI - Takotsubo cardiomyopathy after minor burn injury. AB - The relationship between severe emotional stress and subsequent acute cardiac dysfunction has been anecdotally noted for decades. In fact, cases of "death by fright" have been described since ancient times, and a growing body of evidence suggests that this phenomenon is due to an acute catecholamine-induced cardiomyopathy. The authors present a case of Takotsubo cardiomyopathy complicating a minor burn injury that occurred during an operating room fire. Two PEA arrests occurred immediately after injury, and an intra-aortic balloon pump was required due to hemodynamic instability. The diagnosis was confirmed by echocardiogram and cardiac catherization. This condition is often unrecognized as a cause of hemodynamic instability and may be more common after burn injury than we presently recognize. PMID- 21792070 TI - Microcomputed tomographic evaluation of vertebral microarchitecture in pinealectomized scoliosis chickens. AB - Pinealectomy was used to induce scoliosis in Broiler chickens, and the bone microarchitecture of the concave and convex sides in pinealectomized scoliosis chickens was assessed by microcomputed tomography (micro-CT). Few studies have assessed the vertebrae bone microarchitecture of the concave and convex sides in scoliosis although the curvature of the coronal plane is the main deformity in scoliosis. The purpose of this study was to determine whether there are differences in the bone microarchitecture of the concave and convex sides in pinealectomized scoliosis chickens by the technique of micro-CT. The etiology and the pathogenesis of the idiopathic scoliosis remain unclear. Limited information is available on the microarchitecture of vertebrae bone of the concave and convex sides of scoliosis, especially in the earlier stage in scoliosis development. One hundred female Broiler chickens were divided into three groups as follows: the control group (n=20), the sham operation group (n=20), and the pinealectomy group (n=60). Then the pinealectomy group was divided into three groups according to the time of killing the chickens: 1-week after the operation (group P-1 w, n=20), 2 weeks after the operation (group P-2 w, n=20), and 3 weeks after the operation (group P-3 w, n=20), respectively. Posteroanterior radiographs of the spine were taken to detect spinal curvature. Using micro-CT, the bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation of the concave and convex sides of the apex vertebrae in the scoliotic chickens were determined. Independent t-tests were used to assess differences of bone parameter of the concave and convex sides in each pinealectomized group. The incidences of scoliosis in the pinealectomized Broiler chickens were 84.2% (group P-1 w), 88.9% (group P-2 w), and 89.5% (group P-3 w), respectively. In groups P-1 w and P-2 w, there were no differences between the concave and convex trabecular bone microarchitectures. In group 3 w, the BV/TV, Tb.Th, and Tb.N of the concave side were significantly greater than those of the convex side. In the earlier stage of pinealectomized scoliosis chickens, there are no histological evidence of a metabolic abnormality. The greater BV/TV, Tb.Th, and Tb.N of the concave side in group P-3 w may be consistent with Wolff's law and are the secondary response to the scoliotic deformity. PMID- 21792071 TI - Ten minutes of dynamic stretching is sufficient to potentiate vertical jump performance characteristics. AB - The current literature recommends dynamic rather than static stretching for the athletic warm-up. Dynamic stretching and various conditioning stimuli are used to induce potentiation in subsequent athletic performance. However, it is unknown as to which type of activity in conjunction with dynamic stretching within a warm-up provides the optimal potentiation of vertical jump performance. It was the objective of the study to examine the possible potentiating effect of various types of conditioning stimuli with dynamic stretching. Twenty athletes participated in 6 protocols. All the experimental protocols included 10 minutes of dynamic stretching. After the dynamic stretching, the subjects performed a (a) concentric (DS/CON): 3 sets of 3 repetition maximum deadlift exercise; (b) isometric (DS/ISOM): 3 sets of 3-second maximum voluntary contraction back squats; (c) plyometric (DS/PLYO): 3 sets of 3 tuck jumps; (d) eccentric (DS/ECC): 3 modified drop jumps; (e) dynamic stretching only (DS), and (f) control protocol (CON). Before the intervention and at recovery periods of 15 seconds, 4, 8, 12, 16, and 20 minutes, the participants performed 1-2 maximal countermovement jumps. The DS and DS/CON protocols generally had a 95-99% likelihood of exceeding the smallest worthwhile change for vertical jump height, peak power, velocity and force. However, the addition of the deadlift to the DS did not augment the potentiating effect. Time-to-peak potentiation was variable between individuals but was most consistent between 3 and 5 minutes. Thus, the volume and the intensity associated with 10 minutes of dynamic stretching were sufficient to provide the potentiation of vertical jump characteristics. Additional conditioning activities may promote fatigue processes, which do not permit further potentiation. PMID- 21792072 TI - The effect of whole-body vibration training and conventional strength training on performance measures in female athletes. AB - The purpose of this study was to examine the effects of regular whole-body vibration (WBV) training on lower body strength and power. National Collegiate Athletic Association Division III softball athletes (n = 9) completed the 9-week protocol as part of their off-season strength and conditioning program. The athletes were randomly assigned to 1 of 2 groups. Week 1, pretesting included 3 repetition maximum (3RM) back squat, standing long jump (SLJ), and vertical countermovement jump (VCMJ). Phase I training (weeks 2-4) consisted of either WBV training (group 1) or conventional strength training (CST, group 2). The primary programmatic difference between WBV and CST was the inclusion of WBV sets after squat sets. Posttesting (3RM squat, SLJ, VCMJ) occurred at week 5. Phase II training (weeks 6-8) consisted of either WBV training (group 2) or CST (group 1). Posttesting was repeated at week 9 after the completion of phase II. Three 2 * 2 mixed factorial analyses of variance were computed. No significant differences (p > 0.05) were found between groups or between groups and testing period for the SLJ, VCMJ, and estimated 1RM back squat. Increases (p < 0.05) were observed in SLJ, VCMJ, and back squat from pretest to posttest 1. Back squat increased (p < 0.05) from posttest 1 to posttest 2. All the athletes experienced significantly greater (p < 0.05) percent changes from pretest to posttest 1 for SLJ and VCMJ. These results indicate that the inclusion of WBV as part of an off-season strength and conditioning program has no apparent benefit over CST methods for collegiate softball players. PMID- 21792074 TI - Contemporary results of surgical resection of non-small cell lung cancer after induction therapy: a review of 549 consecutive cases. AB - OBJECTIVE: We previously reported a high mortality after induction therapy and pneumonectomy for non-small cell lung cancer. Recent reports suggest that operative mortality in these patients is declining. We analyzed our contemporary results to define operative mortality and factors determining surgical risk. METHODS: Eligible patients were identified from our prospective surgical database. Complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Uni- and multivariate logistic regression models assessed the association of preoperative tests and clinical characteristics with outcome. Receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) statistics were calculated in a leave-one-out crossvalidation scheme to evaluate the predictive value of various models. RESULTS: From January 2000 to December 2006, 549 patients underwent surgery after induction therapy. Median patient age was 64 years (range: 30-86), and 54% were women (298/549). All received chemotherapy, and 17% also had radiation. Lobectomy (388/549, 71%) and pneumonectomy (70/549, 13%) were the most common procedures. Complications occurred in 250 patients (46%), with grade 3 or higher in 23% (126/549). Inhospital mortality was 1.8% (10/549), with only one death after right pneumonectomy (1/30, 3%). Multivariate analysis showed that predicted postoperative (PPO) pulmonary function was associated with postoperative morbidity. By receiver operating characteristic curves, PPO product (AUC = 0.75, p < 0.001), PPO diffusion capacity (AUC = 0.70, p < 0.001), and preoperative % predicted PPO diffusion capacity (AUC = 0.66, p < 0.001) predicted mortality. CONCLUSION: Our current experience shows that resection of non-small cell lung cancer after induction therapy, including pneumonectomy, is associated with low mortality. PPO pulmonary function is the strongest predictor of operative risk and should be used to select patients for surgery. PMID- 21792073 TI - Development and validation of a quantitative real-time polymerase chain reaction classifier for lung cancer prognosis. AB - INTRODUCTION: This prospective study aimed to develop a robust and clinically applicable method to identify patients with high-risk early-stage lung cancer and then to validate this method for use in future translational studies. METHODS: Three published Affymetrix microarray data sets representing 680 primary tumors were used in the survival-related gene selection procedure using clustering, Cox model, and random survival forest analysis. A final set of 91 genes was selected and tested as a predictor of survival using a quantitative real-time polymerase chain reaction-based assay using an independent cohort of 101 lung adenocarcinomas. RESULTS: The random survival forest model built from 91 genes in the training set predicted patient survival in an independent cohort of 101 lung adenocarcinomas, with a prediction error rate of 26.6%. The mortality risk index was significantly related to survival (Cox model p < 0.00001) and separated all patients into low-, medium-, and high-risk groups (hazard ratio = 1.00, 2.82, 4.42). The mortality risk index was also related to survival in stage 1 patients (Cox model p = 0.001), separating patients into low-, medium-, and high-risk groups (hazard ratio = 1.00, 3.29, 3.77). CONCLUSIONS: The development and validation of this robust quantitative real-time polymerase chain reaction platform allows prediction of patient survival with early-stage lung cancer. Utilization will now allow investigators to evaluate it prospectively by incorporation into new clinical trials with the goal of personalized treatment of patients with lung cancer and improving patient survival. PMID- 21792075 TI - The use of electrocautery as the primary ablation modality for malignant and benign airway obstruction. AB - BACKGROUND: Laser has been the main ablative modality in the airways, but a growing experience with endobronchial electrocautery suggests a comparable efficacy and safety profile. OBJECTIVES: To evaluate the efficacy and safety of electrocautery as the primary heat therapy for malignant and benign airway obstruction. METHODS: A retrospective review of all patients undergoing endobronchial electrocautery, alone or in combination with other airway tools, at Duke University Medical Center between April 2004 and November 2009. Data on efficacy (luminal patency, symptomatic, radiographic, or physiologic improvement) and safety (complication rate) were collected. RESULTS: Ninety-four patients underwent 117 procedures with endobronchial electrocautery for endobronchial malignant and nonmalignant disease. Endoscopic improvement was seen in 94% of cases. Seventy-one percent of patients reported symptomatic improvement. Radiographic studies demonstrated luminal improvement in 78% of patients on chest computed tomography, improved aeration on chest computed tomography and chest x ray in 63% and 43% of patients, respectively. The rate of major complications was 0.8%, whereas minor complications occurred in 6.8% of cases. There was no perioperative mortality. CONCLUSIONS: Endobronchial electrocautery is effective and safe when used as an ablative modality in malignant and benign airway obstruction and has a comparable profile to laser with the advantage of lower cost. PMID- 21792078 TI - In anticipation of menopause. PMID- 21792077 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of intrathoracic lymphadenopathy in patients with extrathoracic malignancy: a multicenter study. AB - INTRODUCTION: Mediastinal lymphadenopathy in patients with an extrathoracic malignancy is a common clinical scenario. Invasive sampling of intrathoracic lymph nodes may be performed by mediastinoscopy or endoscopic ultrasound-guided fine needle aspiration. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an alternative to mediastinoscopy and endoscopic ultrasound in patients with lung cancer and sarcoidosis. The utility of EBUS-TBNA in patients with extrathoracic malignancy was evaluated. METHODS: Consecutive patients who were suspected to have intrathoracic lymph node metastases from an extrathoracic malignancy underwent EBUS-TBNA. When EBUS-TBNA did not provide a specific diagnosis, patients underwent mediastinoscopy or clinical follow-up of at least 6 months duration. RESULTS: One hundred sixty-one patients meeting the inclusion criteria underwent EBUS-TBNA in five UK centers over a 3-year period. EBUS-TBNA diagnosed mediastinal or hilar metastases in 71 (44%) patients, new lung cancer in 20 (12%) patients, and sarcoidosis in 14 (9%) patients. The sensitivity, negative predictive value for malignancy, and overall accuracy for EBUS-TBNA were 87%, 73% and 88%, respectively. One hundred ten (68%) patients in the study had a final diagnosis of malignant intrathoracic lymphadenopathy. CONCLUSION: Because of the high prevalence of alternative diagnoses, pathological evaluation is important in patients with extrathoracic malignancy and suspected mediastinal or hilar lymph node metastases. EBUS-TBNA is a safe and sensitive technique and may be considered a first-line investigation in these patients. PMID- 21792076 TI - Systematic evaluation of genetic variants in three biological pathways on patient survival in low-stage non-small cell lung cancer. AB - INTRODUCTION: Studies from selected candidate genes suggest that single nucleotide polymorphisms (SNPs) involved in glutathione metabolism, DNA repair, or inflammatory responses may affect overall survival (OS) in stages I to II or low-stage non-small cell lung cancer (LS-NSCLC); however, results are inconclusive. In this study, we took a systematic pathway-based approach to simultaneously evaluate the impact of genetic variation from these three pathways on OS after LS-NSCLC diagnosis. METHODS: DNA from 647 patients with LS-NSCLC was genotyped for 480 SNPs (tag-SNPs) tagging 57 genes from the three candidate pathways. Associations of tag-SNPs with OS were assessed at the individual SNP and whole gene levels, adjusting for age, tumor stage, surgery type, and adjuvant therapy. The genotype combinations of the SNPs associated with OS were also estimated. RESULTS: Among the 412 tag-SNPs that were successfully genotyped and passed quality assessments, 28 showed association with OS (p < 0.05). Two of the 28 were estimated to have less than a 20% chance of being false positives (rs3768490 in GSTM5: p = 1.32 * 10, q = 0.06; rs1729786 in ABCC4: p = 9.25 * 10, q = 0.20). Gene-based analysis suggested that in addition to GSTM5 and ABCC4, variation in two other genes, PTGS2 and GSTA2, was also associated with OS. CONCLUSIONS: We describe further evidence that variations in genes involved in the glutathione and inflammatory response pathways are associated with OS in patients with LS-NSCLC. Further studies are warranted to verify our findings and elucidate their functional mechanisms and clinical utility leading to improved survival for patients with lung cancer. PMID- 21792079 TI - Age at menopause and measuring symptoms at midlife in a community in Babol, Iran. AB - OBJECTIVE: The aim of the present study was to determine age at menopause and the prevalence of menopausal symptoms among women in a community in Babol, Iran, and then identify the factors associated with these symptoms and age. METHODS: A retrospective, descriptive, epidemiological study was conducted on the characteristics of perimenopausal and postmenopausal women. A total of 1,397 individuals aged 45 to 63 years were selected using a standard cluster sampling technique. The questionnaire used included menopausal symptoms, menopause status, causes of menopause, use of hormones, reproductive history, and sociodemographic factors. A standard questionnaire named Symptom ScoreCard was used to assess the frequency and severity of menopausal symptoms. The data were analyzed by chi2 analysis, t test, analysis of variance, and adjusted odds ratios with their 95% CIs. RESULTS: Recalled mean +/- SD age at natural menopause was 47.7 +/- 4.9 years. No significant difference by age at menopause was observed in sociodemographic data, smoking status, reproductive history, and oral contraceptive use. The most prevalent symptoms were irritability (72.1%), joint pain (70.6%), and depression (59.7%) during the previous 2 weeks. An increase in the percentage of occurrence and severity of some symptoms with transition to menopause was observed. The total score for menopausal symptoms was 13.0 +/- 7.7. High economic situation (odds ratio, 1.89; 95% CI, 1.37-2.58) was a factor significantly associated with a total menopausal score of higher than 15. CONCLUSIONS: This study shows a high prevalence of menopausal symptoms and an earlier mean age at menopause (47.7 y) for women in a community in Babol, Iran. It would be beneficial to establish a menopausal clinic in primary healthcare centers for the clinical staff to monitor postmenopausal women. PMID- 21792080 TI - Pain and opioid use in chronic pancreatitis. AB - OBJECTIVE: Opioid therapy for pain in chronic pancreatitis (CP) is associated with tolerance and possibly opioid-induced hyperalgesia. We thus examined opioid use and pain rating in CP patients. METHODS: Medical records of patients with established CP treated at the University of Pittsburgh Medical Center's Digestive Disorders Center between April 2008 and December 2009 were retrospectively reviewed. RESULTS: Two hundred nineteen unique patients (53% men; age, 50 +/- 1 years) were identified. At least moderate pain was initially present in 37% of the patients. Half (51%) of the patients received opioids (average morphine equivalent, 78.1 +/- 12.4 mg/d). Pain severity correlated with age (r = -0.22), history of alcohol abuse (r = 0.14), affective spectrum disorders (r = 0.14), presence of coexisting pain syndromes (r = 0.24), opioid use (r = 0.49), and days with concerns about physical (r = 0.55) or mental problems (r = 0.35). In contrast, computed tomography-defined pancreatic abnormalities (calcification, pseudocysts, ductal stones, or dilation) did not correlate with pain rating. Regression analysis identified age, days with physical problems, and a coexisting chronic pain syndrome as best independent predictors of pain. CONCLUSIONS: Chronic pancreatitis etiology, especially alcohol use, and psychosocial factors are important determinants of pain severity in CP. Successful management thus needs to go beyond treatment of changes in pancreatic morphology to effectively improve quality of life and utilization of medical resources. PMID- 21792081 TI - Assessment of trypsinogen-2 levels as an early diagnostic for post-endoscopic retrograde cholangiopancreatography pancreatitis. AB - OBJECTIVES: The objective of the present study was to assess the use of serum trypsinogen-2 (TRY-2) measurements in early diagnosis of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this prospective study, investigation 1 involved collection of blood serum both before and at 2, 4, and 18 hours after ERCP, whereas investigation 2 involved collection before and 1, 2, 3, 4, 6, and 18 hours after ERCP. Total amylase, pancreatic amylase, and TRY-2 levels were measured from serum samples, and values from patients with pancreatitis after ERCP were compared to those from healthy control patients after ERCP. RESULTS: In investigation 1, 8 of the 68 cases examined were diagnosed as post-ERCP pancreatitis. In the healthy group, total- and pancreatic amylase levels peaked 4 hours after ERCP, and TRY-2 levels peaked at 2 hours after ERCP. In contrast, cases of post-ERCP pancreatitis demonstrated prolonged periods of high total-amylase, pancreatic-amylase, and TRY-2 levels. In investigation 2, none of the 23 cases was diagnosed as post-ERCP pancreatitis: Pancreatic amylase levels peaked 4 to 6 hours after ERCP and TRY-2 levels peaked 1 hour after ERCP. CONCLUSION: These results suggest that TRY-2 is a more sensitive marker than amylase, and it can be useful in early diagnosis of post ERCP pancreatitis. PMID- 21792082 TI - Aberrant methylation of RASSF2A in human pancreatic ductal adenocarcinoma and its relation to clinicopathologic features. AB - OBJECTIVES: Tumor suppressor gene Ras-association domain family 2A (RASSF2A) is inactivated by promoter hypermethylation in many cancers. The study was performed to evaluate the methylation status of RASSF2A in pancreatic ductal adenocarcinoma and cell lines and its relation to clinicopathologic features. METHODS: The RASSF2 expression in 8 pancreatic carcinoma cell lines and 1 normal pancreatic tissue was detected. The methylation status of RASSF2A in 8 pancreatic carcinoma cell lines, 41 cases of pancreatic ductal adenocarcinoma, and corresponding normal pancreatic tissue was also examined by methylation-specific PCR. BxPC-3 and AsPC-1 cell lines were treated with 5-aza-2'-deoxycytidine (5-aza-dC), and RASSF2 expression was determined by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: The expression of RASSF2 was down-regulated in all cell lines. Hypermethylation of RASSF2A was detected in all cell lines and 9 of 41 pancreatic ductal adenocarcinomas. Whereas none of hypermethylation of RASSF2A was found in the normal pancreatic tissue. The expression of RASSF2 could be restored by 5-aza-dC in cell lines. CONCLUSIONS: Promoter hypermethylation of RASSF2A is observed in pancreatic ductal adenocarcinoma, while not in normal pancreatic tissue. RASSF2A is inactivated in pancreatic ductal adenocarcinoma by CpG island promoter hypermethylation and may play a role in pancreatic carcinogenesis. PMID- 21792083 TI - Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. AB - OBJECTIVES: In the current study, we have evaluated the clinical and immunological responses in patients with advanced pancreatic carcinoma who received dendritic cell (DC)-based immunotherapy in combination with gemcitabine and/or S-1. METHODS: Dendritic cell-based immunotherapy (DC vaccine alone or DC vaccine plus lymphokine-activated killer [LAK] cell therapy) in combination with gemcitabine and/or S-1 has been carried out in 49 patients with inoperable pancreatic carcinoma refractory to standard treatment. RESULTS: Of 49 patients, 2 patients had complete remission, 5 had partial remission, and 10 had stable disease. Prolongation of survival in this cohort was highly likely (median survival, 360 days). Survival of patients receiving DC vaccine and chemotherapy plus LAK cell therapy was longer than those receiving DC vaccine in combination with chemotherapy but no LAK cells. Increased numbers of cancer antigen-specific cytotoxic T cells and decreased regulatory T cells were observed in several patients on immunotherapy, but increased overall survival time tended to be associated only with the latter. None of the patients experienced grade 3 or worse adverse events during the treatment period. CONCLUSIONS: Dendritic cell vaccine-based immunotherapy combined with chemotherapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment. PMID- 21792084 TI - Akt signals upstream of L-type calcium channels to optimize insulin secretion. AB - OBJECTIVES: Both the serine/threonine protein kinase Akt and the voltage-gated L type calcium channel act as important players in glucose-stimulated insulin secretion. Akt recruits the L-type calcium channel to and maintains them in the plasma membrane. This study aimed to characterize the role of L-type calcium channels in mediation of Akt signaling in glucose-stimulated insulin secretion. METHODS: Insulin secretion was evaluated in rat pancreatic islets and INS-1 pancreatic beta cells by a standard insulin radioimmunoassay. RESULTS: Akt inhibition effectively abrogates not only glucose-stimulated but also potassium depolarization-stimulated insulin secretion from rat islets, the latter critically relying on the voltage-gated calcium channel-mediated Ca(2+) influx without involvement of glucose metabolism. Likewise, Akt inhibition also reduces both glucose-stimulated and potassium depolarization-stimulated insulin secretion from INS-1 cells. Importantly, pharmacological ablation of L-type calcium channels partially blocks Akt inhibition-induced reduction in glucose-stimulated insulin secretion but completely prevents that in potassium depolarization-evoked insulin release from INS-1 cells. Furthermore, Akt inhibition does not influence calcium ionophore A23187-induced insulin secretion from INS-1 cells, which occurred without involvement of L-type calcium channels. CONCLUSIONS: Akt signals upstream of L-type calcium channels to optimize glucose-stimulated insulin secretion. PMID- 21792086 TI - Proteomic identification of RREB1, PDE6B, and CD209 up-regulated in primitive gut tube differentiated from human embryonic stem cells. AB - OBJECTIVES: This study aimed to identify proteins important for the primitive gut tube differentiation from human embryonic stem cells (hESCs) by derivation method for pancreatic cells. METHODS: Proteins with altered expression levels in the process of differentiating to primitive gut tube from definitive endoderm of hESCs were investigated by comparative proteomic analysis using 2-dimensional gel electrophoresis and mass spectrometric analyses. RESULTS: Differentiation to primitive gut tube from hESCs was analyzed using differentiation marker genes and proteins. Twenty-seven protein spots with significant changes in intensity were found by 2-dimensional gel electrophoresis, and 24 proteins were further identified. These proteins were functionally annotated based on gene ontology. The expression levels of 3 proteins, RREB1, PDE6B, and CD209, involved in signal transduction, were validated using quantitative reverse transcription-polymerase chain reaction and Western blot. Their mRNA and protein expression levels increased in primitive gut tube but not in definitive endoderm or embryonic body. CONCLUSIONS: The increase in expression of RREB1, PDE6B, and CD209 suggests that these proteins might play important roles in the differentiation of primitive gut tube cells from hESCs and in human primitive gut tube development into pancreas. Therefore, they could be developed as differentiation markers for identifying primitive gut tube cells. PMID- 21792085 TI - ABO blood group and chronic pancreatitis risk in the NAPS2 cohort. AB - OBJECTIVES: A risk association has been observed between non-O blood groups and pancreatic adenocarcinoma. Chronic pancreatitis also increases risk for pancreatic cancer, raising questions as to whether non-O blood groups are a risk for chronic pancreatitis and whether the pathophysiologic pathways are linked. Our goal was to determine whether ABO blood group may affect the risk of chronic pancreatitis. METHODS: The study cohort included chronic pancreatitis patients (n = 499) and healthy controls (n = 631) from the North American Pancreatitis Study 2 study. Genotyping was performed using Sequenom assay of rs8176746 A/C and rs505922 C/T to classify participants into ABO blood groups. RESULTS: O blood group was nonsignificantly more common among cases (44.7% vs 42.0%; P = 0.36), particularly among cases with alcohol-related chronic pancreatitis (49.3% vs 42%; P = 0.060). Alcoholic patients without coexisting high-risk PRSS1, CFTR, or SPINK1 variants had a significant overrepresentation of O blood type when compared with controls (odds ratio, 1.54; 95% confidence interval, 1.09-2.17; P = 0.01). CONCLUSIONS: A, B, and AB blood groups were not associated with a greater likelihood of having chronic pancreatitis and may decrease the risk of chronic pancreatitis in individuals who are very heavy drinkers. These results suggest that the mechanism linking non-O blood type with pancreatic pathology is specific to carcinogenesis. PMID- 21792087 TI - Simplified method to isolate highly pure canine pancreatic islets. AB - OBJECTIVES: The canine model has been used extensively to improve the human pancreatic islet isolation technique. At the functional level, dog islets show high similarity to human islets and thus can be a helpful tool for islet research. We describe and compare 2 manual isolation methods, M1 (initial) and M2 (modified), and analyze the variables associated with the outcomes, including islet yield, purity, and glucose-stimulated insulin secretion (GSIS). METHODS: Male mongrel dogs were used in the study. M2 (n = 7) included higher collagenase concentration, shorter digestion time, faster shaking speed, colder purification temperature, and higher differential density gradient than M1 (n = 7). RESULTS: Islet yield was similar between methods (3111.0 +/- 309.1 and 3155.8 +/- 644.5 islets/g, M1 and M2, respectively; P = 0.951). Pancreas weight and purity together were directly associated with the yield (adjusted R(2) = 0.61; P = 0.002). Purity was considerably improved with M2 (96.7% +/- 1.2% vs 75.0% +/- 6.3%; P = 0.006). M2 improved GSIS (P = 0.021). Independently, digestion time was inversely associated with GSIS. CONCLUSIONS: We describe an isolation method (M2) to obtain a highly pure yield of dog islets with adequate beta-cell glucose responsiveness. The isolation variables associated with the outcomes in our canine model confirm previous reports in other species, including humans. PMID- 21792088 TI - Pancreatic cancer alters human CD4+ T lymphocyte function: a piece in the immune evasion puzzle. AB - OBJECTIVES: To verify whether the dysregulation of CD4 T cells concurs in worsening the outcome of pancreatic cancer, we compared the effects of pancreatic cancer and other gastrointestinal cancer cell-conditioned media on the (1) proliferation, migration, and differentiation of CD4 T cells and (2) expansion of CD4 memory (CD45RO), naive (CD45RA), activated (CD69), and regulatory (CD25) subsets. METHODS: After culture of CD4 T cells in control, pancreatic (BxPC3, Capan1, MiaPaCa2), or gastrointestinal cancer (AGS, HepG2, HT29) cell-conditioned media, we evaluated proliferation, migration, interferon gamma (IFNgamma) production, and CD45RA, CD45RO, CD69, and CD25 membrane expression in control and conditioned CD4 T cells. RESULTS: Only pancreatic cancer-conditioned media (1) inhibited CD4 T-cell proliferation (P < 0.001) and migration under human stromal cell-derived factor-alpha chemotaxis (P < 0.001) and (2) induced CD4 T-cell IFNgamma production (P < 0.05) and the expansion of the CD69-positive subset (P < 0.001) with respect to the control, with no changes being found in the CD45RA, CD45RO, and CD25 subsets. CONCLUSIONS: The in vitro findings achieved in the present study demonstrate that pancreatic cancer cells inhibit CD4 T-cell proliferation and migration, induce IFNgamma production, and favor a CD69 subset expansion, suggesting that CD4 T cells play an important role in pancreatic cancer immune evasion. PMID- 21792089 TI - Macular features from spectral-domain optical coherence tomography as an adjunct to indirect ophthalmoscopy in retinopathy of prematurity. AB - PURPOSE: To compare vitreoretinal pathology imaged with portable handheld spectral-domain optical coherence tomography (SD-OCT) to conventional indirect ophthalmoscopic examination in neonates undergoing screening for retinopathy of prematurity. METHODS: Spectral-domain optical coherence tomography images were collected from 76 eyes of 38 neonates during 118 routine retinopathy of prematurity examinations. Imaging sessions in the Neonatal Intensive Care Unit were performed immediately after the subjects underwent a standard ophthalmic examination with indirect ophthalmoscopic by a pediatric ophthalmologist. Masked certified SD-OCT graders evaluated scans for preretinal and retinal findings including material in the vitreous, epiretinal membrane, intraretinal cystoid structures and deposits, optic nerve and vascular features, and severity and location of retinopathy of prematurity. The frequency of detection of these features by clinical examination and evaluation of SD-OCT images was compared to determine potential clinical advantages for each modality. RESULTS: Portable SD OCT imaging characterized macular features of retinal cystoid structures in 39% of examinations and epiretinal membrane in 32% of examinations. Neither feature was visualized by indirect ophthalmoscopy in any cases. The clinician using indirect ophthalmoscopy detected stage of retinopathy of prematurity and the presence or absence of Plus or pre-Plus disease. These were not visualized with SD-OCT. CONCLUSION: Spectral-domain optical coherence tomography provides new information about the premature infant retina that is of unknown importance relative to visual development and acuity. As used in this study, SD-OCT does not replace indirect ophthalmoscopy for evaluation of retinopathy of prematurity. PMID- 21792091 TI - Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. AB - BACKGROUND: Degenerative disc disease may cause severe low-back pain, a large public health problem with significant economic and life quality impact. Chronic cases often require surgery, which may lead to biomechanical problems and accelerated degeneration of the adjacent segments. Cell-based therapies may circumvent these problems and have exhibited encouraging results in vitro and in animal studies. We designed a pilot study to assess feasibility and safety and to obtain early indications on efficacy of treatment with mesenchymal stem cells (MSC) in humans. METHODS: Ten patients with chronic back pain diagnosed with lumbar disc degeneration with intact annulus fibrosus were treated with autologous expanded bone marrow MSC injected into the nucleus pulposus area. Clinical evolution was followed for 1 year and included evaluation of back pain, disability, and quality of life. Magnetic resonance imaging measurements of disc height and fluid content were also performed. RESULTS: Feasibility and safety were confirmed and strong indications of clinical efficacy identified. Patients exhibited rapid improvement of pain and disability (85% of maximum in 3 months) that approached 71% of optimal efficacy. This outcome compares favorably with the results of other procedures such as spinal fusion or total disc replacement. Although disc height was not recovered, water content was significantly elevated at 12 months. CONCLUSIONS: MSC therapy may be a valid alternative treatment for chronic back pain caused by degenerative disc disease. Advantages over current gold standards include simpler and more conservative intervention without surgery, preservation of normal biomechanics, and same or better pain relief. PMID- 21792090 TI - Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant. AB - BACKGROUND: Despite the success rate of solitary pancreas transplantation in type 1 diabetes with preserved kidney function has greatly improved in recent years, a residual proportion of failures persists. METHODS: With the aim of investigating autoimmunity as an unrecognized cause of graft failure, we measured autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and the recently discovered zinc transporter 8 antigen (ZnT8A) in 25 recipients of technically successful solitary pancreas transplantation. RESULTS: The overall pancreas graft survival was 92%, 88%, and 80% at 2, 4, and 6 years, respectively. Fourteen patients (56%) had one or more autoantibodies before transplantation, with no effect on subsequent pancreas graft outcome. After transplantation, major autoantibody changes (serum conversion from negative to positive, spreading from one to multiple autoantibodies, or titer increase) were observed in 5 of 25 recipients: in four patients, the autoantibody change was followed by the loss of graft function (95% sensitivity, 80% positive predictive value), with a significantly lower graft survival compared with patients without autoantibodies (P<0.0001). The addition of ZnT8A to GADA and IA 2A increased the number of identified autoantibody changes from three to five of 25 recipients and the number of predicted graft function loss from two to four out of five graft losses. CONCLUSIONS: Detection of major autoantibody changes after technically successful solitary pancreas transplantation is predictive of subsequent loss of graft function. ZnT8A in addition to GADA and IA-2A are a useful marker to be included in the screening panel of posttransplant immune monitoring. PMID- 21792092 TI - Solitary paraganglioma of the hypoglossal nerve: case report. AB - BACKGROUND AND IMPORTANCE: We report the case history of solitary hypoglossal paraganglioma in a 64-year-old woman. The surgical difficulties encountered in the removal of this challenging tumor are discussed and as a literature review provided. CLINICAL PRESENTATION: A 64-year-old woman presented with a short history of dysphonia, occasional dysphagia, tinnitus, altered taste, and unilateral left-sided tongue wasting. On examination, there was left lower motor hypoglossal paralysis. Imaging showed a discrete enhancing lobulated mass, measuring 2 * 2 cm, in the region of the hypoglossal nerve extending into the hypoglossal canal suggestive of hypoglossal paraganglioma. A left dorsolateral suboccipital craniotomy was performed with the patient in the sitting position. The hypoglossal nerve appeared to be enlarged, and the jugular foramen was normal. Complete surgical debulking of the tumor was not attempted because of its vascular nature. The nerve was decompressed, and neuropathology confirmed a low grade paraganglioma arising from the hypoglossal nerve. The patient was scheduled to receive stereotactic radiation for further management. CONCLUSION: When a case of solitary hypoglossal paraganglioma is encountered in clinical practice, the aim of management should be mainly focused on achieving a diagnosis and preserving the hypoglossal nerve function. If there is evidence of vascularity in the lesion noted on magnetic resonance imaging, a preoperative angiogram should be obtained with a view for embolization. We decompressed the hypoglossal canal and achieved good improvement in the patient's symptoms. We recommend stereotactic radiosurgery for remnant and small hypoglossal tumors and regular follow-up with magnetic resonance imaging scans. PMID- 21792096 TI - Nerve grafting for spinal cord injury in cats: are we close to translational research? PMID- 21792097 TI - alpha-1 Adrenergic receptor signaling linked to memory dysfunction following brain trauma. PMID- 21792098 TI - A heterogeneous population of stem cells within glioblastoma tumors in the setting of disease relapse. PMID- 21792099 TI - Reversing pathological neural activity using targeted plasticity. PMID- 21792100 TI - Gabapentin reduces experimental secondary neurologic dysfunction in rats. PMID- 21792101 TI - Creating shared health care value. PMID- 21792102 TI - Wiring the basal ganglia: direct and indirect pathway glutamatergic innervation in mouse striatum. PMID- 21792103 TI - Maximal radiation exposure during minimally invasive spine surgery? PMID- 21792104 TI - mTOR inhibitors in the treatment of subependymal giant-cell astrocytomas associated with tuberous sclerosis. PMID- 21792105 TI - The registrar. PMID- 21792106 TI - Introducing QR codes: linking print and digital content via smartphone. PMID- 21792107 TI - What is the real risk of dislodging thrombi during endovascular revascularization of a proximal internal carotid artery occlusion? AB - BACKGROUND: There is a theoretical concern that a thrombus may be dislodged distally when crossing the occluded segment during recanalization of a complete occlusion. OBJECTIVE: To assess the immediate postprocedural brain diffusion weighted image (DWI) findings following endovascular recanalization using an embolic protection device for proximal internal carotid artery (ICA) occlusion. MATERIALS AND METHODS: We retrospectively identified 12 patients who underwent stent implantation for sudden symptomatic occlusion of the proximal ICA. In 8 patients, no additional intracranial occlusions were identified. In 4 patients, an additional intracerebral thrombus was detected in the middle cerebral artery. Distal protection devices were used in all cases. We evaluated the presence and amount of retrieved embolic fragments in the distal protection devices. The incidence and location of postprocedural emboli were determined using DWI. RESULTS: Recanalization of the proximal ICA was achieved in all patients. After complete occlusion of the proximal ICA was demonstrated, primary passage of the embolic protection device through the occluded ICA was gently navigated in 7 patients. However, this was not possible in 5 patients. Three patients developed new lesions on postprocedural DWI. Of the 12 patients in which distal protection devices were used, debris was detected in 7 patients. CONCLUSION: In endovascular revascularization of proximal ICA occlusion, postprocedural emboli occur less frequently than reported in a systematic review of the DWI literature. The real risk of dislodging thrombi appears to be from plaque fragment mobilization by angioplasty, rather than from crossing an occluded segment. PMID- 21792112 TI - Sea-sea (1970) by Gerhard Richter (b. 1932). PMID- 21792113 TI - Prospective, randomized, double-blind clinical study evaluating the correlation of clinical outcomes and cervical sagittal alignment. AB - BACKGROUND: Sagittal alignment of the cervical spine has received increased attention in the literature as an important determinant of clinical outcomes after anterior cervical diskectomy and fusion. Surgeons use parallel or lordotically fashioned grafts depending on preference or simple availability. OBJECTIVE: To quantitatively assess and compare cervical sagittal alignment and clinical outcome when lordotic or parallel allografts were used for fusion. METHODS: A prospective, randomized, double-blind clinical study that enrolled 122 patients was performed. The mean follow-up was 37.5 months (range, 12-54 months). RESULTS: The mean postoperative cervical sagittal alignment was 19 degrees (range, -7 degrees -36 degrees ) and 18 degrees (range, -7 degrees -37 degrees ) in the lordotic and parallel graft patient groups, respectively. The mean segmental sagittal alignment was 6 degrees (range, -4 degrees -19 degrees ) and 7 degrees (range, -3 degrees -19 degrees ) in the lordotic and parallel graft patient groups, respectively. There were no statistically significant differences in clinical outcome scores between the lordotic and parallel graft patient groups. However, patients who had maintained or improved segmental sagittal alignment, regardless of graft type, achieved a higher degree of improvement in Short Form-36 Physical Component Summary and Neck Disability Index scores. This was statistically significant (P < .038). CONCLUSION: The use of lordotically shaped allografts does not increase cervical/segmental sagittal alignment or improve clinical outcomes. Maintaining a consistent segmental sagittal alignment or increasing segmental lordosis was related to a higher degree of improvement in clinical outcomes. PMID- 21792118 TI - Optogenetics: background and concepts for neurosurgery. PMID- 21792119 TI - Tubular diskectomy vs conventional microdiskectomy for the treatment of lumbar disk herniation: 2-year results of a double-blind randomized controlled trial. AB - BACKGROUND: Transmuscular tubular diskectomy has been introduced to increase the rate of recovery, although evidence is lacking. OBJECTIVE: To evaluate the 2-year results of tubular diskectomy compared with conventional microdiskectomy. METHODS: Three hundred twenty-eight patients with persistent leg pain caused by lumbar disk herniation were randomly assigned to undergo tubular diskectomy (167 patients) or conventional microdiskectomy (161 patients). Main outcome measures were scores from Roland-Morris Disability Questionnaire for Sciatica, Visual Analog Scale for leg pain and low-back pain, and Likert self-rating scale of global perceived recovery. RESULTS: On the basis of intention-to-treat analysis, there was no significant difference between tubular diskectomy and conventional microdiskectomy in Roland-Morris Disability Questionnaire for Sciatica scores during 2 years after surgery (between-group mean difference [Delta] = 0.6; 95% confidence interval [CI], -0.3-1.6). Patients treated with tubular diskectomy reported more leg pain (Delta = 3.3 mm; 95% CI, 0.2-6.2) and more low-back pain (Delta = 3.0 mm; 95% CI, -0.2-6.3) than those patients treated with conventional microdiskectomy. At 2 years, 71% of patients assigned to tubular diskectomy documented a good recovery vs 77% of patients assigned to conventional microdiskectomy (odds ratio, 0.76; 95% CI, 0.45-1.28; P = .35). Repeated surgery rates within 2 years after tubular diskectomy and conventional microdiskectomy were 15% and 10%, respectively (P = .22). CONCLUSION: Tubular diskectomy and conventional microdiskectomy resulted in similar functional and clinical outcomes. Patients treated with tubular diskectomy reported more leg pain and low back pain, although the differences were small and not clinically relevant. PMID- 21792120 TI - Accuracy of postoperative computed tomography and magnetic resonance image fusion for assessing deep brain stimulation electrodes. AB - BACKGROUND: Knowledge of the anatomic location of the deep brain stimulation (DBS) electrode in the brain is essential in quality control and judicious selection of stimulation parameters. Postoperative computed tomography (CT) imaging coregistered with preoperative magnetic resonance imaging (MRI) is commonly used to document the electrode location safely. The accuracy of this method, however, depends on many factors, including the quality of the source images, the area of signal artifact created by the DBS lead, and the fusion algorithm. OBJECTIVE: To calculate the accuracy of determining the location of active contacts of the DBS electrode by coregistering postoperative CT image to intraoperative MRI. METHODS: Intraoperative MRI with a surrogate marker (carbothane stylette) was digitally coregistered with postoperative CT with DBS electrodes in 8 consecutive patients. The location of the active contact of the DBS electrode was calculated in the stereotactic frame space, and the discrepancy between the 2 images was assessed. RESULTS: The carbothane stylette significantly reduces the signal void on the MRI to a mean diameter of 1.4 +/- 0.1 mm. The discrepancy between the CT and MRI coregistration in assessing the active contact location of the DBS lead is 1.6 +/- 0.2 mm, P < .001 with iPlan (BrainLab AG, Erlangen, Germany) and 1.5 +/- 0.2 mm, P < .001 with Framelink (Medtronic, Minneapolis, Minnesota) software. CONCLUSION: CT/MRI coregistration is an acceptable method of identifying the anatomic location of DBS electrode and active contacts. PMID- 21792121 TI - Antifibrinolytic in subarachnoid hemorrhage. PMID- 21792122 TI - Early migration of a self-expanding intracranial stent after the treatment of a basilar trunk aneurysm: report of a second case. PMID- 21792126 TI - Memory training unlocks brain plasticity in prodromal Alzheimer's disease. PMID- 21792127 TI - A new mouse model of dystonia. PMID- 21792128 TI - New guidelines for the management of cerebral venous thrombosis. PMID- 21792129 TI - Surgery can protect elderly patients with odontoid fractures: who benefits the most? PMID- 21792130 TI - Live imaging of dorsal root regeneration and the resurgence of a forgotten idea. PMID- 21792131 TI - Clinical characteristics of ependymoma patients based on patient-reported outcomes. PMID- 21792132 TI - The role of decompressive craniectomy in diffuse traumatic brain injury. PMID- 21792133 TI - Cancer stem cells can arise from differentiated neoplastic cells. PMID- 21792134 TI - Meeting meaningful use objectives for Electronic Health Record implementation. PMID- 21792135 TI - Cover essay. Pablo Picasso (1881-1973), Guitar (c.1914). PMID- 21792136 TI - Use of intravenous conivaptan in neurosurgical patients with hyponatremia from syndrome of inappropriate antidiuretic hormone secretion. AB - BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in hospitalized patients and is frequently associated with neurologic disorders and neurosurgical procedures. Traditional therapies such as fluid restriction, sodium repletion, and diuretics can help correct hyponatremia but do not address the underlying pathophysiology of excess arginine vasopressin secretion. Conivaptan is an arginine vasopressin receptor antagonist that has been shown to be both safe and effective in the treatment of euvolemic and hypervolemic hyponatremia. OBJECTIVE: To analyze the use of conivaptan to treat SIADH in a mixed neurosurgical population. METHODS: We conducted a retrospective review of 13 patients with neurosurgical disorders with SIADH that were treated with intravenous conivaptan at our institution between 2007 and 2009. RESULTS: The mean pretreatment serum sodium concentration was 125.8 +/- 3.5 mEq/L. Conivaptan administration resulted in a rise in serum sodium to 132.5 +/- 5.6 mEq/L at 12 hours (P < .01) and 134.1 +/- 4.7 mEq/L at 24 hours posttreatment (P < .01). The mean time to an increase in serum sodium >= 6 mEq/L was 17.8 hours. There were no instances of rapid overcorrection. There were 3 cases of asymptomatic hyperkalemia, 3 cases of asymptomatic hypotension, and 1 case of elevated creatinine associated with conivaptan administration. CONCLUSION: These data provide further support that conivaptan can be safely used for the treatment of SIADH-induced hyponatremia in the neurosurgical arena. PMID- 21792137 TI - Endovascular treatment of posterior circulation fusiform aneurysms: single-center experience in 31 patients. AB - BACKGROUND: Posterior circulation fusiform aneurysms are rare but difficult to treat. OBJECTIVE: To report our experience with endovascular treatment of posterior circulation fusiform aneurysms. METHODS: A retrospective review of our prospectively maintained database identified all posterior circulation fusiform aneurysms treated by endovascular approach over a 6-year period. Clinical charts, procedural data, and angiographic results were reviewed. RESULTS: From March 2004 to March 2010, 31 patients were identified: 11 asymptomatic patients, 9 who presented with a subarachnoid hemorrhage, 6 with a stroke, and 5 with a mass effect. All but 1 patient (97%), who died before being treated, were successfully treated by parent artery occlusion (n = 10), stenting plus coiling (n = 10), or stenting alone with conventional or flow-diverting stents (n = 10). Twenty-two patients showed a good or an excellent outcome (73%); 3 had a fair or a poor outcome (10%); and 5 patients died (17%). These 8 patients initially presented with severe subarachnoid hemorrhage or mass effect. Procedure-related morbidity includes only one patient who kept a worsening of cranial nerve palsies. There was no definitive procedure-related morbidity or mortality. Immediate aneurysm occlusion was incomplete in 20 cases (67%) and complete in 10 cases (33%). Mean follow-up of 20 months in 23 patients showed 12 further thromboses, 9 stable results, and 2 flow reductions. Final results included 19 complete occlusions (83%) and 4 incomplete occlusions (17%). CONCLUSION: Posterior circulation fusiform aneurysms may be treated by different endovascular approaches with satisfying clinical and anatomical results in most cases. However, patients who present with severe subarachnoid hemorrhage or mass effect still have a poor prognosis. PMID- 21792138 TI - Long-term outcomes after Gamma Knife radiosurgery for patients with a nonfunctioning pituitary adenoma. AB - BACKGROUND: Nonfunctioning pituitary adenomas recur after microsurgery. Gamma Knife radiosurgery (GKRS) has been used to treat recurrent adenomas. OBJECTIVE: To evaluate the long-term rates of tumor control and development of hypopituitarism in patients with nonfunctioning pituitary adenomas after GKRS. METHODS: Forty-eight patients with a nonfunctioning pituitary adenoma treated between 1991 and 2004 at the University of Virginia were studied. All patients had more than 4 years of clinical and imaging follow-up. RESULTS: All patients underwent follow-up imaging and endocrine evaluations, with a duration ranging from 50 to 215 months (median, 80.5 months) and 57 to 201 months (median, 95 months), respectively. New hormone deficiency after GKRS occurred in 19 of 48 patients (39%). Corticotropin/cortisol deficiency developed in 8% of patients, thyroid hormone deficiency in 20.8%, gonadotropin deficiency in 4.2%, growth hormone/insulin-like growth factor 1 in 16.7%, and diabetes insipidus in 2%. Panhypopituitarism including diabetes insipidus developed in 1 patient. Overall, control of tumor volume was 83%. Tumor volume decreased in 36 patients (75%), increased in 8 patients (17%), and was unchanged in 4 patients (8%). Tumor volumes greater than 5 mL at the time of GKRS were associated with a significantly greater rate of growth (P = .003) compared with an adenoma with a volume of 5 mL or less. CONCLUSION: GKRS resulted in a high and durable rate of tumor control in patients with a nonfunctioning pituitary adenoma. A higher preoperative tumor volume was associated with an increased rate of tumor growth. PMID- 21792139 TI - Preoperative evaluation of unruptured cerebral aneurysms by fast imaging employing steady-state acquisition image. AB - BACKGROUND: In aneurysm surgery, understanding the microanatomy around the aneurysm such as perforating arteries and cranial nerves is mandatory. OBJECTIVE: To assess the usefulness in determining the microanatomy around the cerebral aneurysms by the use of fast imaging employing steady-state acquisition (FIESTA) images of magnetic resonance imaging preoperatively, in addition to computed tomography and digital subtraction angiography. METHODS: Between October 2006 and June 2009, 123 patients with 140 unruptured cerebral aneurysms were treated in our institution. Eighty-two patients were assessed with FIESTA by the operators on the workstation of the magnetic resonance image before surgical clipping of the aneurysms. The small vessels and cranial nerves were confirmed intraoperatively before or after obliteration of the aneurysms. RESULTS: Sensitivities and specificities of FIESTA imaging were 100% in detecting hypothalamic artery around anterior communicating artery aneurysms, oculomotor nerve attachment to the posterior communicating artery aneurysm domes, and anterior choroidal artery adhesion to the posterior communicating artery aneurysms. This technique was also useful for predicting adhesion between the aneurysm and adjacent main trunks or perforators. Although the specificity was 100%, sensitivity was 56% in detecting vessel adhesion around the middle cerebral aneurysms. This technique can provide limited information in large aneurysms or aneurysms located in minimal cerebrospinal fluid space. The overall outcomes of the patients included 120 excellent recoveries, 1 moderate deficit, 1 severe deficit, and 1 persistent vegetative state according to the Glasgow Outcome Scale. CONCLUSION: By giving information on the minute anatomical structure around the aneurysm, FIESTA can contribute to thorough preoperative evaluations of cerebral aneurysms. PMID- 21792140 TI - Neurosurgical considerations after bull goring during festivities in Spain and Latin America. AB - Bullfighting is a highly popular activity during festivities in Spain and Latin America. A scientific society for bullfight injuries, Congreso Internacional de Cirugia Taurina, was founded on November 24, 1974, in recognition of the distinctive pattern of injury that results from bull goring, and a subspecialty of general surgical trauma with emphasis on the acute surgical management of bull goring injuries has emerged. Injuries to the head and neck are less frequent than genitourinary, inguinal, and abdominal injuries, but are more severe and more likely to result in death. This report reviews the primary venues in which bull goring and associated injuries occur, including the bullfight and the running of the bulls. The biomechanics of the primary and secondary goring injuries are reviewed, with an emphasis on those with the potential to result in neurosurgical injuries. This results in a very unique and devastating pattern of injury that combines penetrating and blunt mechanisms and results in polytrauma. Neurosurgical expertise should be immediately available on-site in the event of a life-threatening neurological injury. PMID- 21792141 TI - Motor cortex stimulation improves local cerebral glucose metabolism in the ipsilateral thalamus in patients with poststroke pain: case report. AB - BACKGROUND AND IMPORTANCE: Motor cortex stimulation (MCS) is documented as an effective therapeutic option for patients with poststroke pain. However, its underlying mechanism is still unclear. This study aimed to evaluate local cerebral glucose metabolism before and after MCS in patients with poststroke pain. CLINICAL PRESENTATION: Using 18F-fluorodeoxyglucose positron emission tomography, cerebral metabolic rate for glucose (CMRGlu) was measured in 6 patients with poststroke pain before MCS. Their lesions were located in the corona radiata, internal capsule, and thalamus. An epidural electrode was implanted under the monitoring of intraoperative neuronavigation and somatosensory evoked/motor evoked potentials. 18F-fluorodeoxyglucose positron emission tomography was repeated in 4 patients (67%) who underwent successful MCS. Asymmetry of CMRGlu was semiquantitatively analyzed using an automated region of interest setting method. Before MCS, the ratio of CMRGlu in the ipsilateral to contralateral thalamus was 0.81 +/- 0.13 (n = 6), (range, 0.63 0.97). However, there was no significant asymmetry of CMRGlu in other regions. Successful MCS significantly improved the asymmetry of CMRGlu in the ipsilateral thalamus from 0.81 +/- 0.14 to 0.89 +/- 0.17 (P < .01, n = 4). The therapeutic effect was proportional to the improvement of CMRGlu asymmetry (R = 0.79, P = 0.28; single regression analysis). CONCLUSION: Poststroke pain is closely related to the reduced glucose use in the thalamus contralateral to the painful area. Successful MCS significantly improves glucose use in the thalamus ipsilateral to MCS, suggesting that electrical stimulation of the motor cortex may activate the corticothalamic connection from the motor cortex. PMID- 21792142 TI - Combined surgical and endovascular access of the superficial middle cerebral vein to occlude a high-grade cavernous dural arteriovenous fistula: case report. AB - BACKGROUND AND IMPORTANCE: High-grade cavernous sinus (CS) dural arteriovenous fistulae with cortical venous drainage often have a malignant presentation requiring urgent treatment. In the absence of a venous access to the lesion, transarterial embolization can potentially cure these lesions; however, the high concentration of eloquent arterial territories adjacent to the fistula creates a precarious risk of arterial-arterial reflux. In such cases, a combined surgical and endovascular approach may provide the least invasive option. CLINICAL PRESENTATION: We describe a patient presenting with a venous hemorrhagic infarct caused by a high-grade CS dural arteriovenous fistula (Barrow type D caroticocavernous fistula) with isolated drainage via the superficial middle cerebral vein into engorged perisylvian cortical veins. No transfemoral or ophthalmic strategy was angiographically apparent, and the posterior location of the involved CS compartment mitigated a direct puncture. The patient underwent direct puncture of the superficial middle cerebral vein via an orbitozygomatic craniotomy and the CS was catheterized under fluoroscopic guidance. The CS was coil-embolized back into the distal superficial middle cerebral vein with complete obliteration of the fistula. The patient did well with no new deficits and made an uneventful recovery. CONCLUSION: This novel combined open surgical and endovascular approach enables obliteration of a CS dural arteriovenous fistula with isolated cortical venous drainage and avoids the additional manipulation with direct dissection and puncture of the CS itself. PMID- 21792143 TI - Abscess of the medulla oblongata in a toddler: case report and technical considerations based on magnetic resonance imaging tractography. AB - BACKGROUND AND IMPORTANCE: We report a unique case of a toddler (the only one reported) successfully operated on for a medulla oblongata abscess and comment on the influence of neuroimaging modalities in the preoperative planning of the surgical approach. CLINICAL PRESENTATION: We report a case of a 20-month-old child with a solitary medulla oblongata abscess. The abscess appeared to be in close proximity to the anterior medulla oblongata, but preoperative planning based on diffusion tensor imaging (DTI) tractography motivated us to try to remove this lesion through a midline suboccipital approach. The ventral medulla oblongata abscess was surgically removed via a telovelar approach. At the anterior wall of the 4th ventricle, a fenestration was made with pus release and evacuation of the cavity. The child was discharged 1 week later with an uneventful and full recovery. CONCLUSION: Modern imaging modalities of the nervous system can be very helpful in preoperative planning. Functional visualization of the nervous system provided by modern imaging techniques, such as the DTI tractography, can alter the classic topographic concept of surgical approach. In the case presented, approaching an anterior medulla oblongata abscess based on DTI tractography data, through a suboccipital midline transventricular approach, proved to be an effective and safe technique. PMID- 21792144 TI - Association of intracranial aneurysm and Loeys-Dietz syndrome: case illustration, management, and literature review. AB - BACKGROUND AND IMPORTANCE: Loeys-Dietz syndrome (LDS) is a newly described connective tissue disease associated with aortic aneurysms. A strong association between LDS and intracranial aneurysms has not yet been documented in the literature. We present the first detailed report of an intracranial aneurysm finding in an LDS patient. CLINICAL PRESENTATION: The patient is a 20-year-old female recently diagnosed with LDS and found to harbor 2 incidental intracranial aneurysms on a screening magnetic resonance angiography: a 3-mm right carotid ophthalmic aneurysm and an 8-mm partially fusiform paraclinoid carotid artery aneurysm. A standard left pterional craniotomy was performed. Intraoperative adenosine was used instead of temporary clipping because her vessels were extremely friable. After reconstruction, an intraoperative indocyanine green angiogram was obtained, confirming complete aneurysmal obliteration and internal carotid artery patency. CONCLUSION: This is the first detailed report of a clear association between intracranial aneurysms and LDS. An association between LDS and intracranial aneurysms, if substantiated in a larger study, has implications for aneurysm screening in this population. Such an association may shed light on mechanisms of aneurysm formation, growth, and rupture. PMID- 21792145 TI - Motor cortex stimulation in a three-year-old child with trigeminal neuropathic pain caused by a malignant glioma in the cerebellopontine angle: case report. AB - BACKGROUND AND IMPORTANCE: Motor cortex stimulation (MCS) is an accepted treatment in neuropathic pain syndromes. Use of MCS for trigeminal neuropathic pain (TNP) caused by a malignant glioma or in a child has not previously been reported in the literature. CLINICAL PRESENTATION: A 3-year-old boy presented to our department with a right temporal tumor with extension into the cavernous sinus and along the root of the trigeminal nerve up to the protuberance. Six weeks after removal of the temporal part of the tumor, the patient developed medically refractory trigeminal pain associated with tumor progression into the posterior fossa. We decided to remove the tumor from the cerebellopontine angle and residual tumor in the pericavernous area and then gave postoperative radio- and chemotherapy. Five months later, the patient developed unbearable refractory neuropathic pain characterized by a burning sensation in the first and second trigeminal areas. After a multidisciplinary discussion, MCS was recommended. We performed subdural MCS after localization of the central sulcus via anatomic landmarks, neuronavigation, peroperative sensory evoked potentials, and motor evoked potentials. The mother estimated a 75% reduction in the child's pain at 48 hours postoperatively, which continued until the child was pain-free. CONCLUSION: MCS is a minimally invasive surgical technique that seems to be a potential treatment for carefully selected children experiencing very severe and medically refractory neuropathic pain, even in the context of a neoplasm. PMID- 21792146 TI - Posterior fossa subdural hematoma resulting in locked-in syndrome: case report. AB - BACKGROUND AND IMPORTANCE: Locked-in syndrome (LIS) is a well-known and devastating clinical entity, of which stroke is the most common cause; the distant second, trauma, usually results in LIS from basilar artery dissection. Our case report describes a posterior fossa subdural hematoma causing LIS, likely by direct compression of neural structures, which is a unique etiology and prognosis compared with other causes. CLINICAL PRESENTATION: A 34-year-old female experienced a posterior fossa subdural hematoma. She was taken emergently for evacuation, and on postoperative examination was found to be locked-in. The symptom complex, while classic for LIS, resolved at an accelerated rate compared with previous reports. Emergent evacuation of clot and rehabilitation were performed. CONCLUSION: Prompt treatment allowed this patient to experience an accelerated and more complete recovery compared with the ischemic causes of LIS. PMID- 21792147 TI - Design and synthesis of novel antimicrobial acyclic and heterocyclic dyes and their precursors for dyeing and/or textile finishing based on 2-N-acylamino 4,5,6,7-tetrahydro-benzo[b]thiophene systems. AB - A series of novel polyfunctionalized acyclic and heterocyclic dye precursors and their respective azo (hydrazone) counterpart dyes and dye precursors based on conjugate enaminones and/or enaminonitrile moieties were synthesized. The dyes and their precursors are based on 2-cyano-N-(3-cyano-4,5,6,7 tetrahydrobenzo[b]thiophen-2-yl)-acetamide, 2-ethoxycarbonyl-N-(3-cyano-4,5,6,7 tetrahydrobenzo[b]thiophen-2-yl)-acetamide or 2-phenylcarbamoyl-N-(3-cyano 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide systems as precursors. The latter compounds were used to synthesize polyfunctional thiophene-, thiazole-, pyrazole, pyridine-, pyrimidine-, oxazine-, as well as acyclic moieties. The dyes and dye precursors were characterized by elemental analysis and spectral methods. All dyes and their precursors were screened in vitro and evaluated for both their antibacterial and antifungal activities. MIC data of the novel dye systems and their respective precursors showed significant antimicrobial activity against most tested organisms. Some compounds exhibited comparable or even higher efficiency than selected standards. Dyes were applied at 5% depth for disperse dyeing of nylon, acetate and polyester fabrics. Their spectral characteristics and fastness properties were measured and evaluated. PMID- 21792148 TI - Synthesis of both ionic species of ammonium dithiocarbamate derived cholic acid moieties. AB - The reaction of 3-aminopropylamide of cholic acid with CS2 produced a bile acid derivative of dithiocarbamic acid which further formed an ammonium salt with another molecule of 3-aminopropylamide of cholic acid. The cationic 3-ammonium propylamide of cholic acid did not react further with CS2 and the formed salt was stable in the reaction mixture, even when excess CS2 was used. When the reaction was carried out in the presence of aqueous sodium hydroxide, only the bile acid derivative of sodium dithiocarbamate was formed. The dithiocarbamate derivatives were characterized by 1H- and 13C-NMR spectroscopy and ESI-TOF mass spectrometry. PMID- 21792149 TI - A facile synthesis of highly functionalized 4-arylcoumarins via Kostanecki reactions mediated by DBU. AB - An efficient synthesis of 4-arylcoumarins has been accomplished via Kostanecki reactions of 2-hydroxybenzophenones with acetic anhydride employing DBU at ambient temperature. Using the same strategy, several 2-acyloxybenzophenone derivatives were readily converted to 3,4-difunctionalized coumarins. This protocol offers a notable improvement in reaction conditions for coumarin synthesis and takes advantage of its synthetic capability, especially for highly functionalized 4-arylcoumarins with structural diversity. PMID- 21792150 TI - Rhinacanthus nasutus protects cultured neuronal cells against hypoxia induced cell death. AB - Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is an herb native to Thailand and Southeast Asia, known for its antioxidant properties. Hypoxia leads to an increase in reactive oxygen species in cells and is a leading cause of neuronal damage. Cell death caused by hypoxia has been linked with a number of neurodegenerative diseases including some forms of dementia and stroke, as well as the build up of reactive oxygen species which can lead to diseases such as Huntington's disease, Parkinson's disease and Alzeheimer's disease. In this study we used an airtight culture container and the Mitsubishi Gas Company anaeropack along with the MTT assay, LDH assay and the trypan blue exlusion assay to show that 1 and 10 ug mL-1 root extract of R. nasutus is able to significantly prevent the death of HT-22 cells subjected to hypoxic conditions, and 0.1 to 10 ug mL-1 had no toxic effect on HT-22 under normal conditions, whereas 100 ug mL-1 reduced HT-22 cell proliferation. We also used H2DCFDA staining to show R. nasutus can reduce reactive oxygen species production in HT-22 cells. PMID- 21792151 TI - Furocoumarin derivatives from radix Angelicae dahuricae and their effects on RXRalpha transcriptional regulation. AB - A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2-18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 MUM) could significantly promote the gene transcriptional function of nuclear receptor RXRalpha. While 7-9, 13, 14, and the new structure 1 (each at 20 MUM) showed significant reduction in RXRalpha gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRalpha. PMID- 21792152 TI - Advances in the treatment of acute thrombotic and chronic critical limb ischemia. PMID- 21792153 TI - Value of drug-eluting stents after failed percutaneous transluminal angioplasty in the infrapopliteal vessels for the treatment of critical limb ischemia: favorable mid-term patency and limb salvage results. AB - AIM: The endovascular treatment of infrapopliteal arterial disease in the setting of critical limb ischemia (CLI) is increasing in use. In patients in whom percutaneous transluminal angioplasty (PTA) resulted in suboptimal angiographic results, flow limiting dissection or re-coil is thought to limit clinical success. This single-center experience examines the angiographic and clinical results when Drug-Eluting Stents (DES) were placed in a large cohort of patients with CLI after immediate infrapopliteal PTA failure. METHODS: A retrospective review of a prospectively collected single-center endovascular database was performed. Sixty-seven Rutherford grade 4, 5, and 6 patients were treated between October 2005 and February 2010 with PTA because lack of an acceptable autologous vein for bypass-grafting or severe medical comorbidities precluded them from surgical bypass. The study cohort had suboptimal angiographic results immediately after PTA that was subsequently treated with DES. Patients were then placed on clopidogrel and aspirin indefinitely. Angiographic, clinical, and the results of noninvasive vascular examinations were collected. RESULTS: In total, 123 stents (94 sirolimus, 27 everolimus, 2 paclitaxel) were placed in 67 patients to treat a total of 84 angiographic lesions. Simultaneous femoral-popliteal intervention was performed in 66% of the patients while 45% of the treated lesions were total occlusions. Lesion length ranged from 17 mm-142 mm (mean 50 mm). Initial technical success was 100%, with all 84 lesions being treated successfully with less than 10% stenosis after stent implantation. Mean follow-up was 20 months (1 42 months) with 6, 12, and 24-month primary patency rates of 90%, 86%, and 72% respectively. Freedom from major amputation was 91.1% (61/67) with all six amputations occurring in the Rutherford grade 6 group (6/11). Overall mortality rate was 19% (13/67) with one death occurring within 30 days. CONCLUSION: The use of drug-eluting stents following suboptimal PTA for the treatment of infrapopliteal arterial disease in this cohort of patients with CLI produced high primary patency and limb salvage rates supporting the efficacy of this treatment strategy. PMID- 21792154 TI - Ultrasound-accelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review. AB - AIM: This study evaluates the short-term outcome of ultrasound-accelerated thrombolysis in patients with lower extremity ischemia caused by thromboembolic occlusions. METHODS: A retrospective cohort study was conducted from December 2008 to May 2011 of 57 patients (42 men; median age, 66 +/- 11 years) undergoing 62 episodes of ultrasound-accelerated thrombolysis for thromboembolic arterial occlusions of the lower extremities. The EKOS EndoWave System (EKOS Corporation, Bothell, WA, USA) was combined with urokinase (100000 IU/hour). Thirty-day and 6 month follow-up consisted of clinical evaluation, and Duplex scan or magnetic resonance angiography of the treated extremity. RESULTS: Initial technical success was 97%, radiologic success was 82%, and overall clinical success was 77%. Median thrombolysis time was 21 hours (IQR, 15-24). In 38 of 51 procedures with successful lysis (75%) complete lysis was achieved within 24 hours. Major hemorrhage occurred in 2 procedures (3%), and distal embolization in 2 procedures (3%). During the initial hospitalization, the major amputation rate was 8% (N.=5) and the mortality rate was 2% (N.=1). The 30-day patency rate was 81%, without additional mortality. During a median 6-month (range, 2-14) follow-up, 9 reinterventions were performed. Two patients underwent major amputation and 3 patients died; because of malignancy (N.=2) and stroke (N.=1). CONCLUSION: Initial success rates of ultrasound-accelerated thrombolysis are high and complication rate is low. However, reintervention rate during short-term follow up for recurrent ischemia is substantial. Results from a randomized controlled trial comparing ultrasound-accelerated thrombolysis with standard thrombolysis for lower extremity ischemia (DUET, Current Controlled Trials, ISRCTN72676102) are eagerly awaited. PMID- 21792155 TI - Percutaneous mechanical thrombectomy: advantages and limitations. AB - Acute and subacute ischemia of the lower limb are still a common reason for amputation. Surgical thrombectomy according to Fogarty has declined in importance, due to the increased incidence of perioperative complications, while local intraarterial lysis is also associated with an increased rate of hemorrhagic complications, beside the prolonged time up to revascularisation, which additionally results in the need for intensive care monitoring. As an endovascular therapeutic option, various mechanical thrombectomy systems have been available over the past few years that studies have shown to have a low rate of complications, accompanied by a high technical success rate and low amputation rate. This review article will present the mechanism of action of the various mechanical thrombectomy systems that are currently in use and analyze the study results available on the respective systems. PMID- 21792156 TI - Endovascular techniques for limb salvage in diabetics with crural and pedal disease. AB - Diabetics with critical limb ischemia (CLI) usually have significant multilevel arterial disease, very often with compromised outflow on the foot arteries. The combination of severe peripheral arterial occlusion with the increased blood flow requirement, necessary to achieve the healing of the skin lesions or surgical incisions, makes this population particularly challenging. Additionally, diabetics and CLI patients have a high rate of comorbities, that increase the surgical risks or contraindicate surgical by-pass. Since its initial applications, endovascular recanalization for tibial vessels and foot arteries has proven to be feasible and safe, especially in diabetics with CLI. Actually, it is an established treatment option for limb salvage, avoiding amputation in lot of cases and improving lesions healing. The development of new technologies, such as dedicated guidewire's or low profile catheter balloons helps the interventionists, but the knowledge of most important techniques could be indispensable to obtain the procedural success and clinical outcomes. PMID- 21792157 TI - Evolution of atherectomy devices. AB - Percutaneous atherectomy provides an alternative approach to the endovascular treatment of peripheral atherosclerotic occlusive disease beyond angioplasty and stenting, and has the theoretical advantage of lesion debulking and minimizing barotrauma to the vessel wall. Atherectomy has evolved greatly during the last decade, with currently four FDA approved devices for the treatment of peripheral arterial disease. Several reports have focused on the initial technical success rates, and demonstrated the safety and short as well as mid-term efficacy of atherectomy devices. This article will review the evolution of current atherectomy devices and the associated literature. PMID- 21792158 TI - Management of acute type B aortic dissections and acute limb ischemia. AB - AIM: The aim of this study was to review the management of acute type B aortic dissection (TBAD) with acute limb ischemia. A search using the "Pubmed" resulted in 254 records by combining the Medical Subject Heading keywords (listed separately). The articles were assessed for their validity, correct pathology and patient cohort. Inclusion criteria included all patients with complicated acute TBAD who were candidates for open of thoracic endovascular aortic repair (TEVAR). The exclusion criteria included type A, asymptomatic acute or chronic TBAD, penetrating ulcer or intramural hematoma. TBAD with limb ischemia has a poor prognosis if not diagnosed, triaged and treated promptly. Clinical presentation and diagnostic strategy as well as various imaging are reviewed. Early mortality rate for complicated acute TBAD (with malperfusion to lower extremity) is 12%. The management has moved from open operation to primary TEVAR. In cases with anatomic obstruction, open surgical techniques such as femoral-femoral bypass, axillo-femoral bypass or surgical fenestration can be successful in relief of malperfusion to the affected limb. One-year-survival rates are 85%. A complete to partial reverse aortic remodeling occurred in 78% of survivors of acute TBAD, if primary TEVAR is applied. Acute TBAD with limb ischemia remains a clinical challenge that requires prompt diagnosis and treatment. TEVAR of acute TBAD is associated with relatively low morbidity and mortality, and is more often used as primary approach for patients with limb ischemia. The outcomes with TEVAR compare favorably to the open repair, and initiate reverse aortic remodeling in majority of the survivors. PMID- 21792159 TI - Uncomplicated type B dissection: are there any indications for early intervention? AB - Currently thoracic endovascular repair (TEVAR) has a limited role in uncomplicated type B aortic dissection. Aggressive medical therapy is deemed appropriate for most of these patients allowing one-year survival rate of 80-90%. Outcomes are less than optimal in the long term, however, since aorta related complications (disease progression, rapid deterioration, acute rupture and elevated mortality) may occur in up to 50% of patients at five years. Subgroups of patients with uncomplicated type B dissection may benefit from early stent graft placement, but identification of these remains difficult. Only future studies, especially randomized trials, will clarify the utility of early TEVAR in the setting of uncomplicated acute type B dissection. PMID- 21792160 TI - Do branched and fenestrated devices have a role in chronic type B aortic dissection? AB - Morbidity and mortality after conventional open repair of post-dissecting thoracoabdominal aortic aneurysms (TAAA) remain high despite the improvement of results. Recently, "hybrid" open de-branching procedures combined with endovascular stent-grafting of the atherosclerotic thoracic aortic aneurisms have been performed, as an alternative approach. However, patients with significant cardiac, pulmonary or renal comorbidities, may represent an unfit cohort also for such hybrid procedures, and, of consequence, may be resigned to medical treatment. Recent experiences with fenestrated and branched stent-grafts have opened new opportunities in the treatment of extensive aortic aneurysms involving the visceral and renal arteries, particularly in case of atherosclerotic aneurysms. Post-dissection thoracoabdominal aneurysms present with additional challenges such as narrow true lumen at the level of the visceral vessels origin, and the lack of a stable distal landing zone. In this report, we discuss the role of fenestrated and branched stent-grafts as feasible treatment of post-dissecting TAAA. PMID- 21792161 TI - One stage carotid artery stenting and open heart surgery: a novel approach. AB - AIM: The optimal management of the patients requiring cardiac surgery with simultaneous severe carotid disease remains controversial. The traditional approach involves staged or combined carotid endarterectomy and cardiac surgery. This study evaluated the feasibility and safety of angioplasty and stenting for the treatment of carotid stenoses combined with cardiac operations in order to reduce the risk of perioperative stroke. METHODS: In a prospective, non randomized study, we analyzed 70 consecutive patients requiring cardiac surgery with simultaneous severe carotid artery disease that underwent carotid artery stenting (CAS) and cardiac surgery in one stage. Symptomatic patients with >= 60% carotid stenosis, and asymptomatic patients with >= 70% stenosis, were treated using CAS under local anesthesia immediately before the open heart surgery. Cerebral protection devices were used in all cases. RESULTS: Despite the high baseline risk profile, our results were very encouraging. Carotid stenting was successful in all patients. No neurological complications occurred during the carotid stenting procedures. The 30-day death/stroke rate was 1.4% (no deaths, 1 contralateral minor stroke). No myocardial infarctions occurred. The carotid restenosis rate was zero during the long-term follow up. CONCLUSION: The low complication rate suggests that CAS and cardiac surgery in one stage offers a safer therapeutic option compared to combined carotid endarterectomy and cardiac surgery. It may also be safer than with the staged CAS and coronary artery bypass grafting approach as well. PMID- 21792162 TI - Proteomic analyses of aortic wall in patients with abdominal aortic aneurysm. AB - AIM: The mechanisms underlying the formation of abdominal aortic aneurysms have yet to be fully clarified. To identify key proteins generally involved in aneurysmal formation, proteomic profiles were compared between aneurysmal and non aneurysmal regions of aortic walls from patients with abdominal aortic aneurysm. METHODS: Aortic wall specimens were obtained from three patients with abdominal aortic aneurysm. Protein profiles of aortic wall samples including vascular media and adventitia were compared between aneurysmal and non-aneurysmal regions in each patient using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein spots expressed differently between the two regions were identified by tandem mass spectrometry and verified by immunohistochemical investigations. RESULTS: Image analysis of 2D-DIGE gels revealed 22 proteins spots expressed differently between aneurysmal and non-aneurysmal regions in all three patients. Among these, five protein spots that were up-regulated in the AA regions were successfully identified as complement component C4, fragments of the fibrinogen alpha or beta subunits, and actin. Immunohistochemical studies showed massive deposition of fibrin/fibrinogen or its fragments in the media, and complement C1q component, the molecule starting the classical complement pathway, in all three layers of the aneurysmal region. CONCLUSION: Our proteomic and subsequent immunohistochemical studies revealed significant fibrinogenesis and fibrinolysis in the media, and activation of the classical complement pathway in all three layers of the aneurysmal region. These data promote understanding of mechanisms behind the formation of abdominal aortic aneurysms. PMID- 21792163 TI - Visceral artery aneurysms: management of 48 cases. AB - AIM: The purpose of this study was to review the outcomes of endovascular treatment and open repair of visceral artery aneurysms, and to compare their results. METHODS: Between January 1995 and January 2009, 42 patients (22 males) underwent surgical or endovascular treatment for visceral artery aneurysms. Mean age was 60 +/- 13 (range, 35-85). Overall, 12 patients (25%) were asymptomatic, twenty-six patients (54.2%) were symptomatic, and 10 aneurysms (20.8%) were ruptured. The first 12 cases (28.6%) were treated with open repair; thereafter, endovascular techniques were used to treat 30 VAAs (71.4%). RESULTS: Ten patients were treated in emergency setting [8 in the endovascular group (26.6%) and 2 in the open repair group (16.7%), P=0.491]. In the endovascular group, primary technical success was achieved in 29 of 30 VAAs (96.6%). Overall in-hospital mortality was 2.4%. Major complications occurred in 8 patients (3 endovascular vs 5 open repair, P=0.01). Overall, mean hospitalization was 9.7 vs. 13 days (P<0.0001). Mean follow-up was 64 months (range, 3 months-14 years). In the endovascular group, reperfusion was higher in larger (>5 cm) aneurysms (P<0.0001). CONCLUSION: Endovascular techniques could be the first treatment option for all visceral artery aneurysms. PMID- 21792164 TI - Role of oxidative stress in hypoxia preconditioning of cells transplanted to the myocardium: a molecular imaging study. AB - AIM: Cell-based therapies are a potential therapeutic alternative for the treatment of coronary artery disease (CAD). However, transplanted cells undergo significant death in the living subject. Hypoxic preconditioning (HPC) is a potential intervention to increase transplanted cell survival. However, the biological mechanisms of this benefit remain unclear. We hypothesize that the beneficial effect of HPC on stem cell survival is in part due to preservation of oxidant status, an effect that will be monitored using state-of-the-art molecular imaging. METHODS: H9c2 rat cardiomyoblasts expressing the construct CMV-firefly luciferase (h9c2-fluc), with and without HPC, were exposed to hypoxia, and oxidative stress and cell survival were measured. Subsequently, H9c2-fluc cells, with and without HPC, were injected into the myocardium of rats and cell survival was monitored daily with Bioluminescence (BLI) using a CCD camera. RESULTS: Compared to controls, cells exposed to hypoxia had increased amount of reactive oxygen species (ROS, control: 14.1+/-0.9 vs. hypoxia: 19.5 +/- 2.0 RFU/ug protein, P=0.02) and decreased cell survival (control: 0.29 +/- 0.005 vs. hypoxia: 0.24 +/- 0.005 OD, P<0.001). HPC treatment decreased the amount of hypoxia-induced ROS (HPC: 11.5 +/- 0.7RFU/ug protein, P=0.002 vs. hypoxia and P=0.11 vs. control), associated with improved survival (HPC: 0.27 +/- 0.004OD/ug protein, P=0.002 vs. hypoxia and P=0.005 vs. control). Most importantly, compared to un-conditioned cells, HPC-cells had increased cell survival after transplantation to the myocardium (C: 34.7 +/- 6.7% vs. HPC: 83.4 +/- 17.5% at day 5 compared to day 1, P=0.01). CONCLUSION: The beneficial effect of HPC is in part due to preservation of oxidant status. Molecular imaging can assess changes in cell survival in the living subject and has the potential to be applied clinically. PMID- 21792165 TI - Quality of life one year post myocardial revascularization and aortic valve replacement in patients aged 70 year or older. AB - AIM: The aim of this study was to investigate changes of health-related quality of life (HRQOL) at one year post myocardial revascularization (CABG) and post aortic valve replacement (AVR) in patients aged 70 years or older. METHODS: Of 102 CABG patients and 69 AVR patients preoperative and follow-up data on QOL, were completed. For assessing HRQoL, the EuroQol instrument (EQ) was used. The EQ 5D index score was calculated, based on separate scores of 5 health domains, to express the global health status of the patient. The EQ visual analogue scale (VAS) was used to describe patients' subjective HRQoL. RESULTS AND CONCLUSION: At one year postoperative, the EQ-5D index of the CABG group shows a significant increase (P=0.038), while that of the AVR group does not (P=0.26). The EQ-VAS registration, however, shows a significant increase for both the CABG group (P=0.003) and the AVR group (P=0.021). Considering the 5 domains of the registered HRQOL, in the AVR group only the calculated mean of the item "pain and discomfort" shows a significantly better score postoperatively (P=0.006). In the CABG group, mobility (P=0.016), pain and discomfort (P=0.15) and anxiety (P=0.036) get significantly better scores postoperatively. In conclusion, in elderly patients HRQOL strongly increases after CABG and AVR. However the improvement of functional and social quality of life is less far-going in patients undergoing AVR than in CABG patients. PMID- 21792166 TI - Coronary artery bypass grafting in a patient with hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu syndrome) is an autosomal dominant condition which usually presents with recurrent epistaxis, due to the presence of mucocutaneous telangiectasia, and circulatory arteriovenous malformations (pulmonary, hepatic, cerebral and spinal). We present a patient with HHT and coronary artery disease, who underwent coronary artery bypass grafting with a successful outcome. PMID- 21792167 TI - Combined treatment of non-small cell lung cancer with synchronous brain metastases: a single center experience. AB - AIM: The aim of this study was to analyze our experience with combined treatment of non-small cell lung cancer with synchronous brain metastases. METHODS: Between 1992 and 2008, 31 patients were treated by performing neurosurgery (or stereotactic radiosurgery) and lung surgery. Patients were divided into two groups according to their preoperative mediastinal work-up: group A (CT scan) and group B (FDG-PET scan). RESULTS: Twenty-six patients had one brain metastasis and five had two. Neurosurgery was performed in 10 patients, stereotactic radiosurgery in 20 and both approaches in 1. Seven patients underwent chemotherapy after cerebral procedure. Pulmonary resection was complete in 27 cases and incomplete in 4. Histological findings showed: adenocarcinoma in 19 cases, squamous cell carcinoma in 8 and large cell carcinoma in 4. All patients underwent adjuvant chemotherapy. Overall 1, 2 and 5-year survival rates were 83%, 47% and 21%, respectively. The median survival was 22 months. Univariate analysis showed a better prognosis for complete resection (P=0.008), adenocarcinomas (P=0.015), N0 disease (P=0.038), and Group B (P=0.045). Multivariate analysis showed that only the radicality of the resection (P=0.027) and Group B (P=0.047) were independent prognostic factors. CONCLUSION: Our experience confirms that selected patients with non-small cell lung cancer and synchronous brain metastases may be effectively treated by combined therapy. Complete resection, adenocarcinoma histology and N0 disease were prognostic factors. The incorporation of FDG-PET scan into the preoperative work-up may translate into a survival benefit. PMID- 21792168 TI - Global warming: is weight loss a solution? AB - The current climate change has been most likely caused by the increased greenhouse gas emissions. We have looked at the major greenhouse gas, carbon dioxide (CO(2)), and estimated the reduction in the CO(2) emissions that would occur with the theoretical global weight loss. The calculations were based on our previous weight loss study, investigating the effects of a low-carbohydrate diet on body weight, body composition and resting metabolic rate of obese volunteers with type 2 diabetes. At 6 months, we observed decreases in weight, fat mass, fat free mass and CO(2) production. We estimated that a 10 kg weight loss of all obese and overweight people would result in a decrease of 49.560 Mt of CO(2) per year, which would equal to 0.2% of the CO(2) emitted globally in 2007. This reduction could help meet the CO(2) emission reduction targets and unquestionably would be of a great benefit to the global health. PMID- 21792170 TI - Short sleep duration is associated with increased obesity markers in European adolescents: effect of physical activity and dietary habits. The HELENA study. AB - BACKGROUND: Adequate sleep is a critical factor for adolescent's health and health-related behaviors. OBJECTIVE: (a) to describe sleep duration in European adolescents from nine countries, (b) to assess the association of short sleep duration with excess adiposity and (c) to elucidate if physical activity (PA), sedentary behaviors and/or inadequate food habits underlie this association. DESIGN: A sample of 3311 adolescents (1748 girls) aged 12.5-17.49 years from 10 European cities in Austria, Belgium, France, Germany, Greece, Hungary, Italy, Spain and Sweden was assessed in the Healthy Lifestyle in Europe by Nutrition in Adolescence Study between 2006 and 2008. We measured anthropometric data, sleep duration, PA (accelerometers and questionnaire), television watching and food habits (Food Frequency Questionnaire). RESULTS: Average duration of daily sleep was 8 h. Shorter sleepers showed higher values of BMI, body fat, waist and hip circumferences and fat mass index (P<0.05), particularly in females. Adolescents who slept <8 h per day were more sedentary, as assessed by accelerometry, and spent more time watching TV (P<0.05). The proportion of adolescents who eat adequate amounts of fruits, vegetables and fish was lower in shorter sleepers than in adolescents who slept >=8 h per day, and so was the probability of having adequate food habits (P<0.05). Correlation analysis indicated that short sleep is associated with higher obesity parameters. CONCLUSIONS: In European adolescents, short sleep duration is associated with higher adiposity markers, particularly in female adolescents. This association seems to be related to both sides of the energy balance equation due to a combination of increased food intake and more sedentary habits. PMID- 21792169 TI - Food pattern analysis over time: unhealthful eating trajectories predict obesity. AB - BACKGROUND: Analysis of dietary patterns is prominent in nutrition literatures, yet few studies have taken advantage of multiple repeated measurements to understand the nature of individual-level changes over time in food choice, or the relation between these changes and body mass index (BMI). OBJECTIVE: To investigate changes in eating patterns at the individual level across three exam periods, and to prospectively examine the relation of eating trajectories to BMI at the cohort level. DESIGN: The study included 3418 participants at baseline. Clinically measured BMI and dietary intake were assessed during three exam periods between 1991 and 2001 using a validated food frequency questionnaire. An individual's eating trajectory across exam periods was analyzed using sequence analysis, and then used to estimate outcomes of continuous BMI and categorical obesity status. Ordinary least squares regression models with robust standard errors were adjusted for socio-economic and demographic confounders, baseline BMI and baseline eating. RESULTS: A total of 66.2% (n=1614) of participants change their diet pattern during the study period, 33.8% (n=823) remain stable. After accounting for potential confounders, an unhealthful trajectory is significantly associated with a 0.42 kg m(-2) increase in BMI (confidence interval (CI): 0.1, 0.7). Those with an unhealthful trajectory are 1.79 times more likely to be overweight (relative risk ratio, 95% CI: 1.1, 2.8) and 2.4 times more likely to be obese (relative risk ratio, 95% CI: 1.3, 4.4). Moreover, a number of specific diet transitions between exams are predictive of weight gain or loss. CONCLUSION: Contextualizing an individual's current eating behaviors with an eye towards diet history may be an important boon in the reduction of obesity. Although it may not be realistic for many people to shift from the least to most healthful diet, results from this study suggest that consistent movement in an overall healthier direction is associated with less weight gain. PMID- 21792171 TI - Association of adipose tissue blood flow with fat depot sizes and adipokines in women. AB - OBJECTIVE: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women. SUBJECTS: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women. METHODS: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids. RESULTS: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow. CONCLUSION: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow. PMID- 21792172 TI - Cotranslational transport of ABP140 mRNA to the distal pole of S. cerevisiae. AB - In budding yeast, several mRNAs are selectively transported into the daughter cell in an actin-dependent manner by a specialized myosin system, the SHE machinery. With ABP140 mRNA, we now describe the first mRNA that is transported in the opposite direction and localizes to the distal pole of the mother cell, independent of the SHE machinery. Distal pole localization is not observed in mutants devoid of actin cables and can be disrupted by latrunculin A. Furthermore, localization of ABP140 mRNA requires the N-terminal actin-binding domain of Abp140p to be expressed. By replacing the N-terminal localization motif, ABP140 mRNA can be retargeted to different subcellular structures. In addition, accumulation of the mRNA at the distal pole can be prevented by disruption of polysomes. Using the MS2 system, the mRNA was found to associate with actin cables and to follow actin cable dynamics. We therefore propose a model of translational coupling, in which ABP140 mRNA is tethered to actin cables via its nascent protein product and is transported to the distal pole by actin retrograde flow. PMID- 21792173 TI - Vaccinia extracellular virions enter cells by macropinocytosis and acid-activated membrane rupture. AB - Vaccinia virus (VACV), the model poxvirus, produces two types of infectious particles: mature virions (MVs) and extracellular virions (EVs). EV particles possess two membranes and therefore require an unusual cellular entry mechanism. By a combination of fluorescence and electron microscopy as well as flow cytometry, we investigated the cellular processes that EVs required to infect HeLa cells. We found that EV particles were endocytosed, and that internalization and infection depended on actin rearrangements, activity of Na(+)/H(+) exchangers, and signalling events typical for the macropinocytic mechanism of endocytosis. To promote their internalization, EVs were capable of actively triggering macropinocytosis. EV infection also required vacuolar acidification, and acid exposure in endocytic vacuoles was needed to disrupt the outer EV membrane. Once exposed, the underlying MV-like particle presumably fused its single membrane with the limiting vacuolar membrane. Release of the viral core into the host cell cytosol allowed for productive infection. PMID- 21792174 TI - Distinct pathways for modification of the bacterial cell wall by non-canonical D amino acids. AB - Production of non-canonical D-amino acids (NCDAAs) in stationary phase promotes remodelling of peptidoglycan (PG), the polymer that comprises the bacterial cell wall. Impairment of NCDAAs production leads to excessive accumulation of PG and hypersensitivity to osmotic shock; however, the mechanistic bases for these phenotypes were not previously determined. Here, we show that incorporation of NCDAAs into PG is a critical means by which NCDAAs control PG abundance and strength. We identified and reconstituted in vitro two (of at least three) distinct processes that mediate NCDAA incorporation. Diverse bacterial phyla incorporate NCDAAs into their cell walls, either through periplasmic editing of the mature PG or via incorporation into PG precursor subunits in the cytosol. Production of NCDAAs in Vibrio cholerae requires the stress response sigma factor RpoS, suggesting that NCDAAs may aid bacteria in responding to varied environmental challenges. The widespread capacity of diverse bacteria, including non-producers, to incorporate NCDAAs suggests that these amino acids may serve as both autocrine- and paracrine-like regulators of chemical and physical properties of the cell wall in microbial communities. PMID- 21792175 TI - A new basal promoter element recognized by RNA polymerase core enzyme. AB - Bacterial promoters are recognized by RNA polymerase (RNAP) sigma subunit, which specifically interacts with the -10 and -35 promoter elements. Here, we provide evidence that the beta' zipper, an evolutionarily conserved loop of the largest subunit of RNAP core, interacts with promoter spacer, a DNA segment that separates the -10 and -35 promoter elements, and facilitates the formation of stable closed promoter complex. Depending on the spacer sequence, the proposed interaction of the beta' zipper with the spacer can also facilitate open promoter complex formation and even substitute for interactions of the sigma subunit with the -35 element. These results suggest that there exists a novel class of promoters that rely on interaction of the beta' zipper with promoter spacer, along with or instead of interactions of sigma subunit with the -35 element, for their activity. Finally, our data suggest that sequence-dependent interactions of the beta' zipper with DNA can contribute to promoter-proximal sigma-dependent RNAP pausing, a recently recognized important step of transcription control. PMID- 21792176 TI - p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death. AB - Hypoxia stabilizes the tumour suppressor p53, allowing it to function primarily as a transrepressor; however, the function of p53 during hypoxia remains unclear. In this study, we showed that p53 suppressed BNIP3 expression by directly binding to the p53-response element motif and recruiting corepressor mSin3a to the BNIP3 promoter. The DNA-binding site of p53 must remain intact for the protein to suppress the BNIP3 promoter. In addition, taking advantage of zebrafish as an in vivo model, we confirmed that zebrafish nip3a, a homologous gene of mammalian BNIP3, was indeed induced by hypoxia and p53 mutation/knockdown enhanced nip3a expression under hypoxia resulted in cell death enhancement in p53 mutant embryos. Furthermore, p53 protected against hypoxia-induced cell death mediated by p53 suppression of BNIP3 as illustrated by p53 knockdown/loss assays in both human cell lines and zebrafish model, which is in contrast to the traditional pro apoptotic role of p53. Our results suggest a novel function of p53 in hypoxia induced cell death, leading to the development of new treatments for ischaemic heart disease and cerebral stroke. PMID- 21792177 TI - ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. AB - Despite evidence that hyperactivity of the vasodeleterious axis (ACE/angiotensin II (Ang II)/AT1 receptor) of the renin-angiotensin system (RAS) is associated with the pathogenesis of diabetic retinopathy (DR) use of the inhibitors of this axis has met with limited success in the control of this pathophysiology. We investigated the hypothesis that enhancing the local activity of the recently established protective axis of the RAS, ACE2/Ang-(1-7), using adeno-associated virus (AAV)-mediated gene delivery of ACE2 or Ang-(1-7) would confer protection against diabetes-induced retinopathy. Genes expressing ACE2 and Ang-(1-7) were cloned in AAV vector. The effects of ocular AAV-ACE2/Ang-(1-7) gene transfer on DR in diabetic eNOS(-/-) mice and Sprague-Dawley (SD) rats were examined. Diabetes was associated with approximately tenfold and greater than threefold increases in the ratios of ACE/ACE2 and AT1R/Mas mRNA levels in the retina respectively. Intraocular administration of AAV-ACE2/Ang-(1-7) resulted in significant reduction in diabetes-induced retinal vascular leakage, acellular capillaries, infiltrating inflammatory cells and oxidative damage in both diabetic mice and rats. Our results demonstrate that DR is associated with impaired balance of retinal RAS. Increased expression of ACE2/Ang-(1-7) overcomes this imbalance and confers protection against DR. Thus, strategies enhancing the protective ACE2/Ang-(1-7) axis of RAS in the eye could serve as a novel therapeutic target for DR. PMID- 21792178 TI - Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus. AB - Oncolytic adenoviruses are an emerging experimental approach for treatment of tumors refractory to available modalities. Although preclinical results have been promising, and clinical safety has been excellent, it is also apparent that tumors can become virus resistant. The resistance mechanisms acquired by advanced tumors against conventional therapies are increasingly well understood, which has allowed development of countermeasures. To study this in the context of oncolytic adenovirus, we developed two in vivo models of acquired resistance, where initially sensitive tumors eventually gain resistance and relapse. These models were used to investigate the phenomenon on RNA and protein levels using two types of analysis of microarray data, quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Interferon (IFN) signaling pathways were found upregulated and Myxovirus resistance protein A (MxA) expression was identified as a marker correlating with resistance, while transplantation experiments suggested a role for tumor stroma in maintaining resistance. Furthermore, pathway analysis suggested potential therapeutic targets in oncolytic adenovirus-resistant cells. Improved understanding of the antiviral phenotype causing tumor recurrence is of key importance in order to improve treatment of advanced tumors with oncolytic adenoviruses. Given the similarities between mechanisms of action, this finding might be relevant for other oncolytic viruses as well. PMID- 21792179 TI - Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy. AB - We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses. PMID- 21792181 TI - The development of a novel cancer immunotherapeutic platform using tumor targeting mesenchymal stem cells and a protein vaccine. AB - An ideal anticancer strategy should target only the malignant cells but spare the normal ones. In this regard, we established a platform, consisting of an antigen delivering vehicle and a protein vaccine, for developing an immunotherapeutic approach with the potential for eliminating various cancer types. Mesenchymal stem cells (MSCs) have been demonstrated capable of targeting tumors and integrating into the stroma. Moreover, we have developed a protein vaccine PE(DeltaIII)-E7-KDEL3 which specifically recognized E7 antigen and elicited immunity against cervical cancer. Taking advantage of tumor-homing property of MSCs and PE(DeltaIII)-E7-KDEL3, we used E6/E7-immortalized human MSCs (KP-hMSCs) as an E7 antigen-delivering vehicle to test if this protein vaccine could effectively eliminate non-E7-expressing tumor cells. Animals which received combined treatment of KP-hMSCs and PE(DeltaIII)-E7-KDEL3 demonstrated a significant inhibition of tumor growth and lung-metastasis when compared to PE(DeltaIII)-E7-KDEL3 only and KP-hMSCs only groups. The efficiency of tumor suppression correlated positively to the specific immune response induced by PE(DeltaIII)-E7-KDEL3. In addition, this combined treatment inhibited tumor growth via inducing apoptosis. Our findings indicated that KP-hMSCs could be used as a tumor-targeting device and mediate antitumor effect of PE(DeltaIII)-E7 KDEL3. We believe this strategy could serve as a platform for developing a universal vaccine for different cancer types. PMID- 21792182 TI - Stimulated optomechanical excitation of surface acoustic waves in a microdevice. AB - Stimulated Brillouin interaction between sound and light, known to be the strongest optical nonlinearity common to all amorphous and crystalline dielectrics, has been widely studied in fibres and bulk materials but rarely in optical microresonators. The possibility of experimentally extending this principle to excite mechanical resonances in photonic microsystems, for sensing and frequency reference applications, has remained largely unexplored. The challenge lies in the fact that microresonators inherently have large free spectral range, whereas the phase-matching considerations for the Brillouin process require optical modes of nearby frequencies but with different wave vectors. Here we rely on high-order transverse optical modes to relax this limitation and report the experimental excitation of mechanical resonances ranging from 49 to 1,400 MHz by using forward Brillouin scattering. These natural mechanical resonances are excited in ~100 MUm silica microspheres, and are of a surface-acoustic whispering-gallery type. PMID- 21792183 TI - Mesoscale flux-closure domain formation in single-crystal BaTiO3. AB - Over 60 years ago, Charles Kittel predicted that quadrant domains should spontaneously form in small ferromagnetic platelets. He expected that the direction of magnetization within each quadrant should lie parallel to the platelet surface, minimizing demagnetizing fields,and that magnetic moments should be configured into an overall closed loop, or flux-closure arrangement. Although now a ubiquitous observation in ferromagnets, obvious flux-closure patterns have been somewhat elusive in ferroelectric materials. This is despite the analogous behaviour between these two ferroic subgroups and the recent prediction of dipole closure states by atomistic simulations research. Here we show Piezoresponse Force Microscopy images of mesoscopic dipole closure patterns in free-standing, single-crystal lamellae of BaTiO(3). Formation of these patterns is a dynamical process resulting from system relaxation after the BaTiO(3) has been poled with a uniform electric field. The flux-closure states are composed of shape conserving 90 degrees stripe domains which minimize disclination stresses. PMID- 21792180 TI - AAV vectors for cardiac gene transfer: experimental tools and clinical opportunities. AB - Since the first demonstration of in vivo gene transfer into myocardium there have been a series of advancements that have driven the evolution of cardiac gene delivery from an experimental tool into a therapy currently at the threshold of becoming a viable clinical option. Innovative methods have been established to address practical challenges related to tissue-type specificity, choice of delivery vehicle, potency of the delivered material, and delivery route. Most importantly for therapeutic purposes, these strategies are being thoroughly tested to ensure safety of the delivery system and the delivered genetic material. This review focuses on the development of recombinant adeno-associated virus (rAAV) as one of the most valuable cardiac gene transfer agents available today. Various forms of rAAV have been used to deliver "pre-event" cardiac protection and to temper the severity of hypertrophy, cardiac ischemia, or infarct size. Adeno-associated virus (AAV) vectors have also been functional delivery tools for cardiac gene expression knockdown studies and successfully improving the cardiac aspects of several metabolic and neuromuscular diseases. Viral capsid manipulations along with the development of tissue-specific and regulated promoters have greatly increased the utility of rAAV-mediated gene transfer. Important clinical studies are currently underway to evaluate AAV-based cardiac gene delivery in humans. PMID- 21792184 TI - Dust inputs and bacteria influence dissolved organic matter in clear alpine lakes. AB - Remote lakes are usually unaffected by direct human influence, yet they receive inputs of atmospheric pollutants, dust, and other aerosols, both inorganic and organic. In remote, alpine lakes, these atmospheric inputs may influence the pool of dissolved organic matter, a critical constituent for the biogeochemical functioning of aquatic ecosystems. Here, to assess this influence, we evaluate factors related to aerosol deposition, climate, catchment properties, and microbial constituents in a global dataset of 86 alpine and polar lakes. We show significant latitudinal trends in dissolved organic matter quantity and quality, and uncover new evidence that this geographic pattern is influenced by dust deposition, flux of incident ultraviolet radiation, and bacterial processing. Our results suggest that changes in land use and climate that result in increasing dust flux, ultraviolet radiation, and air temperature may act to shift the optical quality of dissolved organic matter in clear, alpine lakes. PMID- 21792185 TI - Detection of focal adhesion kinase activation at membrane microdomains by fluorescence resonance energy transfer. AB - Proper subcellular localization of focal adhesion kinase (FAK) is crucial for many cellular processes. It remains, however, unclear how FAK activity is regulated at subcellular compartments. To visualize the FAK activity at different membrane microdomains, we develop a fluorescence resonance energy transfer (FRET) based FAK biosensor, and target it into or outside of detergent-resistant membrane (DRM) regions at the plasma membrane. Here we show that, on cell adhesion to extracellular matrix proteins or stimulation by platelet-derived growth factor (PDGF), the FRET responses of DRM-targeting FAK biosensor are stronger than that at non-DRM regions, suggesting that FAK activation can occur at DRM microdomains. Further experiments reveal that the PDGF-induced FAK activation is mediated and maintained by Src activity, whereas FAK activation on cell adhesion is independent of, and in fact essential for the Src activation. Therefore, FAK is activated at membrane microdomains with distinct activation mechanisms in response to different physiological stimuli. PMID- 21792186 TI - Encapsulation of single-molecule magnets in carbon nanotubes. AB - Next-generation electronic, photonic or spintronic devices will be based on nanoscale functional units, such as quantum dots, isolated spin centres or single molecule magnets. The key challenge is the coupling of the nanoscale units to the macroscopic world, which is essential for read and write purposes. Carbon nanotubes with one macroscopic and two nanoscopic dimensions provide an excellent means to achieve this coupling. Although the dimensions of nanotube internal cavities are suitable for hosting a wide range of different molecules, to our knowledge, no examples of molecular magnets inserted in nanotubes have been reported to date. Here we report the successful encapsulation of single-molecule magnets in carbon nanotubes, yielding a new type of hybrid nanostructure that combines all the key single-molecule magnet properties of the guest molecules with the functional properties of the host nanotube. The findings may pave the way to the construction of spintronic or ultrahigh-density magnetic data storage devices. PMID- 21792187 TI - Crafting a revision. PMID- 21792188 TI - Prior and prejudice. PMID- 21792189 TI - Anti-TANKyrase weapons promote myelination. PMID- 21792190 TI - What birds have to say about language. PMID- 21792191 TI - An overlooked neurotoxic species in Alzheimer's disease. PMID- 21792192 TI - Reward and autoreceptors. PMID- 21792193 TI - Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. AB - Several lines of recent evidence support a role for chromatin in splicing regulation. Here, we show that splicing can also contribute to histone modification, which implies bidirectional communication between epigenetic mechanisms and RNA processing. Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with histone H3 Lys36 trimethylation (H3K36me3) relative to intronless genes. In intron-containing genes, H3K36me3 marking is proportional to transcriptional activity, whereas in intronless genes, H3K36me3 is always detected at much lower levels. Furthermore, splicing inhibition impairs recruitment of H3K36 methyltransferase HYPB (also known as Setd2) and reduces H3K36me3, whereas splicing activation has the opposite effect. Moreover, the increase of H3K36me3 correlates with the length of the first intron, consistent with the view that splicing enhances H3 methylation. We propose that splicing is mechanistically coupled to recruitment of HYPB/Setd2 to elongating RNA polymerase II. PMID- 21792194 TI - Flawed methods explain the effect of mammography screening in Nijmegen. PMID- 21792195 TI - Radiation-enhancement of MDA-MB-231 breast cancer cell invasion prevented by a cyclooxygenase-2 inhibitor. AB - BACKGROUND: Recent evidences support that radiation can promote the invasion of cancer cells. As interactions between cancer cells and surrounding stromal cells can have an important role in tumour progression, we determined whether an irradiation to fibroblasts can enhance the invasiveness of breast cancer cells. The role of cyclooxygenase-2 (COX-2), an inflammatory enzyme frequently induced by radiotherapy, was investigated. METHODS: Irradiated 3T3 fibroblasts were plated in the lower compartment of invasion chambers and used as chemoattractant for non-irradiated human breast cancer cell MDA-MB-231, which are oestrogen receptor negative (ER(-)) and the oestrogen receptor positive (ER(+)) MCF-7 cells. Stimulation of COX-2 expression in irradiated 3T3 cells was measured by a semi-quantitative qPCR and western blot. Capacity of the major product of COX-2, the prostaglandin E2 (PGE(2)), to stimulate the production of the matrix metalloproteinase-2 (MMP-2) and cancer cell invasion were assessed with a zymography gel and invasion chambers. RESULTS: Irradiation (5 Gy) of 3T3 fibroblasts increased COX-2 expression and enhanced by 5.8-fold the invasiveness of non-irradiated MDA-MB-231 cells, while their migration was not modified. Addition of the COX-2 inhibitor NS-398 completely prevented radiation-enhancement of cancer cell invasion. Further supporting the potential role of COX-2, addition of PGE(2) has increased cancer cell invasion and release of MMP-2 from the MDA-MB 231 cells. This effect of radiation was dependant on the expression of membrane type 1 (MT1)-MMP, which is required to activate the MMP-2, but was not associated with the ER status. Although irradiated fibroblasts stimulated the invasiveness of MDA-MB-231 ER(-) cells, no enhancement was measured with the ER(+) cell line MCF-7. CONCLUSIONS: Radiation-enhancement of breast cancer cell invasion induced by irradiated 3T3 fibroblasts is not dependant on the ER status, but rather the expression of MT1-MMP. This adverse effect of radiation can be prevented by a specific COX-2 inhibitor. PMID- 21792196 TI - Prostate involvement during sexually transmitted infections as measured by prostate-specific antigen concentration. AB - BACKGROUND: We investigated prostate involvement during sexually transmitted infections by measuring serum prostate-specific antigen (PSA) as a marker of prostate infection, inflammation, and/or cell damage in young, male US military members. METHODS: We measured PSA before and during infection for 299 chlamydia, 112 gonorrhoea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases, and 256 controls. RESULTS: Chlamydia and gonorrhoea, but not NCNGU, cases were more likely to have a large rise (?40%) in PSA than controls (33.6%, 19.1%, and 8.2% vs 8.8%, P<0.0001, 0.021, and 0.92, respectively). CONCLUSION: Chlamydia and gonorrhoea may infect the prostate of some infected men. PMID- 21792197 TI - FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy. AB - BACKGROUND: The aim was to investigate the correlation between (18)F fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5 FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage. PMID- 21792198 TI - Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. AB - BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A T patients, a 30-fold increased risk, establishes breast cancer as part of the A T phenotype. CONCLUSION: Overall, a spectrum of tumour types is associated with A T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age. PMID- 21792199 TI - Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma. AB - BACKGROUND: We sought to investigate the role of ErbB3-mediated signalling on the interaction between pancreatic cancer-associated fibroblasts (CAF) and carcinoma cells in an effort to disrupt tumourigenic pancreatic ductal adenocarcinoma (PDAC) stromal-epithelial cross-communication. METHODS: Primary CAF cultures were established from human PDAC surgical specimens. AsPC-1 pancreatic cancer cell murine subcutaneous xenografts were developed in the presence and absence of CAF and were subsequently treated with epidermal growth factor receptor (EGFR) inhibitors (erlotinib) and ErbB3 inhibitors (MM-121, monoclonal ErbB3 antibody). RESULTS: Cancer-associated fibroblasts were found to secrete neuregulin-1 (NRG 1), which promoted proliferation via phosphorylation of ErbB3 and AKT in AsPC-1 PDAC cells. This signalling cascade was effectively inhibited both in vitro and in vivo by specific ErbB3 blockade with MM-121, with greater degree of tumourigenesis inhibition when combined with erlotinib. The CAF-AsPC-1 pancreatic cancer xenografts reached significantly greater tumour volume than those xenografts lacking CAF and were resistant to the anti-tumour effects of EGFR inhibition with erlotinib. CONCLUSION: Cancer-associated fibroblasts-derived NRG 1 promote PDAC tumourigenesis via ErbB3-AKT signalling and overcomes single-agent EGFR inhibition. Disruption of this stromally mediated tumourigenic mechanism is best obtained through combined EGFR-ErbB3 inhibition with both erlotinib and MM 121. We have identified the NRG-1/ErbB3 axis as an attractive molecular target for the interruption of tumourigenic stromal-epithelial interactions within the PDAC microenvironment. PMID- 21792200 TI - Objective assessment of tumour response to therapy based on tumour growth kinetics. AB - BACKGROUND: Current standards for assessment of tumour response to therapy (a) categorise therapeutic efficacy values, inappropriate for patient-specific and deterministic studies, (b) neglect the natural growth characteristics of tumours, (c) are based on tumour shrinkage, inappropriate for cytostatic therapies, and (d) do not accommodate integration of functional/biological means of therapeutic efficacy assessed with, for example, positron emission tomography or magnetic resonance imaging, with data from anatomical changes in tumour. METHODS: A quantity for tumour response was formulated assuming that an effective treatment may decrease the cell proliferation rate (cytostatic) and/or increase the cell loss rate (cytotoxic) of the tumour. Tumour response values were analysed for 11 non-Hodgkin's lymphoma patients treated with (131)I-labelled anti-B1 antibody and 12 prostate cancer patients treated with a nutritional supplement. RESULTS: Tumour response was found to be equal to the logarithm of the ratio of post treatment tumour volume to the volume of corresponding untreated tumour. Neglecting the natural growth characteristics of tumours results in underestimation of treatment effectiveness based on currently used methods. The model also facilitates the integration of data from tumour volume changes, with data from functional imaging. CONCLUSION: Tumour response to therapy can be assessed with a continuous dimensionless quantity for both cytotoxic and cytostatic treatments. PMID- 21792201 TI - Docetaxel and capecitabine for advanced gastric cancer: investigating dose dependent efficacy in two patient cohorts. AB - BACKGROUND: No comparisons of different doses of docetaxel-capecitabine in patients with advanced gastric cancer have been performed. METHODS: Patients with previously untreated metastatic/locally advanced gastro-oesophageal or gastric adenocarcinoma were enrolled in a prospective multicentre phase II trial. Two sequential cohorts received docetaxel 75 mg m(-2) (day 1) plus capecitabine 1000 mg m(-2) twice daily (days 1-14) (cohort I) or docetaxel 60 mg m(-2) (day 1) plus capecitabine 800 mg m(-2) twice daily (days 1-14) (cohort II) every 3 weeks. The primary end point was confirmed overall response rate. RESULTS: In all, 91 patients were enrolled (cohort I, n=40; cohort II, n=51) and 87 were evaluable for efficacy (n=38, 49, respectively). Overall response rate was 50.0% in cohort I and 23.5% in cohort II (exploratory analysis, P=0.014). Median times to tumour progression and overall survival were 5.6 and 10.1 months in cohort I and 3.7 and 7.2 months in cohort II, respectively. Dose reductions for docetaxel and capecitabine were required in 50.0% and 57.5% of patients in cohort I and 11.8% and 15.7% in cohort II, respectively. CONCLUSION: Starting treatment with full doses and reducing promptly seems to be the more promisingly effective strategy than starting cautiously with lower doses. Docetaxel/capecitabine 75/2000 mg m( 2) is a manageable, convenient outpatient combination with promising efficacy against advanced gastric cancer. PMID- 21792203 TI - Comment on 'Hand pattern indicates risk of prostate cancer'. PMID- 21792205 TI - Ganodermycin, a novel inhibitor of CXCL10 expression from Ganoderma applanatum. AB - CXCL10 (inducible protein-10) is a highly inducible chemoattractant, which contributes to the recruitment of inflammatory cells, such as macrophages and T lymphocytes, and thereby has important roles in chronic inflammatory conditions. In a search for new inhibitors of CXCL10 expression in MonoMac6 cells, a novel compound, designated as Ganodermycin, was isolated from fermentations of the basidiomycete Ganoderma applanatum. The structure was determined by a combination of spectroscopic techniques. Ganodermycin inhibited the lipopolysaccharide (LPS)/interferon (IFN)-gamma-induced CXCL10 promoter activity in transiently transfected MonoMac6 cells in a dose-dependent manner with IC(50) values of 15-20 MUg ml(-1) (53-71 MUM). Ganodermycin also reduced LPS/IFN-gamma-induced CXCL10 protein synthesis and excretion. PMID- 21792206 TI - New species of actinomycetes do not always produce new compounds with high frequency. PMID- 21792207 TI - A new cytotoxic indole-3-ethenamide from the halotolerant fungus Aspergillus sclerotiorum PT06-1. AB - A new cytotoxic indole-3-ethenamide (1) and two known compounds, 7-(3-methylbut-2 enyl)-1H-indole-3-carbaldehyde (2) and emodin (3) were isolated and identified from the ethyl acetate extract of Aspergillus sclerotiorum PT06-1 in a hypersaline nutrient-rich medium. On the basis of spectroscopic analysis and amino-acid analysis, the new structure of 1 was determined to be (S,E)-3-methyl-2 (N- methylacetamido)-N-(2-(7-(3-methylbut-2-enyl)-1H-indol-3-yl)vinyl)butanamide within 3:1 ratio of rotamers along the acetamido single bond in DMSO-d(6) at room temperature. Compound 1 showed moderate cytotoxicity against A-549 cells and weak cytotoxicity against HL-60 cells with the IC(50) values of 3.0 and 27 MUM, respectively. Compound 2 has been separated as natural product for the first time, and its NMR data were also reported for the first time in this study. PMID- 21792208 TI - Phylogenetic diversity of acidophilic actinomycetes from Malaysia. PMID- 21792209 TI - Physiological role of germicidins in spore germination and hyphal elongation in Streptomyces coelicolor A3(2). AB - Four germicidin homologs were isolated from a liquid culture of Streptomyces coelicolor A3(2). These were identified as germicidins A, B and C, and surugapyrone A (germicidin D). Absolute stereochemistry of the chiral center in germicidins A and C is determined to be S. All germicidins inhibited germination of S. coelicolor A3(2) spores above 1 MUg ml(-1). S. coelicolor A3(2) spores collected from a single petri dish (9 cm i.d.) contained 5.4 MUg of germicidin A (-2.7 * 10(-14) g per spore), which accounts for 2.3% of the spore extract, and contents of germicidins B, C and D were 0.2-0.8 MUg. The activity of the spore extract corresponded well with the sum of the activity of each germicidin, which was estimated from the content and dose-response curve, which indicates that germicidins functions as self-germination inhibitors in S. coelicolor A3(2). Inhibitory action of germicidin A on spore germination was reversible and germicidin A inhibited not only spore germination but also hyphal elongation. PMID- 21792210 TI - A cryptic antibiotic triggered by monensin. PMID- 21792211 TI - Identification of novel rapamycin derivatives as low-level impurities in active pharmaceutical ingredients. AB - We describe the identification of novel rapamycin derivatives present as low level impurities in active pharmaceutical ingredients using an integrated, multidisciplinary approach. Rapamycin, a fermentation-derived natural product is itself used clinically and provides the starting material for several rapamycin analog drugs, typically used in oncology. LC-MS proved a sensitive means to analyze impurity profiles in batches of rapamycin. MS fragmentation was used to gain structural insight into these impurities, usually fermentation by-products, structurally very similar to rapamycin. In cases where MS fragmentation was unable to provide unambiguous structural identification, the impurities were isolated and purified using orthogonal HPLC methods. Using the higher mass sensitivity of small-volume NMR microprobes, submilligram amounts of isolated impurities were sufficient for further characterization by multidimensional NMR spectroscopy. Full assignment of the (1)H and (13)C NMR signals revealed the structure of these impurities at an atomic level. This systematic workflow enabled the identification of several novel rapamycin congeners from active pharmaceutical ingredient without the need for large-scale isolation of impurities. For illustration, two novel rapamycin derivatives are described in this study: 12-ethyl-rapamycin and 33-ethyl-rapamycin, which exemplify previously unreported modifications on the carbon skeleton of the rapamycin macrocycle. The methodologies described here can be of wide use for identification of closely related structures found; for example as fermentation by-products, metabolites or degradants of natural product-based drugs. PMID- 21792212 TI - Physical activity pattern and activity energy expenditure in healthy pregnant and non-pregnant Swedish women. AB - BACKGROUND/OBJECTIVES: Energy costs of pregnancy approximate 320 MJ in well nourished women, but whether or not these costs may be partly covered by modifications in activity behavior is incompletely known. In healthy Swedish women: (1) to evaluate the potential of the Intelligent Device for Energy Expenditure and Physical Activity (IDEEA) to assess energy expenditure during free-living conditions, (2) to assess activity pattern, walking pace and energy metabolism in pregnant women and non-pregnant controls, and (3) to assess the effect on energy expenditure caused by changes in physical activity induced by pregnancy. SUBJECTS/METHODS: Activity pattern was assessed using the IDEEA in 18 women in gestational week 32 and in 21 non-pregnant women. Activity energy expenditure (AEE) was assessed using IDEEA, as well as using the doubly labelled water method and indirect calorimetry. RESULTS: AEE using the IDEEA was correlated with reference estimates in both groups (r=0.4-0.5; P<0.05). Reference AEE was 0.9 MJ/24 h lower in pregnant than in non-pregnant women. Pregnant women spent 92 min/24 h more on sitting, lying, reclining and sleeping (P=0.020), 73 min/24 h less on standing (P=0.037) and 21 min/24 h less on walking and using stairs (P=0.049), and walked at a slower pace (1.1 +/- 0.1 m/s versus 1.2+/-0.1 m/s; P=0.014) than did non-pregnant controls. The selection of less demanding activities and slower walking pace decreased energy costs by 720 kJ/24 h and 80 kJ/24 h, respectively. CONCLUSION: Healthy moderately active Swedish women compensated for the increased energy costs of pregnancy by 0.9 MJ/24 h. The compensation was mainly achieved by selecting less demanding activities. PMID- 21792214 TI - Impact of gender on vitamin D deficiency in morbidly obese patients: a cross sectional study. AB - BACKGROUND/OBJECTIVE: Obesity is associated with vitamin D deficiency (25 hydroxyvitamin D (25(OH)D) <50 nmol/l). We aimed to examine the effect of gender on vitamin D status in severe obesity. SUBJECTS/METHODS: Cross-sectional study of 2026 morbidly obese patients examined consecutively at a tertiary care centre between November 2005 and June 2010. Serum 25(OH)D concentration and use of vitamin D supplements were registered in all patients. Total vitamin D intake (MUg/day) was assessed in a subgroup of 154 patients using a validated food frequency questionnaire. RESULTS: The male (n=690) and female (n=1336) patients had a mean (s.d.) age of 45.0 (12.1) years and 42.2 (12.2) years (P<0.001), body mass index (BMI) of 44.6 (6.0) kg/m(2) and 44.3 (5.9) kg/m(2) (P=0.30) and waist circumference (WC) of 140 (13) cm and 127 (13) cm (P<0.001), respectively. Male patients had significantly lower mean 25(OH)D concentrations than female patients 50.0 (22.0) nmol/l versus 53.6 (22.4) nmol/l (P=0.001) and a higher rate of vitamin D deficiency (56% versus 47%; P<0.001). Obese men had significantly higher odds of vitamin D deficiency than women (odds ratio=1.41; 95% confidence interval: 1.17-1.70, P<0.001), also after adjustment for season, age, current smoking, intake of vitamin D supplements, BMI and WC (odds ratio=1.39; 95% confidence interval: 1.10-1.76). CONCLUSIONS: Morbidly obese Norwegian men seeking weight loss treatment have significantly higher odds of vitamin D deficiency than women. Monitoring of 25(OH)D concentrations in obese patients should therefore take gender into account. PMID- 21792213 TI - Dietary intake associated with serum versus urinary carboxymethyl-lysine, a major advanced glycation end product, in adults: the Energetics Study. AB - BACKGROUND/OBJECTIVES: Advanced glycation end products (AGEs) are implicated in the pathogenesis of atherosclerosis, diabetes and kidney disease. The objective was to describe dietary intake, the dominant source of exposure to AGEs, with carboxymethyl-lysine (CML), a major AGE, in serum and urine, respectively. SUBJECTS/METHODS: Serum and urinary CML were measured in 261 adults, aged 21-69 years, and compared with diet as assessed by six separate 24-h dietary recalls. RESULTS: Median (25th, 75th percentile) serum and urinary CML concentrations were 686 (598, 803) MUg/l and 1023 (812, 1238) MUg/gm creatinine. There was no correlation between serum and urinary CML (r=-0.02, P=0.78). Serum CML was positively correlated with intake of soy, fruit juice, cold breakfast cereal, non fat milk, whole grains, fruit, non-starchy vegetables and legumes, and negatively correlated with intake of red meat. Intake of fast food was not significantly correlated with serum CML. Urinary CML was positively correlated with intake of starchy vegetables, whole grains, sweets, nuts/seeds and chicken, and negatively correlated with intake of fast foods. Intake of AGE-rich foods such as fried chicken, French fries, bacon/sausage and crispy snacks were not significantly correlated with serum or urinary CML, except for a significant negative correlation between fried chicken and serum CML. CONCLUSIONS: These findings suggest that the high consumption of foods considered high in CML is not a major determinant of either serum or urinary CML. Further work is needed to understand the relationship of AGEs in blood and urine with the metabolism of dietary AGEs. PMID- 21792215 TI - Acute differential effects of milk-derived dietary proteins on postprandial lipaemia in obese non-diabetic subjects. AB - BACKGROUND/OBJECTIVES: Postprandial lipaemia is an established risk factor for atherosclerosis. To investigate the acute effect of four milk-derived dietary proteins (alpha-lactalbumin, whey isolate, caseinoglycomacropeptide and whey hydrolysate) on postprandial lipaemia, we have conducted a randomized, acute, single-blinded clinical intervention study with crossover design. SUBJECTS/METHODS: A total of 11 obese non-diabetic subjects (age: 44-74, BMI: 30 41.4 kg m(-2)) were included. On 4 different days the subjects ingested a high fat meal with the following energy distribution: 66% energy from fat (100 g of butter), 15% of energy from carbohydrate (90 g of white wheat bread) and 19% of energy from protein (45 g of pure protein). Our primary variable was plasma triglyceride measured in the 8-h postprandial period. Secondarily, retinyl palmitate, non-esterified free fatty acids, glucose, insulin, glucagon, GLP-1 and GIP, active and total grehlin and cholecystokinin were measured. RESULTS: We observed no statistically significant (P=0.8) differences between meals on our primary variable that is, triglycerides. Whey hydrolysate was associated with a significantly (P=0.02) smaller postprandial suppression of non-esterified free fatty acids compared with the other dietary proteins. CONCLUSION: We did not observe significant differences in postprandial lipaemia to the four milk-derived dietary proteins. Whey hydrolysate caused less postprandial suppression of free fatty acids. PMID- 21792216 TI - Glia: death receptor deals blow to remyelination. PMID- 21792217 TI - Learning and memory: parallel processing. PMID- 21792219 TI - BAG6 'mops up' mislocalized proteins. PMID- 21792218 TI - Chronic fatigue syndrome: understanding a complex illness. AB - Chronic fatigue syndrome (CFS) is a debilitating illness that affects many people. It has been marred by controversy, from initial scepticism in the medical community about the existence of the condition itself to continuing disagreements -mainly between some patient advocacy groups on one side, and researchers and physicians on the other--about the name for the illness, its aetiology, its pathophysiology and the effectiveness of the few currently available treatments. The role of the CNS in the disease is central in many of these discussions. Nature Reviews Neuroscience asked four scientists involved in CFS research about their views on the condition, its causes and the future of research aimed at improving our understanding of this chronic illness. PMID- 21792220 TI - A steep cline in ladybird melanism has decayed over 25 years: a genetic response to climate change? AB - A cline in the frequency of melanic morphs of the two-spot ladybird, Adalia bipunctata, was first surveyed in 1980 along a transect extending inland from the coast in the Netherlands. At that time, the frequency of melanics increased over some 40 km from 10% near the coast to nearly 60% inland. Additional surveys made in 1991 and 1995 demonstrated some progressive change in cline shape. New samples from 1998 and 2004 confirm these dynamics, and show that over a period of about 50 generations for the beetle, the cline had decayed rapidly to yield rather uniform frequencies of melanic morphs at around 20% along the whole transect by 2004. Climate data and evidence for thermal melanism in this species support our contention that these dynamics reflect a dramatic example of a rapid genetic response within populations to climate change and local selection. PMID- 21792222 TI - Hybrid fitness, adaptation and evolutionary diversification: lessons learned from Louisiana Irises. AB - Estimates of hybrid fitness have been used as either a platform for testing the potential role of natural hybridization in the evolution of species and species complexes or, alternatively, as a rationale for dismissing hybridization events as being of any evolutionary significance. From the time of Darwin's publication of The Origin, through the neo-Darwinian synthesis, to the present day, the observation of variability in hybrid fitness has remained a challenge for some models of speciation. Yet, Darwin and others have reported the elevated fitness of hybrid genotypes under certain environmental conditions. In modern scientific terminology, this observation reflects the fact that hybrid genotypes can demonstrate genotype * environment interactions. In the current review, we illustrate the development of one plant species complex, namely the Louisiana Irises, into a 'model system' for investigating hybrid fitness and the role of genetic exchange in adaptive evolution and diversification. In particular, we will argue that a multitude of approaches, involving both experimental and natural environments, and incorporating both manipulative analyses and surveys of natural populations, are necessary to adequately test for the evolutionary significance of introgressive hybridization. An appreciation of the variability of hybrid fitness leads to the conclusion that certain genetic signatures reflect adaptive evolution. Furthermore, tests of the frequency of allopatric versus sympatric/parapatric divergence (that is, divergence with ongoing gene flow) support hybrid genotypes as a mechanism of evolutionary diversification in numerous species complexes. PMID- 21792223 TI - Bacterial cooperation controlled by mobile elements: kin selection versus infectivity. PMID- 21792224 TI - Is floral divergence sufficient to maintain species boundaries upon secondary contact in Mediterranean food-deceptive orchids? AB - Analyzing the processes that determine whether species boundaries are maintained on secondary contact may shed light on the early phase of speciation. In Anacamptis morio and Anacamptis longicornu, two Mediterranean orchid sister species, we used molecular and morphological analyses, together with estimates of pollination success and experimental crosses, to assess whether floral isolation can shelter the species' genomes from genetic admixture on secondary contact. We found substantial genetic and morphological homogenization in sympatric populations in combination with an apparent lack of postmating isolation. We further detected asymmetric introgression in the sympatric populations and an imbalance in cytotype representation, which may be due either to a difference in flowering phenology or else be a consequence of cytonuclear incompatibilities. Estimates of genetic clines for markers across sympatric zones revealed markers that significantly deviated from neutral expectations. We observed a significant correlation between spur length and reproductive success in sympatric populations, which may suggest that directional selection is the main cause of morphological differentiation in this species pair. Our results suggest that allopatric divergence has not led to the evolution of sufficient reproductive isolation to prevent genomic admixture on secondary contact in this orchid species pair. PMID- 21792225 TI - Dietary stress does not strengthen selection against single deleterious mutations in Drosophila melanogaster. AB - Stress is generally thought to increase the strength of selection, although empirical results are mixed and general conclusions are difficult because data are limited. Here we compare the fitness effects of nine independent recessive mutations in Drosophila melanogaster in a high- and low-dietary-stress environment, estimating the strength of selection on these mutations arising from both a competitive measure of male reproductive success and productivity (female fecundity and the subsequent survival to adulthood of her offspring). The effect of stress on male reproductive success has not been addressed previously for individual loci and is of particular interest with respect to the alignment of natural and sexual selection. Our results do not support the hypothesis that stress increases the efficacy of selection arising from either fitness component. Results concerning the alignment of natural and sexual selection were mixed, although data are limited. In the low-stress environment, selection on mating success and productivity were concordant for five of nine mutations (four out of four when restricted to those with significant or near-significant productivity effects), whereas in the high-stress environment, selection aligned for seven of nine mutations (two out of two when restricted to those having significant productivity effects). General conclusions as to the effects of stress on the strength of selection and the alignment of natural and sexual selection await data from additional mutations, fitness components and stressors. PMID- 21792226 TI - Host genotype changes bidirectional to unidirectional cytoplasmic incompatibility in Nasonia longicornis. AB - Wolbachia are the most abundant maternally inherited endosymbionts of insects and cause various reproductive alterations in their hosts. One such manipulation is cytoplasmic incompatibility (CI), which is a sperm-egg incompatibility typically resulting in zygotic death. Nasonia longicornis (Hymenoptera: Pteromalidae) has an A supergroup and two closely related B supergroup Wolbachia infections. The B supergroup bacteria co-diverged in this host genus. Both triple (wNlonAwNlonB1wNlonB2) and double infections (wNlonAwNlonB1, wNlonAwNlonB2) have been obtained from the field. In the present study, CI was determined among the three Wolbachia types in different host genetic backgrounds. Results show that host genetic background determines whether bidirectional CI or unidirectional CI occurs between the two closely related B group Wolbachia. Results show that the wNlonB1-infected males are bidirectionally incompatible with wNlonB2 in their 'native' nuclear genetic background, whereas wNlonB1 males are compatible with wNlonB2 in two other N. longicornis genetic backgrounds, resulting in unidirectional CI. In contrast, wNlonB2-infected males are incompatible with wNlonB1 females in all three host genetic backgrounds. These changes in incompatibility are not due to the loss of the bacteria. We hypothesize that a repressor gene for sperm modification by wNlonB1 is segregating in N. longicornis populations. The relevance of these findings to the potential role of Wolbachia in host-reproductive divergence and speciation is discussed. PMID- 21792227 TI - Complex genetic nature of sex-independent transmission ratio distortion in Asian rice species: the involvement of unlinked modifiers and sex-specific mechanisms. AB - Transmission ratio distortion (TRD), in which one allele is transmitted more frequently than the opposite allele, is presumed to act as a driving force in the emergence of a reproductive barrier. TRD acting in a sex-specific manner has been frequently observed in interspecific and intraspecific hybrids across a broad range of organisms. In contrast, sex-independent TRD (siTRD), which results from preferential transmission of one of the two alleles in the heterozygote through both sexes, has been detected in only a few plant species. We previously reported an S(6) locus-mediated siTRD, in which the S(6) allele from an Asian wild rice strain (Oryza rufipogon) was transmitted more frequently than the S(6)(a) allele from an Asian cultivated rice strain (O. sativa) through both male and female gametes in heterozygous plants. Here, we report on the effect of a difference in genetic background on S(6) locus-mediated siTRD, based on the analysis using near isogenic lines and the original wild strain as a parental strain for crossing. We found that the degree of TRD through the male gametes varied depending on the genetic background of the female (pistil) plants. Despite the occurrence of TRD through both male and female gametes, abnormality was detected in ovules, but not in pollen grains, in the heterozygote. These results suggest the involvement of unlinked modifiers and developmentally distinct, sex-specific genetic mechanisms in S(6) locus-mediated siTRD, raising the possibility that siTRD driven by a single locus may be affected by multiple genetic factors harbored in natural populations. PMID- 21792228 TI - Developmental plasticity as a cohesive evolutionary process between sympatric alternate-year insect cohorts. AB - Many species, particularly insects, pass through a series of distinct phases during their life history, with the developmental timing directed towards appropriate resources. Any factor that creates variation in developmental timing may partition a population into discrete populations-or 'cohorts'. Where there is continued failure to recruit outside the natal cohort then alternate cohorts will have their own internal dynamics, eventually leading to independent demographic and evolutionary trajectories. By contrast, continued variation in development rates within a cohort-cohort splitting-may homogenise otherwise independent demographic units. Using a panel of 14 microsatellite loci, we quantify the genetic signature of apparent demographic isolation between coexisting, but alternate, semivoltine cohorts of the damselfly Coenagrion mercuriale at locations that span its distribution in the UK. We find consistently low levels of genetic divergence between sympatric cohorts of C. mercuriale, indicative of developmental plasticity during the larval stage (unregulated development) whereby some individuals complete their development outside the predominant 2 year (semivoltine) period. Thus, individuals that alter their developmental rate successfully recruit to a different cohort. Despite maintaining contrasting population sizes, gene flow between alternate cohorts broadly is sufficient to place them on a similar evolutionary trajectory and also buffers against loss of genetic diversity. Such flexible larval development permits a response to local conditions and may facilitate response to environmental change. PMID- 21792229 TI - Simultaneous estimation of multiple quantitative trait loci and growth curve parameters through hierarchical Bayesian modeling. AB - A novel hierarchical quantitative trait locus (QTL) mapping method using a polynomial growth function and a multiple-QTL model (with no dependence in time) in a multitrait framework is presented. The method considers a population-based sample where individuals have been phenotyped (over time) with respect to some dynamic trait and genotyped at a given set of loci. A specific feature of the proposed approach is that, instead of an average functional curve, each individual has its own functional curve. Moreover, each QTL can modify the dynamic characteristics of the trait value of an individual through its influence on one or more growth curve parameters. Apparent advantages of the approach include: (1) assumption of time-independent QTL and environmental effects, (2) alleviating the necessity for an autoregressive covariance structure for residuals and (3) the flexibility to use variable selection methods. As a by product of the method, heritabilities and genetic correlations can also be estimated for individual growth curve parameters, which are considered as latent traits. For selecting trait-associated loci in the model, we use a modified version of the well-known Bayesian adaptive shrinkage technique. We illustrate our approach by analysing a sub sample of 500 individuals from the simulated QTLMAS 2009 data set, as well as simulation replicates and a real Scots pine (Pinus sylvestris) data set, using temporal measurements of height as dynamic trait of interest. PMID- 21792230 TI - Combining gene mapping and phenotype assessment for fast mutation finding in non consanguineous autosomal recessive retinitis pigmentosa families. AB - Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization. PMID- 21792231 TI - Natural positive selection and north-south genetic diversity in East Asia. AB - Recent reports have identified a north-south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals. PMID- 21792232 TI - Fine-grained facial phenotype-genotype analysis in Wolf-Hirschhorn syndrome. AB - Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf Hirschhorn syndrome facial phenotype. PMID- 21792233 TI - Feasibility of using web surveys to collect time-activity data. AB - Time-activity data are traditionally collected by telephone interviews or through paper diaries, which are time consuming and costly. As a potential alternative that may greatly save staff time, a web survey to collect time-activity data was developed and tested in this study. We collected 24-h recall web diaries from 151 parents of young children mostly under 55 years of age (who also answered for their children) and 55 older adults (>= 55 years of age) both on a weekday and a weekend day every 3 months during an 18-month period. The performance and reliability of the web surveys collected were evaluated, including the survey completion rate, and the percentage of surveys with unreasonable time being reported as spent sleeping and with missing reports of being in transit between locations. We also compared the web-survey data with time-activity information we collected from the same subjects in telephone interviews and found that these data sources were fairly consistent with each other. However, we observed slightly more compliance issues for the web than the telephone survey, but most of these issues could be addressed and minimized by refining some questions or the survey interface. Our study suggests that it is critical to reduce participants' burden and improve survey interface design for optimal compliance and data quality. In conclusion, web surveys are a promising method to consider for time-activity data collection. PMID- 21792234 TI - Policy-ready science. PMID- 21792235 TI - Transition zone proteins and cilia dynamics. PMID- 21792236 TI - Epigenetic variation and cellular Darwinism. PMID- 21792237 TI - The timing of mitochondrial DNA mutations in aging. PMID- 21792241 TI - Heterogeneity in the rat brain vasculature revealed by quantitative confocal analysis of endothelial barrier antigen and P-glycoprotein expression. AB - While phenotypic endothelial heterogeneity is well documented in peripheral organs, it is only now being explored in the brain. We used confocal imaging of thick sections of rat brain to qualitatively and quantitatively examine the expression of two key markers of the blood-brain barrier (BBB) in the rat, P glycoprotein (P-gp), and endothelial barrier antigen (EBA). We found that these markers were not uniformly distributed throughout the whole vasculature of the cortex and hippocampus. P-glycoprotein displayed a gradient of expression from an almost undetectable level in large penetrating arterioles to a high and uniform level in capillaries and venules. While EBA was lacking in all cerebral arterioles, regardless of their size, its expression varied greatly among endothelial cells in capillaries and venules, yielding a striking mosaic pattern. A detailed quantitative analysis of the distribution of these markers at the single cell level in capillaries is provided. These results challenge the view of a uniform BBB and suggest that regulatory mechanisms might differentially modulate BBB features not only among arterioles/capillaries/venules but also at the single cell level within the capillaries. Hypotheses are made regarding the underlying mechanisms and physiopathological consequences of this heterogeneity. PMID- 21792242 TI - Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-alpha. AB - Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissue-type plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor alpha. This effect, mediated by plasmin and the N-methyl-D-aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance. PMID- 21792243 TI - alpha(2)-adrenoceptors do not mediate neuroprotection in acute ischemic stroke in mice. AB - We assessed the neuroprotective potential of alpha(2)-adrenoceptors in ischemic stroke using mice with targeted deletions of individual alpha(2)-adrenoceptor subtypes (alpha(2A)(-/-), alpha(2B)(-/-), alpha(2C)(-/-), alpha(2A/C)(-/-)). The effects of the alpha(2)-adrenoceptor agonist clonidine were studied in parallel. Focal cerebral ischemia was induced with or without clonidine pretreatment by transient middle cerebral artery occlusion. Neurologic outcome and infarct volumes were evaluated on day 1. Cerebral blood flow (CBF) and mean arterial pressure were determined. alpha(2)-Adrenoceptor null mice did not display larger infarct volumes compared with wild-type (WT) mice under basal conditions (P>0.05). In line with this finding, pretreatment with clonidine did not protect from ischemic brain damage in WT mice or alpha(2A)(-/-), alpha(2B)(-/-), and alpha(2C)(-/-) mice. Clonidine induced smaller infarct volumes only in alpha(2A/C)(-/-) mice (P<0.05), but this did not translate into improved neurologic function (P>0.05). Importantly, while clonidine caused a significant decrease in arterial blood pressure in all groups, it had no blood pressure lowering effect in alpha(2A/C)(-/-) mice, and this correlated with higher CBF and smaller infarct volumes in this group. In summary, we could not demonstrate a neuroprotective function of alpha(2)-adrenoceptors in focal cerebral ischemia. Careful controlling of physiological parameters relevant for stroke outcome is recommended in experimental stroke studies. PMID- 21792244 TI - In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [11C]ABP688. AB - The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders. Recently, a positron emission tomography (PET) tracer exhibiting high selectivity and specificity for mGluR5, 3 (6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-(11)C-methyl-oxime ([(11)C]ABP688), was developed. In this work, eight healthy adult male humans were imaged twice to assess within-subject [(11)C]ABP688 binding variability using PET. In seven of the eight subjects, significantly higher binding was observed during the second (retest) scan. This binding increase could not be definitively explained by differences in ligand injected mass or dose, or changes in metabolism between scans. In addition, this type of systematic binding increase was not observed in a [(11)C]ABP688 test-retest study performed by our group on anaesthetized baboons. It is therefore possible that the increased binding was because of physiological changes occurring between scans, such as changes in endogenous glutamate levels. If PET imaging with [(11)C]ABP688 could detect such differences, as preliminary evidence suggests, it could be used to help uncover the role of glutamate in the pathophysiology of brain disorders. However, regardless of its ability to detect endogenous glutamate differences, [(11)C]ABP688 binding variability could make accurate assessments of drug occupancy or group differences using this ligand difficult. PMID- 21792248 TI - The crisis, the humanities and medical history. PMID- 21792249 TI - Re-presenting the future of medicine's past: towards a politics of survival. PMID- 21792245 TI - The proteome of mouse brain microvessel membranes and basal lamina. AB - The blood-brain barrier (BBB) is a multicellular vascular structure separating blood from the brain parenchyma that is composed of endothelial cells with tight intercellular junctions, surrounded by a basal lamina, astrocytes, and pericytes. Previous studies have generated detailed databases of the microvessel transcriptome; however, less information is available on the BBB at the protein level. In this study, we specifically focused on characterization of the membrane fraction of cells within the BBB to generate a more complete understanding of membrane transporters, tight junction proteins, and associated extracellular matrix proteins that are functional hallmarks of the BBB. We used Multidimensional Protein Identification Technology to identify a total of 1,143 proteins in mouse brain microvessels, of which 53% were determined to be membrane associated. Analyses of specific classes of BBB-associated proteins in the context of recent transcriptome reports provide a unique database to assess the relative contribution of genes at the level of both RNA and protein in the maintenance of normal BBB integrity. PMID- 21792250 TI - Representing health and illness: thoughts for the twenty-first century. PMID- 21792251 TI - Put out your tongue! The role of clinical insight in the study of the history of medicine. PMID- 21792252 TI - Coronary heart disease and heart attacks, 1912-2010. PMID- 21792253 TI - Smallpox and the epidemiological heritage of modern Japan: towards a total history. PMID- 21792254 TI - Patents, priority disputes and the value of credit: towards a history (and pre history) of intellectual property in medicine. PMID- 21792255 TI - Medical archives and digital culture: from WWI to BioShock. PMID- 21792256 TI - The birth of biopower in eighteenth-century Germany. PMID- 21792258 TI - From Prussia to China: Japanese colonial medicine and Goto Shinpei's combination of medical police and local self-administration. PMID- 21792257 TI - 'Proper motions, actions and uses': physiological knowledge as the only means to rational politics in Restoration England. PMID- 21792259 TI - Cyborg spirituality. PMID- 21792260 TI - Re-imagining bleeders: the medical leech in the nineteenth century bloodletting encounter. PMID- 21792261 TI - Veterinary medicines in Britain: output and industry organisation since 1900. PMID- 21792262 TI - Model organisms and model environments: a rodent laboratory in science, medicine and society. PMID- 21792263 TI - Leviathan and the soft animal: medical humanism and the invertebrate models for higher nervous functions, 1950s-90s. PMID- 21792264 TI - Self-control, selfishness and mutilation: how 'medical' is self-injury anyway? PMID- 21792265 TI - Professional heresy: Edmund Gurney (1847-88) and the study of hallucinations and hypnotism. PMID- 21792266 TI - When misery and metaphysics collide: William James on 'the problem of evil'. PMID- 21792267 TI - Mood disorders and the brain: depression, melancholia, and the historiography of psychiatry. PMID- 21792268 TI - Contested jurisdictions: psychiatry, psychoanalysis, and clinical psychology in the United States, 1940-2010. PMID- 21792269 TI - Shocking waves at the museum: the Bini-Cerletti electro-shock apparatus. PMID- 21792270 TI - Perspectives from the History of Medicine Division of the United States National Library of Medicine, National Institutes of Health. PMID- 21792271 TI - Sisters behind the wire: reappraising Australian military nursing and internment in the Pacific during World War II. PMID- 21792272 TI - Mutagenic Tests Confirm That New Acetylacetonate Pt(II) Complexes Induce Apoptosis in Cancer Cells Interacting with Nongenomic Biological Targets. AB - New platinum(II) complexes [PtCl(O,O'-acac)(L)] (1) and [Pt(O,O'-acac)(gamma acac)(L)] (2) (L = DMSO, a; DMS, b) containing a single chelated (O,O'-acac) (1), or one chelated and one sigma-bonded (gamma-acac) acetylacetonate (2) have been synthesized. The new Pt(II) complexes exhibited high in vitro cytotoxicity on cisplatin sensitive and resistant cell lines and showed negligible reactivity with nucleobases (Guo and 5'-GMP) but selective substitution of DMSO/DMS with soft biological nucleophiles, such as L-methionine. In order to assess the ability of the new complexes with respect to cisplatin to induce apoptosis by interaction with nongenomic targets, the Ames' test, a standard reverse mutation assay, was carried out on two Salmonella typhimurium strains (TA98 and TA100). Interestingly, the new complexes did not show the well-known mutagenic activity exhibited by cisplatin and are, therefore, able to activate apoptotic pathways without interacting with DNA. PMID- 21792274 TI - Three-Dimensional Structure of Arabidopsis thaliana Lipase Predicted by Homology Modeling Method. AB - Triacylglycerol lipases have been thoroughly characterized in mammals and microorganisms. By contrast, very little is known about plant lipases. In this investigation, a homology model of Arabidopsis thaliana lipase (NP_179126) was constructed using a human gastric lipase (PDB ID: 1HLG), as a template for model building. This model was then assessed for stereochemical quality and side chain environment. Natural substrates: tributyrin, trioctanoin and triolen were docked into the model to investigate ligand-substrate interaction. PMID- 21792273 TI - Differential gene expression in sugarcane in response to challenge by fungal pathogen Ustilago scitaminea revealed by cDNA-AFLP. AB - Differential gene expression in sugarcane during sugarcane-Ustilago scitaminea interaction was conducted in a smut-resistant genotype. Using cDNA-AFLP along with silver staining, a total of 136 transcript-derived fragments (TDFs) were found to be differentially expressed in response to challenge by U. scitaminea. Forty TDFs, 34 newly induced plus six with obvious upregulated expression after infection, were sequenced and validated by RT-PCR analysis. These results demonstrated that the expression of 37 out of these TDFs in RT-PCR analysis was consistent with that in cDNA-AFLP analysis. Based on BlastX in NCBI, 28 TDFs were assumed to function in sugarcane under U. scitaminea stress. Analysis of expression profile of three TDFs revealed that they responded differently after infection with U. scitaminea, and the transcription was significantly enhanced. The response of two TDFs, SUC06 and SUC09, occurred before that of SUC10. This study enriches our knowledge of the molecular basis for sugarcane response to U. scitaminea infection. PMID- 21792275 TI - Comparison of liquid chromatography-tandem mass spectrometry and sandwich ELISA for determination of keratan sulfate in plasma and urine. AB - BACKGROUND AND AIM: Mucopolysaccharidosis IVA (MPS IVA) leads to skeletal dysplasia through excessive storage of chondroitin-6-sulfate and keratan sulfate (KS). KS is synthesized mainly in cartilage and released into circulation, making it a critical biomarker for MPS IVA to evaluate clinical course and effectiveness of therapies. Therefore, an accurate and sensitive method is required to measure KS levels. MATERIAL AND METHODS: Using sandwich ELISA and liquid chromatography tandem mass spectrometry (LC/MS/MS) assays, we measured KS levels in blood and urine from MPS IVA patients and healthy controls to evaluate comparability of results. Blood (patients, n = 110; controls, n = 364) and urine (patients, n = 103; controls, n = 326) specimens were obtained. RESULTS: Plasma and urine KS measurements in patients were age-dependent and higher than age-matched controls. We observed a moderate correlation (r = 0.666; P < 0.001) between urine KS measurements and a weak correlation (r = 0.333; P = 0.002) between plasma KS measurements by ELISA and LC/MS/MS methods in patients. No correlation was found between plasma KS measurements in controls. The difference between KS measurements assayed by LC/MS/MS and ELISA was greater in controls than in patients. A moderate correlation between blood and urine KS measurements in the same individual was observed. CONCLUSION: These findings indicate that both methods to measure blood and urine KS are suitable for diagnosis, monitoring therapies, and longitudinal assessment of the disease course in MPS IVA, but the LC/MS/MS method measures over 10 times more KS present in body fluids. PMID- 21792276 TI - Conductimetric biosensor for the detection of uric Acid by immobilization uricase on nata de coco membrane-pt electrode. AB - A conductimetric enzyme biosensor for uric acid detection has been developed. The uricase, as enzyme, is isolated from Candida utilis and immobilized on a nata de coco membrane-Pt electrode. The biosensor demonstrates a linear response to urate over the concentration range 1-6 ppm and has good selectivity properties. The response is affected by the membrane thickness and pH change in the range 7.5 9.5. The response time is three minutes in aqueous solutions and in human serum samples. Application of the biosensor to the determination of uric acid in human serum gave results that compared favourably with those obtained by medical laboratory. The operational stability of the biosensor was not less than three days and the relative error is smaller than 10%. PMID- 21792277 TI - Hallermann-Streiff syndrome with severe bilateral enophthalmos and radiological evidence of silent brain syndrome: a new congenital silent brain syndrome? AB - BACKGROUND: We present the first case of a congenital form of silent brain syndrome (SBS) in a young patient affected by Hallermann-Streiff syndrome (HSS) and the surgical management of the associated eyelid anomalies. METHODS: HSS signs were evaluated according to the Francois criteria. Orbital computed tomography (CT) and genetic analysis were performed. An upper eyelid retractor free recession was performed. Follow-up visits were performed at day 1, weeks 1 and 3, and months 3, 6, 9 (for both eyes), and 12 (for left eye) after surgery. RESULTS: The patient exhibited six of the seven signs of HSS. Orbital CT showed bilateral enophthalmos and upward bowing of the orbital roof with air entrapment under the upper eyelid as previously described for SBS. Genetic analysis showed a 2q polymorphism. During follow-up, the cornea showed absence of epithelial damage and the upper eyelids were lowered symmetrically, with a regular contour. CONCLUSION: Our HSS patient shares features with SBS. We postulate that SBS could include more than one pattern, ie, an acquired form following ventriculoperitoneal shunting and this newly reported congenital form in our HSS patient in whom typical syndromic skull anomalies led to this condition. The surgical treatment has been effective in restoring an appropriate lid level, with good globe apposition and a good cosmetic result. PMID- 21792278 TI - Evaluation of economic efficiencies in clinical retina practice: activity-based cost analysis and modeling to determine impacts of changes in patient management. AB - BACKGROUND: The purpose of this study is to report the use of activity-based cost analysis to identify areas of practice efficiencies and inefficiencies within a large academic retinal center and a small single-specialty group. This analysis establishes a framework for evaluating rapidly shifting clinical practices (anti vascular endothelial growth factor therapy, microincisional vitrectomy surgery) and incorporating changing reimbursements for care delivery (intravitreal injections, optical coherence tomography [OCT]) to determine the impact on practice profitability. Pro forma modeling targeted the impact of declining reimbursement for OCT imaging and intravitreal injection using a strategy that incorporates activity-based cost analysis into a direct evaluation schema for clinical operations management. METHODS: Activity-based costing analyses were performed at two different types of retinal practices in the US, ie, a small single-specialty group practice and an academic hospital-based practice (Bascom Palmer Eye Institute). Retrospective claims data were utilized to identify all procedures performed and billed, submitted charges, allowed charges, and net collections from each of these two practices for the calendar years 2005-2006 and 2007-2008. A pro forma analysis utilizing current reimbursement profiles was performed to determine the impact of altered reimbursement on practice profitability. All analyses were performed by a third party consulting firm. RESULTS: The small single-specialty group practice outperformed the academic hospital-based practice on almost all markers of efficiency. In the academic hospital-based practice, only four service lines were profitable, ie, nonlaser surgery, laser surgery, non-OCT diagnostics, and injections. Profit margin varied from 62% for nonlaser surgery to 1% for intravitreal injections. Largest negative profit contributions were associated with office visits and OCT imaging. CONCLUSION: Activity-based cost analysis is a powerful tool to evaluate retinal practice efficiencies. These two distinct practices were able to provide significant increases in clinical care (office visits, ophthalmic imaging, and patient procedures) through maintaining efficiencies of care. Pro forma analysis of 2011 data noted that OCT payments to facilities and physicians continue to decrease dramatically and that this payment decrease further reduced the profitability for the two largest aspects of these retinal practices, ie, intravitreal injections and OCT retinal imaging. Ultimately, all retinal practices are at risk for significant shifts in financial health related to rapidly evolving changes in patterns of care and reimbursement associated with providing outstanding clinical care. PMID- 21792279 TI - Ophthalmoplegia associated with transorbital penetrating brainstem injury by broken fishing pole. AB - We report our findings in a case of ophthalmoplegia caused by a transorbital penetrating brainstem injury. An 8-year-old boy was accidentally injured by a broken fishing fiberglass pole which penetrated through the right orbit and entered the brainstem. Magnetic resonance imaging showed a linear wound that entered and passed through the pons obliquely and reached the fourth cerebral ventricle and cerebellar vermis. He had a left-sided hemiplegia and left facial nerve palsy and was diagnosed with "one-and-a-half syndrome". His hemiplegia and left facial nerve palsy resolved in 2 weeks leaving only a left abducens nerve palsy. The eye position and eye movements fully recovered within 3 months. These findings suggest a good prognosis for this type of trauma unless life-threatening changes develop. PMID- 21792280 TI - Spontaneous development of macular ischemia in a case of racemose hemangioma. AB - PURPOSE: To report a rare case of racemose hemangioma which developed spontaneous macular ischemia. METHODS: A 32-year-old healthy Caucasian lady presented complaining of recent deterioration of vision in her left eye. At presentation, her best corrected visual acuity (BCVA) was 20/20 in her right eye and counting fingers in her left eye (LE). Fundus examination and fluorescein angiography were performed. The patient had regular follow-up appointments over a period of 8 years. RESULTS: Fundus examination and fluorescein angiography revealed findings consistent with arteriovenous communications of the retina or racemose hemangioma, in the posterior pole of the LE with the presence of macular ischemia. Complete and systemic examination was unremarkable, excluding the possibility of Wyburn-Mason syndrome. Eight years after presentation, findings and BCVA in the LE have remained stable, with no extension of the retinal ischemia or development of neovascularization. CONCLUSION: Although extensive retinal ischemia has been reported to result in complications such as retinal or iris neovascularization, in our case the macular ischemia has not expanded further over a period of 8 years. However, due to this macular ischemia the patient unfortunately lost her central vision. PMID- 21792281 TI - Pattern of intraocular pressure reduction following laser trabeculoplasty in open angle glaucoma patients: comparison between selective and nonselective treatment. AB - OBJECTIVE: To compare the pattern of intraocular pressure (IOP) reduction following selective laser trabeculoplasty (SLT) versus argon laser trabeculoplasty (ALT) in open-angle glaucoma (OAG) patients, and to investigate the ability of initial IOP reduction to predict mid-term success. METHODS: A prospective, nonrandomized, interventional case series was carried out. Consecutive uncontrolled OAG glaucoma patients underwent SLT or ALT; the same preoperative medical regimen was maintained during follow-up. Data collected included age, type of OAG, pre- and postoperative IOP, number of glaucoma medications, and surgical complications. Post-treatment assessments were scheduled at day 1 and 7 and months 1, 3, and 6. RESULTS: A total of 45 patients (45 eyes) were enrolled [SLT group (n = 25); ALT group (n = 20)]. Groups were similar for age, baseline IOP, and number of glaucoma medications (P >= 0.12). We found no significant differences in mean IOP reduction between SLT (5.1 +/- 2.5 mmHg; 26.6%) and ALT (4.4 +/- 2.8 mmHg; 22.8%) groups at month 6 (P = 0.38). Success rates (IOP <= 16 mmHg and IOP reduction >=25%) at last follow-up visit were similar for SLT (72%) and ALT (65%) groups (P = 0.36). Comparing the pattern of IOP reduction (% of IOP reduction at each visit) between groups, we found a greater effect following SLT compared with ALT at day 7 (23.7% +/- 13.7% vs 8.1% +/- 9.5%; P < 0.001). No significant differences were observed at other time points (P >= 0.32). Additionally, the percentage of IOP reduction at day 7 and at month 6 were significantly correlated in the SLT group (R(2) = 0.36; P < 0.01), but not in the ALT group (P = 0.89). Early postoperative success predicted late success in most SLT cases (82%). No serious complications were observed. CONCLUSION: Although mid-term results suggest SLT and ALT as effective and equivalent alternatives, a greater initial IOP reduction was observed following SLT. In addition, the initial IOP reduction was a good predictor of mid-term success in patients undergoing SLT, but not ALT. PMID- 21792282 TI - Use of pars plana vitrectomy with phacoemulsification in vitreous cavity to treat complete posterior dislocation of lens. AB - BACKGROUND: The purpose of this study was to evaluate pars plana vitrectomy (PPV) with phacoemulsification in the vitreous cavity for treatment of complete posterior dislocation of the lens without any damage to the lens capsule. METHODS: We evaluated factors such as cause of dislocation, scleral fixation of an intraocular lens (IOL), preoperative and postoperative visual acuity, corneal endothelial cell density, and intraoperative and postoperative complications. RESULTS: Displacement in the eleven eyes studied was mostly caused by ocular trauma and was idiopathic (four eyes each). Scleral fixation of the IOL was performed in seven of the eyes during first-time PPV. Visual acuity was improved in two eyes, unchanged in eight eyes, and worse in one eye. Mean corneal endothelial cell density was 2485 cells/mm(2) preoperatively and 2301 cells/mm(2) postoperatively. No significant differences were seen before and after the surgeries (P = 0.15, paired t-test). Intraoperative complications included retinal detachment and suprachoroidal hemorrhage in one eye each. The most common postoperative complication was transient ocular hypertension, which occurred in three eyes. IOL dislocation and vitreous incarceration of the anterior chamber in one eye required a second operation, while retinal detachment in one eye required a third operation. CONCLUSION: When treating a completely dislocated lens, prevention of retinal detachment which subsequently can affect the visual prognosis is the most important factor to be addressed after PPV with intravitreal phacoemulsification. PMID- 21792283 TI - Intravitreal pegaptanib for refractory macular edema secondary to retinal vein occlusion. AB - PURPOSE: To assess the efficacy of intravitreal Pegaptanib sodium (Macugen((r))) injection in the management of refractory macular edema secondary to branch retinal vein occlusion. METHODS: This is a prospective, nonrandomized, interventional case series. Five eyes of five patients with macular edema refractory to either bevacizumab or triamcinolone were treated with intravitreal injection of Pegaptanib sodium. RESULTS: After three months follow-up, both visual acuity and macular edema, measured by optical coherence tomography and fluorescence angiography, dramatically improved. CONCLUSION: Pegaptanib sodium is a safe and efficacy treatment for macular edema secondary to branch retinal vein occlusion. PMID- 21792284 TI - Twelve-week, randomized, multicenter study comparing a fixed combination of brimonidine-timolol with timolol as therapy adjunctive to latanoprost. AB - OBJECTIVE: To evaluate the additive intraocular pressure (IOP)-lowering efficacy and safety of fixed-combination brimonidine 0.2%/timolol 0.5% compared with timolol 0.5% at peak and trough effect when used as therapy adjunctive to latanoprost 0.005% in patients with glaucoma or ocular hypertension who require additional IOP lowering. METHODS: In this prospective, randomized, multicenter, investigator-masked, parallel-group study, patients were treated with latanoprost monotherapy for at least four weeks prior to baseline. At baseline on latanoprost, patients with IOP >=21 mmHg in at least one eye were randomized to twice-daily fixed brimonidine-timolol (n = 102) or timolol (n = 102), each adjunctive to latanoprost for 12 weeks. IOP was measured at 8 am and 10 am at baseline, week 6, and week 12 and evaluated in the per protocol population. The primary efficacy endpoint was peak IOP lowering at 10 am, week 12. Safety measures included adverse events. RESULTS: Baseline mean IOP was similar at 10 am in the treatment groups (brimonidine-timolol 23.4 mmHg; timolol 23.0 mmHg). The mean additional reduction from latanoprost-treated baseline IOP was 8.3 mmHg (35.5%) with fixed brimonidine-timolol and 6.2 mmHg (27.0%) with timolol at 10 am, week 12 (P < 0.001). Patients treated with fixed brimonidine-timolol adjunctive to latanoprost were significantly more likely than patients treated with adjunctive timolol to achieve an IOP <18 mmHg (P = 0.028) and a >=20% reduction in IOP from baseline (P = 0.047) at both 8 am and 10 am in week 12. Adverse events occurred in 14.7% of fixed brimonidine-timolol patients and 12.7% of timolol patients. Biomicroscopy findings were similar between the treatment groups after 12 weeks of treatment. CONCLUSION: Fixed-combination brimonidine timolol reduced IOP significantly more effectively than timolol when used as adjunctive therapy to latanoprost in patients with glaucoma and ocular hypertension. Both fixed brimonidine-timolol and timolol were well tolerated as agents adjunctive to latanoprost. PMID- 21792285 TI - Epidemiology of ocular emergencies in the Egyptian population: a five-year retrospective study. AB - BACKGROUND: The purpose of this study was to determine the epidemiology of ocular lesions seen in the ophthalmic casualty room of the largest referral hospital in Egypt over 5 years from 2004 to 2008. METHODS: This epidemiologic database study used the medical records at Cairo University Hospital. Data were recorded using the ICD10 classification. Statistical analysis was based on diagnosis, age, gender, residential area, and year of admission. RESULTS: Over 5 years, 8361 ocular emergencies were admitted as inpatients. Open globe injuries were the most prevalent, comprising 33.46% of emergencies. Most cases were males (69%), in whom the most frequent lesions were open globe injuries, infective keratitis, and lid injuries. The most common ocular emergencies in females were open globe injuries, infective keratitis, endophthalmitis, and glaucoma. The age group 6-16 years accounted for 24% of emergencies, and patients over 45 years accounted for 26.8%. Under the age of 45 years, the most common lesions were open globe injuries (36%), and over this age, the most common lesions were infective keratitis (34.4%). Patients from Upper Egypt accounted for 56.2% of emergencies. A superficial corneal foreign body was the most common reason for attending the ophthalmic casualty room, with 24,844 cases seen over the 5 years of the study, all of which were managed as outpatient procedures. Deep corneal foreign bodies were more common than intraocular foreign bodies. The most common ocular hemorrhage was hyphema. The most common type of glaucoma was acute angle closure. CONCLUSION: Superficial corneal foreign bodies, open globe injuries, and infective keratitis are the main ocular emergencies seen in the Egyptian population. Corneal foreign bodies are mostly the result of occupational accidents in workers not wearing protective goggles. Violent altercations (41.9%), occupational accidents (26.3%), and motor vehicle accidents (24.4%) were the main circumstances involved in open globe injuries. The most common admissions were for open globe injuries under the age of 45 years and infective keratitis above this age. Upper Egypt was the main referring geographic area. PMID- 21792286 TI - Ganglion cell complex and retinal nerve fiber layer measured by fourier-domain optical coherence tomography for early detection of structural damage in patients with preperimetric glaucoma. AB - AIMS: To evaluate the capability of Fourier-domain optical coherence tomography (FD-OCT) to detect structural damage in patients with preperimetric glaucoma. METHODS: A total of 178 Caucasian subjects were enrolled in this cohort study: 116 preperimetric glaucoma patients and 52 healthy subjects. Using three dimensional FD-OCT, the participants underwent imaging of the ganglion cell complex (GCC) and the optic nerve head. Sensitivity, specificity, likelihood ratios, and predictive values were calculated for all parameters at the first and fifth percentiles. Areas under the curves (AUCs) were generated for all parameters and were compared (Delong test). For both the GCC and the optic nerve head protocols, the OR logical disjunction (Boolean logic operator) was calculated. RESULTS: The AUCs didn't significantly differ. Macular global loss volume had the largest AUC (0.81). Specificities were high at both the fifth and first percentiles (up to 97%), but sensitivities were low, especially at the first percentile (55%-27%). CONCLUSION: Macular and papillary diagnostic accuracies did not differ significantly based on the 95% confidence interval. The computation of the Boolean OR operator has been found to boost diagnostic accuracy. Using the software-provided classification, sensitivity and diagnostic accuracy were low for both the retinal nerve fiber layer and the GCC scans. FD OCT does not seem to be decisive for early detection of structural damage in patients with no functional impairment. This suggests that there is a need for analysis software to be further refined to enhance glaucoma diagnostic capability. PMID- 21792288 TI - Torsional ultrasound mode versus combined torsional and conventional ultrasound mode phacoemulsification for eyes with hard cataract. AB - PURPOSE: To compare torsional versus combined torsional and conventional ultrasound modes in hard cataract surgery regarding ultrasound energy and time and effect on corneal endothelium. SETTINGS: Kasr El Aini hospital, Cairo University, and International Eye Hospital, Cairo, Egypt. METHODOLOGY: Ninety eight eyes of 63 patients were enrolled in this prospective comparative randomized masked clinical study. All eyes had nuclear cataracts of grades III and IV using the Lens Opacities Classification System III (LOCS III). Two groups were included, each having an equal number of eyes (49). The treatment for group A was combined torsional and conventional US mode phacoemulsification, and for group B torsional US mode phacoemulsification only. Pre- and post-operative assessments included best corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp evaluation, and fundoscopic evaluation. Endothelial cell density (ECD) and central corneal thickness (CCT) were measured preoperatively, 1 day, 7 days, and 1 month postoperatively. All eyes were operated on using the Alcon Infiniti System (Alcon, Fort Worth, TX) with the quick chop technique. All eyes were implanted with AcrySof SA60AT (Alcon) intraocular lens (IOL). The main phaco outcome parameters included the mean ultrasound time (UST), the mean cumulative dissipated energy (CDE), and the percent of average torsional amplitude in position 3 (%TUSiP3). RESULTS: Improvement in BCVA was statistically significant in both groups (P < 0.001). Comparing UST and CDE for both groups revealed results favoring the pure torsional group (P = 0.002 and P < 0.001 for UST; P = 0.058 and P = 0.009 for CDE). As for %TUSiP3, readings were higher for the pure torsional group (P = 0.03 and P = 0.01). All changes of CCT, and ECD over time were found statistically significant using one-way ANOVA testing (P < 0.001). CONCLUSION: Both modes are safe in hard cataract surgery, however the pure torsional mode showed less US energy used. PMID- 21792289 TI - A comparison of external and endoscopic endonasal dacryocystorhinostomy for acquired nasolacrimal duct obstruction. AB - PURPOSE: To compare success rates of external dacryocystorhinostomy (DCR) and endoscopic endonasal DCR for acquired nasolacrimal duct obstruction (NLDO). DESIGN: Historical cohort study. PARTICIPANTS: 100 patients who underwent external DCR and 105 patients who underwent endoscopic endonasal DCR. METHODS: A retrospective review of medical records of patients with acquired NLDO who underwent DCR from 2004-2010 was performed. Data regarding the lacrimal drainage system, eye examination, surgical outcomes, patient symptom control, and postoperative care were analyzed. MAIN OUTCOME MEASURES: Surgical success was defined by patient's resolution of symptoms with patency on irrigation. Surgical failure was defined as no symptomatic reduction in epiphora and/or an inability to irrigate the lacrimal system postoperatively. RESULTS: A total of 205 patients underwent surgeries for acquired NLDO. The average age was 69 years, and 62.4% of subjects were female. Pooled results showed that both surgical approaches had similar success rates (endoscopic endonasal DCR 82.4% versus external DCR 81.6%; P = 0.895). Complication rates were low in both types of surgery. This included three patients with postoperative hemorrhage (two who had endonasal DCR surgery and one having external DCR surgery). This resolved with conservative treatment. Postoperative problems with lacrimal patency (including canalicular obstruction) occurred to 6.8% of endoscopic patients and 9% of those with the external DCR surgery. Of the 14 patients who had their silicone tubes fall out before the 2 month assessment, 10 were classified as failures (71%), in contrast to only a failure rate of 13.9% of those whose tubes were present for the recommended time. This difference was statistically significant (P < 0.01). CONCLUSION: The success rate of DCR for acquired NLDO in our group of patients was high overall with a low complication rate between the two types of surgery. There was no statistically significant difference between endoscopic and external DCR. Endoscopic surgery may have a benefit of preserving the lacrimal pump system and leaving no surgical scar. Patient preference and availability of each service should direct management. Hence endoscopic endonasal DCR surgery should be considered for primary treatment of nasolacrimal duct obstruction. PMID- 21792290 TI - The potential neuroprotective effects of weekly treatment with glatiramer acetate in diabetic patients after panretinal photocoagulation. AB - PURPOSE: Evaluation of the neuroprotective effect of weekly glatiramer acetate (GA) on retinal structure and function in diabetic patients who underwent panretinal photocoagulation (PRP). PATIENTS AND METHODS: patients with severe nonproliferative or early diabetic proliferative retinopathy and no previous laser treatment were randomly divided into two groups: (1) those who received four GA treatments and (2) those who received placebo treatment. The subcutaneous injections were administered 1 week prior to laser and weekly in the subsequent three sessions of PRP in both groups. All patients underwent a full ophthalmic examination (best-corrected logMAR visual acuity, slit lamp examination, applanation tonometry, fundus biomicroscopy and indirect fundus examination); functional examination (standard automated perimetry, electroretinography and frequency-doubling technology C-20 visual field) and anatomic examination (color photography, optical coherence tomography (OCT) and Heidelberg retinal tomography). The examinations were performed before the photocoagulation and repeated 1,3,6, and 12 months after treatment (in a double-masked manner). To compare the two groups, generalized estimating equation models were performed to account for the dependence between eyes of the same patient. RESULTS: Thirteen patients (23 eyes) were included in the study group and 13 patients (24 eyes) were included in the control group. OCT showed a statistically significant difference in retinal nerve fiber layer (RNFL) thickness in the inferior peripapillary region and average thickness with thinner measurements in the control group at 1-year post-PRP. Functional analysis demonstrated a difference between groups, but it did not reach statistical significance. CONCLUSION: The results of this study suggest that weekly GA treatment has a potential neuro protective effect on the RNFL following photocoagulation for diabetic retinopathy. PMID- 21792291 TI - Infrared imaging of choroidal involvement in Leber's idiopathic stellate neuroretinitis. AB - PURPOSE: Leber's idiopathic stellate neuroretinitis (LIN) is a rare condition that has been always considered an inflammatory disease, with emphasis given to the optic disc and neuroretina alterations. METHODS: A healthy 54-year-old woman presented a sudden loss of vision in the left eye, referring to periocular pain, headache, and mild fever for 1 month. Tests of best-corrected visual acuity, optical coherence tomography, infrared (IR) filter, fluorescein, and indocyanine green angiography were performed at the follow-up. RESULTS: The patient submitted to IR imaging, which revealed diffuse patchy choroidal infiltrates involving the posterior pole midperiphery, which were still present after 3 years of follow-up. CONCLUSION: In this observation, we reported that choroidal involvement may occur in LIN. The IR filter is an important and noninvasive tool able to distinguish and follow choroidal infiltrates to better delineate the pathological process and elucidate the nature of the disease. PMID- 21792292 TI - Effects of unoprostone on diurnal variation of intraocular pressure in healthy volunteers. AB - PURPOSE: To prospectively evaluate the diurnal variation of intraocular pressure (IOP) during unoprostone treatment in 13 healthy volunteers. METHOD: IOP was measured by Goldmann applanation tonometry by the same observer every 3 hours from 9 am to 9 am the next morning. Unoprostone was then instilled at 9 am and 9 pm daily for 1 month. After 1 month, IOP was measured again with unoprostone instilled at 9 am and 9 pm during IOP measurement. We then compared the average daily IOP before and after the treatment (paired t-test). RESULTS: After 1 month of treatment, the average IOP decreased at every time point but one (12 pm, 3 pm, 6 pm, 9 pm, 12 am, 3 am, and 9 am, but not at 6 am). There were no adverse reactions and none of the subjects discontinued unoprostone. CONCLUSION: The hypotensive effects of unoprostone persist throughout the day, but this study suggests that the effects may be weaker at nighttime and early in the morning. PMID- 21792293 TI - Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts. AB - BACKGROUND: To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg). METHODOLOGY: Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well. CONCLUSION AND SIGNIFICANCE: SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart. PMID- 21792294 TI - Effect of surfactant and surfactant blends on pseudoternary phase diagram behavior of newly synthesized palm kernel oil esters. AB - BACKGROUND: The purpose of this study was to select appropriate surfactants or blends of surfactants to study the ternary phase diagram behavior of newly introduced palm kernel oil esters. METHODS: Nonionic surfactant blends of Tween((r)) and Tween((r))/Span((r)) series were screened based on their solubilization capacity with water for palm kernel oil esters. Tween((r)) 80 and five blends of Tween((r)) 80/Span((r)) 80 and Tween((r)) 80/Span((r)) 85 in the hydrophilic-lipophilic balance (HLB) value range of 10.7-14.0 were selected to study the phase diagram behavior of palm kernel oil esters using the water titration method at room temperature. RESULTS: High solubilization capacity was obtained by Tween((r)) 80 compared with other surfactants of Tween((r)) series. High HLB blends of Tween((r)) 80/Span((r)) 85 and Tween((r)) 80/Span((r)) 80 at HLB 13.7 and 13.9, respectively, have better solubilization capacity compared with the lower HLB values of Tween((r)) 80/Span((r)) 80. All the selected blends of surfactants were formed as water-in-oil microemulsions, and other dispersion systems varied in size and geometrical layout in the triangles. The high solubilization capacity and larger areas of the water-in-oil microemulsion systems were due to the structural similarity between the lipophilic tail of Tween((r)) 80 and the oleyl group of the palm kernel oil esters. CONCLUSION: This study suggests that the phase diagram behavior of palm kernel oil esters, water, and nonionic surfactants is not only affected by the HLB value, but also by the structural similarity between palm kernel oil esters and the surfactant used. The information gathered in this study is useful for researchers and manufacturers interested in using palm kernel oil esters in pharmaceutical and cosmetic preparation. The use of palm kernel oil esters can improve drug delivery and reduce the cost of cosmetics. PMID- 21792296 TI - Five-day regimen of intramuscular or subcutaneous self-administered adrenocorticotropic hormone gel for acute exacerbations of multiple sclerosis: a prospective, randomized, open-label pilot trial. AB - BACKGROUND: Despite over 50 years of experience with adrenocorticotropic hormone (ACTH) as a treatment for acute exacerbations of multiple sclerosis, there have been no trials examining the options of the 2-3-week dosing regimen or intramuscular injection protocol used in the original trials. At our clinic, we performed a small, prospective, randomized pilot study to examine the efficacy and safety of, and patient satisfaction with, a short (five-day) self administered ACTH dosing protocol for exacerbations of multiple sclerosis, and to compare the subcutaneous and intramuscular routes of administration. METHODS: Patients for this study were recruited from an outpatient treatment clinic. Each patient self-administered natural ACTH gel 80 U/day by subcutaneous or intramuscular injection for five consecutive days and was evaluated at baseline and on days 7 and 14. Patient feedback was collected using the Patient Global Impression of Change (PGI-C, the primary efficacy measure), a patient global visual analog scale, the Expanded Disability Status Scale, a timed walk, the Nine hole Peg Test, and the Clinical Global Impression of Change. RESULTS: Of the 20 enrolled patients (mean age 39.5 years), 19 completed the study. On day 14, 61.1% of patients (11 of 18 with day 14 scores) were treatment responders, and rated their condition as "very much improved" or "much improved" on the PGI-C. The intramuscular group had numerically more responders, but there was no significant difference in the proportion of responders between the intramuscular and subcutaneous groups at day 14 (P = 0.3). The intramuscular route of injection was associated with more injection site pain than the subcutaneous route. CONCLUSION: A shorter five-day course of intramuscular or subcutaneous ACTH gel may improve symptoms associated with acute exacerbations of multiple sclerosis. Larger studies with standard of care controls are needed to confirm whether this shorter course of intramuscular or subcutaneous ACTH gel is effective and could potentially be substituted for the standard 14-day treatment. PMID- 21792297 TI - Patient experience - the ingredient missing from cost-effectiveness calculations. AB - Standard cost-effectiveness calculations as used by the UK National Institute of Clinical Excellence compare the net benefit of an intervention with the financial costs to the health service. Debates about public health interventions also focus on these factors. The subjective experience of the patient, including financial costs and also transient pain, distress, and indignity, is routinely ignored. I carried out an Internet survey which showed that members of the public assign a high financial cost to routine medical interventions such as taking a tablet regularly or attending a clinic for an injection. It is wrong to ignore such costs when attempting to obtain an overall evaluation of the benefit of medical interventions. PMID- 21792298 TI - Perceived medication benefits and their association with interest in using inhaled insulin in type 2 diabetes: a model of patients' cognitive framework. AB - OBJECTIVE: To examine predictors of patient perceived relevance of different diabetes medication benefits, and to determine how medication benefit ratings of an inhaled insulin were associated with evaluation of, and interest in that inhaled insulin. METHODS: The study was an Internet survey of a US sample (n = 1094) of adults with type 2 diabetes using different medication regimens. Patients were given a brief description of potential clinical benefits and administration procedures for the inhaled insulin described in this study (based on MannKind Corporation's Technosphere insulin). Measures included indicators of medication benefits, needs and relevance, benefit ratings and overall evaluation of the studied inhaled insulin relative to current medication, and interest in the study medication. Multivariate regression assessed significant (P < 0.05) independent associations, controlling for demographic and disease characteristics. RESULTS: Relevance of potential medication benefits (avoidance of hyperglycemia, hypoglycemia, weight gain, discomfort/inconvenience) was significantly associated with objective and subjective indicators of patients' needs. Most need indicators were associated only with the specific benefit to which they apply; concerns about weight and lifestyle were associated with multiple benefits. Ratings of the studied inhaled insulin for avoiding postprandial hyperglycemia and discomfort/inconvenience were associated with overall evaluation of and interest in the inhaled insulin described in this study; rating of this medication for avoiding weight gain was associated with overall evaluation ratings. CONCLUSIONS: Relevance of different potential benefits was based on objective and subjective indicators of need. Perceived efficacy of the inhaled insulin described in this study for avoiding postprandial hyperglycemia and discomfort/inconvenience were the benefits most strongly related to the evaluation of and interest in this medication. PMID- 21792299 TI - Listening to those on the frontline: service users' experiences of London tuberculosis services. AB - AIM: To explore tuberculosis (TB) service users' experiences and satisfaction with care provision. BACKGROUND: Thirty-nine percent of all new UK TB cases occur in London. Prevalence varies considerably between and within boroughs. Overall, research suggests inadequate control of London's TB transmission; TB has become a health care priority for all London Primary Care Trusts. Service users' experiences and satisfaction with care provision have not been explored adequately previously. METHODS: A qualitative research design, using semi structured face-to-face interviews was used. Ten service users, purposively selected in key risk groups across London, were interviewed. All interviews were digitally recorded with users' permission, transcribed verbatim, and analyzed thematically. RESULTS: Participants were treated in local hospitals for 6-12 months. Treatment was administered by TB nurses to inpatients and outpatients receiving directly observed therapy in consultation with medical staff and home visits for complex cases. Two participants did not realize the importance of compliance. Overall, they were satisfied with many TB services' aspects, communication, and service organization. Early access, low suspicion index amongst some GPs, and restricted referral routes were identified as service barriers. Other improvement areas were information provision on drug side effects, diet, nutritional status, and a few health professionals' attitudes. The effects on people varied enormously from minimal impact to psychological shock; TB also affected social and personal aspects of their life. With regard to further support facilities, some positive views on managed accommodation by TB aware professionals for those with accommodation problems were identified. CONCLUSION: This first in-depth study of TB service users' experiences across London offers valuable insights into service users' experiences, providing information and recommendations for a strategic framework for TB service organization and delivery. Overall, further research is needed; TB services - local, national, and international - need to be more closely aligned with service users' complex needs. PMID- 21792300 TI - The problem with health measurement. AB - In this review we discuss health measurement with a focus on psychometric methods and methodology. In particular, we examine some of the key issues currently facing the use of clinician and patient rating scales to measure the health outcomes of disease and treatment. We present three key facts and flag one crucial problem. First, the numbers generated by scales are increasingly used as the measurements of the central dependent variables upon which clinical decisions are frequently made. The rising profile of rating scales has significant implications for scale construction, evaluation, and selection, as well as for interpreting studies. Second, rating scale science is well established. Therefore, it is important to learn the lessons from those who have built and established the science over the last century. Finally, the goal of a rating scale is to measure. As such, over the last half century, developments in rating scale (psychometric) methods have caused a refocus in the way we should be measuring health. In particular, newer methods have significant clinical advantages over traditional approaches. These should be seriously considered for inclusion in everyday practice. This leads us to the central problem with health measurement, which is that we cannot currently be sure what most rating scales are measuring. This is because the methods we have in place to ensure the validity of rating scales fall short of what is actually required. We expand on this point, and provide some potential routes forward to help address this important problem. PMID- 21792301 TI - "What we want": chronically ill adolescents' preferences and priorities for improving health care. AB - BACKGROUND: As important users of health care, adolescents with chronic conditions deserve to be consulted about their experiences and expectations. This study aimed to explore chronically ill adolescents' preferences regarding providers' qualities, and outpatient and inpatient care. Furthermore, suggestions for improvement of service delivery were collected. METHODS: This research was a sequential mixed methods study in adolescents aged 12-19 years with various chronic conditions treated in a university children's hospital. Methods comprised 31 face-to-face interviews at home, a hospital-based peer research project in which nine adolescents interviewed 34 fellow patients, and a web-based questionnaire (n = 990). Emerging qualitative themes were transformed into questionnaire items. RESULTS: Having "a feeling of trust" and "voice and choice" in the hospital were central to these adolescents. Regarding providers' qualities, "being an expert" and "being trustworthy and honest" were ranked highest, followed by "being caring and understanding", "listening and showing respect", and "being focused on me". Regarding outpatient consultations, preferences were ranked as follows: "answering all questions"; "attending to my and my parents' needs"; and "clear communication", while "limited waiting times" and "attractive outpatient surroundings" scored lowest. Regarding hospitalization, adolescents most preferred to "avoid pain and discomfort", "keep in touch with home", and "be entertained", while "being hospitalized with peers" and "being heard" were least important. Regarding priorities for improvement, 52% of the respondents felt that more attention should be paid to older children, followed by enabling more contact with family and friends (45%), shorter waiting times (43%), and more activities to meet fellow patients (35%). CONCLUSION: Adolescents prefer technically competent providers, who are honest and trustworthy, and attend to their needs. As they gradually grow out of the pediatric environment, they desire staff attitudes to become less childish and more age-appropriate, and welcome being treated as an equal partner in care. Health care professionals should inquire into preferences and adjust their communication style accordingly. PMID- 21792302 TI - Patient preferences for reducing toxicities of treatments for gastrointestinal stromal tumor (GIST). AB - PURPOSE: To quantify gastrointestinal stromal tumor (GIST) patients' preferences for reducing treatment toxicities and the likely effect of toxicities on patients' stated adherence. METHODS: English-speaking members of the Life Raft Group, a GIST patient advocacy and research organization, aged 18 years and older, completed a web-enabled survey including a series of treatment-choice questions, each presenting a pair of hypothetical GIST medication toxicity profiles. Each profile was defined by common or concerning toxicities verified via pretest interviews including: severity of edema, diarrhea, nausea, fatigue, rash, hand-foot syndrome, and heart failure; and risk of serious infection. Each subject answered 13 choice-format questions based on a predetermined experimental design with known statistical properties. Subjects were asked to rate the likelihood that they would miss or skip doses of medications with different toxicity profiles. Random-parameters logit was used to estimate a relative preference weight for each level of toxicity. RESULTS: 173 subjects completed the survey. Over the ranges of toxicity levels included in the study, heart failure was the most important toxicity. Edema was the least important. For all toxicities, reducing severity from severe to moderate was more important to subjects than reducing severity from moderate to mild. Reducing heart failure from moderate to mild and diarrhea from severe to moderate had the largest effects on subjects' evaluation of adherence. CONCLUSIONS: All toxicities included in the study are important to patients. Treating or reducing severe toxicities is much more important to patients than treating or reducing moderate toxicities. Focused reductions of certain toxicities may improve treatment adherence. PMID- 21792303 TI - A redesigned follitropin alfa pen injector for infertility: results of a market research study. AB - BACKGROUND: The purpose of this study was to evaluate patient-learning and nurse teaching experiences when using a redesigned prefilled, ready-to-use follitropin alfa pen injector. METHODS: Seventy-three UK women of reproductive age either administering daily treatment with self-injectable gonadotropins or about to start gonadotropin treatment for infertility (aged 24-47 years; 53 self-injection experienced and 20 self-injection-naive) and 28 nurses from UK infertility clinics were recruited for the study. Following instruction, patients and nurses used the redesigned follitropin alfa pen to inject water into an orange and completed questionnaires to evaluate their experiences with the pen immediately after the simulated injections. RESULTS: Most (88%, n = 64) patients found it easy to learn how to use the pen. Among injection-experienced patients, 66% (n = 35) agreed that the redesigned pen was easier to learn to use compared with their current method and 70% (n = 37) also said they would prefer its use over current devices for all injectable fertility medications. All nurses considered the redesigned pen easy to learn and believed it would be easy to teach patients how to use. Eighty-six percent (n = 24) of the nurses thought it was easy to teach patients to determine the remaining dose to be dialed and injected in a second pen if the initial dose was incomplete. Compared with other injection devices, 96% (n = 27) thought it was "much easier" to "as easy" to teach patients to use the redesigned pen. Based on ease of teaching, 68% (n = 19) of nurses would choose to teach the pen in preference to any other injection method. Almost all (93%, n = 26) nurses considered that having the same pen format for a range of injectable gonadotropins would facilitate teaching and learning self-injection. CONCLUSION: In this market research study with infertile patients and infertility nurses, the redesigned follitropin alfa pen was perceived as easy to learn, easy to teach how to use, and well accepted. PMID- 21792304 TI - Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder. AB - OBJECTIVE: Asenapine is approved for acute manic and mixed states in bipolar disorder. The objective is to review the efficacy of asenapine in bipolar disorder, with a particular focus on acceptability and adherence to treatment. METHODS: FIVE CLINICAL TRIALS WERE CONDUCTED IN BIPOLAR DISORDER MANIC OR MIXED STATES: two 3-week trials (n = 976) comparing asenapine to placebo, a 9-week extension (n = 504), and a 40-week extension (n = 107). One trial was conducted comparing asenapine to placebo (n = 326) as adjunctive therapy for subjects with an incomplete response to lithium or valproate. All trials were conducted in the USA and internationally. RESULTS: Asenapine was found to be efficacious for manic and mixed states in bipolar disorder compared with placebo control, and compares equally well to olanzapine on efficacy measures after 3 weeks of treatment. Asenapine was not found to be efficacious for depression symptoms. Common asenapine side effects in the 40-week extension trial were sedation, insomnia, and dizziness, and 31% reported clinically significant weight gain, compared with 55% reporting clinically significant weight gain with olanzapine. Additionally, 18% had clinically significant changes in fasting blood glucose levels compared to 22% of those on olanzapine. In terms of patient acceptability, one concern may be sublingual administration requiring no liquids or food for 10 minutes after dosing and a twice-daily regimen. Suggestions about addressing barriers to adherence and acceptability are provided. CONCLUSION: Asenapine is a promising new medication in bipolar disorder. Asenapine in the long-term has a more favorable weight gain profile compared to olanzapine. No benefit was seen for depression symptoms, a major patient-reported concern. Some side effects do not remit after the short-term trials in at least 10% of patients. PMID- 21792305 TI - Is serum brain-derived neurotrophic factor related to craving for or use of alcohol, cocaine, or methamphetamine? AB - BACKGROUND: Data suggests that brain-derived neurotropic factor (BDNF) plays a neuroadaptive role in addiction. Whether serum BDNF levels are different in alcohol or psychostimulants as a function of craving is unknown. Here, we examined craving and serum BDNF levels in persons with alcohol versus psychostimulant dependence. Our goals were to explore BDNF as an objective biomarker for 1) craving 2) abstinence, and 3) years of chronic substance use. METHODS: An exploratory, cross-sectional study was designed. Men and women between 20-65 years old with alcohol, cocaine, or methamphetamine dependence were eligible. A craving questionnaire was used to measure alcohol, cocaine and methamphetamine cravings. Serum levels of BDNF were measured using enzyme linked immunoassay. Analysis of variance, chi-square, and correlations were performed using a 95% confidence interval and a significance level of P < 0.05. RESULTS: We found a significant difference in the mean craving score among alcohol, cocaine and methamphetamine dependent subjects. There were no significant influences of race, gender, psychiatric disorder or psychotropic medication on serum BDNF levels. We found that among psychostimulant users BDNF levels were significantly higher in men than in women when the number of abstinent days was statistically controlled. Further, a significant correlation between serum BDNF levels and the number of abstinent days since last psychostimulant use was found. CONCLUSION: These data suggest that BDNF may be a biomarker of abstinence in psychostimulant dependent subjects and inform clinicians about treatment initiatives. The results are interpreted with caution due to small sample size and lack of a control group. PMID- 21792306 TI - Update on rufinamide in childhood epilepsy. AB - Rufinamide is an orally active, structurally novel compound (1-[(2,6 difluorophenil1) methyl1]-1 hydro 1,2,3-triazole-4 carboxamide), which is structurally distinct from other anticonvulsant drugs. It was granted orphan drug status for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in the United States in 2004, and released for use in Europe in 2007. In January 2009, rufinamide was approved by the United States Food and Drug Administration for treatment of LGS in children 4 years of age and older. It is also approved for adjunctive treatment for partial seizures in adults and adolescents. Rufinamide's efficacy mainly against atonic/tonic seizures in patients with LGS seems nowadays indubitable and has been confirmed both in randomized controlled trial and in open label extension studies. More recently, rufinamide was evaluated for the adjunctive treatment of childhood-onset epileptic encephalopathies and epileptic syndromes other than LGS, including epileptic spasms, multifocal epileptic encephalopathy with spasm/tonic seizures, myoclonic-astatic epilepsy, Dravet syndrome and malignant migrating partial seizures in infancy. This review updates the existing literature data on the efficacy and safety/tolerability of rufinamide in childhood-onset epilepsy syndromes. PMID- 21792307 TI - Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures. AB - Epilepsy is a common disease with significant morbidity and mortality. Approximately one-third of patients with epilepsy are refractory to available seizure medications, emphasizing the need to develop better drugs with novel mechanisms of action. Ezogabine, also known as retigabine, is a new potential adjunctive treatment for adults with intractable partial seizures. Ezogabine has a unique mechanism of action consisting of activating KCNQ2/3 (Kv7) potassium channels. Ezogabine has undergone a number of Phase II and III trials demonstrating efficacy at 600,900 and 1200 mg/day in a dose-dependent fashion. The most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. Urologic symptoms, particularly urinary retention, represent a rare but unique side effect of ezogabine. Ezogabine is predominantly metabolized via glucuronidation. Its half-life is 8 hours, suggesting a need for three-times-a-day administration. Ezogabine exhibits minimal interactions with other seizure medications, except possibly lamotrigine. Ezogabine has potential for clinical applications in other medical conditions beyond epilepsy, such as neuropathic pain, neuromyotonia, and bipolar disease, but these are based primarily on experimental models. PMID- 21792308 TI - Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia. AB - BACKGROUND: Memantine has shown effects on cortical metabolism in Alzheimer's disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs. METHODS: Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7-8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance. RESULTS: Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [(18)F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding. CONCLUSION: This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted. PMID- 21792295 TI - Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. AB - A recent explosion in the amount of cardiovascular risk and incipient, undetected subclinical cardiovascular pathology has swept across the globe. Nearly 70% of adult Americans are overweight or obese; the prevalence of visceral obesity stands at 53% and continues to rise. At any one time, 55% of the population is on a weight-loss diet, and almost all fail. Fewer than 15% of adults or children exercise sufficiently, and over 60% engage in no vigorous activity. Among adults, 11%-13% have diabetes, 34% have hypertension, 36% have prehypertension, 36% have prediabetes, 12% have both prediabetes and prehypertension, and 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed. About one-third of the adult population, and 80% of the obese, have fatty livers. With 34% of children overweight or obese, prevalence having doubled in just a few years, type 2 diabetes, hypertension, dyslipidemia, and fatty livers in children are at their highest levels ever. Half of adults have at least one cardiovascular risk factor. Not even 1% of the population attains ideal cardiovascular health. Despite falling coronary death rates for decades, coronary heart disease (CHD) death rates in US women 35 to 54 years of age may now be increasing because of the obesity epidemic. Up to 65% of patients do not have their conventional risk biomarkers under control. Only 30% of high risk patients with CHD achieve aggressive low density lipoprotein (LDL) targets. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are titrated to evidence-based targets, about 70% of cardiac events remain unaddressed. Undertreatment is also common. About two-thirds of high risk primary care patients are not taking needed medications for dyslipidemia. Poor patient adherence, typically below 50%, adds further difficulty. Hence, after all such fractional reductions are multiplied, only a modest portion of total cardiovascular risk burden is actually being eliminated, and the full potential of risk reduction remains unrealized. Worldwide the situation is similar, with the prevalence of metabolic syndrome approaching 50%. Primordial prevention, resulting from healthful lifestyle habits that do not permit the appearance of risk factors, is the preferred method to lower cardiovascular risk. Lowering the prevalence of obesity is the most urgent matter, and is pleiotropic since it affects blood pressure, lipid profiles, glucose metabolism, inflammation, and atherothrombotic disease progression. Physical activity also improves several risk factors, with the additional potential to lower heart rate. Given the current obstacles, success of primordial prevention remains uncertain. At the same time, the consequences of delay and inaction will inevitably be disastrous, and the sense of urgency mounts. Since most CHD events arise in a large subpopulation of low- to moderate-risk individuals, identifying a high proportion of those who will go on to develop events with accuracy remains unlikely. Without a refinement in risk prediction, the current model of targeting high-risk individuals for aggressive therapy may not succeed alone, especially given the rising burden of risk. Estimating cardiovascular risk over a period of 10 years, using scoring systems such as Framingham or SCORE, continues to enjoy widespread use and is recommended for all adults. Limitations in the former have been of concern, including the under- or over-estimation of risk in specific populations, a relatively short 10-year risk horizon, focus on myocardial infarction and CHD death, and exclusion of family history. Classification errors may occur in up to 37% of individuals, particularly women and the young. Several different scoring systems are discussed in this review. The use of lifetime risk is an important conceptual advance, since >=90% of young adults with a low 10-year risk have a lifetime risk of >=39%; over half of all American adults have a low 10-year risk but a high lifetime risk. At age 50 the absence of traditional risk factors is associated with extremely low lifetime risk and significantly greater longevity. Pathological and epidemiological data confirm that atherosclerosis begins in early childhood, and advances seamlessly and inexorably throughout life. Risk factors in childhood are similar to those in adults, and track between stages of life. When indicated, aggressive treatment should begin at the earliest indication, and be continued for years. For those patients at intermediate risk according to global risk scores, C-reactive protein (CRP), coronary artery calcium (CAC), and carotid intima-media thickness (CIMT) are available for further stratification. Using statins for primary prevention is recommended by guidelines, is prevalent, but remains underprescribed. Statin drugs are unrivaled, evidence-based, major weapons to lower cardiovascular risk. Even when low density lipoprotein cholesterol (LDL-C) targets are attained, over half of patients continue to have disease progression and clinical events. This residual risk is of great concern, and multiple sources of remaining risk exist. Though clinical evidence is incomplete, altering or raising the blood high density lipoprotein cholesterol (HDL-C) level continues to be pursued. Of all agents available, rosuvastatin produces the greatest reduction in LDL-C, LDL-P, and improvement in apoA-I/apoB, together with a favorable safety profile. Several recent proposals and methods to lower cardiovascular risk are reviewed. A combination of approaches, such as the addition of lifetime risk, refinement of risk prediction, guideline compliance, novel treatments, improvement in adherence, and primordial prevention, including environmental and social intervention, will be necessary to lower the present high risk burden. PMID- 21792310 TI - 3D Symmetry Measure Invariant to Subject Pose During Image Acquisition. AB - In this study we evaluate the influence of subject pose during image acquisition on quantitative analysis of breast morphology. Three (3D) and two-dimensional (2D) images of the torso of 12 female subjects in two different poses; (1) hands on-hip (HH) and (2) hands-down (HD) were obtained. In order to quantify the effect of pose, we introduce a new measure; the 3D pBRA (Percentage Breast Retraction Assessment) index, and validate its use against the 2D pBRA index. Our data suggests that the 3D pBRA index is linearly correlated with the 2D counterpart for both of the poses, and is independent of the localization of fiducial points within a tolerance limit of 7 mm. The quantitative assessment of 3D asymmetry was found to be invariant of subject pose. This study further corroborates the advantages of 3D stereophotogrammetry over 2D photography. Problems with pose that are inherent in 2D photographs are avoided and fiducial point identification is made easier by being able to panoramically rotate the 3D surface enabling views from any desired angle. PMID- 21792309 TI - A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. AB - This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3 dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway. PMID- 21792311 TI - Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2 Overexpressing and Triple Negative Breast Cancer Cell Lines. AB - Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer. PMID- 21792312 TI - Increased Circulating Level of the Survival Factor GP88 (Progranulin) in the Serum of Breast Cancer Patients When Compared to Healthy Subjects. AB - INTRODUCTION: GP88 (PC-Cell Derived Growth Factor, progranulin) is a glycoprotein overexpressed in breast tumors and involved in their proliferation and survival. Since GP88 is secreted, an exploratory study was established to compare serum GP88 level between breast cancer patients (BC) and healthy volunteers (HV). METHODS: An IRB approved prospective study enrolled 189 stage 1-4 BC patients and 18 HV. GP88 serum concentration was determined by immunoassay. RESULTS: Serum GP88 level was 28.7 + 5.8 ng/ml in HV and increased to 40.7 + 16.0 ng/ml (P = 0.007) for stage 1-3 and 45.3 + 23.3 ng/ml (P = 0.0007) for stage 4 BC patients. There was no correlation between the GP88 level and BC characteristics such as age, race, tumor grade, ER, PR and HER-2 expression. CONCLUSION: These data suggest that serial testing of serum GP88 levels may have value as a circulating biomarker for detection, monitoring and follow up of BC. PMID- 21792313 TI - Thyroxine and free thyroxine levels in workers occupationally exposed to inorganic lead. AB - BACKGROUND: The effects of lead exposure on thyroid function are unclear. METHODS: Serum thyroxine (T4) was evaluated among 137 lead-exposed workers and 83 non-exposed workers. Free thyroxine (FT4) was evaluated among a subset of these workers. Exposure metrics included blood lead level (BLL), which reflects recent exposure, zinc protoporphyrin (ZPP), a marker of intermediate-duration lead exposure, exposure duration, and estimated cumulative exposure. Multiple linear regression results were adjusted for age, race, and current smoking status. RESULTS: Mean BLLs were 38.9 MUg/dL in lead exposed workers and 2.1 MUg/dL in non exposed workers. The adjusted mean T4 and FT4 concentrations among exposed and non-exposed workers were similar. While T4 was not significantly related to any of the exposure metrics, FT4 was inversely related to the logged values of both exposure duration and cumulative exposure, but not to ZPP or BLL. CONCLUSIONS: The findings suggest that FT4 levels may be related to long-term lead exposure. PMID- 21792314 TI - Downregulation of CD44 reduces doxorubicin resistance of CD44CD24 breast cancer cells. AB - BACKGROUND: Cells within breast cancer stem cell populations have been confirmed to have a CD44(+)CD24(-) phenotype. Strong expression of CD44 plays a critical role in numerous types of human cancers. CD44 is involved in cell differentiation, adhesion, and metastasis of cancer cells. METHODS: In this study, we reduced CD44 expression in CD44(+)CD24(-) breast cancer stem cells and investigated their sensitivity to an antitumor drug. The CD44(+)CD24(-) breast cancer stem cells were isolated from breast tumors; CD44 expression was downregulated with siRNAs followed by treatment with different concentrations of the antitumor drug. RESULTS: The proliferation of CD44 downregulated CD44(+)CD24( ) breast cancer stem cells was decreased after drug treatment. We noticed treated cells were more sensitive to doxorubicin, even at low doses, compared with the control groups. CONCLUSIONS: It would appear that expression of CD44 is integral among the CD44(+)CD24(-) cell population. Reducing the expression level of CD44, combined with doxorubicin treatment, yields promising results for eradicating breast cancer stem cells in vitro. This study opens a new direction in treating breast cancer through gene therapy in conjunction with chemotherapy. PMID- 21792315 TI - Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate refractory prostate cancer: an update and perspective among other treatments. AB - Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA) approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-therapy, chemotherapy, and other investigational immunotherapies. The sipuleucel-T manufacturing process, toxicity and clinical benefit are reviewed, along with an examination of the issue of clinical benefit to survival, independent of apparent changes of prostate-specific antigen (PSA) levels. Sipuleucel-T therapy is appraised from clinician, patient and immunotherapeutic perspectives, with reference to the clinical data from the pivotal trial, the mechanism of action, and the treatment process. PMID- 21792316 TI - Current therapeutic strategies for invasive and metastatic bladder cancer. AB - BACKGROUND: Bladder cancer is one of the most common cancers in Europe, the United States, and Northern African countries. Muscle-invasive bladder cancer is an aggressive epithelial tumor, with a high rate of early systemic dissemination. Superficial, noninvasive bladder cancer can most often be cured; a good proportion of invasive cases can also be cured by a combined modality approach of surgery, chemotherapy, and radiation. Recurrences are common and mostly manifest as metastatic disease. Those with distant metastatic disease can sometime achieve partial or complete remission with combination chemotherapy. RECENT DEVELOPMENTS: Better understanding of the biology of the disease has led to the incorporation of molecular and genetic features along with factors such as tumor grade, lympho vascular invasion, and aberrant histology, thereby allowing identification of 'favorable' and 'unfavorable' cancers which helps a more accurate informed and objective selection of patients who would benefit from neoadjuvant and adjuvant chemotherapy. Gene expression profiling has been used to find molecular signature patterns that can potentially be predictive of drug sensitivity and metastasis. Understanding the molecular pathways of invasive bladder cancer has led to clinical investigation of several targeted therapeutics such as anti-angiogenics, mTOR inhibitors, and anti-EGFR agents. CONCLUSION: With improvements in the understanding of the biology of bladder cancer, clinical trials studying novel and targeted agents alone or in combination with chemotherapy have increased the armamentarium for the treatment of bladder cancer. Although the novel biomarkers and gene expression profiles have been shown to provide important predictive and prognostic information and are anticipated to be incorporated in clinical decision-making, their exact utility and relevance calls for a larger prospective validation. PMID- 21792317 TI - The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine. AB - BACKGROUND: Activating point mutation of the RAS gene has been generally accepted as an oncogenic event in a variety of malignancies. It represents one of the most common genetic alterations in acute myeloid leukemia (AML). However, little is known about its clinical relevance in the treatment outcome for this leukemia. OBJECTIVE: This study aimed to clarify the biologic and prognostic impact of K RAS mutations in relation to the dose of cytarabine (ara-C) used in postinduction consolidation chemotherapy in adult AML patients. PATIENTS AND METHODS: The study comprised of 71 de novo AML patients with male/ female ratio 1.4:1; their ages ranged from 21-59 years with a median of 37 years. They were subjected to full clinical evaluation, routine laboratory investigations, cytogenetic studies by G banding (Giemsa staining), and K-RAS mutation detection using real-time polymerase chain reaction. The patients were randomized into two groups according to the ara-C dose used in consolidation treatment, the high the dose ara-C (HDAC) group receiving 400 mg ara-C and-low-dose ara-C (LDAC) group receiving 100 mg ara C; they were followed over a period of five years. RESULTS: Mutations in the K RAS gene (mutRAS) were detected in 23 patients (32%) with the remaining 48 patients (68%) having wild-type RAS (wtRAS). The percent of blast cells was significantly lower in mutRAS compared to wtRAS patients (P <= 0.001) while M4 subtype of AML and Inv(16) frequencies were significantly higher in mutRAS compared to wtRAS patients (P = 0.015) and (P = 0.003), respectively. The patients were followed up for a median of 43 months (range 11-57 months). There was no significant difference in overall survival (OS) between mutRAS and wtRAS (P = 0.326). Within the mutRAS patients treated with HDAC, cumulative OS was significantly higher than those treated with LDAC (P = 0.001). This was not the case in the wtRAS group (P = 0.285). There was no significant difference in disease-free survival (DFS) between mutRAS and wtRAS groups (P = 0.923). mutRAS patients treated with HDAC had a statistically higher cumulative DFS than mutRAS patients treated with LDAC (P = 0.001). Patients with wtRAS also benefited from HDAC, but to a lesser extent. Among patients with wtRAS, those treated with HDAC showed higher cumulative and median DFS than patients treated with LDAC (P = 0.031). CONCLUSION: It was concluded that adult AML patients carrying mutations in the K-RAS gene benefit from higher ara-C doses more than wtRAS patients, so pretreatment mutation detection could be an important predictor for treatment strategy and survival of adult AML patients. These findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies. PMID- 21792318 TI - Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval. AB - Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab paclitaxel displays greater antitumor activity and less toxicity than solvent base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m(2) with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m(2) over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m(2) over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nabpaclitaxel was also more active and displayed less toxicity compared with 100 mg/m(2) docetaxel given triweekly. Nab paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent. PMID- 21792319 TI - Update on optimal use of omalizumab in management of asthma. AB - Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing interaction with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include improvements in respiratory symptoms and quality of life, paralleled by a reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well-tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma inadequately controlled by high doses of standard inhaled treatments. PMID- 21792320 TI - Scientific respiratory symposium, paris june 2010. AB - At a 2010 Respiratory Symposium in Paris, chaired by Professors Bousquet and Roche of the University of Paris, recent trends in research, therapy and treatment guidelines for asthma and chronic obstructive pulmonary disease (COPD) were reviewed and discussed by a faculty of expert European and US respiratory physicians. This article reviews five key clinical presentations with particular emphasis given to the importance of small airways in the pathology and treatment of asthma and COPD. Further analysis of the economics of treatment in Europe and the US shows a wide variance in direct and indirect costs. PMID- 21792321 TI - Clinical update on the use of biomarkers of airway inflammation in the management of asthma. AB - Biological markers are already used in the diagnosis and treatment of cardiovascular disease and cancer. Biomarkers have great potential use in the clinic as a noninvasive means to make more accurate diagnoses, monitor disease progression, and create personalized treatment regimes. Asthma is a heterogeneous disease with several different phenotypes, generally triggered by multiple gene environment interactions. Pulmonary function tests are most often used objectively to confirm the diagnosis. However, airflow obstruction can be variable and thus missed using spirometry. Furthermore, lung function measurements may not reflect the precise underlying pathological processes responsible for different phenotypes. Inhaled corticosteroids and beta(2) agonists have been the mainstay of asthma therapy for over 30 years, but the heterogeneity of the disease means not all asthmatics respond to the same treatment. High costs and undesired side effects of drugs also drive the need for better targeted treatment of asthma. Biomarkers have the potential to indicate an individual's disease phenotype and thereby guide clinicians in their decisions regarding treatment. This review focuses on biomarkers of airway inflammation which may help us to identify, monitor, and guide treatment of asthmatics. We discuss biomarkers obtained from multiple physiological sources, including sputum, exhaled gases, exhaled breath condensate, serum, and urine. We discuss the inherent limitations and benefits of using biomarkers in a heterogeneous disease such as asthma. We also discuss how we may modify our study designs to improve the identification and potential use of potential biomarkers in asthma. PMID- 21792322 TI - Predictors of weight loss and maintenance in patients treated with antiobesity drugs. AB - BACKGROUND: The prevalence of obesity and related diseases has increased enormously in the last few decades, becoming a very important medical and social issue. Because of the increasing number of people who need weight loss therapies and the high costs associated with these, the search for reliable predictors of success for weight loss and weight maintenance treatments has become a priority. OBJECTIVE: A literature review was undertaken to identify possible predictors of outcome of weight loss and weight maintenance in patients treated with antiobesity drugs. RESULTS: For the majority of variables, published data are not sufficient to define their role on final outcomes. Among all considered factors, only early response to treatment appeared to be a reliable positive predictor, and diabetes a negative predictor of weight loss and maintenance. CONCLUSION: To date, no definitive results have been obtained. Due to the great benefits of reliable predictors of outcome associated to currently available antiobesity drugs and those under development, identifying these predictors has to be supported and encouraged. PMID- 21792323 TI - Perception of weight and psychological variables in a sample of Spanish adolescents. AB - BACKGROUND: This study explored the relationship between body mass index (BMI) and weight perception, self-esteem, positive body image, food beliefs, and mental health status, along with any gender differences in weight perception, in a sample of adolescents in Spain. METHODS: The sample comprised 85 students (53 females and 32 males, mean age 17.4 +/- 5.5 years) with no psychiatric history who were recruited from a high school in Ecija, Seville. Weight and height were recorded for all participants, who were then classified according to whether they perceived themselves as slightly overweight, very overweight, very underweight, slightly underweight, or about the right weight, using the question "How do you think of yourself in terms of weight?". Finally, a series of questionnaires were administered, including the Irrational Food Beliefs Scale, Body Appreciation Scale, Self Esteem Scale, and General Health Questionnaire. RESULTS: Overall, 23.5% of participants misperceived their weight. Taking into account only those with a normal BMI (percentile 5-85), there was a significant gender difference with respect to those who perceived themselves as overweight (slightly overweight and very overweight); 13.9% of females and 7.9% of males perceived themselves as overweight (chi(2) = 3.957, P < 0.05). There was a significant difference for age, with participants who perceived their weight adequately being of mean age 16.34 +/- 3.17 years and those who misperceived their weight being of mean age 18.50 +/- 4.02 years (F = 3.112, P < 0.05). CONCLUSION: Misperception of overweight seems to be more frequent in female adolescents, and mainly among older ones. Misperception of being overweight is associated with a less positive body image, and the perception of being very underweight is associated with higher scores for general psychopathology. PMID- 21792324 TI - Insulin initiation and intensification in patients with T2DM for the primary care physician. AB - Type 2 diabetes mellitus (T2DM) is characterized by both insulin resistance and inadequate insulin secretion. All patients with the disease require treatment to achieve and maintain the target glycosylated hemoglobin (A1C) level of 6.5%-7%. Pharmacological management of T2DM typically begins with the introduction of oral medications, and the majority of patients require exogenous insulin therapy at some point in time. Primary care physicians play an essential role in the management of T2DM since they often initiate insulin therapy and intensify regimens over time as needed. Although insulin therapy is prescribed on an individualized basis, treatment usually begins with basal insulin added to a background therapy of oral agents. Prandial insulin injections may be added if glycemic targets are not achieved. Treatments may be intensified over time using patient-friendly titration algorithms. The goal of insulin intensification within the primary care setting is to minimize patients' exposure to chronic hyperglycemia and weight gain, and reduce patients' risk of hypoglycemia, while achieving individualized fasting, postprandial, and A1C targets. Simplified treatment protocols and insulin delivery devices allow physicians to become efficient prescribers of insulin intensification within the primary care arena. PMID- 21792325 TI - Patient considerations and clinical utility of a fixed dose combination of saxagliptin/metformin in the treatment of type 2 diabetes. AB - INTRODUCTION: Targeting glycated hemoglobin (HbA(1c)) levels below 7.0% is considered a primary goal of diabetes care, given its importance in obtaining a sustained reduction in microvascular, and possibly macrovascular complications. AIM: The aim of this review was to evaluate the clinical utility of a fixed dose combination of saxagliptin/metformin in the treatment of type 2 diabetes. EVIDENCE REVIEW: The combination of saxagliptin/metformin was well tolerated and produced sustained glycemic control for up to 76 weeks, with greater improvements in glycemic parameters compared with either drug alone. The saxagliptin/metformin combination also proved its non-inferiority compared with either sulfonylurea/metformin or sitagliptin/metformin combinations. PLACE IN THERAPY: Clinical practice recommends lifestyle interventions together with starting metformin at the time that the type 2 diabetes mellitus is diagnosed. Once metformin fails to maintain glycemic control, the addition of DPP-4 inhibitors should be the logical choice because of their effects on HbA(1c) compared to the addition of a sulfonylurea or glitazone, and because of their positive effects on beta cell function and their neutral effects on body weight. Furthermore, DPP-4 inhibitors prevent the risk of hypoglycemia posed by sulfonylureas. PMID- 21792327 TI - Two-way crossover comparison of insulin glargine and insulin detemir in basal bolus therapy using continuous glucose monitoring. AB - OBJECTIVE: This study aimed to compare the glucose-lowering effect and glycemic variability of insulin glargine with those of insulin detemir. MATERIAL AND METHODS: This was an open-label, single-center, randomized, two-way crossover study in patients with diabetes on basal-bolus insulin therapy, with neutral protamine Hagedorn (NPH) insulin as basal insulin. Patients switched from NPH insulin to a course either of insulin glargine followed by insulin detemir, or insulin detemir followed by insulin glargine, continuing the same dose of the prior bolus of insulin. To evaluate the glucose-lowering effect, daily glycemic profiles were recorded for 72 hours by continuous glucose monitoring (CGM) in an outpatient setting. The mean amplitude of glycemic excursions, standard deviation (SD), and the mean of daily difference (MODD) were used to assess intraday and day-to-day glycemic variability. RESULTS: Eleven patients were enrolled and nine completed the study. Mean blood glucose calculated from CGM values was significantly lower with insulin glargine compared with insulin detemir (9.6 +/- 2.4 mmol/L versus 10.4 +/- 2.8 mmol/L, P = 0.038). The SD was significantly lower with insulin glargine versus insulin detemir (2.5 +/- 0.9 mmol/L vs 3.5 +/- 1.6 mmol/L, P = 0.011). The MODD value was significantly lower with insulin glargine than with insulin detemir (2.2 +/- 1.1 mmol/L vs 3.6 +/- 1.7 mmol/L, P = 0.011). There was no significant difference between the two insulin analogs in terms of hypoglycemia. CONCLUSION: This study suggests that insulin glargine leads to more effective and more stable glycemic control than the same dose of insulin detemir. PMID- 21792326 TI - Is obesity in women protective against osteoporosis? AB - The belief that obesity is protective against osteoporosis has recently come into question. The latest epidemiologic and clinical studies have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Further, increasing evidence seems to indicate that different components of the metabolic syndrome, ie, hypertension, increased triglycerides, reduced high-density lipoprotein cholesterol, are also potential risk factors for the development of low bone mineral density and osteoporosis. This review considers both the older and more recent data in the literature in order to evaluate further the relationship between fat tissue and bone tissue. PMID- 21792329 TI - Clinical relevance and treatment of nonautoimmune anemia in chronic lymphocytic leukemia. AB - Anemia has an unfavorable impact on quality of life in chronic lymphocytic leukemia (CLL), increases the likelihood of receiving blood transfusions, and eventually has a negative impact on overall survival. Although discrepancies in perception of health-related quality of life between doctors and patients lead to the undertreatment of anemia, CLL patients undergoing chemotherapy who have a hemoglobin level <10 g/dL should be considered for treatment with erythropoiesis stimulating agents. For hemoglobin values of 10-12 g/dL, the role of performance status and comorbidities should not be underestimated. In this setting, the evaluation of physical fitness using the Cumulative Illness Rating Scale should help physicians to identify those patients with hemoglobin levels of 10-12 g/dL who are suitable for therapy with erythropoiesis-stimulating agents. Finally, the increasing use of aggressive approaches to therapy should encourage physicians towards appropriate management of chemotherapy-induced anemia in CLL patients. PMID- 21792328 TI - Deciding what information is necessary: do patients with advanced cancer want to know all the details? AB - Communicating effectively with patients who have advanced cancer is one of the greatest challenges facing physicians today. Whilst guiding the patient through complex diagnostic and staging techniques, treatment regimens and trials, the physician must translate often imprecise or conflicting data into meaningful personalized information that empowers the patient to make decisions about their life and body. This requires understanding, compassion, patience, and skill. This narrative literature review explores current communication practices, information preferences of oncology patients and their families, and communication strategies that may assist in these delicate interactions. Overwhelmingly, the literature suggests that whilst the majority of patients with advanced cancer do want to know their diagnosis and receive detailed prognostic information, this varies not only between individuals but also for a given individual over time. Barriers to the delivery and understanding of information exist on both sides of the physician-patient relationship, and family dynamics are also influential. Despite identifiable trends, the information preferences of a particular patient cannot be reliably predicted by demographic, cultural, or cancer-specific factors. Therefore, our primary recommendation is that the physician regularly asks the patient what information they would like to know, who else should be given the information and be involved in decision making, and how that information should be presented. PMID- 21792330 TI - Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer. AB - Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease progression in women with recurrent (potentially platinum-sensitive) disease. Current research efforts involving PLD in ovarian cancer are focusing on adding novel targeted drugs to this cytotoxic agent. The utility of such approaches in the platinum resistant population, compared with the sequential administration of single agents active in this setting, remains to be determined. PMID- 21792331 TI - Evaluation of prostate cancer prevalence in Iranian male population with increased PSA level, a one center experience. AB - PURPOSE: This study was conducted to evaluate the incidence of prostate cancer (PCa) in Iranian male patients with increased prostate-specific antigen (PSA), and normal or abnormal digital rectal examination (DRE) that underwent prostate biopsy. MATERIALS AND METHODS: From March 2006 to April 2009, a total of 346 consecutive males suspected of having PCa due to increased PSA levels underwent transrectal ultrasonography (TRUS)-guided sextant biopsy of the prostate. The total PSA (tPSA), demographic data, incidence of PCa, benign prostate hyperplasia (BPH), and prostatitis were assessed. RESULTS: The patients were divided into two groups according to their PSA values (group A serum tPSA level, 4-10 ng/mL; group B serum tPSA level, 10.1-20.0 ng/mL). Of the 346 biopsied cases, 193 cases (56%) had PCa, 80 cases (23%) had BPH, and 73 cases (21%) had prostatitis. The mean PSA and the age of the carcinoma group were significantly higher than those of the benign group (P < 0.01). The biopsy results were grouped as PCa, BPH, and prostatitis. Incidence of PCa for group A and group B cases were 115 cases (51%), and 78 cases (65%), respectively. In the case of PCa, BPH, and prostatitis, the mean PSAs were 10.02 ng/mL, 8.76 ng/mL, and 8.41 ng/mL, respectively (P < 0.40). CONCLUSION: TRUS-guided prostate biopsy and interpretation by a skilled team is highly recommended for early detection of PCa or its ruling-out. It seems that a PSA cutoff value of 4 ng/mL may be applied to the Iranian population. Although the chance of PCa is high in the PSA levels of 4-10 ng/mL, the combination of some data, like age and prostate volume, can decrease the rate of unnecessary prostate biopsies. We recommend prostate biopsy when PSA and/or DRE is elevated in symptomatic patients with obstructive and/or irritative lower urinary tract symptoms (LUTS) such as dysuria, frequency, or nocturia. Due to the very high incidence of PCa in the patients with PSA greater than 10 ng/mL, TRUS-guided biopsy is indicated, whatever the findings on DRE and/or LUTS, since the PCa detection rate is high. PMID- 21792332 TI - Differences in treatment patterns among patients with castration-resistant prostate cancer treated by oncologists versus urologists in a US managed care population. AB - OBJECTIVE: Differences in treatment patterns, health care resource utilization, and costs between patients with castration-resistant prostate cancer (CRPC) treated by oncologists and those treated by urologists were examined. METHODS: Patients aged >=40 with CRPC were identified using claims from a large US managed health care plan between July 2001 and December 2007. A 6-month baseline period was used to assess patient characteristics. Patients with visits to an urologist, without visits to an oncologist, were assigned to the urology cohort, and patients with visits to an oncologist, with or without visits to an urologist, were assigned to the oncology cohort. Treatment patterns, health care resource utilization, and costs during a variable follow-up period were compared between cohorts using descriptive statistics and Lin's regression. RESULTS: The urology cohort had fewer comorbid illnesses (P < 0.001) and patients were less likely to have other cancers during baseline (P < 0.001) or to die during follow-up (P = 0.004) compared with the oncology cohort. The oncology cohort patients were significantly more likely to have a claim for hormones (74.5% vs 61.1%; P < 0.001), chemotherapy (46.9% vs 10.2%, P < 0.001), and radiation (22.3% vs 3.7%, P < 0.0001) over follow-up. Mean unadjusted health care costs were higher in the oncology vs the urology cohort (US$31,896 vs US$15,318, respectively; P < 0.001). At 6 years follow-up, cumulative adjusted CRPC-specific costs were significantly higher among patients treated by oncologists with chemotherapy than among patients treated by urologists. CONCLUSION: CRPC patients treated by oncologists had greater use of hormones, chemotherapy, and radiation; higher percentages of patients with inpatient stays, emergency room, and ambulatory visits; and higher health care costs, than patients treated by urologists. PMID- 21792333 TI - Use of neutral plasma coagulation in groin node dissection for vulvar malignancy: a novel technique. AB - Vulvar cancer is an uncommon disease with approximately 1000 cases reported annually in the UK. Lymph node involvement is an important prognostic indicator. Vulvectomy and bilateral groin node dissection are the preferred surgical treatments for early disease and increase survival. However, significant morbidity with lymphocyst formation and wound breakdown has been reported in more than 50% of cases. We report the first case following use of the PlasmaJet((r)) neutral argon coagulation system to reduce postoperative lymphocyst formation. PMID- 21792334 TI - Latest developments and emerging treatment options in the management of stomach cancer. AB - Gastric cancer remains a significant health burden worldwide. Most of these malignancies are diagnosed at an advanced stage and are associated with a grim prognosis. Complete removal of macroscopic and microscopic tumor masses along with regional lymphnodes (R0 surgical resection) represents the treatment of choice in localized, nonmetastatic gastric cancer. Chemotherapy, either alone as a perioperative treatment, or in combination with radiation therapy in an adjuvant setting, improves the clinical outcome for patients with resectable tumors. In patients suffering from metastatic disease, chemotherapy and the so called targeted therapies play a major role in improving survival and quality of life compared with best supportive care. The emergence of new drugs as well as new administration schedules allow physicians to obtain an objective response of up to 60% and, since the utilization of targeted therapies, overall survival has reached 14 months. In order to situate the standard of care and the latest developments in gastric malignancies better, the pertinent English literature, including major Phase III randomized studies and meta-analyses, has been reviewed. PMID- 21792335 TI - Comparison of risk factors between preterm and term infants hospitalized for severe respiratory syncytial virus in the Russian Federation. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Preterm birth, in addition to several demographic and environmental factors, increases the risk for development of severe RSV infection. The purpose of this study was to describe differences in risk factors and protective factors between preterm birth (up to 35 weeks' gestational age) and term infants hospitalized for RSV lower respiratory tract infection in the Russian Federation during the 2008-2009 RSV season. METHODS: Infants up to two years of age hospitalized for a lower respiratory tract infection in Moscow, St Petersburg, and Tomsk were tested for RSV. Patient data, including risk factors and protective factors for RSV, were captured at admission. Differences in these factors were compared between preterm and term patients. RESULTS: A total of 519 infants hospitalized for lower respiratory tract infection were included in the study. Of these, 197 infants (182 term and 15 preterm) tested positive for RSV. Of all hospitalizations, 51.7% (15/29) of preterm infants versus 37.1% (182/490) of term infants had confirmed RSV (P = 0.118). Among the RSV-positive patients, preterm infants were more likely to have a lower weight at admission (P = 0.050), be of multiple gestation (P < 0.001), have more siblings (P = 0.013), and have more siblings under the age of eight years (P < 0.007) compared with term patients. The preterm infants were less likely to be breastfed (P < 0.001) and more likely to have older mothers (P = 0.050). CONCLUSION: Compared with term infants, RSV was a more prevalent cause of hospitalization for lower respiratory tract infection in preterm infants. Of infants hospitalized for RSV, preterm infants were more likely to have additional risk factors for severe RSV. These findings suggest that preterm infants may be exposed to a combination of more strongly interrelated risk factors for severe RSV than term infants. PMID- 21792336 TI - Evaluation of CYP450 inhibitory effects and steady-state pharmacokinetics of genistein in combination with cholecalciferol and citrated zinc bisglycinate in postmenopausal women. AB - BACKGROUND: The combination of genistein 27 mg, cholecalciferol 200 IU, citrated zinc bisglycinate (4 mg elemental zinc) 20 mg per capsule in Fosteum((r)), a prescription medical food regulated by the FDA and indicated for the dietary management of osteopenia and osteoporosis, was tested for drug interactions and to determine the pharmacokinetic profile for genistein, the principal bone modulating ingredient in the product. METHODS: In vitro human liver microsome cytochrome P450 (CYP450) assays were used to test the product for potential drug interactions with the isoforms 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Due to specific 2C8 and 2C9 inhibition, a steady-state pharmacokinetic study was performed to assess serum genistein concentrations by high-pressure liquid chromatography coupled mass spectroscopy in healthy fasting (n = 10) and fed (n = 10) postmenopausal women. RESULTS: The product showed minimal inhibition of 1A2, 2C19, 2D6, and 3A4, exhibiting IC(50) > 10 MUM, but 2C8 and 2C9 yielded IC(50) of 2.5 MUM and 2.8 MUM, respectively, concentrations which are theroretically achievable when dosing the product twice daily. After seven days of administration in a steady-state pharmacokinetic study, significant differences were found for unconjugated genistein (including free and protein-bound), regarding time to peak concentration (1.88 +/- 1.36 hours), maximum concentration reached (0.052 +/- 0.055 MUM), elimination half-life (2.3 +/- 1.6 hours), and area under the concentration-time curve (53.75 +/- 17.59 ng . hour/mL) compared with results for total genistein (including glucuronidated and sulfonated conjugates) time to peak concentration (2.22 +/- 1.09 hours), maximum concentration reached (2.95 +/- 1.64 MUM), elimination half-life (10.4 +/- 4.1 hours), and area under the concentration-time curve (10424 +/- 6290 ng . hour/mL) in fasting subjects. Coadministration of food tended to extend the time and extent of absorption as well as slow elimination of genistein, but not in a statistically significant manner. CONCLUSION: Because the serum genistein concentrations achieved during pharmacokinetic testing at therapeutic doses were well below those required for enzyme inhibition in the in vitro liver microsome assays, these results indicate a low potential for drug interactions. PMID- 21792337 TI - The role of aspirin in women's health. AB - BACKGROUND: The aim of this review is to discuss the role of aspirin for various conditions in women. METHODS: A nonsystematic review of articles published on PubMed((r)) that examines the role of aspirin in women. RESULTS: Aspirin is associated with a significant reduction of stroke risk in women, which may be linked to age. However, despite this evidence, underutilization of aspirin in eligible women is reported. In women of reproductive age, it may also have a role to play in reducing early-onset preeclampsia and intrauterine growth restriction, and in the prevention of recurrent miscarriage in women with antiphospholipid antibodies; it may also reduce cardiovascular risk in associated systemic conditions such as lupus. Aspirin may reduce colorectal cancer risk in women, but its role in breast cancer warrants further data from controlled trials. CONCLUSIONS: The risk-benefit threshold for aspirin use in women has been established for several conditions. Reasons why women are less likely to be prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed. PMID- 21792338 TI - Neighborhood socioeconomic disadvantage, individual wealth status and patterns of delivery care utilization in Nigeria: a multilevel discrete choice analysis. AB - BACKGROUND: High maternal mortality continues to be a major public health problem in most part of the developing world, including Nigeria. Understanding the utilization pattern of maternal healthcare services has been accepted as an important factor for reducing maternal deaths. This study investigates the effect of neighborhood and individual socioeconomic position on the utilization of different forms of place of delivery among women of reproductive age in Nigeria. METHODS: A population-based multilevel discrete choice analysis was performed using the most recent population-based 2008 Nigerian Demographic and Health Surveys data of women aged between 15 and 49 years. The analysis was restricted to 15,162 ever-married women from 888 communities across the 36 states of the federation including the Federal Capital Territory of Abuja. RESULTS: The choice of place to deliver varies across the socioeconomic strata. The results of the multilevel discrete choice models indicate that with every other factor controlled for, the household wealth status, women's occupation, women's and partner's high level of education attainment, and possession of health insurance were associated with use of private and government health facilities for child birth relative to home delivery. The results also show that higher birth order and young maternal age were associated with use of home delivery. Living in a highly socioeconomic disadvantaged neighborhood is associated with home birth compared with the patronage of government health facilities. More specifically, the result revealed that choice of facility-based delivery is clustered around the neighborhoods. CONCLUSION: Home delivery, which cuts across all socioeconomic strata, is a common practice among women in Nigeria. Initiatives that would encourage the appropriate use of healthcare facilities at little or no cost to the most disadvantaged should be accorded the utmost priority. PMID- 21792339 TI - Dienogest in long-term treatment of endometriosis. AB - Endometriosis is a chronic disease primarily affecting women of childbearing age, in which endometriotic lesions form outside the uterus, typically leading to painful symptoms, fatigue, and infertility. The symptoms of endometriosis may cause significant impairment in quality of life and represent a substantial economic burden to patients, families, and society. There is no cure for endometriosis; management consists of alleviating pain and other symptoms, reducing endometriotic lesions, and improving quality of life. Recurrence after surgical intervention is common, while the clinical evidence to support the efficacy and safety of many medications currently used in endometriosis is limited. Dienogest is an oral progestin that has been investigated extensively in the treatment of endometriosis in two clinical programs performed in Europe and Japan, including dose-ranging, placebo-controlled, active comparator-controlled, and long-term (up to 65 weeks) studies. These studies demonstrated that dienogest 2 mg daily effectively alleviates the painful symptoms of endometriosis, reduces endometriotic lesions, and improves indices of quality of life. Dienogest showed a favorable safety and tolerability profile in these studies, with predictable adverse effects, high rates of patient compliance, and low withdrawal rates. This review article describes the clinical trial evidence that characterizes the efficacy and safety of dienogest in endometriosis, including two studies characterizing dienogest in long-term use. The relevance of these findings to the management of endometriosis in clinical practice is discussed. PMID- 21792340 TI - Usefulness of serum mass spectrometry to identify women diagnosed with higher grades of cervical intraepithelial neoplasia may differ by race. AB - BACKGROUND: An early detection of precursor lesions of cervical cancer will help to eliminate the worldwide burden of cervical cancer. METHODS: This exploratory study aimed to identify, by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS), serum protein profiles that distinguish cervical intraepithelial neoplasia grades CIN 1 or lower (<=CIN 1) from CIN 2+ among 127 women infected with human papillomavirus (HPV) 16. Of these 127 women, 25 and 23 were diagnosed with CIN 2 or CIN 3, respectively (cases), and 79 were diagnosed with <=CIN 1 (non-cases). Serum protein profiles were generated by MALDI-TOF-MS. A total of 95 m/z peaks were tested for association with case status by two racial groups, African American (AAs) and Caucasian American (CAs). RESULTS: Overall, 2 protein peaks identified by our study demonstrated higher specificity for identifying CIN 2+ than previously published studies. An increasing intensity of [m/z 4459] was associated with a higher risk of being a case, regardless of race with a specificity of 58% for CIN 2 and a specificity of 75% for CIN 3. An increasing intensity of [m/z 4154] was not only associated with a higher risk of being a case only among CAs, but also had an opposite effect among AAs. CONCLUSION: Identification of specific proteins associated with the peaks detected in serum and development of antibody-based tests such as ELISA should lead to the development of race-specific, non-invasive and cost effective screening tests with higher specificity for identifying HPV 16 associated CIN 2+. PMID- 21792341 TI - Comparison of stereotactic core breast biopsy and open surgical biopsy results at a tertiary care hospital in Pakistan. AB - BACKGROUND: The purpose of this study was to determine the yield of stereotactic core breast biopsy and its cost-saving potential. METHODS: This observational study was conducted at the Department of Radiology at Aga Khan Hospital in Karachi. All female patients (n = 84) undergoing stereotactic core breast biopsy under mammographic guidance from January 2005 to May 2010 were included. Stereotactic core biopsy was performed on a dedicated mammography unit employing a 14-gauge needle with an automated biopsy device. Ten patients with incomplete medical records were excluded. All breast biopsy results were either compared with surgical findings in cases of malignant histopathological findings or with follow-up needle localization in case of benign core biopsy findings. RESULTS: Fifteen of our 74 patients had malignant findings on stereotactic biopsy, confirmed on histopathology of the final surgical mastectomy specimen. The remaining 59 patients had benign results on histopathology; five patients had needle localization of the same area due to either suspicious mammographic findings or clinical suspicion of malignancy. All were proven to be histopathologically benign on open surgical biopsy. Fifty-four patients with benign results had follow-up mammograms, and the follow-up period was 18 months to 5 years. The sensitivity and specificity was 100%. The cost saving per patient was US$253. CONCLUSION: Stereotactic core breast biopsy is a safe and cost effective method for determining the nature of suspicious mammographic findings. PMID- 21792342 TI - Effect of angiogenesis-related cytokines on rotator cuff disease: the search for sensitive biomarkers of early tendon degeneration. AB - BACKGROUND: Hallmarks of the pathogenesis of rotator cuff disease (RCD) include an abnormal immune response, angiogenesis, and altered variables of vascularity. Degenerative changes enhance production of pro-inflammatory, anti-inflammatory, and vascular angiogenesis-related cytokines (ARC) that play a pivotal role in the immune response to arthroscopic surgery and participate in the pathogenesis of RCD. The purpose of this study was to evaluate the ARC profile, ie, interleukin (IL): IL-1beta, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG), in human peripheral blood serum and correlate this with early degenerative changes in patients with RCD. METHODS: Blood specimens were obtained from 200 patients with RCD and 200 patients seen in the orthopedic clinic for nonrotator cuff disorders. Angiogenesis imaging assays was performed using power Doppler ultrasound to evaluate variables of vascularity in the rotator cuff tendons. Expression of ARC was measured by commercial Bio-Plex Precision Pro Human Cytokine Assays. RESULTS: Baseline concentrations of IL-1beta, IL-8, and VEGF was significantly higher in RCD patients than in controls. Significantly higher serum VEGF levels were found in 85% of patients with RCD, and correlated with advanced stage of disease (r = 0.75; P < 0.0005), average microvascular density (r = 0.68, P < 0.005), and visual analog score (r = 0.75, P < 0.0002) in RCD patients. ANG and IL-10 levels were significantly lower in RCD patients versus controls. IL-1beta and ANG levels were significantly correlated with degenerative tendon grade in RCD patients. No difference in IL-6 and bFGF levels was observed between RCD patients and controls. Patients with degenerative changes had markedly lower ANG levels compared with controls. Power Doppler ultrasound showed high blood vessel density in patients with tendon rupture. CONCLUSION: The pathogenesis of RCD is associated with an imbalance between pro-inflammatory, anti-inflammatory, and vascular ARC. PMID- 21792343 TI - TNF-alpha and TNF-beta Gene Polymorphism in Saudi Rheumatoid Arthritis Patients. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha and -beta are cytokines with a wide range of inflammatory, apoptotic and immunomodulatory activities. TNF-alpha promoter -308 G < A polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. OBJECTIVE: The aim of this study is to elucidate a possible association of TNF-alpha (G-308A) and TNF-beta (A+252G) polymorphisms with the susceptibility of RA in Saudi patients. PATIENTS AND METHODS: This case control study consisted of 232 Saudi subjects including 106 RA patients and 126 matched controls. Genomic DNA was extracted using QIAamp(R) DNA mini kit (Qiagen CA, USA). TNF-alpha and TNF-beta genes were amplified using Arms primers. RESULTS: The frequencies of TNF-alpha (-308) allele G and genotype GG were significantly higher in RA patients as compared to controls while allele A and genotype AA were predominant in control group. On the other hand the frequency of TNF-beta (+252) GG and AA genotypes were significantly higher in RA patients as compared to controls while GA genotype was predominant in controls. It was inferred that genotype GG positive individuals at position -308 of TNF-alpha were susceptible to RA while genotype AA might has a protective effect on RA susceptibility in Saudis. Whereas GG and AA genotype of TNF-beta at +252 position might exert additive susceptibility to RA and GA might be refractory. However, there was no significant association between duration of morning stiffness, RF positivity and number of joints involved and distribution of alleles/genotypes of TNF-alpha (-308) or TNF-beta (+252) polymorphism. It may be concluded that the TNF-alpha (-308) and TNF-beta (+252) polymorphisms might influence the susceptibility to RA in Saudi population. These results might have prognostic value for future clinical observations. PMID- 21792344 TI - Mechanical intervention for maintenance of cartilage and bone. AB - Mechanical loading provides indispensible stimuli for growth and development of the articular cartilage and bone. Interestingly, depending on loading conditions loads applied to the joint can be beneficial as well as harmful to skeletal maintenance and remodeling. Moderate loads to the synovial joint, for instance, suppress the expression levels of matrix metallproteinases (MMPs), while loads above a threshold tend to increase their destructive activities. This report focuses on two recently developed loading modalities from animal studies, joint motion and joint loading. Their unique characteristics and potential usages for maintenance of the articular cartilage and stimulation of bone remodeling are reviewed. Also described are biophysical and molecular mechanisms which likely are responsible for the load-driven maintenance of cartilage and bone, and a possibility of developing load-mediated treatments of osteoporosis and osteoarthritis. PMID- 21792345 TI - Bucindolol: a pharmacogenomic perspective on its use in chronic heart failure. AB - Bucindolol is a non-selective beta-adrenergic receptor blocker with alpha-1 blocker properties and mild intrinsic sympatholytic activity. The Beta-Blocker Evaluation of Survival Trial (BEST), which is the largest clinical trial of bucindolol in patients with heart failure, was terminated prematurely and failed to show an overall mortality benefit. However, benefits on cardiac mortality and re-hospitalization rates were observed in the BEST trial. Bucindolol has not shown benefits in African Americans, those with significantly low ejection fraction and those in NYHA class IV heart failure. These observations could be due to the exaggerated sympatholytic response to bucindolol in these sub-groups that may be mediated by genetic polymorphisms or changes in gene regulation due to advanced heart failure. This paper provides a timely clinical update on the use of bucindolol in chronic heart failure. PMID- 21792347 TI - Developing a Fluorescence-based Approach to Screening for Macromolecule Crystallization Conditions. AB - Current macromolecule crystallization screening methods rely on the random testing of crystallization conditions, in the hope that one or more will yield positive results, crystals. Most plate outcomes are either clear or precipitated solutions, which results are routinely discarded by the experimenter. However, many of these may in fact be close to crystallization conditions, which fact is obscured by the nature of the apparent outcome. We are developing a fluorescence based approach to the determination of crystallization conditions, which approach can also be used to assess conditions that may be close to those that would give crystals. The method uses measurements of fluorescence anisotropy and intensity. The method was first tested using model proteins, with likely outcomes as determined by fluorescence measurements where the plate data showed either clear or precipitated solutions being subjected to optimization screening. The results showed a ~83% increase in the number of crystallization conditions. The method was then tried as the sole screening method with a number of test proteins. In every case at least one or more crystallization conditions were found, and it is estimated that ~53% of these would not have been found using a plate screen. PMID- 21792346 TI - Moving on up: Second-Line Agents as Initial Treatment for Newly-Diagnosed Patients with Chronic Phase CML. AB - The treatment of chronic myelogenous leukemia (CML) was revolutionized by the development of imatinib mesylate, a small molecule inhibitor of several protein tyrosine kinases, including the ABL1 protein tyrosine kinase. The current second generation of FDA-approved ABL tyrosine kinase inhibitors, dasatinib and nilotinib, are more potent inhibitors of BCR-ABL1 kinase in vitro. Originally approved for the treatment of patients who were refractory to or intolerant of imatinib, dasatinib and nilotinib are now also FDA approved in the first-line setting. The choice of tyrosine kinase inhibitor (ie, standard or high dose imatinib, dasatinib, nilotinib) to use for initial therapy in chronic-phase CML (CML-CP) will not always be obvious. Therapy selection will depend on both clinical and molecular factors, which we will discuss in this review. PMID- 21792348 TI - Inadvertent Ingestion of a Press-Through Package Causing Perforation of the Small Intestine within an Incisional Hernia and Panperitonitis. AB - A 90-year-old woman was admitted to the emergency department of our hospital with abdominal pain and a fever of up to 39 degrees C. She had a history of hysterectomy about 30 years previously, and redness and swelling were seen at the abdominal median scar. Serum biochemistry showed minor elevation of C-reactive protein and creatine phosphokinase. Abdominal computed tomography (CT) showed an edematous intestinal tract image over the median abdominal wall. Incarcerated incisional hernia and intestinal necrosis were suspected. Therefore, emergency surgery was performed. On laparotomy, abundant purulent ascitic fluid was found. The small intestine was incarcerated about 100 cm orally from the terminal ileum, and a 2-mm perforation was present in the incarcerated small intestine. In addition, some white areas measuring 1 mm were found in the small intestinal wall. A press-through package (PTP) of a tablet was confirmed in the intestinal tract near the perforated area. We removed the PTP through the perforation and performed direct suture. Postoperatively, we retrospectively reviewed the CT image and found a high-density shadow which seemed to represent the PTP. PMID- 21792349 TI - Long-term survival of resected advanced gastric cancer with hepatic and pancreatic invasion. AB - A 64-year-old man was transferred to our division with a suspicion of gastric cancer. Computed tomography showed widespread irregular thickening of the stomach walls close to the liver and pancreas. Gastrointestinal fiberscopy showed a type 5 tumor in the upper to lower stomach, histologically diagnosed as tubular adenocarcinoma. Gastric cancer with hepatic and pancreatic invasion was diagnosed. Distant metastasis was not proven and complete resection was planned. At laparotomy, the tumor showed general expanding growth and invasion through the lateral segment of the liver and pancreas. Total gastrectomy and combined resection of the distal pancreas, spleen and left segment of the liver were performed. Hepatic and pancreatic invasion and lymph node metastasis were microscopically proven. Pancreatic fistula occurred postoperatively. On postoperative days 40, he was discharged. He received two cycles of adjuvant tegafur/gimeracil/oteracil chemotherapy. He has had no sign of recurrence for 7 years and 8 months. PMID- 21792350 TI - Refractory Hand Ulceration: A Case of Chronic Ulceration and Sporotrichoid Spread in a Fish Tank Hobbyist following Mycobacterium marinum Infection. AB - We report the case of a 35-year-old man with a chronic ulceration of the hand in whom an infection with Mycobacterium marinum was diagnosed. Clarithromycin and doxycycline were prescribed, resulting in a slow resolution of the ulceration. M. marinum is a nontuberculous mycobacterium that causes skin lesions such as nodules, ulcerations, and sporotrichoid spread, but may also be responsible for osteoarticular lesions. In this case report, we discuss the clinical characteristics of this condition, as well as its diagnostic methods and treatments. PMID- 21792351 TI - Linear Basal cell carcinoma: a case report. AB - Basal cell carcinoma (BCC) presents with diverse clinical features, and several morphologic and histologic variants of BCC have been reported [Sexton et al.: J Am Acad Dermatol 1990;23:1118-1126]. Linear BCC was first described as a new clinical subtype in 1985 by Lewis [Int J Dematol 1985;24:124-125]. Here, we present a case of linear BCC that we recently encountered in an elderly Japanese patient, and review other cases reported in Japan. PMID- 21792352 TI - Dynamic 'Spot Sign' Resolution following INR Correction in a Patient with Warfarin-Associated Intracerebral Hemorrhage. AB - Hematoma expansion in intracerebral hemorrhage is associated with poor clinical outcome. The 'spot sign' is a radiological marker that is associated with hematoma expansion, and thought to represent active extravasation of contrast. This case demonstrates the use of dynamic CT angiography in identifying the time dependent appearance of a spot sign in a patient with warfarin-associated intracerebral hemorrhage. Repeat imaging is also presented which verified cessation of the spot sign after INR correction. PMID- 21792353 TI - Alteration of the cardiac sympathetic innervation is modulated by duration of diabetes in female rats. AB - To evaluate the sympathetic innervation of the female diabetic heart, resting heart rate and sympathetic tone were assessed in vivo, and effect of tyramine on spontaneous beating rate, norepinephrine atrial concentrations, uptake, and release were determined in vitro in streptozotocin- (STZ-) treated rats and respective controls aged 3 months to 2 years. Resting bradycardia, decreased sympathetic tone, deceleration of spontaneous beating rate, and slightly declining carrier-mediated, but preserved exocytotic norepinephrine release from the atria were found in younger diabetic rats while the reactivity of the right atria to tyramine was not affected with age and disease duration. Diabetic two year-old animals displayed symptoms of partial spontaneous recovery including normoglycemia, increased plasma insulin concentrations, fully recovered sympathetic tone, but putative change, in releasable norepinephrine tissue stores. Our data suggested that female diabetic heart exposed to long-lasting diabetic conditions seems to be more resistant to alteration in sympathetic innervation than the male one. PMID- 21792354 TI - Transforaminal blood patch for the treatment of chronic headache from intracranial hypotension: a case report and review. AB - This case report describes the successful treatment of chronic headache from intracranial hypotension with bilateral transforaminal (TF) lumbar epidural blood patches (EBPs). The patient is a 65-year-old male with chronic postural headaches. He had not had a headache-free day in more than 13 years. Conservative treatment and several interlaminar epidural blood patches were previously unsuccessful. A transforaminal EBP was performed under fluoroscopic guidance. Resolution of the headache occurred within 5 minutes of the procedure. After three months without a headache the patient had a return of the postural headache. A second transforaminal EBP was performed again with almost immediate resolution. The patient remains headache-free almost six months from the time of first TF blood patch. This is the first published report of the use of transforaminal epidural blood patches for the successful treatment of a headache lasting longer than 3 months. PMID- 21792355 TI - Evaluation of handheld assays for the detection of ricin and staphylococcal enterotoxin B in disinfected waters. AB - Development of a rapid field test is needed capable of determining if field supplies of water are safe to drink by the warfighter during a military operation. The present study sought to assess the effectiveness of handheld assays (HHAs) in detecting ricin and Staphylococcal Enterotoxin B (SEB) in water. Performance of HHAs was evaluated in formulated tap water with and without chlorine, reverse osmosis water (RO) with chlorine, and RO with bromine. Each matrix was prepared, spiked with ricin or SEB at multiple concentrations, and then loaded onto HHAs. HHAs were allowed to develop and then read visually. Limits of detection (LOD) were determined for all HHAs in each water type. Both ricin and SEB were detected by HHAs in formulated tap water at or below the suggested health effect levels of 455 ng/mL and 4.55 ng/mL, respectively. However, in brominated or chlorinated waters, LODs for SEB increased to approximately 2,500 ng/mL. LODs for ricin increased in chlorinated water, but still remained below the suggested health effect level. In brominated water, the LOD for ricin increased to approximately 2,500 ng/mL. In conclusion, the HHAs tested were less effective at detecting ricin and SEB in disinfected water, as currently configured. PMID- 21792356 TI - Diagnosis of Single- or Multiple-Canal Benign Paroxysmal Positional Vertigo according to the Type of Nystagmus. AB - Benign paroxysmal positional vertigo (BPPV) is a common peripheral vestibular disorder encountered in primary care and specialist otolaryngology and neurology clinics. It is associated with a characteristic paroxysmal positional nystagmus, which can be elicited with specific diagnostic positional maneuvers, such as the Dix-Hallpike test and the supine roll test. Current clinical research focused on diagnosing and treating various types of BPPV, according to the semicircular canal involved and according to the implicated pathogenetic mechanism. Cases of multiple-canal BPPV have been specifically investigated because until recently these were resistant to treatment with standard canalith repositioning procedures. Probably, the most significant factor in diagnosis of the type of BPPV is observation of the provoked nystagmus, during the diagnostic positional maneuvers. We describe in detail the various types of nystagmus, according to the canals involved, which are the keypoint to accurate diagnosis. PMID- 21792357 TI - Askin's Tumor: A Dual Case Study. AB - Askin's tumor is a rare tumor arising from the chest wall. It is a subset of Ewing sarcoma characterized histologically by the presence of small round blue cells. It is a highly malignant tumor with guarded prognosis, which is dependent upon the extension of tumor at the time of diagnosis. A dual paper of Askin's tumors in young boys is being presented here. PMID- 21792358 TI - Using CO(2) to determine inhaled contaminant volumes and blower effectiveness in several types of respirators. AB - This experiment was conducted to determine how much contaminant could be expected to be inhaled when overbreathing several different types of respirators. These included several tight-fitting and loose-fitting powered air-purifying respirators (PAPRs) and one air-purifying respirator (APR). CO(2) was used as a tracer gas in the ambient air, and several loose-and tight-fitting respirators were tested on the head form of a breathing machine. CO(2) concentration in the exhaled breath was monitored as well as CO(2) concentration in the ambient air. This concentration ratio was able to give a measurement of protection factor, not for the respirator necessarily, but for the wearer. Flow rates in the filter/blower inlet and breathing machine outlet were also monitored, so blower effectiveness (defined as the blower contribution to inhaled air) could also be determined. Wearer protection factors were found to range from 1.1 for the Racal AirMate loose-fitting PAPR to infinity for the 3M Hood, 3M Breath-Easy PAPR, and SE 400 breath-responsive PAPR. Inhaled contaminant volumes depended on tidal volume but ranged from 2.02 L to 0 L for the same respirators, respectively. Blower effectiveness was about 1.0 for tight-fitting APRs, 0.18 for the Racal, and greater than 1.0 for two of the loose-fitting PAPRs. With blower effectiveness greater than 1.0, some blower flow during the exhalation phase contributes to the subsequent inhalation. Results from this experiment point to different ways to measure respirator efficacy. PMID- 21792359 TI - Antiatherogenic Potential of Nigella sativa Seeds and Oil in Diet-Induced Hypercholesterolemia in Rabbits. AB - Nigella sativa or Black seed (N. sativa L.) is traditionally used for several ailments in many Middle Eastern countries. It is an annual herbaceous plant that belongs to the Ranuculacea family with many beneficial properties as antitumor, antidiabetic, antihypertensive, antioxidative and antibacterial. This work attempted to study the effect of N. sativa seeds powder and oil on atherosclerosis in diet-induced hypercholesterolemic (HC) rabbits in comparison with simvastatin (ST). Twenty-five adult New Zealand male white rabbits, weighing 1.5-2.5 kg, were divided into five groups; normal group (NC, n = 5) and four hypercholesterolemic groups (n = 20): a positive control (PC) and three HC groups force fed diet supplemented with 1000 mg Kg(-1) body weight of N. sativa powder (NSP), 500 mg Kg(-1) body N. sativa oil (NSO) and 10 mg Kg(-1) ST for 8 weeks. Feeding HC rabbits with N. sativa either in powder or oil forms was shown to significantly reduce (P < .05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels and enhance high-density lipoprotein cholesterol (HDL) levels after treatment for 2, 4, 6 and 8 weeks compared to the PC group. Plaque formation was significantly inhibited while the intima: media ratio was significantly reduced in the NSP and NSO supplemented groups compared to the PC group. In conclusion, treatment of HC rabbits with N. sativa seeds powder or oil showed hypocholesterolemic and antiatherogenic cardioprotective properties. PMID- 21792360 TI - The roles of buyang huanwu decoction in anti-inflammation, antioxidation and regulation of lipid metabolism in rats with myocardial ischemia. AB - Buyang Huanwu Decoction (BYHWD) is a well-known Chinese medicine formula. Recent studies have reported that BYHWD can be used to treat ischemic heart disease. This study investigated the potential mechanism underlying the roles of BYHWD in alleviating the myocardial ischemia induced by isoproterenol (ISO) in rats. Different doses of BYHWD (25.68, 12.84 and 6.42 g kg(-1)) were lavaged to rats, respectively. Then the expression of the cluster of differentiation 40 (CD40) in the mononuclear cells was measured using flow cytometry, and the expressions of CD40 and its ligand (CD40L) in myocardial tissues were determined by western blotting. The serum biochemical values of superoxide dismutase (SOD) activity, the malondialdehyde (MDA) level and the free fatty acid (FFA) content were measured. The results showed that the SOD activities of BYHWD groups were significantly higher than that of the ISO group, while the MDA levels and FFA contents of all BYHWD groups were lower than that of the ISO group. BYHWD could decrease the expression of CD40 in the mononuclear cells and the CD40 and CD40L expressions in myocardial tissues. Our data suggest that the roles of BYHWD are not only related to its antioxidative action and regulation of lipid metabolisms, but also to the inhibition of inflammatory pathway by the decreased CD40 and CD40L expressions in rats with myocardial ischemia. PMID- 21792361 TI - Action mechanisms of du-huo-ji-sheng-tang on cartilage degradation in a rabbit model of osteoarthritis. AB - Du-Huo-Ji-Sheng-Tang (DHJST) is a traditional Chinese herbal medicine used to treat osteoarthritis. In the present study, the therapeutic effect of DHJST on cartilage degradation in a rabbit model of osteoarthritis was investigated. In the knee joints of rabbits, anterior cruciate ligament transection (ACLT) was performed to induce experimental osteoarthritis. At the end of the sixth week, 30 rabbits with ACLT were divided into six groups, control group, DHJST group and Osaminethacine (OSA) group, which were followed for another 4 weeks. The other three groups of rabbits with ACLT were untreated with DHJST or OSA, which were sacrificed after 6 weeks, and served as 6-week time point controls. Results indicated that at the end of the sixth week after surgery, there was a significantly histological degeneration in the control group compared with the normal group. In the control group, the mean score for histological degeneration were further increases at 10th week, and there was a significantly lower mean score for histological degeneration in the DHJST group compared with the control group. To research the potential mechanism, the expression level of VEGF and HIF 1alpha were detected. The expression of VEGF mRNA and HIF-1alpha mRNA are low in normal group, while the activities increase gradually in the control group. However, compared to that of the same time point model group, activity of VEGF and HIF-1alpha decreased significantly in DHJST group. In conclusion, DHJST exerts significant therapeutic effect on osteoarthritis rabbits, and mechanisms are associated with inhibition of VEGF and HIF-1alpha expression. PMID- 21792363 TI - Immunomodulatory Polysaccharide from Chlorophytum borivilianum Roots. AB - Chlorophytum borivilianum Santapau & Fernandes (Liliaceae) is an ayurvedic Rasayana herb with immunostimulating properties. The polysaccharide fraction (CBP) derived from hot water extraction of C. borivilianum (CB), comprising of ~31% inulin-type fructans and ~25% acetylated mannans (of hot water-soluble extract), was evaluated for its effect on natural killer (NK) cell activity (in vitro). Human peripheral blood mononuclear cells (PBMCs), isolated from whole blood on a Ficoll-Hypaque density gradient, were tested in the presence or absence of varying concentrations of each C. borivilianum fraction for modulation of NK cell cytotoxic activity toward K562 cells. Preliminary cytotoxicity evaluation against P388 cells was performed to establish non-cytotoxic concentrations of the different fractions. Testing showed the observed significant stimulation of NK cell activity to be due to the CBP of C. borivilianum. Furthermore, in vivo evaluation carried out on Wistar strain albino rats for humoral response to sheep red blood cells (SRBCs) and immunoglobulin level determination using enzyme-linked immunosorbent assay (ELISA), exhibited an effectiveness of C. borivilianum aqueous extract in improving immune function. Present results provide useful information for understanding the role of CBP in modulating immune function. PMID- 21792364 TI - Antioxidant and Anti-Cancer Potentials of Rheum emodi Rhizome Extracts. AB - The objective of this study was to determine antioxidant and cytotoxic efficacies of methanolic and aqueous extracts of Rheum emodi Wall. ex Meissn. rhizome. 2,2 Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities, inhibitory effect on lipid peroxidation and Fe(3+) reducing antioxidant property have been used to investigate antioxidant properties of the extracts. Cytotoxicity of the extracts was tested on MDA-MB-435S and Hep3B cell lines. Both extracts displayed extensive cytotoxicity to the tested cell lines. The extracts were studied for their ability to protect pBR322 DNA from damage by UV induced photolysis of H(2)O(2). The aqueous extract, though inferior to methanolic extract in its antioxidant potential exhibited efficiency in DNA protection, while the methanolic extract failed to protect the DNA. The amount of total polyphenolics in the extracts was measured by spectrophotometric method. The methanolic extract contained higher polyphenolic contents than aqueous extract. Significant positive correlations were observed (P < .05) between results of phenolic content estimation and that of antioxidant assays. Hence, high performance liquid chromatography analysis was performed to identify few major phenolic compounds that might be responsible for these therapeutic properties. These results indicate that rhizome of R. emodi possesses antioxidant and cytotoxic activities and therefore have therapeutic potential. PMID- 21792362 TI - Quercetin and cancer chemoprevention. AB - Several molecules present in the diet, including flavonoids, can inhibit the growth of cancer cells with an ability to act as "chemopreventers". Their cancer preventive effects have been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. The antioxidant activity of chemopreventers has recently received a great interest, essentially because oxidative stress participates in the initiation and progression of different pathological conditions, including cancer. Since antioxidants are capable of preventing oxidative damage, the wide use of natural food-derived antioxidants is receiving greater attention as potential anti-carcinogens. Among flavonoids, quercetin (Qu) is considered an excellent free-radical scavenging antioxidant, even if such an activity strongly depends on the intracellular availability of reduced glutathione. Apart from antioxidant activity, Qu also exerts a direct, pro-apoptotic effect in tumor cells, and can indeed block the growth of several human cancer cell lines at different phases of the cell cycle. Both these effects have been documented in a wide variety of cellular models as well as in animal models. The high toxicity exerted by Qu on cancer cells perfectly matches with the almost total absence of any damages for normal, non-transformed cells. In this review we discuss the molecular mechanisms that are based on the biological effects of Qu, and their relevance for human health. PMID- 21792365 TI - Pharmacodynamic and Pharmacokinetic Interactions of Propranolol with Garlic (Allium sativum) in Rats. AB - Garlic preparations and propranolol (PRO) are agents recognized as cardioprotective and potent antihypertensive agents when they are used individually. However, there is no report available to explain the role of combined therapy during simultaneous hypertension and myocardial damage in rats. We aimed to determine the pharmacokinetic and pharmacodynamic interaction of PRO with garlic homogenate (GH), in rats. The influence of garlic on pharmacokinetics of PRO was determined by HPLC method; while pharmacodynamic interaction was studied in animals with hypertension (10% fructose) and myocardial damage (isoproterenol, 175 mg kg(-1), s.c. 2 days). PRO was given orally at 10 mg kg(-1) for 1 week, whereas, GH was administered at three different doses of 125, 250 and 500 mg kg(-1), p.o. in their respective groups during fourth to sixth week of high fructose (HF) period, once daily. Systolic blood pressure (SBP), heart rate, cholesterol, triglycerides, glucose, creatine phosphokinase-MB, lactate dehydrogenase, superoxide dismutase and catalase were measured and histopathological studies were carried out. The bioavailability and half life of PRO were significantly enhanced by 2- and 3-fold, respectively, in animals pretreated with garlic (250 mg kg(-1)). Administration of PRO and low to moderate doses of GH (125, 250 mg kg(-1)), either alone or together showed fall in fluid intake and body weight. The combined therapy of GH 250 mg kg(-1) and PRO was found to be most effective in reducing SBP, cholesterol, triglycerides and glucose. These observations suggest that careful addition of garlic in moderate doses in PRO regimen might result in beneficial effect during treatment of hypertensive animals with myocardial damage. PMID- 21792366 TI - Garlic Oil Alleviates MAPKs- and IL-6-mediated Diabetes-related Cardiac Hypertrophy in STZ-induced DM Rats. AB - Garlic oil has been reported to protect the cardiovascular system; however, the effects and mechanisms behind the cardioprotection of garlic oil on diabetes induced cardiaomyopathy are unclear. In this study, we used streptozotocin (STZ) induced diabetic rats to investigate whether garlic oil could protect the heart from diabetes-induced cardiomyopathy. Wistar STZ-induced diabetic rats received garlic oil (0, 10, 50 or 100 mg kg(_1) body weight) by gastric gavage every 2 days for 16 days. Normal rats without diabetes were used as control. Cardiac contractile dysfunction and cardiac pathologic hypertrophy responses were observed in diabetic rat hearts. Cardiac function was examined using echocardiography. In addition to cardiac hypertrophy-related mitogen-activated protein kinases (MAPK) pathways (e.g., p38, c-Jun N-terminal kinases (JNK) and extracellularly responsive kinase (ERK1/2)), the IL-6/MEK5/ERK5 signaling pathway was greatly activated in the diabetic rat hearts, which contributes to the up regulation of cardiac pathologic hypertrophy markers including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), and leads to cardiac contractile dysfunction. Garlic oil treatment significantly inhibited the up regulation in MAPK (e.g., p38, JNK and ERK1/2) and IL-6/MEK5/ERK5 signaling pathways in the diabetic rat hearts, reducing the levels of cardiac pathologic hypertrophy markers such as ANP and BNP, and improving the cardiac contractile function. Collectively, data from these studies demonstrate that garlic oil shows the potential cardioprotective effects for protecting heart from diabetic cardiomyopathy. PMID- 21792367 TI - Anti-Cancer Effects of Protein Extracts from Calvatia lilacina, Pleurotus ostreatus and Volvariella volvacea. AB - Calvatia lilacina (CL), Pleurotus ostreatus (PO) and Volvariella volvacea (VV) are widely distributed worldwide and commonly eaten as mushrooms. In this study, cell viabilities were evaluated for a human colorectal adenocarcinoma cell line (SW480 cells) and a human monocytic leukemia cell line (THP-1 cells). Apoptotic mechanisms induced by the protein extracts of PO and VV were evaluated for SW480 cells. The viabilities of THP-1 and SW480 cells decreased in a concentration dependent manner after 24 h of treatment with the protein extracts of CL, PO or VV. Apoptosis analysis revealed that the percentage of SW480 cells in the SubG(1) phase (a marker of apoptosis) was increased upon PO and VV protein-extract treatments, indicating that oligonucleosomal DNA fragmentation existed concomitantly with cellular death. The PO and VV protein extracts induced reactive oxygen species (ROS) production, glutathione (GSH) depletion and mitochondrial transmembrane potential (DeltaPsi(m)) loss in SW480 cells. Pretreatment with N-acetylcysteine, GSH or cyclosporine A partially prevented the apoptosis induced by PO protein extracts, but not that induced by VV extracts, in SW480 cells. The protein extracts of CL, PO and VV exhibited therapeutic efficacy against human colorectal adenocarcinoma cells and human monocytic leukemia cells. The PO protein extracts induced apoptosis in SW480 cells partially through ROS production, GSH depletion and mitochondrial dysfunction. Therefore, the protein extracts of these mushrooms could be considered an important source of new anti cancer drugs. PMID- 21792368 TI - Coprescription of Chinese Herbal Medicine and Western Medications among Prostate Cancer Patients: A Population-Based Study in Taiwan. AB - Use of herbal medicine is popular among cancer patients. This study aimed to explore the coprescription of CHM and WM among prostate cancer patients in Taiwan. This cross-sectional retrospective study used a population-based database containing one million beneficiaries of National Health Insurance. Claims and prescriptions were analyzed. In 2007, 218 (22.4%) prostate cancer patients were CHM users. Among CHM users, 200 (91.7%) patients with 5618 (79.5%) CHM prescriptions were on coprescription of CHM and WM. A total of 484 types of CHM and 930 types of WM were used. The most commonly used CHMs on coprescription were Shu Jing Huo Xue Tang, Ma Zi Ren Wan, and Xue Fu Zhu Yu Tang. The most commonly used WMs on coprescription were magnesium oxide, amlodipine, and aspirin. The average number of prescriptions per user per year was 261.2 versus 151.7 in all (P < 0.001), 123.6 versus 76.9 in WM (P = 0.033), and 34.8 versus 5.1 in CHM (P < 0.001) for patients with and without coprescription, respectively. In conclusion, use of CHM among prostate cancer patients was popular in Taiwan. Most CHMs were used with WM concurrently. The potential drug-herb interactions should be investigated, especially for patients with more prescriptions. PMID- 21792369 TI - Effective Control of Postprandial Glucose Level through Inhibition of Intestinal Alpha Glucosidase by Cymbopogon martinii (Roxb.). AB - Inhibition of intestinal alpha glucosidase plays a major role in preventing rise in postprandial glucose level in diabetics. Cymbopogon martinii (CM) (family Poaceae) is used in traditional Indian medicine in treatment of diabetes mellitus. The alpha glucosidase inhibitory action of the plant is studied. The active component was separated using hot water extraction of the whole plant powder, differential solvent extraction, and silica gel column chromatography. The 30 : 70 toluene : ethyl acetate fraction showed optimum activity. The silica gel chromatography fraction demonstrated 98, 98, and 68% inhibition for starch, maltose, and sucrose, respectively, at 5 mg/kg body weight of rats. Intestinal absorption studies using noneverted intestinal sacs, as well as in vivo studies in streptozotocin-induced diabetic rats using oral glucose tolerance with maltose and sucrose load, revealed better inhibition of alpha glucosidase as compared to acarbose. Kinetic studies using Lineweaver Burk plot showed mixed to noncompetitive type of inhibition by CM. In vivo studies with maltose load of 2 mg and 3 mg/gm body weight showed a noncompetitive pattern of inhibition at 5 mg/kg body weight of CM as against 60 mg/kg body weight of acarbose. Thus CM is more effective alpha glucosidase inhibitor and at lower concentration than acarbose. PMID- 21792370 TI - Effectiveness of core stability exercises and recovery myofascial release massage on fatigue in breast cancer survivors: a randomized controlled clinical trial. AB - The purpose of the present paper was to evaluate the effects of an 8-week multimodal program focused on core stability exercises and recovery massage with DVD support for a 6-month period in physical and psychological outcomes in breast cancer survivors. A randomized controlled clinical trial was performed. Seventy eight (n = 78) breast cancer survivors were assigned to experimental (core stability exercises plus massage-myofascial release) and control (usual health care) groups. The intervention period was 8 weeks. Mood state, fatigue, trunk curl endurance, and leg strength were determined at baseline, after the last treatment session, and at 6 months of followup. Immediately after treatment and at 6 months, fatigue, mood state, trunk curl endurance, and leg strength exhibited greater improvement within the experimental group compared to placebo group. This paper showed that a multimodal program focused on core stability exercises and massage reduced fatigue, tension, depression, and improved vigor and muscle strength after intervention and 6 months after discharge. PMID- 21792371 TI - A review focused on the psychological effectiveness of tai chi on different populations. AB - As a popular exercise form, Tai Chi (TC) has been investigated to determine its contributions to an active and healthy lifestyle. There are an increasing number of researchers who focus on exploring the potential physiological and psychological benefits of TC but only a few systematic reviews of these benefits to a variety of populations. The purpose of this paper is to comprehensively evaluate the reported psychological benefits associated with practicing TC. Although many investigators have reported possible psychological benefits of TC for children, young adults, older healthy adults, and for a variety of patient populations, many of the reports suffer one or more methodological flaws. These flaws include inadequate study design, including lack of control groups, small sample sizes, unsophisticated statistical techniques, or publication without rigorous peer review. After reviewing the results of the existing literature regarding the potential psychological benefits of TC, we recommend that future investigations be conducted with additional adherence to the traditional scientific process. PMID- 21792372 TI - Cognitive-enhancing effect of quercetin in a rat model of Parkinson's disease induced by 6-hydroxydopamine. AB - Oxidative stress has been reported to induce cognitive impairment in Parkinson's disease. This paper aimed to determine the effect of quercetin, a substance possessing antioxidant activity, on the cognitive function in a rat model of Parkinson's disease. Male Wistar rats, weighing 200-250 g, were orally given quercetin at doses of 100, 200, 300 mg/kg BW once daily for a period of 14 days before and 14 days after the unilateral lesion of right substantia nigra induced by 6-hydroxydopamine (6-OHDA). Their spatial memory was assessed at 7 and 14 days of treatment and neuron density was determined, malondialdehyde (MDA) level, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were evaluated at the end of the experiment. In addition, the activity of acetylcholinesterase (AChE) was also measured. It was found that all doses of quercetin enhanced spatial memory. Therefore, it is suggested that the cognitive-enhancing effect of quercetin occurs partly because of decreased oxidative damage resulting in increased neuron density. PMID- 21792373 TI - A comparison of the effectiveness of problem solving training and of cognitive emotional rehabilitation on neurocognition, social cognition and social functioning in people with schizophrenia. AB - OBJECTIVE: Social cognition and Problem Solving (PS) impairments are common characteristics in patients with schizophrenia. Experimental neuropsychological findings support the hypothesis that schizophrenia is characterized by a broad range of heterogeneous cognitive impairments. Since that time Problem Solving Training has been employed as a core strategy in a wide variety of therapeutic settings. Renewed interest in cognitive functioning, including social Problem Solving skills and social cognition in schizophrenia, has led us to reconsider the potential value of metacognitive strategy as a rehabilitation strategy. METHODS: The present study reports the results obtained by 24 persons with schizophrenia who were randomly assigned to one of two training session groups: Cognitive-Emotional Rehabilitation (REC) vs Problem Solving Training (PST). Both treatments were administered to small groups composed of subjects suffering from schizophrenic disorders over a 12 months period: primary measures of clinical, social outcomes and secondary measures of cognitive and Problem Solving functions were conducted at 0, and 12 months. RESULTS: Results showed that both training methods were found to be effective in psychopathological measures and in social functioning. On cognitive function improvements were specific to the rehabilitative approach. PST are mainly improved capacities for planning and memory, while the REC improved measures such as social cognition Theory of mind and emotion recognition. CONCLUSION: The results confirmed that it is no necessary to divide the rehabilitation training in treatments directed to specific domains. The conceptualization and applicability of PST and REC its implications for persons with schizophrenia, and future studies in this research area have also been discussed. PMID- 21792374 TI - Sublethal transient global ischemia stimulates migration of neuroblasts and neurogenesis in mice. AB - Increasing evidence has shown the potential of neuronal plasticity in adult brain after injury. Neural proliferation can be triggered by a focal sublethal ischemic preconditioning event; whether mild global ischemia could cause neurogenesis has been not clear. The present study investigated stimulating effects of sublethal transient global ischemia (TGI) on endogenous neurogenesis and neuroblast migration in the subventricular zone (SVZ), dentate gyrus, and peri-infarct areas of the adult cortex. Adult mice of 129S2/Sv strain were subjected to 8-min bilateral common carotid artery ligation followed by 5-bromo-2'-deoxyuridine (BrdU; 50 mg/kg, intraperitoneal) administration every day until being sacrificed at 1-21 days after reperfusion. The mild TGI did not induce neuronal cell death for up to 7 days after TGI, as evidenced by negative terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining among NeuN-positive cells in the hippocampus and neocortex. In TGI animals, BrdU staining revealed enhanced proliferation of neuroblasts and their migration track from the SVZ into the striatum and neocortex. In the corpus callosum, there were more BrdU-positive cells in the TGI group in the first 2 days. Increasing numbers of BrdU-positive cells were seen 7-21 days later in the striatum and cortex of TGI mice. The cortex of TGI animals showed increased expression of erythropoietin, erythropoietin receptor, fibroblast growth factor 2, vascular endothelial growth factor, and phosphorylated Jun N-terminal kinase; the expression was peaked 2 to 3 days after reperfusion. BrdU and NeuN double staining in the dentate gyrus, striatum, and cortex implied increased neurogenesis induced by the TGI preconditioning. Doublecortin (DCX)-positive cells increased in the cortex of TGI mice, localized to cortical layers II, III, and V, and many stained positive for the mature neuronal markers NeuN, neurofilament, N-methyl-d-aspartic acid receptor subunit gene NR1, or the gamma-aminobutyric-acid-synthesizing enzyme glutamic acid decarboxylase (GAD67). The atypical localization of DCX-positive cells and the colabeling with mature neuronal markers suggested that, in addition to indentifying migrating neuroblasts, DCX might also be a stress marker in the cortex. It is suggested that the sublethal TGI-induced regenerative responses may contribute to the beneficial effects of ischemic preconditioning. PMID- 21792375 TI - Thalidomide Analogues Suppress Lipopolysaccharide-Induced Synthesis of TNF-alpha and Nitrite, an Intermediate of Nitric Oxide, in a Cellular Model of Inflammation. AB - An unregulated neuroinflammation accompanies numerous chronic and acute neurodegenerative disorders and it is postulated that such a neuroinflammatory component likely exacerbates disease progression. A key player in brain inflammation is the microglial cell; a vital soluble factor synthesized by activated microglial cells is the key cytokine, tumor necrosis factor-alpha (TNF alpha). Additionally, microglial cells release IL-1alpha/beta, reactive oxygen species (ROS), such as superoxide (O(2) (-)) and reactive nitrogen species (RNS) like nitric oxide (NO). Nitric oxide reactive oxygen species can undergo various forms of interactions in cells whereby the synthesis of RNS / ROS intermediates are generated that can damage cell membranes. The presence of oxidative damaged cells is implicated with the abnormal cellular activity in brain or in the spinal cord, and is a classical feature of neurodegenerative disorders. To aid characterize this process, a quantitative analysis of nitrite generation was undertaken on agents developed to lower TNF-alpha levels in cell culture. Nitrite is a stable end product of nitric oxide metabolism and, thereby, acts as a surrogate measure of the highly unstable nitric oxide. Utilizing a RAW 264.7 cellular model of lipopolysaccharide-induced inflammation that induces high levels of TNF-alpha protein accompanied by a robust generation of nitrite, the properties of a series of thalidomide-based TNF-alpha synthesis inhibitors were evaluated to reduce the levels of both. Specific analogues of thalidomide effectively suppressed the generation of both TNF-alpha and nitrite at well tolerated doses. PMID- 21792377 TI - Post-traumatic Stress Disorder and Cardiovascular Disease. AB - This review provides an up-to-date summary of the evidence from clinical and epidemiologic studies indicating that persons with post-traumatic stress disorder (PTSD) may have an increased risk of coronary heart disease and possibly thromboembolic stroke. Persons with PTSD, a common anxiety disorder in both veteran and nonveteran populations, have been reported to have an increased risk of hypertension, hyperlipidemia, obesity, and cardiovascular disease. Increased activity of the sympathoadrenal axis may contribute to cardiovascular disease through the effects of catecholamines on the heart, vasculature, and platelet function. Reported links between PTSD and hypertension and other cardiovascular risk factors may partly account for reported associations between PTSD and heart disease. The associations observed between PTSD and cardiovascular diseases have implications for cardiology practice and research. PMID- 21792378 TI - Escherichia coli-Related Diseases in Latin America Remain in the Spotlight: the Brazilian Efforts to Understand E. coli Pathogenesis. PMID- 21792376 TI - Regulation of Inducible Nitric Oxide Synthase (iNOS) and its Potential Role in Insulin Resistance, Diabetes and Heart Failure. AB - Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a reactive oxygen species as well as a reactive nitrogen species. It is a free radical which mediates several biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are regulated and extend to almost every cell type and function within the circulation. In mammals 3 distinct isoforms of NOS have been identified: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The important isoform in the regulation of insulin resistance (IR) is iNOS. Understanding the molecular mechanisms regulating the iNOS pathway in normal and hyperglycemic conditions would help to explain some of vascular abnormalities observed in type 2 diabetes mellitus (T2DM). Previous studies have reported increased myocardial iNOS activity and expression in heart failure (HF). This review considers the recent animal studies which focus on the understanding of regulation of iNOS activity/expression and the role of iNOS agonists as potential therapeutic agents in treatment of IR, T2DM and HF. PMID- 21792379 TI - Distinct Interaction of Two Atypical Enteropathogenic Escherichia coli Strains with Enterocytes In Vitro. AB - Typical and atypical Enteropathogenic Escherichia coli (EPEC) promote attaching effacing lesions in intestinal cells but only typical EPEC carry the EPEC adherence factor plasmid. Atypical EPEC (aEPEC) are emerging agents of acute and persistent diarrhea worldwide. We aimed at comparing the ability of two aEPEC strains, 1711-4 (serotype O51:H40) and 3991-1 (serotype O non-typeable:non motile) to invade, persist inside Caco-2 and T84 cells, and to induce IL-8 production. Typical EPEC strain E2348/69 was used for comparisons. The strains associated more significantly with T84 than with Caco-2 cells, with 3991-1 being the most adherent (P < 0.001). In contrast, aEPEC 1711-4 was significantly more invasive than the other strains in both cell lines, and was found within vacuoles near the basolateral cell surfaces. Strains persisted within both cell lines for at least 48 hours, but the persistence index was higher for 3991-1 in Caco-2 cells. IL-8 production was significantly higher from Caco-2 cells infected with 1711-4 for at least 48 hours (P < 0.001), and from T84 cells after 24 and 48 h than with the other strains (P = 0.001). We demonstrated that aEPEC are heterogeneous in various aspects of their interaction with enterocytes in vitro. PMID- 21792380 TI - Presence of a Human Diarrheagenic Escherichia coli Clone in Captivity Kept Psittacidaes. AB - Bacterial cultures of cloaca swabs from 86 captivity kept psittacidaes revealed 17 Escherichia coli bearing birds sharing strains which, on the basis of enterobacterial repetitive intergenic consensus (ERIC) PCR analysis, proved to be genetically similar. Further, triplex PCR specific for the genetic markers chuA, yjaA, and TSPE4.C2 was used to assign the strains to the E. coli reference collection (EcoR) B2 group. One strain of each, from the enteropathogenic (EPEC), enteroaggregative (EAEC) and Shiga toxin (STEC) E. coli pathovars were found among these isolates. PMID- 21792381 TI - Large diameter femoral heads impose significant alterations on the strains developed on femoral component and bone: a finite element analysis. AB - Total Hip Arthroplasty aims at fully recreating a functional hip joint. Over the past years modular implant systems have become common practice and are widely used, due to the surgical options they provide. In addition Big Femoral Heads have also been implemented in the process, providing more flexibility for the surgeon. The current study aims at investigating the effects that femoral heads of bigger diameter may impose on the mechanical behavior of the bone-implant assembly. Using data acquired by Computed Tomographies and a Coordinate Measurement Machine, a cadaveric femur and a Profemur-E modular stem were fully digitized, leading to a three dimensional finite element model in ANSYS Workbench. Strains and stresses were then calculated, focusing on areas of clinical interest, based on Gruen zones: the calcar and the corresponding below the greater trochanter area in the proximal femur, the stem tip region and a profile line along linea aspera. The performed finite elements analysis revealed that the use of large diameter heads produces significant changes in strain development within the bone volume, especially in the lateral side. The application of Frost's law in bone remodeling, validated the hypothesis that for all diameters normal bone growth occurs. However, in the calcar area lower strain values were recorded, when comparing with the reference model featuring a 28mm femoral head. Along line aspera and for the stem tip area, higher values were recorded. Finally, stresses calculated on the modular neck revealed increased values, but without reaching the yield strength of the titanium alloy used. PMID- 21792382 TI - Genetic Characterization of HIV-1 Strains Among the Injecting Drug Users in Nagaland, India. AB - Global HIV-1 surveillance has led to the detection of its new recombinant forms. This study was carried out for the first time to elucidate the genetic characterization and evolutionary relationship of HIV-1 strains among injecting drug users of Nagaland, northeastern India. A total of 156 injecting drug users participated in this study voluntarily. Among them 18 were seropositive for HIV-1 (11.5%).The Heteroduplex Mobility Assay (HMA) of HIV-1 based on p24-p7 region of gag gene and C2-V3 region of env gene revealed 11 samples to be subtype C (gag/env), 1 sample as subtype B (gag/env) and 6 samples to be recombinants between subtype C and B. Also, the sequencing and phylogenetic analysis of gag (p24-p7) and env (C2-V3) genes from eighteen samples of Nagaland IDUs with different global HIV-1 strains showed the presence of Indian, African, Thai and their recombinant forms. However, more recombinant strains based on different genomic regions of HIV-1 were detected using Multiregional Hybridization Assay (MHA) where 8 out of 18 samples were found to be recombinants between subtype C and B. Thus, multiregional hybridization assay along with heteroduplex mobility assay can serve as an efficient tool in the characterization of recombination pattern among the newly emerging HIV-1 recombinants. PMID- 21792383 TI - Spectral pattern analysis of propofol induced spindle oscillations in the presence of auditory stimulations. AB - This study's primary objective is to analyze human EEG spindle oscillations during propofol-induced anesthesia and to address possible activation sources. Such an analysis also has a secondary role of investigating the short- term spectral patterns and their functional role.Artifact-free epochs of spindle activations were selected from the electroencephalograms of patients undergoing propofol anesthesia. Power spectral analysis and source localization using standardized low-resolution-brain-electromagnetic-tomography (sLORETA) were performed. Additionally, spectrograms were obtained by means of using the Complex Morlet-based algorithm. In order to highlight the functional properties, auditory stimulations were conducted during the propofol administration. The loss of consciousness was reached at a level of 0.8-1.2 ug/mL, which also provided distinct spindle oscillations in the continuous EEG. The un-evoked (spontaneous) and evoked (auditory) conditions were examined across non-medicated and medicated conditions (propofol). The propofol administration resulted in appearance of 12 14 Hz spindle activity mostly localized in BA6, BA9, BA10, BA21, BA24 and BA37 areas. The presence of auditory stimulations slightly shifted these maximum activities to different locations. Between the medicated and non-medicated conditions, there was a significant reduction of spindle activity, which was pinpointed to BA7 (precuneus area). The findings indicate that spindle oscillations may have a dual nature. That is, spindle oscillations may be activity dependent and disruptive for large-scale information processing networks in the brain. Hence, the study of spindle oscillation may provide a basis for understanding the short-term spectral patterns of human EEG. PMID- 21792384 TI - Impact of HIV/AIDS on Social Relationships in Rural China. AB - Social support promotes greater medical compliance, better immune system functioning and slows the progress of HIV/AIDS. One in every 50 People Living With HIV/AIDS (PLWHA) is Chinese, yet little is known about the impact of HIV/AIDS on social relationships in China. This study compares the characteristics of those who report that HIV/AIDS had a substantial impact versus a modest impact on their social relationships. We obtained data from a survey of 866 PLWHA in rural China, which was conducted in 2006-2007 in the three Chinese provinces with the highest prevalence of HIV/AIDS. Chi-square test and multiple logistic regression were performed. The analysis shows that PLWHA who had full blown AIDS (OR= 1.53; 95% CI=1.09-2.13) and those who were poor (OR=2.19; 95% CI=1.52-3.16) reported greater impact on their social relationships. The results lay a solid foundation for designing effective policy initiatives and intervention programs aimed at alleviating the impact of HIV/AIDS on social relationships and improving the quality of life of PLWHA. PMID- 21792385 TI - Curvature-induced dielectrophoresis for continuous separation of particles by charge in spiral microchannels. AB - The separation of particles from a heterogeneous mixture is critical in chemical and biological analyses. Many methods have been developed to separate particles in microfluidic devices. However, the majority of these separations have been limited to be size based and binary. We demonstrate herein a continuous dc electric field driven separation of carboxyl-coated and noncoated 10 MUm polystyrene beads by charge in a double-spiral microchannel. This method exploits the inherent electric field gradients formed within the channel turns to manipulate particles by dielectrophoresis and is thus termed curvature-induced dielectrophoresis. The spiral microchannel is also demonstrated to continuously sort noncoated 5 MUm beads, noncoated 10 MUm beads, and carboxyl-coated 10 MUm beads into different collecting wells by charge and size simultaneously. The observed particle separation processes in different situations are all predicted with reasonable agreements by a numerical model. This curvature-induced dielectrophoresis technique eliminates the in-channel microelectrodes and obstacles that are required in traditional electrode- and insulator-based dielectrophoresis devices. It may potentially be used to separate multiple particle targets by intrinsic properties for lab-on-a-chip applications. PMID- 21792387 TI - Ability of different measures of adiposity to identify high metabolic risk in adolescents. AB - Introduction. This study aimed to evaluate the screening performance of different measures of adiposity: body mass index (BMI), waist circumference (WC), and waist to-height ratio (WHtR) for high metabolic risk in a sample of adolescents. Methods. A cross-sectional school-based study was conducted on 517 adolescents aged 15-18, from the Azorean Islands, Portugal. We measured fasting glucose, insulin, total cholesterol (TC), HDL-cholesterol, triglycerides, and systolic blood pressure. HOMA and TC/HDL-C ratio were calculated. For each of these variables, a Z-score was computed by age and sex. A metabolic risk score (MRS) was constructed by summing the Z-scores of all individual risk factors. High risk was considered when the individual had >=1SD of this score. Receiver-operating characteristics (ROC) were used. Results. Linear regression analyses showed that, after adjusting for age and pubertal stage, all different measures of adiposity are positively and significantly associated with MRS in both sexes, with exception of WHtR for boys. BMI, WC, and WHtR performed well in detecting high MRS, indicated by areas under the curve (AUC), with slightly greater AUC for BMI than for WC and WHtR in both sexes. Conclusion. All measures of adiposity were significantly associated with metabolic risk factors in a sample of Portuguese adolescents. PMID- 21792386 TI - Inflammatory regulation of valvular remodeling: the good(?), the bad, and the ugly. AB - Heart valve disease is unique in that it affects both the very young and very old, and does not discriminate by financial affluence, social stratus, or global location. Research over the past decade has transformed our understanding of heart valve cell biology, yet still more remains unclear regarding how these cells respond and adapt to their local microenvironment. Recent studies have identified inflammatory signaling at nearly every point in the life cycle of heart valves, yet its role at each stage is unclear. While the vast majority of evidence points to inflammation as mediating pathological valve remodeling and eventual destruction, some studies suggest inflammation may provide key signals guiding transient adaptive remodeling. Though the mechanisms are far from clear, inflammatory signaling may be a previously unrecognized ally in the quest for controlled rapid tissue remodeling, a key requirement for regenerative medicine approaches for heart valve disease. This paper summarizes the current state of knowledge regarding inflammatory mediation of heart valve remodeling and suggests key questions moving forward. PMID- 21792388 TI - The impact of fructose on renal function and blood pressure. AB - Fructose is a sugar present in sucrose, high-fructose corn syrup, honey, and fruits. Fructose intake has increased markedly in the last two centuries, primarily due to increased intake of added sugars. Increasing evidence suggests that the excessive intake of fructose may induce fatty liver, insulin resistance, dyslipidemia, hypertension, and kidney disease. These studies suggest that excessive intake of fructose might have an etiologic role in the epidemic of obesity, diabetes, and cardiorenal disease. PMID- 21792389 TI - Metformin-associated acute kidney injury and lactic acidosis. AB - Objectives. Metformin is the preferred oral antidiabetic agent for type 2 diabetes. Lactic acidosis is described as a rare complication, usually during an acute kidney injury (AKI). Material and Methods. We conducted a prospective observational study of metformin-associated AKI cases during four years. 29 cases were identified. Previous renal function, clinical data, and outcomes were recorded. Results. An episode of acute gastroenteritis precipitated the event in 26 cases. Three developed a septic shock. Three patients died, the only related factor being liver dysfunction. More severe metabolic acidosis hyperkalemia and anemia were associated with higher probabilities of RRT requirement. We could not find any relationship between previous renal dysfunction and the outcome of the AKI. Conclusions. AKI associated to an episode of volume depletion due to gastrointestinal losses is a serious complication in type 2 diabetic patients on metformin. Previous renal dysfunction (mild-to-moderate CKD) has no influence on the severity or outcome. PMID- 21792390 TI - Examining the Racial Crossover in Mortality between African American and White Older Adults: A Multilevel Survival Analysis of Race, Individual Socioeconomic Status, and Neighborhood Socioeconomic Context. AB - We examine whether individual and neighborhood socioeconomic context contributes to black/white disparities in mortality among USA older adults. Using national longitudinal data from the Americans' Changing Lives study, along with census tract information for each respondent, we conduct multilevel survival analyses. Results show that black older adults are disadvantaged in mortality in younger old age, but older black adults have lower mortality risk than whites after about age 80. Both individual SES and neighborhood socioeconomic disadvantage contribute to the mortality risk of older adults but do not completely explain race differences in mortality. The racial mortality crossover persists even after controlling for multilevel SES, suggesting that black older adults experience selective survival at very old ages. Addressing the individual and neighborhood socioeconomic disadvantage of blacks is necessary to reduce mortality disparities that culminate in older adulthood. PMID- 21792391 TI - Comparing the Support-Efficacy Model among Centenarians Living in Private Homes, Assisted Living Facilities, and Nursing Homes. AB - We investigated the influence of social relations on health outcomes in very late life by examining the support-efficacy convoy model among older adults who resided in three different residential environments (centenarians in private homes, n = 126; centenarians in assisted living facilities, n = 55; centenarians in nursing homes, n = 105). For each group, path analytic models were employed to test our hypotheses; analyses controlled for sex, mental status, education, perceived economic sufficiency, and activities of daily living. The hypothesized relationships among the models' variables were unique to each of the three groups; three different models fit the data depending upon residential environment. The direct and indirect effects of social relations assessments were positive for the mental and physical health of very old adults, suggesting that participants welcomed the support. However, residential status moderated the associations between the assessments of social relations, self-efficacy, and both outcomes, physical and mental health. PMID- 21792392 TI - Modus operandi of controlled release from mesoporous matrices: a theoretical perspective. AB - The ability to alter the rate at which molecules are released from pores by manipulating structural and surface properties of mesoporous materials was demonstrated consistently in numerous studies. Yet an understanding of the role of pore size, attraction to pore walls and of the release mechanism in general has still been elusive. Here we address these issues by means of a simple 2 dimensional (2D) model of ordered porous matrices with various pore sizes and strengths of molecule-wall attractions. The system dynamics are described with a 2D Fokker-Planck equation which is solved numerically for various cases of initial concentration distribution. We show that the interactions with walls play an essential and fundamental role in controlled release from mesoporous materials, regardless of whether they are additionally functionalized or not. They affect the relative cross-section where the local flux has a non-vanishing axial component and accordingly the effective transfer rate into bulk solution. Furthermore the inclusion of molecule-wall attractions into the theoretical description turns out to be the missing piece of the puzzle that explains the origin of the experimentally observed dependence of release kinetics on the pore size. Our results enable us to reinterpret existing experimental findings and provide a revised view of the mechanism of controlled release from ordered porous matrices. PMID- 21792393 TI - Characterization of reaction intermediates by ion spectroscopy. AB - In the last decade, we have experienced massive progress in spectroscopic methods for mass-selected ions. The aim of this tutorial review is to present action spectroscopy as a powerful tool for the investigation of ionic reaction intermediates. Examples span from ultraviolet and infrared photodissociation spectroscopy of model reaction intermediates to applications of infrared multiphoton dissociation spectroscopy (IRMPD) to intermediates directly sampled from reaction mixtures. The first example of double resonance IR-UV spectroscopy of model intermediates in an organometallic reaction is also mentioned. PMID- 21792394 TI - The amino acid tryptophan prevents the biosynthesis of dermatan sulfate. AB - An important part of the biosynthesis of proteoglycans is the epimerization of glycosaminoglycan chains. As a consequence of the conversion of chondroitin sulfate (CS) to dermatan sulfate (DS), the glycosaminoglycans become more flexible and enable DS to perform more sophisticated signaling functions. In a recent study, we generated a chimera (S222A) composed of a truncated form of a DS (decorin) and CS (CSF-1) containing proteoglycan and analyzed the influence of the core protein on the extent of epimerization. C-terminal truncation constructs from S222A enabled us to identify an amino acid segment that lies within the CSF 1 part which prevents DS synthesis. Co-localization experiments using S222A-HA and DCN-Flag showed different intracellular localizations for the proteoglycans during biosynthesis. A data base search revealed a sequence motif (TNWVP) within the CSF-1 moiety that is found to be important in other proteoglycans. A single substitution of tryptophan-216 to leucine (W216L) in the chimera S222A increased the amount of l-IdoA to 12-16%. Co-localization with an ER-marker demonstrated that the biosynthesis of recombinant decorin is similar to the chimera S222A and S222A(W216L) in HEK293 cells. Co-staining of S222A-HA and S222A(W216L)-Flag showed different intracellular localizations for the proteoglycans. A more detailed analysis of the glycosaminoglycans reflects a similar total sulfate content for S222A and S222A(W216L). The 4/6 sulfation ratio was similar for decorin and S222A, but altered for S222A(W216L). However, the binding of fibroblasts growth factor-1 to CS/DS was only partially dependent on epimerization. These results are consistent with the model in which the core protein, via the amino acid tryptophan, is responsible for routing to subcellular compartments with or without sufficient access to chondroitin-glucuronate 5 epimerase. PMID- 21792395 TI - Production of anticancer polyenes through precursor-directed biosynthesis. AB - The biosynthesis of the pyrrolyl moiety of the fungal metabolite rumbrin originates from pyrrole-2-carboxylic acid. In an effort to produce novel derivatives with enhanced biological activity a series of substituted pyrrole-2 carboxylates were synthesised and incubated with the producing organism, Auxarthron umbrinum. Several 4-halo-pyrrole-2-carboxylic acids were incorporated into the metabolite yielding three new derivatives: 3-fluoro-, 3-chloro- and 3 bromo-isorumbrin, which were generated in milligram quantities enabling cytotoxicity assays to be conducted. The 3-chloro- and 3-bromo-isorumbrins had improved activity against HeLa cells compared with rumbrin; 3-bromoisorumbrin also showed dramatically improved activity towards a lung cancer cell line (A549). PMID- 21792396 TI - A new approach to local hardness. AB - The applicability of the local hardness as defined by the derivative of the chemical potential with respect to the electron density is undermined by an essential ambiguity arising from this definition. Further, the local quantity defined in this way does not integrate to the (global) hardness-in contrast with the local softness, which integrates to the softness. It has also been shown recently that with the conventional formulae, the largest values of local hardness do not necessarily correspond to the hardest regions of a molecule. Here, in an attempt to fix these drawbacks, we propose a new approach to define and evaluate the local hardness. We define a local chemical potential, utilizing the fact that the chemical potential emerges as the additive constant term in the number-conserving functional derivative of the energy density functional. Then, differentiation of this local chemical potential with respect to the number of electrons leads to a local hardness that integrates to the hardness, and possesses a favourable property; namely, within any given electron system, it is in a local inverse relation with the Fukui function, which is known to be a proper indicator of local softness in the case of soft systems. Numerical tests for a few selected molecules and a detailed analysis, comparing the new definition of local hardness with the previous ones, show promising results. PMID- 21792397 TI - Confined crystallization of binary n-alkane mixtures: stabilization of a new rotator phase by enhanced surface freezing and weakened intermolecular interactions. AB - The present work reports the confined crystallization behaviours of binary even even normal alkane (n-alkane) mixtures of n-octadecane (n-C(18)H(38)) and n eicosane (n-C(20)H(42)), which are microencapsulated in monodisperse microcapsules, using the combination of differential scanning calorimetry (DSC) and temperature-dependent X-ray diffraction (XRD). A new metastable rotator phase (RII) absent in the bulk state, has been detected for the n-alkane mixture in confined geometry under all the investigated compositions. Such a crossover is attributed to the lower interfacial energy due to the same in-planar hexagonal structure of the surface monolayer and RII, as well as the weakened intermolecular interaction in alkane mixtures. This is the first time that RII is found in such a binary even-even n-alkane mixture that neither of the components contains RII phase in the crystallization process. Furthermore, based on the variation of alkane molecule conformation and in-planar structure with temperature, the correlations between the phase transition temperature and composition have been discussed. PMID- 21792398 TI - Inhibited and enhanced nucleation of gold nanoparticles at the water|1,2 dichloroethane interface. AB - The deposition of gold at the interface between immiscible electrolyte solutions has been investigated using reduction of tetrachloroaurate or tetrabromoaurate in 1,2-dichloroethane, with aqueous phase hexacyanoferrate as reducing agent. In a clean environment without defects present at the interface, the Au(III) complex was reduced to the Au(I) complex, but no solid phase formation could be observed. A deposition process could only be observed through the addition of artificial nucleation sites in the form of palladium nanoparticles at the interface. This process could be associated with the reduction of the Au(I) halide complex to metallic gold, by determining the gold reduction potentials in 1,2 dichloroethane. XANES measurements indicate that tetrachloroaurate ion transfers intact into the organic phase, with the central Au atom retaining its oxidation state of +3 and the overall anion remaining charged at -1. PMID- 21792399 TI - Examination of a synthetic benzophenone membrane-targeted antibiotic. AB - The enormous success of antibiotics is seriously threatened by the development of resistance to most of the drugs available on the market. Thus, novel antibiotics are needed that are less prone to bacterial resistance and are directed toward novel biological targets. Antimicrobial peptides (AMPs) have attracted considerable attention due to their unique mode of action and broad spectrum activity. However, these agents suffer from liability to proteases and the high cost of manufacturing has impeded their development. Previously, we have reported on a novel class of benzophenone-based antibiotics and early studies suggested that these agents might target the bacterial membrane. In this study, we present our work on the mechanism of action of these novel membrane targeted antibiotics. These compounds have good affinities to polyanionic components of the cell wall such as lipoteichoic acid (LTA) and lipopolysaccharide (LPS). We found that these agents release potassium ions from treated bacteria; thus, resulting in disruption of the bacterial membrane potential. Benzophenone-based membrane targeted antibiotics (BPMTAs) cause membrane disruption in synthetic lipid vesicles that mimic Gram-positive or Gram-negative bacteria. The compounds display no hemolytic activity up to a concentration that is 100 times the MIC values and they are capable of curing mice of a lethal MRSA infection. Repeated attempts to develop a mutant resistant to these agents has failed. Taken together, BPMTAs represent a promising new class of membrane-targeted antibacterial agents. PMID- 21792400 TI - N-heterocyclic carbene-catalyzed cascade epoxide-opening and lactonization reaction for the synthesis of dihydropyrone derivatives. AB - N-Heterocyclic carbene was employed as an efficient organic catalyst to catalyze a cascade epoxide-opening and lactonization reaction. This organocatalytic process could transform various readily accessible gamma-epoxy-alpha,beta-enals into dihydropyrone derivatives in good to excellent yields. PMID- 21792401 TI - Temperature dependent structured absorption spectra of molecular chlorine. AB - A dual wavelength range spectrometer system has been designed and constructed which can simultaneously perform single pass UV absorption spectroscopy and cavity enhanced absorption spectroscopy in the green region of the visible spectrum. Using the system the absorption spectrum of molecular chlorine has been measured, in the wavelength range 509-570 nm, using cavity enhanced absorption spectroscopy. Absolute absorption cross sections were obtained by simultaneous measurement of the UV spectrum to obtain the Cl(2) concentration. These are the first temperature dependent measurements of the Cl(2) absorption cross sections in this region which are vibronically resolved. Laboratory measurements were conducted at four temperatures (298, 273, 233, and 197 K). Spectral modelling of the Cl(2) B(3)Pi(0(u)(+))-X(1)Sigma(g)(+) electronic transition has been performed, the results of which are in good agreement with our measured spectra. PMID- 21792402 TI - Electrochemical investigations on stability and protonation behavior of pyridine terminated aromatic self-assembled monolayers. AB - Based on electrochemical methods such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), Au(111) electrodes modified by self assembled monolayers (SAMs) of a homologous series of pyridine-terminated thiols with aromatic backbones have been investigated. An important correlation between the chain structure and film integrity in electrolytic media was found. Monolayers with odd numbers of methylene spacers in the molecular chain showed superior barrier properties compared to even numbered counterparts. A positive influence of an increase in the number of attached phenyl rings on the integrity of SAMs was observed. Furthermore, cathodic desorption of the investigated SAMs is characterized by multiwave desorption peaks and extraordinarily large cathodic charges indicating an unusual desorption process. Moreover, protonation behavior of the SAMs has been investigated by X-ray photoelectron spectroscopy (XPS) and electrochemical methods. Protonation has been found to be reversible and surface pK(a) values have been determined to be around 5 for all investigated monolayers. PMID- 21792403 TI - Temperature dependence of crystal growth of hexagonal ice (I(h)). AB - The transformations between water and ice have many implications across numerous fields of study. A better understanding of this process would benefit many areas of science and technology such as medicine, biology, and atmospheric and material sciences. In the present work the temperature dependence of the rate of growth (melting) of the basal face of hexagonal ice I(h) and the effect of system size are investigated in molecular dynamics simulations. Using an effective pair potential model of water, systems are studied over temperatures ranging from T(M) - 40 to T(M) + 16 K, where T(M) is the melting temperature of the model. It is found that the growth rates reach a maximum value of 0.7 A ns(-1) (7 cm s(-1)) at about 12 K below the melting temperature. A noticeable effect of the system size on the melting temperature and ice growth rates is observed; it is shown that the size effect arises in smaller systems due to the artificial ordering under periodic conditions. The decrease in melting entropy in the smallest system by 0.4 J (mol K)(-1) relative to the largest system results in an up-shift in the melting temperature by about 2 K. An almost 60% increase in the maximum growth rate is observed for the smallest system. PMID- 21792404 TI - Ion-specific and charge effects in counterion binding to poly(styrenesulfonate) anions. AB - In order to obtain a deeper insight into effects occurring when an electrolyte solution is added to a solution of a strong polyelectrolyte, the microcalorimetric and potentiometric titrations of poly(sodium 4 styrenesulfonate) (Na(+)PSS(-)) solution with different alkali, earth-alkali and tetraalkylammonium nitrate, perchlorate and chloride solutions were performed. From the calorimetric titrations the differences in sign and magnitude of enthalpy change upon addition of various electrolytes were observed depending on the salt used. Potentiometric titrations using a sodium ion selective electrode have revealed that addition of an electrolyte is accompanied by the increase in sodium activity until a certain critical value is reached, which seems to be the consequence of counterion substitution on the polyelectrolyte chain. In the case of addition of lithium and sodium salts the experimental results for DeltaH of mixing can be qualitatively correctly explained by the Poisson-Boltzmann and Monte Carlo calculations based on the continuum solvent models. This is not the case for the mixtures with KNO(3), RbNO(3) and CsNO(3) salts. The results suggest that the ion-specific effects, associated with the changes in the water structure, have to be taken into account when thermodynamic properties of polyelectrolytes in solution are concerned. The calorimetric results imply that the enthalpically observed cation specificity for binding to a poly(styrenesulfonate) group could be correlated with corresponding cation hydration enthalpies. The counterion substitution of sodium with divalent cations was found to be endothermic, which is in qualitative agreement with the electrostatic theory. PMID- 21792405 TI - Facile solvothermal synthesis of mesoporous Cu2SnS3 spheres and their application in lithium-ion batteries. AB - Three dimensional (3D) mesoporous Cu(2)SnS(3) spheres composed of nanoparticles were synthesized by a simple solvothermal route. As anode materials for lithium ion batteries, they delivered remarkably enhanced cycling performances. This could be attributed to the 3D mesoporous structure which may be propitious to the accommodation of volume expansion. Besides, a possible electrochemical reaction mechanism was proposed based on cyclic voltammetry (CV) testing results and confirmed by subsequent ex situ XRD studies. In addition, the influence of testing temperature on cycling performance has also been investigated. PMID- 21792406 TI - Regio- and stereoselective selenium dioxide allylic oxidation of (E)-dialkyl alkylidenesuccinates to (Z)-allylic alcohols: synthesis of natural and unnatural butenolides. AB - The first SeO(2) induced (Z)-selective allylic alcohol formation of dialkyl alkylidenesuccinates has been demonstrated to accomplish one-step syntheses of several essential butenolides and fused butenolides via an unusual E- to Z- carbon-carbon double bond isomerisation followed by the lactonization pathway. The observed regio- and stereoselective SeO(2) allylic oxidation protocol has also been extended to the diastereoselective total synthesis of bioactive natural product isomintlactone, its direct conversion to mintlactone and an example of the base-catalyzed intramolecular rearrangement of gamma-lactone to delta lactone. PMID- 21792423 TI - Encoded dendrimers with defined chiral composition via'click' reaction of enantiopure building blocks. AB - Dendrimers with end-groups of defined chiral composition have been prepared from alkyne functional enantio-pure building blocks obtained by selective enzymatic (ADH) ketone reductions using click chemistry. Optical rotation and enantioselective enzymatic modification is in agreement with the chiral composition of the dendrimers and permits unique molecular-level encoding of stereoisomeric dendritic libraries. PMID- 21792424 TI - An optimized isotopic labelling strategy of isoleucine-gamma2 methyl groups for solution NMR studies of high molecular weight proteins. AB - An efficient synthetic route is proposed to produce 2-hydroxy-2-ethyl-3 oxobutanoate for the specific labelling of Ile methyl-gamma(2) groups in proteins. The (2)H, (13)C-pattern of the biosynthetic precursor has been designed to optimize magnetization transfer, in large proteins, between these important structural probes and their corresponding backbone nuclei. PMID- 21792425 TI - Molecular dynamics studies of native and substituted cyclodextrins in different media: 1. Charge derivation and force field performances. AB - Molecular dynamics simulations describing the solvation process of native and modified cyclodextrins (per-substituted alpha-, beta-, and gamma-cyclodextrins, as well as an amino-acid derived beta-cyclodextrin) have been performed. A homogeneous force field, namely "q4md-CD", has been built from the development of a new force field topology database and from a combination of the GLYCAM04 and Amber99SB force fields to correctly describe the geometrical, structural, dynamical and hydrogen bonding aspects of heterogeneous cyclodextrin based systems. These include native, organo- and peptidic-linked cyclodextrins. q4md-CD features: (i) geometrical parameters from Amber99SB to describe the protein parts, (ii) geometrical parameters from GLYCAM04 for the carbohydrate and organic parts when available or those of Amber99SB otherwise, (iii) partial atomic charges, embedded in force field libraries for the carbohydrate and organic fragments, were derived using the R.E.D. tools according to the "Amber" strategy and (iv) scaling factors of 1.2 and 2.0 were imposed for the 1-4 electrostatic and 1-4 van der Waals interactions, respectively. Results given by q4md-CD on native cyclodextrins have been compared to those obtained with reference to force fields like GLYCAM04, GLYCAM06 and Amber99SB as well as with experimental data. This work not only gives a global view of the performances of the aforementioned force fields towards a correct description of solvated cyclodextrins, but also extends the capabilities of current force fields by addressing some issues concerning hydrogen bonding and opens new possibilities towards studies of glycoconjugates by molecular dynamics. PMID- 21792426 TI - Aromaticity in all-metal annular systems: the counter-ion effect. AB - The effect of counterions on the bonding, stability and aromaticity of trigonal dianion metal clusters has been analyzed through the behavior of various conceptual density functional theory based reactivity descriptors and the nucleus independent chemical shift calculated at different levels of theory, comprising one-determinant approaches and beyond (QCISD, CASSCF(8,8) and NEVPT2), for a proper benchmarking. Although several important insights into the counter-ion effects are obtained, much needs to be done in order to have a transparent idea therein. PMID- 21792427 TI - Intramolecularly coordinated heteroleptic organostannylene tungsten pentacarbonyl complexes 4-tBu-2,6-[P(O)(OiPr)2]2C6H2Sn(X)W(CO)5 (X = Cl, F, PPh2, PPh2[W(CO)5]). Syntheses and reactivity. AB - The synthesis of the intramolecularly coordinated heteroleptic organostannylene tungsten pentacarbonyl complexes 4-tBu-2,6 [P(O)(OiPr)(2)](2)C(6)H(2)Sn(X)W(CO)(5) (1, X = Cl; 2, X = F; 3, X = PPh(2)) and of 4-tBu-2,6-[P(O)(OiPr)(2)](2)C(6)H(2)Sn[W(CO)(5)]PPh(2)[W(CO)(5)], 4, are reported. UV-irradiation of compound 4 in tetrahydrofurane serendipitously gave the bis(organostannylene) tungsten tetracarbonyl complex cyclo O(2)W[OSn(R)](2)W(CO)(4) (R = 4-tBu-2,6-[P(O)(OiPr)(2)](2)C(6)H(2)), 5, that contains an unprecedented W(0)-Sn-O-W(vi) bond sequence. The compounds 1-5 were characterized by means of single crystal X-ray diffraction analysis, (1)H, (13)C, (19)F, (31)P, (119)Sn NMR, and IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and elemental analysis. Compound 4 features a hindered rotation about the Sn-P bond. PMID- 21792428 TI - Self-assembled palladium(II) "click" cages: synthesis, structural modification and stability. AB - Readily synthesised and functionalised di-1,2,3-triazole "click" ligands are shown to self-assemble into coordinatively saturated, quadruply stranded helical [Pd(2)L(4)](BF(4))(4) cages with Pd(II) ions. The cages have been fully characterised by elemental analysis, HR-ESMS, IR, (1)H, (13)C and DOSY NMR, DFT calculations, and in one case by X-ray crystallography. By exploiting the CuAAC "click" reaction we were able to rapidly generate a small family of di-1,2,3 triazole ligands with different core spacer units and peripheral substituents and examine how these structural modifications affected the formation of the [Pd(2)L(4)](BF(4))(4) cages. The use of both flexible (1,3-propyl) and rigid (1,3 phenyl) core spacer units led to the formation of discrete [Pd(2)L(4)](BF(4))(4) cage complexes. However, when the spacer unit of the di-1,2,3-triazole ligand was a 1,4-substituted-phenyl group steric interactions led to the formation of an oligomeric/polymeric species. By keeping the 1,3-phenyl core spacer constant the effect of altering the "click" ligands' peripheral substituents was also examined. It was shown that ligands with alkyl, phenyl, electron-rich and electron-poor benzyl substituents all quantitatively formed [Pd(2)L(4)](BF(4))(4) cage complexes. The results suggest that a wide range of functionalised palladium(II) "click" cages could be rapidly generated. These novel molecules may potentially find uses in catalysis, molecular recognition and drug delivery. PMID- 21792429 TI - The chemistry of hydridocarbonylferrates revisited: syntheses and structures of the new [H2Fe4(CO)12]2- and [HFe5(CO)14]3- anions, and the [Fe(DMF)4][Fe4(CO)12(MU5-eta2-CO)(MU-H)]2 adduct containing an unprecedented isocarbonyl. AB - The di-hydride di-anion [H(2)Fe(4)(CO)(12)](2-) has been quantitatively obtained by protonation of the previously reported mono-hydride tri-anion [HFe(4)(CO)(12)](3-) in DMSO and structurally characterised in its [NEt(4)](2)[H(2)Fe(4)(CO)(12)] salt. It shows some subtle but yet significant differences in the stereochemistry of the ligands in comparison to the heavier Ru(4) and Os(4) congeners. The study of the reactivity of these [H(4 n)Fe(4)(CO)(12)](n-) (n = 2,3) species allowed the serendipitous isolation and structural characterization of the new pentanuclear [HFe(5)(CO)(14)](3-) mono hydride tri-anion. Attempts to obtain the latter in better yields led to the discovery of intermolecular CO/H(-) mutual exchange reactions and isolation and structural characterization of the [Fe(DMF)(4)][Fe(4)(CO)(12)(MU(5)-eta(2)-CO)(MU H)](2).0.5CH(2)Cl(2) and [M(+)][Fe(4)(CO)(12)(MU(4)-eta(2)-CO)(MU-H)](-) (M = K, Cs) adducts, the former containing an unprecedented isocarbonyl group. The isolation of new tetranuclear and, above all, pentanuclear hydridocarbonylferrates indicates that it is possible to further expand the chemistry of homoleptic Fe carbonyl species. PMID- 21792430 TI - Science and strategies to reduce mercury risks: a critical review. AB - Despite decades of scientific research and policy actions to control mercury, exposure to toxic methylmercury continues to pose risks to humans and the environment. This article critically reviews the linkages between scientific advancements and mercury reduction policies aimed at reducing this risk, focusing on the challenges that mercury poses as an issue that crosses both spatial and temporal scales. Scientific aspects of the mercury issue at various spatial and temporal scales are reviewed, and policy examples at global, national and local scale are analysed. Policy activity to date has focused on the mercury problem at a single level of spatial scale, and on near-term timescales. Efforts at the local scale have focused on monitoring levels in fish and addressing local contamination issues; national-scale assessments have addressed emissions from particular sources; and global-scale reports have integrated long-range transport of emissions and commercial trade concerns. However, aspects of the mercury issue that cross the political scale (such as interactions between different forms of mercury) as well as contamination problems with long timescales are at present beyond the reach of current policies. It is argued that these unaddressed aspects of the mercury problem may be more effectively addressed by (1) expanded cross scale policy coordination on mitigation actions and (2) better incorporating adaptation into policy decision-making to minimize impacts. PMID- 21792432 TI - Thermal conductivity reduction through isotope substitution in nanomaterials: predictions from an analytical classical model and nonequilibrium molecular dynamics simulations. AB - We introduce an analytical model to rapidly determine the thermal conductivity reduction due to mass disorder in nanomaterials. Although this simplified classical model depends only on the masses of the different atoms, it adequately describes the changes in thermal transport as the concentrations of these atoms vary. Its predictions compare satisfactorily with nonequilibrium molecular dynamics simulations of the thermal conductivity of (14)C-(12)C carbon nanotubes as well as with previous simulations of other materials. We present it as a simple tool to quantitatively estimate the thermal conductivity decrease that is induced by isotope substitution in various materials. PMID- 21792433 TI - Near-infrared (1550 nm) in vivo bioimaging based on rare-earth doped ceramic nanophosphors modified with PEG-b-poly(4-vinylbenzylphosphonate). AB - A novel poly(ethylene glycol) (PEG)-based block copolymer possessing a 4 vinylbenzylphosphonate repeating unit in another segment (PEG-block-poly(4 vinylbenzylphosphonate)) (PEG-b-PVBP) was designed and successfully synthesized. As a control, an end-functionalized PEG possessing a mono-phosphonate group (PEG PO(3)H(2)) was also synthesized. The surface of near-infrared (NIR) phosphors (i.e., ytterbium (Yb) and erbium (Er) ion-codoped Y(2)O(3) nanoparticles (YNPs)) were modified with PEG-b-PVBP (PEG-YNP(b)s) and PEG-PO(3)H(2) (PEG-YNP(1)s). The adsorption of PEG-b-PVBP and PEG-PO(3)H(2) was estimated by Fourier transform infrared (FT-IR) measurements and thermal gravimetric analysis (TGA). The physicochemical characteristics of the obtained YNP samples were analyzed by zeta potential and dynamic light scattering (DLS) measurements. The zeta-potentials of YNPs modified by these polymers were close to zero, indicating the effective coverage of the YNP surface by our new PEG derivatives. However, the dispersion stability of the PEGylated YNPs was strongly affected by the structure of the PEG terminus. The average diameter of the PEG-YNP(1)s increased, and aggregates precipitated after less than 1 h in phosphate buffer saline (PBS). In contrast, the size did not change at all in the case of PEG-YNP(b)s and the dispersion in PBS was stable for over 1 week. PEG-YNP(b)s also showed high erosion resistance under acidic conditions. The multiple coordinated PVBP segment of the block copolymer on the YNP surface plays a substantial role in improving such dispersion stability. The excellent dispersion stability and strong NIR luminescence of the obtained PEG-YNP(b)s were also confirmed in fetal bovine serum (FBS) solution over 1 week. Furthermore, in vivo NIR imaging of live mice was performed, and the 1550 nm NIR emission of PEG-YNP(b)s from the organ of live mice was confirmed without dissection. PMID- 21792431 TI - Systems biology and physical biology of clathrin-mediated endocytosis. AB - In this review, we describe the application of experimental data and modeling of intracellular endocytic trafficking mechanisms with a focus on the process of clathrin-mediated endocytosis. A detailed parts-list for the protein-protein interactions in clathrin-mediated endocytosis has been available for some time. However, recent experimental, theoretical, and computational tools have proved to be critical in establishing a sequence of events, cooperative dynamics, and energetics of the intracellular process. On the experimental front, total internal reflection fluorescence microscopy, photo-activated localization microscopy, and spinning-disk confocal microscopy have focused on assembly and patterning of endocytic proteins at the membrane, while on the theory front, minimal theoretical models for clathrin nucleation, biophysical models for membrane curvature and bending elasticity, as well as methods from computational structural and systems biology, have proved insightful in describing membrane topologies, curvature mechanisms, and energetics. PMID- 21792434 TI - Self-templating 2D supramolecular networks: a new avenue to reach control over a bilayer formation. AB - One of the greatest challenges in 2D self-assembly at interfaces is the ability to grow spatially controlled supramolecular motifs in the third dimension, exploiting the surface as a template. In this manuscript a concentration dependent study by scanning tunneling microscopy at the solid-liquid interface, corroborated by Molecular Dynamics (MD) simulations, reveals the controlled generation of mono- or bilayer self-assembled Kagome networks based on a fully planar tetracarboxylic acid derivative. By programming the backbone of the molecular building blocks, we present a strategy to gain spatial control over the adlayer structure by conferring self-templating capacity to the 2D self-assembled network. PMID- 21792435 TI - A theoretical study of imine-ene reaction influencing factors. AB - Potential energy surfaces of the imine-ene reaction between methanimine and propene have been calculated using restricted and unrestricted density functional theory at the B3LYP level. The results show that a concerted mechanism with an exo configuration for lone pair electrons transition structure is more favourable for the intermolecular bare imine-ene reaction. In addition, the C-C bond formation and the migration of the propene alpha-hydrogen occur simultaneously. The promoting effect of seventeen Lewis acids was also studied. When a Lewis acid is used as a promoter, the corresponding activation and reaction energies decline greatly compared to those of the bare imine-ene reaction. A good correlation (R(2) > 0.9) was found between the activation barriers and the polar character of the transition states. Lewis acids and electron-withdrawing substituents on methanimine were proven to facilitate the imine-ene reaction, whereas electron donating groups, conjugated groups or a bulky group hinders the reaction. The steric factor is the most unfavourable. The reactivity indices defined by the conceptual density functional theory were also studied and there is a good correlation between the activation barrier and electrophilicity. Frontier molecular orbital theory gives a good explanation for the above results. PMID- 21792436 TI - Generation of diverse 2-pyrones via palladium-catalyzed site-selective Suzuki Miyaura couplings of 3-bromo-4-tosyloxy-2-pyrone. AB - Based on different reactivity of the (pseudo)halide substituents in the 2-pyrone (3-Br and 4-OTs), palladium-catalyzed sequential site-selective Suzuki-Miyaura cross-coupling reactions of 3-bromo-6-methyl-4-tosyloxy-2-pyrone are described, which afford the diverse 2-pyrones in good yields. PMID- 21792437 TI - Imaging of intracellular acidic compartments with a sensitive rhodamine based fluorogenic pH sensor. AB - The parameters of intracellular acidic compartments are altered in apoptosis, autophagy, cancer metastasis, etc. Low background and selective staining of lysosomes and autophagosomes was achieved with N-(rhodamine 6G)-lactam ethylenediamine (R6G-EDA) which fluoresces in acidic vesicles via pH mediated ring opening of the intramolecular lactam. Long retention time of R6G-EDA in lysosomes and its exceptional stability against photo-bleaching allow full time tracking of lysosome morphology changes in tumor necrosis factor-alpha (TNF alpha) triggered cell death, suggesting its utility for acidic vesicle studies in cell biology. PMID- 21792438 TI - Hybridization in ssDNA films--a multi-technique spectroscopy study. AB - A combination of X-ray photoelectron spectroscopy (XPS), high-resolution XPS, near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and sum frequency-generation (SFG) spectroscopy was used to monitor two types of ssDNA films on Au(111) before and after hybridization. As probe systems, films of thiolated and block-oligonucleotides were used, taking thiolated thymine d(T) homo-oligonucleotides and thymine-adenine d(A-T) diblock-oligonucleotides as representative examples. In accordance with previous work, hybridization of the shorter and more densely packed thiolated ssDNA films produced fewer (if any) hybrids, whereas the longer and less densely packed layers exhibited a larger hybridization yield. The above effects were less pronounced in the case of the d(A-T) films where the hybridization yield of the less densely packed monolayers was significantly lower. This was presumably due to the formation of internal dimeric hybrids in the immobilization step of the probe molecules, resulting in the generation of fewer probe-target hybrids upon exposure to the target molecules. In all ssDNA films displaying a reasonable number of hybrids present, significant orientational changes were observed and could be monitored in detail. These results suggest that the given combination of spectroscopic techniques can be a valuable tool to gain molecular-level information about hybrids at interfaces. PMID- 21792439 TI - Understanding microsolvation of Li+: structural and energetical analyses. AB - A stochastic exploration of the quantum conformational space for the (H(2)O)(n)Li(+), n = 3, 4, 5 complexes produced 32 molecular clusters at the B3LYP/6-311++G** and MP2/6-311++G** levels. The first solvation shell is predicted to comprise a maximum of 4 water molecules. Energy decomposition analyses were performed to determine the relationship between the geometrical features of the complexes and the types of interactions responsible for their stabilization. Our findings reveal that electrostatic interactions are major players determining the structures and relative stabilities of the clusters. The formal charge on the Li atom leads to two distinct types of hydrogen bonds, scattered in a wide range of distances (1.61-2.32 A), in many cases affording H bonds that are considerably larger and considerably shorter than those in pure water clusters (typically ~1.97 A). PMID- 21792440 TI - A kinetic and thermodynamic study of the unexpected comproportionation reaction between cis-[Os(VIII)O4(OH)2](2-) and trans-[Os(VI)O2(OH)4](2-) to form a postulated [Os(VII)O3(OH)3](2-) complex anion. AB - A kinetic study of [OsO(4)] reduction by aliphatic alcohols (MeOH and EtOH) was performed in a 2.0 M NaOH matrix at 298.1 K. The rate model that best fitted the UV-VIS data supports a one-step, two electron reduction of Os(VIII) (present as both the [Os(VIII)O(4)(OH)](-) and cis-[Os(VIII)O(4)(OH)(2)](2-) species in a ratio of 0.34:0.66) to form the trans-[Os(VI)O(2)(OH)(4)](2-) species. The formed trans-[Os(VI)O(2)(OH)(4)](2-) species subsequently reacts relatively rapidly with the cis-[Os(VIII)O(4)(OH)(2)](2-) complex anion to form a postulated [Os(VII)O(3)(OH)(3)](2-) species according to: cis-[Os(VIII)O(4)(OH)(2)](2-) + trans-[Os(VI)O(2)(OH)(4)](2-) (k+2) <-> (k-2) 2[Os(VII)O(3)(OH)(3)](2-). The calculated forward, k(+2), and reverse, k(-2), reaction rate constants of this comproportionation reaction are 620.9 +/- 14.6 M(-1) s(-1) and 65.7 +/- 1.2 M(-1) s(-1) respectively. Interestingly, it was found that the postulated [Os(VII)O(3)(OH)(3)](2-) complex anion does not oxidize MeOH or EtOH. Furthermore, the reduction of Os(VIII) with MeOH or EtOH is first order with respect to the aliphatic alcohol concentration. In order to corroborate the formation of the [Os(VII)O(3)(OH)(3)](2-) species predicted with the rate model simulations, several Os(VIII)/Os(VI) mole fraction and mole ratio titrations were conducted in a 2.0 M NaOH matrix at 298.1 K under equilibrium conditions. These titrations confirmed that the cis-[Os(VIII)O(4)(OH)(2)](2-) and trans [Os(VI)O(2)(OH)(4)](2-) species react in a 1:1 ratio with a calculated equilibrium constant, K(COM), of 9.3 +/- 0.4. The ratio of rate constants k(+2) and k(-2) agrees quantitatively with K(COM), satisfying the principle of detailed balance. In addition, for the first time, the molar extinction coefficient spectrum of the postulated [Os(VII)O(3)(OH)(3)](2-) complex anion is reported. PMID- 21792441 TI - Synthesis of 4-methylene-4H-benzo[d][1,3]thiazines via a tandem reaction of 1-(2 alkynylphenyl)ketoximes with Lawesson's reagent. AB - 1-(2-Alkynylphenyl)ketoximes react with Lawesson's reagent catalyzed by InCl(3) and cyanuric chloride leading to 4-methylene-4H-benzo[d][1,3]thiazines in good yields. This tandem reaction proceeds with high efficiency through Beckmann rearrangement, thioamide formation, and intramolecular nucleophilic cyclization. PMID- 21792442 TI - The first metal-free water-soluble cryptophane-111. AB - Cryptophane-111 is one of the best candidates for (129)Xe MRI-based applications. Herein, we report the first metal-free and water-soluble cryptophane-111 core which involves an efficient and unusual post-synthetic sulfonation procedure. PMID- 21792443 TI - Stereocontrolled synthesis of 20,21-dihydro N-methylwelwitindolinone B isothiocyanate. AB - Described is a concise synthesis of the 20,21-dihydro analog of N methylwelwitindolinone B isothiocyanate, wherein a cationic homoallyl to cyclopropylmethyl rearrangement is circumvented by hydrogenation of the offending double bond. PMID- 21792444 TI - Visible light mediated azomethine ylide formation-photoredox catalyzed [3+2] cycloadditions. AB - The synthesis of highly functionalised N-heterocycles has been achieved by the visible light mediated photoredox conversion of tertiary amines to azomethine ylides and their further reaction with maleimide derivatives as dipolarophiles. PMID- 21792445 TI - Preparation of polymer-supported gold nanoparticles based on resins containing ionic liquid-like fragments: easy control of size and stability. AB - Crosslinked polymers containing covalently attached functional sites with chemical structures related to those present in ILs and having macroscopic properties very similar to the ones of the corresponding bulk ILs can be advantageously applied to the preparation of gold nanoparticles (AuNPs). The size and morphology of the resulting metal nanoparticles (MNPs) can be easily modulated through a proper combination of the synthetic method used for the generation of the NPs and the structural elements of the polymer. Additionally, the resulting supported AuNPs are demonstrated to be stable for at least eight months with the vials open to the atmosphere. Several synthetic methodologies have been studied, as well as different structural parameters for the functional polymers. Those include the chemical nature (anions and cations) and loading of the ionic liquid-like fragments and the morphology of the polymeric matrix. The results obtained show the potential to prepare supported AuNPs with narrow size distributions and small diameters that can have potential interest for application in different fields. PMID- 21792446 TI - Extending ligand field molecular mechanics to modelling organometallic pi-bonded systems: applications to ruthenium-arenes. AB - The ligand field molecular mechanics method has been extended to treat eta(6) arene ligands coordinated to a ruthenium(II) centre by employing a dummy atom located at the centroid of the arene ring and distributing the forces on the dummy to the arene carbon atoms. Angular overlap model parameters based on orbital energies derived from Kohn-Sham density functional theory (KS-DFT) calculations show that, relative to the Ru-dummy vector, the arene behaves as a very strong pi donor and weak sigma donor. Based on KS-DFT geometries, partial atomic charges and potential energy scans for a series of homoleptic and half sandwich complexes spanning arene, am(m)ine, imine, pyridyl, hydride and chloride ligands, a new LFMM force field has been developed which accurately reproduces the KS-DFT data. This FF was validated against 47 half-sandwich complexes obtained from the Cambridge Structural Database which, after minor corrections to account for the systematic errors between our chosen functional (BP86) and the experimental structures, yields a 'structurally tuned' FF where 93% of the Ru-L contacts are reproduced to 0.05 A or better and all bar two bond lengths are within 0.1 A of experiment. Over half the systems have non-hydrogen-atom rmsds of less than 0.5 A. Larger differences are usually due to rotation of the arene moiety which is shown by ligand field molecular dynamics (LFMD) simulations to be an inherently low-energy process. Comparisons between LFMD and Car-Parrinello MD for [Ru(p-cymene)(ethylenediamine)Cl](+)show that LFMD is equally accurate but much faster enabling modelling of dynamic properties which occur on a timescale beyond the scope of CPMD. PMID- 21792447 TI - Growth behaviour and plasmon resonance properties of photocatalytically deposited Cu nanoparticles. AB - Cu nanoparticles (NPs) were deposited on UV-irradiated TiO(2) in an aqueous solution containing Cu(CH(3)COO)(2) and ethanol by a photocatalytic reaction. Cu NPs on TiO(2) exhibit an extinction (= absorption + scattering + reflection) peak due to localized surface plasmon resonance at around 600 nm initially. The density and size as well as the extinction of Cu NPs increase during the deposition, accompanied by a slight redshift of the peak. Eventually, TiO(2) is mostly covered with coalesced Cu NPs that exhibit a spectrum less characteristic of Cu NPs, but more characteristic of a Cu layer. PMID- 21792448 TI - Real-time electrochemical monitoring of isothermal helicase-dependent amplification of nucleic acids. AB - We described an electrochemical method to monitor in real-time the isothermal helicase-dependent amplification of nucleic acids. The principle of detection is simple and well-adapted to the development of portable, easy-to-use and inexpensive nucleic acids detection technologies. It consists of monitoring a decrease in the electrochemical current response of a reporter DNA intercalating redox probe during the isothermal DNA amplification. The method offers the possibility to quantitatively analyze target nucleic acids in less than one hour at a single constant temperature, and to perform at the end of the isothermal amplification a DNA melt curve analysis for differentiating between specific and non-specific amplifications. To illustrate the potentialities of this approach for the development of a simple, robust and low-cost instrument with high throughput capability, the method was validated with an electrochemical system capable of monitoring up to 48 real-time isothermal HDA reactions simultaneously in a disposable microplate consisting of 48-electrochemical microwells. Results obtained with this approach are comparable to that obtained with a well established but more sophisticated and expensive fluorescence-based method. This makes for a promising alternative detection method not only for real-time isothermal helicase-dependent amplification of nucleic acid, but also for other isothermal DNA amplification strategies. PMID- 21792449 TI - A two-photon fluorescent probe for ratiometric imaging of hydrogen peroxide in live tissue. AB - We report a two-photon fluorescent probe (PN1) that can be excited by 750 nm femto-second pulses, shows high photostability and negligible toxicity, and can visualize H(2)O(2) distribution in live cells and tissue by two-photon microscopy. PMID- 21792450 TI - Remarkably high catalytic activity of the Ru(III)(edta)/H2O2 system towards degradation of the azo-dye Orange II. AB - The Ru(III)(edta)/H(2)O(2) system (edta(4-) = ethylenediaminetretaacetate) was found to degrade the azo-dye Orange II at remarkably high efficiency under ambient conditions. Catalytic degradation of the dye was studied by using rapid scan spectrophotometry as a function of [H(2)O(2)], [Orange II] and pH. Spectral analyses and kinetic data point towards a catalytic pathway involving the rapid formation of [Ru(III)(edta)(OOH)](2-) followed by the immediate subsequent degradation of Orange II prior to the conversion of [Ru(III)(edta)(OOH)](2-) to [Ru(IV)(edta)(OH)](-) and [Ru(V)(edta)(O)](-)via homolysis and heterolysis of the O-O bond, respectively. The higher oxidation state Ru(IV) and Ru(V) complexes react three orders of magnitude slower with Orange II than the Ru(III) hydroperoxo complex. In comparison to biological oxygen transfer reactions, the Ru(edta) complexes show the reactivity order Compound 0 ? Compounds I and II. PMID- 21792451 TI - Multilayer enzyme-coupled magnetic nanoparticles as efficient, reusable biocatalysts and biosensors. AB - Herein we report the development of a highly active, magnetically retrievable and reusable biocatalyst using multilayer enzyme coupled-magnetic nanoparticles (MNPs) prepared by layer-by-layer assembly using two well-studied enzymes, horseradish peroxidase (HRP) and glucose oxidase (GOX), as a model enzyme system. We show that by combining the use of a biocompatible linker as well as biospecific immobilisation, the first layer enzyme in our HRP(1)-MNP system retains the native activity of the enzyme in solution, and the overall catalytic activity of the multilayer enzyme system, HRP(x)-MNP, increases linearly with the increasing number of enzyme layers. Furthermore, the HRP(x)-MNP system can be conveniently retrieved by using an external magnetic field and reused for 10 consecutive cycles without apparent reduction of catalytic activity. We also report the development of a novel coupled bienzyme, GOX/HRP(x)-MNP, system that can perform bi-enzymatic reactions to couple the colourless GOX-catalyzed reaction to the chromophoric HRP-catalyzed reaction via H(2)O(2) production. This model bienzyme-MNP system can be used for simple, rapid colorimetric quantification of micromolar glucose. PMID- 21792452 TI - Recent applications of thiol-ene coupling as a click process for glycoconjugation. AB - There has been over the past decades a resurgence of the free-radical thiol-ene coupling (TEC) as a method for assembling crosslinked networks and polymer functionalization. On the other hand the use of TEC in carbohydrate chemistry, a field of special importance due to the key role of carbohydrates in living organisms, is represented only by a handful of papers. Nevertheless it appears that TEC possesses many if not all the attributes of a click process proceeding with the assistance of the greenest catalyst such as visible light. This tutorial review focuses on the application of TEC on different topics, all related to glycochemistry, including: (a) carbohydrate modification, (b) oligosaccharide and glycosyl amino acid synthesis, (c) assembly of glycoclusters on rigid molecular platforms (calixarene, cyclodextrin, silsesquioxane, dendrimer), (d) peptide and protein glycosylation. Also the very recent development in peptide glycosylation by the closely related thiol-yne chemistry is described. PMID- 21792453 TI - A DNAzyme based label-free detection system for miniaturized assays. AB - Sensitive detection assays are a prerequisite for the analysis of small amounts of samples derived from biological material. There is a great demand for highly sensitive and robust detection techniques to analyze biomolecules. The combination of catalytic active DNA (DNAzyme) with a peroxidase activity with rolling circle amplification (RCA) is a promising alternative to common detection systems. The rolling circle amplification leads to a product with tandemly linked copies of DNAzymes. The continuous signal generation of the amplified DNAzymes results in an increased sensitivity. The combination of two amplification reactions, namely RCA and DNAzymes, results in increased signal intensity by a factor of 10(6). With this approach the labeling of samples can be avoided. The advantage of the introduced assay is the usage of nucleic acids as biosensors for the detection of biomolecules. Coupling of the analyte molecule to the detection molecules allows the direct detection of the analyte molecule. The described label-free hotpot assay has a broad potential field of applications. The hotpot assay can be adapted to detect and analyze RNA, DNA and proteins down to femtomolar concentrations in a miniaturized platform with a total reaction solution of 50 nl. The applicability of the assay for diagnostics and research will be shown with a focus on high throughput systems using a nano-well platform. PMID- 21792454 TI - Decarboxylative coupling reactions: a modern strategy for C-C-bond formation. AB - This critical review examines transition metal-catalyzed decarboxylative couplings that have emerged within recent years as a powerful strategy to form carbon-carbon or carbon-heteroatom bonds starting from carboxylic acids. In these reactions, C-C bonds to carboxylate groups are cleaved, and in their place, new carbon-carbon bonds are formed. Decarboxylative cross-couplings constitute advantageous alternatives to traditional cross-coupling or addition reactions involving preformed organometallic reagents. Decarboxylative reaction variants are also known for Heck reactions, direct arylation processes, and carbon heteroatom bond forming reactions. PMID- 21792456 TI - Pyrazole analogues of porphyrins and oxophlorins. AB - A series of porphyrin analogues with pyrazole rings replacing one of the usual pyrrole subunits have been synthesized. This was accomplished by reacting 1 phenyl, 1-methyl and 1-ethyl pyrazole-1,3-dicarbaldehydes with a tripyrrane in the presence of TFA, followed by an oxidation step. The initially formed phlorin product was sufficiently stable for the N-phenyl system to be isolated and characterized, although the related N-alkyl phlorin analogues were less stable. Attempts to dehydrogenate the intermediary phlorins with DDQ resulted in decomposition, but the N-alkylphlorins could be oxidized with 0.2% aqueous ferric chloride solutions. Although the phenyl-substituted phlorin could not be oxidized under these conditions, it did afford the pyrazoloporphyrin upon treatment with silver acetate under acidic conditions. Oxidations with silver acetate also afforded oxophlorin analogues where the oxo-linkage was selectively formed at the 5-position. The pyrazole-containing porphyrin analogues are cross-conjugated and exhibit only a small degree of diatropic character. The internal CH resonances were observed between 5.27 and 5.87 ppm, while the external meso-protons fell into a range of 6.84-7.88 ppm. The borderline overall aromatic character was attributed to dipolar resonance contributors. Protonation considerably increased the diatropicity and the diprotonated dications formed from these porphyrin analogues gave the internal CH resonance at upfield values of 2.65-3.20 ppm. The aromatic character was enhanced by the presence of an electron-donating alkyl substituent on the nitrogen compared to the phenyl-substituted species. The pyrazoloporphyrins reacted with nickel(II) acetate in DMF, or palladium(II) acetate in acetonitrile, to give the corresponding organometallic derivatives. The metal complexes showed increased diatropic character but protonation afforded nonaromatic cations. The oxophlorin analogues were also nonaromatic in the free base and protonated forms. This work extends our understanding of carbaporphyrinoid systems and provides the first detailed studies on pyrazole containing porphyrin analogues. PMID- 21792455 TI - A straightforward synthetic access to symmetrical glycosyl disulfides and biological evaluation thereof. AB - Symmetrical glycosyl disulfides can be prepared within a few hours from per-O acetylated precursors via a sequential approach entailing short reactions and no purification of any intermediate. The final thiolate-to-disulfide oxidation step is noticeably accelerated by low amounts of phenyl diselenide under air. Applicability of the strategy to non-saccharidic symmetrical alkyl disulfides has also been examined. A preliminary assay of the cytotoxic activity of symmetrical 1,1'- disulfides was performed on two human tumor cell lines, and a noteworthy activity was recorded for a range of these synthetic compounds. PMID- 21792457 TI - Quantum design rules for single molecule logic gates. AB - Recent publications have demonstrated how to implement a NOR logic gate with a single molecule using its interaction with two surface atoms as logical inputs [W. Soe et al., ACS Nano, 2011, 5, 1436]. We demonstrate here how this NOR logic gate belongs to the general family of quantum logic gates where the Boolean truth table results from a full control of the quantum trajectory of the electron transfer process through the molecule by very local and classical inputs practiced on the molecule. A new molecule OR gate is proposed for the logical inputs to be also single metal atoms, one per logical input. PMID- 21792458 TI - Ordered patterns and structures via interfacial self-assembly: superlattices, honeycomb structures and coffee rings. AB - Self-assembly is now being intensively studied in chemistry, physics, biology, and materials engineering and has become an important "bottom-up" approach to create intriguing structures for different applications. Self-assembly is not only a practical approach for creating a variety of nanostructures, but also shows great superiority in building hierarchical structures with orders on different length scales. The early work in self-assembly focused on molecular self-assembly in bulk solution, including the resultant dye aggregates, liposomes, vesicles, liquid crystals, gels and so on. Interfacial self-assembly has been a great concern over the last two decades, largely because of the unique and ingenious roles of this method for constructing materials at interfaces, such as self-assembled monolayers, Langmuir-Blodgett films, and capsules. Nanocrystal superlattices, honeycomb films and coffee rings are intriguing structural materials with more complex features and can be prepared by interfacial self assembly on different length scales. In this critical review, we outline the recent development in the preparation and application of colloidal nanocrystal superlattices, honeycomb-patterned macroporous structures by the breath figure method, and coffee-ring-like patterns (247 references). PMID- 21792459 TI - Palladium-catalyzed carbonylative coupling reactions between Ar-X and carbon nucleophiles. AB - Palladium-catalyzed carbonylative coupling reactions of aromatic halides and related compounds have undergone a rapid development during recent years. Nowadays, a plethora of palladium catalysts are available for the synthesis of ketones, alkynones, chalcones, etc., which are important intermediates in the manufacture of dyes, pharmaceuticals, agrochemicals, and other industrial products. In this critical review, we summarize the development of these carbonylative transformations with carbon nucleophiles (136 references). PMID- 21792460 TI - C,C-diacetylenic phosphaalkenes in palladium-catalyzed cross-coupling reactions. AB - The reactivity of bis-TMS-substituted C,C-diacetylenic phosphaalkene (A(2)PA) 1 in Sonogashira-Hagihara cross-coupling reactions has been examined. The selective and successive deprotection of the two silyl groups in 1 is enabled by the steric bulk of the Mes* group which renders the acetylene trans to Mes* more reactive and thereby facilitates selective and consecutive couplings with iodoarenes. In situ transformation of the TMS-protected acetylenes into Cu(i)acetylides is the key step in the synthetic sequence and enables the preparation of the first dimeric A(2)PA linked by a phenylene spacer. cis-trans Isomerization across the P[double bond, length as m-dash]C bond is triggered by a tertiary amine and exclusively observed in the case of nitrophenyl-substituted A(2)PAs. The introduced aryl groups are integral parts of the entire pi-system as evidenced by spectroscopic and electrochemical studies. PMID- 21792461 TI - New insights into platelet function testing: from bench to bedside. PMID- 21792462 TI - The genetic basis of platelet responsiveness to clopidogrel. A critical review of the literature. AB - Clopidogrel reduces ischaemic complications in a wide range of patients with coronary artery disease. However, there is much inter-individual variation in clopidogrel-induced platelet inhibition, and a substantial proportion of patients will exhibit non-responsiveness to clopidogrel. Multiple studies have demonstrated an association between the presence of genetic polymorphisms associated with suboptimal clopidogrel-active metabolite generation, decreased platelet responsiveness, and adverse clinical outcomes. However, it is not clear to what extent the genetic polymorphisms account for the observed variability in response to clopidogrel. In this review we provide a critical summary of the available evidence linking genetic factors with response to clopidogrel, and discuss the clinical implications of this association. PMID- 21792463 TI - Clinical significance of circulating microparticles for venous thromboembolism in cancer patients. AB - Cancer patients have a four- to seven-fold increased risk to develop a venous thromboembolic event. Accumulating evidence from experimental and clinical studies indicates that microparticles (MPs), small procoagulant membrane vesicles that are defined by size and a negatively charged phosphatidylserine rich surface, play an important role in the pathogenesis of cancer-related venous thromboembolism (VTE). However, the clinical significance of MPs as a predictive biomarker for VTE in cancer patients has not been fully elucidated yet. This might be due to unresolved methodological problems and a lack of data from large prospective clinical studies that investigate the role of MPs in cancer-related VTE. It is the aim of this review to give an overview on the most important characteristics of MPs and studies dealing with the role of MPs in cancer-related VTE. Also recent progresses, unresolved problems and future perspectives in this research field will be discussed. In the conclusion we will assess the clinical significance of MPs in cancer-related VTE. PMID- 21792464 TI - [Von Willebrand factor and ADAMTS13 balancing primary haemostasis]. AB - Von Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10-1 to 105 s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other. PMID- 21792465 TI - Evaluation of imbalance in stratified blocked randomization: some remarks on the range of validity of the model by Hallstrom and Davis. AB - OBJECTIVES: If in a clinical trial prognostic factors are known in advance, it is often recommended that randomization of patients should be stratified. The best known method is permuted-block randomization within strata. But it suffers from the disadvantage that imbalance still occurs in the trial as a whole if there are a large number of strata, or/and the block sizes are too large for the number of patients. The results of Hallstrom and Davis are appropriate for evaluating the risk of such a troubled situation by using two special cases of their general variance formula. But it is merely generally argued for whichever practical situations these special cases are valid. Consequently, additional investigations are required to reveal the conditions for correct application. METHODS: We investigated the range of validity of special cases by performing computer simulations, varying a number of trial characteristics, and discuss the application of results for practical situations. RESULTS: The validity of special cases is not given in each situation. Depending on block size, a binomial distribution model is valid for a permitted average maximum number of patients per stratum between 36% and 57% of considered block sizes, whereas the uniform distribution model works adequately from at least 70%. In an intermediate range of invalidity, implementation of a simulation study is necessary to compute the probability distribution of differences. CONCLUSIONS: Our results are important if choosing the stratified permuted-block randomization to estimate the risk for an intolerable overall imbalance when planning a trial. PMID- 21792466 TI - Automated classification of free-text pathology reports for registration of incident cases of cancer. AB - OBJECTIVE: Our study aimed to construct and evaluate functions called "classifiers", produced by supervised machine learning techniques, in order to categorize automatically pathology reports using solely their content. METHODS: Patients from the Poitou-Charentes Cancer Registry having at least one pathology report and a single non-metastatic invasive neoplasm were included. A descriptor weighting function accounting for the distribution of terms among targeted classes was developed and compared to classic methods based on inverse document frequencies. The classification was performed with support vector machine (SVM) and Naive Bayes classifiers. Two levels of granularity were tested for both the topographical and the morphological axes of the ICD-O3 code. The ability to correctly attribute a precise ICD-O3 code and the ability to attribute the broad category defined by the International Agency for Research on Cancer (IARC) for the multiple primary cancer registration rules were evaluated using F1-measures. RESULTS: 5121 pathology reports produced by 35 pathologists were selected. The best performance was achieved by our class-weighted descriptor, associated with a SVM classifier. Using this method, the pathology reports were properly classified in the IARC categories with F1-measures of 0.967 for both topography and morphology. The ICD-O3 code attribution had lower performance with a 0.715 F1 measure for topography and 0.854 for morphology. CONCLUSION: These results suggest that free-text pathology reports could be useful as a data source for automated systems in order to identify and notify new cases of cancer. Future work is needed to evaluate the improvement in performance obtained from the use of natural language processing, including the case of multiple tumor description and possible incorporation of other medical documents such as surgical reports. PMID- 21792467 TI - Survey on medical records and EHR in Asia-Pacific region: languages, purposes, IDs and regulations. AB - OBJECTIVES: To clarify health record background information in the Asia-Pacific region, for planning and evaluation of medical information systems. METHODS: The survey was carried out in the summer of 2009. Of the 14 APAMI (Asia-Pacific Association for Medical Informatics) delegates 12 responded which were Australia, China, Hong Kong, India, Indonesia, Japan, Korea, New Zealand, the Philippines, Singapore, Thailand, and Taiwan. RESULTS: English is used for records and education in Australia, Hong Kong, India, New Zealand, the Philippines, Singapore and Taiwan. Most of the countries/regions are British Commonwealth. Nine out of 12 delegates responded that the second purpose of medical records was for the billing of medical services. Seven out of nine responders to this question answered that the second purpose of EHR (Electronic Health Records) was healthcare cost cutting. In Singapore, a versatile resident ID is used which can be applied to a variety of uses. Seven other regions have resident IDs which are used for a varying range of purposes. Regarding healthcare ID, resident ID is simply used as healthcare ID in Hong Kong, Singapore and Thailand. In most cases, disclosure of medical data with patient's name identified is allowed only for the purpose of disease control within a legal framework and for disclosure to the patient and referred doctors. Secondary use of medical information with the patient's identification anonymized is usually allowed in particular cases for specific purposes. CONCLUSION: This survey on the health record background information has yielded the above mentioned results. This information contributes to the planning and evaluation of medical information systems in the Asia-Pacific region. PMID- 21792468 TI - Challenges in measuring the impact of interruption on patient safety and workflow outcomes. AB - OBJECTIVE: To examine the problem of studying interruption in healthcare. METHODS: Review of the interruption literature from psychology, human-computer interaction; experimental studies of electronic prescribing and error behaviour; observational studies in emergency and intensive care. RESULTS: Primary task and interruption variables which contribute to the outcomes of an interruption include the type of task (primary and interrupting task); point of interruption; duration of interruption; similarity of interruptive task to primary task; modality of interruption; environmental cues; and interruption handling strategy. Effects of interruption on task performance can be examined by measuring errors, the time on task, interruption lag and resumption lag. CONCLUSIONS: Interruptions are a complex phenomenon where multiple variables including the characteristics of primary tasks, the interruptions themselves, and the environment may influence patient safety and workflow outcomes. Observational studies present significant challenges for recording many of the process variables that influence the effects of interruptions. Controlled experiments provide an opportunity to examine the specific effects of variables on errors and efficiency. Computational models can be used to identify the situations in which interruptions to clinical tasks could be disruptive and to investigate the aggregate effects of interruptions. PMID- 21792469 TI - Crosstalk between cancer and haemostasis. Implications for cancer biology and cancer-associated thrombosis with focus on tissue factor. AB - Cancer is characterized by bidirectional interrelations between tumour progression, coagulation activation, and inflammation. Tissue factor (TF), the principal initiator of the coagulation protease cascade, is centrally positioned in this complex triangular network due to its pleiotropic effects in haemostasis, angiogenesis, and haematogenous metastasis. While formation of macroscopic thrombi is the correlate of cancer-associated venous thromboembolism (VTE), a major healthcare burden in clinical haematology and oncology, microvascular thrombosis appears to be critically important to blood-borne tumour cell dissemination. In this regard, expression of TF in malignant tissues as well as shedding of TF-bearing microparticles into the circulation are thought to be regulated by defined genetic events relevant to pathological cancer progression, thus directly linking Trousseau's syndrome to molecular tumourigenesis. Because pharmacological inhibition of the TF pathway in selective tumour types and patient subgroups would be in line with the modern concept of individualized, targeted anti-cancer therapy, this review will focus on the role of TF in tumour biology and cancer-associated VTE. PMID- 21792470 TI - Retrospective study of 476 tibial plateau levelling osteotomy procedures. Rate of subsequent 'pivot shift', meniscal tear and other complications. AB - OBJECTIVE: To determine the rate of subsequent 'pivot shift', meniscal tear and risk factors associated with complications of tibial plateau levelling osteotomy (TPLO) and to assess clinical and owner perception outcome. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Three hundred and forty-eight dogs that had undergone TPLO surgical procedures (n = 476 stifles). METHODS: Medical records were reviewed for the retrieval of information on breed, sex, age, body weight, clinical history, radiograph findings, pre- and postoperative tibial plateau angle, limb alignment, unilateral versus bilateral disease, condition of cranial cruciate ligament (CCL) and menisci, implant material, healing time and complications. Clinical and owner-assessed questionnaire outcomes were also recorded. RESULTS: Forty-six (9.7%) postoperative complications were reported. Twenty (4.2%) were classified as major complications requiring an additional surgical intervention, and 26 (5.5%) as minor complications. No risk factors associated with postoperative complications were identified. Ten (2.1%) subsequent meniscal injuries in the stifles with normal un- altered menisci at time of TPLO were reported with a median postoperative time of 9.5 months. Signs of postoperative 'pivot shift' were reported in 15 (3.1%) stifles. All stifles with a 'pivot shift' had a complete CCL rupture or a debrided partial CCL rupture; a medial menisectomy was identified as a risk factor for a 'pivot shift' (p = 0.02). Dogs with intact medial meniscus had a significantly higher activity level (p <0.0001) and a shorter time to peak function (p = 0.02) than dogs that underwent menisectomy according to an owner questionnaire. CONCLUSIONS: Dogs with TPLO and intact meniscus seemed to have a better and faster recovery than dogs with TPLO and menisectomy based on owner questionnaires. 'Pivot shift' was infrequent after TPLO surgery. All dogs with a 'pivot shift' had a complete CCL rupture or a debrided partial CCL rupture and menisectomy was identified as a risk factor for its occurrence. CLINICAL RELEVANCE: Considering the relatively low rate of subsequent meniscal injury after TPLO, systematic medial meniscal release with TPLO may be unnecessary. The 'pivot shift' deserved further investigation to completely understand its mechanism, to identify its anatomic components and potential consequences on the stifle joint. PMID- 21792471 TI - The effect of tibial tuberosity advancement and meniscal release on kinematics of the cranial cruciate ligament-deficient stifle during early, middle, and late stance. AB - OBJECTIVES: To evaluate the effect of tibial tuberosity advancement (TTA) and meniscal release on cranial-caudal and axial rotational displacement during early, middle and late stance phases in the canine cranial cruciate ligament- (CCL) deficient stifle. STUDY DESIGN: In vitro biomechanical study. METHODS: Eighteen pelvic limbs were evaluated for the effects of TTA on cranial-caudal displacement and axial rotation under a load equivalent to 30% bodyweight, and under the following treatment conditions: normal (intact CCL), CCL deficient, TTA treated (CCL deficient + TTA), and meniscal release (TTA treated + meniscal release). The limbs were evaluated in the early, middle, and late stance phases using electromagnetic tracking sensors to determine cranial tibial displacement and tibial rotation relative to the femur. RESULTS: Transection of the CCL resulted in significant cranial tibial displacement during early, middle, and late stance (p < 0.0001) and significant internal rotation during early (p = 0.049) and middle stance (p = 0.0006). Performance of TTA successfully eliminated cranial tibial displacement in early, middle, and late stance (p <0.0001); however, the TTA was unsuccessful in normalizing axial rotation in middle stance (p = 0.030). Meniscal release had no effect on cranial-caudal or rotational displacement when performed in conjunction with the TTA. CLINICAL SIGNIFICANCE: Tibial tuberosity advancement effectively eliminates cranial tibial displacement during early, middle and late stance; however, TTA failed to provide rotational stability in mid-stance. PMID- 21792472 TI - A cryogenic clamping technique that facilitates ultimate tensile strength determinations in tendons and ligaments. AB - OBJECTIVE: To describe the use of a cryogenic clamp of novel design for tensile strength testing of tendinous and ligamentous tissues with inherently high tensile strength. METHODS: Inexpensive, easily machined steel clamps were manufactured to facilitate rapid insertion into a standard wedge-screw grip apparatus installed on a testing system with a control system attached. The deep digital flexor tendon (DDFT) of six horses was trimmed to a uniform dumbbell shape and secured in clamps using partial submersion in liquid nitrogen for approximately 45 seconds and immediately tested. Approximate time between removal from liquid nitrogen and failure of tendon was four minutes. RESULTS: Failure was achieved in all tendons tested in a region approximating a midpoint between the clamps. Ultimate failure loads of up to 6745 N were achieved without slippage of the tissue from the grips. The ultimate tensile strength of the normal equine DDFT determined in this study was 111.82 +/- 11.53 N/mm2, and the stress versus grip-to-grip elongation plots for our equine DDFT were representative of a standard non-linear elastic curve obtained in similar studies. CLINICAL SIGNIFICANCE: We present a low cost device for quantifying physical properties of specimens with high connective tissue concentrations and inherent high tensile strength. Results of this study indicate that this device provides a practical alternative to other more costly methods of adequately securing larger tendons and ligaments for tensile strength testing. PMID- 21792473 TI - Evaluation of the transarticular external skeletal fixator for the treatment of tarsocrural instability in 32 cats. AB - The medical records of all cats with tarsocrural joint instability that were treated between June 2002 and December 2008 at the Royal Veterinary College were retrospectively reviewed. A total of 32 cats were identified. Information gathered included signalment, type of injury (subluxation or luxation), concurrent fractures, presence of soft tissue wounds, transarticular external skeletal fixation (TESF) type, configuration of TESF (number of pins proximal and distal to the joint), duration of hospitalisation, duration of TESF prior to removal, complications and cost. A significant association was identified between the length of hospitalisation and the presence of wounds. Similarly a significant association was present between wounds and final cost of treatment. Additionally, the authors found that a high number of implant related complications were present when only two pins were used proximal and distal to the tarsocrural joint, but this association was not significant. PMID- 21792474 TI - Elbow arthrodesis following a pathological fracture in a dog with bilateral humeral bone cysts. AB - A 10-month-old Yorkshire Terrier was referred for evaluation of an intermittent right thoracic limb lameness that acutely progressed to non-weight-bearing. A diagnosis of bilateral bone cysts of the humeral condyles with a pathologic fracture of the lateral aspect of the right humeral condyle was given following radiographic and histopathologic examination. Bilateral pathology necessitated consideration of treatment modalities other than amputation of the limb, as previously reported. Arthrodesis of the right elbow using a 2.0 mm locking bone plate was performed. The dog did not experience any complications associated with the procedure or the contralateral bone cyst. PMID- 21792475 TI - Osteogenic differentiation of equine cord blood multipotent mesenchymal stromal cells within coralline hydroxyapatite scaffolds in vitro. AB - OBJECTIVE: To investigate the osteogenic differentiation potential of equine umbilical cord blood-derived multipotent mesenchymal stromal cells (CB-MSC) within coralline hydroxyapatite scaffolds cultured in osteogenic induction culture medium. METHODS: Scaffolds seeded with equine CB-MSC were cultured in cell expansion culture medium (control) or osteogenic induction medium (treatment). Cell viability and distribution were confirmed by the MTT cell viability assay and DAPI nuclear fluorescence staining, respectively. Osteogenic differentiation was evaluated after 10 days using reverse transcription polymerase chain reaction, alkaline phosphatase activity, and secreted osteocalcin concentration. Cell morphology and matrix deposition were assessed by scanning electron microscopy (SEM) after 14 days in culture. RESULTS: Cells showed viability and adequate distribution within the scaffold. Successful osteogenic differentiation within the scaffolds was demonstrated by the increased expression of osteogenic markers such as Runx2, osteopontin, osteonectin, collagen IA; increased levels of alkaline phosphatase activity; increased osteocalcin protein secretion and bone-like matrix presence in the scaffold pores upon SEM evaluation. CLINICAL SIGNIFICANCE: These results demonstrate that equine CB-MSC maintain viability and exhibit osteogenic potential in coralline hydroxyapatite scaffolds when induced in vitro . Equine CB-MSC scaffold constructs deserve further investigation for their potential role as biologically active fillers to enhance bone-gap repair in the horse. PMID- 21792476 TI - Arthroscopic surgery of the middle carpal joint in trotting Standardbreds: findings and outcome. AB - OBJECTIVES: To describe the injuries in the middle carpal joint of trotting Standardbred racehorses in relation to future racing and to review the use of synovectomy in clinical cases. METHODS: Review of medical records and racing statistics of clinical cases. RESULTS: Sixty-six percent of horses undergoing arthroscopic surgery of the middle carpal joints returned to racing, but there were only weak associations between future racing success and findings at surgery. Lesions in the middle carpal joint were similar to what have previously been described, but there were no recorded injuries to the intermediate carpal bone in the horses in this sample population. CLINICAL RELEVANCE: Making an accurate prognosis for return to racing based on the findings in the middle carpal joint at the time of surgery appears to be difficult. PMID- 21792477 TI - Quantitative analysis of the intramedullary arterial supply of the feline tibia. AB - OBJECTIVES: To quantitatively describe the intramedullary arterial supply of the adult feline tibia and determine if the arterial supply is significantly different from that of adult small dogs. METHODS: Cadaveric feline and canine pelvic limbs were obtained to prospectively investigate the intramedullary arterial supply of the tibia. A microvascular injection and modified Spalteholz bone clearing technique were used to characterize and quantify the intramedullary arterial supply of the tibia. Statistical comparisons were made between cats and dogs for the percentage of intramedullary arterial supply (arterial density) and the diameter of the nutrient artery. RESULTS: No significant difference was observed in the intramedullary arterial density between dog and cat tibiae. The feline nutrient artery diameter (0.55 +/- 0.1 mm) was significantly greater than the canine nutrient artery (0.30 +/- 0.04 mm) in the distal section of bone. Dogs subjectively had a greater number of branching vessels in the distal and mid diaphyseal sections of bone when compared to cats. CLINICAL SIGNIFICANCE: Delayed fracture healing in the feline tibia does not appear to be associated with a lack of intramedullary arterial supply. A lack of diffuse arborization of the arterial supply to the middle and distal feline tibia may explain, at least in part, why feline tibial delayed or nonunions may be more common than in canine tibial fractures. PMID- 21792478 TI - Protective effect of TRPV1 against renal fibrosis via inhibition of TGF-beta/Smad signaling in DOCA-salt hypertension. AB - To investigate the effects of the transient receptor potential vanilloid type 1 (TRPV1) channel on renal extracellular matrix (ECM) protein expression including collagen deposition and the transforming growth factor beta (TGF-beta)/Smad signaling pathway during salt-dependent hypertension, wild-type (WT) and TRPV1 null (TRPV1-/-) mutant mice were uninephrectomized and given deoxycorticosterone acetate (DOCA)-salt for 4 wks. TRPV1 gene ablation exaggerated DOCA-salt-induced impairment of renal function as evidenced by increased albumin excretion (MUg/24 h) compared with WT mice (83.7 +/- 7.1 versus 28.3 +/- 4.8, P < 0.05), but had no apparent effect on mean arterial pressure (mmHg) as determined by radiotelemetry (141 +/- 4 versus 138 +/- 3, P > 0.05). Morphological analysis showed that DOCA salt-induced glomerulosclerosis, tubular injury and macrophage infiltration (cells/mm2) were increased in TRPV1-/- compared with WT mice (0.74 +/- 0.08 versus 0.34 +/- 0.04; 3.14 +/- 0.26 versus 2.00 +/- 0.31; 68 +/- 5 versus 40 +/- 4, P < 0.05). Immunostaining studies showed that DOCA-salt treatment decreased nephrin but increased collagen type I and IV as well as phosphorylated Smad2/3 staining in kidneys of TRPV1-/- compared with WT mice. Hydroxyproline assay and Western blot showed that DOCA-salt treatment increased collagen content (MUg/mg dry tissue) and fibronectin protein expression (%beta-actin arbitrary units) in the kidney of TRPV1-/- compared with WT mice (26.7 +/- 2.7 versus 17.4 +/- 1.8; 0.93 +/- 0.07 versus 0.65 +/- 0.08, P < 0.05). Acceleration of renal ECM protein deposition in DOCA-salt-treated TRPV1-/- mice was accompanied by increased TGF beta1, as well as phosphorylation of Smad2/3 protein expression (%beta-actin arbitrary units) compared with DOCA-salt-treated WT mice (0.61 +/- 0.07 versus 0.32 +/- 0.05; 0.57 +/- 0.07 versus 0.25 +/- 0.05; 0.71 +/- 0.08 versus 0.40 +/- 0.06, P < 0.05). These results show that exaggerated renal functional and structural injuries are accompanied by increased production of ECM protein and activation of the TGF-beta/Smad2/3 signaling pathway. These data suggest that activation of TRPV1 attenuates the progression of renal fibrosis possibly via suppression of the TGF-beta and its downstream regulatory signaling pathway. PMID- 21792479 TI - Angiotensin-II mediates nonmuscle myosin II activation and expression and contributes to human keloid disease progression. AB - Aberrant fibroblast migration in response to fibrogenic peptides plays a significant role in keloid pathogenesis. Angiotensin II (Ang II) is an octapeptide hormone recently implicated as a mediator of organ fibrosis and cutaneous repair. Ang II promotes cell migration but its role in keloid fibroblast phenotypic behavior has not been studied. We investigated Ang II signaling in keloid fibroblast behavior as a potential mechanism of disease. Primary human keloid fibroblasts were stimulated to migrate in the presence of Ang II and Ang II receptor 1 (AT1), Ang II receptor 2 (AT2) or nonmuscle myosin II (NMM II) antagonists. Keloid and the surrounding normal dermis were immunostained for NMM IIA, NMM IIB, AT2 and AT1 expression. Primary human keloid fibroblasts were stimulated to migrate with Ang II and the increased migration was inhibited by the AT1 antagonist EMD66684, but not the AT2 antagonist PD123319. Inhibition of the promigratory motor protein NMM II by addition of the specific NMM II antagonist blebbistatin inhibited Ang II-stimulated migration. Ang II stimulation of NMM II protein expression was prevented by AT1 blockade but not by AT2 antagonists. Immunostaining demonstrated increased NMM IIA, NMM IIB and AT1 expression in keloid fibroblasts compared with scant staining in normal surrounding dermis. AT2 immunostaining was absent in keloid and normal human dermal fibroblasts. These results indicate that Ang II mediates keloid fibroblast migration and possibly pathogenesis through AT1 activation and upregulation of NMM II. PMID- 21792480 TI - Small-interfering RNA-eluting surfaces as a novel concept for intravascular local gene silencing. AB - New drug-eluting stent (DES) methods have recently been demonstrated to improve outcomes of intravascular interventions. A novel technique is the design of gene silencing stents that elute specific small-interfering RNAs (siRNAs) for better vascular wall regeneration. Although siRNAs used to alter gene expression have surpassed expectations in in vitro experiments, the functional and local delivery of siRNAs is still the major obstacle for the in vivo application of RNA interference. In this preliminary in vitro study we investigated a surface immobilized siRNA delivery technique that would be readily adaptable for local intravascular applications in vivo. The transfection potency of gelatin coatings consisting of a specific siRNA complexed with polyethylenimine (PEI) was examined in primary human endothelial cells by flow cytometry and quantitative real-time polymerase chain reaction. Several media conditions, such as the presence or absence of serum during cultivation, were investigated. Furthermore, different siRNA and PEI amounts, as well as nitrogen/phosphate ratios, were tested for their transfection efficiency. Gelatin coatings consisting of PEI and siRNA against an exemplary endothelial adhesion molecule receptor achieved a significant knockdown of around 70%. The transfection efficiency of the coatings was not influenced by the presence of serum. The results of this preliminary study support the expectation that this novel coating may be favorable for local in vivo gene silencing (for example, when immobilized on stents or balloons for percutanous transluminal coronary angioplasty). However, further animal experiments are needed to confirm the translation into clinical practice. This intriguing technology leads the way to more sophisticated and individualized coatings for the post-DES era, toward silencing of genes involved in the pathway of intimal hyperplasia. PMID- 21792481 TI - Bilateral pathologic hip fractures associated with antiretroviral therapy: a case report. PMID- 21792482 TI - Physeal bar excision: a case report with a forty-two-year follow-up. PMID- 21792483 TI - Surgical reconstruction of a crush injury of the talar body: a case report. PMID- 21792484 TI - Challenging the assumptions about chemical thromboprophylaxis in knee replacement: commentary on an article by Alma B. Pedersen, MD, PhD, et al.: "Venous thromboembolism in patients having knee replacement and receiving thromboprophylaxis: a danish population-based follow-up study". PMID- 21792485 TI - To resurface the patella or not? Better assessments needed to address the benefits for total knee replacement: commentary on an article by George Pavlou, BSc, MRCS, et al.: "Patellar resurfacing in total knee arthroplasty: does design matter? A meta-analysis of 7075 cases". PMID- 21792486 TI - Innovations to speed treatment may be cost-effective for hip fracture: commentary on an article by Christopher J. Dy, MD, MSPH, et al.: "An economic evaluation of a systems-based strategy to expedite surgical treatment of hip fractures". PMID- 21792493 TI - Venous thromboembolism in patients having knee replacement and receiving thromboprophylaxis: a Danish population-based follow-up study. AB - BACKGROUND: We examined the rate of venous thromboembolism, as well as changes over time, in a population-based cohort of patients who underwent knee arthroplasty. METHODS: Using medical databases, we identified all patients who underwent primary knee arthroplasties with pharmacological thromboprophylaxis performed in Denmark from 1997 to 2007. The outcome was hospitalization with symptomatic venous thromboembolism within ninety days of surgery. We examined several potential patient and surgery-related predictors for venous thromboembolism using Cox regression analyses. RESULTS: The overall rate of hospitalization for venous thromboembolism among 37,223 patients within ninety days after primary knee arthroplasty was 1.2% (441 patients) at a median of fifteen days. The rate of hospitalization was 0.9% (323 patients) for deep venous thrombosis and 0.3% (127 patients) for pulmonary embolism, with nine patients who had both. The rate of venous thromboembolism increased during the ten-year study period. Patients with a high score on the Charlson comorbidity index had an increased relative risk for venous thromboembolism compared with patients with a low score (adjusted relative risk = 1.73; 95% confidence interval, 1.24 to 2.41). Patients with a history of cardiovascular disease or a previous venous thromboembolism had an increased risk for postoperative venous thromboembolism compared with patients without these conditions. Surgery-related factors were not predictors for venous thromboembolism. CONCLUSIONS: Despite pharmacological thromboprophylaxis, patients undergoing knee arthroplasty remain susceptible for venous thromboembolism events after surgery. Future efforts should focus on the improvement of prophylaxis following hospital discharge, particularly among elderly patients and those with a history of cardiovascular diseases or previous venous thromboembolism. PMID- 21792494 TI - Prevalence of neurologic lesions after total shoulder arthroplasty. AB - BACKGROUND: Clinically evident neurologic injury of the involved limb after total shoulder arthroplasty is not uncommon, but the subclinical prevalence is unknown. The purposes of this prospective study were to determine the subclinical prevalence of neurologic lesions after reverse shoulder arthroplasty and anatomic shoulder arthroplasty, and to evaluate the correlation of neurologic injury to postoperative lengthening of the arm. METHODS: All patients undergoing either a reverse or an anatomic shoulder arthroplasty were included during the period studied. This study focused on the clinical, radiographic, and preoperative and postoperative electromyographic evaluation, with measurement of arm lengthening in patients who had reverse shoulder arthroplasty according to a previously validated protocol. RESULTS: Between November 2007 and February 2009, forty-one patients (forty-two shoulders) underwent reverse shoulder arthroplasty (nineteen shoulders) or anatomic primary shoulder arthroplasty (twenty-three shoulders). The two groups were similar with respect to sex distribution, preoperative neurologic lesions, and Constant score. Electromyography performed at a mean of 3.6 weeks postoperatively in the reverse shoulder arthroplasty group showed subclinical electromyographic changes in nine shoulders, involving mainly the axillary nerve; eight resolved in less than six months. In the anatomic shoulder arthroplasty group, a brachial plexus lesion was evident in one shoulder. The prevalence of acute postoperative nerve injury was significantly more frequent in the reverse shoulder arthroplasty group (p = 0.002), with a 10.9 times higher risk (95% confidence interval, 1.5 to 78.5). Mean lengthening (and standard deviation) of the arm after reverse shoulder arthroplasty was 2.7 +/- 1.8 cm (range, 0 to 5.9 cm) compared with the normal, contralateral side. CONCLUSIONS: The occurrence of peripheral neurologic lesions following reverse shoulder arthroplasty is relatively common, but usually transient. Arm lengthening with a reverse shoulder arthroplasty may be responsible for these nerve injuries. PMID- 21792495 TI - Minimum clinically important differences in the Cervical Spine Outcomes Questionnaire: results from a national multicenter study of patients treated with anterior cervical decompression and arthrodesis. AB - BACKGROUND: The minimum clinically important difference is a clinically relevant threshold of improvement. A substantial clinical benefit is a threshold of change that correlates with clinically important improvement. The Cervical Spine Outcomes Questionnaire is a disease-specific, patient-reported outcomes instrument that was developed to be sensitive to changes associated with surgical treatment for degenerative cervical disc disease. To determine thresholds for change in these domain scores that are important from the patient's perspective, we estimated the minimum clinically important difference and substantial clinical benefit values for this questionnaire's domain scores. METHODS: We evaluated 252 patients from the Cervical Spine Research Society Outcomes Study at their six month follow-up visits after anterior cervical spine decompression and arthrodesis. Using a receiver operating characteristics curve, with the health transition item of the Short Form-36 as an anchor, we determined that the minimum clinically important difference (the value that maximized sensitivity and specificity to differentiate the "somewhat better" and "much better" responses from others) and the substantial clinical benefit (the value that maximized sensitivity and specificity to differentiate the "much better" response from others) for our questionnaire's domain scores. Responses were scaled between 0 and 1 point; higher scores denoted more severe impairment. Patient and clinical characteristics were tested to determine their influence on score changes. RESULTS: The minimum clinically important difference ranged from 0.13 point (for functional disability) to 0.24 point (for arm/shoulder pain). The substantial clinical benefit score ranged from 0.20 point (for functional disability or physical symptoms other than pain) to 0.30 point (for neck or arm/shoulder pain). Age, sex, and duration of current symptoms were not associated with change in our questionnaire's domain scores. CONCLUSIONS: A 0.13-point change in the functional disability domain score indicated a clinically important difference in a self reported outcome after anterior cervical spine surgery. A 0.30-point change in neck pain after surgery indicated a clinically important clinical benefit. This information, coupled with previous reports of the psychometric stability of the Cervical Spine Outcomes Questionnaire, should increase the clinical utility of this patient-reported outcomes instrument. PMID- 21792496 TI - Patellar resurfacing in total knee arthroplasty: does design matter? A meta analysis of 7075 cases. AB - BACKGROUND: Patellar resurfacing in total knee arthroplasty remains controversial. The aim of this study was to compare outcomes following total knee arthroplasty with patellar resurfacing with those following total knee arthroplasty without patellar resurfacing. We also sought to identify any correlation between outcomes and prosthetic design. METHODS: Eighteen Level-I randomized controlled trials with a cumulative sample size of 7075 knees (3463 in the resurfacing group and 3612 in the non-resurfacing group) satisfied the inclusion criteria. In the primary analysis, patellar resurfacing total knee arthroplasty was compared with non-resurfacing total knee arthroplasty, with use of reoperation rates, incidence of anterior knee pain, and functional scores as outcome measures. The secondary analysis focused on comparing patella-friendly and non-patella-friendly total knee arthroplasty designs with regard to the same three outcome measures. RESULTS: No significant differences were found between the resurfacing and non-resurfacing groups with regard to the incidence of anterior knee pain. A higher rate of reoperations was observed in the non resurfacing group. Analysis of homogeneous data comparing patella-friendly with non-patella-friendly total knee arthroplasty designs demonstrated no differences in the incidence of reoperations. CONCLUSIONS: No evidence was found to suggest that either patellar resurfacing or the prosthetic design affects the clinical outcome of a total knee arthroplasty. The higher incidence of reoperations in the non-resurfacing group may be attributed to the fact that secondary patellar resurfacing adds a surgical option for the treatment of anterior knee pain following total knee arthroplasty, thus artificially increasing the rate of reoperations in the non-resurfacing group. PMID- 21792497 TI - The relationship between anterior tibial acceleration, tibial slope, and ACL strain during a simulated jump landing task. AB - BACKGROUND: Knee joint morphology contributions to anterior cruciate ligament (ACL) loading are rarely considered in the injury prevention model. This may be problematic as the knee mechanical response may be influenced by these underlying morphological factors. The goal of the present study was to explore the relationship between posterior tibial slope (which has been recently postulated to influence knee and ACL loading), impact-induced anterior tibial acceleration, and resultant ACL strain during a simulated single-leg landing. METHODS: Eleven lower limb cadaveric specimens from female donors who had had a mean age (and standard deviation) of 65 +/- 10.5 years at the time of death were mounted in a testing apparatus to simulate single-limb landings in the presence of pre-impact knee muscle forces. After preconditioning, specimens underwent five impact trials (mean impact force, 1297.9 +/- 210.6 N) while synchronous three-dimensional joint kinetics, kinematics, and relative anteromedial bundle strain data were recorded. Mean peak tibial acceleration and anteromedial bundle strain were quantified over the first 200 ms after impact. These values, along with radiographically defined posterior tibial slope measurements, were submitted to individual and stepwise linear regression analyses. RESULTS: The mean peak anteromedial bundle strain (3.35% +/- 1.71%) was significantly correlated (r = 0.79; p = 0.004; beta = 0.791) with anterior tibial acceleration (8.31 +/- 2.77 m/s-2), with the times to respective peaks (66 +/- 7 ms and 66 +/- 4 ms) also being significantly correlated (r = 0.82; p = 0.001; beta = 0.818). Posterior tibial slope (mean, 7.6 degrees +/- 2.1 degrees ) was significantly correlated with both peak anterior tibial acceleration (r = 0.75; p = 0.004; beta = 0.786) and peak anteromedial bundle strain (r = 0.76; p = 0.007; beta = 0.759). CONCLUSIONS: Impact-induced ACL strain is directly proportional to anterior tibial acceleration, with this relationship being moderately dependent on the posterior slope of the tibial plateau. PMID- 21792498 TI - Changes in shape and length of the collateral and accessory collateral ligaments of the metacarpophalangeal joint during flexion. AB - BACKGROUND: Although the collateral and accessory collateral ligaments of the metacarpophalangeal joint contribute to the stability of this joint, the functional role of the various portions of these ligaments during flexion is unclear. We investigated changes in the three-dimensional shape and length of the collateral and accessory collateral ligaments during flexion to determine how each portion stabilized the metacarpophalangeal joint. METHODS: Twelve fingers from three embalmed cadavers were examined. The origin and the insertion point of the dorsal, middle, and volar portions of the radial and the ulnar collateral ligament and of the radial and the ulnar accessory collateral ligament were precisely identified. Microcomputed tomograms were obtained at 10 degrees intervals during passive flexion from 0 degrees to 80 degrees . We created three dimensional models of the metacarpal, the proximal phalange, and the paths of the twelve ligament portions. Finally, we calculated the change in the shape and length of the path of each ligament portion during flexion. RESULTS: The region of contact between each collateral ligament and the lateral edge of the metacarpal gradually lengthened during flexion of the joint, and the ligament gradually stretched to pass around the convex radial or ulnar surface of the metacarpal head. In contrast, each accessory collateral ligament curved around the volar tubercle of the metacarpal head at all flexion angles. The length of the volar portion of each collateral ligament and the length of the dorsal and middle portions of each accessory collateral ligament underwent little change during flexion. However, the lengths of the dorsal and middle portions of each collateral ligament increased significantly during flexion, and the length of the volar portion of each accessory collateral ligament decreased significantly. CONCLUSIONS: The collateral and accessory collateral ligaments can each be functionally divided into three portions-dorsal, middle, and volar. The volar portion of each collateral ligament and the dorsal and middle portions of each accessory collateral ligament are nearly isometric, the dorsal and middle portions of each collateral ligament become taut only in flexion, and the volar portion of each accessory collateral ligament becomes taut only in extension. PMID- 21792499 TI - An economic evaluation of a systems-based strategy to expedite surgical treatment of hip fractures. AB - BACKGROUND: A recent systematic review has indicated that mortality within the first year after hip fracture repair increases significantly if the time from hospital admission to surgery exceeds forty-eight hours. Further investigation has shown that avoidable, systems-based factors contribute substantially to delay in surgery. In this study, an economic evaluation was conducted to determine the cost-effectiveness of a hypothetical scenario in which resources are allocated to expedite surgery so that it is performed within forty-eight hours after admission. METHODS: We created a decision tree to tabulate incremental cost and quality-adjusted life years in order to evaluate the cost-effectiveness of two potential strategies. Several factors, including personnel cost, patient volume, percentage of patients receiving surgical treatment within forty-eight hours, and mortality associated with delayed surgery, were considered. One strategy focused solely on expediting preoperative evaluation by employing personnel to conduct the necessary diagnostic tests and a hospitalist physician to conduct the medical evaluation outside of regular hours. The second strategy added an on-call team (nurse, surgical technologist, and anesthesiologist) to staff an operating room outside of regular hours. RESULTS: The evaluation-focused strategy was cost effective, with an incremental cost-effectiveness ratio of $2318 per quality adjusted life year, and became cost-saving (a dominant therapeutic approach) if =93% of patients underwent expedited surgery, the hourly cost of retaining a diagnostic technologist on call was <$20.80, or <15% of the hospitalist's salary was funded by the strategy. The second strategy, which added an on-call surgical team, was also cost-effective, with an incremental cost-effectiveness ratio of $43,153 per quality-adjusted life year. Sensitivity analysis revealed that this strategy remained cost-effective if the odds ratio of one-year mortality associated with delayed surgery was >1.28, =88% of patients underwent early surgery, or =339.9 patients with a hip fracture were treated annually. CONCLUSIONS: The results of our study suggest that systems-based solutions to minimize operative delay, such as a dedicated on-call support team, can be cost effective. Additionally, an evaluation-focused intervention can be cost-saving, depending on its success rate and associated personnel cost. PMID- 21792500 TI - Comparison of total hip arthroplasty performed with and without cement: a randomized trial. A concise follow-up, at twenty years, of previous reports. AB - Total hip arthroplasty has been associated with excellent implant survival rates, but debate remains concerning the best fixation method for the components. A randomized controlled trial, which included 250 patients (mean age, sixty-four years) with osteoarthritis who were managed with total hip arthroplasty between October 1987 and January 1992, was conducted to compare the results of fixation with and without cement. Patients were followed for a mean of twenty years (range, seventeen to twenty-one years). Kaplan-Meier survivorship analysis at twenty years revealed significantly lower survival rates for cemented implants as compared with cementless implants. The cementless tapered stem had an extremely good survival rate of 99%. Radiographs showed evidence of mild stress-shielding around 95% of the cemented stems and 88% of the cementless stems; stress shielding of grade 3 or greater was seen around the remaining 12% of the cementless stems. PMID- 21792501 TI - Contralateral elbow radiographs can reliably diagnose radial head implant overlengthening. AB - BACKGROUND: Excessive lengthening of the radius with use of a radial head implant, a common cause of capitellar wear and clinical failure, is difficult to identify on radiographs of the injured elbow. The purpose of this study was to determine if a novel measurement technique based on radiographs of the contralateral elbow could be used to accurately estimate the magnitude of overlengthening due to the radial head implant. In part I of this study, we examined the side-to-side consistency of radiographic landmarks used in the measurement technique. In part II, the technique was validated in a cadaveric model with simulated radial head implant overlengthening. METHODS: In part I of the study, a side-to-side comparison of elbow joint dimensions was performed with use of 100 radiographs from fifty patients. In part II, radial head prostheses of varying lengths (leading to 0, 2, 4, 6, and 8 mm of overlengthening) were implanted in four pairs of cadaveric specimens (eight elbows). Radiographic measurements were performed by two examiners blinded to the implant size to determine if radiographs of the contralateral elbow could be used to diagnose, and provide a valid estimate of the magnitude of, implant overlengthening. Intrarater and interrater reliability ratios, absolute measurement errors, and diagnostic accuracy were determined. RESULTS: No significant side-to-side differences (p > 0.2) in radiographic measurements were identified between paired elbows. In the cadaveric model, the measurement technique involving use of radiographs of the contralateral elbow was successful in predicting the implant size (+/- 1 mm) in 104 (87%) of the 120 scenarios tested. The sensitivity of the technique--i.e., the ability of the test to correctly identify overlengthening (within +/- 1 mm) when it was present--was 98%, with a positive likelihood ratio of 49 and a negative likelihood ratio of 0.02. The reliability of the radiographic measurements, based on repeated measurements performed by a single blinded orthopaedic surgeon on two separate occasions or based on separate measurements performed by two different orthopaedic surgeons, was excellent (intraclass correlation coefficient > 0.95). CONCLUSIONS: A measurement technique based on radiographs of the contralateral elbow can be used to diagnose and calculate the magnitude of radial overlengthening due to the use of an incorrectly sized radial head implant. PMID- 21792502 TI - Intermediate to long-term results of periacetabular osteotomy in patients younger and older than forty years of age. AB - BACKGROUND: The treatment of middle-aged patients with periacetabular osteotomy remains controversial. The goal of the present retrospective study was to analyze the intermediate to long-term functional and radiographic results of periacetabular osteotomy in patients below and above the age of forty years. METHODS: Between February 1990 and December 2004, 166 periacetabular osteotomies were performed in 146 patients. We evaluated 158 hips in 139 patients who had a mean age of thirty-two years at the time of surgery. The mean duration of follow up was eleven years (range, five to twenty years). We compared thirty-six patients (forty-one hips) who were forty years of age or older with 103 patients (117 hips) who were younger than forty years of age at the time of surgery. RESULTS: The average Harris hip score increased from 70 points preoperatively to 90 points postoperatively. The mean Harris hip scores at the time of the five year follow-up were similar in the older and younger groups (p = 0.57), although the latest follow-up scores were significantly higher in the younger group than in the older group (91 compared with 88 points; p = 0.02). The average modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score (with 0 representing the worst score and 100 representing the best score) was higher for the younger group than for the older group (92 compared with 90 points; p = 0.03). Kaplan-Meier analysis with progression of the Tonnis grade of osteoarthritis as the end point showed a ten-year survival rate of 90.8% (95% confidence interval, 88.3% to 93.3%) and a fifteen-year survival rate of 83.0% (95% confidence interval, 78.5% to 87.5%); the ten-year survival rates in the younger and older groups were 94.4% and 81.3%, respectively, and the fifteen-year survival rates were 86.9% and 71.2%, respectively (p = 0.025). CONCLUSIONS: Periacetabular osteotomy yielded similar results for the two groups at the time of the five-year follow-up, although the results for the older group deteriorated thereafter. Decrease in physical function due to aging and increased susceptibility to the progression of osteoarthritis may be responsible for the poorer results over time in the older group. PMID- 21792503 TI - American Academy of Orthopaedic Surgeons clinical practice guideline on: the diagnosis of periprosthetic joint infections of the hip and knee. PMID- 21792504 TI - How to do a revision total hip arthroplasty: revision of the acetabulum. PMID- 21792505 TI - What's new in orthopaedic rehabilitation. PMID- 21792506 TI - T3+ and T4 rectal cancer patients seem to benefit from the addition of oxaliplatin to the neoadjuvant chemoradiation regimen. AB - BACKGROUND: To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters. METHODS: Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics. RESULTS: The data of 504 consecutive patients (n = 181 T3+, n = 323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P < .0001) when compared with the CORE scheme. Odds ratios for a R1 resection (3.74, 1.94, 1.14; P = .003) or CRM+ resection (3.78, 2.73, 1.34; P = .001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme. CONCLUSIONS: Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion. PMID- 21792507 TI - Surgical technique, morbidity, and outcome of primary retroperitoneal sarcoma involving inferior vena cava. AB - BACKGROUND: Retroperitoneal sarcomas (RSTS) involving inferior vena cava (IVC) are rare entities. Vascular resection and reconstruction represent a technical challenge. The aim of the study was to review a monoinstitutional series of IVC resections for RSTS (mainly IVC leiomyosarcoma), focusing on the type of vascular replacement, morbidity, and oncologic outcome. METHODS: From January 2004 to January 2011, 15 patients (7 male, 8 female) surgically treated for RSTS involving primarily or secondarily IVC were included. RESULTS: A total of ten patients had IVC replacement and one had partial IVC resection (anterior wall). En bloc organ resection was performed in 14 patients (93%). Major venous reconstructions were performed using PTFE prosthesis (2) or banked venous homografts (8). In four patients IVC reconstruction was not necessary because of the presence of efficient collaterals. Early clinically relevant complications (grade >=3) were detected in one patient (7%) (symptomatic graft thrombosis). No reoperations were needed. No late relevant complications (grade >=3) were observed. Overall graft patency was 60%. At a median follow up of 31.6 months, local recurrence, distant metastases, and survival rate were 20, 26, and 80%, respectively. Complete tumor resection was achieved in all patients. CONCLUSIONS: IVC resection is safe and well tolerated in RSTS patients. The need for vascular reconstruction has to be assessed according to preoperative imaging, intraoperative findings, and extent of resection. The specific role of banked venous homografts needs to be investigated in larger studies. PMID- 21792508 TI - Primum non nocere: a word of caution regarding prophylactic colectomy in the setting of incurable metastatic disease. PMID- 21792509 TI - A comparison of surgical complications between immediate breast reconstruction and mastectomy: the impact on delivery of chemotherapy--an analysis of 391 procedures. AB - PURPOSE: To compare the postoperative complications after immediate breast reconstruction (IBR) versus mastectomy alone and to examine the impact on the delivery of chemotherapy. METHODS: In this prospective series, there were 391 consecutive women who underwent mastectomy (243 mastectomy alone and 148 mastectomy and IBR). The outcome measures were complications (within 3 months after surgery) and time to adjuvant chemotherapy. RESULTS: Compared to the IBR group, patients in the mastectomy alone group were significantly older (P < 0.0001), smokers (P = 0.007) and less likely to have had previous radiation or lumpectomy (P < 0.0001). Overall, the complication rate was significantly greater in the IBR group than mastectomy alone (27.0% vs. 15.6%, P = 0.009). Univariate analyses revealed that mastectomy with IBR [odds ratio (OR) = 2, 95% confidence interval (CI) 1.21-2.30]; bilateral procedure (OR = 1.84, 95% CI 1.07-3.16); previous radiotherapy (OR = 2.4, 95% CI 1.29-4.47); and previous lumpectomy (OR = 1.84, 95% CI 1.11-3.03) were significant predictors of increased complications. With multivariable analysis, none of these variables were significantly associated with increased complications. 106 patients received adjuvant chemotherapy; median time from mastectomy to chemotherapy was 6.8 (0.71-15) weeks in the mastectomy alone group (n = 96) compared to 8.5 (6.3-11) weeks in the IBR group (n = 10) (P = 0.01). CONCLUSIONS: Although the incidence of overall and major postoperative complications was higher after IBR than mastectomy alone, there were no significant relationships in the multivariable analysis. IBR was associated with a modest increase in time to chemotherapy that was statistically but not clinically significant. PMID- 21792510 TI - Sentinel lymph node biopsy using intraoperative indocyanine green fluorescence imaging navigated with preoperative CT lymphography for superficial esophageal cancer. AB - BACKGROUND: The sentinel lymph node (SLN) concept has been gaining attention for gastrointestinal neoplasms but remains controversial for esophageal cancer. This study evaluated the feasibility of SLN identification using intraoperative indocyanine green (ICG) fluorescence imaging (IGFI) navigated by preoperative computed tomographic lymphography (CTLG) to treat superficial esophageal cancer. METHODS: Subjects comprised 20 patients clinically diagnosed with superficial esophageal cancer. Five minutes after endoscopic submucosal injection of iopamidol around the primary lesion using a four-quadrant injection pattern with a 23-gauge endoscopic injection sclerotherapy needle, three-dimensional multidetector computed tomography was performed to identify SLNs and lymphatic routes. ICG solution was injected intraoperatively around the tumor. Fluorescence imaging was obtained by infrared ray electronic endoscopy. Thoracoscope-assisted standard radical esophagectomy with lymphadenectomy was performed to confirm fluorescent lymph nodes detected by CTLG. RESULTS: Lymphatic vessels and SLNs were identified preoperatively using CTLG in all cases. Intraoperative detection rates were 100% using CTLG and 95% using IGFI. Lymph node metastases were found in four cases, including one false-negative case with SLNs occupied by bulky metastatic tumor that were not enhanced with both methods. The other 19 cases, including three cases of metastatic lymph nodes, were accurately identified by both procedures. CONCLUSIONS: Preoperative CTLG visualized the correct number and site of SLNs in surrounding anatomy during routine computed tomography to evaluate distant metastases. Referring to CTLG, SLNs were identified using IGFI, resulting in successful SLN navigation and saving time and cost. This method appears clinically applicable as a less-invasive method for treating superficial esophageal cancer. PMID- 21792511 TI - A simple nomogram to evaluate the risk of nonsentinel node metastases in breast cancer patients with minimal sentinel node involvement. AB - BACKGROUND: Tumor-positive sentinel node biopsy (SNB) suggests a risk of nonsentinel node metastases in breast cancer. This risk is lower after micrometastasis or isolated tumor cells (ITC) in the sentinel node (SN), and recent studies suggest that completion axillary lymph node dissection (ALND) might not improve outcome in these patients. We aim to validate existing predictive models and to develop a new model for micrometastatic and ITC patients. METHODS: A series of 484 patients with micrometastases or ITC in SN followed by ALND was used to evaluate factors affecting nonsentinel node involvement. Logistic regression analysis was performed to construct a predictive model, which was validated by a separate series of 51 patients. RESULTS: Only 7.2% of patients had additional metastases on completion ALND. Tumor diameter and multifocality associated with nonsentinel status on multivariate analysis. A predictive model was constructed showing good [area under the curve (AUC) 0.791] discrimination in the validation series. Previously published models performed poorly in our patient population. CONCLUSIONS: Nonsentinel node metastases are rare with micrometastasis or ITC in SN. Most published predictive models for nonsentinel node involvement perform poorly in the present patient population. We developed a new predictive model which seems to perform well in discriminating patients with more than 10% risk of additional metastases. However, the presented nomogram needs to be validated with an independent patient series to evaluate its accuracy, especially for high-risk patients. PMID- 21792512 TI - Unplanned excision of soft tissue sarcoma results in increased rates of local recurrence despite full further oncological treatment. AB - BACKGROUND: Unplanned excision of soft tissue sarcoma (STS) accounts for up to 40% of all initial operations for STS and is undertaken when the mass is presumed to be benign. The effect this has on outcome has never been fully established. METHODS: Patients with extremity or trunk STS between 2001 and 2005 who were treated by an initial inadvertent operation and then referred immediately to our unit were identified. Outcomes were compared with a control group of patients with STS who were stage-matched and had been treated conventionally by core biopsy and definitive surgery. Endpoints were local recurrence, distant metastases and sarcoma-specific survival. RESULTS: 134 patients who had undergone unplanned excision of STS were identified. One hundred twenty-one underwent further re-excision, and 51 (48%) of these patients had residual tumour identified after surgical re-excision. Two hundred nine stage-matched controls were identified who were treated conventionally. Median follow-up was 51.6 months. Local recurrence rates were considerably higher in the study group (23.8 vs. 11%, p = 0.0016), despite the control group having more stage 3 tumours. When the tumours were matched by stage, an increase in local recurrence was seen across all stages but was most pronounced for stage 3 tumours (37.5 vs. 14.2%, p = 0.005). Metastasis-free and sarcoma-specific survival were also significantly increased for stage 3 tumours. CONCLUSION: Unplanned initial excision of extremity soft tissue sarcoma may compromise long-term local control of extremity STS despite full further oncological management. PMID- 21792513 TI - Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. AB - BACKGROUND: The density of tumor-infiltrating immunocytes (TICs) has been proposed as an independent predictor of intrahepatic recurrence in patients with hepatocellular carcinoma (HCC). However, the relative roles of TIC density in predicting tumor extrahepatic metastasis remain to be elucidated. METHODS: The densities of CD3(+), CD8(+), granzyme B(+), FoxP3(+), CD45RO(+), CD20(+), CD1a(+), CD83(+), CD57(+), and CD68(+) TICs were assessed by immunohistochemistry in tissue microarrays containing paired intratumoral (IT) and peritumoral (PT) tissues from 206 consecutive HCC patients who underwent liver transplantation. Occurrence of extrahepatic metastasis, recurrence-free survival (RFS), and cancer specific survival (CSS) were assessed retrospectively in relation to TIC densities. RESULTS: CD45RO(+) memory T cell density was lower in tumor tissue compared with peritumor, whereas CD57(+) senescent T cell density was higher. Univariate analysis revealed that increased CD45RO (IT) (+) and decreased CD57 (PT) (+) densities were statistically significantly associated with favorable RFS and CSS, while other types of TICs, intratumorally or peritumorally, showed no prognostic values. Further, the CD45RO (IT) (+) /CD57 (PT) (+) ratio could stratify patients more accurately in terms of RFS and CSS than either marker used alone. Finally, multivariate analysis indicated that a high CD45RO (IT) (+) /CD57 (PT) (+) ratio was independently associated with better RFS (hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.42 to 0.98; P = 0.040) and CSS (HR = 0.51; 95% CI, 0.31 to 0.83; P = 0.007), but not CD45RO (IT) (+) or CD57 (PT) (+) individually. CONCLUSIONS: These results suggest that the CD45RO (IT) (+) /CD57 (PT) (+) (memory/senescent T cell) ratio is of vital importance in preventing HCC extrahepatic metastasis and in particular demonstrates its independent prognostic value in liver transplant recipients. PMID- 21792514 TI - Biogeochemistry of the Penobscot River watershed, Maine, USA: nutrient export patterns for carbon, nitrogen, and phosphorus. AB - Watershed exports of carbon, nitrogen, phosphorus, major solutes, and suspended sediments were examined during five water years in the Penobscot River basin, which forms part of the Gulf of Maine watershed. Mean annual exports of dissolved organic carbon (DOC) in the Penobscot River were 58 kg C ha(-1) year(-1), whereas cumulative yearly watershed flux of DOC during the study period ranged from 8.6 to 16.1 * 10(10) g C year(-1) and averaged 11.7 * 10(10) g C year(-1). Watershed exports of total soluble N (TN) and total soluble P in the Penobscot River averaged 1.9 and 0.02 kg ha(-1) year(-1), respectively. Companion studies in two other major Maine rivers indicated that mean annual exports of DOC and TN in the Androscoggin River were 40 kg C ha(-1) year(-1) and 2.0 kg N ha(-1) year(-1), whereas exports in the Kennebec River were 43 kg C ha(-1) year(-1) and 2.2 kg N ha(-1) year(-1). Extrapolation of results from this investigation and a previous complementary study indicates that estuaries and coastal waters in the Gulf of Maine receive at least 1.0 * 10(10) g N year(-1) and 2.5 * 10(11) g C year(-1) in combined runoff from the four largest Maine river basins. Soluble exports of Ca + Mg + Na minus wet deposition inputs of cations in the Penobscot system were approximately 1,840 mol(c) ha(-1) year(-1), which represents a minimum estimate of cation denudation from the watershed. Based on its low N and P export rates, the Penobscot River watershed represents an example of reference conditions for use as a benchmark in ecological assessments of river water quality restoration or impairment. In addition, the biogeochemical metrics from this study provide an historical baseline for analysis of future trends in nutrient exports from the Penobscot watershed as a function of changing climatic and land use patterns. PMID- 21792515 TI - N-nitrosodimethylamine and trihalomethane formation and minimisation in Southeast Queensland drinking water. AB - This study assesses the prevalence of disinfection by-product (DBP) precursors in some Southeast Queensland drinking water sources by conducting formation potential experiments for the four regulated trihalomethanes (THMs), and the potent carcinogen, N-nitrosodimethylamine (NDMA). NDMA formation potentials were consistently low (<5-21 ng/L), and total THM (tTHM) formation potentials were consistently below the Australian Drinking Water Guideline (250 MUg/L). NDMA concentration of finished drinking waters was also monitored and found to be <5 ng/L in all cases. The effect of coagulation and advanced oxidation on the formation of NDMA and THMs is also reported. UV/H(2)O(2) pre-treatment was effective in producing water with very low THMs concentrations, and UV irradiation was an effective method for NDMA degradation. H(2)O(2) was not required for the observed NDMA degradation to occur. Coagulation using alum, ferric chloride or poly(diallyldimethylammonium chloride) (polyDADMAC) was ineffective in removing DBPs precursors from the source water studied, irrespective of the low dissolved organic carbon (DOC) and dissolved organic nitrogen (DON) attained. Rather, coagulation with polyDADMAC caused an increase in NDMA formation potential upon chloramination, and all coagulants led to an increased tTHM formation potential upon chlorination due to the high bromide concentration of the source water studied. PMID- 21792516 TI - Evaluation of microbiological air quality and of microclimate in university classrooms. AB - The proliferation of air-diffused microorganisms inside public buildings such as schools, hospitals, and universities, is often indicated as a possible health risk. In this research, we have illustrated the results of an investigation realized to determine the health of the air in some university classrooms, both from a microbiological and a microclimatic viewpoint, during the normal didactic activity of direct lessons. The results obtained have been expressed by means of contamination indices, already used in previous works. Very little contamination was recorded in the different phases of air treatment, which underlines the efficiency of the system and of the maintenance protocols. The Global Index of Microbial Contamination (GIMC per cubic meter) showed a value greater than the mean during the heating period (290), while the highest values (95th percentile 1,138.45) were recorded in the period using air conditioning. The index of mesophilic bacterial contamination, though it did not show any significant differences in the various modes of air treatment, showed a mean value (1.34) and the 95th percentile value (4.14), which was greater in the air-conditioning phase. Finally, the mean value of the amplification index underlined a decrease in the microbial contamination in comparison to the outside, while showing situations of increased microbial amplification during the period of simple ventilation (95th percentile 4.27). The 95th percentile values found for GICM in the three sampling periods, however, permitted us to identify the value of GIMC per cubic meter equal to 1,000 as a guide to provide a means of self-monitoring the quality of the air inside the classrooms. From a microclimatic viewpoint, two periods of the year manifested discomfort situations: during the heating phase (winter) and during the simple ventilation phase (spring). The results obtained indicate, therefore, a need to intervene on the environmental parameters, not being able, in this particular case, to intervene on other aspects that influence the microclimate. PMID- 21792517 TI - Assessment of sediment quality in the Mediterranean Sea-Boughrara lagoon exchange areas (southeastern Tunisia): GIS approach-based chemometric methods. AB - Concentrations of selected heavy metals (Cd, Pb, Zn, Cu, Mn, and Fe) in surface sediments from 66 sites in both northern and eastern Mediterranean Sea-Boughrara lagoon exchange areas (southeastern Tunisia) were studied in order to understand current metal contamination due to the urbanization and economic development of nearby several coastal regions of the Gulf of Gabes. Multiple approaches were applied for the sediment quality assessment. These approaches were based on GIS coupled with chemometric methods (enrichment factors, geoaccumulation index, principal component analysis, and cluster analysis). Enrichment factors and principal component analysis revealed two distinct groups of metals. The first group corresponded to Fe and Mn derived from natural sources, and the second group contained Cd, Pb, Zn, and Cu originated from man-made sources. For these latter metals, cluster analysis showed two distinct distributions in the selected areas. They were attributed to temporal and spatial variations of contaminant sources input. The geoaccumulation index (I (geo)) values explained that only Cd, Pb, and Cu can be considered as moderate to extreme pollutants in the studied sediments. PMID- 21792518 TI - Evaluating the utility and seasonality of NDVI values for assessing post disturbance recovery in a subalpine forest. AB - Forest disturbances around the world have the potential to alter forest type and cover, with impacts on diversity, carbon storage, and landscape composition. These disturbances, especially fire, are common and often large, making ground investigation of forest recovery difficult. Remote sensing offers a means to monitor forest recovery in real time, over the entire landscape. Typically, recovery monitoring via remote sensing consists of measuring vegetation indices (e.g., NDVI) or index-derived metrics, with the assumption that recovery in NDVI (for example) is a meaningful measure of ecosystem recovery. This study tests that assumption using MODIS 16-day imagery from 2000 to 2010 in the area of the Colorado's Routt National Forest Hinman burn (2002) and seedling density counts taken in the same area. Results indicate that NDVI is rarely correlated with forest recovery, and is dominated by annual and perennial forb cover, although topography complicates analysis. Utility of NDVI as a means to delineate areas of recovery or non-recovery are in doubt, as bootstrapped analysis indicates distinguishing power only slightly better than random. NDVI in revegetation analyses should carefully consider the ecology and seasonal patterns of the system in question. PMID- 21792519 TI - Computed tomography-guided stereotactic biopsy of intracranial lesions in pediatric patients. AB - PURPOSE: The primary objective of this study was to report the results of author's 18-year experience of diagnostic stereotactic biopsy procedures in children with intracranial lesions. METHODS AND MATERIALS: A retrospective analysis was conducted on stereotactic procedures performed on children with brain tumor between 1989 and 2007. RESULTS: Stereotactic biopsy of intracranial tumors was performed in 172 children (69 girls, and 103 boys) with the mean age of 9.17 +/- 3.66 years at the time of diagnosis. The most frequent anatomical location of lesions was brainstem (45.9%). Glioma was the most common diagnosis, represented in 90.7% of patients (156 patients). Other diagnosed tumors (4.7%) were classified as metastatic (1.7%), lymphomas (1.2%), oligodendroglioma (0.6%), craniopharyngioma (0.6%), and pineocytoma (0.6%). Nonneoplastic lesions were revealed in 4.7% of patients. CONCLUSION: The most frequent brain pathology of children is glioma, but the incidence of brain lesions other than gliomas and the frequency of brain lesions in the inoperable areas are compelling reasons to establish tissue diagnosis. PMID- 21792520 TI - Operative treatment for microcephaly secondary to craniosynostosis at the turn of the twentieth century. AB - INTRODUCTION: Microcephaly has been described throughout history, and physicians in the nineteenth and early twentieth centuries struggled to identify the etiology of this condition in order to better treat it. In 1908, Cushing wrote in Surgery of the Head, in Keen's Surgery Its Principles and Practice, that the use of craniotomies for the treatment of microcephaly was a futile practice, with limited post-operative improvement that did not justify the operative risks. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical files of the Johns Hopkins Hospital, from 1896 to 1912, were reviewed. A single case of operative treatment of microcephaly, performed 3 years after Cushing's published opinion on the procedure, was discovered and is described here. RESULTS: In 1911, a 3-year-old girl from Florida presented with complaints of an "inability to walk" and "backward development." The diagnosis of microcephaly, possibly secondary to craniosynostosis, was made. Cushing operated upon her twice, performing bilateral decompressive craniotomies in a two-stage operation, without excision of the synostosis. Post-operatively, he documented improvement in the child's condition and a resolution of some presenting symptoms. CONCLUSIONS: Although Cushing published his disapproval of the use of craniotomies in the treatment of microcephaly in 1908, a review of his early surgical files demonstrates that this opinion was based on cases published in the literature, rather than his own operative experience. In 1911, he performed bilateral craniotomies in a 3-year old patient with microcephaly and documented post-operative improvement in the patient's general condition. PMID- 21792521 TI - Spinal anaesthesia and monitored conscious sedation for repair of infantile meningomyelocele. AB - OBJECTIVES: Monitored conscious sedation combined with spinal anaesthesia (MCSS) to repair myelomeningocoele (MM) has received little attention in the literature. It has the potential of rapid postoperative recovery, minimal perioperative morbidity and probable reduced cost of management. The objective of this study was to prospectively analyze the safety and effectiveness of MCSS during repair of MM in infants. MATERIALS AND METHODS: This series consists of a prospective study of the clinical features, anaesthetic technique and perioperative outcome of 30 infants who underwent repair of MM under MCSS. The procedure was considered safe and effective if no event occurred during anaesthesia resulting in the procedure being aborted or postoperative complication related to the anaesthetic technique. RESULTS: There were 19 males and 11 females. The median age of the patients was 3 months ranging from 2 days to 12 months. The study included patients with lumbar (four patients), lumbosacral (23 patients) and sacral (three patients) MM. None of the cases needed to be converted to general anaesthesia. The mean duration of surgery was 56.4 min (median = 55 min; range of 40-85 min). There was no significant perioperative morbidity or mortality. CONCLUSIONS: The prevailing adverse socioeconomic status, health undermining religious belief, paucity of neurosurgeons/neuroanaesthetists and inadequate facilities in sub Saharan Africa delay the presentation and surgical intervention of patients with MM. This technique is useful if the exclusion criteria are adhered to and should be considered as one of the armamentarium in economically challenged environments as it is probably cheaper than general anaesthesia. PMID- 21792522 TI - Optimizing and evaluating the biocompatibility of fiber composites with calcium phosphate additives. AB - Composite materials based on a polyamide fabric (aramid) and a polydymethylsiloxane (PDMS) matrix were designed for application in bone surgery. In order to increase the bioactivity, 2, 5, 10, 15, 20, and 25 vol.% of nano/micro hydroxyapatite (HA) and tricalcium phosphate (TCP) were added. We studied the effect of the additives on the biocompatibility of the composite. It appears that nano additives have a more favorable effect on mechanical properties than microparticles. 15 vol.% of nano hydroxyapatite additive is an optimum amount for final application of the composites as substitutes for bone tissue: in this case both the mechanical properties and the biological properties are optimized without distinct changes in the inner structure of the composite. PMID- 21792523 TI - Expected frequency of biomechanically adverse values of proximal femur geometric variables for fracture risk in the East Slovak female population (epidemiological study). AB - BACKGROUND: The geometric configuration of the proximal femur predicts the risk for fracture by fall independently of bone mineral density (BMD). The objective of the study was to determine the expected frequency of biomechanically adverse and extremely adverse values of proximal femur geometric variables alpha angle, theta angle, and HAL, increasing the risk of a femoral neck fracture by fall, in the East Slovak female population. METHODS: DXA (dual energy X-ray absorbtiometry) measurements of the left proximal femur were obtained and analysed from sample 3151 East Slovak women aged 20-89 years, [Formula: see text] = 58.9 years, SD = 11.1, with risk factors for the development of osteoporosis, with osteopenia and osteoporosis using bone densitometer (Prodigy - Primo, GE, USA). Measured variables: 1. geometric variables: alpha angle, theta angle, HAL (hip axis length) and 2. biomechanical variable: FNS (femoral neck strength). STATISTICAL ANALYSIS: 1. Goodness-of-Fit Test chi(2)-test (Chi-Squared Test). 2. Logistic regression. RESULTS: Biomechanically adverse value of angle alpha>6.869 degrees can be expected in 10% of the East Slovak female population; extremely adverse value of angle alpha>12.3 degrees in 1%; biomechanically adverse value of angle theta>129.405 degrees in 20%; extremely adverse value of angle theta>132.290 degrees in 10%; biomechanically adverse length of HAL>109.930 mm in 20%; extremely adverse length of HAL>113.015 mm in 10%. CONCLUSIONS: The study brings the first data determining the mean values and 95% C.I. for proximal femur geometric variable values in the East female Slovak population. Biomechanically adverse values of proximal femur geometric variables are values higher than the upper limit of 95% C. I. and these findings enable now physicians to identify the individuals at risk and at high risk of hip fracture by fall. PMID- 21792524 TI - The role of nutrition in the prevention of sarcopenia. AB - Nutrition is regarded as one important contributing factors in the complex etiology of sarcopenia. Associations between several nutritional factors and muscle mass, strength, function and physical performance were reported in a growing number of studies in recent years. Accordingly, the avoidance of weight loss is crucial to prevent the concomitant loss of muscle mass. Adequate amounts of high-quality protein are important for optimal stimulation of muscle protein synthesis. Vitamin D, antioxidants and omega 3-polyunsaturated fatty acids may also contribute to the preservation of muscle function. In order to ensure adequate intake in all elderly, nutritional problems like loss of appetite and weight loss should be recognized early by routine screening for malnutrition in the elderly. Underlying causes need to be identified and subsequently corrected. The importance of physical activity, specifically resistance training, is emphasized, not only in order to facilitate muscle protein anabolism but also to increase energy expenditure, appetite and food intake in elderly people at risk of malnutrition. PMID- 21792525 TI - An evaluation of applied biomechanics as an adjunct to systematic specific causation in forensic medicine. AB - Biomechanical tests of post hoc probability have been proposed by prior authors as reliable tests of causation in forensic settings. Biomechanical assessment of injury kinetics and kinematics is a potentially important tool in forensic medicine, but there is also the potential for misapplication. The most reliable application is when biomechanical analysis is used to explain injury mechanisms, such as how an injury may have occurred. When a biomechanical analysis is used as a means of determining whether, rather than how an injury has resulted from a traumatic exposure, then a lack of reliability of the methodology limits its application in forensic medicine. Herein, we describe a systematic assessment of causation by adapting established general causation principles to specific causation scenarios, and how biomechanical analysis of injury mechanics is properly used to augment such an approach in conjunction with the principles of forensic epidemiology. An example calculation of relative risk associated with cervical spine injury is provided as a representative probabilistic metric for assessing causation. The statistical benefits and limitations of biomechanical analysis are discussed as an adjunct to forensic medicine. PMID- 21792526 TI - Biomechanical factors influencing the beginning and development of osteoarthritis in the hip joint. AB - Osteoarthritis (OA) can be used as a common name for a group of overlapping pathological conditions when the balance between the processes of degradation and synthesis, in individual parts of the cartilage, is disturbed and leads to gradual cartilage destruction. A preventive approach toward OA helps with a timely diagnosis and subsequent treatment of this disease. One of the significant risk factors affecting development of hip joint OA is the mechanism and magnitude of mechanical loading on the joint. The main motivation for this work was to verify the hypothesis involving a pathologic cycle (overloading - change of locomotion - overloading) as contributory to the development of OA and whether it can be stopped, or at least partly decelerated, by a suitable change of movement stereotypes. Providing that there is a natural balance of muscular action, from the beginning of OA, the development of OA can be significantly decelerated. The return to a natural force balance can be achieved using suitable exercise and strengthening of muscular structures. In order to verify the hypothesis, we undertook experimental measurements of gait kinematics and a computational analysis of the hip joint using the Finite Element Method. PMID- 21792527 TI - Comparison of antihyperglycemic effects of creatine and glibenclamide in type II diabetic patients. AB - This study compares the effects of glibenclamide and creatine in type II diabetics. In a 14-day symmetrically randomized crossover trial recently detected type II diabetics received either creatine (3 g) or glibenclamide (3.5 mg) for five successive days, followed by two days of washout, and crossover to the opposite treatment. Glucose, insulin, c-peptide, and creatine were measured. Creatine and glibenclamide decreased glucose concentrations vs. basal glucose [ 15, 60, 90, 120, 180, and 240 min; mol/l]: 12.6+/-0.83 vs. 12.2+/-0.56 vs. 12.1+/ 0.57, 15.3+/-0.63 vs. 13.5+/- 0.70(a ) vs. 13.0+/-0.57(a), 14.8+/-0.57 vs. 13.8+/ 0.59(a) vs. 13.4+/-0.46(a), 14.6+/-0.61 vs. 12.3+/-0.49(b) vs. 12.4+/-0.61(a), 12.8+/-0.76 vs. 10.0+/- 0.40(c) vs. 10.3+/-0.41(c), and 11.4+/-0.67 vs. 8.3+/ 0.40(c) vs. 8.5+/-0.36(c); ((a) p<0.05; (b) p<0.01; (c) p<0.001 vs. basal glucose). Treatment with both creatine and glibenclamide increased insulin and c peptide concentrations after 120 and 240 min (p<0.05 and p<0.01). At the doses applied short-term treatment with creatine and glibenclamide elicits similar glucose lowering effects. PMID- 21792528 TI - Role of optimization criterion in static asymmetric analysis of lumbar spine load. AB - A common method for load estimation in biomechanics is the inverse dynamics optimization, where the muscle activation pattern is found by minimizing or maximizing the optimization criterion. It has been shown that various optimization criteria predict remarkably similar muscle activation pattern and intra-articular contact forces during leg motion. The aim of this paper is to study the effect of the choice of optimization criterion on L4/L5 loading during static asymmetric loading. Upright standing with weight in one stretched arm was taken as a representative position. Musculoskeletal model of lumbar spine model was created from CT images of Visible Human Project. Several criteria were tested based on the minimization of muscle forces, muscle stresses, and spinal load. All criteria provide the same level of lumbar spine loading (difference is below 25%), except the criterion of minimum lumbar shear force which predicts unrealistically high spinal load and should not be considered further. Estimated spinal load and predicted muscle force activation pattern are in accordance with the intradiscal pressure measurements and EMG measurements. The L4/L5 spine loads 1312 N, 1674 N, and 1993 N were predicted for mass of weight in hand 2, 5, and 8 kg, respectively using criterion of mininum muscle stress cubed. As the optimization criteria do not considerably affect the spinal load, their choice is not critical in further clinical or ergonomic studies and computationally simpler criterion can be used. PMID- 21792529 TI - [Psychotropic drugs and diabetes]. AB - Psychotropic drugs, such as antipsychotics and antidepressants, are widely used substances which can display marked metabolic side effects. Psychiatric patients display increased morbidity and mortality which, besides disease specific factors, may be attributed to metabolic side effects of psychotropic drugs. Commonly observed side effects of antipsychotics are weight gain as well as disturbances in glucose and lipid metabolism. Additionally, antipsychotics have been shown to increase diabetes risk. Also, the use of some of the antidepressant substances is associated with an increased diabetes risk. However, large inter substance variations have been observed. Conversely, diabetics have an increased risk of depression. Metabolic side effects of psychotropic drugs pose a serious impairment for psychiatric patients and their management can play a pivotal role in therapeutic compliance and success. This review aims to give an overview of metabolic side effects of commonly used psychotic drugs and to give an insight into possible underlying mechanisms. PMID- 21792530 TI - [Diabetes mellitus and cognitive decline]. AB - From large epidemiological studies, it has been demonstrated that diabetes mellitus is a risk factor for cognitive decline: Compared to healthy controls, patients with diabetes perform worse on cognitive tests, they experience a pronounced cognitive decline over time and have a higher incidence of dementia. Mechanisms contributing to cognitive decline include vascular damage, negative consequences of hypo- and hyperglycemia, and various dysfunctions in insulin action, summarized as insulin resistance. Possible targets for prevention and treatment of cognitive decline have attracted scientific attention. PMID- 21792531 TI - Sarcopenia - pathophysiology and clinical relevance. AB - The causes of sarcopenia are multidimensional. The loss of fast-twitch muscle fibres exceeds the loss of slow-twitch muscle fibres and ends as a clinical relevant loss of muscle power. On a sub-cellular level, age associated changes in the mitochondria lead to functional decline of the muscle. The reduction of motor units causes muscle fibre atrophy and loss of muscle strength. Low levels of anabolic hormones and the imbalance of pro- and anti-inflammatory cytokines are responsible for changes in body composition of older adults. Reduced levels of physical activity, vitamin D and protein are highly associated with muscle loss. Sarcopenia causes loss of independence and high medical and nursing needs resulting in great economic healthcare burden. PMID- 21792533 TI - Subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia. AB - From the clinical practice and some experimental studies, it is apparent that paranoid schizophrenia patients tend to assign emotional salience to neutral social stimuli. This aberrant cognitive bias has been conceptualized to result from increased emotional arousal, but direct empirical data are scarce. The aim of the present study was to quantify the subjective emotional arousal (SEA) evoked by emotionally non-salient (neutral) compared to emotionally salient (negative) social stimuli in schizophrenia patients and healthy controls. Thirty male inpatients with paranoid schizophrenia psychosis and 30 demographically matched healthy controls rated their level of SEA in response to neutral and negative social scenes from the International Affective Picture System and the Munich Affective Picture System. Schizophrenia patients compared to healthy controls had an increased overall SEA level. This relatively higher SEA was evoked only by the neutral but not by the negative social scenes. To our knowledge, the present study is the first designed to directly demonstrate subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia. This finding might explain previous clinical and experimental data and could be viewed as the missing link between the primary neurobiological and secondary psychological mechanisms of paranoid psychotic-symptom formation. Furthermore, despite being very short and easy to perform, the task we used appeared to be sensitive enough to reveal emotional dysregulation, in terms of emotional disinhibition/hyperactivation in paranoid schizophrenia patients. Thus, it could have further research and clinical applications, including as a neurobehavioral probe for imaging studies. PMID- 21792532 TI - Physical activity, exercise, and sarcopenia - future challenges. AB - BACKGROUND: Numerous studies have demonstrated that the etiology of sarcopenia is multi-causal and very complex process. The degradation of muscle mass leads to a loss of strength, later on to a decreased functional status, impaired mobility, a higher risk of falls, and eventually an increased risk of mortality. Present guidelines state that physical inactivity or a decreased physical activity level is a part of the underlying mechanisms of sarcopenia and therefore physical activity can be seen as an important factor to reverse or modify the development of sarcopenia. TOPIC: Results in the area of physical activity and aging have not always been homogeneous. The inconsistent findings in this research area are related to the different understanding of terms and underlying constructs along with different population, type of intervention, or measurement methods. These aspects will be discussed in the paper. With regard to the formulated future role of physical activity this article will discuss in addition different barriers and challenges in the prevention and treatment of sarcopenia. A multitude of studies shows that structured exercise programs including progressive resistance or power training have positive effects on sarcopenia and sarcopenia-related outcomes but less or inconclusive information is available for the transfer to functional outcomes. CONCLUSIONS: Both physical activities and exercise have shown to decrease risk of sarcopenia and onset of functional limitations in older persons. Unfortunately the cohort of older persons is the one with the highest percentage of individuals classified as inactive or sedentary. Therefore motivating older persons to increase their physical activity level as well as providing safe access to exercise programs seems to be a mandatory task. PMID- 21792534 TI - General and domain-specific neurocognitive impairments in deficit and non-deficit schizophrenia. AB - Earlier studies suggested more severe overall cognitive impairments in deficit versus non-deficit schizophrenia; however, the specific contribution of different cognitive domains to this overall cognitive impairment remains unclear. The purpose of this study was to compare the two subtypes in general cognitive functioning as well as in individual cognitive domains using the composite score approach. One hundred and forty-three patients fulfilling the criteria for the deficit syndrome were compared with 123 patients diagnosed with non-deficit schizophrenia. Neurocognitive functioning was assessed by a neuropsychological test battery measuring the domains of sustained vigilance/attention, working memory, short-term memory, verbal memory, cognitive flexibility, and ideation fluency. Using the raw neuropsychological measures, we calculated a global index of cognitive impairment and domain-specific composite z-scores. Association between these composite scores and the deficit syndrome was examined by logistic regression analysis. After adjusting for relevant covariates including sex, age, education, smoking, and antipsychotic dose, results indicated a significant increase in the likelihood of deficit syndrome as a function of global (OR = 5.40; 95% CI 3.02-9.65) as well as domain-specific impairments (OR > 2 for all individual domains except for short-term memory). Cognitive flexibility was an independent predictor (OR = 2.92; 95% CI 1.47-5.80), whereas other cognitive domains demonstrated no unique contribution to the general cognitive impairment. Patients with deficit schizophrenia suffer from a more severe degree of neurocognitive impairment, which is qualitatively similar to the dysfunction seen in non-deficit schizophrenia. However, our results indicate that cognitive flexibility is specifically impaired in deficit versus non-deficit patients and may therefore represent a core feature of this subtype. PMID- 21792535 TI - The past, present, and future of genetic associations in type 1 diabetes. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting approximately one in 300 individuals in the United States. The majority of genetic research to date has focused on the heritability that predisposes to islet autoimmunity and T1DM. The evidence so far points to T1DM being a polygenic, common, complex disease with major susceptibility lying in the major histocompatibility complex (MHC) on chromosome 6 with other smaller effects seen in loci outside of the MHC. With recent advances in technology, novel means of exploring the human genome have given way to new information in the development of T1DM. The newest technologies, namely high-throughput polymorphism typing and sequencing, have led to a paradigm shift in studying common diseases such as T1DM. In this review we highlight the advances in genetic associations in T1DM in the last several decades and how they have led to a better understanding of T1DM pathogenesis. PMID- 21792536 TI - Organochlorine contaminants and quality of olive oil collected from olive oil growers along the Croatian Adriatic coast. AB - In this study we assessed 48 samples of virgin olive oil collected along the Croatian Adriatic coast for quality control, and for the presence of residues of seven organochlorine pesticides and 17 congeners of polychlorinated biphenyls (PCBs). Organochlorine pesticide levels ranged between below the limit of determination and 3.7 ng g(-1) of oil, while PCBs ranged between below the limit of determination and 1.8 ng g(-1) of oil. A larger problem than the presence of organochlorine compounds was that the seven tested oils (out of 48) did not meet some quality standards. PMID- 21792537 TI - Residual fate of the fungicide tetraconazole (4% EW) in mango. AB - A field trial was carried out to understand the persistence behaviour of tetraconazole in mango and also in the soil of mango orchard following five applications @ 50 g a.i./ha (T(1)) and 100 g a.i./ha (T(2)). The initial deposits were found to be 0.23 and 0.38 MUg/g for T(1) and T(2) doses. The theoretical maximum residue contribution (TMRC) of tetraconazole in dietary exposure appeared to be toxicologically safe for consumption as compared with maximum permissible intake (MPI). The half-life values of tetraconazole in mango were in the range of 4-5 days. The harvest samples of mango and soil were free from tetraconazole residues. PMID- 21792538 TI - Occurrence and distribution of sulfonylurea and related herbicides in central Canadian surface waters 2006-2008. AB - Surface water sampling in 2006-2008 measured the occurrence of sulfonylureas and related herbicides (SUs) during base flow conditions and wet weather events. Flumetsulam (29.2%), diuron (36.5%) and fomesafen (25.3%) were most frequently detected over the course of the study. Typical SU concentrations were in the low parts per trillion range; however, maximum concentrations of fomesafen (873 ng/L), linuron (856 ng/L) and diuron (2,900 ng/L) approached or exceeded 1 MUg/L. The temporal trend in SUs showed a correlation with application periods. In general, detections of SUs were more frequent where rotation of row crops was more intense. Sampling during wet-weather events indicated potential for a range of SUs to be flushed into surface waters at relatively high concentrations. PMID- 21792539 TI - Readiness for change predicts outcomes of functional rehabilitation following motor vehicle accident. AB - INTRODUCTION: Previous research has found pre-treatment motivational readiness to engage in pain self-management to be associated with completion of a rehabilitation program. This preliminary study examined this relationship, as well as the ability of pre-treatment readiness to change to predict clinical decisions of post-treatment functional work capacity. METHODS: The sample consisted of 106 individuals involved in a tertiary functional rehabilitation program for motor vehicle accident (MVA) survivors. The Multidimensional Pain Inventory (MPI) and Pain Stages of Change Questionnaire (PSOCQ) were completed prior to treatment. RESULTS: Hierarchical logistic regression analyses revealed that PSOCQ profile scores (P = 0.008), including higher individual PSOCQ contemplation (OR = 5.30; P = 0.017) and action (OR = 5.16; P = 0.049) scores, significantly increased the likelihood of completing the functional rehabilitation program. Clinical decisions about functional work capacity were predicted by MPI profile scores (P = 0.001), and this model was significantly improved by the addition of PSOCQ scores (P = 0.037). Lower MPI interference (OR = 5.41; P = 0.002), and higher MPI affective distress (OR = 2.81; P = 0.010), MPI support (OR = 1.72; P = 0.027), and PSOCQ action (OR = 5.35; P = 0.038) scores were significant predictors of clinicians' decisions regarding functional work capacity in the final model that identified 88% of those judged capable of returning to work and 63% of those who were judged not capable of returning to work. CONCLUSIONS: This preliminary study suggests that readiness to self-manage pain is an important predictor of both completion of functional rehabilitation program and clinicians' decisions regarding functional work capacity after an MVA. The latter outcome appears to be more complex, influenced both by motivational readiness to engage in pain self-management and cognitive-behavioral adaptation to pain. PMID- 21792541 TI - C-reactive protein, statins and the risk of vascular events: a better understanding. AB - The association between C-reactive protein (CRP) and cardiovascular disease has been under investigation for more than sixty years. Lately, findings from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial opened a new frontier: that of prescribing statins for vascular events risk reduction based upon the baseline CRP levels in otherwise healthy adults. Although the results from the JUPITER were impressive, ambiguities and arguments about this association have remained. Moreover, the results of a report by Heart Protection Study investigators have added to the complexities of the correlation between CRP levels and the risk of vascular events. In this review, a summary of the structural and functional properties of CRP and findings from various randomized controlled trials and observational studies is provided. This may lead to a better understanding of the intricate link between CRP levels and the risk of ensuing vascular events and the intermediary role of statins in reducing the vascular risk beyond what is justified by the lipocentric theory, by reducing the levels of CRP. PMID- 21792540 TI - Newly emerging therapies targeting viral-related lymphomas. AB - Gamma-(gamma)-herpes virus lymphomas comprise a heterogenous group of B-cell and T-cell neoplasms most commonly associated with Epstein-Barr virus and rarely human herpes virus-8 infection. Adult T-cell leukemia/lymphoma (ATLL) is a unique disease entity caused by the human T-cell lymphotrophic virus, type 1 (HTLV-I), the only retrovirus known to cause cancer in humans. Viral lymphomas behave aggressively and disproportionally affect immunocompromised individuals and those living in underdeveloped regions. These diseases are often difficult to treat with conventional approaches. Despite recent advancements using cytotoxic, lymphoma-specific, and adoptive therapies, the long-term outcome of patients with gamma-herpesvirus lymphomas occurring in severely immunocompromised patients and ATLL continues to be poor. Lytic-inducing therapies targeting NF-kappaB, and viral and tumor cell epigenetic mechanisms afford the advantage of exploiting the intrinsic presence of oncogenic viruses to eradicate infected tumor cells. In this review, viral-related lymphomas and newly emerging clinical approaches targeting viral latency are discussed. PMID- 21792542 TI - Cue-induced reinstatement of cocaine seeking in the rat "conflict model": effect of prolonged home-cage confinement. AB - RATIONALE AND OBJECTIVES: Drug addiction is not just the repeated administration of drugs, but compulsive drug use maintained despite the accumulation of adverse consequences for the user. In an attempt to introduce adverse consequences of drug seeking to laboratory animals, we have developed the "conflict model," in which the access of rats to a reinforcing lever allowing self-administration requires passing of an electrified grid floor. In this model, the current intensity leading to complete abstinence from drug seeking can be measured individually. The present study was designed to evaluated whether reinstatement of drug or natural reward seeking, despite the presence of the electrical barrier, can be achieved by presentation of discrete cues that were associated with the reward, and whether prolonged home-cage confinement can facilitate such reinstatement in this model. METHODS: The "conflict model" was used to test cue induced reinstatement in the presence of the electrical barrier, after 1 or 14 days of home-cage confinement, in groups of rats that were previously trained to self-administer cocaine or sucrose. RESULTS: Although similar shock intensity was required to suppress sucrose or cocaine self-administration, subjects exhibited significantly lower response to sucrose-associated as compared to cocaine associated cues, during the reinstatement test. Importantly, cue-induced reinstatement of cocaine seeking was attenuated following 14 days of home-cage confinement. CONCLUSIONS: The incorporation of aversive consequence in the self administration model enable detection of what can be interpreted as a compulsive component unique to drug reinforcers. Moreover, the effect of the aversive consequence seems to increase following home-cage confinement. PMID- 21792544 TI - Differentiating food allergies from food intolerances. AB - Adverse reactions to foods are extremely common, and generally they are attributed to allergy. However, clinical manifestations of various degrees of severity related to ingestion of foods can arise as a result of a number of disorders, only some of which can be defined as allergic, implying an immune mechanism. Recent epidemiological data in North America showed that the prevalence of food allergy in children has increased. The most common food allergens in the United States include egg, milk, peanut, tree nuts, wheat, crustacean shellfish, and soy. This review examines the various forms of food intolerances (immunoglobulin E [IgE] and non-IgE mediated), including celiac disease and gluten sensitivity. Immune mediated reactions can be either IgE mediated or non-IgE mediated. Among the first group, Immediate GI hypersensitivity and oral allergy syndrome are the best described. Often, but not always, IgE-mediated food allergies are entities such as eosinophilic esophagitis and eosinophilic gastroenteropathy. Non IgE-mediated immune mediated food reactions include celiac disease and gluten sensitivity, two increasingly recognized disorders. Finally, non-immune mediated reactions encompass different categories such as disorders of digestion and absorption, inborn errors of metabolism, as well as pharmacological and toxic reactions. PMID- 21792543 TI - Update on the management of Crohn's disease. AB - Crohn's disease (CD) is a chronic inflammatory disorder characterized by focal, asymmetric, transmural inflammation of any part of the luminal gastrointestinal tract of uncertain etiology and an unpredictable course. The available treatment options include aminosalicylates, budesonide and systemic corticosteroids, antibiotics, immunomodulators,methotrexate and anti-TNF agents. This review discusses recent developments in the treatment of CD and provides a comprehensive update on management of patients with CD based on the data from randomized controlled trials. PMID- 21792545 TI - ApoE genotypes are associated with age at natural menopause in Chinese females. AB - Ages at natural menarche and menopause are influenced by several genetic factors. This study aimed to investigate the possible relationship between the apolipoprotein E (ApoE) genotype and the age at menarche and natural menopause in Chinese females. In the current study, 398 (elderly group, aged 47-80 years) and 825 (young group, aged 15-25 years) Chinese females were enrolled under informed content. Ages at natural menarche and menopause were obtained by questionnaires. ApoE genotypes were identified by restriction fragment length polymorphism analysis. In the elderly group, the number of pregnancies and live births and breastfeeding were associated with the age at menopause (P = 0.008, P = 0.002, and P = 0.023, respectively). One-way ANOVA analysis revealed that the ApoE genotype was significantly associated with age at natural menopause (ANM; P = 0.010). Compared with ApoE epsilon3/3 carriers, ApoE epsilon3/4 females showed a 1.8-year delay in ANM (P = 0.002). Single ApoE allele-positive/allele-negative analysis also showed that the age at menopause of ApoE epsilon4 carriers was delayed compared with those who were not carriers (P = 0.023). In the young group, no statistical difference was found in the age of menarche between the carriers of ApoE epsilon3/3 and epsilon3/4. Single ApoE allele-positive/allele negative analysis showed that the age at menarche in ApoE epsilon4 carriers was slightly earlier than in those who were not carriers (P = 0.048). Meanwhile, univariate association analysis revealed that the ApoE genotypes were not significantly associated with the age at menarche using age as a covariate in the pooled group (young + elderly) (P = 0.143). We demonstrated that the ApoE genotype is significantly linked to the age at natural menopause. PMID- 21792546 TI - Effectiveness of a combined home visiting and group intervention for low income African American mothers: the pride in parenting program. AB - Intervention strategies are needed to improve maternal and infant outcomes in minority populations living in poverty. Home visiting by nurses has improved outcomes for mothers and young children, but use of professional staff makes these programs expensive. Pride in Parenting was a randomized controlled trial of paraprofessional home visitation to provide health and developmental intervention for high-risk African American mothers in Washington, DC. This study proposed to test whether paraprofessional visitors drawn from the community could effectively influence health and mothers' parenting behaviors and attitudes. African American mothers with inadequate prenatal care were recruited at delivery and randomized to intervention or usual care groups. The intervention curriculum was delivered through both home visitation and parent-infant groups for 1 year. The intervention curriculum was designed to improve knowledge, influence attitudes, and promote life skills that would assist low-income mothers in offering better health oversight and development for their infants. Both intervention and usual care groups received monthly social work contact over the one-year study period to provide referrals for identified needs. The intervention participants improved their home environments, a characteristic important for promoting good child development. Mothers' perceptions of available social support improved and child rearing attitudes associated with child maltreatment were reduced. Paraprofessional home visitors can be successful in improving the child-rearing environments and parenting attitudes for infants at risk, perhaps offering a less costly option to professional home visitors. PMID- 21792547 TI - Fetopathy probably associated to self-medication with a blocker of the renin angiotensin system. PMID- 21792548 TI - Serum concentrations of CA 125, CA 15-3, CA 19-9 and CEA in normal pregnancy: a longitudinal study. AB - PURPOSE: Although cancer diagnosed during pregnancy is rare, the coexistence of pregnancy and malignancy becomes more common in view of prolongation of reproductive age. Therefore, it is important that the specificity of a tumor marker be evaluated during pregnancy to avoid misinterpretation in the follow-up of a pregnant cancer patient. The present study aims to investigate the serum concentrations of CA-125, CA 15-3, CA 19-9 and CEA in healthy pregnant women through gestation. METHODS: In this prospective study, we followed thirty healthy pregnant women. Blood samples were obtained during each trimester of pregnancy (10-12, 22-24 and 34-36 weeks). The maternal serum levels of CA-125, CA 15-3, CA 19-9 and CEA were measured using electrochemiluminescence immunoassay. RESULTS: There was no difference between the first and second trimester serum levels of CA 125, CEA and CA 19-9. However, serum CA 125 levels in third trimester were found to be significantly elevated in pregnants compared to the second trimester (median values 19.6 vs. 15.6 IU/mL, p = 0,009). Similarly, the serum CEA levels in third trimester were significantly higher than those of second trimester (median values 1.1 vs. 0.7 ng/ml, p = 0.001). It is also found that CEA and CA 19 9 assay values were significantly elevated in the third trimester of pregnancy when compared with the first trimester of pregnancy (CEA median values 1.1 vs. 0.7 ng/ml, p = 0.02 and CA 19-9 median values 11.6 vs. 7.7 IU/mL, p = 0,02). Three trimester had statistically similar levels for serum CA 15-3 (median values 17.5, 19.7 and 18.3 U/mL, respectively). The four tumor markers assay values were found generally within the normal range. CONCLUSIONS: These findings suggest that maternal serum levels of CA 125, CEA and CA 19-9 were increased during third trimester of pregnancy. However, these elevations were within the normal range. CA 15-3 is independent of gestation and reliable tumor markers in monitoring malignancy in pregnant patients. PMID- 21792549 TI - Correlation of body mass index with outcome of in vitro fertilization in a developing country. AB - AIMS AND OBJECTIVE: To correlate ovarian response to stimulation and IVF outcome according to the women's body mass index (BMI). MATERIALS AND METHODS: Records of all patients who underwent IVF cycle in our institution from January 2008 to October 2010 were reviewed retrospectively. Three hundred and twenty-eight patients underwent 342 in vitro fertilization (IVF) cycles or intra-cytoplasmic sperm injection (ICSI) and were divided into four subgroups according to BMI; underweight, BMI < 18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; and obese, >30.0. RESULTS: In our study, with increasing BMI negative co-relation was seen with clinical pregnancy rate (CPR) (P value = 0.040). Increased doses of gonadotropins were required with increase in patients BMI (P value = 0.045). In the present study, no difference was seen in the number of oocyte retrieved but a decreased fertilization and cleavage rate was seen with decreased number of cryo preserved embryos with increasing BMI. This study shows that poorer oocyte quality is seen with increasing BMI which results in reduced CPR. In our study no deleterious effect of low BMI was seen on IVF outcome and CPR. CONCLUSION: Female obesity impairs IVF outcome potentially by impairing oocyte quality but does not affect ovarian response to stimulation. PMID- 21792550 TI - When and how to cover for fungal infections in patients with severe sepsis and septic shock. AB - Candida species remain the most frequently isolated fungi in intensive care unit (ICU) patients with severe sepsis or septic shock. Delayed antifungal therapy in these patients is a recognized risk factor for mortality. However, the diagnosis of invasive candidiasis remains difficult and is frequently delayed. Clinical scores have been proposed to assess the risk of development of invasive candidiasis or candidemia. Laboratory tools for early diagnosis are disappointing or still under development. Triazoles, polyenes, and echinocandins are the key drugs used to treat invasive candidiasis in ICU patients with similar efficacy, but very variable tolerability. The increasing incidence of fluconazole-resistant and susceptible-dose dependent strains and the safety profile of antifungal agents must be taken into account when selecting empiric therapy, frequently leading to the initial use of echinocandins in ICU patients with severe sepsis or septic shock. PMID- 21792551 TI - Determination of parabens and endocrine-disrupting alkylphenols in soil by gas chromatography-mass spectrometry following matrix solid-phase dispersion or in column microwave-assisted extraction: a comparative study. AB - Two rapid methods were evaluated for the simultaneous extraction of seven parabens and two alkylphenols from soil based on matrix solid-phase dispersion (MSPD) and microwave-assisted extraction (MAE). Soil extracts were derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide and analyzed by gas chromatography with mass spectrometry. Extraction and clean-up of samples were carried out by both methods in a single step. A glass sample holder, inside the microwave cell, was used in MAE to allow the simultaneous extraction and clean-up of samples and shorten the MAE procedure. The detection limits achieved by MSPD were lower than those obtained by MAE because the presence of matrix interferences increased with this extraction method. The extraction yields obtained by MSPD and MAE for three different types of soils were compared. Both procedures showed good recoveries and sensitivity for the determination of parabens and alkylphenols in two of the soils assayed, however, only MSPD yielded good recoveries with the other soil. Finally, MSPD was applied to the analysis of soils collected in different sites of Spain. In most of the samples analyzed, methylparaben and butylparaben were detected at levels ranging from 1.21 to 8.04 ng g(-1) dry weight and 0.48 to 1.02 ng g(-1) dry weight, respectively. PMID- 21792552 TI - The effect of the once-daily human glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen. AB - INTRODUCTION: Acetaminophen is a commonly used analgesic and antipyretic drug, and is frequently used to study gastric emptying. Due to its high permeability and high solubility, acetaminophen can be used as a pharmacologic model for medications with similar characteristics. The objective of this study was to assess the effect of liraglutide on the pharmacokinetics (PK) of acetaminophen in patients with type 2 diabetes. METHODS: This was a randomized, placebo controlled, two-period crossover trial in which subjects with type 2 diabetes received placebo or liraglutide. After steady state PK of liraglutide 1.8 mg/ placebo were established, a single dose of acetaminophen 1 g was administered at the time of liraglutide C(max) (maximum concentration). The PK profile of acetaminophen was assessed at 18 time points during the 8-hour post-dosing period. Placebo and liraglutide were considered equivalent with respect to area under the curve (AUC)(0-infinity) and AUC(0-480) min of acetaminophen if the 90% CI for the ratio was fully contained within the limits of 0.80 to 1.25. RESULTS: All subjects (n=18; mean [SD] age 59 [7] years, body mass index [BMI] 29.7 [4.2] kg/m(2), and glycated hemoglobin [HbA(1c)] 7.8% [0.6%]) completed the study. Equivalence was demonstrated between liraglutide 1.8 mg at steady state and placebo, with respect to acetaminophen AUC(0-infinity) (estimated ratio 1.04; 90% CI: 0.97, 1.10) and acetaminophen AUC(0-480) min (estimated ratio 0.95; 90% CI: 0.89, 1.01). During liraglutide, a lower C(max) was observed (estimated ratio 0.69; 90% CI: 0.56, 0.85) and the median acetaminophen t(max) occurred 15 minutes later compared with placebo. CONCLUSION: The overall exposure of acetaminophen following a 1 g dose was comparable for subjects taking liraglutide or placebo, and the clinical impact of the lower C(max) and delay in absorption of acetaminophen was considered to be transient and small, and without clinical relevance. No adjustment for acetaminophen is recommended when used concomitantly with liraglutide. PMID- 21792553 TI - Repression of gibberellin biosynthesis or signaling produces striking alterations in poplar growth, morphology, and flowering. AB - We modified gibberellin (GA) metabolism and signaling in transgenic poplars using dominant transgenes and studied their effects for 3 years under field conditions. The transgenes that we employed either reduced the bioactive GAs, or attenuated their signaling. The majority of transgenic trees had significant and in many cases dramatic changes in height, crown architecture, foliage morphology, flowering onset, floral structure, and vegetative phenology. Most transgenes elicited various levels of height reduction consistent with the roles of GA in elongation growth. Several other growth traits were proportionally reduced, including branch length, internode distance, and leaf length. In contrast to elongation growth, stem diameter growth was much less affected, suggesting that semi-dwarf trees in dense stands might provide high levels of biomass production and carbon sequestration. The severity of phenotypic effects was strongly correlated with transgene expression among independent transgenic events, but often in a non-linear manner, the form of which varied widely among constructs. The majority of semi-dwarfed, transgenic plants showed delayed bud flush and early bud set, and expression of a native GAI transgene accelerated first time flowering in the field. All of the phenotypic changes observed in multiple years were stable over the 3 years of field study. Our results suggest that transgenic modification of GA action may be useful for producing semi-dwarf trees with modified growth and morphology for horticulture and other uses. PMID- 21792554 TI - Stable and transient periodic oscillations in a mathematical model for CTL response to HTLV-I infection. AB - The cytotoxic T lymphocyte (CTL) response to the infection of CD4+ T cells by human T cell leukemia virus type I (HTLV-I) has previously been modelled using standard response functions, with relatively simple dynamical outcomes. In this paper, we investigate the consequences of a more general CTL response and show that a sigmoidal response function gives rise to complex behaviours previously unobserved. Multiple equilibria are shown to exist and none of the equilibria is a global attractor during the chronic infection phase. Coexistence of local attractors with their own basin of attractions is the norm. In addition, both stable and unstable periodic oscillations can be created through Hopf bifurcations. We show that transient periodic oscillations occur when a saddle type periodic solution exists. As a consequence, transient periodic oscillations can be robust and observable. Implications of our findings to the dynamics of CTL response to HTLV-I infections in vivo and pathogenesis of HAM/TSP are discussed. PMID- 21792555 TI - Is it possible to predict the development of an incisional surgical site infection and its severity after biliary tract surgery for benign disease? AB - BACKGROUND/PURPOSE: Wound infection; that is, incisional surgical site infection (ISSI), is a common complication after biliary tract surgery. The aim of the present study was to identify the various risk factors for wound infection and to establish a formula to predict the development and severity of wound infections. METHODS: We analyzed the clinical data on 207 consecutive patients who underwent biliary surgery for benign diseases at our hospital. We identified the factors with the greatest influence on wound infection after biliary tract surgery, based on a statistical procedure. An original scoring system (ISSI predictive score) was proposed based on these risk factors. RESULTS: The incidence of postoperative wound infection was 9.7% (20/207). The patient's performance status; bile culture; perioperative fasting period (days); and intraoperative bile spillage were the most influential risk factors for wound infection. The incidences of wound infection in patients with ISSI predictive scores of >2.7 points and those with scores of 0-2.7 points were 75.0% (12/16) and 4.2% (8/191), respectively. Our score also correlated significantly with the severity of wound infection (r = 0.488, P < 0.001) and the length of the postoperative hospital stay (R = 0.508, P < 0.001). CONCLUSION: Our original scoring system makes it possible to predict not only the development of a wound infection and its severity after biliary tract surgery, but also the length of the postoperative hospital stay. PMID- 21792557 TI - Plant-pollinator interactions and floral convergence in two species of Heliconia from the Caribbean Islands. AB - Variation in interspecific interactions across geographic space is a potential driver of diversification and local adaptation. This study quantitatively examined variation in floral phenotypes and pollinator service of Heliconia bihai and H. caribaea across three Antillean islands. The prediction was that floral characters would correspond to the major pollinators of these species on each island. Analysis of floral phenotypes revealed convergence among species and populations of Heliconia from the Greater Antilles. All populations of H. caribaea were similar, characterized by long nectar chambers and short corolla tubes. In contrast, H. bihai populations were strongly divergent: on Dominica, H. bihai had flowers with short nectar chambers and long corollas, whereas on Hispaniola, H. bihai flowers resembled those of H. caribaea with longer nectar chambers and shorter corolla tubes. Morphological variation in floral traits corresponded with geographic differences or similarities in the major pollinators on each island. The Hispaniolan mango, Anthracothorax dominicus, is the principal pollinator of both H. bihai and H. caribaea on Hispaniola; thus, the similarity of floral phenotypes between Heliconia species suggests parallel selective regimes imposed by the principal pollinator. Likewise, divergence between H. bihai populations from Dominica and Hispaniola corresponded with differences in the pollinators visiting this species on the two islands. The study highlights the putative importance of pollinator-mediated selection as driving floral convergence and the evolution of locally-adapted plant variants across a geographic mosaic of pollinator species. PMID- 21792556 TI - The risk factors of fungal infection in living-donor liver transplantations. AB - PURPOSE: The aim of the study was to retrospectively assess in a Japanese university hospital the risk factors for fungal infections and mortality in living-donor liver transplantations (LDLTs). Although fungal infections are an important complication associated with high mortality in liver transplantation, the risk factors for fungal infections developing after LDLT remain poorly understood. METHODS: Patient records for a total of 156 patients undergoing LDLT over a 6-year period in our institution were retrospectively evaluated. All transplant recipients were routinely observed for fungal infections with close monitoring for febrile episodes and collection and culture of saliva, pharynx, sputum, urine, feces, and drain discharge specimens undertaken. Fungal infection was defined as proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group. Patients with definite or probable infection were diagnosed as having specific invasive fungal infection in this study. Data were reviewed and collated from these patients' records, and multivariate analyses were performed to identify possible risk factors for mortality and the development of fungal infections. RESULTS: Nineteen of 156 patients (12.2%) developed invasive fungal infections, involving Candida spp. (n = 13), Pneumocystis jiroveci (n = 4), and Aspergillus spp. (n = 2). Eight of these 19 patients died, 4 from pneumonia, and 1 each from cerebral hemorrhage, chronic rejection, virus-associated hemophagocytic syndrome, and cancer recurrence. The 5 year survival rate was significantly lower in patients with fungal infections than in those without (53 vs. 90%; p < 0.001). Fungal infection was independently associated with reoperation (odds ratio 6.92, 1.82-26.27, p = 0.004), posttransplant dialysis (5.62, 1.51-20.88, p = 0.009), and bacterial infection (3.94, 1.02-15.26, p = 0.04). CONCLUSION: Independent risk factors of fungal infection after LDLT are reoperation, posttransplant dialysis, and bacterial infection. PMID- 21792558 TI - Immunosuppressed patients with pandemic influenza A 2009 (H1N1) virus infection. AB - The purpose of this paper was to prospectively characterize the clinical manifestations and outcomes of confirmed influenza A 2009 (H1N1) virus infection in immunosuppressed patients with hospital admission and compare them with those of a general population. A multicenter prospective cohort study was carried out. All adult patients admitted to 13 hospitals in Spain with confirmed influenza A 2009 (H1N1) virus infection from June 12, 2009 to November 11, 2009 were included. Risk factors for complicated influenza infection were studied in immunosuppressed patients. Overall, 559 patients were included, of which 56 were immunosuppressed, nine with solid or hematological malignancies, 18 with solid organ transplant recipients, 13 with corticosteroid therapy, and six with other types of immunosuppression. Clinical findings at diagnosis were similar in both groups. Nineteen immunosuppressed patients had pneumonia (33.9%). Immunosuppressed patients with pandemic influenza had bacterial co-infection more frequently (17.9% vs. 6.4%, p = 0.02), specifically, gram-negative bacilli and Staphylococcus aureus infections. Mortality was higher in immunosuppressed patients (7.1% vs. 1.8%, p < 0.05). The only modifiable risk factor of complicated influenza A 2009 (H1N1) was delayed antiviral therapy. In immunosuppressed patients, influenza A 2009 (H1N1) virus infection has higher mortality than in non-immunosuppressed individuals. Bacterial co-infection is common in complicated cases. PMID- 21792559 TI - Outbreak of linezolid-resistant Staphylococcus haemolyticus in an Italian intensive care unit. AB - We report an outbreak of linezolid-resistant Staphylococcus haemolyticus strains (MIC 32 mg/L) in patients admitted to the Verona University Hospital Intensive Care Unit. The strains proved to be clonally related at pulsed field gel electrophoresis. All the strains showed the G2576T mutation responsible for linezolid-resistance and retained their resistance even after several passages on antibiotic-free medium. After a decade of linezolid use, multifocal emergence of linezolid resistance in coagulase-negative staphylococci has become an important matter of concern and mandates stricter control over the use of this antibiotic in order to preserve its clinical utility. PMID- 21792560 TI - A decade of developments in chronic heart failure treatment: a comparison of therapy and outcome in a secondary and tertiary hospital setting. AB - AIMS: To investigate determinants and temporal developments of treatment strategies, 5-year survival and heart transplantation rates between patients treated at secondary and tertiary hospitals. METHODS AND RESULTS: Baseline characteristics, treatment and follow-up data from 2,023 patients with chronic systolic heart failure due to ischaemic or dilated cardiomyopathy enrolled between 1995 and 2005 (996 patients treated at a secondary hospital vs. 1,027 patients treated at a tertiary hospital) were prospectively compared. Patients treated at the secondary hospital setting were twice as likely to have ischaemic cardiomyopathy compared to the tertiary hospital setting as the underlying cause of heart failure (59.7% vs. 33.0%, respectively) and were almost a decade older (mean age 65.2 vs. 56.7 years, respectively). The use of guideline-recommended therapy increased in both centres over time. In direct temporal comparison, both guideline-adherent pharmacological therapy and device therapy were implemented earlier at the tertiary hospital. Survival rates were significantly lower among patients treated at the secondary hospital (log-rank test P < 0.0001). The combined endpoint of all-cause mortality and heart transplantation, however, was not significantly different after adjustment for differences in baseline characteristics (P = 0.44). CONCLUSION: This study demonstrates the marked disparity between the patient cohorts with chronic systolic heart failure presenting at secondary and tertiary hospitals. Though patient characteristics particularly age, aetiology of heart failure and the time of implementation of pharmacological and device treatment of heart failure-differed significantly, after adjustment for differences in baseline characteristics, no substantial difference in the combined endpoint of all-cause mortality and HTX was found during the 5-year follow-up period. PMID- 21792561 TI - Cardiac troponin T concentrations above the 99th percentile value as measured by a new high-sensitivity assay predict long-term prognosis in patients with acute coronary syndromes undergoing routine early invasive strategy. AB - OBJECTIVE: A recently developed immunoassay for high-sensitivity measurement of cardiac troponin T (hsTnT) allows measurement at the 99th percentile for a normal population with an assay imprecision <10%. It is unclear whether such a low cutpoint (14 ng/L) is helpful for long-term risk stratification of patients with an acute coronary syndrome (ACS) undergoing routine early invasive strategy. PATIENTS AND MAIN OUTCOME MEASURES: Consecutive patients with ACS admitted to a chest pain unit were studied. The usefulness of hsTnT for early diagnosis of myocardial infarction (MI) and prediction of all-cause death or death/MI over a median of 271 days following presentation was compared against the fourth generation cTnT at the 99th percentile cutpoint. RESULTS: Of 1,384 patients with ACS enrolled, 47.8% had non-ST-segment elevation MI (NSTEMI), 26.4% unstable angina, 21.8% STEMI and 4% had non-ACS. Adjusted risk for all-cause death [adjusted HR 8.26 (95%CI: 1.13-66.33), p = 0.038] and death/MI [adjusted HR 2.71 (95% CI: 1.15-6.38), p = 0.023] were significantly higher with hsTnT above the 99th percentile. In particular, among patients with a standard fourth generation cTnT result below the 99th percentile cutoff (0.01 ng/mL), hsTnT improved risk assessment. Mortality risk associated with an elevated hsTnT was present across the spectrum of ACS, as well as in conditions with hsTnT elevations not related to ACS. CONCLUSION: hsTnT at the 99th percentile cutoff is useful for the diagnostic evaluation of patients with ACS, and provides strong and independent predictive power for adverse long-term outcomes even after early invasive strategy. PMID- 21792563 TI - Differences in the consumption rates and regulatory barriers to the accessibility of strong opioid analgesics in Israel and St. Petersburg. AB - OBJECTIVE: To compare trends in opioid consumption in Israel and St. Petersburg/Russia (morphine, oxycodone, pethidine, fentanyl, methadone, buprenorphine, trimeperidine, and papaveretum) over the period 2000-2008, and to describe the regulatory barriers to their accessibility as an exploratory variable for between-country differences. METHODS: Data were drawn from the databases maintained by the Israel Ministry of Health's Pharmaceutical Administration and the St. Petersburg Central Pharmaceutical Reserve. The data were converted into a defined daily dose (DDD)/1,000 inhabitants/day. Regulation was evaluated according to the WHO guidelines for the assessment of national opioid regulation. RESULTS: The opioid consumption rates in Israel were substantially higher than those in St. Petersburg. The excess in DDD/1,000 inhabitants/day was for fentanyl +0.287 in 2000 and +1.206 in 2008, for morphine +0.245 in 2000 and +0.122 in 2008, and for pethidine/trimeperidine +0.035 in 2000 and +0.007 in 2008. Oxycodone consumption increased in Israel from 0.31 DDD/1,000 inhabitants/day in 2000 to 0.46 DDD/1,000 inhabitants/day in 2008, whereas this analgesic is not available in St. Petersburg. Methadone and buprenorphine consumption rose in Israel, whereas these drugs are not available in Russia. Conversely, omnopon consumption decreased in St. Petersburg from 0.0206 DDD/1,000 inhabitants/day in 2000 to 0.00304 DDD/1,000 inhabitants/day in 2008, whereas the compound is not available in Israel. St. Petersburg differs from Israel with less opioid formulary availability and greater regulatory restrictions. CONCLUSION: The results suggest that strong opioid analgesics consumption rates in St. Petersburg yield those in Israel, and that the between-countries differences in opioid formularies availability and legal and regulatory barriers to opioids accessibility are responsible for the consumption discrepancies. PMID- 21792562 TI - Fluindione and drug reaction with eosinophilia and systemic symptoms: an unrecognised adverse effect? AB - PURPOSE: Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. METHODS: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. RESULTS: Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. CONCLUSIONS: Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment. PMID- 21792564 TI - Online nonlinear sequential Bayesian estimation of a biological wastewater treatment process. AB - Online estimation of unknown state variables is a key component in the accurate modelling of biological wastewater treatment processes due to a lack of reliable online measurement systems. The extended Kalman filter (EKF) algorithm has been widely applied for wastewater treatment processes. However, the series approximations in the EKF algorithm are not valid, because biological wastewater treatment processes are highly nonlinear with a time-varying characteristic. This work proposes an alternative online estimation approach using the sequential Monte Carlo (SMC) methods for recursive online state estimation of a biological sequencing batch reactor for wastewater treatment. SMC is an algorithm that makes it possible to recursively construct the posterior probability density of the state variables, with respect to all available measurements, through a random exploration of the states by entities called 'particle'. In this work, the simplified and modified Activated Sludge Model No. 3 with nonlinear biological kinetic models is used as a process model and formulated in a dynamic state-space model applied to the SMC method. The performance of the SMC method for online state estimation applied to a biological sequencing batch reactor with online and offline measured data is encouraging. The results indicate that the SMC method could emerge as a powerful tool for solving online state and parameter estimation problems without any model linearization or restrictive assumptions pertaining to the type of nonlinear models for biological wastewater treatment processes. PMID- 21792565 TI - Improved production of Pseudomonas sp. ECU1011 acetyl esterase by medium design and fed-batch fermentation. AB - We optimized culture medium and batch-fed fermentation conditions to enhance production of an acetyl esterase from Pseudomonas sp. ECU1011 (PSAE). This enzyme enantioselectively deacetylates alpha-acetoxyphenylacetic acid. The medium was redesigned by single-factor and statistical optimization. The addition of ZnSO(4) enhanced enzyme production by 37%. Yeast extract concentration was directly associated with the enzyme production. The fermentation was scaled up in a 5-l fermenter with the optimized medium, and the correlations between enzyme production and dissolved oxygen, pH, and feeding strategy were investigated. The fermentation process was highly oxygen-demanding, pH sensitive and mandelic acid inducible. The fermentation pH was controlled at 7.5 by a pH and dissolved oxygen feedback strategy. Feeding mandelic acid as both a pH regulator and an enzyme inducer increased the enzyme production by 23%. The results of the medium redesign experiments were confirmed and explained in fed-batch culture experiments. Mathematical models describing the fermentation processes indicated that the enzyme production was strongly associated with cell growth. The optimized pH and dissolved oxygen stat fed-batch process resulted high volumetric production of PSAE (4166 U/l, 7.2-fold higher than the initial) without enantioselectivity decline. This process has potential applications for industrial production of chiral mandelic acid or its derivatives. PMID- 21792566 TI - Identification of peptide sequences that target to the brain using in vivo phage display. AB - Phage display technology could provide a rapid means for the discovery of novel peptides. To find peptide ligands specific for the brain vascular receptors, we performed a modified phage display method. Phages were recovered from mice brain parenchyma after administrated with a random 7-mer peptide library intravenously. A longer circulation time was arranged according to the biodistributive brain/blood ratios of phage particles. Following sequential rounds of isolation, a number of phages were sequenced and a peptide sequence (CTSTSAPYC, denoted as PepC7) was identified. Clone 7-1, which encodes PepC7, exhibited translocation efficiency about 41-fold higher than the random library phage. Immunofluorescence analysis revealed that Clone 7-1 had a significant superiority on transport efficiency into the brain compared with native M13 phage. Clone 7-1 was inhibited from homing to the brain in a dose-dependent fashion when cyclic peptides of the same sequence were present in a competition assay. Interestingly, the linear peptide (ATSTSAPYA, Pep7) and a scrambled control peptide PepSC7 (CSPATSYTC) did not compete with the phage at the same tested concentration (0.2-200 pg). Labeled by Cy5.5, PepC7 exhibited significant brain-targeting capability in in vivo optical imaging analysis. The cyclic conformation of PepC7 formed by disulfide bond, and the correct structure itself play a critical role in maintaining the selectivity and affinity for the brain. In conclusion, PepC7 is a promising brain target motif never been reported before and it could be applied to targeted drug delivery into the brain. PMID- 21792567 TI - Weather conditions and voter turnout in Dutch national parliament elections, 1971 2010. AB - While conventional wisdom assumes that inclement weather on election day reduces voter turnout, there is remarkably little evidence available to support truth to such belief. This paper examines the effects of temperature, sunshine duration and rainfall on voter turnout in 13 Dutch national parliament elections held from 1971 to 2010. It merges the election results from over 400 municipalities with election-day weather data drawn from the nearest weather station. We find that the weather parameters indeed affect voter turnout. Election-day rainfall of roughly 25 mm (1 inch) reduces turnout by a rate of one percent, whereas a 10 degree-Celsius increase in temperature correlates with an increase of almost one percent in overall turnout. One hundred percent sunshine corresponds to a one and a half percent greater voter turnout compared to zero sunshine. PMID- 21792569 TI - A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial). AB - PURPOSE: Bone-seeking radiopharmaceuticals have palliative benefit in castration resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and (186)Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. METHODS: A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m(2) 3-weekly). (186)Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. RESULTS: Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of (186)Re HEDP dose level 4 was not started. CONCLUSION: Combined therapy with docetaxel and (186)Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m(2) 3-weekly followed by (188)Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m(2), followed by (188)Re-HEDP 20 MBq/kg body weight. PMID- 21792570 TI - Functional implications of hippocampal degeneration in early Alzheimer's disease: a combined DTI and PET study. AB - PURPOSE: Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. METHODS: Twenty patients with early AD (Mini-Mental State Examination 25.7 +/- 1.7) were studied with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. RESULTS: Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p < 0.005). The same correlation pattern was found for right hippocampal diffusivity (p < 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. CONCLUSION: These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment. PMID- 21792571 TI - Intra-arterial treatment with 90Y microspheres for hepatocellular carcinoma: 4 years experience at the Ghent University Hospital. AB - PURPOSE: We report on our experience in terms of eligibility, safety, response and survival for treatment of hepatocellular carcinoma (HCC) with (90)Y microspheres. Secondly, we investigated the urinary excretion of (90)Y following treatment. METHODS: We retrospectively reviewed all HCC patients referred to our department for (90)Y microsphere treatment. We recorded reasons for not proceeding to actual treatment. In case treatment was performed, we assessed the tolerance (Common Terminology Criteria for Adverse Events v3.0, CTCAE v3.0), the response [modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria] and long-term survival (Kaplan-Meier). The urinary excretion was estimated by 12-h urine collections post-injection for analysis in a gamma counter. RESULTS: Forty-three HCC patients were referred for radioembolization. Fourteen patients were excluded, mainly due to unfavourable (99m)Tc macroaggregated albumin (MAA) distribution. Twenty-nine patients were treated with (90)Y microspheres (TheraSphere, mean activity 2.17 GBq). In four patients severe clinical adverse events were encountered, however only in one case clearly related to the therapy. Twenty patients were assessable by mRECIST: complete response in 15%, partial response in 35%, stable disease in 30% and progression in 20% were observed. A median survival of 12.3 months (95% confidence interval 9.4-15.2) was estimated. Concerning the substudy on urinary excretion, only 0.0025% of the administered activity was excreted in the urine within the first 12 h following TheraSphere. CONCLUSION: Following a strict workup before admitting patients to radioembolization with TheraSphere, we found good clinical tolerance in the vast majority of patients. Radiological response assessment yielded an overall response rate of 50%, when evaluated early following treatment. Urine analysis showed consistently only low activities of (90)Y excreted in the urine. PMID- 21792572 TI - Focal uptake of 68Ga-DOTATOC in the pancreas: pathological or physiological correlate in patients with neuroendocrine tumours? AB - PURPOSE: Neuroendocrine tumours are frequently located in the upper abdomen and especially in the pancreas. Imaging of the abdomen with somatostatin analogs such as (68)Ga-DOTA-Phe(1)-Tyr(3)-octreotide (DOTATOC) is a standard approach for imaging neuroendocrine cancer, but is still challenging due to physiological and technical considerations in this area. Therefore, the aim of this study was to further investigate the origin of (68)Ga-DOTATOC findings in the pancreas. METHODS: Forty-three consecutive patients with neuroendocrine tumours were examined by (68)Ga-DOTATOC positron emission tomography (PET)/CT for staging or restaging. As imaging of the upper abdomen is frequently affected by breathing artefacts, PET and CT data were analysed for misalignment and rearranged if necessary. Any noticeable uptake in the pancreas was described. Tracer uptake in the head of the pancreas and the liver was measured by means of maximum and average standard uptake value (SUV(max), SUV(av)). The reference standards (malignant versus benign) for correlation with PET findings were clinical and radiological follow-up (mean follow-up time 14 months) (n = 37) or histological confirmation (n = 6). RESULTS: In 23 of 43 studies (54%) misalignment between PET and CT data was found with a mean value of 1.4 cm. Visual assessment demonstrated that 20 of 43 scans (46.6%) showed no uptake in the head of the pancreas. Of 43 scans, 23 (53.4%) showed noticeable uptake with focal pattern in the head of the pancreas in 10 scans and irregular pattern in 13 scans. Follow-up indicated malignant pancreatic lesions in three patients. The pancreatic head to liver SUV(av) ratios in these patients ranged from 1.62 to 6.85, whereas in cases of uptake without known malignancy ratios ranged from 0.56 to 1.19. Considering SUV(max), the ratio ranged from 3.24 to 9.1 and from 0.84 to 1.47, respectively. No statistically significant difference was noted between uptake in the head of the pancreas and the liver in patients without malignant pancreatic tumours (p > 0.05). CONCLUSION: (68)Ga-DOTATOC uptake in the head of the pancreas is a common finding in patients undergoing (68)Ga-DOTATOC PET/CT. However, this finding most likely represents a physiological condition, especially if the uptake in the pancreatic head is similar to the uptake in the liver (uptake ratio head to liver SUV(av) < 1.4). Therefore, quantification is recommended to avoid false-positive diagnosis. Misalignment due to respiratory motion must always be taken into account. PMID- 21792573 TI - Impact of fibrinolysis on immediate prognosis of patients with out-of-hospital cardiac arrest. AB - Fibrinolytic therapy (FT) during out-of-hospital cardiac arrest (OHCA) has been studied in several trials, but they have produced unsatisfactory results even in the most recent Thrombolysis in Cardiac Arrest (TROICA) study. This study aimed to assess the impact of FT provided by an out-of-hospital emergency physician on the immediate prognosis of patients with OHCA. We performed a retrospective study in which the primary endpoint was survival to hospital admission. Among 5,102 patients with OHCA in Paris and the suburban area who received medical care from the Fire Brigade of Paris, 1,261 met the following inclusion criteria: age above 18 years with non-traumatic OHCA. Among 107 patients who received FT, 51 (47.7%) survived to hospital admission whereas 272 out of 1,154 (23.6%) patients who did not receive FT survived to hospital admission. A matching process based on a propensity score used to equalise potential prognosis factors in both groups demonstrated that FT was associated with more frequent survival to hospital admission (OR adjusted: 1.7; CI 95% [1.09-2.68]). This result was observed particularly in patients who were not initially shocked by automatic electrical defibrillator (AED) (OR(a) = 3.61; CI 95% [1.88-6.96]). This study showed that fibrinolysis was associated with improved survival to hospital admission, after performing a propensity analysis. FT may be beneficial in out-of-hospital arrest patients. However, any conclusions drawn are limited by the retrospective nature of the study. PMID- 21792574 TI - Emerging role of extracellular nucleotides and adenosine in multiple sclerosis. AB - Extracellular nucleotides and adenosine play important roles in inflammation. These signaling molecules interact with the cell-surface-located P2 and P1 receptors, respectively, that are widely distributed in the central nervous system and generally exert opposite effects on immune responses. Indeed, extracellular ATP, ADP, UTP, and UDP serve as alarmins or damage-associated molecular patterns that activate mainly proinflammatory mechanisms, whereas adenosine has potent anti-inflammatory and immunosuppressive effects. This review discusses the actual and potential role of extracellular nucleotides and adenosine in multiple sclerosis (MS). PMID- 21792576 TI - Seroprevalence of hepatitis B and C viruses: awareness and safe practices of hairdressers in Izmir: a survey. AB - OBJECTIVES: The aim of the study is to determine the seroprevalence of hepatitis B (HBV) and hepatitis C virus (HCV) infection in barbers and to assess the awareness of these employees related to occupational risks of HBV and HCV. MATERIALS AND METHODS: In this study, 2145 barbers in Izmir were given an occupational safety seminar. Blood samples were collected from 2066 voluntary participants and 1284 individuals completed the questionnaires. Sera were tested for the presence of HBV and HCV markers by ELISA. RESULTS: Our results document low levels of knowledge about HBV and HCV infection, risk perception and adequate protection among participants before the seminar session. Of the participants, 63.5% reported that they had suffered from equipment-related injuries during the last month. The prevalence of HBsAg positive and anti-HCV individuals of the 2066 person was found to be 2.2% and 0.4%, respectively. CONCLUSIONS: Hairdressers' knowledge of HBV, HCV and health hazards associated with their profession was inadequate. The prevalence of HBsAg positive and anti-HCV was similar to that among the general population. PMID- 21792575 TI - P2 receptors and platelet function. AB - Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA(2) and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G protein-coupled ADP receptors, namely the P2Y(1) and P2Y(12) receptor subtypes, while the P2X(1) receptor ligand-gated cation channel is activated by ATP. The P2Y(1) receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y(12) receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X(1) receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs. PMID- 21792577 TI - Occupational allergy to Limonium sinuatum: a case report. AB - Decorative flowers are known to be a cause of occupational allergy in the floral industry. The allergic manifestations induced by flowers include asthma, rhinoconjunctivitis and urticaria. We present a case of a 55-year-old woman, who has been working for the last 30 years as a gardener with various kinds of flowers, e.g., Limonium sinuatum (LS), chrysanthemum, sweet William (Dianthus barbatus) and Lilium. During the last 10 years she has developed nasal and eyes symptoms, dry cough, dyspnoea, chest tightness and wheezing. Clinical examination, routine laboratory testing, chest radiography, skin prick tests (SPT) involving common allergens, native plants pollens and leaves by the prick prick technique, rest spirometry, methacholine challenge test and specific inhalation challenge test (SICT) were conducted. SPT results to common allergens were positive for grass pollens. SPT with native plants pollens and leaves showed a positive reaction only for LS. SICT induced an isolated early asthmatic reaction and significant increase in the number of eosinophils in the nasal lavage fluid. Additionally, significant increase in non-specific bronchial hyperreactivity was observed after SICT. To our knowledge, the presently described report is the first one of Limonium sinuatum induced occupational asthma and rhinitis in a Polish gardener. PMID- 21792578 TI - Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide. AB - OBJECTIVES: Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. MATERIALS AND METHODS: The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. RESULTS: 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. CONCLUSIONS: The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response. PMID- 21792579 TI - Acute complicated pyelonephritis: contrast-enhanced ultrasound. AB - Imaging is required if complication is suspected in acute pyelonephritis to assess the nature and extent of the lesions, and to detect underlying causes. The current imaging modality of choice in clinical practice is computed tomography. Because of associated radiation and potential nephrotoxicity, CEUS is an alternative that has been proven to be equally accurate in the detection of acute pyelonephritis renal lesions. The aims of this study of 48 patients are to describe in detail the CEUS findings in acute pyelonephritis, and to determine if abscess and focal pyelonephritis may be distinguished. Very characteristic morphologic and temporal patterns of enhancement are described. These allow differentiation of focal pyelonephritis from renal abscess, and detection of tiny suppurative foci within focal pyelonephritis. The detection of abscesses is important because follow-up in 25 patients revealed a longer clinical course. Typical pyelonephritis CEUS features permit distinction from other renal lesions. As a whole, CEUS is an excellent tool in the work-up of complicated acute pyelonephritis, so it may be considered as the imaging technique of choice in the evaluation and follow-up of these patients who frequently are very young, so as to minimise radiation exposure. PMID- 21792580 TI - New findings on biological factors predicting addiction relapse vulnerability. AB - Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes. PMID- 21792581 TI - Update on attention-deficit/hyperactivity disorder and tic disorders: a review of the current literature. AB - Tic disorders impact quality of life, but when they are co-occurring with attention-deficit/hyperactivity disorder, the combined impact takes a toll on psychosocial functioning and adds another layer of complexity to treatment approaches. A review of the current literature supports evidence of a unique relationship between comorbid attention-deficit/hyperactivity disorder and tic disorders, emphasizing the intricate phenotype and impairment associated with these co-occurring conditions. The complexity of these symptoms requires careful diagnosis and appropriate treatment as determined by the level of impairment and can include pharmacotherapy, behavioral interventions, or a combination of therapies. To achieve the greatest benefits in improving quality of life and eliminating further comorbidity, an ideal treatment plan would include a comprehensive evaluation as well as a hierarchical treatment approach involving education of the child, family, and teachers; careful medication management; and cognitive and behavioral training. PMID- 21792582 TI - Adult attention-deficit/hyperactivity disorder and driving: why and how to manage it. AB - Driving is a complex task that can be a significant challenge for individuals with attention-deficit/hyperactivity disorder (ADHD). A slight lapse in attention or inhibition while driving (not uncommon in individuals with ADHD) can result in hazardous consequences for these individuals and their families. This is also an interesting clinical scenario for the treating physician, who is always trying to optimize the various treatment options for the patient. Despite such potentially perilous consequences for society, this subject only recently has received researchers' attention. This review paper highlights the psychological differences between drivers with and without ADHD and examines differences between these groups in various driving simulation models. Research updates involving pharmacologic and nonpharmacologic interventions are discussed at length. Although the long-term effects of such interventions may not be clearly defined, there is enough evidence to suggest the public health significance of such interventions for optimally managing adult symptoms of ADHD. PMID- 21792583 TI - Contribution of milk production to global greenhouse gas emissions. An estimation based on typical farms. AB - BACKGROUND, AIM AND SCOPE: Studies on the contribution of milk production to global greenhouse gas (GHG) emissions are rare (FAO 2010) and often based on crude data which do not appropriately reflect the heterogeneity of farming systems. This article estimates GHG emissions from milk production in different dairy regions of the world based on a harmonised farm data and assesses the contribution of milk production to global GHG emissions. MATERIALS, METHODS AND RESULTS: The methodology comprises three elements: (1) the International Farm Comparison Network (IFCN) concept of typical farms and the related globally standardised dairy model farms representing 45 dairy regions in 38 countries; (2) a partial life cycle assessment model for estimating GHG emissions of the typical dairy farms; and (3) standard regression analysis to estimate GHG emissions from milk production in countries for which no typical farms are available in the IFCN database. Across the 117 typical farms in the 38 countries analysed, the average emission rate is 1.50 kg CO(2) equivalents (CO(2)-eq.)/kg milk. The contribution of milk production to the global anthropogenic emissions is estimated at 1.3 Gt CO(2)-eq./year, accounting for 2.65% of total global anthropogenic emissions (49 Gt; IPCC, Synthesis Report for Policy Maker, Valencia, Spain, 2007). DISCUSSION AND CONCLUSION: We emphasise that our estimates of the contribution of milk production to global GHG emissions are subject to uncertainty. Part of the uncertainty stems from the choice of the appropriate methods for estimating emissions at the level of the individual animal. PMID- 21792587 TI - A modified method of 3D-SSP analysis for amyloid PET imaging using [11C]BF-227. AB - OBJECTIVE: Three-dimensional stereotactic surface projection (3D-SSP) analyses have been widely used in dementia imaging studies. However, 3D-SSP sometimes shows paradoxical results on amyloid positron emission tomography (PET) analyses. This is thought to be caused by errors in anatomical standardization (AS) based on an (18)F-fluorodeoxyglucose (FDG) template. We developed a new method of 3D SSP analysis for amyloid PET imaging, and used it to analyze (11)C-labeled 2-(2 [2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) PET images of subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: The subjects were 20 with MCI, 19 patients with AD, and 17 healthy controls. Twelve subjects with MCI were followed up for 3 years or more, and conversion to AD was seen in 6 cases. All subjects underwent PET with both FDG and BF-227. For AS and 3D-SSP analyses of PET data, Neurostat (University of Washington, WA, USA) was used. Method 1 involves AS for BF-227 images using an FDG template. In this study, we developed a new method (Method 2) for AS: First, an FDG image was subjected to AS using an FDG template. Then, the BF-227 image of the same patient was registered to the FDG image, and AS was performed using the transformation parameters calculated for AS of the corresponding FDG images. Regional values were normalized by the average value obtained at the cerebellum and values were calculated for the frontal, parietal, temporal, and occipital lobes. For statistical comparison of the 3 groups, we applied one-way analysis of variance followed by the Bonferroni post hoc test. For statistical comparison between converters and non-converters, the t test was applied. Statistical significance was defined as p < 0.05. RESULTS: Among the 56 cases we studied, Method 1 demonstrated slight distortions after AS of the image in 16 cases and heavy distortions in 4 cases in which the distortions were not observed with Method 2. Both methods demonstrated that the values in AD and MCI patients were significantly higher than those in the controls, in the parietal, temporal, and occipital lobes. However, only Method 2 showed significant differences in the frontal lobes. In addition, Method 2 could demonstrate a significantly higher value in MCI-to-AD converters in the parietal and frontal lobes. CONCLUSIONS: Method 2 corrects AS errors that often occur when using Method 1, and has made appropriate 3D-SSP analysis of amyloid PET imaging possible. This new method of 3D-SSP analysis for BF-227 PET could prove useful for detecting differences between normal groups and AD and MCI groups, and between converters and non converters. PMID- 21792584 TI - Toxicity, dioxin-like activities, and endocrine effects of DDT metabolites--DDA, DDMU, DDMS, and DDCN. AB - BACKGROUND, AIM, AND SCOPE: 2,2-bis(chlorophenyl)-1,1,1-trichloroethane (DDT) metabolites, other than those routinely measured [i.e., 2,2-bis(chlorophenyl)-1,1 dichloroethylene (DDE) and 2,2-bis(chlorophenyl)-1,1-dichloroethane (DDD)], have recently been detected in elevated concentrations not only in the surface water of Teltow Canal, Berlin, but also in sediment samples from Elbe tributaries (e.g., Mulde and Havel/Spree). This was paralleled by recent reports that multiple other metabolites could emerge from the degradation of parent DDT by naturally occurring organisms or by interaction with some heavy metals. Nevertheless, only very few data on the biological activities of these metabolites are available to date. The objective of this communication is to evaluate, for the first time, the cytotoxicity, dioxin-like activity, and estrogenicity of the least-studied DDT metabolites. METHODS: Four DDT metabolites, p,p'-2,2-bis(chlorophenyl)-1-chloroethylene (DDMU), p,p'-2,2 bis(chlorophenyl)-1-chloroethane (DDMS), p,p'-2,2-bis(4-ch1oropheny1)acetonitrile (DDCN), and p,p'-2,2-bis(chlorophenyl)acetic acid (DDA), were selected based on their presence in environmental samples in Germany such as in sediments from the Mulde River and Teltow Canal. O,p'-DDT was used as reference in all assays. Cytotoxicity was measured by neutral red retention with the permanent cell line RTG-2 of rainbow trout (Oncorhynchus mykiss). Dioxin-like activity was determined using the 7-ethoxyresorufin-O-deetylase assay. The estrogenic potential was tested in a dot blot/RNAse protection-assay with primary hepatocytes from male rainbow trout (O. mykiss) and in a yeast estrogen screen (YES) assay. RESULTS: All DDT metabolites tested revealed a clear dose-response relationship for cytotoxicity in RTG-2 cells, but no dioxin-like activities with RTL-W1 cells. The dot blot/RNAse protection-assay demonstrated that the highest non-toxic concentrations of these DDT metabolites (50 MUM) had vitellogenin-induction potentials comparable to the positive control (1 nM 17beta-estradiol). The estrogenic activities could be ranked as o,p'-DDT > p,p'-DDMS > p,p'-DDMU > p,p' DDCN. In contrast, p,p'-DDA showed a moderate anti-estrogenic effect. In the YES assay, besides the reference o,p'-DDT, p,p'-DDMS and p,p'-DDMU displayed dose dependent estrogenic potentials, whereas p,p'-DDCN and p,p'-DDA did not show any estrogenic potential. DISCUSSION: The reference toxicant o,p'-DDT displayed a similar spectrum of estrogenic activities similar to 17beta-estradiol, however, with a lower potency. Both p,p'-DDMS and p,p'-DDMU were also shown to have dose dependent estrogenic potentials, which were much lower than the reference o,p' DDT, in both the vitellogenin and YES bioassays. Interestingly, p,p'-DDA did not show estrogenic activity but rather displayed a tendency towards anti-estrogenic activity by inhibiting the estrogenic effect of 17beta-estradiol. The results also showed that the p,p'-metabolites DDMU, DDMS, DDCN, and DDA do not show any dioxin-like activities in RTL-W1 cells, thus resembling the major DDT metabolites DDD and DDE. CONCLUSIONS: All the DDT metabolites tested did not exhibit dioxin like activities in RTL-W1 cells, but show cytotoxic and estrogenic activities. Based on the results of the in vitro assays used in our study and on the reported concentrations of DDT metabolites in contaminated sediments, such substances could, in the future, pose interference with the normal reproductive and endocrine functions in various organisms exposed to these chemicals. Consequently, there is an urgent need to examine more comprehensively the risk of environmental concentrations of the investigated DDT metabolites using in vivo studies. However, this should be paralleled also by periodic evaluation and monitoring of the current levels of the DDT metabolites in environmental matrices. RECOMMENDATIONS AND PERSPECTIVES: Our results clearly point out the need to integrate the potential ecotoxicological risks associated with the "neglected" p,p'-DDT metabolites. For instance, these DDT metabolites should be integrated into sediment risk assessment initiatives in contaminated areas. One major challenge would be the identification of baseline data for such risk assessment. Further studies are also warranted to determine possible additive, synergistic, or antagonistic effects that may interfere with the fundamental cytotoxicity and endocrine activities of these metabolites. For a more conclusive assessment of the spectrum of DDT metabolites, additional bioassays are needed to identify potential anti-estrogenic, androgenic, and/or anti-androgenic effects. PMID- 21792588 TI - Surface properties and intracellular speciation revealed an original adaptive mechanism to arsenic in the acid mine drainage bio-indicator Euglena mutabilis. AB - Euglena mutabilis is a protist ubiquitously found in extreme environments such as acid mine drainages which are often rich in arsenic. The response of E. mutabilis to this metalloid was compared to that of Euglena gracilis, a protist not found in such environments. Membrane fatty acid composition, cell surface properties, arsenic accumulation kinetics, and intracellular arsenic speciation were determined. The results revealed a modification in fatty acid composition leading to an increased membrane fluidity in both Euglena species under sublethal arsenic concentrations exposure. This increased membrane fluidity correlated to an induced gliding motility observed in E. mutabilis in the presence of this metalloid but did not affect the flagellar dependent motility of E. gracilis. Moreover, when compared to E. gracilis, E. mutabilis showed highly hydrophobic cell surface properties and a higher tolerance to water-soluble arsenical compounds but not to hydrophobic ones. Finally, E. mutabilis showed a lower accumulation of total arsenic in the intracellular compartment and an absence of arsenic methylated species in contrast to E. gracilis. Taken together, our results revealed the existence of a specific arsenical response of E. mutabilis that may play a role in its hypertolerance to this toxic metalloid. PMID- 21792589 TI - cDNA cloning of a novel gene codifying for the enzyme lycopene beta-cyclase from Ficus carica and its expression in Escherichia coli. AB - Lycopene beta-cyclase (beta-LCY) is the key enzyme that modifies the linear lycopene molecule into cyclic beta-carotene, an indispensable carotenoid of the photosynthetic apparatus and an important source of vitamin A in human and animal nutrition. Owing to its antioxidant activity, it is commercially used in the cosmetic and pharmaceutical industries, as well as an additive in foodstuffs. Therefore, beta-carotene has a large share of the carotenoidic market. In this study, we used reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE)-PCR to obtain and clone a cDNA copy of the gene Lyc-beta from Ficus carica (Lyc-beta Fc), which codes for the enzyme lycopene beta-cyclase (beta-LCY). Expression of this gene in Escherichia coli produced a single polypeptide of 56 kDa of weight, containing 496 amino acids, that was able to cycle both ends of the lycopene chain. Amino acid analysis revealed that the protein contained several conserved plant cyclase motifs. beta-LCY activity was revealed by heterologous complementation analysis, with lycopene being converted to beta-carotene as a result of the enzyme's action. The beta-LCY activity of the expressed protein was confirmed by high-performance liquid chromatography (HPLC) identification of the beta-carotene. The lycopene to beta-carotene conversion rate was 90%. The experiments carried out in this work showed that beta-LYC is the enzyme responsible for converting lycopene, an acyclic carotene, to beta carotene, a bicyclic carotene in F. carica. Therefore, by cloning and expressing beta-LCY in E. coli, we have obtained a new gene for beta-carotene production or as part of the biosynthetic pathway of astaxanthin. So far, this is the first and only gene of the carotenoid pathway identified in F. carica. PMID- 21792590 TI - Endophyte-assisted promotion of biomass production and metal-uptake of energy crop sweet sorghum by plant-growth-promoting endophyte Bacillus sp. SLS18. AB - The effects of Bacillus sp. SLS18, a plant-growth-promoting endophyte, on the biomass production and Mn/Cd uptake of sweet sorghum (Sorghum bicolor L.), Phytolacca acinosa Roxb., and Solanum nigrum L. were investigated. SLS18 displayed multiple heavy metals and antibiotics resistances. The strain also exhibited the capacity of producing indole-3-acetic acid, siderophores, and 1 aminocyclopropane-1-carboxylic acid deaminase. In pot experiments, SLS18 could not only infect plants effectively but also significantly increase the biomass of the three tested plants in the presence of Mn/Cd. The promoting effect order of SLS18 on the biomass of the tested plants was sweet sorghum > P. acinosa > S. nigrum L. In the presence of Mn (2,000 mg kg(-1)) and Cd (50 mg kg(-1)) in vermiculite, the total Mn/Cd uptakes in the aerial parts of sweet sorghum, P. acinosa, and S. nigrum L. were increased by 65.2%/40.0%, 55.2%/31.1%, and 18.6%/25.6%, respectively, compared to the uninoculated controls. This demonstrates that the symbiont of SLS18 and sweet sorghum has the potential of improving sweet sorghum biomass production and its total metal uptake on heavy metal-polluted marginal land. It offers the potential that heavy metal-polluted marginal land could be utilized in planting sweet sorghum as biofuel feedstock for ethanol production, which not only gives a promising phytoremediation strategy but also eases the competition for limited fertile farmland between energy crops and food crops. PMID- 21792591 TI - A novel cold-active xylanase from the cellulolytic myxobacterium Sorangium cellulosum So9733-1: gene cloning, expression, and enzymatic characterization. AB - The cellulolytic myxobacterium Sorangium cellulosum is able to efficiently degrade many kinds of polysaccharides, but none of the enzymes involved have been characterized. In this paper, a xylanase gene (xynA) was cloned from S. cellulosum So9733-1 using thermal asymmetric interlaced PCR. The gene is composed of 1,209 bp and has only 52.27% G + C content, which is much lower than that of most myxobacterial DNA reported (67-72%). Gene xynA encodes a 402 amino acid protein that contains a single catalytic domain belonging to the glycoside hydrolase family 10. The novel xylanase gene, xynA, was expressed in Escherichia coli BL21 (DE3) and the recombinant protein (r-XynA) was purified by Ni-affinity chromatography. The r-XynA had the optimum temperature of 30-35 degrees C and exhibited 33.3% activity at 5 degrees C and 13.7% activity at 0 degrees C. Approximately 80% activity was lost after 20-min pre-incubation at 50 degrees C. These results indicate that r-XynA is a cold-active xylanase with low thermostability. At 30 degrees C, the K (m) values of r-XynA on beechwood xylan, birchwood xylan, and oat spelt xylan were 25.77 +/- 4.16, 26.52 +/- 4.78, and 38.13 +/- 5.35 mg/mL, respectively. The purified r-XynA displayed optimum activity at pH 7.0. The activity of r-XynA was enhanced by the presence of Ca(2+). The r-XynA hydrolyzed beechwood xylan, birchwood xylan, and xylooligosaccharides (xylotriose, xylotetraose, and xylopentose) to produce primarily xylose and xylobiose. To our knowledge, this is the first report on the characterization of a xylanase from S. cellulosum. PMID- 21792592 TI - Combinatorial engineering of ldh-a and bcl-2 for reducing lactate production and improving cell growth in dihydrofolate reductase-deficient Chinese hamster ovary cells. AB - In Chinese hamster ovary (CHO) cells, rapid glucose metabolism normally leads to inefficient use of glucose, most of which is converted to lactate during cell cultures. Since lactate accumulation during the culture often exerts a negative effect on cell growth and valuable product formation, several genetic engineering approaches have been developed to suppress lactate dehydrogenase-A (LDH-A), the enzyme converting pyruvate into lactate. However, despite the reduced lactate accumulation, such cell cultures are eventually terminated in the late period of the culture, mainly due to apoptosis. Therefore, we developed an apoptosis resistant, less lactate-producing dhfr(-) CHO cell line (CHO-Bcl2-LDHAsi) by overexpressing Bcl-2, one of the most well-known anti-apoptotic proteins, and by downregulating LDH-A in a dhfr(-) CHO cell line. When the dhfr(-) CHO-Bcl2-LDHAsi cell line was used as a host cell line for the development of recombinant CHO (rCHO) cells producing an Fc-fusion protein, the culture longevity of the rCHO cells was extended without any detrimental effect of genetic engineering on specific protein productivity. Simultaneously, the specific lactate production rate and apparent yield of lactate from glucose were reduced to 21-65% and 37-78% of the control cells, respectively. Taken together, these results show that the use of an apoptosis-resistant, less lactate-producing dhfr(-) CHO cell line as a host cell line saves the time and the effort of establishing an apoptosis resistant, less lactate-producing rCHO cells for producing therapeutic proteins. PMID- 21792593 TI - Characterisation of a gamma-butyrolactone receptor of Streptomyces tacrolimicus: effect on sporulation and tacrolimus biosynthesis. AB - Streptomyces tacrolimicus (ATCC 55098) was reported to produce the immunosuppressant tacrolimus. The wild-type strain sporulates sparsely and produces very low levels of this immunosuppressant. The lack of genetic knowledge of this strain has hampered strain improvement. In this work, we have cloned the gene encoding a gamma-butyrolactone receptor protein (Gbr). The gbr gene is linked to two genes encoding two subunits of the dihydroxyacetone kinase, putatively involved in the biosynthesis of the dihydroxyacetone phosphate precursor of gamma-butyrolactone but is not flanked by gamma-butyrolactone synthetase genes. The Gbr protein was overexpressed in Escherichia coli and purified. Electrophoretic mobility shift assays showed that Gbr binds to a specific autoregulatory element sequence located 338 bp upstream of the gbr gene, indicating that its expression is self-regulated. The deletion mutant Deltagbr showed a very early and intense sporulation in two different media. A phenotype similar to that of the wild-type strain was restored by complementation of the Deltagbr mutant with a wild-type gbr allele. Duplication of the gbr gene resulted in a slower sporulation. The Deltagbr mutant produced much lower amount (32%) of tacrolimus quantified by high performance liquid chromatography. This analysis, using an optimised system, allowed the resolution of tacrolimus from ascomycin and other contaminant metabolites. Our results indicate that the Gbr protein regulates negatively the sporulation and positively the production of tacrolimus. PMID- 21792594 TI - Possible differences in the two Z chromosomes in male chickens and evolution of MHM sequences in Galliformes. AB - The male hypermethylated (MHM) region of the chicken Z chromosome encodes a non coding RNA that is expressed only in females. The MHM sequence is found only in galliform birds, and Z genes near this region show an unusual degree of dosage compensation between males and females despite the overall low level of dosage compensation in Z chromosome gene expression in birds. Here we report that the MHM locus shows a dramatic sex difference in the configuration of chromatin, open in females and condensed in males, based on DNA fluorescent in situ hybridization of an MHM probe in interphase nuclei. The demethylating agent 5-aza-cytidine causes an asymmetric effect on the two Z chromosomes of males, altering the chromatin configuration, MHM RNA expression, and H4K16Ac modification, suggesting an inequality in the methylation status and chromatin of the two Z chromosomes. We identified numerous MHM-related genomic and RNA sequences that possess a short conserved sequence common to the majority of clones, suggesting the functional importance of the MHM region. Some of the RNA sequences, which like MHM are expressed in females but not in males, are likely to be polyadenylated and have genomic intron/exon structure. The turkey, another galliform bird, has repetitive sequences in the predicted turkey MHM region, raising the question of regional dosage compensation in the turkey as in the chicken. PMID- 21792595 TI - Different binding affinities of Pb2+ and Cu2+ to glycosylation variants of human serum transferrin interfere with the detection of carbohydrate-deficient transferrin. AB - Carbohydrate-deficient transferrin (CDT) is a specific biomarker of alcohol abuse, and for diagnosis of chronic alcohol, abuse is often determined using isoelectric focusing (IEF) and chromatographic techniques. To allow this method to be used for the diagnosis of alcohol abuse, inferences of various physical and chemical factors with the detection of CDT have been investigated. However, few reports have focused thus far on whether different metal ions have different binding affinities to CDT and HTf variants or further interfere in the detection of CDT. Here, in order to figure out whether and how metal ions such as Pb(2+) and Cu(2+) bind to holo-human serum transferrin (holo-HTf) and further interfere in CDT detection, the binding characteristics and the binding parameters of holo HTf with metal ions such as Pb(2+) and Cu(2+) were investigated using UV-visible spectroscopy, Fluorescence spectroscopy, and ICP-MS. Moreover, whether the metal ions such as Pb(2+) and Cu(2+) will reduce the diagnostic accuracy of CDT in clinic was investigated using IEF. The present study demonstrates that Pb(2+) and Cu(2+) have different binding affinities to holo-HTf variants and produce different changes in the relative amounts of each glycosylation isoforms of HTf. Accordingly, the glycosylation chains of HTf will affect the binding affinities of glycosylation isoforms with Pb(2+) and Cu(2+), causing further interferences in CDT detection. PMID- 21792596 TI - Reactive oxygen species production and antioxidant enzyme expression after Epstein-Barr virus lytic cycle induction in Raji cell line. AB - In a previous study, we have described oxidative stress during Epstein-Barr virus lytic cycle induction. Oxidative stress was evidenced by the observed high MDA levels and the decreased activities of antioxidant enzymes. We hypothesised that the lower activities of the antioxidant enzymes decrease were the result of either the excessive production of reactive oxygen radical species (ROS) or a negative regulation of the antioxidant enzyme gene expressions. In an attempt to clarify this situation, EBV lytic cycle was induced in Raji cell line by a non stressing dose of 12-0-tetradecanoylphorbol-13-acetate. BZLF-1, superoxide dismutase, and catalase gene expressions were then analysed using semi quantitative RT-PCR, simultaneously at a kinetic of 6, 12, 24, 36, and 48 h. ROS production was evaluated by chemiluminescence. A study was conducted to establish whether ROS production, BZLF-1, and the expression of antioxidant genes were inter-correlated. Induction of the lytic cycle resulted in increased expressions of the genes of superoxide dismutase and catalase, which began at 24 h (p < 0.05) and reached a peak at 48 h (p < 0.05). Significant increases of the ROS levels were observed in TPA-treated Raji cell line at 12 h, as compared with untreated cells, reaching a peak at 48 h after EBV lytic cycle induction. ROS production correlates positively with BZLF-1, SOD, and CAT gene expressions (p < 0.05; r = 0.913, r = 0.978, and r = 0.955, respectively). A positive correlation was also observed between BZLF-1 and antioxidant gene expressions (p < 0.05; r = 0.961 and r = 0.987, respectively). In conclusion, the observed increases of the SOD and CAT gene expressions eliminate the hypothesis of a repression of the respective genes during the induction of the lytic cycle. On the other hand, the observed direct correlation between the BZLF-1 gene expression and the ROS production is indicative of a role of this gene in oxidative stress. PMID- 21792597 TI - Coming of age in an ant colony: cephalic muscle maturation accompanies behavioral development in Pheidole dentata. AB - Although several neurobiological and genetic correlates of aging and behavioral development have been identified in social insect workers, little is known about how other age-related physiological processes, such as muscle maturation, contribute to task performance. We examined post-eclosion growth of three major muscles of the head capsule in major and minor workers of the ant Pheidole dentata using workers of different ages with distinct task repertoires. Mandible closer muscle fibers, which provide bite force and are thus critical for the use of the mandibles for biting and load carrying, fill the posterio-lateral portions of the head capsule in mature, older workers of both subcastes. Mandible closer fibers of newly eclosed workers, in contrast, are significantly thinner in both subcastes and grow during at least the next 6 days in minor workers, suggesting this muscle has reduced functionality for a substantial period of adult life and thus constrains task performance capability. Fibers of the antennal muscles and the pharynx dilator, which control antennal movements and food intake, respectively, also increase significantly in thickness with age. However, these fibers are only slightly thinner in newly eclosed workers and attain their maximum thickness over a shorter time span in minors. The different growth rates of these functionally distinct muscles likely have consequences for how adult P. dentata workers, particularly minors, develop their full and diverse task repertoire as they age. Workers may be capable of feeding and interacting socially soon after eclosion, but require a longer period of development to effectively use their mandibles, which enable the efficient performance of tasks ranging from nursing to foraging and defense. PMID- 21792598 TI - Integument coloration signals reproductive success, heterozygosity, and antioxidant levels in chick-rearing black-legged kittiwakes. AB - Carotenoid pigments are important for immunity and as antioxidants, and carotenoid-based colors are believed to provide honest signals of individual quality. Other colorless but more efficient antioxidants such as vitamins A and E may protect carotenoids from bleaching. Carotenoid-based colors have thus recently been suggested to reflect the concentration of such colorless antioxidants, but this has rarely been tested. Furthermore, although evidence is accruing for multiple genetic criteria for mate choice, carotenoid-based colors have rarely been shown to reflect both phenotypic and genetic quality. In this study, we investigated whether gape, tongue, eye-ring, and bill coloration of chick-rearing black-legged kittiwakes Rissa tridactyla reflected circulating levels of carotenoids and vitamins A and E. We further investigated whether integument coloration reflected phenotypic (body condition and fledging success) and genetic quality (heterozygosity). We found that the coloration of fleshy integuments was correlated with carotenoid and vitamin A levels and fledging success but only in males. Furthermore, the coloration of tongue and eye-ring was correlated with heterozygosity in both males and females. Integument colors might therefore be reliable signals of individual quality used by birds to adjust their parental care during the chick-rearing period. PMID- 21792599 TI - [New tyrosine kinase and EGFR inhibitors in cancer therapy. Cardiac and skin toxicity as relevant side effects. Part A: heart]. AB - Cardiotoxicity is a serious side effect of targeted molecular therapies in cancer treatment. Monoclonal antibodies and tyrosine kinase inhibitors are known to be potent therapies in various neoplastic diseases due to inhibition of specific signal transduction pathways. Although targeted therapies are considered to be less toxic and better tolerated than common chemotherapies certain cardiac side effects have been observed. Cardiac toxicity may range from asymptomatic reduction of left ventricular function to life-threatening events like heart failure and acute coronary syndrome. Further side effects are arterial hypertension, thrombosis and arrhythmias. Cardiovascular side effects are common for anti-HER2 therapy in combination with anthracyclines and for inhibitors of angiogenesis. In these patients careful cardiac monitoring is warranted. Because of missing randomized long-term follow-ups, information about cardiac side effects is limited in newly developed targeted molecular therapies. In case of cardiac side effects or preexisting cardiac disease before therapy initiation, assessments by a cardiologist throughout the course of treatment are important. For patients with severe cardiac side effects, discontinuation of treatment is warranted; in case of asymptomatic cardiac side effects symptom-specific therapy should be performed. PMID- 21792601 TI - The role of intrinsic sphincteric deficiency diagnosis in the era of midurethral sling. AB - The midurethral sling has gained popularity and is the most commonly used treatment of women with stress urinary incontinence (SUI). Whether intrinsic sphincteric deficiency (ISD) still should be used in the preoperative evaluation of patients with SUI and whether it should be considered as a predictor of success in patients undergoing a midurethral sling procedure and as a guide in the choice of surgical approach (retropubic vs transobturator) remain controversial. This article reviews and discusses the definitions of ISD and the latest research into the role of ISD determination in the era of the midurethral sling. PMID- 21792600 TI - [Pregnancy under immunosuppression]. AB - The desire to have children and pregnancy itself are important topics in the treatment of patients under immunosuppression. In this review the risks of frequently prescribed immunosuppressants are discussed regarding the safety of mother and child during and after pregnancy. Knowledge of the specific risks of immunosuppressants in pregnancy is important to balance the therapy between the patients' desire to be treated most effectively and to deliver a healthy child after an uncomplicated pregnancy. Generally, an interdisciplinary approach is advisable in treating and counseling immunosuppressed patients with a desire to have children and during pregnancy. PMID- 21792602 TI - Genistein inhibit cytokines or growth factor-induced proliferation and transformation phenotype in fibroblast-like synoviocytes of rheumatoid arthritis. AB - The purpose of this research is to study the effect of genistein on cytokines or growth factor-induced proliferation and transformation phenotype of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were primarily cultured. With respective stimulation of IL-1beta, TNF-alpha, and EGF, genistein was applied to elucidate its effect on synoviocytes' growth number, cell proliferation assay, cell cycle using cell counts, (3)H-TdR incorporation and flow cytometry, the colony numbers under anchorage-independent condition, and the expression of MMP-2 and MMP-9 in synovial fibroblasts. EGF, IL-1beta, and TNF alpha increased (3)H incorporation in RA-FLS, respectively. EGF augmented clone numbers of RA-FLS under anchorage-independent condition and not IL-1beta and TNF alpha. Genistein had an inhibitory role on cell number and (3)H-TdR incorporation of RA-FLS stimulated with IL-1beta, TNF-alpha and EGF; genistein arrested the cell cycle at G(1) restriction point; genistein decreased colony numbers under anchorage-independent condition stimulated by EGF in serum condition. IL-1beta or TNF-alpha increased expression of MMP-9 and MMP-2 in rheumatoid synoviocytes; EGF stimulated expression of MMP-9 but not of MMP-2; genistein suppressed production of MMP-9 more than MMP-2 induced by IL-1beta or TNF-alpha; rMMP-9, rMMP-2, or their inhibitors had no effect on the (3)H-TdR incorporation of synovial cells. Erk1/2 inhibitor (PD098 059) had obvious inhibitory effect on the (3)H incorporation induced by TNF-alpha or IL-1beta; inhibitors of JNK (SP600 125) had no significant effect on the (3)H incorporation. While pretreatment with PD098059 had no marked inhibitory effect on MMP-9 expression induced by TNF-alpha or IL 1beta, SP600125 decreased significantly the MMP-9 expression induced by TNF-alpha or IL-1beta. Neither PD098059 nor SP600 125 could inhibit the MMP-2 expression induced by TNF-alpha or IL-1beta. Genistein inhibited IL-1beta, TNF-alpha or EGF induced proliferation and MMP-9 expression in fibroblast-like synoviocytes of rheumatoid arthritis; the proliferation of RA-FLS was mediated by Erk1/2 but not JNK activation, while JNK activation was involved in the signal transduction pathway leading to MMP-9 expression in rheumatoid synoviocytes. PMID- 21792603 TI - [Pathobiology of the microRNA system]. AB - MicroRNAs are approximately 22 nucleotides short, non-protein-coding RNA molecules, which bind semi-complementary to mRNA and have an inhibitory effect on protein expression. Aberrant microRNA expression is part of the molecular pathological damage in several degenerative, inflammatory and neoplastic diseases and deregulation can also be virus-associated. Apart from intracellular regulatory functions, microRNA in platelets and exosomes or bound to extracellular protein complexes can also circulate in the blood. Artificial microRNA analogues (small interference RNA/siRNA) and anti-microRNA (antagomir) are used in molecular pathological research of microRNA/mRNA interaction and it is thought that they will also be used as therapeutic agents in the future. PMID- 21792604 TI - [Cytomegalovirus. Pathological-anatomical manifestations and detection methods]. AB - Human cytomegalovirus, a double-stranded DNA virus, is a member of the Herpesviridae family with high rates of transmission. Primary infection is often asymptomatic and leads to life-long latency. Reactivation may induce different organ manifestations, particularly in the setting of immunosuppression. Histopathologically, the virus can be detected by light microscopy. Different cell populations in different organs are transformed into"owl's eye" cells, which are pathognomonic. Immunohistochemistry and electron microscopy can be applied as complementary methods. Various PCR approaches in molecular pathology including nested PCR, capture probe ELISA-PCR and real time PCR confer HCMV tests high sensitivity and specificity. The present article discusses the methods of pathological diagnostic approaches and describes organ manifestations of HCMV. PMID- 21792605 TI - [Infectious lymphadenitis]. AB - Infectious lymphadenitis is often biopsied in the differential diagnoses of malignant disease. Since the repertoire of lymph nodes which react to exogenous stimuli is limited, malignant lymphomas may enter the clinical and morphological differential diagnosis. In a morphological sense, infectious lymphadenitis is defined as an infection of lymph node tissue. Therefore, the effector phase of the inflammatory reaction will act against lymphatic tissue, in contrast to common physiological hyperplasia. Follicular reactions, in addition to follicular hyperplasia, are seen in HIV-associated lymphadenopathy. Other viruses, such as infectious mononucleosis, give rise to a cytotoxic T-cell reaction. Most infections, however, induce a histiocytic reaction; depending on the microorganism, this varies morphologically from a small clustered epithelioid cell reaction or histiocytic abscesses to epithelioid necrotizing granulomata. PMID- 21792606 TI - A rotational ablation tool for calcified atherosclerotic plaque removal. AB - Atherosclerosis is a major cardiovascular disease involving accumulations of lipids, white blood cells, and other materials on the inside of artery walls. Since the calcification found in the advanced stage of atherosclerosis dramatically enhances the mechanical properties of the plaque, restoring the original lumen of the artery remains a challenge. High-speed rotational atherectomy, when performed with an ablating grinder to remove the plaque, produces much better results in the treatment of calcified plaque compared to other methods. However, the high-speed rotation of the Rotablator commercial rotational atherectomy device produces microcavitation, which should be avoided because of the serious complications it can cause. This research involves the development of a high-speed rotational ablation tool that does not generate microcavitation. It relies on surface modification to achieve the required surface roughness. The surface roughness of the tool for differential cutting was designed based on lubrication theory, and the surface of the tool was modified using Nd:YAG laser beam engraving. Electron microscope images and profiles indicated that the engraved surface of the tool had approximately 1 MUm of root mean square surface roughness. The ablation experiment was performed on hydroxyapatite/polylactide composite with an elastic modulus similar to that of calcified plaque. In addition, differential cutting was verified on silicone rubber with an elastic modulus similar to that of a normal artery. The tool performance and reliability were evaluated by measuring the ablation force exerted, the size of the debris generated during ablation, and through visual inspection of the silicone rubber surface. PMID- 21792607 TI - Mitochondrial dysfunction as a therapeutic target in progressive supranuclear palsy. AB - Progressive supranuclear palsy (PSP) is a sporadic and progressive neurodegenerative disease, most often leading to a symmetric, akinetic-rigid syndrome with prominent postural instability, vertical supranuclear gaze palsy, and cognitive decline. It belongs to the family of tauopathies and involves both cortical and subcortical structures. There is evidence from laboratory as well as in vivo studies suggesting that mitochondrial energy metabolism is impaired in PSP. Furthermore, several findings suggest that a failure in mitochondrial energy production might act as an upstream event in the chain of pathological events leading to the aggregation of tau and neuronal cell death. Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study; however, further studies to verify these results need to be conducted. This review will focus on the pathophysiological concept of mitochondrial dysfunction in PSP and its possible role as a therapeutic target. PMID- 21792608 TI - Age-dependent differences in recovered visual responses in Royal College of Surgeons rats transduced with the Channelrhodopsin-2 gene. AB - The objective of this study is to investigate age-related differences in recovered visual function in Royal College of Surgeons (RCS) rats transduced with the Channelrhodopsin-2 (ChR2) gene. An adeno-associated virus vector that contained ChR2 was injected intravitreously into young or aged RCS rats. After 4 months, visual evoked potentials were recorded. To estimate the transduction efficiencies, ChR2V-expressing cells and retrograde labeled retinal ganglion cells (RGCs) were counted. After photoreceptor degradation, immunohistochemistry was used to detect glial fibrillary acidic protein (GFAP) in the retinas. The amplitudes and latencies from young RCS rats were higher and shorter, respectively, than those from aged RCS rats. ChR2V was expressed in the RGCs of both groups of rats; there was no significant difference in the transduction efficiency of either group. However, the number of RGCs in aged RCS rats was significantly less than that in young RCS rats. In addition, strong GFAP immunoreactivity was observed after photoreceptor degeneration, whereas it was weaker in ChR2V-expressing RGCs. ChR2 transduction produced photosensitive RGCs in both young and aged rats. However, the degree of recovery depended on the age at the time of transduction. PMID- 21792609 TI - Retention treatment after periprosthetic total hip arthroplasty infection. AB - PURPOSE: The purpose of this study was to compare infection control rates between implant retention and two-stage revision and assess the effectiveness of retention treatment in THA. METHODS: Twenty-eight debridements with implant retention (retention group) and 65 staged revisions (removal group) were retrospectively analysed and risk factors that can contribute to failure of infection control were explored. RESULTS: For the retention and removal groups, infection control rates were 50% and 78% after initial treatment, and 68% and 82% at latest follow-up, respectively. There were no significant differences in the number of additional operative procedures, total length of hospital stay, and duration of treatment between groups. Infection of revision THA, polybacterial and S. aureus infection were identified as risk factors for infection control. CONCLUSIONS: Retention treatment can be considered an initial treatment option in selected cases of primary THA, with a single organism, non-S. aureus infection with 50% chance of infection control and no disadvantages in terms of additional procedure, hospital stay, and treatment duration. PMID- 21792610 TI - An introductory review of information theory in the context of computational neuroscience. AB - This article introduces several fundamental concepts in information theory from the perspective of their origins in engineering. Understanding such concepts is important in neuroscience for two reasons. Simply applying formulae from information theory without understanding the assumptions behind their definitions can lead to erroneous results and conclusions. Furthermore, this century will see a convergence of information theory and neuroscience; information theory will expand its foundations to incorporate more comprehensively biological processes thereby helping reveal how neuronal networks achieve their remarkable information processing abilities. PMID- 21792612 TI - Excitation energy transfer and trapping dynamics in the core complex of the filamentous photosynthetic bacterium Roseiflexus castenholzii. AB - The light-harvesting core complex of the thermophilic filamentous anoxygenic phototrophic bacterium Roseiflexus castenholzii is intrinsic to the cytoplasmic membrane and intimately bound to the reaction center (RC). Using ultrafast transient absorption and time-resolved fluorescence spectroscopy with selective excitation, energy transfer, and trapping dynamics in the core complex have been investigated at room temperature in both open and closed RCs. Results presented in this report revealed that the excited energy transfer from the BChl 800 to the BChl 880 band of the antenna takes about 2 ps independent of the trapping by the RC. The time constants for excitation quenching in the core antenna BChl 880 by open and closed RCs were found to be 60 and 210 ps, respectively. Assuming that the light harvesting complex is generally similar to LH1 of purple bacteria, the possible structural and functional aspects of this unique antenna complex are discussed. The results show that the core complex of Roseiflexus castenholzii contains characteristics of both purple bacteria and Chloroflexus aurantiacus. PMID- 21792611 TI - Surveillance biopsies in children post-kidney transplant. AB - Surveillance biopsies are increasingly used in the post-transplant monitoring of pediatric renal allograft recipients. The main justification for this procedure is to diagnose early and presumably modifiable acute and chronic renal allograft injury. Pediatric recipients are theoretically at increased risk for subclinical renal allograft injury due to their relatively large adult-sized kidneys and their higher degree of immunological responsiveness. The safety profile of this procedure has been well investigated. Patient morbidity is low, with macroscopic hematuria being the most common adverse event. No patient deaths have been attributed to this procedure. Longitudinal surveillance biopsy studies have revealed a substantial burden of subclinical immunological and non-immunological injury, including acute cellular rejection, interstitial fibrosis and tubular atrophy, microvascular lesions and transplant glomerulopathy. The main impediment to the implementation of surveillance biopsies as the standard of care is the lack of demonstrable benefit of early histological detection on long-term outcome. The considerable debate surrounding this issue highlights the need for multicenter, prospective, and randomized studies. PMID- 21792613 TI - Individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy. AB - AIMS/HYPOTHESIS: The aim of this study was to reduce the frequency of diabetic eye-screening visits, while maintaining safety, by using information technology and individualised risk assessment to determine screening intervals. METHODS: A mathematical algorithm was created based on epidemiological data on risk factors for diabetic retinopathy. Through a website, www.risk.is , the algorithm receives clinical data, including type and duration of diabetes, HbA(1c) or mean blood glucose, blood pressure and the presence and grade of retinopathy. These data are used to calculate risk for sight-threatening retinopathy for each individual's worse eye over time. A risk margin is defined and the algorithm recommends the screening interval for each patient with standardised risk of developing sight threatening retinopathy (STR) within the screening interval. We set the risk margin so that the same number of patients develop STR within the screening interval with either fixed annual screening or our individualised screening system. The database for diabetic retinopathy at the Department of Ophthalmology, Aarhus University Hospital, Denmark, was used to empirically test the efficacy of the algorithm. Clinical data exist for 5,199 patients for 20 years and this allows testing of the algorithm in a prospective manner. RESULTS: In the Danish diabetes database, the algorithm recommends screening intervals ranging from 6 to 60 months with a mean of 29 months. This is 59% fewer visits than with fixed annual screening. This amounts to 41 annual visits per 100 patients. CONCLUSION: Information technology based on epidemiological data may facilitate individualised determination of screening intervals for diabetic eye disease. Empirical testing suggests that this approach may be less expensive than conventional annual screening, while not compromising safety. The algorithm determines individual risk and the screening interval is individually determined based on each person's risk profile. The algorithm has potential to save on healthcare resources and patients' working hours by reducing the number of screening visits for an ever increasing number of diabetic patients in the world. PMID- 21792614 TI - Thin-section computed tomography findings before and after azithromycin treatment of neutrophilic reversible lung allograft dysfunction. AB - OBJECTIVES: Recently a novel subgroup of bronchiolitis obliterans syndrome (BOS) has been described in patients after lung transplantation with high neutrophil counts in broncho-alveolar lavage and recovery of lung functional decline with azithromycin treatment. We aimed to describe the thin-section computed tomography (CT) findings of these neutrophilic reversible allograft dysfunction (NRAD) patients before and after azithromycin. METHODS: A cohort of 100 lung transplant recipients with BOS were treated with azithromycin and underwent lung function testing, broncho-alveolar lavage and CT before azithromycin treatment and during follow-up. The 200 CT data sets were scored for bronchial dilatation, mucus plugging, centrilobular abnormalities, airway wall thickening, consolidation, ground glass and end-expiratory air trapping. RESULTS: NRAD was characterized by more centrilobular abnormalities on CT (p = 0.03 for prevalence and p = 0.06 for severity) compared to non-responders. At follow-up NRAD patients showed improvement in all CT abnormalities including air trapping, but the degree of improvement in all CT abnormalities was significantly different between responders and non-responders (who showed progression of bronchus dilatation, consolidation and air trapping). CONCLUSIONS: Within BOS patients those with NRAD differ from azithromycin non-responders by more centrilobular abnormalities on CT before azithromycin and improvement in bronchus dilatation, consolidation and air trapping during treatment. PMID- 21792615 TI - The value of flat-detector computed tomography during catheterisation of congenital heart disease. AB - OBJECTIVES: To analyse the diagnostic utility of flat-detector computed tomography imaging (FD-CT) in patients with congenital heart disease, including the value of image fusion to overlay three-dimensional (3D) reconstructions on fluoroscopic images during catheter-based interventions. METHODS: We retrospectively analysed 62 consecutive paediatric patients in whom FD-CT was used during catheterisation of congenital heart disease. Expert operators rated the clinical value of FD-CT over conventional fluoroscopic imaging. Added radiation exposure and contrast medium volume were evaluated. RESULTS: During a 12-month period, FD-CT was performed in 62 out of 303 cardiac catheterisations. Median patient age was 3.5 years. In 32/62 cases, FD-CT was used for diagnostic purposes, in 30/62 cases it was used in the context of interventions. Diagnostic utility was never rated as "misleading". It was classified as "not useful" in six cases (9.7%), "useful" in 18 cases (29.0%), "very useful" in 37 cases (59.7%) and "essential" in one case (1.6%). The median added dose-area product was 111.0 MUGym(2), the required additional quantity of contrast medium was 1.6 ml/kg. CONCLUSION: FD-CT provides useful diagnostic information in most of the patients investigated for congenital heart disease. The added radiation exposure and contrast medium volume are reasonable. PMID- 21792616 TI - Accuracy and variability of right ventricular volumes and mass assessed by dual source computed tomography: influence of slice orientation in comparison to magnetic resonance imaging. AB - OBJECTIVE: To evaluate the accuracy and variability of right ventricular (RV) volumes and mass using dual-source computed tomography (DSCT) and the influence of slice orientation in comparison to cardiac magnetic resonance imaging (CMR). METHODS: In 33 patients undergoing cardiac DSCT and CMR, RV parameters were calculated using the short-axis (DSCT, CMR) and axial orientation (DSCT). Intra- and interobserver variability were assessed by Bland-Altman analysis. RESULTS: Short-axis orientation: RV parameters of the two techniques were not statistically different. Axial orientation: RV volumes and mass were significantly overestimated compared with short-axis parameters whereas EF was similar. The short-axis approach resulted in low variability, although the axial orientation had the least amount of intra- and interobserver variability. CONCLUSION: RV parameters can be more accurately assessed by DSCT compared with CMR using short-axis slice orientation. RV volumes and mass are significantly higher using axial compared with short-axis slices, whereas EF is unaffected. RV parameters derived from both approaches yield high reproducibility. PMID- 21792617 TI - Diffusion-weighted imaging findings in brain death. AB - INTRODUCTION: The purpose of the present study was to determine the role of diffusion-weighted imaging (DWI) and to investigate the use of DWI in the diagnosis of brain death (BD). METHODS: We prospectively evaluated 22 patients diagnosed with clinical BD (9 women, 13 men; mean age, 39.63 +/- 15.1 years; age range, 9-66 years). All clinical criteria for BD were present in all 22 patients before magnetic resonance imaging, including a positive apnea test. For all cases, DW images, T2-weighted images, and fluid-attenuated inversion recovery were obtained. Thirteen distinct neuroanatomical structures were selected for analysis in all the cases. For each region of interest, the mean, standard deviation, and range of the average apparent diffusion coefficient (ADCav) values were obtained. RESULTS: For BD patients, ADC values in all neuroanatomical structures were significantly lower than those for control subjects. We determined how ADC values in all structures were related to the diagnostic condition as well as the appropriate threshold ADC values to classify a subject as BD or control. The sensitivity, specificity, positive and negative predictive values, and correct classification rate of ADC cutoff values to distinguish BD from control groups were 100%. CONCLUSIONS: DWI might be used as a noninvasive confirmatory test for the diagnosis of BD in the future. PMID- 21792618 TI - Hepatopulmonary syndrome in children with cirrhotic and non-cirrhotic portal hypertension: a single-center experience. AB - BACKGROUND: Hepatopulmonary syndrome (HPS) is defined as an arterial oxygenation defect induced by intrapulmonary vascular dilatation (IPVD) associated with hepatic disease. The prevalence and clinical characteristics of HPS in portal hypertensive children is not well characterized. AIMS: The aim of this study was to investigate the prevalence and clinical characteristics of HPS in 40 portal hypertensive children. METHODS: We studied 40 children (11 girls and 29 boys; mean age, 111 months +/- 52 months; range, 24-216 months) with portal hypertension (24 cirrhotic, 16 non-cirrhotic) for the presence of HPS using blood gas analysis, contrast-enhanced echocardiography (CEE), and Tc99m-macroaggregated albumin scintigraphy. Clinical and laboratory characteristics of patients were recorded. HPS was considered to be present in a patient with hypoxemia and/or an elevated alveolar-arterial oxygen gradient (PAaO(2)) >= 15 mmHg) and positive CEE and/or scintigraphy. RESULTS: Elevated PAaO(2) was detected in 7 of 24 patients with cirrhosis. Four of them also had IPVD with CEE. An intrapulmonary shunt in Tc99m-MAA with CEE was shown in one patient. A diagnosis of HPS was made in 16.7% of the patients with cirrhosis. Cirrhotic patients without IPVD had significantly better hepatic function and lower pediatric end-stage liver disease scores. Although, 2 of the 16 patients with non-cirrhotic portal hypertension had elevated PAaO(2,) none of them showed IPVD. One normoxemic patient in the non cirrhotic portal hypertension group showed IPVD with CEE. None of the non cirrhotic patients fulfilled the diagnostic criteria of HPS. CONCLUSION: Hepatopulmonary syndrome particularly occurs in cirrhotic portal hypertensive patients with severe hepatic dysfunction. PMID- 21792619 TI - Endoscopic findings and clinical outcomes in ventricular assist device recipients with gastrointestinal bleeding. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is an important clinical problem in recipients of ventricular assist devices (VAD), although data pertaining to the endoscopic evaluation and management of this complication are limited in the medical literature. AIMS: We sought to identify the most common endoscopic findings in VAD recipients with GIB, and to better define the diagnostic and therapeutic utility of endosopy for this patient population. METHODS: Twenty-six subjects with VAD and overt GIB were retrospectively identified. Clinical and endoscopic data were abstracted for each subject on to standardized forms in duplicate and independent fashion. Raw data and descriptive statistics were reported. RESULTS: Non-peptic vascular lesions were the most common cause of GIB. A definitive cause of bleeding was identified by endoscopy in almost 60% of subjects. Endoscopic hemostasis was achieved in 14/15 patients in whom bleeding did not stop spontaneously. Rebleeding occurred in 50% of subjects and was successfully retreated or stopped spontaneously in all cases. Colonoscopy did not establish a definitive diagnosis or deliver hemostatic therapy in any case. CONCLUSIONS: Vascular malformations account for the overwhelming majority of bleeding lesions in VAD patients with GIB. Endoscopy seems to be a safe and effective tool for diagnosing, risk stratifying, and treating this patient population, although multiple endoscopies may be necessary before therapeutic success, and the incidence of rebleeding is high. A prospective multi-center registry is necessary to establish evidence-based management algorithms for VAD recipients with GIB. PMID- 21792621 TI - Comparison of left ventricular volumes and ejection fraction by monoplane cineventriculography, unenhanced echocardiography and cardiac magnetic resonance imaging. AB - Right-anterior-oblique (RAO) monoplane cineventriculography is usually applied in cardiac catheter labs to assess the left ventricular (LV) function. However, it is uncertain whether this technique is reliable in clinical routine. Unenhanced two-dimensional echocardiography was reported to underestimate left ventricular volumes. The aim of this study was to compare these two conventional techniques with cardiac magnetic resonance imaging (MRI), the present gold standard for the determination of LV function, to evaluate whether the results from the conventional techniques are reliable and in accordance with each other. Seventy two patients were retrospectively recruited and analysis of the three techniques was performed. Compared with MRI, RAO cineventriculography underestimated LV end systolic volumes (ESV), and overestimated LV ejection fraction (EF); two dimensional echocardiography underestimated LV end-diastolic volume (EDV) and EF. Correlation coefficients on EDV, ESV, and EF were 0.8806, 0.9201, and 0.8864 between echocardiography and MRI (P < 0.01, for all), followed by 0.7718, 0.8835, and 0.7785, between cineventriculography and MRI (P < 0.01, for all), and 0.7006, 0.7680, and 0.7644 between cineventriculography and echocardiography (P < 0.01, for all). Echocardiography and MRI showed the highest inter-technique correlation coefficients, and the narrowest Bland-Altman limits of agreement for EDV, ESV and EF. EDV, ESV and EF determined by RAO monoplane cineventriculography, unenhanced two-dimensional echocardiography and MRI were in high accordance with each other, with wide variances between the techniques. Although not interchangeable, RAO monoplane cineventriculography, unenhanced two-dimensional echocardiography, and cardiac MRI are reliable tools in clinical routine for the assessment of LV volumes and function. PMID- 21792620 TI - Clinical significance of right ventricular dysfunction in left ventricular non compaction cardiomyopathy. AB - Left ventricular non-compaction (LVNC) is described as the persistence of trabeculated myocardium in the left ventricle (LV) and is optimally assessed by cardiac magnetic resonance (CMR). Right ventricular (RV) involvement in LVNC remains poorly studied. Consecutive patients (N = 14) diagnosed with LVNC by CMR were studied. Their clinical data were analyzed. In addition, CMR assessment included quantification of LV and RV volumes, mass, ejection fraction (EF), LV wall motion score, LV non-compacted segments and non-compacted to compacted myocardium ratios. Average age of presentation was 33.1 +/- 17.6 years old, with 9 males (64%). Of these patients, 7 (50%) presented with acute heart failure and 3 (21%) with syncope, including 1 documented ventricular tachycardia. RV EF < 35% was identified in 7 (50%) of these patients. Patients with RV EF < 35% presented at a higher median New York Heart Association class (1 [IQR 1-2] vs. 3 [IQR 2-4], P = 0.021) and had significantly lower LV EF (50.7% +/- 15.4 vs. 21.8% +/- 19.9, P = 0.029), higher LV end diastolic (100.9 ml/m(2) +/- 22.3 vs. 159.1 ml/m(2) +/- 36.0, P = 0.002) and systolic volume indices (52.0 ml/m(2) +/- 25.8 vs. 129.1 ml/m(2) +/- 48.4, P = 0.002), higher LV wall motion score index (1.3 +/- 0.5 vs. 2.2 +/- 0.6, P = 0.004) and higher ratio of LV non-compacted to compacted myocardium (3.3 +/- 0.6 vs. 4.1 +/- 0.8, P = 0.026). All 4 patients that had ventricular tachycardia also had RV dysfunction. RV dysfunction was present in half of patients with LVNC. Significant RV dysfunction seems to be a marker of advanced LVNC and may carry a worse prognosis. Further studies in a larger sample of patients are needed to confirm those observations. PMID- 21792623 TI - Differential phytate utilization in Candida species. AB - The present study was undertaken to evaluate and characterize the phytase activity in different Candida species. A total of 113 Candida isolates representing eight species were examined for phytase activity by an agar plate assay using the calcium salt of phytic acid as the sole phosphorus source. A phytase-positive phenotype was identified by the formation of a clear halo around a fungal colony. Cell-bound differential phytase activity was observed in Candida isolates at inter- and intra-species levels. Although phytase activity was not affected by the supplementation of external phosphate in C. albicans, C. dubliniensis, C. glabrata, and C. kefyr, elevated phytase activity was evident in C. guilliermondii, C. krusei, C. parapsilosis, and C. tropicalis in phosphate free medium. Further characterization showed that, in general, relatively higher phytase activity was observed at more acidic pHs, and the phytase activity increased with incubation temperature, reaching a maximum at 55 or 65 degrees C. Taken together, the findings demonstrated, for the first time, differential phytase activities in different Candida species. Phytase activity may be a contributing factor to fungal survival and proliferation within the human gastrointestinal tract, where nutrients are usually scarce. PMID- 21792622 TI - Quantitative evaluation of upper-limb motor control in robot-aided rehabilitation. AB - This paper is focused on the multimodal analysis of patient performance, carried out by means of robotic technology and wearable sensors, and aims at providing quantitative measure of biomechanical and motion planning features of arm motor control following rehabilitation. Upper-limb robotic therapy was administered to 24 community-dwelling persons with chronic stroke. Performance indices on patient motor performance were computed from data recorded with the InMotion2 robotic machine and a magneto-inertial sensor. Motor planning issues were investigated by means of techniques of motion decomposition into submovements. A linear regression analysis was carried out to study correlation with clinical scales. Robotic outcome measures showed a significant improvement of kinematic motor performance; improvement of dynamic components was more significant in resistive motion and highly correlated with MP. The analysis of motion decomposition into submovements showed an important change with recovery of submovement number, amplitude and order, tending to patterns measured in healthy subjects. Preliminary results showed that arm biomechanical functions can be objectively measured by means of the proposed set of performance indices. Correlation with MP is high, while correlation with FM is moderate. Features related to motion planning strategies can be extracted from submovement analysis. PMID- 21792624 TI - Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents. AB - Microtubule-targeting agents, including taxanes (Tax) and ixabepilone (Ixa), are important components of modern breast cancer chemotherapy regimens, but no molecular parameter is currently available that can predict for their efficiency. We sought to develop pharmacogenomic predictors of Tax- and Ixa-response from a large panel of human breast tumor cell lines (BTCL), then to evaluate their performance in clinical samples. Thirty-two BTCL, representative of the molecular diversity of breast cancers (BC), were treated in vitro with Tax (paclitaxel (Pac), docetaxel (Doc)), and ixabepilone (Ixa), then classified as drug-sensitive or resistant according to their 50% inhibitory concentrations (IC50s). Baseline gene expression data were obtained using Affymetrix U133 Plus 2.0 human oligonucleotide microarrays. Gene expression set (GES) predictors of response to taxanes were derived, then tested for validation internally and in publicly available gene expression datasets. In vitro IC50s of Pac and Doc were almost identical, whereas some Tax-resistant BTCL retained sensitivity to Ixa. GES predictors for Tax-sensitivity (333 genes) and Ixa-sensitivity (79 genes) were defined. They displayed a limited number of overlapping genes. Both were validated by leave-n-out cross-validation (n = 4; for overall accuracy (OA), P = 0.028 for Tax, and P = 0.0005 for Ixa). The GES predictor of Tax-sensitivity was tested on publicly available external datasets and significantly predicted Pac sensitivity in 16 BTCL (P = 0.04 for OA), and pathological complete response to Pac-based neoadjuvant chemotherapy in BC patients (P = 0.0045 for OA). Applying Tax and Ixa-GES to a dataset of clinically annotated early BC patients identified subsets of tumors with potentially distinct phenotypes of drug sensitivity: predicted Ixa-sensitive/Tax-resistant BC were significantly (P < 0.05, Fischer's exact test) more frequently ER/PR-positive, Ki67-negative, and luminal subtype than predicted Ixa-resistant/Tax-sensitive BC. Genomic predictors for Tax- and Ixa-sensitivity can be derived from BTCL and may be helpful for better selecting cytotoxic treatment in BC patients. PMID- 21792625 TI - Lack of efficacy to systemic chemotherapy for treatment of metaplastic carcinoma of the breast in the modern era. AB - Metaplastic carcinoma of the breast (MCB) is a rare subtype of breast cancer. Anecdotal reports are available regarding its response to systemic chemotherapy. We reviewed the records of patients diagnosed with MCB at National Taiwan University Hospital between 1988 and 2009. A total of 46 MCB cases were identified from 8,695 breast tumor patients who underwent biopsy or resection. About 11 of 25 patients with initial bulky disease (T3-4) received neoadjuvant chemotherapy before surgery, and 2 (18.2%) exhibited a partial response. About 12 of 18 patients who developed distant metastasis received palliative systemic chemotherapy. Of them, only 1 (8.3%), 1 (10%), and none (0%) responded to first-, second-, or third- and beyond line chemotherapy, respectively. None of the patients who received anthracyline- (n = 13), vinorelbine- (n = 7), or cyclophosphamide-based (n = 18) chemotherapy responded, whereas 3 (17.6%) of 17 patients who received taxane-based chemotherapy exhibited a partial response. Tumor response to systemic chemotherapy remains generally poor for MCB patients. Taxanes may have modest activity, but need to be validated in further studies. PMID- 21792627 TI - Mismatch analysis of humeral nailing: antegrade versus retrograde insertion. AB - BACKGROUND: Closed humeral nailing is now considered an alternative treatment for humeral-shaft fracture. The nail can be inserted with either the antegrade or retrograde method. We investigated and compared the problem of geometric mismatch of the humeral nail to the humerus between the two methods of insertion. METHODS: The study was performed using virtual simulation based on computed tomography (CT) data of 76 Thai cadaveric humeri and the commonly used Russell-Taylor humeral nail 8 mm in diameter and 220 mm long. Mismatch of the nail to the intact humerus was analyzed and compared between the antegrade and retrograde nailing approaches. RESULTS: The results showed: (1) the diameter of the medullary canal averaged 7.9-13.8 mm; (2) the minimal reaming diameter to accommodate virtual nail insertion averaged 8.8-14.8 mm for the antegrade and 8.8-29.3 mm for the retrograde approach; (3) the minimal reaming thickness of the inner cortex averaged 0.1-1.5 mm for the antegrade and 0.1-9.9 mm for the retrograde approach; (4) the percentages of cortical bone removed prior to nail insertion were 3.8 107.1% and 3.8-1,287.6% for the antegrade and retrograde approaches, respectively; (5) the eccentricity of the nail-medullary canal center were 0.4 3.4 and 0.4-10.6 mm for the antegrade and retrograde approaches, respectively. CONCLUSIONS: Less mismatching occurred with antegrade nailing than with the retrograde approach. Retrograde nailing requires excessive reaming at the distal part of the humerus to accommodate nail insertion. This may create bone weakness and the risk of supracondylar fracture. PMID- 21792626 TI - A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer. AB - Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors. PMID- 21792628 TI - Long-term memory of color stimuli in the jungle crow (Corvus macrorhynchos). AB - Wild-caught jungle crows (n = 20) were trained to discriminate between color stimuli in a two-alternative discrimination task. Next, crows were tested for long-term memory after 1-, 2-, 3-, 6-, and 10-month retention intervals. This preliminary study showed that jungle crows learn the task and reach a discrimination criterion (80% or more correct choices in two consecutive sessions of ten trials) in a few trials, and some even in a single session. Most, if not all, crows successfully remembered the constantly reinforced visual stimulus during training after all retention intervals. These results suggest that jungle crows have a high retention capacity for learned information, at least after a 10 month retention interval and make no or very few errors. This study is the first to show long-term memory capacity of color stimuli in corvids following a brief training that memory rather than rehearsal was apparent. Memory of visual color information is vital for exploitation of biological resources in crows. We suspect that jungle crows could remember the learned color discrimination task even after a much longer retention interval. PMID- 21792629 TI - Open3DALIGN: an open-source software aimed at unsupervised ligand alignment. AB - An open-source, cross-platform software aimed at conformer generation and unsupervised rigid-body molecular alignment is presented. Different algorithms have been implemented to perform single and multi-conformation superimpositions on one or more templates. Alignments can be accomplished by matching pharmacophores, heavy atoms or a combination of the two. All methods have been successfully validated on eight comprehensive datasets previously gathered by Sutherland and co-workers. High computational performance has been attained through efficient parallelization of the code. The unsupervised nature of the alignment algorithms, together with its scriptable interface, make Open3DALIGN an ideal component of high-throughput, automated cheminformatics workflows. PMID- 21792630 TI - Design of a fragment library that maximally represents available chemical space. AB - Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog). PMID- 21792631 TI - A major locus qS12, located in a duplicated segment of chromosome 12, causes spikelet sterility in an indica-japonica rice hybrid. AB - Chromosome segment duplications are integral in genome evolution by providing a source for the origin of new genes. In the rice genome, besides an ancient polyploidy event known in the rice common ancestor, it had been identified that there was a special segmental duplication involving chromosomes 11 and 12, but the biological role of this duplication remains unknown. In this study, by using a set of chromosome segment substitution lines (CSSLs) and near isogenic lines (NILs) derived from the indica cultivar 9311 and japonica cultivar Nipponbare, a major QTL (qS12) resulting in hybrid male sterility was mapped within ~400 kb region adjacent to the special duplicated segment on the short arm of chromosome 12. Compared to the japonica cultivar Nipponbare, the two sides of the qS12 candidate region were inverted in the indica cultivar 9311. Among 47 of the 111 rice genotypes evaluated by molecular markers, the inverted sides were detected, and found completely homologous to indica cultivar 9311. These results suggested that the two inverted sides protect the sequence in the qS12 regions from recombination. On the short-arm of chromosome 12, two QTLs S-e and S25, in addition to qS12, were previously detected as a distinct segregation distortion and pollen semi-sterility loci. We propose these three hybrid sterility loci are the same locus, and the duplicated segment on chromosome 12 may play a prominent role in diversification, i.e., sub-speciation of cultivated rice. PMID- 21792632 TI - Microsatellite mapping of Ae. speltoides and map-based comparative analysis of the S, G, and B genomes of Triticeae species. AB - The first microsatellite linkage map of Ae. speltoides Tausch (2n = 2x = 14, SS), which is a wild species with a genome closely related to the B and G genomes of polyploid wheats, was developed based on two F(2) mapping populations using microsatellite (SSR) markers from Ae. speltoides, wheat genomic SSRs (g-SSRs) and EST-derived SSRs. A total of 144 different microsatellite loci were mapped in the Ae. speltoides genome. The transferability of the SSRs markers between the related S, B, and G genomes allowed possible integration of new markers into the T. timopheevii G genome chromosomal maps and map-based comparisons. Thirty-one new microsatellite loci assigned to the genetic framework of the T. timopheevii G genome maps were composed of wheat g-SSR (genomic SSR) markers. Most of the used Ae. speltoides SSRs were mapped onto chromosomes of the G genome supporting a close relationship between the G and S genomes. Comparative microsatellite mapping of the S, B, and G genomes demonstrated colinearity between the chromosomes within homoeologous groups, except for intergenomic T6A(t)S.1G, T4AL.5AL.7BS translocations. A translocation between chromosomes 2 and 6 that is present in the T. aestivum B genome was found in neither Ae. speltoides nor in T. timopheevii. Although the marker order was generally conserved among the B, S, and G genomes, the total length of the Ae. speltoides chromosomal maps and the genetic distances between homoeologous loci located in the proximal regions of the S genome chromosomes were reduced compared with the B, and G genome chromosomes. PMID- 21792633 TI - Use of Mutant-Assisted Gene Identification and Characterization (MAGIC) to identify novel genetic loci that modify the maize hypersensitive response. AB - The partially dominant, autoactive maize disease resistance gene Rp1-D21 causes hypersensitive response (HR) lesions to form spontaneously on leaves and stems in the absence of pathogen recognition. The maize nested association mapping (NAM) population consists of 25 200-line subpopulations each derived from a cross between the maize line B73 and one of 25 diverse inbred lines. By crossing a line carrying the Rp1-D21 gene with lines from three of these subpopulations and assessing the F(1) progeny, we were able to map several novel loci that modify the maize HR, using both single-population quantitative trait locus (QTL) and joint analysis of all three populations. Joint analysis detected QTL in greater number and with greater confidence and precision than did single population analysis. In particular, QTL were detected in bins 1.02, 4.04, 9.03, and 10.03. We have previously termed this technique, in which a mutant phenotype is used as a "reporter" for a trait of interest, Mutant-Assisted Gene Identification and Characterization (MAGIC). PMID- 21792634 TI - Cross-talk between one-carbon metabolism and xenobiotic metabolism: implications on oxidative DNA damage and susceptibility to breast cancer. AB - The aim of this case-control study is to explore the role of aberrations in xenobiotic metabolism in inducing oxidative DNA damage and altering the susceptibility to breast cancer. Cytochrome P4501A1 (CYP1A1) m1 (OR: 1.41, 95% CI 1.08-1.84), CYP1A1 m4 (OR: 5.13, 95% CI 2.68-9.81), Catecholamine-O-methyl transferase (COMT) H108L (OR: 1.49, 95% CI 1.16-1.92), and glutathione S transferase (GST) T1 null (OR: 1.68, 95% CI 1.09-2.59) variants showed association with breast cancer risk. Reduced folate carrier 1 (RFC1) 80A/CYP1A1 m1/CYP1A1 m4 and RFC1 80A/thymidylate synthase (TYMS) 5'-UTR 2R/methionine synthase (MTR) 2756G/COMT 108L genetic combinations were found to inflate breast cancer risk under the conditions of low dietary folate (345 +/- 110 vs. 379 +/- 139 MUg/day) and low plasma folate (6.81 +/- 1.25 vs. 7.09 +/- 1.26 ng/ml) by increasing plasma 8-oxo-2'-deoxyguanosine (8-oxodG). This increase in 8-oxodG is attributed to low methionine (49.38 +/- 23.74 vs. 53.90 +/- 23.85 MUmol/l); low glutathione (378 +/- 242 vs. 501 +/- 126 MUmol/l) and GSTT1 null variant; and hypermethylation of CpG island of extracellular-superoxide dismutase (EC-SOD) (92.78 +/- 11.49 vs. 80.45 +/- 9.86%), which impair O-methylation of catechol estrogens to methoxy estrogens, conjugation of glutathione to semiquinones/quinones and free radical scavenging respectively. Our results suggest cross-talk between one-carbon metabolism and xenobiotic metabolism influencing oxidative DNA damage and susceptibility to breast cancer. PMID- 21792635 TI - Transforming Growth Factor-beta1 (TGF-beta1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor alpha (TNFalpha) via Crosstalk Between the SMAD and NF-kappaB Pathways. AB - Epithelial to mesenchymal transition (EMT) is a process by which an epithelial cell alters its phenotype to that of a mesenchymal cell and plays a critical role in embryonic development, tumour invasion and metastasis and tissue fibrosis. Transforming growth factor-beta1 (TGF-beta1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor alpha (TNFalpha) has been demonstrated to accentuate TGF-beta1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-beta1 (10 ng/ml), TNFalpha (20 ng/ml) or a combination of both for 72 h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-kappaB pathways on EMT was assessed. A549 cells treated with TGF-beta1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-beta1 driven EMT is accentuated by co-treatment with TNFalpha. SMAD 3 inhibition attenuated TGF-beta1 driven EMT but has no effect on the accentuation effect of TNFalpha. However, inhibiting IKKbeta blocked both TGF-beta1 driven EMT and the accentuating action of TNFalpha. Inhibiting p38 and ERK signalling had no effect on EMT. TNFalpha accentuates TGF-beta1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-kappaB pathway independent of p38 and ERK 1/2 activation. PMID- 21792636 TI - Bare-metal stents versus drug-eluting stents for primary angioplasty: long-term outcome. AB - Percutaneous transluminal coronary intervention (PCI) is the most used myocardial revascularization technique for patients with coronary artery disease. Primary PCI with stent implantation is widely considered the gold standard for the treatment of ST-elevation myocardial infarction patients. Coronary stents, compared with balloon angioplasty, have reduced focal lesion restenosis. To reduce in-stent restenosis, drug-eluting stents (DES) were designed to locally release drugs inhibiting neointimal growth. Recent concerns have emerged on the potential higher risk of stent thrombosis with DES that might be even more pronounced among myocardial infarction patients. For these reasons, DES for primary PCI remains an "off-label" use. In the last several years, a number of randomized trials and registries have tested the safety and efficacy of DES in primary PCI. Data from these studies were analyzed in several meta-analyses, reasonably consistently demonstrating that the use of DES significantly decreased the need for revascularization without an increase in the incidence of death, recurrent infarction, or stent thrombosis at long-term follow-up. PMID- 21792638 TI - Novel sequencing-based strategies for high-throughput discovery of genetic mutations underlying inherited antibody deficiency disorders. AB - Human inherited antibody deficiency disorders are generally caused by mutations in genes involved in the pathways regulating B-cell class switch recombination; DNA damage repair; and B-cell development, differentiation, and survival. Sequencing a large set of candidate genes involved in these pathways appears to be a highly efficient way to identify novel mutations. Herein we review several high-throughput sequencing approaches as well as recent improvements in target gene enrichment technologies. Systematic improvement of enrichment and sequencing methods, along with refinement of the experimental process is necessary to develop a cost-effective high-throughput resequencing assay for a large cohort of patient samples. The Hyper-IgM/CVID chip is one example of a resequencing platform that may be used to identify known or novel mutations in patents with various types of inherited antibody deficiency. PMID- 21792637 TI - Importance of allergy in asthma: an epidemiologic perspective. AB - There has been a global epidemic of asthma during the past half-century. More recently, the prevalence has leveled off or declined in many Western countries, whereas the prevalence in less affluent nations is still increasing. The reasons for this and the different geographical patterns of asthma prevalence remain unclear. This paper provides an epidemiologic perspective on whether allergen exposure and allergies can explain these trends. In particular, the paper discusses 1) geographical and temporal trends in asthma and the role of allergens and allergy, 2) the importance of nonallergic mechanisms, 3) nonallergenic exposures that may modify the risk of allergies and asthma, and 4) new and emerging risk and protective factors. Although allergy and asthma are closely related, allergen exposure and allergy alone cannot explain current time trends and geographical patterns of asthma. Population-based studies focusing on recently identified risk and protective factors may provide further insight. PMID- 21792639 TI - The role of atherosclerosis imaging in redefining normal and abnormal cholesterol values, and risk reduction in primary prevention statin trials. AB - The emergence of atherosclerosis imaging, using coronary calcium scanning (CAC) and carotid intima media thickness (CIMT) and plaque as stronger predictors of cardiovascular events than risk factors of atherosclerosis, has created a paradigm shift in the primary prevention of cardiovascular disease. Rather than population-derived indices to define normal or abnormal low-density lipoprotein (or other lipid values) in the untreated individual patient, it is more appropriate to define "normal" as "cholesterol values at which level there is no subclinical atherosclerosis" and "abnormal" as "cholesterol values at which level there is subclinical atherosclerosis," with the severity of "abnormal" depending on the degree of subclinical atherosclerosis. Similarly, the low-density lipoprotein treatment goal is the level at which atherosclerosis progression is halted. Extension of the subclinical atherosclerosis risk-based paradigms to primary prevention trials dramatically changes the manner in which trials should be conducted in the future, as well as the results of trials already performed. For example, asymptomatic patients with a CAC score of 0 have an extraordinarily low event rate but have been included in primary prevention statin trials even though their risk without treatment is very small. Reanalysis of the statin primary prevention trials after excluding the percentage (40%) of patients who would be expected to have a CAC score of 0 yields an absolute risk increase of 60% in both the placebo group (from 5.4% to 8.5%), and the statin group (from 3.0% to 4.8%). Absolute risk reduction increased by 58% (from 2.4% to 3.8%). Relative risk reduction of 44% was unchanged. In conclusion, 1) the presence or absence of atherosclerosis as measured by CAC redefines normal or abnormal lipid levels in an individual patient; 2) statin absolute risk reduction is significantly greater than previously appreciated; and 3) patients with a CAC score of 0 should be excluded from primary prevention randomized controlled trials. PMID- 21792640 TI - Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India. AB - The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation and vegetarian diet in univariate and multivariate analyses. There was no significant difference in the genotypic or allelic distribution of MTHFR C677T polymorphism, however, high frequency of CT genotype, as observed, among controls suggests heterozygous advantage probably due to supplementary folate. Among the two communities, Muslim NTD mothers had higher TT genotype showing increased risk for neural tube defects (adjusted OR: 12.9; 95% CI: 1.21-136.8) and lower folic acid supplementation (adjusted OR: 3.5; 95% CI: 1.18-10.22). Whereas, marginal increased risk for NTDs with vegetarian diet was observed among Hindus. Cultural and ethnic variation in the risk factors for neural tube defects is highlighted in the study. PMID- 21792641 TI - Longitudinal myelitis in systemic lupus erythematosus: a paediatric case. AB - Acute transverse myelitis (ATM) is a very rare manifestation of the central nervous system in systemic lupus erythematosus (SLE), especially in case of involvement of continuous segments (longitudinal myelitis). We describe a 12-year old female with lupus correlated with transverse myelitis with a longitudinal involvement of the spinal cord (D2 to D10) at the onset of the disease. Despite the administration of an early aggressive therapy, the outcome proved to be unfavourable. After 2 years of follow-up, the child still complains of paraplegia, sphincter incontinency and ipo-paresthesias of both legs. PMID- 21792642 TI - Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years. AB - Accelerated atherosclerosis is a major cause of mortality in SLE. Mycophenolate mofetil (MMF) has been shown to suppress growth factor-induced proliferation of vascular smooth muscle and endothelial cells in animal models. We hypothesized that MMF might modify the inflammatory component of atherosclerosis in SLE. We examined the effect of MMF on atherosclerosis as measured by changes in carotid intima-media thickness (IMT) or coronary artery calcium (CAC) over 2 years. CAC and carotid IMT were measured at baseline and 2 years later in a cohort of 187 patients with SLE. The cohort was 91% women, 59% Caucasian, and 35% African American, with a mean age of 45 +/- 11 years. Of these, 12.5% (n = 25) received MMF during follow-up. The daily dose ranged from 500 to 3,000 mg/day, and duration ranged from 84 days to the entire 2 years. We divided MMF users into three groups: low exposure (<1,500 mg average daily dose), high exposure (>=1,500 average daily dose), and any exposure of MMF (<1,500 or >=1,500 average daily dose) for 2 years. The mean CAC increased in all four groups: no MMF: 1.17-1.28, low MMF: 1.02-1.13, high MMF: 1.44-1.61, and any MMF: 1.21-1.34 log-Agatston units. Compared to no MMF, there was no statistically different change between the three groups (p = 0.99, 0.87, and 0.91). Similarly, mean carotid IMT increased in all four groups: no MMF: 0.58-0.66, low MMF: 0.55-0.60, high MMF: 0.56-0.71, and any MMF: 0.56-0.66. We then adjusted for statin use, lupus nephritis, body mass index, systolic blood pressure, cholesterol, and age during the 2-year follow-up. The association between MMF exposure and change in CAC or carotid IMT was not statistically significant (p = 0.63 for CAC, and p = 0.085 for carotid IMT). There was no evidence that MMF slowed or decreased the progression of atherosclerosis as measured by carotid IMT or CAC. Because the number of patients taking MMF was only twenty-five, larger studies for longer time periods are needed to explore any effect of MMF on subclinical atherosclerosis in SLE. PMID- 21792643 TI - Evaluation of lower limb disability in joint hypermobility syndrome. AB - The aim of this study is to evaluate degree and possible major determinants of lower limb disability in joint hypermobility syndrome. Forty patients with joint hypermobility syndrome were studied. Lower limb function was evaluated with the lower limb functional scale (LEFS). Intensity of pain was estimated by the numeric rating scale. Rough results were compared with previously published data for osteoarthritis patients. Within the studied population, comparisons were performed by age, sex, numeric rating scale and Beighton scores. In joint hypermobility syndrome, LEFS score was similar to osteoarthritis, but in the former, comparable values were observed with a ~10 year earlier onset. LEFS scores resulted significantly related to age, pain intensity and Beighton score. No correlation with sex was observed. This study demonstrated that, in joint hypermobility syndrome, disability of lower limbs is remarkable and related to the increase in pain and age and to the decrease in residual joint hypermobility. These preliminary results may be relevant for the identification of more efficient and tailored treatment programs. PMID- 21792644 TI - Prevalence and correlates of suicidal ideation in SLE inpatients: Chinese experience. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. Because of double damages of body and mind, SLE patients are in a potential risk of suicide. Many factors may contribute to the occurrence of suicide in SLE: socioeconomic factors, medical factors, mental health, family support and coping style. This study aims to investigate the prevalence and correlates of suicidal ideation in SLE inpatients in China in order to determine whether they had risk of suicide, and if so, what factors should be paid more attention to prevent suicide in wards. A total of 285 SLE patients were interviewed with questionnaires on suicidal ideation and socio-demographic characteristics, Beck Depression Inventory (BDI), Family APGAR and Trait Coping Style Questionnaire (TCSQ). Disease activity was assessed with SLE Disease Activity Index. The other medical information was collected from the patients' medical records. In total, 34.4% of SLE patients had current suicidal ideation. Significant individual risk factors for current suicidal ideation in SLE patients included having religious belief, heavy self-reported financial burdens, long duration of SLE, low level of family functioning and negative coping style. And in the presence of these risk factors, being separated, divorced or widowed, having premorbid suicidal ideation and depression were independent predictors of suicidal ideation. In summary, the rate of suicidal ideation in SLE patients in China is higher than that in other countries. Factors that contribute to risk of suicidal ideation include social and cultural domains and physical and psychological health. Although the association of suicidal ideation to religions and medical factors is still to be investigated, these findings may give some references to suicide prevention efforts for SLE patients in China. PMID- 21792645 TI - Platelet gel in the treatment of severe scleroderma skin ulcers. AB - Systemic sclerosis (SSc) is characterized by microvascular damage and fibrosis of the skin and internal organs. Non-healing skin ulcers, mainly non-venous leg ulcers, represent one of the most challenging complications. Platelet gel (PG) is a hemocomponent containing numerous growth factors, potentially useful for tissue reparation. This pilot open study aimed to evaluate the effect of PG in 12 SSc patients with skin ulcers resistant to conventional therapies from at least 6 months. PG was applied in the wound bed twice weekly for 2 weeks, then once a week for 12 weeks; in all cases, the ongoing treatments remained unchanged at the time of PG applications. Skin ulcers were evaluated at 0, 12 and 24 weeks; the patient's quality of life was also evaluated using the visual analogical scale (VAS) and the health assessment questionnaire (HAQ). During the 6-month follow up, the skin ulcers consistently improved in 10/12 patients, with complete healing in 4. At the last evaluation, wound size reduced from 23.4 +/- 14.9 SD to 2.3 +/- 2.2 SD cm(2) (p < 0.0001). Patient's quality of life markedly improved: VAS decreased from 87.08 +/- 13.5 to 57.9 +/- 12.6; p < 0.0001 and HAQ from 0.73 +/- 0.43 to 0.57 +/- 0.22; p < 0.0001. PG may represent a novel therapeutic option for SSc skin ulcers refractory to conventional treatments. PMID- 21792646 TI - Septic polyarthritis caused by group A streptococcus in an immunocompetent adult: rare case. AB - We report a rare case of multifocal septic arthritis associated to spondylodiscitis and endocarditis caused by group A beta-hemolytic streptococcus (GABHS) in an immunocompetent adult, and we discuss diagnosis and therapeutic difficulties, while insisting into the rational use of corticosteroids that seems to be the only risk factor in our patient. PMID- 21792647 TI - Nephrotic syndrome and juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDM) is a rare autoimmune disease characterized by proximal muscle weakness, skin lesions, gastro intestinal, pulmonary, cardiac and small nerve damage. Renal involvement has been rarely reported in JDM. This is the report of a 7-year-old boy presented with nephrotic syndrome (NS) and subsequent renal failure. Clinical manifestations of JDM appeared gradually. Renal manifestations could be considered as a rare initial presentation of JDM. PMID- 21792649 TI - Anti-arthritic effects of FasL gene transferred intra-articularly by an inducible lentiviral vector containing improved tet-on system. AB - The objective of this study is to construct and identify an inducible lentiviral vector containing improved tet-on system and FasL gene and observe its effects on pristane-induced arthritis (PIA). FasL gene was amplified from the spleen of Lewis rats by RT-PCR. The tet-on system was improved with insertion of a chicken chromatin insulator (cHS4) element and an rtTA-dependent, tet-responsive element containing modifications of the tetO sequence (TRE-tight1). Pro-apoptosis effect of the vector pTREFasLcHS4V16 on synovial cells was evaluated by flow cytometer in vitro. Anti-arthritis effects of the vector on PIA after intra-articular injection were observed by clinical evaluation and joint histology. Cytokines in synovial tissue were measured by ELISA. The recombinant inducible lentiviral vector pTREFasLcHS4V16 was successfully constructed. The expression response and the pro-apoptosis effects of the vector were doxycycline dose-dependent. The vector injected intra-articularly attenuated the severity of PIA and decreased the level of cytokines in inflamed joints. pTREFasLcHS4V16 with an improved tet on system can precisely regulate the expression of FasL gene and apoptosis. Anti arthritis effects were observed after intra-articular injection of the inducible vector. PMID- 21792648 TI - Prevalence and clinical presentations of hepatitis C virus among patients admitted to the rheumatology ward. AB - To study the prevalence of anti-HCV antibodies among patients admitted to the rheumatology department, Cairo University hospitals, in 6-month period as well as to determine whether chronic HCV infection was the primary cause of their admission or just a concomitant association with the rheumatic disease. One hundred and fifty-seven patients were included in this study. They represent all patients admitted to the rheumatology inpatient department of Cairo University hospitals during the study period. Preset questionnaire including detailed demographic data, cause of admission and clinical manifestations of their disease was obtained for every patient. All patients were screened for HCV antibodies using ELISA technique. Other laboratory and imaging investigations were done according to the patient's diagnosis. Twenty-nine patients (18.5%) were positive for HCV antibody. Eleven patients of them (38%) were admitted due to rheumatic manifestations directly related to chronic HCV infection, which represent 7% of all admitted patients (11/157). HCV antibodies were found in 17.6 and 6.7% among patients with rheumatoid and systemic lupus erythematosus. Arthritis, palpaple purpura, digital gangrene and mononeuritis multiplex were the most common causes of admission related to chronic HCV infection. HCV antibodies were found in 18.5% among admitted patients to the rheumatology ward. The rheumatic manifestations of chronic HCV represent the primary cause of admission in 7% of all admitted patients. HCV screening should be included in the routine investigations for patients presenting to rheumatology departments in countries with high prevalence of chronic HCV infection. PMID- 21792650 TI - Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome. AB - PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and the most severe form of functional intestinal obstruction in the newborn. This congenital condition is associated with non-obstructed urinary bladder, microcolon and decreased or absent intestinal peristalsis. This study was designed to determine the incidence and outcome of MMIHS. METHODS: A systematic review of the literature (1976-2011) was performed for key words "megacystis microcolon intestinal hypoperistalsis". Resulting publications were reviewed for epidemiology and outcome. Reference lists were screened for additional cases. RESULTS: A total number of 227 MMIHS cases were reported from 1976 to 2011. A clear preponderance for female infants was found (female 70.6 vs. male 29.4%). One or more surgical interventions were reported in 115 patients (including gastrostomy, ileostomy, jejunostomy, segmental resections of small bowel, adhesiolysis and internal sphincter myectomy). For decompression of the megacystis, vesicostomy was performed in 41 patients. Outcome was reported in a total of 218 patients. Survival rate was 19.7% (survivors: n = 43, non-survivors: n = 175), the oldest survivor being 24 years old. The vast majority of the surviving patients had to be maintained by total or partial parenteral nutrition (TPN). Main causes of death were sepsis, malnutrition and multiple organ failure. Twelve multivisceral transplantations have been reported to date in patients with MMIHS. The majority of the survivors are reported to be free of parenteral nutrition and show improving gastric emptying. However, intermittent catheterisation remains obligatory due to persistent bladder dysfunction. CONCLUSIONS: The survival in MMIHS in recent years has improved. The majority of survivors are either maintained by TPN or have undergone multiorgan transplantations. PMID- 21792651 TI - German network for congenital uro-rectal malformations: first evaluation and interpretation of postoperative urological complications in anorectal malformations. AB - OBJECTIVE: The aim of the German Network for Congenital Uro-REctal Malformations is to collect data of affected patients with anorectal malformation (ARM) or extrophy-epispadias complex, and to investigate molecular causes, clinical implications, and psychosocial outcome. The current issue was to assess the postoperative sequelae related to lower urinary tract dysfunction in patients with ARM. MATERIALS AND METHODS: Two hundred and sixty-seven patients with ARM (112 females, 155 males, median age 6 years, range 0-56 years) were investigated via standardized case report forms comprising interview, analysis of medical data, and personal questionnaires. RESULTS: Thirty-two patients (12%, 23 males, 9 females) suffered from neurogenic bladder dysfunction, mainly associated with recto-urethral fistula (11 cases, 34%), and recto-vesical fistula (6 cases, 19%). Sixty-eight patients (26%, 35 males, 57 females) have experienced lifetime urinary tract infection, primarily associated with recto-urethral fistula (21 cases, 31%), and vestibular fistula (13 cases, 19%). According to type of operation, the highest number of postoperative urologic problems was reported after abdominosacroperineal pull-through. CONCLUSION: Besides reconstructing the ARM, another main goal is the preservation of lower urinary tract function. In our data, there seems to be a close correlation between operative strategies and postoperative complications. PMID- 21792653 TI - Effect of temperature on development and reproduction of Neoseiulus barkeri (Acari: Phytoseiidae) fed on Aleuroglyphus ovatus. AB - The effect of five constant temperatures (16, 20, 24, 28 and 32 degrees C) on the development, survival and reproduction of Neoseiulus barkeri Hughes fed on Aleuroglyphus ovatus Toupeau (Acari: Acaridae) was examined in the laboratory at 85% relative humidity. Development time of different immature stages decreased with increasing temperature, total egg-to-adult development time varied from 5.0 +/- 0.13 to 17.5 +/- 0.29 days. The lower thermal threshold for development was 9.7 +/- 2.48 degrees C and the thermal constant from egg to adult was 111.1 +/- 12.34 degree-days. Pre- and post-oviposition period and female longevity all shortened as temperature increased. The longest oviposition period was observed at 24 degrees C with 20.4 +/- 1.13 days. At 20, 24, 28 and 32 degrees C, mated females laid on average 0.7 +/- 0.08, 1.5 +/- 0.04, 1.6 +/- 0.11 and 1.5 +/- 0.11 eggs per day, respectively, but no eggs were laid at 16 degrees C. Both the maximum fecundity (30.9 eggs per female) and the highest intrinsic rate of increase (r (m) = 0.166) were obtained at 28 degrees C. The results of this study indicated that a mass rearing of N. barkeri with A. ovatus as prey is feasible at the appropriate temperature. PMID- 21792654 TI - Gastroesophageal reflux disease in India: ISG Task Force completes a task! PMID- 21792655 TI - Epidemiology and symptom profile of gastroesophageal reflux in the Indian population: report of the Indian Society of Gastroenterology Task Force. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) and its complications are thought to be infrequent in India; there are no data from India on the prevalence of and risk factors for GERD. The Indian Society of Gastroenterology formed a task force aiming to study: (a) the frequency and profile of GERD in India, (b) factors including diet associated with GERD. METHODS: In this prospective, multi center (12 centers) study, data were obtained using a questionnaire from 3224 subjects regarding the frequency, severity and duration of heartburn, regurgitation and other symptoms of GERD. Data were also obtained regarding their dietary habits, addictions, and lifestyle, and whether any of these were related or had been altered because of symptoms. Data were analyzed using univariate and multivariate methods. RESULTS: Two hundred and forty-five (7.6%) of 3224 subjects had heartburn and/or regurgitation at least once a week. On univariate analysis, older age (OR 1.012; 95% CI 1.003-1.021), consumption of non-vegetarian and fried foods, aerated drinks, tea/coffee were associated with GERD. Frequency of smoking was similar among subjects with or without GERD. Body mass index (BMI) was similar in subjects with and without GERD. On multivariate analysis, consumption of non-vegetarian food was independently associated with GERD symptoms. Overlap with symptoms of irritable bowel syndrome was not uncommon; 21% reported difficulty in passage of stool and 9% had mucus in stools. About 25% of patients had consulted a doctor previously for their gastrointestinal symptoms. CONCLUSION: 7.6% of Indian subjects have significant GERD symptoms. Consumption of non-vegetarian foods was an independent predictor of GERD. BMI was comparable among subjects with or without GERD. PMID- 21792656 TI - Gastroenterology in India - some considerations. PMID- 21792657 TI - The embryo rescue derived intergeneric hybrid between chrysanthemum and Ajania przewalskii shows enhanced cold tolerance. AB - Five intergeneric hybrids between the chrysanthemum cultivar 'Zhongshanjingui' (as female) and Ajania przewalskii (as male) were obtained with the help of embryo culture. While 'Zhongshanjingui' bears a standard anemone type flower and A. przewalskii a non-anemone type one, the inflorescence type of the hybrids varied. The diameter of the hybrids' flowers was intermediate between those of the parents. The chromosome number of the hybrids was 2n = 45, of which GISH analysis was able to establish that 27 were inherited from 'Zhongshanjingui' and the other 18 from A. przewalskii. A combination of various assays was used to show that the cold tolerance of the hybrids was equivalent to that of the highly tolerant A. przewalskii parent. Enhanced cold tolerance was correlated with an increase in free proline and a decrease in malondialdehyde content. PMID- 21792659 TI - Interpretability, validity, and the minimum important difference. AB - Patient-reported outcomes are increasingly used as dependent variables in studies regarding the effectiveness of clinical interventions. But patient-reported outcome measures (PROMs) do not provide intuitively meaningful data. For instance, it is not clear what a five point increase or decrease on a particular scale signifies. Establishing 'interpretability' involves making changes in outcomes meaningful. Attempts to interpret PROMs have led to the development of methods for identifying a minimum important difference (MID). In this paper, however, I draw on Charles Taylor's distinction between weak and strong evaluations to suggest that identifying a MID, specifically, a MID that uses a patient-reported reference group, may not provide an adequate interpretation of these measures. Moreover, I argue that the difficulty with interpreting these measures is tied to a larger problem concerning their validity. If researchers wish to interpret PROMs, they may first need to know more about the constructs they attempt to measure, namely, quality of life. PMID- 21792658 TI - Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface. AB - The huKS-IL2 immunocytokine (IC) consists of IL2 fused to a mAb against EpCAM, while the hu14.18-IL2 IC recognizes the GD2 disialoganglioside. They are under evaluation for treatment of EpCAM(+) (ovarian) and GD2(+) (neuroblastoma and melanoma) malignancies because of their proven ability to enhance tumor cell killing by antibody-dependent cell-mediated cytotoxicity (ADCC) and by antitumor cytotoxic T cells. Here, we demonstrate that huKS-IL2 and hu14.18-IL2 bind to tumor cells via their antibody components and increase adhesion and activating immune synapse (AIS) formation with NK cells by engaging the immune cells' IL-2 receptors (IL2R). The NK leukemia cell line, NKL (which expresses high affinity IL2Rs), shows fivefold increase in binding to tumor targets when treated with IC compared to matching controls. This increase in binding is effectively inhibited by blocking antibodies against CD25, the alpha-chain of the IL2R. NK cells isolated from the peritoneal environment of ovarian cancer patients, known to be impaired in mediating ADCC, bind to huKS-IL2 via CD25. The increased binding between tumor and effector cells via ICs is due to the formation of AIS that are characterized by the simultaneous polarization of LFA-1, CD2 and F-actin at the cellular interface. AIS formation of peritoneal NK and NKL cells is inhibited by anti-CD25 blocking antibody and is 50-200% higher with IC versus the parent antibody. These findings demonstrate that the IL-2 component of the IC allows IL2Rs to function not only as receptors for this cytokine but also as facilitators of peritoneal NK cell binding to IC-coated tumor cells. PMID- 21792660 TI - Mercury temporal trends in top predator fish of the Laurentian Great Lakes. AB - Mercury (Hg) contamination is widespread in the Laurentian Great Lakes region and is a serious environmental concern. In anaerobic environments such as lake sediments, mercury is transformed into methylmercury (MeHg) and can biomagnify up the food chain to toxic concentrations. The Great Lakes Fish Monitoring Program (GLFMP), administered by the US EPA Great Lakes National Program Office (GLNPO), aims to monitor temporal trends of mercury in the five Great Lakes using top predator fish as biomonitors. Total Hg (THg) concentrations were measured in Great Lake fish collected between 1999 and 2009. Single factor ANOVA determined that average fish THg concentrations over this time period in the five lakes were significantly different from one another in the order of Superior > Huron > Michigan > Ontario > Erie. By fitting the data to three different models (linear, quadratic, and two-segment piecewise), it was determined that Hg concentrations in top predator fish (lake trout, or walleye in Lake Erie) are currently increasing in Lake Erie and the Apostle Island sampling site in Lake Superior. Significant decreasing trends are evident in Lakes Michigan, Ontario, and the Rockport sampling site in Lake Huron, although all of the lakes exhibit elevated concentrations in fish compared to historic concentrations. As new Hg emission controls are implemented in the US, continued monitoring of Hg in Great Lakes fish will be needed to determine if they influence the current concentrations and trends. PMID- 21792661 TI - Structural and functional effects of conventional and low pesticide input crop protection programs on benthic macroinvertebrate communities in outdoor pond mesocosms. AB - The impacts of current and alternative wheat crop protection programs were compared in outdoor pond mesocosms in a 10-month long study. Realistic exposure scenarios were built based upon the results of modelling of drift, drainage and runoff of pesticides successively applied under two environmental situations characteristics of drained soils of northern France. Each situation was associated to two crop protection programs ("Conventional" and "Low-input") differing in the nature of pesticides used, number of treatments and application rate. Both programs induced significant direct negative effects on various invertebrate groups. Bifenthrin and cyprodynil were identified as the main responsible for these effects in conventional and low-input program, respectively. Indirect effects were also demonstrated especially following treatments with cyprodynil. Litter breakdown was significantly reduced in all treated mesocosms as the functional consequence of the decrease in the abundance of shredders (asellids, Gammarus pulex) illustrating the link between structural and functional effects of pesticides on macroinvertebrate communities. Recovery was observed for many taxa before the end of the study but not for the most sensitive non mobile taxa such as G. pulex. No influence of the agropedoclimatic situation on the effects was shown, suggesting than the main impacts were associated to inputs from drift. The results confirm that the proposed low-input program was less hazardous than the conventional program but the observed structural and functional impact of the low-input program suggest that further improvement of alternative crop protection programs is still needed. PMID- 21792662 TI - Mercury in breeding saltmarsh sparrows (Ammodramus caudacutus caudacutus). AB - Environmental mercury exposure of birds through atmospheric deposition and watershed point-source contamination is an issue of increasing concern globally. The saltmarsh sparrow (Ammodramus caudacutus) is of high conservation concern throughout its range and the potential threat of mercury exposure adds to other anthropogenic stressors, including sea level rise. To assess methylmercury exposure we sampled blood of the northern nominal subspecies of saltmarsh sparrows (A. c. caudacutus) nesting in 21 tidal marshes throughout most of the species' breeding range. Blood of tree swallows (Tachycineta bicolor) was sampled concurrently at three of these sites to provide a comparison with a well-studied songbird that is a model species in ecotoxicology. Arithmetic means (+/-1 SD) ranged from 0.24 +/- 0.06 MUg g(-1) wet weight (ww) in Connecticut to 1.80 +/- 0.14 MUg g(-1) ww in Massachusetts, differing significantly among sites. Comparison to tree swallows indicates that mercury exposure is significantly higher in saltmarsh sparrows, making them a more appropriate bioindicator for assessing risk to methylmercury toxicity in tidal marsh ecosystems. PMID- 21792663 TI - Narrow-band imaging flexible cystoscopy in the detection of primary non-muscle invasive bladder cancer: a "second look" matters? AB - OBJECTIVE: We investigated whether narrow-band imaging (NBI) was superior to white light imaging (WLI) for detecting primary non-muscle invasive bladder cancer (NMIBC) in a randomized imaging sequence modality, as the increased detection rate by NBI maybe result from the "second look" inspection of the bladder. METHODS: Between February 2009 and May 2010, NBI and WLI flexible cystoscopy were prospectively performed on 78 patients with primary suspected NMIBC. According to randomization protocol, the bladder was mapped using WLI then NBI or vice versa within the same observation time. Suspicious lesions together with controlled normal-appearing mucosa were biopsied and examined by a pathologist blinded to the imaging sequence. The tumors detected on patient and tumor level, sensitivity, specificity, and accuracy were compared in both imaging. RESULTS: Sixty-nine of 78 (88.5%) patients were diagnosed with bladder cancer including 211 tumors totally. Of these, 36 (17.1%) tumors in 13 patients were detected by NBI only, while 4 (1.9%) tumors in 3 patients found by WLI only. NBI identified significantly more additional tumors than WLI (P < 0.01). The sensitivity of WLI versus NBI for detecting primary bladder tumors was 77.7 versus 92.9% (P < 0.0001), the specificity 82.7 versus 73.5% (P > 0.05), and the accuracy 79.3 versus 86.7% (P < 0.05). The sensitivity of WLI versus NBI for detecting carcinoma in situ (CIS) was 68.3 versus 87.8% (P < 0.05), the specificity 82.9 versus 77.1% (P > 0.05), and the accuracy 75 versus 82.9% (P > 0.05). CONCLUSIONS: The "second look" did not compromise the superiority of NBI over standard WLI flexible cystoscopy for detecting primary NMIBC including CIS lesions. PMID- 21792664 TI - FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women. AB - OBJECTIVE: Herein we analyzed FSH-R polymorphism at position 307 aiming (a) to assess the prevalence of the three allelic variants (Ala307Ala, Ala307Thr and Thr307Thr) in relation to the type of ovary and (b) to clarify if the allelic variant could influence the responsiveness to exogenous FSH. STUDY DESIGN: We prospectively studied a group of 106 Italian women undergoing in vitro fertilization (IVF), among which 40 were subjects with polycystic ovary syndrome (PCOS) and 66 were normo-ovulatory women with a normal ovarian morphology at transvaginal ultrasound. DNA extraction, denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing were used to detect the FSH-R 307 polymorphic genotype and the whole exon 10 was analyzed. RESULTS: The heterozygote variant Ala307Thr was significantly more frequent than the homozygote variants in women with PCOS, whereas in normo-ovulatory women with normal ovary the three allelic variants had a comparable prevalence. Women bearing the Ala307Thr variant showed a higher ovarian responsiveness to exogenous FSH than normo-ovulatory subjects. CONCLUSIONS: The heterozygote FSH-R polymorphism Ala307Thr is significantly more frequent in women with PCOS than in normo-ovulatory subjects and is more frequently associated with a higher ovarian responsiveness to exogenous FSH. PMID- 21792665 TI - Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved? AB - PURPOSE: To determine if patients with a low response to controlled ovarian hyperstimulation during IVF benefit from intracytoplasmic sperm injection (ICSI) METHODS: Retrospective analysis of 350 IVF cycles in which four or fewer oocytes were retrieved. Severe male factor cases were excluded from analysis. Conventional insemination (CI) and ICSI were compared, with primary outcome measures of fertilization rate, implantation rate, clinical pregnancy rate per embryo transfer, and pregnancy loss rate. RESULT(S): Fertilization rates per oocyte retrieved for CI and ICSI were comparable (51.5% vs. 51.8%). Parallel implantation rates (22% vs. 25%), clinical pregnancy rates (32.8% vs. 33.3%), and loss rates (26.7% vs. 39.5%) were also noted. No difference in cancelled cycles was reported. CONCLUSION(S): Our results demonstrate that in the presence of normal semen parameters, low egg number is not an indication to perform ICSI. PMID- 21792666 TI - The time interval between hCG priming and oocyte retrieval in ART program: a meta analysis. AB - OBJECTIVE: To evaluate the relationship between different hCG priming-to-oocyte retrieval intervals and assisted reproductive technology (ART) outcome. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library, Science Citation Index, Chinese biomedicine (CBM) literature database, and Chinese Journal Full text Database for randomized controlled trials (RCTs) published up to November 2010. Data was extracted from the studies by two independent reviewers. Statistical analysis was performed with Cochrane Collaboration's Review Manager (RevMan) 5.0.2. From extracted data, Risk Ratio (RR) with 95% confidence interval (CI) was calculated. RESULTS: 5 RCTs totaling 895 participants were included. Oocyte maturation rate was higher in the long interval group compared with short interval group (RR, 0.67; 95% CI, 0.62-0.73). There were no significant difference between the two groups with regard to fertilization rate (RR, 0.99; 95% CI, 0.94-1.04), implantation rate (RR, 0.91; 95% CI, 0.40-2.04), and pregnancy rate (RR, 0.79; 95% CI, 0.58-1.08). CONCLUSION: The percentage of mature (MII) oocytes can be increased by prolonging the interval between hCG priming and oocyte retrieval. The prolonged interval could not increase the fertilization rate, implantation rate, and pregnancy rate. Although there was evidence to confirm the results, they still need to be confirmed by large-sample, multicenter, randomized controlled trials. The time interval dependent mechanisms responsible for ART performance need to be elucidated. PMID- 21792667 TI - Rare histological variants in ependymomas: histopathological analysis of 13 cases. AB - Ependymomas are rare brain tumors representing about 3% of all intra-cerebral and spinal neoplasms. The WHO classification recognizes various rare histological ependymoma variants (i.e., lipidized ependymoma, giant cell ependymoma, etc.). However, a detailed analysis of a larger series of such cases is still lacking. We analyzed 13 case of ependymoma presenting unusual histological features. The data analysis of our series and its comparison to the cases published in literature did not reveal any close association between these features and the clinical parameters (such as age or localization). Moreover, some of these features can be found combined in individual tumors, suggesting that these variants may represent a spectrum of differentiation rather than true specific entities. However, awareness on these rare histological patterns in ependymomas is necessary in the differential diagnosis with other primary or secondary brain tumors. PMID- 21792668 TI - Electrocardiographic characterization of rhesus monkey model of ischemic myocardial infarction induced by left anterior descending artery ligation. AB - Myocardial infarction is a leading cause for morbidity and mortality in the modern society. Rhesus monkeys are excellent animal models for experimental and translational studies of cardiovascular diseases in humans. However, some detailed characterizations of cardiovascular disease, such as myocardial infarction, in Rhesus monkeys have not been available. The present study was undertaken to examine the progressive electrocardiographic changes in Rhesus monkeys after left anterior descending (LAD) artery ligation. Male Rhesus monkeys, aged 2-3 years and weighed 4.5-6.0 kg, were subjected to LAD ligation along with sham-operated controls. At 1 week, 1 month, and 6 months after the LAD ligation, ECG recording was performed to detect the progressive changes in ECG. In addition, cardiac magnetic resonance imaging (MRI) and echocardiography were applied to detect the myocardial infarction induced by LAD ligation, and histopathological examination was performed at the end of the experiment to measure the morphological changes. The results showed that QRS and ST-T changed significantly within 1 month after LAD ligation, but recovered to normal at the end of the experiment. The most significant change was a progressive QTc prolongation, which occurred corresponding to the development of myocardial infarction. Both cardiac MRI and echocardiography detected the myocardial infarction that was confirmed by the histopathological examination. This detailed characterization of ECG changes along with the development of myocardial infarction induced by LAD ligation thus demonstrated that the Rhesus monkey model of ischemic myocardial infarction would be an excellent surrogate for human myocardial infarction. This model would also provide an excellent tool for drug discovery and development for cardiac disease. PMID- 21792669 TI - Carbon monoxide pollution impairs myocardial perfusion reserve: implication of coronary endothelial dysfunction. AB - Chronic exposure to simulated urban CO pollution is reported to be associated with cardiac dysfunction. Despite the potential implication of myocardial perfusion alteration in the pathophysiology of CO pollution, the underlying mechanisms remain today still unknown. Therefore, the aim of this work was to evaluate the effects of prolonged exposure to simulated urban CO pollution on the regulation of myocardial perfusion. Cardiac hemodynamics and myocardial perfusion were assessed under basal conditions and during the infusion of a beta-Adrenergic agonist. The effects of CO exposure on capillary density, coronary endothelium dependent vasodilatation, eNOS expression and eNOS uncoupling were also evaluated. Our main results were that prolonged CO exposure was associated with a blunted myocardial perfusion response to a physiological stress responsible for an altered contractile reserve. The impairment of myocardial perfusion reserve was not accounted for a reduced capillary density but rather by an alteration in coronary endothelium-dependent vasorelaxation (-45% of maximal relaxation to ACh). In addition, though chronic CO exposure did not change eNOS expression, it significantly increased eNOS uncoupling. Therefore, the present work underlines the fact that chronic CO exposure, at levels found in urban air pollution, is associated with reduced myocardial perfusion reserve. This phenomenon is explained at the coronary-vessel level by deleterious effects of CO exposure on the endothelium NO-dependent vasorelaxation via eNOS uncoupling. PMID- 21792670 TI - Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate filament inclusion disease (NIFID). AB - Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or alpha internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or IotaNuAlpha, and (3) the spatial patterns of the FUS immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID. PMID- 21792671 TI - Correlations in state space can cause sub-optimal adaptation of optimal feedback control models. AB - Control of our movements is apparently facilitated by an adaptive internal model in the cerebellum. It was long thought that this internal model implemented an adaptive inverse model and generated motor commands, but recently many reject that idea in favor of a forward model hypothesis. In theory, the forward model predicts upcoming state during reaching movements so the motor cortex can generate appropriate motor commands. Recent computational models of this process rely on the optimal feedback control (OFC) framework of control theory. OFC is a powerful tool for describing motor control, it does not describe adaptation. Some assume that adaptation of the forward model alone could explain motor adaptation, but this is widely understood to be overly simplistic. However, an adaptive optimal controller is difficult to implement. A reasonable alternative is to allow forward model adaptation to 're-tune' the controller. Our simulations show that, as expected, forward model adaptation alone does not produce optimal trajectories during reaching movements perturbed by force fields. However, they also show that re-optimizing the controller from the forward model can be sub optimal. This is because, in a system with state correlations or redundancies, accurate prediction requires different information than optimal control. We find that adding noise to the movements that matches noise found in human data is enough to overcome this problem. However, since the state space for control of real movements is far more complex than in our simple simulations, the effects of correlations on re-adaptation of the controller from the forward model cannot be overlooked. PMID- 21792672 TI - Validation of a statistical shape model-based 2D/3D reconstruction method for determination of cup orientation after THA. AB - PURPOSE: The aim of this study was to validate the accuracy and reproducibility of a statistical shape model-based 2D/3D reconstruction method for determining cup orientation after total hip arthroplasty. With a statistical shape model, this method allows reconstructing a patient-specific 3D-model of the pelvis from a standard AP X-ray radiograph. Cup orientation (inclination and anteversion) is then calculated with respect to the anterior pelvic plane that is derived from the reconstructed model. MATERIALS AND METHODS: The validation study was conducted retrospectively on datasets of 29 patients (31 hips). Among them, there were 15 men (15 hips) and 14 women (16 hips). The average age of the patients was 69.4+/-8.5 (49-82) years. Each dataset has one postoperative X-ray radiograph and one postoperative CT scan. The postoperative CT scan for each patient was used to establish the ground truth for the cup orientation. The cup anteversion and inclination that were calculated from the 2D/3D reconstruction method were compared to the associated ground truth. To validate reproducibility and reliability, two observers performed measurements for each dataset twice in order to measure the reproducibility and the reliability of the 2D/3D reconstruction method. RESULTS: Our validation study demonstrated a mean accuracy of 0.4 +/- 1.8 degrees (-2.6 degrees to 3.3 degrees ) for inclination and a mean accuracy of 0.6+/-1.5 degrees (-2.0 degrees to 3.9 degrees ) for anteversion. Through the Bland-Altman analysis, no systematic errors in accuracy were detected. The method showed very good consistency for both parameters. CONCLUSIONS: Our validation results demonstrate that the statistical shape model-based 2D/3D reconstruction based method is an accurate, consistent, and reproducible technique to measure cup orientation from postoperative X-ray radiographs. The best results were achieved with radiographs including the bilateral anterior superior iliac spines and the cranial part of non-fractured pelvises. PMID- 21792673 TI - A solution for medical and legal problems arising from forgotten ureteral stents: initial results from a reminder short message service (SMS). AB - The objective of this study was to describe and present the initial results of a computer-based system that tracks ureteral stents and automatically sends a reminder through a short message service (SMS) to both the patient's and the urologist's mobile phones Using an integrated stent register program (SRP) and a stent extraction reminder program (SERP) with an electronic patient record program (EPRP) located within our hospital's computer network. In this system, the demographic data of all of the patients are recorded into the password protected EPRP. After a stent is inserted, the surgeon enters the details of the operation into the EPRP. The SRP automatically asks the user to define the "optimal stent life (OSL)". The SERP checks the recorded patients daily and sends an SMS reminder to staff and patient when the OSL is reached. The SERP continues to send reminders via the SMS until stent is removed. We analyzed the success of the SMS recall system. A total of 186 patients received stents over an 11-month period. The patients in group-2 (n = 108) were recalled by the SERP, and the remainder of the patients (n = 78, group-1) were not included in the project. The mean delay from the designated OSL to the time of stent removal was 307 +/- 118.6 (72-1,344) and 14.6 +/- 2.06 (5-36) h in groups 1 and 2, respectively (p < 0.0001). Our initial results showed that the SRP and SERP prevent stent removal from being forgotten, thus preventing related medical and legal problems. PMID- 21792674 TI - A multicenter case-control study of diagnostic tests for urinary tract infection in the presence of urolithiasis. AB - Urinary stone disease (USD) alone can cause much morbidity, but when present in conjunction with urinary tract infection, complications and morbidity increase even more. This study investigated the clinical and laboratory findings in patients who had USD with and without infection and evaluated the most suitable diagnostic value for urinary tract infection parameters before urine culture results were available. In a prospective fashion, patients who presented to the emergency department with a complaint of colicky flank pain (with or without hematuria) and who were diagnosed as having urolithiasis with ultrasound were evaluated for 1 year. The gold standard for the diagnosis of urinary tract infection was urine culture. The most suitable diagnostic value for urinary tract infection parameters was determined by receiver operating characteristic (ROC) curves. Logistic regression was used to identify independent variables that predicted a positive urine culture. Of the 192 eligible patients, 177 agreed to participate in the study. Of the clinical and laboratory characteristics analyzed, urine WBC, blood WBC, and fever were significantly different between culture positive and negative patients (p < 0.001, p = 0.04 p = 0.012, respectively). Using ROC curve analysis, pyuria (over 10 WBCs per HPF), fever over 37.9 degrees C, and leucocytosis over 11,300 were the best predictors of a positive culture result. The logistic regression model for leukocytosis >11,300 (OR 2.1), pyuria (OR 2.8), and temperature >37.9 degrees C (OR 3.1) showed a significantly increased risk of having a positive urine culture (correct class 87.9%). While a single physical examination or laboratory finding cannot predict urinary tract infection in USD patients with complete reliability, the presence of pyruria, fever, and leukocytosis significantly increases the odds of a positive urine culture. PMID- 21792675 TI - Physical exercise reverses cognitive impairment in rats subjected to experimental hyperprolinemia. AB - This study investigated whether physical exercise would reverse proline-induced performance deficits in water maze tasks, as well as its effects on brain-derived neurotrophic factor (BDNF) immunocontent and brain acetylcholinesterase (AChE) activity in Wistar rats. Proline administration followed partial time (6th-29th day of life) or full time (6th-60th day of life) protocols. Treadmill exercise was performed from 30th to 60th day of life, when behavioral testing was started. After that, animals were sacrificed for BDNF and AChE determination. Results show that proline impairs cognitive performance, decreases BDNF in cerebral cortex and hippocampus and increases AChE activity in hippocampus. All reported effects were prevented by exercise. These results suggest that cognitive, spatial learning/memory, deficits caused by hyperprolinemia may be associated, at least in part, to the decrease in BDNF levels and to the increase in AChE activity, as well as support the role of physical exercise as a potential neuroprotective strategy. PMID- 21792676 TI - Hyperacute detection of neurofilament heavy chain in serum following stroke: a transient sign. AB - Serological biomarkers which enable quick and reliable diagnosis or measurement of the extent of irreversible brain injury early in the course of stroke are eagerly awaited. Neurofilaments (Nf) are a group of proteins integrated into the scaffolding of the neuronal and axonal cytoskeleton and an established biomarker of neuro-axonal damage. The Nf heavy chain (NfH(SMI35)) was assessed together with brain-specific astroglial proteins GFAP and S100B in hyperacute stroke (6 and 24 h from symptom onset) and daily for up to 6 days. Twenty-two patients with suspected stroke (median NIHSS 8) were recruited in a prospective observational study. Evidence for an ischaemic or haemorrhagic lesion on neuroimaging was found in 18 (ischaemia n = 16, intracerebral haemorrhage n = 2). Serum NfH(SMI35) levels became detectable within 24 h post-stroke (P < 0.0001) and elevated levels persisted over the study course. While GFAP was not detectable during the entire course, S100B levels peaked at the end of the observation period. The data indicate that significant in vivo information on the pathophysiology of stroke may be obtained by the determination of NfH(SMI35). Further studies are required to evaluate whether NfH(SMI35) in hyperacute stroke reflects the extent of focal ischaemic injury seen on neuroimaging or is a consequence of more diffuse neuro axonal damage. PMID- 21792677 TI - Activation of adenosine A2A receptor up-regulates BDNF expression in rat primary cortical neurons. AB - As a member of neurotrophin family, brain derived neurotrophic factor (BDNF) plays critical roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. There have been reported that adenosine A2(A) receptor subtype is widely distributed in the brain regions, such as hippocampus, striatum, and cortex. Adenosine A2(A) receptor is colocalized with BDNF in brain regions and the functional interaction between A2(A) receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that the activation of A2(A) receptor modulates BDNF production in rat primary cortical neuron. CGS21680, an adenosine A2(A) receptor agonist, induced BDNF expression and release. An antagonist against A2(A) receptor, ZM241385, prevented CGS21680-induced increase in BDNF production. A2(A) receptor stimulation induced the activation of Akt-GSK-3beta signaling pathway and the blockade of the signaling pathway with specific inhibitors abolished the increase in BDNF production, possibly via modulation of ERK1/2-CREB pathway. The physiological roles of A2(A) receptor-induced BDNF production was demonstrated by the protection of neurons from the excitotoxicity and increased neurite extension as well as synapse formation from immature and mature neurons. Taken together, activation of A2(A) receptor regulates BDNF production in rat cortical neuron, which provides neuro-protective action. PMID- 21792678 TI - Influence of fruit ripening stage and harvest period on the antioxidant content of sweet pepper cultivars. AB - Pepper (Capsicum annuum L.) fruits are highly appreciated by producers and consumers for their economical and nutritional value. Four different cultivars of coloured peppers in immature and mature stages were harvested throughout the spring and examined for their content of phenolic compounds, ascorbic acid and total antioxidant capacity (TAA) as well as for lipid peroxidation and carbonyl proteins as index of oxidative stress. Ripening and harvest period influenced the antioxidants and the development of oxidative processes in the cultivars differently: lipid peroxidation increased in mature peppers except in one cultivar (Y1075), while no changes in protein oxidation or in TAA were produced, except in Y1075 in which both parameters increased. Each cultivar presented differences in antioxidant compounds depending on the harvest period, but we could recommend May as the optimal if all cultivars have to be harvested at the same time, when levels of ascorbate, phenols and TAA were not decreased, fresh weight and proteins were elevated, and levels of oxidation were not as high as in June (except for Y1075). A previous study of the response of each cultivar to different environmental conditions results essential to establish a good program of selection of cultivars with high quality and productivity. PMID- 21792679 TI - Comparative study on the chemical composition, antioxidant properties and hypoglycaemic activities of two Capsicum annuum L. cultivars (Acuminatum small and Cerasiferum). AB - The present study aimed to evaluate for the first time the phenols, flavonoids, carotenoids, capsaicin and dihydrocapsaicin content and the antioxidant and hypoglycemic properties of Capsicum annuum var. acuminatum small and C. annuum var. cerasiferum air-dried fruits. The ethanol extract of C. annuum var. acuminatum small, characterized by the major content of total poliphenols, flavonoids, carotenoids and capsaicinoids, showed the highest radical scavenging activity (IC(50) of 152.9 MUg/ml). On the contrary, C. annuum var. cerasiferum showed a significant antioxidant activity evaluated by the beta-carotene bleaching test (IC(50) of 3.1 MUg/ml). The lipophilic fraction of both C. annuum var. acuminatum and C. annuum var. cerasiferum exhibited an interesting and selective inhibitory activity against alpha-amylase (IC(50) of 6.9 and 20.1 MUg/ml, respectively). PMID- 21792680 TI - Chemical and morphological characteristics of new clones and commercial varieties of globe artichoke (Cynara cardunculus var. scolymus). AB - The globe artichoke is a widely consumed vegetable in the Mediterranean Basin, with Italy being the leading producer. In southern Italy, its cultivation contributes to local economic stability and social development. The producers are increasingly choosing to replace autochthonous varieties, such as 'Violetto di Sicilia', with cultivars bred or selected outside of the region, putting pressure on the maintenance of traditional varieties. Here, we have undertaken a detailed morphological and chemical analysis of a group of clones selected from a population of 'Violetto di Sicilia'. All the traits measured displayed genetic variation, particularly the total content of phenolics and minerals. The capitula of the 'Violetto di Sicilia' clones contained, on average, 6.3 g kg(-1) of fresh weight total phenolics, compared with 4.5 g kg(-1) in the two commercial varieties. The clones also had more inulin than commercial varieties (254 vs. 225 g kg(-1) of dry matter), as well as a good mineral content. The set of clones is of interest in the context of the proposed improvement of the crop through breeding and selection of genotypes with high nutritional quality and a specific end-use (industrial processing or fresh consumption). PMID- 21792681 TI - Letter to the editor: Aseptic loosening of total hip arthroplasty: infection always should be ruled out. PMID- 21792682 TI - Obituary: Douglas J. Pritchard MD (1937-2011). PMID- 21792683 TI - Client participation in moral case deliberation: a precarious relational balance. AB - Moral case deliberation (MCD) is a form of clinical ethics support in which the ethicist as facilitator aims at supporting professionals with a structured moral inquiry into their moral issues from practice. Cases often affect clients, however, their inclusion in MCD is not common. Client participation often raises questions concerning conditions for equal collaboration and good dialogue. Despite these questions, there is little empirical research regarding client participation in clinical ethics support in general and in MCD in particular. This article aims at describing the experiences and processes of two MCD groups with client participation in a mental healthcare institution. A responsive evaluation was conducted examining stakeholders' issues concerning client participation. Findings demonstrate that participation initially creates uneasiness. As routine builds up and client participants meet certain criteria, both clients and professionals start thinking beyond 'us-them' distinctions, and become more equal partners in dialogue. Still, sentiments of distrust and feelings of not being safe may reoccur. Client participation in MCD thus requires continuous reflection and alertness on relational dynamics and the quality of and conditions for dialogue. Participation puts the essentials of MCD (i.e., dialogue) to the test. Yet, the methodology and features of MCD offer an appropriate platform to introduce client participation in healthcare institutions. PMID- 21792684 TI - Increased production of succinic acid in Escherichia coli by overexpression of malate dehydrogenase. AB - Escherichia coli NZN111 is a double mutant with inactivated lactate dehydrogenase and pyruvate formate-lyase. It cannot utilize glucose anaerobically because of its unusually high intracellular NADH/NAD(+) ratio. We have now constructed a recombinant strain, E. coli NZN111/pTrc99a-mdh, which, during anaerobic fermentation, produced 4.3 g succinic acid l(-1) from 13.5 g glucose l(-1). The NADH/NAD(+) ratio decreased from 0.64 to 0.26. Furthermore, dual-phase fermentation (aerobic growth followed by anaerobic phase) resulted in enhanced succinic acid production and reduced byproduct formation. The yield of succinic acid from glucose during the anaerobic phase was 0.72 g g(-1), and the productivity was 1.01 g l(-1) h(-1). PMID- 21792685 TI - Taxonomic and functional assignment of cloned sequences from high Andean forest soil metagenome. AB - Total metagenomic DNA was isolated from high Andean forest soil and subjected to taxonomical and functional composition analyses by means of clone library generation and sequencing. The obtained yield of 1.7 MUg of DNA/g of soil was used to construct a metagenomic library of approximately 20,000 clones (in the plasmid p-Bluescript II SK+) with an average insert size of 4 Kb, covering 80 Mb of the total metagenomic DNA. Metagenomic sequences near the plasmid cloning site were sequenced and them trimmed and assembled, obtaining 299 reads and 31 contigs (0.3 Mb). Taxonomic assignment of total sequences was performed by BLASTX, resulting in 68.8, 44.8 and 24.5% classification into taxonomic groups using the metagenomic RAST server v2.0, WebCARMA v1.0 online system and MetaGenome Analyzer v3.8 software, respectively. Most clone sequences were classified as Bacteria belonging to phlya Actinobacteria, Proteobacteria and Acidobacteria. Among the most represented orders were Actinomycetales (34% average), Rhizobiales, Burkholderiales and Myxococcales and with a greater number of sequences in the genus Mycobacterium (7% average), Frankia, Streptomyces and Bradyrhizobium. The vast majority of sequences were associated with the metabolism of carbohydrates, proteins, lipids and catalytic functions, such as phosphatases, glycosyltransferases, dehydrogenases, methyltransferases, dehydratases and epoxide hydrolases. In this study we compared different methods of taxonomic and functional assignment of metagenomic clone sequences to evaluate microbial diversity in an unexplored soil ecosystem, searching for putative enzymes of biotechnological interest and generating important information for further functional screening of clone libraries. PMID- 21792686 TI - Evidence for a causal association for HPV in head and neck cancers. AB - Current data have now attributed a viral etiology and causality of Human papillomavirus (HPV). Epidemiological analysis of the last decade demonstrates a rapid increase of HPV-associated HNSCC. Genomic detection of HPV DNA in the nuclei of certain oro-pharyngeal cancer cells gives strong evidence of a viral etiology in HNSCC. Non-smokers, non-drinkers, and a sexual debut at a younger age and other sexual risk factors have an increased risk of HPV-positive oropharyngeal cancer. Sexual transmission is considered to play a causal role. In contrast to HPV-negative HNSCC most studies reveal a favorable prognosis for HPV positive tumors. There is evidence of alterations in the p53 pathway through expression of E6 oncogene with subsequent induction of tumor cell proliferation. Synergies between viral oncogenes and other carcinogens are hypothesized. HPV alone appears to be insufficient as the sole cause of HNSCC; this may explain the long latency period between HPV infection and cancer development. There is now sufficient evidence for a causal role for HPV in HNSCC. As in cervical cancer, HPV requires oncogenes and co-factors for tumor development. Thus, inhibition or loss of such co-factors may lead to tumor regression. The vast amounts of epidemiological, molecular pathological and in vitro experimental data are consistent with the hypothesis that HPV does indeed have a causal role. We await final validation from animal experimentation in which regression of HPV-positive tumors will follow from loss or inhibition of E6 and E7. PMID- 21792687 TI - 1-year follow-up after radiofrequency tonsillotomy and laser tonsillotomy in children: a prospective, double-blind, clinical study. AB - In the last decade, tonsillotomy has come into vogue again, whereas the number of tonsillectomies is decreasing rapidly. In a previous study, the tonsillotomy with laser or radiofrequency therapy proved as a safe and effective procedure with minimal pain and hemorrhage. This follow-up study determines which method is more effective with respect to long-term outcome, recurrence of tonsillar hyperplasia and recurrence of tonsillitis. A prospective, randomised, double-blinded controlled clinical study was conducted at the Department of Otorhinolaryngology of the Ludwig-Maximilians-University, Munich, Germany. Twenty-six children with tonsillar hypertrophy were included. Tonsillotomy was performed on one side with monopolar radiofrequency and on the other side with a carbon dioxide laser. Exactly 1 year after the procedure, all 26 patients were documented by digital photography to define a possible recurrence of tonsillar hyperplasia. All parents were asked for occurring tonsillitis and fulfilled the Glasgow Children's Benefit Inventory (GCBI) for health-related quality of life after surgical procedures. In seven children, a slightly visible recurrence of the tonsillar hyperplasia occurred, without any symptoms or correlation to the different methods and sides. One child with recurrent tonsillitis and hyperplasia had to be tonsillectomized 8 months after the initial tonsillotomy procedure. The specimen showed open crypts with bacterial infection in the deep. The GCBI resulted in highly significant benefits of the surgery in all categories and subcategories. In conclusion, both methods, the laser tonsillotomy and the radiofrequency method, were equal concerning the effectiveness and safety after 1 year. Further investigations have to aim at the long-term outcome after tonsillotomy in patients with recurrent infections. PMID- 21792689 TI - Compulsive masturbation and chronic penile lymphedema. AB - Chronic penile lymphedema arises from the abnormal retention of lymphatic fluid in the subcutaneous tissues and may be secondary to local and systemic medical conditions such as sexually transmitted diseases, filariasis, malignancy, local radiotherapy, and surgery. This case report aims to consider compulsive masturbation as a possible cause of chronic penile edema. A 40-year-old man was referred to our institute for behavioral disturbance, including compulsive masturbation. Neuropsychiatric evaluation showed moderate mental retardation, mild dysarthria and limb incoordination, anxiety, depressed mood, and impulse dyscontrol. Brain MRI pointed out diffuse white matter lesions. Urogenital examination revealed an uncircumcised penis with non-tender edema of the shaft and prepuce with areas of lichenification. Since the most common local and systemic causes of edema were excluded, chronic penile edema due to compulsive masturbation was diagnosed and the compulsive behavior treated with an antidepressant and low-dose neuroleptics. Compulsive masturbation should be taken into account when counselling patients with penile edema. PMID- 21792688 TI - Initial orienting towards sexually relevant stimuli: preliminary evidence from eye movement measures. AB - It has been proposed that sexual stimuli will be processed in a comparable manner to other evolutionarily meaningful stimuli (such as spiders or snakes) and therefore elicit an attentional bias and more attentional engagement (Spiering and Everaerd, In E. Janssen (Ed.), The psychophysiology of sex (pp. 166-183). Bloomington: Indiana University Press, 2007). To investigate early and late attentional processes while looking at sexual stimuli, heterosexual men (n = 12) viewed pairs of sexually preferred (images of women) and sexually non-preferred images (images of girls, boys or men), while eye movements were measured. Early attentional processing (initial orienting) was assessed by the number of first fixations and late attentional processing (maintenance of attention) was assessed by relative fixation time. Results showed that relative fixation time was significantly longer for sexually preferred stimuli than for sexually non preferred stimuli. Furthermore, the first fixation was more often directed towards the preferred sexual stimulus, when simultaneously presented with a non sexually preferred stimulus. Thus, the current study showed for the first time an attentional bias to sexually relevant stimuli when presented simultaneously with sexually irrelevant pictures. This finding, along with the discovery that heterosexual men maintained their attention to sexually relevant stimuli, highlights the importance of investigating early and late attentional processes while viewing sexual stimuli. Furthermore, the current study showed that sexually relevant stimuli are favored by the human attentional system. PMID- 21792690 TI - Measurement of nontraditional sexuality in women. AB - The Women's Nontraditional Sexuality Questionnaire (WNSQ) was developed, and its factor structure, reliability, and convergent and concurrent validity assessed, in two samples of midwestern U.S. college women. Study 1 (N=243) used exploratory factor analysis to assess the instrument dimensionality. In Study 2 (N=627), the fit of the four-factor solution derived from Study 1 was assessed using confirmatory factor analysis. Results supported a four-factor solution comprising: Involvement in Casual Sex, Self-Pleasuring, Degree of Sexual Interest, and Using Sex as a Means to an End. WNSQ total score and subscales had acceptable internal consistency reliability. Convergent validity was supported by significant correlations of the WNSQ and its subscales with a measure of casual sex (the Sociosexual Orientation Index), and with a measure of adherence to traditional feminine sexual norms (the Purity subscale of the Femininity Ideology Scale). The WNSQ showed weak relationships with a measure of risky sexual health communication practices (Health Protective Sexual Communication Scale). The WNSQ offers promise for study of women's sexual attitudes and behaviors. PMID- 21792691 TI - NYC condom use and satisfaction and demand for alternative condom products in New York City sexually transmitted disease clinics. AB - In 2007, via a high-profile media campaign, the New York City Department of Health and Mental Hygiene (NYC DOHMH) introduced the "NYC Condom," the first specially packaged condom unique to a municipality. We conducted a survey to measure NYC Condom awareness of and experience with NYC Condoms and demand for alternative male condoms to be distributed by the DOHMH. Trained interviewers administered short, in-person surveys at five DOHMH-operated sexually transmitted disease (STD) clinics in Spring 2008. We systematically sampled eligible patients: NYC residents aged >=18 years waiting to see a physician. We approached 539; 532 agreed to be screened (98.7% response rate); 462 completed the survey and provided NYC zip codes. Most respondents were male (56%), non-Hispanic black (64%), aged 18-24 years (43%) or 25-44 years (45%), employed (65%), and had a high school degree/general equivalency diploma or less (53%). Of those surveyed, 86% were aware of the NYC Condom, and 81% of those who obtained the condoms used them. NYC Condom users were more likely to have four or more sexual partners in the past 12 months (adjusted odds ratio [AOR] = 2.0, 95% confidence interval [CI] = 1.0-3.8), use condoms frequently (AOR = 2.1, 95% CI = 1.3-3.6), and name an alternative condom for distribution (AOR = 2.2, 95% CI = 1.3-3.9). The most frequently requested condom types respondents wanted DOHMH to provide were larger size (28%), ultra thin/extra sensitive (21%), and extra strength (16%). We found high rates of NYC Condom use. NYC Condom users reported more sexual partners than others, suggesting the condom initiative successfully reached higher-risk persons within the STD clinic population. Study results document the condom social marketing campaign's success. PMID- 21792692 TI - Clinical characteristics of fulminant type 1 diabetes associated with pregnancy in China. AB - To report 12 cases of pregnancy-associated fulminant type 1 diabetes mellitus (PF) found in China from 2003 to 2010. The clinical and biochemical characteristics of these cases with PF were compared with a group of cases of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF). The clinical and biochemical characteristics of 12 PF cases were analyzed retrospectively and then compared with those characteristics of 20 NPF cases in China. The difference between Chinese and Japanese PF cases was investigated. The mean values of the characteristics from PF and NPF cases in China, including postprandial serum C-peptide concentration, plasma glucose concentration, and serum chloride were different. Compared to the 22 PF cases in Japan, the mean age of these 12 PF cases was much younger. The mean fasting and postprandial serum C-peptide concentration level were lower, and the mean HbA1c levels was higher in 12 PF cases in China. Eight of 12 PF cases in China developed the disease during pregnancy. Other four PF case developed the disease within 2 weeks after delivery. 12 PF cases in China showed more severe beta-cell destruction, the prognosis of their fetuses was extremely poor. PMID- 21792693 TI - MGMT immunoexpression in growth hormone-secreting pituitary adenomas and its correlation with Ki-67 labeling index and cytokeratin distribution pattern. AB - Recent publications suggest the utility of temozolomide (TMZ) in the management of aggressive pituitary adenomas and carcinomas, resistant to conventional treatments. The response to TMZ is inversely correlated with tumoral expression of O-6 methylguanine DNA methyl transferase (MGMT). Therefore, we aimed to assess MGMT immunoexpression in pure GH-secreting pituitary adenomas, in an effort to predict the likelihood of response to TMZ, and to correlate MGMT immunoexpression with Ki-67 LI and cytokeratin (CK) distribution pattern. Our material consisted of 36 GH-secreting pituitary adenomas (21 female,15 male, mean age 42.5+/-10.5), operated at our center between 2003 and 2010. Immunostaining for MGMT, Ki-67, and CK was performed using avidin-biotin-peroxidase complex method. Immunoreactivity for MGMT and Ki-67 was evaluated microscopically and recorded as percentages of positive nuclear immunostaining. CK distribution pattern was also evaluated microscopically and assoreted into dot-like and nondot-like pattern subtypes. MGMT immunoexpression scored as 0=none, 1=<10%, 2=<25%, 3=<50%, and 4=>50%. Staining for MGMT was <10% (score 1) in 30 (83.3%), 10-25% (score 2) in 3 (8.3%), 25-50% (score 3) in 2 (5.6%) and >50% (score 4) in 1 (2.8%) of the tumors, respectively. There was no correlation between Ki-67 LI and CK distribution pattern with MGMT immunoreactivity (P>0.05). Data from the current study suggest a large proportion of GH-secreting adenomas, including those with dot-like CK distribution pattern and high Ki-67 LI, demonstrate negative/low MGMT immunoreactivity and could be treated with TMZ, if conventional treatment fails. PMID- 21792695 TI - Doctors and patients' susceptibility to framing bias: a randomized trial. AB - BACKGROUND: Framing of risk influences the perceptions of treatment benefit. OBJECTIVE: To determine which risk framing format corresponds best to comprehensive multi-faceted information, and to compare framing bias in doctors and in patients. DESIGN: Randomized mail surveys. PARTICIPANTS: One thousand four hundred and thirty-one doctors (56% response rate) and 1121 recently hospitalized patients (65% response rate). INTERVENTION: Respondents were asked to interpret the results of a hypothetical clinical trial comparing an old and a new drug. They were randomly assigned to the following framing formats: absolute survival (new drug: 96% versus old drug: 94%), absolute mortality (4% versus 6%), relative mortality reduction (reduction by a third) or all three (fully informed condition). The new drug was reported to cause more side-effects. MAIN MEASURE: Rating of the new drug as more effective than the old drug. RESULTS: The proportions of doctors who rated the new drug as more effective varied by risk presentation format (abolute survival 51.8%, absolute mortality 68.3%, relative mortality reduction 93.8%, and fully informed condition 69.8%, p < 0.001). In patients these proportions were similar (abolute survival 51.7%, absolute mortality 66.8%, relative mortality reduction 89.3%, and fully informed condition 71.2%, p < 0.001). In both doctors (p = 0.72) and patients (p = 0.23) the fully informed condition was similar to the absolute risk format, but it differed significantly from the other conditions (all p < 0.01). None of the differences between doctors and patients were significant (all p > 0.1). In comparison to the fully informed condition, the odds ratio of greater perceived effectiveness was 0.45 for absolute survival (p < 0.001), 0.89 for absolute mortality (p = 0.29), and 4.40 for relative mortality reduction (p < 0.001). CONCLUSIONS: Framing bias affects doctors and patients similarly. Describing clinical trial results as absolute risks is the least biased format, for both doctors and patients. Presenting several risk formats (on both absolute and relative scales) should be encouraged. PMID- 21792694 TI - Heat shock protein expression and change of cytochrome c oxidase activity: presence of two phylogenic old systems to protect tissues in ischemia and reperfusion. AB - Induction of heat shock proteins (hsp) has been shown to protect cells from ischemia by providing transient tolerance against myocardial injury and improving postischemic functional recovery. Attenuation of ATP depletion and earlier restoration of ATP content on reperfusion are thought to play a role in this scenario. Hsp induction is accompanied by altered enzyme activity of the respiratory chain, the major generator of ATP under physiological conditions. This report addresses the question whether processing and final assembly of the active holoenzyme cytochrome c oxidase (CcO, complex IV), member of the respiratory chain, is compromised under hypoxic conditions unless protected by stress proteins. Special focus is laid on function of the enzyme's subunits and importance of cellular energy availability and maintenance. PMID- 21792696 TI - Comprehensive application of an mtDsRed2-Tg mouse strain for mitochondrial imaging. AB - Mitochondria are essential for many cellular functions such as oxidative phosphorylation and calcium homeostasis; consequently, mitochondrial dysfunction could cause many diseases, including neurological disorders. Recently, mitochondrial dynamics, such as fusion, fission, and transportation, have been visualized in living cells by using time-lapse imaging systems. The changes in mitochondrial morphology could be an indicator for estimating the activity of mitochondrial biological function. Here, we report a transgenic mouse strain, mtDsRed2-Tg, which expresses a red fluorescent protein, DsRed2, exclusively in mitochondria. Mitochondrial morphology could be clearly observed in various tissues of this strain under confocal microscope. Recently, many transgenic mouse strains in which enhanced green fluorescent protein (EGFP)-tagged proteins of interest are expressed have been established for physiological analysis in vivo. After mating these strains with mtDsRed2-Tg mice, red-colored mitochondria and green-colored proteins were detected simultaneously using fluorescent imaging systems, and the interactions between mitochondria and those proteins could be morphologically analyzed in cells and tissues of the F(1) hybrids. Thus, mtDsRed2 Tg mice can be a powerful tool for bioimaging studies on mitochondrial functions. PMID- 21792697 TI - Use of piezosurgery for internal auditory canal drilling in acoustic neuroma surgery. AB - BACKGROUND: Piezosurgery is based on microvibrations generated by the piezoelectrical effect and has a selective bone-cutting ability with preservation of soft tissue. This study examined the applicability of Piezosurgery compared to rotating drills (RD) for internal auditory canal (IAC) opening in acoustic neuroma (AN) surgery. MATERIALS AND METHODS: Piezosurgery was used in eight patients for IAC drilling in AN surgery. After exposition of the IAC and tumor, the posterior wall of the IAC was drilled using Piezosurgery instead of RD. Piezosurgery was evaluated with respect to practicability, safety, preciseness of bone cutting, preservation of cranial nerves, influences on neurophysiological monitoring, and facial nerve and hearing outcome. RESULTS: Piezosurgery was successfully used for selective bone cutting, while cranial nerves were structurally and functionally preserved, which could be measured by means of neuromonitoring. Piezosurgery guaranteed a safe and precise cut by removing bone layer by layer in a shaping way. Compared to RD, limited influence on neurophysiological monitoring attributable to Piezosurgery was noted, allowing for continuous neuromonitoring. No disadvantage due to microvibrations was noticed concerning hearing function. The angled tip showed better handling in right-sided than in left-sided tumors in the hands of a right-handed surgeon. The short, thick handpiece may be improved for more convenient handling. CONCLUSION: Piezosurgery is a safe tool for selective bone cutting for opening of the IAC with preservation of facial nerve and hearing function in AN surgery. Piezosurgery has the potential to replace RD for this indication because of its safe and precise bone-cutting properties. PMID- 21792698 TI - Tumoral presentation of primary central nervous system lymphomatoid granulomatosis. AB - PURPOSE: Lymphomatoid granulomatosis (LYG) is an angiocentric Epstein-Barr virus (EBV) related B-cell proliferation associated with a reactive T-cell component with an uncertain malignant potential. LYG present at diagnosis as a mass lesion in the central nervous system (CNS) is rare, and only a few cases have been reported. In this article we present four cases of tumoral CNS-LYG and propose some guidelines for its management. METHODS: Clinical, pathological, imaging and laboratory information of four immunocompetent patients, all of them treated surgically, with a final diagnosis of LYG and presenting with an isolated intracranial tumoral mass is reviewed. RESULTS: Two parenchymal lesions were located in the cerebellum and temporal lobe, and the other two involved the cavernous sinus. At surgery they were avascular, hard, lard-like, necrotic and plastic well-defined lesions, with invasion of the leptomeninges and thrombosis of the small leptomeningeal arteries and veins. Intraoperative pathology excluded any tumor. Pathological studies showed a polymorphic and polyclonal infiltration around, in the wall and into the lumen of medium-sized cortical and leptomeningeal vessels causing their obstruction and tissular necrosis. EBV infected cells were present. CONCLUSIONS: Making a preoperative diagnosis of CNS LYG appearing initially as a tumoral mass is difficult because of the lack of pathognomonic clinical symptoms or imaging signs. Surgical management with radical resection of the mass is almost always followed by the long-term local control of the lesion, although the disease may have a disseminated, systemic or malignant evolution. PMID- 21792699 TI - Mesh-reinforced hiatal hernia repair: a review on the effect on postoperative dysphagia and recurrence. AB - PURPOSE: The objective of the present study was to review the pertinent literature and analyze the evidence for and against the use of mesh for hiatal hernia repair, with a focus on the effects on recurrence and postoperative dysphagia. METHODS: A literature search was performed between January 1990 and March 2010. Studies were considered for inclusion, provided (1) they comprised a series of at least 20 patients, (2) they documented a follow-up period of at least 6 months, (3) they reported on the outcome as expressed by hernia recurrence rates, and (4) they reported on type of mesh material, hiatal closure, and antireflux surgery. RESULTS: Twenty-three articles enrolling a cumulative number of 1,446 patients fulfilled the inclusion criteria. Polypropylene meshes seem to be associated with low recurrence rates (0-22.7%, median 1.9%) and acceptable dysphagia rates (0-21.7%, median 3.9%). Higher dysphagia rates after polytetrafluoroethylene (PTFE) and expanded PTFE (ePTFE) mesh hiatoplasty have been recorded (15.5-34.3%). Even though the use of novel biologic implants for hiatal repair is still in its infancy, the existing results from clinical research are promising. CONCLUSIONS: Polypropylene meshes seem to provide durable results with low dysphagia rates. Unacceptably high recurrence rates for PTFE/ePTFE meshes have been reported. Biologic implant engineering represents a promising field in hiatal hernia surgery. PMID- 21792700 TI - pS6 Expression in normal renal parenchyma, primary renal cell carcinomas and their metastases. AB - In cancer therapy novel concepts focus on phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) inhibitors. In this context, phosphorylated S6 protein of the 40S ribosomal subunit (pS6) overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study therefore evaluated pS6 expression in normal renal parenchyma (NRP), primary renal cell carcinomas (PRCC) and their metastases. pS6 and pmTOR expression was immunohistochemically analyzed in a tissue microarray (TMA) from localized primary renal cell carcinoma (lPRCC) (n = 35), metastasized primary renal cell carcinoma (mPRCC) (n = 45), their metastases (n = 45), and NRP (n = 45). pS6 expression was stronger in mPRCCs and metastases than in NRP and lPRCCs (p < 0.05). In mPRCCs high-grade and high-stage tumors showed higher pS6 levels. pS6 overexpression was more frequently found in metastases (40/45; 88.9%) than in mPRCC (24/45; 53.3%) (p < 0.05). Overexpression of pS6 in metastases without concomitant overexpression in their primary tumors was found in 16/45 (35.56%) cases. Patients with pS6 overexpression in mPRCCs but also in metastases showed a tendency to shorter overall survival. pS6 score and pmTOR score correlated positively in NRP and in tumorous tissue (mPRCC and metastases). In conclusion, the present study showed stronger pS6 expression and more frequent overexpression in metastases than in corresponding PRCCs. In approximately one-third of the cases pS6 overexpression was found exclusively in metastases, which is interesting with regard to the association between high pS6 expression and sensitivity to mTOR inhibitor therapy. PMID- 21792701 TI - Bayesian quantitative disease-drug-trial models for Parkinson's disease to guide early drug development. AB - The problem we have faced in drug development is in its efficiency. Almost a half of registration trials are reported to fail mainly because pharmaceutical companies employ one-size-fits-all development strategies. Our own experience at the regulatory agency suggests that failure to utilize prior experience or knowledge from previous trials also accounts for trial failure. Prior knowledge refers to both drug-specific and nonspecific information such as placebo effect and the disease course. The information generated across drug development can be systematically compiled to guide future drug development. Quantitative disease drug-trial models are mathematical representations of the time course of biomarker and clinical outcomes, placebo effects, a drug's pharmacologic effects, and trial execution characteristics for both the desired and undesired responses. Applying disease-drug-trial model paradigms to design a future trial has been proposed to overcome current problems in drug development. Parkinson's disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and postural instability. A symptomatic effect of drug treatments as well as natural rate of disease progression determines the rate of disease deterioration. Currently, there is no approved drug which claims disease modification. Regulatory agency has been asked to comment on the trial design and statistical analysis methodology. In this work, we aim to show how disease-drug trial model paradigm can help in drug development and how prior knowledge from previous studies can be incorporated into a current trial using Parkinson's disease model as an example. We took full Bayesian methodology which can allow one to translate prior information into probability distribution. PMID- 21792703 TI - Retraction note to: Hemodynamics, intramucosal pH and regulators of circulation during perioperative epidural analgesia. PMID- 21792704 TI - Retraction note to: Urapidil does not prevent postanesthetic shivering: a dose ranging study. PMID- 21792705 TI - Retraction note to: Dolasetron, but not metoclopramide prevents nausea and vomiting in patients undergoing laparoscopic cholecystectomy. PMID- 21792706 TI - Retraction note to: Volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major abdominal surgery. PMID- 21792707 TI - Retraction note to: Diltiazem may preserve renal tubular integrity after cardiac surgery. PMID- 21792708 TI - The core of mentorship: medical students' experiences of one-to-one mentoring in a clinical environment. AB - Mentoring has been used in different health care educational programmes, but the core of mentorship, i.e., facilitating the development of medical students' professional competence, has not been explored in depth in the literature. In order to create effective and meaningful mentoring programmes, there is a need for deeper knowledge of the meaning of formal mentorship and, for this, the students' experiences are important. A mentoring program was set up where all medical students were offered a mentor during their first clinical courses; years 3-4. The mentors were physicians and their role as mentors was to support the students and act as sounding-boards, not to teach or assess knowledge. This study aimed to get a deeper understanding of the meaning of mentorship seen from the perspective of undergraduate medical students. A qualitative approach with individual interviews (N = 12) and inductive content analysis was chosen to investigate and interpret the meaning of mentorship. The results comprise three overarching themes: Space, Belief in the future and Transition. Having a mentor gave a sense of security and constituted a 'free zone' alongside the undergraduate programme. It gave hope about the future and increased motivation. The students were introduced to a new community and began to identify themselves as doctors. We would argue that one-to-one mentoring can create conditions for medical students to start to develop some parts of the professional competences that are more elusive in medical education programmes, such as reflective capacity, emotional competence and the feeling of belonging to a community. PMID- 21792709 TI - A 10-year review of sports-related spinal injuries. AB - INTRODUCTION: The incidence of traumatic spinal cord injury varies in different countries from 2.5 to 57.8 per million per annum, with sport accounting for 8 12.7% of these injuries. Spinal injuries associated with recreational sport often result in long-term permanent disability in otherwise active individuals. MATERIALS AND METHODS: The aetiology, pattern and mechanism of the 196 sports related spinal injuries treated in the National Spinal Injuries unit in Ireland from 1993 to 2003 is reviewed in this article. RESULTS: Sports-related spinal injuries accounted for 11% of all spinal injury admissions. There were 145 (74%) males and 51 (26%) females, with an average age of 30.2 years (range 14-72 years). The most common sport responsible for a spinal injury was equestrian events (41.8%), rugby (16.3%), diving (15.3%), Gaelic football and hurling (9.6%), cycling (4.2%), and miscellaneous (12.7%). Injury distribution was cervical spine (118 patients, 60%), thoracic (41 patients, 21%), lumbar spine (37 patients, 19%). In 18 patients (9.25%) more than one region was affected. In 78 patients (40%) more than one vertebral level was affected. On admission 71 patients (36%) had a neurological deficit with 46 patients (65%) incomplete and 25 (35%) complete, of which 6 patients (23%) were paraplegic and 19 (77%) were tetraplegic. CONCLUSION: Sport is an important cause of spinal injury among young people in Ireland. This study contributes to our understanding of these injuries aetiology, pattern and mechanism of injury and allows constructive recommendations for injury prevention and management. PMID- 21792711 TI - Right hemicolectomy with central vascular ligation in colon cancer. PMID- 21792710 TI - HLA-G regulators in cancer medicine: an outline of key requirements. AB - HLA-G is unique among the class I human leukocyte antigens. It plays a pivotal role in immune tolerance and a paradoxical role in therapies. Indeed, HLA-G expression is associated with a good prognosis in organ transplantation and an ominous prognosis in cancer. Recent progress has been made in HLA-G regulation identification, especially on human cell lines; however, little is known about their role in cancer therapy. Based on the role of HLA-G expression in cancer, we investigated the potential impact of the regulation of this expression on the outcome of some cancers. In this communication, we emphasize the importance of screening for HLA-G expression after cancer therapy. Future clinical trials could lead to a better understanding of the implication of HLA-G expression in cancer and lead to a better knowledge of cancer monitoring and recurrence. These studies could also implicate HLA-G as a therapeutic target in cancer therapy. PMID- 21792712 TI - Decreasing morbidity and mortality in 100 consecutive minimally invasive esophagectomies. AB - INTRODUCTION: Esophagectomy is a complex invasive procedure that requires exploration of multiple body cavities for removal and subsequent restoration of gastrointestinal continuity. In many institutions, esophagectomy morbidity and mortality rates remain high despite improvement of intensive care treatment. We reviewed our minimally invasive esophagectomy (MIE) experience of a consecutive series of 100 patients to analyze trends in morbidity and mortality as we transitioned from open to MIE. METHODS: A total of 105 consecutive patients who underwent operative exploration for esophagectomy from August 2007 to January 2011 were reviewed. The preoperative evaluation, operative technique, and postoperative care of these cases were evaluated and analyzed for 100 patients who have had a MIE and compared with 32 open esophagectomies 2 years prior. RESULTS: During the time frame of the study, 105 patients underwent an exploration for attempted esophagectomy. Resection was completed in 100 patients and was done for malignant disease in 95 patients and benign disease in 5 patients. There was one in hospital mortality due to a pulmonary embolism. There was no significant difference in postoperative complications consisting of transient left recurrent nerve injury (7 vs. 12.5%) or pneumonia (9 vs. 15.6%) in those who underwent MIE compared with open resection. However, wound infections were significantly less in patients who underwent MIE compared with open esophagectomy (1 vs. 12.5%, respectively, p = 0.01). Anastomotic leak (4 vs. 12.5%, p = 0.05) also was lower in those who underwent MIE. Median length of stay (LOS) was significantly less in patients who underwent MIE compared with open esophagectomy (7.5 vs. 14 days, p < 0.05). Finally, there was a trend toward improvement in median LOS in the 30 patients who underwent MIE during the most recent time period compared with the initial 17 patients who underwent MIE (7.5 vs. 10 days, p = 0.05) CONCLUSIONS: Our results support the continued safe use of esophagectomy for selected esophageal diseases, including malignancy. Morbidity, especially wound infection, anastomotic leak, and length of stay is decreasing with the incorporation of minimally invasive techniques. PMID- 21792713 TI - Laparoscopic versus open surgery for rectal cancer after neoadjuvant chemoradiation: a matched case-control study of short-term outcomes. AB - BACKGROUND: Neoadjuvant chemoradiation (nCRT) currently is commonly incorporated into the multimodal treatment of locally advanced rectal cancers. This study aimed to compare the short-term outcomes and oncologic adequacy of laparoscopic and conventional open surgery for rectal cancer after nCRT. METHODS: A series of 72 patients who underwent laparoscopic surgery (Lap group) for rectal cancer after nCRT were matched for type of surgery, gender, and American Society of Anesthesiologists (ASA) class with 72 patients who underwent conventional surgery during the same time period (Open group). The short-term outcomes were compared between the two groups of patients. RESULTS: No significant difference was found between the two groups in terms of age, distance of tumor from the anal verge, body mass index, or posttreatment pathologic stage of the disease. There were significant differences between the Lap and Open groups in terms of blood loss (median: 200 vs 400 ml; P < 0.001), duration of surgery (median: 270 vs 240 min; P < 0.001), time to passing of first flatus (median: 2 vs 3 days; P < 0.001), time to start of normal diet (median: 5 vs 6 days; P < 0.001), and hospital stay (median: 12 vs 15 days; P < 0.001). A significant difference in the number of lymph nodes harvested was not identified between the two groups, although more patients in the Open group had a positive circumferential resection margin than in the Lap group (10 vs 1%; P = 0.03). The short-term benefits of laparoscopic surgery also were observed when the 64 patients who underwent abdominoperineal resection (APR) in each of the two groups were compared separately. CONCLUSION: Laparoscopic surgery for rectal cancer, especially laparoscopic APR, after nCRT is safe and associated with earlier recovery of bowel function, a shorter hospital stay, and an oncologically adequate specimen compared with conventional open surgery. PMID- 21792714 TI - Laparoscopic colectomy significantly decreases length of stay compared with open operation. AB - INTRODUCTION: Current literature tends not to adjust for biases in patient selection attributable to comorbidities that could provide alternate explanations for length of stay differences in laparoscopic versus open colectomy. We hypothesized that utilizing the National Surgical Quality Improvement Program (NSQIP) dataset and acuity adjustment methods would demonstrate an independent improvement in length of stay for laparoscopic colectomy. METHODS: We used CPT coding to select all colectomies in NSQIP public use files from 2005-2009. Outlier status for surgical length of stay (SLOS) was defined as >75th percentile. Logistic regression analysis was used to predict this outlier status and linear regression to directly predict SLOS. Acuity adjustment was performed by using the most prevalent variables from multiple NSQIP annual reports. This work was done under the approval of our institutional review board and the data use agreement of the American College of Surgeons. Data were analyzed by using SPSS((r)). RESULTS: A total of 45,645 colectomies were reviewed, of which 12,455 (27.3%) were laparoscopic. The 75th percentile for SLOS was 11 days. This implied that 9,249 (27.9%) of the open colectomies were outliers, whereas only 1,152 (9.2%) of laparoscopic colectomies were outliers (p < 0.001). When optimizing a simple linear regression to predict SLOS, using common acuity adjustors (i.e., age, functional status, wound category, etc.), the variable marking open procedures consistently had a coefficient of 1.8, implying that open procedures increased SLOS by 1.8 days (p < 0.001). Utilizing logistic regression to predict outlier status, open colectomies were associated with an odds ratio of 3.79 for outlier status (p < 0.001), thus implying an independent effect on SLOS. CONCLUSIONS: These results indicate that laparoscopic colectomy independently decreases SLOS compared with open colectomy. This study is unique in using statistical methods to control for selection bias of patients who might be more "surgically fit." PMID- 21792715 TI - Laparoscopic transcystic exploration for single-stage management of common duct stones and acute cholecystitis. AB - BACKGROUND: Common bile duct (CBD) stones are found in 10% of patients who undergo elective laparoscopic surgery for gallstone disease and in 10-20% of patients who present with acute cholecystitis (AC). For the latter, the role of laparoscopic transcystic exploration of the common duct (LTCE) as part of a single-stage procedure is still unknown. METHODS: This study, based on a "laparoscopy first" policy, included 201 subjects with cholecystocholedocholithiasis: 104 underwent a scheduled laparoscopic surgery (group A), and 97 where admitted for AC and had urgent laparoscopy (group B). Group B patients were significantly older (68.4 vs. 62.1 years; P = 0.0045), had a higher proportion of women (56% vs. 41%; P = 0.0345), and included more patients in the ASA III-IV class (39% vs. 21%; P = 0.0006). LTCE was performed by using basket-wired catheters. CBD clearance, operating time, conversion rate, morbidity and mortality, postoperative hospital stay, readmission, and residual CBD stones were the main outcome measures. RESULTS: Clearance of CBD was obtained in 84% of patients of group A and in 80% of patients of group B (P = not significant). Time spent in the operating room was longer for group B (175 vs. 141 min; P = 0.0003). There were no significant differences for postoperative hospital stay (group A 4.9 vs. group B 5.2 days), readmission rate (3.7% vs. 3.7%), and residual CBD stones (2.8% vs. 3.1%). Need to convert and morbidity occurred more frequently in group B (11.7% vs. 4.6% and 28.7% vs. 16.8%, respectively), but differences were not significant. In group A, one patient died from MOFS. CONCLUSIONS: LTCE has proved to be a simple technique with a high yield of CBD clearance in the acute setting. Courses are comparable to those observed for the same procedure in elective surgery despite the fact that patients with AC are more at risk for drawbacks. PMID- 21792716 TI - Assessing the invasiveness of NOTES perforated viscus repair: a comparative study of NOTES and laparoscopy. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) repair of perforated peptic ulcers may decrease surgical invasiveness and improve patient outcomes. METHODS: Full thickness gastrotomy was created laparoscopically in swine followed by soilage time. Repair proceeded with a laparoscopic (n = 14) or the NOTES (n = 14) approach. For NOTES repair, the omentum was endoscopically pulled into the gastric lumen and clipped. Intraoperative and postoperative parameters were recorded, including arterial blood gas (ABG) analysis and serum samples for white blood cell (WBC), TNF-alpha, IL-1, and IL-6 analysis. RESULTS: Twenty-four of 28 animals thrived to study completion. NOTES repair could not be accomplished in one animal. At necropsy, all repairs were intact. Blood pressure was equivalent between groups. Pulse examined during the last 30 min of each procedure revealed a slightly higher mean pulse in the animals undergoing NOTES procedures (NOTES, 102 +/- 28; laparoscopy, 83 +/- 24). ABG obtained at the conclusion of the procedure revealed a pH of 7.47 in NOTES animals and 7.43 in the laparoscopy animals (p = 0.06), a change from baseline in both groups. The final pCO(2) was lower in the NOTES group (NOTES, 40.62; laparoscopy, 47.49, p = 0.03). WBC counts were comparable on postoperative day (POD) 1 (NOTES, 21.1; laparoscopy, 19.0; p = 0.49). Mean TNF-alpha serum levels were equivalent at all time points between groups; however, TNF-alpha varied significantly from baseline to POD 7 (p = 0.002). CONCLUSION: NOTES omental repair appears comparable to that of laparoscopy. The lower arterial pCO(2) at the conclusion of the NOTES procedure may be advantageous in critically ill patients. PMID- 21792717 TI - Single-incision versus conventional laparoscopic sigmoid colectomy: a case matched series. AB - BACKGROUND: Single-incision laparoscopic surgery is an emerging modality that has proven to be safe and feasible for colon resection in multiple case reports and series. Nonetheless, comparative analyses with established techniques are limited in the published literature. We evaluated the efficacy of single-incision laparoscopic colectomy (SILC) for the treatment of sigmoid disease through a matched-case comparison with conventional laparoscopic colectomy (CLC). METHODS: Twenty patients who underwent single-incision laparoscopic sigmoid resection for benign or malignant disease between July 2009 and September 2010 were matched to patients who underwent conventional laparoscopic sigmoid colectomy. Demographic, intraoperative, and postoperative data were assessed. RESULTS: Twenty SILC and CLC cases each were paired based on gender (p < 1.0), age (p < 0.47), pathology (p < 1.0), and surgical procedure (p < 1.0). Ten patients (50%) in the SILC group and eight patients (40%) in the CLC group had a history of prior abdominal surgery (p < 0.53). There were no conversions to open surgery; however, one SILC procedure (5%) required conversion to CLC (p < 0.31). There was no significant difference in mean operating time between groups (p < 0.80). Mean estimated blood loss was significantly lower for SILC compared to CLC (p < 0.007). Mean lymph node extraction was comparable between groups in the subset of patients with malignant disease (p < 0.68). Two postoperative complications were encountered in each group. The mean length of hospital stay for SILC and CLC was 3.2 +/- 1.0 and 3.8 +/- 2.1 days, respectively (p < 0.25). There were no readmissions or reoperative interventions in either group. CONCLUSION: Compared with conventional laparoscopic technique, single-incision laparoscopic surgery results in similar intraoperative and postoperative outcomes. The technique avoids use of multiple trocar sites and may safely be performed in patients with a history of previous abdominal surgery while maintaining a short length of hospital stay and low complication rate. PMID- 21792718 TI - Documenting correct assessment of biliary anatomy during laparoscopic cholecystectomy. AB - BACKGROUND: Correct assessment of biliary anatomy can be documented by photographs showing the "critical view of safety" (CVS) but also by intraoperative cholangiography (IOC). METHODS: Photographs of the CVS and IOC images for 63 patients were presented to three expert observers in a random and blinded fashion. The observers answered questions pertaining to whether the biliary anatomy had been conclusively documented. RESULTS: The CVS photographs were judged to be "conclusive" in 27%, "probable" in 35%, and "inconclusive" in 38% of the cases. The IOC images performed better and were judged to be "conclusive" in 57%, "probable" in 25%, and "inconclusive" in 18% of the cases (P < 0.001 compared with the photographs). The observers indicated that they would feel comfortable transecting the cystic duct based on the CVS photographs in 52% of the cases and based on the IOC images in 73% of the cases (P = 0.004). The interobserver agreement was moderate for both methods (kappa values, 0.4-0.5). For patients with a history of cholecystitis, both the CVS photographs and the IOC images were less frequently judged to be sufficient for transection of the cystic duct (P = 0.006 and 0.017, respectively). CONCLUSION: In this series, IOC was superior to photographs of the CVS for documentation of the biliary anatomy during laparoscopic cholecystectomy. However, both methods were judged to be conclusive only for a limited proportion of patients, especially in the case of cholecystitis. This study highlights that documenting assessment of the biliary anatomy is not as straightforward as it seems and that protocols are necessary, especially if the images may be used for medicolegal purposes. Documentation of the biliary anatomy should be addressed during training courses for laparoscopic surgery. PMID- 21792719 TI - Risk for local recurrence of early gastric cancer treated with piecemeal endoscopic mucosal resection during a 10-year follow-up period. AB - BACKGROUND: Endoscopic mucosal resection (EMR) is a therapy for early gastric cancer (EGC) that can be provided relatively easily and safely in any institution. Identification of the resection margin is a problem in EMR, especially in cases of piecemeal EMR. Despite the long-standing widespread use of piecemeal EMR for EGC, its limitation and long-term outcomes in clinical practice have not been fully evaluated. This study aimed to determine the risk factors of piecemeal EMR, the local recurrence rates, and the mortality rate. METHODS: A cross-sectional, retrospective cohort study was performed to investigate the risks of piecemeal EMR for patients with the diagnosis of differentiated adenocarcinoma localized to the mucosa. Local recurrence of EGC was investigated by annual follow-up esophagogastroduodenoscopy (EGD) for 10 years. EMR was performed with snare electrocautery using a two-channel scope. When a resection margin was clearly positive for cancer, additional surgery was performed soon after the initial EMR. RESULTS: For the 149 EGC patients (mean age, 68.8 +/- 9.8; male, 77%) who underwent EMR between 1995 and 2001, EMR was performed en bloc in 66 cases and piecemeal in 83 cases. The comorbid conditions existing in 34 of the 149 patients included other malignancies (n = 12), heart failure (n = 5), pulmonary disease (n = 7), liver cirrhosis (n = 4), and other illness (n = 6). However, EMR was completed without complication. The mean area (length * width) of the lesions was 404 +/- 289 mm(2) in the piecemeal group and 250 +/- 138 mm(2) in the en bloc groups. The en bloc and piecemeal EMR groups differed significantly in terms of unclear horizontal margins but not in terms of unclear vertical margins. Multiple logistic regression suggested that the adjusted odds ratio for maximum diameters exceeding 20 mm for piecemeal EMR was 2.71 (95% confidence interval [CI], 1.30-5.64). According to Kaplan-Meier estimates, the local recurrence rate was 30% (95% CI, 20-40%) at both 5 and 10 years. No recurrence was observed in the en bloc group. The adjusted hazard ratio of unclear horizontal margins for local recurrence was 1.63 (95% CI, 1.12-2.36). A total of 24 patients died after EMR because of comorbid conditions, including other malignancies (n = 11), cardiovascular disease (n = 6), pulmonary disease (n = 4), liver cirrhosis (n = 2), and traffic accident (n = 1). However, no patient died of gastric cancer during the 10-year follow-up period. CONCLUSIONS: An evaluation of horizontal margins in terms of local recurrence after piecemeal EMR is important, and en bloc resection is recommended. Close follow-up assessment is warranted, especially within 5 years in cases of unclear margin resection after piecemeal EMR. The use of EMR is safe even for patients with severe comorbid conditions. PMID- 21792720 TI - New dog, new tricks: trends in performance on the Fundamentals of Laparoscopic Surgery simulator for incoming surgery residents. AB - BACKGROUND: Exposure to laparoscopic surgery during medical school has increased over recent years. The Fundamentals of Laparoscopic Surgery (FLS) simulator allows for objective assessment of laparoscopic skills. This study aimed to determine whether the fundamental laparoscopic skills of incoming surgery residents have improved. METHODS: The initial FLS performance of first-year residents between 2003 and 2008 was identified from a prospective database. Linear regression was used to determine the effect of incoming year on performance of the five FLS simulator tasks (peg transfer, pattern cut, endoloop placement, suture with an extracorporeal knot [EC], suture with an intracorporeal knot [IC]) and the total score. Statistical significance was defined as a p value less than 0.05. RESULTS: A total of 63 first-year residents were identified from the database. The total FLS scores improved over time (r = 0.39; p = 0.001). The scores for peg transfer did not change significantly, but the scores for pattern cutting (r = 0.37; p = 0.002), endoloop placement (r = 0.36; p = 0.004), suture with EC (r = 0.32; p = 0.02), and suture with IC (r = 0.26; p = 0.03) all improved significantly over the 5 years. CONCLUSION: The baseline fundamental laparoscopic skills of incoming surgery residents appear to have improved over time. This may be due to increased clinical laparoscopic exposure and availability of laparoscopic simulation in medical school. PMID- 21792721 TI - The role of clips in preventing migration of fully covered metallic esophageal stents: a pilot comparative study. AB - BACKGROUND: Migration is the most common complication of the fully covered metallic self-expanding esophageal stent (SEMS). This study aimed to determine the potential preventive effect of proximal fixation on the mucosa by clips for patients treated with fully covered SEMS. METHODS: In this study, 44 patients (25 males, 57%) were treated with fully covered SEMS including 22 patients with esophageal stricture (4 malignant obstructions, 6 anastomotic strictures, and 12 peptic strictures) and 22 patients with fistulas or perforations (10 anastomotic leaks, 4 perforations, and 8 postbariatric surgery fistulas). The Hanarostent (n = 25), Bonastent (n = 5), Niti-S (n = 12), and HV-stent (n = 2) with diameters of 18 to 22 mm and lengths of 80 to 170 mm were used. Two to four clips (mean, 2.35 +/- 0.75 clips) were used consecutively in 23 patients to fix the upper flared end of the stent with the esophageal mucosal layer. Stent migration and its consequences were collected in the follow-up assessment with statistical analysis to compare the patients with and without clip placement. RESULTS: No complication with clip placement was observed, and the retrieval of the stent was not unsettled by the persistence of at least one clip (12 cases). Stent migration was noted in 15 patients (34%) but in only in 3 of the 23 patients with clips (13%). The number of patients treated to prevent one stent migration was 2.23. The predictive positive value of nonmigration after placement of the clip was 87%. In the multivariate analysis, the fixation with clips was the unique independent factor for the prevention of stent migration (odds ratio, 2.3; 95% confidence interval, 0.10-0.01; p = 0.03). CONCLUSIONS: Anchoring of the upper flare of the fully covered SEMS with the endoscopic clip is feasible and significantly reduces stent migration. PMID- 21792722 TI - Treatment of band erosion: feasibility and safety of endoscopic band removal. AB - BACKGROUND: Band erosion is reported with a highly variable incidence (0.3-14%) after laparoscopic adjustable gastric banding. Removal of the band is mandatory because the patient regains weight and may become symptomatic, but no consensus exists about the best method, surgical or endoscopic, for this purpose. This study aimed to evaluate the feasibility and effectiveness of endoscopic management of band erosion. METHODS: In this study, 23 patients were treated for band erosion after gastric banding: 8 from the authors' series of 951 patients (incidence, 0.84%) and 15 referred to the authors' surgical department from other hospitals. The endoscopic method of band removal was used in 20 cases. Because of complications associated with erosion, three patients were submitted instead to laparoscopic removal. RESULTS: Endoscopic removal of the band was successful for 16 of 20 patients. Four cases required conversion of the procedure to surgery: in one case due to complications with the endoscopic cutting wire and in the three remaining cases due to dense perigastric adhesions blocking the band. The follow up evaluation of the patients who had the endoscopic removal was uneventful, with quick discharge at resumption of oral feeding. The patients who underwent laparoscopic removal had a longer hospital stay, and one patient had a leak from the anterior gastrotomy. CONCLUSIONS: Despite a few complications, endoscopic removal seems to be the procedure of choice for the treatment of band erosion. It allows quick resumption of oral feeding and rapid discharge of patients and appears to be safer and more effective than laparoscopic removal. Conversion to surgery is unlikely but possible. Therefore, the authors always recommend that the procedure be performed in the operating room. PMID- 21792723 TI - Single-dose antimicrobial prophylaxis in transoral surgical lung biopsy: a preliminary experience. AB - BACKGROUND: The feasibility of the transtracheal approach to the thoracic cavity has been demonstrated, but surgical lung biopsy via the tracheal approach still remains a challenge. This study aimed to evaluate the feasibility and outcome of transoral surgical lung biopsy under a single preoperative dose of parenteral antibiotics. METHODS: Transoral thoracoscopy and surgical lung biopsy were performed for 10 anesthetized dogs after a single intravenous injection of cefazoline (20 mg/kg). A 12-mm transoral incision was created on the vestibulum, and a homemade metallic tube was advanced into the thoracic cavity via the pretracheal and substernal space under endoscopic guidance. After thoracic exploration, surgical lung biopsy was performed using an electrosurgical snare with a flexible bronchoscope inserted through the metallic tube. The resection margin of the lung was secured with a homemade endoloop. The animals were killed by day 14 after the surgery for gross and histologic evaluations. RESULTS: The thoracic cavity was evaluated and lung biopsy was performed successfully (for 3 lobes in the right lung and 2 lobes in the left lung) in 9 of the 10 dogs. Neither mortality nor intraoperative complications were observed. The average time for the transoral thoracoscopy and surgical lung biopsy was 133.5 min. Postmortem examination showed complete healing, with fibrosis and moderate adhesion over the resection margin. No evidence of either mediastinitis or intrathoracic infection was observed. CONCLUSION: This study showed the feasibility of transoral thoracoscopy and surgical lung biospy in dogs. Moreover, single-dose prophylaxis with cefazoline in transoral surgical lung biopsy was found to be effective in preventing potential infection. PMID- 21792724 TI - Establishment and assessment of a simple and easily reproducible incision model of spinal cord neuron cells in vitro. AB - A growing number of in vitro models have been introduced to study the mechanisms of spinal cord injury. A potential drawback of these models is that they are difficult to reproduce. In this study, an in vitro incision model was established using primary cultured neuronal cells from fetal rat spinal cords. The neurons were subjected to incision in a simple and reproducible way. To assess whether this model could simulate the responses of spinal cord neuron cells in vivo after a spinal cord transection, apoptosis, and the expression of immediate early genes were detected in the neurons at various time points after injury. The results indicated that: (1) significantly more terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were observed at 1, 3, and 7 d following injury and (2) the expression of both c-Jun and c-Fos was induced 10 min after incision and had markedly higher levels 2 h post-injury. These results suggested that our model can partially imitate the responses of in vivo neuronal cells after a spinal cord transection and such models may facilitate further understanding of biochemical and cellular events associated with spinal cord injury. PMID- 21792727 TI - Two new indole alkaloids, 2-(3,3-dimethylprop-1-ene)-costaclavine and 2-(3,3 dimethylprop-1-ene)-epicostaclavine, from the marine-derived fungus Aspergillus fumigatus. AB - Two new indole alkaloids, 2-(3,3-dimethylprop-1-ene)-costaclavine (1) and 2-(3,3 dimethylprop-1-ene)-epicostaclavine (2), together with the known compounds costaclavine (3), fumgaclavine A (4) and C (5), were isolated from the marine derived fungus Aspergillus fumigatus. The planar structures of the two new compounds were elucidated on the basis of chemical and physicochemical evidence including MS, UV, IR and NMR spectra. Their stereochemistry was studied by NOESY, (1)H-(1)H coupling constant and CD spectra. The compounds 1, 2, 3 and 5 showed weak cytotoxicity against a mouse leukemia cell line (P388). PMID- 21792726 TI - Insights into mechanisms underlying the gut and airways modulatory effects of Swertia chirata. AB - Swertia chirata is used in folk medicine for the treatment of constipation, colic, diarrhea, and asthma. This study was carried out in order to provide a pharmacological basis for its medicinal use in gastrointestinal and respiratory disorders. Crude extract of Swertia chirata (Sc.Cr) and its fractions were studied using rabbit isolated tissue preparations. In jejunum, Sc.Cr, which tested positive for alkaloids, flavonoids, saponins, tannins, and terpenes, caused stimulation at concentrations of 0.01-1.0 mg/mL, followed by a relaxant effect at higher concentrations. In the presence of atropine, the contractile effect was blocked and only relaxation occurred. Sc.Cr inhibited high K(+) (80 mM)-induced contractions at 0.01-10 mg/mL and shifted Ca(2+) concentration response curves to the right, similar to that caused by verapamil. In trachea, Sc.Cr relaxed the carbachol (1 MUM) and high K(+)-induced contractions, in a pattern similar to that of verapamil. Bioassay directed fractionation revealed the separation of spasmogenic and spasmolytic components in aqueous and organic fractions, respectively. The chloroform fraction exhibited a concentration dependent (0.1-3.0 mg/mL) bronchodilator effect. These results indicate that Swertia chirata exhibits gut excitatory and inhibitory effects, mediated through cholinergic and Ca(2+) antagonist mechanisms, respectively, as well as bronchodilatation, via Ca(2+) channel blockade. Thus, this study provides a sound mechanistic background for the therapeutic application of Swertia chirata in gut motility disorders, such as constipation, colic, and diarrhea, and airways hyperactivity disease, such as asthma. PMID- 21792728 TI - Systemic and cerebral hemodynamics during cognitive testing. AB - OBJECTIVE: Cognitive deficits are reported in 10-60% of individuals with SCI, the primary etiology of these deficits is believed to be concomitant traumatic brain injury (TBI). We recently documented diminished memory and marginally deficient attention and processing speed in individuals with SCI discordant for hypotension but matched for TBI. METHODS: Twenty-nine individuals participated: 16 non-SCI controls, 6 paraplegic (T2-T10) and 7 tetraplegic (C4-C8). The Stroop test was used to measure cognitive function and transcranial Doppler ultrasound was used to measure cerebral blood flow (CBF) while resting (5 min) and continuously during cognitive testing. Mean arterial pressure (MAP) was calculated from three brachial blood pressures and cerebral vascular resistance index was calculated as: CVRi = MAP/CBF. RESULTS: The paraplegia group (54 +/- 6) was marginally older than the non-SCI (42 +/- 15; p = 0.06) and tetraplegic (42 +/- 11; p = 0.09) groups. Compared to non-SCI group, normalized t-score on the Stroop Color (SC) task was significantly lower in the paraplegic group (p < 0.05). In the tetraplegic group, MAP was significantly lower (p < 0.05) than the non-SCI and paraplegic groups, and related to SC t-score (r (2) = 0.873; p < 0.01). In the paraplegic group, CBF was reduced (p < 0.05) and CVRi increased (p < 0.05) compared to the non-SCI group, and CVRi was increased compared to the tetraplegic group (p < 0.05). A significant inverse relationship was noted between change in CVRi and SC t-score in the non-SCI group. CONCLUSION: Asymptomatic hypotension relates to cognitive performance in persons with tetraplegia; therefore, BP normalization should be considered. The inappropriate cerebral vascular response to cognitive testing and poor test performance should be investigated in persons with paraplegia. PMID- 21792730 TI - Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. AB - Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) is a rare, autosomal recessive disorder caused by mutations in the gene encoding a mitochondrial aspartyl-tRNA synthetase, DARS2. The disease is characterized by progressive spastic ataxia and magnetic resonance imaging (MRI) shows a highly characteristic leukoencephalopathy with multiple long tract involvement. We describe the clinical and radiological features of two new cases of LBSL and report a novel pathogenic mutation in the DARS2 gene. Both patients had typical clinical and radiological findings, although no elevated lactate was found. The severity of MRI changes did not correlate with clinical course and severity suggesting that, although of highly specific diagnostic value, MRI does not necessarily reflect clinical activity and should not be used to assess disease severity or prognosis in LBSL. PMID- 21792729 TI - MIBG scintigraphy in differential diagnosis of Parkinsonism: a meta-analysis. AB - OBJECTIVE: Differential diagnosis between Parkinson's disease (PD) and other Parkinsonism using clinical criteria or imaging methods is often difficult. The purpose of this study is to systematically review and meta-analyze published data about the diagnostic performance of myocardial innervation imaging using (123)I metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between PD and other Parkinsonism. METHODS: A comprehensive computer literature search of studies published through March 2011 regarding MIBG scintigraphy in patients with PD and other Parkinsonism was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between PD and other Parkinsonism were selected. Pooled sensitivity, pooled specificity and area under the ROC curve were calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between PD and other Parkinsonism. RESULTS: Nineteen studies comprising 1,972 patients (1,076 patients with PD, 117 patients with other Lewy body diseases and 779 patients with other diseases) were included in this meta-analysis. The pooled sensitivity of MIBG scintigraphy in detecting PD was 88% (95% CI 86-90%); the pooled specificity of MIBG scintigraphy in discriminating between PD and other Parkinsonism was 85% (95% CI 81-88%). The area under the ROC curve was 0.93. CONCLUSIONS: In patients with clinically suspected PD, myocardial innervation imaging demonstrated high sensitivity and specificity. MIBG scintigraphy is an accurate test in this setting. Nevertheless, possible causes of false-negative and false-positive results should be kept in mind when interpreting the scintigraphic results. PMID- 21792731 TI - O6-methylguanine-DNA-methyltransferase promoter methylation assessment by microdissection-assisted methylation-specific PCR and high resolution melting analysis in patients with glioblastomas. AB - We have determined O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status by methylation-specific polymerase chain reaction (MSP) in 22 paraffin-embedded specimens of glioblastoma multiforme. A MGMT methylation specific high resolution melting (HRM) assay was performed to compare the methylation levels of the tumorous and non-tumorous portions of each sample, which were selectively collected using a microdissection technique. MGMT methylation was detected in 10 patients using MSP, while 8 patients had both methylated and unmethylated MGMT promoters. HRM assays showed that there was no difference in the level of methylation between tumorous and non-tumorous portions of each sample. In patients with MSP-positive tumors, the overall survival (median, 22 months) was longer as compared to those with MSP-negative tumors (median, 14 months). A correlation between the methylation status of the MGMT promoter and MGMT protein expression was observed in 12 samples. This study demonstrates that MGMT methylation is not restricted to glioblastoma cells. Additionally, methylation-specific HRM is a feasible approach that can be readily applied to the methylation analysis of MGMT. A further study will be needed to determine the dynamic change of MGMT methylation in the tumor environment. PMID- 21792732 TI - The reliability and validity of Turkish version of Childhood Asthma Control Test. AB - INTRODUCTION: The reliability and validity of Turkish version of Childhood Asthma Control Test (C-ACT). PURPOSE: The management of asthma is an important as well as difficult issue of physician's daily practice particularly in busy clinical settings. C-ACT was created to identify asthma control levels in children aged 4 11 years. Our aim was to evaluate the reliability, validity and responsiveness of C-ACT in a Turkish sample of children with asthma. METHOD: In this multicenter study, 368 children were enrolled. C-ACT was completed every month by parents and patients who were evaluated in 3 visits within 2 month intervals. At each visit, physicians interpret the control level and decided for the treatment step as established in GINA guidelines. RESULTS: The internal consistency reliability of the Turkish version of C-ACT (C-ACT1 to C-ACT5) was found to be 0.82, 0.83, 0.82, 0.82 and 0.80, respectively (reliability statistics, Cronbach's alpha). Test retest reliability was 0.71. There was significant correlation between C-ACT and physician's assessment of asthma control at visit 1 (r = 0.65, P < 0.001). CONCLUSIONS: Turkish version of C-ACT is an accurate and reliable tool to evaluate asthma control in children aged 4-11 years. Its widespread use may facilitate appropriate assessment of asthma control and may lead to decrease the number of uncontrolled patients. PMID- 21792733 TI - Asthma-like symptoms in the first year of life and health-related quality of life at age 12 months: the Generation R study. AB - PURPOSE: This study compares HRQOL among subgroups of infants with asthma-like symptoms to a subgroup without such symptoms and examines independent associations between asthma-like symptoms during the first year of life and HRQOL at age 12 months. METHODS: Our study sample included 5,000 infants participating in the Generation R study. Their parents completed structured questionnaires to obtain information on asthma-like symptoms, HRQOL, infants', and maternal characteristics. Asthma-like symptoms were defined according to the number of positive answers to 12 items on lower respiratory symptoms. HRQOL was measured using the ITQOL. Higher scores indicated better HRQOL. RESULTS: Infants with asthma-like symptoms had significantly lower HRQOL scores for all ITQOL scales. Among the subgroup with severe symptoms (4% of the infants), relevant deficits in HRQOL were observed for most ITQOL scales, particularly for General Health, Bodily Pain, and Family Activities (effect sizes >= 0.8). In multivariate linear models, asthma-like symptoms were independently associated with 6 ITQOL scales. The population attributable risks were especially high for Family Activities, General Health, Parental Emotional, and Parental Time. CONCLUSIONS: Asthma-like symptoms during the first year of life are associated with impaired quality of life at age 12 months. At population level, asthma-like symptoms were associated with lower HRQOL, regardless of symptom severity. PMID- 21792734 TI - Obesity: an independent risk factor for insufficient hemostasis using the AngioSeal vascular closure device after antegrade puncture. AB - PURPOSE: This study was designed to investigate the efficacy of the AngioSeal vascular closure device after antegrade puncture of the femoral artery. METHODS: In a prospective study, 120 consecutive patients underwent lower limb vascular intervention by an antegrade access to the common femoral artery (CFA). After intervention, a 6F (n = 88) or an 8F (n = 32) AngioSeal vascular closure device was used to achieve hemostasis. The technical success or the cause of failure was documented. In addition, the coagulation status (platelets, INR, prothrombin time, atrial thromboplastin time (PTT)), hypertonus, locoregional habitus of the groin, body mass index (BMI), presence of calcifications, and history of previous surgical interventions of the CFA were evaluated. RESULTS: Hemostasis was achieved in 97 patients (81%). In 12 patients (10%), persistent bleeding of the puncture site required manual compression. In another nine patients (8%) a kink of the sheath obviated the passage of the collagen plug toward the vessel, and in two patients the anchor dislodged out of the vessel, requiring manual compression. There were no significant differences between the groups of successful and unsuccessful sealing regarding the mean platelets (241 vs. 254 * 10(9)/l; P = 0.86), INR (1.06 vs. 1.02; P = 0.52), prothrombin time (90% vs. 90%; P = 0.86), and PTT (30 vs. 31 s; P = 0.82). However, unsuccessful sealing was more likely in obese patients with an increased BMI (26.6 vs. 28.8 kg/m(2); P = 0.04). CONCLUSIONS: Obesity seems to be an independent risk factor for insufficient sealing using the AngioSeal vascular closure device after antegrade puncture of the CFA. In 8% of our patients, hemostasis could not be achieved due to kink of the flexible sheath. PMID- 21792735 TI - Radiation exposure in nonvascular fluoroscopy-guided interventional procedures. AB - PURPOSE: To investigate the radiation exposure in non-vascular fluoroscopy guided interventions and to search strategies for dose reduction. MATERIALS AND METHODS: Dose area product (DAP) of 638 consecutive non-vascular interventional procedures of one year were analyzed with respect to different types of interventions; gastrointestinal tract, biliary interventions, embolizations of tumors and hemorrhage. Data was analyzed with special focus on the fluoroscopy doses and frame doses. The third quartiles (Q3) of fluoroscopy dose values were defined in order to set a reference value for our in-hospital practice. RESULTS: Mean fluoroscopy times of gastrostomy, jejunostomy, right and left sided percutaneous biliary drainage, chemoembolization of the liver and embolization due to various hemorrhages were 5.9, 8.6, 13.5, 16.6, 17.4 and 25.2 min, respectively. The respective Q3 total DAP were 52.9, 73.3, 155.1, 308.4, 428.6 and 529.3 Gy*cm2. Overall, around 66% of the total DAP originated from the radiographic frames with only 34% of the total DAP applied by fluoroscopy (P<0.001). The investigators experience had no significant impact on the total DAP applied, most likely since there was no stratification to intervention-complexity. CONCLUSION: To establish Diagnostic Reference Levels (DRLs), there is a need to establish a registry of radiation dose data for the most commonly performed procedures. Documentation of interventional procedures by fluoroscopy "grabbing" has the potential to considerably reduce radiation dose applied and should be used instead of radiographic frames whenever possible. PMID- 21792737 TI - Exploring outcomes through narrative: the long-term impacts of Better Beginnings, Better Futures on the turning point stories of youth at ages 18-19. AB - This study examined the long-term effects of the Better Beginnings, Better Futures project, a community-based early childhood development program, on 18-19 year-old youths' narratives about turning points in their lives. The sample consisted of youth who participated in Better Beginnings from ages 4-8 (n = 62) and youth from a comparison community who did not participate in Better Beginnings (n = 34). Controlling for covariates, significant differences favoring youth from the Better Beginnings sites were found on several dimensions of the turning point stories: ending resolution, personal growth, meaning-making, coherence, and affect transformation. Effect sizes ranged from .45 to .76 for these outcome dimensions, indicating moderate to large effects. Also, turning point story dimensions were found to be significantly correlated with two standardized measures of well-being: youths' self-esteem and community involvement. Youths' self-esteem was directly related to story ending resolution, personal growth, and meaning making, and youths' community involvement was directly related to story specificity, meaning making, and coherence. Family functioning was also examined in relation to these narrative dimensions but was not found to be significantly related to them. The findings suggest the utility of a narrative approach for the evaluation of the long-term outcomes of early childhood development programs. PMID- 21792736 TI - Effect of synthetic ligands of PPAR alpha, beta/delta, gamma, RAR, RXR and LXR on the fatty acid composition of phospholipids in mice. AB - Nuclear hormone receptors are transcription factors that can be activated by nutrition-derived ligands and alter the expression of various specific target genes. Stearoyl-Coenzyme A desaturase (SCD1) converts palmitic acid (16:0) to palmitoleic acid (16:1n-7) as well as stearic acid (18:0) to oleic acid (18:1n 9). At the same time, elongase 6 (ELOVL6) elongates 16:1n-7 and 18:1n-9 to vaccenic acid (18:1n-7) and eicosenoic acid (20:1n-9). We examined how synthetic selective ligands of nuclear hormone receptors alter the gene expression of hepatic enzymes in mice. In addition, we examined how the regulation of these two enzymes influences fatty acid composition of phospholipids in liver and plasma. Mice were gavaged daily for 1 week with synthetic ligands of peroxisome proliferator-activated receptor (PPAR) alpha, beta/delta, gamma, liver X receptor (LXR), retinoic acid receptor (RAR) and retinoid-X receptor (RXR) for 1 week. Phospholipids from liver and plasma were analysed using ESI-MS/MS and GC after saponification. Hepatic gene expression of SCD1 and ELOVL6 was measured using QRT PCR. SCD1 and ELOVL6 expression increased after the gavage of LXR and RXR ligands. The analysis of fatty acid composition of total phospholipids in plasma and liver showed increased percentage contributions of the SCD1 and ELOVL6 products 18:1n-9, 18:1n-7 and 20:1n-9 after LXR and RXR ligand application. Analysis of total phospholipids from plasma and liver revealed a significant increase in monounsaturated fatty acids bound in phosphatidylcholine (PtdCho) and lysophosphatidylcholine (PtdEtn) after LXR and RXR ligand administration. Increased hepatic gene expression of SCD1 and ELOVL6 after gavage of selective RXR or LXR ligands to mice resulted in increased concentrations of their metabolic products in phospholipids of liver and plasma. PMID- 21792738 TI - CAML--maximum likelihood consensus analysis. AB - Consensus analysis enables estimation of individual differences in competencies and response tendencies when answer keys to dichotomous forced-choice questions are unknown. CAML, a set of functions written in R, implements maximum likelihood estimation for the general Condorcet model that underlies consensus analysis. CAML avoids problems of alternative approaches that have often rendered consensus analysis impractical or unfeasible in the past. It provides (1) measures of model fit, (2) a measure of consensus, (3) point and interval estimates of competencies and response tendencies, and (4) an estimate of the unknown answer key. The present article describes the general Condorcet model, the CAML algorithms, and the handling of the software. In addition, the validity of CAML results is tested in a recognition memory study using selective experimental manipulations of the parameters. The results show that CAML works very well in practice and provides valid estimates of competencies, response tendencies, and answer keys. PMID- 21792739 TI - Advances in the assessment of cognitive skills using computer-based measurement. AB - The impact of technology in the field of intellectual assessment has, for the most part, been limited to computerized administration and scoring. Anderson's (2001) theory of intelligence suggests that performance on traditional IQ measures is acquired via two main routes, thinking and dedicated processing systems known as modules. Empirical data used to support this relationship between the speed of basic processing and intellectual functioning have been evidenced primarily by correlations between measures of general intelligence and measures of inspection time (IT). These IT measures allow individuals to make a forced choice discrimination task without a motor component. Because only the time used to cognitively solve the problem is recorded, these responses typically occur in milliseconds. Many theorists (e.g., Burns & Nettelbeck, 2002; Deary, 2000; Jensen, 2006) consider IT to be a more "pure" measure of intelligence, because the influences of verbal skills, memory, and socialization are minimized and results are therefore considered to be more culture-fair. Until relatively recently, IT measurement was restricted to complex and expensive specialized laboratory equipment. This article describes the theoretical background and developmental process of a computer-based IT measure that is easily adaptable to accommodate the needs of the researcher. PMID- 21792740 TI - Pigmented squamous cell carcinoma in situ of the conjunctiva. PMID- 21792741 TI - Necrotizing scleritis in a patient positive for both c- and p-ANCA without underlying systemic vasculitis. PMID- 21792742 TI - Bone marrow stromal cells-loaded chitosan conduits promote repair of complete transection injury in rat spinal cord. AB - In this study, a chitosan conduit loaded with bone marrow stromal cells (BMSCs) was developed to bridge the gap in the transected spinal cord of adult rats, and the nerve repair outcomes were evaluated by functional and histological techniques at 12 weeks after implantation. As compared to chitosan conduits alone, incorporation of BMSCs within chitosan conduits yielded additional improving effects on nerve regeneration and function restoration. The measurements with the Basso, Beattie and Bresnahan locomotor rating scale or of motor evoked potentials indicated that motor functional recovery was enhanced; retrograde tracing confirmed that the ascending tract was regenerated and the neural pathway was established; and histological analyses revealed that axon growth and remyelination in the regenerated nerve was promoted. The three dimensional reconstruction showed that the chitosan conduit loaded with BMSCs significantly reduced the spinal cord cavity volume at the injured site. Taken together, the results collectively suggest that implantation with BMSCs-loaded chitosan conduits may become a promising approach to the repair of spinal cord injury. PMID- 21792743 TI - The role of multi-slice computed tomography in stable angina management: a current perspective. AB - Contrast-enhanced CT coronary angiography (CTCA) has evolved as a reliable alternative imaging modality technique and may be the preferred initial diagnostic test in patients with stable angina with intermediate pre-test probability of CAD. However, because CTCA is moderately predictive for indicating the functional significance of a lesion, the combination of anatomic and functional imaging will become increasingly important. The technology will continue to improve with better spatial and temporal resolution at low radiation exposure, and CTCA may eventually replace invasive coronary angiography. The establishment of the precise role of CTCA in the diagnosis and management of patients with stable angina requires high-quality randomised study designs with clinical outcomes as a primary outcome. PMID- 21792744 TI - Heat shock factors in rice (Oryza sativa L.): genome-wide expression analysis during reproductive development and abiotic stress. AB - Plants respond to heat stress by enhancing the expression of genes encoding heat shock protein (HSPs) genes through activation of heat shock factors (HSFs) which interact with heat shock elements present in the promoter of HSP genes. Plant HSFs have been divided into three conserved classes viz A, B and C. In the present study, a detailed analysis has been done of all rice HSFs, along with their spliced variants. Their chromosomal localization reveals that six HSFs are segmentally duplicated and four pairs of these segmentally duplicated HSF encoding genes show pseudo-functionalization. Expression profiling through microarray and quantitative real-time PCR showed that eight OsHsfs express at a higher level during seed development, while six HSFs are up-regulated in all the abiotic stresses studied. The expression of OsHsfA2a gene in particular was greatly stimulated by heat stress in both root and shoot tissues and also during panicle and seed development. OsHsfA3 was found more responsive to cold and drought stress, while OsHsfA7 and OsHsfA9 showed developing seed-specific expression. This study also revealed that spliced variants generally accumulated at a higher level in all the tissues examined. Different hormones/elicitors like ABA, brassinosteroids and salicylic acid also alter OsHsf gene expression. Calcium in combination with heat stress elevated further the level of HSF transcripts. Expression analysis by both microarray and real-time RT-PCR revealed a unique stable constitutive expression of OsHsfA1 across all the tissues and stresses. A detailed in silico analysis involving identification of unidentified domains has been done by MEME-motif tool in their full-length proteins as well as in DNA-binding domains. Analysis of 1 kb putative promoter region revealed presence of tissue-specific, abiotic stress and hormone-related cis-acting elements, correlating with expression under stress conditions. PMID- 21792746 TI - A change in boundary conditions induces a discontinuity of tissue flow in chicken embryos and the formation of the cephalic fold. AB - The morphogenesis of vertebrate body parts remains an open question. It is not clear whether the existence of different structures, such as a head, can be addressed by fundamental laws of tissue movement and deformation, or whether they are only a sequence of stop-and-go genetic instructions. I have filmed by time lapse microscopy the formation of the presumptive head territory in chicken embryos. I show that the early lateral evagination of the eye cups and of the mesencephalic plate is a consequence of a sudden change in boundary conditions of the initial cell flow occurring in these embryos. Due to tissue flow, and collision of the two halves of the embryo, the tissue sheet movement is first dipolar, and next quadrupolar. In vivo air puff tonometry reveals a simple visco elastic behaviour of the living material. The jump from a dipolar to a quadrupolar flow changes the topology of the early morphogenetic field which is observed towards a complex vortex winding with a trail (the eye cups and brain folds). The hydrodynamical model accounts for the discontinuity of the vector field at the moment of collision of the left and right halves of the embryo, at a quantitative level. This suggests a possible mechanism for the morphogenesis of the head of amniotes, as compared to cephalochordates and anamniotes. PMID- 21792745 TI - Salt-modulated structure of polyelectrolyte-macroion complex fibers. AB - The structure and stability of strongly charged complex fibers, formed by complexation of a single long semi-flexible polyelectrolyte chain and many oppositely charged spherical macroions, are investigated numerically at the ground-state level using a chain-sphere cell model. The model takes into account chain elasticity as well as electrostatic interactions between charged spheres and chain segments. Using a numerical optimization method based on a periodically repeated unit cell, we obtain fiber configurations that minimize the total energy. The optimal fiber configurations exhibit a variety of helical structures for the arrangement of macroions including zig-zag, solenoidal and beads-on-a string patterns. These structures result from the competition between attraction between spheres and the polyelectrolyte chain (which favors chain wrapping around the spheres), chain bending rigidity and electrostatic repulsion between chain segments (which favor unwrapping of the chain), and the interactions between neighboring sphere-chain complexes which can be attractive or repulsive depending on the system parameters such as salt concentration, macroion charge and chain length per macroion (linker size). At about physiological salt concentration, dense zig-zag patterns are found to be energetically most stable when parameters appropriate for the DNA-histone system in the chromatin fiber are adopted. In fact, the predicted fiber diameter in this regime is found to be around 30 nanometers, which roughly agrees with the thickness observed in in vitro experiments on chromatin. We also find a macroion (histone) density of 5-6 per 11nm which agrees with results from the zig-zag or cross-linker models of chromatin. Since our study deals primarily with a generic chain-sphere model, these findings suggest that structures similar to those found for chromatin should also be observable for polyelectrolyte-macroion complexes formed in solutions of DNA and synthetic nano-colloids of opposite charge. In the ensemble where the mean linear density of spheres on the chain is fixed, the present model predicts a phase separation at intermediate salt concentrations into a densely packed complex phase and a dilute phase. PMID- 21792747 TI - Modeling alcohol self-administration in the human laboratory. AB - This review focuses on 27 studies employing experimental alcohol self administration (ASA) in humans which were published between 1989 and 2010. Twelve studies enrolling healthy, non-dependent social drinkers (HSD) were aimed at evaluating physiological and behavioral determinants of alcohol-induced reward or modeling situations of increased risk to develop alcohol use disorders. The remaining 15 studies tested the effect of medications such as naltrexone, nalmefene, nicotine, mecamylamine, varenicline, gabapentin, aripiprazole, and rimonabant on ASA. The participants were either HSD or non-treatment-seeking alcoholics (NTSA). In 25 of these studies, the subjects ingested alcohol orally and reached a mean peak blood alcohol concentration (BAC) during baseline conditions between 43 and 47 mg% (0.043-0.047%). Two recent studies employed computer-assisted self-infusion of ethanol (CASE), where subjects press a button to request multiple sequential alcohol exposures intravenously instead of drinking. This method has been demonstrated to be safe and provides increased experimental control of BAC and keeps subjects blind concerning the amount already self-administered. Peak exposures in the CASE studies ranged from 60 to 80 mg% in HSD and up to 240 mg% in NTSA. PMID- 21792748 TI - Advances in rheumatoid arthritis animal models. AB - Experimental models of rheumatoid arthritis have contributed immensely to our understanding of the pathogenesis as well as the treatment of this debilitating autoimmune disease. Significant progress has been made in the past few years in defining the role of newer cytokines and regulatory T cells, of inflammation mediated bone and cartilage damage, and of the cholinergic anti-inflammatory pathway in modulating the disease process in arthritis. Furthermore, new therapeutic targets, including specific tyrosine kinases and proteasome subunits, have been explored. These advances offer renewed optimism for continued improvements in the management of rheumatoid arthritis. PMID- 21792750 TI - Cytotoxicity of glioblastoma cells mediated ex vivo by varicella-zoster virus specific T cells. AB - Clinical or laboratory evidence of varicella-zoster virus (VZV) infection has been consistently associated with lower glioma risk in case-control studies, suggesting a protective effect of VZV against glioma. We formulated the following explanatory hypotheses: reactivated VZV preferentially infects and kills gliomas compared to normal parenchyma; and VZV-specific cytotoxic T lymphocytes (CTL) cross-react with gliomas. We established an ex vivo model of VZV infection, which showed that glioma cell lines and primary astrocytes were equally permissive to VZV infection and had similar 15% average decrease in viability upon infection. In co-cultures, the relative growth of glioma cells and astrocytes was not affected by the VZV infection. However, VZV stimulated, but not mock stimulated, peripheral blood mononuclear cells from VZV-seropositive individuals recognized and killed HLA class I-matched glioma cells (mean+/-SE decrease in viability of 26 +/- 12%, p = 0.04), but not matched astrocytes. VZV infection of the glioma cells did not affect the T cell-mediated killing. Taken together, these data suggest that ex vivo VZV infection has similar direct effects on glioma cells and astrocytes. The protective effect of prior VZV infection against the incidence of glioma may be mediated by CTL that recognizes epitopes shared by VZV and glioma cells. PMID- 21792749 TI - Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients. AB - There is increasing evidence of an association between human papillomaviruses (HPV) of the beta-genus (beta-PV) and the development of cutaneous squamous cell carcinoma (SCC). The viral DNA load may be an important determinant of pathogenicity, but there are currently no baseline epidemiological data relating to load in people without SCC. We investigated DNA-loads of eight beta-PV types previously associated with risk of SCC. We collected eyebrow hairs from immunocompetent people (ICP) and organ transplant recipients (OTR), determined load by quantitative PCR and obtained demographic, phenotypic, and sun exposure information. Viral loads for ICP from Australia (n = 241) and Italy (n = 223) and OTR from across Europe (n = 318) spanned seven orders of magnitude. The median loads for all types were below one viral DNA copy per 60 cells and were highest for HPV5, HPV8 and HPV20. None of the populations had consistently higher viral loads for all 8 types. However, a higher proportion of OTR were in the top deciles of viral load distributions for six of the eight beta-PV types examined. In a nested analysis of Italian OTR and ICP, this finding was significant for six beta-PV types and cumulative load. Increasing age was significantly associated with higher viral loads in Australia, and there was a weak trend for higher loads with the time elapsed since transplantation in the OTR. We observed a wide distribution of beta-PV loads with OTR significantly more likely to have the highest viral loads. Thus, viral loads may be an important contributor to the higher risk of SCC in OTR. PMID- 21792751 TI - The neurocritical care research network: NCRN. AB - Neurocritical care diseases carry a high morbidity and mortality. Therapeutic and technological advances in neurocritical care have greatly improved the outcome of a variety of life-threatening disorders including traumatic brain injury, acute ischemic stroke, intracerebral and subarachnoid hemorrhage, and anoxic injury following cardiac arrest. These advances have stemmed from a better understanding of the physiology of neurocritical care illnesses, improved neuromonitoring techniques, and the introduction of more efficacious treatments. Despite all the advances in neuromonitoring, diagnostic imaging, and emerging treatments, much research needs to be undertaken in neurocritical care. Many of the clinical trials carried out in the general critical care population have excluded neurocritical care patients. For instance, the landmark ARDSNET trial that demonstrated the beneficial effects of low tidal volume ventilation in patients with ARDS cannot be directly applied to neurocritical care patients who frequently may experience this pulmonary complication. There is a need for a more cohesive and integrated research system or network to establish a track record for high-quality, investigator-initiated clinical research in neurocritical care. Such a system may help us overcome potential impediments to the future advancement of neurocritical care research. We propose the creation of the neurocritical care research network. The mission of the Network is to facilitate multicenter and multidisciplinary collaboration and patient enrollment in clinical trials of specific neurocritical care diseases. PMID- 21792752 TI - Research priorities in neurocritical care. AB - This summary of the last session of the First Neurocritical Care Research Conference reviews the discussions about research priorities in neurocritical care. The first presentation reviewed current projects funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and potential models to follow including an independent Neurocritical Care Network or the creation of such a network with the goal of collaborating with already existing ones. Experienced neurointensivists then presented their views on the most common and important research questions that need to be answered and investigated in the field. Finally, utility of clinical registries was discussed emphasizing their importance as hypothesis generators. During the group discussion, interests in comparative effectiveness research, the use of physiological endpoints from monitoring and alternate trial design were expressed. PMID- 21792755 TI - [Current problems and strategies in the management of intra-abdominal infection]. AB - The incidence of intra-abdominal infection increases annually. The current management of intra-abdominal infection includes immediate resuscitation, prompt source control and appropriate usage of antibiotics. For patients with septic shock, fluid resuscitation should begin immediately when hypotension is present. Fluid resuscitation should be combined with vasoactive drugs. Damage control surgery promotes the development of ultrasound or CT guided percutaneous abscess drainage and open abdomen therapy. Rational use of anti-infective drugs could prevent prevalence of multiple antibiotics resistant bacteria and pan-resistant bacteria. The gut rehabilitation measures can improve the recovery of gut function and restore of enteral nutrition, and thus prevents bacterial translocation in intra-abdominal infection patients. Monitoring and modulations of immune function may further improve the successful rate of treatment of intra abdominal infections. Non-thyroidal illness syndrome may develop in the severe intra-abdominal infection patients and should be promptly corrected. PMID- 21792754 TI - High-volume centers. AB - Outcome from trauma, surgery, and a variety of other medical conditions has been shown to be positively affected by providing treatment at facilities experiencing a high volume of patients with those conditions. An electronic literature search was made to identify English-language articles available through March 2011, addressing the effect of patient treatment volume on outcome for patients with subarachnoid hemorrhage. Limited data were identified, with 16 citations included in the current review. Over 60% of hospitals fall into the lowest case-volume quartile. Outcome is influenced by patient volume, with better outcome occurring in high-volume centers treating >60 cases per year. Patients treated at low volume hospitals are less likely to experience definitive treatment. Furthermore, transfer to high-volume centers may be inadequately arranged. Several factors may influence the better outcome at high-volume centers, including the availability of neurointensivists and interventional neuroradiologists. PMID- 21792753 TI - Clinical trial design in the neurocritical care unit. AB - Clinical trials provide a robust mechanism to advance science and change clinical practice across the widest possible spectrum. Fundamental in the Neurocritical Care Society's mission is to promote Quality Patient Care by identifying and implementing best medical practices for acute neurological disorders that are consistent with the current scientific knowledge. The next logical step will be to foster rapid growth of our scientific body of evidence, to establish and disseminate these best practices. In this manuscript, five invited experts were impaneled to address questions, identified by the conference organizing committee as fundamental issues for the design of clinical trials in the neurological intensive care unit setting. PMID- 21792756 TI - [Impact of complicated intra-abdominal infection on albumin synthesis rate]. AB - OBJECTIVE: To study the impact of complicated intra-abdominal infections on albumin synthesis rate. METHODS: Eight patients with complicated intra-abdominal infections associated with intestinal fistula were admitted to the Research Institute of General Surgery at the Jinling Hospital between December 2009 and October 2010. Eight healthy volunteers matched for age, sex, and body mass index were enrolled as controls. All the subjects were given a primed, constant infusion of sterile L-[ring-(2)H(5)]-phenylalanine solution (priming dose: 4 MUmol/kg, infusion rate: 6 MUmol.kg(-1).min(-1)) via peripheral venous lines in fast state. Arterial blood samples(3 ml) were drawn before and throughout the infusion at hourly intervals. The enrichment of L-[ring-(2)H(5)]-phenylalanine from the plasma free amino acid pool and from albumin were determined by gas chromatography/mass spectrometry analysis. RESULTS: Both plasma total protein concentration(62.2+/-1.0) g/L and plasma albumin concentration (32.5+/-4.0) g/L in patients with complicated intra-abdominal infection were lower compared with controls[(74.2+/-1.7) g/L and (46.1+/-2.6) g/L, both P<0.05]. Body temperature, neutrophil count and plasma C-reactive protein concentration in patients with infection were significantly greater than the levels in control subjects(P<0.05). Albumin synthesis rate in patients with intra-abdominal infection was significantly lower than that in the control group [(5.3+/-1.6)%/d and (7.8+/ 1.2)%/d respectively, P<0.05]. The measurement of plasma free amino acid concentration showed that plasma glutamic acid level was greater than that in control subjects, and that plasma phenylalanine and proline levels were lower than those in controls. CONCLUSION: Complicated intra-abdominal infection inhibits albumin synthesis rate in patients with intestinal fistula, which may partially contribute to the decrease of plasma albumin concentration. PMID- 21792757 TI - [Predictive value of immunological parameters on sepsis following abdominal operation for patients with HIV infection]. AB - OBJECTIVE: To study postoperative sepsis in HIV/AIDS patients who underwent abdominal operations. METHODS: A retrospective analysis was performed to study 34 HIV/AIDS patients treated between January 2009 and December 2010 at the Shanghai Public Health Clinical Center Affiliated to Fudan University. RESULTS: There were 31 males and 3 females in this cohort with a mean age of 45+/-13 years. Nineteen patients developed postoperative sepsis. The levels of preoperative CD4, postoperative CD4, preoperative CD4/CD8, and postoperative platelet were significantly lower than those without sepsis (all P<0.05). Among 19 patients with a preoperative CD4 cell count less than or equal to 200*10(6)/L, the incidence of postoperative sepsis rate was 84.2%(16/19), and for those with a preoperative CD4 cell count greater than 200*10(6)/L, the incidence of postoperative sepsis rate was 20.0%(3/15), the difference was statistically significant(P<0.05). There were 3 postoperative deaths. CONCLUSION: CD4 cell count can be used as a predictive marker for the development of postoperative sepsis in patients with HIV/AIDS. PMID- 21792758 TI - [Effect of neoadjuvant chemotherapy on the postoperative pulmonary infection of patients with advanced gastric cancer]. AB - OBJECTIVE: To evaluate the effect of neoadjuvant chemotherapy on the postoperative pulmonary infection of patient with gastric cancer. METHODS: Between January 2009 and January 2011, 139 patients with curable stage T2N2 or T3N2 gastric cancer were randomly assigned to group 1(69 cases, neoadjuvant chemotherapy with combined preoperative intraarterial infusion and intravenous chemotherapy before gastrectomy and D2 lymphadenectomy) and group 2(70 cases,gastrectomy and D2 lymphadenectomy alone). The morbidity of postoperative pneumonia in the two groups were recorded respectively. RESULTS: The two groups were similar with respect to various clinical or pathological characteristics. All the patients underwent gastrectomy and D2 lymphadenectomy successfully. Eight patients in group 1 suffered from the postoperative pneumonia, accounting for 11.6%. Nine patients in group 2 suffered from the postoperative pneumonia, accounting for 12.9%. There was no significant difference between the two groups about the incidence of postoperative pneumonia. CONCLUSION: Surgery following neoadjuvant chemotherapy with combined preoperative intraarterial infusion and intravenous chemotherapy is safe with similar morbidity of postoperative pneumonia to immediate surgery in patients with locally-advanced resectable gastric carcinoma. PMID- 21792759 TI - [Application of damage control surgery for severe abdominal trauma]. AB - OBJECTIVE: To evaluate the value of damage control surgery(DCS) for severe abdominal trauma. METHODS: Forty-six patients with severe abdominal trauma were treated according to DCS principles and 58 patients were not. Clinical data of the two groups were analyzed retrospectively. DCS included simple surgery, resuscitation, and definitive operation. RESULTS: Perioperative morality was 15.2%(7/46) in the DCS group and 34.5%(20/58) in the non-DCS group, and the difference was statistically significant(chi2=4.954, P=0.026). The perioperative complication rate was 37.0%(17/46) in the DCS group and 67.2%(39/58) in the non DCS group, and the difference was statistically significant(chi2=9.468, P=0.002). CONCLUSION: Damage control surgery can reduce perioperative morbidity and mortality in patients with severe abdominal trauma, and its efficacy is satisfactory. PMID- 21792760 TI - [Placement of double cannula using trocar puncture for abdominal abscess drainage]. AB - OBJECTIVE: To study the effects of placement of double cannula using trocar puncture for intra-abdominal abscess drainage. METHODS: A retrospective study was performed to investigate the clinical data of 32 patients undergoing intra abdominal abscess drainage with double cannula placed using trocar puncture between June 2010 and December 2010. TECHNIQUES: the location and size of the abscess was evaluated by ultrasound and CT. Placement of double cannula using trocar puncture was performed under CT or ultrasound guidance. RESULTS: Trocar puncture was successful in all the patients. One patient died of liver metastasis and multiple organ failure after surgery for pancreatic cancer. One patient required laparotomy and drainage because non-localization of sepsis from intestinal fistula. The remaining 30 patients experienced alleviation of septic symptoms after drainage and eventually cured. The mean healing time was(7+/-3) days. Two patients developed subcutaneous bleeding and were management by local compression. CONCLUSIONS: Placement of double cannula using trocar puncture for intra- abdominal abscess drainage results in satisfactory outcomes. This technique is especially suitable for abscesses with viscous drainage, those with the presence of phlegmon or necrotic debris, and those with multiple large cavities. PMID- 21792761 TI - [Experimental study of liver injury in rats of abdominal infection with abdominal compartment syndrome]. AB - OBJECTIVE: To evaluate the liver injury in rats of abdominal infection complicated with abdominal compartment syndrome(ACS). METHODS: SD rats were divided into four groups, including the sham group, the abdominal infection group, the ACS group, and the abdominal infection plus ACS group (combination group). Rats were sacrificed at 1 h, 6 h, 12 h, 24 h after operation with 6 rats at each time point. Blood specimens were collected for liver function testing. Liver tissues were assessed by pathologically examination with hepatic injury severity scoring(HISS). The expressions of Toll-like receptor 4 (TLR4),TNF-alpha and IL-6 were examined by reverse transcription- polymerase chain reaction. RESULTS: At 24 h after operation, as compared to the sham group(18.2+/-1.3) U/L and (105.6+/-25.5) U/L, ALT and AST increased obviously in the abdominal infection group(68.2+/-17.5) U/L and (184.6+/-36.1) U/L, the ACS group (305.2+/ 128.2) U/L and (638.0+/-104.8) U/L and the combination group (409.2+/-67.1) U/L and (743.2+/-250.2) U/L, while the combination group had a higher level as compared to the infection group and the ACS group(all P<0.05). HISS scores were significantly higher in the abdominal infection group(5.0), the ACS group(5.5) and the combination group(7.0) as compared to the sham group(1.5), but no significant differences were found among the three groups at 24 h after operation. Expressions of TLR4, TNF-alpha and IL-6 were significantly higher in combination group than those in the other three groups. CONCLUSIONS: Liver function can be affected by abdominal infection and ACS. Abdominal infection plus ACS results in more severe liver injury. PMID- 21792762 TI - [Prognostic value of metastatic lymph node ratio for patients with gastric cancer]. AB - OBJECTIVE: To evaluate the prognostic value of metastatic lymph node ratio (MLR) for patients with gastric cancer. METHODS: Data collected from 1247 patients with gastric cancer who underwent radical surgery (pT4 cases were excluded) at the First Affiliated Hospital of Nanjing Medical University between 2005 and 2009 were analyzed retrospectively. MLR was compared to pathological N staging (pN) in terms of prognostic accuracy, homogenicity, and applicability. RESULTS: MLR and pN were both positively correlated with the number of retrieved lymph nodes(both P<0.01). Significant differences were found in 5-year cumulative survival rate (5 YCSR) among different pN stages and MLR classification(all P<0.01). Multivariable analysis showed that both pN and MLR were independent prognostic factors(both P<0.01). The area under ROC curve(AUC) of MLR was larger than pN, however the difference was not statistically significant(P>0.05). There were significant differences in 5-YCSR among different MLR stages within the same pN stages(P<0.05), but not among different pN stages within the same MLR stage(P>0.05). Significant differences in 5-YCSR were also found among different retrieved-node groups within the same pN stage (P<0.05), but not within the same MLR stages (P>0.05). CONCLUSIONS: MLR is an independent prognostic factor for patients with gastric cancer. The prognostic homogenicity and applicability of MLR are better than those of pN, however the prediction accuracy is not favorable. PMID- 21792763 TI - [Influence of microsatellite instability on survival of patients with sporadic colorectal cancer in China]. AB - OBJECTIVE: To investigate the role of microsatellite instability(MSI) in Chinese sporadic coloretal cancer. METHODS: A total of 146 patients with colorectal cancer were treated surgically from August 2004 to September 2006 in the Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine. Data were collected prospectively. Univariate and multivariable analyses were performed for parameters such as age, gender, tumor location, differentiation, MSI, tumor type, lymph node metastasis, TNM stage, and survival. RESULTS: Follow up was available in 134 patients including telephone call and office visit. MSI(P=0.029), tumor type(P=0.000), TNM stage(P=0.000) were independently associated with survival on Cox regression model. There were 26 patients with MSI, and the 1-, 3-, and 5-year survival rates were 100%, 92.3%, and 92.3%, respectively. The remaining 108 patients had microsatellite stable tumor, and the 1-, 3-, and 5-year survival rates were 96.3%, 72.2%, and 63.5%, respectively. The difference was statistically significant(P=0.016). CONCLUSION: Microsatellite instability is an important factor associated with patient survival in Chinese sporadic colorectal cancer. PMID- 21792764 TI - [Goal-directed fluid management prevents gastrointestinal complications in abdominal surgery: a meta-analysis of randomized controlled trials]. AB - OBJECTIVE: To assess whether goal-directed fluid management can prevent gastrointestinal complications in major surgery. METHODS: Electronic databases including Cochrane library(Issue 3,2010), Pubmed, EMbase, Highwire, CBM, and CNKI were searched. The date of search was between January 2000 and December 2010. Randomized controlled trials(RCTs) were indentified studying association of goal directed therapy (GDT) with gastrointestinal complications. Study selection and meta-analysis were conducted according to the Cochrane Handbook for systematic reviews. Data were extracted from these trials by 3 reviewers independently and analyzed by RevMan 5.0 software. RESULTS: Ten trials involving 775 patients were included. GDT significantly improved oxygen supply(WMD=82.95, 95% CI: 17.43 148.46). GDT reduced postoperative hospital stay(WMD=-2.06, 95% CI: -2.95 - 1.17) and decreased postoperative complication rate after major surgery(RR=0.39, 95% CI: 0.29-0.52). CONCLUSION: Goal-directed fluid management can stabilize cardiac output, augment oxygen supply, and therefore reduce postoperative complications. PMID- 21792765 TI - [Application of fat clearance technique in pathologic staging for colon cancer]. AB - OBJECTIVE: To evaluate whether the use of fat clearance technique improves the accuracy of staging for colon cancer. METHODS: Between June 2007 and December 2008, surgical specimens of 91 patients with colon cancer were procured. Between June 2007 and January 2008, routine technique for lymph node harvest including visualization and tactile sensation was used in 45 patients (conventional group), while lymph nodes of 46 patients between February 2008 and December 2008 were examined using fat clearance technique(fat clearance group). RESULTS: The mean of lymph nodes harvested was 32.7 using fat clearance technique, significantly higher than that(15.3) of the conventional group(P<0.01). The mean positive lymph nodes was 2.7 and 1.8 in the two groups, respectively, with a statistically significant difference(P<0.05). There were more stage III( colon cancer in the postoperative staging than that in the preoperative staging using fat clearance technique (31 vs.19, P<0.05), while there was no difference in stage III( colon cancer between postoperative staging and preoperative staging using conventional method (21 vs.19, P>0.05). CONCLUSIONS: Fat clearance technique significantly increases number of lymph node retrieval and positive nodes, therefore the accuracy of postoperative staging is improved. PMID- 21792766 TI - [Clinical study of laparoscopic sphincter-preserving proctectomy for low rectal cancer using transanal telescopic anastomosis]. AB - OBJECTIVE: To investigate the safety, feasibility and clinical outcomes of laparoscopic sphincter-preserving proctectomy for low rectal cancer using transanal telescopic anastomosis. METHODS: Five patients underwent laparoscopic sphincter-preserving proctectomy for low rectal cancer using transanal telescopic anastomosis between March 2011 and April 2011 at the General Hospital of Beijing Military Command. After lymph node dissection around the mesentery using harmonic scalpel, the root of the inferior mesenteric vessel was ligated and transected. Rectal dissection was further carried out until 5 cm distal to the lower margin of the tumor. A circumferential incision was made 1.0 cm above the dentate line using 5 support stitches for exposure. The submucous layer was striped upward to the level of the levator ani, and rectum was transected. Rectum and sigmoid colon were extracted transanally and removed. Finally, colonanal anastomosis was made using telescopic technique. RESULTS: Five patients underwent the procedure successfully. The mean operative time was 178 minutes. The mean intraoperative blood loss was 76 ml. The mean lymph nodes retrieval was 14. Bowel function recovered after a mean of 3 days. There were no postoperative complications. No obvious scars were seen in the abdomen or the anus. The mean hospital stay was 12 days. After one year of follow-up, all the patients survived cancer-free. CONCLUSIONS: Laparoscopic anterior resection with sphincter preservation by transanal telescopic anastomosis for low rectal cancer is feasible and safe. Abdominal incision is minimal. However, the long-term outcomes require further investigation. PMID- 21792767 TI - [Endoscopic management of early postoperative anastomotic hemorrhage]. AB - OBJECTIVE: The study aimed to evaluate the efficacy of endoscopic therapy for early postoperative anastomotic hemorrhage. METHODS: Fourteen patients experienced an episode of early postoperative anastomotic hemorrhage and were treated endoscopically from January 2005 to June 2010. The clinical data was analyzed retrospectively. RESULTS: Fourteen patients(9 males and 5 females, median age 57.5 years, range 26-74 years) were diagnosed with postoperative hemorrhage between 6 hours to 14 days after surgery. The blood loss ranged from 500 to 1500 ml. Sclerosing agent injection, electrocoagulation, and hemoclips were attempted to control the bleeding. Endoscopic approach to control early postoperative anastomotic hemorrhage was successful in all the patients. No recurrent bleeding was observed during the follow-up. No complications associated with endoscopic therapy. CONCLUSION: Endoscopic approach for the management of early postoperative anastomotic hemorrhage is feasible with high success rate and associated with no complications. PMID- 21792768 TI - [Effects of CDH1 gene promoter methylation on expression of E-cadherin and beta catenin and its clinicopathological significance in colon carcinoma]. AB - OBJECTIVE: To investigate the relationship between methylation of the CDH1 gene promoter on the expression of E-cadherin and beta-catenin, and to evaluate the correlation with clinicopathological characteristics of the colonic carcinoma. METHODS: Methylation specific PCR (MSP) was used to detect CDH1 gene promoter methylation in the cancer tissue, adjacent tissues and normal tissues in 68 patients. The expression of E-cadherin and beta-catenin was determined by immunohistochemistry staining. RESULTS: The positive rate of CDH1 gene promoter methylation was 32.4% in adjacent tissues and 57.4% in cancer tissue, while no detectable methylation was found in all the normal tissues. The difference was statistically significant. The positive rate of E-cadherin was 92.6% in the normal tissues, 66.2% in the adjacent tissues and 44.1% in the cancer tissues. In all normal tissues, beta-catenin was expressed only at the cellular membrane but not in the cytosol or nucleus, while the expression of beta-catenin was present in the cytosol or nucleus in 29.4% of the adjacent tissues and 50.0% of the cancer tissues. The positive rate of CDH1 gene promoter methylation was negatively correlated with E-cadherin expression(r=-0.312, P=0.01) and positively correlated with beta-catenin cytosolic/nucleus expression(r=0.309, P=0.018). The differentiation and metastasis of colonic carcinoma were associated with the aberrant expression of E-cadherin, beta-catenin, and methylation of CDH1 promoter (P<0.05). CONCLUSION: CDH1 gene promoter methylation may lead to aberrant expression of E-cadherin and beta-catenin in colonic carcinoma, and may play an important role in promoting the invasion of tumor. PMID- 21792769 TI - [Analysis for myeloperoxidase genetic polymorphism in gastric cancer]. AB - OBJECTIVE: To investigate the association of myeloperoxidase(MPO) genetic polymorphism and gastric cancer. METHODS: A case-control study was performed including 62 patients with gastric cancer and 61 healthy controls. Peripheral blood was collected for genetic analysis of MPO-463. RESULTS: There were no significant differences in gender, age, and smoking between the two groups(P>0.05). However, the two groups differed in drinking, family history of gastric cancer, and Helicobacter pylori(HP) infection(P<0.05). The frequencies of MPO-463GG, GA and AA were 87.1%, 11.3% and 1.6%in the study group, and were 72.1%, 23.0%, and 4.9% in the control group, respectively. Carriers of MPO-463 GA or AA had a significantly higher risk of gastric cancer than those of MPO-463 GG(chi(2)=4.253, P<0.05, OR=0.383, 95% CI: 0.151-0.972). Carriers of G allele had a significantly lower risk of gastric cancer compared to carriers of A allele(chi(2)=4.935, P<0.05, OR=0.399, 95% CI: 0.174-0.916). CONCLUSION: MPO-463 G/A polymorphism is associated with gastric cancer with A being a protective gene. PMID- 21792770 TI - [Hand-assisted laparoscopic versus laparoscopic-assisted right hemicolectomy: a clinical controlled study]. AB - OBJECTIVE: To compare the outcomes of right hemicolectomy performed either by the hand-assisted laparoscopic(HALS) or conventional laparoscopic surgery(LAS). METHODS: Ninety-five patients undergoing HALS(n=47) from March 2002 to November 2006 or by LAS (n=48) from January 2007 to December 2009 were retrospectively studied. All the operations were performed by the same surgical team. Patient safety, postoperative recovery, complications, oncologic outcomes, medical expenses, and the follow-up results were compared between the two groups. RESULTS: No severe complications or perioperative deaths were oberved. There were significant differences between the two groups in terms of intraoperative bleeding, operative time, and length of incision(all P<0.05). However, the conversion rate, intraoperative injuries, time to first bowel movement, postoperative bed-rest time, hospital stay, time to first oral intake, and the number of patients requiring postoperative analgesia were comparable between the two groups(P>0.05). Length of surgical specimen was (25.6+/-9.9) cm in the HALS group and was (26.8+/-7.9) cm in the LAS group, the diffenence was not statistically significant(P<0.05). The mean number of lymph nodes retrieved in HALS group was 18.2+/-12.1, which was significantly lower than that in LAS group(24.1+/-9.3, P<0.05). The medical expense of the LAS group was (28 049.8+/ 7576.1) RMB, which was significantly higher than that of the HALS group(21 132.7+/-5323.4) RMB(P<0.05). A follow-up rate of 93.7% was achieved in the HALS group with 3 patients lost to follow-up. The follow-up duration ranged from 45.4 to 101.9 months with a median of 66.7 months. In LAS group, the follow-up rate was 96% with 2 patients lost to follow-up and the follow-up duration ranged from 12.4 to 45.7 months with a median of 21.6 months. There was no significant difference in 3-year disease-free survival(91.3% vs. 87.9%, P>0.05) between the two groups. CONCLUSION: HALS and LAS can achieve similar minimal invasiveness efficacy and oncologic outcomes for right hemicolectomy. PMID- 21792772 TI - Editorial. PMID- 21792773 TI - New technologies in facial plastic surgery. PMID- 21792774 TI - Laser face-lifts: a new paradigm in face-lift surgery. AB - Laser-assisted liposuction has been successfully applied to remove fat and contract skin in nonfacial areas. This study evaluated the efficacy and safety of this technique in the face. Patients ( N = 40) requesting improvement and a shorter recovery time received one of four laser face-lift (LFL) procedures. The target area was divided into ~15 squares, each around 5 * 5 cm. Each square was treated individually by laser-assisted liposuction to surface temperature end points of 38 degrees C to 40 degrees C. Anatomic areas treated included the submentum, jowls, neck skin, jaw line, cervicomental angle, oral commissures, and nasolabial grooves. Wavelengths were 1064 nm and 1319/1320 nm. Patients returned to their normal lifestyle within 6 to 7 days after treatment. Patient satisfaction was generally higher than that seen in patients receiving a conventional face-lift. Adverse events were limited to burns in two patients. The LFL is a less invasive treatment with acceptable efficacy, reduced downtime, shorter recovery, and lower cost compared with the traditional face-lift. PMID- 21792775 TI - Platelet gels and hemostasis in facial plastic surgery. AB - Over the last decade, the availability of autologous and homogenous platelet-rich and fibrin-rich gels has increased. Due to their more widespread availability and the potential benefits of improved hemostasis and wound healing, their use during facial plastic and reconstructive surgery procedures has also grown. These gels, when applied topically, attract inflammatory cells and fibroblasts and stimulate collagen deposition. Various studies have investigated the potential surgical applications and benefits of these gels. What follows is an in-depth review of the various fibrin and platelet gels available. Furthermore, it clarifies the current applications and proven benefits in facial plastic surgery. PMID- 21792777 TI - Laser-assisted neck-lift: high-tech contouring and tightening. AB - Less invasive procedures for facial rejuvenation are becoming more and more popular as prospective patients seek out treatment options that offer the best possible results with the least amount of downtime. As the demand for "quick recovery" procedures increases and patients spend more time researching options, more informed choices are being made, and many times patients opt for technologically advanced procedures. Less invasive procedures can be so described because they utilize small incisions, less anesthesia, or advanced technology to reduce morbidity. We describe a minimally invasive "laser neck-lift" that utilizes minimal access incisions, no general anesthesia, and an internal aesthetic laser to dissect in the plane between skin and subcutaneous fat and the platysma. The procedure relies on laser lipolysis and skin tightening via dermal heating as well as two QuillTM sutures that serve to define the neck. The procedure is well tolerated and not complicated and gives long-lasting results. PMID- 21792776 TI - Laser-assisted facial contouring using a thermally confined 1444-nm Nd-YAG laser: a new paradigm for facial sculpting and rejuvenation. AB - The micropulsed 1444-nm neodymium-doped lipolysis laser exhibits favorable characteristics for novel application in facial contouring. The study described herein is the first clinical report of laser-assisted facial contouring (LAFC). We retrospectively reviewed records of 478 LAFC patients (mean age 52) who underwent contouring of 1278 individual mid- and lower facial treatment sites over 18 months. Along with clinical assessment, study parameters evaluated among "original" and "modified" (where protocol updates included deep dermal soft tissue coagulation as an optional step) protocol groups included laser power, pulse energy, and total energy delivery as well as lipoaspirate volume at each treatment site. Mean power and pulse energy were similar (within 5%) and total energy use was greater (70% higher for mid- and lower face) in the original protocol group. Lipoaspirate volume was similar for both groups for the midface (within 10%) but elevated in the modified protocol group for the lower face (40% higher). Treatment complications were observed in 47 of 363 treatment sites (13%) in the original and in 12 of 915 treatment sites (1%) in the modified protocol group with the majority (63%) of the complications comprising over- versus undercorrections of desired tissue contour. Clinical efficacy varied with improvements of mid- and/or lower facial contour ranging from marginal to subtle to very apparent. LAFC as detailed herein is a novel treatment modality that enables selective soft tissue removal for greater precision in three-dimensional contouring of the face. Protocol modifications based on laboratory and observed tissue photothermodynamics have improved LAFC safety. PMID- 21792778 TI - Management of facial paralysis in the 21st century. AB - Facial paralysis is a clinical entity associated with significant morbidity, which has a treatment paradigm that is continually evolving. Surgical management of the paralyzed face poses significant challenges to achieve the goal of returning patients to their premorbid states. Here we attempt to review the advances in facial reanimation, in particular with regards to chronic facial paralysis. These include recent developments in static and dynamic rehabilitation including advances like artificial muscles for eyelid reconstruction, dynamic muscle transfer for the eye, and orthodromic temporalis tendon transfer. PMID- 21792780 TI - The latest innovations in hair transplantation. AB - Hair restoration began as a result of the fortuitous finding by Dr. Norman Orentreich that hair follicles taken from an area of nonbalding scalp could be implanted into an area of male pattern hair loss and continue to grow terminal hair. Since that time, hair transplants have progressed from the use of large plugs to the use of follicular units (normally occurring clusters of hairs). This has allowed surgeons to create undetectable results in cases of androgenetic alopecia and well as other conditions associated with hair loss. Advances continue in hair restoration technique ranging from surgical approach to instrumentation and ways to enhance growth. In this article, the more recent surgical and medical innovations in hair reconstruction are reviewed. PMID- 21792779 TI - Computer-assisted innovations in craniofacial surgery. AB - Reconstructive surgery for complex craniofacial defects challenges even the most experienced surgeons. Preoperative reconstructive planning requires consideration of both functional and aesthetic properties of the mandible, orbit, and midface. Technological innovations allow for computer-assisted preoperative planning, computer-aided manufacturing of patient-specific implants (PSIs), and computer assisted intraoperative navigation. Although many case reports discuss computer assisted preoperative planning and creation of custom implants, a general overview of computer-assisted innovations is not readily available. This article reviews innovations in computer-assisted reconstructive surgery including anatomic considerations when using PSIs, technologies available for preoperative planning, work flow and process of obtaining a PSI, and implant materials available for PSIs. A case example follows illustrating the use of this technology in the reconstruction of an orbital-frontal-temporal defect with a PSI. Computer-assisted reconstruction of complex craniofacial defects provides the reconstructive surgeon with innovative options for challenging reconstructive cases. As technology advances, applications of computer-assisted reconstruction will continue to expand. PMID- 21792781 TI - Tissue engineering, regenerative medicine, and rejuvenation in 2010: the role of adipose-derived stem cells. AB - Facial rejuvenation is rapidly evolving sector in the field of facial aesthetics. There is a wide variety of dermal fillers and many more are in development. Over the past few years, the study of adult-derived stem cells has become a very active area of research. Adult stem cells are an attractive option for volume restoration and facial rejuvenation. Adult stem cells are isolated from adipose tissue-adipose derived stem cells and have mesodermal, ectodermal, and endodermal potentials. Adipose-derived stem cells could conceivably be an alternative to pluripotent embryonic stem cells and could play a critical role in the rapidly expanding fields of tissue engineering and regenerative medicine. This article reviews the history of soft tissue augmentation using adipose tissue grafting and the advent of using adipose-derived stem cells. The state-of-the-art stem cell isolation technique as well as anticipated future therapeutic indications are also addressed. PMID- 21792782 TI - Myofibroma of the zygomatic bone in an older child: a case report. AB - Myofibroma/myofibromatosis is a rare mesenchymal disorder that is part of a heterogeneous group of approximately 20 disorders that are classified primarily according to the proliferation of benign fibrous elements. These lesions can arise during a wide range of ages, with many occurring in the first decade of life, and they are slightly more common in males than females. The etiology of this disease is not well understood. Clinically, patients with myofibroma/myofibromatosis present with various signs, ranging from superficial, cutaneous, purplish macules to freely movable subcutaneous masses to deep-seated fixed lesions. The definitive diagnosis is made on histopathologic grounds. The destructive clinical behavior of myofibroma/myofibromatosis in the setting of insufficient pre- or perioperative diagnostic evaluations (e.g., a failure to perform fine-needle aspiration or frozen-section biopsy) may guide the clinician toward a radical surgical procedure rather than a simple excision. PMID- 21792783 TI - Primary nasal tuberculosis-a rare clinical entity. AB - Primary tuberculosis of the nose is very rare. We report a case of a 35-year-old woman who presented with bilateral nasal obstruction and epistaxis of 3 months' duration but who was otherwise healthy. She was diagnosed with primary nasal septal tuberculosis and was treated with antituberculosis DOTS (directly observed treatment, short course) therapy for 6 months with complete recovery. Given the resurgence of tuberculosis in recent times, it is important that clinicians remain aware of this rare and treatable clinical entity. PMID- 21792784 TI - Retropharyngeal abscess from an unusual organism-Kingella denitrificans-in a patient on low-dose methotrexate. AB - Retropharyngeal abscess can be a life-threatening emergency with potential for airway compromise. We report a case of retropharyngeal abscess caused by Kingella denitrificans in a 66-year-old Caucasian man taking low-dose methotrexate for psoriatic arthritis. K denitrificans has not been previously reported as a cause of retropharyngeal abscess. K denitrificans, along with other Kingella species, is often found to be part of the normal upper respiratory tract flora. Potentially life-threatening complications of retropharyngeal abscess can occur in immunocompromised patients. Although complications of immunosuppression are thought to be rare with the use of low-dose pulse methotrexate for non-neoplastic conditions, such complications with prolonged use of low-dose pulse methotrexate may be seen. PMID- 21792785 TI - Paradoxical giant inferior concha. AB - Anatomic variations of the middle and superior conchae are common, but inferior concha anomalies are rare. These anomalies have included pneumatization, agenesis, and duplication. We describe what we believe is the first reported case of a paradoxical curvature of the bony part of the inferior concha. The patient was a 13-year-old girl. The development of a huge inferior concha blocked the left nasal cavity and deviated the nasal septum to the contralateral side, resulting in bilateral obstruction. The patient was successfully treated with surgery. PMID- 21792786 TI - Ballpoint pen ingestion in a 2-year-old child. AB - A 2-year-old girl ingested a ballpoint pen, which was found on chest x-ray to have lodged in the lower esophagus and stomach. The pen, which measured nearly 15 cm in length, was removed via rigid esophagoscopy without complication. To the best of our knowledge, this is the longest nonflexible foreign body ingested by a young child ever reported in the English-language literature. We describe the presentation of this case and the current guidelines for safety as enumerated in the Small Parts Regulations established by the U.S. Consumer Product Safety Commission. PMID- 21792787 TI - Bilateral tonsillar and esophageal Kaposi sarcoma in an HIV-negative patient. AB - Tonsillar involvement in Kaposi sarcoma is extremely rare, as only a few such cases have been reported; all but 1 of these previously reported cases occurred in patients with human immunodeficiency virus (HIV) infection. We describe what to the best of our knowledge is the first reported case of concurrent bilateral tonsillar and esophageal Kaposi sarcoma in an HIV-negative patient. A 68-year-old man presented with sore throat and dysphagia. Clinical examination revealed the presence of bilateral and asymmetrical tonsillar masses, as well as generalized lymphadenopathy in the cervical chain. The masses were resected, and findings on histopathologic analysis were consistent with Kaposi sarcoma. In addition, human herpesvirus 8 was demonstrated on a tonsil specimen by polymerase chain reaction, and microinvasive squamous cell carcinoma was also detected. Later, another Kaposi sarcoma lesion was detected in the lower third of the esophagus. We recommend that clinicians not discount the possibility of oral classic Kaposi sarcoma in the workup of an immunocompetent patient with oral vascular lesions. PMID- 21792788 TI - Anterior and posterior glottic webs. PMID- 21792789 TI - Bilateral sphenoid fungal sinusitis. PMID- 21792791 TI - Myoepithelioma of the vallecula: a case report. AB - Myoepitheliomas are rare and generally benign neoplasms that account for fewer than 1% of all salivary gland tumors. A myoepithelioma neoplasm is almost entirely composed of myoepithelial cells and is most frequently located in the parotid gland and in the minor salivary glands of the hard palate. We report an extremely rare case of myoepithelioma of the vallecular region in a 65-year-old woman and describe this tumor's clinical peculiarity, diagnostic and therapeutic considerations, and prognosis. PMID- 21792790 TI - Malignant proliferating trichilemmal tumor involving the sinuses. AB - Proliferating trichilemmal tumor (PTT) is a rare adnexal neoplasm that arises from the outer sheath of the hair follicle. It is believed that PTTs originate in trichilemmal cysts. These tumors have the potential for malignant transformation; when this occurs, the tumor is known as a malignant PTT (MPTT). Recurrence after simple local excision is common, and it can cause considerable morbidity. We report a case of MPTT that was initially diagnosed as a benign PTT. The primary tumor had arisen from the skin over the glabella. It was excised, but it recurred 3 years postoperatively. The recurrent tumor involved the eyelid, nasal cavity, and frontal and ethmoid sinuses, and it extended into the orbit. The recurrent tumor was excised via combined endoscopic and open surgery. As far as we know, this is the first documented case of an MPTT that involved the sinuses. PMID- 21792792 TI - Tort reform: federal impetus for change. PMID- 21792793 TI - Ear stapling application as an alternative treatment for weight loss. PMID- 21792794 TI - Spontaneous posterior wall external canal cholesteatoma. PMID- 21792795 TI - Meningioma mimicking vestibular schwannoma. PMID- 21792796 TI - Type 1 first branchial cleft anomaly: duplication of the external auditory canal. PMID- 21792797 TI - Ear ceruminous adenoma. PMID- 21792798 TI - Cochlear implant fixation using resorbable mesh. AB - In this article we describe a new method of cochlear implant receiver-stimulator fixation using a resorbable poly (D,L) lactic acid mesh. We conducted a retrospective case review at a tertiary referral center; 10 pediatric and 4 adult patients had undergone cochlear implantation during the period from February to October 2008. Resorbable poly (D,L) lactic acid mesh and pins were used for fixation of the cochlear implant receiver stimulator. The receiver stimulator was assessed for stability/migration, and the scalp flap/incision were evaluated for allergic reactions, infections, and healing problems. With an average follow-up of 17.2 months, no patients had migration of the receiver stimulator, and there was no evidence of infection, wound dehiscence, or allergic reaction. Early results indicate that fixation of a cochlear implant receiver stimulator using resorbable mesh is well tolerated and provides good stability without device migration. Resorbable mesh fixation of the receiver stimulator is a reasonable alternative technique for cochlear implantation. PMID- 21792799 TI - Tracheoinnominate fistula: successful management with endovascular stenting. AB - Tracheoinnominate fistula is a rare complication of tracheostomy that is associated with high rates of morbidity and mortality. Recently, endovascular stents have been described as a viable treatment option for the management of this condition. We report a case of tracheoinnominate fistula in a 40-year-old man that was successfully managed with endovascular stent placement. Our evaluation included bronchoscopy, arteriography, and computed tomographic angiography. Intraoperative localization of the fistula required selective catheterization of the innominate artery. PMID- 21792800 TI - Tapia syndrome caused by a vertebral artery dissection. AB - A 63-year-old man presented to our otorhinolaryngology department with hoarseness and neck pain of 3 weeks' duration. After a thorough workup, we established a diagnosis of Tapia syndrome secondary to a vertebral artery dissection. We review the literature and discuss the clinical presentation of this rare syndrome. PMID- 21792801 TI - Thyroidectomy for goiter relieves obstructive sleep apnea: results of 8 cases. AB - The author conducted a retrospective study of 8 adults with euthyroid goiter that had resulted in tracheal compression and led to moderate to severe obstructive sleep apnea (OSA). The purpose of the study was to evaluate the effects of thyroidectomy on the apnea-hypopnea index (AHI) in these patients and to determine if there is a relationship between tracheal compression and OSA. These patients had been treated by the author in a community hospital over a 4-year period. All 8 patients had reported compressive symptoms of orthopnea and dysphagia, and 3 of them also reported dyspnea. Computed tomography of the neck and chest had been used to confirm the extent of goiter and tracheal compression. OSA had been confirmed with preoperative polysomnography. At 90 days post thyroidectomy, repeat polysomnography had been obtained. At follow-up, all 8 patients had reported symptomatic control of compressive symptoms, and 7 patients had demonstrated postoperative improvement in their AHI. Overall, the mean postoperative AHI had decreased from 52.1 to 36.6-a statistically significant reduction of 29.8% (p < 0.05). The results of this study suggest that thyroidectomy for tracheal compression secondary to goiter can significantly alleviate symptoms and improve AHI in those patients who experience OSA. Evaluation of all patients with OSA should include screening for goiter-induced tracheal compression. PMID- 21792802 TI - [Adverse effects of new oncologic therapies]. PMID- 21792805 TI - [Intracerebral haemorrhage - when is a surgical treatment reasonable?]. AB - Intracerebral haemorrhages (ICH) are responsible for 10-17% of all strokes and are associated with a high mortality and morbidity. More than 50% of the primary cases of ICH are associated with an underlying arterial hypertension and up to 30% with a cerebral amyloidosis. In supratentorial ICH, primary treatment generally should be conservative, as clinical studies could not show favourable outcomes after surgical haematoma evacuation. However, in patients with infratentorial haemorrhages and neurologic deterioration, early surgical evacuation should be considered. Modern therapeutic strategies and the focus of current and recent clinical research include early haemostasis, improvement of intensive care, and less invasive neurosurgical interventions, with the aim to reduce secondary brain damage. This review provides an overview of the clinical presentation of ICH and includes up-to-date recommendations concerning diagnostic and therapeutic options. PMID- 21792806 TI - [The role of surgery in the treatment of cutaneous melanoma]. AB - Historically, melanoma patients were subject to wide local excisions and elective lymph node dissections. Both approaches were the focus of intense scrutiny in the past three decades, and many surgical dogmas were abolished. The role of surgery in providing local control over the primary tumor is largely undisputed. In addition, the surgical management strategies of the regional lymph nodes have undergone considerable change in the past; with lymphatic mapping and sentinel lymph node identification being the most relevant contribution, allowing selection of patients for adjuvant treatment (completion lymph node dissection, Interferon therapy). Surgery has also a place in palliative treatment of isolated systemic metastases for selected cases with good performance status in Stage IV melanoma. PMID- 21792807 TI - [Post hip fracture care]. AB - Hip fractures are common and associated with high mortality and morbidity. Patients with hip fractures have a high risk of refractures. Osteoporosis is the underlying cause. A therapy with bisphosphonates is indicated without the need of further diagnostic testing with a bone marrow densitometry. PMID- 21792808 TI - [Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults]. PMID- 21792809 TI - [Recurrent Baker's cyst]. AB - A 50-year old female patient with unilateral knee pain demonstrated a recurrent ultrasound-proven popliteal cyst (Baker's cyst). Even though a proper differential diagnosis was done, the MRT of the knee showed in a secondary step a tibial fissure as the cause of the treatment-refractory knee pain and Baker's cyst. A fracture of the tibia is a rare cause for a symptomatic Baker's cysts. Mechanical, degenerative or inflamed diseases of the joint are more frequent associated with a Baker's cyst. PMID- 21792810 TI - [Not Available]. PMID- 21792811 TI - [Not Available]. PMID- 21792817 TI - Inverse correlation between plasma Beta-carotene and interleukin-6 in patients with advanced coronary artery disease. AB - The interrelationships between plasma beta-carotene, alpha-tocopherol, and the level of systemic inflammation and oxidative stress were investigated in patients with advanced coronary artery disease (CAD). Plasma beta-carotene, alpha tocopherol, malondialdehyde, free radicals, interleukin-6, high sensitive C reactive protein levels, and other risk factors of CAD were determined in a group of patients with advanced CAD [significant stenosis according to coronarographic examination (n=91) and a control group of examined patients with coronary arteries with no stenosis (n=49)]. Between-group differences in continuous variables were analyzed with the Hotelling T2-test (software NCSS2000), analyses of correlation matrix with the software STATISTICA. Advanced CAD coincided with significantly lower plasma concentrations of high-density lipoprotein (HDL) cholesterol and beta-carotene as well as with elevated levels of all inflammatory markers, but only with mild increase of oxidative stress. Beta-carotene significantly inversely correlated with interleukin-6. This inverse correlation could suggest potential protective effect of beta-carotene on atherosclerosis due to the inhibition of inflammatory processes. PMID- 21792818 TI - Vitamin profile of some standardized nigerian composite dishes. AB - The purpose of the study was to determine the vitamin content of twenty standardized dishes commonly consumed in Nigeria. Representative samples of twenty Nigerian dishes were analyzed for fat-soluble (vitamins A, D, E, and K) and water-soluble (vitamin C and B- complexes) vitamins. The foods analyzed included those based on cereals, starchy tubers and roots, legumes, and vegetables. The analysis was carried out using spectrophotometry. The results revealed the following concentrations (mg/100 g): vitamin C , undetectable to 2.692 mg/100 g; thiamine, 0.011-1.094 mg/100 g; riboflavin, 0.011-0.816 mg/100 g; pyridoxine, undetectable to 0.412 mg/100 g; niacin, 0.070-0.967 mg/100 g; pantothenic acid, 0.060-1.193 mg/100 g; biotin, undetectable to 2.092 mg/100 g; B12, 0.045-2.424 ug/100 g; folate, 7.822-101.764 ug/100 g; total vitamin A, undetectable to 121.444 ug RE/100 g; vitamin D, undetectable to 2.445 IU/100 g; vitamin E, undetectable to 2.627 IU/100 g; and vitamin K, 0.266-13.091 ug/100 g. The results suggest that these dishes are good sources of fat-soluble and water soluble vitamins and will provide baseline data that will be valuable in complementing available food composition data, and in estimating dietary intake of vitamins in Nigeria. PMID- 21792816 TI - Aflatoxin B1 albumin adducts in plasma and aflatoxin M1 in urine are associated with plasma concentrations of vitamins A and E. AB - BACKGROUND: Although aflatoxin exposure has been associated with micronutrient deficiency in animals, there are few investigations on the effects of aflatoxin exposure on micronutrient metabolism in humans. OBJECTIVE: To examine the relationship between aflatoxin B1 (AFB1) albumin adducts (AF-ALB) in plasma and the aflatoxin M1 (AFM1) metabolite in urine and plasma concentrations of retinol (vitamin A) and alpha-tocopherol (vitamin E) in Ghanaians. METHODS: A cross sectional study of 147 adult participants was conducted. Blood and urine samples were tested for aflatoxin and vitamins A and E levels. RESULTS: Multivariable analysis showed that participants with high AF-ALB (>or=0.80 pmol/mg albumin) had increased odds of having vitamin A deficiency compared to those with lower AF-ALB [Odds Ratio (OR)=2.61; CI=1.03-6.58; p=0.04]. Participants with high AF-ALB also showed increased odds of having vitamin E deficiency but this was not statistically significant (OR=2.4; CI=0.96-6.05; p=0.06). Conversely, those with higher AFM1 values had a statistically nonsignificant reduced odds of having vitamin A deficiency (OR=0.31; CI=0.09-1.02; p=0.05) and a statistically significant reduced odds of having vitamin E deficiency (OR=0.31; CI=0.10-0.97; p=0.04). Participants with high AF-ALB or high AFM1 (>or=437.95 pg/dL creatinine) were almost 6 times more likely to be hepatitis B virus surface antigen (HBsAg) positive (OR=5.88; CI=1.71-20.14; p=0.005) and (OR=5.84; CI=1.15-29.54; p=0.03) respectively. CONCLUSIONS: These data indicate that aflatoxin may modify plasma micronutrient status. Thus, preventing aflatoxin exposure may reduce vitamin A and E deficiencies. PMID- 21792819 TI - Paradoxical effect of severe dietary restriction on Long-Evans rat life span. AB - It has been firmly established that the longevity of 20- to 60%-calorie restricted rodents, with malnutrition (essential nutrients deficiency) being avoided, is increased when compared to ad libitum fed rodents. However, the effects on life span of severe dietary restriction (i. e. malnutrition), with limited weight loss, remained unknown. The purpose of this 4-year study was to investigate the effects on longevity of a severe form of dietary restriction, with limited and controlled weight loss. To this end, a group of male Long-Evans rats severely dietary restricted (SDR group), with a weight loss throughout the experiment=150 minutes/week moderate-to-vigorous-intensity activity lasting >=10 minutes). Quantile regression was used to test median sex differences in physical activity levels. RESULTS: Aerobic physical activity guidelines were met by 12.9% of men and 7.7% of women with knee OA. A substantial proportion of men and women (40.1% and 56.5%, respectively) were inactive, having done no moderate-to-vigorous activity that lasted 10 minutes or more during the 7 days. Although men engaged in significantly more moderate-to-vigorous activity (average daily minutes 20.7 versus 12.3), they also spent more time in no or very-low-intensity activity than women (average daily minutes 608.2 versus 585.8). CONCLUSION: Despite substantial health benefits from physical activity, adults with knee OA were particularly inactive based on objective accelerometry monitoring. The proportions of men and women who met public health physical activity guidelines were substantially less than those previously reported based on self-reported activity in arthritis populations. These findings support intensified public health efforts to increase physical activity levels among people with knee OA. PMID- 21792838 TI - Nerve growth factor: A key local regulator in the pathogenesis of inflammatory arthritis. AB - OBJECTIVE: The effect of nerve growth factor (NGF) and its receptor (NGFR) in inflammatory diseases is a novel research field. The purpose of this study was to investigate the role of NGF/NGFR in human T cell subpopulations and fibroblast like synovial cells (FLS) and examine its pathophysiologic significance in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). METHODS: Expression of NGF/NGFR was examined in synovial fluid (SF), FLS, peripheral blood (PB)-derived T cells, and SF-derived T cells from patients with PsA, RA, and osteoarthritis (OA). NGF levels were determined by enzyme-linked immunosorbent assay. NGF induced T cell/FLS proliferation was examined by MTT assay. Low-affinity (p75)/high-affinity (TrkA) NGFR expression was determined by high-dimensional fluorescence-activated cell sorting. A monochlorobimane assay was used to determine the effect of NGF on T cell survival. RESULTS: Levels of NGF were higher in SF samples from PsA and RA patients as compared to SF samples from OA patients. NGF-induced FLS proliferation was more marked in PsA and RA patients. TrkA was up-regulated on activated SF T cells from PsA (mean +/- SD 22 +/- 6.2%) and RA (8 +/- 1.3%) patients, whereas in SF samples from OA patients, TrkA+CD3+ T cells were not detectable. NGF induced the proliferation of PB T cells, induced the phosphorylation of Akt in activated T cells, and consistent with known pAkt activity, inhibited tumor necrosis factor alpha-induced cell death in these T cells. CONCLUSION: Based on our findings, we propose a model in which NGF secreted by FLS into PsA and RA synovium promotes the survival of activated autoreactive T cells as well as FLS proliferation. Thus, NGF has the potential to sustain the chronic inflammatory cascades of arthritis of autoimmune origin. PMID- 21792839 TI - The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. AB - Interleukin-1 receptor antagonist (IL-1Ra) deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. We report the case of a 2-week-old male who presented with a swollen, erythematous left index finger and elevated serum markers of inflammation. He later developed cyclical fevers, diffuse pustular skin lesions, and thrombus formation. After not responding to broad-spectrum antimicrobial therapy and achieving only moderate success with systemic steroid therapy, he was ultimately treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement. Sequencing of his IL1RN gene revealed that the patient was compound heterozygous for a known mutation (E77X) associated with IL-1Ra deficiency and a novel mutation in exon 2 of the gene (c.140delC; p.T47TfsX4). His case highlights IL-1Ra deficiency as an autoinflammatory disease that is distinct from neonatal-onset multisystem inflammatory disease but that also responds well to anakinra. Our patient is the first reported compound heterozygote for E77X and the novel mutation in exon 2 of the gene, the latter of which adds to what will surely be a growing database of pathologic mutations in IL1RN. PMID- 21792837 TI - Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study. AB - OBJECTIVE: Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have largely been performed in lupus patients who are Asian or of European ancestry. This study was undertaken to examine whether some of these same susceptibility loci increase lupus risk in African American individuals. METHODS: Single-nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1,724 lupus patients and 2,024 healthy controls of African American descent. The loci examined included PTPN22, FCGR2A, TNFSF4, STAT4, CTLA4, PDCD1, PXK, BANK1, MSH5 (HLA region), CFB (HLA region), C8orf13-BLK region, MBL2, KIAA1542, ITGAM, and MECP2/IRAK1. RESULTS: We found the first evidence of genetic association between lupus in African American patients and 5 susceptibility loci (C8orf13-BLK, BANK1, TNFSF4, KIAA1542, and CTLA4; P = 8.0 * 10-6, P = 1.9 * 10-5, P = 5.7 * 10-5, P = 0.00099, and P = 0.0045, respectively). Further, we confirmed the genetic association between lupus and 5 additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P = 7.5 * 10-11, P = 5.2 * 10-8, P = 8.7 * 10-7 , P = 0.0058, and P = 0.0070, respectively), and provided evidence, for the first time, of genome-wide significance for the association between lupus in African American patients and ITGAM and MSH5 (HLA region). CONCLUSION: These findings provide evidence of novel genetic susceptibility loci for lupus in African Americans and demonstrate that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicities. PMID- 21792840 TI - Response to rituximab in patients with rheumatoid arthritis in different compartments of the immune system. PMID- 21792841 TI - The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a chronic idiopathic disease of unknown etiology that is characterized by fibrosis of the skin and visceral organs mediated by activated myofibroblasts. The recently identified inflammasomes are cytosolic receptors that tightly regulate the activity of caspase 1 and downstream signaling molecules such as interleukin-1beta (IL-1beta) and IL-18. The nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome has been implicated in the development of idiopathic pulmonary fibrosis. This study was undertaken to assess the role of the inflammasome in SSc related dermal or pulmonary fibrosis. METHODS: Inflammasome gene transcripts were assayed in fibroblasts obtained from patients with SSc. Caspase 1 activation in SSc primary dermal and lung fibroblasts was inhibited, and the levels of hydroxyproline, COL1A1, COL3A1, IL-1beta, IL-18, and alpha-smooth muscle actin (alpha-SMA) were measured. The role of the inflammasome in dermal fibrosis was investigated in NLRP3(-/-) and ASC(-/-) mice. RESULTS: We identified increased expression of 40 genes associated with the inflammasome or downstream signaling molecules in SSc fibroblasts. Inhibition of caspase 1 in SSc dermal and lung fibroblasts abrogated the secretion of collagens, IL-1beta, and IL-18. In addition, we observed decreased expression of the myofibroblast protein alpha-SMA in SSc dermal fibroblasts treated with a caspase 1 inhibitor. Furthermore, NLRP3( /-) mice and ASC(-/-) mice were resistant to bleomycin-induced skin fibrosis, which suggests a key role for the inflammasome in in vivo fibrosis. CONCLUSION: Innate immune signaling contributes to SSc fibrosis via activation of the inflammasome and caspase 1. These results suggest that inflammasome activation may play an important role in the pathogenesis of SSc. PMID- 21792842 TI - Activated memory B cells may function as antigen-presenting cells in the joints of children with juvenile idiopathic arthritis. AB - OBJECTIVE: B cells impact the perpetuation of chronic inflammatory or autoimmune diseases in multiple ways. A role of B cells as antigen-presenting cells (APCs) in the pathogenesis of chronic arthritis in humans has been suggested; however, as of yet the presence of such B cells at the site of inflammation has not been demonstrated. This study was undertaken to investigate whether synovial B cells in patients with juvenile idiopathic arthritis (JIA) might display features of APCs. METHODS: The frequency, phenotype, and immunoglobulin repertoire of synovial B cells were studied by flow cytometry and single-cell polymerase chain reaction (PCR). Cytokine expression by B cells was analyzed by real-time PCR, and interaction between B cells and T cells was investigated in a mixed lymphocyte culture. RESULTS: CD27+IgD- and CD27-IgD- B cells accumulated in the joints of JIA patients and displayed an activated phenotype. Both B cell subsets expressed hypermutated and class-switched immunoglobulins, indicators of memory B cells. The accumulating memory B cells expressed the costimulatory molecules CD80/CD86 and showed a higher capacity to activate allogeneic T cells and prime a Th1 phenotype than their peripheral blood counterparts. CONCLUSION: Activated immunoglobulin class-switched CD27- and CD27+ memory B cells, indicating a phenotype of APCs with expression of costimulatory molecules, accumulate in the joints of patients with JIA and might be involved in the amplification of pathogenic T cell activation. These findings provide evidence that B cells play an antibody-independent immunopathologic role in human chronic inflammatory arthritis of childhood. PMID- 21792844 TI - Characterization of bent helical conformations in polymorphic forms of a designed 18-residue peptide containing a central Gly-Pro segment. AB - An 18-residue sequence Boc-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Gly-Pro-Val-Ala-Leu Aib-Val-Ala-Leu-Aib-OMe (UK18) was designed to examine the effect of introducing a Gly-Pro segment into the middle of a potentially helical peptide. The crystal structures of two polymorphic forms yielded a view of the conformation of three independent molecules. Form 1 (space group P2(1)2(1)2(1,) a = 14.620A; b = 26.506A, c = 28.858A, Z = 4) has one molecule in the asymmetric unit, with one cocrystallized water molecule. Form 2 (space group P2(1)2(1)2(1,) a = 9.696A; b = 19.641A, c = 114.31A, Z = 8) has two molecules in the asymmetric unit with four cocrystallized water molecules. In Form 1, residues 1 to 18 adopt phi,psi values that lie in the right-handed helical (alpha(R) ) region of the Ramachandran map. Two residues, Leu (8) (phi = -92.0 degrees , psi = -7.5 degrees ) and Leu (17) (phi = -94.7 degrees , psi = -1.7 degrees ) adopt conformations that deviate significantly from helical values. In Form 2, molecule A, residues 2 to 16 lie in the alpha(R) region of phi,psi space, with Leu (8) (phi = -94.9 degrees , psi = 2.9 degrees ) deviating significantly from helical values. Aib (1) and Aib (18) adopt left-handed (alpha(L)) helical conformation. Significant distortion is observed at Leu (17) (phi = -121.3 degrees , psi = -31.3 degrees ). Molecule B, Form 2, adopts a right-handed helix over residues 1 to 17. In all three molecules, a distinct bend in the helix is observed, with the bend angle values varying from 40.8 degrees to 58.9 degrees . PMID- 21792845 TI - An amyloidogenic determinant in N-terminal pro-brain natriuretic peptide (NT proBNP): Implications for cardiac amyloidoses. AB - Deposition of amyloid in the atria (isolated atrial/cardiac amyloid) is fairly common in the aging heart. It consists of amyloid fibrils, formed both by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the precursor molecule of ANP, proANP. This study examines whether amyloidogenic determinants (short peptides/amyloid forming favoring regions) exist in the sequence of NT proBNP, the N-terminal part of proBNP, and if these determinants form amyloid like fibrils in vitro. We have predicted a possible amyloidogenic determinant in the sequence of the NT-proBNP, and we conclusively show, after its synthesis, that it forms amyloid-like fibrils in vitro, utilizing transmission electron microscopy, X-ray diffraction, attenuated total reflectance Fourier-transform infrared spectroscopy, and polarizing microscopy. Thus, for the first time, in this study, a possible biological role is attributed to a certain, specific part of this important cardiac prohormone/natriuretic peptide, which acts as an important biomarker indicative of heart failure. Its possible direct involvement in isolated cardiac amyloidosis, atrial fibrillation, and other types of cardiac amyloidoses is indicated and discussed. Since these cardiac hormones and their prohormones play key roles in cardiovascular homeostasis through natriuresis, diuresis, vasorelaxation, and inhibition of renin and aldosterone secretion (pathophysiology of hypertension and cardiovascular regulation), we also try to suggest these specific, short peptides as possible future structural targets of efforts toward inhibiting formation of natriuretic peptide(s) amyloid. PMID- 21792847 TI - Pushing the limits of surgical management in patients with hepatocellular carcinoma. PMID- 21792846 TI - Computer modeling of nitroxide spin labels on proteins. AB - Electron paramagnetic resonance using site-directed spin labeling can be used as an approach for determination of protein structures that are difficult to solve by other methods. One important aspect of this approach is the measurement of interlabel distances using the double electron-electron resonance (DEER) method. Interpretation of experimental data could be facilitated by a computational approach to calculation of interlabel distances. We describe an algorithm, PRONOX, for rapid computation of interlabel distances based on calculation of spin label conformer distributions at any site of a protein. The program incorporates features of the label distribution established experimentally, including weighting of favorable conformers of the label. Distances calculated by PRONOX were compared with new DEER distances for amphiphysin and annexin B12 and with published data for FCHo2 (F-BAR), endophilin, and alpha-synuclein, a total of 44 interlabel distances. The program reproduced these distances accurately (r(2) = 0.94, slope = 0.98). For 9 of the 11 distances for amphiphysin, PRONOX reproduced the experimental data to within 2.5 A. The speed and accuracy of PRONOX suggest that the algorithm can be used for fitting to DEER data for determination of protein tertiary structure. PMID- 21792848 TI - Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria (Br J Surg 2011; 98: 1201 1208). PMID- 21792849 TI - Randomized clinical trial of ischaemic preconditioning in major liver resection with intermittent Pringle manoeuvre (Br J Surg 2011; 98: 1236-1243). PMID- 21792850 TI - Duration of hepatic vascular inflow clamping and survival after liver resection for hepatocellular carcinoma (Br J Surg 2011; 98: 1284-1290). PMID- 21792851 TI - Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria (Br J Surg 2011; 98: 1292-1300). PMID- 21792852 TI - Comparison of open and laparoscopic live donor left lateral sectionectomy (Br J Surg 2011; 98: 1302-1308). PMID- 21792853 TI - Long-term survival following delayed presentation and resection of colorectal liver metastases (Br J Surg 2011: 98: 1309-1317). PMID- 21792854 TI - Negative appendicectomy and perforation rates in patients undergoing laparoscopic surgery for suspected appendicitis (Br J Surg 2011; 98: 589-595). PMID- 21792856 TI - Optimal margins and lymphadenectomy in colonic cancer surgery (Br J Surg 2011; 98: 1171-1178). PMID- 21792858 TI - Logistic risk model for mortality following elective abdominal aortic aneurysm repair (Br J Surg 2011; 98: 652-658). PMID- 21792861 TI - Reported referral for genetic counseling or BRCA 1/2 testing among United States physicians: a vignette-based study. AB - BACKGROUND: Genetic counseling and testing is recommended for women at high but not average risk of ovarian cancer. National estimates of physician adherence to genetic counseling and testing recommendations are lacking. METHODS: Using a vignette-based study, we surveyed 3200 United States family physicians, general internists, and obstetrician/gynecologists and received 1878 (62%) responses. The questionnaire included an annual examination vignette asking about genetic counseling and testing. The vignette varied patient age, race, insurance status, and ovarian cancer risk. Estimates of physician adherence to genetic counseling and testing recommendations were weighted to the United States primary care physician population. Multivariable logistic regression identified independent patient and physician predictors of adherence. RESULTS: For average-risk women, 71% of physicians self-reported adhering to recommendations against genetic counseling or testing. In multivariable modeling, predictors of adherence against referral/testing included black versus white race (relative risk [RR], 1.16; 95% confidence interval [CI], 1.03-1.31), Medicaid versus private insurance (RR, 1.15; 95% CI, 1.02-1.29), and rural versus urban location. Among high-risk women, 41% of physicians self-reported adhering to recommendations to refer for genetic counseling or testing. Predictors of adherence for referral/testing were younger patient age [35 vs 51 years [RR, 1.78; 95% CI, 1.41-2.24]), physician sex (female vs male [RR, 1.30; 95% CI, 1.07-1.64]), and obstetrician/gynecologist versus family medicine specialty (RR, 1.64; 95% CI, 1.31-2.05). For both average-risk and high-risk women, physician-estimated ovarian cancer risk was the most powerful predictor of recommendation adherence. CONCLUSION: Physicians reported that they would refer many average-risk women and would not refer many high-risk women for genetic counseling/testing. Intervention efforts, including promotion of accurate risk assessment, are needed. PMID- 21792862 TI - Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is 1 of the most common and poorly treated tumors. In search of new therapeutic approaches, the oxygen sensors prolyl hydroxylases (PHD) are potential targets. PHD2 is considered the key oxygen sensor-regulating hypoxia-inducible factor (HIF). Currently, there is conflicting evidence regarding the exact role of PHD2 in tumorigenesis. The objective of this study was to investigate the role of PHD2 in pancreatic cancer growth and progression. METHODS: PHD2 expression was analyzed by quantitative real-time polymerase chain reaction analysis and immunohistochemistry in human tissue specimens and cell lines. Knockdown of PHD2 was done by using short-interfering RNAs (siRNAs) specific against PHD2, and PHD2 overexpression was achieved by stable combinational DNA transfection. In vivo, an orthotopic murine model was used. Angiogenic cytokines were assessed with enzyme-linked immunosorbent assays, and invasion was studied with Matrigel assays. RESULTS: PHD2 expression was not altered substantially in cancer tissues and their metastases. Lymph node-negative tissues had higher levels of PHD2 than lymph node-positive tissues. PHD2 was hypoxia-inducible in pancreatic cancer cell lines and regulated cell growth through cyclin D1 down-regulation samples with PHD2 suppression and through p21 up-regulation in samples with of PHD2 overexpression. In vivo, PHD2 caused tumor growth retardation and reduced tumor invasion by inhibiting angiogenesis. This observation was caused by the suppression of angiogenic cytokines and tumor invasion. CONCLUSIONS: The current results indicated that PHD2 plays an important role in pancreatic tumorigenesis. In summary, the authors concluded that PHD2 may function as a tumor suppressor gene in pancreatic cancer and, thus, may define a potential target for the treatment of pancreatic cancer. PMID- 21792863 TI - Cost-effectiveness of epidermal growth factor receptor mutation testing and first line treatment with gefitinib for patients with advanced adenocarcinoma of the lung. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach. METHODS: A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted. RESULTS: EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations. CONCLUSIONS: This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs. PMID- 21792864 TI - Hospital-level variation in the quality of urologic cancer surgery. AB - BACKGROUND: Unexplained variation in outcomes after common surgeries raises concerns about the quality and appropriateness of surgical care. Understanding variation in surgical outcomes may identify processes that could affect the quality of surgical and postoperative care. The authors of this report examined hospital-level variation in outcomes after inpatient urologic oncology procedures. METHODS: Patients who underwent radical cystectomy, radical nephrectomy, and radical prostatectomy were identified from the Washington State Comprehensive Hospital Abstract Reporting System for the years 2003 through 2007. The postoperative length of stay (LOS) was measured, and LOS that exceeded the 75th percentile was classified as prolonged. The occurrence of Agency for Healthcare Quality patient safety indicators (PSIs), readmissions, and deaths also were measured. Analyses were adjusted for patient age and comorbidity in random effects, multilevel, multivariable models that assessed hospital-level outcomes. RESULTS: The authors identified 853 patients from 37 hospitals who underwent cystectomy, 3018 patients who underwent nephrectomy from 51 hospitals, and 8228 patients who underwent prostatectomy from 51 hospitals. Complications captured by PSIs were rare. Hospital-level variation was most profound for LOS outcomes after nephrectomy and prostatectomy (variance in prolonged LOS, 8.1% and 26.7%, respectively), thromboembolic events after nephrectomy (8% of variance), and mortality after cystectomy (7.1% of variance). CONCLUSIONS: Hospital-level variation confounds the care of urologic cancer patients in the state of Washington. The authors concluded that transparent reporting of surgical outcomes and local quality-improvement initiatives should be considered to ameliorate the observed variation and improve the quality of cystectomy, nephrectomy, and prostatectomy care. PMID- 21792865 TI - Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design. AB - BACKGROUND: Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents. METHODS: The characteristics and outcome of refractory GCT patients enrolled in 7 single-agent phase 2 trials conducted at Memorial Sloan-Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all-transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression-free survival (PFS), and overall survival (OS). RESULTS: Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty-six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8-1.3) and 4.7 months (95% CI, 3.5-6.4), respectively. Eighty-six of the 90 patients have died. The 12- and 16-week PFS rates were 9% (95% CI, 3-15%) and 6% (95% CI, 1%-11%), respectively. CONCLUSIONS: Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve-week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. PMID- 21792866 TI - Bevacizumab and daily temozolomide for recurrent glioblastoma. AB - BACKGROUND: The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide. METHODS: There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty-two adult patients were enrolled. Patients received temozolomide 50 mg/m(2) daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks. RESULTS: The authors observed a 6-month progression-free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%-33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6-month OS rate was 62.5% (95% CI, 43.5%-76.7%), and the 12-month OS rate was 31.3% (95% CI, 16.4% 47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia. CONCLUSIONS: The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies. PMID- 21792870 TI - Immunology in Israel: society and research. PMID- 21792872 TI - TLR9 regulation by proteolysis: a friend or a foe. AB - Intracellular TLRs sense viral and bacterial nucleic acids from a wide variety of pathogens. Previous studies have shown that TLR9 requires processing for signalling. Following proteolysis, a fragment corresponding to the C-terminal part of TLR9 was shown to bind MyD88 and to induce signalling when cells were stimulated with TLR9 ligands. In this issue of the European Journal of Immunology, a study provides evidence that another proteolytic fragment of TLR9 is generated, different to that described previously, consisting of amino acids 1 723 which mediates inhibition of TLR9 signalling. These results suggest that proteolysis undoubtedly is a key step in TLR9 regulation. PMID- 21792873 TI - A missing link in thymic dendritic cell development. AB - Negative selection in the thymus prevents the generation of self-reactive T cells through the deletion of thymocytes with high affinity for self-antigens. Within the thymus, self-antigens are presented by thymic epithelial cells and DCs. Both cell types can mediate negative selection, although the relative contribution of each cell type remains elusive. Similar to DCs of other lymphoid organs, thymic DCs come in different flavors. Over the past years, various lines of evidence have emerged that either favor a common origin for some thymic DCs and thymocytes or, conversely, indicate the existence of separate intrathymic T lineage and DC precursors. In this issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T-cell progenitors. Thus this intrathymic DC precursor may constitute a "missing link" between extrathymic DC precursor-types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors. PMID- 21792874 TI - Bcl6: where too much complexity is barely enough. AB - Appropriate B-cell differentiation in response to antigen is fundamental to health. Central to the regulation of this process in circumstances of T-cell dependent immune responses is the transcriptional repressor Bcl6, which is required for germinal centre (GC) formation and function. Within GCs, Bcl6 is already known to regulate many functions including proliferation, assessing DNA damage and terminal differentiation. Targets of Bcl6 repression in B cells have been identified in a variety of systems with some, such as the reciprocal regulation of the Prdm1 gene encoding Blimp1, being particularly well studied and in effect becoming a model for the counter-regulation of Bcl6 and Blimp1 in a variety of cell types. A study in this issue of the European Journal of Immunology examines the regulatory network of Bcl6 in DT40, a chicken lymphoma, and reproduces some of the complexity of other species but also adds new targets for Bcl6 regulation, genes involved in class switch recombination and somatic hypermutation. While this increasing complexity may be daunting, it emphasises the critical importance of understanding how Bcl6 may integrate the multitude of processes occurring in GCs. PMID- 21792875 TI - Epistasis: the key to understanding immunological disease? AB - Epistasis is fast becoming central to the understanding of the complex relationship between genotype and phenotype observed in autoimmune disease. A study in this issue of the European Journal of Immunology uses in-depth analysis of genome-wide mapping by polymorphic microsatellite markers to shed light on the genomic control of autoimmunity and self-tolerance. PMID- 21792876 TI - Intradermal immunization in the ear with cholera toxin and its non-toxic beta subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs. AB - The nature of CD4(+) T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4(+) T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic beta CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-gamma and IL-17 by CD4(+) T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4(+) T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-gamma activity. These results indicate that both CT and CTB induce an efficient CD4(+) T-cell response to a co administered antigen following ear immunization that is dependent on migrating DCs. PMID- 21792877 TI - PD-L1 blockade overrides Salmonella typhimurium-mediated diabetes prevention in NOD mice: no role for Tregs. AB - Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella-modulated protective phenotype. We find that, contrary to other infection-mediated models of type 1 diabetes protection, there was no expansion of Foxp3(+) Tregs. Furthermore, transcriptome analysis of DCs identified a distinct Salmonella-induced signature in which the inhibitory receptor PD-L1 was up-regulated. This was confirmed by flow cytometry. In vivo blockade of the PD1/PD-L1 interaction was found to ablate the protective function of Salmonella infection. These data provide evidence for a novel regulatory DC phenotype proficient at controlling autoreactive T cells for an extended duration in the NOD mouse model of diabetes. PMID- 21792878 TI - SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function. AB - Autosomal-dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses and recurrent pulmonary infections. Given that STAT3 is involved in IL-10 signaling, we examined the immunoregulatory role of IL 10 in inflammation by studying the effects of IL-10 on monocytes, neutrophils and monocyte-derived DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL-10 showed reduced expression of IL1RN, which encodes IL-1 receptor antagonist (IL-1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti-inflammatory protein IL-1ra was reduced in AD HIES patients. DCs from HIES patients secreted higher levels of TNF-alpha, IL-6 and, to a lesser extent, IL-12 when these cells were cultured in the presence of IL-10. These results suggest that IL-10 activity is affected in myeloid cells (e.g. monocytes, DCs) of HIES patients. Impairment of IL-10 signaling in patients with AD-HIES might result in an altered balance between pro-inflammatory and anti inflammatory signals and might lead to persistent inflammation and delayed healing after infections. PMID- 21792879 TI - 1,25-Dihydroxyvitamin D3 enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression. AB - The active metabolite of vitamin D(3), 1alpha,25(OH)(2)D(3) , displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1alpha,25(OH)(2)D(3) increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1alpha,25(OH)(2)D(3) in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1alpha,25(OH)(2)D(3)-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1alpha,25(OH)(2)D(3) showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1alpha,25(OH)(2)D(3) showed significantly increased caspase activity. In addition to Fas up regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1alpha,25(OH)(2) D(3) . Increased expression of Hsp60 by 1alpha,25(OH)(2)D(3) was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1alpha,25(OH)(2)D(3) acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1alpha,25(OH)(2)D(3) treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy. PMID- 21792881 TI - Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells. AB - Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer. PMID- 21792882 TI - Human genetic variants of homologous recombination repair genes first found to be associated with Epstein-Barr virus antibody titers in healthy Cantonese. AB - Epstein-Barr virus (EBV) infection is a major risk factor for nasopharyngeal carcinoma (NPC). Despite high prevalence of infection among the general population worldwide, only a small proportion of infected individuals presents with seropositivity for EBV-specific IgA antibodies. This seropositive subgroup of EBV carriers has an elevated cumulative risk for NPC during their lifetime. Previous studies reported that the host homologous recombination repair (HRR) system participates in EBV lytic replication, suggesting a potential mechanism to influence EBV reactivation status and thus seropositivity. To investigate whether genetic variants of HRR genes are associated with the serostatus in a healthy population, we investigated the association between seropositivity for anti-VCA IgA and 156 tagging SNPs in 35 genes connected with HRR in an observational study among 755 healthy Cantonese speakers in southern China. Six variant alleles of MDC1, RAD54L, TP53BP1, RPA1, LIG3 and RFC1 exhibited associations with seropositivity (p(trend) from 0.0085 to 0.00027). Our study provides evidence that genetic variation within the HRR might affect an individual's propensity for EBV seropositive status of anti-VCA IgA antibody. PMID- 21792883 TI - Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. AB - Breast cancer is the most frequent cancer type among women in western countries. In addition to established risk factors like hormone replacement therapy, oxidative stress may play a role in carcinogenesis through an unbalanced generation of reactive oxygen species that leads to genetic instability. The aim of this study is to assess the influence of common single nucleotide polymorphisms (SNPs) in candidate genes related to oxidative stress on postmenopausal breast cancer risk. We genotyped 109 polymorphisms (mainly tagging SNPs) in 22 candidate genes in 1,639 postmenopausal breast cancer cases and 1,967 controls (set 1) from the German population-based case-control study "MARIE". SNPs showing association in set 1 were tested in further 863 cases and 2,863 controls from MARIE (set 2) using a joint analysis strategy. Six polymorphisms evaluated in the combined set showed significantly modified breast cancer risk per allele in the joint analysis, including SNPs in CYBA (encoding a subunit of the NADPH oxidase: rs3794624), MT2A (metallothionein 2A: rs1580833), TXN (thioredoxin: rs2301241), and in TXN2 (thioredoxin 2: rs2267337, rs2281082, rs4821494). Associations with the CYBA rs3794624 (OR per allele: 0.93, 95% CI 0.87-0.99) and TXN rs2301241 variants (OR per allele: 1.05, 95% CI 1.00-1.10) were confirmed in the summary risk estimate analysis using up to three additional studies. We found some evidence for association of polymorphisms in genes of the thioredoxin system, CYBA, and MT2A with postmenopausal breast cancer risk. Summary evidence including independent datasets indicated moderate effects in CYBA and TXN that warrant confirmation in large independent studies. PMID- 21792884 TI - Occupational and residential exposure to electromagnetic fields and risk of brain tumors in adults: a case-control study in Gironde, France. AB - The etiology of brain tumors remains largely unknown. Among potential risk factors, exposure to electromagnetic fields is suspected. We analyzed the relationship between residential and occupational exposure to electromagnetic field and brain tumors in adults. A case-control study was carried out in southwestern France between May 1999 and April 2001. A total of 221 central nervous system tumors (105 gliomas, 67 meningiomas, 33 neurinomas and 16 others) and 442 individually age- and sex-matched controls selected from general population were included. Electromagnetic field exposure [extremely low frequency (ELF) and radiofrequency separately was assessed in occupational settings through expert judgement based on complete job calendar, and at home by assessing the distance to power lines with the help of a geographical information system. Confounders such as education, use of home pesticide, residency in a rural area and occupational exposure to chemicals were taken into account. Separate analyses were performed for gliomas, meningiomas and acoustic neurinomas. A nonsignificant increase in risk was found for occupational exposure to electromagnetic fields [odds ratio (OR = 1.52, 0.92-2.51)]. This increase became significant for meningiomas, especially when considering ELF separately [OR = 3.02; 95 percent confidence interval (95% CI) =1.10-8.25]. The risk of meningioma was also higher in subjects living in the vicinity of power lines (<100 m), even if not significant (OR = 2.99, 95% CI 0.86-10.40). These data suggest that occupational or residential exposure to ELF may play a role in the occurrence of meningioma. PMID- 21792885 TI - Risk of prostate cancer is not associated with levels of C-reactive protein and other commonly used markers of inflammation. AB - Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). As these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation. A cohort based on four groups of men (n = 34,891), according to age at cohort entry (45, 55, 65 and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin and leukocytes were selected from the Apolipoprotein Mortality Risk database. A total of 17,937 men had measurements of non-high-sensitive CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa. A total of 49 of 12,063 men developed PCa in the age 45 group, whereas 207 of 9,940, 472 of 8,266 and 276 of 3,618 were diagnosed in the age 55, 65 and 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia and hypertriglyceridemia status. The studied markers were not found to be associated with PCa risk. These null findings might be due to methodological issues; however, it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies. PMID- 21792887 TI - Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies. AB - The nuclear factor kappa B (NFkappaB) pathway is essential for many human cancers. Therapeutics such as bortezomib (VelcadeTM) that interfere with NFkappaB signaling are of great clinical interest. NFkappaB signaling, however, is multifaceted and variable among tissues, developmental and disease entities. Hence, targeted biomarkers of NFkappaB pathways are of prime importance for clinical research. We developed a novel real-time qPCR-based NFkappaB array. Only mechanistically validated NFkappaB targets were included. We then used random forest classification to define individual genes and gene combinations within the NFkappaB pathways that define viral lymphoma subclasses as well as Kaposi sarcoma (KS). Few NFkappaB targets emerged that were universally present in all tumor types tested, underscoring the need for additional tumor-type specific biomarker discovery. (i) We uncovered tissue of origin-specific tumor markers, specifically CD69, CSF-1 and complement factor B (C1QBP) for primary effusion lymphoma (PEL); IL1-beta, cyclinD3 and CD48 for KS. We found that IL12, jun-B, msx-1 and thrombospondin 2 were associated with EBV co-infection in PEL. (ii) We defined the NFkappaB signature of Epstein-Barr virus (EBV) positive AIDS-associated Burkitt lymphoma (BL). This signature identified CCR5 as the key marker. (iii) This signature differed from EBV negative BL consistent with the idea that EBV not only activates NFkappaB activity but that this virus also reprograms NFkappaB signaling toward different targets. PMID- 21792888 TI - Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration. AB - There have been recent improvements in the treatment for metastatic renal cell carcinoma (RCC) with receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of Src kinase and the RTK may have synergistic effects to further improve therapies on metastatic RCC. The effects of Src kinase inhibitor saracatinib and multiple RTK inhibitor sunitinib on RCC cell line (ACHN) and Caki-1 were studied. Saracatinib alone or in combination with sunitinib inhibited the migration of ACHN and Caki-1 cells in vitro. Activation of migration related components FAK, P130Cas and Paxillin were blocked by saracatinib at 0.05- to 3-MUM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to sunitinib alone in the metastatic Caki-1 line. Molecular studies in Caki-1 showed that saracatinib alone and in combination with sunitinib inhibited phosphorylation of the cell progression regulator c-Myc in a dose-dependent manner. Sunitinib alone or in combination suppressed cyclin-D1 expression with the combination showing greater dose-dependent effect. Sunitinib inhibited vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 signaling and VEGF biosynthesis. HIF1-alpha expression in normoxic and hypoxic conditions in Caki-1 cells was inhibited by either saracatinib or sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting Src kinase and RTK simultaneously with saracatinib and sunitinib resulted in 70-80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki-1 cells. The results show promise for combination targeted therapy of RCC. PMID- 21792889 TI - Mechanisms of FGFR3 actions in endocrine resistant breast cancer. AB - Although endocrine therapy has dramatically improved the treatment of breast cancer therapeutic resistance and tumour recurrence occurs, even in estrogen receptor (ER) positive cases. Identifying and understanding the molecular mechanisms which underpin endocrine resistance is therefore important if future therapeutic strategies are to be developed. Members of the fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) families have been implicated in breast cancer development and progression. Our results demonstrate that culture of michigan cancer foundation - 1 (MCF)7 cells with FGF1 results in reduced sensitivity to tamoxifen in vitro. Furthermore, our tissue microarray expression data demonstrates that FGFR3 expression is increased in tamoxifen resistant breast tumours. To confirm that activation of FGFR3 reduced sensitivity to tamoxifen we used an inducible activation system and a constitutively active mutant of FGFR3 expressed in MCF7 cells. Activation of FGFR3 reduced sensitivity to tamoxifen and Fulvestrant but did not lead to phosphorylation of ER demonstrating that FGFR3 does not feedback to modulate ER activity. FGFR3 activation in MCF7 cells stimulated activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways, both of which have been implicated in tamoxifen resistance in breast cancer. Furthermore, our data indicates that activation of phospholipase C gamma is a key-signalling event regulating MAPK and PI3K activation and that its activation reduces sensitivity to tamoxifen. Therefore, we hypothesise that FGFRs could play an integral part, not only in breast cancer development but also in resistance to endocrine-therapy. PMID- 21792890 TI - Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma. AB - The protein C4.4A, a structural homologue of the urokinase-type plasminogen activator receptor, is a potential new biomarker in non-small cell lung cancer, with high levels of expression recently shown to correlate to poor survival of adenocarcinoma patients. In this study, C4.4A immunoreactivity in precursor lesions of lung squamous cell carcinoma and adenocarcinoma was investigated by stainings with a specific anti-C4.4A antibody. In the transformation from normal bronchial epithelium to squamous cell carcinoma, C4.4A was weakly expressed in basal cell hyperplasia but dramatically increased in squamous metaplasia. This was confined to the cell membrane and sustained in dysplasia, carcinoma in situ, and the invasive carcinoma. The induction of C4.4A already at the stage of hyperplasia could indicate that it is a marker of very early squamous differentiation, which aligns well with our earlier finding that C4.4A expression levels do not provide prognostic information on the survival of squamous cell carcinoma patients. In the progression from normal alveolar epithelium to peripheral adenocarcinoma, we observed an unexpected, distinct cytoplasmic staining for C4.4A in a fraction of atypical adenomatous hyperplasias, while most bronchioloalveolar carcinomas were negative. Likewise, only a fraction of the invasive adenocarcinomas was positive for C4.4A. With a view to the prognostic impact of C4.4A in adenocarcinoma patients, this finding might suggest that C4.4A could be an early biomarker for a possibly more malignant subtype of this disease. PMID- 21792891 TI - Genetic determinants of oxidative stress-mediated sensitization of drug-resistant cancer cells. AB - Drug resistance in cancer is an overwhelming problem, because drug-resistant cancer cells are harder to kill with the same drug. The mechanism of drug resistance differs for various cancers based on the type of drug being used for its treatment. Most current drugs are shown to increase reactive oxygen species (ROS) in respective cancer cells that induces apoptosis, but continuous treatment with the same drug may reduce cellular ROS levels and may convert drug sensitive cancer cells into drug resistant cells. In addition, exogenous elevation of ROS in conjunction with drug resensitizes drug-resistant cancer cells. Thus, constant maintenance of higher ROS level in cancer cells may be a prerequisite for drug efficacy in certain type of cancer cells. Thus, modulation of ROS-mediated genetic pathway genes could be an efficient alternative to maintain higher ROS level in cancer cells for "combinational chemotherapy" with the drug. In this review, I discuss whether ROS reduction in drug-resistant cancer cells could be a general mechanism of drug resistance for most cancers with its specific drug, and whether elevation of ROS levels with the drug could be a valuable strategy for increasing drug efficacy in most cancers. PMID- 21792892 TI - The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models. AB - Melanoma is a common and deadly tumor that upon metastasis to the central nervous system (CNS) has median survival duration of less than 5 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of cyclophosphamide (CTX) against melanoma, including disease within the CNS. The mechanisms of efficacy were investigated by tumor- and immune-mediated cytotoxic assays, in vivo evaluation of the reduction of regulatory T cells (Tregs) and by determining intratumoral p-STAT3 expression by immunohistochemistry. Combinational therapy of WP1066, with both metronomic and cytotoxic dosing of CTX, was investigated in a model system of systemic and intracerebral melanoma in syngeneic mice. Inhibition of p-STAT3 by WP1066 was enhanced with CTX in a dose-dependent manner. However, in mice with intracerebral melanoma, the greatest therapeutic benefit was seen in animals treated with cytotoxic CTX dosing and WP1066, whose median survival time was 120 days, an increase of 375%, with 57% long-term survivors. This treatment efficacy correlated with p-STAT3 expression levels within the tumor microenvironment. The efficacy of the combination of cytotoxic dosing of CTX with WP1066 is attributed to the direct tumor cytotoxic effects of the agents and has the greatest therapeutic potential for the treatment of CNS melanoma. PMID- 21792893 TI - Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms. AB - Bioflavonoids are of considerable interest to human health as these serve as antioxidant and anticancer agents. Although epidemiological and experimental studies suggest that luteolin, a natural bioflavonoid, exhibits chemopreventive properties, its effectiveness as an antiproliferative agent against multidrug resistant (MDR) cancers is unclear. Thus, we assessed the antiproliferative effects of luteolin and associated molecular mechanisms using two MDR cancer cell lines that express high levels of P-glycoprotein and ABCG2. In this article, we demonstrate that luteolin induces apoptosis in P-glycoprotein- and ABCG2 expressing MDR cancer cells without affecting the transport functions of these drug transporters. Analysis of various proliferative signaling pathways indicated that luteolin-induced apoptosis involves reactive oxygen species generation, DNA damage, activation of ATR -> Chk2 -> p53 signaling pathway, inhibition of NF-kB signaling pathway, activation of p38 pathway and depletion of antiapoptotic proteins. Importantly, use of luteolin in these analyses also identified specific molecular characteristics of NCI-ADR/RES and MCF-7/Mito(R) cells that highlight their different tissue origins. These results suggest that luteolin possesses therapeutic potential to control the proliferation of MDR cancers without affecting the physiological function of drug transporters in the body tissues. PMID- 21792894 TI - Role of BRCA1 in controlling mitotic arrest in ovarian cystadenoma cells. AB - Cancers that develop in BRCA1 mutation carriers are usually near tetraploid/polyploid. This led us to hypothesize that BRCA1 controls the mitotic checkpoint complex, as loss of such control could lead to mitotic errors resulting in tetraploidy/polyploidy and subsequent aneuploidy. We used an in vitro system mimicking premalignant conditions, consisting of cell strains derived from the benign counterparts of serous ovarian carcinomas (cystadenomas) and expressing SV40 large T antigen, conferring the equivalent of a p53 mutation. We previously showed that such cells undergo one or several doublings of their DNA content, as they age in culture and approach the phenomenon of in vitro crisis. Here, we show that such increase in DNA content reflects a cell cycle arrest possibly at the anaphase promoting complex, as evidenced by decreased BrdU incorporation and increased expression of the mitotic checkpoint complex. Down regulation of BRCA1 in cells undergoing crisis leads to activation of the anaphase promoting complex and resumption of growth kinetics similar to those seen in cells before they reach crisis. Cells recovering from crisis after BRCA1 down-regulation become multinucleated, suggesting that reduced BRCA1 expression may lead to initiation of a new cell cycle without completion of cytokinesis. This is the first demonstration that BRCA1 controls a physiological arrest at the M phase apart from its established role in DNA damage response, a role that could represent an important mechanism for acquisition of aneuploidy during tumor development. This may be particularly relevant to cancers that have a near tetraploid/polyploid number of chromosomes. PMID- 21792896 TI - Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? AB - Cancer stem cells (CSCs) are similar to normal stem cells in their ability to self-renew and to generate large populations of more differentiated descendants. In contrast to the hierarchical organization that is presumed to be the prevalent mode of normal tissue homeostasis, phenotypic plasticity allows cancer cells to dynamically enter into and exit from stem-cell states. The epithelial-mesenchymal transition (EMT) has been closely associated with the acquisition of both invasive and stem-cell properties in cancer cells. Thereby, EMT programs emerge as important regulators of phenotypic plasticity in cancer cells including their entrance into stem-cell states. Much is still to be learned about the regulation of EMTs through epigenetic mechanisms in cancer cells and the contributions that EMT programs make to normal tissue homeostasis. PMID- 21792897 TI - The cancer stem cell niche--there goes the neighborhood? AB - The niche is the environment in which stem cells reside and is responsible for the maintenance of unique stem cell properties such as self-renewal and an undifferentiated state. The heterogeneous populations which constitute a niche include both stem cells and surrounding differentiated cells. This network of heterogeneity is responsible for the control of the necessary pathways that function in determining stem cell fate. The concept that cancer stem cells, a subpopulation of cells responsible for tumor initiation and formation, reside in their own unique niche is quickly evolving and it is of importance to understand and identify the processes occurring within this environment. The necessary intrinsic pathways that are utilized by this cancer stem cell population to maintain both self-renewal and the ability to differentiate are believed to be a result of the environment where cancer stem cells reside. The ability of a specific cancer stem cell niche to provide the environment in which this population can flourish is a critical aspect of cancer biology that mandates intense investigation. This review focuses on current evidence demonstrating that homeostatic processes such as inflammation, epithelial to mesenchymal transition, hypoxia and angiogenesis contribute to the maintenance and control of cancer stem cell fate by providing the appropriate signals within the microenvironment. It is necessary to understand the key processes occurring within this highly specialized cancer stem cell niche to identify potential therapeutic targets that can serve as the basis for development of more effective anticancer treatments. PMID- 21792895 TI - Toward standardizing and reporting colorectal cancer screening indicators on an international level: The International Colorectal Cancer Screening Network. AB - The International Colorectal Cancer Screening Network was established in 2003 to promote best practice in the delivery of organized colorectal cancer screening programs. To facilitate evaluation of such programs, we defined a set of universally applicable colorectal cancer screening measures and indicators. To test the feasibility of data collection, we requested data on these variables and basic program characteristics from 26 organized full programs and 9 pilot programs in 24 countries. The size of the target population for each program varied considerably from a few thousand to 36 million. The majority of programs used fecal occult blood tests for primary screening, with more using guaiac than immunochemical tests. There was wide variation in the ability of screening programs to report the requested measures and in the values reported. In general, pilot programs were more likely to provide screening measure values than were full programs. As expected, detection rates for polyps and neoplasia were substantially higher in programs screening with endoscopy than in those using fecal occult blood tests. It is hoped that the screening measures and indicators, once revised in the light of this survey, will be adopted and used by existing programs and those in the early planning stages, allowing international comparison with the goal of improved colorectal cancer screening quality. PMID- 21792898 TI - The sole presence of CDK4 is not a solid criterion for discriminating between tumor and healthy pancreatic tissues. PMID- 21792899 TI - Toll-like receptor genes and their association with colon and rectal cancer development and prognosis. AB - Toll-like receptors (TLRs) are mediators of inflammation in the gut and potentially important modulators of colon and rectal cancer risk. We use data from a population-based study of incident colon cancer cases (n = 1,555) and controls (n = 1,956) and rectal cancer cases (n = 754) and controls (n = 959). We evaluate genetic variation in TLR2 (six SNPs), TLR3 (four SNPs) and TLR4 (eight SNPs) with risk of developing colon or rectal cancer and survival after diagnosis. TLR3 rs11721827 was associated with rectal cancer (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.02, 1.58 for AC/CC vs. AA genotype, Wald p = 0.035; adjusted p = 0.126); TLR3 rs3775292 and TLR4 rs11536898 were associated with colon cancer (OR 0.68, 95% CI 0.49, 0.95 for GG vs. CC/CG and OR 0.50. 95% CI 0.29, 0.87 for AA vs. CA/CC, respectively; Wald p = 0.023 and 0.015; adjusted p = 0.085 and 0.101, respectively). TLR2 rs7656411 and rs3804099, respectively, interacted with nonsteroidal anti-inflammatory drug (NSAID) use and cigarette smoking to alter risk of colon cancer (adjusted p = 0.034 and 0.077); TLR3 rs11721827 interacted with NSAID use to alter risk of colon cancer (adjusted p = 0.071). TLR3 rs3775292 interacted with dietary carbohydrates to alter colon cancer risk and with dietary carbohydrates and saturated fat to alter rectal cancer risk (adjusted p = 0.064, 0.0035 and 0.025, respectively). Multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival. Although few independent associations with TLR genes were observed, we observed significant interaction of TLR2 and TLR3 with hypothesized lifestyle factors. Interaction with dietary factors remained significant for rectal cancer after adjustment for multiple comparisons. PMID- 21792900 TI - Progress against cancer in the Netherlands since the late 1980s: an epidemiological evaluation. AB - Progress against cancer through prevention and treatment is often measured by survival statistics only instead of analyzing trends in incidence, survival and mortality simultaneously because of interactive influences. This study combines these parameters of major cancers to provide an overview of the progress achieved in the Netherlands since 1989 and to establish in which areas action is needed. The population-based Netherlands Cancer Registry and Statistics Netherlands provided incidence, 5-year relative survival and mortality of 23 major cancer types. Incidence, survival and mortality changes were calculated as the estimated annual percentage change. Optimal progress was defined as decreasing incidence and/or improving survival accompanied by declining mortality, and deterioration as increasing incidence and/or deteriorating survival accompanied by increasing mortality rates. Optimal progress was observed in 12 of 19 cancer types among males: laryngeal, lung, stomach, gallbladder, colon, rectal, bladder, prostate and thyroid cancer, leukemia, Hodgkin and non-Hodgkin lymphoma. Among females, optimal progress was observed in 12 of 21 cancers: stomach, gallbladder, colon, rectal, breast, cervical, uterus, ovarian and thyroid cancer, leukemia, Hodgkin and non-Hodgkin lymphoma. Deterioration occurred in three cancer types among males: skin melanoma, esophageal and kidney cancer, and among females six cancer types: skin melanoma, oral cavity, pharyngeal, esophageal, pancreatic and lung cancer. Our conceptual framework limits misinterpretations from separate trends and generates a more balanced discussion on progress. PMID- 21792901 TI - Administration of 6-gingerol greatly enhances the number of tumor-infiltrating lymphocytes in murine tumors. AB - Tumor-infiltrating lymphocytes (TILs) play critical roles in host antitumor immune responses. It is known that cancer patients with tumor-reactive lymphocyte infiltration in their tumors have better prognoses, while patients with tumors infiltrated by immunosuppressive cells have worse prognoses. We found that administration of 6-gingerol, which is a component of ginger, inhibited tumor growth in several types of murine tumors, such as B16F1 melanomas, Renca renal cell carcinomas and CT26 colon carcinomas, which were established by inoculating tumor cells on the flanks of mice. However, administration of 6-gingerol did not lead to complete eradication of the tumors. 6-Gingerol treatment of tumor-bearing mice caused massive infiltration of CD4 and CD8 T-cells and B220(+) B-cells, but reduced the number of CD4(+) Foxp3(+) regulatory T-cells. The CD8 tumor infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN gamma, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5. To test whether 6-gingerol could promote infiltration of tumor antigen-specific CD8 T-cells into tumors, we adoptively transferred CFSE-labeled OT-1 CD8 T-cells into EG7 tumor-bearing mice. We found that CD8 T cells isolated from 6-gingerol pretreated OT-1 mice, but not from control OT-1 mice, massively infiltrated tumors and tumor draining lymph nodes and divided several times. Our results strongly suggest that 6-gingerol can be used in tumor immunotherapy to increase the number of TILs. PMID- 21792904 TI - The requirement for proteomics to unravel stem cell regulatory mechanisms. AB - Stem cells are defined by their ability to self-renew and to differentiate, the processes whereby these events are achieved is the subject of much investigation. These studies include cancer stem cell populations, where eradication of this specific population is the ultimate goal of treatment. Whilst cellular signalling events and transcription factor complex-mediated changes in gene expression have been analysed in some detail within stem cells, full systematic understanding of the events promoting self-renewal or the commitment process leading to formation of a specific cell type require a systems biology approach. This in turn demands a need for proteomic analysis of post-translational regulation of protein levels, protein interactions, protein post-translational modification (e.g. ubiquitination, methylation, acetylation, phosphorylation) to identify networks for stem cell regulation. Furthermore, the phenomenon of induced pluripotency via cellular reprogramming also can be understood optimally using combined molecular biology and proteomics approaches; here we describe current research employing proteomics and mass spectrometry to dissect stem cell regulatory mechanisms. PMID- 21792906 TI - Towards gene therapy for deafness. AB - Many hearing disorders are associated with the damage or loss of sensory hair cells (HC) which can produce a profound and irreversible deafness. Apoptosis pathway is reported to play an important role leading to rapid expansion of the HC lesion after exposure to intense noise. Furthermore, progress made over the last year in understanding molecular mechanisms involved in the proliferative and regenerative capacity of sensory cells in the mammalian inner ear has raised the possibility that targeted therapies might prevent the loss of these cells and preserve the patient's hearing. A first step towards the successful therapeutic exploitation is a better understanding of the different pathways that control survival and proliferation of sensory cells. In this review, we provide an overview of recent findings concerning the possibility to prevent apoptosis in auditory cells. We also show the current knowledge on the molecular mechanisms involved in the potential regenerative behavior of these cells and the progress of gene therapy to prevent deafness noise-induced. PMID- 21792905 TI - Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. AB - Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5 kb human EAAT2 promoter showed that NF-kappaB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many beta-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a beta-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-kappaB signaling pathway. The NF-kappaB binding site at -272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration. PMID- 21792907 TI - Mospd1, a new player in mesenchymal versus epidermal cell differentiation. AB - Mospd1 codes for a small protein with unknown physiological function, which is part of a family of genes, including Mospd2 and Mospd3, defined by the presence of the major sperm protein domain and two transmembrane domains. This work characterizes the Mospd1 gene, the intracellular location of the protein and its expression in different mouse tissues and mesenchymal cell lines during differentiation. The role of Mospd1 in mesenchymal cellular differentiation was studied by siRNA knockdown experiments in mouse osteoblastic MC3T3-E1 cells. Transfection experiments of the targeted cDNA show MOSPD1 located in the endoplasmatic reticulum and in the Golgi apparatus. Removal of the last exon of the gene resulted in localization of the protein in the nucleus, which was attributed to a nuclear export sequence in the N-terminal part. In mouse tissues the gene was generally strongly expressed while mesenchymal tissues showed the highest expression. In mesenchymal cell lines Mospd1 mRNA was higher expressed in cells with advanced differentiation status. In osteoblastic, myoblastic, and adipocytic cell lines Mospd1 was up-regulated during differentiation. Genome-wide gene expression analysis after knockdown of Mospd1 by siRNA in MC3T3-E1 cells revealed a shift in the gene expression pattern from mesenchymal to epithelial genes featuring up-regulation of the epithelial cadherin Cdh1 and down-regulation of its inhibitors Snail1 and 2 and the mesenchymal cadherin Cdh11, suggesting a mesenchymal to epithelial transition. From these data we conclude that Mospd1 plays a pivotal role in the developmental regulation at the switch between mesenchymal and epithelial cells. PMID- 21792908 TI - ClC-3 is a main component of background chloride channels activated under isotonic conditions by autocrine ATP in nasopharyngeal carcinoma cells. AB - In this study, the activation mechanisms of the background chloride current and the role of the current in maintaining of basal cell volume were investigated in human nasopharyngeal carcinoma CNE-2Z cells. Under isotonic conditions, a background chloride current was recorded by the patch clamp technique. The current presented the properties similar to those of the volume-activated chloride current in the same cell line and was inhibited by chloride channel blockers or by cell shrinkage induced by hypertonic challenges. Extracellular applications of reactive blue 2, a purinergic receptor antagonist, suppressed the background chloride current in a concentration-dependent manner under isotonic conditions. Depletion of extracellular ATP with apyrase or inhibition of ATP release from cells by gadolinium chloride decreased the background current. Extracellular applications of micromolar concentrations of ATP activated a chloride current which was inhibited by chloride channel blockers and hypertonic solutions. Extracellular ATP could also reverse the action of gadolinium chloride. Transfection of CNE-2Z cells with ClC-3 siRNA knocked down expression of ClC-3 proteins, attenuated the background chloride current and prevented activation of the ATP-induced current. Furthermore, knockdown of ClC-3 expression or exposures of cells to ATP (10 mM), the chloride channel blockers 5-nitro-2-(3 phenylpropylamino) benzoic acid (NPPB) and tamoxifen, or reactive blue 2 increased cell volume under isotonic conditions. The results suggest that ClC-3 protein may be a main component of background chloride channels which can be activated under isotonic conditions by autocrine/paracrine ATP through purinergic receptor pathways; the background current is involved in maintenance of basal cell volume. PMID- 21792909 TI - Functional role of Rho-kinase in ameloblast differentiation. AB - During tooth development, inner enamel epithelial (IEE) cells differentiate into enamel-secreting ameloblasts, a polarized and elongated cellular population. The molecular underpinnings of this morphogenesis and cytodifferentiation, however, are not well understood. Here, we show that Rho-associated coiled-coil-containing protein kinase (ROCK) regulates ameloblast differentiation and enamel formation. In mouse incisor organ cultures, inhibition of ROCK, hindered IEE cell elongation and disrupted polarization of differentiated ameloblasts. Expression of enamel matrix proteins, such as amelogenin and ameloblastin, and formation of the terminal band structure of actin and E-cadherin were also perturbed. Cultures of dental epithelial cells revealed that ROCK regulates cell morphology and cell adhesion through localization of actin bundles, E-cadherin, and beta-catenin to cell membranes. Moreover, inhibition of ROCK promoted cell proliferation. Small interfering RNA specific for ROCK1 and ROCK2 demonstrated that the ROCK isoforms performed complementary functions in the regulation of actin organization and E cadherin-mediated cell-cell adhesion. Thus, our results have uncovered a novel role for ROCK in amelogenesis. PMID- 21792910 TI - Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon beta-induced inhibition of hepatic stellate cell proliferation. AB - Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN beta induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-beta down regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3'UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-beta. In conclusion, IFN-beta inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. PMID- 21792911 TI - Analysis of p53 and NF-kappaB signaling in modulating the cardiomyocyte fate during hypertrophy. AB - Cardiac hypertrophy leading to eventual heart failure is the most common cause of mortality throughout the world. The triggering mechanisms for cardiac hypertrophy are not clear but both apoptosis and cell proliferation have been reported in sections of failing hearts. In this study, we utilized both angiotensin II (AngII) treatment of cardiomyocytes and aortic ligation in rats (Rattus norvegicus, Wistar strain) for induction of hypertrophy to understand the cellular factors responsible for activation of apoptotic or anti-apoptotic pathway. Hypertrophy markers (ANF, beta-MHC), apoptotic proteins (Bax, Bad, Fas, p53, caspase-3, PARP), and anti-apoptotic or cell proliferation marker proteins (Bcl2, NF-kappaB, Ki-67) were induced significantly during hypertrophy, both in vitro as well as in vivo. Co-localization of both active caspase-3 and Ki-67 was observed in hypertrophied myocytes. p53 and NF-kappaBp65 binding to co-activator p300 was also increased in AngII treated myocytes. Inhibition of p53 resulted in downregulation of apoptosis, NF-kappaB activation, and NF-kappaB-p300 binding; however, NF-kappaB inhibition did not inhibit apoptosis or p53-p300 binding. Blocking of either p53 or NF-kappaB by specific inhibitors resulted in decrease in cell proliferation and hypertrophy markers, suggesting that p53 initially binds to p300 and then this complex recruits NF-kappaB. Thus, these results indicate the crucial role of p53 in regulating both apoptotic and cell proliferation during hypertrophy. PMID- 21792912 TI - The effect of endothelin-1 on Src-family tyrosine kinases and Na,K-ATPase activity in porcine lens epithelium. AB - Previous studies show Src family kinase (SFK) activation is involved in a response that stimulates Na,K-ATPase. Here, we tested whether SFK activation is involved in the Na,K-ATPase response to endothelin-1 (ET-1). Intact porcine lenses were exposed to 100 nM ET-1 for 5-30 min. Then, the epithelium was removed and used for Na,K-ATPase activity measurement and Western blot analysis of SFK activation. Na,K-ATPase activity was reduced by ~30% in lenses exposed to ET-1 for 15 min. The response was abolished by the SFK inhibitor PP2 or the ET receptor antagonist, PD145065. Activation of a ~61 kDa SFK was evident from an increase in Y416 phosphorylation, which reached a maximum at 15 min ET-1 treatment, and a decrease in Y527 phosphorylation. PP2 prevented SFK activation. Since Fyn, Src, Hck, and Yes may contribute to the observed 61 kDa band, these SFKs were isolated by immunoprecipitation and analyzed. Based on Y416 phosphorylation, ET-1 appeared to activate Fyn, while Src and Hck were inhibited and Yes was unaltered. ET-1 requires SFK activation to cause Na,K-ATPase inhibition. ET-1 elicits a different pattern of SFK activation from that reported earlier for purinergic agonists that stimulate Na,K-ATPase activity and activate Src. In the ET-1 response Src is inhibited and Fyn is activated. The findings suggest SFK phosphorylation is involved in a regulatory mechanism for Na,K ATPase. Knowing this may help us understand drug actions on Na,K-ATPase. Faulty regulation of Na,K-ATPase in the lens could contribute to cataract formation since an abnormal sodium content is associated with lens opacification. PMID- 21792913 TI - The metabolism of human mesenchymal stem cells during proliferation and differentiation. AB - Human mesenchymal stem cells (MSCs) reside under hypoxic conditions in vivo, between 4% and 7% oxygen. Differentiation of MSCs under hypoxic conditions results in inhibited osteogenesis, while chondrogenesis is unaffected. The reasons for these results may be associated with the inherent metabolism of the cells. The present investigation measured the oxygen consumption, glucose consumption and lactate production of MSCs during proliferation and subsequent differentiation towards the osteogenic and chondrogenic lineages. MSCs expanded under normoxia had an oxygen consumption rate of ~98 fmol/cell/h, 75% of which was azide-sensitive, suggesting that these cells derive a significant proportion of ATP from oxidative phosphorylation in addition to glycolysis. By contrast, MSCs differentiated towards the chondrogenic lineage using pellet culture had significantly reduced oxygen consumption after 24 h in culture, falling to ~12 fmol/cell/h after 21 days, indicating a shift towards a predominantly glycolytic metabolism. By comparison, MSCs retained an oxygen consumption rate of ~98 fmol/cell/h over 21 days of osteogenic culture conditions, indicating that these cells had a more oxidative energy metabolism than the chondrogenic cultures. In conclusion, osteogenic and chondrogenic MSC cultures appear to adopt the balance of oxidative phosphorylation and glycolysis reported for the respective mature cell phenotypes. The addition of TGF-beta to chondrogenic pellet cultures significantly enhanced glycosaminoglycan accumulation, but caused no significant effect on cellular oxygen consumption. Thus, the differences between the energy metabolism of chondrogenic and osteogenic cultures may be associated with the culture conditions and not necessarily their respective differentiation. PMID- 21792914 TI - Overexpression of gastrokine 1 in gastric cancer cells induces Fas-mediated apoptosis. AB - Gastrokine 1 (GKN1) is involved in the replenishment of the surface lumen epithelial cell layer, in maintaining the mucosal integrity, and could play a role in cell proliferation and differentiation. In fact, after injury of the gastric mucosa, restoration may occur very rapidly in the presence of GKN1. In contrast, if the protein is downregulated, the repair process may be hampered; however, application of GKN1 to gastrointestinal cells promoted epithelial restoration. Because GKN1 possesses some mitogenic effects on intestinal epithelial cells (IEC-6) whereas this protein was also capable of inhibiting proliferation in gastric cancer cells (MKN28), we decided to study its involvement in apoptosis to understand the role of GKN1 in the modulation of inflammatory damage or tumorigenesis in gastric mucosa. We found by cytofluorimetry, Western blot and RT-PCR that the overexpression of GKN1 in gastric cancer cell lines (AGS and MKN28) stimulated the expression of Fas receptor. Moreover, compared to control cells, a significant increase of apoptosis, evaluated by TUNEL, was observed when GKN1 transfected cells were treated with a monoclonal antibody (IgM) anti-Fas. The activation of Fas expression was also observed by the overexpression of GKN1 in other cancer cell lines. Moreover, in GKN1-overexpressing gastric cancer cells exposed to FasL, the activation of caspase-3 was also observed by Western blot and fluorescence assays. Our data represent the first report for GKN1 as modulator of apoptotic signals and suggest that GKN1 might play an important role for tissue repair during the early stages of neoplastic transformation. PMID- 21792915 TI - Long-term in vitro expansion of osteoarthritic human articular chondrocytes do not alter genetic stability: a microsatellite instability analysis. AB - In this study, we investigated genetic damage acquisition during in vitro culture of human osteoarthritic (OA) chondrocytes to evaluate their safety for use in regenerative medicine clinical applications. In particular, we have addressed the impact of long-term in vitro culture on simple sequence repeat stability, to evaluate the involvement of the mismatch repair system (MMR) in the accumulation of genetic damage. MMR, the main post-replicative correction pathway, has a fundamental role in maintaining genomic stability and can be monitored by assessing microsatellite instability (MSI). MMR activity has been reported to decrease with age not only in vivo, but also in vitro in relationship to culture passages. OA chondrocytes from seven donors were cultured corresponding to 13-29 population doublings. Aliquots of the cells were collected and analyzed for MSI at five DNA loci (CD4, VWA, FES, TPOX, and P53) and for MMR gene expression at each subculture. Genetic stability was confirmed throughout the culture period. MMR genes demonstrated a strong coordination at the transcriptional level among the different components; expression levels were very low, in accordance with the observed genetic stability. The reduced expression of MMR genes might underline no need for increasing DNA repair control in the culture conditions tested, in which no genetic damage was evidenced. These data argue for the safety of chondrocytes for cellular therapies and are encouraging for the potential use of in vitro expanded OA chondrocytes, supporting the extension of autologous cell therapy procedures to degenerative articular diseases. PMID- 21792916 TI - TGFBR3, a potential negative regulator of TGF-beta signaling, protects cardiac fibroblasts from hypoxia-induced apoptosis. AB - A lot of evidence indicates that cardiac fibroblasts are essential for maintaining the structure and function of heart. The present study examined whether TGFBR3 (transforming growth factor type III receptor, also known as betaglycan) could prevent hypoxia-induced injury in neonatal mice cardiac fibroblasts, if so, its possible molecular targets. MTT, electron microscopy and TUNEL assay were used to identify cell viability and apoptosis in neonatal mice cardiac fibroblasts. Results showed that hypoxia for 24 h markedly reduce cell viability by 49.8 +/- 8.9%, largely via apoptosis. However, hypoxia-induced apoptosis in cardiac fibroblasts were almost completely prevented by overexpression of TGFBR3. In the present study, hypoxia also induced TGF-beta1, p Smad2/3 expression, TGFBR1-TGFBR2 complex formation and collagen production in cardiac fibroblasts, which were attenuated substantially by TGFBR3 overexpression. TGFBR3 also reversed Bax up-regulation, Bcl-2 down-regulation and Caspase-3 activation induced by hypoxia in cardiac fibroblasts. Hypoxia or TGF beta1 itself triggered an increase of [Ca(2+) ](i) in cardiac fibroblasts, which were both inhibited by TGFBR3 overexpression. Taken together, our results indicate that TGFBR3 may act as a protective factor in apoptotic process of cardiac fibroblasts by negative regulation of TGF-beta signaling and represent a potential therapeutic target for heart remodeling after hypoxia injury. PMID- 21792917 TI - Expression and regulation of B7-H3 immunoregulatory receptor, in human mesothelial and mesothelioma cells: immunotherapeutic implications. AB - No treatment prolongs the survival of malignant mesothelioma (MM) patients. Since MM elicits anti-tumor host's immune responses, immunotherapy represents a promising strategy for its control. Immunomodulatory antibodies against components of the B7 family of immunomodulatory molecules that regulate T cell activation are being investigated in human malignancies including MM. The expression of B7-H3, a new component of the B7 family was investigated in primary cultures of human mesothelial cells (HMC) and in MM cell lines by flow cytometry and molecular analyses, and in MM tissues by immunohistochemistry. The role of DNA hypomethylating agents in modulating levels of B7-H3 expression in MM cells was also studied. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that B7-H3 mRNA was consistently detectable in mesothelial and MM cells investigated; however, real-time quantitative RT-PCR analyses showed highly heterogeneous levels of B7-H3 mRNA among investigated MM cells. The analysis of B7-H3 protein expression indicated that comparable levels of B7-H3 were expressed on both cell types. Treatment with the DNA hypomethylating agent 5-aza-2' deoxycytidine did not significantly affect the expression of B7-H3 mRNA in MM cells. In vivo, while B7-H3 was expressed in all 13 tumor biopsies of the epithelial variant, with high levels in 54% of cases, it was rarely detectable in spindle type MM in which 1/5 biopsies weakly expressed B7-H3. These findings suggest that B7-H3 is a promising target for new immunotherapeutic strategies in MM, with particular emphasis in the epithelial variant. PMID- 21792918 TI - Group X secreted phospholipase A2 specifically decreases sperm motility in mice. AB - Different mammalian secreted phospholipases A(2) (sPLA(2) s) are expressed in male reproductive organs and/or in sperm cells but their cellular functions are still not fully characterized. Because several reports indicate a link between cellular lipids and sperm motility, we have investigated the effect of mouse group IIA, IID, IIE, V, and X sPLA(2) s on sperm motility. Among these enzymes, only mouse group X sPLA(2) (mGX sPLA(2) ) acts as a potent inhibitor of sperm motility that decreases track speed (VCL) and lateral displacement of the head (ALH) of both noncapacitated and capacitated sperm. The inhibitory effect of mGX sPLA(2) is dependent on its enzymatic activity because (i) both the proenzyme form of mGX sPLA(2) (pro-mGX) and the H48Q mutant of mGX sPLA(2) have very weak enzymatic activity and are unable to modulate sperm motility and (ii) LY329722, a specific inhibitor of sPLA(2) s, blocks the inhibitory effect of mGX sPLA(2) . Moreover, mGX sPLA(2) exerts a gradual potency on sperm subpopulations with different velocities, an effect which may be linked to the heterogeneity of lipid composition in these sperm subpopulations. Finally, we found that endogenous mGX sPLA(2) released during spontaneous acrosome reaction modulates sperm motility of capacitated sperm. Together, our results suggest a new role of sPLA(2) in sperm physiology where the sPLA2 selects a sperm subpopulation for fertilization based on its effect on sperm motility. PMID- 21792919 TI - Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor. AB - To determine whether differences in LDLr behavior in extra-hepatic tissues and whether extra-hepatic receptors could differentially contribute to cholesterol homeostasis under physiological conditions, we evaluated the presence and regulation of LDLr from both a gender and an aging perspective. We used the brain cortex, the gastrocnemius, and the heart ventricle of 3- and 12-month-old male and female rats. We observed a protein decrease of total LDLr in 12-month-old female rat brains that was completely restored by 17-beta estradiol treatment. In the gastrocnemius, LDLr accumulates in the skeletal muscle in both male and female aged rats as a precursor probably due to a glycosylation impairment. In the heart, no modifications were observed in either older rats or rats of a specific gender. These data highlight a tissue-specific dysregulation of LDLr that is age- and gender-dependent. PMID- 21792920 TI - Tenascin-C enhances crosstalk signaling of integrin alphavbeta3/PDGFR-beta complex by SRC recruitment promoting PDGF-induced proliferation and migration in smooth muscle cells. AB - Migration and proliferation of smooth muscle cells (SMCs) are key events during neointimal formation in pathological conditions of vessels. Tenascin-C (TNC) is upregulated in the developing neointima of lesions. We evaluated the effects of TNC on responses of SMCs against platelet-derived growth factor (PDGF) stimulation. TNC coated on substrate promoted PDGF-BB-induced proliferation and migration of rat SMC cell line A10 in BrdU incorporation and transwell assays, respectively. Immunoblotting showed that TNC substrate enhanced autophosphorylation of PDGFR-beta after PDGF-BB stimulation. Integrin alphavbeta3 is known to be a receptor for TNC in SMCs. In immunofluorescence and immunoblot of integrin alphav subunit, clustering of alphav-positive focal adhesions and upregulated alphav expression were observed in the cells on TNC substrate. Immunoprecipitation using anti-integrin alphavbeta3 antibody demonstrated that PDGFR-beta and integrin alphavbeta3 were co-precipitated and that the relative amount of PDGFR-beta after the stimulation was increased by TNC treatment. TNC also promoted phosphorylation of focal adhesion kinase (FAK) at tyrosine (Y) 397 and Y925. The phosphorylated FAK was localized at focal adhesions in immunofluorescence. Phosphorylated SRC at Y418 was also seen at focal adhesions. Immunoprecipitation with alphav antibody showed increased SRC association with the integrin signaling complex in the cells on TNC after PDGF treatment. In the cells on TNC substrate, crosstalk signaling between integrin alphavbeta3 and PDGFR-beta could be amplified by SRC and FAK recruited to focal adhesions, followed by enhanced proliferation and migration of A10 cells by PDGF-BB. PMID- 21792921 TI - Thyroid hormone promotes insulin-induced glucose uptake by enhancing Akt phosphorylation and VAMP2 translocation in 3T3-L1 adipocytes. AB - The purpose of this study was to test a hypothesis that T3 promotes glucose uptake via enhancing insulin-induced Akt phosphorylation and VAMP2 translocation in 3T3-L1 adipocytes. T3 significantly enhanced insulin-induced phosphorylation of Akt, cytoplasma to cell membrane translocations of vesicle-associated membrane protein 2 (VAMP2) and glucose transporter 4 (GLUT4), and glucose uptake in adipocytes. Akt inhibitor X abolished the promoting effects of T3, suggesting that Akt activation is essential for T3 to enhance these insulin-induced events in adipocytes. Knockdown of VAMP2 using siRNA abrogated the effects of T3 on insulin-induced GLUT4 translocation and glucose uptake, suggesting that VAMP2 is an important mediator of these processes. These data suggest that T3 may promote glucose uptake via enhancing insulin-induced phosphorylation of Akt and subsequent translocations of VAMP2 and GLUT4 in 3T3-L1 adipocytes. Akt phosphorylation is necessary for the promoting effects of T3 on insulin stimulated VAMP2 translocation. Further, VAMP2 is essential for T3 to increase insulin-stimulated translocation of GLUT4 and subsequent uptake of glucose in adipocytes. PMID- 21792922 TI - Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction. AB - The molecular mechanisms underlying hypoxic pulmonary vasoconstriction (HPV) are not yet properly understood. Mitochondrial electron transport chain (ETC) and NADPH oxidase have been proposed as possible oxygen sensors, with derived reactive oxygen species (ROS) playing key roles in coupling the sensor(s) to the contractile machinery. We have recently reported that activation of neutral sphingomyelinase (nSMase) and protein kinase C zeta (PKCzeta) participate in the signalling cascade of HPV. Herein, we studied the significance of nSMase in controlling ROS production rate in rat pulmonary artery (PA) smooth muscle cells and thereby HPV in rat PA. ROS production (analyzed by dichlorofluorescein and dihydroethidium fluorescence) was increased by hypoxia in endothelium-denuded PA segments and their inhibition prevented hypoxia-induced voltage-gated potassium channel (K(V) ) inhibition and pulmonary vasoconstriction. Consistently, H(2) O(2) , or its analogue t-BHP, decreased K(V) currents and induced a contractile response, mimicking the effects of hypoxia. Inhibitors of mitochondrial ETC (rotenone) and NADPH oxidase (apocynin) prevented hypoxia-induced ROS production, K(V) channel inhibition and vasoconstriction. Hypoxia induced p47(phox) phosphorylation and its interaction with caveolin-1. Inhibition of nSMase (GW4869) or PKCzeta prevented p47(phox) phosphorylation and ROS production. The increase in ceramide induced by hypoxia (analyzed by immunocytochemistry) was inhibited by rotenone. Exogenous ceramide increased ROS production in a PKCzeta sensitive manner. We propose an integrated signalling pathway for HPV which includes nSMase-PKCzeta-NADPH oxidase as a necessary step required for ROS production and vasoconstriction. PMID- 21792923 TI - Decorin and chondroitin-6 sulfate inhibit B16V melanoma cell migration and invasion by cellular acidification. AB - In vivo, cells are embedded in an environment generated and maintained by multiple cell-cell and cell-matrix interactions. While transiting the dermis metastasizing melanoma cells interact with the extracellular matrix (ECM) and fibroblasts. To study the roles of ECM components and fibroblasts in melanoma (B16V) cell migration and invasion, we established a co-culture system consisting of fibroblasts, their collagen-rich matrix and B16V cells. The crosstalk between B16V cells and fibroblasts was indicated by a clear increase in release and activity of matrix-metallo-protease-2. Time-lapse microscopy revealed that in B16V cells exposed to either decorin or chondroitin sulfates migration and invasion decreased by more than 50%. Decorin led to a reversible, chondroitin-6 sulfate to an irreversible, cytosolic acidification of B16V cells. Interestingly, decorin lowered NHE1 activity whereas chondroitin-6-sulfate did not. Furthermore, decorin and chondroitin-6-sulfate also acidified the pH at the cell surface which might prevent migration due to strong adhesion. In conclusion, the present co culture system is an appropriate tool to analyze migration, invasion, and MMP release depending on cell-matrix interactions and the crosstalk between the invasive cells and those surrounded by their self-made matrix. We show a so far unknown function of decorin and chondroitin-6-sulfate: their ability to inhibit B16V cell migration by intracellular acidification. PMID- 21792924 TI - Proteomic and functional analysis of human sperm detergent resistant membranes. AB - Mammalian spermatozoa attain the ability to fertilize an oocyte as they negotiate the female reproductive tract. This acquisition of functional competence is preceded by an intricate cascade of biochemical and functional changes collectively known as "capacitation." Among the universal correlates of the capacitation process is a remarkable remodeling of the lipid and protein architecture of the sperm plasma membrane. While the mechanisms that underpin this dynamic reorganization remain enigmatic, emerging evidence has raised the prospect that it may be coordinated, in part, by specialized membrane microdomains, or rafts. In the present study we have demonstrated that human spermatozoa express recognized markers of membrane rafts. Further, upon depletion of membrane cholesterol through either physiological (capacitation) or pharmacological (methyl-beta-cyclodextrin) intervention, these membrane rafts appear to undergo a polarized redistribution to the peri-acrosomal region of the sperm head. This finding encourages speculation that membrane rafts represent platforms for the organization of proteins involved in sperm-oocyte interactions. Support for this notion rests with the demonstration that membrane rafts isolated on the basis of their biochemical composition in the form of detergent resistant membranes (DRMs), possess the ability to adhere to homologous zona pellucidae. Furthermore a comprehensive proteomic analysis of the DRMs identified a number of proteins known for their affinity for the zona pellucida in addition to other candidates putatively involved in the mediation of downstream binding and/or fusion with the oolemma. Collectively these data afford novel insights into the subcellular localization and potential functions of membrane rafts in human spermatozoa. PMID- 21792926 TI - TGFbeta receptor activation enhances cardiac apoptosis via SMAD activation and concomitant NO release. AB - Transforming growth factor beta (TGFbeta) expression is induced in the myocardium during transition from compensated hypertrophy to heart failure. In cardiomyocytes, stimulation with TGFbeta results in restricted contractile function and enhanced apoptosis. Nitric oxide (NO) also induces apoptosis and influences cardiac function. Therefore, we wanted to know whether NO is causally involved in TGFbeta-induced apoptosis. In isolated ventricular cardiomyocytes of adult rat incubation with TGFbeta(1) increased NO release which was inhibited by NOS inhibitor ETU but not with iNOS inhibitor (1400 W) or nNOS inhibitor (TFA). In addition, TGFbeta-induced apoptosis was blocked with ETU and ODQ, but not with 1400 W or TFA. The consequent assumption that endothelial NOS is involved in TGFbeta-induced NO formation and apoptosis was supported by increased phosphorylation of eNOS at serine 1177 and by the fact that TGFbeta did not increase NO release in eNOS KO mice. Furthermore, TGFbeta-induced apoptosis, NO formation, SMAD binding activity and SMAD2 phosphorylation were blocked by a TGFbeta receptor antagonist, but only apoptosis and NO formation could be blocked with ETU. Expression of SMAD7 was increased after TGFbeta stimulation and blocked with TGFbeta receptor antagonist but not after blocking NO synthase with ETU. CONCLUSION: In cardiomyocytes TGFbeta-induced apoptosis is mediated via TGFbeta receptor activation that concomitantly activates SMAD transcription factors and the eNOS/NO/sGC pathway. Both of these pathways are needed for apoptosis induction by TGFbeta. This reveals a new pathway of cardiac NO release and identifies NO as a possible contributor to heart failure progression mediated by TGFbeta. PMID- 21792925 TI - How dynein and microtubules rotate the nucleus. AB - In living cells, a fluctuating torque is exerted on the nuclear surface but the origin of the torque is unclear. In this study, we found that the nuclear rotation angle is directionally persistent on a time scale of tens of minutes, but rotationally diffusive on longer time scales. Rotation required the activity of the microtubule motor dynein. We formulated a model based on microtubules undergoing dynamic instability, with tensional forces between a stationary centrosome and the nuclear surface mediated by dynein. Model simulations suggest that the persistence in rotation angle is due to the transient asymmetric configuration of microtubules exerting a net torque in one direction until the configuration is again randomized by dynamic instability. The model predicts that the rotational magnitude must depend on the distance between the nucleus and the centrosome. To test this prediction, rotation was quantified in patterned cells in which the cell's centrosome was close to the projected nuclear centroid. Consistent with the prediction, the angular displacement was found to decrease in these cells relative to unpatterned cells. This work provides the first mechanistic explanation for how nuclear dynein interactions with discrete microtubules emanating from a stationary centrosome cause rotational torque on the nucleus. PMID- 21792927 TI - Smooth muscle phenotypic diversity is mediated through alterations in myocardin gene splicing. AB - Myocardin (MYOCD) is a smooth and cardiac muscle-specific transcriptional coactivator that is required for the proper expression of contraction-related genes. Through its function to transactivate effector genes, MYOCD plays an essential role in mediating the switch between contractile and non-contractile phenotypes, particularly in smooth muscle cells (SMC). There are at least two known transcript variants of MYOCD that are expressed in SMC, differing only by the presence (+) or absence (Delta) of Exon 11. To date, no functional role has been assigned to the domain encoded by Exon 11, nor have any notable differences between the ability of each isoform to activate contraction-related genes been observed. In this study we compared sequences for Exon 11 among several mammalian species and identified a highly conserved, putative target sequence for glycogen synthase kinase 3 (GSK3) phosphorylation, suggesting a regulatory role for Exon 11 that can be modulated by alternative splicing. The function of Exon 11 was investigated by altering MYOCD splice selection in cultured porcine SMC with small interfering RNAs (siRNA) and specific chemical inhibitors, resulting in a relative increase in expression of DeltaExon 11 variants in the endogenous pool of MYOCD mRNA. The relative increase in DeltaExon 11 mRNAs correlated with a reduction of contractile phenotype in the porcine SMC as evidenced by morphological assessment and molecular analysis of effector genes. Together, these data suggest that MYOCD DeltaExon 11 may participate in modulating SMC phenotype, potentially acting as a dominant-negative repressor of contraction related genes. PMID- 21792929 TI - The anti-cancer effects of (-)-epigallocatechin-3-gallate on the signaling pathways associated with membrane receptors in MCF-7 cells. AB - (-)-Epigallocatechin-3-gallate (EGCg) has been implicated in cancer chemo prevention in studies using many different kinds of cancer cells. The present study measured cell viability, osteopontin (OPN) secretion, fatty acid synthase (FAS) expression, and cytosolic Ca(2+) and verified the anti-cancer activities of EGCg in MCF-7 human breast cancer cells. EGCg-induced apoptosis was evidenced by nuclear condensation, increased protein levels of activated caspase-3, down regulation of gelsolin and tropomyosin-4 (Tm-4), and up-regulation of tropomyosin 1(Tm-1). By disrupting adherens junction formation, EGCg caused accumulation of extra-nuclear beta-catenin aggregates in the cytosol and alterations of the protein content and mRNA expression of E-cadherin and beta-catenin, but not N cadherin, in MCF-7 cells. To identify the putative mechanisms underlying the EGCg signaling pathways, EGFP (enhanced green fluorescence protein) was ectopically expressed in MCF-7 cells. This allowed us to monitor the EGCg-induced fluorescence changes associated with the effects of Triton X-100 (to remove plasma membrane) or the addition of laminin, anti-laminin receptor (LR) antibody, epidermal growth factor (EGF), and genistein on the cells. Our results indicated that EGCg acts via the signaling pathways associated with cell membrane to suppress cell proliferation, provoke apoptosis, and disturb cell-cell adhesion in MCF-7 cells. The altered events include the EGFR, LR, FAS, intracellular Ca(2+) , OPN secretion, caspace-3, gelsolin, Tm-4, Tm-1, and adherens junction proteins, E cadherin and beta-catenin. PMID- 21792928 TI - Folic acid improves acetylcholine-induced vasoconstriction of coronary vessels isolated from hyperhomocysteinemic mice: an implication to coronary vasospasm. AB - Human atherosclerotic coronary vessels elicited vasoconstriction to acetylcholine (Ach) and revealed a phenomenon of vasospasm. Homocysteine (Hcy) levels are elevated in the atherosclerotic plaque tissue, suggesting its pathological role in endothelial damage in atherosclerotic diseases. Accordingly, we examined the role hyperhomocysteinemia in coronary endothelial dysfunction, vessel wall thickness, lumen narrowing, leading to acute/chronic coronary vasospasm. The therapeutic potential and mechanisms of folic acid (FA) using hyperhomocysteinemic cystathionine beta synthase heterozygote (CBS-/+) and wild type (CBS+/+) mice were addressed. The CBS-/+ and CBS+/+ mice were treated with or without a Hcy lowering agent FA in drinking water (0.03 g/L) for 4 weeks. The isolated mouse septum coronary artery was cannulated and pressurized at 60 mmHg. The wall thickness and lumen diameters were measured by Ion-Optic. The vessels were treated with Ach (10(-8) -10(-5) M) and, for comparison, with non endothelial vasodilator sodium nitroprusside (10(-5) M). The endothelium impaired arteries from CBC-/+ mice constricted in response to Ach and this vasoconstriction was mitigated with FA supplementation. The level of endothelial nitric oxide synthase (eNOS) was lower in coronary artery in CBS-/+ than of CBS+/+ mice. Treatment with FA increased the levels of Ach-induced NO generation in the coronary artery of CBS-/+ mice. The results suggest that Ach induced coronary vasoconstriction in CBS-/+ mice and this vasoconstriction was ameliorated by FA treatment. The mechanisms for the impairment of vascular function and therapeutic effects of FA may be related to the regulation of eNOS expression, NO availability and tissue homocysteine. PMID- 21792930 TI - Heat shock factor 4a (HSF4a) represses HSF2 expression and HSF2-mediated transcriptional activity. AB - Heat shock factors (HSFs) are the main transcriptional regulators of the stress induced expression of heat shock protein genes. HSF2, which is one of the HSFs, is activated during differentiation and development but it is unclear how they regulate during cellular processes. Here, we examined the role of HSF4a on the regulation of HSF2 in HEK 293 cells. We found that HSF2 levels are negatively correlated with HSF4a expression and that overexpression of HSF4a reduces hemin induced HSF2 mRNA and protein levels. Moreover, hemin-induced activation of HSF2 was also markedly inhibited in HSF4a expressed cells. Immunoprecipitation assay showed that HSF2 binds to the oligomerization domain of HSF4a. Hemin treatment inhibited their interaction and induced localization of HSF2 and HSF4a in nuclear. In addition, we found that HSF4a or HSF4a DNA binding domain (117 aa) inhibited the activity of hemin-induced HSP70 promoter. Consequently, HSF4a inhibits HSF2 expression or transcriptional activity through negative regulation of HSF2 binding to the HSP70 promoter. In summary, our findings suggest novel mechanisms of HSF2 regulation controlled by HSF4a. PMID- 21792931 TI - Basigin interacts with both MCT1 and MCT2 in murine spermatozoa. AB - Lactate is provided to spermatogenic cells by Sertoli cells as an energy substrate and its transport is regulated by H(+)-monocarboxylate co-transporters (MCTs). In the case of several cell types it is known that MCT1 is associated with basigin and MCT2 with embigin. Here we demonstrate co-localization and co immunoprecipitation of basigin with both MCT1 and MCT2 in sperm, whereas no interaction with embigin was detectable. An investigation of the functional activity of MCT proteins revealed that it was mainly the application of L-lactate which resulted in a decrease in pH(i) . The pH(i) changes were blocked with alpha cyano-4-OH cinnamate and the preference for L-lactate-as opposed to D-Lactate-was demonstrated by the determination of ATP after exposure to both lactate isomers. We propose that basigin interacts with MCT1 and MCT2 to locate them properly in the membrane of spermatogenic cells and that this may enable sperm to utilize lactate as an energy substrate contributing to cell survival. PMID- 21792933 TI - Seeing the smoking gun: a sensitive and specific method to visualize loss of the tumour suppressor, fumarate hydratase, in human tissues. AB - In this issue of the Journal of Pathology, Bardella et al report a method for identifying tumours that lack fumarate hydratase. The approach they use is immunodetection of proteins that have been modified by a non-enzymatic reaction of thiol groups in proteins with fumarate, which is termed succination. Validation included the use of mice with targeted inactivation of fumarate hydratase in the kidney, extensive studies of normal human tissues and examination of over 1000 specimens from human cancers not associated with FH mutations. Detection of protein succination is likely to provide a sensitive and specific method for pathologists to identify the small proportion of papillary renal cell carcinomas that are associated with germline mutations in the FH gene. PMID- 21792932 TI - Extracellular matrix deposited by synovium-derived stem cells delays replicative senescent chondrocyte dedifferentiation and enhances redifferentiation. AB - The aim of this study was to assess the effect of extracellular matrix (ECM) deposited by synovium-derived stem cells (SDSCs) on articular chondrocyte expansion and maintenance of differentiation status and redifferentiation capacity. Passage 0 (P0) pig articular chondrocytes were expanded for six passages on plastic flasks (Plastic), SDSC-derived ECM (ECM), or substrate switching from either Plastic to ECM (PtoE) or ECM to Plastic (EtoP). Cell morphology, gene expression profiles, and immunophenotypes at each passage were used to characterize differentiation status of expanded cells. Chondrocytes at P0, P2, and P6 were assessed for redifferentiation capacity in a pellet culture system treated with either TGF-beta1- or serum-containing medium for 14 days, using histology, immunohistochemistry, biochemistry, Western blot, and real-time PCR. We found that ECM not only greatly enhanced chondrocyte expansion but also delayed dedifferentiation of expanded chondrocytes. Intriguingly, compared to a dramatic decrease in CD90+/CD105+ cells and CD90+ cells, CD105+ cells dramatically increased when chondrocytes were plated on Plastic; on the contrary, ECM expansion dramatically increased CD90+ cells and delayed the decrease of CD90+/CD105+ cells. Interestingly, expanded chondrocytes on ECM also acquired a strong redifferentiation capacity, particularly in the pellets treated with TGF beta1. In conclusion, the ratio of CD90 to CD105 may serve as a marker indicative of proliferation and redifferentiation capacity of dedifferentiated chondrocytes. ECM deposited by SDSCs provides a tissue-specific three-dimensional microenvironment for ex vivo expansion of articular chondrocytes while retaining redifferentiation capacity, suggesting that ECM may provide a novel approach for autologous chondrocyte-based cartilage repair. PMID- 21792934 TI - Using next-generation sequencing for the diagnosis of rare disorders: a family with retinitis pigmentosa and skeletal abnormalities. AB - Linkage analysis with subsequent candidate gene sequencing is typically used to diagnose novel inherited syndromes. It is now possible to expedite diagnosis through the sequencing of all coding regions of the genome (the exome) or full genomes. We sequenced the exomes of four members of a family presenting with spondylo-epiphyseal dysplasia and retinitis pigmentosa and identified a six-base pair (6-bp) deletion in GNPTG, the gene implicated in mucolipidosis type IIIgamma. The diagnosis was confirmed by biochemical studies and both broadens the mucolipidosis type III phenotype and demonstrates the clinical utility of next-generation sequencing to diagnose rare genetic diseases. PMID- 21792936 TI - The novel insights into spatiotemporal cell biology and its schematic frame, triple W. AB - Numerous research results have suggested that the events occurred in a selected cell target and the fates of the cells are spatiotemporally regulated. It has been paying much attention to study the cell events with spatiotemporal proposal designation and analysis. We have been tracking and thinking the new scientific area for many years. Spatiotemporal cell biology and its schematic frame, triple W (when, where, which), are systemically introduced in this study. The triple W under pathological conditions is also discussed. PMID- 21792935 TI - The inflammatory response of keratinocytes and its modulation by vitamin D: the role of MAPK signaling pathways. AB - The hormonal form of vitamin D, calcitriol, and its analogs are known for their beneficial effect in the treatment of inflammatory skin disorders. Keratinocytes play a role in epidermal inflammatory responses invoked by breeching of the epidermal barrier, by infectious agents and by infiltrating immune cells. We studied the role of calcitriol in the initiation of keratinocyte inflammatory response by the viral and injury mimic polyinosinic-polycytidylic acid (poly(I:C)) and in its maintenance by tumor-necrosis-factor alpha (TNFalpha) and investigated the role of the mitogen-activated protein kinase cascades in these processes and their regulation by calcitriol. The inflammatory response of human HaCaT keratinocytes to poly(I:C) or TNFalpha was assessed by measuring mRNA levels of 13 inflammation-related molecules by real-time PCR microarray and by in depth investigation of the regulation of interleukin 8, intercellular-adhesion molecule 1, and TNFalpha expression. We found that while calcitriol had only a minor effect on the keratinocyte response to poly(I:C) and a modest effect on the early response (2 h) to TNFalpha, it markedly attenuated the later response (16 24 h) to TNFalpha. The expression of CYP27B1, the enzyme responsible for calcitriol production, was marginally increased by poly(I:C) and markedly by TNFalpha treatment. This pattern suggests that while allowing the initial keratinocyte inflammatory response to proceed, calcitriol contributes to its timely resolution. Using pharmacological inhibitors we found that while the p38 MAPK and the extracellular signal-regulated kinase have only a minor role, c-Jun N-terminal kinase plays a pivotal role in the induction of the pro-inflammatory genes and its modulation by calcitriol. PMID- 21792937 TI - Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1. AB - The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers. PMID- 21792938 TI - Blood derived stem cells: an ameliorative therapy in veterinary ophthalmology. AB - Stem cell technology has evoked considerable excitement among people interested in the welfare of animals, as it has suggested the potential availability of new tools for several pathologies, including eye disease, which in many cases is considered incurable. One such example is ulcerative keratitis, which is very frequent in horses. Because some of these corneal ulcers can be very severe, progress rapidly and, therefore, can be a possible cause of vision loss, it is important to diagnose them at an early stage and administer an appropriate treatment, which can be medical, surgical, or a combination of both. The therapeutic strategy should eradicate the infection in order to reduce or stop destruction of the cornea. In addition, it should support the corneal structures and control the uveal reaction, and the pain associated with it, in order to minimize scarring. In this study, we address how stem cells derived from peripheral blood can be used also in ophthalmological pathologies. Our results demonstrate that this treatment protocol improved eye disease in four horse cases, including corneal ulcers and one case of retinal detachment. In all cases, we detected a decrease in the intense inflammatory reaction as well as the restoration of the epithelial surface of the central cornea. PMID- 21792939 TI - Galectin-3 is a new MerTK-specific eat-me signal. AB - Phagocytosis of apoptotic cells and cellular debris is a critical process of maintaining tissue and immune homeostasis. Defects in the phagocytosis process cause autoimmunity and degenerative diseases. Phagocytosis ligands or "eat-me" signals control the initiation of the process by linking apoptotic cells to receptors on phagocyte surface and triggering signaling cascades for cargo engulfment. Eat-me signals are traditionally identified on a case-by-case basis with challenges, and the identification of their cognate receptors is equally daunting. Here, we identified galectin-3 (Gal-3) as a new MerTK ligand by an advanced dual functional cloning strategy, in which phagocytosis-based functional cloning is combined with receptor-based affinity cloning to directly identify receptor-specific eat-me signal. Gal-3 interaction with MerTK was independently verified by co-immunoprecipitation. Functional analyses showed that Gal-3 stimulated the phagocytosis of apoptotic cells and cellular debris by macrophages and retinal pigment epithelial cells with MerTK activation and autophosphorylation. The Gal-3-mediated phagocytosis was blocked by excessive soluble MerTK extracellular domain and lactose. These results suggest that Gal-3 is a legitimate MerTK-specific eat-me signal. The strategy of dual functional cloning with applicability to other phagocytic receptors will facilitate unbiased identification of their unknown ligands and improve our capacity for therapeutic modulation of phagocytic activity and innate immune response. PMID- 21792940 TI - The living-tissue microscope: the importance of studying stem cells in their natural, undisturbed microenvironment. AB - Advances in stem cell research highlight the importance of analysing multicellular interactions in vivo before modelling them in cell culture systems. Gain-of-function assays such as transplantation are useful, but are not equivalent to studying cells in their natural, undisturbed microenvironment. PMID- 21792941 TI - The ratio of intra-tumoral regulatory T cells (Foxp3+)/helper T cells (CD4+) is a prognostic factor and associated with recurrence pattern in gastric cardia cancer. AB - BACKGROUND: TILs have been reported to be a prognostic factor in human cancers. We assessed the prognostic significance of tumor-infiltrating regulatory T cells in gastric cardia cancer. METHODS: We retrospectively reviewed the database of Severance Hospital for patients who underwent curative resection of gastric cardia cancer from Jan 2000 to Dec 2006 and identified 180 patients. Immunohistochemistry for TIL subsets was performed against CD3, CD4, CD8, Foxp3, and granzyme B in the resected tumor specimens. The absolute numbers and relative ratios of positively stained lymphocytes for each subset were evaluated. RESULTS: A high Foxp3/CD4 ratio was identified as an unfavorable prognostic factor for overall survival (OS) using univariate and multivariate analysis of all immunologic variables. Patients group with high Foxp3/CD4 ratio was associated with loco-regional recurrence (P = 0.033). In multivariate analysis for clinical and immunologic variables, the nodal status (hazards ratio--HR: 3.863, confidence interval--CI: 1.664-8.966, P = 0.002), depth of invasion (HR: 3.607, CI: 1.443 9.019, P = 0.006), and Foxp3/CD4 ratio (HR: 1.812, CI: 1.022-3.212, P = 0.042) were identified as independent prognostic factors for OS. CONCLUSIONS: A higher regulatory T cells/helper T cells ratio is associated with an unfavorable prognosis and loco-regional recurrence pattern in gastric cardia cancer. PMID- 21792942 TI - Is advanced hepatocellular carcinoma amenable of cure by liver transplantation with sorafenib as a neoadjuvant approach plus m-TOR inhibitors monotherapy? PMID- 21792943 TI - Safety and efficacy of hepatectomy for colorectal metastases in the elderly. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the safety and efficacy of hepatic metastasectomy in elderly patients with colorectal liver metastases (CLM). METHODS: A retrospective review of a hepatobiliary database was performed on consecutive patients treated with metastasectomy for CLM. Patients were stratified by age (<70 years old vs. >=70). Patient and tumor characteristics as well as operative factors were compared, as were morbidity, mortality, and length of stay. Logistic regression and Cox proportional hazards were used to evaluate the association of age and postoperative outcomes. RESULTS: There were 59 elderly (median age 75) and 220 non-elderly (median age 58) patients analyzed over a 13 year period. The Charlson comorbidity index was higher in the elderly group (mean 4.7 vs. 4.4 P = 0.005). Postoperative morbidity and mortality were 52.5 and 0% vs. 48.2 and 4.1% in the elderly and non-elderly groups, respectively (P = 0.56 and P = 0.21). There were no differences in median DFS (21.8 months vs. 28.9 months; P = 0.157) or OS (36 months vs. 47.7 months; P = 0.070) between the elderly and non-elderly groups, respectively. CONCLUSIONS: Age itself does not appear to be a significant contraindication to liver resection, including major hepatectomy, when patients are appropriately selected. PMID- 21792944 TI - False-negative sentinel node biopsy in melanoma. PMID- 21792945 TI - Negative impact of leakage on survival of patients undergoing curative resection for advanced gastric cancer. AB - BACKGROUND AND OBJECTIVES: Leakage has been shown to adversely affect survival in patients undergoing surgery for gastrointestinal malignancies. However, the effect of leakage following radical gastrectomy in patients with gastric cancer remains unclear. METHODS: In total, 478 patients with advanced gastric cancer who underwent surgery with curative intent were reviewed. Anastomosis or duodenal stump leakage was diagnosed clinically or radiologically. Risk factors for leakage were evaluated by univariate and multivariate analyses. The impact of leakage on patient survival was analyzed using the Kaplan-Meier method. RESULTS: Leakage was diagnosed in 32 of 478 patients (6.7%); 14 patients (2.9%) exhibited esophagojejunal anastomotic leakage, 14 (2.9%) showed duodenal stump leakage, and four (0.8%) showed gastroduodenal anastomotic leakage. Poor performance status [odds ratio (OR): 4.01, 95% confidence interval (CI): 1.80-8.93] and tumor location (OR: 3.74, 95% CI: 1.56-8.89) were risk factors for postoperative leakage. Overall mean survival of patients with leakage was significantly lower than that of patients without leakage (30.5 vs. 96.2 months; P < 0.001). Leakage was one of the independent predictive factor for overall survival [hazard ratio (HR): 3.58, 95% CI: 2.29-5.59]. CONCLUSIONS: Postoperative inflammation due to leakage is a negative prognostic factor for patients with advanced gastric cancer. PMID- 21792947 TI - Does concomitant mastoidectomy improve outcomes for patients undergoing repair of tympanic membrane perforations? PMID- 21792948 TI - Anterior pedicle lateral nasal wall flap: a novel technique for the reconstruction of anterior skull base defects. AB - OBJECTIVES: Expansion of the clinical indications for ablative endoscopic endonasal approaches has behooved us to search for new reconstruction alternatives. We present the anatomic foundations of a novel anterior pedicled lateral wall flap (Hadad-Bassagaisteguy 2 or HB2 flap) for the vascularized reconstruction of anterior skull base defects. STUDY DESIGN: Anatomic description. Feasibility study. Technical report METHODS: Using a cadaveric model, we investigated the feasibility of harvesting an anteriorly based mucoperiosteal flap from the lateral nasal wall. We then applied the techniques developed in the anatomical laboratory to reconstruct two patients with defects resulting from the endoscopic endonasal resection of esthesioneuroblastomas and one patient with an extensive meningoencephalocoele of the anterior cranial fossa. RESULTS: HB2 flaps were harvested and transposed to reconstruct anterior skull base defects in cadaveric specimens, and subsequently, in three patients. The HB2 flap provided adequate coverage in the cadaveric model, as well as clinically in our three patients. Their postoperative healing was uneventful. CONCLUSIONS: The HB2 flap is a feasible alternative for the reconstruction of anterior skull base defects in select patients. PMID- 21792949 TI - Sutureless repair of the facial nerve using biodegradable glass fabric. AB - OBJECTIVES/HYPOTHESIS: To compare a sutureless method of facial nerve repair using a biodegradable glass fabric with the standard method of microsurgical suture. STUDY DESIGN: The facial nerve was transected in groups of six sheep and repaired by either entubulation with a biodegradable glass fabric or standard microsurgical epineurial suture repair. METHODS: Both methods of repair were compared with each other and with a normal control group using electrophysiological and morphometric analysis. RESULTS: Maximum conduction velocity, axon and fiber diameter, and myelin-sheath thickness were all reduced in the repaired nerves when compared with the normal nerves. There was no significant difference among any of the outcome variables between the repair groups. CONCLUSIONS: Repair of nerve injuries by entubulation has several theoretical advantages over standard suture repair: less trauma to nerve ends, no need for microsurgical skills, and delivery of neurotrophic growth factors. It is concluded that repair of the facial nerve by glass-wrap entubulation offers an alternative to standard suture repair without the demands of microsurgery on both time and surgical expertise. PMID- 21792950 TI - The laryngeal mask airway and otorhinolaryngology head and neck surgery. AB - OBJECTIVES/HYPOTHESIS: To review the use of the laryngeal mask airway (LMA) in otorhinolaryngology, as well as the advantages and disadvantages across the range of procedures typically performed. STUDY DESIGN: Contemporary review. METHODS: Published articles identified through PubMed, Medline, and conference proceedings were reviewed. RESULTS: With only minimal stimulation of the oropharyngeal airway at the time of insertion and removal, the LMA provides safe, hands-free airway maintenance and is ideally suited to many of the procedures performed in otorhinolaryngology. CONCLUSIONS: The relationship between surgeon and anesthetist is particularly strong in otorhinolaryngology. The impact of airway management on the surgical field and perioperative conditions requires the surgeon to be aware of contemporary tools and techniques available. The LMA has been shown to be safe and efficacious by both the literature and clinical practice. Its use in selected patients should be encouraged. PMID- 21792951 TI - Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies. AB - Varicella zoster virus (VZV) infection of the head and neck region may present with various clinical symptoms, involving different entities and different routes of viral spreading. We present a case of VZV infection of the pharynx and larynx with multiple cranial nerve (CN) neuropathies (CN VII, VIII, IX, and X) of a 52 year-old woman who complained of the sudden onset of hoarseness, odynophagia, dysphagia, and hearing loss in the left ear, followed by left-side facial weakness lasting for 1 week. Endoscopic examination revealed multiple mucosal erosions over the oropharynx, with extension upward to the nasopharynx and downward to the mucosa overlying the epiglottis, arytenoid, and vocal cord. All of these lesions tended to lateralize to the left side, suggesting a VZV infection diagnosis; this was confirmed by polymerase chain reaction on eruptional exudates, as well as serologic examination. PMID- 21792952 TI - Recruitment patterns of side population cells during wound healing in rat vocal folds. AB - OBJECTIVES/HYPOTHESIS: Despite big advances in understanding the mechanisms of wound healing in vocal fold injury, it still remains unclear which are the decisive factors that lead to a complete restoration or to scarring. Among several other factors, stem cells are believed to play an important role in vocal fold restoration. Side population (SP) cells are considered to contain high numbers of stem cells and have gained great interest in the tissue engineering community. The aim of the following study was to investigate the recruitment pattern of SP cells in a rat vocal fold injury model. STUDY DESIGN: Experimental animal study. METHODS: Unilateral vocal fold scarring was performed in Sprague Dawley rats. Larynges were harvested 1, 3, 5, 7, 14, 21, and 35 days after initial injury and were examined immunohistochemically for the presence of SP cells. This was done in coronal sections of the posterior and anterior macula flava as well as in the midportion of the vocal fold investigating the lamina propria. RESULTS: The number of SP cells peaked significantly after 7 days in the midportion of injured vocal folds, with a return to pre-injury levels after 14 days. No increase was detected throughout the observed time in the contralateral side. The number of SP cells increased slightly but not significantly in both anterior and posterior macula flava. CONCLUSIONS: Our findings suggest that SP cells may play an important role in early vocal fold wound healing and may serve as a possible therapeutic target. PMID- 21792953 TI - Transoral robotic resection and reconstruction for head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: To evaluate the patterns of failure, survival, and functional outcomes for patients treated with transoral robotic surgery (TORS) and compare these results with those from a cohort of patients treated with concurrent chemoradiation (CRT). STUDY DESIGN: Prospective non-randomized case control study. METHODS: Between April 2007 and April 2009, 30 patients with head and neck squamous cell carcinoma were treated with primary TORS and adjuvant therapy as indicated on an institutional review board-approved protocol. Patients were evaluated before treatment, after treatment, and at subsequent 3-month intervals after completing treatment to determine their disease and head and neck specific functional status using the Performance Status Scale for Head and Neck Cancer and the Functional Oral Intake Score (FOIS). Functional scores were compared to a matched group of head and neck patients treated with primary CRT. RESULTS: The TORS patient population included 73% stage III-IV and 23% nonsmokers. The median follow-up was 20.4 months (range, 12.8-39.6 months). The 18-month locoregional control, distant control, disease-free survival, and overall survival were 91%, 93%, 78%, and 90%, respectively. Compared to the primary CRT group, TORS was associated with better short-term eating ability (72 vs. 43, P = .008), diet (43 vs. 25, P = .01), and FOIS (5.5 vs. 3.3, P < .001) at 2 weeks after completion of treatment. In contrast to TORS patients who returned to baseline, the CRT group continued to have decreased diet (P = .03) and FOIS (P = .02) at 12 months. CONCLUSIONS: Our early experience in treating selected head and neck cancers with TORS is associated with excellent oncologic and functional outcomes that compare favorably to primary CRT. PMID- 21792954 TI - Meta-analysis of minimally invasive video-assisted thyroidectomy. AB - OBJECTIVES: The aim of this study is to compare minimally invasive video-assisted thyroidectomy (MIVAT) to conventional thyroidectomy. STUDY DESIGN: A systematic review of the literature and meta-analysis. METHODS: All published prospective controlled trials that compared MIVAT to conventional thyroidectomy were identified. The trials data were extracted and statistical analyzed using Statsdirect 2.5.7. RESULTS: Five trials were identified. The total number of patients was 318. The primary outcome measures were pain, postoperative hypocalcaemia, and postoperative recurrent laryngeal nerve palsy. There was no difference in rates of postoperative hypocalcaemia or postoperative recurrent laryngeal nerve palsy between the techniques. Reported pain scores at 24 hours were significantly lower in MIVAT compared to conventional surgery. Pooled effect size was -4.496 (95% confidence interval [CI] = -7.146 to -2.045, P = .0004). The secondary outcome measures were operative time, blood loss, and cosmesis. There was significant improvement in patient reported scores for cosmesis with MIVAT. The pooled effect size was 3.669 (95% CI 0.636-60.702, P = .0178). MIVAT was associated with a significant increase in operative time. Pooled effect size was 1.681 (95% CI 0.600-2.762, P = .0023). There was no difference in blood loss between the groups. CONCLUSIONS: This study demonstrates that MIVAT is as safe as the existing gold standard operation. Furthermore, it has better cosmetic and pain outcomes for patients when compared to conventional surgery. MIVAT is a promising new technique, with obvious benefits over the established surgery, for small-volume thyroid disease that mainly affects a young female patient population. PMID- 21792955 TI - Diagnosis and treatment of congenital dilatation of Stensen's duct. AB - OBJECTIVES/HYPOTHESIS: This study aimed to describe the diagnosis and management of congenital dilation of Stensen's duct (CDSD) in seven cases. STUDY DESIGN: Retrospective study. METHODS: We collected data including medical records, radiology, and histopathology findings and follow-up for seven patients (four males) with CDSD. The mean age was 23.9 years (range, 2-72 years). RESULTS: The clinical features of CDSD were the primary presentation of painless swelling in the cheek without an obvious cause that was unilateral or bilateral and occurred at any age, and a swelling along Stensen's duct. In patients without a history of inflammation, aggressive massage of the swelling could produce abundant intraoral salivary flow. Parotid sialography demonstrated a dilated Stensen's duct with a smooth margin but no obvious obstruction. All seven patients underwent superficial parotidectomy including the intact Stensen's duct. No patient showed recurrent swelling after a follow-up of 6 to 65 months. CONCLUSIONS: CDSD is an uncommon congenital disorder of the parotid gland. Management with parotidectomy is effective. PMID- 21792956 TI - Immunohistochemical characterization of human olfactory tissue. AB - OBJECTIVES/HYPOTHESIS: The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction. STUDY DESIGN: An immunohistochemical analysis of human olfactory tissue using a comprehensive battery of proven antibodies. METHODS: Human olfactory mucosa obtained from 21 autopsy specimens was analyzed with immunohistochemistry. The position and extent of olfactory mucosa was assayed by staining whole mounts (WMs) with neuronal markers. Sections of the OE were analyzed with an extensive group of antibodies directed against cytoskeletal proteins and transcription factors, as were surgical specimens from an esthesioneuroblastoma. RESULTS: Neuron-rich epithelium is always found inferior to the cribriform plate, even at advanced age, despite the interruptions in the neuroepithelial sheet caused by patchy respiratory metaplasia. The pattern of immunostaining with our antibody panel identifies two distinct types of basal cell progenitors in human OE similar to rodents. The panel also clarifies the complex composition of esthesioneuroblastoma. CONCLUSIONS: The extent of human olfactory mucosa at autopsy can easily be delineated as a function of age and neurologic disease. The similarities in human versus rodent OE will enable us to translate knowledge from experimental animals to humans and will extend our understanding of human olfactory pathophysiology. PMID- 21792957 TI - The results of temporal bone surgery for advanced or recurrent tumors of the parotid gland. AB - OBJECTIVES/HYPOTHESIS: To describe the results of temporal bone surgery in managing advanced or recurrent tumors of the parotid gland. STUDY DESIGN: Retrospective review. METHODS: Patients with advanced or recurrent tumors involving the parotid gland who underwent either mastoidectomy or temporal bone resection were reviewed for treatment outcomes. RESULTS: Forty-nine patients were identified who required either mastoidectomy (n = 33) or temporal bone resection (n = 16) for malignancies involving the parotid gland. Facial nerve sacrifice was required in 35 patients (71.4%). Perineural invasion was found in 51.1% of patients; and negative margins were achieved in 78.2% patients. Six of 10 patients presenting with normal facial function (House-Brackmann I) and recurrent tumors maintained normal facial function following salvage surgery. Trismus, tumors larger than 4 cm, and the need for mandibulectomy were significantly correlated with higher recurrence rates (P = .025, P = .004, and P = .002, respectively). Patients with preoperative House-Brackmann I or II had a lower risk for recurrence (P = .035) and more favorable survival at 3 years (P = .024). Patients who required parapharyngeal space dissection and those with metastatic neck disease had the poorest survival rates. The overall survival at 3 years was 72.4%. CONCLUSIONS: Mastoidectomy and temporal bone resection permit preservation of the facial nerve when oncologically safe; they may help to achieve negative margins, and they allow facial nerve grafting when nerve sacrifice is required. Despite the poor prognostic indicators of facial paralysis, recurrent tumors, and perineural invasion, a significant number of patients can be salvaged successfully when a temporal bone procedure is combined with parotidectomy. PMID- 21792958 TI - Tracheal autotransplantation: guidelines for optimal functional outcome. AB - OBJECTIVES/HYPOTHESIS: Tracheal autotransplants can repair extensive hemilaryngectomy defects. This technique was introduced into the clinic some 10 years ago as a means of avoiding the mutilation of a total laryngectomy in selected patients with laryngeal cancer. Our goal was to give the morphometric guidelines that guarantee an optimal functional outcome. STUDY DESIGN: Retrospective case study. METHODS: We morphometrically evaluated the structure and function of the larynx after autotransplantation. The close anatomic relationship between the larynx and the trachea made it possible to perform a morphometric analysis of the defect and the repair tissue before and after transplantation. Computed tomography images were used to measure the laryngeal and tracheal airway lumen and the length and width of the tracheal autotransplant. A 4-cm long cartilaginous tracheal transplant was available for reconstruction. RESULTS: Laryngeal repair was achieved with optimal restoration of the airway lumen at all laryngeal levels. We used the maximal amount of trachea that might reasonably be available for autotransplantation. This optimal morphologic repair led to the restoration of speech, swallowing, and respiratory functions. CONCLUSIONS: This study highlights a standardized approach for repairing a hemilaryngeal defect and selecting the appropriate amount of repair tissue. A unique characteristic of vascularized cartilaginous trachea is that it restores the airway lumen after extensive hemilaryngectomy. Tracheal autotransplantation should be included in the armamentarium of reconstructive laryngeal procedures. PMID- 21792959 TI - A new method of nasal dermoplasty (MW grafting method) in patients with large septal perforation. AB - Nasal dermoplasty is effective in controlling epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). Skin graft take failure occurs mostly in cases of large septal perforation. The MW method was developed as a modification of nasal dermoplasty designed for patients with HHT having a large septal perforation. It seems to be a safe and effective approach and should be tried for recurrent bleeders with septal perforation. PMID- 21792960 TI - Association between Epstein-Barr virus seroconversion and immunohistochemical changes in tonsils of pediatric solid organ transplant recipients. AB - OBJECTIVES/HYPOTHESIS: Assess whether changes in Epstein-Barr virus (EBV) serology status relates to immunohistochemical evidence of active EBV infection in tonsillar tissue of pediatric organ transplant recipients. Children who seroconvert from EBV seronegative to seropositive status following organ transplantation are more likely to develop evidence of active EBV tonsillar infection than those who do not seroconvert. Active EBV infection is a potential early precursor of post-transplantation lymphoproliferative disorder (PTLD), a life- and/or organ-threatening disease. STUDY DESIGN: Retrospective analysis of pathology specimens and EBV serology titers of pediatric organ transplant recipients at a tertiary care academic medical center. METHODS: Immunohistochemical staining of tonsillectomy specimens and analysis of EBV serology titers were performed on 47 post-transplantation children. Eligible patients included those under age 21 years referred for tonsillectomy who had undergone solid organ transplantation. Data reviewed included gender, age at transplantation, age at tonsillectomy, interval between organ transplantation and tonsillectomy, and type of organ transplanted. EBV was detected in tonsil specimens by in situ hybridization for EBV-encoded small nuclear RNA (EBV-EBER), an indicator of active EBV infection, and EBV-encoded latent membrane protein (EBV-LMP), an indicator of latent EBV infection. Immunohistochemical staining of B-cell clonality was performed for kappa and lambda light chains. EBV serologies pre- and post-transplantation were obtained from electronic medical record data. RESULTS: Forty-seven children having tonsillectomy following solid organ transplantation were included. Of the 47 patients, 25 (53.5%) were EBV seronegative both before transplantation and at the time of tonsillectomy, eight (17.0%) were EBV seronegative prior to transplantation but converted to EBV seropositivity in the early (<= 6 months) post-transplantation period, eight (17.0%) were seronegative prior to transplantation but converted to EBV seropositive in the late (>= 6 months) post-transplantation period, and six (12.8%) were EBV seropositive prior to transplantation and remained so at the time of tonsillectomy. Overall, 20 specimens (42.6%) were positive for EBV-EBER, and three specimens (6.4%) were positive for EBV-LMP. There was significant difference in the percentage of EBV-EBER positive specimens among the four groups (P = .020). One out of eight (12.5%) of the early seroconversion group had specimens showing EBV-EBER, wheras seven out of eight (87.5%) of the late seroconversion group had tonsil specimens showing EBV-EBER (P = .005). There was no significant difference in presence of EBV-LMP among the four groups (P = .667). CONCLUSIONS: Almost one half of post-transplantation children undergoing tonsillectomy have evidence of active EBV tonsillar infection, which was more likely in children who seroconverted from EBV-seronegative to EBV-seropositive in the late post-transplantation period than those who seroconverted in the early post-transplantation period. Based on these novel findings, continued surveillance of EBV status and adenotonsillar hypertrophy in this population should include monitoring of pretransplantation EBV status and timing of seroconversion. PMID- 21792961 TI - Optimal concentration of hepatocyte growth factor for treatment of the aged rat vocal fold. AB - OBJECTIVES/HYPOTHESIS: Hepatocyte growth factor (HGF) demonstrates beneficial properties in the treatment of aged vocal folds. However, the optimal concentration of HGF remains unknown. The purpose of the present study was to investigate the effects of HGF concentration on treatment of the aged rat vocal fold. STUDY DESIGN: Prospective animal study. METHODS: Seventy-five rats were studied. The rats were divided into five groups and received serial injections of HGF in 10 MUL of phosphate-buffered saline (PBS) at the following concentrations: 10 ng/10 MUL, 50 ng/10 MUL, 100 ng/10 MUL, 200 ng/10 MUL, or control (PBS only). Alcian blue staining was performed to investigate hyaluronan (HA), and immunohistochemistry was performed to investigate collagen type I and III. Gene expression of hyaluronic acid synthase (HAS)-1, -2, matrix metalloproteinases (MMP)-2, -9, and procollagen I and III were also investigated using real-time polymerase chain reaction (RT-PCR). RESULTS: Histologic analyses revealed increased HA and decreased collagen type I in rats receiving injections of HGF at 100 ng/10 MUL. Results were supported by RT-PCR revealing upregulated expression of HAS-2, decreased expression of procollagen I, and a significant increase of MMP-9 mRNA in rats receiving HGF at 100 ng/10 MUL. CONCLUSIONS: We report the first in vivo concentration study of HGF for treatment of the aged vocal fold. Results revealed desirable biochemical effects of HGF at 100 ng/10 MUL. These data will be used to provide immediate direction to programmatic efforts aimed at examining future applications of HGF for treatment of the aged vocal fold. PMID- 21792962 TI - Tracheocele--a case report. AB - A tracheocele is a rarely encountered entity that may be congenital or acquired. This tracheal lesion is characterized by the presence of a single cystic pouch filled with air or a mixture of liquid and air. We recently managed a case of a large voluminous acquired tracheocele originating from the right posterolateral tracheal wall. A 39-year-old male patient presented with chronic cough and breathy voice. Rigid laryngoscopy revealed a right immobile vocal fold. Computed tomography scan revealed a tracheocele that was excised externally with recurrent laryngeal nerve preservation. PMID- 21792963 TI - Novel CO2 laser robotic controller outperforms experienced laser operators in tasks of accuracy and performance repeatability. AB - OBJECTIVES/HYPOTHESIS: To introduce a novel method of combining robotics and the CO(2) laser micromanipulator to provide excellent precision and performance repeatability designed for surgical applications. STUDY DESIGN: Pilot feasibility study. METHODS: We developed a portable robotic controller that appends to a standard CO(2) laser micromanipulator. The robotic accuracy and laser beam path repeatability were compared to six experienced users of the industry standard micromanipulator performing the same simulated surgical tasks. Helium-neon laser beam video tracking techniques were employed. RESULTS: The robotic controller demonstrated superiority over experienced human manual micromanipulator control in accuracy (laser path within 1 mm of idealized centerline), 97.42% (standard deviation [SD] 2.65%), versus 85.11% (SD 14.51%), P = .018; and laser beam path repeatability (area of laser path divergence on successive trials), 21.42 mm(2) (SD 4.35 mm(2) ) versus 65.84 mm(2) (SD 11.93 mm(2) ), P = .006. CONCLUSIONS: Robotic micromanipulator control enhances accuracy and repeatability for specific laser tasks. Computerized control opens opportunity for alternative user interfaces and additional safety features. PMID- 21792964 TI - Phonation threshold pressure and flow in excised human larynges. AB - OBJECTIVES/HYPOTHESIS: To determine the phonation threshold pressure (PTP) and phonation threshold flow (PTF) in excised human larynges; determine the effects of posterior glottal width, glottal area, and gender on PTP and PTF; test the hypothesis that hysteresis is present in excised human laryngeal phonation; and compare these results to those from canine experiments and human subject measurements. STUDY DESIGN: Induced phonation of excised human larynges in the laboratory. METHODS: Nine human larynges were harvested within 24 hours postmortem. PTP and PTF at phonation onset and offset were measured on a bench apparatus. The effects of posterior glottal width, glottal area, and gender were examined. RESULTS: Large intersubject variability was observed in PTP and PTF. PTP was comparable to those measured in vivo, whereas PTF was substantially higher. One-way ANOVA showed no significant dependence of PTP and PTF on posterior glottal width. Hysteresis was observed, with offset PTP and PTF lower than onset values. Offset measurements had significantly less variability than onset measurements (P = .012 for PTP, P = .0001 for PTF). CONCLUSIONS: This study is one of the first to report onset and offset PTP and PTF in fresh excised human larynges. The high PTF observed likely reflects a large direct current flow component due to vocal fold bowing. Offset PTP and PTF values may be intrinsically more reliably measured than onset values. The large intersubject variability in PTP and PTF may have implication for the clinical application of these aerodynamic parameters of phonation. PMID- 21792965 TI - Coprevalence of tremor with spasmodic dysphonia: a case-control study. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to define the coprevalence of tremor with spasmodic dysphonia (SD). STUDY DESIGN: A single-institution, prospective, case-control study was performed from May 2010 to July 2010. METHODS: Consecutive patients with SD (cases) and other voice disorders (controls) were enrolled prospectively. Each participant underwent a voice evaluation and an evaluation for tremor. RESULTS: There were 146 voice disorder controls and 128 patients with SD enrolled. Of patients with SD 26% had vocal tremor, 21% had nonvocal tremor. Patients with SD were 2.8 times more likely to have coprevalent tremor than the control group (odds ratio = 2.81; 95% confidence interval, 1.55-5.08), and only 35% of patients with SD had been seen by a neurologist for the evaluation of dystonia and tremor. CONCLUSIONS: Tremor is highly prevalent in patients with SD. It is important for each patient diagnosed with SD to undergo an evaluation for tremor, and this is especially important in patients diagnosed with vocal tremor. PMID- 21792966 TI - Association of common variants, not rare mutations, in IRF6 with nonsyndromic clefts in a Honduran population. AB - OBJECTIVES/HYPOTHESIS: Cleft lip with or without cleft palate (CL/P) is a common birth defect throughout the world. Linkage studies have shown interferon regulatory factor 6 (IRF6) to be associated with CL/P in multiple populations, including one in Honduras. It is unknown, however, whether rare sporadic mutations or common variants are the cause of this association, and reports exist supporting both hypotheses. Thus, it is important to determine the cause for this association in a Honduran population. STUDY DESIGN: Case-control and family-based association studies. METHODS: Families with two or more members affected by CL/P were identified. We collected DNA from affected and unaffected family members (608 total), and from 100 gender-matched controls from Honduras. We sequenced the exons of IRF6 for mutations in probands and controls. All patients were genotyped for single nucleotide polymorphisms (SNPs) rs642961 and rs2235371, which are proposed to have potential biological significance to IRF6 expression and function. RESULTS: We found no mutations in IRF6 in our CL/P probands. We found a risk association with the G allele of rs2235371 in both case-control (P = .01) and family-based association (P = .01) studies. We found no association with either allele of rs642961. CONCLUSIONS: This study suggests that common variants, rather than rare mutations, are the cause for association between IRF6 and nonsyndromic CL/P. rs2235371, but not rs642961, shows association with CL/P, suggesting a functional role for this polymorphism in our Honduran population. rs642961 has been previously reported to have an effect in other populations, suggesting that different populations may be affected by different polymorphisms. PMID- 21792967 TI - Is the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene due to a founder effect in Chinese head and neck paraganglioma patients? AB - OBJECTIVES/HYPOTHESIS: Three Chinese patients with head and neck paragangliomas have been reported to carry the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene. In addition, in our hospital, two further patients were identified who have the same mutation. It is unclear whether the c.3G>C mutation in Chinese patients is a recurrent mutation or if it is due to a founder effect. We conducted haplotype analysis on these patients to answer this question. STUDY DESIGN: Individual case-control study. METHODS: Germ-line mutations were confirmed in the patients and their families examined in this study using direct sequencing. We also constructed and analyzed haplotypes in four Chinese families. Genotype frequencies were compared to the control group. RESULTS: Three of four families shared the same haplotype, which rarely occurred in the control group. The last family shared a very short area on the physical map with the other three families. CONCLUSIONS: There is a founder effect in Chinese head and neck paraganglioma patients carrying the SDHD c.3G>C mutation. PMID- 21792968 TI - The cochleovestibular nerve identified during auditory brainstem implantation in patients with narrow internal auditory canals: can preoperative evaluation predict cochleovestibular nerve deficiency? AB - OBJECTIVES/HYPOTHESIS: To analyze the value of preoperative diagnostic tools in predicting the status of the cochleovestibular nerve (CVN) in patients with narrow internal auditory canals (IAC). STUDY DESIGN: Retrospective case series at a tertiary hospital. METHODS: Eight profoundly deaf patients with narrow IACs who received auditory brainstem implantation were included in this study. The results of preoperative imaging, electrophysiologic, and auditory tests were correlated with the CVN status identified during auditory brainstem implantation. RESULTS: Temporal bone computed tomography (CT) findings, including the patency of the bony cochlear nerve canal and the diameter of the IAC, were limited in accurately reflecting the status of the CVN. Magnetic resonance imaging (MRI) and preoperative auditory responses to either pure tone or environmental sounds were more accurate markers for detecting the presence of a CVN than CT; however, there were limitations in cases with a very thin CVN or combined severe mental retardation. Absence of promontory or intracochlear electrically evoked auditory brainstem responses were not always indicative of an absent CVN. CONCLUSIONS: Visualization on MRI and detection of auditory responses suggested the presence of a CVN in patients with narrow IACs; however, the possibility of the presence of a CVN should be considered even when there is no clear evidence of a CVN on preoperative evaluations. Therefore, physicians should be prudent when determining candidacy for cochlear implantation or auditory brainstem implantation in patients with narrow IACs. PMID- 21792969 TI - Outcome of cochlear implantation in asymptomatic congenital cytomegalovirus deafened children. AB - OBJECTIVES/HYPOTHESIS: Congenital cytomegalovirus (cCMV) infection is a common cause of sensorineural hearing loss (SNHL). The incidence of SNHL is higher in symptomatic cCMV infants and is usually identified early. By contrast, the incidence of SNHL is lower in children with asymptomatic cCMV, and the hearing loss can be delayed in onset and progressive. The objective was to compare the outcome of cochlear implantation in children deafened by cCMV with a control group of children with implants who do not have the condition. STUDY DESIGN: Retrospective review of case notes and data base. METHODS: Retrospective review of 14 children with asymptomatic cCMV who underwent cochlear implantation. Their outcome measures were compared with those of a matched population by using standard assessment tools. RESULTS: In the study group, the Modified Categories of Auditory Performance (M-CAP) score (range, 1-7) ranged from 2 to 7 (mean, 4.2). In the control group, the M-CAP ranged from 5 to 7 (mean, 6.0). In the study group, the Manchester Spoken Language Development Scale (MSLDS) score (range, 1-10) ranged from 1 to 9 (mean, 5.4). In the control group, the MSLDS ranged from 3 to 10 (mean, 8.1). CONCLUSIONS: Children with asymptomatic deafness caused by cCMV benefit from cochlear implantation but perform less well than a comparable group of children with implants who do not have cCMV. There is a range of performance in the cCMV group that may relate to the degree of motor or cognitive disabilities. PMID- 21792970 TI - Effects of acoustic complexity on processing sound intensity in 10- to 11-year old children: evidence from cortical auditory evoked potentials. AB - OBJECTIVES/HYPOTHESIS: The environmental complexity that sounds are presented in, as well as the stimulus presentation rate, influences how sound intensity is centrally encoded with differences between children and adults. STUDY DESIGN: Cortical auditory evoked potential (CAEP) comparison study in children and adults examining two stimulus rates and three different stimulus contexts. METHODS: Twelve 10 and 11 year olds and 11 adults were studied in two experiments examining the CAEP to a 1-KHz, 50-ms tone. A Slow-Rate experiment at 750-ms stimulus onset asynchrony (SOA) compared the CAEPs of 78 dB to 86 dB SPL in 2 complexity conditions. A Fast-Rate experiment was performed at 125 ms SOA with the same conditions plus an additional complexity condition. Repeated measures and mixed-model analysis of variance (ANOVA) was used to examine the latency and amplitude of the CAEP components. RESULTS: CAEP amplitudes and latencies were significantly affected by rate, intensity, and age with complexity interacting in multiple mixed-mode ANOVAs. P1 was the only CAEP component present at the Fast Rate. There were main effects of rate, age, and stimulus intensity level on the CAEP amplitudes and latencies. Maturational differences were seen in the interactions of intensity with complexity for the different CAEP components. CONCLUSIONS: Complexity of the sound environment was reflected in the relative amplitude of the CAEPs evoked by sound intensity. The effect of stimulus intensity depended on the complexity of the surrounding environment. Effects of the surrounding sounds were different in children than in adults. PMID- 21792971 TI - An evaluation of preservation of residual hearing using the suprameatal approach for cochlear implantation: can this implantation technique be used for preservation of residual hearing? AB - OBJECTIVES/HYPOTHESIS: The preservation of residual hearing has become a high priority in cochlear implant surgery. This study was designed to substantiate whether conservation of residual hearing can be preserved after cochlear implantation using the suprameatal approach. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective chart review was performed in 109 severely to profoundly hearing impaired cochlear recipients who had some measurable hearing preoperatively. Subsequently, the pre- and postoperative pure-tone thresholds were analyzed by three different analyses to observe the degree of hearing preservation. RESULTS: Single-subject results showed a complete conservation of residual hearing (change in pure-tone average [DeltaPTA] <= 10 dB) in 27 of 109 patients (24.7%). Partial conservation of residual hearing (DeltaPTA > 10 dB) was observed in 77 patients (70.6%), but these percentages have been affected severely by ceiling effects. Furthermore, group-subject results demonstrated that the median postoperative PTA was 11.7 dB worse than the preoperative PTA. For individual frequencies, the median deteriorations were 15, 20, 10, and 5 dB at 250, 500, 1,000, and 2,000 Hz, respectively. Stratification for the absence of postoperative hearing thresholds showed a conservation of measurable postoperative hearing levels in 17.4% of all study patients. CONCLUSIONS: The results of this study demonstrate that complete preservation of residual hearing is possible in a limited number of patients using the suprameatal approach technique for cochlear implantation. For a reliable analysis of the audiometric effects of cochlear implant surgery, it is important to take into account the ceiling effects, therefore using different calculation methods to estimate the accurate deterioration of hearing thresholds. PMID- 21792972 TI - The right not to hear: the ethics of parental refusal of hearing rehabilitation. AB - OBJECTIVE: To explore the ethics of parental refusal of auditory-oral hearing rehabilitation. STUDY DESIGN: Case study with medical ethical discussion and review. METHODS: Two young brothers present with severe-to-profound congenital sensorineural hearing loss. The parents, both of whom have normal hearing and work as sign language interpreters, have decided to raise their children with American Sign Language as their only form of communication. They have chosen not to pursue cochlear implantation nor support the use of hearing aids. DISCUSSION: This case raises significant questions concerning whether hearing rehabilitation should be mandated, and if there are circumstances in which parental preferences should be questioned or overridden with regard to this issue. In addition, legal concerns may be raised regarding the possible need to file a report with Child Protective Services. Although similar cases involving the Deaf community have historically favored parental rights to forego hearing rehabilitation with either cochlear implantation or hearing aids, we explore whether conclusions should be different because the parents in this case are not hearing impaired. CONCLUSIONS: The ethics of parental rights to refuse hearing rehabilitation are complex and strikingly context-dependent. A comprehensive appreciation of the medical, practical, and legal issues is crucial prior to intervening in such challenging situations. PMID- 21792973 TI - The frontal intersinus septum takedown procedure: revisiting a technique for surgically refractory unilateral frontal sinus disease. AB - OBJECTIVES/HYPOTHESIS: Unilateral frontal sinus obstruction presents a surgical challenge when outflow tract osteoneogenesis or dense scarring is present. Frontal sinus obliteration is often employed as a last resort, but this procedure has potential long-term complications. In some cases, endoscopic modified Lothrop or unilateral drillout procedures may be effective options; however, restenosis rates are often high. Here we report our experience using frontal intersinus septum takedown (FISST) to address unilateral obstruction while preserving the opposite frontal outflow tract. STUDY DESIGN: A retrospective review was performed of 12 patients with unilateral frontal sinus opacification due to irreversible frontal recess obstruction who underwent FISST. Surgical outcomes were assessed based on symptoms and computed tomography (CT) resolution of frontal sinus disease. RESULTS: All 12 patients undergoing FISST had significant improvement in their symptoms. Ten postoperative CT scans were available for review, all showing continued patency of the interfrontal connection, and nine out of 10 with resolution of radiographic frontal sinus disease. Eleven of the procedures were performed via trephination, and one was achieved endoscopically. CONCLUSIONS: In patients with one obstructed frontal sinus and a functional contralateral sinus, removal of the intersinus septum allows for adequate sinus drainage and significant clinical improvement. The success of FISST may be surprising given knowledge of mucociliary clearance patterns, but may be effective because of the naturally dependent position of the frontal sinus ostium. PMID- 21792975 TI - Persistent positional nystagmus: a case of superior semicircular canal benign paroxysmal positional vertigo? AB - Involvement of the superior semicircular canal (SSC) in benign paroxysmal positional vertigo (BPPV) is rare. SSC BPPV is distinguished from the more common posterior semicircular canal (PSC) variant by the pattern of nystagmus triggered by the Dix-Hallpike position: down-beating torsional nystagmus in SSC BPPV versus up-beating torsional nystagmus in PSC BPPV. SSC BPPV may be readily treated at the bedside, which is a key component in excluding central causes of down-beating nystagmus. We present an unusual video case report believed to represent refractory SSC BPPV based on the pattern of nystagmus and the absence of any other central signs. PMID- 21792974 TI - Cluster analysis of auditory and vestibular test results in definite Meniere's disease. AB - OBJECTIVES/HYPOTHESIS: To determine whether patients with Meniere's disease can be grouped into distinct subtypes based on a cluster analysis of distinct disease parameters. STUDY DESIGN: Prospective study at a tertiary center associated with a university hospital. METHODS: The study included 153 patients diagnosed with unilateral definite Meniere's disease. The main variables employed were taken from auditory, vestibular, posturographic, and disability assessments. RESULTS: A four-cluster solution best fitted the data. Each cluster represented a distinct patient profile. Cluster 1 patients (13.1%) were the eldest, with the worst hearing bilaterally and good vestibular function but with a significant postural impact and a low level of disability. Cluster 2 patients (41.2%) were the least affected in all the parameters that were close to normal. Cluster 3 patients (34.6%) were the most affected, experiencing frequent and intense vertigo attacks, and they were visually dependent. Cluster 4 patients (11.1%) had strong asymmetric hearing between both ears and the most uncompensated vestibular deficit; they were moderately disabled. CONCLUSIONS: We have identified four distinct profiles of patients with definite Meniere's disease that we consider as "mildly active elderly," "mildly active young," "active compensated," and "active uncompensated." We have demonstrated that only in a restricted population of patients can the American Academy of Otolaryngology-Head and Neck Surgery staging system provide analysis of subtypes of the disease. PMID- 21792976 TI - The mitochondrial A3243G mutation involves the peripheral vestibule as well as the cochlea. AB - OBJECTIVES/HYPOTHESIS: To evaluate vestibular function in patients with the mitochondrial A3243G mutation. STUDY DESIGN: Data from patients with the A3243G mutation attending an academic tertiary referral center were prospectively recorded. METHODS: The clinical histories of 13 unrelated patients with the mitochondrial A3243G mutation (six mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; and seven maternally inherited diabetes and deafness) were recorded, in particular their history of vestibular symptoms. Vestibular examinations including caloric testing and vestibular evoked myogenic potentials in response to air-conducted sound (ACS-VEMPs) were performed. In seven patients who showed abnormal ACS-VEMP, VEMP in response to galvanic stimuli (galvanic-VEMP) were also recorded. RESULTS: Eleven of the 13 patients had vestibular symptoms. The age of onset of vestibular symptoms was significantly later than the ages of onset of hearing loss and diabetes mellitus (P < .05). Ten of the 13 patients showed abnormal caloric responses, whereas 12 patients showed abnormal ACS-VEMPs on one or both sides. All of the seven patients who underwent galvanic-VEMP testing showed normal responses. CONCLUSIONS: The A3243G mutation is associated with vestibular dysfunction involving both the superior and inferior vestibular nerve systems. Furthermore, our results from galvanic-VEMP testing suggests that a labyrinthine lesion is primarily responsible for the symptoms of vestibular dysfunction. PMID- 21792977 TI - Effect of intra-operative fluid volume on peri-operative outcomes after pancreaticoduodenectomy for pancreatic adenocarcinoma. AB - BACKGROUND: Excess use of intravenous fluid can increase post-operative complications. We examined the influence of intra-operative crystalloid (IOC) administration on complications following pancreaticodudenectomy (PD) for pancreatic adenocarcinoma. METHODS: We categorized 188 patients who underwent PD for adenocarcinoma (1990-2009) into two groups: Group I received <6,000 ml and Group II received >=6,000 ml IOC. Differences between groups in length of stay, overall morbidity, and 30-day mortality were evaluated. RESULTS: There were 86 patients in Group I and 102 in Group II. Group I patients were older and with higher percentage of women, but similar in regards to performance status, ASA score, underlying comorbidities, and administration of neo-adjuvant treatment. Group II patients had longer operations, increased blood loss, and higher rates of intra-operative blood transfusions. There were two post-operative deaths, both in the Group II (P = 0.5). Post-operative overall morbidity was 45.7%, without differences between the two groups (44.2% vs. 47.1%, P = 0.7). Likewise, length of post-operative stay was similar in both groups (13.8 days vs. 14.5 days, P = 0.5). CONCLUSIONS: The volume of IOC increased with duration of surgery, intra operative blood losses, and intra-operative blood transfusion, but did not correlate with post-operative morbidity. PMID- 21792978 TI - Relevance of both individual risk factors and occupational exposure in cancer survival studies: the example of intestinal type sinonasal adenocarcinoma. AB - OBJECTIVES/HYPOTHESIS: Wood dust is a well-established risk factor for intestinal type sinonasal adenocarcinoma. The 5-year overall survival has varied from 20% to 80% according T1-T4 stages; 5-year survival according to histologic subtype has varied from 20% to 50%. To date, no study has evaluated whether environmental, occupational, and personal risk factors have any impact on both overall and cancer-specific survival. We aimed to determine whether exposure to carcinogenic risk factors besides wood exposure can influence the survival of patients with sinonasal ethmoid carcinoma. STUDY DESIGN: Retrospective cohort study of the association of survival data and occupational and personal carcinogenic risk factors. METHODS: All patients hospitalized for ethmoid adenocarcinoma at the Nantes University Hospital between 1988 and 2004 were included . Data concerning TNM classification, histology, type and quality of tumor resection at the macro- and microscopic level, and occupational and personal exposure to carcinogens were collected. Statistical analysis was conducted using univariate and multivariate linear regression. RESULTS: A total of 98 patients were included with a response rate of 98%. Data showed 86% of patients had been exposed to wood dust. The 5 year survival was 62%. We first identified four factors that independently influenced overall survival: diplopia (P = .0159), spread to the orbit (P = .0113), bilateral involvement (P = .0134), TNM stage (P < .001). When the analysis included all occupational environmental factors (wood dust, solvent, and metals exposure) as well as personal risk factors, the length of exposure to metals (P = .0307) and tobacco exposure (P = .0031) also were found to influence 5-year overall survival. We identified high prevalence of colon cancer (4%) and double cancer (18%). CONCLUSIONS: We showed exposure to both environmental (tobacco) and occupational (metal dust) factors could influence survival in the diagnosis of a cancer. Our study suggests that screening for colon cancer should be offered to wood dust workers. A prospective multicentric study should be necessary to confirm our results. PMID- 21792979 TI - The prognostic value of early left ventricular longitudinal systolic dysfunction in asymptomatic subjects with cardiovascular risk factors. AB - BACKGROUND: Early diagnosis of left ventricular (LV) dysfunction represents a major challenge in asymptomatic subjects with cardiovascular (CV) risk factors. Tissue Doppler imaging (TDI) has emerged as an important tool with clinical relevance in several cardiac diseases. HYPOTHESIS: To evaluate the prognostic ability of TDI in detecting early longitudinal ventricular dysfunction in a large group of asymptomatic subjects with CV risk factors (RsF), normal LV systolic function, and normal diastolic function. METHODS: A total of 554 subjects (mean age 55 +/- 13 years, 39% men) formed our study population: controls, 144 healthy subjects; group 1, 163 subjects with 1 CV RsF; group 2, 147 subjects with 2 CV RsF; group 3, 100 subjects with >=3 CV RsF. All subjects underwent a comprehensive standard echo-Doppler evaluation, including posterior wall TDI study. Follow-up data were available in all the studied samples (mean 28 +/- 16 mo). RESULTS: Upon follow-up, 18 individuals (3.2%) developed a first overt CV event. The presence of a peak systolic velocity <7.5 cm/second showed a significant additional predictive value compared with the presence of CV RsF (P<0.001). CONCLUSIONS: Tissue Doppler imaging is able to identify early longitudinal LV systolic abnormalities in the presence of apparently normal systolic and diastolic function. It demonstrated a significant additional prognostic value compared with the simple presence of coexisting CV RsF. These findings could be clinically relevant in identifying asymptomatic subjects with CV RsF who need early, tailored preventive treatment. PMID- 21792980 TI - Lysis of interarytenoid synechia (Type I Posterior Glottic Stenosis): vocal fold mobility and airway results. AB - BACKGROUND: The Type I Posterior Glottic Stenosis (PGS-I) is a well-described but uncommon clinical entity. Despite this, there is little known about the outcome of surgical treatment. METHODS: Retrospective case series. RESULTS: Thirteen cases met inclusion criteria. All but one patient had a tracheostomy at the time of initial evaluation. At the postoperative visit, seven patients (54%) had completely normal vocal fold motion. Of the verbal patients, 6 (50%) had normal vocal function as reported by both the patient/caregiver and the physician, and 10 (83%) patients were successfully decannulated. CONCLUSIONS: Patients with an isolated interarytenoid synechia have an excellent prognosis with regard to decannulation. Although many patients regain normal vocal fold motion and a return to their preintubation vocal function, a significant proportion can have persistent deficits in vocal fold mobility and some level of dysphonia. This report represents the largest known series of PGS-I cases. PMID- 21792981 TI - Influence of low-dose aspirin (81 mg) on the incidence of definite stent thrombosis in patients receiving bare-metal and drug-eluting stents. AB - BACKGROUND: Dual antiplatelet therapy with aspirin plus clopidogrel is the mainstay of therapy in patients undergoing percutaneous coronary intervention (PCI). However, the optimal dose of aspirin following PCI has not been established. HYPOTHESIS: There is no difference for definite stent thrombosis in patients taking low dose versus standard aspirin. METHODS: Low-dose (81 mg) aspirin was used as part of a standard dual antiplatelet therapy in patients receiving bare-metal stents (BMS) or drug-eluting stents (DES) at a large tertiary medical center. We retrospectively analyzed 5368 consecutive cases treated with stent placement and dual antiplatelet therapy. The incidence of definite stent thrombosis (DST) at our institution was compared to DST as reported in a large, published cohort of 24 trials and 12973 patients. We stratified DST events into early (<30 days) and late (>30 days) timing and also stratified by stent type. The effect of aspirin dosing was evaluated using chi(2) , Cochran-Mantel-Haenszel, and homogeneity testing. RESULTS: A total of 5187 patients underwent 7604 stent implantations during the study period. The cumulative incidence of DST was 0.60% (95% confidence interval [CI], 0.42%-0.84%) at 30 days and 0.76% (95% CI, 0.56%-1.03%) at 1 year. The overall incidence of DST during the study period was not different based on type of stent (0.53% for DES and 0.75% for BMS, P = 0.36). Compared to the historic, standard-dose aspirin (162-325 mg) cohort, DST in our low-dose aspirin (81 mg) cohort was not significantly different at either 30 days (0.72% vs 0.60%, P = 0.39) or at 1 year (1.08% vs 0.76%, P = 0.07). There was no appreciable interaction of aspirin dose on the incidence of DST, controlling for stent type, or timing of the event. CONCLUSIONS: Low-dose aspirin therapy in combination with clopidogrel following implantation of either BMS or DES in our cohort does not appear to increase the risk of DST compared to a higher-dose aspirin regimen. PMID- 21792982 TI - Applications of multifunctional magnetic nanoparticles for the enrichment of proteins for PAGE separation. AB - This paper describes the applications of multifunctional magnetic nanoparticles (MNPs) for the enrichment of low-abundance proteins for polyacrylamide gel electrophoresis (PAGE) separation. The hemoglobin-functionalized MNPs, named Hb MNPs, were obtained based on electrostatic interactions and covalent binding between the hemoglobin (Hb) and the MNPs. It was demonstrated that the proteins in human serum were selectively conjugated to Hb-MNPs, which can be used for the selective enrichment of low-abundance proteins. Three and seven kinds of proteins were identified by MS after 1-D and 2-D PAGE, respectively. Comparing with native PAGE without the treatment of MNPs, some proteins were observed, such as human serum amyloid P component (SAP), vitamin D-binding protein, and serine peptidase inhibitor. Because the high concentration of SAP can be considered as a signal for the neurodegeneration of Alzheimer's disease, the present Hb-MNPs-based method was applied to investigate the serum level of SAP for the diagnosis of Alzheimer's disease, and the results are satisfying. PMID- 21792985 TI - Biomarker discovery and related topics. PMID- 21792987 TI - Metabolomic assessment with CE-MS of the nutraceutical effect of Cystoseira spp extracts in an animal model. AB - There is a need of scientific evidence of claimed nutraceutical effects, but also there is a social movement towards the use of natural products and among them algae are seen as rich resources. Within this scenario, the development of methodology for rapid and reliable assessment of markers of efficiency and security of these extracts is necessary. The rat treated with streptozotocin has been proposed as the most appropriate model of systemic oxidative stress for studying antioxidant therapies. Cystoseira is a brown alga containing fucoxanthin and other carothenes whose pressure-assisted extracts were assayed to discover a possible beneficial effect on complications related to diabetes evolution in an acute but short-term model. Urine was selected as the sample and CE-TOF-MS as the analytical technique to obtain the fingerprints in a non-target metabolomic approach. Multivariate data analysis revealed a good clustering of the groups and permitted the putative assignment of compounds statistically significant in the classification. Interestingly a group of compounds associated to lysine glycation and cleavage from proteins was found to be increased in diabetic animals receiving vehicle as compared to control animals receiving vehicle (N6,N6,N6 trimethyl-L-lysine, N-methylnicotinamide, galactosylhydroxylysine, L-carnitine, N6-acetyl-N6-hydroxylysine, fructose-lysine, pipecolic acid, urocanic acid, amino isobutanoate, formylisoglutamine. Fructoselysine significantly decreased after the treatment changing from a 24% increase to a 19% decrease. CE-MS fingerprinting of urine has provided a group of compounds different to those detected with other techniques and therefore proves the necessity of a cross platform analysis to obtain a broad view of biological samples. PMID- 21792986 TI - Difference gel electrophoresis identifies differentially expressed proteins in endoscopically collected pancreatic fluid. AB - Alterations in the pancreatic fluid proteome of individuals with chronic pancreatitis (CP) may offer insights into the development and progression of the disease. The endoscopic pancreatic function test (ePFT) can safely collect large volumes of pancreatic fluid that are potentially amenable to proteomic analyses using difference gel electrophoresis (DIGE) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS). Pancreatic fluid was collected endoscopically using the ePFT method following secretin stimulation from three individuals with severe CP and three chronic abdominal pain (CAP) controls. The fluid was processed to minimize protein degradation and the protein profiles of each cohort, as determined by DIGE and LC-MS/MS, were compared. This DIGE-LC MS/MS analysis reveals proteins that are differentially expressed in CP compared with CAP controls. Proteins with higher abundance in pancreatic fluid from CP individuals include: actin, desmoplankin, alpha-1-antitrypsin, SNC73, and serotransferrin. Those of relatively lower abundance include carboxypeptidase B, lipase, alpha-1-antichymotrypsin, alpha-2-macroglobulin, actin-related protein (Arp2/3) subunit 4, glyceraldehyde-3-phosphate dehydrogenase, and protein disulfide isomerase. Endoscopic collection (ePFT) in tandem with DIGE-LC-MS/MS is a suitable approach for pancreatic fluid proteome analysis; however, further optimization of our protocol, as outlined herein, may improve proteome coverage in future analyses. PMID- 21792988 TI - Joule heating effects on electroosmotic flow in insulator-based dielectrophoresis. AB - Insulator-based dielectrophoresis (iDEP) is an emerging technology that has been successfully used to manipulate a variety of particles in microfluidic devices. However, due to the locally amplified electric field around the in-channel insulator, Joule heating often becomes an unavoidable issue that may disturb the electroosmotic flow and affect the particle motion. This work presents the first experimental study of Joule heating effects on electroosmotic flow in a typical iDEP device, e.g., a constriction microchannel, under DC-biased AC voltages. A numerical model is also developed to simulate the observed flow pattern by solving the coupled electric, energy, and fluid equations in a simplified two dimensional geometry. It is observed that depending on the magnitude of the DC voltage, a pair of counter-rotating fluid circulations can occur at either the downstream end alone or each end of the channel constriction. Moreover, the pair at the downstream end appears larger in size than that at the upstream end due to DC electroosmotic flow. These fluid circulations, which are reasonably simulated by the numerical model, form as a result of the action of the electric field on Joule heating-induced fluid inhomogeneities in the constriction region. PMID- 21792989 TI - A promising capillary electrophoresis-electrospray ionization-mass spectrometry method for carbohydrate analysis. AB - A method for adapting widely used CE conditions for the separation of fluorescently labeled carbohydrates to permit online ESI-MS detection is presented. Reverse polarity separations were performed in bare fused-silica capillaries with an acidic BGE. Under these conditions, negatively charged 8 aminopyrene 1,3,6-trisulfonate-labeled carbohydrates migrate forward against the EOF, which is towards the capillary inlet. Therefore, the CE-MS interface must simultaneously back-fill the capillary, in order to maintain the CE circuit, and provide a stable forward flow at the sprayer tip to support the electrospray process. This was achieved using a junction-at-the-tip interface, which provides a flow of solution to the junction formed by the capillary terminus and the inner wall of the emitter needle tip. Because the flow rate required for this arrangement is much less than in conventional sheath flow interfaces, dilution of the analytes is minimized. Optimized separation conditions permit baseline resolution of glucose oligomers containing up to 15 glucose units, while longer oligomers, up to 33 glucose units, were observed as resolved peaks in the negative ion mode mass spectrum. PMID- 21792991 TI - A novel approach to dielectrophoresis using carbon electrodes. AB - Carbon-electrode dielectrophoresis (carbon-DEP) is demonstrated here as an alternative to more traditional DEP techniques. Carbon-DEP combines advantages of metal-electrode and insulator-based DEP by using low-cost fabrication techniques and low voltages for particle manipulation. The use of 3-D electrodes is proved to yield significant advantages over the use of traditional planar electrodes. This paper details the fabrication of dense arrays of tall high aspect ratio carbon electrodes on a transparent fused-silica substrate. The shrinkage of the SU-8 structures during carbonization is characterized and a design tool for future devices is provided. Applications of carbon electrodes in DEP are then detailed and include particle positioning, high-throughput filtering and cell focusing using positive-DEP. Manipulated cells include Saccharomyces cerevisiae and Drosophila melanogaster. The advantages and disadvantages of carbon-DEP are discussed at the end of this work. PMID- 21792990 TI - Immunoglobulin G and bovine serum albumin streaming dielectrophoresis in a microfluidic device. AB - Dielectrophoresis (DEP) has demonstrated to be a versatile tool to manipulate micro- and nanoparticles with applications for positioning, separation and fractionation. Recent developments of DEP have also shown that DEP can be used for the manipulation of biomolecules, such as DNA. Here, we focus on the manipulation of proteins using insulator-based dielectrophoresis (iDEP). We designed suitable post arrays in a microfluidic channel and use numerical simulations to calculate the electric field distribution as well as concentration of proteins according to a convection-diffusion model for both negative and positive DEP. Experimentally, we find DEP trapping of mainly protein aggregates in phosphate buffer. However, when adding a charged zwitterionic detergent, we observed DEP streamlining of immunoglobulin G (IgG) and bovine serum albumin (BSA). Our experimental observations are in excellent agreement with numerical simulations and indicate positive DEP behavior of IgG and BSA under the employed experimental conditions. Our results demonstrate DEP streaming of proteins in an iDEP device for the first time and indicate the potential of protein DEP for separation and fractionation. PMID- 21792992 TI - Simultaneous analysis of six cardiovascular drugs by capillary electrophoresis coupled with electrochemical and electrochemiluminescence detection, using a chemometrical optimization approach. AB - CE coupled with dual electrochemical (EC) and electrochemiluminescence (ECL) detection was optimized for simultaneous analysis of six cardiovascular drugs (alprenolol, propafenone, acebutolol, verapamil, atenolol and metoprolol) via central composite design. Following this study, three critical electrophoretic factors governing the CE separation were investigated: Tris-H(3)PO(4) buffer concentration, buffer pH value and separation voltage. A modified chromatographic response was adopted for evaluating CE separation quality. Optimum conditions were achieved using Tris-H(3)PO(4) buffer 35.6 mM (pH 2.3) separated at 13.9 kV, which was employed experimentally and led to the successful simultaneous separation of the above six drugs. The good agreement of the chromatographic response was observed between predicted data and actual experimental results using these optimized conditions (RSD=3.75%). The proposed method was validated for linearity, repeatability and sensitivity, and subsequently successfully applied to determine six basic drugs in urine samples. PMID- 21792993 TI - Determination of nicotine and its metabolite cotinine in urine and cigarette samples by capillary electrophoresis coupled with electrochemiluminescence. AB - In this paper, CE coupled with electrochemiluminesence (ECL) detection using a 76 MUm Pt disk as working electrode was developed for nicotine (NIC) determination. The major metabolite of NIC is cotinine (COT), which has a similar tertiary amine structure to NIC. However, there is a carbonyl group attached in the structure of COT, which leads to the great decrease in ECL response. In order to improve the ECL response of COT, NaBH(4) was used for carbonyl reduction. After reduction, NIC and COT were separated and detected by CE-ECL. ECL response plotted with NIC concentration was linear between 5.0*10(-7) and 5.0*10(-5) mol/L (81-8100 MUg/L), with LOD of 5.0*10(-8) mol/L (8.1 MUg/L). The developed CE-ECL method was applied for NIC determination in urine and cigarette samples. PMID- 21792994 TI - Capillary electrophoretic mobility shift assay for binding of DNA with NFAT3, a transcription factor from H9c2 cardiac myoblast cells. AB - Nuclear factor of activated T-cells (NFAT) is a transcription factor involved in the development of cardiac and skeletal muscle and the nervous system. NFAT is activated by calcium signal pathway and translocated into the nucleus. The quantification of binding between NFAT and NFAT-specific DNA gives important information about cardiac hypertrophy. We investigated the binding of NFAT3 in nuclear extracts from H9c2 cells to its specific DNA by capillary electrophoretic mobility shift assay. The binding reaction time required for stable formation of the DNA-NFAT3 complex was 3 h and the separation of the complex and free DNA was achieved within 10 min by CE. The formation of NFAT3-DNA complex was confirmed by the competitive reaction. Comparison of the ratios of complex/free DNA peak area for 1 MUM endothelin-1 (ET-1)-treated cells and control cells showed the NFAT3 translocation into the nucleus promoted by ET-1. The binding constant between NFAT3 and DNA was estimated to be 7.7*10(9) M(-1) at 4 degrees C. PMID- 21792995 TI - Blue native/SDS-PAGE combined with iTRAQ analysis reveals advanced glycation end product-induced changes of synaptosome proteins in C57 BL/6 mice. AB - Evidence shows that administration of high-level D-galactose induces the production of advanced glycation end-products (AGEs) that have been implicated in the development of diabetic complications such as neuropathy. The deterioration of learning and memory during neuropathy might be associated with the altered expression of proteins in synapse. To evaluate AGE-induced protein network alterations in synapse, blue native/SDS-PAGE and iTRAQ proteomic methods were used to screen for differentially expressed synaptic proteins of cerebral cortex in D-galactose-induced C57 BL/6 mice. In total, the expression level of 84 proteins is changed during AGE accumulation. The significantly differentially expressed proteins mainly participate in neurotransmission, energy metabolism and signal transduction pathway, suggesting that energy metabolism is damaged and neurotransmission is attenuated in synapse. The results of in vivo activities of malondialdehyde and superoxide dismutase suggested that AGE accumulation in the brain leads to the generation of reactive oxygen species. Therefore, elucidating the differentially expressed proteins underlying the AGE accumulation will open a new window to the mechanism of learning and memory impairments in neuropathy. PMID- 21792996 TI - Dispersive liquid-liquid microextraction coupled with capillary electrophoresis for simultaneous determination of sulfonamides with the aid of experimental design. AB - A novel method for the simultaneous determination of sulfonamides (SAs) in water samples has been developed by using dispersive liquid-liquid microextraction (DLLME) coupled with CE. Orthogonal and Box-Behnken designs were employed together to assist the optimization of DLLME parameters, including volumes of extraction and disperser solvents, ionic strength, extraction time, and centrifugation time and speed as variable factors. Under the optimum extraction and detection conditions, successful separation of the five SAs was achieved within 5 min, and excellent analytical performances were attained, such as good linear relationships (R>0.980) between peak area and concentration for each SA from 0.5 to 50 MUg/mL, low limits of detection for the five SAs between 0.020 and 0.570 MUg/mL and the intra-day precisions of migration time below 0.80%. The method recoveries obtained at fortified 10 MUg/mL for three water samples ranged from 53.6 to 94.0% with precisions of 1.23-5.60%. The proposed method proved highly sensitive and selective, rapid, convenient and cost-effective, showing great potential for the simultaneous determination of SAs in water samples. PMID- 21792997 TI - Trapping and imaging of micron-sized embryos using dielectrophoresis. AB - Development of dielectrophoretic (DEP) arrays for real-time imaging of embryonic organisms is described. Microelectrode arrays were used for trapping both embryonated eggs and larval stages of Antarctic nematode Panagrolaimus davidi. Ellipsoid single-shell model was also applied to study the interactions between DEP fields and developing multicellular organisms. This work provides proof-of concept application of chip-based technologies for the analysis of individual embryos trapped under DEP force. PMID- 21792998 TI - Thermal stabilization of tissues and the preservation of protein phosphorylation states for two-dimensional gel electrophoresis. AB - 2-DE is typically capable of discriminating proteins differing by a single phosphorylation or dephosphorylation event. However, a reliable representation of protein phosphorylation states as they occur in vivo requires that both phosphatases and kinases are rapidly and completely inactivated. Thermal stabilization of mouse cerebral cortex homogenates effectively inactivated these enzymes, as evidenced by comparison with unstabilized tissues where abscissal pI shifts were a common feature in 2-D gels. Of the 588 matched proteins separated on 2-D gels comparing stabilized and unstabilized tissues, 53 proteins exhibited greater than twofold differences in spot volume (ANOVA, p<0.05). Phosphoprotein specific staining was corroborated by the identification of 16 phosphoproteins by nano-LC MS/MS and phosphotyrosine kinase activity assay. PMID- 21792999 TI - Determination of gadolinium-based magnetic resonance imaging contrast agents by micellar electrokinetic capillary chromatography. AB - MEKC with DAD was applied to detect six Gd-based contrasting agents (CAs) (Gd DTPA-BMA (Omniscan), Gd-HPDO3A (ProHance), Gd-DOTA (Dotarem), Gd-AAZTA, Gd-BOPTA (Multihance) and Gd-DTPA (Magnevist)) commonly used in MRI diagnostics. The achieved LODs ranged between 0.40 and 20 MUM and the optimized method gave excellent precision, especially when two internal standards were applied (less than 0.34 RSD% for migration time). The MEKC technique made it possible to determine the CAs in urine and serum samples of patients having a therapeutic dose. Due to the SDS content of the running buffer, the serum samples can be directly injected to analyze Gd-based CAs without interference of high protein content. PMID- 21793000 TI - High-throughput functional marker assay for detection of Xa/xa and fgr genes in rice (Oryza sativa L.). AB - We apply CE for high-throughput analysis of functional markers for marker assisted selection in rice. The accuracy, throughput and reproducibility of CE analysis for sequence-tagged site (STS) and simple sequence repeat (SSR) markers for bacterial blight resistance and aroma genes are demonstrated by using a CE system. Multiplex PCR products displayed well-differentiated allelic variants using different STS and SSR markers for identification of xa13, Xa21 and fgr genes using the CE system compared to 1.2% agarose gel images. Moreover, consumption of PCR product is much less in the CE system compared to traditional agarose gel systems. Sample consumption is less than 0.1 MUL per analysis, thereby conserving samples for further downstream analysis. Out of 29 genotypes in BC(1)F(3) generation, 16 plants were found homozygous for all the three genes, viz., xa13, Xa21 and fgr. These homozygous lines can be used as potential donors in rice breeding programmes. PMID- 21793001 TI - Capillary electrophoresis-electrochemiluminescence detection method for the analysis of ibandronate in drug formulations and human urine. AB - A simple, rapid and sensitive CE method coupled with electrochemiluminescence (ECL) detection for direct analysis of ibandronate (IBAN) has been developed. Using a buffer solution of 20 mM sodium phosphate (pH 9.0) and a voltage of 13.5 kV, separation of IBAN in a 30-cm length capillary was achieved in 3 min. ECL detection was performed with an indium tin oxide working electrode bias at 1.6 V (versus a Pt wire reference) in a 200-mM sodium phosphate buffer (pH 8.0) containing 3.5 mM Ru(bpy)(3)(2+) (where bpy=2,2'-bipyridyl). Derivatization of IBAN prior to CE-ECL analysis was not needed. Linear correlation (r=0.9992, n=7) between ECL intensity and analyte concentration was obtained in the range of 0.25 50 MUM IBAN. The LOD of IBAN in water was 0.08 MUM. The developed method was applied to the analysis of IBAN in a drug formulation and human urine sample. SPE using magnetic Fe(3)O(4)@Al(2)O(3) nanoparticles as the extraction phase was employed to pretreat the urine sample before CE-ECL analysis. The linear range was 0.2-12.0 MUM IBAN in human urine (r=0.9974, n=6). The LOD of IBAN in urine was 0.06 MUM. Total analysis time including sample preparation was <1 h. PMID- 21793002 TI - Many-body exchange-repulsion in polarizable molecular mechanics. I. Orbital-based approximations and applications to hydrated metal cation complexes. AB - We have quantified the extent of the nonadditivity of the short-range exchange repulsion energy, E(exch-rep), in several polycoordinated complexes of alkali, alkaline-earth, transition, and metal cations. This was done by performing ab initio energy decomposition analyses of interaction energies in these complexes. The magnitude of E(exch-rep(n-body, n > 2)) was found to be strongly cation dependent, ranging from close to zero for some alkali metal complexes to about 6 kcal/mol for the hexahydrated Zn(2+) complex. In all cases, the cation-water molecules, E(exch-rep(three-body)), has been found to be the dominant contribution to many-body exchange-repulsion effects, higher order terms being negligible. As the physical basis of this effect is discussed, a three-center exponential term was introduced in the SIBFA (Sum of Interactions Between Fragments Ab initio computed) polarizable molecular mechanics procedure to model such effects. The three-body correction is added to the two-center (two-body) overlap-like formulation of the short-range repulsion contribution, E(rep), which is grounded on simplified integrals obtained from localized molecular orbital theory. The present term is computed on using mostly precomputed two-body terms and, therefore, does not increase significantly the computational cost of the method. It was shown to match closely E(three-body) in a series of test cases bearing on the complexes of Ca(2+), Zn(2+), and Hg(2+). For example, its introduction enabled to restore the correct tetrahedral versus square planar preference found from quantum chemistry calculations on the tetrahydrate of Hg(2+) and [Hg(H(2)O)(4)](2+). PMID- 21793004 TI - Acceleration of self-consistent-field convergence by combining conventional diagonalization and a diagonalization-free procedure. AB - A new scheme that combines conventional matrix diagonalization with the recently proposed diagonalization-free algorithm has been developed to obtain the density matrix for the next self-consistent-field iteration from the Fock matrix of the current iteration. In this manner, the advantages of the two methods are combined. The more rapid convergence of the diagonalization-free algorithm for density matrices rather close to self consistence and the more robust convergence of the conventional matrix diagonalization further away from self-consistence. The scheme has been implemented in the one- and two-component self-consistent field procedures in the program system TURBOMOLE. The number of iterations is typically reduced by about 10%, but savings are usually much larger for slowly converging cases. PMID- 21793003 TI - Structural, dynamic, and electrostatic properties of fully hydrated DMPC bilayers from molecular dynamics simulations accelerated with graphical processing units (GPUs). AB - We present results of molecular dynamics simulations of fully hydrated DMPC bilayers performed on graphics processing units (GPUs) using current state-of-the art non-polarizable force fields and a local GPU-enabled molecular dynamics code named FEN ZI. We treat the conditionally convergent electrostatic interaction energy exactly using the particle mesh Ewald method (PME) for solution of Poisson's Equation for the electrostatic potential under periodic boundary conditions. We discuss elements of our implementation of the PME algorithm on GPUs as well as pertinent performance issues. We proceed to show results of simulations of extended lipid bilayer systems using our program, FEN ZI. We performed simulations of DMPC bilayer systems consisting of 17,004, 68,484, and 273,936 atoms in explicit solvent. We present bilayer structural properties (atomic number densities, electron density profiles), deuterium order parameters (S(CD)), electrostatic properties (dipole potential, water dipole moments), and orientational properties of water. Predicted properties demonstrate excellent agreement with experiment and previous all-atom molecular dynamics simulations. We observe no statistically significant differences in calculated structural or electrostatic properties for different system sizes, suggesting the small bilayer simulations (less than 100 lipid molecules) provide equivalent representation of structural and electrostatic properties associated with significantly larger systems (over 1000 lipid molecules). We stress that the three system size representations will have differences in other properties such as surface capillary wave dynamics or surface tension related effects that are not probed in the current study. The latter properties are inherently dependent on system size. This contribution suggests the suitability of applying emerging GPU technologies to studies of an important class of biological environments, that of lipid bilayers and their associated integral membrane proteins. We envision that this technology will push the boundaries of fully atomic-resolution modeling of these biological systems, thus enabling unprecedented exploration of meso-scale phenomena (mechanisms, kinetics, energetics) with atomic detail at commodity hardware prices. PMID- 21793005 TI - Density functional study of neutral and anionic AlO(n) and ScO(n) with high oxygen content. AB - The electronic and geometrical structures of neutral and negatively charged AlO(5), AlO(6), AlO(7), AlO(8), AlO(9), AlO(10), AlO(11), AlO(12), AlO(15), AlO(16), and AlO(18) along with the corresponding series of ScO(n) and ScO n- oxides were investigated using density functional theory with generalized gradient approximation. We found that these species possess geometrically stable isomers for all values of n = 5-12, 15, 16, 18 and are thermodynamically stable for n = 5-7. The species with n = 16 are found to be octa-dioxides M(eta(1) O(2))(8) while the species with n = 15 and 18 are penta-ozonides (eta(2) O(3))M(eta(1)-O(3))(4) and hexa-ozonides M(eta(1)-O(3))(6), respectively. Geometrical configurations of a number of the lowest total energy states of Al and Sc oxides are different. Especially, drastic differences are found for the anion AlO n- and ScO n- pairs at n = 9, 10, and 11. The Sc-O bonds are longer than the Al-O bonds by ~0.2 A, which, in turn, slightly affects the corresponding interoxygen bond lengths. The charges on metal atoms are close to +2e in both Al series and to +1.5e in both Sc series. As an extra electron is delocalized over ligands in the presence of a large positive charge on the metal atom of the anions, the electron affinity (EA) of the neutrals along with the ionization energies of the anions are large and exceed the EAs of the halogen atoms in a number of cases. PMID- 21793006 TI - Intramolecular hydrogen bond energy and cooperative interactions in alpha-, beta , and gamma-cyclodextrin conformers. AB - Accurate estimation of individual intramolecular hydrogen bond (H-bond) energies is an intricate task for multiply H-bonded systems. In such cases, the hydrogen bond strengths could be highly influenced by the cooperative interactions, for example, those between hydroxyl groups in sugars. In this work, we use the recently proposed molecular tailoring approach-based quantification (Deshmukh, Gadre, and Bartolotti, J Phys Chem A 2006, 110, 12519) to the extended systems of cyclodextrins (CDs). Further, the structure and stability of different conformers of alpha-, beta-, and gamma-CDs are explained based on the energetics and cooperative contribution to the strength of these H-bonds. The estimated O-H...O H-bond energies in the various CD conformers are found to vary widely from 1.1 to 8.3 kcal mol(-1). The calculated energy contributions to cooperativity toward the H-bond strengths fall in the range of 0.25-2.75 kcal mol(-1). PMID- 21793007 TI - The distributed diagonal force decomposition method for parallelizing molecular dynamics simulations. AB - Parallelization is an effective way to reduce the computational time needed for molecular dynamics simulations. We describe a new parallelization method, the distributed-diagonal force decomposition method, with which we extend and improve the existing force decomposition methods. Our new method requires less data communication during molecular dynamics simulations than replicated data and current force decomposition methods, increasing the parallel efficiency. It also dynamically load-balances the processors' computational load throughout the simulation. The method is readily implemented in existing molecular dynamics codes and it has been incorporated into the CHARMM program, allowing its immediate use in conjunction with the many molecular dynamics simulation techniques that are already present in the program. We also present the design of the Force Decomposition Machine, a cluster of personal computers and networks that is tailored to running molecular dynamics simulations using the distributed diagonal force decomposition method. The design is expandable and provides various degrees of fault resilience. This approach is easily adaptable to computers with Graphics Processing Units because it is independent of the processor type being used. PMID- 21793008 TI - Comparison between self-guided Langevin dynamics and molecular dynamics simulations for structure refinement of protein loop conformations. AB - This article presents a comparative analysis of two replica-exchange simulation methods for the structure refinement of protein loop conformations, starting from low-resolution predictions. The methods are self-guided Langevin dynamics (SGLD) and molecular dynamics (MD) with a Nose-Hoover thermostat. We investigated a small dataset of 8- and 12-residue loops, with the shorter loops placed initially from a coarse-grained lattice model and the longer loops from an enumeration assembly method (the Loopy program). The CHARMM22 + CMAP force field with a generalized Born implicit solvent model (molecular-surface parameterized GBSW2) was used to explore conformational space. We also assessed two empirical scoring methods to detect nativelike conformations from decoys: the all-atom distance scaled ideal-gas reference state (DFIRE-AA) statistical potential and the Rosetta energy function. Among the eight-residue loop targets, SGLD out performed MD in all cases, with a median of 0.48 A reduction in global root-mean-square deviation (RMSD) of the loop backbone coordinates from the native structure. Among the more challenging 12-residue loop targets, SGLD improved the prediction accuracy over MD by a median of 1.31 A, representing a substantial improvement. The overall median RMSD for SGLD simulations of 12-residue loops was 0.91 A, yielding refinement of a median 2.70 A from initial loop placement. Results from DFIRE-AA and the Rosetta model applied to rescoring conformations failed to improve the overall detection calculated from the CHARMM force field. We illustrate the advantage of SGLD over the MD simulation model by presenting potential-energy landscapes for several loop predictions. Our results demonstrate that SGLD significantly outperforms traditional MD in the generation and populating of nativelike loop conformations and that the CHARMM force field performs comparably to other empirical force fields in identifying these conformations from the resulting ensembles. PMID- 21793009 TI - Reconsideration on hydrogen bond strengthening or cleavage of photoexcited coumarin 102 in aqueous solvent: a DFT/TDDFT study. AB - In this work, the excited-state hydrogen bonding dynamics of photoexcited coumarin 102 in aqueous solvent is reconsidered. The electronically excited states of the hydrogen bonded complexes formed by coumarin 102 (C102) chromophore and the hydrogen donating water solvent have been investigated using the time dependent density functional theory method. Two intermolecular hydrogen bonds between C102 and water molecules are considered. The previous works (Wells et al., J Phys Chem A 2008, 112, 2511) have proposed that one intermolecular hydrogen bond would be strengthened and the other one would be cleaved upon photoexcitation to the electronically excited states. However, our theoretical calculations have demonstrated that both the two intermolecular hydrogen bonds between C102 solute and H(2)O solvent molecules are significantly strengthened in electronically excited states by comparison with those in ground state. Hence, we have confirmed again that intermolecular hydrogen bonds between C102 chromophore and aqueous solvents are strengthened not cleaved upon electronic excitation, which is in accordance with Zhao's works. PMID- 21793010 TI - Theoretical study on the molecular structures of X-, alpha-, and beta-types of lithium phthalocyanine dimer. AB - We report here the results from theoretical calculations of the potential energy curves, the geometry optimizations, and the electronic structures for three dimers of lithium phthalocyanine (LiPc) by using three types of functional systems: PBE1PBE, B3LYP, and M06. The results were discussed in comparison with those obtained for the dimers of magnesium phthalocyanine (MgPc). The long-range dispersive interactions were considered in part using these functional systems in the increasing order of PBE1PBE, B3LYP, and M06. The mechanism whereby the dispersive interactions affect the geometric and electronic structures of the LiPc and MgPc dimers is discussed. The calculated results provide insight into the computational methods for both open- and closed-shell metal phthalocyanine (MPc) dimers: Although the PBE1PBE and B3LYP functional systems cannot evaluate a weak dispersion interaction appropriately, the M06 functional can estimate a weak dispersion interaction well in both open- and closed-shell MPc dimers. Basis set superposition error (BSSE) corrections play an important role for the quantitative analysis; however, the calculation results without BSSE corrections may be sufficient for the qualitative discussion on the properties of these dimers such as geometries, stabilities, electronic structures, and so on. PMID- 21793011 TI - Impact of different potentials on the structures and energies of clusters. AB - Cluster studies have attracted much interest in the past decades because of their extraordinary properties. To describe the interaction between atoms or molecules and predict the energies and structures, potential functions are developed. However, different potentials generally produce different structures and energies for a cluster. To study the effect of potentials on the structure of a cluster, He clusters in the size range of 13-140 are investigated by Lennard-Jones (LJ), Pirani, and Hartree-Fock-dispersion individual damping (HFD-ID) potential with dynamic lattice searching (DLS) method. Potential function curves, cluster structures, bonds, and energies of the global minima are compared. The results show that cluster energies decrease with the values of the potential functions, the differences between structures depend upon the disagreements of the potentials, and the preferable motif of a cluster changes from icosahedron to decahedron with the increase of the derivative of the short-range part of the potentials. PMID- 21793012 TI - Cell-free fetal DNA testing: a pilot study of obstetric healthcare provider attitudes toward clinical implementation. AB - OBJECTIVE: To provide a preliminary assessment of obstetric healthcare provider opinions surrounding implementation of cell-free fetal DNA testing. METHODS: A 37 question pilot survey was used to address questions around the translation and use of non-invasive prenatal testing using cell-free fetal DNA. The survey was distributed and collected at a Continuing Medical Education course on obstetrics and gynecology. RESULTS: Of 62 survey respondents, 73% were female and 87% held MD/DO degrees. Respondents generally agreed that patients want prenatal diagnostic information to help make decisions about a pregnancy and that cell free fetal DNA testing would encourage the testing of more patients for more conditions. However, there was an overall lack of knowledge or conviction about using this technology. Genetic counseling and professional society approval were deemed important to implementation, whereas the possibility of direct-to-consumer testing and government regulation produced mixed responses. Respondents indicated that they would be more likely to offer cell-free fetal DNA testing for chromosomal abnormalities and single-gene disorders, but would be cautious with respect to determination of sex and behavioral or late-onset conditions. CONCLUSION: Preliminary assessment indicates uncertainty among obstetric providers about the details of implementing cell-free fetal DNA testing and suggests expanded research on perspectives of this stakeholder group. PMID- 21793013 TI - Stem cell microRNAs in senescence and immortalization: novel players in cancer therapy. AB - The molecular etiology of malignancy remains one of the most challenging disease processes under scientific investigation; therefore, improved approaches for their treatment are urgently needed. MicroRNAs are highly conserved nonprotein coding RNAs that regulate gene expression. They are involved in important homeostatic processes, such as cellular proliferation, cell death and development, and affect many diseases, including cancer. High-throughput screenings based on microRNAs related to senescence/immortalization are potential tools for identifying novel proliferative microRNAs that might be involved in carcinogenesis. Recently, a subgroup of highly proliferative microRNAs, which belong to a cluster expressed exclusively in embryonic stem cells and their malignant derivatives (embryonic carcinoma cells), was revealed to play a role in senescence bypass, thereby providing immortalization to human cells. This finding supports the cancer stem cell theory and the relevance of microRNAs in human tumors. This article recapitulates the role of microRNAs that are associated with stem cell properties and their possible link in common pathways related to immortalization and cancer. Ultimately, cancer therapy that is based on the induction of a senescence response is proposed to be highly associated with the loss of stemness properties. Thus, it would be possible to "kill two birds with one stone": along with the inhibition of stemness properties in cancer stem cells, the senescence response could be induced to destroy the cancer stem cell population within a tumor. PMID- 21793014 TI - Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. AB - With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one-compound-one-target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid beta (Abeta) aggregation to form plaques, tau hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of beta and gamma secretase, vaccines or antibodies that clear Abeta, metal chelators to inhibit Abeta aggregation, blockers of glycogen synthase kinase 3beta, enhancers of mitochondrial function, antioxidants, modulators of calcium-permeable channels such as voltage-dependent calcium channels, N-methyl-D-aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one-compound-various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. PMID- 21793015 TI - Therapeutic potential of Galectin-9 in human disease. AB - In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) in health and disease. In normal physiology, Gal-9 seems to be a pivotal modulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations. Because these T-cell populations are associated with autoimmunity, inflammatory disease, and graft rejection, it was postulated that application of exogenous Gal-9 may limit pathogenic T-cell activity. Indeed, treatment with recombinant Gal-9 ameliorates disease activity in various preclinical models of autoimmunity and allograft graft rejection. In many solid cancers, the loss of Gal-9 expression is closely associated with metastatic progression. In line with this observation, treatment with recombinant Gal-9 prevents metastatic spread in various preclinical cancer models. In addition, various hematological malignancies are sensitive to apoptotic elimination by recombinant Gal-9. Here, we review the biology and physiological role of this versatile lectin and discuss the therapeutic potential of Gal-9 in various diseases, including autoimmunity, asthma, infection, and cancer. PMID- 21793016 TI - Radiohalogenated nonnatural amino acids as PET and SPECT tumor imaging agents. AB - Radiohalogenated alpha-amino acids are a diverse and useful class tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased rates of amino acid transport exhibited by many tumor cells. The most established clinical use for radiolabeled amino acids is imaging primary and recurrent gliomas, and there is growing evidence that they may also be useful for other oncologic applications, including neuroendocrine tumors and prostate cancer. This review focuses on the synthesis, radiolabeling, and preclinical evaluation of three series of nonnatural radiohalogenated amino acids: alicyclic, alpha,alpha-dialkyl, and 1H [1,2,3]triazole amino acids which target system L, system A, and cationic amino acid transport systems, respectively. PMID- 21793017 TI - Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. AB - Exogenous 5-aminolevulinic acid (ALA) is taken up directly by bacteria, yeasts, fungi, and some parasites, which then induces the accumulation of protoporphyrin IX (PPIX). Subsequent light irradiation of PPIX leads to the inactivation of these organisms via photodamage to their cellular structures. ALA uptake and light irradiation of PPIX produced by host cells leads to the inactivation of other parasites, along with some viruses, via the induction of an immune response. ALA-mediated PPIX production by host cells and light irradiation result in the inactivation of other viruses via either the induction of a host cell response or direct photodynamic attack on viral particles. This ALA-mediated production of light-activated PPIX has been extensively used as a form of photodynamic therapy (PDT) and has shown varying levels of efficacy in treating conditions that are associated with microbial infection, ranging from acne and verrucae to leishmaniasis and onychomycosis. However, for the treatment of some of these conditions by ALA-based PDT, the role of an antimicrobial effect has been disputed and in general, the mechanisms by which the technique inactivates microbes are not well understood. In this study, we review current understanding of the antimicrobial mechanisms used by ALA-based PDT and its role in the treatment of microbial infections along with its potential medical and nonmedical applications. PMID- 21793018 TI - Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. AB - This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice. PMID- 21793019 TI - MicroRNA-199a/b-3p: a new star in the liver microcosmos. PMID- 21793020 TI - Sinusoidal endothelium is essential for liver regeneration. PMID- 21793021 TI - Von Meyenburg complexes mimicking liver metastases. PMID- 21793022 TI - Hepatic tuberculosis in a patient treated with infliximab. PMID- 21793023 TI - Prominent regulatory but weak antigen-presenting cell function of hepatic stellate cells. PMID- 21793024 TI - Noninvasive assessment of liver fibrosis: the clinical context and question are important. PMID- 21793025 TI - I148M variant of PNPLA3 confer increased risk for nonalcoholic fatty liver disease not only in European population, but also in Chinese population. PMID- 21793027 TI - Prevention of recurrence after resection of hepatocellular carcinoma: a daunting challenge. PMID- 21793026 TI - Identification and expansion of a unique stem cell population from adult mouse gallbladder. AB - The identification of resident stem cells in the mouse gallbladder is, to date, unexplored. In addition, the relationship between adult gallbladder stem cells and intrahepatic bile duct (IHBD) cells is not well understood. The aim of this study was to isolate stem cells from an adult mouse gallbladder and determine whether they were unique, compared to IHBD cells. By limiting dilution analyses and index sorts, we found that an EpCAM(+) CD49f(hi) epithelial cell subpopulation from primary gallbladder is enriched in colony-forming cells, compared to EpCAM(+) CD49f(lo) cells. EpCAM(+) CD49f(hi) cells expressed cluster of differentiation (CD)29, CD133, and stem cell antigen-1, but were negative for lineage markers CD31, CD45, and F4/80. Using a novel feeder cell-culture system, we observed long-term (>passage 20) and clonal expansion of the EpCAM(+) CD49f(hi) cells in vitro. In a matrigel differentiation assay, EpCAM(+) CD49f(+) cells expanding in vitro underwent organotypic morphogenesis forming ductular structures and cysts. These structures are similar to, and recapitulate a transport function of, primary gallbladder. EpCAM(+) CD49f(+) cells also engraft into the subcutaneous space of recipient mice. We compared primary gallbladder and IHBD cells by flow cytometry and found phenotypic differences in the expression of CD49f, CD49e, CD81, CD26, CD54, and CD166. In addition, oligonucleotide microarrays showed that the expanded EpCAM(+) CD49f(+) gallbladder cells and IHBD cells exhibit differences related to lipid and drug metabolism. Notable genes that were different are cytochrome P450, glutathione S transferase, Indian hedgehog, and solute carrier family genes. CONCLUSION: We have isolated an epithelial cell population from primary mouse gallbladder with stem cell characteristics and found it to be unique, compared to IHBD cells. PMID- 21793028 TI - Cancer surveillance in patients with primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory syndrome involving the biliary tract, often accompanied by inflammatory bowel disease (IBD). This syndrome is a prototype disease linking chronic inflammation to carcinogenesis. Indeed, PSC is associated with an increased risk of cholangiocarcinoma (CCA), gallbladder cancer, hepatocellular carcinoma (HCC), and colorectal cancer. Herein, we review the risk for these malignancies in PSC and discuss rational cancer surveillance strategies for these patients. Where evidence is limited, we suggest a pragmatic approach. In this regard, we recommend interval screening for CCA with noninvasive imaging modalities and serum carbohydrate antigen 19-9 determinations annually. These imaging studies also serve to screen for gallbladder cancer and HCC. Screening for colorectal cancer is more firmly established in PSC patients with IBD and includes colonoscopy at the time of PSC diagnosis and, thereafter, at 1-2-year intervals. We also highlight areas where more information is required, such as management of biliary tract dysplasia and cancer chemoprevention in PSC. PMID- 21793029 TI - Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. AB - Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-epsilon activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a ~ 70% increase in hepatic triglyceride uptake and ~ 50% reduction hepatic triglyceride secretion. CONCLUSION: These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance. PMID- 21793030 TI - Hepatocytes internalize trophic receptors at large endocytic "Hot Spots". AB - Clathrin-mediated endocytosis in mammalian epithelial cells is believed to require the synergistic action of structural coat proteins and mechanochemical enzymes to deform and sever the plasma membrane (PM) into discreet vesicles. It is generally believed that the formation of clathrin-coated pits in epithelial cells occurs randomly along the apical and basolateral plasma membranes. In this study we visualized the endocytic machinery in living hepatocytes using green fluorescent protein (GFP)-tagged dynamin, a large mechanochemical guanosine triphosphate (GTP)ase implicated in the liberation of nascent vesicles from the plasma membrane and a variety of internal membrane compartments. Confocal microscopy of living cells expressing the epithelial isoform of GFP-tagged dynamin [Dyn2-GFP] revealed a distribution along the ventral PM in discrete vesicle-like puncta or in large (2-10 MUm) tubuloreticular plaques. Remarkably, these large structures are dynamic as they form and then disappear, while generating large numbers of motile endocytic vesicles with which dynamin associates. Inhibiting dynamin function by microinjection of purified dynamin antibodies increases the number and size of the tubuloreticular plaques. Importantly, these "hot spots" sequester specific trophic receptors and cognate ligands such as transferrin receptor 1 (TfR1), but not TfR2. CONCLUSION: These findings suggest that hepatocytes sequester or prerecruit both structural and enzymatic components of the clathrin-based endocytic machinery to functional hot spots, from which large numbers of coated pits form and vesicles are generated. This process may mimic the endocytic organization found at the synapse in neuronal cells. PMID- 21793031 TI - The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. AB - Cholangiocarcinoma (CCA) is a biliary cancer arising from damaged bile ducts. Epithelial-mesenchymal transition (EMT) occurs as epithelial cells begin to resemble mesenchymal cells leading to increased invasion potential as the extracellular matrix (ECM) degrades. Histamine exerts its effects by way of four receptors (H1-H4 HRs). Clobenpropit, a potent H4HR agonist, inhibits mammary adenocarcinoma growth. We have shown that (1) cholangiocytes and CCA cells express H1-H4 HRs and (2) the H3HR decreases CCA proliferation. We evaluated the effects of clobenpropit on CCA proliferation, invasion, EMT phenotypes, and ECM degradation. In vitro, we used CCA cell lines to study proliferation, signaling pathways, and the morphological invasive potential. Gene and protein expression of the hepatobiliary epithelial markers CK-7, CK-8, and CK-19, the focal contact protein paxillin, and the mesenchymal markers fibronectin, s100A4, and vimentin were evaluated. Cell invasion across an ECM layer was quantitated and matrix metalloproteinase-1, -2, -3, -9, and -11 gene and protein expression was examined. Evaluation of the specific role of H4HR was performed by genetic knockdown of the H3HR and overexpression of H4HR. Proliferation was evaluated by proliferating cellular nuclear antigen immunoblotting. In vivo, xenograft tumors were treated with either vehicle or clobenpropit for 39 days. Tumor volume was recorded every other day. Clobenpropit significantly decreased CCA proliferation by way of a Ca(2+) -dependent pathway and altered morphological development and invasion. Loss of H3HR expression or overexpression of H4HR significantly decreased CCA proliferation. In vivo, clobenpropit inhibited xenograft tumor growth compared with controls. CONCLUSION: Modulation of H4HR by clobenpropit disrupts EMT processes, ECM breakdown, and invasion potential and decreases tumor growth. Interruption of tumorigenesis and invasion by histamine may add to therapeutic advances for CCAs. PMID- 21793032 TI - Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. AB - Vitamin D supplementation was reported to improve the probability of achieving a sustained virological response when combined with antiviral treatment against hepatitis C virus (HCV). Our aim was to determine the in vitro potential of vitamin D to inhibit HCV infectious virus production and explore the mechanism(s) of inhibition. Here we show that vitamin D(3) remarkably inhibits HCV production in Huh7.5 hepatoma cells. These cells express CYP27B1, the gene encoding for the enzyme responsible for the synthesis of the vitamin D hormonally active metabolite, calcitriol. Treatment with vitamin D(3) resulted in calcitriol production and induction of calcitriol target gene CYP24A1, indicating that these cells contain the full machinery for vitamin D metabolism and activity. Notably, treatment with calcitriol resulted in HCV inhibition. Collectively, these findings suggest that vitamin D(3) has an antiviral activity which is mediated by its active metabolite. This antiviral activity involves the induction of the interferon signaling pathway, resulting in expression of interferon-beta and the interferon-stimulated gene, MxA. Intriguingly, HCV infection increased calcitriol production by inhibiting CYP24A1 induction, the enzyme responsible for the first step in calcitriol catabolism. Importantly, the combination of vitamin D(3) or calcitriol and interferon-alpha synergistically inhibited viral production. CONCLUSION: This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system. It proposes an interplay between the hepatic vitamin D endocrine system and HCV, suggesting that vitamin D has a role as a natural antiviral mediator. Importantly, our study implies that vitamin D might have an interferon-sparing effect, thus improving antiviral treatment of HCV-infected patients. PMID- 21793034 TI - MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. AB - Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. We previously found that microRNA-29b (miR-29b) down-regulation was significantly associated with poor recurrence-free survival of HCC patients. Therefore, the role of miR-29b in tumor angiogenesis, invasion, and metastasis was further investigated in this study using in vitro capillary tube formation and transwell assays, in vivo subcutaneous and orthotopic xenograft mouse models, and Matrigel plug assay, and human HCC samples. Both gain- and loss-of-function studies showed that miR-29b dramatically suppressed the ability of HCC cells to promote capillary tube formation of endothelial cells and to invade extracellular matrix gel in vitro. Using mouse models, we revealed that tumors derived from miR-29b-expressed HCC cells displayed significant reduction in microvessel density and in intrahepatic metastatic capacity compared with those from the control group. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) was a direct target of miR-29b. The blocking of MMP-2 by neutralizing antibody or RNA interference phenocopied the antiangiogenesis and antiinvasion effects of miR 29b, whereas introduction of MMP-2 antagonized the function of miR-29b. We further disclosed that miR-29b exerted its antiangiogenesis function, at least partly, by suppressing MMP-2 expression in tumor cells and, in turn, impairing vascular endothelial growth factor receptor 2-signaling in endothelial cells. Consistently, in human HCC tissues and mouse xenograft tumors miR-29b level was inversely correlated with MMP-2 expression, as well as tumor angiogenesis, venous invasion, and metastasis. CONCLUSION: miR-29b deregulation contributes to angiogenesis, invasion, and metastasis of HCC. Restoration of miR-29b represents a promising new strategy in anti-HCC therapy. PMID- 21793033 TI - Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication. AB - Studies of the hepatitis C virus (HCV) life-cycle rely heavily on Huh7.5 cells, but the reasons why these cells are exceptionally permissive for HCV replication are not clear. Based on recent clinical observations, we hypothesized that the Hedgehog (Hh) pathway, which has not been previously associated with HCV replication, may be involved in the Huh7.5 phenotype of increased permissiveness. We tested this hypothesis by comparing levels of a variety of Hh-related cellular markers in Huh7.5 cells with the parental Huh7 cells, which are far less permissive. Here we demonstrate that Huh7.5 cells, when compared with Huh7 cells, have substantially decreased expression of epithelial markers, increased levels of mesenchymal markers, and markedly up-regulated Hh pathway activity: Shh, >100 fold, Gli1, >30-fold, Ptc, 2-fold. In Huh7.5 cells, we found that cyclopamine, an Hh pathway antagonist, reduced HCV RNA levels by 50% compared with vehicle and inactive isomer controls. Moreover, in Huh7 cells treatment with recombinant Shh ligand and SAG, both Hh pathway agonists, stimulated HCV replication by 2-fold and 4-fold, respectively. These effects were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. CONCLUSION: We have identified a relationship between HCV and Hh signaling where up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics. PMID- 21793036 TI - Model-based analyses of bioequivalence crossover trials using the stochastic approximation expectation maximisation algorithm. AB - In this work, we develop a bioequivalence analysis using nonlinear mixed effects models (NLMEM) that mimics the standard noncompartmental analysis (NCA). We estimate NLMEM parameters, including between-subject and within-subject variability and treatment, period and sequence effects. We explain how to perform a Wald test on a secondary parameter, and we propose an extension of the likelihood ratio test for bioequivalence. We compare these NLMEM-based bioequivalence tests with standard NCA-based tests. We evaluate by simulation the NCA and NLMEM estimates and the type I error of the bioequivalence tests. For NLMEM, we use the stochastic approximation expectation maximisation (SAEM) algorithm implemented in monolix. We simulate crossover trials under H(0) using different numbers of subjects and of samples per subject. We simulate with different settings for between-subject and within-subject variability and for the residual error variance. The simulation study illustrates the accuracy of NLMEM based geometric means estimated with the SAEM algorithm, whereas the NCA estimates are biased for sparse design. NCA-based bioequivalence tests show good type I error except for high variability. For a rich design, type I errors of NLMEM-based bioequivalence tests (Wald test and likelihood ratio test) do not differ from the nominal level of 5%. Type I errors are inflated for sparse design. We apply the bioequivalence Wald test based on NCA and NLMEM estimates to a three-way crossover trial, showing that Omnitrope(r); (Sandoz GmbH, Kundl, Austria) powder and solution are bioequivalent to Genotropin(r); (Pfizer Pharma GmbH, Karlsruhe, Germany). NLMEM-based bioequivalence tests are an alternative to standard NCA-based tests. However, caution is needed for small sample size and highly variable drug. PMID- 21793037 TI - Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. AB - Endothelial dysfunction is a trigger for the formation of cerebral aneurysm (CA). The circulating endothelial progenitor cell (EPC) plays an important role in postnatal vasculogenesis and reduction of endothelial injury. In this study, we tested the hypothesis that decreased number and impaired function of circulating EPCs correlate with CA formation in patients. Blood circulating EPCs were identified by flow cytometry. The level of plasma vascular endothelial growth factor (VEGF) was measured by ELISA. Circulating EPCs from patients (n = 27) were cultured in vitro, and the function of EPCs was evaluated by cell migration and senescence-associated beta-galactosidase activity. The number of circulating EPCs was significantly decreased in both unruptured and ruptured CA patients compared with healthy control subjects. Impaired migratory capacity and elevated cellular senescence of cultured EPCs were observed in patients with CA (ruptured and unruptured). The percentages of EPC senescence in patients with CAs were significantly and negatively correlated with the number of circulating EPCs. In addition, there were higher levels of plasma VEGF in CA patients compared with healthy control subjects. Our results show that the numbers and functions of circulating EPCs are reduced in patients with CAs. These findings suggest that the decreased number and impaired function of circulating EPCs in CA patients may contribute to the pathophysiological process of aneurysm formation. PMID- 21793038 TI - Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease. AB - Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin-treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid-beta deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin. PMID- 21793039 TI - Migration and remyelination by oligodendrocyte progenitor cells transplanted adjacent to focal areas of spinal cord inflammation. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Exogenous cell replacement in MS lesions has been proposed as a means of achieving remyelination when endogenous remyelination has failed. However, the ability of exogenous cells to remyelinate axons in the presence of inflammation remains uncertain. We have explored the remyelinating capacity of an oligodendrocyte progenitor cell line CG-4 transduced with the GFP gene and transplanted adjacent to a zymosan-induced focal demyelination model in the rat spinal cord. The resulting zymosan-induced lesions were characterized by persistent macrophage/microglia activation, focal demyelination, degeneration of axons, and reactive astrogliosis. GFP(+) CG-4 cells were found to migrate preferentially toward the inflammatory lesion and survive inside the lesion. A proportion of GFP(+) CG-4 cells differentiated into mature oligodendrocytes and remyelinated axons within the lesion. These findings suggest that grafted oligodendrocyte progenitors may migrate toward areas of inflammation in the adult rat spinal cord, where they can survive and differentiate into myelinating oligodendrocytes. PMID- 21793040 TI - Estradiol attenuates the adenosine triphosphate-induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat dorsal root ganglion neurons. AB - Estradiol attenuates the ATP-induced increase of intracellular calcium concentration ([Ca(2+)](i)) in rat dorsal root ganglion (DRG) neurons by blocking the L-type voltage gated calcium channel (VGCC). Because ATP is a putative nociceptive signal, this action may indicate a site of estradiol regulation of pain. In other neurons, 17beta-estradiol (E(2)) has been shown to modulate L-type VGCC through a membrane estrogen receptor-group II metabotropic glutamate receptor (mGluR(2/3)). The present study investigated whether the rapid estradiol attenuation of the ATP-induced increase in [Ca(2+)](i) requires mGluR(2/3). Previously we showed that DRG (L(1)-S(3)) express ERalpha, P2X(3), and mGluR(2/3) receptors. DRG were acutely dissociated by enzyme digestion and grown in short term culture for imaging analysis. DRG neurons were stimulated twice, once with ATP (50 MUM) for 5 sec and then again in the presence of E(2) (100 nM) or E(2) (100 nM) + LY341495 (100 nM), an mGluR(2/3) inhibitor. ATP induced a transient increase in [Ca(2+)](i) (216.3 +/- 41.2 nM). This transient increase could be evoked several times in the same DRG neurons if separated by a 5-min washout. Treatment with estradiol significantly attenuated the ATP-induced [Ca(2+)](i) increase in 60% of the DRG neurons, to 163.3 +/- 20.9 nM (P < 0.001). Coapplication of E(2) and the mGluR(2/3) inhibitor LY341495 blocked the 17beta estradiol attenuation of the ATP-induced [Ca(2+) ](i) transient (209.1 +/- 32.2 nM, P > 0.05). These data indicate that the rapid action of E(2) in DRG neurons is dependent on mGluR(2/3) and demonstrate that membrane estrogen receptor-alpha initiated signaling involves interaction with mGluRs. PMID- 21793041 TI - High CJD infectivity remains after prion protein is destroyed. AB - The hypothesis that host prion protein (PrP) converts into an infectious prion form rests on the observation that infectivity progressively decreases in direct proportion to the decrease of PrP with proteinase K (PK) treatment. PrP that resists limited PK digestion (PrP-res, PrP(sc)) has been assumed to be the infectious form, with speculative types of misfolding encoding the many unique transmissible spongiform encephalopathy (TSE) agent strains. Recently, a PK sensitive form of PrP has been proposed as the prion. Thus we re-evaluated total PrP (sensitive and resistant) and used a cell-based assay for titration of infectious particles. A keratinase (NAP) known to effectively digest PrP was compared to PK. Total PrP in FU-CJD infected brain was reduced to <=0.3% in a 2 h PK digest, yet there was no reduction in titer. Remaining non-PrP proteins were easily visualized with colloidal gold in this highly infectious homogenate. In contrast to PK, NAP digestion left 0.8% residual PrP after 2 h, yet decreased titer by >2.5 log; few residual protein bands remained. FU-CJD infected cells with 10* the infectivity of brain by both animal and cell culture assays were also evaluated. NAP again significantly reduced cell infectivity (>3.5 log). Extreme PK digestions were needed to reduce cell PrP to <0.2%, yet a very high titer of 8 logs survived. Our FU-CJD brain results are in good accord with the only other report on maximal PrP destruction and titer. It is likely that one or more residual non-PrP proteins may protect agent nucleic acids in infectious particles. PMID- 21793043 TI - Stem cell activation in adults can reverse detrimental changes in body composition to reduce fat and increase lean mass in both sexes. AB - Detrimental changes in body composition are often associated with declining levels of testosterone. Here, we evaluated the notion that multipotent mesenchymal stem cells, that give rise to both fat and muscle tissue, can play a significant role to alter existing body composition in the adult. Transgenic mice with targeted androgen receptor (AR) overexpression in stem cells were employed. Wild-type littermate and AR-transgenic male and female mice were gonadectomized and left untreated for 2 months. After the hypogonadal period, mice were then treated with 5alpha-dihydrotestosterone (DHT) for 6 weeks. After orchidectomy (ORX), wild-type males have reduced lean mass and increased fat mass compared to shams. DHT treatment was beneficial to partially restore body composition. In wild-type females, ovariectomy (OVX) produced a similar change but there was no improvement with DHT. In targeted AR transgenic mice, DHT treatment increased lean and reduced fat mass to sham levels. In contrast to wild-type females, DHT treatment in female transgenic mice significantly ameliorated the increased fat and decreased lean mass changes that result after OVX. Our results show that DHT administration reduces fat mass and increases lean mass in wild-type males but not females, indicating that wild-type females are not as sensitive to androgen treatment. Because both male and female transgenic mice are more responsive than wild-type, results suggest that body composition remains linked to stem cell fate in the adult and that targeted androgen signaling in stem cells can play a significant role to reverse detrimental changes in body composition in both sexes. PMID- 21793042 TI - Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. AB - Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent progenitors that can commit to osteoblast, chondrocyte, adipocyte, and several other lineages. The proper utilization of stem cells for clinical applications requires an integrated understanding of multiple signal inputs that control maintenance of stemness, proliferation, commitment, and differentiation. Various signaling pathways have been implicated in the regulation of MSC differentiation; however, complexities of pathway interactions, as well as seemingly contradictory results in the literature, create an often confusing and disjointed knowledge base. Several recent publications explore the integration of signaling pathways such as BMP, Wnt, Notch, Hedgehog, and Fibroblast Growth Factors in MSC osteoblast differentiation. The transcription factor Cbfa1/Runx2 has been implicated in these pathways as a potential focal point for signaling integration. This review will outline the current understanding of these pathways and indicate where both spatiotemporal effects during differentiation and comparable experimental conditions need to be considered in order to clarify the outcome(s) of differing regulatory levels of these signaling pathways. PMID- 21793044 TI - Physical and functional interactions between Runx2 and HIF-1alpha induce vascular endothelial growth factor gene expression. AB - Angiogenesis and bone formation are intimately related processes. Hypoxia during early bone development stabilizes hypoxia-inducible factor-1alpha (HIF-1alpha) and increases angiogenic signals including vascular endothelial growth factor (VEGF). Furthermore, stabilization of HIF-1alpha by genetic or chemical means stimulates bone formation. On the other hand, deficiency of Runx2, a key osteogenic transcription factor, prevents vascular invasion of bone and VEGF expression. This study explores the possibility that HIF-1alpha and Runx2 interact to activate angiogenic signals. Runx2 over-expression in mesenchymal cells increased VEGF mRNA and protein under both normoxic and hypoxic conditions. In normoxia, Runx2 also dramatically increased HIF-1alpha protein. In all cases, the Runx2 response was inhibited by siRNA-mediated suppression of HIF-1alpha and completely blocked by the HIF-1alpha inhibitor, echinomycin. Similarly, treatment of preosteoblast cells with Runx2 siRNA reduced VEGF mRNA in normoxia or hypoxia. However, Runx2 is not essential for the HIF-1alpha response since VEGF is induced by hypoxia even in Runx2-null cells. Endogenous Runx2 and HIF-1alpha were colocalized to the nuclei of MC3T3-E1 preosteoblast cells. Moreover, HIF-1alpha and Runx2 physically interact using sites within the Runx2 RUNT domain. Chromatin immunoprecipitation also provided evidence for colocalization of Runx2 and HIF 1alpha on the VEGF promoter. In addition, Runx2 stimulated HIF-1alpha-dependent activation of an HRE-luciferase reporter gene without requiring a separate Runx2 binding enhancer. These studies indicate that Runx2 functions together with HIF 1alpha to stimulate angiogenic gene expression in bone cells and may in part explain the known requirement for Runx2 in bone vascularization. PMID- 21793045 TI - Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-kappaB inactivation to regulate breast cancer cell invasion. AB - Transcriptional factor nuclear factor-kappaB (NF-kappaB) plays a crucial role in human breast cancer cell invasion and metastasis. The carboxyl terminus of Hsc70 interacting protein (CHIP) is a U-box-type ubiquitin ligase that induces ubiquitination and proteasomal degradation of its substrate proteins. In this study, we investigated the role of CHIP in the NF-kappaB pathway in the invasion of MDA-MB-231 cells, a highly aggressive breast cancer cell line. We showed that overexpression of CHIP significantly inhibits the invasion of the MDA-MB-231 cells. The overexpression of CHIP suppressed expression of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in MDA-MB-231 cells. Moreover, CHIP strongly inhibited the nuclear localization and the transcriptional activity of NF-kappaB. The activation of the IkappaB kinase complex (IKK) was also blocked by CHIP overexpression. Importantly, CHIP overexpression resulted in a significant decrease in the level of TNF receptor associated factor 2 (TRAF2), an upstream key player in the NF-kappaB pathway. However, the level of TRAF2 was restored after treatment with a proteasome inhibitor, MG-132. Moreover, CHIP overexpression promoted the ubiquitination of TRAF2. We also found cell invasion significantly decreased in cells transfected with TRAF2 small interfering RNA (siRNA). In contrast, when CHIP expression was suppressed by siRNA in poorly invasive MCF-7 cells, cell invasion significantly increased in conjunction with enhanced NF-kappaB activation and TRAF2 levels. Taken together, these results suggest that CHIP regulates NF-kappaB-mediated cell invasion via the down-regulation of TRAF2. PMID- 21793046 TI - Trauma centrality and PTSD symptom severity in adult survivors of childhood sexual abuse. AB - Theorists have posited that regarding a trauma as central to one's identity leads to greater posttraumatic stress disorder (PTSD) symptom severity. To test this hypothesis, we administered the Centrality of Events Scale (CES) to women reporting a history of childhood sexual abuse (N = 102). The CES scores were correlated with PTSD symptom severity, depression severity, and self-esteem. In addition, we conducted a principal component analysis (PCA) to evaluate factors underlying the CES. The PCA yielded 3 factors reflecting (a) the centrality and integration of the trauma, (b) whether the event is regarded as a turning point in one's life story, and (c) whether the event is a reference point for expectations about the future. Each factor was associated with PTSD symptom severity. PMID- 21793047 TI - Group cognitive processing therapy delivered to veterans via telehealth: a pilot cohort. AB - The authors report clinical findings from the pilot cohort of the first prospective, noninferiority-designed randomized clinical trial evaluating the clinical outcomes of delivering a cognitive-behavioral group intervention for posttraumatic stress disorder (PTSD), cognitive processing therapy (CPT), via video teleconferencing (VT) compared to the in-person modality. The treatment was delivered to 13 veterans with PTSD residing on the Hawaiian Islands. Results support the general feasibility and safety of using VT. Both groups showed clinically meaningful reductions in PTSD symptoms and no significant between group differences on clinical or process outcome variables. In keeping with treatment manual recommendations, a few changes were made to the CPT protocol to accommodate this population. Novel aspects of this trial and lessons learned are discussed. PMID- 21793050 TI - Capsosomes with "free-floating" liposomal subcompartments. PMID- 21793051 TI - Bio-inspired borate cross-linking in ultra-stiff graphene oxide thin films. AB - Adjacent graphene oxide nanosheets in a thin-film structure have been covalently cross-linked in a fashion similar to the cell walls of higher-order plants. The resulting ultra-stiff structure exhibits a maximum storage modulus of 127 GPa that can be tuned by varying borate concentration. PMID- 21793052 TI - PZT Nanoactive Fiber Composites for Acoustic Emission Detection. PMID- 21793053 TI - Macroscopic alignment of lyotropic liquid crystals using magnetic nanoparticles. PMID- 21793054 TI - Photoinduced dispersibility tuning of carbon nanotubes by a water-soluble stilbene as a dispersant. PMID- 21793055 TI - Organic electrochemical transistors integrated in flexible microfluidic systems and used for label-free DNA sensing. PMID- 21793056 TI - Supramolecular hydrogel of bile salts triggered by single-walled carbon nanotubes. PMID- 21793057 TI - Total synthesis of bryostatins: the development of methodology for the atom economic and stereoselective synthesis of the ring C subunit. AB - Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins. PMID- 21793058 TI - Versatile low-molecular-weight hydrogelators: achieving multiresponsiveness through a modular design. AB - Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic-hydrophilic balance of the LMWH. PMID- 21793059 TI - Conception, synthesis, and biological evaluation of original discodermolide analogues. AB - Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM. PMID- 21793060 TI - Mechanisms and efficiency of the simultaneous removal of metals and cyanides by using ferrate(VI): crucial roles of nanocrystalline iron(III) oxyhydroxides and metal carbonates. AB - The reaction of potassium ferrate(VI), K(2)FeO(4), with weak-acid dissociable cyanides--namely, K(2)[Zn(CN)(4)], K(2)[Cd(CN)(4)], K(2)[Ni(CN)(4)], and K(3)[Cu(CN)(4)]--results in the formation of iron(III) oxyhydroxide nanoparticles that differ in size, crystal structure, and surface area. During cyanide oxidation and the simultaneous reduction of iron(VI), zinc(II), copper(II), and cadmium(II), metallic ions are almost completely removed from solution due to their coprecipitation with the iron(III) oxyhydroxides including 2-line ferrihydrite, 7-line ferrihydrite, and/or goethite. Based on the results of XRD, Mossbauer and IR spectroscopies, as well as TEM, X-ray photoelectron emission spectroscopy, and Brunauer-Emmett-Teller measurements, we suggest three scavenging mechanisms for the removal of metals including their incorporation into the ferrihydrite crystal structure, the formation of a separate phase, and their adsorption onto the precipitate surface. Zn and Cu are preferentially and almost completely incorporated into the crystal structure of the iron(III) oxyhydroxides; the formation of the Cd-bearing, X-ray amorphous phase, together with Cd carbonate is the principal mechanism of Cd removal. Interestingly, Ni remains predominantly in solution due to the key role of nickel(II) carbonate, which exhibits a solubility product constant several orders of magnitude higher than the carbonates of the other metals. Traces of Ni, identified in the iron(III) precipitate, are exclusively adsorbed onto the large surface area of nanoparticles. We discuss the relationship between the crystal structure of iron(III) oxyhydroxides and the mechanism of metal removal, as well as the linear relationship observed between the rate constant and the surface area of precipitates. PMID- 21793061 TI - Unusually long, multicenter, cation(delta+)...anion(delta-) bonding observed for several polymorphs of [TTF][TCNE]. AB - The alpha, beta, and delta polymorphs of [TTF][TCNE] (TTF=tetrathiafulvalene; TCNE=tetracyanoethylene) exhibit a new type of long, multicenter bonding between the [TTF](delta+) and [TCNE](delta-) moieties, demonstrating the existence of long, hetero-multicenter bonding with a cationic(delta+)...anionic(delta-) zwitterionic-like structure. These diamagnetic pi-[TTF](delta+) [TCNE](delta-) heterodimers exhibit a transfer of about 0.5 e(-) from the TTF to the TCNE fragments, as observed from experimental studies, in accord with theoretical predictions, that is, [TTF(delta+)...TCNE(delta-)] (delta?0.5). They have several interfragment distances <3.4 A, and a computed interaction energy of -21.2 kcal mol(-1), which is typical of long, multicenter bonds. The lower stability of [TTF](delta+) [TCNE](delta-) with respect to typical ionic bonds is due, in part, to the partial electron transfer that reduces the electrostatic bonding component. This reduced electrostatic interaction, and the large interfragment dispersion stabilize the long, heterocationic/anionic multicenter interaction, which in [TTF(delta+)...TCNE(delta-)] always involves two electrons, but have ten, eight, and eight bond critical points (bcps) involving C-C, N-S, and sometimes C-S and C-N components for the alpha, beta, and delta polymorphs, respectively. In contrast, gamma-[TTF][TCNE] possesses [TTF](2)(2+) and [TCNE](2)(2-) dimers, each with long, homo-multicenter 2e(-)/12c (c=center, 2 C+4 S) [TTF](2)(2+) cationic(+)...cationic(+) bonds, as well as long, homo multicenter 2e(-)/4c [TCNE](2)(2-) anionic(-)...anionic(-) bonding. The MO diagrams for the alpha, beta, and delta polymorphs have all of the features found for conventional covalent C-C bonds, and for all of the previously studied multicenter long bonds, for example, pi-[TTF](2)(2+) and pi-[TCNE](2)(2-). The HOMOs for alpha-, beta-, and delta-[TTF][TCNE] have 2c C-S and 3c C-C-C orbital overlap contributions between the [TTF](delta+-) and [TCNE](delta-) moieties; these are the shortest intra [TTF...TCNE] separations. Thus, from an orbital overlap perspective, the bonding has 2c and 3c components residing over one S and four C atoms. PMID- 21793062 TI - Probing lipid peroxidation by using linoleic acid and benzophenone. AB - A thorough mechanistic study has been performed on the reaction between benzophenone (BZP) and a series of 1,4-dienes, including 1,4-cyclohexadiene (CHD), 1,4-dihydro-2-methylbenzoic acid (MBA), 1,4-dihydro-1,2-dimethylbenzoic acid (DMBA) and linoleic acid (LA). A combination of steady-state photolysis, laser flash photolysis (LFP), and photochemically induced dynamic nuclear polarization (photo-CIDNP) have been used. Irradiation of BZP and CHD led to a cross-coupled sensitizer-diene product, together with 6, 7, and 8. With MBA and DMBA as hydrogen donors, photoproducts arising from cross-coupling of sensitizer and diene radicals were found; compound 7 was also obtained, but 6 and o-toluic acid were only isolated in the irradiation of BZP with MBA. Triplet lifetimes were determined in the absence and in the presence of several diene concentrations. All three model compounds showed similar reactivity (k(q) ~10(8) M(-1) s(-1)) towards triplet excited BZP. Partly reversible hydrogen abstraction of the allylic hydrogen atoms of CHD, MBA, and DMBA was also detected by photo CIDNP on different timescales. Polarizations of the diamagnetic products were in full agreement with the results derived from LFP. Finally, LA also underwent partly reversible hydrogen abstraction during photoreaction with BZP. Subsequent hydrogen transfer between primary radicals led to conjugated derivatives of LA. The unpaired electron spin population in linoleyl radical (LA(.)) was predominantly found on H(1-5) protons. To date, LA-related radicals were only reported upon hydrogen transfer from highly substituted model compounds by steady state EPR spectroscopy. Herein, we have experimentally established the formation of LA(.) and shown that it converts into two dominating conjugated isomers on the millisecond timescale. Such processes are at the basis of alterations of membrane structures caused by oxidative stress. PMID- 21793063 TI - C-N bond formation by O(2)-mediated dehydrogenative coupling of phenyl and NH pyridylidene ligands on Tp (Me 2)Ir(III) complexes. PMID- 21793064 TI - Palladium-catalyzed regioselective aerobic oxidative C-H/N-H carbonylation of heteroarenes under base-free conditions. PMID- 21793065 TI - Diverted domino reactivity in tertiary skipped diynes: a convenient access to polyfunctionalized cyclohexadienones and multivalent aromatic scaffolds. PMID- 21793066 TI - Specific cleavage at peptide backbone Calpha-C and CO-N bonds during matrix assisted laser desorption/ionization in-source decay mass spectrometry with 5 nitrosalicylic acid as the matrix. AB - The use of 5-nitrosalicylic acid (5-NSA) as a matrix for in-source decay (ISD) of peptides during matrix-assisted laser desorption/ionization (MALDI) is described herein. Mechanistically, the decay process is initiated by a hydrogen abstraction from a peptide backbone amide nitrogen by 5-NSA. Hydrogen abstraction results in formation of an oxidized peptide containing a radical amide nitrogen. Subsequently, the C(alpha)-C bond N-terminal to the peptide bond is cleaved to form an a./x fragment pair. The C(alpha)-C bonds C-terminal to Gly residues were less susceptible to cleavage than were those of other residues. C(alpha)-C bonds N-terminal to Pro and Sar residues were not cleaved by the aforementioned mechanism; instead, after hydrogen abstraction from a Pro or Sar C(alpha)-H bond, the peptide bond N-terminal to the Pro was cleaved yielding b- and y-series ions. We also show that fragments produced by MALDI 5-NSA-induced ISD were formed independently of the ionization process. PMID- 21793067 TI - Increasing the rate of sample vaporization in an open air desorption ionization source by using a heated metal screen as a sample holder. AB - Rapid vaporization of sample into the ionizing gas exiting a direct analysis in real time (DART(r)) source has been enabled by directing a high electrical current through a metal wire screen to which sample has been applied. This direct heating of the screen enables rapid vaporization of sample as the wire temperature rises from room temperature to greater than 400 degrees C in less than 20 s. Positioning the screen between the DART source and atmospheric pressure inlet of the mass spectrometer ensures that the ionizing gas is in close proximity to the sample molecules, resulting in efficient ionization while significantly reducing the time required for mass spectrometric analysis. The capability to modulate the electrical current flow through the wires facilitates either rapid desorption for the determination of single component samples or slower desorption where analysis of mixtures might be desired. The technology also enables deployment of strategies for the determination of chemicals present as powders that might otherwise require dissolution prior to analysis. Results from the use of this thermally assisted DART ('TA-DART') system for the analysis of pure compounds, simple mixtures, solids and low vapor pressure samples are presented. PMID- 21793068 TI - Direct sampling and analysis from solid-phase extraction cards using an automated liquid extraction surface analysis nanoelectrospray mass spectrometry system. AB - Direct liquid extraction based surface sampling, a technique previously demonstrated with continuous flow and autonomous pipette liquid microjunction surface sampling probes, has recently been implemented as a liquid extraction surface analysis (LESA) mode on a commercially available chip-based infusion nanoelectrospray ionization (nanoESI) system. In the present paper, the LESA mode was applied to the analysis of 96-well format custom-made solid-phase extraction (SPE) cards, with each well consisting of either a 1 or a 2 mm diameter monolithic hydrophobic stationary phase. These substrate wells were conditioned, loaded with either single or multi-component aqueous mixtures, and read out using the commercial nanoESI system coupled to a hybrid triple quadrupole/linear ion trap mass spectrometer or a linear ion trap mass spectrometer. The extraction conditions, including extraction/nanoESI solvent composition, volume, and dwell times, were optimized in the analysis of targeted compounds. Limit of detection and quantitation as well as analysis reproducibility figures of merit were measured. Calibration data was obtained for propranolol using a deuterated internal standard which demonstrated linearity and reproducibility. A 10* increase in signal and cleanup of micromolar angiotensin II from a concentrated salt solution was demonstrated. In addition, a multicomponent herbicide mixture at ppb concentration levels was analyzed using MS(3) spectra for compound identification in the presence of isobaric interferences. PMID- 21793069 TI - Alpha-tocopherol protects against memory impairment caused by L-NAME and modulates the injury marker and blood coagulant parameters. AB - Cerebrovascular disease studies have shown similarity between humans and spontaneously hypertensive rats stroke-prone rats in the development of spontaneous stroke and transitory ischemic attacks (TIA). In addition, nitric oxide (NO) suppression by L-arginine methyl ester (L-NAME) can precipitate several vascular diseases including TIA and strokes. On the other hand, alpha tocopherol (AT) has been associated with beneficial effects on vascular disorders. Four groups were tested to evaluate AT effects on NO inhibition: AT, control (C), AT + L-NAME, and L-NAME. During 4 weeks, all groups had their physiologic parameters evaluated and were submitted to neurological tests. After the sacrifice of the animals, total L-lactate dehydrogenase, fibrinogen levels, and platelet counts were measured. Our results demonstrated improvement in memory function and sensory-motor function of the rats treated with AT. The AT treatment also demonstrated a significant difference on the injury identifier, fibrinogen levels, and platelet count between the treated groups and the L-NAME group. In conclusion, AT reversed damaging L-NAME neurological effects and could be considered as a possible protective agent in neurological diseases. PMID- 21793070 TI - Molecular imaging of tumor invasion and metastases: the role of MRI. AB - The processes of tumor invasion and metastasis have been well characterized at the molecular level, and numerous biomarkers of tumor aggressiveness have been discovered. Molecular imaging offers the opportunity to depict specific cell markers relevant to tumor aggressiveness. Here, we describe the role of MRI in identifying tumor invasiveness and metastasis with reference to other methods. Target-specific molecular imaging probes for tumor invasiveness have been developed for positron emission tomography and optical imaging, but progress in MRI has been slower. For example, proteases associated with tumor invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted in vivo using optical and positron emission tomography methods, but have not yet been successful with MRI. In addition, we describe the use of MRI to detect metastases. Novel MR contrast agents based on iron oxide and dendrimer nanomaterials allow for better characterization of tumor metastases. Organ specific MR contrast agents are used to identify metastatic disease in the liver. Finally, diffusion-weighted whole-body MRI is discussed as an alternative offered by MRI that does not require the use of molecular probes to screen distant metastases. PMID- 21793071 TI - Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis. AB - Tumors emerge as a result of the sequential acquisition of genetic, epigenetic and somatic alterations promoting cell proliferation and survival. The maintenance and expansion of tumor cells rely on their ability to adapt to changes in their microenvironment, together with the acquisition of the ability to remodel their surroundings. Tumor cells interact with two types of interconnected microenvironments: the metabolic cell autonomous microenvironment and the nonautonomous cellular-molecular microenvironment comprising interactions between tumor cells and the surrounding stroma. Hypoxia is a central player in cancer progression, affecting not only tumor cell autonomous functions, such as cell division and invasion, resistance to therapy and genetic instability, but also nonautonomous processes, such as angiogenesis, lymphangiogenesis and inflammation, all contributing to metastasis. Closely related microenvironmental stressors affecting cancer progression include, in addition to hypoxia, elevated interstitial pressure and oxidative stress. Noninvasive imaging offers multiple means to monitor the tumor microenvironment and its consequences, and can thus assist in the understanding of the biological basis of hypoxia and microenvironmental stress in cancer progression, and in the development of strategies to monitor therapies targeted at stress-induced tumor progression. PMID- 21793072 TI - Exploiting the tumor microenvironment for theranostic imaging. AB - The integration of chemistry and molecular biology with imaging is providing some of the most exciting opportunities in the treatment of cancer. The field of theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease as complex as cancer, especially now that genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. Using this information, theranostic agents can be shaped for personalized treatment to target specific compartments, such as the tumor microenvironment (TME), whilst minimizing damage to normal tissue. These theranostic agents can also be used to target multiple pathways or networks by incorporating multiple small interfering RNAs (siRNAs) within a single agent. A decade ago genetic alterations were the primary focus in cancer research. Now it is apparent that the tumor physiological microenvironment, interactions between cancer cells and stromal cells, such as endothelial cells, fibroblasts and macrophages, the extracellular matrix (ECM), and a host of secreted factors and cytokines, influence progression to metastatic disease, aggressiveness and the response of the disease to treatment. In this review, we outline some of the characteristics of the TME, describe the theranostic agents currently available to target the TME and discuss the unique opportunities the TME provides for the design of novel theranostic agents for cancer therapy. PMID- 21793074 TI - Correlation of phospholipid metabolites with prostate cancer pathologic grade, proliferative status and surgical stage - impact of tissue environment. AB - This study investigates the relationship between phospholipid metabolite concentrations, Gleason score, rate of cellular proliferation and surgical stage in malignant prostatectomy samples by performing one- and two-dimensional, high resolution magic angle spinning, total correlation spectroscopy, pathology and Ki 67 staining on the same surgical samples. At radical prostatectomy, surgical samples were obtained from 49 patients [41 with localized TNM stage T1 and T2, and eight with local cancer spread (TNM stage T3)]. Thirteen of the tissue samples were high-grade prostate cancer [Gleason score: 4 + 3 (n = 7); 4 + 4 (n = 6)], 22 low-grade prostate cancer [Gleason score: 3 + 3 (n = 17); 3 + 4 (n = 5)] and 14 benign prostate tissues. This study demonstrates that high-grade prostate cancer shows significantly higher Ki-67 staining and concentrations of phosphocholine (PC) and glycerophosphocholine (GPC) than does low-grade prostate cancer (2.4 +/- 2.8% versus 7.6 +/- 3.5%, p < 0.005, and 0.671 +/- 0.461 versus 1.87 +/- 2.15 mmolal, p < 0.005, respectively). In patients with local cancer spread, increases in [PC + GPC + PE + GPE] (PE, phosphoethanolamine; GPE, glycerophosphoethanolamine] and Ki-67 index approached significance (4.2 +/- 2.5 versus 2.7 +/- 2.4 mmolal, p = 0.07, and 5.3 +/- 3.8% versus 2.9 +/- 3.8%, p = 0.07, respectively). PC and Ki-67 were significantly lower and GPC higher in prostate tissues when compared with cell cultures, presumably because of a lack of important stromal-epithelial interactions in cell cultures. The findings of this study will need to be validated in a larger cohort of surgical patients with clinical outcome data, but support the role of in vivo (1)H MRSI in discriminating between low- and high-grade prostate cancer based on the magnitude of elevation of the in vivo total choline resonance. PMID- 21793073 TI - MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer. AB - MRS and MRSI are valuable tools for the detection of metabolic changes in tumors. The currently emerging era of molecular medicine, which is shaped by molecularly targeted anticancer therapies combined with molecular imaging of the effects of such therapies, requires powerful imaging technologies that are able to detect molecular information. MRS and MRSI are such technologies that are able to detect metabolites arising from glucose and choline metabolism in noninvasive in vivo settings and at higher resolution in tissue samples. The roles played by MRS and MRSI in the diagnosis of different types of cancer, as well as in the early monitoring of the tumor response to traditional chemotherapies, are reviewed. The emerging roles of MRS and MRSI in the development and detection of novel targeted anticancer therapies that target oncogenic signaling pathways or markers in choline or glucose metabolism are discussed. PMID- 21793076 TI - Hepatic tumor response evaluation by MRI. AB - Noninvasive evaluation of hepatic tumor response is necessary to improve the survival rate and quality of life of cancer patients. Among radiologic imaging modalities, MRI plays a significant role in the management of patients with hepatic tumor and is crucial for diagnosis, treatment planning and assessment of response or recurrence, because of its high contrast resolution, lack of ionizing radiation and the possibility of performing functional imaging sequences. This review provides an overview of the MRI findings after various treatments in patients with primary and secondary focal liver malignancies. The imaging methods described focus on the recent trends of using MRI techniques as biomarkers for disease. We also describe the appearance of successful and incomplete response for the various forms of treatment, including transcatheter arterial chemoembolization, ablative therapy, systemic chemotherapy and radiation therapy. Dynamic contrast-enhanced MRI is regarded as an established noninvasive method and potential biomarker for tumor detection, as well as for the characterization of the tumor response. Diffusion-weighted MRI, perfusion-weighted MRI and MRS are also promising functional biomarkers to help select patients for various therapies and to assess the response to treatments. However, further validation and standardization should be performed before their widespread use as imaging biomarkers. PMID- 21793075 TI - In vivo 1H MRS in the assessment of the therapeutic response of breast cancer patients. AB - MRI and in vivo MRS have rapidly evolved as sensitive tools for diagnosis and therapeutic monitoring in cancer research. In vivo MRS provides information on tumor metabolism, which is clinically valuable in the diagnosis and assessment of tumor response to therapy for the management of women with breast diseases. Several centers complement breast MRI studies with (1)H MRS to improve the specificity of diagnosis. Malignant breast tissues show elevated water-to-fat ratio and choline-containing compounds (total choline, tCho), and any effect of therapy on tissue viability or metabolism will be manifested as changes in these levels. Sequential (1)H MRS studies have shown significantly reduced tCho levels during the course of therapy in patients who were responders. However, there are challenges in using in vivo MRS because of the relatively low sensitivity in detecting the tCho resonance with decreased lesion size or significant reduction in the tumor volume during therapy. MRS is also technically challenging because of the low signal-to-noise ratio and heterogeneous distribution of fat and glandular tissues in the breast. MRS is best utilized for the diagnosis of focal masses, most commonly seen in patients with ductal-type neoplasms; however, it has limitations in detecting nonfocal masses, such as the linear pattern of tumors seen in invasive lobular carcinoma. Further work is required to assess the clinical utility of quantitative MRS, with the goal of automation, which will reduce the subjectivity currently inherent in both qualitative and semi quantitative MRS. PMID- 21793078 TI - In vivo 1H MRS for musculoskeletal lesion characterization: which factors affect diagnostic accuracy? AB - In vivo (1)H MRS is a noninvasive imaging technique for the identification of malignancy. Musculoskeletal lesions vary in their composition, causing field inhomogeneity and magnetic susceptibility effects which may be technical and diagnostic challenges for MRS. This study investigated the factors that affect diagnostic accuracy in the use of MRS for the characterization of musculoskeletal neoplasms. During a 7-year period, 210 consecutive patients with musculoskeletal lesions larger than 1.5 cm in diameter were examined. MRS of a single-voxel point resolved spectroscopy sequence with TE = 135 ms was undertaken using a 1.5-T scanner. Lesions with a choline signal-to-noise ratio larger than 3.0 were considered to be malignant tumors. The diagnostic accuracy was calculated for all lesions and for subgroups on the basis of lesion type (bone and soft tissue), lesion composition (mixed and solid nonsclerotic), lesion size (<=4, >4-10 and >10 cm), MR scanner (MR scanner 1 and 2) and selected voxel size (<=3, >3-8 and >8 cm(3)). Multivariate logistic regressions were performed to estimate the associations between each factor and diagnostic accuracy. The diagnostic accuracy was 73.3% for all lesions. The accuracy was 54.4% for mixed lesions and 80.4% for solid nonsclerotic lesions (p < 0.001). The diagnostic accuracy was lower for larger lesions [86.8% for lesions of <=4 cm, 71.6% for lesions of >4-10 cm (p = 0.04) and 63.6% for lesions of >10 cm (p = 0.007)]. There was no difference in diagnostic accuracy for bone versus soft-tissue lesions or as a function of MR scanner or voxel size. By the use of multivariate logistic regression, a solid nonsclerotic lesion was 3.15 times (95% confidence interval, 1.59-6.27) more likely than a mixed lesion to have a diagnosis (p = 0.001). MRS can be used to characterize musculoskeletal lesions, particularly solid nonsclerotic lesions. PMID- 21793077 TI - Therapeutic response in musculoskeletal soft tissue sarcomas: evaluation by MRI. AB - This article provides a literature review of the use of MRI in monitoring the treatment response of soft tissue sarcomas. The basic classification and physiology of soft tissue tumors are introduced. Then, the major treatment options for soft tissue sarcomas are summarized with brief coverage of possible responses and grading systems. Four major branches of MRI techniques are covered, including conventional T(1) - and T(2) -weighted imaging, contrast-enhanced MRI, MR diffusion and perfusion imaging, and MRS, with a focus on the tumor microenvironment. Although this literature survey focuses on recent clinical developments using these MRI techniques, research venues in preclinical studies, as well as in potential applications other than soft tissue sarcomas, are also included when comparable and/or mutually supporting. Examples from other less discussed MRI modalities are also briefly covered, not only to complement, but also to expand, the scope and depth of information for various kinds of lesions. PMID- 21793079 TI - Quantitative pharmacologic MRI in mice. AB - Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (DeltaCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios >= 20 and apparent half-lives >= 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue. PMID- 21793080 TI - Embryo volume measurement: an intraobserver, intermethod comparative study of semiautomated and manual three-dimensional ultrasound techniques. AB - OBJECTIVE: To compare the reliability of our recently introduced technique for first-trimester embryo volume measurement, the 'semiautomated technique' using both Virtual Organ Computer-aided AnaLysis (VOCAL(TM) ) and Sonography-based Automated Volume Count (SonoAVC) with a manual technique using VOCAL alone. METHODS: Seventy-four subjects with viable, singleton first-trimester in-vitro fertilization (IVF) pregnancies were recruited. Each subject underwent transvaginal sonography, at which a three-dimensional ultrasound dataset of the entire gestational sac was acquired. Each embryo volume was measured by two techniques, each performed twice. In the semiautomated technique VOCAL was used to calculate the volume of the gestational and yolk sacs, and SonoAVC was used to quantify the fluid volume within the amniotic and extra-amniotic cavities. Embryo volume was calculated by subtracting the sum of yolk sac, amniotic and extra amniotic fluid volumes from gestational sac volume. In the manual technique, VOCAL was used to delineate the entire embryo using 9 degrees rotations. Reliability was assessed using limits of agreement and intraclass correlation coefficient. RESULTS: Datasets were included from 52 eligible subjects. Median gestational age was 7 + 4 weeks; median crown-rump length (CRL) was 13 (range, 2 29) mm; and median embryo volume was 1.8 (range, 0.03-8.1) cm(3) using the semiautomated technique and 0.7 (range 0.009-3.6) cm(3) using the manual technique. There was a significant discrepancy in the volumes measured by the two different techniques. Assessment of the limits of agreement suggested that the semiautomated technique (-15.8% to 14.0% of the mean embryo volume) was more reliable than was the manual technique (-22.4% to 26.6%). CONCLUSION: The semiautomated technique is more reliable than is the manual technique for embryo volume measurement. However, the discrepancy in measurements between the two methods raises concerns over the validity of the semiautomated technique that require further investigation. PMID- 21793081 TI - Outcome of fetal exomphalos diagnosed at 11-14 weeks of gestation. AB - OBJECTIVE: To determine whether sonographic findings in cases of exomphalos detected at the 11-14-week scan can be used to guide pregnancy management. METHODS: Retrospective study of cases of exomphalos identified from the Fetal Medicine Unit database, University College London Hospitals between January 1998 and January 2010. Pregnancy and neonatal data were ascertained from maternal and neonatal records. Fetal exomphalos was categorized into three groups: exomphalos associated with other major structural malformation(s), isolated exomphalos with increased nuchal translucency (NT) and isolated exomphalos with normal NT. RESULTS: A total of 98 cases of exomphalos were identified, of which 45 (45.9%) were associated with other major structural malformation(s), identified antenatally. Isolated exomphalos was found with increased NT in 22 cases (22.4%) and with normal NT in 31 cases (31.6%). Of 80 (81.6%) fetuses that were karyotyped, 43 (53.8%) had a chromosomal abnormality; the most common aneuploidy was trisomy 18 (n = 31; 72.1%). Where exomphalos was associated with other major structural abnormalities, or was isolated with increased NT, the incidence of aneuploidy was high, at 78.9% and 72.2%, respectively. Cases of isolated exomphalos with normal NT were all euploid. In 21 cases (21.4%), exomphalos resolved later in pregnancy and none had apparent abnormalities at birth; isolated exomphalos persisted in only three neonates (3.1%). CONCLUSIONS: The finding of a major structural abnormality or of increased NT in association with exomphalos in the first trimester implies a high risk of aneuploidy. Parents can be reassured that fetuses with isolated exomphalos and normal NT are likely to be euploid. PMID- 21793082 TI - Reproducibility of constituent time intervals of right and left fetal modified myocardial performance indices on pulsed Doppler echocardiography: a short report. AB - OBJECTIVE: To assess reproducibility of constituent time intervals measured by pulsed Doppler echocardiography for calculation of the right and left fetal myocardial performance indices (MPIs). METHODS: This was a prospective study of 30 normal singleton pregnancies (19-36 weeks). In each, five different time intervals were measured from the Doppler waveform and four repeated measures were taken for each time interval. Three were from the left heart: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET); two were from the right heart: 'a-interval' and 'b-interval'. The left and right modified MPIs (Mod-MPIs) generated by these constituent time intervals were also evaluated. Two operators evaluated the reproducibility of all measures. RESULTS: There was generally good intra- and interobserver reproducibility for all time intervals and resultant Mod-MPIs: ICT, range, 19-43 ms with intraclass correlation coefficient (ICC), 0.91 (95% CI, 0.85-0.95); ET, range, 160-184.8 ms with ICC, 0.90 (95% CI, 0.84-0.95); IRT, range, 35.8-48.5 ms with ICC, 0.67 (95% CI, 0.52-0.81); a-interval, range 208-265 ms with ICC, 0.89 (95% CI, 0.82-0.94); b-interval, range, 163.1-188.3 ms with ICC, 0.82 (95% CI, 0.71-0.90); left Mod MPI, range, 0.33-0.48 with ICC, 0.84 (95% CI, 0.74-0.91); right Mod-MPI, range, 0.21-0.49 with ICC, 0.82 (95% CI, 0.71-0.90). The 95% limits of agreement showed no statistically significant difference in measurements between the two examiners for all time intervals. CONCLUSION: This is the first study to evaluate the reproducibility of the component time intervals of both right and left fetal Mod MPIs in the second and third trimesters and supports the reproducibility of fetal functional cardiac assessment. The IRT is the main source of variation for the left Mod-MPI so should be the focus of further investigation. Even using two separate pulsed-wave Doppler gates and therefore separate cardiac cycles, the right Mod-MPI is reproducible. PMID- 21793083 TI - Accuracy of imaging parameters in the prediction of lethal pulmonary hypoplasia secondary to mid-trimester prelabor rupture of fetal membranes: a systematic review and meta-analysis. AB - In women who have suffered mid-trimester prelabor rupture of membranes (PPROM), prediction of pulmonary hypoplasia is important for optimal management. We performed a systematic review to assess the capacity of imaging parameters to predict pulmonary hypoplasia. We searched for published articles that reported on biometric parameters and allowed the construction of a 2 * 2 table, comparing at least one of these parameters with the occurrence of pulmonary hypoplasia. The selected studies were scored on methodological quality and we calculated sensitivity and specificity of the tests in the prediction of pulmonary hypoplasia and lethal pulmonary hypoplasia. Overall performance was assessed by summary receiver-operating characteristics (sROC) analyses that were performed with bivariate meta-analysis. We detected 13 studies that reported on the prediction of lethal pulmonary hypoplasia. The quality of the included studies was poor to mediocre. The estimated sROC curves for the chest circumference/abdominal circumference ratio and other parameters showed limited accuracy in the prediction of pulmonary hypoplasia. In women with mid-trimester PPROM, the available evidence indicates limited accuracy of biometric parameters in the prediction of pulmonary hypoplasia. PMID- 21793084 TI - Can we place tension-free vaginal tape where it should be? The one-third rule. AB - OBJECTIVES: The tension-free vaginal tape (TVT) insertion technique generally does not take into account individual urethral length. In this study we investigated whether preoperative sonographic measurement of individual urethral length allows for reliable TVT positioning under the midurethra, which is a critical segment for the continence mechanism. METHODS: Urethral length was measured by preoperative introital ultrasonography in 102 consecutive female patients with stress urinary incontinence. TVT procedures were performed as recommended by the manufacturer. The suburethral incisions were initiated at one third of the sonographically measured urethral length. TVT position and tape urethra distance were followed up 6 months postoperatively. RESULTS: At 6-month examination of the 102 study participants, 93.1% were cured and 6.9% showed improved continence. TVTs were found in the target range of 50-70% of the urethral length in 88.2% of the cohort. Women with the TVT in the 50-70% urethral length range and a 3-5-mm tape-longitudinal smooth muscle distance had a greater likelihood of being cured without complications (P < 0.001). CONCLUSIONS: Preoperative sonographic measurement of urethral length, combined with the one third rule, may aid in reliable midurethral TVT positioning. PMID- 21793085 TI - First-trimester screening for chromosomal abnormalities by integrated application of nuchal translucency, nasal bone, tricuspid regurgitation and ductus venosus flow combined with maternal serum free beta-hCG and PAPP-A: a 5-year prospective study. AB - OBJECTIVE: To investigate the performance of first-trimester screening for chromosomal abnormalities by integrated application of nuchal translucency thickness (NT), nasal bone (NB), tricuspid regurgitation (TR) and ductus venosus (DV) flow combined with maternal serum free beta-human chorionic gonadotropin (fbeta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at a one-stop clinic for assessment of risk (OSCAR). METHODS: In total, 13,706 fetuses in 13,437 pregnancies were screened for chromosomal abnormalities during a period of 5 years. Maternal serum biochemical markers and maternal age were evaluated in combination with NT, NT + NB, NT + NB + TR, and NT + NB + TR + DV flow data in 8581, 242, 236 and 4647 fetuses, respectively. RESULTS: In total, 51 chromosomal abnormalities were identified in the study population, including 33 cases of trisomy 21, eight of trisomy 18, six of sex chromosome abnormality, one of triploidy and three of other unbalanced abnormalities. The detection rate and false-positive rate (FPR) for trisomy 21 were 93.8% and 4.84%, respectively, using biochemical markers and NT, and 100% and 3.4%, respectively, using biochemical markers, NT, NB, TR and DV flow. CONCLUSION: While risk assessment using combined biochemical markers and NT measurement has an acceptable screening performance, it can be improved by the integrated evaluation of secondary ultrasound markers of NB, TR and DV flow. This enhanced approach would decrease the FPR from 4.8 % to 3.4 %, leading to a lower number of unnecessary invasive diagnostic tests and subsequent complications, while maintaining the maximum level of detection rate. Pre- and post-test genetic counseling is of paramount importance in either approach. PMID- 21793086 TI - Endometriosis of the abdominal wall: ultrasonographic and Doppler characteristics. AB - OBJECTIVES: To describe the sonographic and clinical features of abdominal wall endometriosis (AWE), a frequently misdiagnosed condition. METHODS: This was a retrospective study of 21 consecutive women with pathologically proven endometriosis of the abdominal wall. Ultrasonographic and Doppler examinations were performed, before surgery, with a high-frequency linear transducer. The clinical data and the results of the sonographic examinations were reviewed and described. RESULTS: At ultrasound, all the nodules appeared as discrete solid masses that were less echogenic than the surrounding hyperechoic fat. The nodules had a median diameter of 20 (range, 5-50) mm and in 18/21 (86%) cases the nodules had a round/oval shape. In eight of 21 (38%) women the AWE was located at the umbilicus, in six of 21 (29%) it was between the transverse suprapubic line and the umbilicus, in five of 21 (24%) it was found along the scar of a previous Cesarean section and in two of 21 (9%) it was in the right inguinal canal. The content was homogeneously hypoechoic in 12/21 (57%) women and inhomogeneous in the other nine (43%). The outer borders were invariably ill defined. Scarce blood vessels were found by power Doppler. Cyclic or continuous spontaneous pain at the level of the AWE was present in 19/21 (91%) cases, and two (9%) patients were asymptomatic. CONCLUSIONS: Hypoechoic round/oval nodules with ill-defined borders and a hyperechoic rim should raise the suspicion of abdominal wall endometriosis, even in patients with no history of endometriosis or previous laparotomic surgery. Pressing the ultrasound probe against the nodule should reinforce a suspected diagnosis because of the pain it induces. PMID- 21793087 TI - Aberrant right subclavian artery: incidence and correlation with other markers of Down syndrome in second-trimester fetuses. AB - OBJECTIVE: To assess the incidence of aberrant right subclavian artery (ARSA) and other strong markers of Down syndrome and their correlation in a large population of second-trimester Down syndrome fetuses assessed in a tertiary referral center. METHODS: Presence or absence of ARSA and other major ultrasound markers of Down syndrome was assessed in a population of 106 second-trimester Down syndrome fetuses referred to our unit for expert assessment and/or termination of pregnancy after karyotyping performed for positive first- or second-trimester screening or advanced maternal age or on maternal request. All cases in which the diagnosis of Down syndrome followed the ultrasound detection of major anomalies or soft markers were excluded from the study, as were all cases with a gestational age less than 14 + 0 weeks. We searched for the ARSA on the three vessels and trachea view using color or power Doppler. All fetuses underwent a thorough anatomic assessment and fetal echocardiography. The other Down syndrome markers assessed were: absent or hypoplastic nasal bone (NB-), defined as length < 5(th) centile; nuchal fold >= 5 mm; and mild pyelectasis (> 5 mm). In addition, the presence of major cardiac and extracardiac defects was recorded. A correlation analysis was then performed in order to investigate possible associations between markers and/or major anomalies. Postmortem or postnatal diagnostic confirmation was available in all cases. RESULTS: The mean (SD) gestational age at ultrasound assessment was 20.4 (4.1) weeks. The incidence of the various variables in the population of Down syndrome fetuses was: ARSA, 25%; NB-, 43%; nuchal fold >= 5 mm, 16%; pyelectasis, 17%; major heart defects, 41%; atrioventricular septal defect, 25%; and extracardiac anomaly, 24%. The presence of ARSA did not correlate with any of the other variables. The only positive correlations (P < 0.05) were between NB- and pyelectasis, and between cardiac and extracardiac defects. CONCLUSIONS: This represents the largest Down syndrome population assessed for ARSA. In this series, the incidence of ARSA was 25%, lower than previously reported in much smaller series. Its presence did not correlate with the presence of any other marker or major anomaly, including heart defects. PMID- 21793088 TI - Synthesis of Well-defined Amphiphilic Block Copolymers by Organotellurium Mediated Living Radical Polymerization (TERP). AB - Low-molecular weight amphiphilic diblock copolymers, polystyrene-block-poly (2 vinylpyridine) (PS-b-P2VP), and (P2VP-b-PS) with different block ratios were synthesized for the first time via organotellurium-mediated living radical polymerization (TERP). For both the homo- and block copolymerizations, good agreement between the theoretical, and experimental molecular weights was found with nearly 100% yield in every case. The molecular weight distribution for all the samples ranged between 1.10 and 1.24, which is well below the theoretical lower limit of 1.50 for a conventional free radical polymerization. Furthermore, a very simple approach to producing highly dense arrays of titania nanoparticles (TiO2 ) is presented using a site-selective reaction of titanium tetraisopropoxide within the P2VP domains of micellar film of P2VP-b-PS in toluene through the sol-gel method. PMID- 21793089 TI - A New Strategy to Prepare Polymer-based Shape Memory Elastomers. AB - A new strategy that utilizes the microphase separation of block copolymer and phase transition of small molecules for preparing polymer-based shape memory elastomer has been proposed. According to this strategy, a novel kind of shape memory elastomer comprising styrene-b-(ethylene-co-butylene)-b-styrene (SEBS) and paraffin has been prepared. Because paraffins are midblock-selective molecules for SEBS, they will preferentially enter and swell EB blocks supporting paraffins as an excellent switch phase for shape memory effect. Microstructures of SEBS/paraffin composites have been characterized by transmission electron microscopy, polarized light microscopy, and differential scanning calorimetry. The composites demonstrate various phase morphologies with regard to different paraffin loading. It has been found that under low paraffin loading, all the paraffins precisely embed in and swell EB-rich domains. While under higher loading, part of the paraffins become free and a larger-scaled phase separation has been observed. However, within wide paraffin loadings, all composites show good shape fixing, shape recovery performances, and improved tensile properties. Compared to the reported methods for shape memory elastomers preparation, this method not only simplifies the fabrication procedure from raw materials to processing but also offers a controllable approach for the optimization of shape memory properties as well as balancing the rigidity and softness of the material. PMID- 21793090 TI - Functional microgels tailored by droplet-based microfluidics. AB - Monodisperse polymer gel particles with micrometer-scale dimensions serve for a variety of applications, including those as microcapsules for actives or as micrometer-sized matrixes for mesoscopic additives. These particles can be produced with exquisite control through the use of droplet-based microfluidic templating followed by subsequent droplet solidification. This can be achieved by two ways: One way is to use pre-microgel solutions of low molecular weight monomers and to form microgels by polymerizing these monomers. Another way is to use pre-polymerized, high molecular weight precursors and to gel them by polymer analogous crosslinking. Both approaches have their specific advantages, allowing microgels to be tailored and optimized for specific needs such as those as delivery systems or scaffolds for living cells. This article highlights some recent achievements in the development and use of these microfluidic techniques to fabricate functional microgel particles. PMID- 21793092 TI - Body fat is differentially related to body mass index in U.S.-born African American and East African immigrant girls. AB - OBJECTIVE: To examine ethnic differences in adiposity at a given body mass index (BMI) in a sample of U.S.-born African-American and East African immigrant adolescent girls. METHODS: In a sample of black adolescent girls (n = 79; ages 14 20) we compared measures of adiposity across the range of BMI-for-age among 55 U.S.-born African-American (mean BMI: 30.4; age: 15.4) and 24 East African immigrant girls (mean BMI: 21.8; age: 16.7). Fat and fat-free mass were assessed with dual-energy X-ray absorptiometry (DXA). We used spline regression to examine the distributions of fat mass index and percent body fat across the range of BMI for-age z-scores. RESULTS: Compared with African-American girls, East African girls were smaller on all body measures, but appeared to have higher fat mass index and percent body fat at the same BMI-for-age. CONCLUSIONS: Our findings indicate that at a given BMI East African immigrants may have greater adiposity than African-American girls. If corroborated in larger samples, our data suggest that the cardiometabolic risks attendant to elevated adiposity may affect East African girls at a lower BMI than in African-American girls. PMID- 21793091 TI - Behavioral and perceived stressor effects on urinary catecholamine excretion in adult Samoans. AB - OBJECTIVES: The effects of perceptions and behaviors related to culturally patterned socioeconomic obligations on catecholamine excretion rates were studied in a cross-sectional sample of Samoan adults. METHODS: A total of 378 participants, ages 29-62 years, from 9 villages throughout Samoa, provided timed overnight urine specimens, and self-reported perceptions and behaviors associated with contributions to one's family, aiga, and chief, matai, and communal gift exchanges, fa'alavelave. Urinary norepinephrine and epinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection. Age (<=40 vs. >40 years) and gender-specific regression models were estimated to detect associations with catecholamine excretion. RESULTS: Young women who contribute more to their matai, who consider fa'alavelave to be a financial strain, and who view their contribution to their matai to be "just right," had significantly higher residence-adjusted norepinephrine excretion. Young women who contribute more to their matai, who consider fa'alavelave to be a financial strain, and who consider their contribution to their aiga not to be a burden, had higher epinephrine excretion. Older men who contribute more to their aiga and who perceive their contribution to their aiga to be "just right" had increased residence-adjusted epinephrine excretion. CONCLUSIONS: Individual-level perceptions and behaviors related to traditional socioeconomic obligations are a significant correlate of increased overnight catecholamine excretion rates. Higher excretion rates may be attributed to psychosocial stress arousal associated with a discordance between personal desires for upward social mobility, and family and community-based socioeconomic obligations. Changes in patterns of individual-level psychosocial stress arousal may contribute to cardiovascular disease risk in modernizing Samoans. PMID- 21793094 TI - Adiposity and blood pressure in 7- to 11-year-old children: comparison of British Pakistani and white British children, and of British Pakistani children of migrant and British-born mothers. AB - OBJECTIVES: This study tested hypotheses that: (1) levels of adiposity, as assessed by triceps and subscapular skinfold thicknesses (SFTs), and blood pressure would be higher in British Pakistani children than in white British children; and (2) British Pakistani children of mothers born in the UK would have smaller SFTs and lower blood pressure than children of mothers born in Pakistan. METHODS: Participants aged 7 to 11 years were recruited from five primary schools in a deprived urban area. BMI, waist circumference, triceps and subscapular SFT, and blood pressure were measured. RESULTS: Participants comprised 209 white British and 132 British Pakistani children, including 79 children born in the UK to migrant mothers and 49 children born to British-born mothers. In comparisons by ethnic group, triceps SFT was significantly higher in British Pakistani children only after controlling for BMI. Subscapular SFT was higher in British Pakistani children, a finding strengthened after controlling for BMI. Systolic blood pressure was significantly higher in British Pakistani children, but not after controlling for socioeconomic status (SES). There were no significant differences between British Pakistani children born to migrant or British-born mothers, except that systolic blood pressure was lower in children of British born mothers after controlling for SES, a finding that was not significant after controlling for BMI. CONCLUSIONS: This study confirms previous findings of larger SFTs and higher blood pressure in British children of Pakistani origin than in children of white European origin. Further work with larger sample sizes is needed to investigate differences between generations. PMID- 21793093 TI - Why does starvation make bones fat? AB - Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. PMID- 21793095 TI - High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma. AB - Well-differentiated liposarcoma (WDLS) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma (DDLS) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component. Cytogenetically, WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes, including MDM2, TSPAN31, CDK4, and others mainly derived from chromosome bands 12q13-15. However, the 12q13-15 amplicon is large and discontinuous. The focus of this study was to identify novel critical genes that are consistently amplified in primary (nonrecurrent) WDLS and with potential relevance for future targeted therapy. Using a high resolution (5.0 kb) "single nucleotide polymorphism"/copy number variation microarray to screen the whole genome in a series of primary WDLS, two consistently amplified areas were found on chromosome 12: one region containing the MDM2 and CPM genes, and another region containing the FRS2 gene. Based on these findings, we further validated FRS2 amplification in both WDLS and DDLS. Fluorescence in situ hybridization confirmed FRS2 amplification in all WDLS and DDLS tested (n = 57). Real time PCR showed FRS2 mRNA transcriptional upregulation in WDLS (n = 19) and DDLS (n = 13) but not in lipoma (n = 5) and normal fat (n = 9). Immunoblotting revealed high expression levels of phospho-FRS2 at Y436 and slightly overexpression of total FRS2 protein in liposarcoma but not in normal fat or preadipocytes. Considering the critical role of FRS2 in mediating fibroblast growth factor receptor signaling, our findings indicate that FRS2 signaling should be further investigated as a potential therapeutic target for liposarcoma. PMID- 21793096 TI - Epigenetic consequences of foreign DNA insertions: de novo methylation and global alterations of methylation patterns in recipient genomes. AB - The insertion of foreign DNA into mammalian or plant genomes is a frequent event in biology. My laboratory has pursued a long-standing interest in the structure of integrated adenovirus genomes and in the mechanism of foreign DNA insertions in mammalian cells. The long-term consequences of the integration of alien DNA are only partly known, and even less well understood are the mechanisms that bring them about. Evidence from viral systems has contributed to the realization that foreign DNA insertions entail a complex of sequelae that have also become apparent in non-viral systems: (i) The de novo methylation of integrated foreign DNA sequences has frequently been observed. (ii) Alterations of DNA methylation patterns in the recipient genome at and remote from the site of foreign DNA insertion have been demonstrated but it remains to be investigated how generally this phenomenon occurs. Many viral genomes find and have found entry into the genomes of present-day organisms. A major portion of mammalian genomes represents incomplete retroviral genomes that frequently have become permanently silenced by DNA methylation. It is still unknown how and to what extent the insertion of retroviral or retrotransposon sequences into established genomes has altered and shaped the methylation and transcription profiles of present day genomes. An additional reason for concern about the effects of foreign DNA integration is the fact that in all fields of molecular biology and medicine, the generation of transgenic or transgenomic cells and organisms has become a ubiquitously applied experimental technique. PMID- 21793097 TI - Exposure to antipsychotic medications over a 4-year period among children who initiated antipsychotic treatment before their sixth birthday. AB - PURPOSE: This study aims the following: (i) to describe the exposure to antipsychotic medications over a 4-year period experienced by a cohort of children who initiated antipsychotic treatment before their sixth birthday; and (ii) to identify variables associated with the risk of antipsychotic exposure. METHODS: Children were identified who initiated an index episode of antipsychotic treatment before their sixth birthday in Florida's fee for service Medicaid program. With the use of claims data, the medication utilization of these children was tracked during the year before and the 4 years following the start of their index episodes (pre-index and four post-index periods). Generalized estimating equations were used to identify variables associated with the risk of additional days of antipsychotic exposure. RESULTS: Five hundred twenty-eight children were included in the cohort. The mean total number of days of exposure was 821.9 (+/- 431.9), representing 56.3% of all days during the four post-index periods. The mean days of exposure to combinations of antipsychotics and other classes of psychotherapeutic medications were 623.8 +/- 447.6 days. Children with primary diagnoses of pervasive developmental disorders and affective disorders were at greater risk of additional days of exposure than children with attention deficit/hyperactivity disorder. Exposure tended to be greater among children with indicators of clinical complexity including the presence of secondary diagnoses and the use of other classes of psychotherapeutic medications in addition to antipsychotics. CONCLUSIONS: Exposure to antipsychotic mediations was extensive. Although these children may have had complex and severe problems, additional research is urgently needed on the benefits and risks of long-term antipsychotic exposure among very young children. PMID- 21793098 TI - The lack of knowledge about the voluntary reporting system of adverse drug reactions as a major cause of underreporting: direct survey among health professionals. AB - BACKGROUND: Underreporting suspected adverse drug reactions (ADRs) is one of the main problems that face the pharmacovigilance (PhV) systems based on yellow card schemes. OBJECTIVES: To measure the knowledge level on the suspected ADR voluntary reporting system among physicians and pharmacists in Venezuela and to study its relationship with different variables. METHODS: A population-based, anonymous, and self-administered questionnaire was addressed to health professionals along the national territory of Venezuela. An algorithm was developed to classify the knowledge level on the voluntary reporting system. RESULTS: Taken as a whole, the level of knowledge on the voluntary reporting system was "poor." Among the 515 participant physicians, 62.3% (95%CI = 58.0 66.5%) had a "poor" level of knowledge; PhV was associated with "control" of medicines use, and only 24.7% had ever reported a suspected ADR. "Medical specialty" was the only variable that showed a relationship with the knowledge level (p = 0.0041). Among the 78 participant pharmacists, 66.7% had a "poor" knowledge level (95%CI = 55.1-76.9%). CONCLUSIONS: The knowledge level on the voluntary reporting system among physicians and pharmacists in Venezuela is poor. These results strengthen the hypothesis that being unaware of the adverse effects of medicines and not knowing the existence of a PhV system is a major cause of underreporting. A careful study of the actual knowledge of PhV could be the basis to set up interventions specifically designed to overcome misleading concepts and to improve the reporting rate at a national level. PMID- 21793099 TI - Requirements for mediator complex subunits distinguish three classes of notch target genes at the Drosophila wing margin. AB - Spatial and temporal gene regulation relies on a combinatorial code of sequence specific transcription factors that must be integrated by the general transcriptional machinery. A key link between the two is the mediator complex, which consists of a core complex that reversibly associates with the accessory kinase module. We show here that genes activated by Notch signaling at the dorsal ventral boundary of the Drosophila wing disc fall into three classes that are affected differently by the loss of kinase module subunits. One class requires all four kinase module subunits for activation, while the others require only Med12 and Med13, either for activation or for repression. These distinctions do not result from different requirements for the Notch coactivator Mastermind or the corepressors Hairless and Groucho. We propose that interactions with the kinase module through distinct cofactors allow the DNA-binding protein Suppressor of Hairless to carry out both its activator and repressor functions. PMID- 21793100 TI - A re-evaluation of two key reagents for in vivo studies of Wnt signaling. AB - Conditional mutations and transcription-based reporters are important new tools for exploring the dynamic functions of biological pathways in vivo. While studying the role of the Wnt signaling pathway in cartilage, we observed that the beta-catenin-dependent reporter TOPGAL was expressed in chondrocytes in which beta-catenin was conditionally inactivated using a Col2a1::cre driver. Here we show that in these embryos recombination is complete and full-length beta-catenin protein is absent in chondrocytes. Although a null allele in this context, the recombined beta-catenin locus produces a stable transcript that encodes a truncated protein. The truncated protein alone fails to activate TOPFLASH, but strongly potentiates reporter activity in the presence of expressed beta-catenin or Tcf4. Together, these data show that each mouse model exhibits specific undesirable properties, findings that strongly suggest the need for specific standards to ensure proper validation of this new generation of genetic tools. PMID- 21793101 TI - Stepwise arteriovenous fate acquisition during mammalian vasculogenesis. AB - Arteriovenous (AV) differentiation is a critical step during blood vessel formation and stabilization. Defects in arterial or venous fate lead to inappropriate fusion of vessels, resulting in damaging arteriovenous shunts. While many studies have unraveled the molecular underpinnings that drive AV fate, surprisingly, the spatiotemporal emergence of arteries and veins in mammalian embryos remains unknown. Here, we examine artery and vein specification and differentiation during vasculogenesis. We show that the first intraembryonic vessels formed are arteries, which differentiate in a stepwise manner. By contrast, veins emerge later, progressively forming after embryonic turning. In addition, we demonstrate that hemodynamic flow is not required for arterial specification, but is required for maintenance of select arterial markers. Together, our results provide a first spatiotemporal analysis of mammalian AV cell fate establishment and anatomy, as well as a delineation of a molecular toolkit for analysis of arteries and veins during early vessel development. PMID- 21793104 TI - Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2. AB - Serpentine fibula-polycystic kidney syndrome (SFPKS) is a rare disorder characterized by the association of craniofacial anomalies, radiological findings (wormian bones, elongated and bowed fibulae), polycystic kidneys, and normal intelligence. SFPKS shares many similarities with Hajdu-Cheney syndrome (HCS). We and others recently showed that truncating mutations in the last exon of NOTCH2 cause HCS. Here, we identify by Sanger sequencing two different heterozygous truncating mutations in the last exon of NOTCH2 in two unrelated patients with SFPKS. In one family, we show that the mutation occurred de novo. These findings demonstrate that SFPKS and HCS are both conditions caused by NOTCH2 mutations. PMID- 21793103 TI - Inference-based therapy for body dysmorphic disorder. AB - Body dysmorphic disorder (BDD) is a debilitating disorder characterized by an excessive pre-occupation with an imagined or very slight defect in one's physical appearance. Despite the overall success of cognitive behavioural therapy (CBT) in treating BDD, some people do not seem to benefit as much from this approach. Those with high overvalued ideation (OVI), for instance, have been shown to not respond well with CBT. The purpose of this study was to evaluate the efficacy of an inference-based therapy (IBT) in treating BDD. IBT is a cognitive intervention that was first developed for obsessive-compulsive disorder with high OVI, but whose focus on beliefs can also apply to a BDD population. IBT conceptualizes BDD obsessions (e.g., 'I feel like my head is deformed') as idiosyncratic inferences arrived at through inductive reasoning processes. Such primary inferences represent the starting point of obsessional doubt and the treatment focuses on addressing the faulty inferences that maintain the doubt. Thirteen BDD participants, of whom 10 completed, underwent a 20-week IBT for BDD. The participants improved significantly over the course of therapy, with large diminutions in BDD and depressive symptoms. OVI also decreased throughout therapy and was not found to be related to reduction in BDD symptoms. Although a controlled-trial comparing CBT with IBT is needed, it is proposed that IBT constitutes a promising treatment alternative for BDD especially in cases where OVI is high. PMID- 21793105 TI - DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. AB - By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype phenotype correlations in DYT6 dystonia. PMID- 21793107 TI - FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. AB - Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma. PMID- 21793106 TI - FAS mRNA editing in Human Systemic Lupus Erythematosus. AB - FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human Systematic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNF receptor (TNFR) family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T-cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases. PMID- 21793108 TI - Motivation-focused treatment for eating disorders: a sequential trial of enhanced cognitive behaviour therapy with and without preceding motivation-focused therapy. AB - OBJECTIVE: To evaluate the effectiveness of a motivation-focused intervention prior to individual cognitive behavioural eating disorder treatment. METHOD: Enhanced cognitive-behavioural therapy (CBT-E) in its usual form was compared with CBT-E preceded by four sessions of motivation-focused therapy (MFT) (MFT + CBT-E). Participants were adult outpatients seen at a specialist eating disorder clinic in Western Australia, who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition eating disorder. A sequential trial of CBT-E as usual (n = 43) and MFT + CBT-E (n = 52) was conducted over a 40-month period. RESULTS: The MFT phase was associated with significant increases in readiness to change. There were no significant between-group differences in treatment completion rates, and treatment completers in both conditions reported comparable reductions in eating disorder symptoms over time. CONCLUSION: In this sample, MFT + CBT-E was not associated with superior treatment outcome when compared with CBT-E as usual. PMID- 21793110 TI - Resilience. PMID- 21793109 TI - The Meaning of Food (MOF): the development of a new measurement tool. AB - This paper aimed to develop a reliable measurement tool to evaluate the meanings of food that could be used in both practice and research and to examine possible gender differences. A new meaning of food questionnaire (MOF) was refined across two studies (study 1, n = 451 and study 2, n = 170). The final questionnaire consisted of 25 items and 8 reliable subscales: food and sex, emotional regulation, treat, guilt, social interaction, control over life, control over food, family. The new Meaning of Food (MOF) questionnaire could be used in both research and clinical practice to profile patients and explore predictors of eating behaviour. PMID- 21793111 TI - The challenge of change. AB - This article provides the Risk Manager with a framework for dealing with today's challenging times and how much uncertainty an organization is willing to accept. The frame work is ERM: Enterprise Risk Management. An argument is made that by applying an established ERM decision-making framework, Risk Managers can integrate governance, risk management, compliance, quality performance, and technology which allows organizations to explore, evaluate, predict, mitigate, and even prevent adverse events from occurring in the first place. PMID- 21793112 TI - Establishing a culture of perinatal safety in a community hospital. AB - While unsafe behavior of frontline hospital staff, primarily physicians and nurses, is sometimes the proximal cause of adverse events, the critical importance of system-wide, hospital organizational factors is now being acknowledged(1,2). These organizational factors create the "safety culture" that influences the occurrence of these proximal failures.(3) The concept of safety culture originated in high-reliability organization theory, which was largely developed by a group of social scientists at the University of California at Berkeley who studied high-risk organizations that have achieved very low accident and error rates, for example, aircraft carrier flight decks, nuclear power plants and air-traffic control systems.(4-6) Safety culture refers to the enduring and shared beliefs and practices of organization members regarding the organization's willingness to detect and learn from errors.(7). PMID- 21793114 TI - Perspectives on healthcare reform: a year later, what more do we know? AB - PPACA or the Affordable Care Act(1) was signed into law on March 23, 2010.(2) To many, the Affordable Care Act offers the promise of far greater access to high quality, affordable care. But to others, PPACA risks unsustainable cost increases, diminished freedoms, and irreparable harm to the world's finest healthcare delivery system. Which characterization will ultimately be proved correct? Or might the actual reforms surprise both proponents and skeptics? With a year of experience under our belts, it seems appropriate to ask: What more do we know about the new law, now? PMID- 21793113 TI - The OB hospitalist and the risk manager: ready for prime time. AB - In 1996, Wachter and Goldman described a new model of care in which hospital based physicians provided patients' inpatient care in lieu of the patient's primary physician.(1) They termed these physicians hospitalists. The hospitalist movement had taken hold, and by 1999, 65% of internists had hospitalists in their community and 28% reported using them for inpatient care.(2) In 2003, Louis Weinstein, in an article entitled "The Laborist: A New Focus of Practice for the Obstetrician"(3) advocated for the adoption of the hospitalist model to obstetrical care. In a 2010 study, of 28,545 members of the American College of Obstetricians and Gynecologists (ACOG) contacted in a national survey, 7,044 clinicians responded, which yielded a response rate of 25%. Of the respondents, 1,020 clinicians (15% of respondents, 3.6% of the entire sample) described themselves as obstetrics/gynecology hospitalists or laborists.(4) According to the web site www.obgynhospitalist.com, there are at least 115 hospitals in the country that utilize a laborist or OB hospitalist model of care.(5). PMID- 21793115 TI - Ethics, risk, and patient-centered care: how collaboration between clinical ethicists and risk management leads to respectful patient care. AB - Patient-centered care is driven in part by the ethical principle of autonomy and considers patients' cultural traditions, personal preferences, values, family situations, and lifestyles. Patient decision-making capacity, surrogate decision making with or in the absence of a patient's advance directive, and the right to refuse treatment are three patient-care issues that are central to the work done by both the risk manager and the clinical ethicist that have strong relevance to patient-centered care. This article discusses these three issues briefly and offers two challenging case studies involving patient-centered care that illustrate how a clinical ethics consultation may help to avert the escalation that can lead to a tort claim. PMID- 21793116 TI - Back to basics--just how much should a risk manager know about risk financing? AB - Whether directly involved in development and implementation of the organization's risk financing program or not, risk management professionals, at the very least, need to be familiar with and understand the various risk financing strategies available to address all areas of exposure. This article addresses the types of coverages and risk financing options that should be considered when developing a comprehensive risk-financing program, and why it is important for risk management professionals to have some knowledge about these products, in order for their true value to be fully appreciated. PMID- 21793117 TI - Case law update: vicarious liability. Abshure v. Methodist Healthcare-Memphis Hospitals, 325 S.W.3d 98 (Tenn. 2010). PMID- 21793119 TI - Predicting dyslexia at age 11 from a risk index questionnaire at age 5. AB - This study focused on predicting dyslexia in children ahead of formal literacy training. Because dyslexia is a constitutional impairment, risk factors should be seen in preschool. It was hypothesized that data gathered at age 5 using questions targeting the dyslexia endophenotype should be reliable and valid predictors of dyslexia at age 11. A questionnaire was given to caretakers of 120 5-year-old children, and a risk index score was calculated based on questions regarding health, laterality, motor skills, language, special needs education and heredity. An at-risk group (n = 25) and matched controls (n = 24) were followed until age 11, when a similar questionnaire and literacy tests were administered to the children who participated in the follow-up study (22 at risk and 20 control). Half of the at-risk children and two of the control children at age 5 were identified as having dyslexia at age 11 (8 girls and 5 boys). It is concluded that it is possible to identify children at the age of 5 who will have dyslexia at the age of 11 through a questionnaire approach. PMID- 21793120 TI - Which tasks best discriminate between dyslexic university students and controls in a transparent language? AB - The need for a battery for testing adult dyslexia, and especially university students, is being increasingly recognized in view of the increased number of adult requests for a dyslexia examination in relation to both assistance and protection from discrimination. The present study examines the discriminative validity of a battery we have developed-the Battery for the Assessment of Reading and Writing in Adulthood-through comparison of the performance of 24 university students with a history of severe developmental dyslexia and 99 controls. All the reading, writing, lexical decision and spelling tasks of the battery, except omissions in a lexical decision task and reading comprehension, showed a good discriminatory power. In addition, use of just two of these tasks (fluency in reading a text and spelling under articulatory suppression) gave 87% sensitivity and 97% specificity. Our results confirm that in transparent languages, measures of phonological automaticity are the best indexes of reading decoding competence, particularly in adults. PMID- 21793121 TI - Component processes subserving rapid automatized naming in dyslexic and non dyslexic readers. AB - The current study investigated which time components of rapid automatized naming (RAN) predict group differences between dyslexic and non-dyslexic readers (matched for age and reading level), and how these components relate to different reading measures. Subjects performed two RAN tasks (letters and objects), and data were analyzed through a response time analysis. Our results demonstrated that impaired RAN performance in dyslexic readers mainly stem from enhanced inter item pause times and not from difficulties at the level of post-access motor production (expressed as articulation rates). Moreover, inter-item pause times account for a significant proportion of variance in reading ability in addition to the effect of phonological awareness in the dyslexic group. This suggests that non-phonological factors may lie at the root of the association between RAN inter item pauses and reading ability. In normal readers, RAN performance was associated with reading ability only at early ages (i.e. in the reading-matched controls), and again it was the RAN inter-item pause times that explain the association. PMID- 21793122 TI - The cost-effectiveness of an intensive treatment protocol for severe dyslexia in children. AB - Studies of interventions for dyslexia have focused entirely on outcomes related to literacy. In this study, we considered a broader picture assessing improved quality of life compared with costs. A model served as a tool to compare costs and effects of treatment according to a new protocol and care as usual. Quality of life was measured and valued by proxies using a general quality-of-life instrument (EQ-5D). We considered medical cost and non-medical cost (e.g. remedial teaching). The model computed cost per successful treatment and cost per quality adjusted life year (QALY) in time. About 75% of the total costs was related to diagnostic tests to distinguish between children with severe dyslexia and children who have reading difficulties for other reasons. The costs per successful treatment of severe dyslexia were ?36 366. Successful treatment showed a quality-of-life gain of about 11%. At primary school, the average cost per QALY for severe dyslexia amounted to ?58 647. In the long term, the cost per QALY decreased to ?26 386 at secondary school and ?17 663 thereafter. The results of this study provide evidence that treatment of severe dyslexia is cost-effective when the investigated protocol is followed. PMID- 21793123 TI - Eliciting dyslexic symptoms in proficient readers by simulating deficits in grapheme-to-phoneme conversion and visuo-magnocellular processing. AB - Among the cognitive causes of dyslexia, phonological and magnocellular deficits have attracted a substantial amount of research. Their role and their exact impact on reading ability are still a matter of debate, partly also because large samples of dyslexics are hard to recruit. Here, we report a new technique to simulate dyslexic symptoms in normal readers in two ways. Although difficulties in grapheme-to-phoneme conversion were elicited by manipulating the identifiability of written letters, visual-magnocellular processing deficits were generated by presenting letters moving dynamically on the screen. Both factors were embedded into a lexical word-pseudoword decision task with proficient German readers. Although both experimental variations systematically increased lexical decision times, they did not interact. Subjects successfully performed word pseudoword distinctions at all levels of simulation, with consistently longer reaction times for pseudowords than for words. Interestingly, detecting a pseudoword was more difficult in the grapheme-to-phoneme conversion simulation as indicated by a significant interaction of word type and letter shape. These behavioural effects are consistent with those observed in 'real' dyslexics in the literature. The paradigm is thus a potential means of generating novel hypotheses about dyslexia, which can easily be tested with normal readers before screening and recruiting real dyslexics. PMID- 21793124 TI - Neurophysiological and behavioural correlates of coherent motion perception in dyslexia. AB - Coherent motion perception was tested in nine adolescents with dyslexia and 10 control participants matched for age and IQ using low contrast stimuli with three levels of coherence (10%, 25% and 40%). Event-related potentials (ERPs) and behavioural performance data were obtained. No significant between-group differences were found in performance accuracy and response latencies of correct responses, for early (P1, N1, and P2) or late (P3) ERP peaks. However, attenuated early ERPs in the 10% coherent condition correlated significantly with lower performance accuracy (r = -.66) and with the magnitude of literacy deficit (r = .46). PMID- 21793125 TI - Association of the OCTN1/1672T variant with increased risk for colorectal cancer in young individuals and ulcerative colitis patients. AB - BACKGROUND: Ulcerative colitis (UC) is associated with colorectal cancer. Chronic inflammation may also play a role in the pathogenesis of sporadic colorectal cancer (SCC), particularly in younger patients (<55 years). We evaluated whether single nucleotide polymorphisms of the OCTN1 and OCTN2 genes are associated with UC, SCC, and with UC cases with cancer progression (UCCP). METHODS: We evaluated the OCTN1 and OCTN2 polymorphisms in 200 patients with UC, 59 patients with UCCP, 200 patients with SCC, and 200 controls (HC). IL-8 expression was also assessed by real-time polymerase chain reaction (PCR). Additionally, we transfected human colon carcinoma Caco2 cells, homozygous for OCTN1/1672T variant, with the OCTN1/1672C allele and NF-kappaB activity was evaluated by luciferase based reporter assay and IL-8 mRNA expression by real-time PCR. RESULTS: OCTN2 polymorphisms did not present a significant association with any group of patients compared to normal controls. Conversely, homozygosity for the OCTN1/1672T variant was significantly associated with UC (P = 0.047 vs. HC), with UCCP (UCCP vs. HC, P < 0.001), and with SCC developing in early age (<55 years) (P = 0.021 vs. HC). Importantly, IL-8 mRNA expression was higher in UC and UCCP patients homozygous for the OCTN1 1672T variant compared to the other genotypes. Moreover, in Caco2 cells transfection of the OCTN1/1672C variant reduced the activity of the proinflammatory factor NF-kappaB. CONCLUSION: Our data demonstrate that OCTN1 could have a role in modulating the severity of chronic inflammation associated with SCC in early age and in UC patients, and that its polymorphisms may help to predict malignant progression of IBD. PMID- 21793126 TI - Review of the disease course among adult ulcerative colitis population-based longitudinal cohorts. AB - BACKGROUND: Ulcerative colitis (UC) has a large impact on patients' lives. Clinical course studies of population-based cohorts contribute to our understanding of the disease as it progresses. We reviewed the clinical course of UC as reported in adult population-based longitudinal cohort studies. METHODS: A MEDLINE literature search to identify all adult population-based studies published up to June 2010 with data on the clinical course of UC was performed. Demographic and clinical data were reviewed. RESULTS: Twenty-two studies reporting data from seven prospective longitudinal cohorts were identified. Extension from initial location varied from 10%-19% of the patients after 5 years of disease and from 11%-28% after 10 years in two of the cohorts. Disease activity appeared to improve over the disease course. The majority of patients had relapses in the first years of disease. The cumulative relapse rate varied from 67%-83% after 10 years of disease. From 1962-2004 a decreasing trend in the proportion of colectomies was observed. Most colectomies were performed during the first 2 years of disease and in patients with pancolitis. Salycilates were the most consumed medication followed by systemic steroids, immunosuppressors, and antitumor necrosis factors, with the latter two showing a substantial increased intake over time. Mortality increased with disease duration. CONCLUSIONS: This review shows how the clinical course of UC has changed over time and alerts to the need for more prospective cohort studies to evaluate long term outcomes especially to study the impact of biologic agents on UC. PMID- 21793127 TI - Hemophagocytic lymphohistiocytosis in Crohn's disease associated with primary infection by Epstein-Barr virus. PMID- 21793128 TI - Influence of age at diagnosis and sex on clinical course and long-term prognosis of intestinal Behcet's disease. AB - BACKGROUND: The aim of this study was to examine the influence of age at diagnosis and sex on the clinical course and long-term prognosis of intestinal Behcet's disease (BD). METHODS: We reviewed the medical records of 291 patients with intestinal BD who underwent regular follow-up at a single tertiary academic medical center. The patients were divided into two groups according to their age at diagnosis of intestinal BD or sex. The cumulative probabilities of operation, admission, corticosteroid use, and immunosuppressant use after diagnosis were analyzed using the Kaplan-Meier method and a log-rank test. RESULTS: Of the 291 patients, 154 (52.9%) were diagnosed with intestinal BD when younger than 40 years old, and 132 (45.4%) were male. Younger age at diagnosis was associated with a higher leukocyte count, C-reactive protein (CRP) level, and disease activity index for intestinal BD, and with a greater prevalence of volcano-shaped ulcers and a definite diagnostic subtype. Moreover, the cumulative probabilities of operation, admission, and corticosteroid use were significantly higher in the younger group. Male sex was associated with a higher CRP level and a greater prevalence of volcano-shaped ulcers. However, there were no significant differences in cumulative probabilities of operation, admission, corticosteroid use, and immunosuppressant use according to sex. CONCLUSIONS: In intestinal BD, younger age at diagnosis is associated with a more severe clinical course and a poorer prognosis. However, although some clinical manifestations at initial diagnosis tend to be more severe in male patients, clinical outcomes do not differ significantly according to sex. PMID- 21793131 TI - Modern biomolecular mass spectrometry and its role in studying virus structure, dynamics, and assembly. AB - Over a century since its development, the analytical technique of mass spectrometry is blooming more than ever, and applied in nearly all aspects of the natural and life sciences. In the last two decades mass spectrometry has also become amenable to the analysis of proteins and even intact protein complexes, and thus begun to make a significant impact in the field of structural biology. In this Review, we describe the emerging role of mass spectrometry, with its different technical facets, in structural biology, focusing especially on structural virology. We describe how mass spectrometry has evolved into a tool that can provide unique structural and functional information about viral-protein and protein-complex structure, conformation, assembly, and topology, extending to the direct analysis of intact virus capsids of several million Dalton in mass. Mass spectrometry is now used to address important questions in virology ranging from how viruses assemble to how they interact with their host. PMID- 21793132 TI - A biologically relevant Co1+...H bond: possible implications in the protein induced redox tuning of Co2+/Co1+ reduction. PMID- 21793133 TI - Cyclobutanes in catalysis. AB - The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. The most prominent and most frequently used compound classes in this respect are oxiranes and cyclopropanes. For rather a long time, cyclobutanes lagged behind these three membered-ring compounds in their development as reactive substrates, but during the past decade an increasing number of useful reactions of four-membered-ring substrates have emerged. This Minireview examines corresponding catalytic reactions ranging from Lewis or Bronsted acid catalyzed processes to enzymatic reactions. The main focus is placed on transition-metal-catalyzed C-C bond insertion and beta-carbon-elimination processes, which enable exciting downstream reactions that deliver versatile building blocks. PMID- 21793134 TI - DNA-controlled bivalent presentation of ligands for the estrogen receptor. PMID- 21793135 TI - Assembly of the first fullerene-type metal-organic frameworks using a planar five fold coordination node. PMID- 21793136 TI - Synthesis of covalently linked molecular bridges between silicon electrodes in CMOS-based arrays of vertical Si/SiO2/Si nanogaps. PMID- 21793137 TI - Organocatalytic, oxidative, intramolecular C-H bond amination and metal-free cross-amination of unactivated arenes at ambient temperature. PMID- 21793138 TI - Precision synthesis of biodegradable polymers. PMID- 21793139 TI - Second-generation total synthesis of spirastrellolide F methyl ester: the alkyne route. PMID- 21793140 TI - Solid-state redox solutions: microfabrication and electrochemistry. PMID- 21793141 TI - Intermolecular and selective synthesis of 2,4,5-trisubstituted oxazoles by a gold catalyzed formal [3+2] cycloaddition. PMID- 21793142 TI - Total syntheses of heimiol A, hopeahainol D, and constrained analogues. PMID- 21793143 TI - Copper-catalyzed asymmetric allylic substitution of allyl phosphates with aryl- and alkenylboronates. PMID- 21793144 TI - Concise total synthesis of the frog alkaloid (-)-205B. PMID- 21793145 TI - Covalent protein labeling with a lanthanide complex and its application to photoluminescence lifetime-based multicolor bioimaging. PMID- 21793146 TI - Direct observation of single RNA polymerase processing through a single endogenous gene in a living yeast cell. AB - Rapid advances in live-cell imaging have now enabled direct observation of the transcription of single nascent mRNA molecules from an endogenous yeast gene. A novel quantitative fluctuation analysis of fluorescently labeled mRNA revealed the kinetics of transcription initiation and the dynamics of elongation and termination. PMID- 21793147 TI - Enantioselective Michael/Mannich polycyclization cascade of indolyl enones catalyzed by quinine-derived primary amines. PMID- 21793148 TI - Indium tribromide catalyzed cross-Claisen condensation between carboxylic acids and ketene silyl acetals using alkoxyhydrosilanes. PMID- 21793149 TI - Piezoelectric actuator design for MR elastography: implementation and vibration issues. AB - BACKGROUND: MR elastography (MRE) is an emerging technique for tumor diagnosis. MRE actuation devices require precise mechanical design and radiofrequency engineering to achieve the required mechanical vibration performance and MR compatibility. METHOD: A method of designing a general-purpose, compact and inexpensive MRE actuator is presented. It comprises piezoelectric bimorphs arranged in a resonant structure designed to operate at its resonant frequency for maximum vibration amplitude. An analytical model was established to understand the device vibration characteristics. RESULTS: The model-predicted performance was validated in experiments, showing its accuracy in predicting the actuator resonant frequency with an error < 4%. The device MRI compatibility was shown to cause minimal interference to a 1.5 tesla MRI scanner, with maximum signal-to-noise ratio reduction of 7.8% and generated artefact of 7.9 mm in MR images. CONCLUSIONS: A piezoelectric MRE actuator is proposed, and its implementation, vibration issues and future work are discussed. PMID- 21793151 TI - Selective imaging of mitochondrial surfaces with novel fluorescent probes. PMID- 21793150 TI - Development of SNAP-tag fluorogenic probes for wash-free fluorescence imaging. AB - The ability to specifically attach chemical probes to individual proteins represents a powerful approach to the study and manipulation of protein function in living cells. It provides a simple, robust and versatile approach to the imaging of fusion proteins in a wide range of experimental settings. However, a potential drawback of detection using chemical probes is the fluorescence background from unreacted or nonspecifically bound probes. In this report we present the design and application of novel fluorogenic probes for labeling SNAP tag fusion proteins in living cells. SNAP-tag is an engineered variant of the human repair protein O(6)-alkylguanine-DNA alkyltransferase (hAGT) that covalently reacts with benzylguanine derivatives. Reporter groups attached to the benzyl moiety become covalently attached to the SNAP tag while the guanine acts as a leaving group. Incorporation of a quencher on the guanine group ensures that the benzylguanine probe becomes highly fluorescent only upon labeling of the SNAP tag protein. We describe the use of intramolecularly quenched probes for wash free labeling of cell surface-localized epidermal growth factor receptor (EGFR) fused to SNAP-tag and for direct quantification of SNAP-tagged beta-tubulin in cell lysates. In addition, we have characterized a fast-labeling variant of SNAP tag, termed SNAP(f), which displays up to a tenfold increase in its reactivity towards benzylguanine substrates. The presented data demonstrate that the combination of SNAP(f) and the fluorogenic substrates greatly reduces the background fluorescence for labeling and imaging applications. This approach enables highly sensitive spatiotemporal investigation of protein dynamics in living cells. PMID- 21793152 TI - Nondestructive, histologically compatible tissue imaging by desorption electrospray ionization mass spectrometry. PMID- 21793153 TI - Spin enhancement by grinding of Cu-TANC coordination polymer crystals showing d pi interactions. PMID- 21793154 TI - Single alkaline-ion (Li(+), Na(+)) conductors by ion exchange of proton conducting ionomers and polyelectrolytes. PMID- 21793155 TI - Induction of apoptosis by curcumin in murine myelomonocytic leukemia WEHI-3 cells is mediated via endoplasmic reticulum stress and mitochondria-dependent pathways. AB - Curcumin, derived from the food flavoring spice turmeric (Curcuma longa), has been shown to exhibit anticancer activities and induce apoptosis in many types of cancer cell lines. In our previous study, curcumin was able to inhibit murine myelomonocytic leukemia WEHI-3 cells in vivo. However, there is no report addressing the cytotoxic responses and the mechanisms underlying curcumin-induced apoptotic cell death in WEHI-3 cells. Therefore, we hypothesized that that curcumin affected WEHI-3 cells and triggered cell death through apoptotic signaling pathways. The effects of curcumin on WEHI-3 cells were investigated by using flow cytometric analysis, comet assay, confocal laser microscopy and Western blotting. In this study, we found that curcumin induced apoptosis in WEHI 3 cells in a dose-dependent (5-20 MUM) manner. Interestingly, curcumin enhanced the level of the antiapoptotic protein Bcl-2 which might show that curcumin induced apoptosis is done through the ER stress signaling pathways based on the increase of CIEBP homologous protein (CHOP), activating transcription factor 6 (ATF-6), inositol-requiring enzyme 1 (IRE1), and caspase-12 in WEHI-3 cells. Moreover, curcumin increased the reactive oxygen species (ROS) production and cytosolic Ca2+ release, and induced DNA damage, but decreased the level of mitochondrial membrane potential (DeltaPsim ) in WEHI-3 cells. In conclusion, curcumin-induced apoptosis occurs through the ROS-affected, mitochondria-mediated and ER stress-dependent pathways. The evaluation of curcumin as a potential therapeutic agent for treatment of leukemia seems warranted. PMID- 21793156 TI - Resveratrol protects against methylglyoxal-induced apoptosis and disruption of embryonic development in mouse blastocysts. AB - Methylglyoxal (MG) is a glucose metabolite. Diabetic patients have increased serum levels of MG, and MG is also implicated in tissue injury during embryonic development. In the present work, we show that MG induces apoptosis in the inner cell mass of mouse blastocysts and inhibits cell proliferation. Both effects are suppressed by resveratrol, a grape-derived phytoalexin with known antioxidant and anti-inflammatory properties. MG-treated blastocysts displayed lower levels of implantation (compared to controls) when plated on culture dishes in vitro and a reduced ability to proceed to later stages of embryonic development. Pretreatment with resveratrol prevented MG-induced disruption of embryonic development, both in vitro and in vivo. Further investigation of these processes revealed that MG directly promotes reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (MMP), and activation of caspase-3, whereas resveratrol effectively blocks MG-induced ROS production and the accompanying apoptotic biochemical changes. Our results collectively imply that MG triggers the mitochondrion-dependent apoptotic pathway via ROS generation, and the antioxidant activity of resveratrol prevents MG-induced toxicity. PMID- 21793157 TI - Lanthanum chloride promotes mitochondrial apoptotic pathway in primary cultured rat astrocytes. AB - Population surveys and animal experiments have shown that rare earth elements (REEs) cause neurological defects. However, the detailed mechanisms underlying these effects are still unclear. Given that lanthanum is commonly used for investigating into REEs-induced neurological defects, this study chose lanthanum chloride (LaCl3 ) to show that LaCl3 promotes mitochondrial apoptotic pathway in primary cultured rat astrocytes by regulating expression of Bcl-2 family proteins. The main findings of this study are (1) LaCl3 treatment (0.25, 0.5, and 1.0 mM for 12-48 h) induced the astrocytes damages with a concentration-dependent manner, which were confirmed with methyl thiazolyl tetrazolium and lactate dehydrogenase release assays, and morphological examination. (2) A 24 h treatment of LaCl3 concentration-dependently decreased mitochondrial membrane potential, increased cytochrome c release from mitochondria into cytosol, elevated caspase 9 and 3 expression, and promoted astrocyte apoptosis. (3) LaCl3 treatment increased the ratio of pro-apoptotic Bax and antiapoptotic Bcl-2 proteins, which in turn broke the balance among pro-apoptotic and antiapoptotic Bcl-2 family proteins, leading to astrocyte apoptosis. Our results indicate that LaCl3 alters Bcl-2 family protein expressions, which in turn promote mitochondrial apoptotic pathway, and thus astrocytic damage. PMID- 21793158 TI - Maternal exposure to the mixture of organophosphorus pesticides induces reproductive dysfunction in the offspring. AB - Organophosphorus pesticide residues are found in many food samples due to increasing use of multiple organophosphorus pesticides (OPs) in agriculture. Toxicity of individual organophosphorus has been well-studied in previous epidemiological and laboratory investigations. This study focused on reproductive toxicity of perinatal exposure to the mixture of organophosphorus pesticides (MOPs). The MOPs consists of three most commonly used pesticides, i.e., Dichlorovos, Dimethoate, and Malathion which individually does not cause significant effects on the reproductive system at the similar concentration levels based on previous studies. Using the Sprague-Dawley rats, we established a perinatal exposure model by oral gavage and observed significant endometrial hyperplasia and thickened uterine walls in the F0 rats after administration of high doses of the MOPs. We further monitored several key developmental and behavioral indices in the F1 generation after maternal exposure to the MOPs, and observed significantly delayed physical development and weakened mental development. Moreover, we found increased weights of the reproductive organs (the uterus and the testis) and abnormal levels of key sex hormones (progestin and testosterone) in the MOPs groups. It is more important that we observed a significantly lower pregnancy rate and live birth rate in the high-dose MOPs group. These results indicate that the MOPs may be more detrimental to the maternal endometria and the reproductive functions in the offspring than individual organophosphorus. PMID- 21793160 TI - The signal transduction branch of the Mexican Society of Biochemistry. PMID- 21793161 TI - The structural and molecular biology of type I galactosemia: Enzymology of galactose 1-phosphate uridylyltransferase. AB - Reduced galactose 1-phosphate uridylyltransferase (GALT) activity is associated with the genetic disease type I galactosemia. This results in an increase in the cellular concentration of galactose 1-phosphate. The accumulation of this toxic metabolite, combined with aberrant glycoprotein and glycolipid biosynthesis, is likely to be the major factor in molecular pathology. The mechanism of GALT was established through classical enzymological methods to be a substituted enzyme in which the reaction with UDP-glucose results in the formation of a covalent, UMP histidine adduct in the active site. The uridylated enzyme can then react with galactose 1-phosphate to form UDP-galactose. The structure of the enzyme from Escherichia coli reveals a homodimer containing one zinc (II) and one iron (II) ion per subunit. This enzymological and structural knowledge provides the basis for understanding the biochemistry of this critical step in the Leloir pathway. However, a high-resolution crystal structure of human GALT is required to assist greater understanding of the effects of disease-associated mutations. PMID- 21793162 TI - Axons and myelinating glia: An intimate contact. AB - The coordination of the vertebrate nervous system requires high velocity signal transmission between different brain areas. High speed nerve conduction is achieved in the myelinated fibers of both the central and the peripheral nervous system where the myelin sheath acts as an insulator of the axon. The interactions between the glial cell and the adjacent axon, namely axo-glial interactions, segregate the fiber in distinct molecular and functional domains that ensure the rapid propagation of action potentials. These domains are the node of Ranvier, the paranode, the juxtaparanode and the internode and are characterized by multiprotein complexes between voltage-gated ion channels, cell adhesion molecules, members of the Neurexin family and cytoskeletal proteins. In the present review, we outline recent evidence on the key players of axo-glial interactions, depicting their importance in myelinated fiber physiology and disease. PMID- 21793163 TI - Flipping and flopping--lipids on the move. AB - The rapid movement of polar lipids from one membrane leaflet to the other is facilitated by lipid flippases or translocases. Although their activity was first observed over 30 years ago, the structures, physiological roles, and molecular mechanisms of this group of proteins remain enigmatic. Lipid flippases maintain membrane lipid asymmetry, and in eukaryotes they are also intimately involved in membrane budding and vesicle trafficking. The ATP-dependent flippases are members of well-characterized protein families, whose other members transport nonlipid substrates across cell membranes. The P(4)-type ATPases carry out the inward translocation of phospholipids, and various ABC transporters are involved in outward lipid movement. The ATP-independent flippases move lipid substrates in both directions between membrane leaflets. With only a few exceptions, the molecular identity of these proteins is still unknown, despite their involvement in key biosynthetic pathways in both bacteria and eukaryotes. This review provides an overview of the different classes of flippases, and summarizes recent progress in their identification and functional characterization. The possible mechanisms of action of lipid flippases are discussed, and future directions explored. PMID- 21793164 TI - Coronary stenting through 4 French diagnostic catheter. AB - A first case of coronary stent implantation through a 4 French diagnostic catheter is described. PMID- 21793165 TI - Comparison of zotarolimus- versus everolimus-eluting stents in the treatment of coronary bifurcation lesions. AB - OBJECTIVES: To compare zotarolimus-eluting stent (Endeavor Sprint(r); ZES-S) and the everolimus-eluting stent (Xience V(r); EES) in the treatment of coronary bifurcation lesions. BACKGROUND: Both these stents have demonstrated good outcomes in the treatment of coronary lesions. However, the outcomes with respect to treatment of bifurcation lesions have yet to be conclusively demonstrated. METHODS: In this single centered, nonrandomized, open label study, we treated, between August 2006 and December 2008, 110 bifurcations with ZES-S and, in a second stage of the study, 129 bifurcations with EES. The primary end point was to compare the rate of major adverse cardiac events (MACE) (death, myocardial infarction, and new target lesion revascularization) in-hospital and at 12 months of follow-up. Provisional T stenting was the strategy used in the majority of cases. Angiographic follow-up was performed only in patients who presented signs or symptoms suggestive of angina or ischemia. RESULTS: There were no significant differences in in-hospital MACE between the groups (ZES-S: 8.1%; EES: 6.2%; P = 0.5). At 12 months, the ZES-S group had significantly more MACE than the EES group (23.1% vs. 4.5%; P < 0.001) and an elevated index of new revascularization of the bifurcation (17.5% vs. 3.2%; P < 0.001). There were no significant differences in mortality (four patients in ZES-S vs. one in EES; P = 0.14). CONCLUSION: The treatment of coronary bifurcation lesions using everolimus eluting stents results in better outcomes at 12 months of follow-up than zotarolimus-eluting stents. PMID- 21793166 TI - Correlates on MSCT of paravalvular aortic regurgitation after transcatheter aortic valve implantation using the Medtronic CoreValve prosthesis. AB - BACKGROUND: To investigate the causes of paravalvular aortic regurgitation (PAR) after the implantation of the Medtronic CoreValve prosthesis (MCRS). METHODS AND RESULTS: Fifty-six patients underwent MSCT before TAVI with a MCRS and PAR was assessed with transthoracic echocardiography (TTE) between 5 and 10 days after TAVI. The aortic annulus smallest and largest orthogonal diameters and the mean diameter from the area were determined on MSCT on an axial image at the nadir of all three native leaflets. PAR was related to relevant anatomical structures on MSCT according to a clockface in the orientation of the parasternal short axis view on TTE. PAR >= 1 was present in 25% of the patients and was associated with a larger annulus, a lower degree of over sizing and with more aortic root calcification. On MSCT post TAVI malapposition was seen predominantly at the aorto-mitral fibrous continuity and the aspect of the largest diameter of the aortic annulus on the inside curve of the ascending aorta. PAR was predominantly seen at these two anatomic locations and less frequent in the area that contains the ventricular membranous septum and the area between the non- and right coronary sinus. CONCLUSIONS: Mild to moderate PAR is common after TAVI with the MCRS. The availability of additional (larger) prosthesis sizes in combination with improved sizing based on mean annulus diameter (e.g., D(CSA)) may help to reduce PAR. PMID- 21793167 TI - Percutaneous treatment of severe diffuse stenosis in heavily calcified infrarenal abdominal aorta using iliac extender endoprosthesis: a case series. AB - Severe, concentric calcific stenosis of the infrarenal abdominal aorta (IAA) is an uncommon but technically challenging problem. In diffuse, heavily calcific lesions are generally not treated with balloon expandable or self-expanding stents. There is concern of aortic rupture, incomplete apposition, and underexpansion. Such lesions are mostly treated with aortobifemoral or extra anatomic bypass surgery. Using three case examples, we describe the feasibility of endovascular treatment for severely calcific IAA with use of iliac extender limbs of commercially available aortic stent grafts and discuss the role of preprocedural CT scan in case planning. PMID- 21793168 TI - Predictors of moderate-to-severe paravalvular aortic regurgitation immediately after CoreValve implantation and the impact of postdilatation. AB - OBJECTIVE: To investigate the predictors of moderate-to-severe aortic regurgitation (AR>=2+) after CoreValve implantation and evaluate the feasibility and safety of postdilatation in reducing the degree of AR. BACKGROUND: Although transcatheter aortic valve implantation is an alternative treatment for high surgical risk patients with severe aortic stenosis, post-implantation paravalvular AR remains a complication. METHODS: From July 2008 to July 2010, we enrolled 79 consecutive patients with severe aortic stenosis who underwent CoreValve implantation. RESULTS: On univariable analysis, the predictors of AR>=2+ immediately after CoreValve implantation were: larger annulus size, low implantation, prosthesis mismatch, chronic renal insufficiency, a history of heart failure, and peripheral vascular disease. On multivariable analysis, the independent predictors of AR>=2+ were: larger annulus diameter (OR 1.78, 95%CI 1.25-2.55; P = 0.002), low implantation (OR 3.67, 95%CI 1.01-13.35, P = 0.05), and peripheral vascular disease (OR 3.54, 95%CI 1.19-10.56, P = 0.02). Post CoreValve implantation, AR >= 2 was seen in 40.5% (32/79). Twenty-one patients underwent postdilatation with improvement in AR grade in the majority (17/21). Of the four patients who did not respond to postdilatation, two underwent valve-in valve implantation. In one patient, the valve was pulled more proximally by the snare technique. The remaining 10 patients were treated conservatively. CONCLUSION: The appropriate strategy for treating patients with AR>=2+ depends on the causes and severity of AR post-TAVI. This study suggests that we should carefully select the size of CoreValve prosthesis to prevent prosthesis mismatch, especially when implanted in larger annulus sizes. For valves implanted in the appropriate position, postdilatation appears effective in reducing the degree of AR. PMID- 21793169 TI - Migrating type A intramural hematoma after repair of an anomalous right coronary artery aortocoronary dissection with a covered stent. AB - Iatrogenic aortocoronary dissection is a rare and potentially life-threatening complication of percutaneous coronary intervention (PCI). Prompt coronary stenting can stop progression and avoid the need for surgical intervention. Herein, we describe a case of migrating aortic intramural hematoma (IMH) after repair of an anomalous right coronary artery aortocoronary dissection with a covered stent. PMID- 21793170 TI - Percutaneous treatment of aortic stenosis and mitral regurgitation in the same patient: first human cases description. AB - Transcatheter valve therapy is becoming an established treatment for aortic stenosis (AS) and it is very promising for mitral regurgitation (MR). There are no formal reports of percutaneous treatment of both AS and MR in the same patient. Here, we report on the first human cases of successful totally percutaneous management of combined severe AS and MR as a planned staged approach and using MitraClip((r)) implantation as a procedure necessitated by an unpredictable complication of self-expanding CoreValve device, respectively. PMID- 21793171 TI - Primary angioplasty in patients following coronary artery bypass surgery: trends in application and outcome. Results from the acute coronary syndrome Israeli Survey (ACSIS) 2000-2008. AB - OBJECTIVES: We aimed to study the trends in management and outcome of post CABG patients presenting with acute MI. BACKGROUND: Primary angioplasty is the treatment of choice in patients with acute myocardial infarction. Saphenous vein grafts used for CABG are large-diameter conduits that tend to accumulate a large mass of thrombus when they are the culprit artery for acute myocardial infarction (MI). We hypothesized that performing PCI in these patients is more complex and possibly results in worse outcome compared to non-CABG patients. METHODS: Data for patients with STEMI was obtained from five acute coronary syndromes Israeli biennial Surveys (ACSIS) during 2000-2008. Baseline characteristics, management and outcome of post-CABG patients were compared to non-post CABG patients during 2006-2008 surveys. RESULTS: A total of 9,781 patients were included. About 1,002 (10.2%) were post-CABG. Reperfusion therapy for post-CABG patients (34-48%) was consistently lower compared to non-CABG patients (57-65%). Angiographic outcome in patients with STEMI who underwent primary PCI (17 post-CABG, mean age 66.6 +/- 9.1 and 821 non-CABG, age 60.1 +/- 12.9) was successful (TIMI flow 3) in 86 and 88%, respectively. Thirty-day mortality was 5.9 and 5.1% (P = 0.89) and MACE rates were 17.6 and 12.5%, respectively (P = 0.54). CONCLUSIONS: Use of primary PCI in post-CABG patients was lower than in non-CABG patients but increased steadily and to a similar extent in both groups. Angiographic and clinical outcome was similar despite assumingly larger thrombus burden in post CABG patients. Therefore, primary angioplasty is appropriate also in post-CABG patients presenting with STEMI. PMID- 21793172 TI - Percutaneous coronary intervention of unprotected left main coronary artery disease: procedural strategies and technical considerations. AB - Data have emerged demonstrating the safety and efficacy of percutaneous coronary intervention (PCI) of the unprotected left main (ULM) artery. The 2009 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions focused guidelines for PCI no longer state that ULM PCI is contraindicated in patients with anatomic conditions that are associated with a low risk of procedural complications and clinical conditions that predict an increased risk of adverse surgical outcomes. ULM PCI should be performed by operators with experience in the management of the anatomic complexities of left main and multivessel disease, specifically in issues relating to bifurcation disease, calcification, and hemodynamic support. Patients with ostial or shaft disease have lower risk of restenosis compared with distal bifurcation disease. Drug-eluting stents (DES) should be used whenever possible as they reduce clinical restenosis. Intravascular ultrasound is an integral component of the procedure as it provides accurate assessment of lesion severity and can confirm optimal stent expansion and apposition. Compliance with dual antiplatelet therapy for at least 12 months is essential if DES are used. A collaborative, multidisciplinary approach with a "Heart Team" represented by a cardiac surgeon, interventional cardiologist, and non-invasive cardiologist may optimize patient education and objective decision making when obtaining informed consent. Application of clinical and angiographic variables into risk models facilitates appropriate patient selection. Randomized clinical trials will address unanswered issues and help build consensus between cardiology and surgical societies to inform clinical decision making and optimize the outcomes for patients with ULM coronary artery disease. PMID- 21793173 TI - GuideLiner, a child-in-a-mother catheter for successful retrieval of an entrapped rotablator burr. AB - Entrapment of the rotablator burr within heavily calcified lesions is a recognized complication, which usually necessitates sternotomy and open surgical intervention to retrieve the trapped burr. In some cases, the trapped burr can be retrieved using simple traction, but this is potentially hazardous with possible trauma and perforation of the vessel. Passing a wire alongside the trapped burr with ballooning to free the burr can be attempted. We describe a novel technique to remove a trapped rotablator burr from a heavily calcified lesion using counter traction with a GuideLiner, child-in-a-mother catheter, which successfully removed the entrapped burr without the need for surgery when simple traction alone had been ineffective. PMID- 21793174 TI - Transaortic transcatheter aortic valve implantation within a previous bioprosthetic aortic valve replacement. AB - This report documents the first reported case of transaortic transcatheter aortic valve implantation (TAVI) using the CoreValve ReValving system (Medtronic CoreValve System, Luxembourg), within a previous bioprosthetic aortic valve replacement. TAVI has become a recognized percutaneous treatment for patients with severe native or bioprosthetic aortic valve stenosis. However, as the number of patients screened for TAVI increases, a number of patients are found with absolutely no option for peripheral arterial access, either from the femoral or subclavian routes. Transaortic CoreValve placement offers an alternate minimally invasive hybrid surgical/interventional technique when peripheral access is not possible. A CoreValve prosthesis was implanted via the transaortic route in an 81 year-old woman with severe bioprosthetic aortic valve stenosis (21 mm Mitroflow pericardial valve, peak instantaneous gradient of 99 mmHg, effective valve orifice area (EOA) of 0.3 cm(2) , as ilio-femoral and left subclavian angiography revealed small calibre vessels (<6 mm). Access was achieved via a mini thoracotomy via the left anterior second intercostal space. The procedure went without complication. Post procedure the patient was transferred directly to the Cardiac Care Unit for recuperation. Post procedure echocardiography showed that the TAVI was well positioned with no para-valvular leak and a reduction in peak instantaneous gradient to 30 mmHg and an increase in EOA to 1.5 cm(2) . She was discharged on the third post-procedural day in sinus rhythm with a narrow QRS complex. CoreValve implantation within previous surgical bioprosthesis is now an established treatment. The transaortic approach to transcatheter implantation is a promising recent development, when due to anatomical reasons, transfemoral or subclavian TAVI is not feasible. PMID- 21793175 TI - Treatment of children with poor risk solid tumors by further escalation of the VETOPEC regimen including very high-dose cyclophosphamide and peripheral stem cell support: an Australian and New Zealand Children's Hematology and Oncology Group study. AB - BACKGROUND: Children with solid tumors deemed to be poor risk at diagnosis and those who fail to respond or recur after chemotherapy have adverse outcomes. We sought to increase the dosage of cyclophosphamide (CPA) in the VETOPEC regimen (vincristine, etoposide, and CPA) with a view to improving the response rate and survival. PROCEDURE: Patients underwent peripheral blood stem cell (PBSC) harvest after standard dose VETOPEC (CPA 40 mg/kg/day for 3 days) followed by filgrastim. Those with sufficient PBSC received up to four intensive cycles (ICs) of VETOPEC with CPA dosages of 60-90 mg/kg/day for 3 days (escalated by 5 mg/kg/day in cohorts of at least five patients) followed by PBSC and filgrastim. RESULTS: Of the 59 enrolled patients, 58 were treated with mobilization chemotherapy and 57 proceeded to PBSC harvest. From 1 to 4 VETOPEC ICs were administered to 51 patients. The maximum tolerated dosage of CPA was not reached. The best response rate during the ICs for patients with recurrent or refractory/progressive disease was 67%; overall survival was 28% at 5 years and 25% at 10 years. The response rate for patients with newly diagnosed high-risk tumors was 89%. CONCLUSIONS: The VETOPEC regimen with CPA dosages up to 90 mg/kg/day for 3 days followed by PBSC and filgrastim can be given in a timely manner with manageable toxicity. Outcomes were not improved when compared to prior VETOPEC studies. VETOPEC produces high response rates and warrants further evaluation in appropriate patients with newly diagnosed high-risk solid tumors. PMID- 21793176 TI - Short echo time single voxel 1H magnetic resonance spectroscopy in the diagnosis and characterisation of pineal tumours in children. AB - BACKGROUND: Magnetic resonance spectroscopy (MRS) has been successful in characterising a range of brain tumours and is a useful aid to non-invasive diagnosis. The pineal region poses considerable surgical challenges and a major surgical resection is not required in the management of all tumours. Improved non invasive assessment of pineal region tumours would be of considerable benefit. METHODS: Single voxel MRS (TE 30 ms, TR 1500, 1.5 T) was performed on 15 pineal tumours: 5 germinomas, 1 non-germinomatous secreting germ cell tumour (GCT), 2 teratomas, 5 pineoblastomas, 1 pineal parenchymal tumour (PPT) of intermediate differentiation and 1 pineocytoma. Two germinomas outside the pineal gland were also studied. Metabolite, lipid and macromolecule concentrations were determined with LCModelTM. RESULTS: Germ cell tumours had significantly higher lipid and macromolecule concentrations than other tumours (t-test; P < 0.05). The teratomas had significantly lower total choline and creatine levels than germinomas (z test; P < 0.05). Taurine was convincingly detected in germinomas as well as PPTs. CONCLUSIONS: Magnetic resonance spectroscopy is useful for characterising pineal region tumours, aiding the non-invasive diagnosis and giving additional biological insight. PMID- 21793177 TI - Intralesional interferon-alpha for the treatment of bilateral conjunctival mucosa associated lymphoid tissue lymphoma. AB - We describe a case of bilateral conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma in a 14-year-old female treated with intralesional interferon alpha. Interferon-alpha-2b was injected three times a week for 6 weeks, then once weekly for 12 weeks. Marked tumor reduction was observed by week 5 of treatment, with complete resolution by week 8. There was no sign of recurrence through 27 months of follow-up. Intralesional interferon-alpha was an effective treatment for this unusual case of conjunctival MALT lymphoma in a very young female. It presents an attractive alternative to traditional treatment modalities in this patient population. PMID- 21793178 TI - Red blood cell transfusion in pediatric patients with severe chronic anemia: how slow is necessary? AB - Historic practice recommends slow transfusion for children with chronic anemia and hemoglobin less than 5.0 g/dl due to the theoretical risk of transfusion associated circulatory overload (TACO). In our pediatric intensive care unit (PICU), we have been utilizing a more liberal transfusion practice in patients without underlying cardiopulmonary disease, and a faster transfusion rate appears safe in this population. Rate of transfusion must be based on multiple factors including convenience, timeliness of procedures and transport to an appropriate care facility, risk of alloimmunization and wastage of blood, stress for the family, and need for PICU monitoring. PMID- 21793179 TI - Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia. AB - BACKGROUND: Long-term survivors of acute lymphoblastic leukemia (ALL) in childhood are at increased risk of late effects of cancer treatment, among which are cardiovascular sequelae. Purpose of this study was to assess blood pressure and body composition in childhood ALL survivors and compare data to reference values from the general population. PROCEDURE: This single-center retrospective study included 68 survivors of childhood ALL with a median age of 25 years (range 16.4-39.5) and a median follow-up of 16.0 years (range 5.3-30.4). Data on previous treatment, blood pressure and measurements of weight and height at diagnosis and at long-term follow-up (from which body mass index (BMI) was calculated) were obtained from medical records. All data were converted to control-referenced standard deviation scores. RESULTS: Of the ALL survivors 481/2% were prehypertensive and 22.1% were hypertensive. Both the mean systolic (mean SDS 0.736, P < 0.001) and diastolic blood pressure (mean SDS 0.409, P < 0.001) of survivors was significantly higher compared to reference control values. Based on BMI values, 38.2% of the survivors were considered overweight/obese and females, in contrast to males had a significantly higher BMI (mean SDS 1.355, P < 0.001) compared to reference values. In addition, females who had received cranial radiotherapy (mean SDS 2.078) had a significantly higher BMI than females who had not (mean SDS 0.512) (P = 0.009). CONCLUSIONS: Both diastolic and systolic blood pressure are significantly increased in survivors of childhood ALL. Female survivors treated with cranial radiation therapy have the highest prevalence and greatest risk of overweight/obesity. Therefore, survivors of childhood ALL are likely to be at an increased risk of cardiovascular disease later in life, which stresses the need for follow-up and adequate medical and/or life style interventions. PMID- 21793180 TI - Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance Epidemiology and End Results database. AB - BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal malignancies that occur throughout the lifespan. The impact of age on disease features and outcome is unclear. METHODS: We analyzed the clinical features and outcome of all STS cases registered between 1973 and 2006 in the SEER database. RESULTS: There were 48,012 cases that met the selection criteria. Individuals less than 20 years of age represented 5.6%, with rhabdomyosarcoma being the most common subtype. In adults, the most common types were Kaposi sarcoma, fibrohistiocytic tumors, and leiomyosarcoma. Rhabdomyosarcoma was the only entity with a median age <20 years. Male predominance (male/female of 1.5:1) was noticed for almost all types of STS, except for alveolar soft part sarcoma and leiomyosarcoma. Tumor stage was similar across different age groups. Younger patients (<50 years) had significantly better survival than older patients (88.8 +/- 0.2% vs. 40 +/- 0.3%, P < 0.001), but for most histologies the survival decline with advancing age was gradual and did not occur abruptly at the onset of adulthood. The decline in survival with advancing age was particularly significant for rhabdomyosarcoma. CONCLUSION: With few exceptions, the clinical features of STS are similar in children and adults. However, individuals over 50 years of age have an inferior survival. PMID- 21793181 TI - Formation of cyclophosphamide specific DNA adducts in hematological diseases. AB - BACKGROUND: Fanconi anemia (FA) patients are hypersensitive to DNA alkylating agents and require lower doses than non-FA patients to minimize serious toxicity. The mechanism by which hypersensitivity occurs is thought to be due to the inability of these individuals to effectively repair drug-induced interstrand DNA DNA crosslinks. We recently developed a highly sensitive assay for cyclophosphamide specific interstrand DNA-DNA crosslinks (G-NOR-G) and are able to quantify and compare formation of these adducts in the blood of patients. Therefore we sought to determine whether FA patients have higher in vivo exposure to the cyclophosphamide specific interstrand DNA crosslink, G-NOR-G, relative to patients without FA. PROCEDURE: Cyclophosphamide interstrand DNA crosslinks were measured with the first dose of cyclophosphamide in FA and non-FA patients receiving a cyclophosphamide based preparative regimen prior to hematopoietic cell transplantation (HCT). FA patients received a lower cyclophosphamide dose than the non-FA patients (5-10 mg/kg/day vs. 50-60 mg/kg/day). RESULTS: Despite the lower cyclophosphamide dose and lower plasma concentrations in FA patients, they had G-NOR-G amounts similar to the non-FA patients (area under the curve (AUC)(0-infinity) , 99.8 vs. 144.9 G-NOR-G adducts/10(6) nucleotides hour, respectively, P = 0.47). When G-NOR-G AUC was normalized for cyclophosphamide plasma concentrations, FA study subjects produced 15-fold higher adducts than non FA patients (P = 0.05). CONCLUSIONS: FA patients are hypersensitive to DNA alkylating agents possibly as a result of greater formation of cyclophosphamide specific interstrand DNA crosslinks and/or diminished capacity for DNA repair. Identification and quantification of these adducts may be important determinant of cyclophosphamide related toxicity. PMID- 21793182 TI - Successful treatment of gastrointestinal mucormycosis in an adolescent with acute lymphoblastic leukaemia (ALL). PMID- 21793183 TI - Myelodysplastic syndrome in children: changing definitions from FAB 1976 to WHO 2008 classification systems. PMID- 21793184 TI - Impact of treatment reduction for childhood acute lymphoblastic leukemia on serum immunoglobulins and antibodies against vaccine-preventable diseases. AB - BACKGROUND: The consequences of current intensive chemotherapy for childhood acute lymphoblastic leukemia (ALL) for immune defense are a matter of concern. The purpose of this study was to examine the effect of reduced compared with intensive (conventional) ALL chemotherapy on serum immunoglobulin levels and specific antibody concentrations against vaccine-preventable diseases. PROCEDURE: Patients treated according to Dutch Childhood Oncology Group ALL 10 protocol were stratified by minimal residual disease to receive reduced (standard risk; SR) or intensive (medium risk; MR) intensification/maintenance treatment. Between November 2004 and July 2009 we compared serum immunoglobulins of 110 patients and specific antibodies against diphtheria toxin, tetanus toxin, and Bordetella pertussis antigens of 41 patients of SR and MR groups during chemotherapy. RESULTS: Immunoglobulin levels showed significantly different patterns between the SR and MR groups. In the MR group IgG, IgA, and IgM levels decreased towards the end of intensive treatment; in the SR group IgG levels increased while IgA and IgM stabilized. In both groups IgM and IgG levels were most affected. Specific antibody levels against vaccine-preventable diseases decreased in both groups, but more profound in MR group. CONCLUSIONS: Although reduced chemotherapy is beneficial for immunoglobulin level recovery and might prevent susceptibility for infections, specific antibodies remain decreased. PMID- 21793185 TI - Hospitalization for invasive pneumococcal disease in a national sample of children with sickle cell disease before and after PCV7 licensure. AB - OBJECTIVE: To estimate national hospitalization rates for invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) before and after the 2000 licensure of the heptavalent pneumococcal conjugate vaccine (PCV7). PROCEDURE: We performed a retrospective trend analysis of the 1994-2007 Nationwide Inpatient Sample databases. Hospitalizations involving children with SCD and IPD were identified by ICD-9CM code. The primary outcomes, the annual hospitalization rate for IPD in children with SCD and the proportion of hospitalizations for IPD per 100 total SCD hospitalizations, were analyzed using multivariable linear regression and contingency analysis, respectively. RESULTS: A total of 1,242 hospitalizations for IPD in SCD patients were identified from 1994-2007, with a mortality rate of 2.4%. The national mean annual rate of IPD hospitalization decreased by 65%, from 131.8 cases/year from 1994 to 2000 to 45.5 cases/year from 2001 to 2007 (P = 0.001). The national proportion of hospitalizations for IPD per 100 total SCD hospitalizations decreased from 0.4 to 0.15 (P < 0.0001) over the same interval. Following PCV7 licensure, the mean annual cumulative hospital days and cumulative hospital charges decreased nationally by 53% and 36%, respectively. CONCLUSION: In a national sample, PCV7 licensure is temporally associated with a nearly threefold reduction in IPD hospitalizations in children with SCD. PMID- 21793186 TI - Association of a glucose-6-phosphate deficiency and a Gilbert syndrome as risk factors for a severe choledocholithiasis in a 2-month-old male infant. PMID- 21793187 TI - Evaluation of polymorphisms in EWSR1 and risk of Ewing sarcoma: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology. PROCEDURE: Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests. RESULTS: One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79-21.7; P = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%. CONCLUSIONS: Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be an Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown. PMID- 21793188 TI - A two-event in vitro model of acute chest syndrome: the role of secretory phospholipase A2 and neutrophils. AB - BACKGROUND: Acute chest syndrome (ACS) in sickle cell disease is associated with elevation of secretory phospholipase A(2) (sPLA(2) ). We hypothesize that sPLA(2) cleaves membrane lipids from sickled red blood cells (RBCs) causing PMN-mediated endothelial cell injury (ECI) as the second event in a two-event model. METHODS: Whole blood was collected from children when in steady state or daily during admissions for vaso-occlusive pain (VOC) or ACS. The plasma and RBCs were separated, sPLA(2) levels were measured, and the RBCs were incubated with sPLA(2) . Plasma and lipids, extracted from the plasma or the supernatant of sPLA(2) treated RBCs, were assayed for PMN priming activity and used as the second event in a model of PMN-mediated ECI. Phosphatidylserine (PS) surface expression on RBCs was quantified by flow cytometry. RESULTS: Increased sPLA(2) -IIa levels were associated with ACS. SPLA(2) -liberated lipids from VOC and the plasma, plasma lipids and sPLA(2) -liberated lipids from ACS primed PMNs and caused PMN mediated ECI (P < 0.01). RBCs from VOC had increased in PS surface expression versus steady state. CONCLUSIONS: ACS plasma and lipids and sPLA(2) -released lipids from RBCs during VOC or ACS induce PMN-mediated ECI. VOC elicited increases in PS surface expression providing a membrane substrate for sPLA(2) lysis of sickle RBCs. PMID- 21793189 TI - Birth weight and childhood leukemia: time to tackle bigger lessons. PMID- 21793190 TI - Insights on neoplastic stem cells from gel-based proteomics of childhood germ cell tumors. AB - BACKGROUND: Childhood germ cell tumors (cGCTs), believed to arise from transformed primordial germ cells by an unknown mechanism, provide a unique model system for investigating cell signaling, pluripotency, and the microenvironment of neoplastic stem cells (NSCs) in vivo. This is the first report of proteomics of cGCTs. PROCEDURE: Four dysgerminomas (DYSs) and four childhood endodermal sinus tumors (cESTs), resembling self-renewing and differentiating NSCs, respectively, were selected. Proteomic studies were performed by 2-DE, SDS-PAGE, and cLC/MS/MS with protein database searching. RESULTS: 2-DE: 9 of 941 spots were differentially regulated with greater than a twofold change in spot volume for at least three of four gels in each group. Two of nine spots had P values for the t test analysis of comparisons less than 0.001, while the remaining spots had P values from 0.013 to 0.191. Top-ranked proteins were identified in nine of nine spots with 4.0-38% sequence coverage. APOA1, CRK, and PDIA3 were up-regulated in cESTs. TFG, TYMP, VCP, RBBP, FKBP4, and BiP were up-regulated in DYSs. SDS-PAGE: Up-regulation of NF45 and FKBP4 was observed in four of four cESTs and DYSs, respectively. The fold-changes observed correspond with characteristic genetic changes. CONCLUSION: Differential regulation of FKBP4 and NF45, combined with previous research on immunosuppressant binding, suggests that glucocorticoid receptor signaling merits further investigation in cGCTs and NSCs. PMID- 21793191 TI - Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low-dose regimens. AB - BACKGROUND: Inhibitory antibodies against infused clotting factor VIII concentrates (FVIII) developed in 20-30% of patients with hemophilia A. Bypass therapy may control the bleeds in patients with FVIII inhibitors, however, immune tolerance induction (ITI) therapy is the only proven modality for eradicating FVIII inhibitors. Since the cost of high-dose (200 IU/kg) ITI is extremely expansive, we conducted this study to identify whether low-dose ITI can be an alternative strategy besides high-dose ITI or bypass therapy. PROCEDURE: Patients with hemophilia A and FVIII inhibitors treated by ITI in Kaohsiung Medical University Hospital from January 2000 to January 2010 were enrolled. Regimens of ITI therapy included high-dose (100 IU/kg) and low-dose (30-50 IU/kg). RESULTS: High-dose ITI therapy for two high responders (HRs) and low-dose ITI therapy for three HRs and all low responders (LRs) were performed. Complete tolerance was achieved in 2 HRs with high-dose regimen, and in one HR and 19 LRs with low-dose regimens. We administered low-dose ITI combined with immune suppressants treatment for one of the patient with extremely high FVIII inhibitor titers and the inhibitor level markedly declined and no spontaneous bleeding episode was noticed during the treatment period. CONCLUSIONS: The outcome of ITI in our study was satisfactory without clinically significant complications. Low-dose ITI regimens can effectively treat patients with high responder inhibitors, including one patient with extremely high inhibitor levels over 700 BU. Low-dose ITI may be an alternative modality for FVIII inhibitors management, especially in countries with limited resources. PMID- 21793192 TI - Coralline hydroxyapatite granules inferior to morselized allograft around uncemented porous Ti implants: unchanged fixation by addition of concentrated autologous bone marrow aspirate. AB - We compared early fixation of titanium implants grafted with impacted allograft bone or coralline hydroxyapatite (HA) granules (Pro Osteon 200) with and without the addition of concentrated bone marrow cells (BMC). Autologous bone marrow aspirate was centrifuged to increase the BMC concentration. Four nonloaded cylindrical, porous coated titanium implants with a circumferential gap of 2.3 mm were inserted in the proximal humeri of eight dogs. Coralline HA granules +/- BMC were impacted around the two implants on one side, and allograft +/- BMC was impacted around the contra lateral implants. Observation time was 4 weeks. The implants surrounded by allograft bone had a three-fold better fixation than the HA-grafted implants. The concentration of BMC after centrifugation was increased with a factor 2.1. The addition of BMC to either of the bone graft materials had no statistically significant effects on implant fixation. The allografted implants were well osseointegrated, whereas the HA-grafted implants were largely encapsulated in fibrous tissue. The addition of concentrated autologous BMCs to the graft material had no effect on implant fixation. The HA-grafted implants were poorly anchored compared with allografted implants, suggesting that coralline HA granules should be considered a bone graft extender rather than a bone graft substitute. PMID- 21793193 TI - Mechanical improvements to reinforced porous silk scaffolds. AB - Load-bearing porous biodegradable scaffolds are required to engineer functional tissues such as bone. Mechanical improvements to porogen leached scaffolds prepared from silk proteins were systematically studied through the addition of silk particles in combination with silk solution concentration, exploiting interfacial compatibility between the two components. Solvent solutions of silk up to 32 w/v % were successfully prepared in hexafluoroisopropanol (HFIP) for the study. The mechanical properties of the reinforced silk scaffolds correlated to the material density and matched by a power law relationship, independent of the ratio of silk particles to matrix. These results were similar to the relationships previously shown for cancellous bone. From these data we conclude that the increased mechanical properties were due to a densification effect and not due to the inclusion of stiffer silk particles into the softer silk matrix. A continuous interface between the silk matrix and the silk particles, as well as homogeneous distribution of the silk particles within the matrix was observed. Furthermore, we note that the roughness of the pore walls was controllable by varying the ratio of the particles matrix, providing a route to control topography. The rate of proteolytic hydrolysis of the scaffolds decreased with increase in mass of silk used in the matrix and with increasing silk particle content. PMID- 21793194 TI - Polymerizable superoxide dismutase mimetic protects cells encapsulated in poly(ethylene glycol) hydrogels from reactive oxygen species-mediated damage. AB - A polymerizable superoxide dismutase mimetic (SODm) was incorporated into poly(ethylene glycol) (PEG) hydrogels to protect encapsulated cells from superoxide-mediated damage. Superoxide and other small reactive oxygen species (ROS) can cause oxidative damage to donor tissue encapsulated within size exclusion barrier materials. To enzymatically breakdown ROS within biomaterial cell encapsulation systems, Mn(III) Tetrakis[1-(3-acryloxy-propyl)-4-pyridyl] porphyrin (MnTTPyP-acryl), a polymerizable manganese metalloporphyrin SOD mimetic, was photopolymerized with PEG diacrylate (PEGDA) to create functional gels. In unmodified PEG hydrogels, a significant reduction in metabolic activity was observed when encapsulated Min6 beta-cells were challenged with chemically generated superoxide. Cells encapsulated within MnTPPyP-co-PEG hydrogels, however, demonstrated greatly improved metabolic activity following various superoxide challenges. Further, cells were encapsulated and cultured for 10 days within MnTPPyP-co-PEG hydrogels and challenged with superoxide on days 4, 6, and 8. At the conclusion of this study, cells in blank PEG hydrogels had no observable metabolic activity but when encapsulated in MnTPPyP-functionalized hydrogels, cells retained 60 +/- 5% of the metabolic activity compared to untreated controls. PMID- 21793195 TI - Triblock copolymers of epsilon-caprolactone, L-lactide, and trimethylene carbonate: biodegradability and elastomeric behavior. AB - For the triblock copolymer of epsilon-caprolactone, trimethylene carbonate, and L lactide, where L-lactide blocks form the two ends, there is a range of compositions over which elastomeric behavior is obtained. Within this composition range, these polymers show good creep and recovery at ambient temperature, and exhibit high elongations to break. Additionally, we demonstrate that the recovery is independent of stress and strain for the elastomer compositions. The range of compositions that yield elastomeric character is rationalized based on the structure; specifically, there must be a minimum crystallinity of the end blocks and no crystallinity in the midblock, in addition to molar mass requirements. These polymers degrade by simple hydrolysis, and the rate of degradation is potentially programmable by manipulation of the molar ratio of hard segment to soft segment. Compared to biodegradable polyurethane, these polymers are expected to yield less harmful degradation products, and offer more variables for manipulation of properties. These polymers are also processable from the melt at temperatures exceeding about 130 degrees C. We expect to use these polymers in a variety of applications, including stent coatings, fully-degradable stents, and atrial septal defect occluders. PMID- 21793196 TI - Covalent stabilization of alginate hydrogel beads via Staudinger ligation: assessment of poly(ethylene glycol) and alginate cross-linkers. AB - Cellular encapsulation within alginate hydrogel capsules has broad applications in tissue engineering. In seeking to improve the inherent instability of ionically cross-linked alginate hydrogels, we previously demonstrated the covalent stabilization of Ba(2+) cross-linked alginate-azide beads via chemoselective Staudinger ligation using a 1-methyl-2-diphenylphosphino terephthalate (MDT) terminated poly(ethylene glycol) (PEG) linker. In this study, we functionalized variant PEG, linear and branched, and alginate polymers with MDT groups to evaluate the effect of size, structural design, number of functional groups, and charge on the resulting hydrogel bead. All cross-linkers resulted in enhanced covalent stabilization of alginate beads, with significant decreases in swelling and resistance to dissolution via Ba(2+) chelation. The MDT functionalized alginate resulted in the most stable and homogeneous bead, with the most restrictive permeability even after EDTA exposure. Co-encapsulation of MIN6 cells within the cross-linked alginate hydrogel beads resulted in minimal effects on viability, whereas the degree of proliferation following culture varied with cross-linker type. Altogether, the results illustrate that manipulating the cross-linker structural design permits flexibility in resulting alginate beads characteristics. Covalent stabilization of alginate hydrogel beads with these chemoselective alginate and PEG-based cross-linkers provides a unique platform for cellular encapsulation. PMID- 21793197 TI - Binding affinity of surface functionalized gold nanoparticles to hydroxyapatite. AB - Gold nanoparticles (Au NPs) have been investigated for a number of biomedical applications, including drug and gene delivery vehicles, thermal ablation therapy, diagnostic sensors, and imaging contrast agents. Surface functionalization with molecular groups exhibiting calcium affinity can enable targeted delivery of Au NPs to calcified tissue, including damaged bone tissue. Therefore, the objective of this study was to investigate the binding affinity of functionalized Au NPs for targeted delivery to bone mineral, using hydroxyapatite (HA) crystals as a synthetic analog in vitro. Au NPs were synthesized to a mean particle size of 10-15 nm and surface functionalized with either L-glutamic acid, 2-aminoethylphosphonic acid, or alendronate, which exhibit a primary amine for binding gold opposite carboxylate, phosphonate, or bisphosphonate groups, respectively, for targeting calcium. Bisphosphonate functionalized Au NPs exhibited the most rapid binding kinetics and greatest binding affinity to HA, followed by glutamic acid and phosphonic acid. All functional groups reached complete binding after 24 h. Equilibrium binding constants in de-ionized water, determined by nonlinear regression of Langmuir isotherms, were 3.40, 0.69, and 0.25 mg/L for bisphosphonate, carboxylate, and phosphonate functionalized Au NPs, respectively. Functionalized Au NPs exhibited lower overall binding in fetal bovine serum compared to de-ionized water, but relative differences between functional groups were similar. PMID- 21793198 TI - Secondary poisoning risk assessment of terrestrial birds and mammals exposed to nickel. AB - The European Union's Existing Substances regulation (EEC 793/93) was developed to assess the ecological risks posed by chemical substances such as Ni and includes the assessment of secondary poisoning risks. The basic structure of this secondary poisoning risk assessment followed the Technical Guidance Document on Risk Assessment and thus included development of predicted exposure concentrations (PECs) and predicted no-effect concentrations (PNECs). A PEC to PNEC ratio greater than 1.0 is indicative of potential risk. The Technical Guidance Document on Risk Assessment provides a generic framework for assessing secondary poisoning risks and prescribes the following terrestrial food chain: soil -> earthworm -> worm-eating bird or mammal. This secondary poisoning evaluation was conducted at the regional level, and it was found that the generic approach resulted in widespread estimates of potential risk, even at ambient Ni soil concentrations. Accordingly, a tiered approach was used with increasing levels of refinement, including consideration of bioavailability, consideration of a variable diet, and development of dose-based PNEC values. Based on the refined approach, all PEC to PNEC ratios were less than 1.0, except for a ratio of 1.4 in a scenario focused on a regional clay soil, which was of natural origin. This regional-level secondary poisoning evaluation highlighted key risk assessment components that should be considered in future localized secondary poisoning assessments of Ni and other metals, including ingestion rate to body weight ratios for the test organisms used to derive PNECs versus the representative wildlife species evaluated, the appropriateness of high assessment factors for deriving PNECs for naturally occurring essential elements, representative dietary compositions, relative metal bioavailability between the dietary toxicity study and natural diets, and ground-truthing of the risk predictions versus background concentrations. PMID- 21793200 TI - Comparing laboratory and field measured bioaccumulation endpoints. AB - An approach for comparing laboratory and field measures of bioaccumulation is presented to facilitate the interpretation of different sources of bioaccumulation data. Differences in numerical scales and units are eliminated by converting the data to dimensionless fugacity (or concentration-normalized) ratios. The approach expresses bioaccumulation metrics in terms of the equilibrium status of the chemical, with respect to a reference phase. When the fugacity ratios of the bioaccumulation metrics are plotted, the degree of variability within and across metrics is easily visualized for a given chemical because their numerical scales are the same for all endpoints. Fugacity ratios greater than 1 indicate an increase in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biomagnification). Fugacity ratios less than 1 indicate a decrease in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biodilution). This method provides a holistic, weight-of-evidence approach for assessing the biomagnification potential of individual chemicals because bioconcentration factors, bioaccumulation factors, biota-sediment accumulation factors, biomagnification factors, biota-suspended solids accumulation factors, and trophic magnification factors can be included in the evaluation. The approach is illustrated using a total 2393 measured data points from 171 reports, for 15 nonionic organic chemicals that were selected based on data availability, a range of physicochemical partitioning properties, and biotransformation rates. Laboratory and field fugacity ratios derived from the various bioaccumulation metrics were generally consistent in categorizing substances with respect to either an increased or decreased thermodynamic status in biota, i.e., biomagnification or biodilution, respectively. The proposed comparative bioaccumulation endpoint assessment method could therefore be considered for decision making in a chemicals management context. PMID- 21793201 TI - Assessment of risks to ground-feeding songbirds from lead in the Coeur d'Alene Basin, Idaho, USA. AB - Previous assessment of ecological risks within the Coeur d'Alene River Basin identified Pb as a key risk driver for ground-feeding songbirds. Because this conclusion was based almost exclusively on literature data, its strength was determined to range from low to moderate. With the support of the US Environmental Protection Agency (USEPA), the US Fish and Wildlife Service collected site-specific data to address the uncertainty associated with Pb risks to songbirds. These data, plus those from the previous Coeur d'Alene Basin ecological risk assessment, were integrated, and risks to ground-feeding songbirds were reevaluated. These site-specific data were also used to develop updated preliminary remedial goals (PRGs) for Pb in soils that would be protective of songbirds. Available data included site-specific Pb concentrations in blood, liver, and ingesta from 3 songbird species (American robin, song sparrow, and Swainson's thrush), colocated soil data, and soil data from other locations in the basin. Semi-log regression models based on the association between soil Pb and tissue Pb concentrations were applied to measured soil concentrations from the previous risk assessment to estimate Pb exposures in riparian and adjacent upland habitats throughout the Coeur d'Alene Basin. Measured and estimated tissue or dietary exposure was tabulated for 3 areas plus the reference, and then compared to multiple effects measures. As many as 6 exposure-effect metrics were available for assessing risk in any one area. Analyses of site-specific tissue- and diet-based exposure data indicate that exposure of ground-feeding songbirds to Pb in the Coeur d'Alene Basin is sufficient to result in adverse effects. Because this conclusion is based on multiple exposure-effect metrics that include site-specific data, the strength of this conclusion is high. Ecological PRGs were developed by integrating the site specific regression models with tissue and dietary effect levels to create exposure models, which were solved for the soil concentration that produced an exposure estimate equal to the effect level (i.e., the ecological PRG). The lowest PRG obtained for any species' exposure-effect measure combination was 490 mg/kg for subclinical effects due to Pb in the blood of American robins; the highest was 7200 mg/kg for severe clinical effects due to Pb in the blood of song sparrows. Because the lowest ground-feeding songbird PRG was comparable to multiple cleanup goals developed for the basin (i.e., soil invertebrates, wildlife populations, and human health), in addition to the site-specific cleanup level of 530 mg Pb/kg sediment for the protection of waterfowl (USEPA 2002) the USEPA has made a risk-management determination that a site-specific Pb cleanup level of 530 mg/kg in soil would be protective of songbirds in the Coeur d'Alene Basin. PMID- 21793202 TI - Cationized bovine serum albumin with pendant RGD groups forms efficient biocoatings for cell adhesion. AB - Cationized bovine serum albumin (cBSA-147) has been modified by attaching the cyclic pentapeptide cRGDfK to its surface through linkers of different length. Coatings of these bioconjugates on glass surfaces were studied for their ability to stimulate cell adhesion. These chemically modified albumins combine a high number of positive charges which facilitate the initial cell adhesion to the surface with multiple Arg-Gly-Asp groups which enable focal adhesion of fibroblast cells by specific interactions with cell-surface receptors. The biocoatings are easily prepared within a few minutes by simple incubation from a dilute solution of the modified albumin. This constitutes a convenient approach for preparing surfaces for cell adhesion. Excellent focal adhesion of NIH 3T3 fibroblast cells on the biocoatings was observed. About 75% of the seeded cells attached to the cRGDfK-cBSA-147 coated surfaces, and 97% of them underwent focal adhesion. Adhering cells were able to grow and proliferate on the coated surfaces, confirming the outstanding biocompatibility of these biocoatings. PMID- 21793199 TI - Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins. AB - The primary aim of this article is to provide an overview of perfluoroalkyl and polyfluoroalkyl substances (PFASs) detected in the environment, wildlife, and humans, and recommend clear, specific, and descriptive terminology, names, and acronyms for PFASs. The overarching objective is to unify and harmonize communication on PFASs by offering terminology for use by the global scientific, regulatory, and industrial communities. A particular emphasis is placed on long chain perfluoroalkyl acids, substances related to the long-chain perfluoroalkyl acids, and substances intended as alternatives to the use of the long-chain perfluoroalkyl acids or their precursors. First, we define PFASs, classify them into various families, and recommend a pragmatic set of common names and acronyms for both the families and their individual members. Terminology related to fluorinated polymers is an important aspect of our classification. Second, we provide a brief description of the 2 main production processes, electrochemical fluorination and telomerization, used for introducing perfluoroalkyl moieties into organic compounds, and we specify the types of byproducts (isomers and homologues) likely to arise in these processes. Third, we show how the principal families of PFASs are interrelated as industrial, environmental, or metabolic precursors or transformation products of one another. We pay particular attention to those PFASs that have the potential to be converted, by abiotic or biotic environmental processes or by human metabolism, into long-chain perfluoroalkyl carboxylic or sulfonic acids, which are currently the focus of regulatory action. The Supplemental Data lists 42 families and subfamilies of PFASs and 268 selected individual compounds, providing recommended names and acronyms, and structural formulas, as well as Chemical Abstracts Service registry numbers. PMID- 21793203 TI - Easy fabrication of electrically insulating nanogaps by transfer printing. AB - An easy and cost-effective method to reproducibly fabricate nanogaps over a large area is introduced. Gold is evaporated on low-aspect-ratio polydimethylsiloxane (PDMS) stamps at an angle of 60 degrees . Afterwards, the stamp is brought into contact with a silicon/silicon dioxide substrate and subsequently peeled at rates varying from 1 to 3 mm s(-1), resulting in the fabrication of nanogaps between two gold electrodes. The fabrication of insulating nanogaps with a width down to 50 nm is demonstrated. PMID- 21793204 TI - U-shaped switches for optical information processing at the nanoscale. PMID- 21793205 TI - Vertically aligned TiO2 nanotubes on plastic substrates for flexible solar cells. AB - Electrochemical anodization of a titanium film on a Kapton HN substrate leads to the formation of closely packed aligned nanotubes, whose shape can be finely tuned by tailoring the anodization parameters. An amorphous-to-anatase phase transition is induced on nanotubes by annealing at 350 degrees C. The nanotubes are applied as photoanodes in flexible dye-sensitized solar cells (N719 dye; I3 /I- redox couple), resulting in a photoconversion efficiency of up to 3.5% under simulated sunlight irradiation air mass 1.5 global (AM 1.5G). PMID- 21793206 TI - Self-assembled highly ordered ethane-bridged periodic mesoporous organosilica and its application in HPLC. AB - Monodisperse spherical periodic mesoporous organosilicas (PMOs) with ethane integrated in the framework were synthesized and their application as stationary phase for chromatographic separation is demonstrated. The ethane-PMOs were prepared by condensation of 1,2-bis(triethoxysilyl)ethane (BTSE) in basic condition using octadecyltrimethylammonium chloride (C(18)TMACl) as template and ethanol as co-solvent. The morphology and mesoporous structure of ethane-PMOs were controlled under different concentrations of sodium hydroxide (NaOH) and EtOH. The results of scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), nitrogen sorption measurement, Fourier transform infrared spectroscopy (FT-IR) and elemental analysis showed that ethane-PMOs have spherical morphology, uniform particle distribution, highly ordered pore structure, high surface area and narrow pore-size distribution. The column packed with these materials exhibits good permeability, high chemical stability and good selectivity of mixtures of aromatic hydrocarbons in normal phase high-performance liquid chromatography (HPLC). PMID- 21793207 TI - Method validation for the determination of propellant components by Soxhlet extraction and gas chromatography/mass spectrometry. AB - A fast, sensitive, and accurate GC/MS method for the quantification of aliphatic nitroesters (ethylene glycol dinitrate, nitroglycerin, and triethylene glycol dinitrate) and aromatic amines (diphenylamine, 2-nitrodiphenylamine, and triphenylamine) in propellants was developed and validated. This method comprises a Soxhlet extraction step with dichloromethane, followed by separation on a capillary column MDN-5. Ionization of the analytes is carried out using electron ionization. The limit of quantification of the method was 1% w/w for aliphatic nitroesters and 0.1% w/w for aromatic amines (diphenylamine and triphenylamine). Values of repeatability and reproducibility for analyzed compounds were smaller than values of the maximum allowed tolerances of the Horwitz-equation RSD(max) and 2/3 RSD(max). Values of accuracy for selected compounds were below the acceptable threshold of 15% for all tested levels in the range of calibration curve excepting the lowest concentration of calibration curve for nitroglycerin and aromatic amines. During the validation of method, temperature instability in injection port of gas chromatograph and column was observed for 2 nitrodiphenylamine. Hence, it follows worse results of accuracy and linearity and 2-nitrodiphenylamine was not validated successfully. PMID- 21793208 TI - High-sensitivity capillary and microchip electrophoresis using electrokinetic supercharging. AB - Electrokinetic supercharging (EKS) is considered as one of the most powerful online preconcentration techniques in electrophoresis. It combines the efficient preconcentration power of field-amplified sample injection and the exceptional selective nature of transient isotachophoresis. It has a wide range of applications to different types of analytes ranging from small ions to large proteins and DNA fragments. This comprehensive review--up to date--provides listing for all the works, developments, and advances in EKS. The review will pay particular attention to innovations, new methodologies for manipulation, challenges for improving the detection sensitivity, and various applications of EKS in capillaries and microchips. PMID- 21793209 TI - Monolithic media for applications in affinity chromatography. AB - Affinity chromatography presents a highly versatile analytical tool, which relies on exploiting highly specific interactions between molecules and their ligands. This review covers the most recent literature on the application of monoliths as stationary phases for various affinity-based chromatographic applications. Different affinity approaches as well as separations using molecularly imprinted monoliths are discussed. Hybrid stationary phases created by embedding of particles or nanoparticles into a monolithic stationary phase are also considered in this review article. The ease of preparation of monoliths and the multitude of functionalization techniques, which have matured during the past years, make monoliths interesting for an increasing number of biochemical and medical applications. PMID- 21793210 TI - Simultaneous determination of three naturally occurring estrogens in environmental waters by high-performance liquid chromatography. AB - A simple, sensitive and accurate reversed-phase high-performance liquid chromatographic (HPLC) method for simultaneous determination of three naturally occurring estrogenic steroids including estrone (E1), 17beta-estradiol (E2) and estriol (E3) in environmental water samples was developed. Analytes were extracted with ethyl acetate solvents and preconcentrated prior to HPLC analysis. Separations were accomplished in <20 min using a reversed-phase C(18) column (4.6*250 mm id, 5 MUm) with a gradient elution of mobile phase containing 3.0 mM ammonium acetate/acetonitrile mixtures (flow rate, 1.0 mL/min). UV light absorption responses at 205 nm were linear over a wide concentration range from 100,000 MUg/L to the detection limits of 0.96 MUg/L E1, 0.64 MUg/L E2 and 0.78 MUg/L E3. Quantitation was carried out by the peak area method. The relative standard deviation for the analysis of three estrogens was <3.0%. This method was applied for the simultaneous determination of estrogens in environmental water samples collected in Zhejiang, China. The higher concentrations of both E2 and E3 were found in Tang River and West Lake waters, and E1 was detected in lake water only. All three estrogens were below the detection limits in rain waters. PMID- 21793211 TI - How to integrate biological motors towards bio-actuators fueled by ATP. AB - Biological motors, driven by the conversion of chemical energy into mechanical energy, are much more efficient than man-made machines. The development of such efficient biomimetic motor systems in vitro is currently a vital need. However, great difficulty lies in how to integrate the sophisticated functions of the constituent components to obtain a performance as in the case of natural living systems. Based on 'active' and 'passive' self-organization principles, it has been demonstrated that the functions of motor protein systems can be integrated to obtain complex hierarchical structures that can work as actuators. Most of the works discussed here concern two-dimensional behavior, and recent works aim to explore the three-dimensional features of such artificial bio-mechanical systems. PMID- 21793212 TI - Efficient intracellular siRNA delivery by ethyleneimine-modified amphiphilic macromolecules. AB - New materials that can bind and deliver oligonucleotides such as short interfering RNA (siRNA) without toxicity are greatly needed to fulfill the promise of therapeutic gene silencing. Amphiphilic macromolecules (AMs) were functionalized with linear ethyleneimines to create cationic AMs capable of complexing with siRNA. Structurally, the parent AM is formed from a mucic acid backbone whose tetra-hydroxy groups are alkylated with 12-carbon aliphatic chains to form the hydrophobic component of the macromolecule. This alkylated mucic acid is then mono-functionalized with poly(ethylene glycol) (PEG) as a hydrophilic component. The resulting AM contains a free carboxylic acid within the hydrophobic domain. In this work, linear ethyleneimines were conjugated to the free carboxylic acid to produce an AM with one primary amine (1N) or one primary amine and four secondary amines (5N). Further, an AM with amine substitution both to the free carboxylic acid in the hydrophobic domain and also to the adjacent PEG was synthesized to produce a polymer with one primary amine and eight secondary amines (9N), four located on each side of the AM hydrophobic domain. All amine-functionalized AMs formed nanoscale micelles but only the 5N and 9N AMs had cationic zeta potentials, which increased with increasing number of amines. All AMs exhibited less inherent cytotoxicity than linear polyethyleneimine (L PEI) at concentrations of 10 uM and above. By increasing the length of the cationic ethyleneimine chain and the total number of amines, successful siRNA complexation and cellular siRNA delivery was achieved in a malignant glioma cell line. In addition, siRNA-induced silencing of firefly luciferase was observed using complexes of siRNA with the 9N AM and comparable to L-PEI, yet showed better cell viability at higher concentrations (above 10 uM). This work highlights the promise of cationic AMs as safe and efficient synthetic vectors for siRNA delivery. Specifically, a novel polymer (9N) was identified for efficient siRNA delivery to cancer cells and will be further evaluated. PMID- 21793213 TI - Poly(methyl malate) nanoparticles: formation, degradation, and encapsulation of anticancer drugs. AB - PMLA nanoparticles with diameters of 150-250 nm are prepared, and their hydrolytic degradation is studied under physiological conditions. Degradation occurs by hydrolysis of the side chain methyl ester followed by cleavage of the main-chain ester group with methanol and L-malic acid as the final degradation products. No alteration of the cell viability is found after 1 h of incubation, but toxicity increases significantly after 3 d, probably due to the noxious effect of the released methanol. Anticancer drugs temozolomide and doxorubicin are encapsulated in the NPs with 20-40% efficiency, and their release is monitored using in vitro essays. Temozolomide is fully liberated within several hours, whereas doxorubicin is steadily released from the particles over a period of 1 month. PMID- 21793214 TI - Enhancement of cellular uptake and antitumor efficiencies of micelles with phosphorylcholine. AB - Internalization of drug delivery micelles into cancer cells is a crucial step for antitumor therapeutics. Novel amphiphilic star-shaped copolymers with zwitterionic phosphorylcholine (PC) block, 6-arm star poly(epsilon-caprolactone) b-poly(2-methacryloyloxyethyl phosphorylcholine) (6sPCL-b-PMPC), have been developed for encapsulation of poorly water-soluble drugs and enhancement of their cellular uptake. The star-shaped copolymers were synthesized by a combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The copolymers self-assembled to form spherical micelles with low critical micelle concentration (CMC). The sizes of the micelles range from 80 to 170 nm and increase 30 ~ 80% after paclitaxel (PTX) loading. Labeled with fluorescein isothiocyanate (FITC), the micelles were confirmed by fluorescence microscopy to have been internalized efficiently by tumor cells. Direct visualization of the micelles within tumor cells by transmission electron microscopy (TEM) confirmed that the 6sPCL-b-PMPC micelles were more efficiently uptaken by tumor cells compared to PCL-b-PEG micelles. When incorporated with PTX, the 6sPCL-b-PMPC micelles show much higher cytotoxicity against Hela cells than PCL-b-PEG micelles, in response to the higher efficiency of cellular uptake. PMID- 21793215 TI - In situ photopolymerization of biomaterials by thiol-yne click chemistry. AB - The thiol-yne click chemistry reaction has been used for the in situ photocrosslinking of an aliphatic hyperbranched polyester. The biocompatibility of the resulting networks has been studied and marked cytotoxicity was not found for HeLa (human cervical carcinoma) tumoral cells and COS7 fibroblasts. The photoinduced thiol-yne process allows the generation of patterned structures with different geometries in films by DLW and these materials can be used as substrates for cell adhesion. The influence of the substrate geometry on cell adhesion has been studied by culturing cells onto these substrates and a preference for the photopatterned polymeric material can be seen in some of the structures by contrast phase microscopy. Actin and vinculin fluorescent staining revealed different adhesion behavior for HeLa cells and COS7 fibroblasts and this could be assigned to the different motility of cells. The thiol-yne photoreaction has proven to be an attractive approach for the preparation of micropatterned biomaterials. PMID- 21793216 TI - Effect of replicated polymeric substrate with lotus surface structure on adipose derived stem cell behaviors. AB - We fabricated polystyrene substrates with lotus leaf surface structure (LLSS) and investigated cell behaviors, including attachment, morphology, proliferation, and differentiation of adipose-derived stem cells (ASCs) on them. Compared to the flat substrate, the LLSS substrate induced higher cell attachment rate, but did not significantly change the cell proliferation rate. In addition, ASCs on the LLSS substrate exhibited relatively narrower spreading morphology and less organized cytoskeleton, there by resulting in smaller sizes of cells than those on the flat substrate. According to histochemical staining and RT-PCR analysis, the LLSS substrate induced higher adipogenic differentiation of ASCs than the flat substrate, while chondrogenic and osteogenic differentiation were decreased. PMID- 21793217 TI - Poly(vinyl alcohol) physical hydrogels: new vista on a long serving biomaterial. AB - Poly(vinyl alcohol), PVA, and physical hydrogels derived thereof have an excellent safety profile and a successful history of biomedical applications. However, these materials are hardly in the focus of biomedical research, largely due to poor opportunities in nano- and micro-scale design associated with PVA hydrogels in their current form. In this review we aim to demonstrate that with PVA, a (sub)molecular control over polymer chemistry translates into fine-tuned supramolecular association of chains and this, in turn, defines macroscopic properties of the material. This nano- to micro- to macro- translation of control is unique for PVA and can now be accomplished using modern tools of macromolecular design. We believe that this strategy affords functionalized PVA physical hydrogels which meet the demands of modern nanobiotechnology and have a potential to become an indispensable tool in the design of biomaterials. PMID- 21793218 TI - Regulating iron storage and metabolism with RNA: an overview of posttranscriptional controls of intracellular iron homeostasis. AB - Iron (Fe) is a double-edged sword for most living organisms. Although it is essential for the catalytic activity of a large number of enzymes, ferrous iron (Fe(2+) ) becomes cytotoxic in the presence of normal respiratory by-products such as H(2) O(2) . Because of this toxicity, intracellular iron concentrations ought to be regulated by elaborated homeostasis systems that, despite decades of extensive studies, have not yet revealed all of their surprising arrays of mechanistic details. Within the last few years, our understanding of iron metabolism has revealed that posttranscriptional regulation represents a major contribution to iron homeostasis in a host of organisms. While the small RNA RyhB regulates iron homeostasis in bacteria, its functional homolog protein Cth2 performs a similar task in yeasts. Recent advances in the elucidation of the mechanism of action and functions of RyhB have been made in Escherichia coli. In addition, other RyhB-like small RNAs have been identified in several bacterial species, such as Pseudomonas aeruginosa, Salmonella enterica, Vibrio cholerae, Neisseria meningitidis, and Shigella spp. These recent findings have shed light on the complexity of iron homeostasis. PMID- 21793219 TI - (S)- and (R)-fluoxetine as native markers in mass spectrometry (MS) binding assays addressing the serotonin transporter. AB - A recently established and validated LC-ESI-MS/MS method for quantification of fluoxetine was used to implement MS binding assays for the human serotonin transporter (hSERT)-the primary target in the treatment of depression and emotional disorders. As a label-free screening technique, MS binding assays offer the opportunity to perform kinetic, saturation and competition assays using both (S)- and (R)-fluoxetine as native markers. In kinetic experiments, an association rate constant (k(+1) of 0.92+/-0.17*10(6) M(-1) s(-1) and a dissociation rate constant (k(-1)) of 0.0032+/-0.0002 s(-1) for (S)-fluoxetine binding to hSERT were determined. Saturation experiments provided K(d) values of 4.4+/-0.4 nM and 5.2+/-0.9 nM for (S)- and (R)-fluoxetine, respectively; statistical analysis revealed that the two enantiomers are equipotent. In competitive experiments with (S)-fluoxetine as a marker, K(i) values were obtained for various known inhibitors with a broad range of affinities for hSERT that correlate well with literature data obtained from radioligand binding experiments with [(3)H]imipramine. Additional competitive experiments using (R)-fluoxetine as a marker led to K(i) values for SERT inhibitors that deviate only marginally from those determined using the (S)-enantiomer. No changes in the rank order of affinities occurred, indicating that there is no difference in the binding characteristics of the two enantiomers. PMID- 21793220 TI - Preparation and antitumour properties of the enantiomers of a hypoxia-selective nitro analogue of the duocarmycins. AB - Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2 carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An intermediate in the synthesis of this prodrug was resolved by chiral HPLC and the absolute configuration assigned by X-ray crystallography. The intermediate was used to prepare the prodrug's enantiomers, and also the enantiomers of the active nitro and amino metabolites. In vitro analysis in the human cervical carcinoma cell line SiHa showed that both nitro enantiomers are hypoxia-selective cytotoxins, but the "natural" S enantiomer is at least 20-fold more potent. Examination of extracellular amino metabolite concentrations demonstrated no enantioselectivity in the hypoxia-selective reduction of nitro to amino. Low levels of amino derivative were also found in aerobic cell suspensions, sufficient to account for the observed oxic toxicity of the nitro form. At an equimolar dose in SiHa-tumour bearing animals, the (-)-R enantiomer of the prodrug was inactive, while the (+)-S enantiomer caused significantly more hypoxic tumour cell kill than the racemate. At this dose, the combination of (+) S-prodrug and radiation eliminated detectable colony-forming cells in four out of five treated tumour-bearing animals. PMID- 21793221 TI - Synthesis of mannose-6-phosphate analogues and their utility as angiogenesis regulators. PMID- 21793222 TI - "On water" nucleophilic addition of formaldehyde N,N-dialkylhydrazones to alpha keto esters. PMID- 21793223 TI - An easy and general iron-catalyzed reductive amination of aldehydes and ketones with anilines. PMID- 21793224 TI - Simple and efficient iridium(III)-catalyzed water oxidations. PMID- 21793225 TI - Oxidative stress in synapse development and function. AB - Oxidative stress, caused by increased levels of reactive oxidative species (ROS), is considered a major contributor to the aging process. How oxidative stress may bring about changes to structures and function in the aging brain is poorly understood. Oxidative stress activates a number of cellular responses, including activation of the Jun-N-terminal kinase (JNK) pathway and autophagy. In addition to their pathological role, ROS also act as signaling molecules. ROS such as nitric oxide have a well-known role in learning and memory. In addition, activation of JNK and its transcriptional effector AP-1 are well-known mediators of synaptic function and growth. Both are essential mediators of physiological correlates of learning and memory such as long-term potentiation. JNK and AP-1 are potently activated and regulated by oxidative stress and mediate protective cellular responses such as autophagy. Recent work at the Drosophila neuromuscular junction implicates autophagy as a regulator of synaptic growth via activation of the JNK signaling pathway. We here outline a framework predicating oxidative stress as a major regulator of synaptic function and growth by the activation of JNK/AP-1 and autophagy. Such responses, we suggest, may underpin some forms of synaptic growth responses and synaptic aging. PMID- 21793226 TI - Extracellular matrix molecules, their receptors, and secreted proteases in synaptic plasticity. AB - Neural cells secrete diverse molecules, which accumulate in the extracellular space and form the extracellular matrix (ECM). Interactions between cells and the ECM are well recognized to play the crucial role in cell migration and guidance of growing axons, whereas formation of mature neural ECM in the form of perineuronal nets is believed to restrict certain forms of developmental plasticity. On the other hand, major components of perineuronal nets and other ECM molecules support induction of functional plasticity, the most studied form of which is long-term potentiation. Here, we review the underlying mechanisms by which ECM molecules, their receptors and remodeling proteases regulate the induction and maintenance of synaptic modifications. In particular, we highlight that activity-dependent secretion and activation of proteases leads to a local cleavage of the ECM and release of signaling proteolytic fragments. These molecules regulate transmitter receptor trafficking, actin cytoskeleton, growth of dendritic spines, and formation of dendritic filopodia. PMID- 21793227 TI - Dynamic morphometrics reveals contributions of dendritic growth cones and filopodia to dendritogenesis in the intact and awake embryonic brain. AB - Using in vivo rapid and long-interval two-photon time-lapse imaging of brain neuronal growth within the intact and unanesthetized Xenopus laevis tadpole, we characterize dynamic dendritic growth behaviors of filopodia, branches, and dendritic growth cones (DGCs), and analyze their contribution to persistent arbor morphology. The maturational progression of dynamic dendritogenesis was captured by short-term, 5 min interval, imaging for 1 h every day for 5 days, and the contribution of short-term growth to persistent structure was captured by imaging at 5 min intervals for 5 h, and at 2 h intervals for 10 h during the height of arbor growth. We find that filopodia and branch stability increases with neuronal maturation, and while the majority of dendritic filopodia rapidly retract, 3% to 7% of interstitial filopodia transition into persistent branches with lifetimes greater than 90 min. Here, we provide the first characterization of DGC dynamics, including morphology and behavior, in the intact and awake developing vertebrate brain. We find that DGCs occur on all growing branches indicating an essential role in branch elongation, and that DGC morphology correlates with dendritic branch growth behavior and varies with maturation. These results demonstrate that dendritogenesis involves a remarkable amount of continuous remodeling, with distinct roles for filopodia and DGCs across neuronal maturation. (c) 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 615-627, 2012. PMID- 21793228 TI - Application of immunocytochemistry and BRAF mutational analysis to direct smears of metastatic melanoma. AB - BACKGROUND: The cytodiagnosis of melanoma in fine-needle aspiration (FNA) specimens can be challenging, often requiring the use of immunocytochemistry. As constitutively activating mutations in the BRAF oncogene are present in at least 40% of melanomas, the use of FNA material to interrogate the BRAF mutational status is likely to increase. Because cell blocks, traditionally used for these studies, can occasionally exhibit insufficient tumor cellularity, the authors investigated the utility of direct smears for immunocytochemistry and BRAF mutational analysis. METHODS: Immunocytochemistry for S-100, HMB-45, and Mart-1 was prospectively performed on direct smears in 17 FNAs of metastatic melanoma. Next, BRAF sequencing was performed using DNA isolated from archived Diff-Quik stained direct smears for 15 cases. In parallel, sequencing was performed using DNA obtained from corresponding cell blocks. RESULTS: S-100 positivity in the tumor cells was observed in all 17 cases. HMB-45 and Mart-1 positivity was noted in 81% and 88% of cases, respectively. All 3 markers were positive in 76% of cases. Next, of the 15 archived melanoma FNAs tested, BRAF mutations were observed in 8 (53%); 5 and 3 melanomas harbored the V600E and V600K mutation, respectively. Corresponding cell blocks were also tested for all 15 cases, yielding concordant BRAF results in 14 (93%); 1 cell block yielded a false negative result. CONCLUSIONS: Cytologic direct smears represent a robust and valuable source of cellular material for immunocytochemistry and molecular studies, especially in instances in which inadequate cell block cellularity is anticipated or encountered. PMID- 21793229 TI - Balance, gait, falls, and fear of falling in women with the hypermobility type of Ehlers-Danlos syndrome. AB - OBJECTIVE: To investigate balance, gait, falls, and fear of falling in patients with the hypermobility type of Ehlers-Danlos syndrome (EDS-HT). METHODS: Twenty two women with EDS-HT and 22 sex- and age-matched healthy control subjects participated in the study. Each subject performed the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) and the Tandem Stance test (TS) on an AccuGait force platform to assess balance by center of pressure-based postural sway measures. The GAITRite walkway system was used to record spatial-temporal gait variables during 3 walking conditions (single task, cognitive task, and functional task). Data about fall frequency and circumstances were collected by retrospective recall, and fear of falling was assessed by the modified Falls Efficacy Scale. RESULTS: Compared with healthy subjects, EDS-HT subjects showed significantly impaired balance, reflected by increased sway velocity, mediolateral and anteroposterior sway excursion, and sway area during mCTSIB and TS. Gait velocity, step length, and stride length were significantly smaller during all walking conditions, and a significant dual-task-related decrement was found for gait velocity, step and stride length, and cadence in the EDS-HT subjects compared to the control group. Ninety-five percent of the patients fell during the past year, and some fear of falling was measured. CONCLUSION: To our knowledge, this study is the first to establish that EDS-HT is associated with balance and gait impairments, increased fall frequency, and poorer balance confidence, implying a decrease in the safety of standing in everyday life situations. Whether these deficits can be improved by appropriate exercise programs needs to be addressed in future research. PMID- 21793230 TI - Burden of musculoskeletal disease and its determination by urbanicity, socioeconomic status, age, and sex: Results from 14,507 subjects. AB - OBJECTIVE: The availability of reliable estimates of the burden of musculoskeletal disease is of considerable importance for policymakers. METHODS: This study uses data from the 14,507 participants of the European Health Interview Survey conducted in Austria in 2006/2007 to calculate estimates of the prevalence of osteoarthritis, spinal conditions, and osteoporosis in a population representative of other European Union or Organisation for Economic Co-operation and Development member states. Urbanicity, socioeconomic status, and age and sex were included as determinants of musculoskeletal disease. RESULTS: The prevalence of arthritis was 18.8% (95% confidence interval [95% CI] 18.2-19.4%), of spinal conditions was 38.4% (95% CI 37.6-39.2%), and of osteoporosis was 6.6% (95% CI 6.3-7.0%). The census data showed strong evidence for an association between urbanicity and arthritis (P = 0.012) and osteoporosis (P < 0.001), but not spinal conditions (P = 0.721). Arthritis and spinal conditions were associated with socioeconomic status (P < 0.001 for all). Osteoporosis showed the same associations with age, income, and education. For arthritis, a combined model showed a substantial attenuation of the effect of urbanicity on arthritis prevalence after adjustment for socioeconomic status. CONCLUSION: These data suggest that the burden of musculoskeletal disease is determined by both urbanicity and socioeconomic status; however, the effect of urbanicity seems to be attributable to differences in socioeconomic status and demographics across geographic regions. PMID- 21793232 TI - Economic burden of obesity in primary total knee arthroplasty. AB - OBJECTIVE: To compare the hospital inpatient costs between nonobese and obese patients and estimate the economic burden of obesity in primary total knee arthroplasty (TKA). METHODS: A cost identification study was conducted in a consecutive cohort of 530 patients who underwent TKA between 2006 and 2007 at a university-affiliated tertiary referral center in Melbourne, Australia. Total hospital inpatient costs incurred at the study institution associated with the index surgery and subsequent related emergency presentations and readmissions during the episode of care were captured. Predictor variables of interest were obesity and body mass index (BMI), and the outcomes of interest were total hospital inpatient costs for the index surgery and episode of care, defined as the first 12 months following TKA. Multivariate linear regression techniques were used to examine the association between the predictors of interest and hospital costs, adjusting for clinically relevant variables. RESULTS: Economic data were analyzed in 521 patients, of which 317 (60.8%) were obese. Obesity was associated with higher inpatient index surgery costs (+$1,226.89 [95% confidence interval (95% CI) $82.25, $2,371.52]; P = 0.036) and episode of care costs (+$1,821.36 [95% CI $244.93, $3,397.79]; P = 0.024). Each unit increase in BMI was also associated with higher inpatient index surgery costs ($128.91 [95% CI $34.53, $223.28]; P = 0.008) and total episode of care costs ($158.79 [95% CI $28.54, $289.05]; P = 0.017). CONCLUSION: The estimated significant additional annual obesity-related expenditure reported in this study establishes a rationale to trial and evaluate interventions that target weight loss in obese patients undergoing TKA from both a quality of life and economic perspective. PMID- 21793231 TI - Prevalence of falls and the association with knee osteoarthritis and lumbar spondylosis as well as knee and lower back pain in Japanese men and women. AB - OBJECTIVE: There is little information on falls by sex and age strata in Japan, and few factors associated with falls have been established. However, the association between bone and joint diseases and falls remains unclear. We examined prevalence of falls by sex and age strata, determined its association with radiographic osteoarthritis (OA) of the knee and lumbar spine, and determined knee and lower back pain after single and multiple falls. METHODS: A questionnaire assessed the number of falls during 12 months preceding baseline. Knee and lumbar spine radiographs were read by Kellgren/Lawrence (K/L) grade; radiographic knee OA and lumbar spondylosis were defined as a K/L grade of 3 or 4. Knee and lower back pain were estimated by an interview. RESULTS: A total of 587 men and 1,088 women (mean +/- SD age 65.3 +/- 12.0 years) were analyzed. During 1 year, 79 (13.5%) men and 207 (19.0%) women reported at least 1 fall. With increasing age, the prevalence of multiple falls was higher in women, but lower in elderly men age >60 years. In men, few factors were significantly associated with falls. In women, radiographic knee OA and lumbar spondylosis, as well as knee and lower back pain, were significantly associated with multiple falls without adjustment. Lower back pain and knee pain were independently associated with multiple falls in women after adjustment. CONCLUSION: Lower back pain and knee pain were significantly associated with multiple falls in women. PMID- 21793233 TI - Scale-up of mouse embryonic stem cell expansion in stirred bioreactors. AB - The aim of this study was to develop a robust, quality controlled and reproducible large-scale culture system using serum-free (SF) medium to obtain vast numbers of embryonic stem (ES) cells as a starting source for potential applications in tissue regeneration, as well as for drug screening studies. Mouse ES (mES) cells were firstly cultured on microcarriers in spinner flasks to investigate the effect of different parameters such as the agitation rate and the feeding regimen. Cells were successfully expanded at agitation rates up to 60 rpm using the SF medium and no significant differences in terms of growth kinetics or metabolic profiles were found between the two feeding regimens evaluated: 50% medium renewal every 24 h or 25% every 12 h. Overall, cells reached maximum concentrations of (4.2 +/- 0.4) and (5.6 +/- 0.8) *10(6) cells/mL at Day 8 for cells fed once or twice per day; which corresponds to an increase in total cell number of 85 +/- 7 and 108 +/- 16, respectively. To have a more precise control over culture conditions and to yield a higher number of cells, the scale-up of the spinner flask culture system was successfully accomplished by using a fully controlled stirred tank bioreactor. In this case, the concentration of mES cells cultured on microcarriers increased 85 +/- 15-fold over 11 days. Importantly, mES cells expanded under stirred conditions, in both spinner flask and fully controlled stirred tank bioreactor, using SF medium, retained the expression of pluripotency markers such as Oct-4, Nanog, and SSEA-1 and their differentiation potential into cells of the three embryonic germ layers. PMID- 21793234 TI - I've had catheter ablation treatment for my atrial fibrillation, but I'm concerned about a recurrence. Can you tell me anything about this and what I can do about it? PMID- 21793235 TI - I'm confused by the numbers of fad diets available that tout great weight loss. Are there any basic, simple weight loss strategies I can follow? PMID- 21793236 TI - Abstracts of the American Society of Breast Surgeons 12th Annual Meeting. April 27-May 1, 2011. Washington, D.C., USA. PMID- 21793237 TI - Abstracts of the Summer Scientific Meeting of the Faculty of Public Health Medicine of the Royal College of Physicians of Ireland. May 25-26, 2011. Dublin, Ireland. PMID- 21793238 TI - Abstracts of the 19th Biennial Conference of the International Society for Sexually Transmitted Diseases Research. July 10-13, 2011. Quebec City, Quebec, Canada. PMID- 21793239 TI - The factor structure of posttraumatic stress disorder: a literature update, critique of methodology, and agenda for future research. AB - We present an update of recent literature (since 2007) exploring the factor structure of posttraumatic stress disorder (PTSD) symptom measures. Research supporting a four-factor emotional numbing model and a four-factor dysphoria model is presented, with these models fitting better than all other models examined. Variables accounting for factor structure differences are reviewed, including PTSD query instructions, type of PTSD measure, extent of trauma exposure, ethnicity, and timing of administration. Methodological and statistical limitations with recent studies are presented. Finally, a research agenda and recommendations are offered to push this research area forward, including suggestions to validate PTSD's factors against external measures of psychopathology, test moderators of factor structure, and examine heterogeneity of symptom presentations based on factor structure examination. PMID- 21793240 TI - A global view of funding for the plant sciences. PMID- 21793241 TI - Global change on infectious disease. Frederick Cohan. PMID- 21793242 TI - Origins of the International Symposium on Biological Reactive Intermediates and some thoughts on homeostasis and the biological significance of widespread covalent binding of biological reactive metabolites. PMID- 21793243 TI - Slovenia to welcome the 86th EOS Congress in 2010. PMID- 21793244 TI - [At the sea]. PMID- 21793245 TI - Clark H. Millikan, MD, FAAN (1915-2011). PMID- 21793246 TI - Evidence-based guideline: the role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Subcommittee of the American Academy of Neurology. PMID- 21793248 TI - PA: hospital 'misled' employees--RN quit: court held 'just cause' to quit & awarded UIB. Kuzyck v. Unemployment Compensation Board of Review, 1652 C.D. 2010 (5/20/2011)-PA. PMID- 21793247 TI - The evolution of flower development: current understanding and future challenges. PMID- 21793249 TI - [Prophylaxis and treatment of hemorrhagic complications of operative interventions in patients with hemophilia A and Villebrand's disease]. AB - Hemophilia A and Villebrand's disease owe similar clinical features, for their treatment the preparations, containing factor VIII and Villebrand's factor are used. Preoperatively it is necessary, first of all, to establish the disease diagnosis and its form definitely and then an optimal scheme of hemostatic therapy must be selected with its intraoperative and postoperative correction under control of laboratory monitoring. It is important to reveal timely a hemostasis disorders and a hemophilia of inhibitory form occurrence. Modern rational methods of prophylaxis and treatment of hemorrhage, using desmopresin (for mild forms of hemophilia A and Villebrand's disease type III) as well as preparations of restoration therapy, containing factor VIII and Villebrand's factor, are recommended. Preparations of auxiliary therapy are applied according to certain indications present for elimination of vascular-thrombocytic disorders, fibrinolysis activation, hemophilia of inhibitory form and hormonal disorders occurrence. It is also stressed, that, while these diseases are present, it is necessary to follow direct indications for the operations performance and guaranteeing a reserve of sufficient quantity of corresponding hemostatic preparations. PMID- 21793250 TI - [Stem cells as bone marrow residents]. AB - In addition to being a source of hematopoietic and mesenchymal stromal cells, bone marrow is known to be the source of stem cell populations, which express pluripotential markers and are capable of differentiating into cells of three blastophyllums (ectoderm, mesoderm, and endoderm). Recently, a new population of so-called "very small embryonic like cells" (VSELs) has been identified in the bone marrow in addition to well-known pluripotential cells, such as MIAMI, MSC, and MAPS. The presence of stem cells with a wide spectrum of differentiation capacities in the bone marrow allows an alternative interpretation of the phenomenon of plasticity and the possibility of their switch from a canonical to a nontrivial path of differentiation. The phenotypic features of VSELs, their differentiation capacities, ontogenetic origins, and relationships with other types of stem cells are studied. The role of bone marrow stem cells and induced pluripotential stem cells in regeneration processes and their possible therapeutic application are discussed. PMID- 21793251 TI - [Variability of mitochondrial DNA cytochrome b gene in the red vole Clethrionomys rutilus pallas, 1779, population in the flood-plain middle stream of the Kolyma River]. AB - The intrapopulation variability of a cytochrome b gene fragment and the corresponding amino acid sequence was studied in the red vole Clethrionomys rutilus Pallas, 1779 from the flood-plain of the Kolyma River. Wide polymorphic variability of these properties was observed. Differences in the cytochrome b gene sequence were determined between the red voles of the studied population and the species collected in neighborhoods of Novosibirsk and Omsk. The revealed results point to the urgency of the cytochrome b gene nucleotide sequence and the variants of the respective amino acid sequence as genetic markers of originality of different red vole populations. PMID- 21793252 TI - [Specific features of plants at early stages of the colonization of loose volcanic matter]. AB - Plant morphology and seed germination have been studied in several species joining monodominant beds of pioneer plant species on loose volcanic matter on the Kamchatka Peninsula and Kuril Islands. The competition of these species is discussed. PMID- 21793253 TI - [The structure of a beetle (Coleoptera, Insecta) complex attracted by a light source in Galich'ya Gora Nature Reserve]. AB - In Morozova Gora tract, Galich'ya Gora Nature Reserve, 33,973 beetles of 542 species from 66 families were collected with the help of a 100-W light trap between 1996 and 2008. The structure of the beetle complex attracted by light is studied, as are the seasonal and annual dynamics of abundance and species composition of this group. The structure of the beetle complex attracted by light is unraveled based on the data on their daily activity. The influence of weather conditions in various seasons on beetles flight towards the light source is studied. PMID- 21793254 TI - [On the controversial questions of the taxonomy of Bivalvia (Mollusca): too many species or too few characters?]. AB - Problems emerging in the course of taxonomic studies and species diagnostics of freshwater bivalves are discussed by the example of one of the bivalve groups (the family Unionidae). It is shown that one of the causes of the current, diametrically opposing views on specific and generic systematics of Bivalvia is the fact that researchers revising taxonomic groups ignore complex analysis of several independent characters (conchological, anatomical, biochemical, genetic, etc.). PMID- 21793255 TI - Who're you calling midlevel? PMID- 21793256 TI - Quality & safety. Alarming: Joint Commission, FDA set to tackle alert fatigue. PMID- 21793257 TI - Effective dashboards. What to measure and how to show it. AB - Today, hospitals must measure not only financial health, but also operational efficiency and quality of care. Redesigned dashboards make the data more accessible. PMID- 21793258 TI - [Clinical occupational psychology]. PMID- 21793259 TI - [Should the population be offered general health screenings?]. PMID- 21793260 TI - Positional changes of the lips concomitant to incisor retraction: an important issue in orthodontics. AB - Lip response to incisor retraction following extraction therapy is continuously investigated. The following is a summary of available evidence in this regard. The reaction of the lips to incisor retraction cannot be predicted with certainty. This is due to many variables such as gender, growth, morphology, and function. Also, for some patients, it is difficult to completely relax their lips during cephalogram taking. All these variables interact in studies on this topic. PMID- 21793261 TI - A review of the clinical applications of elastic tractions in orthodontics. AB - Intermaxillary elastic traction to correct various malocclusions was first introduced in 1892 by Calvin Case. The types of elastics are distinguished according to their material, force production, and mode of application. All elastics vary in their characteristics presenting both advantages and disadvantages. Their composition plays an important role in their behavior when worn. The biomechanics of intermaxillary elastics determine their indications and contraindications. PMID- 21793262 TI - Cardiac involvement in hypereosinophilic syndrome. AB - Hypereosinophilic syndrome is a heterogeneous group of disorders characterised by hypereosinophilia and organ involvement of varying intensity. We describe involvement of the heart in patients with hypereosinophilic syndrome,and the diagnostic and therapeutic clinical management of these patients. PMID- 21793264 TI - [Suggestions to the management of drug-resistant tuberculosis]. PMID- 21793263 TI - Doctors applaud call for diversity. PMID- 21793265 TI - [Guidelines to prevent specific infections related to tuberculosis]. PMID- 21793266 TI - CriticaL appraisal. Visible light-curing. PMID- 21793267 TI - Symposium report: The role of science journals in population health intervention research. PMID- 21793268 TI - Chronic pelvic pain--traditional and novel therapies: part II medical therapy. AB - PURPOSE: To describe medical therapeutic options for chronic pelvic pain. Furthermore to describe some new concepts in the etiology of chronic pelvic pain leading to some novel therapies. METHODS: The benefits and risks of various medical treatments for chronic pelvic pain including central pain, cyclic pain, vulvar pain and bladder pain are discussed. RESULTS: Among various conventional therapies the medical therapy with the most benefit with the least risks are low dose impeded androgens, oral contraceptives, or low dosage progesterone/progestins. CONCLUSIONS: The various types of pelvic pain may all be different manifestations of a common etiology related to defects in the sympathetic nervous system. Sympathomimetic amine therapy may be the most effective therapy with the least side-effects. However, at the moment this schedule II drug has not been approved for this use and thus must be used off label. PMID- 21793269 TI - Anti-mullerian hormone is the best predictor of poor response in ICSI cycles of patients with endometriosis. AB - PURPOSE: To correlate ovarian reserve (OR) markers with response in assisted reproduction techniques (ART) and determine their ability to predict poor response among patients with endometriosis (EDT). METHODS: We evaluated ART cycles of 27 women with EDT and 50 with exclusive male factor. Basal follicle stimulating hormone (FSH) and anti-mullerian hormone (AMH) levels were determined. Ovarian response to gonadotropin stimulation was assessed and correlation coefficients calculated between the variables and reserve markers. Areas under the curve (AUC) determined ability of tests to predict poor response. RESULTS: AMH was significantly correlated with response in both groups and it was the only marker with significant discriminative capacity to predict poor response among EDT (AUC = 0.842; 95% CI: 0.651-0.952) and control group (AUC = 0.869; 95% CI: 0.743-0.947). CONCLUSION: Infertile patients with endometriosis can benefit from the pre-therapeutic assessment of OR markers. However, regardless of disease presence, only AMH predicts poor response to stimulus. PMID- 21793270 TI - Fetal heart rate monitoring during nocturnal polysomnography. AB - STUDY OBJECTIVES: To evaluate the success rate of adding continuous electronic fetal heart rate monitoring (EFM) during full night polysomnography (PSG), in women with both gestational hypertension (GH) with uncomplicated singleton pregnancies. METHOD: As part of a larger study evaluating for the presence of sleep disordered breathing (SDB) in women with GH compared to women with uncomplicated pregnancies, continuous EFM was added to usual polysomnography. RESULTS: Forty-eight EFM studies (26 with GH and 22 with uncomplicated pregnancies) were evaluated. EFM studies were categorized by the percentage of time that interpretable tracings were obtained: < 25% of the time; 25-50% of the time; or > 50% of the time. We deemed > 50% of the time to be ideal, but under the test conditions 25-50% of the time to be acceptable. For women with GH, 71% of women had ideal or acceptable overnight EFM tracings compared to 82% for women with uncomplicated pregnancies. Of those women who were diagnosed with SDB, 77% had an acceptable or ideal EFM tracing. CONCLUSIONS: Adding EFM to conventional polysomnography is feasible and safe. It may prove an important adjunct as interest in sleep disorders of pregnancy continues to expand. PMID- 21793271 TI - Effects of the association zidovudine plus ritonavir on the liver and kidneys of pregnant rats. Morphological and biochemical aspects. AB - PURPOSE: To evaluate biochemical and morphological effects on rats submitted to three different doses of the association zidovudine and ritonavir administered throughout pregnancy. METHODS: Forty pregnant EPM-1 Wistar rats weighing about 200 g were randomly divided into the control group (Ctr = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of zidovudine/ritonavir (Exp1 = 10/20 mg/kg bw, n = 10; Exp2 = 30/60 mg/kg bw, n = 10; Exp3 = 90/180 mg/kg bw, n = 10) from 'day 0' up to the 20th day of pregnancy. At term (20th day) the rats were anesthetized. Blood and fetal and maternal organ samples (livers and kidneys) were taken for morphological and biochemical analyses. RESULTS: Upon histological examinations fetal livers and kidneys appeared normal. In contrast the maternal samples revealed structural alterations. Maternal kidneys of the three experimental groups exhibited progressive and dose-dependent histological alterations; liver alterations were detected only in Exp3. Blood levels of AST and ALT were not significantly different from the control group but urea and creatinine levels were lower in groups Exp3 and Exp1. CONCLUSIONS: The administration of zidovudine plus ritonavir throughout rat pregnancy can cause morphological as well as functional changes in maternal kidneys. PMID- 21793272 TI - Effectiveness of emergency cervical cerclage in patients with cervical dilation in the second trimester. AB - OBJECTIVE: Efficacy of emergency cerclage commensed in the second trimester is a controversial issue. In this study, we aimed to assess the success and associated complications of emergency cerclage in patients with cervical dilatation in the second trimester. MATERIAL AND METHODS: In this retrospective study, medical records of 75 pregnant women who had clinically and ultrasonographically confirmed cervical dilatation in the second trimester who had undergone cervical cerclage were analyzed. Pregnancy prolongation was the main outcome measure. RESULTS: Seventy-five women were included to the study. Mean age was 27 and mean gravidity of the patients was three. Mean cervical length was 28.5 mm (12-41 mm). The rate of spontaneous abortion, immature deliveries, prematurity and deliveries after 34 weeks were 2.7% (n = 2), 8% (n = 6), 12 (n = 9) and 77.7 (n = 58), respectively. Fetal survival rate was 89.1% (n = 65). Serious vaginal bleeding from the suture area was noted in two patients (2.6%). No postoperative complications occurred. CONCLUSION: Emergency cerclage is a simple surgical procedure with lower complication rates and can effectively prolong gestation to viability. It can be considered as a useful measure for patients with evidence of cervical changes in the second trimester. PMID- 21793273 TI - Correlation between asymmetric dimethylarginine maternal plasma levels and preeclampsia. AB - OBJECTIVE: To aim of our study is to support the correlation between blood pressure and asymmetric dimethyl argine (ADMA) concentrations as a possible marker for early diagnosis of the preeclampsia syndrome. STUDY DESIGN: We attempted to calculate in 38 pregnant women with preeclampsia (group A) plasma levels of the main inhibitor to nitric oxide synthase (NOS), which is ADMA, and to compare our findings with the levels of ADMA in 36 non preeclamptic pregnant women (group C) and also with the levels in 29 pregnant women who had a history of preeclampsia in previous pregnancies (group B). Maternal venous EDTA plasma samples of 5 ml were collected and analyzed to measure the ADMA concentrations in each subject. Statistical analysis was performed using the Graph Pad Instat Mann Whitney test, unpaired, non parametric test, two-tail p values. RESULTS: There was no statistical difference between the three groups regarding maternal and gestational age (24-32 weeks). There was a significant statistical difference between the three groups regarding ADMA levels. The two-tailed p value between group A and group C (normal group) was < 0.001, between group A and group B < 0.002 and between group B and group C < 0.002. CONCLUSION: In conclusion we have observed that ADMA probably fulfills many of the criteria to be characterized as a preeclamptic factor and an accurate cut-off point matched to each week of pregnancy should be determined. PMID- 21793274 TI - Changes in ultrasound shear wave elastography properties of normal breast during menstrual cycle. AB - Elastography is a novel technique capable of noninvasively assessing the elastic properties of breast tissue. Because the risk factors for breast cancer include hormonal status and proliferation, the aim of our study was to estimate the intensity of sonoelastographic changes during the menstrual cycle. METHODS: Eight women aged 20-23 years with regular menstrual cycles underwent B-mode sonography and sonoelastography (ShearWave on Aixplorer, France) on days 3, 10, 17 and 24. RESULTS: Mean values of glandular and fat tissue elasticity did not change statistically significantly during the menstrual cycle as well as glandular to fat tissue ratio. During almost the whole cycle differences between outer and inner quadrants in glandular and fat tissue were statistically significant. The lowest values of elasticity occurred on the 10th day and the highest on the 24th of the menstrual cycle. There were statistically significant differences in elasticity between inner and outer quadrants of both breasts close to day 3 and 17 of the menstrual cycle. PMID- 21793275 TI - Efficacy of vaginal use of topical estriol in postmenopausal women with urogenital atrophy. AB - OBJECTIVE: This study evaluates the effect of intravaginal estriol on urogenital atrophy, Pap smear parameters, colposcopy parameters and discomfort during gynecological examination. METHODS: 31 postmenopausal women who had not used hormone therapy in the previous six months were studied. All women used intravaginal estriol, 1 mg/day for 21 days. The following variables were analyzed before and after treatment: complaints of urogenital atrophy; cytological parameters, colposcopic parameters, and subjective evaluation of discomfort during gynecologic examination. RESULTS: All urogenital atrophy complaints improved after treatment. At the first visit, 45.2% of women presented a predominance of profound cells, 51.6% with predominance of intermediate cells, and 3.2% with predominance of superficial cells. At the second visit, these rates were 35.5%, 64.5%, and 0%, respectively. Evaluation of the maturation index showed that 83.9% of women had atrophic Pap smears, and 16.1% showed good estrogenic level before treatment. At the second visit, atrophic smears occurred in 12.9%, and 87.1% of women exhibited good estrogenic level (chi2 = 20.045; p = 0.000). Colposcopy showed that 71% of women had atrophic colpitis and/or petequiae before treatment, while atrophy after therapy was present in only 6.4%. The evaluation of other colposcopic parameters also improved after treatment. Great discomfort was reported by 19.4% before and by 0% after treatment. CONCLUSION: Intravaginal estriol 1 mg/day for a period of 21 days was efficient in improving urogenital atrophy, Pap smear parameters and colposcopic evaluation in postmenopausal women. PMID- 21793276 TI - Parity affects pregnancy outcomes in women 35 and older. AB - PURPOSE OF INVESTIGATION: The objective of the study was to examine the impact of parity on pregnancy outcomes in women 35 years and older. METHODS: The study was a retrospective cohort of singleton pregnancies of women aged > or = 35 years old during the period 2004-2008. Women were divided in two groups: group 1 included primigravidas and group 2 those with at least one past labor. Epidemiological characteristics, obstetric and neonatal outcomes were analyzed using the t test and chi-square test. RESULTS: 816 out of 5834 (14%) cases involved women aging > or = 35 years, 234 (28.7%) of which were nulliparous and 582 (61.3%) multiparous. Rate of cesarean section was 2.4 fold higher for primigravidas (p < .0001). Fetal distress, prolonged labor and Neonate Intensive Care Unity (NICU) admission were also significantly higher in group 1. CONCLUSION: Adverse pregnancy outcomes were increased in primigravidas of 35 years and older compared to multigravidas of the same age. PMID- 21793277 TI - Maternal hemoglobin level and red cell indices as predictors of gestational diabetes in a multi-ethnic Asian population. AB - OBJECTIVE: To evaluate maternal hemoglobin levels and red cell indices as predictive factors for gestational diabetes (GDM). METHOD: Data from 1,538 women were analyzed. At the first visit for prenatal care, the 50-gram glucose challenge test was followed by the 75-gram glucose tolerance test in those who screened positive. GDM was diagnosed based on the WHO (1999) criteria. Maternal complete blood count was obtained at the first visit, hospitalization for birth, and after birth. Receiver operator characteristic curves were generated to establish thresholds. Multivariable logistic regression analyses were performed to establish independent predictors of GDM. RESULTS: GDM was diagnosed in 182/1,538 (11.8%). GDM was associated with hemoglobin level, hematocrit and erythrocyte count at the first visit for prenatal care only. Hemoglobin threshold at the first visit was established at 11.5 g/dl. After adjustment, high hemoglobin [AOR 1.5 (95% CI 1.0-2.1); p = 0.027] remained predictive of GDM. CONCLUSIONS: High maternal hemoglobin level at the first prenatal visit is independently predictive of GDM. PMID- 21793278 TI - Exteriorized versus in-situ repair of the uterine incision at cesarean delivery: a randomized controlled trial. AB - PURPOSE OF INVESTIGATION: To compare advantages and disadvantages of exteriorized and in situ repair techniques of uterine incision during cesarean section. METHODS: A total of 338 patients delivered by cesarean section were included in the study. Patients were randomized according to the location of uterine incision repair; the uterus was exteriorized (n = 171) or not (in situ repair group) (n = 167) during cesarean section. Two groups were compared in terms of blood loss, operation time, temperature patterns, analgesic dosage, length of hospital stay, incidence of nausea and vomiting. RESULTS: There was no significant difference in postoperative analgesic dosage, temperature patterns, drops in hemoglobin or hematocrit levels and in the incidence of postoperative nausea and vomiting between the two groups. Operation time and length of hospital stay were significantly shorter in the in situ repair group, when it was compared to those of which the uterus was exteriorized (30.64 +/- 8.65 vs 33.02 +/- 9.54 min., p = 0.011 and 2.23 +/- 0.49 vs 2.45 +/- 0.94 days, p = 0.045). CONCLUSIONS: Exteriorized and in situ repair of uterine incisions have similar effects on blood loss, temperature patterns, postoperative analgesic dosage and the incidence of postoperative nausea and vomiting. Although both methods of uterine incision repair are valid options during surgery, cesarean sections took less time and length of hospital stay was shorter when uterine incision was repaired in situ. PMID- 21793279 TI - Total infusion of low molecular weight iron-dextran for treating postpartum anemia. AB - AIM: 135 puerperal women with iron deficiency anemia participated in our prospective randomized controlled trial in order to investigate alternative treatments to blood transfusion for anemia. MATERIALS AND METHODS: The criteria for the diagnosis of anemia were Hb < 8 g/dl and ferritine < 10 microg/dl. Women were randomly separated in two groups, A and B. Women of group A (n = 109 women) received a total amount of 1000 mg low molecular weight (LMW) iron-dextran intravenously in two doses. Group B (n = 26) was the control group. They received orally 800 mg daily for 30 days of iron protein-succinylate. Three weeks later women of both groups underwent a full blood count analysis. RESULTS: Hemoglobin and ferritin levels increased significantly in group A compared to group B (p < 0.0001). No adverse side-effects due to the treatment were noted in either group. CONCLUSION: It seems that total iron-dextran infusion is a safe and rapid therapy of iron-deficiency postpartum anemia increases the Hb level more rapidly than oral ferrous sulfate, and it also appears to replenish iron stores more rapidly. PMID- 21793280 TI - Is there any effect of fetal gender on the markers of first trimester Down's syndrome screening? AB - INTRODUCTION: At present, the most effective trisomy 21-screening method is the estimate of risk combining maternal age, fetal nuchal translucency, beta-hCG and pregnancy-associated PAPP-A. OBJECTIVE: The aim of this study was to investigate the possible effect of fetal gender in first trimester Down's syndrome screening markers. DESIGN: Retrospective study. SETTING: Prenatal Diagnosis Centre in a tertiary hospital in Lagos. METHODS: Of a total of 350 pregnancies in which fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A were performed were included in this study. These markers were investigated to see if they differed on the basis of fetal gender. RESULTS: PAPP-A levels were higher in female fetuses although the difference was not statistically significant. Nuchal translucency was 0.099 mm more in male fetuses. CONCLUSION: The results suggest that first trimester markers differ on gender but are of no clinical significance, confirming the result of other authors. PMID- 21793281 TI - Comparison of single versus multiple courses of antenatal betamethasone in patients with threatened preterm labor. AB - PURPOSE OF INVESTIGATION: To compare single versus multiple courses of antenatal betamethasone administration with regards to the morbidity and mortality of preterm neonates. METHODS: One-hundred and twenty-two women with threatened preterm labor were allocated to three different betamethasone schedules: 1) two doses of betamethasone 12 mg, intramuscularly, 24 hours apart (standard treatment) (n = 41); 2) standard treatment plus a third dose of 12 mg after seven days (n = 41); and, 3) standard treatment plus one dose of 12 mg every seven days until delivery (n = 40). Neonatal morbidity and mortality as well as maternal morbidity were evaluated. RESULTS: Neonatal parameters, such as frequency of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis and neonatal mortality were not significantly different among the three groups for both singleton and multiple pregnancies. Similarly, maternal parameters were not significantly different among the three groups. CONCLUSION: The administration of multiple betamethasone courses in threatened preterm labor is not superior to single courses with regards to neonatal morbidity and mortality, as well as to maternal morbidity. PMID- 21793282 TI - Marked hyperandrogenemia and acne associated with polycystic ovaries in Greek women with polycystic ovary syndrome. AB - PCOS represents the commonest endocrinopathy among women of reproductive age. We conducted this study to evaluate the association between polycystic ovaries and clinical and biochemical features of the syndrome. TVS was performed in 74 women with the clinical diagnosis of PCOS. The findings were compared to biochemical, hormonal and clinical features of the syndrome. Statistical analysis revealed a significantly higher prevalence of acne, LH/FSH ratios and testosterone levels in women with PCO compared to those with normal ovarian morphology. In the subgroup analysis, total ovarian volume correlated significantly with hirsutism scores. Our study revealed a great prevalence of polycystic ovaries in Greek women with PCOS, and emphasizes the significance of transvaginal ultrasound in establishment of the diagnosis of the syndrome. The presence of PCO may not be clinically important when present alone without clinical manifestations but reflects the underlying hyperandrogenemia in PCOS women, representing a useful tool in the management of these patients. PMID- 21793283 TI - Seroprevalence of other antibodies (herpes, CMV, rubella, varicella, hepatitis B and C, syphilis, chlamydia, mumps, toxoplasmosis) in HIV-positive patients. AB - We attempted to determine the seropositivity of HIV-positive patients to other antibodies (herpes, CMV, rubella, varicella, hepatitis B, hepatitis C, syphilis, chlamydia, mumps, toxoplasmosis). The study was carried out at the Prenatal Diagnosis and Therapy Centre of a Tertiary Hospital in Lagos, Nigeria. A total of 70 patients (50 females and 20 males) attending the centre between June 1997 and December 2005 who were screened and found to be HIV-seropositive were further screened for herpes simplex IgG/IgM, CMV IgG/IgM, rubella IgG/IgM, varicella IgG/IgM, mumps IgG/IgM, toxoplasmosis IgG/IgM, chlamydia IgG/IgM, hepatitis B and hepatitis C IgG/IgM using ELISA kits and syphilis (THPA) using the HAE method. Our study showed that a large number of HIV-positive patients are carriers of other antibodies and should be screened for them before therapy. PMID- 21793284 TI - Sympathetic nervous system disorder of women that leads to pelvic pain and symptoms of interstitial cystitis may be the cause of severe backache and be very responsive to medical therapy rather than surgery despite the presence of herniated discs. AB - PURPOSE: To describe a unique pharmacologic treatment for backache that seemed to be related to herniated discs. METHODS: Dextroamphetamine sulfate was prescribed to a woman who developed acute lower backache which was attributed to herniated lumbar discs. RESULTS: Within hours the pain diminished and she was pain free within a week. The 100% relief has persisted for months. CONCLUSIONS: Acute backache can be added to the long list of pain syndromes related to impairment of the sympathetic nervous system that is effectively treated with sympathomimetic amines. PMID- 21793285 TI - Two cases of measles in pregnant women immediately preceding delivery (case reports). AB - Measles is an acute exanthema spread by airborne infection and still occurs sporadically in Japan. Its mortality rate is estimated to be 0.1% and it has no specific therapy. Here, we present two cases of measles in pregnant women immediately preceding delivery. It is required to prevent the perinatal spread of measles when pregnant women are infected immediately preceding delivery. We measured the measles antibody titer of 1,393 pregnant women by enzyme immunoassay between 2004 and 2008. The antibody-positive rate was 87.7%, but the antibody titer tended to be low in childbearing age. Preventive treatment with measles vaccination is extremely important before pregnancy in order to prevent perinatal measles. PMID- 21793286 TI - Evidence that migraine headaches in women may be related to a common defect in the sympathetic nervous system as evidenced by marked improvement following treatment with sympathomimetic amines. AB - PURPOSE: To describe a novel therapy for women with intractable migraine headaches. METHODS: Dextroamphetamine sulfate was prescribed to a 33-year-old woman with intractable migraine headaches resistant to standard therapy. Her only abnormality noted was unexplained weight gain. She failed a water load test. RESULTS: The headaches were 100% relieved by dextroamphetamine sulfate (Spansule 45 mg/day). CONCLUSIONS: Intractable migraine headaches can be added to the list of various pain syndromes related to a disorder of the sympathetic nervous system resistant to standard therapy but showing dramatic improvement with treatment with sympathomimetic amines. PMID- 21793287 TI - Successful water birth in a woman with vaginismus. AB - Vaginismus is a common sexual dysfunction. The case of a successful water birth in a woman with vaginismus is presented. Water birth should be considered as an alternative method of birth in women with vaginismus. PMID- 21793288 TI - Novel [corrected] medical management of primary bladder endometriosis with dienogest: a case report. AB - BACKGROUND: Because of its low incidence, medical treatment of has not yet been well established although surgical excision is generally considered effective. We report the first case of primary bladder endometriosis successfully managed with a novel progestin dienogest. CASE: A 39-year-old woman, nulligravida, presented with lower urinary tract symptoms, especially during menstruation. Cystoscopy, with subsequent cold cup biopsy, revealed a solitary submucosal mass (2 x 2 cm) in the bladder on the posterior wall; histopathology revealed the diagnosis of extraperitoneal endometriosis. MRI and laparoscopy confirmed no peritoneal endometriosis implants or adenomyosis. She was treated with oral 2 mg/day dienogest for six months. The measurable lesion exhibited a remarkable reduction in its size, accompanied with immediate relief of the lesion-related symptoms. At one year after medication cessation, she is well and symptom-free. CONCLUSION: Dienogest may be a novel conservative alternative for bladder endometriosis, in particular for women who wish to avoid surgical intervention. PMID- 21793289 TI - Endometrial tuberculosis: a clinical case. AB - Genital tuberculosis is a bacterial infection still frequent in less developed countries where lots of cases are not diagnosed nor treated. In this work we describe a rare case of primary endometrial tuberculosis in a woman of 50 years old. The diagnosis was confirmed by an ultrasonography of the pelvis and an endometrial biopsy followed by a histological examination. The patient after the diagnosis was put under antiturbecular treatment for six months with complete healing. PMID- 21793290 TI - Outcome of arterial embolization of uterine leiomyoma: case report. AB - OBJECTIVE: To describe the outcomes after uterine artery embolization treatment of leiomyoma. DESIGN: Case report. SETTING: Department of Gynecology - Federal University of Sao Paulo. PATIENT: a 34-year-old woman with a diagnosis of leiomyoma for two years. INTERVENTION: embolization of uterine arteries with 500 to 700-microm diameter polyvinyl alcohol particles. MAIN OUTCOME MEASURE: pregnancy and delivery. RESULTS: After embolization, the follow-up revealed a good clinical response with significant reduction in uterus and leiomyoma volume. Also, the patient became spontaneously pregnant, but the delivery was cesarean section due to placenta accreta.. CONCLUSION: Regardless of arterial embolization results for controlling uterine bleeding, this procedure might have some consequences on pregnancy outcome. PMID- 21793291 TI - [Neuroradiological diagnostics of atherosclerotic lesions and kinking of the carotid arteries in determination of indications to surgical treatment]. AB - Range of methods for diagnostics of extracranial arterial stenosis includes both untrasonic techniques (transcranial Doppler study, duplex sonography, which are not only screening methods, but also used in surgery as well) and high-tech imaging methods--spiral CT scans and MR angiography with visualization of structural changes in vascular wall, quantitative and functional assessment of blood flow in vessels. Aim of this study was to determine the effective of non invasive diagnostic techniques--MR angiography (MRA), including phase-contrast MRA (PCMRA), and spiral CT angiography (SCTA) in identification and comprehensive assessment of stenosis of internal carotid artery and comparison of capabilities of these methods with gold standard--direct angiography. PMID- 21793292 TI - [The role of susceptibility-weighted MRI in detection of ruptured aneurysm in multiple aneurysms]. AB - Since 2008 till 2010 years 22 patients with multiple aneurysms were examined in Burdenko Neurosurgical Institute (Moscow, Russia). The series included 13 female and 9 male patients, age ranged from 28 to 62 years (mean 45 years). 68 aneurysms of different localization were discovered in these 22 patients. We also analyzed results of examination of 2 patients with solitary aneurysms in which SW-MRI was performed to confirm or exclude the fact of hemorrhage due to rupture of the aneurysm. All patients were operated microsurgically. SW-MRI is effective technique for identification of source of hemorrhage in patients with multiple aneurysms thus allowing selection of correct tactics of management. Information value of the method declines with increase of time after hemorrhage (over 2 years). SW-MRI enables verification of the fact of hemorrhage due to aneurysm in disputable cases (minimal non-specific clinical presentation, absence of hemorrhage verification). PMID- 21793293 TI - [Selection criteria for parameters of electric current in trans-CSF brain stimulation in patients with posttraumatic vegetative state]. AB - Trans-CSF brain stimulation is on of applied methods of stimulation in posttraumatic vegetative state. The paper analyzes application of this technique under the control by different methods of electrophysiological monitoring. Authors suggest principles of selection of stimulation parameters and detectable criteria of its effectiveness. PMID- 21793294 TI - [Reconstructive surgery of cranio-orbital injuries]. AB - The aim of study was to optimize evaluation and surgery of cranioorbital injuries in different periods after trauma. Material and methods. We analyzed 374 patients with cranioorbital injuries treated in Burdenko Neurosurgery Institute in different periods after trauma from January 1998 till April 2010. 288 (77%) underwent skull and facial skeleton reconstructive surgery within 24 hours - 7 years after trauma. Clinical and CT examination data were used for preoperative planning and assessment of surgery results. Stereolithographic models (STLM) were applied for preoperative planning in 89 cases. The follow-up period ranged from 4 months up to 10 years. Results. In 254 (88%) of 288 patients reconstruction of anterior skull base, upper and/or midface with restoration of different parts of orbit was performed. Anterior skull base CSF leaks repair, calvarial vault reconstruction, maxillar and mandibular osteosynthesis were done in 34 (12%) cases. 242 (84%) of 288 patients underwent one reconstructive operation, while 46 (16%)--two and more (totally 105 operations). The patients with extended frontoorbital and midface fractures commonly needed more than one operation--in 27 (62.8%) cases. Different plastic materials were used for reconstruction in 233 (80.9%) patients, of those in 147 (51%) cases split calvarial bone grafts were preferred. Good functional and cosmetic results were achieved in 261 (90.6%) of 288 patients while acceptable were observed in 27 (9.4%). Conclusion. Active single-stage surgical management for repair of combined cranioorbital injury in acute period with primary reconstruction optimizes functional and cosmetic outcomes and prevents the problems of delayed or secondary reconstruction. Severe extended anterior skull base, upper and midface injuries when intracranial surgery is needed produced the most challenging difficulties for adequate reconstruction. Randomized trial is required to define the extent and optimal timing of reconstructive surgery in patients with severe traumatic brain injury and craniofacial injury in acute period of trauma. PMID- 21793295 TI - [Complications of treatment of prolactinoma by dopamine agonists]. AB - Treatment of prolactin-secreting pituitary adenomas by dopamine agonists is highly effective and currently is used as basic treatment in most cases, however, literature sources practically do not contain data about possible complications of this therapy. We described a total of 11 cases of deterioration due to primary treatment of macroprolactinomas by cabergoline in the series of 176 patients. The first group included patients with enlargement of the tumor producing deterioration of the symptoms (onset of visual disorders and/or cephalgia). This occurred in 3 (1.7%) cases due to intratumoral hemorrhage or cystic transformation, and in 1 (0.6%) case as a result of growth of cabergoline resistant tumor. The second group was made up of 6 (3.4%) cases of nasal CSF leak which developed within 3 to 6 weeks after start of treatment. All patients with CSF leak had adenomas with high sensitivity to the drug which produced rapid and significant shrinking of the tumor. The third group was presented by the single case (0.6%) of visual deterioration due to development of empty sella syndrome with dislocation of chiasm and optic nerves into sellar cavity. PMID- 21793296 TI - [Radiofrequency denervation of intervertebral joints in management of facet pain syndrome]. AB - Back pain is very widespread and represents a socially significant problem of modern health care. During lifetime 90% of population experiences 1 or more episodes of back pain. This study focuses on assessment of effectiveness of radiofrequency denervation of intervertebral joints in management of patients with low back pain caused by facet pain syndrome. From 2007 till 2008 124 patients were examined in spinal clinic "Axiso". In 112 (80%) patients pain regressed. Clinical series was analyzed using the scale for assessment of severity of lumbosacral spinal degenerative disease developed in Burdenko Neurosurgical Institute (Moscow, Russia). The performed study confirmed effectiveness of the assessed technique which allowed including of radiofrequency denervation of intervertebral joints in the algorithm of management of patients with degenerative changes in the lumbosacral spine as the surgical method used in case of ineffectiveness of conservative treatment. PMID- 21793297 TI - [Management of facet pain syndrome in patients treated by microdiscectomy]. AB - Aim of this study was to assess effectiveness of high-frequency denervation of facet joints in facet pain syndrome in patients who underwent microdiscectomy. The analyzed series included 42 patients treated by microdiscectomy 2 to 56 months before minimally invasive manipulation. The control group was made of 50 patients of similar age with facet pain syndrome who did not undergo spinal surgery. Effectiveness of treatment in the main group reached 62% while in the control group it was 82%. VAS score after 6-12 months changed from 7.6 to 3.2 and from 7.9 to 2.2 in control and mail groups, respectively. Conclusions are made about effectiveness of high-frequency denervation of facet joints in patients with failed back surgery syndrome in conditions of their careful selection for this procedure. PMID- 21793298 TI - [Meningioma with extracranial metastases]. AB - The paper discusses a case of recurrent posterior skull base meningioma with extracranial metastases. Metastases of meningioma may spread through venous system, lymphatic vessels and cerebrospinal fluid, and also via contact route (implantation). Penetration of dura mater of venous sinuses leads to invasion of tumor cells and their spread into pulmonary circulation, system of vena azygos and hemiazygos, vertebral venous plexuses which may facilitate further dissemination of the tumor. Histological examination of recurrent meningiomas requires additional immunohistochemical investigation with estimation of proliferative activity. PMID- 21793299 TI - [Cystic sphenoid wing meningioma mimicking astrocytic glioma]. AB - In spite of rare incidence, cystic intracranial meningiomas deserve interest due to difficulties in correct preoperative diagnosis. Authors present a case report of a patient with cystic meningioma mimicking astrocytoma. In addition, review of literature is performed. PMID- 21793300 TI - [Non-convulsive epileptic status]. PMID- 21793301 TI - [Predisposing factors, etiology and pathogenesis of spontaneous nasal CSF leak]. PMID- 21793302 TI - [Necessity of development of Russian vertebrologic registry]. AB - Development of national and international registers for the most socially significant diseases is an important problem of contemporary medicine. Importance and priority of vertebrological register is explained by relatively young age of spinal neurosurgery as specialty, in which many questions concerning indications and optimal methods of treatment remain unsolved, and accumulated experience is quite limited. Nevertheless, vertebrology is on the way from opinions of certain experts to evidence-based scientific proofs. This transition needs generally accepted and convenient instruments for assessment of outcomes of treatment and procedures which should be presented by national vertebrological register. Aims of its development include accumulation of clinically valuable resources and knowledge in vertebrology by means of organization of society of interested professionals and patients. The paper discusses architecture, contents and importance of development of Russian vertebrological register targeted on neurosurgeons, orthopaedic surgeons, vertebrologists and other specialists dealing with this problem. Foreign vertebrological registers are analyzed, their advantages and disadvantages are summarized, requirements for inclusion of criteria in the register are investigated. PMID- 21793303 TI - Construction of three different recombinant scorpion fusion proteins with bifunctional activity. AB - This is the first report of three different fusion proteins with an antitumor analgesic peptide obtained from Chinese scorpion Buthus martensii Karsch (BmKAGAP). The fusion proteins were constructed in the form of chimeric toxins, aiming to obtain bifunctional analgesic and antitumor activity. The fusion proteins consisted of luteinizing hormone-releasing hormone (LHRH), three different types of flexible linkers (L1, Ser-Ser-His-His-His-His-His-His-Ser-Ser Gly-Leu-Val-Pro-Arg-Gly-Ser-His-Met; L2, Gly-Gly-Gly-Ser-Gly-Gly-Gly-Ser; L3, Ser Gly-Gly-Ser-Gly-Gly-Ser-Gly-Gly-Gly-Ser-Ser-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly Gly-Gly-Gly-Ser), and BmKAGAP. The genes coding three fusion proteins were cloned and expressed in E. coli in soluble form. Following two successive column chromatographic separations, purified fusion proteins were obtained. These fusion proteins exhibited analgesic activity in mice and were cytotoxic to a hepatocellular carcinoma cell line Hep3B. PMID- 21793304 TI - Biochemical characterization of a calcium-sensitive protein kinase LeCPK2 from tomato. AB - LeCPK2 (GenBank GQ205414), a versatile calcium-dependent protein kinase (CDPK or CPK) gene was isolated from tomato in our previous study. In this study, the biochemical properties of LeCPK2 were further investigated. To examine the role of the C-terminal calmodulin-like domain (CLD) of LeCPK2 with respect to Ca2+ activation, the kinase activities of recombinant full-length and truncated LeCPK2 were measured by Kinase-Glo Luminescent kinase assay (Promega). The results showed that LeCPK2 activity was Ca(2+)-dependent and the C-terminal CLD of 161 residues was essential for the activation of LeCPK2. The activity of LeCPK2 was sharply stimulated by Ca2+ with K0.5 (concentration of Ca2+ for half-maximal activity) of 48.8 and 45.5 nM with substrate histone IIIs and syntide 2, respectively. The optimal concentration of Mg2+ for LeCPK2 activity was 20 and 10 mM for substrate histone IIIs and syntide 2, respectively. The K(m) value of LeCPK2 towards histone IIIs and syntide 2 was 44.9 microg/ml and 89.52 microM, respectively. The determination of biochemical properties of LeCPK2 would provide some clues on how its activity was regulated in vivo. PMID- 21793305 TI - ENOS-G894T polymorphism is a risk factor for essential hypertension in China. AB - Vascular endothelial cells produce nitric oxide (NO), which contributes to the regulation of blood pressure and regional blood flow. Polymorphisms of the endothelial nitric oxide synthase (eNOS) gene are associated with coronary artery disease; however, associations between polymorphism (G894T) of the eNOS gene and essential hypertension remain unclear. This study was designed to investigate the association between a eNOS-G894T polymorphism and essential hypertension (EH). A total of 190 Chinese EH patients (EH group) and 94 healthy participants (control group) were included in the study. eNOS-G894T was determined using multi polymerase chain reaction and polymorphisms in eNOS-G894T were genotyped using gene chip technology. Patients carrying eNOS GT + TT genotypes had a higher risk of EH than those carrying the GG genotype (OR = 2.82, 95% CI: 1.05-7.60, P = 0.033). The EH group showed a significantly higher frequency of the T-allele compared with controls (OR = 3.48, 95% CI: 1.34-9.07; P = 0.007). eNOS-894T was found to be significantly associated with EH in the dominant genetic model. Thus, the study demonstrated a significant and independent association between a eNOS G894T polymorphism and EH in the Chinese patients. The study also showed that eNOS-G894T polymorphism is a risk factor for EH in Chinese patients. PMID- 21793306 TI - A QSAR study on a series of simplified digitalis-like compounds acting on Na+,K(+)-ATPase. AB - Among the cardiotonics (agents against congestive heart failure), the most important group is of the digitalis cardiac glycosides, but since these compounds suffer from a low therapeutic index, attention has been paid to investigating safer cardiotonic agents through the inhibition of Na+,K(+)-ATPase, the mechanism by which the digitalis cardiac glycosides elicit their action. Recently, a series of perhydroindenes were studied for their Na+,K(+)-ATPase inhibition activity. We report here a QSAR study on them to investigate the physicochemical and structural properties of the molecules that govern their activity in order to rationalize the structural modification to have more potent drugs. A multiple regression analysis reveals a significant correlation between the Na+,K(+)-ATPase inhibition activity of the compounds and Kier's first order valence molecular connectivity index of their R5-substituents and some indicator parameters, suggesting that the R5-substituents of the compounds containing atoms with low valence and high saturation and the R1-substituents having =N-O- moiety will be conducive to the activity. PMID- 21793307 TI - Molecular modeling of 2-nitropropane dioxygenase domain of Mycobacterium tuberculosis H37Rv and docking of herbal ligands. AB - The 3D structure of enoyl reductase (ER) domain generated by the SWISS MODEL server contains the 2-nitropropane dioxygenase (2NPD) structure displaying the TIM barrel fold. Though TIM barrel fold is made up of both main and inserted domains, in our study, we could only predict the structure of the main domain, which had central barrel of eight beta-strands surrounded by eight alpha-helices. Superimposition of the 2NPD region of ER domain of Mycobacterium tuberculosis H37Rv on to the corresponding region of 2UVA_G revealed a good structural alignment between the two, suggesting this template to be a good structural homologue. Among various herbal ligands that were screened as inhibitors, daucosterol was found to bind in closest proximity to the flavin mono nucleotide (FMN) binding site with the lowest docking energy. PMID- 21793308 TI - A choline monooxygenase gene promoter from Salicornia europaea increases expression of the beta-glucuronidase gene under abiotic stresses in tobacco (Nicotiana tabacum L.). AB - A 1312 bp 5' flanking region of Salicornia europaea choline monooxygenase (SeCMO) gene was isolated using the anchored PCR. To investigate the mechanism of regulation for this stress-induced gene, the SeCMO promoter-beta-glucuronidase (GUS) chimeric gene constructs containing five deletions F1, F2, F3, F4 and F5 were introduced into tobacco (Nicotiana tabacum L.) by Agrobacterium-mediated transformation. The functional properties of each promoter fragment were examined by assaying GUS activity in the leaves of transgenic tobacco treated with abiotic stresses (NaCl, PEG6000 and low temperature). The GUS activity in transgenic tobacco with F2 (-1056 to +8) construct showed highest increase under all the three abiotic stresses. Thus, the study provided a potential promoter induced by the salt, dehydration and cold for the plant genetic manipulation. PMID- 21793309 TI - Anti-venom potential of aqueous extract of stem bark of Mangifera indica L. against Daboia russellii (Russell's viper) venom. AB - Several plant extracts rich in pharmacologically active compounds have shown to antagonize venom of several species. Mangifera indica has been used against snakebite by the traditional healers. However, there is paucity of scientific data in support. In this study, we evaluated the antivenom potential of aqueous extract of stem bark of M. indica against D. russellii venom-induced pharmacological effects such as life myotoxicity, edema, LD50 etc. The extract inhibited the phospholipase, protease, hyaluronidase, 5'nucleotidase, ATPase and alkaline phosphomonoesterase activities with varying IC50 values. It significantly inhibited both metalloproteases and serine proteases activities. Further, the extract significantly reduced the myotoxicity of the venom, as evident by the reduction of serum creatin kinase and lactate dehydrogenase activities. Though the extract completely inhibited in vitro PLA2 activity, it was unable to completely inhibit in situ hemolytic and in vivo edema-inducing activities, usually brought about by PLA2s. In lethality studies, co-injection of the venom preincubated with the extract showed higher protection than the independent injection of venom, followed by the extract in the mice. However, in both the cases the extract -a cocktail of inhibitors significantly increased the survival time, when compared to that of mice injected (i.p) with the venom alone. These results encourage further studies on the potential use of cocktail of inhibitors in improving the treatment of snake envenomation. Further, this study substantiates the use of M. indica as an antidote against snakebite by the traditional healers. PMID- 21793310 TI - Lindane-induced biochemical perturbations in rat serum and attenuation by omega-3 and Nigella sativa seed oil. AB - Lindane (gamma-hexachlorocyclohexane, gamma-HCH), a highly persistent organochlorine insecticide is neurotoxic at acute doses and has been reported to induce oxidative stress in cells and tissues. In this study, we investigated the antioxidant property of Nigella sativa seed oil (N.O) and omega-3 polyunsaturated fatty acids (omega3) against gamma-HCH-induced oxidative hepatic and renal damage in male rats serum. Rats were orally given sublethal dose of gamma-HCH (12 mg/kg, 24 h prior to decapitation), while N.O (0.3 ml/kg) and omega3 (20 mg/kg) were given every 48 h for 20 days single or together, or also combined with gamma-HCH. gamma-HCH caused a significant increase in the levels of serum total lipids, cholesterol, and triglycerides by 49, 61 and 30% respectively, while HDL cholesterol decreased by 45% compared to control group. Pretreatment with omega3 and N.O prior gamma-HCH administration re-established the altered biochemical features and alleviated the harmful effects of gamma-HCH on lipid profile. The concentration of serum total protein and albumin was significantly decreased by 35 and 45% respectively in rats treated with gamma-HCH compared to control. gamma HCH also caused hepatic and renal damage, as observed from the elevated serum levels of urea, creatinine, total bilirubin and uric acid contents and aminotransferases (AST and ALT), phosphatases (ACP and ALP) and lactate dehydrogenase (LDH) activities. Co-administration of omega3 and N.O reversed the hazardous effects induced by gamma-HCH on the liver and kidney and also protected acetylcholinesterase from the inhibitory action of gamma-HCH as well as suppressed the lipid peroxidation. Thus, the results show that omega3 and N.O might prevent oxidative stress and attenuate the changes in the biochemical parameters induced by gamma-HCH in male rats. PMID- 21793311 TI - Alpha-tocopherol ameliorates cypermethrin-induced toxicity and oxidative stress in the nematode Caenorhabdtis elegans. AB - Oxidative stress and other effects induced by cypermethrin (CYP, 15 mM) and their amelioration by alpha-tocopherol (400 microM) was studied in the nematode Caenorhabditis elegans. The worms exposed for 4 h to CYP showed increased levels of reactive oxygen species (46%), H2O2 (37%) and protein carbonyls (29%), accompanied by decreased lifespan and brood size. However, exposure to both CYP and alpha-tocopherol resulted in diminution of above alterations with the worms exhibiting relatively lower levels of ROS (30%), H2O2 (15%), protein carbonyls (14%), altered antioxidant enzyme activities and normal lifespan and brood size. The results suggest that CYP induces oxidative stress in C. elegans and the strategy of intervention with alpha-tocopherol could be exploited to offset this induced oxidative stress. PMID- 21793312 TI - Neuroprotective potential of ethanolic extract of Pseudarthria viscida (L) Wight and Arn against beta-amyloid(25-35)-induced amnesia in mice. AB - The neuroprotective potential of ethanolic extract of roots of Pseudarthria viscida (L) Wight and Arn (EEPV) was investigated against beta-amyloid(25-35) induced amnesia in mice which is a suitable animal model for Alzheimer's disease (AD). The senile plaques of beta-amyloid (Abeta) are major constituents accumulated during the progression of AD as a potent neurotoxicant. In our investigation, intracerebroventricular injection of Abeta(25-35) in mice induced the neurodegeneration, exhibited the increased time of escape latency in behavioral pattern using water maze and decreased the levels of antioxidants namley superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and vitamin C with elevated level of acetylcholinesterase enzyme (AChE). The neuroprotective potential of EEPV was determined by behavioral pattern using water maze and biochemical parameters such as SOD, CAT and GPx and vitamin C content as well as AChE. Mice were treated with EEPV at 200 and 400 mg/kg doses for 21 days. Except control, all animals received a single injection of neurotoxicant Abeta(25-35) on 14th day. In behavioural assessment, treatment with ethanolic extract improved the cognitive function in the water maze and attenuated the elevated levels of AChE with increase in antioxidant enzymes, indicating the neuroprotection with increased levels of vitamin C. These findings suggest that ethanolic extract of P. viscida exerts anti-amnesiac effects and enhances cognitive function. PMID- 21793313 TI - Growth inhibition of struvite crystals by the aqueous root extract of Rotula aquatica. AB - Formation of urinary stone is a serious and debilitating problem throughout the world. In the present study, the inhibitory effect of aqueous extract of root of Rotula aquatica was investigated against struvite crystals (one of the components of urinary stone) grown in vitro using single diffusion gel growth technique. For setting the gel, sodium metasilicate solution (specific gravity 1.05) and 0.5 M aqueous solution of ammonium dihydrogen phosphate were mixed, so that the pH of the mixture could be set at 7.0. Equal amounts of supernatant solution of magnesium acetate (1.0 M) prepared with 0.0%, 0.5% and 1% concentrations of the extract were gently poured on the set gels. It was observed that the number, dimension, total mass, total volume, growth rate and depth of growth of struvite crystals decreased with the increasing extract concentrations in the supernatant solutions. The enhancement of dissolution rate and fragmentation of struvite crystals suggested potential application of the extract for inhibition of struvite type urinary stone. PMID- 21793314 TI - Physiological rhythms, dynamical diseases and acupuncture. AB - Physiological rhythms are ubiquitous and essential to our life. They usually interact with one another and also with the outside environment. Disappearance of normal rhythms and emergence of abnormal rhythms are called dynamical diseases. In this article, we will first review the current knowledge on the genesis of physiological rhythms. Then, models of rhythmic interactions among themselves and with external stimuli will be reviewed. Particular emphasis will be placed on the methods that can diagnose abnormal rhythms. Finally, treatment of dynamical diseases will be discussed. It turns out that the models of fractional Brownian motion and fractional Gaussian noise based on dynamical systems have the potential to become biomarkers in differentiating and evaluating normal from abnormal physiological rhythms in dynamical diseases. Meanwhile, in order to explain how acupuncture works, a feasible model of meridians based on communication networks is also included. PMID- 21793315 TI - Glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners. AB - The aim of this study was to determine glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners. Positron emission tomography (PET) using 18F-fluoro-2-deoxyglucose (FDG) was performed to determine the patterns of glucose uptake in lower limbs of short-distance (SD group, n=8) and long-distance (LD group, n=8) male runners after a modified 20 min Bruce treadmill test. Magnetic resonance imaging (MRI) was used to delineate the muscle groups in lower limbs. Muscle groups from hip, knee, and ankle movers were measured. The total FDG uptake and the standard uptake value (SUV) for each muscle group were compared between the 2 groups. For the SD and LD runners, the 2 major muscle groups utilizing glucose during running were knee extensors and ankle plantarflexors, which accounted for 49.3 +/- 8.1% (25.1 +/- 4.7% and 24.2 +/- 6.0%) of overall lower extremity glucose uptake for SD group, and 51.3 +/- 8.0% (27.2 +/- 2.7% and 24.0 +/- 8.1%) for LD group. No difference in muscle glucose uptake was noted for other muscle groups. For SD runners, the SUVs for the muscle groups varied from 0.49 +/- 0.27 for the ankle plantarflexors, to 0.20 +/- 0.08 for the hip flexor. For the LD runners, the highest and lowest SUVs were 0.43 +/- 0.15 for the ankle dorsiflexors and 0.21 +/- 0.19 for the hip. For SD and LD groups, no difference in muscle SUV was noted for the muscle groups. However, the SUV ratio between the ankle dorsiflexors and plantarflexors in the LD group was significantly greater than that in the SD group. We thus conclude that the major propelling muscle groups account for approximately 50% of lower limb glucose utilization during running. Thus, the other muscle groups involving maintenance of balance, limb deceleration, and shock absorption utilize an equal amount. This result provides a new insight into glucose distribution in skeletal muscle, suggesting that propellers and supporters are both energetically important during running. Furthermore, for each unit muscle volume, movers of ankle are more glucose-demanding than those of hip. PMID- 21793316 TI - Effects of propofol intravenous injection bolus on the left ventricular function and the myocardial beta-adrenoceptor in rats. AB - Propofol bolus injection has been reported to influence cardiovascular functions. However, the detailed mechanism underlying this action has not been elucidated. This study was designed to investigate the effects of propofol i.v. bolus on the left ventricular function, the myocardial beta-adrenoceptor (beta-AR) binding site density (Bmax) and Kd (apparent dissociation constant) in a 30-minute period. One hundred and four male Wistar rats were randomly divided into four groups: group C (control group), group I (intralipid group), group P1 (5 mg/kg propofol) and group P2 (10 mg/kg propofol). The results showed a significant downregulation of HR, LVSP, +dp/dtmax and -dp/dtmax in both groups P1 and P2 (especially after bolus injection in 7 min) than those of group C (P < 0.05), whereas no significant difference was found between the P1 and P2 groups (P > 0.05). Likely, Bmax was remarkably upregulated in both groups P1 and P2 (P < 0.05, vs. groups C and I), and there was no significant difference between these two groups (P > 0.05). Of note, the Kd value in group P2 (10 mg/kg propofol) was found dramatically increased in 30 min than that in the low-dose propofol-treated group (group P1) as well as in groups C and I (P < 0.05). In conclusion, these results indicate that intravenous injection of propofol bolus can inhibit the cardiac function partially via upregulation of Bmax and downregulation of the beta-AR affinity at higher-dose injection of propofol bolus. PMID- 21793317 TI - The effect of eight weeks of supplementation with Eleutherococcus senticosus on endurance capacity and metabolism in human. AB - The aim of this study was to examine the effects of Eleutherococcus senticosus (ES) supplementation on endurance capacity, cardiovascular functions and metabolism of recreationally trained males for 8 weeks. Nine recreationally trained males in college consumed 800 mg/d of ES or starch placebo (P) for 8 weeks according to a double-blind, randomized, placebo controlled and crossover design with a washout period of 4 weeks between the cycling trials. Subjects cycled at 75% VO2 peak until exhaustion. The examined physiological variables included endurance time, maximal heart rate during exhaustion exercise, VO2, rating of perceived exertion and respiratory exchange ratio. The biochemical variables including the plasma free fatty acid (FFA) and glucose were measured at rest, 15 min, 30 min and exhaustion. The major finding of this study was the VO2 peak of the subjects elevated 12% (P < 0.05), endurance time improved 23% (P < 0.05) and the highest heart rate increased 4% (P < 0.05) significantly. The second finding was at 30 min of 75% VO2 peak cycling, the production of plasma FFA was increased and the glucose level was decreased both significantly (P < 0.05) over 8-week ES supplementation. This is the first well-conducted study that shows that 8-week ES supplementation enhances endurance capacity, elevates cardiovascular functions and alters the metabolism for sparing glycogen in recreationally trained males. PMID- 21793318 TI - Protein kinase C alpha location and the expression of phospho-MEK and MDR1 in hepatitis virus-related hepatocellular carcinoma biopsies. AB - The purpose of this study was to elucidate the function of protein kinase C (PKC) alpha in human hepatocellular carcinoma (HCC). Histoimmunopathologic techniques were used to determine the localization and/or expression of PKCalpha, phospho mitogen-acrivated protein kinase (MEK) and multidrug resistance 1 (MDR1) in HCC biopsies. Expression of PKCalpha, phospho-MEK and MDR1 was significantly increased in the region of HCC location compared with the non-tumor location. The HCC tissues were classified as cytosolic type, where PKCalpha was deposited in the cytoplasm in > 50% of cells, or membranous type for others. The results showed that the higher expression levels of phospho-MEK and MDR1 in HCC location were significantly associated with those patients whose cells were of the membranous type. Moreover, the expression of MDR1 in HCC location was also significantly associated with the phospho-MEK, and was significantly higher in the patients with anti-HCV negative readings. The results indicate that elevated expression of MDR1 in HCC patients with non-HCV infection may be mediated through PKC signaling pathway. PMID- 21793319 TI - Recovery cycle of neurons in the inferior colliculus of the FM bat determined with varied pulse-echo duration and amplitude. AB - The recovery cycle of auditory neurons is an important neuronal property which underlies a bat's ability in analyzing returning echoes and to determine target distance (i.e., echo ranging). In the same token, duration selectivity of auditory neurons plays an important role in pulse recognition in bat echolocation. Because insectivorous bats progressively vary the pulse parameters (repetition rate, duration, and amplitude) during hunting, the recovery cycle of auditory neurons is inevitably affected by their selectivity to other co-varying echo parameters. This study examines the effect of pulse duration and amplitude on recovery cycle of neurons in the central nucleus of the inferior colliculus (IC) of the FM bat, Pipistrellus abramus, using biologically relevant pulse-echo (P-E) pairs with varied duration and amplitude difference. We specifically examine how duration selectivity may affect a neuron's recovery cycle. IC neurons have wide range of recovery cycle and best duration (BD) covering P-E intervals and duration occurring different phases of hunting. The recovery cycle of most IC neurons increases with P-E duration and amplitude difference. Most duration selective IC neurons recover rapidly when stimulated with biologically relevant P E pairs. As such, neurons with short BD recover rapidly when stimulated with P-E pairs of short duration and small P-E amplitude difference. Conversely, neurons with long BD recover rapidly when stimulated with P-E pairs of long duration and large P-E amplitude difference. These data suggest that bats may potentially utilize the response of IC neurons with different BD and recovery cycle to effectively perform echo detection, recognition of echo duration and echo ranging throughout a target approaching sequence. PMID- 21793320 TI - Significant association of XPD Asp312Asn polymorphism with breast cancer in Taiwanese patients. AB - The DNA repair gene XPD, an important caretaker of the overall genome stability, is thought to play a major role in the development of human malignancy. Polymorphic variants of XPD, at Asp312Asn (rs1799793), Lys751Gln (rs13181), and promoter C-114G (rs3810366), were chosen to be studied of their association with breast cancer susceptibility in a central Taiwanese population. In this hospital based case-control study, the associations of XPD Asp312Asn, Lys751Gln and promoter C-114G polymorphisms with breast cancer risk were investigated. In total, 1232 patients with breast cancer and 1433 healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant difference in the frequency of the XPD Asp312Asn genotype, but not the XPD Lys751Gln or promoter C-114G genotypes, between the breast cancer and control groups. Those who had G/A or A/A at XPD Asp312Asn showed a 1.78-fold (95% confidence interval = 1.53-2.08) increased risk of breast cancer compared to those with G/G. As for XPD Lys751Gln or promoter C-114G, there was no difference in distribution between the breast cancer and control groups. Our findings suggest that the heterozygous and homozygous A allele of the XPD Asp312Asn may be associated with the development of breast cancer and may be a useful marker for primary prevention and anticancer intervention. PMID- 21793321 TI - Protection by 3'-methoxypuerarin of rat hippocampal neurons against ischemia/reperfusion injury. AB - 3'-Methoxypuerarin (3'-MOP) is an isoflavone extracted from radix puerariae. The aim of this study was to investigate the role and the mechanism of 3'-MOP in the protection of hippocampal neurons against cerebral ischemia/reperfusion (I/R) injury in rats. I/R injury was induced by a modified four-vessel occlusion model. Rats were randomly divided into an I/R group, an I/R + 3'-MOP group and a control group. Histological changes in the neurons of the hippocampal CA1 region were observed with hematoxylin and eosine (H&E) staining. The apoptotic neurons in the hippocampal CA1 area were counted with the terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) staining. The results showed that compared with the I/R group, 3'-MOP increased the number of surviving neurons in the hippocampal CA1 region (P < 0.001) and markedly reduced the number of apoptotic pyramidal neurons (P < 0.001) after I/R injury. In conclusion, 3'-MOP can protect hippocampal neurons against I/R injury by inhibiting apoptosis. PMID- 21793322 TI - Protective effects of leptin on ischemia/reperfusion injury in rat bladder. AB - The aim of the study was to evaluate protective effects of exogenous leptin on ischemia/reperfusion (I/R)-induced injuries to the urinary bladder tissue and to investigate the effect on tumor necrosis factor alpha (TNF-alpha) levels and apoptotic cells during I/R injury. Bladder I/R injury was induced by abdominal aorta occlusion by ischemia for 45 min, followed by 60 min of reperfusion in rats. The rats were divided into three groups: control (n = 8 + 8), I/R (n = 8 + 8) and I/R+leptin group (n = 8 + 8). The rats in the I/R+leptin group were treated intraperitoneally with leptin (10 microg/kg) 60 min prior to ischemia induction. At the end of the reperfusion period, urinary bladders of the first eight rats from each group were removed for TUNEL staining processing while the others were removed for biochemical analyses for MDA and TNF-alpha levels. In the I/R group, the ratios of TUNEL-positive nuclei were higher than the control and the I/R+leptin groups. The MDA and TNF-alpha levels of the bladder tissue in the I/R group were higher than the control and leptin-treated groups. TUNEL-staining and biochemical studies revealed that leptin has a protective effect on urinary bladder I/R injury. PMID- 21793323 TI - Effect of m-3M3FBS on Ca2+ movement in PC3 human prostate cancer cells. AB - The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl) benzenesulfonamide (m-3M3FBS), a presumed phospholipase C activator, on cytosolic free Ca2+ concentrations ([Ca2+]i) in PC3 human prostate cancer cells is unclear. This study explored whether m-3M3FBS changed basal [Ca2+]i levels in suspended PC3 cells by using fura-2 as a Ca2+-sensitive fluorescent dye. M-3M3FBS at concentrations between 10-50 microM increased [Ca2+]i in a concentration dependent manner. The Ca2+ signal was reduced by 60% by removing extracellular Ca2+. M-3M3FBS-induced Ca2+ influx was inhibited by the store-operated Ca2+ channel blockers nifedipine, econazole and SK&F96365, and by the phospholipase A2 inhibitor aristolochic acid. In Ca2+-free medium, 30 microM m-3M3FBS pretreatment greatly inhibited the [Ca2+]i rise induced by the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin or BHQ. Conversely, pretreatment with thapsigargin, BHQ or cyclopiazonic acid reduced the major part of m-3M3FBS-induced [Ca2+]i rise. Inhibition of phospholipase C with U73122 did not much alter m-3M3FBS-induced [Ca2+]i rise. Collectively, in PC3 cells, m-3M3FBS induced [Ca2+]i rises by causing phospholipase C-independent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via store-operated Ca2+ channels. PMID- 21793324 TI - A comparison of throwing kinematics between youth baseball players with and without a history of medial elbow pain. AB - Risk factors in throwing factors associated to little league elbow have not been adequately explored. Whether these factors also affect the players' performance is also important to elucidate while modifying throwing pattern to reduce injury. The purpose of this study was to compare the differences in throwing kinematics between youth baseball players with or without a history of medial elbow pain (MEP) and to determine the relationship between their throwing kinematics and ball speed. Fifteen players with previous MEP were matched with 15 healthy players by age, height and weight. Throwing kinematics was recorded by an electromagnetic motion analysis system. A foot switch was used for determining foot off and foot contact. Ball speed was recorded with a sports radar gun. The group with a history of MEP demonstrated less elbow flexion angle at maximum shoulder external rotation and had more lateral trunk tilt at ball release compared to the healthy group. The group with a history of MEP also had faster maximum upper torso rotation velocities, maximum pelvis rotation velocities and ball speeds. Maximum shoulder external rotation angle (r = 0.458, P = 0.011), elbow flexion angle at maximum shoulder external rotation (r = -0.637, P = 0.0003), and maximum upper torso rotation velocity (r = 0.562, P = 0.002) had significant correlation with ball speed. Findings of this study can be treated as elbow injury-related factors that clinicians and coaches can attend to when taking care of youth PMID- 21793325 TI - Involvement of ERK phosphorylation in the prevention of ischemia-induced ovarian follicular depletion by stem cells. AB - Ovarian failure is commonly caused by aging, autoimmune disease, menopause and cancer therapy. We used an ischemic model in the ovary to test the hypothesis that stem cells are helpful for ovarian regeneration after injury. Three treatment regimes were employed: sham-operated control, ligation plus PBS, and ligation plus immortalized human bone marrow stromal cells (stem cells) groups. After ligation-induced ischemia, stem cells or PBS were injected into rat ovaries. Then, pregnant mare serum gonadotropin was given intra-peritoneally to initiate folliculogenesis. The animals were then sacrificed. The ovary gland was weighed, and ovarian folliculogenesis, stem cell differentiation and vascular neogenesis were evaluated. In order to study improvement of folliculogenesis after ovarian ischemia, steroidogenic acute regulatory protein (StAR), p44/p42 MAPK (T-ERK1/2), and phospho-p44/ p42 MAPK (P-ERK1/2) expression were specifically evaluated. Results indicated that ovarian size was smaller and that the rate of folliculogenesis was lower in ovarian ischemic-reperfusion animals, but both recovered after stem cell treatment. The stem cells migrated into the ovary and differentiated into theca cells, granulosa cells, corona radiata cells and vascular endothelial cells. In addition, von Willebrand factor (vWF) expression was increased; 17beta-estradiol (E2), progesterone (P4), P-ERK1/2 and StAR protein expression was recovered by stem cells treatment in the ischemic ovaries. The serum LH was significantly increased in ovaries of ischemia reperfusion animals, but the stem cell treatment restored the effects. These results suggest that stem cells might be helpful for ovarian regeneration after injuries by promoting vascular neogenesis and steroidogenesis through the MAPK pathway. PMID- 21793326 TI - Effect of nortriptyline on Ca2+ handling in SIRC rabbit corneal epithelial cells. AB - To explore the effect of nortriptyline, a tricyclic antidepressant, on cytosolic free Ca2+ concentrations ([Ca2+]i) in corneal epithelial cells, [Ca2+]i levels in suspended SIRC rabbit corneal epithelial cells were measured by using fura-2 as a Ca2+-sensitive fluorescent dye. Nortriptyline at concentrations between 20-200 microM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced partly by removing extracellular Ca2+. Nortriptyline-induced Ca2+ influx was inhibited by the store-operated Ca2+ channel blockers econazole and SK&F96365, the phospholipase A2 inhibitor aristolochic acid, and alteration of activity of protein kinase C. In Ca2+-free medium, 200 microM nortriptyline pretreatment greatly inhibited the rise of [Ca2+]i induced by the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin. Conversely, pretreatment with thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ; another endoplasmic reticulum Ca2+ pump inhibitor) nearly abolished nortriptyline-induced [Ca2+]i rise. Inhibition of phospholipase C with U73122 decreased nortriptyline-induced [Ca2+]i rise by 75%. Taken together, nortriptyline induced [Ca2+]i rises in SIRC cells by causing phospholipase C-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via store-operated Ca2+ channels. PMID- 21793327 TI - Effects of one-year swimming training on blood pressure and insulin sensitivity in mild hypertensive young patients. AB - Swimming is a lifestyle intervention recommended by many clinicians in the prevention and treatment of hypertension. Yet, not all studies have agreed that swimming training can reduce blood pressure (BP). Inclusion of normotensive subjects could be a confounder for discrepancies among studies. In this one-year longitudinal study, long-term effects of swimming training on BP were investigated in 7 mild hypertensive patients (systolic BP (SBP) > 140 mmHg) and 16 normotensive controls. At baseline, these subjects (aged 21.5 +/- 0.1 years) did not participate in any form of sport training activity for the previous 3 months before enrollment into the training program. The training distance progressed from 0 (baseline) to 7 kilometers per week. BP and the homeostasis model assessment for insulin resistance (HOMA-IR) were determined under fasted condition at baseline and 48 h after the last swimming bout. The hypertensive patients displayed significantly greater HOMA-IR than age-matched normotensive controls. When data of all subjects were pooled, plasma glucose concentration was only slightly lowered after training, but weight, height, body mass index, SBP, diastolic BP (DBP) and HOMA-IR values were not significantly altered. However, when observation was restricted to the hypertensive patients, swimming training significantly lowered SBP by approximately 17 mmHg, concurrent with 41% reduction in HOMA-IR. Intriguingly, SBP in the normotensive subjects was elevated by approximately 6 mmHg after training. CONCLUSIONS: The present study found normalization rather than universal reduction effect of swimming training on BP. Furthermore, the BP-lowering effect of training in hypertensive patients appears to be associated with improvement in insulin sensitivity. PMID- 21793328 TI - Protection of thymosin beta-4 on corneal endothelial cells from UVB-induced apoptosis. AB - Cornea absorbs most of daily ultraviolet (UV) light. An excess of UV damages results in not only keratopathy and cataract but also maculopathy. It has been reported that thymosin beta-4 (Tbeta4) promotes wound healing, decreases inflammatory response and prevents apoptosis of corneal epithelial cells. However, it is not clear whether Tbeta4 protects UVB-induced corneal injury, particularly in corneal endothelial cells because of its non-proliferation in nature. The purpose of this study is to compare the protective effects of Tbeta4 on bovine corneal endothelial (BCE) cells from low- and high-dose UVB damage. In this study, 1 microg/ml of Tbeta4 was added to BCE cells 2 h before low (12.5 mj/cm2) or high dosage (100 mj/cm2) UVB exposure. Using a fluorogenic substrate cleavage assay, we found that Tbeta4 diminished the reactive oxygen species level in BCE cells elicited by UVB. However, the protection of viability by Tbeta4 could only be detected under low-dose UVB exposure. Moreover, both caspase-9 activity and annexin V/propidium iodine staining demonstrated that Tbeta4 only protected BCE cells from low-dose UVB-induced apoptosis but not high-dose UVB induced necrosis. Together, Tbeta4 protected corneal endothelial cells from UVB induced oxidative stress and apoptosis after low-dose UVB exposure. The results support further investigation towards topical use or anterior chamber injection of this small hydrophilic peptide in treating and preventing UVB-induced corneal endothelial damage. PMID- 21793329 TI - An open-label, multicentre study of levocetirizine for the treatment of allergic rhinitis and urticaria in Taiwanese patients. AB - Levocetirizine has been shown in observational studies in the west as an effective and satisfactory therapy for patients with allergic respiratory and skin disease. An open-label, multicentre observational study was conducted to investigate the patients' perception of levocetirizine in the treatment of allergic rhinitis (AR) and urticaria in Taiwanese patients. Three hundred and thirty-three patients (236 AR and 97 urticaria patients) attending out-patient clinics of medical centres across Taiwan were included in the study. Patients were treated with levocetirizine 5 mg once daily (AR patients for 2-4 weeks and urticaria patients for 2-6 weeks) and at the end of treatment, they evaluated for symptoms of disease, perception of change in symptoms, global efficacy and tolerability, global preference over previous antiallergic treatment, change in quality of sleep/daily activities, and safety and adverse events (AEs). Levocetirizine markedly improved the symptoms of AR and urticaria; with 70-75% of AR patients and 60-80% of urticaria patients reporting complete or marked improvements in individual symptoms. Asthma symptoms were completely or markedly improved in 44% of patients with AR and concomitant asthma. A majority of the patients was satisfied with levocetirizine therapy and 50-70% indicated preference for levocetirizine over previous therapy. Overall, 50-74% of all patients perceived improvements in quality of sleep/daily activities and 50-65% of the patients rated the onset of action for levocetirizine as very rapid or rapid. Somnolence was the most common AE, reported by 7.4% of AR and 7.0% of urticaria patients. The results of this study indicated that levocetirizine is an effective and satisfactory therapy for the management of allergic respiratory and skin disease in Taiwanese subjects. PMID- 21793330 TI - Survival and differentiation of neuroepithelial stem cells on chitosan bicomponent fibers. AB - Chitosan is a popular biomaterial used in tissue engineering. Fibers of chitosan could provide a favorable anatomical substrate for cell growth which provides a promising application for axonal regeneration during peripheral injury. Neuroepithelial stem cells (NEPs) are the most primitive neural stem cells with multipotential for neuronal and glia differentiation. To assess the biocompatibility between NEPs and chitosan fibers, and to explore whether the NEPs have the ability to differentiation on chitosan fibers, NEPs were harvested from the neural tube and seeded on chitosan fibers in in vitro culture. The biocompatibility of chitosan fibers was tested by MTT assays. The growth and survival were observed by light and scanning electronic microscope at different times in culture. And, the differentiation of NEPs was examined by immunocytochemical staining. The results indicated that NEPs could grow on the chitosan fibers and attach firmly to the surface of fibers. On chitosan fibers, NEPs could differentiate into neurons and glia. Our study demonstrated that chitasan fibers had a good biocompatibility with NEPs which affords a potential alternative for the repair of peripheral nerve injury. PMID- 21793331 TI - Independent effects of the broccoli-derived compound sulforaphane on Ca2+ influx and apoptosis in Madin-Darby canine renal tubular cells. AB - This study explored whether sulforaphane changed basal [Ca2+]i levels in suspended Madin-Darby canine kidney (MDCK) cells by using fura-2 as a Ca2+ sensitive fluorescent dye. Sulforaphane at concentrations between 2.5-10 microM increased [Ca2+]i in a concentration-dependent manner. This Ca2+ influx was inhibited by phospholipase A2 inhibitor aristolochic acid but not by Ca2+ channel blockers such as nifedipine, nimodipine, nicardipine, diltiazem, verapamil, econazole and SK&F96365. The Ca2+ signal was abolished by removing extracellular Ca2+. In Ca2+-free medium, pretreatment with sulforaphane did not alter the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin-induced Ca2+ release suggesting sulforaphane did not induce slow Ca2+ release from endoplasmic reticulum. At concentrations between 1 and 20 microM, sulforaphane induced concentration-dependent decrease in cell viability which was not affected by pre chelation of cytosolic Ca2+ with BAPTA/AM. Flow cytometry data suggest that 20 (but not 5 and 10) microM sulforaphane induced significant increase in sub G1 phase indicating involvement of apoptosis. Collectively, in MDCK cells, sulforaphane induced [Ca2+]i rises by causing Ca2+ entry through phospholipase A2 sensitive pathways without inducing Ca2+ release from the endoplasmic reticulum. Sulforaphane also induced Ca2+-independent cell death that might involve apoptosis. PMID- 21793332 TI - Effects of Shugan-Huayu powder, a traditional Chinese medicine, on hepatic fibrosis in rat model. AB - Shugan-Huayu powder (SHP) has been administered to outpatients with chronic liver disease without clear anti-fibrosis mechanism. To investigate the anti-fibrotic effects of SHP on liver fibrosis in a rat model and in hepatic stellate cells (HSCs) in vitro, rats were gavaged with CCl4 at 1.0 g/kg body weight twice a week for 8 weeks to induce liver fibrosis and the rats were randomly assigned to one of the three groups: -CCl4 alone, low-dose SHP and high-dose SHP. SHP was given by gavages 5 times a week for 8 weeks. Serum, livers and HSCs were assayed for serology, pathology, western blot, zymography and quantitative RT-PCR. Hepatic function improved as decreased serum aspartate aminotransferase and alanine aminotransferase, and collagen deposition and active HSCs were significantly reduced in CCl4-induced liver by SHP treatment. The expression of matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta1 (TGF-beta1) mRNA in fibrotic liver showed significant downregulation after SHP treatment. In vitro, inhibition of alpha-smooth muscle actin (alpha-SMA) expression and MMP-2 secretion of active HSCs were also noticed by SHP treatment. SHP has an antifibrotic effect on CCl4-induced liver fibrosis in rats. Anti-fibrotic mechanisms were probably inhibiting activation of HSCs and decreased expression of MMP-2 and TGF-beta1. PMID- 21793333 TI - Cortactin, fascin and survivin expression associated with clinicopathological parameters in brain gliosarcoma. AB - Gliosarcoma is a very rare primary neoplasm of the central nervous system classified as a variant of glioblastoma. Cortactin, fascin and survivin have been found in several human cancers to play important roles in tumor progression, but the expression pattern of these biomarkers in gliosarcoma is unclear. Immunostaining for cortactin, fascin and survivin was assessed in 6 surgical specimens of brain gliosarcoma, and the relationship between the expression of these biomarkers and tumor size or clinical parameters were examined. Five of our six patients with gliosarcoma survived 3-17 months. One patient is still alive for more than 24 months. The mean immunostaining scores for cortactin were significantly higher in the gliomatous (score 236.6 +/- 45.4) and sarcomatous (score 233.3 +/- 51.4) components than in normal brain tissues (score 21.6 +/- 6.6). The mean cytoplasmic immunostaining scores for fascin and survivin were also significantly higher in the gliomatous and sarcomatous components than in normal brain tissues. In addition, survivin was also stained in the nucleus of tumor cells. Linear regression analysis showed that fascin score in the gliomatous component was significantly associated with tumor size (R = 0.69) and the fascin score in the sarcomatous component was significantly associated with patient's age (R = 0.87). In addition, the survivin cytoplasmic scores in the gliomatous and sarcomatous components were inversely associated with tumor size. Our results demonstrated that over-expression of cortactin, fascin and survivin is associated with malignant transformation of brain gliosarcoma. Development of drugs that target cortactin, fascin and survivin expression may be therapeutic to patients with gliosarcoma. PMID- 21793334 TI - Oscillating gas bubbles as the origin of bowel sounds: a combined acoustic and imaging study. AB - Bowel sounds have been speculated to stem from the movement of gas or a mixture in the bowel lumen, with gas as the major component. The exact role and the mechanism through which gas participates have not been elucidated. Video images of actively moving bubbles under either real-time ultrasonography (RU, n = 4) or videofluoroscopy (VF, n = 4) with synchronous sound recording were studied and a total of 24 bubbling bowel sounds (BBS's) were obtained. The physical dimensions and acoustic parameters of bubbles were analyzed. Freely oscillating bubbles were demonstrated clearly in both groups. Bubble radii ranged from 1.5 to 7.2 mm and frequencies from 258.3 to 1,078 Hz. The bubble frequency correlated inversely with the radius (P < 0.01). The relevant acoustic features and parameters of bubble dynamics further supported the identification of gas bubbles. Although the acoustic features seemed to be of minor clinical significance, increased number of clustering or fixed, repetitive pattern of occurrences might suggest a poorer prognosis. In summary, oscillating gas bubbles are capable of producing BBS's and may play a central role in this newly recognized model of bowel sound genesis. The patterns of BBS's may be of prognostic value in clinical application, underlining the need for further study. PMID- 21793335 TI - Effects of profuse sweating induced by exercise on urinary uric acid excretion in a hot environment. AB - In order to determine whether exercise-induced profuse sweating could reduce urinary uric acid excretion, we simulated badminton players training and measured their uric acid in urine, sweat and blood during the training period. Thirteen male volunteers who were well-trained badminton players were recruited in this study. On the first 2 days and the last 2 days of the study period none of the subjects engaged in any intense exercise- or activity-inducing profuse sweat, but they accepted routine training 2 h per day during the middle 3 days. The results show that mean serum urate levels of thirteen volunteers rose significantly on day 4, when the concentrations increased by 18.2% over day 2 (P < 0.05). The mean ten-hour urinary uric acid excretion of seven volunteers on the 3 training days was significantly less at 178.5 micromol/day and 118.3 micromol/day than those on the preceding and subsequent days of the training days, respectively (P < 0.05). Furthermore, for six volunteers, the mean ratio of clearance of uric acid to creatinine was 6.6% on day 2, which significantly decreased to 5.4% on day 4 (P < 0.05). It is concluded profuse sweating exercise results in a decrease of urinary uric acid excretion amounts and leads to increased serum uric acid after the exercise. We suggest that persons who take vigorous exercise or are exposed to hot environments need drinking enough fluids to prevent dehydration and maintain adequate urinary output. People with profuse sweat after rigorous exercise are recommended taking sports drinks containing abundant sodium in order to decrease serum uric acid. PMID- 21793336 TI - Cardiac fibrosis in diabetic rats: regulation and mechanism of activation of the PPARgamma signal pathway. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily which affects organic fibrosis. The aims of the study were to approach the effects of activation of the PPARgamma signal pathway on cardiac fibrosis in diabetic rats, and also the effects on cardiac remodeling and function. Type 1 diabetic models were used in the study. All the animals were divided into 3 groups: I: control group; II: diabetic group; III: diabetes+Pioglitazone (Piog, a PPARgamma ligand) administration group. After 14 weeks of feeding, general condition, fibrosis indices, echocardiography and interventricular pressures parameters were detected. At the 14th week, compared with group I, the hydroxyproline concentration in group II significantly increased, and CO I and III distribution was more obvious by sirius red staining. Reduction of LVSP (left ventricular systolic pressure) and increase of LVEDP (left ventricular end-diastolic pressure) were also significant in group II. But these situations were changed by the administration of Piog in group III. Furthermore, results of RT-PCR and immunohistochemistry showed that Piog administration reduced angiotensin II type 1 receptor (AT1-R) expression in diabetic models. Hence, activation of the PPARgamma signal pathway could repress cardiac fibrosis in diabetic rats, and partly improve cardiac remodeling and function by down-regulating activity of RAS at the receptor level. PMID- 21793337 TI - Impact factor of the Chinese Journal of Physiology in 2009: meet the readers. PMID- 21793339 TI - Aging effects on the BDNF mRNA and TrkB mRNA expression of the hippocampus in different durations of stress. AB - Brain-derived neurotrophins factor (BDNF) belongs to the neurotrophins family which acts on neuronal survival and growth and has been associated with cognition process. TrkB is the primary signal transduction receptor for BDNF. In the present study, hippocampal BDNF and TrkB mRNA were detected by RT-PCR in 2- and 22-month rats, respectively, which were exposed to different durations of mild stress protocol of 8-day, 21-day and 28-day chronic unpredictable mild stress (CUMS). Observation of exploratory behavior in an open field (OF) test indicated stress levels and changes of spontaneous activity. We demonstrated that CUMS induced decrease of BDNF mRNA in two aged groups, but the increase change of TrkB mRNA compared with those of the control groups. Moreover, the changes of BDNF mRNA and TrkB mRNA measured in both the 21-day and 28-day stress groups represent obvious decrease than those of the 8-day stress groups, and the expression examined in young groups appeared to be higher than those of the aged group, especially in the 28-day stress groups. Results of OF test showed that explicit behaviors in two age groups decreased gradually with the process of stress revealing a depressive state under the stress condition. Meanwhile, the behaviors of young rats seemed to be more active than those of the aged rats, exhibiting weak adaptation to the stress. The study suggested that stress paradigm and aging certainly had effect on the regulation of BDNF mRNA and TrkB mRNA which might be related to damage and protection function of the hippocampus. PMID- 21793338 TI - Action potential bursts in central snail neurons elicited by procaine: roles of ionic currents. AB - The role of ionic currents on procaine-elicited action potential bursts was studied in an identifiable RP1 neuron of the African snail, Achatina fulica Ferussac, using the two-electrode voltage clamp method. The RP1 neuron generated spontaneous action potentials and bath application of procaine at 10 mM reversibly elicited action potential bursts in a concentration-dependent manner. Voltage clamp studies revealed that procaine at 10 mM decreased [1] the Ca2+ current, [2] the Na+ current, [3] the delayed rectifying K+ current I(KD), and [4] the fast-inactivating K+ current (I(A)). Action potential bursts were not elicited by 4-aminopyridine (4-AP), an inhibitor of I(A), whereas they were seen after application of tetraethylammonium chloride (TEA), a blocker of the I(K)(Ca) and I(KD) currents, and tacrine, an inhibitor of I(KD). Pretreatment with U73122, a phospholipase C inhibitor, blocked the action potential bursts elicited by procaine. U73122 did not affect the I(KD) of the RP1 neuron; however, U73122 decreased the inhibitory effect of procaine on the I(KD). Tacrine decreased the TEA-sensitive I(KD) of RP1 neuron but did not significantly affect the I(A). Tacrine also successfully induced action potential bursts in the RP1 neuron. It is concluded that the inhibition on the I(KD) is responsible for the generation of action potential bursts in the central snail RP1 neuron. Further, phospholipase C activity is involved in the procaine-elicited I(KD) inhibition and action potential bursts. PMID- 21793340 TI - Effect of hyperglycemia on the changes of intracellular [Ca2+]i in heart myoblast. AB - A rise in cytosolic free Ca2+ is the immediate trigger for contraction in heart muscle. In the present study, we investigated changes of intracellular Ca2+ increased by potassium chloride (KCl) and phenylephrine (PE) under hyperglycemia in rat heart myoblast H9c2 cells (BCRC 60096), respectively. We employed the fluorescent Ca2+-indicator, fura-2, and digital imaging microscopy to measure [Ca2+]i in H9c2 cells. Cells were cultured in hyperglycemic (30 mM glucose) Dulbecco's Modified Eagle's Medium. The variation of [Ca2+]i induced by KCI and PE in hyperglycemia was examined, respectively. Moreover, tiron, one of the antioxidants, was pretreated in hyperglycemia-treated H9c2 cells to measure the role of free radicals in the changes of intracellular [Ca2+]i. An influx in intracellular Ca2+ induced by KCl or PE was observed in a dose-dependent manner and reached the highest concentration of 434 +/- 42.3 nM and 443 +/- 42.8 nM (n = 24 cells), respectively. Moreover, this increase of intracellular [Ca2+]i induced by KCl or PE was markedly reduced in cells exposed to hyperglycemia (434 +/- 42.3 vs. 1.26 +/- 0.21 nM and 443 +/- 42.8 vs. 2.54 +/- 0.25 nM, n = 24 cells, P < 0.001, respectively). Similar changes were not observed in cells received mannitol showing same osmolarity. However, the reduction of intracellular [Ca2+]i induced by hyperglycemia was abolished significantly in the presence of tiron. Our results suggest that an increase of intracellular Ca2+ by KCl or PE in heart cell was markedly reduced by hyperglycemic treatment; mediation of free radicals in this action can be considered because it was reversed in the presence of tiron. PMID- 21793341 TI - Role of ERK signaling in the neuroprotective efficacy of magnesium sulfate treatment during focal cerebral ischemia in the gerbil cortex. AB - Magnesium sulfate (MgSO4) ameliorates focal ischemia-induced neuronal death in the rat and gerbil models. However, the molecular mechanisms for this neuroprotection are not known. Focal cerebral ischemia was produced by unilateral occlusion of the right common carotid artery and the right middle cerebral artery (CCAO + MCAO) for 30 min or 60 min. Treatment with MgSO4 significantly increased the level of mitogen-activated protein kinase/extra-cellular signal-regulated kinase kinase 1/2 (MEK1/2), extra-cellular signal-regulated kinase 1/2 (ERK1/2), cyclic-AMP response element binding protein (CREB) phosphorylation and the anti apoptotic protein Bcl-2 both in the non-ischemic (contralateral) and ischemic (ipsilateral) cortex. However, these effects were reversed by administration of U0126, a MEK kinase inhibitor. In the ipsilateral cortex, a significant increase in the level of the proapoptotic proteins Bax, Bad, BNIP3 and activated caspase 3 were detected at the end of focal ischemia compared to the non-ischemic cortex. Treatment of MgSO4 prevented these ischemia-induced activations of the death cascade. Collectively, these data indicate that the ERK-CREB-Bcl-2 signaling pathway might be involved in MgSO4-induced neuroprotection following focal ischemia. Moreover, MgSO4 treatment also resulted in a reduction in pro-apoptotic proteins. These results enhance our understanding on the role of MgSO4 in treating cerebral ischemia. PMID- 21793342 TI - Antioxidant effects of melatonin and coenzyme Q10 on oxidative damage caused by single-dose ochratoxin A in rat kidney. AB - In the study, the effects of relatively high single-dose of Ochratoxin A (OTA) and the antioxidant effects of Melatonin (Mel) and Coenzyme Q10 (CoQ10) on OTA induced oxidative damages in rats were investigated. A total of 28 male Sprague Dawley rats were divided into four groups of 7 rats each: Control, OTA, Mel+OTA and CoQ10+OTA groups. Malondialdehyde (MDA) levels in the plasma and glutathione (GSH) levels in whole blood were measured; kidneys (for histological inspection and for apoptosis detection by TUNEL method) and bone marrow samples (for chromosome aberration and mitotic index) were taken. The rats in the OTA group showed limited degeneration of tubular cells. In some tubules karyomegaly, desquamated cells and vacuolization were observed by light microscopy. Mel and CoQ10 treatment significantly reduced the severity of the lesions. MDA levels of the OTA group were significantly higher than the control, OTA+Mel and OTA+CoQ10 groups, while GSH levels were significantly lower than the control, OTA+Mel and OTA+CoQ10 groups. Higher incidences of apoptotic bodies were observed in the kidneys of the OTA group although OTA administration did not significantly change the incidence of apoptotic bodies when compared to the control and antioxidant administrated groups. Although the percentage of the mitotic index was lowest in the OTA group, no statistical difference was found among the groups. Additionally, OTA had no numerical and structural significant effects on chromosomes. It was observed that single-dose OTA administration caused oxidative damages in rat kidney and Mel or CoQ10 treatment appeared to ameliorate the OTA induced tissue injuries. PMID- 21793343 TI - Behavioral and cross sensitization after repeated exposure to modafinil and apomorphine in rats. AB - Repeated exposure to psychostimulant drugs has been known to produce behavioral sensitization, a phenomenon explicitly indexed by locomotion (LM) and stereotyped movements (SM). So far, no evidence has demonstrated that this phenomenon can be displayed following the administration of modafinil (MOD) in animal study. We, therefore, assessed the possibility of behavioral sensitization of MOD and a direct dopamine agonist, apomorphine (APO), and cross-sensitization of these two drugs with one other. Pretreatment with MOD (64 mg/kg) or APO (0.5 mg/kg or 1.0 mg/kg) for 10 consecutive days was followed by a short-term (3 days) or long-term (21 days) withdrawal. Rats were then challenged with the drug and reciprocally re challenged with the counterpart drug. The results showed that following short term and long-term washout periods, both MOD and APO successfully induced sensitization in LM and SM. There was no cross-sensitization; an even lesser magnitude in LM when MOD-sensitized rats were challenged with APO was observed. However, after both the short-term and long-term withdrawal periods, APO (1.0 mg/kg)-sensitized rats showed cross-sensitization in LM and SM to MOD (64 mg/kg) challenge. The magnitude of APO-MOD cross-sensitization was lesser than the behavioral sensitization induced by APO alone. Our results indicated behavioral sensitization could be induced in rats exposed to MOD. In addition, changes in dopaminergic receptor activities could be involved in cross-sensitization of APO to MOD but not vice versa. PMID- 21793344 TI - Increased expression of phospho-cofilin in CA1 and subiculum areas after theta burst stimulation of Schaffer collateral-commissural fibers in rat hippocampal slices. AB - Activity-dependent structural plasticity of dendritic spines of pyramidal neurons in the central neuron system has been proposed to be a cellular basis of learning and memory. Long-term potentiation (LTP) is accompanied by changes in synaptic morphology and structural remodeling of dendritic spines. However, there is considerable uncertainty as to the nature of the adjustment. The present study tested whether immunoreactive phospho-cofilin, an index of altered actin filament assembly, could be increased by theta-burst stimulations (TBS), which is an effective stimulation pattern for inducing LTP in the hippocampus. The slope of fEPSPs evoked by TBS to Schaffer collateral-commissural fibers in hippocampal slices was measured, and p-cofilin expression was examined using immunofluorescence techniques. Results indicated that saturated L-LTP was produced by multiple TBS episodes to Schaffer collateral-commissural fibers in the hippocampal CA1 area, and TBSs also increased immunoreactive p-cofilin expression in the stratum radiatum of the hippocampal CA1 area and pyramidal layer of the subiculum. D-2-amino-5-phosphonovalerate (D-APV) prevented LTP and expression of p-cofilin immunoreactive induced by multiple TBS episodes in the stratum radiatum of the hippocampal CA1 area. Two paired-pulse low-frequency stimulation (PP-LFS) episodes to Schaffer collateral-commissural fibers induced long-term depression (LTD), and did not affect p-cofilin expression in the stratum radiatum of the hippocampal CA1 area. These results suggest that LTP induction is associated with altered actin filament assembly. Moreover, the CA1 and subiculum areas of the hippocampal formation possibly cooperate with each other in important physiological functions, such as learning and memory, or in pathological diseases, such as epilepsy. PMID- 21793345 TI - Effects of insulin-like growth factor 1 on muscle atrophy and motor function in rats with brain ischemia. AB - Although insulin-like growth factor 1 (IGF 1) has been used in immobilizated muscles to prevent muscle atrophy, its effects on muscle atrophy after brain ischemia are not known. This study aimed to determine the effects of IGF 1 on preventing muscle atrophy in rats with brain ischemia. Middle cerebral artery occlusion (MCAO) was used to induce the brain ischemia. In the first part of the study, rats were assigned to sham control, ischemic control, and ischemia with different dosages of IGF 1 injection groups to determine the optimal dosage of IGF 1 on preventing muscle atrophy after brain ischemia. In the second part of the study, rats were assigned to sham control, ischemic control, ischemia with IGF 1, or with IGF 1 receptor inhibitor (AG1024) injection groups to determine the specificity of IGF 1 on preventing muscle atrophy after brain ischemia. IGF 1 or AG1024 was injected locally to calf muscles and anterior tibialis (TA) starting from one day after brain ischemia and injections were carried out every other day for 4 times. Muscle weight and myosin heavy chain (MHC) expression in both red (red gastrocnemius and soleus) and white (white gastrocnemius and TA) muscles were significantly decreased after brain ischemia. With at least moderate dosage (200 ng/100 microl PBS) IGF 1 injection, the muscle weight and MHC protein could be restored in both red and white muscles resulting in better motor performance. However, the high-dose injection of IGF 1 (400 ng/100 microl PBS) did not result in further effects. IGF 1 increased the expression of p-Akt, but such effects were prevented by AG1024 resulting in muscle atrophy and poor motor function. In conclusion, peripheral application of IGF 1 not only prevented muscle atrophy but also enhanced motor function in rats with brain ischemia. The IGF 1-induced PI3K/Akt pathways are important for preventing muscle atrophy induced by brain ischemia. PMID- 21793346 TI - Neurolinguistic findings on the language lexicon: the special role of proper names. AB - Cognitive linguistics proposes the existence of a human language lexicon as a necessary subsystem of language production and comprehension. While the inner structure of the lexicon remains speculative, measures of its function may distinguish separate processing paths for different types of lexical entries. Based upon the presented findings on nomina from reaction time measurements, event-related potentials (ERP) analysis, and functional magnetic resonance imaging (fMRI), the special role of proper names in language--in contrast to common nouns--appears to be grounded in a neurocognitive reality. PMID- 21793347 TI - Messages in spike timing-dependent plasticity: pros and cons. AB - Spike-timing dependent plasticity (STDP), a synaptic modification depending on a relative timing of presynaptic and postsynaptic spikes, has fascinated researchers in the fields of neurophysiology and computational neuroscience, because it is not only conceptually simple or biologically reasonable but is also versatile in neural network simulations. The STDP rule may be valid only under specific conditions, however. We propose herein a method that could find more natural and potent rules of synaptic plasticity. PMID- 21793348 TI - Odour transduction in olfactory receptor neurons. AB - The molecular mechanisms that control the binding of odorant to olfactory receptors and transduce this signal into membrane depolarization are reviewed. They are compared in vertebrates and insects for interspecific (allelochemicals) and intraspecific (pheromones) olfactory signals. Attempts to develop quantitative models of these multistage signalling networks are presented. Computational analysis of olfactory transduction is still in its infancy and appears as a promising area for future developments. PMID- 21793349 TI - The copula approach to characterizing dependence structure in neural populations. AB - The question as to the role that correlated activity plays in the coding of information in the brain continues to be one of the most important in neuroscience. One approach to understanding this role is to formally model the ensemble responses as multivariate probability distributions. We have previously introduced alternatives to linear assumptions of multivariate Gaussian dependence for spike timing in neural ensembles using the probabilistic copula approach. In probability theory the copula "couples" marginal distributions to form flexible multivariate distribution functions for characterizing ensemble behavior. The parametric copula can be factored out of the joint probability density, and as such is independent and isolated from the marginal densities. This greatly simplifies the analysis, and allows a direct examination of the shape of the dependence independent of the marginals. The shape of the copula function goes beyond describing the dependence with a single summarizing statistic. In this review, we illustrate the construction of the copula, and how it contributes to the analysis of information conveyed by populations of neurons. PMID- 21793350 TI - Functional interactions in hierarchically organized neural networks studied with spatiotemporal firing patterns and phase-coupling frequencies. AB - A scalable hardware/software hybrid module--called Ubidule--endowed with bio inspired ontogenetic and epigenetic features is configured to run a neural networks simulation with developmental and evolvable capabilities. We simulated the activity of hierarchically organized spiking neural networks characterized by an initial developmental phase featuring cell death followed by spike timing dependent synaptic plasticity in presence of background noise. An upstream 'sensory' network received a spatiotemporally organized external input and downstream networks were activated only via the upstream network. Precise firing sequences, formed by recurrent patterns of spikes intervals above chance levels, were observed in all recording conditions, thus suggesting the build-up of a connectivity able to sustain temporal information processing. The activity of a Ubinet--a network of Ubidules--is analyzed by means of virtual electrodes that recorded neural signals similar to EEG. The analysis of these signals was compared with a small set of human recordings and revealed common patterns of shift in quadratic phase coupling. The results suggest some interpretations of changes and plasticity of functional interactions between cortical areas driven by external stimuli and by learning/cognitive PMID- 21793351 TI - Leaky integrate and fire models coupled through copulas: association properties of the interspike intervals. AB - We propose a model able to describe the Interspike Intervals of two or more neurons subject to common inputs from the network. The single neuron dynamic is described through a classical Leaky Integrate and Fire model, but the model also catches the joint behavior of two neurons resorting to the use of copulas. Copulas are mathematical objects largely used to describe dependencies laws. Synchronous and delayed dependencies are considered by means of a set of examples. Results are discussed making use of crosscorrelograms. PMID- 21793352 TI - A hierarchical classification of first-order recurrent neural networks. AB - We provide a decidable hierarchical classification of first-order recurrent neural networks made up of McCulloch and Pitts cells. This classification is achieved by proving an equivalence result between such neural networks and deterministic Buuchi automata, and then translating the Wadge classification theory from the abstract machine to the neural network context. The obtained hierarchy of neural networks is proved to have width 2 and height omega + 1, and a decidability procedure of this hierarchy is provided. Notably, this classification is shown to be intimately related to the attractive properties of the considered networks. PMID- 21793353 TI - Accuracy in estimating motor commands using neuronal population coding. AB - We consider the problem of estimating motor commands from an ensemble of neuronal activities. The population vector algorithm proposed by Georgopoulos provides largely biased estimations when preferred directions of neurons are non-uniformly distributed. To improve this, various decoding methods have been proposed. However, dependence of decoding accuracy on the motor command and other features of neural activities, such as baseline firing rates or amplitudes of tuning curves, have not been quantitatively discussed. In this study, we propose a new method to estimate the motor command in the maximum likelihood estimation framework, which is analytically tractable. We find that the estimation accuracy is independent of the motor command. Using our estimation method, we can estimate the motor command with equal accuracy in all directions. PMID- 21793354 TI - Effects of transient receptor potential-like current on the firing pattern of action potentials in the Hodgkin-Huxley neuron during exposure to sinusoidal external voltage. AB - Transient receptor potential vanilloid-1 (TRPV1) channels play a role in several inflammatory and nociceptive processes. Previous work showed that magnetic electrical field-induced antinociceptive [corrected] action is mediated by activation of capsaicin-sensitive sensory afferents. In this study, a modified Hodgkin-Huxley model, in which TRP-like current (ITRP) was incorporated, was implemented to predict the firing behavior of action potentials (APs), as the model neuron was exposed to sinusoidal changes in externally-applied voltage. When model neuron is exposed to low-frequency sinusoidal voltage, increased maximal conductance of ITRP can enhance repetitive bursts of APs accompanied by a shortening of inter-spike interval (ISI) in AP firing. The change in ISIs with number of interval is periodic with the phase-locking. In addition, increased maximal conductance of ITRP can abolish chaotic pattern of AP firing in model neuron during exposure to high-frequency voltage. The ISI pattern is converted from irregular to constant, as maximal conductance of ITRP is increased under such high-frequency voltage. Our simulation results suggest that modulation of TRP-like channels functionally expressed in small-diameter peripheral sensory neurons should be an important mechanism through which it can contribute to the firing pattern of APs. PMID- 21793355 TI - Fine frequency-modulation trigger features of midbrain auditory neurons extracted by the progressive thresholding method--a preliminary study. AB - Spectro-temporal receptive fields (STRFs) are commonly used to characterize response properties of central auditory neurons and for visualizing 'trigger features'. However, trigger features in STRF maps typically have a blurry appearance. Therefore it is unclear what details could be embedded in them. To investigate this, we developed a new method called 'progressive thresholding' to resolve fine structures in the STRFs, and applied the method to FM responses recorded from single units at the auditory midbrain of anesthetized rats. Random FM tones of a narrow frequency range (approximately 0.5 octave) were first presented to evoked spike responses at the cell's best frequency. Perispike modulating time waveforms collected (50 msec long, n = 1500 to 4000 tracings) were used to generate STRF based on spike-triggered-averaging. After supra threshold areas of pixel counts had been determined through a step of progressive thresholding in the map, those peri-spike modulating waveforms passing through each area were dejittered systematically. At what seemed to be an optimal threshold, multiple trigger features (up to a maximum of 4 fine bands) were extracted from the initially simple-looking STRF. Results show that fine FM trigger features are present in STRFs and that they can be resolved with the present method of analysis. PMID- 21793356 TI - Stochastic model shows how cochlear implants process azimuth in real auditory space. AB - Interaural time difference (ITD) is a major cue for sound azimuth localization at lower sound frequencies. We review two theories of how the sound localization neural circuit works. One of them proposes labeling of sound direction in the array of delay lines by maximal response of the tuning curve (Jeffress model). The other proposes detection of the direction by calculating the maximum slope of tuning curves. We formulate a simple hypothesis from this that stochastic neural response infers sound direction from this maximum slope, which supports the second theory. We calculate the output spike time density used in the readout of sound direction analytically. We show that the numerical implementation of the model yields results similar to those observed in experiments in mammals. We then go one step further and show that our model also gives similar results when a detailed implementation of the cochlear implant processor and simulation of implant to auditory nerve transduction are used, instead of the simplified model of auditory nerve input. Our results are useful in explaining some recent puzzling observations on the binaural cochlear implantees. PMID- 21793357 TI - Spiking neural networks with different reinforcement learning (RL) schemes in a multiagent setting. AB - This paper investigates the effectiveness of spiking agents when trained with reinforcement learning (RL) in a challenging multiagent task. In particular, it explores learning through reward-modulated spike-timing dependent plasticity (STDP) and compares it to reinforcement of stochastic synaptic transmission in the general-sum game of the Iterated Prisoner's Dilemma (IPD). More specifically, a computational model is developed where we implement two spiking neural networks as two "selfish" agents learning simultaneously but independently, competing in the IPD game. The purpose of our system (or collective) is to maximise its accumulated reward in the presence of reward-driven competing agents within the collective. This can only be achieved when the agents engage in a behaviour of mutual cooperation during the IPD. Previously, we successfully applied reinforcement of stochastic synaptic transmission to the IPD game. The current study utilises reward-modulated STDP with eligibility trace and results show that the system managed to exhibit the desired behaviour by establishing mutual cooperation between the agents. It is noted that the cooperative outcome was attained after a relatively short learning period which enhanced the accumulation of reward by the system. As in our previous implementation, the successful application of the learning algorithm to the IPD becomes possible only after we extended it with additional global reinforcement signals in order to enhance competition at the neuronal level. Moreover it is also shown that learning is enhanced (as indicated by an increased IPD cooperative outcome) through: (i) strong memory for each agent (regulated by a high eligibility trace time constant) and (ii) firing irregularity produced by equipping the agents' LIF neurons with a partial somatic reset mechanism. PMID- 21793358 TI - Neuronal jitter: can we measure the spike timing dispersion differently? AB - We propose a novel measure of statistical dispersion of a positive continuous random variable: the entropy-based dispersion (ED). We discuss the properties of ED and contrast them with the widely employed standard deviation (SD) measure. We show that the properties of SD and ED are different: while SD is a second moment characteristics measuring the dispersion relative to the mean value, ED measures an effective spread of the probability distribution and is more closely related to the notion of randomness of spiking activity. We apply both SD and ED to analyze the temporal precision of neuronal spiking activity of the perfect integrate-and-fire model, which is a plausible neural model under the assumption of high input synaptic activity. We show that SD and ED may give strikingly different results for some widely used models of presynaptic activity. PMID- 21793360 TI - [Motivation at work, a rupture?]. PMID- 21793359 TI - Responses of midbrain auditory neurons in rats to FM and AM tones presented simultaneously. AB - Speech and other communication signals contain components of frequency and amplitude modulations (FM, AM) that often occur together. Auditory midbrain (or inferior colliculus, IC) is an important center for coding time-varying features of sounds. It remains unclear how IC neurons respond when FM and AM stimuli are both presented. Here we studied IC neurons in the urethane-anesthetized rats when animals were simultaneously stimulated with FM and AM tones. Of 122 units that were sensitive to the dual stimuli, the responses could be grossly divided into two types: one that resembled the respective responses to FM or AM stimuli presented separately ("simple" sensitivity, 45% of units), and another that appeared markedly different from their respective responses to FM or AM tones ("complex" sensitivity, 55%). These types of combinational sensitivities were further correlated with individual cell's frequency tuning pattern (response area) and with their common response pattern to FM and AM sounds. Results suggested that such combinational sensitivity could reflect local synaptic interactions on IC neurons and that the neural mechanisms could underlie more developed sensitivities to acoustic combinations found at the auditory cortex. PMID- 21793361 TI - [New professions in the world of health?]. PMID- 21793362 TI - [Indications of advances in psychiatry]. PMID- 21793363 TI - [Autonomy of the aged patient with Alzheimer disease]. PMID- 21793364 TI - [Severe depression in the adolescent relapses in half the cases]. PMID- 21793365 TI - [Better adapting nursing care to the homeless]. PMID- 21793366 TI - [Destigmatizing psychiatry. Implementing a campaign]. PMID- 21793367 TI - [Fighting against stigmatisation: a major stake for mental health care]. AB - The way in which society considers people who have been identified as psychiatric patients is part of the professional's work in mental health care. It is an essential problem in the everyday life of carers and patients. Different strategies exist which enable to combat stigmatisation and discriminations. PMID- 21793368 TI - [Stigmatisation and destigmatisation in segregation]. AB - Psychoanalysis sheds fundamental light on the problems of stigmatisation and destigmatisation. Jacques Lacan's works, in particular, calls upon segregation as a reference. This "protective segregation" enables the preservation of patient's singularity and otherness. PMID- 21793369 TI - [The way out of discrimination: a process of social change]. AB - When dealing with stigmatisation, it is necessary to work on destigmatisation. The group as a community has social values of which "stigma" is an indicator. Psychiatry professionals have a major role to play in the process of destigmatisation. PMID- 21793370 TI - [Imprisonment, stigmatisation and society]. AB - Philosophic reflection suggests that every human being is different and that the difference is apparent in the light of other people. Thinking about the destigmatisation of psychically disabled persons requires understanding that identity is not an objective reality. Self-esteem, mirror, difference or resemblance, so many terms which remind us that we are imperfect.... PMID- 21793371 TI - [Stigmatisation and mental illness: medical workers, politics and journalists]. AB - Stigmatisation of mental health patients results from our social representations. The destigmatisation for which medical workers aim towards falls within the political sphere of psychiatry. The other actors, journalists and politicians, also have an important role to play. They can strengthen stigmatisation when their personal interests go before their professional missions. PMID- 21793373 TI - [Selected bibliography]. PMID- 21793372 TI - [The challenge of talking about mental illness]. AB - The National Union of friends and families of psychic patients (Unafam) helps families in everyday life when one of its members suffers from psychological disorders. Actions are centred on meetings which help to combat patient stigmatisation and encourage their social, family and professional reintegration. PMID- 21793374 TI - [New inter-activity cooperation providing an improved healthcare offer]. AB - The Authorities aim to establish new cooperation between the various healthcare activities. This recommendation can be practically applied in the field of primary care within the psychiatric and addiction treatment sectors. This development involves implementing advanced nursing practices. PMID- 21793375 TI - [Harassment in the workplace: clinic and psychopathological factors]. AB - Harassment may be either moral, physical or sexual. It is defined as a phenomenon that happens repeatedly. It is underestimated in professional environments and probably even more so in private life. Without referring to a pathological personality, harassers have common pathological traits. PMID- 21793376 TI - [A young girl with an inconsistent identity]. AB - Lola experiences herself as "too beautiful" and attemps to invest a body that she ignores, the meaning of which she gauges only through the adornment. In her quest of men that might teach her being as a woman, this teenager ends up loosing herself. Lola acts "as if" in placing herself in the posture of object of the mother or object of men. PMID- 21793377 TI - [A journey in the universe of psychiatry]. AB - The career development of a nurse in psychiatry from 1968 up until 2004 conveys the evolutions in asylum, care and therapeutics. Working as a nurse in a home for children enables us to see the actual roots of this profession. PMID- 21793378 TI - [Effect of plasma of healthy subjects undergoing moxibustion on ethanol-injured human gastric epithelial GES-1 cells in vitro and the involved mitochondrial apoptosis pathway]. AB - OBJECTIVE: To observe the effect of plasma derived from healthy volunteers undergoing moxibustion (moxibustion plasma) on alchol-injured human gastric epithelial GES-1 cells in vitro, and expression of heat shock protein 70 (HSP 70, cell apoptosis inhibitory protein), apoptosis inducing factor (AIF), Smac (a mitochondrial protein), and Caspase 3 and Caspase 9 (the latter 3 proteins are also involved in cell apoptosis) in order to study its mechanisms underlying protecting gastric mucous membrane. METHODS: Twenty-four healthy volunteer subjects (half men and half women) were randomized into acupoint-moximustion (A M) [Zhongwan(CV 12), Guanyuan (CV 4) and Zusanli (ST 36)] group and non-acupoint moxibustion (NA-M, 3 cun right to CV 12 and CV 4.1 cun medial to ST 36 ) group (n = 12/group). Moxibustion was applied to the above-mentioned 3 acupoints and non acupoints for 30 min, once daily for 10 days. Venous blood of the subjects was collected before and after moxibustion. The cultured GES-1 cells were divided into: control group. ethanol-injury group (model), A-M plasma group (A-M-P, plasma got from volunteers undergoing A-M), and NA-M plasma group (NA-M-P,plasma got from volunteers accepting NA-M). The GES-1 cells of the latter 3 groups were treated with 8% ethanol for duplicating cell injury model. Apoptosis was detected by flowcytometry. Expression of HSP 70, second mitochondria-derived activator of Caspase (Smac) and AIF proteins of GES-1 cells were assayed by western blotting, and the immunoactivity of cysteinyl aspirate-specific proteinase-3 and 9 (Caspase 3, 9) was detected by immunocytochemistry. RESULTS: In comparison with the control group, the apoptosis rate, the expression of HSP 70, Smac and AIF proteins, and the immunoactivity of Caspase-3 and Caspase-9 of the model group were increased significantly (P < 0.01). Compared with the model group, the apoptosis rate of GES-1 cells, the expression of Smac and AIF proteins, and the immunoactivity of Caspase-3 and Caspase-9 in the A-M-P group, the apoptosis rate, the expression of Smac and the immunoactivity of Caspase-3 and Caspase-9 in the NA-M-P group were all down-regulated considerably (P < 0.05, P < 0.01). In comparison with the model group, HSP 70 expression of the A-M-P group was up regulated significantly (P < 0.01). The apoptosis rate of GES-1 cells, the expression levels of Smac, AIF, Caspase-3 and Caspase-9 were significantly lower in the A-M-P group than in the NA-M-P group (P < 0.05, P < 0.01), while the expression of HSP 70 was apparently higher in the A-M-P group than in the NA-M-P group (P < 0.01). CONCLUSION: Plasma derived from the subjects undergoing moxibustion of Zusanli (ST 36), Zhongwan (CV 12) and Guanyuan (CV 4) can inhibit apoptosis of GES-1 cells in vitro, which is closely related to its effects in up regulating intracellular HSP 70 expression and down-regulating mitochondrial apoptosis protein expression of AIF. Smac, Caspase-3 and Caspase-9. PMID- 21793379 TI - [Influence of electroacupuncture plus intragastric administration of extract of hypericum perforatum L on ethology and brain microcirculation in depression rats]. AB - OBJECTIVE: To observe the effect of combined administration of intragastric perfusion of extract of Hypericum Perforatum L (HP-L) and electroacupuncture (EA) of "Baihui" (GV 20) and "Yamen" (GV 15) on behavior and brain microcirculation in depression rats. METHODS: Female SD rats were randomized into control, model, lower-dose of HP-L (lower-dose in short, 10 mg/kg), lower-dose+ EA, higher-dose (20 mg/kg) and higher-dose+ EA groups (n = 10/group). Depression model was established by lonely raising and chronic unpredictable mild stress (tail cramping, water-deprivation, fasting, electrical shock stimulation, etc. ) for 21 days. EA (2 Hz, 1 mA) was applied to "Baihui"(GV 20) and "Yamen"(GV 15) for 20 min, once daily for 14 days. Changes of ethology including glucose-consumption during 1 h, crossing and rearing scores of open-field test during 3 min (for assessing the rats' locomoto)and laser Doppler flowmetry values of cortical regional cerebral bloodflow (r CBF) were detected, and Morris water maze test (for assessing the rats' learning-memory ability) was conducted. RESULTS: In comparison with the control group, the sucrose consumption, crossing and rearing scores of open-field test, the average swimming velocity (ASV). the ratios of path length and swimming duration near the hidden-platform and the path length and swimming duration far from the platform of Morris water maze test during 70 seconds, and the cortical r CBF value in the model group were decreased significantly (P < 0.01), while the total swimming distance and escape latency in the model group increased apparently (P < 0.01). Compared to the model group, the average sucrose consumption, crossing and rearing scores of open-field test, the ASV, and the ratios of path length and swimming duration near the platform and those far from the platform in the lower-dose. lower-dose + EA, higher-dose and higher-dose + EA groups, and the cortical r CBF in the lower-dose + EA and higher dose + EA groups were increased considerably (P < 0.05, P < 0.01). The total swimming distances and escape latencies of lower-dose, lower-dose + EA, higher dose and higher-dose + EA groups were significantly shortened in comparison with the model group (P < 0.05, P < 0.01). The sucrose consumption and crossing score were significantly higher in the higher-dose + EA group than the lower-dose group (P < 0.05). The escape latency was significantly shorter in the higher-dose + EA group than in the lower-dose group (P < 0.05). No significant differences were found among the lower-dose, lower-dose + EA and higher-dose groups the sucrose consumption, crossing score and escape latency: among the lower-dose, lower-dose + EA, higher-dose and higher-dose + EA groups in the rearing score and ASV; among the lower-dose, higher-dose and model groups in the cortical r CBF (P > 0.05). CONCLUSION: EA can enhance the effect of extract of HP-L in increasing sucrose consumption, crossing score and cerebral blood flow, and in shortening escape latency in depression rats, which may contribute to their effect in improving depression. But HP-L itself has no effect on cortical microcirculation. PMID- 21793380 TI - [Effect of electroacupuncture at "Tianshu"(ST 25) on colonic smooth muscle structure and interstitial cells of cajal in slow transit constipation rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Tianshu" (ST 25) on colonic smooth muscle structure and interstitial cells of Cajal (ICC) in slow transit constipation (STC) rats, so as to investigate its mechanism underlying improving STC. METHODS: Wistar rats (n = 56) were randomly allocated to control (n = 20), model and EA groups (n = 18/ group). STC model was established by feeding the rats with forage containing compound Diphenoxylate. EA (0.8 - 1.3 mA, 2 Hz/15 Hz) was applied to bilateral "Tianshu" (ST 25) for 15 min, once daily for 14 days. The treatment was given beginning from the next day on after the rat's first black stool excretion was found. The colonic smooth muscle structure was observed under microscope after sectioning and HE staining. The immunoactivity (average optical density, OD) of intestinal immuno-reaction (IR) po-sitive ICC product was detected by immunohistochemistry. RESULTS: (1) Microscopic observation displayed that after modeling, the rat's intestinal mucosa gland showed atrophy with reduction in the acinar number, being sparse in distribution; and the smooth muscle thickness was obviously thinner compared with the normal control group (P < 0.05). Whereas this situation of the colonic smooth muscle in the EA group was close to that of the normal control group. Compared with the model group, the thickness of the intestinal smooth muscle in the EA group was significantly bigger (P < 0.05). (2) Immunohistochemical results showed that the average OD values and number of IR-positive colonic ICC in the model group were obviously decreased in comparison with the normal control group (P < 0.05). Compared with the model group, the average OD values and the number of IR positive coIonic ICC in the EA group were upregulated considerably (P < 0.05). CONCLUSION: EA of bilateral "Tianshu"(ST 25) is able to improve STC-induced structural changes of the colonic smooth muscle, and upregulate expression of colonic ICC in STC rats, which may be responsible for its efficacy in improving STC. PMID- 21793381 TI - [Effect of acupuncture on gastrointestinal stem cell factor/kit system after colocolic anastomosis in rats]. AB - OBJECTIVE: To observe the effect of acupuncture on colonic stem cell factor (SCF) receptor tyrosine kinase (Kit, a transmembrane protein c-kit) system in colocolic anastomosis rats so as to explore its underlying mechanism in regulating intestinal motility after enteroenterostomy. METHODS: Thirty SD rats were randomized into control, model (colocolic anastomosis) and acupuncture groups (n = 10/group). Acupuncture was applied to bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and "Taichong" (LR 3), once a day for 3 days. The fecal-excretion time and the propulsive rate of the small intestine were measured. The immunoactivity of c kit immunoreaction positive products in the colon tissue 2 cm below the caecum was detected using immunohistochemistry and the expression of SCF mRNA detected using real time-polymerase chain reaction (RT-PCR) method. RESULTS: Following colocolic anastomosis, the intestinal propulsive rate in the model group was decreased considerably in comparison with the control group (P < 0.01). Compared with the model group, the first fecal-excretion time and the intestinal propulsive rate were improved significantly in the acupuncture group (P < 0.05). In comparison with the control group, the immunoactivity of c-kit and the expression of SCF mRNA in colon tissue were down-regulated obviously in the model group (P < 0.05, P < 0.01), while in comparison with the model group, the expression levels of c-kit and SCF mRNA were increased in the acupuncture group significantly (P < 0.05). CONCLUSION: Acupuncture can suppress enteroenterostomy induced down-regulation of the expression of c-kit protein and SCF mRNA in colocolic anastomosis rats, which may contribute to its effect in regulating the intestinal motility after enteroenterostomy. PMID- 21793382 TI - [Effect of acupuncture of different acupoints on immune function in rats with exhausted swimming]. AB - OBJECTIVE: To observe the effect of acupuncture of "Zusanli" (ST 36) on immune function in progressively exhausted swimming rats so as to reveal its mechanism underlying improvement of strenuous exercise. METHODS: Thirty-two SD rats were randomly allocated into control group, strenuous exercise (model) group, acupuncture-Xuehai (SP 10) group, Acupuncture-Zusanli (ST 36) group (n = 8/group). The rats were forced to have a swimming in a water tank for 15-90 min in the first 8 days (once daily), then, a progressively exhausted load swimming 1 - 3 times everyday from day 9 to 13. Bilateral SP 10 and ST 36 were punctured with filiform needles and stimulated with uniform reinforcing and reducing manipulation, once daily, after termination of the swimming and for 13 days. Serum interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) contents were assayed by using enzyme linked immunosorbent assay. The rat's body weight and the spleen weight were weighted by using an electronic balance for calculating the spleen index (spleen weight /body weight x 100%) after killing the rat under deep anesthesia. RESULTS: Compared with the model group, the time of swimming-induced exhaustion appearing at the first time from day 9 to day 13 in the SP 10 and ST 36 groups was apparently lengthened (P < 0.01). No significant difference was found between SP 10 and ST 36 groups in the time of swimming-induced exhaustion appearing at the first time of the forced swimming. Compared with the control group, the spleen index, serum IFN-gamma contents and IFN-gamma/IL-4 in the model group were decreased significantly (P < 0.01, P < 0.05). In comparison with the model group, the serum IL-4 contents in the SP 10 and ST 36 groups were decreased markedly (P < 0.05, P < 0.01), and serum IFN-gamma content and IFN-gamma/IL-4 in the ST 36 group were increased significantly (P < 0.05, P < 0.01). The IFN-gamma level was significantly higher in the ST 36 group than in the SP 10 group (P < 0.05). No significant differences were found between SP 10 and ST 36 groups in the spleen index, IL-4 and IFN-gamma/IL-4 (P > 0.05). CONCLUSION: Acupuncture at "Zusanli" (ST 36) can lengthen the time of forced swimming-induced exhaustion, and upregulate serum IFN-gamma content and IFN-gamma/IL-4 in exhausted swimming rats, which may contribute to its effect in correcting Th1/Th2 imbalance after strenuous exercise. The effect of acupuncture of ST 36 is superior to that of acupuncture of SP 10. PMID- 21793383 TI - [Effect of electroacupuncture of auricular concha on inflammatory reaction in endotoxaemia rats]. AB - OBJECTIVE: To evaluate the effect of electroacupuncture (EA) of the auricular concha (EA-AC) on serum cytokines contents and pulmonary transcription factor nuclear factor-kappaB (NF-kappaB) expression in lipopolysaccharide (LPS) induced endotoxaemia rats so as to study its mechanism underlying cholinergic anti inflammatory efficacy. METHODS: Male SD rats were randomized into normal control, model (LPS), simple EA-AC, EA-AC + LPS, vagal nerve stimulation (VNS) + LPS, and EA-Zusanli (ST 36) + LPS groups (n = 12/group). Endotoxaemia model was duplicated by intravenous (tail vein) injection of LPS (0.5 mL/kg). Two intradermal needles were inserted into the central sites of the cavity of concha and cymba of auricular concha respectively on each side and stimulated electrically by using an electrical stimulator (i.e, EA-AC). VNS was applied to the left cervical vagal nerve, and EA (1 mA, 10 Hz, pulse-width 1 ms) was also applied to bilateral "Zusanli" (ST 36). Serum cytokines (TNF-alpha IL-6) contents 2 h after modeling were determined by using enzyme linked immunosorbent assay (ELISA), and pulmonary NF-kappaB p 65 expression 2 h after modeling was detected by using western blotting. RESULTS: Compared with the normal control group, serum TNF-alpha and IL 6 contents, and pulmonary NF-kappaB p65 expression level in the model group were increased significantly (P < 0.01). In comparison with the model group, serum TNF alpha contents in the simple EA-AC, EA-AC + LPS, VNS+ LPS and ST 36 + LPS groups, and serum IL-6 contents and pulmonary NF-kappaB p 65 expression levels in the simple EA-AC, EA-AC + LPS and VNS + LPS groups were down-regulated considerably (P < 0.05, P < 0.01). Compared with the VNS + LPS group, serum TNF-alpha -28) and IL-6 contents, and pulmonary NF-kappaB p 65 expression level in the ST 36 + LPS group were increased significantly (P < 0.05, P < 0.01). In comparison with the EA-AC + LPS group, pulmonary NF-kappaB p 65 expression level in the ST 36 + creased remarkably (P < 0.05). CONCLUSION: Both EA of auricular concha and vagus nerve stimulation can serum TNF-alpha and IL-6 contents, and down-regulate pulmonary NF-kappaB p 65 expression level in endotoxaemia similar cholinergic anti-inflammatory mechanism between them. PMID- 21793384 TI - [Effects of scalp acupuncture on expression of hippocampal MMP-9 in cerebral ischemia injury rats]. AB - OBJECTIVE: To observe the effect of scalp-acupuncture on the expression of matrix metalloproteinase 9 (MMP-9) in the endothelium of the microvessels in the hippocampal CA 3 area in local cerebral ischemia (CI) rats, so as to study its underlying mechanism in improving CI. METHODS: Eighty male Wistar rats were randomized into normal control (n = 8), sham-operation (n = 8), CI model (n = 32), and scalp-acupuncture (n = 32) groups. The later two groups were further equally and respectively divided into 1, 3, 5 and 10 d subgroups. CI model was established by occlusion of the middle cerebral artery (MCAO). "Baihui" (GV 20) and "Qubin"(GB 7) were punctured with filiform needles and stimulated by twirling the needle at a frequency of about 200 revolutions/min for 1 min. The needles were retained for 30 min and re-manipulated once again every 10 min. The treatment was given once daily, continuously for 1, 3, 5 and 10 days respectively in different subgroups. MMP-9 immunoactivity of hippocampal CA 3 area was assayed by immunohistochemistry (SABC). RESULTS: Following CI, the CI rats' neural deficit scores in the model and scalp-acupuncture (treatment) groups had no apparent difference (P > 0.05). After acupuncture, the neural deficit score in the treatment group decreased gradually, and was significantly lower than that in the 10 d subgroup of model group (P < 0.05). Compared with the 1, 3, 5 and 10 d subgroups of control group, the total area and integral optical density (IOD) values of MMP-9 immunoactivity of hippocampal CA 3 area were all increased significantly in the corresponding 4 subgroups of model group (P < 0.01). Compared with the 3, 5 and 10 d subgroups of the model group, the total area and IOD values of MMP-9 immunoreaction positive products in the corresponding 3 subgroups of scalp-acupuncture group were decreased significantly (P < 0.05, P < 0.01). CONCLUSION: Scalp-acupuncture can effectively down-regulate MMP-9 expression in the hippocampal CA 3 area in focal cerebral ischemia rats, which may contribute to its effect in improving the neural deficit. PMID- 21793385 TI - [Morphological study on commonly-used acupoints for thyroid surgery under acupuncture anesthesia]. AB - OBJECTIVE: To study the morphologic structure, afferent projections of "Neiguan" (PC6), "Hegu" (LI 4) and "Futu" (LI 18) acupoint regions so as to understand their underlying mechanisms in acupuncture anesthesia for thyroid surgery. METHODS: A total of 66 Wistar rats were used in the present study. (1) Horseradish peroxidase (HRP, 10%, 10 microL) was injected into PC 6, LI 4 and LI 18 acupoints and the thyroid area on the right side, respectively (n = 6). (2) Propidium iodide (PI, 10% 10 microL) or Bisbenzimide (Bb, 5%, 10 microL) was injected into above-mentioned 3 acupoints and the thyroid region on the right side, respectively (n = 6). The numbers and percentages of the labeled neurons in the dorsal root ganglia (DRGs, C 1 - C 8 and T 1) were observed under microscope. (3) Cutaneous connexin (Cx) 43 immunoactivity of LI 18, PC 6, LI 4 and "Zusanli" (ST 36) regions and their individual non-acupoint regions (about 0.5 cm lateral to LI 18, PC 6, LI 4, and ST 36, n = 12) was determined by immunohistochemistry. RESULTS: 1) HRP-labeled neurons after injection of HRP into LI 18 were found in DRGs of C 1 - C 5, predominantly C 2 - C 4, those from LI 4 found in DRGs of C 3 C 8. mainly C 5 - C 7, those from PC 6 found in DRGs of C 3 -T 1, chiefly C 5 - C 8, and those from the thyroid region found in C 1 - C 6, predominantly C 2 - C 5, suggesting an overlap or convergence of afferent projections from the 3 acupoints and the thyroid regions being in C 3 - C 5. 2) After injection of PI into LI 18, LI 4 and PC 6. and Bb into the thyroid region, the percentages of PI- and Bb-labelted neurons in DRGs of C 1 - C 8 and T 1 were from 46.4% to 50.0% and the percentages of the double labeled neurons were 3.8% in the LI 18-thyroid group, 3.1% in the LI 4-thyroid group and 3.6% in the PC 6-thyroid group, respectively, suggesting a bifurcate innervation of DRG neurons between theseacupoints and the thyroid region. 3) In comparison with the individual non acupuncture and non-acupoint subgroups, the immunoactivity of cutaneous Cx 43 in the LI 18, LI 4, PC 6, and ST 36 subgroups was upregulated considerably after acupuncture stimulation (P < 0.05). CONCLUSION: Neurons of DRGs of C 1-C 8 and T 1 innervating "Futu" (Ll 18), "Hegu" (LI 4) and "Neiguan" (PC 6) and the thyroid gland have an overlap or convergence in DRGs of C 3 - C 5 and a bifurcate innervation. Acupuncture stimulation may upregulate cutaneous Cx 43 expression in the acupoint regions. PMID- 21793386 TI - [Relatively specific effect of electroacupuncture of different acupoints on hypothalamic monoamine neurotransmitters in myocardial ischemia rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Shenmen" (HT 7), "Neiguan" (PC 6), etc. on monoamine neurotransmitter contents of hypothalamic paraventricular nucleus (PVN) region in myocardial ischemia (MI) rats, so as to analyze the substantial basis of efficacy specificity of acupoints in improving MI. METHODS: SD rats were randomized into normal control, model, EA-Shenmen (HT7), EA-Neiguan (PC 6) and EA-Taiyuan (LU 9) groups (n = 10/group). MI model was duplicated by occlusion of the anterior descending branch of the left coronary artery. EA (2 Hz, 1. 1 mA) was applied to left "Shenmen" (HT 7), "Neiguan" (PC 6) and "Taiyuan" (LU 9) for 10 min, once daily for 3 days. The hypothalamic PVN region tissue was collected for assaying the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) by using enzyme linked immunosorbent assay. RESULTS: In comparison with the normal control group, the contents of NE, DA and 5-HT in hypothalamic PVN in the model group were decreased significantly (P < 0.01). Compared with the model group, the contents of NE, DA and 5-HT in hypothalamic PVN in the EA-Neiguan (PC 6) and EA-Shenmen (HT 7) groups, and that of NE in the EA-Taiyuan (LU 9) group were increased significantly (P < 0.01, P < 0.05). The effects of EA-Neiguan (PC 6) and EA Shenmen (HT 7) were significantly superior to that of EA-Taiyuan (LU 9) in increasing the contents of hypothalamic NE, DA and 5-HT (P < 0.05, P < 0.01). CONCLUSION: Electroacupuncture of PC 6 and HT 7 can suppress MI-induced decrease of NE, DA and 5-HT contents in the hypothalamic PVN region in rats, which may contribute to its effect in resisting myocardial ischemia. The effects of EA-PC 6 and EA-HT 7 are superior to those of EA-LU 9. PMID- 21793387 TI - [Evaluation on efficacy of Jin's "Sanzhen" therapy combined with rehabilitation training for hemiplegia of stroke patients by Fugl-Meyer scale]. AB - OBJECTIVE: To assess the therapeutic effect of Jin's "Sanzhen" therapy combined with rehabilitation training on limb-motor function of stroke patients by using Fugl-Meyer scale. METHODS: A total of 254 hemiplegic stroke outpatients and inpatients from 7 hospitals were randomly divided into Jin's "Sanzhen" (JSZ) group (n = 83), rehabilitation group (n = 84) and combination group (n = 87). Acupuncture was applied to acupoints of Jin's "Sanzhen" including Quchi (LI 11), Waiguan (SJ 5) and Hegu (LI 4); Futu (ST 32). Zusanli (ST 36) and Sanyinjiao (SP 6); etc. The acupuncture needles were retained for 30 min after "Deqi". Rehabilitation training included passive joint movement, standing-sitting training, tapping-pressing stimulation, walking training, etc. The treatment was conducted once daily, 5 sessions a week and for 4 weeks. Fugl-Meyer scale composed of 100-point motor domain of the upper- and lower-extremity sections was used to assess the patients' motor function. RESULTS: On day 28 after the treatment, of the 83.84 and 87 hemiplegic stroke patients in the JSZ, rehabilitation and combination groups, 48 (57.8%), 31 (36.9%) and 50 (57.5%) experienced marked improvement in their clinical symptoms and signs, 26 (31.3%), 44 (52.4%) and 31(35.6%) had an improvement, and 9 (10.8%), 9 (10.7%) and 6 (6.9%) failed in the treatment, with the total effective rates being 89.2%, 89.3% and 93.1%, respectively. The neurological deficit score (NDS) of the combination group was significantly lower than that of the rehabilitation group (P < 0.05). The Fugl-Meyer assessment score (FMAS) for extremity motor function of the combination group was apparently higher than those of the JSZ and rehabilitation groups (P < 0.05). No significant differences were found between the JSZ and rehabilitation groups in both NDS and FMAS (P > 0.05). CONCLUSION: Jin's "Sanzhen" therapy combined with rehabilitation training can significantly improve the limb motor function of hemiplegic stroke patients, and has a good synergistic effect. PMID- 21793388 TI - [Randomized controlled clinical trials for acupuncture treatment of spastic cerebral palsy children by bilateral horizontal puncturing from Yuzhen (BL 9) to Tianzhu (BL 10)]. AB - OBJECTIVE: To observe the effect of acupuncture of the body surface projection region of the pyramidal decussationes on spastic cerebral palsy (CP) so as to explore an effective therapy for it. METHODS: A total of 120 CP infant patients were randomized into control group (treated with modern rehabilitation training, n = 60) and acupuncture group (treated with acupuncture combined with modern rehabilitation training, n = 60). Four acupuncture needles were penetrated subcutaneously through the region between Yuzhen (BL 9) and Tianzhu (BL 10)equidistantly (the superficial projection region of the pyramidal decussationes), once daily for 3 months. The modified Ashworth rating, gross motor function measure (GMFM)-88 scores and synthetic function scale were adopted to assess the therapeutic effect after the treatment. RESULTS: After the treatment, of the 59 and 58 CP children in the control and acupuncture groups, 17 (28.81%) and 26 (44.83%) experienced marked improvement in their symptoms, 33 (55.84%) and 27 (46.55%) had an improvement, 9 (15.25%) and 5 (8.62%) failed in the treatment, with the total effective rates being 84.75% and 91.38%, respectively. The effective rate of the acupuncture group was significantly superior to that of the control group (P < 0.05). The scores of modified Ashworth rating and GMFM-88 of the control group were significantly lower than those of the acupuncture group after the treatment (P < 0.05). CONCLUSION: Acupuncture combined with modern rehabilitation training is effective in the treatment of CP children patients. PMID- 21793389 TI - [Effects of different frequencies of electroacupuncture on blood glucose level in impaired glucose tolerance patients]. AB - OBJECTIVE: To Investigate the clinical efficacy of electroacupuncture (EA) at different frequencies for patients with impaired glucose tolerance (IGT). METHODS: A total of 120 IGT outpatients were randomly divided into control, EA-5 Hz, EA-50 Hz, and EA-100 Hz groups (n = 30/group). EA (1 mA) was applied to bilateral Pishu (BL 20), Shenshu (BL23), Zusanli (ST 36) and Sanyinjiao (SP6) for 20 min, once daily for 60 sessions. Body mass index (BMI), fasting blood glucose (FBG) and 2-hour post-prandial blood glucose (2 h PBG) contents were detected by using BAYER Blood Sugar Analyzer and glycosylated haemoglobin (HbA1c) content was detected by enzymatic assay. RESULTS: Following the treatment, both HbA1c and 2 h PBG levels in the EA-5 Hz group were significantly lower than those of the control group and those of pre-treatment in the same one group (P < 0.05, P < 0.01). No significant differences were found between the EA-5 Hz and control groups, between pre-treatment and post-treatment in the EA-5 Hz group in BMI and FBG levels; between the EA-50 Hz and control groups, between the EA-100 Hz and control groups, and between pre-treatment and post-treatment in the EA-50 Hz and EA-100 Hz groups in BMI, FBG,2 h PBG and HbA1c levels (P > 0.05). CONCLUSION: Lower frequency EA of BL 20, BL 23, ST 36 and SP 9 can reduce HbA1c and 2 h PBG levels in IGT patients, suggesting a helpful effect of EA in controlling the development of diabetes. PMID- 21793390 TI - [Considerations about study on mechanisms of acupuncture underlying efficacy enhancement and toxicity-attenuation of digitalis drugs for heart failure]. AB - Digitalis glycosides, a group of cardiotonic agents for heart failure, have been used for a long time, but may often trigger arrhythmias as a result of digitalis intoxication. It is of great significance in finding a method to reduce their toxicity and improve clinical curative effects simultaneously in the application of digitalis glycosides. It has been well documented that acupuncture has good therapeutic effects in improving cardiac function and inhibiting arrhythmia induced by myocardial ischemia. Acupuncture combined with chemotherapeutics can reduce the adverse effects of chemotherapeutics. Accordingly, acupuncture combined with digitalis is likely to reduce the side effects of digitalis by regulating intracellular Ca2+, improving the function of Ca(2+)-ATPase in the sarcoplasmic reticulum, increasing calcium sensitivity of cardiac troponin, etc. These considerations may provide a novel clue for treatment of heart failure by joint administration of acupuncture and drugs. PMID- 21793391 TI - [Survey on clinical evidence of acupuncture therapy for fibromyalgia syndrome]. AB - OBJECTIVE: To evaluate the clinical effect of acupuncture therapy for fibromyalgia syndrome (FMS) by analyzing the available studies so as to provide clinical decision-making reference. METHODS: The published papers on clinical trails for acupuncture treatment of FMS were widely retrieved from Chinese Biomedical Databases (1979 - 2010), www. cnki. net (1979-2010), VIP China Scientific Journal Database (1989- 2010), Digital Periodicals on Wanfang Data (1998 - 2010), PubMed (1966-2010), etc. and by using key words of fibromyalgia syndrome and acupuncture. According to criterion of evidence-based medicine, the evidence from high to low quality levels was selected to answer corresponding clinical questions, and software RevMan 5.0 was used to analyze the final results. RESULTS: There has been no enough clinical evidence showing definite efficacy of acupuncture for FMS. However, a Level-A study (being in line with conditions of large sample, multi-centers, randomized controlled trails) and a level-C study (having control group, but without distinct randomizing method) showed respectively that acupuncture might be superior to Amitriptyline and Brufen in relieving FMS. Moreover, a piece of evidence that acupuncture combined with western medicine was superior to western medicine alone was allocated to a level-B (having correct randomizing method and control group). Finally, only a level-C evidence proved that laser irradiation on acupoint might be superior to traditional acupuncture in improving FMS. CONCLUSION: Acupuncture for FMS has a positive effect, and acupuncture combined with western medicine can strengthen the curative effect. However this conclusion should be proved further by randomized controlled double blind clinical trials with large samples. PMID- 21793392 TI - Chemical cleaning of fouled PVC membrane during ultrafiltration of algal-rich water. AB - Cleaning of hollow-fibre polyvinyl chloride (PVC) membrane with different chemical reagents after ultrafiltration of algal-rich water was investigated. Among the tested cleaning reagents (NaOH, HCl, EDTA, and NaClO), 100 mg/L NaClO exhibited the best performance (88.4% +/- 1.1%) in removing the irreversible fouling resistance. This might be attributed to the fact that NaClO could eliminate almost all the major foulants such as carbohydrate-like and protein like materials on the membrane surface, as confirmed by Fourier transform infrared spectroscopy analysis. However, negligible irreversible resistance (1.5% +/- 1.0%) was obtained when the membrane was cleaning by 500 mg/L NaOH for 1.0 hr, although the NaOH solution could also desorb a portion of the major foulants from the fouled PVC membrane. Scanning electronic microscopy and atomic force microscopy analyses demonstrated that 500 mg/L NaOH could change the structure of the residual foulants on the membrane, making them more tightly attached to the membrane surface. This phenomenon might be responsible for the negligible membrane permeability restoration after NaOH cleaning. On the other hand, the microscopic analyses reflected that NaClO could effectively remove the foulants accumulated on the membrane surface. PMID- 21793393 TI - Effects of activated sludge flocs and pellets seeds on aerobic granule properties. AB - Aerobic granules seeded with activated sludge flocs and pellets (obtained from activated sludge flocs) were cultivated in two sequencing batch reactors and their characteristics were compared. Compared with granules seeded with activated sludge flocs, those seeded with pellets had shorter start-up time, larger diameter, better chemical oxygen demand removal efficiency, and higher hydrophobicity, suspended solid concentration, and Mg2+ content. The different inocula led the granule surface with different microbial morphologies, but did not result in different distribution patterns of extracellular polymeric substances and cells. The anaerobic bacterium Anoxybacillus sp. was detected in the granules seeded with pellets. These results highlighted the advantage of pellet over activated sludge floc as the seed for aerobic granulation and wastewater treatment. PMID- 21793394 TI - Destruction of methylphosphonic acid in a supercritical water oxidation bench scale double wall reactor. AB - The destruction of methylphosphonic acid (MPA), a final product by hydrolysis/neutralization of organophosphorus agents such as sarin and VX (O ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothionate), was investigated in a a bench-scale, continuous concentric vertical double wall reactor under supercritical water oxidation condition. The experiments were conducted at a temperature range of 450-600 degrees C and a fixed pressure of 25 MPa. Hydrogen peroxide was used as an oxidant. The destruction efficiency (DE) was monitored by analyzing total organic carbon (TOC) and MPA concentrations using ion chromatography on the liquid effluent samples. The results showed that the DE of MPA up to 99.999% was achieved at a reaction temperature of 600 degrees C, oxygen concentration of 113% storichiometric requirement, and reactor residence time of 8 sec. On the basis of the data derived from experiments, a global kinetic rate equation for the DE of MPA and DE of TOC were developed by nonlinear regression analysis. The model predictions agreed well with the experimental data. PMID- 21793395 TI - Petroleum hydrocarbons and their effects on fishery species in the Bohai Sea, North China. AB - Systematic studies on the changes in concentrations of petroleum hydrocarbons (PHs) and their effects on fishery species in the Bohai Sea during 1974-2004 are presented. Changes in PHs concentrations were closely related to Yellow River runoff. Concentrations of PHs accumulated in fish and shrimp increased by about 0.712 mg/kg dry weight when trophic level of fish and shrimps increased by 1. Attention should also be paid to the high PHs concentrations in mollusks along the coastal waters of the Bohai Sea. Average concentration of PHs in the adjacent coastal waters of Tianjin City during 1996-2005 decreased the population growth rates of fish, crustaceans and mollusks in the Bohai Sea by 2.58%, 6.59% and 2.33%, respectively. Therefore, PHs have significantly contributed to the decline in fisheries in the Bohai Sea, and they must be reduced to realize the sustainable fisheries. PMID- 21793396 TI - Coupling of zero valent iron and biobarriers for remediation of trichloroethylene in groundwater. AB - This study attempted to construct a three series barrier system to treat high concentrations of trichloroethylene (TCE; 500 mg/L) in synthetic groundwater. The system consisted of three reactive barriers using iron fillings as an iron-based barrier in the first column, sugarcane bagasse mixed with anaerobic sludge as an anaerobic barrier in the second column, and a biofilm coated on oxygen carbon inducer releasing material as an aerobic barrier in the third column. In order to evaluate the extent of removal of TCE and its metabolites in the aquifer down gradient of the barrier system, a fourth column filled with sand was applied. Residence time of the system was investigated by a bromide tracer test. The results showed that residence time in the column system of the control set and experimental set were 23.62 and 29.99 days, respectively. The efficiency of the three series barrier system in removing TCE was approximately 84% in which the removal efficiency of TCE by the iron filling barrier, anaerobic barrier and aerobic barrier were 42%, 16% and 25%, respectively, cis-Dichloroethylene (cis DCE), vinyl chloride (VC), ethylene and chloride ions were observed as metabolites following TCE degradation. The presence of chloride ions in the effluent from the column system indicated the degradation of TCE. However, cis DCE and VC were not fully degraded by the proposed barrier system which suggested that another remediation technology after the barrier treatment such as air sparging and adsorption by activated carbon should be conducted. PMID- 21793397 TI - Inhibition and recovery of nitrification in treating real coal gasification wastewater with moving bed biofilm reactor. AB - Moving bed biofilm reactor (MBBR) was used to treat real coal gasification wastewater. Nitrification of the MBBR was inhibited almost completely during start-up period. Sudden increase of influent total NH3 concentration was the main factor inducing nitrification inhibition. Increasing DO concentration in the bulk liquid (from 2 to 3 mg/L) had little effect on nitrification recovery. Nitrification of the MBBR recovered partially by the addition of nitrifying sludge into the reactor and almost ceased within 5 days. Nitrification ratio of the MBBR achieved 65% within 12 days by increasing dilute ratio of the influent wastewater with tap water. The ratio of nitrification decreased to 25% when influent COD concentration increased from 650 to 1000 mg/L after nitrification recovery and recovered 70% for another 4 days. PMID- 21793398 TI - Cyanobacteria-/cyanotoxin-contaminations and eutrophication status before Wuxi drinking water crisis in Lake Taihu, China. AB - After the appalling "Wuxi Drinking Water Crisis", increasing investigations concerning the contaminations of cyanobacterial blooms and their toxins in Lake Taihu have been performed and reported in the last two years. However, information regarding these issues before the crisis in 2007 remained insufficient. To provide some background data for further comparisons, the present study reported our investigations conducted in 2004, associated with the cyanotoxin contaminations as well as the eutrophication status in Lake Taihu. Results from the one-year-study near a drinking water resource for Wuxi City indicated that, unlike the status in recent two years, cyanobacteria and chlorophyta are the co-dominance species throughout the year. The highest toxin concentration (34.2 ng/mL) in water columns occurred in August. In bloom biomass, the peak value of intracellular toxin (0.59 microg/mg DW) was determined in October, which was lag behind that in water column. In addition, MC-RR was the major toxin variant throughout the year. During the study period, nutrients levels of total nitrogen and phosphorus were also recorded monthly. Results from the present study will lead to a better understanding of the eutrophication status and the potential risks before "Wuxi Drinking Water Crisis". PMID- 21793399 TI - Changes in different organic matter fractions during conventional treatment and advanced treatment. AB - XAD-8 resin isolation of organic matter in water was used to divide organic matter into the hydrophobic and hydrophilic fractions. A pilot plant was used to investigate the change in both fractions during conventional and advanced treatment processes. The treatment of hydrophobic organics (HPO), rather than hydrophilic organicas (HPI), should carry greater emphasis due to HPO's higher trihalomethane formation potential (THMFP) and haloacetic acid formation potential (HAAFP). The removal of hydrophobic matter and its transmission into hydrophilic matter reduced ultimate DBP yield during the disinfection process. The results showed that sand filtration, ozonation, and biological activated carbon (BAC) filtration had distinct influences on the removal of both organic fractions. Additionally, the combination of processes changed the organic fraction proportions present during treatment. The use of ozonation and BAC maximized organic matter removal efficiency, especially for the hydrophobic fraction. In sum, the combination of pre-ozonation, conventional treatment, and O3-BAC removed 48% of dissolved organic carbon (DOC), 60% of HPO, 30% of HPI, 63% of THMFP, and 85% of HAAFP. The use of conventional treatment and O3-BAC without pre-ozonation had a comparable performance, removing 51% of DOC, 56% of HPO, 45% of HPI, 61% of THMFP, and 72% of HAAFP. The effectiveness of this analysis method indicated that resin isolation and fractionation should be standardized as an applicable test to help assess water treatment process efficiency. PMID- 21793400 TI - Evaluation of reusing alum sludge for the coagulation of industrial wastewater containing mixed anionic surfactants. AB - A coagulation-flocculation process is typically employed to treat the industrial wastewater generated by the consumer products industry manufacturing detergents, soaps, and others. The expenditure of chemicals including coagulants and chemicals for pH adjustment is costly for treating this wastewater. The objective of this study was to evaluate the feasibility of reusing the aluminum sulfate (alum) sludge as a coagulant or as a coagulation aid so that the fresh alum dosage can be minimized or the removal efficiency can be enhanced. The experiments were conducted in a jar-test apparatus simulating the coagulation flocculation process for simultaneous removals of organic matters, anionic surfactants, suspended solids, and turbidity. At the optimum initial pH value of 10 and the fresh alum concentration of 400 mg/L, the total suspended solids (TSS), total chemical oxygen demand (TCOD), total anionic surfactants, and turbidity removal efficiencies were 71.5%, 76.4%, 95.4%, and 98.2%, respectively. The addition of alum sludge as a coagulant alone without any fresh alum addition could significantly remove the turbidity, TCOD, and anionic surfactants. The TSS was left in the supernatants after the settling period, but would subsequently be removed by adding the fresh alum. The TSS, TCOD, and turbidity removal efficiencies were also enhanced when both the alum sludge and the fresh alum were employed. The TCOD removal efficiency over 80% has been accomplished, which has never fulfilled by using the fresh alum alone. It is concluded that the alum sludge could be reused for the treatment of industrial wastewater generated by the consumer products industry. PMID- 21793401 TI - Development and application of a water pollution emergency response system for the Three Gorges Reservoir in the Yangtze River, China. AB - There are many watercraft and production accidents in the Three Gorges Reservoir Area (TGRA) of the Yangtze River in China every year. Accidents threaten the water quality of the 1085 km2 surface area of the TGRA and millions of local people if oil and chemical leakage were to occur. A water pollution management system for emergency response (WPMS_ER) was therefore designed for the management of pollution in this area. An integrated geographic information system (GIS) based water pollution management information system for the TGRA, called WPMS_ER_TGRA, was developed in this study. ArcGIS engine was used as the system development platform, and Visual Basic as the programming language. The models for hydraulic and water quality simulation and the generation of body-fitted coordinates were developed and programmed as a dynamically linked library file using Visual Basic, and they can be launched by other computer programs. Subsequently, the GIS-based information system was applied to the emergency water pollution management of a shipwreck releasing 10 tons of phenol into the Yangtze River during two hours. The results showed that WPMS_ER_TGRA can assist with emergency water pollution management and simulate the transfer and diffusion of accidental pollutants in the river. Furthermore, it can quickly identify the affected area and how it will change over time within a few minutes of an accident occurring. PMID- 21793402 TI - Arsenic uptake, accumulation and phytofiltration by duckweed (Spirodela polyrhiza L.). AB - This study investigates arsenic (As) accumulation and tolerance of duckweed Spirodela polyrhiza L. and its potential for As phytofiltration. S. polyrhiza was able to survive in high concentration of As(V) solution. The EC50 values (+/- SE) based on the external As(V) were (181.66 +/- 20.12) micromol/L. It accumulated (999 +/- 95) mg As/kg dw when exposed in 320 micromol/L As(V) solution for one week, and was able to take up appropriately 400 mg As/kg dw in tissues without a significant biomass loss. The EC50 values (the effective concentration of As(V) in the nutrient solution that caused a 50% inhibition on biomass production) was (866 +/- 68) mg/kg dw for the tissues, indicating that S. polyrhiza had a high capability of As accumulation and tolerance. The uptake kinetic parameters Vmax was (55.33 +/- 2.24) nmol/(g dw min) and Km was (0.144 +/- 0.011) mmol/L. Within 72 hr, S. polyrhiza decreased As concentration in the solution from 190 to 113 ng/mL with a removal rate of 41%. The study suggested that this floating aquatic plant has some potential for As phytofiltration in contaminated water bodies or paddy soils. PMID- 21793403 TI - Mineral materials as feasible amendments to stabilize heavy metals in polluted urban soils. AB - Four minerals, agricultural limestone (AL), rock phosphate (RP), palygorskite (PG), and calcium magnesium phosphate (CMP), were evaluated by means of chemical fractions of heavy metals in soils and concentrations of heavy metals in leachates from columns to determine their ability to stabilize heavy metals in polluted urban soils. Two urban soils (calcareous soil and acidic soil) polluted with cadmium, copper, zinc and lead were selected and amended in the laboratory with the mineral materials) for 12 months. Results indicated that application of the mineral materials reduced exchangeable metals in the sequence of Pb, Cd > Cu > Zn. The reduction of exchangeable fraction of heavy metals in the soils amended with different mineral materials followed the sequence of CMP, PG > AL > RP. Reductions of heavy metals leached were based on comparison with cumulative totals of heavy metals eluted through 12 pore volumes from an untreated soil. The reductions of the metals eluted from the calcareous soil amended with the RP, AL, PG and CMP were 1.98%, 38.89%, 64.81% and 75.93% for Cd, 8.51%, 40.42%, 60.64% and 55.32% for Cu, 1.76%, 52.94%, 70.00% and 74.12% for Pb, and 28.42%, 52.74%, 64.38% and 49.66% for Zn. Those from the acidic soil amended with the CMP, PG, AL, and RP were 25.65%, 68.06%, 78.01% and 79.06% for Cd, 26.56%, 49.64%, 43.40% and 34.68% for Cu, 44.44%, 33.32%, 61.11% and 69.44% for Pb, and 18.46%, 43.77%, 41.98% and 40.68% for Zn. The CMP and PG treatments were superior to the AL and RP for stabilizing heavy metals in the polluted urban soils. PMID- 21793404 TI - Impacts of wastewater sludge amendments in restoring nitrogen cycle in p nitrophenol contaminated soil. AB - The possible impacts on nitrogen-cycle in a p-nitrophenol (PNP) polluted soil and the effectiveness of wastewater sludge amendments in restoring nitrification potential and urease activity were evaluated by an incubation study. The results indicated that PNP at 250 mg/kg soil inhibited urease activity, nitrification potential, arginine ammonification rate and heterotrophic bacteria counts to some extents. After exposure to PNP, the nitrification potential of the tested soil was dramatically reduced to zero over a period of 30 days. Based on the findings, nitrification potential was postulated as a simple biochemical indicator for PNP pollution in soils. Nitrogen-cycling processes in soils responded positively to the applications of wastewater sludges. A sludge application rate of 200 tons/ha was sufficient for successful biostimulation of these nitrogen processes. The microbial activities in sludge-amended, heavy PNP-polluted soils seemed to recover after 30-45 days, indicating the effectiveness of sludge as a useful soil amendment. PMID- 21793405 TI - Speciation and bioaccessibility of lead and cadmium in soil treated with metal enriched Indian mustard leaves. AB - Indian mustard (Brassica juncea (L.) Czern.) has shown good potential for the phytoremediation of soil contaminated with heavy metals. However, there is little information about the speciation and bioaccessibility of heavy metals in soil during the decomposition of metal-rich Indian mustard leaves. Incubation experiments (1-, 3-, and 6-month) were carried out in Beijing and Hunan soil with metal-rich Indian mustard leaves addition (1% and 3%) and the effects of mustard leaves addition on the speciation and bioaccessibility of heavy metals were studied. The results showed that the addition of mustard leaves led to significant increases in pH and DOC in the Hunan soil. Both 1% and 3% of mustard leaf amendment caused the percentage of the exchangeable (F1), precipitated with carbonates (F2), bound to Fe/Mn oxides (F3) and bound to organic matter (F4) fractions of Pb and Cd to increase dramatically, while the percentage of the residual fraction (F5) of Cd and Pb significantly dropped in both Beijing and Hunan soils. Mustard leaf addition caused the bioaccessibility of Pb to decrease in the gastric phase, whereas the values increased in the small intestinal phase. The Cd bioaccessibility increased with mustard leaf addition in both the gastric and small intestinal phases. In conclusion, the metal-enriched mustard leaves addition induces Pb and Cd concentrations and their mobility increasing in the Beijing and Hunan soils. Therefore, heavy metal risk in metal-enriched plant leaves should be considered in phytoremediation system in which heavy metal might be brought back to soil and changed over time. PMID- 21793406 TI - Effect of water regimes and organic matters on transport of arsenic in summer rice (Oryza sativa L.). AB - The arsenic contamination in soil-water-plant systems is a major concern of where, the groundwater is being contaminated with arsenic (above 0.01 mg/L) in the Indian subcontinent. The study was conducted with organic matter to find out the reducing effect on arsenic load to rice (cv. Khitish). It was observed that intermittent ponding reduced arsenic uptake (23.33% in root, 13.84% in shoot and 19.84% in leaf) at panicle initiation stage, instead of continuous ponding. A decreasing trend of arsenic accumulation (root > straw > husk > whole grain > milled grain) was observed in different plant parts at harvest. Combined applications of lathyrus + vermicompost + poultry manure reduced arsenic transport in plant parts (root, straw, husk, whole grains and milled grain) which was significantly at par (p > 0.05) with chopped rice straw (5 tons/ha) + lathyrus green manuring (5 tons/ha) in comparison to control and corresponding soils. A significant negative correlation of arsenic with phosphorus (grain P with arsenic in different parts R2= 0.627-0.726 at p > 0.01) was observed. Similarly, soil arsenic had a negative correlation with soil available phosphorus (R2 = 0.822 at p > 0.001) followed by soil nitrogen (R2 = 0.762 at p > 0.01) and soil potassium (R2 = 0.626 at p > 0.01). Hence, effective management of contaminated irrigation water along with organic matter could reduce the arsenic build up to plants and soil. PMID- 21793407 TI - Effect of pH on transport of Pb2+, Mn2+, Zn2+ and Ni2+ through lateritic soil: column experiments and transport modeling. AB - This study investigated the effects of pH on the transport of Pb2+, Mn2+, Zn2+ and Ni2+ through lateritic soil columns. Model results by fitting the symmetric breakthrough curves (BTCs) of bromide (Br-) with CXTFIT model suggested that physical non-equilibrium processes were absent in the columns. The heavy metal BTCs were, however, asymmetrical and exhibited a tailing phenomenon, indicating the presence of chemical non-equilibrium processes in the columns. The retardation factors of Pb2+ were the largest of the four metal ions at both pH 4.0 (33.3) and pH 5.0 (35.4). The use of Langmuir isotherm parameters from batch studies with HYDRUS-1D did not predict the BTCs well. Rather the two-site model (TSM) described the heavy metal BTCs better than the equilibrium linear/nonlinear Langmuir model. The fraction of instantaneous sorption sites (f) of all four metal ions on the lateritic soil was consistently about 30%-44% of the total sorption sites. PMID- 21793409 TI - Competition of bloom-forming marine phytoplankton at low nutrient concentrations. AB - Competition of three bloom-forming marine phytoplankton (diatom Skeletonema costatum, and dinoflagellates Prorocentrum minimum and Alexandrium tamarense) was studied through a series of multispecies cultures with different nitrate (NaNO3) and phosphate (NaH2PO4) levels and excess silicate to interpret red tide algae succession. S. costatum outgrew the other two dinoflagellates in nitrate and phosphate replete cultures with 10 micromol/L Na2SiO3. Under nitrate limited (8.82 micromol/L NaNO3) conditions, the growth of S. costatum was also dominant when phosphate concentrations were from 3.6 to 108 micromol/L. Cell density of the two dinoflagellates only increased slightly, to less than 400 and 600 cells/mL, respectively. Cell density of S. costatum decreased with time before day 12, and then increased to 4000 cells/mL (1.5 mg/L dry biomass) at NaNO3 concentrations between 88.2 and 882 micromol/L with limited phosphate (0.36 micromol/L NaH2PO4) levels. In addition, P. minimum grew well with a maximal cell density of 1690-2100 cells/mL (0.5-0.6 mg/L dry biomass). Although S. costatum initially grew fast, its cell density decreased quickly with time later in the growth phase and the two dinoflagellates were dominant under the nitrate-limited and high nitrate conditions with limited phosphate. These results indicated that the diatom was a poor competitor compared to the two dinoflagellates under limited phosphate; however, it grew well under limited nitrate when growth of the dinoflagellates was near detection limits. PMID- 21793408 TI - Characterization of the effective cellulose degrading strain CTL-6. AB - An efficient cellulose degrading bacteria exists in the thermophilic wheat straw degrading community, WDC2. However, this strain cannot be isolated and cultured using conventional separation techniques under strict anaerobic conditions. We successfully isolated a strain of effective cellulose degrading bacteria CTL-6 using a wash, heat shock, and solid-liquid alternating process. Analysis of its properties revealed that, although the community containing the strain CTL-6 grew under aerobic conditions, the purified strain CTL-6 only grew under anaerobic culture conditions. The strain CTL-6 had a striking capability of degrading cellulose (80.9% weight loss after 9 days of culture). The highest efficiency value of the endocellulase (CMCase activity) was 0.404 micromol/(min mL), cellulose degradation efficiency by CTL-6 was remarkably high at 50-65 degrees C with the highest degradation efficiency observed at 60 degrees C. The 16S rRNA gene sequence analysis indicated that the closest relative to strain CTL-6 belonged to the genus Clostridium thermocellum. Strain CTL-6 was capable of utilizing cellulose, cellobiose, and glucose. Strain CTL-6 also grew with Sorbitol as the sole carbon source, whereas C. thermocellum is unable to do so. PMID- 21793410 TI - Differential response of multiple zebrafish hepatic F-box protein genes to 17alpha-ethinylestradiol treatment. AB - Estrogens are accumulating in environment and their effects on a variety of reproductive processes and tumorigenesis were reported by previous study, but the mechanism of estrogen promoting neoplasia was still not clear. F-box protein (FBP) is the component of E3 ubiquitin ligase which takes part in a variety of key biological processes. In this study, using mature male zebrafish, which are more sensitive to estrogen treatment, we examined influence of 17alpha ethinylestradiol (EE2) exposure on the expression of a series of hepatic FBP genes, which take part in a variety of biological processes, including tumorigenesis. The influence of EE2 on the expression of hepatic mRNA concentrations of FBP genes were quantified based on the expression of the optimal internal control gene in male zebrafish after 7-day exposure to EE2, from a low-dose concentration (1 ng/L) to environmentally relevant concentrations (10, 100 ng/L). Our results showed that EE2 exposure reduced the expression of fbxl14a, fbxl14b, fbxo25 and beta-TRCP2b, but enchanced the expression of skp2. While the alterations in fbxl2, fbxw7, fbxo9, beta-TRCP2a, fbxl18 and fbxo45 mRNA levels were not observed after EE2 exposure. Thus, our results showed that the expression of hepatic FBP genes exhibited differentially in male zebrafish exposed EE2. The changes of the expression level of FBP genes induced by EE2 may be an important clue to elucidate the correlations of estrogen and hepatic tumors. PMID- 21793411 TI - In vitro thyroid disrupting effects of organic extracts from WWTPs in Beijing. AB - It is generally known that there are many endocrine disrupting compounds (EDCs) in the effluents from wastewater treatment plants (WWTPs). Most research has focused on the occurrence of estrogenic or androgenic activities, while ignoring that there are environmental chemicals disrupting thyroid system, which is essential for growth and development in both humans and animals. In the present work, a two-hybrid yeast assay was conducted to evaluate the removal efficiencies of agonistic or antagonistic thyroid receptor (TR) mediated effects in different treatment processes of three WWTPs located in Beijing. We found no TR agonistic, but TR antagonistic activities in all processes from the WWTPs. The TR antagonistic activities in organic extracts of water samples were then calibrated regarding to a known TR-inhibitor, amiodarone hydrochloride (AH). The observed concentration of TR disrupting substances ranged from 2.35 x 10(-8) to 6.19 x 10( 7) mol/L AH in Gaobeidian WWTP, 3.76 x 10(-8) to 8.75 x 10(-8) mol/L AH in Lugouqiao WWTP, and 4.80 x 10(-9) to 2.55 x 10(-8) mol/L AH in Beixiaohe WWTP. Of the three WWTPs, the removal rates were 92.7%, 42.2%, and 23.1% respectively. Industrial sewage may contain more TR disrupting substances compared with domestic sewage. The recipient waters were found to contain considerable concentrations of TR disrupting substances that may cause adverse effects on the exposed organisms. PMID- 21793412 TI - Individual and combined toxic effects of cypermethrin and chlorpyrifos on earthworm. AB - Toxicities were assessed for a pyrethroid (cypermethrin) and an organophosphate insecticide (chlorpyrifos) individually and in combination. A series of tests were conducted on different responses (acute, chronic, behavioral) of earthworms of species Eisenia fetida andrei in the ecological risk assessment of these pesticides. The results showed that the toxicity of the mixture of cypermethrin and chlorpyrifos was significantly higher than either of these pesticides individually, especially on the earthworm's chronic responses. At a concentration of 5 mg/kg, the mixture caused significant reductions on the growth and reproduction rates of earthworms, but did not cause any significant effect when the individual was tested. The increase in toxicity of the pesticide mixture means that the use of toxicity data obtained exclusively from single-pesticide experiments may underestimate the ecological risk of pesticides that actually present in the field. PMID- 21793413 TI - Experimental and density functional theory study of the adsorption of N2O on ion exchanged ZSM-5: part II. The adsorption of N2O on main-group ion-exchanged ZSM 5. AB - The adsorption and desorption of N2O on main-group ion-exchanged ZSM-5 was studied using temperature-programmed desorption (TPD) and density functional theory (DFT) calculations. TPD experiments were carried out to determine the desorbed temperature Tmax corresponding to the maximum mass intensity of N2O desorption peak and adsorption capacity of N2O on metal-ion-exchanged ZSM-5s. The results indicated that Tmax followed a sequence of Ba2+ > Ca2+ > Cs+ > K+ > Na+ > Mg2+ and the amount of adsorbed N2O on main-group metal cation followed a sequence of Ba2+ > Mg2+ > Ca2+ > Na+ > K+ > Cs+. The DFT calculations were performed to obtain the adsorption energy (Eads), which represents the strength of the interaction between metal cations and the N-end or O-end of N2O. The calculation results showed that the N-end of the N2O molecule was favorably adsorbed on ion-exchanged ZSM-5, except for Cs-ZSM-5. For alkali metal cations, the Eads of N2O on cations followed the order which was the same to that of Tmax: Cs+ > K+ > Na+. The calculated and experimental results consistently showed that the adsorption performances of alkaline-earth metal cations were better than those of alkali metal cations. PMID- 21793414 TI - Effect of platinum on the photocatalytic degradation of chlorinated organic compound. AB - TiO2 nanoparticles, doped with different Pt contents, were prepared by a modified photodeposition method using Degussa P-25 TiO2, H2PtCl6 6H2O and methanol as the solvents. The physicochemical properties of Pt/TiO2 were investigated by the nitrogen adsorption and desorption isotherm measurement technique, X-ray diffraction analysis and photoluminescence spectra, respectively. Reaction rates from photocatalytic removal of dichloromethane over Degussa P-25 TiO2 and Pt/TiO2 were evaluated. The average diameter and BET surface area of the TiO2 catalyst particles were 300 nm and 50 m2/g, respectively. The degradation efficiency was 99.0%, 82.7%, 55.2%, and 57.9% with TiO2 at inlet concentrations of 50, 100, 200, and 300 ppm, respectively. And the degradation efficiency was 99.3%, 79.7%, 76.5%, and 73.4% with a 0.005 wt.% Pt/TiO2 at inlet concentrations of 50, 100, 200, and 300 ppm, respectively. In addition, we found that the photoluminescence emission peak intensities decreased with increases in the doping amount of Pt, which indicates that the irradiative recombination was weakened. Furthermore, the results showed that the UV/0.005 wt.% Pt/TiO2 process was capable of efficiently decomposing gaseous DCM in air. PMID- 21793415 TI - Improved method for analyzing the degradation of estrogens in water by solid phase extraction coupled with ultra performance liquid chromatography-ultraviolet detection. AB - We established an improved method for the determination of four estrogens including estriol (E3), 17beta-estradiol (E2), 17alpha-ethynylestrodiol (EE2) and estrone (El) in water. The method consisted of solid-phase extraction (0.5 L water) and subsequent analysis of analytes by ultra-performance liquid chromatography (UPLC) with an ultraviolet detector (UVD). Base-line separation was achieved for all studied estrogens using a column (50 mm x 2.1 mm) packed with 1.7 microm particle size stationary phase. Recovery was higher than 88% and detection limits ranged between 12.5-23.7 ng/L for the four estrogens, with the RSD ranging from 7% to 11%. The method was successfully applied to determine E2 and EE2 in simulated natural water, which found that about 70% of E2 was degraded (with a half-life of about 30 hr) within 48 hr and about 55% of EE2 was degraded (with a half-life of about 36 hr). Low levels of E1 were found, however E3 was undetectable during the process. PMID- 21793416 TI - Catalytic oxidation of gas-phase elemental mercury by nano-Fe2O3. AB - Heterogeneous oxidation of gas-phase Hg0 by nano-Fe2O3 was investigated on a fixed bed reactor, and the effects of oxygen concentration, bed temperature, water vapour concentration and particle size have been discussed. The results showed that Hg0 could be oxidized by active oxygen atom on the surface of nano Fe2O3 as well as lattice oxygen in nano-Fe2O3. Among the factors that affect Hg0 oxidation by nano-Fe2O3, bed temperature plays an important role. More than 40% of total mercury was oxidized at 300 degrees C, however, the test temperature at 400 degrees C could cause sintering of nano-catalyst, which led to a lower efficiency of Hg0 oxidation. The increase of oxygen concentration could promote mercury oxidation and led to higher Hg0 oxidation efficiency. No obvious mercury oxidation was detected in the pure N2 atmosphere, which indicates that oxygen is required in the gas stream for mercury oxidation. The presence of water vapour showed different effects on mercury oxidation depending on its concentration. The lower content of water vapour could promote mercury oxidation, while the higher content of water vapour inhibits mercury oxidation. PMID- 21793417 TI - [Osteoporosis in Switzerland in 2011: change since 2008]. PMID- 21793418 TI - [General trend of hip fractures]. AB - Osteoporosis constitutes a major public health problem and hip fractures are a major cause of burden associated with osteoporosis in terms of mortality, disability, and costs. Since around 1990, a trend for a decrease of the age adjusted incidence of hip fractures has been observed in western countries, particularly in women. In Geneva, with a confirmation at the Swiss level, a similar secular trend was observed. Nevertheless, due to the ageing of the population, this decrease of the incidence of hip fracture will probably not be sufficient to reduce the absolute number of these fractures over the next decades. Furthermore, age-adjusted hospitalizations in Switzerland for major non hip osteoporotic fractures have continued to increase these last years. PMID- 21793419 TI - [Selective serotonin reuptake inhibitors (SSRI) and osteoporosis]. AB - Selective serotonin reuptake inhibitors (SSRI) represent the first-line treatment of depression. Several studies demonstrate that use of therapeutical doses of SSRI is associated with a decreased bone mineral density (BMD) and an increased risk of fracture. Mechanisms of action of SSRI on bone tissue are not totally clarified. These treatments would be associated with an increased risk of falls and would also have a direct effect on bone metabolism. Regarding proofs existing of the implication of SSRI on osteoporosis, while waiting for larger-scale prospective studies, it appears reasonable that practitioners assess bone loss within risk groups of patients treated with SSRI. PMID- 21793420 TI - ["Jaques-Dalcroze eurhythmics" improves gait and prevents falls in the elderly]. AB - Given the significant health and socioeconomic consequences of falls, to develop and promote effective falls prevention strategies among older adults represents a major issue. Jaques-Dalcroze eurhythmics is a music education program through movement method developed in Geneva, Switzerland, in the early 20th century. This new exercise form, adapted for elderly people, features various multitask exercises performed to the rhythm of improvised piano music and mainly challenge gait and balance, but also memory, attention and coordination. We report here the results of a randomized controlled trial conducted in Geneva showing that Jaques Dalcroze eurythmics practice can improve gait performance under single and dual task conditions, and balance, as well as reduce both rate of falls and the risk of falling in at-risk elderly community-dwellers. PMID- 21793421 TI - [Testosterone and bone: indications and limitations]. AB - Osteoporosis incidence increases exponentially with age in men and hypogonadism represents a risk factor. Sex steroids levels are correlated to bone mineral density and to fracture prevalence. Most studies demonstrate an improvement in bone mineral density in men with hypogonadism as a result of testosterone therapy. Nevertheless there are no data evaluating the effect of testosterone therapy on fractures in men. Approximately 20% of men older than 60 have a total testosterone level lower than the lower limit of the reference range but there is no true consensus on the definition of hypogonadism in older men. In older men we recommend to treat only if total morning testosterone levels are < 8 nmol/l or even < 6,9 nmol/l on several occasions in the absence of any reversible illness and if there is no contraindication for treatment. PMID- 21793422 TI - [Adherence and chronic disease: what's about osteoporosis]. AB - Osteoporosis is a silent chronic disease. The human, medical and economic impacts, as well as the easy access to the screening and specific treatments incite us to introduce a treatment as soon as this one is justified. The maximal efficiency of treatments is possible only if the therapeutic adherence (which includes compliance and persistence) is good. Regrettably, as frequently in the chronic diseases, this one is often bad. It can be strengthened by a better patient's education and information, a better follow-up, but also by a today available variety of treatments. PMID- 21793423 TI - [And primary care physicians?]. PMID- 21793425 TI - [Portable, cancer and conditional mood]. PMID- 21793424 TI - [Takayasu's disease associated with Crohn's disease: two identical diseases at different sites?]. AB - The literature reports more than 40 cases of Takayasu disease associated with a Crohn disease. On the occasion of a case hospitalized in our service, we made a review of the literature describing this association and we tried to understand the pathogenesis who could underlie such an association. If both affections have a similar granulomatous vasculitis but arising in different sites, we shall see that the pathological mechanisms at the origin of the disease are complexes and multiples. PMID- 21793426 TI - [Reverberations of the past or the pitfalls of statistical and data manipulation]. PMID- 21793427 TI - [Medicine--emerging from the premordial waters]. PMID- 21793428 TI - [Health according to the Swiss economy]. PMID- 21793429 TI - Safety evaluation and immunogenicity of arabinose-based conditional lethal Salmonella Gallinarum mutant unable to survive ex vivo as a vaccine candidate for protection against fowl typhoid. AB - In seeking to develop a safe fowl typhoid (FT) vaccine, a novel candidate lacking cpxR, lon, and asd Salmonella Gallinarum (SG) genes was constructed with the plasmid-containing araC::P(araBAD)::asd system. A balanced-lethal host-vector system based on the essential bacterial gene for aspartate beta-semialdehyde dehydrogenase (asd) was used to construct the SG mutant strain. A plasmid (p15A ori) with an araC::P(araBAD)::asd cassette was introduced into an auxotrophic mutant to prevent ex vivo survival. The safety, immunity, and protective properties of the SG mutant were evaluated. Inoculation of the mutant at 10(6) colony-forming units (CFU) did not result in recovery in feces and internal organs, whereas inoculation at 10(8) and 10(10) CFU resulted in moderate bacterial recovery from feces and organs. Birds immunized with the mutant were challenged with a virulent SG strain at day 14 postimmunization; significantly reduced mortality and induced plasma immunoglobulin (Ig)G and mucosal IgA responses were noted. Cellular immune responses as evaluated by a peripheral lymphocyte proliferation assay were also significantly induced. The balanced lethal host-vector system for construction of SG mutants is an effective and improved approach for safe vaccine construction against FT. PMID- 21793430 TI - Evaluation of factors affecting vaccine efficacy of recombinant Marek's disease virus lacking the Meq oncogene in chickens. AB - We previously reported that deletion of the Meq gene from the oncogenic rMd5 virus rendered it apathogenic for chickens. Here we examined multiple factors affecting Marek's disease vaccine efficacy of this nonpathogenic recombinant Meq null rMd5 virus (rMd5deltaMeq). These factors included host genetics (MHC haplotype), strain or dose of challenge virus, vaccine challenge intervals, and maternal antibody status of the vaccinated chicks. Studies on host genetics were carried out in five chicken lines comprising four different MHC B-haplotypes. Results showed that chicken lines tested were highly protected, with protective indexes of 100% (B*2/*15), 94% (B*2/*2), 87% (B*19/*19), and 83% (B*21/*21). At a challenge dose above 8000 plaque-forming units, differences in protection were observed between the two highly virulent strains examined (648A and 686). The interval between vaccination and challenge indicated a protective efficacy from 0 to 2 days varied greatly (12%-82%) after challenge with vv+686, the most virulent virus. Less variation and significant protection began at 3 days post vaccination and reached a maximum at 5 days post vaccination with about 80%-100% protection. Taken together, our results indicate that the factors examined in this study are important for vaccine efficacy and need to be considered in comparative evaluations of vaccines. PMID- 21793431 TI - Biosecurity and bird movement practices in upland game bird facilities in the United States. AB - Since 1996, the emergence of Asian-origin highly pathogenic avian influenza subtype H5N1 has spurred great concern for the global poultry industry. In the United States, there is concern over the potential of a foreign avian disease incursion into the country. Noncommercial poultry operations, such as upland game bird facilities in the United States, may serve as a potential source of avian disease introduction to other bird populations including the commercial poultry industry, backyard flocks, or wildlife. In order to evaluate how to prevent disease transmission from these facilities to other populations, we examined biosecurity practices and bird movement within the upland game bird industry in the United States. Persons that held a current permit to keep, breed, or release upland game birds were surveyed for information on biosecurity practices, flock and release environments, and bird movement parameters. Biosecurity practices vary greatly among permit holders. Many facilities allow for interaction between wild birds and pen-reared birds, and there is regular long-distance movement of live adult birds among facilities. Results suggest that upland game bird facilities should be targeted for biosecurity education and disease surveillance efforts. PMID- 21793432 TI - Genotyping of Japanese field isolates of Mycoplasma synoviae and rapid molecular differentiation from the MS-H vaccine strain. AB - Mycoplasma synoviae is an important causative agent of avian mycoplasmosis. In the present study the conserved domain of the variable lipoprotein and hemagglutinin (vlhA) gene of M. synoviae was sequenced and analyzed for 19 field strains of M. synoviae isolated from chickens across Japan. This analysis revealed that there were at least nine genotypes of M. synoviae present in Japan. Furthermore, we found a single nucleotide polymorphism (SNP) within this region in all the Japanese isolates, and based on this finding, we established a PCR method with cycling probe technology to differentiate between these field isolates and the live M. synoviae vaccine strain Mycoplasma synoviae-H (MS-H). PMID- 21793433 TI - Study of infection with an Iranian field-isolated H9N2 avian influenza virus in vaccinated and unvaccinated Japanese quail. AB - In the present study, we examined the mortality rate, egg production, and clinical signs of quail experimentally infected with a field isolate of A/Chicken/Iran/339/02 (H9N2) avian influenza virus obtained from an infected commercial layer farm with severe morbidity and mortality. A total of 120 quail at 14 days old were randomly divided into four groups of vaccinated (B and C) and unvaccinated (A and D) birds. Vaccination was done on days 20 and 32, and viral inoculation of birds in groups C and D was then carried out on day 43. For evaluation of viral transmission, at 24 hr postinoculation additional unvaccinated birds were placed in direct contact with challenged birds. All the birds were evaluated for clinical signs, egg production, antibody production, viral titration in lung homogenates, and viral transmission following inoculation. All unvaccinated-challenged birds were infected and showed clinical signs, whereas the infection rate along with clinical signs of vaccinated challenged birds reached 30%-40%. Although vaccination induced high antibody titers, reduction in food and water consumption was evident in this vaccinated challenged group compared with the unchallenged control group. These results could indicate that inactivated vaccine did not fully prevent the infection, although it was capable of protecting birds against clinical signs and significantly decreased viral titers in lungs after intranasal challenge. PMID- 21793434 TI - Efficacy of Newcastle disease virus recombinant expressing avian influenza virus H6 hemagglutinin against Newcastle disease and low pathogenic avian influenza in chickens and turkeys. AB - A recombinant Newcastle disease virus (NDV) expressing H6 hemagglutinin (HA) of a low pathogenic avian influenza virus (LPAIV) was generated by reverse genetics (NDVH6). The H6 open reading frame was inserted as an additional transcription unit between the fusion and hemagglutinin-neuraminidase (HN) gene of lentogenic NDV clone 30. Expression of the foreign gene was demonstrated by northern blot, western blot, and indirect immunofluorescence analyses. The protective efficacy against Newcastle disease and avian influenza of subtype H6 was evaluated in 3-wk old chickens and turkeys. A single vaccination protected specific-pathogen-free (SPF) chickens against a subsequent lethal NDV infection and prevented shedding of AIV after homologous H6 LPAIV infection. Furthermore, vaccinated and AIV infected animals could be differentiated by detection of AIV nucleoprotein specific antibodies. Three-week-old commercial turkeys, exhibiting NDV-specific maternal antibodies, were partially protected against a lethal NDV challenge infection. The mortality rate of NDVH6-immunized turkeys was reduced to 40% compared to 90% in unvaccinated birds. After H6 LPAIV infection, shedding in NDVH6-immunized turkeys was only marginally reduced compared to NDV-immunized control birds. We previously described HA-expressing NDV recombinants as potent bivalent vaccines against Newcastle disease and highly pathogenic avian influenza of subtype H5 or H7. The results presented here are in contrast to the high protective efficacy in SPF chickens, as a single vaccination with NDVH6 was insufficient in turkeys in the presence of maternal antibodies against NDV. Therefore, the vector virus has to be improved to overcome these limitations. PMID- 21793435 TI - Molecular characterization of Mycoplasma gallisepticum isolates from Jordan. AB - Two groups of Mycoplasma gallisepticum (MG) isolates (n = 24) from Jordan were analyzed by molecular methods and compared with other Middle Eastern isolates, related international isolates, and reference strains. The first group (n = 19) was isolated from July 2004 to January 2005 (isolation period A), and the newer group (n = 5) from June 2007 to April 2008 (isolation period B). The groups of isolates are from chicken flocks from northern Jordan, but are not from the same farms. None of the flocks were vaccinated for MG. Random amplified polymorphic DNA analysis, targeted sequencing of the partial MG cytadhesin 2 (mgc2), and the MG 16S-23S rRNA intergenic spacer region (IGSR) divided the Jordanian isolates into two groups. All of the 19 isolates from time period A, in addition to two isolates from time period B, were indistinguishable from the F strain. Three of five isolates from time period B were characterized as wild types and were indistinguishable from each other. The wild-type field strain was readily distinguished from the F strain. It was 91% and 96.4% similar to the F strain based on Clustal-W alignments of sequences of mgc2 and IGSR, respectively. Sequence similarity of mgc2 gene of the Jordan wild-type strain to isolates from Israel and Egypt ranged from 96.5% to 100%, whereas for IGSR it was 99.4%-100%. We theorize that the F-strain live MG vaccine, commonly used in Jordan prior to 2007, was transmitted to nonvaccinated poultry in the region and was a predominant genotype during time period A. PMID- 21793436 TI - Emergence of Salmonella enterica serovar Potsdam as a major serovar in waterfowl hatcheries and chicken eggs. AB - Salmonellosis is a common food-borne illness in humans caused by Salmonella contaminated poultry and their products. In hatcheries, 110 Salmonella isolates were identified, mostly from first enrichment, and few from delayed enrichment. The Salmonella prevalence in goose and duck hatcheries was higher when measured by four multiplex PCR methods than by traditional culture (73.8% vs. 44.35%, P < 0.05); 97.3% of 110 isolates were Salmonella Potsdam of serogroup C1 and other isolates were Salmonella Montevideo of C1 and Salmonella Albany of C2. Plasmid and pulsed field gel electrophoresis genetic analysis revealed that isolates from duck hatcheries were more diverse than those from goose hatcheries. In Salmonella Potsdam, host species-specific genotypes were observed in geese for genotypes 3, 4, and 5 and in ducks for genotypes 7, 8, and 9, suggesting that Salmonella Potsdam may evolve into goose- and duck-specific isolates. An examination of 1121 eggs found that only Salmonella Potsdam was identified in 1.8% (7/591) of eggs from chickens fed on the ground, not housed in cages, and in egg content (6/7) as well as eggshell membrane (1/7). In conclusion, Salmonella Potsdam may be a major Salmonella infection in waterfowl and chicken eggs. PMID- 21793437 TI - Baculovirus virions displaying infectious bursal disease virus VP2 protein protect chickens against infectious bursal disease virus infection. AB - Infectious bursal disease (IBD) is an acute and contagious viral infection of young chickens caused by IBD virus (IBDV). The VP2 protein of IBDV is the only antigen for inducing neutralizing antibodies and protective immunity in the natural host. In the current study, we have succeeded in construction of one recombinant baculovirus BacSC-VP2 expressing His6-tagged VP2 with the baculovirus envelope protein gp64 transmembrane domain (TM) and cytoplasmic domain (CTD). The His6-tagged recombinant VP2 was expressed and anchored on the plasma membrane of Sf-9 cells, as examined by western blot and confocal microscopy. Immunogold electron microscopy demonstrated that the VP2 protein of IBDV was successfully displayed on the viral surface. Vaccination of chickens with the VP2-pseudotyped baculovirus vaccine (BacSC-VP2) elicited significantly higher levels of VP2 specific enzyme-linked immunosorbent assay antibodies and neutralizing antibodies than the control groups. IBDV-specific proliferation of lymphocytes was observed in chickens immunized with the recombinant BacSC-VP2. An in vivo challenge study of the recombinant baculovirus BacSC-VP2 showed effective protection against a very virulent (vv) IBDV infection in chickens. In addition, mortality and gross and histopathological findings in the bursa demonstrated the efficacy of the vaccine in reducing virulence of the disease. These results indicate that the recombinant baculovirus BacSC-VP2 can be a potential vaccine against IBDV infections. PMID- 21793438 TI - Surveillance and characterization of Newcastle disease viruses isolated from northern pintail (Anas acuta) in Japan during 2006-09. AB - A total of 38 Newcastle disease virus (NDV) isolates were obtained from 6060 fecal samples from northern pintail (Anas acuta) ducks collected in the Tohoku district in Japan during 2006-09. One isolate from each sampling location and date was selected for a total of 38 isolates, then 15 of these were characterized for their pathogenicity by mean death time of minimum lethal dose (MDT/MLD) using chicken embryos and by plaque formation on chicken embryo fibroblasts. Furthermore, nine isolates were randomly selected from these 15 isolates, and the fusion protein genes were sequenced to characterize amino acid sequences around the cleavage site. All 15 were confirmed to be nonvirulent by MDT/MLD test, and nine isolates were also confirmed as nonvirulent by the cleavage site of the fusion protein 112G/E-K/R-Q-G/E-R*L117 that was specific for nonvirulent NDVs. The characteristics of nine isolates identified by phylogenic analysis of the fusion protein gene indicated that the isolates belong to genotype I or II. In addition, we also isolated 68 avian influenza viruses and 28 other hemagglutinating viruses. Our data indicate that northern pintails are subclinically infected by, perpetuate, and distribute NDV along with different subtypes of avian influenza viruses and other hemagglutinating viruses during their migrations across vast areas over the Northern Hemisphere to Japan. PMID- 21793440 TI - The relationship between the numbers of Salmonella Enteritidis, Salmonella Heidelberg, or Salmonella Hadar colonizing reproductive tissues of experimentally infected laying hens and deposition inside eggs. AB - Contamination of eggs by Salmonella Enteritidis has been a prominent cause of human illness for several decades and is the focus of a recently implemented national regulatory plan for egg-producing flocks in the United States. Salmonella Heidelberg has also been identified as an egg-transmitted pathogen. The deposition of Salmonella strains inside eggs is a consequence of reproductive tract colonization in infected laying hens, but prior research has not determined the relationship between the numbers of Salmonella that colonize reproductive organs and the associated frequency of egg contamination. In the present study, groups of laying hens in two trials were experimentally infected with large oral doses of strains of Salmonella Enteritidis (phage type 13a), Salmonella Heidelberg, or Salmonella Hadar. Reproductive tissues of selected hens were cultured to detect and enumerate Salmonella at 5 days postinoculation, and the interior contents of eggs laid between 6 and 25 days postinoculation were tested for contamination. Significantly more internally contaminated eggs were laid by hens infected with Salmonella Enteritidis (3.58%) than with strains of either Salmonella Heidelberg (0.47%) or Salmonella Hadar (0%). However, no significant differences were observed between Salmonella strains in either isolation frequency or the number of colony-forming units (CFU) isolated from ovaries or oviducts. Salmonella isolation frequencies ranged from 20.8% to 41.7% for ovaries and from 8.3% to 33.3% for oviducts. Mean Salmonella colonization levels ranged from 0.10 to 0.51 log CFU/g for ovaries and from 0.25 to 0.46 log CFU/g for oviducts. Although parallel rank-orders were observed for Salmonella enumeration (in both ovaries and oviducts) and egg contamination frequency, a statistically significant relationship could not be established between these two parameters of infection. PMID- 21793439 TI - Prevalence of low pathogenicity avian influenza virus during 2005 in two U.S. live bird market systems. AB - Oropharyngeal and cloacal swabs were collected from poultry sold in two live bird market (LBM) systems to estimate the prevalence of low pathogenicity avian influenza virus (LPAIV) shedding during the summer and fall of 2005. Random sampling was conducted in three LBMs in Minnesota where 50 birds were sampled twice weekly for 4 wk, and in three LBMs in a California marketing system. A stratified systematic sampling method was used to collect samples from Southern California LBMs, where LPAIV was detected during routine surveillance. No LPAIV was detected in the LBM system in Minnesota where realtime reverse transcription PCR (RT-PCR) was conducted on oropharyngeal samples. RT-PCR was performed on swabs taken from 290 of 14,000, 65 of 252, and 60 of 211 birds at the three Southern California LBMs. The number of samples collected was based on the number of birds, age of the birds, and number of species present in the LBM. Virus isolation, subtyping, and sequencing of the hemagglutinin, neuraminidase, and other internal protein genes was performed on AIV-positive samples. The estimated prevalence of LPAIV in California was 0.345% in an LBM/supply farm with multiple ages of Japanese quail, 3% in an LBM with multiple ages and strains of chickens present, and 49.8% in an LBM with multiple species, multiple strains, and multiple ages. The positive virus samples were all LPAIV H6N2 and closely related to viruses isolated from Southern California in 2001 and 2004. Little or no comingling of poultry may contribute to little or no LPAIV detection in the LBMs. PMID- 21793441 TI - Comparison of real-time PCR with conventional PCR and culture to assess the efficacy of a live attenuated Salmonella enterica serovar Typhimurium vaccine against Salmonella enterica serovar Enteritidis in commercial leghorn chicks vaccinated under field and laboratory conditions. AB - The efficacy of a live attenuated Salmonella Typhimurium Megan Vac 1 vaccine (MV1) was evaluated against Salmonella Enteritidis in chicken pullets with the use of PCR and culture methods. Two hundred Hyline W-32 white leghorn chicks were obtained from a local hatchery and divided into four treatment groups. Two of the groups served as positive and negative controls. The MV1 vaccine was administered to the chicks in the remaining two groups at 1 and 35 days old by either the coarse spray (field) or the oral route (laboratory) method. The chicks were challenged with a high dose of a Salmonella Enteritidis strain at 10 wk old and euthanatized 3 days postinoculation. Samples for PCR analysis were collected prior to enrichment, after pre-enrichment in buffered peptone water (BPW) and after primary enrichment from the ceca, liver, and spleen. None of the samples tested yielded positive results for the Salmonella Typhimurium vaccine strain by either the culture or PCR methods. Results from the standard culture method showed that vaccinating the birds with MV1 reduced the counts of Salmonella Enteritidis recovered from the challenged birds. In addition, fewer pre-enriched samples tested positive for Salmonella Enteritidis among the challenged groups that were vaccinated when compared to the unvaccinated challenged group. Under the conditions of this study, MV1 was unable to prevent colonization of other internal organs such as the liver and spleen. Real-time PCR was significantly more sensitive than conventional PCR (C-PCR) prior to enrichment, but after enrichment the sensitivities of the two methods were similar. Enrichment significantly increased the sensitivity of both PCR methods for the detection of Salmonella Enteritidis in cecal samples, but did not significantly increase the sensitivity for detection of Salmonella Enteritidis in liver and spleen samples that were pre-enriched in BPW. There was no significant difference between the laboratory or field vaccination methods with respect to either the prevalence of Salmonella Enteritidis isolation or the bacterial loads in culture-positive samples. Collectively, the data suggest that MV1 offered some protection against Salmonella Enteritidis in commercial layer chick pullets under the conditions of this study. Given the labor and time required to perform the C-PCR and culture methods, the real-time PCR method may prove to be a more useful method to use in diagnostics. PMID- 21793442 TI - Infectious bronchitis virus in testicles and venereal transmission. AB - Even though males represent only 8%-12% of the birds of a breeder flock, their role in infectious bronchitis virus (IBV) dissemination is largely unknown. We first assessed the effect of IBV replication in the chicken testes. Ten-week-old males were inoculated with Arkansas (Ark) or Massachusetts (Mass) IBV virulent strains. Seven days postinoculation (DPI) IBV RNA was detected in testicles of 100% of M41- and in 96% of Ark-infected males. Marginal nonsynonymous variation was detected in spike (S) gene of the predominant population of IBV replicating in the testes compared to the S gene of the predominant population of viruses prior to inoculation. IBV M41 and Ark were detected in spermatogonia and Sertoli cells of testicles of infected roosters by immunofluorescence, without evident histopathological changes. We next assessed venereal transmission of IBV by artificially inseminating 54-wk-old hens either with semen from IBV-infected roosters or with IBV suspended in naive semen. IBV RNA was detected in the trachea of all hens inseminated with IBV-spiked semen and in 50% of hens inseminated with semen from IBV-infected males. The egg internal and external quality was negatively affected in hens inseminated with semen containing IBV. These results provide experimental evidence for IBV venereal transmission. PMID- 21793443 TI - Isolation of H5 avian influenza viruses from waterfowl in the upper Midwest region of the United States. AB - In recent years, the H5N1 subtype of avian influenza virus (AIV) has become an important zoonotic pathogen. The surveillance of AIV in its natural host, the waterfowl, is crucial to monitoring and controlling the disease in poultry and other species. In this study, we report on the isolation of H5 AIV from cloacal swabs of waterfowl captured in Minnesota and South Dakota. We screened a total of 7260 cloacal samples from waterfowl using matrix gene-directed, real-time reverse transcription-(rRT-PCR) and H5-specific rRT-PCR and found 148 samples to be positive for the H5 subtype. On inoculation of 71 of these samples in embryonated chicken eggs, 25 samples yielded H5 AIV. On subtyping with N-specific primers, we detected a mixture of subtypes in 15 isolates. Molecular pathotyping confirmed the isolated H5 subtypes to be low pathogenicity avian influenza. Continuation of AIV surveillance programs should help in understanding the epidemiology and ecology of AIV. PMID- 21793444 TI - Effect of diluting Marek's disease vaccines on the outcomes of Marek's disease virus infection when challenged with highly virulent Marek's disease viruses. AB - Dilution of Marek's disease (MD) vaccines is a common practice in the field to reduce the cost associated with vaccination. In this study we have evaluated the effect of diluting MD vaccines on the protection against MD, vaccine and challenge MD virus (MDV) kinetics, and body weight when challenged with strains Md5 (very virulent MDV) and 648A (very virulent plus MDV) by contact at day of age. The following four vaccination protocols were evaluated in meat-type chickens: turkey herpesvirus (HVT) at manufacturer-recommended full dose; HVT diluted 1:10; HVT + SB-1 at the manufacturer-recommended full dose; and HVT + SB 1 diluted 1:10 for HVT and 1:5 for SB-1. Vaccine was administered at hatch subcutaneously. One-day-old chickens were placed in floor pens and housed together with ten 15-day-old chickens that had been previously inoculated with 500 PFU of either Md5 or 648A MDV strains. Chickens were individually identified with wing bands, and for each chicken samples of feather pulp and blood were collected at 1, 3, and 8 wk posthatch. Body weights were recorded at 8 wk for every chicken. Viral DNA load of wild-type MDV, SB-1, and HVT were evaluated by real time-PCR. Our results showed that dilution of MD vaccines can lead to reduced MD protection, reduced relative body weights, reduced vaccine DNA during the first 3 wk, and increased MDV DNA load. The detrimental effect of vaccine dilution was more evident in females than in males and was more evident when the challenge virus was 648A. However, lower relative body weights and higher MDV DNA load could be detected in chickens challenged with strain Md5, even in the absence of obvious differences in protection. PMID- 21793445 TI - Experimental reproduction of enterococcal spondylitis in male broiler breeder chickens. AB - There has been a recent emergence of epidemic spinal infections with necrosis causing lameness and mortality in male broilers and broiler breeders. Mortality in affected flocks may be as high as 15%. The disease has been called enterococcal spondylitis (ES), based on the frequent isolation of Enterococcus cecorum from the lesions and necrosis and inflammation observed in the free thoracic vertebrae (FTV) of affected birds. Male broiler breeders in an experimental setting were challenged with pure E. cecorum isolates obtained from ES-affected commercial flocks. Challenge routes included oral gavage (10(8)), intravenous (i.v.; 10(3)), and air sac (AS; 10(3)). Half the study birds in each group were chemically immunosuppressed with dexamethasone. Spinal lesions were observed grossly in birds challenged intravenously (2.9%) and birds challenged orally (6.1%). Microscopic spinal lesions consistent with ES were more frequently identified compared with gross lesions in the orally challenged group (30.3%). Chemical immunosuppression with dexamethasone was not associated with a greater incidence of ES in this study. By recreating the disease experimentally, the study design reported here may help in the further development of an experimental challenge model for future studies on risk factors, prevention, and therapeutic intervention of ES. PMID- 21793446 TI - Molecular characterization of a virulent genotype VIId strain of Newcastle disease virus from farmed chickens in Shanghai. AB - A virulent Newcastle disease virus strain was isolated from diseased chickens in Shanghai, China. The isolated strain was initially characterized as highly virulent because of a short mean death time in embryonated chicken eggs and specific-pathogen-free chickens and was typed as neurotropic by intracloacal inoculation of chickens. The isolated strain had a dibasic amino acid motif in the fusion protein cleavage site sequence required for systemic replication in the host cell. The strain fell into subgenotype VIId by phylogenetic analysis of the fusion protein gene. Although these results demonstrated some sequence similarity between the isolated strain and strains responsible for outbreaks of Newcastle disease in China and Taiwan, the unusually high mortality (86.4%) set this strain aside from other VII strains. Finally, a cross-protection assay demonstrated that La Sota and clone 30 live vaccines could not protect chickens from infection with the isolated strain, with a zero survival rate being observed when chickens were challenged with a high dose of virulent VIId virus. PMID- 21793447 TI - Avian influenza in ovo vaccination with replication defective recombinant adenovirus in chickens: vaccine potency, antibody persistence, and maternal antibody transfer. AB - Protective immunity against avian influenza (AI) can be elicited in chickens in a single-dose regimen by in ovo vaccination with a replication-competent adenovirus (RCA)-free human adenovirus serotype 5 (Ad)-vector encoding the AI virus (AIV) hemagglutinin (HA). We evaluated vaccine potency, antibody persistence, transfer of maternal antibodies (MtAb), and interference between MtAb and active in ovo or mucosal immunization with RCA-free recombinant Ad expressing a codon-optimized AIV H5 HA gene from A/turkey/WI/68 (AdTW68.H5(ck)). Vaccine coverage and intrapotency test repeatability were based on anti-H5 hemagglutination inhibition (HI) antibody levels detected in in ovo vaccinated chickens. Even though egg inoculation of each replicate was performed by individuals with varying expertise and with different vaccine batches, the average vaccine coverage of three replicates was 85%. The intrapotency test repeatability, which considers both positive as well as negative values, varied between 0.69 and 0.71, indicating effective vaccination. Highly pathogenic (HP) AIV challenge of chicken groups vaccinated with increasing vaccine doses showed 90% protection in chickens receiving > or = 10(8) ifu (infectious units)/bird. The protective dose 50% (PD50) was determined to be 10(6.5) ifu. Even vaccinated chickens that did not develop detectable antibody levels were effectively protected against HP AIV challenge. This result is consistent with previous findings ofAd-vector eliciting T lymphocyte responses. Higher vaccine doses significantly reduced viral shedding as determined by AIV RNA concentration in oropharyngeal swabs. Assessment of antibody persistence showed that antibody levels of in ovo immunized chickens continued to increase until 12 wk and started to decline after 18 wk of age. Intramuscular (IM) booster vaccination with the same vaccine at 16 wk of age significantly increased the antibody responses in breeder hens, and these responses were maintained at high levels throughout the experimental period (34 wk of age). AdTW68.H5(ch)-immunized breeder hens effectively transferred MtAb to progeny chickens. The level of MtAb in the progenies was consistent with the levels detected in the breeders, i.e., intramuscularly boosted breeders transferred higher concentrations of antibodies to the offspring. Maternal antibodies declined with time in the progenies and achieved marginal levels by 34 days of age. Chickens with high maternal antibody levels that were vaccinated either in ovo or via mucosal routes (ocular or spray) did not seroconvert. In contrast, chickens without MtAb successfully developed specific antibody levels after either in ovo or mucosal vaccination. These results indicate that high levels of MtAb interfered with active Ad-vectored vaccination. PMID- 21793448 TI - Serial transfer of a transplantable tumor: implications for Marek's vaccine mechanisms. AB - The mechanism of Marek's disease (MD) vaccination to prevent the lymphoproliferative disease in chickens is not well understood. It is generally recognized that vaccination prevents disease, including the induction of T-cell tumors, but it does not prevent the pathogenic virus from infecting and replicating in the vaccinated host, nor does it prevent bird to bird spread of the oncogenic virus. The stage at which the vaccinated immune system intervenes in the process from infection to the induction of tumors remains obscure. Using a transplantable tumor induced by the Md5 strain of MD virus (MDV), we show that CVI988 vaccination does not prevent the induction of transplantable tumors in the 15I(5) x 7(1) chicken line. A monoclonal tumor with a V beta 1 T-cell receptor spectratype of 207 base pairs was used to follow the transplantable tumor in serial passages in vivo. This transplantable tumor could be passed in vaccinated birds. The length of time between vaccination and challenge (5 to 12 days) had little or no influence on the ability to transfer the tumor. There was variability in the manifestation of the disease produced by the transplanted tumor. Some chickens presented as normal but were still capable of transmitting the transplanted tumor to newly vaccinated recipients via their blood. This indicates that some chickens can control, but not eliminate, the tumor. The variables inducing health or disease in the challenged chickens remain obscure, but environmental or other factors likely depress the immune system allowing the tumor to overwhelm the immune system. PMID- 21793449 TI - Comparison of blood and feather pulp samples for the diagnosis of Marek's disease and for monitoring Marek's disease vaccination by real time-PCR. AB - Comparison of blood and feather pulp (FP) samples for the diagnosis of Marek's disease (MD) and for monitoring Marek's diseases vaccination in chickens (serotypes 2 and 3 vaccines) by real time-PCR was evaluated. For diagnosis of MD, quantification of serotype 1 Marek's disease virus (MDV) DNA load was evaluated in 21 chickens suffering from MD. For each chicken, samples of blood and FP were collected and MDV DNA load was quantified. Solid tumors are the sample of choice for MD diagnosis by real time-PCR and, hence, 14 solid tumors were included in the study as positive controls. Load of MDV DNA in FP was equivalent to that detected in solid tumors (threshold cycle [Ct] ratio above 1.7). MDV DNA load in blood samples was lower than in solid tumors and FP samples. Nonetheless, there was a statistically significant correlation of the results obtained from FP and blood (r = 0.92). Results of the Pearson correlation test showed that Ct ratio values of 1.7 in FP correspond to Ct ratio values of 1.2 in peripheral blood. For monitoring vaccines, serotypes 2 and 3 MDV DNA load was evaluated in blood and FP samples of vaccinated chickens. Serotype 2 MDV DNA load was evaluated in samples of blood and FP from 34 chickens vaccinated with SB-1 strain. Serotype 3 MDV DNA load was evaluated in blood and FP samples from 53 chickens vaccinated with HVT strain. For both serotypes, frequency of positive samples and load of vaccine DNA was higher in FP than in blood samples. There was not a statistically significant correlation between the load of SB-1 DNA (r = 0.17) or HVT DNA (r = -0.04) in FP and blood. Our results show that the load of serotypes 1, 2, and 3 DNA is higher in FP than in blood. Diagnosis of MD could be done using both FP and blood samples. Monitoring of MD vaccination by real time-PCR required the use of FP samples. There were a high percentage of false negative samples when using blood to detect serotypes 2 and 3 MDV by real time-PCR. PMID- 21793450 TI - Genetic diversity and genotype analysis of duck circovirus. AB - To investigate the genetic diversity and genotype of duck circovirus (DuCV), nine full-length DuCV genomes were determined from clinical samples. Multiple sequence alignment and phylogenetic analyses were performed on the nine viral genome sequences as well as on 27 genome sequences retrieved from the GenBank database. Pairwise analysis showed that the determined genome sequences have a genome organization identical to the 27 sequences and share 83.3%-99.8% identity among themselves and 82.6%-99.9% with the other 27 sequences. Phylogenetic analysis revealed that all 36 viral genome sequences are divided into two lineages, DuCV1 and DuCV2, in which the nucleotide diversity between genome sequences in these two lineages ranged from 13.2%-17.4%; these may be regarded as two types of viruses. Viruses under DuCV1 and DuCV2 are further clustered into different sublineages. When analyzed using the method for genotype definition proposed by Grau-Roma et al, these different sublineages can be defined as genotypes DuCV1a, DuCV1b, DuCV2a, DuCV2b, and DuCV2c. In addition, the viral sequences obtained from mainland China are different in genomic size and share a diversity of no less than 13.2%, including the sequences that came from all genotypes. This suggests that the DuCVs prevalent in domestic duck flocks in China are ecologically divergent. PMID- 21793451 TI - The role of an early Salmonella Typhimurium infection as a predisposing factor for necrotic enteritis in a laboratory challenge model. AB - Necrotic enteritis (NE) caused by Clostridium perfringens (CP) in poultry is an important bacterial disease in terms of economic implications. The disease is multifactorial and is invariably associated with predisposing factors. In the present experiments, we investigated the potential predisposing role of neonatal Salmonella Typhimurium (ST) infection for NE-associated mortality in a laboratory challenge model. In two experiments, day-of-hatch chicks were randomly assigned to four groups: Group 1, nonchallenged control; Group 2, chickens received Eimeria maxima (EM) and CP; Group 3, chickens received EM and CP and were also challenged with ST at day 1 of age; Group 4, chickens received EM and CP and were also challenged with ST at day 17 of age. Challenged groups received an oral dose of EM at 18 days of age and CP (10(8) colony-forming units/chick) at 22-23 days of age. When compared to EM and CP, chicks challenged with ST (day 1) had increased NE-associated mortality and CP-associated lesion scores (P < 0.05) in both experiments. Furthermore, body weight and body weight gain were lower (P < 0.05) in chicks infected with ST (day 1) in the first experiment, even though no differences (P > 0.05) were observed in weight gain in the second experiment. Chicks challenged with ST (day 17) were similar to the EM and CP group in all of the above-mentioned parameters, indicating that a paratyphoid infection in younger chicks remarkably alters the susceptibility to secondary bacterial infections. Based on this work, the authors suggest that an ST infection early in the age of a chick may be important for altering susceptibility to NE, an observation that may be useful from the perspective of experimental reproduction of this disease and, perhaps, as an economically important reason to address the problem of paratyphoid Salmonella infections in young chicks. PMID- 21793452 TI - High seroprevalence of Histomonas meleagridis in Dutch layer chickens. AB - Histomona meleagridis is a protozoan parasite that may cause outbreaks of histomonosis with high mortality, especially in turkey flocks. Chickens are less susceptible to the disease than are turkeys, but are considered to act as an important reservoir. To determine the seroprevalence of H. meleagridis in Dutch layer chicken flocks, a large scale seroepidemiologic study (3376 samples) was performed by sampling 12 organic flocks, 24 free-ranging flocks, 40 flocks with floor housing, and 40 flocks with cage housing. At the end of the laying period, approximately 30 blood samples per flock were collected for serology. The seroprevalence found was high. In every flock, at least one of the samples tested positive while in 87% of the flocks, at least one of the samples was strongly positive. There were no significant statistical differences in seropositivity between the housing types. To confirm the enzyme-linked immunosorbent assay (ELISA) results, a small-scale seroepidemiologic study (576 samples) was performed in 29 additional layer chicken flocks kept in different housing systems. Subsequently, a subset of five seropositive flocks was selected. Five birds were obtained from each of these flocks in order to detect the parasite using culture and PCR. In all five flocks, H. meleagridis was either isolated from (culture), detected in (PCR), or both, the birds sampled. Together with the previously performed validation studies, the latter results confirm that the positive ELISA serology found is genuine. We conclude that the seroprevalence of H. meleagridis in layers is, as anticipated, high. PMID- 21793453 TI - Recurring histomonosis on an organic farm. AB - This report describes outbreaks of histomonosis, a severe disease caused by the protozoan parasite Histomonas meleagridis, which occurred over a period of 3 yr on an organic farm in southern Germany. Among other species, the farm houses layers, broilers, and turkeys. In August 2005 one group of turkeys was naturally infected with H. meleagridis. The strain causing infection was typed by C profiling as genotype B. A second outbreak occurred 3 yr later. Again, a group of turkeys was naturally infected. The strain causing the infection belonged to genotype A. Two months later one group of broilers became infected with H. meleagridis type B and a group of turkeys with H. meleagridis type A. Four weeks later two further groups of broilers showed symptoms. DNA of H. meleagridis was detected but genotyping was not possible. In conclusion, genotyping of the histomonal strains causing the disease showed that at least two different histomonal strains caused the outbreaks and that the strains circulated on the farm at the same time. PMID- 21793454 TI - Macrorhabdus ornithogaster (Megabacterium) infection in adult hobby chickens in North America. AB - A field investigation was conducted on a flock of adult hobby chickens showing intermittent signs of enteritis. Roosters examined in the initial field visit and postmortem had cecal worms, roundworms, tetratrichomonads, and coccidiosis. Macrorhabdus ornithogaster was diagnosed histologically in the mucosal isthmus of the proventriculus and ventriculus. Three roosters and two hens were examined in a follow-up investigation of the flock conducted 9 days later. Macrorhabdus ornithogaster was confirmed in one hen. PMID- 21793455 TI - A sharp saw. PMID- 21793456 TI - Visit, revamp, and revitalize your business plan: Part 2. AB - The diagnostic imaging department strives for the highest quality outcomes in imaging quality, in diagnostic reporting, and in providing a caring patient experience while also satisfying the needs of referring physicians. Understand how tools such as process mapping and concepts such as Six Sigma and Lean Six Sigma can be used to facilitate quality improvements and team building, resulting in staff led process improvement initiatives. Discover how to integrate a continuous staff management cycle to implement process improvements,capture the promised performance improvements, and achieve a culture change away from the "way it has always been done". PMID- 21793457 TI - New codes, new rules: CT abdomen and pelvis. AB - With the introduction of new combined CT abdomen and pelvis codes it is important that all organizations ensure correct coding and claim submission for multiple exams and that the orders support the performed exam(s). PMID- 21793458 TI - ICD-10: neoplasm coding. PMID- 21793459 TI - A Lean Six Sigma journey in radiology. AB - The department of radiology at Akron Children's Hospital embarked on a Lean Six Sigma mission as part of a hospital wide initiative to show increased customer satisfaction, reduce employee dissatisfaction and frustration, and decrease costs. Three processes that were addressed were reducing the MRI scheduling back log, reconciling discrepancies in billing radiology procedures, and implementing a daily management system. Keys to success is that managers provide opportunities to openly communicate between department sections to break down barriers. Executive leaders must be engaged in Lean Six Sigma for the company to be successful. PMID- 21793460 TI - Improving safety in CT through the use of educational media. AB - With a grant from the AHRA and Toshiba Putting Patients First program, Community Hospital in Indianapolis, IN set out to reduce the need for patient sedation, mechanical restraint, additional radiation dosage,and repeat procedures for pediatric patients. An online video was produced to educate pediatric patients and their caregivers about the diagnostic imaging process enabling them to be more comfortable and compliant during the procedure. Early information and results indicate a safer experience for the patient.The goal is for the video to become a new best practice tool for improving patient care and safety in diagnostic imaging. PMID- 21793461 TI - A few more hours. PMID- 21793462 TI - When time matters. AB - The most important organizational resource is energy. The most important resource in time management is energy. Managing energy, not time, can help create encouraging time management skills and appropriate work life balance. Once a leader understands that time should be spent on things that are important instead of everything that is urgent, you can begin to develop a balance that will support your values, your family, and your organization. When leaders find meaningful ways to add a sense of purpose to their work they can personally improve themselves and their organizations. If your personal values do not align with the values of your organization you will never work with a true sense of purpose. Make the time to manage your energy. You will be surprised how much free time you find. PMID- 21793463 TI - A culture of extraordinary care: Part 2. PMID- 21793464 TI - Adaptability through cross-training in radiology departments. AB - Subject research was conducted to determine if certified radiographic technologists (CRTs) would be adaptable to learning new modalities within the radiographic field. A questionnaire was completed by a total of 248 CRTs where 70.6% were females and 29.4% were male. The questionnaire probed various stages of acceptance to learning new modalities via cross-training. Results support CRTs, adaptability to learning new modalities via cross-training. Findings indicated that the question "Did you enjoy learning new modalities?" had statistical significance and CRTs with 0-7 years of experience showed significance over those with 16 plus years of experience. PMID- 21793465 TI - Japan: some perspective. PMID- 21793466 TI - Miscarriages of justice: the role of homicide review. AB - Miscarriages of justice within the United Kingdom have received much publicity since the early nineties and served to undermine confidence in the Criminal Justice system. One fairly recent activity on the part of the Association of Chief Police Officers which has served to reduce the likelihood of such miscarriages is the principle of the review of major crime investigations and in particular murder inquiries. This paper reflects upon the possible causes of flawed investigations which have led to miscarriages of justice over the recent past and refers to the major academic work which supports the principle of reviewing murder inquiries. PMID- 21793467 TI - Hart-Devlin revisited: law, morality and consent in parenthood. AB - The debate about law and morality is not new but changing social structures and advances in science, medicine and technology have impacted the decisions courts have to make. Within the fast-changing societies of the 21st century, is judicial decision-making cognisant of these advances and how do the judiciary currently reconcile difficult emergent issues concerning law, science and morality? The dilemma of decision-making regarding frozen embryos, the gametes of deceased donors and the issue of consent is analysed by reference to recent case law and the problem of decision-making in relation to the newly possible. PMID- 21793468 TI - Advance directives in therapeutic intervention: a review of the Italian bioethical and juridical debate. AB - The authors present a review of the Italian bioethical and juridical debate about advance directives. The relevant points of difference between desistence from therapy and euthanasia and of the definition of the concept of therapy are also examined. The Italian Senate has passed a bill in which the value of advance health-care directives is affirmed. However, it is also affirmed that in conditions of emergency or when the subject's life is at immediate risk, the advance health-care directives should not be applied and artificial nutrition and hydration cannot be included in advance directives. In fact, these practices are thought to be of vital support and physiologically aimed at alleviating suffering until the end of life. Therefore, they cannot be the object of advance health care directives. It is the authors' view that it is not at all desirable to trust legislative choices about a subject which continually varies in relation to scientific and clinical knowledge, options and alternatives. The physician is rather asked for a behaviour inspired by the value of the dignity and autonomy of the persons involved, by the respect of wishes previously expressed or, in any case, objectively proved. PMID- 21793469 TI - Role of the greater sciatic notch of the hip bone in sexual dimorphism: a morphometric study of the north Indian population. AB - The distinctive morphology and sexual dimorphism of the human hip bone makes it of interest from the anatomical, anthropological and forensic points of view. The shape of the greater sciatic notch has attracted great attention in the past. In the current investigation, an attempt has been made to find the baseline data of various parameters pertaining to the greater sciatic notch of 100 hip bones of known sex (male:female = 80:20) and side (right:left = 50:50), obtained from the Department of Anatomy, Government Medical College, Amritsar, Punjab, India, during the period 2007-2009. Seven parameters of the notch, viz. width, depth, posterior segment width, total angle, posterior segment angle, index I and index II of the greater sciatic notch were studied. The results thus obtained were compiled, tabulated, statistically analysed and were compared with the accessible literature. Out of all the parameters studied, width of the notch, posterior segment width, total angle, posterior segment angle and index II of notch were found to be significantly greater in women as compared with men. Thus the greater sciatic notch can serve as a reliable sex indicator even when the complete hip bone has not been well preserved. PMID- 21793470 TI - Murder-suicide in the province of Milan, Italy: criminological analysis of cases 1990-2009. AB - Murder-suicide is a relatively rare event, and familicide is rarer still. However, it is certainly not unknown, and has been described in the scientific literature from both a socio-criminological and pathological-forensic perspective since the last century. In a civilized urban area such as Milan and province, where there is a general reduction in the homicide rate, homicide-suicide occurs almost exclusively within the family, and has specific features that differentiate it from other types of homicide, whether connected with general criminality or organized crime. This article analyses the quantitative and qualitative features of cases of homicide-suicide occurring in Milan and province between 1990 and 2009 (20 years), considering temporal aspects and the development of the events, the weapons used, and the epidemiological and psychopathological features of the perpetrators and their victims. PMID- 21793471 TI - Pattern of chest injuries in road traffic incident victims: a six-year retrospective study. AB - INTRODUCTION: The young are the most common victims of trauma and trauma is the leading cause of death in the first four decades of life. Injury accounts for more than 50% of deaths in children and is the third leading cause of death after cancer and atherosclerosis in all age groups. Thoracic trauma is one of the leading causes of death in all age groups and accounts for 25-50% of all traumatic injuries in the world. MATERIAL AND METHODS: In this retrospective study, fatal cases of thoracic trauma autopsied during the period 1 January 2004 to 31 December 2009 were analysed at the Department of Forensic Medicine & Toxicology, JN Medical College, Belgaum, Karnataka. RESULTS AND DISCUSSION: In the present study, 67.8% of victims were 40 years old or younger. Women were less involved than men, with a ratio of 1:2.2. CONCLUSION: Further establishment of 'hi-tech trauma centres' at each district level is the present need. PMID- 21793472 TI - What do newly appointed health staff know about the Mental Capacity Act (2005)? AB - OBJECTIVES: The study aimed to assess the extent of knowledge of the Mental Capacity Act (MCA) (2005) among new recruits to a National Health Service (NHS) Trust. DESIGN: Respondents were assessed before and after a brief training experience. SETTING: Data were collected while respondents attended their mandatory Trust induction training. MAIN OUTCOME MEASURE: Assessment was by means of a 16-item true-false questionnaire. RESULTS: While respondents' knowledge appeared reasonably good for some important features of the MCA, these results may have been exaggerated by a strong tendency to respond 'true', which persisted despite instructions intended to counteract it. Some significant areas of ignorance were also identified. Scores showed a small but significant improvement when participants were reassessed following a 10-minute talk on the MCA; the improvements were specific to certain items that were included in the training presentation. There were no significant differences in performance between non clinical staff, naive clinicians and clinicians who reported having previously received training on the MCA. CONCLUSIONS: Knowledge of the MCA among newly appointed NHS staff is patchy, with some strengths but also significant weaknesses. The results demonstrate a benefit of the brief training experience, but also question how much information is retained by participants in MCA training. PMID- 21793473 TI - Is acute alveolar dilation an indicator of strangulation homicide? AB - Some cases of suspected homicidal strangulation are difficult to diagnose if the classical injuries of strangulation are few or lacking. The main purpose of this study was to determine if abnormal distension of alveolar airspaces is present in strangulation deaths and whether or not it can be used to support this diagnosis. Another purpose was to see how often the gross examination of the lungs was in agreement with the microscopic examination. The material comprised 33 victims of homicidal strangulation above the age of 15 years, autopsied at the Department of Forensic Medicine in Copenhagen between 1998 and 2007. The results were compared with a control group of the same size, matched for gender and age, all of whom died naturally of cerebral or other neurological causes. The autopsy reports provided the results of the gross examination of the lungs. Regular haematoxylin eosin stained sections were made from the histological specimens. The microscopic examination was performed by computerized image analysis using stereological methods in an attempt to objectify the observations. The results showed an almost complete concordance between the findings of the gross and the microscopic examination. Stereologically the study showed that the alveoli in the strangulation cases were twice the size of those in the control group which was highly statistically significant concluding that abnormal distension of alveolar airspaces. PMID- 21793474 TI - Prevalence of HIV in the Mthatha area of South Africa, as estimated from the testing of rape victims. AB - BACKGROUND: Tremendous challenges remain in the field of HIV education, prevention and care in South Africa. There is conflicting data on the prevalence of HIV in South Africa from two major studies. Antenatal surveillance showed 29.5% prevalence whereas a household HIV survey showed a prevalence nearly half of that, at 16.2%. There is therefore a need for a third estimate in this situation. OBJECTIVE: To estimate HIV prevalence in the Mthatha area of South Africa. METHODS: Retrospective review of HIV testing results among victims of sexual assault who presented for the first time to the Sinawe Referral Centre, Mthatha General Hospital, for the period 2001-2005 (inclusive). RESULTS: Between 2001 and 2005, 1691 victims of sexual assault presented to the Sinawe Referral Centre. Of these 1435 (84.8%) were tested for HIV at the time of first consultation. One hundred and ninety-seven were found to be HIV positive on the screening test. In a space of five years (2001-2005), there was an increase in HIV prevalence from 0.9% to 6.4%. The highest HIV positive rate (3.7%) was found in the 16-20 year age group. CONCLUSION: The HIV prevalence rate is 13.7% in the Mthatha area, and just over a half (7%) of HIV-positive rape survivors were aged 16-25 years. PMID- 21793475 TI - Causes of laryngeal cartilage and hyoid bone fractures found at postmortem. AB - The principal aims of this retrospective study were to assess the prevalence and causes of laryngo-hyoid fractures found in coroners' adult postmortem examinations over a five-year period. In 78 of 1930 cases (4%), there was a fracture of the larynx (thyroid or cricoid cartilage) or hyoid bone. The thyroid cartilage alone was fractured in 38 cases; the hyoid bone alone was fractured in 19 cases; the larynx and hyoid bone were both fractured in 21 cases, including one which involved the cricoid cartilage. There was no evidence of surface injury to the neck in 14.1% of cases. The majority (44/78; 56.4%) involved classical manual or ligature 'pressure to the neck', i.e. hanging (32) or strangulation (12) but a significant minority (35.9%) involved other circumstances: road/rail traffic collision (12; 15.4%); falls (6; 7.7%); assaults involving blunt force trauma to the head and neck (4; 5.1%); incised wounds (3; 3.8%); gunshot wounds (2; 2.6%); and explosion (1; 1.3%). The circumstances of death and cause of fracture(s) were 'unascertained' in four cases (5.1%). Postmortem artefact accounted for two cases (2.6%). PMID- 21793476 TI - Cataract as the root cause of fatal road traffic accidents in pedestrians. AB - Senile cataract is an important cause of preventable blindness, affecting 12-15 million people worldwide. In India, approximately 3.8 million people become blind from cataract each year. Moreover, in India, senile cataract develops at a relatively younger age than that seen in developed countries. However, during routine postmortem examination, search for cataract is often ignored, although it could be a major factor responsible for many road traffic accidents. This paper reports two cases of road traffic accident, where the judgement of the court exonerated the accused drivers based on the findings of eye examination during autopsy. Routine examination of the eye for cataract is recommended in every person involved in a road traffic accident irrespective of whether he is a victim or an accused. PMID- 21793477 TI - Aluminium phosphide (tank pill) poisoning in the Transkei region of South Africa: a case report. AB - About half a million people die each year as a result of various kinds of poisoning. The incidence of pesticide poisoning, which is high in developing countries, has doubled over the past 10 years. Aluminium phosphide is a deadly fumigant pesticide. A 21-year-old man committed suicide by ingesting aluminium phosphide, which he had available in his home. He had been charged with rape, and was to appear in court. Soon after ingestion, he told his grandmother about the suicide attempt. He was taken to a nearby hospital, where he was dead within an hour of arriving. The mechanism of action, symptoms and signs will be discussed in this report. The purpose of this case report is to highlight the problem of aluminium phosphide poisoning in the Transkei region of South Africa. PMID- 21793478 TI - 'Withdrawal neuroleptic malignant syndrome': a phantom explanatory cause for a fatality. PMID- 21793479 TI - Mergers and acquisitions: coming together without falling apart. PMID- 21793480 TI - Healthcare mergers and acquisitions: strategies for consolidation. AB - The passage of federal healthcare reform legislation, in combination with other factors, makes it likely that the next few years will be a major period of consolidation for healthcare organizations. This article examines the seven key forces reshaping healthcare delivery--from insurance industry consolidation to cost inflation to the increasing gap between financially strong and struggling providers--and provides advice for organizations on both sides of an acquisition. PMID- 21793481 TI - Successful affiliations: principles and practices. AB - An affiliation can help a healthcare provider prepare for the challenges of healthcare reform, the rapidly changing landscapes of the commercial insurance industry, and the public's expectations about service and quality. UC Davis Medical Center, a 645-bed tertiary hospital in Sacramento, California, with many hospital-based clinics and a community-based group of primary care clinics, has developed a number of principles for affiliation. These principles are based on its experience in legal and financial affiliations with an academic practice group, with individual and small groups of primary care physicians, and with community hospitals around oncology services linked with U.C. Davis' National Cancer Institute-designated cancer center. This article offers a process for evaluating the appropriateness of an affiliation. The chances for a successful affiliation improve if each party has indicated the value it hopes to derive and how to measure that value, has communicated with all affected constituents, and has an agreed-upon method for resolving disputes. PMID- 21793482 TI - Lessons learned in mergers and acquisitions. PMID- 21793483 TI - Integration: an inclusive approach to provider affiliations. PMID- 21793484 TI - Stronger together: merging to serve the community. PMID- 21793486 TI - Planar hydrocarbons more optically active than their isomeric helicenes. AB - Comparisons are made of the calculated optical rotation tensors of C(2v) symmetric, polyaromatic hydrocarbons and their [5]helicene, [6]helicene, and [7]helicene isomers. Seven ?-shaped, planar compounds had, in each case, larger computed tensor elements than the chiral helicenes. Merely obviating the condition of solution averaging wholly changes expectations of the magnitudes and etiologies of optical activity. Symmetries of achiral compounds facilitate semiquantitative correlations between structure and optical rotation. PMID- 21793485 TI - Critical tissue residue approach linking accumulated metals in aquatic insects to population and community-level effects. AB - Whole body Zn concentrations in individuals (n = 825) from three aquatic insect taxa (mayflies Rhithrogena spp. and Drunella spp. and the caddisfly Arctopsyche grandis) were used to predict effects on populations and communities (n = 149 samples). Both mayflies accumulated significantly more Zn than the caddisfly. The presence/absence of Drunella spp. most reliably distinguished sites with low and high Zn concentrations; however, population densities of mayflies were more sensitive to increases in accumulated Zn. Critical tissue residues (634 MUg/g Zn for Drunella spp. and 267 MUg/g Zn for Rhithrogena spp.) caused a 20% reduction in maximum (90th quantile) mayfly densities. These critical tissue residues were associated with exposure to 7.0 and 3.9 MUg/L dissolved Zn for Drunella spp. and Rhithrogena spp., respectively. A threshold in a measure of taxonomic completeness (observed/expected) was observed at 5.4 MUg/L dissolved Zn. Dissolved Zn concentrations associated with critical tissue residues in mayflies were also associated with adverse effects in the aquatic community as a whole. These effects on populations and communities occurred at Zn concentrations below the U.S. EPA hardness-adjusted continuous chronic criterion. PMID- 21793488 TI - K2CO3-promoted domino reactions: construction of functionalized 2,3 dihydrobenzofurans and clofibrate analogues. AB - The K(2)CO(3)-catalyzed domino reactions (Michael alkylation, Mannich alkylation, and aldol alkylation) of salicylic aldehyde derivatives (2-hydroxyaryl-alpha,beta unsaturated ketones, 2-hydroxyarylnitroalkenes, 2-hydroxyarylimines, and salicylic aldehydes) and 2-halo-1,3-dicarbonyl compounds (diethyl alpha bromomalonate, diethyl alpha-chloromalonate, ethyl 2-chloroacetoacetate, and 3 chloropentane-2,4-dione) were carried out under mild conditions to provide a series of functionalized 2,3-dihydrobenzofurans in moderate to excellent yields. The novel transformations simultaneously gave a series of clofibrate analogues, which possess various substitution patterns. PMID- 21793487 TI - Modulating distal cavities in the alpha and beta subunits of human HbA reveals the primary ligand migration pathway. AB - The free volume in the active site of human HbA plays a crucial role in governing the bimolecular rates of O(2), CO, and NO binding, the fraction of geminate ligand recombination, and the rate of NO dioxygenation by the oxygenated complex. We have decreased the size of the distal pocket by mutating Leu(B10), Val(E11), and Leu(G8) to Phe and Trp and that of other more internal cavities by filling them with Xe at high gas pressures. Increasing the size of the B10 side chain reduces bimolecular rates of ligand binding nearly 5000-fold and inhibits CO geminate recombination due to both reduction of the capture volume in the distal pocket and direct steric hindrance of Fe-ligand bond formation. Phe and Trp(E11) mutations also cause a decrease in distal pocket volume but, at the same time, increase access to the Fe atom because of the loss of the gamma2 CH(3) group of the native Val(E11) side chain. The net result of these E11 substitutions is a dramatic increase in the rate of geminate recombination because dissociated CO is sequestered close to the Fe atom and can rapidly rebind without steric resistance. However, the bimolecular rate constants for binding of ligand to the Phe and Trp(E11) mutants are decreased 5-30-fold, because of a smaller capture volume. Geminate and bimolecular kinetic parameters for Phe and Trp(G8) mutants are similar to those for the native HbA subunits because the aromatic rings at this position cause little change in distal pocket volume and because ligands do not move past this position into the globin interior of wild-type HbA subunits. The latter conclusion is verified by the observation that Xe binding to the alpha and beta Hb subunits has little effect on either geminate or bimolecular ligand rebinding. All of these experimental results argue strongly against alternative ligand migration pathways that involve movements through the protein interior in HbA. Instead, ligands appear to enter through the His(E7) gate and are captured directly in the distal cavity. PMID- 21793489 TI - Using gene expression to assess the status of fish from anthropogenically influenced estuarine wetlands. AB - The diverse mixture of contaminants frequently present in estuaries complicates their assessment by routine chemical or biological analyses. We investigated the use of gene expression to assess contaminant exposure and the condition of southern California estuarine fish. Liver gene expression, plasma estradiol concentrations, and gonad histopathology were used to study biological condition in longjaw mudsuckers (Gillichthys mirabilis). Metals, legacy organochlorine pesticides, PCBs, and contaminants of emerging concern were detected in sediments and whole fish. Overall gene expression patterns were characteristic to each of four sites investigated in this study. Differentially expressed genes belonged to several functional categories including xenobiotic metabolism, detoxification, disease, and stress responses. In general, plasma estradiol concentrations were similar among fish from all areas. Some fish gonads had pathologic changes (e.g., infection, inflammation) that could indicate weakened immune systems and chronic stress. The differential expression of some genes involved in stress responses correlated with the prevalence of histologic gonad lesions. This study indicates that gene expression is a promising tool for assessing the biological condition of fish exposed to environmental contaminants. PMID- 21793490 TI - Complementary methods for the determination of dissolved oxygen content in perfluorocarbon emulsions and other solutions. AB - Perfluorocarbons (PFCs) are compounds with increased oxygen solubility and effective diffusivity, making them ideal candidates for improving oxygen mass transfer in numerous biological applications. Historically, quantification of the mass transfer characteristics of these liquids has relied on the use of elaborate laboratory equipment and complicated methodologies, such as in-line gas chromatography coupled with temperature-controlled glass fritted diffusion cells. In this work, we present an alternative method for the determination of dissolved oxygen content in PFC emulsions and, by extrapolation, pure PFCs. We implemented a simple stirred oxygen consumption microchamber coupled with an enzymatic reaction for the quantitative determination of oxygen by optical density measurements. Chambers were also custom fitted with lifetime oxygen sensors to permit simultaneous measurement of internal chamber oxygen levels. Analyzing the consumption of oxygen during the enzymatic reaction via recorded oxygen depletion traces, we found a strong degree of correlation between the zero-order reaction rate and the total measured oxygen concentrations, relative to control solutions. The values obtained were in close agreement with published values in the literature, establishing the accuracy of this method. Overall, this method allows for easy, reliable, and reproducible measurements of oxygen content in aqueous solutions, including, but not limited to PFC emulsions. PMID- 21793491 TI - Kinetic cellular phenotypic profiling: prediction, identification, and analysis of bioactive natural products. AB - Natural products have always been a major source of therapeutic agents; however, the development of traditional herbal products has been currently hampered by the lack of analytic methods suitable for both high-throughput screening and evaluating the mechanism of action. Cellular processes such as proliferation, apoptosis, and toxicity are well-orchestrated in real time. Monitoring these events and their perturbation by natural products can provide high-rich information about cell physiological relevancies being involved. Here, we report a novel cell-based phenotypic profiling strategy that uses electronic impedance readouts for real-time monitoring of cellular responses to traditional Chinese medicines (TCMs). The utility of this approach was used to screen natural herbs that have been historically documented to cure human diseases and that have been classified into seven clusters based on their mechanisms of action. The results suggest that herbal medicines with similar cellular mechanisms produce similar time/dose-dependent cell response profiles (TCRPs). By comparing the TCRPs produced by the Chinese medicinal Cordyceps sinensis with similar TCRPs of chemical compounds, we explored the potential use of herbal TCRPs for predicting cellular mechanisms of action, herbal authentications, and bioactive identification. Additionally, we further compared this novel TCRP technology with high-performance liquid chromatography (HPLC)-based methods for herbal origin tracing authentication and identification of bioactive ingredients. Together, our findings suggest that using TCRP as an alternative to existing spectroscopic techniques can allow us to analyze natural products in a more convenient and physiologically relevant manner. PMID- 21793492 TI - Exploring the structure and properties of transition metal templated {VM17(VO4)2} Dawson-like capsules. AB - Vanadate(V)-templated Dawson-type capsules {V(IV)M(VI)(17)(VO(4))(2)} (M = Mo, W; 1-2) have been synthesized and investigated by electrochemical methods in aqueous and organic media using spectroscopic techniques, EPR, UV-vis/NIR, IR, and CSI-MS (cryospray ionization mass spec.), and the clusters have been examined in the solid state by magnetic studies. The collision-induced dissociation (CID-MS) studies confirmed the solution structures as well as helped pinpoint the position of the vanadium ion on the {VM(17)}-type shell, which was corroborated by EPR and theoretical studies. PMID- 21793494 TI - CsTe2O(6-x): novel mixed-valence tellurium oxides with framework-deficient pyrochlore-related structure. AB - Structures of CsTe2O(6-x) phases were investigated by single-crystal X-ray diffraction and neutron powder diffraction. Stoichiometric CsTe2O6 is a mixed valence Cs2Te4+Te36+O12 compound with a rhombohedral pyrochlore-type structure where there is complete order of Te4+ and Te6+. On heating, this compound develops significant electrical conductivity. As CsTe2O6 becomes oxygen deficient above 600 degrees C, the rhombohedral pyrochlore-type structure is replaced by a cubic pyrochlore-type structure with disordered Te4+/Te6+ and oxygen vacancies. However, for CsTe2O(6-x) phases prepared at 500 degrees C, the observed pyrochlore-type structure has symmetry. The Te4+ and O vacancies are all on chains running along the b axis, and the maximum value of x observed is about 0.3. At still higher values of x a new compound was discovered with a structure related to that reported for Rb4Te34+Te56+O23. PMID- 21793493 TI - An oxidized active site model for the FeFe hydrogenase: reduction with hydrogen gas. AB - Models for the oxidized form of the FeFe hydrogenase active site have been prepared. These cationic complexes contain two iron atoms, carbonyl ligands, a propanedithiolate bridge, and one other bridging group. Reduction of these complexes with hydrogen gas is demonstrated. PMID- 21793495 TI - Synthesis and characterization of large-area graphene and graphite films on commercial Cu-Ni alloy foils. AB - Controlling the thickness and uniformity during growth of multilayer graphene is an important goal. Here we report the synthesis of large-area monolayer and multilayer, particularly bilayer, graphene films on Cu-Ni alloy foils by chemical vapor deposition with methane and hydrogen gas as precursors. The dependence of the initial stages of graphene growth rate on the substrate grain orientation was observed for the first time by electron backscattered diffraction and scanning electron microscopy. The thickness and quality of the graphene and graphite films obtained on such Cu-Ni alloy foils could be controlled by varying the deposition temperature and cooling rate and were studied by optical microscopy, scanning electron microscopy, atomic force microscopy, and micro-Raman imaging spectroscopy. The optical and electrical properties of the graphene and graphite films were studied as a function of thickness. PMID- 21793496 TI - Palladium-catalyzed direct cross-coupling reaction of glycals with activated alkenes. AB - An efficient method for a Pd(OAc)(2)-catalyzed cross-coupling reaction of glycals with activated alkenes under mild conditions has been developed. This transformation provides an expedient synthetic method to C(2)-functionalized glycals, which are common structural building blocks in natural products and other biologically active compounds. The reaction scope includes different kinds of carbohydrates, protecting groups and substituents on alkene. Moderate to excellent yields and pure E configuration selectivity were obtained. PMID- 21793497 TI - Source truncation and exhaustion: insights from quantitative in situ TEM tensile testing. AB - A unique method for quantitative in situ nanotensile testing in a transmission electron microscope employing focused ion beam fabricated specimens was developed. Experiments were performed on copper samples with minimum dimensions in the 100-200 nm regime oriented for either single slip or multiple slip, respectively. We observe that both frequently discussed mechanisms, truncation of spiral dislocation sources and exhaustion of defects available within the specimen, contribute to high strengths and related size-effects in small volumes. This suggests that in the submicrometer range these mechanisms should be considered simultaneously rather than exclusively. PMID- 21793498 TI - Evaluating the transcriptomic and metabolic profile of mice exposed to source drinking water. AB - Transcriptomic and metabonomic methods were used to investigate mice's responses to drinking source water (DSW) exposure. After mice were fed with DSW for 90 days, hepatic transcriptome was characterized by microarray and serum metabonome were determined by (1)H nuclear magnetic resonance (NMR) spectroscopy. A total of 243 differentially expressed genes (DEGs) were identified, among which 141 genes were up-regulated and 102 genes were down-regulated. Metabonomics revealed significant changes in concentrations of creatine, pyruvate, glutamine, lysine, choline, acetate, lipids, taurine, and trimethylamine oxide. Four biological pathways were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis where both gene expression and metabolite concentrations were altered in response to DSW exposure. These results highlight the significance of combined use of transcriptomic and metabonomic approaches in evaluating potential health risk induced by DSW contaminated with various hazardous materials. PMID- 21793499 TI - Synthesis and characterization of silica nanoparticles with well-defined thermoresponsive PNIPAM via a combination of RAFT and click chemistry. AB - Covalent functionalization of azide-modified SiO(2) with well-defined, alkyne terminated poly(N-isopropylacrylamide) was accomplished by the Cu(I)-catalyzed [3 + 2] Huisgen cycloaddition. The alkyne-terminated RAFT chain transfer agent was first synthesized, and then the alkyne-terminated thermoresponsive poly(N isopropylacrylamide) (PNIPAM) with different molecular weights were synthesized by the RAFT of NIPAM monomer. The polymerization kinetics and the evolution of number-average molecular weights (M(n)), and polydispersities (M(w)/M(n)), with monomer conversions were investigated. A copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "grafting to" method was used to attach thermoresponsive polymers onto the exterior surface of SiO(2) nanoparticles which produced relatively high grafting density. The as-synthesized hybrid nanoparticles showed thermoresponsive behavior and were characterized by FTIR, XPS, TGA, DLS, and TEM, etc. PMID- 21793500 TI - Simple one-center model for linear molecules: application to carbon dioxide. AB - With computational efficacy in mind, a one-center model for linear molecules is heuristically sketched. When parametrized for CO(2), all parameters save for two are supplied from literature quantum chemistry calculation or, in one case, heuristic argument. Using the remaining two adjustable parameters, the mean unsigned relative errors (predicted/observed) over the temperature range 220-290 K are 4.7% for the energy of vaporization, 0.6% for the liquid, and 8.0% for the vapor coexistence densities, respectively. The critical temperature is estimated at T(c) = 308 K, the critical density at rho(c) = 0.460 g/cm(3), and the critical pressure at p(c) = 8.26 +/- 0.11 MPa. This order of accuracy is comparable to that of many all-atom potential descriptions of CO(2) but is obtained at roughly nine times the speed. When supplied with the experimental bond length, somewhat worse agreement with experiment is exhibited for the neutron-weighted atomic pair distribution function of the liquid. This disparity is tentatively attributed to an overestimated electrostatic quadrupole-quadrupole interaction relative to the other forces present. PMID- 21793501 TI - X-ray absorption and micro X-ray fluorescence spectroscopy investigation of copper and zinc speciation in biosolids. AB - Despite its pivotal role in determining the risks and time frames associated with contaminant release, metal speciation remains a poorly understood aspect of biosolids chemistry. The work reported here used synchrotron-based spectroscopy techniques to investigate the speciation of copper and zinc in a range of Australian biosolids. High resolution element mapping of biosolids samples using micro X-ray fluorescence spectroscopy revealed considerable heterogeneity in key element associations, and a combination of both organic and inorganic copper and zinc binding environments. Linear combination fitting of K-edge X-ray absorption spectra indicated consistent differences in metal speciation between freshly produced and stockpiled biosolids. While sulfide minerals play a dominant role in metal binding in freshly dewatered biosolids, they are of lesser importance in dried biosolids that have been stockpiled. A degree of metal binding with iron oxide minerals was apparent but the results did not support the hypothesis that biosolids metals are chiefly associated with iron minerals. This work has potential implications for the long-term stability of metals in biosolids and their eventual fate following land application. PMID- 21793502 TI - Interfacial synthesis: amphiphilic monomers assisted ultrarefining of mesoporous manganese oxide nanoparticles and the electrochemical implications. AB - Amphiphilic monomers, namely pyrrole and aniline, were used to reduce permanganate ion (MnO(4)(-)) at the dichloromethane/water interface for the preparation of ultrafine manganese oxide (MnO(x), x <= 2) nanoparticles (NPs). These monomers did not undergo polymerization upon oxidation by MnO(4)(-), but exerted an interesting effect of ultrarefining the produced MnO(x) NPs from reducing MnO(4)(-) at the organoaqueous interface. This was attributed to the ability of the monomer to access the interfacial reaction sites from both organic and aqueous phases, and hence retard the as-produced MnO(x) nuclei from aggregation at the interface. Such obtained products were mesoporous matrixes of three-dimensionally interconnected and uniform pseudospherical MnO(x) NPs (<20 nm). On the contrary, using a more hydrophobic monomer, i.e., o-aminophenol, to reduce MnO(4)(-) produced a composite of nanobelts of poly(o-aminophenol) embedded in micrometer-sized MnO(x) blocks. The ultrafine MnO(x) NPs prepared from using aniline or pyrrole exhibited highly capacitive behavior in aqueous Na(2)SO(4), promising their use in supercapacitors. It was also found that the MnO(x) NPs prepared from pyrrole-assisted synthesis possessed higher specific capacitance than that from aniline-assisted synthesis, despite the latter having a higher specific surface area. This difference is discussed in terms of crystallographic properties and water contents of these two samples. PMID- 21793503 TI - Self-assembly of phospholipid-PEG coating on nanoparticles through dual solvent exchange. AB - We coated nanoparticles including iron oxide nanoparticles and quantum dots with phospholipid-PEG using the newly developed dual solvent exchange method and demonstrated that, compared with the conventional film hydration method, the coating efficiency and quality of coated nanoparticles can be significantly improved. A better control of surface coating density and the amount of reactive groups on nanoparticle surface is achieved, allowing conjugation of different moieties with desirable surface concentrations, thus facilitating biomedical applications of nanoparticles. PMID- 21793504 TI - Effects of thymol on mushroom tyrosinase-catalyzed melanin formation. AB - The novel inhibitory mechanism of thymol (2-isopropyl-5-methylphenol) on dopachrome formation by mushroom tyrosinase (EC 1.14.18.1) was identified. The UV vis spectrum and oxygen consumption assays showed dopachrome formation using L tyrosine as a substrate was suppressed by thymol. This inhibitory activity was reversed by the addition of a well-known radical scavenger, butylated hydroxyanisole (BHA). Further investigations using N-acetyl-L-tyrosine as a substrate with HPLC analysis suggested that thymol inhibits chemical redox reactions between dopaquinone and leukodopachrome instead of enzymatic reaction. This redox inhibitory activity of thymol was examined by using a model redox reaction with L-dihydroxyphenylalanine (L-DOPA) and p-benzoquinone. Thymol successfully inhibited oxidation of L-DOPA to dopaquinone, coupled with reduction of p-benzoquinone. Hence, the suppression of dopachrome formation by thymol is due to the inhibition of conversion of leukodopachrome to dopachrome. The antioxidant property of thymol is a key characteristic for the inhibitory mechanism of melanin synthesis. PMID- 21793505 TI - Thieno[3,4-c]pyrrole-4,6-dione-based polymer semiconductors: toward high performance, air-stable organic thin-film transistors. AB - We report a new p-type semiconducting polymer family based on the thieno[3,4 c]pyrrole-4,6-dione (TPD) building block, which exhibits good processability as well as good mobility and lifetime stability in thin-film transistors (TFTs). TPD homopolymer P1 was synthesized via Yamamoto coupling, whereas copolymers P2-P8 were synthesized via Stille coupling. All of these polymers were characterized by chemical analysis as well as thermal analysis, optical spectroscopy, and cyclic voltammetry. P2-P7 have lower-lying HOMOs than does P3HT by 0.24-0.57 eV, depending on the donor counits, and exhibit large oscillator strengths in the visible region with similar optical band gaps throughout the series (~1.80 eV). The electron-rich character of the dialkoxybithiophene counits in P8 greatly compresses the band gap, resulting in the lowest E(g)(opt) in the series (1.66 eV), but also raising the HOMO energy to -5.11 eV. Organic thin-film transistor (OTFT) electrical characterization indicates that device performance is very sensitive to the oligothiophene conjugation length, but also to the solubilizing side chain substituents (length, positional pattern). The corresponding thin-film microstructures and morphologies were investigated by XRD and AFM to correlate with the OTFT performance. By strategically varying the oligothiophene donor conjugation length and optimizing the solubilizing side chains, a maximum OTFT hole mobility of ~0.6 cm(2) V(-1) s(-1) is achieved for P4-based devices. OTFT environmental (storage) and operational (bias) stability in ambient was investigated, and enhanced performance is observed due to the low-lying HOMOs. These results indicate that the TPD is an excellent building block for constructing high-performance polymers for p-type transistor applications due to the excellent processability, substantial hole mobility, and good device stability. PMID- 21793506 TI - Comparison of the chemical constituents of aged pu-erh tea, ripened pu-erh tea, and other teas using HPLC-DAD-ESI-MSn. AB - Pu-erh tea is a popular beverage in southwestern China and South Asian countries. To explain the differences of aged pu-erh tea and ripened pu-erh tea, the chemical constituents of these teas were identified by HPLC-DAD-ESI-MS(n). In addition, HPLC was used to determine the contents of the major polyphenols, gallic acid, caffeine, and theobromine, in various types of teas. These results showed that the majority of chemical constituents in ripened pu-erh tea and aged pu-erh tea were similar, but the contents of catechins and gallic acid presented significant differences between these two teas. After fermentation by microorganism, the levels of catechins in ripened pu-erh tea were decreased, but the contents of gallic acid and caffeine were conversely elevated compared with aged pu-erh tea. PMID- 21793507 TI - Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry. AB - Tyrosine sulfate-mediated interactions play an important role in HIV-1 entry. After engaging the CD4 receptor at the cell surface, the HIV-1 gp120 glycoprotein binds to the CCR5 co-receptor via an interaction that requires two tyrosine sulfates, at positions 10 and 14 in the CCR5-N terminus. Building on previous structure determinations of this interaction, here we report the targeting of these tyrosine sulfate binding sites for drug design through in silico screening of small molecule libraries, identification of lead compounds, and characterization of biological activity. A class of tyrosine sulfate-mimicking small molecules containing a "phenyl sulfonate-linker-aromatic" motif was identified that specifically inhibited binding of gp120 to the CCR5-N terminus as well as to sulfated antibodies that recognize the co-receptor binding region on gp120. The most potent of these compounds bound gp120 with low micromolar affinity and its CD4-induced conformation with K(D)'s as tight as ~50 nM. Neutralization experiments suggested the targeted site to be conformationally inaccessible prior to CD4 engagement. Primary HIV-1 isolates were weakly neutralized, preincubation with soluble CD4 enhanced neutralization, and engineered isolates with increased dependence on the N terminus of CCR5 or with reduced conformational barriers were neutralized with IC(50) values as low as ~1 MUM. These results reveal the potential of targeting the tyrosine sulfate interactions of HIV-1 and provide insight into how mechanistic barriers, evolved by HIV-1 to evade antibody recognition, also restrict small-molecule-mediated neutralization. PMID- 21793508 TI - Plasmonic-based imaging of local square wave voltammetry. AB - Square wave voltammetry (SWV) is widely used in electrochemical analysis and sensors because of its high sensitivity and efficient rejection of background current, but SWV by the conventional electrochemical detection method does not provide spatial resolution. We report here a plasmonic method to image local SWV, which opens the door for analyzing heterogeneous electrochemical reactions and for high-throughput detections of microarrays. We describe the basic principle, validate the principle by comparing the plasmonic-based SWV with those obtained with the conventional method, and demonstrate imaging capability for local electrochemical analysis. PMID- 21793509 TI - Tandem catalytic allylic amination and [2,3]-Stevens rearrangement of tertiary amines. AB - We have developed a catalytic allylic amination involving tertiary aminoesters and allylcarbonates, which is the first example of the use of tertiary amines as intermolecular nucleophiles in metal-catalyzed allylic substitution chemistry. This process is employed in a tandem ammonium ylide generation/[2,3] rearrangement reaction, which formally represents a palladium-catalyzed Stevens rearrangement. Low catalyst loadings and mild reaction conditions are compatible with an unprecedented substrate scope for the ammonium ylide functionality, and products are generated in high yields and diastereoselectivities. Mechanistic studies suggested the reversible formation of an ammonium intermediate. PMID- 21793510 TI - Nonadiabatic QM/MM simulations of fast charge transfer in Escherichia coli DNA photolyase. AB - In this report, we study the photoactivation process in Escherichia coli DNA photolyase, involving long-range electron transport along a conserved chain of Trp residues between the protein surface and the flavin adenine dinucleotide (FAD) cofactor. Fully coupled nonadiabatic (Ehrenfest) quantum mechanics/molecular mechanics (QM/MM) simulations allow us to follow the time evolution of charge distributions over the natural time scale of multiple charge transfer events and conduct rigorous statistical analysis. Charge transfer rates in excellent agreement with experimental data are obtained without the need for any system-specific parametrization. The simulations are shown to provide a more detailed picture of electron transfer than a classical analysis of Marcus parameters. The protein and solvent both strongly influence the localization and transport properties of a positive charge, but the directionality of the process is mainly caused by solvent polarization. The time scales of charge movement, delocalization, protein relaxation and solvent reorganization overlap and lead to nonequilibrium reaction conditions. All these contributions are explicitly considered and fully resolved in the model used and provide an intricate picture of multistep biochemical electron transfer in a flexible, heterogeneous environment. PMID- 21793512 TI - A dyad as photocatalyst for light-driven sulfide oxygenation with water as the unique oxygen atom source. AB - With the objective to convert light energy into chemical oxidation energy, a ruthenium-based dyad constituted of the assembly of a photosensitizer and a catalytic fragment was synthesized. Upon irradiation with blue LEDs, and in the presence of an electron acceptor, the complex is able to catalyze selective sulfide oxygenation involving an oxygen atom transfer from water to the substrate. Electrochemical and photophysical studies highlighted a proton-coupled electron transfer (PCET) to access to a high valent oxidant Ru(IV) oxo species. PMID- 21793511 TI - Structural diversity in metal complexes with a dinucleating ligand containing carboxyamidopyridyl groups. AB - The synthesis of a (carboxyamido)pyridinepyrazolate (H(5)bppap) dinucleating ligand is described. Bimetallic iron and cobalt complexes of H(5)bppap ([M(II)(2)H(2)bppap](+)) showed structural differences in both their primary and secondary coordination spheres. The binding of small molecules into the preorganized ligand cavity is verified by the hydration of [Fe(II)(2)H(2)bppap](+) and [Co(II)(2)H(2)bppap](+), leading to the formation of complexes [{Co(II)(OH)}Co(II)H(3)bppap](+) and [{Fe(II)(OH)}Fe(II)H(3)bppap](+), in which one of the metal centers has a terminal hydroxo ligand. PMID- 21793513 TI - Permanganate oxidation of alpha-amino acids: kinetic correlations for the nonautocatalytic and autocatalytic reaction pathways. AB - The reactions of permanganate ion with seven alpha-amino acids in aqueous KH(2)PO(4)/K(2)HPO(4) buffers have been followed spectrophotometrically at two different wavelengths: 526 nm (decay of MnO(4)(-)) and 418 nm (formation of colloidal MnO(2)). All of the reactions studied were autocatalyzed by colloidal MnO(2), with the contribution of the autocatalytic reaction pathway decreasing in the order glycine > l-threonine > l-alanine > l-glutamic acid > l-leucine > l isoleucine > l-valine. The rate constants corresponding to the nonautocatalytic and autocatalytic pathways were obtained by means of either a differential rate law or an integrated one, the latter requiring the use of an iterative method for its implementation. The activation parameters for the two pathways were determined and analyzed to obtain statistically significant correlations for the series of reactions studied. The activation enthalpy of the nonautocatalytic pathway showed a strong, positive dependence on the standard Gibbs energy for the dissociation of the protonated amino group of the alpha-amino acid. Linear enthalpy-entropy correlations were found for both pathways, leading to isokinetic temperatures of 370 +/- 21 K (nonautocatalytic) and 364 +/- 28 K (autocatalytic). Mechanisms in agreement with the experimental data are proposed for the two reaction pathways. PMID- 21793514 TI - Equilibrated high-density amorphous ice and its first-order transition to the low density form. AB - We investigate the downstroke transition from high- (HDA) to low-density amorphous ice (LDA) at 140 (H(2)O) and 143 K (D(2)O). The visual observation of sudden phase separation at 0.07 GPa is evidence of the first-order character of the transition. Powder X-ray diffractograms recorded on chips recovered from the propagating front show a double halo peak indicative of the simultaneous presence of LDA and HDA. By contrast, chips picked from different parts of the sample cylinder show either HDA or LDA. Growth of the low-density form takes place randomly somewhere inside of the high-density matrix. The thermal stability of HDA against transformation to LDA at ambient pressure significantly increases with decreasing recovery pressure and reaches its maximum at 0.07 GPa. A sample decompressed to 0.07 GPa is by ~17 K more stable than an unannealed HDA sample. An increasingly relaxed nature of the sample is also evident from the progressive disappearance of the broad calorimetric relaxation exotherm, preceding the sharp transition to LDA. Finally, we show that two independent thermodynamic paths lead to a very similar state of (relaxed) HDA at 140 K and 0.2 GPa. We argue that these observations imply an equilibrated nature of the amorphous sample in the pressure range of p ? 0.2 GPa and speculate that the observation of macroscopic phase separation involves two ultraviscous liquid phases at 140 K. This supports the scenario of a first-order liquid-liquid transition in bulk water. PMID- 21793516 TI - On the stability, electronic structure, and nonlinear optical properties of HXeOXeF and FXeOXeF. AB - The electronic ground state, stability, and linear and nonlinear optical properties of HXeOXeF and FXeOXeF have been studied theoretically by employing complete active space valence bond (CASVB), multistate complete active space perturbation theory (MS-CASPT2), and coupled cluster methods. It is shown that the oxygen inserted between the two Xe atoms significantly modifies the ground state electronic configuration of the formed derivative by increasing the closed shell contribution (sigma(2)) and removing the diradicaloid character observed in HXe(2)F. The electronic charge distribution has been analyzed by employing the atoms-in-molecules (AIM) method. The dissociation channels of HXeOXeF and FXeOXeF have been studied in detail. It was found that these compounds are metastable, protected by substantial energy barriers and, thus, they can be prepared under appropriate conditions. Both two- and three-body dissociation reactions have been considered. The effects of inserting O in HXe(2)F and substituting H (HXeOXeF) by F, leading to FXeOXeF, on the energy barriers are discussed. The significant effects of the inserted oxygen on the polarizability and even more on the first hyperpolarizability have been computed and rationalized. PMID- 21793515 TI - On-bead combinatorial synthesis and imaging of chemical exchange saturation transfer magnetic resonance imaging agents to identify factors that influence water exchange. AB - The sensitivity of magnetic resonance imaging (MRI) contrast agents is highly dependent on the rate of water exchange between the inner sphere of a paramagnetic ion and bulk water. Normally, identifying a paramagnetic complex that has optimal water exchange kinetics is done by synthesizing and testing one compound at a time. We report here a rapid, economical on-bead combinatorial synthesis of a library of imaging agents. Eighty different 1,4,7,10 tetraazacyclododecan-1,4,7,10-tetraacetic acid (DOTA)-tetraamide peptoid derivatives were prepared on beads using a variety of charged, uncharged but polar, hydrophobic, and variably sized primary amines. A single chemical exchange saturation transfer image of the on-bead library easily distinguished those compounds having the most favorable water exchange kinetics. This combinatorial approach will allow rapid screening of libraries of imaging agents to identify the chemical characteristics of a ligand that yield the most sensitive imaging agents. This technique could be automated and readily adapted to other types of MRI or magnetic resonance/positron emission tomography agents as well. PMID- 21793518 TI - White light-emitting electrochemical cell. AB - We report a light-emitting electrochemical cell (LEC) with air-stable electrodes and a solution-processed single-layer active material that emits warm-white light (CIE coordinates = (0.39, 0.43); color rendering index =83) with significant brightness (B) at a low voltage. The carefully tuned trichromatic device exhibits a short turn-on time (~5 s to B > 100 cd/m(2)), high efficiency (3.1 cd/A at B = 240 cd/m(2)) and good operational stability (17 h at B > 100 cd/m(2)). We also report a blue LEC with a highly respectable set of device properties in the form of a turn-on time of ~5 s, an efficiency of 3.6 lm/W and 5.6 cd/A, and an uninterrupted operational lifetime of 25 h. Finally, by analyzing data from trichromatic and monochromatic devices as well as from the constituent fluorescent CPs, we are able to point out a viable path toward further improvements in the performance of the white-emitting LEC. PMID- 21793519 TI - Reversible and irreversible vapor-induced guest molecule exchange in spin crossover compounds. AB - Spin-crossover (SCO) complex [Fe(tpa)(NCS)(2)] (tpa = tri(2-pyridylmethyl)amine) crystallized in two solvate forms, yellow [Fe(tpa)(NCS)(2)].X [Fe:X = 1:1; X = n PrOH (complex is named as n-PrOH), i-PrOH (i-PrOH), CH(2)Cl(2) (CH(2)Cl(2)), CHCl(3) (CHCl(3)), MeCN (MeCN)] and red [Fe(tpa)(NCS)(2)](2).Y [Fe:Y = 2:1; Y = MeOH (MeOH), EtOH (EtOH)], respectively. Between the two forms, interesting solvent-vapor induced in situ reversible and irreversible guest molecule exchanges, [Fe(tpa)(NCS)(2)].X ? [Fe(tpa)(NCS)(2)](2).Y, occurred in the solid state followed by dramatic color changes as well as distinct structural and SCO behavior transformations. Comprehensive studies on structures and SCO behaviors associating guest exchanges have been conducted by X-ray single-crystal diffraction, PXRD, IR, elemental analysis, and magnetic measurements, respectively. This discrete molecular system shows unique solvent-dependent SCO behavior related to the nature of solvent molecules; the distinct color changes during guest exchange originate from the alternations of electronic states of the guest-sensitive Fe(II) centers, providing an effective route to fine-tune and optimize materials' properties by systematic structural perturbation, or serving for detection of toxic gases, such as CH(2)Cl(2) and CHCl(3). PMID- 21793520 TI - Thorium oxo and sulfido metallocenes: synthesis, structure, reactivity, and computational studies. AB - The synthesis, structure, and reactivity of thorium oxo and sulfido metallocenes have been comprehensively studied. Heating of an equimolar mixture of the dimethyl metallocene [eta(5)-1,2,4-(Me(3)C)(3)C(5)H(2)](2)ThMe(2) (2) and the bis amide metallocene [eta(5)-1,2,4-(Me(3)C)(3)C(5)H(2)](2)Th(NH-p-tolyl)(2) (3) in refluxing toluene results in the base-free imido thorium metallocene, [eta(5) 1,2,4-(Me(3)C)(3)C(5)H(2)](2)Th?N(p-tolyl) (4), which is a useful precursor for the preparation of oxo and sulfido thorium metallocenes [eta(5)-1,2,4 (Me(3)C)(3)C(5)H(2)](2)Th?E (E = O (5) and S (15)) by cycloaddition-elimination reaction with Ph(2)C?E (E = O, S) or CS(2). The oxo metallocene 5 acts as a nucleophile toward alkylsilyl halides, while sulfido metallocene 15 does not. The oxo metallocene 5 and sulfido metallocene 15 undergo a [2 + 2] cycloaddition reaction with Ph(2)CO, CS(2), or Ph(2)CS, but they show no reactivity with alkynes. Density functional theory (DFT) studies provide insights into the subtle interplay between steric and electronic effects and rationalize the experimentally observed reactivity patterns. A comparison between Th, U, and group 4 elements shows that Th(4+) behaves more like an actinide than a transition metal. PMID- 21793521 TI - Synthesis of enantiomerically enriched amino sulfide building blocks from acyclic chiral amino allylsilanes. AB - An efficient synthesis of various protected syn-beta-sulfenyl amides is described. These are prepared from the corresponding enantiopure amino allylsilanes which are in turn obtained from naturally occurring amino acids. The key step for introduction of the sulfur substituent is a diastereoselective electrophilic sulfodesilylation which is carried out with phthalimidesulfenyl chloride. The resulting homochiral beta-phthalimidesulfenyl amines with an allylic sulforated stereogenic center are useful building blocks, as they represent a starting point for subsequent functional manipulations. PMID- 21793522 TI - Revision of the absolute configurations of bethosides B and C and their aglycone. AB - The absolute stereochemistry of the steroidal saponins bethosides B and C was previously assigned as (22R,25R) on the basis of work that employed Horeau's method. Our studies of helosides A and B created doubt about both the original assignment and consequently our conclusion that relied upon it. The absolute configurations of bethosides B and C are revised to (22S,25R) following X-ray crystallographic analysis of their aglycone. Synthesis and full spectral characterization of both the 22R and 22S aglycones is reported to facilitate future stereochemical assignments in this series of saponins. PMID- 21793523 TI - Iodinated aluminum(III) corroles with long-lived triplet excited states. AB - The first reported iodination of a corrole leads to selective functionalization of the four C-H bonds on one pole of the macrocycle. An aluminum(III) complex of the tetraiodinated corrole, which exhibits red fluorescence, possesses a long lived triplet excited state. PMID- 21793524 TI - Chemoenzymatic dynamic kinetic resolution of primary amines catalyzed by CAL-B at 38-40 degrees C. AB - The (R)-selective chemoenzymatic dynamic kinetic resolution of primary amines was performed at 38-40 degrees C in MTBE, in good to high yields and with high enantiomeric excesses. These reactions associating CAL-B to octanethiol as radical racemizing agent were carried out in the presence of methyl beta-methoxy propanoate as acyl donor, under photochemical irradiation at 350 nm in glassware. PMID- 21793525 TI - The "neutral" hydrolysis of simple carboxylic esters in water and the rate enhancements produced by acetylcholinesterase and other carboxylic acid esterases. AB - Experiments at elevated temperatures permit the determination of rate constant and thermodynamic activation parameters for the neutral hydrolysis of the neurotransmitter acetylcholine in water. At 25 degrees C, the extrapolated rate constant for the uncatalyzed (or neutral) hydrolysis of acetylcholine is 3.9 * 10(-7) s(-1) at 25 degrees C (DeltaH(?) = 20.0 kcal/mol; TDeltaS(?) = -6.1 kcal/mol). Acetylcholine is more susceptible to neutral and base-catalyzed hydrolysis than ethyl acetate but less susceptible to acid-catalyzed hydrolysis. For acetylcholinesterase from the electric eel, the catalytic proficiency [(k(cat)/K(m))/k(neutral)] is 2 * 10(16) M(-1), comparable in magnitude with the catalytic proficiencies of aminohydrolases that act on peptides and nucleosides. PMID- 21793526 TI - Characterization and properties of novel gallium-doped calcium phosphate ceramics. AB - Addition of a gallium (Ga) precursor in the typical reaction protocols used for the preparation of beta-tricalcium phosphate (beta-TCP) led to novel Ga-doped beta-TCP ceramics with rhombohedral structures (R3c space group). From the refinement of their X-ray diffraction patterns, it was found that the incorporation of Ga in the beta-TCP network occurs by substitution of one of the five calcium (Ca) sites, while occupation of another Ca site decreases in inverse proportion to the Ga content in the structure. The Ga local environment and the modification of the phosphorus environments due to the Ga/Ca substitution in Ga doped beta-TCP compounds are probed using (31)P and (71)Ga magic-angle spinning NMR. A decrease of the unit cell volume is observed with increasing Ga content, together with improved mechanical properties. Indeed, the compressive strength of these new bioceramics is enhanced in direct proportion of the Ga content, up to a 2.6-fold increase as compared to pure beta-TCP. PMID- 21793527 TI - Ladder-type P,S-bridged trans-stilbenes. AB - Phosphole-containing pi-systems have emerged as building blocks with enormous potential as electronic materials because of the tunability of the phosphorus center. Among these, asymmetric P-bridged trans-stilbenes are still rare, and here an elegant and efficient synthesis toward such fluorescent molecular frameworks is described. Fine-tuning of the photophysical properties is attempted by enforcing the planarization of the phosphorus tripod and thus increasing the interaction between the phosphorus lone pair and the pi-system. The electronic structure of the pi-conjugated frameworks is analyzed with NMR, UV-vis and fluorescence spectroscopy, and time-dependent density functional theory (TD-DFT) calculations. PMID- 21793528 TI - Stereoselective synthesis of 2,3-diamino-2,3-dideoxy-beta-D-mannopyranosyl uronates. AB - With the aim to find an efficient synthetic procedure for the construction of 2,3 diamino-2,3-dideoxy-beta-D-mannuronic acids, we evaluated three mannosyl donors: (S)-phenyl 4,6-di-O-acetyl-2,3-diazido mannopyranoside, (S)-phenyl 2,3-diazido 4,6-O-benzylidene mannopyranoside, and (S)-phenyl 2,3-diazido mannopyranosyl methyl uronate. The first two mannosylating agents are rather unselective or slightly alpha-selective in their condensation with three different acceptors. The mannuronic acid donor on the other hand reliably provides the desired beta mannosidic linkage. A mechanistic rationale is put forward to account for the different behavior of the three donor types. Suitably protected 2,3-diazido mannuronic acids were employed to construct the all-cis-linked tetrasaccharide repeating unit of the capsular polysaccharide of Bacillus stearothermophilus , featuring two 2,3-diacetamido-2,3-dideoxy-beta-D-mannuronic acids. PMID- 21793529 TI - Ennobling an old molecule: thiazyl trifluoride (N=SF3), a versatile synthon for Xe-N bond formation. AB - The fields of sulfur-nitrogen-fluorine chemistry and noble-gas chemistry have been significantly extended by the syntheses and characterizations of four new Xe N-bonded cations derived from N=SF(3). The adduct-cation, F(3)S=NXeF(+), has provided the entry point to a significant chemistry through HF solvolysis of the coordinated N=SF(3) ligand and HF-catalyzed and solid-state rearrangements of F(3)S=NXeF(+). The HF solvolyses of [F(3)S=NXeF][AsF(6)] in anhydrous HF (aHF) and aHF/BrF(5) solutions yield the F(4)S?NXe(+) cation, which likely arises from an HF-catalyzed mechanism. The F(4)S?NXe(+) cation, in turn, undergoes HF displacement to form F(4)S?NH(2)(+) and XeF(2), as well as HF addition to the S?N bond to form F(5)SN(H)Xe(+). Both cations undergo further solvolyses in aHF to form the F(5)SNH(3)(+) cation. The F(4)S?NXe(+) and F(4)S?NH(2)(+) cations were characterized by NMR spectroscopy and single-crystal X-ray diffraction and exhibit high barriers to rotation about their S?N double bonds. They are the first cations known to contain the F(4)S?N- group and significantly extend the chemistry of this ligand. The solid-state rearrangement of [F(3)S=NXeF][AsF(6)] at 22 degrees C has yielded [F(4)S?NXe][AsF(6)], which was characterized by Raman spectroscopy, providing the first examples of xenon bonded to an imido nitrogen and of the F(4)S?N- group bonded to a noble-gas element. The rearrangement of [F(3)S=NXeF][AsF(6)] in a N=SF(3) solution at 0 degrees C also yielded [F(4)S?NXe-N=SF(3)][AsF(6)], which represents a rare example of a N-Xe-N linkage and the first to be characterized by X-ray crystallography. Solvolysis of N=SF(3) in aHF was previously shown to give the primary amine F(5)SNH(2), whereas solvolysis in the superacid medium, AsF(5)/aHF, results in amine protonation to give [F(5)SNH(3)][AsF(6)]. Complete structural characterizations were not available for either species. Isolation of F(5)SNH(2).nHF from the reaction of N=SF(3) with HF has provided a structural characterization of F(5)SNH(2) by Raman spectroscopy. Crystal growth by sublimation of F(5)SNH(2).nHF at -30 to -40 degrees C has resulted in the X-ray crystal structure of F(5)SNH(2).2[F(5)SNH(3)][HF(2)].4HF and structural characterizations of F(5)SNH(2) and F(5)SNH(3)(+). The redox decomposition of [F(4)S?NXe N=SF(3)][AsF(6)] in N=SF(3) at 0 degrees C generated Xe, cis-N(2)F(2), and [F(3)S(N=SF(3))(2)][AsF(6)]. PMID- 21793531 TI - Titanocene(III) chloride mediated radical induced allylation of aldimines: formal synthesis of C-linked 4'-deoxy aza-disaccharide. AB - Titanocene(III) chloride (Cp(2)TiCl) mediated radical induced allylation of aldimines for the preparation of homoallyl amines is described. The radical was generated from the allyl bromide using Cp(2)TiCl as the radical source. Formal synthesis of C(4)-C(5')-linked 4'-deoxy aza-disaccharide is demonstrated and a study toward the bicyclic skeleton of alkaloids was also accomplished. The radical initiator Cp(2)TiCl was prepared in situ from commercially available titanocene dichloride (Cp(2)TiCl(2)) and Zn dust in THF under argon. PMID- 21793532 TI - Synthesis and characterization of nickel inverse 9-metallacrown-3, palladium silver, and dinuclear platinum complexes containing pyrazole-functionalized NHC ligands. AB - Three metallacrown nickel complexes [Ni(3)(MU-OH)(L1)(3)](PF(6))(2) (1, L1 = 3 ((N-methylimidazolylidenyl)methyl)-5-methylpyrazolate), [Ni(3)(MU OH)(L2)(3)](PF(6))(2) (2, L2 = 3-((N-mesitylimidazolylidenyl)methyl)-5 methylpyrazolate), and [Ni(3)(MU-OH)(L3)(3)](PF(6))(2) (3, L3 = 3-((N-pyrimidin-2 ylimidazolylidenyl)methyl)-5-methylpyrazolate) were obtained by the reactions of corresponding silver-NHC complexes with Raney nickel powder at 45 degrees C. The same reaction at 80 degrees C afforded [Ni(3)(L2)(4)](PF(6))(2) (4). The carbene transfer reaction of the silver-carbene complex with [(eta(3)-C(3)H(5))PdCl](2) yielded the heterotrimetallic complex [AgPd(2)(eta(3)-C(3)H(5))(2)(L2)(2)](PF(6)) (5), whereas the carbene-transfer reaction with Pt(cod)Cl(2) gave [Pt(2)(L3)(2)](PF(6))(2) (6). All of these complexes have been fully characterized by ESI-MS, NMR spectroscopy, and elemental analysis. The molecular structures of 1-6 were also studied by X-ray diffraction analysis. In 1-3, three nickel centers are bridged together by three pyrazole-NHC ligands and a hydroxide group, forming a 9-metallacrown-3 topology. Complex 4 is paramagnetic, consisting of two square-planar nickel(II) ions and one tetrahedral nickel ion in which three Ni ions are bridged by four pyrazolate units. In the mixed Pd-Ag complex 5, two palladium and one silver centers are bridged by two pyrazole-NHC ligands. Complex 5 showed good catalytic activity in the Sonogashira coupling reaction of aryl bromides and phenylacetylene under mild conditions typically catalyzed by Pd Cu systems. PMID- 21793533 TI - Acid-base jointly promoted copper(I)-catalyzed azide-alkyne cycloaddition. AB - In this novel acid-base jointly promoted CuAAC, the combination of CuI/DIPEA/HOAc was developed as a highly efficient catalytic system. The functions of DIPEA and HOAc have been assigned, and HOAc was recognized to accelerate the conversions of the C-Cu bond-containing intermediates and buffer the basicity of DIPEA. As a result, all drawbacks occurring in the popular catalytic system CuI/NR(3) were overcome easily. PMID- 21793530 TI - Reactivity of thioredoxin as a protein thiol-disulfide oxidoreductase. PMID- 21793534 TI - Rhodium-catalyzed oxidative ortho-acylation of benzamides with aldehydes: direct functionalization of the sp2 C-H bond. AB - A rhodium-catalyzed oxidative acylation of benzamides with aryl aldehydes via direct sp(2) C-H bond cleavage is described. In the presence of [Cp*RhCl(2)](2), AgSbF(6), and silver carbonate as an oxidant, N,N-diethyl benzamides can be effectively carbonylated to yield ortho-acyl benzamides. PMID- 21793536 TI - Syntheses of chloroisosulochrin and isosulochrin and biomimetic elaboration to maldoxin, maldoxone, dihydromaldoxin, and dechlorodihydromaldoxin. AB - An efficient synthesis of chloroisosulochrin was accomplished using a novel ortho selective chlorination of a phenol with sulfuryl chloride and 2,2,6,6 tetramethylpiperidine as the key step. Further elaboration by a biomimetic route converted chloroisosulochrin to dihydromaldoxin, maldoxone (lactone formed by dehydration of dihydromaldoxin), and maldoxin and isosulochrin to dechlorodihydromaldoxin and dechloromaldoxin. PMID- 21793535 TI - Quantitative photochemical immobilization of biomolecules on planar and corrugated substrates: a versatile strategy for creating functional biointerfaces. AB - Methods for the generation of substratespresenting biomolecules in a spatially controlled manner are enabling tools for applications in biosensor systems, microarray technologies, fundamental biological studies and biointerface science. We have implemented a method to create biomolecular patterns by using light to control the direct covalent immobilization of biomolecules onto benzophenone modified glass substrates. We have generated substrates presenting up to three different biomolecules patterned in sequence, and demonstrate biomolecular photopatterning on corrugated substrates. The chemistry of the underlying monolayer was optimized to incorporate poly(ethylene glycol) to enable adhesive cell adhesion onto patterned extracellular matrix proteins. Substrates were characterized with contact angle goniometry, AFM, and immunofluorescence microscopy. Importantly, radioimmunoassays were performed to quantify the site density of immobilized biomolecules on photopatterned substrates. Retained function of photopatterned proteins was demonstrated both by native ligand recognition and cell adhesion to photopatterned substrates, revealing that substrates generated with this method are suitable for probing specific cell receptor-ligand interactions. This molecularly general photochemical patterning method is an enabling tool for the creation of substrates presenting both biochemical and topographical variation, which is an important feature of many native biointerfaces. PMID- 21793537 TI - Preparation and characterization of novel micro- and nanocomposite hydrogels containing cellulosic fibrils. AB - The main objective of this article was to report a simple, fast, and low cost strategy for the synthesis of micro- and nanocomposites by adding cellulose nanofibers, obtained by acid hydrolysis, and added to hydrogels as reinforcing agents. Specifically, when cellulose nanofibers were added to hydrogels, morphologic analyses showed significant decreases in pore size and formation of three-dimensional well-oriented porous microstructure. It was also observed that cellulose nanoparticles improved the mechanical and structural network properties without negatively impacting their thermal and hydrophilic properties. The value of maximum compressive stress was 2.1 kPa for the PAAm-MC, and it increased to 4.4 kPa when the cellulose nanofiber was incorporated into the hydrogel. By investigation of XRD patterns, it was found that the incorporation of cellulose nanofiber affected the crystallinity of PAAm-MC hydrogels, thus contributing to improvements in mechanical, structural, and hydrophilic properties of the PAAm-MC hydrogels. PMID- 21793538 TI - Hexaazatriphenylene derivatives with tunable lowest unoccupied molecular orbital levels. AB - A series of n-type hexaazatriphenylene derivatives were synthesized by condensation coupling of 1,2-diamines and 1,2-diketones. The study of their photophysical and electrochemical properties showed that their lowest unoccupied molecular orbital (LUMO) energy levels could be effectively tuned from -3.54 to 4.02 eV simply by increasing the number of pyrazine units in their molecular structures. PMID- 21793539 TI - TPAP-catalyzed direct oxidation of primary alcohols to carboxylic acids through stabilized aldehyde hydrates. AB - We present a simple, mild, and highly effective method for the direct conversion of primary alcohols to carboxylic acids. TPAP serves as the catalyst, and NMO.H(2)O plays a dual role, acting as the co-oxidant and as a reagent for aldehyde hydrate stabilization. This previously unknown stabilizing effect of geminal diols by N-oxides is the key for the efficiency of the overall transformation. PMID- 21793540 TI - Lateral flow immunochromatographic assay for sensitive pesticide detection by using Fe3O4 nanoparticle aggregates as color reagents. AB - Magnetic Fe(3)O(4) particle aggregates were prepared by cross-linking Fe(3)O(4) nanoparticles bearing surface carbonyl groups with poly-L-lysine. Upon further coupling with antiparaoxon methyl polyclonal antibody, the resultant particle aggregate-based probes were used in a lateral flow immunochromatographic assay (LFIA) of pesticide residue of paraoxon methyl. The results were compared with that achieved by using the mother Fe(3)O(4) nanoparticles. More quantitative results on the signal amplification effect endowed by the controlled aggregation of Fe(3)O(4) nanoparticles were extracted by relative optical density analysis. Under optimized conditions, a detection limit of 1.7 ng/mL for paraoxon methyl was achieved by using the particle aggregates, which is almost 40-fold lower than that based on the mother Fe(3)O(4) nanoparticles. PMID- 21793541 TI - Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. AB - The culture of bone marrow derived mesenchymal stem cells (MSCs), as well as the control of its differentiation toward different tissue lineage, is a very important part of tissue engineering, where cells are combined with artificial scaffold to regenerate tissues. Graphene (G) and graphene oxide (GO) sheets are soft membranes with high in-plane stiffness and can potentially serve as a biocompatible, transferable, and implantable platform for stem cell culture. While the healthy proliferation of stem cells on various carbon platforms has been demonstrated, the chemical role of G and GO, if any, in guiding uncommitted stem cells toward differentiated cells is not known. Herein, we report that the strong noncovalent binding abilities of G allow it to act as a preconcentration platform for osteogenic inducers, which accelerate MSCs growing on it toward the osteogenic lineage. The molecular origin of accelerated differentation is investigated by studying the binding abilities of G and GO toward different growth agents. Interestingly, differentiation to adipocytes is greatly suppressed on G because insulin, which is a key regulator for the synthesis of fatty acids, is denatured upon pi-pi adsorption on G; in contrast, GO does not interfere with adipogenesis due to electrostatic binding with insulin. The different binding interactions and their subsequent influence on stem cell growth and differentiation are ascribed to different degrees of pi-pi stacking and electrostatic and hydrogen bonding mediated by G and GO. PMID- 21793542 TI - Cost-efficiency trade-off and the design of thermoelectric power generators. AB - The energy conversion efficiency of today's thermoelectric generators is significantly lower than that of conventional mechanical engines. Almost all of the existing research is focused on materials to improve the conversion efficiency. Here we propose a general framework to study the cost-efficiency trade-off for thermoelectric power generation. A key factor is the optimization of thermoelectric modules together with their heat source and heat sinks. Full electrical and thermal co-optimization yield a simple analytical expression for optimum design. Based on this model, power output per unit mass can be maximized. We show that the fractional area coverage of thermoelectric elements in a module could play a significant role in reducing the cost of power generation systems. PMID- 21793543 TI - Two-dimensional transport-induced linear magneto-resistance in topological insulator Bi2Se3 nanoribbons. AB - We report the study of a novel linear magneto-resistance (MR) under perpendicular magnetic fields in Bi(2)Se(3) nanoribbons. Through angular dependence magneto transport experiments, we show that this linear MR is purely due to two dimensional (2D) transport, in agreement with the recently discovered linear MR from 2D topological surface state in bulk Bi(2)Te(3), and the linear MR of other gapless semiconductors and graphene. We further show that the linear MR of Bi(2)Se(3) nanoribbons persists to room temperature, underscoring the potential of exploiting topological insulator nanomaterials for room-temperature magneto electronic applications. PMID- 21793544 TI - Access to optically active 3-azido- and 3-aminopiperidine derivatives by enantioselective ring expansion of prolinols. AB - The activation of N-alkyl prolinols by XtalFluor E allowed the formation of an aziridinium intermediate that can react with tetrabutylammonium azide (nBu(4)NN(3)) to produce 3-azidopiperidines and/or 2-(azidomethyl)pyrrolidines, in a ratio up to 100/0. These 3-azidopiperidines can be reduced to the corresponding 3-aminopiperidines. PMID- 21793545 TI - Modular synthesis of naphthothiophenes by Pd-catalyzed tandem direct arylation/Suzuki coupling. AB - A short and highly modular three-step synthesis of a new class of substituted naphthothiophenes has been developed exploiting a Pd-catalyzed tandem direct arylation/Suzuki coupling transformation as the key step. PMID- 21793546 TI - Syntheses, electrochemistry, and photodynamics of ferrocene-azadipyrromethane donor--acceptor dyads and triads. AB - A near-IR-emitting sensitizer, boron-chelated tetraarylazadipyrromethane, has been utilized as an electron acceptor to synthesize a series of dyads and triads linked with a well-known electron donor, ferrocene. The structural integrity of the newly synthesized dyads and triads was established by spectroscopic, electrochemical, and computational methods. The DFT calculations revealed a 'molecular clip'-type structure for the triads wherein the donor and acceptor entities were separated by about 14 A. Differential pulse voltammetry combined with spectroelectrochemical studies have revealed the redox states and estimated the energies of the charge-separated states. Free-energy calculations revealed the charge separation from the covalently linked ferrocene to the singlet excited ADP to yield Fc(+)-ADP(*-) to be energetically favorable. Consequently, the steady-state emission studies revealed quantitative quenching of the ADP fluorescence in all of the investigated dyads and triads. Femtosecond laser flash photolysis studies provided concrete evidence for the occurrence of photoinduced electron transfer in these donor-acceptor systems by providing spectral proof for formation of ADP radical anion (ADP(*-)) which exhibits a diagnostic absorption band in the near-IR region. The kinetics of charge separation and charge recombination measured by monitoring the rise and decay of the ADP(*-) band revealed ultrafast charge separation in these molecular systems. The charge separation performance of the triads with two ferrocenes and a fluorophenyl modified ADP macrocycle was found to be superior. Nanosecond transient absorption studies revealed the charge-recombination process to populate the triplet ADP as well as the ground state. PMID- 21793547 TI - Rearrangement of 3-deoxy-D-erythro-hexos-2-ulose in aqueous solution: NMR evidence of intramolecular 1,2-hydrogen transfer. AB - Selective (13)C- and (2)H-labeling, and (13)C NMR spectroscopy, have been used to show that the 1,2-dicarbonyl compound (osone), 3-deoxy-D-erythro-hexos-2-ulose (3 deoxy-D-glucosone) (1; 3DG), degrades to 3-deoxy-D-ribo-hexonic acid 2 and 3 deoxy-D-arabino-hexonic acid 3 exclusively via an intramolecular 1,2-hydrogen transfer mechanism in aqueous phosphate buffer at pH 7.5 at 37 degrees C. Acids 2 and 3 are produced in significantly different amounts (1:6 ratio) despite the prochiral C3 in 1, and two potential reaction mechanisms are considered to explain the observed stereoselectivity. One mechanism involves acyclic forms of 1 as reactants, whereas the other assumes cyclic pyranose reactants. In the former (2-keto-hydrate or 2KH mechanism), putative transition state structures based on density functional theory (DFT) calculations arise from the C1 hydrate form of acyclic 1 having the C1-H1 bond roughly orthogonal to the C2 carbonyl plane. The relative orientation of the alkoxide oxygen atom at C1 and the C2 carbonyl oxygen, and H-bonding between C(1)OH and the C2 carbonyl oxygen, contribute to the stability of the transition state. DFT calculations of the natural charges on individual atoms in the transition state show the migrating hydrogen to have an almost neutral charge, implying that it may more closely resemble a hydrogen atom than a hydride anion during transfer from C1 to C2. A second mechanism (2-keto pyranose or 2KP mechanism) involving the cyclic 2-keto-pyranoses of 1 as reactants aligns the C1-H1 bond orthogonal to the C2 carbonyl plane in different ring conformations of both anomers, with the beta-pyranose giving 3 and the alpha pyranose giving 2. While both the 2KH and 2KP mechanisms are possible, the latter readily leads to a prediction of the reaction stereospecificity that is consistent with the experimental data. PMID- 21793548 TI - Enantioselective formal synthesis of palmerolide A. AB - Enantioselective formal synthesis of macrolactone palmerolide A, a polyketide marine natural product, is described. Key strategies in the synthesis include the oxidative furan ring-opening of a chiral furyl carbinol for the installation of the 1,4-dienol core and a Jung nonaldol-aldol reaction for the dienamide core. PMID- 21793549 TI - Palladium(II)-catalyzed cycloisomerization of functionalized 1,5-hexadienes. AB - Scope and limitations of the Pd(II)-catalyzed cycloisomerization of functionalized 1,5-hexadienes have been studied. In situ NMR experiments indicate a challenging competition between various reaction pathways. A careful balance between substrate structure, nature of the precatalyst, and reaction conditions was required to gain access to a useful building block for sesquiterpene total synthesis. PMID- 21793550 TI - Chemical vapor deposition and etching of high-quality monolayer hexagonal boron nitride films. AB - The growth of large-area hexagonal boron nitride (h-BN) monolayers on catalytic metal substrates is a topic of scientific and technological interest. We have used real-time microscopy during the growth process to study h-BN chemical vapor deposition (CVD) from borazine on Ru(0001) single crystals and thin films. At low borazine pressures, individual h-BN domains nucleate sparsely, grow to macroscopic dimensions, and coalescence to form a closed monolayer film. A quantitative analysis shows borazine adsorption and dissociation predominantly on Ru, with the h-BN covered areas being at least 100 times less reactive. We establish strong effects of hydrogen added to the CVD precursor gas in controlling the in-plane expansion and morphology of the growing h-BN domains. High-temperature exposure of h-BN/Ru to pure hydrogen causes the controlled edge detachment of B and N and can be used as a clean etching process for h-BN on metals. PMID- 21793551 TI - Tetra-2,3-pyrazinoporphyrazines with externally appended thienyl rings: synthesis, UV-visible spectra, electrochemical behavior, and photoactivity for the generation of singlet oxygen. AB - A series of pyrazinoporphyrazine macrocycles carrying externally appended 2 thienyl rings, represented as [Th(8)TPyzPzM], where Th(8)TPyzPz = tetrakis-2,3 [5,6-di(2-thienyl)pyrazino]porphyrazinato anion and M = Mg(II)(H(2)O), Zn(II), Co(II), Cu(II), or 2H(1), were prepared and isolated as solid air-stable hydrated species. All of the compounds, completely insoluble in water, were characterized by their UV-visible spectra and electrochemical behavior in solutions of dimethylformamide (DMF), dimethyl sulfoxide, and pyridine. Molecular aggregation occurs at concentrations of ca. 10(-4) M, but monomers are formed in more dilute solutions of 10(-5) M or less. The examined octathienyl compounds [Th(8)TPyzPzM] behave as electron-deficient macrocycles, and UV-visible spectral measurements provide useful information about how the peripheral thienyl rings influence the electronic distribution over the entire macrocyclic framework. Cyclic voltammetric and spectroelectrochemical data confirm the easier reducibility of the compounds as compared to the related phthalocyanine analogues, and the overall redox behavior and thermodynamic potentials for the four stepwise one electron reductions of the compounds are similar to those of the earlier examined octapyridinated analogues [Py(8)TPyzPzM]. Quantum yields (Phi(Delta)) for the generation of singlet oxygen, (1)O(2), the cytotoxic agent active in photodynamic therapy (PDT), and fluorescence quantum yields (Phi(F)) were measured for the Zn(II) and Mg(II) complexes, [Th(8)TPyzPzZn] and [Th(8)TPyzPzMg(H(2)O)], and the data were compared to those of corresponding octapyridino macrocycles [Py(8)TPyzPzZn] and [Py(8)TPyzPzMg(H(2)O)] and their related octacations [(2 Mepy)(8)TPyzPzZn](8+) and [(2-Mepy)(8)TPyzPzMg(H(2)O)](8+). These measurements were carried out in DMF and in DMF preacidified with HCl (ca. 10(-4) M). All of the examined Zn(II) compounds behave as excellent photosensitizers (Phi(Delta) = 0.4-0.6) both in DMF and DMF/HCl solutions, whereas noticeable fluorescence activity (Phi(F) = 0.36-0.43) in DMF/HCl solutions is shown by the Mg(II) derivatives; these data might provide perspectives for applications in PDT (Zn(II)) and imaging response and diagnosis (Mg(II)). PMID- 21793552 TI - Convective mixing induced by acid-base reactions. AB - When two miscible solutions, each containing a reactive species, are put in contact in the gravity field, local variations in the density due to the reaction can induce convective motion and mixing. We characterize here both experimentally and theoretically such buoyancy-driven instabilities induced by the neutralization of a strong acid by a strong base in aqueous solutions. The diverse patterns obtained are shown to depend on the type of reactants used and on their relative concentrations. They have their origin in a combination of classical hydrodynamic instabilities including differential diffusion of the solutes involved while temperature effects only play a marginal role. PMID- 21793554 TI - Biomass fractionation for the biorefinery: heteronuclear multiple quantum coherence-nuclear magnetic resonance investigation of lignin isolated from solvent fractionation of switchgrass. AB - Two-dimensional heteronuclear multiple quantum coherence and quantitative (13)C nuclear magnetic resonance spectroscopy are used to identify the structural features of lignin isolated from solvent fractionation of switchgrass at several different severities. The spectra are consistent with a progressive deconstruction of the lignin as the fractionation severity increases, with structural units involved in cross-linking and capping of the bulk lignin polymer removed first, followed by increasing levels of acid-catalyzed, solvolytic cleavage of the bulk lignin. The results show that solvent fractionation conditions between about 120 degrees C and 0.1 M H(2)SO(4) and 160 degrees C and 0.025 M H(2)SO(4) are optimal for separating biomass in the biorefinery to give process streams most suitable for biobased fuel and chemical production. PMID- 21793553 TI - Swelling the hydrophobic core of surfactant-suspended single-walled carbon nanotubes: a SANS study. AB - Localized solvent environments form around single-wall carbon nanotubes (SWCNTs) because of the ability of surfactant molecules to solubilize immiscible organic solvents. Although these microenvironments around SWCNTs have already been used for fundamental and applied studies, small-angle neutron scattering (SANS) was used here to assess the size and shape of the solvent domains, their uniformity and distribution on the sidewalls, and the effect of solvent swelling on the aggregation state of the suspension. SANS measurements confirm both the formation of local solvent environments and that no irreversible aggregation of the nanotube suspension occurs after the SDS molecules are swollen in solvent. The results also corroborate prior conclusions based on photoluminescence that the structure formed is dependent of the nature of the solvent-surfactant combination; SWCNTs suspended with SDS and swelled with benzene have a more uniform coating on the sidewall than those swelled with o-dichlorobenzene. These differences can be important to understanding the effect of the local environment on the photoluminescence properties and the interaction of SWCNTs with interfaces. PMID- 21793555 TI - Directed self-assembly of microcomponents enabled by laser-activated bubble latching. AB - This article introduces a method for microscale assembly using laser-activated bubble latching. The technique combines the advantages of directed fluidic assembly and surface tension-driven latching to create arbitrarily complex and irregular structures with unique properties. The bubble latches, generated through the laser degradation of the tile material, are created on the fly, reversibly linking components at user-determined locations. Different phases of latching bubble growth are analyzed, and shear force calculations show that each bubble is able to support a tensile force of approximately 0.33 MUN. We demonstrate that by exploiting the compressibility of bubbles, assembled objects can be made to switch between rigid and flexible states, facilitating component assembly and transport. Furthermore, we show reconfiguration capabilities through the use of bubble hinging. This novel hybrid approach to the assembly of microscale components offers significant user control while retaining a simplistic design environment. PMID- 21793556 TI - Inorganic-organic hybrid vesicles with counterion- and pH-controlled fluorescent properties. AB - Two inorganic-organic hybrid clusters with one or two covalently linked pyrene fluorescent probes, [(n C(4)H(9))(4)N](2)[V(6)O(13){(OCH(2))(3)C(NH(CO)CH(2)CH(2)CH(2)C(16)H(9))}{(OCH(2) (3)C-(NH(2))}] ((TBA(+))(2)1) and [(n C(4)H(9))(4)N](2)[V(6)O(13){(OCH(2))(3)C(NH(CO)CH(2)CH(2)CH(2)C(16)H(9))}(2)] ((TBA(+))(2)2), respectively, are synthesized from Lindqvist type polyoxometalates (POMs). The incorporation of pyrene into POMs results in amphiphilic hybrid molecules and simultaneously offers a great opportunity to study the interaction between hybrid clusters and their counterions. 2D-NOESY NMR and fluorescence techniques have been used to study the role of counterions such as tetrabutyl ammonium (TBA) in the vesicle formation of the hybrid clusters. The TBA(+) ions not only screen the electrostatic repulsions between the POM head groups but also are involved in the hydrophobic region of the vesicular structure where they interrupt the formation of pyrene excimers that greatly perturbs the luminescence signal from the vesicle solution. By replacing the TBA(+) counterions with protons, the new vesicles demonstrate interesting pH-dependent fluorescence properties. PMID- 21793557 TI - An entry into hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives. AB - Hexahydro-2H-thieno[2,3-c]pyrrole is proposed as a low molecular weight polar scaffold to construct compound libraries used in the search for new drugs. Practical syntheses of derivatives of this bicyclic scaffold were developed, based on [3 + 2] cycloaddition of the ylide generated from N-benzyl-1-methoxy-N ((trimethylsilyl)methyl)methanamine and 4-substituted 2,3-dihydrothiophene 1,1 dioxides. All of the 3-substituted hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives were obtained as single diastereomers. Conformational properties of the hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives were explored using X-ray diffraction studies. The potential of the scaffold to generate libraries of 3D-shaped molecules was demonstrated. PMID- 21793559 TI - Identification and characterization of GABA(A) receptor modulatory diterpenes from Biota orientalis that decrease locomotor activity in mice. AB - An ethyl acetate extract of Biota orientalis leaves potentiated GABA-induced control current by 92.6% +/- 22.5% when tested at 100 MUg/mL in Xenopus laevis oocytes expressing GABA(A) receptors (alpha1beta2gamma(2S) subtype) in two microelectrode voltage clamp measurements. HPLC-based activity profiling was used to identify isopimaric acid (4) and sandaracopimaric acid (5) as the compounds largely responsible for the activity. Sandaracopimaradienolal (3) was characterized as a new natural product. Compounds 4 and 5 were investigated for GABA(A) receptor subtype selectivity at the subtypes alpha1beta1gamma(2S), alpha1beta2gamma(2S), alpha1beta3gamma(2S), alpha2beta2gamma(2S), alpha3beta2gamma(2S), and alpha5beta2gamma(2S). Sandaracopimaric acid (5) was significantly more potent than isopimaric acid (4) at the GABA(A) receptor subtypes alpha1beta1gamma(2S), alpha2beta2gamma(2S), and alpha5beta2gamma(2S) (EC504: 289.5 +/- 82.0, 364.8 +/- 85.0, and 317.0 +/- 83.7 MUM vs EC505: 48.1 +/- 13.4, 31.2 +/- 4.8, and 40.7 +/- 14.7 MUM). The highest efficiency was reached by 4 and 5 on alpha2- and alpha3-containing receptor subtypes. In the open field test, ip administration of 5 induced a dose-dependent decrease of locomotor activity in a range of 3 to 30 mg/kg body weight in mice. No significant anxiolytic-like activity was observed in doses between 1 and 30 mg/kg body weight in mice. PMID- 21793558 TI - Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. AB - Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compound, SAHA (vorinostat, Zolinza; 1), and one natural product, FK228 (depsipeptide, romidepsin, Istodax; 2), approved by FDA for clinical use. Our studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A (6) and thailandepsin B (7). HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GI50 for over 90% of the tested cell lines at low nanomolar concentrations and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development. PMID- 21793560 TI - Syntheses, molecular structures, electrochemical behavior, theoretical study, and antitumor activities of organotin(IV) complexes containing 1-(4-chlorophenyl)-1 cyclopentanecarboxylato ligands. AB - The organotin(IV) compounds [Me(2)Sn(L)(2)] (1), [Et(2)Sn(L)(2)] (2), [(n)Bu(2)Sn(L)(2)] (3), [(n)Oct(2)Sn(L)(2)] (4), [Ph(2)Sn(L)(2)] (5), and [PhOSnL](6) (6) have been synthesized from the reactions of 1-(4-chlorophenyl)-1 cyclopentanecarboxylic acid (HL) with the corresponding diorganotin(IV) oxide or dichloride. They were characterized by IR and multinuclear NMR spectroscopies, elemental analysis, cyclic voltammetry, and, for 2, 3, 4 and 6, single crystal X ray diffraction analysis. While 1-5 are mononuclear diorganotin(IV) compounds, the X-ray diffraction of 6 discloses a hexameric drumlike structure with a prismatic Sn(6)O(6) core. All these complexes undergo irreversible reductions and were screened for their in vitro antitumor activities toward HL-60, BGC-823, Bel 7402, and KB human cancer cell lines. Within the mononuclear compounds, the most active ones (3, 5) are easiest to reduce (least cathodic reduction potentials), while the least active ones (1, 4) are the most difficult to reduce. Structural rearrangements (i.e., Sn-O bond cleavages and trans-to-cis isomerization) induced by reduction, which eventually can favor the bioactivity, are disclosed by theoretical/electrochemical studies. PMID- 21793562 TI - Total synthesis of (-)-histrionicotoxin. AB - A total synthesis of (-)-histrionicotoxin was achieved. Our synthesis features preparation of a pseudosymmetrical dienyne through chirality transfer from an allenylsilane, a dienyne metathesis to produce the bicyclo [5.4.0] system in optically active form, selective functionalization of a diene via a 5-exo-trig iodoetherification, and an asymmetric propargylation. PMID- 21793561 TI - Estimation of interdomain flexibility of N-terminus of factor H using residual dipolar couplings. AB - Characterization of segmental flexibility is needed to understand the biological mechanisms of the very large category of functionally diverse proteins, exemplified by the regulators of complement activation, that consist of numerous compact modules or domains linked by short, potentially flexible, sequences of amino acid residues. The use of NMR-derived residual dipolar couplings (RDCs), in magnetically aligned media, to evaluate interdomain motion is established but only for two-domain proteins. We focused on the three N-terminal domains (called CCPs or SCRs) of the important complement regulator, human factor H (i.e., FH1 3). These domains cooperate to facilitate cleavage of the key complement activation-specific protein fragment, C3b, forming iC3b that no longer participates in the complement cascade. We refined a three-dimensional solution structure of recombinant FH1-3 based on nuclear Overhauser effects and RDCs. We then employed a rudimentary series of RDC data sets, collected in media containing magnetically aligned bicelles (disklike particles formed from phospholipids) under three different conditions, to estimate interdomain motions. This circumvents a requirement of previous approaches for technically difficult collection of five independent RDC data sets. More than 80% of conformers of this predominantly extended three-domain molecule exhibit flexions of <40 degrees . Such segmental flexibility (together with the local dynamics of the hypervariable loop within domain 3) could facilitate recognition of C3b via initial anchoring and eventual reorganization of modules to the conformation captured in the previously solved crystal structure of a C3b:FH1-4 complex. PMID- 21793563 TI - How do 2D fingerprints detect structurally diverse active compounds? Revealing compound subset-specific fingerprint features through systematic selection. AB - In independent studies it has previously been demonstrated that two-dimensional (2D) fingerprints have scaffold hopping ability in virtual screening, although these descriptors primarily emphasize structural and/or topological resemblance of reference and database compounds. However, the mechanism by which such fingerprints enrich structurally diverse molecules in database selection sets is currently little understood. In order to address this question, similarity search calculations on 120 compound activity classes of varying structural diversity were carried out using atom environment fingerprints. Two feature selection methods, Kullback-Leibler divergence and gain ratio analysis, were applied to systematically reduce these fingerprints and generate alternative versions for searching. Gain ratio is a feature selection method from information theory that has thus far not been considered in fingerprint analysis. However, it is shown here to be an effective fingerprint feature selection approach. Following comparative feature selection and similarity searching, the compound recall characteristics of original and reduced fingerprint versions were analyzed in detail. Small sets of fingerprint features were found to distinguish subsets of active compounds from other database molecules. The compound recall of fingerprint similarity searching often resulted from a cumulative detection of distinct compound subsets by different fingerprint features, which provided a rationale for the scaffold hopping potential of these 2D fingerprints. PMID- 21793564 TI - Alkyl group effect on the conformational isomerism of trans-2 bromoalkoxycyclohexanes analyzed by nmr spectroscopy and theoretical calculations. AB - Suitable (3)J(H,H) coupling constants and theoretical calculations were used to define the conformational preferences of trans-2-bromoalkoxycyclohexanes (alkoxy = OMe, OEt, O(i)Pr, and O(t)Bu) for the isolated molecule and as a function of the medium. The diaxial conformer was preponderant, or at least similarly populated to the diequatorial form, for the tert-butoxy derivative only, while the diequatorial conformer was prevalent for the remaining alkoxy derivatives (except for the OMe derivative in CCl(4) solution). The conformational behavior of these compounds was analyzed on the basis of classical steric effects and attractive electron delocalizations, by means of natural bond orbital analysis. PMID- 21793565 TI - Photophysical investigation of neutral and diprotonated free-base bis(arylethynyl)porphyrins. AB - The photophysical properties for a series of free-base arylethynyl porphyrins and the corresponding trans-disubstituted tetraphenylporphyrin (H(2)TPP) derivatives lacking arylethynyl functionalities have been studied via electronic absorption and emission spectroscopy in both neutral and diacid forms. Enhanced substituent effects on porphyrin absorption spectra are observed in the arylethynyl porphyrins relative to the H(2)TPP derivatives, owing to the presence of the ethynyl spacer that allows for a coplanar geometry between the porphyrin macrocycle and the appended phenyl substituents. Upon protonation, both series of porphyrins exhibit substantially red shifted absorption and emission spectra and enhanced oscillator strengths, with the magnitude of the spectral shifts being more substantial in the presence of the ethynyl functionalities. Spectral features of the arylethynyl porphyrin bearing p-dimethylamino substituents closely resemble those previously classified as "hyperporphyrin spectra" and are indicative of excited-state charge-transfer character. Protonation of both series of porphyrins results in reduced fluorescence lifetimes and enhanced nonradiative decay rates, and the impact of protonation on these parameters is attenuated in the presence of the arylethynyl functionalities. Our results coupled with previous structural data showing that arylethynyl porphyrins exhibit less structural distortion upon diacid formation relative to H(2)TPP further substantiate the proposal that significant alteration of porphyrin photophysical properties upon diacid formation can be attributed to nonplanar structural distortions induced by protonation. PMID- 21793566 TI - Observations of shape-dependent hydrogen uptake trajectories from single nanocrystals. AB - In this work, H(2) absorption and desorption in faceted, crystalline Au/Pd core/shell nanocrystals and their interaction with a SiO(x)/Si support were studied at the single-particle level. Dark-field microscopy was used to monitor the changing optical properties of these Au/Pd nanoparticles (NPs) upon exposure to H(2) as reversible H(2) uptake from the Pd shell proceeded. Analysis of the heterogeneous ensemble of NPs revealed the H(2) uptake trajectory of each nanocrystal to be shape-dependent. Differences in particle uptake trajectories were observed for individual particles with different shapes, faceting, and Pd shell thickness. In addition to palladium hydride formation, the single-particle trajectories were able to decipher specific instances where palladium silicide formation and Au/Pd interdiffusion occurred and helped us determine that this was more frequently seen in those particles within an ensemble having thicker Pd shells. This noninvasive, plasmonic-based direct sensing technique shows the importance of single-particle experiments in catalytically active systems and provides a foundation for studying more complex catalytic processes in inhomogeneous NP systems. PMID- 21793567 TI - Fully activated MEK1 exhibits compromised affinity for binding of allosteric inhibitors U0126 and PD0325901. AB - Kinases catalyze the transfer of gamma-phosphate from ATP to substrate protein residues triggering signaling pathways responsible for a plethora of cellular events. Isolation and production of homogeneous preparations of kinases in their fully active forms is important for accurate in vitro measurements of activity, stability, and ligand binding properties of these proteins. Previous studies have shown that MEK1 can be produced in its active phosphorylated form by coexpression with RAF1 in insect cells. In this study, using activated MEK1 produced by in vitro activation by RAF1 (pMEK1(in vitro)), we demonstrate that the simultaneous expression of RAF1 for production of activated MEK1 does not result in stoichiometric phosphorylation of MEK1. The pMEK1(in vitro) showed higher specific activity toward ERK2 protein substrate compared to the pMEK1 that was activated via coexpression with RAF1 (pMEK1(in situ)). The two pMEK1 preparations showed quantitative differences in the phosphorylation of T-loop residue serine 222 by Western blotting and mass spectrometry. Finally, pMEK1(in vitro) showed marked differences in the ligand binding properties compared to pMEK1(in situ). Contrary to previous findings, pMEK1(in vitro) bound allosteric inhibitors U0126 and PD0325901 with a significantly lower affinity than pMEK1(in situ) as well as its unphosphorylated counterpart (npMEK1) as demonstrated by thermal-shift, AS MS, and calorimetric studies. The differences in inhibitor binding affinity provide direct evidence that unphosphorylated and RAF1-phosphorylated MEK1 form distinct inhibitor sites. PMID- 21793568 TI - In situ measurements of the formation and morphology of intracellular beta amyloid fibrils by super-resolution fluorescence imaging. AB - Misfolding and aggregation of peptides and proteins is a characteristic of many neurodegenerative disorders, including Alzheimer's disease (AD). In AD the beta amyloid peptide (Abeta) aggregates to form characteristic fibrillar structures, which are the deposits found as plaques in the brains of patients. We have used direct stochastic optical reconstruction microscopy, dSTORM, to probe the process of in situ Abeta aggregation and the morphology of the ensuing aggregates with a resolution better than 20 nm. We are able to distinguish different types of structures, including oligomeric assemblies and mature fibrils, and observe a number of morphological differences between the species formed in vitro and in vivo, which may be significant in the context of disease. Our data support the recent view that intracellular Abeta could be associated with Abeta pathogenicity in AD, although the major deposits are extracellular, and suggest that this approach will be widely applicable to studies of the molecular mechanisms of protein deposition diseases. PMID- 21793569 TI - Crossing turbulent boundaries: interfacial flux in environmental flows. AB - Advances in the visualization and prediction of turbulence are shedding new light on mass transfer in the turbulent boundary layer. These discoveries have important implications for many topics in environmental science and engineering, from the transport of earth-warming CO2 across the sea-air interface, to nutrient processing and sediment erosion in rivers, lakes, and the ocean, to pollutant removal in water and wastewater treatment systems. In this article we outline current understanding of turbulent boundary layer flows, with particular focus on coherent turbulence and its impact on mass transport across the sediment-water interface in marine and freshwater systems. PMID- 21793571 TI - Water behavior in mesoporous materials as studied by NMR relaxometry. AB - Water in mesoporous materials possessing a two-dimensional hexagonal structure has been studied by the variation of its NMR longitudinal relaxation time T(1) as a function of the static magnetic field value, or equivalently of the NMR measurement frequency. This technique, dubbed relaxometry, has been applied from 5 kHz (measurement frequency) up to 400 MHz with various instruments including a variable-field spectrometer operating between 8 and 90 MHz. Moreover, the range 0 5 kHz could be investigated by transverse relaxation, T(2) denoting the corresponding relaxation time, and relaxation in the rotating frame, T(1rho) denoting the corresponding relaxation time. Measurements of proton relaxation rates (inverse of relaxation times) have been performed with H(2)O and HOD (residual protons of heavy water) at water volumes of 80%, 60%, and 40% relative to the porous volume. Comparison between H(2)O and HOD shows clearly that, above 1 MHz where both sets of data are superposed, relaxation is purely intermolecular and due to paramagnetic relaxation (dipolar interactions of water protons with unpaired electrons of paramagnetic entities). Below 1 MHz, it is possible to subtract the intermolecular contribution (given by HOD data) from H(2)O data so that one is left with intramolecular relaxation which is solely due to water reorientational motions. The analysis of these low-frequency data (in terms of Lorentzian functions) reveals two types of water within the pores: one interacting strongly with the surface and the other corresponding to a second layer. High-frequency data, which arise from paramagnetic relaxation, exhibit again two types of water. Due to their correlation times, one type is assigned to relatively free water within the pores while the other type corresponds to bulk (interparticular) water. Their proportions, given as a function of the volume fraction, are consistent with the above assignments. PMID- 21793570 TI - Examination of the discrepancy between size estimates for ovalbumin from small angle X-ray scattering and other physicochemical measurements. AB - Examination of the solution behavior of ovalbumin by small-angle X-ray scattering, dynamic light scattering, and analytical ultracentrifugation methods confirms its existence as a 44-kDa monomer in 20 mM phosphate, pH 7.0, thereby contradicting the discord introduced by published SAXS studies in favor of a dimeric state for this protein at neutral pH. Although the theoretical interpretation of SAXS measurements considers the consequences of thermodynamic nonideality arising from the repulsive interactions between molecules only if they give rise to a positive second virial coefficient, the fact that A(2) is negative for the present system does not account for the earlier findings. PMID- 21793572 TI - A class of benzene backbone-based olefin-sulfoxide ligands for Rh-catalyzed enantioselective addition of arylboronic acids to enones. AB - A class of readily available and easily tunable benzene backbone-based olefin sulfoxide ligands was developed for the rhodium-catalyzed asymmetric conjugate addition reaction of arylboronic acids to enones with up to 97% yield and 97% ee. PMID- 21793573 TI - Cationic intermediates in the Pd-catalyzed negishi coupling. kinetic and density functional theory study of alternative transmetalation pathways in the Me-Me coupling of ZnMe2 and trans-[PdMeCl(PMePh2)2]. AB - The complexity of the transmetalation step in a Pd-catalyzed Negishi reaction has been investigated by combining experiment and theoretical calculations. The reaction between trans-[PdMeCl(PMePh(2))(2)] and ZnMe(2) in THF as solvent was analyzed. The results reveal some unexpected and relevant mechanistic aspects not observed for ZnMeCl as nucleophile. The operative reaction mechanism is not the same when the reaction is carried out in the presence or in the absence of an excess of phosphine in the medium. In the absence of added phosphine an ionic intermediate with THF as ligand ([PdMe(PMePh(2))(2)(THF)](+)) opens ionic transmetalation pathways. In contrast, an excess of phosphine retards the reaction because of the formation of a very stable cationic complex with three phosphines ([PdMe(PMePh(2))(3)](+)) that sequesters the catalyst. These ionic intermediates had never been observed or proposed in palladium Negishi systems and warn on the possible detrimental effect of an excess of good ligand (as PMePh(2)) for the process. In contrast, the ionic pathways via cationic complexes with one solvent (or a weak ligand) can be noticeably faster and provide a more rapid reaction than the concerted pathways via neutral intermediates. Theoretical calculations on the real molecules reproduce well the experimental rate trends observed for the different mechanistic pathways. PMID- 21793574 TI - Screw motion regulates multiple functions of T4 phage protein gene product 5 during cell puncturing. AB - Bacteriophage T4 penetrates the outer membrane of Escherichia coli using a multifunctional device composed of a gene product 5 (gp5) protein trimer. We report that gp5 sequentially exerts distinct functions along the course of penetration stages induced by screw motion. A triple-stranded beta-helix of gp5 acts as a cell-puncturing drill bit to make a hole on the membrane and then send the lipids upward efficiently by strong charge interactions. The gp5 lysozyme domains, which degrade the peptidoglycan layer later, are shown to play novel roles to enlarge the hole and control the release of the beta-helix. The lysozyme active site is protected from lipid binding during the penetration and is exposed after the beta-helix release. Intrinsic multiple functions of gp5 are shown to be served in turn regulated by gradual change of interdomain interactions, which enables the initial infection process with single protein trimer by continuous screw motion. The results of lysozyme domain should be understood as the case where a single-function protein acquired multiple chemical functions through interplay with other domains in a multidomain protein. PMID- 21793575 TI - Pyrano[4,3-b]quinolines library generation via iodocyclization and palladium catalyzed coupling reactions. AB - Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4 iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity. PMID- 21793576 TI - Synergistic induction of apoptosis in brain cancer cells by targeted codelivery of siRNA and anticancer drugs. AB - Multiple dysregulated pathways in tumors necessitate targeting multiple oncogenic elements by combining orthogonal therapeutic moieties like short-interfering RNAs (siRNA) and drug molecules in order to achieve a synergistic therapeutic effect. In this manuscript, we describe the synthesis of cyclodextrin-modified dendritic polyamines (DexAMs) and their application as a multicomponent delivery vehicle for translocating siRNA and anticancer drugs. The presence of beta-cyclodextrins in our DexAMs facilitated complexation and intracellular uptake of hydrophobic anticancer drugs, suberoylanilide hydroxamic acid (SAHA) and erlotinib, whereas the cationic polyamine backbone allowed for electrostatic interaction with the negatively charged siRNA. The DexAM complexes were found to have minimal cytotoxicity over a wide range of concentrations and were found to efficiently deliver siRNA, thereby silencing the expression of targeted genes. As a proof of concept, we demonstrated that upon appropriate modification with targeting ligands, we were able to simultaneously deliver multiple payloads--siRNA against oncogenic receptor, EGFRvIII and anticancer drugs (SAHA or erlotinib)- efficiently and selectively to glioblastoma cells. Codelivery of siRNA-EGFRvIII and SAHA/erlotinib in glioblastoma cells was found to significantly inhibit cell proliferation and induce apoptosis, as compared to the individual treatments. PMID- 21793577 TI - Graphene as a spacer to layer-by-layer assemble electrochemically functionalized nanostructures for molecular bioelectronic devices. AB - This study demonstrates the capability of graphene as a spacer to form electrochemically functionalized multilayered nanostructures onto electrodes in a controllable manner through layer-by-layer (LBL) chemistry. Methylene green (MG) and positively charged methylimidazolium-functionalized multiwalled carbon nanotubes (MWNTs) were used as examples of electroactive species and electrochemically useful components for the assembly, respectively. By using graphene as the spacer, the multilayered nanostructures of graphene/MG and graphene/MWNT could be readily formed onto electrodes with the LBL method on the basis of the electrostatic and/or pi-pi interaction(s) between graphene and the electrochemically useful components. Scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV-vis), and cyclic voltammetry (CV) were used to characterize the assembly processes, and the results revealed that nanostructure assembly was uniform and effective with graphene as the spacer. Electrochemical studies demonstrate that the assembled nanostructures possess excellent electrochemical properties and electrocatalytic activity toward the oxidation of NADH and could thus be used as electronic transducers for bioelectronic devices. This potential was further demonstrated by using an alcohol dehydrogenase-based electrochemical biosensor and glucose dehydrogenase based glucose/O(2) biofuel cell as typical examples. This study offers a simple route to the controllable formation of graphene-based electrochemically functionalized nanostructures that can be used for the development of molecular bioelectronic devices such as biosensors and biofuel cells. PMID- 21793578 TI - Comprehensive quality evaluation of corn steep liquor in 2-keto-L-gulonic acid fermentation. AB - Corn steep liquor (CSL) is one of the main raw materials in 2-keto-L-gulonic acid (2-KLG) fermentation by Ketogulonicigenium vulgare and Bacillus megaterium . Due to its natural origin and variations in the manufacturing process, unpredicted and uncontrolled variability of CSL has a great influence on 2-KLG production; however, conventional quality specifications are not enough to ensure stability of fermentation behaviors. A process analytical technology (PAT) could be considered to explore the relationship between CSL quality and 2-KLG production comprehensively. The compositions of CSL from six manufacturers were profiled by gas chromatography with time-of-flight mass spectrometry (GC-TOFMS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES), combined with orthogonal partial least-squares discriminant analysis (OPLS-DA). Seventeen components were identified as the most discriminant marker compounds related to 2 KLG production. Results revealed that they were responsible for providing nutrients and protecting osmotic pressure. Furthermore, nine amino acids were verified as potential group markers by addition to the medium and demonstration of the correlation to 2-KLG production. The comprehensive approach provided an important platform to explore CSL marker compounds for quality evaluation in 2 KLG fermentation. PMID- 21793579 TI - Cyclopropylhydroxycarbene. AB - Cyclopropylhydroxycarbene was generated by high-vacuum flash pyrolysis of cyclopropylglyoxylic acid at 960 degrees C. The pyrolysis products were matrix isolated in solid Ar at 11 K and characterized by means of IR spectroscopy. Upon photolysis, the carbene undergoes ring expansion, thereby paralleling the reactivity of other known cyclopropylcarbenes. The ring expansion product, cyclobut-1-en-1-ol, was characterized for the first time. Matrix-isolated cyclopropylhydroxycarbene undergoes [1,2]H-tunneling through a barrier of approximately 30 kcal.mol(-1), yielding cyclopropylcarboxaldehyde. The cyclopropyl moiety acts as a pi-donor and increases the half-life by almost a factor of 10 compared to parent hydroxymethylene, resulting in a temperature independent half-life of tau = 17.8 h at both 11 and 20 K. Hence, cyclopropylhydroxycarbene is the first hydroxycarbene that differs from other members of its family by a significantly prolonged half-life. As expected, the O deuterated analogue does not show tunneling. Our findings are rationalized by accurate CCSD(T)/cc-pVnZ (n = D, T)//M06-2X/6-311++G(d,p) computations. The half life of cyclopropylhydroxycarbene was verified by tunneling computations employing the Wentzel-Kramers-Brillouin formalism. By comparison with other experimentally known hydroxycarbenes, we determine the electronic donor capabilities of the carbenes' substituents to be a dominant factor governing their half-lives. PMID- 21793580 TI - Synthesis of gold nanoparticle catalysts based on a new water-soluble ionic polymer. AB - A new water-soluble methyl-imidazolium-based ionic polymer was synthesized by ring-opening metathesis polymerization that was subsequently used to prepare aqueous gold nanoparticle solutions which were characterized by UV-vis spectroscopy and transmission electron microscopy (TEM). The aqueous gold nanoparticle solutions were employed as catalysts in the reduction of p nitrophenol and in the hydrogenation of cinnamaldehyde and were found to exhibit excellent activity under mild conditions. PMID- 21793582 TI - Effect of molecular packing on corannulene-based materials electroluminescence. AB - The present investigation reports for the first time a detailed theoretical analysis of the optical absorption spectra of corannulene-based materials using state-of-the-art first-principles many-body GW-BSE theory. The study specifically addresses the nature of optical excitations for predictions regarding suitability for device fabrication. The well-defined structure-correlation relationship in functionalized corannulenes is used in a focused investigation of the predicted optoelectronic properties in both the isolated state and bulk crystals. The findings suggest that the excitonic properties are strongly dependent on the specific substituent group as well as the crystalline arrangement. Arylethynyl substituted corannulene derivatives are shown to be the most suitable for device purposes. PMID- 21793581 TI - Determinants of serum polybrominated diphenyl ether (PBDE) levels among pregnant women in the CHAMACOS cohort. AB - We measured levels of 10 polybrominated diphenyl ether (PBDE) congeners in serum collected during pregnancy and at delivery from 416 pregnant, predominantly immigrant, women living in Monterey County, CA. The most frequently detected congeners were BDE-47, -99, -100, and -153, all components of the penta mixture, detected in >97% of samples. We used multivariable regression models to examine factors associated with exposure to individual PBDE congeners as well as their total summed concentration (ng/g lipid). Prenatal and delivery total PBDE levels were correlated between sampling times (n = 21; Pearson r = 0.99, p < 0.001). In multivariable models, total PBDE levels increased significantly with time residing in the U.S. (p < 0.001) and among women with >=3 pieces of stuffed furniture in their homes (p < 0.05). Women's total PBDE levels increased 4.0% (95% CI = 2.8, 5.3) for each additional year residing in the U.S., after adjustment for prepregnancy BMI, weight gain during pregnancy, and SES. Having >=3 pieces of stuffed furniture in the home was associated with a 26.8% (95% CI = 2.0, 57.5) increase in women's serum PBDE levels. Findings suggest PBDE indoor contamination in California homes is contributing to human exposures in a population of recent immigrants. PMID- 21793583 TI - Significantly enhancing catalytic activity of tetrahexahedral Pt nanocrystals by Bi adatom decoration. AB - Tetrahexahedral Pt nanocrystals (THH Pt NCs) bounded by high-index facets possess a high density of active sites and display therefore a higher catalytic activity in comparison with those enclosed by low-index facets. In the current communication, we report, for the first time, the decoration of THH Pt NC surfaces by using Bi adatoms and have demonstrated that the catalytic activity of the Bi decorated THH Pt NCs toward HCOOH electrooxidation has been drastically enhanced in comparison with bare THH Pt NCs. It has also been revealed that the catalytic activity of Bi decorated THH Pt NCs for all coverages investigated always exhibits a higher catalytic activity that is about double that of Bi decorated Pt nanospheres. The study is of great importance regarding both fundamentals and applications. PMID- 21793584 TI - Sensing or no sensing: can the anomeric effect be probed by a sensing molecule? AB - The anomeric effect plays a central role in carbohydrate chemistry, but its origin is controversial, and both the hyperconjugation model and the electrostatic model have been proposed to explain this phenomenon. Recently, Cocinero et al. designed a peptide sensor, which can bind to a sugar molecule methyl D-galactose, and claimed that the anomeric effect can be sensed by the spectral changes from the beta- to the alpha-complex, which are ultimately attributed to the lone pair electron density change on the endocyclic oxygen atom [Nature 2011, 469, 76; J. Am. Chem. Soc. 2011, 133, 4548]. Here, we provide strong computational evidence showing that the observed spectral changes simply come from the conformational differences between the alpha- and beta-anomers, as the replacement of the endocyclic oxygen atom with a methylene group, which disables both the endo- and the exo-anomeric effects in methyl D-galactose, leads to similar spectral shifts. In other words, the "sensor" cannot probe the anomeric effect as claimed. We further conducted detailed energetic and structural analyses to support our arguments. PMID- 21793585 TI - Two-dimensional 1H-13C nuclear magnetic resonance (NMR)-based comprehensive analysis of roasted coffee bean extract. AB - Coffee was characterized by proton and carbon nuclear magnetic resonance (NMR) spectroscopy. To identify the coffee components, a detailed and approximately 90% signal assignment was carried out using various two-dimensional NMR spectra and a spiking method, in which authentic compounds were added to the roasted coffee bean extract (RCBE) sample. A total of 24 coffee components, including 5 polysaccharide units, 3 stereoisomers of chlorogenic acids, and 2 stereoisomers of quinic acids, were identified with the NMR spectra of RCBE. On the basis of the signal assignment, state analyses were further launched for the metal ion citrate complexes and caffeine-chlorogenate complexes. On the basis of the signal integration, the coffee components were successfully quantified. This NMR methodology yielded detailed information on RCBE using only a single observation and provides a systemic approach for the analysis of other complex mixtures. PMID- 21793586 TI - Planar tetracoordinate carbon versus planar tetracoordinate boron: the case of CB4 and its cation. AB - In this study, we analyzed CB(4) and its cation, CB(4)(+). Using CCSD(T)/aug-cc pVQZ//CCSD(T)/aug-cc-pVTZ quantum-chemical calculations, we found that the neutral molecule is in accord with the results of Boldyrev and Wang, having a C(s) global minimum with a planar tricoordinate carbon structure, contradicting previous studies. In contrast, CB(4)(+), which was reported by an early mass spectroscopic study, has a planar tetracoordinate carbon (ptC) atom, demonstrating that a modification of the charge can promote the stabilization of a ptC structure. PMID- 21793587 TI - Design of aptamer-based sensing platform using triple-helix molecular switch. AB - For successful assay development of an aptamer-based biosensor, various design principles and strategies, including a highly selective molecular recognition element and a novel signal transduction mechanism, have to be engineered together. Herein, we report a new type of aptamer-based sensing platform which is based on a triple-helix molecular switch (THMS). The THMS consists of a central, target specific aptamer sequence flanked by two arm segments and a dual-labeled oligonucleotide serving as a signal transduction probe (STP). The STP is doubly labeled with pyrene at the 5'- and 3'-end, respectively, and initially designed as a hairpin-shaped structure, thus, bringing the two pyrenes into spacer proximity. Bindings of two arm segments of the aptamer with the loop sequence of STP enforce the STP to form an "open" configuration. Formation of aptamer/target complex releases the STP, leading to new signal readout. To demonstrate the feasibility and universality of our design, three aptamers which bind to human alpha-thrombin (Tmb), adenosine triphosphate (ATP), and L-argininamide (L-Arm), respectively, were selected as models. The universality of the approach is achieved by virtue of altering the aptamer sequence without change of the triple helix structure. PMID- 21793588 TI - Ionization energies, proton affinities, and pKa values of a large series of edaravone derivatives: implication for their free radical scavenging activity. AB - The electron-donating capability (EDC) and the ease of deprotonation (ED) of 26 edaravone derivatives have been evaluated. Their first ionization energies have been used to assess their EDC. Four different approaches to obtain vertical ionization energies were tested, using a set of structurally related compounds. Those based on the electron propagator theory (EPT) were identified as the best ones. In particular, the partial third order (P3) approximation led to the lowest mean unsigned error (MUE = 0.10 eV). Two descriptors were used to evaluate ED: the proton affinity (PA) and the pK(a). It was found that pK(a) values are better descriptors than PA values. Ideal candidates to perform as efficiently as, or even better than, edaravone itself are proposed. The recommendations were based on the simultaneous analyses of EDC and ED, and they should be particularly valid when the electron transfer mechanism plays an important role in the antioxidant activity of the studied compounds. PMID- 21793589 TI - Solvent-induced shift of the lowest singlet pi -> pi* charge-transfer excited state of p-nitroaniline in water: an application of the TDDFT/EFP1 method. AB - The combined time-dependent density functional theory effective fragment potential method (TDDFT/EFP1) is applied to a study of the solvent-induced shift of the lowest singlet pi -> pi* charge-transfer excited state of p-nitroaniline (pNA) from the gas to the condensed phase in water. Molecular dynamics simulations of pNA with 150 EFP1 water molecules are used to model the condensed phase and generate a simulated spectrum of the lowest singlet charge-transfer excitation. The TDDFT/EFP1 method successfully reproduces the experimental condensed-phase pi -> pi* vertical excitation energy and solvent-induced red shift of pNA in water. The largest contribution to the red shift comes from Coulomb interactions, between pNA and water, and solute relaxation. The solvent shift contributions reflect the increase in zwitterionic character of pNA upon solvation. PMID- 21793590 TI - Isoenergetic microarrays to study the structure and interactions of DsrA and OxyS RNAs in two- and three-component complexes. AB - Information on the secondary structure and interactions of RNA is important to understand the biological function of RNA as well as in applying RNA as a tool for therapeutic purposes. Recently, the isoenergetic microarray mapping method was developed to improve the prediction of RNA secondary structure. Herein, for the first time, isoenergetic microarrays were used to study the binding of RNA to protein or other RNAs as well as the interactions of two different RNAs and protein in a three-component complex. The RNAs used as models were the regulatory DsrA and OxyS RNAs from Escherichia coli, the fragments of their target mRNAs (fhlA and rpoS), and their complexes with Hfq protein. The collected results showed the advantages and some limitations of microarray mapping. PMID- 21793591 TI - Polymers from fatty acids: poly(omega-hydroxyl tetradecanoic acid) synthesis and physico-mechanical studies. AB - This Article describes the synthesis and physicomechanical properties of bioplastics prepared from methyl omega-hydroxytetradecanoic acid (Me-omega OHC14), a new monomer available by a fermentation process using an engineered Candida tropicalis strain. Melt-condensation experiments were conducted using titanium tetraisopropoxide (Ti[OiPr](4)) as a catalyst in a two-stage polymerization (2 h at 200 degrees C under N(2), 4 h at 220 degrees C under 0.1 mmHg). Poly(omega-hydroxytetradecanoate), P(omega-OHC14), M(w), determined by SEC MALLS, increased from 53K to 110K as the Ti(OiPr)(4) concentration increased from 50 to 300 ppm. By varying the polymerization conditions (catalyst concentration, reaction time, second-stage reaction temperature) a series of P(omega-OHC14) samples were prepared with M(w) values from 53K to 140K. The synthesized polyesters with M(w) ranging from 53K to 140K were subjected to characterization by DSC, TGA, DMTA, and tensile testing. Influences of P(omega-OHC14) molecular weight, melting point, and enthalpies of melting/crystallization on material tensile properties were explored. Cold-drawing tensile tests at room temperature for P(omega-OHC14) with M(w) 53K-78K showed a brittle-to-ductile transition. In contrast, P(omega-OHC14) with M(w) 53K undergoes brittle fracture. Increasing P(omega-OHC14) M(w) above 78K resulted in a strain-hardening phenomena and tough properties with elongation at break ~700% and true tensile strength of ~50 MPa. Comparisons between high density polyethylene and P(omega-OHC14) mechanical and thermal properties as a function of their respective molecular weights are discussed. PMID- 21793592 TI - Hydrogenation of azides over copper nanoparticle surface using ammonium formate in water. AB - Aryl azides undergo clean reduction by copper nanoparticles and ammonium formate in water. The surface hydrogen on copper nanoparticles is considered to be the active reducing species. A variety of functionalized aryl azides and aryl sulfonyl azides are reduced by this procedure to the corresponding amines with excellent chemoselectivity in high yields. PMID- 21793595 TI - Hydrogen-atom tunneling in isomerization around the C-O bond of 2-chloro-6 fluorophenol in low-temperature argon matrixes. AB - Infrared spectra of 2-chloro-6-fluorophenol in argon matrixes at 20 K revealed the presence of a "Cl-type" isomer, which has the OH...Cl hydrogen bond, but no "F-type" isomer with OH...F bonding, in striking contrast to the existence of both isomers in the gas and liquid phases at room temperature. This finding suggests that the F-type isomer changes to the more stable Cl-type one by hydrogen-atom tunneling in the matrixes. Similar experiments on the OD...X analog species were performed to confirm the tunneling isomerization, resulting in an O D stretching band of the F-type isomer appearing as well as that of the Cl type, like the spectra reported in the gas and liquid phases. This implies that tunneling migration of the D atom is inhibited in the argon matrix. In addition, UV-induced photoreactions of 2-chloro-6-fluorophenol were studied by a joint use of matrix-isolation IR spectroscopy assisted by density functional theory calculations. It was found that 2-fluorocyclopentadienylidenemethanone and 4 chloro-2-fluorocyclohexadienone were produced from the Cl type; the former was by the Wolff rearrangement after dissociation of the H atom in the OH group and the Cl atom, and the latter was by intramolecular migration of the H and Cl atoms. As for the deuterated F-type isomer, however, 2-chlorocyclopentadienylidenemethanone was produced by the Wolff rearrangement after dissociation of the D atom in the OD group and the F atom, besides other photoproducts of the deuterated Cl-type isomer. It is thus concluded that the tunneling isomerization around the C-O bond occurs in the OH...X species but not in the OD...X species. PMID- 21793596 TI - Voltage-induced swelling and deswelling of weak polybase brushes. AB - We have investigated a novel method of remotely switching the conformation of a weak polybase brush using an applied voltage. Surface-grafted polyelectrolyte brushes exhibit rich responsive behavior and show great promise as "smart surfaces", but existing switching methods involve physically or chemically changing the solution in contact with the brush. In this study, high grafting density poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) brushes were grown from silicon surfaces using atom transfer radical polymerization. Optical ellipsometry and neutron reflectivity were used to measure changes in the profiles of the brushes in response to DC voltages applied between the brush substrate and a parallel electrode some distance away in the surrounding liquid (water or D(2)O). Positive voltages were shown to cause swelling, while negative voltages in some cases caused deswelling. Neutron reflectometry experiments were carried out on the INTER reflectometer (ISIS, Rutherford Appleton Laboratory, UK) allowing time-resolved measurements of polymer brush structure. The PDMAEMA brushes were shown to have a polymer volume fraction profile described by a Gaussian-terminated parabola both in the equilibrium and in the partially swollen states. At very high positive voltages (in this study, positive bias means positive voltage to the brush-bearing substrate), the brush chains were shown to be stretched to an extent comparable to their contour length, before being physically removed from the interface. Voltage-induced swelling was shown to exhibit a wider range of brush swelling states in comparison to pH switching, with the additional advantages that the stimulus is remotely controlled and may be fully automated. PMID- 21793594 TI - Self-assembly of Escherichia coli MutL and its complexes with DNA. AB - The Escherichia coli MutL protein regulates the activity of several enzymes, including MutS, MutH, and UvrD, during methyl-directed mismatch repair of DNA. We have investigated the self-association properties of MutL and its binding to DNA using analytical sedimentation velocity and equilibrium. Self-association of MutL is quite sensitive to solution conditions. At 25 degrees C in Tris at pH 8.3, MutL assembles into a heterogeneous mixture of large multimers. In the presence of potassium phosphate at pH 7.4, MutL forms primarily stable dimers, with the higher-order assembly states suppressed. The weight-average sedimentation coefficient of the MutL dimer in this buffer ( s(20,w)) is equal to 5.20 +/- 0.08 S, suggesting a highly asymmetric dimer (f/f(o) = 1.58 +/- 0.02). Upon binding the nonhydrolyzable ATP analogue, AMPPNP/Mg(2+), the MutL dimer becomes more compact ( s(20,w) = 5.71 +/- 0.08 S; f/f(o) = 1.45 +/- 0.02), probably reflecting reorganization of the N-terminal ATPase domains. A MutL dimer binds to an 18 bp duplex with a 3'-(dT(20)) single-stranded flanking region, with apparent affinity in the micromolar range. AMPPNP binding to MutL increases its affinity for DNA by a factor of ~10. These results indicate that the presence of phosphate minimizes further MutL oligomerization beyond a dimer and that differences in solution conditions likely explain apparent discrepancies in previous studies of MutL assembly. PMID- 21793598 TI - Realization and properties of biochemical-computing biocatalytic XOR gate based on enzyme inhibition by a substrate. AB - We consider a realization of the XOR logic gate in a process biocatalyzed by an enzyme which can be inhibited by a substrate when the latter is inputted at large enough concentrations. A model is developed for describing such systems in an approach suitable for evaluation of the analog noise amplification properties of the gate. The obtained data are fitted for gate quality evaluation within the developed model, and we discuss aspects of devising XOR gates for functioning in "biocomputing" systems utilizing biomolecules for information processing. PMID- 21793599 TI - Scaling between relaxation, transport, and caged dynamics in polymers: from cage restructuring to diffusion. AB - The slow relaxation, the diffusivity, and the fast cage-dynamics of a melt of fully flexible unentangled polymer chains is studied by molecular-dynamics simulations. States with different nonbonding potential, chain length, density and temperature are considered. The scaling between the slow dynamics and the fast dynamics, as characterized by the amplitude of the rattling motion inside the cage, is evidenced. The analysis carried out in terms of the van Hove function shows that: (i) the scaling does not depend on the specific quantity used to quantify both the relaxation times and the amplitude of the rattling motion; (ii) it holds on the length scale of the jump-like dynamics; (iii) it also holds on the time scale of the diffusive regime if the chain-length effect is taken into proper account, thus extending analogous results already known for atomic liquids. PMID- 21793600 TI - Update: malaria, U.S. Armed Forces, 2010. PMID- 21793601 TI - Diagnoses of overweight/obesity, active component, U.S. Armed Forces, 1998-2010. PMID- 21793602 TI - Multiple sclerosis, active component, U.S. Armed Forces, 2000-2009. PMID- 21793603 TI - Causes of medical evacuations from Operations Iraqi Freedom (OIF), New Dawn (OND) and Enduring Freedom (OEF), active and reserve components, U.S. Armed Forces, October 2001-September 2010. PMID- 21793604 TI - Cruciate ligament injuries, active component, U.S. Armed Forces, 2000-2009. PMID- 21793605 TI - Surveillance snapshot: acute myocardial infarction, active component, U.S. Armed Forces, 2000-2009. PMID- 21793606 TI - Motorcycle and other motor vehicle accident-related deaths, U.S. Armed Forces, 1999-2010. PMID- 21793607 TI - Update: heat injuries, active component, U.S. Armed Forces, 2010. PMID- 21793608 TI - Update: exertional rhabdomyolysis, active component, U.S. Armed Forces, 2010. PMID- 21793609 TI - Update: exertional hyponatremia, active component, U.S. Armed Forces, 1999-2010. PMID- 21793610 TI - Absolute and relative morbidity burdens attributable to various illnesses and injuries, U.S. Armed Forces, 2010. PMID- 21793611 TI - Hospitalizations among members of the active component, U.S. Armed Forces, 2010. PMID- 21793612 TI - Ambulatory visits among members of the active component, U.S. Armed Forces, 2010. PMID- 21793613 TI - Surveillance snapshot: illness and injury burdens among U.S. military recruits, 2010. PMID- 21793614 TI - Surveillance snapshot: hospitalizations for suicidal ideation, active component, U.S. Armed Forces, 2005-2010. PMID- 21793615 TI - Eye injuries, active component, U.S. Armed Forces, 2000-2010. PMID- 21793616 TI - Stress fractures, active component, U.S. Armed Forces, 2004-2010. PMID- 21793617 TI - Trends in emergency medical and urgent care visits, active component, U.S. Armed Forces, 2000-2010. PMID- 21793618 TI - Surveillance snapshot: emergency department visits for traumatic brain injury. PMID- 21793619 TI - Duration of service after overweight-related diagnoses, active component, U.S. Armed Forces, 1998-2010. PMID- 21793620 TI - Noise-induced hearing injuries, active component, U.S. Armed Forces, 2007-2010. PMID- 21793621 TI - Acute gastroenteritis outbreak at the Armed Forces Retirement Home, Washington, DC, January 2011. PMID- 21793622 TI - Surveillance snapshot: gastroenteritis-related hospitalizations, 2001-2010. PMID- 21793623 TI - Detection of circulating tumor cells in metastatic breast cancer patients. AB - OBJECTIVE: The objective of this study was the detection of circulating tumor cells (CTCs) in metastatic breast cancer patients. METHODS: Since only small numbers of circulating tumor cells (CTCs) are found in peripheral blood, at first we performed immunomagnetic separation as a concentration method suitable for selecting circulating tumor cells in peripheral blood. This was followed by analysis of isolated cells with the aid of laser scanning cytometry (LSC). Twenty eight patients with metastatic breast cancer were enrolled in the study and the control group consisted of 19 clinically healthy women. Six milliliters of peripheral blood was drawn for the analyses, but only in two patients the blood has been drawn twice. Blood samples were taken when no chemotherapy was administered, but hormonal therapy has been allowed. RESULTS: The positivity for CTCs was found in 20 (50.0 %) patients with metastatic breast cancer patients, while in 6 (31.6 %) healthy controls false positive circulating epithelial-like cells were detected. Because we did not use CD45 staining, we could not distinguish these circulating epithelial-like cells from CTCs. In a majority of metastatic breast cancer patients we found a mixed population of HER-2 gene expressing CTCs. We found that HER2+ CTCs in high numbers are CK19 + CTCs, while almost all HER2-CTCs are CK19- CTCs. CONCLUSION: The described method was found promising for estimating HER2 status on CTCs from peripheral blood in metastatic breast cancer patients. PMID- 21793624 TI - The ability of hydroxylated estrogens (2-OH-E2 and 4-OH-E2) to increase of SHBG gene, protein expression and intracellular levels in MCF-7 cells line. AB - OBJECTIVE: Sex Hormone-Binding Globulin (SHBG) - specific carrier for sex steroids - regulates hormone bioavailable fraction and estrogen signaling system in breast cancer cells. This study was conducted to elucidate the effects of hydroxylated estrogen (E2) metabolites (2-OH-E2 and 4-OH-E2) on sex hormone binding globulin (SHBG) mRNA and protein expression as well as on intracellular and extracellular SHBG levels. METHODS: MCF-7 human breast cancer cells were cultured with 2-OH-E2 or 4-OH-E2 in concentration of 1, 10 and 100 nM for 24 h, 17beta-estradiol being used as a positive control. SHBG levels were measured in medium and cells by ELISA, SHBG mRNA expression was evaluated by real-time-PCR and protein expression by Western blot analysis. RESULTS: 4-OH-E2 in high doses and 2-OH-E2 in the highest dose, while 17beta-estradiol in all doses used increased intracellular but not extracellular SHBG levels. Both metabolites increased SHBG mRNA expression, the rank order of potency being E2 > 4-OH-E2 > 2 OH-E2. Both E2 and its metabolites increased SHBG protein expression. CONCLUSION: Although the metabolites showed a lower potency than 17beta-estradiol, further studies are needed to clarify whether hydroxylated metabolites of E2 are potent ligands for SHBG. PMID- 21793625 TI - 7-hydroxylated derivatives of dehydroepiandrosterone as possibly related to menstrual mood change in healthy women. AB - OBJECTIVE: Mood changes occur often in the luteal phase of menstrual cycle. Steroids modulating GABAA and NAMD receptors in the brain, namely allopregnanolone, were suggested as a factor of premenstrual syndrome. Another neurosteroid influencing the well-being is dehydroepiandrosterone. In the past decade it was shown by several authors that some dehydroepiandrosterone derivatives, especially those with 7-hydroxy- or 7-oxo group, exert a higher activity than dehydroepiandrosterone itself. It was also reasonable to see whether the levels of circulating 7-hydroxy-derivatives of dehydroepiandrosterone differ in the follicular and luteal phase of the menstrual cycle. METHODS: Steroids known to exert neuroprotective effects, namely 7alpha- and 7beta-hydroxy dehydroepiandrosterone, 5-androstene-3beta,7alpha,17beta-triol and 5-androstene 3beta,7beta,17beta-triol, were determined in midfollicular and midluteal phase of the menstrual cycle of 22 healthy women with a regular menstruation cycle. RESULTS: Whereas the maternal steroids, dehydroepiandrosterone and androstene 3beta,17beta-diol showed no significant difference between the phases of menstrual cycle, the levels of their 7-hydroxylated metabolites were significantly lower in the luteal phase. CONCLUSION: It is suggested that the observed decrease of 7-hydroxylated metabolites during the luteal phase may be a factor related to the etiopathogenesis of mood change and neurocognitive disturbances, which are known to be more accented in that particular phase of the menstrual cycle. PMID- 21793626 TI - Effect of ginseng extract supplementation on testicular functions in diabetic rats. AB - OBJECTIVE: It was aimed to investigate the effect of standardized ginseng extract on fertility parameters in diabetic rats. METHODS: Thirty male rats were randomly allocated into three groups of 10 rats each: 1. controls, 2. diabetes (D) and 3. diabetes + ginseng (DG). The latter two groups were rendered diabetic by i.p. injection of streptozotocin (STZ; 50 mg/kg). Standardized ginseng extract (Dansk Droge A/S, Copenhagen, Denmark) was administered per os (100 mg/kg BW) by stomach tube daily for 90 days starting one week after STZ. Ninety days post STZ the rats were sacrificed, and testis, epididymis, prostate, and seminal vesicles were weighed and subjected to histological examination. In addition, spermiogram, testicular enzyme markers, intratesticular steroid hormonal profile and testicular antioxidant status were estimated. RESULTS: The administration of ginseng extract resulted in a significant improvement of fertility parameters and testicular antioxidants together with a decrease in malondialdehyde and testicular pathological signs including degenerative changes of the seminiferous tubules. CONCLUSION: Ginseng extract may be a beneficial adjuvant therapy for diabetics suffering from infertility as a complication. PMID- 21793627 TI - Alpha-fetoprotein, carcinoembryonic antigen and beta2-microglobulin in adult population highly exposed to organochlorinated pollutants (PCB, DDE and HCB). AB - OBJECTIVE: It is aimed to obtain some general information about the prevalence of certain biomarkers in highly exposed population and on the interrelations between their serum level as related to that of some major organochlorines (OCs). METHODS: The level of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and beta2-microglobulin (beta2-MG) as well as that of polychlorinated biphenyls (Sigma15PCBs), dichlorodiphenyl-dichloroethylene (DDE) and hexachlorobenzene (HCB) was estimated in 2046 adults (834 males and 1212 females) from highly polluted Eastern Slovakia. RESULTS: Great majority of blood levels was lower than two specific units used for individual markers, while the prevalence of values higher than two specific units of appropriate markers. At the same time, the prevalence of all markers level higher than 2 specific units was highly significantly increasing with of stratified PCBs level quintiles which were also positively related to these of DDE and HCB. Some significant correlations between biomarkers level and age were also observed. CONCLUSIONS: Although from the data obtained within this multipurpose field survey any notable interrelations between AFP, CEA and beta2-MG and some specific diseases and/or malignant processes could not be retrospectively specified, from the data obtained it appears that some of such interrelations cannot be definitely excluded. PMID- 21793628 TI - Central hypothyroidism in patients with chronic hepatitis C and relation with interferon-alpha treatment. AB - OBJECTIVE: Since some authors referred to panhypopituitarism or central hypothyroidism during the treatment of chronic hepatitis C virus (HCV) infection using interferon-alpha, it is intended to evaluate the prevalence of central hypothyroidism (CH) in HCV patients before and during interferon-alpha therapy. PATIENTS AND METHODS: We evaluated 308 HCV patients treated with standard interferon-alpha (IFN) and/or pegylated-interferon-alpha (PEG-IFN) associated with ribavirin. Free thyroxine (FT4) and thyrotropin (TSH) levels were measured before, during and after treatment. CH was diagnosed when the level of FT4 was lower than normal values with concomitant normal or lower TSH as verified at least in two consecutive measures. RESULTS: Before treatment, 18 (5.8 %) patients presented CH Twelve patients maintained laboratory changes during the treatment and 17 new patients developed central hypothyroidism. Among the 29 patients (9.4 %) with CH, 11 used IFN, six used PEG-IFN and 12 patients used two or more therapeutic schedules. The differences in gender, age, cirrhosis, viral genotype, duration of treatment and the type of interferon used were not statistically significant. The absence of sustained virologic response was associated with central hypothyroidism (OR=3.83). CONCLUSION: HCV patients may develop CH due to viral infection or during the interferon treatment. These patients presented 3.83 times more chance of not obtaining sustained virologic response. PMID- 21793629 TI - Brain-liver interactions during liver ischemia reperfusion injury: a minireview. AB - KEYWORDS: The liver is a vital organ, with a wide range of functions. This organ plays an important role in the metabolism, including the glycogen storage, decomposition of red blood cells, plasma protein synthesis, hormone production, and detoxification. The liver is innervated by sympathetic and parasympathetic nerves which are involved in the regulation of the hepatic metabolism. Tissue injury connected with ischemia and reperfusion has been implicated in several clinical settings, including myocardial infarction, brain ischemia, and organ transplantation. Consequences of the liver ischemia reperfusion injury (LIRI) induce first of all an organ failure and afterwards multiorgan system damages that may eventually lead to a death. Many models with an attempt to reduce harmful consequences of the LIRI, directing to develop a variety of prophylactic strategies, has been introduced including models of warm, cold or normothermic ischemia, ischemic pre- and post-conditionings, pharmacological interventions, etc. In spite of the improvements in the medical care and accumulation of a large amount of experimental data concerning the prevention of ischemia and reperfusion related injuries, many destructive processes explanation still remains problematic. PMID- 21793630 TI - Association of rs2200733 at 4q25 with early onset of lone atrial fibrillation in young patients. AB - OBJECTIVE: Genome wide association studies have shown an association between rs2200733 at 4q25 and atrial fibrillation (AF). In this case-control study we investigate the association of rs2200733 and lone AF in young patients. METHODS: We included 196 young patients with lone AF and the first episode before the age of 40 years. We analyzed the single nucleotide polymorphism (SNP) rs2200733 for the lone AF patients and compared them to a control group of 176 age matched healthy individuals. RESULTS: No significant differences, in neither genotype distribution, nor minor allele frequencies were found between the lone AF patients and the healthy controls. CONCLUSION: Our results suggest that the rs220733 is not a risk factor for AF in patients with no other cardiovascular disease and with early onset of the arrhythmia. PMID- 21793631 TI - Short-term effects of inspiratory muscle training in coronary artery bypass graft surgery: a randomized controlled trial. AB - OBJECTIVE: To investigate the efficiency of inspiratory muscle training (IMT) on postoperative respiratory muscle strength, functional capacity, quality of life, and psychosocial status in patients with coronary artery bypass graft (CABG) surgery. DESIGN: Forty-three patients undergoing CABG surgery were randomly assigned to the one of two groups. All subjects received usual care. In addition, subjects in the intervention group received IMT training pre- and postoperatively. Pulmonary function testing, six minute walk test (6MWT), quality of life and psychosocial parameters were assessed preoperatively and the fifth day after the surgery. RESULTS: The mean inspiratory muscle strength increased from 82.64 cmH(2)O at baseline to 95.45 cmH(2)O five days postoperatively in the intervention group. The intervention group (319.55 +/- 72.17 m before and 387.91 +/- 65.69 m after surgery) covered further distance during the 6MWT than usual care (355.43 +/- 56.08 m before and 357.69 +/- 43.42 m after surgery). The improvement in quality of life was greater in the intervention group for the dimension of sleep. The anxiety scores were significantly lower in the intervention group than the usual care group. The length of intensive care unit stay was significantly shorter in the intervention group than the usual care group (p < 0.05). CONCLUSION: IMT results in faster recovery of inspiratory muscle strength, functional capacity, intensive care unit stay, quality of life and psychosocial status after CABG. PMID- 21793632 TI - Long-term complications to reflux disease in community practice. A 17-year cohort study of 4706 patients. AB - OBJECTIVE: To examine the risk of developing strictures in patients with erosive and non-erosive gastroesophageal reflux disease in a community-based setting, since controlled trials indicate that the use of proton pump inhibitors renders the risk of strictures insignificant. MATERIAL AND METHODS: A 17-year cohort study of 4706 patients referred to endoscopy due to upper GI symptoms, with a population comparison cohort of 47,060 individuals. All patients were followed and treated according to prevailing guidelines by their usual care provider. Main outcomes were relative risks (RR) and 95% confidence intervals (CI) for incident strictures and dilatations. RESULTS: 776 (16.5%) patients were diagnosed with erosive esophagitis, particularly men (61.2%). Over a period of 1-17 years (mean 10.5), 20 patients (2.6%) in the esophagitis group developed a peptic stricture, necessitating one or more dilatations in 16 patients (2.1%). Among the non esophagitis patients, the incidences for both outcomes were 1.2%. Male gender doubled the risk of developing strictures, and alcohol abuse raised the risk four folds. Erosive patients had a risk of developing strictures eight times (95% CI: 5.0-13.0) higher than controls, whereas non-erosive patients' risk was 4.0 (95% CI: 2.8-5.7). The majority of strictures developed within the first 10 years after a diagnosis of esophagitis. CONCLUSION: Patients with esophagitis had eight times higher risk of strictures than population controls and two times higher than dyspeptic patients without esophagitis. This indicates that long-term outcomes in general practice are poorer than in controlled trials, most likely due to a lack of compliance with medication. PMID- 21793633 TI - Adalimumab treatment in Crohn's disease does not induce early changes in regulatory T cells. AB - OBJECTIVE: Anti-TNF-alpha antibodies has been suggested to modulate regulatory T cell (Treg) percentages in rheumatoid arthritis, but results from studies of Crohn's disease (CD) are conflicting. We investigated dynamic changes of circulating Tregs in CD during treatment with the anti-TNF-alpha-antibody adalimumab (Humira(r), Abbott Laboratories A/S, Emdrupvej 28C, DK-2100 Copenhagen). MATERIAL AND METHODS: Blood samples from 26 CD patients were analysed using flow cytometry before and 1 and 26 weeks after initiation of adalimumab treatment to determine the percentage of Tregs among CD4+ T cells. RESULTS: In spite of a significant decline in disease activity scores and biochemical markers of inflammation, during the first week of treatment, we did not observe early modulating effects of adalimumab on Treg percentages. However, we found a long-term increase in Treg percentages in responders who had low Treg percentages (<5%) at baseline (p = 0.04). Treg percentage was inversely associated with disease activity (CD activity index or CDAI) (Spearman's rank correlation, rho = -0.47, p = 0.02). High Treg percentages among CD4+ T cells at baseline predicted clinical response to adalimumab. CONCLUSIONS: Adalimumab treatment did not induce early modulatory effects on Treg percentage, even in responders. This finding suggests that adalimumab does not have a direct or selective effect on Tregs. However, Treg percentage was associated with disease activity and high Treg percentage predicted response to adalimumab. PMID- 21793634 TI - How are thiopurines used and monitored by Swedish gastroenterologists when treating patients with inflammatory bowel disease? AB - OBJECTIVE: To perform a survey of thiopurine treatment in inflammatory bowel disease (IBD) among Swedish gastroenterologists. MATERIAL AND METHODS: A web based questionnaire consisting of 25 multiple-choice questions was sent to 322 gastroenterologists in adult practice. RESULTS: A total of 132 questionnaires were received giving a response rate of 41%. Thiopurines were used by all 122 gastroenterologists in IBD practice and azathioprine was the first-choice thiopurine among 118 (97%) of them. Almost all gastroenterologists (97%) used weight-based dosing that was gradually escalated. The vast majority (89%) considered that efficacy should be evaluated within 6 months of therapy, while opinions regarding the optimal duration of therapy varied considerably. It was seen that 74% switched thiopurine in case of intolerance to the first-line substance. Thiopurine S-methyltransferase (TPMT) determinations were performed by 74% of the gastroenterologists and 67% used metabolite measurements. TPMT analyzers were more likely to measure metabolites (74 vs. 43%, p = 0.002). A quarter of the respondents were familiar with unconventional immunomodulation (co administration of allopurinol, 6-thioguanine, mycophenolate mofetil or tacrolimus) and these respondents were also more likely to measure metabolites (79 vs. 52%; p = 0.002). CONCLUSIONS: Thiopurines are well established in the treatment of IBD among Swedish gastroenterologists. New and evolving knowledge about thiopurine therapy in IBD has been adapted to a large extent. Whether this change in clinical practice will have an impact on treatment outcomes has yet to be proven. PMID- 21793635 TI - Influence of aquaporin-1 gene polymorphism on water retention in liver cirrhosis. AB - Water retention is a major clinical problem in patients with liver cirrhosis. The factors that predispose to water retention are poorly understood but may involve genetic factors. Recent research suggests that renal aquaporins may be a pathophysiological factor involved in this condition. Aquaporin-1 (AQP1) is expressed in the proximal tubule and aquaporin-2 (AQP2) in the renal collecting duct cells. The aim of our study was to investigate the distribution of single nucleotide polymorphisms (SNPs) of AQP1: rs1049305 (C/G) and AQP2: rs3741559 (A/G) and rs467323 (C/T) in 100 cirrhotic patients with ascites and to analyze their relationship with dilutional hyponatremia. METHODS: Genomic DNA was extracted from peripheral blood. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman SNP Genotyping Assays. The possible influence of rs1049305 (C/G) in AQP1 gene expression was evaluated by luciferase assays in vitro. RESULTS: The allelic frequencies of the AQP1 gene were the following: CC = 15%; CG = 49%; GG = 36%. Patients with CC genotype had significantly lower plasma sodium concentration than those with CG or GG genotype. Luciferase assays showed that the rs1049305 (C/G) in the AQP1 gene functionally affected the expression level in vitro. In addition, we did not find any relationship between AQP2 SNPs observed and plasma sodium concentration. CONCLUSIONS: Our results suggest that the rs1049305 (C/G, UTR3) AQP1 polymorphism could be involved in the genetic susceptibility to develop water retention in patients with liver cirrhosis. PMID- 21793636 TI - Long-term risk of progression of carcinoma in situ of the bladder and impact of bacille Calmette-Guerin immunotherapy on the outcome. AB - OBJECTIVE: This study aimed to determine the long-term risk of cancer progression of carcinoma in situ (CIS) of the urinary bladder, and whether intravesical bacille Calmette-Guerin (BCG) immunotherapy can reduce the risk of progression of CIS. MATERIAL AND METHODS: From a prospectively enrolled cohort of bladder cancer patients treated at Arhus University Hospital Skejby, Denmark, between 1994 and 2008, all 163 cases with CIS in the bladder, and a history free of invasive bladder cancer (stage T1-4) at least 1 year prior to inclusion were included in the study. RESULTS: Median follow-up was 51 (0-253) months for progression. Initial treatment consisted of transurethral resection (TUR) alone (109 patients) or TUR plus BCG (54 patients). Twenty-eight patients underwent delayed treatment with BCG. Twenty-one patients in the TUR-alone group (19%) and 42 BCG-treated patients (51%) were free of disease at the end of follow-up (p < 0.001). Progression occurred in 18 BCG-treated patients (22%) versus 31 patients (41%) treated by TUR alone. The 10-year progression-free survival was 62% overall, 50% without BCG and 71% after BCG treatment (p = 0.04). BCG reduced the risk of progression by 46% (hazard ratio 0.54, 95% confidence interval 0.3-0.97). Thirteen patients (9%) experienced progression in the prostate and nine (6%) showed extravesical progression (upper urinary tract or metastases). This was independent of BCG treatment. CONCLUSION: CIS in the absence of invasive (T1) disease carried a 10-year risk of progression of 29?48%. Although BCG was effective against CIS, this effect was limited to the bladder. BCG provided a marginal, but significant reduction in the overall long-term risk of progression. PMID- 21793637 TI - In vitro long-term degradation of aesthetic restorative materials in food simulating media. AB - OBJECTIVE: The aim of this study was to evaluate the effect of long-term food simulating media storage on degradation of restorative materials through roughness measurements. MATERIALS AND METHODS: Sixty cylindrical specimens of each material (Filtek Z250, Esthet X, Filtek Flow, Dyract AP and Vitremer) were prepared, stored for 24 h, and polished. The surface roughness analysis was conducted using Surfcorder (SE1700) roughness-measuring instrument. Three traces were recorded on each specimen at three different locations. The specimens were randomly distributed into five groups (n = 12) according to the storage media: (water, ethanol, Coca-Cola(r), citric acid and lactic acid). Roughness measurements were recorded after 1 week, 1, 3 and 6 months. The storage solutions were weekly changed. Data were submitted to ANOVA and Tukey test (p < 0.05). RESULTS: There was no significant increase on roughness means for Filtek Z250, Filtek Flow and Vitremer over time, regardless the storage media. Significant increase on surface roughness was observed for Esthet X after 1 month of storage in Coca-Cola(r) and after 3 months of storage in citric acid and for Dyract AP after 6 months in water. There were no significant differences on surface roughness between resin composites and compomer. Resin-modified glass ionomer showed a significantly higher surface roughness mean than the other materials. CONCLUSIONS: Food-simulating media affects the surface roughness of the materials. Biodegradation is material-, solution- and time-dependent. PMID- 21793638 TI - Evaluation of two different approaches to learning shade matching in dentistry. AB - STATEMENT OF THE PROBLEM: An important aspect of dental education is teaching and learning shade matching. OBJECTIVE: To assess the success of two different strategies for learning shade matching. MATERIALS AND METHODS: Seventy-one pre clinical students (mean age 23; 33.3% men) were divided into two groups. One group (TTB) formed teams of two and they matched three pre-determined teeth on each other using the 3D-Master shade guide. After this exercise, they learned shade matching using a standardized device (Tooth Guide Training Box, TTB) by matching shade tabs in an artificial environment. The other group (GL) matched tooth color in a pre-defined clinical setting in groups of four students. After this, they matched the same teeth as before training, again in groups of two, similarly to group TTB. The reference tooth color was determined by two experienced prosthodontic clinicians. The L*a*b* values for the tabs were provided by the manufacturer and the color difference (DeltaE(ab)) between the chosen tab and the reference was calculated. Linear general estimation equation models were used for statistical evaluation (p = 0.05). RESULTS: In the TTB group, the difference between DeltaE(ab) values before and after training was 0.03, which was not significant (p = 0.927; 95% CI: -0.70/0.77). In the GL group, DeltaE(ab) was 0.98 smaller after training, which was significant (p < 0.001; 95% CI: 0.50/1.50). CONCLUSION: The ability to match tooth color could be improved by using a group-learning approach in a clinical setting and implementation of such a training session should be considered in undergraduate and postgraduate dental education. PMID- 21793639 TI - Evaluation of changes in trabecular alveolar bone during growth using conventional panoramic radiographs. AB - OBJECTIVE: To assess changes of the alveolar trabecular bone during growth using panoramic radiographs and to detect possible differences in trabecular bone patterns when comparing individuals of various ages and genders. MATERIALS AND METHODS: Conventional panoramic radiographs of 18 young (eight females, 10 males) and 21 adult (12 females, nine males) subjects were taken at 2 years (T1) and 10 years (T2) after the end of orthodontic treatment. At T1, mean ages were 15.6 +/- 0.9 years and 31.3 +/- 9.7 years in the young and the adult groups, respectively. A three-scale visual analysis was used to evaluate bilaterally the alveolar bone trabeculation in the interdental spaces, from the distal side of the first mandibular premolar to the mesial side of the second lower molar. An analysis of variance (ANOVA), associated with t-tests whenever significance was found, was used to appraise the role of the age, the extent of the follow-up period and the gender on trabecular bone structure. RESULTS: The adult group had a denser alveolar bone trabeculation, compared to the young group. This was also observed in the 8 years follow-up recordings among the adults, but no statistically significant differences were found in the growing individuals. No gender discrepancy was detected. CONCLUSIONS: From puberty to the middle age adulthood, denser alveolar bone trabeculation in the mandible seems to be related to the age. No differences were found between male and female subjects in the sample. PMID- 21793640 TI - Developmentally regulated expression of Sema3A chemorepellant in the developing mouse incisor. AB - OBJECTIVE: Semaphorin 3A (Sema3A) is an essential chemorepellant controlling peripheral axon pathfinding and patterning, but also serves non-neuronal cellular functions. Incisors of rodent are distinctive from molars as they erupt continuously, have only one root and enamel is present only on the labial side. The aim of this study is to address putative regulatory roles of Sema3A chemorepellant in the development of incisor innervation and formation. MATERIALS AND METHODS: This study analyzed expression of Sema3A mRNAs during embryonic and early post-natal stages of mouse mandibular incisor using sectional radioactive in situ hybridization. RESULTS: Although Sema3A mRNAs were observed in condensed dental mesenchyme during the early bud stage, they were absent in dental papilla or pulp at later stages. Sema3A mRNAs were observed in the dental epithelium including the cervical loops and a prominent expression was also seen in alveolar bone. Interestingly, transcripts were absent from the mesenchymal dental follicle target area (future periodontal ligament) throughout the studied stages. CONCLUSION: The expression patterns of Sema3A indicate that it may control the timing and patterning of the incisor innervation. In particular, Sema3A appears to regulate innervation of the periodontal ligament, while nerve penetration into the incisor dental pulp appears not to be dependent on Sema3A. Moreover, Sema3A may regulate the functions of cervical loops and the development of alveolar bone. Future study with Sema3A deficient mice will help to elucidate the putative neuronal and non-neuronal functions of Sema3A in incisor tooth development. PMID- 21793641 TI - Radiation treatment outcomes for unresectable hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is one of the most common cancers worldwide. Data regarding the use of radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with radiotherapy in the modern era at a single institution. MATERIAL AND METHODS: A total of 29 patients with localized hepatocellular carcinoma treated from 2000-2010 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30 to 75 Gy) with a median biologically effective dose of 80.6 (range 60 to 138.6). Median tumor size at the time of radiation was 5.2 cm (range 2 to 25 cm). RESULTS: Eighty three percent of all patients had either stable disease or a partial response to radiation, based on RECIST criteria. Median change in tumor size following radiation was -17% (range -73.5 to 177.8%). Estimated one-year overall survival and in-field progression-free survival rates for the study population were 56% and 79%, respectively. One-year overall survival in patients treated to a biologically effective dose <75 was significantly lower than in patients treated to a biologically effective dose >=75 (18% vs. 69%). One-year in-field progression-free survival rate (60% vs. 88%) and biochemical progression-free survival duration (median 6.5 vs. 1.6 months) were also significantly improved in patients treated to a biologically effective dose >=75. Grade 3 toxicity was seen in 13.8% of patients. DISCUSSION: In a population without endemic viral hepatitis, unresectable hepatocellular carcinoma demonstrates significant response to radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased biologically effective dose is associated with improved survival and local tumor control. PMID- 21793642 TI - Associations of cytokine gene polymorphisms with post-stroke depression. AB - OBJECTIVES: Inflammatory cytokines are implicated in the pathophysiology of both stroke and depression, and their production is influenced by the transcriptional activity of particular gene polymorphisms. We hypothesised that alleles related to higher pro-inflammatory and/or lower anti-inflammatory cytokine production would be associated with post-stroke depression (PSD). METHODS: In 276 stroke cases, depression was diagnosed using DSM-IV, and classified into major PSD (N = 29), all (major plus minor) PSD (N = 77), and control (N = 199) groups. Genotyping for six pro-inflammatory polymorphisms (TNF-alpha -850C/T and -308G/A, IL-1beta -511C/T and + 3953C/T, IL-6 -174G/C, and IL-8 -251T/A) and two anti inflammatory polymorphisms (IL-4 + 33T/C and IL-10 -1082G/A) was conducted. Individual associations with PSD were estimated using logistic regression models. Total numbers of potential risk alleles were calculated for pro-inflammatory and anti-inflammatory cytokine genes and analysed against depression using chi(2) tests. RESULTS: The IL-4 + 33C/C genotype was associated with major PSD, and the IL-10 -1082A/A genotype was associated with all PSD. Increasing numbers of risk alleles for these two anti-inflammatory cytokine genotypes were significantly associated with both PSD categories. No significant associations were found with any pro-inflammatory cytokine allele. CONCLUSIONS: Alleles associated with reduced anti-inflammatory cytokine function were associated with PSD, supporting the cytokine hypothesis in its etiology. PMID- 21793643 TI - Effect of thermal shock on mechanical properties of injection-molded thermoplastic denture base resins. AB - OBJECTIVE: This study investigated the effect of thermal shock on the mechanical properties of injection-molded thermoplastic denture base resins. MATERIALS AND METHODS: Four thermoplastic resins (two polyamides, one polyethylene terephthalate, one polycarbonate) and, as a control, a conventional heat polymerized polymethyl methacrylate (PMMA), were tested. Specimens of each denture base material were fabricated according to ISO 1567 and were either thermocycled or not thermocycled (n = 10). The flexural strength at the proportional limit (FS-PL), the elastic modulus and the Charpy impact strength of the denture base materials were estimated. RESULTS: Thermocycling significantly decreased the FS-PL of one of the polyamides and the PMMA and it significantly increased the FS-PL of one of the polyamides. In addition, thermocycling significantly decreased the elastic modulus of one of the polyamides and significantly increased the elastic moduli of one of the polyamides, the polyethylene terephthalate, polycarbonate and PMMA. Thermocycling significantly decreased the impact strength of one of the polyamides and the polycarbonate. CONCLUSIONS: The mechanical properties of injection-molded thermoplastic denture base resins changed after themocycling. PMID- 21793644 TI - Implementation and experience of a new method for posterior vertical bite reconstruction using direct resin composite restorations in the private practice- a survey. AB - OBJECTIVE: The purpose of the present survey was to evaluate the implementation and experience of a new method for posterior vertical bite reconstruction using direct resin composite restorations by private practitioners who attended a hands on continuing education course on this technique. MATERIALS AND METHODS: In the years 2007 and 2008, 17 1-day continuing education courses on vertical bite reconstruction in the worn dentition by using direct resin composite restorations were attended by 310 participants. A 13-item questionnaire was posted to all course participants in April 2009 seeking information on the acceptance, implementation and experience of the presented technique in the private practice. RESULTS: A total of 97 (31%) questionnaires were returned, whereas 67% of the respondents had used the presented technique. Analysis of the overall experience and satisfaction with the placed resin composite restorations using visual analog scale (VAS) revealed a mean VAS score of 7.2 +/- 1.7 (0 = maximal unsatisfied, 10 = maximal satisfied). The direct resin composite restorations were predominantly rated 'good' within the assessed criteria surface texture, anatomical form, marginal integrity, marginal discoloration and color match. Ninety-eight percent of the private practitioners stated that they would continue to carry out vertical bite reconstructions according to this technique. The three most frequently observed clinical problems were related to marginal discolorations, bulk fractures and adhesive failures. CONCLUSION: The presented restoration method was well accepted by private practitioners who used this treatment approach at least once after course participation, even though some clinical problems were observed. PMID- 21793645 TI - Relationship between oral health-related knowledge, attitudes and behavior among 15-16-year-old adolescents: a structural equation modeling approach. AB - OBJECTIVE: The aim of this study was to confirm the previously observed attitudinal factor structure related to behavioral change and the knowledge attitude-behavior model on dental health and hygiene among adolescents. MATERIALS AND METHODS: The study population consisted of all 8(th) and 9(th) graders (15-16 years) who started the 2004-2005 school year in Rauma, Finland (n = 827). Data on knowledge, attitudes, toothbrushing and using fluoride toothpaste were gathered by questionnaires. Hypothesized structure included four attitudinal factors related to dental health and hygiene: 'importance of toothbrushing when participating in social situations' (F1), 'importance of toothbrushing for health related reasons and better appearance' (F2), 'being concerned about developing caries lesions' (F3) and 'importance of toothbrushing for feeling accepted' (F4). Structural equation modeling (SEM) was used to test the hypothesized model: pathways lead from knowledge to behavior both directly and via attitudes. The hypothesized model was also modified by removing non-significant pathways and studying the inter-relationships between attitudes. RESULTS: A confirmatory factor analysis revealed that factor F4 had to be removed. In the final model, knowledge influenced behavior directly and via two attitude factors, F1 and F2, which were inter-related. 'Concern about developing caries lesions' was a background factor influencing only knowledge. The final factor structure and SEM model were acceptable-to-good fit. Knowledge had a smaller effect on behavior than on attitudes. CONCLUSIONS: Our results support theories about the causal knowledge-attitudes-behavior chain, also for adolescents' oral health-related behaviors. PMID- 21793646 TI - Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States. AB - BACKGROUND: The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ~15-52 per million. METHODS: Using a privately insured claims database (1999-2007) for the under age 65 population and a Medicare claims database for the 65+ population, and following the current clinical classification of PH, CTEPH patients were identified as having: >=2 claims for pulmonary hypertension (PH) [ICD-9-CM: 416.0, 416.8]; >=1 claim for pulmonary embolism (PE) <=12 months prior or 1 month after the initial PH claim (index date). PAH patients were identified: >=2 claims for primary PH [416.0]; no left heart disease, lung diseases, CTEPH, or miscellaneous PH diagnoses <=12 months prior or 1 month after the index date. Both cohorts were required to have >=1 claim for right heart catheterization <=6 months prior to any PH claim, or >=1 claim for echocardiogram <=6 months prior to a specialist diagnosed PH claim. Age- and gender-standardized prevalence rates per million individuals (PMI) were calculated using appropriate population weights. RESULTS: Prevalence rates (95% CI) of CTEPH were estimated at 63 (34-91) PMI among the privately insured (<65), and 1007 (904-1111) PMI among the Medicare population (>=65). The corresponding estimates for PAH were 109 (71-146) PMI among the <65 population, and 451 (384-519) PMI for Medicare. LIMITATIONS: Identification of PAH and CTEPH patients in administrative claims data is challenging, due to lack of specific ICD-9-CM codes for the conditions and risk of misdiagnosis. CONCLUSIONS: Prevalence rates of CTEPH and PAH increase with age, and are higher among women. The increased risk of PE may explain the sharp age gradient for CTEPH prevalence. The estimated US prevalence of PAH is higher than existing estimates. PMID- 21793647 TI - Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid. AB - The aim of this study was to prepare spray dried inhalable powders containing isoniazid-loaded chitosan/tripolyphosphate (TPP) nanoparticles for sustained delivery of the drug to the lung. Nanoparticles were prepared by ionic gelation method. In-vitro drug release study indicated that the rate of drug release from nanoparticles was decreased by increasing the amount of chitosan. Entrapment of isoniazid into chitosan/TPP nanoparticles decreased minimum inhibitory concentrations (MIC) of the drug against mycobacterium avium intracellulare. Nanoparticles were spray dried using excipients such as lactose, mannitol and maltodextrin alone or with leucine. Results showed that the obtained powders had different aerosolization property. It was observed that by adding leucine, the particle size of microparticles deceased and the process yield and fine particle fraction (FPF) increased significantly. The in-vitro deposition data indicated that spray drying of isoniazid-loaded nanoparticles with lactose in the presence of leucine resulted in the production of inhalable powders with the highest FPF (45%). PMID- 21793648 TI - Hydrophobic microspheres for in situ removal of 2-phenylethanol from yeast fermentation. AB - The commercial production of the fragrance compound 2-phenylethanol (2-PE) from phenylalanine by yeast is limited by the accumulation of the toxic product, and therefore, in situ product removal techniques are required. We describe the use of hydrophobic polymethylmethacrylate (PMMA) microspheres of narrow size distribution of 1.53 +/- 0.10 um diameter for continuous removal of 2-PE from the fermentation medium by a mechanism of swelling. In shake flask experiments with conditions simulating 2-PE stress, a 10-fold increase in productivity was measured for systems containing >10% (w/v) microspheres. A 1 L fed-batch fermentation with 8% (w/v) of PMMA microspheres resulted in a total 2-PE concentration of 7.05 g/L, from which 5.40 g/L was incorporated inside the resin, implying 76% encapsulation. This ratio of 0.07 g/g of product per resin is among the highest reported to date. Scanning electron microscopy revealed a concomitant increase in sphere diameter confirming that swelling occurred. PMID- 21793649 TI - Inventors and their attorneys must beware of their actions before the US Patent and Trademark Office. AB - Inventors and their legal representative have a duty to disclose all material information of which they are aware to the United States Patent and Trademark Office (USPTO). Breach of this duty, combined with an intent to deceive the USPTO, can result in a court finding of inequitable conduct. Consequently, a patent will be rendered unenforceable upon a court's determination of inequitable conduct. To help understand the requirements of the duty of disclosure, a discussion highlighting recent court decisions pertaining to the issue of inequitable conduct is presented. PMID- 21793650 TI - Natural, synthetic and semisynthetic glycolipid inhibitors of glioma growth. AB - Neurostatin, a natural glycosphingolipid inhibitor of astroblast and astrocytoma division, present in mammalian brain, is the modified ganglioside O-acetylated GD1b. It is cytostatic for rat astroblasts, C6 glioma cells and various human astrocytoma lines grades III and IV, with median inhibitory dose values ranging 1 - 5 MUM. Neurostatin was shown not to affect primary or transformed fibroblast division at concentrations of >= 10 MUM. A synthetic neurostatin analogue, NF 115, consisting of an octyl N-acetylglucosaminide derivative with a pentaerythritol chain at position 6, loaded on a slow-delivery polymer disc, caused the destruction of cultured human astroblastoma, obtained after surgical biopsy, and destroyed human neuroectodermic tumours implanted in rats and human astrocytoma implanted in immunodeficient mice. Future antitumourals should combine the high activity of neurostatin with the ease of synthesis of NF-115. PMID- 21793651 TI - Recent advances in the treatment of psoriatic arthritis. AB - This article provides an overview of recent developments in the treatment of psoriatic arthritis with an emphasis on patent literature for the period January 1998 to December 2002. The main pathogenic pathways thought to be operative in psoriatic arthritis are highlighted and some novel compounds that can potentially interfere with such pathways at different levels are discussed. Among the new agents proposed, the inhibitors of cytokine signaling, angiogenesis, and extracellular matrix degradation appear to be of particular interest for the treatment of psoriatic arthritis resistant to conventional therapies. Finally, new formulations of existing drugs and natural remedies claimed to be useful for the treatment of psoriatic arthritis are reviewed. PMID- 21793653 TI - Annotated patent selections. PMID- 21793652 TI - Recent developments in the prevention and treatment of Epstein-Barr virus associated lymphoproliferative diseases. AB - Epstein-Barr virus (EBV) infection and its relevance in post-transplant lymphoproliferative diseases (PTLDs) is an increasing area of concern. PTLD can differ clinically from a mononucleosis-like syndrome to malignant lymphoma. The incidence varies between < 1 and > 20% depending on different risk factors and the kind of transplant. Despite several treatment regimens, including reduction of immunosuppression, antiviral drugs, adoptive immunotherapy and administration of anti-CD20 monoclonal antibodies, the mortality rate is still high. Novel therapeutic strategies for managing PTLD use pharmacological induction of the viral thymidine kinase gene in tumour cells, the target of antivirals based on nucleoside analogues, followed by treatment with ganciclovir. Further treatment modalities include the development of vaccines and targeting of the latent EBV episomes. Prevention of PTLD by pre-emptive therapy based on molecular monitoring of EBV load will represent the main aim to reduce occurrence. This review examines patents and literature for the treatment of EBV-associated lymphoproliferative diseases. PMID- 21793654 TI - Stem cell therapy for erectile dysfunction: a critical review. AB - Erectile dysfunction (ED) is a prevailing health problem that seriously impacts quality of life. Current treatment options are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED. These 2 types of ED are thus the main focus of past and current stem cell (SC) therapy studies. In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle. For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2 phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation. SC transplantation was done exclusively by intracavernous (IC) injection, which has been recently shown to have systemic effects. Functional assessment was done exclusively by measuring increases of IC pressure during electrostimulation of CN. Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis. In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial. Recent studies have shown that intracavernously injected SCs rapidly escaped the penis and homed into bone marrow. This could perhaps explain why intracavernously injected SCs had systemic antidiabetic effects and prolonged anti-ED effects. These hypotheses and the differentiation-versus-paracrine debate require further investigation. PMID- 21793655 TI - Use of pyrosequencing and denaturing gradient gel electrophoresis to examine the effects of probiotics and essential oil blends on digestive microflora in broilers under mixed Eimeria infection. AB - A protective digestive microflora helps prevent and reduce broiler infection and colonization by enteropathogens. In the current experiment, broilers fed diets supplemented with probiotics and essential oil (EO) blends were infected with a standard mixed Eimeria spp. to determine effects of performance enhancers on ileal and cecal microbial communities (MCs). Eight treatment groups included four controls (uninfected-unmedicated [UU], unmedicated-infected, the antibiotic BMD plus the ionophore Coban as positive control, and the ionophore as negative control), and four treatments (probiotics BC-30 and Calsporin; and EO, Crina Poultry Plus, and Crina PoultryAF). Day-old broilers were raised to 14 days in floor pens on used litter and then were moved to Petersime batteries and inoculated at 15 days with mixed Eimeria spp. Ileal and cecal samples were collected at 14 days and 7 days postinfection. Digesta DNA was subjected to pyrosequencing for sequencing of individual cecal bacteria and denaturing gradient gel electrophoresis (DGGE) for determination of changes in ileal and cecal MC according to percentage similarity coefficient (%SC). Pyrosequencing is very sensitive detecting shifts in individual bacterial sequences, whereas DGGE is able to detect gross shifts in entire MC. These combined techniques offer versatility toward identifying feed additive and mild Eimeria infection modulation of broiler MC. Pyrosequencing detected 147 bacterial species sequences. Additionally, pyrosequencing revealed the presence of relatively low levels of the potential human enteropathogens Campylobacter sp. and four Shigella spp. as well as the potential poultry pathogen Clostridiun perfringens. Pre- and postinfection changes in ileal (56%SC) and cecal (78.5%SC) DGGE profiles resulted from the coccidia infection and with increased broiler age. Probiotics and EO changed MC from those seen in UU ilea and ceca. Results potentially reflect the performance enhancement above expectations in comparison to broilers not given the probiotics or the specific EO blends as feed supplements. PMID- 21793656 TI - Presence of glycopeptide-encoding plasmids in enterococcal isolates from food and humans in Denmark. AB - Enterococci and especially glycopeptides-resistant enterococci (GRE) are a growing concern due to their ability to cause infections in hospitals. Transmission of antimicrobial resistance between reservoirs such as animals, meat, and humans are in most cases linked to transmission of mobile genetic elements (MGE) such as plasmids and transposons. Presence of MGE was tested in all GRE isolated from food in Denmark in 2005-2007 including the first vanA mediated Enterococcus faecalis isolated from food. The ability of these plasmids to transfer and persist among enterococci was investigated using newly developed techniques for classification of plasmids. Replicons associated with sex pheromone-inducible plasmids were detected in all GR E. faecalis, whereas GR Enterococcus faecium contained plasmids known to be widely distributed among enterococci. vanA resistance is common in E. faecium isolates from meat and animals in Europe and is rarely found in E. faecalis. This article describes the first characterization of MGE from vanA mediated E. faecalis, thus linking this resistance genotype to pheromone responding plasmids. PMID- 21793657 TI - Molecular characterization of ochratoxigenic fungi associated with raisins. AB - Dried grapes (raisin) may carry a significant mycological load contaminated via cultivation, postharvest processing practices, and drying processing. The contamination of raisin with fungi can accelerate spoilage or illness, if pathogens are present. Since raisins are used as food additives in many dishes in Saudi kitchen, there are healthy concerns on the safety of raisins consumed. In this article, the mycological profile of raisins sold in different markets at Jeddah, Kingdom of Saudi Arabia, was studied. The black raisin samples showed high fungal load compared with the white samples. Aspergillus, Alternaria, Cladosporium, Epicoccum Fusarium, and Rhizopus were the most prevalent genera isolated from raisin samples. Among six Aspergillus species isolated in this study, As. carbonarius and As. niger were the most frequently isolated species. Ochratoxin A (OTA) production in raisins was investigated using a combination of chromatographical (thin layer) and molecular (random amplified polymorphic DNA and Multiplex polymerase chain reaction) techniques. The OTA was detected in 70% of the raisin samples. Also, As. carbonarius (14 out of 19 isolates) and As. niger (2 isolates out of 9) were recognized as potential producers for OTA. Also, some molecular markers for detecting the contamination of raisin samples with OTA directly without isolating the producers were tested. PMID- 21793658 TI - Downregulation of H19 improves the differentiation potential of mouse parthenogenetic embryonic stem cells. AB - Parthenogenetic embryonic stem cells (P-ESCs) offer an alternative source of pluripotent cells, which hold great promise for autologous transplantation and regenerative medicine. P-ESCs have been successfully derived from blastocysts of several mammalian species. However, compared with biparental embryonic stem cells (B-ESCs), P-ESCs are limited in their ability to fully differentiate into all 3 germ layers. For example, it has been observed that there is a differentiation bias toward ectoderm derivatives at the expense of endoderm and mesoderm derivatives-muscle in particular-in chimeric embryos, teratomas, and embryoid bodies. In the present study we found that H19 expression was highly upregulated in P-ESCs with more than 6-fold overexpression compared with B-ESCs. Thus, we hypothesized that manipulation of the H19 gene in P-ESCs would alleviate their limitations and allow them to function like B-ESCs. To test this hypothesis we employed a small hairpin RNA approach to reduce the amount of H19 transcripts in mouse P-ESCs. We found that downregulation of H19 led to an increase of mesoderm derived muscle and endoderm in P-ESCs teratomas similar to that observed in B ESCs teratomas. This phenomenon coincided with upregulation of mesoderm-specific genes such as Myf5, Myf6, and MyoD. Moreover, H19 downregulated P-ESCs differentiated into a higher percentage of beating cardiomyocytes compared with control P-ESCs. Collectively, these results suggest that P-ESCs are amenable to molecular modifications that bring them functionally closer to true ESCs. PMID- 21793663 TI - Comparing two-zone models of dust exposure. AB - The selection and application of mathematical models to work tasks is challenging. Previously, we developed and evaluated a semi-empirical two-zone model that predicts time-weighted average (TWA) concentrations (Ctwa) of dust emitted during the sanding of drywall joint compound. Here, we fit the emission rate and random air speed variables of a mechanistic two-zone model to testing event data and apply and evaluate the model using data from two field studies. We found that the fitted random air speed values and emission rate were sensitive to (i) the size of the near-field and (ii) the objective function used for fitting, but this did not substantially impact predicted dust Ctwa. The mechanistic model predictions were lower than the semi-empirical model predictions and measured respirable dust Ctwa at Site A but were within an acceptable range. At Site B, a 10.5 m3 room, the mechanistic model did not capture the observed difference between PBZ and area Ctwa. The model predicted uniform mixing and predicted dust Ctwa up to an order of magnitude greater than was measured. We suggest that applications of the mechanistic model be limited to contexts where the near-field volume is very small relative to the far-field volume. PMID- 21793661 TI - Efficient differentiation of human pluripotent stem cells into mesenchymal stem cells by modulating intracellular signaling pathways in a feeder/serum-free system. AB - Mesenchymal stem cells (MSCs) derived from human pluripotent stem cells (hPSC derived MSCs) will be one promising alternative cell source for MSC-based therapies. Here, an efficient protocol is demonstrated for generating hPSC derived MSCs under a feeder-free culture system by regulating signaling pathways. Simultaneous treatments with Activin A, BIO (6-bromoindirubin-3'-oxime), and bone morphogenetic protein 4 (ABB) activated the transcription of mesoderm-lineage genes such as T, MIXL1, and WNT3 in hPSCs. The ABB-treated hPSCs could develop into CD105(+) cells with a high efficiency of 20% in the MSC-induction medium. The properties of the hPSC-derived CD105(+) cells were similar to those of adult MSCs in terms of surface antigens. Also, hPSC-derived MSCs had the potential to differentiate into adipocytes, osteoblasts, and chondrocytes in vitro. The results demonstrated that functional MSCs could be generated efficiently from hPSCs by the combined modulation of signaling pathways. PMID- 21793664 TI - Tubocutaneous fistula in a premature infant. AB - Fistulous tracts between the uterus and skin were more common in the preantibiotic era and most often occurred after pelvic surgery. Tubocutaneous fistulas constituted a subset of this form of operative complication. With the improvement of operative techniques and use of antibiotics, the incidence of these fistulas is greatly reduced. In cases reported since 1963, the youngest patient to develop a tubocutaneous fistula was 15 years old. Reported here is an infant delivered at 25 weeks' gestation, who developed necrotizing enterocolitis requiring 2 surgical interventions. At the time of insertion of a tunneled central venous catheter, the surgeon noted a mass in the right lower quadrant, which he excised. A noninflamed tubocutaneous fistula was identified pathologically with only the distal portion of the tube present. The child's history is similar to other reports in that she had previous operations and had developed significant fibrous abdominal adhesions. Her history is unique in that she is the youngest reported case and hers is the 1st report of this complication following surgery for necrotizing enterocolitis. PMID- 21793665 TI - Yolk sac tumor of the thyroid gland: a case report. AB - Extragonadal yolk sac tumors are uncommon and usually seen in sacrococcygeal, mediastinal, intracranial, and retroperitoneal sites. Yolk sac tumors of the head and neck region are rare, and the few reported cases have arisen in neonates or infants in conjunction with a teratoma or other germ cell tumor subtypes. We report a unique case of a pure yolk sac tumor presenting as a primary lesion in the right thyroid lobe of a 10-year-old girl. The diagnosis was suspected after fine-needle aspiration, and extensive sampling of the thyroidectomy specimen revealed no teratoma or other germ cell tumor. Serum alpha-fetoprotein levels were markedly elevated 6 days after excision, and imaging disclosed numerous bilateral pulmonary nodules suggestive of metastatic disease but did not reveal a mediastinal mass. The tumor has shown a favorable response to bleomycin, etoposide, and cisplatin chemotherapy. To the best of our knowledge, this is the 1st description of a primary pure yolk sac tumor of the thyroid. PMID- 21793666 TI - Polyps and masses of the pediatric urinary bladder: a 21-year pathology review. AB - Although not uncommon in adults, bladder tumors are rare in children. In addition, the histologic types of tumors seen in the pediatric population differ from those seen in adults. Although rhabdomyosarcoma is the most common pediatric bladder tumor, many other benign, malignant, and reactive lesions can be encountered. All may present clinically as a mass or polyp in the bladder. This study was designed to describe the pathology and patient demographics of pediatric bladder masses, because there are few studies describing these entities. Retrospectively reviewing our experience over a 21-year period, we identified 98 specimens from 65 patients with polyps or masses in the urinary bladder. As expected, the most frequent diagnosis was rhabdomyosarcoma. This was followed by fibroepithelial polyp and a variety of additional nonurothelial tumors. Only 7 urothelial tumors were identified, including 1 low-grade papillary urothelial carcinoma. Inflammatory lesions, such as cystitis cystica and nephrogenic adenoma, were invariably associated with an irritating factor when a history was provided. Our findings emphasize that diagnoses made in the pediatric urinary bladder are distinct from those in adults, although a wide variety of lesions may still be seen. PMID- 21793667 TI - HIV infection associated post-traumatic stress disorder and post-traumatic growth -a systematic review. AB - The phenomenon of post-traumatic stress has been well documented in the literature as a lasting mental health condition associated with exposure to traumatic life events. The diagnosis and experience of human immunodeficiency virus (HIV) disease may be such a trauma. On the other hand, the phenomenon of post-traumatic growth (PTG) has been described, whereby people show positive mental health growth in the face of such trauma. This systematic review was set out to explore post-traumatic stress disorder (PTSD) and PTG in people with HIV to monitor prevalence, measurement and efficacy of interventions to reduce stress and/or promote growth. Standardised review techniques were used to track reports on both PTSD and PTG. A total of 206 papers were retrieved from the PTSD and HIV searches, and 13 from the PTG and HIV searches. After reviewing the papers for inclusion according to adequacy and relevance criteria and to remove duplicates, 33 PTSD papers and three PTG were available for full coding. Prevalence of PTSD in HIV ranged from 5% to 74%, which were much greater than the 7-10% in the general population. Seven studies showed a relation between trauma and PTSD, while six showed a link between PTSD diagnosis and reduced antiretroviral treatment adherence. Women were more likely to be diagnosed with PTSD. Only three intervention reports were identified that fitted our inclusion criteria. All of these reported on psychological interventions for HIV+ individuals with trauma. The interventions utilised HIV education, training in coping techniques and support groups. Only coping interventions were shown to be effective. PTG was under researched but showed a promising avenue of study. There needs to be harmonised measurement and the evidence base would need strengthening in order to build on the understanding of the impact of PTSD and PTG over the course of HIV disease. There is good evidence to associate HIV diagnosis and experiences during the course of illness as traumatic. PTSD has been shown to be prevalent and there seems to be good evidence to incorporate standardised measures to track the course of the disorder. There is extremely limited evidence that interventions may affect the course of symptom experience. The evidence and insight into PTG show promise but is currently inadequate. PMID- 21793668 TI - Season of birth and morningness: comparison between the northern and southern hemispheres. AB - The present study explored the possible role of the photoperiod at birth on morningness by collecting data in the northern (Italy) and southern (Australia) hemispheres. To assess circadian typology, the Composite Scale of Morningness (CS) was administered to a sample of 1734 university students (977 Italian and 757 Australian; 1099 females and 635 males; age 24.79 +/- 7.45 yrs [mean +/- SD]). Consistent with the literature, females reported higher CS scores (morningness) than males, and Australian participants reported higher CS scores than Italian participants. Allowing for the fact the seasons are reversed between the hemispheres, the results are in line with previous studies. The authors found more evening types were born during the seasons associated with longer photoperiod (spring and summer), and more morning types were born during the seasons associated with shorter photoperiod (autumn and winter), indirectly supporting an imprinting-like phenomenon played by the photoperiod at birth. PMID- 21793669 TI - Nanotoxicology: toxicity and biological effects of nanoparticles for new evaluation standards. PMID- 21793670 TI - Researchers highlight possible toxicology effects of nano-alumina. AB - Scientists have investigated whether nanoparticulate aluminum oxide can cause neurobehavioral defects in mice PMID- 21793671 TI - Cellular uptake mechanisms and toxicity of quantum dots in dendritic cells. AB - Quantum dots (QDs) are nanoparticles with strong fluorescent emission and are novel tools used in biomedical applications, but the toxicity and mechanism of cellular uptake are poorly understood. QD655-COOH (negative charge, 18 nm) consist of a cadmium/selenide core and a zinc sulfide shell with a carboxylic acid coating with an emission wavelength of 655 nm. MATERIALS & METHODS: Peripheral blood mononuclear cells were isolated from porcine blood by gradient centrifugation, and monocytes, which are CD14 positive, were purified. Monocytes were differentiated into dendritic cells (DCs) with GM-CSF and IL-4. RESULTS: Monocytes showed cellular uptake of QD655-COOH, while lymphocytes did not. Monocyte differentiation into DCs increased the cellular uptake by sixfold when dosed with 2 nM of QD655-COOH. Transmission electron microscopy depicted QD655 COOH in the cytoplasmic vacuoles of DCs. Twelve endocytic inhibitors demonstrated QD655-COOH endocytosis in DCs, which was recognized by clathrin and scavenger receptors and regulated by F-actin and phospholipase C. In addition, DC maturation with lipopolysaccharide (LPS) caused an increase in QD655-COOH uptake compared with DCs without LPS stimulation. Viability assays, including 96AQ, CCK 8, alamar blue and ApoTox, exhibited minimal toxicity in DCs dosed with QD655 COOH at 24 h. However, glutathione levels showed a significant decrease with 10 nM of QD655-COOH. Finally, QD655-COOH exposure was associated with a decrease in CD80/CD86 expression after LPS stimulation, suggesting suppression with DC maturation. CONCLUSION: These findings shed light on the mechanism of QD655-COOH uptake in DCs and that cellular uptake pathways are dependent on cell type and cell differentiation. PMID- 21793672 TI - Attenuation of the in vivo toxicity of biomaterials by polydopamine surface modification. AB - AIMS: Polydopamine coating is emerging as a useful method of surface functionalization due to the ability of this compound to form a nanometer-scale organic thin film on virtually any material surface to which proteins, peptides, oligonucleotides, metal ions or synthetic polymers are able to be attached. The unique properties of polydopamine make this technique suitable for nanomedicine. To facilitate the use of polydopamine, evaluation of toxicity is of great importance. In this article, we investigated the in vivo toxicity of polydopamine. RESULTS: We found that the polydopamine functions as a biocompatible layer, attenuating adverse biological responses caused by intrinsic properties of the coated material. One-step polydopamine coating greatly reduced the inflammatory response to poly-L-lactic acid surfaces and the immunological responses of blood on quantum dots were also reduced. CONCLUSION: Our results indicate that polydopamine provides a versatile platform that can reduce the in vivo toxicity of biomaterials that contact tissue or blood. PMID- 21793673 TI - Layered double hydroxide nanoparticles as target-specific delivery carriers: uptake mechanism and toxicity. AB - Layered double hydroxides (LDHs), also known as anionic nanoclays or hydrotalcite like compounds, have attracted a great deal of interest for their potential as delivery carriers. In this article, we describe the cellular uptake behaviors and uptake pathway of LDHs in vitro and in vivo, which can not only explain the mechanism by which high efficacy of biomolecules delivered through LDH nanocarriers could be obtained, but also provide novel strategies to enhance their delivery efficiency. Toxicological effects of LDHs in cell lines and in animal models are also present, aiming at providing critical information about their toxicity potential, which should be carefully considered for their biomedical application. Understanding the uptake behaviors, uptake mechanism and toxicity of LDHs in terms of dose-response relationship, diverse physicochemical properties and interaction with different biological systems is important to optimize delivery efficiency as well as biocompatibility. PMID- 21793674 TI - In vivo biodistribution of nanoparticles. AB - Nanoparticles have potential applications in diagnostics, imaging, gene and drug delivery and other types of therapy. Iron oxide nanoparticles, gold nanoparticles and quantum dots have all generated substantial interest and their properties and applications have been thoroughly studied. Yet, metal-containing particles raise biodistribution and toxicity concerns because they can be quickly cleared from the blood by the reticuloendothelial system and can remain in organs, such as the liver and spleen, for prolonged periods of time. Design considerations, such as size, shape, surface coating and dosing, can be manipulated to prolong blood circulation and enhance treatment efficacy, but nonspecific distribution has thus far been unavoidable. Renal excretion of nanoparticles is possible and is size dependent, but the need to incorporate coatings to particles for increased circulation can hinder such excretion. Further long-term studies are needed because recent work has shown varying degrees of in vivo toxicity as well as varying levels of nanoparticle excretion over time. The interaction of these particles with immune cells and their effect on the innate and adaptive immune response also needs further characterization. Finally, more systematic in vitro approaches are needed to both guide in vivo work and better correlate nanoparticle properties to their biological effects. PMID- 21793675 TI - Nanomaterial cell interactions: are current in vitro tests reliable? AB - New properties of engineered nanomaterials raise great expectations for industrial, scientific as well as medical applications. At the same time concerns among consumers regarding the safety aspects of this new technology emerge. Furthermore, among the multitude of published studies, a considerable number do not reveal reliable data. Thus, standardized, validated, reliable, robust, reproducible and intelligent testing strategies are urgently needed that address nanomaterial toxicity. This article discusses the reliability of currently used in vitro toxicity assays. It covers major problems, pitfalls and challenges of assay performance and validation. We recommend a series of different controls to improve the experimental quality and, thus, also the reliability and reproducibility of current in vitro systems. These recommendations consequently applied in the future will increase the safe and sustainable use of nanotechnology. PMID- 21793676 TI - Imaging methods for determining uptake and toxicity of carbon nanotubes in vitro and in vivo. AB - Demand for carbon nanotubes (CNTs) is increasing rapidly in electrical, mechanical, and health and medical applications due to their thermal, electrical conductive and other properties. The continued commercial up-scaling of CNT production and application needs to be accompanied by an understanding of the occupational health, public safety and environmental implications of these materials. An increasing volume of literature on the toxicity of CNTs is being published; however, the results of these studies are frequently inconclusive. Due to the enormous number of permutations of nanoparticle shape, dimensions, composition and surface chemistry, only a fundamental understanding of the processes by which CNTs interact with cells will allow a realistic, practical assessment of the risks of the wide range of possible products. Alternatively, by understanding how the physicochemical properties of CNTs relate to their interaction with cells, it will be possible to design 'medical grade' CNTs, which can be used as diagnostic agents or as vectors to deliver therapeutic agents to cell and tissue targets. This article discusses the challenges associated with characterizing the toxicity of CNTs and the need for complimentary nanometrology techniques to relate their physicochemical properties to their toxicity. PMID- 21793677 TI - Synthesis, toxicology and potential of ordered mesoporous materials in nanomedicine. AB - Although ordered mesoporous silica materials have been studied for almost 20 years, their utilization within life science applications is relatively new and unexplored. An increasing number of researchers are transcending their respective fields in order to bridge the knowledge gap between materials chemistry and biotechnology, and to exploit the potential of mesoporous materials. Their intricate porosity with order in the nanoscale translates into high surface areas above 1000 m(2)/g, high selectivity for the encapsulation of biorelevant molecules as well as controlled surface chemistry. Their uses in pharmaceutics to improve drug formulation, drug bioavailability, mitigate drug toxicity and in cellular targeting, through controlled drug delivery strategies, have been shown. The incorporation of a high concentration of fluorescent and nuclear markers within their pores, whilst retaining good diffusion through their porous matrix, has shown them to be ideal candidates for sensing devices, in immunoassays such as flow cytometry and for their use in novel theranostic applications. This article aims to bring to the forefront some of the most important properties of mesoporous materials, which prove advantageous for their use in nanomedical applications and to highlight some of the potential areas into which the field may now emerge. PMID- 21793679 TI - Effect of chemical composition and state of the surface on the toxic response to high aspect ratio nanomaterials. AB - Nanomaterials often act as a double sword. On the one hand they offer exceptional new properties, but on the other hand show signs of toxicity. High aspect ratio nanomaterials (HARNs) cause more concern than isometric nanoparticles owing to their physical similarity with asbestos. Many compounds may be prepared in fibrous shape with nano-sized diameter differing one from the other in various ways. This article reports a comparative picture of the chemical features and related toxic responses to a variety of HARNs, namely carbon nanotubes, asbestos, carbon nanofibers, oxide and metal wires and rods. In spite of similarities in form, durability and several biological responses elicited in vitro and in vivo, carbon nanotubes - opposite to asbestos - quench radicals, are hydrophobic and may be fully purified from metal impurities. Most of the other HARNs produced so far are metal or metal oxide compounds, less biopersistent than carbon nanotubes. PMID- 21793678 TI - Toxicological studies on silver nanoparticles: challenges and opportunities in assessment, monitoring and imaging. AB - Silver nanoparticles (Ag NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products may lead to an increase in toxic levels of environmental silver, but regulatory control over the use or disposal of such products is lagging due to insufficient assessment on the toxicology of Ag NPs and their rate of release into the environment. In this article we discuss recent research on the transport, activity and fate of Ag NPs at the cellular and organismic level, in conjunction with traditional and recently established methods of nanoparticle characterization. We include several proposed mechanisms of cytotoxicity based on such studies, as well as new opportunities for investigating the uptake and fate of Ag NPs in living systems. PMID- 21793680 TI - Nanodetoxification: emerging role of nanomaterials in drug intoxication treatment. AB - Treatment for intoxication involves the neutralization or clearance of a toxic compound, but the current methods of treatment are limited in their ability to safely and effectively detoxify the patient. Emerging research has focused on using nanoparticles as parenteral detoxifying agents to circulate through the body and capture toxins. The variable compositions of these nanoparticles control the mechanism in which they capture and remove specific compounds. As discussed in this article, the recent methods for utilizing nanoparticles for detoxification show great potential for intoxication treatment. However, several challenges must be overcome before a universal nanoparticle detoxification method is available for clinical use. PMID- 21793683 TI - A virtual environment for learning to view during aerial movements. AB - Training the gymnasts to view the landing area when learning aerial skills may lead to more consistent landings but can be problematic and potentially dangerous. A virtual environment allowing gymnasts to get introduced to viewing techniques safely is presented. The system is based on existing simulation models and visualisation software, and is implemented using client-server technology to allow reuse with new simulation models in the future. PMID- 21793684 TI - Fumonisin B1 and B2 occurrence in dried fig fruits (Ficus carica L.) under Meander Valley's climatic conditions and relationship with fruit quality. AB - Fusarium is the agent causing endosepsis (internal rot) in fig fruits and it is widespread in fig orchards in the Aegean region. This research was conducted to determine the natural occurrence of fumonisin B(1) (FB(1)) and B(2) (FB(2)) on dried fig fruits of Sarilop (syn. Calimyrna) variety which are mainly grown in the Big and Small Meander Basins in the Aegean region, representing 60% of world dried fig production. A total of 262 samples belonging to two quality classes, Class A and Class cull, were collected from 12 different locations during the two crop years in 2004 and 2005. The fumonisin detection method is based on extraction with methanol-acetonitrile-water, derivatization with o-phthaldehyde and quantification by reversed-phase high-performance liquid chromatography with fluorescence detection. The mean concentrations of FB(1) and FB(2) in fumonisin positive samples were 0.080 +/- 0.047 ug g(-1) and 0.055 +/- 0.031 ug g(-1) and ranged from LOD to 0.332 ug g(-1) and from LOD to 0.198 ug g(-1), respectively. The incidence of fumonisins significantly differed between the two crop years. This difference can be attributed to the alteration in the rainfall regime from mid-May to mid-August (7.2 mm in 2004, 90.9 mm in 2005) and number of humid wind currents from a westerly direction (183 in 2004, 492 in 2005) from the end of July and mid-August that may have triggered a higher incidence of Fusarium spp. and thus fumonisin production. PMID- 21793681 TI - Experimental considerations on the cytotoxicity of nanoparticles. AB - Engineered nanoparticles are one of the leading nanomaterials currently under investigation due to their applicability in various fields, including drug and gene delivery, biosensors, cancer treatment and diagnostic tools. Moreover, the number of commercial products containing nanoparticles released on the market is rapidly increasing. Nanoparticles are already widely distributed in air, cosmetics, medicines and even in food. Therefore, the unintended adverse effect of nanoparticle exposure is a growing concern both academically and socially. In this context, the toxicity of nanoparticles has been extensively studied; however, several challenges are encountered due to the lack of standardized protocols. In order to improve the experimental conditions of nanoparticle toxicity studies, serious consideration is critical to obtain reliable and realistic data. The cell type must be selected considering the introduction route and target organ of the nanoparticle. In addition, the nanoparticle dose must reflect the realistic concentration of nanoparticles and must be loaded as a well dispersed form to observe the accurate size- and shape-dependent effect. In deciding the cytotoxicity assay method, it is important to choose the appropriate method that could measure the toxicity of interest without the false-negative or positive misinterpretation of the toxicity result. PMID- 21793685 TI - Emerging risk of infestation and contamination of dried fruits by mites in the Czech Republic. AB - The introduction of live insects into human food is rare in developed countries. However, we report, for the first time, an emerging risk that exists from dried fruit in Central Europe. Recently, massive and frequent infestation of dried fruit imported from the Mediterranean region by the mite, Carpoglpyhus lactis L. (Acarina: Carpoglyphidae), has been found. In 180 samples taken from supermarkets, 13% were contaminated; the contamination levels ranged from 0 to 660 mites per g of dried fruit. The contamination was found in dried apricots, figs, plums and raisins. To estimate the risks and food preferences of C. lactis, its growth rate was examined under laboratory conditions. Starting with a hypothetical population of 10 mites per g of dried fruit, the risk level of 1000 mites per g of dried fruit is reached at 42 days for dried figs, 49 days for dried pineapple and 63 days for dried apricots, dates and plums at 25 degrees C and 85% relative humidity. We found that mites are able to enter every dried fruit packing material tested, including polypropylene and aluminum foils. This indicates that mites can move from package to package in supermarkets. Mites are known as allergen producers and vectors of mycotoxin-producing fungi. These findings indicate that an increased risk of C. lactis contamination exists in dried fruit. PMID- 21793686 TI - Migration of bisphenol A from polycarbonate baby bottles purchased in the Spanish market by liquid chromatography and fluorescence detection. AB - During the last decade the safety of bisphenol A (BPA) monomer in polycarbonate baby bottles has drawn the attention of both the public and the scientific community. This paper presents the results of BPA migration from polycarbonate baby bottles bought in the Spanish market, into simulant B (3% acetic acid), 50% ethanol and into real food (reconstituted infant formula). Furthermore, it was also the objective of this study to assess the suitability of 50% ethanol as a simulant for infant formula. BPA was analysed by a multi-analyte liquid chromatography method with fluorescence detection and mass spectrometry confirmation. The method was in-house validated and accredited by the national accreditation body. The validation results for this analyte in the previous mentioned matrices were: LOD = 0.004-0.007 mg kg(-1); LOQ (validated) = 0.03 mg kg(-1); RSD% = 3.4-5.8; and recovery = 106.6-118.2%. A collection of 72 different baby bottle samples from 12 different brands were analysed. Baby bottle material was identified by FTIR. The migration test conditions used were those recommended for baby bottles in the Guidelines on testing conditions for articles in contact with foodstuffs (with a focus on kitchenware), prepared by the European network of laboratories for food-contact materials. In most of the migration assays the results were below the LOD. In four of the commercial brands there was detectable migration into the simulant 50% ethanol and BPA was detected in only two samples of infant formula (0.01 mg kg(-1)). Migration results obtained were in compliance with European Union regulations. PMID- 21793687 TI - Rapid and sensitive enzyme-linked immunosorbent assay and immunochromatographic assay for the detection of chlortetracycline residues in edible animal tissues. AB - Two rapid and sensitive enzyme-linked immunosorbent assays (ELISA) and an immunochromatographic assay (ICA) for the detection of chlortetracycline (CTC) residues in edible animal tissues were developed based on a monoclonal antibody (MAb) produced by using the chlortetracycline-bovine serum albumin (CTC-BSA) conjugate as the immunogen. A total of 50% inhibiting concentration (IC(50)) of the modified ELISA was 0.66 ng ml(-1) and the recoveries from spiked chicken muscle and liver were 78.8-92.2% and 80.3-90.2%, respectively. The corresponding coefficient variations (CVs) were 3.2-9.5% and 6.5-10.2%. The detection limit was 0.06 ng g(-1) in chicken muscle and 0.07 ng g(-1) in liver. However, the detection limit of ICA was 0.12 ng ml(-1), and the recoveries in negative samples spiked at concentrations of 10, 50 and 100 ng g(-1) ranged from 79.0% to 88.6% for muscle samples and from 75.2% to 87.0% for liver samples. The cut-off values for the test lines were 80 ng g(-1) and the analysis can be completed within 5-10 min. Comparisons with an HPLC method were performed by testing 200 swine muscle samples and chicken muscle samples from local markets, and an agreement rate of 99.5% was obtained between the three methods. PMID- 21793688 TI - Assessment of adherence and competence in cognitive therapy: comparing session segments with entire sessions. AB - The aim of the study was to compare the reliability and validity of adherence and competence judgments of four raters, based on session segments on the one hand and on entire sessions on the other. The global adherence/competence judgments based on the middle section of 34 therapy sessions demonstrated satisfactory interrater reliability (ICC=.81/.71) and the highest correlations with therapy outcome (r=.55/.45). These results were comparable with judgments based on entire therapy sessions. However, the reliability of specific aspects of adherence and competence was higher when judgments were based on the entire session. The implications of these results are important in terms of reducing time and costs associated with the judgment process. PMID- 21793689 TI - Benchmarking of cognitive-behavioral therapy for depression in efficacy and effectiveness studies--how do exclusion criteria affect treatment outcome? AB - OBJECTIVE: Little is known about how exclusion criteria applied in randomized controlled trials (RCTs) affect the transfer of psychotherapy outcome research to naturalistic settings. This study evaluated the effects of naturalistic depression therapies and benchmarked them with published RCTs. METHOD: Commonly used exclusion criteria were applied to n=338 depressive patients receiving cognitive-behavioral therapy. Outcomes of the resulting subsample eligible for RCTs were compared to those reported in RCTs. RESULTS: Treatment outcomes of the total sample (d=1.16) and the subsample eligible for RCTs (d=1.15) were highly similar. Therapy outcome was worse than in high-quality RCTs (d=1.39). CONCLUSIONS: No systematic bias was demonstrated due to patient selection criteria that are typically applied in RCTs. The comparability of psychotherapies conducted in RCTs and in real-world settings might be underestimated. Conclusions concerning the improvement of therapies in naturalistic settings are discussed. PMID- 21793690 TI - Differential change in integrative psychotherapy: a re-analysis of a change factor based RCT in a naturalistic setting. AB - General Psychotherapy (GPT; Grawe, 1997) is a research-informed psychotherapy that combines cognitive-behavioral and process-experiential techniques and that assumes motivational clarification and problem mastery as central mechanisms of change. To isolate the effect of motivational clarification, GPT was compared to a treatment that proscribed motivational clarification (General Psychotherapy Minus Clarification, GPT-C) in a randomized-controlled trial with 67 diagnostically heterogeneous outpatients. Previous analyses demonstrated equal outcomes and some superiority for highly avoidant patients in GPT. Re-analyses using causal-analytic methods confirmed equal changes, but also showed superior effects for GPT in highly symptomatic patients. Results are discussed regarding theory, methodological limitations, and implications for research and practice. PMID- 21793691 TI - Circadian typology, age, and the alternative five-factor personality model in an adult women sample. AB - Research on personality and circadian typology indicates evening-type women are more impulsive and novelty seeking, neither types are more anxious, and morning types tend to be more active, conscientious, and persistent. The purpose of this study is to examine the differences between circadian typologies in the light of the Zuckerman's Alternative Five-Factor Model (AFFM) of personality, which has a strong biological basis, in an adult sample of 412 women 18 to 55 yrs of age. The authors found morning-type women had significant higher scores than evening-type and neither-type women on Activity, and its subscales General Activity and Work Activity. In contrast, evening-type women scored significantly higher than morning-type women on Aggression-Hostility, Impulsive Sensation Seeking, and its subscale Sensation Seeking. In all groups, results were independent of age. These findings are in accordance with those previously obtained in female student samples and add new data on the AFFM. The need of using personality models that are biologically based in the study of circadian rhythms is discussed. PMID- 21793692 TI - Changes in rigidity and symptoms among adolescents in psychodynamic psychotherapy. AB - The present study examined changes in the rigidity of interpersonal patterns and symptoms in adolescents (ages 15-18) in a year-long psychodynamic psychotherapy. Seventy-two adolescents (30 in treatment and 42 in a non-treatment "community group") underwent Relationship Anecdote Paradigm (RAP) interviews according to the Core Conflictual Relationship Theme method (CCRT; Luborsky & Crits-Christoph, 1998), and completed outcome measures at two time points. RESULTS: Adolescents in the treatment group became less rigid in their interpersonal patterns and improved significantly in their symptoms, whereas no such changes were observed in the community group. Levels of rigidity were not related to initial symptom distress; however, changes in rigidity were related to improvement in symptoms within the treatment group. PMID- 21793693 TI - Crosstalk between environmental light and internal time in humans. AB - Daily exposure to environmental light is the most important zeitgeber in humans, and all studied characteristics of light pattern (timing, intensity, rate of change, duration, and spectrum) influence the circadian system. However, and due to lack of current studies on environmental light exposure and its influence on the circadian system, the aim of this work is to determine the characteristics of a naturalistic regimen of light exposure and its relationship with the functioning of the human circadian system. Eighty-eight undergraduate students (18-23 yrs) were recruited in Murcia, Spain (latitude 38 degrees 01'N) to record wrist temperature (WT), light exposure, and sleep for 1 wk under free-living conditions. Light-exposure timing, rate of change, regularity, intensity, and contrast were calculated, and their effects on the sleep pattern and WT rhythm were then analyzed. In general, higher values for interdaily stability, relative amplitude, mean morning light, and light quality index (LQI) correlated with higher interdaily stability and relative amplitude, and phase advance in sleep plus greater stability in WT and phase advance of the WT circadian rhythm. On the other hand, a higher fragmentation of the light-exposure rhythm was associated with more fragmented sleep. Naturalistic studies using 24-h ambulatory light monitoring provide essential information about the main circadian system input, necessary for maintaining healthy circadian tuning. Correcting light-exposure patterns accordingly may help prevent or even reverse health problems associated with circadian disruption. PMID- 21793694 TI - Diurnal variation in Wingate-test performance and associated electromyographic parameters. AB - The present study was designed to evaluate time-of-day effects on electromyographic (EMG) activity changes during a short-term intense cycling exercise. In a randomized order, 22 male subjects were asked to perform a 30-s Wingate test against a constant braking load of 0.087 kg.kg(-1) body mass during two experimental sessions, which were set up either at 07:00 or 17:00 h. During the test, peak power (P(peak)), mean power (P(mean)), fatigue index (FI; % of decrease in power output throughout the 30 s), and evolution of power output (5-s span) throughout the exercise were analyzed. Surface EMG activity was recorded in both the vastus lateralis and vastus medialis muscles throughout the test and analyzed over a 5-s span. The root mean square (RMS) and mean power frequency (MPF) of EMG were calculated. Neuromuscular efficiency (NME) was estimated from the ratio of power to RMS. Resting core temperature, P(peak), P(mean), and FI were significantly higher (p < .05) in the evening than morning test (e.g., P(peak): 11.6 +/- 0.8 vs. 11.9 +/- 1 W.kg(-1)). The results showed that power output decreased following two phases. During the first phase (first 20s), power output decreased rapidly and values were higher (p < .05) in the evening than in the morning. During the second phase (last 10s), power decreased slightly and appeared independent of the time of day of testing. This power output decrease was paralleled by evolution of the MPF and NME. During the first phase, NME and MPF were higher (p < .05) in the evening. During the second phase, NME and MPF were independent of time of day. In addition, no significant differences were noticed between 7:00 and 17:00 h for EMG RMS during the whole 30 s. Taken together, these results suggest that peripheral mechanisms (i.e., muscle power and fatigue) are more likely the cause of the diurnal variation of the Wingate test performance rather than central mechanisms. PMID- 21793695 TI - Masking responses to light in period mutant mice. AB - Masking is an acute effect of an external signal on an overt rhythm and is distinct from the process of entrainment. In the current study, we investigated the phase dependence and molecular mechanisms regulating masking effects of light pulses on spontaneous locomotor activity in mice. The circadian genes, Period1 (Per1) and Per2, are necessary components of the timekeeping machinery and entrainment by light appears to involve the induction of the expression of Per1 and Per2 mRNAs in the suprachiasmatic nuclei (SCN). We assessed the roles of the Per genes in regulating masking by assessing the effects of light pulses on nocturnal locomotor activity in C57BL/6J Per mutant mice. We found that Per1(-/-) and Per2(-/-) mice had robust negative masking responses to light. In addition, the locomotor activity of Per1(-/-)/Per2(-/-) mice appeared to be rhythmic in the light-dark (LD) cycle, and the phase of activity onset was advanced (but varied among individual mice) relative to lights off. This rhythm persisted for 1 to 2 days in constant darkness in some Per1(-/-)/Per2(-/-) mice. Furthermore, Per1(-/ )/Per2(-/-) mice exhibited robust negative masking responses to light. Negative masking was phase dependent in wild-type mice such that maximal suppression was induced by light pulses at zeitgeber time 14 (ZT14) and gradually weaker suppression occurred during light pulses at ZT16 and ZT18. By measuring the phase shifts induced by the masking protocol (light pulses were administered to mice maintained in the LD cycle), we found that the phase responsiveness of Per mutant mice was altered compared to wild-types. Together, our data suggest that negative masking responses to light are robust in Per mutant mice and that the Per1(-/ )/Per2(-/-) SCN may be a light-driven, weak/damping oscillator. PMID- 21793696 TI - Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction. AB - Osteoarthritis (OA) is one of the most common chronic diseases, with increasing importance due to increased life expectancy. On a cellular level, the pathophysiology of joint function impairment and ultimate destruction associated with OA remains poorly understood. Free radicals are highly reactive molecules involved in both normal intracellular signal transduction and degenerative cellular processes. An imbalance between the free radical burden and cellular scavenging mechanisms, defined as oxidative stress, has been identified as a relevant factor in OA pathogenesis. This literature review elucidates the involvement of nitrosative and oxidative stress in cellular ageing in joints, cell senescence, and apoptosis. Free radical exposure is known to promote cellular senescence and apoptosis, and the involvement of radical oxygen species (ROS) in inflammation, fibrosis control, and pain nociception has been proven. A relatively novel approach to OA pathophysiology considers the joint to be a dynamic system consisting of 3, continuously interacting compartments, cartilage, synovial tissue, and subchondral bone. Current knowledge concerning free radical involvement in paracrine signalling in OA is reviewed. The interrelationship between oxidative imbalances and OA pathophysiology may provide a novel approach to the comprehension, and therefore modification, of OA disease progression and symptom control. PMID- 21793697 TI - Genetic dissection of the resistance to Rice stripe virus present in the indica rice cultivar 'IR24'. AB - Rice stripe disease, caused by Rice stripe virus (RSV) and transmitted by the small brown planthopper (Laodelphax striatellus Fallen), is one of the most serious viral diseases of rice in temperate East Asian production regions. Prior quantitative trait loci (QTL) mapping has established that Oryza sativa L. subsp. indica 'IR24' carries positive alleles at the three loci qSTV3, qSTV7, and qSTV11 i. Here, we report an advanced backcross analysis based on three selected chromosome segment substitution lines (CSSLs), each predicted to carry one of these three QTL. Three sets of BC(4)F(2:3) populations were bred from a cross between the critical CSSL and its recurrent parent Oryza sativa L. subsp. japonica 'Asominori'. Both qSTV3 and qSTV11-i were detected in their respective population, but qSTV7 was not. An allelic analysis based on a known carrier of the major RSV resistance gene Stvb-i, which is located on chromosome 11, showed that qSTV11-i was not allelic with Stvb-i. A large mapping population was used to delimit the location of qSTV11-i to a 73.6-kb region. The de novo markers developed for this purpose will be useful as marker-assisted selection tools in efforts to introduce qSTV11-i into breeding programmes aiming to improve the level of RSV resistance. PMID- 21793699 TI - Complete chloroplast genome sequence of Magnolia kwangsiensis (Magnoliaceae): implication for DNA barcoding and population genetics. AB - Here, we report a completely sequenced plastome using Illumina/Solexa sequencing by-synthesis (SBS) technology. The plastome of Magnolia kwangsiensis Figlar & Noot. is 159 667 bp in length with a typical quadripartite structure: 88 030 bp large single-copy (LSC) and 18 669 bp small single-copy (SSC) regions, separated by two 26 484 bp inverted repeat (IR) regions. The overall predicted gene number is 129, among which 17 genes are duplicated in IR regions. The plastome of M. kwangsiensis is identical in its gene order to previously published plastomes of magnoliids. Furthermore, the C-to-U type RNA editing frequency of 114 seed plants is positively correlated with plastome GC content and plastome length, whereas plastome length is not correlated with GC content. A total of 16 potential putative barcoding or low taxonomic level phylogenetic study markers in Magnoliaceae were detected by comparing the coding and noncoding regions of the plastome of M. kwangsiensis with that of Liriodendron tulipifera L. At least eight markers might be applied not only to Magnoliaceae but also to other taxa. The 86 mononucleotide cpSSRs that distributed in single-copy noncoding regions are highly valuable to study population genetics and conservation genetics of this endangered rare species. PMID- 21793700 TI - Parasites of fishes in the Colorado River and selected tributaries in Grand Canyon, Arizona. AB - As part of the endangered humpback chub (HBC; Gila cypha ) Adaptive Management Program, a parasite survey was conducted from 28 June to 17 July 2006 in 8 tributaries and 7 adjacent sections of the main stem of the Colorado River, U.S.A. In total, 717 fish were caught, including 24 HBC. Field necropsies yielded 19 parasite species, 5 of which (Achtheres sp., Kathlaniidae gen. sp., Caryophyllaidae gen. sp., Myxidium sp., and Octomacrum sp.) are new records for Grand Canyon, Arizona, U.S.A. Spearman's correlation coefficient analyses showed no correlations between parasite burden and fork length for various combinations of fish and parasite species. Regression analyses suggest that no parasite species had a strong effect on fish length. The most diverse parasite community (n = 14) was at river kilometer (Rkm) 230, near the confluence of Kanab Creek. The most diverse parasite infracommunity (n = 12) was found in the non-native channel catfish (CCF; Ictaluris punctatus). Overall parasite prevalence was highest in CCF (85%) followed by that in HBC (58%). The parasite fauna of humpback chub was mainly composed of Bothriocephalus acheilognathi and Ornithodiplostomum sp. metacercariae. PMID- 21793701 TI - Noninvasive measurement of local arterial pulse wave velocity in humans by ultrasound. AB - An improved method for noninvasive measurement of the local velocity of arterial pulse wave propagation by an echo-tracking-based ultrasound system is described. A data acquisition image interface was programmed in the ultrasound machine simultaneously to record M-mode ultrasound signals at two locations of a given distance apart along an artery. The selections of measurement sites, separation, and time resolution were performed on the control interface. The temporal sampling frequency could be as high as 10 kHz. The displacements of the blood vessel wall along the time axis were calculated from the M-mode signals by cross correlation of the radio-frequency data and the distension waveforms were obtained. The temporal separation of the feet of the distension curves from the two measurement locations was derived to give the travel time of the pulse wave. Measurements were made in vivo on human carotid arteries. The pulse wave velocities measured from four volunteers were from 4.1 to 7.2 m/s with coefficients of variation from 5.9 to 29.5%. Some of the factors contributing to the variation in measured values of the velocity are discussed. The method is simple to implement and should be suitable for clinical research into local pulse wave velocity. PMID- 21793702 TI - Estrogen requirements in girls with Turner syndrome; how low is enough for initiating puberty and uterine development? AB - We conducted this study to find the adequate initial estrogen dose for adolescent girls with Turner Syndrome (TS). We reviewed the medical records of 19 girls with TS and premature ovarian failure (POF), aged 13 to 17 years, who were referred to our adolescent gynecology clinic for ERT. Nine patients were treated with 0.5 mg estradiol valerate (EV) and 10 patients were treated with 1 mg EV as an initial estrogen dose for 1 year. Breast development, changes in uterine size and bone mineral density were measured before and after 1 year of ERT. All patients showed breast budding after 1 year of ERT regardless of estrogen dosage. Uterine development in patients treated with 1 mg EV advanced farther in 1 year of treatment than in patients given 0.5 mg EV. In patients treated with 1 mg EV, uterine length increased by 39.8% and AP fundal diameter by 46%, increments greater than in patients receiving 0.5 mg EV. After 1 year of ERT, bone mineral densities (BMD) increased significantly in both groups, although BMD did not differ significantly between the groups. In conclusion, ERT with 1mg of EV, as a starting dose induced better uterine development than 0.5 mg in prepubertal girls with TS. PMID- 21793703 TI - Aorta-derived mesoangioblasts differentiate into the oligodendrocytes by inhibition of the Rho kinase signaling pathway. AB - Mesoangioblasts are vessel-derived stem cells that differentiate into mesodermal derivatives. We have isolated postnatal aorta-derived mesoangioblasts (ADMs) that differentiate into smooth, skeletal, and cardiac muscle, and adipocytes, and regenerate damaged skeletal muscle in a murine model for Duchenne muscular dystrophy. We report that the marker profile of ADM is similar to that of mesoangioblasts isolated from embryonic dorsal aorta, postnatal bone marrow, and heart, but distinct from mesoangioblasts derived from skeletal muscle. We also demonstrate that ADM differentiate into myelinating glial cells. ADM localize to peripheral nerve bundles in regenerating muscles and exhibit morphology and marker expression of mature Schwann cells, and myelinate axons. In vitro, ADM spontaneously express markers of oligodendrocyte progenitors, including the chondroitin sulphate proteoglycan NG2, nestin, platelet-derived growth factor (PDGF) receptor alpha, the A2B5 antigen, thyroid hormone nuclear receptor alpha, and O4. Pharmacological inhibition of Rho kinase (ROCK) initiated process extension by ADM, and when combined with insulin-like growth factor 1, PDGF, and thyroid hormone, enhanced ADM expression of oligodendrocyte precursor markers and maturation into the oligodendrocyte lineage. ADM injected into the right lateral ventricle of the brain migrate to the corpus callosum, and cerebellar white matter, where they express components of myelin. Because ADM differentiate or mature into cell types of both mesodermal and ectodermal origin, they may be useful for treatment of a variety of degenerative diseases, or repair and regeneration of multiple cell types in severely damaged tissue. PMID- 21793705 TI - Homocysteine metabolism in polycystic ovary syndrome. AB - Homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, exert cytotoxic effects on vascular endothelium. Molecular mechanisms of homocysteine-induced cellular dysfunction include increased inflammatory cytokine expression, altered nitric oxide bioavailability, induction of oxidative stress, activation of apoptosis and defective methylation. Hyperhomocysteinemia is associated with an increased risk of atherosclerotic and thromboembolic disorders, as well as hyperinsulinemia and may partially account for increased risk of cardiovascular disease associated with insulin resistance. Women with PCOS are more likely to develop components of the metabolic syndrome such as disturbances of carbohydrate metabolism, obesity, hypertension and dyslipidemia, which in turn are risk factors for cardiovascular disease. A number of studies confirmed the presence of increased serum homocysteine concentration in PCOS patients and the possible determinants of this observation are still debated. PCOS treatment options can influence homocysteine levels. PMID- 21793706 TI - Pyelonephritis during pregnancy as a marker for quality of prenatal care. PMID- 21793707 TI - ENC training reduces perinatal mortality in Karnataka, India. AB - OBJECTIVE: To evaluate the effect of World Health Organization Essential Newborn Care course and the American Academy of Pediatrics Neonatal Resuscitation Program training on perinatal mortality in rural India. METHODS: This study was part of a multi-country prospective, community-based cluster randomized controlled trial. Birth, 7-day and 28-day neonatal outcomes for all women with pregnancies greater than 28 weeks in the 26 study communities in Karnataka, India were included. Mortality rates pre- and post-Essential Newborn Care training were collected prospectively and then communities randomized to either receive neonatal resuscitation or refresher newborn care training in the control clusters. RESULTS: Consent was obtained on 99% of the 25,096 births. Perinatal mortality for infants >=500 g decreased from 52 to 36/1000 after newborn care training (RR 0.7; 95% CI 0.5, 0.9); stillbirth decreased from 23 to 14/1000 (RR 0.62; 95% CI 0.46, 0.83) and early neonatal mortality decreased from 29 to 22/1000 (RR 0.74; 95% CI 0.53, 1.03). Mortality was not reduced further with resuscitation training. CONCLUSIONS: Using a pre-post design, World Health Organization Essential Newborn Care community birth attendant training resulted in a significant reduction in perinatal mortality. In low-resource settings, the newborn care training package appears to be an effective intervention to decrease perinatal mortality. PMID- 21793708 TI - Endoglin in pregnancy complicated by fetal intrauterine growth restriction in normotensive and preeclamptic pregnant women: a comparison between preeclamptic patients with appropriate-for-gestational-age weight infants and healthy pregnant women. AB - OBJECTIVE: The aim of this study was to determine the maternal serum endoglin concentration in pregnancies with intrauterine growth restriction (IUGR) in the presence or absence of preeclampsia and to compare the results with preeclamptic pregnant women with appropriate-for-gestational-age weight infants and with healthy pregnant controls. PATIENTS AND METHODS: The study was performed on 52 normotensive pregnant patients with pregnancy complicated by isolated IUGR, 33 patients with preeclampsia complicated by IUGR and 33 preeclamptic patients with appropriate-for-gestational-age weight infants. The control group consisted of 54 healthy normotensive pregnant patients with singleton uncomplicated pregnancies. The maternal serum endoglin concentrations were determined using a sandwich enzyme-linked immunosorbent assay assay. RESULTS: Our study revealed increased levels of endoglin in the serum of women with normotensive pregnancy complicated by isolated IUGR, and in both groups of preeclamptic patients with and without IUGR. The levels of endoglin were the highest in pregnancy complicated by fetal intrauterine growth restriction (IUGR) in the course of preeclampsia. The mean values were 12.2 +/- 4.3 ng/ml in the IUGR group, 14.1 +/- 3.6 ng/ml in preeclamptic patients with normal intrauterine fetal growth, 15.1 +/- 3.2 ng/ml in preeclamptic pregnant women with IUGR and 10.6 +/- 3.7 ng/ml in the healthy controls. We also found positive correlations between serum endoglin levels and systolic and diastolic blood pressure and inverse correlations between maternal endoglin and infant birth weight. CONCLUSIONS: Our results suggest that increased endoglin concentration may be at least responsible for the pathogenesis of preeclampsia and/or intrauterine fetal growth restriction. It seems that the pathomechanism underlying the development of preeclampsia and isolated IUGR is similar, but that their beginning or intensity may be different in these two pregnancy complications. The positive correlation between endoglin and blood pressure and inverse correlation between endoglin and infant birth weight and additionally higher levels of ENG in patients with pregnancy complicated by HELLP syndrome (hemolysis, increased liver enzymes, low platelet count) or eclampsia suggest that endoglin may be a marker of severity of these pregnancy disorders. PMID- 21793709 TI - The Amyl Nitrite Expectancy Questionnaire for Men who have Sex with Men (AEQ MSM): a measure of substance-related beliefs. AB - A measure of perceived reinforcement associated with amyl nitrite was developed and evaluated among gay and bisexual men. This is the first known expectancy measure to date for this drug class. The Amyl Nitrite Expectancy Questionnaire for Men who have Sex with Men (AEQ-MSM) was completed online by 102 gay and bisexual men, between 2006 and 2008 in Queensland, Australia. The AEQ-MSM demonstrated good psychometric properties and was associated with consumption patterns. Factor analysis revealed three distinct reinforcement domains: "Enhanced sexual desire and pleasure," "Disorientation," and "Sexual negotiation." Limitations include sampling via self-selection, recruitment through health centers and self-report data. Implications for sexual activity and risk-taking, including reducing associated harm (e.g., HIV transmission), and future directions are discussed. PMID- 21793710 TI - Langerhans cell histiocytosis preceding the development of juvenile xanthogranuloma: a case and review of recent developments. AB - Langerhans cell histiocytosis (LCH) and juvenile xanthogranuloma (JXG) both belong to the histiocytosis group of disorders, which have varied prognostic and clinical significance. Their normal cellular counterparts share a common CD34 positive hematopoietic stem cell precursor that matures along CD14-negative or positive pathways. Rare cases of LCH and JXG show overlapping findings, suggesting that this divergent maturation is not irreversible. We report a case of an infant diagnosed with cutaneous LCH shortly after birth. Two years after diagnosis, a recurrent lesion in his external auditory canal contained lipidized cells with CD68 and factor XIIIa expression and lacked Birbeck granules and CD1a, consistent with JXG. Our case and previous reports of this phenomenon raise the question of a histogenic relationship between LCH and JXG, and we speculate that the lesional cells of origin are subjected to therapy-induced modulation that results in a varied differentiation. PMID- 21793711 TI - Long-term variability of desmosine/isodesmosine as biomarker in alpha-1 antritrypsin deficiency-related COPD. AB - Desmosine and isodesmosine are products of elastin breakdown which are candidate biomarkers to measure lung destruction in COPD. Data exist on the burden of desmosines in urine and plasma in COPD but long-term changes have never been investigated. We determined the changes of desmosine levels over 14 months in urine and plasma of patients with type ZZ alpha-1-antitryspsin deficiency-related COPD. Urines and plasma for determination of desmosines were collected from 11 ex smokers with moderate/severe emphysema at monthly intervals for 14 months. Spirometry and gas transfer were assessed at baseline and 6-month intervals. At baseline and month 14, eleven healthy partners of patients volunteered to give a blood sample for detection of desmosines. Desmosines were determined by capillary electrophoresis combined with laser-induced fluorescence. Urine and plasma desmosines were significantly increased after 14 months in patients (p = 0.027 and p = 0.0005, respectively). Plasma desmosines of healthy partners at baseline were 4-fold lower than from patients and not significantly different from values at month 14. Only a significant decline in lung gas transfer occurred in patients (p = 0.015). The variability of desmosines was higher in urine than in plasma (coefficient of variation 0.17 and 0.087, respectively). As longitudinal desmosine changes likely reflect the elevated elastic fiber turnover associated with the progression of lung damage and destruction in COPD, they appear to be a suitable marker for application in long-term studies. Plasma desmosines were more stable long-term biomarkers than desmosines in urine. PMID- 21793712 TI - Changes of pharyngeal airway size and hyoid bone position following orthodontic treatment of Class I bimaxillary protrusion. AB - OBJECTIVES: To test the hypothesis that the sagittal position of the anterior teeth has no effect on pharyngeal airway dimension or hyoid bone position and to investigate the influence of orthodontic retraction of the anterior teeth on each section of pharynx and hyoid position. MATERIALS AND METHODS: Forty-four Class I bimaxillary protrusion adults, treated with preadjusted appliances and maximum anchorage after extraction of four premolars, were divided into two groups according to their vertical craniofacial skeletal patterns. Pretreatment and posttreatment variables were compared using paired t-test, and the relationship between pharyngeal airway size and dentofacial variables was analyzed using Pearson correlation coefficient. The changes of pharyngeal airway size and hyoid position after treatment were compared between two groups using independent t test. RESULTS: Upon retraction of the incisors, the upper and lower lips were retracted by 2.60 mm and 3.87 mm, respectively. The tip of upper incisor was retracted by 6.84 mm and lower incisor retracted by 4.95 mm. There was significant decrease in SPP-SPPW, U-MPW, TB-TPPW, V-LPW, VAL, C3H, and SH (P < .05). No statistically significant different changes were observed in the dentofacial structures, pharyngeal airway, and hyoid position between the two groups after the treatment. There was a significant correlation between the retraction distance of lower incisor and the airway behind the soft palate, uvula, and tongue. CONCLUSIONS: The pharyngeal airway size became narrower after the treatment. Extraction of four premolars with retraction of incisors did affect velopharyngeal, glossopharyngeal, hypopharyngeal, and hyoid position in bimaxillary protrusive adult patients. PMID- 21793713 TI - Evaluation of dehiscences using cone beam computed tomography. AB - OBJECTIVE: To validate the use of three-dimensional (3-D) surface rendering (SR) images to quantify the height of alveolar dehiscences. MATERIALS AND METHODS: Twenty-four dehiscences were created on 9 incisors, 9 canines, and 6 premolars on 4 cadaver skulls. i-CAT cone beam computed tomography scans (CBCTs) were taken of each skull at .2 mm voxel size. Each dehiscence was quantified by 21 orthodontic residents using 3-D SR. The principal investigator (PI) also quantified each dehiscence using the 2-D multiplanar (MP) image and the 3-D SR image. RESULTS: Results of this study showed an average method error of the residents as a group to be 0.57 mm with an intraclass correlation (ICC) of 0.77%. Residents' method error ranged from 0.45 mm to 1.32 mm, and the ICC ranged from 0.201% to 0.857%. Systematic error was low at -0.01 mm for the direct measurement compared with the residents' average 3-D SR at 1365 density value (DV) measurement. The 3-D SR at 1365 DV images were compared with the MP and 3-D SR images at 1200 DV, and no significant differences in measurements and low systematic error were noted. The method error of the PI was 0.45 mm, 0.45 mm, and 0.41 mm for 3-D SR at 1365 DV, 3 D SR at 1200 DV, and 2-D MP, respectively. CONCLUSIONS: 3-D SR and 2D MRP can be used to measure dehiscences of the periodontium with similar levels of accuracy. PMID- 21793714 TI - Shear bond strength of brackets to demineralize enamel after different pretreatment methods. AB - OBJECTIVE: To compare the influence of demineralized and variously pretreated demineralized enamel on the shear bond strength of orthodontic brackets. MATERIALS AND METHODS: Sixty bovine enamel specimens were allocated to five groups (n = 12). Specimens of group 1 were not demineralized and were not pretreated, but served as controls. The other specimens were demineralized to form artificial carious lesions. Samples from group 2 were only demineralized and were kept untreated in artificial saliva. The other samples were pretreated with highly concentrated fluoride preparations (group 3: Elmex Gelee, 1.23% F; group 4: Clinpro White Varnish, 2.23% F) or with an infiltrating resin (group 5: Icon). After respective pretreatments, brackets were adhesively fixed on all specimens with an adhesive system after etching with 35% phosphoric acid and application of a primer and bracket resin cement (Transbond XT). Bracket shear bond strength was evaluated with a universal testing machine. Statistical analysis was performed by one-way analysis of variance followed by a post-hoc Scheffe test. RESULTS: Shear bond strength in control group 1 was statistically significantly greater compared with that in all other groups. Application of the infiltrating resin Icon (group 5) as pretreatment resulted in statistically significantly greater bond strength as compared with pretreatments with fluoride compounds (groups 3 and 4) and treatment provided without pretreatment (group 2). Groups 2, 3, and 4 did not significantly differ from each other. CONCLUSION: Pretreatment with the infiltrating resin is a beneficial approach to increasing the shear bond strength of brackets to demineralized enamel. PMID- 21793715 TI - Distribution properties of lentiviral vectors administered into the striatum by convection-enhanced delivery. AB - Before the successful use of lentiviral vectors in clinical trials it is essential that strategies for direct vector delivery into the brain be evaluated in vivo, particularly as these vectors are significantly larger than the brain extracellular space. To date no such studies have been undertaken. In this study, convection-enhanced delivery (CED) was employed in an attempt to achieve widespread lentiviral delivery in the striatum. Infusions of equine infectious anemia virus (EIAV) and HIV vector constructs expressing the reporter gene beta galactosidase (beta-Gal) were undertaken into the striatum at a range of flow rates and viral titers. In rats, all EIAV and HIV infusions led to the extensive transduction of cells in perivascular spaces throughout the brain. Although infusions were performed under standardized conditions, the number and volume of distribution of transduced cells were highly variable, with approximately one third of EIAV infusions leading to no concentrated cell transduction in the striatum. Heparin coinfusion had no effect on EIAV distribution, although coinfusion of nimodipine resulted in a significant reduction in the number and volume of distribution of transduced cells. Intrastriatal EIAV delivery in pigs led to extensive transduction of mainly neurons, which could be effectively visualized in real time by T(2)-weighted magnetic resonance imaging. No infusions were associated with a significant inflammatory response. Therefore, despite its large size, lentiviral vectors can be administered by CED to the striatum in both small and large animal models. However, the variability in vector distribution under standardized conditions and widespread vector distribution through the perivascular spaces raise serious concerns regarding the practicality of lentivirus-mediated gene therapy in the brain in clinical practice. PMID- 21793716 TI - Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD. AB - Indacaterol is a novel, inhaled once-daily ultra long-acting beta2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two period crossover study evaluated the effect of two-week treatment with indacaterol 300 MUg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 >= 40% and <= 80%, smoking history >= 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 MUg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 MUg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation. PMID- 21793717 TI - Aerosolized gemcitabine in patients with carcinoma of the lung: feasibility and safety study. AB - BACKGROUND: We investigated the biodistribution, pharmacokinetics, safety profile, and feasibility of aerosolized gemcitabine (GCB) in patients with lung carcinoma. METHOD: Eleven patients with carcinoma localized in the lungs were studied in a dose escalation study of aerosolized GCB administered 1 day/week for 9 consecutive weeks. Safety data, scintigraphic assessment of the delivered dose and pharmacokinetic monitoring were analyzed. Patients were treated with doses of between 1 mg/kg and 4 mg/kg (dose in the nebulizer), using a new inhaler device (Aeroneb Pro with an Idehaler Chamber). RESULTS AND CONCLUSIONS: The total dose of GCB delivered to the patient's lung was 42+/-16% of the initial amount of dose in the nebulizer. Safety data showed no hematologic toxicity, nephrotoxicity or neurotoxicity. At 4 mg/kg, one patient experienced grade 4 pulmonary toxicity (bronchospasm), which was the dose-limiting toxicity. Grade 2 and 3 toxic effects included fatigue, vomiting, dyspnea, and cough. Overall response: minor response in one patient, stable disease in four patients, progressive disease in four patients. Pharmacokinetic data showed very low plasma GCB levels. Maximal plasma concentration was observed at the end of nebulization. Aerosolized gemcitabin was safe, with minimal toxicity, for patients with lung carcinoma. PMID- 21793718 TI - c-erbB2 and c-myb induce mouse oocyte maturation involving activation of maturation promoting factor. AB - Proto-oncogenes are involved in cell growth, proliferation, and differentiation. In the present study, we investigated the roles and mediating pathways of proto oncogenes c-erbB(2) and c-myb in mouse oocyte maturation by RT-PCR, real-time quantitative PCR, western blot, and recombinant proto-oncogene protein microinjection. Results showed that both c-erbB(2) and c-myb antisense oligodeoxynucleotides (c-erbB(2) ASODN and c-myb ASODN) inhibited germinal vesicle breakdown and the first polar body extrusion in a dose-dependent manner. However, microinjection of recombinant c-erbB(2) or c-myb protein into germinal vesicle stage oocytes stimulated oocyte meiotic maturation. In addition, the expression of c-erbB(2) and c-myb mRNA was detected in oocytes; and c-erbB(2) ASODN and c-myb ASODN inhibited c-erbB(2) mRNA and c-myb mRNA expression, respectively. Maturation promoting factor (MPF) inhibitor roscovitine did not affect the expression of c-erbB(2) mRNA and c-myb mRNA, but blocked the effects of recombinant c-erbB(2) and c-myb protein-induced oocyte maturation. Further, cyclin B1 protein expression in oocytes was remarkably inhibited by c-erbB(2) ASODN, c-myb ASODN, and roscovitine. Nonsense tat ODN had no effect on the expression of c-erbB(2), c-myb, and cyclin B1. These results suggest that c erbB(2) and c-myb may induce oocyte maturation through mediating a pathway involving the activation of MPF. PMID- 21793720 TI - Where do all the postdocs go? PMID- 21793721 TI - Increased risk for gastric cancer in carriers of the lymphotoxin-alpha+252G variant infected by Helicobacter pylori. AB - The objective of this study is to determine whether polymorphisms in the lymphotoxin-alpha (LTA) and interleukin-10 (IL-10) genes were associated with gastric cancer (GC) in a Chinese population. One hundred ninety-six patients with GC and 248 healthy individuals were enrolled in this case-control study. The LTA 252G was associated with an increased risk of GC, with an adjusted odds ratio (OR) of 1.74 (95% confidence interval [CI]: 1.12-2.69) for the LTA 252G heterozygotes and 2.42 (95% CI: 1.28-4.58) for the LTA 252G homozygotes as compared with noncarriers. In contrast, such association is not found in polymorphisms in IL-10; however, a potential interaction between LTA +252 G allele and IL-10-1082 G/A was found to be associated with the occurrence of GC (adjusted OR: 1.91; 95% CI: 1.01-3.64). This study indicates that the LTA +252G allele is associated with increased risk for the presence of GC in a Helicobacter pylori infection positive subgroup and potential interaction between IL-10 and LTA may contribute to the risk of GC. PMID- 21793722 TI - Fructose malabsorption and intolerance: effects of fructose with and without simultaneous glucose ingestion. AB - Concern exists that increasing fructose consumption, particularly in the form of high-fructose corn syrup, is resulting in increasing rates of fructose intolerance and aggravation of clinical symptoms in individuals with irritable bowel syndrome. Most clinical trials designed to test this hypothesis have used pure fructose, a form not commonly found in the food supply, often in quantities and concentrations that exceed typical fructose intake levels. In addition, the amount of fructose provided in tests for malabsorption, which is thought to be a key cause of intolerance, often exceeds the normal physiological absorption capacity for this sugar. To help health professionals accurately identify and treat this condition, this article reviews clinical data related to understanding fructose malabsorption and intolerance (i.e., malabsorption that manifests with symptoms) relative to usual fructose and other carbohydrate intake. Because simultaneous consumption of glucose attenuates fructose malabsorption, information on the fructose and glucose content of foods, beverages, and ingredients representing a variety of food categories is provided. PMID- 21793723 TI - United States pharmacopeia safety evaluation of spirulina. AB - The Dietary Supplements Information Expert Committee (DSI-EC) of the United States Pharmacopeial Convention (USP) reviews the safety of dietary supplements and dietary supplement ingredients for the purpose of determining whether they should be admitted as quality monographs into the United States Pharmacopeia and National Formulary (USP-NF). The United States Food and Drug Administration (FDA) has enforcement authority to pursue a misbranding action in those instances where a dietary supplement product indicates that it conforms to USP standards but fails to so conform. Recently DSI-EC undertook a safety evaluation of spirulina, a widely used dietary ingredient. DSI-EC reviewed information from human clinical trials, animal studies, and regulatory and pharmacopeial sources and analyzed 31 adverse event reports regarding spirulina to assess potential health concerns. At the conclusion of this review, DSI-EC assigned a Class A safety rating for Spirulina maxima and S. platensis, thereby permitting the admission of quality monographs for these dietary supplement ingredients in USP-NF. DSI-EC continually monitors reports concerning the safety of dietary supplements and dietary supplement ingredients for which USP dietary supplement monographs are developed. The DSI-EC may revisit the safety classification of spirulina as new information on this dietary ingredient becomes available. PMID- 21793724 TI - Perfluorinated compounds in food: a global perspective. AB - Perfluorinated compounds (PFCs) are resistant to breakdown and are turning up in unexpected places around the world, becoming emerging food contaminants. Although these chemicals have been used in countless products since the 1950s, they have been subject to little control until now. There is still an insufficient knowledge of their sources, occurrence, and hazards for food safety decision making. This article provides a comprehensive review of the food contamination levels and dietary intake risks posed by PFCs, as well as the specific methods developed for their determination. It is based on the evaluation of the published literature between 2004 and the beginning of 2010, with special emphasis on those reports of the last two years and in the examination of the growing body of studies on the exposure assessment and food occurrence of PFCs. The current state of-the art and future perspectives in extraction, clean-up, detection, identification, confirmation, and quantification highlighting the advantages and limitations of each technique have been summarized. How much is known about the sources and pathways of food web and human exposure, which is needed to control and manage the release of these emerging toxic contaminants, has also been explained. PMID- 21793725 TI - The bioactivity of pomegranate: impact on health and disease. AB - The aim of the present review is to discuss the cumulative evidence that suggests that pomegranate consumption possesses a diverse array of biological actions and may be helpful in the prevention of some inflammatory-mediated diseases including cancer. The pomegranate fruit can be divided into at least three parts-seeds, peel, and juice. All these components have been studied for their antioxidant properties in a chemoprevention approach. Pomegranate exerts antiproliferative, anti-invasive, and antimetastatic effects, induces apoptosis through modulation of Bcl-2 proteins, increases p21 and p27, and downregulates cyclin-cdk network. In addition, pomegranate inhibits the activation of inflammatory pathways including, but not limited to, the NFkappa-B pathway. Anti-cancer effects with the most impressive data have been demonstrated so far in prostate cancer. PMID- 21793726 TI - Proteins of Brassicaceae oilseeds and their potential as a plant protein source. AB - Among the commercially cultivated Brassicaceae (Cruciferae) plants, Brassica juncea, Brassica napus, Brassica rapa, and Sinapis alba store significant amounts of oil and protein in the seed. At present, Brassica seed proteins are primarily used for livestock feeding based on the nutritional value. The point of curiosity is whether the present knowledge on the protein structure, biochemical characteristics, nutritive value, and the recovery processes are inadequate to develop Brassica proteins into a usable plant protein source or these proteins are of substandard for uses beyond animal nutrition applications. Cruciferin (11S) and napin (2S) are the predominant storage proteins of Brassicaceae seeds that contribute to different properties and functions. A gamut of information is available on the chemistry, nutritional value, as well as the functionality in foods, and associated non-protein components of canola/rapeseed storage proteins. The intention of this article is to critically review what is known about the predominant storage proteins of commercially produced Brassicaceae seeds relative to the above aspects and identify the knowledge gaps. PMID- 21793727 TI - Chlorophylls in olive and in olive oil: chemistry and occurrences. AB - The chlorophylls are responsible for the characteristic green color of the olive fruits and their products. Virgin olive oil (VOO) is obtained from processing olives only by mechanical and physical means under conditions ensuring that the natural characteristics of the fruit composition are maintained as far as possible. In terms of the total chlorophyll content of oil, the extraction process entails a loss of chlorophyll of up to 80%. Many factors, both agronomical and technological, can affect the presence of green pigments in VOO. The analysis of green pigments in olives and/or oil requires an initial phase of extraction of these compounds from the solid and fluid matrix, followed by the selective separation and subsequent identification of the different components of the chlorophyll fraction. The aim of this review article is to summarize and critically analyze the available information about chlorophylls in VOO. PMID- 21793728 TI - Biogenic amines in dairy products. AB - Biogenic amines (BA) are organic, basic, nitrogenous compounds with biological activity, mainly formed by the decarboxylation of amino acids. BA are present in a wide range of foods, including dairy products, and can accumulate in high concentrations. In some cheeses more than 1000 mg of BA have been detected per kilogram of cheese. The consumption of food containing large amounts of these amines can have toxicological consequences. Although there is no specific legislation regarding the BA content in dairy products, it is generally assumed that they should not be allowed to accumulate. Greater knowledge of the factors involved in the synthesis and accumulation of BA should lead to a reduction in their incidence in foods. This article focuses on the factors that affect BA production, in particular environmental conditions, the microorganisms that produce them, the genetic organization and regulation of the biosynthetic pathways involved, and the available methods for detecting the presence of BA or BA-producing microorganisms in dairy products. PMID- 21793729 TI - Clinical outcomes and contributors to weight loss in a cancer cachexia clinic. AB - BACKGROUND: Cancer cachexia is considered intractable, with few therapeutic options. Secondary nutrition impact symptoms (S-NIS) such as nausea may further contribute to weight loss by decreasing nutrient intake. In addition, treatable metabolic abnormalities such as hypogonadism, vitamin B12 deficiency, hypothyroidism, and hypoadrenalism could exacerbate anorexia and muscle wasting in patients with cancer cachexia. We determined the frequency and type of contributors to appetite and weight loss, and the effect of the cachexia clinic on clinical outcomes. METHODS: Review of 151 consecutive patients referred to a cachexia clinic. All received dietary counseling and exercise recommendations. Assessments included weight, body mass index (BMI), S-NIS, resting energy expenditure by indirect calorimetry, serum thyroid stimulating hormone (TSH), cortisol, total testosterone, and vitamin B12. RESULTS: Median weight loss in the 100 days before referral was 9% (4%-13%); median BMI at presentation was 20.8. Median number of S-NIS was 3 (2-4), most commonly treated by metoclopramide, laxatives, and antidepressants. Forty-one percent (24/59) of patients were hypermetabolic and 73% (52/71) of males hypogonadic, whereas hypoadrenalism (0/101, 0%), hypothyroidism (4/113, 4%), and low vitamin B12 (3/107, 3%) were uncommon. Poor appetite and weight loss before referral (r = 0.18, p = 0.036) were associated with increased S-NIS (r = 0.22, p = 0.008). Appetite improved (p < 0.001) and 31/92 (34%) of patients returning for a second visit gained weight. CONCLUSIONS: Patients had a high frequency of multiple S-NIS, hypogonadism, and hypermetabolism. A combination of simple pharmacological and nonpharmacological interventions improved appetite significantly, and increased weight in one third of patients who were able to return for follow-up. Cachexia clinics are feasible and effective for many patients with advanced cancer. PMID- 21793730 TI - Being aware of the prognosis: how does it relate to palliative care patients' anxiety and communication difficulty with family members in the Hong Kong Chinese context? AB - Chinese family members play an important role in end-of-life decision making. Culturally, they may believe that a patient's awareness of a poor prognosis could harm his or her well-being, and thus they may avoid telling the truth to the patient. To examine this cultural belief empirically, this study aimed to explore the relationships among the patient's awareness of the prognosis, the family's awareness of the prognosis, the patient's anxiety, and difficulty in communicating with family members. Clinical data mining was the research method. Clinical records of deceased cancer patients in the palliative care unit of a hospital during 2003-2005 were reviewed, and 935 patients were included in this study. Logistic regression analyses indicated that patients who did not have a clear awareness of their prognosis were more likely to experience anxiety (odds ratio [OR] = 1.44, 95% CI = 1.14-1.82, p = 0.002) and difficulty communicating with family members (OR = 2.11, 95% CI = 1.62-2.76, p < 0.001). Patients whose family members were less aware of the prognosis were more likely to experience difficulty communicating with family members (OR = 4.48, 95% CI = 1.93-10.42, p < 0.001). This study further suggests that awareness of prognosis may not harm Chinese patients. Instead, unrealistic incomplete awareness of prognosis by patients and family members may be associated with patient anxiety and difficulty communicating. PMID- 21793731 TI - The NYC native air sampling pilot project: using HVAC filter data for urban biological incident characterization. AB - Native air sampling (NAS) is distinguished from dedicated air sampling (DAS) devices (eg, BioWatch) that are deployed to detect aerosol disseminations of biological threat agents. NAS uses filter samples from heating, ventilation, and air conditioning (HVAC) systems in commercial properties for environmental sampling after DAS detection of biological threat agent incidents. It represents an untapped, scientifically sound, efficient, widely distributed, and comparably inexpensive resource for postevent environmental sampling. Calculations predict that postevent NAS would be more efficient than environmental surface sampling by orders of magnitude. HVAC filter samples could be collected from pre-identified surrounding NAS facilities to corroborate the DAS alarm and delineate the path taken by the bioaerosol plume. The New York City (NYC) Native Air Sampling Pilot Project explored whether native air sampling would be acceptable to private sector stakeholders and could be implemented successfully in NYC. Building trade associations facilitated outreach to and discussions with property owners and managers, who expedited contact with building managers of candidate NAS properties that they managed or owned. Nominal NAS building requirements were determined; procedures to identify and evaluate candidate NAS facilities were developed; data collection tools and other resources were designed and used to expedite candidate NAS building selection and evaluation in Manhattan; and exemplar environmental sampling playbooks for emergency responders were completed. In this sample, modern buildings with single or few corporate tenants were the best NAS candidate facilities. The Pilot Project successfully demonstrated that in one urban setting a native air sampling strategy could be implemented with effective public-private collaboration. PMID- 21793732 TI - Review: Lead exposure in battery manufacturing and recycling in developing countries and among children in nearby communities. AB - The battery industry is the largest consumer of lead, using an estimated 80% of the global lead production. The industry is also rapidly expanding in emerging market countries. A review of published literature on exposures from lead-acid battery manufacturing and recycling plants in developing countries was conducted. The review included studies from 37 countries published from 1993 to 2010 and excluded facilities in developed countries, such as the United States and those in Western Europe, except for providing comparisons to reported findings. The average worker blood lead level (BLL) in developing countries was 47 MUg/dL in battery manufacturing plants and 64 MUg/dL in recycling facilities. Airborne lead concentrations reported in battery plants in developing countries averaged 367 MUg/m3, which is 7-fold greater than the U.S. Occupational Safety and Health Administration's 50 MUg/m3 permissible exposure limit. The geometric mean BLL of children residing near battery plants in developing countries was 19 MUg/dL, which is about 13-fold greater than the levels observed among children in the United States. The blood lead and airborne lead exposure concentrations for battery workers were substantially higher in developing countries than in the United States. This disparity may worsen due to rapid growth in lead-acid battery manufacturing and recycling operations worldwide. Given the lack of regulatory and enforcement capacity in most developing countries, third-party certification programs may be the only viable option to improve conditions. PMID- 21793734 TI - Switching the microglial harmful phenotype promotes lifelong restoration of subtantia nigra dopaminergic neurons from inflammatory neurodegeneration in aged mice. AB - Aging represents a major risk factor for the development and progression of Parkinson disease (PD), a chronic degenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). Emerging evidence highlights the glia as a pivotal factor in PD etiology, and epidemiological studies indicate that certain nonsteroidal antiinflammatory drugs (NSAIDs) may prevent or delay the progression of PD. Given that the exaggerated inflammatory response observed in old age may play a critical role in exacerbating DAergic vulnerability, we hypothesize here that switching the harmful glial response to inflammation and oxidative stress might increase the ability of the SN to resist inflammatory attacks. To this end, we developed a treatment in which we combined the effects of nitric oxide (NO) with nonsteroidal antiinflammatory activity by using HCT1026, a NO-donating derivative of flurbiprofen that has a safe profile and additional immunomodulatory properties. Young and aged mice fed with control or HCT1026 (30 mg kg(-1) day( 1)) diet were exposed to a single systemic injection of a subtoxic dose (0.2 mg kg(-1)) of lipopolysaccharide (LPS), one of the most extensively used glial activators. HCT1026 efficiently reversed the age-dependent increase of microglial activation in response to LPS to levels measured in younger mice. In aged mice, LPS induced a progressive loss of DAergic neurons with no recovery for their entire life span, whereas younger mice or aged mice fed with HCT1026 were resistant to systemic LPS-induced DAergic neurodegeneration, underscoring glia as a key pharmacological target for DAergic neuroprotection. PMID- 21793733 TI - Occluding the mannose moieties on human immunodeficiency virus type 1 gp120 with griffithsin improves the antibody responses to both proteins in mice. AB - To assess the influence of mannosylated glycans on the immunogenicity of human immunodeficiency virus type 1 (HIV-1) Env proteins, we immunized mice with monomeric gp120 in the presence and absence of the mannose-binding protein, griffithsin (GRFT). For comparison, other groups of mice received the nonglycosylated HIV-1 Gag protein, with and without GRFT. Coimmunization with GRFT increased the anti-gp120 IgG reactivity significantly, but had no effect on the anti-Gag response. We also investigated the IgG response to GRFT and found that gp120, but not Gag, enhanced its immunogenicity. For both proteins, IgG1 antibodies dominated the IgG response, with IgG2b as the next most prevalent subclass. We conclude that gp120-GRFT complexes are more immunogenic than the free proteins, for both components, and that occluding the mannose moieties on monomeric gp120 can improve the humoral immune response to this protein. PMID- 21793735 TI - Hemangioma curative effect of PDL, alexandrite, Er:YAG and CO(2) lasers. AB - OBJECTIVE: Hemangioma is a mesenchymal benign tumor formed by blood vessels. Anomalies affect up to 10% of children and they are more common in females than in males. The aim of this study was to evaluate hemangioma treatment using four different types of lasers, namely, alexandrite, Er:YAG, CO(2), and pulsed dye laser (PDL). BACKGROUND DATA: The argon laser was the first to be used for dermatological patients, namely, with port wine stains (PWS) in the late 1960s and early 1970s. A variety of different lasers and light sources were useful in the treatment of vascular lesions, e.g., KTP, Nd:YAG, CO(2), PDL, and Er:YAG. METHODS: A group of 869 consecutive patients with hemangioma was retrospectively reviewed. The patients including in our study were divided into four groups according to the type of laser used: Alexandrite laser (n=85, 58 women and 20 men), CO(2) laser (n=78, 58 women and 20 men), Er:YAG laser (n=105, 87 women and 18 men), and PDL laser (n=601, 453 women and 148 men). All patients were treated in one session without anesthesia application. The ablative systems vaporized the tissues until the hemangioma was removed. The non-ablative systems used one shot, which destroyed the hemangioma blood vessels. RESULTS: For the treatment efficacy analysis, the following factors were evaluated: therapeutic effect (yes vs. no), loss of pigment (yes vs. no), and appearance of scar (yes vs. no). From results it was evident that the therapeutic effect of all the lasers except alexandrite was very high; almost 100%. In the CO(2) and the Er:YAG laser groups a high percentage of side effects was also observed. Exposure to these lasers caused loss of pigment and scar formation in many cases. The best therapeutic effect, with only minor side effects, has been achieved with the PDL laser. CONCLUSION: It was confirmed that PDL (595 nm, 1.5 ms, 7 mm, 9 - 11 J/cm(2)) had optimal effect without scars. Er:YAG or CO(2) laser radiation with specific characteristics was also useful for small superficial lesions. PMID- 21793736 TI - Open-source genomic analysis of Shiga-toxin-producing E. coli O104:H4. AB - An outbreak caused by Shiga-toxin-producing Escherichia coli O104:H4 occurred in Germany in May and June of 2011, with more than 3000 persons infected. Here, we report a cluster of cases associated with a single family and describe an open source genomic analysis of an isolate from one member of the family. This analysis involved the use of rapid, bench-top DNA sequencing technology, open source data release, and prompt crowd-sourced analyses. In less than a week, these studies revealed that the outbreak strain belonged to an enteroaggregative E. coli lineage that had acquired genes for Shiga toxin 2 and for antibiotic resistance. PMID- 21793737 TI - Hamartoma syndromes, exome sequencing, and a protean puzzle. PMID- 21793738 TI - A mosaic activating mutation in AKT1 associated with the Proteus syndrome. AB - BACKGROUND: The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS: We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS: Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G->A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS: The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.). PMID- 21793739 TI - Taking the mystery out of "mystery shopper" studies. PMID- 21793741 TI - Images in clinical medicine. Tongue mucocele. PMID- 21793740 TI - Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. AB - BACKGROUND: A large outbreak of diarrhea and the hemolytic-uremic syndrome caused by an unusual serotype of Shiga-toxin-producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin-producing E. coli have been reported--3167 without the hemolytic uremic syndrome (16 deaths) and 908 with the hemolytic-uremic syndrome (34 deaths)--indicating that this strain is notably more virulent than most of the Shiga-toxin-producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS: We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS: The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS: Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin-producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens. PMID- 21793742 TI - Integrating social media into emergency-preparedness efforts. PMID- 21793743 TI - One hundred years of Salvarsan. PMID- 21793744 TI - Desensitization in HLA-incompatible kidney recipients and survival. AB - BACKGROUND: More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS: We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or transplantation group). RESULTS: In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS: Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.). PMID- 21793745 TI - Protective effect of natural rotavirus infection in an Indian birth cohort. AB - BACKGROUND: More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected). METHODS: We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3. RESULTS: Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P[8], the most common viral strain, there was no evidence of homotypic protection. CONCLUSIONS: Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.). PMID- 21793747 TI - Images in clinical medicine. Small-intestinal volvulus. PMID- 21793746 TI - Microbial genomics and infectious diseases. PMID- 21793748 TI - Case records of the Massachusetts General Hospital. Case 23-2011. A 40-year-old pregnant woman with placenta accreta who declined blood products. PMID- 21793749 TI - Stem cells and eye development. PMID- 21793750 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793751 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793752 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793753 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793754 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793755 TI - Craniectomy in diffuse traumatic brain injury. PMID- 21793757 TI - Bisphosphonates and atypical femoral shaft fractures. PMID- 21793759 TI - Counterfeit bevacizumab and endophthalmitis. PMID- 21793761 TI - Neonatal cyanosis from a hemoglobin variant. PMID- 21793762 TI - Drug-induced effects on erlotinib metabolism. PMID- 21793763 TI - Formulation of plumbagin loaded long circulating pegylated liposomes: in vivo evaluation in C57BL/6J mice bearing B16F1 melanoma. AB - CONTEXT AND OBJECTIVE: Plumbagin (2-methyl, 5-hydroxy, 1, 4-naphthoquinone), an anticancer agent is encapsulated either as conventional or long circulating liposomal formulations to enhance its biological half-life and antitumor efficacy. METHODS: The liposomes were prepared by thin film hydration method and in vitro characterization was carried out to examine the particle size, zeta potential, drug encapsulation efficiency and in vitro release. The optimized formulations were tested for pharmacokinetic and pharmacodynamic efficacy against mice bearing B16F1 melanoma. Also in vivo toxicity studies were carried out. RESULTS AND DISCUSSION: The optimum particle size and entrapment efficiency was observed at drug to lipid molar ratio of 1:20. The in-vitro release of plumbagin from the liposomal formulations in phosphate-buffered saline (pH 7.4) showed biphasic release with an initial burst release followed by sustained release phase. Elimination half life (T(1/2)) of pegylated, conventional and free plumbagin was 1305.76 +/- 278.16, 346.87 +/- 33.82 and 35.89 +/- 7.95 min respectively. Further, plumbagin exhibited better antitumor efficacy in vivo when administered as long circulating liposomes with no signs of normal tissue toxicity. CONCLUSION: It can be concluded that the pegylated liposomes could provide a promising parenteral platform for plumbagin with enhanced plasma half life and therapeutic efficacy. PMID- 21793764 TI - A sulphated flavone glycoside from Livistona australis and its antioxidant and cytotoxic activity. AB - A new flavone glycoside tricin 7-O-beta-glucopyranoside-2"-sulphate sodium salt along with 14 known flavonoid compounds were isolated and identified from the aqueous methanol extract of Livistona australis leaves. Their structures were established on the basis of extensive NMR (1H, 13C, HSQC and H-H COSY) and ESIMS data. Antioxidant and cytotoxicity properties of the methanol extract of the leaves as well as the new compound were investigated. PMID- 21793765 TI - Antioxidant and antibacterial activity of six edible wild plants (Sonchus spp.) in China. AB - The total phenolic and flavonoid, antioxidant and antibacterial activities of six Sonchus wild vegetables (Sonchus oleraceus L., Sonchus arvensis L., Sonchus asper (L.) Hill., Sonchus uliginosus M.B., Sonchus brachyotus DC. and Sonchus lingianus Shih) in China were investigated. The results revealed that S. arvensis extract and S. oleraceus extract contained the highest amount of phenolic and flavonoid, respectively. Among the methanol extracts of six Sonchus species, S. arvensis extract exhibited the highest radical (DPPH and ABTS+ scavenging power and lipid peroxidation inhibitory power. It also exhibited the highest reducing power at 500 ug mL-1 by A (700) = 0.80. The results of antibacterial test indicated that the S. oleraceus extract showed higher activity than the other five Sonchus wild vegetables extracts, both in Gram-negative bacteria (Escherichia coli, Salmonella enterica and Vibrio parahaemolyticus) and in a Gram-positive bacterium (Staphylococcus aureus). These results indicate that Sonchus wild food plants might be applicable in natural medicine and healthy food. PMID- 21793766 TI - Nutrition for power sports: middle-distance running, track cycling, rowing, canoeing/kayaking, and swimming. AB - Contemporary training for power sports involves diverse routines that place a wide array of physiological demands on the athlete. This requires a multi-faceted nutritional strategy to support both general training needs--tailored to specific training phases--as well as the acute demands of competition. Elite power sport athletes have high training intensities and volumes for most of the training season, so energy intake must be sufficient to support recovery and adaptation. Low pre-exercise muscle glycogen reduces high-intensity performance, so daily carbohydrate intake must be emphasized throughout training and competition phases. There is strong evidence to suggest that the timing, type, and amount of protein intake influence post-exercise recovery and adaptation. Most power sports feature demanding competition schedules, which require aggressive nutritional recovery strategies to optimize muscle glycogen resynthesis. Various power sports have different optimum body compositions and body weight requirements, but increasing the power-to-weight ratio during the championship season can lead to significant performance benefits for most athletes. Both intra- and extracellular buffering agents may enhance performance, but more research is needed to examine the potential long-term impact of buffering agents on training adaptation. Interactions between training, desired physiological adaptations, competition, and nutrition require an individual approach and should be continuously adjusted and adapted. PMID- 21793767 TI - Energy availability in athletes. AB - This review updates and complements the review of energy balance and body composition in the Proceedings of the 2003 IOC Consensus Conference on Sports Nutrition. It argues that the concept of energy availability is more useful than the concept of energy balance for managing the diets of athletes. It then summarizes recent reports of the existence, aetiologies, and clinical consequences of low energy availability in athletes. This is followed by a review of recent research on the failure of appetite to increase ad libitum energy intake in compensation for exercise energy expenditure. The review closes by summarizing the implications of this research for managing the diets of athletes. PMID- 21793768 TI - Retrospective comparison of early versus late treatment with fluticasone propionate/salmeterol after an asthma exacerbation. AB - BACKGROUND: The benefits of inhaled corticosteroids in asthma are well established. Early use of inhaled anti-inflammatories following and exacerbation could be beneficial. METHODS: A retrospective observational cohort study compared the risk of asthma-related exacerbations [hospitalization, emergency department visit, and/or treatment with systemic corticosteroid] in patients receiving treatment with fluticasone propionate/salmeterol in a single inhaler (FSC) within 90 days following an initial asthma-related exacerbation (early treatment) versus patients receiving the treatment subsequently (late treatment). Data were from a large health insurance claims database spanning from January 1998 to April 2008. Subjects included patients with >=1 prescription for FSC <= 1 year after first asthma-related exacerbation. Patients with early treatment were matched to those with late treatment by propensity score and compared in terms of healthcare utilization and costs after initiation of FSC. RESULTS: A total of 14,861 patients met study inclusion criteria, including 10,793 early and 4068 late treatment patients. After matching, 3555 pairs were well matched on all pretreatment characteristics and duration of follow-up (mean 722 vs. 717 days, p = .634). Early versus late treatment was associated with longer time to first asthma-related exacerbation (hazard ratio = 0.82, 95% CI 0.75-0.88, p < .001), fewer short-acting beta-agonists prescriptions (3.3 vs. 3.6, p = .031), higher outpatient yearly per patient pharmacy costs ($1320 vs. $1163, p = .008), and lower yearly per patient asthma-related emergency department visit costs ($80 vs. $105, p = .032). Total yearly per patient asthma-related costs were similar ($2197 vs. $2064, p = .203). CONCLUSIONS: Earlier use of FSC following an asthma exacerbation was associated with reduced risk of future asthma-related exacerbation and lower use of rescue medications. PMID- 21793769 TI - Cervical ripening with foley balloon plus fixed versus incremental low-dose oxytocin: a randomized controlled trial. AB - OBJECTIVE: To evaluate cervical ripening with foley balloon combined with a fixed vs. incremental low-dose oxytocin infusion. METHODS: Women presenting for term labor induction were randomized to fixed low-dose or standard incremental low dose oxytocin infusion following foley balloon placement. The primary outcome was time from foley balloon placement to delivery. RESULTS: Among 116 subjects, there was no difference in median time to delivery among subjects receiving fixed low dose vs. standard incremental low-dose oxytocin during induction of labor with a foley balloon (23.7 vs. 19.2 hours). There were no differences between the two groups in median time to foley bulb extrusion, active labor and second stage of labor or incidence of uterine tachysystole, fetal heart rate abnormalities, mode of delivery or maternal hemorrhage. CONCLUSIONS: There is no difference in median time to delivery in women undergoing cervical ripening with a foley balloon combined with a fixed low-dose or standard incremental low-dose oxytocin. PMID- 21793770 TI - Size and surface charge significantly influence the toxicity of silica and dendritic nanoparticles. AB - The influence of size, surface charge and surface functionality of poly(amido amine) dendrimers and silica nanoparticles (SNPs) on their toxicity was studied in immunocompetent mice. After systematic characterization of nanoparticles, they were administered to CD-1 (caesarean derived-1) mice to evaluate acute toxicity. A distinct trend in nanotoxicity based on surface charge and functional group was observed with dendrimers regardless of their size. Amine-terminated dendrimers were fatal at doses >10 mg/kg causing haematological complications such as disseminated intravascular coagulation-like manifestations whereas carboxyl- and hydroxyl-terminated dendrimers of similar sizes were tolerated at 50-fold higher doses. In contrast, larger SNPs were less tolerated than smaller SNPs irrespective of their surface functionality. These findings have important implications in the use of these nanoparticles for various biomedical applications. PMID- 21793771 TI - Importance of agglomeration state and exposure conditions for uptake and pro inflammatory responses to amorphous silica nanoparticles in bronchial epithelial cells. AB - Amorphous silica nanoparticles (SiNPs, 30 and 50 nm) and rhodamine-coated SiNPs (50 nm) were examined for their ability to induce pro-inflammatory responses and cytotoxicity in BEAS-2B cells under different experimental conditions. The SiNPs formed micrometre-sized agglomerates in the absence of bovine serum albumin (BSA) in the culture medium, whereas with BSA (0.1%) they were much less agglomerated. All the SiNPs induced IL-6 and IL-8 responses, as measured by ELISA and real-time PCR. The responses were more marked without BSA and higher for the rhodamine SiNPs than the plain ones. Rhodamine SiNPs were not taken up by cells during a 3 h exposure, even though cytokine mRNAs were up-regulated. In conclusion, agglomerated SiNPs induced more potent cytokine responses than the non agglomerated ones; either due to the agglomeration state per se or more conceivably to a change in surface reactivity against cellular targets due to BSA. Furthermore, cytokine expression was up-regulated independently of SiNP uptake. PMID- 21793772 TI - Trefoil factor 2 regulates airway remodeling in animal models of asthma. AB - BACKGROUND: Epithelial denudation and metaplasia are important in the pathogenesis of airway remodeling and asthma. Trefoil factor 2 (TFF2) is a member of a family of peptides involved in protection and healing of the gastrointestinal epithelium but which are also secreted in the airway mucosa. METHODS: We investigated the role of TFF2 in airway remodeling by histological and morphometric analysis of lung tissue from TFF2-deficient mice subjected to two relevant animal models of asthma: an ovalbumin model of allergic airways disease and an Aspergillus fumigatus antigen sensitization model. RESULTS: In the ovalbumin model TFF2-deficient mice had increased goblet cell hyperplasia, but not epithelial thickening compared to wild-type (WT) counterparts. In the Aspergillus model TFF2-deficient mice also had increased goblet cell hyperplasia, and epithelial thickness was also increased in the Aspergillus-sensitized mice compared to WT controls. TFF2 deficiency was also associated with increased subepithelial collagen layer thickness. DISCUSSION: The current study demonstrates a role of TFF2 in airway remodeling in mouse models of airway disease. Further studies into the mechanisms of action of TFF2 and its role in asthma are warranted. PMID- 21793773 TI - Children's views of communication and speech-language pathology. AB - Children have the right to express their views and influence decisions in matters that affect them. Yet decisions regarding speech-language pathology are often made on their behalf, and research into the perspectives of children who receive speech-language pathology intervention is currently limited. This paper reports a qualitative study which explored experiences of communication and of speech language pathology from the perspectives of children with speech, language, and communication needs (SLCN). The aim was to explore their perspectives of communication, communication impairment, and assistance. Eleven school-children participated in the study, aged between 7-10 years. They were recruited through a speech-language pathology service in south west England, to include a range of ages and severity of difficulties. The study used open-ended interviews within which non-verbal activities such as drawing, taking photographs, and compiling a scrapbook were used to create a context for supported conversations. Findings were analysed according to the principles of grounded theory. Three ways of talking about communication emerged. These were in terms of impairment, learning, and behaviour. Findings offer insight into dialogue between children with SLCN and adults; the way communication is talked about has implications for children's view of themselves, their skills, and their participation. PMID- 21793774 TI - The use of definite and indefinite articles by children with specific language impairment. AB - Among the grammatical limitations seen in English-speaking children with specific language impairment (SLI) is a prolonged period of using articles (e.g., a, the) inconsistently. Most studies documenting this difficulty have focused on article omission and have not made the distinction between definite and indefinite article contexts. In this study, there were 36 participants: 12 5-year-olds with SLI, 12 typically-developing children matched for age, and 12 younger, typically developing children matched with participants in the SLI group according to mean length of utterance. All 36 children participated in a task requiring indefinite article use, and a task requiring use of the definite article, in which the referent of the noun had already been established in the discourse. The children with SLI showed less use of definite articles in particular, relative to both groups of typically-developing children. Substitutions as well as omissions were seen. The findings suggest that the article limitations of the children with SLI were attributable in part to an incomplete understanding of how definite articles are to be used. PMID- 21793775 TI - North-American Lidcombe Program file audit: replication and meta-analysis. AB - Thousands of North American clinicians have trained for the Lidcombe Program of Early Stuttering Intervention, yet there are no benchmark data for that continent. This retrospective file audit includes logistical regression of variables from files of 134 children younger than 6 years who completed Stage 1 of the Lidcombe Program. Benchmarking data for clinic visits to Stage 2 is available for these files. Meta-analysis supplements worldwide Lidcombe Program benchmark data. The median number of clinic visits to Stage 2 was 11. High pre treatment stuttering severity predicted more clinic visits than low severity. A trend toward statistical significance was found for the frequency of clinic visits. Frequent attendance of mean less than 11 days was associated with longer treatment times than infrequent attendance of mean 11 days or more. Results for North America were consistent with benchmark data from the UK and Australia. The mean attendance trend is clinically important and requires further investigation because of its potential clinical significance. PMID- 21793776 TI - Investigating parent delivery of the Lidcombe Program. AB - The Lidcombe Program is an early childhood stuttering treatment delivered by parents in the child's everyday environment, under the guidance of a speech language pathologist (SLP). Given the parents' central role in the treatment delivery, the way it is implemented away from the clinic and away from the SLP's input is very important. And yet, to date there has been very little investigation into this process. This study investigated to what extent parents deliver contingencies for stuttering and stutter-free speech, in structured and unstructured conversations, as directed in the treatment manual. Participants were three mothers and their children who were receiving the Lidcombe Program. They recorded two treatment sessions each week and completed a daily treatment diary. The recordings were analysed for the use of parent verbal contingencies (PVCs). This method detected differences in PVC delivery by the mothers both across and within cases over time. The results show that valuable information can be gained from analysing home treatment sessions in this way and with a few modifications this methodology would be useful in larger scale studies. The strengths and limitations of this methodology are discussed with future larger studies of this type recommended. PMID- 21793777 TI - "Well it has to be language-related": speech-language pathologists' goals for people with aphasia and their families. AB - Goal-setting is considered an essential part of rehabilitation practice and integral to person-centredness. However, people with aphasia are not always satisfied with goal-setting, and speech-language pathologists are concerned about the appropriateness of therapy. Furthermore, family members are often excluded from goal-setting, despite the impact aphasia has on them. The actual goals set by clinicians for clients with aphasia and their family members have not yet been investigated. This study aimed to examine the goals that clinicians set for their clients with aphasia and their family members. Data from in-depth interviews with 34 speech-language pathologists describing 84 goal-setting experiences with people with aphasia were coded into superordinate goals for both groups. Clinicians expressed a wide range of goals for people with aphasia and their family members, relating to communication, coping and participation factors, and education. In addition, evaluation was considered a goal for the clients. There were clients for whom no goals were set, particularly for family members, due to a lack of/limited contact. The goals described broadly addressed all aspects of the International Classification of Functioning, Disability and Health (ICF) and reflected the use of both functional and impairment-based therapeutic approaches; they also emphasize the importance of providing goal-setting options for the family members of these clients. PMID- 21793778 TI - Factors contributing to the brain drain in speech-language pathology: a New Zealand example. AB - The aim of this research was to determine what attracts students to speech language pathology (SLP), and the influence of intrinsic and extrinsic factors on two types of "brain drain" in SLP: emigration and career shift. Fifty undergraduate students and 13 recent graduates completed a questionnaire that tapped three main areas, level of student debt, intentions to emigrate, and career intentions. Ninety-seven per cent of respondents were female, with a median age of 25 years. Most SLP students and graduates had high levels of debt on graduation. Debt contributed to levels of worry and the ability to participate in education. However, debt alone did not influence career choice or long-term career planning. Over half of the respondents intended to leave New Zealand within 2 years of graduation, citing salary, travel, and training opportunities as factors. Incentives to remain in the profession included increased salary, more training opportunities, and student debt repayment. SLP students' career decisions were mainly influenced by interest in the profession. The conclusion was that three main factors need to be explored in an effort to increase the likelihood that SLPs remain in New Zealand: salary levels, increased training opportunities, and contributions to reduce student debt. PMID- 21793779 TI - Colon-targeted celecoxib-loaded Eudragit(r) S100-coated poly-epsilon-caprolactone microparticles: preparation, characterization and in vivo evaluation in rats. AB - CONTEXT: Celecoxib suffers from low and variable bioavailability following oral administration of solutions or capsules. Recent studies proved that chemoprevention of colorectal cancer is possible with celecoxib. OBJECTIVE: This work aimed to tailor colon-targeted celecoxib-loaded microparticles using time dependant and pH-dependant coats. Estimation of drug pharmacokinetics following oral administration to fasted rats was another goal. METHODS: A 23 factorial design was adopted to develop poly-epsilon-caprolactone (PCL) celecoxib-loaded microparticles (F1-F8). To minimize drug-percentages released before colon, another coat of Eudragit(r) S100 was applied. In vitro characterization of microparticles involved topography, determination of particle size and entrapment efficiency (EE %). Time for 50% drug release (t(50%)) and drug-percentages released after 2 hours (Q(2h)) and 4 hours (Q(4h)) were statistically compared. Estimation of drug pharmacokinetics following oral administration of double-coat microparticles (F10) was studied in rats. RESULTS: PCL-single-coat microparticles were spherical, discrete with a size range of 60.66 +/- 4.21-277.20 +/- 6.10 MUm. Direct correlations were observed between surfactant concentration and EE%, Q(2h) and Q(4h). The PCL M.wt. and drug: PCL ratio had positive influences on EE% and negative impacts on Q(2h) and Q(4h). When compared to the best achieved PCL single-coat microparticles (F2), the double-coat microparticles (F10) showed satisfactory drug protection; Q(2h) and Q(4h) were significantly (P < 0.01) decreased from 31.84 +/- 1.98% and 54.72 +/- 2.10% to 15.92 +/- 1.78% and 26.93 +/- 2.76%, respectively. When compared to celecoxib powder, F10 microparticles enhanced the bioavailability and extended the duration of drug-plasma concentration in rats. CONCLUSION: The developed double-coat microparticles could be considered as a promising celecoxib extended-release colon-targeting system. PMID- 21793780 TI - Does a parent-reported history of pneumonia increase the likelihood of respiratory symptoms needing therapy in asthmatic children and adolescents? AB - BACKGROUND: Asthmatic children and adolescents attending outpatient clinics often have a history of pneumonia. Whether respiratory symptoms, lung function, and airway inflammation differ in asthmatic patients with and without a history of pneumonia remains controversial. AIMS: To compare clinical, lung functional, and inflammatory variables in asthmatic outpatients with and without a history of pneumonia. Methods. In 190 asthmatic outpatients, aged 6-18 years, we assessed respiratory symptoms, lung function (flows, volumes, and pulmonary diffusion capacity, DLCO/VA), and atopic-airway inflammation as measured by the fractional concentration of exhaled nitric oxide (FE(NO)). A previous medical and radiological diagnosis of pneumonia was defined as "recurrent pneumonia" if subjects had at least three pneumonia episodes or two episodes within a year. RESULTS: Of the 190 outpatients studied, 38 (20%) had a history of pneumonia. These patients had more frequent upper-respiratory symptoms, nighttime awakenings in the past 4 weeks, daily use of inhaled corticosteroids, and lower FE(NO) than the 152 asthmatic children without previous pneumonia (FE(NO): 20.6 ppb, 95% CI: 15.2-28.0 vs. 31.1 ppb, 95% CI: 27.0-35.8; p < .05). Of the 38 patients with previous pneumonia, 14 had recurrent pneumonia. Despite comparable lung volumes and flows, they also had lower DLCO/VA than asthmatic children with no recurrent pneumonia and asthmatic children without previous pneumonia (DLCO/VA%: 91.2 +/- 11.3 vs. 108.5 +/- 14.7 vs. 97.9 +/- 18.6, p < .05). CONCLUSION: Respiratory assessment in asthmatic children and adolescents with a history of pneumonia, especially recurrent pneumonia, often discloses symptoms needing corticosteroid therapy, and despite normal lung volumes and flows, mild reductions in the variables reflecting gas diffusion and atopic-airway inflammation (DLCO/VA and FE(NO)). Whether these respiratory abnormalities persist in adulthood remains an open question. PMID- 21793781 TI - Sashimi NOTES--extraction of bulky specimens in no-scar operations. AB - A major obstacle in no-scar surgery is the extraction of large, bulky or rigid specimen. Thus, a method is needed that allows for extraction of large specimens without situs contamination in women and men. It should enable safe treatment of infectious or malignant disease while preserving pathologic workup. Five patients suffering from diverticulitis with expected bulky and rigid specimen were enrolled into this early series. Preparation was performed transumbilically in single-port technique. To prevent new scar formation, the incision was limited to the base of the umbilicus without extension onto the sound abdominal skin. A functionally and topologically extracorporeal compartment was created within the abdomen by introduction and insufflation of a tear-proof impermeable retrieval bag. The specimen was sliced in a controlled fashion inside the compartment along a pre-marked geometry. Controlled specimen dissection in a dedicated intraabdominal resection compartment was feasible. The dissected specimen could be retrieved through the 1.5 cm umbilical incision without spillage of material. The geometry of the extracted organ was reconstructed in detail allowing for uncompromised pathological workup. Extraction of bulky and rigid specimen is possible through natural orifices by the proposed controlled dissection method enabling the pathologist to reconstruct anatomical affiliation. PMID- 21793782 TI - Proficiency in English sentence stress production by Cantonese speakers who speak English as a second language (ESL). AB - The present study examined English sentence stress produced by native Cantonese speakers who were speaking English as a second language (ESL). Cantonese ESL speakers' proficiency in English stress production as perceived by English speaking listeners was also studied. Acoustical parameters associated with sentence stress including fundamental frequency (F0), vowel duration, and intensity were measured from the English sentences produced by 40 Cantonese ESL speakers. Data were compared with those obtained from 40 native speakers of American English. The speech samples were also judged by eight native listeners who were native speakers of American English for placement, degree, and naturalness of stress. Results showed that Cantonese ESL speakers were able to use F0, vowel duration, and intensity to differentiate sentence stress patterns. Yet, both female and male Cantonese ESL speakers exhibited consistently higher F0 in stressed words than English speakers. Overall, Cantonese ESL speakers were found to be proficient in using duration and intensity to signal sentence stress, in a way comparable with English speakers. In addition, F0 and intensity were found to correlate closely with perceptual judgement and the degree of stress with the naturalness of stress. PMID- 21793783 TI - A modified rabbit model of carotid atherosclerotic plaque suitable for the stroke study and MRI evaluation. AB - In order to induce a modified rabbit model of carotid atherosclerotic plaque suitable for the stroke study and to evaluate the lesion with magnetic resonance imaging (MRI). Eight rabbits of group A were fed with high-fat diet only. Atherosclerosis at the right common carotid artery was induced in rabbits of group B (n = 12) by high-fat diet and balloon catheter injury to the endothelium 4 weeks later. The rabbits were examined in vivo with a 1.5-T MRI. After 4 weeks on the high-fat diet, the serum lipid levels were markedly increased, which became significantly higher than the baseline levels. The lesions on both MRI and histology were remarkable. One week after balloon injury, the signal of injured right common carotid was higher on all the contrast-weighted images than the left side. The extent of abnormal signal was reduced 9 weeks after balloon injury. Hemorrhage was detected on all the contrast-weighted images. In conclusion, the rabbit model established by the authors is such a feasible one to the study of stroke caused by carotid atherosclerosis. PMID- 21793784 TI - Electromagnetic hypersensitivity: evidence for a novel neurological syndrome. AB - OBJECTIVE: We sought direct evidence that acute exposure to environmental strength electromagnetic fields (EMFs) could induce somatic reactions (EMF hypersensitivity). METHODS: The subject, a female physician self-diagnosed with EMF hypersensitivity, was exposed to an average (over the head) 60-Hz electric field of 300 V/m (comparable with typical environmental-strength EMFs) during controlled provocation and behavioral studies. RESULTS: In a double-blinded EMF provocation procedure specifically designed to minimize unintentional sensory cues, the subject developed temporal pain, headache, muscle twitching, and skipped heartbeats within 100 s after initiation of EMF exposure (p < .05). The symptoms were caused primarily by field transitions (off-on, on-off) rather than the presence of the field, as assessed by comparing the frequency and severity of the effects of pulsed and continuous fields in relation to sham exposure. The subject had no conscious perception of the field as judged by her inability to report its presence more often than in the sham control. DISCUSSION: The subject demonstrated statistically reliable somatic reactions in response to exposure to subliminal EMFs under conditions that reasonably excluded a causative role for psychological processes. CONCLUSION: EMF hypersensitivity can occur as a bona fide environmentally inducible neurological syndrome. PMID- 21793786 TI - Selection of the most potent specific on/off adaptor-hepatitis delta virus ribozymes for use in gene targeting. AB - The Hepatitis Delta Virus (HDV) ribozyme, which is well adapted to the environment of the human cell, is an excellent candidate for the future development of gene-inactivation systems. On top of this, a new generation of HDV ribozymes now exists that benefits from the addition of a specific on/off adaptor (specifically the SOFA-HDV ribozymes) which greatly increases both the ribozyme's specificity and its cleavage activity. Unlike RNAi and hammerhead ribozymes, the designing of SOFA-HDV ribozymes to cleave, in trans, given RNA species has never been the object of a systematic optimization study, even with their recent use for the gene knockdown of various targets. This report aims at both improving and clarifying the design process of SOFA-HDV ribozymes. Both the ribozyme and the targeted RNA substrate were analyzed in order to provide new criteria that are useful in the selection of the most potent SOFA-HDV ribozymes. The crucial features present in both the ribozyme's biosensor and blocker, as well as at the target site, were identified and characterized. Simple rules were derived and tested using hepatitis C virus NS5B RNA as a model target. Overall, this method should promote the use of the SOFA-HDV ribozymes in a plethora of applications in both functional genomics and gene therapy. PMID- 21793787 TI - Addition of the immunostimulatory oligonucleotide IMT504 to a seasonal flu vaccine increases hemagglutinin antibody titers in young adult and elder rats, and expands the anti-hemagglutinin antibody repertoire. AB - Flu vaccines are partially protective in infants and elder people. New adjuvants such as immunostimulatory oligonucleotides (ODNs) are strong candidates to solve this problem, because a combination with several antigens has demonstrated effectiveness. Here, we report that IMT504, the prototype of a major class of immunostimulatory ODNs, is a potent adjuvant of the influenza vaccine in young adult and elderly rats. Flu vaccines that use virosomes or whole viral particles as antigens were combined with IMT504 and injected in rats. Young adult and elderly animals vaccinated with IMT504-adjuvated preparations reached antibody titers 20-fold and 15-fold higher than controls, respectively. Antibody titers remained high throughout a 120 day-period. Animals injected with the IMT504 adjuvated vaccine showed expansion of the anti-hemagglutinin antibody repertoire and a significant increase in the antibody titer with hemagglutination inhibition capacity when confronted to viral strains included or not in the vaccine. This indicates that the addition of IMT504 in flu vaccines may contribute to the development of significant cross-protective immune response against shifted or drifted flu strains. PMID- 21793788 TI - RNA aptamer therapy for vaso-occlusion in sickle cell disease. AB - Patients with sickle cell disease (SCD) often suffer painful vaso-occlusive episodes caused in part by the adhesion of sickle erythrocytes (SS-RBC) to the vascular endothelium. To investigate inhibition of SS-RBC adhesion as a possible treatment for vaso-occlusion, 2 adhesion molecules, alpha(v)beta(3) and P selectin, were targeted by high-affinity RNA aptamers. An in vitro flow chamber assay was used to test the antiadhesion activity of alpha(v)beta(3) aptamer clone 17.16. Human SS-RBC were passed across a confluent monolayer of thrombin stimulated human umbilical vein endothelial cells (HUVEC) at a constant rate. alpha(v)beta(3) aptamer reduced SS-RBC adhesion to activated endothelial cells to the level seen with untreated HUVEC. An aptamer reactive with complement component 8 was used as a negative control and exerted no inhibition, confirming the specificity of alpha(v)beta(3) aptamer (P=0.04). At 2 dyn/cm(2) shear stress, 30 nM alpha(v)beta(3) aptamer showed maximal effect in decreasing SS-RBC adhesion to HUVEC. The antiadhesive activity of the P-selectin aptamer clone PF377 was also tested using HUVEC pretreated with IL-13 to upregulate expression of P selectin as seen in activated endothelial cells. At 1 dyn/cm(2) shear stress, 60 nM of P-selectin aptamer had antiadhesion activity similar to heparin, a known inhibitor of SS-RBC adhesion to P-selectin. A negative control did not prevent adhesion (P=0.05). These data show the potential utility of aptamers to block endothelial adhesion molecules to prevent or treat vaso-occlusion in SCD. PMID- 21793789 TI - Nucleotide bias observed with a short SELEX RNA aptamer library. AB - Systematic evolution of ligands by exponential enrichment (SELEX) is a powerful in vitro selection process used for over 2 decades to identify oligonucleotide sequences (aptamers) with desired properties (usually high affinity for a protein target) from randomized nucleic acid libraries. In the case of RNA aptamers, several highly complex RNA libraries have been described with RNA sequences ranging from 71 to 81 nucleotides (nt) in length. In this study, we used high throughput sequencing combined with bioinformatics analysis to thoroughly examine the nucleotide composition of the sequence pools derived from several selections that employed an RNA library (Sel2N20) with an abbreviated variable region. The Sel2N20 yields RNAs 51 nt in length, which unlike longer RNAs, are more amenable to large-scale chemical synthesis for therapeutic development. Our analysis revealed a consistent and early bias against inclusion of adenine, resulting in aptamers with lower predicted minimum free energies (DeltaG) (higher structural stability). This bias was also observed in control, "nontargeted" selections in which the partition step (against the target) was omitted, suggesting that the bias occurred in 1 or more of the amplification and propagation steps of the SELEX process. PMID- 21793790 TI - Plasma fatty acid composition in continuous ambulatory peritoneal dialysis patients: an increased omega-6/omega-3 ratio and deficiency of essential fatty acids. AB - Patients with end-stage renal disease, including those treated with peritoneal dialysis, have a high risk for death, particularly from cardiovascular causes. Plasma fatty acid (FA) composition is used as an indicator of disease risk, because its alteration has been related to metabolic disease and cardiovascular disease. For this purpose, we have measured plasma FA composition in continuous ambulatory peritoneal dialysis (CAPD) patients and compared them with those of healthy subjects. This study was performed on 51 (21 M, 30 F) CAPD patients at least 6 months under dialysis, aged 20-75 years (mean 47.81 +/- 11.8 years) and 45 (25 M, 20 F) healthy control subjects aged 20-60 years (mean 38.62 +/- 12.9 years). Plasma 10-cis-pentadecanoic acid, 10-cis-heptadecanoic acid, heneicosanoic acid, tricosanoic acid, nervonic acid, saturated fatty acid, and monounsaturated FA levels and delta 9 desaturase activity were significantly higher whereas linoleic acid, linolenic acid, 11,14-eicosedienoic acid, arachidonic acid, docosahexaenoic acid, and omega-3 FA levels were significantly lower in the CAPD group than those in the healthy group. Our results show that there are FA abnormalities and especially a depletion in essential FA levels and a high level of omega-6/omega-3 ratio in CAPD patients, the underlying mechanism of which is not known and needs to be investigated. Therefore, we believe that essential FA supplementation should be encouraged for CAPD patients. PMID- 21793791 TI - Discontinued drugs 2010: rheumatology, allergy and dermatology, pulmonary. AB - This is the annual perspective paper on the discontinued drugs in the field of pulmonary disease allergy, rheumatology, and dermatology. It is part of series of papers discussing drugs dropped from clinical development in the previous year and presented according to therapeutic indication. Specifically, this paper presents the four rheumatology and dermatology, four pulmonary and three allergy drugs discontinued in 2010. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I - III clinical trials. PMID- 21793792 TI - Constraints on task-based control of behaviour following frontal lobe damage: a single-case study. AB - What factors determine stimulus-driven responses in patients with utilization behaviour? We examined this question by assessing the influence of an irrelevant cue on visual search in a patient showing evidence of utilization behaviour (F.K.), following bilateral damage to the medial frontal and temporal lobes. Despite being able to repeat the instructions, F.K. often responded to an item in the search display that matched the cue rather than the target. This effect was reduced under certain conditions: (a) when the cue-search interval increased, (b) when F.K. paid less attention to the cue, and (c) when the target discrimination task was made more difficult. On the other hand, the effect arose even when the cue was always invalid. We suggest that information from the cue competed with the top-down set to determine search. F.K.'s lesion makes it difficult for him to impose top-down knowledge rapidly, leading to responses automatically being based on attended, but irrelevant, cues under short cue-display intervals. PMID- 21793793 TI - Working memory and multidimensional schizotypy: dissociable influences of the different dimensions. AB - Compromised working memory is considered a core deficit of schizophrenia and a potential endophenotype for the liability to develop schizophrenia. In keeping with this suggestion, working memory has also been found to be disrupted in people with high levels of schizotypy. However, it is unclear whether this disruption is linked to positive, negative, or disorganized symptoms/characteristics. This issue is the focus of the present investigation. The relationship between multidimensional schizotypy and working memory performance was investigated in 289 participants. Working memory was measured using an n-back task with three conditions; 0-back, 1-back, and 2-back. Covarying for the effect of shared variance between the schizotypy dimensions, we found reduced working memory performance in participants who displayed high levels of positive schizotypy and, to some extent, in participants with low levels of negative schizotypy. The results are discussed in terms of Baddeley's (1986) model of working memory and potential underlying neurological mechanisms. PMID- 21793794 TI - Different letter-processing strategies in diagnostic subgroups of developmental dyslexia also occur in a transparent orthography: reply to a commentary by Spinelli et al. AB - The article was motivated by a commentary of Spinelli et al. (2010) , who commented on our experimental study with dyslexic children (Lachmann & van Leeuwen, 2008). They questioned the unusually large reversed lexicality effect we reported for three of our dyslexic children for which word reading times were considerably longer than nonword reading times. We argued that, in principle, in a transparent orthography, such as German, children exist who have significant problems in word reading, but for whom nonword reading is normal. The extreme reversed lexically effect, however, may not be representative for the dyslexic population. Since we do not want to give the impression that our results were based on these three participants, we reran analyses on reaction times presented in Lachmann and van Leeuwen, this time excluding the data from the three individuals. Results were replicated. The constructive criticism has helped put both the diagnostics and our experimental results on even firmer ground. Both yield a consistent interpretation, in which two subgroups of dyslexics can be distinguished: one with generic activation problems; the other with a specific problem in phoneme-grapheme conversion. PMID- 21793795 TI - beta-Thalassemia trait association with autoimmune diseases: beta-globin locus proximity to the immunity genes or role of hemorphins? AB - Thalassemia major continues to be a significant health problem for Mediterranean, Afro-Arabic countries, India and South Easth Asia. It was generally assumed that the beta-thalassemia heterozygotes do not bear significant medical risks except a mild microcytic anemia. Nonetheless, increasing number of reports associate beta thalassemia trait with autoimmune conditions, nephritis, diabetes, arthritis, fibromyalgia and asthma. Available sparse data indicate reduced incidence of systemic lupus erythematosus (SLE) in beta-thalassemia heterozygotes; yet, if two conditions coexist, the SLE manifestations occur much severer. These associations make sense when considering that the hemoglobin beta-chain locus at 11p15.5 resides in close proximity to eight genes with profound roles in immune regulation: STIM1, CD151, TC21/RRAS2, SIGIRR/TOLL/IL1R8, pp52/LSP1 (lymphocyte specific protein), TRIM21, toll interacting protein (TOLLIP) and SLEN3. beta Thalassemia trait accompaniment to autoimmune disease may be the result of haplotypal associations between the close proximity genes. An alternative explanation to thalassemia heterozygosity: autoimmune disease association may be the changed concentrations of hemorphins. Hemorphins are endogenous opioid peptides derived via proteolytical cleavage of hemoglobin. They are shown to bind diverse opioid receptors and act anti-inflammatory. Their reduced expression in thalassemia heterozygosity may explain a proinflammatory stage and autoimmunity vulnerability. PMID- 21793798 TI - Trefoil factor family peptides are increased in the saliva of children with mucositis. AB - BACKGROUND: Mucositis is a painful ulcerative condition of the oral cavity and gastrointestinal tract, occurring in association with chemotherapy and radiotherapy regimes. Trefoil factor family peptides (TFF, trefoil peptides), present in saliva, contribute to epithelial restitution and repair and are therefore potentially important in the healing phase of mucositis. This study aimed to assess any changes in the levels of trefoil peptides in oncology patients with and without mucositis. METHODS: Saliva was collected from healthy children, pretreatment oncology patients, neutropenic patients on treatment with no oral disease and mucositic patients. TFF1, 2 and 3 were quantified using ELISA. RESULTS: In healthy children TFF2 and 3 were positively correlated with age (r = 0.454, p = 0.01 for TFF2; r = 0.410, p = 0.05 for TFF3 Spearman rank correlation). TFF3 was higher in mucositis compared to all other groups. A linear regression prediction model indicated that TFF3, but not TFF1 and TFF2, was significantly different in mucositic and healthy controls, suggesting an altered pattern of trefoil peptide secretion (p = 0.021). CONCLUSIONS: This study is the first to focus on trefoil peptides in paediatric saliva. It shows the correlation between TFF2, TFF3 and age in healthy children. Paediatric mucositis disease occurs in the presence of increased concentrations and an altered pattern of trefoil peptides. PMID- 21793797 TI - beta2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity. AB - Mercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl2-induced autoimmunity (mHgIA) requires MHC Class II, CD4+ T-cells, co-stimulatory molecules, and interferon-gamma (IFN-gamma), similar to spontaneous models of systemic lupus erythematosus (SLE). beta2-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal F(c) receptor (F(c)Rn). Deficiency of B2m in lupus-prone strains is consistently associated with reduced IgG levels, but with variable effects on other manifestations. Herein, we examined the role of B2m in mHgIA and show that in the absence of B2m, mercury-exposed mice failed to exhibit hypergammaglobulinemia, had reduced anti-nucleolar autoantibodies (ANoA), and had a lower incidence of immune complex deposits in splenic blood vessels, whereas IgG anti-chromatin autoantibodies and renal immune deposits were largely unaffected. Subclass analysis of the IgG anti-chromatin, however, revealed a significant reduction in the IgG1 subtype. Examination of IFNgamma, IL-4, and IL-2 in exposed skin, draining lymph nodes, and spleen following mercury exposure showed reduced IL-4 in the spleen and skin in B2m-deficient mice, consistent with the lower IgG1 anti chromatin levels, and reduced IFNgamma expression in the skin. These findings demonstrate how a single genetic alteration can partially but significantly modify the clinical manifestations of systemic autoimmunity induced by exposure to xenobiotics. PMID- 21793799 TI - Methylenetetrahydrofolate reductase C677T polymorphism and congenital heart disease: a meta-analysis. AB - BACKGROUND: As a key enzyme in folate metabolism, 5,10- methylenetetrahydrofolate reductase (MTHFR) regulates the homeostasis between DNA synthesis and methylation. Data on the association between the MTHFR C677T polymorphism and congenital heart disease (CHD) are conflicting. METHODS: To assess the relationship between the MTHFR 677TT genotype and the risk of CHD, we performed a metaanalysis, searching in Pubmed for studies on this topic published in the English language up to 1 December 2010. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs), assuming frequency of allele comparison, homozygote comparison, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Thirteen studies were included in the meta-analysis. RESULTS: The MTHFR T allele was associated with a borderline significantly increased risk of CHD in the frequency of allele comparison (T vs. C: OR = 1.160; 95% CI = 0.990- 1.359; p = 0.001 for heterogeneity). The MTHFR TT genotype was not associated with the risk of CHD in the homozygote comparison (TT vs. CC: OR = 1.272; 95% CI = 0.947-1.707; p = 0.028 for heterogeneity), the dominant genetic model (TT + CT vs. CC: OR = 1.127; 95% CI = 0.937-1.355; p = 0.034 for heterogeneity) and the recessive genetic model (TT vs. CTqCC: OR = 1.272; 95% CI = 0.975-1.659; p = 0.030 for heterogeneity). However, a stratification analysis showed that the association between the MTHFR C677T polymorphism and the risk of CHD was evident among Caucasians instead of Asians. CONCLUSIONS: Our meta-analysis suggests that genotypes for the MTHFR C677T polymorphism might be associated with the risk of CHD among Caucasians. PMID- 21793800 TI - Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice. AB - PAH (pulmonary arterial hypertension) is a debilitating and life-threatening disease, often affecting young people. We specifically expressed human MMP-1 (matrix metalloproteinase-1) in mouse macrophages and examined its effects in attenuating the decompensating features of MCT (monocrotaline)-induced PAH. Measurement of RV (right ventricular) pressure revealed a 2.5-fold increase after treatment with MCT, which was reduced to 1.5-fold in MMP-1 transgenic mice. There was conspicuous pulmonary inflammation with chronic infiltration of mononuclear cells after the administration of MCT, which was significantly diminished in transgenic mice. Furthermore, transgenic mice showed decreased collagen deposition compared with WT (wild-type). Staining for Mac-3 (macrophage-3) and alpha-SMA (alpha-smooth muscle actin) revealed extensive infiltration of macrophages and medial hypertrophy of large pulmonary vessels with complete occlusion of small arteries respectively. These changes were markedly reduced in MMP-1 transgenic mice compared with WT. Western blotting for molecules involved in cell multiplication and proliferation depicted a significant decrease in the lung tissue of transgenic mice after the treatment with MCT. In conclusion, the present study demonstrated that transgenic expression of human MMP-1 decreased proliferation of smooth muscle cells and prevented excessive deposition of collagen in the pulmonary arterial tree. Our results indicate that up-regulation of MMP-1 could attenuate the debilitation of human PAH and provide an option for therapeutic intervention. PMID- 21793801 TI - Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells. AB - S49 mouse lymphoma cells undergo apoptosis in response to the ALP (alkyl lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3 phosphocholine), FasL (Fas ligand) and DNA damage. S49 cells made resistant to ALP (S49(AR)) are defective in sphingomyelin synthesis and ALP uptake, and also have acquired resistance to FasL and DNA damage. However, these cells can be re sensitized following prolonged culturing in the absence of ALP. The resistant cells show sustained ERK (extracellular-signal-regulated kinase)/Akt activity, consistent with enhanced survival signalling. In search of a common mediator of the observed cross-resistance, we found that S49(AR) cells lacked the PtdIns(3,4,5)P(3) phosphatase SHIP-1 [SH2 (Src homology 2)-domain-containing inositol phosphatase 1], a known regulator of the Akt survival pathway. Re sensitization of the S49(AR) cells restored SHIP-1 expression as well as phosphoinositide and sphingomyelin levels. Knockdown of SHIP-1 mimicked the S49(AR) phenotype in terms of apoptosis cross-resistance, sphingomyelin deficiency and altered phosphoinositide levels. Collectively, the results of the present study suggest that SHIP-1 collaborates with sphingomyelin synthase to regulate lymphoma cell death irrespective of the nature of the apoptotic stimulus. PMID- 21793802 TI - Isoprenoid is a perfect fit for fat factor. AB - In humans, there are 48 members of the superfamily of nuclear receptors. These ligand-activated transcription factors help to integrate our growth, reproduction and metabolism via environmental, nutritional and intrinsic cues. It is therefore not surprising that nuclear receptors are commonly used as drug targets. However, perhaps in the rush to discover new drugs that target these receptors, we sometimes lose sight of their 'real' physiological ligands. In this issue of the Biochemical Journal Goto et al. present evidence that the isoprenoid FPP (farnesyl pyrophosphate) may be a bona fide ligand for the master controller of adipocyte differentiation PPARgamma (peroxisome-proliferator-activated receptor gamma). This work has wide-ranging implications not only for obesity and diabetes, but also for osteoporosis and the control of circadian rhythms in which PPARgamma also plays an important role. PMID- 21793803 TI - In vivo biochemistry: quantifying ion and metabolite levels in individual cells or cultures of yeast. AB - Over the past decade, we have learned that cellular processes, including signalling and metabolism, are highly compartmentalized, and that relevant changes in metabolic state can occur at sub-second timescales. Moreover, we have learned that individual cells in populations, or as part of a tissue, exist in different states. If we want to understand metabolic processes and signalling better, it will be necessary to measure biochemical and biophysical responses of individual cells with high temporal and spatial resolution. Fluorescence imaging has revolutionized all aspects of biology since it has the potential to provide information on the cellular and subcellular distribution of ions and metabolites with sub-second time resolution. In the present review we summarize recent progress in quantifying ions and metabolites in populations of yeast cells as well as in individual yeast cells with the help of quantitative fluorescent indicators, namely FRET metabolite sensors. We discuss the opportunities and potential pitfalls and the controls that help preclude misinterpretation. PMID- 21793805 TI - The light intensity under which cells are grown controls the type of peripheral light-harvesting complexes that are assembled in a purple photosynthetic bacterium. AB - The differing composition of LH2 (peripheral light-harvesting) complexes present in Rhodopseudomonas palustris 2.1.6 have been investigated when cells are grown under progressively decreasing light intensity. Detailed analysis of their absorption spectra reveals that there must be more than two types of LH2 complexes present. Purified HL (high-light) and LL (low-light) LH2 complexes have mixed apoprotein compositions. The HL complexes contain PucAB(a) and PucAB(b) apoproteins. The LL complexes contain PucAB(a), PucAB(d) and PucB(b)-only apoproteins. This mixed apoprotein composition can explain their resonance Raman spectra. Crystallographic studies and molecular sieve chromatography suggest that both the HL and the LL complexes are nonameric. Furthermore, the electron-density maps do not support the existence of an additional Bchl (bacteriochlorophyll) molecule; rather the density is attributed to the N-termini of the alpha polypeptide. PMID- 21793806 TI - Incidence of multiple sclerosis in Chile. A hospital registry study. AB - OBJECTIVE: To study the incidence of MS in Chile by examining the hospitalizations across all geographical regions of the country and to examine whether there is a correlation between these rates and the latitude or ultraviolet radiation. METHODS: This is a descriptive study examining the national registry of hospitalizations because of MS (code G35 in ICD-10) from January 1, 2001, to December 31, 2006. Incidence rates were calculated by gender and geographical region and standardized to the world population estimated for 2010. RESULTS: A total of 6857 hospitalizations were analyzed. There were 935 individuals; 63.9% were women. The mean incidence rate for 2002-2006 period was 0,90 (95% CI: 0.75-1.05). The annualized incidence rates for regions from North to South were as follows: I Tarapaca 0.54 (95% CI: 0.0-1.21), II Antofagasta 0,93 (0.10-1.75), III Atacama 1.07 (0.0-2.31), IV Coquimbo 0.63 (0.01-1.24), V Valparaiso 0.83 (0.38-1.27), VI O'Higgins 0.72 (0.14-1.30), VII Maule 0.52 (0.06 0.98), VIII BIO BIO 0.81 (0.41-1.21), IX Araucania 0.43 (0.0-0.86), X Los Lagos 0.91 (0.35-1.46), XI Aysen 0.99 (0.0-2.98), XII Magallanes 3.54 (0.57-6.51), and XIII Metropolitana 1.10 (0.84-1.36). There were no significant correlations between hospitalization rates and latitude, except for region XII. UV radiation levels showed significant differences only for region XII. CONCLUSION: There is a moderate risk of MS in Chile. The southernmost region showed significantly higher incidence rates than those in the rest of the country (a cluster zone). We did not find any correlation between incidence rates and latitude or UV radiation. PMID- 21793804 TI - Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor. AB - LIF (leukaemia inhibitory factor) is a key cytokine for maintaining self-renewal and pluripotency of mESCs (mouse embryonic stem cells). Upon binding to the LIF receptor, LIF activates three major intracellular signalling pathways: the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3), PI3K (phosphoinositide 3-kinase)/AKT and SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase 2]/MAPK (mitogen-activated protein kinase) pathways. These pathways converge to orchestrate the gene expression pattern specific to mESCs. Among the many signalling events downstream of the LIF receptor, activation and DNA binding of the transcription factor STAT3 plays a central role in transducing LIF's functions. The fundamental role of LIF for pluripotency was highlighted further by the discovery that LIF accelerates the conversion of epiblast-derived stem cells into a more fully pluripotent state. In the present review, we provide an overview of the three major LIF signalling pathways, the molecules that interact with STAT3 and the current interpretations of the roles of LIF in pluripotency. PMID- 21793807 TI - Cognitive deficits in multiple sclerosis: correlations with T2 changes in normal appearing brain tissue. AB - OBJECTIVES: Although disease load in multiple sclerosis (MS) often is based on T2 lesion volumes, the changes in T2 of normal appearing brain tissue (NABT) are rarely considered. By means of magnetic resonance, (MR) we retrospectively investigated whether T2 changes in NABT explain part of the cognitive impairment seen in MS and constitute a supplement to traditional measurement of T2 lesion volume. MATERIALS AND METHODS: Fifty patients with clinically definite MS were included (38 women, 12 men). Patients were MR scanned, neuropsychologically tested, and evaluated clinically with the Kurtzke Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Impairment Scale (MSIS). Voxel-wise T2 estimates and total T2 lesion volume were tested for correlations with eight cognitive domains, a general cognitive dysfunction factor (CDF), and the two clinical scales. RESULTS: We found distinct clusters of voxels with T2 estimates correlating with CDF, mental processing speed, complex motor speed, verbal fluency, and MSIS. A significant negative correlation was found between total lesion volume and CDF (r = -0.34, P = 0.02), verbal intelligence (r = -0.40, P = 0.005), mental processing speed (r = -0.34, P = 0.03), visual problem solving (r = -0.40, P = 0.01), and complex motor speed (r = -0.39, P = 0.01). No significant correlation was detected between total lesion load and the clinical measures EDSS and MSIS. CONCLUSION: Our results suggest that even in the NABT MR detects changes likely to be associated with an underlying pathology and possibly contributes to the cognitive impairment in MS. PMID- 21793808 TI - Risk factors for aneurysmal subarachnoid hemorrhage - BMI and serum lipids: 11 year follow-up of the HUNT and the Tromso Study in Norway. AB - OBJECTIVES: Life-style factors have been associated with the risk for aneurysmal subarachnoid hemorrhage (aSAH), but it is not clear whether body mass index (BMI) and serum lipids are associated with risk. We prospectively assessed these associations in two large population studies. METHODS: A total of 65,526 participants in the Nord-Trondelag Health Study (1995-1997) and 26,882 participants in the Tromso Study (1994-1995) were included. Studies included measurements of body weight and height, serum lipids, and self-administered questionnaires. Participants who experienced aSAH were identified, and hazard ratios (HRs) were estimated using Cox regression analysis. RESULTS: During 11 years of follow-up, aSAH was diagnosed in 122 participants. Overweight (BMI 25 29.9) was negatively associated with the risk of aSAH (HR 0.7, 95% CI 0.4-1.0). There was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH, but in participants younger than 50 years, HDL cholesterol was inversely associated with the risk (HR per standard deviation increase 0.6, 95% CI 0.4-0.9). CONCLUSIONS: Overweight may be associated with reduced risk of aSAH, but there was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH in this prospective study. PMID- 21793809 TI - 'Dealing with ambiguity'- the role of obstetricians in gestational diabetes mellitus. AB - OBJECTIVE: Gestational diabetes mellitus is a pregnancy-related complication and therefore obstetricians counsel and manage the maternal health care for these women. This study describes obstetricians' experiences of management of pregnant women with gestational diabetes mellitus. DESIGN: Interview study. SETTING: Hospital-based specialist maternal health care clinics in Sweden. POPULATION: A consecutive purposive national sample of 17 obstetricians providing maternal health care to pregnant women diagnosed with gestational diabetes mellitus. METHODS: Interviews were recorded and transcribed. The data were analyzed using qualitative content analysis. RESULT: The overall theme describing the experiences of the obstetricians was labeled 'Dealing with ambiguity'. This ambiguity permeated all aspects of working as an obstetrician within the maternal health care; the role of the obstetrician, the context of organization, the multifaceted maternal and fetal interests to balance, and lack of consensus, recommendations and evidence-based knowledge. CONCLUSIONS: The study revealed the ambiguous situation experienced and managed by obstetricians providing maternal health care to pregnant women diagnosed with gestational diabetes mellitus. This indicates a need for national guidelines and standardized maternal health care services regarding gestational diabetes mellitus to fulfill the intentions of the health care system. Such recommendations may be beneficial and supportive for the health care professionals as well as for the mother-to-be and her fetus. PMID- 21793810 TI - Impact of medico-legal findings on charge filing in cases of rape in adult women. AB - OBJECTIVE: To assess the impact of the medical documentation and biological trace evidence in rape cases on the legal process. DESIGN: Retrospective descriptive study. SETTING AND SAMPLE: Police-reported cases of rape of women >=16 years old in the Norwegian county of Sor-Trondelag from January 1997 to June 2003. METHODS: Police data were merged with data from the Sexual Assault Center at St Olav's Hospital. Charged and non-charged cases were compared. MAIN OUTCOME MEASURES: Medico-legal findings and legal outcome. RESULTS: A total of 185 police-reported cases were identified. Of the 101 cases examined at Sexual Assault Center, charges were filed in 18 cases. Extragenital injuries were documented in 49 women; five were life threatening. Anogenital injuries were documented in 14 women; eight had multiple anogenital injuries. Documentation of injuries was not associated with charge filing. In only 33% of the cases were swabs collected from women's genitals used as trace evidence by the police. When used, this increased the likelihood for charge filing. A DNA profile matching the suspect was identified in four of the 18 charged cases and in only one among the 54 non charged cases. CONCLUSIONS: Half of the women had one or more documented injury. Only one-third of the trace evidence kits collected from the women's anogenital area were analyzed. The analysis of swabs was associated with charge filing, regardless of test results. Increased use of such medical evidence, especially in cases of stranger rape, may ensure women's rights and increase available information to the legal system. PMID- 21793811 TI - Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage-dependent interference. AB - OBJECTIVE: Endometriosis is a frequent indication for in vitro fertilization and embryo transfer (IVF-ET). Its influence on IVF-ET cycles remains controversial. We evaluated the impact of the severity of endometriosis on IVF-ET cycles in young women. DESIGN: Retrospective cohort study. SETTING: Academic tertiary referral centre. SAMPLE AND METHODS: In a retrospective cohort analysis, 164 IVF ET cycles in 148 women with endometriosis-associated infertility were analyzed. Eighty cycles performed during the same period on 72 consecutive women with tubal infertility were considered as controls. All patients were younger than 35 years old. MAIN OUTCOME MEASURES: Response to controlled ovarian hyperstimulation (COH), number of oocytes retrieved, fertilization, implantation and pregnancy rate (PR). RESULTS: Clinical PR was lower in the group with endometriosis (all stages) in comparison with the tubal factor group. Higher total gonadotropin requirements, lower response to COH and lower oocyte yield were also found in the endometriosis group. Stage-stratified analysis showed a lower fertilization rate in stage I-II (52.6% stage I-II, 70.5% stage III-IV and 71.9% tubal factor). In stage III-IV endometriosis there was a higher cycle cancellation rate, a reduced response to COH and a lower PR compared with both the stage I-II and the tubal infertility groups (PR 9.7, 25 and 26.1%, respectively). CONCLUSIONS: Stage III IV was strongly associated with poor IVF outcome. A decreased fertilization rate in stage I-II might be a cause of subfertility in these women, owing to a hostile environment caused by the disease. PMID- 21793812 TI - Long-term follow up of posterior vestibulectomy for treating vulvar vestibulitis. AB - OBJECTIVE: To evaluate the safety and the effectiveness of posterior vestibulectomy in the treatment of vulvar vestibulitis syndrome. DESIGN: A retrospective cohort study. SETTING: University Hospital, tertiary referral center. POPULATION: Seventy women treated by posterior vestibulectomy for severe vulvar vestibulitis syndrome during 1995-2007 at the Department of Obstetrics and Gynecology, University Hospital, Helsinki. METHODS: All operated women were invited to a long-term follow-up study. Patient characteristics, baseline visual analog scale (VAS) for dyspareunia and data from the postoperative period were collected. Of the 70 women, 57 attended the follow-up visit including face-to face interview, gynecological examination with swab-touch test for vestibular tenderness, current VAS score for dyspareunia and McCoy questionnaire for sexual problems. MAIN OUTCOME MEASURES: Short-term and long-term complication rates, dyspareunia by VAS score, vestibular tenderness, sexual problem index and overall patient satisfaction. RESULTS: Ninety-one per cent were satisfied with the outcome. The VAS for dyspareunia decreased from a median of 9 to 3 (66.7% decrease; p<0.001). Posterior vestibular tenderness was absent in 34 patients (64.2%). Six (8.6%) patients developed postoperative bleeding and 11 (15.7%) mild wound infection. Bartholin's cysts occurred in four (5.7%) patients. CONCLUSIONS: Posterior vestibulectomy is effective and safe in the treatment of severe vulvar vestibulitis syndrome and provides long-term patient satisfaction. PMID- 21793813 TI - Maternal mortality in Ghana: a hospital-based review. AB - OBJECTIVE: This study examines the leading causes of maternal mortality in Ghana, classifies the main causes of maternal deaths and suggests how maternal care can be improved. DESIGN: Retrospective review. SETTING: Komfo Anokye Teaching Hospital, Ghana. SAMPLE: Three hundred and twenty-two maternal deaths with 30 269 live births in the period 1 January 2008 to 30 June 2010. METHODS: Data on maternal mortality and morbidity were retrieved from the Biostatistics Unit of the hospital. MAIN OUTCOME MEASURES: Maternal mortality ratio (MMR), case fatality rate, leading causes of maternal deaths, duration of admission and staff/patient ratio. RESULTS: The MMR was calculated to be 1 004 per 100 000 live births (95% confidence interval 895.0-1113.2). Of these, 71.1% were direct deaths, 22.4% were indirect deaths and 6.5% were unclassified. Hypertensive states of pregnancy were the leading cause of mortality (26.4%) and, together with hemorrhage, genital tract sepsis and early pregnancy deaths, accounted for 62.2% of all-cause maternal deaths and 87.3% of direct deaths. Infection and sickle cell disease accounted for 13.7% of all-cause maternal deaths and 61.1% of indirect deaths. CONCLUSIONS: Hypertensive states of pregnancy were the current leading cause of maternal mortality. Adopting a multi-pronged approach through reducing delays in access to emergency obstetric care, promoting contraceptive use, encouraging early, regular antenatal attendance and shared antenatal care with the medical team is essential to tackle the situation. PMID- 21793814 TI - Relapse after systemic treatment in paediatric morphoea. PMID- 21793816 TI - Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduction of neonatal screening. AB - This study analyzed the mortality and causes of death in sickle cell disease patients in the Netherlands, to provide a baseline for monitoring the effect of the recently introduced neonatal screening programme and to indicate areas of improvement in the care for these patients. All children (<18 years) diagnosed with sickle cell disease in a tertiary hospital from 1985 to 2007 were included. Vital status was determined up to March 2008. A total of 298 children were included: 189 (63%) patients had HbSS, 17 (6%) HbSbeta(0) thalassaemia, 72 (24%) HbSC and 20 (7%) HbSbeta(+) thalassaemia. Twelve patients (4%) died during a total follow-up of 3896 patient years. All known deaths were sickle cell disease related. Meningitis/sepsis (n=4; 33%), stroke (n=3; 25%) and death during a visit to the country of origin (n=3; 25%) were the most common causes of death. The overall mortality rate was 0.27 deaths/100 patient years [95% confidence interval (CI): 0.15-0.43]. The estimated survival at the age of 18 years was 97.3% (95% CI: 95-99%). This report confirms that the burden of mortality in sickle cell disease is increasingly shifting to adults. It is recommended that compliance to antibiotic prophylaxis, thorough counselling and support for patients travelling abroad and specialized peri-operative care should receive continuous attention. PMID- 21793815 TI - Membrane compartmentalization in Southeast Asian ovalocytosis red blood cells. AB - Red blood cells (RBCs) from individuals with Southeast Asian ovalocytosis (SAO) contain a mutant band 3 protein that causes the formation of unique linear oligomers in the RBC membrane. We used single-particle tracking to measure the lateral diffusion of individual glycophorin C (GPC), band 3, and CD58 proteins in membranes of intact SAO RBCs and normal RBCs (nRBCs). GPC, an integral protein that binds with high affinity to the RBC membrane skeleton, showed oscillatory motion within confinement areas that were smaller in SAO RBCs than in nRBCs. The additional confinement in SAO RBCs could be due to membrane stiffening associated with the SAO phenotype. Band 3 in both SAO RBCs and nRBCs also showed confined motion over short times (ms) and distances (nm), and the area of confinement was smaller in SAO RBCs than in nRBCs. These data presumably reflect the constraints imposed by band 3 oligomerization. Similarly, the glycosylphosphatidylinositol linked protein CD58 showed loosely confined diffusion in nRBCs and a substantially higher degree of confinement in SAO RBCs. Restricted protein mobility could contribute to the altered adherence of parasite-infected RBCs to vascular endothelium that is thought to protect individuals with SAO from severe manifestations of malaria. PMID- 21793817 TI - Benefits of practicing 4 = 2 + 2: nontraditional problem formats facilitate children's understanding of mathematical equivalence. AB - This study examined whether practice with arithmetic problems presented in a nontraditional problem format improves understanding of mathematical equivalence. Children (M age = 8;0; N = 90) were randomly assigned to practice addition in one of three conditions: (a) traditional, in which problems were presented in the traditional "operations on left side" format (e.g., 9 + 8 = 17); (b) nontraditional, in which problems were presented in a nontraditional format (e.g., 17 = 9 + 8); or (c) no extra practice. Children developed a better understanding of mathematical equivalence after receiving nontraditional practice than after receiving traditional practice or no extra practice. Results suggest that minor differences in early input can yield substantial differences in children's understanding of fundamental concepts. PMID- 21793818 TI - A longitudinal examination of African American adolescents' attributions about achievement outcomes. AB - Developmental, gender, and academic domain differences in causal attributions and the influence of attributions on classroom engagement were explored longitudinally in 115 African American adolescents. In Grades 8 and 11, adolescents reported attributions for success and failure in math, English and writing, and science. In Grade 11, English and mathematics teachers rated students' classroom engagement. Boys were more likely than girls to attribute math successes to high ability and to attribute English failures to low ability. Both genders' ability attributions for math became more negative from eighth to eleventh grades. Grade 8 attributions of math failure to lack of ability were negatively related to Grade 11 math classroom engagement. Results illustrate the gendered nature of motivational beliefs among Black youth. PMID- 21793819 TI - Children's judgments of emotion from conflicting cues in speech: why 6-year-olds are so inflexible. AB - Six-year-old children can judge a speaker's feelings either from content or paralanguage but have difficulty switching the basis of their judgments when these cues conflict. This inflexibility may relate to a lexical bias in 6-year olds' judgments. Two experiments tested this claim. In Experiment 1, 6-year-olds (n = 40) were as inflexible when switching from paralanguage to content as when switching from content to paralanguage. In Experiment 2, 6-year-olds (n = 32) and adults (n = 32) had more difficulty when switching between conflicting emotion cues than conflicting nonemotional cues. Thus, 6-year-olds' inflexibility appears to be tied to the presence of conflicting emotion cues in speech rather than a bias to judge a speaker's feelings from content. PMID- 21793820 TI - Reciprocal associations between family and peer conflict in adolescents' daily lives. AB - Using a daily diary method, this study assessed daily episodes of family and peer conflict among 578 adolescents in the 9th grade to examine potential bidirectional associations between the family and peer domains. Adolescents completed a daily diary checklist at the end of each day over a 14-day period to report events of conflict and their emotional states for a given day. Overall, the within-person models provided evidence for the bidirectional nature of family peer linkages across gender and ethnicity. Adolescents experienced more peer conflict on days in which they argued with parents or other family members, and vice versa. Effect of family conflict further spilled over into peer relationships the next day and 2 days later, whereas peer conflict predicted only the following day family conflict. Adolescents' emotional distress partially explained these short-term spillovers between family and peer conflict. PMID- 21793821 TI - Liver stiffness and 30-day mortality in a cohort of patients admitted to hospital. AB - BACKGROUND: Transient elastography (TE) is a new noninvasive method to assess the degree of liver fibrosis by measuring liver stiffness. The objective of this study was to determine whether increased liver stiffness in patients admitted to medical wards was associated with increased 30-day mortality. MATERIALS AND METHODS: A prospective cohort study at the medical admissions ward at Odense University Hospital, Denmark, covering a population of 300 000 inhabitants. Consecutive patients >= 18 years of age were examined by TE (Fibroscan) at admission. Outcome measure was 30-day mortality. RESULTS: Among 568 patients admitted during 24 days, 289 (50.8%) were included in the study, 212 (73.4%) with valid TE measurement. Increased liver stiffness (TE value > 8 kPa) was found in 22.6% (48/212). This was independently associated with cirrhosis of the liver (P < 0.001) and congestive heart failure (CHF) (P < 0.001). The estimated prevalence of cirrhosis was 7% (95% CI 4-11%). The 30-day mortality among patients with TE value > 8 kPa was 20.8% (10/48, 95%CI 10.5-35.0%) compared to patients with TE value <= 8 kPa 3.7% (6/164, 95%CI 1.3-7.8%) (P < 0.001), and TE value > 8 kPa was an independent predictor of death. CONCLUSIONS: Elevated TE value at admission is associated with increased mortality, cirrhosis of the liver and CHF. This information may potentially be used to improve the outcome of high-risk patients admitted to hospital. PMID- 21793822 TI - Visceral fat positively correlates with cholesterol synthesis in dyslipidaemic patients. AB - BACKGROUND: Quantification of plasma noncholesterol sterols allows the study of cholesterol absorption and synthesis. A pattern of low cholesterol absorption and high synthesis has been demonstrated in patients with obesity and insulin resistance. To understand the relationship between cholesterol absorption/synthesis and visceral obesity, we investigated surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) in dyslipidaemic patients with different representation of abdominal fat, estimated by ultrasonographic measurement of visceral fat area (VFA). METHODS: In 126 patients with primary hyperlipaemias, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled with mass spectrometry. Visceral and subcutaneous fats were evaluated by ultrasonography. The study population was divided into two groups on the basis of VFA median values, below/equal and above 154 cm(2) . RESULTS Patients with higher VFA had significantly higher lathosterol levels (median 109 vs. 76 * 10(2) MUmol/mmol cholesterol P < 0.004), body mass index, waist circumference, blood pressure, triglycerides, insulin, homoeostatic model assessment (HOMA)-IR and lower high density lipoprotein (HDL)-C. VFA was positively correlated with lathosterol (rho = 0.35, P < 0.001) and negatively with HDL-C (rho = -0.43, P < 0.001), campesterol (rho = -0.23, P = 0.01) and sitosterol (rho = -0.35, P < 0.001). VFA was an independent predictor of lathosterol values (beta = 0.389, P < 0.0001, P of the model < 0.0001);age, systolic blood pressure, BMI, waist circumference, triglycerides, HDL-C and HOMA failed to enter the final equation. CONCLUSIONS: In hyperlipidaemic patients, the amount of visceral fat correlates with cholesterol synthesis; the use of ultrasonographic detection of abdominal adiposity allows a better characterization of cholesterol pathway, potentially useful for a tailored therapeutic approach. PMID- 21793823 TI - In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. AB - BACKGROUND: Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies. MATERIALS AND METHODS: Narrative review. RESULTS: Various studies showed generalised hyperalgesia in CFS for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia in CFS is augmented, rather than decreased, following various types of stressors like exercise and noxious heat pain. Endogenous inhibition is not activated in response to exercise and activation of diffuse noxious inhibitory controls following noxious heat application to the skin is delayed. CONCLUSIONS: The observation of central sensitisation in CFS is in line with our current understanding of CFS. The presence of central sensitisation in CFS corroborates with the presence of several psychological influences on the illness, the presence of infectious agents and immune dysfunctions and the dysfunctional hypothalamus-pituitary adrenal axis as seen in these severely debilitated patients. PMID- 21793824 TI - Editorial: ADHD as a reinforcement disorder - moving from general effects to identifying (six) specific models to test. PMID- 21793825 TI - Developmental aspects of error and high-conflict-related brain activity in pediatric obsessive-compulsive disorder: a fMRI study with a Flanker task before and after CBT. AB - BACKGROUND: Heightened error and conflict monitoring are considered central mechanisms in obsessive-compulsive disorder (OCD) and are associated with anterior cingulate cortex (ACC) function. Pediatric obsessive-compulsive patients provide an opportunity to investigate the development of this area and its associations with psychopathology. METHODS: Repeated measures were carried out using functional magnetic resonance imaging (fMRI) during the performance of an interference task, the arrow version of the Flanker paradigm, before and after cognitive-behavioral treatment of 25 medication-free pediatric obsessive compulsive patients compared with age- and gender-matched healthy controls. RESULTS: During error trials compared to correct trials, pediatric OCD patients and controls showed an interaction effect of Group * Time * Age in the ACC and insula. This effect was mainly driven by an increased activation in older OCD subjects, which was also present after treatment. During high-conflict trials compared with low-conflict trials, a Group * Time * Age interaction effect was found in bilateral insula. This effect was driven by an increase of BOLD (blood oxygen level dependent) signal in older OCD patients before but not after treatment. In addition, a Group * Time interaction effect in dorsomedial prefrontal cortex, premotor region and ACC was found. This effect was driven by an increase of BOLD signal in OCD subjects relative to controls over time. CONCLUSIONS: Compared to healthy controls, children and adolescents with OCD show increased activation of the ACC during error responses and in bilateral insular cortex during high-conflict tasks, which is age dependent and which is only partially affected by cognitive-behavioral therapy (CBT). Therefore, we suggest that ACC functioning is a vulnerability marker in pediatric OCD, whereas insular dysfunction may be state dependent. PMID- 21793826 TI - Prevotella nigrescens and Porphyromonas gingivalis are associated with signs of carotid atherosclerosis in subjects with and without periodontitis. AB - BACKGROUND AND OBJECTIVE: Oral microorganisms may be involved in the development of cardiovascular diseases, and Porphyromonas gingivalis is one of the periodontal microorganisms that has been found in carotid atheroma. The aim of this work was to study subgingival microorganisms and early carotid lesions in subjects with and without periodontitis. MATERIAL AND METHODS: Eighty-eight subjects with periodontitis and 40 subjects without periodontitis underwent dental examinations in 2003. The presence of the periodontal microorganisms Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens and Tannerella forsythia was analyzed from subgingival plaque using PCR amplification. The common carotid artery was scanned using ultrasound and the calculated intima-media area (cIMA) was measured. The association between periodontitis, the cIMA value and the presence of periodontal microorganisms, together with several confounders, was studied in a multiple logistic regression model. RESULTS: Smoking [odds ratio (OR) = 5.64; p = 0.001), level of education (OR = 5.02; p < 0.05) and the presence of P. gingivalis (OR = 6.50; p < 0.05) were associated with periodontitis. Explanatory factors for the increased cIMA were periodontitis (OR = 4.22; p < 0.05), hypertension (OR = 4.81; p < 0.05), high body mass index (OR = 5.78; p < 0.01), male gender (OR = 3.30; p < 0.05) and poor socioeconomic status (OR = 4.34; p < 0.05). P. nigrescens (OR 4.08; p < 0.05) and P. gingivalis (OR 7.63; p < 0.01) also appeared as explanatory variables associated with increased cIMA values. CONCLUSION: This cross-sectional study showed that P. nigrescens and P. gingivalis were significantly associated with increased cIMA values. PMID- 21793827 TI - Expression of MMP-2, 9 and 13 in newly formed bone after sinus augmentation using inorganic bovine bone in human. AB - BACKGROUND AND OBJECTIVE: The aim of the present study was to analyse the expression of MMP-2, MMP-9 and MMP-13 in newly formed bone following maxillary sinus augmentation using inorganic bovine bone substitute, because these MMPs play a major role in bone remodeling and bone resorption. MATERIAL AND METHODS: Deproteinized bovine bone (Bio-Oss((r))) was used to fill cavities after elevating the sinus mucosa. Twenty patients with edentulous posterior maxilla were treated with 20 sinus-augmentation procedures using a two-stage technique. Forty-nine Straumann((r)) endosseous implants were used to complete the implant prosthetic rehabilitation. One cylinder-shaped bone biopsy from each patient was taken from the augmented maxillary region using trephine burs at the second stage of surgery, 8 months after grafting. A biopsy was also taken as a control from the upper molar region from six different patients who did not undergo the sinus procedure. All biopsies were subjected to biochemical analysis and staining for TRAP. RESULTS: No implant losses or failures occurred. The large number of TRAP positive multinucleated osteoclasts in resorption lacunae indicated that the resorption was very active in all grafts, in contrast with the control group. Zymography and western blot analysis demonstrated a significantly increased expression of MMP-2, MMP-9 and MMP-13 in the newly formed bone compared with controls (p < 0.05). CONCLUSION: The quantity of osteoclastic cells and the increased expression of proteolytic enzymes suggest that 8 months after grafting, inorganic bovine bone is slowly resorbing and is the site of important remodeling of the newly formed bone by means of resorption and synthesis. PMID- 21793828 TI - Conservation and clade-specific diversification of pathogen-inducible tryptophan and indole glucosinolate metabolism in Arabidopsis thaliana relatives. AB - * A hallmark of the innate immune system of plants is the biosynthesis of low molecular-weight compounds referred to as secondary metabolites. Tryptophan derived branch pathways contribute to the capacity for chemical defense against microbes in Arabidopsis thaliana. * Here, we investigated phylogenetic patterns of this metabolic pathway in relatives of A. thaliana following inoculation with filamentous fungal pathogens that employ contrasting infection strategies. * The study revealed unexpected phylogenetic conservation of the pathogen-induced indole glucosinolate (IG) metabolic pathway, including a metabolic shift of IG biosynthesis to 4-methoxyindol-3-ylmethylglucosinolate and IG metabolization. By contrast, indole-3-carboxylic acid and camalexin biosyntheses are clade-specific innovations within this metabolic framework. A Capsella rubella accession was found to be devoid of any IG metabolites and to lack orthologs of two A. thaliana genes needed for 4-methoxyindol-3-ylmethylglucosinolate biosynthesis or hydrolysis. However, C. rubella was found to retain the capacity to deposit callose after treatment with the bacterial flagellin-derived epitope flg22 and pre-invasive resistance against a nonadapted powdery mildew fungus. * We conclude that pathogen-inducible IG metabolism in the Brassicaceae is evolutionarily ancient, while other tryptophan-derived branch pathways represent relatively recent manifestations of a plant-pathogen arms race. Moreover, at least one Brassicaceae lineage appears to have evolved IG-independent defense signaling and/or output pathway(s). PMID- 21793829 TI - Selenium accumulation in flowers and its effects on pollination. AB - * Selenium (Se) hyperaccumulation has a profound effect on plant-arthropod interactions. Here, we investigated floral Se distribution and speciation in flowers and the effects of floral Se on pollen quality and plant-pollinator interactions. * Floral Se distribution and speciation were compared in Stanleya pinnata, an Se hyperaccumulator, and Brassica juncea, a comparable nonhyperaccumulator. Pollen germination was measured from plants grown with varying concentrations of Se and floral visitation was compared between plants with high and low Se. * Stanleya pinnata preferentially allocated Se to flowers, as nontoxic methyl-selenocysteine (MeSeCys). Brassica juncea had higher Se concentrations in leaves than flowers, and a lower fraction of MeSeCys. For B. juncea, high floral Se concentration impaired pollen germination; in S. pinnata Se had no effect on pollen germination. Floral visitors collected from Se-rich S. pinnata contained up to 270 MUg g(-1), concentrations toxic to many herbivores. Indeed, floral visitors showed no visitation preference between high- and low-Se plants. Honey from seleniferous areas contained 0.4-1 MUg Se g(-1), concentrations that could provide human health benefits. * This study is the first to shed light on the possible evolutionary cost, through decreased pollen germination in B. juncea, of Se accumulation and has implications for the management of seleniferous areas. PMID- 21793830 TI - Cell-cell communication and signalling pathways within the ovule: from its inception to fertilization. AB - Cell-cell communication pervades every aspect of the life of a plant. It is particularly crucial for the development of the gametes and their subtle interaction leading to double fertilization. The ovule is composed of a funiculus, one or two integuments, and a gametophyte surrounded by nucellus tissue. Proper ovule and embryo sac development are critical to reproductive success. To allow fertilization, the correct relative positioning and differentiation of the embryo sac cells are essential. Integument development is also intimately linked with the normal development of the female gametophyte; the sporophyte and gametophyte are not fully independent tissues. Inside the gametophyte, numerous signs of cell-cell communication take place throughout development, including cell fate patterning, fertilization and the early stages of embryogenesis. This review highlights the current evidence of cell-cell communication and signalling elements based on structural and physiological observations as well as the description and characterization of mutants in structurally specific genes. By combining data from different species, models of cell-cell interactions have been built, particularly for the establishment of the germline, for the progression through megagametogenesis and for double fertilization. PMID- 21793831 TI - Introduction to Nutrition and physical activity in aging, obesity, and cancer. PMID- 21793832 TI - Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals. AB - A wide variety of phytochemicals present in our diet, including fruits, vegetables, and spices, have been shown to possess a broad range of health beneficial properties. The cytoprotective and restorative effects of dietary phytochemicals are likely to result from the modulation of several distinct cellular signal transduction pathways. Many dietary phytochemicals that are synthesized as secondary metabolites function as toxins, that is, "phytoalexins," and hence protect plants against insects and other damaging organisms and stresses. However, at the relatively low doses consumed by humans and other mammals, these same toxic plant-derived chemicals, as mild stressors, activate adaptive cellular response signaling, conferring stress resistance and other health benefits. This phenomenon has been referred to as xenohormesis. This review highlights the xenohormesis mechanisms underlying chemopreventive effects of some dietary chemopreventive phytochemicals, with special focus on the nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) as a key player. PMID- 21793833 TI - Dietary energy balance modulation of epithelial carcinogenesis: a role for IGF-1 receptor signaling and crosstalk. AB - Obesity affects more than one third of the U.S. population and is associated with increased risk and/or disease severity for several chronic diseases, including cancer. In contrast, calorie restriction (CR) consistently inhibits cancer across species and cancer types. Differential effects on globally active circulatory proteins, particularly insulin-like growth factor-1 (IGF-1), provide a plausible mechanistic explanation for the energy balance-cancer link. Diet-induced changes in circulating IGF-1 modulate IGF-1R/EGFR activation and downstream signaling to Akt and mTOR. These dietary energy balance effects on signaling ultimately modulate the levels and/or activity of cell cycle regulatory proteins, regulating proliferation, and modulating susceptibility to tumor development. Selective targeting of mTORC1 potently inhibits tumorigenesis in several model systems producing CR mimetic effects. Targeting this and other pathways modulated by dietary energy balance may lead to the development of strategies for cancer chemoprevention and for reversing the effects of obesity on cancer development and progression. PMID- 21793834 TI - Tocotrienols: inflammation and cancer. AB - Inflammation is an organism's response to environmental assaults. It can be classified as acute inflammation that leads to therapeutic recovery or chronic inflammation, which may lead to the development of cancer and other ailments. Genetic changes that occur within cancer cells themselves are responsible for many aspects of cancer development but are dependent on ancillary processes for tumor promotion and progression. Inflammation has long been associated with the development of cancer. The distinct characteristics of cancer cells to proliferate, metastasize, evade apoptotic signals, and develop chemoresistance have been linked to the inflammatory response. Due to the involvement of multiple genes and various pathways, current drugs that target single genes have not been effective in providing a therapeutic cure. On the other hand, natural products target multiple genes and therefore have better success compared to drugs. Tocotrienols, the potent isoforms of vitamin E, are such a natural product. This review will discuss the relationship between cancer and inflammation with particular focus on the roles played by NF-kappaB, STAT3, and COX-2. PMID- 21793835 TI - Neurogenic contributions made by dietary regulation to hippocampal neurogenesis. AB - Adult neural stem cells in the dentate gyrus of the hippocampus are negatively and positively regulated by a broad range of environmental stimuli that include aging, stress, social interaction, physical activity, and dietary modulation. Interestingly, dietary regulation has a distinct outcome, such that reduced dietary intake enhances neurogenesis, whereas excess calorie intake by a high-fat diet has a negative effect. As a type of metabolic stress, dietary restriction (DR) is also known to extend life span and increase resistance to age-related neurodegenerative diseases. However, the potential application of DR as a "neurogenic enhancer" in humans remains problematic because of the severity of restriction and the protracted duration of the treatment required. Therefore, the authors consider that an understanding of the neurogenic mechanisms of DR would provide a basis for the identification of the pharmacological and nutraceutical interventions that mimic the beneficial effects of DR without limiting caloric intake. The current review describes the regulatory effect of DR on hippocampal neurogenesis and presents a possible neurogenic mechanism. PMID- 21793836 TI - Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism. AB - The liver is a primary target of growth hormone (GH). GH signals are mediated by the transcription factor signal transducer and activator of transcription 5 (STAT5). Here, we focus on recent discoveries about the role of GH-STAT5 signaling in hepatic physiology and pathophysiology. We discuss roles of the GH STAT5 axis in body growth, lipid metabolism, and the cell cycle pertaining to hepatosteatosis, fibrosis, and hepatocellular carcinoma. Finally, we discuss recent discoveries about the role of GH-STAT5 in sex-specific gene expression and bile acid, steroid, and drug metabolism. PMID- 21793837 TI - Practical issues in genome-wide association studies for physical activity. AB - Genome-wide association studies (GWAS) have successfully identified many genetic variants that are associated with many complex traits. For example, GWAS can be useful for understanding the genetic basis of physical activity (PA). To date, however, there have been only a few GWAS regarding PA. In this article, we overview some practical issues for more efficient GWAS for PA: phenotype definition of PA, the analysis method, population stratification, replication, and sample size. We discuss these issues within a large-scale GWA data set from the Korea Association REsource (KARE) project, including 8,842 samples and 352,228 single nucleotide polymorphism (SNP) markers. Information on PA was obtained from questionnaires, and GWA analysis was performed to find genetic associations between PA and SNP markers in the Korean population. PMID- 21793838 TI - The growing challenge of obesity and cancer: an inflammatory issue. AB - The prevalence of obesity, an established risk factor for many cancers, has risen steadily for the past several decades in the United States and in many parts of the world. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on the impact of energy balance modulation, such as diet-induced obesity and calorie restriction, on growth factor signaling pathways and inflammatory processes. Particular attention is placed on the proinflammatory environment associated with the obese state, specifically highlighting the involvement of obesity-associated hormones/growth factors in crosstalk between macrophages, adipocytes, and epithelial cells in many cancers. Understanding the contribution of obesity to growth factor signaling and chronic inflammation provides mechanistic targets for disrupting the obesity-cancer link. PMID- 21793839 TI - Metabolic approaches to overcoming chemoresistance in ovarian cancer. AB - The poor prognosis in the treatment of ovarian cancer is mainly attributed to chemoresistance. The development of new strategies is urgently necessary to overcome chemoresistance because of the low efficacy of the current standard chemotherapy in ovarian cancer. Metabolic alterations have been suggested to have a crucial role in cancer development. The key metabolic changes in cancer include aerobic glycolysis and macromolecular synthesis, causing antiapoptosis in cancer cells. Therefore, the manipulation of the metabolic derangement could be an effective strategy to overcome chemoresistance in ovarian cancer. In this review, we will discuss metabolic interventions as promising anticancer strategies in ovarian cancer, focusing on the glycolytic, mitochondrial apoptotic, and necrotic pathways. In addition, the role of p53 in relation to metabolic alterations in cancer will be mentioned. PMID- 21793840 TI - Obesity-induced metabolic stresses in breast and colon cancer. AB - Epidemiological studies have suggested that excess body weight gain may be a major risk factor for colon and breast cancer. A positive energy balance creates metabolic stresses, including the excess production of reactive oxygen species (ROS), hyperinsulinemia, the elevated adipokine secretion, and increased gut permeability. Obesity is a risk factor for breast cancer in postmenopausal women, and overweight women are more likely to have poor outcomes. The higher circulating concentration of insulin-like growth factor 1 (IGF-1) in overweight and obese women is thought to be an important mediator to promote cell proliferation and survival via the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/p38 signaling pathways. In an animal model of colon carcinogenesis, overweight mice fed a high-fat diet exhibited a greater number of colon tumors than lean animals. The increased abdominal fat was associated with higher concentrations of leptin, insulin, and IGF-1, which possibly mediate tumor growth. These data suggest that the metabolic burden created by excess adiposity accelerates uncontrolled cell growth and survival, thereby increasing the risk of developing breast and colon cancer. PMID- 21793841 TI - Avian biomodels for use as pharmaceutical bioreactors and for studying human diseases. AB - Animal-based biotechnologies involve the use of domestic animals for the production of pharmaceuticals and various proteins in milk and eggs, as disease models, as tools for stem cell research and animal cloning, and as sources of organs for xenotransplantation into humans. Avian species offer several advantages over mammalian models, and they have been used historically to advance the fields of embryology, immunology, oncology, virology, and vaccine development. In addition, avian species can be used for studying the etiology of human ovarian cancer and other human diseases such as disorders based on the abnormal metabolism of lipids and as unique mechanisms for the biosynthesis and transport of cholesterol. This review integrates recent progress and insight into the molecular and physiologic mechanisms associated with transgenic birds and gives an overview of the use of avian models as pharmaceutical bioreactors and as tools for studying human diseases. PMID- 21793842 TI - Telomere dynamics: the influence of folate and DNA methylation. AB - Since the suggestion of their existence, a wealth of literature on telomere biology has emerged aimed at solving the DNA end-underreplication problem identified by Olovnikov in 1971. Telomere shortening/dysfunction is now recognized as increasing degenerative disease risk. Recent studies have suggested that both dietary patterns and individual micronutrients--including folate--can influence telomere length and function. Folate is an important dietary vitamin required for DNA synthesis, repair, and one-carbon metabolism within the cell. However, the potential mechanisms by which folate deficiency directly or indirectly affects telomere biology has not yet been reviewed comprehensively. The present review summarizes recent published knowledge and identifies the residual knowledge gaps. Specifically, this review addresses whether it is plausible that folate deficiency may (1) cause accelerated telomere shortening, (2) intrinsically affect telomere function, and/or (3) cause increased telomere end fusions and subsequent breakage-fusion-bridge cycles in the cell. PMID- 21793843 TI - Stem cell engineering: limitation, alternatives, and insight. AB - The 21st century will see improvements in the quality of human life. The development of new therapeutic technologies will prevent prevalent diseases and enable recovery from currently incurable diseases. The development of cell and tissue replacement therapies using stem cells and their progenitors will accelerate the development of causative treatments. The effort expended thus far in developing cell therapies has revealed many technical limitations. Thus, we must explore conceptual changes in the feasibility of stem cell therapy. This paper introduces the current limitations to stem cell engineering and ways to overcome these limitations, which will provide new insight into their clinical application. PMID- 21793844 TI - Inhibitory mechanism of lycopene on cytokine expression in experimental pancreatitis. AB - Reactive oxygen species (ROS) are important mediators to induce pancreatitis. Serum levels of antioxidant enzymes and carotenoids including lycopene are lower in patients with pancreatitis than those of healthy subjects. The cholecystokinin (CCK) analog cerulein induces similar pathologic events as shown in human pancreatitis. Recent studies show that high doses of cerulein activate NF-kappaB and induce the expression of inflammatory cytokines, in pancreatic acinar cells, which is mediated by the activation of NADPH oxidase. Lycopene functions as a very potent antioxidant to suppress the induction of inflammatory cytokines, in pancreatic acinar cells stimulated with cerulein. In this review, the possible beneficial effect of lycopene on experimental pancreatitis shall be discussed based on its antioxidant activity. PMID- 21793845 TI - Genomic biomarkers and clinical outcomes of physical activity. AB - Clinical and experimental studies in humans provide evidence that moderate physical activity significantly decreases artery oxidative damage to nuclear DNA, DNA-adducts related to age and dyslipedemia, and mitochondrial DNA damage. Maintenance of adequate mitochondrial function is crucial for preventing lipid accumulation and peroxidation occurring in atherosclerosis. Studies performed on human muscle biopsies analyzing gene expression in living humans reveal that physically active subjects improve the expression of genes involved in mitochondrial function and of related microRNAs. The attenuation of oxidative damage to nuclear and mitochondrial DNA by physical activity resulted in beneficial effects due to polymorphisms of glutathione S-transferases genes. Subjects bearing null GSTM1/T1 polymorphisms have poor life expectancy in the case of being sedentary, which was increased 2.6-fold in case they performed physical activity. These findings indicate that the preventive effect of physical activity undergoes interindividual variation affected by genetic polymorphisms. PMID- 21793846 TI - Impact of endurance and ultraendurance exercise on DNA damage. AB - Regular moderate physical activity reduces the risk of several noncommunicable diseases. At the same time, evidence exists for oxidative stress resulting from acute and strenuous exercise by enhanced formation of reactive oxygen and nitrogen species, which may lead to oxidatively modified lipids, proteins, and possibly negative effects on DNA stability. The limited data on ultraendurance events such as an Ironman triathlon show no persistent DNA damage after the events. However, when considering the effects of endurance exercise comparable to a (half) marathon or a short triathlon distance, no clear conclusions could be drawn. In order to clarify which components of exercise participation, such as duration, intensity, frequency, or training status of the subjects, have an impact on DNA stability, more information is clearly needed that combines the measurement of DNA damage, gene expression, and DNA repair mechanisms before, during, and after exercise of differing intensities and durations. PMID- 21793847 TI - Myricetin is a potent chemopreventive phytochemical in skin carcinogenesis. AB - Myricetin is a widely distributed flavonol that is found in many plants, including tea, berries, fruits, vegetables, and medicinal herbs. Abundant sources provide interesting insights into the multiple mechanisms by which myricetin mediates chemopreventive effects on skin cancer. Myricetin strongly inhibited tumor promoter-induced neoplastic cell transformation by inhibiting MEK, JAK1, Akt, and MKK4 kinase activity directly. In a mouse skin model, myricetin attenuated the ultraviolet B (UVB)-induced COX-2 expression and skin tumor formation by regulating Fyn. Myricetin-mediated inactivation of Akt in the UVB response plays a role in regulating UVB-induced carcinogenesis. Recently, myricetin was found to inhibit UVB-induced angiogenesis by targeting PI3-K in an SKH-1 hairless mouse skin tumorigenesis model. Raf kinase is a critical target for myricetin in inhibiting the UVB-induced formation of wrinkles and suppression of type I procollagen and collagen levels in mouse skin. Accumulated data suggest that myricetin acts as a promising agent for the chemoprevention of skin cancer. PMID- 21793848 TI - Culinary plants and their potential impact on metabolic overload. AB - Contemporary human behavior has led a large proportion of the population to metabolic overload and obesity. Postprandial hyperlipidemia and hyperglycemia evoke redox imbalance in the short term and lead to complex chronic disease in the long term with repeated occurrence. Complex diseases are best prevented with complex components of plants; thus, current nutrition research has begun to focus on the development of plant-based functional foods and dietary supplements for health and well-being. Furthermore, given the wide range of species, parts, and secondary metabolites, culinary plants can contribute significant variety and complexity to the human diet. Although understanding the health benefits of culinary plants has been one of the great challenges in nutritional science due to their inherent complexity, it is an advantageous pursuit. This review will address the challenges and opportunities relating to studies of the health benefits of culinary plants, with an emphasis on obesity attributed to metabolic overload. PMID- 21793849 TI - Inflammation-mediated obesity and insulin resistance as targets for nutraceuticals. AB - Obesity-induced inflammation plays an important role in the development of insulin resistance, type 2 diabetes (T2D), and metabolic dysfunctions. Chronic activation of proinflammatory pathways within insulin target cells can lead to obesity-related insulin resistance. The inflammatory mediators consist of immune cells, cytokines, adipokines, and inflammatory signaling molecules. Targeting obesity-associated inflammation has been shown to protect experimental animals and human subjects from obesity-induced insulin resistance. Modulation of the inflammatory responses associated with obesity may help prevent or improve obesity-induced metabolic dysfunctions. In this review, we introduce the beneficial effects of nutraceuticals for targeting inflammation in the treatment of obesity-induced insulin resistance and metabolic dysfunctions. PMID- 21793851 TI - The role of carbon monoxide in metabolic disease. AB - Metabolic disease is a complex disorder defined by various factors that increase the risk of cardiovascular disease and type 2 diabetes mellitus. In recent years, the incidence of chronic metabolic disease has dramatically increased throughout the world. These chronic metabolic diseases are associated with elevated inflammatory activities. In addition, endoplasmic reticulum (ER) stress leads to metabolic syndrome. Inflammation and ER stress are linked in the context of metabolic homeostasis and disease. Carbon monoxide (CO), a reaction product of heme oxygenase-1 (HO-1), reduces oxidative stress and inflammatory response and protects cells from ER stress. CO has anti-inflammatory effects via induction of HO-1 expression and prevents ER stress-induced apoptosis by inhibiting the C/EBP homologous protein expression. In addition to its anti-inflammatory effects and antiapoptotic effects, HO-1 plays an important role in insulin release and glucose metabolism. In our study, inhalation of CO gas or CO-releasing molecule injection ameliorates 30% fructose or methionine-deficient- and choline-deficient diet-induced hepatic steatosis. Therefore, CO can be studied in the search for potential therapeutic targets for metabolic diseases via inhibition of inflammatory response and ER stress. PMID- 21793852 TI - Combinatorial strategies employing nutraceuticals for cancer development. AB - Cancer is the second leading cause of death worldwide. Therefore, the fight against cancer is one of the most important areas of research in medicine, and one that possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. Cancer prevention by nutraceuticals present in fruits and vegetables has received considerable attention because of their low cost and wide safety margin. A substantial amount of evidence from human, animal, and cell culture studies has shown cancer chemopreventive effects from these natural products. However, single-agent intervention has failed to produce the expected outcome in clinical trials; therefore, combinations of nutraceuticals are gaining increasing popularity. Thus, combinations of nutraceuticals that mimic real-life situations and are competent in targeting multiple targets with very little or virtually no toxicity are needed. In this review, we summarize the results of those studies that report combinatorial cancer chemopreventive action of various nutraceuticals and their combinations with anticancer drugs. PMID- 21793850 TI - Assessing estrogen signaling aberrations in breast cancer risk using genetically engineered mouse models. AB - Aberrations in estrogen signaling increase breast cancer risk. Molecular mechanisms that impact breast cancer initiation, promotion, and progression can be investigated using genetically engineered mouse models. Increasing estrogen receptor alpha (ERalpha) expression levels twofold is sufficient to initiate and promote breast cancer progression. Initiation and promotion can be increased by p53 haploinsufficiency and by coexpressing the nuclear coactivators amplified in breast cancer 1 (AIB1) or the splice variant AIB1Delta3. Progression to invasive cancer is found with coexpression of these nuclear coactivators as well as following a single dose of 7,12-dimethylbenz(a)anthracene. Loss of signal transducer and activator of transcription 5a reduces the prevalence of initiation and promotion but does not protect from invasive cancer development. Cyclin D1 loss completely interrupts mammary epithelial proliferation and survival when ERalpha is overexpressed. Loss of breast cancer gene 1 increases estrogen signaling and cooperates with ERalpha overexpression in initiation, promotion, and progression of mammary cancer. PMID- 21793853 TI - Effects of physical activity on cancer prevention. AB - Results of most epidemiological and laboratory studies suggest an inverse relationship between regular exercise and the risk of certain malignancies, such as intestinal, colon, pancreatic, breast, lung, skin, mammary, endometrial, and prostate cancer. However, physical activity can have different influence on carcinogenesis, depending on energy supply and the age of the subject as well as strength, frequency, and length of exercise. The biochemical and molecular basis of the interaction between aerobic physical activity and tumorigenic processes remains poorly understood. Physical activity may generate reactive oxygen species (ROS) to a different extent. Mild oxidative stress caused by moderate physical activity can activate cellular stress response signaling and potentiate cellular antioxidant defense capacity. However, accumulation of relatively large amounts of ROS as a consequence of exhaustive exercise can either directly damage DNA, causing mutation, or promote tumorigenesis by activating proinflammatory signaling. This review highlights the effects of physical activity on various malignancies in the context of redox status modulated during exercise. PMID- 21793854 TI - Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications. AB - The chemopreventive agent sulforaphane is an isothiocyanate derived from cruciferous vegetables. Transcriptional activation of antioxidant response element (ARE)-regulated phase II detoxification and antioxidant genes through the induction of transcription factor NF-E2-related factor-2 (Nrf2) is considered as the prime mechanism of its chemopreventive action. Cellular level of Nrf2 is tightly regulated by proteolysis through Cullin3 (Cul3)/Kelch-like ECH-associated protein 1 (Keap1)-dependent polyubiquitination. Sulforaphane is an electrophile that can react with protein thiols to form thionoacyl adducts and is believed to affect the Cys residues in Keap1 protein. In addition, sulforaphane might affect the activity of a variety of intracellular kinases to phosphorylate Nrf2 proteins, which dictates the nucleocytoplasmic trafficking of Nrf2 or modulates the Nrf2 protein stability. This review is designed to briefly account for the regulatory mechanism of Nrf2 protein expression by Cul3/Keap1 E3 ligase and for the possible roles of posttranslational modifications of cellular Keap1 or Nrf2 proteins by sulforphane in the regulation of ARE-dependent gene activation. PMID- 21793855 TI - Cestode genomics - progress and prospects for advancing basic and applied aspects of flatworm biology. AB - Characterization of the first tapeworm genome, Echinococcus multilocularis, is now nearly complete, and genome assemblies of E. granulosus, Taenia solium and Hymenolepis microstoma are in advanced draft versions. These initiatives herald the beginning of a genomic era in cestodology and underpin a diverse set of research agendas targeting both basic and applied aspects of tapeworm biology. We discuss the progress in the genomics of these species, provide insights into the presence and composition of immunologically relevant gene families, including the antigen B- and EG95/45W families, and discuss chemogenomic approaches toward the development of novel chemotherapeutics against cestode diseases. In addition, we discuss the evolution of tapeworm parasites and introduce the research programmes linked to genome initiatives that are aimed at understanding signalling systems involved in basic host-parasite interactions and morphogenesis. PMID- 21793856 TI - Leishmania infantum LeIF and its recombinant polypeptides modulate interleukin IL 12p70, IL-10 and tumour necrosis factor-alpha production by human monocytes. AB - Leishmania eukaryotic initiation factor (LeIF) antigen, a Leishmania protein, was shown to induce IL-12, IL-10 and tumour necrosis factor-alpha (TNF-alpha) production by human monocytes-derived macrophages and dendritic cells from healthy individuals. This cytokine-inducing activity was previously found to be located in the amino-terminal region of LeIF protein. This study aimed at characterizing the cytokine-inducing activity of Leishmania infantum LeIF [Leishmania (L.) infantum (LieIF)] and at defining the fragments necessary for inducing cytokine secretion. Eleven rationally designed recombinant polypeptides, corresponding to the entire LeIF protein or parts of it, were expressed and used to stimulate monocytes from healthy individuals. Leishmania (L.) infantum was able to induce IL-12p70, IL-10 and TNF-alpha secretion in human monocytes. In addition, both amino- (1-226) and carboxyl-terminal (196-403) parts of the protein were shown to induce significant levels of the three cytokines analysed. However, IL-12p70-inducing activity was not significant when monocytes were stimulated with the fragments 129-226 and 129-261, inferring that IL-12p70 inducing activity was primarily located within amino acids 1-129 and 261-403. Although the full-length LieIF protein was a more potent inducer than the tested fragments, a significant cytokine-inducing activity was maintained in smaller amino acid regions. This work suggests that cytokine-inducing activity of LieIF or its parts could be exploited in vaccination or immunotherapy protocols. PMID- 21793857 TI - Contribution of human neutrophils in the development of protective immune response during in vitro Leishmania major infection. AB - Stimulation of neutrophils may potentiate immunity to Leishmania major. CpG containing oligodeoxynucleotide (ODN) has immune stimulatory effects and has been suggested as adjuvants and therapeutics to potentiate efficacy of vaccines and treatments against leishmaniasis. Here, we examined the stimulatory effect of synthetic ODN containing CpG motifs class A and B on cytokine production by neutrophils. Neutrophils from healthy donors responded to CpG-ODN type A, but not to class B, with secretion of IL-8 and following GM-CSF pretreatment with TNF alpha production. To test whether neutrophil responses were altered in cutaneous leishmaniasis (CL) and to better understand the role of neutrophils in susceptibility and resistance to disease, we evaluated cytokine responses in GM CSF preconditioned neutrophils from asymptomatic (Leishmanin skin test positive, LST+) and nonhealing CL individuals to CpG-ODN class A and assessed the expression levels of toll-like receptors (TLR2), 4 and 9. LST+ and healthy donor, but not nonhealing CL neutrophils, responded with TNF-alpha secretion. Neutrophils from nonhealing CL displayed increased mRNA expression levels of TLR2, 4 and 9 compared to neutrophils from LST+ or healthy donors. Therefore, failure to cure CL is associated with reduced ability of neutrophils to secrete TNF-alpha and correlates with high TLR 2, 4 and 9 expressions. PMID- 21793858 TI - Trichinella spiralis antigens prime mixed Th1/Th2 response but do not induce de novo generation of Foxp3+ T cells in vitro. AB - Many parasitic helminth infections induce Th2-type immune responses and engage the regulatory network. In this study, we specifically investigated the influence of antigens derived from different life stages of the helminth Trichinella spiralis on the polarization of naive CD4(+) T cells by dendritic cells. Results obtained from C57BL/6 mice showed that T. spiralis derived antigens have the capacity to induce bone marrow-derived dendritic cells to acquire an incompletely mature phenotype that promotes a significant proliferation of naive CD4(+) T cells and a mixed Th1/Th2 cytokine profile with the predominance of Th2 cytokines. Increased production of IL-4, IL-9, IL-10 and IL-13 accompanied increased IFN-gamma. Furthermore, dendritic cells pulsed with T. spiralis antigens did not induce an increase in the population of Foxp3(+) T regulatory cells. Although other helminth antigens have demonstrated the capacity to induce de novo generation of Foxp3(+) T regulatory cells, here our in vitro studies provide no evidence that T. spiralis antigens have this capacity. PMID- 21793859 TI - Attempts to immunize sheep against Teladorsagia circumcincta using fourth-stage larval extracts. AB - A ConcanavilinA (ConA)-binding fraction of a detergent-soluble membrane extract from Teladorsagia circumcincta (formerly Ostertagia circumcincta) fourth-stage larvae was isolated, and two vaccine trials were conducted with this preparation in groups of 7 worm-free sheep. All groups were challenged with a total of 5000 T. circumcincta larvae from 1 week after the final immunization and protection assessed by comparing the egg and worm counts, and length of developing worms, of the immunized groups with their respective controls. Immunization with the ConA binding antigen induced high-titre serum antibody responses in both trials. However, no significant reduction in either egg count or worm burdens was observed in the vaccinated groups in either trial. It was concluded that detergent-soluble, ConA-binding extracts prepared from T. circumcincta fourth stage larvae did not contain significantly protective antigens, despite the fact that an extract prepared in a similar manner from Ostertagia ostertagi had previously significantly protected calves against homologous challenge. PMID- 21793860 TI - 'Rallying around the flag': Can an intergroup contact intervention promote national unity? AB - A longitudinal study evaluated the success of a contact-based nation-building intervention (the Malaysian National Service Programme) in promoting various facets of national unity. The study assessed how post-test measures of quality of intergroup contact, outgroup evaluations, and levels of identification changed compared to their respective pre-test levels, for both National Service and control group participants. The intervention did not lead to a worsening of any of the constructs related to intergroup relations, which is noteworthy given the novelty for many participants of mixing in a multi-ethnic setting. Furthermore, all rater groups (Malays, Chinese, and Indians) maintained their ethnic identity, even in the presence of high levels of national identity, which we discuss with respect to past research on the effects of positive intergroup contact on minority group identification. However, the changes associated with the intervention yielded only small effect sizes, and, on the whole, National Service participants did not show significantly greater improvement than that experienced by control participants. We discuss the value of intergroup contact in this novel setting, considering various features of this programme that may have limited its effectiveness and discuss how such interventions can more successfully meet their goals. PMID- 21793861 TI - Vagal stimulation promotes atrial electrical remodeling induced by rapid atrial pacing in dogs: evidence of a noncholinergic effect. AB - BACKGROUND: Atrial electrical remodeling (AER) is one of the mechanisms by which atrial fibrillation (AF) begets AF. It is known that vagal activity increases the propensity for AF. However, vagal effects on AER have not been fully investigated. METHODS: Adult mongrel dogs were divided in four groups: group I, rapid atria pacing (RAP); group II, RAP plus vagal nerve stimulation (VNS); group III, RAP and VNS with atropine (0.2 mg/kg/h, intravenous), and group IV, group III plus vasoactive intestinal polypeptide (VIP) antagonist ([D-p-Cl-Phe(6), Leu(17)]-VIP, 0.125 MUg/kg/h). VNS was performed bilaterally through vagosympathetic trunks to achieve second-degree AV block or sinus rate slowing of >30 beats per minute. Atrial effective refractory periods (AERPs) were determined in the coronary sinus and right atrial appendage every hour at drive cycle lengths (DCLs) 350 ms, 300 ms, and 250 ms. RESULTS: During 5 hours RAP with or without VNS, AERP shortened progressively from baseline at both pacing sites and at all DCLs (P < 0.01). Furthermore, RAP-induced AERP shortening was more pronounced with VNS (P < 0.01). With atropine, the AERP shortening during VNS was blunted (P < 0.01), but was still significantly more pronounced than that in group I (P < 0.05). However, VNS effect on AERP shortening was eliminated completely with the combination of atropine and VIP antagonist (P = 0.15 vs group I). CONCLUSION: Increased vagal activity promotes RAP-induced AER, which could not be totally accounted for by cholinergic effect but could be blocked by the combination of atropine and VIP antagonist. Vagally released VIP may have important role in the vagal promotion of AER. PMID- 21793862 TI - Effect of pulsatility on the mathematical modeling of rotary blood pumps. AB - In this study, the effect of time derivatives of flow rate and rotational speed was investigated on the mathematical modeling of a rotary blood pump (RBP). The basic model estimates the pressure head of the pump as a dependent variable using measured flow and speed as predictive variables. Performance of the model was evaluated by adding time derivative terms for flow and speed. First, to create a realistic working condition, the Levitronix CentriMag RBP was implanted in a sheep. All parameters from the model were physically measured and digitally acquired over a wide range of conditions, including pulsatile speed. Second, a statistical analysis of the different variables (flow, speed, and their time derivatives) based on multiple regression analysis was performed to determine the significant variables for pressure head estimation. Finally, different mathematical models were used to show the effect of time derivative terms on the performance of the models. In order to evaluate how well the estimated pressure head using different models fits the measured pressure head, root mean square error and correlation coefficient were used. The results indicate that inclusion of time derivatives of flow and speed can improve model accuracy, but only minimally. PMID- 21793863 TI - Effects of intra-aortic balloon pump on coronary artery bypass grafts blood flow: differences by graft type and coronary target. AB - The intra-aortic balloon pump (IABP) is used worldwide as an anti-ischemic strategy. However, little is known about the modifications of the graft blood flow during IABP. A retrospective study aimed at analyzing transit-time flow measurements during 1:1 IABP and during its cessation in 401 consecutive patients receiving IABP before coronary artery bypass grafting (n = 880 graft segments) was reported. All normally functioning grafts were considered. Mean diastolic and mean blood flow improved significantly during 1:1 IABP compared with during IABP cessation (P < 0.001), although mean and end-diastolic arterial pressures were significantly lower (P = 0.001). Arterial and sequential saphenous vein (SV) grafts showed greater improvements in mean diastolic and mean flow compared with single venous grafts. Higher flows were also observed in the grafts directed to the circumflex territory. Surplus graft flow (SGF, defined as mean flow during 1:1 IABP/mean flow with IABP off) was recruited (SGF >1) during 1:1 IABP, with higher values in single arterial or sequential SV grafts versus single venous grafts (both P < 0.001). Y-conduit radial artery (RA) grafts showed higher maximum diastolic flow, mean flow, and SGF compared to aortocoronary RA or SV grafts. In this retrospective analysis, IABP was associated with improved diastolic and mean blood flow in bypass grafts. Arterial, sequential, and Y conduit grafts were associated with greater improvements in blood flow and SGF than aortocoronary SV grafts. PMID- 21793865 TI - Effect of exogenous l-arginine and ageing on NO and ET-1 in penile tissue of rat. AB - The aim of this study was to investigate the effect and significance of l arginine and ageing on nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway and ET-1 in penile tissue of rats. The different months old rats were divided into control group and experiment group randomly, the content of NO, cGMP, the changes of activity of Nitrous Oxide Systems (NOS) and the content of endothelin-1(ET-1) in penile tissue were determined. Along with ageing, NO and the activity of NOS in penile tissue increased at first and then decreased (P < 0.001). The content of cGMP reduced obviously (P < 0.001), the content of ET-1 had a tendency to increase, and the ratio of ET-1/NO increased significantly (P < 0.001 or P < 0.01). After feeding rats with l-arginine for some time, both the activity of NOS and the content of cGMP increased significantly in penile tissue (P < 0.001), while there was no obvious change in the content of ET-1. Our study shows that whether the smooth muscle cells relax or contract might be decided by the content of cGMP and value of ET-1/NO in penile tissue. l-arginine had significant effect on increasing the activity of NOS and the content of NO and cGMP, indicating that l-arginine has potential clinical value to be used in treating ED. PMID- 21793864 TI - Gastric emptying and different types of reflux in adult patients with cystic fibrosis. AB - BACKGROUND: Increased gastro-oesophageal reflux (GER) is common in patients with cystic fibrosis (CF). Previous studies showed delayed gastric emptying (GE) and a high prevalence of bile acids in saliva suggesting duodenogastro-oesophageal reflux (DGER). AIM: To assess different types of reflux (acid, weakly acidic and bile) and their relationship with rate of GE in adult CF patients. METHODS: Gastric emptying was assessed in 33 CF patients using breath tests, reflux was monitored in 42 patients using impedance-pH-metry and 14 CF patients underwent combined impedance-pH-Bilitec monitoring. RESULTS: Delayed GE was found in 33%, increased GER (predominantly acid) in 67% and pathological DGER in 35% of the CF patients. There was a significant correlation between oesophageal bile and acid exposure (P < 0.0001, r = 0.85). Patients with increased DGER had a higher proximal extent of reflux compared to those without DGER [17 (9-35) vs. 5 (1-12), P = 0.04]. There was no correlation between GE and reflux parameters, however, in a subgroup of 10 patients studied by impedance-pH-Bilitec and GE, there was a strong correlation between GE rate and bile exposure (P = 0.005, r = 0.83). CONCLUSIONS: Delayed gastric emptying is present in 1/3 of patients with cystic fibrosis. There is a subgroup of these patients with both delayed gastric emptying and increased acidic duodenogastro-oesophageal reflux with high proximal extent and risk of aspiration. Controlled studies should be performed to evaluate the effect of prokinetics or antireflux surgery on the clinical cystic fibrosis evolution in these patients. PMID- 21793866 TI - Effects of phosphodiesterase-5 inhibitor vardenafil on testicular androgen binding protein secretion, the maintenance of foci of advanced spermatogenesis and the sperm fertilising capacity in azoospermic men. AB - We evaluated the effects of vardenafil on testicular androgen-binding protein secretion (ABP). Bilaterally obstructed azoospermic (OA)-men (n = 19) (group A) underwent unilateral testicular biopsy. A group of nonobstructed azoospermic (NOA)-men (n = 68) (group B) underwent bilateral testicular biopsy. ABP secretion in vitro by testicular tissue was assessed in each participant of every group. In addition, intracytoplasmic sperm injection (ICSI) cycles were performed in several couples of group A or group B using frozen/thawed spermatozoa from the biopsy material. Ten OA-men (group A1), 14 NOA-men (group B1), and nine different NOA-men (group B2) had been positive for spermatozoa in the biopsy but pregnancies were not achieved in the respective female partners. Men of groups A1, B1 and B2 were treated with vardenafil, vardenafil and L-carnitine respectively. Then, the men of groups A1, B1 and B2 underwent a second testicular (unilateral) biopsy. Within the group A1 and within the group B1, ABP secretion rate was significantly larger after vardenafil treatment than prior to vardenafil treatment. In addition, fertilisation rates in ICSI cycles within groups A1 or B1 were not affected by vardenafil administration. Vardenafil administration in NOA men increased ABP secretion and did not affect detrimentally the presence of testicular foci of advanced spermatogenesis. PMID- 21793867 TI - High frequency of sexual dysfunction in patients with male accessory gland infections. AB - The aim of this study was to administer to two groups of patients with male accessory gland infection (MAGI), respectively, with positive or negative alterations in ultrasonography, a new diagnostic interview, arbitrarily named structured interview about MAGI (SI-MAGI), to evaluate differences between these groups, especially about the prevalence of sexual dysfunction. After ultrasound examinations, patients with MAGI were divided into two age-matched groups: positive and negative for ultrasound signs (US+ and US-). The SI-MAGI was structured into four domains (urinary tract symptoms, ejaculatory pain or discomfort, sexual dysfunction and quality-of-life impact) for a total of 30 questions with four possible answers. Infertile patients of MAGI US+ group showed scores significantly higher than MAGI US- and healthy control group in all domains (anovaP < 0.005) in relation to scores of patients with MAGI US+ and US-: in domain 1 = 16.0 +/- 0.5 vs 9.0 +/- 0.5, domain 2 = 21.0 +/- 1.0 vs 11.0 +/- 1.0, domain 3 = 23.0 +/- 0.5 vs 12.0 +/- 1.0 and, finally, in domain 4 = 13.0 +/- 2.0 vs 6.0 +/- 1.0. In particular, a higher frequency of sexual dysfunction (52%) was detected in MAGI US+ group when compared with MAGI US- (28%). This study introduces a specific set of questions, which combined with the sperm analysis, microbiological and ultrasound investigations, that altogether better express the clinical presentation of MAGI. Finally, MAGI US+ group showed a high percentage of sexual dysfunction. PMID- 21793868 TI - Poor oral hygiene and gingivitis are associated with obesity and overweight status in paediatric subjects. AB - AIM: The association between obesity and periodontitis has been extensively investigated in adults but not in young people. Our aim is to evaluate whether overweight/obese paediatric patients have a greater chance of being affected by gingivitis than those of normal weight. SUBJECTS AND METHODS: Ninety-eight subjects ranging between 10 and 17 years of age were classified as obese/overweight or normal weight on the basis of body mass index. Auxological data, blood pressure, insulin resistance, psychological profile, oral hygiene habits, plaque and gingival indices were collected. RESULTS: Anthropometric measurements and blood pressure were significantly higher in overweight/obese subjects than in the normal-weight subjects (p<0001). The overweight/obese subjects showed a worse attitude towards oral hygiene. Two-way anova revealed a significant effect of obesity status (p<0001) on the gingival index. Logistic and linear regression analyses identified gingivitis as dependent on insulin resistance and bad oral hygiene rather than on the overweight/obese status simply defined. Negative psychological features related to physical and academic self concept were also risk factors for gingivitis probably because they were related to a generic poor self-awareness. CONCLUSION: The gingivitis observed in overweight and obese young subjects is probably due to a combination of metabolic and inflammatory profiles and neglected attitude towards oral hygiene. PMID- 21793869 TI - A retrospective survey of autotransplantation of teeth in dental clinics. AB - The aim of this study was to investigate the usage of tooth autotransplantation in dental clinics which offer the treatment and evaluate its practicality. Participating dentists were requested to provide information on transplantations they had undertaken from 1 January 1990 to 31 December 2010. A total of 614 teeth from 552 patients (37 dentists) ranging in age from 17 to 79 (mean age: 44.1) were examined. Cumulative survival rate and mean survival time were calculated using the Kaplan-Meier method, and log rank test was used for analysis of factors. The mean number of autotransplantation patients per clinic per year was 1.4. Upper third molars constituted 36.8% of donor teeth, while 37.1% were lower third molars. The lower first molar region was the most common recipient site at 32.6%, followed by the lower second molar region (28.0%). Prosthodontic treatment of transplanted teeth involved coverage with a single crown (72.5%) and abutment of bridge (18.9%). A total of 102 transplanted teeth were lost owing to complications such as attachment loss (54.9%) and root resorption (25.7%). The cumulative survival rate in cases where donor teeth had complete root formation was 90.1% at 5 years, 70.5% at 10 years and 55.6% at 15 years. The mean survival time was 165.6 months. Older age was a significant risk factor (P < 0.05) for survival. In cases where suitable donor teeth are available, autotransplantation of teeth may be a plausible treatment option for dealing with missing teeth in dental clinics. PMID- 21793870 TI - Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay. AB - Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150 kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 degrees C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P < 0.05). Complete reversal of thermal hyperalgesia symptoms was obtained with a 200 pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 degrees C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay. PMID- 21793871 TI - In discourse: Bourdieu's theory of practice and habitus in the context of a communication-oriented nursing interaction model. AB - AIMS: This paper presents a discussion on the potential of the theories of practice and habitus as espoused by the sociologist Bourdieu. BACKGROUND: The interaction between nurses and patients is a constitutive element in the nursing process and a central aspect in the theories developed by Paterson and Zderad, and Orlando. Bourdieu's theory of habitus and practices assists in understanding and explaining differentiated results concerning nurse-patient interaction. DATA SOURCES: In a study on interactions with paraplegic patients, distinguished levels of interactions, which show considerable diversity among one another, could be identified. The data were collected over a period of 20 months in 2004 2006. The results present the central topics of interaction and show that understanding-oriented interaction is rare. DISCUSSION: Communicative acting in nursing always takes place in a social context. In the interaction with patients, nurses assign a higher distinctive value to the standardized concepts of care facilities than to the actually perceived need of care. An understanding-oriented interaction assumes that the nurses with their own contributions, themes and authorities, prove themselves in the eyes of the patient. It is expected from nurses that they habitualize their own concepts so that they can be represented in a convincing manner. CONCLUSION: If an understanding-oriented interaction is to extend into the practice of nursing, it is of crucial importance that both interaction partners assure each other how and with what capital their interaction is to be realized. Nurses need professional habitus to become agents in the social field of health. PMID- 21793872 TI - Predictors of caregiver burden in caregivers of individuals with dementia. AB - AIMS: This article is a report on a study of the multidimensional predictors of caregiver burden in caregivers of individuals with dementia using nationally representative data. BACKGROUND: Caregiver burden affects the health of both caregivers and their care-recipients. Although previous studies identified various predictors of caregiver burden, these predictors have not been confirmed in nationally representative population. METHODS: Data for this secondary analysis was provided by the National Alliance for Caregiving, American Association of Retired Persons. The data were collected through a telephone survey of randomly selected adults in seven states in 2003 (weight adjusted n = 302). Descriptive statistics, inter-correlation analysis and a hierarchical multiple regression analysis were performed. RESULTS/FINDINGS: Disease-related factors were the most significant predictors, explaining 16% of caregiver burden; these were followed by caregiver socio-demographical factors and caregiving related factors (F = 21.28, P < 0.01). Significant individual predictors were impairment of activities of daily living or instrumental activities of daily living, the number of hours of caregiving, use of coping strategies, co residence, spousal status and caregiver gender (P < 0.05). CONCLUSION: Impaired function in care-recipients predicts caregiver burden, and also interacts with demographical- and caregiving-related factors. Thus, it will be beneficial to both care-recipients and caregivers to target nursing interventions and community services to improve the functional abilities of individuals with dementia. PMID- 21793873 TI - The missing piece: a sociological autopsy of firearm suicide in the United States. AB - Social, economic, violence, political, and gun access predictors of suicide and gun suicide were examined via sociological autopsy. The model predicting suicide rates overall had the best results, chi(2) (9, N=50)=5.279 (CMIN, the goodness of fit statistic that represents the minimum discrepancy between the unrestricted sample covariance matrix and the restricted covariance matrix) p=.809, [the goodness of fit statistic that represents the minimum discrepancy between the unrestricted sample covariance matrix and the restricted covariance matrix] indicating an excellent fit of the data and theoretical model. The model explained 76% of the variance in state suicide rates and was a significantly better predictor than one could expect by chance, F(6,43)=22.889, p<.001). All path coefficients were significant predictors of suicide with the exception of violence climate, which was not included. This study contributes to the theoretical knowledge by adding a comprehensive framework of analysis and model useful for prevention. PMID- 21793874 TI - "Let me count the ways:" fostering reasons for living among low-income, suicidal, African American women. AB - Protective factors for fostering reasons for living were examined among low income, suicidal, African American women. Bivariate logistic regressions revealed that higher levels of optimism, spiritual well-being, and family social support predicted reasons for living. Multivariate logistic regressions indicated that spiritual well-being showed unique predictive value for reasons for living. Further, the multivariate model accurately predicted reasons for living 72% of the time. Partial support was found for a cumulative protective model hypothesizing a linear relationship between the number of protective factors endorsed and increased reasons for living. Implications for community-based preventive and recovery-oriented intervention efforts and future research are discussed. PMID- 21793876 TI - Successful treatment of equine sarcoids with cisplatin electrochemotherapy: a retrospective study of 48 cases. AB - REASONS FOR PERFORMING STUDY: Sarcoids are the commonest form of equine skin tumour. Several therapeutic measures have been described but none is considered to be universally effective. Electrochemotherapy (ECT) is a new anticancer therapy that utilises electrical field pulses to induce increased cell membrane permeability to antitumour hydrophilic drugs, such as cisplatin. The increased intracellular concentration of the drugs has a significant therapeutic benefit. The procedure has not been previously reported in a large number of horses. OBJECTIVE: To validate ECT as a novel alternative treatment for equine sarcoids. METHODS: A retrospective study evaluating the efficacy of cisplatin ECT in the treatment of equine sarcoids was performed. Electrochemotherapy treatments were applied under general anaesthesia at 2 week intervals with or without prior excision or debulking. Electric pulses were directly applied to the lesions following intra-tumoural injections of an aqueous solution of cisplatin. RESULTS: One-hundred-and-ninety-four sarcoids on 34 horses, 2 ponies, 11 donkeys and one mule were treated with ECT. The 4 year nonrecurrence rate was 97.9% for animals (47/48) and 99.5% (193/194) for tumours. When ECT was used as a single treatment, a significant influence of tumour size (rho= 0.55) on the number of treatments required for cure was shown. When prior surgery was performed, there was a significant influence (P<0.001) of the excision quality (complete or incomplete) and the healing mode (closed or open wound) on the number of treatments. The most common adverse effect was a slight oedematous reaction for lesions located on thin skin regions. CONCLUSION AND CLINICAL RELEVANCE: Results demonstrate that ECT, with or without concurrent tumour debulking, is an effective alternative for treatment of equine sarcoids. PMID- 21793875 TI - High school bullying as a risk for later depression and suicidality. AB - This is the first study to examine whether high school students experiencing frequent bullying behaviors are at risk for later depression and suicidality. A total of 236 students who reported frequent bullying behavior without depression or suicidality during a suicide screening were interviewed 4 years later to reassess depression, suicidal ideation, attempts, substance problems, and functional impairment and were compared to at-risk youth identified during the screen, including 96 youth who also experienced bullying behavior. Youth who only reported frequent bullying behaviors (as bullies, victims, or both) did not develop later depression or suicidality and continued to have fewer psychiatric problems than students identified as at-risk for suicide. Students who experienced bullying behaviors and depression or suicidality were more impaired 4 years later than those who had only reported depression or suicidality. Thus, assessment of bullying behaviors in screening protocols is recommended. PMID- 21793877 TI - Distal border fragments and shape of the navicular bone: radiological evaluation in lame horses and horses free from lameness. AB - REASONS FOR PERFORMING STUDY: The significance of distal border fragments of the navicular bone is not well understood. There are also no objective data about changes in thickness and proximal/distal extension of the palmar cortex of the navicular bone. OBJECTIVES: To describe the distribution of distal border fragments and their association with other radiological abnormalities of the navicular bone and describe the shape of the navicular bone in sound horses and horses with foot-related lameness, including navicular pathology. METHODS: Sound horses had radiographs acquired as part of a prepurchase examination. Lame horses had forelimb lameness abolished by palmar nerve blocks performed at the base of the proximal sesamoid bones. Diagnosis was assigned prospectively based on results of local analgesia and all imaging findings. The thickness of the palmar cortex of the navicular bone and size of proximal/distal extensions were measured objectively. Other radiological abnormalities were evaluated subjectively and each navicular bone graded. RESULTS: Fifty-five sound and 377 lame horses were included. All measurements were larger in lame compared with sound horses except the size of the distal extension of the palmar cortex. Fragments were observed in 3.6 and 8.7% of sound and lame horses respectively and in 24.1% of horses with a diagnosis of primary navicular pathology. There was an association between fragments and overall navicular bone grade, radiolucent areas at the angles of the distal border of the navicular bone and number and size of the synovial invaginations. CONCLUSIONS AND POTENTIAL RELEVANCE: The palmar cortex of the navicular bone was thicker in lame compared with sound horses. Distal border fragments were most frequent in horses with navicular pathology. Evaluation of changes in shape of the navicular bone may also be important for recognition of pathological abnormalities of the bone. PMID- 21793878 TI - Clinical expression of lolitrem B (perennial ryegrass) intoxication in horses. AB - REASONS FOR PERFORMING STUDY: Perennial ryegrass staggers is purported to be a common neurological mycotoxicosis of horses but the case description lacks detail and evidence. OBJECTIVE: To describe the clinical syndrome of lolitrem B intoxication in horses, limiting tests to those that are applicable to clinical practice, and to assess the potential value of enzyme-linked immunosorbent assay (ELISA) tests for lolitrem B in horse body fluids. METHODS: Seven horses in 2 separate groups were fed perennial ryegrass seed and hay containing 2 ppm lolitrem B. Paired data were collected prior to and after 2 weeks exposure to lolitrem B, including video-documented neurological examination and clinical examination. RESULTS: All horses developed a variable degree of tremor and ataxia when exposed to lolitrem B. Tremor depended on the level of activity and included a subtle, rapid tremor of the eyeball. Ataxia was exaggerated by blindfolding and primarily involved a truncal sway and irregular, but predictable, limb placements. No change was detected in urine lolitrem B levels and, although plasma lolitrem B increased during the treatment period, levels did not correlate with the severity of clinical signs displayed. Limb swelling, heel lesions and serous nasal discharge were also observed in horses most severely intoxicated. CONCLUSIONS: The clinical effects of lolitrem B intoxication in horses primarily involve action-related tremors and symmetrical vestibular ataxia. Ergovaline may have caused the limb swelling, heel lesions and serous nasal discharge. Plasma ELISA for lolitrem B may be of diagnostic use in the future. POTENTIAL RELEVANCE: This study provides a clearer appreciation of the clinical signs and variability of perennial ryegrass intoxication in horses. PMID- 21793879 TI - Juvenile dermatomyositis: immunopathogenesis, role of myositis-specific autoantibodies, and review of rituximab use. AB - Juvenile dermatomyositis (JDM) is an autoimmune disease of the skin and muscle that affects children. The etiology is poorly understood, but genetic susceptibility, environmental triggers, and abnormal immune responses are each thought to play a part. T cells have traditionally been implicated in the immunopathogenesis of JDM, but dendritic cells, B cells, and microchimerism are increasingly associated. Additionally, myositis-specific autoantibodies (MSA) can be present in the sera of affected patients and may correlate with distinct clinical phenotypes. Given the role of humoral immunity and MSA, there has been recent interest in the use of rituximab to treat JDM. Early results are mixed, but it is hoped that a prospective clinical trial will shed light on the issue in the near future. PMID- 21793880 TI - Frequency and severity of diaper dermatitis with use of traditional Chinese cloth diapers: observations in 3- to 9-month-old children. AB - Chinese cloth diapers differ from disposable diapers in several respects that are central to our understanding of the etiology of diaper dermatitis (DD), yet there are no published reports on the dermatological correlates of this manner of infant care, which is prevalent among the world's second-largest pediatric population. The objective was to determine the prevalence and severity of DD in exclusive users of Chinese cloth diapers. This observational study was conducted during a single home visit to 694 Chinese children who were exclusive users of cloth diapers in five inland cities of China. During each home visit, study nurses documented the presence and severity of DD using a visual dermatological scale and conducted transepidermal water loss (TEWL) and pH measurements. Diaper dermatitis was rare in the buttocks and genital area of the children (<20%) but was common in the perianal and intertriginous regions (50-70%). TEWL and pH were mildly higher in babies with DD than in those without DD in the genital and buttocks area. Diaper dermatitis is common in children who use traditional Chinese cloth diapers, especially in the perianal and intertriginous regions. PMID- 21793881 TI - Physiological skin manifestations in twins: association with maternal and neonatal factors. AB - There is paucity of literature on the incidence and clinical associations of transient benign dermatological conditions in twin neonates. This prospective study evaluated 253 live-born twin babies (>=23 wks) at a tertiary care hospital in Delhi, India. All study subjects were observed for the first 7 days of life, and regular dermatological examination was performed. The primary focus was on palatine Epstein pearls (PEP), milia, erythema toxicum neonatorum (ETN), and physiological skin desquamation (PDS). Zygosity was determined with the help of sex combination of the pairs, chorionicity of the placentae, and seven blood group phenotypes. Chi-square test, Cohen's kappa test, and logistic regression analysis were done. PEP, milia, ETN, and PDS were seen in 88.1%, 83.4%, 2.4%, and 4.3% twin babies, respectively. Preputial Epstein pearls were not seen. Birth order, maternal anemia, route of delivery, meconium staining of amniotic fluid, gestational maturity, birth weight, and presence of intrauterine growth restriction were found to be associated with one or more of the studied skin conditions (p < 0.05), but maternal age, pregnancy-induced hypertension, and sex of the baby did not affect incidence of any (p > 0.05). The intrapair concordance was highly significant (p < 0.001) in mono- and dizygotic twins. PEP and milia were equally common in the evaluated twins as compared to reports in singletons, while ETN and PDS were less common in this twin cohort. Environmental and genetic factors may regulate physiological skin manifestations in newborns. PMID- 21793882 TI - Neonatal lupus erythematosus in identical twins, showing transient bullous lesions. AB - One of identical twin girls was born with ulcers on her leg, and shortly after birth developed a flaccid blister on the leg. Subepidermal blister with vacuolar degeneration of basal cell layer and the heavy infiltration of mononuclear cells in the upper dermis were observed in the blister lesion. She also had generalized livedo. Her identical twin sister did not exhibit ulcers or blisters, but was born with milia on her limbs. Their mother was found to have lupus erythematosus with positive anti-Ro/SSA antibodies and developed Sjogren syndrome. We emphasize neonatal blistering and congenital milia unique manifestations of neonatal lupus erythematosus. PMID- 21793883 TI - Urticaria multiforme--a case report. AB - The term "urticaria multiforme" has recently been proposed to replace acute annular urticaria and refers to a benign cutaneous hypersensitivity reaction characterized by the acute onset of large, polycyclic, and annular wheals with ecchymotic centers. It is associated with acral and facial angioedema, dermatographism, favorable response to antihistamines, and a self-limited course. It is most often mistaken for erythema multiforme and occasionally for serum sickness-like reaction. We report a case of urticaria multiforme in a 4-month-old infant, followed by a review of the literature. PMID- 21793884 TI - Successful treatment with topical N-acetylcysteine in urea in five children with congenital lamellar ichthyosis. AB - We reported the efficacy of topical cutaneous N-acetylcysteine in children with type I lamellar ichthyosis. The drug was applied on predetermined body surface areas two times a day for 6 weeks, followed by a daily maintenance application. During the first 2 weeks of treatment, a significant improvement occurred. After 4 months of maintenance application, a marked overall improvement occurred in all the treated areas. Only two patients showed mild adverse effects such as light burning, pruritus, and irritation. Even though a larger group of patients should be necessary to confirm the data, topical 10% N-acetylcysteine emulsion prepared in urea 5% seems to be a valuable and safe therapeutic option for lamellar ichthyosis in children, with benefit not only for skin lesions but also for ectropion avoiding a surgical procedure. PMID- 21793885 TI - What is your diagnosis? Periorbital granulomatous plaque. PMID- 21793886 TI - What is your diagnosis? An 18-month-old child with ornithine transcarbamylase deficiency and a rash. PMID- 21793887 TI - What is your diagnosis? Multiple cobblestone-like papules on the inner aspect of the lip. PMID- 21793888 TI - A comparative trial comparing the efficacy of tacrolimus 0.1% ointment with Aquaphor ointment for the treatment of keratosis pilaris. AB - Keratosis pilaris is common, but little information exists regarding effective therapy for this sometimes clinically and often cosmetically troublesome disorder. This small pilot study compared the efficacy of Aquaphor ointment with tacrolimus ointment 0.1% and found that both were effective and well tolerated by patients. PMID- 21793889 TI - Congenital cutaneous angioleiomyoma. AB - Congenital cutaneous angioleiomyoma is an extremely rare benign smooth muscle tumor. We present a case of a firm, painful subcutaneous mass noticed at birth on the left leg that on surgical excision proved to be an angioleiomyoma. Prognosis is good, and recurrences are uncommon. To our knowledge, this is the second report of a congenital angioleiomyoma. PMID- 21793890 TI - Multiple cutaneous angiomyxomas in a child. AB - Cutaneous myxomas are rare, benign, connective tissue tumors composed of stellate cells set in a loose mucoid stroma containing delicate reticulin fibers running in various directions. They are also called angiomyxomas to reinforce their vascular component. These lesions have been recognized as part of Carney complex. We report an 11-year-old boy affected by disseminated cutaneous angiomyxomas since the age of 2, without any other component of Carney complex. PMID- 21793891 TI - Multiple, recurrent, refractory vascular malformations as the primary presenting feature of a PTEN mutation. AB - Complete history and physical examinations are very important in patients with a vascular anomaly. This brief report highlights the case of a five-year-old male who presented with recurrent arteriovenous malformations of the hand and forearm. The patient also demonstrated additional clinical and diagnostic imaging features consistent with a PTEN Hamartoma-Tumor syndrome. The prompt identification of individuals with this condition is important, given the more locally aggressive nature to the malformations and the increased potential for future malignant disease. The etiology and clinical features associated with PTEN Hamartoma-Tumor syndromes are reviewed in this case. PMID- 21793892 TI - Linear IgA disease: complicated by alpha thalassemia. AB - Dapsone is regarded as the treatment of choice for linear immunoglobulin A disease (chronic bullous disease of childhood). It is associated with both hemolytic anemia and methemoglobinemia. The hematotoxic effects are dose related and can result in significant hemolysis. We present a case of a patient with chronic bullous disease of childhood and alpha thalassemia trait. Complete resolution occurred on a standard dose of dapsone without significant hemolysis. PMID- 21793893 TI - Granular cell tumor on the sole of a child: a case report. AB - Granular cell tumor, also known as Abrikossoff tumor, is a rare infrequent neoplasm of unclear etiology which has been rarely described in children. Involvement of the feet is extremely rare. We report a 7-year-old boy presenting a granular cell tumor on the sole. PMID- 21793894 TI - A novel method for calculating the volume of hemangiomas. AB - Accurately measuring the size of infantile hemangiomas is critical for objectively quantifying their growth, involution, and treatment response. Volumetric measurements are particularly appropriate because hemangiomas tend to mark out their territory early on and then grow and involute volumetrically. To our knowledge, only two publications have proposed bedside methods for measuring hemangioma volume. In these two publications, the authors modeled hemangiomas as perfect spheres or half-spheres, but many hemangiomas more closely approximate ellipsoids, with each of their axes in three dimensions having different, rather than equal, lengths. We present an alternative bedside method for calculating hemangioma volume, using a formula derived with calculus requiring only three bedside measurements using a disposable paper tape measure. PMID- 21793895 TI - Bullous lupus in an 18-year-old. PMID- 21793896 TI - Matrix metalloproteinases and bullae in pediatric Henoch Schonlein purpura. PMID- 21793897 TI - Melatonin alleviates cadmium-induced cellular stress and germ cell apoptosis in testes. AB - Increasing evidence demonstrates that melatonin has an anti-apoptotic effect in somatic cells. However, whether melatonin can protect against germ cell apoptosis remains obscure. Cadmium (Cd) is a testicular toxicant and induces germ cell apoptosis. In this study, we investigated the effects of melatonin on Cd-evoked germ cell apoptosis in testes. Male ICR mice were intraperitoneally (i.p.) injected with melatonin (5 mg/kg) every 8 hr, beginning at 8 hr before CdCl(2) (2.0 mg/kg, i.p.). As expected, acute Cd exposure resulted in germ cell apoptosis in testes, as determined by terminal dUTP nick-end labeling (TUNEL) staining. Melatonin significantly alleviated Cd-induced testicular germ cell apoptosis. An additional experiment showed that spliced form of XBP-1, the target of the IRE-1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an endoplasmic reticulum (ER) chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly increased testicular eIF2alpha and JNK phosphorylation, indicating that the unfolded protein response (UPR) pathway was activated by CdCl(2). Interestingly, melatonin almost completely inhibited Cd induced ER stress and the UPR in testes. In addition, melatonin obviously attenuated Cd-induced heme oxygenase (HO)-1 expression and protein nitration in testes. Taken together, these results suggest that melatonin alleviates Cd induced cellular stress and germ cell apoptosis in testes. Melatonin may be useful as pharmacological agents to protect against Cd-induced testicular toxicity. PMID- 21793898 TI - Chemotherapy and targeted agents for colorectal cancer in a real-life setting anticipate guidelines: the COLCHIC cohort study. AB - Introduction of new agents for the treatment for colorectal cancer (CRC) has been accompanied by the publication of guidelines. The COLCHIC cohort was set up to evaluate CRC treatment practices and the use of these innovative and expensive agents. Patients initiating CRC treatment at the Bordeaux teaching hospital between 1 March 2005 and 1 March 2006 were identified, and treatment courses from 1 March 2005 to 31 December 2006 were studied; 192 patients were included, 188 with analysable data: 43 patients initiated 51 courses for non-metastatic cancer, 153 initiated 366 courses for metastatic cancer, eight patients initiated courses for both non-metastatic and metastatic cancer. Most treatments were used for indications found in guidelines published during the study (83.9%). Of the others, nearly half were approved in guidelines published subsequently. In this teaching hospital, prescribing practice was generally in line with recommendations, with an anticipation of future guidelines. This mostly concerned monoclonal antibodies, which were new at the time of the study. PMID- 21793899 TI - Novel intraocular and systemic absorption drug delivery and efficacy of N acetylcarnosine lubricant eye drops or carcinine biologics in pharmaceutical usage and therapeutic vision care. AB - The latest estimates of the World Health Organization indicate that there are 161 million visually impaired individuals worldwide, 37 million of whom are blind, with a yearly increase of 1-2 million. The scientists developed and patented the lubricant eye drops formulated as 1%N-acetylcarnosine prodrug of l-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in an ocular drug delivery system. Carcinine is suitable for the systemic administration (per oral) for ophthalmic therapeutic indications. The HPLC analysis was developed to search the pathways of ocular metabolic activities of 1%N-acetylcarnosine and the bioactivation of this drug molecule promoting transcorneal uptake of l-carnosine in the aqueous humor. A meta analysis of phase 2 randomized double-blind placebo-controlled clinical trial data was conducted. The intraocular absorbed l-carnosine demonstrated a number of pharmacological mechanisms of prevention and reversal of cataracts. Results of systemic absorption of l-carnosine provide tuberomammillary activation that regulates neuronal functions such as hypothalamic control promoting sensory input in the primary vision perceptual pathway. The parabulbar, subconjunctival, and intravitreal injection of carcinine with most of the vehicle removed is not toxic to intraocular structures, reduces postoperative intraocular inflammation, is a potentially useful tool in the treatment of proliferative vitreoretinopathy as well as considered as the antiapoptotic drug for the protection of photoreceptor cells from oxidative light-induced stress. The discovery of naturally occurring carnosine derivatives introduces N-acetylcarnosine and carcinine as effective medical treatment for sight-threatening eye disorders. PMID- 21793900 TI - Evidence for the involvement of the serotonergic, noradrenergic, and dopaminergic systems in the antidepressant-like action of riparin III obtained from Aniba riparia (Nees) Mez (Lauraceae) in mice. AB - Previous work has shown that intraperitoneal administration of riparin III (ripIII) reduces immobility time in the forced swimming test (FST), which suggests potential antidepressant activity. As the mechanism of action is not completely understood, this study is aimed at investigating the antidepressant like action of ripIII. Following intraperitoneal administration of ripIII at doses of 25 and 50 mg/kg, there were decreases in the immobility time in the FST and tail suspension test without accompanying changes in ambulation (data not shown). The pretreatment of mice with sulpiride (50 mg/kg, i.p.), prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), and p-chlorophenylalanine (PCPA, 100 mg/kg, i.p. for, four consecutive days) significantly prevented the anti immobility effect of ripIII in the FST. On the other hand, the anti-immobility effect of ripIII (50 mg/kg, v.o.) was not altered by pretreatment of mice with SCH23390 (15 MUg/kg, i.p.) Furthermore, ripIII potentiated the sleeping latency and sleeping time of the pentobarbital-induced sleeping time test and also potentiated apomorphine (16 mg/kg, i.p.)-induced hypothermia in mice. In conclusion, the present study provides evidence that the antidepressant-like effect of ripIII is dependent on its interaction with the serotonergic, noradrenergic (alpha1- and alpha2- receptors), and dopaminergic (dopamine D2 receptors) systems. PMID- 21793901 TI - Late-onset Leclercia adecarboxylata bacteraemia in a premature infant in the NICU. AB - Late-onset sepsis is a unique entity in the neonatal intensive care unit (NICU), as organisms involved are, by definition, nosocomial. As such, a limited number of microbes are characteristically involved. Leclercia adecarboxylata is a gram negative bacillus rarely cultured in a clinical context, with the few published cases primarily involving immunocompromised adults. We present an ex-26-week newborn girl who developed late-onset sepsis with Leclercia adecarboxylata bacteraemia in the NICU. The infection was successfully treated with gentamicin and cefotaxime. This is the fifth paediatric report of Leclercia adecarboxylata infection, and the first in a neonate. The case raises the possibility that prior courses of antibiotics may have predisposed this individual to a rare infection essentially limited to immunocompromised individuals. CONCLUSION: Leclercia adecarboxylata is a rare infection, particularly in immunocompetent individuals. In neonates, the clinical course can be good with timely initiation of appropriate antibiotics. PMID- 21793902 TI - Endoscopic papillary large balloon dilation in Billroth II gastrectomy patients with bile duct stones. AB - BACKGROUND AND AIMS: Patients with Billroth II (B-II) gastrectomy present technical difficulties during endoscopic stone removal due to altered anatomy. Although endoscopic sphincterotomy alone or endoscopic balloon dilation alone has been used for removal of bile duct stones in patients with B-II gastrectomy, the results are not satisfactory. The aim of this study was to evaluate the efficacy and safety of endoscopic papillary large balloon dilation (EPLBD) for removal of bile duct stones in patients with B-II gastrectomy. METHODS: Twenty-six patients (20 men and six women; median age 72 years) with bile duct stones and a history of B-II gastrectomy were enrolled. After cannulation, limited endoscopic sphincterotomy was performed. Then, balloon dilation (balloon size, 10-15 mm) was performed and stones were removed conventionally or via mechanical lithotripsy. Successful stone removal and complications were evaluated. RESULTS: In all cases, stones were successfully removed. The median number of sessions for complete stone removal was one (range 1-3). Stone removal by mechanical lithotripsy was achieved in three patients (11.5%). There were no significant complications, such as bleeding, pancreatitis, or perforation. CONCLUSIONS: Endoscopic papillary large balloon dilation is an effective and safe method for removal of bile duct stones. We suggest consideration of this technique for removal of bile duct stones in patients with B-II gastrectomy. PMID- 21793903 TI - Transition from hepatic steatosis to steatohepatitis: unique microRNA patterns and potential downstream functions and pathways. AB - BACKGROUND AND AIM: This study aimed to explore the unique miRNA responsible for transition from hepatic steatosis to steatohepatitis and to investigate the functions and pathways of their downstream targets. METHODS: Microarray and stem loop reverse transcription-polymerase chain reaction were utilized to detect dysregulated miRNA in a rat model. SAM, PAM and clustering analysis were jointly applied to calculate significantly changed miRNA. The targets of miRNA were predicted through web server "microrna." The functions and pathways of those predicted genes were analyzed using databases of Gene Ontology and KEGG by the web server "DAVID." RESULTS: Fourteen upregulated and six downregulated miRNA were selected as an accurate molecular signature in distinguishing hepatic steatohepatitis from steatosis. Through Gene ontology, 499 and 287 enriched functional categories were found for the target genes of upregulated and downregulated miRNA, including ion homeostasis, protein transport and so on. Through KEGG, 46 and 41 enriched pathways were collected for the target genes of upregulated and downregulated miRNA, including apoptosis, fatty acid metabolism and so on. Analysis of common target genes of all downregulated miRNA revealed potential involvement of ion transport and the membrane structure in steatohepatitis. CONCLUSION: We reported the dysregulated miRNA in transition from hepatic steatosis to steatohepatitis and showed potential clinical application in disease differentiation. This study provided data reservoir for miRNA exploration and revealed novel disease-specific Gene Ontology functions and KEGG pathways such as uncoupling-protein-guided membrane change. Our data contributes to further researches on the pathogenesis and treatment of non alcoholic steatohepatitis. PMID- 21793904 TI - Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study. AB - BACKGROUND AND AIM: The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. METHODS: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. RESULTS: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4). CONCLUSIONS: Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups. PMID- 21793905 TI - Safety evaluation of self-expanding metallic biliary stents eluting gemcitabine in a porcine model. AB - BACKGROUND AND AIM: Palliative biliary decompression by metal stent is the treatment of choice for unresectable malignant biliary obstruction; however, conventional stents provide only mechanical palliation and exert no anti-tumor effects. Gemcitabine (GEM) has been reported to be more effective in unresectable pancreatic cancer and biliary cancer compared with other chemotherapeutic drugs. We evaluated the safety of a GEM-eluting stent by analyzing histologic responses of the porcine bile duct. METHODS: Stents containing GEM (0%, 10%, 15%, and 20% [w/v]) were surgically inserted into bile ducts of pigs (each group, n = 2). The animals were euthanized after 4 weeks, and the stented bile duct segment underwent gross and microscopic examination. Laboratory assay was performed for aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, and gamma-glutamyl transferase (gamma-GTP). RESULTS: Moderate to severe inflammation was observed in the bile ducts in contact with stents containing 15 and 20% GEM, compared with no inflammation with 0% GEM and mild inflammation with 10% GEM. Fibrous reactions observed in the submucosal layer did not differ among groups. Transmural necrosis and perforations were not observed in any animal. No abnormal laboratory test findings were directly caused by GEM. CONCLUSION: Our newly developed GEM eluting stents can be used safely in normal bile ducts. Our results indicated that 10% GEM produced mild histologic changes in the stented segment and adjacent tissue; this concentration may be appropriate for clinical application. PMID- 21793906 TI - Early on-treatment predictions of clinical outcomes using alpha-fetoprotein and des-gamma-carboxy prothrombin responses in patients with advanced hepatocellular carcinoma. AB - BACKGROUND AND AIM: The clinical utility of alpha-fetoprotein (AFP) and des-gamma carboxy prothrombin (DCP) as a predictor of treatment outcome in patients with advanced hepatocellular carcinoma (HCC) receiving hepatic artery infusional chemotherapy (HAIC) or concurrent chemoradiation therapy (CCRT) has been poorly defined. METHODS: Between January 2003 and December 2007, we enrolled 127 treatment-naive patients who received HAIC (n = 60) or CCRT (n = 67) as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 20% from the baseline level. RESULTS: AFP responders showed significantly better overall survival (OS) than non-responders among patients with HAIC (median 17.3 vs 6.4 months, P < 0.001) and with CCRT (median 17.6 vs 8.7 months, P = 0.014). DCP responders in the CCRT group also showed significantly better progression-free survival (PFS) than non-responders (median 9.2 vs 3.1 months, P < 0.001). Multivariate Cox regression analyses showed that AFP response was independently predictive of OS in both groups (P = 0.009 in HAIC and P = 0.008 in CCRT) whereas DCP only predicted PFS in patients with CCRT (P = 0.015). CONCLUSIONS: Early on-treatment AFP response was predictive of OS in treatment-naive patients with advanced HCC receiving HAIC and CCRT as an initial treatment modality. Furthermore, DCP response was useful for predicting PFS in patients with CCRT. PMID- 21793907 TI - Comparison of patients of chronic laryngitis with and without troublesome reflux symptoms. AB - BACKGROUND AND AIM: Little is known about the difference between patients of chronic laryngitis with and without troublesome reflux symptoms. The aim of this study was to compare the clinical characteristics and response to acid suppression between patients of chronic laryngitis with and without troublesome reflux symptoms. METHODS: Consecutive patients with chronic laryngitis were enrolled. The frequency and severity of reflux and laryngeal symptoms were scored. All the patients underwent laryngoscopy, esophagogastroduodenoscopy and 24-h multichannel intraluminal impedance and pH monitoring before receiving rabeprazole 10 mg b.i.d. for 3 months. Mild typical reflux symptoms (heartburn or regurgitation) occurring >= 2 days/week or moderate/severe symptoms occurring >= 1 day/week were defined as troublesome reflux symptoms. RESULTS: Compared to patients without troublesome reflux symptoms, those with troublesome reflux symptoms were older and had more episodes of acid and liquid gastroesophageal reflux (GER) and acid and weakly acidic laryngopharyngeal reflux (LPR). They also had higher percentages of both bolus exposure time and acid exposure time of GER and LPR. Patients with troublesome reflux symptoms responded to acid suppression more often at 12 weeks (67.3% vs 20.9%, P < 0.001) and more rapidly (40.8% vs 14.0%, 3 weeks after the start of acid suppression; P = 0.004) compared to those without. CONCLUSION: Difference in reflux profile of GER and LPR between patients with and without troublesome reflux symptoms could partly explain the discrepancy of response to acid suppression among patients with chronic laryngitis. Acid suppression therapy may provide limited therapeutic benefits to patients of chronic laryngitis without troublesome reflux symptoms. PMID- 21793908 TI - Laparoscopic splenectomy with interferon therapy in 100 hepatitis-C-virus cirrhotic patients with hypersplenism and thrombocytopenia. AB - BACKGROUND AND AIM: We intended to determine whether laparoscopic splenectomy (Lap-Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)-cirrhotic patients with thrombocytopenia caused by hypersplenism. METHODS: From December 2004 to August 2008, 100 cirrhotic patients (54 men and 46 women) underwent Lap-Sp for a clinical application of interferon therapy. All the patients were Child-Pugh class A or B with thrombocytopenia (average platelet count, 56 * 10(3) /mm(3)). The HCV genotype was type 1 in 80 patients and type 2 in 20 patients. RESULTS: Pure laparoscopic or hand-assisted laparoscopy was performed in 78 and 22 patients, respectively, without mortality. Conversion to open surgery was not required in any of the patients. The platelet counts improved (mean platelet count 172 * 10(3) /mm(3) 1 month after surgery) and interferon (IFN) therapy was started in 97 patients. In this study period, 36 patients obtained a sustained virologic response. Eight patients discontinued IFN therapy because of depression, neutropenia or other reasons. CONCLUSIONS: Lap-Sp permits most patients with HCV cirrhosis and hypersplenism to receive sufficient IFN therapy. Therefore, Lap-Sp can become a strong supportive surgery for cirrhotic patients who require antiviral therapy. PMID- 21793909 TI - Hepatocellular carcinoma with duodenal invasion and metastasis. AB - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the leading cause of cancer related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments. METHODS: Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records. RESULTS: Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months). CONCLUSIONS: Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities. PMID- 21793910 TI - Colorectal cancer screening practise is influenced by ethnicity of medical practitioner and patient. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) screening improves survival and requires appropriate recommendation by general practitioners (GPs). Screening practises may be influenced by barriers related to ethnicity and training. METHODS: A mail survey assessed GPs' practises and the barriers towards CRC screening. The association of screening practises and demography, including GP ethnicity, medical training and practise characteristics, were evaluated. RESULTS: Of 212 GPs (median age 54 years, 73% men, 27% Caucasian, 38% foreign graduates), 87% agreed that fecal occult blood test (FOBT) screening improved survival in the average-risk patient. Considerable variations existed in the starting age (40-49 years: 31%; 50 years: 65%) and frequency (1-2 years: 77%; 3-5 years: 22%) of screening. FOBT was used for indications other than screening: anemia (59%), altered bowel habits (54%), abdominal pain (24%), and rectal bleeding (23%), and these were significantly more frequent in Asian GPs independent of medical training. GPs were less likely to recommend screening to immigrants, and most reported that immigrants were less likely to participate. More Asian and Middle Eastern GPs reported a major barrier with FOBT inaccuracy compared with Caucasian GPs (22% vs 9%, P = 0.03; and 27% vs 9%, P = 0.03, respectively). CONCLUSIONS: Considerable differences existed in GPs' CRC screening practises. Indications for use of FOBT and the subsequent investigation of a positive FOBT also varied according to GPs' ethnicity, independent of medical training. Patient's ethnicity and associated language and cultural barriers may affect screening uptake, which may negatively affect the health of immigrants. Resources and culture-specific interventions are recommended to improve overall screening participation. PMID- 21793911 TI - Long-term cohort study of chronic hepatitis C according to interferon efficacy. AB - BACKGROUND AND AIM: We investigated the prognosis of patients with C-viral chronic liver disease (C-CLD) according to the efficacy of interferon (IFN) therapy in a long-term retrospective cohort study. METHODS: Of 721 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005, 577 were treated with IFN, and 221 of these patients achieved sustained virological response (SVR) with a follow-up period of 9.9 +/- 5.3 years. RESULTS: The annual rate of HCC development was 2.71%/year, 2.31%/year, and 0.24%/year in untreated, non-SVR, and SVR patients, respectively. Multivariate Cox proportional regression analysis showed that the risk of HCC development was significantly lower in SVR patients than in untreated or non-SVR patients; moreover, this risk was similar in non-SVR patients and untreated patients. The annual mortality rate in overall death was 3.19%/year, 1.98%/year, and 0.44%/year in untreated, non-SVR, and SVR patients, respectively. Multivariate Cox proportional hazards regression analysis showed that the SVR status reduced the risk ratio for overall death to 0.173, whereas the non-SVR status did not significantly reduce the risk ratio. CONCLUSIONS: The risk ratio of overall death and HCC development was significantly reduced in SVR patients, whereas no significant reduction was found in non-SVR patients in a long-term cohort study. PMID- 21793912 TI - Resistance of Helicobacter pylori strains to antibiotics in Korea with a focus on fluoroquinolone resistance. AB - BACKGROUND AND AIM: New regimens, including those with new fluoroquinolones, have been developed to overcome the antibiotic resistance of Helicobacter pylori. We aimed to assess the antibiotic resistance rates, as well as the molecular mechanisms of fluoroquinolone resistance, of the clinical isolates obtained in Korea. METHODS: The minimal inhibitory concentration (MIC) values of ciprofloxacin, amoxicillin, clarithromycin, metronidazole and tetracycline were determined by the agar dilution method for 185 treatment-naive Helicobacter pylori isolates. The resistant strains were evaluated for the presence of point mutations in the quinolone resistance-determining region (QRDR) of the gyrA and gyrB genes by direct nucleotide sequencing. RESULTS: Twenty-nine (29/185, 15.7%) of the strains were found to be resistant to ciprofloxacin. The resistance rates to amoxicillin, clarithromycin, metronidazole and tetracycline were 2.2% (four of 185), 10.8% (20 of 185), 30.3% (56 of 185) and 0.5% (one of 185), respectively. The most common mutations in the H. pylori gyrA gene were found at codons corresponding to Asp87 (16/29, 55.2%) and Asn91 (10/29, 34.5%). CONCLUSIONS: Primary H. pylori resistance to ciprofloxacin occurred at a high frequency. The fluoroquinolone resistance is most likely mediated through amino acid point mutation in the gyrA gene at Asn87 and Asp91. PMID- 21793913 TI - DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway. AB - BACKGROUND AND AIM: 7-Carboxymethyloxy-3',4',5-trimethoxy flavone (DA6034), a synthetic derivative of eupatilin, has a protective effect on gastric mucosa against various ulcerogens, and is currently in the phase III clinical trial in the treatment of peptic ulcer disease. Cell migration and/or growth plays a role in the repair process of gastric ulcer, so this study investigated the effect of DA6034 on the movement and proliferation of gastric epithelial cells and its associated signaling pathway. METHODS: The migration of AGS or SNU484 human gastric epithelial cells was shown by scratch-induced wound healing and transwell assays, and the proliferation of the cells was assessed by FACS and proliferation assays. RESULTS: Treatment of DA6034 promoted the migration of gastric epithelial cells in a concentration-dependent manner. DA6034 treatment facilitated the phosphorylation of mTOR that led to an increase in the activity of S6K1, indicating its ability to activate mTOR and S6K1. Rapamycin aborted the wound healing effect of DA6034, which supported the role of mTOR activation in the wound-healing process. In addition, DA6034 treatment increased PI3K-dependent Akt phosphorylation, which was necessary for the enhancement of cell migration. DA6034, however, did not stimulate the proliferation of gastric epithelial cells, being consistent with no activation of ERK1/2 by the agent. CONCLUSIONS: DA6034 has the ability to heal scratch wounds, which may result from an increase in gastric epithelial cell migration as mediated by PI3K-Akt-dependent activation of mTOR and S6K1. Our finding may be of help in understanding the molecular basis of the anti-ulcer effect of DA6034. PMID- 21793915 TI - Effect of melatonin and misoprostol on bacterial translocation in portal hypertensive rats. AB - BACKGROUND AND AIM: Portal hypertension is the main complication of cirrhosis and it is responsible for its most common complications. Bacterial translocation increases the morbidity and mortality rates in patients with portal hypertension. We aimed to investigate the effects of melatonin and misoprostol on bacterial translocation induced by portal hypertension. METHODS: We established four groups, each containing eight rats. Except for the control and sham groups, the animals in the other groups (treatment groups) received misoprostol or melatonin for 3 days after the first operation. In the sham group, a laparotomy was carried out and only the portal vein was dissected. Calibrated portal vein ligation was carried out in the other groups. All animals were given 10(10) Escherichia coli by orogastric intubation 12 h before sampling. Seventy-two hours after the first operation, mesenteric lymph node and blood samples were obtained and cultured. Two cc blood samples were obtained for a polymerase chain reaction study. A piece of terminal ileum was also sampled for histopathologic examination. RESULTS: Mesenteric lymph node and blood cultures of all control animals were positive for microbiological growth, and polymerase chain reaction results were positive in seven of the eight rats. Histopathologically, edema, vasodilatation and inflammatory cell infiltration were found to be less in the other groups in comparison to the control group. The incidence of bacterial translocation was decreased in all treatment groups as compared to the control group. CONCLUSIONS: In this study, bacterial translocation occurred in portal hypertension. Melatonin and misoprostol reduced the incidence of bacterial translocation in portal hypertensive rats. PMID- 21793914 TI - Increasing the duration of dual amoxicillin plus omeprazole Helicobacter pylori eradication to 6 weeks: a pilot study. AB - BACKGROUND AND AIM: Helicobacter pylori infections have become increasingly difficult to treat as antimicrobial resistance has increased. The aim of this study was to test the hypothesis that a 6-week dual regimen of amoxicillin 1 gm and omeprazole 20 gm therapy b.i.d. would cure at least 90% of treatment-naive H. pylori infections. METHODS: This was an open-label prospective pilot study in which treatment-naive subjects with active H. pylori infection (positive by two tests) received dual amoxicillin 1 g and omeprazole 20 mg, b.i.d. daily for 6 weeks. Success was accessed by urea breath test 4-6 weeks later. A tentatively effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as unacceptable. RESULTS: Sixteen patients were included in the study (14 men, two women) with an average age of 49 years. At 16 patients, the prespecified stopping rule of six treatment failures was achieved (i.e. the 95% confidence interval excluded achieving the required 90% success rate even if 50 patients were entered). As per protocol, enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 62.5% (95% confidence interval, 35-84%). Compliance was greater than 99%. Five patients (31%) reported side-effects, all of which were mild and none interrupted therapy. CONCLUSION: Despite the theory and pre-existing data from Japan, in the USA, prolonging the duration of dual amoxicillin-PPI therapy did not improve treatment outcome in 90% or more of our patients. PMID- 21793916 TI - Narrow-band imaging in the colon: limitations and potentials. AB - Narrow-band imaging (NBI) is a new endoscopic technology that highlights surface structures and superficial mucosal capillaries during colonoscopy at a single push of a button. NBI has a high sensitivity and specificity for differentiating neoplastic and non-neoplastic polyps by means of mucosal and capillary patterns. It is also useful in determining the invasion depth of early colorectal cancers and evaluating free margins after endoscopic resection. However, it has not been shown to improve the adenoma detection rate compared with white-light endoscopy. Although narrow-band imaging is now available commercially, its role in routine clinical practice during colonoscopy is not well defined. The difficulties in interpreting results partly relate to different NBI nomenclatures used in classifying colonic adenomas and their lack of standardization. Future research should focus on establishing a reliable NBI nomenclature for capillary patterns, defining the learning curve and interobserver variation, and validating the effectiveness of NBI in routine colonoscopy. PMID- 21793917 TI - Continuous proton pump inhibitor treatment decreases upper gastrointestinal bleeding and related death in rural area in Japan. AB - BACKGROUND AND AIMS: Proton pump inhibitors (PPI) have been rarely used for prevention of upper gastrointestinal bleeding (UGIB) induced by non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin in Japan. The increased incidence of UGIB in the aged society is becoming a serious problem. The aim of this study was to retrospectively evaluate whether PPI can prevent UGIB. METHODS: We examined records of 2367 patients (aged 67.9 +/- 15.1 years, male 1271) attending the only hospital serving the rural area, with little population movement. We investigated the correlation between the frequency of usage of medicine (PPI, histamine 2 receptor antagonists [H2RA], NSAIDs, aspirin) and incidence of UGIB over 12 years. UGIB was defined as cases with hematemesis and/or melena and definite bleeding at upper gastrointestinal endoscopy. The annual incidence of UGIB of inhabitants (16,065 +/- 375.3 persons/year) was evaluated. The frequency of usage of medicine was compared with the total number of patients prescribed any medication (1080 +/- 33.2 persons/year). RESULTS: The frequency of PPI usage has increased significantly 4.6%->30.8% (P < 0.05). NSAIDs and aspirin usage increased significantly in the latter half of the survey period (P < 0.05). The annual incidence of UGIB significantly decreased 160.8 ->23.6/100,000 inhabitants per annum (P <= 0.05) due to widespread use of PPI. No patients died due to UGIB after 2006. The incidence of UGIB and the prevalence of PPI usage were found to have a negative correlation (r = -0.804, P = 0.0016). CONCLUSIONS: By widespread use of PPI, UGIB and related death has declined significantly. This survey showed that continuous PPI treatment decreases UGIB and related death in community medicine. PMID- 21793918 TI - Grading of tarsal conjunctiva of young adults in Malaysia. AB - BACKGROUND: The monitoring and assessment of the upper tarsal conjunctiva can be enhanced by the use of a grading scale. The aim of this study was to categorise the appearance of normal tarsal conjunctiva among young adults in Malaysia using the Institute for Eye Research grading scale and to investigate inter- and intra observer agreement. METHODS: The appearance of the upper tarsal conjunctiva of 416 non-contact lens wearing subjects aged between 19 to 24 years was assessed by two separate observers for roughness and redness in three separate zones using the Institute for Eye Research grading scale. The average grade for each zone and overall grade for roughness and redness were calculated. Inter- and intra observer agreements were analysed. RESULTS: Subjects were categorised for ethnicity and the roughness and redness were calculated. No significant differences were found between Malay and Chinese eyes (p > 0.05). The average grades for the upper tarsal conjunctiva redness and roughness were 0.90 +/- 0.25 and 0.86 +/- 0.43, respectively. Significantly higher roughness scores were found in zone 1 compared to the other two zones (p = 0.03). Significant association was also found between tarsal conjunctiva redness and roughness (Spearman rho= 0.45, p < 0.001). Correlation between redness and roughness with age (p = 0.48, p = 0.65) and gender (p = 0.30, p = 0.79) were not significant. Only 2.2 per cent of subjects had scores higher than 2.0 for roughness or redness. Inter- and intra observer analysis showed good agreement between two observers during the study. CONCLUSION: The roughness and redness of normal tarsal conjunctiva among young adults in Malaysia were found to be less than two units. Results of this study might be beneficial in clinical trials using contact lenses where changes in the tarsal conjunctiva are commonly used as an outcome measure. PMID- 21793920 TI - Cerebral embolic exposure during transfemoral and transapical transcatheter aortic valve replacement. AB - AIM OF STUDY: To characterize the cerebral embolic exposure during transfemoral (TF) and transapical (TA) TAVR. METHODS: To detect cerebral embolic events during TAVR, intraoperative neuromonitoring using transcranial Doppler (TCD) was utilized in 28 patients (Edwards SAPIEN valve TF n = 18, TA n = 10). High intensity transient signals (HITS) reflective of embolic events were recorded. RESULTS: The mean age was 83.4 +/- 7.4 years. The Society of Thoracic Surgeons predicted risk of mortality score was 11.7 +/- 2.9. The total number of HITS during TAVR was not significantly different between the TF and the TA groups, respectively (375 +/- 301, 440 +/- 283, p = 0.58). The highest number of HITS occurred during wire manipulation in the arch and valve insertion (TF, 80 +/- 110, 107 +/- 81; TA, 120 +/- 80, 92 +/- 80). In the TF group only, severe arch calcification was associated with significantly higher number of HITS both in total number of HITS (Grade I/II, 278 +/- 71; Grade III/IV, 568 +/- 479, p = 0.05) and during wire manipulation in the arch and valve insertion (Grade I/II, 140 +/- 46, Grade III/IV 294 +/- 239, p = 0.04). CONCLUSIONS: Highest cerebral embolic exposure occurred during wire manipulation in the arch and valve insertion in both the TF and TA groups. Arch calcification appears to be associated with increased embolic risk, specifically in the TF approach. Understanding of the mechanism of cerebral embolism is needed for future strategies of cerebral protection during TAVR. PMID- 21793921 TI - Cardiac myxomas: experience over one decade. AB - BACKGROUND: This single-center study reviews our experience with cardiac myxomas over the past decade. METHODS: Sixty-two patients (23 male) with median age 38 years (range: 8 to 69 years) underwent excision of primary or recurrent cardiac myxomas between 2000 and 2009. Patients were evaluated with echocardiography preoperatively and annually postoperatively. Follow-up is current for all survivors (range 13 months to 10 years). RESULTS: Fifty-two patients had left atrial myxomas, seven right atrial, two biatrial, and one right ventricular. Three cases were familial. Maximum number of myxomas in a single patient was four. Symptom duration ranged from two to eight months. Two early deaths were due to low cardiac output and embolic cerebrovascular accident; one late death was due to a noncardiac cause. Actuarial survival was 96.8 +/- 1.8% at 10 years. Most patients were asymptomatic following surgery. No sporadic, multiple, or biatrial myxomas recurred. Recurrence occurred in two familial cases, both with single, left atrial myxoma. Freedom from reoperation was 98.4 +/- 1.3% at five years and 96.8 +/- 1.8% at 10 years. CONCLUSIONS: Biatrial involvement or multiplicity of myxomas does not mandate recurrence. Surgical excision has excellent overall survival and freedom from reoperation rates, but annual follow-up including echocardiographic surveillance is recommended as familial cases tend to recur. PMID- 21793922 TI - Survival and durability of mitral valve repair surgery for degenerative mitral valve disease. AB - AIM OF THE STUDY: To evaluate the results after standardized techniques of mitral valve repair (MVr) for treatment of degenerative mitral regurgitation (MR) and to analyze risk factors for late outcomes. METHODS: Two hundred and sixty-one patients (mean age 63 +/- 12 years) underwent MVr between January 1999 and January 2010 for degenerative MR. In the last five years, all repair techniques were performed routinely using annuloplasty prosthetic ring, with or without quadrangular or triangular resection of posterior leaflet and/or edge-to-edge technique as always indicated by intraoperative transesophageal echocardiography. Mean follow-up (99% complete) was 54 +/- 38 (range, 6 to 137) months. RESULTS: Operative mortality was 0.8% (2/261), 10-year actuarial survival 89%+/- 3%. At 10 years of follow-up freedom from cardiac death was 94%+/- 2.6%, from reoperation 95%+/- 2.4%, from thromboembolism 96%+/- 2.1%, and from endocarditis 100%. Independent predictor of late all-causes mortality was advanced age at operation (71 +/- 10 years vs. 62 +/- 12 years, p = 0.0068). Late progression to moderate or severe MR was observed in 12/256 patients (4.7%). Independent predictor of late progression to moderate or severe MR was annuloplasty without the use of prosthetic ring (p = 0.04). Reoperation was required in six patients (2.3%). Follow-up echocardiography showed improvement of MR, left ventricular end diastolic and end-systolic diameters, left atrial diameter, and systolic pulmonary artery pressure (p < 0.0001 for all comparisons with preoperative values). CONCLUSIONS: MVr is a low-risk, durable surgical procedure. Standardized techniques, with the routine use of prosthetic ring, improve late results. PMID- 21793923 TI - Repair of intervalvular fibrous body rupture during aortic valve replacement. AB - The intervalvular fibrosa, the structure that connects the mitral and the aortic valves, can be injured during aortic valve replacement. Although this complication is rare, it may require complex and extensive repair. Herein, we describe management of a damaged aortic-mitral curtain and fibrous body during tissue aortic valve replacement in a patient with mixed connective tissue disorder. A "U" suture repair combining an external and internal reinforcement repair technique via the aorta, without explanting the prosthetic valve technique, is described. The purpose of using the "externalized" buttressed U stitch was to obliterate any residual cavity and to assure control of hemorrhage externally. Repair of damaged fibrous body during aortic valve replacement (AVR) is challenging. We managed this difficult situation in a satisfactory surgical approach without explanting the aortic prosthesis. PMID- 21793924 TI - Atrial myxoma and bone changes: a paraneoplastic syndrome? AB - Atrial myxomas are the most common benign tumors of the heart and are difficult to diagnose due to a wide variety of presenting symptoms. We present a patient with a five-year history of visual loss, vertigo, ataxia, tinnitus, and bone lesions that resolved after diagnosis and resection of an atrial myxoma. This case not only highlights an unusual presentation of atrial myxomas but also raises the question of whether atrial myxomas can produce paraneoplastic syndromes, including bone abnormalities. PMID- 21793925 TI - Unusual association of left ventricular diverticulum and hypertrophic cardiomyopathy in an adult. AB - A 68-year-old female with hypertrophic obstructive cardiomyopathy (HOCM), fibrous subaortic stenosis, mitro-aortic valve insufficiencies, and congenital left ventricular diverticulum (CLVD) at apical level was diagnosed after syncope. Although the association between HOCM and CLVD has been previously reported, no case has ever been disclosed in advanced adulthood. PMID- 21793926 TI - Right coronary artery aneurysm with right atrial fistula. PMID- 21793927 TI - Delayed left ventricle posterior wall rupture following mitral replacement detected by multislice CT-scan. PMID- 21793928 TI - Respective prevalence of the different carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. AB - OBJECTIVES: To determine the prevalence of mitral regurgitation (MR) in the U.S. adult population by classifying its mechanisms according to Carpentier's functional class. BACKGROUND: MR is the most common clinically recognizable valvular heart condition in the U.S. affecting 2 to 2.5 million people in 2000. A true estimate of the prevalence of MR in accordance to the functional class and etiology is unavailable. METHODS: We conducted a Medline search regarding prevalence and etiologies of MR. Etiologies were grouped by Carpentier's functional classification, and estimated prevalence numbers were projected to U.S. adult population of 200 million. Moderate-to-severe grades of MR were included. RESULTS: Carpentier type I, including congenital MR and endocarditis, has a prevalence of less than 20 per million. Myxomatous infiltration leading to mitral valve prolapse is the largest group associated with a type II mechanism with 15,000 per million prevalence. Type IIIa includes rheumatic heart disease, systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and rare infiltrative and tropical disorders. SLE and APS have a mean prevalence of 10,520 per million. Carpentier IIIb is the largest group leading to MR, which is mostly functional, and includes ischemic cardiomyopathy, left ventricular (LV) dysfunction, and dilated cardiomyopathies. The estimated prevalence of MR in ischemic cardiomyopathy is 7500 to 9000 per million, and in LV dysfunction, 16,250 per million. CONCLUSIONS: The largest number of people with MR is in type IIIb. Certain etiologies show overlap within functional classes due to multiple mechanisms of MR. We attempted to classify etiologies of MR by a functional class to determine the disease burden. PMID- 21793929 TI - Interrupted aortic arch in the adult. AB - Interrupted aortic arch (IAA) is a rare condition in infants that occurs approximately three times per million births. It is considered incompatible with life after the ductus arteriosus closes if it is not surgically corrected. A review found 37 reported cases not identified until the patient was over the age of 18, and analysis of these cases and of our own case is reported. PMID- 21793930 TI - Chylothorax complicating thoracic aortic surgery. AB - OBJECTIVE: Chylothorax is a very rare complication of patients undergoing thoracic aortic aneurysm repair. Possible mechanisms of this condition during thoracic aorta operations and current therapeutic strategies are analyzed according to our experience and thorough search of the English literature. METHODS: Current experience with chylothorax occurring during thoracic aortic surgery is analyzed in this review by collecting data retrieved from English literature research. RESULTS: Significant risk factors for postoperative chylothorax development after thoracic aorta surgical procedures are thoracic aortic reoperations and descending thoracic repairs. Various treatment modalities from conservative to operative intervention have been proposed. CONCLUSION: Currently, the morbidity and mortality have improved due to prompt management. Surgical intervention is needed when response to conservative treatment has failed. PMID- 21793931 TI - Surgical closure of sinus venosus atrial septal defect using a single patch- transcaval repair technique. AB - OBJECTIVE: We would like to share our experience of surgical repair of sinus venosus atrial septal defect (ASD) using a simple "transcaval repair technique." METHOD: Between January 2007 and October 2010, 48 consecutive patients of sinus venosus ASD underwent surgical repair using transcaval repair technique at our institute. Their ages ranged from 5 to 15 years and male to female ratio was 1.6:1. The principles of the technique were longitudinal incision over the lateral aspect of superior vena cava (SVC) at the entry point of anomalous right pulmonary veins, use of a single autologous untreated pericardial patch, and finally closure of the caval incision in such a way that the patch gets sandwiched between two caval lips. RESULTS: All 48 patients came off cardiopulmonary bypass in sinus rhythm. The average pressure gradient across the patch was 3 mmHg. Immediate postoperative electrocardiograms and echocardiograms showed all patients were in sinus rhythm with no residual shunt and no pulmonary or systemic venous obstruction respectively, except in one patient who required SVC augmentation. The follow-up was done at three months (100%), one year, and two years. All patients were asymptomatic and their electrocardiograms and transthoracic echocardiograms revealed sinus rhythm, no residual shunt, and no obstruction to systemic or pulmonary venous drainage, respectively. There was no early or late mortality. CONCLUSION: We conclude that this technique is safe and simple for the repair of selected cases of sinus venosus atrial septal defect with partial anomalous pulmonary venous connection and it preserves the sinoatrial node function after surgery. PMID- 21793932 TI - A 23-year-old male with Uhl's anomaly. AB - We report a case of a 23-year-old male with Uhl's anomaly who presented with nonparoxysmal atrioventricular junctional tachycardia with Mobitz I. The patient underwent successful total cavopulmonary conversion. PMID- 21793933 TI - Aorto-left ventricular tunnel with its origin in the left sinus of valsalva associated with a single coronary artery and aortic insufficiency in an adult. AB - Aorto-ventricular tunnel is a rare congenital anomaly, an abnormal paravalvular communication between the aorta and the left ventricle. We report successful surgical correction in a patient with aorto-left ventricular tunnel associated with a single coronary artery and aortic insufficiency who had undergone surgical correction a year before. PMID- 21793934 TI - Orthotopic heart transplantation in patients with persistent left superior vena cava and agenesis of left brachiocephalic vein. AB - Persistent left superior vena cava (PLSVC) is an infrequent abnormality. Anatomical variations can be unexpectedly identified during cardiac procedures. Modifications of surgical techniques become a must during these operations, especially during orthotopic heart transplantation. We present two cases of patients with PLSVC and discuss the anatomy, embryology, diagnosis, and modifications in transplant techniques. PMID- 21793935 TI - Time-related prevalence of postoperative atrial fibrillation after stand-alone minimally invasive radiofrequency ablation. AB - BACKGROUND AND AIM OF THE STUDY: We present our results with minimally invasive surgical treatment of lone atrial fibrillation (LAF) employing a radiofrequency (RF) source through a bilateral thoracoscopy. METHODS: Between January 2007 and January 2011, 28 consecutive patients (85.7% male, mean age 67.1 +/- 9.1 years) with LAF underwent video-assisted bilateral RF ablation. Fourteen patients (50%) had paroxysmal, five (17.8%) persistent, and nine (32.2%) long-persistent LAF. All patients were followed-up according to the Heart Rhythm Society/ European Heart Rhythm Association/European Cardiac Arrhythmia Society (HRS/EHRA/ECA) and success/failure was reported as suggested by Society of Thoracic Surgeon (STS) guidelines. Mean follow-up was 27.8 +/- 8.6 months. RESULTS: Time-related prevalence of postoperative AF was 4.5% at 36 months. Success was much more likely in subjects with paroxysmal (3-year prevalence, 0%) or persistent (3-year prevalence, 0%) than long-standing persistent LAF (3-year prevalence, 8.3%). At 36 months the estimated prevalence of antiarrhythmic drugs was 11.3% (8.8 to 13.7). No major thromboembolic events were detected during the follow-up period and 36-month prevalence of Warfarin use was 15.2% (11.5 to 18.1). Finally, no patient underwent electrical cardioversion. CONCLUSIONS: This approach yielded satisfactory results with a high degree of safety. Further larger studies are necessary to confirm our findings. PMID- 21793936 TI - Long-term sequential receptor activator of NF-kappaB ligand (RANKL) and osteoprotegrin (OPG) expression in lipopolysaccharide-induced rat periapical lesions. AB - BACKGROUND: Long-term sequential expression of receptor activator of NF-kappaB ligand (RANKL) and osteoprotegrin (OPG) in lipopolysaccharide (LPS)-induced rat periapical lesions has not been studied. MATERIALS: Seventy-two 4-week-old Wistar rats were divided into eight experimental groups and one control group (eight animals in each). METHODS: Lipopolysaccharide-induced periapical lesions were produced in rats by occlusal exposure of the pulp of their lower first molars in all experimental groups but not the control group. The extent of periapical destruction was measured by radiographic imaging. RANKL and OPG mRNA were measured in all tissue sections containing the periapical lesions as well as the control group every week from week 1 to week 8 by real-time quantitative reverse transcription polymerase chain reaction. RANKL and OPG protein were determined by immunohistochemistry. Osteoclasts were identified by enzyme histochemistry. RESULTS: The sequential changes in the mRNA and protein expression of RANKL and OPG were largely compatible with the occurrence of osteoclasts histologically and enzymes histochemically, as well as the mean areas of the periapical lesions radiographically during long-term observation of the LPS-induced rat periapical lesions. CONCLUSION: This study may be the first to demonstrate the long-term RANKL and OPG expression every week from week 1 to week 8 using LPS to produce periapical infection in a Wistar rat model. The long-term findings of high expressions of RANKL and OPG further extend the potential application of the Wistar rat model for future experimental trials using RANKL inhibitor to evaluate the treatment outcome for LPS-induced rat periapical lesions. PMID- 21793937 TI - The expression and significance of MRP1, LRP, TOPOIIbeta, and BCL2 in tongue squamous cell carcinoma. AB - BACKGROUND: Multiple drug resistance protein 1 (MRP1), lung resistance protein (LRP), topoisomerase IIbeta (TOPOIIbeta) and B-cell lymphoma 2 (BCL2) are well known in the development of drug resistance in cancer cells. The aim of this study was to evaluate the relationship between them and the clinicopathological features, their expression differences between tumor tissue and experimental drug resistant model in tongue carcinoma. MATERIALS AND METHODS: Multiple drug resistance protein 1, LRP, TOPOIIbeta, and BCL2 expression was examined by immunohistochemistry in specimens from radical surgeries of 65 patients with tongue carcinoma. A cisplatin-resistance cell line, SCC-15/cisplatin, was established from a cisplatin-sensitive cell line, SCC-15. A MTT-based method was used to analyze drug potencies. Immunofluorescence was used to detect protein expression in both cell lines. Western blot was used to compare the protein expressions in specimens and SCC-15/cisplatin cells. RESULTS: We found higher expression of MRP1, LRP, and BCL2 and lower expression of TOPOIIbeta in tongue carcinoma compared with adjacent non-neoplastic tongue tissues (P < 0.05). In addition, MRP1 and TopoIIbeta expression were significantly associated with clinical stage, lymph node metastasis and histologic grade, and LRP was significantly associated with histologic grade in the samples (P < 0.05). Finally, Western blot showed that higher expressions of MRP1, LRP, and BCL2 and lower expression of TopoIIbeta were observed in SCC-15/cisplatin cells than in clinical samples. CONCLUSION: Our results suggest that the high expressions of MRP1, LRP, and BCL2 and low expression of TOPOIIbeta in patients with tongue carcinoma indicates that intrinsic drug resistance may exist in tongue carcinoma, and is associated with tumor differentiation and cisplatin resistance in tongue carcinoma. PMID- 21793938 TI - Role of cytochrome P-450 genetic polymorphisms in oral carcinogenesis. AB - Oral cancer is one of the most frequent head and neck cancers, and epidemiological studies have shown that smoking is a major risk factor in this pathology. However, as not all smokers develop oral cancer, some individuals must be more susceptible to develop this disease. This individual susceptibility has been related to different genetic variants in metabolizing enzymes. The cytochrome P-450 (CYP) family of enzymes metabolizes tobacco-related carcinogens producing reactive metabolites, which could cause DNA damage. Because of their functional role in the metabolism of tobacco-related compounds, the genetic polymorphisms found in the genes that code for CYP enzymes have been suggested to modulate oral cancer risk and contribute to individual susceptibility. In this review, we analyze and update the available evidence in the literature regarding the polymorphisms of CYP genes in relation to the susceptibility of developing oral cancer. PMID- 21793939 TI - Ex vivo demonstration of a synergistic effect of Adapalene and benzoyl peroxide on inflammatory acne lesions. AB - Acne is a chronic inflammatory disease of the pilosebaceous follicle. Thanks to its ability to reduce both comedones and inflammatory lesions, the association of a retinoid and benzoyl peroxide (BPO) is now recommended for the treatment of acne. However, the mechanisms of action of this combined therapy on inflammatory acne lesions are not well understood. In an ex vivo immunohistochemistry study, we investigated the potential synergistic modulator effect of Adapalene associated with BPO on keratinocytes proliferation/differentiation and innate immunity in inflammatory acne lesions. We demonstrated that proliferation (Ki 67), adhesion/differentiation (integrin alpha(2), alpha(3) and alpha(6)) and innate immunity (TLR-2, beta-defensin 4, IL-8) markers are overexpressed in inflammatory acne skin compared with uninvolved acne skin. Association of Adapalene and BPO significantly decreased expression of Ki67, alpha(2) and alpha(6) integrins, TLR-2, beta-defensin 4 and IL-8 in inflammatory acne skin, whereas single treatments with Adapalene or BPO alone were less effective. These results contribute to explain the comedolytic and anti-inflammatory activities of this combined therapy observed in recent clinical trials. PMID- 21793940 TI - Animal model for the study of the relationship between lower urinary tract symptoms/bladder outlet obstruction and erectile dysfunction. AB - OBJECTIVES: Lower urinary tract symptoms (LUTS) are frequently associated with erectile dysfunction (ED) in aged men, and both significantly influence quality of life. However, the mechanism linking LUTS to ED has not been clarified completely. The purpose of the present study was to establish an animal model of ED following LUTS/bladder outlet obstruction (BOO) and investigate the expression of molecules related to the cause of this type of ED. METHODS: Male Sprague Dawley rats with partial BOO were used as an experimental model of LUTS. Sham operated animals served as controls. Voiding and erectile function were evaluated 4, 8, and 16 weeks after obstruction or sham operation. The mRNA expression of penile tissue genes related to penile corporal smooth muscle relaxation was examined by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Voiding and bladder function of BOO rats were significantly worse than in sham-operated rats 4, 8, and 16 weeks after obstruction. The erectile function of BOO rats was significantly decreased compared with that of the sham-operated controls (P < 0.01) 16 weeks after obstruction, although it was similar to that of sham-operated animals at 4 and 8 weeks after obstruction. The expression of endothelial nitric oxide synthase (eNOS) mRNA was significantly decreased 16 weeks after obstruction compared with that in sham-operated rats (P < 0.01). CONCLUSION: An animal model for investigations into the association between LUTS and ED is described herein. Endothelial dysfunction induced by impaired eNOS function is likely to be involved in ED following LUTS/BOO. PMID- 21793941 TI - Can carotenoids mediate the potentially harmful effects of ultraviolet light in Silurana (Xenopus) tropicalis larvae? AB - Amphibians have recently experienced unprecedented declines in the wild, the causes of which are often difficult to mitigate. This has increased the importance of ex situ conservation; however, long-term maintenance and breeding of amphibians in captivity often has limited success. In vertebrates, vitamin D is required for calcium homeostasis and is produced endogenously in skin exposed to ultraviolet (UV) light; however, UV light can be harmful to amphibians in some instances. Carotenoids are dietary pigments that may provide protection from UV light. The aim of this study was to assess the protective capability of carotenoids against the potentially harmful effects of UV light in Silurana (=Xenopus) tropicalis larvae raised in an enhanced or limited UV environment. Tadpole survival and the size and developmental stage reached by the end of the study period were measured. Carotenoids had a significantly positive effect on developmental rate in both UV-limited and UV-enhanced environments. Larvae in an enhanced UV environment were significantly larger than those raised under a limited UV environment, irrespective of diet. Carotenoid-fed larvae tended to have increased survival in relation to those raised without carotenoids, but only in a limited UV environment. Carotenoids appear to provide little protection against UV light in this case. The role of carotenoids in amphibian health has not previously been studied. We show that carotenoid availability significantly influences development and may increase survival in S. (X.) tropicalis larvae. This finding may have important implications for recommendations made on the nutrition of amphibians in captivity. PMID- 21793942 TI - Cytotoxicity and metabolic stress induced by deoxynivalenol in the porcine intestinal IPEC-J2 cell line. AB - The digestive tract is a target for the Fusarium toxin deoxynivalenol (DON), a major cereal grain contaminant of animal and public health concern. Toxic effects of DON range from diarrhoea, vomiting and gastrointestinal inflammation to necrosis of several tissues. Following ingestion of contaminated food or feed, intestinal epithelial cells are exposed to a high concentration of ingested DON, potentially affecting intestinal functions. Pigs are considered to be the species most sensitive to DON toxicity. However, only few studies directly evaluated DON effects on porcine intestinal epithelial cells. Therefore, we used the porcine intestinal cell line (IPEC-J2) to assess short-term effects of DON on functional characteristics of the intestinal epithelial cells. The cytotoxic effect of DON on IPEC-J2 cells was evaluated by measuring the count of living cells and the activity of lactate dehydrogenase (LDH) released in the culture media at a DON concentration range from 0, 0.5, 2.5 and 10 MUm. We demonstrated that DON at concentrations of 2.5 and 10 MUm decreased significantly (p < 0.001) the cell count in a dose-dependent manner. At a concentration of 10 MUm, DON caused cell damage, including rounding of cells, autolysis and cell loss from the monolayer. The mycotoxin, DON, increased LDH release into the culture medium compared with the control value. The alterations of LDH showed a good agreement with the decrease in cell count. Deoxynivalenol decreased the l-lactate concentration in the fluid supernatant of IPEC-J2 cells at 2.5 MUm (p < 0.05) with a maximal effect at 10 MUm of DON. To determine whether the altered lactate production may be linked to alterations of energy balance, we measured cellular ATP levels in IPEC-J2 cells. A significant decrease in ATP levels was seen at 48 h in a dose dependent manner. It could be demonstrated that DON has a distinct cytotoxic effect on IPEC-J2 cells. PMID- 21793943 TI - Antifungal susceptibility of Candida albicans in biofilms. AB - Candida albicans are the most common fungi associated with biofilm-related infections. Biofilms are defined as microbial communities encased in a matrix of extracellular polymeric substances. The most important feature of biofilm growth is the high resistance to antimicrobial agents that can be up to 1000-fold greater than that of planktonic cells. This review discusses the factors affecting antifungal resistance as well as activity of mono- and combination therapy of different antifungal classes and antifungal activity in vitro and in vivo against C. albicans biofilms. PMID- 21793944 TI - Adherence to immunosuppression: a critical aspect for the success of organ transplantation. PMID- 21793945 TI - Presence of nitric oxide synthase immunoreactivity and mRNA in buffalo (Bubalus bubalis) oocytes and embryos. AB - This study examined the presence of immunoreactivity and mRNA for different nitric oxide synthase (NOS) isoforms in immature and in vitro matured oocytes and in embryos at two-, four- and eight-cell, and morula and blastocyst stages in buffalo. Oocytes obtained from slaughterhouse buffalo ovaries were subjected to in vitro maturation in TCM-199 + 10% FBS + 5 MUg/ml pFSH + 1 MUg/ml estradiol 17beta + 0.81 mm sodium pyruvate + 10% buffalo follicular fluid + 50 MUg/ml gentamycin sulphate for 24 h in a CO(2) incubator (5% CO(2) in air) at 38.5 degrees C. Following in vitro fertilization carried out by incubating them with 2 4 million spermatozoa/ml for 18 h, the presumed zygotes were cultured in mCR2aa medium containing 0.6% BSA and 10% FBS for up to 8 days post insemination. Immunofluorescence staining of NOS using antibodies that cross-reacted either with all the NOS isoforms i.e., universal (uNOS) or specifically with inducible (iNOS) or endothelial (eNOS) isoforms revealed that NOS was present in oocytes and embryos at all the stages examined. Examination of the semi-quantitative expression of NOS genes by RT-PCR revealed that the iNOS, eNOS and nNOS mRNA was present in the immature and mature oocytes and in all the embryonic stages examined. In conclusion, it was demonstrated in the present study that immunoreactivity and mRNA for different NOS isoforms was present in buffalo oocytes and pre-implantation stage embryos. PMID- 21793946 TI - Kisspeptin cells in the ovine arcuate nucleus express prolactin receptor but not melatonin receptor. AB - Melatonin is secreted at night by the pineal gland and governs the reproductive system in seasonal breeders, such as sheep. The mechanism by which melatonin regulates reproduction is not known. The circannual rhythmicity of other factors, including prolactin, is also regulated by photoperiod via changes in melatonin secretion. In sheep, plasma prolactin levels are higher in the nonbreeding season than the breeding season. Kisspeptin, synthesised by neurones in the ovine arcuate nucleus (ARC) and preoptic area, is a key regulator of reproduction through stimulation of gonadotrophin-releasing hormone secretion and its expression in the ARC is reduced during the nonbreeding season. We hypothesised that kisspeptin expression is directly, or indirectly, regulated by melatonin and/or prolactin. We first examined the expression of melatonin receptor (MTNR1A) in kisspeptin (Kiss1 mRNA) neurones in the ARC of ovariectomised (OVX) sheep using double-label in situ hybridisation. MTNR1A mRNA was not expressed by kisspeptin neurones, whereas strong expression was detected in the pars tuberalis. We then examined the expression of the long-form prolactin receptor (PRLR-L) in ARC kisspeptin neurones. In OVX ewes, approximately 60% of kisspeptin neurones expressed PRLR-L mRNA at similar levels in the breeding and nonbreeding seasons. We then aimed to determine whether prolactin treatment during the breeding season regulates kisspeptin expression in the ARC. Continuous central infusion of prolactin (20 MUg/h for 7 days) in oestradiol-treated OVX sheep did not alter Kiss1 mRNA expression or luteinising hormone secretion, although it induced substantial phosphorylated signal transducer and activator of transcription 5-immunoreactive nuclei staining in the mediobasal hypothalamus. We conclude that the seasonal change in kisspeptin neurones cannot be regulated directly by melatonin, although it may be a result of changes in prolactin levels. Despite this, kisspeptin expression was unchanged after exogenous prolactin treatment in breeding season ewes. PMID- 21793947 TI - Effects of neonatal treatment with valproic acid on vasopressin immunoreactivity and olfactory behaviour in mice. AB - Recent findings demonstrate that epigenetic modifications are required for the sexual differentiation of the brain. For example, neonatal administration of the histone deacetylase inhibitor, valproic acid, blocks masculinisation of cell number in the principal nucleus of the bed nucleus of the stria terminalis (BNST). In the present study, we examined the effects of valproic acid on neurochemistry and behaviour, focusing on traits that are sexually dimorphic and linked to the BNST. Newborn mice were treated with saline or valproic acid and the effect on vasopressin immunoreactivity and olfactory preference behaviour was examined in adulthood. As expected, males had more vasopressin immunoreactive fibres than females in the lateral septum and medial dorsal thalamus, which are two projection sites of BNST vasopressin neurones. Neonatal valproic acid increased vasopressin fibre density specifically in females in the lateral septum, thereby reducing the sex difference, and increased vasopressin fibres in both sexes in the medial dorsal thalamus. The effects were not specific to BNST vasopressin projections, however, because valproic acid also significantly increased vasopressin immunoreactivity in the anterior hypothalamic area in both sexes. Subtle sex-specific effects of neonatal valproic acid treatment were observed on olfactory behaviour. As predicted, males showed a preference for investigating female-soiled bedding, whereas females showed a preference for male soiled bedding. Valproic acid did not significantly alter olfactory preference, per se, although it increased the number of visits females made to female-soiled bedding and the overall time females spent investigating soiled versus clean bedding. Taken together, these results suggest that a transient disruption of histone deacetylation at birth does not have generalised effects on sexual differentiation, although it does produce lasting effects on brain neurochemistry and behaviour. PMID- 21793948 TI - Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. AB - OBJECTIVES: Impaired cardiac function has been confirmed in patients with chronic fatigue syndrome (CFS). Magnetic resonance cardiac tagging is a novel technique that assesses myocardial wall function in vivo. We hypothesized that patients with CFS may have impaired development and release of myocardial torsion and strain. METHODS: Cardiac morphology and function were assessed using magnetic resonance imaging and cardiac tagging methodology in 12 CFS patients (Fukuda) and 10 matched controls. RESULTS: Compared to controls, the CFS group had substantially reduced left ventricular mass (reduced by 23%), end-diastolic volume (30%), stroke volume (29%) and cardiac output (25%). Residual torsion at 150% of the end-systolic time was found to be significantly higher in the patients with CFS (5.3 +/- 1.6 degrees ) compared to the control group (1.7 +/- 0.7 degrees , P = 0.0001). End-diastolic volume index correlated negatively with both torsion-to-endocardial-strain ratio (TSR) (r = -0.65, P = 0.02) and the residual torsion at 150% end-systolic time (r = -0.76, P = 0.004), so decreased end-diastolic volume is associated with raised TSR and torsion persisting longer into diastole. Reduced end-diastolic volume index also correlated significantly with increased radial thickening (r = -0.65, P = 0.03) and impaired diastolic function represented by the ratio of early to late ventricular filling velocity (E/A ratio, r = 0.71, P = 0.009) and early filling percentage (r = 0.73, P = 0.008). CONCLUSION: Patients with CFS have markedly reduced cardiac mass and blood pool volumes, particularly end-diastolic volume: this results in significant impairments in stroke volume and cardiac output compared to controls. The CFS group appeared to have a delay in the release of torsion. PMID- 21793949 TI - Introduction: HMGB1 in inflammation and innate immunity. PMID- 21793950 TI - Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. AB - Inflammatory processes in brain tissue have been described in human epilepsy of various aetiologies and in experimental models of seizures. This, together with the anticonvulsant properties of anti-inflammatory therapies both in clinical and in experimental settings, highlights the important role of brain inflammation in the aetiopathogenesis of seizures. Preclinical investigations in experimental models using pharmacological and genetic tools have identified a significant contribution of interleukin-1 (IL-1) type 1 receptor/Toll-like receptor (IL 1R/TLR) signalling to seizure activity. This signalling can be activated by ligands associated with infections (pathogen-associated molecular patterns) or by endogenous molecules, such as proinflammatory cytokines (e.g. IL-1beta) or danger signals [damage-associated molecular patterns, e.g. high-mobility group box 1 (HMGB1)]. IL-1beta and HMGB1 are synthesized and released by astrocytes and microglia in the rodent brain during seizures. Notably, a rapid release of HMGB1 from neurons appears to be triggered by proconvulsant drugs even before seizure occurrence and is involved in their precipitation of seizures. The activation of IL-1R/TLR signalling mediates rapid post-translational changes in N-methyl-d aspartate-gated ion channels in neurons. A long-term decrease in seizure threshold has also been observed, possibly mediated by transcriptional activation of genes contributing to molecular and cellular plasticity. This emerging evidence identifies specific targets with potential anticonvulsant effects in drug-resistant forms of epilepsy. PMID- 21793951 TI - High-mobility group box 1 represents a potential marker of disease activity and novel therapeutic target in systemic lupus erythematosus. AB - High-mobility group box 1 (HMGB1) protein is a nuclear DNA-binding protein, which functions as an alarmin when released from cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of systemic lupus erythematosus (SLE), a prototypical autoimmune disease characterized by the formation of multiple autoantibodies, especially those directed against nucleosomes and double-stranded (ds)DNA. Elevated concentrations of HMGB1 are observed in sera as well as in skin lesions of patients with lupus. Of importance, serum HMGB1 and anti-HMGB1 autoantibody levels correlate with disease activity. In the blood of patients with SLE, HMGB1 is complexed with nucleosomes, at least partially. Moreover, HMGB1-nucleosome complexes from apoptotic cells activate antigen-presenting cells. Injection of HMGB1-nucleosome complexes into nonautoimmune mice results in the formation of autoantibodies against dsDNA and histones in a Toll-like receptor (TLR) 2-dependent manner. Additionally, HMGB1, as a part of DNA-anti-DNA immune complexes, can interact with receptor for advanced glycation end products (RAGE) on the surface of plasmacytoid dendritic cells and B cells leading to TLR9 dependent interferon (IFN)alpha release and activation of autoreactive B cells, respectively. HMGB1 attached to neutrophil extracellular traps may contribute to IFNalpha production by facilitating the recognition of self-nucleic acids. Furthermore, HMGB1, complexed with DNA and pathogenic anti-DNA autoantibodies, activates its receptors, TLR2, TLR4 and RAGE, and may thereby be involved in anti DNA autoantibody-induced kidney damage in lupus nephritis. Collectively, these findings suggest that HMGB1 is a potential marker of disease activity and, because of its probable involvement in the pathogenesis, a novel therapeutic target in SLE. PMID- 21793952 TI - Essential role of high-mobility group box proteins in nucleic acid-mediated innate immune responses. AB - Central to protective and pathological immunity is the activation of innate immune responses upon recognition of nucleic acids by transmembrane Toll-like receptors (TLRs) and cytosolic receptors. In mammals, the transmembrane pattern recognition receptors TLR3, TLR7 and TLR9 recognize double-stranded RNA, single stranded RNA and hypomethylated DNA, respectively, while the retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), RIG-I and MDA5 are known to be cytosolic RNA-sensing receptors. In addition, cytosolic DNA-sensing receptors that include DAI, RIG-I/MDA5 and AIM2 also trigger innate immune responses. High mobility group box (HMGB)1, 2 and 3 proteins, which also bind immunogenic nucleic acids, are generally involved in the nucleic acid receptor-mediated activation of innate immune responses. There is a hierarchy in the nucleic acid-mediated activation of immune responses, wherein the selective activation of the nucleic acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. The aim of this review is to summarize this novel feature of HMGB proteins, as essential frontline instigators of nucleic acid-mediated activation of innate immune responses. In addition, we will discuss the therapeutic implications of these findings. PMID- 21793954 TI - Rice 14-3-3 protein (GF14e) negatively affects cell death and disease resistance. AB - Plant 14-3-3 proteins regulate important cellular processes, including plant immune responses, through protein-protein interactions with a wide range of target proteins. In rice (Oryza sativa), the GF14e gene, which encodes a 14-3-3 protein, is induced during effector-triggered immunity (ETI) associated with pathogens such as Xanthomonas oryzae pv. oryzae (Xoo). To determine whether the GF14e gene plays a direct role in resistance to disease in rice, we suppressed its expression by RNAi silencing. GF14e suppression was correlated with the appearance of a lesion-mimic (LM) phenotype in the transgenic plants at 3 weeks after sowing. This indicates inappropriate regulation of cell death, a phenotype that is frequently associated with enhanced resistance to pathogens. GF14e silenced rice plants showed high levels of resistance to a virulent strain of Xoo compared with plants that were not silenced. Enhanced resistance was correlated with GF14e silencing prior to and after development of the LM phenotype, higher basal expression of a defense response peroxidase gene (POX22.3), and accumulation of reactive oxygen species (ROS). In addition, GF14e-silenced plants also exhibit enhanced resistance to the necrotrophic fungal pathogen Rhizoctonia solani. Together, our findings suggest that GF14e negatively affects the induction of plant defense response genes, cell death and broad-spectrum resistance in rice. PMID- 21793953 TI - FADS gene variants modulate the effect of dietary fatty acid intake on allergic diseases in children. AB - BACKGROUND: The association between dietary fatty acid intake and the development of atopic diseases has been inconsistent. This could be due to inter-individual genetic differences in fatty acid metabolism. OBJECTIVE: The aim of the current study was to assess the influence of FADS1 FADS2 gene cluster polymorphisms on the association between dietary fatty acid intake and atopic diseases and allergic sensitization in 10-year-old children. METHODS: The analysis was based on data from two German prospective birth cohort studies. Data on margarine and fatty acid intake were collected using a food frequency questionnaire. Information on atopic diseases was collected using a questionnaire completed by the parents. Specific IgE against common food and inhalant allergens were measured. Six variants of the FADS1 FADS2 gene cluster (rs174545, rs174546, rs174556, rs174561, rs174575 and rs3834458) were tested. Logistic regression modelling, adjusted for gender, age, maternal education level and study centre, was used to analyse the association between fatty acid intake and atopic diseases stratified by genotype. RESULTS: No significant association was found between the six FADS single nucleotide polymorphisms (SNPs) and allergic diseases or atopic sensitization. The total n-3/total n-6 ratio was positive associated with an increased risk of hayfever in homozygous major allele carriers ranging from an adjusted odds ratios of 1.25 (95%-CI: 1.00-1.57) to 1.31 (95%-CI: 1.01-1.69) across the six tested SNPs although this association was not significant anymore after correcting for multiple testing. Daily margarine intake was significantly associated with asthma [1.17 (1.03-1.34) to 1.22 (1.06-1.40)] in individuals carrying the homozygous major allele. This association was also significant after correcting for multiple testing. CONCLUSIONS & CLINICAL RELEVANCE: The association between dietary intake of fatty acids and allergic diseases might be modulated by FADS gene variants in children. PMID- 21793955 TI - Prevalence and associated factors of dental erosion in children and adolescents of a private dental practice. AB - BaCKGROUND. The prevalence of dental erosion seems to be rising in young populations, particularly among individuals of higher socioeconomic status. AIM. To assess the prevalence and associated factors of dental erosion in children and adolescents of a private dental practice. DESIGN. A total of 232 participants, aged 2-20 years, were examined. Dietary habits, oral hygiene, and medical data were collected from dental records. Logistic regression analyses were conducted. RESULTS. Dental erosion prevalence was of 25.43% and was highest on the occlusal surfaces (76%). Associated factors were: frequent consumption of soft drinks (OR = 2.33; 95% CI = 1.01-5.38) and candies (OR = 3.23; 95% CI = 1.25-8.32); and interaction between these two factors (OR = 3.95; 95% CI = 1.60-9.75). On anterior teeth, associated factors were: frequent consumption of fruits (OR = 2.53; 95% CI = 1.09-5.91); and age (OR = 1.07 95% CI = 1.01-1.14). Milk consumption was associated with a lower prevalence of dental erosion (OR = 0.40; 95% CI = 0.17-0.94). CONCLUSIONS. A relatively high prevalence of erosion was found in association with frequent intake of soft drinks, candies, and fruits. The consumption of milk seemed to protect against dental erosion on anterior teeth. PMID- 21793956 TI - Identification and expression analysis of nervous wreck, which is preferentially expressed in the brain of the male silkworm moth, Bombyx mori. AB - Sexually dimorphic neural circuits are essential for reproductive behaviour. The molecular basis of sexual dimorphism in the silkworm moth (Bombyx mori) brain, however, is unclear. We conducted cDNA subtraction screening and identified nervous wreck (Bmnwk), a synaptic growth regulatory gene, whose expression is higher in the male brain than in the female brain of the silkworm. Bmnwk was preferentially expressed in the brain at the late pupae and adult stages. In situ hybridization revealed that Bmnwk is highly expressed in the optic lobe of the male moth brain. These findings suggest that Bmnwk has a role in the development and/or maintenance of the optic lobe in the male silkworm brain. PMID- 21793957 TI - Estimating the rate of usage of varenicline and other medication for smoking cessation. PMID- 21793959 TI - The challenge of scar and the search for new means to control healing and scarring. PMID- 21793958 TI - Effects of a randomized contingency management intervention on opiate abstinence and retention in methadone maintenance treatment in China. AB - AIMS: Methadone maintenance treatment has been made available in China in response to the rapid spread of human immunodeficiency virus (HIV), but high rates of dropout and relapse are problematic. The aim of this study was to apply and test if a contingency management (or motivational incentives) intervention can improve treatment retention and reduce drug use. DESIGN: Random assignment to usual care with (n = 160) or without (n = 159) incentives during a 12-week trial. Incentives participants earned draws for a chance to win prizes on two separate tracks targeting opiate-negative urine sample or consecutive attendance; the number of draws increased with continuous abstinence or attendance. SETTING: Community-based methadone maintenance clinics in Shanghai and Kunming. PARTICIPANTS: The sample was 23.8% female, mean age was 38, mean years of drug use was 9.4 and 57.8% had injected drugs in the past 30 days. MEASUREMENTS: Treatment retention and negative drug urine. FINDINGS: Relative to the treatment as-usual (control) group, better retention was observed among the incentive group in Kunming (75% versus 44%), but no difference was found in Shanghai (90% versus 86%). Submission of negative urine samples was more common among the incentive group than the usual care (74% versus 68% in Shanghai, 27% versus 18% in Kunming), as was the longest duration of sustained abstinence (7.7 weeks versus 6.5 in Shanghai, 2.5 versus 1.6 in Kunming). The average total prize amount was 371 Yuan (or $55) per participant (527 for Shanghai versus 216 in Kunming). CONCLUSIONS: Contingency management improves treatment retention and drug abstinence in methadone maintenance treatment clinics in China, although there can be considerable site differences in magnitude of effects. PMID- 21793960 TI - Mechanisms of pathological scarring: role of myofibroblasts and current developments. AB - Myofibroblasts play a key role in the wound-healing process, promoting wound closure and matrix deposition. These cells normally disappear from granulation tissue by apoptosis after wound closure, but under some circumstances, they persist and may contribute to pathological scar formation. Myofibroblast differentiation and apoptosis are both modulated by cytokines, mechanical stress, and, more generally, cell-cell and cell-matrix interactions. Tissue repair allows tissues and organs to recover, at least partially, functional properties that have been lost through trauma or disease. Embryonic skin wounds are repaired without scarring or fibrosis, whereas skin wound repair in adults always leads to scar formation, which may have functional or esthetic consequences, as in the case of hypertrophic scars, for example. Skin wound repair involves a precise remodeling process, particularly in the dermal compartment, during which fibroblasts/myofibroblasts play a central role. This article reviews the origins of myofibroblasts and their role in normal and pathological skin wound healing. This article focuses on traumatic skin wound healing, but largely, the same mechanisms apply in other physiological and pathological settings. Tissue healing in other organs is examined by comparison, as well as the stromal reaction associated with cancer. New approaches to wound/scar therapy are discussed. PMID- 21793962 TI - Mechanobiology of scarring. AB - The mechanophysiological conditions of injured skin greatly influence the degree of scar formation, scar contracture, and abnormal scar progression/generation (e.g., keloids and hypertrophic scars). It is important that scar mechanobiology be understood from the perspective of the extracellular matrix and extracellular fluid, in order to analyze mechanotransduction pathways and develop new strategies for scar prevention and treatment. Mechanical forces such as stretching tension, shear force, scratch, compression, hydrostatic pressure, and osmotic pressure can be perceived by two types of skin receptors. These include cellular mechanoreceptors/mechanosensors, such as cytoskeleton (e.g., actin filaments), cell adhesion molecules (e.g., integrin), and mechanosensitive (MS) ion channels (e.g., Ca(2+) channel), and sensory nerve fibers (e.g., MS nociceptors) that produce the somatic sensation of mechanical force. Mechanical stimuli are received by MS nociceptors and signals are transmitted to the dorsal root ganglia that contain neuronal cell bodies in the afferent spinal nerves. Neuropeptides are thereby released from the peripheral terminals of the primary afferent sensory neurons in the skin, modulating scarring via skin and immune cell functions (e.g., cell proliferation, cytokine production, antigen presentation, sensory neurotransmission, mast cell degradation, vasodilation, and increased vascular permeability under physiological or pathophysiological conditions). Mechanoreceptor or MS nociceptor inhibition and mechanical force reduction should propel the development of novel methods for scar prevention and treatment. PMID- 21793961 TI - The role of the epidermis and the mechanism of action of occlusive dressings in scarring. AB - The problem of cutaneous scarring has conventionally been approached as a pathology of the dermis. Multiple lines of evidence from the clinic, in vitro experiments, and in vivo animal and human studies, however, increasingly suggest that the epidermis plays a major role in the control of underlying dermal scar. Building on the demonstrated efficacy of silicone gel occlusion, in this paper we review the evidence for epidermal regulation of scar, and propose the novel hypothesis that dermal fibrosis is exquisitely linked to the inflammatory state of the epidermis, which in turn is linked to hydration state as a function of epidermal barrier function. In the spectrum of factors contributing to dermal scar, the epidermis and its downstream effectors offer promising new targets for the development of antiscar therapies. PMID- 21793963 TI - New potential antiscarring approaches. AB - Significant progress has been made in scar research in which an anti-transforming growth factor-beta strategy has already been translated from an experimental study to a clinical trial. However, scar reduction and elimination remain an unmet medical need because of the difficulty in its treatment. The authors of this article would like to propose several new potential antiscarring approaches for scar prevention including anti-transforming growth factor-beta, multifactor therapies, tissue regeneration, and tissue-engineered skin. In addition, scar remodeling is also proposed as an alternative new potential approach for scar therapy. We hope that some of these potential approaches might be translated into clinical scar therapies in the near future. PMID- 21793964 TI - Recommendations on clinical proof of efficacy for potential scar prevention and reduction therapies. AB - Cutaneous scarring is an enormous medical problem with approximately 100 million patients acquiring scars each year. Scar prevention/reduction represents a significant, and largely unmet, clinical need. Research into the prophylactic modulation of scar outcome differs from research into other disease processes as the scar is not present at the start of the study; measurements of changes from baseline are impossible. Final scar morphology is influenced by many variables. A fundamental principle that should be observed in the prospective evaluation of scar prevention/reduction therapies is that, if left untreated, wounds in treatment and control groups should have healed with identical scars. Observation of this principle will allow the detection of true treatment effects. The many variables that influence scar morphology mean that the evaluation of potential pharmaceutical products for this indication favors the use of self-controlled designs in clinical trials. In this article, we review variables that affect scar morphology and recommend the self-controlled design for clinical trials aiming to establish proof of efficacy of scar prevention and reduction pharmaceuticals. With no pharmaceutical products currently licensed for this indication, this represents a new therapeutic area. The principles discussed will also have direct relevance to the wider fields of wound healing and regenerative medicine. PMID- 21793965 TI - Discovery and development of avotermin (recombinant human transforming growth factor beta 3): a new class of prophylactic therapeutic for the improvement of scarring. AB - Scarring in the skin following surgery or trauma may be associated with adverse aesthetic, functional, growth and psychological effects, such that both physicians and patients regard it as important to minimize the appearance of scars. The prophylactic improvement of cutaneous scar appearance represents a significant opportunity to improve the well-being of patients. Human recombinant transforming growth factor beta 3 (avotermin) is the first in a new class of therapeutic agents to address this medical need. Herein we describe scar-free healing in early embryonic development, including the identification of the cellular and molecular mechanisms underpinning the scarring process. This understanding has led to the discovery of novel therapeutics such as transforming growth factor beta 3, which can be administered to improve scar appearance in human subjects through pharmacological action. We discuss the pioneering development of transforming growth factor beta 3 in this new therapeutic area showing how it has been possible to translate preclinical concepts into clinical application, namely the improvement of scar appearance following surgery. PMID- 21793966 TI - The use of noncellularized artificial dermis in the prevention of scar contracture and hypertrophy. AB - Abnormal scarring occurring after wounds and burns remains a major source of functional and cosmetic disorders. The dermal part of the skin is recognized as playing a major role in the contraction process. The skin dermis may be involved in superficial wounds, but when the basal membrane and the sources of keratinocytes, like hair follicles and adnexa, are left intact, little visible scarring is observed. The skin elasticity may be preserved, even when the extracellular matrix is somehow altered. On the opposite extreme, in wounds of extended depth, the loss of dermal component results in the absence of elasticity and fibroblastic cell proliferation, leading to hypertrophy and contracture. These phenomena may be explained either by differences in cell populations, by extracellular matrix reactions to different stimuli, or by chemical control of interactions between cells and matrix. PMID- 21793967 TI - New dermal substitutes. AB - The quality of skin wound healing can be improved by the application of scaffolds as skin replacement materials. Although the clinical requirements for the function of such materials are defined, the translation of these requirements into physical and mechanobiological properties of scaffolds is difficult. Natural as well as constructed biological materials and synthetic substitutes are discussed. Furthermore, new techniques such as electrospinning and solid freeform fabrication as well as new types of materials such as self-assembling peptides are reviewed with regard to their potential role in the production of skin substitute materials. PMID- 21793968 TI - Using 'payment by results' to fund the treatment of dependent drug users--proceed with care! AB - The UK government is changing its system of payment for drug treatment services in order to reward the achievement of better patient outcomes. This is a model that may be taken up internationally. This 'payment by results' funding system will reward providers for achieving good outcomes in terms of whether clients are drug free, employed and/or not convicted of a criminal offence. Providers will also receive a payment based on health and wellbeing outcome measurement. The definition and measurement of success in achieving these outcomes is complex and challenging, as is the need to bridge treatment costs during the period in which outcomes are pursued. This experiment requires careful evaluation if the delivery of drug treatment is not to be jeopardized or fragmented. PMID- 21793969 TI - Disulfiram in a 'traditional' medicine sold to patients with alcohol dependence in India. PMID- 21793970 TI - It is time for low-risk drinking goals to come out of the closet. PMID- 21793971 TI - Compulsive use of dopamine replacement therapy: a model for stimulant drug addiction? AB - The compulsive use of dopamine replacement therapy (DRT) or dopamine dysregulation syndrome (DDS) is one of the behavioural disturbances reported in some patients with Parkinson's disease (PD) and other disorders who are receiving DRT. We draw this phenomenon to the attention of the addiction field as a topic deserving of more systematic study. We outline: the clinical features, epidemiology and clinical correlates of the disorder; the unresolved issues in its definition and diagnosis; and its potential relevance to neurobiological models of psychostimulant addiction. We argue that compulsive DRT use may provide a useful model for drug addiction, while advancing our understanding of the neurobiology of addiction and improving the management of PD patients with the disorder. PMID- 21793973 TI - Is it time to start focusing on the content of computer-delivered interventions? PMID- 21793974 TI - Relationships between medical beliefs of superiority of Chinese or Western medicine, medical behaviours and glycaemic control in diabetic outpatients in Taiwan. AB - A considerable proportion of Taiwanese people believe that Chinese medicine is superior for treating the cause of disease (curative therapy) whereas western medicine is mostly concerned with treating symptoms (symptomatic therapy). As a result, when illness arises, the combined use of both Chinese and western medicine is a common practice and referred to as pluralistic health-seeking behaviour. The purpose of this cross-sectional study was to explore the relationship between beliefs of superiority of western or Chinese medicine, utilisation of therapy and glycaemic control in patients with diabetes from outpatient departments. The study was conducted between 20 December 2005 and 20 January 2006. We approached 176 patients consecutively, and 151 (85.8%) completed the survey. Seventy-nine patients with diabetes from a municipal Chinese medicine hospital and 72 patients from a near by western medicine hospital in southern Taiwan were recruited. Participants were asked to fill in a structured questionnaire. For those who could not fill in the questionnaire, interviews were conducted. Sixty-four participants took western medicine (42.4%), 65 people (43.0%) used the combination of western and Chinese medicine and 22 (14.6%) used Chinese medicine only. Beliefs about the superiority of Chinese versus western medicine were associated with the patients' utilisation of those therapies. Patients using a combination of Chinese and western medicine had significantly better glycaemic control than patients using Chinese medicine alone. Further research is needed to clarify whether better glycaemic control was the result of the combined therapy, a higher motivation for self-care or both. Nevertheless, a combination of traditional and western medicine plays an important role and should not be ignored in controlling diabetes. However, the cost-effectiveness of such a plural therapy needs to be investigated. PMID- 21793975 TI - Genetic alterations in microRNAs in medulloblastomas. AB - MicroRNAs (miRNAs) regulate a variety of cellular processes via the regulation of multiple target genes. We screened 48 medulloblastomas for mutation, deletion and amplification of nine miRNA genes that were selected on the basis of the presence of potential target sequences within the 3'-untranslated region of the MYCC mRNA. Differential PCR revealed deletions in miR-186 (15%), miR-135a-1 (33%), miR-548d 1 (42%), miR-548d-2 (21%) and miR-512-2 (33%) genes, whereas deletion or amplification was detected in miR-135b (23%) and miR-135a-2 (15%). In miR-33b, deletion, amplification or a mutation at the precursor miRNA were detected in 10% of medulloblastomas. Overall, 35/48 (73%) medulloblastomas had at least one alteration. Real-time RT-PCR revealed MYCC overexpression in 11 of 37 (30%) medulloblastomas, and there was a correlation between MYCC overexpression and miR 512-2 gene deletion (P = 0.0084). Antisense-based knockdown of miR-512-5p (mature sequence of miR-512-2) resulted in significant upregulation of MYCC expression in HeLa and A549 cells, while forced overexpression of miR-512-2 in medulloblastoma/PNET cell lines DAOY, UW-228-2, PFSK resulted in the downregulation of MYCC protein. Furthermore, the results of luciferase reporter assays suggested that miR-512-2 targets the MYCC gene. These results suggest that alterations in the miRNA genes may be an alternative mechanism leading to MYCC overexpression in medulloblastomas. PMID- 21793976 TI - A hitch-hiker's guide to the intravenous PK/PD galaxy. PMID- 21793977 TI - Brave new world: do we need it, do we want it, can we afford it? PMID- 21793978 TI - Dexmedetomidine for co-analgesia in chemotherapy-induced severe enterocolitis. PMID- 21793979 TI - Continuous oblique subcostal transversus abdominis plane block: an alternative for pain management after upper abdominal surgery in children. PMID- 21793980 TI - Difficult Airway Course in Novi Sad, Serbia 2011. PMID- 21793981 TI - Usefulness of Airtraq in a 3-month-old child with Apert Syndrome. PMID- 21793982 TI - Use of BiPAP for safe anesthesia in a child with a large anterior mediastinal mass. PMID- 21793983 TI - Reply to 'Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery'. PMID- 21793984 TI - Video laryngoscopy in infants: one device does not fit all. PMID- 21793985 TI - Balloon dilatation of tracheal restenosis in a patient with unilateral lung agenesis - an anesthetic challenge. PMID- 21793986 TI - Taking the nervousness out of nerve catheter removal: smart phone to the rescue. PMID- 21793987 TI - Selective endobronchial intubation in a child using a rigid bronchoscope. PMID- 21793988 TI - Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. AB - Many different definitions for multidrug-resistant (MDR), extensively drug resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. PMID- 21793989 TI - Immediate re-transplantation following early kidney transplant thrombosis. AB - Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis. PMID- 21793990 TI - Common poison, uncommon urine. PMID- 21793991 TI - Crescentic glomerulonephritis and leucocytoclastic vasculitis associated with acute EBV infection. PMID- 21793992 TI - Analysis of placental weight centiles is useful to estimate cause of fetal growth restriction. AB - AIM: To establish a nomogram of placental weight at delivery and to clarify the associations among standardized placental weights and known risk factors of fetal growth restriction (FGR). MATERIAL AND METHODS: Consequent cases who delivered singleton babies after 22 weeks of gestation at our hospital between 2005 and 2009 were retrospectively analyzed using the hospital database. The data of neonatal birth weight, placental weight, maternal demographics and variables associated with FGR were collected. From these data, we established the nomogram of neonatal and placental weight, and fetal:placental weight ratio against gestational age at the delivery. According to regression formula, the z-score of the neonatal and placental weights were calculated, and the relation between the standardized placental weights and risk factors associated with growth restriction were analyzed. RESULTS: Nomograms of neonatal and placental weight, and fetal:placental weight ratio were demonstrated using 3434 cases. Z-scores of placental weights were low in cases with low maternal body mass index, preeclampsia, abnormal placental forms and short umbilical cord. They were also low in cases with 'placental dysfunction', which we usually defined when any other known risk factor was not seen in FGR cases. CONCLUSION: A standard curve of placental weight would be a useful tool to explain a certain degree of placental development and the cause of FGR, and to use for further research. PMID- 21793993 TI - Pre-vaccination epidemiology of human papillomavirus infections in Japanese women with abnormal cytology. AB - AIM: To investigate the pre-vaccination epidemiology of genital human papillomavirus (HPV) infections and genotypes in women with abnormal cytology in Nagasaki, Japan. MATERIAL AND METHODS: We performed Pap smear tests, biopsies and HPV genotype testing in Nagasaki Prefecture from August 2007 through November 2009. RESULTS: During the study period, serial samples of uterine cervical specimens were obtained from 539 subjects with abnormal cytology and/or squamous intraepithelial lesions (SIL) confirmed previously, or with clinically suspected invasive cervical cancer. In 119 HPV-positive subjects with low-grade SIL, the three most prevalent high-risk HPV genotypes were HPV52 (21.8%; 26/119), HPV16 (20.2%; 24/119) and HPV56 (17.6%; 21/119). In 199 women, 127 HPV-positive subjects with high-grade SIL and 67 HPV-positive subjects with squamous cell carcinoma (SCC), the three most prevalent high-risk HPV genotypes were HPV16 (44.3%; 86/194), HPV52 (20.6%; 40/194) and HPV58 (16.0%; 31/194). CONCLUSION: Compared with the distribution of high-risk HPV genotypes in other countries, HPV52 was a more common genotype in Nagasaki. With disease progression to SCC, the distribution of high-risk HPV56 belonging to the A6 HPV family decreased, while HPV16 and HPV52 belonging to the A9 HPV family persisted. Our data provide an important resource to address the case for vaccination against HPV genotypes other than HPV16 and HPV18 in Japan. PMID- 21793994 TI - Fetal hemodynamic changes following maternal betamethasone administration in monochorionic twin pregnancies featuring one twin with selective growth restriction and abnormal umbilical artery Doppler. AB - AIM: To evaluate fetal hemodynamic changes following maternal betamethasone administration in monochorionic twin pregnancies featuring one twin with selective intrauterine growth restriction (sIUGR) and absence of end-diastolic velocity in umbilical artery (UA) Doppler. MATERIAL AND METHODS: sIUGR was defined as fetal weight below the 10th percentile in one twin and inter-twin birth weight discordance >25%. The results of Doppler examinations including UA, middle cerebral artery (MCA) and ductus venosus directly prior to (D0), at 24 h (D1) and 48 h (D2) after administration of the first dose of betamethasone were recorded. Cerebral-placenta ratio was defined as MCA pulsatility index (PI) divided by UA-PI. RESULTS: In four (20%) of the 20 cases, the UA Doppler of the growth-restricted twin returned to positive end-diastolic velocity after betamethasone administration. The UA-PI and MCA-PI of the sIUGR twin changed significantly after betamethasone administration: UA-PI was decreased at D1, the MCA-PI was reduced at both D1 and D2, and the cerebral-placenta ratio was not altered after betamethasone administration in the sIUGR twin. CONCLUSION: The hemodynamic changes after betamethasone administration were different between the two monochorionic twin fetuses where one presented with sIUGR and absence of UA end-diastolic velocity. The etiology of a low rate of return of end-diastolic velocity in the sIUGR twin needs further evaluation. PMID- 21793995 TI - Mothers' experiences of the time after the diagnosis of an intrauterine death until the induction of the delivery: a qualitative Internet-based study. AB - AIM: This study aims to describe how mothers spend the period of time between being diagnosed with a dead baby in utero and the induction of the delivery. MATERIAL AND METHODS: Data were collected using a web questionnaire. Five hundred and fifteen women who had experienced a stillbirth after the 22nd week of gestation answered the open question: 'What did you do between the diagnosis of the child's death and the beginning of the delivery?' A qualitative content analysis method was used. RESULTS: The results show that some mothers received help to adapt to the situation, while for others, waiting for the induction meant further stress and additional psychological trauma in an already strained situation. CONCLUSION: There is no reason to wait with the induction unless the parents themselves express a wish to the contrary. Health care professionals, together with the parents, should try to determine the best time for the induction of the birth after the baby's death in utero. That time may vary, depending on the parents' preferences. PMID- 21793996 TI - Primary transitional cell carcinoma of the fallopian tube. AB - The fallopian tube is the least common site for origin of malignancy in the female genital tract. Most primary fallopian tube malignancies are adenocarcinomas. Primary transitional cell carcinoma (TCC) of the fallopian tube is an extremely rare tumor with a small number of cases reported in the literature. We present a 67-year-old woman who was found incidentally to have a left adnexal mass on a screening pelvic ultrasound. Subsequently the patient underwent laparoscopic left salpingo-oophorectomy and the specimen was submitted for intraoperative frozen section, which revealed a high-grade carcinoma; therefore, she underwent a laparotomy and total abdominal hysterectomy, right salpingo-oophorectomy and omentectomy. Histopathology revealed high-grade transitional cell carcinoma in the left fallopian tube. Post-surgery she was treated with four cycles of adjuvant chemotherapy with carboplatin and paclitaxel with no complications. Our patient had a family history of malignancy, so genetic testing for BRCA1 and BRCA2 mutations was undertaken and did not reveal any mutation or unclassified variants. Multiplex ligation-dependent probe amplification (MLPA) was normal. PMID- 21793997 TI - Five-year study assessing the feasibility and safety of autologous blood transfusion in pregnant Japanese women. AB - AIM: To assess the feasibility and safety of autologous blood donation during pregnancy in Japanese women. MATERIAL AND METHODS: We enrolled patients who were either at high risk for massive blood loss during delivery or had blood that was difficult to match for transfusion between March 2005 and February 2010. After delivery, we reviewed hospital records of these patients to collect data on blood donation procedures, obstetric outcome and blood transfusions received. RESULTS: We enrolled 314 patients during the study period and performed 809 blood donations. The median volume of donated blood was 1200 mL (range, 400-2000 mL). Vasovagal reflex as an adverse donor reaction occurred in 10 of the 314 patients (3.2%) during 11 of the 809 donations (1.4%). There were no cases of non reassuring fetal heart rate patterns during blood donations. Twenty-five (7.8%) of the 322 neonates were admitted to the neonatal intensive care unit. All 322 infants were healthy 1 month after delivery. Among 314 patients, autologous blood re-transfusion was performed for 56 (17.8%) and homologous blood transfusion was performed concurrently for 5 (1.6%). Placenta previa was the indication with the highest re-transfusion rate (42.4%). All re-transfusions were performed without side-effects. CONCLUSION: Autologous blood donation is feasible and safe for pregnant women and their infants. Although indications of autologous blood donation are controversial, it should be considered for cases of placenta previa. PMID- 21793998 TI - Endothelial nitric oxide synthase gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population. AB - AIM: To evaluate endothelial nitric oxide synthase (eNOS) gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population. MATERIAL AND METHODS: Fifty-seven preeclamptic and 60 normotensive women were enrolled in the present study. The study focused on two functional variants: a variant in exon 7 G to T conversion at nucleotide position 894 resulting in the replacement of glutamic acid with aspartic acid at codon 298 (Glu298Asp) and a variant variable number of 27 bp tandem repeats in intron 4 (VNTR intron 4). Two polymorphisms in the maternal eNOS gene were characterized by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Preeclamptic pregnant women were evaluated into two subgroups according to the presence of eclampsia. RESULTS: We demonstrated a significant difference in patients with preeclampsia in terms of Glu298Asp/eNOS genotype frequency. G/G homozygotes of Glu298Asp among healthy pregnancies were significantly frequent when T/T homozygotes were significantly frequent among preeclamptic pregnancies. We showed that G/T heterozygotes of Glu298Asp/eNOS gene were significantly frequent among preeclamptic pregnant women who did not develop eclampsia than in preeclamptic pregnant women with eclampsia. CONCLUSION: Glu298Asp polymorphism in the eNOS gene could be an individual's risk factor and may modulate progression to an eclampsia complication of preeclampsia in the Turkish population. PMID- 21793999 TI - Prediction model for the incidence of emergent cesarean section during induction of labor specialized in nulliparous low-risk women. AB - AIM: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS). MATERIAL AND METHODS: By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed. RESULTS: The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) * 100, odds = e(X) and X = 8.18 + 1.23 * BW (kg)- 7.74 * MH (m)- 0.253 * BS. CONCLUSION: This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome. PMID- 21794000 TI - Predictors associated with severity of pelvic actinomycosis. AB - AIM: To evaluate the clinical features of pelvic actinomycosis and to identify predictive factors associated with severity of pelvic actinomycosis. MATERIAL AND METHODS: Medical records of 25 patients diagnosed with pelvic actinomycosis and treated by surgery between September 1994 and March 2010 at Cheil General Hospital and Women's Healthcare Center were reviewed retrospectively. RESULTS: Of the 25 patients, 15 (60%) had mild pelvic actinomycosis with adhesion and abscess but no complications. The other 10 patients (40%) had an aggressive state of pelvic actinomycosis accompanied by diverse complications, such as hydroureter, abscess rupture, bowel obstruction and cystoenteric fistula. The aggressive actinomycosis correlated with fever, higher neutrophil percentage and a higher white blood cell count to hemoglobin ratio compared to those with mild pelvic actinomycosis. However, there were no significant differences in the use of intrauterine devices, C-reactive peptide level or mass size between those with mild and aggressive pelvic actinomycosis. CONCLUSION: Using the clinical factors, such as fever, neutrophil percentage and white blood cell count to hemoglobin ratio, the surgeons can more accurately predict the severity of pelvic actinomycosis, thus being helpful for more proper disease management. PMID- 21794001 TI - Relationships between fetal growth and maternal body mass indices, plasma glucose level, and plasma insulin level in Japanese women with mildly impaired glucose tolerance. AB - AIM: To identify variables which are strongly associated with fetal growth. MATERIAL AND METHODS: The study subjects were 203 Japanese women who had a plasma glucose level >=140 mg/dL (7.8 mmol/L) on a 50-g glucose challenge test but were normoglycemic when challenged with a 75-g oral glucose tolerance test (GTT) according to the criteria previously used in Japan. All the subjects subsequently gave birth to singleton infants. The correlations between the standard deviation for birthweight (birthweight SD) and 15 other variables, including the maternal body mass index (BMI), plasma levels of glucose and insulin on the GTT, and various indices calculated using data from the GTT, were then examined. Univariate and multivariate regression analyses were performed. RESULTS: Univariate analyses revealed significant correlations between the birthweight SD and the fasting plasma glucose level (P = 0.0063), the pre-pregnancy BMI (P = 0.0001), and the BMI at delivery (P < 0.0001). Only the BMI at delivery remained as a significant factor that was independently correlated with the birthweight SD after a multivariate regression analysis. CONCLUSION: The suppression of maternal weight gain, rather than the suppression of the plasma glucose level, may be effective for avoiding infants with overgrowth among Japanese women with mildly impaired glucose tolerance. PMID- 21794002 TI - Evaluation of visual inspection with acetic acid as a feasible screening test for cervical neoplasia. AB - AIM: Alternative methods for cervical cancer screening have been sought. One method, direct visualization with acetic acid (VIA), has proven itself in many clinical trials as an adequate alternative to Pap-smears in developing countries. This study was designed to assess if visual inspection with acetic acid (VIA test) could be an appropriate alternative method for cervical cancer screening. Therefore, we compared VIA, as a stand-alone test, with the gold standard test (colposcopy) in detecting significant cervical pathology in our setting. MATERIALS AND METHODS: The study population consisted of the women who attended the Gynecological Clinic in Ghaem Hospital from April 2008 to April 2009. All of them were tested with VIA. Then, 100 test-positive women and 100 test-negative women were randomly selected and underwent cytology and colposcopy. Cervical biopsies were conducted for the women with abnormal colposcopic findings. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for each test and then were compared. RESULTS: Sixty-nine women in the VIA-positive group and 61 women in the VIA-negative group had abnormal cytology. After studying the biopsies, 58 women with positive VIA, and two women with negative VIA had a final diagnosis of dysplasia. Positive predictive value for VIA and cytology were 58% and 33%, respectively. CONCLUSION: The results of this study indicate that VIA may be a useful and feasible alternative screening test for cervical precancerous and cancerous lesions. PMID- 21794003 TI - Metastatic urachal carcinoma of the ovary. AB - A 52-year-old woman had undergone a partial cystectomy for a cystic mass at the dome of the urinary bladder in 1997. The pathological diagnosis was a urachal mucinous cystadenoma with borderline malignancy. Twelve years later, multiple masses were noted on the uterus, ovaries and abdominal wall. She underwent debulking surgery, including a total hysterectomy, bilateral salpingo oophorectomy, pelvic lymph node dissection, infracolic omentectomy, appendectomy, colon mass removal and abdominal wall mass removal. Remnants of the tumor were seeded throughout the abdominal cavity. The pathological evaluation confirmed metastatic urachal mucinous adenocarcinoma in both ovaries, the abdominal wall, the colon mass, the uterosacral ligament and the bladder. Adjuvant chemotherapy with paclitaxel and carboplatin was administered, which showed stable disease. She is now undergoing second-line chemotherapy. PMID- 21794004 TI - Impact of a single perioperative dose of dexamethasone on the incidence of surgical site infections: a case-control study. AB - AIMS: Dexamethasone is recommended in several international guidelines to prevent postoperative nausea and vomiting, a problem especially frequent in gynecological patients. Despite the increasing use of dexamethasone for this indication there are limited data concerning potential harmful effects of corticosteroids in surgical patients, especially the potential negative impact on wound healing and surgical site infection (SSI). This case-control study was conducted to look for potentially harmful effects of a single perioperative dose of dexamethasone with respect to the occurrence of SSI in gynecological and obstetric surgery patients. MATERIALS AND METHODS: We retrospectively analyzed 3449 patients undergoing inpatient gynecological or obstetric surgical procedures for the occurrence of deep SSI requiring surgical intervention or prolonged antibiotic treatment. These case patients were matched to control patients according to the surgeon performing the procedure, the type of surgery, biometric data, and known risk factors for SSI. Furthermore, timely linearity of dexamethasone use and SSI rate was exploratorily analyzed using several auto-regressive, integrated, moving average models. RESULTS: Forty patients with deep SSI were matched to 158 controls. The risk profile for wound infections of both groups was comparable. Forty-five percent (95% confidence interval: 29-62%) of the case patients were treated with dexamethasone and 49% (95% confidence interval: 41-57%) of the control group received the drug. An increasing use of dexamethasone over time was not followed by an increased SSI rate. There were no timely correlations between dexamethasone usage and the occurrence of SSI. CONCLUSION: In this case-control study we could not detect any evidence for an increased risk for SSI after a single-dose of dexamethasone (4-8 mg) in gynecological patients. PMID- 21794005 TI - Xenografting of gonadal tissues into mice as a possible method for conservation and utilization of porcine genetic resources. AB - In vitro production of embryos, including in vitro maturation, fertilization of oocytes and their subsequent culture to the embryo stage, has become the most popular method of studying gametogenesis and embryogenesis in pigs. As well as their utility for basic studies, these procedures now enable us to generate viable embryos and offspring as a means of conserving genetic resources and rare animal breeds. Recently, more advanced technologies such as xenografting of gonadal (testicular and ovarian) tissues into immunodeficient experimental animals have been developed. In combination with in vitro embryo production techniques, this approach may provide many benefits. We have been carrying out studies to acquire basic information about the application of this method to porcine species, and to improve the existing techniques. Recently, we obtained oocytes from ovarian tissue xenografted and grown in nude mice that had the capacity to be fertilized and the ability to develop into early-stage embryos. We also obtained spermatozoa from the xenografted testicular tissues and injected them intracytoplasmically into in vitro-matured oocytes to produce piglets. Here we discuss the further possibilities of conservation and utilization of porcine gonadal tissue by xenografting into immunodeficient mice. PMID- 21794006 TI - Tumor necrosis factor-alpha-induced inflammatory responses in cattle. AB - Tumor necrosis factor-alpha (TNF-alpha) is recognized as a cytokine because of its involvement in inflammation-mediated biological defense functions. Although TNF-alpha is primarily produced by macrophages, it is also produced by other cells, including lymphocytes, Kupffer cells, natural killer cells and adipocytes. While TNF-alpha has diverse immune system functions, including antitumor activity, antimicrobial activity and mediation of inflammation, it also regulates a number of physiological functions, including appetite, fever, energy metabolism and endocrine activity. Factors such as viruses, parasites, other cytokines, and endotoxins induce TNF-alpha production. In combination with other cytokines, TNF alpha plays a clinically important role in cattle by mediating immune inflammatory responses such as mastitis and endotoxic shock. It has been reported that cytokines such as TNF-alpha are involved in metabolic disease such as acidosis. On the other hand, several data suggest that lactoferrin (LF) acts to prevent the release of a number of inflammatory mediators from various activated cells, and further suggest that the prophylactic effect of LF involves inhibition of cytokine production, including TNF-alpha, that are principal mediators of the inflammatory response leading to death from toxic shock. This review discusses the role of TNF-alpha in pathological conditions in cattle, including infections and metabolic diseases caused by perturbation of metabolism and endocrine functions. PMID- 21794007 TI - The effect of beta and kappa casein genes on milk yield and milk composition in different percentages of Holstein in crossbred dairy cattle. AB - The objective of this study was to compare the genotype, and composite genotype frequency, and the association between beta and kappa casein genes and milk yield (MY), percentage of fat (%Fat), protein (%Prot), and solids non-fat (%SNF) between two groups of crossbred Holstein: G1 <= 87.5% Holstein = 89 cows and G2 > 87.5% Holstein = 142 cows. Five genotypes of beta casein gene were observed. A1A2 and A1B were the most and rarest frequency, respectively, in both groups. Five genotypes of kappa casein gene were found. The highest and the lowest frequency were AA, and BB and BE, respectively, in both groups. Composite genotype A1A2AA was the most frequent in both groups. Linkage disequilibrium (LD) between two genes was detected. Significant differences of frequencies between both groups of both genes were not found. The association of the genes and the traits was different between G1 and G2. Negative effects on the traits were found in both groups. In addition, the stronger effect of the beta casein gene was observed in most of the traits. The conclusions were that different %Holstein caused different significant effects of these genes. A study of the association of these genes within each percentage of Holstein is strongly recommended. PMID- 21794008 TI - Analysis of genetic diversity and phylogenetic relationship of red deer subspecies in XinJiang, China. AB - Polymorphisms for seven microsatellite loci in three red deer subspecies (9 populations) found in XinJiang were detected by polymerase chain reaction (PCR), 12% nondenaturation polyacrylamide gel electrophoresis and the Sanguinetti silver staining method. Numbers of alleles, average effective numbers of alleles (E) and the average rate of homozygosity, allelic frequencies of seven microsatellite loci, polymorphism information content (PIC), mean heterozygosity (H) and genetic distances among the populations were calculated for each population. Dendrograms were constructed based on genetic distances by the neighbor-joining method (NJ), utilizing molecular evolutionary genetics analysis software PHYLIP (3.6). The phylogenetic tree was constructed based on allelic frequencies using maximum likelihood (ML); the bootstrap value was estimated by bootstrap test in the tree. Lastly, phylogenesis was analyzed. The results showed that four of the seven microsatellite loci were highly polymorphic, but BMS2508 and Celjp0023 showed no polymorphism and BM5004 was a neutral polymorphism. It is our conclusion that the four microsatellite loci are effective DNA markers for the analysis of genetic diversity and phylogenetic relationships among the three red deer subspecies. The mean PIC, H and E-values across the microsatellite loci were 0.5393, 0.5736 and 2.64, which showed that these microsatellite loci are effective DNA markers for the genetic analysis of red deer. C.e. songaricus populations from Regiment 104, 151 and Hami are clustered together. C.e. yarkandensis populations from Regiment 35, Xaya and Alaer are clustered together. These two clusters also cluster together. Lastly, C.e. sibiricus populations from Burqin, Regiment 188 and the first two clusters were clustered together. The phylogenetic relationship among different red deer populations is consistent with the known origin, history of breeding and geographic distributions of populations. PMID- 21794009 TI - DNA methylation analysis on satellite I region in blastocysts obtained from somatic cell cloned cattle. AB - Many observations have been made on cloned embryos and on adult clones by somatic cell nuclear transfer (SCNT), but it is still unclear whether the progeny of cloned animals is presenting normal epigenetic status. Here, in order to accumulate the information for evaluating the normality of cloned cattle, we analyzed the DNA methylation status on satellite I region in blastocysts obtained from cloned cattle. Embryos were produced by artificial insemination (AI) to non cloned or cloned dams using semen from non-cloned or cloned sires. After 7 days of AI, embryos at blastocyst stage were collected by uterine flushing. The DNA methylation levels in embryos obtained by using semen and/or oocytes from cloned cattle were similar to those in in vivo embryos from non-cloned cattle. In contrast, the DNA methylation levels in SCNT embryos were significantly higher (P < 0.01) than those in in vivo embryos from non-cloned and cloned cattle, approximately similar to those in somatic cells used as donor cells. Thus, this study provides useful information that epigenetic status may be normal in the progeny of cloned cattle, suggesting the normality of germline cells in cloned cattle. PMID- 21794010 TI - Effects of high ambient temperature on urea-nitrogen recycling in lactating dairy cows. AB - Effects of exposure to hot environment on urea metabolism were studied in lactating Holstein cows. Four cows were fed ad libitum a total mixed ration and housed in a temperature-controlled chamber at constant moderate (18 degrees C) or high (28 degrees C) ambient temperatures in a cross-over design. Urea nitrogen (N) kinetics was measured by determining urea isotopomer in urine after single injection of [(15) N(2) ]urea into the jugular vein. Both dry matter intake and milk yield were decreased under high ambient temperature. Intakes of total N and digestible N were decreased under high ambient temperature but urinary urea-N excretion was increased. The ratio of urea-N production to digestible N was increased, whereas the proportion of gut urea-N entry to urea-N production tended to be decreased under high ambient temperature. Neither return to the ornithine cycle, anabolic use nor fecal excretion of urea-N recycled to the gut was affected by ambient temperature. Under high ambient temperature, renal clearance of plasma urea was not affected but the gut clearance was decreased. Increase of urea-N production and reduction of gut urea-N entry, in relative terms, were associated with increased urinary urea-N excretion of lactating dairy cows in higher thermal environments. PMID- 21794011 TI - Influences of grassland degradation on forage availability by sheep in the inner Mongolian steppes of China. AB - In China and throughout the world, evaluation of the nutrient values of forages has always lagged behind research regarding the nutrient requirements of animals. In this study, the effective degradability and availability of forages were evaluated on undegraded and degraded grassland using a technique where nylon bags were incubated in sheep rumen. We found that the concentrations of organic matter (OM), neutral detergent fiber (NDF), non-fiber carbohydrates (NFC) and carbohydrates (CHO) of forage were higher (P < 0.05) and the crude protein (CP) concentration was lower (P < 0.05) in the degraded grassland than in the undegraded grassland. The effective degradability (ED) of NFC (ED(NFC) ) was higher (P < 0.05) and ED(CHO) and ED(NDF) were lower in the undegraded grassland than in the degraded grassland. The ED(OM) and ED(CP) were not affected by the type of grassland, which may explain why ED is an inadequate parameter for the evaluation of forage availability. According to an analysis of the ratio of effectively degraded N to OM and NFC, plants of the undegraded grassland can provide more digestive nutrients to meet the requirements of grazing animals compared to plants of the degraded grassland. Results suggested that it is inadequate to consider only chemical composition and effective degradability when evaluating forage availability with grassland degradation. The ratio of effectively degraded N to OM and NFC was an appropriate indicator. PMID- 21794012 TI - Effect of cellooligosaccharide or synbiotic feeding on growth performance, fecal condition and hormone concentrations in Holstein calves. AB - We investigated the effect of cellooligosaccharide (CE) or a combination of dextran and Lactobacillus casei ssp. casei strain JCM1134(T) (synbiotic; SB) feeding on growth performance, fecal condition and hormone concentrations in Holstein calves. Fifty-two female Holstein calves were randomly assigned to three treatment groups: CE feeding group (n = 16), SB feeding group (n = 18), and control group (n = 18). Body weight at 90 days of age, as well as daily body weight gain (DG) and feed efficiency after weaning to 90 days of age were greater (P < 0.05) in the CE feeding group than in the control group. The total fecal score tended to be lower (P < 0.1) in the SB feeding group than in the control group. Plasma insulin concentration was higher (P < 0.05) in the CE feeding group than in the control group at 90 days of age. Our results indicate that CE feeding improved DG and feed efficiency in calves. On the other hand, there was less effect on growth performance and fecal Escherichia coli counts in calves fed SB. PMID- 21794013 TI - The effects of wilting and storage temperatures on the fermentation quality and aerobic stability of stylo silage. AB - In order to clarify the ensiling characteristics of stylo (Stylosanthes guianensis Swartz), the effects of wilting (no wilting, light wilting and heavy wilting) and storage temperatures (10 degrees C, 20 degrees C, 30 degrees C and 40 degrees C) on the fermentation quality and aerobic stability of stylo silage were investigated. Wilting had no significant influence on the contents of crude protein, ether extract and acid detergent fiber, and numbers of lactic acid bacteria, aerobic bacteria, yeasts and mold (P > 0.05). Heavy wilted material, wilted for 12 h, had higher neutral detergent fiber content and lower water soluble carbohydrate content than unwilted and light wilted materials (P < 0.05). Wilting and storage temperatures had significant effects on pH value, acetic acid, butyric acid and NH(3) -N contents of stylo silage (P < 0.01 or P < 0.05). Wilting tended to reduce acetic acid and NH(3) -N contents and improve the fermentation quality of stylo silage. In all the silages, no wilting silage ensiled at 30 degrees C had the highest butyric acid content (P < 0.05). High temperature of 40 degrees C markedly restricted the growth of lactic acid bacteria and aerobic bacteria in silage, irrespective of wilting. The wilted silage or silage stored at low temperature had poor aerobic stability. PMID- 21794014 TI - Effect of supplementation of soy sauce oil and Ca salts of fatty acids on rumen fermentation, milk production and conjugated linoleic acid in milk of dairy cows. AB - Eight cows were used to evaluate the effects of supplementation of soy sauce oil (SO) or Ca salts of fatty acids (FA) on rumen fermentation and milk production. The control diet (CO) consisted mainly of hay, corn silage and a concentrate. In the experimental diets, 400 g/day per cow of SO or FA (soybean oil and rapeseed oil) was supplemented to the CO diet. Experimental period for the three treatments was 14 days, and milk samples were taken during the last 2 days and rumen sample was taken on the last day. Dry matter intake was not affected by the treatments. The number of rumen protozoa at 0 h increased by SO and FA diets. Total volatile fatty acids at 2 h after feeding of SO diet was decreased compared to CO. The milk composition yield did not differ among treatments, although the percentages of fat and protein were decreased by SO and FA diets. The proportions of C8-C16 fatty acids in milk fat decreased, and those of C18 increased by SO and FA diets. The proportion of cis-9, trans-11 conjugated linoleic acid in milk fat by SO and FA diets increased by 120% and 135%, respectively. In spite of the slight suppression of rumen fermentation by SO diet, negative effects on feed intake and milk production were not detected. PMID- 21794015 TI - Alleviation of body weight loss by dietary methionine is independent of insulin like growth factor-I in protein-starved young chickens. AB - It is well known that in protein-starved chickens, small amounts of amino acid supplement, especially methionine, reduces nitrogen excretion and thereby improves nitrogen balance. On the other hand, excess intake of methionine causes growth depression and the growth-depressive effect of excess methionine can be alleviated by consumption of dietary glycine. Insulin-like growth factor-I (IGF I) is one of various growth-promoting factors relating to the efficiency of animal production and is known to be very sensitive to changes in nutritional status. In the present study, the interactive effect of glycine on nitrogen sparing effect of methionine in protein-starved chickens was examined. In addition, the relation of IGF-I and its specific binding protein to the nitrogen sparing effect of supplemented methionine was also investigated. Two-days refeeding of methionine supplemented to protein-free diet could promptly alleviate body weight loss in protein-starved chickens, and the alleviation of body weight loss by methionine was not improved by glycine supplements. Moreover, such acute alleviation of body weight loss by dietary methionine was independent of the change in plasma IGF-I concentration. PMID- 21794016 TI - The effects of concentrations of lysine in media on differentiation of 3T3-L1 preadipocytes. AB - Intramuscular fat content is increased by feeding of low lysine diets in pigs. Reduction in dietary lysine intake results in low plasma lysine concentration and low cytosolic lysine concentration in skeletal muscles. From these observations, we hypothesized that low plasma lysine concentration in pigs fed on low lysine diets reduced supply of lysine from blood circulation to preadipocytes, and this limited supply of lysine might promote adipocyte differentiation in porcine muscles. In order to verify the hypothesis, we investigated the effects of low concentrations of lysine in culture medium on differentiation of 3T3-L1 preadipocytes. Low concentration of lysine suppressed lipid accumulation and messenger RNA (mRNA) expression and enzyme activity of fatty acid synthase. mRNA expressions of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha) were lower in cells cultured in low lysine medium. On the other hand, mRNA and protein expressions of C/EBPbeta and C/EBPdelta were not inhibited by low concentrations of lysine in culture medium. These results indicate that low lysine concentrations in culture medium inhibit differentiation of 3T3-L1 preadipocytes through inhibiting the mRNA expressions of PPARgamma and C/EBPalpha. PMID- 21794017 TI - The investigation of probiotic potential of lactic acid bacteria isolated from traditional Mongolian dairy products. AB - The aims of this study were to investigate the diversity of lactic acid bacteria (LAB) isolated from traditional Mongolian dairy products, and to estimate the probiotic potential of the isolated strains. We collected 66 samples of the traditional Mongolian dairy products tarag (n = 45), airag (n = 7), aaruul (n = 8), byasulag (n = 1) and eezgii (n = 5), from which 543 LAB strains were isolated and identified based on 16S ribosomal DNA sequence. The predominant species of those products were Lactobacillus (L.) delbrueckii ssp. bulgaricus, L. helveticus, L. fermentum, L. delbrueckii ssp. lactis and Lactococcus lactis ssp. lactis. However, we could not detect any LAB strains from eezgii. All LAB isolates were screened for tolerance to low pH and to bile acid, gas production from glucose, and adherence to Caco-2 cells. In vitro, we found 10 strains possess probiotic properties, and almost identified them as L. plantarum or L. paracasei subspecies, based on 16S ribosomal DNA and carbohydrate fermentation pattern. These strains were differentiated from each other individually by randomly amplified polymorphic DNA analysis. Additionally, it was notable that 6/10 strains were isolated from camel milk tarag from the Dornogovi province. PMID- 21794018 TI - Effects of the feeding of wild Yeso sika deer (Cervus nippon yesoensis) on the prevention of damage due to bark stripping and the use of feeding sites. AB - Feeding sites for wild Yeso sika deer around Lake Akan, Japan, were established. Effects on the number of deer using the feeding sites, the prevention of bark stripping damage, the amount of feeding, and eating time in a 5-year period (1999 2003) were evaluated. The number of deer using feeding sites increased with years during the feeding period. The damaged tree ratio after the initiation of feeding markedly decreased compared with 16.5% before the initiation of feeding. After the start of feeding, there were no trees with damage the entire circumference. According to tree species, the number of damaged trees of Ulmus laciniata Mayr as a percentage of all investigated trees was high (5.2%). The total amount of beet pulp feeding increased with the feeding year, showing 4.5-fold increase. At feeding sites in deer culling, eating behavior was observed during the night. The preventive effects on bark stripping damage continued during the 5-year feeding period. However, with the course of feeding years, the number of deer using feeding sites and the level of feeding increased. PMID- 21794019 TI - Effects of haul distance and stocking density on young suckling calves transported in Japan. AB - We conducted applicability evaluation of recommendations of the European Union (EU) and the Royal Society for Prevention of Cruelty to Animals (RSPCA) for suckling calves. Nineteen calves (14 Holstein aged 11-26 days and five cross-bred aged 13-45 days) were divided into six groups. Three groups were allocated into the stocking densities of 0.25, 0.35, 0.45 m2 /head and were weekly transported 50, 100, 150 km in this order. Another three groups were allocated and transported in reverse order. Observation was conducted during and after transportation. Blood sampling was performed before and after transportation. The occurrences of lying and turning round on the truck were significantly associated with stocking density (P < 0.05), but not with haul distance. Scratching was observed only in one calf. Incidence of watery feces was not associated with both factors. There were significant effects of haul distance on the concentrations of plasma cortisol and noradrenaline, and serum aspartate aminotranserase (AST) and IgM (P < 0.05). These concentrations, except cortisol, were higher after transportation at 150 km compared to the pre-transportation value (AST and IgM P < 0.05; noradrenaline P < 0.10). Results suggest that haul distances greater than 100 km should not be recommended even for suckling calves transported in Japan. PMID- 21794020 TI - Heat tolerance and the effects of shade on the behavior of Simmental bulls on pasture. AB - The objectives were to assess the degree of thermolysis capacity as a characteristic of heat tolerance of the Simmental beef cattle and evaluate the effects of shade and shade type (artificial: AS, trees: TS, or no shade: NS) on daily behavior patterns during summer. Black globe temperature (BGT) was different under the two types of shade (P < 0.05) and was lower under the TS (P < 0.01) and under AS (P > 0.01) than average BGT in the sun. Animals when in AS used more intensely the shade (P = 0.002) mostly lying down under it (10.00-14.00 hours), while time standing was similar (P = 0.107) between TS and NS. Bulls without shade (NS) spent significantly more time at the water trough and most part of the day standing idle (72.4%, 10.1 h/14 h). TS bulls spent more time grazing/standing (P < 0.001). The Simmental bulls that were in TS and AS spent more time ruminating than bulls that stay without shade (NS). The availability of shade changes grazing, rumination and idling behavior of cattle in response to environmental conditions. Shade provided by trees can be more efficient than artificial shading as cattle spent more time grazing when tree shade was available. Thermolysis capacity can be used to select heat-tolerant animals. PMID- 21794021 TI - The effects of chronic intermittent noise exposure on broiler chicken performance. AB - Effects of different noise levels (70 or 80 dB) that broilers were exposed to during the entire fattening period and also the effect of the timing of the first exposure to intermittent noise in the course of fattening (day 1 vs. day 7) were monitored. After 7 days of exposure to intermittent noise, experimental chickens already showed a significant decrease in live body weight in comparison with the control group. The difference between the group exposed to intermittent noise at 70 dB and the group exposed to 80 dB levels was not statistically significant, although the mean live body weight of broilers in the latter was lower during the entire fattening period. The chickens exposed to intermittent noise from day 1 of age showed lower mean live weight throughout the fattening period compared to chickens exposed to the same level of intermittent noise only from day 7 of age, although at the end of fattening the difference was statistically significant only in chickens exposed to the higher level of intermittent noise (80 dB). PMID- 21794022 TI - Effect of liquid whey feeding on fecal microbiota of mature and growing pigs. AB - The effect of liquid whey feeding on fecal bacteria and their metabolites was assessed in five pregnant sows and 66 growing pigs. Sows were fed a control diet for 4 weeks (control period) followed by the same diet but with whey feeding (5 L/day/pig) for 4 weeks (whey period). One group of growing pigs was given 267 L of whey per pig (whey group), while the other group was not (control group). In both cases, liquid whey was given separately from control diet. Sows in the whey period had feces showing lower pH, lower ammonia concentration, and larger population sizes of total bacteria, lactobacilli and bifidobacteria. The bacterial gene library analysis indicated that Mitsuokella and Megasphaera were more frequently detected, while Clostridium disporicum were detected less frequently in the whey period. Feces from whey-fed growing pigs showed lower pH than that from control pigs in the early stage of growing. Also, larger populations of total bacteria, lactobacilli and bifidobacteria were recorded in the whey group. From the bacterial gene library analysis, the detection frequency of Lactobacillus reuteri tended to be higher in the whey group. These results indicate that whey feeding influences the hindgut microbiota of pigs, possibly leading to a fermentation shift that is favorable for animal health. PMID- 21794023 TI - Non-invasive sampling technique for DNA extraction from captive Japanese Crested Ibis on Sado Island. AB - The Japanese Crested Ibis Nipponia nippon is a critically threatened bird. The post-hatch eggs of the current captive population of this species on Sado Island have been stored at room temperature for the long-term. In this study, we investigated the suitability of the vascularized chorioallantois membrane from the eggs as a non-invasive DNA source. Using microsatellite loci developed for the Japanese Crested Ibis, we performed three experiments for comparison of genotypes obtained among DNA. First, DNA from five different sites of the identical membrane showed the same genotypes at either of two loci examined. Second, DNA from the membrane of each full-sibling birds and blood of their parents showed the genotypes that were consistent with Mendelian parent-offspring relationships at any of eight loci examined. Third, DNA from the membrane and blood of the same bird showed the matched genotypes at any of eight loci examined. These results indicate that the vascularized chorioallantois membrane from post-hatch eggs stored at room temperature for the long- term can be used as a reliable DNA source of offspring that had hatched from the egg. This study will promote a molecular genetics study on genetic diversity of the current captive Japanese Crested Ibis population on Sado Island. PMID- 21794024 TI - The affect of chronic hepatitis C infection on dendritic cell function: a summary of the experimental evidence. AB - Chronic hepatitis C virus (HCV) infection occurs in patients who fail to mount an effective T-cell response against the virus. One hypothesis for poor anti-viral immunity in these patients is that the virus impedes the immune response by disabling dendritic cells (DCs), cells that play a key role in pathogen recognition and initiation of adaptive immunity. Initial studies in the 1990s supported this hypothesis, as they clearly demonstrated that monocyte-derived DCs obtained from patients with chronic HCV infection displayed a reduced ability to stimulate lymphocyte proliferation. However, over the last 20 years, the situation has become more ambiguous. Many studies support the initial observation of a DC defect, while others using different patient cohorts or technologies have clearly demonstrated intact DC function in patients with chronic HCV. It is likely that the true situation lies somewhere in between. Just as there is a spectrum of disease in patients with chronic HCV, DCs obtained from different patients may display different properties. It is important to reconcile these divergent findings, as a clearer understanding of how the virus affects DC function will facilitate the development of immunotherapy and therapeutic vaccination strategies for patients with chronic HCV infection. PMID- 21794025 TI - There were no differences in serum HBV DNA level between HBeAg-positive and HBeAg negative chronic hepatitis B with same liver histological necroinflammation grade but differences among grades 1, 2, 3 and 4 apportioned by the same hepatic parenchyma cell volume. AB - Hepatitis B virus (HBV) DNA levels and liver histological necroinflammation grades are correlated with the antiviral efficacy. It is necessary to clarify the relationship between HBV replication levels apportioned by the same hepatic parenchyma cell volume and severity of liver histological necroinflammation grades in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B. The serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume were compared between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4, respectively. There were no differences in the serum HBV DNA levels between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4. However, there were differences in the serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume among liver histological necroinflammation grades 1, 2, 3 and 4 in both HBeAg-positive and HBeAg-negative chronic hepatitis B, respectively. There were no differences in HBV DNA levels with the same liver histological necroinflammation grade activated by HBV wild-type and variant strains. After the differences in hepatic parenchyma cell volume for HBV replication of the same liver histological necroinflammation grade accompanied by different hepatic fibrosis stages were adjusted, the serum HBV DNA level apportioned by the same hepatic parenchyma cell volume was correlated with the severity of liver histological necroinflammation grade. PMID- 21794027 TI - Models in the balance: evidence-based medicine versus evidence-informed individualized care. PMID- 21794028 TI - Enhancement of B-cell receptor signaling by a point mutation of adaptor protein 3BP2 identified in human inherited disease cherubism. AB - Tyrosine phosphorylation of adaptor protein c-Abl-Src homology 3 (SH3) domain binding protein-2 (3BP2, also referred to SH3BP2) positively regulates the B-cell antigen receptor (BCR)-mediated signal transduction, leading to the activation of nuclear factor of activated T cells (NFAT). Here we showed the effect of the proline to arginine substitution of 3BP2 in which is the most common mutation in patients with cherubism (P418R) on B-cell receptor signaling. Comparing to the wild type, overexpression of the mutant form of 3BP2 (3BP2-P416R, corresponding to P418R in human protein) enhanced BCR-mediated activation of NFAT. 3BP2-P416R increased the signaling complex formation with Syk, phospholipase C-gamma2 (PLC gamma2), and Vav1. In contrast, 3BP2-P416R could not change the association with the negative regulator 14-3-3. Loss of the association mutant that was incapable to associate with 14-3-3 could not mimic BCR-mediated NFAT activation in Syk deficient cells. Moreover, BCR-mediated phosphorylation of extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was not affected by P416R mutation. These results showed that P416R mutation of 3BP2 causes the gain of function in B cells by increasing the interaction with specific signaling molecules. PMID- 21794029 TI - Influenza virus infection induces cellular Ebp1 gene expression. AB - Influenza virus RNA-dependent RNA polymerase is composed of three viral proteins, PB1, PB2, and PA. The host protein Ebp1 (ErbB3-binding protein1) interacts with PB1, and inhibits both in vitro RNA synthesis and virus replication. On Western blotting, the induction of Ebp1 was observed after influenza virus infection. To understand the induction of Ebp1 by influenza virus infection, we introduced a series of deletions within the 981-nucleotide long sequence located upstream of the Ebp1 gene (-664 to +317 nt from the transcription initiation site) and ligated them to the GFP gene. GFP expression assays indicated that the 981-nt upstream region was required for expression of GFP in not all cells but some cells. Microscopic analysis of the transformants showed that GFP expression was up-regulated by the influenza virus infection. Furthermore, quantitative real time PCR indicated that influenza virus infection induced Ebp1 mRNA expression. Our data showed that (i) the newly synthesized vRNP of influenza virus induces Ebp1 expression; (ii) the Ebp1 promoter localizes between -664 nt and the initiation site of the Ebp1 gene, +317-nt long sequence in the noncoding region is required for regulation of Ebp1 gene expression; and (iii) Ebp1 expression level is correlated with virus protein expression level. PMID- 21794030 TI - Alternative splicing of myomesin 1 gene is aberrantly regulated in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by a CTG repeat expansion in the 3'-UTR of dystrophia myotonica-protein kinase. Aberrant regulation of alternative splicing is a characteristic feature of DM. Dozens of genes have been found to be abnormally spliced; however, few reported splicing abnormalities explain the phenotypes of DM1 patients. Thus, we hypothesized that other, unknown abnormal splicing events exist. Here, by using exon array, we identified aberrant inclusion of myomesin 1 (MYOM1) exon 17a as a novel splicing abnormality in DM1 muscle. A cellular splicing assay with a MYOM1 minigene revealed that not only MBNL1-3 but also CELF1 and 2 decreased the inclusion of MYOM1 exon 17a in HEK293T cells. Expression of expanded CUG repeat impeded MBNL1 activity but did not affect CELF1 activity on the splicing of MYOM1 minigene. Our results suggest that the downregulation of MBNL proteins should lead to the abnormal splicing of MYOM1 exon 17a in DM1 muscle. PMID- 21794031 TI - Rapid and sensitive detection of Pseudomonas aeruginosa in chlorinated water and aerosols targeting gyrB gene using real-time PCR. AB - AIMS: For the rapid detection of Pseudomonas aeruginosa from chlorinated water and aerosols, gyrB gene-based real-time PCR assay was developed and investigated. METHODS AND RESULTS: Two novel primer sets (pa722F/746MGB/899R and pa722F/746MGB/788R) were designed using the most updated 611 Pseudomonas and 748 other bacterial gyrB genes for achieving high specificity. Their specificity showed 100% accuracy when tested with various strains including clinical isolates from cystic fibrosis patients. The assay was tested with Ps. aeruginosa containing chlorinated water and aerosols to simulate the waterborne and airborne transmission routes (detection limit 3.3 * 102 CFU per PCR-2.3 * 103 CFU per PCR). No chlorine interference in real-time PCR was observed at drinking water level (c. 1 mg l-1), but high level of chorine (12 mg l-1) interfered the assay, and thus neutralization was needed. Pseudomonas aeruginosa in aerosol was successfully detected after capturing with gelatin filters with minimum 2 min of sampling time when the initial concentration of 104 CFU ml-1 bacteria existed in the nebulizer. CONCLUSIONS: A highly specific and rapid assay (2-3 h) was developed by targeting gyrB gene for the detection of Ps. aeruginosa in chlorinated water and aerosols, combined with optimized sample collection methods and sample processing, so the direct DNA extraction from either water or aerosol was possible while achieving the desired sensitivity of the method. SIGNIFICANCE AND IMPACT OF THE STUDY: The new assay can provide timely and accurate risk assessment to prevent Ps. aeruginosa exposure from water and aerosol, resulting in reduced disease burden, especially among immune-compromised and susceptible individuals. This approach can be easily utilized as a platform technology for the detection of other types of micro-organisms, especially for those that are transmitted via water and aerosol routes, such as Legionella pneumophila. PMID- 21794032 TI - Preparation of reference strains for validation and comparison of mycoplasma testing methods. AB - AIMS: To optimize growth conditions for preparation of stocks of mycoplasma reference strains to obtain highly viable and disperse samples with low ratios of genomic copy (GC) number to that of colony forming units (CFU). These stocks are required for assessment of relative limits of detection (LOD) of alternative nucleic acid testing (NAT)-based methods in comparison to the conventional microbiological methods. METHODS AND RESULTS: A kinetics study was used to assess the changes in ratios between the numbers of GC and CFU at different growth phases of six different mycoplasma cultures Acholeplasma laidlawii, Mycoplasma gallisepticum, Mycoplasma arginini, Mycoplasma fermentans, Mycoplasma orale and Mycoplasma pneumoniae. All tested mycoplasmas demonstrated low GC/CFU ratios (<= 10) within the log and early stationary growth phases. A significant increase in GC/CFU ratios was observed at the very late stationary and death phases, when the titre of cultures has declined. Similar patterns of GC/CFU profiles were observed for A. laidlawii and Myc. gallisepticum co-cultured with suspension of Chinese hamster ovary (CHO) cells. CONCLUSIONS: Tested mycoplasma strains harvested at the exponential-early stationary phases of growth demonstrated the lowest GC/CFU ratios and low propensity to form filamentous structures or aggregates under proposed conditions and can be used for the preparation of a mycoplasma reference panel for methods comparability study. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that the preparation and use of viable mycoplasma reference strains with low CG/CFU ratios is the most reliable way to adequately evaluate the LOD of alternative NAT-based mycoplasma testing methods. PMID- 21794033 TI - Azotobacter vinelandii gene clusters for two types of peptidic and catechol siderophores produced in response to molybdenum. AB - AIM: To characterize the complementary production of two types of siderophores in Azotobacter vinelandii. METHODS AND RESULTS: In an iron-insufficient environment, nitrogen-fixing A. vinelandii produces peptidic (azotobactin) and catechol siderophores for iron uptake to be used as a nitrogenase cofactor. Molybdenum, another nitrogenase cofactor, was also found to affect the production level of siderophores. Wild-type cells excreted azotobactin into molybdenum-supplemented and iron-insufficient medium, although catechol siderophores predominate in molybdenum-free environments. Two gene clusters were identified to be involved in the production of azotobactin and catechol siderophores through gene annotation and disruption. Azotobactin-deficient mutant cells produced catechol siderophores under the molybdenum-supplemented and iron-insufficient conditions, whereas catechol siderophore-deficient mutant cells extracellularly secreted excess azotobactin under iron-deficient condition independent of the concentration of molybdenum. This evidence suggests that a complementary siderophore production system exists in A. vinelandii. CONCLUSIONS: Molybdenum was found to regulate the production level of two types of siderophores. Azotobacter vinelandii cells are equipped with a complementary production system for nitrogen fixation in response to a limited quantity of metals. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study identifying A. vinelandii gene clusters for the biosynthesis of two types of siderophores and clarifying the relationship between them. PMID- 21794034 TI - In vitro efficacy of bismuth thiols against biofilms formed by bacteria isolated from human chronic wounds. AB - AIMS: The purpose of this study was to evaluate the antimicrobial efficacy of thirteen bismuth thiol preparations for bactericidal activity against established biofilms formed by two bacteria isolated from human chronic wounds. METHODS: Single species biofilms of a Pseudomonas aeruginosa or a methicillin-resistant Staphylococcus aureus were grown in either colony biofilm or drip-flow reactors systems. Biofilms were challenged with bismuth thiols, antibiotics or silver sulfadiazine, and log reductions were determined by plating for colony formation. CONCLUSIONS: Antibiotics were ineffective or inconsistent against biofilms of both bacterial species tested. None of the antibiotics tested were able to achieve >2 log reductions in both biofilm models. The 13 different bismuth thiols tested in this investigation achieved widely varying degrees of killing, even against the same micro-organism in the same biofilm model. For each micro organism, the best bismuth thiol easily outperformed the best conventional antibiotic. Against P. aeruginosa biofilms, bismuth-2,3-dimercaptopropanol (BisBAL) at 40-80 MUg ml-1 achieved > 7.7 mean log reduction for the two biofilm models. Against MRSA biofilms, bismuth-1,3-propanedithiol/bismuth-2 mercaptopyridine N-oxide (BisBDT/PYR) achieved a 4.9 log reduction. SIGNIFICANCE AND IMPACT OF THE STUDY: Bismuth thiols are effective antimicrobial agents against biofilms formed by wound bacteria and merit further development as topical antiseptics for the suppression of biofilms in chronic wounds. PMID- 21794036 TI - Characterization of a Yersinia enterocolitica biotype 1A strain harbouring an ail gene. AB - AIMS: The chromosomal ail gene (attachment and invasion locus) is commonly used as target gene for the detection of pathogenic Y. enterocolitica strains in food testing. The ail PCR does not detect strains of biotype 1A (BT1A), which are regarded as non-pathogenic because BT1A strains lack the virulence plasmid and chromosomally encoded virulence genes. In some recent reports, however, BT1A strains were discovered that harboured the ail gene. We isolated an ail-positive strain and characterized this strain with phenotypic and genotypic methods to study its possible relation to pathogenic Y. enterocolitica strains. METHODS AND RESULTS: The ail region of the BT1A strain was sequenced and compared with the corresponding region of nonpathogenic BT1A strains and pathogenic strains. Pulsed field gel electrophoresis (PFGE) analysis was applied revealing no similarity of the PFGE pattern of this strain to the patterns of pathogenic strains. Virulence gene-based PCR analyses showed the strain to be positive for ystB, but negative for virulence genes ystA, virF and yadA. Whole-cell MALDI-TOF MS combined with a shrinkage discriminant analysis approach was applied and clearly classified the ail-positive biotype 1A strain within the cluster of BT1A strains. CONCLUSIONS: PCR detection of ail sequences in food matrices should be followed by the isolation of the responsible strain and its characterization using phenotypic or genotypic methods. SIGNIFICANCE AND IMPACT OF THE STUDY: The ail gene may be present in Y. enterocolitica BT1A strains, which are commonly considered as nonpathogenic. Efficient methods such as PCR typing of other virulence genes or rapid MALDI-TOF MS-based bacterial profiling allow a more comprehensive assessment of the pathogenicity potential of Yersinia strains. PMID- 21794035 TI - Prior frozen storage enhances the effect of edible coatings against Listeria monocytogenes on cold-smoked salmon during subsequent refrigerated storage. AB - AIMS: Listeria monocytogenes is a major safety concern for ready-to-eat foods. The overall objective of this study was to investigate whether prior frozen storage could enhance the efficacy of edible coatings against L. monocytogenes on cold-smoked salmon during subsequent refrigerated storage. METHODS AND RESULTS: A formulation consisting of sodium lactate (SL, 1.2-2.4%) and sodium diacetate (SD, 0.125-0.25%) or 2.5% Opti.Form (a commercial formulation of SL and SD) was incorporated into each of five edible coatings: alginate, kappa-carrageenan, pectin, gelatin and starch. The coatings were applied onto the surface of cold smoked salmon slices inoculated with L. monocytogenes at a level of 500 CFU cm-2. In the first phase, the slices were first frozen at -18 degrees C for 6 days and stored at 22 degrees C for 6 days. Alginate, gelatin and starch appeared to be the most effective carriers. In the second phase, cold-smoked salmon slices were inoculated with L. monocytogenes, coated with alginate, gelatin or starch with or without the antimicrobials and stored frozen at -18 degrees C for 12 months. Every 2 months, samples were removed from the freezer and kept at 4 degrees C for 30 days. Prior frozen storage at -18 degrees C substantially enhanced the antilisterial efficacy of the edible coatings with or without antimicrobials during the subsequent refrigerated storage. CONCLUSIONS: Plain coatings with >= 2 months frozen storage and antimicrobial edible coatings represent an effective intervention to inhibit the growth of L. monocytogenes on cold-smoked salmon. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the effectiveness of the conjunct application of frozen storage and edible coatings to control the growth of L. monocytogenes to enhance the microbiological safety of cold-smoked salmon. PMID- 21794037 TI - Meta-analysis of alcohol consumption and risk of extrahepatic bile system cancer. AB - AIM: Alcohol consumption increases the risk of liver cancer. However, there is still controversy regarding alcohol consumption and the risk of extrahepatic bile system cancer (EBSC). We performed a meta-analysis to provide an overview of the relevant studies and gain more robust estimates of the relationship between alcohol consumption and risk of EBSC. METHODS: Relevant studies published between January 1966 and October 2010 were identified by searching Medline, Embase and the Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between alcohol consumption and risk of EBSC was assessed by adjusted odds ratio (OR). RESULTS: A total of 113 767 participants from 10 studies (nine case-control studies and one cohort study) were identified in this meta-analysis. The studies provided adjusted overall OR estimates for drinkers versus non-/low drinkers, leading to a pooled adjusted OR of 0.82 (95% confidence interval [CI] = 0.72-0.94, P for heterogeneity = 0.194, I(2) = 27.2%). The overall adjusted OR of hospital-based studies and population based studies were 0.80 (95% CI = 0.65-0.99, P = 0.260) and 0.79 (95% CI = 0.64 0.98, P = 0.119), respectively. For the heavy drinkers, the adjusted OR significance increased to 1.58 (95% CI = 0.97-2.57, P for heterogeneity = 0.055, I(2) = 65.4%), but it had no statistical significance. CONCLUSION: There is evidence that moderate alcohol consumption lowers the risk of EBSC compared with non-/low alcohol consumption, but not heavy alcohol consumption. Further multicenter and better controlled studies are required to confirm these findings. PMID- 21794038 TI - Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels. AB - AIM: Non-alcoholic steatohepatitis (NASH) is associated with increased hepatic insulin resistance. Ceramides and other toxic sphingolipids promote inflammation, lipotoxicity and insulin resistance; however, the role of ceramides in the pathogenesis of NASH has not been determined. This study characterizes expression of ceramide-related genes in human livers with NASH and examines the effects of weight loss on NASH and pro-ceramide gene expression in liver. METHODS: Liver biopsies were obtained to assess the histopathological status of non-alcoholic fatty liver disease/NASH prior to and following completion of a 1-year course of implementing either lifestyle changes or a standard enrichment protocol designed to encourage weight loss. Liver biopsy samples were used to measure pro-ceramide gene expression by quantitative reverse transcriptase polymerase chain reaction analysis (qRT-PCR), and serum was used to measure ceramide immunoreactivity. RESULTS: At baseline, serine palmitoyltransferase (SPTLC)2 (P = 0.02) and ceramide synthase (CER)1 (P = 0.001) mRNA transcripts were less abundantly expressed in livers with NASH relative to normal controls. After weight loss (average 9.3%), SPTLC1 (P = 0.005) and uridine diphosphate glucose ceramide glucosyltransferase (UGCG) (P = 0.001) expression significantly declined while CER1 increased (P = 0.001) among subjects randomized to the lifestyle change subgroup. Reductions in calorie and fat consumption were significantly correlated with changes in ceramide-related gene expression. Finally, both net and relative reductions in serum ceramide levels were significantly greater in the lifestyles compared with the standard enrichment (control) protocol group (both P < 0.005). CONCLUSION: NASH is associated with increased insulin resistance and altered ceramide gene expression in liver. Weight loss-mediated reversal of NASH is associated with reduced pro-ceramide gene expression in liver. PMID- 21794039 TI - Diagnostic value of hepatic intercellular adhesion molecule-1 expression in Egyptian infants with biliary atresia and other forms of neonatal cholestasis. AB - AIM: The diagnosis of biliary atresia (BA) is challenging as no single preoperative test is 100% accurate, especially for distinguishing it from other causes of neonatal cholestasis (NC). Intercellular adhesion molecule (ICAM) elevation was reported in BA as a part of the immune-mediated inflammatory process. The use of ICAM-1 as a discriminative tool between BA and other causes of NC has never been addressed before. This study was to evaluate the diagnostic potentials of ICAM-1 in BA versus other forms of NC. METHODS: For this purpose, serum ICAM-1 (sICAM-1) and ICAM-1 expression, in liver biopsy using immunohistochemistry, were estimated in 30 patients with BA and compared to that in 20 patients with other forms of NC. sICAM-1 levels were compared to that in 20 healthy controls. RESULTS: sICAM-1 levels were significantly higher in BA (1055.9 +/- 230.2 ng/mL) than that in cholestasis (604.8 +/- 194.8 ng/mL) and the control groups (158.9 +/- 78.7 ng/mL) (P < 0.0001). A cut-off value of 793.8 ng/mL had 86.7% sensitivity and 95% specificity in discriminating the BA from the cholestasis group. The biliary expression score of ICAM-1 at a cut-off value of 110 could discriminate between BA and other causes of NC with 100% sensitivity and specificity. Neither serum levels nor liver expression of ICAM-1 scores correlated with disease severity or with fibrosis stage. CONCLUSION: These results suggest that ICAM-1 has a diagnostic value in patients with BA and would be a promising helpful tool when investigating patients with NC. PMID- 21794040 TI - The use of recombinant human activated protein C (drotrecogin alpha) in solid organ transplant recipients: case series and review of the literature. AB - Septic shock occurs frequently in solid organ transplant (SOT) recipients. Standard therapy includes fluid resuscitation, the administration of antimicrobials, and source control of the infection. Adjunctive therapy with recombinant human activated protein C (rhaPC), also called drotrecogin alpha, is another treatment that is used in patients but has not been studied in SOT patients. Concerns regarding the use of this drug in this patient population include the risk of bleeding and the potential to adversely affect graft survival. Here we report the largest case series of SOT recipients with septic shock who received rhaPC. This was a retrospective chart review that looked at the impact of this drug in the SOT population. In this single-center study, we identified 17 patients with a SOT and septic shock who received rhaPC. Six of the patients underwent kidney transplants, 5 received lung transplants, 4 received cadaveric liver transplants, and 2 received combined kidney/pancreas transplants. The average APACHE II score was 26.6 +/- 5.5; all patients were undergoing mechanical ventilation and receiving vasopressors at the time of rhaPC administration. Overall mortality in the group was 23.5% (4/17) at 28 days post infusion. All of the deaths were due to complications of septic shock. Allograft survival was present in 13/17 (76.5%) of the patients at 28 days. Bleeding occurred in 17.6% of patients (3/17). The use of rhaPC appears to be associated with a favorable effect on mortality, with the potential for increased risk of bleeding. Clinicians must balance this risk with the potential benefit of this drug until further research can be conducted. PMID- 21794041 TI - Incidence and risk factors for infections after liver transplant: single-center experience at the University Hospital Fundacion Santa Fe de Bogota, Colombia. AB - The incidence of infections in liver transplant patients is higher compared with recipients of other organs, and infections are one of the major complications after transplantation. The aim of our study was to evaluate the incidence, presentation and risk factors of infections in liver transplant recipients in a Latin-American population, and to compare the results with data worldwide. We performed a retrospective analysis of 94 consecutive patients undergoing liver transplantation between 2004 and 2008 at the University Hospital Fundacion Santa Fe de Bogota, Colombia. The patients contributed a total of 64.4 person years (PY). Fifty-two patients (55.3%) developed one or more infections, in total 83 events (128.9 infections/100 PY). Bacterial infections represented the most frequent event (71.1%), followed by viral (19.3%) and fungal infections (8.4%). In 1%, no causative organism was identified. More than one-third of infections (37%) occurred during the first 30 days, whereas 83% of all events were seen during the first 6 months. The most common site of pathogen localization was the bloodstream (25.3%), followed by the urinary tract (15.7%), liver with bile tract (14.5%), abdomen (10.8%), surgical site (7.2%), and lungs (9.6%). The overall mortality after 1 year was 14.9%, and 57.1% of the deaths were attributed to infections. We found that risk factors significantly associated with increased incidence rate ratio for infection were prolonged stay at the intensive care unit, the need for parenteral nutrition, and blood transfusion requirement. Our data provide additional information about etiology and epidemiology of infections after liver transplantation. PMID- 21794042 TI - Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation. AB - STUDY OBJECTIVES: To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. DESIGN: Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. SETTING: Medical school-affiliated teaching hospital. PATIENTS: Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). INTERVENTIONS: None. MAIN RESULTS: Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26+/-0.1 to 0.16+/-0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8+/-0.8 to 8.4+/-8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3+/-32.3 to 50.2+/-15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7+/-2.5 and 7.6+/ 1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and >=6 weeks post transplant, based on available data. Clearance and Vd >=6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. CONCLUSIONS: The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant. PMID- 21794043 TI - Safety of pre-engraftment prophylactic foscarnet administration after allogeneic stem cell transplantation. AB - Human herpesvirus-6 (HHV-6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic stem cell transplantation (SCT). Because our previous trial of preemptive therapy with foscarnet sodium (phosphonoformic acid; PFA) failed to prevent HHV-6 encephalitis, we conducted a prospective study to examine the safety of prophylactic PFA administration and elucidate the changes in the plasma HHV-6 DNA levels in the early post-SCT period. Plasma HHV-6 DNA was measured thrice weekly from day 6. PFA, 90 mg/kg/day, was administered from days 7 to 21 after bone marrow or peripheral blood SCT and to day 25 after umbilical cord blood transplantation. Of the 10 patients enrolled, 2 dropped out of the study, 1 because of early death, and 1 with a low glomerular filtration rate. Grade 3 or greater adverse events occurred in 9 of the 10 prophylactic PFA patients and in 7 of the 10 control patients who had clinical backgrounds similar to the study subjects and underwent SCT during the same period. Neurological disorders developed in none of the study subjects but in 4 of the 10 control patients, including 2 with HHV-6 encephalitis. HHV-6 reactivation occurred in 3 of the 10 study subjects. The prophylactic PFA regimen was thus safe and it may reduce the risk of limbic encephalitis, but is not considered to be potent enough to prevent HHV-6 reactivation. PMID- 21794044 TI - The exercise-induced inflammatory and oxidative state paradox. PMID- 21794045 TI - Expert opinion and clinical experience regarding patients with type 1 diabetes mellitus fasting on Yom Kippur. AB - This commentary constitutes the opinions of the endocrinologists whose names are appended. The commentary is based on articles published in peer-reviewed journals as listed in the cited references, as well as cumulative experience in treating patients with type 1 diabetes mellitus (T1DM). This commentary applies only to patients with T1DM, and does not apply to patients with type 2 DM who are being treated with insulin even though the principles may be similar. The recommendations outlined also do NOT apply to the pregnant woman with T1DM, who should not fast. Additionally, this commentary does not preclude an individual from directing any questions having to do with religious observance to a competent Rabbi. For example, with regard to fingerstick blood glucose testing, which requires the use of an electronic meter, we have received written council from Rabbi Yosef Shalom Eliashiv and Rabbi Joseph Efrati (Jerusalem, Israel), and Rabbi M. Weissmandl and Rabbi Mordechai Willig (NY) that the procedure is permissible when performed appropriately for the patient's welfare and health while fasting on Yom Kippur. PMID- 21794047 TI - Anatomy of medial canthal tendon in Caucasians. AB - BACKGROUND: To analyse the anatomy of the medial canthal tendon in Caucasians and to clarify the true anatomical nature of its posterior limb. METHODS: This was an experimental anatomic study. Seven Caucasian cadavers (11 eyelids; age range: 78 101years at death). Anatomical dissection and histological examination of cadaveric eyelids fixed in 10% buffered formalin was performed. The axial sections were made in parallel with the eyelid margin at 1mm superior or inferior to the upper or lower eyelid margins, respectively. The histological specimens were first dehydrated and embedded in paraffin and then divided into 7um thickness sections and stained with Masson's trichrome. Microscopic photographs were taken with a digital camera system attached to the microscope. RESULTS: The posterior limb of the medial canthal tendon was not detected in any of the specimens. The medial check ligament supported the posterior aspect of Horner's muscle and inserted into the medial orbital wall through the periosteum. The lacrimal diaphragm around the posterior lacrimal crest ran almost parallel to Horner's muscle and was usually difficult to distinguish from the tendon of Horner's muscle. CONCLUSIONS: The posterior limb of the medial canthal tendon was not detected in any of the studied specimens. This anatomical structure appears to be Horner's muscle, and the lacrimal diaphragm. PMID- 21794046 TI - Caveolin-1 expression regulates blood-retinal barrier permeability and retinal neovascularization in oxygen-induced retinopathy. AB - BACKGROUND: Caveolin-1 expression correlates with the permeability of endothelial barriers and angiogenesis. However, the role of caveolin-1 in retinal neovascularization remains unknown. We evaluated the effect of caveolin-1 on the blood-retina barrier and retinal neovascularization in a murine model of oxygen induced retinopathy. METHODS: Starting at postnatal day 7, mice were exposed to 75 +/- 5% oxygen for 5 days and then returned to room air conditions to induce retinal neovascularization. Effects on blood-retina barrier were evaluated by Western blot analysis of extravasated albumin in the retina. Retinal neovascularization morphology was studied by fluorescence angiography and was quantified by counts of the endothelial nuclei that protruded into the vitreous cavity. Reverse transcription-polymerase chain reaction and Western blot analysis was used to examine retinal expression levels of caveolin-1. siRNA against caveolin-1 was injected intravitreally in the oxygen-induced retinopathy models. Effects on caveolin-1 mRNA and protein, and retinal neovascularization were assessed as described above. RESULTS: Caveolin-1 expression was found to increase during hypoxia and overexpression of caveolin-1 correlated with the appearance of extravascular albumin. Caveolin-1 siRNA reduced caveolin-1 mRNA and protein levels by 47.94% and 54.76%, respectively. Furthermore, caveolin-1 siRNA inhibition reduced retinal neovascularization by 51.3% and reduced albumin leakage by 56.32%. CONCLUSIONS: Caveolin-1 may play an important role in induction of retinal neovascularization. SiRNA against caveolin-1 can inhibit experimental retinal hyperpermeability and neovascularization. Therefore, the inhibition of caveolin-1 may be a powerful and novel therapeutic tool for the treatment of ischaemia-induced retinal diseases. PMID- 21794048 TI - Differences in iris structural measurements among American Caucasians, American Chinese and mainland Chinese. AB - BACKGROUND: To assess the distribution of iris structural measurements among American Caucasians, American Chinese and mainland Chinese aged 40years and over, in order to determine associated factors of increased risk for angle closure in Chinese. DESIGN: Prospective multicentre cross-sectional study. PARTICIPANTS: Four gender- and age-matched cohorts: Caucasians, American Chinese, Southern Chinese from Guangzhou and Northern Chinese from Beijing were enrolled in this study. METHODS: Anterior segment optical coherence tomography was utilized to image the anterior chamber. Customized software was used to calculate the related parameters from anterior segment optical coherence tomography images. MAIN OUTCOME MEASURES: Iris thickness at 750um from the scleral spur, iris curvature, iris area, pupil diameter. RESULTS: Data from 121, 124, 121 and 120 subjects were available for American Caucasian, American Chinese, Southern and Northern Mainland Chinese subjects, respectively. The Chinese cohorts did not differ with regard to any of the parameters. Multiple linear regressions indicated that Caucasians had thinner iris thickness at 750um from the scleral spur and smaller iris area than Chinese after controlling for potential confounders. Female Caucasians had thinner irides (P=0.015) and smaller iris area (P=0.001) than male Caucasians. Female Chinese tended to have more convex irides (P=0.021) than male Chinese. Pupil size was inversely associated with age (P<0.001) in both ethnicities. CONCLUSIONS: In dark conditions, Chinese have thicker irides and greater iris area than Caucasians independent of pupil size. Among Chinese, more convex irides in women may account for the higher rate of narrow angles identified in this segment of the Chinese population. PMID- 21794049 TI - Ipsilateral pupil dilation associated with unilateral intermittent exotropia: a new observation. PMID- 21794050 TI - Prevalence of potentially reversible conditions in dementia and mild cognitive impairment in a geriatric clinic. AB - AIM: To examine the prevalence of potentially reversible conditions in dementia and mild cognitive impairment (MCI) patients in a geriatric clinic. METHODS: We retrospectively reviewed the medical records of patients who attended the outpatient geriatric clinic at Siriraj Hospital, Bangkok between January 2005 and December 2010. We collected the data regarding potentially reversible conditions of cognitive impairment. RESULTS: There were 233 patients newly diagnosed with dementia and 60 patients diagnosed with MCI. We found potentially reversible causes of dementia in 17 patients (7.3%). The causes were hypothyroidism (2.6%), B12 deficiency (1.7%), normal pressure hydrocephalus (NPH) (0.9%), depression (0.9%), folate deficiency (0.4%), reactive Venereal Disease Research Laboratory (VDRL; 0.4%) and chronic subdural hematoma (CSH; 0.4%). The patients with NPH and CSH were clinically suspicious for having such conditions before the investigations, while patients with low B12 level, low folate level, hypothyroidism and VDRL+ were not. In the MCI group, we found potentially reversible causes in two patients (3.3%), these were B12 deficiency (1.7%) and hypothyroidism (1.7%). Clinical improvement after treatment of the potentially reversible conditions was seen in four patients (one NPH, one subdural hematoma and two with depression) in dementia group (1.7%) and none in the MCI group. All were partially reversed. CONCLUSION: Routine investigations might be more warranted for metabolic conditions (B12 level and hypothyroidism) as clinical presentations are not suggestive of the conditions. However, reversibility of dementia might not occur in these cases. Neuroimaging should be performed selectively as clinically indicated. Truly reversible conditions are rare and occur in surgical and depressive patients. PMID- 21794051 TI - Role of the mTOR complex 1 pathway in the in vivo maintenance of the intestinal mucosa by oral intake of amino acids. AB - AIM: Oral intake of nutrients is often compromised in elderly, multimorbid patients, but parenteral nutrition causes intestinal atrophy and impairs intestinal function. To uncover the molecular mechanisms by which amino acids are involved in intestinal atrophy and recovery, we studied whether the rapamycin sensitive mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway is involved in this process. METHODS: C57BL/6N mice were fed a glucose solution alone, glucose solution with amino acids or normal chow diet for various lengths of time. Intestinal sections were prepared from these mice and the villus height and villus density were quantified. As a readout for the mTORC1 pathway, the phosphorylation of the ribosomal S6 protein (S6) was analyzed by immunostaining and immunoblotting. To confirm the role of the mTORC1 pathway, the inhibitory effect of a specific mTOR inhibitor, rapamycin, was examined. RESULTS: Inducing fasting in mice fed only glucose caused time-dependent intestinal mucosal atrophy, whereas supplementation with amino acids protected the intestinal mucosa from atrophy. Phosphorylation of S6 decreased in the intestinal mucosa of mice fed only glucose, whereas supplementation with amino acids increased S6 phosphorylation. Importantly, intraperitoneal injection of rapamycin attenuated the protective effect of amino acids on the intestinal mucosa in a pattern consistent with the decrease of S6 phosphorylation. CONCLUSIONS: These results indicate that the mTORC1 pathway plays a crucial role in the in vivo maintenance of the intestinal mucosa by the oral intake of amino acids. PMID- 21794052 TI - Phylogenetic grouping, curvature and metabolic scaling in terrestrial invertebrates. AB - For more than a century, the scaling of animal metabolic rates with individual body masses and environmental temperature has predominantly been described by power-law and exponential relationships respectively. Many theories have been proposed to explain these scaling relationships, but were challenged by empirically documented curvatures on double-logarithmic scales. In the present study, we present a novel data set comprising 3661 terrestrial (mainly soil) invertebrate respiration rates from 192 independent sources across a wide range in body masses, environmental temperatures and phylogenetic groups. Although our analyses documented power-law and exponential scaling with body masses and temperature, respectively, polynomial models identified curved deviations. Interestingly, complex scaling models accounting for phylogenetic groups were able to remove curvatures except for a negative curvature at the highest temperatures (>30 degrees C) indicating metabolic down regulation. This might indicate that the tremendous differences in invertebrate body architectures, ecology and physiology may cause severely different metabolic scaling processes. PMID- 21794053 TI - Eco-evolutionary dynamics of dispersal in spatially heterogeneous environments. AB - Ecology Letters (2011) 14: 1025-1034 ABSTRACT: Evolutionary changes in natural populations are often so fast that the evolutionary dynamics may influence ecological population dynamics and vice versa. Here we construct an eco evolutionary model for dispersal by combining a stochastic patch occupancy metapopulation model with a model for changes in the frequency of fast-dispersing individuals in local populations. We test the model using data on allelic variation in the gene phosphoglucose isomerase (Pgi), which is strongly associated with dispersal rate in the Glanville fritillary butterfly. Population specific measures of immigration and extinction rates and the frequency of fast dispersing individuals among the immigrants explained 40% of spatial variation in Pgi allele frequency among 97 local populations. The model clarifies the roles of founder events and gene flow in dispersal evolution and resolves a controversy in the literature about the consequences of habitat loss and fragmentation on the evolution of dispersal. PMID- 21794054 TI - Collagen IV-derived peptide binds hydrophobic cavity of Legionella pneumophila Mip and interferes with bacterial epithelial transmigration. AB - The Legionella virulence factor Mip (macrophage infectivity potentiator) contributes to bacterial dissemination within infected lung tissue. The Mip protein, which belongs to the enzyme family of FK506-binding proteins (FKBP), binds specifically to collagen IV. We identified a surface-exposed Mip-binding sequence in the NC1 domain of human collagen IV alpha1. The corresponding collagen IV-derived peptide (P290) co-precipitated with Mip and competitively inhibited the Mip-collagen IV binding. Transmigration of Legionella pneumophila across a barrier of NCI-H292 lung epithelial cells and extracellular matrix was efficiently inhibited by P290. This significantly reduced transmigration was comparable to the inefficient transmigration of PPIase-negative Mip mutant or rapamycin-treated L. pneumophila. Based on NMR data and docking studies a model for the mode of interaction of P290 and Mip was developed. The amino acids of the hydrophobic cavity of Mip, D142 and to a lesser extent Y185 were identified to be part of the interaction surface. In the complex structure of Mip(77-213) and P290, both amino acid residues form hydrogen bonds to P290. Utilizing modelling, molecular dynamics (MD) simulations and structural data of human PPIase FKBP12, the most related human orthologue of Mip, we were able to propose optimized P290 variants with increased binding specificity and selectivity for the putative bacterial drug target Mip. PMID- 21794055 TI - Stabilization of HIV incidence in women of reproductive age in southern Mozambique. AB - INTRODUCTION: The collection of incidence data on HIV infection is necessary to evaluate the status and dynamics of the epidemic and the effectiveness of intervention strategies. However, this is usually difficult in low-income countries. METHODS: Five yearly point HIV prevalence estimations (in 1999, 2003, 2004, 2005 and 2008) were obtained for women between 15 and 45 years of age participating in three studies carried out for other purposes at the Antenatal Clinic (ANC) in Manhica, Mozambique. HIV incidence was estimated between prevalence points using a previously validated methodology. Two methods were used, one based on mortality rates for three HIV epidemic scenarios, and the other based on survival information after infection. The pattern over time was captured by fitting a log-regression model. RESULTS: The prevalence of HIV infection ranged from 12% in 1999 to 49% in 2008. The HIV incidence increased from approximately 3.5 cases per 100 person-years in 2001 to 14 per 100 person years in 2004, with stabilization thereafter to levels of around 12 cases per 100 person-years. The incidence estimates were comparable for the two methods used. CONCLUSION: These findings indicate an increase in the prevalence and incidence of HIV infection among women of reproductive age over the 9 years of the analysis, with a plateau in the incidence of infection since 2005. However, the very high figures for both prevalence and incidence highlight the importance of the continuation of the prevention and treatment programmes that already exist, and suggest that implementation of preventive measures is needed in this area. PMID- 21794056 TI - Renal cell carcinoma: stage, grade and histology migration over the last 15 years in a large Australian surgical series. PMID- 21794057 TI - Changing antibiotic prophylaxis for transrectal ultrasound-guided prostate biopsies: are we putting our patients at risk? PMID- 21794058 TI - Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. PMID- 21794059 TI - Change and innovation. PMID- 21794060 TI - 'Aha' moments in Urology: Pioneers share the discoveries that shaped the history of urology. PMID- 21794062 TI - Compartment syndrome after positioning in lithotomy: what a urologist needs to know. PMID- 21794063 TI - Percivall Pott, the environment and cancer. PMID- 21794064 TI - Prognostic implications of lymph node involvement in bladder cancer: are we understaging using current methods? AB - To review the current and newer, alternative methods for evaluating lymph nodes for tumor involvement in bladder cancer as relapse rates for organ-confined disease remain high despite improvements in surgical technique, suggesting the possibility of understaging. To propose a research agenda based on these findings. A PubMed literature search was performed to identify studies examining the prognostic implications of and outcomes associated with lymph node involvement in bladder cancer as well as those that utilized newer methodologies to identify the possibility for metastatic disease. Lymph node involvement remains one of the strongest predictors of clinical outcome in bladder cancer. Histologic and molecular techniques for identification of lymph node metastasis provide a sensitivity and specificity equal to if not higher than standard pathologic evaluation. Further research into this field would help to elucidate the potential utility of these techniques with regard to proper staging and potential relevance to clinical outcomes. PMID- 21794065 TI - Editorial comment: Impact of smoking on outcomes after intravesical bacillus Calmette-Guerin therapy for urothelial carcinoma not invading muscle of the bladder. PMID- 21794066 TI - Surgery illustrated--focus on details: Access sheath-aided percutaneous antegrade ureteroscopy; a novel approach to the ureter. PMID- 21794067 TI - Feasibility and early outcomes of robotic-assisted laparoscopic Mitrofanoff appendicovesicostomy in patients with prune belly syndrome. AB - OBJECTIVES: To evaluate the feasibility and report our initial experience with Robotic-Assisted Laparoscopic Mitrofanoff Appendicovesicostomy (RALMA) in patients with prune belly syndrome. The Mitrofanoff appendicovesicostomy procedure uses the appendix to create an easily accessible continent, catheterizable channel into the urinary bladder. Historically, the procedure is performed by an open surgical approach in prune belly patients. We describe our initial experience herein. MATERIALS AND METHODS: Between October 2008 and February 2010 three patients with prune belly syndrome underwent RALMA. The appendicovesicostomy anastomosis was performed on the anterior bladder wall and the stoma was brought to the umbilical site or right lower quadrant. At least 4 cm of detrusor backing was ensured. The appendicovesicostomy stent was left in place for 4 weeks postoperatively before initiation of catheterization. RESULTS: Mean age at surgery was 9.7 years (range 5-14 years). Blood loss volume was 20 mL in each case. Overall mean operative time was 352 min (range 319-402 min). There were no intraoperative complications and no open conversions. There was one postoperative complication in the form of wound infection. All patients are catheterizing their stomas and are continent at an average follow-up of 14.7 months (range 5-21 months). CONCLUSION: In our initial experience, RALMA is a feasible option with encouraging early experience for creating a continent catheterizable channel into the urinary bladder in patients with prune belly syndrome. PMID- 21794068 TI - Morbidity of tumour enucleation for renal cell carcinoma (RCC): results of a single-centre prospective study. AB - OBJECTIVE: To evaluate the incidence and risk factors of adverse events (AEs) after tumour enucleation (TE). PATIENTS AND METHODS: Between 2006 and 2009, clinical, surgical and functional data were prospectively gathered from 200 consecutive patients who had open TE. TE was done by blunt dissection using the natural cleavage plane between the tumour capsule and normal parenchyma. All the AEs were stratified for severity according to the National Cancer Institute Common Toxicity Criteria version 2.0 grading system. Risk factors for AEs were determined by univariate analysis. RESULTS: The mean (range) tumour size was 3.2 (0.8-10.0) cm, and mean (range) warm ischaemia time (WIT) was 16.5 (5-31) min. Overall, 32 AEs (six grade I, 20 grade II, and six grade III) occurred after TE in 30 patients and of those 27 were surgical (13.5%) and five were medical AEs (2.5%). On univariate analysis, imperative/relative surgical indication was the only predictive factor for the development of medical AEs. Statistically significant predictors of overall surgical AEs and urinary fistula were clinical tumour dimension, completely endorenal tumour growth and a positive tumour relationship with the urinary collecting system (UCS). A completely endorenal tumour growth and a positive tumour relationship with the UCS also correlated with bleeding requiring transfusions. Completely endorenal tumour growth was significantly associated with major (grade III) AEs. CONCLUSIONS: The TE technique was associated with a 16% AE rate and of those only 3% required re intervention (grade III). Urinary fistula occurred in six patients (3%) and ureteric stenting was required in 0.5% of cases. PMID- 21794070 TI - Introducing HPV vaccine and scaling up screening procedures to prevent deaths from cervical cancer in Japan: a cost-effectiveness analysis. AB - OBJECTIVE: To assess the cost-effectiveness of universal vaccination of 11-year old girls against human papillomavirus (HPV) infection and increased screening coverage to prevent cervical cancer in Japan where the coverage of Papanicolaou smears is very low. DESIGN: A cost-utility analysis from a societal perspective. SETTING: Japan, 2010. POPULATION: The female Japanese population aged 11 years or older. METHODS: A Markov model of the natural history of cervical cancer was constructed to compare six strategies: i.e. a screening coverage rate of 20, 50 and 80% with and without routine vaccination at age 11. MAIN OUTCOME MEASURES: Cervical cancer incidence, quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratios. RESULTS: Expanding the coverage of Papanicolaou smears from the current level of 20-50 and 80% yields a 45.5 and 63.1% reduction in cervical cancer incidence, respectively. Impact of combined strategies increases with coverage. Coverages of 20, 50 and 80% showed a 66.1, 80.9 and 86.8% reduction in disease, respectively. The costs of strategies with vaccination are four times higher than the cost of strategies without vaccination. Vaccinating all 11-year-old girls with bivalent vaccines with a Papanicolaou smear coverage rate of 50% is likely to be the most cost-effective option among the six strategies. CONCLUSIONS: The introduction of HPV vaccination in Japan is cost-effective as in other countries. It is more cost-effective to increase the coverage of the Papanicolaou smear along with the universal administration of HPV vaccine. PMID- 21794071 TI - Sex selection abortion in Kazakhstan: understanding a cultural justification. AB - The topic of abortion has been extensively researched, and the research has produced a large number of arguments and discussions. Missing in the literature, however, are discussions of practices in some areas of the Developing or Third World. In this paper, we examine the morality of sex selection abortions in Kazakhstan's Kazakh culture, and argue that such abortions can be ethically justified based, in part, on the unique perspectives of Kazakh culture. PMID- 21794073 TI - Controlling cancer growth from within the blood coagulation mechanism. PMID- 21794072 TI - The reporting of IRB review in journal articles presenting HIV research conducted in the developing world. AB - OBJECTIVES: We investigated how often journal articles reporting on human HIV research in four developing world countries mention any institutional review boards (IRBs) or research ethics committees (RECs), and what factors are involved. METHODS: We examined all such articles published in 2007 from India, Nigeria, Thailand and Uganda, and coded these for several ethical and other characteristics. RESULTS: Of 221 articles meeting inclusion criteria, 32.1% did not mention IRB approval. Mention of IRB approval was associated with: biomedical (versus psychosocial) research (P=0.001), more sponsor-country authors (P=0.003), sponsor-country corresponding author (P=0.047), mention of funding (P<0.001), particular host-country involved (P=0.002), journals having sponsor-country editors (P<0.001), and journal stated compliance with International Committee of Medical Journal Editors (ICMJE) guidelines (P=0.003). Logistic regression identified 3 significant factors: mention of funding, journal having sponsor country editors and research being biomedical. CONCLUSIONS: One-third of articles still do not mention IRB approval. Mention varied by country, and was associated with biomedical research, and more sponsor country involvement. Recently, some journals have required mention of IRB approval, but allow authors to do so in cover letters to editors, not in the article itself. Instead, these data suggest, journals should require that articles document adherence to ethical standards. PMID- 21794074 TI - ISTH/SSC lupus anticoagulant testing guidelines: how far have these been adopted by laboratories? PMID- 21794075 TI - Involvement of circulating platelets on the hyperalgesic response evoked by carrageenan and Bothrops jararaca snake venom. AB - BACKGROUND: The role of platelets in hemostasis is well known, but few papers have reported their role in pain and edema induced by inflammatory agents. OBJECTIVE: To evaluate the role of circulating platelets in the local injury induced by two diverse inflammatory agents, Bothrops jararaca venom (Bjv) and carrageenan. METHODS: Rats were (i) rendered thrombocytopenic by administration of polyclonal anti-rat platelet IgG (ARPI) or busulfan, or (ii) treated with platelet inhibitors (aspirin or clopidogrel). Edema formation, local hemorrhage and the pain threshold were assessed after intraplantar injection of Bjv or carrageenan in rat hind paws. Additionally, whole platelets or platelet releasate were tested whether they directly induced hyperalgesia. RESULTS: Platelet counts were markedly diminished in rats administered with either ARPI (+/- 88%) or busulfan (+/- 96%). Previous treatment with ARPI or busulfan slightly reduced edema induced by Bjv or carrageenan. Injection of Bjv, but not of carrageenan, induced a statistically significance increase in hemorrhage in the hind paws of thrombocytopenic rats. Remarkably, hyperalgesia evoked by Bjv or carrageenan was completely blocked in animals treated with ARPI or busulfan, or pre-treated with aspirin or clopidogrel. On the other hand, intraplantar administration of whole platelets or platelet releasate evoked hyperalgesia, which was inhibited by pre incubation with alkaline phosphatase. CONCLUSIONS: Thrombocytopenia or inhibition of platelet function drastically reduced hyperalgesia induced by injection of carrageenan or Bjv; moreover, platelets per se secrete phosphorylated compounds involved in pain mediation. Thus, blood platelets are crucial cells involved in the pain genesis, and their role therein has been underestimated. PMID- 21794076 TI - Aspirin has little additional anti-platelet effect in healthy volunteers receiving prasugrel. AB - BACKGROUND: Strong P2Y(12) blockade, as can be achieved with novel anti-platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A(2) -mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin. OBJECTIVE: The present study investigated the hypothesis that aspirin provides little additional anti aggregatory effect in a group of healthy volunteers taking prasugrel. STUDY PARTICIPANTS/METHODS: In all, 9 males, aged 18 to 40 years, enrolled into the 21 day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow and urine samples were collected for quantification of prostanoid metabolites. RESULTS: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP-6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose. CONCLUSIONS: In healthy volunteers, prasugrel produces a strong anti-aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual-therapy with potent P2Y(12) receptor inhibitors warrants further investigation. PMID- 21794077 TI - Identification of miRNAs as potential modulators of tissue factor expression in patients with systemic lupus erythematosus and antiphospholipid syndrome. AB - BACKGROUND: Tissue factor (TF) is the main initiator of the coagulation cascade and elements that may upregulate its expression might provoke thrombotic events. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune diseases characterized by a high TF expression in monocytes. OBJECTIVES: To examine the role of microRNAs (miRNAs) in TF expression and to evaluate their levels in SLE and APS patients. METHODS: An in silico search was performed to find potential putative binding sites of miRNAs in TF mRNA. In vitro validation was performed transfecting cells expressing TF (THP-1 and MDA-MB-231) with oligonucleotide miRNA precursors and inhibitors. Additionally, reporter assays were performed to test for the binding of miR-20a to TF mRNA. Levels of miRNAs and TF were measured by quantitative (qRT-PCR) in patients with APS and SLE. RESULTS: Overexpression of miRNA precursors, but not inhibitors, of two of the members of cluster miR-17~92, for example miR-19b and miR-20a, in cells expressing TF decreased TF mRNA, protein levels, and procoagulant activity between 30% and 60%. Reporter assays showed that miR-20a binds to TF mRNA. Finally, we measured levels of miR-19b and miR-20a in monocytes from patients with APS and SLE and observed significantly lower miRNAs levels in comparison with healthy subjects inversely correlated with the levels of TF. CONCLUSIONS: Down-regulation of miR-19b and miR-20a observed in patients with SLE and APS could contribute to increased TF expression and thus provoke the hypercoagulable state characteristic of these patients. PMID- 21794078 TI - A new oncolytic adenoviral vector carrying dual tumour suppressor genes shows potent anti-tumour effect. AB - Cancer Targeting Gene-Viro-Therapy (CTGVT) is a promising cancer therapeutical strategy that strengthens the anti-tumour effect of oncolytic virus by expressing inserted foreign anti-tumour genes. In this work, we constructed a novel adenoviral vector controlled by the tumour-specific survivin promoter on the basis of the ZD55 vector, which is an E1B55KD gene deleted vector we previously constructed. Compared with the original ZD55 vector, this new adenoviral vector (ZD55SP/E1A) showed much better ability of replication and reporter gene expression. We then combined anti-tumour gene interleukine-24 (IL-24) with an RNA polymerase III-dependent U6 promoter driving short hairpin RNA (shRNA) that targets M-phase phosphoprotein 1 (MPHOSPH1, a newly identified oncogene) by inserting the IL-24 and the shRNA of MPHOSPH1 (shMPP1) expression cassettes into the new ZD55SP/E1A vector. Our results demonstrated excellent anti-tumour effect of ZD55SP/E1A-IL-24-shMPP1 in vitro on multiple cancer cell lines such as lung cancer, liver cancer and ovarian caner. At high multiplicity-of-infection (MOI), ZD55SP/E1A-IL-24-shMPP1 triggered post-mitotic apoptosis in cancer cells by inducing prolonged mitotic arrest; while at low MOI, senescence was induced. More importantly, ZD55SP/E1A-IL-24-shMPP1 also showed excellent anti-tumour effects in vivo on SW620 xenograft nude mice. In conclusion, our strategy of constructing an IL-24 and shMPP1 dual gene expressing oncolytic adenoviral vector, which is regulated by the survivin promoter and E1B55KD deletion, could be a promising method of cancer gene therapy. PMID- 21794080 TI - Traumatic dental injuries and their association with malocclusion in the primary dentition of Irish children. AB - AIMS: This study sought to establish the prevalence of traumatic dental injuries in the primary dentition of Irish children and to investigate the relationship between dental trauma and non-nutritive sucking habits. MATERIALS AND METHODS: Following ethical approval, a variety of schools and creches in an urban setting were identified and parents of over 1000 children were contacted. Consent was obtained, and parental questionnaires were completed prior to a clinical examination of the children by one operator in a non-dental setting. Signs of previous dental trauma were noted, and overbite and overjet were measured. RESULTS: Eight hundred and thirty-nine children were examined. The prevalence of dental trauma was 25.6%, with boys more frequently affected. The most commonly observed dental injury was fracture of enamel (39.4%), followed by crown discolouration (20.2%). Only 38.8% of the children with a reported history of trauma sought dental care. Non-nutritive sucking habits were reported in 63.5% of the sample, and these habits, if prolonged, were significantly associated with anterior open bites and increased overjet (P<0.001). Using regression analysis, it was established that the risk of dental injury is 2.99 times greater if the child has an overjet >6mm and 2.02 times greater if the child has an anterior open bite. CONCLUSIONS: Non-nutritive sucking habits are associated with the establishment of anterior open bite and increased overjet in the primary dentition. These malocclusions are, in turn, significantly associated with an increased prevalence of dental trauma in the primary dentition. PMID- 21794079 TI - P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: relationship to pathology and potential target for treatment. AB - Duchenne muscular dystrophy (DMD) is a lethal inherited muscle disorder. Pathological characteristics of DMD skeletal muscles include, among others, abnormal Ca(2+) homeostasis and cell signalling. Here, in the mdx mouse model of DMD, we demonstrate significant P2X7 receptor abnormalities in isolated primary muscle cells and cell lines and in dystrophic muscles in vivo. P2X7 mRNA expression in dystrophic muscles was significantly up-regulated but without alterations of specific splice variant patterns. P2X7 protein was also up regulated and this was associated with altered function of P2X7 receptors producing increased responsiveness of cytoplasmic Ca(2+) and extracellular signal-regulated kinase (ERK) phosphorylation to purinergic stimulation and altered sensitivity to NAD. Ca(2+) influx and ERK signalling were stimulated by ATP and BzATP, inhibited by specific P2X7 antagonists and insensitive to ivermectin, confirming P2X7 receptor involvement. Despite the presence of pannexin-1, prolonged P2X7 activation did not trigger cell permeabilization to propidium iodide or Lucifer yellow. In dystrophic mice, in vivo treatment with the P2X7 antagonist Coomassie Brilliant Blue reduced the number of degeneration regeneration cycles in mdx skeletal muscles. Altered P2X7 expression and function is thus an important feature in dystrophic mdx muscle and treatments aiming to inhibit P2X7 receptor might slow the progression of this disease. PMID- 21794081 TI - Recommendations for using regenerative endodontic procedures in permanent immature traumatized teeth. AB - The regeneration of immature permanent teeth following trauma could be beneficial to reduce the risk of fracture and loss of millions of teeth each year. Regenerative endodontic procedures include revascularization, partial pulpotomy, and apexogenesis. Several case reports give these procedures a good prognosis as an alternative to apexification. Care is needed to deliver regenerative endodontic procedures that maintain or restore the vitality of teeth, but which also disinfect and remove necrotic tissues. Regeneration can be accomplished through the activity of the cells from the pulp, periodontium, vascular, and immune system. Most therapies use the host's own pulp or vascular cells for regeneration, but other types of dental stem cell therapies are under development. There are no standardized treatment protocols for endodontic regeneration. The purpose of this article is to review the recent literature and suggest guidelines for using regenerative endodontic procedures for the treatment of permanent immature traumatized teeth. Recommendations for the selection of regenerative and conventional procedures based on the type of tooth injury, fracture type, presence of necrosis or infection, periodontal status, presence of periapical lesions, stage of tooth development, vitality status, patient age, and patient health status will be reviewed. Because of the lack of long-term evidence to support the use of regenerative endodontic procedures in traumatized teeth with open apices, revascularization regeneration procedures should only be attempted if the tooth is not suitable for root canal obturation, and after apexogenesis, apexification, or partial pulpotomy treatments have already been attempted and have a poor prognosis. PMID- 21794082 TI - Immunosuppression, generic drugs and the FDA. PMID- 21794083 TI - Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and epstein-barr virus-induced gene 3. AB - Innovative therapeutic strategies are needed to diminish the impact of harmful immunosuppression in transplantation. Dendritic cell (DC)-based therapy is a promising approach for induction of antigen-specific tolerance. Using a heart allograft model in rats, we analyzed the immunoregulatory mechanisms by which injection of autologous tolerogenic DCs (ATDCs) plus suboptimal immunosuppression promotes indefinite graft survival. Surprisingly, we determined that Interferon gamma (IFNG), a cytokine expected to be propathogenic, was threefold increased in the spleen of tolerant rats. Importantly, its blockade led to allograft rejection [Mean Survival Time (MST) = 25.6 +/- 4 days], showing that IFNG plays a critical role in immunoregulatory mechanisms triggered by ATDCs. IFNG was expressed by TCRalphabeta(+) CD3(+) CD4(-) CD8(-) NKRP1(-) cells (double negative T cells, DNT), which accumulated in the spleen of tolerant rats. Interestingly, ATDCs specifically induced IFNG production by DNT cells. ATDCs expressed the cytokinic chain Epstein-Barr virus-induced gene 3 (EBI3), an IL-12 family member. EBI3 blockade or knock-down through siRNA completely abolished IFNG expression in DNT cells. Finally, EBI3 blockade in vivo led to allograft rejection (MST = 36.8 +/- 19.7 days), demonstrating for the first time a role for EBI3 in transplantation tolerance. Taken together our results have important implications in the rationalization of DC-based therapy in transplantation as well as in the patient immunomonitoring follow-up. PMID- 21794084 TI - Pregnancy outcomes in kidney transplant recipients: a systematic review and meta analysis. AB - Approximately 50,000 women of reproductive age in the United States are currently living after kidney transplantation (KT), and another 2800 undergo KT each year. Although KT improves reproductive function in women with ESRD, studies of post-KT pregnancies are limited to a few voluntary registry analyses and numerous single center reports. To obtain more generalizable inferences, we performed a systematic review and meta-analysis of articles published between 2000 and 2010 that reported pregnancy-related outcomes among KT recipients. Of 1343 unique studies, 50 met inclusion criteria, representing 4706 pregnancies in 3570 KT recipients. The overall post-KT live birth rate of 73.5% (95%CI 72.1-74.9) was higher than the general US population (66.7%); similarly, the overall post-KT miscarriage rate of 14.0% (95%CI 12.9-15.1) was lower (17.1%). However, complications of preeclampsia (27.0%, 95%CI 25.2-28.9), gestational diabetes (8.0%, 95%CI 6.7-9.4), Cesarean section (56.9%, 95%CI 54.9-58.9) and preterm delivery (45.6%, 95%CI 43.7-47.5) were higher than the general US population (3.8%, 3.9%, 31.9% and 12.5%, respectively). Pregnancy outcomes were more favorable in studies with lower mean maternal ages; obstetrical complications were higher in studies with shorter mean interval between KT and pregnancy. Although post-KT pregnancy is feasible, complications are relatively high and should be considered in patient counseling and clinical decision making. PMID- 21794085 TI - Ex vivo cryoablation of Wolff-Parkinson-white in a donor heart prior to pediatric heart transplantation. AB - This report describes the use of a donor heart with ventricular pre-excitation for pediatric orthotopic heart transplantation and the successful surgical cryoablation of the donor heart prior to transplantation. The issues related to the preoperative evaluation and surgical management of the donor heart with Wolff Parkinson White syndrome are discussed. PMID- 21794086 TI - Targeted gene silencing of TLR4 using liposomal nanoparticles for preventing liver ischemia reperfusion injury. AB - RNAi-based therapy is a promising strategy for the prevention of ischemia reperfusion injury (IRI). However, systemic administration of small interfering RNA (siRNA) may cause globally nonspecific targeting of all tissues, which impedes clinical use. Here we report a hepatocyte-specific delivery system for the treatment of liver IRI, using galactose-conjugated liposome nanoparticles (Gal-LipoNP). Heptocyte-specific targeting was validated by selective in vivo delivery as observed by increased Gal-LipoNP accumulation and gene silencing in the liver. Gal-LipoNP TLR4 siRNA treatment resulted in a significant decrease of serum alanine transferase (ALT) and aspartate transaminase (AST) in a hepatic IRI model. Histopathology displayed an overall reduction of the injury area in the Gal-LipoNP TLR4 siRNA treated mice. Additionally, neutrophil accumulation and lipid peroxidase-mediated tissue injury, detected by MPO, MDA and ROS respectively, were attenuated after Gal-LipoNP TLR4 siRNA treatment. Moreover, therapeutic effects of Gal-LipoNP TLR4 siRNA were associated with suppression of the inflammatory cytokines IL-1 and TNF-alpha. Taken together, this study is the first demonstration of liver IRI treatment using liver-specific siRNA delivery. PMID- 21794087 TI - Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome. AB - Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1-2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time-dependent variable (HR 2.1 [1.3-3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long-term outcome in lung transplantation. PMID- 21794089 TI - Letters from transplant recipients to the family of their donors are a positive experience for both, and can help donation. PMID- 21794090 TI - MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA. AB - Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise correlation with paired urine samples and potential utility in prospective evaluation of graft function. MiRNA signatures were established between CAD with IF/TA versus normal allografts by microarray. Validation of the microarray results and prospective evaluation of urine samples was performed using real-time quantitative-PCR (RT-qPCR). Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for further validation based on array fold change, p-value and in silico predicted mRNA targets. We confirmed the differential expression of these five miRNAs by RT qPCR using an independent set of samples. Differential expression was detected for miR-142-3p, miR-204, miR-107 and miR-211 (p < 0.001) and miR-32 (p < 0.05). Furthermore, differential expression of miR-142-3p (p < 0.01), miR-204 (p < 0.01) and miR-211 (p < 0.05) was also observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. These results support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function. PMID- 21794091 TI - Clinical and plasma proteomic markers correlating with chronic kidney disease after liver transplantation. AB - Chronic kidney disease (CKD) occurs frequently after liver transplantation (LT) and is associated with significant morbidity and mortality. Thus, there is a pressing need to identify characteristics and biomarkers diagnostic of CKD to enable early diagnosis allowing preemptive interventions, as well as mechanistic insights into the progression from kidney injury to irreversible kidney failure. We analyzed 342 patients who had baseline glomerular filteration rate (GFR) >60 at the time of LT and are now >3 years post-LT. Risk factors for post-LT CKD were compared between three different groups defined by current GFR: >90 (n = 40), 60 90 (n = 146) and <60 (n = 156) mL/min. Age, cyclosporine use and pre-LT GFR were independently associated with new onset CKD. A subset (n = 64) without viral/immune disease or graft dysfunction underwent multianalyte plasma proteomic evaluations for correlation with CKD. Plasma proteomic analysis of two independent cohorts, test (n = 22) and validation (n = 42), identified 10 proteins highly associated with new onset CKD. In conclusion, we have identified clinical characteristics and a unique plasma proteomic signature correlating with new onset CKD after LT. These preliminary results are currently being validated in a prospective, multicenter study to determine if this signature precedes the onset of CKD and resolves with early interventions aimed at preserving kidney function. PMID- 21794092 TI - A synchrotron X-ray diffraction characterization of the structure of complexes formed between sphingomyelin and cerebroside. AB - Specific lipid-lipid interactions are believed to be responsible for lateral domain formation in the lipid bilayer matrix of cell membranes. The miscibility of glucocerebroside and sphingomyelin extracted from biological tissues has been examined by synchrotron X-ray powder diffraction methods. Fully hydrated binary mixtures of egg-sphingomyelin codispersed with glucosylceramide rich in saturated C22 and C24 N-acyl fatty acids were subjected to heating scans between 20 and 90 degrees C at 2 degrees C.min(-1). X-ray scattering intensity profiles were recorded at 1 degrees C intervals simultaneously in both small-angle and wide angle scattering regions. A gel phase characterized by a single symmetric peak in the wide-angle scattering region was transformed in all mixtures examined to a fluid phase at about 40 degrees C, similar to dispersions of pure egg sphingomyelin. A coexisting lamellar structure was identified at temperatures up to about 75 degrees C which was characterized by a broad Bragg reflection. The scattering intensity of this structure increased relative to the structure assigned as bilayers of pure sphingomyelin with increasing proportions of glucosylceramide in the mixture. The relationship between the scattering intensities of the two peaks and the relative mass fractions of the two lipids showed that the bilayers assigned to a glucosylceramide-rich structure were composed of sphingomyelin and glucosylceramide in molar ratios of 1 : 1 and 2 : 1, respectively, at temperatures below and above the order-disorder phase transition temperature of the sphingomyelin (40 degrees C). PMID- 21794093 TI - Shuttling SR proteins: more than splicing factors. AB - Serine-arginine (SR) proteins commonly designate a family of eukaryotic RNA binding proteins containing a protein domain composed of several repeats of the arginine-serine dipeptide, termed the arginine-serine (RS) domain. This protein family is involved in essential nuclear processes such as constitutive and alternative splicing of mRNA precursors. Besides participating in crucial activities in the nuclear compartment, several SR proteins are able to shuttle between the nucleus and the cytoplasm and to exert regulatory functions in the latter compartment. This review aims at discussing the properties of shuttling SR proteins with particular emphasis on their nucleo-cytoplasmic traffic and their cytoplasmic functions. Indeed, recent findings have unravelled the complex regulation of SR protein nucleo-cytoplasmic distribution and the diversity of cytoplasmic mechanisms in which these proteins are involved. PMID- 21794094 TI - Dipeptidyl peptidase III: a multifaceted oligopeptide N-end cutter. AB - Dipeptidyl peptidase III (DPP III), the sole member and representative of the M49 family of metallopeptidases, is a zinc-dependent aminopeptidase. It sequentially hydrolyses dipeptides from the N-terminal of oligopeptides ranging from three to 10 amino acid residues. Although implicated in an array of pathophysiological phenomena, the precise function of this peptidase is still unclear. However, a number of studies advocate its contribution in terminal stages of protein turnover. Altered expression of DPP III which suggests its involvement in primary ovarian carcinoma, oxidative stress (Nrf2 nuclear localization), pain, inflammation and cataractogenesis has recently led to resurgence of interest in delineating the role of the peptidase in these pathophysiological processes. This review article intends to bring forth the latest updates in this arena which may serve as a base for future studies on the peptidase. PMID- 21794095 TI - Centrifugation speed affects light transmission aggregometry. AB - BACKGROUND: Light transmission aggregometry (LTA) is considered the gold standard for investigating platelet activity ex vivo. However, LTA protocols are not standardized, and differences in LTA procedure are a potential source of variance in results. Centrifugation speed is an essential component of platelet preparation in LTA, has yet to be standardized, and may affect platelet aggregation results. We sought to investigate the effect of relative centrifugal force (RCF) intensity on LTA results. METHODS: Ten healthy controls had venous blood drawn and centrifuged at 150, 200, 300, and 500 g for 10 min. Cell counts in whole blood and platelet-rich plasma (PRP) were measured using a hematology analyzer. LTA was performed using 1.0 MUm adenosine diphosphate (ADP) and 0.4 MUm epinephrine as an agonist. Aggregation (%) was compared at 60, 120, 180, and 300 s and at maximum aggregation. RESULTS: Centrifugation speed was associated with decreasing platelet count (P < 0.001) and decreasing mean platelet volume (P < 0.001) in PRP. Maximum aggregation decreased with increasing speeds for ADP 1.0 MUm (150 g- 89%, 200 g- 93%, 300 g- 71%, 500 g- 17%; P < 0.001). Similar findings were noted at 120 s (150 g- 69%, 200 g- 50%, 300 g- 35%, 500 g- 12%; P < 0.001), 180 s (150 g- 82%, 200 g- 74%, 300 g- 44%, 500 g- 13%; P < 0.001), and 300 s (150 g- 85%, 200 g- 88%, 300 g- 55%, 500 g- 14%; P < 0.001). Consistently, platelet aggregation in response to epinephrine 0.4 MUm decreased significantly with increasing centrifuge RCF at 60, 120, 180, 300 s and at maximum aggregation (P < 0.05 for each comparison). CONCLUSION: Our data demonstrate the importance of centrifugation speed in the interpretation of LTA results, supporting the need for standardization of centrifugation RCF in LTA protocols. PMID- 21794096 TI - Distinguishing types 1 and 2M von Willebrand disease. AB - Discrimination of types 1 and 2M von Willebrand disease (VWD) is problematic. Type 1 VWD represents a quantitative deficiency of von Willebrand factor and type 2M a qualitative disorder. 2M VWD is considered a potentially more serious bleeding disorder than type 1 VWD and may also require a differential management approach given the higher bleeding risk and that desmopressin may be less effective. We describe a case of 2M VWD 'masquerading' as type 1 and show how the differential diagnosis can be obtained using standard laboratory assays. The case was genetically confirmed as a 3943C>T mutation, leading to R1315C. PMID- 21794097 TI - Accuracy and precision of hemoglobin point-of-care testing during major pediatric surgery. AB - INTRODUCTION: The aim of the study was to compare accuracy and reproducibility of four point-of-care testing (POCT) devices (GEM(r) Premier 3000, ABL 800 flex, GEM(r) OPLTM, HemoCue(r) B-Hemoglobin) for hemoglobin (Hb) analyzes as compared with the reference laboratory method (Sysmex XE 2100) in children undergoing major surgery. METHODS: Pediatric patients undergoing craniofacial, spine, hip, or cancer surgery were included. Blood samples for Hb testing were taken at several intraoperative time points and generally withdrawn from the arterial catheter, if accessible. RESULTS: A total of 256 blood samples were taken intraoperatively from 71 pediatric patients. All POCT devices showed very small bias (maximum -0.46 g/dL) to reference method as well as very good reproducibility (maximum coefficient of variation of 0.99%). However, in two cases (HemoCue), potential clinical relevant differences were observed beyond a range of 2 g/dL. CONCLUSION: All POCT devices tested and operated by trained staff for hemoglobinometry showed reliable test results. They all allow for simple, fast, and precise bedside determination of hemoglobin concentration in the intraoperative setting. PMID- 21794098 TI - Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in isolated vitiligo: a genotype-phenotype correlation. PMID- 21794099 TI - Gastrointestinal complaints in runners are not due to small intestinal bacterial overgrowth. AB - BACKGROUND: Gastrointestinal complaints are common among long distance runners. We hypothesised that small intestinal bacterial overgrowth (SIBO) is present in long distance runners frequently afflicted with gastrointestinal complaints. FINDINGS: Seven long distance runners (5 female, mean age 29.1 years) with gastrointestinal complaints during and immediately after exercise without known gastrointestinal diseases performed Glucose hydrogen breath tests for detection of SIBO one week after a lactose hydrogen breath test checking for lactose intolerance. The most frequent symptoms were diarrhea (5/7, 71%) and flatulence (6/7, 86%). The study was conducted at a laboratory.In none of the subjects a pathological hydrogen production was observed after the intake of glucose. Only in one athlete a pathological hydrogen production was measured after the intake of lactose suggesting lactose intolerance. CONCLUSIONS: Gastrointestinal disorders in the examined long distance runners were not associated with small intestinal bacterial overgrowth. PMID- 21794100 TI - Verbal autopsy and global mortality statistics: if not now, then when? PMID- 21794101 TI - Drug use and nightlife: more than just dance music. AB - BACKGROUND: Research over the last decade has focused almost exclusively on the association between electronic music and MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") or other stimulant drug use in clubs. Less attention has been given to other nightlife venues and music preferences, such as rock music or southern/funky music. This study aims to examine a broader spectrum of nightlife, beyond dance music. It looks at whether certain factors influence the frequency of illegal drug and alcohol use: the frequency of going to certain nightlife venues in the previous month (such as, pubs, clubs or goa parties); listening to rock music, dance music or southern and funky music; or sampling venues (such as, clubs, dance events or rock festivals). The question of how these nightlife variables influence the use of popular drugs like alcohol, MDMA, cannabis, cocaine and amphetamines is addressed. METHODS: The study sample consisted of 775 visitors of dance events, clubs and rock festivals in Belgium. Study participants answered a survey on patterns of going out, music preferences and drug use. Odds ratios were used to determine whether the odds of being an illegal substance user are higher for certain nightlife-related variables. Furthermore, five separate ordinal regression analyses were used to investigate drug use in relation to music preference, venues visited during the last month and sampling venue. RESULTS: Respondents who used illegal drugs were 2.5 times more likely to report that they prefer dance music. Goa party visitors were nearly 5 times more likely to use illegal drugs. For those who reported visiting clubs, the odds of using illegal drugs were nearly 2 times higher. Having gone to a pub in the last month was associated with both more frequent alcohol use and more frequent illegal substance use. People who reported liking rock music and attendees of rock festivals used drugs less frequently. CONCLUSIONS: It was concluded that a more extended recreational environment, beyond dance clubs, is associated with frequent drug use. This stresses the importance of targeted prevention in various recreational venues tailored to the specific needs of the setting and its visitors. PMID- 21794102 TI - Vitamin C partially attenuates male reproductive deficits in hyperglycemic rats. AB - BACKGROUND: Hyperglycemia can impair the male reproductive system in experimental animals and in men during reproductive age. Studies have shown that vitamin C has some good effects on male reproductive system, and therefore vitamin C treatment could attenuate the dysfunctions in this system caused by hyperglycemia. Thus, the objective of this work was to evaluate whether vitamin C treatment could attenuate reproductive dysfunctions in hyperglycemic male rats. METHODS: Adult male rats were divided into 3 groups: a normoglycemic (n = 10) and two hyperglycemic (that received a single dose of streptozotocin - 40 mg/kg BW). The two last groups (n = 10 per group) were divided into: hyperglycemic control (Hy) and hyperglycemic + 150 mg of vitamin C (HyC), by gavage during 30 consecutive days. The normoglycemic and hyperglycemic control groups received the vehicle (water). The first day after the treatment, the rats were anesthetized and killed to evaluate oxidative stress biomarkers (TBARS, SOD, GSHt and GSH-Px) in the erythrocytes, body and reproductive organ weights, sperm parameters, plasma hormone levels (FSH, LH and testosterone), testicular and epididymal histo morphometry and histopathology. RESULTS: Compared with the normoglycemic animals, hyperglycemic control rats showed reduced weight of the body and reproductive organ but testis weight was maintained. It was also observed reduction of testosterone and LH levels, seminiferous tubular diameter, sperm motility and sperm counts in the epididymis. In addition, there was an increase in morphological abnormalities on spermatozoa as well as in oxidative stress level. Vitamin C reduced the oxidative stress level, diminished the number of abnormal sperm, and increased testosterone and LH levels and seminiferous tubular diameter but did not show improvement of sperm motility in relation to the hyperglycemic control group. Hyperglycemia caused a rearrangement in the epididymal tissue components (stroma, ephitelium and lumen) as demonstrated by the stereological analysis results. However, this alteration was partially prevented by vitamin C treatment. CONCLUSIONS: We conclude that vitamin C partially attenuated some male reproductive system dysfunctions in hyperglycemic rats. PMID- 21794103 TI - Differences in cortical response to acupressure and electroacupuncture stimuli. AB - BACKGROUND: FMRI studies focus on sub-cortical effects of acupuncture stimuli. The purpose of this study was to assess changes in primary somatosensory (S1) activity over the course of different types of acupuncture stimulation. We used whole head magnetoencephalography (MEG) to map S1 brain response during 15 minutes of electroacupuncture (EA) and acupressure (AP). We further assessed how brain response changed during the course of stimulation. RESULTS: Evoked brain response to EA differed from AP in its temporal dynamics by showing clear contralateral M20/M30 peaks while the latter demonstrated temporal dispersion. Both EA and AP demonstrated significantly decreased response amplitudes following five minutes of stimulation. However, the latency of these decreases were earlier in EA (~30 ms post-stimulus) than AP (> 100 ms). Time-frequency responses demonstrated early onset, event related synchronization (ERS), within the gamma band at ~70-130 ms and the theta band at ~50-200 ms post-stimulus. A prolonged event related desynchronization (ERD) of alpha and beta power occurred at ~100 300 ms post-stimulus. There was decreased beta ERD at ~100-300 ms over the course of EA, but not AP. CONCLUSION: Both EA and AP demonstrated conditioning of SI response. In conjunction with their subcortical effects on endogenous pain regulation, these therapies show potential for affecting S1 processing and possibly altering maladaptive neuroplasticity. Thus, further investigation in neuropathic populations is needed. PMID- 21794104 TI - IsoformEx: isoform level gene expression estimation using weighted non-negative least squares from mRNA-Seq data. AB - BACKGROUND: mRNA-Seq technology has revolutionized the field of transcriptomics for identification and quantification of gene transcripts not only at gene level but also at isoform level. Estimating the expression levels of transcript isoforms from mRNA-Seq data is a challenging problem due to the presence of constitutive exons. RESULTS: We propose a novel algorithm (IsoformEx) that employs weighted non-negative least squares estimation method to estimate the expression levels of transcript isoforms. Validations based on in silico simulation of mRNA-Seq and qRT-PCR experiments with real mRNA-Seq data showed that IsoformEx could accurately estimate transcript expression levels. In comparisons with published methods, the transcript expression levels estimated by IsoformEx showed higher correlation with known transcript expression levels from simulated mRNA-Seq data, and higher agreement with qRT-PCR measurements of specific transcripts for real mRNA-Seq data. CONCLUSIONS: IsoformEx is a fast and accurate algorithm to estimate transcript expression levels and gene expression levels, which takes into account short exons and alternative exons with a weighting scheme. The software is available at http://bioinformatics.wistar.upenn.edu/isoformex. PMID- 21794105 TI - Socioeconomic trajectory from birth to adolescence and lung function: prospective birth cohort study. AB - BACKGROUND: Socioeconomic status (SES) has been shown to be an important contributor to lung function. The aim of this study was to evaluate the association between lung function in adolescence and (a) SES at birth; (b) SES in adolescence; (c) SES trajectory from birth to adolescence ('never poor', 'non poor-poor', 'poor-non poor' and 'always poor'). Additionally, we investigate the role of adolescent and parental variables at mediating these associations. METHODS: Prospective birth cohort study in Pelotas, Brazil, including 4,005 adolescents (mean age: 14.7 years) followed up from birth. Lung function was measured by spirometry. Outcome variables were forced expiratory volume in one second in liters (FEV1) and forced vital capacity also in liters (FVC). RESULTS: Mean FEV1 was 3.46 L (95%CI 3.43-3.49) among boys and 2.93 L (95%CI 2.91-2.95) among girls. Mean FVC was 4.00 L (95%CI 3.97; 4.04) among boys and 3.30 L (95%CI 3.27; 3.32) among girls. SES at birth, in adolescence and its trajectory from birth to adolescence were inversely associated with lung function in both adolescent boys and girls. After adjustment for mediating variables, coefficients were largely reduced, particularly among boys, and the main predictor of change in coefficients was the inclusion of height in the models. CONCLUSION: Low income adolescents from Brazil present impaired lung function as compared to the better off, and this is largely explained by height. PMID- 21794106 TI - HIV-1 mutational pathways under multidrug therapy. AB - BACKGROUND: Genotype-derived drug resistance profiles are a valuable asset in HIV 1 therapy decisions. Therapy decisions could be further improved, both in terms of predicting length of current therapy success and in preserving followup therapy options, through better knowledge of mutational pathways- here defined as specific locations on the viral genome which, when mutant, alter the risk that additional specific mutations arise. We limit the search to locations in the reverse transcriptase region of the HIV-1 genome which host resistance mutations to nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors (as listed in the 2008 International AIDS Society report), or which were mutant at therapy start in 5% or more of the therapies studied. METHODS: A Cox proportional hazards model was fit to each location with the hazard of a mutation at that location during therapy proportional to the presence/absence of mutations at the remaining locations at therapy start. A pathway from preexisting to occurring mutation was indicated if the covariate was both selected as important via smoothly clipped absolute deviation (a form of regularized regression) and had a small p-value. The Cox model also allowed controlling for non-genetic parameters and potential nuisance factors such as viral resistance and number of previous therapies. Results were based on 1981 therapies given to 1495 distinct patients drawn from the EuResist database. RESULTS: The strongest influence on the hazard of developing NRTI resistance was having more than four previous therapies, not any one existing resistance mutation. Known NRTI resistance pathways were shown, and previously speculated inhibition between the thymidine analog pathways was evidenced. Evidence was found for a number of specific pathways between NRTI and NNRTI resistance sites. A number of common mutations were shown to increase the hazard of developing both NRTI and NNRTI resistance. Viral resistance to the therapy compounds did not materially effect the hazard of mutation in our model. CONCLUSIONS: The accuracy of therapy outcome prediction tools may be increased by including the number of previous treatments, and by considering locations in the HIV genome which increase the hazard of developing resistance mutations. PMID- 21794107 TI - Predictors of switching from beta-blockers to other anti-hypertensive drugs: a review of records of 19,177 Chinese patients seen in public primary care clinics in the New Territory East, Hong Kong. AB - BACKGROUND: Beta-blocker drugs are commonly used in family practice and studies showed that they were the most popularly prescribed medications among all antihypertensive agents. This study aimed to identify the factors associated with medication switching from a beta-blocker to another antihypertensive drug among Chinese patients. METHODS: We used a validated database which consisted of the demographic and clinical information of all Chinese patients prescribed a beta blocker from any public, family practice clinics between 01 Jan 2004 to 30 June 2007 in one large Territory of Hong Kong. The proportion of patients switched from beta-blockers to another antihypertensive agent 180 days within their first prescription was studied, and the factors associated with medication switching were evaluated by using multivariate regression analyses. RESULTS: From 19,177 eligible subjects with a mean age of 59.1 years, 763 (4.0%) were switched from their beta-blockers within 180 days of commencing therapy. A binary logistic regression model used medication switching as the outcome variable and controlled for age, gender, socioeconomic status, clinic setting (general out-patient clinics, family medicine specialist clinic or staff clinics), district of residence, visit type (new vs. follow-up attendance), the number of concomitant co-morbidities, and the calendar year of prescription. It was found that older patients (age 50-59 years: adjusted odds ratio [AOR] 1.38, 95% C.I. 1.12-1.70; p = 0.002; age 60-69 years: AOR 1.63 95% C.I. 1.30-2.04, p < 0.001; age >= 70 years: AOR 1.82, 95% C.I. 1.46-2.26, p < 0.001; referent age < 50 years) and new visitors (AOR 0.57, 95% C.I. 0.48-0.68, p < 0.001) were more likely to have their medication switched. CONCLUSIONS: Closer monitoring of the medication taking behavior among the older patients and the new clinic visitors prescribed a beta blocker is warranted. Future studies should evaluate the reasons of drug switching. PMID- 21794108 TI - Changing patterns in diagnostic strategies and the treatment of blunt injury to solid abdominal organs. AB - BACKGROUND: In recent years there has been increasing interest shown in the nonoperative management (NOM) of blunt traumatic injury. The growing use of NOM for blunt abdominal organ injury has been made possible because of the progress made in the quality and availability of the multidetector computed tomography (MDCT) scan and the development of minimally invasive intervention options such as angioembolization. AIM: The purpose of this review is to describe the changes that have been made over the past decades in the management of blunt trauma to the liver, spleen and kidney. CONCLUSIONS: The management of blunt abdominal injury has changed considerably. Focused assessment with sonography for trauma (FAST) examination has replaced diagnostic peritoneal lavage as diagnostic modality in the primary survey. MDCT scanning with intravenous contrast is now the gold standard diagnostic modality in hemodynamically stable patients with intra-abdominal fluid detected with FAST. One of the current discussions in the literature is whether a whole body MDCT survey should be implemented in the primary survey. The progress in imaging techniques has contributed to NOM being currently the treatment of choice for hemodynamically stable patients. Angioembolization can be used as an adjunct to NOM and has increased the success rate to 95%. However, to date many controversies exist about the optimum patient selection for NOM, the proper role of angioembolization in NOM, the best technique and material to use in angioembolization, and the right follow-up strategy of patients sustaining blunt abdominal injury. Conducting a well designed prospective clinical trial or a Delphi study would be preferable. PMID- 21794109 TI - Towards successful coordination of electronic health record based-referrals: a qualitative analysis. AB - BACKGROUND: Successful subspecialty referrals require considerable coordination and interactive communication among the primary care provider (PCP), the subspecialist, and the patient, which may be challenging in the outpatient setting. Even when referrals are facilitated by electronic health records (EHRs) (i.e., e-referrals), lapses in patient follow-up might occur. Although compelling reasons exist why referral coordination should be improved, little is known about which elements of the complex referral coordination process should be targeted for improvement. Using Okhuysen & Bechky's coordination framework, this paper aims to understand the barriers, facilitators, and suggestions for improving communication and coordination of EHR-based referrals in an integrated healthcare system. METHODS: We conducted a qualitative study to understand coordination breakdowns related to e-referrals in an integrated healthcare system and examined work-system factors that affect the timely receipt of subspecialty care. We conducted interviews with seven subject matter experts and six focus groups with a total of 30 PCPs and subspecialists at two tertiary care Department of Veterans Affairs (VA) medical centers. Using techniques from grounded theory and content analysis, we identified organizational themes that affected the referral process. RESULTS: Four themes emerged: lack of an institutional referral policy, lack of standardization in certain referral procedures, ambiguity in roles and responsibilities, and inadequate resources to adapt and respond to referral requests effectively. Marked differences in PCPs' and subspecialists' communication styles and individual mental models of the referral processes likely precluded the development of a shared mental model to facilitate coordination and successful referral completion. Notably, very few barriers related to the EHR were reported. CONCLUSIONS: Despite facilitating information transfer between PCPs and subspecialists, e-referrals remain prone to coordination breakdowns. Clear referral policies, well-defined roles and responsibilities for key personnel, standardized procedures and communication protocols, and adequate human resources must be in place before implementing an EHR to facilitate referrals. PMID- 21794110 TI - Sequencing of a QTL-rich region of the Theobroma cacao genome using pooled BACs and the identification of trait specific candidate genes. AB - BACKGROUND: BAC-based physical maps provide for sequencing across an entire genome or a selected sub-genomic region of biological interest. Such a region can be approached with next-generation whole-genome sequencing and assembly as if it were an independent small genome. Using the minimum tiling path as a guide, specific BAC clones representing the prioritized genomic interval are selected, pooled, and used to prepare a sequencing library. RESULTS: This pooled BAC approach was taken to sequence and assemble a QTL-rich region, of ~3 Mbp and represented by twenty-seven BACs, on linkage group 5 of the Theobroma cacao cv. Matina 1-6 genome. Using various mixtures of read coverages from paired-end and linear 454 libraries, multiple assemblies of varied quality were generated. Quality was assessed by comparing the assembly of 454 reads with a subset of ten BACs individually sequenced and assembled using Sanger reads. A mixture of reads optimal for assembly was identified. We found, furthermore, that a quality assembly suitable for serving as a reference genome template could be obtained even with a reduced depth of sequencing coverage. Annotation of the resulting assembly revealed several genes potentially responsible for three T. cacao traits: black pod disease resistance, bean shape index, and pod weight. CONCLUSIONS: Our results, as with other pooled BAC sequencing reports, suggest that pooling portions of a minimum tiling path derived from a BAC-based physical map is an effective method to target sub-genomic regions for sequencing. While we focused on a single QTL region, other QTL regions of importance could be similarly sequenced allowing for biological discovery to take place before a high quality whole-genome assembly is completed. PMID- 21794111 TI - Cardiac surgery: what the future holds? AB - Cardiac surgery has been scrutinized and challenged as no other specialty has. That has brought new ideas and structural frameworks but has also brought uncertainty and scepticism.This report identifies the challenges that the specialty is facing, and suggests solutions and strategies for the future. PMID- 21794112 TI - Building an international network for a primary care research program: reflections on challenges and solutions in the set-up and delivery of a prospective observational study of acute cough in 13 European countries. AB - BACKGROUND: Implementing a primary care clinical research study in several countries can make it possible to recruit sufficient patients in a short period of time that allows important clinical questions to be answered. Large multi country studies in primary care are unusual and are typically associated with challenges requiring innovative solutions. We conducted a multi-country study and through this paper, we share reflections on the challenges we faced and some of the solutions we developed with a special focus on the study set up, structure and development of Primary Care Networks (PCNs). METHOD: GRACE-01 was a multi European country, investigator-driven prospective observational study implemented by 14 Primary Care Networks (PCNs) within 13 European Countries. General Practitioners (GPs) recruited consecutive patients with an acute cough. GPs completed a case report form (CRF) and the patient completed a daily symptom diary. After study completion, the coordinating team discussed the phases of the study and identified challenges and solutions that they considered might be interesting and helpful to researchers setting up a comparable study. RESULTS: The main challenges fell within three domains as follows:i) selecting, setting up and maintaining PCNs;ii) designing local context-appropriate data collection tools and efficient data management systems; andiii) gaining commitment and trust from all involved and maintaining enthusiasm.The main solutions for each domain were:i) appointing key individuals (National Network Facilitator and Coordinator) with clearly defined tasks, involving PCNs early in the development of study materials and procedures.ii) rigorous back translations of all study materials and the use of information systems to closely monitor each PCNs progress;iii) providing strong central leadership with high level commitment to the value of the study, frequent multi-method communication, establishing a coherent ethos, celebrating achievements, incorporating social events and prizes within meetings, and providing a framework for exploitation of local data. CONCLUSIONS: Many challenges associated with multi-country primary care research can be overcome by engendering strong, effective communication, commitment and involvement of all local researchers. The practical solutions identified and the lessons learned in implementing the GRACE-01 study may assist in establishing other international primary care clinical research platforms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00353951. PMID- 21794113 TI - Communication patterns in a psychotherapy following traumatic brain injury: a quantitative case study based on symbolic dynamics. AB - BACKGROUND: The role of psychotherapy in the treatment of traumatic brain injury is receiving increased attention. The evaluation of psychotherapy with these patients has been conducted largely in the absence of quantitative data concerning the therapy itself. Quantitative methods for characterizing the sequence-sensitive structure of patient-therapist communication are now being developed with the objective of improving the effectiveness of psychotherapy following traumatic brain injury. METHODS: The content of three therapy session transcripts (sessions were separated by four months) obtained from a patient with a history of several motor vehicle accidents who was receiving dialectical behavior therapy was scored and analyzed using methods derived from the mathematical theory of symbolic dynamics. RESULTS: The analysis of symbol frequencies was largely uninformative. When repeated triples were examined a marked pattern of change in content was observed over the three sessions. The context free grammar complexity and the Lempel-Ziv complexity were calculated for each therapy session. For both measures, the rate of complexity generation, expressed as bits per minute, increased longitudinally during the course of therapy. The between-session increases in complexity generation rates are consistent with calculations of mutual information. Taken together these results indicate that there was a quantifiable increase in the variability of patient therapist verbal behavior during the course of therapy. Comparison of complexity values against values obtained from equiprobable random surrogates established the presence of a nonrandom structure in patient-therapist dialog (P = .002). CONCLUSIONS: While recognizing that only limited conclusions can be based on a case history, it can be noted that these quantitative observations are consistent with qualitative clinical observations of increases in the flexibility of discourse during therapy. These procedures can be of particular value in the examination of therapies following traumatic brain injury because, in some presentations, these therapies are complicated by deficits that result in subtle distortions of language that produce significant post-injury social impairment. Independently of the mathematical analysis applied to the investigation of therapy-generated symbol sequences, our experience suggests that the procedures presented here are of value in training therapists. PMID- 21794114 TI - Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101--Breast): a randomized, placebo controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI. AB - BACKGROUND: MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. METHODS/DESIGN: One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. DISCUSSION: Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01016886. PMID- 21794115 TI - Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide. AB - INTRODUCTION: Mechanical ventilation (MV) could prime the lung toward an inflammatory response if exposed to another insult such as bacterial invasion. The underlying mechanisms are not so far clear. Toll-like receptors (TLRs) allow the host to recognize selectively bacterial pathogens and in turn to trigger an immune response. We therefore hypothesized that MV modulates TLR2 expression and in turn modifies responsiveness to agonists such as bacterial lipopeptide (BLP). METHOD: Both in vitro and in vivo experiments were conducted. First, TLR2 expression and protein were measured in the A549 pulmonary epithelial cell line submitted to 8-hour cyclic stretch (20% elongation; 20/minute rate). After a 24 hour period of cyclic stretch, the inflammatory response of the A549 cells to the synthetic BLP, Pam3CSK4, was tested after 8 hours of exposure. In a second set of experiments, healthy anesthetized and paralyzed rabbits were submitted to 8-hour MV (tidal volume = 12 ml/kg, zero end-expiratory pressure; FIO2 = 50%; respiratory rate = 20/minute) before being sacrificed for TLR2 lung expression assessment. The lung inflammatory response to BLP was then tested in animals submitted to 24-hour MV before being sacrificed 8 hours after the tracheal instillation of Pam3CSK4. RESULTS: Cyclic stretch of human pulmonary epithelial cell lines increased both TLR2 mRNA and protein expression. Cells submitted to cyclic stretch also increased IL-6 and IL-8 secretion in response to Pam3CSK4, a classical TLR2 ligand. A mild-stretch MV protocol induced a 60-fold increase of TLR2 mRNA expression in lung tissue when compared with spontaneously breathing controls. Moreover, the combination of MV and airway exposure to Pam3CSK4 acted synergistically in causing lung inflammation and injury. CONCLUSIONS: Mild stretch MV increases lung expression of TLR2 and sensitizes the lung to bacterial TLR2 ligands. This may account for the propensity of mechanically ventilated patients to develop acute lung injury in the context of airway bacterial colonization/infection. PMID- 21794116 TI - Model-based optimal PEEP in mechanically ventilated ARDS patients in the intensive care unit. AB - BACKGROUND: The optimal level of positive end-expiratory pressure (PEEP) is still widely debated in treating acute respiratory distress syndrome (ARDS) patients. Current methods of selecting PEEP only provide a range of values and do not provide unique patient-specific solutions. Model-based methods offer a novel way of using non-invasive pressure-volume (PV) measurements to estimate patient recruitability. This paper examines the clinical viability of such models in pilot clinical trials to assist therapy, optimise patient-specific PEEP, assess the disease state and response over time. METHODS: Ten patients with acute lung injury or ARDS underwent incremental PEEP recruitment manoeuvres. PV data was measured at increments of 5 cmH2O and fitted to the recruitment model. Inspiratory and expiratory breath holds were performed to measure airway resistance and auto-PEEP. Three model-based metrics are used to optimise PEEP based on opening pressures, closing pressures and net recruitment. ARDS status was assessed by model parameters capturing recruitment and compliance. RESULTS: Median model fitting error across all patients for inflation and deflation was 2.8% and 1.02% respectively with all patients experiencing auto-PEEP. In all three metrics' cases, model-based optimal PEEP was higher than clinically selected PEEP. Two patients underwent multiple recruitment manoeuvres over time and model metrics reflected and tracked the state or their ARDS. CONCLUSIONS: For ARDS patients, the model-based method presented in this paper provides a unique, non-invasive method to select optimal patient-specific PEEP. In addition, the model has the capability to assess disease state over time using these same models and methods. PMID- 21794117 TI - Brain tissue- and region-specific abnormalities on volumetric MRI scans in 21 patients with Bardet-Biedl syndrome (BBS). AB - BACKGROUND: Bardet-Biedl syndrome (BBS) is a heterogeneous human disorder inherited in an autosomal recessive pattern, and characterized by the primary findings of obesity, polydactyly, hypogonadism, and learning and behavioural problems. BBS mouse models have a neuroanatomical phenotype consisting of third and lateral ventriculomegaly, thinning of the cerebral cortex, and reduction in the size of the corpus striatum and hippocampus. These abnormalities raise the question of whether humans with BBS have a characteristic morphologic brain phenotype. Further, although behavioral, developmental, neurological and motor defects have been noted in patients with BBS, to date, there are limited reports of brain findings in BBS. The present study represents the largest systematic evaluation for the presence of structural brain malformations and/or progressive changes, which may contribute to these functional problems. METHODS: A case control study of 21 patients, most aged 13-35 years, except for 2 patients aged 4 and 8 years, who were diagnosed with BBS by clinical criteria and genetic analysis of known BBS genes, and were evaluated by qualitative and volumetric brain MRI scans. Healthy controls were matched 3:1 by age, sex and race. Statistical analysis was performed using SAS language with SAS STAT procedures. RESULTS: All 21 patients with BBS were found to have statistically significant region- and tissue-specific patterns of brain abnormalities. There was 1) normal intracranial volume; 2) reduced white matter in all regions of the brain, but most in the occipital region; 3) preserved gray matter volume, with increased cerebral cortex volume in only the occipital lobe; 4) reduced gray matter in the subcortical regions of the brain, including the caudate, putamen and thalamus, but not in the cerebellum; and 5) increased cerebrospinal fluid volume. CONCLUSIONS: There are distinct and characteristic abnormalities in tissue- and region- specific volumes of the brain in patients with BBS, which parallel the findings, described in BBS mutant mouse models. Some of these brain abnormalities may be progressive and associated with the reported neurological and behavioral problems. Further future correlation of these MRI scan findings with detailed neurologic and neuropsychological exams together with genotype data will provide better understanding of the pathophysiology of BBS. PMID- 21794118 TI - Sinonasal neuroendocrine carcinoma: impact of differentiation status on response and outcome. AB - BACKGROUND: The impact of tumor differentiation on the behavior and response of sinonasal neuroendocrine carcinoma is unknown. METHODS: We performed a retrospective review of the patients treated for neuroendocrine carcinoma (NEC) of the nasal cavity or paranasal sinuses from 1992 to 2008 at MDACC. RESULTS: The results of our study suggest that pathologic differentiation may not be a critical factor in the clinical management of patients with NEC of the sinonasal tract. This is in contrast to laryngeal and lung NEC for which pathological differentiation has traditionally guided clinical management. CONCLUSION: Multimodality approach should be the cornerstone of treating sinonasal NEC regardless of their differentiation. Specifically, RT may provide durable local control for patients with moderately differentiated NEC if resection is not feasible or desirable, while surgical resection can benefit patients with chemo resistant or radio-resistant disease. PMID- 21794119 TI - Gemcitabine/cisplatin versus 5-fluorouracil/mitomycin C chemoradiotherapy in locally advanced pancreatic cancer: a retrospective analysis of 93 patients. AB - BACKGROUND: Despite of a growing number of gemcitabine based chemoradiotherapy studies in locally advanced pancreatic cancer (LAPC), 5-fluorouracil based regimens are still regarded to be standard and the debate of superiority between the two drugs is going on. The aim of this retrospective analysis was to evaluate the effect of two concurrent chemoradiotherapy regimens using 5-fluorouracil or gemcitabine to compare their effect and tolerance. METHODS: We have performed a single centre retrospective analysis of 93 patients treated with conventionally fractionated radiotherapy of 55.8 Gray using either concurrent 5-fluorouracil, 1 g/m2 on days 1-5 and 29-33 of radiotherapy and 10 mg/m2 of mitomycin C on day 1, 29 of radiotherapy (FM group, 35 patients) versus gemcitabine (300 mg/m2) and cisplatin, (30 mg/m2) on days 1, 8, 22, and 29 (GC group, 58 patients). Primary endpoint was the median overall survival (OS) rate. RESULTS: The median OS rate was 12.7 months in the GC group and 9.7 months in the FM group. The 1-year OS rate was 53% versus 40%, respectively (p = 0.009). GC led to more grade 3 leukocytopenia and thrombocytopenia than FM, but not to more grade 4 myelosuppression. Thrombocytopenia was the most frequently observed grade 4 toxicity in both groups (11% after FM versus 12% after GC). No grade 3/4 febrile neutropenia was observed. Grade 3 nausea was more common in the FM group (20% versus 9%) and grade 4 nausea was observed in one patient per group only. CONCLUSIONS: GC was superior to FM for overall survival and both regimens were similar in terms of tolerance. We conclude that GC leads to encouraging results and that the use of FM for chemoradiotherapy in LAPC cannot be recommended without concerns. PMID- 21794120 TI - Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators. AB - BACKGROUND: Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats. RESULTS: We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL 1beta, IL-6 and TNF-alpha) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue. CONCLUSIONS: From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy. PMID- 21794121 TI - The Risk of Paradoxical Embolism (RoPE) Study: developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke. AB - BACKGROUND: Despite the diffusion into practice of percutaneous closure of a patent foramen ovale (PFO) in patients with cryptogenic stroke (CS), the benefits have not been demonstrated, and remain unclear. For any individual presenting with a PFO in the setting of CS, it is not clear whether the PFO is pathogenically-related to the index event or an incidental finding. Further, the overall rate of stroke recurrence is low in patients with CS and PFO. How patient specific factors affect the likelihood that a discovered PFO is related to an index stroke or affect the risk of recurrence is not well understood. These probabilities are likely to be important determinants of the benefits of PFO closure in CS. DESIGN/METHODS: The goal of the Risk of Paradoxical Embolism (RoPE) Study is to develop and test a set of predictive models that can identify those patients most likely to benefit from preventive treatments for PFO-related stroke recurrence, such as PFO closure. To do this, we will construct a database of patients with CS, both with and without PFO, by combining existing cohort studies. We will use this pooled database to identify patient characteristics associated with the presence (versus the absence) of a PFO, and to use this "PFO propensity" to estimate the patient-specific probability that a PFO was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit. PMID- 21794123 TI - Garlic improves insulin sensitivity and associated metabolic syndromes in fructose fed rats. AB - BACKGROUND: Type 2 diabetes mellitus, characterized by peripheral insulin resistance, is a major lifestyle disorder of the 21st Century. Raw garlic homogenate has been reported to reduce plasma glucose levels in animal models of type 1 diabetes mellitus. However, no specific studies have been conducted to evaluate the effect of raw garlic on insulin resistance or type 2 diabetes mellitus. This study was designed to investigate the effect of raw garlic on fructose induced insulin resistance, associated metabolic syndrome and oxidative stress in diabetic rats. METHODS: Male Sprague Dawley rats weighing 200-250 gm body weight were divided into 3 groups (n = 7 per group) and fed diet containing 65% cornstarch (Control group) and 65% fructose (Diabetic group) for 8 weeks. The third group (Dia+Garl group) was fed both 65% fructose and raw garlic homogenate (250 mg/kg/day) for 8 weeks. Whole garlic cloves were homogenized with water to make a fresh paste each day. RESULTS: At the end of 8 weeks, serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance, as measured by glucose tolerance test, were significantly (p < 0.01) increased in fructose fed rats (Diabetic group) when compared to the cornstarch fed (Control) rats. Administration of raw garlic to fructose fed rats (Dia+Garl group) significantly (p < 0.05) reduced serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance when compared with fructose fed rats. Garlic also normalised the increased serum levels of nitric oxide (NO) and decreased levels of hydrogen sulphide (H2S) after fructose feeding. Although body weight gain and serum glycated haemoglobin levels of fructose fed rats (Diabetic group) were not significantly different from control rats, significant (p < 0.05) reduction of these parameters was observed in fructose fed rats after garlic administration (Dia+Garl group). Significant (p < 0.05) increase in TBARS and decrease in GSH was observed in diabetic liver. Catalase was not significantly affected in any of the groups. Administration of raw garlic homogenate normalised both hepatic TBARS and GSH levels. CONCLUSIONS: Our study demonstrates that raw garlic homogenate is effective in improving insulin sensitivity while attenuating metabolic syndrome and oxidative stress in fructose-fed rats. PMID- 21794122 TI - Cytotoxic T lymphocyte responses against melanocytes and melanoma. AB - BACKGROUND: Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels. METHODS: To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines. RESULTS: CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201 restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry. CONCLUSIONS: Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo. PMID- 21794124 TI - Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. AB - BACKGROUND: Tumor patients exhibit an increased peripheral demand of fatty acids and protein. Contrarily, tumors utilize glucose as their main source of energy supply. Thus, a diet supplying the cancer patient with sufficient fat and protein for his demands while restricting the carbohydrates (CHO) tumors thrive on, could be a helpful strategy in improving the patients' situation. A ketogenic diet (KD) fulfills these requirements. Therefore, we performed a pilot study to investigate the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors. METHODS: Sixteen patients with advanced metastatic tumors and no conventional therapeutic options participated in the study. The patients were instructed to follow a KD (less than 70 g CHO per day) with normal groceries and were provided with a supply of food additives to mix a protein/fat shake to simplify the 3-month intervention period. Quality of life [assessed by EORTC QLQ-C30 (version 2)], serum and general health parameters were determined at baseline, after every two weeks of follow-up, or after drop out. The effect of dietary change on metabolism was monitored daily by measuring urinary ketone bodies. RESULTS: One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period. These five and the one who resumed chemotherapy after 6 weeks report an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened, reflecting their very advanced disease. Except for temporary constipation and fatigue, we found no severe adverse side effects, especially no changes in cholesterol or blood lipids. CONCLUSIONS: These pilot data suggest that a KD is suitable for even advanced cancer patients. It has no severe side effects and might improve aspects of quality of life and blood parameters in some patients with advanced metastatic tumors. PMID- 21794125 TI - Angiogenesis gene expression in murine endothelial cells during post pneumonectomy lung growth. AB - Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21 days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR) arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p <.05) within 21 days of pneumonectomy. Cluster analysis of the 22 genes indicated that changes in gene expression did not occur in a single phase, but in at least four waves of gene expression: a wave demonstrating decreased gene expression more than 3 days after pneumonectomy and 3 sequential waves of increased expression on days 6, 14, and 21 after pneumonectomy. These findings indicate that a network of gene interactions contributes to angiogenesis during compensatory lung growth. PMID- 21794126 TI - Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits. AB - BACKGROUND: Cathepsin K is a cysteine peptidase known for its importance in osteoclast-mediated bone resorption. Inhibitors of cathepsin K are in clinical trials for treatment of osteoporosis. However, side effects of first generation inhibitors included altered levels of related cathepsins in peripheral organs and in the central nervous system (CNS). Cathepsin K has been recently detected in brain parenchyma and it has been linked to neurobehavioral disorders such as schizophrenia. Thus, the study of the functions that cathepsin K fulfils in the brain becomes highly relevant. RESULTS: Cathepsin K messenger RNA was detectable in all brain regions of wild type (WT) mice. At the protein level, cathepsin K was detected by immunofluorescence microscopy in vesicles of neuronal and non neuronal cells throughout the mouse brain. The hippocampus of WT mice exhibited the highest levels of cathepsin K activity in fluorogenic assays, while the cortex, striatum, and cerebellum revealed significantly lower enzymatic activities. At the molecular level, the proteolytic network of cysteine cathepsins was disrupted in the brain of cathepsin K-deficient (Ctsk-/-) animals. Specifically, cathepsin B and L protein and activity levels were altered, whereas cathepsin D remained largely unaffected. Cystatin C, an endogenous inhibitor of cysteine cathepsins, was elevated in the striatum and hippocampus, pointing to regional differences in the tissue response to Ctsk ablation. Decreased levels of astrocytic glial fibrillary acidic protein, fewer and less ramified profiles of astrocyte processes, differentially altered levels of oligodendrocytic cyclic nucleotide phosphodiesterase, as well as alterations in the patterning of neuronal cell layers were observed in the hippocampus of Ctsk-/- mice. A number of molecular and cellular changes were detected in other brain regions, including the cortex, striatum/mesencephalon, and cerebellum. Moreover, an overall induction of the dopaminergic system was found in Ctsk-/- animals which exhibited reduced anxiety levels as well as short- and long-term memory impairments in behavioral assessments. CONCLUSION: We conclude that deletion of the Ctsk gene can lead to deregulation of related proteases, resulting in a wide range of molecular and cellular changes in the CNS with severe consequences for tissue homeostasis. We propose that cathepsin K activity has an important impact on the development and maintenance of the CNS in mice. PMID- 21794127 TI - Expression cartography of human tissues using self organizing maps. AB - BACKGROUND: Parallel high-throughput microarray and sequencing experiments produce vast quantities of multidimensional data which must be arranged and analyzed in a concerted way. One approach to addressing this challenge is the machine learning technique known as self organizing maps (SOMs). SOMs enable a parallel sample- and gene-centered view of genomic data combined with strong visualization and second-level analysis capabilities. The paper aims at bridging the gap between the potency of SOM-machine learning to reduce dimension of high dimensional data on one hand and practical applications with special emphasis on gene expression analysis on the other hand. RESULTS: The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories (adipose, endocrine, homeostasis, digestion, exocrine, epithelium, sexual reproduction, muscle, immune system and nervous tissues). SOM mapping reduces the dimension of expression data from ten of thousands of genes to a few thousand metagenes, each representing a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of genes related to specific molecular processes in the respective tissue. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering are better represented and provide better signal-to-noise ratios if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues broadly into three clusters containing nervous, immune system and the remaining tissues. CONCLUSIONS: The SOM technique provides a more intuitive and informative global view of the behavior of a few well-defined modules of correlated and differentially expressed genes than the separate discovery of the expression levels of hundreds or thousands of individual genes. The program is available as R-package 'oposSOM'. PMID- 21794128 TI - Attention Network Test in adults with ADHD--the impact of affective fluctuations. AB - BACKGROUND: The Attention Network Test (ANT) generates measures of different aspects of attention/executive function. In the present study we investigated whether adults with ADHD performed different from controls on measures of accuracy, variability and vigilance as well as the control network. Secondly, we studied subgroups of adults with ADHD, expecting impairment on measures of the alerting and control networks in a subgroup with additional symptoms of affective fluctuations. METHODS: A group of 114 adults (ADHD n = 58; controls n = 56) performed the ANT and completed the Adult ADHD Rating Scale (ASRS) and the Mood Disorder Questionnaire (MDQ). The latter was used to define affective fluctuations. RESULTS: The sex distribution was similar in the two groups, but the ADHD group was significantly older (p = .005) and their score on a test of intellectual function (WASI) significantly lower than in the control group (p = .007). The two groups were not significantly different on measures of the three attention networks, but the ADHD group was generally less accurate (p = .001) and showed a higher variability through the task (p = .033).The significance was only retained for the accuracy measure when age and IQ scores were controlled for. Within the ADHD group, individuals reporting affective fluctuations (n = 22) were slower (p = .015) and obtained a lower score on the alerting network (p = .018) and a higher score on the conflict network (p = .023) than those without these symptoms. The significance was retained for the alerting network (p = .011), but not the conflict network (p = .061) when we controlled for the total ASRS and IQ scores. DISCUSSION: Adults with ADHD were characterized by impairment on accuracy and variability measures calculated from the ANT. Within the ADHD group, adults reporting affective fluctuations seemed to be more alert (i.e., less impacted by alerting cues), but slower and more distracted by conflicting stimuli than the subgroup without such fluctuations. The results suggest that the two ADHD subgroups are characterized by distinct patterns of attentional problems, and that the symptoms assessed by MDQ contribute to the cognitive heterogeneity characterizing groups of individuals with ADHD. PMID- 21794129 TI - Highly localized interactions between sensory neurons and sprouting sympathetic fibers observed in a transgenic tyrosine hydroxylase reporter mouse. AB - BACKGROUND: Sprouting of sympathetic fibers into sensory ganglia occurs in many preclinical pain models, providing a possible anatomical substrate for sympathetically enhanced pain. However, the functional consequences of this sprouting have been controversial. We used a transgenic mouse in which sympathetic fibers expressed green fluorescent protein, observable in live tissue. Medium and large diameter lumbar sensory neurons with and without nearby sympathetic fibers were recorded in whole ganglion preparations using microelectrodes. RESULTS: After spinal nerve ligation, sympathetic sprouting was extensive by 3 days. Abnormal spontaneous activity increased to 15% and rheobase was reduced. Spontaneously active cells had Aalphabeta conduction velocities but were clustered near the medium/large cell boundary. Neurons with sympathetic basket formations had a dramatically higher incidence of spontaneous activity (71%) and had lower rheobase than cells with no sympathetic fibers nearby. Cells with lower density nearby fibers had intermediate phenotypes. Immunohistochemistry of sectioned ganglia showed that cells surrounded by sympathetic fibers were enriched in nociceptive markers TrkA, substance P, or CGRP. Spontaneous activity began before sympathetic sprouting was observed, but blocking sympathetic sprouting on day 3 by cutting the dorsal ramus in addition to the ventral ramus of the spinal nerve greatly reduced abnormal spontaneous activity. CONCLUSIONS: The data suggest that early sympathetic sprouting into the sensory ganglia may have highly localized, excitatory effects. Quantitatively, neurons with sympathetic basket formations may account for more than half of the observed spontaneous activity, despite being relatively rare. Spontaneous activity in sensory neurons and sympathetic sprouting may be mutually re enforcing. PMID- 21794130 TI - Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective. AB - Warfarin has a long history of benefit and has become the gold standard medication for the prevention of ischemic stroke in patients with atrial fibrillation. Nevertheless, it is far from perfect and there is no doubt that new drugs must be found to replace warfarin. The new oral anticoagulants that are on the market or awaiting approval or under research offer some benefits but not enough to replace warfarin until results of additional studies can show an adequate balance between effectiveness/safety and cost/benefit. There are several issues concerning the new oral anticoagulants. It is essential that the effect of any anticoagulant can be measured in plasma. But to date, there is no test to assess the effect or therapeutic range for the new oral anticoagulants. There is no antidote to neutralize the action of the new drugs in cases of bleeding or when acute surgical intervention is necessary. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal failure. Rivaroxaban should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not yet been determined. How anticoagulant bridging can be done before surgery has not yet been established. In conclusion, although thousands of patients have been treated in phase III studies, additional data are necessary before conclusions can be drawn on the potential for these new anticoagulant drugs to replace warfarin in patients with atrial fibrillation. PMID- 21794131 TI - Seroprevalence and distribution of arboviral infections among rural Kenyan adults: a cross-sectional study. AB - BACKGROUND: Arthorpod-borne viruses (arboviruses) cause wide-spread morbidity in sub-Saharan Africa, but little research has documented the burden and distribution of these pathogens. METHODS: Using a population-based, cross sectional study design, we administered a detailed questionnaire and used ELISA to test the blood of 1,141 healthy Kenyan adults from three districts for the presence of anti-viral Immunoglobulin G (IgG) antibodies to the following viruses: dengue (DENV), West Nile (WNV), yellow fever (YFV), Chikungunya (CHIKV), and Rift Valley fever (RVFV). RESULTS: Of these, 14.4% were positive for DENV, 9.5% were WNV positive, 9.2% were YFV positive, 34.0% were positive for CHIKV and 0.7% were RVFV positive. In total, 46.6% had antibodies to at least one of these arboviruses. CONCLUSIONS: For all arboviruses, district of residence was strongly associated with seropositivity. Seroprevalence to YFV, DENV and WNV increased with age, while there was no correlation between age and seropositivity for CHIKV, suggesting that much of the seropositivity to CHIKV is due to sporadic epidemics. Paradoxically, literacy was associated with increased seropositivity of CHIKV and DENV. PMID- 21794132 TI - Nanoparticle exposure at nanotechnology workplaces: a review. AB - Risk, associated with nanomaterial use, is determined by exposure and hazard potential of these materials. Both topics cannot be evaluated absolutely independently. Realistic dose concentrations should be tested based on stringent exposure assessments for the corresponding nanomaterial taking into account also the environmental and product matrix. This review focuses on current available information from peer reviewed publications related to airborne nanomaterial exposure. Two approaches to derive realistic exposure values are differentiated and independently presented; those based on workplace measurements and the others based on simulations in laboratories. An assessment of the current available workplace measurement data using a matrix, which is related to nanomaterials and work processes, shows, that data are available on the likelihood of release and possible exposure. Laboratory studies are seen as an important complementary source of information on particle release processes and hence for possible exposure. In both cases, whether workplace measurements or laboratories studies, the issue of background particles is a major problem. From this review, major areas for future activities and focal points are identified. PMID- 21794133 TI - Complete motor recovery after acute paraparesis caused by spontaneous spinal epidural hematoma: case report. AB - BACKGROUND: Spontaneous spinal epidural hematoma is a relatively rare but potentially disabling disease. Prompt timely surgical management may promote recovery even in severe cases. CASE PRESENTATION: We report a 34-year-old man with a 2-hour history of sudden severe back pain, followed by weakness and numbness over the bilateral lower limbs, progressing to intense paraparesis and anesthesia. A spinal magnetic resonance imaging scan was performed and revealed an anterior epidural hematoma of the thoracic spine. He underwent an emergency decompression laminectomy of the thoracic spine and hematoma evacuation. Just after surgery, his lower extremity movements improved. After 1 week, there was no residual weakness and ambulation without assistance was resumed, with residual paresthesia on the plantar face of both feet. After 5 months, no residual symptoms persisted. CONCLUSIONS: The diagnosis of spontaneous spinal epidural hematoma must be kept in mind in cases of sudden back pain with symptoms of spinal cord compression. Early recognition, accurate diagnosis and prompt surgical treatment may result in significant improvement even in severe cases. PMID- 21794134 TI - "I could cry, the amount of shoes I can't get into": A qualitative exploration of the factors that influence retail footwear selection in women with rheumatoid arthritis. AB - BACKGROUND: Studies have reported that women with rheumatoid arthritis (RA) are not wearing NHS supplied therapeutic footwear; therefore it is likely they are wearing footwear sourced through retailers. Previous research gives limited information (largely associated with cosmesis) on people's perceptions on the relationships that exist between retail footwear, well-being and quality of life. This study aimed to explore the perceptions of women with RA regarding their choice of retail footwear and identify the factors influencing retail footwear selection. METHODS: Eleven women with RA wearing normal retail footwear were recruited from an out-patient podiatry clinic in the south east of England. Semi structured interviews were carried out and an interpretative phenomenological approach was adopted for data collection and transcript analysis. RESULTS: Six key themes were revealed from the analysis: (1) the nature of foot complaints and deformities, (2) aesthetic appearance and design of footwear, (3) body image, (4) psychosocial aspects, (5) Perceptions of footwear and (6) the therapeutic value of retail shoes. These contributed to an overarching concept of loss of choice associated with retail footwear. In particular, the areas discussed most frequently throughout were themes (2), (3) and (4), which were notably more 'emotional' in nature. CONCLUSIONS: Limitations in retail footwear for these women have impacted on their individuality, linking significantly with their body image. The loss of choice in footwear as a consequence of the disease impacts negatively on emotions, wellbeing and was identified in reduced self-perceived quality of life. PMID- 21794135 TI - Bilateral herpetic keratitis presenting with unilateral neurotrophic keratitis in pemphigus foliaceus: a case report. AB - INTRODUCTION: We report a case of bilateral herpetic keratitis developing after rapid oral corticosteroid tapering in a patient with pemphigus foliaceus, which was followed by unilateral neurotrophic keratitis that was treated with amniotic membrane transplantation. CASE PRESENTATION: A 71-year-old Korean man developed bilateral herpetic keratitis one week after rapid tapering of systemic corticosteroid. He had been on high-dose oral corticosteroid and azathioprine therapy for six months for treatment of pemphigus foliaceus. Topical acyclovir ointment was prescribed. A week later, our patient's right eye had healed, but his left eye showed increased stromal edema with enlarged epithelial defects. He was prescribed oral acyclovir with topical broad-spectrum antibiotics applied to his left eye. The stromal edema cleared within a week but the epithelial defect remained unchanged. An amniotic membrane transplantation was performed on our patient's left eye, and his epithelial defect had totally healed three weeks later. CONCLUSIONS: Patients with autoimmune disease or who are on immunosuppressive therapy have a higher chance of developing bilateral herpetic keratitis. Although rare, the condition may be followed by unilateral neurotrophic keratitis. Rapid corticosteroid tapering may act as a triggering factor for viral infection or reactivation of herpes. PMID- 21794136 TI - The short form endometriosis health profile (EHP-5): translation and validation study of the Iranian version. AB - BACKGROUND: Endometriosis Health Profile (EHP-5) is a valid instrument to measure health-related quality of life in endometriosis. This study was conducted to culturally adapt and validate the EHP-5 in Iran. METHODS: Using a standard "forward-backward' translation procedure, the English language version of the questionnaire was translated into Persian (Iranian language). Then a sample of 199 women aged 18-50 years completed the questionnaire. To test reliability the internal consistency was assessed by Cronbach's alpha coefficient. Validity was evaluated using known groups comparison. RESULTS: The mean age of respondents was 31.4 (SD = 5.4) years. Reliability analysis showed satisfactory result (Cronbach's alpha coefficient = 0.71). The questionnaire discriminated well between sub-groups of women differing in infertility and premenstrual syndrome (PMS) in the expected direction. CONCLUSION: This preliminary validation study of the Iranian version of the EHP-5 proved that it is an acceptable, reliable and valid measure of quality of life in endometriosis patients. PMID- 21794137 TI - 'Score to Door Time', a benchmarking tool for rapid response systems: a pilot multi-centre service evaluation. AB - INTRODUCTION: Rapid Response Systems were created to minimise delays in recognition and treatment of deteriorating patients on general wards. Physiological 'track and trigger' systems are used to alert a team with critical care skills to stabilise patients and expedite admission to intensive care units. No benchmarking tool exists to facilitate comparison for quality assurance. This study was designed to create and test a tool to analyse the efficiency of intensive care admission processes. METHODS: We conducted a pilot multicentre service evaluation of patients admitted to 17 intensive care units from the United Kingdom, Ireland, Denmark, United States of America and Australia. Physiological abnormalities were recorded via a standardised track and trigger score (VitalPACTM Early Warning Score). The period between the time of initial physiological abnormality (Score) and admission to intensive care (Door) was recorded as 'Score to Door Time'. Participants subsequently suggested causes for admission delays. RESULTS: Score to Door Time for 177 admissions was a median of 4:10 hours (interquartile range (IQR) 1:49 to 9:10). Time from physiological trigger to activation of a Rapid Response System was a median 0:47 hours (IQR 0:00 to 2:15). Time from call-out to intensive care admission was a median of 2:45 hours (IQR 1:19 to 6:32). A total of 127 (71%) admissions were deemed to have been delayed. Stepwise linear regression analysis yielded three significant predictors of longer Score to Door Time: being treated in a British centre, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and increasing age. Binary regression analysis demonstrated a significant association (P < 0.045) of APACHE II scores >20 with Score to Door Times greater than the median 4:10 hours. CONCLUSIONS: Score to Door Time seemed to be largely independent of illness severity and, when combined with qualitative feedback from centres, suggests that admission delays could be due to organisational issues, rather than patient factors. Score to Door Time could act as a suitable benchmarking tool for Rapid Response Systems and helps to delineate avoidable organisational delays in the care of patients at risk of catastrophic deterioration. PMID- 21794138 TI - Fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation--a feasibility study. AB - INTRODUCTION: Noninvasive ventilation (NIV) is a standard procedure in selected patients with acute respiratory failure. Previous studies have used noninvasive ventilation to ensure adequate gas exchange during fiberoptic bronchoscopy in spontaneously breathing hypoxemic patients, thus avoiding endotracheal intubation. However, it is unknown whether bronchoscopy can be performed safely in patients with acute hypoxemic respiratory failure already in need of NIV prior to the decision for bronchoscopy. METHODS: We prospectively investigated 40 consecutive, critically ill, adult patients with acute hypoxemic respiratory failure (14 women, 26 men, age 61 +/- 15 years, partial pressure for oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 under noninvasive ventilation, Simplified Acute Physiology scores (SAPS II) 47 +/- 9.9 points). All patients required noninvasive ventilation prior to the decision to perform bronchoscopy (median 10.5 h; range 2.2 to 114). Blood gases, heart rate, blood pressure and ventilation were monitored before, during and up to 120 minutes after bronchoscopy. RESULTS: Bronchoscopy could be completed in all patients without subsequent complications. Oxygen saturation fell to < 90% in two patients (5%), and the lowest value during the procedure was 84%. The mean PaO2/FiO2 ratio improved from 176 +/- 54 at baseline to 240 +/- 130 (P < 0.001) at the end of bronchoscopy and 210 +/- 79 after 120 minutes. The transient mean partial pressure of carbon dioxide in the arterial blood (PaCO2) increase was 9.4 +/- 8.1 mm Hg. Four patients (10%) required endotracheal intubation during the first eight hours after the procedure. Bronchoalveolar lavage yielded diagnostic information in 26 of 38 (68%) patients. CONCLUSIONS: In critically ill patients with acute hypoxemic respiratory failure requiring noninvasive ventilation, bronchoscopy can be performed with an acceptable risk. Since these patients per se have a high likelihood of subsequent endotracheal intubation due to failure of NIV, bronchoscopy should only be performed by experienced clinicians. PMID- 21794139 TI - Compliance with eight years of annual ivermectin treatment of onchocerciasis in Cameroon and Nigeria. AB - BACKGROUND: As the African Programme for Onchocerciasis Control (APOC) matured into its 10th year of ensuring community involvement in mass annual treatment of onchocerciasis with ivermectin, there was recognition of a need to study not only annual coverage of ivermectin in villages but also the compliance of individual villagers with these annual treatments. This was based on the concern that while population coverage goals may be achieved each year, there might be segments of the population who systematically are not complying with the annual regimen, thus creating a reservoir of infection and threatening program gains. METHODS: A multi site study in five APOC sponsored projects in Nigeria and Cameroon was undertaken to identify the socio-demographic correlates of compliance with ivermectin treatment. A total of 8,480 villagers above 9 years of age selected through a systematic random sampling from 101 communities were surveyed to ascertain their levels of compliance, by adapting APOC's standard household ivermectin survey form. Community leaders, community directed distributors (CDDs) of ivermectin and health workers were interviewed with in-depth interview guides, while focus group discussions were held with community members to help explain how socio demographic factors might affect compliance. RESULTS: Eight-year compliance ranged from 0 to 8 times with 42.9% taking ivermectin between 6-8 times annually (high compliance). In bivariate analysis high compliance was positively associated with being male, over 24 years of age, having been married, not being Christian, having little or no formal education and being in the ethnic majority. These variables were also confirmed through regression analysis based on total times ivermectin was taken over the period. While these factors explained only 8% of the overall variation in compliance, ethnic status and education appeared to be the strongest factors. Those with higher education may be more mobile and harder to reach while neglect of ethnic minorities has also been documented in other programs. CONCLUSION: These findings can help managers of CDTI programmes to ensure ivermectin reaches all segments of the population equally. PMID- 21794140 TI - Molecular characterization of cathepsin B from Clonorchis sinensis excretory/secretory products and assessment of its potential for serodiagnosis of clonorchiasis. AB - BACKGROUND: Cathepsin cysteine proteases play multiple roles in the life cycle of parasites such as food uptake, immune invasion and pathogenesis, making them valuable targets for diagnostic assays, vaccines and drugs. The purpose of this study was to identify a cathepsin B of Clonorchis sinensis (CsCB) and to investigate its diagnostic value for human helminthiases. RESULTS: The predicted amino acid sequence of the cathepsin B of C. sinensis shared 63%, 52%, 50% identity with that of Schistosoma japonicum, Homo sapiens and Fasciola hepatica, respectively. Sequence encoding proenzyme of CsCB was overexpressed in Escherichia coli. Reverse transcription PCR experiments revealed that CsCB transcribed in both adult worm and metacercaria of C. sinensis. CsCB was identified as a C. sinensis excretory/secretory product by immunoblot assay, which was consistent with immunohistochemical localization showing that CsCB was especially expressed in the intestine of C. sinensis adults. Both ELISA and western blotting analysis showed recombinant CsCB could react with human sera from clonorchiasis and other helminthiases. CONCLUSIONS: Our findings revealed that secreted CsCB may play an important role in the biology of C. sinensis and could be a diagnostic candidate for helminthiases. PMID- 21794141 TI - Temporal stability in the genetic structure of Sarcoptes scabiei under the host taxon law: empirical evidences from wildlife-derived Sarcoptes mite in Asturias, Spain. AB - BACKGROUND: Implicitly, parasite molecular studies assume temporal genetic stability. In this study we tested, for the first time to our knowledge, the extent of changes in genetic diversity and structure of Sarcoptes mite populations from Pyrenean chamois (Rupicapra pyrenaica) in Asturias (Spain), using one multiplex of 9 microsatellite markers and Sarcoptes samples from sympatric Pyrenean chamois, red deer (Cervus elaphus), roe deer (Capreolus capreolus) and red fox (Vulpes vulpes). RESULTS: The analysis of an 11-years interval period found little change in the genetic diversity (allelic diversity, and observed and expected heterozygosity). The temporal stability in the genetic diversity was confirmed by population structure analysis, which was not significantly variable over time. Population structure analysis revealed temporal stability in the genetic diversity of Sarcoptes mite under the host-taxon law (herbivore derived- and carnivore derived-Sarcoptes mite) among the sympatric wild animals from Asturias. CONCLUSIONS: The confirmation of parasite temporal genetic stability is of vital interest to allow generalizations to be made, which have further implications regarding the genetic structure, epidemiology and monitoring protocols of the ubiquitous Sarcoptes mite. This could eventually be applied to other parasite species. PMID- 21794142 TI - Wide cross-reactivity between Anopheles gambiae and Anopheles funestus SG6 salivary proteins supports exploitation of gSG6 as a marker of human exposure to major malaria vectors in tropical Africa. AB - BACKGROUND: The Anopheles gambiae gSG6 is an anopheline-specific salivary protein which helps female mosquitoes to efficiently feed on blood. Besides its role in haematophagy, gSG6 is immunogenic and elicits in exposed individuals an IgG response, which may be used as indicator of exposure to the main African malaria vector A. gambiae. However, malaria transmission in tropical Africa is sustained by three main vectors (A. gambiae, Anopheles arabiensis and Anopheles funestus) and a general marker, reflecting exposure to at least these three species, would be especially valuable. The SG6 protein is highly conserved within the A. gambiae species complex whereas the A. funestus homologue, fSG6, is more divergent (80% identity with gSG6). The aim of this study was to evaluate cross-reactivity of human sera to gSG6 and fSG6. METHODS: The A. funestus SG6 protein was expressed/purified and the humoral response to gSG6, fSG6 and a combination of the two antigens was compared in a population from a malaria hyperendemic area of Burkina Faso where both vectors were present, although with a large A. gambiae prevalence (>75%). Sera collected at the beginning and at the end of the high transmission/rainy season, as well as during the following low transmission/dry season, were analysed. RESULTS: According to previous observations, both anti-SG6 IgG level and prevalence decreased during the low transmission/dry season and showed a typical age-dependent pattern. No significant difference in the response to the two antigens was found, although their combined use yielded in most cases higher IgG level. CONCLUSIONS: Comparative analysis of gSG6 and fSG6 immunogenicity to humans suggests the occurrence of a wide cross-reactivity, even though the two proteins carry species-specific epitopes. This study supports the use of gSG6 as reliable indicator of exposure to the three main African malaria vectors, a marker which may be useful to monitor malaria transmission and evaluate vector control measures, especially in conditions of low malaria transmission and/or reduced vector density. The Anopheles stephensi SG6 protein also shares 80% identity with gSG6, suggesting the attractive possibility that the A. gambiae protein may also be useful to assess human exposure to several Asian malaria vectors. PMID- 21794143 TI - A multi locus variable number of tandem repeat analysis (MLVA) scheme for Streptococcus agalactiae genotyping. AB - BACKGROUND: Multilocus sequence typing (MLST) is currently the reference method for genotyping Streptococcus agalactiae strains, the leading cause of infectious disease in newborns and a major cause of disease in immunocompromised children and adults. We describe here a genotyping method based on multiple locus variable number of tandem repeat (VNTR) analysis (MLVA) applied to a population of S. agalactiae strains of various origins characterized by MLST and serotyping. RESULTS: We studied a collection of 186 strains isolated from humans and cattle and three reference strains (A909, NEM316 and 2603 V/R). Among 34 VNTRs, 6 polymorphic VNTRs loci were selected for use in genotyping of the bacterial population. The MLVA profile consists of a series of allele numbers, corresponding to the number of repeats at each VNTR locus. 98 MLVA genotypes were obtained compared to 51 sequences types generated by MLST. The MLVA scheme generated clusters which corresponded well to the main clonal complexes obtained by MLST. However it provided a higher discriminatory power. The diversity index obtained with MLVA was 0.960 compared to 0.881 with MLST for this population of strains. CONCLUSIONS: The MLVA scheme proposed here is a rapid, cheap and easy genotyping method generating results suitable for exchange and comparison between different laboratories and for the epidemiologic surveillance of S. agalactiae and analyses of outbreaks. PMID- 21794144 TI - A systematic review of the psychometric properties of self-report research utilization measures used in healthcare. AB - BACKGROUND: In healthcare, a gap exists between what is known from research and what is practiced. Understanding this gap depends upon our ability to robustly measure research utilization. OBJECTIVES: The objectives of this systematic review were: to identify self-report measures of research utilization used in healthcare, and to assess the psychometric properties (acceptability, reliability, and validity) of these measures. METHODS: We conducted a systematic review of literature reporting use or development of self-report research utilization measures. Our search included: multiple databases, ancestry searches, and a hand search. Acceptability was assessed by examining time to complete the measure and missing data rates. Our approach to reliability and validity assessment followed that outlined in the Standards for Educational and Psychological Testing. RESULTS: Of 42,770 titles screened, 97 original studies (108 articles) were included in this review. The 97 studies reported on the use or development of 60 unique self-report research utilization measures. Seven of the measures were assessed in more than one study. Study samples consisted of healthcare providers (92 studies) and healthcare decision makers (5 studies). No studies reported data on acceptability of the measures. Reliability was reported in 32 (33%) of the studies, representing 13 of the 60 measures. Internal consistency (Cronbach's Alpha) reliability was reported in 31 studies; values exceeded 0.70 in 29 studies. Test-retest reliability was reported in 3 studies with Pearson's r coefficients > 0.80. No validity information was reported for 12 of the 60 measures. The remaining 48 measures were classified into a three-level validity hierarchy according to the number of validity sources reported in 50% or more of the studies using the measure. Level one measures (n = 6) reported evidence from any three (out of four possible) Standards validity sources (which, in the case of single item measures, was all applicable validity sources). Level two measures (n = 16) had evidence from any two validity sources, and level three measures (n = 26) from only one validity source. CONCLUSIONS: This review reveals significant underdevelopment in the measurement of research utilization. Substantial methodological advances with respect to construct clarity, use of research utilization and related theory, use of measurement theory, and psychometric assessment are required. Also needed are improved reporting practices and the adoption of a more contemporary view of validity (i.e., the Standards) in future research utilization measurement studies. PMID- 21794145 TI - Leishmania infantum HSP70-II null mutant as candidate vaccine against leishmaniasis: a preliminary evaluation. AB - BACKGROUND: Visceral leishmaniasis is the most severe form of leishmaniasis and no effective vaccine exists. The use of live attenuated vaccines is emerging as a promising vaccination strategy. RESULTS: In this study, we tested the ability of a Leishmania infantum deletion mutant, lacking both HSP70-II alleles (DeltaHSP70 II), to provide protection against Leishmania infection in the L. major-BALB/c infection model. Administration of the mutant line by either intraperitoneal, intravenous or subcutaneous route invariably leads to the production of high levels of NO and the development in mice of type 1 immune responses, as determined by analysis of anti-Leishmania IgG subclasses. In addition, we have shown that DeltaHSP70-II would be a safe live vaccine as immunodeficient SCID mice, and hamsters (Mesocricetus auratus), infected with mutant parasites did not develop any sign of pathology. CONCLUSIONS: The results suggest that the DeltaHSP70-II mutant is a promising and safe vaccine, but further studies in more appropriate animal models (hamsters and dogs) are needed to appraise whether this attenuate mutant would be useful as vaccine against visceral leishmaniasis. PMID- 21794146 TI - Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs. AB - The removal of AMPA receptors from synapses is a major component of long-term depression (LTD). How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation. In the present study we have compared the effect of NMDA receptor and group I mGluR activation, using GluA2 tagged with super ecliptic pHluorin (SEP-GluA2) expressed in cultured hippocampal neurons. Surprisingly, agonists of the two receptors, which are both able to induce chemical forms of LTD, had clearly distinct effects on AMPA receptor trafficking. In agreement with our previous work we found that transient NMDA receptor activation results in an initial decrease in surface GluA2 from extrasynaptic sites followed by a delayed reduction in GluA2 from puncta (putative synapses). In contrast, transient activation of group I mGluRs, using DHPG, led to a pronounced but more delayed decrease in GluA2 from the dendritic shafts. Surprisingly, there was no average change in the fluorescence of the puncta. Examination of fluorescence at individual puncta, however, indicated that alterations did take place, with some puncta showing an increase and others a decrease in fluorescence. The effects of DHPG were, like DHPG-induced LTD, prevented by treatment with a protein tyrosine phosphatase (PTP) inhibitor. The electrophysiological correlate of the effects of DHPG in the SEP-GluA2 infected cultures was a reduction in mEPSC frequency with no change in amplitude. The implications of these findings for the initial mechanisms of expression of both NMDA receptor- and mGluR-induced LTD are discussed. PMID- 21794147 TI - The dynamics of social networks among female Asian elephants. AB - BACKGROUND: Patterns in the association of individuals can shed light on the underlying conditions and processes that shape societies. Here we characterize patterns of association in a population of wild Asian Elephants at Uda Walawe National Park in Sri Lanka. We observed 286 individually-identified adult female elephants over 20 months and examined their social dynamics at three levels of organization: pairs of individuals (dyads), small sets of direct companions (ego networks), and the population level (complete networks). RESULTS: Corroborating previous studies of this and other Asian elephant populations, we find that the sizes of elephant groups observed in the field on any particular day are typically small and that rates of association are low. In contrast to earlier studies, our longitudinal observations reveal that individuals form larger social units that can be remarkably stable across years while associations among such units change across seasons. Association rates tend to peak in dry seasons as opposed to wet seasons, with some cyclicity at the level of dyads. In addition, we find that individuals vary substantially in their fidelity to companions. At the ego-network level, we find that despite these fluctuations, individuals associate with a pool of long-term companions. At the population level, social networks do not exhibit any clear seasonal structure or hierarchical stratification. CONCLUSIONS: This detailed longitudinal study reveals different social dynamics at different levels of organization. Taken together, these results demonstrate that low association rates, seemingly small group sizes, and fission-fusion grouping behavior mask hidden stability in the extensive and fluid social affiliations in this population of Asian elephants. PMID- 21794148 TI - A targeted lipidomics approach to the study of eicosanoid release in synovial joints. AB - INTRODUCTION: Articular tissues are capable of producing a range of eicosanoid mediators, each of which has individual biological effects and may be affected by anti-inflammatory treatment. We set out to develop and evaluate a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) approach for the simultaneous analysis of multiple eicosanoid lipid mediators in equine synovial fluid (SF), and to illustrate its use for investigation of the in vivo effects of non-steroidal anti-inflammatory drug (NSAID) treatment. METHODS: Synovial fluid samples were obtained from normal joints of 6 adult horses at baseline (0 hr) and at 8, 24 and 168 hours after experimental induction of transient acute synovitis, with horses treated once daily with oral NSAID (meloxicam, 0.6 mg/kg) or placebo. Following solid-phase extraction, SF lipid mediator quantitation was based on liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) analysis, and results were compared between disease states using linear discriminant analysis (LDA) and analysis of variance (ANOVA) with multiple comparisons corrections. RESULTS: Of a total of 23 mediators targeted, 14 could be reliably identified and quantified in SF samples based on detection of characteristic fragment ions at retention times similar to those of commercial standards. LDA analysis of baseline, 8, 24 and 168 hour synovial fluid samples revealed a separation of these groups into discrete clusters, reflecting dynamic changes in eicosanoid release over the course of synovitis. Prostaglandin (PG) E(2) was significantly lower in NSAID vs. placebo treated samples at all time points; PGE(1), 11-hydroxyeicosatetraenoic acid (11 HETE) and 13,14-dihydro-15keto PGF(2)alpha were reduced at 8 and 24 hours by NSAID treatment; while 15-HETE, 6-keto PGF(1)alpha, PGF(2)alpha, 13,14-dihydro 15keto PGE(2) and thromboxane B(2) (TXB(2)) were reduced at the 8 hour time point only. An interesting pattern was seen for Leukotriene B(4) (LTB(4)), NSAID treatment causing an initial increase at 8 hours, but a significant reduction by 168 hours. CONCLUSIONS: The described method allows a comprehensive analysis of synovial fluid eicosanoid profiles. Eicosanoid release in inflamed joints as well as differences between NSAID treated and placebo treated individuals are not limited to PGE(2) or to the early inflammatory phase. PMID- 21794150 TI - Development of an optimized method for the detection of airborne viruses with real-time PCR analysis. AB - BACKGROUND: Airborne viruses remain one of the major public health issues worldwide. Detection and quantification of airborne viruses is essential in order to provide information regarding public health risk assessment. FINDINGS: In this study, an optimized new, simple, low cost method for sampling of airborne viruses using Low Melting Agarose (LMA) plates and a conventional microbial air sampling device has been developed. The use of LMA plates permits the direct nucleic acids extraction of the captured viruses without the need of any preliminary elution step. Molecular detection and quantification of airborne viruses is performed using real-time quantitative (RT-)PCR (Q(RT-)PCR) technique. The method has been tested using Adenoviruses (AdVs) and Noroviruses (NoVs) GII, as representative DNA and RNA viruses, respectively. Moreover, the method has been tested successfully in outdoor experiments, by detecting and quantifying human adenoviruses (HAdVs) in the airborne environment of a wastewater treatment plant. CONCLUSIONS: The great advantage of LMA is that nucleic acids extraction is performed directly on the LMA plates, while the eluted nucleic acids are totally free of inhibitory substances. Coupled with QPCR the whole procedure can be completed in less than three (3) hours. PMID- 21794149 TI - Formation of translational risk score based on correlation coefficients as an alternative to Cox regression models for predicting outcome in patients with NSCLC. AB - BACKGROUND: Personalised cancer therapy, such as that used for bronchial carcinoma (BC), requires treatment to be adjusted to the patient's status. Individual risk for progression is estimated from clinical and molecular biological data using translational score systems. Additional molecular information can improve outcome prediction depending on the marker used and the applied algorithm. Two models, one based on regressions and the other on correlations, were used to investigate the effect of combining various items of prognostic information to produce a comprehensive score. This was carried out using correlation coefficients, with options concerning a more plausible selection of variables for modelling, and this is considered better than classical regression analysis. METHODS: Clinical data concerning 63 BC patients were used to investigate the expression pattern of five tumour-associated proteins. Significant impact on survival was determined using log-rank tests. Significant variables were integrated into a Cox regression model and a new variable called integrative score of individual risk (ISIR), based on Spearman's correlations, was obtained. RESULTS: High tumour stage (TNM) was predictive for poor survival, while CD68 and Gas6 protein expression correlated with a favourable outcome. Cox regression model analysis predicted outcome more accurately than using each variable in isolation, and correctly classified 84% of patients as having a clear risk status. Calculation of the integrated score for an individual risk (ISIR), considering tumour size (T), lymph node status (N), metastasis (M), Gas6 and CD68 identified 82% of patients as having a clear risk status. CONCLUSION: Combining protein expression analysis of CD68 and GAS6 with T, N and M, using Cox regression or ISIR, improves prediction. Considering the increasing number of molecular markers, subsequent studies will be required to validate translational algorithms for the prognostic potential to select variables with a high prognostic power; the use of correlations offers improved prediction. PMID- 21794151 TI - High-precision, large-domain three-dimensional manipulation of nano-materials for fabrication nanodevices. AB - Nanoscaled materials are attractive building blocks for hierarchical assembly of functional nanodevices, which exhibit diverse performances and simultaneous functions. We innovatively fabricated semiconductor nano-probes of tapered ZnS nanowires through melting and solidifying by electro-thermal process; and then, as-prepared nano-probes can manipulate nanomaterials including semiconductor/metal nanowires and nanoparticles through sufficiently electrostatic force to the desired location without structurally and functionally damage. With some advantages of high precision and large domain, we can move and position and interconnect individual nanowires for contracting nanodevices. Interestingly, by the manipulating technique, the nanodevice made of three vertically interconnecting nanowires, i.e., diode, was realized and showed an excellent electrical property. This technique may be useful to fabricate electronic devices based on the nanowires' moving, positioning, and interconnecting and may overcome fundamental limitations of conventional mechanical fabrication. PMID- 21794152 TI - The evolution of rectal and urinary toxicity and immune response in prostate cancer patients treated with two three-dimensional conformal radiotherapy techniques. AB - BACKGROUND: Our research compared whole pelvic (WP) and prostate-only (PO) 3 dimensional conformal radiotherapy (3DCRT) techniques in terms of the incidence and evolution of acute and late toxicity of the rectum and urinary bladder, and identified the PTV-parameters influencing these damages and changes in antitumor immune response. METHODS: We analyzed 197 prostate cancer patients undergoing 3DCRT for gastrointestinal (GI) and genitourinary (GU) toxicities, and conducted a pilot immunological study including flow cytometry and an NK cell cytotoxicity assay. Acute and late toxicities were recorded according to the RTOG and the LENT SOMA scales, respectively. Univariate and multivariate analyses were conducted for factors associated with toxicity. RESULTS: In the WP group, an increase of acute rectal toxicity was observed. A higher incidence of late GI/GU toxicity appeared in the PO group. Only 18 patients (WP-7.76% and PO-11.11%) suffered severe late GI toxicity, and 26 patients (WP-11.21% and PO-16.05%) severe late GU toxicity. In the majority of acute toxicity suffering patients, the diminution of late GI/GU toxicity to grade 1 or to no toxicity after radiotherapy was observed. The 3DCRT technique itself, patient age, T stage of TNM classification, surgical intervention, and some dose-volume parameters emerged as important factors in the probability of developing acute and late GI/GU toxicity. The proportion and differentiation of NK cells positively correlated during 3DCRT and negatively so after its completion with dose-volumes of the rectum and urinary bladder. T and NKT cells were down-regulated throughout the whole period. We found a negative correlation between leukocyte numbers and bone marrow irradiated by 44-54 Gy and a positive one for NK cell proportion and doses of 5-25 Gy. The acute GU, late GU, and GI toxicities up-regulated the T cell (CTL) numbers and NK cytotoxicity. CONCLUSION: Our study demonstrates the association of acute and late damage of the urinary bladder and rectum, with clinical and treatment related factors. The 3DCRT itself does not induce the late GI or GU toxicity and rather reduces the risk of transition from acute to late toxicity. We have described for the first time the correlation between organs at risk, dose-volume parameters, and the immunological profile. PMID- 21794153 TI - QTLRel: an R package for genome-wide association studies in which relatedness is a concern. AB - BACKGROUND: Existing software for quantitative trait mapping is either not able to model polygenic variation or does not allow incorporation of more than one genetic variance component. Improperly modeling the genetic relatedness among subjects can result in excessive false positives. We have developed an R package, QTLRel, to enable more flexible modeling of genetic relatedness as well as covariates and non-genetic variance components. RESULTS: We have successfully used the package to analyze many datasets, including F34 body weight data that contains 688 individuals genotyped at 3105 SNP markers and identified 11 QTL. It took 295 seconds to estimate variance components and 70 seconds to perform the genome scan on an Linux machine equipped with a 2.40GHz Intel(R) Core(TM)2 Quad CPU. CONCLUSIONS: QTLRel provides a toolkit for genome-wide association studies that is capable of calculating genetic incidence matrices from pedigrees, estimating variance components, performing genome scans, incorporating interactive covariates and genetic and non-genetic variance components, as well as other functionalities such as multiple-QTL mapping and genome-wide epistasis. PMID- 21794154 TI - Operational research in Malawi: making a difference with cotrimoxazole preventive therapy in patients with tuberculosis and HIV. AB - BACKGROUND: In Malawi, high case fatality rates in patients with tuberculosis, who were also co-infected with HIV, and high early death rates in people living with HIV during the initiation of antiretroviral treatment (ART) adversely impacted on treatment outcomes for the national tuberculosis and ART programmes respectively. This article i) discusses the operational research that was conducted in the country on cotrimoxazole preventive therapy, ii) outlines the steps that were taken to translate these findings into national policy and practice, iii) shows how the implementation of cotrimoxazole preventive therapy for both TB patients and HIV-infected patients starting ART was associated with reduced death rates, and iv) highlights lessons that can be learnt for other settings and interventions. DISCUSSION: District and facility-based operational research was undertaken between 1999 and 2005 to assess the effectiveness of cotrimoxazole preventive therapy in reducing death rates in TB patients and subsequently in patients starting ART under routine programme conditions. Studies demonstrated significant reductions in case fatality in HIV-infected TB patients receiving cotrimoxazole and in HIV-infected patients about to start ART. Following the completion of research, the findings were rapidly disseminated nationally at stakeholder meetings convened by the Ministry of Health and internationally through conferences and peer-reviewed scientific publications. The Ministry of Health made policy changes based on the available evidence, following which there was countrywide distribution of the updated policy and guidelines. Policy was rapidly moved to practice with the development of monitoring tools, drug procurement and training packages. National programme performance improved which showed a significant decrease in case fatality rates in TB patients as well as a reduction in early death in people with HIV starting ART. SUMMARY: Key lessons for moving this research endeavour through to policy and practice were the importance of placing operational research within the programme, defining relevant questions, obtaining "buy-in" from national programme staff at the beginning of projects and having key actors or "policy entrepreneurs" to push forward the policy-making process. Ultimately, any change in policy and practice has to benefit patients, and the ultimate judge of success is whether treatment outcomes improve or not. PMID- 21794156 TI - Nano-embossing technology on ferroelectric thin film Pb(Zr0.3,Ti0.7)O3 for multi bit storage application. AB - In this work, we apply nano-embossing technique to form a stagger structure in ferroelectric lead zirconate titanate [Pb(Zr0.3, Ti0.7)O3 (PZT)] films and investigate the ferroelectric and electrical characterizations of the embossed and un-embossed regions, respectively, of the same films by using piezoresponse force microscopy (PFM) and Radiant Technologies Precision Material Analyzer. Attributed to the different layer thickness of the patterned ferroelectric thin film, two distinctive coercive voltages have been obtained, thereby, allowing for a single ferroelectric memory cell to contain more than one bit of data. PMID- 21794157 TI - High-efficiency dye-sensitized solar cells based on robust and both-end-open TiO2 nanotube membranes. AB - In the present work, dye-sensitized solar cells (DSSCs) were fabricated by incorporating transparent electrodes of ordered free-standing TiO2 nanotube (TNT) arrays with both ends open transferred onto fluorine-doped tin oxide (FTO) conductive glass. The high-quality TiO2 membranes used here were obtained by a self-detaching technique, with the superiorities of facile but reliable procedures. Afterwards, these TNT membranes can be easily transferred to FTO glass substrates by TiO2 nanoparticle paste without any crack. Compared with those DSSCs consisting of the bottom-closed membranes or attached to Ti substrate, the carefully assembled and front-side illuminated DSSCs showed an enhanced solar energy conversion efficiency as high as 5.32% of 24-MUm-thick TiO2 nanotube membranes without further treatments. These results reveal that by facilitating high-quality membrane synthesis, this kind of DSSCs assembly with optimized tube configuration can have a fascinating future. PMID- 21794155 TI - Protocol for an economic evaluation alongside the University Health Network Whiplash Intervention Trial: cost-effectiveness of education and activation, a rehabilitation program, and the legislated standard of care for acute whiplash injury in Ontario. AB - BACKGROUND: Whiplash injury affects 83% of persons in a traffic collision and leads to whiplash-associated disorders (WAD). A major challenge facing health care decision makers is identifying cost-effective interventions due to lack of economic evidence. Our objective is to compare the cost-effectiveness of: 1) physician-based education and activation, 2) a rehabilitation program developed by Aviva Canada (a group of property and casualty insurance providers), and 3) the legislated standard of care in the Canadian province of Ontario: the Pre approved Framework Guideline for Whiplash developed by the Financial Services Commission of Ontario. METHODS/DESIGN: The economic evaluation will use participant-level data from the University Health Network Whiplash Intervention Trial and will be conducted from the societal perspective over the trial's one year follow-up. Resource use (costs) will include all health care goods and services, and benefits provided during the trial's 1-year follow-up. The primary health effect will be the quality-adjusted life year. We will identify the most cost-effective intervention using the incremental cost-effectiveness ratio and incremental net-benefit. Confidence ellipses and cost-effectiveness acceptability curves will represent uncertainty around these statistics, respectively. A budget impact analysis will assess the total annual impact of replacing the current legislated standard of care with each of the other interventions. An expected value of perfect information will determine the maximum research expenditure Canadian society should be willing to pay for, and inform priority setting in, research of WAD management. DISCUSSION: Results will provide health care decision makers with much needed economic evidence on common interventions for acute whiplash management. TRIAL REGISTRATION: http://ClinicalTrials.gov identifier NCT00546806 [Trial registry date: October 18, 2007; Date first patient was randomized: February 27, 2008]. PMID- 21794158 TI - Combinatorial growth of Si nanoribbons. AB - Silicon nanoribbons (Si NRs) with a thickness of about 30 nm and a width up to a few micrometers were synthesized. Systematic observations indicate that Si NRs evolve via the following sequences: the growth of basal nanowires assisted with a Pt catalyst by a vapor-liquid-solid (VLS) mechanism, followed by the formation of saw-like edges on the basal nanowires and the planar filling of those edges by a vapor-solid (VS) mechanism. Si NRs have twins along the longitudinal < 110 > growth of the basal nanowires that also extend in < 112 > direction to edge of NRs. These twins appear to drive the lateral growth by a reentrant twin mechanism. These twins also create a mirror-like crystallographic configuration in the anisotropic surface energy state and appear to further drive lateral saw like edge growth in the < 112 > direction. These outcomes indicate that the Si NRs are grown by a combination of the two mechanisms of a Pt-catalyst-assisted VLS mechanism for longitudinal growth and a twin-assisted VS mechanism for lateral growth. PMID- 21794159 TI - Short-term and medium-term clinical outcomes of laparoscopic-assisted and open surgery for colorectal cancer: a single center retrospective case-control study. AB - BACKGROUND: Laparoscopic procedure is a rapid developed technique in colorectal surgery. In this investigation we aim at assessing the diversities of short-term and medium-term clinical outcomes of laparoscopic-assisted versus open surgery for colorectal cancer. METHODS: A total number of 519 patients with non metastatic colorectal cancer were enrolled for this study. The patients underwent either laparoscopic-assisted surgery (LAP) (n = 254) or open surgery (OP) (n = 265). Surgical techniques, perioperative managements and clinical follow-ups were standardized. Short-term perioperative data and medium-term recurrence and survival were compared and analyzed between the two groups. RESULTS: There were no differences in perioperative parameters between the two groups except in regards to a trend of faster recovery in laparoscopic procedures. There was no statistically significant difference in postoperative complications, reoperation rate, or perioperative mortality. Statistically significant differences in a faster return of gastrointestinal function and shorter hospital stay were identified in favor of laparoscopic-assisted resection. In colon and rectal cancer cases separately, the overall survival, cancer-free survival and recurrence rate were similar in two groups. There was also no tendency of significant differences in overall survival, cancer-free survival and recurrence in stage I-II and stage III patients in two cancer categories between the two groups, respectively. pT, lymph node metastasis, and clinical stage were independent predictors of overall death risk, while pT, pN, lymph node metastasis and clinical stage were found to be the independent predictors of recurrence risk in enrolled patients database. CONCLUSIONS: Laparoscopic-assisted procedure has more benefits on postoperative recovery, while has the same effects on medium term recurrence and survival compared with open surgery in the treatment of non metastatic colorectal cancer. PMID- 21794160 TI - Effects of light deprivation on visual evoked potentials in migraine without aura. AB - BACKGROUND: The mechanisms underlying the interictal habituation deficit of cortical visual evoked potentials (VEP) in migraine are not well understood. Abnormal long-term functional plasticity of the visual cortex may play a role and it can be assessed experimentally by light deprivation (LD). METHODS: We have compared the effects of LD on VEP in migraine patients without aura between attacks (MO, n = 17) and in healthy volunteers (HV, n = 17). Six sequential blocks of 100 averaged VEP at 3.1 Hz were recorded before and after 1 hour of LD. We measured VEP P100 amplitude of the 1st block of 100 sweeps and its change over 5 sequential blocks of 100 responses. RESULTS: In HV, the consequence of LD was a reduction of 1st block VEP amplitude and of the normal habituation pattern. By contrast, in MO patients, the interictal habituation deficit was not significantly modified, although 1st block VEP amplitude, already lower than in HV before LD, further decreased after LD. CONCLUSIONS: Light deprivation is thought to decrease both excitatory and subsequent inhibitory processes in visual cortex, which is in line with our findings in healthy volunteers. The VEP results in migraine patients suggest that early excitation was adequately suppressed, but not the inhibitory mechanisms occurring during long term stimulation and habituation. Accordingly, deficient intracortical inhibition is unlikely to be a primary factor in migraine pathophysiology and the habituation deficit. PMID- 21794161 TI - Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study. AB - INTRODUCTION: Several factors, including diuretic use and sepsis, interfere with the fractional excretion of sodium, which is used to distinguish transient from persistent acute kidney injury (AKI). These factors do not affect the fractional excretion of urea (FeUrea). However, there are conflicting data on the diagnostic accuracy of FeUrea. METHODS: We conducted an observational, prospective, multicenter study at three ICUs in university hospitals. Unselected patients, except those with obstructive AKI, were admitted to the participating ICUs during a six-month period. Transient AKI was defined as AKI caused by renal hypoperfusion and reversal within three days. The results are reported as medians (interquartile ranges). RESULTS: A total of 203 patients were included. According to our definitions, 67 had no AKI, 54 had transient AKI and 82 had persistent AKI. FeUrea was 39% (28 to 40) in the no-AKI group, 41% (29 to 54) in the transient AKI group and 32% (22 to 51) in the persistent AKI group (P = 0.12). FeUrea was of little help in distinguishing transient AKI from persistent AKI, with the area under the receiver operating characteristic curve being 0.59 (95% confidence interval, 0.49 to 0.70; P = 0.06). Sensitivity was 63% and specificity was 54% with a cutoff of 35%. In the subgroup of patients receiving diuretics, the results were similar. CONCLUSIONS: FeUrea may be of little help in distinguishing transient AKI from persistent AKI in critically ill patients, including those receiving diuretic therapy. Additional studies are needed to evaluate alternative markers or strategies to differentiate transient from persistent AKI. PMID- 21794162 TI - A single-blind randomized controlled trial to evaluate the effect of extended counseling on uptake of pre-antiretroviral care in Eastern Uganda. AB - BACKGROUND: Many newly screened people living with HIV (PLHIV) in Sub-Saharan Africa do not understand the importance of regular pre-antiretroviral (ARV) care because most of them have been counseled by staff who lack basic counseling skills. This results in low uptake of pre-ARV care and late treatment initiation in resource-poor settings. The effect of providing post-test counseling by staff equipped with basic counseling skills, combined with home visits by community support agents on uptake of pre-ARV care for newly diagnosed PLHIV was evaluated through a randomized intervention trial in Uganda. METHODS: An intervention trial was performed consisting of post-test counseling by trained counselors, combined with monthly home visits by community support agents for continued counseling to newly screened PLHIV in Iganga district, Uganda between July 2009 and June 2010, Participants (N = 400) from three public recruitment centres were randomized to receive either the intervention, or the standard care (the existing post-test counseling by ARV clinic staff who lack basic training in counseling skills), the control arm. The outcome measure was the proportion of newly screened and counseled PLHIV in either arm who had been to their nearest health center for clinical check-up in the subsequent three months +2 months. Treatment was randomly assigned using computer-generated random numbers. The statistical significance of differences between the two study arms was assessed using chi square and t-tests for categorical and quantitative data respectively. Risk ratios and 95% confidence intervals were used to assess the effect of the intervention. RESULTS: Participants in the intervention arm were 80% more likely to accept (take up) pre-ARV care compared to those in the control arm (RR 1.8, 95% CI 1.4-2.1). No adverse events were reported. CONCLUSIONS: Provision of post test counseling by staff trained in basic counseling skills, combined with home visits by community support agents had a significant effect on uptake of pre-ARV care and appears to be a cost-effective way to increase the prerequisites for timely ARV initiation. TRIAL REGISTRATION: The trial was registered by Current Controlled Trials Ltd C/OBioMed Central Ltd as ISRCTN94133652 and received financial support from Sida and logistical support from the European Commission. PMID- 21794163 TI - Inactivation and sub-lethal injury of salmonella typhi, salmonella typhimurium and vibrio cholerae in copper water storage vessels. AB - BACKGROUND: This study provides information on the antibacterial effect of copper against the water-borne pathogens Salmonella Typhi, Salmonella Typhimurium and Vibrio cholerae. METHODS: Suspensions of each pathogen were kept in water within a traditional copper vessel at 30 degrees C for 24 h. Samples were withdrawn, diluted and plated onto suitable growth media. Conventional enumeration of healthy (uninjured) bacteria was carried out using standard aerobic incubation conditions. Additionally, reactive oxygen species-neutralised (ROS-n) conditions were achieved by adding the peroxide scavenger sodium pyruvate to the medium with anaerobic incubation, to enumerate uninjured (ROS-insensitive) and injured (ROS sensitive) bacteria. Differences between log-transformed means of conventional (aerobic) and ROS-n counts were statistically evaluated using t tests. RESULTS: Overall, all three pathogens were inactivated by storage in copper vessels for 24 h. However, for shorter-term incubation (4-12 h), higher counts were observed under ROS-n conditions than under aerobic conditions, which demonstrate the presence of substantial numbers of sub-lethally injured cells prior to their complete inactivation. CONCLUSIONS: The present study has for the first time confirmed that these bacterial pathogens are inactivated by storage in a copper vessel within 24 h. However, it has also demonstrated that it is necessary to account for short-term sub-lethal injury, manifest as ROS-sensitivity, in order to more fully understand the process. This has important practical implications in terms of the time required to store water within a copper vessel to completely inactivate these bacteria and thereby remove the risk of water-borne disease transmission by this route. PMID- 21794164 TI - A short account of metastatic bone disease. AB - In adults, bone is the preferential target site for metastases from primary cancers of prostate, breast, lungs and thyroid. The tendency of these cancers to metastasize to bone is determined by the anatomical distribution of the blood vessels, by the genetic profile of the cancer cells and by the biological characteristics of the bone microenvironment that favour the growth of metastatic cells of certain cancers.Metastases to bone may have either an osteolytic or an ostoblastic phenotype. The interaction in the bone microenvironment between biological factors secreted by metastatic cells, and by osteoblasts and osteoclasts, and the osteolytic and osteoblastic factors released from the organic matrix mediate a vicious cycle characterized by metastatic growth and by ongoing progressive bone destruction. This interaction determines the phenotype of the metastatic bone disease. PMID- 21794165 TI - Room-temperature nonequilibrium growth of controllable ZnO nanorod arrays. AB - In this study, controllable ZnO nanorod arrays were successfully synthesized on Si substrate at room temperature (approx. 25 degrees C). The formation of controllable ZnO nanorod arrays has been investigated using growth media with different concentrations and molar ratios of Zn(NO3)2 to NaOH. Under such a nonequilibrium growth condition, the density and dimension of ZnO nanorod arrays were successfully adjusted through controlling the supersaturation degree, i.e., volume of growth medium. It was found that the wettability and electrowetting behaviors of ZnO nanorod arrays could be tuned through variations of nanorods density and length. Moreover, its field emission property was also optimized by changing the nanorods density and dimension. PMID- 21794166 TI - Big fish in a big pond: a study of academic self concept in first year medical students. AB - BACKGROUND: Big-fish-little-pond effect (BFLPE) research has demonstrated that students in high-ability environments have lower academic self-concepts than equally able students in low-ability settings. Research has shown low academic self-concepts to be associated with negative educational outcomes. Social comparison processes have been implicated as fundamental to the BFLPE. METHODS: Twenty first-year students in an Australian medical school completed a survey that included academic self-concept and social comparison measures, before and after their first written assessments. Focus groups were also conducted with a separate group of students to explore students' perceptions of competence, the medical school environment, and social comparison processes. RESULTS: The quantitative study did not reveal any changes in academic self-concept or self evaluation. The qualitative study suggested that the attributions that students used when discussing performance were those that have been demonstrated to negatively affect self-concept. Students reported that the environment was slightly competitive and they used social comparison to evaluate their performance. CONCLUSIONS: Although the BFLPE was not evident in the quantitative study, results from the qualitative study suggest that the BFLPE might be operating In that students were using attributions that are associated with lower self-concepts, the environment was slightly competitive, and social comparisons were used for evaluation. PMID- 21794167 TI - Risk factors and psychosocial characteristics of potential problematic and problematic internet use among adolescents: a cross-sectional study. AB - BACKGROUND: Problematic internet use (PIU) is associated with a plethora of psychosocial adversities. The study objectives were to assess the determinants and psychosocial implications associated with potential PIU and PIU among adolescents. METHODS: A cross-sectional study design was applied among a random sample (n = 866) of Greek adolescents (mean age: 14.7 years). Self-completed questionnaires, including internet use characteristics, Young Internet Addiction Test, and Strengths and Difficulties Questionnaire, were utilized to examine the study objectives. RESULTS: Among the study population, the prevalence rates of potential PIU and PIU were 19.4% and 1.5%, respectively. Multinomial logistic regression indicated that male gender (Odds Ratio, OR: 2.01; 95% Confidence Interval, 95% CI: 1.35-3.00), as well as utilizing the internet for retrieving sexual information (OR: 2.52; 95% CI: 1.53-4.12), interactive game playing (OR: 1.85; 95% CI: 1.21-2.82), and socialization, including chat-room use (OR: 1.97; 95% CI: 1.36-2.86) and email (OR: 1.53; 95% CI: 1.05-2.24), were independently associated with potential PIU and PIU. Adolescents with potential PIU had an increased likelihood of concomitantly presenting with hyperactivity (OR: 4.39; 95% CI: 2.03-9.52) and conduct (OR: 2.56; 95% CI: 1.46-4.50) problems. Moreover, adolescent PIU was significantly associated with hyperactivity (OR: 9.96; 95% CI: 1.76-56.20) and conduct (OR: 8.39; 95% CI: 2.04-34.56) problems, as well as comprehensive psychosocial maladjustment (OR: 8.08; 95% CI: 1.44-45.34). CONCLUSIONS: The determinants of potential PIU and PIU include accessing the internet for the purposes of retrieving sexual information, game playing, and socialization. Furthermore, both potential PIU and PIU are adversely associated with notable behavioral and social maladjustment among adolescents. PMID- 21794168 TI - Reverse genetics in Chlamydomonas: a platform for isolating insertional mutants. AB - A method was developed to identify insertional mutants of Chlamydomonas reinhardtii disrupted for selected target genes. The approach relies on the generation of thousands of transformants followed by PCR-based screenings that allow for identification of strains harboring the introduced marker gene within specific genes of interest. Our results highlight the strengths and limitations of two independent screens that differed in the nature of the marker DNA used (PCR-amplified fragment containing the plasmid-free marker versus entire linearized plasmid with the marker) and in the strategies used to maintain and store transformants. PMID- 21794169 TI - Verbal autopsy: advancing science, facilitating application. PMID- 21794170 TI - Is ultra-violet radiation the main force shaping molecular evolution of varicella zoster virus? AB - BACKGROUND: Varicella (chickenpox) exhibits a characteristic epidemiological pattern which is associated with climate. In general, primary infections in tropical regions are comparatively less frequent among children than in temperate regions. This peculiarity regarding varicella-zoster virus (VZV) infection among certain age groups in tropical regions results in increased susceptibility during adulthood in these regions. Moreover, this disease shows a cyclic behavior in which the number of cases increases significantly during winter and spring. This observation further supports the participation of environmental factors in global epidemiology of chickenpox. However, the underlying mechanisms responsible for this distinctive disease behavior are not understood completely. In a recent publication, Philip S. Rice has put forward an interesting hypothesis suggesting that ultra-violet (UV) radiation is the major environmental factor driving the molecular evolution of VZV. DISCUSSION: While we welcomed the attempt to explain the mechanisms controlling VZV transmission and distribution, we argue that Rice's hypothesis takes lightly the circulation of the so called "temperate VZV genotypes" in tropical regions and, to certain degree, overlooks the predominance of such lineages in certain non-temperate areas. Here, we further discuss and present new information about the overwhelming dominance of temperate VZV genotypes in Mexico regardless of geographical location and climate. SUMMARY: UV radiation does not satisfactorily explain the distribution of VZV genotypes in different tropical and temperate regions of Mexico. Additionally, the cyclic behavior of varicella does not shown significant differences between regions with different climates in the country. More studies should be conducted to identify the factors directly involved in viral spreading. A better understanding of the modes of transmissions exploited by VZV and their effect on viral fitness is likely to facilitate the implementation of preventive measures for disease control. PMID- 21794171 TI - Verbal autopsy: who needs it? PMID- 21794172 TI - Mechanisms of gap gene expression canalization in the Drosophila blastoderm. AB - BACKGROUND: Extensive variation in early gap gene expression in the Drosophila blastoderm is reduced over time because of gap gene cross regulation. This phenomenon is a manifestation of canalization, the ability of an organism to produce a consistent phenotype despite variations in genotype or environment. The canalization of gap gene expression can be understood as arising from the actions of attractors in the gap gene dynamical system. RESULTS: In order to better understand the processes of developmental robustness and canalization in the early Drosophila embryo, we investigated the dynamical effects of varying spatial profiles of Bicoid protein concentration on the formation of the expression border of the gap gene hunchback. At several positions on the anterior-posterior axis of the embryo, we analyzed attractors and their basins of attraction in a dynamical model describing expression of four gap genes with the Bicoid concentration profile accounted as a given input in the model equations. This model was tested against a family of Bicoid gradients obtained from individual embryos. These gradients were normalized by two independent methods, which are based on distinct biological hypotheses and provide different magnitudes for Bicoid spatial variability. We showed how the border formation is dictated by the biological initial conditions (the concentration gradient of maternal Hunchback protein) being attracted to specific attracting sets in a local vicinity of the border. Different types of these attracting sets (point attractors or one dimensional attracting manifolds) define several possible mechanisms of border formation. The hunchback border formation is associated with intersection of the spatial gradient of the maternal Hunchback protein and a boundary between the attraction basins of two different point attractors. We demonstrated how the positional variability for hunchback is related to the corresponding variability of the basin boundaries. The observed reduction in variability of the hunchback gene expression can be accounted for by specific geometrical properties of the basin boundaries. CONCLUSION: We clarified the mechanisms of gap gene expression canalization in early Drosophila embryos. These mechanisms were specified in the case of hunchback in well defined terms of the dynamical system theory. PMID- 21794173 TI - Teaching evidence based medicine literature searching skills to medical students during the clinical years - a protocol for a randomised controlled trial. AB - BACKGROUND: Two of the key steps in evidence based medicine (EBM) are being able to construct a clinical question and effectively search the literature to source relevant information. No evidence currently exists that informs whether such skills should be taught to medical students during their pre-clinical years, or delivered to include both the pre-clinical and clinical years of study. This is an important component of curriculum design as the level of clinical maturity of students can affect their perception of the importance and uptake of EBM principles in practice. METHODS/DESIGN: A randomised controlled trial will be conducted to identify the effectiveness of delivering a formal workshop in EBM literature searching skills to third year medical students entering their clinical years of study. The primary outcome of EBM competency in literature searching skills will be evaluated using the Fresno tool. DISCUSSION: This trial will provide novel information on the effectiveness of delivering a formal education workshop in evidence based medicine literature searching skills during the clinical years of study. The result of this study will also identify the impact of teaching EBM literature searching skills to medical students during the clinical years of study. PMID- 21794174 TI - Whole genome characterization of non-tissue culture adapted HRSV strains in severely infected children. AB - BACKGROUND: Human respiratory syncytial virus (HRSV) is the most important virus causing lower respiratory infection in young children. The complete genetic characterization of RSV clinical strains is a prerequisite for understanding HRSV infection in the clinical context. Current information about the genetic structure of the HRSV genome has largely been obtained using tissue culture adapted viruses. During tissue culture adaptation genetic changes can be introduced into the virus genome, which may obscure subtle variations in the genetic structure of different RSV strains. METHODS: In this study we describe a novel Sanger sequencing strategy which allowed the complete genetic characterisation of 14 clinical HRSV strains. The viruses were sequenced directly in the nasal washes of severely hospitalized children, and without prior passage of the viruses in tissue culture. RESULTS: The analysis of nucleotide sequences suggested that vRNA length is a variable factor among primary strains, while the phylogenetic analysis suggests selective pressure for change. The G gene showed the greatest sequence variation (2-6.4%), while small hydrophobic protein and matrix genes were completely conserved across all clinical strains studied. A number of sequence changes in the F, L, M2-1 and M2-2 genes were observed that have not been described in laboratory isolates. The gene junction regions showed more sequence variability, and in particular the intergenic regions showed a highest level of sequence variation. Although the clinical strains grew slower than the HRSVA2 virus isolate in tissue culture, the HRSVA2 isolate and clinical strains formed similar virus structures such as virus filaments and inclusion bodies in infected cells; supporting the clinical relevance of these virus structures. CONCLUSION: This is the first report to describe the complete genetic characterization of HRSV clinical strains that have been sequenced directly from clinical material. The presence of novel substitutions and deletions in the vRNA of clinical strains emphasize the importance of genomic characterization of non tissue culture adapted primary strains. PMID- 21794175 TI - Pilot study on developing a decision support tool for guiding re-administration of chemotherapeutic agent after a serious adverse drug reaction. AB - BACKGROUND: Currently, there are no standard guidelines for recommending re administration of a chemotherapeutic drug to a patient after a serious adverse drug reaction (ADR) incident. The decision on whether to rechallenge the patient is based on the experience of the clinician and is highly subjective. Thus the aim of this study is to develop a decision support tool to assist clinicians in this decision making process. METHODS: The inclusion criteria for patients in this study are: (1) had chemotherapy at National Cancer Centre Singapore between 2004 to 2009, (2) suffered from serious ADRs, and (3) were rechallenged. A total of 46 patients fulfilled the inclusion criteria. A genetic algorithm attribute selection method was used to identify clinical predictors for patients' rechallenge status. A Naive Bayes model was then developed using 35 patients and externally validated using 11 patients. RESULTS: Eight patient attributes (age, chemotherapeutic drug, albumin level, red blood cell level, platelet level, abnormal white blood cell level, abnormal alkaline phosphatase level and abnormal alanine aminotransferase level) were identified as clinical predictors for rechallenge status of patients. The Naive Bayes model had an AUC of 0.767 and was found to be useful for assisting clinical decision making after clinicians had identified a group of patients for rechallenge. A platform independent version and an online version of the model is available to facilitate independent validation of the model. CONCLUSION: Due to the limited size of the validation set, a more extensive validation of the model is necessary before it can be adopted for routine clinical use. Once validated, the model can be used to assist clinicians in deciding whether to rechallenge patients by determining if their initial assessment of rechallenge status of patients is accurate. PMID- 21794176 TI - Strategies to improve palatability and increase consumption intentions for Momordica charantia (bitter melon): a vegetable commonly used for diabetes management. AB - BACKGROUND: Although beneficial to health, dietary phytonutrients are bitter, acid and/or astringent in taste and therefore reduce consumer choice and acceptance during food selection. Momordica charantia, commonly known as bitter melon has been traditionally used in Ayurvedic and Chinese medicine to treat diabetes and its complications. The aim of this study was to develop bitter melon containing recipes and test their palatability and acceptability in healthy individuals for future clinical studies. METHODS: A cross-sectional sensory evaluation of bitter melon-containing ethnic recipes was conducted among 50 healthy individuals. The primary endpoints assessed in this analysis were current consumption information and future intentions to consume bitter melon, before and after provision of attribute- and health-specific information. A convenience sample of 50, self-reported non-diabetic adults were recruited from the University of Hawaii. Sensory evaluations were compared using two-way ANOVA, while differences in stage of change (SOC) before and after receiving health information were analyzed by Chi-square (chi2) analyses. RESULTS: Our studies indicate that tomato-based recipes were acceptable to most of the participants and readily acceptable, as compared with recipes containing spices such as curry powder. Health information did not have a significant effect on willingness to consume bitter melon, but positively affected the classification of SOC. CONCLUSIONS: This study suggests that incorporating bitter foods in commonly consumed food dishes can mask bitter taste of bitter melon. Furthermore, providing positive health information can elicit a change in the intent to consume bitter melon-containing dishes despite mixed palatability results. PMID- 21794177 TI - Identification of azurocidin as a potential periodontitis biomarker by a proteomic analysis of gingival crevicular fluid. AB - BACKGROUND: The inflammatory disease periodontitis results in tooth loss and can even lead to diseases of the whole body if not treated. Gingival crevicular fluid (GCF) reflects the condition of the gingiva and contains proteins transuded from serum or cells at inflamed sites. In this study, we aimed to discover potential protein biomarkers for periodontitis in GCF proteome using LC-MS/MS. RESULTS: We identified 305 proteins from GCF of healthy individuals and periodontitis patients collected using a sterile gel loading tip by ESI-MS/MS coupled to nano LC. Among these proteins, about 45 proteins were differentially expressed in the GCF proteome of moderate periodontitis patients when compared to the healthy individuals. We first identified azurocidin in the GCF, but not the saliva, as an upregulated protein in the periodontitis patients and verified its increased expression during periodontitis by ELISA using the GCF of the classified periodontitis patients compared to the healthy individuals. In addition, we found that azurocidin inhibited the differentiation of bone marrow-derived macrophages to osteoclasts. CONCLUSIONS: Our results show that GCF collection using a gel loading tip and subsequent LC-MS/MS analysis following 1D-PAGE proteomic separation are effective for the analysis of the GCF proteome. Our current results also suggest that azurocidin could be a potential biomarker candidate for the early detection of inflammatory periodontal destruction by gingivitis and some chronic periodontitis. Our data also suggest that azurocidin may have an inhibitory role in osteoclast differentiation and, thus, a protective role in alveolar bone loss during the early stages of periodontitis. PMID- 21794178 TI - Feather barbs as a good source of mtDNA for bird species identification in forensic wildlife investigations. AB - BACKGROUND: The ability to accurately identify bird species is crucial for wildlife law enforcement and bird-strike investigations. However, such identifications may be challenging when only partial or damaged feathers are available for analysis. RESULTS: By applying vigorous contamination controls and sensitive PCR amplification protocols, we found that it was feasible to obtain accurate mitochondrial (mt)DNA-based species identification with as few as two feather barbs. This minimally destructive DNA approach was successfully used and tested on a variety of bird species, including North American wild turkey (Meleagris gallopavo), Canada goose (Branta canadensis), blue heron (Ardea herodias) and pygmy owl (Glaucidium californicum). The mtDNA was successfully obtained from 'fresh' feathers, historic museum specimens and archaeological samples, demonstrating the sensitivity and versatility of this technique. CONCLUSIONS: By applying appropriate contamination controls, sufficient quantities of mtDNA can be reliably recovered and analyzed from feather barbs. This previously overlooked substrate provides new opportunities for accurate DNA species identification when minimal feather samples are available for forensic analysis. PMID- 21794179 TI - Effects of different initial bundle tensioning strategies on the outcome of double-bundle ACL reconstruction: a cohort study. AB - BACKGROUND: This study was performed to investigate the effects of different strategies and initial tension applied to each one of the bundles, antero-medial (AM) and postero-lateral (PL), on clinical outcome in double bundle (DB) ACL reconstruction. METHODS: One hundred fifty-one primary unilateral DB ACL reconstructions performed by a single surgeon from 1994 through 2002 were included in the study with a follow-up of at least 24 months. They were divided in the following 3 groups: Group I - Higher initial tension applied manually in the AM bundle compared to PL. II - Higher tension applied in the PL bundle compared to AM. III - The 2 bundles were attempted to be equally tensioned. All fixations were performed in 30 degrees of flexion. Group I = 59 patients, group II = 53 patients and group III = 39 patients. The groups had no statistical differences concerning demographic distribution. Clinical outcome was retrospectively evaluated by use of knee range of motion, manual knee laxity tests, KT-1000, Lysholm knee scale, subjective recovery scale and sports performance recovery scale. The differences of data were analyzed among the three groups. RESULTS: Group I showed a significant extension deficit compared with groups II and III. ANOVA revealed a significant difference of anterior laxity measured by the KT-1000 (average KT difference of 2.1, 2.1 and 1.2 mm in Group I, II and III, respectively). A statistical difference was found among the three groups regarding subjective and sports performance recovery scales with Group II showing higher scores in recovery than Group I. CONCLUSIONS: The current clinical study does not recommend manual maximum of initial tension applied to the anteromedial or posterolateral bundles with graft tension imbalance at 30 degrees of flexion in double-bundle ACL reconstruction to achieve a better clinical outcome. PMID- 21794181 TI - Pre-ejection period by radial artery tonometry supplements echo Doppler findings during biventricular pacemaker optimization. AB - BACKGROUND: Biventricular (Biv) pacemaker echo optimization has been shown to improve cardiac output however is not routinely used due to its complexity. We investigated the role of a simple method involving computerized pre-ejection time (PEP) assessment by radial artery tonometry in guiding Biv pacemaker optimization. METHODS: Blinded echo and radial artery tonometry were performed simultaneously in 37 patients, age 69.1 +/- 12.8 years, left ventricular (LV) ejection fraction (EF) 33 +/- 10%, during Biv pacemaker optimization. Effect of optimization on echo derived velocity time integral (VTI), ejection time (ET), myocardial performance index (MPI), radial artery tonometry derived PEP and echo radial artery tonometry derived PEP/VTI and PEP/ET indices was evaluated. RESULTS: Significant improvement post optimization was achieved in LV ET (286.9 +/- 37.3 to 299 +/- 34.6 ms, p < 0.001), LV VTI (15.9 +/- 4.8 cm to 18.4 +/- 5.1 cm, p < 0.001) and MPI (0.57 +/- 0.2 to 0.45 +/- 0.13, p < 0.001) and in PEP (246.7 +/- 36.1 ms to 234.7 +/- 35.5 ms, p = 0.003), PEP/ET (0.88 +/- 0.21 to 0.79 +/- 0.17, p < 0.001), and PEP/VTI (17.3 +/- 7 to 13.78 +/- 4.7, p < 0.001). The correlation between comprehensive echo Doppler and radial artery tonometry PEP guided optimal atrioventricular delay (AVD) and optimal interventricular delay (VVD) was 0.75 (p < 0.001) and 0.69 (p < 0.001) respectively. In 29 patients with follow up assessment, New York Heart Association (NYHA) class reduced from 2.5 +/- 0.8 to 2.0 +/- 0.9 (p = 0.004) at 1.8 +/- 1.4 months. CONCLUSION: An acute shortening of PEP by radial artery tonometry occurs post Biv pacemaker optimization and correlates with improvement in hemodynamics by echo Doppler and may provide a cost-efficient approach to assist with Biv pacemaker echo optimization. PMID- 21794182 TI - Relationship between Tei Index and left ventricular geometric patterns in a hypertensive population: a cross-sectional study. AB - BACKGROUND: The relationship between Tei Index (TI) and left ventricular (LV) geometric patterns has not been previously well described. The present study therefore set out to describe the nature of this relationship if any, and to also assess whether a relationship exists between the geometric patterns and LV ejection fraction (LVEF) so as to establish a basis for comparison. METHODS: The study was carried out in the echocardiography laboratory of Aminu Kano Teaching Hospital (AKTH) in Kano, North-Western Nigeria. The study was cross-sectional in design. Hypertensive subjects referred for echocardiography to AKTH were serially recruited from October 2008 to September 2009. TI was defined as the sum of isovolumic contraction and relaxation times divided by the ejection time, and values of LV TI < 0.40 were considered normal, while higher values were considered abnormal. Four patterns of LV geometry (normal, concentric remodelling, concentric LV hypertrophy and eccentric LV hypertrophy) were determined from the LV mass index and LV relative wall thickness as previously described. Binary logistic regression models and Pearson's Correlation (r) Coefficient were used to analyse the associations between TI or LVEF and a number of variables. RESULTS: A total of 142 subjects were recruited into the study. The prevalence of abnormal TI (26.8%; 38 persons) in the total population was lower than that of reduced LV ejection fraction (< 50%) (38.0%; 54 persons) (p = 0.335). There was no association between any LV geometric pattern and abnormal TI. However, there was significant relationship between the geometric patterns and low LVEF (< 50%); tested in a binary logistic regression model. HR was a significant predictor of TI with regression coefficient of -0.218, 95% confidence interval (CI) of -0.005 - < -0.001 and p-value of 0.011. Similarly, HR was the only variable that significantly predicted abnormal TI in a binary logistic regression model with an odds ratio of 1.058 (95% CI = 1.002-1.118; p = 0.044), and also the only variable that correlated with TI significantly (r = -0.212; p value = 0.014). CONCLUSION: This study has found that LV geometric patterns and LVEF were not associated with TI in hypertensives, but there was strong association between LV geometric patterns and LVEF. TI was found to be dependent on HR. PMID- 21794180 TI - Reticulate evolution: frequent introgressive hybridization among Chinese hares (genus lepus) revealed by analyses of multiple mitochondrial and nuclear DNA loci. AB - BACKGROUND: Interspecific hybridization may lead to the introgression of genes and genomes across species barriers and contribute to a reticulate evolutionary pattern and thus taxonomic uncertainties. Since several previous studies have demonstrated that introgressive hybridization has occurred among some species within Lepus, therefore it is possible that introgressive hybridization events also occur among Chinese Lepus species and contribute to the current taxonomic confusion. RESULTS: Data from four mtDNA genes, from 116 individuals, and one nuclear gene, from 119 individuals, provides the first evidence of frequent introgression events via historical and recent interspecific hybridizations among six Chinese Lepus species. Remarkably, the mtDNA of L. mandshuricus was completely replaced by mtDNA from L. timidus and L. sinensis. Analysis of the nuclear DNA sequence revealed a high proportion of heterozygous genotypes containing alleles from two divergent clades and that several haplotypes were shared among species, suggesting repeated and recent introgression. Furthermore, results from the present analyses suggest that Chinese hares belong to eight species. CONCLUSION: This study provides a framework for understanding the patterns of speciation and the taxonomy of this clade. The existence of morphological intermediates and atypical mitochondrial gene genealogies resulting from frequent hybridization events likely contribute to the current taxonomic confusion of Chinese hares. The present study also demonstrated that nuclear gene sequence could offer a powerful complementary data set with mtDNA in tracing a complete evolutionary history of recently diverged species. PMID- 21794183 TI - Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. AB - BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or chronic fatigue syndrome (CFS) has been used to name a range of chronic conditions characterized by extreme fatigue and other disabling symptoms. Attempts to estimate the burden of disease have been limited by selection bias, and by lack of diagnostic biomarkers and of agreed reproducible case definitions. We estimated the prevalence and incidence of ME/CFS in three regions in England, and discussed the implications of frequency statistics and the use of different case definitions for health and social care planning and for research. METHODS: We compared the clinical presentation, prevalence and incidence of ME/CFS based on a sample of 143,000 individuals aged 18 to 64 years, covered by primary care services in three regions of England. Case ascertainment involved: 1) electronic search for chronic fatigue cases; 2) direct questioning of general practitioners (GPs) on cases not previously identified by the search; and 3) clinical review of identified cases according to CDC-1994, Canadian and Epidemiological Case (ECD) Definitions. This enabled the identification of cases with high validity. RESULTS: The estimated minimum prevalence rate of ME/CFS was 0.2% for cases meeting any of the study case definitions, 0.19% for the CDC-1994 definition, 0.11% for the Canadian definition and 0.03% for the ECD. The overall estimated minimal yearly incidence was 0.015%. The highest rates were found in London and the lowest in East Yorkshire. All but one of the cases conforming to the Canadian criteria also met the CDC-1994 criteria, however presented higher prevalence and severity of symptoms. CONCLUSIONS: ME/CFS is not uncommon in England and represents a significant burden to patients and society. The number of people with chronic fatigue who do not meet specific criteria for ME/CFS is higher still. Both groups have high levels of need for service provision, including health and social care. We suggest combining the use of both the CDC-1994 and Canadian criteria for ascertainment of ME/CFS cases, alongside careful clinical phenotyping of study participants. This combination if used systematically will enable international comparisons, minimization of bias, and the identification and investigation of distinct sub-groups of patients with possibly distinct aetiologies and pathophysiologies, standing a better chance of translation into effective specific treatments. PMID- 21794184 TI - Explaining gender differences in non-fatal suicidal behaviour among adolescents: a population-based study. AB - BACKGROUND: While suicide is the second leading cause of death among young people in most industrial countries, non-fatal suicidal behaviour is also a very important public health concern among adolescents. The aim of this study was to investigate gender differences in prevalence and emotional and behavioural correlates of suicidal behaviour in a representative school-based sample of adolescents. METHODS: A cross-sectional design was used to assess suicidal behaviour and various areas of emotional and behavioural problems by using a self report booklet including the Youth Self-Report. One hundred sixteen schools in a region of Southern Germany agreed to participate. A representative sample of 5,512 ninth-grade students was studied. Mean age was 14.8 years (SD 0.73); 49.8% were female. RESULTS: Serious suicidal thoughts were reported by 19.8% of the female students and 10.8% of the females had ever attempted suicide. In the male group, 9.3% had a history of suicidal thoughts and 4.9% had previously attempted suicide. Internalizing emotional and behavioural problems were shown to be higher in the female group (difference of the group means 4.41) while externalizing emotional and behavioural problems slightly predominated in male students (difference of the group means -0.65). However, the total rate of emotional and behavioural problems was significantly higher in the adolescent female group (difference of the group means 4.98). Using logistic regression models with suicidal thoughts or attempted suicide as dependent variables, the pseudo-R2 of gender alone was only 2.7% or 2.3%, while it was 30% or 23.2% for emotional and behavioural problems measured by the YSR syndrome scales. By adding gender to the emotional and behavioural problems only an additional 0.3% of information could be explained. CONCLUSIONS: The findings suggest that gender differences in non fatal suicidal behaviour among adolescents can to a large extent be explained by the gender differences in emotional and behavioural problems during this age. PMID- 21794185 TI - Strategies for controlled placement of nanoscale building blocks. AB - The capability of placing individual nanoscale building blocks on exact substrate locations in a controlled manner is one of the key requirements to realize future electronic, optical, and magnetic devices and sensors that are composed of such blocks. This article reviews some important advances in the strategies for controlled placement of nanoscale building blocks. In particular, we will overview template assisted placement that utilizes physical, molecular, or electrostatic templates, DNA-programmed assembly, placement using dielectrophoresis, approaches for non-close-packed assembly of spherical particles, and recent development of focused placement schemes including electrostatic funneling, focused placement via molecular gradient patterns, electrodynamic focusing of charged aerosols, and others. PMID- 21794186 TI - HighP-TNano-Mechanics of Polycrystalline Nickel. AB - We have conducted highP-Tsynchrotron X-ray and time-of-flight neutron diffraction experiments as well as indentation measurements to study equation of state, constitutive properties, and hardness of nanocrystalline and bulk nickel. Our lattice volume-pressure data present a clear evidence of elastic softening in nanocrystalline Ni as compared with the bulk nickel. We show that the enhanced overall compressibility of nanocrystalline Ni is a consequence of the higher compressibility of the surface shell of Ni nanocrystals, which supports the results of molecular dynamics simulation and a generalized model of a nanocrystal with expanded surface layer. The analytical methods we developed based on the peak-profile of diffraction data allow us to identify "micro/local" yield due to high stress concentration at the grain-to-grain contacts and "macro/bulk" yield due to deviatoric stress over the entire sample. The graphic approach of our strain/stress analyses can also reveal the corresponding yield strength, grain crushing/growth, work hardening/softening, and thermal relaxation under highP Tconditions, as well as the intrinsic residual/surface strains in the polycrystalline bulks. From micro-indentation measurements, we found that a low temperature annealing (T < 0.4 Tm) hardens nanocrystalline Ni, leading to an inverse Hall-Petch relationship. We explain this abnormal Hall-Petch effect in terms of impurity segregation to the grain boundaries of the nanocrystalline Ni. PMID- 21794187 TI - Hydrothermal synthesis of amorphous MoS2nanofiber bundles via acidification of ammonium heptamolybdate tetrahydrate. AB - MoS2nanofiber bundles have been prepared by hydrothermal method using ammonium molybdate with sulfur source in acidic medium and maintained at 180 degrees C for several hours. The obtained black crystalline products are characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectrometer (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The PXRD pattern of the sample can be readily indexed as hexagonal 2H-MoS2. FTIR spectrum of the MoS2shows the band at 480 cm-1corresponds to the gammaas(Mo-S). SEM/TEM images of the samples exhibit that the MoS2nanofiber exist in bundles of 120-300 nm in diameter and 20-25 MUm in length. The effects of temperature, duration and other experimental parameters on the morphology of the products are investigated. PMID- 21794188 TI - Submonolayer quantum dots for high speed surface emitting lasers. AB - We report on progress in growth and applications of submonolayer (SML) quantum dots (QDs) in high-speed vertical-cavity surface-emitting lasers (VCSELs). SML deposition enables controlled formation of high density QD arrays with good size and shape uniformity. Further increase in excitonic absorption and gain is possible with vertical stacking of SML QDs using ultrathin spacer layers. Vertically correlated, tilted or anticorrelated arrangements of the SML islands are realized and allow QD strain and wavefunction engineering. Respectively, both TE and TM polarizations of the luminescence can be achieved in the edge-emission using the same constituting materials. SML QDs provide ultrahigh modal gain, reduced temperature depletion and gain saturation effects when used in active media in laser diodes. Temperature robustness up to 100 degrees C for 0.98 MUm range vertical-cavity surface-emitting lasers (VCSELs) is realized in the continuous wave regime. An open eye 20 Gb/s operation with bit error rates better than 10-12has been achieved in a temperature range 25-85 degrees Cwithout current adjustment. Relaxation oscillations up to ~30 GHz have been realized indicating feasibility of 40 Gb/s signal transmission. PMID- 21794190 TI - Strain Relief Analysis of InN Quantum Dots Grown on GaN. AB - We present a study by transmission electron microscopy (TEM) of the strain state of individual InN quantum dots (QDs) grown on GaN substrates. Moire fringe and high resolution TEM analyses showed that the QDs are almost fully relaxed due to the generation of a 60 degrees misfit dislocation network at the InN/GaN interface. By applying the Geometric Phase Algorithm to plan-view high-resolution micrographs, we show that this network consists of three essentially non interacting sets of misfit dislocations lying along the directions. Close to the edge of the QD, the dislocations curve to meet the surface and form a network of threading dislocations surrounding the system. PMID- 21794191 TI - ZnO Nanorods via Spray Deposition of Solutions Containing Zinc Chloride and Thiocarbamide. AB - In this work we present the results on formation of ZnO nanorods prepared by spray of aqueous solutions containing ZnCl2and thiocarbamide (tu) at different molar ratios. It has been observed that addition of thiocarbamide into the spray solution has great impact on the size, shape and phase composition of the ZnO crystals. Obtained layers were characterized by scanning electron microscopy (SEM) equipped with energy selected backscattered electron detection system (ESB), X-ray diffraction (XRD) and photoluminescence spectroscopy (PL). Small addition of thiocarbamide into ZnCl2solution (ZnCl2:tu = 1:0.25) supports development of significantly thinner ZnO nanorods with higher aspect ratio compared to those obtained from ZnCl2solution. Diameter of ZnO rods decreases from 270 to 100 nm and aspect ratio increases from ~2.5 to 12 spraying ZnCl2and ZnCl2:tu solutions, respectively. According to XRD, well crystallized (002) orientated pure wurtzite ZnO crystals have been formed. However, tiny 'spot'-like formations of ZnS were detected on the side planes of hexagonal rods prepared from the thiocarbamide containing solutions. Being adsorbed on the side facets of the crystals ZnS inhibits width growth and promotes longitudinalc-axis growth. PMID- 21794189 TI - Nanoparticles for applications in cellular imaging. AB - In the following review we discuss several types of nanoparticles (such as TiO2, quantum dots, and gold nanoparticles) and their impact on the ability to image biological components in fixed cells. The review also discusses factors influencing nanoparticle imaging and uptake in live cells in vitro. Due to their unique size-dependent properties nanoparticles offer numerous advantages over traditional dyes and proteins. For example, the photostability, narrow emission peak, and ability to rationally modify both the size and surface chemistry of Quantum Dots allow for simultaneous analyses of multiple targets within the same cell. On the other hand, the surface characteristics of nanometer sized TiO2allow efficient conjugation to nucleic acids which enables their retention in specific subcellular compartments. We discuss cellular uptake mechanisms for the internalization of nanoparticles and studies showing the influence of nanoparticle size and charge and the cell type targeted on nanoparticle uptake. The predominant nanoparticle uptake mechanisms include clathrin-dependent mechanisms, macropinocytosis, and phagocytosis. PMID- 21794192 TI - Bio-nanopatterning of Surfaces. AB - Bio-nanopatterning of surfaces is a very active interdisciplinary field of research at the interface between biotechnology and nanotechnology. Precise patterning of biomolecules on surfaces with nanometre resolution has great potential in many medical and biological applications ranging from molecular diagnostics to advanced platforms for fundamental studies of molecular and cell biology. Bio-nanopatterning technology has advanced at a rapid pace in the last few years with a variety of patterning methodologies being developed for immobilising biomolecules such as DNA, peptides, proteins and viruses at the nanoscale on a broad range of substrates. In this review, the status of research and development are described, with particular focus on the recent advances on the use of nanolithographic techniques as tools for biomolecule immobilisation at the nanoscale. Present strengths and weaknesses, as well future challenges on the different nanolithographic bio-nanopatterning approaches are discussed. PMID- 21794193 TI - Chemotherapy for gynecologic cancers occurring during pregnancy. AB - Chemotherapy treatment of gynecologic malignancies during pregnancy should provide maternal benefit without undue fetal harm. We review the treatment regimens for gynecologic cancers occurring during pregnancy and the effects of chemotherapy on fetal development, parturition, and lactation. Women diagnosed with a gynecologic cancer during pregnancy require individualized treatment plans from a multidisciplinary team. TARGET AUDIENCE: Obstetricians & gynecologists, family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to specify the indications for chemotherapy in gynecologic cancers during pregnancy and postpartum periods, discuss the risks and benefits of chemotherapy for gynecologic cancer during pregnancy and postpartum periods. In addition, they should also be able to distinguish the mechanism of action of various chemotherapy agents to choose the best treatment options for patients and monitor for impacts of chemotherapy on fetal growth to determine the best treatment and management strategies. PMID- 21794194 TI - Vulvodynia interventions--systematic review and evidence grading. AB - INTRODUCTION: State of the art guidance exists for management of vulvodynia, but the scientific basis for interventions has not been well described. Although there are many interventional therapies, and their use is increasing, there is also uncertainty or controversy about their efficacy. OBJECTIVE: To systematically assess benefits and harms of interventional therapies for vulvodynia and vestibulodynia. METHODS: The following databases were searched, using MeSH terms for studies related to the treatment of vulvodynia or vulva pain/pruritus/dysesthesia/hyperesthesia/hypersensitivity: MEDLINE, PsycINFO, Scopus, Cochrane Library, EBSCO Academic, and Google Scholar. Using Medical Subject Reference sections of relevant original articles, reviews, and evidence based guidelines were screened manually. Manual searching for indirect evidence supporting interventions was done whenever no direct evidence was found for a treatment described within a review or guideline. Each modality is assessed with a grading system similar to the Grades of Recommendation, Assessment, Development, and Evaluation system. The grading system assesses study quality, effect size, benefits, risks, burdens, and costs. RESULTS: For improvement of pain and/or function in women with vestibulodynia (provoked localized vulvodynia), there was fair evidence that vestibulectomy was of benefit, but the size of the effect cannot be determined with confidence. There was good evidence of a placebo effect from multiple studies of nonsurgical interventions. There was fair evidence of lack of efficacy for several nonsurgical interventions. There were several interventions for which there were insufficient evidence to reliably evaluate. There was insufficient evidence to judge harms or to judge long-term benefits. For clinically meaningful improvement of pain in women with generalized unprovoked vulvodynia, there was insufficient evidence for benefit of any intervention. There was fair evidence of a placebo effect in people with neuropathic pain and functional pain syndromes, from multiple studies of interventions. Based on indirect evidences from studies of patients with other pain disorders, interventions may be selected for future research. CONCLUSION: There is fair evidence for effectiveness of vestibulectomy for vestibulodynia; however, there is uncertainty about the size of the absolute effect, because of the risk of bias inherent in studies of pain interventions without a placebo control group. Providers and patients looking for evidence-based interventions for generalized unprovoked vulvodynia may need to rely on indirect evidences from studies of neuropathic pain and functional pain syndromes. TARGET AUDIENCE: Obstetricians & gynecologists, family physicians. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to identify potential causes of vulvar pain to facilitate diagnosis of vulvodynia and vestibulodynia, distinguish between the symptoms of localized, provoked vulvodynia and generalized unprovoked vulvodynia to select the most appropriate therapies, evaluate the efficacy of surgical and nonsurgical interventions for the treatment of generalized unprovoked and localized, provoked vulvodynia. In addition, assess the benefits and risks of interventional therapies for vulvodynia and vestibulodynia to improve patient care. PMID- 21794195 TI - Obstetrician-gynecologists and women's mental health: findings of the Collaborative Ambulatory Research Network 2005-2009. AB - BACKGROUND: Many mental illnesses are more prevalent in women than men (e.g., depression). Obstetrician-gynecologists (ob-gyns) are frequent medical contacts for women, and so can play an important role in screening for mental illness. METHODS: This review summarizes studies published between 2005 and 2009 by the Research Department of the American College of Obstetricians and Gynecologists that encompass depression, anxiety, and eating disorders (EDs). RESULTS: Ob-gyns were more accurate in identifying depression than anxiety. Treatment with antidepressants was reported as a course of action twice as often as referral to a mental health professional. Physicians were moderately confident that they could recognize anxiety, but were less confident regarding treatment. One-fifth routinely screen pregnant patients for anxiety; level of interest in anxiety was the only significant predictor of screening rates. The main barriers to anxiety screening in pregnancy were time constraints and perceived inadequate training. Almost all believed EDs can harm pregnancy outcome, although few ask about ED histories. Only half view assessment of ED as within routine ob-gyn practice. Those who self-identify as primary care providers, and those who more strongly believe EDs can harm pregnancy outcomes, agreed more strongly that ED assessment is within their role. Ob-gyns perceived training regarding EDs to be poor. Knowledge of risks associated with EDs was low. CONCLUSIONS: Ob-gyns view mental health issues as important topics; however, they are not confident in their abilities to diagnose these conditions and are also concerned about the adequacy of their training. Additional training could prepare ob-gyns to incorporate mental health screening into their practices. TARGET AUDIENCE: Obstetricians & gynecologists, family physicians. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologists should be better able to evaluate their role relative to diagnosing and treating mental illness; state the negative consequences and signs of major depressive disorder, anxiety, eating disorder, and premenstrual dysphoric disorder (PMDD) in women; examine their peers' attitudes, referral patterns, and preferred treatment methods for mental disorders; and prevent negative health consequences for women and babies resulting from mental illnesses. PMID- 21794196 TI - Progress in defining the biological causes of schizophrenia. AB - Schizophrenia is a common mental illness resulting from a complex interplay of genetic and environmental risk factors. Establishing its primary molecular and cellular aetiopathologies has proved difficult. However, this is a vital step towards the rational development of useful disease biomarkers and new therapeutic strategies. The advent and large-scale application of genomic, transcriptomic, proteomic and metabolomic technologies are generating data sets required to achieve this goal. This discovery phase, typified by its objective and hypothesis free approach, is described in the first part of the review. The accumulating biological information, when viewed as a whole, reveals a number of biological process and subcellular locations that contribute to schizophrenia causation. The data also show that each technique targets different aspects of central nervous system function in the disease state. In the second part of the review, key schizophrenia candidate genes are discussed more fully. Two higher-order processes - adult neurogenesis and inflammation - that appear to have pathological relevance are also described in detail. Finally, three areas where progress would have a large impact on schizophrenia biology are discussed: deducing the causes of schizophrenia in the individual, explaining the phenomenon of cross-disorder risk factors, and distinguishing causative disease factors from those that are reactive or compensatory. PMID- 21794197 TI - Studies with low micromolar levels of ascorbic and dehydroascorbic acid fail to unravel a preferential route for vitamin C uptake and accumulation in U937 cells. AB - Mammalian cells accumulate vitamin C either as ascorbic acid (AA), via Na+-AA co transport, or dehydroascorbic acid (DHA, the oxidation product of AA), via facilitative hexose transport. As the latter, unlike the former, is a high capacity transport mechanism, cultured cells normally accumulate greater levels of vitamin C when exposed to increasing concentrations of DHA as compared with AA. We report herein similar results using the U937 cell clone used in our laboratory only under conditions in which DHA and AA are used at concentrations greater than 50-60 MUm. Below 60 MUm, i.e. at levels in which AA is normally found in most biological fluids, AA and DHA are in fact taken up with identical rates and kinetics. Consequently, extracellular oxidation of AA switches the mode of uptake with hardly any effect on the net amount of vitamin C accumulated. As a final note, under these conditions, neither AA nor DHA causes detectable toxicity or any change in the redox status of the cells, as assessed by the reduced glutathione/reduced pyridine nucleotide pool. These findings therefore imply that some cell types do not have a preferential route for vitamin C accumulation, and that the uptake mechanism is uniquely dependent on the extracellular availability of AA v. DHA. PMID- 21794198 TI - Prolonged high iodine intake is associated with inhibition of type 2 deiodinase activity in pituitary and elevation of serum thyrotropin levels. AB - Our previous epidemiological study indicated that excessive intake of iodine could potentially lead to hypothyroidism. In the present study, we aimed to investigate the time and dose effect of iodine intake on serum thyrotropin (thyroid-stimulating hormone, TSH) levels and to explore the non-autoimmune regulation of serum TSH by pituitary type 2 deiodinase (D2). A total of 360 Wistar rats were randomly divided into five groups depending on administered iodine dosages (folds of physiological dose): normal iodine (NI), 3-fold iodine (3HI), 6-fold iodine (6HI), 10-fold iodine (10HI) and 50-fold iodine (50HI). At 4, 8, 12 and 24 weeks after administration of sodium iodide, blood was collected for serum TSH measurement by chemiluminescent immunoassay. Pituitaries were also excised for measurement of TSHbeta subunit expression, D2 expression and activity, monocarboxylate transporter 8 (MCT8) and thyroid hormone receptor beta2 isoform (TRbeta2) levels. The results showed that iodine intake of 10HI and 50HI significantly increased pituitary and serum TSH levels from 8 to 24 weeks (P < 0.05 v. NI). Excess iodine had no effect on D2 mRNA or protein expression; however, 10HI and 50HI administration significantly inhibited pituitary D2 activities from 8 to 24 weeks (P < 0.05 v. NI). Iodine had no effect on MCT8 or TRbeta2 protein levels. We conclude that prolonged high iodine intake inhibits pituitary D2 activity and induces elevation of serum TSH levels. These findings may provide a potential mechanism of iodine excess-induced overt and subclinical hypothyroidism. PMID- 21794199 TI - Sensitivity and specificity of the Geriatric Anxiety Inventory and the Hospital Anxiety and Depression Scale in the detection of anxiety disorders in older people with chronic obstructive pulmonary disease. AB - BACKGROUND: Anxiety and depression are prevalent in patients with chronic obstructive pulmonary disease (COPD). This study evaluates the sensitivity and specificity of two self-administered anxiety rating scales in older people with COPD. The Geriatric Anxiety Inventory (GAI) and the Hospital Anxiety and Depression Scale (HADS) are established useful screening tools but they have not been previously validated in this population. METHODS: Older people with COPD completed the GAI and the HADS along with a structured diagnostic psychiatric interview, the Mini International Neuropsychiatric Interview (MINI). The outcomes of both rating scales were compared against the diagnosis of anxiety disorders based on the MINI. Receiver operating characteristic (ROC) curves were used to identify the optimal diagnostic cut points for each scale. RESULTS: Fourteen (25.5%) of the 55 participants, were diagnosed with an anxiety disorder. Mean GAI and HADS-anxiety subscale scores were significantly higher in subjects with an anxiety disorder than those without the diagnosis (p = 0.002 and 0.005 respectively). Both scales demonstrated moderate diagnostic value (area under the ROC curve was 0.83 for GAI and 0.79 for HADS). Optimal cut points were >=3 (GAI) and >=4 (HADS-anxiety subscale). At these cut-points, the GAI had a sensitivity of 85.7%, specificity of 78.0% and the HADS had a sensitivity of 78.6%, specificity 70.7%. CONCLUSION: Our results support the use of the GAI and HADS as screening instruments for anxiety disorders in older people with COPD. The optimal cut points in this population were lower than previously recommended for both rating scales. The results of this study should be replicated before these cut points can be recommended for general use in older people with COPD. PMID- 21794200 TI - Geographical variation and migration analysis of height, weight and body mass index in a British cohort study. AB - Using a sample of 2090 father and son pairs, the regional variation in height, weight and body mass index (BMI) with intra- and inter-generational migration within Britain was examined. Highly significant regional differences in means were found only for fathers. The overall mean height difference between regions ranged from about 2.7 cm to 3.1 cm, with the tallest fathers being found in the East & South-East region and the shortest in Wales. The variation in mean weight between regions was less significant, with the difference between the heaviest region (West Midlands) and lightest (South-West) being about 3.5 kg. For BMI the highest mean was in the North and Wales and the lowest in the South-West (difference of about 1 kg m-2). Intra-generational migrants were, on average, significantly taller than non-migrants for both fathers (+1.4 cm) and sons (+2 cm), but BMI was only significant in fathers, with migrant fathers, on average, having a lower BMI. There were no significant differences in weight between geographically mobile groups for either fathers or sons. Differentiating between regional in- and out-migration revealed that in the fathers' generation in migrants were taller, on average, in six of the nine regions. The tallest in migrants among fathers came into the North region; the tallest out-migrants were from Yorkshire & Humberside and the shortest were from Scotland. The largest positive gain on fathers' height was in the West Midlands region and Scotland, while negative effects were found in the Yorkshire & Humberside, East Midlands and East & South-East regions. For sons in-migrants were taller in all regions except Wales, with the largest differences between in-migrants and non-migrants being in the South-East and South-West. For out-migrants, the tallest sons came from Wales, while the shortest came from the East Midlands region. The North, East Midlands, East & South-East and West Midlands regions were net gainers, while Wales and Scotland were net losers. For BMI among fathers, in-migrants were of lower BMI than non-migrants. For out-migrant fathers, the North-West and South West regions were the only two regions showing positive values, with the largest negative values being found in the East Midlands and Yorkshire & Humberside. The net effect of migration indicated that the largest gains were in the East Midlands and Yorkshire & Humberside regions and the largest losses were in Scotland and Wales. The inter-generational migration for BMI showed that in migrating sons into the North-West and Wales had higher BMI than sedentes, while in-migrants into Yorkshire & Humberside were lower in BMI. In all regions out migrants had lower BMI than non-migrants. The net effect of migration revealed that six of the nine regions were net gainers, while the Yorkshire & Humberside region was a net loser. PMID- 21794201 TI - The anthelmintic efficacy of papaya latex in a rodent-nematode model is not dependent on fasting before treatment. AB - In earlier studies of the anthelmintic activity of plant cysteine proteinases (CPs), a period of food deprivation was routinely employed before administration of CPs, but there has been no systematic evaluation as to whether this does actually benefit the anthelmintic efficacy. Therefore, we assessed the effect of fasting on the efficacy of CPs from papaya latex (PL) against Heligmosomoides bakeri in C3H mice. We used a refined, supernatant extract of papaya latex (PLS) with known active enzyme content. The animals were divided into three groups (fasted prior to treatment with PLS, not fasted but treated with PLS and fasted but given only water). The study demonstrated clearly that although food deprivation had been routinely employed in much of the earlier work on CPs in mice infected with nematodes, fasting has no beneficial effect on the efficacy of PLS against H. bakeri infections. Administration of CPs to fed animals will also reduce the stress associated with fasting. PMID- 21794202 TI - The effect of growth hormone (GH) and insulin-like growth factor-I (IGF-I) on in vitro maturation of equine oocytes. AB - The objective of this study was to test the hypothesis that equine growth hormone (eGH), in combination with insulin growth factor-I (IGF-I), influences positively in vitro nuclear and cytoplasmic maturation of equine oocytes. Cumulus-oocyte complexes were recovered from follicles that were < 25 mm in diameter, characterized by morphology and were allocated randomly as follow: (a) control (no additives); (b) 400 ng/ml eGH; (c) 200 ng/ml IGF-I; (d) eGH + IGF-I; and (e) eGH + IGF-I + 400 ng/ml anti-IGF-I antibody. Oocytes were matured for 30 h at 38.5 degrees C in air with 5% CO2 and then stained with 10 MUg/ml propidium iodide (PI) to evaluate nuclear status and 10 MUg/ml Lens culinaris agglutinin fluorescein complex (FITC-LCA) to assess cortical granule migration by confocal microscopy. The proportion of immature oocytes that developed to the metaphase II (MII) stage in the eGH + IGF-I group (15 of 45) was greater than in the groups that were treated only with IGF-I (7 of 36, p = 0.03). Oocytes that reached MII in the control group (20 of 56; 35.7%) showed a tendency to be different when compared with eGH + IGF-I group (15 of 45; 33.3%, p = 0.08). The treated group that contained anti-IGF-I (15 of 33; 45.4%) decreased the number of oocytes reaching any stage of development when compared with eGH (47 of 72; 65.3%) and eGH + IGF-I (33 of 45; 73.3%) groups (p = 0.05) when data from MI and MII were combined. We concluded that the addition of eGH to in vitro maturation (IVM) medium influenced the in vitro nuclear and cytoplasmic maturation of equine oocytes. The use of GH and IGF-I in vitro may represent a potential alternative for IVM of equine oocytes. PMID- 21794203 TI - Acculturation, physical activity and television viewing in Hispanic women: findings from the 2005 California Women's Health Survey. AB - OBJECTIVE: To assess the relationship of acculturation with physical activity and sedentary behaviours among Hispanic women in California. DESIGN: Data from the 2005 California Women's Health Survey (CWHS) - a cross-sectional telephonic survey of health indicators and health-related behaviours and attitudes - were used. SETTING: Using a random-digit dialling process, data were collected monthly from January to December 2005. SUBJECTS: A total of 1298 women aged >=18 years in California who self-identified as Hispanic. RESULTS: Of the participants included in the analysis, 49 % were adherent to physical activity recommendations (with 150 min of weekly activity signifying adherence). There was no significant association between language acculturation and moderate or vigorous physical activity after controlling for potential confounders such as smoking, age and employment status. There was also no association between duration of residence in the USA and moderate or vigorous physical activity. Language acculturation was positively associated with television (TV) viewing, with highly acculturated women reporting more hours of TV viewing compared with women with an intermediate acculturation score (P = 0.0001), and those with an intermediate score reporting more hours of TV viewing compared with those with a low score (P = 0.003). This relationship persisted after inclusion of smoking, employment status, age and education in the model. CONCLUSIONS: Higher levels of language acculturation may be associated with increased sedentary behaviours because of the influence of US culture on those women who have assimilated to the culture. Acculturation is an important factor to be taken into account when designing health education interventions for the Hispanic female population. PMID- 21794204 TI - Gram-negative outer membrane vesicles in vaccine development. AB - Gram-negative bacteria naturally and constitutively release lipid bilayer vesicles from the outer membrane. Outer membrane vesicles (OMVs) range in size from approximately 20-200 nanometers in diameter and enclose many native bacterial antigens in the spherical particles. Composed of outer membrane and periplasmic constituents, the vesicles function in diverse roles that, ultimately, make them a transportable part of the bacterial arsenal and survival system. These functional roles entail mediation of bacterial envelope stress, biofilm formation, virulence, and transformation. With their immunogenic properties, self-adjuvanticity, ability to be taken up by mammalian cells, and capacity for enhancement by recombinant engineering, OMVs are attractive candidates for vaccine delivery platforms. The first OMV vaccines were shown to be protective against clonal serogroup B meningococci outbreaks in Cuba, Norway, Brazil, and New Zealand, although there is still no global vaccine against serogroup B meningococci. However, interest in OMVs as vaccine carriers is growing as research exposes more of the molecular intricacies of vesiculation and how the vesicles can be co-opted to fight infectious bacterial agents. PMID- 21794205 TI - Is obstructive sleep apnea a risk factor for diabetes? AB - Obstructive sleep apnea (OSA) and type 2 diabetes are both closely related to obesity and their prevalence is increasing due to the rising average body weight in Western countries. The findings of epidemiological studies have implicated that OSA increases the risk for cardiovascular disease, and metabolic disturbances, such as insulin resistance, may link OSA to vascular morbidity. A number of observational clinical studies have evaluated the relationship between OSA and insulin resistance, suggesting an independent association. However, the confounding effect of obesity complicates the establishment of a causal relationship between OSA and insulin resistance. Potential mechanisms that may underpin this relationship were evaluated in animal and human experimental studies and include intermittent hypoxia, arousals from sleep with concomitant sympathetic activation and sleep fragmentation. Currently only three randomized controlled trials investigating the effects of OSA on insulin resistance have been published. In these trials OSA patients were randomly assigned to treatment with continuous positive airway pressure (CPAP) or subtherapeutic CPAP and treatment effects on various measures of insulin resistance were examined. In two of these trials there was no effect of CPAP on glucose metabolism and in one trial a small beneficial effect of CPAP was observed. Further carefully conducted clinical studies and randomized controlled interventional CPAP trials are needed to determine the extent to which OSA is a risk factor for diabetes and its effect on glucose metabolism. PMID- 21794206 TI - Convergent mechanisms of somatic mutations in polycythemia vera. AB - Polycythemia vera (PV) is an acquired blood disorder, with variable increase of clonal myeloid cells (erythrocytes, granulocytes and platelets) and mostly normal polyclonal T lymphocytes. Most patients have a somatic V617F gain-of-function mutation in JAK2 associated with acquired uniparental disomy (UPD) on chromosome 9p. Yet, the JAK2 V617F mutation is not a PV-initiating event and the family clustering of PV suggests a contribution of inherited genetic events. Using whole genome SNP arrays, we assayed 34 T-cells and 66 granulocytes (including 32 pairs from the same patients), and identified multiple SNPs around JAK2 that are associated with PV susceptibility (rs11999802, P=1.8E-8, OR=4.4). We also developed a quantitative measure of the fraction of somatic single nucleotide variants (SNVs) based on allele-specific PCR, and a quantitative measure of somatic UPD based on "fractional copy-neutral loss-of-heterozygosity (LOH)" on SNP arrays. Somatic genomic changes in granulocytes revealed strong genetic heterogeneity, including 9p UPD and chromosomal gain. The magnitude of somatic 9p UPD was strongly associated with V617F dosage (r2=0.74, P=4.8E-12), suggesting that UPD preferentially increases the V617F subclone. In granulocytes with heterozygous rs11999802 genotypes, UPD increased the relative fraction of germline risk alleles (P=0.03). Thus, germline risk variants at JAK2 predispose to somatic point mutations within JAK2, whose allelic dosage can be further increased by a serial subclonal expansion of allele-specific UPD or copy number alteration, contributing to PV pathogenesis. We argue that PV represents a unique disease model to study the interplay between germline risk variants and convergent mechanisms of somatic mutations. PMID- 21794207 TI - Computer assisted quantitative immunofluorescence of tumor tissue marker expression and clinical outcome to chemotherapy in advanced breast cancer patients. AB - Chemotherapy is frequently used in the treatment of advanced breast cancer. The identification of patient-specific tumor characteristics that can improve the ability to predict response to chemotherapy would help optimize advanced breast cancer treatment approaches. Quantitative immunofluorescence (QIF) may be applied to the standardization of protein analysis, resulting in increased sensitivity and reproducibility. In the current pilot study, QIF was used to correlate the expression of beta tubulin III and thymidylate synthase with clinical outcome associated with taxane and capecitabine treatment, respectively. QIF analysis is based on fluorescent dye-labeled monoclonal antibody staining followed by computer-assisted microscopy to measure the expression of molecular markers in tumor samples derived from a retrospective database. The interpretation of the tumor marker expression levels results in classification of breast tumors as sensitive or resistant to a mechanistically related drug. Overall diagnostic accuracy of QIF for taxane based therapy was 88% (CI 75.0 - 95.3) with a positive predictive value of 86% and a negative predictive value of 100%, while diagnostic accuracy QIF for capecitabine therapy was 86% (CI 88.0-96.0) with a positive predictive value of 80% and a negative predictive value of 100%. In this study, QIF showed retrospectively a potential for predictive value when analyzing chemotherapeutic treatments for individual advanced stage breast cancer patients. The predictive power of the QIF for chemotherapy confirms that further studies utilizing larger clinical cohorts are warranted. PMID- 21794209 TI - Chlamydia trachomatis infection during pregnancy: known unknowns. AB - Genital Chlamydia trachomatis infection is the commonest bacterial sexually transmitted infection worldwide. Infection prevalence peaks in young women aged between 18-25 years. Infection in women has been associated with reproductive tract pathology, infertility, and adverse pregnancy outcomes including miscarriage, early membrane rupture, pre-term labor, and postpartum endometritis. However, the evidence base varies with the population studied and the methods used to detect infection. There may be differential consequences for pathology associated with primary or recurrent infection during pregnancy. These differences may be potentiated by physiological differences in the host response to infection in the pregnant state. Such changes have particular relevance for infections of the reproductive tract. Cost effectiveness estimates for screening during pregnancy require basic knowledge of the natural history of infection and the host response to calculate associated risks. Our level of knowledge is hampered by the lack of good experimental models for human pregnancy. To make rational decisions about screening of pregnant women there is a need for case control studies that compare detection of infection by nucleic acid amplification tests with evaluation of immunity to the infection. PMID- 21794208 TI - Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications. AB - Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject's exome readily identified two rare non synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers. PMID- 21794210 TI - Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. AB - The inflammasome is a highly regulated protein complex that triggers caspase-1 activation and subsequent secretion of IL-1beta and IL-18. Recognition of microbial components and danger signals by NOD-like receptor (NLR) family members in the cytosol promotes inflammasome activation and downstream inflammatory cytokine production. Pathogen recognition by NLRs and downstream release of inflammasome-derived cytokines are important in host defense against numerous infections. Recent studies have also identified a unique role for inflammasome regulation in the induction and pathogenesis of multiple autoimmune and inflammatory disorders. We now know that obesity-related factors and endogenous markers of cellular stress can lead to unchecked activation of the inflammasome and provoke inflammation and subsequent destruction of vital organs. This review will highlight recent findings that link inflammasome signaling to the progression of autoinflammatory and autoimmune diseases. We will focus on the contribution of inflammasome activation to the pathogenesis of autoinflammatory and autoimmune diseases that are of major significance to human health including type 2 diabetes, atherosclerosis, multiple sclerosis, and type 1 diabetes. PMID- 21794214 TI - Authors reply: Prioritisation of infectious diseases in public health: feedback on the prioritisation methodology, 15 July 2008 to 15 January 2009. PMID- 21794211 TI - Tendon phenotype should dictate tissue engineering modality in tendon repair: a review. AB - Advancements in the technical aspects of tendon repair have significantly improved the treatment of tendon injuries. Arthroscopic techniques, suture material, and improved rehabilitation have all been contributing factors. Biological augmentation and tissue engineering appear to have the potential to improve clinical outcomes as well. After review of the physiology of tendon repair, three critical components of tissue engineering can be discerned: the cellular component, the carrier vehicle (matrix or scaffold), and the bioactive component (growth factors, platelet rich plasma). These three components are discussed with regard to each of three tendon types: Intra-synovial (flexor tendon), extra-synovial (Achilles tendon), and extra-synovial tendon under compression (rotator cuff). Scaffolds, biologically enhanced scaffolds, growth factors, platelet rich plasma, gene therapy, mesenchymal stem cells, and local environment factors in combination or alone may contribute to tendon healing. In the future it may be beneficial to differentiate these modes of healing augmentation with regard to tendon subtype. PMID- 21794215 TI - Letter to the editor: Prioritisation of infectious diseases in public health: feedback on the prioritisation methodology, 15 July 2008 to 15 January 2009. PMID- 21794216 TI - Surveillance of influenza in Finland during the 2009 pandemic, 10 May 2009 to 8 March 2010. PMID- 21794217 TI - The Chlamydia surveillance system in Sweden delivers relevant and accurate data: results from the system evaluation, 1997-2008. PMID- 21794218 TI - Lyme borreliosis in Europe. PMID- 21794221 TI - Investigation of a spatiotemporal cluster of verotoxin-producing Escherichia coli O157 infections in eastern England in 2007. AB - An outbreak of verotoxin-producing Escherichia coli O157 (VTEC O157) infections linked to an open farm occurred in eastern England in April and May 2007. This paper describes the investigation and highlights the importance of multidisciplinary collaboration for successful control of such outbreaks. There was a temporal cluster of 12 confirmed symptomatic cases of VTEC O157 and one asymptomatic carrier, from five families. The investigation revealed that four of these cases formed part of an outbreak involving two families who visited an open farm. The phenotypic and genotypic characteristics of the isolates from the two families and the putative farm animal contacts were indistinguishable, indicating that the animals were the source of the primary infections. No epidemiological link could be established between the remaining three families affected and the open farm or people having visited the farm. Control measures included improved hand washing facilities on the farm, information for visitors and staff, restricted access and suspended petting and feeding of animals, and thorough cleaning and disinfection of affected areas. PMID- 21794222 TI - A venue-based HIV prevalence and behavioural study among men who have sex with men in Antwerp and Ghent, Flanders, Belgium, October 2009 to March 2010. AB - This venue-based, cross-sectional study reports on human immunodeficiency virus (HIV) prevalence and behaviour of 649 men who have sex with men (MSM) in Antwerp and Ghent, Flanders, Belgium, from October 2009 to March 2010. Using time location sampling, we found that HIV prevalence in MSM who attended different types of venue ranged from a high of 14.5% (95% CI: 8.9-20.1; n=22 in cruising venues to 4.9% (95% CI: 1.9-7.9; n=10) in more general gay venues to 1.4% (95% CI: 0.0-3.6; n=3) at younger MSM venues. Of those who tested HIV positive (n=35, five were unaware of their HIV status or self-reported as being HIV negative. One in five respondents were of non-Belgian nationality. The results showed relatively high rates of testing for HIV (52.2%; 95 % CI: 47.8-56.2; n=288) and other sexually transmitted infections (STIs) (57.4%; 95% CI: 52.6-62.0; n=248) in the last 12 months. A majority of the men (n=233) used condoms consistently during their last anal sexual contact with a casual partner; however, HIV positive men who were aware of their serostatus (n=30) reported less condom use with casual partners. This is the first such study in Belgium and the results constitute the evidence base for local, targeted interventions. Furthermore, our findings underscore the need for European cross-border cooperation to prevent HIV infection and other STIs among MSM. PMID- 21794223 TI - Effective control of an acute gastroenteritis outbreak due to norovirus infection in a hospital ward in Athens, Greece, April 2011. AB - In April 2011, an acute gastroenteritis outbreak due to norovirus infection occurred in a hospital ward in Athens, Greece, affecting 28 people: 16 staff members, 10 inpatients and two relatives of symptomatic inpatients. The attack rate among the patients and staff was 16.4% (10/61) and 31.4% (16/51), respectively. The outbreak lasted eight days and the clinical symptoms were mild. Effective infection control measures prevented the spread of the virus to other hospital wards. PMID- 21794224 TI - Outbreak of tularaemia in brown hares (Lepus europaeus) in France, January to March 2011. AB - We report an outbreak of tularaemia in brown hares (Lepus europaeus) in France, which occurred from January to March 2011 and was characterised by a high mortality rate in the local hare population. In France, hare tularaemia is usually sporadic and does not significantly affect hare populations. The epizootic form of the outbreak reported here led us to reconsider the potential associated risks for hare populations and public health. PMID- 21794225 TI - Stepping up European measles surveillance. PMID- 21794226 TI - Cholinesterase inhibition and behavioral toxicity of carbofuran on Oreochromis niloticus early life stages. AB - Nile tilapia Oreochromis niloticus at 9 days post-hatch were exposed in semi static experiments to the carbamate insecticide carbofuran, which is applied in agricultural systems in Brazil. Although the molecular mechanism of carbofuran toxicity is well known, a detailed understanding of the ecological mechanisms through which carbofuran effects can propagate towards higher levels of biological organization in fish is incomplete. Mortality rates were quantified for larvae exposed for 96 h to 8.3, 40.6, 69.9, 140, 297 and 397 MUg/L carbofuran, and the LC(50) 96 h was 214.7 MUg/L. In addition, the biochemical biomarker cholinesterase inhibition and behavioral biomarkers related to vision, swimming, prey capture and predator avoidance were quantified in individual larvae, as well as their growth in weight. The behavioral parameters were quantified by analysis of digitally recorded videos of individual larvae within appropriate experimental setups. The activity of the enzyme cholinesterase decreased after exposure to carbofuran with a lowest observed effects concentration (LOEC) of 69.9 MUg/L. Visual acuity deficits were detected after carbofuran exposure with a LOEC of 40.6 MUg/L. Swimming speed decreased with carbofuran exposure, with a LOEC of 397.6 MUg/L. The number of attacks to prey (Daphnia magna nauplii) decreased in larvae exposed to carbofuran, with a LOEC of 397.6 MUg/L. Growth in weight was significantly reduced in a dose dependent manner, and all carbofuran groups exhibited a statistically significant decrease in growth when compared to controls (p<0.05). The number of predator attacks necessary to capture larvae decreased after exposure to carbofuran, and the LOEC was 69.9 MUg/L. These results show that exposure of sensitive early life stages of tilapia O. niloticus to sublethal concentrations of carbofuran can affect fundamental aspects of fish larval ecology that are relevant to recruitment of fish populations, and that can be better understood by the application of behavioral biomarkers. PMID- 21794227 TI - Minimization of amorphous layer in Ar+ ion milling for UHR-EM. AB - We present a comprehensive study on the influence of Ar(+) ion milling parameters in the range of low acceleration voltages (0.5-6 kV) and etching angles (3-10( degrees )) on the quality of standard high resolution Si TEM samples. The quality was assessed by the evaluation of HR-TEM images acquired from real TEM samples considering the thickness of the amorphous layer and the interlocking between crystalline and amorphous parts of the sample created by ion-beam induced amorphization, as well as topographical BSE-SEM investigation of the surface of those TEM samples. Increasing voltage clearly results in increased amorphous layer thickness as well as interlocking. The impact of the etching angle is less significant but still influences the amorphous layer thickness. It has, however, a strong effect on the preparation time, which is inversely correlated to the etching angle. Finally the experimental data were compared to model estimations by TRIM and the Schuhrke-Winterbon approximation, which fitted well to the experimental data for low voltage and angle, but were less accurate for higher voltage and angle. Despite their limitations, the models could reproduce trend and order of magnitude of the data, thus making them a useful tool for estimating the amorphous layer thickness after TEM sample preparation. PMID- 21794228 TI - [Not Available]. PMID- 21794229 TI - [Not Available]. PMID- 21794230 TI - [Osteoporosis in men with chronic obstructive pulmonary disease. Utility of phalangeal densitometry (AccuDEXA) as a screening method]. AB - OBJECTIVE: To analyze the prevalence of osteoporosis in men with chronic obstructive pulmonary disease (COPD) and to evaluate whether phalangeal densitometry (AccuDEXA) could be a useful screening method for identifying osteoporosis in these patients. PATIENTS AND METHODS: We performed a cross sectional study in male patients with COPD who were assessed by a pulmonologist in primary care and in our hospital as out-patients. The diagnosis of osteoporosis was established by conventional DEXA (lumbar spine and total hip), according to the WHO criteria. Bone mineral density (BMD) was assessed by AccuDEXA. We used a ROC curve to determine the best cut-off point for screening with this technique. RESULTS: One hundred fifty male patients with COPD were included. The mean age was 67 +/- 3 years. The prevalence of osteoporosis by DEXA was 34%. BMD in phalanx was significantly correlated with BMD in lumbar spine and hip (r: 0.6). The sensitivity and specificity of AccuDEXA in identifying osteoporosis was 29% and 85%, respectively. The best cut-off point for AccuDEXA was a T-score of -0.8 (sensitivity 85%, specificity 63%, positive predictive value 56%, negative predictive value 89%). Glucocorticoid treatment and COPD severity were significantly associated with the presence of osteoporosis in these patients (p=0.005 and p=0.023 respectively). CONCLUSION: The prevalence of osteoporosis in men with COPD is high. This complication seems to be associated with glucocorticoid treatment and COPD severity. AccuDEXA could be a useful screening method for osteoporosis in these patients and could almost halve the number of conventional DEXAs performed. PMID- 21794231 TI - [Prevalence of criteria indicating bone densitometry and risk factors for low bone mass and fracture in rheumatology outpatient units]. AB - Many organisms have proposed criteria to identify individuals with low bone mass or increased risk for osteoporotic fracture in order to provide them with the available diagnostic and therapeutic resources. Among these organisms are the WHO, the Catalan Agency for Health Technology Assessment (CAHTA) and the International Committee for Osteoporosis Clinical Guidelines (ICOCG). We designed a prospective multicenter study to determine the prevalence of indications for bone densitometry in rheumatology outpatient clinics by applying the criteria of these three organisms. Two hundred sixty-two women and 98 men aged 18 years or older who attended five rheumatology outpatient clinics were interviewed and their medical records were reviewed. The mean age was 58.3+/-13.4 years. Bone densitometry was indicated in 45% of the patients interviewed according to the CAHTA criteria, in 77% according to the WHO criteria and in 62% according to the ICOCG criteria (applicable only to women). The proportion of patients with indications for bone densitometry increased with age, and was higher in women. The concordance among criteria was low. PMID- 21794232 TI - [Perception of sexuality in women with rheumatic disease: case-control pilot study]. AB - INTRODUCTION: Rheumatic diseases are characterized by chronic inflammation with systemic involvement and are often accompanied by functional limitation and depression. Their effect on sexual response has been little studied. The objective of the present study was to evaluate perception of sexuality in women with rheumatic disease. PATIENTS AND METHODS: We administered a questionnaire that included general data, socioeconomic aspects, disease characteristics, serum markers of inflammation and measured perception of sexuality, depression traits and self-esteem. RESULTS: Sixteen patients were interviewed, of which nine had rheumatoid arthritis, six had systemic lupus erythematosus and one had psoriatic arthritis. Twentyfive women were selected as controls. All patients were receiving treatment and had a functional class that allowed them to be self dependent. Patients presented a worse perception of sexuality than controls (p=0.001) with a trend to more depressive traits and lower self-esteem. CONCLUSIONS: Patients with rheumatic disease gain benefits from treatment in terms of quality of life and functionality. Perception of sexuality is affected by chronic inflammatory disease but is independent of the patient's functional class. PMID- 21794233 TI - [Extra-articular manifestations and complications of ankylosing spondylitis]. AB - Extra-articular manifestations can be defined as all symptoms and signs etiopathogenically related, at least in part, to ankylosing spondylitis (AS) that arise in the various organs and tissues of the locomotor apparatus. Thus, ocular, intestinal and cardiac manifestations, which are common to all spondylarthritides through their association with HLA-B27, are grouped under this heading. Complications include clinical manifestations that result from persistent spondylitic activity and/or treatment. Table 1 provides a list and the main characteristics of these manifestations. Obviously, this classification is far from perfect since, among other factors, knowledge of the etiopathogenesis of AS is still fairly limited. PMID- 21794234 TI - [Not Available]. PMID- 21794235 TI - [Not Available]. PMID- 21794236 TI - [Not Available]. PMID- 21794237 TI - [Vasculitis associated with anti-neutrophil cytoplasmic autoantibodies in rheumatoid arthritis. Report of a case of microscopic polyangiitis and another case of Wegener's granulomatosis]. AB - Vasculitis is an uncommon complication of rheumatoid arthritis that is associated with a clear increase in morbidity and mortality, although systemic manifestations such as glomerulonephritis, cerebral vasculitis or pulmonary vasculitis are very rare. Systemic vasculitis with renal involvement is associated with overt polyarthritis in less than 5% and association with rheumatoid arthritis is exceptional. Determination of anti-neutrophil cytoplasmic autoantibodies (ANCA), used in the appropriate clinical context, has become an important diagnostic tool in small-vessel systemic vasculitides. We present two patients with rheumatoid arthritis who subsequently developed systemic vasculitis. ANCA determination was decisive in the early diagnosis of these patients. PMID- 21794238 TI - [Not Available]. PMID- 21794239 TI - [Not Available]. PMID- 21794240 TI - [Not Available]. PMID- 21794241 TI - [Not Available]. PMID- 21794242 TI - [Not Available]. PMID- 21794243 TI - [Patterns of health care in an out patient rheumatologic clinic]. AB - INTRODUCTION: Studies evaluating the pattern of diseases evaluated by rheumatology services are required to improve the planning of healthcare resource distribution. AIM: To describe the pattern of diseases motivating consultations in an outpatient clinic of a secondary care center in Guadalajara, Mexico. MATERIAL AND METHODS: A cross-sectional, descriptive study was performed. Data on the diseases evaluated in the rheumatology service and other healthcare indicators were obtained through a search of the hospital's computerized database. The number of initial and repeat consultations, their distribution by age and sex, the mean monthly number of prescriptions, and other indicators of performance were identified. RESULTS: There were 5,790 consultations in 1 year (26% were initial visits). The three most frequent diseases were: rheumatoid arthritis (47.1%, 95% CI 46-48%), systemic lupus erythematosus (12.7%, 95% CI 12 14%), and ankylosing spondylitis (7.7%, 95% CI 7-8%). Four women were attended for each man. Consultations were most frequent in the group aged 30-59 years old. The mean number of consultations per rheumatologist/month was 242, with a mean of 2.5 prescriptions per patient. The rate of compliance with appointments was 85%. A mean of 7.5 were diagnosed with temporary work disability for each rheumatologist/month. CONCLUSIONS: The most prevalent disorders in our outpatient rheumatology clinic were inflammatory joint diseases and systemic autoimmune diseases. These disorders required a high proportion of health-care resource. Further studies are required to evaluate the costs of these resources with the aim of establising better strategies for the health care needs in these patients. PMID- 21794244 TI - [Spanish registry of adverse events of biological therapies in rheumatic diseases (BIOBADASER): report as of january 14, 2005]. AB - BIOBADASER is a registry of rheumatic patients treated with biological therapies. The purpose of thisregistry is to provide information on long-term survival and the safety of these agents. As of January 14th 2005, 5361 patients from 100 centers were included in BIOBADASER. In total, 6109 treatments with biological therapies have been registered. Treatment was discontinued on 1515 occasions (25%), mainly because of an adverse event (666 [44%]) or inefficacy (581 [38%]). A total of 1814 adverse events were notified. Of these, the most frequent were infections (649 [36%]), followed by post-infusion reactions (384 [21%]), skin lesions (162 [9%]), and cardiovascular events (127 [7%]). This analysis confirms the increased rate of infections with biological therapies. However, these therapies do not significantly increase the rate of neoplasms or cardiac failure. Specific measures have proved useful in preventing the occurrence of some well defined events. PMID- 21794245 TI - [Musculoskeletal manifestations in allogenic hematopoietic stem cell transplantation]. AB - INTRODUCTION: Few studies have examined musculoskeletal manifestations after allogenic hematopoietic stem cell transplantation (AHSCT). OBJECTIVE: To investigate the musculoskeletal symptoms observed after AHSCT for distinct hematological and non-hematological diseases. MATERIAL AND METHODS: We performed a retrospective, observational study through review of medical records. RESULTS: There were 123 patients who underwent AHSCT from 1996 to 2000: 34 children (aged 5 months-14 years) and 81 adults (aged 15-55 years). There were 48 women (39%) and 75 men (61%). Of these patients, 43 (34.90%) had acute graft-versus-host disease (aGVHD). Thirty-three out of 106 patients (31.1%) had chronic GVHD (cGVDH) and 50 patients (40.65%) died during follow-up. Musculoskeletal manifestations were found in 14 patients (13.2%): aseptic necrosis in six (5.6%), scleroderma in five (4.7%), arthralgia and bronchiolitis obliterans in one, polyarthralgia in one, and knee monoarthritis in one. CONCLUSIONS: Musculoskeletal manifestations after AHSCT cannot be attributed to a single cause. Inflammatory and fibrosing manifestations can be due to the inflammatory process of cGVHD or to the treatments administered during transplantation. PMID- 21794246 TI - Drug-drug interactions of non-steroidal anti-inflammatory drugs with other drugs in patients with rheumatic diseases. AB - OBJECTIVE: To determine the prevalence of and identify drug-drug interactions (DDI) between non-steroidal anti-inflammatory drugs (NSAID) and other drugs in a prescription database of patients with rheumatic iseases. MATERIAL AND METHODS: This is a cross-sectional study of a drug prescription database saving information on 35,000 individuals who benefited from a pre-paid medical system serving bank employees and their relatives. The analysis included one year period (from January to December 1998). NSAID-DDI were listed and classified into 3 levels (1: minor; 2: moderate, and 3: high health risk or death risk) according to DRUGDEX(r) as well as MEDLINE and EMBASE search. RESULTS: We analyzed 3,207 NSAID prescriptions (1.7+/-1.6 per patient) to 1,855 rheumatic patients (adults: 76.7%; geriatric: 20.2%, and pediatric: 3.0%; soft tissue rheumatism: 52%; osteoarthritis: 19%, and rheumatoid arthritis: 10%). There were 648 (20.20%) NSAID-DDI prescriptions: 594 (91.66%) corresponded to level 1; 46 (7.09%) to level 2, and 8 (1.23%) to level 3. In addition, 96 (2.99%) prescriptions included NSAID duplications. Interestingly, we found no NSAID-DDI with anticoagulants, anticonvulsants, and oral hypoglycemiants were found. CONCLUSIONS: The prevalence of NSAID-DDI prescriptions to 1,855 rheumatic patients was 20.20% in one year. NSAID-DDI was mostly (91.66%) level 1, and rarely (1.23%) level 3. NSAID duplications were found in 2.99%. These results provides information on the frequency of prescriptions with DDI, which might potentially produce harmful effects and data, which may help in the development of studies searching for the clinical relevance of NSAID-DDI. PMID- 21794247 TI - The gut: beyond immunology. AB - The immune system is characterized by the ability to distinguish self from non self. The intestinal immune system bears this latter property but, furthermore, it must discriminate among nutritious and beneficial substances from toxic or harmful ones. Considering that the gut has to be colonized by commensal bacteria participating in digestion as well as in the control of pathogen microorganisms, it is not surprising that mucosal surfaces are the largest and probably the most exquisitely specialized immune system's compartment. This means that not only innate and adaptive immunity are present, but further, particular structures, cells, and mechanisms such as physical barrriers, epithelia, Peyer's patches, M cells among others, which together are involved in the dynamic control of the homeostasis between gut and its flora. The present review deals with some popular conceptions about the digestive system with particular emphasis on the gut's immunology. PMID- 21794248 TI - [Not Available]. PMID- 21794249 TI - [Young male with pachydermodactyly: imaging findings]. AB - Pachydermodactyly (PDD) is a rare, benign form of digital fibromatosis characterized by an asymptomatic soft-tissue swelling affecting the skin of the lateral spects of the proximal interphalangeal joints of the fingers, and sometimes can be misdiagnosed with some rheumatic conditions. Magnetic resonance images changes have not been described in any of the case reports in the literature. We report here a case of PDD in a 19-year-old male and we describe its findings on X-ray and magnetic resonance images. We briefly discuss PDD. PMID- 21794250 TI - [Not Available]. PMID- 21794251 TI - [Not Available]. PMID- 21794252 TI - [Not Available]. PMID- 21794253 TI - [Resource utilization in a cohort of rheumatoid arthritis patients attended in rheumatology units in Spain]. AB - OBJECTIVE: To determine resource use over a 1-year period in patients with rheumatoid arthritis (RA) attended in rheumatology units in hospitals within the Spanish public health system. PATIENTS AND METHODS: An observational, longitudinal, prospective, multicenter, 1-year study was performed in randomly selected rheumatology units in hospitals of the Spanish public health system. Patients with RA were randomly selected in each hospital. Four visits (at baseline and every 4 months) were conducted by a rheumatologist not routinely involved in the care of the patient. Demographic and disease-related variables were collected. Patient diaries and systematic interviews were used to gather data on resource use. RESULTS: A total of 301 patients were included and 190 (83% females) completed the study. The mean age was 59 +/- 13 years and the mean disease duration was 10 +/- 10 years. The resources most heavily used were medical. All of the patients made medical visits with a median of four visits to rheumatologists (1-13). Ninetynine percent of the patients took at least one drug. The most frequent drugs were paracetamol (41%), deflaza-cort (32%), and methotrexate (24%). Laboratory tests were performed in all patients, and x-rays were performed in 59%. Sixty-one patients (32%) were hospitalized; 75% of these patients were non-surgical. The most frequently used non-medical direct resources were meals and home visits by non-medical staff (39%). Thirtyone patients (16%) had some type of work disability. CONCLUSIONS: AR is associated with substantial utilization of medical and non-medical resources related to the disease and work disability. PMID- 21794254 TI - [Effect of chondroitin sulfate and hyaluronic acid (500-730 kDa) on synthesis of stromelysin (MMP-3) and MMP-1 in human chondrocyte cultures]. AB - INTRODUCTION: Chondroitin sulfate (CS) and hyaluronic acid (HA) are used in the symptomatic treatment of osteoarthritis (OA). Cholagenase-1 (MMP-1) and stromelysin-1 (MMP-3), are responsible for degradation of the extracellular matrix in OA. Few studies have determined the in vitro effect of CS and HA on MMP 1 synthesis and that of HA on MMP-3 expression in human OA chondrocyte culture. In the literature reviewed, there were no studies evaluating the effect of CS on MMP-3. OBJECTIVES: To analyze the effect of CS and HA (500-730 kDa) on MMP-3 and MMP-1 synthesis induced by interleukin-1beta (IL-1beta) in OA chondrocytes. MATERIAL AND METHODS: Chondrocytes were incubated for 48 hours with IL-1beta (2.5 ng/ml) in the presence or absence of different HA concentrations (Hyalgan(r), Bioiberica Farma) (10, 50, 100, 150, 200 and 1000 MUg/ml). Functional evaluation of chondrocytes was performed by enzyme-immunoanalysis of MMP-1 and MMP-3 levels. RESULTS: CS and HA inhibited IL-1beta-induced MMP-3 synthesis, without significantly modifying MMP-1. CS and HA reduced levels of MMP-3 expression at all the studied concentrations, with no statistically significant differences among these concentrations. CONCLUSIONS: The results of this study show for the first time that CS inhibits MMP-3 synthesis in OA cartilage. and corroborates the few existing data on the ability of HA to inhibit this enzyme. PMID- 21794255 TI - [Study of the extent and rate of bioavailability of ibuprofen tablets]. AB - The extent and rate of bioavailability of ibuprofen tablets were determined in a crossover clinical trial in 18 healthy subjects of both sexes. The study was approved by the local ethical committee and was authorized by the Spanish Medicines Agency. Volunteers signed an informed consent form and were included in accordance with the standard procedures for this type of study. In two distinct sessions participants received a single 600 mg ibuprofen dose as Gelofeno((r)) 600 mg tablets (Laboratorios Gelos S.L.), or as the reference formulation, Neobrufen((r)) 600 mg tablets. Ibuprofen concentrations in plasma were determined immediately before (0 h) and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 h after drug administration. The pharmacokinetic parameters were then calculated. In all subjects, Gelofeno((r)) 600 mg tablets produced plasma concentrations above the quantification limit between 15 and 30 minutes after administration, and in 9 (50%) of these subjects maximal plasma concentrations were reached at 1 h. The median t(max) was 1.25 h, and the average maximal plasma concentration was 40.7 mg/l. Gelofeno((r)) 600 mg tablets were bioequivalent both in extent and in rate of bioavailability compared with the reference drug. The formulation showed good tolerability and no medication-related adverse effects were observed. PMID- 21794256 TI - [Clinical and radiological evaluation in hemiarthroplasty of the shoulder]. AB - OBJECTIVE: To determine the medium-term functional and radiological results in patients with hemiarthroplasty of the shoulder. MATERIAL AND METHODS: A descriptive cross-sectional study was performed in 25 patients with glenohumeral osteoarthritis of any etiology, age, sex and occupation who underwent hemiarthroplasty of the shoulder using a deltopectoral approach with placement of a cemented modular hemiprosthesis; between November 2000 and December 2002. Functional evaluation (Constant 0-100 points) and radiological assessment were performed to determine the "radiological risk" of prosthetic clinical loosening. Descriptive and inferential statistics for the study variables were performed. RESULTS: The prevalence of surgical disease was 0.4% of all first-time orthopedic consultations. The mean age was 61.7+/-12.49 (range 32-85 years); men accounted for 8.6% and women for 91.4%. The most frequent etiology was degenerative (45.8%). The most frequently affected side was the left (54.3%). With a mean follow-up of 19+/-8.6 months, functional evaluation was 60+/-12 points; radiological evaluation showed that 20.8% of the patients presented "radiological risk" for prosthetic clinical loosening whereas only 4.2% showed no line of radiolucency. Postoperative pain was significantly lower than preoperative pain (p<0.05); mean satisfaction was 72%. Complications occurred in 8.3%. CONCLUSION: The functionality of the operated shoulder was good and radiological evaluation showed satisfactory medium-term results in patients with hemiarthroplasty of the shoulder. PMID- 21794257 TI - [The qualitative approach in health: an alternative to clinical research in rheumatic diseases]. AB - Qualitative research in a clinical environment is an alternative in the study of the complexity of rheumatic diseases and takes patients' perspectives and their cultural contexts, as well as the biomedical system, into account. Given that the main objective of this type of research is to provide information on what a given disease means to patients and their families, it is complementary to the experimental and quantitative studies that prevail in the present clinical setting. The process of qualitative research differs from that of other approaches in the data obtained and their analysis. This type of research is used in many different settings of clinical medicine, ranging from epidemiological to clinical ethics studies. PMID- 21794258 TI - [Not Available]. PMID- 21794259 TI - [Microscopic polyangiitis in a patient with systemic sclerosis]. AB - The coexistence of systemic sclerosis (SSc) and vasculitis has been infrequently reported. We present a 65-year-old man who, 6 years previously, had been diagnosed with limited SSc, and who developed a focal segmental necrotizing crescent glomerulonephritis associated with perinuclear antineutrophil cytoplasmic antibodies with antimyeloperoxidase specificity in the absence of Dpenicillamine exposure. PMID- 21794260 TI - [Not Available]. PMID- 21794261 TI - [Not Available]. PMID- 21794262 TI - [Not Available]. PMID- 21794263 TI - [The search for new autoantigens in Sjogren's syndrome]. AB - OBJECTIVE: To identify new autoantigens related to Sjogren's syndrome and to determine their prevalence in patients and healthy individuals. MATERIAL AND METHODS: Serological sampling was performed in a patient with Sjogren's syndrome through the use of a human brain expression genotec (SEREX technique) to determine expression of known autoantigens and previously undescribed proteins. The presence of a previously unknown protein was found. Several proteins were obtained and two were selected to be studied (a human protein called Tau and an unknown protein described by our group and named hlscA). Both Tau and hIscA cDNA were transformed into an expression plasmid to obtain their recombinant proteins. RESULTS: Using a Western-blot technique we investigated the presence of anti-Tau and anti-hlscA autoantibodies in the sera of 19 patients with Sjogren's syndrome and in the sera of 20 controls. No statistically significant differences were found in the expression of anti-Tau antibodies between patients with Sjogren's syndrome and controls but values of anti-hlscA autoantibodies were significantly lower in patients with Sjogren's syndrome. CONCLUSION: We identified Tau and hIscA proteins as new autoantigens in Sjogren's syndrome. Anti-hlscA antibody values were significantly lower in patients with Sjogren's syndrome than in healthy controls. Although no statistically significant differences in values of anti-Tau antibodies were found between Sjogren's syndrome patients and controls, this is the first time antibodies against this protein have been detected in Sjogren's syndrome. PMID- 21794264 TI - [Cost analysis in a cohort of rheumatoid arthritis patients managed in rheumatology units in Spain]. AB - OBJECTIVE: To assess the annual costs of rheumatoid arthritis (RA) patients attended at rheumatology units in Spanish public hospitals. METHODS: A longitudinal, prospective, multicenter, observational, 1-year study was performed in the rheumatology units of randomly selected Spanish public hospitals. Randomly selected RA patients were included. The patients made four visits (at baseline and every 4 months). Resource use and costs were collected from patient diaries and structured questionnaires. RESULTS: A total of 301 patients were included and 190 (83% women) completed the study. The mean (+/- SD) age was 59+/-13 years and the mean disease duration was 10+/-10 years. The median annual cost per patient was 3,845 euros (318-36,783). The estimated total annual cost of the Spanish RA population managed in the rheumatology units of public hospitals was 590,110,000 euros. Of total costs, 74% were direct costs and 26% were indirect costs. Medical costs represented 81% of direct costs. The main components of medical costs were drugs (56%), medical visits (21%), complementary tests (12%), and hospitalizations (11%). Permanent work disability represented 66% of indirect costs. CONCLUSIONS: Direct costs were substantially higher than indirect costs. The main components of medical costs were drugs. There was high variability in resource use with a wide range of annual costs per patient. PMID- 21794265 TI - [Is there an association between fibromyalgia and an increase in comorbidity: neoplastic and cardiovascular diseases, infections and mortality?]. AB - OBJECTIVE: To determine whether fibromyalgia (FM) is associated with an increase in comorbidity (infections, neoplastic and cardiovascular disease) as well as with an increase in mortality. MATERIAL AND METHODS: We performed a systematic review. Using a sensitive search strategy, all studies published in PubMed (from 1961), Embase (from 1991), Cochrane Library Plus and abstracts of rheumatology congresses (ACR and EULAR, from 1999) until May 2005 were selected. Cohort, descriptive and comparative studies were selected. The results of the search were screened through a review of the titles and abstracts. RESULTS: Of the 562 references retrieved by the search, 33 potentially relevant studies were selected. Patients with FM showed greater comorbidity and medical resource use than did the general population and patients with other rheumatic diseases. FM was more frequent in hospitalized patients and in the context of HIV and hepatitis C infections. Some studies found a high risk of developing cancer in FM patients. Several studies found an increased mortality rate in FM, mainly due to cancer and suicide. CONCLUSIONS: Despite the high comorbidity and medical resource use in FM, there is no evidence that this entity is associated with an increase in comborbidity due to cardiovascular disease or infections. The association between FM and HIV and hepatitis C virus infections suggests a possible relationship between FM and chronic viral infection. Patients with chronic generalized pain may have an increased risk of developing cancer. FM may also carry an increased risk of accidental death and death from cancer. PMID- 21794266 TI - [Manpower of rheumatology in catalonia (Spain)]. AB - OBJECTIVE: To determine the changes in Rheumatology provision and working practice that have occurred on the basis of the 1990, 1996 surveys carried out to update the Catalan Society for Rheumatology register METHODS: The register includes all rheumatologists in Catalonia (Spain) who are registered and who do clinical work. Questionnaires were sent to all rheumatologists on the register. The questionnaires asked about location and clinical commitments. RESULTS: One hundred twenty-four rheumatologists work at the public system in Catalonia, 80 (65%) work at hospitals. The majority of rheumatologists (105; 84,6%) are located in the province of Barcelona. One fith of the rheumatologists have a temporal work. Ten general hospitals are still lacking of rheumatologists. CONCLUSION: Although the number of rheumatologists in Catalonia has increased there are ongoing inequalities in the provision of Rheumatology, especially between Barcelona and the rest of provinces. PMID- 21794267 TI - [Psoriatic synovitis: pathogenic and therapeutic implications]. AB - Psoriatic arthritis (PsA) is a chronic inflammatory autoimmune disease characterized by arthritis and psoriasis of the skin. It is classified within the spondyloarthropathies (SpA) group. The wide clinical heterogeneity of PsA has hampered research into its pathogenesis and the performance of large randomized clinical trials with disease-modifying anti-rheumatic drugs. The success of biologic agents in PsA has stimulated wide interest in this disease as well as in its clinical classification and underlying pathogenic mechanisms. Several recent articles on the pathogenesis of PsA are reviewed, focussing on the potential of synovial angiogenesis as a therapeutic target and on synovial expression of macrophages and p53 protein related to joint damage in rheumatoid arthritis (RA) and PsA. Finally, the question of whether the polyarticular variant of PsA shares immunohistochemical features with RA or SpA is also discussed. Although the success of tumor necrosis factor-alpha antagonists in both RA and PsA supports a similar pathogenesis in both disorders, these and other studies suggest that there are differences in the synovial expression and pathogenic significance of certain cells and molecules. If confirmed, this phenomenon could open new avenues in specific therapy for PsA. PMID- 21794268 TI - [Not Available]. PMID- 21794269 TI - [Charcot's neuroarthropathy]. AB - Diabetes is the most common cause of neuropathic arthropathy. The most frequent localization is the tarsus. In clinical practice, the insidious painful onset and discrete inflammatory signs of this disease often lead to a mistaken interpretation by the physicians who usually manage these patients (endocrinologists, rheumatologists, podiatrists, etc.), delaying diagnosis with devastating consequences. We report four cases of neuropathic arthropathy in diabetic patients diagnosed in our service. The clinical features that may suggest a diagnosis in the early stages of this entity are stressed. PMID- 21794270 TI - [Not Available]. PMID- 21794271 TI - [Not Available]. PMID- 21794272 TI - [I Spondyloarthritis Symposium of the Spanish Society of Rheumatology]. PMID- 21794273 TI - [Not Available]. PMID- 21794274 TI - [Not Available]. PMID- 21794275 TI - [Is it possible to classify patients with early spondyloarthritis?]. PMID- 21794276 TI - [Not Available]. PMID- 21794278 TI - [Not Available]. PMID- 21794277 TI - [Not Available]. PMID- 21794279 TI - [Not Available]. PMID- 21794280 TI - [Not Available]. PMID- 21794281 TI - [Not Available]. PMID- 21794282 TI - [Not Available]. PMID- 21794283 TI - [Not Available]. PMID- 21794284 TI - [Regisponser]. PMID- 21794285 TI - [New therapies in rheumatology]. PMID- 21794286 TI - [Treatment of arthritis of recent onset]. PMID- 21794287 TI - [Effectiveness of biological agents in ankylosing spondylitis]. PMID- 21794288 TI - [Efficacy of local treatment with glucocorticoids in regional pain syndromes appendix. A review of current knowledge]. PMID- 21794289 TI - [Treatment of neuropsychiatric manifestations of systemic lupus erythematosus]. PMID- 21794290 TI - [Treatment of systemic lupus erythematosus in the pregnant patient]. PMID- 21794291 TI - [Antiphospholipid syndrome treatment, to whom, when and how long?]. PMID- 21794292 TI - [Hormone therapy in autoimmune rheumatic diseases]. PMID- 21794293 TI - [Current therapeutic approach osteoarthritis]. PMID- 21794294 TI - [Not Available]. PMID- 21794295 TI - [Atypical presentation and clinical course in mesangial lupus nephritis]. AB - Mesangial lupus nephritis (type II according to the WHO classification) is usually considered a benign variant. Its clinical manifestations are minimal: hematuria and proteinuria, normal sediment, and normal renal function. To evaluate the clinical manifestations and course in mesangial nephritis, we studied 20 patients with a histological diagnosis of type II lupus nephritis who attended our clinic. We found that clinical presentation was atypical in a significant proportion of these patients. Data from the two groups of patients were compared: those with classical presentation and those with atypical presentation. The results were analyzed with descriptive and inferential statistics. Twenty patients (19 women and 1 man) were included. The mean age at nephritis onset was 33.9 years and the mean length of follow-up was 4.2 years. Clinical presentation was atypical in 17 patients, with active urinary sediment in 12, urine protein>1 g/24 h in 7, and reduction in creatinine clearance in 14. Clinical remission was achieved with treatment in 16 patients, with subsequent flares in 8. All flares responded well to treatment. Biopsies in 5 patients with flares showed progression to type III and IV nephritis. At the end of the follow up period, 4 patients had chronic renal failure. Some of our patients with mesangial lupus nephritis did not have the benign course that is usually described. Despite a good initial response, 20% of the patients progressed to chronic renal failure. Initial hyperlipidemia and proteinuria seem to correlate with a more aggressive course. PMID- 21794296 TI - [Effect of short-term nonsteroidal antiinflammatory therapy on mean blood pressure. A prospective, randomized clinical trial]. AB - Our objective was to evaluate the effect of short-term therapy with nonsteroidal antiinflammatory drugs (NSAID) on mean blood pressure (MBP). Two hundred thirty three consecutive patients (185 women, 54 men; 53.9+/-13.5 years) requiring NSAID therapy were prospectively randomized to: indomethacin (21 patients), naproxen (33 patients), diclofenac (40 patients), sulindac (42 patients), meloxicam (35 patients) and celecoxib (40 patients) for 8.5+/-2 days. BP was measured at the beginning and end of follow-up using a Kenz OS22 monitor. At the end of follow up, 211 (88%) patients were still available for evaluation. A slight posttreatment decrease in MBP (-1.4+/-9.0 mm Hg, 95%CI: -2.7 to -0.2) was found. No significant differences in posttreatment changes in MBP were found among the distinct NSAIDs evaluated. Fifty-five patients (23%; 95% CI: 18-29) showed a posttreatment increase in MBP of>5 mm Hg. This increase was not associated with hypertension, old age, or any specific NSAID. We conclude that, overall, shortterm NSAID therapy does not seem to have a clinically significant effect on MAP. However, 23% of patients undergoing this therapy showed an increase in MBP that, if persistent, could lead to a higher risk of cardiovascular disease. Further research is needed to identify whether this outcome persists in long-term NSAID therapy. PMID- 21794297 TI - [Efficacy and safety of intraarticular injections of hyaluronic acid in knee osteoarthritis: clinical and ultrasonographic evaluations]. AB - OBJECTIVES: To evaluate the efficacy and safety of hyaluronic acid (HA) therapy in patients with osteoarthritis of the knee. MATERIALS AND METHODS: We performed a prospective, multicenter, noncontrolled study with a 6-month followup. One hundred eleven outpatients with a diagnosis of knee osteoarthritis based on clinical and radiological criteria (except for Kellgren grade IV) were enrolled in the four participating centers. Five sequential intraarticular injections of HA (Adant((r)), Tedec-Meiji Farma, S.A.) were administered over a 4-week period. Efficacy was evaluated at the follow-up visits (2, 12 and 24 weeks after the final injection) by comparing posttreatment with baseline scores for the following variables: overall knee pain on a visual analog scale, Lequesne Index, WOMAC Index, patient and investigator overall assessment of efficacy on a 5-point Likert scale, knee range of movement, and analgesic consumption. Knee ultrasonography was performed at baseline and at the end of the study. Safety was evaluated by systematic recording of adverse events (AE). RESULTS: A statistically significant improvement in all the efficacy variables analyzed (p<=0.01) compared with baseline values was found at each of the follow-up visits. At 24 weeks, more than 68% of the patients rated their status as better or much better. The presence and amount of intraarticular fluid in the knee joint, assessed by ultrasonography, diminished dramatically after HA treatment. Most of the adverse events were local and were mainly due to the administration technique; the incidence of AEs due to injection was 2.4%. CONCLUSION: Intraarticular administration of HA is an effective, safe and well-tolerated alternative in the treatment of mild-to-moderate osteoarthritis with symptomatic improvement lasting up to 6 months. PMID- 21794299 TI - [Enthesis as a target element in spondylarthritides]. AB - Enthesis is a structure frequently involved in spondyloarthritides. According to a recent hypothesis, it may play a key role in the pathogenesis of these entities. The present review discusses the most important aspects of current knowledge of enthesis, such as its anatomy and the extracellular matrix components present within it. Clinical evaluation and the new imaging techniques (magnetic resonance imaging and ultrasound) that complement its evaluation will be briefly described. Immunohistological studies as well as animal models developed with enthesis molecules underline the importance of enthesis in the pathogenesis of spondyloarthritides. Finally, the latest research assessing the T cell response to enthesis components in patients with ankylosing spondylitis will be reviewed. PMID- 21794298 TI - [Experience with rituximab in the treatment of systemic erythematosus lupus]. AB - OBJECTIVE: To assess the short-term effectiveness and tolerance of rituximab in patients with systemic lupus erythematous and distinct clinical manifestations. PATIENTS AND METHODS: Thirteen patients were studied. Rituximab (RTX) was indicated for refractory nephritis in 6 patients, severe thrombocytopenia in 5, aplastic anemia in 1 and peritoneal vasculitis associated with nephritis in 1. All patients received 4 weekly doses of 375 mg/m(2) of RTX. The mean length of follow-up was 12+/-8.5 months. Response was favorable in 9 patients: 3 with nephritis, 5 with thrombocytopenia and 1 with peritoneal vasculitis and nephritis. The mean SLE disease activity index decreased from 11 to 6.5 points. Thrombocytopenia recurred in 2 patients, who responded well to retreatment. CONCLUSIONS: The present study demonstrates that RTX is safe and effective as short-term therapy for distinct clinical manifestations associated with SLE. PMID- 21794300 TI - [Hyaluronic acid in the treatment of osteoarthritis]. AB - Hyaluronic acid is a glycosaminoglycan composed of disaccharides of glucuronic acid and N-acetylglucosamine. It is present at high concentrations in mammalian connective tissues. Since the length and concentration of HA decrease in osteoarthritis (AO), intraarticular HA injections began to be used in the early 1970s to restore the rheological properties of synovial fluid. Despite the widespread use of HA, many questions about its mechanism of action and properties remain to be clarified. A literature review presented in this article reveals that HA is a symptomatic slow-acting drug in osteoarthritis (SYSADOA) and that there is insufficient evidence to qualify it as a disease modifying osteoarthritis drug (DMOAD). HA is involved in many mechanisms of action ranging from interaction with mechanosensitive articular pain receptors to its ability to modulate extracellular matrix homeostasis. Although low molecular weight HA has a better safety profile and is slightly superior in in vitro studies and animal experimentation, clinical trials evaluating the efficacy of the drug show insufficient evidence to enable one type of HA to be recommended in preference to any other. PMID- 21794301 TI - [Atypical pulmonary nodules in a patient with rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is associated with a wide variety of lung manifestations, including rheumatoid nodules. We report the case of woman with a diagnosis of RA who underwent thoracic computed axial tomography (CAT) scan because of cough and effort dyspnea. The CAT scan revealed the presence of small lung nodules. After biopsy, these nodules were diagnosed as cholesterol granulomas. PMID- 21794302 TI - [Not Available]. PMID- 21794303 TI - [Not Available]. PMID- 21794304 TI - [Systematic review: does a diagnosis of fibromyalgia per se have a harmful effect on prognosis?]. AB - OBJECTIVE: The aim of the present study was to determine the extent to which a label of fibromyalgia (FM) could have a harmful effect on short- and long-term prognosis. METHODS: We performed a systematic review using a sensitive search strategy. All studies published in PubMed (since 1961), Embase (since 1991) and Cochrane Library Plus (up to 2005) were selected. The titles and abstracts of articles retrieved from the search were reviewed and clinical trials and studies on prognosis were included. RESULTS: Of a total of 650 references retrieved, only 5 were analyzed in detail. Two were longitudinal studies that completely fulfilled the inclusion criteria. These studies were performed in different countries (Canada and the United Kingdom) with sufficient and representative samples. Both studies reported lower resource utilization after a diagnosis of FM. The remaining studies were analyzed in detail, although they did not fulfill the inclusion criteria: there was one longitudinal study to determine the accuracy of the diagnosis of FM, one qualitative study, and a review article. No studies against the hypothesis that a diagnosis of FM worsens prognosis were found. CONCLUSIONS: There is no evidence that a diagnosis of FM per se could worsen prognosis in patients with this condition. Indeed, the available evidence, which is of moderate-good quality, suggests that, on the contrary, diagnosis reduces healthcare utilization by patients. PMID- 21794305 TI - [Synovial chondromatosis. A study of 39 patients]. AB - OBJECTIVE: To study the clinical manifestations, use of diagnostic imaging techniques and outcome of patients with synovial chondromatosis in our health area. PATIENTS AND METHODS: POVISA Hospital provides health services to a population of 127,000 inhabitants. The clinical histories of all the patients in this area who were histologically diagnosed with synovial chondromatosis between January 1992 and December 2003 were reviewed. RESULTS: There were 38 cases of joint chondromatosis, all monoarticular, and one case of extra-articular chondromatosis in 20 men and 19 women aged 56.5+/-12.7 years (mean+/-SD) at diagnosis (range: 16-79 years). The main joint affected was the knee (15; 39.5%), followed by the hip (8; 21%) and the temporomandibular joint and elbow, both of these in three patients (7.9%). Previous arthropathy was recorded in 18 patients (18/38, 47.4%). Symptom duration prior to diagnosis was 25.4+/-34 months. The most frequent clinical manifestations were joint pain (100%), restricted movement (77%) and swelling (57%). Plain radiographs were carried out in all patients and suggested the diagnosis in 20 (51.3%). Magnetic resonance imaging findings led to a diagnosis in 12 out of 15 patients in whom this procedure was required (80%). In all patients loose bodies were removed and synovectomy was performed by arthroscopic procedures in six. In 16 patients (42%) total joint replacement was required. The mean postoperative follow-up was 23.7+/-5.3 months. No cases of chondrosarcoma were identified and the recurrence rate was low (7.9%). CONCLUSIONS: In our setting, almost half (47.4%) of the cases of synovial chondromatosis occurred in a previously damaged joint: the correct diagnosis was delayed by more than 2 years and total arthroplasty was required in 42% of the patients. PMID- 21794306 TI - [Cross-cultural adaptation and validation of a Spanish version of a specific instrument to measure health-related quality of life in patients with ankylosing spondylitis]. AB - OBJECTIVE: To make a cross-cultural adaptation and validation of a version in Spanish of the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) for assessing the health-related quality of life (HRQL) of patients with Ankylosing Spondylitis (AS). PATIENTS AND METHODS: A cross-sectional study with test-retest. AS patients (modified New York criteria) were included. Cross-cultural adaptation was done. Construct validity was assessed comparing the ASQoL scores with the SF 36 and EuroQol scores and diseaserelated variables. Internal consistency and reliability (test-retest) were assessed. Feasibility was assessed by the time spent to complete the questionnaire and the number of items without answer. Spearman correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis test were used in the statistical analysis. Cronbachalpha coefficient and statistic kappa were used for assessing internal consistency and reliability. RESULTS: Fifty-four patients, 37 males (68.5%), with age (mean+/-SD) 40.5+/-10.5 years, were included. The ASQoL global score was 6.8+/-4.7 (median, 7; range, 0-17). The ASQoL scores had high correlations with physical (rho = 0.79) and mental (0.69) SF-36 components, the SF-36 domains pain (0.82), vitality (0.75), and role physical (0.68), and the most of the disease-related variables. The ASQoL scores were significantly different between patients with different response levels in the health profile of the EuroQol. The Cronbachalpha coefficient was 0.86. The reliability had kappa = 1 in 12 items and rho = 0.98. The time spent to complete the ASQoL was from 2 to 5 minutes and there only was a missing answer in one patient. CONCLUSION: The Spanish ASQoL is valid, reliable, and feasible instrument for assessing the HRQL of the AS patients. PMID- 21794307 TI - [Thyroid dysfunction in women with suspected fibromyalgia]. AB - BACKGROUND AND OBJECTIVE: Due to its prevalence, morbidity, and frequency rate, fibromyalgia (FM) represents a health problem and produces high healthcare resource utilization. Serum thyrotropin (TSH) measurement is recommended as a first-line laboratory test to exclude hypothyroidism as a cause of FM syndrome. The aim of this study was to analyze the prevalence of thyroid dysfunction (TD), the frequency of TSH measurement, the effect of levothyroxine treatment, and whether screening for TD is justified in women with suspected FM. PATIENTS AND METHODS: A cross-sectional descriptive study was performed in 400 consecutive female outpatients with suspected FM and in 384 controls from January 2001 to October 2004. TSH measurement was used as the first line test to detect TD. RESULTS: The prevalence of TD in patients with suspected FM (40/400; 10%; 95% CI: 7-13%) and controls was similar (46/384; 12%; 95% CI: 9-15%). No differences were found in the types and grades of TD. The prevalence of TD was higher in patients with suspected FM and connective tissue diseases (12%) than in those without these diseases (5%). The most frequent TD was subclinical hypothyroidism (5.5% in suspected FM and 6.7% in controls), and in 93% of these cases TSH concentrations were <10 mIU/L. FM persisted in all women with hypothyroidism even after euthyroidism was achieved with levothyroxine. A total of 870 TSH determinations were performed in 360 euthyroid patients with suspected FM. CONCLUSIONS: The prevalence of TD in women with suspected FM does not differ from that in the general population. Screening for TD does not appear to be justified in women without diseases that increase their risk. In many cases the request for thyroid function tests is excessive. Treatment for hypothyroidism does not affect FM. PMID- 21794308 TI - [Not Available]. PMID- 21794309 TI - [Hormone therapy, fertility and pregnancy in antiphospholipid syndrome]. AB - Antiphospholipid syndrome (APS) carries a risk of thrombosis and infertility. Consequently the use of any type of hormone therapy and pregnancy in APS requires special considerations. The present article provides a broad review of all these issues. The use of contraception, hormone replacement therapy and selective estrogen receptor modulators in APS are described. In vitro fertilization/embryo transfer and ovarian induction in these patients are reviewed. Lastly, the possible fetal and maternal complications that can occur during pregnancy are described and, based on the literature, recommendations for the management of pregnancy in women with APS are provided. PMID- 21794310 TI - [Not Available]. PMID- 21794311 TI - [Paravertebral pyomyositis in childhood following closed injury]. AB - Pyomyositis is an acute bacterial infection that affects striated muscle and is generally accompanied by the formation of an abscess. In most cases, the microorganism involved is Staphylococcus aureus. Clinical findings are characterized by pain, swelling and muscular edema, together with variable general symptoms. Complications include arthritis, osteomyelitis and even septic shock with a mortality of 1.8%. We report the case of an 8-year-old boy who sustained a closed lumbar injury on banging his shoulder while he was playing on a trampoline and who developed paravertebral pyomyositis complicated by sepsis. S. aureus was isolated in the blood culture. The boy subsequently developed a perivertebral abscess and finally contiguous osteomyelitis in the L3 spinous process. The patient received treatment with vancomycin and metronidazole for 6 weeks followed by cloxacillin therapy for 2 weeks (a total of 8 weeks of intravenous antibiotic therapy). Physical examination 3 months after discharge revealed no abnormalities. The possibility of pyomyositis should be borne in mind, especially in children with fever, localized muscular pain and a history of accidental or sports injuries. Early diagnosis and treatment are important to reduce the risk of possibly fatal complications. PMID- 21794312 TI - [Not Available]. PMID- 21794313 TI - [Not Available]. PMID- 21794314 TI - [Ozone therapy in rheumatic diseases: a systematic review]. AB - OBJECTIVE: To perform a systematic review to analyze the efficacy on which the use of ozone therapy in musculoskeletal diseases is based. METHODS: A literature search was performed in PubMed, Embase and the Cochrane Library using highly sensitive search terms to identify all studies on ozone therapy. All studies showing the efficacy or effectiveness of ozone therapy in any musculoskeletal disease were selected. RESULTS: Only 6 relevant studies were identified, 5 in lumbar disk herniation and 1 in Raynaud's syndrome. Of the 5 studies in disk herniation, only 3 were clinical trials and none used random allocation. Study participants were generally patients with symptomatic small discal hernias. There was wide variability in the dose of ozone injected as well as in the controls used for comparison. All outcome measures were subjective and there was no blinded evaluation of the results. The study in Raynaud's syndrome included only 4 patients. Adverse effects were not evaluated in detail. CONCLUSIONS: The use of ozone therapy in musculoskeletal diseases is based on poor quality studies. Currently, data supporting an adequate risk/benefit ratio for ozone therapy in rheumatic diseases is lacking. PMID- 21794315 TI - Costs of the standard rheumatology care in active rheumatoid arthritis patients seen in a tertiary care center in Mexico City. AB - OBJECTIVE: To assess the costs of standard care in patients with active rheumatoid arthritis (RA) seen in a tertiary care center in Mexico City in the context of a clinical trial. To analyze the relationship between costs and utility units obtained by the patients in this scenario. PATIENTS AND METHODS: This economic evaluation was performed during a clinical trial with a 48-week followup in a tertiary care center in Mexico City. The trial compared the efficacy of omega-3 fatty acids versus placebo in patients with active RA who also received standard rheumatology care. The costs of medical consultations, complementary tests and drugs were assessed. Other direct costs were also measured. Hypothetical scenarios with fewer medical consultations and complementary tests than those in the clinical trial were also analyzed. Utilities were assessed by the Health Utility Index. A cost-utility ratio was calculated using the baseline utilities score as comparator. A descriptive statistical analysis was performed. RESULTS: Ninety RA patients (83 women [92%], age [X +/- SD] 43.2 +/- 14.2 years with disease duration of 3.3 +/- 4.6 years) were included. Data from 88 patients were analyzed. The total direct costs were 152,704.11 US$ 2005 divided into medical attention (78,386.43 US$ 2005, 51.33%), drugs (39,339.5 US$ 2005, 25.76%) and other direct costs (34,978.18 US$ 2005. 22.91%). In scenarios with fewer medical consultations and complementary tests than those in the clinical trial, the total direct costs ranged from 39,507.4 to 103,880.6 US$ 2005. Patients improved by a mean of 0.18 utility units on a 0-1 scale equivalent to 0.18 quality adjusted lifeyears (QALYs). The cost-utility ratios ranged from 2,494.1 to 9,640.38 US$ 2005 per QALY in the scenarios analyzed. CONCLUSIONS: The direct costs of the standard care of RA in the scenarios analyzed are substantial in the social and economic context of Mexico. The cost per gained QALY is high. PMID- 21794316 TI - [Registrolesaf. Features of patients with systemic lupus erythematosus and antiphospholipid syndrome registered by rheumatologists and internists]. AB - BACKGROUND AND OBJECTIVE: Registrolesaf (Spanish Registry of Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome through Internet) enables little known aspects of systemic lupus erythematosus and antiphospholipid syndrome to be studied simply. The aim of this study was to analyze the features of patients included in Registrolesaf by rheumatologists and internists. PATIENTS AND METHOD: Among other data, Registrolesaf collects data on the specialty of physicians using the registry and patients' initials, date of birth, diagnosis, sex, vital status and, optionally, the ACR criteria on lupus and consensus statement criteria on antiphospholipid syndrome. RESULTS: From May 2003 to November 2004, 1421 patients were included in the registry (1269 with lupus and 152 with antiphospholipid syndrome). Rheumatologists included 462 (47.8%) lupus patients and 24 (16.7%) with antiphospholipid syndrome, while internists included 490 patients (50.7%) with lupus and 119 (82.6%) with antiphospholipid syndrome. Logistic regression analysis, controlled for age at diagnosis, disease duration and sex, showed that lupus patients included by internists had a higher frequency of malar rash (OR 1.6; 95% CI 1.2-2.2), oral ulcers (OR 1.2; 95% CI 1.4-2.7), neuro-psychiatric manifestations (OR 2.2; 95% CI 1.3- 3.8), kidney disease (OR 1.5; 95% CI 1-2) andantinuclear antibodies (OR 2.1; 95% CI 0.97-4.7), while the frequency of antiphospholipid antibodies (OR 0.6; 95% CI 0.4-0.9) and the number of lupus criteria (P=.002) were lower. CONCLUSIONS: Rheumatologists and internists have a similar approach to patients with lupus and antiphospholipid syndrome, although internists could include more seriously ill patients. PMID- 21794317 TI - [Development and validation of a satisfaction questionnaire in patients with rheumatoid arthritis]. AB - OBJECTIVE: The aim of this study was to develop and validate a specific tool to assess satisfaction with treatment in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: The questionnaire was developed in three stages: firstly, a literature review was performed by experts in developing patient-centered measures; secondly, items selected by 4 experts in RA were assessed for comprehensibility, format and applicability, and thirdly, administration of the questionnaire was evaluated through a personal interview of a group of 14 patients with RA under treatment with infliximab. Validation of the questionnaire was performed in patients with RA who met the ACR criteria, were older than 18 years, and had started treatment with infliximab due to inadequate disease control. Questionnaires were administered at the baseline visit (beginning of treatment) and at 2, 6 and 14 weeks, coinciding with infliximab infusions. The questionnaire validity was evaluated in terms of construct validity (factorial analysis) and content validity. Content validity was assessed by analysing the relationship between satisfaction and different measures used for treatment effectiveness as well as fulfillment of treatment expectations. RESULTS: Validation of the questionnaire was performed in a sample of 180 patients with a mean (SD) age of 52 (13) years. A total of 80.7% were women. In 72.4% disease duration was longer than 3 years. The scores obtained on the satisfaction questionnaire were related to the aspects defined as ACR criteria (except ESR and CRP), fulfillment of ACR20, ACR50 and ACR70 response criteria, and fulfillment of treatment expectations (p<0,01). DISCUSSION: The results confirm the questionnaire's validity in assessing patient satisfaction with RA treatment, both in routine clinical practice and in research conditions. PMID- 21794318 TI - [Hematopoietic stem cell transplantation in systemic autoimmune diseases. State of the art]. AB - The use of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy arose from two discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. Experimental data and early phase I-II trials in highly selected patients suggest that highdose chemotherapy followed by autologous hematopoietic stem cell transplantation can arrest progression of severe autoimmune diseases with an acceptable risk/benefit ratio. The present article reviews the phase II-III prospective, multicenter, randomized trials that have been performed in distinct autoimmunediseases. In addition, allogeneic stem cell transplantation for autoimmune diseases is being cautiously explored in current protocols. PMID- 21794319 TI - [Not Available]. PMID- 21794320 TI - [Rowell's syndrome or systemic lupus erythematosus and erythema multiforme. Association or coincidence?]. AB - Rowell's syndrome is characterized by the association of systemic lupus erythematosus (SLE) and erythema multiforme-like lesions with the presence of immunological markers such as antinuclear antibodies with speckled pattern, anti La antibodies and rheumatoid factor. We present the case of a 22-year-old woman with a diagnosis of SLE and erythema multiforme and discuss the possibility of distinguishing these entities from Rowell's syndrome. PMID- 21794321 TI - [Not Available]. PMID- 21794322 TI - [Not Available]. PMID- 21794323 TI - [Identification of the best sites for the histopathological study of tarsitis in patients with spondyloarthropathies]. AB - BACKGROUND: Foot involvement in patients with spondyloarthropathies (SpA) includes a peculiar clinical spectrum ranging from tarsal swelling to bone ankylosis similar to axial disease in patients with ankylosing spondylitis. Hypothetically, the study of these lesions could help to explain phenomena that occur in the vertebral column. OBJECTIVE: To identify the best site for sampling foot tissues in cadavers with a view to implementing the procedure in patients with SpA. MATERIAL AND METHODS: Six sites including foot tendons and entheses from the cadavers of individuals<50 years with no musculoskeletal disease were selected by consensus. Tissue samples included>1 cm of endon and synovial sheath and 0.2 mm of periosteum, which were fixed in 5-formaldheid solution, 70% alcohol and paraffin. Paraffin blocks were then cut into 3? slices and stained with hematoxylin, eosin and Masson trichromic. RESULTS: There were 31 pieces of tendon, 8 pieces of entheses and 5 pieces of periosteum, but no synovial membrane was identified. Tendons were identified in more than a half of the sites biopsied and entheses in 50% of samples from the upper segment of the tendon and synovial sheath of the tibialis posterior and the peroneus brevis insertion on the 5th metatarsal head. Tendon tissues consisted of fusiform cells in an undulated pattern separated by fine bands of loose and dense connective tissue. Entheses included tendon, epitendon and endotendon attachments to bone through a small fragment of non-calcified fibrocartilage. CONCLUSION: Slightly more than 50% of the sites selected for study contained tendon tissues useful for histologic examination. The same results were obtained for enthuses in only one site. Overall, these sites appear suitable for study in patients with SpA. PMID- 21794324 TI - [Relationship between COMT gene genotypes and severity of fibromyalgia]. AB - BACKGROUND AND AIM: To determine the possible relationship between Val158Met genotypes of the COMT gene and the severity of fibromyalgia (FM) syndrome. PATIENTS AND METHODS: The study included 110 patients aged between 45 and 55 years old diagnosed with FM (ACR, 1990) and 110 samples from control subjects with no pain and no abnormal fatigue (National DNA Bank, Spain). To measure the severity of fibromyalgia, the Fibromyalgia Impact Questionnaire (FIQ) was used. Severe FM was defined as an FIQ of >= 70 and was found in 35.5% of the patients. Polymorphisms were analyzed using standard polymerase chain reaction techniques. All the groups met the Hardy-Weinberg equilibrium. RESULTS: The frequency of the Met/Met genotype was lower in controls (20.9%) than in patients (34.5%), whereas that of the Val/Val genotype was higher in controls (30.9%) than in patients (20.0%), with significant differences (p=0.048). The mean FIQ values were higher in the Met/Met genotypes (71.67) and Val/Met genotypes (68.27) and were lower in the Val/Val genotype (58.93). Tukey's multiple comparison test indicated that FIQ values presented significant differences when Met/Met/Val/Val (Tukey, p<0.001) and Val/Val/Val/Met (Tukey, p=0.003) were compared. CONCLUSIONS: Our results appear to indicate that the Met/Met genotype is associated with greater severity of FM symptoms. PMID- 21794325 TI - [Systematic review: can botulinum toxin be recommended as treatment for pain in myofascial syndrome?]. AB - Myofascial pain syndrome (MPS) may have an intrinsic muscle spasm component. AIM: Since botulinum toxin has been successfully used to reduce hypertonicity in several neurological disorders, we analyzed the efficacy of botulinum toxin A or B in reducing pain in MPS. METHODS: We performed a systematic review through an electronic search in MEDLINE, EMBASE, and Cochrane Library Plus. All clinical trials of botulinum toxin and regional pain were selected. In addition, the abstracts of the ACR and EULAR meetings in the previous 3 years were searched manually. The studies identified were reviewed and analyzed by 2 independent reviewers. RESULTS: Eight studies met the inclusion criteria. The methodological quality was generally low. Botulinum toxin was compared to saline solution (6 studies), to steroids (2 studies), and to lidocaine and dry needle (1 study arm). The population studied included persons with neck pain (n=3), low back pain (n=2), piriformis syndrome (n=2), several trigger points (n=1), and healthy volunteers in whom pain was provoked (n=1). Botulinum toxin showed a certain advantage over saline solution and steroids in pain control. A meta-analysis of the 3 studies with efficacy measures that could be combined showed a weighted mean difference in pain on a 0-10 visual analogue scale of -2.72 (95% CI: -3.86; 1.58). However, botulinum toxin showed no advantage over lidocaine (p>0.016). CONCLUSIONS: Currently, there is insufficient evidence to confirm the real efficacy of botulinum toxin A and B in the treatment of MPS. Given the high cost of botulinum toxin, long-term high quality studies are required. PMID- 21794326 TI - [Complementary and alternative medicine in patients attending a rheumatology department for the first time. Analysis of 800 patients]. AB - OBJECTIVES: To determine the frequency of the use of complementary and alternative medicine (CAM) in patients attending a rheumatology department in a general hospital for the first time. SUBJECTS AND METHODS: We included consecutive patients attending our rheumatology department for the first time. All the patients completed a self-administered questionnaire containing items on demographic data, and prior diagnosis. The patients were also given a list of 22 different CAM and marked those they had previously used. RESULTS: Eight hundred patients were studied. Eighty percent were women. The mean age was 44.8+/-14.9 years and the mean number of years of education was 7+/-4. The main diagnoses were osteoarthritis (29.4%), rheumatoid arthritis (22.3%), and fibromyalgia (6.5%). Seventy-one percent had previously used CAM, with a median of two (0-14) different types. The most common were vitamin supplements (38%), arnica (18%), Aloe vera (15%) and homeopathy (15%). No significant differences were found in sex, age, educational level, or diagnosis. The use of CAM was more frequent in patients with longer disease duration. CONCLUSIONS: The frequency of use of CAM is high in patient with rheumatologic manifestations. PMID- 21794327 TI - [Antimalarials: an update in rheumatic diseases]. AB - Antimalarials are long-standing drugs that have been used since the nineteenth century for the treatment of skin rashes and lesions in lupus and rheumatoid arthritis. In recent decades, their use in these disorders has been consolidated, and new mechanisms of action have been incorporated, broadening the therapeutic perspectives of these drugs. Antimalarials are the treatment of choice in mild and moderate manifestations of systemic lupus erythematosus and are established as part of combined therapy in rheumatoid arthritis. They have been shown to have beneficial effects on atherosclerosis, as well as a possible role in the early treatment of antiphospholipid syndrome. Lastly, they have been shown to have a potential use in other rheumatic diseases such as Sjogren's Syndrome and palindromic rheumatism. This review aims to provide an update on the use of these drugs in rheumatology and to discuss their toxicity profile. PMID- 21794328 TI - [Fetal microchimerism in rheumatic diseases]. AB - Fetal microchimerism is the presence of fetal cells inmaternal tissues and vice versa, i.e., the coexistence of2 different cellular populations from genetically differentindividuals within a single person. The most frequentcause of microchimerism is pregnancy, in which there is abi-directional fetal-maternal interchange of cells duringpregnancy and delivery. Fetal cells have been demonstrated in the tissues ofpatients with rheumatic, endocrine or infectious diseases,as well as in those of healthy individuals. Microchimerism has been most extensively studied insystemic sclerosis. It seems that during pregnancyallogenic fetal or maternal cells cross the placenta bidirectionallyand persist in the systemic circulation andtissues of both mother and child. Subsequently, they areactivated, resulting in is a graft-against-host reactionassociated with the onset of clinical manifestations.Microchimerism has been also studied in otherconnective tissue diseases. PMID- 21794329 TI - [Not Available]. PMID- 21794330 TI - [Necrotizing fasciitis as the first manifestation of tuberculosis in a immunocompromised patient]. AB - Disseminated tuberculosis is a process that mainly affects immunocompromised hosts. Its initial appearance as necrotising fasciitis is exceptional especially if it is not associated to a bone disorder. The diagnosis of this rare complication requires a high degree of suspicion and the evidence of Mycobacterium tuberculosis in the muscular tissue, since the symptoms may mimic the underlying illness itself, for this reason the most sensitive method for demonstrating tuberculous infection is a muscular biopsy. Here we present the case of a patient who was receiving immunosuppressant therapy for nephrotic syndrome by minimal lesion glomerulonephritis and who developed this rare complication, where diagnosis was made by muscular biopsy. So we do a review of similar case reports in the literature. PMID- 21794331 TI - [Not Available]. PMID- 21794332 TI - [Not Available]. PMID- 21794333 TI - [Not Available]. PMID- 21794334 TI - [ArtRoCad: health resources utilization and socioeconomic impact of knee and hip osteoarthritis. I. Methods and population characteristics]. AB - OBJECTIVE: The ArtRoCad study analyzes healthcare resource utilization and the socioeconomic impact of knee and hip osteoarthritis in primary care in Spain. The present study describes the methodology of the ArtRoCad study and presents the main characteristics of the population included. METHODS: We performed a cross sectional study of ambulatory patients in primary care, aged >= 50 years old, with a diagnosis of knee or hip osteoarthritis and a history of pain for 3 months in the previous year. The patients were selected consecutively on a country-wide basis, proportional to the general population aged >= 50 years. The most important localization for healthcare demand was considered the main affected joint. The study was performed in October and November, 2003. Information on clinical data, quality of life and resource consumption, sick leave from work or days of disability in the previous 6 months were gathered through 2 structured interviews. RESULTS: Eighty-seven percent of the physicians predicted by sampling participated in the study, accounting for 82% of the predetermined sample size. A total of 1,071 patients were interviewed. The distribution of the main affected joint was as follows: knee 710 (66.3%), hip 252 (23.5%) and both knee and hip 109 (10.2%). Seventy-five percent of the sample was aged 65 years or older and 74% were women. Most of the patients had moderate or severe osteoarthritis with a median pain duration of between 6 and 10 years. More than half the patients experienced additional limitations due to musculoskeletal problems other than knee and/or hip osteoarthritis. CONCLUSIONS: Participation in the ArtRoCad study was excellent. The sample obtained was representative of the population with symptomatic moderate or severe osteoarthritis of the knee and hip in primary care, with substantial comorbidity. PMID- 21794335 TI - [Criterios utilizados por medicos de atencion primaria para el diagnostico y derivacion al reumatologo del paciente con artritis reumatoide]. AB - INTRODUCTION: Rheumatoid arthritis (RA), an important cause of disability, affects 1% of the population. Early diagnosis and referral to a rheumatologist are positive prognostic factor but diagnosis in many cases is in the hands of primary care physicians (PCP). OBJECTIVE: To determine the criteria used by PCP for diagnosis of RA and referral of these patients to a rheumatologist; to evaluate how many cases can be classified as RA according to the ACR. METHODS: Retrospective study of 530 patients referred by PCP and seen as outpatients at a rheumatology clinic in 2002. Patients with referral diagnosis of RA were identified and symptoms, signs, functional capacity and ACR criteria for RA were evaluated by 2 rheumatologists. RESULTS: 302 patients had a referral diagnosis of RA, 33 male (10.9%) and 269 female (89.1%), median age 50.5 years, with a median time since diagnosis of 45.2 months. 57.9% had FC stage II. 100% of cases had "generalized" joint pain, 67.5% arthritis of 3 or more joints and 51.7% arthritis of hand joints. Arthritis was symmetrical in 58.9% and 77.2% of the patients had morning stiffness (> 30 min). 49.7% of the cases had positive rheumatoid factor, 19.2% had a negative RF and 31.1% had none reported. In 2% ESR was measured. X ray erosions were reported in 6.6% of cases. When using the ACR criteria, 17.8% of patients had 1, 28.7% had 2 and 53.5% had 3 or more criteria. In only 59 cases (20%) did the rheumatologist agree with the referral diagnosis of RA. CONCLUSIONS: 80% of PCP referrals of RA to the rheumatologist were another disease. A poor clinical evaluation and little support from laboratory and x-rays was noticed. The delay in diagnosis and referral was 3 years, worsening prognosis. A vigorous effort in educating PCP is needed to achieve early diagnosis and referral of RA cases. PMID- 21794336 TI - [Clinical activity in outpatient rheumatology clinics in Galicia (Spain)]. AB - OBJECTIVES: To analyze patients attending rheumatology units of the public health service in Galicia (Spain). PATIENTS AND METHODS: We performed a multicenter study. Outpatients from all rheumatology clinics of the Galician health service were included over a 1-week period. RESULTS: A total of 1,357 outpatients were studied (422 new patients and 935 follow-up patients). The mean ages were 55.1+/ 15.6 and 56.9 +/- 16.7 years, respectively. Among new patients, 22.5% had inflammatory disease, and 77.5% had noninflammatory disorders. The main source of patient referral was primary care. The overall kappa index in the analysis of agreement between the diagnosis of the referring physician and that of the rheumatologist was 0.8 (95% CI: 0.73-0.86). Agreement was appreciably lower in the group with inflammatory diseases. Among follow-up patients, those with a diagnosis of inflammatory disorders represented 63.4% of the total. This group showed a higher score in the HAQ test and had a greater frequency of patients with permanent work disability. Overall, patients with inflammatory disease required longer consultations than the remaining patients, and their discharge rate was considerably lower. CONCLUSIONS: In rheumatology outpatient clinics, patients with inflammatory diseases are more numerous, spend longer in consultations, have greater disability, are more likely to show permanent work disability, and tend to accumulate with the passage of time. Agreement was high in the diagnosis of noninflammatory diseases, contrasting with the high referral rate. PMID- 21794337 TI - [Mycophenolate mofetil in lupus nephritis refractory to intravenous cyclophosphamide]. AB - OBJECTIVE: To evaluate the use of mycophenolate mofetil (MMF) in lupus nephritis (LN) patients with prior failure to intravenous cyclophosphamide over a 12-month follow-up. PATIENTS AND METHODS: Eleven patients with LN were included. MMF doses ranged from 1.5-2 grams per day. In all patients, 24-h urinary protein excretion, creatinine clearance, and serum creatinine were evaluated. Treatment-related adverse effects were recorded over the 12-month follow-up. RESULTS: Basal proteinuria decreased from 1.63 g/L (95% CI: 0.78-2.5) to 0.93 (95% CI: 0.1-1.62) g/L at the end of the follow-up period (p = 0.04). Creatinine clearance showed a tendency to improve but no statistically significant differences were found, 69.2 (95% CI 51.4- 87.4) vs. 79.29 (IC 95% 49.2-109.3) ml/min, respectively; p = 0.90). No significant differences were found in the remaining variables. Patients without response to MMF had a higher chronicity index than those with good or average response. CONCLUSION: MMF doses of 1.5-2 grams per day are a good alternative in LN patients without response to intravenous cyclophosphamide and a low chronicity index. No severe adverse effects were found. PMID- 21794338 TI - [Considerations on alterations in brain activity in patients with fibromyalgia]. AB - Fibromyalgia is a chronic musculoskeletal pain disorder of unknown etiology, characterized by widespread pain. Clinical and experimental research has demonstrated that patients with fibromyalgia may have enhanced pain sensitivity at several points of the body, together with neuroendocrine abnormalities, and abnormal activation of pain-related brain regions. Recent data have also shown that affective and cognitive processing of pain-related information could also be disturbed in fibromyalgia. In our opinion, all these findings suggest the existence of abnormal central pain processing, which could be responsible for the persistence of chronic pain in these patients. PMID- 21794339 TI - [Upper gastrointestinal events associated with nonsteroidal anti-inflammatory drugs usage. An unsolved problem]. AB - Before nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated, risk factors such as age, the use of other drugs potentially harmful to the gastrointestinal tract, smoking, and concomitant use of aspirin should be evaluated, to select the most appropriate option for each patient and determine the need for gastroprotective therapy. Because of the possibility of cardiovascular risk posed by COX-2 selective NSAIDs, cardiovascular risk factors should also be analyzed in each patient before starting treatment of this type, mainly bearing in mind that the protective effect of COX-2 selective NSAIDs is substantially reduced in patients taking aspirin. PMID- 21794340 TI - [Not Available]. PMID- 21794341 TI - [Stevens-Johnson syndrome due to prednisone in a patient with systemic lupus erythematosus]. AB - Stevens-Johnson syndrome is a systemic, mucocutaneous disease, frequently related to drugs. We present the case of a 35-year old patient with a diagnosis of systemic lupus erythematous treated with prednisone who developed a Stevens Johnson syndrome and was treated with methylprednisolone. PMID- 21794342 TI - [Not Available]. PMID- 21794343 TI - [Not Available]. PMID- 21794344 TI - [Evaluation of patients with fibromyalgia. Comparative study of 4 Spanish versions of the Fibromyalgia Impact Questionnaire (FIQ)]. AB - OBJECTIVE: To describe and compare the process of transcultural adaptation in the 4 validated Spanish versions of the Fibromyalgia Impact Questionnaire (FIQ). MATERIAL AND METHODS: a) Questionnaires. The first version (FIQ1) appeared as a doctoral thesis in 1988; the second (FIQ2) was published in a Spanish psychology journal; the third (FIQ3) was published in an English language journal; and the last (FIQ4) appeared in November 2004 in the Revista Espanola de Reumatologia. b) Methods In each of the versions the following were assessed: 1) the semantic equivalence with respect to the original FIQ, 2) each version's degree of development following a standardized method based on the GRAQoL Index (GI), and 3) the impact of publication. RESULTS: The FIQ4 showed a greater semantic equivalency. The degree of development shown by the GI produced the following results: FIQ1, 56%; FIQ2, 50%; FIQ3, 75%; FIQ4, 31%. Only the FIQ3 results were published in Medline-indexed journals. CONCLUSION: The Spanish FIQ3 version presents a greater degree of development and an acceptable semantic equivalency with respect to the original, and has achieved a greater impact. PMID- 21794345 TI - [Pattern of serum cytokines in patients with rheumatoid artritis according to PPD reactivity]. AB - INTRODUCTION: We demonstrated, in a recently published study, far more PPD negative reactivity among patients who had RA (70%) than among controls (30%). To evaluate the hypothesis that different response to PPD in RA patients is associated with different profiles of serum cytokines, we compared the serum levels of IL-2, IL-4, IL-6, IL-10, TNF alpha and IFN gamma from PPD negative and PPD positive RA patients. We also evaluated any correlations between serum cytokines and RA activity. MATERIAL AND METHODS: Forty RA patients and 21 controls were enrolled. Those with an induration < 5mm were considered as negative and those with >= 5mm as positive PPD. Disease activity was calculated using DAS28. Plasma levels of cytokines were determined using the multiplex BD TM Cytometric Bead Array Kit Assay. RESULTS: Of the RA patients, 27 (67.5%) had negative reaction to PPD and 13 (32.5%) a positive reaction to PPD. There was no statistical difference in sex profile, age or activity index between both negative and positive PPD RA patients. There was no significant difference in all the cytokines measured between PPD positive and PPD negative RA patients. Index activity show a positive correlation with IFN gamma (r = 0.433; p = 0.005) and IL 6 (r = 0.325; p = 0.041) in RA patients. CONCLUSIONS: Positive and negative tuberculin RA patients seem to show a similar cytokine serum profile. PMID- 21794346 TI - [Complete auriculoventricular blockage in adult patients with systemic lupus erythematosus. Case series and a review of the literature]. AB - BACKGROUND AND OBJECTIVE: Congenital complete atrioventricular heart block (CHB) is due to the lesion of the cardiac conduction system by specific transplacental antibodies of maternal origin. In adults with systemic lupus erythematosus (SLE), cardiac toxicity is very questionable and has been related to treatment with synthetic antimalarial drugs (AM). Here we evaluate, in our geographic area, the presence of non congenital CHB in adult patients with SLE and its possible association with AM treatment. PATIENTS AND METHODS: The frequency of CHB has been studied revising the clinical records of 595 SLE patients followed at the Unit for Systemic Diseases. RESULTS: Five women (0.8% of the total series) suffered from CHB (2 patients developed it during a lupic crisis). All were on treatment with AM (100 versus 60% of the rest of the series) and maintained a dose of 250 mg/day (except one, with a dose of 500 mg/day) for a mean period of 90 months. The accumulated mean dose of AM was 753 g. Three patients developed cardiac insufficiency; 2 nephropathy; 2 myopathy; and one maculopathy. As accompanying processes we detected Sjogren's syndrome (2) and hypothyroidism (3). The frequency of HLA DR3, positive in 80% of the cases, is higher than observed in the total series, 34% (p = 0.053). CONCLUSIONS: We detected the presence of CHB in 0.8% of SLE patients. They were all treated with AM. We did not verify any relationship with anti-ENA (anti-Ro/La and anti-RNP) antibodies, as communicated by others, but rather a trend to the association with HLA DR3 (at the limit of statistical significance). PMID- 21794347 TI - [Quality of life in osteomuscular chronic pain]. AB - BACKGROUND AND OBJECTIVE: To value the quality of life of the patients with osteomuscular chronic pain users of two Primary Care Centres, by means of the application of questionnaire COOP-WONCA adapted to the Spanish during the second semester of 2003 and first of 2004. MATERIAL AND METHODS: Cross-sectional observational descriptive design. Systematic random sample. 320 users of the Health Centres of Puerto de Sagunto (Valencia) and Alto Palancia (Castellon) that suffer chronic pain of osteomuscular origin. Collection of data from the application of Questionnaire COOP-WONCA adapted to Spanish. RESULTS: The subjective perception of health of the great majority of our population is regular or bad. Greater deterioration of the physical state than of the mental one. Badly pharmacologic control of pain. CONCLUSIONS: The musculoskeletal chronic pain has a noticeable repercussion on the quality of life. PMID- 21794348 TI - [Biologic therapy and infections]. AB - Biologic therapy is an important therapeutic arsenal in rheumatic diseases. Anti TNF therapies affect host defenses against infections, since TNF mediates inflammation and modulates cellular immune responses. Cases of tuberculosis have been observed in patients treated with TNF antagonists, mainly due to the presence of latent or "dormant" tuberculosis infection (LTB1). Other microorganisms responsible for the infectious complications associated with biologic therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic latent state: Mycobacterium sp., Listeria monocytogenes, Legionella sp., Brucella sp., toxoplasmosis and deep mycoses, that are normally held in control by cell-mediated immunity. Diagnosis may require a high index of suspicion and prompt acquisition of appropriate tissue samples for microscopic examination and microbiologic culture. Patients who develop a new infection while undergoing treatment with biologic therapy should be monitored closely. Administration of anti-TNF should be discontinued if a patient develops a serious infection or sepsis. The relationship between TNF-inhibition and infection risk remains unclear, many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to severe rheumatic diseases, could predispose them to infections, and most reports present low level of evidence. Nevertheless, prompt diagnosis and empiric therapy infections is necessary to prevent mortality. PMID- 21794349 TI - [Immunosuppresive treatment in patients with lupus glomerulonephritis. Review of adverse events]. AB - The prognosis of lupus nephritis has improved significantly over the past few decades. This has been partly contributed to by a better understanding of the natural history of the disease, improved treatment regimens, and the use of adjunctive treatments. Despite the development of new modalities, cyclophosphamide (CYC) remains the preferred initial treatment for severe proliferative lupus nephritis. Controversies continue about the best route, dosage, and duration of CYC treatment. However, adverse events as major infections, neoplasia and permanent amenorrhea, remain as a great concern for physicians and patients. For recalcitrant disease, new immunosuppresive and immunomodulating agents, nucleoside analogues and the biological response modifiers can be considered. New treatments directed against more specific targets may theoretically be associated with higher efficacy and lower toxicity. Longterm studies are needed with new treatments to verify this assumed lower toxicity. PMID- 21794350 TI - [Not Available]. PMID- 21794351 TI - [Septic pseudopodagra by Streptococcus agalactiae]. AB - Pseudopodagra is an unusual cause of first metatarsophalangeal arthritis. There are multiple causes, and an infectious cause always has to be excluded. We report a septic pseudopodagra by Streptococcus agalactiae in a patient with chronic hepatopathy with an indolent evolution and a consequent delay in diagnosis. Antibiotic treatment was installed with a favourable outcome without functional sequelae. The pseudopodagra reports in the bibliography are reviewed with special attention on those of infectious aetiology. PMID- 21794352 TI - [Spondylodiskitis caused by enterococcus: an unusual entity. A case report and literature review]. AB - Spondylodiskitis caused by enterococcus is an entity anecdoticaly described in medical literature. We report a case of lumbar spondylodiskitis caused by enterococcus faecalis of urinary origin in a male patient after being operated because of prostate benign hyperplasia. Clinical, radiologic and evolutive features were revised. Through a bibliographical search 9 cases have been found in medical literature, although 2 of them were included in etiologic series of infectious spondylodiskitis with no more information. Together with our case we describe briefly the published characteristics of the 7 patients. PMID- 21794353 TI - [Not Available]. PMID- 21794354 TI - [Not Available]. PMID- 21794355 TI - [Not Available]. PMID- 21794356 TI - [Not Available]. PMID- 21794357 TI - [Not Available]. PMID- 21794358 TI - [Not Available]. PMID- 21794359 TI - [Not Available]. PMID- 21794360 TI - [Not Available]. PMID- 21794361 TI - [Not Available]. PMID- 21794362 TI - [Not Available]. PMID- 21794363 TI - [Not Available]. PMID- 21794364 TI - [Not Available]. PMID- 21794365 TI - [Not Available]. PMID- 21794366 TI - [Not Available]. PMID- 21794367 TI - [Not Available]. PMID- 21794368 TI - Recent evidence for the achievement of remission in rheumatoid arthritis through early aggressive therapy. PMID- 21794369 TI - [Not Available]. PMID- 21794370 TI - [Not Available]. PMID- 21794371 TI - [Not Available]. PMID- 21794372 TI - [Not Available]. PMID- 21794373 TI - [Not Available]. PMID- 21794374 TI - [Not Available]. PMID- 21794375 TI - [Not Available]. PMID- 21794376 TI - [Not Available]. PMID- 21794378 TI - [Not Available]. PMID- 21794377 TI - [Not Available]. PMID- 21794379 TI - [Not Available]. PMID- 21794380 TI - [Raynaud's phenomenon]. AB - Raynaud's phenomenon is characterized by repeated daily attacks of ischemia followed by reperfusion at the acrallevel. It is a frequent syndrome found in medical practice; and it can be considered as primary or secondary to other conditions, including rheumatic autoimmune diseases. Current classification had clinical and therapeutic implications. Careful clinical evaluation is the most reliable and reproducible method in the diagnosis of Raynaud's phenomenon. Several risk factors had been associated in the genesis of Raynaud's phenomenon; however, its pathogenesis remains elusive although recently, considerable progress in disease mechanism had been described. Such advances are directing new lines of therapy. PMID- 21794381 TI - [Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension]. AB - Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension Lung disease is present in most of the patients with systemic sclerosis and is now the most important cause of mortality. Interstitial lung disease and pulmonary hypertension are, so far, the main disorders found and both are difficult to detect at the earliest stages. However, diagnostic tools such as immunological test, lung function test, high resolution CT, bronchoalveolar lavage, echocardiography, right-side cardiac catheterization, or lung biopsy are necessary to accurately evaluate the clinical status and allow to improve the management organ-specific ad hoc. Progress in immunological and vascular therapies as well as other emergence drugs offer new expectations to scleroderma patients. PMID- 21794382 TI - [Epidemiology. Ethnic differences in systemic sclerosis]. AB - To review the differences in the epidemiology, clinical manifestations, and severity of systemic sclerosis in different ethnic groups. This review considers only limited and diffuse forms of systemic sclerosis. The most relevant articles about ethnic differences in systemic sclerosis were selected. The information is presented in three sections: differences in the epidemiology of systemic sclerosis between ethnic groups; differences in clinical manifestations between ethnic group, and factors that may explain these differences. Of the different ethnic groups studied, whites have less incidence and prevalence of systemic sclerosis. Whites also have less frequency of inflammatory manifestations, and have a higher frequency of limited skin disease compared with other ethnic groups. These differences may result in the better survival of whites compared with no whites. The origin of these differences has not been discovered so far. Is probable that genetic and environmental factors may play a role in the expression of disease, producing the differences found among the ethnic groups. PMID- 21794383 TI - [Renal involvement in systemic sclerosis]. AB - Renal crisis is one of the most severe complications of systemic sclerosis, and its frequency is 10%, and it is characterized by malignant hypertension, hyperreninemia, azotemia, microangiopathic hemolytic anemia, and renal failure. In the pathogenesis of renal affection, the main mechanism is the endothelial damage (thickness of arterial vessels), decrease of blood flow and hyperplasia of the yuxtaglomerular apparatus as well as release of renina. Pathological changes of scleroderma kidney are similar to those observed in other forms of malignant hypertension. Renal crisis was considered as fatal complications, however it is now successfully treated with angiotensin- converting enzyme inhibitors. PMID- 21794384 TI - [Systemic sclerosis and the gastrointestinal tract. Diagnostic and therapeutic approach]. AB - In systemic sclerosis esophagus is affected in 90% followed by anal and rectal involvement (50-70%), stomach (40-70%), colon (10-50%) and small bowel (40%). The main clinical findings are esophagic: dysphagia and sign of gastroesophageal reflux and its complications. Gastric symptomatology is a consequence of gastroparesis (postprandial fullness, nausea). Intestinal affection produces hypomotility (abdominal distention, deficient intestinal absorption, bacterial overgrowth). In colon there are diverticula, intestinal constipation, and fecal incontinence. For the diagnosis of GIT involvement the following are useful: studies of digestive tract with contrast media, endoscopy of upper GIT; gastric emptying; pH metry; esophageal and rectal manometry, as well as test to investigate deficient intestinal absorption syndrome. The prokinetic are a cornerstone for the treatment of hypomotility of GIT, along with pump proton inhibitors for the esophageal alteration and antibiotics for bacterial overgrowth. PMID- 21794385 TI - [Cardiac involvement in systemic sclerosis]. AB - Systemic sclerosis (SS) can involve the pericardium, myocardium, conduction system, and cardiac valves. The presence of overt clinical signs of cardiac disease is a poor prognostic sign. Clinical manifestations include dyspnea, palpitations, chest pain, syncope, and symptoms of right heart failure. Prevalence of clinically symptomatic pericardial disease is 5-16%. However, ecocardiographic prevalence is 5.4- 41% and at autopsy is 33-77.5%. Patchy fibrosis is the characteristic myocardial finding in SS. Contraction band necrosis is the typical pathological finding. Important complications of fibrosis include left ventricular hypertrophy, as well as systolic and diastolic dysfunction of both ventricles. Early detection of these abnormalities is very important, mainly of the diastolic dysfunction, since it occurs before the systolic dysfunction and can predict important cardiac damage. Association of skeletal myositis with myocardial disease has been described. Patients with skeletal myositis are more likely to develop congestive heart failure, sustained symptomatic arrythmias, and cardiac sudden death. Coronary arteries are normal in systemic sclerosis, but there is no endomyocardial vessel involvement. There is an increased prevalence of arrhytmias, mainly premature atrial and ventricular contractions, as well as conduction system disease. Cardiac valvular involvement is minor in systemic sclerosis; mitral valve is the most frequently affected. Other abnormalities described in this disease include peripheral large vessels stiffness and secondary cardiac involvement due to pulmonary and systemic arterial hypertension. Cardiac involvement confers a high morbi-mortality risk in systemic sclerosis. PMID- 21794386 TI - [Endocrinological alterations in systemic sclerosis]. AB - In systemic sclerosis, the frequency of thyroid derangements (clinical and subclinical hypothyroidism) is 43 and 73% respectively; in its pathogenesis participate structural, autoimmune and genetic mechanisms. It is important to run thyroid function test and to investigate the manifestation of clinical and subclinical hypothyroidism and to initiate treatment with levothyroxine. The frequency of hyperprolactinemia in SS goes from 13 to 59% and the implied mechanisms are the hypothalamic dysfunction and prolactinomas. The frequency of prolactinomas runs up to 66%. The frequency of osteopenia and osteoporosis is from 3 to 35 and from 35 to 44% respectively. The osteoporosis in escleroderma is multifactorial (ischemia, immobilization, intestinal malabsorption syndrome, steroids, menopause, hyperprolactinemia, among other). It is important to erform bone densitometry in these patients and to identify the cases of osteoporosis and to start opportune treatment. PMID- 21794387 TI - [Treatment of systemic sclerosis]. AB - Treatment of systemic sclerosis is based upon 3 types of medications modifiers of disease: drugs which prevent vascular damage, antifibrotric agents, and immunomodulators and immunosupressors. Drugs that prevent vascular damage such as: calcium antagonists, prostaglandins analogues, receptors of endothelin blockers (bosentan), inhibitors of angiotensin converting enzyme, receptors of angiotensin antagonists and inhibitors of 5'-phosphodiesterase have been successful in treating the Raynaud's phenomenon, renal crisis and pulmonary arterial hypertension. In contrast, the results of treatment of fibrosis are discouraging and the D-penicilamine continues being a matter of controversy. The immunosupressor therapy with cyclophosphamide and the transplant of hematopoietic cells, may be beneficial. The knowledge of the pathogenesis of systemic sclerosis to molecular level will lead to new treatment strategies. PMID- 21794388 TI - [Etiopathogenesis. New concepts]. AB - Systemic sclerosis is a complex, progressive autoimmune disease. The origin is, so far, unknown and it is characterized by immunological and endothelial damage followed by fibrosis. Interaction between the host genetic backgrounds with environmental factors is thought to turn out an abnormal immune response characterized by clonal expansion of Th2 repertoire, upregulation of pro-fibrotic cytokines and dysregulated B cells. Specific autoantibodies profiles are associated with clinical subtypes of the diseases. Endothelial activation is an early feature with damage of the vasocontrictive and vasodilation response. Finally, persistent tissue ischemia and abnormal immune response produce myofibroblast proliferation andoverproduction of extracellular matrix proteins and fibrosis. PMID- 21794389 TI - [Not Available]. PMID- 21794390 TI - [Spanish Registry for Adverse Events of Biological Therapy in Rheumatic Diseases (BIOBADASER): state report, January 26 th, 2006]. AB - OBJECTIVE: BIOBADASER is a prospective registry of rheumatic patients treated with biological therapies, which aim is the analysis of long-term survival and safety of these agents. PATIENTS AND METHODS: As of January 26(th) 2006, 6,969 patients from 100 centers were included in BIOBADASER. In total, 8,321 treatments with biological therapies have been registered. RESULTS: Treatment was discontinued in 2,351 (28%) occasions, mostly as a result of an adverse event (960;41%) or inefficacy (942;40%). A total of 2,503 adverse events were notified. Of these, the most frequent ones were infections (909;36%), followed by postinfusion reactions (500;20%), skin lesions (255;10%) and cardiovascular events (165;7%). CONCLUSIONS: The analysis reassures us in the increased rate of infections with biological therapies. Neither the rates of neoplasm nor of cardiac failure are significantly increased with these therapies. Specific measures have proved useful in preventing the occurrence of defined events. PMID- 21794391 TI - [Proposal for a consensus version of the Fibromyalgia Impact Questionnaire (FIQ) for the Spanish population]. AB - OBJECTIVE: To obtain an updated FIQ consensus version for patients in Spain, the Cuestionario de Impacto de la Fibromialgia (CIF). MATERIAL AND METHODS: The CIF elaboration was carried out with the participation of all the groups of researchers in the 4 previous FIQ Spanish versions, and taking into account the recent updated version of the original FIQ. The CIF was completed by a sample of fibromialgia patients to explore how comprensible its items are and to compare its global score with 2 fibromialgia composite severity indexes, one semi objective and one subjective. The corresponding Spearman correlation coefficients were determined RESULTS: The main modifications introduced in the questionnaire are shown. Some patients were confused in their responses to subitem "j" and item 3, but not with regard to the remaining items or subitems. Correlation coeficients between the CIF and the semi-objective and subjective fibromialgia severity indexes were 0.57 and 0.76 respectively (P<001). CONCLUSION: The CIF is proposed as an updated Spanish version of the FIQ. PMID- 21794392 TI - [Influence of non-complicated urinary tract infection on renal relapses in proliferative lupus nephritis]. AB - OBJECTIVE: In patients with proliferative lupus nephritis treated with IV cyclophosphamide, analyze urinary tract infection (UTI) as a cause of treatment delay and renal relapses, compared with lupus nephritis patients without infection. PATIENTS AND METHODS: We studied SLE patients (ACR criteria) with renal biopsy showing nephritis class IV. All patients received monthly intravenous cyclophosphamide (CYC) treatment during 6 months. Thereafter patients were assigned to 2 groups: patients who developed UTI, and those who did not; renal function tests, UTI and renal relapses were bimonthly evaluated during one year (follow-up period). To analyze data, t student test, chi(2), Fisher exact (when appropiate), and bivariate analysis, were performed. RESULTS: We studied 50 patients, 25 with UTI (Group I) and 25 without UTI (G-II).The mean age was 30.07 +/- 8.15 years, 82% were female. E. coli was the pathogen most frequently isolated (73%). UTI (G-I) was the cause for treatment delay in 19 cases (76%), compared with 3 patients (12%) in G-II whose treatment was delayed because of some other causes (severe leucopenya, hypersensibility and gastrointestinal side effects) (OR 23.22, 95% CI, 5.26-105.1; P=001). During the follow up, 90.9% of patients in G-I reached partial or complete renal remission within 3 months, but only 35% mantained remission after the year of follow up. Meanwhile, patients in G-II had complet and partial renal remission of 85% and 63%, respectively. In the first group we observed persistent albuminuria (P<05), low complement levels and high ab-dsDNA titers. Renal flares were present in 18 patients in G-I and 9 in G II. CONCLUSIONS: UTI in lupus nephritis patients has a negative impact. It leads to delayed CYC therapy and to a higher renal flare rate. PMID- 21794393 TI - [The fibromyalgia treatment with physical exercise in warm water reduces the impact of the disease on female patients' physical and mental health]. AB - INTRODUCTION: Fibromyalgia (FM) patients present pain, muscle stiffness, reduced physical condition and fatigue that limit their daily life activities. The purpose of this study was to evaluate the effects of the addition of 12 weeks of physical exercise in warm water to usual medical care on the impact of FM on physical and mental health in female patients. PATIENTS, MATERIALS AND METHODS: Thirty four physically untrained females with FM were randomly assigned into two groups: an experimental group (n=17), to perform 3 weekly sessions for 60 minutes of physical exercise in warm water; and control group (n=17), who did not receive the additional treatment. The impact of the FM on patients' physical and mental health was assessed using the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: After 12 weeks of physical exercise, the experimental group showed improvements compared to the control group in physical function (35%, P=0.016), feel good (34%, P=0.003), job ability (14%, P=0.046), pain (26%, P=0.030), stiffness (33%, P=0.038), anxiety (36%, P=0.044), depression (26%, P=0.046), and FIQ total scores (27%, P=0.004). CONCLUSIONS: The addition of the aquatic physical exercise programme to usual care was effective to decrease the impact of the disease on physical and mental health. However, the placebo effect could have contributed to this effectiveness. PMID- 21794394 TI - [How do we evaluate an inadequate response in a patient with rheumaoid arthritis in the clinical praxis P?]. AB - Rheumatoid arthritis (RA) is a chronic disease that particularly affects the joints, causing their destruction, changes in its functional capacity and considerably compromising the quality of life. It is known that early treatment can reduce structural damage and improve the disability in the long term, but the optimal therapeutic strategies are still not universally accepted. As with diabetes and hypertension, strict control of the disease is required, with the objective of achieving no disease activity, which may be seen as a remission, or if this is not possible, to keep the inflammatory activity as low as possible so that the unfavourable consequences, such as the articular damage process and the risks that the patients assume deriving from treatment, do not occur. The improvement criteria of the American College of Rheumatology (ACR) are useful for comparing the efficacy of treatment in clinical trials, but they must not be used as a therapeutic objective, since they do not evaluate the final activity, which can be as important as having an improvement. To evaluate the response, the most logical and convenient for the doctor is to use the same tools that are used to evaluate the activity of the disease in clinical practice, such as the DAS and SDAI activity scores. Some limits which separate the different levels of activity have been proposed to improve their interpretation and establish therapeutic objectives. The categorisation into classes according to activity is important for starting or changing treatment (when it is moderate or high) and to define stages of conceptually different activity (activity or remission). The cut-off points that separate these categories were proposed years ago when the therapeutic possibilities of RA were limited and their long term consequences were not known. The therapeutic objective of remission or lower activity is much easier to achieve these days, therefore the therapeutic categories need to be reconsidered and the definition of lower activity levels as a potential objective. Nowadays, to assume moderate or high activity as a result of treatment is unacceptable, particularly when our therapeutic arsenal is already considerable and strategies and therapeutic combinations have been proposed which have demonstrated higher efficacy with tolerable risks. Although changes happen gradually in all aspects of life, there is no reason not to accept remission of RA as not only a desirable objective, but also an achievable one. PMID- 21794395 TI - [Relapsing polychondritis associated with a lymphoplasmocytic lymphoma and erythema nodosum]. AB - Relapsing polychondritis is a disease of unknown etiology characterized by episodic inflammation of cartilaginous tissues. More rarely, it has been described as a paraneoplastic phenomenon mainly associated with myelodysplastic syndromes or other haematologic diseases. We present a case of relapsing polychondritis associated to low degree lymphoplasmocytic lymphoma whose picture was punctuated by cutaneous erythema nodosum and anterior uveitis. The clinical evolution was satisfactory with glucocorticoids and rituximab treatment. PMID- 21794396 TI - [Not Available]. PMID- 21794397 TI - [Not Available]. PMID- 21794398 TI - [Not Available]. PMID- 21794399 TI - [A bibliometric approach to research into fibromyalgia]. AB - OBJECTIVES: To obtain a general and updated vision of research into fibromyalgia for its better understanding. A productivity analysis (by year and author) and a content analysis (by journal and topic) was carried out. METHODOLOGY: The computer databases of the Web of Knowledge: Science Citation Index Expanded (SCIEXPANDED) and Social Sciences Citation Index (SSCI) of the Web of Science were used. For the exploration of the topics a content analysis was done on a sample of 356 articles, obtained using a simple randomized procedure based on a random number table (risk alpha=0.05; z(alpha)=1.96~2; p=q=0.5) with a sample error of 5%, with the purpose of reaching some general conclusions in the study of this topic area. RESULTS AND CONCLUSIONS: Overall, 3,201 article references have been obtained. In the years 1998 to 2003 the production of scientific articles increased considerably (43.5%) in comparison to the previous period, from 1992 to 1997 (27.4%). In the past decade (1996-2005) the production of articles tripled with respect to the first fifteen years (1980-1995). There is an overall 306 different journals that publish on this subject. The topic area that received most attention has been the study of the physiopathologic mechanisms (31.01%). There is an increment in the articles of psychiatry and psycology in the last few years. PMID- 21794400 TI - [Evaluation of two proposals based on clinical factors for selecting what male patients with rheumatoid arthritis should undergo a bone densitometry]. AB - Criteria based on age, inflammation, and immobility have been proposed to identify which patients with rheumatoid arthritis (RA) should be examined by dual energy X-ray absorptiometry (DXA) to diagnose osteoporosis. Recently, a modified version of the criteria by including weight and the use of corticosteroids has been proposed. These two set of criteria have not been tested in male patients in a clinical setting. OBJECTIVE: To analyse, in a group of patients followed in a teaching hospital, the value of two proposals to select men with RA for bone densitometry. PATIENTS AND METHOD: Clinical and demographic data were collected from the charts of a total of 65 men with RA, submitted to the bone densitometry unit during a fouryear period. Bone mineral density (BMD) was measured in spine and femoral neck by DXA. Two set of criteria were tested: a) three item criteria (age, inflammation and immobility), and b) five item criteria (age, inflammation, immobility, weight, and ever use of corticosteroids). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Thirty five (54%) patients fulfilled the three item criteria and 38 (59%) the five item criteria. For the diagnosis of osteoporosis using the three item criteria, the sensitivity was 62%, specificity 48%, PPV 23% and NPV 83%; using the 5 item criteria the sensitivity was 90%, specificity 47%, PPV 23%, and NPV 96%. CONCLUSIONS: The five item criteria are a more accurate tool to identify, in clinical practice, male patients with RA and osteoporosis than the three item criteria. It seems a good screening method for the selection of those patients with RA whose BMD should be assessed, as the sensitivity and NPV seem acceptable. PMID- 21794401 TI - [Factors related to temporal incapacity in patients with fibromyalgia]. AB - OBJECTIVE: To know the sociodemographic, clinical and working conditions characteristics related with temporary disability (TWD) in patients with fibromyalgia syndrome (FS). PATIENTS AND METHOD: Patients diagnosed with FS who met the American College of Rheumatology's criteria, attending an outpatient clinic for at least three months prior were included. We performed a standard clinical protocol with sociodemographic, clinical and working conditions, dates and number of TWD during the last year. All patients were asked to complete a questionnaire with 40 items [Fibromyalgia impact questionnaire (FIQ) inclusive]. RESULTS: The participants were 51 women with FS, 32 of whom needed one or more TWD during the last year. The mean TWD was 83.73 days (DS 98). There was not a statistically significant relationship between the TWD and sociodemographic characteristics in a bivariate analysis. There is a significant trend with hard physical work and with the presence of triggering factors. There was evidence of a significant statistical relationship between TWD with a lack of response to selective serotonin re-uptake inhibitors (SSRIs). We noticed that the highest marks in the FIQ have a direct relationship with patients in a TWD situation. CONCLUSIONS: The lack of response to SSRIs was related with TWD process. The patients in TWD situation scored the highest FIQ. There is a trend towards an increase in the TWD with jobs that required physical effort. PMID- 21794402 TI - [Transverse myelitis in systemic lupus erythematosus]. AB - OBJECTIVE: Transverse myelitis (TM) is a rare complication in patients with systemic lupus erithematosus (SLE). We reviewed a series of our SLE patients to determine the prevalence of TM, and evaluate the clinical characteristics, medical tests, evolution and response to the treatment. PATIENTS AND METHOD: Six patients with TM were identified and underwent a neurological evaluation, MRI, electrophysiologic study and were all subjected to the same treatment. A descriptive statistical study was conducted. RESULTS: We observed a prevalence of 0.92% in our patients with SLE. Eighty three point three per cert had antiphospholipid antibodies and/or lupus anticoagulant. The MRI confirmed the diagnosis in 5 cases. Of the 5 patients with antiphospholypid antibodies, 3 were anticoagulated or took aspirin with a good neurological outcome, leaving 2 of them without posterior complications. CONCLUSIONS: We found a prevalence similar to that observed in other series, around 1%. The high prevalence of antiphospholypid antibodies in these patients, with good outcome in those anticoagulated or treated with antiplatelet agents suggests an important pathogenic role in the development of TM, and emphasized the possibility of adding to the standard treatment, antiplatelet agents or anticoagulation. PMID- 21794403 TI - [Osteonecrosis. What is new?]. AB - Osteonecrosis, also known as aseptic necrosis, is a pathological process that has been associated with numerous conditions. The pathogenesis of osteonecrosis and especially the treatment both remain an area of controversy. In this article we review the etiology and pathogenesis of osteonecrosis as well as the main therapeutic options. PMID- 21794404 TI - [Not Available]. PMID- 21794405 TI - [An infrequent presentation of SAPHO syndrome]. AB - We describe a case of SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) with an unusual presentation in a 14 year-old girl with low grade fever which lasts 8 months, left low back pain and elevated erythrocyte sedimentation rates and protein C-reactive with chronic anaemia. A radiograhy of the lower limbs showed a lytic image with osteitis and hyperostose in the right fibula, as a casual finding. This information, in addition to the acne, pustulosis, sternoclavicular arthritis and the studies got from the magnetic resonance image (MR) of spine, pointed out the diagnosis of SAPHO. PMID- 21794406 TI - [Not Available]. PMID- 21794407 TI - [Not Available]. PMID- 21794408 TI - [Not Available]. PMID- 21794409 TI - [Not Available]. PMID- 21794410 TI - [Diagnostic accuracy of physical examination of the knee in rheumatoid arthritis: clinical and ultrasonographic study of joint effusion and BakerOs cyst]. AB - INTRODUCTION: In patients with rheumatoid arthritis (RA), knee pain can be inflammatory, mechanical or extraarticular. The physical examination (PE) doesn't always detect the presence of knee joint effusion or Baker's cyst (BC) in the knees of these patients. OBJECTIVE: To determine the diagnostic accuracy of PE in the diagnosis of effusion and BC in patients with RA evaluated with musculoskeletal ultrasound (MSUS), using this technique as the gold standard for comparison. MATERIAL AND METHOD: Three different models of ultrasound machines with a 7.5 MHz linear probe were used (Toshiba Tosbee, Toshiba Capasee and Siemens Sonoline). A rheumatologist evaluated the presence or absence of knee joint effusion or BC in patients. We registered age, gender, time of evolution of RA, rheumatoid factor, treatment, functional class of RA (FCRA) and previous clinical diagnosis to the MSUS study. RESULTS: 40 patients (80 knees) with RA were evaluated. Eighty percent were women, mean age 61.3+/-15 years. Time since onset of RA was 9.5+/-11.3 years, rheumatoid factor was positive in 80%, FCRA I (3 patients), FCRA II (27), FCRA III (8), FCRA IV (2). Fifty five percent of the patients received methotrexate. Patients reffered pain in 26 knees (32.5%). Joint effusion was reported by the clinician in 35 knees (43.7%) and corroborated by MSUS in 31 knees (38.75%), BC was reported by the clinician in 12 knees (15%) and corroborated by MSUS in 6 knees (7.5%). The sensitivity of the PE for detection of joint effusion was 0.63 and specificity of 0.87, for the detection of BC was 0.43 and 0.91, respectively. CONCLUSIONS: The PE showed acceptable diagnostic accuracy for the clinician. The complementary use of the MSUS can change the therapeutic and diagnostic approach in patients with RA. PMID- 21794411 TI - [Cognition and perception deficits in fibromyalgia and rheumatoid arthritis]. AB - INTRODUCTION: Cognitive disturbance in patients with fibromyalgia and rheumatoid arthritis is today a topic of a great clinical interest, largely due to the fact that these persons often complain about cognitive problems. OBJECTIVE: This study is aimed to assess the visuospatial memory, attention and perceptive capacities in chronic pain patients. MATERIAL AND METHODS: Groups were constituted by fibromyalgia patients and rheumatoid arthritis patients, as well as a control group. All the subjects completed a battery of visual and spa-tial memory, speed of processing, working memory, attention, orientation and visuoperceptive abilities. A cognitive reserve measurement was obtained. RESULTS: Results show that chronic pain patients displayed worse cognitive performance than controls. Moreover, arthritis patients execute poorly when compared to the group of fibromyalgia in tasks that demand visuoperceptive integration and visuomotor processing. Patients suffering fibromyalgia obtained worse punctuations than those with arthritis in spatial memory and spatial orientation tasks. CONCLUSIONS: Both groups developed important cognitive deficits, which cannot be explained by the collateral effects of such pathologies, because cognitive profiles are not similar and appear from the beginning of the disease. PMID- 21794412 TI - [Clinical utility of specialized immunologic testing in rheumatology in a secondary level hospital in Mexico]. AB - INTRODUCTION: Laboratory tests have an important role in rheumatology for evaluation, diagnosis and follow up in several diseases. Specialized tests such as antinuclear antibodies (ANA), anti single or double stranded DNA antibodies (anti DNA) and anticardiolipin antibodies (AcACL) are frequently used and its diagnostic performance is well known in tertiary care centers. Our setting is a secondary care center that implemented these tests two years ago. After one year of implementation, we decided to evaluate the frequency of use, who orders these tests, and their diagnostic properties for the diagnosis of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APLS). PATIENST AND METHOD: All patients with clinical charts and a request for these tests were evaluated from September 1, 2005 to June 30, 2006. These evaluations were done prospectively by a single, trained evaluator following a standardized format looking at pretest clinical information such as pretest diagnosis, physician's level of training, service and posttest results as well as therapeutic changes after results. STATISTICAL ANALYSIS: descriptive statistics and 2 by 2 tables to estimate diagnostic performance of most common indications. RESULTS: Two hundred and eighty six requests were reviewed and only 157 were evaluated. Rheumatology and Internal Medicine services sent 63 and 31 requests for these tests respectively. Diagnostic properties of ANA for SLE were sensitivity (sen) 70%, specificity (spec): 92%, positive predictive value (PPV): 81%, negative predictive value (NPP): 86%, positive likelihood ratio (PLR): 8.73 and negative likelihood ratio (NLR): 0.33. Anti double stranded DNA Sen: 78%, spec: 50%, PPV: 80%, NPP: 46%, PLR: 1.56, NLR: 0.44. ACACL Sen: 78% spec: 92%, PPV: 78%, NPV 92%, PLR: 10, NLR 0.24. CONCLUSIONS: These specialized tests are not frequently used in our setting. Their diagnostic properties are not as accurate as those published in medical literature. Guidelines are needed in our hospital to improve their diagnostic performance. PMID- 21794413 TI - [Ying-Yang (YY-1) expression and Fas in biopsies of children with type IV lupus nephritis correlates with the clinical condition]. AB - BACKGROUND: It has been demonstrated that Fasmediated apoptosis participates in the physiopathology of lupus nephritis, although it is not clear whether it contributes to the development of the tissue damage.Since YY-1 down regulates Fas in cancer cell lines, it is reasonable to consider that this transcription factor may control Fas expression in lupus nephritis. The objective was to determine the correlation between YY-1 and Fas expression in renal biopsies from children with type IV lupus nephritis, and their association with the clinical condition of the patients. MATERIAL AND METHODS: Eighteen biopsies from children with type IV lupus nephritis and 5 controls were studied. Fas and YY-1 expression were determined by immunochemistry and quantified by densytometric analysis. The clinical conditions at the moment the biopsy were obtained from the clinical records and the results were analyzed through a one-way ANOVA with p<0.005. RESULTS: The results of the densytometric analysis showed an inverse relationship between YY-1 and Fas expression. YY-1 was grouped according to the intensity of expression in low, moderate and high and compared with the expression of Fas. The lupus nephritis biopsies, which revealed high expression of YY-1, corresponded to patients with less number of clinical complications,better outcome and fewer alterations on renal function.In contrast, low expression of YY-1 correlated with high Fas expression and worst clinical conditions. CONCLUSIONS: The present study suggests that YY-1regulates Fas expression in lupus nephritis and that it is associated with the clinical outcome of the patients,although further studies are necessary to determine weather it factor may serve as a prognosis factor. This is the first evidence of YY-1 participation in the physiopathology of lupus nephritis. PMID- 21794414 TI - [Magnetic resonance of the hand in rheumatoid arthritis. Review of methodology, and its use in diagnosis, monitoring and prognosis]. AB - The ideal aim of treatment in rheumatoid arthritis (RA) is to suppress synovial inflammation and to stop or reduce structural joint damage progression. To evaluate joint damage in RA, radiographic assessment of hands and feet is the traditional method. Nevertheless, plain film radiography can only evaluate bone damage (erosion) and, indirectly, joint cartilage. Magnetic resonance imaging presents important advantages since allows to study, not only the cortical bone and the marrow, but also the synovial membrane, tendon and ligament structures,and adjacent soft tissue that usually are involved in early disease. Moreover, hand-magnetic resonance (h-MRI) has shown to be more sensitive than plain radiography in detecting early erosions and predicting progression of bone damage, allowing a rapid diagnosis and to start the most efficient therapy as well as to achieve better outcomes for this disease. PMID- 21794415 TI - [Not Available]. PMID- 21794417 TI - [Not Available]. PMID- 21794416 TI - [Cystic lesion of the calcaneus. Intraosseous lipoma]. AB - We report two cases of intraosseous lipoma in the calcaneus of a 38 year old man, complaining about heel pain and a 27 year old woman with no pain. Plain radiographs showed a well-defined cystic lesion in the calcaneus with sclerotic margins. Computed tomography (CT) detected a well-defined, low-density lesion with attenuation values equal to adipose tissue. Magnetic resonance (MR) findings show similar signal intensity with subcutaneous adipose tissue on T1-weighted and T2-weighted images, and STIR-T2 imaging showing low signal intensity with complete suppression indicating the presence of normal fat. As a result, at first intraosseous lipomas could only be identified pathologically, but now it is easy to perform radiological diagnosis using MR. PMID- 21794418 TI - [Not Available]. PMID- 21794419 TI - [Not Available]. PMID- 21794420 TI - [Treatment of rheumatoid arthritis with anakinra: a systematic review]. AB - OBJECTIVE: To perform a systematic review for evaluating efficacy and safety of anakinra in the treatment of rheumatoid arthritis (RA). MATERIAL AND METHOD: The MedLine, Embase, and Cochrane Library databases were searched from January 2000 to February 2006 by using a high sensitive search that included every randomised controlled trial (RCTs) or controlled trial (CTs) that evaluated either efficacy or safety of Anakinra for the treatment of RA. RESULTS: The search identified four relevant studies to evaluate efficacy. Patients treated with anakinra achieved significantly better clinical responses than those treated with placebo. Anakinra combined with methotrexate provided significantly greater clinical benefit than methotrexate alone. Combination therapy with etanercept and anakinra provides no added benefit and an increased safety risk compared with etanercept alone. Results from a large, placebo-controlled safety study demonstrate that anakinra is safe and well tolerated. The most common adverse effect was a mild local inflammation over the puncture area. CONCLUSIONS: This review confirmed both the efficacy and the safety of anakinra in the short term for the treatment of RA. Anakinra provides adequate clinical responses without major safety problems. This systematic review does not allow us to conclude on Anakinra responses in the long term. PMID- 21794421 TI - [Plantar fascitis: evidence-based review of treatment]. AB - OBJECTIVE: To analyze the effectiveness of the interventions in the management of plantar fasciitis. MATERIAL AND METHOD: The main medical and biomedical databases have been used: MedLine, Evidence Based Medicine, Cochrane Database of Systematic Review, Cochrane Register of Controlled Trials, EMBASE and PEDRO (Physiotherapy Evidence Database). Meta-analysis, systematic reviews, reviews, and controlled or randomized clinical trials of interventions for heel pain have been selected. RESULTS: After an updated review of the treatment of plantar fascitis, we have found several therapy options to treat this problem, but their efficacy is variable, and none show strong evidence of benefit. The use of plantar insoles and stretching exercises focused on plantar fascia have demonstrated limited evidence of benefit. Corticosteroid injections and iontophoresis with steroids have also demonstrated evidence of benefit, although limited and during a short time. The rest of interventions have not demonstrated enough evidence of benefit. CONCLUSIONS: An evidence-based review of treatments of plantar fasciitis suggests that we must first recommend the use of conservative measures, easy to perform and of low cost, such as plantar soft insoles, plus specific stretching plantar fascia exercises. Limited evidence suggest that steroid injection or iontophoresis may be useful, but of transient effect, when conservative options fail. PMID- 21794422 TI - [Relapsing polychondritis: an analysis of 11 patients]. AB - OBJECTIVE: To analyze 11 patients with relapsing polychondritis reported by 3 hospitals in our country. PATIENTS AND METHOD: We describe 11 cases of relapsing polychondritis reported by 3 hospitals in our country, analizing gender, age at the beginning of the disease, delay time in diagnosis, clinical manifestations at the beginning of the disease and during follow-up, initial treatment, and treatment in the "chronic phase" of the disease. RESULTS: We described 8 female patients and 4 males, with a mean age of 40.8 years. The delay time in diagnosis was from 4 months to 4 years. The main manifestations were: auricular chondritis in 8 patients (72.7%), hearing loss in 4 (36.3%), and dysphonia in 4 (36.3%). The complications included subglotic stenosis in 4 patients (36.3%), epiescleritis in 2 (18.1%), 1 retinal and corneal dettachment with macular lesion (9%), conductive and sensorial hearing loss in 2 (18.1%), glomerulonephritis in 2 (18.1%), and mitral and tricuspid insufficiency in one patient (9.0%). All of them received prednisone. Cyclophosphamide, methotrexate, and azathioprine were the most common immunosupressors used. CONCLUSIONS: This is the largest cohort reported in our country, sharing clinical and outcome patterns reported in other series and in the literature. Response to steroids is good, however, we need to consider other therapeutic options because the disease continues progressing and relapsing. PMID- 21794423 TI - [Rapid application of infliximab. Efficacy and complications]. AB - OBJECTIVE: To compare the clinical safety of the rapid infusion of infliximab (30 45 min) with the traditional one (2 h). PATIENTS AND METHOD: Open, prospective study with the consecutive inclusion of 150 patients with rheumatoid arthritis (RA) and/or spondyloarthritis (AS), resistant to conventional treatment. Patients were randomly distributed to receive 1.5 or 3 mg/kg (according to medical criteria) into 2 groups of 75 patients. Group A: patients received a rapid infusion of infliximab (30-45 min) and group B: traditional intravenous infusion (2 h). The rhythm of infusion was regulated through drip counts and the rule of threes and time was counted on a digital chronometer. Data was obtained from all patients included on possible side effects, as well as efficacy parameters (visual analog scale for pain, tender, and swollen joint counts), and comparisons were made between the rapid infusion group and the traditional infusion group. RESULTS: All patients concluded the study without serious complications. In the rapid infusion group 3 patients had hypersensitivity in the infusion arm and erythema was present in 7 more. The presence of side effects was not significantly different in relation with the infusion speed. Differences were not found in relation to the dosage or the type of illness (RA and/or AS) either. The efficacy of Infliximab for symptom control showed no differences using both types of infusion. CONCLUSIONS: The absence of noticeable secondary effects associated with the reduction in the time of infusion of infliximab permits us to point out that a reduction in the time of infusion of infliximab can be a method to optimize hospital resources concerning the outpatient clinic for biologic therapy. PMID- 21794424 TI - [The B cell in the pathogenesis of rheumatoid arthritis]. AB - Classically, B-cells have been considered to play a secondary role in the pathogenesis of rheumatoid artritis, restricted to the production of auto antibodies. Nevertheless, the unexpected good clinical response that the systemic depletion of B-cells has demonstrated in a well-controlled clinical trial in patients with rheumatoid artritis has revitalized the interest in this cell type in the pathogenesis of this autoimmune disease. Several evidences suggest that B cells can regulate the course of the immune response through antibody productionindependent mechanisms. These mechanisms include antigen presentation and the release of soluble factors such as proinflammatory cytokines, metalloproteinases, and chemokines. This article reviews experimental data supporting that the participation of B-cells in the pathogenesis of rheumatoid arthritis occurs through multiple mechanisms. PMID- 21794425 TI - [Not Available]. PMID- 21794426 TI - [Rheumatoid arthritis and myocardiopathy. A patient awaiting a heart transplant]. AB - Cardiovascular pathology is common in rheumatoid arthritis. However, myocardial affection is unusual and clinical disease is rare. We report a case of dilated cardiomyopathy in a patient with rheumatoid arthritis and progressive heart failure that required inclusion into a heart transplantation list. PMID- 21794427 TI - [A Case of Cutaneous Tuberculosis is Simulating Paraneoplastic Vasculitis]. AB - We present the case of a patient with type T non-Hodgkin lymphoma, in clinical remission after treatment with chemo and radiotherapy, who was hospitalized due to hemorrhagic and necrotic skin lesions on his right hand and a clinical suspicion of paraneoplasic vasculitis. Nonetheless, study of the patient and complementary testing led to the diagnosis of disseminated tuberculosis with skin and lung involvement (cutaneous milliary tuberculosis). Anti-tuberculosis treatment was initiated with a satisfactory resolution of symptoms and signs. PMID- 21794428 TI - [Not Available]. PMID- 21794429 TI - [Not Available]. PMID- 21794430 TI - [Not Available]. PMID- 21794431 TI - [Mesenchymal cells and fibrocytes in peripheral blood. Culture conditions]. AB - OBJECTIVES: The fibrocytes, the mesenchymal cells and the colony forming units are included in the concept fibroblast-like, peripheral-blood circulating stem cells. The aim of this work was to establish the culture conditions. MATERIAL AND METHOD: Peripheral blood mononuclear cells were isolated from 25 samples collected from the cephalic vein. These were cultured in McCoy's 5A enriched with 20% of foetal bovine serum. The culture was read at 7, 14 and 21 days, evaluating the proliferation, confluence and the round cell/spindle cell ratio. Moreover the 21st day surface markers and phagocytic activity testing was carried out. RESULTS: Growth was achieved in all the cases but only in two dishes were confluence areas retrieved. Spindle cells were 36 +/- 3.71% (mean +/- SD). All the cells showed intense signal against vimentin, CD34 marker and the NBT test were positives. CONCLUSIONS: Clear CD34 expression, positivity against a connective tissue marker such as vimentin and positivity in a phagocytic assay like the NBT-test, support that stem cells, monocytes and fibroblasts share common characteristics. PMID- 21794432 TI - [Meta-analysis of efficacy of anti-TNF alpha therapy in ankylosing spondylitis patients]. AB - INTRODUCTION: Tumor necrosis factor (TNF) plays an important role in the pathology of ankylosing spondylitis (AS). Therefore, anti-TNF antibody based therapies could hopefuly be a treatment in AS patients without response to current drugs, mainly non-steroidal antiinflammatory drugs (NSAIDs). OBJECTIVE: To assess the evidence from clinical trials on the efficacy of anti-TNF alpha for the treatment of AS by performing a meta-analysis to derive estimates of responses occurring in randomized trials employing anti-TNF therapy. METHODS: A systematic literature search of EMBASE, PubMed, Cochrane Library and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through August 2006. To be selected, the studies had to fulfil all of the followings conditions: a) randomized controlled trial comparing one therapy anti-TNF alpha (infliximab, etanercept or adalimumab) versus placebo. Used between 6 and 24 weeks in patients with AS; b) diagnosis based on the New York modified criteria for AS; c) the primary end point had to be the proportion of patients with a 20% improvement response according to the criteria of the Assessment in Ankylosing Spondylitis (ASAS) International Working Group (ASAS20 responders). RESULTS: Seven trials met our inclusion criteria and were selected for meta-analysis and were considered of high methodological quality with a total of 1,094 patients, 660 patients in treatment group and 434 patients in control-placebo group. In anti-TNF alpha treatment group, the ASAS20 response rate improvement was 60.4% and 22.1% in placebo group at 6-24 weeks period. The relative risk was 2.78 (95% CI, 2.3-3.4), favourable to treatment group. The number needed to treat was 3 (95% CI, 2-4). CONCLUSIONS: There is evidence of an increased relative benefit of improved clinical outcomes in patients with AS, treated with anti-TNF antibody therapy with two assessment criteria ASAS20 at short term (6 to 24 weeks) treatment periods; with an evidence level I and recommendation level A. PMID- 21794433 TI - [Neurophysiologic study in patients with rheumatoid arthritis with atlantoaxial subluxation]. AB - INTRODUCTION: Radiological studies show that 80% of rheumatoid arthritis (RA) patients with more than 10 years present spinal afflictions and 40% of those patients will present neurological deterioration. The somatesthetic evoked potential (SEP) and the transcranial magnetic stimulation (TMS) are neurophysiologic studies that may be useful in early diagnosis of neurological damage. OBJECTIVE: To compare the results of the neurophysiologic studies (SEP and TMS) carried out on patients affected with RA without neurological clinic, with or without atlantoaxial suluxation (AAS), and in this way evaluate the efficacy of early diagnosis of the affection of the spinal medulla by electrodiagnostic methods. MATERIAL AND METHODS: Cases and controls study that included 29 patients affected with RA of more than 3 years evolution. All of the patients had 2 electrophysiological techniques carried out on them: SEP and TMS in the neurophysiologic laboratory. RESULTS: 29 patients participated in the study, of which 21 were females and 8 males. In the group affected with AAS 2 patients presented anomaly in the SEP (11.7%) and 7 in the TMS (41.1%). In the group without AAS 2 presented an altered TMS (16.6%), but no alteration in the SEP. No patient affected or not with AAS, presented alteration of both electrophysiological tests. No significant differences were found between the positivity of the RF or the presence of erosions and the affection of the atloaxoid joint. No differences between the age of outset or years of evolution and the AAS. CONCLUSIONS: In our study patients with AAS showed a greater trend towards the presence of alterations in the electrophysiological studies than the patients without AAS. PMID- 21794434 TI - [Asistance quality standards in rheumatology]. AB - OBJECTIVE: To developed standards for quality of care and processing times in rheumatology. MATERIALS AND METHODS: After a systematic review of the literature, a working group of 10 rheumatologists and 2 methodologists selected 164 indicators of quality of care and processing times. A panel of 65 experts rated the indicators following a Delphi methodology. RESULTS: Among the most important of the 164 standards obtained were: maximum number of inhabitants per rheumatologist (40,000-50,000); minimum number of rheumatologists in a Rheumatology Unit (3); duration of the first visit (30 minutes) and successive visits (19 minutes), ratio of successive/first visits (3.2); a rheumatologist should receive no more than 5 first visits/day and no more than 11 successive visits/day, and should spend no more than 5 hours on patients visits/day nor more than 4 days/week; the maximum waiting time for first visits should not exceed 4 weeks; the time needed to visit hospitalised patients (43 minutes on admission, 17 minutes for daily visit and 40 minutes at discharge); and time to carry out some of the most frequent procedures in rheumatology (12 minutes for arthrocentesis and infiltrations and 17 minutes for synovial fluid analysis). CONCLUSIONS: This study establishes basic standards for quality of care, organisation and process times. It is a useful tool for organizing a Rheumatology Unit which can facilitate dialogue with health administrators and help improve the quality of rheumatology care. PMID- 21794435 TI - [Etiologic possibilities for the development of rheumatic diseases through environmental mechanisms]. AB - Living beings and the environment that supports them have a mutual interdependence and therefore any event that occurs within an ecosystem affects all parts. The influence that the environment has on subjects that maydevelop an illness has been amply recognized. For some autoimmune diseases such as systemic lupus erythematosus (SLE), the possibility of its development under ultraviolet light and prolonged exposure to sunlight has been recognized. Microorganisms may activate other illnesses such as reactive arthritis. Substances such as alfalfa are also able to unleash disease activity. Laboratory workers who manipulate sera of patients with autoimmune rheumatic disorders develop antibodies to the sera that they are working with. It is thus that environmental sciences and focused research allow the development of a new approach to the study of possible pathogenic mechanisms in the appearance of certain rheumatic disorders. This article reviews the main existing evidence and proposes certain hypotheses derived from it. PMID- 21794436 TI - [Not Available]. PMID- 21794437 TI - [Carpal tunnel syndrome as a predictor of isolated systemic primary AL amyloidosis]. AB - The diagnosis of common carpal tunnel syndrome, usually relies only on clinical grounds and electromyographic study. We present a 60-year-old woman who was diagnosed with systemic primary AL amyloidosis many years after the carpal tunnel syndrome had begun. PMID- 21794438 TI - [Septic arthritis due to Bacteroides fragilis in a patient with non-Hodgkin lymphoma and mixed connective tissue disease]. AB - We present a 53 year old woman with pre-existing mixed collagen tissue disease who developped highly-malignant non-Hodgkin lymphoma and 2 years later had left groin abscess, then septic tenosynovitis of the left ankle, septic artrhritis of the right shoulder and purulent tenosynovitis of the right hand. Bacteroides fragilis was identified in synovial fluid drawn from the right shoulder, in blood cultures and in culture of a central venous catheter tip. The primary infection site is presumed to have been the abdominal cavity, and the presence of an indwelling central venous catheter the reason for recurrence of infection. We treated her empyrically with intravenous ampicillin/sulbactam and clindamycine then oral metronidazol until definite resolution of the infection. Septic artrhritis due to Bacteroides fragilis is a rare entity mainly occurring in immunocompromised patients, as shown in this case. PMID- 21794439 TI - [Not Available]. PMID- 21794440 TI - [Not Available]. PMID- 21794441 TI - [Reduction in time until first treatment with disease modifying treatment in patients with rheumatoid arthritis]. AB - OBJECTIVE: To analyze changes in the lag time to first disease modifying antirheumatic drug (DMARD) prescription since onset of symptoms of rheumatoid arthritis (RA) over the last 2 decades in Spain. PATIENTS AND METHOD: Review of medical records of 865 patients diagnosed with RA living in Spain and attended in specialty care settings of the National Health System. The principal variable was the lag time between the onset of symptoms of RA and the date of first DMARD therapy prescription. Analyses were performed by year and five-year periods and differences between groups were assessed by chi(2) test, Student t test and analysis of variance. RESULTS: Sociodemographic and clinical characteristics corresponded to a typical cross-sectional population of patients diagnosed with RA. The median lag time between symptom onset and first DMARD therapy was 14 months (6-36) for the whole group. However, a significant shortening of time to first DMARD was observed over the last two decades (-4.59+/-0.2 months by year; P<001). Shortening of time to first DMARD was mainly due to a shortening of time to first visit with specialists since onset of symptoms with a smaller decrease in time from first visit to first prescription of a DMARD agent. CONCLUSIONS: A significant shortening in the lag time to first DMARD therapy was observed over the last 2 decades in Spain, being a significant reduction in the time to first visit with a specialists its major cause. PMID- 21794442 TI - [Indication for Anti-TNF-alpha Treatment in Patients With Ankylosing Spondylitis in Spain]. AB - OBJECTIVES: To know the perception of Spanish rheumatologists of the profile of the patient with ankylosing spondyloarthritis, candidate for biological therapy treatment. To determine what proportion of patients with ankylosing spondylitis is considered a candidate for this therapy and to know up to what point this decision agrees with the recommendations of the ASAS working group on anti-TNF therapies and with the consensus of the SER METHOD: Rheumatologists from 19 Spanish centers who are experts in treating patients with AS and in the use of anti-TNF drugs participated in this study but they were not aware of the recommendations of the ASAS group and of the SER (unpublished until this work). RESULTS: One hundred and eighty five patients were included in the study. Spanish rheumatologists indicated that they would start therapy with anti-TNF drugs in altogether 37.8% of the patients. The candidates had the highest values of disease activity, of acute-phase reactants, the worst spinal mobility, worst function, more hip damage, and high sick leave prevalence. Out of the total of the patients considered as candidates for treatment with biological therapies by their rheumatologists, 45.7% did not comply with the ASAS recommendations with respect to prior treatments with NSAIDs and BASDAI and 48.6% did not comply with the SER criteria; 29.1% of the patients who did not comply with the ASAS criteria (NSAIDs-BASDAI) were considered to be candidates for treatment with anti-TNF drugs; 29.6% of the patients who did not comply with the SER criteria were also considered to be candidates. The most important criterion was the clinical activity of the disease. CONCLUSIONS: The agreement between the criteria applied by the Spanish rheumatologist and proposed by ASAS working group and the SER consensus is low. Axial affectation, activity, and severity in their disease were the criteria used but frequently by the Spanish rheumatologist to indicate biological therapy in patients with AS. PMID- 21794443 TI - [Usefulness of Pamidronate in the Treatment of Charcot's Arthropathy]. AB - OBJECTIVE: To investigate the usefulness of pamidronate in the management of active Charcot's arthropathy. MATERIAL AND METHODS: Open prospective study with a follow-up of 12 months, including patients with active neuroarthropathy seen over a period of 3 years in our rheumatology unit. Patients received three pamidronate infusions at 0, 2, and 4 months. Clinical assessment, serum and urine bone turnover markers, radiological exam, and scintigraphy were performed before and after treatment. RESULTS: Seven patients were ncluded (4F/3M), mean age, 51.3 years (30-64). The underlying disease was diabetes mellitus in 4 cases, syringomyelia in 2, and sensory and autonomic neuropathy in 1. The joints affected were shoulder, ankle, tarsians, metacarpophalaneal, and metatarsophalangeal. All patients showed a rapid resolution of clinical symptoms, with a clear reduction of all bone remodeling markers that achieved statistical significance for urine NTX and urinary pyridoline (P=.04 and P=.03, respectively). Six of 7 patients disclosed at the end of follow-up a radiological healing. Quantitative scyntigraphy showed a clear reduction of the bone (99)Tm uptake. No important side affects were reported. CONCLUSIONS: Pamidronate appears as a useful treatment for neuroarthropathy independently of the underlying disease. A rapid diagnosis and early pamidronate treatment could avoid severe articular consequences. PMID- 21794444 TI - [Use of glucocorticosteroids in rheumatoid arthritis. How and when should steroids be used in rheumatoid arthritis?]. AB - Glucocorticoids (GC) are a mainstay of the therapy in rheumatoid arthritis (RA). Currently, and despite their extensive use, the discussion about the benefits and adverse effects of low dose GC in the management of RA persists. In recent years, a number of clinical trials have attempted to establish the benefits of long-term GC use as a disease-modifying antirheumatic drug in RA, and to define their side effects. Results of these clinical trials provide solid evidence that low-dose GC can inhibit radiographic damage in early RA, and that side effects of GC, when used in that clinical framework, are limited to hyperglycaemia, cataracts, and transient weight gain. PMID- 21794445 TI - [Nephrotic syndrome in scleroderma]. AB - The renal affectation is infrequent in scleroderma, unlike other collagen diseases. The appearance of nephrotic syndrome has been related to the drug use, specially the D-penicilamine, or rarely as a manifestation of secondary amilodosis, quite infrequent in scleroderma. We report a case of nephrotic syndrome in a patient with systemic scleroderma, produced by a membranous glomerulonephritis, exceptionally described in literature. PMID- 21794447 TI - [Antisynthetase syndrome without muscle involvement]. AB - Antisynthetase syndrome is a well defined syndrome characterized by the presence of interstitial lung disease in association with arthritis, miositis, mechanic's hands and Ruynaud's phenomenon in the presence of antisynthetase antibodies, especially Ac anti-Jo1. We described the case of a 68-year-old man with this syndrome in the absence of inflammatory muscle disease. PMID- 21794446 TI - [Clinical review: Fever and arthritis. Diagnosis: endocarditis due to enterococcus]. AB - Clinical signs of infective endocarditis are inespecific. Fever and heart murmur are the most frequent symptoms. Arthralgias's association is fairly common but presentation as polyarthritis is inusual. We report a cse of infective endocarditis that begins with subacute fever and polyarthritis. PMID- 21794448 TI - [Not Available]. PMID- 21794450 TI - [Not Available]. PMID- 21794449 TI - [Not Available]. PMID- 21794451 TI - [Not Available]. PMID- 21794452 TI - [Not Available]. PMID- 21794453 TI - [Not Available]. PMID- 21794454 TI - [Not Available]. PMID- 21794455 TI - [Not Available]. PMID- 21794456 TI - [Not Available]. PMID- 21794457 TI - [Not Available]. PMID- 21794458 TI - [Not Available]. PMID- 21794459 TI - [Not Available]. PMID- 21794460 TI - [Not Available]. PMID- 21794461 TI - [Not Available]. PMID- 21794462 TI - [Not Available]. PMID- 21794463 TI - [Not Available]. PMID- 21794464 TI - [Not Available]. PMID- 21794465 TI - [Not Available]. PMID- 21794466 TI - [Not Available]. PMID- 21794467 TI - [Not Available]. PMID- 21794468 TI - [Not Available]. PMID- 21794469 TI - [Not Available]. PMID- 21794470 TI - [Not Available]. PMID- 21794471 TI - [Not Available]. PMID- 21794472 TI - [Not Available]. PMID- 21794473 TI - [Not Available]. PMID- 21794474 TI - [Genetics in osteoarthritis]. AB - Osteoarthritis is a degenerative articular pathology with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. In spite of the multifactorial nature of this pathology, from years 50 one knows that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidates genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this pathology are not known, however, which seems clear is that levels of expression of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthitis. PMID- 21794475 TI - [Tissue engineering and osteoarthritis]. AB - Articular cartilage lesions predispose to the development of early osteoarthritis. Most current surgical techniques give rise to the formation of fibrocartilage with biochemical and biomechanical properties inferior to those or articular cartilage. Tissue engineering could offer a modern alternative to the treatment of these lesions and in this way, prevent the development of early osteoarthritis in young active patients. Different tissue engineering approaches rely on the current use of autologous chondrocytes, or the potential use of mesenchymal stem cells. Other variables rely on the type of scaffold to use such as synthetic biodegradable polymers, fibrin or collagen-derived scaffolds of different sources, bovine, porcine, rat tail, etc, in the form of gels, sponges, mesh, etc, and all of these with or without growth factors. The use of autologous chondrocytes is a reality at the present time, whether injected under a periosteum patch or seeded on collagen. However, most investigators and biotech companies are in search of onestep surgical procedures, for which reason stem cells have to be kept in mind, as well as systems that will allow arthroscopic implantation. PMID- 21794476 TI - [Joint cartilage differentiation and osteoarthritis]. AB - During skeletal development, the mechanisms of formation, differentiation and maturation of the cartilage are important steps in the skeleton morphogenesis; these mechanisms regulate growth of long bones and joint formation. Although cartilage in the growth plate and articular cartilage are very similar, they have some differences in the differentiation mechanisms. Growth plate cartilage regulates the growth of long bones by cartilage substitution of bone, while articular cartilage is maintained by delay of chondrocyte maturation and hypertrophy. Maybe, the mechanism of cartilage maturation is activated and increased during osteoarthritis, resulting in loss of the biomechanical properties required by the joints to resist the impact required by the skeleton to move. PMID- 21794477 TI - [Evidence of inflammatory mechanisms in osteoarthritis]. AB - Classically, osteoarthritis (OA) is not considered an inflammatory arthropathy, because of the presence of a small number of neutrophils in the synovial fluid and the absence of systemic manifestations of inflammation. Besides, the characteristics of articular cartilage (avascular, alymphatic and aneural) do disable to fulfill with the classical signs of inflammation (redness, swelling, heat, pain). However, thanks to development of molecular and cellular biology, there are multiple studies which shown that different proinflammatory mediators, such as the cytokines IL-1beta and TNFalpha, could be important in the development of this disease. Therefore, the stimulation of chondrocytes, the only cell type living in the cartilage matrix and for this reason the principal responsible of integrity of cartilage matrix extracellular, with these proinflamatory cytokines increases the production of metalloproteinases, keys molecules in the irreversible degradation of normal architecture of cartilage. As well, inhibits the synthesis of cartilage proteoglycans and type II collagen, stimulates the production of reactive oxygen species such as nitric oxide, and increases the production of prostaglandin E(2). Likewise, the effects of synovial inflammation expected contribute to deregulation of chondrocyte function in a similar fashion, favouring the lost of equilibrium between the catabolic and anabolic activities of the chondrocyte necessary for maintaining the extracellular cartilage matrix. PMID- 21794478 TI - [Imaging: new techniques used in osteoarthritis]. AB - Nowadays, one of the critical challenges for imaging techniques is the development of more sensitive methods to assess osteoarthritis. This review is focused on the main methods used to evaluate anatomical damage in osteoarthritis patients. Conventional radiography is the more accessible and well known method, but can not evaluate non-calcified tissues. Magnetic resonance imaging allows visualization of articular and extraarticular soft tissues, including the morphologic and biochemical characteristics of cartilage, but it is an expensive and less accessible method. Increasing interest has been shown in ultrasonography as a suitable, non expensive and accurate method which can evaluate articular (including cartilage) and extraarticular structures, with the disadvantage of a limited acoustic window and impossibility to evaluate joint space width. PMID- 21794479 TI - [Do disease modifying drugs exist for osteoarthritis]. AB - The osteoarthritis is a disease with high epidemiological, social, and economic impact in health systems. Its treatment has been focused on diminishing pain and inflammation joint; in last years there has appeared on the market a series of drugs that, in studies in vitro show mechanisms of action that might have a modifying effect of disease, since they diminish the proinflammatory cytokines and metalloproteinases involved in degradation of cartilage matrix and it have effect in anti-apoptotics mechanisms in chondrocyte. Clinical studies have showed efficacy against pain and improving joint function; some studies have showed that there is not loss of joint space evaluated by conventional x-ray with longitudinal follow-up of patients. We describe new in vitro action mechanisms of theses new drugs and the clinical evidence of its efficacy in symptoms and potentially modifying effect of the natural history of osteoarthritis. PMID- 21794480 TI - [Arthroscopic treatment for osteoarthritis: knee and shoulder]. AB - We discuss the role of arthroscopy in the treatment of knee and shoulder osteoarthritis. The most widely used arthroscopic techniques used in these joints for the treatment of osteoarthritis are arthroscopic lavage, arthroscopic debridement, abrasion arthrosplasty and microfractures. Even though arthroscopic techniques are only useful for a specific group of patients and that the procedure does not modify disease's natural history, it is an accessible therapeutic option. PMID- 21794481 TI - [Surgical treatment of hip osteoarthritis: hpdete on hip arthroscopy]. AB - Arthroscopic surgery of the hip is a routine procedure in an increasing number of institutions around the world. Indications for this procedure increase as more experience is developed. Thanks to hip arthroscopy some intraarticular lesions like labral or ligamentum teres tears and cartilage lesions have been recognized. All of these have the potential to develop hip osteoarthritis. Open techniques for the treatment of femoroacetabular impingement have been transformed to arthroscopic techniques. Femoroacetabular impingement has the potential to cause hip osteoarthritis. The role of hip arthroscopy in the treatment of formally established hip osteoarthritis is limited and has better results in young patients with early degenerative changes. PMID- 21794482 TI - [Update in joint reconstructive surgery of the knee]. AB - Alterations in the mechanical axis, complications of traumatic injuries and osteoarthritis are the leading causes for surgical reconstruction of the knee. According to the degree of the alteration, different surgical procedures are carried out, among which we find arthroscopy, mechanical axis aligning osteotomy, single compartment prosthesis, or total knee prosthesis. Indications for each one of these procedures depend on the type and degree of lesion. These treatments are not currently considered definitive or curative for osteoarthritis and their aim is mainly to improve the clinical conditions of the patient and to reduce as much as possible the evolution of the joint degenerative process. Even total knee arthroplasty, considered a definitive surgical procedure, is temporary due to its natural tendency to loosen and wear out. PMID- 21794483 TI - [Surgical treatment of hip osteoarthritis: update in total hip arthroplasty]. AB - Total hip replacement is one of the most successful procedures in orthopaedic surgery. There are two different technologies for implant fixation in total hip replacement: cemented and cementless, both can be combined, which is called Hybrid arthroplasty. Long term implant stability results in long term function. The most important factor that limits longevity of well-fixed implants is the wear of the articular surfaces. Wear of the polyethylene from the acetabulum generates particles that access the implant bone or the implant-cement-bone interface. This produces an inflammatory reaction, osteolysis and implant loosening. Polyethylene of higher resistance to wear and prosthetic articulations without polyethylene (hard on hard bearings), have been introduced to improve wear particle generation. Minimally invasive surgical techniques minimize surgical trauma to sort tissue around the hip joint, facilitating a better and more rapid recovery. PMID- 21794484 TI - [Prevalence and risk factors in osteoarthritis]. AB - Osteoarthritis is one of the most common chronic conditions; it is a leading cause of disability in older adults and generates high costs. Incidence and prevalence of the disease varies according to the definition used. Diagnosis is established according to clinical or radiological, and ideally according to both. Joints most frequently affected are hands, knees and hip, although population distribution varies depending on the population studied. We review the prevalence of these three groups of osteoarthritis in the five continents, and we discuss the risk factors most frequently associated to each one. PMID- 21794485 TI - [Treatment of joint cartilage lesions with cell therapy]. AB - Articular cartilage lesions which do not affect the integrity of subchondral bone, they are not able to repair it expontaneously. The asymptomatic nature of these lesions induces articular cartilage degeneration and development of an arthrosic process. To avoid the necessity to receive joint replacement surgery, it has been developed different treatments of cellular therapy which are focused to create new tissues whose structure, biochemistry composition and function will be the same than native articular cartilage. Approaches used to access the stream produce a fibrocartilaginose tissue which is not an articular cartilage. Implantation of autologous chondrocytes and autologous mosaicplasties induces a quality better articular cartilage. Furthermore both techniques involve damage in the sane cartilage; because of trying to get a big amount of chondrocytes or because of extraction osteochondral cylinder which will be implanted in the injured joint. The stem cells are a promising toll to repair articular cartilage, however they are in a previous experimentation step yet. Although the present studies using cellular therapy improves clinically and functionally, it is not able to regenerate an articular cartilage which offer resistance the degeneration process. PMID- 21794486 TI - [Not Available]. PMID- 21794487 TI - [Lower incidence of severe damage to target organs in mexican patients with systemic sclerosis and diffuse skin affection]. AB - OBJECTIVE: To determine the cumulative incidence of severe organ involvement in Mexican patients with systemic sclerosis (SS) and diffuse scleroderma at 3 years from the onset of SS symptoms, and to compare itwith the cumulative incidence observed in a cohort of white patients with SS. PATIENTS AND METHOD: Patients with SS and diffuse scleroderma were evaluated within the first 2 years from the onset of SS symptoms and were included. An estimation of the cumulative incidence of severe involvement to the skin, kidney, heart, lungs, and gastrointestinal track at 3 years from the onset of SS symptoms was carried out. This cumulative incidence was compared with that of white SS patients with diffuse scleroderma, using the one sample test for a binomial proportion. RESULTS: Sixty-three patients were included. The cumulative incidence of severe involvement to the skin was 3.17% (2/63) (95% CI, 0.04%-11); kidney involvement in 4.17% (3/63) (95% CI, 0.99%-13.29%); heart involvement in 1.6% (1/63) (95% CI, 0.04%-8.5%); lung involvement in 11.11% (7/63) (95% IC, 4.5%-21.5%); and gastrointestinal involvement in 4.7% (3/63) (95% IC, 0.99%-13.3%). Mexican patients had a lower Reumatol Clin. 2008;4(1):3-7 3 02 ORIG 2582 (3-7).qxp 23/1/08 11:09 Pagina 4 Rojas-Serrano J et al. Incidencia de dano grave en pacientes mexicanos con esclerosis sistemica incidence of severe skin involvement (P=.0001), kidney involvement (P=.03) and heart involvement (P=.03) compared to white SS patients with diffuse scleroderma. CONCLUSIONS: The cumulative incidence of severe organ involvement in SS Mexican patients with diffuse scleroderma was determined. The incidence of severe skin, kidney and heart involvement is lower than in white SS patients with diffuse scleroderma. PMID- 21794488 TI - [Relationship between cardio-respiratory parameters and women with fibromyalgia]. AB - OBJECTIVE: To determine groups in women with fibromyalgia syndrome (FM) based on symptoms and determine their cardiovascular parameters during treadmill exercise to prescribe them physical activity. PATIENTS AND METHOD: Women (n=32; age, 53.3+/-6.6 years) were assigned into 2 different groups according to their functional capacity and symptoms. During incremental treadmill exercise test, exercise intensity was increased until participants achieved volitional exhaustion. Expired respiratory gases, ventilator parameters, and heart rate (HR) were measured continuously during exercise and rating of perceived exertion (RPE) was assessed each minute during the test. RESULTS: Peak VO(2) values for the group 1 were significantly different than for group 2 (24.9+/-3.2 ml/kg/min [group 1] and 21.5+/-2.1 mL/kg/min [group 2]) similar ones to the found in other studies with women with FM, although lower than in other populations without this pathology. On the other hand, if we take into account the VO(2VT), we found no significant differences between groups in both trials. We found also differences in all the evaluated parameters. CONCLUSIONS: Depending on the level of affectation and the symptoms of the FM patients, their aerobic capacities were different; therefore, we are not be able to prescribe physical activity with the same intensity for both groups. According to those results, professionals could prescribe physical activity with a high security and control. PMID- 21794489 TI - [Prevalence of atherosclerotic vascular disease in cuban patients with systemic lupus erythematosus]. AB - Atherosclerotic vascular disease-associated mortality and morbidity has increased in sick patients with with systemic erythematosus lupus (SLE). OBJECTIVES: To determine frequency of atherosclerotic vascular disease (AVD) in our patients, and to identify associations of some risk factors associated to its presence. METHOD: Study included 51 patients and 51 controls paired by age, sex, and skin colour, who underwent carotid ultrasound (US) to measure thickness of intimamedial complex, and to determine presence of plaques. In patients and controls we analyzed the presence of classic risk factors, eg age, smoking, high blood pressure, diabetes mellitus, and hyperlipidemia. In addition in SLE we also analyzed the influencie on AVD of the clinical features of disease, as well as treatments applied. RESULTS: Risk factors were similar between patients and controls, except for hypertriglyeridemia, which was more frequent in patients. Presence of plaque was more prevalent in patients than in controls (59.9 vs 23.5%, P=.001). In multivariate analysis age (OR, 1.31; 95% CI, 1.038-1.253; P=.005), diagnosis of SLE (OR, = 3.872; CI 95%, 1.4-10.2; p = 0.005), and presence of damage by SLICC/ACR (OR, 34.884; 95% CI, 1.1-12.9; P=.006) were the only variables independently associated to the presence of atherosclerosis in our patients. CONCLUSIONS: Frequency of atherosclerosis is increased in patients presenting with SLE, risk factors independent of those classics, seem to be associated with this presence. PMID- 21794490 TI - [Toward a non-empirical treatment for rheumatoid arthritis based on its molecular pathology]. AB - Rheumatoid arthritis (RA) is a chronic, disabbling disease that affects individuals during the productive years of their lives. Modern treatment for RA includes the so called "biologic" therapy, which is based on recombinant proteins that modify the biologic processes. These agents have potent therapeutic effects and different mechanisms of action. Nevertheless, therapeutic failure still prevails. Treatment that prevents disability in RA must be started in an early manner, before the development of complications and, ideally, with a minimum possibility of therapeutic failure. As yet, there are no clinical or laboratory criteria to identify those patients with a higher probability of responding to particular types of therapy, delaying control of RA ad affecting the prevention of incapacity. Research into gene diversity through single-nucleotide polymorphisms (SNPs) by means of microarray systems, allows the detailed analysis of gene factors associated to a given disease. SNPs have been recently applied to the study of RA, where the major polymorphisms associated to RA occur primarily in genes that code for proteins related to the initiation of an immune response and/or the control of cellular activity in the immune system, in addition to genes related to tissue repair. The specific meaning of these findings is in its initial stages of research. On the other hand, proteomics relate to the analysis of protein expression profiles at multiple levels. Both types of studies will contribute to the knowledge of patterns of gene expression in RA compared to the general population, and will allow an understanding of the pathogenesis of RA. Moreover, proteomic and genomic profiles can be employed to designs probes that identify individuals with the risk of developing RA, individually predict the response to different therapeutic modalities (pharmacogenomics) and for the follow-up of the biologic response to therapy. PMID- 21794491 TI - [Not Available]. PMID- 21794492 TI - [Hematomyelia in systemic lupus erythematosus and secondary antiphospholipid syndrome: case report]. AB - Intraspinal hemorrhage is very rare and intramedullary hemorrhage, also called "hematomyelia," is the rarest form of intraspinal hemorrhage. There are few reports in medical literature. We report the case of a woman of 43 years with diagnosis of systemic lupus erythematosus and secondary antiphospholipid syndrome under anticoagulant therapy that presented hematomyelia. We describe the clinical course, the findings in the image studies and surgery, and the available information in the literature. PMID- 21794493 TI - [Chondrocalcinosis and hypomagnesemia: clinical and radiological progression]. AB - Hypomagnesemia is a rare secundary metabolic disorder associated with calcium pyrophosphate dihydrate cristal deposition disease in joint structures and may cause asymptomatic chondrocalcinosis (linear calcification of cartilage), pseudogout, and chronic arthropathy. We report 2 young men with relapsing acute knee monoarthritis with chondrocalcinosis and hypomagnesemia. After follow-up clinical and radiological events al least for 5 years and treatment with magnesium lactate, these patients have not shown new pseudogout attacks. We discuss knee radiological evolution in both patients, outstanding major knee radiological deterioration in the patient with early symptoms and a familial chondrocalcinosis association, in spite of clinical asymptomatic status. PMID- 21794494 TI - [Not Available]. PMID- 21794495 TI - [Not Available]. PMID- 21794496 TI - [Not Available]. PMID- 21794497 TI - [Efficacy of the local injection of methylprednisolone acetate in the subacromial impingement syndrome. A randomized, double-blind trial]. AB - BACKGROUND: Local glucocorticosteroid injections are frequently used in the treatment of subacromial impingement syndrome (SIS), however its efficacy is still controversial. OBJECTIVE: To compare the efficacy of the subacromial injection of methylprenisolone acetate plus lidocaine (MPL) versus lidocaine alone (LA) in SIS. MATERIAL AND METHOD: Consecutive SIS subjects, defined as a positive Neer's injection test were randomized to a subacromial injection of 2 mL methylprednisolone acetate (40 mg/mL) plus 1 mL of 1% lidocaine (27 patients); or 3 mL of 1% lidocaine (29 patients) were studied. The change from baseline of the score of a Spanish validated version of the Shoulder Disability Questionnaire (S SDQ), pain intensity, and shoulder range of motion were measured at 15 and 30 days, and afterward every month for five months. RESULTS: After adjusting for duration of symptoms and pain intensity at baseline by way of a general lineal model,we did not find differences in the change of S-SDQ scores and shoulder range of motion between the study groups. Subjects randomized to LA had greater improvement of pain intensity than MPL subjects during the entire follow-up. CONCLUSIONS: A subacromial injection of methylprednisolone acetate was not more efficacious than the injection of lydocaine alone in patients with SIS. PMID- 21794498 TI - [Eosynophilic fasciitis. Favorable response to treatment with cyclosporin a]. AB - INTRODUCTION: Eosinophilic fasciitis (EF) is a disease of unknown aetiology characterized by cutaneous swelling and indurations. The disease affects predominantly the extremities and usually show an elevation of serum immunoglobulins, and eosinophilia. OBJECTIVE: Evaluation of the efficacy of cyclosporine A as a therapeutic alternative in patients with EF refractory to steroids. PATIENTS AND METHOD: We report 3 patients with clinical, laboratory and pathologic characteristics of EF who did not show a satisfactory response to steroids treatment. All patients disclosed scleroderma-like signs with orange skin, groove sign, and indurations of the affected extremities associated to peipheral eosinophilia and increased creatine-kinase. Epidermis histological findings were normal and intense linfocitary inflammation of the fascia was observed in all patients' biopsies. All patients were treated for average of 8 months with prednisone 30-50 mg daily with an insufficient clinical response. RESULTS: Patients started on cyclosporine A 5-7mg/kg/day, showing a fast improvement (2 months). The treatment induces a clinical remission that permits to reduce or even stops the cyclosporine A treatment during follow-up. CONCLUSIONS: It seems that cyclosporine A may be a effective therapeutic alternative in patients with EF refractory to steroids. PMID- 21794499 TI - [Not Available]. PMID- 21794500 TI - [Not Available]. PMID- 21794501 TI - [Acute leukemia in children erroneously diagnosed as idiopathic juvenile arthritis]. AB - We here present 3 Venezuelan children with acute leukemia, initially diagnosed as idiopathic juvenile arthritis because of the occurrence of pain and joint swelling at the onset of disease. Joint pain was aggravated at night and the arthritis showed a migratory pattern, mainly affecting large joints in an asymmetrical fashion. One patient presented with persistent unilateral sacroiliac pain leading to a wrong diagnosis of spondyloarthritis. The elevation of acute phase reactants, disproportionate to the extent of joint disease, and marked elevation of serum lactate dehydrogenase, as well as characteristicradiological changes allowed the correct diagnosis in all cases. This combination of clinical manifestations, clinical laboratory findings, and joint and bone imaging should prompt the clinician to an early diagnosis of acute leukemia in children with arthritis. PMID- 21794502 TI - [Aquired inhibitors of coagulation in a patient with systemic lupus erythematosus and antiphospholipid antibodies: response to rituximab]. AB - Hematologic signs of systemic lupus erythematosus are diverse (SLE). Although a delayed coagulation time is anti-phospholipid antibody related, thrombotic events are the usual clinical manifestation. Spontaneous appearance of circulating anticoagulant in the absence of a previous coagulation disorder is secondary to the development of antibodies to factors II, V, VIII, IX, XI, XII,vonWillebrand, and other membrane glucoproteins, all of them uncommon causes (1 case per million persons per year) of life threatening coagulopathies. We report a case of SLE and antiphospholipid antibodies in a woman with a hemorrhagic syndrome, probably caused by multiple antibodies to coagulation factors, unresponsive to steroids and high-dose immunosupressive therapy and a favorable response to rituximab. PMID- 21794503 TI - [Strongyloides stercolaris in a Patient With Rheumatoid Arthritis Undergoing Treatment With Etanercept]. AB - Biologic therapy for the treatment of autoimmune diseases such as rheumatoid arthritis leads to a series of secondary effects and complications which are ever more frequent and increasingly complicate both the management as well as the associated comorbidity. We present the case of a patient who had one of theses associated complications. PMID- 21794504 TI - [Not Available]. PMID- 21794505 TI - [Not Available]. PMID- 21794506 TI - [Not Available]. PMID- 21794507 TI - [Adverse Reactions Related to the Administration of TNF Inhibitors. Analysis of a Registry of Biologic Therapy]. AB - OBJECTIVE: To estimate the frequency of administration related reactions (ARR), the risk window from the starting date, and finally if there are any differences between infliximab, etanercept and adalimumab. PATIENTS AND METHOD: BIOBADASER is an adverse events registry established in 2001 for active long-term follow-up of safety of biological therapies in rheumatic patients. Data from patients, diagnosis, treatment, and adverse events are recorded. RESULTS: Four-hundred ninety six relevant ARR were registered, 19.6% (496/2531) of all the adverse events communicated and 6.3% (496/2531) of all the patients registered. The incidence rate per 1000 patients-year with infliximab is 28 cases (95% CI, 25 31), with etanercept 0.2 (95% CI, 0.1-0.4) and with adalimumab 0.2 (95% CI, 0.07 0.7). Treatment was interrupted in more than 50% of all the ARR and 5% of all patients were hospitalized. More than 20% ARR happened after 15 months of treatment; in addition 2 appeared after 5 years of treatment. In delayed reactions the symptoms that most frequently were recorded were rash, fever, malaise, and myalgia. CONCLUSIONS: ARR can appear in any moment of the treatment; they are among the most frequent causes of treatment interruption. Although with less frequency, ARR are also associated with etanercept and adalimumab with symptoms that cannot be identified as such. PMID- 21794508 TI - [Effect of the Coexistence of Fibromyalgia in the DAS28 Index in Women With Rheumatoid Arthritis]. AB - OBJECTIVE: To compare the effect of coexisting fibromyalgia in DAS28 in RA female patients. PATIENTS AND METHOD: Fifty-three RA women seen consecutively in an outpatient rheumatology clinic were included and classified according to the presence (9 women) or absence (44 women) of fibromyalgia. ESR, number of tender and swollen joints, and global assessment by the patient through a visual analogue scale were recorded, as well as other functional and emotional variables. RESULTS: There were no differences in age, time since onset of the arthritis, number of swollen joints, ESR, and CRP. Number of tender joints, global assessment by the patient, and functional and emotional aspects were worse in patients with fibromyalgia. DAS28 was higher when fibromyalgia was associated to RA (5.55 +/- 0.78 vs 3.39 +/- 1.15; P = .000). CONCLUSIONS: Coexistence of fibromyalgia increases DAS28 in women with RA. PMID- 21794510 TI - [Not Available]. PMID- 21794509 TI - [Validity and usefulness of echography in the carpal tunnel syndrome]. AB - OBJECTIVE: To evaluate the accuracy and utility of ultrasonography for the diagnosis of carpal tunnel syndrome (CTS). MATERIAL AND METHOD: Prospective and blind study of 75 wrists in 42 consecutive patients with suspected CTS. Electrodiagnostic testing (EDT) was used as gold standard. We measure different ultrasonographic parameters and based on a fitted receiver operating characteristic curve, we estimated post-test probabilities for the proximal, middle and distal cross-sectional area of median nerve. We analyzed interobserver and interreader reliability by 3 different explorers and 2 different readers, cost and the patient discomfort. RESULTS: Mean ultrasound measurements were significantly higher in the EDT positive group. There was a high concordance between sonography and nerve conduction. A cut-off of 9.5 mm(2) resulted in the correct classification of 83% of cases (sensitivity 88% and specificity 67%). Conversely, a cut-off of >14 mm(2) or <7 mm(2) had excellent power to rule in CTS, with a post-test probability of 100% of specificity and sensitivity respectively. The interobserver acquisition ICC was 0.915-0.980, and the inter reader ICC was 0.912-0.987. Ultrasound cost savings in this study were ?J3217.59 (?42.9 per symptomatic wrist) and the discomfort perceived by the patient was significantly lesser 6.3 vs 56 in EDT (P <.0005). CONCLUSIONS: Ultrasound median nerve crosssectional area is reliable and may be used to accurately rule in or rule out CTS. Sonography as a first-line test is cost-effective and is more satisfactory to the patients. PMID- 21794511 TI - [Not Available]. PMID- 21794512 TI - [Septic arthritis due to meningococcus. Report an atypical case presentation]. AB - We have observed the case of a 73-years-old man with a septic monoarthritis affecting the left knee due to Neisseria meningitidis serogroup B, without previous traumatism, fever, headache or meningeal symptoms. The patient didnt present risk factors of meningococcal infection. The infection was resolved satisfactorily with parenteral ceftriaxone during 2 weeks and oral ciprofloxacin during 1 month. PMID- 21794513 TI - [Gangrene as an initial manifestation of a catastrophic antiphospholipid syndrome]. AB - Catastrophic antiphospholipid syndrome (CAPS) is an unusual form of presentation of antiphospholipid syndrome with a poor prognosis, so early diagnosis and treatment are necessary. We report a patient who had gangrene as the initial manifestation of CAPS. PMID- 21794514 TI - Laryngopharyngeal reflux mimicking limited wegener granulomatosis. AB - We present a case of subglottic stenosis (SGS) in a young patient with positive ANCA but a wrong diagnosis of Wegener granulomatosis (WG). Instead, she was diagnosed as having laryngopharyngeal reflux (LPR). Pitfalls of ANCA testing in this scenario, the route to diagnosis of LPR and the contribution of this entity to subglottic stenosis (SGS) in WG are discussed. Caution when interpreting ANCA results is mandatory to avoid improper management. PMID- 21794515 TI - [Not Available]. PMID- 21794516 TI - [Not Available]. PMID- 21794517 TI - [Not Available]. PMID- 21794518 TI - [Susceptibility of the spanish population to adverse effects by sulfasalazine: systematic review]. AB - BACKGROUND: Clinical experience raises suspicion that the spanish population could suffer higher rates of side effects of sulfasalazine (SSZ) therapy. We conducted a systematic review of existing literature to analyze the susceptibility to developing adverse events produced by SSZ in the Spanish population. MATERIAL AND METHOD: A literature search was conducted in EMBASE, IBECS, and MEDLINE from 1973 to March 2007. The items sought were those describing adverse effects, both in text and tables, and reasons for withdrawal, the population under study and discussion of differences in side effects of the different treatment groups. RESULTS: Of the 106 retrieved articles, 36 were selected for review and detailed analysis. 34 articles were selected from MEDLINE and EMBASE and 2 from IBECS. We did not find any study that showed that the Spanish population was more susceptible to SSZ. CONCLUSIONS: The adverse effects of SSZ vary with the pattern of acetylation. Thus, in slow-acetylators, depending on the dosage of SSZ, the side effects increase significantly. In the Spanish population slow-acetylators prevalence is higher than in other ethnic groups. Therefore, one could infer that the incidence of adverse side effects by SSZ could be higher in the Spanish population than in others different ethnic groups. We found no evidence that the Spanish population was more likely to suffer adverse effects by SSZ than other ethnic groups. PMID- 21794519 TI - Correlation between cytokines and anxious-depressive symptoms in patients with fibromyalgia. AB - OBJECTIVE: To establish the influence of cytokines on anxious-depressive manifestations in fibromyalgia (FM) patients. MATERIAL AND METHOD: The study comprised 56 women (50.5+/-7.8 years) with FM and 32 healthy female controls (39.65+/-9.24 years). Psychiatric symptoms were analyzed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS), while pain was assessed by means of a Visual Analog Scale (VAS). Proinflammatory cytokines IL-6, IL-8, IL-10, and TNFalpha were assayed in serum using the Luminex xMAP method. The statistical analysis was carried out using the SSPS statistical package. RESULTS: IL-8 values were significantly lower (p=.013) in patients than in controls. No differences were observed among IL-6, IL-10, and TNFalpha levels. When comparing cytokine levels with patient age, we observed a significant reduction in IL-6, IL-8, and TNFalpha in older patients. The values of these cytokines showed no relationship to the anxious-depressive symptoms. CONCLUSIONS: In our series no differences in serum cytokines were seen between patients with FM and controls, with the exception of a reduction in IL-8 among patients with FM, and which could be attributed to the older age of these patients. PMID- 21794520 TI - [Treatment of lupus nephritis]. AB - Lupus nephritis is a relevant source of morbidity and mortality in patients with systemic lupus erythematosus. The standard therapy of remission induction in severe lupus nephritis is based on the use of monthly intravenous cyclophosphamide. Recent data have established that the maintenance of remission in lupus nephritis can be achieved with azathioprine or mycophenolate mofetil, with less adverse effects than quarterly intravenous cyclophosphamide. In recent years, a number of controlled randomized clinical trials have been published, opening new therapeutic options in the induction of remission in lupus nephritis, such as less aggressive regimens of intravenous cyclophosphamide or mycophenolate mofetil. Further studies are needed for establishing the optimal therapy of lupus nephritis patients. PMID- 21794521 TI - [Not Available]. PMID- 21794522 TI - [Joint Infections Due to Streptococcus agalactiae in Non Immunocompromised Adults: Presentation of Two Cases]. AB - Streptococcus agalactiae (S agalactiae) is a germ habitually associated with infections in neonates and women during the pregnancy and the immediate puerperiumum. S. agalactiae has also been related with bacteriemias, endocarditis and bone, joint, skin and soft tissues infections in adults with concomitant diseases and even in immunocompetent patients. In the last years more than 70 cases of septic arthritis in adults due to this germ have been communicated. We present two cases of axial and peripheral joint infection due to S. agalactiae, comparing finds, treatment and evolution with the cases published until April, 2008. PMID- 21794523 TI - [Infliximab in ankylosing spondylitis associated with chronic hepatitis B infection. Role of Lamivudine therapy]. AB - Anti-tumor necrosis factor-a (TNF) therapy has been associated with reactivation of hepatitis B virus infection. Case reports have suggested the concomitant need of lamivudine treatment in patients with HBV infection treated with antiTNFa agents. We describe a case of ankylosing spondylitis with positive HBV surface antigen (HBsAg) treated with infliximab and lamivudine. Clinical response was excellent but when lamivudine therapy was stopped, reactivation of replication viral occurred. After the reintroduction of lamivudine, viral replication was controlled and liver function tests were normalized. Preventive long-term lamivudine therapy is mandatory when anti-TNFa therapy is maintained in patients with chronic HBV infection. PMID- 21794524 TI - [Vertebral osteonecrosis and percutaneous vertebroplasty]. AB - Vertebral osteonecrosis is characterized by the presence of the intravertebral vacuum phenomenon. It is a relatively uncommon disease and although it may be caused by different pathologies, the most frequent cause is posttraumatic. The explanation for the presence of intravertebral gas is not known completely. We present the case of a 74-year-old patient who after suffering a vertebral traumatism, to complain of intense vertebral pain. A simple radiological study, CT scan, and magnetic resonance confirmed the presence of intravertebral vacuum phenomenon. We studied this radiological sign and then commented on its evolution after percutaneous vertebroplasty. PMID- 21794525 TI - [Not Available]. PMID- 21794526 TI - [Not Available]. PMID- 21794527 TI - [Systematic review: is the use of NSAIDs effective and safe in the elderly?]. AB - OBJECTIVE: To analyze the efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAID) in the elderly. METHODS: We performed a systematic review using a sensitive search strategy. All studies published in MEDLINE (since 1961), EMBASE (since 1961) and Cochrane Library (up to December 2007) were selected. We defined the population (elderly as subjects aged 60 years or above with musculoskeletal diseases), the intervention (use of NSAID), and the results related to efficacy (pain, function and quality of life) and safety (gastrointestinal, cardiovascular or renal toxicity). Randomized clinical trials (RCT), (Jadad 4 or 5) and high quality cohort studies were included. RESULTS: A total of 101 studies were analyzed in detail, and 16 were included. More than 50,000 patients aged 60 years or above were analyzed from 1 week, up to 4 years. Different NSAID were included as well as different outcomes. Four meta-analyses, 9 RCT, 2 cohort studies, and one cross-sectional study were included. NSAID are effective for the treatment of musculoskeletal pain, stiffness or joint function. However, NSAID are associated with an increased risk of any serious adverse events, especially serious gastrointestinal adverse events (death, hospitalization, bleeding, ulcers, obstruction). This risk decreased with the use of proton pump inhibitors. CONCLUSIONS: Based on the evidence, NSAID in the elderly are effective for the treatment of different musculoskeletal diseases, although the risk of serious adverse events (mainly gastrointestinal) is also clearly increased. PMID- 21794528 TI - [Is the DAS28 Score the Most Adequate Method to Estimate Activity in Rheumatoid Arthritis? Clinimetric Considerations and Simulations Scenarios]. AB - INTRODUCTION: The DAS28 score has now consolidated as a fundamental variable for the assessment of rheumatoid arthritis activity and is the main parameter used to establish therapeutic decisions in this disease, including the start and change of biologic therapies. OBJECTIVES: We have studied the clinimetric properties of DAS28, including ceiling and floor effects and its behavior in several clinical scenarios. MATERIAL AND METHOD: Individualized study of the variables included in the DAS28 formula along its possible range. Sensitivity analysis of the results of the DAS28 of 4 variables in four theoretical scenarios corresponding to low (DAS28=2.43), fair (DAS28=4.05), high (DAS28=6.32) or very high (DAS28=8.40) clinical activity. RESULTS: Tender joint count (NAD) and erithrosedimentation rate (ESR) have a weight of 35- 40% each on the total DAS28 score, while swollen join count (SJC) and global health assessed by the patient (GH) only contribute with 15% each. As tender joints weights double than swollen joints, in the simulation models having one swollen joint needed just 3 tender joints to get the DAS28 above the non remission level (DAS28>2.6), while having one tender joint needed 5 swollen joints to be above remission. Given its logarithmic calculation in the DAS28 formula, ESR contribution is much higher in its lower range, and thus small variations of ESR in the normal range can influence decisively in the final DAS28 score. CONCLUSIONS: The asymmetric weight of each component in the complex DAS28 formula must be taken into account when interpreting changes in the DAS28 lower range as they influence the estimation of clinical remission and thus can be relevant when taking therapeutic decisions. PMID- 21794529 TI - [Systematic review: is the use of NSAIDs safe during pregnancy in women with rheumatic disease?]. AB - OBJECTIVE: To analyze the security of non-steroidal anti-inflammatory drugs (NSAID) in rheumatic disease patients during pregnancy. METHODS: We performed a systematic review using a sensitive search strategy. All studies published in MEDLINE (since 1961), EMBASE (since 1961) and Cochrane Library (up to January 2008) were selected. We defined the population (pregnant women 16 years or above with a musculoskeletal disease), the intervention (use of NSAID), and the outcomes related to safety (number of live births, stillbirths, length of gestation and of labour, birth-weight, number and type of congenital malformations). The titles and abstracts of articles retrieved from the search were reviewed and high quality cohorts and case-control studies were included. RESULTS: Of a total of 149 references retrieved, only 8 were analyzed in detail, and 3 were finally included. More than 2600 pregnant patients were analyzed. There are many different NSAIDs as well as many different outcomes. Different NSAID were included as well as different outcomes. There was no increased risk of congenital malformations in two of the studies. In the third one there was an increased risk for cardiac malformations (OR=1.86; 95% CI, 1.32-2.62) and orofacial clefts (OR=2.61; 95% CI, 1.01-6.78). CONCLUSIONS: There is not enough information to support the negative effects of NSAIDs during pregnancy. On the other hand there is one study suggesting that the use of NSAIDs could increase the risk of cardiac and orofacial malformations in newborns, therefore these drugs should be used with caution. PMID- 21794530 TI - [Inflammatory myopathies. Dermatomyositis, polymyositis, and inclusion body myositis]. AB - Idiopathic inflammatory myopathies are a group of heterogeneous, acquired systemic diseases characterized by progressive symmetrical muscle weakness, elevated serum levels of muscle enzymes, electromyographic abnormalities, and inflammatory infiltrates on muscle biopsy. Characteristic histopathologic features allow classification of idiopathic inflammatory myopathies into polymyositis, dermatomyositis, and sporadic inclusion-body myositis. These are commonly regarded as autoimmune disorders, and various autoantibodies directed to specific nuclear and cytoplasmic antigens are found. Other organs besides the muscle can be involved being the skin and lung the most frequent. Occasionally dermatomyositis and polymyositis can be associated with cancer in a paraneoplastic manner. Corticosteroids and immunosuppressive agents are the mainstay therapy, although in refractory cases biologic therapy can be used. Physical therapy can not be forgotten. PMID- 21794531 TI - [Not Available]. PMID- 21794532 TI - [Dorso-lumbar pain caused by a schmorl hernia]. AB - Thoracic and lumbar spine conditions cause primarily mechanical back pain, although the clinician has to ensure that the symptoms are not from another etiology. We present the case of a patient with thoracic and lumbar non mechanical pain, resistant to treatment, diagnosed with a herniation of the intervertebral disc through the vertebral end-plate. We also performed a literature review. PMID- 21794533 TI - [Not Available]. PMID- 21794534 TI - [Not Available]. PMID- 21794535 TI - [Not Available]. PMID- 21794536 TI - [Not Available]. PMID- 21794537 TI - [Not Available]. PMID- 21794538 TI - [Systematic review: is there contraindication to the concomitant use of non sterodial anti-inflammatory drugs and steroids?]. AB - OBJECTIVES: To analyze the safety of combining nonsteroidal anti-inflammatory drugs (NSAID) and steroids. METHODS: A systematic review following a sensitive search strategy was performed. All articles published in MEDLINE (since 1961), EMBASE (since 1961), and Cochrane Library, up to December 2007 were examined. SELECTION CRITERIA: the population (subjects with musculoskeletal diseases on steroids), the intervention (concomitant use of NSAID), and outcomes related to drugs safety (gastrointestinal, renal, and cardiovascular toxicity). Titles and abstracts of retrieved articles meeting inclusion criteria from the search were reviewed. Only randomized controlled trials (RCT) or high quality cohort studies with a control group were included. RESULTS: Of a total of 4164 references retrieved, 42 were analyzed in detail, and 10 were finally included, 6 RCT and 4 prospective cohort studies, which included more than 20 000 patients. CONCLUSIONS: The use of NSAID and low dose of steroids in patients with musculoskeletal diseases does not seem to increase the risk of gastrointestinal adverse events. PMID- 21794539 TI - [Clinical role for the professional nurse in rheumatology]. AB - OBJECTIVE: To evaluate the activity of the Nurses Clinic in the Rheumatology Unit of the San Juan de Alicante Hospital, Spain. METHODS: After reaching a consensus, the nurses' functions were defined using a pre-defined scale (supported by medical objectives) and codes were assigned to perform future metrics. Afterwards, three roles were assigned to the rheumatology nurse practitioner: 1. Procedures (nursing techniques); 2. Educational Health Related Services; and 3. Osteoporosis Nursery Clinic. RESULTS: Measurement of the rheumatology nurse activity during 2006: Assignment 1, 1592 procedures; Assignment 2, 2604 services; Assignment 3, 331 visits (95 first visits y 236 revisions). CONCLUSIONS: These metrics support the fact that the activity shown in the Nurses' Clinic is enough to justify a full-time professional and the importance of designating their own specific planning and personal space in the Unit. The structure and roles in our Nurses' Clinic could be a role model to other Rheumatology Departments. PMID- 21794540 TI - [Systematic review on the safety of concomitant use of hypoglycemia-inducing drugs and non-steroidal anti-inflammatory drugs in patients with musculoskeletal pathology]. AB - OBJECTIVES: To analyze the safety of combining nonsteroidal anti-inflammatory drugs (NSAID) and hypoglycemia-inducing drugs. METHODS: A systematic review following a sensitive search strategy was performed. All articles published in MEDLINE (since 1961), EMBASE (since 1961), and Cochrane Library, up to December 2007, were examined. SELECTION CRITERIA: the population (subjects taking hypoglycemia-inducing drugs: insulin or oral antidiabetic drugs [OAD]), the intervention (concomitantly use of NSAID), and the outcomes related to safety (gastrointestinal, renal, cardiovascular toxicity) and glycemic control. Titles and abstracts of retrieved articles meeting inclusion criteria from the search were reviewed. Only randomized controlled trials (RCT), or cohort studies were included. RESULTS: A total of 33 studies were reviewed in detail, and 11 were finally included, 10 low quality RCT, and 1 prospective cohort study with moderate quality, which included 199 patients. All patients were diabetics; mostly young or middle aged men, on different NSAID and hypoglycemic drugs. There was no evidence of important changes in patient's glycemic controls, nor in their renal function, when combining NSAID with hypoglycemiainducing drugs. Moreover, there is no clear increase in the number of serious side effects. CONCLUSIONS: According to the published evidence, there are not enough arguments to contraindicate the use of NSAID with hypoglycemia-inducing drugs (insulin or OAD). PMID- 21794541 TI - [Responsiveness of outcome measures]. AB - In medical research, particularly in the field of rheumatology, there is great interest about the concept of responsiveness of outcome measures as a sign of changes in the patient's health status. However, the terminology sorrounding this concept and the methods of analysis are confusing and lacking in consensus. We present a review about the concept and analysis of responsiveness taking into account both, the characteristics of the responsiveness and the type of design and predictable change in the sample being studied. PMID- 21794542 TI - [Juvenile dermatomyositis and extensive calcinosis. Treatment with methylprednisolone and methotrexate]. AB - Juvenile dermatomyositis (JDM) is considered a multisystemic disease of uncertain etiology. The clinical manifestation is a non-suppurative inflammation of the striated muscle, gastrointestinal tract and skin. Dystrophic calcifications are present in 30%-70% of children with JDM. The clinical case we are presenting is a 4 years old female with diagnosis of JDM in accordance to the Bohan and Peters criteria (very early presentation age) with extensive calcinosis, classified as functional class III, without being able to sit down or flex her knees. She was treated with IV methylprednisolone (MPS) bolus every 14 days and oral methotrexate, with improvement of her clinical condition. Even though calcinosis is a frequent finding in connective tissue disease and can cause severe disability, there are no treatment protocols at this time. The simultaneous use of IV MPS and oral methotrexate allows for a faster control of the disease, improvement in muscular force, reduction of erythema and regression of the calcinosis without important collateral effects. PMID- 21794543 TI - [Systemic lupus erythematosus in a 6 year old female child]. AB - Systemic lupus erythematosus (SLE) is an uncommon disease, particularly in the first decade of life. Finding it before the first year of life is very rare and it entails a difficult diagnosis to document because the clinical manifestations can be very variable and can simulate a great variety of diseases. In the pediatric age, incidence of SLE is 0.36-0.9/100 000 children, with greater prevalence in females 3:1 under 12 years of age and 10:1 in patients over 12 years. There is a very low incidence of SLE before 4 years of age. We present the clinical case of a 9 month-old female in whom four criteria of SLE were clearly documented at 6 months of age. In a review of literature, this is the youngest patient reported with SLE. Physicians must be very alert of the higher risk of systemic complications in children that are diagnosed with SLE at an early age. PMID- 21794544 TI - [Not Available]. PMID- 21794545 TI - [Common genetic factors in autoimmunity]. AB - Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs. PMID- 21794546 TI - [Contribution of animal models to the study and treatment of systemic autoimmune disease]. AB - Animal models of autoimmune diseases, either spontaneous or induced, have been very useful tools to investigate the mechanisms involved in the pathogenesis of human autoimmune diseases as well as in the design of new therapeutic strategies for their treatment. The development of biotechnology and molecular biology resulted in the production of transgenic animals overexpressing or lacking a given protein. As a result of this technology, a great number of animal models of human diseases have been developed in recent years. A further evolution in transgenic methodology allows the selective control of gene expression in a particular organ or tissue at desired time points during embryonic or postnatal development. In the present article the authors discuss the advantages and inconveniences of animal models and describe the most frequently employed models in the study of 4 rheumatologic syndromes with an autoimmune origin: rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and spondiloarthritis. PMID- 21794547 TI - [Antibodies in systemic autoimmune diseases. Special mention to systemic lupus erythematosus]. AB - Autoantibodies are the expression of humoral response to self-antigens and they may be diagnostic of autoimmune diseases. Studies in systemic lupus erythematosus (SLE) have shown that autoantibodies react with macromolecular structures such as the nucleosome or the spliceosome. These self-antigens are complexes of protein DNA or protein-RNA like those recognized by anti-dsDNA or anti-RNPs (U1, Sm, Ro, La) antibodies respectively. Recent knowledge on innate immunity has shed more light on the pathological role of these autoantibodies. The antigen-antibody complexes formed as the result of an increase of sel-antigens in the blood as a consequence of an increase in apoptosis, attach to dendritic FcgammaII or B cell receptors. Through the attachment to the receptor, the macrocomplex is internalized within the cell and recognized in the endosomic membranes by receptors of the innate immune system named TLR (Toll-like receptor). There are at least 13 TLRs localized either in the cellular or the endosomic membranes. Of the latter group, TLR-7 is specific for ssRNA, and TLR-9 is specific for CpG DNA. The reaction of the immunocomplexes with the receptor triggers a kinase cascade that leads to IFNalpha production. The IFNalpha is a molecule of the innate and adaptative immune system responsible for the immune deregulation and pathological signs in the SLE. It plays an important role in antigen presentation to the autoreactive quiescent autoreactive T cells and in increasing the life span of dendritic and B cells. In addition, the increase in self-antigens released by greater apoptosis enhances the production of autoantibodies and their effect on the increase of IFNalpha production. PMID- 21794548 TI - [Comorbidity of systemic lupus erythematosus]. AB - Patients with systemic lupus erythematosus (SLE) suffer a series of incidence associated pathologies more frequent than general population. Comorbility includes: infections, arteriosclerosis, coronary arteriopathy, osteoporosis, and avascular necrosis of the bone, to name the more frequent ones. In general, such complications are related, above all, to the degree of SLE activity and the dosages of daily and accumulated corticoids. It is a matter of highlighting the importance of the associated pathologies in regards to our patients' prognosis and of taking them into consideration when we establish a treatment for our patients' during each one of their visits. PMID- 21794549 TI - [Sjogren's Syndrome]. AB - Sjogren's syndrome is a systemic autoimmune disease that is characterized by the presence of keratoconjunctivitis sicca, xerostomy and a large spectrum of signs and symptoms that translate into a very heterogeneous disease. The mild form that affects mucosal tissues is the most frequent, but there are more severe and active patterns, manifested by the presence of extraglandular affection with a worse prognosis. The clinical spectrum includes anything from mucosal alterations, Raynaud's phenomenon, parotid enlargement or arthritis, but can be aggravated by the presence of neurological, lung or renal affection. Initial therapy includes topical treatment with artificial tears, nocturnal cream and drugs that stimulate secretion for important glandular affection, while severe systemic affection merits immunosuppressant therapy. There has been recent evidence that biologic therapy is useful for the treatment of severe and resistant cases. PMID- 21794550 TI - [Systemic lupus erythematosus. Infrequent clinical aspects]. AB - The SLE is a systemic autoimmune disease that presents a tremendous variability regarding its clinical presentation and immunologic expression. This disease can affect any organ, both as clinical onset or during the course of the disease. People in their second and third decade are most frequently affected, but the illness can debut at any age, with some different clinical peculiarities. SLE associated clinical situations like hemophagocytic syndrome and some recently published clinical aspects like posterior reversible encephalopathy syndrome are reviewed here. PMID- 21794551 TI - [Results of biological treatments in autoimmune diseases]. AB - The use of the biological therapies has revolutionized in the last years the handling of numerous autoimmune processes. It has taken to numerous physicians and investigators to try to apply these therapies in other diseases (lupus, Sjogren, vasculitis, etc). From the introduction of corticosteroids and immunosupressives, vasculitis were no more a mortal diseases, and it was possible to obtain high rates of remission. Nevertheless, they are delayed, they are not sustained, and require of the use of maintained drugs. Against this background, the new biological drugs have to surpass the challenge to induce an earlier and permanent remission that diminishes irreversible organ damage, to reduce (or to eliminate) the exposition to steroids and immunesupressives and to improve the patient function. This article reviews data present until now in literature with respect to the utility of biological drugs in systemic vasculitis. PMID- 21794552 TI - [New therapeutic targets]. AB - The success obtained with biologic therapies in rheumatoid arthritis and other inflammatory arthropathies has led to its use in other rheumatic diseases such as systemic lupus erythematosus (SLE) and, to a lesser degree, in Sjogren's syndrome (SS) and progressive systemic sclerosis (PSS). This review summarizes the biologic therapies that are still in a development phase, albeit a relatively advanced one, with the aim of applying them clinically in the near future. In this sense, SLE is the disease for which most trials are being carried out, including treatment with agents such as sodic abetimus (LJP 394) a synthetic analog of DNA, edratide (TV4710) a peptide from the antigen-binding site of anti double stranded DNA, or monoclonal antibodies with different effects: B cell depletion (rituximab [anti-CD20+] and epratuzumab [anti-CD22]), lymphocyte proliferation inhibitors (belimumab [anti-BAFF]) or inhibition of costimulation (BG9588 [anti-CD40L] and abatacept [CTLA-4Ig]). In SS the agent that shows the most promise is rituximab though there are some studies with efalizumab, a monoclonal antibody directed against the LFA-1 (CD-11) molecule. Finally, in PSS there is development of monoclonal antibodies against TGFbeta a cytokine implicated in the fibrotic reaction that is the result of this disease, as well as one trial that is employing abatacept. However, in this disease the most important advances are being seen with the use of agents such as endothelin inhibitors or tyrosin-kinases, which are not considered biologic therapies. PMID- 21794553 TI - [Inflammatory myopathies. New concepts]. AB - Myopathies are diseases characterized by the primary affection of skeletal muscle. In general they present with muscle weakness, pain, contracture, paresthesias, rigidity, or fatigue. They can be hereditary, such as muscle dystrophies, congenital, myotonic, metabolic, and myasthenic, or acquired. Among the latter ones we include idiopathic inflammatory myopathies (IIM), toxic, endocrine, or infectious myopathies and myasthenia gravis. There is a current acceptance of considerable clinical and histopathological overlap among some muscle dystrophies and some IIM. However, the molecular profile is different and characteristic in each myopathy and the study into the patterns of expression of genes in the muscle can be useful in their differential diagnosis, including that of IIM. PMID- 21794554 TI - [New clinical features in scleroderma]. AB - Systemic sclerosis (SS) is a disease whose handling is, in many occasions, frustrating for the patient as for the doctor, given the lack of effective therapies. It is hopeful at least, the fact that in the last decade new features have taken place that help us to make a better pursuit of the patients and who have opened the doors towards new and future therapies. PMID- 21794555 TI - [New Clinical Aspects of Behcet's Disease]. AB - Behcet's disease/syndrome (BD) continues being aloof in his etiopathogenesis and very complex in its clinical manifestations. BD generates a good amount of scientific articles. For example, a simple search in PubMed sample that in the last 5 years has been published 1394 articles, 159 of them revisions. In addition to the basic studies on etiopahtogenesis and disease mechanisms, the diverse clinical manifestations and their treatments, also the own definition of the disease, its classification and the criteria of classification and diagnosis are debate source. In this article we reviewed some aspects in discussin as well as the last therapeutic alternatives and the situation of the EB in Spain. PMID- 21794556 TI - [Infections in the immunocompromised host. What is the role of the medications?]. AB - Infections in patients with connective tissue diseases (CTD) are associated to considerable morbidity and mortality. Some patients with CTD suffer a certain degree of immune deregulation inherent to their rheumatic disease. Other factors such as advanced age, and the coexistence of other chronic diseases such as diabetes mellitus can also lead to the development of infection. Glucocoticosteroids induce a reduction in the synthesis of most of the known cytokines, an alteration in the migration of leukocytes from the blood with an alteration in antigen presentation and an abnormal cytotoxic response. Immunosuppresants fundamentally affect cellular immunity and its effect is related to the duration of treatment and dose. There is a clear relationship between the use of anti-TNF drugs and the reactivation of tuberculosis. Its clinical and histological manifestations are frequently atypical. In those cases in which active tuberculosis is suspected, anti-TNF must be suspended until infection is ruled out. Prophylactic treatment when faced with Pneumocystis jiroveci with cotrimoxazole has been recommended in patients that receive steroids and immunosuppressants, especially if the agent employed is cyclophosphmide or if lymphopenia develops. PMID- 21794557 TI - [Infection in Joint Prosthesis. When Should it Be Suspected?]. AB - Joint prosthesis constitute one of the major advances of medicine in the treatment of patients with osteoarticular disease. Infections of prosthetic material, though having a low frequency (1%-3% according to the series and type of prosthesis) constitute one of the larger complications of this surgery and a diagnostic challenge for the physician. The concept of prosthesis infection includes colonization due to germs in periprosthetic material that also leads to clinical manifestations. There are diverse classifications of the prosthetic infections, most of which are based in the form of clinical presentation which largely depends on the germ which is responsible for the infection. In this sense, late forms are generally caused by poorly virulent germs (plasma coagulase negative staphilococcus is the most frequent) and are the most difficult to diagnose. Diagnostic suspicion must be established in relation to the clinical manifestations and a series of accompanying clinical signs. In this sense, in the abscense of baseline inflammatory rheumatism, the persistent elevation of CRP (which normalizes 1-2 weeks after the surgery), or the presence of inflammatory joint fluid (with cell counts over 1700 cells/MUL and especially with a predominance of PMN>68%) are signs that strenghten the diagnostic suspicion of bacterial infection. The definitive diagnosis is established by the isolation of the causal germ in culture and, in this sense, the biopsy of periprosthetic material and its study by the pathology department as well as its culture, allow for a trustworthy diagnosis in 80%-90% of cases. PMID- 21794558 TI - [Infectious spondylodiskitis]. AB - Vertebral osteomyelitis is a rare entity. Its diagnosis is often difficult because of nonspecific symptons and the high frequency of back pain in general population. Aetiologic diagnosis is essential in order to perform specific treatment. Thus, blood cultures, serology, and culture of samples obtained by bone biopsy are the basis of the diagnosis. Magnetic resonance imaging permits an accurate diagnosis showing neurological involvement when it is present. ESR and CRP are good outcome markers. Endocarditis must be suspected in patients with predisposing heart condition, heart failure, positive blood cultures and infectyions caused by gram-positive organisms. Indications of surgery are severe neurological involvement, spinal instability and drainage of big abscesses. In Spain, as well as bacteria, we should consider M. tuberculosis, B. melitensis, and fungi as a potential aetiologic agents causing the infection. PMID- 21794559 TI - [Infections in Patients With Rheumatoid Arthritis Undergoing Anti-TNFalpha Drug Therapy]. AB - Infections are more frequent in patients with rheumatoid arthritis (RA). The capacity of the anti-TNF drugs (infliximab, etanercept, and adalimumab) to increase the risk of infections has been a motive of discussion during the past years. Only in two of the trials that have allowed the marketing of the infliximab and adalimumab more serious infections were observed. TB was not observed in the trials. Nevertheless, later they have been published not controlled studies that show infections and TB in patients with RA that receive anti-TNFalpha drugs. The disagreement between the trials and the not controlled studies has been the motive of the accomplishment of metaanalysis which study the frequency of infections in patients with RA that receive anti-TNFalpha drugs. The three metaanalysis published show an increase of the risk of infections in patients with AR in treatment with infliximab and with adalimumab, specially when they administer high doses. This risk does not seem to increase with etanercept, probably due to the fact that doses superior to the recommended ones have not been used in the analyzed trials. Increased risk of infections was not detected in the trials, but the metaanalysis increases the statistical power and allow demonstrating increased risk of infections. A causal relation exists between the administration of anti-TNFalpha and the development of infections, fulfilling all the criteria of causality. PMID- 21794560 TI - [Septic arthritis: practical diagnosis and new treatments]. AB - Septic arthritis remains a major challenge to physicians because the increasing frequency of certain microorganisms to become in antibiotic-resistant and persistent difficulties regarding both early diagnostics and proper treatment of subjects with joint infections. This paper will review current diagnostics test and their contribution to the rapid evaluation of joint infection. Importantly, updated therapeutic suggestions will be presented which, when appropriately applied, should diminish the risks of sequelae following infectious arthritis. PMID- 21794561 TI - [Infectious agents in the etiopathogenesis of rheumatic diseases]. AB - This article is an author's view of how to face the knowledge about infectious agents and their pathogenic role in the starting immune mechanisms, trying to clarify its role in the origin of some rheumatic diseases. From the basic immune responds, recent evidence and newly molecular mechanisms are dissected as well as diagnostic and therapeutic implications. PMID- 21794562 TI - [Soft-tissue infections]. AB - One of the soft-tissue infections with a large clinical relevance is necrotizing fascitis produced by Streptococcus pyogenes and skin infections produced by Staphylococcus aureus, particularly due to the evermore frequent methylcillin (MRSA) resistant varieties. In necrotizing fascitis the diagnostic delay as well as the delay in the indication for surgical debridement influence both the prognosis and a high mortality related to these infections. Two clinical forms have been described: Type I caused by at least one anaerobic species in combination with facultative anaerobes, more frequent in diabetics or patients with peripheral vascular disease; type II, monomicrobial, produced by group A beta hemolytic Streptococcus and with a lesser frequency by Staphylococcus aureus. Among the recognized risk factors diabetes mellitus, peripheral vascular disease, chronic renal failure, alcoholism, cancer, malnutrition, steroid and/or immunosuppressant treatment and the use of intravenous parenteral drugs are widely recognized. Therapeutics is based on hemodynamic support, antibiotic therapy and an early surgical approach with the elimination of all of the necrotic and devitalized tissue. Infections frequently associated to community acquired MRSA are those present in skin and soft-tissue. Some population groups have been described as at-risk, but there is also an increase in the number of patients with no risk factors. Also, national and international registries of anti-TNF therapies have demonstrated the increase of soft-tissue infections in patients with rheumatoid arthritis treated with these agents. Other biologic drugs such as rituximab, abatacept or anakinra do not seem to be associated to an increase in these infections. PMID- 21794563 TI - [Treatment of Gout: Reflections From the GEMA Study]. AB - Evaluation of clinical handling of gout come from published surveys, but no audit on daily clinical practice has been published yet. The present study issues an audit of rheumatology practice in Spain for the diagnosis and treatment of gout from data of 803 patients from 41 rheumatology units, and related to the EULAR recommendations. Gout diagnosis was crystal-based in 26% of the patients. Treatment of acute gout was mostly adequate to recommendations, although adjustment for co-morbidities was not discussed in the EULAR recommendations. Serum urate levels <6 mg/dL, as recommended, were retrieved from less than half the files of the patients. No tendency to rise, swift or combine urate-lowering drugs was observed despite poor control of serum urate levels. PMID- 21794564 TI - [Diagnosis of microcrystalline arthropathy]. AB - Both gout and calcium pyrophosphate dihydrate (CPPD) arthropathies are crystal deposit diseases; finding monosodium urate (MSU) or CPPD crystals in a synovial fluid sample, or in a tophi in the case of gout, provide a definitive, unequivocal diagnosis. Despite having such a simple and precise diagnostic test, in both crystal arthitides there is the accepted habit of approaching their diagnosis on clinical grounds (accompanied by hyperuricemia for gout, or chondrocalcinosis for the CPPD related arthropathy). Typical clinical presentations suggesting crystal arthitides may be due to other causes, and more important, less typical presentations, which are not uncommon, will pass undiagnosed unless crystals are systematically searched for in a synovial fluid sample from all undiagnosed arthropathies. Finally the precision of a clinical diagnosis made by an expert rheumatologist is higher than that of a less experienced or less specialized physician, and by approaching the diagnosis of the crystal arthritides on clinical grounds, expert rheumatologists support the inaccurate approach of other physicians with a wider margin of error. PMID- 21794565 TI - [Role of ultrasound in microcrystalline arthritis]. AB - Ultrasound is a new imaging technique that allows accurately visualize normal and pathological musculoskeletal structures and provide real-time information on the vascular flow. There are a number of ultrasound elemental lesions that alone or in combination are characteristics of gout and chondrocalcinosis. Gout ultrasound is proving to be valid in the diagnosis and monitoring of disease, both in acute as in the chronic and even in asymptomatic hyperuricemia and it is probably the most reliable technique for assessing the size and reduction of tophy. In chondrocalcinosis ultrasound is also proving a superior diagnostic value to other imaging techniques and possibly in the future may be used to monitoring treatment response. PMID- 21794566 TI - [Utility and future direction of echography in the diagnosis of giant cell arteritis]. PMID- 21794567 TI - [Appropriate use of non-steroidal anti-inflammatory drugs in rheumatology: guidelines from the Spanish Society of Rheumatology and the Mexican College of Rheumatology]. AB - OBJECTIVE: To develop guidelines for the appropriate use of NSAIDs in rheumatology. METHODS: We used a methodology modified from the one developed by RAND/UCLA. Two groups of panellists were selected, one by the CMR and another by the SER. Recommendations were proposed from nominal groups and the agreement to them was tested among rheumatologists from both societies by a tworound Delphi survey. The analysis of the second Delphi round supported the generation of the final set of recommendations and the assignment of a level of agreement to each of them. Systematic reviews of five recommendations in which the agreement was low or was divided were also carried out. RESULTS: Here we present recommendations for the safe use of NSAIDs in rheumatic diseases, based on the best available evidence, expert opinion, the agreement among rheumatologists, and literature review. The trend is to reduce the frequency, duration and dose of NSAIDs in favour of non-pharmacological measures, analgesic drugs or disease modifying drugs. In addition, the recommendations help to identify profiles for increased toxicity, with an emphasis on gastrointestinal and cardiovascular risks. The recommendations deal with the course of action and monitoring in different risk groups and in patients using antiplatelet or anticoagulant drugs. The overall level of agreement is high. CONCLUSIONS: The NSAIDs are safe and effective drugs for the treatment of rheumatic diseases. However, it is necessary to individualize its use according to their risk profile. PMID- 21794568 TI - [Osteopenia in primary health care patients: ?do we need to be more rigorous?]. AB - AIM: To describe the treatment prescribed to osteopenic women seen at an urban primary health care centre and the treatment compliance of those patients with a prescription of calcium and/or vitamin D. MATERIALS AND METHOD: Cross-sectional study, osteopenic women diagnosed by bone densitometry between February 2005 and January 2006 (n=121). Clinical history review: demographic information; previous clinical history of bone fracture, type of fracture; parental history of fractures; tobacco use; osteoporosis-related medication or disease; dietary and sun exposure assessment; calcium, vitamin D and raloxiphene/bisphosphonates prescription; mean daily dose of calcium and vitamin D supplements collected at the pharmacy by patients. Analysis of treatment prescription and compliance according to the information collected was performed. RESULTS: Mean age, 61.9+/ 9.1 years; 90.7% post-menopausic. The dietary assessment was performed in 30.5% of the women included in the study. The drug prescription was as follows: calcium 74.6%, vitamin D 68.6% and raloxiphene/bisphosphonates 16.1%. All drug prescriptions were associated with lower T-score values. The patient's compliance of calcium supplements has been calculated as mean of 423.8+/-321.7 mg/day, and 343.1+/-225.9 IU of vitamin D; with no association with any of the studied variables. CONCLUSIONS: We identified greater drug prescription in those patients with a lower T-score. The clinical history of previous fracture did not show association with drug prescription nor a better compliance. There was a lack of information about relevant issues in the clinical history of the osteopenic women included in the study. The patient's compliance of calcium and vitamin-D supplements is very variable. PMID- 21794569 TI - [Polyarticular septic arthritis: analysis of 19 cases]. AB - OBJECTIVE: Polyarticular septic arthritis accounts for 15% of all septic arthritis, but there are few references in the literature. We describe characteristics of patients with polyarticular septic arthritis in a rheumatology service. PATIENTS AND METHOD: Retrospective analysis of patients with septic arthritis involving more than one joint. Only patients with positive culture of synovial fluid were included. Clinical, analytical and radiological variables are reviewed. RESULTS: 19 patients (14 male) had a polyarticular infection. Mean age was 55 years. Mean time from onset to diagnosis was 6 days. The knee was the most commonly involved joint, followed by ankle. The mean number of joints involved per patient was 3. Risk factors included diabetes, chronic renal or hepatic disease, gout and rheumatoid arthritis. Most commonly isolated agents were S. aureus (47%) and S. agalactiae (21%). Blood cultures were positive in 52,6% and 15.8% had septic shock. Scintygraphic bone scan showed a polyarticular uptake. Mean duration of antibiotic therapy was 46+/-27 days. Clinical outcome was good in 52,6%, complicated in 26%, and mortality rate was 15.8% (3 cases). Joint debridement was performed in 21%. CONCLUSIONS: Multiple joint involvement does not exclude the diagnosis of septic arthritis. Inflammatory arthritis is an important risk factor. S. aureus in the main infectious agent. The morbidity and mortality of this condition are important, so we need to maintain a high index of suspicion for the condition. PMID- 21794570 TI - [The therapeutic blockade of TNF reduces serum levels of interleukin 15 in patients with rheumatoid arthritis]. AB - OBJECTIVE: To analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL-15). To determine whether baseline IL15 serum levels or their response to aTNF therapy can predict the clinical response to this treatment. PATIENTS AND METHOD: We studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after three months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying anti-rheumatic drugs (DMARD), etc. We defined remission as a DAS28 < 2.6 and clinical response when the decrease in DAS28 value was higher than 1.2. RESULTS: There was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after three months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 were associated with a specific pattern of response to aTNF. CONCLUSIONS: Our data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy. PMID- 21794571 TI - [Efficacy of rituximab combined with cyclophosphamide in a patient with systemic lupus erythematosus and peritoneal vasculitis refractory to conventional inmunosupressive therapy]. AB - Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis). PMID- 21794572 TI - [Sarcoidosis-lymphoma syndrome]. AB - Sarcoidosis may occur in association with lymphoma (sarcoidosis-lymphoma syndrome), it is an uncommon but well-known association. Some clinical features can be similar and clinicians have the challenge to differentiate between these two diseases or prove their co-existence. Clinical and laboratory data are not characteristic in any of them, and an anatomopathological study of lymphadenopathy is necessary to establish the diagnosis. The sarcoidosis-lymphoma syndrome could occur as a result of a disturbance in the host immune system in sarcoidosis and in some patients with solid tumors or hematologic malignancies who have received chemotherapy. We present a case report of a patient with sarcoidosis-lymphoma syndrome. PMID- 21794573 TI - [Interleukin 6 in the physiopathology of rheumatoid arthritis]. AB - Interleukin (IL) 6 was identified in 1986 as a factor produced by T lymphocytes, that mediates growth and immunoglobulin synthesis on B lymphocytes. IL-6 is a member of a large cytokine family sharing a gp130 membrane receptor. This receptor mediates specific Jak/STAT3 activation, which induces widespread expression of pro-inflammatory and immunoregulatory genes. IL-6 mediates potent systemic responses, in organs distant from its local inflammatory sources, in a prominent fashion compared to other cytokines. Most specific effects involve hematopoiesis and hepatic acute phase reactants synthesis. IL-6 became a rheumatoid arthritis (RA) target due to its pro-inflammatory and joint destructive potential, as well as its participation in T and B immunoregulation. The therapeutic success of tocilizumab has confirmed IL-6 as an RA target. Although additional studies on the participation of IL-6 in RA physiopathology are needed, a number of indirect data point to a relevant position in this setting. PMID- 21794574 TI - [Sacroiliac joints: osteoarthritis or arthritis]. AB - One of the most challenging aspects of treating the sacroiliac joint (SIJ) pain is the complexity of diagnosis. Imaging methods have gained importance for the diagnosis of SIJ diseases. CT and MR exams had equal efficacy superior to radiography in staging structural changes in the SIJ due to osteoarthritis or sacroiliitis. The diagnosis of spondyloarthropaty can be delayed for several years using certain radiography studies. MR imaging reveal early cartilage changes and active inflammatory changes in the subchondral bone and surrounding ligaments in spondyloarthropaties, as well as subperiosteal and transcapsular yuxtaarticular infiltrations characteristic of septic sacroiliitis, which could not be found by either CT of radiography. T1-WI with fat suppression (FS) and STIR images improve the demonstration of erosions and inflammatory changes respectively, on MR studies. Additional T1-FS after i.v. contrast has proven valuable in demonstrating the extension of inflammatory changes and abscesses in septic sacroiliitis, and in spondyloartropaties may be useful although this is debatable. Scintigraphy gives high sensibility only in early inflammatory changes and low specificity for the diagnosis of sacroiliitis due to high bone turnover in the SIJ, although specific radioprobes are useful in confirming the septic etiology and evaluating additional foci. This complex joint of very limited mobility shows a lot of structural variations and some anatomical degenerative changes due to age, which are necessary to know to an adequate image interpretation and diagnosis of disease. PMID- 21794575 TI - [Septic arthritis caused by Staphylococcus lugdunensis]. PMID- 21794576 TI - [Communication skills with patients. The psychologists' point of view]. PMID- 21794577 TI - [A study on the subjective compliance and acceptance of oral lanzoprazole in traumatology. The ECOFT-TR Study]. AB - OBJECTIVE: To assess compliance with oral lansoprazole disintegrating tablets (LODT) in patients treated by traumatology specialists. MATERIAL AND METHOD: A multicenter, observational, cross-sectional study involving 370 traumatology specialists and patients aged 18 or more. Study logistics were sponsored by Almirall Laboratories, S.A.; neither investigators nor patients received any economic compensation for their participation. Patient subjective compliance with LODT was assessed with the Haynes Sackett test. Acceptability was based on patients' global assessments of the drug's organoleptic characteristics and properties of use, and preferences regarding previous treatments, recorded by means of a self-administered 15-item ad hoc questionnaire with a 2-5-point Likert type scale, that patients fulfilled once. RESULTS: One thousand and eighty five patients were evaluable for the main endpoint. Mean age was 56.09+/-13.8 years; 56.77% were women. Mean treatment duration was 51.24+/-38.8 days. 94.74% of the patients complied with the treatment. Mean percentage of compliance was 94.5+/ 12.12; 91.09% of patients rated the treatment as "acceptable or highly acceptable". No significant differences were observed between compliant and non compliant patients in terms of demographic or clinical variables. Mean percentage of compliance was significantly higher among patients without concomitant illness or treatment and without difficulties in taking tablets. One non-serious adverse reaction was reported in one (0.09%) patient. CONCLUSIONS: Compliance with lansoprazole orally disintegrating tablets was high. Patients reported that this formulation improved their compliance and that they preferred LODT to previous medication. Tolerability was excellent. PMID- 21794578 TI - [Classification of fibromyalgia. A systematic review of the literature]. AB - OBJECTIVE: To review the scientific literature concerning the classification of fibromyalgia (FM), including previous studies focusing on the gnosologic evaluation of FM, with the aim of proposing a classificatory hypothesis based on the current scientific evidence. METHODS: Systematic review using a baseline MEDLINE search. Search terms included "fibromyalgia" and "classification". Additional articles were identified through a comprehensive manual search of the references of retrieved articles. RESULTS: This systematic review has identified, on the one hand, several classificatory proposals based on psychopathological aspects, and, on the other hand, the key role of associated diseases. Based on the scientific evidence currently available, the following FM subsets were defined: patients with no associated processes (type I FM), patients with associated rheumatic/autoimmune chronic diseases (type II FM), patients with severe psychiatric disorders (type III FM) and patients with simulated FM (type IV FM). CONCLUSIONS: Few studies have specifically analysed the classification of FM into subgroups with a more homogeneous clinical expression. Correct classification of patients with FM requires the integration of two key concepts (psychopathological evaluation and coexistence of comorbid processes), with an individual diagnostic evaluation by a multidisciplinary team. PMID- 21794579 TI - [Differences in the frequency of osteoporosis according to the skeletal site evaluated. Analysis in 987 Spanish postmenopausal women referred to a bone densitometry unit]. AB - OBJECTIVE: To analyze the differences in the frequency of osteoporosis according to the skeletal site evaluated in a group of Spanish postmenopausal women. METHODS: We reviewed the data of 987 postmenopausal women (mean age, 53.8+/-5.5 years). BMD status was evaluated by DXA. We used the WHO thresholds to classify the patients. T-score was obtained from the single evaluation of each lumbar vertebra (L2, L3 and L4), the mean value of lumbar spine (L2-L4), femoral neck and total hip. RESULTS: In 144 (14.7%) women, discrepancies were observed when we considered the single vertebral analysis versus the L2-L4 analysis; 62 (6%) women who presented osteoporosis in at least one vertebra would have been due to the osteopenia category when L2-L4 value was selected. In 271 (27.8%) women, discrepancies were observed when we considered the total hip analysis versus the femoral neck analysis. The frequency of osteoporosis ranged from 3% when only the analysis of the total hip was considered to 16% when the results of L2-L4 and proximal femur (total hip or femoral neck) measurements were selected. CONCLUSIONS: Frequency of osteoporosis varies notably according to the skeletal zone considered. PMID- 21794580 TI - [A comparison of leflunomide and subcutaneous methotrexate in the treatment of rheumatoid arthritis: an approximation based on the number needed to treat]. AB - OBJECTIVE: To compare, in the Spanish setting, two drugs for adults with rheumatoid artritis (RA): leflunomide and subcutaneous methotrexate (SC). The high price of methotrexate SC compared with traditional presentations of methotrexate justifies conducting an economic evaluation comparing it with leflunomide. METHODS: The analysis considered the annual costs of the drugs and their effectiveness, measured with a Number Needed to Treat (NNT) approach, considering both the ACR20 and ACR50 criteria for effectiveness. Data about efficacy and dosage were derived from the clinical trial US310, a randomized, doble-blinded controlled trial, which compared efficacy and safety of leflunomide (20mg/daily) vs placebo vs methotrexate (7.5-15mg/weekly) in 482 patients with active RA. Data about use of medical resources for drug monitoring (visits to rheumatologists and diagnostic procedures) were derived from the manufacturers' summary of product characteristics. Direct costs (drugs and monitoring) were obtained from two Spanish databases. The analysis has been performed under the Spanish National Health System perspective. RESULTS: Using the ACR20 criteria, the NNT with leflunomide and methotrexate are 4 (95% CI, 2.56-7.71) and 5 (95% CI, 3.03-14.3) respectively. Using the ACR50 criteria, NNT are 4 (95% CI, 2.72 6.54) and 7 (95% CI, 4.03-19.3). In the case of leflunomide, annual treatment costs per patient-year equals 1,793.30?; in the case of methotrexate total treatment costs amounts to 2,149.20?. CONCLUSIONS: Combining these results the cost of a controlled patient according to ACR20 would amount 7,173? for leflunomide and 10,746? for methotrexate SC. Results considering ACR50 are 7,173? and 15,044? for leflunomide and methotrexate respectively. PMID- 21794581 TI - [Extrahepatic manifestations in patients with chronic infections due to the hepatitis C virus]. AB - Autoimmunity and viral infections are closely related, and viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SAD). The hepatitis C virus (HCV), a linear, single-stranded RNA virus, identified in 1989, is recognized as one of the viruses most often associated with autoimmune features. The association between HCV and SAD has generated growing interest in recent years. The extrahepatic manifestations often observed in patients with chronic HCV infection (both clinical and immunological) may lead to the fulfilment of the current classification criteria for some SAD. PMID- 21794582 TI - [Pneumomediastinum and diffuse alveolar pain. Severe interstitial pneumopathy due to dermatomyositis]. AB - We have recently observed the case of a 36-year-old man with dermatomyositis of recent onset, who developed masive pneumomediastinum and subcutaneous emphysema at the onset of a progresive and severe pulmonary disease. Although there were no sign of parenchymal cysts, after the bronchoscopy it was possible to observe endobronchial necrotic injury which was considered as the likely source of the air leak. He was treated with high dose of corticosteroids, cyclophosphamide and cyclosporin A which resulted in the disappearance of the pneumomediastinum and subcutaneous emphysema and the progressive improvement of both parenchymal lung disease and respiratory insufficiency, enabled us to progressively taper the dose of corticosteroids. PMID- 21794583 TI - [Fracture and dislocation of the atlanto-axial joint after mild trauma in a patient with rheumatoid arthritis]. PMID- 21794584 TI - [Follow up and prognostic value using magnetic resonance imaging in patients with spondyloarthritis treated with biologic agents]. AB - Early diagnosis and assessment of the response to treatment in patients suffering from spondyloarthritis have always been challenging due to the lack of imaging techniques able to demonstrate spinal and sacroiliac inflammation. The last 2 years have seen important advances in the use of magnetic resonance imaging (MRI) for the study of spondyloarthritis. The possibility of quantification of inflammatory lesions using different scoring systems allows not only an early diagnosis, but the assessment of the response to several therapeutic agents, especially those known as "biological therapies". A number of randomized controlled trials of anti-tumor necrosis factor agents have been published showing regression of inflammatory lesions in MRI. This review discusses briefly the techniques and scoring systems used and all the evidences that exist about assessing treatment in spondyloarthritis. PMID- 21794585 TI - [Dyspnea in a patient with systemic lupus erythematosus]. AB - A 33-year-old woman with a previous history of systemic lupus erythematosus complained of exerptional dyspnea and pleuritic chest pain accompanied by polyarthritis. Chest-X-rays revealed an elevation of the right hemidiaphragm. We discuss the diagnostic and therapeutic approach. PMID- 21794586 TI - [Cardiovascular risk associated to NSAID: increased or reduced?]. PMID- 21794587 TI - [Replay]. PMID- 21794588 TI - [Cardiovascular disease in rheumatoid arthritis. Importance and clinical management]. PMID- 21794589 TI - [Relationship between individual radiographic findings and disability in rheumatoid arthritis]. AB - OBJECTIVE: To evaluate if the duration of disease influences the link between different radiographic specific features and disability in rheumatoid arthritis (RA) and the influence of disease duration on this relationship. METHODS: Conventional X- rays of both hands of 96 patients with RA were evaluated independently by 2 readers using Kayes' modification of the Sharp method. Disability was evaluated with the Spanish version of the HAQ questionnaire. RESULTS: The mean HAQ was 1, 39 +/- 0, 79. The mean total radiographic score was 0.8 (18% of the maximum possible score). Total and joint space narrowing scores only displayed a statistically significant correlation (r=0.33, r=.37, respectively, P<.05) with disability in the late RA group (>7 years). Erosion and malalignment scores were not correlated with HAQ. There was a statistically significant correlation between the eating, dressing and reach HAQ-categories and the total radiographic score in the late RA group (r=0.48, P<.001, r=0.42, P<.01, r=0.3, P<.05, respectively). CONCLUSION: This work suggests that HAQ disability and radiographic damage are only related in cases with late RA. In this group, the subtotal radiographic score most related with disability is the joint space narrowing score. PMID- 21794590 TI - [Measurement of health-related quality of life and functional capacity in patients with chronic tophaceous gout]. AB - INTRODUCTION: In gout there are few instruments validated for the evaluation of activity, functional capacity or quality of life. It is not known if generic instruments such as the MOS-20, or specific for other illnesses, such as the AIMS, can be applied to patients with Gout. OBJECTIVE: To evaluate the clinimetric characteristic of the MOS-20 and AIMS questionnaires, and their correlation with HAQ-DI, as well as with clinical variables in patient with tophaceous gout (TG). METHODS: 49 patients with TG were included. Demographic and clinical variables were obtained. The 3 questionnaires were applied at the basal evaluation. A second evaluation was applied to 20 patients, 8 weeks later. RESULTS: All patients were male. The time of since onset of the illness was 14.9+/-8.3 years. The HAQ-DI was 0.43+/-0.56 with an alpha of Cronbach (alphaC) of 0.95 and the intraclass correlation coefficient (ICC) was 0.86. The MOS-20 had an alphaC of 0.68 to 1.0 and a ICC of 0.27 to 0.61 between the several components. The AIMS had an alphaC of 0.66 to 0.96, and a ICC of 0.11 to 0.79 between the several components. Reliability was better between the physical components in MOS-20 and AIMS. The MOS-20, AIMS and the HAQ-DI correlated with the presence of joints with functional limitation. There weren't any significant differences among the patients with inflamed joints, nor in those with tophi. The HAQ-DI was best correlated with the physical component than with the mental component of the AIMS and the MOS-20. CONCLUSION: The AIMS, the MOS-20 and the HAQ-DI are useful in measuring the functional capacity and the quality of life in patient with TG. PMID- 21794591 TI - [Characteristics of Paget's disease in Spain. Data from the National Paget's Register]. AB - OBJECTIVES: To describe the clinical and epidemiological characteristics of patients included in the National Register of Paget's disease. METHODS: A Register of patients with Paget disease (PD), radiologically confirmed, and pertaining to 25 hospitals was analysed. Clinical and epidemiological data were collected, including age, sex, date and presentations at time of diagnosis, treatment, quality of life (QL) (EuroQol 5D) and perceived health, environmental factors (profession, history of measles, contact with animals, dairy consumption, housing conditions, place of birth and address) and family history (PD history, origin of the ancestors, number of children). We conducted a statistical description of the data. RESULTS: The register included 602 patients with an average age of 62+/-11 years and a predominance of male (55%). Of the patients included, 79% showed symptoms at the time of diagnosis, mainly pain (83%); 82% had received treatment, mainly bisphosphonates (47% more than one drug). Despite treatment, a significant proportion had limitations in their QL, especially related to pain (64%), mobility (47%) and anxiety/depression (33%). Most of the patients had been exposed to situations which were considered as risk factors. Of the patients included, 14% had family history of PD and 1.5% had children with PD. The ancestors of the familial cases came more frequently from Avila, Salamanca, La Coruna and Malaga. CONCLUSIONS: The pain and the limitation of mobility decrease the QL of patients with PD despite treatment. Frequently, patients have a history of exposure to risk factors. PMID- 21794592 TI - [What are patients with early rheumatoid arthritis like in Spain? Description of the PROAR cohort]. AB - OBJECTIVE: To identify factors present in recent onset arthritis that may help to predict rheumatoid arthritis (RA), and to describe a cohort of recent onset RA. PATIENTS AND METHOD: A 5 year prospective cohort of patients with early oligo and polyarthritis (< 1 year of evolution) from 34 rheumatology units, was studied. Sociodemographic, clinical features and RA risk factors were recorded. Rheumatoid factor (RF), anti-CCP determinations and radiographs of hands and feet were analyzed too. After three years, a diagnosis of certainty and the variables that determined the evolution to RA, were evaluated. RESULTS: One hundred and seventy one patients were included; 161 (94.2%) fulfilled RA diagnostic criteria; most of them (157; 97.5%) in the first visit. Factors associated with RA diagnosis were: positive RF, anti-CCP and DAS-28; 65% of the patients had radiological erosions in the first visit. CONCLUSIONS: Positive RF, anti-CCP and the disease activity are predictive factors of RA. Radiological damage exists very early in most of patients, that's why it is more important to treat the disease aggressively instead than achieving an RA diagnosis of certainty. PMID- 21794593 TI - [Inhibition of interleukin 6, a new therapeutic option in rheumatoid arthritis]. AB - Tocilizumab (TCZ) is a humanized monoclonal antibody which targets the receptor for IL-6, developed by the Japanese pharmaceutical company Chugai and the swiss company Roche. In Japan it is already under use for Castleman's disease, rheumatoid arthritis (RA) and Juvenile Idiopathic Arthritis. The clinical development outside Japan is very extensive and has shown efficacy in possible RA scenarios; early RA (part of the AMBITION study), established, MTX-resistant RA (OPTION) and RA resistant to other DMARD (TOWARD), and anti-TNF-alpha resistant RA (RADIATE). Both monotherapy with TCZ (AMBITION) and associated to other background drugs. Radiological efficacy has also been proven (LITHE). So TCZ is probably the biologic therapy with the most extensive clinical development before marketing in the western hemisphere. In this review we will specifically deal with clinical and radiological efficacy, as wel as its safety profile. PMID- 21794594 TI - [Lipoma arborescens of the bicipital bursa]. AB - Lipoma arborescens is a rare benign entity characterized by proliferation of villous fat tissue in subsynovial layer that usually affects the knee joint. We report a case of lipoma arborescens in bicipitoradial bursa of the elbow in a 44 year-old female patient. In spite of this rare location, radiographic findings by ultrasonography and magnetic resonance imaging made diagnosis possible. PMID- 21794595 TI - [Right elbow pain and inflamation in a 55 year-old woman]. PMID- 21794596 TI - [Imaging studies in cases with painful shoulder]. AB - Painful shoulder is a frequent clinical problem in musculoskeletal pathology. Imaging plays an essential role in the etiologic diagnosis. Simple X-rays are usually the first performed diagnostic test, and on occasion, it is enough to establish a diagnosis. Tendinous calcifications are clearly depicted on plain radiographs, which are a first option modality in the evaluation of bone tumors. Tendinous pathology is the most common cause of shoulder pain. It may be analysed either by ultrasound or magnetic resonance (MR). MR is the most sensitive technique to detect early pathological changes. MR is usually used in the presurgical evaluation of the shoulder and in local staging of bone and soft tissue tumors. PMID- 21794597 TI - [Mexican rheumatologists. National distribution in 2007 and projected distribution for 2025]. PMID- 21794598 TI - [Not Available]. PMID- 21794599 TI - Treating severe systemic lupus erythematosus with rituximab. An open study. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that may be associated to high morbidity and mortality. Disease course is variable and unpredictable and although the prognosis and survival of these patients has dramatically improved, treatment of severe multiorganic organic affection in this condition remains a therapeutic challenge. Since B lymphocytes have an important role in the pathogenesis of SLE, it is expected that the targeting of these cells exerts a significant therapeutic effect in SLE patients with severe multiorganic manifestations. In an open clinical trial, we have explored the therapeutic potential of Rituximab (an anti-CD20 monoclonal antibody) administration in SLE patients with severe nephritis (n=22) or neuropsychiatric manifestations (n=6) or massive pulmonary hemorrhage (n=3). In most cases, we observed significant improvement in both clinical and laboratory parameters, with good tolerance and few side effects. Thus, patients with severe lupus nephritis showed improvement in disease activity (MEX-SLEDAI index) with a significant reduction (p<0.05), as well as proteinuria in most of them (from 3.710g/L to 1.786g/L, p<0.05); patients with serious neurologic involvement had complete remission of their manifestations; but those with pulmonary massive hemorrhage did not have any response. Rituximab could have an important therapeutic potential in severe SLE, and that it is necessary to carry out a controlled blinded clinical trial to further support this point. PMID- 21794600 TI - [Characterization of patients with rheumatoid arthritis according to the health care level]. AB - OBJECTIVE: To characterize rheumatoid arthritis patients seen in Rheumatology Units at different health care levels. MATERIAL AND METHODS: Questionnaire and clinical examination of rheumatoid arthritis patients seen as outpatients in Rheumatology Units from Primary Care, county Hospitals and Reference Hospitals. Demographic, social, labour and disease data were collected. Statistical study included a description of the variables and a multiple correspondence analysis to define patient profiles. RESULTS: Eight hundred and twelve patients with rheumatoid arthritis were included. There were significant differences in patient profiles at the different care level. In Primary Care, patients were older, with basic studies, and with short duration and generally mild rheumatoid arthritis. In local hospitals the typical patient was a man, qualified worker, with low income, and an erosive disease with extraarticular manifestations. At reference Hospitals prevailing patients were young women with a long duration disease and requiring biological therapy. CONCLUSION: There are significant differences in rheumatoid arthritis patient profiles at different health care levels. PMID- 21794601 TI - [Clinical characteristics of children with scleroderma in a referral hospital]. AB - INTRODUCTION: Scleroderma is an autoimmune disease that involves the connective tissue characterized by skin fibrosis, classified as localized and systemic (participation of one or more internal organs). The primary objective of this study is to describe and analyze the clinical and laboratory findings in a group of children diagnosed with scleroderma at a referral hospital. MATERIAL AND METHODS: Extraction of data from clinical charts of children with scleroderma in the rheumatology department at the Hospital Infantil de Mexico Federico Gomez, between January 2000 and December 2007. RESULTS: Sixty two patients were included in the group. All of them completed the classification criteria for juvenile sclerodema, both systemic and localized. The mean age at diagnosis was 7.8 (1-14) years. The mean time from disease onset to diagnosis, based on clinical manifestations, was 23 months. The lesions found were: linear scleroderma (42%), mixed morphea (22%), circumscribed morphea (19%), generalized morphea (13%) and panclerotic morphea (4%). Involvement associated with Systemic Scleroderma was gastrointestinal 100% (18 patients), pulmonary 100% (18/18), Raynaud's phenomenon 89% (16/18), proximal sclerosis 89% (16/18), sclerodactilia 67% (12/18), joint pain 28% (5/18), calcinosis 56% (10/18). Positive antinuclear antibodies (ANA) were present in 14/62 (23%) patients (10 with systemic range and 4 localized), antiSCL 70 in 2/62 (4%) cases. The most common drug used was methotrexate. CONCLUSION: The most common skin lesions found were linear morphea, followed by the mixed and circumscribed types. In systemic scleroderma the most involved systems are the gastrointestinal, respiratory and vascular (associated with Raynaud's phenomenon). There is a special need for knowledge of this disease in first contact physicians for a faster and better diagnosis and treatment, in order to avoid complications. It is also necessary to improve resources in developing countries for complimentary studies, classification, treatment and follow-up. PMID- 21794602 TI - [Effect of low-intensity pulsed ultrasound on regeneration of joint cartilage in patients with second and third degree osteoarthritis of the knee]. AB - OBJECTIVE: To determine if the application of low intensity pulsed ultrasound (LIPUS) therapy has a positive effect over the cartilage repair, functional status and reduction of pain in patients with grade 2 or 3 osteoarthrosis of the knee. DESIGN: This trial was an observational, before and after study without a control group, in which 10 patients (eleven knees) were studied. We applied LIPUS therapy with an intensity of 0.3W/cm(2), duty cycle of 50%, giving a total of 36J/cm(2) per session during 36 sessions (three months). The clinical measures were obtained before the first session and at the end of the 36th session, and were: cartilage thickness by the analysis of magnetic resonance images (MRI) measured by two rheumatologists and a radiology specialist, pain by a visual analog scale (1-10cm) and function/severity by the Lequesne index. We used the non parametric tests of Wilcoxon for comparing medians and the Spearmans rho for the correlation of the inter observer cartilage thickness measurements defining a p value of<0.05 as significant. RESULTS: We observed an effect on pain (VAS mean before 7.09+-2.54 mean after 4.18+-2.22 p 0.005) and on the function/severity index (Lequesne mean before 10.55+-5.42 mean after 5+-4.45 p 0.008). There was poor consistency regarding the cartilage thickness measures by resonance imaging between the three observers (2 rheumatologists and 1 radiologist) so we were not able to define the presence or absence of effect on cartilage thickness augmentation. CONCLUSIONS: LIPUS has a benefic effect over pain and functionality/severity in patients with Kellgren and Lawrence grade 2 and 3 osteoarthritis of the knee. Unfortunately in this study we did not count with a reliable measure method to conclude on its effect over cartilage thickness measured by MRI. PMID- 21794603 TI - [NeuroBehcet: A case]. AB - Behcet's disease is an inflammatory systemic disorder, with oral and genital ulcers, as well as ophthalmologic and cutaneous disturbances. 5% of the patients have neurological alterations. We present a case of neuroBehcet with a rare neurological involvement. A 28 years-old male patient with recurrent oral and genital ulcer history and folliculitis presents 48h progressive fever, headache, nausea, right sixth cranial nerve palsy and right upper limb paresis. The CSF showed lymphocyte pleocytosis and high proteinorrachia, so antibiotic treatment was initiated. Cerebral MR found hyperintense enhancing lesions in the brainstem and left transverse sinus thrombosis. Patient improved with endovenous corticosteroids and was discharged asymptomatic. Neurological involvement in Behcet's disease is rare and moreover the coexistence of parenchymatous and non parenchymatous alterations in the same patient. It normally has a good response to immunosuppressant treatment. PMID- 21794604 TI - [Validation of questionnaires]. AB - The development of a questionnaire or a measuring instrument is a laborious and complex process and requires verification of its usefulness before implementation. We present a methodological work on the psychometric characteristics of assessment instruments and analysis of their main features, reliability and validity. PMID- 21794605 TI - [Imaging techniques for the evaluation of systemic manifestations of vasculitis]. AB - Vasculitides create a local inflammatory process in the vessel wall, which determines the different organic manifestations according to vessel size and location. Imaging techniques play a key role in the characterization and detection of large and medium size vessel vasculitides. Imaging is able to detect the vessel wall edema and to monitor the therapeutic response. In small vessel vasculitis, imaging can indirectly analyse the organic and/or systemic manifestations, because at present, none of the imaging techniques has the necessary spatial resolution to directly visualize small vessels. PMID- 21794606 TI - [Chronic tophaceous gout: An uncommon localization]. PMID- 21794607 TI - [Auditory damage as part of neurological signs in Behcet disease]. PMID- 21794608 TI - [The great moment of Spanish Rheumatology]. PMID- 21794609 TI - [Assessing the efficacy of non-arthroscopic joint lavage in patients with osteoarthritis of the knee]. AB - OBJECTIVE: To evaluate the efficacy of joint lavage in patients with osteoarthritis of the knee. DESIGN: We conducted an open prospective study involving 111 patients of whom 77% were females. The patients' age range was 43 81 years and the average age 64+/-8.7 years. All patients had gonarthrosis as diagnosed according to the (ACR) American College of Rheumatology criteria (Kellgren radiographic grades II and III). Patients were randomly distributed between two treatment groups: a) Joint lavage without non-steroidal anti inflammatory drugs (NAJL, n=57), and b) non-steroidal anti-inflammatory drugs alone (NSAIDs, n=54). Evaluations were done at baseline and one, three, and six months after enrollment. Clinical and demographic variables, and WOMAC index scores, were recorded and patient improvement was determined by following the OARSI guidelines. Statistical analyses included chi-square, analysis of covariance (baseline WOMAC) with one between-subject factor (treatment). Post-hoc comparisons were made with Sidak's adjustment. RESULTS: The respective improvement rates as measured by the OARSI index for the patients in the JL and NSAIDs groups were 50.9 and 31.5% at 1 month; 55.4 and 38.9% at three months; and 63.2 and 64.8% at six months. The patients in both groups were seen to improve from the first month (P=.038). At the end of the six-month follow-up period, the WOMAC score had decreased significantly in both groups (P=.000), with no significant differences between them. CONCLUSIONS: Six months after treatment, joint lavage proved as effective as NSAIDs in patients with gonarthrosis, so it constitutes an effective therapeutic choice in those cases where NSAIDs are contraindicated. PMID- 21794610 TI - [Synovial sarcomas in Lugo between 2002-2006]. AB - OBJECTIVE: To study the clinical and epidemiological characteristics of all adults patients as having synovial sarcoma in the Hospital Xeral-Calde (Lugo) between 2002 and 2006. PATIENTS AND METHOD: We conducted a retrospective study of the case records of all adults patients diagnosed with synovial sarcoma from January 2002 through December 2006. Patients were considered to be adults if they were more than 18. In all cases a tissue-biopsy sample showing synovial sarcoma was required. The Hospital Xeral-Calde is the only referral center for a population of almost 250.000 people. RESULTS: Four cases (3 women) met the classification criteria for this study. The mean age was 35 years old (range, 22 41). The most common presentation was a palpable mass (mean 6.7cm.) associated with pain in lower extremities. The mean delay for the diagnosis was 17 months, but in one case has been noted as long as 2.5 years. Unlike the neck synovial sarcoma case, a long delay in the diagnosis implied a major tumor size and a higher histologic grade. The mean follow-up was 25.5 months; one patient died 1.5 years after the diagnosis. CONCLUSIONS: The overall annual incidence rate of synovial sarcoma in the Lugo region between January 2002 and 2006 for the population older than 18 years was a minimum estimate 0.32/10(5). Better physician awareness may contribute to the progressive increase in the recognition of this condition, especially in young people presenting with palpable mass. A long delay at the diagnosis implied a poor prognosis. PMID- 21794611 TI - [A bibliometric approach to the Spanish scientific production on rheumatology during the 1997-2006 period]. AB - BACKGROUND: Bibliometric studies have shown their usefulness in the evaluation of science. This methodology was adopted for the analysis of Spanish rheumatologic scientific production during 1997-2006. METHODS: Search phrases were constructed for databases (PubMed, Science Citation Index (SCI), Indice Medico Espanol (IME)). The analysis was based on the results of SCI with bibliometric indicators for scientific production, collaboration, type of document, times cited and the measure of impact factor (FI). RESULTS: The scientific production in Spanish rheumatology recovered 602 documents in PubMed, 1073 in ISI, 627 in IME. The mapping of scientific productivity is similar to other studies (Madrid, Cataluna, Galicia). The "items citables" (citable items, articles and reviews) raised 54 to 98 and the international collaboration raised 3 to 33 documents (1997-2006). The FI for all documents in 1997-2001 was=6,79+/-0,54 and during 2002-2006=9,60+/ 1,24. CONCLUSIONS: This confirms an upward trend in Spanish scientific production in rheumatology with regard to previous studies. PMID- 21794613 TI - [Legionella in a patient with rheumatoid arthritis receiving abatacept]. AB - Abatacept is a new drug available for refractory Rheumatoid Arthritis (RA), as other biologic therapies this drug is not free of potentially serious adverse events. We present a case of a 73 year-old patient treated with abatacept who suffered a Legionella pneumophila type 1 pneumoniae. PMID- 21794612 TI - Clinical significance of antiphospholipid syndrome nephropathy (APSN) in patients with systemic lupus erythematosus (SLE). AB - Antiphospholipid syndrome nephropathy (APSN) is now a well recognized vaso occlusive renal lesion associated with acute thrombosis and chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. Our objective was to evaluate the prevalence and clinical significance of APSN in patients with Systemic Lupus Erythematosus (SLE). METHODS: Kidney biopsy specimens obtained from 162 patients with lupus glomerulonephritis were retrospectively examined for the presence of APSN. Clinical and laboratory data obtained at the time of kidney biopsy and during a mean follow-up of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APSN was examined. RESULTS: We found APSN in 17 (10.4%) patients with lupus glomerulonephritis (GN), 12 with focal or proliferative lesions. Both activity and chronicity indexes were higher in patients with APSN when compared with lupus nephritis without APSN. Patients with APSN had a higher frequency of hypertension and elevated serum creatinine levels at the time or kidney biopsy, as well as a higher frequency of rapidly progressive GN, nephrotic syndrome and death at the end of the follow-up. Anticardiolipin antibodies were found in 52% of those with APSN and in 27% of those without APSN. Serial kidney biopsy specimens were available from 18 patients. An increase of glomerular sclerosis was found in the second biopsy particularly in those patients with APSN in the first biopsy. CONCLUSIONS: APSN is a risk factor that contributes to an elevated prevalence of hypertension, elevated serum creatinine, nephrotic syndrome and increased glomerular sclerosis. APSN should be included in the classification criteria of APS, and the use of appropriate anticoagulant therapy should be tested. PMID- 21794614 TI - [Dermatomyositis]. AB - Dermatomyositis is a form of idiopathic inflammatory myopathy that involves skeletal muscle and skin. The objectives of this review are to briefly describe the cutaneous manifestations of the disease, to raise some questions still debated about amyopathic dermatomyositis, and to reflect current knowledge of an interesting aspect in dermatomyositis as it is the risk to develop malignancy. Although clear evidence for a significant dermatomyositis-cancer association exists, optimal clinical or biological factors that predict an association with cancer have not been identified. Recently, some specific autoantibodies in dermatomyositis have been shown to be associated with internal malignancy. They open up the possibility to have available serological markers for detecting cancer-associated myositis in the near future. PMID- 21794615 TI - [From bone marrow edema to osteonecrosis. New concepts]. AB - The widespread use of MRI in the diagnosis of articular pathology has allowed for an improved knowledge of a series of disturbances that occur with epiphyseal bone edema as a main radiological sign, featured as low signal intensity of the bone marrow on T1 and high signal on STIR and fat saturated T2 sequences. The new etiopathogenic theories postulate a clear differentiation between primary and secondary osteonecrosis. While secondary osteonecrosis is related to risk factors, primary osteonecrosis is a result of a subcondral insufficiency fracture. Both have different characteristic and MRI criteria. The pathogenesis of transient bone edema syndrome (BMES) is currently under discussion, divided between the biomechanic theory and the more classic one that relates to the complex and poorly understood mechanisms associated with complex regional pain syndrome type I (reflex sympathetic dystrophy). The BMES, classically considered a reversible form of osteonecrosis, has enough differentiated features to be considered as a distinct disease. Bone marrow edema can be as extensive in either insufficiency or fatigue stress fractures than in BMES. The diagnostic key is the display of a subcondral bone fracture. These can be resolved or occasionally evolve into a primary osteonecrosis. PMID- 21794616 TI - [Can we see pain?]. AB - Pain is a highly subjective experience that is difficult to measure objectively due to its varied expression. It is defined as a complex sensory-emotional experience, it is modulated by cognitive factors and involves a broad neural system. Functional neuroimaging has helped to define that neural circuit involved in the perception, modulation and response to painful experience, both in healthy controls and in patients with acute and chronic pain disorders. However, functional activation of the so-called "pain matrix" may also be differentially modulated by sensory and emotional processing components. The latter, for example, can influence the intensity to which a stimulus is perceived as painful. Such a threshold seems to be lower in patients with clinical diagnosis of fibromyalgia (FM) and has been linked to an abnormal pattern of activation of the "pain matrix" when assessed with functional magnetic resonance imaging (fMRI), considering a "syndrome of central susceptibility". Supporting an aetiological explanation for FM, studies have noted that a significant proportion of patients with FM demonstrate this abnormal pattern of activation to stimuli of low intensity. Additionally, there is an important and significant temporal dimension to this activation pattern observed in FM patients, where areas commonly associated with the emotional experience of pain show a prolonged response to painful stimuli compared to healthy subjects. Accordingly, fMRI may assist in objectifying the experience of pain in patients with FM in response to nociceptive stimulation. PMID- 21794617 TI - [Bilateral chondritis of the ears]. PMID- 21794618 TI - [Overdose of etoricoxib: 840mg]. PMID- 21794619 TI - [Introducing the new editor of ReumatologiaClinica]. PMID- 21794620 TI - [Reumatologia Clinica. A 5-year review]. PMID- 21794621 TI - [ReumatologiaClinica. A promising future to walk together]. PMID- 21794622 TI - [Economic evaluation of health interventions: the opportunity cost of not evaluating]. PMID- 21794623 TI - [The joint hypermobility syndrome in a Cuban juvenile population]. AB - In order to review the rise in joint hypermobility syndrome, identify the patterns associated with this diagnosis and correlate its most relevant symptoms, we did a descriptive transversal analytic study in a group of 280 young people of both genders between 15 and 17 years of age. A survey was carried out by the authors in order to get reach these objectives. The data were analyzed by means of descriptive statistics and processed with the Epidat3.1 software package. Results are shown in charts. RESULTS: The joint hypermobility syndrome (JHS) was diagnosed in 32 people (11,4% of the population studied) with mean age 15,7 years, predominance in the female sex and in the white skin group (p<0,01) 53.1% of those patients with hypermobility presented skin lesions associated to hereditary diseases of the connective tissue; among them the most relevant clinical sign was the presence of hematomas (p=0.003). Symptoms of dysautonomia were associated to JHS (p?0.05) and correlated positively with the presence of hematomas. Moderate and severe chronic pain was also a feature of patients with the syndrome (p=0.001) and was correlated in a positive manner to the hematomas. CONCLUSIONS: Vascular affection as demonstrated by the formation of hematomas was the skin lesion more important among young people with JHS in this study. These lesions can be representative of the syndrome and a translate a larger damage at the connective tissue level. PMID- 21794624 TI - [Influence of the natural history of disease on a previous diagnosis in patients with gout]. AB - The clinical diagnosis of gout can be quite precise in clinically typical forms. However, in chronic or atypical forms, such precision tends to be diminished in clinical practice. A cohort of 248 patients with a diagnosis of urate crystal arthropathy was studied, sent with a definite clinical evaluation, and data such as severity of the disease, joint distribution and the presence of tophi were gathered. Precision data was analyzed with respect to the referral diagnosis according to the severity parameters and the type of physician sending the patient. The best diagnostic precision was seen in the monoarticular forms that were sent both by the emergency room as well as by family physicians, but not in those sent by other specialists. The presence of oligoarticular forms reduced significantly the diagnostic precision in all of the specialties referring patients. The presence of tophi did not improve diagnostic precision. Chronic and severe forms of gout are frequently wrongly evaluated from the clinical standpoint. PMID- 21794625 TI - Pattern of use and safety of non-steroidal anti-inflammatory drugs in rheumatoid arthritis patients. A prospective analysis from clinical practice. AB - OBJECTIVE: The aim of this study was to determine the prescription pattern and the safety profile of non-steroidal anti-inflammatory drugs (NSAID), including cyclooxygenase-2 inhibitors (COXIB) in patients with rheumatoid arthritis (RA) under a real life clinical setting. PATIENTS AND METHODS: Data was obtained from the EMECAR study, a prospective cohort of randomly selected RA patients (n=789) followed up from 1999 to 2004 in Spain. RESULTS: Upon entry into the cohort, 613 (78%) patients included took or had taken NSAID because of RA. Patients treated with NSAID, compared to those who did not take these compounds, were younger (60 versus 66 years of age) and have had both less cardiovascular (11 versus 20%; p<0.001) and gastric ulcer (11 versus 23%; p<0.001) complications. In the group of patients that used NSAID, RA had been diagnosed earlier (age at onset 47 versus 53; p<0.001) and was more active (DAS28: 4.4 versus 3.7; p<0.001). During follow-up, the percentage of RA patients using NSAID decreased from 78% in year 2000 to 66% in 2004. The use of antiulcer agents increased from 11% in 2000 to 60% in 2004, independently of both the use of classic NSAID or COXIB and the presence of risk factors for NSAID-induced gastropathy. Severe gastric complications and cardiovascular events were infrequent and the incidence was not different between patient who took NSAID and those who did not, as well as between patients treated with classic NSAID or with COXIB. CONCLUSIONS: NSAID are commonly used in the management of RA. These compounds are well tolerated and the frequency of severe adverse events attributed to them is relatively low under daily practice conditions in these patients. PMID- 21794626 TI - [Primary hypertrophic osteoarthropathy (pachydermoperiostosis). Report of two familial cases and literature review]. AB - The primary hypertrophic osteoarthropathy (pachydermoperiostosis) is a hereditary disease characterized by skin thickening (pachydermia), finger clubbing, and proliferation of periosteum (periostitis) with subperiosteal new bone formation. We describe the cases of two brothers of 30 and 24 years, who consulted due to bone pain, arthralgia and oligoarthritis. Pachydermia, hyperhidrosis, seborrhea, digital clubbing, periostosis and non-inflammatory effusions of the knees. The first had been diagnosed with juvenile idiopathic arthritis at age 15, while the youngest also presented with a thoracic scoliosis, hypertrophic gastritis, iron deficiency anemia and glucose intolerance by pancreatic endocrine dysfunction. In both patients, symptoms were controlled satisfactorily with etoricoxib (90mg/day) and risedronate (35mg/week). PMID- 21794627 TI - Nephrogenic systemic fibrosis in a patient with a p-ANCA systemic vasculitis. AB - Nephrogenic systemic fibrosis (NSF) is a fibrosing skin condition of unknown origin. Most cases have been described in patients with acute or chronic renal failure. The cutaneous changes include firm and thickened, indurate skin plaques and papules on the extremities and trunk. Histopathology typically shows an increase in dermal fibroblast-like cells associated with mucin deposition. Previous exposition to gadolinium-based contrast agents was closely associated with its onset. We described a patient with the clinical and pathologic picture of NSF presented after an acute renal failure in the course of a perinuclear antineutrophil cytoplasmic antibodies associated systemic vasculitis. PMID- 21794628 TI - [Gene polymorphisms and pharmacogenetics in Rheumatoid Arthritis]. AB - Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown aetiology with a genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying anti rheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response regarding disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient's genetic profile. PMID- 21794629 TI - [Fiftieth anniversary of the description of the chemical structure of antibodies]. AB - The identification of the antitoxic property of serum in 1890 by Emil von Behring and the introduction of the term "Antikorper" by Paul Ehrlich in 1891 referring to one of the most relevant mechanisms of defense of the adaptive immune system, i.e., the humoral immune response mediators, mark the beginning of modern immunology. The "Y" structure was described 50 years ago by Gerald M. Edelman and Rodney R. Porter. Thus, on the fiftieth anniversary of the description of the chemical structure of antibodies, we consider it appropriate to celebrate this fact by sketching a brief outline and review of these epoch-making achievements. PMID- 21794630 TI - [New imaging techniques in the evaluation of joint cartilage]. AB - Magnetic resonance (MR) imaging provides an excellent spatial resolution to visualize cartilage and define its main properties. Both 1.5 and especially 3 Tesla equipments have become very efficient in showing the whole articular cartilage and classifying the degenerative damage by analyzing morphological, structural and physical properties. MR evaluation of articular cartilage is of great clinical importance due to the prevalence of degenerative lesions and the development of new drugs and surgery-based treatments. In this work we explain the advances in the MR quantitation of the articular cartilage properties, particularly focusing on T2 and T1 relaxation times, the distribution of first pass contrast agent (pharmacokinetic study) and late enhancement percentage. By using specific sequences and adequate measuring techniques, MR allows the evaluation of important parameters such as cartilage surface, thickness and volume; signal intensity and the physical properties related to collagen integrity and edema; cartilage perfusion and endothelial permeability related to neovascularization; and the presence of late enhancement areas, related to proteoglycan concentrations. This information will aid early diagnosis, establishment of the degree of degeneration, assessment of prognosis, definition of therapeutic options and evaluation of treatment effectiveness. The study of the cartilage structural and functional alterations by MR imaging is an excellent biomarker of tissue degeneration. PMID- 21794631 TI - [Massive pleural effusion in systemic lupus erythematosus]. PMID- 21794632 TI - [Cost-effectiveness study of leflunomide vs. methotrexate]. PMID- 21794633 TI - [Response of the author to the letter "Cost-effectiveness study of leflunomide vs. methotrexate"]. PMID- 21794634 TI - [Helper (TH1, TH2, TH17) and regulatory cells (Treg, TH3, NKT) in rheumatoid arthritis]. AB - The immune response foreign antigens require a perfect coordination of cells that participate in its different phases. The objective of the response is the rapid destruction of the microorganisms with a minimum repercussion on self-cells and tissues. The regulation of this process is carried out fundamentally by T lymphocytes. There are two main types of coordinator cells: helper cells, what organize the initial immune response, and regulatory cells, what avoid immune attack against self and once the infection is controlled, disassemble the response. There are three types of helper cells which coordinate answers to intracellular parasites (TH1), helmints (TH2) and extracellular bacteria and fungi (TH17). The hyperfunction of TH17 cells is associated with diseases as reumatoid arthritis, due to the hypersecretion of the proinflammatory citoquine IL17. The condition of helper or regulatory cell is the current object of review. TH1, TH2 and TH17 cells have helper and also regulatory functions. In addition, regulatory T cells play an important role in the coordination of the first moments of the response to viral infection in a direct and indirect way, inducing differentiation of TH17 cells. PMID- 21794635 TI - [Adipocytokines: emerging mediators of the immune response and inflammation]. AB - Scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the effects of leptin, the product of the ob gene, has started to clarify the role of adipose tissue in the physiopathology of obesity related diseases and has helped in the identification of a great number of other molecules (named adipocytokines), some of them with a proinflammatory nature. In rheumatic diseases, adipocytokines derived from the WAT are among the most important factors related to obesity and promote inflammatory and/or autoimmune conditions. In this review we will present the most recent advances in adipocytokine research, with special attention to the role of leptin, adiponectin, resistin and visfatin and inflammatory, autoimmune and rheumatic diseases. PMID- 21794636 TI - [Non-cytokine therapeutic targets]. AB - The arrival of anti-TNF-alpha to the clinic has been the most successful example of translational research. However, clinical experience has shown that these compounds do not induce clinical remission in half of rheumatoid arthritis (RA) patients. Recently, new biological drugs against non-cytokine targets have been available for RA patients. These compounds deplete B cells or interfere with the activation of T cells and have also shown effectiveness in controlling signs, symptoms and structural damage progression in RA. Second generation B-cell depletion therapies are progressing in the pipeline of several pharmaceutical companies. These compounds will likely improve the immunogenicity and formulation of rituximab, but it is improbable that they will improve the remission rate achieved by the anti-TNF-alpha deltarhoupsilongammasigma. Currently, regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors for a number of pathways are tested as new anti inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds representing a significant advance over p38 mitogen-activated protein kinase (MAPK) inhibitors. PMID- 21794637 TI - [Are imaging techniques necessary for defining remission in rheumatoid arthritis?]. AB - Accurate assessment of inflammatory activity in rheumatoid arthritis (RA) is essential to evaluate response to therapy and disease remission. RA remission has been classically assessed by clinical and laboratory parameters. However, subclinical synovitis may explain progression of joint damage in spite of apparent clinical remission in RA patients. Imaging techniques, such as magnetic resonance imaging and high-resolution ultrasonography (US) with Doppler technique, provide a sensitive measure and monitoring of joint inflammatory activity and a more accurate assessment of RA remission than clinical evaluation which may contribute to make optimal treatment decisions. Within the last decade, an increasing number of rheumatologists have progressively incorporated musculoskeletal US as a valuable diagnostic tool in their clinical practice. This technique facilitates the scanning of all peripheral joints as many times as required at the time of consultation. PMID- 21794638 TI - [Biologics as first line therapy in the treatment of rheumatoid arthritis. A posture a favor]. AB - Changes in diagnosis and treatment of rheumatoid arthritis oblige us to question clinical practice. Evidence demonstrates that the combination of biologics and methotrexate in rapid increments leads to larger remission rates than methotrexate alone. The combination has a faster clinical response in activity, physical function, quality of life, fatigue and sleep. But the most significant effect of biologics is on radiographic progression. The reduction in radiological damage has a spectrum that goes from anti-TNF+methotrexate to anti-TNF monotherapy, being less with methotrexate, and independent from improvement in activity; it occurs with all of the anti-TNF drugs and with other targets with different mechanisms of action (anti-CD20, T cell costimulation inhibitors and anti IL-6). The clinical significance of this finding will be seen in the future, when more is known of its impact on the poor outcomes of RA patients. Because methotrexate is an excellent drug, it seems madness to say that all patients should receive biologics+methotrexate, but it is reasonable to consider that a subgroup must receive them from the start. The American College of Rheumatology recommends their use in patients with RA of less than 6 months since onset, with no previous exposure to methotrexate, persistent and elevated activity (<3 months) and poor prognostic factors or those with persistent and elevated activity (3-6 months) independent of poor prognostic factors, and if the patient "has insurance". A final thought would be: Is there a new treatment pyramid which has cost at its base now? PMID- 21794639 TI - [Biologics as first line therapy in the treatment of rheumatoid arthritis. An opposing point of view]. AB - The development of biologic therapies has improved the prognosis of rheumatoid arthritis (RA). However, at present there is not enough evidence supporting that TNF antagonists, anti CD20 therapy or abatacept used as first line therapy provide relevant long-term benefits in daily clinical practice. Furthermore, clinical trials that analyze the effect of the combination of methotrexate (MTX) plus TNF antagonists against MTX monotherapy have shown that the later provides significant clinical responses and relevant radiological damage arrest in patients with early RA. Therefore, considering that in 5-6 months we can detect which patients do not respond adequately to MTX, we can select those patients for biologic therapy avoiding the exposure to the putative adverse events of combination therapy to those patients with optimal response to MTX monotherapy. PMID- 21794641 TI - Inflammation in the molecular pathogenesis of cancer and atherosclerosis. AB - Chronic inflammation, atherosclerosis and cancer are leading causes of death in industrialized society. Epidemiological studies have shown that chronic inflammation predisposes individuals to certain cancers, while anti-inflammatory and anti-oxidant agents may protect against cancer development and metastasis. Inflammation supports the different phases of cancer development through the inflammatory molecules produced by infiltrating immune cells, resident stromal cells and even cancer cells. Although atherosclerosis has been considered to be multi-factorial disease, in which genetic and environmental factors have been implicated, inflammation also significantly contributes to plaque formation and progression, and to stenosis of atherosclerotic lesions. Major nuclear transcription factors and molecular mediators of inflammation that induce altered cell expression of adhesion molecules, proteases, and growth factors are common factors in the microenvironment leading to disease development and progression of both atherosclerosis and cancer. Important pathogenic pathways on atherosclerosis and cancer follow endothelial cell dysfunction and the activation of the hemostatic system and angiogenesis via inflammation-dependent mechanisms represent important features of this dysfunction. Therefore, novel target oriented therapies affecting altered mechanisms of inflammation, angiogenesis and tissue proliferation may similarly inhibit atherosclerosis and cancer. Main treatment strategies include reducing oxidative stress; inhibiting chemokine, cytokine, and growth factor cell signal transmit; down-regulating excess matrix digestion; inactivating nuclear factor-kappa B signal pathway, and interfering with cell cycle regulation. PMID- 21794640 TI - [Treating undifferentiated arthritis. What, when, how and how long?]. AB - With the establishment of early arthritis clinics, patients can now be increasingly attended early in the course of their disease. This means that a significant proportion of these patients cannot be classified into a specific diagnosis using the traditional American College of Rheumatology (ACR) classification criteria. In these patients with undifferentiated arthritis (UA), even more important than assigning a diagnosis is the need to distinguish between patients who will develop a persistent and/or erosive disease and will be candidates for prompt treatment with disease-modifying antirheumatic drugs (DMARD), and patients in whom the disease is self limiting. Serologic markers in combination with clinical features at presentation, integrated into predictive models, are the tools currently available to the clinician for identifying these patients. Several studies have demonstrated the advantages of early treatment in UA. PMID- 21794642 TI - [Management of difficult situations in patients with RA: Cancer]. AB - Rheumatoid arthritis (RA) patients have a higher risk of developing some types of cancer, such as lymphoma or lung cancer. The severity of the disease is associated with a higher risk of developing lymphoma. Anti-TNF-alpha agents do not increase the incidence of neoplasm, but could trigger the onset of lymphoma in a subgroup of RA patients. Anti-TNF-alpha agents have been associated with a higher frequency of non-melanoma skin cancer. Although methotrexate does not increase the overall incidence of lymphoma or solid neoplasm, its use is sporadically associated with the development of lymphoma. These methotrexate induced lymphomas occasionally disappear after withdrawal of the drug. PMID- 21794643 TI - [Management of difficult clinical situations in patients with rheumatoid arthritis: Pregnancy]. AB - Rheumatoid arthritis does not produce special damaging effects on pregnancy and/or fetal health, without taking into account the different risks the diverse medications to which these patients are normally exposed. Globally, non-steroidal anti-inflammatory drugs (NSAID) do not seem to produce fetal alterations when taken during the first part of pregnancy, but their use in the third trimester is contraindicated because of the possibility of an early closure of the arteriovenous ductus. Steroids, such as prednisone, barely cross the placental barrier and can be used safely during pregnancy. With regard to the use of DMARDs during pregnancy, both methotrexate and leflunomide are contraindicated, although experience accumulated through involuntary pregnancies in rheumatic patients exposed to these drugs has not shown an increase in teratogenicity at the doses commonly employed for these diseases. Sulphasalazine or hidroxycloroquine can be used safely in pregnant patients and azathioprine and cyclosporin A do not seem to be teratogenic either, although the use of azathioprine is not recommended due to its mechanism of action. With respect to the use of biologic therapy during pregnancy, available data currently is limited to anti-TNF agents and does not seem to show noxious effects on the fetus nor on the progression of pregnancy. However, experience is still limited and the current recommendation is to avoid pregnancy while under treatment with these drugs. PMID- 21794644 TI - [Management of difficult clinical situations in rheumatoid arthritis: hepatitis]. AB - Treatment of patients with Rheumatoid Arthritis (RA) who also present a chronic infection by the hepatitis B or C virus represents a therapeutic challenge due to the possibility that treatments used for RA can aggravate or reactivate hepatitis, either due to the drugs hepatic toxicity or the increase in viral replication after immunosuppresive treatment. The problem of reactivation of hepatitis has assumed a larger importance in the past 5 years with the publication of several cases of reactivation of hepatitis B associated with anti TNF therapy. In this article we revise both problems, hepatotoxicity and the increase of viral replication, as well as the better strategies to treat these patients. PMID- 21794645 TI - [Management of problematic clinical situations in rheumatoid arthritis patients. Surgery]. AB - Even though clinical management and treatment of rheumatoid arthritis patients has improved, orthopedic surgery is now a common situation in daily clinical practice. Usually, the rheumatologist is who manages the anti-rheumatic treatment in the perioperative period and decisions are not always supported by scientific information of suitable quality. PMID- 21794646 TI - [Update of BIOBADASER]. AB - As of September 1st, 2008 BIOBADASER has included 9352 patients from 100 centers that provide information on 12,136 treatments with biological therapies. Treatment was discontinued in 4281 (35%) occasions, in the same proportion as a result of an adverse event [1,782 (42%)] and inefficiency or loss of effectiveness [1,816 (42%)]. There have been reported 6814 adverse events, of which the most frequent are infections [2,656 (39%)], followed by disorders related to the administration [1,009 (15%)] and disorders of the skin and subcutaneous tissue [521 (8%)]. PMID- 21794647 TI - [Anti-TNF drugs: New results on efficacy]. AB - Anti-TNF drugs have represented a great advancement in the treatment of rheumatoid arthritis since their introduction in the late 1990s. The development of these products has been very similar for etanercept, infliximab and adalimumab, the 3 approved TNF blockers for the treatment of RA. The first studies centered their attention on patients with active disease and refractory to several disease modifying treatments, finding very significant differences when compared to placebo or methotrexate in the ACR improvement scores. Trials in patients who had not been previously treated with methotrexate show less differences between anti-TNF and methotrexate, but becomes more significant when the two drugs are used combined. In this manuscript we analyze the results of the registry of anti-TNF studies with regard to other improvement indexes such as quality of life, reduction in cardiovascular risk, maintained efficacy through time and progression of joint erosions. We also contemplate the possibility of using lower doses than those authorized for rheumatoid arthritis and analyze factors related to a poor prognosis in patients refractory to methotrexate, which is currently the indication for the use of anti-TNF in RA accordiong to the SER consensus. PMID- 21794648 TI - [Rituximab and abatacept in rheumatoid arthritis]. AB - Abatacept and rituximab are two biologic drugs approved in patients with rheumatoid arthritis who have an inadequate response or intolerance to other disease modifying antirheumatic drugs, including one or more tumor necrosis factor (TNF) inhibitors. The current indication for use is the only thing that both drugs have in common because they are different molecules (abatacept is a fusion molecule and rituximab a monoclonal antibody) with different mechanisms of action and different patterns of administration. Both treatments have shown their clinical efficacy, the stop of structural damage and medium term safety in randomized, double-blind clinical trials. In this paper we will review the structure and mechanisms of action of both drugs, presenting studies in which the efficacy and safety data are based and will finally postulate different controversial questions in the use of these drugs. PMID- 21794649 TI - [TNF and cytokines and pain: Beyond the tisular inflammation]. AB - Numerous studies support the participation of cytokines in the transmission of pain, especially in neuropathic pain. Results obtained both from different experimental pain models as well as studies from a clinical perspective implicate diverse cytokines, especially some of a proinflammatory nature, in the physiopathology of chronic pain. Selective pharmacologic manipulation of these pathways key molecules represents and constitutes a treatment opportunity and an answer to this painful pathology which currently has a difficult solution. PMID- 21794650 TI - [Cannabinoid and opioid system in the mechanisms and control of pain]. AB - Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint. PMID- 21794651 TI - [Cognitive and affective aspects of pain]. AB - The influence of cognitive and emotional variables in the perception of pain is currently subject to no doubt, with the admittance that both the intensity and the characteristics of pain are influenced by the subject's cognitive processing. Catastrophism and acceptance seem to be the psychological constructs that are better able to explain the results of treatment applied to pathologies that are accompanied by pain (e.g. fibromyalgia), sometimes having more importance than even the intensity of pain. This review will attempt to describe the main cognitive constructs implicated in pain and the way they act. PMID- 21794652 TI - [Stress and chronic pain: An endocrine perspective]. AB - Chronic stress, understood as a disturbance of the body homeostasis, is partially driven by many hormonal pathways. Prolactine, TSH (Thyrotropin), vasopresin, FSH (Follicle-Stimulating Hormone), LH (Luteinizing Hormone), and GH (Growth Hormone) have been involved in many stress reactions. In acute stress, there are many evidences for the increased both cathecolaminergic and hypothalamic-pituitary adrenal axis. In chronic conditions, these hyperactivations are controversial and some cases may present a true hypoadrenalism. There is no evidence that treating such androgen/glucocorticoids deficiency may relief chronic pain processes such as fibromyalgia. However, treating somatotroph axis dysfunctions (somatostatin, GH/IGF1 [growth hormone/ insulin-like growth factor-1]) with recombinant GH in carefully seleccioned subgroups of fibromyalgic syndrome, offers us an in-vivo model of the capacity of some hormones to modulate pain. PMID- 21794653 TI - [Opioid use in osteoarthritis: From guidelines to clinical care]. AB - Three treatment guidelines for the treatment of knee and hip osteoarthritis (OA) which pick up the aspects of treatment supported by evidence have been published. Opioid drugs have an important role in symptomatic treatment. The guidelines, the effectiveness, and the safety of opioid analgesics in osteoarthritis, as well as its implications in clinical practice are reviewed. Tramadol is the opioid with the biggest evidence of effectiveness and safety, besides being the most used in clinical practice. Strong opioids (transdermic brupenorphine or fentanyl, oxycodone, and morphine) can be used in severe pain that does not respond to other treatments. Opioids can be used in patients that have moderate or severe pain or in those with inadequate response or intolerance to NSAID's. The opioids also have a sedative effect that facilitates sleep and can improve functional limitations and anxiety. The side effects are frequent; they usually appear at the beginning of treatment and are rarely severe, but frequently force to stop treatment. PMID- 21794654 TI - [Non-specific lower back pain: In search of the origin of pain]. AB - Lower back pain is a condition considered benign and with a specific cause determined only in 15% of patients. In the past years this concept has varied, because many papers have described no benign condition leading to back pain, citing their capacity to cause disability. Through many different diagnostic techniques it is possible to identify the structures capable of producing back pain. This identification, and the level of evidence of the interventional techniques, is the aim of this paper. PMID- 21794655 TI - [Pharmacologic treatment of fibromyalgia: Towards chemical neuromodulation]. AB - Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients. PMID- 21794656 TI - [Acute vertebral fracture and vertebral reinforcement techniques]. AB - The high incidence of fractures by fragility and, especially of the vertebral fractures in osteoporotic postmenopausal women, forces us to approach this subject once more. In this manuscript epidemiological data that indicates the magnitude of the problem will be updated. Treatment alternatives to decrease back pain produced by vertebral fracture are will be reviewed, and the prevention of the occurrence of new osteoporotic fractures of any type, through the administration of suitable antiresorptive and bone-forming pharmacological agents to increase bone mineral density will also be addressed. In some patients with painful vertebral compression fractures it is possible obtain an analgesic effect by percutaneous vertebroplasty or by kiphoplasty using polymethylmetacrilate cement or calcium- phosphate cement, injected into vertebral bodies. PMID- 21794657 TI - [Myofascial pain syndrome]. AB - Myosfascial pain syndrome is characterized by regional pain originating in muscle groups or a single muscle, with a tense band of increased consistency and painful to the touch, in which center a trigger point (TP) is found and generates referred pain, spontaneous pain or pain upon palpation. Causes are related to biomechanical over weight factors or muscle over usage and repetitive microtrauma. Its physiopathology is unknown but it is thought to be due to a dysfunction of the neuromotor plate due to excessive acetylcholine liberation. Clinical history, examination and an adequate review of the TG are fundamental to diagnosis. Treatment requires a multidimensional approach. Eliminating the perpetuating factors, patient education and a home-based exercise program are the cornerstone of patient treatment. Physiotherapy, pharmacotherapy and several behavioral treatments are employed in an individualized manner. In treatment resistant cases, infiltration of TP ("dry" puncture, local anesthetics, steroids or botulinic toxin), performed by an experienced physician, has been efficacious. PMID- 21794658 TI - [Idiopathic inflammatory myopathies]. PMID- 21794659 TI - [Epidemiology, etiology and classification]. AB - Idiopathic inflammatory myopathies are a group of heterogeneous striated muscle acquired autoimmune diseases, characterized by progressive symmetrical muscle weakness, elevated serum levels of muscle enzymes, electromyographic abnormalities and inflammatory infiltrates on muscle biopsy. This group of diseases comprises polymyositis, dermatomyositis and inclusion-body myositis. They are considered rare autoimmune diseases, with an overall incidence range of 2 to 10 new cases per million persons at risk per year, with differences in distribution according to age, gender and race. Their etiology is largely unknown, but it likely involves both genetic and environmental factors that contribute to autoimmune disorders, with striated muscle as a common target. PMID- 21794660 TI - [Pathogenesis of the idiopathic inflammatory myopathies]. AB - The inflammatory myopathies, commonly described as idiopathic, are a group of acquired diseases characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical and immuno-pathological features, three major diseases can be identified: dermatomiositis (DM), polymyositis (PM) and inclusion body myositis (IBM). Immunopathogenesis mechanisms are crucial for discriminating between the three different subsets of inflammatory myopathies. DM is a complement-mediated microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens. This article summarizes the main immunopathological markers. The impact of this new knowledge must be defined in relation to potential therapeutic targets for idiopathic inflammatory myopathies. PMID- 21794661 TI - [Outcome measures]. AB - Inflammatory myositis are rare and heterogeneous diseases. Most clinical and therapeutic studies differ in diagnostic and inclusion criteria as well as in improvement measures. Several collaborative study groups have recently developed and validated outcome measures for both activity and damage of these diseases. The broad use of these core set measures will result in standardized clinical studies, with more reliable results that will allow comparing between individual studies. PMID- 21794662 TI - [Clinical manifestations]. AB - Idiopathic inflammatory myopathies are a group of autoimmune diseases that characteristically affect striated muscle. Nevertheless their spectrum of manifestations is very broad, not only muscular. This chapter describes both muscular and extramuscular manifestations of inflammatory myopathies. PMID- 21794663 TI - [Laboratory abnormalities and autoantibodies]. AB - Laboratory tests in inflammatory myopathies (IIM) are of great help in the diagnosis of these diseases. Two main groups can be defined, one of them quantifies the muscle enzymes that reflect muscle inflammation and the other one detects the presence of autoantibodies which reflect the autoimmune process in these diseases. The most important muscle enzyme is creatine kinase and other enzymes to take into consideration are aspartate and alanine aminotransferase, aldolase and lactic dehydrogenase. In the autoantibodies group, antinuclear antibodies are the most important, since they occur in approximately 50-80% of patients with IIM and help define the distinct disease sub-groups. They are divided into myositis specific antibodies (MSA) and myositis associated antibodies (MAA). The most important MSA are anti-Jo-1 antibody which occur in patients with Polymyositis and anti-Mi-2 antibody that occur in patients with Dermatomyositis. PMID- 21794664 TI - [Histological and molecular alterations in inflammatory myopathies]. AB - The histological findings in muscle biopsies of inflammatory myopathies have been divided into 2 groups: A) Endomisial infiltrates mainly by T CD8+, CD4+ and macrophages and B) Perivascular infiltrates by CD4+, B cells and macrophages. The first kind of infiltrate suggests an immune reaction against muscle fibers very common in PM and inclusion body myositis, On the other hand the perivascular infiltrate is a hallmark of DM. It has ben shown that autoantigens related with myopathies such as Mi-2, Jo-1, OJ, PL12, Ku, PM/Scl are able to suffer proteolytic cleavage by granzyme B and other stimulus induced by cytotoxic T cells. In this chapter we will review the histological and molecular findings of inflammatory myopathies but we will also discuss a special group of myopathies related to the presence of antibodies against the SRP complex, in particular the SRP72 and SRP54 antibodies, which are associated with a poor prognosis and clinical outcome and present an inadequate response to conventional treatment. PMID- 21794665 TI - [Imaging techniques and electromyography in inflammatory myopathies]. AB - Different imaging techniques are used for the diagnosis, evaluation and follow-up of inflammatory myopathies; of these techniques, the ones that provide the largest amount of information are ultrasonography and magnetic resonance imaging. Electrodiagnosis in inflammatory myopathies is based mainly on electromyography (EMG), which shows different patterns according to the different disease presentations. In the acute phase, polyphasic potentials with diminished amplitude and duration are seen, whereas in its chronic phases, mixed neuropathic and myopathic patterns are found. After corticosteroid treatment, EMG tends to return to normal. PMID- 21794666 TI - [Myopathies and malignancy]. AB - There is a greater risk of developing cancer among patients with inflammatory myositis, specifically dermatomyositis. This relationship was first described in 1916 by Sterz and has been corroborated in population based studies. This chapter describes clinical and serological characteristics of patients with myositis and cancer, as well as the most common malignancies and diagnostic and prognostic considerations in this group of patients. PMID- 21794667 TI - [Approach to the differential diagnosis of inflammatory myopathies]. AB - Inflammatory myopathies are a group of idiopathic diseases characterized by an inflammatory infiltrate of the skeletal muscles that includes Polymyositis, Dermatomyositis, and Inclusion Body Myositis, each one displaying distinctive histopathological, immunological, and pathogenic features. The diagnosis of Inflammatory Myopathies is suspected on the basis of clinical features and supported by evidence obtained from laboratory tests, plasma levels of muscle enzymes, detection of autoantibodies, electromyography and, recently, magnetic resonance and ultrasonographic image studies have been included into the diagnostic arsenal. A definitive diagnosis relies on the findings in the muscle biopsy, performed before treatment and preferably before severe muscle atrophy has developed. Precision in diagnosis plays a fundamental role in the evaluation of these patients, allowing conclusions to be drawn regarding the response to treatment and prognosis. PMID- 21794668 TI - [Treatment and prognosis]. AB - Diagnosis should include mandatory muscle biopsy to identify inclusion body myositis. Most forms of inflammatory myopathies are still treated similarly, although treatment strategies remain empirical and controlled trials are few. Muscle strength and CPK levels remain the most frequently used measures to monitor disease activity and response to therapy. Corticosteroids are the main pillar of drug therapy but simultaneous use of corticosteroid-sparing drugs may be considered from the start. The most frequently used drugs for combined therapy are methotrexate, azathioprine and antimalarials in cases of dermatomyositis. In refractory cases, especially if life threatening, rituximab has appeared to be effective although there are no controlled trials, and there is some consensus that this should be used prior to Immunoglobulin. Anti TNF antibodies have not been useful in these diseases. Cyclosporin (especially with lung involvement) and Mofetil mycophenolate may also have a role in non responding cases. Treatment of inclusion body myositis remains unsatisfactory. PMID- 21794669 TI - [Systemic lupus erythematosus. "What do we know and where are we heading?"]. PMID- 21794670 TI - New drugs for rheumatoid arthritis: The industry point of view. PMID- 21794671 TI - [Hiperlaxity ligamentous (Beighton test) in the 8 to 12 years of age school population in the province of Granada]. AB - The Beighton test is the most commonly used tool for detecting ligamentous hiperlaxity, characterized by excessive joint mobility. This descriptive transversal study examines a sample of 2956 children (49,9% boys and 50,1% girls), from eight to twelve years of age, living in the province of Granada, The study aims to show the incidence level of hiperlaxity among the school-aged population, while establishing its frequency in relation to gender and age, and determining the area with the highest number of cases within the province of Granada. The Beighton test was used for data collection. The sample showed that 25, 4% of individuals got a positive Beighton result (laxity), and girls had a higher incidence level (62,1%) than boys. The results show as well a similar level of incidence among boys and girls between eight and ten years of age; however, the incidence decreases among younger children (under 8 years). Regarding the geographical areas, the distribution is quite heterogeneous, but we were able to highlight the difference between a result of 50% in Area 4 and 12% in Area 2, due to genetic and racial factors. In conclusion, the results obtained through this study show a lower hiperlaxity incidence compared to the results found in the American continent and they are slightly higher than those from other European and African countries. PMID- 21794672 TI - [Damage in cuban patients with systemic lupus erythematosus. Relation with disease features]. AB - OBJECTIVE: To determine damage presence and predictors factors for its appearance in a cohort of cuban patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: A retrospective cohort study included 80 patients presenting with SLE seen in Rheumatology Service of "Hermanos Ameijeiras" Clinical Surgical Hospital in Havana City, Cuba. Damage was assessed using The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SLIC/ACR), a tool approved for damage measurement. Damage presence was related to initial disease features to diagnose this condition, to sociodemographic elements, to treatments used, and to the disease course time. Statistical analysis had two variants: the univariate and multivariate type using Chi2 and statistical significance was established in p<0, 05. RESULTS: We found that 39 patients (48,8%) had some degree of damage. More involved domains were the musculoskeletal (18,8%), neuropsychiatric, and skin, 16,3%, pulmonary and ocular, present in 15% of cases. In the multivariate analysis, damage was associated with the use of higher than 30 mg/day Prednisone doses for more of 4 weeks (OR=54,68, CI 95%=3,56-97,45, p=0.001), presence of leukopenia (RO=18,73, CI 95%=2,74-62,23m p=0,004), and time course of disease (OR=1,02, CI 95%=1,00 2 1,09, p=0.006). CONCLUSIONS: Damage was practically present in half of the study patients, the most involved domain was the musculoskeletal, and use of higher than 30mg prednisone doses were the factor most associated with the presence of damage. PMID- 21794673 TI - [Fibromyalgia: Patient perception on their disease and health system. Qualitative research study]. AB - OBJECTIVE: To know the experiences and expectations of persons with fibromyalgia towards the health system and its professionals. METHODS: Qualitative study with three focal groups. The first focal group included patients with fibromyalgia, 20 women and 1 man, receiving care in the public health system, with different assistance paths and progression. Informed Consent was required. Content analysis was done. RESULTS: Patients describe a difficult experience, with symptoms that may involve incapacity for daily activities. Until knowing their diagnosis, they feel a lack of understanding and also loneliness. They develop different coping strategies, as looking for information or association. From the health system they expect: attention and a fast diagnosis, accessibility to consultations, medical exams and therapies or an impulse for research. They want trained professionals, proactive attitudes, interest, empathy and information. DISCUSSION: Qualitative methods seem suitable for delving into patient experience. Health assistance must improve patients' quality of life, facilitating their assistance process and offering companionship, interest, comprehension and support. PMID- 21794675 TI - [Therapeutic strategies in antiphospholipid syndrome]. AB - The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous or arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant, anticardiolipin antibodies or antibodies directed to various proteins, mainly beta2 glycoprotein I, or all three. Apart from being "primary" (without any discernable underlying systemic autoimmune disease), or associated to another disease (usually to systemic lupus erythematosus), it may also occur rapidly over days or weeks when it has been termed "catastrophic" APS. Therapy should not primarily be directed at effectively reducing the aPL levels and the use of immunotherapy (including high dose steroid administration, immunosuppression or plasma exchange) is generally not indicated, unless in the catastrophic APS. Treatment of APS patients should be based on the use of antiaggregant and anticoagulant therapy. PMID- 21794674 TI - [Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis]. AB - OBJECTIVE: To provide a reference to rheumatologists and to those involved in the treatment of RA who are using, or about to use biologic therapy. METHODS: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. RESULTS: We have produced recommendations on the use of the seven biologic agents available for RA in our country. The objective of treatment is to achieve the remission of the disease as quickly as possible. Indications and nuances regarding the use of biologic therapy were reviewed as well as the evaluation that should be performed prior to administration and the follow up of patients undergoing this therapy. CONCLUSIONS: We present an update on the SER recommendations for the use of biologic therapy in patients with RA. PMID- 21794676 TI - [Drugs employed during pregnancy and contraceptive methods in rheumatic disease. New evidence]. AB - Voluntary birth control, the ability to identify the best moment for becoming pregnant depending on disease activity, and the need to avoid conception during the administration of teratogenic drugs are the main reasons for the use of contraceptive methods among women with rheumatic diseases. This article reviews the risks that antirheumatic drugs represent during conception, pregnancy and lactation and the contraceptive methods that are currently available to patients. Hormonal therapy has developed considerably and can further our understanding of safety aspects, especially for systemic lupus erythematosus patients. Recently the methods of administration have evolved, and now include transdermal and intravaginal routes, a progesterone-releasing intrauterine device, and an extended-cycle oral contraceptive. Rheumatologists work increasingly in conjunction with patients to assist in choices regarding contraceptive methods and pregnancy planning. Each decision should be individualized according to the personal preference and the stage of reproductive life. PMID- 21794677 TI - [New advances on diagnostic imaging in spinal pathology]. AB - In the past years, there has been a remarkable improvement on imaging technology. Magnetic resonance (MR) is the method of choice for detection, diagnosis and therapeutic management for many disorders of the spine. A variety of innovative new MR methods have been developed. These new techniques include molecular diffusion sequences, MR myelography, a complete study of the entire spine, kinematic MR imaging of the spine, whole body MR exam and the fusion of different imaging modalities. These new technological developments have the potential to profoundly impact and modify imaging interpretation to offer a more efficient diagnostic and work-up of patients suffering from spinal disease. PMID- 21794678 TI - [Septic arthritis in a case of hyper-IgE syndrome]. AB - Hyper-IgE syndrome (HIES) is characterized by recurrent skin and pulmonary infections (mainly bacterial), eczematous dermatitis and elevated serum IgE levels. Associated abnormalities in some patients include coarse facial features, failure or delay of shedding of primary teeth, recurrent fractures, hyperextensible joints, and scoliosis. Laboratory abnormalities include elevated total serum IgE levels, typically ranging from 1000 to greater than 50,000IU/mL and variable eosinophilia. The diagnosis of HIES is based upon the presence of suggestive clinical and laboratory findings. A definitive laboratory test is not commercially available at present. Management of patients with HIES is focused on skin care, prevention of infection, prompt and complete treatment of infections that do develop, and control of pulmonary complications. PMID- 21794679 TI - [Response to rituximab in a patient with Wegener's granulomatosis refractory to conventional therapies]. AB - Male with diagnosis of Wegener's granulomatosis associated to anti-proteinase 3 antibodies that improved initially to the treatment with high dose glucocorticoids and ciclophosphamide, but in a relapse he did not have good response to glucocorticoid treatment, ciclophosphamide, methotrexate nor azathioprine. The patient received treatment with rituximab in 4 doses with clinical and radiographic improvement. PMID- 21794680 TI - [Young woman with relapsing arthritis]. AB - A 28-years old lady complains of self-limited episodes of relapsing knee arthritis of 48-72h of duration every 2 weeks. Immunological profile was all negative. At the same time, radiological images did not reveal any abnormality. She underwent to knee arthroscopy, however, a definite diagnosis was not reached. We discuss the differential diagnosis of relapsing arthritis. PMID- 21794681 TI - [Recommendations for the management of influenza A (H1N1) in rheumatic patients with immunosuppression]. AB - The Spanish Society of Rheumatology (SER), through a multidiscipline task force, has elaborated a document with specific recommendations for specialists in Rheumatology, emphasizing the special needs of patients with rheumatic diseases, with the objective of informing and orienting health professionals about the current influenza A/H1N1 virus pandemic. All of the recommendations are based on prior documents elaborated by the Ministry of Health and Social Policy task forces, as well as those from the autonomous communities, which are themselves based on the guidelines and documents routinely published by the Centers for Disease Control (CDC) in the US, this being the center designated by WHO for the coordination of efforts against the pandemic. All rheumatologists and potential users of these recommendations are encouraged to consult the original documents, as well as the general guidelines established at each health center. PMID- 21794682 TI - [A woman with rheumatoid arthritis and a pleural effusion]. PMID- 21794683 TI - [Ageusia associated to treatment with pregabalin]. PMID- 21794684 TI - [Deciphering the association of anti P ribosomal antibodies and neuropsychiatric affection in systemic lupus erythematosus]. PMID- 21794685 TI - [Churg-Strauss Vasculitis. Description of 9 cases]. AB - INTRODUCTION: Churg-Strauss Sindrome (SCS) is a necrotizing vasculitis affecting small to medium-sized vessels, characterized by lung involvement, asthma and peripheral blood eosinophilia, and pathologically by the presence of granulomas and eosinophilic infiltrates. OBJECTIVES: This report analizes the characteristics of 9 patients with SCS diagnosed in an university referral center. PATIENTS AND METHODS: Retrospective study. Between 1984 and 2007 nine patients with SCS were diagnosed in our center. Epidemiological, clinical, laboratory test as well as pathologic studies and treatment required were retrospectively analyzed. RESULTS: Nine patients (7 males). The mean age at the time of diagnosis was 51 years (range 23-76 years). Eight of these patients had history of asthma. The more frequent organs involved were the skin (66%), musculoesqueletical system (66%), peripheral nervous system (55%) and the lung (55%). All patients presented peripheral eosinophilia. ANCA positivity was demonstrated in 6 patients (66%), most of the patients with the p-ANCA pattern. All patients were treated with corticosteroids, and in 8 immunosupressant treatment was required, mainly cyclophosphamide. CONCLUSIONS: In this report, 9 patients with SCS are presented. Clinical characteristics are similar with the observed in other reports. We observed a major positivity of ANCA. Most of the patients were treated with corticosteroids and inmunosupresants, but the treatment should be tailored depending on the involvement of the patient. PMID- 21794686 TI - [Treatment with rituximab for thrombocytopenia due to systemic lupus erythematosus]. AB - Some patients with thrombocytopenia due SLE fail to respond to conventional therapies. Rituximab has been reported to be an alternative for patient treatment. OBJECTIVE: To evaluate the response of thrombocytopenia due to Systemic Lupus Erythematosus to the use of Rituximab and patient relapse time at our hospital. PATIENTS AND METHODS: We analyzed patients with SLE than received a 2 gram rituximab treatment for thrombocytopenia. We analyzed the rate of patients that achieved complete remission (CR), defined as a platelet count over 100mil/mm(3), partial remission (PR) described as platelets within 50 100mil/mm(3) and no response (NR) if platelets remained unchanged and the time the remission was sustained. RESULTS: 16 treatments were applied to 13 patients, aged 28+/-9 years of age and SLE mean duration time of 68+/-44 months with a mean platelet count of 38+/-29mil. In 14 treatments (87%) remission was achieved after 5+/-2 weeks where 2 patients (12.5%) were non respondent. One of them died due to a massive hemorrhage. The mean response time without relapse was 15.6+/-6 months. Follow up of three patients was not possible and 3 other died due to infections. CONCLUSIONS: Rituximab is an alternative for treatment of thrombocytopenia due to Systemic Lupus Erythematosus. PMID- 21794687 TI - [Haematogenous vertebral osteomyelitis. Experience of a primary care hospital]. AB - OBJECTIVES: To describe a series of patients with haematogenous vertebral osteomyelitis (HVO) in a primary care hospital. The results were compared with other Spanish and foreign series. PATIENTS AND METHODS: The files of patients with HVO diagnosed in the Viladecans hospital from 1993 through 2008, were retrospectively reviewed. Only patients with microbiological demonstration of infection were included. Patients with HVO after surgical procedures were excluded. RESULTS: Twenty six patients had inclusion criteria, 9 females and 17 males, with a mean age of 61 years (range 36-83). The most patients had any predisposing factor, generally diabetes mellitus. Pyogenic microorganisms were the most frequent aetiological agents (77%). Back pain was by far the most common presenting symptom (88,4%), followed by peripheral septic arthritis in two patients (7,6%), and acute abdominal pain in one. Fever was found in 22 cases (84,6%). None of our patients died, but the sequelae were non rare. CONCLUSION: We did not find difference between our series and others. It is noteworthy that the streptococcal species represents the most frequently isolated organism, followed by Staphylococcus aureus, more common in other series. Remarkably, none of our patients died. HVO is a infrequent disease. However, evidence suggest that the incidence is increasing. Early diagnosis can avoid potential serious sequelae. PMID- 21794688 TI - [Oxidative stress biomarkers as indicator of chronic inflammatory joint diseases stage]. AB - OBJECTIVE: To evaluate the participation of oxidative stress (OS) on chronic inflammatory joint disease (CIJD), as well as its possible use as a diagnostic biomarker. PATIENTS AND METHODS: The study population comprised 29 patients with CIJD: 18 with rheumatoid arthritis (RA: 13 active/5 inactive); 11 with ankylosing spondylitis (AS: 7 active/4 inactive) and 13 healthy subjects. Activity of the disease was assessed by: RA patients, Disease Activity Score (DAS 28) and AS patients by means of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Oxidative stress biomarkers were determined in plasma using spectrophotometrical techniques. The statistical analysis was carried out using the SSPS statistical package. RESULTS: Active CIJD showed a high oxidative stress characterized by increases in oxidative damage markers and a reduction in antioxidative systems, together with a higher myeloperoxidase (MPO) concentration. Inactive CIJD only showed changes in oxidized glutathione (GSSG) and reduced glutathione (GSH)/GSSG ratio levels, without changes in oxidative damage parameters or in antioxidative systems. CONCLUSIONS: Our data revealed that: i) CIJD presents with a high oxidative stress; ii) inactive CIJD shows a production of reactive species without triggering oxidative damage and maintaining red-ox homeostasis, and iii) the combination of oxidative stress biomarkers may be used as markers of active inactive stages of CIJD. PMID- 21794689 TI - [Septic arthritis complicating neuropathic shoulder due to cervical syringomyelia]. AB - One of the main causes of neuropathic osteoarthropathy of the shoulder is cervical syringomyelia. Chronic pain and swelling of the shoulder are the most frequent manifestations, but it occasionally can develop rapid osteoarticular destructive lesions (in less than six weeks), which raise the diagnostic possibility of septic arthritis and some tumours We present the report of two men with septic arthritis of the shoulder associated with neuropathic arthropathy secondary to syringomyelia. Both patients presented with sudden shoulder pain exacerbated by either passive or active joint movements, malaise and fever. The first patient, a 39-year-old man, suffered left shoulder arthritis due to Staphylococcus aureus. The second patient, a 59-year-old man presented with right shoulder arthritis caused by to Staphylococcus epidermidis. The last microorganism also was isolated in three blood cultures. Infection should certainly be considered as a possible complication of the natural history of the neuropathic shoulder. PMID- 21794690 TI - [Acute knee pain in pregnancy. Case report of Regional Transient Osteoporosis]. AB - The article presents the case of a patient who after her first pregnacy, during the immediate postpartum period, suffered a femoral supracondylar fracture complicated by bone marrow edema syndrome (BMES), also known as regional temporary osteoporosis (RTO). The fracture of the distal femur was treated with an open reduction and internal fixation of the distal femur by means of a minimally invasive procedure. PMID- 21794691 TI - [Anti-TNF therapy and cancer]. AB - Tumor necrosis factor (TNF) is implicated in the control of tumoral growth in addition to the systemic inflammatory response. TNF blockage produces a comprensible reservation in patients with risk factors for cancer. No clear evidence for this came out from pre-clinical or clinical trials. Biosafety registries established in the post-marketing phase have concluded that, in general, cancer cases have not increased over what is expected in a population with RA exposed to the prolongued use of anti-TNF drugs. A meta-analysis of clinical trials which used infliximab and adalimumab for RA treatment showed an increase of up to three times the risk of developing cancer, but this dissapeared after correcting for time. Biobadaser shows evidence that support long-term safety. In the long-term, and if the inflammatory disease activity is truly under control, the risk of developing cancer is the same as with any other patient. PMID- 21794692 TI - [Does early treatment of Rheumatoid Arthritis lead to a better long-term prognosis?]. AB - Time is a crucial dimension in most chronic diseases, especially in inflammatory rheumatic disease, which it affects in many ways. Early treatment in rheumatoid arthritis (RA) is an essential issue, as joint damage occurs within the first weeks or months of the disease process and inflammatory activity maintained over time is responsible for all of the consequences of the disease. The introduction of new drugs with faster and more effective action, such as tumor necrosis factor (TNF) inhibitors, has represented a major shift in the strategy of RA treatment, allowing the clinician to aim for remission and prevention of structural damage as realizable goals. PMID- 21794693 TI - [Evaluation through imaging of early rheumatoid arthritis]. AB - Radiography is the most widely utilized imaging modality for measuring joint damage in early rheumatoid arthritis. Conventional radiography is, however, insensitive for showing bone erosions and is totally unsuitable for assessing synovial inflammation. The recognition of these limitations has led to intense interest in ultrasonography and magnetic resonance imaging for assessing synovitis and bone erosions. Magnetic resonance imaging allows detection of bone marrow edema, which is considered to be a very early marker of inflammation as well as a "forerunner" of erosions. PMID- 21794694 TI - [An atypical cause of intestinal occlusion and hidronephrosis]. PMID- 21794695 TI - [Pleuroperitoneal serositis as a manifestation of pyrazolone (metamizole) induced lupus]. PMID- 21794696 TI - [Utility of a specialized nursing department in rheumatology]. PMID- 21794697 TI - [Systematic review on the use of adalimumab in autoinmune. Efficacy and safety in 54 patients]. AB - OBJECTIVE: To analyze published evidence about adalimumab use in autoimmune diseases. METHODS: Systematic review of MEDLINE database of citations included from January 1990 to December 2008 employing the terms "adalimumab" and the different systemic autoimmune diseases. RESULTS: Our search identified 241 potentially relevant citations. 154 were retrieved for detailed evaluation. Finally, 18 were selected as relevant, including 54 patients. The reported diseases were as follow: Behcet disease in 16 patients, idiopathic uveitis in 13, sarcoidosis in 5, uveitis associated with rheumatologic diseases in 5 (psoriasis in 2, ankylosing spondylitis in 1, juvenile idiopathic arthritis in 1, Crohn disease in 1), Vogt-Koyanagi-Harada disease in 4, Birdshot uveitis in 4, vasculitis in 3 (1 temporal arteritis, 1 Takayasu's disease, 1 skin vasculitis associated with rheumatoid arthritis), adult onset Still disease in 2, relapsing polychondritis in 1 and systemic sclerosis in 1. The clinical spectrum included uveitis (39 cases), skin and/or mucosae (9), vasculitis (3), arthritis (6), lung (3). These patients were refractory to standard therapy, including corticosteroids (42 cases, 78%), immunosuppressants (42, 78%) and biologics (29, 54%). Fifty (93%) patients responded to adalimumab. The clinical response was similar in those patients who had been treated with other biologic and in those who had not received biologic therapy before adalimumab. The patients were followed for 11.9 months. Twelve (22%) patients relapsed. Five (9%) patients suffer some side effect (3 local skin reaction, 1 angioedema, 1 lung fibrosis). One patient (2%) died due to progression of her disease. CONCLUSIONS: Available data about the use of adalimumab in autoinmune diseases come from case reports and uncontrolled studies, that include patients with severe disease and refractory to standard therapy. In this setting, it seems to be an effective and safe treatment option, especially in patients with uveitis and Behcet's disease. This initial data must be confirmed by controlled assays before extending adalimumab use. PMID- 21794698 TI - [Elaboration, implementation and follow-up of a postmenopausal osteoporosis protocol: Collaboration between the Primary care and Rheumatology departments]. AB - OBJECTIVE: To improve the clinical management of postmenopausal osteroporosis, an intervention based on the implementation of a guideline agreed to between the Primary Care and Specialized departments of all centers at "Mutua of Terrassa" was carried out. METHODS: Descriptive and interventional study. The intervention consisted of the elaboration of a consensus guideline that was presented in all centers. Results were assessed from bone densitometry studies requested by family physicians over 1 year. RESULTS: 1.165 densitometric studies were requested, of which 689 were for the diagnosis of new patients. For the evaluation of the guidelines, details were obtained from 560. 502 studies (89,6% IC95% 87,1-92,2) complied with indication criteria established in the guideline. Of the total of patients who received bisphosphonates and other drugs affecting bone metabolism (43 osteopenic and 167 osteoporotic), 83,7% (IC95% 69,3-93,2) and 89,8% (IC95% 85,2-94,4) respectively complied with drug recommendations. Drug consumption during the year 2007 was reduced by 152.745 euros (-6,3%) although the number of patients increased in 565 (+4,9%) with respect to the previous year. 442 (78,9% IC95% 75,6-82,3) densitometries presented a result in the osteopenia or osteroporosis category. There were statistically significant differences of the results according to the patients' age and the motive for the bone densitometry request. CONCLUSIONS: Implementation of the guideline allowed for the effective management of the clinical process of osteroporosis in our field. PMID- 21794699 TI - [Influence of gender on treatment response in a cohort of patients with early rheumatoid arthritis in the area 2 of Madrid]. AB - OBJECTIVE: To evaluate the differences between the responses to treatment using DAS28 based on erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in male and female patients. We then analyzed the individual behaviour of each component in a cohort of early arthritis patients in zone 2 of Madrid. PATIENTS AND METHODS: We studied a total of 134 patients (77.6% women) who met the American College of Rheumatology (ACR) criteria for the diagnosis of rheumatoid arthritis (RA) belonging to an early arthritis register of the Hospital de La Princesa. We performed 4 visits following a standardized protocol which included necessary variables to calculate the DAS28 with ESR and CRP as well as determining the treatment received by the patients. We analyzed the differences in responses to treatment in males and females using both indexes, as well as their component and the assessment of the disease by the physician. RESULTS: Women had higher disease activity and disability at baseline. Although they received more intensive treatment, their average value of DAS28 remained significantly higher compared to men during the follow-up. By contrast, the global disease assessment evaluated by the patient and by the physician remained similar in both gender. When we analyze the DAS28 components separately, it was observed that this discrepancy was due mainly to the tender joints count and the ESR. CONCLUSIONS: Women with early RA have higher DAS28ESR scores as a result of higher tender joint counts and ESR. This may represent bias when assessing the response to treatment using the DAS28ESR. PMID- 21794700 TI - [Assessment of functional capacity in fibromyalgia. Comparative analysis of construct validity of three functional scales]. AB - OBJECTIVE: To compare the construct validity of three functional capacity questionnaires in patients with fibromyalgia. PATIENTS AND METHODS: Transversal multicentric study of 301 patients from fifteen rheumatology outpatient clinics in Spain. Scores of Health Assessment Questionnaire (HAQ), Fibromyalgia Health Assessment Questionnaire (FHAQ) and the physical function scale of the Fibromyalgia Impact Questionnaire (PF-FIQ) were compared with extreme groups of patients defined by four external indirect measures: 6Min Walk Test, a modified Borg Fatigue Scale, Lumbar Spine Flexion Test and Patient Global Passive Mobility Assessment. Standardized differences were determined and correlation coefficients were calculated between the three questionnaires scores. RESULTS: All three questionnaires showed good construct validity, but the results obtained with the PF-FIQ were poorer. Correlations between HAQ and FHAQ were very high (0.92), but correlations between these two questionnaires and PF-FIQ were only moderate (0.59). CONCLUSIONS: HAQ and FHAQ are more valid measures of functional capacity than the PF-FIQ. HAQ could be substituted by FHAQ in some settings because of its shorter format (only 8 items). PMID- 21794701 TI - [Bilateral calcifying tendinitis of the long tendon of the biceps associated with a SLAP lesion]. AB - Calcifying tendinitis is a common disorder related to deposition of hidroxyapatite crystals, which is most common around the shoulder joint, involving the supraespinosus tendon. It can however, affect almost any tendon at its insertion. Clinical features are variable and include pain and inflammation that often resolves spontaneously. We present a case of bilateral calcifying tendinitis of the long head of the biceps tendon at its insertion on the superior glenoid rim associated with superior labrum antero-posterior tears (SLAP) confirmed by arthroscopy. Calcium deposits were surgically removed and the SLAP lesions were repaired. PMID- 21794702 TI - [Pyogenic arthritis caused by Streptococcus agalactiae: report of four cases and a review of the literature]. AB - Most infections by group B streptococcus of the Lancefield classification (Streptococcus agalactiae), were reported in pregnant women or during the puerperal period, as well as in neonates. During the past three decades there have been reports of increasingly invasive infections in adults unrelated to pregnancy, although arthritis and osteomyelitis are still very rare. In this article, we describe four new adult patients with arthritis by S. agalactiae (two postmenopausal women and two men), two of them with affection of the sternoclavicular joint. We also review the medical literature. PMID- 21794703 TI - [Physical exercise as non pharmacologic therapy in knee osteoarthritis]. AB - Knee osteoarthritis is one of the most frequent joint disorders, and its major symptoms are pain and physical disability. Cartilage regeneration therapies are still under development, and current treatments target pain and disability. Physical activity could be a cheap and effective therapeutic option. However, it is not yet known which types of exercise are the most beneficial, as well as its load or intensity. Therefore, the objective of this work is to integrate all the information about the design of training programs for knee osteoarthritis treatment. All of the selected articles by Talbot and colleagues (except one), showed significant improvement in knee pain, physical performance, or both. However, many authors do not describe the main elements of the programs, so its application as a therapy or for contrasting the results is not possible. PMID- 21794704 TI - [Treatment of ANCA-associated systemic vasculitis]. AB - The treatment of systemic vasculitis has undergone important changes in recent years. Cyclophosphamide still plays a crucial role in the induction of remission in severe forms, reducing the mortality. However, its use entails a significant long-term toxicity and the accumulation of damage resulting from a sub-optimal control of the process. Strategies has been developed to limit exposure to the drug and minimize its toxicity, such as using intravenous pulses as an alternative to oral administration and a sequential strategy. Both induce remission in less severe cases and work also for the maintenance of remission; the use of alternative immunosuppressants, such as methotrexate, azathioprine or leflunomide has been advocated. In life-threatening situations, options such as plasmapheresis or intravenous inmunoglobulins are available. Biologic therapies are a promising alternative, but their use must be limited for now to refractory cases. PMID- 21794705 TI - [Immunological Techniques that Support the Diagnosis of the Autoimmune Diseases]. AB - During the past few years technological advance have been allowed the developing of techniques that help to the diagnosis of multiple diseases. In the case of the autoimmune diseases, immunological techniques are helpful since they allow the detection of multiple autoantibodies at the same time with small volumes of sample. Together with the development of the new techniques, sensitivity and specificity in the detection of the antibodies specificities' also have been increased, in such a way that the clinicians can count with tests that allow them to make early diagnoses with greater certainty and also to follow the course of the disease based on the variation of the antibodies presents in the patient's samples. It is important to emphasize that the new techniques of laboratory that are used for the support of the diagnosis of autoimmune diseases, no longer are exclusive for research laboratories but by their facility of standardization, quality control and reproducibility they can be used in clinical laboratory of medium and small sizes. In the present paper we describe those techniques with greater application in the clinical laboratory of autoimmune diseases. PMID- 21794706 TI - [A case of osteopoikilosis]. PMID- 21794707 TI - [Calcinosis cutis in a patient with systemic lupus erythematosus]. PMID- 21794708 TI - [Osteopoichylosis: An incidental radiological finding]. PMID- 21794709 TI - What is the importance of nutrition in rheumatoid arthritis? PMID- 21794710 TI - [Understanding chronic fatigue syndrome]. PMID- 21794711 TI - [An economic evaluation of chondroitin sulfate and non-steroidal anti inflammatory drugs for the treatment of osteoarthritis. Data from the VECTRA study]. AB - OBJECTIVE: Our aim was to investigate: a) the average cost per patient with osteoarthritis treated with chondroitin sulfate compared with NSAIDs for 6 months and b) the possible impact that the reduction NSAID use due to monotherapy with or combined administration of chondroitin sulfate treatment may have on the budget of the Spanish National Health System. METHODS: A cost-minimization model compared both treatments (efficacy equivalence assumption), used at the recommended doses and regimens during a 6-month period. Data used in the model was obtained from the VECTRA study, a retrospective study of 530 patients with osteoarthritis treated with chondroitin sulfate or NSAIDs that was conducted to determine the consumption of health care resources. The efficacy and incidence of adverse events was estimated from meta-analysis based on randomized clinical trials. Univariate sensitivity analysis was performed for the base case scenario. RESULTS: The overall 6-month cost per patient given chondroitin sulfate was 141 ? compared with 182 ? when treated with NSAIDs. If during the forthcoming 3 years, 5%, 10%, and 15% of patients currently treated with NSAIDs would gradually be replaced by treatment with chondroitin sulfate, the expected savings for the Spanish National Health System during these 3 years would be over 38,700,000 ?. In addition, 2,666 cases of gastrointestinal adverse events (including 90 serious adverse events) will have been avoided for every 10,000 patients treated with chondroitin sulfate instead of NSAID. Sensitivity analysis confirmed the strength of base-case in all scenarios. CONCLUSIONS: On the basis of these findings, chondroitin sulfate is a treatment for osteoarthritis with a lesser cost and better gastrointestinal tolerability compared with NSAIDs. PMID- 21794712 TI - [Diffuse alveolar hemorrhage: Causes and outcomes in a referral center]. AB - OBJECTIVE: To identify the most common causes of diffuse alveolar hemorrhage (DAH) and the evolution of cases during hospitalization. PATIENTS AND METHODS: A review of cases diagnosed with DAH; the diagnoses were classified according to existing criteria and the progression of the cases was determined. RESULTS: We identified 17 cases of DAH, with the leading cause being ANCA associated vasculitis (41% of cases), followed by cases secondary to drugs (18%). In 35% of the cases, there was a failure in identifying an etiology. Six patients died (35%), the only factor associated with mortality was male gender 5/6 vs 3/11, p=0.05. CONCLUSIONS: The most frequent cause of alveolar hemorrhage was ANCA associated vasculitis. The mortality in DAH is about 35%, males seem to have a worse prognosis. PMID- 21794713 TI - [Ormond's disease: Experience with five cases]. AB - Ormond's disease (OD) is an uncommon process with an annual incidence nearing 1 per million inhabitants. The etiology in most of the cases is unknown and several pathogenic mechanisms are implicated in secondary OD. Ormond disease is characterized by a fibrotic and inflammatory mass with three different clinical features: i) retroperitoneal fibrosis, ii) perianeurysmatic retroperitoneal fibrosis and iii) inflammatory abdominal aortic aneurysms. Classic management is based on surgical treatment associated or not with steroids. Immunosuppressive agents have been used in the last years with unclear results. We report five cases from the University Hospital of Salamanca occurring during 2000-2008. We highlight the lack of trials designed to establish clinical guidelines for the treatment of the disease and improvement of outcome. PMID- 21794714 TI - [Pharmacoeconomic analysis of Metoject((r)) in the treatment of rheumatoid arthritis in Spain]. AB - OBJECTIVES: The aim of this study was to compare the clinical and economic consequences of using subcutaneous methotrexate (Metoject((r))) with respect to oral methotrexate in the management of rheumatoid arthritis (RA) in Spain. METHODS: A cost-effectiveness analysis was performed to compare early treatment of RA using a Markov model. The model allowed us to estimate long term efficacy of RA treatment based on data from the literature and expert opinion, and to combine this data with costs of managing RA in Spain. The perspective of the study was from the National Health System point of view, using a time horizon of 5 years and patient lifetime. All costs were expressed in 2009 euros and a 3% discount rate was applied. RESULTS: The cost (only pharmacologic costs) per quality-adjusted life year (QALY) gained with Metoject((r)) went from 25,173 to 35,807? at 5 years and from 19,056 to 25,351? for patient lifetime. When direct costs in RA treatment were considered, it was observed that cost-effectiveness at 5 years went from 29,682 to 42,175?/QALY gained, and for patient lifetime from 22,514 to 29,848?/ QALY gained. CONCLUSIONS: Additional costs of Metoject((r)) with respect to oral methotrexate would be offset by their improved effectiveness, expressed in QALY, showing that Metoject((r)) could be a cost effective treatment option for RA in the Spanish Health System assuming a spanish threshold. PMID- 21794715 TI - Juvenile Systemic Lupus Erythematosus associated with Klinefelter's syndrome: A case report. AB - We present the first reported case of juvenile Systemic Lupus Erythematosus with Klinefelter's syndrome in a 14-year-old Iranian boy who had leg ulcers and arthritis. He had low level of testosterone accompanied with hypergonadotropic hypogonadism. This case emphasizes the importance of two X chromosomes as a risk factor for Systemic Lupus Erythematosus in women and men with Klinefelter's syndrome (47, XXY). PMID- 21794716 TI - [Resistant orbital pseudotumor treated with rituximab in a patient with systemic lupus erythematosus. A case presentation]. AB - Ocular manifestations in Systemic Lupus Erythematosus (SLE) are relatively frequent, with a major prevalence of the Keratoconjunctivitis sicca. Nevertheless, the appearance of unilateral exophthalmos secondary to orbital pseudotumor in patients with SLE is extremely rare(1-7), and on occasion it can be refractory to conventional pharmacological treatment (glucocorticoids and immunosuppressants). We present the case of a patient with SLE and orbital pseudotumor refractory to treatment with Cyclophosphamide (CF) and an excellent clinical response, with disappearance of the ophthalmological condition after the beginning of therapy with Rituximab (1g*2), continuing after the infusion of two complete cycles without incidents. PMID- 21794717 TI - [Osteoporosis in young individuals]. AB - Although there are some differential aspects related to peak bone mass acquisition and later bone loss throughout life between genders, the frequency of osteoporosis in young individuals is similar for both genders. In addition, in this population group, the development of osteoporosis is frequently associated with secondary causes. Indeed, nearly 50% of young individuals with osteoporosis have diseases or therapies related to the development of this disorder, with glucocorticoid therapy being one of the most frequently associated conditions. There are several other processes, which have also been associated with such a disorder in these individuals, but the causes differ between genders. In addition, idiopathic osteoporosis is also a frequent condition in these patients. In this subgroup of patients, a family history of osteoporosis or hypercalciuria is also a frequently associated finding. Because of that, in order to rule out secondary causes of osteoporosis, the laboratory studies performed to these patients should be extensive. Although there is few data on the treatment of these patients, basic rules such as exercise, correct calcium and vitamin D consumption, and avoiding alcohol and tobacco consumption should be advised. Drug therapy will depend on the cause of osteoporosis. However, it should be taken into account that most young women are of childbearing age, so drug therapy in these patients should be evaluated cautiously. PMID- 21794718 TI - [Antinuclear antibodies]. AB - Anti-nuclear antibodies (ANA) are immunoglobulin directed against autologous cell nuclear and cytoplasmic components. Besides the autoimmune ANA there are other ANA that can be detected in circulation, like natural and infectious ANA. Because of its high sensibility, detection of the ANA must be done by indirect immunofluorescence (IIF) as screening test and all of those positive samples are convenient to confirm its specificity by ELISA, western blot or other techniques. Positive ANA detected by IIF must be evaluated taking in to account the pattern and titer. The following recommended step is the specificity characterization (reactivity against extractable nuclear antigens [ENA], dsDNA, etc.) which is useful for the diagnosis and follow up of patients with autoimmune diseases, and by such reasoning, its detection must be performed in an orderly and reasonable way using guides or strategies focused to the good use and interpretation of the autoantibodies. The objective of this review is to present a compilation of the literature and our experience in the detection and study of the ANA. PMID- 21794719 TI - [Not Available]. PMID- 21794720 TI - [Comparison of rulings on permanent disability due to fibromyalgia in Spain: differences according to whether the resolution is favorable to the patient or to the National Institute of Social Security]. PMID- 21794721 TI - [Predictive value of questionnaires: what is it and why is it important to know?]. PMID- 21794722 TI - [Anti-TNF therapy in Ankylosing Spondylitis (AS). Is it possible to suspend treatment?]. PMID- 21794723 TI - [Biobadaser 2.0: analysis and trends in 2009]. AB - OBJECTIVE: To update the information on long-term safety of biological therapies used for the treatment of rheumatic diseases. METHODS: BIOBADASER is a safety registry of biological therapies established by the Spanish Society of Rheumatology. A description of BIOBADASER 2.0, a cohort composed of 14 centres within BIOBADASER is reported from 2000 until 2009. RESULTS: The 14 centres have registered 5,493 patients, who have received 8,081 cycles of treatment with biological therapies. 30% (1,666) has received treatment with more than one biologic agent during follow-up. There have been 3,784 treatment discontinuations, with inefficacy or loss of efficacy being the most frequent cause (1,453; 38%), followed by adverse events (1,297; 34%). Up to 7,289 adverse events (AE) have been reported, of which 80% (5,764) were considered as non serious, nearly 19% (1,340) were notified as serious and about 2% (110) were fatal. The most frequent AE were infections (2,668; 37%), followed by general problems and administration related events (10%). Cardiovascular events and cancer amounted a 7% of the total AE. CONCLUSIONS: There does not seem to be a trend regarding different risks in BIOBADASER 2.0 with respect to the general registry, or to previous years. PMID- 21794724 TI - [Current status of day care units where rheumatology treatments are administered in the autonomous community of Valencia]. AB - OBJECTIVE: To evaluate and characterize the current status of the Rheumatology Day Hospital Care units in the Autonomous Community of Valencia. MATERIAL AND METHOD: A structured brainstorming meeting was organized with 12 rheumatologists and a nurse and, after that, a questionnaire was sent to 20 rheumatologists to know more about the centers. RESULTS: Variability was found in the services that the day care units have for their own operation and for patient care. Rheumatologists place more importance on having some services that are not present in all centers at the moment: specialized nursing, quick drug delivery from the pharmacy and administration supervision by a rheumatologist. The following deficiencies were identified: sharing the workspaces with other specialties, drug delivery delays from the pharmacy, few resources (few spaces, few locations and little time for drug administration), lack of specialized nursing, lack of some services for patients (i.e. hot-line telephone service or patient education), few clinical sessions and lack of some procedures. CONCLUSIONS: It is necessary to establish measures that lead to the resolution of deficiencies and improve the services offered to patients. PMID- 21794725 TI - [Efficacy of rituximab versus cyclophosphamide in lupus patients with severe manifestations. A randomized and multicenter study]. AB - There are no controlled studies that compare the efficacy of RTX with standard treatment, such as cyclophosphamide, in patients with systemic lupus erythematosus (SLE). OBJECTIVE: The objective of this study was to compare the efficacy of rituximab to that of cyclophosphamide in patients with severe manifestations of SLE. MATERIALS AND METHOD: This is a multicenter, randomized open and controlled trial in adults with a diagnosis of active SLE. Patients were randomized into two groups; group 1: treated with RTX and group 2: cyclophosphamide pulses with the same steroid scheme. We registered MEX-SLEDAI, steroid requirements and adverse events for 12 months. Descriptive and comparative statistic analysis was performed. RESULTS: 19 patients were included, 17 females, mean age 35.7+/-12.1 years and duration of disease 5.6 years (range 0.35 to 30.8 years). There were no differences at baseline regarding gender, age, duration of disease, previous treatments or disease activity between both groups. MEX-SLEDAI was reduced from 12 to 3 in group 1 and from 9 to 2 in group 2 (p=0.80). Nevertheless, patients treated with RTX had a faster improvement. There was no difference in the cumulative steroid dose. Both groups had significant reduction in antinuclear antibody levels and similar increase in C3 levels. Adverse events were similar in both groups. CONCLUSION: This comparative clinical study in patients with SLE shows that rituximab can be as useful as cyclophosphamide for severe manifestations, maybe showing a faster response. Adverse events were no different. Rituximab should be considered as an adequate alternative for this group of patients. PMID- 21794726 TI - [Tuberculosis in a cohort of patients with systemic lupus erythematosus]. AB - OBJECTIVES: 1) To study tuberculosis (TB) infection in a cohort of patients with systemic lupus erythematosus (SLE) and to compare its frequency and characteristics with that of others series. 2) To look for differential characteristic among SLE patients with and without TB. 3) To investigate if there was any relationship between TB's most severe forms and higher doses of glucocorticoids (GC) or other immunosuppressants. PATIENTS AND METHOD: Retrospective review of medical records of 789 SLE patients and description of the clinical characteristics of 13 cases of active TB infection among them. Bibliographical search in MEDLINE-PubMed of the SLE/TB series published, using the terms: infection, tuberculosis, systemic lupus erythematosus. Comparative study of clinical, biological and therapeutic differences between cases (SLE/TB+) and controls (SLE/TB) using chi(2) and Fisher exact test. RESULTS: Thirteen patients with active tuberculosis were detected (10 women, average age 36 years/SD 11,2/prevalence 1,6%). Nine (69,2%) of them were primary infections and 4 (30,8%) reactivations. Microbiological diagnosis (smear examination for acid fast bacilli and/or culture on Lowestein-Jensen medium) was established in 11 patients (84,6%). TB Pulmonary manifestations was present in 9 patients (69,2%) and extra-pulmonary manifestations were found in 8 [(61,5%); 6 of them (46%) were disseminated forms]. Nine (69,2%) patients were on GC therapy at the moment TB was diagnosed. Four of the TB patients died (30,8%). Myositis was more frequent in TB cases (p < 0,05). This data is similar to that reported in the literature. CONCLUSIONS: In our series, TB mortality was high (30,8%) in a patients with SLE. Frequency of extrapulmonary forms was double than that described in the Spanish population. Patients with higher GC dose had more severe forms of TB. PMID- 21794727 TI - [Atypical presentation of microscopic polyangiitis]. AB - Microscopic polyangiitis is a systemic vasculitis that affects small caliber vessels, with renal and lung compromise. We present the case of a patient with an atypical presentation of this disease and an onset characterized by central nervous system affection in the form of a motor deficit. PMID- 21794728 TI - [Utilization of hyperestrogenic therapies in systemic lupus erythematosus]. AB - The use of treatments that increase the estrogenic levels has been usually deemed risky in lupus patients. Past studies about the utilization of oral contraceptive drugs and hormone replacement therapy (HRT) have shown contradictory results. More recently, prospective studies about this issue suggest that either oral anticonceptive and HRT can be used in patients with stable disease without special risk for increments in clinical activity. Neither, it has been observed an association with the development of arterial or venous thrombosis. Although, to this regard, several methodological limitations preclude to establish definitive conclusions. Regarding to the use of assisted reproduction techniques in lupus patients, only retrospective data are available. Overall they indicate that the real risk of disease worsening is quite low, being the flares mostly mild when these procedures are performed in patients with stable disease. PMID- 21794729 TI - [Urinary sediment analysis]. AB - Urinary analysis is one of the most requested tests in the clinical laboratory. This test includes the physical, chemical and microscopic analysis of urine. This last one allows for the observation of urinary sediment (US) in search of formed elements (cellular cast, leukocytes, etc.), with different diagnostic uses. Urinary analysis can be assessed by manual or automated methods. In the laboratory diagnosis of autoimmune diseases, US analysis is mainly oriented towards the assessment of renal function in patients with lupus nephritis (LN) as this is a common clinical manifestation associated to systemic lupus erythematosus (SLE). Additionally, its value lies mainly for diagnostic criteria and evaluation of kidney injury, as well as for several damage indexes directed to patients with SLE. In the last years, several groups have sought to establish new urinary biomarkers of kidney damage in patients with SLE; however, this requires a greater number of studies to determine their true diagnostic value in this patients group. PMID- 21794730 TI - [Chronic back pain as the first symptom in the rupture of an abdominal aortic aneurism: presentation of 2 cases]. PMID- 21794731 TI - [Muscle weakness and dyspnea]. PMID- 21794732 TI - [New accreditation criteria for reumatology teaching units]. PMID- 21794733 TI - [Reliability and reproducibility of a morpho-textural image analysis method over a patellar ligament ultrasonography]. AB - OBJECTIVE: Image analysis techniques over ultrasonograms may be useful to extract quantitative information. Because ecography and the selection of the area of interest are technician-dependent, the objective of this work was to calculate the reliability and the reproducibility of the analysis method. MATERIAL AND METHODS: Test-retest reliability study on 60 cross-sectional patellar ligament ultrasonograms on 1cm of patella were carried out. Sonosite Titan L-38 (5-10 MHz) and the Image analysis software J v1.40 were used. Morphometric variables were: perimeter, area, width, thickness, and mean echogenity; textural variables were: uniformity, homogeneity and entropy. The intraclass correlation coefficient (ICC) was calculated with a confidence interval of 95%. RESULTS: Intraclass correlation coefficients over 0.70 were found, with an agreement ranging from good to very good in all of the variables both for the intra ecography and inter ecography studies. CONCLUSION: Very good levels of reliability and internal consistency were seen, demonstrating that from the statistical point of view, the variability introduced by the technician is not significant. This method can be taken as a reference to analyze the reliability between several ultrasonographers. PMID- 21794734 TI - [Clinical characteristics of reflex sympathetic dystrophy in Aragon (Spain). A prospective study of 171 patients]. AB - We followed a total of 171 patients diagnosed with Reflex Sympathetic Dystrophy (RSD). This enigmatic condition normally has a secondary origin, being trauma the unleashing cause in most cases. Psychological predisposition plays a major role in developing the clinical state, which affects lower extremities more frequently. In this series, patients were first seen during the acute "warm" phase and the final outcome was generally good after a period of treatment with non-steroidal anti-inflammatory drugs (NSAID), calcitonin and physical therapy. However, a comprehensive review of the literature revealed the heterogeneity of this condition. PMID- 21794735 TI - [Primary Sjogren's syndrome: Expression of NF-kappaB in minor salivary glands]. AB - PURPOSE: To evaluate nuclear NF-kappa B translocation in minor salivary glands (mSG) of human primary Sjogren Syndrome (pSS). METHODS: Lip biopsies' mSG were done in 24 female patients with pSS from the Rheumatology Service of Rivadavia Hospital. Glands were stained with H&E and immunostained for NF-kappa B. Specimens were classified according to the Chisholm and Masson score. RESULTS: The biopsies (H&E staining) showed lymphoplasmocitic infiltrates, forming periacini and periductal focuses which number depending on the stage of the disease. In stages III and IV there was acini destruction and, in some cases, fibrosis. In the biopsies with a diagnosis of sialadenitis we observed interstitially-dispersed lymphoplasmocitic elements and also polimorphonuclear neutrophils. The lip biopsies' mSG of patients with clinical-serological diagnosis of pSS showed nuclear translocation of NF-kappa B in lymphocytes of focal infiltrates and in the acini epithelium adjacent to the infiltrates. In distal acini and ductal structures from the infitrates we did not observe nuclear translocation. However, in SSp patients with sialadenitis interstitial lymphocytes with nuclear translocation were observed but neither in the acini or the ducts. SSp patients with normal glands did not show nuclear translocation of NF-kappa B factor either in the acini or in the ducts. CONCLUSIONS: These results allow us to infer the importance of lymphocyte-epithelium interaction on the activation of NF-kappa B in human pSS. PMID- 21794736 TI - [MCP-1 in urine as biomarker of renal lupus in absence of cytokines, interferon gamma and growth factors]. AB - OBJECTIVE: To characterize 17 immunological markers in the Urine of patients with SLE. INTRODUCTION: Lupus nephritis is an inflammatory disease affecting the renal parenchyma. Cytokines and chemokines are key immune mediators that have been related with the pathogenesis of the disease. Obtaining non invasive prognosis markers is a highly desirable objective in order to improve the clinical management of these patients. PATIENTS AND METHODS: In this study we profiled 17 immune mediators (Th1, Th2, Th17 cytokines, chemokines and growth factors) in the urine of 25 patients with systemic lupus erythematosus with active renal disease by using a Biorad(c) 17-plex kit on a Luminex(c) platform. A group of healthy volunteers of similar age and comparable sex distribution was recruited as control (n=10). RESULTS: Results evidenced that the only detectable mediators in urine were IL-8, MCP-1 and MIP-1 beta. When levels of these mediators were compared between patients and controls, significantly higher levels of MCP-1 were observed in the urine of the patients. MCP-1 levels in urine correlated positively with the SLEDAI score in a significant way and negatively with plasma levels of complement C4. CONCLUSIONS: Our results reinforce the role of MCP-1 in urine as biomarker of disease activity in renal lupus, excluding the detection of other soluble immune mediators such as Th1, Th2 ,Th17 cytokines and growth factors as suitable markers in this non invasive sample. PMID- 21794737 TI - [Frequency of systemic manifestations in patients with primary Sjogren's syndrome in Argentina]. AB - Twenty to 71% of patients with Sjogren's syndrome (SS) will develop systemic manifestations. OBJECTIVE: To characterize the clinical-serological presentation and the frequency of systemic manifestations in patients with primary SS. METHODS: Retrospective study including patients with SS visited in "Hospital Britanico de Buenos Aires" during the period from January 2000 to August 2008. RESULTS: Forty-one patients fulfilled the 2002 American-European classification criteria for SS. All patients were women. Mean age at enrollment was 57.85 +/- 12.42 years (range 26-79). Mean duration of the disease was 9.28 years (range 0.08-24). Thirty-three (80.49%) developed systemic manifestations. The most frequent were arthritis, cutaneous vasculitis and polyneuropathy. This group featured more frequently ANA titles >= 1/640 and hypocomplementemia; although no statistical significance was found. The frequency of systemic manifestations found was greater than reported in the literature. CONCLUSIONS: A multidisciplinary approach focusing also on systemic manifestations should be the new standard for management of SS. PMID- 21794738 TI - [Severe flare of Behcet's disease with intense mucucutaneous manifestations]. AB - Behcet's disease is a multisystemic inflammatory disease with various manifestations at the skin level, especially in the form of acne-like lesions or erythema nodosum. Susceptibility to this disease is strongly linked to the presence of the HLA_B51 allele, although certain environmental factors such as infectious agents have also been implicated in its pathogenesis. We present the case of a patient with Behcet's disease who developed a severe flare characterized by lesions similar to those seen in Sweet's syndrome. Histologically we observed granulomatous vasculitis. PMID- 21794739 TI - [Epigenetic therapies, a step beyond biologics for rheumatoid arthritis]. AB - Over the last decade, the management of rheumatoid arthritis has evolved as a result of both the understanding of disease-related processes and the availability of the necessary high-throughput technology to provide patients with molecule-based therapies. New therapies allow the classification of patients into subsets as regards clinical response, at the same time adding to our knowledge of rheumatoid arthritis pathogenesis. New generations of molecules will likely soon be ready for "a la carte" treatment of patients. A promising field of research is epigenetics. Epigenetic regulatory mechanisms switch on and off the transcription of specific genes in individual cells. Acting as observers on non-adequate gene expression, these mechanisms yield protection against the development of tumours. The major achievement of epigenetic therapies could be their selective action on cells with altered epigenetic programs, and it is our challenge to recognize these alterations among patients with rheumatoid arthritis. Although safety concerns may arise, epigenetic drugs will likely be used to treat autoimmune diseases. PMID- 21794740 TI - [Formation of specialists in rheumatology: Accreditation criteria]. AB - The National Rheumatology Board is responsible for postgraduate formation in rheumatology. Herein we present the new criteria for accreditation of teaching units. These criterion contemplate four domains, namely: structure, clinical work, teaching and research. Each domain is divided in subdomains and items. Some of them are of an obligatory nature. This document serves as reference for future applications. The document may be reviewed in the future. PMID- 21794741 TI - [Synovial fluid analysis]. AB - At present, the study of the synovial fluid (SF) is a tool that is used frequently in specialized laboratories because it allows the establishment of diagnosis of crystal associated arthropathies, supports the diagnosis of septic arthritis and helps establish other rheumatologic diagnoses such as monoarthritis or joint effusion. The complete study of the SF includes the following analyses: 1. Macroscopic; 2. Microscopic; and 3. Specific stains. Each one provides information of the joint's state and helps in the establishment of diagnosis and treatment. The characteristics that must be described in the macroscopic analysis are: color, volume and viscosity. Microscopic analysis of the SF confirms the presence of an inflammatory or infectious processes and allows for the detection and identification of crystals. Polarized light microscope is a fundamental tool for the analysis of SF and for the identification of the crystals present in the samples, which not only depend on the form, but also of their birefringence. It is important to mention that in the microscopic analysis, artifacts can confuse the inexperienced observer. A suitable interpretation of the analysis of SF requires the observation by at least two experienced observers. The information that the analysis of SF provides to the clinicians gives them the necessary elements to establish the diagnosis and to decide on treatment. Specific stains in the analysis of SF help in the identification of non-birefringent crystals as those of calcium hydroxypatite. In SF analysis, new fields are being explored that include quantification of cytokines, chemokines, immunoglobulins and the characterization of cell lineages. PMID- 21794742 TI - [Chronic tophaceous gout]. PMID- 21794743 TI - [Painful shoulder in ulcerative colitis]. PMID- 21794744 TI - [Progression of an untreated case of giant cell artheritis]. PMID- 21794745 TI - [Management of spondyloarthritis (ESPOGUIA): methodology and general data from the document]. AB - BACKGROUND: The need for clinical practice guidelines for spondyloarthritis (SpA) comes from the complexity of its management and the great advances that both its treatment and its diagnosis have experiences, which come accompanied by a great variability in its management that exceeds what is considered acceptable. The objective of the ESPOGUIA is to reduce the variability in the management of SA, improving the quality of care through clinical recommendations adapted to their particular environment and based on the best available evidence. METHODS: For the development of ESPOGUIA the following methods have been employed: nominal group, systematic review and Delphi surveys. The expert panel is voluntary, with multiple disciplines participating and based on selection criteria. For the first time in a SER recommendation document, the opinion of the patient was included. In a meeting of the nominal group, the reach, objective, users, organization and needs of the systematic review were established. The elaboration of the guideline, along with its recommendations, was performed in parallel to the systematic reviews, with a meeting for agreement held afterward. The scoring of the degree of evidence and the level of the recommendation was established from the evidence levels proposed by the Oxford Center of Evidence-Based Medicine and the degree of agreement was obtained through a two-round Delphi exercise. RESULTS: We have produced a clinical guideline that encompasses all of the SpA, although it has two sub-guidelines, one for ankylosing spondylitis and the other one for psoriatic arthritis. The target users are mainly rheumatologists, although other specialists and paramedical staff, such as nurses or patient associations, might benefit. Its content envelops all of the management aspects of SpA, from clinical suspicion to treatment, follow-up and day-to-day activities of the patient. CONCLUSIONS: ESPOGUIA can become a very useful instrument for the management of SA and an interactive reference. PMID- 21794746 TI - [Diagnosing early spondyloarthritis in Spain: the ESPeranza program]. AB - Spondyloarthropathies are a group of diseases with an important social and health care impact. Their prevalence is not low, affecting around 1,9% of the general population and represents around 13% of patients of the Spanish Rheumatology departments, according to the National Spondyloarthropathy Validation Study. On the other hand, it is estimated that ankylosing spondylitis, the paradigmatic disease in the group, leads to a mean yearly loss of work of 62 days per patient, leading 20% of patients to change professions and another 20% to a situation of permanent incapacity. However, up to this moment it has not received the same degree of attention as other rheumatic diseases, such as rheumatoid arthritis or osteoporosis. PMID- 21794747 TI - [Measuring spondyloarthritis]. AB - The ASAS group recommendations as well as those from the SER consensus for the treatment of spondyloarthritis with TNF inhibitors advise for the performance of spinal motility tests among the response to treatment measures. The clinical variability between rheumatologists when performing these types of measurements is well documented. Recently, the GRESSER group in our country has created a school to improve knowledge in the area of spondyloarthritis among rheumatologists. One of their objectives is the standardization in the ways measurements are performed in this group of diseases. This document summarizes the activities developed in a recent workshop with a detailed description of the procedures followed to perform each one of the important measurements affecting the axial skeleton. With this we hope to contribute to the much desired standardization in the field of metrology in spondyloarthritis. PMID- 21794748 TI - [Use and application in clinical practice of the CASPAR criteria]. AB - Several classification criteria for psoriatic arthritis have been proposed in the literature but it is still unclear which one of them best represents the diseases' ample spectrum. None of these classification criteria have been universally accepted. New classification criteria (CASPAR) have been recently published. Their application is simple, fast and easy to perform. In addition, they show two important qualities. One is that they allow for the diagnosis of psoriatic arthritis even when there is no skin disease present at the moment of diagnosis. The other is is that it enables us to classify a patient as having psoriatic arthritis in spite of a positive rheumatoid factor. The CASPAR criteria have a sensitivity of 91.4% and a specificity of 98.7%. It seems, in contrast, that it is not as high for recent-onset psoriatic arthritis. Therefore establishing the definition of inflammatory arthritis becomes paramount. PMID- 21794749 TI - [Axial psoriatic arthritis]. AB - Spinal involvement in PsA is a controversial issue. Currently, in spite of clinical recognition of axial involvement in axial PsA, there is a lack of consensus that impedes elaborating a definition for axial Psa. Recent advances in classification, clinical features, outcome measures and therapeutics are reviewed in this paper. PMID- 21794750 TI - [Common aspects between psoriatic spondylitis and ankylosing spondylitis]. AB - In this article we review the common aspects between ankylosing spondylitis and psoriatic arthritis. These aspects are discussed at 3 fundamental levels: concept and diagnostic focus, clinical expression and impact the main domains of disease and therapeutic approach. It is concluded that there are enough arguments to consider both entities within the same concept of axial spondyloarthritis. PMID- 21794751 TI - [What the clinician needs to know about the relationship between inflammation and bone formation. Is blocking inflammation enough to prevent ossification?]. AB - In spondyloarthropathies, the distinctive evidence of skeletal damage is de novo bone formation in the form of an ossifying enthesopathy, be it axial or peripheral, and bony ankylosis. Biologic therapy that neutralize the tumor necrosis factor have shown to be effective controlling the inflammatory activity of these diseases. However, data from animal models, clinical imaging studies and ecographic data seem to indicate that inflammation and bone formation could be independent processes and that control of inflammation might not be enough to impede the development of ankylosis in these patients. In the osteoblasts' differentiation and activation that leads to bone formation, the Wnt (wingless) pathway and the bone morphogenic proteins acquire a special role and might be determinant in the onset and progression of enthesopathic ossification, as well as become therapeutic targets. On the other hand, clinical and imaging findings as well as the determination of bone markers support the hypothesis that that ossification is initially related to inflammation as a repair process. These facts are reviewed and the latest theories are exposed, in an attempt to establish a link between inflammation and bone formation. PMID- 21794752 TI - [Conventional Radiology: Total BASRI and SASSS]. AB - Conventional radiology is a very important tool used to evaluate patients with spondyloarthropathies. It is necessary not only to evaluate the efficacy of the different treatments but also to reflect the history of the disease, maintaining a registry of the progression of the destructive process, evaluating the affection and quantifying the damage. We have at our disposal three methods specifically designed for the evaluation of structural damage in SA: the BSARI (Bath Ankylosing Spondylitis Radiology Index), the SASSS (Stoke Ankylosing Spondylitis Spine Score) and a modification of the latter. This review intends to perform a detailed description of each one of these methods and expose the advantages and disadvantages of their use. PMID- 21794753 TI - [Ultrasound scores in spondyloarthritis]. AB - Ultrasound is proving its validity in the assessment of patients with spondyloarthritis. This paper reviews the various indices validated for the quantification of the activity or for the diagnosis of involvement of peripheral joints, enthesis and sacroiliac joints of these patients. The studies are still preliminary but point to future uses of ultrasound in spondyloarthritis. PMID- 21794754 TI - [Biologic therapies different from the anti-TNFalpha therapy in psoriasis and psoriatic arthritis]. AB - Psoriasis and psoriatic arthritis (PsA) are common conditions in the clinical practice of both dermatologists and rheumatologists. Both entities may cause an important loss in quality of life, and in the case of PsA, joint structural damage may arise over time. For these reasons, clinicians may be faced with the need for treating these cases with highly effective therapies, such as TNFalpha blocking agents, although these drugs may be paradoxically related with de novo onset (or exacerbation of previous lesions) of psoriasis or psoriasiform lesions. In spite of the clinical efficacy of these therapies, recent registry studies show that up to 25% of PsA cases exposed to anti-TNF therapies are withdrawn from these drugs within the first year of therapy. Therefore, there is a need for the use of alternative biologic therapies in this context. The present review deals with this subject. PMID- 21794755 TI - [Management of the patient with ankylosing spondylitis (AS) in partial remission with biologic therapy: is it possible to suspend treatment?]. AB - The management of patients with AS and a good clinical response to biologic therapy is controversial. The results of the different published papers suggest that the suspension of treatment is not a good therapeutic option in these patients. There is currently no validated definition for clinical remission in patients with AS. A hypothetical definition should include the absence of signs and symptoms of disease in any localization, associated to the lack of progression of the disease and all of this during a period of time long enough to establish its persistence with time. In our experience, those patients presenting an apparent clinical remission, based on the previously established definition, could be considered for temporary treatment suspension, especially if we take into account that the reintroduction of treatment is safe and effective. PMID- 21794756 TI - [Etiologic treatment of sicca syndrome. What can the rheumatologist offer?]. AB - No effective treatment has been documented for the glandular primary Sjogren syndrome (PSS) despite the development of oral and biologic agents that have significant activity against other autoimmune disorders. Some disease-modifying agents have been empirically evaluated for the treatment of PSS. Targeting B cells also seems very promising in SSP because of the B-cell hyperactivity recognized in this desease. This article reviews existing data on the use of disease-modifying therapy for glandular of SSP. To date, published studies and trials of oral DMARDs for the treatment of SSP have shown disappointing results. B-cell modulation is clearly a promising therapy for PSS. Many challenges in trial design and execution are evident from the studies reviewed. PMID- 21794757 TI - [Management of the extraglandular manifestations of primary Sjogrens syndrome]. AB - Primary Sjogren's syndrome (pSS) is a chronic systemic autoimmune disease, of slow progression, characterized by lymphocytic infiltration of the exocrine glands, that leads to sicca symptoms, mainly xerophtalmia and xerostomia. It may involve any organ and lead to extraglandular manifestations, which also can precede typical glandular manifestations and delay the diagnosis of pSS. In the past years, better knowledge of the disease has led to improvement in treatment management. PMID- 21794758 TI - [Genetics in scleroderma]. AB - Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA DRB1*11/*06/*16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as "genome wide association studies" the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease. PMID- 21794759 TI - [Useful imaging techniques in the diagnosis and follow up of large vessel vasculitis: eco-doppler, angio-CT, angio-RM]. AB - Although most vasculitis require histological proof for a definitive diagnosis, diagnostic imaging can be very helpful in this regard, allowing a proper evaluation of the vascular system and monitoring the response to treatment. Even though vasculitis is constituted by different pathological substrates, they show a common semiologic pattern from a radiological standpoint which is represented by inflammation, arterial wall thickening, and potential secondary development of vascular stenosis, occlusions or aneurysms. Differential diagnosis among diverse entities is based, beside clinical criteria, on the anatomical location and topography of the affected vascular territory. The general radiologic semiology is described in this paper from the perspective of the different imaging techniques, addressing their main advantages and drawbacks. Proper knowledge of this techniques will allow us to select the most appropiate one for each clinical condition. PMID- 21794760 TI - [Pathogenic basis of B cell targeted therapy in systemic lupus erythematosus (SLE)]. AB - Recent success of B-cell targeted therapies in rheumatoid arthritis suggests their potential efficacy for other auntoantibody-mediated autoimmune diseases. Currently, multiple agents directed toward different B-cell specific targets are under development. Although the best strategy is yet to be defined, multiple functional inhibitors or cytolitic agents such as anti-CD20 or anti-CD19 are available. According to studies in RA, the most likely mechanism of action of rituximab (anti-CD20) consists of a secondary reduction in local (synovial) or systemic autoantibody producing short-lived plasma cells. According to this data, it is expected that these therapies will be efficacious in SLE, were B-cell enhanced function and autoantibodies play relevant pathogenetic roles. Clinical trials confirm B-cell effects, delayed activity on autoantibody synthesis, and most importantly, the feasibility of these therapies to treat SLE. However, there are no sufficient data confirming their therapeutic value when added to convencional therapy. Although multiple open trials suggest that rituximab might be useful for refractory manifestations of SLE, more controlled trials are needed in order to establish the indications and strategies of its use in SLE. PMID- 21794761 TI - [Drug induced myopathies]. AB - Drug related myopathies are frequent. A history of use of medication is essential for its diagnosis. Without taking into account alcohol, drugs that frequently induce myopathies are steroids, colchicine, antimalarials, statins and cocaine. They can present muscle pain, proximal weakness and an increase in muscle enzymes. Suspension of the offending drug can lead to a cure in most of the cases. PMID- 21794762 TI - [Use of rituximab in the treatment of lupus patients. The LESIMAB database]. AB - Systemic lupus erythematosus is an autoimmune disease that may involve the function of organs and reduce the survival of patients. Advances in the diagnosis and treatment have improved the short-term prognosis.However, most therapeutic improvements come from progress in other areas of medicine and only in recent years is this trend changing. Unfortunately, the development of new drugs for lupus is facing specific difficulties and the development of rituximab in lupus has been stopped despite good results in the observational studies. This review examines some of the aspects that influence these difficulties from the perspective of the LESIMAB database. PMID- 21794763 TI - [Safety of biological therapies: new data from BIOBADASER]. AB - The study of the long-term safety of biological therapies has been made possible because of the creation of several national registries. These have resolved some of the safety-derived doubts from the initial clinical trials, observational studies and meta-analyses. The main problem associated with biological therapy use is a moderate increase in the risk of serious infections when compared to conventional therapies. However, this risk can be reduced with adequate preventative measures. It seems that there is neither an increased risk of cancer nor elevated mortality with the use of biological drugs. These adverse events, along with others such as paradoxical induction of psoriasis, demyelinating diseases and administration-related reactions, have been studied in BIOBADASER, the Spanish Registry of Biological Therapies. This paper reviews the safety of biological agents with a special focus on BIOBADASER studies. PMID- 21794764 TI - [Certolizumab pegol]. AB - Certolizumab pegol is a new anti-TNF drug formed by the Fab' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol. Certolizumab pegol recognizes and binds to human TNF-alpha, both in its soluble and membrane bound form, and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns' disease. In this review we summarize the structural characteristics and clinical efficacy data, as well as safety data of this anti-TNF agent in patients with RA. PMID- 21794765 TI - [Defining remission in Rheumatoid Arthritis. New ACR/EULAR criteria]. AB - Remission is the ideal treatment objective in the management of rheumatoid arthritis. To define remission, stringent criteria are needed which allow clinicians to assess the presence of active disease and which should be reliable enough to support therapeutic decisions. Currently there are many different remission classifications and none has been validated against important outcome measures such as the absence of progression of joint damage and disability. Recently, a subcommittee of the ACR and EULAR has proposed new criteria for remission based on a categorical classification and a composite score like SDAI allowing their use in clinical practice. PMID- 21794766 TI - [Contribution of nurse-led clinics in the management of the patient with rheumatoid arthritis]. AB - The goal of a nurse-led clinic in the management of rheumatoid arthritis patients is to promote patient independence. Patient education and empowerment are efficacious tools for achieving this. The main nursing care roles are vigilance of physical symptoms, drug toxicity and co-morbidities; management of physical and psychological symptoms; to provide continuity of care. There is evidence supporting the effectiveness of nurse-led clinics and the economic benefits related to it. PMID- 21794767 TI - [Interleukins network in rheumatoid arthritis pathophysiology: beyond proinflammatory cytokines]. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis and progressive destruction of the joint cartilage and underlying bone, together with diverse extra-articular manifestations. Cytokines act as soluble effector mediators of the inflammatory process. Therapeutic neutralization with monoclonal antibodies against the pro-inflammatory cytokines TNF-alpha and interleukin 1 (IL-1) has shown a clear efficacy on inflammation and clinical manifestations of RA, although a percentage of patients do not respond. This review covers new relevant cytokines in the RA physiopathology and potential biomarkers of inflammation. The current challenge is to develop biomarkers that enable an earlier diagnosis, as well as prognostic markers and new therapeutic candidates. Combined administration of several of these cytokines could eventually address a personalized treatment approach for each patient. PMID- 21794768 TI - [Biomarkers in rheumatoid arthritis]. AB - The search for biomarkers in rheumatoid arthritis (RA) has been the object of interesting research in the past few years, although results have not always been relevant. Several biomarkers, from several different locations (blood, urine, synovial fluid, synovial tissue) and of different nature (autoantibodies, genetic markers, joint remodeling markers), and related to different outcomes, diagnostic and prognostic markers (joint destruction, disability, lack of remission, mortality, response to anti-rheumatic treatment, etc.) have been studied. The present article reviews research only on soluble biomarkers, mainly those in serum, related to the diagnosis and joint destruction in RA. PMID- 21794769 TI - [Tocilizumab in rheumatoid arthritis]. AB - Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the receptor for IL-6, approved for the treatment of rheumatoid arthritis (RA) in Japan, Europe and the US. Wide clinical development has shown the efficacy of TCZ in most of the possible situations of RA: RA without prior failure to MTX (AMBITION), RA unresponsive to MTX (SATORI, OPTION, LITHE) or any DMARD (TOWARD, ROSE) as well as RA refractory to anti-TNFa agents (RADIATE). In addition to its early onset, efficacy was constant and even increased as time passed (GROWTH95, GROWTH96). TCZ has shown great efficacy in correcting laboratory alterations in RA, both in acute phase reactants as well as anemia of inflammatory disease. Although in RA TCZ us initially indicated in combination with MTX, it has also shown its efficacy as monotherapy (AMBITION). TCZ is equally effective in the prevention of structural damage (SAMURAI, LITHE). In addition, it has shown to be a safe and well-tolerated drug, similar to other biologic therapies. All of these aspects make TCZ an adequate therapeutic alternative to be considered in any RA scenario. PMID- 21794770 TI - [New criteria for the classification of rheumatoid arthritis]. AB - In September 2010, new criteria for the classification of rheumatoid arthritis (RA) were published, with the intention of allowing an early diagnosis of the disease. These new criteria are targeted to an earlier form of RA than allowed by the criteria that had been used up to that point. In this review we comment the methodology used for the creation of the new classification criteria, its advantages with respect to the older ones, its shortcomings and the consequences their application will have. PMID- 21794771 TI - [Better informed decisions in the management of osteoporosis]. PMID- 21794772 TI - Multiethnic lupus cohorts: what have they taught us? PMID- 21794773 TI - [Analysis of the body composition of Spanish women with fibromyalgia]. AB - OBJECTIVES: To describe the anthropometric profile and body composition of women from Southern Spain diagnosed with fibromyalgia (FM) and to compare the observed values with values from other studies conducted on FM patients and with national reference values. MATERIALS AND METHODS: The body composition of 104 women diagnosed with FM was assessed using an eight-electrode impedance meter. The reliability of the body composition measurement was tested in a randomly selected sub-sample (n=28). The reliability study showed a test-retest systematic error close to zero in most of the parameters studied. RESULTS: The women with FM who were studied had a mean weight of 71.3+/-13.4 kg, height of 158+/-6 cm, body mass index of 28.6+/-5.1 kg/m(2), body fat mass of 38.6+/-7.6%, total body water of 31.6+/-3.8 l and muscle mass of 23.4+/-3.0 kg. In general, there were no substantial differences in weight and body mass index between women with FM and those analyzed in other Spanish and European studies involving FM patients, nor when they were compared with regional or national reference values. However, the prevalence of obesity in the women with FM under study was 33.7%, a higher figure than that from the national reference data for obesity in similarly aged women (i.e. 26,4%). CONCLUSIONS: The results suggest that obesity is a common condition in women diagnosed with FM, its prevalence in this population being higher than the national reference values. This study provides detailed information about the body composition characteristics of women with FM. PMID- 21794774 TI - [Rheumatology and osteoporosis (RETOSS): a vision of postmenopausal osteoporosis in rheumatology departments throughout Spain]. AB - OBJECTIVE: To know the characteristics of the postmenopausal women with osteoporosis consulting Rheumatology Hospital Divisions in Spain. METHODS: An epidemiologic, observational, transverse and multicentric study was performed from June to September 2008 in 63 rheumatology divisions in Spain. Six hundred and twenty nine osteoporotic postmenopausal women were studied using a questionnaire designed to get demographic, clinical, radiological, bone density, and functional information. Every physician had to choose only one patient per day, usually the first woman to come in and fulfill the inclusion and exclusion criteria. RESULTS: Mean age of included women was 66,6 [9,2) years, weight:64,6[10,1] kg and body mass index: 26,1[4,1] kg/m(2). They were 3,1[2,8] cm shorter than the maximal historical height. 35,7% of them had a family history of fracture and 40,7% had a past history of fracture, of which 54,8% were vertebral fractures. Patients who received calcidiol <20 ng/ml sustained more falls (p=0,033) and fractures (p=0,006) than women receiving calcidiol >20 ng/ml. Risk of falls and fractures increased with advancing age and 51,5% of women who fell, had a fracture. 75% of women had poor calcium intake (<=400 mg/day). The Get up & go test showed a linear trend to an increased probability of >20s in relationship with the age as well as with an increased incidence of fractures. 71,8% of patients had back pain and in 85,3% it went from moderate to severe. IN CONCLUSION: Most osteoporotic postmenopausal Spanish women have a low calcium intake, one out of three has a family history of fractures that increases fracture incidence and this shows a relationship with age and functional capacity; four out of ten have had any type of fractures, one out of three have fallen during the past year and half of these present back pain. Calcidiol levels have been evaluated in a small group of patients. PMID- 21794775 TI - [Prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics]. AB - FUNDAMENTAL AND OBJECTIVE: Psychological impairment is frequent in patients with rheumatic diseases. The aim of the study was to assess the prevalence of symptoms of anxiety and depression in patients with psoriatic arthritis attending rheumatology clinics. PATIENTS AND METHOD: Multicentre cross-sectional study conducted in rheumatology clinics. Patients with psoriatic arthritis were recruited; variables retrieved were sociodemographic, clinical and patient centered (Hospital Anxiety and Depression scale o HADs, EQ-5D questionnaire, etc.). Prevalence in the study population was calculated as anxiety or depression symptoms by an HADs score >=11 or those receiving pharmacological treatment. A logistics regression model was used to know which variables were related to symptoms of anxiety or depression. RESULTS: A total of 495 patients were included, 42.8% were women and median (SD) age was 50.4 (12.7) years. Prevalence of symptoms of anxiety were 29.7% and prevalence of symptoms of depression was 17,6%. Patients with anxiety or depression symptoms had all EQ-5D dimensions affected (p<0.01). Higher prevalence of anxiety was related to being a woman, a mixed onset pattern with respect to peripheral joints and those treated with DMARD alone with respect to DMARD+NSAID or biologic alone. A higher depression prevalence was related to being a woman and a mixed onset pattern with respect to peripheral joints. CONCLUSION: The prevalence of anxiety symptoms and the prevalence of depression symptoms are high among patients suffering psoriatic arthritis in the studied population. PMID- 21794776 TI - [Anti-transglutaminase, antigladin and ultra purified anti-gladin antibodies in patients with a diagnosis of rheumatoid arthritis]. AB - Celiac disease (CD) is an enteric disease caused by dietary gluten in individuals with genetic predisposition. One of the clinical manifestations of CD is the peripheral arthritis that may simulate RA. OBJECTIVE: To determine the frequency of anti-gliadin (aGL), anti-tissue transglutaminase (aTGT) and ultra purified anti-gliadin (AGLU) antibodies in patients with RA. METHODS: Cross-sectional study. We included consecutive patients diagnosed as RA (ACR). Demographic and clinical data was registered by direct interview and serum levels of aGL, aTGT y aGLU were determined using ELISA. RESULTS: Eighty-five RA patients were included; 87% were women. Mean age was 44+/-12 years, mean disease duration 12 +/-9 years. aGL IgG antibodies were positive in 16 patients, IgA aGL antibodies in 29 patients, aGLU in 14 patients and only one patient had aTGT. CONCLUSIONS: It is possible that CD may be the correct diagnosis in a patient with polyarthritis, even if the patient meets the ACR criteria for RA. In other words, CD should be considered among the differential diagnoses in a patient with poly-arthritis. PMID- 21794777 TI - [Consensus on the Use of Rituximab in Rheumatoid Arthritis. A document with evidence-based recommendations. Grupo de Expertos en Rituximab. ]. AB - INTRODUCTION: Rituximab has been employed successfully for the treatment of Rheumatoid Arthritis (RA). However, its particular mechanism of action, as well as a lack of concrete guidelines for its management have generated doubts on its use. OBJECTIVE: To establish recommendations that facilitates the use of rituximab in common clinical practice. METHODS: In a first Delphi round, 9 expert rheumatologists got together to develop questions on those subjects generating most doubts on the efficacy and safety of the drug. These were adapted to perform a systematic review of the evidence, which was presented in a second meeting. Nominal groups were formed to respond to each question and give a recommendation. These recommendations were presented in a second Delphi round to a larger group of experts in rheumatology. Once again recommendations were discussed, modified and voted upon. Once approved, a vote on the degree of agreement for each recommendation was carried out. RESULTS: 17 recommendations were established, 10 regarding efficacy and 7 safety. All of the efficacy recommendations except 3 presented a good or moderate degree of evidence. Among the safety recommendations, 3 had a good or moderate degree of evidence while in the rest it was indirect, scarce or non-existent and a product of expert recommendation. The degree of agreement between experts was elevated for most of the recommendations. CONCLUSIONS: These recommendations attempt to clear doubts on the use of rituximab and establish guidelines for its use in daily practice. Efficacy recommendations have a high degree of evidence, allowing the clinician to be guided in therapeutic decisions. Safety recommendations have a lower degree of evidence. PMID- 21794778 TI - [Hereditary systemic autoinflammatory diseases]. AB - Systemic autoinflammatory diseases encompass different rare clinical entities characterized by recurrent acute inflammatory episodes secondary to a dysregulated inflammatory process. Since their first clinical descriptions, the Mendelian hereditary nature of some of them became evident, with their genetic and molecular basis being recently elucidated. There are disease-causing mutations in genes encoding for different proteins involved in the innate immune response and inflammation. Herein, we will introduce the reader to an updated review of the main clinical, physiopathological and therapeutic features of the different hereditary systemic autoinflammatory diseases. PMID- 21794779 TI - [Anti-TNFalpha therapy in ankylosing spondylitis: symptom control and structural damage modification]. AB - Anti-TNFalpha agents represent an outstanding advance in the symptomatic control of patients with ankylosing spondylitis presenting an inadequate response to non steroidal anti-inflammatory drugs. Anti-TNFalpha antagonists have demonstrated efficacy and safety in the long-term but continuous therapy is needed for an adequate control of symptoms. After the failure to a first anti-TNFalpha agent, the use of a second TNFalpha antagonist seems to be effective and safe. Despite the fast and continuous suppression of bone inflammation, demonstrated by magnetic resonance imaging, the beneficial effect of treatment with TNFalpha antagonists on the radiological evolution has not been demonstrated to date in ankylosing spondylitis. It seems that insights into new therapeutic molecular targets implicated in the process of ossification are needed. PMID- 21794780 TI - [Rapidly destructive osteoarthritis of the hip: case presentation]. AB - The rapidly destructive osteoarthritis of the hip is a variant of osteoarthritis that is characterized by hip pain during one to twelve months and rapid destruction of the femoral head, in absence of infectious, neurologic, metabolic or inflammatory disease. We present the case of a 66 year- old male with severe COPD that referred pain in both hips and was unable to walk. In the radiography of the pelvis complete destruction of both femoral heads was observed. The patient did not have abnormalities in blood tests that were related to infectious, neurologic or metabolic diseases. The patient underwent bilateral total hip replacement with prosthesis and physical therapy later. The patient functional status greatly improved with this treatment. PMID- 21794781 TI - Sildenafil in severe peripheral ischemia induced by terlipressin. A case report. AB - A female patient in the sixth decade of life developed renal failure secondary to gastrointestinal bleeding, which was non-responsive to conventional therapy. She was treated with terlipressin iv; showing improvement but developing, over the next few days, ischemia and necrosis of the toes in the lower extremities, simulating necrotizing vasculitis, without response to regular management. An alternative therapy, oral sildenafil 50mg BID, was used, with a rapid reversal of the clinical picture. The vasodilator action of sildenafil is useful in cases of ischemia induced by some drugs. The objective this report is to warm about the utility of sildenafil in some potentially severe cases, like the one above. PMID- 21794782 TI - [Rapidly progressive fatal interstitial lung disease in a patient with an overlap syndrome of systemic lupus erythematosus and systemic sclerosis]. AB - A 31-year-old woman with a prior history of an overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) developed fever, pericarditis with pericardial effusion and a rapidly progressive fatal interstitial lung disease. Diagnostic test and procedures, differential diagnosis and therapeutic approach are discussed. PMID- 21794783 TI - [Citrullinated proteins in rheumatoid arthritis]. AB - Rheumatoid arthritis is an autoimmune disease of multifactorial etiology characterized by inflammation of the joints and presence of autoantibodies directed against multiple autoantigens. Recently the study of the anti citrullinated protein antibodies (ACP) has acquired great interest due to its high specificity and sensitivity for diagnosis, in addition to which it has shown to be a predictor of severity in patients with rheumatoid arthritis, suggesting an important participation in the pathogenesis of the disease. PMID- 21794784 TI - [Pathogenic mechanisms of the anti-phospholipid antibodies]. AB - The antiphospolipid syndrome (APS) is an autoimmune disease characterized by recurrent fetal loss, thrombotic events (arterial or venous) and hemocytopenic disorders associated to high titers of circulating aPL. Two variants of the APS have been described. Primary APS is a clinical entity without evidence of any other autoimmune disease and secondary APS is a clinical disorder mainly associated with Systemic Lupus Erithematosus (SLE). aPL are a widely group of immunoglobulins directed against different components or proteins factors. In 1990 three groups of researchers identified that beta(2)GP-I is the mainly antigenic target of aPL in APS patients. There are evidences that show that more than one pathogenic mechanism is involved in the development of the APS. The best documented clinical manifestations associated with the APS are recurrent fetal loss and thrombotic disorders. The latter is based on observations in vivo in animal models and in vitro on the effects caused by abeta(2)GP-I antibodies from patients with APS or from animals which cause experimental APS. The objective of the present paper is to show the pathogenic mechanisms that participate in the development of the APS. We also presented evidence that shows that abeta(2)GP-I induces pro-inflammatory, pro-adhesive and pro-coagulant disorder. PMID- 21794785 TI - [Muscle metastasis of a coroid melanoma]. PMID- 21794786 TI - [Exostosis, a complication of transiliac bone biopsy]. PMID- 21794787 TI - [It is necessary to develop medical professionalism]. PMID- 21794788 TI - [Classification of constitutional disorders of bone: a new perspective]. PMID- 21794789 TI - [Neuroimmunoendocrine interaction in autoimmune rheumatic diseases: a new challenge for the rheumatologist]. PMID- 21794790 TI - [Descriptive study of the use of DMARD in patients with rheumatoid arthritis or persistent arthritis who start drug treatment in Spain (FIRST)]. AB - INTRODUCTION: Rheumatoid arthritis is clinically very heterogeneous and variable in its progression, and no one treatment works the same for all patients, as this will depend on the clinical course and specific situations. OBJECTIVE: To describe the treatment with DMARDs established for the first time in patients with rheumatoid arthritis (RA) or persistent arthritis (PA) in routine clinical practice in Spain. MATERIAL AND METHODS: Epidemiological, cross-sectional, uncontrolled, multicenter study in 15 regions of Spain during a period of five months (July to November 2006). We included patients of both genders, aged 18 years and diagnosed with RA according to ACR criteria or PA defined as any arthritis (oligoarthritis or polyarthritis) lasting >=12 weeks, which would be given DMARD to treat their disease. RESULTS: 1079 patients were recruited, 915 analyzed (33% ?/? 67%) meeting all the criteria required to be evaluated in the study. Mean age of patients was 54.6 (SD=15.4) years. The mean time from onset of symptoms until the 1st visit with the rheumatologist was 6.3 (11.3) months and the time from the 1st visit with the rheumatologist and the start of treatment was 4 (13.5) months. Of the patients tested, 96.7% was treated with at least one DMARD, 62.1% were given NSAIDs, corticosteroids to 59.2% and 3.8% biological therapy. In patients who received DMARDs, 90.3% received treatment with a single DMARD, 9.5% with 2 DMARDs and 0.2% with three DMARDs. In polytherapy, the DMARDs that are most often administered together were MTX + hydroxychloroquine (4.8%), MTX + leflunomide (2.0%) and MTX + sulfasalazine (1.5%). The most frequently used DMARD in monotherapy was MTX (81.3%), followed by leflunomide (4.1%) and hydroxychloroquine (3.2%). In 89.6%, the treatment of first choice was adequate according to the SER. CONCLUSION: The most common pattern of initial treatment of RA is MTX monotherapy. Treatment of RA by rheumatologists has been homogenized in recent years. PMID- 21794791 TI - [Using a laser based program in patients diagnosed with fibromyalgia]. AB - In this study, the benefits of a program of treatment by laser were evaluated on the improvement of symptoms associated with fibromyalgia. A total of 31 participants took part in the study, all of them women, randomized into two groups: intervention with laser and placebo. The intervention with girlase E11010 consisted of the individual application of six frequencies on seven anatomical zones of the body. The results were statistically significant differences for "weariness" and "difficulty sleeping" variables. In the rest of the variables, we did not find any statistical significance. One of the conclusions from the present study is the need for development of new research to verify the influence of girlase E1.1010 in the improvement of symptoms associated with fibromyalgia. PMID- 21794792 TI - [Adaptation and validation of the Rheumatoid Arthritis Quality of Life Scale (RAQoL) to Mexican Spanish]. AB - OBJECTIVE: To develop and validate the Mexican-Spanish version of the Rheumatoid Arthritis Quality of Life questionnaire (RAQoL). METHODS: The original UK English version of RAQoL was translated into Mexican-Spanish version by a bilingual translation panel. An independent lay panel reviewed the instrument's item phrasing to ensure comprehensiveness and appropriateness in colloquial Mexican Spanish. Structured cognitive debriefing interviews were conducted with 15 Rheumatoid Arthritis (RA) patients to assess face and content validity. Finally, an independent sample of RA patients completed the RAQoL and additional assessments were performed to assess reproducibility and construct validity. RESULTS: Translation and adaptation was successful as both the lay panel and cognitive debriefing participants considered the new language version to be appropriate. Fifty-seven patients were included in the final evaluation of the Mexican-Spanish version of RAQoL (73.8% female, mean age 52.4 years, SD 14.1, RA duration range 2-27 years). Cronbach's alpha for the new RAQoL was 0.91 and the test-retest reliability 0.92, indicating that the measure has good internal consistency and low random measurement error. The Mexican-Spanish version of RAQoL could discriminate between patients who differed on their perception of disease activity, general health status, current rating of perceived RA severity and whether or not they were experiencing a disease flare. CONCLUSIONS: The Mexican-Spanish version of RAQoL was well accepted by RA patients. The psychometric quality of the adapted questionnaire shows that it is suitable for use in clinical studies and trials of patients with RA. PMID- 21794793 TI - [Systematic review: safety and efficacy of anti-TNF in elderly patients]. AB - OBJECTIVE: To evaluate whether the safety and efficacy of anti-TNF treatments in elderly patients with rheumatic diseases is similar than the safety and efficacy of the same drugs in younger patients. METHODS: Systematic review. We performed a systematic search in MEDLINE (Pubmed), EMBASE (Ovid), and the Cochrane Library Plus. Abstracts published in the American and European rheumatology congresses and articles in Reumatologia Clinica were also reviewed. RESULTS: Ten studies fulfilled the inclusion criteria. Studies show a similar efficacy in elderly and younger patients. The differences between the young and the elderly regarding DAS28 reductions before and after are very small: 0.04 in the Geneway et al study and 0.0 in the Mariette et al study, as well as in the before and after HAQ: 0.04 (Geneway et al), 0.18 (Schiff et al) and 0.06 (Mariette et al).Adverse events reported in elderly and younger patients are 83.3% and 77.1% respectively with etanercept, as reported by Fleischmann; 27.2% vs 12.5%, p=0.19, as reported by Chevillotte, and the rate of withdrawal due to an adverse event was 57,8% vs 29,2% with infliximab, p=0.03, 36% vs 15% p=0.06 with adalimumab and 10,3% and 9,5%, with no significant p value, as reported by Massara. CONCLUSIONS: The information to assess the efficacy and safety of anti-TNF therapy in elderly patients was obtained in all cases from sub analyses and therefore bias is possible. We can say, with a low to moderate level of evidence, that elderly patients undergoing anti-TNF treatments have a higher number of adverse events, and similar efficacy, when compared with younger patients. PMID- 21794794 TI - [Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in spondyloarthritis except for psoriatic arthritis]. AB - OBJECTIVE: Due to the amount and variability in quality regarding the use of biologic therapy (BT) in patients with spondyloarthritis (SpA), except for psoriatic arthritis (PsA) patients, the Spanish Society of Rheumatology has promoted the generation of recommendations based on the best evidence available. These recommendations should be a reference for rheumatologists and those involved in the treatment of patients with spondyloarthritis (SpA), except for psoriatic arthritis (PsA), who are using, or about to use BT. METHODS: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. RESULTS: We have produced recommendations on the use of BT currently available for SpA (but not PsA) in our country. These recommendations include disease assessment, treatment objectives, therapeutic scheme and switching. CONCLUSIONS: We present an update on the SER recommendations for the use of BT in patients with SpA, except for PsA. PMID- 21794795 TI - [Insulin resistance and rheumatoid arthritis]. AB - Resistance to insulin action is a feature that accompanies certain diseases among which chronic inflammatory states like rheumatoid arthritis are included. What is, what its pathogenesis is, how it is measured, and what clinical and therapeutic implications have in rheumatoid arthritis patients is a topic not familiar to rheumatologists that is reviewed in this paper. PMID- 21794796 TI - [Sjogren's syndrome and pancreatic affection]. AB - Sjogren's syndrome (SS) is an autoimmune disorder affecting primarily the exocrine glands, leading to keratoconjunctivitis sicca (KCS) and xerostomia, but that can also include extraglandular features(1). Due the anatomical, physiological and pathological similarity between the pancreas and the salivary glands, it has been described that the pancreas it is not exempt from the damage produced by this syndrome. Some authors have assessed pancreatic involvement of SS by analyzing the histopathological changes, evaluating the pancreatic endocrine and exocrine function (serum pancreatic enzymes, elastase, lipase or trypsin determinations, N-benzoyl-L-tyrosyl-para-aminobenzoic acid excretion test, etc), searching specific pancreatic antibodies (antiductal) or performing endoscopic retrograde colangiopancreatography or noninvasive imaging studies such as computed tomography or ultrasound. Herein we review the literature regarding the prevalence and type of pancreatic involvement in the SS and we discuss the differential diagnosis with multiorganic Lymphoproliferative Syndrome. PMID- 21794797 TI - [Manolo Hugue: from sculpture to painting due to arthritis]. AB - There are several artists that have suffered rheumatic diseases. Even then, they continued their creative activity. Paul Klee suffered from systemic sclerosis, Dufy and Renoir suffered from rheumatoid arthritis and Gaudi and Boticelli had systemic-onset juvenile idiopathic arthritis. The famous noucentism sculptor, Manolo Hugue, presented chronic polyarthritis that suggested rheumatoid arthritis. Although he underwent several treatments, such as hydrotherapy or diathermic therapy, he had to stop sculpting. Using the chisel was too painful for his hands. He began, then, painting and composing poetry. PMID- 21794798 TI - [Popliteal aneurysm simulating a Baker's cyst in a patient with rheumatoid arthritis: a case presentation]. AB - Baker's cyst is the most common mass located in the back side of the knee, the popliteal fossa, in patients with degenerative and inflamatory disease of the knee. Popliteal mass may also be due to proliferation of adipose tissue, popliteal artery aneurysm, thrombotic vein, or tumor. These lesions are rarer and may easily be misinterpreted as cysts. We show a man with rheumatoid arthritis who is presenting a palpable mass in the popliteal fossa. Ultrasonography examination demostrated a popliteal artery aneurysms. PMID- 21794799 TI - [Burkitt's lymphoma presenting as an intermittent limp]. AB - Musculoskeletal pain is a frequent complaint in pediatrics usually related to benign conditions. However, it may also represent the initial symptom of serious diseases such as infections, malignancies or orthopedic emergencies. We present the case of a child diagnosed with Burkitt's lymphoma whose initial presentation was a limp. This is, to the best of our knowledge, the first case reported in the literature with this type of debut. This case illustrates the importance of including neoplasms in the differential diagnosis of atypical musculoskeletal pain, since early diagnosis can significantly improve their prognosis. PMID- 21794800 TI - [Predictors of response to biologic therapies in rheumatoid arthritis]. AB - The advent of biological therapies has revolutionized the management of rheumatoid arthritis, demonstrating effectiveness in controlling clinical and radiological damage. However, 20 to 40% of the patients will not respond to these therapies, which are associated to a very high cost. In addition, non-responder patients are exposed to possible adverse effects. For these reasons, we need to identify predictors of response to these treatments. These predictors are reviewed in this evidence-based paper and classified into genetic and non genetic. Despite extensive search, nowadays there are no predictors powerful enough to be used in regular clinical practice. Serum factors, the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies, are the only factors currently being used to predict the response to specific biological therapy. In the future, probably thanks to new technologies based on genomics, transcriptomics and proteomics, it will be possible to identify genetic predictors of response to biological drugs that will allow us to select suitable patients for a specific biological therapy. PMID- 21794801 TI - [Non secreting multiple myeloma]. PMID- 21794802 TI - [Cutaneous cryptococosis in a patient with Behcet's disease and colon cancer]. PMID- 21794803 TI - [Septic arthritis due to Escherichia coli in a patient with multiple myeloma and left knee pain]. PMID- 21794804 TI - Antiphospholipid syndrome: coming of age. PMID- 21794805 TI - [Direct measurement of bone mechanical strength]. PMID- 21794806 TI - [Conditions mimicking polymyalgia rheumatica]. AB - OBJECTIVE: To examine the main clinical and laboratory data of patients initially diagnosed with polymyalgia rheumatica (PMR), which then developed another conditions. MATERIAL AND METHODS: We reviewed the clinical records of patients diagnosed with PMR in three hospitals in Argentina. Patients had a diagnosis of PMR if they met the following criteria: age >= 50 years, erythrocyte sedimentation rate (ESR) at the time of diagnosis > 40 mm, persistent pain and stiffness of at least one month of evolution in two of the following areas: neck, shoulders or proximal arms, hips or proximal lower limbs. Special attention was paid to symptoms or signs of "alarm" (beginning or during disease progression) for suspecting the presence of other non PMR disease within a period of <= 12 months. RESULTS: Sixteen of the 200 patients (8%) had other diseases during follow up. Malignancies (n=4) and rheumatic diseases (n=4) were the most common entities, in addition to infective endocarditis (n=1), narrow cervical canal (n=1), Parkinson's disease (n=1), statin-related myalgia (n=1), hypothyroidism (n=1), vitamin D deficiency (n=1) and Calcium Pyrophosphate Deposition Disease (CPDD) (n=2). The average length change of diagnosis was 4.5+/-3 months. Ten patients had no response to steroids and two had persistently elevated ESR. CONCLUSION: In this study we highlight the importance of recognizing signs and symptoms along with laboratory data and lack of response to treatment as suspects for the diagnosis of other disease manifestations in patients with PMR symptoms. PMID- 21794807 TI - [Sensitivity, specificity, positive and negative predictive values of the criteria for indicating a bone densitometry in the evaluation of medical techniques and research in Cataluna]. AB - The Catalan Agency for Health Technology Assessment and Research (AETIM) proposed, in 2001, criteria for performing a bone densitometry (BD) for use in the consultations of the public health system. OBJECTIVE: To determine the sensitivity, specificity, positive predictive value and negative predictive value of the criteria to indicate BD. MATERIAL AND METHODS: Five groups of volunteers (premenopausal women aged 46 to 65 years, postmenopausal women aged 46 to 65 years, postmenopausal women aged> 65 years and men 46 to 65 years and> 65 years) underwent BD and a questionnaire on risk factors. The results obtained with the AETIM criteria are related to criteria for indication of BD proposed by the World Health Organization (1999 and 2003 criteria), the National Osteoporosis Foundation (1998 amd 2010 criteria) and the International Committee of Clinical Guidelines on Osteoporosis. RESULTS: Criteria from the Catalan Agency have low sensitivity to detect both low bone mass (T index<-1) and osteoporosis (T index< 2.5), specificity varied according to the group. The positive predictive value is low, but the negative predictive value for osteoporosis is high in all groups (except for postmenopausal women aged> 65 years). The remaining criteria have a high negative predictive value and, in women, good sensitivity and low specificity, especially for identifying patients with osteoporosis. CONCLUSION: Catalan Agency criteria are useful for selecting patients who would not need BD, but lack sufficient sensitivity to identify individuals with low bone mass. The other criteria also have a high negative predictive value for osteoporosis, and a better sensitivity. PMID- 21794808 TI - [The impact of therapy with TNF-blockers on health-related quality of life in rheumatoid arthritis patients. A pilot study]. AB - INTRODUCTION: The aim of this pilot study was to evaluate the initial response to 16 weeks of treatment with infliximab and etanercept of disease activity and quality of life in a cohort of 37 patients with established rheumatoid arthritis. PATIENTS AND METHOD: Patients were selected from the Unit of Rheumatology in Hospital Clinico San Cecilio from Granada, refractory to conventional treatment with disease modifying antirheumatic drugs. To assess the disease activity, Disease activity score (DAS28) was used and the measurement of quality of life was evaluated with the Spanish version of the SF-36 Health Survey (SF-36) and the RA-specific questionnaire QoL Scale (Quality of Life in Rheumatoid Arthritis). RESULTS: Preliminary results show a significant decrease in inflammatory activity of the disease and consequently in HRQL scores. The comparison with the general reference population shows a deviation well below average, especially in the "physical function" dimension with a rising response pattern in all dimensions. The correlation between specific scores (QoL-RA scale) and generic ones (SF-36) for HQ-treatment also showed significance, especially with the physical aggregate. DISCUSSION: An important limitation of the present study is the number of patients and the duration of the treatment; despite this, improvements in functional parameters and quality of life are evident and remain roughly stable since the first weeks of treatment. This allow us to continue the study and increase the number of patients. CONCLUSIONS: The preliminary results obtained with TNF-blockers after 16 weeks of treatment in RA objectively show the effectiveness of these drugs and also the perception by the patients of the effect on their quality of life. PMID- 21794809 TI - [Differences in the management of early and established rheumatoid arthritis]. AB - OBJECTIVE: To assess the differences in the clinical and therapeutic management of early and established rheumatoid arthritis (RA) in clinical practice. METHODS: Retrospective and multicentre study including 360 patients diagnosed with RA. During the 12 months prior to the study, onset, sociodemographic, clinical and therapeutic data were collected by clinical chart review. RESULTS: A total of 152 patients with early RA and 208 with established RA were studied. 97.5% had received disease-modifying anti-rheumatic drugs (DMARDs) and 43.6% a TNFa blocker between the diagnosis and the start of the study. Established RA patients used TNFa blockers more frequently than early RA patients (60,1% vs 21,1%, p<0,001). Methotrexate was the most commonly used drug (70.6%). A treatment change was seen in 79% of patients with early RA and 60.6% of those with established RA. A dose change was the most frequent modification and an inadequate response the most frequent reason. A 25.8% of treatments were stopped due to adverse events. The mean (SD) decrease on DAS28 score was 0.9 (1.5) on early RA and 0.2 (1.0) on established RA patients. A 35.8% of early RA patients showed a good EULAR response, while only 16.2% among established RA patients (p<0.001). Rheumatoid factor and radiological progression assessment were the most requested determinations in early RA (p<0.05). CONCLUSIONS: Spanish rheumatologists used biological drugs with a higher frequency in patients with more advanced disease, as recommended in the main clinical practice guidelines. PMID- 21794810 TI - [Consensus statement of the Spanish Society of Rheumatology on the management of biologic therapies in psoriatic arthritis]. AB - OBJECTIVE: Due to the amount and quality variability regarding the use of biologic therapy (BT) in psoriatic arthritis (PsA) patients, the Spanish Society of Rheumatology (SER) has promoted the generation of recommendations based on the best evidence available. These recommendations should serve as reference to rheumatologists and those involved in the treatment of patients with PsA, who are using, or about to use BT. METHODS: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and degree of recommendation was classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. RESULTS: We have produced recommendations for the use of TB currently available for PsA in our country. These recommendations include disease assessment, treatment objectives, therapeutic scheme and switching. CONCLUSIONS: We present an update on the SER recommendations for the use of BT in patients with PsA. PMID- 21794811 TI - [Adverse effects of bisphosphonates]. AB - Aminobisphosphonates are drugs that have been used successfully in the treatment of osteoporosis for more than 20 years. Although main registry studies found a scarcity of relevant adverse events, in recent years and as a result of pharmacovigilance, different complications have been reported, some potentially serious. This has raised questions on the safety of these drugs, especially in high doses, like those used in oncology and long-term treatment, as needed in patients with osteoporosis. In this review, based on the analysis of relevant scientific evidence from clinical trials, case series, cohort studies and databases published to date, we summarize the clinical and epidemiological characteristics of the adverse effects of these drugs. PMID- 21794812 TI - [Skin necrosis in a patient with temporal arteritis]. AB - We present the case of a 91 years old patient diagnosed through biopsy with temporal arteritis who, in addition, had scalp necrosis. We briefly review the literature for published cases. PMID- 21794813 TI - [Reactivation of hepatitis B in a patient with spondyloarthritis after the suspension of methotrexate and efficacy of treatment with antivirals in association to adalimumab]. AB - We report the case of a male chronic hepatitis B virus (HBV) carrier with HLA-B27 spondyloarthrititis who developed fulminant hepatitis after discontinuation of methotrexate (MTX). Full recovery after therapy with lamivudine and adefovir allowed treatment with adalimumab which was well tolerated. Reactivation of hepatitis B after MTX withdrawal is a very rare complication, which can also occur in association with anti-TNF agents. In patients with positive serology for HBV prophylactic antiviral therapy is recommended. PMID- 21794814 TI - [How does one manage patients with rheumatoid arthritis and positive serology to hepatitis B, hepatitis C, human immunodeficiency virus?]. AB - Chronic viral infections in rheumatic patients are a diagnostic and therapeutic challenge. Some of the disease-modifying antirheumatic drugs (DMARD) commonly used in rheumatoid arthritis, such as methotrexate and leflunomide, are hepatotoxic. With biological therapy, which is now widely used in patients refractory to these and other DMARD, some cases of reactivation of hepatitis B, even fulminant cases, have been reported, especially when employing TNF antagonists and rituximab, so their use must be carefully assessed and usually accompanied by antiviral therapy. However, there have not been reports of reactivation of hepatitis C after immunosuppressive therapy. In patients with HIV infection, administration of immunosuppressive therapy carries a high risk of opportunistic infections, although the new highly active antiviral therapy allows the use of some drugs in selected cases. PMID- 21794816 TI - [A woman with joint pain and enlarged upper limbs]. PMID- 21794815 TI - [68 years old woman with right leg weakness and colostasis]. PMID- 21794818 TI - [A case of primary hypertrophic osteoarthropathy]. PMID- 21794819 TI - [Clinical anatomy: a basic discipline for the rheumatologist]. PMID- 21794817 TI - [Primary pulmonary hypertension in Sjogren's syndrome: a rare association]. PMID- 21794820 TI - [Gout: past, present, and future]. PMID- 21794821 TI - [The influence of consumption of phytate on the bone mass in posmenopausal women of Mallorca]. AB - BASIS: Osteoporosis is a serious health problem in the population, mainly for postmenopausal women. Therefore, it is important to develop programs to decrease prevalence. The main objective of this study is to determine the influence of phytate consumption on bone mineral density. PATIENTS AND METHOD: The bone mineral density was evaluated in postmenopausal women by means of dual X-ray double energy absorptiometry for calcaneous (C), lumbar spine (LS) and femoral neck (FN). The results obtained were related to the consumption of phytate by means of a dietary questionnaire. RESULTS: In the three different areas (C, LS, FN) we observed significantly higher values of T-score in women that consumed adequate amounts of phytate as opposed to those that did not, (C 0.1 vs. -0.5, LS -1.2 and -2.5 and FN -0.2 and -1.2). There is also an increase in the T-score as more phytate is consumed, up to a maximum of two times a week (C -0.7 in non consumers, -0.2 in those that consume phytate once a week and 0.2 in those that consume phytate twice a week; LS -2.8, -1.7 and 1.1 and finally, CF -1.3, -0.6 and -0.1). CONCLUSION: The results obtained seem to indicate that the adequate consumption of phytate may play an important role in the prevention of bone mineral density loss in postmenopausal women. PMID- 21794822 TI - [Influence of the physical therapy on the health and quality of life of the rheumatic patient]. AB - OBJECTIVE: To evaluate the effectiveness of a specific physical therapy treatment on stiffness, pain and quality of life (HRQL) in rheumatic patients. METHODS: Experimental, prospective, longitudinal and intervention study. It involved 29 individuals with a mean age (SD) of 54.16 (11,9) years, belonging to the Salmantina Association of Rheumatoid Arthritis Patients, randomized into 2 groups: treatment (GT) and control (GC). The study analyzed the time in minutes of morning stiffness, pain -using the Downie Scale- and CVRS through the Nottingham Health Profile (NHP) and the Health Questionnaire SF-36 (SF-36). It carries out an individual treatment that includes mainly physiotherapy manual techniques in one or two sessions per week for six months. RESULTS: The time of early morning stiffness showed a mean (SD) 21.38 (29.99) minutes (GC=20,38, GT=22.19), increasing in GC (26.82) and decreasing in GT (12,5). Pain presented at the beginning a mean (SD) 3.6 (2.03) points (GC=2,85, GT=4.22) decreasing in GT (3.68) and increasing in GC (3.45). There was an improvement of CVRS in the GT with decreased scores on four dimensions of NHP (pain, sleep, physical mobility and emotional reactions) and increases in SF-36 (physical problems, social function, pain, function physics). In any case the results were statistically significant. CONCLUSION: The study cannot conclude the effectiveness of physiotherapy in the treatment of rheumatoid arthritis although the results show a decrease of morning stiffness and pain and increased CVRS, which is clinically interesting. PMID- 21794823 TI - [One year clinical and ultrasonographic follow up of the pilot study for the referral of patients with early spondyloarthritis (ESPIDEP)]. AB - OBJECTIVES: To characterize a cohort of early spondyloarthritis (SpA) patients, to demonstrate the usefulness of enthesis ultrasonography for the diagnosis and follow up, and to develop a statistical model to predict persitent activity. PATIENTS AND METHODS: A 1 year prospective study with clinical, radiological and ultrasonographic evaluations was performed in patients with SpA from the Pilot Study for the Referral of Patients with Early SpA (ESPIDEP). Enthesis ultrasonography was explored by the MAdrid Sonographic Enthesis Index (MASEI), and its diagnostic utility was determined to be a cutoff score of >= 18 points. The clinical, radiological and MASEI scores were studied. Finally, a statistical model from factors predicting persitent activity was developed. RESULTS: A 1 year follow-up of 32 patients was carried out. The baseline MASEI reached a sensitivity and specificity of 78,12% and 84,37% respectively, positive and negative predictive value was 83,3% and 79,41% respectively, and positive and negative likelihood ratios were 5 and 0,26, respectively. The improvement of BASMI and the MASEI scores were significant (p = 0,001 and p = 0,007, respectively). From the beginning, women had more peripheral affectation, and men had higher axial radiological progression and higher CRP (p < 0,05).The statistical model that best predicted persitent activity was constituted by nocturnal back pain, BASDAI and CRP. CONCLUSIONS: Enthesis ultrasonography can be useful when begining the evaluation and follow-up of early SpA. Disease patterns are different according to sex. The ability to predict persitent activity in early stages supports the use of more intensive treatments. PMID- 21794824 TI - [Characteristics of early arthritis units that may be associated with better referral efficiency: survey of SERAP units]. AB - OBJECTIVE: To identify characteristics of early arthritis units, that may be associated with better referral eficiency. METHODS: A national survey of the 36 early arthritis units (EAU) in Spanish Rheumatology Units in 2004 (SERAP project). Survey collected information about general practitioners (GP) educational program to improve knowledge and practical skills of early arthritis, networking and feed-back system and referral efficiency. EAU were classified in two groups according to 25 and 50% of inappropriate referral process, respectively. RESULTS: Thirty four of the 36 (94%) EAU, answered the survey. GP were trained in only 1 medical meeting in the primary care clinic, with one or more rheumatologists responsible of GP education. Fourteen of the 34 EAU (42.4%) regularly interacted with GP and only 20 (39.4%) contacted the GP who were responsible for the wrong referral process. Median lag time for referral to the Rheumatology out-patient clinic, was 73 days (15-365 days). The percentage of wrongly referred patients was between 0 and 80% (38% +/- 21). Only 10 EAU (27.8%) referred patients appropriately according to the most strict criteria (25% of inappropriate referral) and 27 EAU (75%), according to 50% of inappropriate referral criteria. CONCLUSIONS: Only two aspects of the EAU implementation strategy were associated with better referral efficiency: 1) interaction with the GP responsible of the inappropriate referral process and 2) a lower median lag time for referral to the Rheumatology out-patient clinic. PMID- 21794825 TI - [Economic evaluation of tramadol/paracetamol in the management of pain in patients with osteoarthritis in Spain]. AB - OBJECTIVE: To compare the costs of treating osteoarthritis (OA) pain using combination tramadol/paracetamol tablets, Non-Steroidal Anti-Inflammatory Agents (NSAID) alone or NSAID plus proton pump inhibitors (PPI) from the perspective of the Spanish National Health System. METHODS: A decision-analytical model was constructed to analyze the cost associated with three treatment strategies over 6 months. A cost-minimization approach was used, which considered data related to resource use, medication costs and costs for the treatment of adverse events. RESULTS: In the base-case analysis, costs for 6 months of treatment of OA pain using tramadol/paracetamol were ?232.86, compared with ?274.60 for NSAID + PPI and ?133.75 for NSAID alone. This provided a savings of ?41.74 per patient over 6 months for tramadol/paracetamol compared with NSAID + PPI and a cost increase of ?99.11 compared with NSAID alone. When renal adverse events associated with NSAID were considered, tramadol/paracetamol was cost saving compared with all NSAID based regimens (saving ?140.02 vs NSAID alone, ?280.86 vs NSAID + PPI). CONCLUSION: Based on the results of a theoretical decision-analytic model, the data obtained may suggest that tramadol/paracetamol is cost saving compared with NSAID + PPI for the treatment of OA pain over a period of 6 months. Tramadol/paracetamol is also cost saving compared with treatment with NSAID alone if considering renal adverse events. PMID- 21794826 TI - [Implications of the new etiophatogenic approach in the classification of constitutional and genetic bone diseases]. AB - Recent years have seen an unprecedented increase in the knowledge and understanding of biochemical disturbances involved on constitutional bone disorders. Recognition of the genetic background as the common cause of these diseases prompted the substitution of the term "constitutional" by "genetic", in referring to them. Understanding physiopathological bases by finding out the altered metabolic pathways as well as their regulatory and control systems, favours an earlier and more accurate diagnosis based on interdisciplinary collaboration. Although clinical and radiological assessment remains crucial in the study of these disorders, ever more often the diagnosis is achieved by molecular and genetic analysis. Elucidation of the damaged underlying molecular mechanisms offers targets potentially useful for therapeutic research in these complex and often disabling diseases. PMID- 21794827 TI - [Celiac disease in 3 patients with Takayasu's arteritis]. AB - Takayasu's arteritis (TA) is a chronic vasculitis of unknown etiology. Celiac disease (CD) is an autoimmune disease caused by the ingestion of gluten. TA and CD have been associated with many other autoimmune conditions. However, only five cases with this association have been reported. In this series, three patients with TA and CD were included; all were female, 21, 30 and 54 years old. TA clinical manifestations preceded CD diagnosis in all patients. Aortic arch branches were affected in all of them. Serologic markers were positive and a small intestine biopsy showed typical findings of CD in the three patients. Special attention should be given to this possible association because these entities may be asymptomatic; the recognition of new disease variants modifies treatment, and sometimes CD constitutes a differential diagnosis of mesenteric ischemia. PMID- 21794828 TI - [Efficacy of adalimumab in Behcet's disease. Description of 6 cases]. AB - Behcet's disease (BD) is a systemic vasculitis, with a more aggressive course in young males. Orogenital ulcers, uveitis and cutaneous lesions are the most frequent manifestations. We analyzed the effects of adalimumab on six patients with BD pretreated with inmunosupressive therapy, two of whom had received infliximab. We observed a good clinical response in all patients. To date, after a mean follow-up of 26.8 months, patients continue receiving adalimumab, with good clinical control, no adverse effects have been reported with adalimumab. PMID- 21794829 TI - [Rheumatoid arthritis: how to use drugs during pregnancy and lactation?]. AB - Rheumatoid arthritis is a disease that is highly prevalent in women of childbearing age. A review is done about the characteristics of the placental barrier, the passage of drugs through it and the use of drugs during pregnancy: those which are potentially safe drugs, those drugs that can only be used if there is a life threatening condition for the mother, drugs that are contraindicated and those with insufficient data on safety and therefore should be avoided, the latter group comprises biological drugs. Also a review is done about the use of drugs during lactation, a period that a flare of rheumatoid arthritis can occur. PMID- 21794830 TI - [Spondyloepiphyseal dysplasia in a middle aged male]. PMID- 21794831 TI - [Calcic tenosynovitis in a patient with undifferentiated connective tissue disease]. PMID- 21794832 TI - [Streptococcus pneumoniae septic oligoarthritis in a patient with chondrocalcinosis: a case report]. PMID- 21794833 TI - GI bleed in a case of chronic pancreatitis. PMID- 21794834 TI - Doxorubicin and sorafenib for treatment of advanced hepatocellular cancer. PMID- 21794835 TI - Indigenous clostridium species regulate systemic immune responses by induction of colonic regulatory T cells. PMID- 21794836 TI - Learning influence on the behavioral structure of rat response to pain in hot plate. AB - Aim of the research was to study, by means of descriptive and multivariate analyses, whether, and how, learning influences the behavioral structure of rat response to pain. To this purpose, a hot-plate test daily repetition procedure was carried out on male Wistar rats for five days. A 6-day interval without stimulation elapsed before last test was carried out on day 12. After composition of an ethogram, descriptive (number, latency, per cent distribution) and multivariate analyses (cluster, stochastic) were carried out for each scheduled test day. One-way ANOVA and Newman-Keuls post-hoc test for multiple comparisons revealed significant changes for climbing, jumping, front-paw licking and stamping mean latencies. Student's t-test, carried out between days 1 and 12, showed that significant modifications persisted over time only for climbing and jumping. Cluster analysis evidenced three different clusters: exploratory (sniffing, walking), primary noxious evoked elements (front-paw licking, hind-paw licking, stamping), and escape (climbing and jumping), each showing modifications during test repetition. Comparison between days 1 and 12 revealed substantial differences in similarity values of escape patterns whereas, for the response to pain ones, a conservative structure of dendrograms was maintained. Stochastic analysis revealed a progressive increase of transitions toward jumping and a significant reduction of the ones between sniffing and walking. Such modifications persisted also after 6 days without any stimulation. Present study shows that learning provokes a complex and fine temporal evolution of the innermost behavioral structure of rat response to pain aiming at a more efficient escape strategy. PMID- 21794837 TI - Production of biohydrogen by heterologous expression of oxygen-tolerant Hydrogenovibrio marinus [NiFe]-hydrogenase in Escherichia coli. AB - Oxygen sensitivity of hydrogenase is a critical issue in efficient biological hydrogen production. In the present study, oxygen-tolerant [NiFe]-hydrogenase from the marine bacterium, Hydrogenovibrio marinus, was heterologously expressed in Escherichia coli, for the first time. Recombinant E. coli BL21 expressing H. marinus [NiFe]-hydrogenase actively produced hydrogen, but the parent strain did not. Recombinant H. marinus hydrogenase required both nickel and iron for biological activity. Compared to the recombinant E. coli [NiFe]-hydrogenase 1 described in our previous report, recombinant H. marinus [NiFe]-hydrogenase displayed 1.6- to 1.7-fold higher hydrogen production activity in vitro. Importantly, H. marinus [NiFe]-hydrogenase exhibited relatively good oxygen tolerance in analyses involving changes of surface aeration and oxygen proportion within a gas mixture. Specifically, recombinant H. marinus [NiFe]-hydrogenase produced ~7- to 9-fold more hydrogen than did E. coli [NiFe]-hydrogenase 1 in a gaseous environment containing 5-10% (v/v) oxygen. In addition, purified H. marinus [NiFe]-hydrogenase displayed a hydrogen evolution activity of ~28.8 nmol H2/(minmg protein) under normal aerobic purification conditions. Based on these results, we suggest that oxygen-tolerant H. marinus [NiFe]-hydrogenase can be employed for in vivo and in vitro biohydrogen production without requirement for strictly anaerobic facilities. PMID- 21794838 TI - Production of Rous sarcoma virus-like particles displaying human transmembrane protein in silkworm larvae and its application to ligand-receptor binding assay. AB - Two types of Rous sarcoma virus (RSV) group-antigen protein (Gag) virus like particles (VLPs), full-length Gag (Gag701) and RSV protease domain (PR)-deleted mutant (Gag577) were expressed in silkworm larvae. Gag577 was secreted into hemolymph efficiently using wild type bacmid (WT), cysteine protease-deficient bacmid (CP(-)), cysteine protease and chitinase-deficient bacmid (CP(-)Chi(-)) bacmids, but comparatively Gag701 secretion levels were low. VLPs were purified on 10-60% (v/v) sucrose density gradient by ultracentrifugation and their structures confirmed under electron microscope. When hPRR and RSV Gag577 were co expressed in silkworm larvae, human prorenin receptor (hPRR) was displayed on the surface of RSV VLPs, which was detected by Western blotting and immunoelectron microscopy. Moreover, binding of hPRR localized on the surface of VLPs to human prorenin was confirmed by ELISA. These results indicate that active hPRR was displayed on the surface of RSV VLPs, which can be utilized for drug discovery of hPRR blockers to prevent nephropathy. Moreover, this transmembrane protein display system using RSV Gag in silkworm larvae is applicable to expression of intact transmembrane proteins and binding assay of transmembrane proteins to its ligands, especially for transmembrane proteins which cannot be purified from membrane fractions in active states. PMID- 21794840 TI - Anterior segment tumor biopsy using an aspiration cutter technique: clinical experience. AB - PURPOSE: To report the results and complications of an aspiration cutter-assisted anterior segment tumor biopsy performed under viscoelastic. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Fifty-five patients with anterior segment tumors underwent aspiration cutter-assisted biopsy at a single center. Fifty-six biopsies were performed, because 1 eye underwent biopsy twice. Indications for biopsy included: suspected anterior segment malignancy, patient's desire for pathologic confirmation before treatment, atypical tumor, and genetic tumor analysis. The main evaluated outcomes were the perioperative visual acuity, the biopsy technique, and related complications. RESULTS: The initial sample comprised 55 consecutively biopsied patients, from which a minimum 1-month follow-up existed for 52 biopsy samples. The median total follow-up was 30.4 months (range, 1 to 190 months). The mean initial visual acuity was 20/50 before and 20/50 1 month after biopsy. No patient lost vision. Most cases were suspected iris melanoma (n = 39/56; 69.6%), followed by suspicious iris nevi (n = 4/56; 7.1%) and melanocytoma (n = 4/56; 7.1%). Seven (n = 7/52; 13.4%) wounds required a single 10-0 nylon suture to achieve negative Seidel test results at the corneal entry site. Postoperative surgical findings included transiently increased intraocular pressure (n = 6/52; 11.5%), 1 hyphema, 1 flare, and 1 persistent pupillary defect. All but the pupillary defect resolved within 4 weeks of the biopsy procedure. There were no secondary infections or cataracts. CONCLUSIONS: This study suggests that small-incision, aspiration cutter-assisted anterior segment biopsy seems to be a safe and effective procedure. No short- or long-term complications that would prevent its use were noted. PMID- 21794839 TI - Drosha regulates hMSCs cell cycle progression through a miRNA independent mechanism. AB - Recently we demonstrated that the miRNA regulate human mesenchymal stem cells (hMSCs) differentiation. To determine the role of the miRNA pathway in hMSCs proliferation, Drosha and Dicer knockdown hMSCs were generated using a lentiviral based tetracycline inducible shRNA. hMSCs with reduced Drosha expression had a significantly reduced proliferation rate, while hMSCs with reduced Dicer expression displayed a proliferation rate similar to untransduced cells. Cell cycle analysis identified that unlike Dicer knockdown, Drosha knockdown hMSCs contained an increased number of G1 phase cells, with a reduced level of cells in S phase, compared to controls. ELISAs of hMSCs revealed decreased levels of pRB and stable levels of total RB with Drosha knockdown. Two key regulators of the G1/S phase transition, cyclin dependent kinase inhibitor 2A (p16) and cyclin dependent kinase inhibitor 2B (p15), were increased in Drosha knockdown cells but not in Dicer knockdown. Transcripts of 28S and 18S rRNA were significantly reduced in Drosha knockdown hMSCs, with no change in rRNA levels in Dicer knockdown hMSCs. 45S pre-rRNA transcripts were not significantly different in either knockdown model. The above results indicate that Drosha modifies hMSCs proliferation through a miRNA independent mechanism, potentially by regulating rRNA processing. PMID- 21794841 TI - Comparison of macular thickness measured by optical coherence tomography after deep anterior lamellar keratoplasty and penetrating keratoplasty. AB - PURPOSE: To compare the postoperative macular thickness changes using optical coherence tomography (OCT) in eyes that underwent deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP). DESIGN: Prospective, nonrandomized clinical trial. METHODS: Sixty eyes of 60 patients (32 male, 28 female) with keratoconus who underwent corneal transplant surgery in an institutional setting were included in the study. Thirty eyes underwent DALK and 30 eyes underwent PKP. All eyes underwent corrected visual acuity (CVA) measurement and macular thickness measurement using spectral-domain OCT preoperatively, and 1 week, 1 month, 3 months, and 6 months postoperatively. The main outcome measures were CVA and macular thickness. RESULTS: The DALK group had significantly better mean CVA than that of the PKP group at 1-month (P < .001), 3 month (P = .002), and 6-month (P = .040) follow-ups. The mean macular thickness significantly increased at 1 week after PKP surgery, remained stable at 1-month follow-up, and decreased at 3- and 6-month follow-ups. On the other hand, the mean macular thickness remained stable during 6 months after DALK. Although there was no significant difference between groups preoperatively (P = .970) and at 6 month follow-up (P = .339), the PKP group had significantly higher mean macular thickness than that of the DALK group at 1-week (P < .001), 1-month (P < .001), and 3-month (P = .005) follow-ups. CONCLUSION: Although mean macular thickness increases and peaks around 1 month and returns back to normal levels at 6 months after PKP surgery, it does not change after DALK. PMID- 21794842 TI - The incidence of central retinal artery occlusion in Olmsted County, Minnesota. AB - PURPOSE: To determine the incidence of central retinal artery occlusion in Olmsted County, Minnesota. DESIGN: Retrospective chart review. METHODS: Medical records of all patients living in Olmsted County, Minnesota between 1976 and 2005 diagnosed with central retinal artery occlusion were identified using the Rochester Epidemiology Project medical records linkage system. RESULTS: Forty three cases were identified for an unadjusted annual incidence in the female population of 1.02 per 100,000 and 1.67 per 100,000 in the male population, with a combined incidence of 1.33. Incidence rates were also age- and/or sex-adjusted to the 2000 census figures for the US white population using direct standardization. Age-adjusted annual incidence per 100,000 for the female population was 1.15 (95% confidence interval [CI], 0.60-1.71), for the male population was 2.78 (95% CI, 1.69-3.86), and combined was 1.87 (95% CI, 1.31 2.43). When adjusted for age and sex, the incidence was 1.90 per 100,000 (95% CI, 1.33-2.47). CONCLUSION: Central retinal artery occlusion is a rare event. The incidence is 1.3 per 100,000 in Olmsted County, Minnesota, or 1.90 per 100,000 when age- and sex-adjusted for the United States white population. PMID- 21794843 TI - Cataract surgery in ranibizumab-treated patients with neovascular age-related macular degeneration from the phase 3 ANCHOR and MARINA trials. AB - PURPOSE: To investigate whether cataract surgery was beneficial in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) phase 3 trials. DESIGN: Retrospective analysis. METHODS: Patients were identified who underwent cataract surgery during the 2 pivotal trials. For this analysis, the best-corrected visual acuity (VA) just prior to cataract surgery was referred to as the redefined baseline VA. For the period after cataract surgery, endpoints included change in VA, time to first postsurgery injection, and total number of injections. Monthly follow-up visits after surgery were defined at 30-day intervals +/- 15 days. RESULTS: Three subgroups were identified: study eyes of ranibizumab-treated patients (758 eyes [23 undergoing surgery]), fellow eyes of ranibizumab-treated patients (758 eyes [28 undergoing surgery]), and eyes of non ranibizumab patients (762 [16 undergoing surgery]). Three months postsurgery, the VA of ranibizumab-treated eyes improved by a mean of 10.4 (+/- 3.4) letters compared to the redefined baseline (n = 20; 95% confidence interval +3.3 letters to +17.5 letters). The mean VA change from redefined baseline VA was not significantly different between the 3 groups at any of the evaluated time points postsurgery (P > .44 for all comparisons between each pair of the 3 groups at 1, 2, 3, and 4 months following surgery). CONCLUSIONS: In the phase 3 trials, cataract surgery appeared to be safe and beneficial for all eyes with AMD, including ranibizumab-treated eyes with neovascular AMD. An average VA improvement of more than 2 lines was typically observed. PMID- 21794844 TI - Pars plana vitrectomy, fluocinolone acetonide implantation, and silicone oil infusion for the treatment of chronic, refractory uveitic hypotony. AB - PURPOSE: To assess the feasibility and outcomes of combining fluocinolone acetonide sustained drug delivery implant insertion, pars plana vitrectomy, and silicone oil infusion to treat patients with chronic, refractory ocular hypotony resulting from uveitis. DESIGN: Retrospective chart review. METHODS: A retrospective, institutional chart review was performed. Outcome measures included visual acuity, intraocular pressure, and adverse events. RESULTS: A total of 13 eyes of 11 patients were studied. All patients were women, had a mean age of 57 years (range, 26 to 73 years), and had a diagnosis of panuveitis. The mean duration of preoperative hypotony was 42 months (range, 11 to 108 months). Patients were followed up on average for 22 months (range, 9 to 46 months) after the combined surgical procedure. The mean preoperative visual acuity was 20/1000 (logarithm of the minimal angle of resolution, 1.7). At the 6- and 12-month visits, the mean visual acuity remained stable at 20/800 (logarithm of the minimal angle of resolution, 1.6; P = .74) and 20/600 (P = .34), respectively. At baseline, the mean intraocular pressure (IOP) was 2.3 mm Hg. The average IOP was 5.9 mm Hg, 5.1 mm Hg, and 5.0 mm Hg at 6, 12, and 24 months after surgery, respectively. The increase in IOP relative to the baseline IOP was statistically significant at 6 and 12 months (P = .027 and P = .004, respectively). The duration of preoperative hypotony inversely correlated with the IOP at 6 months (P = .027). No intraoperative complications were encountered and the procedure was well tolerated. CONCLUSIONS: Fluocinolone acetonide implantation combined with pars plana vitrectomy and silicone oil infusion is feasible and is well tolerated in the management of chronic, refractory ocular hypotony associated with uveitis. PMID- 21794845 TI - Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. AB - PURPOSE: To evaluate the ocular hypotensive efficacy of 0.05%, 0.1% and 0.25% AR 12286 Ophthalmic Solutions in patients diagnosed with ocular hypertension or glaucoma. DESIGN: Parallel comparison, vehicle-controlled, double-masked, 3-week randomized clinical trial. METHODS: Subjects (n = 89) with elevated intraocular pressure (IOP) were assigned randomly to receive either 1 of 3 concentrations of AR-12286 or its vehicle. Dosing was once-daily in the morning for 7 days, then once-daily in the evening for 7 days, then twice daily for 7 days. Primary and secondary efficacy end points were mean IOP at each diurnal time point (8 am, 10 am, 12 pm, and 4 pm) and mean change in IOP from baseline, respectively. RESULTS: All 3 concentrations of AR-12286 produced statistically and clinically significant reductions in mean IOP that were dose dependent, with peak effects occurring 2 to 4 hours after dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg (-6.8 to -4.4 mm Hg) for the 3 concentrations. The largest IOP reductions were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg; 28%). The 0.25% concentration dosed once-daily in the evening produced highly significant IOP reductions throughout the following day (-5.4 to -4.2 mm Hg). The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting 4 hours or less. After once-daily evening dosing, hyperemia was seen in less than 10% of patients. CONCLUSIONS: AR-12286 was well tolerated and provided clinically and statistically significant ocular hypotensive efficacy in patients with ocular hypertension and glaucoma. PMID- 21794846 TI - Simultaneous topography-guided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. AB - PURPOSE: To present the long-term results after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. DESIGN: Prospective, interventional, consecutive case series. METHODS: In this study, 26 patients (31 eyes) with progressive keratoconus were included. All patients underwent customized topography-guided photorefractive keratectomy immediately followed by corneal collagen cross-linking with the use of riboflavin and ultraviolet A irradiation. Epithelium was removed by transepithelial phototherapeutic keratectomy in all cases. RESULTS: Mean follow-up was 19.53 +/- 3.97 months (range, 12 to 25 months). Mean preoperative spherical equivalent was 2.3 +/- 2.8 diopters (D), whereas at the last follow-up examination, it was significantly (P < .001) reduced to -1.08 +/- 2.41 D. Logarithm of the minimal angle of resolution uncorrected and best-corrected visual acuity were reduced significantly by 0.46 and 0.084 (P < .001), respectively, at the last follow-up examination. Finally, mean steep and flat keratometry readings were reduced by 2.35 (P < .001) and 1.18 (P = .013) at the last follow-up examination. CONCLUSIONS: Simultaneous photorefractive keratectomy followed by corneal collagen cross-linking seems to be a promising treatment alternative in our series of keratoconic patients. PMID- 21794847 TI - Continuous progression of tubercular serpiginous-like choroiditis after initiating antituberculosis treatment. AB - PURPOSE: To describe the frequency, risk factors, management, and outcome of eyes with tubercular serpiginous-like choroiditis showing continued progression following initiation of antituberculosis treatment. DESIGN: Retrospective, comparative, interventional case series. METHODS: SETTING: Institutional. PATIENT POPULATION: One hundred ten patients of serpiginous-like choroiditis with 1) complete records, 2) tuberculin skin test, 3) active lesions in at least 1 eye, and 4) minimum 18 months follow-up. INTERVENTION: Based on the positivity of tuberculin skin test, the patients were categorized in Group A (84 patients with positive tuberculin test) and Group B (26 patients with negative tuberculin test). Of the 84 patients in Group A, 19 received systemic corticosteroids while 65 also received 4-drug antituberculosis treatment in addition. All patients in Group B received corticosteroids. Patients with continued progression received an increased dose of corticosteroids with or without immunosuppressive agents. MAIN OUTCOME MEASURE: Development of continued progression. RESULTS: There were 61 men and 23 women in Group A and 19 men and 7 women in Group B. Continued progression was observed in 12 patients (14.28%) in Group A and none in Group B (P = .04). Of the 12 patients in Group A showing progression, 11 (16.9%) were receiving antituberculosis treatment and corticosteroids. The lesions responded in all eyes, and final visual acuity of 20/40 or better could be achieved in 10 eyes (75%). CONCLUSION: Continued progression of choroiditis lesions occurs in 14% of patients after initiating antituberculosis treatment in tubercular serpiginous like choroiditis. Increased immunosuppression with continuation of antituberculosis treatment resulted in good outcome. PMID- 21794848 TI - Anterior segment tumor aspiration cutter-assisted biopsy: experience with pathology. AB - PURPOSE: To report pathologic evaluation and diagnostic yield of an aspiration cutter-assisted biopsy of anterior segment tumors. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Fifty-five eyes of 55 patients with iris and iridociliary tumors underwent an aspiration cutter-assisted biopsy at a single institution. Cytospin and cell-block preparations were performed on all biopsy samples. Bleached preparations and a panel of immunohistochemical stains were performed in selected cases. Cytologic diagnosis was correlated with clinical diagnosis and with histopathologic diagnosis, when available. Main outcome measures were (1) specimen cellularity, (2) diagnostic studies performed, (3) cytopathologic diagnosis, and (4) concordance with histopathologic diagnosis. RESULTS: Specimen cellularity was adequate for cytopathologic interpretation of cytospin preparations in 55 (98.2%) of 56 biopsies. Twenty-three (41%) of 56 biopsy samples had diagnostic material in cell-block preparations. The most common cytopathologic diagnoses were melanoma (n = 39/56; 69.6%), melanocytoma (n = 4/56; 7.1%), nevus (n = 4/56; 7.1%), lymphoma (n = 2/56; 3.6%), and epithelial implantation cyst (n = 2/56; 3.6%). One biopsy sample (1.8%) yielded nondiagnostic material. Wide incisional or excisional biopsy confirmation was available in 13 (23.2%) of 56 aspiration cutter-assisted biopsy cases. Cytopathologic diagnoses were consistent with histopathologic diagnosis in 12 (92.3%) of 13 cases. CONCLUSIONS: Although specialized pathologic techniques were necessary to maximize material available for diagnosis, all biopsies yielded cellular material and 41% yielded diagnostic tissue in cell block preparation. Although lower than the yield of wide incisional or excisional biopsy, aspiration cutter-assisted biopsy of anterior segment tumors achieved a diagnostic yield of 98.2%. PMID- 21794849 TI - Tomographic findings are not always predictive of failed nonoperative management in blunt hepatic injury. AB - BACKGROUND: Nonoperative management (NOM) has become the standard treatment of blunt hepatic injury (BHI) for stable patients. Contrast extravasation (CE) on computed tomography (CT) scan had been reported as a sign that is associated with NOM failure. The goal of this study was to further investigate the risk factors of NOM failure in patients with CE on CT scan. METHODS: From January 2005 to September 2009, patients with CE noted on a CT scan as a result of BHI were studied retrospectively. Physiological parameters, severity of injury, amount of transfusion, type of contrast extravasation, as well as treatment outcome were compared between patients with NOM failure and NOM success. RESULTS: A total of 130 patients were enrolled. Injury severity scores, amount of blood transfusion before hemostatic procedure, and grade of liver injury were significantly higher in NOM failure than in NOM success patients. There was no statistical difference in the NOM success rate between patients with contrast leakage into the peritoneum and those with contrast confined in the hepatic parenchyma. CONCLUSIONS: Higher injury severity score, more blood transfusion, and higher grade of liver injury are factors that correlate with NOM failure in patients with BHI. Contrast leakage into the peritoneum is not always a definite sign of NOM failure in BHI. Early and aggressive angioembolization is an effective adjunct of NOM in BHI patients, even with contrast leakage into peritoneum. PMID- 21794850 TI - Would you follow your own route description? Cognitive strategies in urban route planning. AB - This paper disentangles cognitive and communicative factors influencing planning strategies in the everyday task of choosing a route to a familiar location. Describing the way for a stranger in town calls for fundamentally different cognitive processes and strategies than actually walking to a destination. In a series of experiments, this paper addresses route choices, planning processes, and description strategies in a familiar urban environment when asked to walk to a goal location, to describe a route for oneself, or to describe a route for an addressee. Results show systematic differences in the chosen routes with respect to efficiency, number of turns and streets, and street size. The analysis of verbal data provides consistent further insights concerning the nature of the underlying cognitive processes. Actual route navigation is predominantly direction-based and characterized by incremental perception-based optimization processes. In contrast, in-advance route descriptions draw on memory resources to a higher degree and accordingly rely more on salient graph-based structures, and they are affected by concerns of communicability. The results are consistent with the assumption that strategy choice follows a principle of cognitive economy that is highly adaptive to the degree of perceptual information available for the task. PMID- 21794851 TI - Review of advanced techniques for the estimation of brain connectivity measured with EEG/MEG. AB - Brain connectivity can be modeled and quantified with a large number of techniques. The main objective of this paper is to present the most modern and widely established mathematical methods for calculating connectivity that is commonly applied to functional high resolution multichannel neurophysiological signals, including electroencephalographic (EEG) and magnetoencephalographic (MEG) signals. A historical timeline of each technique is outlined along with some illustrative applications. The most crucial underlying assumptions of the presented methodologies are discussed in order to help the reader understand where each technique fits into the bigger picture of measuring brain connectivity. In this endeavor, linear, nonlinear, causality-assessing and information-based techniques are summarized in the framework of measuring functional and effective connectivity. Model based vs. data-driven techniques and bivariate vs. multivariate methods are also discussed. Finally, certain important caveats (i.e. stationarity assumption) pertaining to the applicability of the methods are also illustrated along with some examples of clinical applications. PMID- 21794852 TI - The right hemisphere is not unitary in its role in aphasia recovery. AB - Neurologists and aphasiologists have debated for over a century whether right hemisphere recruitment facilitates or impedes recovery from aphasia. Here we present a well-characterized patient with sequential left and right hemisphere strokes whose case substantially informs this debate. A 72-year-old woman with chronic nonfluent aphasia was enrolled in a trial of transcranial magnetic stimulation (TMS). She underwent 10 daily sessions of inhibitory TMS to the right pars triangularis. Brain activity was measured during picture naming using functional magnetic resonance imaging (fMRI) prior to TMS exposure and before and after TMS on the first day of treatment. Language and cognition were tested behaviorally three times prior to treatment, and at 2 and 6 months afterward. Inhibitory TMS to the right pars triangularis induced immediate improvement in naming, which was sustained 2 months later. fMRI confirmed a local reduction in activity at the TMS target, without expected increased activity in corresponding left hemisphere areas. Three months after TMS, the patient suffered a right hemisphere ischemic stroke, resulting in worsening of aphasia without other clinical deficits. Behavioral testing 3 months later confirmed that language function was impacted more than other cognitive domains. The paradoxical effects of inhibitory TMS and the stroke to the right hemisphere demonstrate that even within a single patient, involvement of some right hemisphere areas may support recovery, while others interfere. The behavioral evidence confirms that compensatory reorganization occurred within the right hemisphere after the original stroke. No support is found for interhemispheric inhibition, the theoretical framework on which most therapeutic brain stimulation protocols for aphasia are based. PMID- 21794853 TI - [Mushroom poisoning in the southeast of Spain. A new case of Amanita proxima poisoning?]. PMID- 21794854 TI - [Chronic fatigue syndrome: study of a consecutive series of 824 cases assessed in two specialized units]. AB - BACKGROUND AND OBJECTIVE: The chronic fatigue syndrome (CFS) is a disabling disorder. Few studies are available in our area on the prevalence and characteristics of CFS. Therefore, we carried out a study of a consecutive series of 824 cases diagnosed in two specialized units. PATIENTS AND METHODS: We evaluated all of the CFS patients seen from January 2008 to June 2010. We analyzed social and demographic data, employment status, time of clinical evolution, trigger factors and onset, Fukuda and Canadian criteria, associated comorbidities and treatment. RESULTS: A total of 824 patients were included, 748 (91%) woman, mean age 48+/-9 years. Average age of onset of symptoms was 35+/-11 years, time to diagnosis 108+/-88 month. A precipitating factor was identified in 481 (58%) patients, the onset was gradual in 517 (63%) and 515 (62.5%) were not employed. The most outstanding diagnostic criteria of Fukuda were prolonged generalized fatigue after exercise, sleep disturbance and impairments in concentration and short-term memory. The different groups of symptoms defined by the Canadian consensus showed that CFS is a homogeneous entity. Accompanying comorbidity phenomena were anxiety 691 (83%), sicca syndrome 678 (82%), fibromyalgia 450 (55%). A total of 63% of patients (520) received pharmacological treatment. CONCLUSIONS: CFS is an illness that preferentially affects young women and results in employment absenteeism. The most relevant clinical features were prolonged generalized fatigue after exercise, neurocognitive impairment and sleep disturbance. In the evaluation of the patient, it is very important to apply the Canadian criteria and to assess comorbidity. PMID- 21794855 TI - [Aerococcus urinae infective endocarditis]. PMID- 21794856 TI - Reproductive medicine and inheritance of infertility by offspring: the role of fetal programming. AB - OBJECTIVE: To summarize the molecular processes involved in fetal programming, to describe how assisted reproduction technologies (ART) may affect the epigenetic pattern of the embryo, and to highlight the current knowledge of the role of perinatal events in the subsequent development of reproductive pathology affecting infertile patients. DESIGN: A literature review of fetal programming of adulthood gynecologic diseases and ART. A Medline search was performed with the following keywords: (fetal programming OR epigenetics OR methylation OR acetylation) AND (IVF OR ART) AND (gynecology). Articles up to October 2010 were selected. Articles and recent reviews were classified by human and animals studies and also according to their experimental or observational design. SETTING: University hospital research center. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Data from experimental animal models and case-control studies support the potential effect of ART in changing methylation patterns in gametes and embryos. However, these findings are not supported by population studies or experimental studies performed in human gametes/embryos. Experimental and epidemiologic studies support the hypothesis that some adult gynecologic diseases causing infertility may have a fetal origin. CONCLUSION(S): Although it seems clear that some adult gynecologic diseases causing infertility may have a fetal origin, there is insufficient evidence to confirm that ART is the origin of later onset, adulthood diseases. Further research in this field must be conducted. PMID- 21794857 TI - Macrophages induce the adhesion phenotype in normal peritoneal fibroblasts. AB - OBJECTIVE: To determine whether macrophages, exposed to hypoxia, stimulate primary cultures of fibroblasts to acquire the adhesion phenotype. The adhesion phenotype has been previously characterized, in part, by increased fibroblast expression of transforming growth factor (TGF) beta1, vascular endothelial growth factor (VEGF), and type I collagen. DESIGN: Media collected from human macrophages cultured under hypoxic conditions (2% O(2)) were used to treat human peritoneal fibroblasts. Additionally, human peritoneal fibroblasts were treated with varying concentrations of TGF-beta1. Real-time reverse-transcription polymerase chain reaction and Western blot analysis were used to measure mRNA and protein levels, respectively, for select adhesion markers: TGF-beta1, VEGF, and, type I collagen. We hypothesized that macrophage secretion, under hypoxic conditions, is responsible for inducing the adhesion phenotype in human peritoneal fibroblasts. SETTING: University research laboratory. PATIENT(S): Human macrophages and peritoneal fibroblasts. INTERVENTION(S): Macrophage fibroblast interaction. MAIN OUTCOME MEASURE(S): Ability of macrophages to induce the adhesion phenotype in human peritoneal fibroblasts. RESULT(S): Hypoxia treatment resulted in a significant increase in TGF-beta1 expression in human macrophages. Additionally, hypoxia treatment resulted in a significant increase in TGF-beta1, VEGF, and type I collagen mRNA and protein levels in normal peritoneal fibroblasts compared with normoxic conditions. Similarly, normal peritoneal fibroblasts treated with media collected from macrophages cultured under hypoxic conditions resulted in a significant increase in TGF-beta1, VEGF, and type I collagen mRNA and protein levels compared with normal peritoneal fibroblasts treated with media collected from macrophages cultured under normoxic conditions. Additionally, human peritoneal fibroblasts exposed to varying concentrations of TGF-beta1 exhibited a dose-dependent response in the expression of TGF-beta1, VEGF, and type I collagen. At a low TGF-beta1 concentration (12.5 ng TGF-beta1/mL medium), TGF-beta1, VEGF, and type I collagen were significantly increased. In contrast, at higher TGF-beta1 concentrations (25 and 50 ng TGF beta1/mL media), TGF-beta1, VEGF, and type I collagen mRNA levels were significantly reduced compared with 12.5 ng TGF-beta1/mL medium. CONCLUSION(S): Human macrophages, cultured under hypoxic conditions, release factors that induce the expression of the adhesion phenotype in normal peritoneal fibroblasts. Particularly, TGF-beta1 reproduces this response by regulating the expression of TGF-beta1, VEGF, and type I collagen in a dose-dependent manner. Therefore, these findings highlight an important role for human macrophages in peritoneal wound healing. PMID- 21794858 TI - Comparing focused ultrasound and uterine artery embolization for uterine fibroids rationale and design of the Fibroid Interventions: reducing symptoms today and tomorrow (FIRSTT) trial. AB - OBJECTIVE: To present the rationale, design, and methodology of the Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT) study. DESIGN: Randomized clinical trial. SETTING: Two academic medical centers. PATIENT(S): Premenopausal women with symptomatic uterine fibroids. INTERVENTION(S): Participants are randomized to two U.S. Food and Drug Administration-approved minimally invasive treatments for uterine leiomyomas: uterine artery embolization and magnetic resonance-guided focused ultrasound. MAIN OUTCOME MEASURE(S): The primary endpoint is defined as the need for an additional intervention for fibroid symptoms following treatment. Secondary outcomes consist of group differences in symptom alleviation, recovery trajectory, health-related quality of life, impairment of ovarian reserve, treatment complications, and the economic impact of these issues. RESULT(S): The trial is currently in the phase of active recruitment. CONCLUSION(S): This randomized clinical trial will provide important evidence-based information for patients and health care providers regarding optimal minimally invasive treatment approach for women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: NCT00995878. PMID- 21794859 TI - Duodenal invasion is a risk factor for the early dysfunction of biliary metal stents in unresectable pancreatic cancer. AB - BACKGROUND: Although the placement of self-expandable metal stents (SEMSs) has been widely accepted as palliation for distal malignant biliary obstruction, the risk factors for their early dysfunction remain unclear. OBJECTIVE: To identify risk factors for early (<3 months) SEMS dysfunction in unresectable pancreatic cancer. DESIGN: A multicenter retrospective study. SETTING: Five tertiary referral centers. PATIENTS: Patients were included who underwent first-time SEMS placement for distal malignant biliary obstruction caused by pancreatic cancer between April 1994 and August 2010. MAIN OUTCOME MEASUREMENTS: Rates and causes of early dysfunction were evaluated, and risk factors were analyzed. RESULTS: In all, 317 eligible patients were identified. Covered SEMSs were placed in 82% of patients. Duodenal invasion was observed endoscopically in 37%. The median time to dysfunction was 170 days. The rates of all and early SEMS dysfunction were 55% and 31%, respectively. The major causes of SEMS dysfunction were food impaction and nonocclusion cholangitis (21% each) in early dysfunction and sludge (29%) in nonearly dysfunction. The rate of early dysfunction was 42% with duodenal invasion and 24% without duodenal invasion (P = .001). Early dysfunction caused by food impaction was more frequent in patients with duodenal invasion (10% and 4%, P = .053). Duodenal invasion was a risk factor (odds ratio 2.35; 95% CI, 1.43 3.90; P = .001) in a multiple logistic regression model. LIMITATIONS: A retrospective design. CONCLUSIONS: Duodenal invasion is a risk factor for early SEMS dysfunction in patients with pancreatic cancer. PMID- 21794860 TI - GI involvement in disseminated Mycobacterium genavense: endoscopy and histology. PMID- 21794861 TI - Depression among women with obstetric fistula in Kenya. AB - OBJECTIVE: To establish the prevalence of depression and describe associated factors among fistula patients attending an obstetric fistula surgical camp in Kenya. METHODS: A cross-sectional study was conducted focusing on obstetric fistula patients attending a national fistula camp held in August 2008 at Kenyatta National Hospital, Nairobi, Kenya. A structured questionnaire was used to obtain sociodemographic data and medical histories for all consenting patients before surgery. Depression measures were obtained using the Patient Health Questionnaire-9. RESULTS: Of the 70 women interviewed, 2 (2.9%) and 12 (17.1%) reported a history of psychiatric illness and suicidal ideations, respectively. Depression was present in 51 (72.9%) patients, with 18 (25.7%) meeting criteria for severe depression. Depression was significantly associated with women older than 20 years of age (P=0.01), unemployment (P=0.03), lack of social support following fistula (P=0.04), and living with fistula for over 3 months (P=0.01). CONCLUSION: Women with obstetric fistula are predisposed to high levels of depression. A holistic management approach, including mental health care and family support, is recommended. PMID- 21794862 TI - Treatment of typhoid perforation during pregnancy and the postpartum period. PMID- 21794863 TI - Comparison of pregnancy outcome among nulliparas with and without microalbuminuria at the end of the second trimester. AB - OBJECTIVE: To evaluate the rate of poor pregnancy outcome among nulliparas who had microalbuminuria at the end of the second trimester of their pregnancy. METHODS: A prospective cohort study was performed on 490 nulliparous women who were at the end of the second trimester of pregnancy. Urine tests for albuminuria and creatinine measurements were performed in all women and the albumin to creatinine ratio (ACR) was calculated. The women with microalbuminuria (exposed group) and those without microalbuminuria (nonexposed group) were monitored until the end of their pregnancy and compared for pregnancy outcome. RESULTS: Preterm labor (57.9% versus 13.5%), preeclampsia (50.0% versus 8.6%), intrauterine growth restriction (42.1% versus 6.4%), and preterm premature rupture of membranes (31.6% versus 10.2%) were significantly more common in the exposed group. The rates of gestational diabetes did not differ significantly between the 2 groups. In multivariate logistic regression analyses, microalbuminuria increased the risks for preterm labor (adjusted OR 2.4; 95% CI 1.1-5.5, P=0.03) and preeclampsia (adjusted OR 9.5; 95% CI 4.6-19.3, P<0.001). CONCLUSION: Microalbuminuria at the end of the second trimester of pregnancy might increase the risks of preterm labor, preeclampsia, intrauterine growth restriction, and preterm premature rupture of membranes. PMID- 21794864 TI - Single- versus double-layer closure of the hysterotomy incision during cesarean delivery and risk of uterine rupture. AB - OBJECTIVE: To evaluate the best available evidence regarding the association between single-layer closure and uterine rupture. METHODS: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for relevant observational and experimental studies that included women with a previous single, low, transverse cesarean delivery who had attempted a trial of labor (TOL). The risks of uterine rupture and uterine dehiscence were assessed by pooled odds ratios (OR) calculated with a random effects model. RESULTS: Nine studies including 5810 women were reviewed. Overall, the risk of uterine rupture during TOL after a single-layer closure was not significantly different from that after a double-layer closure (OR 1.71; 95% confidence interval [CI] 0.66-4.44). However, a sensitivity analysis indicated that the risk of uterine rupture was increased after a locked single-layer closure (OR 4.96; 95% CI 2.58-9.52, P<0.001) but not after an unlocked single-layer closure (OR 0.49; 95% CI 0.21 1.16), compared with a double-layer closure. CONCLUSION: Locked but not unlocked single-layer closures were associated with a higher uterine rupture risk than double-layer closure in women attempting a TOL. PMID- 21794865 TI - 3-Month physical activity checklist: development and validation with Taiwanese adults with mental illness. AB - BACKGROUND: Physical activity has been shown to be an effective intervention to improve psychological and emotional functions for individuals with mental illness. Many scales have been used to measure physical activity in general populations, but most existing scales may not be easily applied to individuals with mental illness. OBJECTIVE: The aim of this study was to test the reliability and validity of the 3-Month Physical Activity Checklist developed to measure physical activity performance in Taiwanese adults with mental illness. DESIGN: A survey questionnaire design was used to gather cross-sectional data for the scale. DATA COLLECTION AND PARTICIPANTS: Data were collected from a convenience sample of patients recruited in 2007-2010 from two mental health clinics in central Taiwan. The study was conducted in three phases: test-retest reliability and scale restructuring (n=28), test-retest reliability and criterion-validity testing of the restructured scale (n=60), and cross-sample testing (n=273). In third phase, participants were diagnosed with anxiety disorders (n=153), schizophrenia (n=98), and bipolar disorders (n=22). MEASURES AND ANALYSIS: Data were collected by self-report 3-Month Physical Activity Checklist and an administered Chinese version of the 7-Day Physical Activity Recall. Data were analyzed by intraclass correlation coefficients and chi-square test. RESULTS: The restructured scale had 2-week test-retest reliability coefficients for light, moderate, and vigorous activity of 0.71, 0.78, and 0.86, respectively. Moderate to high agreement was found between the two scales for light (r=0.47), moderate (r=0.64), and vigorous activities (r=0.73). Recommended physical activity levels were achieved by 28.6% of participants (n=78) and differed significantly by type of mental disorder (chi(2)=21.98, p<0.000). CONCLUSIONS: The 3-Month Physical Activity Checklist has acceptable reliability and criterion validity to measure physical activity performance of Taiwanese adults with mental illness. The scale can be used by mental health professionals to identify levels and types of physical activity, which may be used to evaluate treatment effects or nursing care outcomes for patients with mental illness. PMID- 21794866 TI - Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC. AB - OBJECTIVE: The soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient's oxidative burden. We here describe two platelet-based assays that allow determining the extent of oxidised sGC and thus provide a basis for an individualised pharmacotherapy. METHODS/RESULTS: Platelets obtained from patients with (n=12) and without (n=12) coronary artery disease (CAD) were examined by flow cytometry (P-selectin expression), and Western blots (vasodilator associated phosphoprotein, VASP phosphorylation). Results were compared to maximal oxidation of sGC achieved by the oxidising agent ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). Treatment of platelets with Cinaciguat resulted in differential activation of oxidised sGC. Platelet P-selectin expression and VASP-phosphorylation revealed significant differences (p=0.012, p=0.039, respectively) between CAD and non-CAD patients. CONCLUSION: We describe platelet-based assays that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators. PMID- 21794867 TI - Determination of mechanical properties of soft tissue scaffolds by atomic force microscopy nanoindentation. AB - While the determination of mechanical properties of a hard scaffold is relatively straightforward, the mechanical testing of a soft tissue scaffold poses significant challenges due in part to its fragility. Here, we report a new approach for characterizing the stiffness and elastic modulus of a soft scaffold through atomic force microscopy (AFM) nanoindentation. Using collagen-chitosan hydrogel scaffolds as model soft tissue scaffolds, we demonstrated the feasibility of using AFM nanoindentation to determine a force curve of a soft tissue scaffold. A mathematical model was developed to ascertain the stiffness and elastic modulus of a scaffold from its force curve obtained under different conditions. The elastic modulus of a collagen-chitosan (80%/20%, v/v) scaffold is found to be 3.69 kPa. The scaffold becomes stiffer if it contains more chitosan. The elastic modulus of a scaffold composed of 70% collagen and 30% chitosan is about 11.6 kPa. Furthermore, the stiffness of the scaffold is found to be altered significantly by extracellular matrix deposited from cells that are grown inside the scaffold. The elastic modulus of collagen-chitosan scaffolds increased from 10.5 kPa on day 3 to 63.4 kPa on day 10 when human foreskin fibroblast cells grew inside the scaffolds. Data acquired from these measurements will offer new insights into understanding cell fate regulation induced by physiochemical cues of tissue scaffolds. PMID- 21794868 TI - Preparation of magnetic core mesoporous shell microspheres with C18-modified interior pore-walls for fast extraction and analysis of phthalates in water samples. AB - In this study, core-shell magnetic mesoporous microspheres with C18 functionalized interior pore-walls were synthesized through coating Fe(3)O(4) microspheres with a mesoporous inorganic-organic hybrid layer with a n octadecyltriethoxysilane (C18TES) and tetraethyl orthosilicate (TEOS) as the silica source and cetyltrimethylammonia bromide (CTAB) as a template. The obtained C18-functionalized Fe(3)O(4)@mSiO(2) microspheres possess numerous C18 groups anchored in the interior pore-walls, large surface area (274.7 m(2)/g, high magnetization (40.8 emu/g) and superparamagnetism, uniform mesopores (4.1 nm), which makes them ideal absorbents for simple, fast, and efficient extraction and enrichment of hydrophobic organic compounds in water samples. Several kinds of phthalates were used as the model hydrophobic organic compounds to systematically evaluate the performance of the C18-functionalized Fe(3)O(4)@mSiO(2) microspheres in extracting hydrophobic molecules by using a gas chromatography-mass spectrometry. Various parameters, including eluting solvent, the amounts of absorbents, extraction time and elution time were optimized. Hydrophobic extraction was performed in the interior pore of magnetic mesoporous microspheres, and the materials had the anti-interference ability to macromolecular proteins, which was also investigated in the work. Under the optimized conditions, C18-functionalized Fe(3)O(4)@mSiO(2) microspheres were successfully used to analyze the real water samples. The results indicated that this novel method was fast, convenient and efficient for the target compounds and could avoid being interfered by macromolecules. PMID- 21794869 TI - Planar solid phase extraction--a new clean-up concept in multi-residue analysis of pesticides by liquid chromatography-mass spectrometry. AB - Efficient clean-up is indispensable for preventing matrix effects in multi residue analysis of pesticides in food by liquid and gas chromatography coupled to mass spectrometry. As a completely new approach, highly automated planar chromatographic tools were applied for powerful clean-up, called high-throughput planar solid phase extraction (HTpSPE). Thin-layer chromatography (TLC) was used to completely separate pesticides from matrix compounds and to focus them into a sharp zone, followed by extraction of the target zone by the TLC-MS interface. HTpSPE resulted in extracts nearly free of interference and free of matrix effects, as shown for seven chemically representative pesticides in four different matrices (apples, cucumbers, red grapes, tomatoes). Regarding the clean up step, quantification by LC-MS provided mean recovery (against solvent standards) of 90-104% with relative standard deviations of 0.3-4.1% (n=5) for two spiking levels of 0.1 and 0.5 mg/kg. Clean-up of one sample was completed in a manner of minutes, while running numerous samples in parallel at reduced costs, with very low sample and solvent volumes. PMID- 21794870 TI - Optical, morphological and structural characterization of Langmuir-Schaefer films of a functionalized copper phthalocyanine. AB - Langmuir-Schaefer (LS) films of copper(II) tetrakis-(isoprpoxy-carbonyl) phthalocyanine (TiPCuPc) have been deposited onto various solid supports. Its floating film have been characterized at the air-water interface by means of Brewster Angle Microscopy and Langmuir curves. Vibrational modes of multilayer transferred LS film have been studied by Raman spectroscopy and the optical parameters (refractive index n and extinction coefficient k) have been determined in the visible range of the electromagnetic spectrum. Linearly polarized light absorbance measurements have been performed at room temperature in the 400-800 nm spectral range and the average orientation of the phthalocyanine rings have been estimated. Transmission electron microscopy has been also used to characterize the morphological properties of the LS film and a close packed arrangement of the deposited molecules has been observed. PMID- 21794871 TI - A pH dependent thermo-sensitive copolymer drug carrier incorporating 4-amino 2,2,6,6-tetramethylpiperidin-1-oxyl (4-NH2-TEMPO) residues for electron spin resonance (ESR) labeling. AB - The fabrication of a new amphiphilic block copolymer composed of a poly DL-lactic acid (PLA) hydrophobic backbone and pH dependent thermo-sensitive poly (N isopropyl) methacrylamide-co-N-isopropylmaleamic acid-co-10-undecenoic acid (PNIPAAm-co-NIPMMA-co-UA) entities as hydrophilic domains as well as carrying 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) residues for electron spin resonance (ESR) labeling is reported. The lower critical solution temperature (LCST) of the copolymer was determined by optical absorbance measurements. The LCST was pH dependent and varied in a narrow practical range, 35.4 degrees C at pH 5.0, 37.5 degrees C at pH 6.5 and 39.4 degrees C at pH 7.4, which was below, near and above nominal physiological temperature respectively. The assembly of the copolymer into micelles in aqueous solution at temperatures below the LCST was confirmed by FT-IR, (1)H NMR and fluorescence spectroscopy. It is demonstrated that the anticancer drug, 5-fluorouracil (5-FU) can be loaded effectively within the polymeric micelles and released in response to environmental stimuli- namely, pH and temperature. PMID- 21794872 TI - A molecular dynamics study of the interaction of oleate and dodecylammonium chloride surfactants with complex aluminosilicate minerals. AB - Surface characteristics of complex aluminosilicate minerals like spodumene [LiAl(SiO(3))(2)], jadeite [NaAl(SiO(3))(2)], feldspar [KAlSi(3)O(8)], and muscovite [K(2)Al(4)(Al(2)Si(6)O(20))(OH)(4)]) are modeled. Surface energies are computed for the cleavage planes of these minerals. Adsorption mechanisms of anionic chemisorbing type oleate and cationic physisorbing type dodecylammonium chloride molecules on two different crystal planes, that is (110) and (001), of spodumene and jadeite are studied in terms of the surface-surfactant interaction energies computed using molecular dynamics (MD) simulations. The conclusions drawn from purely theoretical computations match remarkably well with our experimental results. PMID- 21794873 TI - Extending the use of Spanish Computer-assisted Anomia Rehabilitation Program (CARP-2) in people with aphasia. AB - PURPOSE: To extend the use of the Spanish Computer-assisted Anomia Rehabilitation Program (CARP-2) for anomia from a single case to a group of 15 people with aphasia. To evaluate whether the treatment is active (Phase 1) for this group (Robey & Schultz, 1998), providing potential explanations as to why. METHODS: Fifteen participants with chronic aphasia (with a range from moderate to mild anomia) were recruited to 15 weeks of computer-assisted therapy for anomia. A single treatment period with pre- and post-treatment assessments evaluated participants' ability to name 200 words using the multiple cues provided by the computer. Pre- and post-naming measures of all items examined the effect of treatment. Background linguistic and cognitive skills were measured before and after the therapy to investigate whether the improvements in naming were therapy specific. RESULTS: All 15 participants showed significant benefits in their naming skills after the therapy. There were no changes to cognitive and linguistic skills unrelated to anomia. There was evidence of some carry-over effects in naming. CONCLUSION: The Spanish Computer-assisted Anomia Rehabilitation Program (CARP-2) for anomia is an active treatment for a range of people who have anomia as part of their aphasia profile. LEARNING OUTCOMES: By the end of the paper you will be able to answer the CEU questions and consider whether to use computer assisted therapy on a wide range of clients with anomia difficulties. PMID- 21794874 TI - Impact of dexamethasone metabolism on dex/CRH-test. PMID- 21794875 TI - Population-level prevalence estimate and characteristics of psychiatric disability among Chinese adults. AB - Psychiatric disability is a population health problem, and understanding its magnitude is essential to informing population health policies. This paper aims to describe the prevalence rates, causes, and severity of psychiatric disability in Chinese adults, and to explore daily activities and social functions for people with psychiatric disability. We used the second China National Sample Survey on Disability, comprising 2,526,145 persons from 771,797 households. Identification and classification for psychiatric disability was based on consensus manuals. We used standard weighting procedures to construct sample weights considering the multistage stratified cluster sampling survey scheme. Population weighted prevalence and 95% Confidence Intervals (CI) were evaluated. An estimate of 8 million adults with psychiatric disability was identified. The weighted prevalence rate of psychiatric disability was 8.14 per 1000 people (95% CI, 7.95-8.33). More rural residents suffered from psychiatric disability than their urban counterparts, and more females had psychiatric disability than males. Schizophrenia, schizotypal and delusional disorders accounted for more than half of the psychiatric disability in Chinese adults. People with psychiatric disability had more severe difficulties in most daily activities and social functions than in people with other disabilities. This study demonstrates psychiatric disability causes social burden to the Chinese communities. Strategies including case identification, treatment, and rehabilitation should be developed and countermeasures are warranted for females and rural residents to reduce the burden caused by psychiatric disability. PMID- 21794876 TI - Mitochondrial neurogastrointestinal encephalopathy in an Indian family with possible manifesting carriers of heterozygous TYMP mutation. AB - BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a distinctive autosomal recessive disorder with mitochondrial alterations due to mutations TYMP gene encoding thymidine phosphorylase. MATERIALS AND METHODS: Study of clinical and biochemical characteristics of a family with MNGIE. RESULTS: Index case was a 32 year old man presenting with recurrent vomiting, early satiety and progressive weight loss. He had ptosis, restricted eye movements, generalized muscle wasting, and absent tendon reflexes. Lactate levels were elevated in venous blood and CSF lactate. MRI brain showed diffuse leucoencephalopathy. Barium swallow showed near total obstruction at mid portion of vertical limb of duodenum with ileus. Esophageal manometry suggested myopathy. Muscle biopsy revealed moderate numbers of ragged blue and ragged red fibers as well as cytochrome c oxidase deficient fibers. An elder brother had similar symptoms and expired after a surgical procedure and a 28 year old brother has similar illness. The father had asymptomatic bilateral ptosis with mild ophthalmoparesis. The paternal grandfather and paternal aunt also had bilateral ptosis. Clinical diagnosis of MNGIE was confirmed in the two living brothers by demonstrating severe defects of thymidine phosphorylase activity in buffy coat, elevated thymidine and deoxyuridine in plasma, and a homozygous TYMP c.893G>A mutation. CONCLUSIONS: This family with biochemically and genetically confirmed mitochondrial neurogastrointestinal encephalopathy syndrome uncharacteristically included heterozygous TYMP mutation carriers manifesting extra-ocular weakness. It is important to identify MNGIE patients early because therapeutic options are emerging. PMID- 21794877 TI - Is repeat transurethral resection needed for minimally invasive T1 urothelial cancer? Con. PMID- 21794878 TI - Can patterns in benthic communities be explained by an environmental pressure index? AB - Many studies have assessed in unison specific biological attributes and certain environmental impacts but few studies have analyzed multiple biological variables and pressures from multiple sites at the same time. Our study's goal was to quantify the major potential human pressures in the shallow subtidal rocky reefs along a tropical Atlantic coast; propose a relative environmental pressure index and investigate the relationships between environmental pressures, the benthic community and coral population attributes. The analysis of human pressures suggests that one-third of sites were under high or very high proportional stress. Sites with high human pressure had lower live cover, higher percent of recent mortality and density of Siderastrea stellata. These relations were species specific. The coral species S. stellata seemed to be the best indicator of present environmental stress. These findings demonstrate the need to include multiple species and stressors in monitoring programs designed to contribute to coastal management initiatives. PMID- 21794879 TI - Variation of particulate organic carbon and its relationship with bio-optical properties during a phytoplankton bloom in the Pearl River estuary. AB - In this study, variations in the particulate organic carbon (POC) were monitored during a phytoplankton bloom event, and the corresponding changes in bio-optical properties were tracked at one station (114.29 degrees E, 22.06 degrees N) located in the Pearl River estuary. A greater than 10-fold increase in POC (112.29-1173.36 mg m-3) was observed during the bloom, with the chlorophyll a concentration (Chl-a) varying from 0.984 to 25.941 mg m-3. A power law function is used to describe the relationship between POC and Chl-a, and the POC:Chl-a ratio tends to change inversely with Chl-a. Phytoplankton carbon concentration is indirectly estimated using the conceptual model proposed by Sathyendranath et al. (2009), and this carbon is found to contribute 47.21% (+/-10.65%) to total POC. The estimated carbon-to-chlorophyll ratio of phytoplankton in diatom-dominated waters is found to be comparable with results reported in the literature. Empirical algorithms for determining the concentrations of Chl-a and POC were developed based on the relationships of these variables with the blue-to-green reflectance ratio. With these bio-optical models, the levels of particulate organic carbon and Chl-a could be predicted from the radiometric data measured by a marine optical buoy, which showed much more detailed information about the variability in biogeochemical parameters during this bloom event. PMID- 21794880 TI - [Treatment and control of patients with phenylketonuria: results from the Collaborative Group of Spanish Follow-up Units]. AB - BACKGROUND AND OBJECTIVE: To evaluate the management of phenylketonuria (PKU) in Spanish metabolic units and to develop a patients registry. PATIENTS AND METHODS: PKU patients diagnosed and/or followed up in Spain, with phenylalanine values before treatment > 360 MUmol/L. Registered anonymous data are those yielded by the units during 2010. RESULTS: Data from the 18 Spanish Follow-up Units were collected. Eighty-three per cent of Units are multidisciplinary, all of them corresponding to control patients of all ages, with uniform management criteria. Data of 688 PKU patients were registered (median: 14 years [1 month-53 years], 41.5% are presently > 18-year-old. 71.8% patients came from neonatal screening; 15.8% have mild-PKU, 26% moderate-PKU and 51.5% classic-PKU. 78.6% patients are treated with protein-restricted diet, 9.3% with BH4 and free diet and 7.8% with BH4 and diet. Dietary control was good in 58.6% patients, intermediate in 26% and poor in 15.3%. Median (range) intellectual quotients was 97 (25-145). The number of neurological complications in late diagnosed patients was three-times higher than those of neonatal screening patients. 13.3% of adults had university studies and 37.5% had a stable couple. CONCLUSIONS: This study allows for the first time the evaluation of the PKU management by Spanish PKU Follow-up Units, as well as the analysis and registry of controlled PKU patients. The study makes evident the need of adult Follow-up Units and the importance of neonatal screening for PKU patients prognosis. PMID- 21794881 TI - [Risk factors for Clostridium difficile infections in hospitalized patients]. AB - BACKGROUND AND OBJECTIVES: To identify risk factors, and to estimate the crude effects attributable to hospital acquired Clostridium difficile infection (CDI). PATIENTS AND METHODS: Case-control study matched by age, gender, and admission date. Patient and healthcare risk factors were evaluated. Hospital stays and mortality were compared. RESULTS: Thirty-eight cases and 76 controls were included (mean age 73 years). Cases presented worse Charlson index (P .02), higher pre-infection stay (median 10 vs. 5.5 days) and had received antibiotic treatment more frequently (89.5 vs. 40.7%) than their control counterparts. Albuminemia < 3.5 gr/dL (OR 7.1; 1.4-37), having received cephalosporins (OR 10.1; 1.8-55.1), quinolones (OR 9.4; 1.1-41.1), or proton pump inhibitors (OR 6.6; 1.1-41.1) were associated with an independent higher risk of CDI. Total hospital stay (31 vs. 5.5 days), as well as crude mortality, was higher for cases than for control patients (31.6 vs. 6.6%). CONCLUSIONS: Receiving cephalosporins, quinolones and proton pump inhibitors, as well as hyponutrition, increase the risk of CDI. CDI is associated with relevant crude effects on mortality and excess of stay. PMID- 21794882 TI - [About medical interconsultation]. PMID- 21794884 TI - Epidemiology of hospitalization due to alcohol-related harm: evidence from a Scottish cohort study. AB - OBJECTIVE: To examine a broad range of risk factors and their association with alcohol-related hospital admissions in a Scottish general population. DESIGN: Observational record-linkage study in Scotland from 1998 to 2008 involving 8305 respondents aged 16-74 years who participated in the 1998 Scottish Health Survey. Outcome was defined as first-time hospital admission with at least one alcohol related diagnosis. METHODS: Cox proportional hazards modelling was applied to estimate the hazard ratio (HR) of first-time hospitalization with an alcohol related condition associated with a range of behavioural, social and biological risk factors. FINDINGS: In total, 287 (3.4%) respondents experienced at least one alcohol-related hospitalization during the observation period. Moderate to excessive drinking was the strongest predictor of subsequent admission to hospital with an alcohol-related diagnosis, with clear evidence of a dose - response relationship. Moderate and heavy smoking were also significant predictors of subsequent admission to hospital with an alcohol-related problem. Social factors - such as being in receipt of income-related benefits [HR 1.68, 95% confidence interval (CI) 1.25-2.28]; being retired or economically inactive; and being separated, divorced or widowed (HR 2.34, 95% CI 1.70-3.22) - were also significant predictors of alcohol-related hospitalization. CONCLUSIONS: Moderate and higher levels of weekly alcohol consumption, moderate to heavy smoking, economic circumstances and marital status are the main risk factors for alcohol related hospitalization in the Scottish population. These findings add to the evidence that population-based strategies are needed to limit alcohol-related morbidity. PMID- 21794883 TI - Volatiles that encode host-plant quality in the grapevine moth. AB - Plant volatiles are signals used by herbivorous insects to locate host plants and select oviposition sites. Whether such volatiles are used as indicators of plant quality by adult insects in search of host plants has been rarely tested. We tested whether volatiles indicate plant quality by studying the oviposition of the grapevine moth Lobesia botrana on the grapevine plant Vitis vinifera. Host plants were infected with a variety of microorganisms, and larval fitness was correlated to the infected state of the substrate. Our results show an oviposition preference for volatiles that is significantly correlated with the fitness of the substrate. The chemical profiles of the bouquets from each V. vinifera-microorganism system are clearly differentiated in a PCA analysis. Both the volatile signal and the quality of the plant as larval food were affected by the introduction of microorganisms. Our study represents a broad approach to the study of plant-insect interactions by considering not only the direct effect of the plant but also the effect of plant-microorganism interactions on insect population dynamics. PMID- 21794885 TI - Public awareness of colorectal cancer and screening in a Spanish population. AB - OBJECTIVES: To investigate screening intentions and previous uptake of colorectal cancer (CRC) screening tests in a general population in Spain; and to determine knowledge about CRC, risk perceptions, major barriers to screening and perceived benefits of screening. STUDY DESIGN: Cross-sectional study. METHODS: Six hundred consecutive Spanish individuals over 50 years of age completed a questionnaire to determine their screening intentions, previous CRC diagnostic procedures, and knowledge about screening procedures, risk factors for CRC, 5-year prognosis, warning signs and symptoms, incidence, age-related risk and perceived barriers to screening. RESULTS: Although 78.8% of subjects reported that they were willing to participate in CRC screening, only 12% had ever undergone a screening test, and none with screening intention. Awareness of a breast cancer screening test [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.04-2.70; P = 0.035], visiting a general practitioner in the preceding year (OR 3.08, 95% CI 1.86-5.08; P < 0.0001), awareness of risk factors (OR 2.32, 95% CI 1.49-3.61; P < 0.001), awareness of CRC signs or symptoms (OR 1.65, 95% CI 1.03-2.64; P = 0.04) and belief in the efficacy of CRC screening (OR 8.85, 95% CI 1.53-51.3; P = 0.01) were independent predictors for intention to participate in CRC screening. The most common reasons given for refusing screening were 'CRC tests might be dangerous' (28.2%), 'CRC tests might be painful' (17.9%) and 'feeling healthy' (16.2%). CONCLUSION: Although reported willingness to undergo CRC screening was high, CRC knowledge and actual uptake of CRC screening were low. An educational intervention to reduce barriers and increase awareness could improve uptake of CRC screening. PMID- 21794886 TI - The Glasgow effect: useful construct or epidemiological dead end? PMID- 21794887 TI - Community-based service provision for the prevention and management of maternal obesity in the North East of England: a qualitative study. AB - OBJECTIVES: This study was conducted to develop a better understanding of community-based initiatives relating to maternal obesity, and to gain community service providers' views on maternal obesity services and their perceived role in the management and prevention of maternal obesity. STUDY DESIGN: An interpretive constructionist approach using semi-structured interviews and focus groups. METHODS: Semi-structured interviews and focus groups were carried out with community service providers in the North East of England, UK. Data were analysed using thematic content analysis. RESULTS: Five dominant themes emerged: community based obesity services, understanding maternal obesity services, participation in maternal obesity services, challenges in the development of community maternal obesity services, and factors contributing to successful maternal obesity services. Community service providers identified their role in tackling maternal obesity alongside maternity services. Participants identified a lack of community maternal obesity services, distinct training requirements, and felt that a multi agency approach was likely to be required. CONCLUSIONS: Increasing rates of maternal obesity and the relationship between maternal obesity and childhood obesity mean that the preconception, pregnancy and postnatal periods are important and timely stages in the life course for public health intervention. However, current public health and community service provision lacks structured maternal obesity objectives. PMID- 21794888 TI - [Autologous tissue engineering by means of distraction osteogenesis: Biomechanical considerations]. AB - Tissue engineering consists in producing functional replacement tissue. Distraction osteogenesis is a tissue engineering technique that uses the mechanical environment of cells to induce tissue regeneration, without need for exogenous biochemical factors. A better understanding of the optimal mechanical conditions of distraction callus stretching may reduce the duration, discomfort, and even social impact of distraction protocols, and complications and failures. We present the current state of knowledge in this field by addressing the fundamentals of elongating bone tissue biomechanics, the influence of rhythm and rate of distraction, and that of vectors and stability. Finally, we present the innovations currently studied, which may modify our clinical protocol in the short term. PMID- 21794889 TI - Identification of functional domains of the IR2 protein of equine herpesvirus 1 required for inhibition of viral gene expression and replication. AB - The equine herpesvirus 1 (EHV-1) negative regulatory IR2 protein (IR2P), an early 1,165-amino acid (aa) truncated form of the 1487-aa immediate-early protein (IEP), lacks the trans-activation domain essential for IEP activation functions but retains domains for binding DNA, TFIIB, and TBP and the nuclear localization signal. IR2P mutants of the N-terminal region which lack either DNA-binding activity or TFIIB-binding activity were unable to down-regulate EHV-1 promoters. In EHV-1-infected cells expressing full-length IR2P, transcription and protein expression of viral regulatory IE, early EICP0, IR4, and UL5, and late ETIF genes were dramatically inhibited. Viral DNA levels were reduced to 2.1% of control infected cells, but were vey weakly affected in cells that express the N-terminal 706 residues of IR2P. These results suggest that IR2P function requires the two N terminal domains for binding DNA and TFIIB as well as the C-terminal residues 707 to 1116 containing the TBP-binding domain. PMID- 21794890 TI - Remediation of groundwater contaminated with MTBE and benzene: the potential of vertical-flow soil filter systems. AB - Field investigations on the treatment of MTBE and benzene from contaminated groundwater in pilot or full-scale constructed wetlands are lacking hugely. The aim of this study was to develop a biological treatment technology that can be operated in an economic, reliable and robust mode over a long period of time. Two pilot-scale vertical-flow soil filter eco-technologies, a roughing filter (RF) and a polishing filter (PF) with plants (willows), were operated independently in a single-stage configuration and coupled together in a multi-stage (RF+PF) configuration to investigate the MTBE and benzene removal performances. Both filters were loaded with groundwater from a refinery site contaminated with MTBE and benzene as the main contaminants, with a mean concentration of 2970+/-816 and 13,966+/-1998 MUg L(-1), respectively. Four different hydraulic loading rates (HLRs) with a stepwise increment of 60, 120, 240 and 480 L m(-2) d(-1) were applied over a period of 388 days in the single-stage operation. At the highest HLR of 480 L m(-2) d(-1), the mean concentrations of MTBE and benzene were found to be 550+/-133 and 65+/-123 MUg L(-1) in the effluent of the RF. In the effluent of the PF system, respective mean MTBE and benzene concentrations of 49+/-77 and 0.5+/-0.2 MUg L(-1) were obtained, which were well below the relevant MTBE and benzene limit values of 200 and 1 MUg L(-1) for drinking water quality. But a dynamic fluctuation in the effluent MTBE concentration showed a lack of stability in regards to the increase in the measured values by nearly 10%, which were higher than the limit value. Therefore, both (RF+PF) filters were combined in a multi-stage configuration and the combined system proved to be more stable and effective with a highly efficient reduction of the MTBE and benzene concentrations in the effluent. Nearly 70% of MTBE and 98% of benzene were eliminated from the influent groundwater by the first vertical filter (RF) and the remaining amount was almost completely diminished (~100% reduction) after passing through the second filter (PF), with a mean MTBE and benzene concentration of 5+/-10 and 0.6+/-0.2 MUg L(-1) in the final effluent. The emission rate of volatile organic compounds mass into the air from the systems was less than 1% of the inflow mass loading rate. The results obtained in this study not only demonstrate the feasibility of vertical-flow soil filter systems for treating groundwater contaminated with MTBE and benzene, but can also be considered a major step forward towards their application under full-scale conditions for commercial purposes in the oil and gas industries. PMID- 21794891 TI - Distributions, historical trends, and source investigation of polychlorinated biphenyls in Dianchi Lake, China. AB - Six commonly occurring polychlorinated biphenyl congeners (PCB28, PCB52, PCB101, PCB138, PCB153 and PCB180) were measured in water, surface sediments, and sediment core samples from 10 monitoring stations across Dianchi Lake in Kunming, China to determine the distributions, historical trends, and sources of PCBs to this ecologically and regionally important water body. The summed total concentration of all six PCB congeners ranged from 13 to 72 ng L(-1) in water, 0.6-2.4 ng g(-1) dry weight (d.w.) in surface sediment, and from non-detectable to 2.2 ng g(-1) d.w. in sediment core samples. The six PCB congeners were found to demonstrate similar distribution characteristics across water and surface sediment samples, with PCB28 and PCB52 accounting for more than 67% of the total summed concentration in both matrices. The concentration of individual congeners in each media decreased in the order of PCB28>PCB52>PCB101~PCB138~PCB153~PCB180. Analysis of PCB congeners in sediment core layers as a function of depth revealed two distinct peaks occurring in the top velocity layer and in the layer between 25 and 30 cm in depth (corresponding to 1970s). Core sediment analysis showed PCBs are currently being released to Dianchi Lake and showed the historical trends of PCB deposition into the lake sediment. Data from this multi-media exploration of PCBs can be used by researchers, regulators, and policy makers to understand the fate of PCBs in Dianchi Lake, and also to begin to identify current sources of PCBs to the lake. PMID- 21794892 TI - Development of a novel mathematical model using a group contribution method for prediction of ionic liquid toxicities. AB - A new mathematical model has been developed that expresses the toxicities (EC50 values) of a wide variety of ionic liquids (ILs) towards the freshwater flea Daphnia magna by means of a quantitative structure-activity relationship (QSAR). The data were analyzed using summed contributions from the cations, their alkyl substituents and anions. The model employed multiple linear regression analysis with polynomial model using the MATLAB software. The model predicted IL toxicities with R2=0.974 and standard error of estimate of 0.028. This model affords a practical, cost-effective and convenient alternative to experimental ecotoxicological assessment of many ILs. PMID- 21794893 TI - Partial skeleton of Theropithecus brumpti (Primates, Cercopithecidae) from the Chemeron Formation of the Tugen Hills, Kenya. AB - Here we describe a complete skull and partial skeleton of a large cercopithecoid monkey (KNM-TH 46700) discovered in the Chemeron Formation of the Tugen Hills at BPRP Site #152 (2.63 Ma). Associated with the skeleton was a mandible of an infant cercopithecoid (KNM-TH 48364), also described here. KNM-TH 46700 represents an aged adult female of Theropithecus brumpti, a successful Pliocene papionin taxon better known from the Omo Shungura Formation in Ethiopia and sites east and west of Lake Turkana, Kenya. While the morphology of male T. brumpti is well-documented, including a partial skeleton with both cranial and postcranial material, the female T. brumpti morphotype is not well-known. This skeleton represents some of the first associated evidence of cranial and postcranial female T. brumpti remains. In addition to the complete skull, postcranial material includes elements of the axial skeleton and lower limb. While aspects of the skeleton conform to those of specimens previously assigned to T. brumpti, other features on the femur and tibia appear to differ from those previously described for this species. It is unclear whether these differences represent general variation within the T. brumpti population, variation between the sexes in T. brumpti, or the incorrect assignment of previous isolated hindlimb specimens. In total, the observable morphological features of the hindlimb suggest that KNM-TH 46700 was a terrestrial quadruped similar to modern savannah baboons (Papio). From the available evidence, it is difficult to assess whether or not KNM-TH 46700 frequently engaged in the specialized squatting and shuffling behavior observed in extant geladas (Theropithecus gelada). PMID- 21794894 TI - Water toxicity assessment and spatial pollution patterns identification in a Mediterranean River Basin District. Tools for water management and risk analysis. AB - In compliance with the requirements of the EU Water Framework Directive, monitoring of the ecological and chemical status of Catalan river basins (NE Spain) is carried out by the Catalan Water Agency. The large amount of data collected and the complex relationships among the environmental variables monitored often mislead data interpretation in terms of toxic impact, especially considering that even pollutants at very low concentrations might contribute to the total toxicity. The total dataset of chemical monitoring carried out between 2007 and 2008 (232 sampling stations and 60 pollutants) has been analyzed using sequential advanced modeling techniques. Data on concentrations of contaminants in water were pre-treated in order to calculate the bioavailable fraction, depending on substance properties and local environmental conditions. The resulting values were used to predict the potential impact of toxic substances in complex mixtures on aquatic biota and to identify hot spots. Exposure assessment with Species Sensitivity Distribution (SSD) and mixture toxicity rules were used to compute the multi-substances Potentially Affected Fraction (msPAF). The combined toxicity of the pollutants analyzed in the Catalan surface waters might potentially impact more than 50% of the species in 10% of the sites. In order to understand and visualize the spatial distribution of the toxic risk, Self Organising Map (SOM), based on the Kohonen's Artificial Neural Network (ANN) algorithm, was applied on the output data of these models. Principal Component Analysis (PCA) was performed on top of Neural Network results in order to identify main influential variables which account for the pollution trends. Finally, predicted toxic impacts on biota have been linked and correlated to field data on biological quality indexes using macroinvertebrate and diatom communities (IBMWP and IPS). The methodology presented could represent a suitable tool for water managers in environmental risk assessment and management. PMID- 21794895 TI - Leaf litter recycling in benthic and hyporheic layers in agricultural streams with different types of land use. AB - Changes in land use and intensification of agricultural pressure have greatly accelerated the alteration of the landscape in most developed countries. These changes may greatly disturb the adjacent ecosystems, particularly streams, where the effects of pollution are amplified. In this study, we used the leaf litter breakdown rate to assess the functional integrity of stream ecosystems and river sediments along a gradient of either traditional extensive farming or a gradient of vineyard area. In the benthic layer, the total litter breakdown process integrates the temporal variability of the anthropogenic disturbances and is strongly influenced by land use changes in the catchment even though a low concentration of toxics was measured during the study period. This study also confirmed the essential role played by amphipods in the litter breakdown process. In contrast, microbial processes may have integrated the variations in available nutrients and dissolved oxygen concentrations, but failed to respond to the disturbances induced by vineyard production (the increase in pesticides and metal concentrations) during the study period. The response of microbes may not be sensitive enough for assessing the global effect of seasonal agricultural practices. Finally, the leaf litter breakdown measured in the hyporheic zone seemed mainly driven by microbial activities and was hence more affected by vertical exchanges with surface water than by land use practices. However, the breakdown rate of leaf litter in the hyporheic zone may constitute a relevant way to evaluate the impact on river functioning of any human activities that induce massive soil erosion and sediment clogging. PMID- 21794896 TI - Contribution of ozone to airborne aldehyde formation in Paris homes. AB - Indoor aldehydes may result from ozone-initiated chemistry, mainly documented by experimental studies. As part of an environmental investigation included in the PARIS birth cohort, the aim of this study was to examine ozone contribution to airborne aldehyde formation in Paris homes. Formaldehyde, acetaldehyde and hexaldehyde levels, as well as styrene, nitrogen dioxide and nicotine concentrations, comfort parameters and carbon dioxide levels, were measured twice during the first year of life of the babies. Ambient ozone concentrations were collected from the closest background station of the regional air monitoring network. Traffic-related nitrogen oxide concentrations in front of the dwellings were estimated by an air pollution dispersion model. Home characteristics and families' way of life were described by questionnaires. Stepwise multiple linear regression models were used to link aldehyde levels with ambient ozone concentrations and a few aldehyde precursors involved in oxidation reactions, adjusting for other indoor aldehyde sources, comfort parameters and traffic related nitrogen oxides. A 4 and 11% increase in formaldehyde and hexaldehyde levels was pointed out when 8-hour ozone concentrations increased by 20 MUg/m(3). The influence of potential precursors such as indoor styrene level and frequent use of air fresheners, containing unsaturated volatile organic compounds as terpenes, was also found. Thus, our results suggest that ambient ozone can significantly impact indoor air quality, especially with regard to formaldehyde and hexaldehyde levels. PMID- 21794897 TI - A common matrix metalloproteinase (MMP)-2 polymorphism affects plasma MMP-2 levels in subjects environmentally exposed to mercury. AB - Mercury (Hg) exposure is associated with disease conditions, including cardiovascular problems. Although the mechanisms implicated in these complications have not been precisely defined yet, matrix metalloproteinases (MMPs) may be involved. The gene encoding MMP-2 presents genetic polymorphisms which affect the expression and activity level of this enzyme. A common polymorphism of MMP-2 gene is the C(-1306)T (rs 243865), which is known to disrupt a Sp1-type promoter site (CCACC box), thus leading to lower promoter activity associated with the T allele. This study aimed at examining how this polymorphism affects the circulating MMP-2 levels and its endogenous inhibitor, the tissue inhibitor of metalloproteinase-2 (TIMP-2) in 210 subjects environmentally exposed to Hg. Total blood and plasma Hg concentrations were determined by inductively coupled plasma-mass spectrometry (ICP-MS). MMP-2 and TIMP-2 concentrations were measured in plasma samples by gelatin zymography and ELISA, respectively. Genotypes for the C(-1306)T polymorphism were determined by Taqman(r) Allele Discrimination assay. We found a positive association (p=0.0057) between plasma Hg concentrations and MMP-2/TIMP-2 (an index of net MMP-2 activity). The C(-1306)T polymorphism modified MMP-2 concentrations (p=0.0465) and MMP-2/TIMP-2 ratio (p=0.0060) in subjects exposed to Hg, with higher MMP-2 levels been found in subjects carrying the C allele. These findings suggest a significant interaction between the C(-1306)T polymorphism and Hg exposure, possibly increasing the risk of developing diseases in subjects with the C allele. PMID- 21794898 TI - Association of genetic variants in CYP2C19 and adverse clinical outcomes after treatment with clopidogrel: an updated meta-analysis. PMID- 21794899 TI - The occurrence of antibodies to heparin-platelet factor 4 in cardiac and thoracic surgical patients receiving desirudin or heparin for postoperative venous thrombosis prophylaxis. AB - INTRODUCTION: This randomized, exploratory study compared the incidence of heparin-dependent antibodies associated with subcutaneous (SC) desirudin or heparin given for deep-vein thrombosis prophylaxis following cardiac and thoracic surgery. MATERIALS AND METHODS: Adult patients scheduled for elective cardiac or thoracic surgery received desirudin 15 mg SC twice daily or unfractionated heparin 5000 units SC thrice daily. Duration of thrombosis prophylaxis was determined by the treating physician. Primary outcome measure was the incidence of new antibody formation directed against platelet factor 4 (PF4)/heparin complex. Secondary outcomes included bleeding and thrombotic complications. Blood was tested for anti-PF4/heparin antibodies at baseline, after surgery prior to study drug administration, postdrug day (PDD) 2, PDD 7, and at 1 month. Doppler studies were done before discharge. RESULTS: Of 120 patients, 61 received desirudin, 59 received heparin. New PF4/heparin antibodies occurred in 10.2% and 13.6% of desirudin- and heparin-treated patients, respectively. Among desirudin patients with no heparin exposure, none (0/36) developed PF4/heparin antibodies versus 17.1% with heparin exposure. Incidence of deep venous thrombosis was 4.9% and 3.4% in the desirudin and heparin groups, respectively. Two heparin-group patients developed pulmonary embolism. Two patients per group had bleeding events; no patients required re-exploration for bleeding complications. Median chest tube output was similar with desirudin (900 mL) and heparin (692 mL) as was blood transfusion requirements of more than 2 units (5/61, desirudin; 2/59 heparin). CONCLUSIONS: The incidence of thrombotic events was low in both groups. There were no safety concerns, and desirudin was not associated with anti PF4/heparin antibodies. PMID- 21794900 TI - The thymus and tail regenerative capacity in Xenopus laevis tadpoles. AB - A morphofunctional analysis of the thymus from differently aged Xenopus laevis tadpoles during regeneration of the tail is reported. In stage 50 larvae, competent to regenerate, the appendage cut provoked thymic structural modifications that affected the medullary microenvironment cells and changes in TNF-alpha immunoreactivity. Mucocyte-like cells, multicellular epithelial cysts, myoid cells and cells immunoreactive to TNF-alpha increased in number. Increased numbers of lymphocytes were also found in regenerating areas and, at the end of regeneration, thymic structural and immunocytochemical patterns were restored to control levels. The observed cellular responses and the induction of molecules critical for thymus constitutive processes suggest a stimulation of thymic function after tail amputation. In older larvae, whose capacity to form a new complete and correctly patterned tail was reduced, thymic morphological changes were more severe and may persist throughout the regeneration process with a significant reduction in organ size. In these larvae the histological patterns and the marked thymic decrease may be related to the events occurring during regeneration, i.e. the higher inflammatory response and the reduced tail regenerative potential. PMID- 21794901 TI - Addition of bevacizumab to weekly paclitaxel significantly improves progression free survival in heavily pretreated recurrent epithelial ovarian cancer. PMID- 21794902 TI - Morbidity, mortality and overall survival in elderly women undergoing primary surgical debulking for ovarian cancer: a delicate balance requiring individualization. AB - OBJECTIVE: To assess outcomes and identify underlying predictors of outcomes in a cohort of women over the age of 65 treated for primary ovarian cancer (OC). METHODS: Consecutive patients >= 65 with stage IIIC or IV OC treated with primary surgery and adjuvant chemotherapy at Mayo Clinic between January 1, 1994 and December 31, 2004 were retrospectively assessed. We analyzed the impact of perioperative factors (age, albumin, CA125, American Society of Anesthesiologist (ASA) score, amount of ascites, presence of carcinomatosis, creatinine, need for urgent surgery, stage of disease, surgical complexity score and amount of residual disease) on surgical outcomes (morbidity, mortality, overall survival (OS) and ability to receive chemotherapy). RESULTS: Two hundred eighty patients met inclusion criteria. Age was associated with higher ASA score, lower albumin, and higher creatinine; stage, diffuse peritoneal disease, and surgical complexity were not associated with age. Median OS decreased with increasing age and residual disease (RD), and the impact of RD was greater on older patients. All patients benefited similarly when RD=0 [median OS 5.9 years for age 65-69 vs. 5.0 years in those >= 80 (p=0.5516)], for RD<1cm, and OS was 3.4 vs. 2.1 years respectively for youngest vs. oldest patients (p=0.068). Perioperative morbidity was observed in 37.5% of patients >= 75. Independent predictors of poor perioperative outcome included preoperative albumin <= 3g/dL, urgent surgery, age, and stage (p<0.05). Independent predictors of overall survival included creatinine, albumin, surgical complexity score, amount of residual disease, stage and age. CONCLUSION: Age is an independent predictor of OS in OC. A significant number of elderly women are able to undergo a complete cytoreduction and experience OS similar to that of younger patients. However, the benefits to incomplete cytoreduction are less clear in women >= 75. These observations highlight the need to use emerging predictors of outcomes in decision making and to focus care in centers able to render patients with no visible residual disease. PMID- 21794903 TI - Normal endometrial stromal cells regulate survival and apoptosis signaling through PI3K/AKt/Survivin pathway in endometrial adenocarcinoma cells in vitro. AB - OBJECTIVE: Stroma-tumor communication plays an important role in the genesis of neoplasia. In the current study, we investigated the effect of normal stromal cells on the survival and apoptosis signaling of endometrial cancer cells and further explored the possible mechanism implied in this communication. METHODS: Using primarily cultured normal endometrial stromal cells and an endometrial adenocarcinoma cell line, Ishikawa cells, we established a 2D-coculture system to observe the stromal cell-tumor cell crosstalk in endometrial carcinomas. Using methyl thiazolyl tetrazolium (MTT) assays, cell counting and colony formation assays, we analyzed the effect of stomal cells on the growth and proliferation of Ishikawa cells under different conditions. Using western blot analysis, we determined the effect of stromal cells on the activity of PI3K/AKt/Survivin signaling in Ishikawa cells under different conditions. Using immunohistochemistry analysis, we determined the expression of Survivin in normal endometria and endometrial adenocarcinomas. RESULTS: We found that the paracrine factors from normal endometrial stromal cells grown on Matrigel repeatedly and significantly decreased hormone-stimulated activity of PI3K/AKt/Survivin signaling in Ishikawa cells, which were proved to be increased in endometrial adenocarcinoma and essential in hormone-induced cell growth in Ishikawa cells. CONCLUSION: Paracrine factors from normal endometrial stromal cells can inhibit hormone-stimulated cell proliferation in Ishikawa cells by regulating cell survival and apoptosis through PI3K/AKt/Survivin signaling. PMID- 21794904 TI - IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen induced eosinophilic airway inflammation. AB - BACKGROUND: IL-22 functions as both a proinflammatory cytokine and an anti inflammatory cytokine in various inflammations, depending on the cellular and cytokine milieu. However, the roles of IL-22 in the regulation of allergic airway inflammation are still largely unknown. OBJECTIVE: We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS: We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration, on antigen-induced airway inflammation. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS: Antigen inhalation induced IL-22 production in the airways of sensitized mice. CD4(+) T cells, but not other lymphocytes or innate cells, infiltrating in the airways produced IL-22, and one third of IL-22 producing CD4(+) T cells also produced IL-17A. The neutralization of IL-22 by anti-IL-22 antibody enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of recombinant IL-22 attenuated antigen-induced eosinophil recruitment into the airways. Moreover, anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1beta- or LPS-stimulated MLE-15 cells. CONCLUSION: IL 22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells. PMID- 21794905 TI - Intestinal microbial diversity in infancy and allergy risk at school age. PMID- 21794907 TI - Impact of running away on girls' pregnancy. AB - This study assessed the impact of running away on pregnancy in the subsequent year among U.S. adolescents. We also investigated interactions between running away and sexual assault, romance, and school disengagement. Pregnancy among females between 11 and 17 years (n = 6100) was examined utilizing the Longitudinal Study of Adolescent Health (Add Health) data from Waves 1 and 2. The odds of pregnancy in the next year were 1.67 times greater for runaways net of other factors. A history of sexual assault and romantic involvement increased the likelihood of pregnancy. The relationship between pregnancy and runaway behavior in the general population is understudied. Our findings suggest that runaway youth have a multiplicity of needs that require a complex array of medical, social, emotional, and academic resources to promote positive sexual health outcomes. PMID- 21794906 TI - Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from patients with food allergy: Extended phase I study. AB - BACKGROUND: Food allergy is a common and increasing health concern in westernized countries. No effective treatment is available, and accidental ingestion can be life-threatening. Food Allergy Herbal Formula-2 (FAHF-2) blocks peanut-induced anaphylaxis in a murine model of peanut-induced anaphylaxis. It was found to be safe and well tolerated in an acute phase I study of patients with food allergy. OBJECTIVE: We sought to assess the safety of FAHF-2 in an extended phase I clinical trial and determine the potential effects on peripheral blood basophils from patients with food allergy. METHODS: Patients in an open-label study received 3.3 g (6 tablets) of FAHF-2 three times a day for 6 months. Vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiographic data were acquired at baseline and at 2-month intervals. During the course of the study, basophil activation and basophil and eosinophil numbers were evaluated by using CCR3/CD63 staining and flow cytometry. RESULTS: Of 18 patients enrolled, 14 completed the study. No significant drug-associated differences in laboratory parameters, pulmonary function study results, or electrocardiographic findings before and after treatment were found. There was a significant reduction (P < .010) in basophil CD63 expression in response to ex vivo stimulation at month 6. There was also a trend toward a reduction in eosinophil and basophil numbers after treatment. CONCLUSION: FAHF-2 was safe and well tolerated and had an inhibitory effects on basophil numbers in an extended phase I clinical study. A controlled phase II study is warranted. PMID- 21794908 TI - Immobilization of anticoagulant-loaded liposomes on cell surfaces by DNA hybridization. AB - An unresolved obstacle in transplantation of islets of Langerhans is the early graft loss caused by thrombotic reactions on the surface of islets after intraportal transplantation. We investigated a versatile method for modifying the surface of islets with liposomes carrying the anticoagulant argatroban using an amphiphilic poly(ethylene glycol)-phospholipid conjugate derivative (PEG-lipid) and DNA hybridization. Argatroban was gradually released from the liposomes on the islets, and antithrombic activity was detected in culture medium. Modified islets retained the ability to control insulin release in response to glucose concentration changes. Although we mainly examined surface modification of islets, this technique may be useful for immobilizing various types of small molecules on cells and tissues and thus may have many applications in cell therapy and regenerative medicine. PMID- 21794910 TI - A computational modeling approach for enhancing self-assembly and biofunctionalisation of collagen biomimetic peptides. AB - Collagen fibers are essential components of tissues, which are highly conserved across the animal kingdom and could be extremely useful in tissue engineering. The formation of these macromolecular fibers depends on molecular interactions based self-assembly of the basic building blocks of collagen called tropocollagens. Several attempts to produce biomimetic collagen have been described, however the best method to achieve the optimal material for tissue engineering has not been established. Here, we describe a bottom-up approach to design two computationally mutated molecular models that use non-covalent interactions to cross-link triple helices of tropocollagen molecules and thus promote self-association. Implementing a graph theory approach in the software FIRST reveals the hotspots that are crucial for the overall rigidity of the supramolecular helical structures and the remaining non-hotspots available for mutations. The mutated models were further decorated with GFOGER, a known collagen cell binding motif, to depict a biofunctional model. In addition to their recognized role of cell binding, the charged residues of the binding motif appeared to enhance further the supramolecular helical association. These findings could help to produce biomimetic collagen for biomedical applications. PMID- 21794909 TI - Carboxyl-ebselen-based layer-by-layer films as potential antithrombotic and antimicrobial coatings. AB - A carboxyl-ebselen-based layer-by-layer (LbL) film was fabricated by alternatively assembling carboxyl-ebselen immobilized polyethylenimine (e-PEI) and alginate (Alg) onto substrates followed by salt annealing and cross-linking. The annealed films exhibiting significantly improved stability are capable of generating nitric oxide (NO) from endogeneous S-nitrosothiols (RSNOs) in the presence of a reducing agent. The NO generation behaviors of different organoselenium species in solution phase are compared and the annealing mechanism to create stable LbL films is studied in detail. An LbL film coated polyurethane catheter is capable of generating physiological levels of NO from RSNOs even after blood soaking for 24 h, indicating potential antithrombotic applications of the coating. Further, the LbL film is also demonstrated to be capable of reducing living bacterial surface attachment and killing a broad spectrum of bacteria, likely through generation of superoxide (O(2)(.-)) from oxygen. This type of film is expected to have potential application as an antithrombotic and antimicrobial coating for different biomedical device surfaces. PMID- 21794911 TI - Effects of n-6 polyunsaturated fatty acids on prostaglandin production in ovine fetal chorion cells in vitro in late gestation ewes. AB - OBJECTIVE: To use an in vitro model of the ovine placenta to determine effects of n-6 polyunsaturated fatty acid (PUFA) supplementation on prostaglandin (PG) production. PGs are key regulators of fetal maturation and parturition. STUDY DESIGN: Fetal allantochorion tissue (FC) was collected in late pregnancy (day 135). FC cells were isolated and cultured with 0-100 MUM of linoleic acid (LA), gamma-linolenic acid (GLA) or arachidonic acid (AA) in serum free medium and challenged with control medium, lipopolysaccharide (LPS, 0.1 MUg/ml), dexamethasone (DEX, 5 MUM) or a combination of LPS (0.1 MUg/ml) with DEX (5 MUM). Spent medium was harvested at 2 h and 24 h post challenge for measuring PGs. MAIN OUTCOME MEASURES: To assess the effects of treatment on placental 1- and 2-series PGE production. RESULTS: LA supplementation inhibited both PGE(1) and PGE(2) production. GLA predominantly stimulated PGE(1) generation, although it also increased PGE(2) production. AA supplementation predominantly increased PGE(2) production, but also stimulated PGE(1). DEX treatment with or without LPS inhibited PG production. Supplementation with n-6 PUFAs attenuated or neutralised the stimulatory effect of LPS challenge on FC cells for both PGE(1) and PGE(2) production. CONCLUSION: These data show that supplementation with n-6 PUFAs alters placental PG production, but their precise effects depend on their position in the biosynthetic pathway for PG synthesis. This study supports the possibility that GLA containing oils, widely promoted as dietary supplements, might reduce the risk of pre-term labour by inhibiting the responsiveness of PGE(2) production to LPS challenge in the placenta. PMID- 21794912 TI - AMP-deaminase from human preterm placenta--kinetic regulatory properties of enzyme. AB - During pregnancy the isoform composition of human placental AMP-deaminase changes. This may reflect the adaptation of enzyme to changing metabolic requirements of the growing fetus. In this paper kinetic and regulatory properties of AMP-deaminase purified from human preterm (~ 25 week of gestation) placenta were described and compared with these of the enzyme purified from term placenta. AMP-deaminase from preterm placenta was less sensitive to pH changes and in contrast to the enzyme from the term organ, at low range of substrate concentrations was not inhibited but activated by physiological concentrations of orthophosphate. This may significantly improve the catalytic efficiency of enzyme at early phase of the pregnancy. PMID- 21794913 TI - LNK can also be mutated outside PH and SH2 domains in myeloproliferative neoplasms with and without V617FJAK2 mutation. PMID- 21794914 TI - Weekly standard doses of rh-EPO are highly effective for the treatment of anemic patients with low-intermediate 1 risk myelodysplastic syndromes. AB - For more than 20 years erythropoietin (rHEPO) has largely been used to treat anemia in myelodysplastic syndromes (MDS). Early clinical trials showed erythroid responses in no more than 15-25% of patients. In the last decade, a better selection of MDS patients suitable for a therapeutic challenge with rHEPO, alone or in combination with G-CSF, allowed for an increased response-rate, averaging around 40%. More recently, an even higher percentage of responses have been obtained using higher-doses of rHEPO (up to 80,000 IU/weekly) in lower-risk MDS patients. This treatment however, especially at such high doses, is costly and not easily affordable for prolonged periods. The aim of this study was to verify if the use of "standard" doses of rHEPO could induce a satisfying response-rate with a less expensive treatment schedule in IPSS-defined "lower-risk" MDS anemic patients. From January 2005 to December 2009 a total of 55 consecutive anemic (Hb <= 10 g/dL) patients (29 males, 26 females, median age 78 years) with low intermediate-1 risk MDS were treated after informed consent with rHEPO (40,000 IU once a week subcutaneously) for at least 3 months; at the end of this period, erythroid response was assessed, and responders were allowed to continue the treatment indefinitely, whereas non-responders were considered "off study". Both efficacy and safety of the treatment were recorded and evaluated. After 3 months of treatment, 36 out of 55 (65.5%) patients achieved an erythroid response to rHEPO according to IWG 2006 criteria. Higher response-rates to rHEPO were related with both lower IPSS and particularly WPSS scores. Treatment was safe, and only 1 patient had to discontinue the treatment because of unmanageable side-effects. Among the 36 responders, 28 (77%) maintained the response after a median follow up of 46 months. Our data indicate that standard doses of rHEPO are at least as effective as higher-doses for correcting anemia in lower-risk MDS patients; in this clinical scenario, this schedule allows for a consistent reduction of costs without precluding the achievement of a durable erythroid response. PMID- 21794915 TI - Decreased TET2 gene expression during chronic myeloid leukemia progression. AB - Recently it has been demonstrated that ten-eleven-translocation-2 (TET2) gene alterations may represent a crucial event in the pathogenesis of various myeloid malignancies. To date, the loss of TET2 function has been solely ascribed to mutations in the gene coding region. In this study, we report a chronic myeloid leukemia (CML) case showing a TET2 single copy partial deletion associated to a t(4;6;11) rearrangement, appearing during the progression of the disease and responsible for a decreased TET2 gene expression. A putative role for TET2 haploinsufficiency in this patient's CML progression is discussed. PMID- 21794916 TI - Dasatinib-induced rapid regression and complete molecular remission of multiple subcutaneous tumours presenting as relapsed chronic myeloid leukaemia after cord blood transplantation. PMID- 21794917 TI - Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells. AB - Synthetic glucocorticoids (GCs) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11beta-HSD2 expression in human T-cell leukemic cell lines. 11beta-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11beta-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assessed by methyl-thiazol-tetrazolium assay and caspase-3/7 assay, suggesting that 11beta-HSD2 is a cause of GC-resistance in ALL. PMID- 21794918 TI - Validation of a three-factor measurement model of dyspnea in hospitalized adults with heart failure. AB - OBJECTIVE: The purpose of this study was to validate a 3-factor measurement model of dyspnea sensory quality (WORK-EFFORT, TIGHTNESS, SMOTHERING-AIR HUNGER) originally derived in patients with exacerbated chronic obstructive pulmonary disease. METHODS: In this validation study, adult patients with heart failure were enrolled after hospital admission (median hospital day 1) and asked to rate the intensity of dyspnea sensory quality descriptors on the day of enrollment (study day 1; N = 119) and in a recall version for the day of admission (study day 0; n = 97). RESULTS: Confirmatory factor analysis demonstrated good model fit for both days. Cronbach's alpha for each factor was greater than .87 for both study days. CONCLUSION: This is the first study to validate a previously specified measurement model of dyspnea sensory quality in an independent sample. Results indicate that measurement of dyspnea sensory quality in exacerbated cardiopulmonary disease does not necessarily require disease-specific questionnaires. PMID- 21794920 TI - The public health implications of United Kingdom offender healthcare policy: a holistic approach to achieve individual and societal gains. AB - In 2009, two seminal documents were published by the United Kingdom (UK) government concerning healthcare services for offenders. The Bradley review into diversion for people with mental health problems and learning disabilities emphasised a need to improve offender health, not least because of the high economic costs to society as a whole resulting from unresolved mental illness, physical ill-health and substance abuse problems commonly experienced by offenders. The Bradley review made wide-reaching recommendations for change, requiring strong partnership between health and justice agencies at both central government and local levels. A framework for the delivery of Bradley's recommendations has been set out in Improving health, supporting justice, the Department of Health's offender health strategy which sets out the direction of travel for the next 10 years. This paper discusses the reality of working toward improving health services for this marginalised group in the context of the influence of the current straitened financial climate on the allocation of resources to publically funded healthcare in the UK; it examines the historically based, and widely held, belief in the principle of "less eligibility" within our society, whereby there is much public and media resistance to allocating resources to improving care for offenders when other, more "deserving", groups are perceived to be in continuing need. PMID- 21794919 TI - Education, empowerment and community based structural reinforcement: an HIV prevention response to mass incarceration and removal. AB - In the context of US urban jails, incarceration is often seen as an opportune intervention point for prevention interventions in public health. For the detained individual, it is an opportunity to reflect on individual choices and the potential for changes in one's life course. For population focused public health professionals, jail detention facilities represent a concentration of health risks, and an opportunity to have an impact on a significant portion of those at risk for HIV and other health concerns. This paper presents an innovative education and empowerment model that bridges across jail walls, beginning on the inside, and continuing on the outside of jail where individuals continue to be challenged and supported toward positive health and social choices. The intervention also seeks to foment community activism in the communities to which jail detainees return, thus aiming to have a structural impact. This paper examines both the intervention model and the challenges of examining the effectiveness claims for the intervention at multiple levels. PMID- 21794921 TI - 4-Nonylphenol, bisphenol-A and triclosan levels in human urine of children and students in China, and the effects of drinking these bottled materials on the levels. AB - 4-Nonylphenol (4-NP), bisphenol-A (BPA) and triclosan (TCS) are three industrial chemicals used widely in daily products. This study investigated 4-NP, BPA and TCS levels in urine samples of 287 children and students aged from 3 to 24 years old in Guangzhou, China. Total (free and conjugated) amounts of 4-NP, BPA and TCS in the urine samples were detected using gas chromatography-mass spectrometry with negative chemical ionization. The detection rates of 4-NP, BPA and TCS were 100%, 100% and 93% respectively, given the detection limits of 3.8, 0.5 and 0.9 ng/L respectively. Data for 4-NP, BPA and TCS were presented in both creatinine adjusted (microgram per gram creatinine) and unadjusted (microgram per liter) urinary concentrations. The geometric mean (GM) concentrations of urinary 4-NP, BPA and TCS were 15.92 MUg/g creatinine (17.40 MUg/L), 2.75 MUg/g creatinine (3.00 MUg/L) and 3.55 MUg/g creatinine (3.77 MUg/L) respectively. Multiple regression models considering age, gender, preferred drinking bottle and log transformed creatinine were used to calculate the adjusted least square geometric mean (LSGM). Among these subjects, the females had higher LSGM concentrations of 4-NP, BPA and TCS than the males; and the only statistically significant difference was found for the LSGM concentrations of triclosan (p=0.031). Participants who reported to use ceramic cups more frequently had significantly lower LSGM concentrations of BPA than those who used plastic cups (p=0.037). Meanwhile, a three-week test of using polycarbonate bottles and ceramic cups to drink bottled water and boiled tap-water was carried out among 12 graduate students of 25 years old. The GM concentrations of urinary BPA at the end of the first week after using ceramic cups to drink bottled water were 7.16 MUg/g creatinine, then decreased significantly to 3.49 MUg/g creatinine after the second week of using ceramic cups to drink boiled tap-water (p<0.05), and finally increased to 4.15 MUg/g creatinine after the third week of using polycarbonate bottles in drinking boiled tap-water. The results indicate that in daily life the use of polycarbonate bottles or drinking of bottled water is likely to increase the ingestion of BPA, resulting in an increase in urinary BPA levels. PMID- 21794922 TI - You must have been a beautiful baby: ratings of infant facial attractiveness fail to predict ratings of adult attractiveness. AB - Facial attractiveness has been studied extensively, but little research has examined the stability of facial attractiveness of individuals across different stages of development. We conducted a study examining the relationship between facial attractiveness in infants (age 24 months and under) and the same individuals as young adults (age 16-18 years) using infant and adult photographs from high school yearbooks. Contrary to expectations, independent raters' assessments of infant facial attractiveness did not correlate with adult facial attractiveness. These results are discussed in terms of the adaptive function of heightened attractiveness in infancy, which likely evolved to elicit and maintain parental care. PMID- 21794923 TI - Is depression in Parkinson's disease (PD) a specific entity? AB - BACKGROUND: Clinical lore and research have suggested for a long time that depression and PD are closely related. We examined the validity of depression associated with PD (dPD) as a specific subtype of depression according to face validity, descriptive validity, construct validity and predictive validity. METHODS: The English literature was reviewed after searching the MEDLINE database up to June 2010. RESULTS: There appears to be three possible subtypes of comorbid depression: 1) patients who would have been depressed even if they had no PD (nonspecific-casual comorbid dPD), 2) patients who would have been depressed if they had had another disabling medical illness (nonspecific-reactive comorbid dPD) 3) those for which depression is directly related to the underlying pathophysiology of PD (specific comorbid dPD). These latter patients may more often present with particular clinical characteristics (descriptive validity): absence of history of depression or only within 5 years prior to onset of PD, absence of guilty thoughts and self-blame, absence of suicidal behavior, right sided onset. However, dPD is only partly responsive to dopamine replacement and cannot be solely explained by dopamine deficiency. Other neurotransmitter systems are affected in PD and are involved in the pathophysiology of dPD. Their relative involvement however may differ from that in idiopathic depression (i.e.: lesser involvement of serotonergic systems). LIMITATIONS: Therapeutic data are limited to few controlled trials. CONCLUSIONS: Further research may allow differential diagnosis between dPD subtypes (i.e.: those who do and do not result from the underlying pathophysiological process of PD) and help inform treatment choice. PMID- 21794924 TI - Anxiety symptom presentations in Han Chinese and Euro-Canadian outpatients: is distress always somatized in China? AB - BACKGROUND: Cultural variations in the relative emphasis on somatic versus psychological symptoms of distress are a common topic in cultural psychopathology. The most well-known example involves people of Chinese heritage, who are found to emphasize somatic symptoms in presenting depression as compared with people of Western European heritage. It remains unknown whether a similar cultural difference is found for anxiety disorders. METHODS: Euro-Canadian (n=79) and Han Chinese (n=154) psychiatric outpatients with clinically significant concerns about both depression and anxiety were selected from a larger dataset based on their responses to a structured interview. They also completed two self report questionnaires assessing somatization of depression and anxiety. RESULTS: As expected, Chinese participants reported a greater tendency to emphasize somatic symptoms of depression, as compared to the Euro-Canadians. Contrary to expectations, the tendency to emphasize somatic symptoms of anxiety was higher among the Euro-Canadians as compared to the Chinese participants. LIMITATIONS: Characteristics of our participants limit the generalizability of our findings. The current study is preliminary and requires replication. CONCLUSIONS: Despite the exploratory nature of this study, the results suggest that the popular notion of 'Chinese somatization' should not be over-generalized. Our findings also imply that there may be important differences in the cultural understanding of depression and anxiety in both Chinese and 'Western' contexts. Future studies should seek to unpack potential cultural explanations for why Euro-Canadian outpatients may emphasize somatic symptoms in the presentation of anxiety to a greater degree than Chinese outpatients. PMID- 21794925 TI - Differentiating men and women with schizophrenia according to their cognitive profiles. PMID- 21794926 TI - Lifespan attention deficit/hyperactivity disorder and borderline personality disorder symptoms in female patients: a latent class approach. AB - Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are frequently comorbid. To contribute to a better understanding of the associations regularly found between ADHD and BPD, on the one hand, and the developmental pathways for these disorders, on the other hand, latent class analyses (LCA) were undertaken to identify classes differing in profiles of childhood symptoms of ADHD and adult symptoms of ADHD and BPD. Diagnostic interviews with 103 female outpatients meeting the criteria for ADHD and/or BPD were used to assess current DSM-IV symptoms; childhood symptoms of ADHD were assessed in parent interviews. The latent classes were examined in relation to the DSM-IV conceptualizations of ADHD and BPD. And relations between childhood and adult classes were examined to hypothesize about developmental trajectories. LCA revealed an optimal solution with four distinct symptom profiles: only ADHD symptoms; BPD symptoms and only ADHD symptoms of hyperactivity; BPD symptoms and ADHD symptoms of inattention and hyperactivity; BPD symptoms and ADHD symptoms of inattention, hyperactivity and impulsivity. All patients with BPD had some ADHD symptoms in both adulthood and childhood. Hyperactivity was least discriminative of adult classes. Adult hyperactivity was not always preceded by childhood hyperactivity; some cases of comorbid ADHD and BPD symptoms were not preceded by significant childhood ADHD symptoms; and some cases of predominantly BPD symptoms could be traced back to combined symptoms of ADHD in childhood. The results underline the importance of taking ADHD diagnoses into account with BPD. ADHD classification subtypes may not be permanent over time, and different developmental pathways to adult ADHD and BPD should therefore be investigated. PMID- 21794927 TI - The chicken leukocyte receptor cluster. AB - Receptors of the immunoglobulin-like superfamily are critically involved in virtually every aspect of immune responses. One large chromosomal area encoding such immunoregulatory receptors is the leukocyte receptor cluster. Here we review various aspects of the chicken Ig-like receptor (CHIR) family, located on microchromosome 31, an orthologous position to the mammalian leukocyte receptor cluster. The CHIR family has been massively expanded with over hundred CHIR genes that are further distinguished into activating, inhibitory and bifunctional receptors. Comparisons of various features such as amino acid motifs, genomic structure, expression and associated adaptor molecules reveal the homology of CHIR to both the killer Ig-like and the leukocyte Ig-like receptor families, with most pronounced correlation of certain CHIR to the NK cell receptor KIR2DL4. To date the CHIR ligands remain largely obscure with the exception of CHIR-AB1 that binds to chicken IgY. Detailed analyses of CHIR-AB1, its crystal structure, the interaction to IgY and functional capabilities allow us to draw conclusions regarding Fc receptor phylogeny and function. PMID- 21794928 TI - Detection of elevated antibodies against SR protein kinase 1 in the serum of Alzheimer's disease patients. AB - Autoantibodies targeting specific cellular antigens are often present in sera and cerebrospinal fluids (CSFs) of patients with Alzheimer's disease (AD) and could play a role in the onset and/or progression of the disease. In this study we identified SR Protein Kinase 1 (SRPK1) as a new autoantigen elevated in AD. SRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, cell proliferation, chromatin structure, nuclear import and germ cell development. Using an ELISA assay, anti-SRPK1 antibodies, targeting mainly the first catalytic domain of the kinase, were detected in sera of patients with AD, at significantly elevated levels as compared to control subjects. The findings of this study document for the first time the existence of antibodies targeting SRPK1 in human sera and are indicative of a correlation between the levels of a SRPK1 antibodies and the incidence of AD. PMID- 21794929 TI - Microparticles: targets and tools in cardiovascular disease. AB - Cells communicate with other cells not only via direct cell-cell contact and the production of signaling molecules but also through release of microparticles (MPs). MPs are small vesicles released from stimulated and/or apoptotic cells. They harbor membrane proteins that are characteristic of the original parent cell and intracellular components involved in cell signaling. MPs are considered to be both biomarkers and effectors of cell signaling that maintain and/or initiate cell dysfunction. Thus, MPs can evoke endothelial dysfunction by decreasing nitric oxide (NO) production and promoting vascular inflammation which favor the prothrombotic state in atherosclerosis. Novel pharmacological approaches targeting MP production or properties could be used to treat cardiovascular pathologies. Paradoxically, another useful approach might be to employ engineered MPs with modified compositions as therapeutic agents to correct cardiovascular pathologies. This review is focused on the mechanisms of MP formation and their effects on target cells under physiological or pathophysiological conditions. PMID- 21794930 TI - Severity of injuries associated with falls in the community dwelling elderly are not affected by fall characteristics and physical function level. AB - Many elderly people experience difficulty with independent living after injuries associated with falls. This study aimed to examine the influence of fall characteristics and physical function level on the severity of fall related injuries. The surveys were conducted in 1955 community dwelling elderly. The questions regarded the following: fall experience within the past year, fall direction, fall cause, injured parts and degree of injury, and an activity of daily living (ADL) questionnaire from the Ministry of Education, Culture, Sports, Science and Technology Japan. Data of 1850 subjects with available and complete responses were used for analysis. Three hundred and eighty-six (20.9%) elderly people experienced a fall within the past year and 257 (66.7%) were injured. ADL score was significantly higher in the elderly without fall experience than the elderly with fall experience. No significant difference was found in frequency of fall cause and fall direction between the elderly with and without injuries caused by falling. Significant correlations were found between fall direction and fall cause and injured parts (phi=0.49 and 0.32). ADL score of the elderly who fell by leg backlash was significantly lower than that of the elderly who fell by tripping, slipping and staggering. A decrease of ADL affects the rate of falls in the elderly, but not the degree of injury. Fall characteristics may not be related to the extent of fall injury. PMID- 21794931 TI - Intramyocardial transplantation of human adipose-derived stromal cell and endothelial progenitor cell mixture was not superior to individual cell type transplantation in improving left ventricular function in rats with myocardial infarction. AB - BACKGROUND: Both adipose-derived stromal cells (ASCs) and endothelial progenitor cells (EPCs) have high potential for promoting tissue revascularization and functional recovery in acute myocardial infarction (AMI) models. We investigated the functional effects of intramyocardial transplantation of a human ASC and EPC mixture in immunodeficient rats after MI. METHODS: MI was induced by ligating left anterior descending coronary artery. Survived rats were randomly assigned to 1 of 4 different groups: the control group (n=10, saline in 100MUL), the ASC group (n=10, 10(6) ASCs), the EPC group (n=10, 10(6) EPCs), or the ASC+EPC group (n=10, 2*10(5) ASCs+8*10(5) EPCs). Left ventricular (LV) function was compared using echocardiography during the 28-day follow-up. GAP43+ nerve sprouting and smooth muscle alpha-actin+angiogenesis were also compared. RESULTS: Serial changes in LV ejection fraction (EF) and fractional shortening revealed significant increases in the ASC, EPC, and ASC+EPC groups when compared to the control group during the follow-up (49+/-3%, 49+/-4%, 47+/-4%, 39+/-2%, P<0.001, respectively for LVEF) (33+/-4%, 32+/-2%, 31+/-2%, 23+/-2%, P=0.002, respectively for fractional shortening). The number of alpha-actin+arterioles and GAP43+ nerve area was significantly greater in the ASC, EPC, and ASC+EPC groups when compared to the control group in the peri-infarct area (34.4+/-1.0/mm(2), 35.9+/ 1.1/mm(2), 35.3+/-0.9/mm(2), 17.4+/-0.7/mm(2), P<0.001, respectively for angiogenesis) (346.2+/-10.7MUm(2)/mm(2), 357.2+/-12.8MUm(2)/mm(2), 368.0+/ 9.7MUm(2)/mm(2), 174.6+/-7.9MUm(2)/mm(2), P<0.001, respectively for nerve sprouting). CONCLUSIONS: [corrected] Intramyocardial injections of ASCs, EPCs, or ASCs+EPCs are effective modalities for the treatment of myocardial damage in rats and may expand the potential clinical application of ASC or EPC therapy in patients with ischemic heart disease. PMID- 21794932 TI - Elective Impella Recover LP 5.0 utilization for postcardiotomy low-output syndrome after aortic valve replacement. PMID- 21794933 TI - The pathophysiology of heart failure with preserved ejection fraction: from molecular mechanisms to exercise haemodynamics. AB - The pathophysiology of HfpEF is complex. In this review we discuss the molecular aspects of HfpEF as well as the profoundly disturbed haemodynamics with particular focus on exercise haemodynamic abnormalities. PMID- 21794934 TI - Macrophages overexpressing VEGF target to infarcted myocardium and improve neovascularization and cardiac function. AB - BACKGROUND: Clinical trials of vascular endothelial growth factor (VEGF) gene therapy have proven that VEGF has beneficial effects on the ischemic heart disease; however, the lack of a delivery system targeted to the injured myocardium reduces the local therapeutic efficacy of VEGF and increases its possible adverse effects. This study was performed to determine if macrophages transfected with human VEGF165 could incorporate into blood vessels and target to ischemic myocardial tissue to induce neovascularization and improve cardiac function. METHODS: Macrophages, macrophages transfected with hVEGF165 or phosphate buffered saline (PBS) were injected intravenously into the mice immediately after coronary artery ligation. Seven days after myocardial infarction (MI), protein expression of VEGF in border zone tissue was quantified by Western blot, and the location of the injected cells was determined by immunofluorescence. Twenty-eight days after MI, capillary density and cardiac function were measured. RESULTS: The level of VEGF expression in the mice injected with macrophages overexpressing VEGF was much higher than that in the mice injected with macrophages or PBS (p<0.01for both). Macrophages transfected with hVEGF165 could incorporate into the blood vessels. Furthermore, injection of macrophages overexpressing VEGF significantly augmented capillary density and improved cardiac function. CONCLUSIONS: Macrophages transfected with hVEGF165 incorporate into blood vessels and act as a carrier of VEGF that can target ischemic myocardial tissue and contribute to neovascularization and improve cardiac function. PMID- 21794935 TI - A conceptual paradigm of heart failure and systems biology approach. AB - PURPOSE OF REVIEW: The understanding of heart failure syndrome is increased and the interpretation of the related underlying mechanisms is improved by the integrated molecular, network and phenotype analyses of systems biology methodology. Heart failure can be explained as a complex, unstable, adaptive and self-organized biological phenomenon with intrinsic regulatory mechanisms. RECENT FINDINGS: The systems biology approach, that synthesizes information from biological molecules and networks involved in heart failure progression, leads from the regulatory modules of natriuretic peptide system and RAAS, to a more comprehensive network-based biological system with clinical significance. This kind of biological and clinical analysis of heart failure is based: a) in three fields of research or disciplines, modeling, omics and complex networks, and b) in the two directions of systems biology, functional composition (bottom-up direction) and functional decomposition (top-down direction). SUMMARY: This systems biology approach, with a new conceptual paradigm of heart failure progression and mechanisms, is explaining the physiological and pathological conditions of heart failure with an integrated and more meaningful method. PMID- 21794936 TI - Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography. AB - BACKGROUND: Elevated plasma level of asymmetric dimethylarginine (ADMA) was reported to be associated with endothelial dysfunction and atherosclerotic risk factors. We assessed the prognostic value of plasma ADMA levels in 997 consecutive individuals referred for coronary angiography from July 2006 to June 2009. METHODS: ADMA was measured by high performance liquid chromatography. All subjects were followed for a median period of 2.4years for the occurrence of all cause mortality, major adverse cardiovascular events (MACE, defined as cardiovascular death, non-fatal myocardial infarction and stroke), and MACE plus clinically-driven target vessel revascularization (TVR). RESULTS: Plasma ADMA levels were significantly higher in patients with significant coronary artery disease (CAD) (>=50% stenosis, n=655) than those with insignificant CAD (20-50% stenosis, n=272) and normal coronary artery (<20% stenosis, n=70) (0.47+/ 0.10MUmol/l vs 0.44+/-0.10MUmol/l vs 0.42+/-0.08MUmol/l, p <0.001). By multivariate analysis, plasma ADMA level was identified as a significant independent risk factor of significant CAD (OR: 1.29, 95% CI: 1.10-1.50; p=0.002). Moreover, multivariate Cox regression analysis showed that, comparing with the ADMA tertile I, the highest ADMA tertile was a significant independent predictor for all adverse long-term clinical outcomes. Notably, plasma ADMA level remained associated with the long-term outcomes in non-diabetic individuals, but not in those with diabetes (interaction p=0.04 for MACE plus TVR). CONCLUSIONS: Our findings suggest that elevated plasma ADMA level might be a risk factor of significant CAD, and might predict worse long-term clinical outcomes in subjects referred for cardiac catheterization, especially in non-diabetic individuals. PMID- 21794937 TI - Short QT and dilated cardiomyopathy. A phenotype with a good prognosis? PMID- 21794938 TI - Aspirin resistance in cerebrovascular patients. PMID- 21794939 TI - C-reactive protein is released in the coronary circulation and causes endothelial dysfunction in patients with acute coronary syndromes. AB - BACKGROUND: C-reactive protein (CRP) plasma levels correlate with cardiovascular events. Although a direct role for CRP in atherothrombosis has been suggested, at the moment little is known about its involvement in the pathophysiology of acute coronary syndromes (ACS). Thus, the aim of this study was to determine whether CRP is produced in the culprit lesion and released within the coronary circulation of patients with ACS and whether it may affect coronary endothelial function. METHODS: Blood samples were simultaneously obtained from the aorta (Ao) and the coronary sinus (CS) of patients with normal coronary artery (n=16), stable angina (n=30), and ACS (n=29) for later measurement of plasma CRP levels. Endothelium-dependent and -independent coronary vasodilation were evaluated by means of a Doppler Flow Wire in response to the increasing intracoronary doses of acetylcholine and adenosine, respectively. RESULTS: CRP plasma levels were significantly higher across the coronary circulation only in ACS patients with the culprit lesion located in the left coronary artery, while no differences between CS and Ao CRP plasma levels were observed in all other groups. Transcardiac CRP levels were correlated with impairment in coronary endothelium dependent vasodilation. In six additional patients (SA=3 and ACS=3), subjected to coronary atherectomy, real-time quantitative PCR revealed presence of CRP mRNA only in unstable plaques. CONCLUSIONS: Thus, CRP is produced and released within the coronary circulation of patients with ACS; this is associated with impairment of endothelial function, suggesting a new pathophysiological link between CRP and ACS. PMID- 21794940 TI - Is multidetector computed tomography a suitable alternative to MR imaging for the assessment of myocardial necrosis after alcohol septal ablation? AB - BACKGROUND: To compare magnetic resonance (MR) imaging and multidetector computed tomography (MDCT) for the assessment of myocardial infarction (MI) after alcohol septal ablation (ASA). METHODS: Ten patients (mean age, 60 years +/- 16) were examined with both MDCT and 1.5-T MR imaging performed 10 minutes after injection, within 3 days after ASA. Half of them had a temporary pacemaker (PM) during MDCT examination. Global image quality (IQ) and localization of MI were noticed on both MDCT and MR images. Volumes of MI, contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) were also calculated. ASA effectiveness was evaluated by echocardiography immediately and 3 months after procedure. RESULTS: Global IQ was considered adequate for both procedures. In 8 patients, MI reached the basal part of the septum on both MDCT and MR images. The 2 remaining patients exhibited sparing of the basal septum on MDCT and MR images. Volumes of MI were within the same range with the 2 techniques (MDCT: 22.1 +/- 8.8 mL; MR imaging: 23.8 +/- 9.4 mL) and correlated well each other (R(2)=0.85, p<0.002). The 2 patients with sparing of the basal interventricular septum had persistent gradient on echocardiography 3 months after ASA, suggesting failure of the procedure. The volumes of MI didn't correlate with the reduction of pressure gradient on echocardiography 3 months after ASA (R(2)=0.02, p<0.05). CONCLUSIONS: Evaluation of post ASA MI is feasible with MDCT by comparison with MR imaging. MDCT might serve as an alternative imaging method in case of PM implantation. PMID- 21794941 TI - Efficient H2 production via Chlamydomonas reinhardtii. AB - Molecular hydrogen (H(2)) obtained from biological sources provides an alternative to bulk chemical processes that is moving towards large-scale, economical generation of clean fuel for automotive engines. This opinion article examines recent improvements in H(2) production by wild and mutant strains of Chlamydomonas reinhardtii - the green microalga currently considered the best eukaryotic H(2) producer. Here, we review various aspects of genetic and metabolic engineering of C. reinhardtii, as well as of process engineering. Additionally, we lay out possible scenarios that would lead to more efficient research approaches in the near future, as part of a consistent strategy for sustainable biohydrogen supply. PMID- 21794942 TI - A stochastic approach for integrating strain variability in modeling Salmonella enterica growth as a function of pH and water activity. AB - Strain variability of the growth behavior of foodborne pathogens has been acknowledged as an important issue in food safety management. A stochastic model providing predictions of the maximum specific growth rate (MU(max)) of Salmonella enterica as a function of pH and water activity (a(w)) and integrating intra species variability data was developed. For this purpose, growth kinetic data of 60 S. enterica isolates, generated during monitoring of growth in tryptone soy broth of different pH (4.0-7.0) and a(w) (0.964-0.992) values, were used. The effects of the environmental parameters on MU(max) were modeled for each tested S. enterica strain using cardinal type and gamma concept models for pH and a(w), respectively. A multiplicative without interaction-type model, combining the models for pH and a(w), was used to describe the combined effect of these two environmental parameters on MU(max). The strain variability of the growth behavior of S. enterica was incorporated in the modeling procedure by using the cumulative probability distributions of the values of pH(min), pH(opt) and a(wmin) as inputs to the growth model. The cumulative probability distribution of the observed MU(max) values corresponding to growth at pH 7.0-a(w) 0.992 was introduced in the place of the model's parameter MU(opt). The introduction of the above distributions into the growth model resulted, using Monte Carlo simulation, in a stochastic model with its predictions being distributions of MU(max) values characterizing the strain variability. The developed model was further validated using independent growth kinetic data (MU(max) values) generated for the 60 strains of the pathogen at pH 5.0-a(w) 0.977, and exhibited a satisfactory performance. The mean, standard deviation, and the 5th and 95th percentiles of the predicted MU(max) distribution were 0.83, 0.08, and 0.69 and 0.96h(-1), respectively, while the corresponding values of the observed distribution were 0.73, 0.09, and 0.61 and 0.85h(-1). The stochastic modeling approach developed in this study can be useful in describing and integrating the strain variability of S. enterica growth kinetic behavior in quantitative microbiology and microbial risk assessment. PMID- 21794943 TI - HIV testing in Europe: mapping policies. AB - OBJECTIVES: In the absence of treatment and in the context of discrimination, HIV testing was embedded within exceptional procedures. With increasing treatment effectiveness, early HIV diagnosis became important, calling for the normalization of testing. National HIV testing policies were mapped to explore the characteristics and variations across European countries. METHODS: Key informants within the health authorities of all EU/EEA countries were questioned on HIV testing policies, which were assessed within a conceptual framework and the level of exceptionalism and normalization was scored based on defined attributes. RESULTS: Twenty-four out of 31 countries participated in the survey. Policies tended to support confidential voluntary testing, informed consent, and counselling. In the majority of countries, specific groups were targeted for provider-initiated testing. Taking together all attributes of HIV testing, 14 countries obtained a high score for exceptionalism, while only 3 achieved a high score on normalization. Italy, Lithuania and Romania had primarily exceptional procedures; Norway leant more towards normalization; Netherlands, the United Kingdom, and Denmark scored high in both. CONCLUSIONS: In most EU/EEA countries, policies are integrating HIV testing in health care settings, through voluntary and targeted testing strategies. Current HIV testing policies exhibited a high level of exceptionalism with varying degrees of normalization. Further research should compare HIV testing policies with practices. PMID- 21794944 TI - Polycomb group proteins: repression in 3D. AB - Polycomb group (PcG) proteins are well-conserved chromatin factors that repress the transcription of their target genes. They bind to the genome at specific sites and act on chromatin through the regulation of both post-translational histone modifications and higher-order chromatin structure. Recent work has revealed that PcG-bound regulatory regions can interact with promoters and modulate their activity via mechanisms involving looping between regulatory elements and also long-distance interactions in cis or in trans (on different chromosomes). This indicates that the 3D organization of PcG proteins contributes significantly to their function. Moreover, because long-range chromosomal contacts have been shown to involve many genomic loci in addition to Polycomb target genes, their regulatory impact could extend beyond the function of Polycomb proteins. PMID- 21794945 TI - Global cellular changes induced by Legionella pneumophila infection of bone marrow-derived macrophages. AB - The nucleotide-binding oligomerization domain (Nod)-like receptor (NLR) family member Naip5 plays an essential role in restricting Legionella pneumophila growth inside primary macrophages. Upon interaction with bacterial flagellin, the intracellular receptor Naip5 forms a multi-protein complex, the inflammasome, which activation has a protective role against infection. The A/J mouse strain carries a Naip5 allele (Naip5(A/J)), which renders its macrophages susceptible to Legionella infection. However, Naip5(A/J) is still competent for inflammasome activation suggesting that an as yet unidentified signaling pathway located downstream of Naip5 and defective in Naip5(A/J) macrophages regulates macrophage defenses against Legionella. Therefore, transcriptional profiling experiments with macrophages from C57BL/6J mice (B6), and from congenic mice (BcA75) carrying the partial loss-of-function A/J-derived allele (Naip5(A/J)) on a B6 background, infected or not with wild-type L. pneumophila or flagellin-deficient mutant were carried out to identify genes regulated by flagellin and by Naip5. Both the Legionella infection per se and the presence of flagellin had very strong effects on transcriptional responses of macrophages, 4h following infection, including modulation of cellular pathways associated with inflammatory response and cell survival. On the other hand, the presence of wild type or partial loss of function allele (Naip5(A/J)) at Naip5 did not cause large effects on transcriptional responses of macrophages to infection. We also examined in L. pneumophila infected macrophages, the effect of Naip5 alleles on expression and phosphorylation of 524 phosphoproteins, kinases and phosphatases involved in cell proliferation, immune response, stress and apoptosis. Naip5 alleles had an effect on the TLR-Il1R signaling pathway, the cell cycle and the caveolin-mediated response to pathogen. The results of transcriptome and proteome analyses were organized into cellular pathways in macrophages that are modulated in response to Legionella infection. PMID- 21794946 TI - FtsZ degradation in the cyanobacterium Anabaena sp. strain PCC 7120. AB - In prokaryotes, cell division is normally achieved by binary fission, and the key player FtsZ is considered essential for the complete process. In cyanobacteria, much remains unknown about several aspects of cell division, including the identity and mechanism of the various components involved in the division process. Here, we report results obtained from a search of the players implicated in cell division, directly associating to FtsZ in the filamentous, heterocyst forming cyanobacterium Anabaena sp. PCC 7120. Histidine tag pull-downs were used to address this question. However, the main observation was that FtsZ is a target of proteolysis. Experiments using various cell-free extracts, an unrelated protein, and protein blot analyses further supported the idea that FtsZ is proteolytically cleaved in a specific manner. In addition, we show evidence that both FtsZ termini seem to be equally prone to proteolysis. Taken together, our data suggest the presence of an unknown player in cyanobacterial cell division, opening up the possibility to investigate novel mechanisms to control cell division in Anabaena PCC 7120. PMID- 21794947 TI - Identification of calcium stress induced genes in amaranth leaves through suppression subtractive hybridization. AB - Calcium (Ca(2+)) is a critical ion for the growth and development of plants and plays an important role in signal transduction pathways in response to biotic and abiotic stresses. We investigated the Ca(2+) stress responsive-genes in amaranth leaves by using the suppression subtractive hybridization technique. Screening of the libraries generated 420 up-regulated transcripts and 199 down-regulated transcripts. The differentially expressed transcripts were associated with general stress response, transcription factors, gene regulation, signal transduction, and some other with unknown function. Selected genes were used to study their differential regulation by sqRT-PCR. Among the up-regulated transcripts, a fragment containing the motif of C3HC4-type RING-Zinc family was further characterized. The ORF of amaranth zinc finger protein (AhZnf) has a closer relationship with its ortholog from Ricinus communis while is distantly related to the Arabidopsis thaliana C3HC4-type ortholog. We have identified a novel putative zinc finger protein along with other novel proteins such as the wall associated kinase, phosphoinositide binding protein, and rhomboid protease involved in response to Ca(2+) stress in amaranth leaves. PMID- 21794948 TI - Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dube syndrome not linked to the FLCN locus. AB - BACKGROUND: Previously, we proposed that familial multiple trichodiscomas (OMIM 190340) is distinct from Birt-Hogg-Dube syndrome (BHD) (OMIM #135150). BHD is characterized by multiple fibrofolliculomas/trichodiscomas, lung cysts, pneumothorax, and renal cell cancer. Germline FLCN mutations can be detected in most but not all BHD families. OBJECTIVE: We sought to evaluate familial multiple trichodiscomas at a clinical and genetic level. We now renamed this condition "familial multiple discoid fibromas" (FMDF) to emphasize the distinction from BHD. METHODS: In 8 additional families with an autosomal dominant pattern of multiple discoid fibromas we assessed the clinical findings and the histopathological features of skin lesions. FLCN germline mutation analysis was completed in 7 families. In two of these families segregation analysis was performed using polymorphic DNA markers in and around the FLCN locus. RESULTS: The clinical findings in FMDF are different from those in BHD with early onset of skin lesions, prominent involvement of the pinnae, and discoid fibromas without the follicular epithelial component characteristic of the fibrofolliculoma/trichodiscoma spectrum of BHD. In addition, there were no evident pulmonary or renal complications. In none of the families were pathogenic FLCN germline mutations identified. Using segregation analysis we could exclude involvement of the FLCN locus in the two kindreds tested. LIMITATIONS: The prevalence of FMDF is presently unknown. The underlying gene defect has not yet been identified. CONCLUSIONS: FMDF is clinically distinct from BHD and is not linked to the FLCN locus. PMID- 21794949 TI - Everyday hearing functioning in unilateral versus bilateral hearing aid users. AB - PURPOSE: The purpose of the present study was to assess hearing functioning in everyday listening situations of bilateral and unilateral hearing aid (HA) users. METHOD: 80 Arabic-speaking HA users: 46 bilateral and 34 unilateral HA users with various degrees of HL. Participants completed the Speech, Spatial, and Qualities (SSQ) self-report questionnaire. RESULTS: In general, bilateral users performed better than unilateral users on the speech and spatial scales. For participants with symmetrical unaided HL, the bilateral group significantly surpassed the unilateral group on all three scales. For participants with asymmetrical unaided HL, no significant intergroup differences emerged. Regarding degree of HL, the moderate HL group outperformed the severe, and profound HL groups. No differences emerged between the severe and profound groups. Finally, more severe HL correlated with poorer SSQ performance. Similarly, better speech discrimination scores correlated with better SSQ performance. CONCLUSION: Results support the need for subjective questionnaires when assessing HA benefits. PMID- 21794950 TI - A Clostridium difficile infection "intervention": change in toxin assay results in fewer C difficile infection cases without changes in patient outcomes. AB - BACKGROUND: Clostridium difficile infection (CDI) is most commonly diagnosed using toxin enzyme immunoassays (EIAs). A sudden decrease in CDI incidence was noted after a change in the EIA used at Barnes-Jewish Hospital in St Louis. The objective of this study was to determine whether the decreased CDI incidence related to the change in EIA resulted in adverse patient outcomes. METHODS: Electronic hospital databases were used to collect data on demographics, outcomes, and treatment of inpatients who had a C difficile toxin assay performed between January 4, 2009, and April 3, 2009 (period A, preassay change) and between May 21, 2009, and August 17, 2009 (period B, postassay change). RESULTS: Assays were positive in 240 of 1,221 patients (19.7%) during period A and in 106 of 1160 patients (9.1%) during period B (P < .01). There was no difference in mortality or discharge to hospice between the 2 periods (10.3% vs 10.1%; P = .90). Patients tested in period B were less likely to receive metronidazole or oral vancomycin (P < .01). CONCLUSIONS: The new EIA resulted in fewer positive tests and reduced anti-CDI therapy. There was no difference in mortality between the 2 periods, suggesting that the decreased incidence was due to increased assay specificity, not decreased sensitivity. PMID- 21794951 TI - No evidence of substantia nigra telomere shortening in Parkinson's disease. AB - Telomeres are repetitive tracts of DNA which protect chromosomal integrity. Increased oxidative stress leads to shorter telomeres, which have been associated with several late-onset human diseases. Given independent evidence of oxidative stress and Parkinson's disease (PD), and conflicting reports of the role of telomere length in PD, we measured telomere length in both PD peripheral blood monocytes and in substantia nigra from affected individuals and controls. We confirmed previous findings of a paradoxically longer telomere length in blood from PD patients, but found no difference in telomere length in substantia nigra. Confounding factors provide a likely explanation for the findings in blood, and possibly the reduced frequency of cigarette smoking in PD patients. We conclude that telomere shortening is unlikely to be involved in the pathogenesis of PD. PMID- 21794952 TI - Altered intrinsic neuronal excitability and reduced Na+ currents in a mouse model of Alzheimer's disease. AB - Transgenic mice that overproduce beta-amyloid (Abeta) peptides can exhibit central nervous system network hyperactivity. Patch clamp measurements from CA1 pyramidal cells of PSAPP and wild type mice were employed to investigate if altered intrinsic excitability could contribute to such network hyperfunction. At approximately 10 months, when PSAPP mice have a substantial central nervous system Abeta load, resting potential and input resistance were genotype independent. However, PSAPP mice exhibited a substantially more prominent action potential (AP) burst close to the onset of weak depolarizing current stimuli. The spike afterdepolarization (ADP) was also larger in PSAPP mice. The rate of rise, width and height of APs were reduced in PSAPP animals; AP threshold was unaltered. Voltage-clamp recordings from nucleated macropatches revealed that somatic Na(+) current density was depressed by approximately 50% in PSAPP mice. K(+) current density was unaltered. All genotype-related differences were absent in PSAPP mice aged 5-7 weeks which lack a substantial Abeta load. We conclude that intrinsic neuronal hyperexcitability and changes to AP waveforms may contribute to neurophysiological deficits that arise as a consequence of Abeta accumulation. PMID- 21794953 TI - Aging impairs the control of prefrontal cortex on the release of corticosterone in response to stress and on memory consolidation. AB - This study investigated the role of the dorsomedial prefrontal cortex (dmPFC) on the activity of the hypothalamus-pituitary-adrenal axis and memory consolidation in young and aged rats. The messenger RNA (mRNA) expression of several gamma aminobutyric acid (GABA) and glutamate receptor subunits were also evaluated in the prefrontal cortex (PFC) of young and aged rats. Microinjections of picrotoxin (GABA(A) antagonist), muscimol (GABA(A) agonist), or vehicle were performed into the dmPFC of young adult (3 months) and aged (27 months) male Wistar rats. Plasma corticosterone was measured under acute stress (30-minute restraint) conditions following microinjections. The retention of an inhibitory avoidance response was also evaluated in response of the same treatments. Picrotoxin microinjections into the dmPFC reduced the stress-induced corticosterone concentrations on young but not on aged animals. Aging did not modify the mRNA content of any of the receptor subunits analyzed. Picrotoxin into the dmPFC reduced inhibitory avoidance response in young but not aged animals. Muscimol treatment did not modify any of the parameters evaluated. These results suggest that prefrontal cortex loses its capacity to control hypothalamo-pituitary-adrenal (HPA) axis activity and the consolidation of emotional memory during aging. PMID- 21794955 TI - Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson's disease. AB - Histamine is a central neurotransmitter degraded by histamine-N-methyltransferase (HNMT). Several abnormalities in the histaminergic system were found in patients with Parkinson's disease (PD), thus we tested the possible association of a Thr105Ile functional polymorphism in HNMT with PD. A total of 913 patients with PD and 958 controls were genotyped using a TaqMan RT-PCR Genotyping Assay (Foster City, California, USA). Lower frequency of HNMT Ile105 allele that is associated with decreased enzymatic activity was found in patients compared with controls (chi(2) = 11.65; p = 0.0006). We performed meta-analysis to confirm the association of Thr105Ile functional polymorphism with PD. Our results indicate that lower HNMT activity plays a role in the pathogenesis of PD. PMID- 21794954 TI - Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. AB - Alzheimer's disease (AD) and other tauopathies are characterized by fibrillar inclusions composed of the microtubule-associated protein, tau. Recently, we demonstrated that the N-terminus of tau (amino acids [aa] 2-18) in filamentous aggregates or N-terminal tau isoforms activate a signaling cascade involving protein phosphatase 1 and glycogen synthase kinase 3 that results in inhibition of anterograde fast axonal transport (FAT). We have termed the functional motif comprised of aa 2-18 in tau the phosphatase-activating domain (PAD). Here, we show that phosphorylation of tau at tyrosine 18, which is a fyn phosphorylation site within PAD, prevents inhibition of anterograde FAT induced by both filamentous tau and 6D tau. Moreover, Fyn-mediated phosphorylation of tyrosine 18 is reduced in disease-associated forms of tau (e.g., tau filaments). A novel PAD specific monoclonal antibody revealed that exposure of PAD in tau occurs before and more frequently than tyrosine 18 phosphorylation in the evolution of tangle formation in AD. These results indicate that N-terminal phosphorylation may constitute a regulatory mechanism that controls tau-mediated inhibition of anterograde FAT in AD. PMID- 21794956 TI - Contribution of the portable gamma camera to detect the sentinel node in breast cancer during surgery. AB - AIM: To show our experience using the portable gamma camera during surgery in the detection of the sentinel node in breast cancer. MATERIAL AND METHODS: A total of 46 women diagnosed with breast cancer were included. This study was carried out by means of the periareolar intradermal injection. Planar images and SPECT/CT were acquired. On the following day, the sentinel nodes were localized intraoperatively with a portable gamma camera and a gamma probe. Images of the anterior axillary line projection and lateral axillary line projection were acquired before and after extraction of all the sentinel nodes. RESULTS: The images acquired with the portable gamma-camera during the operation showed no activity in all of the patients after the removal of the sentinel nodes. In four out of the 46 cases, the portable gamma camera provided relevant information during the procedure (it detected a sentinel node in two cases in which it had not been detected prior to the surgery and it oriented the surgeon in the localization of low activity nodes when the probe screening had been negative). CONCLUSIONS: The use of the intraoperative portable gamma camera to detect the sentinel node in breast cancer patients is useful in order to ensure, independently of the surgeon, that all the sentinel nodes have been removed. It can also help guide the surgeon in the event of a single low activity sentinel node. PMID- 21794957 TI - Current status of the use of 18F-sodium fluoride in bone disease. PMID- 21794958 TI - Bicephalic amphiphile architecture affects antibacterial activity. AB - A series of cationic amphiphiles, each with an aromatic core, was prepared and investigated for antimicrobial properties. The synthesized amphiphiles in this study are bicephalic (double-headed) in that they each possess two trimethylammonium head groups and a single linear alkoxy tail. Minimum inhibitory and minimum bactericidal concentrations of these amphiphiles were in the low micromolar range. Antimicrobial activities are highly sensitive to the chain length of the hydrophobic region, and modestly reliant on the relative positioning of the head groups on the aromatic core. These trends were more pronounced in time kill assays, wherein longer chain compounds required significantly shorter times to completely kill bacteria. Microscopy suggested that the mode of cell death was lysis. Strong inhibition was observed with both biscationic compounds and monocationic comparisons against Gram-positive bacteria; only biscationic amphiphiles maintained good activity versus the Gram negative bacteria tested. These observations provide direction for future antimicrobial structural investigations. PMID- 21794959 TI - Synthesis and studies of novel 2-(4-cyano-3-trifluoromethylphenyl amino)-4 (quinoline-4-yloxy)-6-(piperazinyl/piperidinyl)-s-triazines as potential antimicrobial, antimycobacterial and anticancer agents. AB - A series of novel s-triazine analogs were synthesized and characterized by IR, (1)H NMR, (13)C NMR, (19)F NMR spectroscopy and elemental analysis. Preliminary screening of target compounds against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneria), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv indicated that 5d, 5h, 5n, 5p, 5q, 5r, 5s, 5t and 5u were the most active compounds among twenty one studied. Thus, they were further subjected to in vitro biological evaluation against human prostate cancer cell line (DU-145) and the results indicate that two compounds 5n and 5s were markedly active. PMID- 21794960 TI - Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors. AB - The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells. PMID- 21794961 TI - Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities. AB - A series of novel fluconazoliums were synthesized and their bioactive evaluation as potential antibacterial and antifungal agents were described. Some target compounds displayed good and broad-spectrum antimicrobial activities with low MIC values ranging from 0.25 to 64 MUg/mL against all the tested strains, including three Gram-positive bacteria (Staphylococcus aureus, MRSA and Bacillus subtilis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Bacillus proteus) as well as two fungi (Candida albicans and Aspergillus fumigatus). Among all tested title compounds, the octyl, dichlorobenzyl, naphthyl and naphthalimino derivatives gave comparable or even better antibacterial and antifungal efficiency in comparison with the reference drugs Fluconazole, Chloromycin and Norfloxacin. PMID- 21794962 TI - Prediction of post-treatment trismus in head and neck cancer patients. AB - Our aim was to establish the incidence of trismus over time, together with risk factors (including quality of life (QoL)) for the prediction of trismus after treatment in patients with cancer of the head and neck. It was a longitudinal study of 152 patients accepted for primary operation who attended the head and neck cancer clinic of a tertiary referral cancer centre in the United Kingdom. A total of 87 patients was studied prospectively. Our results showed that 41/87 (47%) of patients presented with trismus, 57/80 (71%) had postoperative trismus, and 41/52 (79%) had trismus 6 months after operation or radiotherapy (trismus defined as a maximum mouth opening of <= 35 mm). Men and those who drank a lot of alcohol were less likely to have trismus after treatment. QoL variables showed that pain, eating, chewing, taste, saliva, social functioning, social contact, and dry mouth were significantly more impaired in the trismus group than among those without trismus. Postoperative differences in QoL between the two groups highlighted problems with social function and role-playing, fatigue, activity, recreation, and overall reduction in QoL. Women, and those who do not drink alcohol, are at particularly high risk of developing trismus, and, to prevent it and treat it, patients may benefit from multidisciplinary management at an early stage during treatment. PMID- 21794963 TI - The nasolabial approach: a potential alternative to the lip-splitting incision for maxillectomy. AB - First described by Weber and later modified by Fergusson, the Weber-Fergusson incision has undergone numerous modifications, but the fundamental approach to maxillectomy has largely remained the same. We report the potential benefit of a nasolabial incision for partial maxillectomy. The incision is hidden within the nasolabial fold and obviates the need for division of the upper lip, which may undergo atrophy and shortening after radiotherapy. PMID- 21794964 TI - Wound healing differences between Yorkshire and red Duroc porcine medial collateral ligaments identified by biomechanical assessment of scars. AB - BACKGROUND: Currently, there are no large animal models to assess potential genetic contributions to ligament biomechanics during an injury repair response. Yorkshire and red Duroc pigs display phenotypically and genetically different skin wound healing responses; red Duroc skin scars were hyper-contracted and hyper-pigmented, whereas Yorkshire skin scars were not. Such findings raise the question whether connective tissues of synovial joints display a similar differential healing response in these pig breeds. This study assessed medial collateral ligament healing in Yorkshire and red Duroc pigs at the functional (biomechanical) level. METHODS: Surgical injury was created in the right hind limb medial collateral ligament of Yorkshire and red Duroc pigs. After 10 weeks of healing, low-load (laxity and creep) and high-load (failure) mechanical properties were measured. FINDINGS: Large, complete ligament scars formed by 10 weeks post-injury. A differential healing response was observed between the breeds, where red Duroc ligament scars had larger cross-sectional areas, exhibited greater static and total creep responses, failed at greater deformations and strains (P <= 0.05), and failed with strong trends for higher loads and lower moduli (P=0.06) than Yorkshire ligament scars. INTERPRETATION: The ligament healing response of red Duroc pigs differs from Yorkshire pigs. Previously observed breed differences in dorsal skin wound healing are not restricted to skin. Such findings support a genetic basis for breed differences in response to connective tissue injury. Since this animal model is physiologically comparable to humans, these findings could provide further insight into identification of specific genetic contributions to ligament repair in human populations. PMID- 21794965 TI - Transtibial prosthetic socket pistoning: static evaluation of Seal-In((r)) X5 and Dermo((r)) Liner using motion analysis system. AB - BACKGROUND: The method of attachment of prosthesis to the residual limb (suspension) and socket fitting is a critical issue in the process of providing an amputee with prosthesis. Different suspension methods try to minimize the pistoning movement inside the socket. The Seal-In((r)) X5 and Dermo((r)) Liner by Ossur are new suspension liners that intend to reduce pistoning between the socket and liner. Since the effects of these new liners on suspension are unclear, the objective of this study was to compare the pistoning effect of Seal In((r)) X5 and Dermo((r)) Liner by using Vicon Motion System. METHODS: Six transtibial amputees, using both the Iceross Seal-In((r)) X5 and the Iceross Dermo((r)) Liner, participated in the study. The vertical displacement (pistoning) was measured between the liner and socket in single limb support on the prosthetic limb (full-weight bearing), double limb support (semi-weight bearing), and non-weight bearing on the prosthetic limb, and also under three static vertical loading conditions (30 N, 60 N, and 90 N). FINDINGS: The results demonstrated that the pistoning within the socket when Seal-In((r)) X5 was used, decreased by 71% in comparison to the Iceross Dermo((r)) Liner. In addition, a significant difference between the two liners under different static conditions was found (p<0.05). INTERPRETATION: Participants needed to put in extra effort for donning and doffing the prosthesis with Seal-In((r)) X5; however, this type of liner provided less pistoning. The new approach that uses the motion analysis system in this study might be an alternative for measuring the pistoning effect in the prosthetic socket. PMID- 21794966 TI - Approach to the evaluation of a patient with an increased serum osmolal gap and high-anion-gap metabolic acidosis. AB - An increase in serum osmolality and serum osmolal gap with or without high-anion gap metabolic acidosis is an important clue to exposure to one of the toxic alcohols, which include methanol, ethylene glycol, diethylene glycol, propylene glycol, or isopropanol. However, the increase in serum osmolal gap and metabolic acidosis can occur either together or alone depending on several factors, including baseline serum osmolal gap, molecular weight of the alcohol, and stage of metabolism of the alcohol. In addition, other disorders, including diabetic or alcoholic ketoacidosis, acute kidney injury, chronic kidney disease, and lactic acidosis, can cause high-anion-gap metabolic acidosis associated with an increased serum osmolal gap and therefore should be explored in the differential diagnosis. It is essential for clinicians to understand the value and limitations of osmolal gap to assist in reaching the correct diagnosis and initiating appropriate treatment. In this teaching case, we present a systematic approach to diagnosing high serum osmolality and increased serum osmolal gap with or without high-anion-gap metabolic acidosis. PMID- 21794967 TI - Labeling of mental disorders and stigma in young people. AB - Mental disorders are common in young people, yet many do not seek help. The use of psychiatric labels to describe mental disorders is associated with effective help-seeking choices, and is promoted in community awareness initiatives designed to improve help-seeking. However these labels may also be coupled with stigmatizing beliefs and therefore inhibit help-seeking: lay mental health or non specific labels may be less harmful. We examined the association between labeling of mental disorders and stigma in youth using data from a national telephone survey of 2802 Australians aged 12-25 years conducted from June 2006 to August 2006. Label use and stigmatizing beliefs were assessed in response to vignettes of a young person experiencing depression, psychosis or social phobia. Logistic regressions examined the association between a range of labels commonly used, including psychiatric labels, and a range of stigma components. There were no significant associations between label use and the stigma components of "stigma perceived in others", "reluctance to disclose" and for the most part "social distance". Most mental health labels were associated with seeing the person as "sick" rather than "weak" and accurate psychiatric labels had the strongest effect sizes. However, for the psychosis vignette, the "dangerous/unpredictable" component was predicted by the labels "schizophrenia/psychosis", "mental illness" and "psychological problem", and the accurate psychiatric label showed the strongest association. For all vignettes, generic lay labels were not associated with stigma, but also rarely had a counter stigma effect. These findings suggest that the use of accurate psychiatric labels by young people is seldom associated with stigma and may assist young people by reducing perceptions of weakness. However, community education that promotes accurate labeling of psychosis should proceed with caution and address beliefs about dangerousness and unpredictability. PMID- 21794968 TI - Vulnerability to fat-stigma in women's everyday relationships. AB - Obesity is understood as a major medical and public health challenge, but the stigma attached to it also creates extraordinary suffering. The pervasiveness of morally negative views toward the overweight and obese, such as laziness and lack of self-control, are undeniable in mainstream U.S. society, situated both institutionally (such as health care barriers or media stereotypes) and interpersonally (such as the negative comments of others). To test basic pathways related to the etiology of women's vulnerability to feeling "fat-stigma" in interpersonal relationships, we present a study conducted between August and November 2009 that combines social network, anthropometric, body image, and interview data for 112 women aged 18-45 years, living in Phoenix, Arizona, U.S., and linked follow-up interviews with 823 of their social ties. Based on the proposition that some social network characteristics should amplify the personal experience of stigma, and others should ameliorate it, we ask: what relationship qualities make women more sensitive to the judgments of others about their weight? We find that what others say about women has only a very limited influence on how women judge others' negative views of their weight once actual body size is taken into account, but that women are more influenced by the opinions of those they are closer to and interact with more often. Ultimately, the degree to which women perceive themselves to be judged by others regarding their weight is not well explained by the actual opinions of people in their networks, either known or unknown to them. The assumption that social network norms exert considerable influence on people's stigma experiences needs to be carefully evaluated, at least in the domain of overweight and obesity. PMID- 21794969 TI - Socioeconomic status and depression across Japan, Korea, and China: exploring the impact of labor market structures. AB - This study explores the effects of socioeconomic status on depression in Japan, Korea, and China, focusing on the differences in their labor market structures. Comparative studies among East Asian societies allow researchers studying depression to analyze the effects of unique institutions within each society while holding constant, to a certain extent, cultural attitudes toward mental disorders. This study uses data from National Family Research of Japan 2003, Korean National Family Survey 2003, and Family Survey of China 2006 to examine the effects of education and labor market positions on depression. The results show that the relationship between socioeconomic status and depression differs among the three societies. In Japan, the type of employment contract has a significant impact on depression, while in Korea, higher educational attainment negatively relates to depression. In China, the type of work organization has a significant impact on depression. Based on these results, two types of labor market structures, aimed at differentiating the relationship between socioeconomic status and depression, are delineated: labor markets with a secured sector, and flexible labor markets. PMID- 21794970 TI - On the automaticity of emotion processing in words and faces: event-related brain potentials evidence from a superficial task. AB - The degree to which emotional aspects of stimuli are processed automatically is controversial. Here, we assessed the automatic elicitation of emotion-related brain potentials (ERPs) to positive, negative, and neutral words and facial expressions in an easy and superficial face-word discrimination task, for which the emotional valence was irrelevant. Both emotional words and facial expressions impacted ERPs already between 50 and 100 ms after stimulus onset, possibly reflecting rapid relevance detection. Following this initial processing stage only emotionality in faces but not in words was associated with an early posterior negativity (EPN). Therefore, when emotion is irrelevant in a task which requires superficial stimulus analysis, automatically enhanced sensory encoding of emotional content appears to occur only for evolutionary prepared emotional stimuli, as reflected in larger EPN amplitudes to faces, but not to symbolic word stimuli. PMID- 21794971 TI - Chronic infective endarteritis due to Propionibacterium acnes on aortic prosthetic graft. PMID- 21794972 TI - Rescuing A Patient In Deteriorating Situations (RAPIDS): an evaluation tool for assessing simulation performance on clinical deterioration. AB - AIM: This article is a report of a study which developed and tested the validity and reliability of the RAPIDS-Tool to measure student nurses' simulation performance in assessing, managing and reporting of clinical deterioration. BACKGROUND: The importance for nurses to recognize and respond to deteriorating patients has led educators to advocate for increasing use of simulation for developing this competency. However, there is a lack of evaluation tools to objectively evaluate nurses' simulation performance on clinical deterioration. METHOD: The study was conducted in three phases. Phase 1 began with development of items for the RAPIDS-Tool from the basis of a literature review and a panel of national experts' consensus. Phase 2 established the content validity of the RAPIDS-Tool by a panel of international experts and by undertaking a pilot test. Phase 3 involved testing the psychometric properties of the RAPIDS-Tool, on 30 video-recorded simulation performances, for construct validity, inter-rater reliability, and correlation between two scoring systems. RESULTS: The process of development and validation produced a 42-item RAPIDS-Tool. Significant differences (t=15.48, p<0.001) in performance scores among participants with different levels of training supported the construct validity. The RAPIDS-Tool demonstrated a high inter-rater reliability (ICC=0.99) among the three raters and a high correlation between the global rating and checklist scores (r=0.94, p<0.001). CONCLUSION: The RAPIDS-Tool provides a valid and reliable tool to evaluate nurses' simulation performances in clinical deterioration. This may prove useful for future studies that investigate outcomes of simulation training. PMID- 21794973 TI - Utilization of calcite and waste glass for preparing construction materials with a low environmental load. AB - In this study, porous calcite materials are hydrothermally treated at 200 degrees C using powder compacts consisting of calcite and glasses composed of silica-rich soda-lime. After treatment, the glasses are converted into calcium aluminosilicate hydrates, such as zeolite phases, which increase their strength. The porosity and morphology of new deposits of hydrothermally solidified materials depend up on the chemical composition of glass. The use of calcite and glass in the hydrothermal treatment plays an important role in the solidification of calcite without thermal decomposition. PMID- 21794974 TI - Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer. AB - BACKGROUND: Cigarette smoking is the most well-established risk factor for developing bladder cancer. OBJECTIVE: To investigate the role of smoking status on the clinical outcome of patients with non-muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Data obtained during a prospective phase 3 study with three schedules of epirubicin were used for statistical analysis. Smoking status (obtained when entering the study), other prognostic variables, and clinical outcome measures of 718 patients were analyzed. Mean follow-up was 2.5 yr. MEASUREMENTS: The primary outcome measure was recurrence-free survival (RFS). RESULTS AND LIMITATIONS: Demographics were similar for nonsmokers versus ex-smokers and current smokers, except for gender (p<0.001) and grade (p=0.022). In univariate analyses, RFS was significantly shorter in male patients (p=0.020), in patients with a history of recurrences (p<0.003), in patients with multiple tumors (p<0.004), in patients with a history of intravesical therapy (p=0.037), and in ex-smokers and current smokers (p=0.005). In multivariate analyses, a history of recurrences, multiplicity, and smoking status remained significant factors for predicting RFS. Gender and initial therapy were no longer a significant influence on RFS. Because progression was uncommon (n=25) and follow up was short and focused only on recurrences, no conclusion can be drawn on progression-free survival. A limitation of the study were the questionnaires. They were only used when entering the study, and there were no questions about passive smoking and other causal factors. CONCLUSIONS: In this prospective study, the significance of known factors (history of recurrences and number of tumors) in predicting RFS was confirmed. Another significant factor that appears to predict RFS is smoking status: ex-smokers and current smokers had a significantly shorter RFS compared with nonsmokers. PMID- 21794975 TI - S-allylmercaptocysteine effectively inhibits the proliferation of colorectal cancer cells under in vitro and in vivo conditions. AB - S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has been demonstrated as a suppressive agent against some tumors. The effects of SAMC on the proliferation and metastasis of colorectal cancer (CRC) under in vitro and in vivo conditions were evaluated here. The viabilities and migrations of CRC cells SW480, SW620, Caco-2 treated with SAMC were measured by MTT, scratch-wound, and transwell assays. The in vivo anticancer effect of SAMC against luciferase-expressing SW620 xenografts in mice was determined by bioluminescence imaging and histopathology observation. The apoptosis of SAMC treated CRC cells was examined by Western blotting. The results demonstrate that SAMC could effectively suppress the growth and metastasis of colorectal cancer cells both in vivo and in vitro. The anticancer effect of SAMC was related to the decreased proliferation and increased apoptosis as well as necrosis of cancer cells. Oral administration of SAMC in the quantity/concentration used had no apparent toxic side effect on the vital organs of the experimental mice. Taken together, the proliferation and metastasis of CRC cells can be significantly suppressed by SAMC treatment under both in vitro and in vivo conditions. SAMC may thus be a promising candidate for CRC chemotherapy. PMID- 21794976 TI - Resveratrol inhibits the epidermal growth factor-induced epithelial mesenchymal transition in MCF-7 cells. AB - Carcinoma progression is associated with the loss of epithelial features, and the acquisition of a mesenchymal phenotype by tumour cells. Herein we show that exposure of MCF-7 cells to epidermal growth factor (EGF) resulted in morphological alterations characteristic of epithelial-to-mesenchymal transition (EMT). EGF treatment resulted in increased motility along with an up-regulation of transcription factors Slug, Zeb1, Zeb2, and mesenchymal markers Vimentin and N cadherin. Treatment of MCF-7 cells with a combined stimulation of EGF and resveratrol, a naturally occurring stilbene with antitumor properties, failed to alter cell morphology, motility and overexpression of EMT markers induced by EGF. Using specific chemical inhibitors, we demonstrated that EGF-induced EMT is mediated by extracellular signal-regulated kinase 1/2 (ERK 1/2) signalling pathway and that resveratrol is able to repress EGF-induced ERK activation. In summary, these data provide new evidence of the inhibitory effect of resveratrol on EGF-induced EMT cell transformation. PMID- 21794977 TI - 3D Bi12TiO20/TiO2 hierarchical heterostructure: synthesis and enhanced visible light photocatalytic activities. AB - A three-dimensional (3D) multicomponent oxide, Bi(12)TiO(20)/TiO(2) hierarchical heterostructure was successfully synthesized via a one-step and template-free hydrothermal route. X-ray diffraction and X-ray photoelectron spectroscopy measurements confirm that the composition of the as-fabricated sample is Bi(12)TiO(20)/TiO(2) composite. Scanning and transmission electron microscopy observation reveals that the as-synthesized sample is microsized flower-like hierarchical networks consisted of Bi(12)TiO(20) nanorods decorated with the primary TiO(2) nanoparticles. Extension of the light absorption from the ultraviolet region to the visible-light region was confirmed by UV-vis absorption spectra. Due to the structure-property relationships, the 3D Bi(12)TiO(20)/TiO(2) heterostructure exhibited enhanced visible photocatalytic activity over that of Bi(12)TiO(20) and TiO(2) samples in the decomposition of Rhodamine B in water which is a typical model pollutant. The enhanced photocatalytic activity can be attributed to the extended absorption in the visible light region resulting from the 3D Bi(12)TiO(20)/TiO(2) heterostructures, and the effective separation of photogenerated carriers driven by the photoinduced potential difference generated at the Bi(12)TiO(20)/TiO(2) junction interface, demonstrating that the Bi(12)TiO(20)/TiO(2) heterostructure is a promising candidate as a visible light photocatalyst. PMID- 21794978 TI - Effects of engineered nano-titanium dioxide on pore surface properties and phosphorus adsorption of sediment: its environmental implications. AB - Understanding the environmental safety and human health implications of engineered nanoparticles (ENPs) is of worldwide importance. As an important ENPs, engineered nano-TiO(2) (Enano-TiO(2)) may have been substantially deposited in aquatic sediments because of its widely uses. Sediment pore surface properties would be thus significantly influenced due to the large surface area of Enano TiO(2). In this study, Enano-TiO(2) was found to greatly impact on sediment pore surface properties. The attachment of Enano-TiO(2) particles to sediment surfaces enhanced markedly BET specific surface area and t-Plot external specific surface area, and thereby increased sediment phosphorus (P) adsorption maximum (S(max)). Contrarily, the fill of Enano-TiO(2) particles into the micropores of sediments could significantly reduce t-Plot micropore specific surface area, and cause slight decrease in sediment P binding energy (K). Clearly, P sorbed in sediment would be easily released because of the decreasing P binding energy of the sediment with elevated Enano-TiO(2). Enano-TiO(2) would thus cause aggravated endogenous pollution in water if such sediment was re-suspended on disturbance. The results obtained in this study contribute to our increasing knowledge of how to regulate physicochemical behavior of pollutants in sediments under the influences of Enano-TiO(2) and/or similar ENPs. PMID- 21794979 TI - Theoretical investigation on the inclusion of TCDD with beta-cyclodextrin by performing QM calculations and MD simulations. AB - The rapid enrichment and detection of trace polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are currently challenging issues in the field of environmental science. In this paper, by performing quantum chemistry (QM) calculations and molecular dynamics (MD) simulations, we studied the inclusion complexation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a representative PCDD molecule, with beta-cyclodextrin (beta-CD), one of the widely used compounds in supramolecular chemistry. The calculated results reveal that the stable inclusion complex can be formed in both the gas phase and solvent, which proposes that beta-CD may serve as a potential substrate enriching TCDD. The calculated vibrational spectra indicate that the infrared (IR) and Raman spectroscopy may be suitable for the detection of beta-CD-modified TCDD. The present theoretical results may be informative to environmental scientists who are devoting themselves to developing effective methods for detection and treatment of POPs. PMID- 21794980 TI - Enhanced performance of a submerged membrane bioreactor with powdered activated carbon addition for municipal secondary effluent treatment. AB - The aim of this study was to investigate the feasibility of PAC-MBR process treating municipal secondary effluent. Two laboratory-scale submerged MBRs (SMBR) with and without PAC addition were continuously operated in parallel for secondary effluent treatment. Approximately 63%TOC, 95% NH(4)(+)-N and 98% turbidity in secondary effluent were removed by the PAC-MBR process. Most organics in the secondary effluent were found to be low molecular weight (MW) substances, which could be retained in the reactor and then removed to some extent by using PAC-MBR process. Parallel experiments showed that the addition of PAC significantly increased organic removal and responsible for the largest fraction of organic removal. Membrane fouling analysis showed the enhanced membrane performance in terms of sustainable operational time and filtration resistances by PAC addition. Based on these results, the PAC-MBR process was considered as an attractive option for the reduction of pollutants in secondary effluent. PMID- 21794981 TI - Characteristics of diethylenetriamine-crosslinked cotton stalk/wheat stalk and their biosorption capacities for phosphate. AB - Two polymeric biosorbents were prepared from cotton stalk (CS) and wheat straw (WS) by the epichlorohydrin-diethylenetriamine-trimethylamine method. Amine crosslinked cotton stalk (AC-CS) and wheat stalk (AC-WS) were used for the adsorption of phosphate, and their physicochemical properties as well as biosorption properties for phosphate were discussed intensively. Results indicated that the contents of holocellulose in CS and WS corresponded to the distinct phosphate adsorption capacities between AC-CS and AC-WS. Zeta potential and Raman spectra analysis illustrated the electrostatic attraction between phosphate ions and biosorbents. The adsorption of phosphate was not strongly pH dependent when the pH was about 4.0-9.0. The Langmuir isotherm provided the better fit and the maximum adsorption capacity (Q(max)) was 51.54 mg/g for AC-CS and 60.61 mg/g for AC-WS. The saturated adsorption capacities of AC-CS and AC-WS in column were 49.05 and 41.9 mg/g, which accounted for about 80.3% and 81.4% of these biosorbents'Q(max). NaCl and HCl solutions demonstrated the excellent regeneration capacities for the biosorbents, and after three times of adsorption desorption cycles, the column adsorption capacities of these biosorbents were still higher than 92%. PMID- 21794982 TI - Synthesis and application of chloromethylated polystyrene modified with 1-phenyl 1,2-propanedione-2-oxime thiosemicarbazone (PPDOT) as a new sorbent for the on line preconcentration and determination of copper in water, soil, and food samples by FAAS. AB - In this paper, we report a simple and sensitive on-line solid phase extraction system for the preconcentration and determination of Cu(II) by flame atomic absorption spectrometry (FAAS). This method is based upon the on-line retention of copper at pH 5.0 on a minicolumn packed with chloromethylated polystyrene modified by 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone (PPDOT) as a new solid-phase extraction (SPE) sorbent. The retained Cu(II) ions were eluted with 1.0M HNO(3), and transported directly to FAAS for determination. Several chemical and flow variables were studied and optimized for a quantitative preconcentration and determination of copper(II). At the optimized conditions, for preconcentration of 10.0 mL of a sample solution, a linear calibration graph was obtained over the concentration range of 3.00-120.0 MUg L(-1) for Cu(II). The limit of detection (3sigma), limit of quantification (10sigma), and enrichment factor are 0.56 MUg L(-1), 2.0 MUg L(-1) and 41, respectively. The relative standard deviation (n = 6) at 20 MUg L(-1) of Cu(II) is 2.0%. This method could be applied for determination of trace amounts of Cu(II) in water, soil, and food samples with satisfactory results. PMID- 21794983 TI - Modelling inorganic biocide emission from treated wood in water. AB - The objective of this work is to develop a chemical model for explaining the leaching behaviour of inorganic biocides from treated wood. The standard leaching test XP CEN/TS14429 was applied to a commercial construction material made of treated Pinus sylvestris (Copper Boron Azole preservative). The experimental results were used for developing a chemical model under PHREEQC((r)) (a geochemical software, with LLNL, MINTEQ data bases) by considering the released species detected in the eluates: main biocides Cu and B, other trace biocides (Cr and Zn), other elements like Ca, K, Cl, SO(4)(-2), dissolved organic matter (DOC). The model is based on chemical phenomena at liquid/solid interfaces (complexation, ion exchange and hydrolysis) and is satisfactory for the leaching behaviour representation. The simulation results confronted with the experiments confirmed the hypotheses of: (1) biocide fixation by surface complexation reactions with wood specific sites (carboxyl and phenol for Cu, Zn, Cr(III), aliphatic hydroxyl for B, ion exchange to a lesser extent) and (2) biocide mobilisation by extractives (DOC) coming from the wood. The maximum of Cu, Cr(III) and Zn fixation occurred at neutral pH (including the natural pH of wood), while B fixation was favoured at alkaline pH. PMID- 21794984 TI - Enantioselective degradation and unidirectional chiral inversion of 2 phenylbutyric acid, an intermediate from linear alkylbenzene, by Xanthobacter flavus PA1. AB - Microbial degradation of the chiral 2-phenylbutyric acid (2-PBA), a metabolite of surfactant linear alkylbenzene sulfonates (LAS), was investigated using both racemic and enantiomer-pure compounds together with quantitative stereoselective analyses. A pure culture of bacteria, identified as Xanthobacter flavus strain PA1 isolated from the mangrove sediment of Hong Kong Mai Po Nature Reserve, was able to utilize the racemic 2-PBA as well as the single enantiomers as the sole source of carbon and energy. In the presence of the racemic compounds, X. flavus PA1 degraded both (R) and (S) forms of enantiomers to completion in a sequential manner in which the (S) enantiomer disappeared much faster than the (R) enantiomer. When the single pure enantiomer was supplied as the sole substrate, a unidirectional chiral inversion involving (S) enantiomer to (R) enantiomer was evident. No major difference was observed in the degradation intermediates with either of the individual enantiomers when used as the growth substrate. Two major degradation intermediates were detected and identified as 3-hydroxy-2 phenylbutanoic acid and 4-methyl-3-phenyloxetan-2-one, using a combination of liquid chromatography-mass spectrometry (LC-MS), and (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy. The biochemical degradation pathway follows an initial oxidation of the alkyl side chain before aromatic ring cleavage. This study reveals new evidence for enantiomeric inversion catalyzed by pure culture of environmental bacteria and emphasizes the significant differences between the two enantiomers in their environmental fates. PMID- 21794985 TI - Nociceptive thresholds are controlled through spinal beta2-subunit-containing nicotinic acetylcholine receptors. AB - Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic transmission through spinal beta(2)-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in beta(2)(*)-knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that beta(2)(*)-nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic beta(2)(*)-nAChR control of mechanical nociceptive thresholds might implicate GABAergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the GABA(A) receptor antagonist bicuculline decreased the mechanical threshold in wild-type but not beta(2)(*)-KO mice, and the agonist muscimol restored basal mechanical threshold in beta(2)(*)-KO mice. Thus, beta(2)(*)-nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, beta(2)(*)-KO mice were also hyperresponsive to capsaicin induced C-fiber stimulation. Our results indicate that beta(2)(*)-nAChRs are implicated in the recruitment of inhibitory control of nociception, as shown by delayed recovery from capsaicin-induced allodynia, potentiated nociceptive response to inflammation and neuropathy, and by the loss of high-frequency transcutaneous electrical nerve stimulation (TENS)-induced analgesia in beta(2)(*)-KO mice. As high-frequency TENS induces analgesia through Abeta-fiber recruitment, these data suggest that beta(2)(*)-nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling through beta(2)(*)-nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord. PMID- 21794986 TI - Acaricidal activity of thymol on larvae and nymphs of Amblyomma cajennense (Acari: Ixodidae). AB - The aim of the present study was to evaluate the acaricidal efficacy of thymol on unengorged and engorged larvae and engorged nymphs of Amblyomma cajennense. To perform the test for unengorged larvae, the larval packet technique was employed and mortality was evaluated 24h after the test, while for engorged larvae and engorged nymphs the immersion technique was employed and mortality was evaluated after 15 days. In all the experiments, the following concentrations of thymol were tested: 2.5, 5.0, 10.0, 15.0 and 20.0mg the thymol/ml. The control group was exposed to water and 1% DMSO and there were 10 repetitions for each treatment. The values found for mortality of unengorged larvae were 18.2%, 51.8%, 97.6%, 93.5% and 94.5%, and for engorged nymphs the values were 26.0%, 92.2%, 100.0%, 100.0%, 100.0%, in concentrations of 2.5, 5.0, 10.0, 15.0 and 20.0mg of thymol/ml, respectively. In the test with engorged larvae, mortality was 100.0% in all treatments. Based on the results, it is possible to conclude that thymol has acaricidal activity against immature stages of A. cajennense. PMID- 21794987 TI - Transitions between tobacco and cannabis use among adolescents: a multi-state modeling of progression from onset to daily use. AB - Use of a given substance may follow a stage process leading from onset to regular use, and use of one substance can be strongly associated with use of another. The aim of this study was to describe the transitions between tobacco and cannabis use. Data was derived from a French nationwide survey involving 29,393 teenagers. A homogenous Markov multi-state model (MSM) was fitted. The substance use pattern modeled was: no lifetime use->1 (2) substance(s) initiation->1 (2) daily substance(s) use, with pathways between tobacco and cannabis. The likelihood of first initiating tobacco appeared 17.6 times greater than the likelihood of initiating cannabis. Once a subject has experimented with one substance, the risk of another substance experiment was much greater. Transition intensity from tobacco initiation to daily use was 4.8 times higher than that from cannabis. Our results are compatible with a process mixing the gateway theory, the reverse gateway theory and the route of administration model, but do not explore a common liability to addictions, which could be explored by using a MSM on a prospective cohort with initial collection of some explanatory factors. PMID- 21794988 TI - Biochemical basis of circadian rhythms and diseases: With emphasis on post traumatic stress disorder. AB - Circadian rhythms affect several processes in the body physiology. This commentary revisits the topic of 'metabolic basis of diseases' with a view to shed light on how cellular energy requirements feed-forward to a sequential signaling of hormonal response, blood glucose metabolism, antioxidant activities, and pathophysiology. Attempt is made to explain how diseases that may not appear to be closely related, such as bone metabolism and vasculopathy, have an increase in oxidative damage as a common underlying biochemistry. Importantly, this article identifies oxidative damage as an outcome of sleep disturbance and hypothesize that sleep complaint is not merely one of many resulting symptoms of PTSD, but a core feature that arise from trauma and gives rise to the stress biochemistry, which in turn manifests symptomatically. Further, we suggest that the current non-pharmacologic and pharmacologic therapeutic options attenuate oxidative stress. Implication for clinical diagnosis and evaluations is also suggested. PMID- 21794989 TI - The role of the sociotype in managing chronic disease: integrating bio-psycho sociology with systems biology. AB - THE PROBLEM: Attempts have been made to replace the bio-medical approach with that of systems biology, which considers dynamic human behavior (internal factors) for chronic (rather than acute) disease management. They have not yet incorporated the Bio-psycho-social (BPS) model of Engel which adds patients' background and cultural beliefs (external factors) contributing to their susceptibility to, and coping strategies for, non-communicable diseases (NCDs) the increasing domain of global Public Health. The problem is how to include the social determinants of disease in a comprehensive model of care, especially in the management of chronic disease. THE SOLUTION HYPOTHESIS: The concept of "sociotype" is proposed as a framework for understanding the interactions between the social, cultural and environmental inputs that influence the growth, development and life-long behavior of a person, including relationships, lifestyle and coping strategies. Pre-/peri-natal influences on development and subsequent susceptibility to chronic disease are examples of interactions between the sociotype, genotype and phenotype. Disorders of the sociotype, encompassing social determinants (e.g. poverty, education, networking), of disease are major contributors to the increase in NCDs, as well as for mental illness and absenteeism. Thus, people are the product of a threefold cord--genotype, phenotype and sociotype. WHAT NEXT?: Holistic management of patients through the BPS model have to be aligned with the relevant elements of systems biology- context, space, time and robustness--that pertain to the sociotype. Medical curricula should balance basic sciences with disciplines such as psychology, sociology, anthropology and public health that attempt to explain human behavior and the social determinants of disease. This requires methodologies combining qualitative and quantitative research to study simultaneous interactions (and their possible mechanisms) between systems biology and the BPS model. The neologism "sociotype" highlights the importance of the social dimension of the BPS model in a novel and useful way. The sociotype, with its effects on genotype and phenotype, will bring psychosocial variables into a paradigm of medical practice to promote health and improve the management of chronic illness. PMID- 21794990 TI - Factors associated with patient satisfaction. AB - PURPOSE: This investigation tested the null hypothesis that psychological factors have no effect on patient satisfaction in a hand and upper limb practice. METHODS: The Center for Epidemiologic Studies Depression Scale, the Pain Catastrophizing Scale, and the Disabilities of the Arm, Shoulder, and Hand questionnaire were administered to 248 new patients presenting to a hand and upper limb practice. After the appointment, the treating physician was asked to rate the patient's uneasiness with his or her symptoms. The Consumer Assessment of Health Care Providers and Systems questionnaire was mailed to patients 2 weeks after their visit. A total of 178 patients returned this questionnaire. RESULTS: There were small but significant correlations between (1) depression and perception of how well the doctor (a) listens carefully, (b) gives easy-to understand instructions, and (c) spends enough time; (2) pain catastrophizing and the degree to which doctor gives enough information about a procedure; and (3) the doctor's perception of inordinate patient concern and (a) the impression that the doctor gives easy-to-understand explanations, (b) the impression that the doctor listens carefully, (c) the impression that the doctor gives enough information about surgical procedures, and (d) the patient's overall rating of the doctor. In multivariable models, the doctor's perception of disproportionate uneasiness was the only significant predictor of "doctor gave enough information" and "doctor listened carefully." CONCLUSIONS: In this study, the provider's sense that the patient was disproportionately uneasy with his or her symptoms was the only significant predictor of patient satisfaction, and this accounted for a small percentage of the variance in responses to these items. Patient satisfaction is complex, and the divide between medical advice and a patient's expectations are not easily reduced to one or more disease-specific or patient specific factors. PMID- 21794991 TI - Can intranasal drug use reduce HCV infection among injecting drug users? AB - BACKGROUND: Preventing HCV infection among people who inject drugs is a difficult public health challenge. We examined the potential role of intranasal drug use in reducing HCV acquisition. METHODS: Subjects were recruited from IDUs entering the Beth Israel drug detoxification program from 2005 to 2010. A structured interview was administered and serum samples were collected for HCV testing. RESULTS: 726 active injecting drug users were recruited from 2005 to 2010. HCV prevalence was 71%, 90% reported recent heroin injection and 44% reported recent intranasal heroin use. In a multiple logistic regression analysis, being HCV seropositive was associated with more years injecting, Latino ethnicity, previous testing for HCV, and recent injection of speedball, and negatively associated with recent intranasal use of heroin (AOR=0.52, 95% CI 0.33-0.82) and intranasal use of speedball (AOR=0.41, 95% CI 0.31-0.80). The association between intranasal heroin use and lower HCV seroprevalance was observed among both new injectors and persons with long injecting histories (16+ years since first injection). CONCLUSION: Encouraging intranasal use as an alternative to injection among persons currently injecting drugs may be a viable strategy for reducing HCV transmission. PMID- 21794993 TI - Age-related distribution of longitudinal pre-strain in abdominal aorta with emphasis on forensic application. AB - It is a well-known fact that the length of an artery in situ and the length of an excised artery differs. Retraction of blood vessels is usually observed. This pre tension plays crucial role in arterial biomechanics. It augments an artery wall load-bearing capacity. This paper presents the longitudinal pre-strain of the human aorta as an index of human age. The length of abdominal aortas was measured during autopsies before and after segment resection. The longitudinal pre-strain was calculated in 130 donors; 100 male and 30 female bodies. The pre-strain was defined as the ratio between in situ length and the length after the excision. The mean pre-strain was found to be 1.18+/-0.10 for male and 1.14+/-0.10 for female sample (mean+/-standard deviation). The age in the male group was 41.6+/ 15.9 years; and 47.7+/-17.7 years in the female group. Statistical analysis revealed the correlation coefficient between age and pre-strain r=-0.821 and r= 0.839 in male and female group, respectively. The analysis also confirmed close correlation between aortic circumference and age; and between circumference and pre-strain. Linear and power law regression equations were employed and prediction intervals were computed. The power law estimates the age more accurately than linear one model. Nevertheless, especially for small values of the pre-strain (aged individuals) the linear model can be advantageous. PMID- 21794992 TI - Increased risk of Parkinson's disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. AB - BACKGROUND: Since methamphetamine and other amphetamine-type stimulants (meth/amphetamine) can damage dopaminergic neurons, researchers have long speculated that these drugs may predispose users to develop Parkinson's disease (PD), a dopamine deficiency neurological disorder. METHODS: We employed a retrospective population-based cohort study using all linked statewide California inpatient hospital episodes and death records from January 1, 1990 through December 31, 2005. Patients at least 30 years of age were followed for up to 16 years. Competing risks analysis was used to determine whether the meth/amphetamine cohort had elevated risk of developing PD (ICD-9 332.0; ICD-10 G20) in comparison to a matched population-proxy appendicitis group and a matched cocaine drug control group. Individuals admitted to hospital with meth/amphetamine-related conditions (n=40,472; ICD-9 codes 304.4, 305.7, 969.7, E854.2) were matched on age, race, sex, date of index admission, and patterns of hospital admission with patients with appendicitis conditions (n=207,831; ICD-9 codes 540-542) and also individuals with cocaine-use disorders (n=35,335; ICD-9 codes 304.2, 305.6, 968.5). RESULTS: The meth/amphetamine cohort showed increased risk of PD compared to both that of the matched appendicitis group [hazard ratio (HR)=1.76, 95% CI: 1.12-2.75, p=0.017] and the matched cocaine group [HR=2.44, 95% CI: 1.32-4.41, p=0.004]. The cocaine group did not show elevated hazard of PD compared to the matched appendicitis group [HR=1.04, 95% CI: 0.56-1.93, p=0.80]. CONCLUSION: These data provide evidence that meth/amphetamine users have above normal risk for developing PD. PMID- 21794994 TI - Aortic dissecting aneurysms--histopathological findings. AB - Acute aortic dissection is a life-threatening disease with a high rate of mortality. At the Institute of Legal Medicine of the Hanover Medical School, 30 cases with aortic dissections were found during autopsy and examined histologically between 2006 and 2009. The grade of medial alterations in the form of cystic medial necrosis, elastin fragmentation, fibrosis and medionecrosis were estimated semi-quantitatively. In order to assess the normal aging process, samples of the aortic wall of 25 decedents without dissecting aneurysms were analyzed histologically. This study demonstrates that there are partly quantitative differences, particularly with a statistically significant increase in cystic medial necrosis (p<0.001) and elastin fragmentation (p<0.001), between aortas from dissecting aneurysms and the normal aging aorta, which may help to identify genetically predisposed relatives of patients with a dissection of the aorta. PMID- 21794995 TI - Geranylgeranylacetone suppresses noise-induced expression of proinflammatory cytokines in the cochlea. AB - OBJECTIVE: Heat shock transcription factor 1 (HSF1) is a master regulator of heat shock response, and also inhibits expression of inflammatory cytokines directly or indirectly. Here, we examined effects of HSF1 activation on the expression of proinflammatory cytokines in mouse cochlea after exposure to noise. METHODS: Male CBA/N mice with normal Preyer's reflex were exposed to intense noise for 3h. Three hours after noise exposure, bilateral cochleae were removed and expression of major inflammatory cytokines was examined. RESULTS: We found that interleukin 6 (IL-6) and interleukin-1beta (IL-1beta) expression increased significantly after noise exposure, and the expression was suppressed significantly in mice administered with geranylgeranylacetone (GGA), which activates HSF1. Seven days after noise exposure, thresholds for auditory brainstem response were elevated, and GGA administration significantly suppressed this elevation. CONCLUSION: These results suggest that HSF1-mediated suppression of proinflammatory cytokines in the cochlea by GGA administration could be an important means of inner ear protection. PMID- 21794996 TI - Growth rate of lung cancer recognized as small solid nodule on initial CT findings. AB - INTRODUCTION: To study the characteristics of lung cancer, appearing as small solid nodules on initial computed tomography (CT) findings, and to determine an appropriate follow-up duration so as to differentiate between malignancy and benign tumor. METHODS: We analyzed the records of 34 patients who had undergone surgical resection of lung cancer, which appeared as small solid nodules on initial CT findings. We studied the CT findings, volume doubling times (VDT), follow-up durations, pathological and clinical findings. RESULTS: VDT is classified as follows: (1) slow growth group (SGG), with a VDT of more than 700 days and (2) rapid growth group (RGG), with a VDT of less than 700 days. The median VDT of the SGG was 1083 days, and the RGG was 256 days (p<0.01). The median duration for follow-up of the SGG was 1218 days, and 179 days for the RGG. A statistical difference was noted in the follow-up durations (p<0.01). There were no statistical differences in the preoperative thin-section CT (TSCT) findings, or in the pathological findings. The RGG included more patients with smoking histories. The CT findings of RGG tended to reveal changed in base lung field such as emphysema, and lung fibrosis. CONCLUSIONS: Generally, lung cancer appearing as small solid nodules on initial CT findings grew rapidly, but there were some cases which displayed slow growth patterns. These cases required follow up for over two years, before diagnosis was possible. We concluded the appropriate maximum followup duration is three years. PMID- 21794997 TI - Intraobserver and interobserver agreement of volume perfusion CT (VPCT) measurements in patients with lung lesions. AB - OBJECTIVES: To evaluate intraobserver and interobserver agreement of manually encompassed lung lesions for perfusion measurements using volume-perfusion computed tomography (VPCT). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. HIPAA guidelines were followed. A 65 s dynamic study was acquired with scan parameters 80 kV, 60 mAs (80 mAs for patients >= 70 kg), 128 * 0.6mm collimation. Blood flow (BF), blood volume (BV) and K(trans) parameters were determined by syngo volume perfusion CT body with 88 lesions analyzed retrospectively. RESULTS: Within-subject coefficients of variation for intraobserver agreement (range 6.59-12.82%) were superior to those for interobserver agreement (range 21.75-38.30%). Size-dependent analysis revealed lower agreements for lesions <4 cm as compared to larger lesions. Additionally, agreements of the upper, middle and lower lung zones were different. CONCLUSIONS: Intraobserver agreement was substantial for VPCT lung cancer perfusion measurements encouraging the use for tumor characterization and therapy response monitoring. Interobserver agreement is limited and unexperienced readers should be trained before using this new method. PMID- 21794998 TI - Study on the absolute configuration of levetiracetam via density functional theory calculations of electronic circular dichroism and optical rotatory dispersion. AB - Theoretical calculation of chiroptical properties has been a powerful tool for the absolute configuration assignment of chiral compounds including synthetic drugs and natural products. In the present work, time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) were employed to investigate the absolute configuration of levetiracetam, which is a widely used anticonvulsant drug. Nine conformers were generated by conformation search using the MMFF94 molecular mechanics force field, and the geometries were then optimized using the Becke 3 Lee-Yang-Parr (B3LYP) exchange-correlation functional. The population-averaged ECD spectrum was obtained by adding ECD spectrum of each conformer using Boltzmann statistics. The predicted ECD spectrum is in excellent agreement with the measured ECD spectrum of levetiracetam. Theoretical ORD spectra show the same tendency as the experimental data of levetiracetam, further confirming the absolute configuration derived from the ECD spectra. Our results demonstrated that the only chiral carbon atom of levetiracetam is unambiguously to be S configuration. PMID- 21794999 TI - Simultaneous determination of lidocaine hydrochloride, hydrocortisone and nystatin in a pharmaceutical preparation by RP-LC. AB - A liquid chromatographic (LC) method was developed to analyze a formulation (mouthwash) containing lidocaine hydrochloride, hydrocortisone and nystatin. A single LC method with UV detection was developed. A Waters Symmetry C18 HPLC column (150 mm * 4.6 mm, 5 MUm) was used as stationary phase and the assay was performed with gradient elution using mobile phases containing methanol - 0.1M NaH(2)PO(4) with a pH that was previously adjusted to 4.5 with dilute phosphoric acid. The sample pretreatment was performed by treating the formulation with methanol followed by filtration. After method development, the influence of the different chromatographic parameters on the separation, the interference of other active compounds and excipients, linearity, accuracy, repeatability and intermediate precision were investigated. The method was shown to be selective, linear, accurate, precise and repeatable. Finally, the content of the compounds in the formulation was determined. PMID- 21795000 TI - Determination and pharmacokinetics of DT-13 in rat plasma by LC-MS. AB - A sensitive and specific LC-MS assay for DT-13 in rat plasma was developed. DT-13 is an active steroidal saponin present in Liriopes Radix and is developed as an anti-tumor drug candidate. The samples were extracted by acetonitrile-mediated plasma protein precipitation. The chromatographic separation was carried out using a Ultimate C(18) column (250 mm * 4.6 mm, i.d., 5 MUm) with a mobile phase composed of acetonitrile: 5 mmol/L aqueous ammonium acetate (60:40, v:v). The method was validated and the specificity, linearity (r(2)=0.9980 within 10-1000 ng/mL), lower limit of quantitation (LLOQ, 10 ng/mL), precision (intra- and inter day <12.3%), accuracy (93.4-106.3%), recovery (91.0 +/- 4.7%) and stability were determined. The method was applied to the pharmacokinetic study of DT-13 in rat plasma after intravenous and intragastric administration. The results showed DT 13 underwent a prolonged absorption and slow elimination with a low oral bioavailability (5.51%) in rats. PMID- 21795001 TI - Development and validation of an ion-pair RP-HPLC method for the determination of oligopeptide-20 in cosmeceuticals. AB - Oligopeptide-20 is a growth-factor mimicking peptide used in cosmeceuticals. This article describes the development and validation of an ion-pair reversed-phase liquid chromatography method that allows, after liquid-liquid extraction, the quantification of oligopeptide-20 in cosmetic creams. Chromatographic separation was achieved on a cyanopropyl Hypersil analytical column (100 mm * 2.1 mm i.d., 5 MUm particle size), using a mobile phase of acetonitrile-heptafluorobutyric acid (pH=2.5, 9.0 mM) (70:30, v/v) containing 0.045% diethylamine at a flow rate of 0.50 mL min(-1). Ultraviolet (UV) spectrophotometric detection at 225 nm was used. The method had linear calibration curve over the range 1.35-4.95 MUg mL(-1) for oligopeptide-20. The intra- and inter-day RSD values were less than 3.3%, while the relative percentage error, %E(r), was less than 1.9. The developed method was applied successfully to the quality control of a cosmetic cream containing 0.003% (w/w) oligopeptide-20. PMID- 21795002 TI - Evaluation of the Biolog system for the identification of certain closely related Pasteurella species. AB - The zoonotic impact of Pasteurella species in human wounds caused by cats and dogs has increased recently. In this study, the effectiveness of the Biolog Microstation ID System (Biolog, Hayward, CA) for the identification of certain species of Pasteurella sensu stricto was analysed. Thirty-eight isolates originating from dogs and cats were studied by pheno- and genotypic methods. The classical biochemical tests identified these isolates as P. multocida, P. dagmatis, and P. canis, while the Biolog system distinguished only 2 categories: P. multocida and P. dagmatis. The sodA gene sequence-based phylogenetic analysis revealed that the isolates identified as P. dagmatis by the Biolog system were either P. dagmatis, P. canis, or P. dagmatis-like genomospecies. The low discrimination power of the Biolog system in the case of these closely related Pasteurella species draws attention to the need of continuously improving the database of automated microbial identification systems. PMID- 21795003 TI - Comparison of time to positivity of the VersaTREK(r) REDOX 80-mL and the REDOX EZ draw 40-mL blood culture bottles for common bacterial bloodstream pathogens. AB - The VersaTREK((r)) microbial detection system offers 2 media formulations, an aerobic and an anaerobic bottle available in a 40-mL direct draw format and an 80 mL format. The 40-mL EZ Draw((r)) bottle can be inoculated with a maximum volume of 5 mL, while the REDOX 80-mL bottle accommodates a 10-mL volume. The effect of volume of blood inoculum on time to positivity (TTP) has not been clearly established with these bottle types. This study utilized simulated blood cultures seeded with clinically relevant microorganisms in human blood to evaluate the impact of inoculum volume and organism load on TTP for the 2 bottle types. For 13/15 organisms, the EZ Draw bottle flagged positive earlier than the REDOX 80-mL bottles. The lower volume of blood inoculum did not negatively impact TTP using the EZ Draw blood culture bottles as compared to REDOX 80-mL bottles. PMID- 21795004 TI - Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome. AB - A recent report suggested an association between xenotropic murine leukemia virus related virus (XMRV) and chronic fatigue syndrome (CFS). If confirmed, this would suggest that antiretroviral therapy might benefit patients suffering from CFS. We validated a set of assays for XMRV and evaluated the prevalence of XMRV in a cohort of monozygotic twins discordant for CFS. Stored peripheral blood mononuclear cell (PBMC) samples were tested with 3 separate polymerase chain reaction (PCR) assays (one of which was nested) for XMRV DNA, and serum/plasma was tested for XMRV RNA by reverse transcription (RT)-PCR. None of the PBMC samples from the twins with CFS or their unaffected co-twins was positive for XMRV, by any of the assays. One plasma sample, from an unaffected co-twin, was reproducibly positive by RT-PCR. However, serum from the same day was negative, as was a follow-up plasma sample obtained 2 days after the positive specimen. These data do not support an association of XMRV with CFS. PMID- 21795005 TI - The diagnostic accuracy of tuberculosis real-time polymerase chain reaction analysis of computed tomography-guided bronchial wash samples. AB - We evaluated the diagnostic accuracy of real-time polymerase chain reaction (RT PCR) analysis of bronchoscopic wash specimens obtained using computed tomography (CT) guidance for diagnosis of pulmonary tuberculosis (TB) patients who were unable to produce sputum samples or were sputum smear-negative. Data from patients who had lesions likely to be pulmonary TB on CT images were analyzed retrospectively. Twenty-seven patients (23.1%) were diagnosed with definite pulmonary TB, and 72 patients (61.5%) were classified as not having TB. The sensitivity, specificity, positive predictive value, and negative predictive value of RT-PCR were 0.78 (95% CI, 0.57-0.91), 0.93 (95% CI, 0.84-0.97), 0.81 (95% CI, 0.60-0.93), and 0.92 (95% CI, 0.82-0.97), respectively. We concluded that most of the sputum-smear negative TB cases could be diagnosed microbiologically or ruled out rapidly and accurately by RT-PCR analysis of bronchial wash fluid. PMID- 21795006 TI - Medical consultations and the sharing of medical images involving spinal injury over mobile phone networks. AB - BACKGROUND: The transmission of medical images and other data over mobile phone networks may facilitate remote medical consultations between neurosurgeons and regional hospitals treating spinal injury patients. The aim of this study was to compare the efficacy of mobile phone consultations with standard hospital workstation consultations in spinal injury patients. METHODS: The images were exported over the Internet from surrounding local hospitals through the Picture Archiving and Communication System, in DICOM III format, to the central hospital server. The xVision browser was used to view the acquired images on a standard workstation. The data were also exported to the secured hospital Web server IIS60 and converted to JPEG format to enable remote physician access and consultation. The remote consulting physician connected to this server by mobile phone using the phone's Internet browser. A second physician, blind to the mobile phone results, evaluated the same images at a workstation in the hospital. The results of the mobile phone consultations were compared with the results from standard workstation consultations. RESULTS: There was no difference in the quality of spinal computed tomographic/magnetic resonance images viewed on the phone screen compared with on the workstation. More importantly, the final diagnoses made by mobile phone did not differ from those made by workstation consultations. A transfer to the department of neurosurgery was required after consultation in 11 patients. CONCLUSION: Mobile phone consultations for patients with spinal injuries was as effective as workstation consultations. Mobile phone consultations can increase the expertise available to regional hospitals, which are often the first responders to medical emergencies. PMID- 21795007 TI - How to make the medical consultation more successful from a patient's perspective? Tips for doctors and patients from lay people in the United Kingdom, Italy, Belgium and the Netherlands. AB - OBJECTIVE: The aim of this study is to generate empirically based 'tips' from lay people on how medical consultations could become more successful from a patient perspective. METHODS: 258 Lay people in the United Kingdom, Italy, Belgium and the Netherlands, distributed over 32 focus groups, were invited to formulate 'tips' for doctors as well as patients after rating the quality of communication from videotaped consultations and discussing their arguments in focus groups. RESULTS: Tips were remarkably similar across the four countries. Most tips reflect the professional literature, such as the importance of nonverbal communication, personal attention and empathy, but also addressed issues as how to deal with new technologies and new accessibility arrangements (triage). The tips were targeted to the consultation itself, its preparation and the aftercare. Tips for doctors were mirrored in tips for patients. CONCLUSION: Lay people seem to be competent in participating in quality-of-care debates. They are well aware of patients' own responsibilities. Besides, they have clear opinions about novel technology and healthcare arrangements (triage). PRACTICE IMPLICATIONS: Listening to patients, showing empathy and personal attention seem to have a universal value. Doctors should be trained to practice these behaviors, healthcare managers in involving patients in practice reorganisations. PMID- 21795008 TI - Recognition can leave room for disagreement in the doctor-patient consultation. AB - OBJECTIVE: We wanted to explore how recognising interaction, as described by psychologist Schibbye, is played out in a patient doctor encounter including the behaviour of both parties and their simultaneous communication. METHODS: We selected videotapes from five doctor-patient encounters where a recognising attitude was identified. The episodes were analysed using a qualitative method for studying interaction and relationship at the micro-level. We describe an episode which is suitable for demonstrating how a recognizing attitude can leave room for disagreement. RESULTS: The doctor's recognising attitude with a basic respect for the other person's experience perspective has a crucial effect on the doctor-patient relationship. In this consultation, the doctor succeeds in taking the patient's experience perspective by listening, wondering and exploring to check that he has interpreted the patient correctly. A potential conflict situation arises, but there is no conflict. When the relationship is characterised by recognition, disagreement is allowed, without doing any damage. CONCLUSION: Schibbye's ideas and terms can provide new perspectives on the doctor patient interaction. PRACTICE IMPLICATIONS: For the doctor, a fundamental respect for the patient's perspective may make it easier to tolerate when patients have values and preferences that conflict with the doctor or with sound medical practice. PMID- 21795009 TI - Perception of care and experience of examination in women at risk of breast cancer undergoing intensive surveillance by standard imaging with or without MRI. AB - OBJECTIVE: Intensive surveillance in women at breast cancer risk is currently investigated in a French prospective, non-randomized, multicenter study, in which standard imaging--mammography+/-ultrasound ('Mx') and standard imaging combined with magnetic resonance imaging ('MRI') are compared with regard to perception of care and examination experience. METHODS: 1561 women were invited to complete the STAI-State Anxiety Inventory and breast cancer risk perception items at baseline (T0), and MGQ (MammoGraphy Questionnaire) and MRI discomfort items within 2 days after examinations (T1). RESULTS: Baseline compliance was high (>91%). Women from the 'MRI' group were significantly younger and displayed higher education level and risk perception. MRI discomfort related to the duration, immobility, prone position or noise was experienced by more than 20% of women. In multivariate analyses, 'MRI' was associated with more favorable examination psychological experience (p<=.001), especially in women younger than 50; baseline STAI-State anxiety was associated with lower MGQ scores (p<=.001) and higher MRI discomfort (p<=.001). CONCLUSION: In spite of the discomfort experienced with MRI, perception of care and experience with this surveillance procedure was more positive than with standard imaging. PRACTICE IMPLICATIONS: Information and support may assuage some of the adverse effects of an uncomfortable examination technique. PMID- 21795010 TI - [Bowel preparation before colonoscopy]. AB - Colonoscopy is a routinely performed procedure in adults. Completion of the procedure and proper visualization of the intestinal mucosa are highly dependent on the quality of the bowel preparation. The ideal bowel preparation should be safe, well-tolerated and effective. No bowel preparation method meets the ideal criteria for bowel-cleansing prior to colonoscopy. However, polyethylene glycol electrolyte lavage solution and sodium phosphate are the most commonly used bowel preparations before colonoscopy and colon surgery. NaP preparations appear more effective and better tolerated than standard PEG solutions but should be administered with caution in patients with preexisting or at an increased risk for electrolyte disturbances. Timing and dose are important considerations regardless of the method used. The last generation of preparations improves safety and acceptability by reducing volume of liquid ingested. PMID- 21795011 TI - [Crystal arthropathies: what's new?]. PMID- 21795012 TI - [The stroke secondary to vertebral artery dissection: a rare complication of eclampsia]. PMID- 21795013 TI - Cardiomyopathies (hypertrophy and failure): what can offer cardiac magnetic resonance imaging? AB - In routine, cardiomyopathy, confirmed or not, is a frequent reason for cardiac MRI evaluation. Step by step, by using a wide panel of sequences, cardiac MRI is able to characterize cardiomyopathies by their morphologic and functional phenotype as well as by tissue characterization. Cardiac-MRI is also considered as the most appropriate technique for the follow-up of this disease. The purpose of this article is to browse an overview of the main MRI features of cardiomyopathy, focusing the purpose on hypertrophic forms and myocardial diseases leading to cardiac failure. PMID- 21795014 TI - CT features of primary systemic pulmonary amyloidosis mimicking pulmonary sarcoidosis. PMID- 21795015 TI - 2010 Canadian Cardiovascular Society/Canadian Society of Echocardiography Guidelines for Training and Maintenance of Competency in Adult Echocardiography. AB - Guidelines for the provision of echocardiography in Canada were jointly developed and published by the Canadian Cardiovascular Society and the Canadian Society of Echocardiography in 2005. Since their publication, recognition of the importance of echocardiography to patient care has increased, along with the use of focused, point-of-care echocardiography by physicians of diverse clinical backgrounds and variable training. New guidelines for physician training and maintenance of competence in adult echocardiography were required to ensure that physicians providing either focused, point-of-care echocardiography or comprehensive echocardiography are appropriately trained and proficient in their use of echocardiography. In addition, revision of the guidelines was required to address technological advances and the desire to standardize echocardiography training across the country to facilitate the national recognition of a physician's expertise in echocardiography. This paper summarizes the new Guidelines for Physician Training and Maintenance of Competency in Adult Echocardiography, which are considerably more comprehensive than earlier guidelines and address many important issues not previously covered. These guidelines provide a blueprint for physician training despite different clinical backgrounds and help standardize physician training and training programs across the country. Adherence to the guidelines will ensure that physicians providing echocardiography have acquired sufficient expertise required for their specific practice. The document will also provide a framework for other national societies to standardize their training programs in echocardiography and will provide a benchmark by which competency in adult echocardiography may be measured. PMID- 21795016 TI - Diffuse ischemia in noncontrast computed tomography predicts outcome in patients in intensive care unit. AB - PURPOSE: In the intensive care unit (ICU), prognosticating patients who are comatose or defining brain death can be challenging. Currently, the criteria for brain death are clinical supported by paraclinical tests. Noncontrast computed tomography (CT) shows diffuse loss of grey-white differentiation consistent with infarction. We hypothesize that the extent of hypodensity is predictive of poor neurologic outcome or brain death. MATERIALS AND METHODS: A total of 235 consecutive adult patients with cardiac arrest or with serious trauma admitted to ICU in 1 year were studied. Seventy met inclusion criteria. CT images were reviewed by multiple observers blinded to final outcome who assessed for loss of grey-white conspicuity. A modification of the validated Alberta Stroke Program Early CT Score (ASPECTS) was used to include non-middle cerebral artery territories. Primary outcome was death or functional disability at 3 months. Dichotomized CT scores were correlated with poor clinical status (Glasgow Coma Score < 5 and APACHE [Acute Physiology and Chronic Health Evaluation] score >19) and poor outcome (modified Rankin Scale >2). RESULTS: The CT score was <=10 in 7 patients and >10 in 63 patients. The CT score value correlated with the severity of baseline clinical status on the Glasgow Coma Score (r = 0.53, P < .01) and negatively with the APACHE-II score (r = -0.27, P < .05). The CT score value negatively correlated with functional outcome (r = -0.40, P < .01). All the patients with a CT score <=10 died. The sensitivity of the CT score for functional outcome was 24%, and specificity was 100%. Agreement among observers for the CT score was good (Intraclass correlation coefficient = 0.77). CONCLUSION: Diffuse loss of grey-white matter differentiation is subtle but specific for poor neurologic outcome, which may allow earlier prognostication of patients in whom clinical parameters are difficult to assess. PMID- 21795017 TI - Diaphragmatic patch: a useful adjunct in surgical treatment of recurrent catamenial hemothorax. AB - Although catamenial hemothorax compared to pneumothorax is a rarer clinical presentation of thoracic endometriosis syndrome (TES), it is more commonly associated with diaphragmatic fenestrations. These openings may serve as entry portals for peritoneal fluid to access into the pleural space thereby perpetuating recurrent pleural effusion even after prior surgical pleurodesis. We report our experience with two patients with recurrent right catamenial hemothorax after previous interventions that were subsequently treated by talc pleurodesis and goretex diaphragmatic patch, and who have had no further recurrence at a mean follow up of 15 months. We therefore recommend that diaphragmatic patch should be considered as an adjunct to talc pleurodesis in patients with recurrent catamenial hemothorax when either multiple diaphragmatic fenestrations are seen at surgery or if there is concomitant bloody peritoneal fluid which could potentially lead to recurrence. The patch by sealing any occult pores and possible future fenestrations appear to decrease recurrent pleural effusion at an intermediate term follow up. PMID- 21795018 TI - A successful intervention combined with surgical treatment of a pulmonary dissection secondary to an acute type B aortic dissection. AB - Pulmonary dissection is an acute, lethal disease to patients. Pulmonary dissection occurs secondary to type B aorta dissection in some cases, as seen in surviving patients with the development of imaging techniques. A patient presenting with pulmonary dissection secondary to an acute type B aortic dissection was treated by proper interventional therapy combined with surgical treatment, which made him survive till now. It is crucial to establish tunica intima laceration position and then design a proper treatment plan rapidly for patients affected by this condition. PMID- 21795019 TI - Factors determining outcomes of aortic valve surgery in patients with aortic regurgitation due to Behcet's disease: impact of preoperative echocardiographic features. AB - BACKGROUND: Paravalvular leakage after open heart surgery is notoriously common in patients with aortic regurgitation (AR) due to Behcet's disease. The aim of this study was to test whether initial echocardiographic findings are useful to predict recurrent AR. METHODS: Lesion severity on preoperative echocardiography was scored for redundant aortic valve cusp (0-2 points), aortic pseudoaneurysm (0 2 points), and dissection of the adjacent interventricular septum (0-2 points) in 22 patients with severe AR due to Behcet's disease (13 men; mean age, 42.4 +/- 11.5 years), which was confirmed by histologic examination after open heart surgery. RESULTS: Recurrent AR developed in 13 patients at a median of 12.6 months (range, 2.4-70.3 months) after the first operation, and 10, four, and one patient underwent second, third, and fourth surgery, respectively, to control recurrent AR; three patients died. Those patients with recurrent AR had a significantly higher incidence of repeat surgery or death (84.6% [11 of 13] vs 0%, P = .015). Multivariate analysis showed that perioperative immunotherapy (hazard ratio, 0.002; 95% confidence interval, 0.001-0.1761; P = .006) and total echocardiographic score (hazard ratio, 2.843; 95% confidence interval, 1.350 5.991; P = .006) were independent factors associated with recurrent AR. The 1 year, 3-year, and 5-year AR-free survival rates were 73 +/- 10%, 46 +/- 12%, and 39 +/- 12%. The optimal cutoff value for total echocardiographic score was 3.0, and the 5-year AR-free survival rates were significantly lower in patients with scores >= 3 (20 +/- 13% vs 50 +/- 19%, P = .022). CONCLUSIONS: This retrospective study confirms that initial echocardiographic features can provide useful prognostic information in patients with AR due to Behcet's disease. PMID- 21795020 TI - Pericardial rather than epicardial fat is a cardiometabolic risk marker: an MRI vs echo study. AB - BACKGROUND: Several studies using echocardiography identified epicardial adipose tissue (EPI) as an important cardiometabolic risk marker. However, validation compared with magnetic resonance imaging (MRI) or computed tomography has not been performed. Moreover, pericardial adipose tissue (PERI) has recently been shown to have some correlation with cardiovascular disease risk factors. The aims of this study were to validate echocardiographic analyses compared with MRI and to evaluate which cardiac fat depot (EPI or PERI) is the most appropriate cardiovascular risk marker. METHODS: Forty-nine healthy subjects were studied (age range, 25-68 years; body mass index, 21-40 kg/m(2)), and PERI and EPI fat depots were measured using echocardiography and MRI. Findings were correlated with MRI visceral fat and subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, insulin, glucose, and 10-year coronary heart disease risk. RESULTS: Most cardiac fat was constituted by PERI (about 77%). PERI thickness by echocardiography was well correlated with MRI area (r = 0.36, P = .009), and independently of the technique used for quantification, PERI was correlated with body mass index, waist circumference, visceral fat, subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, glucose, and coronary heart disease risk. On the contrary, EPI thicknesses correlated only with age did not correlate significantly with MRI EPI areas, which were found to correlate with age, body mass index, subcutaneous fat, and hip and waist circumferences. CONCLUSIONS: Increased cardiac fat in the pericardial area is strongly associated with features of the metabolic syndrome, whereas no correlation was found with EPI, indicating that in clinical practice, PERI is a better cardiometabolic risk marker than EPI. PMID- 21795021 TI - Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. AB - Autoimmune hepatitis (AIH) is a serious chronic inflammatory disease of the liver with yet unknown etiology and largely uncertain immunopathology. The hallmark of type 2 AIH is the generation of liver kidney microsomal-1 (LKM-1) autoantibodies, which predominantly react to cytochrome P450 2D6 (CYP2D6). The identification of disease initiating factors has been hampered in the past, since antibody epitope mapping was mostly performed using serum samples collected late during disease resulting in the identification of immunodominant epitopes not necessarily representing those involved in disease initiation. In order to identify possible environmental triggers for AIH, we analyzed for the first time the spreading of the anti-CYP2D6 antibody response over a prolonged period of time in AIH patients and in the CYP2D6 mouse model, in which mice infected with Adenovirus-human CYP2D6 (Ad-h2D6) develop antibodies with a similar specificity than AIH patients. Epitope spreading was analyzed in six AIH-2-patients and in the CYP2D6 mouse model using SPOTs membranes containing peptides covering the entire CYP2D6 protein. Despite of a considerable variation, both mice and AIH patients largely focus their humoral immune response on an immunodominant epitope early after infection (mice) or diagnosis (patients). The CYP2D6 mouse model revealed that epitope spreading is initiated at the immunodominant epitope and later expands to neighboring and remote regions. Sequence homologies to human pathogens have been detected for all identified epitopes. Our study demonstrates that epitope spreading does indeed occur during the pathogenesis of AIH and supports the concept of molecular mimicry as a possible initiating mechanism for AIH. PMID- 21795023 TI - Do patients with osteogenesis imperfecta need individualized nutritional support? AB - OBJECTIVE: Information regarding nutrition and body composition in patients diagnosed with osteogenesis imperfecta (OI) is scarce. In the present study, nutritional status, bone mineral density, and biochemical parameters of subjects with OI were evaluated. METHODS: Patients with type I OI (n = 13) and type III OI (n = 13) and healthy controls (n = 8) were selected. Nutritional status and bone mineral density were assessed by a 3-d food diary and dual-energy X-ray absorptiometry at the lumbar spine, respectively. Body mass index, serum albumin, calcium, creatinine, cross-linked C-telopeptide, parathyroid hormone, and 25 hydroxivitamin D(3) were also evaluated. RESULTS: Patients with OI had lower bone mineral density (P < 0.05 versus controls). Patients with type III OI had the highest body mass index (P < 0.05 versus patients with type I OI and controls) and the lowest lean body mass (P < 0.05 versus patients with type I OI and controls). In patients with OI, the number of fractures was positively correlated with body mass index (r = 0.581, P = 0.002) and the percentage of body fat (r = 0.451, P = 0.027) and negatively correlated to lean body mass (r = -0.523, P = 0.009). Even when taking dietary supplements, 58% and 12% of subjects with OI did not achieve the calcium and vitamin D recommendations, respectively. CONCLUSIONS: Body composition is a risk factor for bone fractures in subjects with OI. Individualized nutritional support is recommended not only to improve body composition but also to potentiate pharmacologic and physical therapies. PMID- 21795022 TI - Dietary walnuts inhibit colorectal cancer growth in mice by suppressing angiogenesis. AB - OBJECTIVE: Animal studies have demonstrated that dietary supplementation with flaxseed oil inhibits colorectal cancer growth. Recent data indicate that walnuts have strong antiproliferative properties against colon cancer cells in vitro but no previous study has assessed the effects of walnuts in vivo or performed a joint evaluation of flaxseed oil and walnuts. The aim of the present study was to examine the effect of dietary walnuts on colorectal cancer in vivo and to comparatively evaluate their efficacy in relation to flaxseed oil. METHODS: HT-29 human colon cancer cells were injected in 6-wk-old female nude mice. After a 1-wk acclimation period, mice (n = 48) were randomized to diets containing ~19% of total energy from walnuts, flaxseed oil, or corn oil (control) and were subsequently studied for 25 d. RESULTS: Tumor growth rate was significantly slower in walnut-fed and flaxseed-fed mice compared with corn oil-fed animals (P < 0.05) by 27% and 43%, respectively. Accordingly, final tumor weight was reduced by 33% and 44%, respectively (P < 0.05 versus control); the differences between walnut and flaxseed diets did not reach significance. We found no differences among groups in metabolic and hormonal profile, serum antioxidant capacity, or inflammation (P > 0.05). However, walnuts and flaxseed oil significantly reduced serum expression levels of angiogenesis factors, including vascular endothelial growth factor (by 30% and 80%, respectively), and approximately doubled total necrotic areas despite smaller tumor sizes (P < 0.05 versus control). Dietary walnuts significantly decreased angiogenesis (CD34 staining; P = 0.017 versus control), whereas this effect did not reach significance in the flaxseed oil group (P = 0.454 versus control). CONCLUSION: We conclude that walnuts in the diet inhibit colorectal cancer growth by suppressing angiogenesis. Further studies are needed to confirm our findings in humans and explore underlying mechanisms. PMID- 21795024 TI - Exploring the tolerability of spatiotemporally complex electrical stimulation paradigms. AB - A modified cortical stimulation model was used to investigate the effects of varying the synchronicity and periodicity of electrical stimuli delivered to multiple pairs of electrodes on seizure initiation. In this model, electrical stimulation of the motor cortex of rats, along four pairs of a microwire electrode array, results in an observable seizure with quantifiable electrographic duration and behavioural severity. Periodic stimuli had a constant inter-stimulus intervals across the two-second stimulus duration, whilst synchronous stimuli consisted of singular biphasic, bipolar pulses delivered to the four pairs of electrodes at precisely the same time for the entire two second stimulation period. In this way four combinations of stimulation were possible; periodic/synchronous (P/S), periodic/asynchronous (P/As), aperiodic/synchronous (Ap/S) and aperiodic/asynchronous (Ap/As). All stimulation types were designed with equal pulse width, current intensity and mean frequency of stimulation (60 Hz), standardizing net charge transfer. It was expected that the periodicity of the stimulus would be the primary determinant of seizure initiation and therefore severity and electrographic duration. However, the results showed that significant differences in both severity and duration only occurred when the synchronicity was altered. For periodic stimuli, synchronous delivery increased median seizure duration from 5 s to 13 s and increased median Racine severity from 1 to 3. In the aperiodic case, synchronous stimulus delivery increased median duration from 5.5 s to 11s and resulted in seizures of median severity 3 vs. 0 in the asynchronous case. These findings may have implications for the design of future neurostimulation waveform designs as higher numbers of electrodes and stimulator output channels become available in next generation implants. PMID- 21795025 TI - Successful computer-based visual training specifically predicts visual memory enhancement over verbal memory improvement in schizophrenia. AB - We investigated whether improved early visual processing on cognitive remediation (CR) exercises generalizes to visual and auditory learning and information manipulation in schizophrenia. Fourteen participants received neuropsychological testing before and after CR consisting of visual, auditory and cognitive control training. Achievement on visual training exercises was strongly and significantly correlated with improved visual learning, but not improved verbal learning or increased ability to manipulate visual information. Improvement in training, not training time, predicted cognitive gain. Implications for improving cognitive outcomes from CR include ensuring the trained task is learned and providing exercises of multiple modalities. PMID- 21795026 TI - [Neonatal seizures revealing incontinentia pigmenti]. AB - Incontinentia pigmenti (IP) is a rare affection inherited as X-linked dominant disease. It is usually lethal in male infants. IP can affect ectodermal tissues such as the skin, teeth, eyes, bones, and the central nervous system. Skin lesions occur mostly during the neonatal period and are characterized by a classic progression in 4 stages leading to hyperpigmentation. We report on the case of a female neonate presenting on the 3rd day of life with seizures without obvious cause, in which the diagnosis of IP was made 1 week later when skin lesions appeared. PMID- 21795027 TI - [Prenatal breastfeeding information: survey in Pays de Loire, France]. AB - OBJECTIVES: The main aim of this study was to evaluate how well expectant mothers were informed on breastfeeding by healthcare professionals. The secondary objective was to determine the factors associated with the initiation of breastfeeding. POPULATION AND METHODS: The survey was conducted in a group of 500 women who had delivered at the Angers Hospital (France), based on a questionnaire filled out by the postpartum women during their hospital stay. RESULTS: The rate of breastfeeding was 61.2%. More than a quarter (26.9%) of the women did not receive any prenatal breastfeeding information. The survey showed that 77.8% of the women had been informed of breastfeeding advantages for infants and 51.5% of breastfeeding advantages for themselves. Only 27.5% had received the advice of exclusive breastfeeding for 6months. Only 5.2% had been informed of the uselessness of breast preparation during pregnancy and a minority had been informed of correct and incorrect breastfeeding contraindications. Only 15.4% of fathers had been involved in a discussion on infant feeding practices during prenatal consultations. Only 4.8% of the women had come to prenatal classes on breastfeeding with a relative. The maternal factors positively associated with breastfeeding initiation were age between 25 and 34 years, non-French origin, a high socioeconomic status, being married, having been breastfed, and having previous experience with breastfeeding. Breastfeeding initiation was negatively associated with maternal smoking. All the factors concerning prenatal breastfeeding information in women were associated with the choice of breastfeeding. CONCLUSION: This study pointed out the populations at risk of not breastfeeding. Breastfeeding information given to pregnant women by healthcare professionals may influence them on whether or not they choose to breastfeed their newborn. However, this survey showed that women are insufficiently informed on prenatal breastfeeding. Therefore, prenatal breastfeeding information should be improved. PMID- 21795028 TI - [Comparison of two protocols of febrile urinary tract infection management in children]. AB - PURPOSE: To compare two first febrile urinary tract infection (UTI) management protocols with regards to the diagnosis of high-grade vesicoureteral reflux (VUR) and cost. METHODS: This study compared two cohorts of children under 16 years of age, admitted for a first episode of febrile UTI. The first group (in 2005) was managed according to previous recommendations (IV treatment and cystography performed for all children under 3 years of age). The second group (in 2006) was managed according to age and procalcitonin level. High-grade VUR frequency, UTI recurrence, hospitalization rate, and cost were compared between the two cohorts. RESULTS: A total of 225 children were included in 2005 and 116 in 2006. High grade VUR was found in 6.2 and 9.5% of the patients in 2005 and 2006, respectively (P=0.274). There was no statistically significant difference in the UTI recurrence rate between the two cohorts (5.3% in 2005 and 8.6% in 2006; P=0.237). The mean cost of an episode of febrile UTI was not significantly different in 2005 and 2006 (?2235 in 2005, ?2256 in 2006; P=0.902), but was lower for children older than 6 months in 2006 (?1292 versus ?1882 in 2005; P=0.0042). CONCLUSION: Our management protocol for a first febrile UTI episode in children based on procalcitonin levels seems to be suitable for the diagnosis of high grade VUR. The hospitalization rate and the mean cost of management for children older than 6 months of age was significantly reduced in 2006. The management guidelines for a first occurrence of febrile UTI in children should be reconsidered. PMID- 21795029 TI - Resistance of the golden hamster to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity is not only related with low levels of cerebral monoamine oxidase-B. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been proved to be a potent neurotoxin on dopaminergic neurons inducing most of the symptoms and cerebral lesions observed in the idiopathic Parkinson's disease (PD). Although there is a substantial body of theory and researches about the effects of MPTP on susceptible mice and nonhuman primates, there are only few studies in resistant animals, such as golden hamsters (GH). The low levels of cerebral monoamine oxidase-B (MAO-B) enzyme have been proposed as the cause of the GH insensitivity to MPTP. The aim of this study was to elucidate whether MAO-B is the only factor which confer GH resistance to MPTP. Neither loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) nor cell death in the subventricular zone (SVZ) were found in female GH in response to an acute intraperitoneal (ip) MPTP treatment. To prove the role of MAO-B in the MPTP-resistance, female and male GH was intracerebroventricularly (icv) injected with either MPTP or 1-methyl-4 phenylpyridinum (MPP(+)). Neither depletion in the number of dopaminergic neurons, nor astrogliosis, cell death in the SVZ of female and male GH were registered after an icv treatment with MPTP or MPP(+). Furthermore, we demonstrated that MAO-B is located predominantly within the endothelial cells in the blood brain barrier (BBB), but not in the astroglia. The present results raise the possibility that, in GH, other mechanisms, apart from the low levels of regional MAO-B, confer resistance to MPTP and its metabolites. PMID- 21795031 TI - Cardioprotective effect of polydatin against ischemia/reperfusion injury: roles of protein kinase C and mito K(ATP) activation. AB - Polydatin preconditioning (PPC) has been reported to be protective against brain and intestine ischemia/reperfusion injury (I/R injury), but whether polydatin exerts cardioprotective effect against myocardial ischemia/reperfusion and the underlying mechanisms remain unclear. Previous studies have demonstrated that oxidative stress plays an important role in the process of I/R. Elevation of oxidative agents and decline in anti-oxidant substance would promote I/R. Meanwhile, the activation of PKC signaling seems to mediate the cardioprotective effects of many drugs by alleviating Ca(2+) influx. In the present study, we reported for the first time that intravenous administration of polydatin before I/R significantly limited the infarct size, creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) leakage from the damaged myocardium after I/R. The activity of SOD and the content of MDA remarkably changed in the presence of polydatin as well. However, the cardiac function-preserving and myocardial enzymes leakage-limiting effects of polydatin vanished in the presence of PKC inhibitors and mito K(ATP) channel blockers. But there was not a significant change in the activity of SOD and MDA content. We therefore conclude that PPC exerts cardioprotective effect by the activation of PKC-K(ATP)-dependent signaling and the direct anti-oxidative stress mechanisms. PMID- 21795030 TI - Inactivation of the ftsH gene of Lactobacillus plantarum WCFS1: effects on growth, stress tolerance, cell surface properties and biofilm formation. AB - FtsH proteins are ubiquitous membrane-bound, ATP-dependent metalloproteases of the AAA family. In eubacteria, FtsH is involved in protein quality control under stress conditions. Lactobacillus plantarum is a widespread lactic acid bacterium that is encountered in several fermented food, including dairy products, vegetables and meat. In the present work the expression of the ftsH gene of L. plantarum was studied by quantitative real time RT-PCR in bacterial cultures subjected to various abiotic stresses. Both oxidative stress and addition of a membrane-fluidizing agent induced ftsH transcription, while a depletion of carbon source repressed its mRNA level. Mutants deprived of the FtsH protease exhibited remarkable sensitivity to elevated temperature and increased salt concentration; conversely, overexpression of ftsH resulted in increased thermotolerance and resistance to salt. FtsH mutant had a reduced capacity to form biofilms on abiotic surfaces and exhibited different cell surface physico-chemical properties with respect to the wild type strain. PMID- 21795032 TI - Anti-tumor potential of ethanol extract of Curcuma phaeocaulis Valeton against breast cancer cells. AB - Curcuma phaeocaulis Valeton is a commonly prescribed Chinese medical herb for tumor therapy. In this study, an extract of Curcuma phaeocaulis Valeton referred as Cpv was prepared and its anti-tumor effect was evaluated with MCF-7 and MDA-MB 231 cells. Curcuma phaeocaulis Valeton power was extracted with ethanol and the main components of the extract (Cpv) were analyzed with HPLC. The effect of Cpv on MCF-7 cells proliferation, intracellular reactive oxygen species (ROS) formation, mitochondrial membrane potential (DeltaPsim), apoptosis, apoptotic related proteins, MDA-MB-231 cell migration, and integrins expression were determined. Furthermore, the effect of Cpv on some key signal transduction molecules was also investigated. Furanodienone, germacrone and furanodiene were identified as the main components of Cpv. Cpv treatment significantly inhibited cell proliferation, increased LDH release, induced intracellular ROS formation, and decreased DeltaPsim in a dose-dependent manner in MCF-7 cells. Cpv induced apoptosis without affecting cell migration. Cpv increased protein expression of Bax, PARP, cleaved PARP, caspase-3, 7, JNK1, p-p42/44MAPK, NF-kappaB, IKKalpha, IKKbeta, decreased protein expression of Bcl-2, Bcl-xL, Bim, Bik, Bad, integrin beta5, p42/44MAPK without affecting integrin alpha5, beta1, and p38MAPK protein expression. We concluded that Cpv inhibited MCF-7 cells proliferation by inducing apoptosis mediated by increasing ROS formation, decreasing DeltaPsim, regulating Bcl-2 family proteins expression, and activating caspases. Cpv treatment also modulated several signaling transduction pathways. These results might provide some molecular basis for the anti-tumor activity of Curcuma phaeocaulis Valeton. PMID- 21795033 TI - Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana wallichii Patchouli alcohol chemotype. AB - Valeriana wallichii DC (Valerianaceae), popularly named as Indian valerian has been shown to exist as three chemotypes. The present study evaluated the antidepressant like effect of root essential oil of Valeriana wallichii patchouli alcohol chemotype in both acute and chronic treatment study using forced swim test (FST). Mice (n=6 per group) received 10, 20 and 40 mg/kg p.o. doses of test drug. Single administration of oil significantly inhibited the immobility period (57.6% and 46.9%) at doses 20 and 40 mg/kg respectively without changing the motor function (p<0.05). Similarly, daily administration of essential oil (20mg/kg) for 14 days significantly reduced the immobility period (69.9%) in FST (p<0.05). The neurotransmitter levels in mouse brain were estimated on day 14 after the behavioral study. Significant increase in the level of norepinephrine (29%) and serotonin (19%) (p<0.05) was found at 20mg/kg dose, while no change was observed at 10 and 40 mg/kg doses. The antidepressant-like effect of essential oil (20mg/kg) was prevented by pretreatment of mice with l-arginine (750 mg/kg i.p.) and sildenafil (5mg/kg i.p). On the contrary, pretreatment of mice with l NAME (10mg/kg i.p.) or methylene blue (10mg/kg i.p.) potentiated the antidepressant action of essential oil (10mg/kg). Taken together, these findings demonstrated that nitric oxide pathway is involved in mediating antidepressant like effect of essential oil from this chemotype. PMID- 21795034 TI - Brain and systemic glucose metabolism in the healthy elderly following fish oil supplementation. AB - Cerebral metabolic rate of glucose (CMRg) is lower in individuals affected by cognitive decline and dementia, especially in Alzheimer's disease. However, as yet there is no consensus as to whether CMRg decreases during healthy aging. Epidemiological studies show that weekly consumption of fish abundant in omega3 fatty acids has a protective effect on cognition during aging. Thus, the primary objective of this human study was to use positron emission tomography analysis with (18)F-fluorodeoxyglucose to evaluate whether supplementation with a fish oil rich in omega3 fatty acids increases cerebral glucose metabolism in young or elderly adults. Healthy young (23+/-5y old; n=5) and elderly (76+/-3y old; n=6) women and men were included in the study. Semi-quantitative expression of the data as 'standardized uptake values' showed that elderly participants had significantly lower cerebral glucose metabolism compared with the young group. However, when expressed quantitatively a CMRg, there was no effect of age or omega3 supplementation on glucose metabolism in any of the brains regions studied. Higher plasma triglyceride levels and higher plasma insulin levels were associated with lower CMRg in several regions, suggesting that a trend towards the metabolic syndrome may be associated with cerebral hypometabolism. We conclude that under these experimental conditions, omega3 supplementation did not affect brain glucose metabolism in the healthy elderly. Future studies in this area should address whether glucose intolerance or other conditions linked to the metabolic syndrome impact negatively on brain glucose metabolism and cognition. PMID- 21795035 TI - Beneficial effects of the n-3 long-chain polyunsaturated fatty acids in surgical patients: updating the evidence. AB - The use of n-3 polyunsaturated fatty acids in surgical patients has risen by the fact that this may attenuate systemic and acute inflammatory responses secondary to surgical trauma through modulation of inflammatory mediators and cell membrane interactions. Moreover, the inclusion of n-3 fatty acids in clinical trials as part of the therapy in patients, who expect to undergo a surgical stress, suggests benefits on clinical progress. Therefore, the objective of this article is to review data from n-3 polyunsaturated fatty acid effects on biochemical parameters and on reduced length of hospitalization, number of infections, and mortality as main clinical outcomes in human surgical patients. PMID- 21795036 TI - Anammox: an option for ammonium removal in bioreactor landfills. AB - Experiments carried out in bioreactor landfill simulators demonstrated that more than 40% of the total N was transferred into the liquid and gas phases during the incubation period of 380 days. Ammonium, an end product of protein degradation and important parameter to consider during landfill closure, tends to accumulate up to inhibitory levels in the leachate of landfills especially in landfills with leachate recirculation. Most efforts to remove ammonium from leachate have been focused on ex situ and partial in situ methods such as nitrification, denitrification and chemical precipitation. Besides minimal contributions from other N-removal processes, Anammox (Anaerobic Ammonium Oxidation) bacteria were found to be active within the simulators. Anammox is considered to be an important contributor to remove N from the solid matrix. However, it was unclear how the necessary nitrite for Anammox metabolism was produced. Moreover, little is known about the nature of residual nitrogen in the waste mass and possible mechanisms to remove it. Intrusion of small quantities of O2 is not only beneficial for the degradation process of municipal solid waste (MSW) in bioreactor landfills but also significant for the development of the Anammox bacteria that contributed to the removal of ammonium. Volatilisation and Anammox activity were the main N removal mechanisms in these pilot-scale simulators. The results of these experiments bring new insights on the behaviour, evolution and fate of nitrogen from solid waste and present the first evidence of the existence of Anammox activity in bioreactor landfill simulators. PMID- 21795037 TI - Pyrolysis of plastic packaging waste: A comparison of plastic residuals from material recovery facilities with simulated plastic waste. AB - Pyrolysis may be an alternative for the reclamation of rejected streams of waste from sorting plants where packing and packaging plastic waste is separated and classified. These rejected streams consist of many different materials (e.g., polyethylene (PE), polypropylene (PP), polystyrene (PS), polyvinyl chloride (PVC), polyethylene terephthalate (PET), acrylonitrile butadiene styrene (ABS), aluminum, tetra-brik, and film) for which an attempt at complete separation is not technically possible or economically viable, and they are typically sent to landfills or incinerators. For this study, a simulated plastic mixture and a real waste sample from a sorting plant were pyrolyzed using a non-stirred semi-batch reactor. Red mud, a byproduct of the aluminum industry, was used as a catalyst. Despite the fact that the samples had a similar volume of material, there were noteworthy differences in the pyrolysis yields. The real waste sample resulted, after pyrolysis, in higher gas and solid yields and consequently produced less liquid. There were also significant differences noted in the compositions of the compared pyrolysis products. PMID- 21795039 TI - What is 'current opinion' in structural biology? PMID- 21795040 TI - Chronic lymphocytic leukaemia in the Netherlands: trends in incidence, treatment and survival, 1989-2008. AB - We present trends in incidence, early treatment and survival of Chronic Lymphocytic Leukaemia (CLL) between 1989 and 2008, based on population-based data from the Netherlands Cancer Registry. Incidence rates were stable at 5.1 per 100,000 person-years for males, but increased from 2.3 to 2.5 for females, especially for females aged 50-64 years (from 3.6 to 4.3). Patients were less likely to receive chemotherapy within six months, i.e. from 29% to 24% among males and from 25% to 21% among females. Five-year relative survival increased from 61% in 1989-1993 to 70% 2004-2008 for males, and from 71% to 76% for females. The relative excess risk of dying decreased in time to 0.7 (males) and 0.9 (females) in 2004-2008, reference 1989-1993, and increased with age to 2.9 (males) and 1.8 (females) in patients aged 75-94 years, reference 30-64 years. The increasing incidence among females aged 50-64 coincided with the introduction of mass screening for breast cancer, which resulted in a large group of women under increased surveillance and possibly led to increased detection of CLL. The increase in survival might be underestimated due to possible decreased or delayed registration of indolent cases and the retroactive effect of the introduction of new therapies. PMID- 21795038 TI - Fabrication of nitric oxide-releasing polyurethane glucose sensor membranes. AB - Despite clear evidence that polymeric nitric oxide (NO) release coatings reduce the foreign body response (FBR) and may thus improve the analytical performance of in vivo continuous glucose monitoring devices when used as sensor membranes, the compatibility of the NO release chemistry with that required for enzymatic glucose sensing remains unclear. Herein, we describe the fabrication and characterization of NO-releasing polyurethane sensor membranes using NO donor modified silica vehicles embedded within the polymer. In addition to demonstrating tunable NO release as a function of the NO donor silica scaffold and polymer compositions and concentrations, we describe the impact of the NO release vehicle and its release kinetics on glucose sensor performance. PMID- 21795041 TI - Second generation ethanol in Brazil: can it compete with electricity production? AB - Much of the controversy surrounding second generation ethanol production arises from the assumed competition with first generation ethanol production; however, in Brazil, where bioethanol is produced from sugarcane, sugarcane bagasse and trash will be used as feedstock for second generation ethanol production. Thus, second generation ethanol production may be primarily in competition with electricity production from the lignocellulosic fraction of sugarcane. A preliminary technical and economic analysis of the integrated production of first and second generation ethanol from sugarcane in Brazil is presented and different technological scenarios are evaluated. The analysis showed the importance of the integrated use of sugarcane including the biomass represented by surplus bagasse and trash that can be taken from the field. Second generation ethanol may favorably compete with bioelectricity production when sugarcane trash is used and when low cost enzyme and improved technologies become commercially available. PMID- 21795042 TI - Development of net energy ratio and emission factor for biohydrogen production pathways. AB - This study investigates the energy and environmental aspects of producing biohydrogen for bitumen upgrading from a life cycle perspective. Three technologies are studied for biohydrogen production; these include the Battelle Columbus Laboratory (BCL) gasifier, the Gas Technology Institute (GTI) gasifier, and fast pyrolysis. Three different biomass feedstocks are considered including forest residue (FR), whole forest (WF), and agricultural residue (AR). The fast pyrolysis pathway includes two cases: truck transport of bio-oil and pipeline transport of bio-oil. The net energy ratios (NERs) for nine biohydrogen pathways lie in the range of 1.3-9.3. The maximum NER (9.3) is for the FR-based pathway using GTI technology. The GHG emissions lie in the range of 1.20-8.1 kg CO2 eq/kg H2. The lowest limit corresponds to the FR-based biohydrogen production pathway using GTI technology. This study also analyzes the intensities for acid rain precursor and ground level ozone precursor. PMID- 21795043 TI - The Mycobacterium tuberculosis CysQ phosphatase modulates the biosynthesis of sulfated glycolipids and bacterial growth. AB - CysQ is a 3'-phosphoadenosine-5'-phosphatase that dephosphorylates intermediates from the sulfate assimilation pathway of Mycobacterium tuberculosis (Mtb). Here, we demonstrate that cysQ disruption attenuates Mtb growth in vitro and decreases the biosynthesis of sulfated glycolipids but not major thiols, suggesting that the encoded enzyme specifically regulates mycobacterial sulfation. PMID- 21795044 TI - Design, synthesis and biological evaluation of novel nitroaromatic compounds as potent glutathione reductase inhibitors. AB - Discovery of GR inhibitors has become very popular recently due to antimalarial and anticancer activities. In this study, the synthesis and GR inhibitory capacities of novel nitroaromatic compounds (NCs) (1-3) were reported. Some commercially available molecules were also tested for comparison reasons. The novel NCs were obtained in high yields using simple chemical procedures and exhibited much potent inhibitory activities against GR at low micromolar concentrations with K(i) values ranging from 0.211 to 4.57 MUM as compared with well-known agents. Inhibition mechanism was assessed as being due to occlusion of the active site entrance by means of the NCs. Molecular docking results have shown that docking poses of ligands are able to construct binding interactions with the essential amino acids. PMID- 21795045 TI - Synthesis, antiproliferative activities and in vitro biological evaluation of novel benzofuransulfonamide derivatives. AB - In a cell-based screen of novel antiproliferative agents, the hit compound 1a, which bears a benzofuransulfonamide scaffold, exhibited broad-spectrum antiproliferative activities against a panel of tumor cell lines. The promising in vitro antiproliferative activity and structural novelty of 1a prompted us to investigate the synthesis of five analogs of 1a and test their antiproliferative activities. The most potent analogue, 1h, exhibited enhanced antiproliferative activities compared with the parent 1a, and exhibited an IC(50) value against NCI H460 cells of 4.13 MUM compared with 4.52 MUM for the positive control cisplatin. Flow cytometric analysis revealed that 1h induces significant levels of apoptosis in NCI-H460 cells in vitro at low micromolar concentrations. These results suggest that 1a and analogs based on its benzofuransulfonamide scaffold may constitute a novel class of antiproliferative agents, which deserve further study. PMID- 21795046 TI - Effect of plantar desensitization on postural adjustments prior to step initiation. AB - Plantar cutaneous afferent provides information about the contact between the body and the support surface and could affect the anticipatory postural adjustments (APAs). This study investigated the effect of plantar desensitization on the APAs for step initiation. Twenty-five healthy young adults participated in this study and were instructed to begin walking as fast as possible under 4 plantar desensitization conditions, none (NoneD), and desensitization of the stepping, supporting or bilateral (BilD) plantar surfaces, with eyes open or closed. The desensitization was achieved by cold water immersion of the plantar surface for 15 min. Foot switches recorded the timing of the stepping events. Surface electromyography (EMG) recorded the activation of bilateral tibialis anterior. The center of pressure (COP) and ground reaction force (GRF) data were derived from the force platform on which the subject initiated walking. The results showed that during the anticipation phase, the peak COP displacement toward the stepping leg was significantly smaller in BilD than in unilateral desensitization, which in turn was smaller than in NoneD, regardless of vision. The time to reach the peak COP displacement was significantly sooner with plantar desensitization in the eyes open condition. The GRF, EMG and anteroposterior COP displacement or the timing of the stepping events was not affected by plantar desensitization. These findings indicate that plantar cutaneous afferent contributed to the control of the APAs for step initiation by scaling the displacement of the mediolateral COP displacement and loss of its sensitivity could not be compensated by visual inputs. PMID- 21795047 TI - HIV-Nef and AIDS pathogenesis: are we barking up the wrong tree? AB - After two decades of research the Nef protein of human immunodeficiency virus (HIV) remains a mysterious protein with an indisputable role in HIV pathogenesis. The ability to downregulate CD4 and major histocompatibility complex class I (MHC I) was the first ascribed function of Nef and, whereas the number of downmodulated receptors by Nef is rising, so are the explanations for how their downregulation could contribute to HIV pathogenesis. At the same time there is increasing evidence that Nef not only induces endocytosis but also exocytosis, namely of cytokines and microvesicles that contain Nef itself. Because endocytosis and exocytosis are connected events, this is not surprising - and raises the intriguing possibility that HIV aims at secretion rather than ingestion. Have we therefore barked up the wrong tree over the past two decades? In this opinion article I argue that Nef-induced secretion is most probably the pathogenesis-relevant function behind this elusive viral effector. PMID- 21795048 TI - Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. AB - Growing evidence suggests that interleukin (IL)-17 and IL-17-secreting CD4(+)T (Th17) cells are involved in the pathogenic mechanisms of multiple sclerosis (MS). IL-17-secreting CD8(+)T cells were recently identified as a novel subset of CD8(+)T cells. We aimed to analyze the role of Th17 and IL-17 secreting CD8(+)T cells in the pathogenesis of neuromyelitis optica (NMO) as well as MS. Fourteen patients with NMO, 20 with MS and 16 control participants (CTL) were enrolled between November 2008 and December 2009. The proportion of Th17 cells and IL-17 secreting CD8(+)T cells were counted using flow cytometry, and serum levels of IL 6, IL-17, IL-21, IL-23, and transforming growth factor-beta (TGF-beta) were measured by enzyme-linked immunosorbent assay. Patients with NMO had a larger proportion of Th17 cells than patients with MS (3.72% versus [vs.] 2.58%, p=0.02) and CTL (3.72% vs. 1.36%, p<0.001). The proportion of Th17 cells in patients with MS was also markedly higher than in the CTL (2.58% vs. 1.36%, p<0.001). IL-17 secreting CD8(+)T cell counts in NMO patients were markedly higher than in MS patients (1.61% vs. 1.09%, p=0.036) and CTLs (1.61% vs. 0.58%, p<0.001). The proportion of IL-17-secreting CD8(+)T cells in MS patients was also higher than in CTLs (1.09% vs. 0.58%, p=0.002). Serum IL-17 and IL-23 levels were increased in patients with NMO and MS, while serum IL-21 concentration was higher only in NMO patients compared to CTL. We concluded that Th17 cells were highly activated in patients with NMO. IL-17-secreting CD8(+)T cells were increased in patients with NMO and MS during relapse and have an important role in the pathological mechanism of NMO and MS. PMID- 21795049 TI - Balloon-assisted looping technique to perform carotid artery stenting. AB - An acute angle, <90 degrees, at the origin of the internal carotid artery from the common carotid artery poses a significant impediment to carotid artery stenting. We present a "balloon-assisted looping technique" that may facilitate successful crossing of the guidewire over this acute angle and enable successful carotid stenting in protected and unprotected endovascular procedures in patients with these challenging stenoses. PMID- 21795050 TI - A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis. AB - We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed. PMID- 21795051 TI - Current status of computational fluid dynamics for cerebral aneurysms: the clinician's perspective. AB - The ultimate management goal for unruptured intracranial aneurysms is to select the aneurysms at risk of rupture and treat them. Computational fluid dynamics (CFD) utilizes mechanical engineering principles to explicate what occurs in tubes (vessels) and bulges (aneurysms). CFD parameters have been related to the biological processes that occur in the aneurysm wall, and models have been developed to predict the risk of aneurysm rupture. A PubMed search from 1 January 1970 to 30 November 2010 was carried out using the keywords "computational fluid dynamics" AND "cerebral aneurysm". References were also reviewed for relevant articles. All relevant articles were then reviewed by a vascular neurosurgeon, who found that the hemodynamic parameters of wall shear stress (WSS), WSS gradient, inflow jet, impingement zone, and aneurysm inflow-angle (IA) lack the predictive values required for clinical practice. CFD study can now be simulated and reproduced in a simple and fast analysis of steady, non-pulsatile flow with phase contrast magnetic resonance-derived volumetric inflow rate but the key question of whether a patient-specific CFD model can predict the rupture risk of unruptured intracranial aneurysms remains to be determined in future studies incorporating multivariate analysis. CFD models will become available for routine clinical practice as the computational power of computers further improves. PMID- 21795052 TI - Clinical features and microsurgical treatment of pediatric patients with cerebral cavernous malformation. AB - The aim of the present study was to describe the clinical features and to evaluate the surgical treatment outcomes of pediatric patients with cerebral cavernous malformations (CCM). We investigated 85 children (53 boys and 32 girls), aged from 6 months to 17.9 years with CCM. Seizures and symptomatic hemorrhages, which were the most frequent symptoms, occurred in 81 patients. Nine patients had a positive family history of CCM. Eighty patients underwent microsurgical treatment after strict operative indications were met. Neuronavigation, combined with intraoperative ultrasonography or functional MRI, was used for precise localization of the lesions. The principles of minimally invasive techniques were followed during surgery. A total of 89 lesions were removed in 80 patients, and there were no deaths. During their hospital stay, only nine patients suffered from postoperative seizures, which were controlled with medication. Postoperative neurological deficits improved in 27 patients, were unchanged in nine, and worsened in two. With the help of advanced neuroimaging, a satisfactory surgical outcome was achieved for 10 lesions located in eloquent brain areas and four lesions in the brain stem. A follow-up study of 66 patients showed that all of these patients remained seizure-free, and nine patients with postoperative neurological deficits gradually recovered. Microsurgical treatment should be performed early for pediatric patients with CCM. Accurate localization of the lesions and the use of minimally invasive techniques and functional MRI monitoring were the key features of the surgical procedures. PMID- 21795053 TI - Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis. AB - Novel vitamin D(3) analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1alpha-hydroxy group and/or 3beta-hydroxy group of 1alpha,25-dihydroxyvitamin D(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration. PMID- 21795054 TI - Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2'-C-piperazino-UNA monomer. AB - Thrombin binding aptamer is a DNA 15-mer which forms a G-quadruplex structure and possess promising anticoagulant properties due to specific interactions with thrombin. Herein we present the influence of a single 2'-C-piperazino-UNA residue and UNA residues incorporated in several positions on thermodynamics, kinetics and biological properties of the aptamer. 2'-C-Piperazino-UNA is characterized by more efficient stabilization of quadruplex structure in comparison to regular UNA and increases thermodynamic stability of TBA by 0.28-0.44 kcal/mol in a position depending manner with retained quadruplex topology and molecularity. The presence of UNA-U in positions U3, U7, and U12 results in the highest stabilization of G quadruplex structure (DeltaDeltaG(37)( degrees )=-1.03kcal/mol). On the contrary, the largest destabilization mounting to 1.79 kcal/mol was observed when UNA residues were placed in positions U7, G8, and U9. Kinetic studies indicate no strict correlation between thermodynamic stability of modified variants and their binding affinity to thrombin. Most of the studied variants bind thrombin, albeit with decreased affinity in reference to unmodified TBA. Thrombin time assay studies indicate three variants as being as potent as TBA in fibrin clotting inhibition. PMID- 21795055 TI - 15Mcps photon-counting X-ray computed tomography system using a ZnO-MPPC detector and its application to gadolinium imaging. AB - 15Mcps photon-counting X-ray computed tomography (CT) system is a first generation type and consists of an X-ray generator, a turntable, a translation stage, a two-stage controller, a detector consisting of a 2mm-thick zinc-oxide (ZnO) single-crystal scintillator and an MPPC (multipixel photon counter) module, a counter card (CC), and a personal computer (PC). High-speed photon counting was carried out using the detector in the X-ray CT system. The maximum count rate was 15Mcps (mega counts per second) at a tube voltage of 100kV and a tube current of 1.95mA. Tomography is accomplished by repeated translations and rotations of an object, and projection curves of the object are obtained by the translation. The pulses of the event signal from the module are counted by the CC in conjunction with the PC. The minimum exposure time for obtaining a tomogram was 15min, and photon-counting CT was accomplished using gadolinium-based contrast media. PMID- 21795056 TI - Thirty years' experience of open-repair surgery for pectus excavatum: development of a metal-free procedure. AB - OBJECTIVE: Throughout the history of surgery for pectus excavatum (PE), the Nuss procedure and open repair have been performed with many modifications, with most of these procedures using a metal bar. However, the use of a metal bar has several drawbacks. Thus, we aimed to develop a procedure that did not require a metal bar. METHODS: Through our experience of 426 pediatric cases that underwent various procedures for open repair of PE at Nagoya City University, we arrived at the current procedure that we describe herein. We have evaluated this procedure by review of clinical results and deformity indices (Haller's, steepness, excavation volume, and asymmetry index). RESULTS: The latest and current procedure that supports the sternum with a bridge constructed by the 4th or 5th costal cartilages is associated with fewer complications, a lower re-operation rate, and striking improvement in the indices examined. CONCLUSIONS: Our current open-repair procedure that does not require a metal bar is recommended for correction of deformities of PE in children. PMID- 21795058 TI - The 2010 ESC/EACTS guidelines on myocardial revascularization does not present suggestions about disease-free saphenous vein grafts at the time of redo coronary artery bypass grafting. PMID- 21795059 TI - The danger of conversion. PMID- 21795060 TI - Anomalous right coronary artery from the left sinus: a minimally invasive approach. AB - OBJECTIVE: Anomalous right coronary artery arising from the left sinus (ARCA) is a known cause of sudden cardiac death, particularly in young athletes. Surgery is recommended for all adult patients who are symptomatic or who have evidence of exercise-induced myocardial ischemia. Surgical options include coronary artery bypass grafting (CABG) and anatomic correction by unroofing the ostium or by reimplanting the ostium into the right sinus of Valsalva. We describe the rationale and technique of a minimally invasive right thoracotomy approach for correction of ARCA. METHODS: We reviewed all patients with coronary artery disease operated upon at Mount Sinai Medical Center. Between March 2008 and September 2010, 17 patients underwent surgery for anomalous coronary origin from the opposite sinus of Valsalva. Nine of these patients had ARCA. We describe four adult patients with ARCA who were operated upon using a small right anterior thoracotomy incision to perform a right internal mammary artery (RIMA) to right coronary artery (RCA) bypass with ligation of the proximal RCA. This was performed under direct vision and without cardiopulmonary bypass. RESULTS: There were two male and two female patients. Mean age was 55.3 +/- 4.8 years (range 50 61 years). Three of the patients manifested chest pain and one each syncope, dyspnea, and palpitations. Two patients had preoperative stress testing that was positive for ischemia. Postoperative follow-up (mean 14 months and range 5-37 months) is complete. All patients are alive and asymptomatic. CONCLUSIONS: ARCA can be managed with good early and midterm results using a minimally invasive right thoracotomy approach. PMID- 21795061 TI - Effect of N-methyl-D-aspartate receptor antagonist on T helper cell differentiation induced by phorbol-myristate-acetate and ionomycin. AB - AIM: To investigate the effect of N-methyl-D-aspartate (NMDA) receptor antagonist on T helper (TH) cell differentiation and intracellular transcriptional factors in vitro. METHODS: Ten male healthy volunteers (aged 20-45 y, BMI 18-25) were enrolled in this study. Twenty milliliters peripheral blood was collected in the morning from fasted volunteers and peripheral blood mononuclear cells (PBMC) were isolated. PBMC were incubated with phorbol-myristate-acetate (25 ng/ml) (PMA) plus ionomycin (1 MUg/ml) in the presence of ketamine or MK-801 at 37 degrees C. TH subsets, supernatant interferon gamma (IFN-gamma), interleukin 4 (IL-4), and intracellular transcriptional factors T-bet and GATA3 were analyzed 4 h later. RESULTS: The number of TH0 cells was kept constant and at baseline before PMA and ionomycin stimulation in each group. TH1 cells, TH2 cells, IFN-gamma and IL-4 levels were significantly increased after PMA and ionomycin stimulation. Ketamine and MK-801 decreased TH1 cells, TH2 cells, IFN-gamma and IL-4 levels but increased the ratio of TH1/TH2 and IFN-gamma/IL-4 in the presence of PMA and ionomycin. Ketamine or MK-801 alone had no effect on either of them. T-bet and GATA3 activities in PBMC were significantly increased after PMA and ionomycin stimulation. Ketamine and MK-801 decreased T-bet and GATA3 activities but increased the ratio of T-bet/GATA3 following PMA and ionomycin stimulation. Ketamine or MK-801 alone had no effect on the activity of T-bet, GATA3 or T bet/GATA3. CONCLUSION: NMDA antagonist can suppress TH cell differentiation and subsequent cytokines production but increase TH1/TH2 ratio following PMA and ionomycin stimulation, it may be related to its regulation on T-bet and GATA3 activities. PMID- 21795062 TI - Trans-10, cis-12-conjugated linoleic acid attenuates tumor necrosis factor-alpha production by lipopolysaccharide-stimulated porcine peripheral blood mononuclear cells through induction of interleukin-10. AB - Conjugated linoleic acid (CLA) can stimulate or inhibit immune cell function, and among CLA isomers, trans-10, cis-12 (t10c12)-CLA was shown to participate in the modulation of pro- or anti-inflammatory cytokine secretion. The objective of this study was to examine the effect of t10c12-CLA on tumor necrosis factor (TNF) alpha production by lipopolysaccharide (LPS)-stimulated porcine peripheral blood mononuclear cells (PBMCs). In addition, we determined whether these effects were associated with the induction of interleukin (IL)-10. Treatment of LPS unstimulated porcine PBMCs with t10c12-CLA increased both TNF-alpha expression and IL-10 production. However, treatment of LPS-stimulated porcine PBMCs with t10c12-CLA suppressed TNF-alpha production and increased the levels of IL-10. Furthermore, treatment of LPS-stimulated porcine PBMCs with IL-10 suppressed the production of TNF-alpha. The effects of t10c12-CLA on TNF-alpha expression by both LPS-naive and LPS-stimulated PBMCs were inhibited by IL-10 treatment. The suppressive effects of t10c12-CLA on TNF-alpha production by LPS-stimulated porcine PBMCs were inhibited by an anti-IL-10 polyclonal antibody. These findings suggest that t10c12-CLA has an immunostimulatory effect on porcine PBMCs mediated via the up-regulation of TNF-alpha production, and an anti-inflammatory effect in LPS-stimulated PBMCs mediated via the down-regulation of TNF-alpha production, and that both is likely to be associated with the induction of IL-10. PMID- 21795063 TI - Serum levels of interleukin (IL)-27 in patients with ischemic heart disease. AB - OBJECTIVE: Cytokines, the key mediators of immune responses, play an important role in the pathogenesis of cardiovascular diseases. The aim of this study was to evaluate the serum levels of IL-27 in patients with ischemic heart disease (IHD) and also to clarify its association with traditional risk factors of the disease. METHODS: A total of 120 patients with IHD as having acute myocardial infarction (AMI; n=60) or unstable angina (UA; n=60) and 60 sex- and age-matched healthy subjects as a control group were enrolled in this cross-sectional, case controlled study. Serum samples were collected from all participants (for AMI patients at 3-5 days after events and for UA at admission time) and tested for the levels of IL-27 by use of ELISA method. RESULTS: The mean serum levels of IL 27 in AMI group (38.00+/-14.38 Pg/ml) and UA group (35.77+/-18.93 Pg/ml) were significantly higher than those observed in the control group (24.91+/-14.96 Pg/ml; P<0.0001 and 0.001, respectively). The mean serum levels of IL-27 in IHD patients with or without a certain traditional risk factor including hypertension, dyslipidemia, diabetes smoking were significantly higher as compared to those in the control group. CONCLUSIONS: These results showed that the higher serum levels of IL-27 were associated with IHD. The presence or absence of certain traditional risk factors of IHD did not influence the serum levels of cytokine. PMID- 21795064 TI - An in vitro evaluation of inflammation response of titanium functionalized with heparin/fibronectin complex. AB - Immobilization of biomolecules with a variety of biological functions has been a promising method to improve the biocompatibility of biomaterials. However, little is known about their inflammatory property and cytotoxicity, which are both key aspects to most biomaterials designed for tissue engineering applications and in vivo implantation. In this in vitro study, heparin/fibronectin complex (Hep/Fn) was coimmobilized onto titanium surface (HF-Ti), which had been proven to have the properties of both anticoagulation and endothelialization in our previous study. Fourier transform infrared (FTIR) spectroscopy and water contact angle measurement were utilized to determine the surface chemical compositions and physical properties. Toluidine Blue O (TBO) and immunochemistry methods were performed to quantify the surface-immobilized heparin and fibronectin. The early inflammatory responses elicited by pristine Ti and HF-Ti were investigated by proinflammatory cytokine secretion of tumor necrosis factor-alpha (TNF-alpha) released by attached peritoneal macrophages, monocyte chemoattractant protein-1 (MCP-1) and interleukin-1beta (IL-1beta) released by attached human umbilical vein endothelial cells (ECs), respectively. Scanning electronic microscopy (SEM) and immunofluorescence were employed to investigate the changes in macrophages and ECs morphologies. The incubation period for both cells was 24h and the results showed that HF-Ti revealed a weaker inflammatory response than pristine Ti, which provoked a stronger inflammatory response and higher activation of macrophages. Our data suggest that Hep/Fn coimmobilized biomaterials surface may develop to be a new generation of biomaterials with both biocompatibility and anti-inflammatory properties, especially for used as cardiovascular implants and in tissue engineering applications. PMID- 21795065 TI - Diffusion tensor imaging for intracerebral hemorrhage outcome prediction: comparison using data from the corona radiata/internal capsule and the cerebral peduncle. AB - BACKGROUND: Magnetic resonance-diffusion tensor imaging (DTI) was used to predict motor outcome for patients with intracerebral hemorrhage. We compared the predictive accuracy of data sampled from the cerebral peduncle with data from the corona radiata/internal capsule. This study included 32 subjects with thalamic or putaminal hemorrhage or both. METHODS: DTI data were obtained on days 14 to 18. Mean values of fractional anisotropy (FA) within the cerebral peduncle and the corona radiata/internal capsule were analyzed using a computer-automated method. Applying ordinal logistic regression analyses, the ratios between FA values in the affected and unaffected hemisphere (rFA) were modeled in relation to motor outcome scores at 1 month after onset, assessed using the Medical Research Council (MRC) scale (0 = null to 5 = full). RESULTS: For both cerebral peduncle and corona radiata/internal capsule, the relationships between rFA and MRC matched logistic probabilities. While cerebral peduncle rFA values had statistically significant relationships with MRC scores (upper extremity R(2) = 0.271; lower extremity R(2) = 0.191), rFA values for the corona radiata/internal capsule showed less significant relationships (upper extremity R(2) = 0.085; lower extremity R(2) = 0.080). When estimated cerebral peduncle rFA values were <0.7, estimated probability of MRC 0 to 2 was close to 85% for the upper and 60% for the lower extremities. Meanwhile, when estimated rFA values were >0.9, estimated probability for MRC 4 to 5 nearly equaled 50% for the upper and 60% for the lower extremities. CONCLUSIONS: FA values from within the cerebral peduncle more accurately predicted motor outcome and is a promising technique for clinical application. PMID- 21795067 TI - Inflammatory response to recombinant human bone morphogenetic protein-2 use in the treatment of a proximal humeral fracture: a case report. PMID- 21795066 TI - Early aggressive medical management for patients with symptomatic intracranial stenosis. AB - BACKGROUND: There are limited data on the effect of an early aggressive risk factor modification program to achieve risk factor targets and its impact on clinical outcomes among patients with symptomatic intracranial stenosis. METHODS: We prospectively identified patients with symptomatic intracranial stenosis of 50% to 99% (using computed tomographic angiography or cerebral angiography) who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial but elected to receive aggressive medical management. Aggressive medical management was defined as aspirin plus clopidogrel therapy for a minimum of 3 months, blood pressure control, statin use with a low-density lipoprotein (LDL) goal of <70 mg/dL, smoking cessation, and body mass index <25 kg/m(2). RESULTS: Of 22 patients, the mean age was 65.6 +/- 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 +/- 9.5% (55% with 70% to 99% stenosis). Median time from symptomatic event to first evaluation was 3 days. All patients completed 3 months of dual antiplatelet therapy, and at last follow-up, 86% had met their blood pressure goal, all were on statin therapy although only 73% had met their LDL goal, 96% reported no active tobacco use, and 36% had lost weight, but only 23% had achieved the BMI target. Over a mean follow-up of 1.2 years, there was no ischemic stroke, brain hemorrhage, or death from other vascular causes. CONCLUSIONS: An early aggressive risk factor modification program achieved high levels of blood pressure and cholesterol targets for patients with symptomatic intracranial stenosis and when combined with dual antiplatelet therapy was effective for the prevention of recurrent vascular events in this cohort. PMID- 21795068 TI - Patients with epilepsy and patients with psychogenic non-epileptic seizures: video-EEG, clinical and neuropsychological evaluation. AB - PURPOSE: The incidence of psychogenic non-epileptic seizures (PNES) is 4.9/100,000/year and it is estimated that about 20-30% of patients referred to tertiary care epilepsy centers for refractory seizures have both epilepsy and PNES. The purpose of our study is to evaluate psychiatric disorders and neuropsychological functions among patients with PNES, patients with epilepsy associated with PNES and patients with epilepsy. METHODS: We evaluated 66 consecutive in-patients with video-EEG recordings: 21 patients with epilepsy, 22 patients with PNES and 10 patients with epilepsy associated with PNES; 13 patients were excluded (8 because of mental retardation and 5 because they did not present seizures or PNES during the recording period). RESULTS: All patients with PNES had a psychiatric diagnosis (100%) vs. 52% of patients with epilepsy. Cluster B personality disorders were more common in patients with PNES. We observed fewer mood and anxiety disorders in patients with PNES compared with those with epilepsy. We did not find statistically significant differences in neuropsychological profiles among the 3 patient groups. CONCLUSION: This study can help to contribute to a better understanding of the impact of PNES manifestations, in addition to the occurrence of seizures, in order to provide patients with more appropriate clinical, psychological and social care. PMID- 21795069 TI - MRI diagnosis of pelvic organ prolapse compared with clinical examination. AB - RATIONALE AND OBJECTIVES: The aims of this study were to determine agreement between clinical examination and magnetic resonance imaging (MRI) (rectal contrast and noncontrast MRI) for pelvic organ prolapse using both the pubococcygeal line (PCL) and the midpubic line (MPL) and to assess the relationship between measurements performed relative to each line. MATERIALS AND METHODS: Dynamic MRI exams in 88 women (with rectal contrast, n = 39; noncontrast, n = 49) were evaluated, followed by review of clinical exam notes. Agreement between clinical exam and MRI and the difference between PCL and MPL measurements were evaluated. RESULTS: Agreement of rectal contrast MRI with clinical exam was 79% for PCL and 85% for MPL (P = .17) for cystoceles, 50% for PCL and 59% for MPL (P = .20) for vaginal prolapse, 56% for PCL for enteroceles, and 61% for rectoceles. Agreement of noncontrast MRI with clinical exam was 67% for PCL and 78% for MPL (P = .19) for cystoceles, 58% for PCL and 71% for MPL (P = .10) for vaginal prolapse, 65% for enteroceles, and 40% for rectoceles. The average difference between the PCL and the MPL was 3.12 +/- 0.24 cm at the bladder base and 4.88 +/- 0.37 cm at the vaginal apex. CONCLUSIONS: Agreement of MRI with clinical exam was highest for cystoceles. There was no significant difference in agreement using the MPL or PCL, suggesting that either line can be used on MRI. The average differences between the PCL and MPL at the bladder base and vaginal apex were approximately 3 and 5 cm, respectively. PMID- 21795070 TI - Population based analysis of survival in patients with renal cell carcinoma and venous tumor thrombus. AB - OBJECTIVES: To identify prognostic factors for renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and determine the significance of thrombus level on survival. MATERIALS AND METHODS: Patients within the Surveillance, Epidemiology, and End Results (SEER) database with RCC and VTT were identified and included if managed surgically. The Kaplan-Meier method and Cox regression analyses were performed to identify factors associated with disease-specific survival. RESULTS: A total of 1,875 patients met the inclusion criteria. One-year survival for patients undergoing surgery was 60% for patients with metastases and 90% for those without. Factors associated with worse survival included larger tumor size (HR 1.2, 95% CI 1.0-1.4), medullary, collecting duct, or sarcomatoid histology (HR 2.2, 95% CI 1.5-3.3), Fuhrman grade 3 (HR 2.2, 95% CI 1.5-3.3) or grade 4 (HR 2.9, 95% CI 1.8-4.5) tumors, positive lymph nodes (HR 1.5, 95% CI 1.0-2.0), and metastases (HR 3.5, 95% CI 2.6-4.8). Thrombus level above the diaphragm (T3c) was not significantly associated with worse survival (HR 1.4, 95% CI 0.8-2.5). CONCLUSIONS: In this large, population-based study of patients with RCC and VTT, we identify several disease-specific factors strongly associated with cancer specific mortality. After controlling for adverse prognostic factors, thrombus level was not associated with worse outcome. PMID- 21795071 TI - Characterization of microRNAs expression profiling in one group of Chinese urothelial cell carcinoma identified by Solexa sequencing. AB - OBJECTIVE: The goal of this study was to extend the known repertoire of microRNAs (miRNAs) expressed in urothelial bladder cancer (BCa) of the Chinese population and further understand the molecular events of miRNAs underlying urothelial bladder tumorigenesis at the global genome level. MATERIALS AND METHODS: We separated well-characterized epithelial tumor cells from 20 moderately differentiated or poorly differentiated BCa specimens by laser capture microdissection (LCM) and pooled these cells of interest prior to RNA analysis. Ten normal bladder epithelia (NBE) samples were pooled as the control. After preparation of small RNAs library, the 2 samples were sequenced simultaneously by the next generation high through-put Solexa sequencing technology. RESULTS: We employed the next generation high through-put Solexa sequencing technology to clone and identify miRNAs in BCa and NBE, and generated 11,146,610, and 10,263,845 high quality sequence reads, respectively. According to the analysis of size distribution, 22 nt class was the most abundant group of small RNAs in the BCa. Likewise, the 20 and 22 nt sequences were significantly greater than shorter or longer sequences, and accounted for 59.55% of the total sequence number of NBE library. The whole-genome-scale data mining suggested that BCa and NBE libraries both contained multiple and heterogeneous small RNA species. On further analysis, the sequencing data revealed that different miRNAs showed clearly in-house differential expression levels in BCa and NBE and 74 miRNAs aberrantly expressed between BCa and NBE at the global genome level. We also predicted 13 novel miRNAs in both BCa and NBE libraries. CONCLUSIONS: Our results suggest that BCa miRNAs include a large proportion of conserved miRNAs and a set of non-conserved miRNAs with low expression levels. These known and newly identified miRNAs at the population level significantly enhance our knowledge of BCa miRNAs expression profiling and provide insights into miRNAs oncogenesis and oncotherapy in BCa. Further studies are necessary to elucidate the roles of miRNAs in urothelial bladder tumorigenesis and determine the potential of miRNAs as diagnostic and prognostic tools or therapeutic targets for BCa in the future. PMID- 21795072 TI - Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients. AB - PURPOSE: To evaluate the tumor-related expression profile of cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein (cIAP2) in patients with bladder cell carcinoma (BCC) and to investigate its potential prognostic value. METHODS: The expression of cIAP1 and cIAP2 was examined immunohistochemically in archival bladder specimens from 32 normal controls and 102 consecutive patients who underwent surgical operations at our department from January 2004 through December 2005. Cytoplasm cIAP1 and cIAP2 expression was scored as 0 (negative), +1 (weak), +2 (medium), and +3 (strong). Nuclear cIAP1 expression was scored as 0 (0%), +1 (1%-25%), +2 (26%-50%), and +3 (>50%). Proliferation was determined by Ki67 staining as percentage of positive cells. RESULTS: cIAP1 and cIAP2 expression were significantly increased in bladder cancer compared with normal bladder urothelium (cIAP1-C: P < 0.01, cIAP2 C: P = 0.017, cIAP1-N: P < 0.01). Nuclear staining of cIAP1 (cIAP1-N) was significantly associated with tumor stage (muscle invasive vs. non-muscle invasive, P = 0.03) and tumor grade (low vs. high, P = 0.01). Both the mean overall survival and mean recurrence-free survival were significantly decreased in the high cIAP1-N group compared to the low cIAP1-N group (low cIAP1-N: mean overall survival 62.7 months, high cIAP1-N: mean overall survival 45.6 months, P < 0.01; low cIAP1-N: mean recurrence-free survival 44.2 months, high cIAP1-N: mean recurrence-free survival 30.1 months, P < 0.01). cIAP1-N expression correlated strongly with KI67 expression (r = 0.744, P < 0.01). CONCLUSION: Nuclear cIAP-1 expression strongly correlated to bladder cancer stage, tumor grade, tumor recurrence and tumor related death. This marker expression was also appears to be a marker in bladder cancer prognosis. PMID- 21795073 TI - Low-dose diethylstilbestrol for the treatment of advanced prostate cancer. AB - OBJECTIVES: The purpose of this study was to assess the efficacy and safety of low-dose (1 mg) daily diethylstilbestrol (DES) for the treatment of castrate resistant prostate cancer (CRPC). MATERIALS AND METHODS: A retrospective chart review was performed on patients treated with low-dose DES who had CRPC despite anti-androgen withdrawal. The study population consists of 63 patients treated in the pre- and post-chemotherapy settings based on a database review; 58 had sufficient data for efficacy, all were analyzed for safety. RESULTS: A PSA decrease of >=50% was observed in 19 of 49 pre-chemotherapy patients (39%) with a median time to progression (TTP) of 30 weeks (95% CI, 21.9, 68.7). A PSA decrease of <50% was seen in another 16 patients (33%) with a median TTP of 16.4 weeks (95% CI, 13.0, 37.6). Fourteen patients (29%) had progressive disease by PSA testing; their median TTP was 6.9 weeks (95% CI, 5.6, 12.9). Thromboembolic events included 2 patients with DVTs and 1 patient who developed primary fibrinolysis syndrome. Additional adverse events included gynecomastia in 37 of 63 patients (59%). Secondary observations included PSA responses in 3 of 9 patients treated with DES after chemotherapy progression and a high rate of PSA responses in patients re-treated with DES after a drug holiday. CONCLUSIONS: Low dose DES is safe and effective in a modern cohort of men with CRPC despite anti androgen treatment. Its potential role in the post-chemotherapy setting and the suggestion of efficacy on re-challenge merits additional consideration. PMID- 21795074 TI - Combination of docetaxel and vandetanib in docetaxel-sensitive or resistant PC3 cell line. AB - OBJECTIVE: To examine the anti-proliferative effect of the combination of docetaxel, the cornerstone of modern chemotherapy for prostate cancer, and vandetanib, a potent inhibitor of VEGFR-2 tyrosine kinase, applied to the representative hormone-refractory human prostate cancer cell line PC3. The aim is to analyze if a supra-additive/synergic effect of the combined treatment on cell viability exists and to understand the molecular key-factors involved. We first hypothesized an effect of vandetanib in modulation the function of MDR1, leading to a longer retention of docetaxel inside the cell. It may also be possible that vandetanib could modulate the docetaxel-induced changes in expression of prosurvival and proapoptotic proteins, leading to a positive balance forward cell death. MATERIALS AND METHODS: We used PC3 cells either wild type (PC3wt) or with acquired resistance to docetaxel (PC3R), characterized by a higher expression of MDR1. We studied both mRNA and protein, the expression of EGF and VEGF receptors at a basal level and after each treatment, as well as the expression of cell cycle and apoptosis related genes. RESULTS: Cell proliferation data suggested a supra-additive cytotoxic effect of the combination of docetaxel plus vandetanib, when given together or with the sequence vandetanib followed by docetaxel. We did not observe any effect of vandetanib on MDR1, in the PC3R cell lines, characterized by a higher pump expression than PC3wt. On the other side, we defined a number of key factors involved in the pro- and anti-survival balance, which regulation, by single drugs and/or by combined treatment, could explain the effect on cell cytotoxicity; also where there are apparently contradictory results. CONCLUSIONS: Our data suggest that combined treatment with vandetanib and docetaxel alters the balance of proapoptotic and prosurvival proteins, ultimately leading to potentiation of docetaxel-induced apoptosis in human prostate cancer cells in vitro, irrespective of cells being sensitive or resistant to docetaxel. PMID- 21795075 TI - Perineural invasion detection in prostate biopsy is related to recurrence-free survival in patients submitted to radical prostatectomy. AB - OBJECTIVE: Perineural invasion (PNI) is detected in almost 20% of prostate biopsies and has been related to worse prognostic factors in radical prostatectomy (RP) specimens and lower disease-free survival rates. The aim of this study was to evaluate the importance of PNI during periods of extended prostate biopsies and to determine the value of this preoperative parameter as a predictor of pathologic findings in surgical specimens and in biochemical recurrence. MATERIALS AND METHODS: Between 2001 and 2009, 599 prostate biopsies and their respective RP specimens were examined in our laboratory. The RP specimens were always examined completely. The mean age of the patients was 61 years, and the mean PSA was 6.4 ng/mL. The mean and median number of biopsy cores obtained was 14.4 and 14, respectively. PNI was identified in 105 biopsies (17.5%). We studied the ability of PNI in prostate biopsies to determine the tumor stage in surgical specimens and the relationship of PNI with biochemical recurrence during a mean follow-up time of 51.4 months. RESULTS: The presence of PNI in prostate biopsies was observed in older patients (63 vs. 61 years old, P = 0.008). All of the prognostic factors determined for the RP specimens were significantly worse in patients with PNI compared with those without PNI. PNI was strongly associated with a higher pathologic stage (87% specificity, 40% sensitivity, odds ratio 4.8). Stage pT3 prostatic cancer was determined in 46 (43.8%) of 105 patients with PNI on biopsy compared to 69 (14%) of 494 patients without PNI (P = 0.01). Fifty-six (19.6%) patients had a biochemical recurrence, and PNI correlated significantly with PSA recurrence. A Kaplan-Meier analysis revealed a significant difference in recurrence-free survival between patients with and without PNI (45% vs. 53%, respectively, P = 0.021, log-rank test = 0.19). CONCLUSION: PNI is an important morphologic preoperative predictor of the pathologic stage as well as biochemical recurrence and must always be mentioned when adenocarcinoma is diagnosed on prostate biopsies. PMID- 21795076 TI - Candidacy for active surveillance may be associated with improved functional outcomes after prostatectomy. AB - OBJECTIVE: In an effort to curb overtreatment, active surveillance (AS) has grown in popularity as an option for men with low-risk prostate cancer. We evaluated the histopathologic and functional outcomes of patients who qualified for AS, but opted for robotic-assisted laparoscopic prostatectomy (RALP), and compared them to non-AS candidates. METHODS: An institutional database of 1,477 RALP performed by a single surgeon was queried for AS candidates, defined as PSA <10 ng/mL, biopsy Gleason score <=6 with a minimum of 10 biopsy cores, <3 positive cores with <50% tumor volume in a single core and clinical stage <=T2a. RESULTS: Of the 352 patients who would have qualified for AS, 159 (45%) were upgraded: 143 (41%) to Gl 3 + 4, 16 (4.5%) to 4 + 3, zero to Gleason 8 or higher. Seventeen (4.8%) patients were upstaged to pT3. AS candidates were younger and had more favorable tumor characteristics, but similar preoperative functional status. Bilateral nerve sparing was performed on 96% of AS candidates vs. 86% of non-AS candidates (P < 0.001). After 12 months of follow-up in patients who received bilateral nerve sparing, continence was higher in the AS cohort (98% vs. 92%, P < 0.001) but potency was equivalent (87% in each, P = 0.89). On multivariable analysis, candidacy for AS was independently associated with improved continence, but not potency. CONCLUSIONS: In addition to having the expected favorable histopathologic features, AS candidates who desire definitive therapy have a high likelihood of achieving excellent functional outcomes, perhaps superior to non-AS candidates, following RALP. PMID- 21795077 TI - Attenuation of androgenic regulation by brefeldin A in androgen-responsive prostate cancer cells. AB - OBJECTIVES: To investigate the effects of an antibiotic brefeldin A (BFA) on androgen-regulated cellular events in androgen-responsive prostate cancer cells, focusing on PSA (prostate-specific antigen) status, cell growth, and bioactivity of androgen receptor (AR). MATERIALS AND METHODS: Androgen-responsive human prostate cancer LNCaP cells were employed and 5alpha-dihydrotestosterone (DHT) was used as an androgenic mediator to induce androgen-modulated cellular events. Effects of BFA on synthesis and secretion of PSA, cell growth, and AR activity were assessed using Tandem PSA assay, trypan blue exclusion method, and AR binding assay, respectively. RESULTS: BFA (30 ng/ml) dramatically (90%) blocked secretion of PSA and also reduced cell growth by >75% under non-androgen regulated condition. Under androgen-stimulated condition using DHT (1 nM), both the cellular and secreted PSA levels as well as cell growth was significantly elevated or stimulated by DHT (compared with controls); however, BFA was capable of completely inhibiting such DHT-stimulated cellular events. In addition, AR binding assay revealed that AR activity has been drastically (~90%) diminished by BFA, likely resulting in interruption of DHT-mediated events. CONCLUSIONS: BFA is capable of attenuating androgenic regulation in LNCaP cells such as androgen stimulated PSA synthesis/secretion and cell growth. This BFA-blocked androgen action appears to be primarily attributed to severe inactivation of AR with BFA because AR is a crucial factor for relaying androgenic messages (to DNA). Therefore, BFA could be considered a promising agent for a more effective treatment of hormone-dependent prostate cancer. PMID- 21795079 TI - WITHDRAWN: Rationale and Design of a Randomised Controlled Trial Comparing Stent Protected Angioplasty with Bypass Surgery for Intermittent Claudication: The ABC Study. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21795078 TI - Pretreatment depressive symptoms and treatment modality predict post-treatment disease-specific quality of life among patients with localized prostate cancer. AB - PURPOSE: This study examines the prevalence of depressive symptoms before prostate cancer treatment and explores associations among pre-treatment depressive symptoms and post-treatment disease-specific QOL, controlling for treatment modality, and demographic and clinical covariates. MATERIALS AND METHODS: A case series of patients diagnosed with localized prostate cancer (T1 2N0M0) at a comprehensive cancer center was assessed. Of the 1,370 eligible patients, 869 (63.34%) completed questionnaires at diagnosis (baseline) and 6 months following treatment. Patients were treated with surgery (16.8%), brachytherapy (27.6%), or external beam radiation (EBRT; 55.6%). Depressive symptoms and disease-specific QOL were assessed with established measures (i.e., Center for Epidemiologic Studies Depression Scale (CES-D); sexual adjustment questionnaire (SAQ); and the American Urological Association symptom index). RESULTS: A fifth of the sample (19.7%) reported clinically elevated levels of depressive symptoms at baseline. The proportion of clinically elevated levels of baseline depressive symptoms was higher among surgery patients compared with patients treated with brachytherapy or external beam radiation. Depressive symptoms at baseline and treatment modality significantly predicted sexual and urinary dysfunction, related bother, activity limitation due to urinary dysfunction at 6 months, controlling for, age, PSA level, Gleason score, relevant baseline indicators of sexual and urinary dysfunction, related bother, and activity limitation (P < 0.05). CONCLUSIONS: Pretreatment depressive symptoms and treatment modality predict QOL after PrCa treatment. Health care providers should be sensitive to the display of depressive symptoms before PrCa treatment and consider preventative interventions, including preparing patients for the changes in disease-specific QOL and related bother following prostate cancer treatment. PMID- 21795080 TI - The impact of gender on prognosis after non-cardiac vascular surgery. AB - OBJECTIVES: The objective was to evaluate the impact of gender on long-term survival of patients who underwent non-cardiac vascular surgery. DESIGN, MATERIAL AND METHODS: Our prospectively collected data contained information on 560 patients undergoing carotid endarterectomy (CEA), 923 elective abdominal aortic aneurysm repairs (AAA) and 1046 lower limb reconstructions (LLR). Patient characteristics and long-term mortality of women were compared to that of men. Kaplan-Meier (KM) survival curves were constructed for men and women, on which we superimposed age- and sex-matched KM survival curves of the general population. Cox proportional hazards regression was used to identify risk factors for mortality. RESULTS: Men in the CEA group had statistically significant higher all cause mortality, hazard rate ratio (HRR) 1.41 (95% CI 1.01-1.98) No differences in mortality between the genders were observed in the AAA and LLR groups. Overall, men had more co-morbidities but received more disease-specific medication compared to women. Women retained their higher life expectancy after CEA but lost it in the AAA and LLR groups. CONCLUSION: Women retain their higher life expectancy after CEA; however, after AAA repair and LLR, this advantage is lost. Both men and women received too little disease-specific medication, but women were worse off. PMID- 21795082 TI - Comparison of thyroid analytes in dogs aggressive to familiar people and in non aggressive dogs. AB - A cross-sectional study was performed in order to examine the association between canine aggression to familiar people and serum concentrations of total thyroxine (TT4), free thyroxine (fT4), thyroxine autoantibodies (T4AA), total triiodothyronine (TT3), free triiodothyronine (fT3), triiodothyronine autoantibodies (T3AA), thyroid stimulating hormone (TSH), and thyroglobulin autoantibodies (TgAA). The subjects were 31 dogs historically aggressive to familiar people and 31 dogs with no history of aggression. Behavioral evaluation and physical examination were completed for each dog in addition to a complete blood count, serum chemistry panel, TT4, fT4 by equilibrium dialysis, TT3, fT3, TgAA, T3AA, and T4AA. Significant differences were found between the two groups with respect to only T4AA, which was increased in the aggressive group, but the concentrations for both groups were within the normal reference range. There were no differences between the two groups in the thyroid analytes most commonly measured by veterinary practitioners evaluating thyroid function in dogs. The results of this study revealed no significant difference between aggressive and non-aggressive dogs in the thyroid concentrations most commonly used to diagnose canine hypothyroidism. PMID- 21795081 TI - Epidemiology of restless legs syndrome: a synthesis of the literature. AB - Restless legs syndrome (RLS) has gained considerable attention in the recent years: nearly 50 community-based studies have been published in the last decade around the world. The development of strict diagnostic criteria in 1995 and their revision in 2003 helped to stimulate research interest on this syndrome. In community-based surveys, RLS has been studied as: 1) a symptom only, 2) a set of symptoms meeting minimal diagnostic criteria of the international restless legs syndrome study group (IRLSSG), 3) meeting minimal criteria accompanied with a specific frequency and/or severity, and 4) a differential diagnosis. In the first case, prevalence estimates in the general adult population ranged from 9.4% to 15%. In the second case, prevalence ranged from 3.9% to 14.3%. When frequency/severity is added, prevalence ranged from 2.2% to 7.9% and when differential diagnosis is applied prevalence estimates are between 1.9% and 4.6%. In all instances, RLS prevalence is higher in women than in men. It also increases with age in European and North American countries but not in Asian countries. Symptoms of anxiety and depression have been consistently associated with RLS. Overall, individuals with RLS have a poorer health than non-RLS but evidence for specific disease associations is mixed. Future epidemiological studies should focus on systematically adding frequency and severity in the definition of the syndrome in order to minimize the inclusion of cases mimicking RLS. PMID- 21795083 TI - Pseudorandom selective excitation in NMR. AB - In this work, average Hamiltonian theory is used to study selective excitation under a series of small flip-angle theta-pulses [theta?pi/3] applied either periodically [corresponding to the DANTE pulse sequence] or aperiodically to a spin-1/2 system. First, an average Hamiltonian description of the DANTE pulse sequence is developed that is valid for frequencies either at or very far from integer multiples of 1tau, where tau is the interpulse delay. For aperiodic excitation, a single resonance, nusel, can be selectively excited if the theta pulse phases are modulated in concert with the interpulse delays. The conditions where average Hamiltonian theory can be accurately applied to describe the dynamics under aperiodic selective pulses, which are referred to as pseudorandom DANTE or p-DANTE sequences, are similar to those found for the DANTE sequence. Signal averaging over different p-DANTE sequences improves the apparent selectivity at nusel by reducing the excitations at other frequencies. Experimental demonstrations of p-DANTE sequences and comparisons with the theory are presented. PMID- 21795084 TI - The evolution of the search for novel genes in mammalian sex determination: from mice to men. AB - Disorders of sex determination are a genetically heterogeneous group of rare disorders, presenting with sex-specific phenotypes and variable expressivity. Prior to the advent of the Human Genome Project, the identification of novel mammalian sex determination genes was hindered by the rarity of disorders of sex determination and small family sizes that made traditional linkage approaches difficult, if not impossible. This article reviews the revolutionary role of the Human Genome Project in the history of sex determination research and highlights the important role of inbred mouse models in elucidating the role of identified sex determination genes in mammalian sex determination. Next generation sequencing technologies has made it possible to sequence complete human genomes or exomes for the purpose of providing a genetic diagnosis to more patients with unexplained disorders of sex determination and identifying novel sex determination genes. However, beyond novel gene discovery, these tools have the power to inform us on more intricate and complex regulation-taking place within the heterogeneous cells that make up the testis and ovary. PMID- 21795086 TI - Cystatin C and NT-proBNP as prognostic biomarkers in Fabry disease. AB - Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. It is characterized by the deposition of the incompletely metabolized substrate globotriaosylceramide in several cell types and multisystem involvement. Major morbidity results from renal, cardiac and cerebrovascular pathology, mediated by endothelial dysfunction. We examined the potential utility of Cystatin C and natriuretic peptides as biomarkers in FD, and evaluated serum levels in 89 FD patients with varying degrees of disease severity. The results revealed that as a prognostic marker, Cystatin C is a good and cost effective indicator of early renal dysfunction and/or heart failure in FD. It is also more useful than serum creatinine in detecting mild renal damage and small decreases in glomerular filtration. In addition, the natriuretic peptide NT-proBNP, was elevated in patients with FD and cardiac involvement, and found to be an adequate detection marker, not only of cardiac involvement, but also of diastolic dysfunction. PMID- 21795085 TI - Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. AB - Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n=197), mild statin myopathy (n=163), statin tolerant controls (n=133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n=392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology. PMID- 21795087 TI - Glucose detection and concentration estimation in feline urine samples with the Bayer Multistix and Purina Glucotest. AB - The Bayer Multistix are commonly used for detection and estimation of feline glucosuria by veterinarians and cat owners. A newer product, the Purina Glucotest, utilizes the same enzymatic technology for detection of glucose, but has been designed for home use as a litter additive that allows interpretation of glucosuria over an 8-h period. The objectives of this study were to assess the sensitivity, specificity, and accuracy of the Glucotest and Multistix, and to assess the 8-h color stability of the Glucotest. Overall, the Glucotest had greater sensitivity and specificity than the Multistix, and more accurately estimated urine glucose concentration if evaluated at least 30 min after exposure to urine. A significant lack of agreement between the results obtained immediately after exposure to urine vs after 30 min and 8 h contradicts the 8-h color stability claim, but the change in urine glucose concentration estimation over time resulted in improved test accuracy at the 30 and 480 min time points. PMID- 21795088 TI - Complex partial cluster seizures in cats with orofacial involvement. AB - Seventeen cats were presented with acute onset of complex partial seizures with orofacial involvement (salivation, facial twitching, lip smacking, chewing, licking or swallowing), motor arrest (motionless starring) and behavioural changes. In 11 cats hippocampal necrosis (HN) was confirmed by histopathology. In a further six cats hippocampal changes were suggested by magnetic resonance imaging. The mean monitoring time of eight cats which were not euthanased in the acute phase of the disease, was 408 days (60-908): four cats are still alive. In all surviving cases, the owners reported a good quality of life. We conclude that an acute cluster of complex partial seizures with orofacial involvement are often associated with HN and that HN is not necessarily a fatal condition. Supportive and antiepileptic therapy can result in remission. The long-term outcome can be good to excellent; therefore, euthanasia should be avoided in the acute phase of the signs. PMID- 21795089 TI - Vaginourethroplasty as a salvage procedure for management of traumatic urethral rupture in a cat. AB - This report describes a cat that suffered pelvic urethral rupture associated with multiple pelvic fractures. A vaginourethroplasty was performed as a salvage procedure, via intrapelvic anastomosis of the proximal urethra to the caudal vagina, following failure of a primary urethral anastomosis. Urinary diversion was achieved via tube cystostomy and a vagino-urethral catheter was maintained for 3 days postoperatively. Anterograde cystourethrography was performed at 7 days and 14 days postoperatively. Absence of contrast leakage from the vagino urethral anastomosis was documented at 14 days postoperatively and the tube cystostomy was removed. An Escherichia coli urinary tract infection was treated following removal of the tube cystostomy and subsequent urine culture revealed no evidence of urinary tract infection. The cat retained normal urinary continence and elimination behaviour during the 7-month follow-up period. Vaginourethroplasty could be considered as a salvage option for management of traumatic pelvic urethral rupture in the neutered female cat. PMID- 21795090 TI - The education and training of clinical medical physicists in 25 European, 2 North American and 2 Australasian countries: similarities and differences. AB - PURPOSE: The clinical medical physicist is part of a team responsible for safe and competent provision of radiation-based diagnostic examinations and therapeutic practices. To ensure that the physicist can provide an adequate service, sufficient education and training is indispensable. The aim of this study is to provide a structured description of the present status of the clinical medical physicist education and training framework in 25 European, 2 North American and 2 Australasian countries. METHODS: For this study, data collection was based on a questionnaire prepared by the European Federation of Organizations in Medical Physics (EFOMP) and filled-in either by the corresponding scientific societies-organizations or by the authors. RESULTS: In the majority of cases, a qualified medical physicist should have an MSc in medical physics and 1-3 years of clinical experience. Education and training takes place in both universities and hospitals and the total duration of the programs ranges from 2.5 to 9 years. In 56% of all European countries, it is mandatory to hold a diploma or license to work as a medical physicist, the situation being similar in Australasian and 4 states of USA. Generally, there are national registers of medical physicists with inclusion on the register being voluntary. There are renewal mechanisms in the registers usually based on a Continuing Professional Development (CPD) system. CONCLUSIONS: In conclusion, a common policy is followed in general, on topics concerning education and training as well as the practice of the medical physicist profession, notwithstanding the presence of a few differences. PMID- 21795091 TI - [Debate about breast cancer: "Cons: Intraoperative radiotherapy"]. AB - Early breast cancer incidence increases owing to mammography screening. Hypofractionated radiotherapy is more and more proposed in women with low local relapse risk breast cancer, especially accelerated partial breast irradiation. Various irradiation modalities have been reported: brachytherapy, intraoperative irradiation, 3D-conformal accelerated partial breast irradiation. We describe limitations of intraoperative irradiation and the advantages of alternative techniques. PMID- 21795092 TI - Assessment of cardiac exposure in left-tangential breast irradiation. AB - PURPOSE: To assess the value of treatment-planning related parameters namely, the breast volume; the distance of the inferior field border to diaphragm; and the cardiothoracic ratio for left-tangential breast irradiation. PATIENTS AND METHODS: Treatment plans of 27 consecutively left-sided breast cancer patients after breast conserving surgery were evaluated for several parameters concerning heart-irradiation. We measured the heart distance respective to the cardiothoracic ratio and the distance of the inferior field border to diaphragm, as well as the breast volume in correlation with the irradiated heart volume. RESULTS: The mean heart and left breast volumes were 504 cm(3) and 672.8 cm(3), respectively. The mean heart diameter was 13.4 cm; the mean cardiothoracic ratio 0.51 and the mean distance of the inferior field border to diaphragm was 1.4 cm. Cardiothoracic ratio (p=0.01), breast volume (p=0.0002), distance of the inferior field border to diaphragm (p=0.02) and central lung distance (p=0.02) were significantly correlated with the measured heart distance. A significant correlation was also found between cardiothoracic ratio, breast volume and distance of the inferior field border to diaphragm with the irradiated heart volume measured by V10, V20 and V40. CONCLUSION: The verification of parameters like cardiothoracic ratio, distance of the inferior field border to diaphragm and breast volume in left-sided breast cancer patients may help in determining which patients could benefit from more complex planning techniques such as intensity modulated radiotherapy to reduced risk of late cardiac injury. PMID- 21795093 TI - [Surveillance after prostate cancer radiotherapy]. AB - Follow-up after prostate cancer radiotherapy aims at detecting local or metastatic relapse, as well as long-term toxicity, requiring adapted treatments. Several scientific societies have published guidelines including clinical, biological and imaging recommendations. More data suggest a role for aggressive salvage therapy in case of local failure following radiotherapy. An adequate follow-up is required for the sake of patients' safety, i.e. to a posteriori validate dose constraints and radiation technique in each radiotherapy department. PMID- 21795094 TI - [Holoprosencephaly: pathogenesis, phenotypic characteristics. About four cases]. AB - Holoprosencephaly is a rare brain abnormality resulting from an incomplete cleavage of the primitive prosencephalon of forebrain during early embryogenesis. It includes a series of rare complex and heterogenosis disorders. Alobar form is associated with an extremely poor fetal prognosis. Here we report three cases of alobar holoprosencephaly and one case of semilobar holoprosencephaly diagnosed at the third trimester. Causes, diagnosis and management of holoprosencephaly are discussed referring to literature. PMID- 21795095 TI - Isolated scaphoid fracture with anterosuperior dislocation of the proximal fragment. AB - Isolated fracture of the scaphoid with an associated anterosuperior dislocation of the proximal fragment is an extremely rare injury. We present two cases where open reduction and internal fixation through a palmar and dorsal approach was performed. No instances of non-union, necrosis of the proximal fragment of the scaphoid or scapholunate dissociation were noted during a mean follow-up period of 18 months. Clinical results (active motion, power grip, DASH) following such injury and intervention are presented. The aetiology of this rare injury is discussed. PMID- 21795096 TI - "Buckle" rib fracture: an artifact following cardio-pulmonary resuscitation detected on postmortem CT. AB - Buckle rib fractures are incomplete fractures involving the inner cortex alone, and are rarely detected on routine chest X-ray or at autopsy. The characteristics of these fractures have not been well evaluated in situ although they are commonly observed on postmortem CT images especially following CPR. The postmortem CT findings in 42 cases showing buckle rib fractures caused by CPR were reviewed. The cause of death in all cases was non-traumatic. The shape, number, location, and distribution of these buckle rib fractures and their relationship to other types of rib fractures were evaluated using a novel oblique axial multiplanar reconstruction technique. Almost all incomplete rib fractures associated with CPR are buckle rib fractures (90.5%). All rib fractures were distributed from the second to ninth ribs with over 95% being within the second to seventh ribs. Buckle rib fractures are dominant in the seventh to ninth ribs and the proportion of buckle rib fractures located in the vicinity of the costochondral junctions increases with the lower ribs. Over 97% of all CPR associated rib fractures are located in the anterior one third of the ribs based on a new measurement method utilizing oblique axial multiplanar reconstruction of the CT data. When recognition of incomplete or buckle rib fractures on postmortem CT is taken into account, detection of symmetry and continuity of rib fractures typically associated with CPR is improved compared with the detection of complete fractures alone. Recognition of buckle rib fractures and their characteristics on postmortem CT is of benefit to the forensic pathologist in evaluating the possibility of CPR and the differentiation of resuscitative artifact from forensically significant visceral injury observed at autopsy. PMID- 21795097 TI - Do children's individual correlates of physical activity differ by home setting? AB - We investigated whether physical activity (PA) correlates differed for 9-10 year old British children living in urban, suburban and rural settings. We analysed cross-sectional data on 1653 children (SPEEDY study). Exposure variables were self-reported, whilst PA was measured using Actigraph accelerometers. Data were analysed using multilevel hierarchical regression models, stratified by home setting. PA levels did not differ by home setting. Boys, those of normal weight and those having a preference for PA had higher PA levels in all strata, but additional correlates were identified within each setting. These results highlight the potential importance of tailoring interventions to specific environmental and population strata. PMID- 21795098 TI - Prevalence of contact lens related complications in a tertiary eye centre in India. AB - AIM: To determine the prevalence of contact lens related complications in a tertiary eye care centre in India. METHODS: A retrospective review of the charts of 1255 patients who visited our contact lens clinic during 2001-2004 was conducted. The inclusion criteria included patients of at least 18 years of age, having refractive errors and keratoconus. Exclusion criteria included previous corneal surgeries and pediatric patients. 190 subjects with lens related complications were identified from among 923 patients who were using lenses. RESULTS: The prevalence of contact lens complications was 20.58%. Females with complications were more common (59.47%). The complications were more common in students. The most common complications were contact lens induced papillary conjunctivitis (CLPC) (6.39%), corneal vascularisation (4%), and superficial punctate keratitis (SPK) (3.5%). The total complications were less prevalent in patients wearing rigid gas permeable (RGP) lenses as compared to soft contact lenses. Infectious keratitis was noted in 8 eyes. Pseudomonas aeuroginosa was the most common organism isolated. The average daily wear with RGP lenses was 11.04+/ 3.7h and 10.96+/-3h with soft contact lens. The highest number of complications was noted in 47.89% patients who were wearing lenses for excess of 11h. The number of patients with complications arising due to sleeping with the lenses was 74 (38.95%). CONCLUSION: Prevalence of contact lens complications was more in soft contact lens wearers compared to RGP wearers. CLPC was the most common complication followed by vascularisation and SPK. PMID- 21795099 TI - Enforcing host cell polarity: an apicomplexan parasite strategy towards dissemination. AB - The propagation of apicomplexan parasites through transmitting vectors is dependent on effective dissemination of parasites inside the mammalian host. Intracellular Toxoplasma and Theileria parasites face the challenge that their spread inside the host depends in part on the motile capacities of their host cells. In response, these parasites influence the efficiency of dissemination by altering adhesive and/or motile properties of their host cells. Theileria parasites do so by targeting signalling pathways that control host cell actin dynamics. The resulting enforced polar host cell morphology facilitates motility and invasiveness, by establishing focal adhesion and invasion structures at the leading edge of the infected cell. This parasite strategy highlights mechanisms of motility regulation that are also likely relevant for immune or cancer cell motility. PMID- 21795100 TI - Experimental and theoretical study of three new benzothiazole-fused carbazole derivatives. AB - Three new D-pi-A type compounds, each containing one benzothiazole ring as an electron acceptor and one N-ethylcarbazole group as electron donor, were synthesized and characterized by elemental analysis, NMR, MS and thermogravimetric analysis. The absorption and emission spectra of three compounds were experimentally determined in several solvents and were simultaneously computed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The calculated reorganization energy for hole and electron indicates that three compounds are in favor of hole transport than electron transport. The calculated absorption and emission wavelengths are well coincident with the measured data. The calculated lowest-lying absorption spectra can be mainly attributed to intramolecular charge transfer (ICT). And the calculated fluorescence spectra can be mainly described as originating from an excited state with intramolecular charge transfer (ICT) character. The results show that three compounds exhibited excellent thermal stability and high fluorescence quantum yields, indicating their potential applications as excellent optoelectronic material in optical field. PMID- 21795101 TI - Chemiluminescence enzyme immunoassay for the determination of sulfamethoxydiazine. AB - Sulfamethoxydiazine (SMD), which is often used for animal disease treatment, is harmful to human health. No SMD residue should be detected in food in some countries, such as USA and Japan. Therefore, it is significant to develop a high throughput, high-sensitivity and accurate method for the determination of the content of SMD in food. In this paper, chemiluminescence enzyme immunoassay (CLEIA) was developed for quantification of SMD. For this method, the limit of detection was 3.2 pg/ml, the linear range was from 10 to 2000 pg/ml, the within day and inter-day precision were below 13% and below 18%, respectively, and the recovery was from 85% to 105%. Milk and egg were selected as samples to be examined with this method, and the result indicated that this CLEIA method was suitable for screening and quality control of food. PMID- 21795102 TI - Sensitive and selective determination of glucose in human serum and urine based on the peroxyoxalate chemiluminescence reaction of a new fluorophore. AB - A novel method for simple and sensitive determination of glucose based on the peroxyoxalate chemiluminescence (PO-CL) detection of enzymatically generated H(2)O(2) was investigated. Influence of various experimental parameters on glucose sensing, including the action time of the enzyme, solution pH, interferents and the concentration of CL reagents was investigated. Under the optimum condition, the linear response range of glucose was found to be 2.50*10( 6) to 1.75*10(-4) mol/L, and the detection limit (defined as the concentration that could be detected at the signal-to-noise ratio of 3) was 1.10*10(-6) mol/L. The present method has been used to determine the glucose concentrations in real serum and urine samples with satisfactory results. PMID- 21795103 TI - Identification of the C2?-X2Sigma+ band system of AlO in the ultraviolet galvanoluminescence obtained during aluminum anodization. AB - The first galvanoluminescence spectrum in the ultraviolet region obtained during anodization of high purity aluminum samples annealed at temperature above 525 degrees C is presented. An intense broad peak with the maximum at about 31,900 cm(-1) is assigned to the transitions (some of them heretofore unobserved) between vibrational levels of the C(2)?->X(2)Sigma(+) spectral system of AlO, partly overlapped with the A(2)Sigma(+)->X(2)? system of OH. PMID- 21795104 TI - New copper(II) complexes with dopamine hydrochloride and vanillymandelic acid: spectroscopic and thermal characterization. AB - The dopamine derivatives participate in the regulation of wide variety of physiological functions in the human body and in medication life. Increase and/or decrease in the concentration of dopamine in human body reflect an indication for diseases such as Schizophrenia and/or Parkinson diseases. The Cu(II) chelates with coupled products of dopamine hydrochloride (DO.HCl) and vanillymandelic acid (VMA) with 4-aminoantipyrine (4-AAP) are prepared and characterized. Different physico-chemical techniques namely IR, magnetic and UV-vis spectra are used to investigate the structure of these chelates. Cu(II) forms 1:1 (Cu:DO) and 1:2 (Cu:VMA) chelates. DO behave as a uninegative tridentate ligand in binding to the Cu(II) ion while VMA behaves as a uninegative bidentate ligand. IR spectra show that the DO is coordinated to the Cu(II) ion in a tridentate manner with ONO donor sites of the phenolic-OH, -NH and carbonyl-O, while VMA is coordinated with OO donor sites of the phenolic-OH and -NH. Magnetic moment measurements reveal the presence of Cu(II) chelates in octahedral and square planar geometries with DO and VMA, respectively. The thermal decomposition of Cu(II) complexes is studied using thermogravimetric (TG) and differential thermal analysis (DTA) techniques. The activation thermodynamic parameters, such as, energy of activation, enthalpy, entropy and free energy change of the complexes are evaluated and the relative thermal stability of the complexes are discussed. PMID- 21795105 TI - Vibrational spectroscopic (FTIR and FT Raman) studies, first order hyperpolarizabilities and HOMO, LUMO analysis of p-toluenesulfonyl isocyanate using ab initio HF and DFT methods. AB - The Fourier transform infrared (FTIR) and FT Raman spectra of p-toluenesulfonyl isocyanate (p-tosyl isocyanate) have been measured. The molecular geometry, vibrational frequencies, infrared intensities, Raman activities and atomic charges have been calculated by using ab initio HF and density functional theory calculation (B3LYP) with 6-311+G(d,p) basis set. Complete vibrational assignment and analysis of the fundamental modes of the compound were carried out using the observed FTIR and FT Raman data. The thermodynamic functions of the title compound were also performed with the aid of HF/6-311+G(d,p) and B3LYP/6 311+G(d,p) levels of theory. Simulated FTIR and FT Raman spectra for p-tosyl isocyanate showed good agreement with the observed spectra. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. The dipole moment (MU), polarizability (alpha) and the hyperpolarizability (beta) values of the investigated molecule have been computed using HF and B3LYP methods. PMID- 21795106 TI - An efficient and simple approach for the synthesis of pyranopyrazoles using imidazole (catalytic) in aqueous medium, and the vibrational spectroscopic studies on 6-amino-4-(4'-methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4 dihydropyrano[2,3-c]pyrazole using density functional theory. AB - We describe a one-pot four component synthesis of pyranopyroles from aryl aldehydes, ethyl acetoacetate, malononitrile and hydrazine hydrate in the presence of catalytic amounts of an organocatalyst imidazole in water as medium. A plausible mechanism for the formation of imidazole catalyzed pyranopyrazoles has been envisaged. This method is rapid, simple, provides products in good yield, and is eco-friendly. In addition, based on the optimized geometry, the frequency and intensity of the vibrational bands of 6-amino-4-(4'-methoxyphenyl) 5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole were obtained by the density functional theory (DFT) calculations using 6-31G(d,p) basis set. The vibrational frequencies were calculated and the scaled values have been compared with experimental FT-IR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. PMID- 21795107 TI - Synthesis, spectral studies, antimicrobial, antioxidant and insect antifeedant activities of some 9H-fluorene-2-yl keto-oxiranes. AB - Thirteen ee (alphaS, betaR) 9H-fluorene-2-yl keto-oxiranes (2-(9H)-fluorene-4 yl[3-(substituted phenyl)oxiran-2-yl]methanones) have been synthesized by phase transfer catalysed epoxidation of 9H-fluorene-2-yl chalcones. The yields of oxiranes are more than 95%. The synthesized oxiranes have been characterized by IR, (1)H, (13)C and GC-MS spectral data. The spectral data are correlated with Hammett substituent constants and Swain-Lupton parameters. From the regression analysis, the effect of substituents on the group frequencies has been predicted. The antimicrobial, antioxidant and insect antifeedant activities of all the synthesized oxiranes have been studied. PMID- 21795108 TI - Theoretical investigation of the molecular structures and excitation spectra of triphenylamine and its derivatives. AB - The molecular geometries, electronic structures, and excitation energies of NPh(3), NPh(2)Me, NPhMe(2), and NMe(3), were investigated using DFT and post Hartree Fock methods. When the structural stabilities of these compounds were compared to results obtained by using MP4(SDQ) method, it was confirmed that the optimized geometries by using MP2 method were sufficiently reliable. The excited states with large oscillator strengths consisted of transition components from the HOMO. It should be noted that the orbitals of the nitrogen atom mix with the pi-orbital of the phenyl group in an anti-bonding way in the HOMO, and the orbital energy increases with this mixing. The unoccupied orbitals are generated from bonding and anti-bonding type interactions between the pi-orbitals of the phenyl groups; therefore, the number of phenyl groups strongly affects the energy diagram of the compounds studied. The differences in the energy diagram cause a spectral change in these compounds in the ultraviolet region. PMID- 21795109 TI - Synthesis and physicochemical studies of some novel picrate derivatives. AB - (1)H and (13)C NMR spectra were recorded for some novel picrate derivatives derived from some 3,3-methyl-2,6-diarylpiperidin-4-ones and 3-benzyl-2,6 diarylpiperidin-4-one. The difference in the chemical shift of equatorial methylene proton and axial methylene proton at C(5) [Delta = delta(eq)-delta(ax)] is highly negative which is in contrast to the value observed in the corresponding parent piperidin-4-ones and this is attributed to the syn 1,3 diaxial interaction between the axial N-H bond and axial hydrogen at C-5. The effect of protonation on the chemical shifts was studied in detail. The chemical shifts of the heterocyclic ring protons are influenced by the picrate anion. Solvatochromism of picrates were studied in detail. DFT calculations were carried out in order to find out the NBO analysis, HOMO-LUMO energies, MEP studies and hyperpolarisability behaviour. The electric dipole moment (MU) and the first hyperpolarisability (beta) value of the investigated molecules have been studied theoretically which reveal that the synthesized molecules have microscopic non linear optical (NLO) behaviour with non-zero values. PMID- 21795110 TI - Synthesis, crystal structure and luminescent properties of one 3D Cd(II) coordination polymer [Cd(H3BPTC)2(bpy)]n (H4BPTC = 1,1'-biphenyl-2,2',6,6' tetracarboxylic acid, bpy = 4,4'-bipyridine). AB - A new 3D metal-organic coordination polymer [Cd(H(3)BPTC)(2)(bpy)](n) (1) (H(4)BPTC = 1,1'-biphenyl-2,2',6,6'-tetracarboxylic acid, bpy =4,4'-bipyridine) has been synthesized and characterized by single X-ray diffraction and IR spectroscopy. The one-dimensional metal-organic chains of the title complex, namely [Cd(H(3)BPTC)(2)](n), are held together through hydrogen bonding and bridging "second" ligand 4,4'-bpy to give a three-dimensional metal-organic network. The thermal stability of complex 1 was studied by thermal gravimetric (TG) and differential thermal analysis (DTA). Compound 1 exhibits photoluminescence with an emission maximum at ca. 380 nm upon excitation at ca. 251 nm. PMID- 21795111 TI - Chromenone 12-crown-4 substituted zinc phthalocyanine complexes: investigation of spectral, photophysical and photochemical properties. AB - The synthesis of novel 6,7-[(12-crown-4)-3-[p-(3,4-dicyanophenoxy)phenyl]coumarin (1), 6,7-[(12-crown-4)-3-[p-(2,3-dicyanophenoxy)phenyl]coumarin (2), and their corresponding tetra-(chromenone 12-crown-4)-substituted zinc (II) phthalocyanine complexes (3 and 4) have been prepared. These new compounds have been characterized by elementel analysis, (1)H NMR (1 and 2), MALDI-TOF, IR and UV-Vis spectral data. The fluorescence intensity changes for 1 and 2 by addition of Na(+) or K(+) ions have been determined at 25 degrees C in THF. Intensity of the binding Na(+)- and K(+)-complexes (1 and 2) have decreased. The effects of the chromenone crown ether on the phthalocyanine molecule concerning photophysical and photochemical properties are also investigated. Photodegredation, singlet oxygen, fluorescence quantum yields, and fluorescence lifetimes of zinc phthalocyanine complexes (3 and 4) are also examined in DMSO. PMID- 21795112 TI - 2-[(1H-benzimidazol-2-ylmethyl)-amino]-benzoic acid methyl ester: crystal structure, DFT calculations and biological activity evaluation. AB - In the present study, structural properties of 2-[(1H-benzimidazol-2-ylmethyl) amino]-benzoic acid methyl ester have been studied extensively by spectral methods and X-ray crystallography. Quantum mechanical calculations of energies, geometries, vibrational wavenumbers, NMR and electronic transitions were carried out by DFT using B3LYP functional combined with 6-31G(d) basis set. Natural bond orbitals (NBO) analysis and frontier molecular orbitals were performed at the same level of theory. DFT calculations showed good agreement between the theoretical and experimental values of optimized and X-ray structure as well as between the vibrational and NMR spectroscopy. The title compound was screened for its antibacterial activity referring to Tetracycline as standard antibacterial agent. PMID- 21795113 TI - Identifications of polyphyletic variants in acute hepatitis suggest an underdiagnosed circulation of hepatitis E virus in Argentina. AB - BACKGROUND: In recent years, an increasing number of infections with genotype 3 hepatitis E virus (HEV) have been reported in western countries. Data in South America, however, are still scarce. Swine and human variants previously described in Argentina are closely related to a human Austrian one. OBJECTIVE: To identify whether HEV is still circulating in Argentina. STUDY DESIGN: Sera and stool samples from adults and children with unexplained acute liver disease referred to our center during the last six years were prospectively studied. Dual infection with hepatitis A was retrospectively studied in a group of children with fulminant hepatic failure. RESULTS: Fifteen new cases (13 adults and 2 children), seven of whom required hospitalization, were diagnosed. Nine had detectable HEV RNA, and one had imported genotype 1. Subgenotype 3i HEV-related variants are still circulating. Five autochthonous sequences, related to European, American and Japanese ones, grouped in subgenotype 3a. One case had a subgenotype 3b variant. DISCUSSION: The polyphyletic variants widespread in Argentina suggest multiple sources of infection. Whether or not their reservoir is swine merits further investigation. Since hepatitis E is still considered rare, differential laboratory testing in unexplained acute liver disease is not routinely performed in Argentina. Broadening awareness of this disease is important in light of the decrease in hepatitis A incidence since universal vaccination was implemented in 2005. The diagnosis of hepatitis E with a combination of serological and molecular tools is needed to better understand its epidemiology and impact on the clinical management of patients with unexplained increased transaminases. PMID- 21795115 TI - Clinical and molecular aspects of malaria fever. AB - Although clinically benign, malaria fever is thought to have significant relevance in terms of parasite growth and survival and its virulence which in turn may alter the clinical course of illness. In this article, the historical literature is reviewed, providing some evolutionary perspective on the genesis and biological relevance of malaria fever, and the available molecular data on the febrile-temperature-inducible parasite factors that may contribute towards the regulation of parasite density and alteration of virulence in the host is also discussed. The potential molecular mechanisms that could be responsible for the induction and regulation of cyclical malaria fevers caused by different species of Plasmodium are also discussed. PMID- 21795114 TI - Presenilins in synaptic function and disease. AB - The presenilin genes harbor approximately 90% of mutations linked to early-onset familial Alzheimer's disease (FAD), but how these mutations cause the disease is still being debated. Genetic analysis in Drosophila and mice demonstrate that presenilin plays essential roles in synaptic function, learning and memory, as well as neuronal survival in the adult brain, and the FAD-linked mutations alter the normal function of presenilin in these processes. Presenilin has also been reported to regulate the calcium homeostasis of intracellular stores, and presynaptic presenilin controls neurotransmitter release and long-term potentiation through modulation of calcium release from intracellular stores. In this review, we highlight recent advances in deciphering the role of presenilin in synaptic function, calcium regulation and disease, and pose key questions for future studies. PMID- 21795116 TI - Pyrazinamide pharmacokinetics and efficacy in adults and children. AB - Pyrazinamide (PZA) is an essential sterilizing drug and with rifampicin enables six-month short-course antituberculosis chemotherapy. Despite routine use for nearly forty years uncertainty remains regarding the most appropriate PZA dosage for children. In view of this uncertainty literature relating to the efficacy and pharmacokinetics of PZA in children treated for tuberculosis and in adult volunteers and patients was reviewed. Making use of the PZA maximum concentration (C(max)) following various PZA dosages in different groups straight line regression of concentration on dosage was fitted through the origin by least squares and weighted for the numbers of subjects. The fitted line offers an approximation of the likely PZA C(max) that would result from a particular dosage. The slopes of C(max)/dosage of the fitted lines are 1.32 (SE 0.099) for paediatric patients, 1.36 (SE 0.051) for adult volunteers and 1.35 (SE 0.037) for adult patients; there is little difference between the C(max) concentrations achieved in children and adults, whether patients or healthy volunteers, following various mg/kg body weight dosages, suggesting that children and adults receiving the same mg/kg body weight PZA dosage will reach a similar C(max). Children can receive the same mg/kg body weight PZA dosage as adults. PMID- 21795117 TI - Donor recruitment in the 21st century: Challenges and lessons learned in the first decade. AB - The first decade of the millennium has seen a fundamental shift in global sufficiency. In many developing countries the major challenge remains the need to collect sufficient, safe blood from volunteer non-remunerated blood donors to support developing health care needs. However, in the developed world the current challenges faced by blood services are more complex and constantly changing. This article will explore the impact of these challenges and consider the implications for blood services in the next decade in donor management and recruitment. The authors discuss the major strategic challenges of: PMID- 21795118 TI - Disaster response from Australia: what is the role of Forward Teams? AB - Large scale Australian civilian medical assistance teams were first deployed overseas in 2004. The deployment of small Forward Teams in the early phase of a health disaster response allows for informed decisions on whether, and in what form, to deploy larger medical assistance teams. The prime consideration is to support the capacity of local services to respond to the specific needs of the affected population. In addition, Australian citizens caught up in large numbers in overseas disasters may need health assistance. PMID- 21795119 TI - Statewide evaluation of local wellness policies in Georgia: an examination of policy compliance, policy strength, and associated factors. AB - OBJECTIVE: To analyze relationships between demographic characteristics of Georgia school systems and: (1) compliance with the Child Nutrition and WIC Reauthorization Act (CNRA); and (2) strength of wellness policy goals in nutrition, physical activity, and other school-based activities. DESIGN: Each local school district submitted their school-board-approved wellness policy to researchers. Each policy was reviewed and coded for compliance with CNRA and evaluated on the strength of its goals. SETTING: Public school districts. PARTICIPANTS: One hundred seventy-six of 180 Georgia public school systems participated. MAIN OUTCOME MEASURES: Independent variables were demographic characteristics of Georgia school systems. Dependent variables were ratings from the policy evaluation instrument, grouped into composite indices to compare the strength (ie, ratings) of wellness policy goals. ANALYSIS: Pearson correlation, cross-tabulation. RESULTS: Significant positive associations were found between academic performance and: strength of overall wellness policy goals (P < .05), goals in nutrition education (P < .01), and other school-based activities (P < .01). Economic status of the student population was found to be positively associated with strength of nutrition education goals (P < .05). CONCLUSIONS AND IMPLICATIONS: Districts with stronger academic performance had more comprehensive overall wellness policy goals and stronger goals in nutrition education and other school-based activities. PMID- 21795120 TI - Food shopping perceptions, behaviors, and ability to purchase healthful food items in the lower Mississippi delta. AB - OBJECTIVE: To examine the agreement between perceptions, behaviors, and ability to purchase healthful food in the Lower Mississippi Delta (LMD). DESIGN: A regional food store survey of healthful food options in supermarkets, small/medium stores, and convenience stores. Focus group discussions were conducted on shopping perceptions and behaviors. SETTING: Counties in Arkansas, Louisiana, and Mississippi. PARTICIPANTS: Eighty-one LMD residents, 18-60+ years of age. MAIN OUTCOME MEASURE: Perceptions of healthful food and ability to acquire these food items across store types. ANALYSIS: Focus group data were analyzed using thematic coding. Summary food store statistics were weighted, and estimates were constructed using SUDAAN 9. Data triangulation was achieved by comparing focus group findings with food availability data. RESULTS: A majority (> 85%) of supermarkets had selected vegetables, breads, and cereals perceived as healthful, whereas availability was limited in small to medium grocery stores and convenience stores. Skim milk, perceived as healthful, was limited in all store types. CONCLUSIONS AND IMPLICATIONS: Limited availability and perceived costs of healthful food in the LMD influenced purchasing behaviors. Attitudes and perceptions should be incorporated into intervention development to improve food choices in conjunction with increasing the availability of healthful food in the LMD. PMID- 21795121 TI - Knowledge and attitudes toward epilepsy among primary and secondary schoolteachers in Italy. AB - A nationwide telephone interview was conducted on a random sample of Italian schoolteachers (300 from primary and 300 from secondary schools) to ascertain knowledge and attitudes about epilepsy. Included were 516 women and 84 men aged 22 to 70 years. Thirty-seven percent of the teachers believed epilepsy starts only in childhood, 55% considered it hereditary, 46.8% declared it incurable, and only 10.5% knew surgery is a therapeutic option. Thirty-three percent considered epilepsy a moderate-to-strong limitation for marriage, 24.6% for having children, 39.7% for regular employment, and 32.8% for sports and leisure activities. Among the teachers, 66.4% declared they were unable to manage a seizing child, 24.7% were convinced that epilepsy impairs learning, 26.0% believed that it carries mental/behavioral alterations, and 36.4% thought it requires support at school. Differences in knowledge and attitudes were predicted by teachers' age and area of residency. There were no major differences between teachers and the Italian population in their knowledge and attitudes. PMID- 21795122 TI - Future directions in the neuropsychology of epilepsy. AB - Two important themes for future clinical research in the neuropsychology of epilepsy are proposed: (1) the neurobiological abnormalities that underlie neuropsychological impairment in people with epilepsy, and (2) neuropsychological status of persons with new-onset epilepsy. PMID- 21795123 TI - Direct electrochemistry and electrocatalysis of hemoglobin on chitosan-room temperature ionic liquid-TiO(2)-graphene nanocomposite film modified electrode. AB - TiO(2)-graphene nanocomposite was prepared by hydrolysis of titanium isopropoxide in colloidal suspension of graphene oxide and in situ hydrothermal treatment. The direct electrochemistry and electrocatalysis of hemoglobin in room temperature ionic liquid 1-Butyl-3-methylimidazolium hexafluorophosphate, chitosan and TiO(2) graphene nanocomposite modified glassy carbon electrode were investigated. The biosensor was examined by using UV-vis spectroscopy, scanning electron microscopy and electrochemical methods. The results indicated that hemoglobin remained its bioactivity on the modified electrode, showing a couple of well-defined and quasi reversible redox peaks, corresponding to hemoglobin Fe(III)/Fe(II) couple. The kinetic parameters for the electrode reaction, such as the formal potential (E(o')), the electron transfer rate constant (k(s)), the apparent coverage (Gamma), and Michaelis-Menten constant (K(m)) were evaluated. The biosensor showed good electrochemical responses to the reduction of H(2)O(2) in the ranges of 1-1170 MUM. The detection limit was 0.3 MUM (S/N=3). The properties of this composite film, together with the bioelectrochemical catalytic activity, could make them useful in the development of bioelectronic devices, and investigation of electrochemistry of other heme proteins at functional interface. PMID- 21795124 TI - Constructal Law: From law of physics to applications and conferences: comment on "The constructal law and the evolution of design in nature" by Adrian Bejan and Sylvie Lorente. PMID- 21795125 TI - Constructal law in technology, thermofluid and energy systems, and in design education: comment on "The constructal law and the evolution of design in nature" by A. Bejan and S. Lorente. PMID- 21795126 TI - Design in nature, and the laws of physics: comment on "The constructal law and the evolution of design in nature" by Adrian Bejan and Sylvie Lorente. PMID- 21795127 TI - The physics principle of the generation of flow configuration: comment on "The constructal law and the evolution of design in nature" by Adrian Bejan and Sylvie Lorente. PMID- 21795129 TI - Treatment of giant congenital melanocytic nevus of the left upper extremity with staged expanded flap. AB - Excision of a congenital giant nevus is advised due to the possibility of it degenerating into a malignant melanoma or for aesthetic concerns. Tissue expansion has emerged as the primary treatment of giant congenital nevi because it enables the body to produce extra skin with excellent texture, better colour match, less severe donor-site deformity and repeated usage of an expanding donor site. We present a multi-staged expansion/local flap technique to treat a case of a circumferential nevus from the acromioclavicular joint and axillary area throughout the upper extremity excluding the hand. The affected skin was approximately 10% of the total body surface area. The patient underwent eight operations and a total of 11 rounds of tissue expansions (500 cc * 9 rounds, 600 cc * 1 round, 300 cc * 1 round) were completed over a 2-year period prior to the removal of the nevus. A good aesthetic and functional outcome in the left upper extremity was gained. It is recommended that the treatment of giant nevi is best if completed at preschool age after taking several factors into consideration. PMID- 21795128 TI - Transcriptional modulation induced by ionizing radiation: p53 remains a central player. AB - The cellular response to DNA damage is vital for maintaining genomic stability and preventing undue cell death or cancer formation. The DNA damage response (DDR), most robustly mobilized by double-strand breaks (DSBs), rapidly activates an extensive signaling network that affects numerous cellular systems, leading to cell survival or programmed cell death. A major component of the DDR is the widespread modulation of gene expression. We analyzed together six datasets that probed transcriptional responses to ionizing radiation (IR) - our novel experimental data and 5 published datasets - to elucidate the scope of this response and identify its gene targets. According to the mRNA expression profiles we recorded from 5 cancerous and non-cancerous human cell lines after exposure to 5 Gy of IR, most of the responses were cell line-specific. Computational analysis identified significant enrichment for p53 target genes and cell cycle-related pathways among groups of up-regulated and down-regulated genes, respectively. Computational promoter analysis of the six datasets disclosed that a statistically significant number of the induced genes contained p53 binding site signatures. p53-mediated regulation had previously been documented for subsets of these gene groups, making our lists a source of novel potential p53 targets. Real time qPCR and chromatin immunoprecipitation (ChIP) assays validated the IR induced p53-dependent induction and p53 binding to the respective promoters of 11 selected genes. Our results demonstrate the power of a combined computational and experimental approach to identify new transcriptional targets in the DNA damage response network. PMID- 21795130 TI - Nose and upper lip reconstruction for purpura fulminans. AB - BACKGROUND: Purpura fulminans (PF) is a rare syndrome of intravascular thrombosis and haemorrhagic infarction of the skin. The initial symptom of PF is peripheral purpura which progresses to necrosis very rapidly. The prognosis of PF is poor, and the mortality is reported to be around 40%. Even if the patient survives, the patient may require amputation or reconstruction for limbs and facial necrosis. CASE REPORT: A 48-year-old male suffered from PF following a left cerebellopontine angle tumour excision. His nose and upper lip fell into necrosis afterwards. We performed nose and upper lip reconstruction at 8 months after the onset. We used a forehead flap for the nasal reconstruction and a free forearm flap for the lining. His upper lip was reconstructed with bilateral nasolabial orbicularis oris myocutaneous flaps. RESULTS: The colour and texture match of the reconstructed nose and lip is good. He could open his mouth wide enough and close completely. CONCLUSIONS: Facial reconstruction after PF is very difficult, because the patient has extensive scarring around the defect and there is little intact facial tissue. However, we performed a facial reconstruction using local flaps as much as possible, and obtained good results. PMID- 21795131 TI - Invited commentary. PMID- 21795134 TI - Three short items worth noting. PMID- 21795133 TI - The impact of peer social networks on adolescent alcohol use initiation. AB - OBJECTIVE: Early adolescent alcohol use is a major public health problem. Drinking before the 14th birthday is associated with a fourfold increase in risk of alcohol dependence in adulthood. The objective of this study is to evaluate the association between adolescent social network characteristics and alcohol initiation prospectively over time. METHODS: The study analyzes data from the National Longitudinal Study of Adolescent Health, a nationally representative survey of 7th- through 11th-grade students enrolled between 1995 and 1996. Generalized estimating equations are used to model the risk of alcohol use initiation at 1-year follow-up among nondrinkers at wave 1 of the study. RESULTS: Both an adolescent's friends' alcohol use and the adolescent's social network characteristics displayed an independent main effect on alcohol initiation. In comparison with abstainers, alcohol initiators had more popular friends as measured by more peer nominations as friends (indegree) and having more friends up to 3 steps removed (3-step reach), and more friends who drank. An adolescent's risk of alcohol use onset increased 13% (95% CI, 4%-22%) for every additional friend with high indegree, 3% (95% CI, 0.3%-6%) for every additional 10 friends within 3-step reach, and 34% (95% CI, 14%-58%) for each additional friend who drank alcohol, and after controlling for confounders. CONCLUSION: The findings suggest that, in addition to well-established demographic risk factors, adolescents are at heightened risk of alcohol use onset because of their position in the social network in relationship to their friends and the friends of their friends. PMID- 21795135 TI - Iris thickness is independently associated with angle closure glaucoma. PMID- 21795232 TI - Optometry and the private health insurance provisions in the Patient Protection and Affordable Care Act (PPACA). PMID- 21795233 TI - The 2010 Eyeglasses and Eye Care Services Index. PMID- 21795234 TI - Medicare quality initiatives and provider communications. PMID- 21795236 TI - Internships can be practice management training opportunities. PMID- 21795235 TI - Difficult times. PMID- 21795237 TI - Perceived threat and corroboration: key factors that improve a predictive model of trust in internet-based health information and advice. AB - BACKGROUND: How do people decide which sites to use when seeking health advice online? We can assume, from related work in e-commerce, that general design factors known to affect trust in the site are important, but in this paper we also address the impact of factors specific to the health domain. OBJECTIVE: The current study aimed to (1) assess the factorial structure of a general measure of Web trust, (2) model how the resultant factors predicted trust in, and readiness to act on, the advice found on health-related websites, and (3) test whether adding variables from social cognition models to capture elements of the response to threatening, online health-risk information enhanced the prediction of these outcomes. METHODS: Participants were asked to recall a site they had used to search for health-related information and to think of that site when answering an online questionnaire. The questionnaire consisted of a general Web trust questionnaire plus items assessing appraisals of the site, including threat appraisals, information checking, and corroboration. It was promoted on the hungersite.com website. The URL was distributed via Yahoo and local print media. We assessed the factorial structure of the measures using principal components analysis and modeled how well they predicted the outcome measures using structural equation modeling (SEM) with EQS software. RESULTS: We report an analysis of the responses of participants who searched for health advice for themselves (N = 561). Analysis of the general Web trust questionnaire revealed 4 factors: information quality, personalization, impartiality, and credible design. In the final SEM model, information quality and impartiality were direct predictors of trust. However, variables specific to eHealth (perceived threat, coping, and corroboration) added substantially to the ability of the model to predict variance in trust and readiness to act on advice on the site. The final model achieved a satisfactory fit: chi(2) (5) = 10.8 (P = .21), comparative fit index = .99, root mean square error of approximation = .052. The model accounted for 66% of the variance in trust and 49% of the variance in readiness to act on the advice. CONCLUSIONS: Adding variables specific to eHealth enhanced the ability of a model of trust to predict trust and readiness to act on advice. PMID- 21795239 TI - Disinvestment from low value clinical interventions: NICEly done? PMID- 21795238 TI - Persuasive features in web-based alcohol and smoking interventions: a systematic review of the literature. AB - BACKGROUND: In the past decade, the use of technologies to persuade, motivate, and activate individuals' health behavior change has been a quickly expanding field of research. The use of the Web for delivering interventions has been especially relevant. Current research tends to reveal little about the persuasive features and mechanisms embedded in Web-based interventions targeting health behavior change. OBJECTIVES: The purpose of this systematic review was to extract and analyze persuasive system features in Web-based interventions for substance use by applying the persuasive systems design (PSD) model. In more detail, the main objective was to provide an overview of the persuasive features within current Web-based interventions for substance use. METHODS: We conducted electronic literature searches in various databases to identify randomized controlled trials of Web-based interventions for substance use published January 1, 2004, through December 31, 2009, in English. We extracted and analyzed persuasive system features of the included Web-based interventions using interpretive categorization. RESULTS: The primary task support components were utilized and reported relatively widely in the reviewed studies. Reduction, self monitoring, simulation, and personalization seem to be the most used features to support accomplishing user's primary task. This is an encouraging finding since reduction and self-monitoring can be considered key elements for supporting users to carry out their primary tasks. The utilization of tailoring was at a surprisingly low level. The lack of tailoring may imply that the interventions are targeted for too broad an audience. Leveraging reminders was the most common way to enhance the user-system dialogue. Credibility issues are crucial in website engagement as users will bind with sites they perceive credible and navigate away from those they do not find credible. Based on the textual descriptions of the interventions, we cautiously suggest that most of them were credible. The prevalence of social support in the reviewed interventions was encouraging. CONCLUSIONS: Understanding the persuasive elements of systems supporting behavior change is important. This may help users to engage and keep motivated in their endeavors. Further research is needed to increase our understanding of how and under what conditions specific persuasive features (either in isolation or collectively) lead to positive health outcomes in Web based health behavior change interventions across diverse health contexts and populations. PMID- 21795240 TI - Surgical meshes containing animal products should be labelled. PMID- 21795244 TI - Chamber for testing asbestos-containing products: validation and testing of a re created chrysotile-containing joint compound. AB - Joint compound products containing chrysotile asbestos were commonly used for building construction from the late 1940s through the mid-1970s. Few relevant data exist to support reconstructing historical worker exposures to fibers generated by working with this material. Therefore, we re-created 1960s-era chrysotile-containing joint compound (JCC) and compared its characteristics to a current-day asbestos-free joint compound (JCN). Validation studies showed that a bench-scale chamber with controlled flow dynamics, designed to quantify particulate emissions from joint compound products, provided precise and reliable measurements of generated airborne dust mass, chrysotile fiber concentrations, and corresponding activity-specific emission rates. Subsequent chamber studies characterized fibers counted by phase contrast microscopy (PCM) per mass of respirable dusts and total suspended particulate dusts (total dusts), generated during JCC sanding or sweeping, as well as corresponding dust emission rates for JCC and JCN, and the ratio of total to respirable dust mass for JCN. From these data we estimated factors, F(CH-rd) and F(CH-td) (in units of f cm(-3) per mg m( 3)), by which respirable JCN dust mass concentrations collected during construction use can be converted to corresponding airborne PCM fiber concentrations generated by sanding or sweeping JCC. For sanding, median values (95% confidence limits) of F(CH-rd) and F(CH-td) were estimated to be 0.044 (0.039-0.050) and 0.212 (0.115-0.390) f cm(-3) per mg m(-3), respectively. The F(CH-td) to F(CH-rd) ratio indicates that approximately five times as many airborne PCM fibers are anticipated per unit air volume sampled when JCC dust is collected on cassettes (as done historically), than when respirable JCC dust is collected on cyclones. As the sizes of individual fibers collected appear to be primarily respirable, this difference may be a sampling artifact and suggests caution in interpreting historical fiber concentration measures made using cassettes during work with JCC-like materials. F(CH-rd) can be used with published and newly generated field measurements of respirable dust mass concentrations associated with the use of JCN or equivalent JCN materials to better characterize historical worker exposures to PCM fibers from use of JCC or equivalent JCCs. The experimental process described also can be used to develop conversion factors for other combinations of modern-day asbestos-free and historical chrysotile-containing products. PMID- 21795245 TI - Barriers to exercise participation among dialysis patients. AB - BACKGROUND: Physical inactivity is a strong predictor of mortality in patients with end-stage renal disease and is associated with poor physical functioning. Patients with end-stage renal disease are inactive even compared to sedentary individuals without kidney disease. We sought to identify patient barriers to physical activity. METHODS: Adult patients on hemodialysis in the San Francisco Bay Area were recruited and asked to complete a study survey composed of questions about self-reported level of physical functioning, physical activity participation, patient physical activity preference and barriers to physical activity. Univariate and multivariable linear regression analyses were performed to study the association between barriers to physical activity and participation in physical activity. RESULTS: A total of 100 patients participated in the study, the majority of whom were male (73%), with a mean age of 60 +/- 15 years. Twenty seven percent identified themselves as white, 30% black and 21% Hispanic. The majority of participants strongly agreed that a sedentary lifestyle was a health risk (98%) and that increasing exercise was a benefit (98%). However, 92% of participants reported at least one barrier to physical activity. The most commonly reported barriers were fatigue on dialysis days and non-dialysis days (67 and 40%, respectively) and shortness of breath (48%). In multivariate analysis, a greater number of reported barriers was associated with lower levels of physical activity (P < 0.02). Post-dialysis fatigue was not associated with differences in activity level in multivariate analysis. Lack of motivation was associated with less physical activity. Endorsement of too many medical problems and not having enough time on dialysis days were also associated with less activity in adjusted analysis. CONCLUSION: We have identified a number of barriers to physical activity that can be addressed in studies aimed at increasing levels of physical activity. Inconsistent with nephrologists' reported assumptions, dialysis patients were interested in physical activity. PMID- 21795246 TI - Chronic kidney disease-mineral bone disorder (CKD-MBD) management and associated cost in an Irish haemodialysis cohort. PMID- 21795247 TI - Primary (de novo) dedifferentiated liposarcoma in the extremities: a multi institution Tohoku Musculoskeletal Tumor Society study of 18 cases in northern Japan. AB - OBJECTIVE: Dedifferentiated liposarcomas usually occur in the retroperitoneal space and relatively rarely in the extremities. METHODS: We identified 18 patients with primary dedifferentiated liposarcoma in the extremities from the files of Tohoku Musculoskeletal Tumor Society and analyzed demographics, histologic findings, treatments and prognostic factors. The average follow-up period was 58 months. RESULTS: The subjects were 12 men and 6 women with a mean age of 65 years. All tumors were in the thigh. Nine patients noticed a rapid enlargement of the long-standing tumor. Histologic subtypes of the dedifferentiated area were undifferentiated pleomorphic sarcoma (n = 12), osteosarcoma (n = 2), rhabdomyosarcoma (n = 2), leiomyosarcoma (n = 1) and malignant peripheral nerve sheath tumor (n = 1). In the patient with rhabdomyosarcoma-like dedifferentiated area, extensive necrosis was observed after the preoperative chemotherapy. One patient who underwent marginal excision developed a local recurrence, but inadequate surgical margin was not associated with a risk of local recurrence. Three patients had lung metastasis at initial presentation, and four other patients developed lung metastases during the follow up period. The overall survival rate was 61.1% at 5 years. On univariate analyses, large size of the dedifferentiated area (>8 cm), high MIB-1-labeling index (>30%) for the dedifferentiated area and lung metastasis at initial presentation were significantly associated with poor prognosis. CONCLUSIONS: Primary dedifferentiated liposarcoma in the extremities predominantly occurred in the thigh and a rapid enlargement of long-standing tumors was a characteristic symptom. Although the local behavior of these tumors was less aggressive than that of retroperitoneal dedifferentiated liposarcomas, they had a relatively high metastatic potential. PMID- 21795248 TI - Human meiotic progression and recombination are affected by Bisphenol A exposure during in vitro human oocyte development. AB - BACKGROUND: Bisphenol A (BPA) is a 'weak' endocrine disruptor. The effect of BPA on human reproduction is controversial but has been related to meiotic anomalies, recurrent miscarriages and abnormal karyotypes. METHODS: To evaluate the effects of BPA on survival, pairing-synapsis and meiotic recombination of human fetal oocytes, 21 510 oocytes from 12 cultured fetal ovaries were analyzed. Ovaries were cultured for 7, 14 or 21 days in control medium, dimethylsulfoxide-medium, BPA-medium and estradiol (E(2))-medium. Meiotic pairing-synapsis and recombination were studied by immunofluorescence against lateral element protein, central element protein of the synaptonemal complex and chromosome axis cohesin REC8. Mismatch repair protein, MLH1, was used as a crossover (CO) marker. Meiotic progression was analyzed following the number of surviving oocytes at different meiotic stages found in each culture time and condition, and the total number of MLH1 foci found in oocytes from cultured ovaries. RESULTS: Oocyte survival in vitro decreased with the addition of BPA to the medium (1 uM or greater). Oocyte degeneration was up to five times higher when BPA was added to culture medium. Moreover, oocytes exposed to BPA concentrations of 10 uM or higher presented approximately two times more MLH1 foci than unexposed cultured oocytes (P = 0.01). This was also observed in chromosome 21 from BPA-exposed oocytes, which had double the average number of MLH1 foci found in control oocytes (P = 0.001). E(2) was used as a positive control of estrogen receptors activity, and E(2) addition to the medium had similar effects on meiotic progression of oocytes from cultured ovaries. CONCLUSIONS: Our findings show that BPA concentrations of 1 uM or higher decrease the survival of human fetal oocytes in vitro, and concentrations of 10 uM or higher increase MLH1 foci number. MLH1 is considered a CO marker, and thus an increase in MLH1 foci could indicate an increase in COs in BPA-exposed oocytes. These data suggest that BPA can act as a toxic substance, which has particular implications for human females and the critical events of meiotic prophase, such as pairing-synapsis and recombination processes, as well as oocyte survival. PMID- 21795249 TI - Primary cardiac sarcoma mimicking mural thrombus. PMID- 21795250 TI - Tricky image of exuberant accessory mitral valve tissue with partial interchordal space obliteration. PMID- 21795251 TI - Infective endocarditis in mitral mechanical prosthesis: the role of three dimensional transoesophageal echocardiography. PMID- 21795252 TI - Independent effects of alternative splicing and structural constraint on the evolution of mammalian coding exons. AB - Alternative splicing (AS) is known to significantly affect exon-level protein evolutionary rates in mammals. Particularly, alternatively spliced exons (ASEs) have a higher nonsynonymous-to-synonymous substitution rate (dN/dS) ratio than constitutively spliced exons (CSEs), possibly because the former are required only occasionally for normal biological functions. Meanwhile, intrinsically disordered regions (IDRs), the protein regions lacking fixed 3D structures, are also reported to have an increased evolutionary rate due to lack of structural constraint. Interestingly, IDRs tend to be located in alternative protein regions. Yet which of these two factors is the major determinant of the increased dN/dS in mammalian ASEs remains unclear. By comparing human-macaque and human mouse one-to-one orthologous genes, we demonstrate that AS and protein structural disorder have independent effects on mammalian exon evolution. We performed analyses of covariance to demonstrate that the slopes of the (dN/dS-percentage of IDR) regression lines differ significantly between CSEs and ASEs. In other words, the dN/dS ratios of both ASEs and CSEs increase with the proportion of IDR (PIDR), whereas ASEs have higher dN/dS ratios than CSEs when they have similar PIDRs. Since ASEs and IDRs may less frequently overlap with protein domains (which also affect dN/dS), we also examined the correlations between dN/dS ratio and exon type/PIDR by controlling for the density of protein domain. We found that the effects of exon type and PIDR on dN/dS are both independent of domain density. Our results imply that nature can select for different biological features with regard to ASEs and IDRs, even though the two biological features tend to be localized in the same protein regions. PMID- 21795254 TI - Study of nuclear medicine practices in Portugal from an internal dosimetry perspective. AB - Nuclear medicine practices involve the handling of a wide range of pharmaceuticals labelled with different radionuclides, for diagnostic and therapeutic purposes. This work intends to evaluate the potential risks of internal contamination of nuclear medicine staff in several Portuguese nuclear medicine services and to conclude about the requirement of a routine internal monitoring. A methodology proposed by the International Atomic Energy Agency (IAEA), providing a set of criteria to determine the need, or not, for an internal monitoring programme, was applied. The evaluation of the risk of internal contaminations in a given set of working conditions is based on the type and amount of radionuclides being handled, as well as the safety conditions with which they are manipulated. The application of the IAEA criteria showed that 73.1% of all the workers included in this study should be integrated in a routine monitoring programme for internal contaminations; more specifically, 100% of workers performing radioimmunoassay techniques should be monitored. This study suggests that a routine monitoring programme for internal exposures should be implemented in Portugal for most nuclear medicine workers. PMID- 21795255 TI - A preliminary study into performing routine tube output and automatic exposure control quality assurance using radiology information system data. AB - Data are currently being collected from hospital radiology information systems in the North West of the UK for the purposes of both clinical audit and patient dose audit. Could these data also be used to satisfy quality assurance (QA) requirements according to UK guidance? From 2008 to 2009, 731 653 records were submitted from 8 hospitals from the North West England. For automatic exposure control QA, the protocol from Institute of Physics and Engineering in Medicine (IPEM) report 91 recommends that milliamperes per second can be monitored for repeatability and reproducibility using a suitable phantom, at 70-81 kV. Abdomen AP and chest PA examinations were analysed to find the most common kilovoltage used with these records then used to plot average monthly milliamperes per second with time. IPEM report 91 also recommends that a range of commonly used clinical settings is used to check output reproducibility and repeatability. For each tube, the dose area product values were plotted over time for two most common exposure factor sets. Results show that it is possible to do performance checks of AEC systems; however more work is required to be able to monitor tube output performance. Procedurally, the management system requires work and the benefits to the workflow would need to be demonstrated. PMID- 21795256 TI - Detection of the staphylococcal multiresistance gene cfr in Proteus vulgaris of food animal origin. AB - OBJECTIVES: To investigate the presence and the genetic environment of the multiresistance gene cfr in naturally occurring Gram-negative bacteria of pigs. METHODS: A total of 391 bacterial isolates with florfenicol MICs of >=16 mg/L, obtained from 557 nasal swabs of individual pigs, were screened by PCR for the known florfenicol resistance genes. The species assignment of the cfr-carrying isolate was based on the results of Gram's staining, colony morphology, 16S rDNA sequencing and biochemical profiling. The location of the cfr and floR genes was determined by Southern blotting and the regions flanking the cfr gene were sequenced by a modified random primer walking strategy. RESULTS: A single Proteus vulgaris isolate, which carried the genes floR and cfr, was detected in this study. A cfr-carrying segment of 7 kb with homology to a staphylococcal plasmid was found to be inserted into the chromosomal fimD gene of P. vulgaris. This segment was flanked by two IS26 elements located in the same orientation, which are believed to have played a role in this integration process. Stability testing via inverse PCR approaches showed that this integrate is not entirely stable, but the cfr-carrying centre region plus one IS26 copy can be looped out via IS26 mediated recombination. CONCLUSIONS: To the best of our knowledge, this is the first report of the cfr gene in a naturally occurring Gram-negative bacterium. Surveillance and monitoring of the cfr gene in Gram-negative bacteria are warranted with respect to food safety and consumer protection. PMID- 21795257 TI - ISEcp1-mediated transposition of linked blaCTX-M-3 and blaTEM-1b from the IncI1 plasmid pEK204 found in clinical isolates of Escherichia coli from Belfast, UK. AB - OBJECTIVES: Linked bla(CTX-M-3)-bla(TEM-1b) genes, as found on the IncI1 plasmid pEK204 prevalent in Belfast, also occur on plasmids belonging to other rep types in Escherichia coli isolated from nursing-home residents in Belfast. We investigated the mechanisms for their joint dissemination among diverse plasmids. METHODS: Plasmid pEK204 was transferred by electroporation into E. coli DH5alpha harbouring derivative pBAD Myc-His vectors. Transposition experiments were then performed at 37 degrees C. Transposition of bla genes onto the derivative pBAD Myc-His vector was confirmed by sequencing. RESULTS: ISEcp1 mediated transposition of bla(CTX-M-3) alone from pEK204, as well as both bla(CTX-M-3) and bla(TEM-1b) jointly. The 5' and 3' termini of the transposed fragments were identical to or resembled the ISEcp1 IR(L) and IR(R), respectively, thereby replicating the environments previously found in various Belfast clinical plasmids harbouring bla(CTX-M-3). CONCLUSIONS: Simultaneous dissemination of bla(CTX-M-3) and bla(TEM-1b) among plasmids in Belfast's nursing homes is facilitated by ISEcp1-mediated transposition of these bla genes from pEK204-like and other plasmids. Such transposition events are of public health concern, as they potentially allow wider dissemination of CTX-M-3 enzyme than would be possible through the spread of extended-spectrum beta-lactamase-encoding plasmids and strains alone. PMID- 21795258 TI - High prevalence of multidrug-resistant tuberculosis in Zunyi, Guizhou Province of China. PMID- 21795259 TI - Prevalence and antifungal susceptibility patterns of new cryptic species inside the species complexes Candida parapsilosis and Candida glabrata among blood isolates from a Spanish tertiary hospital. AB - OBJECTIVES: There is scarce information on the clinical relevance and antifungal susceptibility of Candida bracarensis, Candida nivariensis, Candida orthopsilosis and Candida metapsilosis. The objective of this study was to assess the prevalence and in vitro antifungal susceptibility of these cryptic species among 173 blood isolates previously identified as Candida glabrata or Candida parapsilosis at the Hospital of Cruces (Barakaldo, Spain). The survey was extended to 518 clinical isolates from the culture collection of the Universidad del Pais Vasco-Euskal Herriko Unibertsitatea (UPV-EHU; Bilbao, Spain). METHODS: In vitro susceptibilities to 5-fluorocytosine, amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole and voriconazole were tested. RESULTS: All isolates of C. glabrata were identified as C. glabrata sensu stricto. Inside the C. parapsilosis complex, 2.4% of isolates from the Hospital of Cruces and 5.8% from the UPV-EHU were C. metapsilosis or C. orthopsilosis. Of 457 isolates, 435 (95.19%) were C. parapsilosis sensu stricto, 11 (2.41%) C. metapsilosis and 11 (2.41%) C. orthopsilosis. Only seven blood isolates were C. metapsilosis (0.44%) or C. orthopsilosis (1.09%). These cryptic species were also isolated from other relevant clinical specimens. Four C. parapsilosis sensu stricto (5.6%) were susceptible dose-dependent, and one was resistant to both fluconazole and voriconazole (1.4%). Moreover, 19 isolates of C. parapsilosis sensu stricto (26.4%) were intermediately susceptible to itraconazole and higher concentrations of echinocandins were needed to inhibit this species. Most C. orthopsilosis and C. metapsilosis were susceptible to all antifungal agents tested, but one otic isolate of C. metapsilosis was resistant to fluconazole and 5-fluorocytosine. CONCLUSIONS: C. metapsilosis and C. orthopsilosis are associated with human disease and show a different antifungal susceptibility profile compared with C. parapsilosis sensu stricto. PMID- 21795260 TI - In vitro interaction of caspofungin and immunosuppressives against agents of mucormycosis. AB - OBJECTIVES: Mucormycosis is a rare but refractory mycosis with high mortality. Few therapeutic options are available and novel strategies are needed. Calcineurin inhibitors are known to have antifungal activity, including synergy with various antifungals. We examined the interaction of caspofungin with calcineurin inhibitors and sirolimus against Glomeromycetes. METHODS: Twenty-six strains of Glomeromycetes representing seven species (Rhizopus arrhizus, Rhizopus microsporus, Mucor sp., Rhizomucor pusillus, Cunninghamella berthollettiae, Mycocladus corymbifera and Apophysomyces elegans) were studied. Antifungal susceptibility testing was performed according to CLSI M38-A2, modified for chequerboard dilution testing using the minimum effective concentration (MEC) endpoint for caspofungin and calcineurin inhibitors/sirolimus. Synergy was defined as a fractional inhibitory concentration index <=0.5, indifference >0.5 to <=4.0 and antagonism >4.0. RESULTS: Caspofungin had no intrinsic activity against Glomeromycetes (MEC >8 mg/L). The combination of caspofungin with calcineurin inhibitors and sirolimus showed synergy in seven isolates. In the presence of calcineurin inhibitors and sirolimus, the MEC of caspofungin was significantly lowered (>4-fold) in 24 and 7 isolates, respectively. All species showed lower MECs of caspofungin with calcineurin inhibitors and only R. arrhizus, Mucor sp. and R. pusillus showed lower MECs with sirolimus. No antagonism was observed. CONCLUSIONS: Calcineurin inhibitors and sirolimus significantly lowered MECs of caspofungin for Glomeromycetes, with occasional synergy observed. The clinical significance of this should be further investigated. PMID- 21795261 TI - Genome-wide identification, classification, and expression analysis of autophagy associated gene homologues in rice (Oryza sativa L.). AB - Autophagy is an intracellular degradation process for recycling macromolecules and organelles. It plays important roles in plant development and in response to nutritional demand, stress, and senescence. Organisms from yeast to plants contain many autophagy-associated genes (ATG). In this study, we found that a total of 33 ATG homologues exist in the rice [Oryza sativa L. (Os)] genome, which were classified into 13 ATG subfamilies. Six of them are alternatively spliced genes. Evolutional analysis showed that expansion of 10 OsATG homologues occurred via segmental duplication events and that the occurrence of these OsATG homologues within each subfamily was asynchronous. The Ka/Ks ratios suggested purifying selection for four duplicated OsATG homologues and positive selection for two. Calculating the dates of the duplication events indicated that all duplication events might have occurred after the origin of the grasses, from 21.43 to 66.77 million years ago. Semi-quantitative RT-PCR analysis and mining the digital expression database of rice showed that all 33 OsATG homologues could be detected in at least one cell type of the various tissues under normal or stress growth conditions, but their expression was tightly regulated. The 10 duplicated genes showed expression divergence. The expression of most OsATG homologues was regulated by at least one treatment, including hormones, abiotic and biotic stresses, and nutrient limitation. The identification of OsATG homologues showing constitutive expression or responses to environmental stimuli provides new insights for in-depth characterization of selected genes of importance in rice. PMID- 21795262 TI - Unmet need for effective family planning in HIV-infected individuals: results from a survey in rural Uganda. AB - BACKGROUND AND METHODOLOGY: This study determined the unmet need for family planning among HIV-positive and HIV-negative individuals living in western Uganda. Semi-structured interviews were conducted with individuals who were randomly selected from HIV testing lists. Of those individuals, further analysis was conducted on a subset of 206 participants who did not desire more children and were not using a highly effective method of contraception. Descriptive, bivariate and multivariate methods were performed to assess the relationship between HIV status and unmet need for effective family planning. RESULTS: The unmet need for effective family planning was much greater in HIV-infected individuals compared to HIV-negative individuals [75.0% vs 33.8%, adjusted odds ratio (OR) 3.97, 95% confidence interval (CI) 1.97-8.03, p<0.001]. Females were more likely to report an unmet need compared to males (69.0% vs 49.5%; adjusted OR 1.94, 95% CI 0.94-4.00, p=0.071). Other predictors of unmet need for effective family planning were older age (adjusted OR 1.08 for each year of age, 95% CI 1.00-1.16, p=0.018) and single/cohabiting vs being married (OR 2.36, 95% CI 1.16 4.80, p=0.036). Being on antiretroviral therapy was not a predictor of having a lower unmet need for effective family planning methods. DISCUSSION AND CONCLUSIONS: There is high unmet need for effective family planning in HIV positive study participants in a region of western Uganda, which should be of concern. This suggests that HIV-infected individuals do not want to use family planning or encounter barriers to accessing and utilising family planning services. Family planning programmes and HIV care and prevention services have to work together more effectively to create services conducive to clients from both programmes. PMID- 21795263 TI - Latitudinal variation in light levels drives human visual system size. AB - Ambient light levels influence visual system size in birds and primates. Here, we argue that the same is true for humans. Light levels, in terms of both the amount of light hitting the Earth's surface and day length, decrease with increasing latitude. We demonstrate a significant positive relationship between absolute latitude and human orbital volume, an index of eyeball size. Owing to tight scaling between visual system components, this will translate into enlarged visual cortices at higher latitudes. We also show that visual acuity measured under full-daylight conditions is constant across latitudes, indicating that selection for larger visual systems has mitigated the effect of reduced ambient light levels. This provides, to our knowledge, the first support that light levels drive intraspecific variation in visual system size in the human population. PMID- 21795264 TI - Post-allogrooming reductions in self-directed behaviour are affected by role and status in the green woodhoopoe. AB - Allogrooming occurs in a wide range of species and can serve both hygienic and social functions. While the latter have long been thought to be underpinned by reductions in tension for recipients, recent work has suggested that donors may also benefit in this way. Here, I show that, in cooperatively breeding green woodhoopoes Phoeniculus purpureus, involvement in allogrooming is followed by a reduction in self-grooming by both recipients and donors, but that the former exhibit a greater decrease. Moreover, I demonstrate for the first time that the dominance status of the allogrooming participant is important, with subordinate group members reducing subsequent self-grooming to a greater extent than the dominant pair. If avian self-directed behaviour reflects current distress levels in the same way as found in various primates, my results would indicate that allogrooming benefits are not confined to mammals, and would have important implications both for accurate assessments of the true costs and benefits of affiliative behaviour and for our understanding of the evolution of sociality. PMID- 21795265 TI - Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common. AB - We explored associations between the common protozoan parasite Toxoplasma gondii and brain cancers in human populations. We predicted that T. gondii could increase the risk of brain cancer because it is a long-lived parasite that encysts in the brain, where it provokes inflammation and inhibits apoptosis. We used a medical geography approach based on the national incidence of brain cancers and seroprevalence of T. gondii. We corrected reports of incidence for national gross domestic product because wealth probably increases the ability to detect cancer. We also included gender, cell phone use and latitude as variables in our initial models. Prevalence of T. gondii explained 19 per cent of the residual variance in brain cancer incidence after controlling for the positive effects of gross domestic product and latitude among nations. Infection with T. gondii was associated with a 1.8-fold increase in the risk of brain cancers across the range of T. gondii prevalence in our dataset (4-67%). These results, though correlational, suggest that T. gondii should be investigated further as a possible oncogenic pathogen of humans. PMID- 21795266 TI - Modelling rate distributions using character compatibility: implications for morphological evolution among fossil invertebrates. AB - Rate distributions are important considerations when testing hypotheses about morphological evolution or phylogeny. They also have implications about general processes underlying character evolution. Molecular systematists often assume that rates are Poisson processes with gamma distributions. However, morphological change is the product of multiple probabilistic processes and should theoretically be affected by hierarchical integration of characters. Both factors predict lognormal rate distributions. Here, a simple inverse modelling approach assesses the best single-rate, gamma and lognormal models given observed character compatibility for 115 invertebrate groups. Tests reject the single-rate model for nearly all cases. Moreover, the lognormal outperforms the gamma for character change rates and (especially) state derivation rates. The latter in particular is consistent with integration affecting morphological character evolution. PMID- 21795267 TI - The evolutionary basis of human social learning. AB - Humans are characterized by an extreme dependence on culturally transmitted information. Such dependence requires the complex integration of social and asocial information to generate effective learning and decision making. Recent formal theory predicts that natural selection should favour adaptive learning strategies, but relevant empirical work is scarce and rarely examines multiple strategies or tasks. We tested nine hypotheses derived from theoretical models, running a series of experiments investigating factors affecting when and how humans use social information, and whether such behaviour is adaptive, across several computer-based tasks. The number of demonstrators, consensus among demonstrators, confidence of subjects, task difficulty, number of sessions, cost of asocial learning, subject performance and demonstrator performance all influenced subjects' use of social information, and did so adaptively. Our analysis provides strong support for the hypothesis that human social learning is regulated by adaptive learning rules. PMID- 21795268 TI - A palaeobiogeographic model for biotic diversification within Amazonia over the past three million years. AB - Many hypotheses have been proposed to explain high species diversity in Amazonia, but few generalizations have emerged. In part, this has arisen from the scarcity of rigorous tests for mechanisms promoting speciation, and from major uncertainties about palaeogeographic events and their spatial and temporal associations with diversification. Here, we investigate the environmental history of Amazonia using a phylogenetic and biogeographic analysis of trumpeters (Aves: Psophia), which are represented by species in each of the vertebrate areas of endemism. Their relationships reveal an unforeseen 'complete' time-slice of Amazonian diversification over the past 3.0 Myr. We employ this temporally calibrated phylogeny to test competing palaeogeographic hypotheses. Our results are consistent with the establishment of the current Amazonian drainage system at approximately 3.0-2.0 Ma and predict the temporal pattern of major river formation over Plio-Pleistocene times. We propose a palaeobiogeographic model for the last 3.0 Myr of Amazonian history that has implications for understanding patterns of endemism, the temporal history of Amazonian diversification and mechanisms promoting speciation. The history of Psophia, in combination with new geological evidence, provides the strongest direct evidence supporting a role for river dynamics in Amazonian diversification, and the absence of such a role for glacial climate cycles and refugia. PMID- 21795269 TI - Floral signposts: testing the significance of visual 'nectar guides' for pollinator behaviour and plant fitness. AB - Nectar guides, contrasting patterns on flowers that supposedly direct pollinators towards a concealed nectar reward, are taxonomically widespread. However, there have been few studies of their functional significance and effects on plant fitness. Most previous studies focused on pollinator behaviour and used artificial flowers in laboratory settings. We experimentally investigated the role of putative nectar guides in a natural system: the South African iris Lapeirousia oreogena, whose flowers have a clearly visible pattern of six white arrow-markings pointing towards the narrow entrance of the long corolla tube, and its sole pollinator, a long-proboscid nemestrinid fly. We painted over none, some or all of the white arrow-markings with ink that matched the colour of the corolla background. Although arrow-marking removal had little effect on the approaches by flies to flowers from a distance, it dramatically reduced the likelihood of proboscis insertion. Export of pollen dye analogue (an estimate of male fitness) was reduced to almost zero in flowers from which all nectar guides had been removed, and fruit set (a measure of female fitness) was also significantly reduced. Our results confirm that the markings on L. oreogena flowers serve as nectar guides and suggest that they are under strong selective maintenance through both male and female fitness components in this pollination system. PMID- 21795270 TI - Sex-biased dispersal, haplodiploidy and the evolution of helping in social insects. AB - In his famous haplodiploidy hypothesis, W. D. Hamilton proposed that high sister sister relatedness facilitates the evolution of kin-selected reproductive altruism among Hymenopteran females. Subsequent analyses, however, suggested that haplodiploidy cannot promote altruism unless altruists capitalize on relatedness asymmetries by helping to raise offspring whose sex ratio is more female-biased than the population at large. Here, we show that haplodiploidy is in fact more favourable than is diploidy to the evolution of reproductive altruism on the part of females, provided only that dispersal is male-biased (no sex-ratio bias or active kin discrimination is required). The effect is strong, and applies to the evolution both of sterile female helpers and of helping among breeding females. Moreover, a review of existing data suggests that female philopatry and non-local mating are widespread among nest-building Hymenoptera. We thus conclude that Hamilton was correct in his claim that 'family relationships in the Hymenoptera are potentially very favourable to the evolution of reproductive altruism'. PMID- 21795271 TI - Electroreception in the Guiana dolphin (Sotalia guianensis). AB - Passive electroreception is a widespread sense in fishes and amphibians, but in mammals this sensory ability has previously only been shown in monotremes. While the electroreceptors in fish and amphibians evolved from mechanosensory lateral line organs, those of monotremes are based on cutaneous glands innervated by trigeminal nerves. Electroreceptors evolved from other structures or in other taxa were unknown to date. Here we show that the hairless vibrissal crypts on the rostrum of the Guiana dolphin (Sotalia guianensis), structures originally associated with the mammalian whiskers, serve as electroreceptors. Histological investigations revealed that the vibrissal crypts possess a well-innervated ampullary structure reminiscent of ampullary electroreceptors in other species. Psychophysical experiments with a male Guiana dolphin determined a sensory detection threshold for weak electric fields of 4.6 uV cm(-1), which is comparable to the sensitivity of electroreceptors in platypuses. Our results show that electroreceptors can evolve from a mechanosensory organ that nearly all mammals possess and suggest the discovery of this kind of electroreception in more species, especially those with an aquatic or semi-aquatic lifestyle. PMID- 21795272 TI - Identifying indicators of illegal behaviour: carnivore killing in human-managed landscapes. AB - Managing natural resources often depends on influencing people's behaviour, however effectively targeting interventions to discourage environmentally harmful behaviours is challenging because those involved may be unwilling to identify themselves. Non-sensitive indicators of sensitive behaviours are therefore needed. Previous studies have investigated people's attitudes, assuming attitudes reflect behaviour. There has also been interest in using people's estimates of the proportion of their peers involved in sensitive behaviours to identify those involved, since people tend to assume that others behave like themselves. However, there has been little attempt to test the potential of such indicators. We use the randomized response technique (RRT), designed for investigating sensitive behaviours, to estimate the proportion of farmers in north-eastern South Africa killing carnivores, and use a modified logistic regression model to explore relationships between our best estimates of true behaviour (from RRT) and our proposed non-sensitive indicators (including farmers' attitudes, and estimates of peer-behaviour). Farmers' attitudes towards carnivores, question sensitivity and estimates of peers' behaviour, predict the likelihood of farmers killing carnivores. Attitude and estimates of peer-behaviour are useful indicators of involvement in illicit behaviours and may be used to identify groups of people to engage in interventions aimed at changing behaviour. PMID- 21795273 TI - Photic niche invasions: phylogenetic history of the dim-light foraging augochlorine bees (Halictidae). AB - Most bees rely on flowering plants and hence are diurnal foragers. From this ancestral state, dim-light foraging in bees requires significant adaptations to a new photic environment. We used DNA sequences to evaluate the phylogenetic history of the most diverse clade of Apoidea that is adapted to dim-light environments (Augochlorini: Megalopta, Megaloptidia and Megommation). The most speciose lineage, Megalopta, is distal to the remaining dim-light genera, and its closest diurnal relative (Xenochlora) is recovered as a lineage that has secondarily reverted to diurnal foraging. Tests for adaptive protein evolution indicate that long-wavelength opsin shows strong evidence of stabilizing selection, with no more than five codons (2%) under positive selection, depending on analytical procedure. In the branch leading to Megalopta, the amino acid of the single positively selected codon is conserved among ancestral Halictidae examined, and is homologous to codons known to influence molecular structure at the chromophore-binding pocket. Theoretically, such mutations can shift photopigment lambda(max) sensitivity and enable visual transduction in alternate photic environments. Results are discussed in light of the available evidence on photopigment structure, morphological specialization and biogeographic distributions over geological time. PMID- 21795274 TI - Self-recognition of avatar motion: how do I know it's me? AB - When motion is isolated from form cues and viewed from third-person perspectives, individuals are able to recognize their own whole body movements better than those of friends. Because we rarely see our own bodies in motion from third person viewpoints, this self-recognition advantage may indicate a contribution to perception from the motor system. Our first experiment provides evidence that recognition of self-produced and friends' motion dissociate, with only the latter showing sensitivity to orientation. Through the use of selectively disrupted avatar motion, our second experiment shows that self-recognition of facial motion is mediated by knowledge of the local temporal characteristics of one's own actions. Specifically, inverted self-recognition was unaffected by disruption of feature configurations and trajectories, but eliminated by temporal distortion. While actors lack third-person visual experience of their actions, they have a lifetime of proprioceptive, somatosensory, vestibular and first-person-visual experience. These sources of contingent feedback may provide actors with knowledge about the temporal properties of their actions, potentially supporting recognition of characteristic rhythmic variation when viewing self-produced motion. In contrast, the ability to recognize the motion signatures of familiar others may be dependent on configural topographic cues. PMID- 21795275 TI - A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's muscular dystrophy for 20 years. AB - A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years ago by another physician presented with gradually progressive proximal muscle weakness since teenage years. Family history revealed a strong paternal familial inheritance pattern of similar distribution of weakness-face, forearm flexion, knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing. FSHD is the third most common muscular dystrophy. Clinical diagnosis is made from the distinctive pattern of weakness, autosomal-dominant inheritance, and confirmed by genetic testing. This case strongly demonstrates the importance of a thorough and careful clinical evaluation even in a case with a long standing diagnosis. PMID- 21795276 TI - Age-related differences in postprandial glycaemia and glycaemic index. PMID- 21795277 TI - Pollen-pistil interactions and early fruiting in parthenocarpic citrus. AB - BACKGROUND AND AIMS: An intense pollen-pistil interaction precedes fertilization. This interaction is of particular relevance in agronomically important species where seeds or fruits are the edible part. Over time some agronomically species have been selected for the ability to produce fruit without seeds. While this phenomenon is critical for commercial production in some species, very little is known about the events behind the production of seedless fruit. In this work, the relationship between pollen-pistil interaction and the onset of fruiting was investigated in citrus mandarin. METHODS: Pistils were sequentially examined in hand-pollinated flowers paying attention to pollen-tube behaviour, and to cytochemical changes along the pollen-tube pathway. To evaluate which of these changes were induced by pollination/fertilization and which were developmentally regulated, pollinated and unpollinated pistils were compared. Also the onset of fruiting was timed and changes in the ovary examined. KEY RESULTS: Conspicuous changes occurred in the pistil along the pollen-tube pathway, which took place in a basipetal way encompassing the timing of pollen-tube growth. However, these changes appear to be developmentally regulated as they happened in the same way and at the same time in unpollinated flowers. Moreover, the onset of fruiting occurred prior to fertilization and the very same changes could be observed in unpollinated flowers. CONCLUSIONS: Pollen-pistil interaction in citrus showed similarities with unrelated species and families belonging to other taxa. The uncoupling of the reproductive and fruiting processes accounts for the parthenocarpic ability of unpollinated flowers to produce fruit in citrus. However, the maintenance of a functional reproductive process reflects the potential to produce seeded fruits, providing a basis for the understanding of the production of seeded or unseeded fruits and further understanding of the process of parthenocarpy in other species. PMID- 21795278 TI - Functional traits and root morphology of alpine plants. AB - BACKGROUND AND AIMS: Vegetation has long been recognized to protect the soil from erosion. Understanding species differences in root morphology and functional traits is an important step to assess which species and species mixtures may provide erosion control. Furthermore, extending classification of plant functional types towards root traits may be a useful procedure in understanding important root functions. METHODS: In this study, pioneer data on traits of alpine plant species, i.e. plant height and shoot biomass, root depth, horizontal root spreading, root length, diameter, tensile strength, plant age and root biomass, from a disturbed site in the Swiss Alps are presented. The applicability of three classifications of plant functional types (PFTs), i.e. life form, growth form and root type, was examined for above- and below-ground plant traits. KEY RESULTS: Plant traits differed considerably among species even of the same life form, e.g. in the case of total root length by more than two orders of magnitude. Within the same root diameter, species differed significantly in tensile strength: some species (Geum reptans and Luzula spicata) had roots more than twice as strong as those of other species. Species of different life forms provided different root functions (e.g. root depth and horizontal root spreading) that may be important for soil physical processes. All classifications of PFTs were helpful to categorize plant traits; however, the PFTs according to root type explained total root length far better than the other PFTs. CONCLUSIONS: The results of the study illustrate the remarkable differences between root traits of alpine plants, some of which cannot be assessed from simple morphological inspection, e.g. tensile strength. PFT classification based on root traits seems useful to categorize plant traits, even though some patterns are better explained at the individual species level. PMID- 21795279 TI - A critical balance between Cyclin B synthesis and Myt1 activity controls meiosis entry in Xenopus oocytes. AB - In fully grown oocytes, meiosis is arrested at first prophase until species specific initiation signals trigger maturation. Meiotic resumption universally involves early activation of M phase-promoting factor (Cdc2 kinase-Cyclin B complex, MPF) by dephosphorylation of the inhibitory Thr14/Tyr15 sites of Cdc2. However, underlying mechanisms vary. In Xenopus oocytes, deciphering the intervening chain of events has been hampered by a sensitive amplification loop involving Cdc2-Cyclin B, the inhibitory kinase Myt1 and the activating phosphatase Cdc25. In this study we provide evidence that the critical event in meiotic resumption is a change in the balance between inhibitory Myt1 activity and Cyclin B neosynthesis. First, we show that in fully grown oocytes Myt1 is essential for maintaining prophase I arrest. Second, we demonstrate that, upon upregulation of Cyclin B synthesis in response to progesterone, rapid inactivating phosphorylation of Myt1 occurs, mediated by Cdc2 and without any significant contribution of Mos/MAPK or Plx1. We propose a model in which the appearance of active MPF complexes following increased Cyclin B synthesis causes Myt1 inhibition, upstream of the MPF/Cdc25 amplification loop. PMID- 21795280 TI - Differential adhesion and actomyosin cable collaborate to drive Echinoid-mediated cell sorting. AB - Cell sorting involves the segregation of two cell populations into 'immiscible' adjacent tissues with smooth borders. Echinoid (Ed), a nectin ortholog, is an adherens junction protein in Drosophila, and cells mutant for ed sort out from the surrounding wild-type cells. However, it remains unknown which factors trigger cell sorting. Here, we dissect the sequence of this process and find that cell sorting occurs when differential expression of Ed triggers the assembly of actomyosin cable. Conversely, Ed-mediated cell sorting can be rescued by recruitment of Ed, via homophilic or heterophilic interactions, to the wild-type cell side of the clonal interface, even when differential Ed expression persists. We found, unexpectedly, that when actomyosin cable was largely absent, differential adhesion was sufficient to cause limited cell segregation but with a jagged tissue border (imperfect sorting). We propose that Ed-mediated cell sorting is driven both by differential Ed adhesion that induces cell segregation with a jagged border and by actomyosin cable assembly at the interface that smoothens this border. PMID- 21795281 TI - Ezh2 regulates anteroposterior axis specification and proximodistal axis elongation in the developing limb. AB - Specification and determination (commitment) of positional identities precedes overt pattern formation during development. In the limb bud, it is clear that the anteroposterior axis is specified at a very early stage and is prepatterned by the mutually antagonistic interaction between Gli3 and Hand2. There is also evidence that the proximodistal axis is specified early and determined progressively. Little is known about upstream regulators of these processes or how epigenetic modifiers influence axis formation. Using conditional mutagenesis at different time points, we show that the histone methyltransferase Ezh2 is an upstream regulator of anteroposterior prepattern at an early stage. Mutants exhibit posteriorised limb bud identity. During later limb bud stages, Ezh2 is essential for cell survival and proximodistal segment elongation. Ezh2 maintains the late phase of Hox gene expression and cell transposition experiments suggest that it regulates the plasticity with which cells respond to instructive positional cues. PMID- 21795282 TI - Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. AB - Proper regulation of Indian hedgehog (Ihh) signaling is vital for chondrocyte proliferation and differentiation in the growth plate. Its dysregulation causes skeletal dysplasia, osteoarthritis or cartilaginous neoplasia. Here, we show that Suppressor of fused (Sufu) and Kif7 are essential regulators of Ihh signaling. While Sufu acts as a negative regulator of Gli transcription factors, Kif7 functions both positively and negatively in chondrocytes. Kif7 plays a role in the turnover of Sufu and the exclusion of Sufu-Gli complexes from the primary cilium. Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. Furthermore, Kif7 also inhibits Gli transcriptional activity in the chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and -independent mechanisms. PMID- 21795283 TI - Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser. AB - The midbrain-hindbrain interface gives rise to a boundary of particular importance in CNS development as it forms a local signalling centre, the proper functioning of which is essential for the formation of tectum and cerebellum. Positioning of the mid-hindbrain boundary (MHB) within the neuroepithelium is dependent on the interface of Otx2 and Gbx2 expression domains, yet in the absence of either or both of these genes, organiser genes are still expressed, suggesting that other, as yet unknown mechanisms are also involved in MHB establishment. Here, we present evidence for a role for Notch signalling in stabilising cell lineage restriction and regulating organiser gene expression at the MHB. Experimental interference with Notch signalling in the chick embryo disrupts MHB formation, including downregulation of the organiser signal Fgf8. Ectopic activation of Notch signalling in cells of the anterior hindbrain results in an exclusion of those cells from rhombomeres 1 and 2, and in a simultaneous clustering along the anterior and posterior boundaries of this area, suggesting that Notch signalling influences cell sorting. These cells ectopically express the boundary marker Fgf3. In agreement with a role for Notch signalling in cell sorting, anterior hindbrain cells with activated Notch signalling segregate from normal cells in an aggregation assay. Finally, misexpression of the Notch modulator Lfng or the Notch ligand Ser1 across the MHB leads to a shift in boundary position and loss of restriction of Fgf8 to the MHB. We propose that differential Notch signalling stabilises the MHB through regulating cell sorting and specifying boundary cell fate. PMID- 21795284 TI - Notch-mediated repression of bantam miRNA contributes to boundary formation in the Drosophila wing. AB - Subdivision of proliferating tissues into adjacent compartments that do not mix plays a key role in animal development. The Actin cytoskeleton has recently been shown to mediate cell sorting at compartment boundaries, and reduced cell proliferation in boundary cells has been proposed as a way of stabilizing compartment boundaries. Cell interactions mediated by the receptor Notch have been implicated in the specification of compartment boundaries in vertebrates and in Drosophila, but the molecular effectors remain largely unidentified. Here, we present evidence that Notch mediates boundary formation in the Drosophila wing in part through repression of bantam miRNA. bantam induces cell proliferation and we have identified the Actin regulator Enabled as a new target of bantam. Increased levels of Enabled and reduced proliferation rates contribute to the maintenance of the dorsal-ventral affinity boundary. The activity of Notch also defines, through the homeobox-containing gene cut, a distinct population of boundary cells at the dorsal-ventral (DV) interface that helps to segregate boundary from non boundary cells and contributes to the maintenance of the DV affinity boundary. PMID- 21795285 TI - Keratopigmentation (corneal tattooing) for the management of visual disabilities of the eye related to iris defects. AB - AIM: To investigate the functional and cosmetic outcomes of keratopigmentation (KTP) in cases of moderate to severe visual dysfunctions owing to different iris disorders. METHODS: 11 eyes with moderate to severe visual disabilities related to iris defects underwent KTP for functional and cosmetic restoration using micronised mineral pigments and assisted with modern technologies such as femtosecond laser and new automated keratopigmentation instruments for the intrastromal and superficial application of the pigments. RESULTS: Following the KTP surgery, the visual-function-related symptoms improved in all cases, from significant improvement to total elimination. Eight patients were asymptomatic after the surgery. In two patients, minimal non-disabling symptoms remained after surgery. One patient with traumatic aniridia complained of significant residual glare at the 3-month postoperative visit and was reoperated to reduce the simulated pupil to 4 mm. The cosmetic outcomes were analysed and classified as excellent in eight patients and good in three. CONCLUSION: KTP using new micronised mineral pigments and new surgical protocols has proven in this series to be an effective surgical technique for the management of moderate to severe visual dysfunctions related to iris defects. PMID- 21795286 TI - Influence of contact lens wear on the results of ultraviolet A/riboflavin cross linking for progressive keratoconus. AB - AIMS: To report on the influence of rigid gas permeable contact lens (CL) wear on the results of ultraviolet A/riboflavin cross-linking (CXL) for stabilisation of progressive keratoconus. METHODS: Prospective non-comparative study of 15 eyes without CL and 12 eyes fitted with CL from 1 to 10 weeks post-CXL. None of the patients had been wearing CL before CXL. The effect of the CXL treatment was measured by the change from the baseline of best spectacle corrected visual acuity (BSCVA), refractive sphere and cylinder, maximal keratometry value (K max), simulated keratometry steep, flat, astigmatism, refractive power (RP) steep, flat and astigmatism, I-S value on EyeSys (EyeSys Vision Inc, Houston, Texas, USA) and K max on Pentacam (Oculus Optikgerate, Wetzlar, Germany). The results of these measurements are reported pre-CXL and at 6-month intervals up to 18 months post-CXL. Results In the eyes without CL, none of the study parameters showed a significant change from baseline. Only in the group of eyes fitted with CL post-CXL, several parameters showed a significant improvement: I-S value and K max on EyeSys (all time points), RP steep and simulated astigmatism (6 and 12 months) and RP flat (12 months). CONCLUSION: CL can be a confounding factor in interpreting the results of CXL: lens wear itself leads to improved topographic parameters. PMID- 21795287 TI - Estimating person-based injury incidence: accuracy of an algorithm to identify readmissions from hospital discharge data. AB - BACKGROUND: Effective use of routinely collected hospital discharge data (HDD) to estimate injury incidence requires a separate identification of new injuries from readmissions for a previous injury. The aim was to determine the accuracy of a computerised algorithm to identify injury readmissions in HDD. METHODS: A random sample of 2000 events ('key events') were selected from the 2006 injury subset of New Zealand's HDD. Discharge histories from 1989 to 2007 were extracted for individuals and manually reviewed by at least two people to determine the 'gold standard' readmission status of each key event. The algorithm relies on four variables: unique national person identifier, dates of injury, admission and discharge. Reviewers were provided with these variables as well as additional discharge information (eg, discharge type and external cause code narrative) recorded in the HDD. Results of the manual review were compared to those obtained from the algorithm. RESULTS: The algorithm assigned 1811 (90.6%) as incident admissions compared to 1800 (90.0%) classified by the gold standard. Agreement was 97.9%, and accuracy measures (sensitivity, specificity, negative predictive value and positive predictive value) ranged from 87% to 99%. No statistically significant differences between readmission assignation by the algorithm and the gold standard were observed by age, nature of injury, external cause of injury or body region. CONCLUSIONS: Any country with electronic HDD could readily identify readmissions and, thus, accurately estimate injury incidence from HDD, providing that a unique person identifier and the date of injury were included in addition to the obligatory dates of admission and discharge. PMID- 21795288 TI - Speed cameras in an urban setting: a cost-benefit analysis. AB - BACKGROUND: To perform a cost-benefit analysis of the installation of speed cameras on the beltways of Barcelona. METHODS: The analysis was performed from the society perspective over a 2-year period using a controlled before-and-after study design. The net benefit was calculated using, as benefits, the willingness to pay for the estimated number of people who avoided injury as a consequence of the intervention, subtracting costs and savings. Sensitivity analyses were performed using the maximum and minimum estimated number of people who avoided injury, assuming that there was a minimum of one death avoided, using the maximum value of a statistical life, assigning all implementation costs to the first year and assuming there was no time lost due to speed reduction. RESULTS: Base case results showed a net benefit of ?6.8 million. Sensitivity analyses suggested that net benefits could range from ?5.6 to ?23.1 million over 2 years. CONCLUSIONS: The use of speed cameras in urban areas has a favourable economic impact even when assessed using conservative assumptions. PMID- 21795289 TI - Acceptability of self-testing for trichomoniasis increases with experience. AB - OBJECTIVES: Self-testing and point-of-care (POC) tests could improve the detection of sexually transmitted infections (STIs) in adolescents. This study aimed to (1) validate a scale measuring acceptability of self-testing for trichomoniasis, (2) compare acceptability of self versus clinician testing using a POC test for trichomoniasis, (3) examine changes in acceptability after experience and review of results, and (4) examine predictors of acceptability. METHODS: Women (14-22 years old) performed the POC test and completed surveys assessing acceptability of self and clinician testing at baseline, after testing, and after discussion of results. Factor analysis examined scale structure; changes in mean scale scores were assessed with mixed models. Generalised linear models examined predictors of acceptability. RESULTS: Of 247 participants, 54 (22%) had a positive POC test for trichomoniasis. Factor analysis confirmed four acceptability subscales: trust of results, confidence, comfort, and effects of testing. At baseline, trust and confidence were higher, and comfort was lower, for clinician versus self testing. For self-testing, all subscale scores increased from baseline to after testing, and trust increased from after testing to after discussion. Trust of self and clinician results was not significantly different after discussion. A positive attitude towards home testing predicted higher self-test acceptability on all subscales. Tampon use was associated with increased self-test comfort at baseline. Concordance between self and clinician results predicted increased trust of self testing after discussion. CONCLUSIONS: Many young women lack confidence in their ability to self-test for trichomoniasis. Allowing women to try a POC test and review the results with a clinician increases acceptability of self-testing. PMID- 21795290 TI - Can we improve partner notification rates through expedited partner therapy in the UK? Findings from an exploratory trial of Accelerated Partner Therapy (APT). AB - OBJECTIVES: To develop two new models of expedited partner therapy for the UK, and evaluate them for feasibility, acceptability and preliminary outcome estimates to inform the design of a randomised controlled trial (RCT). METHODS: Two models of expedited partner therapy (APTHotline and APTPharmacy), known as 'Accelerated Partner Therapy' (APT) were developed. A non-randomised comparative study was conducted of the two APT models and routine partner notification (PN), in which the index patient chose the PN option for his/her partner(s) in two contrasting clinics. RESULTS: The proportion of contactable partners treated when routine PN was chosen was 42/117 (36%) and was significantly higher if either APT option was chosen: APTHotline 80/135 (59%), p=0.003; APTPharmacy 29/44 (66%) p=0.001. However, partner treatment was often achieved through other routes. Although 40-60% of partners in APT groups returned urine samples for sexually transmitted infection (STI) testing, almost none accessed HIV and syphilis testing. APT options appear to facilitate faster treatment of sex partners than routine PN. Preferences and recruitment rates varied between sites, related to staff satisfaction with existing routine PN; approach to consent; and possibly, characteristics of local populations. CONCLUSIONS: Both methods of APT were feasible and acceptable to many patients and led to higher rates of partner treatment than routine PN. Preferences and recruitment rates varied greatly between settings, suggesting that organisational and cultural factors may have an important impact on the feasibility of an RCT and on outcomes. Mindful of these factors, it is proposed that APT should now be evaluated in a cluster RCT. PMID- 21795291 TI - Evaluating patient self-assessment of health as a predictor of hospital admission in emergency practice: a diagnostic validity study. AB - BACKGROUND: Emergency departments deal with large patient loads on a day-to-day basis. The importance of patient self-assessment in the triage process has not been fully considered when determining the need for hospital admission. OBJECTIVE: To determine the validity of a series of self-administered triage questions in determining the need for hospitalisation in the emergency setting. DESIGN: Prospective cohort study. SETTING: Emergency department in a tertiary care, municipal hospital in Japan. PARTICIPANTS: 5380 consecutive walk-in patients visiting the emergency department of Okazaki City Hospital were asked to self-evaluate the urgency and severity of their condition and their perceived need for hospital admission. These patients were then assessed by emergency physicians blinded to the results from each patient's self-assessment. MAIN OUTCOME MEASURES: Sensitivity, specificity and likelihood ratios were calculated for each self-assessment by comparing these with findings from assessments made by emergency physicians. RESULTS: Patient-perceived need for hospitalisation had a sensitivity of 0.79 (95% CI 0.76 to 0.82) and a specificity of 0.93 (95% CI 0.92 to 0.93) in determining hospital admission. The positive and negative likelihood ratios for self-assessments were 10.68 (95% CI 9.59 to 11.90) and 0.22 (95% CI 0.19 to 0.26), respectively, in the diagnosis of hospital admission (p<0.01). CONCLUSIONS: The patient self-triage questions concerning condition with five categories (medication only to life threatening) seem to supplement the triage process for hospital admission in emergency departments. PMID- 21795292 TI - Chilaiditi's sign. PMID- 21795294 TI - The prehospital simplified motor score is as accurate as the prehospital Glasgow coma scale: analysis of a statewide trauma registry. AB - OBJECTIVES: The simplified motor score (SMS) is a three-point measure of traumatic brain injury (TBI) severity, which is easier to calculate than the 15 point Glasgow coma scale (GCS). Using a state trauma registry, the accuracy of the emergency medical services (EMS)-obtained SMS was compared with the GCS for predicting neurological outcomes and mortality. METHODS: A retrospective, observational analysis was performed of patients aged 16 years and older in the 2002-7 Ohio Trauma Registry. Those not initially transported by EMS or with incomplete EMS GCS scores were excluded. Outcomes included inhospital mortality, TBI, neurosurgical intervention, any emergency intubation and emergency department intubation. Discriminatory ability was compared using area under the receiver-operating characteristic curves (AUC). Sensitivity and specificity for each outcome were calculated at a SMS cutoff of one or less (any abnormal SMS) and a GCS cutoff of 13 or less. RESULTS: 52,412 patients were identified. Sensitivity, specificity and AUC were similar between the SMS and GCS for all outcomes. Sensitivity for mortality was 72.2% for SMS and 74.6% for GCS. Sensitivity for TBI was 40.8% for SMS and 45.4% for GCS. Sensitivity for neurosurgical intervention was 52.9% for SMS and 60.0% for GCS. Sensitivity for any intubation was 72.7% for SMS and 75.5% for GCS. Specificity was less than 2% different for all outcomes. Discriminatory ability was similar with the difference in AUC between SMS and GCS no greater than 6% for any outcome. CONCLUSIONS: In a state trauma registry including both trauma and non-trauma centres, the EMS-obtained SMS performs as well as the 15-point GCS. PMID- 21795293 TI - A multinational randomised study comparing didactic lectures with case scenario in a severe sepsis medical simulation course. AB - BACKGROUND: Medical simulation has been used to teach critical illness in a variety of settings. This study examined the effect of didactic lectures compared with simulated case scenario in a medical simulation course on the early management of severe sepsis. METHODS: A prospective multicentre randomised study was performed enrolling resident physicians in emergency medicine from four hospitals in Asia. Participants were randomly assigned to a course that included didactic lectures followed by a skills workshop and simulated case scenario (lecture-first) or to a course that included a skills workshop and simulated case scenario followed by didactic lectures (simulation-first). A pre-test was given to the participants at the beginning of the course, post-test 1 was given after the didactic lectures or simulated case scenario depending on the study group assignment, then a final post-test 2 was given at the end of the course. Performance on the simulated case scenario was evaluated with a performance task checklist. RESULTS: 98 participants were enrolled in the study. Post-test 2 scores were significantly higher than pre-test scores in all participants (80.8 +/- 12.0% vs 65.4 +/- 12.2%, p<0.01). There was no difference in pre-test scores between the two study groups. The lecture-first group had significantly higher post-test 1 scores than the simulation-first group (78.8 +/- 10.6% vs 71.6 +/- 12.6%, p<0.01). There was no difference in post-test 2 scores between the two groups. The simulated case scenario task performance completion was 90.8% (95% CI 86.6% to 95.0%) in the lecture-first group compared with 83.8% (95% CI 79.5% to 88.1%) in the simulation-first group (p=0.02). CONCLUSIONS: A medical simulation course can improve resident physician knowledge in the early management of severe sepsis. Such a course should include a comprehensive curriculum that includes didactic lectures followed by simulation experience. PMID- 21795295 TI - Prehospital endotracheal intubation and chest tubing does not prolong the overall resuscitation time of severely injured patients: a retrospective, multicentre study of the Trauma Registry of the German Society of Trauma Surgery. AB - BACKGROUND: The aim of this study was to determine whether prehospital endotracheal intubation (ETI) and chest tube placement is unnecessarily time consuming in severely injured patients. PATIENTS AND METHODS: A retrospective, multicentre study including all adult patients (ISS >=9; 2002-7) of the Trauma Registry of the German Society of Trauma Surgery who were not secondarily transferred to a trauma centre and received a definitive airway and a chest tube. Creating four groups: AA (n=963) receiving ETI and chest tube on scene, AB (n=1547) ETI performed in the prehospital setting but chest tubing later in the emergency department (ED) and BB (n=640) receiving both procedures in the ED. The BA collective (ETI performed in the ED, but chest tubing on scene) was excluded from the study because of the small sample size (n=41). The trauma resuscitation time (TRT), demographic data, injuries, treatment and outcome of the remaining three collectives were compared. RESULTS: The prehospital TRT of the AA collective was longer than the AB and BB subgroups (80+/-37 min vs 77+/-44 min 65+/-46 min; p<0.01). Although the AA and AB subgroups were more severely injured (ISS 35+/-15 vs 38+/-15 vs 31+/-12; p<0.01) and showed poorer vital parameters on scene, the overall TRT (accident until end of ED treatment) were equal for all three groups (152+/-59 min vs 151+/-62 min vs 148+/-68 min; p=0.07). The TRISS adjusted mortality was also equal in all three groups. CONCLUSIONS: In a physician-based emergency medical service, prehospital ETI and chest tube placement do not prolong the total TRT of severely injured patients. PMID- 21795296 TI - NICE guidance for off-pump CABG: turn off the pump. PMID- 21795297 TI - Effect of clopidogrel withdrawal on platelet reactivity and vascular inflammatory biomarkers 1 year after drug-eluting stent implantation: results of the prospective, single-centre CESSATION study. AB - BACKGROUND: The optimal duration of clopidogrel treatment, particularly following drug-eluting stent (DES) implantation, remains contentious. Previous studies have observed a clustering of adverse events following clopidogrel cessation 1 year after DES, the aetiology of which is poorly understood. OBJECTIVE: To investigate, in the prospective CESSATION study, the effect of clopidogrel withdrawal at 1 year after DES implantation on (i) arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation, and (ii) biomarkers of vascular inflammation, including soluble CD40 ligand (sCD40L), high-sensitivity C reactive protein (hsCRP) and interleukin 6 (IL-6). METHODS AND RESULTS: The prospective CESSATION study was undertaken in 33 patients receiving aspirin and due to discontinue clopidogrel 1 year after DES. Platetet reactivity was measured using short thromboelastography, and compliance with aspirin determined from serum thromboxane B(2) (TXB(2)) levels. Venesection was performed at 4 weeks and 24 h before, and at 24 h, 48 h, 1, 2 and 4 weeks after, clopidogrel cessation. Following clopidogrel withdrawal, there was (i) a predictable increase in ADP induced platelet aggregation (ii) an unexpected significant increase in AA induced platelet aggregation (iii) a decline in IL-6 and hsCRP at 1 week and 4 weeks respectively; and (iv) a non-significant increase in sCD40L at 4 weeks TXB(2) levels were consistently suppressed, indicating complete inhibition of cyclo-oxygenase-1 by aspirin. CONCLUSION: An aspirin-independent, time-dependent increase in AA-induced platelet activation following clopidogrel withdrawal in patients with a DES has been described. New insights into a potential mechanism for the observed clustering of adverse events that occur early after clopidogrel cessation have been provided. These findings raise the question as to whether AA induced clotting is an appropriate test of aspirin sensitivity. PMID- 21795298 TI - Infrequent physician use of implantable cardioverter-defibrillators risks patient safety. AB - CONTEXT: Implantable cardioverter-defibrillators (ICDs) have diffused rapidly into clinical practice with little evaluation of their real-world effectiveness. OBJECTIVES: To determine the effect of the adoption of ICD on patient safety, particularly with respect to physician volume and early outcomes. DESIGN: Retrospective cohort of all ICD implantations in New York state from 1997 to 2006, with follow-up at 90 days and 1 year. Setting New York state non-federal hospital discharges in which an ICD was implanted during the admission. Patients were followed forward for 1 year for subsequent admissions. Patients New York state residents undergoing ICD implantation. MAIN OUTCOME MEASURES: Effects of annual and career ICD implantation volume on 90-day complication, readmission, reprogramming, mortality and revision of the ICD within 1 year. RESULTS: This cohort (N = 38,992) represents a period of rapid adoption and implementation of this new technology, with frequency more than tripling between 1997 and 2006. We identified 6439 (16.5%) post-implantation complications and 1093 (2.8%) deaths within 90 days of implantation. The majority (73.4%) of physicians implanted one or fewer ICDs per year, and 11.0% of all implantations were performed by these very-low-volume operators. Patients treated by very-low-volume operators were more likely to die (RR = 1.8, 95% CI 1.3 to 2.4) or experience cardiac complications (RR = 4.7, 95% CI 3.3 to 6.8) even after the adjustment for case mix compared to operators who frequently performed ICD implantation. CONCLUSIONS: These findings suggest a need for safe and effective implementation strategies for new medical technologies, which minimize patient risk due to rapid diffusion among inexperienced providers and assure that the intended benefit can be maximised rapidly. PMID- 21795299 TI - Prevalence of geriatric syndromes and impact on clinical and functional outcomes in older patients with acute cardiac diseases. AB - OBJECTIVE: To assess the prevalence of major geriatric syndromes (MGSs)-frailty, cognitive impairment, severe dependence and depression-and their influence on outcomes in unselected patients with acute cardiac diseases. DESIGN: Observational prospective study with 12-month clinical and functional follow-up. SETTING: Clinical cardiology unit of a university hospital in Madrid, Spain. PATIENTS: Consecutive patients >=75 years old urgently admitted to the cardiology unit. INTERVENTION: Systematic comprehensive geriatric assessment. MAIN OUTCOME MEASURES: 12-month rates of mortality, readmission, functional decline and need for new social help. RESULTS: Among the 211 patients studied, 127 (60.2%) presented at least one MGS on admission: 86 frailty (40.8%), 67 cognitive impairment (31.8%), 31 severe dependency (14.7%) and 9 depression (4.3%). Patients with MGSs were slightly older (82+/-5 vs 81+/-4 years, p=0.02) but did not show greater disease severity or comorbidity. The presence of MGSs was associated with a higher incidence of functional decline during hospitalisation (35.7% vs 8.6%, p=0.002) and higher 12-month age-, comorbidity- and diagnosis adjusted risks of readmission (OR, 2.1.92; 95% CI 0.98 to 3.7), functional decline (OR, 2.86; 95% CI 1.41 to 5.79) and need for new social help (OR, 3.10; 95% CI 1.45 to 6.60). MGSs were also associated with a higher 12-month mortality rate, which was only obvious in patients hospitalised for heart failure but not for other reasons. CONCLUSIONS: A majority of older patients hospitalised for acute cardiac conditions in a cardiology department show at least one MGS on admission. MGSs are associated with poorer inhospital and postdischarge functional and clinical outcomes, particularly in patients with heart failure. PMID- 21795300 TI - The possibility of unmeasured confounding variables in observational studies: a forgotten fact? PMID- 21795301 TI - Assessment of vascular phenotype using a novel very-high-resolution ultrasound technique in adolescents after aortic coarctation repair and/or stent implantation: relationship to central haemodynamics and left ventricular mass. AB - OBJECTIVES: Coarctation of the aorta (CoA) has been associated with abnormal vascular function, increased blood pressure (BP) and premature cardiovascular disease even after a successful intervention. The objective was to determine the severity of residual cardiovascular abnormalities in youths after CoA repair and their relation to regional BP. DESIGN: Cross-sectional study in tertiary healthcare setting. METHODS: Thirty-six youths with CoA (age 16+/-1 years; neonatal surgery only: n=16; surgery and/or stent implantation: n=20) and 37 age matched controls were prospectively examined using a very-high-resolution vascular ultrasound imaging, echocardiography and applanation tonometry. RESULTS: CoA was associated with increased right arm systolic BP (p<0.001), intima-media thickness (IMT) in the common carotid (p<0.001), right brachial (p<0.05) and radial (p<0.05) arteries and ascending aortic stiffness (p<0.05). Carotid IMT correlated positively with age at first intervention (r=0.36, p<0.05). With left subclavian flap-type repair, left-arm systolic BP (p<0.001) and left brachial (p<0.001), radial (p<0.001) and ulnar (p<0.05) arterial IMTs were all reduced. When adjusted for BP, body mass index, age and gender, only carotid IMT (p<0.001) and left ventricular mass (p=0.013) of stented patients, as well as left-arm arterial IMTs (p<0.01) in subclavian flap-type repair patients, remained different from the controls. The significant associations of the stented patients disappeared after the adjustment for later patient age at intervention (median 8.7 vs 0.03 years, p<0.001). Residual arm-leg BP gradients correlated positively with carotid and brachial IMT. No differences between the CoA patients and the controls were found for arterial adventitial thicknesses, lumen dimensions, thigh systolic BP, abdominal aorta and carotid stiffness and right carotid to radial pulse wave velocity. CONCLUSION: CoA repair in early childhood is associated with increased preductal arterial IMT, left ventricular mass and ascending aortic stiffness in adolescents. The more pronounced cardiovascular abnormalities after CoA stent implantation are likely related to older patient age at the time of intervention. PMID- 21795302 TI - Systematic review of discharge coding accuracy. AB - INTRODUCTION: Routinely collected data sets are increasingly used for research, financial reimbursement and health service planning. High quality data are necessary for reliable analysis. This study aims to assess the published accuracy of routinely collected data sets in Great Britain. METHODS: Systematic searches of the EMBASE, PUBMED, OVID and Cochrane databases were performed from 1989 to present using defined search terms. Included studies were those that compared routinely collected data sets with case or operative note review and those that compared routinely collected data with clinical registries. RESULTS: Thirty-two studies were included. Twenty-five studies compared routinely collected data with case or operation notes. Seven studies compared routinely collected data with clinical registries. The overall median accuracy (routinely collected data sets versus case notes) was 83.2% (IQR: 67.3-92.1%). The median diagnostic accuracy was 80.3% (IQR: 63.3-94.1%) with a median procedure accuracy of 84.2% (IQR: 68.7 88.7%). There was considerable variation in accuracy rates between studies (50.5 97.8%). Since the 2002 introduction of Payment by Results, accuracy has improved in some respects, for example primary diagnoses accuracy has improved from 73.8% (IQR: 59.3-92.1%) to 96.0% (IQR: 89.3-96.3), P= 0.020. CONCLUSION: Accuracy rates are improving. Current levels of reported accuracy suggest that routinely collected data are sufficiently robust to support their use for research and managerial decision-making. PMID- 21795303 TI - Development of a culturally tailored Internet intervention promoting hepatitis B screening in the Turkish community in the Netherlands. AB - Hepatitis B virus infections are an important health problem in the Turkish community in the Netherlands. Screening for hepatitis B should be promoted through public health interventions, which take into account the socio-cultural and behavioural determinants that influence screening. The Intervention Mapping protocol was used to develop a culturally tailored Internet intervention for first-generation Turkish immigrants in Rotterdam, aged 16-40 year. Behavioural factors and cultural motivators and barriers, identified in the first steps of the protocol, were incorporated in the intervention. To ensure participation, members of the target population were involved in all steps of programme development. A theory- and evidence-based culturally tailored intervention was developed. Both surface structure and deep structure elements were used; surface structure tailoring resulting in different Internet skins and peer-stories for subgroups, such as young women. Deep structure elements comprised cultural motivators such as the religiously inspired feelings of responsibility and strong family values, and perceived community rules regarding health and disease. Cultural barriers that were addressed were the satisfaction and trust in Dutch health care, and the association of hepatitis B screening with sexual behaviour. Intervention Mapping provided a useful framework for the systematic development of our theory- and evidence-based intervention to promote hepatitis B screening in the Turkish community in the Netherlands. PMID- 21795304 TI - Processing of proglucagon to GLP-1 in pancreatic alpha-cells: is this a paracrine mechanism enabling GLP-1 to act on beta-cells? AB - Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic alpha-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and beta-cell mass. The alpha-cell line, alphaTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25 mM) also increased GLP-1 but decreased glucagon secretion from alphaTC1-6 cells suggesting a switch in processing to favour GLP 1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in alphaTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused beta cell toxicity as evidenced by decreased glucose-stimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and beta-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect beta-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes. PMID- 21795305 TI - The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside. AB - 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 5'-AMP activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPK-mediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anti-cancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects. AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation. PMID- 21795306 TI - Clinicopathological findings and echocardiographic prediction of the localisation of bovine endocarditis. AB - Thirty-six cows with confirmed vegetative endocarditis at postmortem examination were examined in this study. In 33 cows, echocardiography showed lesions of the pulmonic, tricuspid and mitral valves. Ten healthy cows were enrolled in the study as controls. In diseased cows, clinical signs included recurrent fever, dyspnoea, epistaxis, tachycardia, murmurs, weight loss, decreased milk production, jugular and mammary vein distension with palpable pulse, and ventral and submandibular oedema. Laboratory abnormalities included neutrophilic leukocytosis, elevated protein concentrations, hypoalbuminaemia, hypergammaglobulinaemia, azotaemia and elevated serum creatinine concentration. High serum activities of aspartate aminotransferase, gamma-glutamyl transpeptidase and lactate dehydrogenase were also detected. Echocardiography showed small, medium-sized or large hyperechogenicity, thickening, and proliferative or vegetative lesions of the tricuspid (n=11), mitral (n=5) and pulmonic valves (n=19). Confirmatory diagnosis was made at postmortem examination. Echocardiography could detect vegetations in 33 of the 36 cows (92 per cent). The sensitivity of ultrasound in detecting valvular endocarditis was 89 per cent for tricuspid valves, 83 per cent for mitral valves and 95 per cent for pulmonic valves. PMID- 21795307 TI - Coprological survey in pet reptiles in Italy. AB - Faecal samples were collected from 324 pet reptiles showing no clinical signs, including 28 saurian species (n=192), three ophidian species (n=74) and three chelonian species (n=58). Samples were examined for the presence of intestinal parasites by direct smear and faecal flotation, while direct immunofluorescence assays were used to reveal the presence of Cryptosporidium oocysts and Giardia cysts. Overall, 57.4 per cent of the reptiles were harbouring intestinal parasites. These included oxyurids (16 per cent), coccidia (12.3 per cent), flagellates (9.3 per cent), strongyles (6.8 per cent), coccidia plus oxyurids (4.9 per cent), coccidia plus flagellates (1.8 per cent), coccidia plus strongyles (1.8 per cent), oxyurids plus strongyles (1.2 per cent), oxyurids plus flagellates (1.2 per cent), Cryptosporidium species (1.2 per cent) and strongyles plus flagellates (0.6 per cent). Intestinal parasites were more prevalent in saurians than in ophidians and chelonians, in insectivores than in carnivores, omnivores and herbivores, and in wild-caught than in captive-born reptiles. A highly significant difference was observed for saurians versus chelonians (odds ratio [OR]=2.20, 95 per cent confidence interval [CI] 1.21 to 3.99), insectivores versus herbivores (OR=2.38, 95 per cent CI 1.26 to 4.49) and in wild-caught versus captive-born pet reptiles (OR=2.36, 95 per cent CI 1.27 to 4.40). PMID- 21795308 TI - Feasibility of single-portal access laparoscopic ovariectomy in 17 cats. AB - Laparoscopic ovariectomy (LapOVE) using single-portal access was attempted in 17 client-owned cats of different breeds admitted for elective ovariectomy. A 12 mm umbilical portal was placed 1 cm caudal to the umbilicus with the cat in dorsal recumbency. Then, a laparoscope with an operating channel was introduced into the portal with the cat in lateral recumbency. The right ovary was pulled to the abdominal wall using grasping forceps and fixed to the abdominal wall by a transabdominal suspension suture. The ovarian vasculature, suspensory ligament and proper ligament were progressively cauterised and transected with multifunction bipolar electrocoagulation forceps. The resected right ovary was exteriorised through the umbilical portal cannula. The left ovary was then removed from the abdomen in a similar fashion. Surgical time, intraoperative haemorrhage, amount of fat in the ovarian ligament, surgical complications and postoperative pain were recorded. The mean (sd) surgical time was 23 minutes and seven seconds (five minutes and 55 seconds). Intraoperative blood loss and fat deposition of the ovarian ligament were minimal. No intra- and postoperative complications were encountered. No cats needed rescue analgesia within 24 hours postsurgery. PMID- 21795309 TI - Haematological analysis of calves with bovine neonatal pancytopenia. AB - Blood was obtained from 61 neonatal Holstein calves originating from a farm in Germany with a high incidence of bovine neonatal pancytopenia (BNP). In order to detect alterations that might be related to BNP, selected haematological analytes were determined. Haematological examinations demonstrated alterations in at least two of the three cell lineages in 10 calves (16.39 per cent). Six animals (9.84 per cent) developed a bleeding disorder indicative of BNP at approximately two weeks of age. None of these animals showed alterations in complete blood cell count at sampling in the first week of life. In weeks when calves with BNP were born, an increase in the number of apparently healthy calves demonstrating decreases in blood cell counts was observed. PMID- 21795310 TI - Home-based subcutaneous continuous glucose monitoring in 10 diabetic dogs. AB - A subcutaneous continuous glucose monitoring system (GlucoDay; Menarini Diagnostics) based on microdialysis was investigated for its clinical applicability in veterinary medicine. Ten diabetic dogs, referred as clinically stable, were equipped with this system and sent home for a maximum observation period of 48 hours. Time of insulin administration, feeding and other events were written in a diary and plotted afterwards in the glucose graph. Implantation of the microdialysis fibre, acceptance of the device and evaluation of individual canine glucose profiles were without complication. Based on the monitoring data, recommended treatment adjustments were given to the referring veterinarians in all 10 dogs; hypoglycaemic or prolonged hyperglycaemic episodes were detected in six dogs. PMID- 21795311 TI - Subclinical diseases underlying poor performance in endurance horses: diagnostic methods and predictive tests. AB - Thirty-eight endurance horses underwent clinical and ancillary examinations, including haematological and biochemical evaluation, standardised exercise tests both on a treadmill and in the field, Doppler echocardiography, impulse oscillometry, video endoscopy and collection of respiratory fluids. All of the examined poorly performing horses were affected by subclinical diseases, and most of them had multiple concomitant disorders. On the contrary, the well-performing horses were free of any subclinical disease. The most frequently diagnosed diseases were respiratory disorders, followed by musculoskeletal and cardiac problems. Poor performers exhibited lower speeds at blood lactate concentration of 4 mmol/l (VLA4) and at heart rates of 160 (V160) and 200 bpm (V200) on the treadmill and in the field, as well as slower recovery of heart rate. PMID- 21795314 TI - The press release, relative risks, and the polypill. PMID- 21795317 TI - Chronic diseases among the over 40s in China are set to double over the next 20 years. PMID- 21795320 TI - Letter concerning: 'Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo'. PMID- 21795323 TI - RseqFlow: workflows for RNA-Seq data analysis. AB - SUMMARY: We have developed an RNA-Seq analysis workflow for single-ended Illumina reads, termed RseqFlow. This workflow includes a set of analytic functions, such as quality control for sequencing data, signal tracks of mapped reads, calculation of expression levels, identification of differentially expressed genes and coding SNPs calling. This workflow is formalized and managed by the Pegasus Workflow Management System, which maps the analysis modules onto available computational resources, automatically executes the steps in the appropriate order and supervises the whole running process. RseqFlow is available as a Virtual Machine with all the necessary software, which eliminates any complex configuration and installation steps. AVAILABILITY AND IMPLEMENTATION: http://genomics.isi.edu/rnaseq CONTACT: wangying@xmu.edu.cn; knowles@med.usc.edu; deelman@isi.edu; tingchen@usc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21795324 TI - Found in translation: annals of oncology and translational research. PMID- 21795326 TI - Spinoculation triggers dynamic actin and cofilin activity that facilitates HIV-1 infection of transformed and resting CD4 T cells. AB - Centrifugal inoculation, or spinoculation, is widely used in virology research to enhance viral infection. However, the mechanism remained obscure. Using HIV-1 infection of human T cells as a model, we demonstrate that spinoculation triggers dynamic actin and cofilin activity, probably resulting from cellular responses to centrifugal stress. This actin activity also leads to the upregulation of the HIV 1 receptor and coreceptor, CD4 and CXCR4, enhancing viral binding and entry. We also demonstrate that an actin inhibitor, jasplakinolide, diminishes spin mediated enhancement. In addition, small interfering RNA (siRNA) knockdown of LIMK1, a cofilin kinase, decreases the enhancement. These results suggest that spin-mediated enhancement cannot be explained simply by a virus-concentrating effect; rather, it is coupled with spin-induced cytoskeletal dynamics that promote receptor mobilization, viral entry, and postentry processes. Our results highlight the importance of cofilin and a dynamic cytoskeleton for the initiation of viral infection. Our results also indicate that caution needs to be taken in data interpretation when cells are spinoculated; some of the spin-induced cellular permissiveness may be beyond the natural capacity of an infecting virus. PMID- 21795327 TI - Epstein-Barr virus nuclear antigen 1 replication and segregation functions in nasopharyngeal carcinoma cell lines. AB - Nasopharyngeal carcinomas (NPC) are usually Epstein-Barr virus (EBV) positive, but, with the exception of C666-1 cells, these cells lose the EBV genomes when grown in culture. Maintenance of EBV requires the viral EBV nuclear antigen 1 (EBNA1) protein, which ensures the replication and mitotic segregation of the genomes through interactions with OriP. Here we compare the abilities of C666-1 and NPC cells that have lost EBV genomes to replicate and segregate OriP plasmids. We found that either cell line can replicate and maintain OriP plasmids for extended periods under conditions where low levels of EBNA1 are expressed but that high EBNA1 levels selectively interfered with mitotic segregation. PMID- 21795328 TI - Creation of a recombinant Rift Valley fever virus with a two-segmented genome. AB - Rift Valley fever virus (RVFV; family Bunyaviridae) is a clinically important, mosquito-borne pathogen of both livestock and humans, which is found mainly in sub-Saharan Africa and the Arabian Peninsula. RVFV has a trisegmented single stranded RNA (ssRNA) genome. The L and M segments are negative sense and encode the L protein (viral polymerase) on the L segment and the virion glycoproteins Gn and Gc as well as two other proteins, NSm and 78K, on the M segment. The S segment uses an ambisense coding strategy to express the nucleocapsid protein, N, and the nonstructural protein, NSs. Both the NSs and NSm proteins are dispensable for virus growth in tissue culture. Using reverse genetics, we generated a recombinant virus, designated r2segMP12, containing a two-segmented genome in which the NSs coding sequence was replaced with that for the Gn and Gc precursor. Thus, r2segMP12 lacks an M segment, and although it was attenuated in comparison to the three-segmented parental virus in both mammalian and insect cell cultures, it was genetically stable over multiple passages. We further show that the virus can stably maintain an M-like RNA segment encoding the enhanced green fluorescent protein gene. The implications of these findings for RVFV genome packaging and the potential to develop multivalent live-attenuated vaccines are discussed. PMID- 21795329 TI - The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2 mediated translational suppression of vesicular stomatitis virus. AB - Eukaryotic translation initiation factor 2B (eIF2B) is a heteropentameric guanine nucleotide exchange factor that converts protein synthesis initiation factor 2 (eIF2) from a GDP-bound form to the active eIF2-GTP complex. Cellular stress can repress translation initiation by activating kinases capable of phosphorylating the alpha subunit of eIF2 (eIF2alpha), which sequesters eIF2B to prevent exchange activity. Previously, we demonstrated that tumor cells are sensitive to viral replication, possibly due to the occurrence of defects in eIF2B that overcome the inhibitory effects of eIF2alpha phosphorylation. To extend this analysis, we have investigated the importance of eIF2Balpha function and report that this subunit can functionally substitute for its counterpart, GCN3, in yeast. In addition, a variant of mammalian eIF2Balpha harboring a point mutation (T41A) was able overcome translational inhibition invoked by amino acid depravation, which activates Saccharomyces cerevisiae GCN2 to phosphorylate the yeast eIF2alpha homolog SUI2. Significantly, we also demonstrate that the loss of eIF2Balpha, or the expression of the T41A variant in mammalian cells, is sufficient to neutralize the consequences of eIF2alpha phosphorylation and render normal cells susceptible to virus infection. Our data emphasize the importance of eIF2Balpha in mediating the eIF2 kinase translation-inhibitory activity and may provide insight into the complex nature of viral oncolysis. PMID- 21795330 TI - Variable prevalence and functional diversity of the antiretroviral restriction factor TRIMCyp in Macaca fascicularis. AB - The retroviral restriction factor TRIMCyp, derived from the TRIM5 gene, blocks replication at a postentry step. TRIMCyp has so far been found in four species of Asian macaques, Macaca fascicularis, M. mulatta, M. nemestrina, and M. leonina. M. fascicularis is commonly used as a model for AIDS research, but TRIMCyp has not been analyzed in detail in this species. We analyzed the prevalence of TRIMCyp in samples from Indonesia, Indochina, the Philippines, and Mauritius. We found that TRIMCyp is present at a higher frequency in Indonesian than in Indochinese M. fascicularis macaques and is also present in samples from the Philippines. TRIMCyp is absent in Mauritian M. fascicularis macaques. We then analyzed the restriction specificity of TRIMCyp derived from three animals of Indonesian origin. One allele, like the prototypic TRIMCyp alleles described for M. mulatta and M. nemestrina, restricts human immunodeficiency virus type 2 (HIV 2) and feline immunodeficiency virus (FIV) but not HIV-1. The others restrict HIV 1 and FIV but not HIV-2. Mutagenesis studies confirmed that polymorphisms at amino acid residues 369 and 446 in TRIMCyp (or residues 66 and 143 in the cyclophilin A [CypA] domain) confer restriction specificity. Additionally, we identified a polymorphism in the coiled-coil domain that appears to affect TRIMCyp expression or stability. Taken together, these data show that M. fascicularis has the most diverse array of TRIM5 restriction factors described for any primate species to date. These findings are relevant to our understanding of the evolution of retroviral restriction factors and the use of M. fascicularis models in AIDS research. PMID- 21795331 TI - Identification of nuclear and nucleolar localization signals of pseudorabies virus (PRV) early protein UL54 reveals that its nuclear targeting is required for efficient production of PRV. AB - The pseudorabies virus (PRV) early protein UL54 is a homologue of herpes simplex virus 1 (HSV-1) immediate-early protein ICP27, which is a multifunctional protein that is essential for HSV-1 infection. In this study, the subcellular localization and nuclear import signals of PRV UL54 were characterized. UL54 was shown to predominantly localize to the nucleolus in transfected cells. By constructing a series of mutants, a functional nuclear localization signal (NLS) and a genuine nucleolar localization signal (NoLS) of UL54 were for the first time identified and mapped to amino acids (61)RQRRR(65) and (45)RRRRGGRGGRAAR(57), respectively. Additionally, three recombinant viruses with mutations of the NLS and/or the NoLS in UL54 were constructed based on PRV bacterial artificial chromosome (BAC) pBecker2 to test the effect of UL54 nuclear targeting on viral replication. In comparison with the wild-type virus, a recombinant virus harboring an NLS or NoLS mutation of UL54 reduced viral production to different extents. However, mutations of both the NLS and NoLS targeted UL54 to the cytoplasm in recombinant virus-infected cells and significantly impaired viral replication, comparable to the UL54-null virus. In addition, a virus lacking the NLS or the NoLS displayed modest defects in viral gene expression and DNA synthesis. However, deletion of both the NLS and the NoLS resulted in severe defects in viral gene expression and DNA synthesis, as well as production of infectious progeny. Thus, we have identified a classical NLS and a genuine NoLS in UL54 and demonstrate that the nuclear targeting of UL54 is required for efficient production of PRV. PMID- 21795332 TI - Emergence of avian influenza viruses with enhanced transcription activity by a single amino acid substitution in the nucleoprotein during replication in chicken brains. AB - To explore the genetic basis of the pathogenesis and adaptation of avian influenza viruses (AIVs) to chickens, the A/duck/Yokohama/aq10/2003 (H5N1) (DkYK10) virus was passaged five times in the brains of chickens. The brain passaged DkYK10-B5 caused quick death of chickens through rapid and efficient replication in tissues, accompanied by severe apoptosis. Genome sequence comparison of two viruses identified a single amino acid substitution at position 109 in NP from isoleucine to threonine (NP (I)109(T)). By analyzing viruses constructed by the reverse-genetic method, we established that the NP (I)109(T) substitution also contributed to increased viral replication and polymerase activity in chicken embryo fibroblasts, but not in duck embryo fibroblasts. Real time RT-PCR analysis demonstrated that the NP (I)109(T) substitution enhances mRNA synthesis quickly and then cRNA and viral RNA (vRNA) synthesis slowly. Next, to determine the mechanism underlying the appearance of the NP (I)109(T) substitution during passages, four H5N1 highly pathogenic AIVs (HPAIVs) were passaged in the lungs and brains of chicken embryos. Single-nucleotide polymorphism analysis, together with a database search, suggests that the NP (I)109(T) mutation would be induced frequently during replication of HPAIVs in brains, but not in lungs. These results demonstrate that the amino acid at position 109 in NP enhances viral RNA synthesis and the pathogenicity of highly pathogenic avian influenza viruses in chickens and that the NP mutation emerges quickly during replication of the viruses in chicken brains. PMID- 21795333 TI - Epstein-Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. AB - Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), the principal viral oncoprotein and a member of the tumor necrosis factor receptor superfamily, is a constitutively active membrane signaling protein that regulates multiple signal transduction pathways via its C-terminal-activating region 1 (CTAR1) and CTAR2, and also the less-studied CTAR3. Because protein sumoylation among other posttranslational modifications may regulate many signaling pathways induced by LMP1, we investigated whether during EBV latency LMP1 regulates sumoylation processes that control cellular activation and cellular responses. By immunoprecipitation experiments, we show that LMP1 interacts with Ubc9, the single reported SUMO-conjugating enzyme. Requirements for LMP1-Ubc9 interactions include enzymatically active Ubc9: expression of inactive Ubc9 (Ubc9 C93S) inhibited the LMP1-Ubc9 interaction. LMP1 CTAR3, but not CTAR1 and CTAR2, participated in the LMP1-Ubc9 interaction, and amino acid sequences found in CTAR3, including the JAK-interacting motif, contributed to this interaction. Furthermore, LMP1 expression coincided with increased sumoylation of cellular proteins, and disruption of the Ubc9-LMP1 CTAR3 interaction almost completely abrogated LMP1-induced protein sumoylation, suggesting that this interaction promotes the sumoylation of downstream targets. Additional consequences of the disruption of the LMP1 CTAR3-Ubc9 interaction revealed effects on cellular migration, a hallmark of oncogenesis. Together, these data demonstrate that LMP1 CTAR3 does in fact function in intracellular signaling and leads to biological effects. We propose that LMP1, by interaction with Ubc9, modulates sumoylation processes, which regulate signal transduction pathways that affect phenotypic changes associated with oncogenesis. PMID- 21795334 TI - The fecal viral flora of California sea lions. AB - California sea lions are one of the major marine mammal species along the Pacific coast of North America. Sea lions are susceptible to a wide variety of viruses, some of which can be transmitted to or from terrestrial mammals. Using an unbiased viral metagenomic approach, we surveyed the fecal virome in California sea lions of different ages and health statuses. Averages of 1.6 and 2.5 distinct mammalian viral species were shed by pups and juvenile sea lions, respectively. Previously undescribed mammalian viruses from four RNA virus families (Astroviridae, Picornaviridae, Caliciviridae, and Reoviridae) and one DNA virus family (Parvoviridae) were characterized. The first complete or partial genomes of sapeloviruses, sapoviruses, noroviruses, and bocavirus in marine mammals are reported. Astroviruses and bocaviruses showed the highest prevalence and abundance in California sea lion feces. The diversity of bacteriophages was higher in unweaned sea lion pups than in juveniles and animals in rehabilitation, where the phage community consisted largely of phages related to the family Microviridae. This study increases our understanding of the viral diversity in marine mammals, highlights the high rate of enteric viral infections in these highly social carnivores, and may be used as a baseline viral survey for comparison with samples from California sea lions during unexplained disease outbreaks. PMID- 21795335 TI - Herpesvirus entry mediator and nectin-1 mediate herpes simplex virus 1 infection of the murine cornea. AB - Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that enters cells by the receptor-mediated fusion of the viral envelope with a host cell membrane. The envelope glycoprotein gD of HSV must bind to one of its receptors for entry to take place. Recent studies using knockout (KO) mice demonstrated that the gD receptors herpesvirus entry mediator (HVEM) and nectin-1 are the primary entry receptors for HSV-2 in the mouse vagina and brain. Nectin-1 was most crucial for the neuronal spread of HSV-2, particularly in the brain. HVEM was dispensable for infection in these models, but when both HVEM and nectin-1 were absent, infection was completely prevented. We sought to determine the receptor requirements of HSV 1 in an ocular model of infection using knockout mice. Wild-type, HVEM KO, nectin 1 KO, and HVEM/nectin-1 double-KO mice were infected via corneal scarification and monitored for clinical signs of infection and viral replication in various tissues. We report that either HVEM or nectin-1 must be present for HSV-1 infection of the cornea. Additionally, we observed that the infection was attenuated in both HVEM KO and nectin-1 KO mice. This is in contrast to what was reported for studies of HSV-2 in vagina and brain and suggests that receptor requirements for HSV vary depending on the route of inoculation and/or serotype. PMID- 21795336 TI - The major determinant of attenuation in mice of the Candid1 vaccine for Argentine hemorrhagic fever is located in the G2 glycoprotein transmembrane domain. AB - Candid1, a live-attenuated Junin virus vaccine strain, was developed during the early 1980s to control Argentine hemorrhagic fever, a severe and frequently fatal human disease. Six amino acid substitutions were found to be unique to this vaccine strain, and their role in virulence attenuation in mice was analyzed using a series of recombinant viruses. Our results indicate that Candid1 is attenuated in mice through a single amino acid substitution in the transmembrane domain of the G2 glycoprotein. This work provides insight into the molecular mechanisms of attenuation of the only arenavirus vaccine currently available. PMID- 21795337 TI - Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. AB - The dengue viruses (DENVs) exist as numerous genetic strains that are grouped into four antigenically distinct serotypes. DENV strains from each serotype can cause severe disease and threaten public health in tropical and subtropical regions worldwide. No licensed antiviral agent to treat DENV infections is currently available, and there is an acute need for the development of novel therapeutics. We found that a synthetic small interfering RNA (siRNA) (DC-3) targeting the highly conserved 5' cyclization sequence (5'CS) region of the DENV genome reduced, by more than 100-fold, the titers of representative strains from each DENV serotype in vitro. To determine if DC-3 siRNA could inhibit DENV in vivo, an "in vivo-ready" version of DC-3 was synthesized and tested against DENV 2 by using a mouse model of antibody-dependent enhancement of infection (ADE) induced disease. Compared with the rapid weight loss and 5-day average survival time of the control groups, mice receiving the DC-3 siRNA had an average survival time of 15 days and showed little weight loss for approximately 12 days. DC-3 treated mice also contained significantly less virus than control groups in several tissues at various time points postinfection. These results suggest that exogenously introduced siRNA combined with the endogenous RNA interference processing machinery has the capacity to prevent severe dengue disease. Overall, the data indicate that DC-3 siRNA represents a useful research reagent and has potential as a novel approach to therapeutic intervention against the genetically diverse dengue viruses. PMID- 21795338 TI - Cross-clade HIV-1 neutralizing antibodies induced with V3-scaffold protein immunogens following priming with gp120 DNA. AB - The V3 epitope is a known target for HIV-1 neutralizing antibodies (NAbs), and V3 scaffold fusion proteins used as boosting immunogens after gp120 DNA priming were previously shown to induce NAbs in rabbits. Here, we evaluated whether the breadth and potency of the NAb response could be improved when boosted with rationally designed V3-scaffold immunogens. Rabbits were primed with codon optimized clade C gp120 DNA and boosted with one of five V3-cholera toxin B fusion proteins (V3-CTBs) or with double combinations of these. The inserts in these immunogens were designed to display V3 epitopes shared by the majority of global HIV-1 isolates. Double combinations of V3-CTB immunogens generally induced more broad and potent NAbs than did boosts with single V3-CTB immunogens, with the most potent and broad NAbs elicited with the V3-CTB carrying the consensus V3 of clade C (V3(C)-CTB), or with double combinations of V3-CTB immunogens that included V3(C)-CTB. Neutralization of tier 1 and 2 pseudoviruses from clades AG, B, and C and of peripheral blood mononuclear cell (PBMC)-grown primary viruses from clades A, AG, and B was achieved, demonstrating that priming with gp120 DNA followed by boosts with V3-scaffold immunogens effectively elicits cross-clade NAbs. Focusing on the V3 region is a first step in designing a vaccine targeting protective epitopes, a strategy with potential advantages over the use of Env, a molecule that evolved to protect the virus by poorly inducing NAbs and by shielding the epitopes that are most critical for infectivity. PMID- 21795339 TI - Enterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design. AB - Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of hand, foot, and mouth disease (HFMD), which is prevalent in Asia. Thus far, there are no prophylactic or therapeutic measures against HFMD. The 3C proteases from EV71 and CVA16 play important roles in viral replication and are therefore ideal drug targets. By using biochemical, mutational, and structural approaches, we broadly characterized both proteases. A series of high-resolution structures of the free or substrate-bound enzymes were solved. These structures, together with our cleavage specificity assay, well explain the marked substrate preferences of both proteases for particular P4, P1, and P1' residue types, as well as the relative malleability of the P2 amino acid. More importantly, the complex structures of EV71 and CVA16 3Cs with rupintrivir, a specific human rhinovirus (HRV) 3C protease inhibitor, were solved. These structures reveal a half-closed S2 subsite and a size-reduced S1' subsite that limit the access of the P1' group of rupintrivir to both enzymes, explaining the reported low inhibition activity of the compound toward EV71 and CVA16. In conclusion, the detailed characterization of both proteases in this study could direct us to a proposal for rational design of EV71/CVA16 3C inhibitors. PMID- 21795340 TI - Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope specific broadly neutralizing antibodies and their inferred unmutated common ancestors. AB - V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope specific antibodies. PMID- 21795341 TI - Molecular evolution analysis of the human immunodeficiency virus type 1 envelope in simian/human immunodeficiency virus-infected macaques: implications for challenge dose selection. AB - Since the demonstration that almost 80% of human immunodeficiency virus type 1 (HIV-1) infections result from the transmission of a single variant from the donor, biological features similar to those of HIV mucosal transmission have been reported for macaques inoculated with simian immunodeficiency virus (SIV). Here we describe the early diversification events and the impact of challenge doses on viral kinetics and on the number of variants transmitted in macaques infected with the chimeric simian/human immunodeficiency virus SHIV(sf162p4). We show that there is a correlation between the dose administered and the number of variants transmitted and that certain inoculum variants are preferentially transmitted. This could provide insight into the viral determinants of transmission and could aid in vaccine development. Challenge through the mucosal route with high doses results in the transmission of multiple variants in all the animals. Such an unrealistic scenario could underestimate potential intervention measures. We thus propose the use of molecular evolution analysis to aid in the determination of challenge doses that better mimic the transmission dynamics seen in natural HIV-1 infection. PMID- 21795342 TI - Multiple functional domains and complexes of the two nonstructural proteins of human respiratory syncytial virus contribute to interferon suppression and cellular location. AB - Human respiratory syncytial virus (RSV), a major cause of severe respiratory diseases, efficiently suppresses cellular innate immunity, represented by type I interferon (IFN), using its two unique nonstructural proteins, NS1 and NS2. In a search for their mechanism, NS1 was previously shown to decrease levels of TRAF3 and IKKepsilon, whereas NS2 interacted with RIG-I and decreased TRAF3 and STAT2. Here, we report on the interaction, cellular localization, and functional domains of these two proteins. We show that recombinant NS1 and NS2, expressed in lung epithelial A549 cells, can form homo- as well as heteromers. Interestingly, when expressed alone, substantial amounts of NS1 and NS2 localized to the nuclei and to the mitochondria, respectively. However, when coexpressed with NS2, as in RSV infection, NS1 could be detected in the mitochondria as well, suggesting that the NS1-NS2 heteromer localizes to the mitochondria. The C-terminal tetrapeptide sequence, DLNP, common to both NS1 and NS2, was required for some functions, but not all, whereas only the NS1 N-terminal region was important for IKKepsilon reduction. Finally, NS1 and NS2 both interacted specifically with host microtubule-associated protein 1B (MAP1B). The contribution of MAP1B in NS1 function was not tested, but in NS2 it was essential for STAT2 destruction, suggesting a role of the novel DLNP motif in protein-protein interaction and IFN suppression. PMID- 21795343 TI - Molecular surveillance of HIV-1 in Madrid, Spain: a phylogeographic analysis. AB - The molecular epidemiology of HIV-1 is constantly changing, mainly as a result of human migratory flows and the high adaptive ability of the virus. In recent years, Spain has become one of Europe's main destinations for immigrants and one of the western European countries with the highest rates of HIV-positive patients. Using a phylogeographic approach, we have analyzed the relationship between HIV-1 variants detected in immigrant and native populations of the urban area of Madrid. Our project was based on two coincidental facts. First, resistance tests were extended to naive and newly diagnosed patients, and second, the Spanish government legislated the provision of legal status to many immigrants. This allowed us to obtain a large data set (n = 2,792) from 11 Madrid hospitals of viral pol sequences from the two populations, and with this unique material, we explored the impact of immigration in the epidemiological trends of HIV-1 variants circulating in the largest Spanish city. The prevalence of infections by non-B HIV-1 variants in the studied cohort was 9%, rising to 25% among native Spanish patients. Multiple transmission events involving different lineages and subsubtypes were observed in all the subtypes and recombinant forms studied. Our results also revealed strong social clustering among the most recent immigrant groups, such as Russians and Romanians, but not in those groups who have lived in Madrid for many years. Additionally, we document for the first time the presence of CRF47_BF and CRF38_BF in Europe, and a new BG recombinant form found in Spaniards and Africans is tentatively proposed. These results suggest that the HIV-1 epidemic will evolve toward a more complex epidemiological landscape. PMID- 21795345 TI - Major histocompatibility complex-dependent cytotoxic T lymphocyte repertoire and functional avidity contribute to strain-specific disease susceptibility after murine respiratory syncytial virus infection. AB - Susceptibility to respiratory syncytial virus (RSV) infection in mice is genetically determined. While RSV causes little pathology in C57BL/6 mice, pulmonary inflammation and weight loss occur in BALB/c mice. Using major histocompatibility complex (MHC)-congenic mice, we observed that the H-2(d) allele can partially transfer disease susceptibility to C57BL/6 mice. This was not explained by altered viral elimination or differences in the magnitude of the overall virus-specific cytotoxic T lymphocyte (CTL) response. However, H-2(d) mice showed a more focused response, with 70% of virus-specific CTL representing Vbeta8.2(+) CTL directed against the immunodominant epitope M2-1 82, while in H 2(b) mice only 20% of antiviral CTL were Vbeta9(+) CTL specific for the immunodominant epitope M187. The immunodominant H-2(d)-restricted CTL lysed target cells less efficiently than the immunodominant H-2(b) CTL, probably contributing to prolonged CTL stimulation and cytokine-mediated immunopathology. Accordingly, reduction of dominance of the M2-1 82-specific CTL population by introduction of an M187 response in the F1 generation of a C57BL/6N * C57BL/6-H 2(d) mating (C57BL/6-H-2(dxb) mice) attenuated disease. Moreover, disease in H 2(d) mice was less pronounced after infection with an RSV mutant failing to activate M2-1 82-specific CTL or after depletion of Vbeta8.2(+) cells. These data illustrate how the MHC-determined diversity and functional avidity of CTL responses contribute to disease susceptibility after viral infection. PMID- 21795344 TI - Escape from transcriptional shutoff during poliovirus infection: NF-kappaB responsive genes IkappaBa and A20. AB - It has been known for a long time that infection of cultured cells with poliovirus results in the overall inhibition of transcription of most host genes. We examined whether selected host genes can escape transcriptional inhibition by thiouridine marking newly synthesized host mRNAs during viral infection. Using cDNA microarrays hybridized to cDNAs made from thiolated mRNAs, a small set of host transcripts was identified and their expression verified by quantitative PCR and Northern and Western blot analyses. These transcripts were synthesized from genes that displayed enrichment for NF-kappaB binding sites in their promoter regions, suggesting that some NF-kappaB-regulated promoters can escape the virus induced inhibition of transcription. In particular, two negative regulators of NF kappaB, IkappaBa and A20, were upregulated during viral infection. Depletion of A20 enhanced viral RNA abundance and viral yield, arguing that cells respond to virus infection by counteracting NF-kappaB-induced proviral effects. PMID- 21795346 TI - Mechanisms controlling virulence thresholds of mixed viral populations. AB - The propensity of RNA viruses to revert attenuating mutations contributes to disease and complicates vaccine development. Despite the presence of virulent revertant viruses in some live-attenuated vaccines, disease from vaccination is rare. This suggests that in mixed viral populations, attenuated viruses may limit the pathogenesis of virulent viruses, thus establishing a virulence threshold. Here we examined virulence thresholds using mixtures of virulent and attenuated viruses in a transgenic mouse model of poliovirus infection. We determined that a 1,000-fold excess of the attenuated Sabin strain of poliovirus was protective against disease induced by the virulent Mahoney strain. Protection was induced locally, and inactivated virus conferred protection. Treatment with a poliovirus receptor-blocking antibody phenocopied the protective effect of inactivated viruses in vitro and in vivo, suggesting that one mechanism controlling virulence thresholds may be competition for a viral receptor. Additionally, the type I interferon response reduces poliovirus pathogenesis; therefore, we examined virulence thresholds in mice lacking the alpha/beta interferon receptor. We found that the attenuated virus was virulent in immunodeficient mice due to the enhanced replication and reversion of attenuating mutations. Therefore, while the type I interferon response limits the virulence of the attenuated strain by reducing replication, protection from disease conferred by the attenuated strain in immunocompetent mice can occur independently of replication. Our results identified mechanisms controlling the virulence of mixed viral populations and indicate that live-attenuated vaccines containing virulent virus may be safe, as long as virulent viruses are present at levels below a critical threshold. PMID- 21795347 TI - Reassortment events among swine influenza A viruses in China: implications for the origin of the 2009 influenza pandemic. AB - That pigs may play a pivotal role in the emergence of pandemic influenza was indicated by the recent H1N1/2009 human pandemic, likely caused by a reassortant between viruses of the American triple-reassortant (TR) and Eurasian avian-like (EA) swine influenza lineages. As China has the largest human and pig populations in the world and is the only place where both TR and EA viruses have been reported to cocirculate, it is potentially the source of the H1N1/2009 pandemic virus. To examine this, the genome sequences of 405 swine influenza viruses from China were analyzed. Thirty-six TR and EA reassortant viruses were identified before and after the occurrence of the pandemic. Several of these TR-EA reassortant viruses had genotypes with most segments having the same lineage origin as the segments of the H1N1/2009 pandemic virus. However, these viruses were generated from independent reassortment events throughout our survey period and were not associated with the current pandemic. One TR-EA reassortant, which is least similar to the pandemic virus, has persisted since 2007, while all the other variants appear to be transient. Despite frequent reassortment events between TR and EA lineage viruses in China, evidence for the genesis of the 2009 pandemic virus in pigs in this region is still absent. PMID- 21795348 TI - Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors. AB - Circulating HIV-1-infected monocytes have been identified in patients on highly active antiretroviral therapy and may represent an important barrier to viral eradication. The nature of these cells in HIV-1-infected patients who maintain undetectable viral loads and preserved CD4(+) T cell counts without antiretroviral therapy (known as elite controllers or elite suppressors [ES]) is unknown. We describe here infrequent recovery of proviral HIV-1 DNA from circulating monocytes relative to CD4(+) T cells in ES, despite permissiveness of these cells to HIV-1 viral entry ex vivo. Thus, monocytes do not appear to be a major reservoir of HIV-1 in ES. PMID- 21795349 TI - Expression profiling of the intermediate and late stages of poxvirus replication. AB - The double-stranded DNA genome of vaccinia virus (VACV), the prototype poxvirus, contains approximately 200 open reading frames (ORFs) that are transcribed at early, intermediate, and late stages of infection. Previous high-throughput deep RNA sequencing allowed us to map 118 VACV early genes that are expressed before viral DNA replication and 93 postreplicative genes. However, the intermediate- and late-stage postreplicative genes could not be differentiated. Here, we synchronized infections with a reversible inhibitor of DNA replication and used a VACV mutant that conditionally transcribes late genes to sequence the two classes of mRNAs. In addition, each postreplicative ORF was individually expressed under conditions that distinguished intermediate and late classes. We identified 38 VACV genes that belong to the late class and 53 that belong to the intermediate class, with some of the latter continuing to be expressed late. These data allowed us to prepare a genome-wide early, intermediate, and late transcription map. Inspection of sequences upstream of these ORFs revealed distinctive characteristics of intermediate and late promoters and suggested that some promoters have intermediate and late elements. The intermediate genes encoded many DNA binding/packaging and core-associated proteins in addition to late transcription factors; the late genes encoded many morphogenesis and mature virion membrane proteins, including those involved in entry, in addition to early transcription factors. The top-ranked antigens for CD4(+) T cells and B cells were mainly intermediate rather than late gene products. The differentiation of intermediate and late genes may enhance understanding of poxvirus replication and lead to improvements in expression vectors and recombinant vaccines. PMID- 21795350 TI - Longitudinal analysis of the human T cell response during acute hantavirus infection. AB - Longitudinal studies of T cell immune responses during viral infections in humans are essential for our understanding of how effector T cell responses develop, clear infection, and provide long-lasting immunity. Here, following an outbreak of a Puumala hantavirus infection in the human population, we longitudinally analyzed the primary CD8 T cell response in infected individuals from the first onset of clinical symptoms until viral clearance. A vigorous CD8 T cell response was observed early following the onset of clinical symptoms, determined by the presence of high numbers of Ki67(+)CD38(+)HLA-DR(+) effector CD8 T cells. This response encompassed up to 50% of total blood CD8 T cells, and it subsequently contracted in parallel with a decrease in viral load. Expression levels of perforin and granzyme B were high throughout the initial T cell response and likewise normalized following viral clearance. When monitoring regulatory components, no induction of regulatory CD4 or CD8 T cells was observed in the patients during the infection. However, CD8 as well as CD4 T cells exhibited a distinct expression profile of inhibitory PD-1 and CTLA-4 molecules. The present results provide insight into the development of the T cell response in humans, from the very onset of clinical symptoms following a viral infection to resolution of the disease. PMID- 21795351 TI - Construction of a lytically replicating Kaposi's sarcoma-associated herpesvirus. AB - Karposi's sarcoma-associated herpesvirus (KSHV) is found predominantly in a latent state in most cell types, impeding investigations of the lytic replication cycle. Here, we engineered the cloned KSHV genome, bacterial artificial chromosome 36 (BAC36), to enforce constitutive expression of the main lytic switch regulator, the replication and transcription activator (RTA) (open reading frame 50 [ORF50]). The resulting virus, KSHV-lyt, activated by default the lytic cycle and replicated to high titers in various cells. Using KSHV-lyt, we showed that ORF33 (encoding a tegument protein) is essential for lytic KSHV replication in cell culture, but ORF73 (encoding the latent nuclear antigen [LANA]) is not. Thus, KSHV-lyt should be highly useful to study viral gene function during lytic replication. PMID- 21795352 TI - Infection of lymphoblastoid cell lines by Kaposi's sarcoma-associated herpesvirus: critical role of cell-associated virus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) displays strong lymphotropism in vivo, but paradoxically, established B cell lines have largely been refractory to infection by soluble KSHV virions. Here we show that this block can be overcome by exposure to cell-associated virus. Doxycycline-inducible recombinant KSHV.219 (rKSHV.219)-harboring SLK (iSLK.219) cells were employed as KSHV donors. Cocultivation of lymphoid cell lines with reactivated iSLK.219 cells resulted in readily demonstrable viral entry into each cell line; similar observations were made in primary tonsillar B cell cultures. Moreover, infected lymphoid cells were able to outgrow upon puromycin selection, indicating development of persistent infection. Infected BJAB cells display signatures of latent infection, including classical latency-associated transcripts, a punctate pattern of LANA expression, and episomal maintenance of the KSHV genome. However, when lytically activated by various chemical stimuli, infected BJAB cells were able to produce only low levels of infectious virions. These data demonstrate that (i) cell-associated viruses can bypass viral entry blocks in most lymphoid cell lines, (ii) the determinants of cell-associated virus entry differ from those of soluble virion infection, and (iii) immortalized lymphoblastoid lines have partial postentry blocks to efficient lytic reactivation. PMID- 21795353 TI - Amiloride is a competitive inhibitor of coxsackievirus B3 RNA polymerase. AB - Amiloride and its derivative 5-(N-ethyl-N-isopropyl)amiloride (EIPA) were previously shown to inhibit coxsackievirus B3 (CVB3) RNA replication in cell culture, with two amino acid substitutions in the viral RNA-dependent RNA polymerase 3D(pol) conferring partial resistance of CVB3 to these compounds (D. N. Harrison, E. V. Gazina, D. F. Purcell, D. A. Anderson, and S. Petrou, J. Virol. 82:1465-1473, 2008). Here we demonstrate that amiloride and EIPA inhibit the enzymatic activity of CVB3 3D(pol) in vitro, affecting both VPg uridylylation and RNA elongation. Examination of the mechanism of inhibition of 3D(pol) by amiloride showed that the compound acts as a competitive inhibitor, competing with incoming nucleoside triphosphates (NTPs) and Mg(2+). Docking analysis suggested a binding site for amiloride and EIPA in 3D(pol), located in close proximity to one of the Mg(2+) ions and overlapping the nucleotide binding site, thus explaining the observed competition. This is the first report of a molecular mechanism of action of nonnucleoside inhibitors against a picornaviral RNA dependent RNA polymerase. PMID- 21795354 TI - Characterization of the interaction between human respiratory syncytial virus and the cell cycle in continuous cell culture and primary human airway epithelial cells. AB - Viruses can modify conditions inside cells to make them more favorable for replication and progeny virus production. One way of doing this is through manipulation of the cell cycle, a process that describes the ordered growth and division of cells. Analysis of model cell lines, such as A549 cells and primary airway epithelial cells, infected with human respiratory syncytial virus (HRSV) has shown alteration of the cell cycle during infection, although the signaling events were not clearly understood. In this study, targeted transcriptomic analysis of HRSV-infected primary airway epithelial cells revealed alterations in the abundances of many mRNAs encoding cell cycle-regulatory molecules, including decreases in the D-type cyclins and corresponding cyclin-dependent kinases (CDK4 and CDK6 [CDK4/6]). These alterations were reflected in changes in protein abundance and/or relocalization in HRSV-infected cells; taken together, they were predicted to result in G(0)/G(1) phase arrest. In contrast, there was no change in the abundances of D-type cyclins in A549 cells infected with HRSV. However, the abundance of the G(1)/S phase progression inhibitor p21(WAF1/CIP1) was increased over that in mock-treated cells, and this, again, was predicted to result in G(0)/G(1) phase arrest. The G(0)/G(1) phase arrest in both HRSV infected primary cells and A549 cells was confirmed using dual-label flow cytometry that accurately measured the different stages of the cell cycle. Comparison of progeny virus production in primary and A549 cells enriched in G(0)/G(1) using a specific CDK4/6 kinase inhibitor with asynchronously replicating cells indicated that this phase of the cell cycle was more efficient for virus production. PMID- 21795355 TI - Deletion of Kaposi's sarcoma-associated herpesvirus FLICE inhibitory protein, vFLIP, from the viral genome compromises the activation of STAT1-responsive cellular genes and spindle cell formation in endothelial cells. AB - Kaposi's sarcoma herpesvirus (KSHV) Fas-associated death domain (FADD)-like interleukin-1 beta-converting enzyme (FLICE)-inhibitory protein, vFLIP, has antiapoptotic properties, is a potent activator of the NF-kappaB pathway, and induces the formation of endothelial spindle cells, the hallmark of Kaposi's sarcoma, when overexpressed in primary endothelial cells. We used a reverse genetics approach to study several functions of KSHV vFLIP in the context of the whole viral genome. Deletion of the gene encoding vFLIP from a KSHV genome cloned in a bacterial artificial chromosome (BAC) reduced the ability of the virus to persist and induce spindle cell formation in primary human umbilical vein endothelial cells (HUVECs). Only a few, mainly interferon (IFN)-responsive, genes were expressed in wild-type KSHV (KSHV-wt)-infected endothelial cells at levels higher than those in KSHV-DeltaFLIP-infected endothelial cells, in contrast to the plethora of cellular genes induced by overexpressed vFLIP. In keeping with this observation, vFLIP induces the phosphorylation of STAT1 and STAT2 in an NF kappaB-dependent manner in endothelial cells. vFLIP-dependent phosphorylation of STAT1 and STAT2 could be demonstrated after endothelial cells were infected with KSHV-wt, KSHV-DeltaFLIP, and a KSHV-vFLIP revertant virus. These findings document the impact of KSHV vFLIP on the transcriptome of primary endothelial cells during viral persistence and highlight the role of vFLIP in the activation of STAT1/STAT2 and STAT-responsive cellular genes by KSHV. PMID- 21795356 TI - Sumoylation of the P protein at K254 plays an important role in growth of parainfluenza virus 5. AB - The P protein of parainfluenza virus 5 (PIV5) is an essential cofactor of the viral RNA-dependent RNA polymerase. Phosphorylation of the P protein can positively or negatively regulate viral gene expression, depending on the precise phosphorylation sites. Sumoylation, a process of adding small ubiquitin-like modifier (SUMO) to proteins posttranslationally, plays an important role in regulating protein function. In this study, we have found that the P protein of PIV5 was sumoylated with SUMO1 in both transfected and infected cells. The K254 residue of the P protein is within a consensus sumoylation motif. Mutation of the P protein at K254 to arginine (P-K254R) reduced PIV5 minigenome activity, as well as the sumoylation level of the P protein. Incorporation of K254R into a recombinant PIV5 (rPIV5-P-K254R) resulted in a virus that grew to a lower titer and had lower levels of viral RNA synthesis and protein expression than wild-type PIV5, suggesting that sumoylation of the P protein at K254 is important for PIV5 growth. Biochemical studies did not reveal any defect of P-K254R in its interactions with viral proteins NP and L or formation of homotetramers. We propose that sumoylation of the P protein at K254 regulates PIV5 gene expression through a host protein. PMID- 21795357 TI - Galectin-1 binds to influenza virus and ameliorates influenza virus pathogenesis. AB - Innate immune response is important for viral clearance during influenza virus infection. Galectin-1, which belongs to S-type lectins, contains a conserved carbohydrate recognition domain that recognizes galactose-containing oligosaccharides. Since the envelope proteins of influenza virus are highly glycosylated, we studied the role of galectin-1 in influenza virus infection in vitro and in mice. We found that galectin-1 was upregulated in the lungs of mice during influenza virus infection. There was a positive correlation between galectin-1 levels and viral loads during the acute phase of viral infection. Cells treated with recombinant human galectin-1 generated lower viral yields after influenza virus infection. Galectin-1 could directly bind to the envelope glycoproteins of influenza A/WSN/33 virus and inhibit its hemagglutination activity and infectivity. It also bound to different subtypes of influenza A virus with micromolar dissociation constant (K(d)) values and protected cells against influenza virus-induced cell death. We used nanoparticle, surface plasmon resonance analysis and transmission electron microscopy to further demonstrate the direct binding of galectin-1 to influenza virus. More importantly, we show for the first time that intranasal treatment of galectin-1 could enhance survival of mice against lethal challenge with influenza virus by reducing viral load, inflammation, and apoptosis in the lung. Furthermore, galectin-1 knockout mice were more susceptible to influenza virus infection than wild-type mice. Collectively, our results indicate that galectin-1 has anti-influenza virus activity by binding to viral surface and inhibiting its infectivity. Thus, galectin-1 may be further explored as a novel therapeutic agent for influenza. PMID- 21795358 TI - Generation of replication-defective virus-based vaccines that confer full protection in sheep against virulent bluetongue virus challenge. AB - The reverse genetics technology for bluetongue virus (BTV) has been used in combination with complementing cell lines to recover defective BTV-1 mutants. To generate a potential disabled infectious single cycle (DISC) vaccine strain, we used a reverse genetics system to rescue defective virus strains with large deletions in an essential BTV gene that encodes the VP6 protein (segment S9) of the internal core. Four VP6-deficient BTV-1 mutants were generated by using a complementing cell line that provided the VP6 protein in trans. Characterization of the growth properties of mutant viruses showed that each mutant has the necessary characteristics for a potential vaccine strain: (i) viral protein expression in noncomplementing mammalian cells, (ii) no infectious virus generated in noncomplementing cells, and (iii) efficient replication in the complementing VP6 cell line. Further, a defective BTV-8 strain was made by reassorting the two RNA segments that encode the two outer capsid proteins (VP2 and VP5) of a highly pathogenic BTV-8 with the remaining eight RNA segments of one of the BTV-1 DISC viruses. The protective capabilities of BTV-1 and BTV-8 DISC viruses were assessed in sheep by challenge with specific virulent strains using several assay systems. The data obtained from these studies demonstrated that the DISC viruses are highly protective and could offer a promising alternative to the currently available attenuated and killed virus vaccines and are also compliant as DIVA (differentiating infected from vaccinated animals) vaccines. PMID- 21795359 TI - Expression of herpes simplex virus 1-encoded microRNAs in human trigeminal ganglia and their relation to local T-cell infiltrates. AB - Herpes simplex type 1 (HSV-1) is a neurotropic virus which establishes lifelong latency in human trigeminal ganglia (TG). Currently, two nonexclusive control mechanisms of HSV-1 latency are discussed: antiviral CD8(+) T cells and viral microRNAs (miRNAs) encoded by the latency associated transcript (LAT). We investigate here to what extent these mechanisms may contribute to the maintenance of HSV-1 latency. We show that only a small proportion of LAT(+) neurons is surrounded by T cells in human TG. This indicates that viral latency in human TG might be controlled by other mechanisms such as viral miRNAs. Therefore, we assessed TG sections for the presence of HSV-1 miRNA, DNA, and mRNA by combining LAT in situ hybridization, T-cell immunohistochemistry, and single cell analysis of laser-microdissected sensory neurons. Quantitative reverse transcription-PCR (RT-PCR) revealed that LAT(+) neurons with or without surrounding T cells were always positive for HSV-1 miRNAs and DNA. Furthermore, ICP0 mRNA could rarely be detected only in LAT(+) neurons, as analyzed by single cell RT-PCR. In contrast, in LAT(-) neurons that were surrounded by T cells, neither miRNAs nor the DNA of HSV-1, HSV-2, or varicella-zoster virus could be detected. These data indicate that the majority of LAT(+) neurons is not directly controlled by T cells. However, miRNA expression in every latently infected neuron would provide an additional checkpoint before viral replication is initiated. PMID- 21795360 TI - Widespread endogenization of densoviruses and parvoviruses in animal and human genomes. AB - Parvoviruses infect humans and a broad range of animals, from mammals to crustaceans, and generally are associated with a variety of acute and chronic diseases. However, many others cause persistent infections and are not known to be associated with any disease. Viral persistence is likely related to the ability to integrate into the chromosomal DNA and to establish a latent infection. However, there is little evidence for genome integration of parvoviral DNA except for Adeno-associated virus (AAV). Here we performed a systematic search for homologs of parvoviral proteins in publicly available eukaryotic genome databases followed by experimental verification and phylogenetic analysis. We conclude that parvoviruses have frequently invaded the germ lines of diverse animal species, including mammals, fishes, birds, tunicates, arthropods, and flatworms. The identification of orthologous endogenous parvovirus sequences in the genomes of humans and other mammals suggests that parvoviruses have coexisted with mammals for at least 98 million years. Furthermore, some of the endogenized parvoviral genes were expressed in eukaryotic organisms, suggesting that these viral genes are also functional in the host genomes. Our findings may provide novel insights into parvovirus biology, host interactions, and evolution. PMID- 21795361 TI - Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. AB - Quality of life (QOL) is an important outcome in cancer therapy. In this study, we investigated the QOL and symptoms after [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) therapy in patients with inoperable or metastasized gastroenteropancreatic or bronchial neuroendocrine tumors (NETs). METHODS: Two hundred sixty-five Dutch patients completed the QOL questionnaire of the European Organization for the Research and Treatment of Cancer after being treated for NETs. ANOVA was used for statistical analyses, with a P value of 0.05 or less being considered significant. Differences of at least 10 points in global health status (GHS)/QOL scores, symptom scores, and Karnofsky performance scores (KPS) before and after therapy were regarded as indicating an improvement. RESULTS: Regardless of the treatment outcome, GHS/QOL, insomnia, appetite loss, and diarrhea improved significantly in the total group. These improvements were also seen in patients with bone metastases or a decrease of 50% or more in chromogranin A. Improvement in the scores by at least 10 points was also analyzed in a subgroup of patients with decreased GHS/QOL or symptoms at the start of therapy: in 36% of these patients, GHS/QOL improved after therapy; in 49%, fatigue; in 70%, nausea plus vomiting; in 53%, pain; in 44%, dyspnea; in 59%, insomnia; in 63%, appetite loss; in 60%, constipation; and in 67%, diarrhea. Additionally, we did not see a statistically significant deterioration in patients who had GHS/QOL 100, KPS 100, or no symptoms at the start. In patients with initial stable disease or remission after treatment, GHS/QOL and KPS decreased significantly when regrowth of the tumors occurred. CONCLUSION: GHS/QOL, KPS, and symptoms improved significantly after (177)Lu-octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GHS/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that (177)Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL. PMID- 21795362 TI - Preoperative central benzodiazepine receptor binding potential and cerebral blood flow images on SPECT predict development of new cerebral ischemic events and cerebral hyperperfusion after carotid endarterectomy. AB - Risk factors for cerebrovascular complications developing during or after carotid endarterectomy (CEA) include preoperative impairments in cerebral hemodynamics, as detected by the demonstration of decreased cerebrovascular reactivity (CVR) to acetazolamide on brain perfusion SPECT. Central benzodiazepine receptor binding potential (CBRBP) and cerebral blood flow (CBF) images on SPECT provide high sensitivity and high specificity for detecting misery perfusion in patients with chronic unilateral major cerebral artery occlusive disease. The aim of the present study was to determine whether preoperative CBRBP/CBF images on SPECT could identify patients at risk for new cerebral ischemic events, including neurologic deficits and cerebral ischemic lesions on diffusion-weighted MRI, or cerebral hyperperfusion after CEA and to compare the predictive accuracy of CBRBP/CBF with that of CVR to acetazolamide on SPECT. METHODS: CBF, CVR, and CBRBP were assessed using N-isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP) and (123)I-iomazenil SPECT before CEA in 112 patients with unilateral internal carotid artery stenosis (>= 70%). CBF measurement using (123)I-IMP SPECT was also performed immediately and 3 d after CEA. A region of interest was automatically placed in the middle cerebral artery territory in both cerebral hemispheres using a 3-dimensional stereotactic region-of-interest template. Diffusion-weighted MRI was performed within 3 d before and 24 h after surgery. RESULTS: A preoperative increase in the affected side-to-contralateral side asymmetry on CBRBP/CBF value was the only significant independent predictor of postoperative new cerebral ischemic events (95% confidence intervals [CI], 1.145-1.608; P = 0.0004) or post CEA hyperperfusion (95% CI, 1.244-2.252; P = 0.0007). There was no difference in the ability to predict post-CEA hyperperfusion when comparing the area under the receiver-operating-characteristic curve of the affected side-to-contralateral side asymmetry on CBRBP/CBF and that of the CVR in the affected hemisphere. However, the former value (0.924; 95% CI, 0.854-0.972) was significantly greater than the latter value (0.782; 95% CI, 0.697-0.852) for the prediction of new postoperative cerebral ischemic events (P < 0.05). CONCLUSION: Preoperative CBRBP/CBF images on SPECT can more accurately identify patients at risk for cerebrovascular complications occurring during or after CEA when compared with preoperative CVR to acetazolamide. PMID- 21795363 TI - Scintigraphy for pulmonary embolism: too old to rock 'n' roll, too young to die? PMID- 21795364 TI - Patient-specific radiation dosimetry of 99mTc-HYNIC-Tyr3-octreotide in neuroendocrine tumors. AB - (99m)Tc-hydrazinonicotinamide-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC) is increasingly gaining acceptance as a new radiopharmaceutical for the diagnosis of pathologic lesions overexpressing somatostatin receptors. However, little information has been published about the radiation dosimetry of this agent. The aim of this study was to assess the biodistribution and radiation dosimetry of commercially available (99m)Tc-HYNIC-TOC. A dose calculation procedure designed to be feasible to implement in a busy clinical environment was used. METHODS: Twenty-eight patients were imaged for suspected neuroendocrine tumors using a series of whole-body planar, dynamic planar, and SPECT/CT studies, after injection with (99m)Tc-HYNIC-TOC. Patient-specific dosimetry was performed using the OLINDA/EXM software with time-integrated activity coefficients estimated from a hybrid planar/SPECT technique. A phantom experiment was performed to establish adaptive thresholds for determination of source region volumes and activities. RESULTS: Pathologic uptake, diagnosed as due to neuroendocrine tumors, was observed in 12 patients. Normal organs with significant uptake included the kidneys, liver, and spleen. The mean effective dose after (99m)Tc-HYNIC-TOC injection was 4.6 +/- 1.1 mSv. Average normal-organ doses were 0.030 +/- 0.012, 0.021 +/- 0.007, and 0.012 +/- 0.005 mGy/MBq for the spleen, kidneys, and liver, respectively. The interpatient kidney dose ranged from 0.011 to 0.039 mGy/MBq, whereas the range of tumor doses varied from 0.003 to 0.053 mGy/MBq. The ratio of tumor to kidney dose ranged from 0.13 to 2.9. The optimal thresholds for recovery of true activity in the phantom study were significantly lower than those used for volume determination. CONCLUSION: The patient-specific 3-dimensional dosimetry protocol used in this study is a clinically feasible technique that has been applied to demonstrate large dose variations in tumors and normal organs between patients imaged with (99m)Tc-HYNIC-TOC. PMID- 21795365 TI - Extravasation of a therapeutic dose of 131I-metaiodobenzylguanidine: prevention, dosimetry, and mitigation. AB - After the extravasation of a therapeutic dose of (131)I-metaiodobenzylguanidine that produced a radiation burn to a patient's forearm, we instituted a catheter placement verification protocol. METHODS: Before therapy infusion, proper placement is verified by administering 37 MBq of (99m)Tc-pertechnetate through the catheter, and monitoring activity at the administration site and on the contralateral extremity. A dosimetric model describing both high-rate and low rate dose components was developed and predicted that the basal epidermal layer received a radiation dose consistent with the observed moist desquamation radiation skin toxicity. RESULTS: No extravasation incidents have occurred since the verification procedure was instituted. CONCLUSION: To protect against radiation injury from extravasation of therapeutic radionuclides, test administration of a small (99m)Tc dose with probe monitoring of comparable sites in both upper extremities appears to be an effective preventive measure. PMID- 21795366 TI - Imaging infection and inflammation in children with (18)F-FDG PET and (18)F-FDG PET/CT. AB - The goal of this article is to delineate indications for (18)F-FDG PET/CT pertaining to inflammation in the pediatric population, with emphasis on those that have been described in the literature. The limitations of (18)F-FDG PET/CT in this type of evaluation are also described, and the importance of using as low a dose as feasible is discussed. After reading this article, the reader should be able to list several clinical situations in which (18)F-FDG PET/CT may be appropriate, describe some limitations of (18)F-FDG PET/CT, and explain why dose is particularly important in the pediatric population. PMID- 21795367 TI - Radiopharmaceutical research and production in Brazil: a 30-year history of participation in the nuclear medicine scenario. AB - This article describes the 30-y history of nuclear medicine in Brazil, including reactors, production of radiopharmaceuticals, and trends. PMID- 21795368 TI - Suppression of 18F-FDG Myocardial Uptake Using a Fat-Allowed, Carbohydrate Restricted Diet. AB - Patients prepared by the generally used fasting protocol show variable myocardial (18)F-FDG uptake, which may result in difficult interpretation of mediastinal (18)F-FDG uptake. This retrospective study described the effect of a 1-d fat allowed, carbohydrate-restricted diet on myocardial (18)F-FDG uptake. METHODS: The study included 100 patients on a carbohydrate-restricted diet from the Medical Center Leeuwarden and 100 patients on an unrestricted diet from the University Medical Center of Utrecht. A visual uptake scale was used, with category 0 indicating myocardial uptake less than liver uptake, category 1 indicating myocardial uptake comparable to liver uptake, and category 2 indicating myocardial uptake considerably higher than liver uptake. RESULTS: After a carbohydrate-restricted diet, 68% of patients had a homogeneously low myocardial uptake of (18)F-FDG (category 0), 14% had moderate myocardial uptake (category 1), and 18% had homogeneously intense myocardial uptake (category 2). Without a carbohydrate-restricted diet, 69% of patients showed a homogeneously intense myocardial uptake (category 2), 16% a moderate myocardial uptake (category 1), and 15% a homogeneously low myocardial uptake (category 0). CONCLUSION: A fat-allowed, carbohydrate-restricted diet starting the day before (18)F-FDG administration suppresses myocardial (18)F-FDG uptake satisfactorily. PMID- 21795369 TI - The role of PET and PET/CT in managing the care of lymphoma patients. AB - The clinical use of PET and PET/CT aids physicians and patients in developing lymphoma prognoses, specifically for Hodgkin disease and aggressive types of non Hodgkin lymphoma. PET and PET/CT are used to initially stage lymphoma, restage disease, and check for remission or recurrence of malignant tissue after treatment. PET/CT is more sensitive and specific than CT alone and has better accuracy concerning lymphoma relapse and remission. In conjunction with other tests, such as blood laboratory work and biopsy, PET and PET/CT allow the lymphoma to be staged appropriately and treated correctly. Results from PET and PET/CT contribute to the formation of a specialized treatment plan that leads to the best possible care for each individual patient. PET and PET/CT positively affect the management of patients with lymphoma. PMID- 21795370 TI - Determining the pregnancy status of patients before diagnostic nuclear medicine procedures: the Australian experience. AB - Ionizing radiation used in diagnostic nuclear medicine procedures has the potential to have biologic effects on a fetus. Nuclear medicine technologists (NMTs) therefore have a responsibility to ensure that they question all patients of childbearing age about their pregnancy status before starting any procedure, to avoid unnecessary fetal irradiation. In Australia, there are no clearly defined practice guidelines to assist NMTs in determining whom to question or how to question their patients. METHODS: Semistructured interviews were conducted with chief NMTs and staff NMTs in 8 nuclear medicine departments in Australia. Questions were based around 5 areas: regulations and policy, fetal radiation exposure, questioning of the patient, difficulties in determining pregnancy status, and the impact of the use of hybrid imaging. Audio files of the interviews were transcribed and coded. RESULTS: Topics were coded into 5 themes: policy and awareness of guidelines, questioning the patient, radiation knowledge, decisions and assumptions made by NMTs, and the use of pregnancy testing. There was a wide variation in practice between and within departments. NMTs demonstrated a lack of knowledge and awareness of the possible biologic effects of radiation. CONCLUSION: This study identified a need in Australia for nuclear medicine to arrive at a consensus approach to verifying a patient's pregnancy status so that NMTs can successfully question patients about their pregnancy status. Continuing education programs are also required to keep NMTs up to date in their knowledge. PMID- 21795371 TI - Parathyroid imaging and localization using SPECT/CT: initial results. AB - Primary hyperparathyroidism is caused by a single parathyroid adenoma in up to 90% of clinical cases. Selective surgical excision of the hyperfunctioning parathyroid gland is the treatment of choice for this condition, and parathyroid scintigraphy is one of the primary and standard methods used for preoperative localization. SPECT/CT is advantageous over planar imaging because SPECT/CT provides useful anatomic information, improving overall diagnostic confidence. This paper evaluates the initial findings of a hybrid parathyroid imaging technique that was put into effect after the installation of a SPECT/CT system in the nuclear medicine department at Torbay Hospital, Torquay, United Kingdom. The key findings from 3 of the initial sets of patient studies are discussed, along with the key learning points after the introduction of this new clinical service. METHODS: From January 2009 until December 2009, 9 patients underwent a parathyroid study at Torbay Hospital (8 women [87.5%] and 1 man [12.5%]; mean age [+/-SD], 61 +/- 10.12 y). All patients were referred from the endocrinology department because they had clinical signs of parathyroid adenoma (67%) or required preoperative localization of parathyroid adenoma (33%). For parathyroid scintigraphy, 640-990 MBq of (99m)Tc-sestamibi were administrated intravenously. A SPECT/CT system was used to acquire images from the level of the submandibular glands through the basal third of the heart. Three sets of images were acquired, and the processed images were reviewed for quality, attenuation correction, and registration. RESULTS: Two (22%) of the 9 studies were negative for possible adenoma, and 7 (78%) were positive. Of the positive studies, 6 (86%) showed an adenoma on the left inferior gland and only 1 (14%) showed an adenoma in an eccentric position. CONCLUSION: The introduction of parathyroid SPECT/CT has resulted in the development of new imaging and processing protocols within our nuclear medicine department. Introducing any new technique requires knowledge, understanding, and practical skills. The additional information gained from the parathyroid SPECT/CT technique has provided new skills for practitioners and increased reporting confidence for physicians. PMID- 21795372 TI - Extrinsic Versus Intrinsic Uniformity Correction for gamma-cameras. AB - SPECT produces nuclear medicine images using a 3-dimensional diagnostic tool that eliminates the superimposition of adjacent structures, thus providing improved disease localization. Another method of uniformity correction-to use the complete capabilities of this tool-is discussed and evaluated in this article. The conventional method of intrinsic uniformity correction accounts only for nonuniformities within the gamma-camera, excluding the collimator. If SPECT image quality is related to overall camera performance, then using an extrinsic uniformity correction method rather than an intrinsic method will improve image quality. METHODS: SPECT uniformity images were obtained using a SPECT phantom with application of intrinsic and extrinsic uniformity correction tables with 2 different gamma-imaging systems. The image results were qualitatively assessed. RESULTS: Even with acceptable nonuniformity analyses, significant ring artifacts within the intrinsic uniformity-corrected images are observed, whereas the artifacts are considerably less significant with the extrinsic uniformity correction and disappear completely in some of these images. CONCLUSION: Extrinsic uniformity correction may significantly improve the overall image quality by taking into account nonuniformities that arise from the collimator. This method will result in fewer image artifacts and improved image quality, thereby improving patient care. PMID- 21795373 TI - The diagnostic value of (99m)Tc-IgG scintigraphy in the diabetic foot and comparison with (99m)Tc-MDP scintigraphy. AB - Diabetic foot infection is the most common etiology of nontraumatic amputation of the lower extremities, and early diagnosis is of great importance in its management. The aim of this prospective study was to evaluate the strength of (99m)Tc-IgG scintigraphy in diagnosis of osteomyelitis of the diabetic foot and to compare (99m)Tc-IgG scintigraphy with (99m)Tc-methylene diphosphonate (MDP) scintigraphy. METHODS: A prospective university hospital-based study was performed over 24 mo. Eighteen patients with type II diabetes and foot ulcers (15 men and 3 women; age range, 45-80 y) were referred for imaging because of clinically suspected osteomyelitis. Early (5-h) and late (24-h) (99m)Tc-IgG scanning and 3-phase skeletal scintigraphy were completed for all patients at a 3 to 4-d interval. Regions of interest over the involved bony sites and the contralateral normal sites were drawn, and the abnormal-to-normal ratios were acquired for both (99m)Tc-IgG and (99m)Tc-MDP studies. RESULTS: From a total of 23 lesions, we observed 10 sites of osteomyelitis, 10 sites of cellulitis, and 3 sites of aseptic inflammation confirmed by MRI, clinical presentation, histopathologic examination, and follow-up evaluation as a gold standard. Both (99m)Tc-IgG and (99m)Tc-MDP scanning showed excellent sensitivity for diagnosis of osteomyelitis, but the specificity was significantly lower (69.2% and 53.8%, respectively). Sensitivity, specificity, and accuracy in the diagnosis of osteomyelitis were, respectively, 100%, 53.8%, 73.9% for (99m)Tc-MDP scanning; 100%, 69.2%, 82.6% for 5-h (99m)Tc-IgG scanning; and 60%, 76.9%, 69.5% for 24-h (99m)Tc-IgG scanning. There was no significant difference between the semiquantitative indices of 5-h and 24-h (99m)Tc-IgG scanning for inflammation, cellulitis, and osteomyelitis. CONCLUSION: Although both (99m)Tc-IgG and (99m)Tc MDP scintigraphy have high sensitivity for the diagnosis of osteomyelitis, the specificity of these studies is poor. For (99m)Tc-IgG scintigraphy, 5-h images appear to be adequate, and there is little benefit to performing additional imaging at 24 h. PMID- 21795374 TI - The incremental value of SPECT/CT in characterizing solitary spine lesions. AB - The purpose of this study was to investigate the incremental value and diagnostic impact of SPECT/CT in patients who had a solitary spinal lesion on a bone scan. METHODS: A prospective study was performed on 80 patients (50 with known cancer) who underwent (99m)Tc-methylene diphosphonate whole-body planar bone scintigraphy and had a solitary spinal lesion. These lesions were then further evaluated using SPECT/CT. RESULTS: Lesions were localized to the vertebral body in 38 patients (47.5%), pedicle in 15 (18.8%), facet joint in 15 (18.8%), transverse process in 2 (2.5%), spinous process in 2 (2.5%), lamina in 3 (3.8%), and end plates in 5 (6.2%). Although the specificity of planar bone scans was excellent (100%), sensitivity was only 6.1% but increased to 78.8% after the addition of SPECT/CT. The results provide evidence of a substantial incremental increase in diagnostic accuracy using SPECT/CT over planar imaging alone for patients in whom a solitary spinal lesion is noted. CONCLUSION: The addition of SPECT/CT significantly reduced the number of false-negative results and increased the number of true positive results. SPECT/CT also reduced the number of equivocal reports. A definitive diagnosis was given for most patients, indicating improved diagnostic confidence with the addition of SPECT/CT, compared with planar imaging alone, in patients with solitary spinal lesions. PMID- 21795375 TI - Effect of prefiltering cutoff frequency and scatter and attenuation corrections during normal database creation for statistical imaging analysis of the brain. AB - The present study aimed to quantify which image reconstruction conditions for normal databases and patients affect statistical brain function image analysis using an easy z score imaging system (eZIS) and 3-dimensional stereotactic surface projections (3D-SSP). METHODS: We constructed normal databases based on cerebral perfusion SPECT images obtained from 15 healthy individuals. Each normal database was created with the following unique conditions: a variable Butterworth filter cutoff frequency (fc) with and without scatter and attenuation corrections. To simulate patient data, we selected 1 dataset from among those created from the 15 healthy individuals. The simulated patient data were designed to include hypoperfused regions with prespecified volumes. Using 3D-SSP and eZIS, we compared how the above processing conditions affect the distribution of SD in normal database images and the accuracy of detecting specific regions. RESULTS: The SD for the SPECT images increased with the fc of the Butterworth filter. The z score decreased by 30% for 3D-SSP and by 14% for eZIS, indicating that the prefilter significantly affected z scores. The accuracy of detecting the hypoperfused regions was significantly influenced by the fc; 3D-SSP decreased by 7.51%, and eZIS decreased by 55.34%. The detection accuracy with eZIS, which involves a smoothing process, was significantly decreased. The error of the area of hypoperfused regions was minimized when normal database and patient data were both corrected for scatter and attenuation. CONCLUSION: When the reconstruction conditions (fc, scatter correction, and attenuation correction) at normal database creation differed from those at patient data processing, the z scores widely underestimated the analytic results because the SD varied according to the reconstruction conditions. The accuracy of brain function image analysis can be improved by considering the reconstruction conditions and correcting for scatter and attenuation on both normal databases and patient data. PMID- 21795376 TI - Gibbs artifact reduction by nonnegativity constraint. AB - This paper proposes a 2-step image reconstruction method in which the nonnegativity constraint in the iterative maximum-likelihood expectation maximization (MLEM) algorithm is used to effectively reduce Gibbs ringing artifacts. METHODS: Gibbs artifacts are difficult to control during imaging reconstruction. The proposed method uses the postprocessing strategy to suppress Gibbs artifacts. In the first step, a raw image is reconstructed from projections without correction for point spread function (PSF). The attenuation correction can be performed in the first step by using, for example, the iterative MLEM or ordered-subsets expectation maximization (OS-EM) algorithm. The second step is a postprocessing procedure that corrects for the PSF blurring effect. If the target features (e.g., hot lesions) have a positive background, removing the background before application of the postprocessing filter significantly helps with target deblurring and Gibbs artifact suppression. This postprocessing filter is the image-domain MLEM algorithm. The background activity is attached back to the foreground after lesion sharpening. RESULTS: Computer simulations and PET phantom studies were performed using the proposed 2-step method. The background removal strategy significantly reduced Gibbs artifacts. CONCLUSION: Gibbs ringing artifacts generated during image reconstruction are difficult to avoid if compensation for the PSF of the system is needed. The strategy of separating image reconstruction from PSF compensation has been shown effective in removal of Gibbs ringing artifacts. PMID- 21795377 TI - The bidirectional association between daytime affect and nighttime sleep in youth with anxiety and depression. AB - OBJECTIVE: This study examines relationships between affect and sleep in youth with affective disorders using ecological momentary assessment (EMA). METHODS: Participants included 94 youth, ages 8-16 (M = 11.73, 53% female) years with an anxiety disorder only (n = 23), primary major depressive disorder (with and without a secondary anxiety diagnoses; n = 42), and healthy controls (n = 29). A cell phone EMA protocol assessed affect and actigraphy measured sleep. RESULTS: The patterns of bidirectional relationships between affect and sleep differed across diagnostic groups. Higher daytime positive affect and positive to negative affect ratios were associated with more time in bed during the subsequent night for youth with primary depression and less time in bed for youth with anxiety only. More time asleep was associated with more positive affect for both diagnostic groups the following day. CONCLUSIONS: This relationship may be important to consider in the treatment of youth affective disorders. PMID- 21795378 TI - CAG repeats mimic CUG repeats in the misregulation of alternative splicing. AB - Mutant transcripts containing expanded CUG repeats in the untranslated region are a pathogenic factor in myotonic dystrophy type 1 (DM1). The mutant RNA sequesters the muscleblind-like 1 (MBNL1) splicing factor and causes misregulation of the alternative splicing of multiple genes that are linked to clinical symptoms of the disease. In this study, we show that either long untranslated CAG repeat RNA or short synthetic CAG repeats induce splicing aberrations typical of DM1. Alternative splicing defects are also caused by translated CAG repeats in normal cells transfected with a mutant ATXN3 gene construct and in cells derived from spinocerebellar ataxia type 3 and Huntington's disease patients. Splicing misregulation is unlikely to be caused by traces of antisense transcripts with CUG repeats, and the possible trigger of this misregulation may be sequestration of the MBNL1 protein with nuclear RNA inclusions containing expanded CAG repeat transcripts. We propose that alternative splicing misregulation by mutant CAG repeats may contribute to the pathological features of polyglutamine disorders. PMID- 21795379 TI - c-MYC promoter G-quadruplex formed at the 5'-end of NHE III1 element: insights into biological relevance and parallel-stranded G-quadruplex stability. AB - We studied the structures and stabilities of G-quadruplexes formed in Myc1234, the region containing the four consecutive 5' runs of guanines of c-MYC promoter NHE III(1,) which have recently been shown to form in a supercoiled plasmid system in aqueous solution. We determined the NMR solution structure of the 1:2:1 parallel-stranded loop isomer, one of the two major loop isomers formed in Myc1234 in K(+) solution. This major loop isomer, although sharing the same folding structure, appears to be markedly less stable than the major loop isomer formed in the single-stranded c-MYC NHE III(1) oligonucleotide, the Myc2345 G quadruplex. Our NMR structures indicated that the different thermostabilities of the two 1:2:1 parallel c-MYC G-quadruplexes are likely caused by the different base conformations of the single nucleotide loops. The observation of the formation of the Myc1234 G-quadruplex in the supercoiled plasmid thus points to the potential role of supercoiling in the G-quadruplex formation in promoter sequences. We also performed a systematic thermodynamic analysis of modified c MYC NHE III(1) sequences, which provided quantitative measure of the contributions of various loop sequences to the thermostabilities of parallel stranded G-quadruplexes. This information is important for understanding the equilibrium of promoter G-quadruplex loop isomers and for their drug targeting. PMID- 21795380 TI - An activated triple bond linker enables 'click' attachment of peptides to oligonucleotides on solid support. AB - A general procedure, based on a new activated alkyne linker, for the preparation of peptide-oligonucleotide conjugates (POCs) on solid support has been developed. With this linker, conjugation is effective at room temperature (RT) in millimolar concentration and submicromolar amounts. This is made possible since the use of a readily attachable activated triple bond linker enhances the Cu(I) catalyzed 1,3 dipolar cycloaddition ('click' reaction). The preferred scheme for conjugate preparation involves sequential conjugation to oligonucleotides on solid support of (i) an H-phosphonate-based aminolinker; (ii) the triple bond donor p-(N propynoylamino)toluic acid (PATA); and (iii) azido-functionalized peptides. The method gives conversion of oligonucleotide to the POC on solid support, and only involves a single purification step after complete assembly. The synthesis is flexible and can be carried out without the need for specific automated synthesizers since it has been designed to utilize commercially available oligonucleotide and peptide derivatives on solid support or in solution. Methodology for the ready conversion of peptides into 'clickable' azidopeptides with the possibility of selecting either N-terminus or C-terminus connection also adds to the flexibility and usability of the method. Examples of synthesis of POCs include conjugates of oligonucleotides with peptides known to be membrane penetrating and nuclear localization signals. PMID- 21795381 TI - Efficient internal exon recognition depends on near equal contributions from the 3' and 5' splice sites. AB - Pre-mRNA splicing is carried out by the spliceosome, which identifies exons and removes intervening introns. In vertebrates, most splice sites are initially recognized by the spliceosome across the exon, because most exons are small and surrounded by large introns. This gene architecture predicts that efficient exon recognition depends largely on the strength of the flanking 3' and 5' splice sites. However, it is unknown if the 3' or the 5' splice site dominates the exon recognition process. Here, we test the 3' and 5' splice site contributions towards efficient exon recognition by systematically replacing the splice sites of an internal exon with sequences of different splice site strengths. We show that the presence of an optimal splice site does not guarantee exon inclusion and that the best predictor for exon recognition is the sum of both splice site scores. Using a genome-wide approach, we demonstrate that the combined 3' and 5' splice site strengths of internal exons provide a much more significant separator between constitutive and alternative exons than either the 3' or the 5' splice site strength alone. PMID- 21795382 TI - Quantitative single cell monitoring of protein synthesis at subcellular resolution using fluorescently labeled tRNA. AB - We have developed a novel technique of using fluorescent tRNA for translation monitoring (FtTM). FtTM enables the identification and monitoring of active protein synthesis sites within live cells at submicron resolution through quantitative microscopy of transfected bulk uncharged tRNA, fluorescently labeled in the D-loop (fl-tRNA). The localization of fl-tRNA to active translation sites was confirmed through its co-localization with cellular factors and its dynamic alterations upon inhibition of protein synthesis. Moreover, fluorescence resonance energy transfer (FRET) signals, generated when fl-tRNAs, separately labeled as a FRET pair occupy adjacent sites on the ribosome, quantitatively reflect levels of protein synthesis in defined cellular regions. In addition, FRET signals enable detection of intra-populational variability in protein synthesis activity. We demonstrate that FtTM allows quantitative comparison of protein synthesis between different cell types, monitoring effects of antibiotics and stress agents, and characterization of changes in spatial compartmentalization of protein synthesis upon viral infection. PMID- 21795383 TI - Phenotypic profiling of the human genome reveals gene products involved in plasma membrane targeting of SRC kinases. AB - SRC proteins are non-receptor tyrosine kinases that play key roles in regulating signal transduction by a diverse set of cell surface receptors. They contain N terminal SH4 domains that are modified by fatty acylation and are functioning as membrane anchors. Acylated SH4 domains are both necessary and sufficient to mediate specific targeting of SRC kinases to the inner leaflet of plasma membranes. Intracellular transport of SRC kinases to the plasma membrane depends on microdomains into which SRC kinases partition upon palmitoylation. In the present study, we established a live-cell imaging screening system to identify gene products involved in plasma membrane targeting of SRC kinases. Based on siRNA arrays and a human model cell line expressing two kinds of SH4 reporter molecules, we conducted a genome-wide analysis of SH4-dependent protein targeting using an automated microscopy platform. We identified and validated 54 gene products whose down-regulation causes intracellular retention of SH4 reporter molecules. To detect and quantify this phenotype, we developed a software-based image analysis tool. Among the identified gene products, we found factors involved in lipid metabolism, intracellular transport, and cellular signaling processes. Furthermore, we identified proteins that are either associated with SRC kinases or are related to various known functions of SRC kinases such as other kinases and phosphatases potentially involved in SRC-mediated signal transduction. Finally, we identified gene products whose function is less defined or entirely unknown. Our findings provide a major resource for future studies unraveling the molecular mechanisms that underlie proper targeting of SRC kinases to the inner leaflet of plasma membranes. PMID- 21795384 TI - Trans genomic capture and sequencing of primate exomes reveals new targets of positive selection. AB - Comparison of protein-coding DNA sequences from diverse primates can provide insight into these species' evolutionary history and uncover the molecular basis for their phenotypic differences. Currently, the number of available primate reference genomes limits these genome-wide comparisons. Here we use targeted capture methods designed for human to sequence the protein-coding regions, or exomes, of four non-human primate species (three Old World monkeys and one New World monkey). Despite average sequence divergence of up to 4% from the human sequence probes, we are able to capture ~96% of coding sequences. Using a combination of mapping and assembly techniques, we generated high-quality full length coding sequences for each species. Both the number of nucleotide differences and the distribution of insertion and deletion (indel) lengths indicate that the quality of the assembled sequences is very high and exceeds that of most reference genomes. Using this expanded set of primate coding sequences, we performed a genome-wide scan for genes experiencing positive selection and identified a novel class of adaptively evolving genes involved in the conversion of epithelial cells in skin, hair, and nails to keratin. Interestingly, the genes we identify under positive selection also exhibit significantly increased allele frequency differences among human populations, suggesting that they play a role in both recent and long-term adaptation. We also identify several genes that have been lost on specific primate lineages, which illustrate the broad utility of this data set for other evolutionary analyses. These results demonstrate the power of second-generation sequencing in comparative genomics and greatly expand the repertoire of available primate coding sequences. PMID- 21795385 TI - Regulation of nucleosome landscape and transcription factor targeting at tissue specific enhancers by BRG1. AB - Enhancers of transcription activate transcription via binding of sequence specific transcription factors to their target sites in chromatin. In this report, we identify GATA1-bound distal sites genome-wide and find a global reorganization of the nucleosomes at these potential enhancers during differentiation of hematopoietic stem cells (HSCs) to erythrocytes. We show that the catalytic subunit BRG1 of BAF complexes localizes to these distal sites during differentiation and generates a longer nucleosome linker region surrounding the GATA1 sites by shifting the flanking nucleosomes away. Intriguingly, we find that the nucleosome shifting specifically facilitates binding of TAL1 but not GATA1 and is linked to subsequent transcriptional regulation of target genes. PMID- 21795386 TI - Dynamics of the epigenetic landscape during erythroid differentiation after GATA1 restoration. AB - Interplays among lineage-specific nuclear proteins, chromatin modifying enzymes, and the basal transcription machinery govern cellular differentiation, but their dynamics of action and coordination with transcriptional control are not fully understood. Alterations in chromatin structure appear to establish a permissive state for gene activation at some loci, but they play an integral role in activation at other loci. To determine the predominant roles of chromatin states and factor occupancy in directing gene regulation during differentiation, we mapped chromatin accessibility, histone modifications, and nuclear factor occupancy genome-wide during mouse erythroid differentiation dependent on the master regulatory transcription factor GATA1. Notably, despite extensive changes in gene expression, the chromatin state profiles (proportions of a gene in a chromatin state dominated by activating or repressive histone modifications) and accessibility remain largely unchanged during GATA1-induced erythroid differentiation. In contrast, gene induction and repression are strongly associated with changes in patterns of transcription factor occupancy. Our results indicate that during erythroid differentiation, the broad features of chromatin states are established at the stage of lineage commitment, largely independently of GATA1. These determine permissiveness for expression, with subsequent induction or repression mediated by distinctive combinations of transcription factors. PMID- 21795387 TI - A proteogenomic analysis of Anopheles gambiae using high-resolution Fourier transform mass spectrometry. AB - Anopheles gambiae is a major mosquito vector responsible for malaria transmission, whose genome sequence was reported in 2002. Genome annotation is a continuing effort, and many of the approximately 13,000 genes listed in VectorBase for Anopheles gambiae are predictions that have still not been validated by any other method. To identify protein-coding genes of An. gambiae based on its genomic sequence, we carried out a deep proteomic analysis using high-resolution Fourier transform mass spectrometry for both precursor and fragment ions. Based on peptide evidence, we were able to support or correct more than 6000 gene annotations including 80 novel gene structures and about 500 translational start sites. An additional validation by RT-PCR and cDNA sequencing was successfully performed for 105 selected genes. Our proteogenomic analysis led to the identification of 2682 genome search-specific peptides. Numerous cases of encoded proteins were documented in regions annotated as intergenic, introns, or untranslated regions. Using a database created to contain potential splice sites, we also identified 35 novel splice junctions. This is a first report to annotate the An. gambiae genome using high-accuracy mass spectrometry data as a complementary technology for genome annotation. PMID- 21795388 TI - Kinesin molecular motor Eg5 functions during polypeptide synthesis. AB - The kinesin-related molecular motor Eg5 plays roles in cell division, promoting spindle assembly. We show that during interphase Eg5 is associated with ribosomes and is required for optimal nascent polypeptide synthesis. When Eg5 was inhibited, ribosomes no longer bound to microtubules in vitro, ribosome transit rates slowed, and polysomes accumulated in intact cells, suggesting defects in elongation or termination during polypeptide synthesis. These results demonstrate that the molecular motor Eg5 associates with ribosomes and enhances the efficiency of translation. PMID- 21795389 TI - MICAL-like1 mediates epidermal growth factor receptor endocytosis. AB - Small GTPase Rabs are required for membrane protein sorting/delivery to precise membrane domains. Rab13 regulates epithelial tight junction assembly and polarized membrane transport. Here we report that Molecule Interacting with CasL (MICAL)-like1 (MICAL-L1) interacts with GTP-Rab13 and shares a similar domain organization with MICAL. MICAL-L1 has a calponin homology (CH), LIM, proline rich and coiled-coil domains. It is associated with late endosomes. Time-lapse video microscopy shows that green fluorescent protein-Rab7 and mcherry-MICAL-L1 are present within vesicles that move rapidly in the cytoplasm. Depletion of MICAL-L1 by short hairpin RNA does not alter the distribution of a late endosome/lysosome associated protein but affects the trafficking of epidermal growth factor receptor (EGFR). Overexpression of MICAL-L1 leads to the accumulation of EGFR in the late endosomal compartment. In contrast, knocking down MICAL-L1 results in the distribution of internalized EGFR in vesicles spread throughout the cytoplasm and promotes its degradation. Our data suggest that the N-terminal CH domain associates with the C-terminal Rab13 binding domain (RBD) of MICAL-L1. The binding of Rab13 to RBD disrupts the CH/RBD interaction, and may induce a conformational change in MICAL-L1, promoting its activation. Our results provide novel insights into the MICAL-L1/Rab protein complex that can regulate EGFR trafficking at late endocytic pathways. PMID- 21795390 TI - Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor. AB - The nuclear envelope of metazoans disassembles during mitosis and reforms in late anaphase after sister chromatids have well separated. The coordination of these mitotic events is important for genome stability, yet the temporal control of nuclear envelope reassembly is unknown. Although the steps of nuclear formation have been extensively studied in vitro using the reconstitution system from egg extracts, the temporal control can only be studied in vivo. Here, we use time lapse microscopy to investigate this process in living HeLa cells. We demonstrate that Cdk1 activity prevents premature nuclear envelope assembly and that phosphorylation of the inner nuclear membrane protein lamin B receptor (LBR) by Cdk1 contributes to the temporal control. We further identify a region in the nucleoplasmic domain of LBR that inhibits premature chromatin binding of the protein. We propose that this inhibitory effect is partly mediated by Cdk1 phosphorylation. Furthermore, we show that the reduced chromatin-binding ability of LBR together with Aurora B activity contributes to nuclear envelope breakdown. Our studies reveal for the first time a mechanism that controls the timing of nuclear envelope reassembly through modification of an integral nuclear membrane protein. PMID- 21795391 TI - The period of the somite segmentation clock is sensitive to Notch activity. AB - The number of vertebrae is defined strictly for a given species and depends on the number of somites, which are the earliest metameric structures that form in development. Somites are formed by sequential segmentation. The periodicity of somite segmentation is orchestrated by the synchronous oscillation of gene expression in the presomitic mesoderm (PSM), termed the "somite segmentation clock," in which Notch signaling plays a crucial role. Here we show that the clock period is sensitive to Notch activity, which is fine-tuned by its feedback regulator, Notch-regulated ankyrin repeat protein (Nrarp), and that Nrarp is essential for forming the proper number and morphology of axial skeleton components. Null-mutant mice for Nrarp have fewer vertebrae and have defective morphologies. Notch activity is enhanced in the PSM of the Nrarp(-/-) embryo, where the ~2-h segmentation period is extended by 5 min, thereby forming fewer somites and their resultant vertebrae. Reduced Notch activity partially rescues the Nrarp(-/-) phenotype in the number of somites, but not in morphology. Therefore we propose that the period of the somite segmentation clock is sensitive to Notch activity and that Nrarp plays essential roles in the morphology of vertebrae and ribs. PMID- 21795392 TI - Vacuolar H(+)-ATPase subunits Voa1 and Voa2 cooperatively regulate secretory vesicle acidification, transmitter uptake, and storage. AB - The Vo sector of the vacuolar H(+)-ATPase is a multisubunit complex that forms a proteolipid pore. Among the four isoforms (a1-a4) of subunit Voa, the isoform(s) critical for secretory vesicle acidification have yet to be identified. An independent function of Voa1 in exocytosis has been suggested. Here we investigate the function of Voa isoforms in secretory vesicle acidification and exocytosis by using neurosecretory PC12 cells. Fluorescence-tagged and endogenous Voa1 are primarily localized on secretory vesicles, whereas fluorescence-tagged Voa2 and Voa3 are enriched on the Golgi and early endosomes, respectively. To elucidate the functional roles of Voa1 and Voa2, we engineered PC12 cells in which Voa1, Voa2, or both are stably down-regulated. Our results reveal significant reductions in the acidification and transmitter uptake/storage of dense-core vesicles by knockdown of Voa1 and more dramatically of Voa1/Voa2 but not of Voa2. Overexpressing knockdown-resistant Voa1 suppresses the acidification defect caused by the Voa1/Voa2 knockdown. Unexpectedly, Ca(2+)-dependent peptide secretion is largely unaffected in Voa1 or Voa1/Voa2 knockdown cells. Our data demonstrate that Voa1 and Voa2 cooperatively regulate the acidification and transmitter uptake/storage of dense-core vesicles, whereas they might not be as critical for exocytosis as recently proposed. PMID- 21795393 TI - Condensins I and II are essential for construction of bivalent chromosomes in mouse oocytes. AB - In many eukaryotes, condensins I and II associate with chromosomes in an ordered fashion during mitosis and play nonoverlapping functions in their assembly and segregation. Here we report for the first time the spatiotemporal dynamics and functions of the two condensin complexes during meiotic divisions in mouse oocytes. At the germinal vesicle stage (prophase I), condensin I is present in the cytoplasm, whereas condensin II is localized within the nucleus. After germinal vesicle breakdown, condensin II starts to associate with chromosomes and becomes concentrated onto chromatid axes of bivalent chromosomes by metaphase I. REC8 "glues" chromosome arms along their lengths. In striking contrast to condensin II, condensin I localizes primarily around centromeric regions at metaphase I and starts to associate stably with chromosome arms only after anaphase I. Antibody injection experiments show that condensin functions are required for many aspects of meiotic chromosome dynamics, including chromosome individualization, resolution, and segregation. We propose that the two condensin complexes play distinctive roles in constructing bivalent chromosomes: condensin II might play a primary role in resolving sister chromatid axes, whereas condensin I might contribute to monopolar attachment of sister kinetochores, possibly by assembling a unique centromeric structure underneath. PMID- 21795394 TI - The budding yeast polo-like kinase Cdc5 regulates the Ndt80 branch of the meiotic recombination checkpoint pathway. AB - Defects in chromosome synapsis and/or meiotic recombination activate a surveillance mechanism that blocks meiotic cell cycle progression to prevent anomalous chromosome segregation and formation of aberrant gametes. In the budding yeast zip1 mutant, which lacks a synaptonemal complex component, the meiotic recombination checkpoint is triggered, resulting in extremely delayed meiotic progression. We report that overproduction of the polo-like kinase Cdc5 partially alleviates the meiotic prophase arrest of zip1, leading to the formation of inviable meiotic products. Unlike vegetative cells, we demonstrate that Cdc5 overproduction does not stimulate meiotic checkpoint adaptation because the Mek1 kinase remains activated in zip1 2MU-CDC5 cells. Inappropriate meiotic divisions in zip1 promoted by high levels of active Cdc5 do not result from altered function of the cyclin-dependent kinase (CDK) inhibitor Swe1. In contrast, CDC5 overexpression leads to premature induction of the Ndt80 transcription factor, which drives the expression of genes required for meiotic divisions, including CLB1. We also show that depletion of Cdc5 during meiotic prophase prevents the production of Ndt80 and that CDK activity contributes to the induction of Ndt80 in zip1 cells overexpressing CDC5. Our results reveal a role for Cdc5 in meiotic checkpoint control by regulating Ndt80 function. PMID- 21795395 TI - Genetic interaction between Caenorhabditis elegans teneurin ten-1 and prolyl 4 hydroxylase phy-1 and their function in collagen IV-mediated basement membrane integrity during late elongation of the embryo. AB - Teneurins are a family of phylogenetically conserved proteins implicated in pattern formation and morphogenesis. The sole orthologue in Caenorhabditis elegans, ten-1, is important for hypodermal cell migration, neuronal migration, path finding and fasciculation, gonad development, and basement membrane integrity of some tissues. However, the mechanisms of TEN-1 action remain to be elucidated. Using a genome-wide RNA interference approach, we identified phy-1 as a novel interaction partner of ten-1. phy-1 codes for the catalytic domain of collagen prolyl 4-hydroxylase. Loss of phy-1 significantly enhanced the embryonic lethality of ten-1 null mutants. Double-mutant embryos arrested during late elongation with epidermal defects, disruption of basement membranes, and detachment of body wall muscles. We found that deletion of phy-1 caused aggregation of collagen IV in body wall muscles in elongated embryos and triggered the loss of tissue integrity in ten-1 mutants. In addition, phy-1 and ten-1 each genetically interact with genes encoding collagen IV. These findings support a functional mechanism in which loss of ten-1, together with a reduction of assembled and secreted basement membrane collagen IV protein, leads to detachment of the epidermis from muscle cells during late elongation of the embryo when mechanical stress is generated by muscle contractions. PMID- 21795396 TI - S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. AB - The calcium-binding protein S100A4 is a central mediator of metastasis formation in colon cancer. S100A4 is a target gene of the Wnt/beta-catenin pathway, which is constitutively active in the majority of colon cancers. In this study a high throughput screen was performed to identify small-molecule compounds targeting the S100A4-promoter activity. In this screen calcimycin was identified as a transcriptional inhibitor of S100A4. In colon cancer cells calcimycin treatment reduced S100A4 mRNA and protein expression in a dose- and time-dependent manner. S100A4-induced cellular processes associated with metastasis formation, such as cell migration and invasion, were inhibited by calcimycin in an S100A4-specific manner. Calcimycin reduced beta-catenin mRNA and protein levels despite the expression of Delta45-mutated beta-catenin. Consequently, calcimycin inhibited Wnt/beta-catenin pathway activity and the expression of prominent beta-catenin target genes such as S100A4, cyclin D1, c-myc, and dickkopf-1. Finally, calcimycin treatment of human colon cancer cells inhibited metastasis formation in xenografted immunodeficient mice. Our results demonstrate that targeting the expression of S100A4 with calcimycin provides a functional strategy to restrict cell motility in colon cancer cells. Therefore calcimycin may be useful for studying S100A4 biology, and these studies may serve as a lead for the development of treatments for colon cancer metastasis. PMID- 21795397 TI - An active kinase domain is required for retention of PKCtheta at the T cell immunological synapse. AB - Protein kinase Ctheta (PKCtheta) is a serine/threonine kinase that plays an essential role in antigen-regulated responses of T lymphocytes. Upon antigen stimulation, PKCtheta is rapidly recruited to the immunological synapse (IS), the region of contact between the T cell and antigen-presenting cell. This behavior is unique among T cell PKC isoforms. To define domains of PKCtheta required for retention at the IS, we generated deletion and point mutants of PKCtheta. We used quantitative imaging analysis to assess IS retention of PKCtheta mutants in antigen-stimulated T cell clones. Deletion of the kinase domain or site-directed mutation of a subset of known PKCtheta phosphorylation sites abrogated or significantly reduced IS retention, respectively. IS retention did not correlate with phosphorylation of specific PKCtheta residues but rather with kinase function. Thus PKCtheta catalytic competence is essential for stable IS retention. PMID- 21795398 TI - Caldesmon regulates actin dynamics to influence cranial neural crest migration in Xenopus. AB - Caldesmon (CaD) is an important actin modulator that associates with actin filaments to regulate cell morphology and motility. Although extensively studied in cultured cells, there is little functional information regarding the role of CaD in migrating cells in vivo. Here we show that nonmuscle CaD is highly expressed in both premigratory and migrating cranial neural crest cells of Xenopus embryos. Depletion of CaD with antisense morpholino oligonucleotides causes cranial neural crest cells to migrate a significantly shorter distance, prevents their segregation into distinct migratory streams, and later results in severe defects in cartilage formation. Demonstrating specificity, these effects are rescued by adding back exogenous CaD. Interestingly, CaD proteins with mutations in the Ca(2+)-calmodulin-binding sites or ErK/Cdk1 phosphorylation sites fail to rescue the knockdown phenotypes, whereas mutation of the PAK phosphorylation site is able to rescue them. Analysis of neural crest explants reveals that CaD is required for the dynamic arrangements of actin and, thus, for cell shape changes and process formation. Taken together, these results suggest that the actin-modulating activity of CaD may underlie its critical function and is regulated by distinct signaling pathways during normal neural crest migration. PMID- 21795399 TI - Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S preinitiation complex accumulation, while the pentose phosphate pathway is coordinately up-regulated. AB - Cellular stress can globally inhibit translation initiation, and glucose removal from yeast causes one of the most dramatic effects in terms of rapidity and scale. Here we show that the same rapid inhibition occurs during yeast growth as glucose levels diminish. We characterize this novel regulation showing that it involves alterations within the 48S preinitiation complex. In particular, the interaction between eIF4A and eIF4G is destabilized, leading to a temporary stabilization of the eIF3-eIF4G interaction on the 48S complex. Under such conditions, specific mRNAs that are important for the adaptation to the new conditions must continue to be translated. We have determined which mRNAs remain translated early after glucose starvation. These experiments enable us to provide a physiological context for this translational regulation by ascribing defined functions that are translationally maintained or up-regulated. Overrepresented in this class of mRNA are those involved in carbohydrate metabolism, including several mRNAs from the pentose phosphate pathway. Our data support a hypothesis that a concerted preemptive activation of the pentose phosphate pathway, which targets both mRNA transcription and translation, is important for the transition from fermentative to respiratory growth in yeast. PMID- 21795400 TI - Effects of integrin-mediated cell adhesion on plasma membrane lipid raft components and signaling. AB - Anchorage dependence of cell growth, which is mediated by multiple integrin regulated signaling pathways, is a key defense against cancer metastasis. Detachment of cells from the extracellular matrix triggers caveolin-1-dependent internalization of lipid raft components, which mediates suppression of Rho GTPases, Erk, and phosphatidylinositol 3-kinase in suspended cells. Elevation of cyclic adenosine monophosphate (cAMP) following cell detachment is also implicated in termination of growth signaling in suspended cells. Studies of integrins and lipid rafts, however, examined mainly ganglioside GM1 and glycosylphosphatidylinositol-linked proteins as lipid raft markers. In this study, we examine a wider range of lipid raft components. Whereas many raft components internalized with GM1 following cell detachment, flotillin2, connexin43, and Galpha(s) remained in the plasma membrane. Loss of cell adhesion caused movement of many components from the lipid raft to the nonraft fractions on sucrose gradients, although flotillin2, connexin43, and H-Ras were resistant. Galpha(s) lost its raft association, concomitant with cAMP production. Modification of the lipid tail of Galpha(s) to increase its association with ordered domains blocked the detachment-induced increase in cAMP. These data define the effects of that integrin-mediated adhesion on the localization and behavior of a variety of lipid raft components and reveal the mechanism of the previously described elevation of cAMP after cell detachment. PMID- 21795401 TI - Evidence for a fence that impedes the diffusion of phosphatidylinositol 4,5 bisphosphate out of the forming phagosomes of macrophages. AB - To account for the many functions of phosphatidylinositol 4,5-bisphosphate (PIP(2)), several investigators have proposed that there are separate pools of PIP(2) in the plasma membrane. Recent experiments show the surface concentration of PIP(2) is indeed enhanced in regions where phagocytosis, exocytosis, and cell division occurs. Kinases that produce PIP(2) are also concentrated in these regions. However, how is the PIP(2) produced by these kinases prevented from diffusing rapidly away? First, proteins could act as "fences" around the perimeter of these regions. Second, some factor could markedly decrease the diffusion coefficient, D, of PIP(2) within these regions. We used fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP) to investigate these two possibilities in the forming phagosomes of macrophages injected with fluorescent PIP(2). FCS measurements show that PIP(2) diffuses rapidly (D ~ 1 MUm(2)/s) in both the forming phagosomes and unengaged plasma membrane. FRAP measurements show that the fluorescence from PIP(2) does not recover (>100 s) after photobleaching the entire forming phagosome but recovers rapidly (~10 s) in a comparable area of membrane outside the cup. These results (and similar data for a plasma membrane-anchored green fluorescent protein) support the hypothesis that a fence impedes the diffusion of PIP(2) into and out of forming phagosomes. PMID- 21795402 TI - EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenic differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines. AB - Insulin-like growth factor-I (IGF-I) activates not only the phosphatidylinositol 3-kinase (PI3K)-AKT cascade that is essential for myogenic differentiation but also the extracellular signal-regulated kinase (ERK) 1/2 cascade that inhibits myogenesis. We hypothesized that there must be a signal that inhibits ERK1/2 upon cell-cell contact required for skeletal myogenesis. Cell-cell contact-induced engagement of ephrin ligands and Eph receptors leads to downregulation of the Ras ERK1/2 pathway through p120 Ras GTPase-activating protein (p120RasGAP). We therefore investigated the significance of the ephrin/Eph signal in IGF-I-induced myogenesis. EphrinA1-Fc suppressed IGF-I-induced activation of Ras and ERK1/2, but not that of AKT, in C2C12 myoblasts, whereas ephrinB1-Fc affected neither ERK1/2 nor AKT activated by IGF-I. IGF-I-dependent myogenic differentiation of C2C12 myoblasts was potentiated by ephrinA1-Fc. In p120RasGAP-depleted cells, ephrinA1-Fc failed to suppress the Ras-ERK1/2 cascade by IGF-I and to promote IGF I-mediated myogenesis. EphrinA1-Fc did not promote IGF-I-dependent myogenesis when the ERK1/2 was constitutively activated. Furthermore, a dominant-negative EphA receptor blunted IGF-I-induced myogenesis in C2C12 and L6 myoblasts. However, the inhibition of IGF-I-mediated myogenesis by down-regulation of ephrinA/EphA signal was canceled by inactivation of the ERK1/2 pathway. Collectively, these findings demonstrate that the ephrinA/EphA signal facilitates IGF-I-induced myogenesis by suppressing the Ras-ERK1/2 cascade through p120RasGAP in myoblast cell lines. PMID- 21795404 TI - Responsiveness of Goal Attainment Scaling in comparison to two standardized measures in outcome evaluation of children with cerebral palsy. AB - OBJECTIVES: To assess the responsiveness of Goal Attainment Scaling compared with the Pediatric Evaluation of Disability Inventory (PEDI) and the 66-item Gross Motor Function Measure (GMFM-66) in multidisciplinary rehabilitation practice. DESIGN: Observational study. Pretest-posttest design. SUBJECTS/PATIENTS: Twenty three children with cerebral palsy, aged 2-13 years. METHODS: Goal Attainment Scaling, PEDI and GMFM-66 assessments were performed before and after six months of treatment. Physical, occupational and speech therapists constructed and scored 6-point Goal Attainment Scaling scales meeting predetermined criteria, describing the main functional goal per discipline. The contents of the three measures were compared using International Classification of Functioning, Disability and Health child and youth version (ICF-CY) codes. Spearman's rho correlations between Goal Attainment Scaling change scores per discipline and change scores obtained with the PEDI functional skills scales and GMFM-66 were calculated. Complete goal attainment was compared with significant change in terms of the standardized measures. RESULTS: Twenty per cent of the Goal Attainment Scaling items were not covered by items of the PEDI or the GMFM-66. Inconclusive correlations were found between Goal Attainment Scaling and PEDI change scores (r 0.28-0.64). Even after exclusion of the non-corresponding items, correlations were moderate (r 0.57 0.73). Of 39/64 Goal Attainment Scaling scales scored as complete goal attainment, 16 individual PEDI scores did not show change on the corresponding scale. Low correlation was found between Goal Attainment Scaling change scores and GMFM-66 change scores. CONCLUSION: Goal Attainment Scaling, PEDI and GMFM-66 were complementary in their ability to measure individual change over time in children with cerebral palsy. Using only the standardized instruments could have caused many individual rehabilitation goals actually attained being missed in the outcome evaluation. PMID- 21795403 TI - GSK3beta inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb. AB - Glycogen synthase kinase 3beta (GSK3beta) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3beta kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3beta regulates the survival of leukemia cells. We demonstrate that upon GSK3beta kinase inhibition different types of leukemia cells show severe proliferation defects as a result of apoptosis. The transcription factor c-Myb is found to be the main target of GSK3beta inhibition in cell survival. GSK3beta inactivation reduces the expression of c-Myb by promoting its ubiquitination-mediated degradation, thereby inhibiting the expression of c-Myb-dependent antiapoptotic genes Bcl2 and survivin. Coimmunoprecipitation, reporter assays, chromatin immunoprecipitation, and knockdown studies show that c-Myb needs to interact and cooperate with transcription factor LEF-1 in the activation of Bcl2 and survivin and that both transcription factors are required for cell survival. These data reveal an as-yet unknown mechanism by which GSK3beta controls cell survival. PMID- 21795405 TI - Orientation and mobility training for partially-sighted older adults using an identification cane: a systematic review. AB - OBJECTIVE: This study aimed to provide an overview of the development, content, feasibility, and effectiveness of existing orientation and mobility training programmes in the use of the identification cane. DATA SOURCES: A systematic bibliographic database search in PubMed, PsychInfo, ERIC, CINAHL and the Cochrane Library was performed, in combination with the expert consultation (n = 42; orientation and mobility experts), and hand-searching of reference lists. REVIEW METHODS: Selection criteria included a description of the development, the content, the feasibility, or the effectiveness of orientation and mobility training in the use of the identification cane. Two reviewers independently agreed on eligibility and methodological quality. A narrative/qualitative data analysis method was applied to extract data from obtained documents. RESULTS: The sensitive database search and hand-searching of reference lists revealed 248 potentially relevant abstracts. None met the eligibility criteria. Expert consultation resulted in the inclusion of six documents in which the information presented on the orientation and mobility training in the use of the identification cane was incomplete and of low methodological quality. CONCLUSION: Our review of the literature showed a lack of well-described protocols and studies on orientation and mobility training in identification cane use. PMID- 21795406 TI - Foot posture after stroke: frequency, nature and clinical significance. AB - OBJECTIVES: Clinical convention suggests that foot posture and movements are adversely affected by stroke and cause walking difficulties but there is little objective data to support or refute these beliefs. This study explores static foot posture in people with stroke and their relationship to weakness and spasticity and walking limitations. DESIGN: Cross-sectional survey. SETTING: Stroke services and support groups of two acute hospitals. SUBJECTS: Seventy-two stroke survivors with mobility limitations. MAIN MEASURES: Foot Posture Index; Demographics; Motricity Index (weakness); modified Ashworth Scale (spasticity); Walking Handicap Scale (walking limitations). RESULTS: About one-third of participants had abnormal foot posture on the weak side, which was associated with walking limitations. Most (70%) had a symmetrical foot posture with similar frequencies of supination (13%) and pronation (16%) abnormalities. There was no relationship between foot posture and weakness and spasticity; age was the only independent predictor of foot posture abnormalities. CONCLUSIONS: A minority of people with stroke had abnormal or asymmetrical foot posture and equal numbers suffered pronation and supination abnormalities; these findings challenge the beliefs that underpin the clinical management of stroke-related foot problems. PMID- 21795407 TI - Metrological traceability in clinical biochemistry. AB - True and precise routine measurements of quantities of clinical interest are essential if results are to be optimally interpreted for patient care. Additionally, results produced by different measurement procedures for the same measurand must be comparable if common diagnostic decision values and clinical research findings are to be broadly applied. Metrology, the science of measurement, provides laboratory medicine with a structured approach to the development and terminology of reference measurement systems which, when implemented, improve the accuracy and comparability of patients' results. The metrological approach is underpinned by the concepts of common measurement units, traceability of measured values, measurement uncertainty and commutability. Where traceability to the International System of Units (SI units) is not yet realized for a measurand, result comparability may be achievable by other, less ideal, approaches. Measurements are the core activity of clinical laboratories, and clinical biochemists should ensure that patients' results are traceable to the highest available reference. This review introduces and illustrates the principles of metrological traceability, describes its critical importance to improving the quality of patients' results and highlights the need to actively promote traceability in clinical laboratories. PMID- 21795408 TI - Interference in the autoDELFIA(R) hAFP immunoassay and effect on second-trimester Down's syndrome screening. AB - BACKGROUND: Falsely decreased serum alphafetoprotein (AFP) concentrations are reported in the autoDELFIA((r)) hAFP immunoassay due to interference by complement. AFP is measured, using this assay, as part of second-trimester and integrated Down's syndrome screening tests. Decreased AFP concentrations increase the calculated risk of Down's syndrome; therefore falsely low AFP, due to assay interference, may artificially increase a patient's risk, and have the potential to cause false screen positive results. It was our aim to assess whether negative interference in the autoDELFIA((r)) hAFP assay was a cause of very low AFP concentrations, and to examine the effect of falsely decreased concentrations on the calculated risk of Down's syndrome. METHODS: Three hundred and twenty-three sequential Down's screening serum samples with very low serum AFP concentration (<15 KU/L) using the autoDELFIA((r)) hAFP immunoassay were selected and AFP re measured using the E170 AFP immunoassay. RESULTS: Interference was detected in nine samples (from eight patients) on the basis of discordant AFP concentrations. The interference decreased following storage of samples at 4 degrees C to deplete complement. Use of the falsely low AFP concentrations to calculate risk of Down's syndrome resulted in significantly increased calculated risk compared with complement depleted results. CONCLUSIONS: Laboratories should be aware that falsely low AFP concentrations due to complement interference may be obtained using the autoDELFIA((r)) hAFP immunoassay. We have shown that falsely low AFP concentrations increase the calculated risk of Down's syndrome. This is a potential cause of false Down's syndrome screen positive results. PMID- 21795410 TI - The role of SmpB and the ribosomal decoding center in licensing tmRNA entry into stalled ribosomes. AB - In bacteria, stalled ribosomes are recycled by a hybrid transfer-messenger RNA (tmRNA). Like tRNA, tmRNA is aminoacylated with alanine and is delivered to the ribosome by EF-Tu, where it reacts with the growing polypeptide chain. tmRNA entry into stalled ribosomes poses a challenge to our understanding of ribosome function because it occurs in the absence of a codon-anticodon interaction. Instead, tmRNA entry is licensed by the binding of its protein partner, SmpB, to the ribosomal decoding center. We analyzed a series of SmpB mutants and found that its C-terminal tail is essential for tmRNA accommodation but not for EF-Tu activation. We obtained evidence that the tail likely functions as a helix on the ribosome to promote accommodation and identified key residues in the tail essential for this step. In addition, our mutational analysis points to a role for the conserved K(131)GKK tail residues in trans-translation after peptidyl transfer to tmRNA, presumably EF-G-mediated translocation or translation of the tmRNA template. Surprisingly, analysis of A1492, A1493, and G530 mutants reveals that while these ribosomal nucleotides are essential for normal tRNA selection, they play little to no role in peptidyl transfer to tmRNA. These studies clarify how SmpB interacts with the ribosomal decoding center to license tmRNA entry into stalled ribosomes. PMID- 21795411 TI - Oriented texture detection: ideal observer modelling and classification image analysis. AB - Perception of visual texture flows contributes to object segmentation, shape perception, and object recognition. To better understand the visual mechanisms underlying texture flow perception, we studied the factors limiting detection of simple forms of texture flows composed of local dot dipoles (Glass patterns) and related stimuli. To provide a benchmark for human performance, we derived an ideal observer for this task. We found that human detection thresholds were 8.0 times higher than ideal. We considered three factors that might account for this performance gap: (1) false matches between dipole dots (correspondence errors), (2) loss of sensitivity with increasing eccentricity, and (3) local orientation bandwidth. To estimate the effect of correspondence errors, we compared detection of Glass patterns with detection of matched line-segment stimuli, where no correspondence uncertainty exists. We found that eliminating correspondence errors reduced human thresholds by a factor of 1.8. We used a novel form of classification image analysis to directly estimate loss of sensitivity with eccentricity and local orientation bandwidth. Incorporating the eccentricity effects into the ideal observer model increased ideal thresholds by a factor of 2.9. Interestingly, estimated orientation bandwidth increased ideal thresholds by only 8%. Taking all three factors into account, human thresholds were only 58% higher than model thresholds. Our findings suggest that correspondence errors and eccentricity losses account for the great majority of the perceptual loss in the visual processing of Glass patterns. PMID- 21795409 TI - Interleukin-6 as a therapeutic target in human ovarian cancer. AB - PURPOSE: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. EXPERIMENTAL DESIGN: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. RESULTS: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6 producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. CONCLUSION: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. PMID- 21795412 TI - The structure of face--space is tolerant to lighting and viewpoint transformations. AB - According to the face-space framework, faces are represented as locations in a multidimensional space, where the distance separating representations is proportional to the degree of dissimilarity between faces. The present study tested whether similarities between faces, and thus the structure of face-space, were tolerant to ("invariant" under) identity-preserving transformations such as changes in lighting or view. To examine the correspondence between the configurations of face-space under different transformations, perceived similarity was rated for two variants of a set of faces, differing either in illumination (Experiment 1) or viewpoint (Experiment 2). We found that similarity ratings within the first variant were highly correlated with ratings within the second variant. In addition, based on these ratings, a separate face-space was constructed for each variant using multidimensional scaling. Procrustean analysis revealed that the different spaces shared comparable structures. This correspondence serves as a face-space manifestation of the tolerance of identity representations. Accordingly, we suggest that tolerance may rely on the fact that similarities between faces under one transformation are isomorphic to similarity patterns under a different transformation. Thus, recognizing faces under varying viewing conditions may only require similarity evaluations within--rather than across--different transformations. PMID- 21795414 TI - Internal snaring of the caval veins by Foley catheters in case of reoperation via right thoracotomy. AB - Use of the Foley catheter has been described in cardiac surgery over a wide range of applications. In recent years, the interest in minimally-invasive surgery has increased, providing several advantages in terms of mortality and morbidity. Unfortunately, challenging situations, such as re-do surgery may be encountered, and innovative strategies to reduce the invasiveness of the surgical approach need to be developed. External snaring of the caval veins in re-do patients is hazardous when a minimally-invasive approach is used because the tissues are usually fragile and sudden bleeding can be difficult to control. We propose a simple strategy using Foley catheters to provide 'internal snaring' of both caval veins, avoiding surgical dissection of the adhesions around the vessels. Three re do patients were operated on for combined mitral/tricuspid surgery using internal snaring: the occlusion of the veins was satisfactory in all cases, with no complications reported so far. Even though the 'trick' described is not spectacular, it might be very helpful to be prepared to use this technique either on a routine basis or in special situations when the risk of injury to the atrial or caval structures appears to be increased. PMID- 21795413 TI - The safe use of spinal drains in thoracic aortic surgery. AB - Paraplegia is a devastating complication which may occur following surgery on the thoracic aorta. The use of a cerebrospinal fluid drain (CSFD) has helped reduce the incidence of neurological deficit; however, the management of patients with a CSFD postsurgery requires nurses and doctors to have expertise and awareness of the associated complications. The National Patient Safety Agency (UK) has highlighted a number of cases involving inadvertent spinal injections throughout the UK National Health Service (NHS). To this end we have introduced a protocol or 'care bundle' for safe CSFD care as well as drain management. The protocol was developed by medical and nursing staff at our institution based on clinical experience and literature reviews over a two-year period (2008-2010). Interventions undertaken during the development of the protocol included discussion with the UK National Patient Safety Agency (NPSA). Content of the protocol was reviewed by internal regulatory bodies within the hospital prior to ratification and general dissemination. Clear guidance is given within the policy on the standards expected when caring for the line and managing drainage according to agreed parameters of spinal cord perfusion pressure. The protocol constitutes five documents which guide staff in the care of CSFD, its routine management, documentation and interventions necessary once neurological deficit is detected. Document 1 which is a checklist, communication tool and aide-memoire was developed to ensure effective management, when the patient arrives in intensive care unit (ICU) from theatre. Document 2 ensures that early detection of a neurological deficit is noted and with Document 3 is acted upon immediately to reverse the injury. Document 4 provides information on the safe administration of analgesia via the spinal drain and has reference to the Glasgow Coma Scale. Document 5 is a bespoke observation chart for documenting CSFD pressure and cerebrospinal fluid drainage. In conclusion, the protocol acts as a guide for safe management of the CSFD and directs staff in reacting to detection of neurological deficit. PMID- 21795415 TI - European (IUSTI/WHO) guideline on the management of vaginal discharge, 2011. AB - Three common infections are associated with vaginal discharge: bacterial vaginosis, trichomoniasis and candidiasis, of which trichomoniasis is a sexually transmitted infection (STI). This guideline covers the presentation and clinical findings of these infections and outlines the differential diagnoses. Recommendations for investigation and management based on currently available evidence are made, including the management of persistent and recurrent infections. PMID- 21795416 TI - Patient-derived outcome measures for HIV services in the developed world: a systematic review. AB - This review sought to establish the themes and approaches used in the measurement of patient satisfaction regarded by HIV service users as crucial to improving service quality. It also investigated how feedback has been measured previously and whether a gold standard instrument exists that is generalizable across HIV inpatient and clinic settings. Twelve databases and other sources yielded 1474 titles. Using a clinically-focused question and pre-defined inclusion and exclusion criteria, 32 articles were retrieved and reviewed for quality using a quality appraisal checklist. Two reviewers used a data extraction form to identify and verify key patient experiences. Thematic analysis revealed that clinic staffs' current knowledge of HIV was an essential factor in positive feedback. Treating patients with dignity and respecting their autonomy and confidentiality were also important. Developments in treatment, extended life expectancy and quality of life have altered patients' experience and level of satisfaction. Three instruments developed to assess patient satisfaction with HIV care were identified but there was no gold standard method of measuring it. There is a need to develop a specific, valid instrument that is easy to complete and analyse, and the data should be used to inform the redesign of services to promote a dynamic model of care. PMID- 21795417 TI - Asking about condom use: a key to individualized care when screening for chlamydia. AB - Chlamydia trachomatis (CT) infection has been a target for both selective and national screening programmes, and Sweden has an opportunistic approach. A national plan of action states that risk groups should be identified and offered risk reduction counselling. Patients attending a drop-in sexually transmitted infection (STI) clinic reception at the University Hospital, Umea, Sweden, were invited to complete a questionnaire regarding sociodemographic characteristics, symptoms and sexual risk behaviour; all had a CT test taken. A total of 1305 patients were included, 58% men, mean age 27.8 years. CT prevalence was 11%; 51% of those with CT were >= 25 years old. Only 5% used a condom during the entire sexual intercourse with their last new/temporary partner. Sexually active inconsistent condom users comprised 62% of the study population and contributed to 81% of the chlamydia infections. Asking whether a condom was used could quickly triage patients into groups with a 'higher risk' (none or inconsistent use of condoms and at least one new/temporary partners), and 'lower risk' (with more consistent condom use, although not always accurate) allowing for individualized care and counselling when screening for chlamydia. Evaluating whether a condom was used throughout the sexual intercourse did not add any useful information. PMID- 21795418 TI - Abnormalities in body composition and nutritional status in HIV-infected children and adolescents on antiretroviral therapy. AB - This cross-sectional study aimed to compare growth, nutritional status and body composition outcomes between a group of 94 HIV-infected children and adolescents on antiretroviral therapy (ART) and 364 healthy controls, and to evaluate their association with clinical and lifestyle variables within the HIV-infected group. When compared with the control group, HIV patients had higher risk of stunting (odds ratio [OR] 5.33, 95% confidence interval [CI]: 2.83-10.04) and thinness (OR 4.7, 95% CI: 2.44-9.06), higher waist-to-hip ratios (medians 0.89 versus 0.82 for boys and 0.90 versus 0.77 for girls, P < 0.001), and lower prevalence of overweight or obesity (OR 0.33, 95% CI: 0.14-0.78). Protease inhibitor usage was associated with thinness (OR 3.51, 95% CI 1.07-11.44) and lipoatrophy (OR 3.5, 95% CI 1.37-8.95). HIV-infected children on ART showed significant nutritional status and body composition abnormalities, consistent with the severity of vertical HIV infection and the consequences of prolonged ART. PMID- 21795419 TI - The prevalence of renal impairment among adults with early HIV disease in Blantyre, Malawi. AB - We determined the prevalence of renal impairment and possible HIV-associated nephropathy (HIVAN) in adults with World Health Organization (WHO) stages I or II HIV, presenting to the antiretroviral therapy (ART) clinic in a central hospital in Malawi. We enrolled 526 ART-naive subjects, 67% women, median age 34 (17-73) years and mean CD4 count 305 (3-993) cells/MUL. Blood pressure, weight, urine dipstick and microscopy, CD4 cell count and serum creatinine were measured. Creatinine clearance (CrCL) was estimated using the Cockcroft-Gault equation. Possible HIVAN was diagnosed based on levels of proteinuria and CrCl. In all, 23.3% had proteinuria (>= 1+). 57.4% had reduced CrCl (< 90 mL/minute): 18.8% had moderate (CrCl 30-59 mL/minute) and 2.2% severe (CrCl <30 mL/minute) renal dysfunction. Extrapolating from renal biopsy studies that confirmed HIVAN, the proportion of patients with HIVAN in our clinic ranges from 1.8-21.2%. We conclude that renal impairment was common, though rarely severe, among HIV infected adults with clinically non-advanced HIV disease. Renal dysfunction has been demonstrated to be a risk factor for (early) mortality. These results are relevant for ART programmes, such as those in Malawi, where renal function is not routinely assessed. PMID- 21795420 TI - In-hospital mortality rates and HIV: a medical ward review, Lilongwe, Malawi. AB - In order to determine inpatient hospital mortality rates, causes of mortality and characteristics of inpatients at Kamuzu Central Hospital (KCH) in Lilongwe, Malawi, we conducted a prospective observational study of all patients admitted to KCH medical ward from 20 September 2008 to April 2, 2009. All admission diagnoses, HIV status and antiretroviral therapy (ART) use were recorded. Patients' vital status was determined at discharge. A descriptive analysis and two logistic regression models were used for the analysis. Of the 1895 enrolled patients, the overall hospital mortality rate was 14.6%, substantially higher among known HIV-infected patients (24.2% versus 10.8%, P = 0.0009) and men (17.1% versus 12%, P = 0.033). Patients with multiple diagnoses had significantly higher mortality (odds ratio [OR] 2.33; 95% confidence interval [CI] 1.47, 3.71). Most patients (62.3%) had unknown HIV status at admission. Among HIV-infected patients, ART use did not reduce hospital mortality or alter the spectrum of diseases. The majority of diagnoses were infectious (63.4%). The high inpatient mortality rate, especially among HIV-infected patients combined with the limited spectrum of diagnoses, emphasizes the need for improved inpatient management and diagnostic services. Expansion of HIV testing is warranted. Despite the rollout of ART, there remains a significant need for treatment of HIV-infected individuals. PMID- 21795421 TI - Finding cases of Trichomonas vaginalis infection in England. AB - We describe the use of a new molecular assay for Trichomonas vaginalis (TV), the Gen-Probe Aptima TV (ATV) in female attendees at community clinics, a genitourinary (GU) medicine clinic and a prison GU medicine service. Positivity rates at community clinics and GU medicine were 0/382 (0%) and 3/358 (0.8%, 95% confidence interval [CI] 0-1.7%), respectively. Positivity was significantly higher, 29/269 (10.8%, 95% CI 7.1-14.5%), odds ratio (OR) 14.3 (4.11 < OR < 59.55), in those tested at the prison. A questionnaire survey of English GU medicine clinics and data from the UK Health Protection Agency (HPA) for England both demonstrated the large variation in case rates by region and testing methods employed. Higher rates were seen in women, in prison GU medicine services and in London GU medicine clinics. The ATV assay is now CE-marked (Conformite Europeenne) and so a larger prospective study of its potential application is warranted. PMID- 21795422 TI - Exercise after diagnosis of breast cancer in association with survival. AB - It has been suggested that exercise following breast cancer diagnosis is inversely associated with mortality. However, controversy exists regarding the causality of such associations. We evaluated associations of exercise after breast cancer diagnosis with total mortality and recurrence/disease-specific mortality, accounting for conditions that restrict exercise participation. The analysis included 4,826 women with stage I to III breast cancer identified 6 months after diagnosis through the population-based Shanghai Cancer Registry and recruited into the study between 2002 and 2006. Exercise was assessed approximately 6, 18, and 36 months postdiagnosis, and metabolic equivalent (MET) scores were derived. Information on medical history, cancer diagnosis, treatments, quality of life (QOL), anthropometrics, and lifestyles were obtained by in-person interviews at 6 months postdiagnosis. Medical charts were abstracted to verify clinical information. During the median follow-up of 4.3 years, 436 deaths and 450 recurrences/cancer-related deaths were documented. After adjustment for QOL, clinical prognostic factors, and other covariates, exercise during the first 36 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with HRs of 0.70 (95% CI: 0.56-0.88) and 0.60 (95% CI: 0.47-0.76), respectively. Significant dose-response relationships between total and recurrence/disease-specific mortality rates and exercise duration and MET scores were observed (all values for P(trend) < 0.05). The exercise-mortality associations were not modified by menopausal status, comorbidity, QOL, or body size assessed at approximately 6 months postdiagnosis. An interaction between disease stage and hormone receptor status and total mortality was noted. Our study suggests that exercise after breast cancer diagnosis may improve overall and disease-free survival. PMID- 21795423 TI - Copy number imbalances between screen- and symptom-detected breast cancers and impact on disease-free survival. AB - Screening mammography results in the increased detection of indolent tumors. We hypothesized that screen- and symptom-detected tumors would show genotypic differences as copy number imbalances (CNI) that, in part, explain differences in the clinical behavior between screen- and symptom-detected breast tumors. We evaluated 850 women aged 40 and above diagnosed with stage I and II breast cancer at the University of Texas MD Anderson Cancer Center between 1985 and 2000 with information available on method of tumor detection (screen vs. symptoms). CNIs in screen- and symptom-detected tumors were identified using high-density molecular inversion probe arrays. Cox proportional modeling was used to estimate the effect of method of tumor detection on disease-free survival after adjusting for age, stage, and the CNIs. The majority of tumors were symptom detected (n = 603) compared with screen detected (n = 247). Copy number gains in chromosomes 2p, 3q, 8q, 11p, and 20q were associated with method of breast cancer detection (P < 0.00001). We estimated that 32% and 63% of the survival advantage of screen detection was accounted for by age, stage, nuclear grade, and Ki67 in women aged 50 to 70 and aged 40 to 87, respectively. In each age category, an additional 20% of the survival advantage was accounted for by CNIs associated with method of detection. Specific CNIs differ between screen- and symptom-detected tumors and explain part of the survival advantage associated with screen-detected tumors. Measurement of tumor genotype has the potential to improve discrimination between indolent and aggressive screen-detected tumors and aids patient and physician decision making about use of surgical and adjuvant treatments. PMID- 21795425 TI - Genetic variation in myeloperoxidase modifies the association of serum alpha tocopherol with aggressive prostate cancer among current smokers. AB - We investigated associations of serum alpha- and gamma-tocopherols and their effect modification by polymorphisms in oxidative stress regulatory enzymes in relation to prostate cancer risk. In a nested case-control study in the Carotene and Retinol Efficacy Trial, prerandomized serum alpha- and gamma-tocopherol were assayed among 684 men with incident prostate cancer [375 nonaggressive and 284 aggressive cancer (stage III/IV or Gleason score >=7)] and 1441 controls. Manganese superoxide dismutase Ala-16Val (rs4880), glutathione peroxidase 1 Pro200Leu (rs1050450), catalase -262 C > T (rs1001179), and myeloperoxidase (MPO) G-463A (rs2333227) were genotyped. A multivariate-adjusted inverse association of serum alpha-tocopherol with total prostate cancer risk was observed in current smokers (OR = 0.62, 95% CI = 0.40-0.96, 4th vs. 1st quartiles). High (>=median) compared to low serum concentrations of alpha- and gamma-tocopherol were inversely associated with aggressive prostate cancer in current smokers (OR = 0.50, 95% CI = 0.32-0.78 and OR = 0.64, 95% CI = 0.43-0.95, respectively). The association was stronger among those with MPO G/A+A/A genotypes. Among current smokers with low serum alpha-tocopherol concentrations, MPO G/A+A/A, the genotypes downregulating oxidative stress, were associated with an increased risk for aggressive prostate cancer (OR = 2.06, 95% CI = 1.22-3.46). Conversely, current smokers with these genotypes who had high alpha-tocopherol concentrations had a reduced risk for aggressive prostate cancer (OR = 0.34, 95% CI = 0.15-0.80; P-interaction = 0.001). In conclusion, among current smokers, both high serum alpha- and gamma-tocopherol concentrations were associated with reduced risks of aggressive prostate cancer. The alpha-tocopherol-associated risks are modified by polymorphism in MPO G-463A. PMID- 21795424 TI - Phenylbutyl isoselenocyanate modulates phase I and II enzymes and inhibits 4 (methylnitrosamino)-1-(3-pyridyl)- 1-butanone-induced DNA adducts in mice. AB - Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 MUmol ISC-4 resulted in a time dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung, it inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent. PMID- 21795427 TI - Food insecurity is associated with diet and bone mass disparities in early adolescent males but not females in the United States. AB - Food insecurity is associated with decreased nutrient intake and poor health and possibly low bone mass in children. The purpose of this study was to formally investigate the relationship of diet, bone mass, and food insecurity among children aged 8-19 y (n = 5270). The data used in this cross-sectional study were drawn from children participating in the NHANES 2001-2004. Data were collected from homes and NHANES mobile examination centers across the United States. Food security status was classified using the US Children's Food Security Scale and the US Household Food Security Scale. Dietary measures were quantified by 24-h dietary recall and bone mineral content (BMC) was determined with whole body DXA. Results indicated that males 8-11 y from households with food insecurity among children were 2.5 times [OR = 2.5 (95% CI = 1.1-5.8)] more likely to have fewer than the USDA Food Guide recommended servings of dairy foods, 2.3 times [OR = 2.3 (95% CI = 1.3-4.0)] more likely to have less than the estimated average requirement for calcium intake, and more likely to have a significantly lower estimated total body (P = 0.04), trunk (P = 0.05), lumbar spine (P = 0.02), pelvis (P = 0.05), and left arm (P = 0.05) BMC compared with males 8-11 y old from households with food security among children. Calcium-related dietary factors and BMC did not differ among females by food security status. These results are evidence that health disparities persist among 8- to 11-y-old, food insecure boys. Successful interventions to improve diet and bone health and reduce food insecurity among children are a continuing need in the United States. PMID- 21795426 TI - The selenium deficiency disease exudative diathesis in chicks is associated with downregulation of seven common selenoprotein genes in liver and muscle. AB - Fast-growing broiler chicks are susceptible to Se deficiency diseases including exudative diathesis (ED). Our objective was to determine if ED could be induced by feeding a current, practical diet and if the incidence was related to selenogenome expression in liver and muscle of chicks. Four groups of day-old broiler chicks (n = 60/group) were fed a corn-soy basal diet (BD; 14 MUg Se/kg; produced in the Se-deficient area of Sichuan, China and not supplemented with Se or vitamin E), the BD and all-rac-alpha-tocopheryl acetate at 50 mg/kg and Se (as sodium selenite) at 0.3 mg/kg, or both of these nutrients for 6 wk. A high incidence of ED and mortality of chicks were induced by the BD. The incidences and mortality were completely prevented by supplemental dietary Se but were only partially decreased by supplemental alpha-tocopherol acetate. Dietary Se deficiency decreased (P < 0.05) mRNA levels of 7 common selenoprotein genes (Gpx1, Gpx4, Sepw1, Sepn1, Sepp1, Selo, and Selk) in muscle and liver. Whereas supplementing alpha-tocopherol acetate enhanced (P < 0.05) only the muscle Sepx1 mRNA level, it actually decreased (P < 0.05) hepatic Gpx1, Seli, Txnrd1, and Txnrd2 mRNA levels. In conclusion, dietary Se protected chicks from the Se deficiency disease ED, probably by upregulating selenoprotein genes coding for oxidation- and/or lesion-protective proteins. The protection by vitamin E might be mediated via selenoproteins not assayed in this study and/or Se-independent mechanisms. The inverse relationship between hepatic expression of 4 redox related selenoprotein genes and vitamin E status revealed a novel interaction between Se and vitamin E in vivo. PMID- 21795428 TI - Oxidation of dietary stearic, oleic, and linoleic acids in growing pigs follows a biphasic pattern. AB - We used the pig as a model to assess the effects of dietary fat content and composition on nutrient oxidation and energy partitioning in positive energy balance. Pigs weighing 25 kg were assigned to either: 1) a low fat-high starch diet, or 2) a high saturated-fat diet, or 3) a high unsaturated-fat diet. In the high-fat treatments, 20% starch was iso-energetically replaced by 10.8% lard or 10.2% soybean oil, respectively. For 7 d, pigs were fed twice daily at a rate of 1200 kJ digestible energy . kg(-0.75) . d(-1). Oral bolus doses of [U-(13)C] glucose, [U-(13)C] alpha-linoleate, [U-(13)C] stearate, and [U-(13)C] oleate were administered on d 1, 2, 4, and 6, respectively, and (13)CO(2) production was measured. Protein and fat deposition were measured for 7 d. Fractional oxidation of fatty acids from the low-fat diet was lower than from the high-fat diets. Within diets, the saturated [U-(13)C] stearate was oxidized less than the unsaturated [U-(13)C] oleate and [U-(13)C] linoleate. For the high unsaturated fat diet, oxidation of [U-(13)C] oleate was higher than that of [U-(13)C] linoleate. In general, recovery of (13)CO(2) from labeled fatty acids rose within 2 h after ingestion but peaked around the next meal. This peak was induced by an increased energy expenditure that was likely related to increased eating activity. In conclusion, oxidation of dietary fatty acids in growing pigs depends on the inclusion level and composition of dietary fat. Moreover, our data suggest that the most recently ingested fatty acids are preferred substrates for oxidation when the direct supply of dietary nutrients has decreased and ATP requirements increase. PMID- 21795429 TI - Substituting white rice with brown rice for 16 weeks does not substantially affect metabolic risk factors in middle-aged Chinese men and women with diabetes or a high risk for diabetes. AB - Epidemiologic studies have suggested that higher consumption of white rice (WR) is associated with increased risk for type 2 diabetes mellitus. However, it is unclear whether substituting brown rice (BR) for WR can improve metabolic risk factors. A total of 202 middle-aged adults with diabetes or a high risk for diabetes were randomly assigned to a WR (n = 101) or BR group (n = 101) and consumed the rice ad libitum for 16 wk. Metabolic risk markers, including BMI, waist circumference, blood pressure, glycated hemoglobin, and serum lipid, glucose, and insulin concentrations were measured before and after the intervention. Over the course of the intervention, no between-group differences were found for any markers except the serum LDL cholesterol concentration, which decreased more in the WR group compared to the BR group (P = 0.02). However, this effect was observed only among participants with diabetes (n = 47). The reversion rate of reduced serum HDL cholesterol was marginally higher in the BR group (14.9%) than in the WR group (6.9%) (P = 0.07). Among participants with diabetes, a greater reduction in diastolic blood pressure was observed in the BR group compared to the WR group (P = 0.02). Our study suggests that incorporating BR into the daily diet for 16 wk did not substantially improve metabolic risk factors. Further studies with larger sample sizes, longer durations of follow-up, and different varieties of rice are needed to carefully examine the role of BR in the prevention and management of diabetes. PMID- 21795430 TI - Calcium does not inhibit the absorption of 5 milligrams of nonheme or heme iron at doses less than 800 milligrams in nonpregnant women. AB - Calcium is the only known component in the diet that may affect absorption of both nonheme and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses >=1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme (as sulfate) and heme (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. PMID- 21795431 TI - Neoplastic meningitis from solid tumors: new diagnostic and therapeutic approaches. AB - Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%-15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography-computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches. PMID- 21795432 TI - A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer. AB - PURPOSE: For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC. METHODS: Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily. RESULTS: Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty-seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab-based therapy. Forty-nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for >=6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1-2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade >=3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%). CONCLUSIONS: Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients. PMID- 21795433 TI - Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. AB - Chymase is activated after acute myocardial ischemia/reperfusion (AMI-R) and is associated with an early activation of matrix metalloproteinase-9 (MMP-9), which increases infarct size after experimental AMI, and late fibrosis. We assessed the effect of chymase inhibition on myocardial protection and early signs of fibrosis after AMI-R. Fourteen pigs underwent AMI-R and received intravenously either vehicle (V; n = 7) or chymase inhibitor (CM; n = 7). Separately, rat myocardial fibroblast was incubated with vehicle (n = 4), low-dose chymase (n = 4), high dose chymase (n = 4), or high-dose chymase plus chymase inhibitor (n = 4). Infarct size (V, 41 +/- 5; CM, 24 +/- 5; P < 0.01) and serum troponin T (P = 0.03) at the end of reperfusion were significantly reduced in CM. Chymase activity in both the area at risk (AAR) (P = 0.01) and nonischemic area (P = 0.02) was significantly lower in CM. Myocardial levels of pro, cleaved, and cleaved/pro-MMP-9 in the AAR were significantly lower in CM than V (P < 0.01, < 0.01, and = 0.02, respectively), whereas phospho-endothelial nitric-oxide synthase (eNOS) (P < 0.01) and total eNOS (P = 0.03) were significantly higher in CM. Apoptotic cells (P = 0.05), neutrophils (P < 0.05), and MMP-9-colocalizing mast cells (P < 0.05) in the AAR were significantly reduced in CM. Interleukin-18 (P < 0.05) and intercellular adhesion molecule-1 (P < 0.05) mRNA levels were significantly lower in CM. In cultured cardiac fibrosis, Ki-67-positive cells were significantly higher in the high-dose chymase groups (P < 0.03). This study demonstrates that chymase inhibition plays crucial roles in myocardial protection related to MMP-9, inflammatory markers, and the eNOS pathway. It may also attenuate fibrosis induced by activated chymase after AMI-R. PMID- 21795434 TI - Bromoenol lactone inhibits voltage-gated Ca2+ and transient receptor potential canonical channels. AB - Circulating hormones stimulate the phospholipase Cbeta (PLC)/Ca(2+) influx pathway to regulate numerous cell functions, including vascular tone. It was proposed previously that Ca(2+)-independent phospholipase A(2) (iPLA(2)) dependent store-operated Ca(2+) influx channels mediate hormone-induced contractions in isolated arteries, because bromoenol lactone (BEL), a potent irreversible inhibitor of iPLA(2), inhibited such contractions. However, the effects of BEL on other channels implicated in mediating hormone-induced vessel contractions, specifically voltage-gated Ca(2+) (Ca(V)1.2) and transient receptor potential canonical (TRPC) channels, have not been defined clearly. Using isometric tension measurements, we found that thapsigargin-induced contractions were ~34% of those evoked by phenylephrine or KCl. BEL completely inhibited not only thapsigargin- but also phenylephrine- and KCl-induced ring contractions, suggesting that Ca(V)1.2 and receptor-operated TRPC channels also may be sensitive to BEL. Therefore, we investigated the effects of BEL on heterologously expressed Ca(V)1.2 and TRPC channels in human embryonic kidney cells, a model system that allows probing of individual protein function without interference from other signaling elements of native cells. We found that low micromolar concentrations of BEL inhibited Ca(V)1.2, TRPC5, TRPC6, and heteromeric TRPC1 TRPC5 channels in an iPLA(2)-independent manner. BEL also attenuated PLC activity, suggesting that the compound may inhibit TRPC channel activity in part by interfering with an initial PLC-dependent step required for TRPC channel activation. Conversely, BEL did not affect endogenous voltage-gated K(+) channels in human embryonic kidney cells. Our findings support the hypothesis that iPLA(2) dependent store-operated Ca(2+) influx channels and iPLA(2)-independent hormone operated TRPC channels can serve as smooth muscle depolarization triggers to activate Ca(V)1.2 channels and to regulate vascular tone. PMID- 21795435 TI - Effects of an enteral glucose supply on protein synthesis, proteolytic pathways, and proteome in human duodenal mucosa. AB - BACKGROUND: Previous studies have shown that the glucose supply reduces postoperative insulin resistance and improves patient outcomes. However, the effects of luminal glucose on intestinal mucosal proteins remain unknown. OBJECTIVE: We aimed to assess the effects of an enteral glucose supply on protein synthesis, proteolytic pathways, and proteome in human duodenal mucosa. DESIGN: Twenty healthy volunteers received a 5-h enteral infusion of either saline or glucose (0.12 g . kg(-1) . h(-1)). Simultaneously, a continuous intravenous infusion of l-[1-(13)C]leucine (12 MUmol . kg(-1) . h(-1)) was maintained until endoscopy. The duodenal mucosal protein fractional synthesis rate (FSR) was calculated from leucine enrichments assessed in protein and free amino acid pools by gas chromatography-mass spectrometry. Cathepsin D, calpains, and chymotrypsin like proteasome mucosal activities were evaluated by using specific fluorogenic substrates. A 2-dimensional PAGE-based comparative proteomics analysis was also performed on additional duodenal mucosal biopsy samples to identify differentially expressed proteins. RESULTS: Duodenal mucosal protein FSR and protease activities were not affected by glucose infusion relative to saline. Nevertheless, the comparative proteomics analysis indicated that 10 protein spots were significantly differentially expressed (ie, at least +/-1.5-fold modulated; Student's t test, P < 0.05) in response to the glucose infusion relative to saline. Of the 8 proteins identified by mass spectrometry, alpha-enolase, cytoplasmic aconitate hydratase, and glutathione S-transferase omega-1 were upregulated, whereas epoxide hydrolase 2 was downregulated. CONCLUSION: Enteral glucose supply affected neither duodenal mucosal protein FSR nor activities of mucosal proteases but altered the duodenal mucosal proteome by modulating the expression of several enzymes involved mainly in carbohydrate and xenobiotic metabolism. This trial is registered at clinicaltrials.gov as NCT00213551. PMID- 21795436 TI - Effects of sleep fragmentation in healthy men on energy expenditure, substrate oxidation, physical activity, and exhaustion measured over 48 h in a respiratory chamber. AB - BACKGROUND: Epidemiologic studies show an inverse or U-shaped relation between sleep duration and BMI. Decreases in total energy expenditure (TEE) and physical activity have been suggested to be contributing factors. OBJECTIVE: The objective was to assess the effect of sleep fragmentation on energy metabolism and energy balance in healthy men. DESIGN: Fifteen healthy male subjects [mean +/- SD BMI (in kg/m(2)): 24.1 +/- 1.9; age: 23.7 +/- 3.5 y] were included in a randomized crossover study in which energy expenditure, substrate oxidation, and physical activity (by radar) were measured twice for 48 h in a respiration chamber while subjects were monitored by electroencephalography to determine slow-wave sleep (SWS), rapid eye movement (REM) sleep, and total sleeping time (TST). During 2 nights, sleep (2330-0730 h) was either fragmented or nonfragmented. RESULTS: Fragmented sleep led to reductions in TST, SWS, and REM sleep (P < 0.001). TEE did not differ (9.96 +/- 0.17 compared with 9.83 +/- 0.13 MJ/d, NS) between the sleep groups, nor did the components of energy expenditure, with the exception of activity-induced energy expenditure (AEE; 1.63 +/- 0.15 compared with 1.42 +/- 0.13 MJ/d for fragmented and nonfragmented sleep, respectively; P < 0.05). Physical activity, exhaustion, sleepiness, respiratory quotient (RQ), and carbohydrate oxidation were elevated in comparison with nonfragmented sleep [physical activity counts: 2371 +/- 118 compared with 2204 +/- 124 counts/d, P < 0.02; exhaustion: 40.1 +/- 3.8 compared with 21.8 +/- 2.4 mm (by using a visual analog scale; VAS), P < 0.001; sleepiness: 47.4 +/- 4.2 compared with 33.9 +/- 4.6 mm (VAS), P < 0.001; RQ: 0.94 +/- 0.04 compared with 0.91 +/- 0.03, P < 0.05; and carbohydrate oxidation: 346.3 +/- 23.8 compared with 323.7 +/- 22.5 g/d, P < 0.05], whereas fat oxidation was reduced (29.1 +/- 9.1 compared with 61.0 +/- 6.6 g/d, P < 0.01). CONCLUSIONS: Fragmented compared with nonfragmented sleep induced reductions in the most important sleep phases, which coincided with elevated AEE, physical activity, exhaustion, and sleepiness. RQ and carbohydrate oxidation increased and fat oxidation decreased, which may predispose to overweight. This trial is registered at www.who.int/ictrp and www.trialregister.nl as NTR1919. PMID- 21795438 TI - Changes in resting and walking energy expenditure and walking speed during pregnancy in obese women. AB - BACKGROUND: Energy-conserving processes reported in undernourished women during pregnancy are a recognized strategy for providing the energy required to support fetal development. Women who are obese before conceiving arguably have sufficient fat stores to support the energy demands of pregnancy without the need to provoke energy-conserving mechanisms. OBJECTIVE: We tested the hypothesis that obese women would show behavioral adaptation [ie, a decrease in self-selected walking (SSW) speed] but not metabolic compensation [ie, a decrease in resting metabolic rate (RMR) or the metabolic cost of walking] during gestation. DESIGN: RMR, SSW speed, metabolic cost of walking, and anthropometric variables were measured in 23 women aged 31 +/- 4 y with a BMI (in kg/m(2)) of 33.6 +/- 2.5 (mean +/- SD) at ~15 and 30 wk of gestation. RMR was also measured in 2 cohorts of nonpregnant control subjects matched for the age, weight, and height of the pregnant cohort at 15 (n = 23) and 30 (n = 23) wk. RESULTS: Gestational weight gain varied widely (11.3 +/- 5.4 kg), and 52% of the women gained more weight than is recommended. RMR increased significantly by an average of 177 +/- 176 kcal/d (11 +/- 12%; P < 0.0001); however, the within-group variability was large. Both the metabolic cost of walking and SSW speed decreased significantly (P < 0.01). Whereas RMR increased in >80% of the cohort, the net oxygen cost of walking decreased in the same proportion of women. CONCLUSION: Although the increase in RMR was greater than that explained by weight gain, evidence of both behavioral and biological compensation in the metabolic cost of walking was observed in obese women during gestation. The trial is registered with the Australian Clinical Trials Registry as ACTRN012606000271505. PMID- 21795437 TI - Is lost lean mass from intentional weight loss recovered during weight regain in postmenopausal women? AB - BACKGROUND: Despite the well-known recidivism of obesity, surprisingly little is known about the composition of body weight during weight regain. OBJECTIVE: The objective of this study was to determine whether the composition of body weight regained after intentional weight loss is similar to the composition of body weight lost. DESIGN: The design was a follow-up to a randomized controlled trial of weight loss in which body composition was analyzed and compared in 78 postmenopausal women before the intervention, immediately after the intervention, and 6 and 12 mo after the intervention. RESULTS: All body mass and composition variables were lower immediately after weight loss than at baseline (all P < 0.05). More fat than lean mass was lost with weight loss, which resulted in body composition changes favoring a lower percentage of body fat and a higher lean-to fat mass ratio (P < 0.001). Considerable interindividual variability in weight regain was noted (CV = 1.07). In women who regained >=2 kg body weight, a decreasing trend in the lean-to-fat mass ratio was observed, which indicated greater fat mass accretion than lean mass accretion (P < 0.001). Specifically, for every 1 kg fat lost during the weight-loss intervention, 0.26 kg lean tissue was lost; for every 1 kg fat regained over the following year, only 0.12 kg lean tissue was regained. CONCLUSIONS: Although not all postmenopausal women who intentionally lose weight will regain it within 1 y, the data suggest that fat mass is regained to a greater degree than is lean mass in those who do experience some weight regain. The health ramifications of our findings remain to be seen. PMID- 21795439 TI - Changes in gut hormone and glucose concentrations in relation to hunger and fullness. AB - BACKGROUND: The search for biomarkers of appetite is very active. OBJECTIVES: The aims were to compare dynamics of hunger and fullness ratings on a visual analog scale (VAS) with dynamics of glucagon-like peptide 1, peptide tyrosine-tyrosine, ghrelin, glucose, and insulin concentrations throughout different meal patterns and thus different timings of nutrient delivery to the gut-by using a statistical approach that focuses on within-subject relations of these observations and to investigate whether appetite ratings are synchronized with or lag behind or in front of changes in hormone and glucose concentrations. DESIGN: Subjects (n = 38) with a mean (+/-SD) age of 24 +/- 6 y and BMI (in kg/m(2)) of 25.1 +/- 3.1 came to the university twice for consumption of a 4-course lunch in 0.5 or 2 h (randomized crossover design). Per subject regression slopes and R(2) values of VAS scores on hormone and glucose concentrations were calculated. We tested whether the means of the slopes were different from zero. Regarding possible lags in the relations, the analyses were repeated with VAS scores related to hormone and glucose concentrations of the relevant previous and following measurement periods. RESULTS: VAS scores and hormone and glucose concentrations changed synchronously (P < 0.005, R(2) = 0.4-0.7). Changes in ghrelin concentrations lagged behind (10-30 min) changes in hunger scores (P < 0.005, R(2) = 0.7) and insulin concentrations (P < 0.005, R(2) = 0.6), which suggests a role for insulin as a possible negative regulator of ghrelin. No major differences in slopes and R(2) values were found between the meal patterns. CONCLUSIONS: This method may be useful for understanding possible differences in relations between VAS scores and hormone and glucose concentrations between subjects or conditions. Yet, the reported explained variation of 40% to 70% seems to be too small to use hormone and glucose concentrations as appropriate biomarkers for appetite, at least at the individual level and probably at the group level. This study started in 2007, which means that it was not registered as a clinical trial. PMID- 21795440 TI - Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. AB - BACKGROUND: Aging is associated with oxidative stress, but underlying mechanisms remain poorly understood. OBJECTIVE: We tested whether glutathione deficiency occurs because of diminished synthesis and contributes to oxidative stress in aging and whether stimulating glutathione synthesis with its precursors cysteine and glycine could alleviate oxidative stress. DESIGN: Eight elderly and 8 younger subjects received stable-isotope infusions of [2H(2)]glycine, after which red blood cell (RBC) glutathione synthesis and concentrations, plasma oxidative stress, and markers of oxidant damage (eg, F(2)-isoprostanes) were measured. Elderly subjects were restudied after 2 wk of glutathione precursor supplementation. RESULTS: Compared with younger control subjects, elderly subjects had markedly lower RBC concentrations of glycine (486.7 +/- 28.3 compared with 218.0 +/- 23.7 MUmol/L; P < 0.01), cysteine (26.2 +/- 1.4 compared with 19.8 +/- 1.3 MUmol/L; P < 0.05), and glutathione (2.08 +/- 0.12 compared with 1.12 +/- 0.18 mmol/L RBCs; P < 0.05); lower glutathione fractional (83.14 +/ 6.43% compared with 45.80 +/- 5.69%/d; P < 0.01) and absolute (1.73 +/- 0.16 compared with 0.55 +/- 0.12 mmol/L RBCs per day; P < 0.01) synthesis rates; and higher plasma oxidative stress (304 +/- 16 compared with 346 +/- 20 Carratelli units; P < 0.05) and plasma F(2)-isoprostanes (97.7 +/- 8.3 compared with 136.3 +/- 11.3 pg/mL; P < 0.05). Precursor supplementation in elderly subjects led to a 94.6% higher glutathione concentration, a 78.8% higher fractional synthesis rate, a 230.9% higher absolute synthesis rate, and significantly lower plasma oxidative stress and F(2)-isoprostanes. No differences in these measures were observed between younger subjects and supplemented elderly subjects. CONCLUSIONS: Glutathione deficiency in elderly humans occurs because of a marked reduction in synthesis. Dietary supplementation with the glutathione precursors cysteine and glycine fully restores glutathione synthesis and concentrations and lowers levels of oxidative stress and oxidant damages. These findings suggest a practical and effective approach to decreasing oxidative stress in aging. PMID- 21795441 TI - Periconceptional multivitamin use and risk of preterm or small-for-gestational age births in the Danish National Birth Cohort. AB - BACKGROUND: The intake of periconceptional multivitamins may decrease the risk of preterm births (PTBs) or small-for-gestational-age (SGA) births. OBJECTIVE: We related the timing and frequency of periconceptional multivitamin use to SGA births and PTBs and its clinical presentations (ie, preterm labor, premature rupture of membranes, and medical induction). DESIGN: Women in the Danish National Birth Cohort (n = 35,897) reported the number of weeks of multivitamin use during a 12-wk periconceptional period. Cox regression was used to estimate the relation between any multivitamin use and PTBs (<37 wk) or SGA births (birth weight adjusted for gestational age >2 SDs below the mean on the basis of fetal growth curves). The timing (preconception and postconception) and frequency of use were also analyzed. Regular users (4-6 wk) and partial users (1-3 wk) in each period were compared with nonusers. RESULTS: The association between periconceptional multivitamin use and PTBs varied according to prepregnancy overweight status (P-interaction = 0.07). Regular preconception and postconception multivitamin use in women with a prepregnancy BMI (in kg/m(2)) <25 was associated with reduced risks of a PTB (HR: 0.84; 95% CI: 0.73, 0.95) and preterm labor (HR: 0.80; 95% CI: 0.69, 0.94). No similar associations were shown for overweight women. The adjusted risk of an SGA birth was reduced in multivitamin users regardless of their prepregnancy BMI (HR: 0.83; 95% CI: 0.73, 0.95), with the strongest association in regular users in the postconception period. CONCLUSION: Regular periconceptional multivitamin use was associated with reduced risk of SGA births and PTBs in nonoverweight women. PMID- 21795442 TI - Substrate oxidation influences liking, wanting, macronutrient selection, and consumption of food in humans. AB - BACKGROUND: Several carbohydrate-based models of feeding have been described. The influence of the substrate oxidation rate on liking, wanting, and macronutrient selection, however, is not known in humans. OBJECTIVE: The aim of this study was to investigate the influence of the substrate oxidation rate on the above variables. DESIGN: A randomized 4-condition study was conducted in 16 normal weight men (mean +/- SD age: 23 +/- 3 y). The sessions differed in the composition of breakfast, which was either high in carbohydrates (HC) or low in carbohydrates (LC) or high in fat (HF) or low in fat (LF). Two hours and 20 minutes after breakfast, energy expenditure (EE) and respiratory exchange ratios (RERs) were measured. Next, olfactory liking for 4 foods (sweet and fatty) and ad libitum energy intake (carbohydrate- and fat-rich bread) were evaluated. RESULTS: EE was higher (P < 0.001) and subsequent intake was lower (P < 0.01) after the HC and HF breakfasts than after the LC and LF breakfasts. The HC and LC breakfasts induced a higher RER (P < 0.001), lower olfactory liking for sweet foods (P < 0.05), and the consumption of a lower proportion of carbohydrate-rich bread (P< 0.05) than did the HF and LF breakfasts. The HF breakfast induced the lowest RER (P < 0.001), the lowest olfactory liking for fatty foods (P < 0.05), and the lowest proportion of fat-rich bread consumed (P < 0.01). Above all, a negative correlation was found between the RER and olfactory liking for sweet foods (P < 0.001). CONCLUSION: A high fat oxidation rate induces a strong liking for carbohydrates and a low liking for fats, which lends new support to the carbohydrate-based model of feeding. This trial is registered at clinicaltrials.gov as NCT01122082. PMID- 21795443 TI - Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise. AB - BACKGROUND: Ingestion of whey or casein yields divergent patterns of aminoacidemia that influence whole-body and skeletal muscle myofibrillar protein synthesis (MPS) after exercise. Direct comparisons of the effects of contrasting absorption rates exhibited by these proteins are confounded by their differing amino acid contents. OBJECTIVE: Our objective was to determine the effect of divergent aminoacidemia by manipulating ingestion patterns of whey protein alone on MPS and anabolic signaling after resistance exercise. DESIGN: In separate trials, 8 healthy men consumed whey protein either as a single bolus (BOLUS; 25-g dose) or as repeated, small, "pulsed" drinks (PULSE; ten 2.5-g drinks every 20 min) to mimic a more slowly digested protein. MPS and phosphorylation of signaling proteins involved in protein synthesis were measured at rest and after resistance exercise. RESULTS: BOLUS increased blood essential amino acid (EAA) concentrations above those of PULSE (162% compared with 53%, P < 0.001) 60 min after exercise, whereas PULSE resulted in a smaller but sustained increase in aminoacidemia that remained elevated above BOLUS amounts later (180-220 min after exercise, P < 0.05). Despite an identical net area under the EAA curve, MPS was elevated to a greater extent after BOLUS than after PULSE early (1-3 h: 95% compared with 42%) and later (3-5 h: 193% compared with 121%) (both P < 0.05). There were greater changes in the phosphorylation of the Akt-mammalian target of rapamycin pathway after BOLUS than after PULSE. CONCLUSIONS: Rapid aminoacidemia in the postexercise period enhances MPS and anabolic signaling to a greater extent than an identical amount of protein fed in small pulses that mimic a more slowly digested protein. A pronounced peak aminoacidemia after exercise enhances protein synthesis. This trial was registered at clinicaltrials.gov as NCT01319513. PMID- 21795444 TI - Measuring body composition and energy expenditure in children with severe neurologic impairment and intellectual disability. AB - BACKGROUND: Accurate prediction equations for estimating body composition and total energy expenditure (TEE) in children with severe neurologic impairment and intellectual disability are currently lacking. OBJECTIVE: The objective was to develop group-specific equations to predict body composition by using skinfold thickness measurements and bioelectrical impedance analysis (BIA) and to predict TEE by using data on mobility, epilepsy, and muscle tone. DESIGN: Measures of body composition with the use of skinfold-thickness measurements (percentage of body fat) and BIA (total body water) were compared with those from isotope dilution (reference method) by using intraclass correlation coefficients (ICCs) and Bland and Altman limits of agreement analyses. With the use of the same methods, the outcomes of cerebral palsy-specific TEE equations were compared with those of the doubly labeled water method (reference method). Group-specific regression equations were developed by using forward-stepwise-multiple correlation-regression analyses. RESULTS: Sixty-one children with a mean (+/-SD) age of 10.1 +/- 4.3 y (32 boys) were studied. A new equation based on the sum of 4 skinfold-thickness measurements did not improve agreement (n = 49; ICC = 0.61), whereas the newly developed BIA equation-which includes tibia length as an alternative for standing height-did improve agreement (n = 61; ICC = 0.96, SEE = 1.7 kg, R(2) = 0.92). The newly developed TEE equation, which uses body composition, performed better (n = 52; ICC = 0.87, SEE = 180 kcal, R(2) = 0.77) than did the equation of Schofield (n = 52; ICC = 0.82, SEE = 207 kcal, R(2) = 0.69). CONCLUSIONS: Current cerebral palsy-specific equations for measuring body composition and energy expenditure are inaccurate. BIA is more accurate at assessing nutritional status in this population than is the measurement of skinfold thickness. The newly developed TEE equation, which uses body composition, provides a reasonable estimate of energy expenditure in these children despite its variability. PMID- 21795445 TI - The impact of a Mediterranean diet and healthy lifestyle on premature mortality in men and women. AB - BACKGROUND: The Mediterranean diet has been associated with reduced mortality; few studies have investigated the combined impact of the Mediterranean diet with other modifiable lifestyle factors. OBJECTIVES: The objectives were to investigate the association between adherence to the Mediterranean diet and total mortality and to estimate the overall impact of a combined healthy lifestyle on premature death. DESIGN: In 1986 a cohort of 120,852 men and women aged 55-69 y provided information on dietary and other lifestyle habits. A mortality follow-up until 1996 was established by linkage to the Dutch Central Bureau of Genealogy. A combined lifestyle score was constructed by allocating one point per the following healthy lifestyle factors: adhering to the Mediterranean diet, nonsmoking, normal weight [BMI (in kg/m(2)): 18.5 to <25], and regular physical activity. The lifestyle score ranged from 0 to 4 points (least healthy to healthiest). The multivariate case-cohort analysis was based on 9691 deaths and 3576 subcohort members. RESULTS: Adherence to the Mediterranean diet was significantly related to lower mortality in women but not significantly in men. The healthy lifestyle score was strongly inversely related to mortality in women and men. When the least-healthy to the healthiest lifestyle scores were compared, HRs of 4.07 (95% CI: 2.59, 6.40; P-trend <0.001) and 2.61 (95% CI: 1.79, 3.80; P trend <0.001) were shown in women and men, respectively. For the same comparison, the mortality rate advancement period ("aging effect") was 15.1 y (95% CI: 9.9, 20.2 y) in women and 8.4 y (95% CI: 5.0, 11.8 y) in men. CONCLUSION: This study suggests that adherence to 4 modifiable healthy lifestyle factors can substantially reduce premature mortality in women and men. PMID- 21795447 TI - Association of the Pro12Ala and C1431T variants of PPARgamma and their haplotypes with susceptibility to gestational diabetes. AB - BACKGROUND: The protective role of the Ala allele in the Pro12Ala polymorphism of PPARgamma on type 2 diabetes has been well established but not confirmed in the context of pregnancy, for gestational diabetes, a known predictor of later type 2 diabetes onset. Another PPARgamma polymorphism, the C1431T, is in strong linkage disequilibrium with Pro12Ala and has been shown to be associated with body weight, but its association with diabetes is controversial. RESEARCH DESIGN AND METHODS: In 1708 women of the EDEN mother-child cohort, the PPARgamma Pro12Ala and C1431T polymorphisms were genotyped and analyzed in association with maternal prepregnancy body mass index, obesity before pregnancy, and gestational diabetes, separately and also combined in haplotypes. RESULTS: The prevalence of obesity was significantly higher in mothers with the Ala/Ala genotype compared with carriers of the Pro allele (35 vs. 9%, P < 0.0001), but there was no cases of gestational diabetes in Ala/Ala mothers. Mothers homozygous for the T allele of C1431T were also more obese (24 vs. 9%, P = 0.035), and three times more had gestational diabetes (18 vs. 6%, P = 0.044). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in mothers with and without gestational diabetes; in comparison with the Pro-C haplotype, the Pro-T haplotype conferred the highest risk [odds ratio (95% CI) = 1.89 (1.05-3.40)], and the Ala-C the lowest risk [odds ratio (95% CI) = 0.12 (0.52-1.70)]. CONCLUSIONS: These results from a haplotype analysis, show for the first time that genetic variations in the PPARgamma gene could play a role in the susceptibility to develop gestational diabetes. PMID- 21795446 TI - A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. AB - CONTEXT: Lorcaserin is a novel selective agonist of the serotonin 2C receptor. OBJECTIVE: Our objective was to evaluate the effects of lorcaserin on body weight, cardiovascular risk factors, and safety in obese and overweight patients. DESIGN AND SETTING: This randomized, placebo-controlled, double-blind, parallel arm trial took place at 97 U.S. research centers. PATIENTS: Patients included 4008 patients, aged 18-65 yr, with a body mass index between 30 and 45 kg/m(2) or between 27 and 29.9 kg/m(2) with an obesity-related comorbid condition. INTERVENTIONS: Patients were randomly assigned in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily (BID), lorcaserin 10 mg once daily (QD), or placebo. All patients received diet and exercise counseling. MAIN OUTCOME MEASURES: The ordered primary endpoints were proportion of patients achieving at least 5% reduction in body weight, mean change in body weight, and proportion of patients achieving at least 10% reduction in body weight at 1 yr. Serial echocardiograms monitored heart valve function. RESULTS: Significantly more patients treated with lorcaserin 10 mg BID and QD lost at least 5% of baseline body weight (47.2 and 40.2%, respectively) as compared with placebo (25.0%, P < 0.001 vs. lorcaserin BID). Least squares mean (95% confidence interval) weight loss with lorcaserin BID and QD was 5.8% (5.5-6.2%) and 4.7% (4.3-5.2%), respectively, compared with 2.8% (2.5-3.2%) with placebo (P < 0.001 vs. lorcaserin BID; least squares mean difference, 3.0%). Weight loss of at least 10% was achieved by 22.6 and 17.4% of patients receiving lorcaserin 10 mg BID and QD, respectively, and 9.7% of patients in the placebo group (P < 0.001 vs. lorcaserin BID). Headache, nausea, and dizziness were the most common lorcaserin-related adverse events. U.S. Food and Drug Administration-defined echocardiographic valvulopathy occurred in 2.0% of patients on placebo and 2.0% on lorcaserin 10 mg BID. CONCLUSIONS: Lorcaserin administered in conjunction with a lifestyle modification program was associated with dose-dependent weight loss that was significantly greater than with placebo. PMID- 21795448 TI - Clinical review: The effect of vitamin D on falls: a systematic review and meta analysis. AB - CONTEXT: Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. OBJECTIVE: The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls. DATA SOURCES: We searched electronic databases from inception through August 2010. STUDY SELECTION: Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported. DATA EXTRACTION: Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data. DATA SYNTHESIS: Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model. RESULTS: We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias. CONCLUSIONS: Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women. PMID- 21795449 TI - Efficacy and survival analysis of 131I therapy for bone metastases from differentiated thyroid cancer. AB - OBJECTIVE: Our objective was to investigate the clinical efficacy of (131)I therapy for bone metastases from differentiated thyroid cancer (DTC) and prognostic factors as well as to assess patient survival and variables influencing survival. METHODS: One hundred six DTC patients with bone metastases treated with (131)I were retrospectively analyzed. The therapeutic efficacy was evaluated based on the change in serum thyroglobulin (Tg), the palliation of bone pain, and the anatomical imaging changes in bone lesions. The overall survival rates were estimated using the life-table method. RESULTS: After (131)I therapy, a significant decrease in serum Tg was seen in 37 cases (34.9%), and serum Tg remained stable in 56 patients (52.8%). Among the 61 patients with painful bone metastases, 39 patients obtained a significant relief of bone pain, and the effective rate was 63.9%. The majority of DTC patients (76.4%) exhibited no obvious anatomical imaging changes in metastatic bone lesions after (131)I therapy. Only histopathological type and whether combined with nonosseous distant metastases had statistically significant impacts on changes in serum Tg (P = 0.009 and 0.023), and age over 45 yr and papillary thyroid carcinoma had favorable response on changes in anatomical imaging (P = 0.027 and 0.014). The 5- and 10-yr survival rates were 86.5 and 57.9%, respectively. Multivariate analyses showed that the presence of solitary bone metastases, only bone metastases, and (131)I therapy with previous bone surgery were independent factors associated with a better prognosis (P = 0.024, 0.009, and 0.031). CONCLUSION: (131)I therapy is a feasible and effective treatment for DTC bone metastases. A better prognosis can be accomplished in patients who had a single metastatic lesion, only bone metastasis, or underwent bone surgery before (131)I therapy. PMID- 21795450 TI - Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. AB - CONTEXT: IGF-I plays a central role in metabolism and growth regulation. High IGF I levels are associated with increased cancer risk and low IGF-I levels with increased risk for cardiovascular disease. OBJECTIVE: Our objective was to determine the relationship between circulating IGF-I levels and mortality in the general population using random-effects meta-analysis and dose-response metaregression. DATA SOURCES: We searched PubMed, EMBASE, Web of Science, and Cochrane Library from 1985 to September 2010 to identify relevant studies. STUDY SELECTION: Population-based cohort studies and (nested) case-control studies reporting on the relation between circulating IGF-I and mortality were assessed for eligibility. DATA EXTRACTION: Data extraction was performed by two investigators independently, using a standardized data extraction sheet. DATA SYNTHESIS: Twelve studies, with 14,906 participants, were included. Overall, risk of bias was limited. Mortality in subjects with low or high IGF-I levels was compared with mid-centile reference categories. All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08-1.49) and HR of 1.18 (95% CI = 1.04-1.34), respectively. Dose-response metaregression showed a U-shaped relation of IGF-I and all-cause mortality (P = 0.003). The predicted HR for the increase in mortality comparing the 10th IGF-I with the 50th percentile was 1.56 (95% CI = 1.31-1.86); the predicted HR comparing the 90th with the 50th percentile was 1.29 (95% CI = 1.06-1.58). A U shaped relationship was present for both cancer mortality and cardiovascular mortality. CONCLUSIONS: Both low and high IGF-I concentrations are associated with increased mortality in the general population. PMID- 21795451 TI - MTCH2 in human white adipose tissue and obesity. AB - CONTEXT: Genome-wide association studies have identified single-nucleotide polymorphisms in approximately 40 loci associated with obesity-related traits. How these loci regulate obesity is largely unknown. One obesity-associated single nucleotide polymorphism is close to the MTCH2 gene (mitochondrial carrier homolog 2). OBJECTIVE: The objective of the study was to assess the expression of genes in obesity-associated loci in abdominal sc white adipose tissue (scWAT) in relation to obesity. A more comprehensive expression study was performed on MTCH2. DESIGN: mRNA levels of 66 genes from 40 loci were determined by microarray in scWAT from lean and obese women (n = 30). MTCH2 mRNA was measured by quantitative RT-PCR in lean and obese before and after weight loss in intact adipose pieces and isolated adipocytes, paired samples of scWAT and omental WAT, and primary adipocyte cultures (n = 191 subjects in total). MTCH2 genotypes were compared with mRNA expression in 96 women. MTCH2 protein was examined in scWAT of 38 individuals. RESULTS: Adipose expression of eight genes was significantly associated with obesity; of these, MTCH2 displayed the highest absolute signal. MTCH2 mRNA and protein expression was significantly increased in obese women but was not affected by weight loss. MTCH2 was enriched in isolated fat cells and increased during adipocyte differentiation. There was no cis influence of MTCH2 genotypes on mRNA levels. CONCLUSION: MTCH2 is highly expressed in human WAT and adipocytes with increased levels in obese women. These results suggest that MTCH2 may play a role in cellular processes underlying obesity. PMID- 21795452 TI - Management of papillary thyroid cancer patients in absence of postoperative radioiodine remnant ablation: tailoring follow-up by neck sonography. PMID- 21795453 TI - Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy. AB - CONTEXT: Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy. OBJECTIVE: Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status. DESIGN, SETTING, AND PARTICIPANTS: We conducted a survey field study that included 495 adult residents. MAIN OUTCOMES: We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale. RESULTS: Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females). CONCLUSIONS: A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes. PMID- 21795454 TI - Fractures during childhood and adolescence in healthy boys: relation with bone mass, microstructure, and strength. AB - CONTEXT: In healthy boys, fractures result from trauma of various severity, suggesting contribution of an intrinsic biomechanical fragility. OBJECTIVES: Our objective was to characterize bone mineral mass, microstructure, and strength in boys with and without fractures. PARTICIPANTS AND DESIGN: We followed 176 healthy boys from 7.4 +/- 0.5 to 15.2 +/- 0.5 (mean +/- sd) yr of age. OUTCOMES: Areal (a) bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry at radius metaphysis and diaphysis, total hip, femoral neck and diaphysis, and L2 L4 vertebrae. Volumetric (v) BMD and microstructure were assessed by high resolution peripheral computerized tomography at both distal tibia and radius. Bone strength was evaluated by micro-finite element analysis. RESULTS: A total of 156 fractures were recorded in 87 of 176 boys with peak incidence between 10 and 13 yr. At 7.4 yr, subjects with fractures had lower aBMD in all sites and at 15.2 yr in femoral and spinal, but not in radius, sites. At that age, boys with fractures displayed lower trabecular (Tb) vBMD (P = 0.029) and number (P = 0.040), stiffness (P = 0.024), and failure load (P = 0.016) at distal tibia, but not distal radius. Odds ratios of fracture risk per 1 sd decrease were 1.80 (P = 0.006) for femoral neck aBMD and 1.46 (P = 0.038) for distal tibia Tb vBMD, 1.59 (P = 0.031) for Tb number, 1.53 (P = 0.072) for stiffness, and 1.60 (P = 0.056) for failure load. CONCLUSION: In a homogeneous cohort of healthy boys, fractures recorded until 15.2 +/- 05 yr of age were associated with lower femoral neck aBMD and with lower distal tibia trabecular vBMD and number, stiffness and failure load. These deficits in bone mineral mass, microstructure and strength could contribute to the occurrence of fractures during growth. PMID- 21795455 TI - Preadipocyte factor-1 levels are higher in women with hypothalamic amenorrhea and are associated with bone mineral content and bone mineral density through a mechanism independent of leptin. AB - CONTEXT: Preadipocyte factor 1 (pref-1) is increased in anorexia nervosa and is associated negatively with bone mineral density (BMD). No previous studies exist on pref-1 in women with exercise-induced hypothalamic amenorrhea (HA), which similar to anorexia nervosa, is an energy-deficiency state associated with hypoleptinemia. OBJECTIVE: Our objective was to evaluate whether pref-1 levels are also elevated and associated with low BMD and to assess whether leptin regulates pref-1 levels in women with HA. DESIGN: Study 1 was a double-blinded, placebo-controlled randomized clinical trial of metreleptin administration in women with HA. Study 2 was an open-label study of metreleptin administration in low physiological, supraphysiological, and pharmacological doses in healthy women volunteers. SETTING AND PATIENTS: At Beth Israel Deaconess Medical Center, 20 women with HA and leptin levels higher than 5 ng/ml and nine healthy control women participated in study 1, and five healthy women participated in study 2. INTERVENTION: For study 1, 20 HA subjects were randomized to receive either 0.08 mg/kg metreleptin (n = 11) or placebo (n = 9). For study 2, five healthy subjects received 0.01, 0.1, and 0.3 mg/kg metreleptin in both fed and fasting conditions for 1 and 3 d, respectively. MAIN OUTCOME MEASURES: Circulating pref-1 and leptin levels were measured. RESULTS: Pref-1 was significantly higher in HA subjects vs. controls (P = 0.035) and negatively associated with BMD (rho = -0.38; P < 0.01) and bone mineral content (rho = -0.32; P < 0.05). Metreleptin administration did not alter pref-1 levels in any study reported herein. CONCLUSIONS: Pref-1 is higher in HA subjects than controls. Metreleptin administration at low physiological, supraphysiological, and pharmacological doses does not affect pref 1 levels, suggesting that hypoleptinemia is not responsible for higher pref-1 levels and that leptin does not regulate pref-1. PMID- 21795456 TI - Clinical Review: The 2011 report on dietary reference intake for vitamin D: where do we go from here? AB - CONTEXT: The Institute of Medicine (IOM) report on dietary reference intakes (DRI) for vitamin D is reviewed, along with its implications. EVIDENCE ACQUISITION: Evidence-based reviews were completed; the IOM committee conducted its own literature search, an open public workshop, and two open sessions, and maintained a public web site for stakeholder input. The consensus report of the 14 scientists on the committee was reviewed by a panel of experts. EVIDENCE SYNTHESIS: Only bone health could be used as an indicator for DRI development. Evidence for extraskeletal outcomes was inadequate, inconsistent, or insufficient to develop DRI. The recommended dietary allowance was found to be 600 IU/d for ages 1-70 yr, corresponding on average to a serum 25-hydroxyvitamin D (25OHD) level of at least 50 nmol/liter (20 ng/ml), and 800 IU/d for those older than 70 yr. Comparison with current levels of 25OHD in the National Health and Nutrition Examination Survey population survey revealed that the vitamin D intake in the United States and Canada is adequate. An upper limit was set at 4000 IU/d for adults, corresponding to an average serum 25OHD level of 125 nmol/liter (50 ng/ml). CONCLUSION: Previous reports of an epidemic of vitamin D deficiency in North America were based on an overestimation of adequacy. Population screening with serum 25OHD is therefore not warranted. Current laboratory reference ranges for serum 25OHD are overestimated and should be revised. Practice guidelines to treat disease should not be applied to the healthy American population where use of the DRI is appropriate. PMID- 21795457 TI - Acute life-threatening presentation of vitamin D deficiency rickets. AB - CONTEXT: Clinical manifestations of vitamin D deficiency rickets are widely described; however cardiorespiratory arrest is an extremely rare presentation. OBJECTIVE: The aim of this paper is to present the symptoms of severe vitamin D deficiency rickets and to highlight the importance of vitamin D prophylaxis in infants. RESULTS: We report a case of a 16-month-old infant who presented to emergency room with a stridor that evolved into a full cardiorespiratory arrest secondary to hypocalcemia. Medical history revealed that the infant was exclusively breastfed without vitamin D supplementation until the age of 10 months. Due to cultural habits, his diet was also grossly deficient in dairy products. Physical exam revealed clinical signs of rickets. Laboratory test showed severe hypocalcemia, elevated alkaline phosphatase, normal serum phosphorous, decreased 25(OH) cholecalciferol, increased intact parathyroid hormone level, and normal urine calcium excretion. The radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. The bone mineral density of the lumbar spine measured by dual x-ray absorptiometry showed a Z-score below -2 SD. His cardiorespiratory arrest secondary to hypocalcemia was therefore attributed to severe nutritional rickets. CONCLUSION: Vitamin D deficiency rickets can be life threatening. Vitamin D supplementation is therefore crucial, especially in breastfed infants and some ethnic minorities (dark-skinned people, poor sun exposure), more at risk for developing severe rickets if not supplemented. PMID- 21795458 TI - Long-term immunogenicity after one and two doses of a monovalent MF59-adjuvanted A/H1N1 Influenza virus vaccine coadministered with the seasonal 2009-2010 nonadjuvanted Influenza virus vaccine in HIV-infected children, adolescents, and young adults in a randomized controlled trial. AB - Few data are available on the safety and long-term immunogenicity of A/H1N1 pandemic influenza vaccines for HIV-infected pediatric patients. We performed a randomized controlled trial to evaluate the safety and long-term immunogenicity of 1 versus 2 doses of the 2009 monovalent pandemic influenza A/H1N1 MF59 adjuvanted vaccine (PV) coadministered with the seasonal 2009-2010 trivalent nonadjuvanted influenza vaccine (SV) to HIV-infected children, adolescents, and young adults. A total of 66 HIV-infected patients aged 9 to 26 years were randomized to receive one (group 1) or two (group 2) doses of PV coadministered with 1 dose of SV. The main outcome was the seroconversion rate for PV at 1 month. Secondary outcomes were the geometric mean titer ratios and the seroprotection rates at 1 month for all vaccines, seroconversion rates at 1 month for SV, and longitudinal changes of antibody titers (ABTs) at 1, 2, 6, and 12 months for all vaccines. Groups 1 and 2 had similar CD4 counts and HIV RNA levels during the study. The seroconversion rate for PV was 100% at 1 month in both groups. ABTs for PV were high during the first 6 months and declined below seroprotection levels thereafter. Longitudinal changes in ABTs were similar in groups 1 and 2 for both PV and SV. The side effects of vaccination were mild and mostly local. In HIV-infected children, adolescents, and young adults, the immune response triggered by a single dose of PV was similar to that obtained with a double dose and was associated with long-term antibody response. PMID- 21795459 TI - Immunogenicity, boostability, and sustainability of the immune response after vaccination against Influenza A virus (H1N1) 2009 in a healthy population. AB - The emergence of a new influenza A virus (H1N1) variant in 2009 led to a worldwide vaccination program, which was prepared in a relatively short period of time. This study investigated the humoral immunity against this virus before and after vaccination with a 2009 influenza A virus (H1N1) monovalent MF59-adjuvanted vaccine, as well as the persistence of vaccine-induced antibodies. Our prospective longitudinal study included 498 health care workers (mean age, 43 years; median age, 44 years). Most (89%) had never or only occasionally received a seasonal influenza virus vaccine, and 11% were vaccinated annually (on average, for >10 years). Antibody titers were determined by a hemagglutination inhibition (HI) assay at baseline, 3 weeks after the first vaccination, and 5 weeks and 7 months after the second vaccination. Four hundred thirty-five persons received two doses of the 2009 vaccine. After the first dose, 79.5% developed a HI titer of >=40. This percentage increased to 83.3% after the second dose. Persistent antibodies were found in 71.9% of the group that had not received annual vaccinations and in 43.8% of the group that had received annual vaccinations. The latter group tended to have lower HI titers (P=0.09). With increasing age, HI titers decreased significantly, by 2.4% per year. A single dose of the 2009 vaccine was immunogenic in almost 80% of the study population, whereas an additional dose resulted in significantly increased titers only in persons over 50. Finally, a reduced HI antibody response against the 2009 vaccine was found in adults who had previously received seasonal influenza virus vaccination. More studies on the effect of yearly seasonal influenza virus vaccination on the immune response are warranted. PMID- 21795460 TI - Mycobacterium bovis BCG-mediated protection against W-Beijing strains of Mycobacterium tuberculosis is diminished concomitant with the emergence of regulatory T cells. AB - Despite issues relating to variable efficacy in the past, the Mycobacterium bovis BCG vaccine remains the basis for new-generation recombinant vaccines currently in clinical trials. To date, vaccines have been tested mostly against laboratory strains and not against the newly emerging clinical strains. In this study, we evaluated the ability of BCG Pasteur to protect mice from aerosol infections with two highly virulent W-Beijing clinical strains, HN878 and SA161. In a conventional 30-day protection assay, BCG was highly protective against both strains, but by day 60 of the assay, this protection was diminished. Histological examination of the lungs of vaccinated animals showed reduced lung consolidation and smaller and more-organized granulomas in the vaccinated mice after 30 days, but in both cases, these tissues demonstrated worsening pathology over time. Effector T cell responses were increased in the vaccinated mice infected with HN878, but these diminished in number after day 30 of the infections concomitant with increased CD4(+) Foxp3(+) T cells in the lungs, draining lymph nodes, and the spleen. Given the concomitant decrease in effector immunity and continued expansion of regulatory Foxp3(+) cells observed here, it is reasonable to hypothesize that downregulation of effector immunity by these cells may be a serious impediment to the efficacy of BCG-based vaccines. PMID- 21795461 TI - Diverse cytokine profile from mesenteric lymph node cells of cull cows severely affected with Johne's disease. AB - Mycobacterium avium subsp. paratuberculosis, the causative agent of Johne's disease, is able to dampen or distort immune responses at the mucosal sites and coexist with a massive infiltration of immune cells in the gastrointestinal tract. Knowledge of the mechanism by which M. avium subsp. paratuberculosis subverts the immune response at the mucosal level in cattle is important for the development of improved disease control strategies, including new vaccines and diagnostic tests. In this study, 38 cull cows from herds infected with M. avium subsp. paratuberculosis were divided into four groups, based on M. avium subsp. paratuberculosis culture from gut tissues and histopathological lesion scores. Cytokine gene expression and secretion from M. avium subsp. paratuberculosis sonicate-stimulated peripheral blood mononuclear cell (PBMC) and mesenteric lymph node (MLN) cultures of the animals were compared. Antigen stimulation of MLN cells from the severely lesioned group resulted in significant upregulation of the mRNA expression of five cytokines, gamma interferon (IFN-gamma), interleukin 10 (IL-10), IL-13, IL-17A, and tumor necrosis factor alpha (TNF-alpha), which have a diverse range of functions, while there was no significant upregulation of these cytokines by the other groups. There were major differences between the responses of the PBMC and MLN cultures, with higher levels of secreted IFN-gamma released from the MLN cultures and, conversely, higher levels of IL-10 released from the PBMC cultures. The upregulation of all five cytokines from cells at the site of infection in the severely lesioned animals suggested a dysregulated immune response, contributing to a failure to clear infection in this group of animals. PMID- 21795462 TI - Bursopentine as a novel immunoadjuvant enhances both humoral and cell-mediated immune responses to inactivated H9N2 Avian Influenza virus in chickens. AB - There is an urgent need for identification of a new adjuvant capable of selectively promoting an efficient immune response for use with vaccines and especially subunit vaccines. Our pervious study showed that Bursopentine (BP5) is a novel immunomodulatory peptide and has the ability to significantly stimulate an antigen-specific immune response in mice. In this study, the potential adjuvant activities of BP5 were examined in chickens by coinjection of BP5 and an inactivated avian influenza virus (AIV) (A/Duck/Jiangsu/NJ08/05 [AIV H9N2 subtype]). The results suggested that BP5 markedly elevated serum hemagglutination inhibition (HI) titers and antigen-specific antihemagglutinin (anti-HA) antibody (IgG) levels, induced both Th1 (interleukin 2 [IL-2] and gamma interferon [IFN-gamma])- and Th2 (IL-4)-type cytokines, promoted the proliferation of peripheral blood lymphocytes, and increased populations of CD3(+) T cells and their subsets CD4(+) (CD3(+) CD4(+)) T cells and CD8(+) (CD3(+) CD8(+)) T cells. Furthermore, a virus challenge experiment revealed that BP5 contributes to protection against homologous avian influenza virus challenge by reducing viral replication in chicken lungs. This study indicates that the combination of inactivated AIVs and BP5 gives a strong immune response at both the humoral and cellular levels and implies that BP5 is a novel immunoadjuvant suitable for vaccine design. PMID- 21795463 TI - Evaluation of the Bio-Rad BioPlex Measles, Mumps, Rubella, and Varicella-Zoster Virus IgG multiplex bead immunoassay. AB - The goal of this study was to compare the BioPlex 2200 measles, mumps, rubella, and varicella-zoster virus (MMRV) IgG multiplex assays (Bio-Rad Laboratories, Hercules, CA) to routine testing by enzyme immunoassay (EIA). Serum specimens (n = 500) submitted to our reference laboratory for routine MMRV IgG testing by EIA were also tested by the BioPlex assays. Following testing, the BioPlex measles, mumps, rubella, and varicella-zoster virus assays demonstrated agreements of 91.6% (95% confidence interval [CI], 88.8% to 93.7%), 94.2% (95% CI, 91.7% to 95.7%), 94.4% (95% CI, 92.0% to 96.1%), and 91.8% (95% CI, 89.0% to 93.9%), respectively, compared to the results of EIA. Timing studies showed that the BioPlex MMRV assay could provide complete analysis of 100 serum specimens in 1.7 h, compared to 5.5 h by EIA. These data indicate that the BioPlex MMRV IgG assays exhibit comparable performance (93% overall agreement [1,860/2,000 results]; kappa = 0.67) to routine testing by EIA. The BioPlex assays allow for the simultaneous detection of all four analytes, thereby eliminating potential aliquot errors and reducing turnaround time. PMID- 21795464 TI - Novel epitopic region of glucosyltransferase B from Streptococcus mutans. AB - In the development of a component vaccine against caries, the catalytic region (CAT) and glucan-binding domain (GBD) of glucosyltransferase B (GtfB) from Streptococcus mutans have been employed as target antigens. These regions were adopted as primary targets because they theoretically include epitopes associated with enzyme function. However, their antigenicities have not been fully evaluated. Although there are many reports about successful vaccination using these components, the principle has not yet been put to practical use. For these reasons, we came to doubt the effectiveness of the epitopes in vaccine production and reevaluated the antigenic region of GtfB by using in silico analyses combined with in vitro and in vivo experiments. The results suggested that the ca. 360 amino-acid variable region (VR) in the N terminus of GtfB is more reactive than CAT and GBD. This region is S. mutans and/or GtfB specific, nonconserved among other streptococcal Gtfs, and of unknown function. Immunization using an adenovirus vector-borne DNA vaccine confirmed that VR is an epitope that shows promise for the development of a caries vaccine. PMID- 21795465 TI - Neutralizing activity of saliva against cytomegalovirus. AB - Congenital cytomegalovirus (CMV) disease is the leading cause of permanent disability in neonates in the United States. Neutralizing antibodies in saliva may protect against maternal CMV infection by blocking viral entry into oral epithelial cells, but the antibody response to CMV in the saliva following natural infection is not well characterized. Saliva specimens from naturally infected individuals were tested for CMV-neutralizing activity using epithelial and fibroblast cells. Saliva from seronegative adults had no inherent anti-CMV activity. Neutralizing activity of saliva from naturally infected adults was not detectable using fibroblast cells, and saliva from young children, adolescents, and Towne vaccine recipients did not have activity using either cell type. However, when using epithelial cells, neutralizing activity was present in saliva from 50% of seropositive adults, correlated with serum-neutralizing activity, and was more prevalent in mothers of children in day care than in non-day care associated adults. Three day care mothers with high salivary neutralizing activities (>1:20) had exceptionally high serum-neutralizing titers (3- to 8-fold higher than typical seropositives) and were immunoblot positive for serum antibodies to the epithelial entry mediator UL130. These results suggest that salivary neutralizing activities are attainable by induction of high serum IgG levels and could be utilized to evaluate candidate cytomegalovirus vaccines. PMID- 21795466 TI - Investigation on the enantioselectivity of the sulfation of the methylenedioxymethamphetamine metabolites 3,4-dihydroxymethamphetamine and 4 hydroxy-3-methoxymethamphetamine using the substrate-depletion approach. AB - Different pharmacokinetic properties are known for the two enantiomers of the entactogen 3,4-methylendioxy-methamphetamine (MDMA), most likely due to enantioselective metabolism. The aim of the present work was 1) the investigation of the main sulfotransferases (SULT) isoenzymes involved in the sulfation of the main MDMA phase I metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4-hydroxy-3 methoxymethamphetamine (HMMA) and 2) the evaluation of a possible enantioselectivity of this phase II metabolic step. Therefore, racemic DHMA and HMMA were incubated with heterologously expressed SULTs, and quantification of the sulfates by liquid chromatography-high-resolution mass spectrometry was conducted. Because separation of DHMA and HMMA sulfate could not be achieved by liquid chromatography, enantioselective kinetic parameters were determined using the substrate-depletion approach with enantioselective quantification of substrate consumption by gas chromatography-negative ion chemical ionization mass spectrometry. SULT1A1 and SULT1A3 catalyzed sulfation of DHMA, and SULT1A3 and SULT1E1 catalyzed sulfation of HMMA. SULT1A1 and SULT1E1 revealed classic Michaelis-Menten kinetics, whereas SULT1A3 kinetics showed deviation from the typical Michaelis-Menten kinetics, resulting in a concentration-dependent self inhibition. SULT1A3 showed the highest affinity and capacity of the SULT isoforms. Marked enantioselectivity could be observed for S-DHMA sulfation by SULT1A3 and in human liver cytosol, whereas no differences were observed for HMMA sulfation. Finally, comparison of K(m) and V(max) values calculated using achiral product formation and chiral substrate depletion showed good correlation within 2 fold of each other. In conclusion, preferences for S-enantiomers were observed for DHMA sulfation, but not for HMMA sulfation. PMID- 21795467 TI - Cytochrome P450 Pig liver pie: determination of individual cytochrome P450 isoform contents in microsomes from two pig livers using liquid chromatography in conjunction with mass spectrometry [corrected]. AB - The cytochrome P450 (P450) family of enzymes is a major player in the metabolism of therapeutic drugs available on the market, and the development of novel drugs has to take into account these enzymes in the fate of new drugs. Testing the pharmacokinetic behavior of new drugs in animals is a common part of the drug development process. Pigs are increasingly used for this purpose because of their similarity of enzymatic pattern to humans. In this study, adult Suffolk White pig liver microsomal samples were analyzed using mass-spectrometry-based techniques to identify and relatively quantify the porcine hepatic P450 enzymes. The total corrected microsomal protein content (milligrams of protein per gram of liver tissue) was estimated at 32.6 and 36.2 mg/g liver tissue in two samples, and the main identified liver P450 subfamilies were CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, and CYP3A. Label-free quantification was performed using the exponentially modified protein abundance index, and the highest abundance enzymes were CYP2A19 at 34% and CYP2D25 at 26% of the total identified drug-metabolizing P450 enzymes. The highest abundance subfamilies were CYP2A (34%), CYP2C (16%), CYP2D (26%), and CYP3A (14%). Moreover, primary sequence alignment was used to identify human homologs of the identified porcine P450s. Porcine CYP1A2 and CYP2E1 were shown to be equivalent to human CYP1A2 and CYP2E1, respectively. Porcine CYP2A19 has the highest sequence homology to human CYP2A6 and CYP2A13, and pig CYP2C33v4 and CYP2C49 are the porcine equivalent of human CYP2C9 and CYP2C18, respectively. Both identified pig CYP3A enzymes (CYP3A29 and CYP39) were highly homologous to CYP3A4/5. PMID- 21795468 TI - The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel. AB - As a direct-acting inhibitor of CYP2C19 in vitro, lansoprazole is more potent than omeprazole and other proton pump inhibitors (PPIs), but lansoprazole does not cause clinically significant inhibition of CYP2C19 whereas omeprazole does. To investigate this apparent paradox, we evaluated omeprazole, esomeprazole, R omeprazole, lansoprazole, and pantoprazole for their ability to function as direct-acting and metabolism-dependent inhibitors (MDIs) of CYP2C19 in pooled human liver microsomes (HLM) as well as in cryopreserved hepatocytes and recombinant CYP2C19. In HLM, all PPIs were found to be direct-acting inhibitors of CYP2C19 with IC(50) values varying from 1.2 MUM [lansoprazole; maximum plasma concentration (C(max)) = 2.2 MUM] to 93 MUM (pantoprazole; C(max) = 6.5 MUM). In addition, we identified omeprazole, esomeprazole, R-omeprazole, and omeprazole sulfone as MDIs of CYP2C19 (they caused IC(50) shifts after a 30-min preincubation with NADPH-fortified HLM of 4.2-, 10-, 2.5-, and 3.2-fold, respectively), whereas lansoprazole and pantoprazole were not MDIs (IC(50) shifts < 1.5-fold). The metabolism-dependent inhibition of CYP2C19 by omeprazole and esomeprazole was not reversed by ultracentrifugation, suggesting that the inhibition was irreversible (or quasi-irreversible), whereas ultracentrifugation largely reversed such effects of R-omeprazole. Under various conditions, omeprazole inactivated CYP2C19 with K(I) (inhibitor concentration that supports half the maximal rate of inactivation) values of 1.7 to 9.1 MUM and k(inact) (maximal rate of enzyme inactivation) values of 0.041 to 0.046 min(-1). This study identified omeprazole, and esomeprazole, but not R-omeprazole, lansoprazole, or pantoprazole, as irreversible (or quasi-irreversible) MDIs of CYP2C19. These results have important implications for the mechanism of the clinical interaction reported between omeprazole and clopidogrel, as well as other CYP2C19 substrates. PMID- 21795469 TI - Avian and mammalian reoviruses use different molecular mechanisms to synthesize their {micro}NS isoforms. AB - Previous reports revealed that the M3 gene of both avian and mammalian reoviruses express two isoforms of the non-structural protein MUNS in infected cells. The larger isoforms initiate translation at the AUG codon closest to the 5' end of their respective m3 mRNAs, and were therefore designated MUNS. In this study we have performed experiments to identify the molecular mechanisms by which the smaller MUNS isoforms are generated. The results of this study confirmed the previous findings indicating that the smaller mammalian reovirus MUNS isoform is a primary translation product, the translation of which is initiated at the internal AUG-41 codon of mammalian reovirus m3 mRNA. Our results further revealed that the smaller avian reovirus MUNS isoform originates from a specific post translational cleavage site near the amino terminus of MUNS. This cleavage produces a 55 kDa carboxy-terminal protein, termed MUNSC, and a 17 kDa amino terminal polypeptide, designated MUNSN. These results allowed us to extend the known avian reovirus protein-encoding capacity to 18 proteins, 12 of which are structural proteins and six of which are non-structural proteins. Our finding that avian and mammalian reoviruses use different mechanisms to express their MUNSC isoforms suggests that these isoforms are important for reovirus replication. PMID- 21795470 TI - The effects of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization. AB - Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is a multi-functional protein that is expressed in basally phosphorylated (p56) and in hyperphosphorylated (p58) forms. NS5A phosphorylation has been implicated in regulating multiple aspects of HCV replication. We recently reported the identification of a class of compounds that potently inhibit HCV RNA replication by targeting NS5A. Although the precise mechanism of inhibition of these compounds is not well understood, one activity that has been described is their ability to block expression of the hyperphosphorylated form of NS5A. Here, we report that an NS5A inhibitor impaired hyperphosphorylation without affecting basal phosphorylation at the C-terminal region of NS5A. This inhibitor activity did not require NS5A domains II and III and was distinct from that of a cellular kinase inhibitor that also blocked NS5A hyperphosphorylation, results that are consistent with an inhibitor-binding site within the N-terminal region of NS5A. In addition, we observed that an NS5A inhibitor promoted the accumulation of an HCV polyprotein intermediate, suggesting that inhibitor binding to NS5A may occur prior to the completion of polyprotein processing. Finally, we observed that NS5A p56 and p58 separated into different membrane fractions during discontinuous sucrose gradient centrifugation, consistent with these NS5A phosphoforms performing distinct replication functions. The p58 localization pattern was disrupted by an NS5A inhibitor. Collectively, our results suggest that NS5A inhibitors probably impact several aspects of HCV expression and regulation. These findings may help to explain the exceptional potency of this class of HCV replication complex inhibitors. PMID- 21795471 TI - Baculovirus IAP1 induces caspase-dependent apoptosis in insect cells. AB - Baculoviruses encode inhibitors of apoptosis (IAPs), which are classified into five groups, IAP1-5, based on their sequence homology. Most of the baculovirus IAPs with anti-apoptotic functions belong to the IAP3 group, with certain exceptions. The functional roles of IAPs from other groups during virus infection have not been well established. We have previously shown that Hyphantria cunea multiple nucleopolyhedrovirus (HycuMNPV) encodes three iap genes, hycu-iap1, hycu iap2 and hycu-iap3, and that only Hycu-IAP3 has anti-apoptotic activity against actinomycin D-induced apoptosis of Spodoptera frugiperda Sf9 cells. In the present study, we demonstrate that transient expression of Hycu-IAP1 is capable of inducing apoptosis and/or stimulating caspase-3-like protease activity in various lepidopteran and dipteran cell lines. Transient-expression assay analysis also demonstrates that not only Hycu-IAP1 but also IAP1s from Autographa californica MNPV, Bombyx mori NPV and Orgyia pseudotsugata MNPV (OpMNPV) are capable of inducing apoptosis, and that apoptosis induced by Hycu-IAP1 is precluded by the functional anti-apoptotic baculovirus protein Hycu-IAP3. In HycuMNPV-infected Spilosoma imparilis (SpIm) cells and OpMNPV-infected Ld652Y cells, caspase-3-like protease activity is markedly stimulated during the late stages of infection, and the caspase-3-like protease activity stimulated in HycuMNPV-infected SpIm cells is repressed by RNA interference-mediated silencing of hycu-iap1. In addition, initiator caspase Bm-Dronc, the B. mori homologue of Dronc, is cleaved upon transfection of BM-N cells with a plasmid expressing Hycu IAP1. These results provide the first evidence that baculovirus IAP1s act to induce caspase-dependent apoptosis, possibly by replacing the cellular IAP1 that prevents Dronc activation. PMID- 21795472 TI - Ultracentrifugation deforms unfixed influenza A virions. AB - Negatively stained influenza virions sometimes show irregular morphology and are often referred to as pleomorphic. However, this irregular morphology has not been visualized when ultrathin-section transmission and scanning electron microscopies are used. This study focused on the effects of ultracentrifugation on influenza A virion morphology, as negative staining often involves ultracentrifugation to concentrate or purify virions. The morphologies of unfixed, glutaraldehyde-fixed and osmium tetroxide-fixed virions were quantitatively compared before and after ultracentrifugation, and it was found that, without chemical fixation, approximately 30% of virions were altered from oval to irregular shapes following ultracentrifugation. By contrast, most glutaraldehyde-fixed virions remained uniformly elliptical, even after ultracentrifugation. When a virus with an 11 aa deletion at the C terminus of its M2 cytoplasmic tail was ultracentrifuged, its morphology was appreciably deformed compared with that of the wild-type virus. These results demonstrate that the native morphology of influenza A virions is regular but is disrupted by ultracentrifugation, and that the cytoplasmic tail of M2 is important for virion integrity. PMID- 21795473 TI - Genetic diversity of novel circular ssDNA viruses in bats in China. AB - Novel circular ssDNA genomes have recently been detected in animals and in the environment using metagenomic and high-throughput sequencing approaches. In this study, five full-length circular ssDNA genomes were recovered from bat faecal samples using inverse PCR with sequences designed based on circovirus-related sequences obtained from Solexa sequencing data derived from a random amplification method. These five sequences shared a similar genomic organization to circovirus or the recently proposed cyclovirus of the family Circoviridae. The newly obtained circovirus/cyclovirus-like genomes ranged from 1741 to 2177 bp, and each consisted of two major ORFs, ORF1 and ORF2, encoding putative replicase (Rep) and capsid (Cap) proteins, respectively. The potential stem-loop region was predicted in all five genomes, and three of them had the typical conserved nonanucleotide motif of cycloviruses. A set of primers targeting the conserved Rep region was designed and used to detect the prevalence of circovirus/cyclovirus sequences in individual bats. Among 199 samples tested, 47 were positive (23.6%) for the circovirus genome and two (1.0%) were positive for the cyclovirus genome. In total, 48 partial Rep sequences plus the five full length genomes were obtained in this study. Detailed analysis indicated that these sequences are distantly related to known circovirus/cyclovirus genomes and may represent 22 novel species that belong to the family Circoviridae. PMID- 21795474 TI - High rate of viral evolution in the capsid protein of porcine parvovirus. AB - In recent years, it has been shown that some parvoviruses exhibit high substitution rates, close to those of RNA viruses. In order to monitor and determine new mutations in porcine parvovirus (PPV), recent PPV field isolates from Austria, Brazil, Germany and Switzerland were sequenced and analysed. These samples, together with sequences retrieved from GenBank, were included in three datasets, consisting of the complete NS1 and VP1 genes and a partial VP1 gene. For each dataset, the nucleotide substitution rate and the molecular clock were determined. Analysis of the PPV field isolates revealed that a recently described amino acid substitution, S436T, appeared to be common in the VP2 protein in the Austrian, Brazilian and German virus populations. Furthermore, new amino acid substitutions were identified, located mainly in the viral capsid loops. By inferring the evolutionary dynamics of the PPV sequences, nucleotide substitution rates of approximately 10(-5) substitutions per site per year for the non structural protein gene and 10(-4) substitutions per site per year for the capsid protein gene (for both viral protein datasets) were found. The latter rate is similar to those commonly found in RNA viruses. An association of the phylogenetic tree with the molecular clock analysis revealed that the mutations on which the divergence for both capsid proteins was based occurred in the past 30 years. Based on these findings, it was concluded that PPV variants are continuously evolving and that vaccines, which are based mainly on strains isolated about 30 years ago, should perhaps be updated. PMID- 21795475 TI - Discovery of an orthoreovirus in the aborted fetus of a Steller sea lion (Eumetopias jubatus). AB - An aborted mid-gestational male Steller sea lion fetus with an attached placenta was recovered on the floor of an open floating capture trap located off Norris Rock near Denman Island, British Columbia. Viral culture of the placenta demonstrated cytopathic effect. Although no specific signal was obtained in microarray experiments using RNA obtained from viral culture, elution and sequence analysis revealed the presence of a reovirus. Complete genome pyrosequencing led to the identification of an orthoreovirus that we have tentatively named Steller sea lion reovirus (SSRV). Phylogenetic analysis revealed similarities between SSRV and orthoreoviruses of birds, bats and other mammals that suggests potential for interspecies transmission. PMID- 21795477 TI - The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. AB - The incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a function-based screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis. PMID- 21795476 TI - Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. AB - A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker gammaH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in gammaH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic. PMID- 21795479 TI - Previously reported sonographic appearances of regional melanoma metastases are not likely due to necrosis. AB - OBJECTIVES: Sonography has proven to be a reliable tool in early detection of lymph node and in-transit cutaneous-subcutaneous metastases. Those metastases normally appear as hypoechoic or even anechoic lesions on sonography. It has been assumed that this appearance is due to necrosis of the lesions, but so far, that assumption has never been proven. The purpose of this retrospective study was to evaluate whether the hypoechoic appearance of melanoma metastasis is really due to tumor necrosis. METHODS: From a radiographic database, we retrieved 212 melanoma cases imaged with sonography over a 2-year period for disease staging or follow-up. We selected 37 positive cases with 84 nodal and extranodal (satellite and in-transit) metastatic lesions and reviewed the sonograms and pathologic slides (slides available for 40 of 84 lesions). We retrospectively assessed the vascularization pattern (color Doppler images available for 78 of 84 lesions), categorizing it as poor, intermediate, or consistent. We also looked for necrosis on the histopathologic material, categorizing it into scores of 0, 1, 2, and 3 for absence of necrosis, less than 20% necrosis, 20% to 40% necrosis, and greater than 40% necrosis, respectively. RESULTS: Despite their gray scale appearance, most melanoma lesions were vascularized on color Doppler imaging and showed limited necrosis at histopathologic analysis. Consistent vascularization on Doppler imaging, excluding substantial necrosis, was found in 44 of 78 lesions (56.4%). Poor vascularization on Doppler imaging, suggesting necrosis, was present in only 14% of the lesions. Substantial necrosis (scores of 2 and 3) was found pathologically in only 10% of the lesions. CONCLUSIONS: Necrosis seems to be an uncommon event in melanoma metastasis and is probably not the basis for its low-level echo pattern on sonography. The hypoechoic appearance is very typical of melanoma metastasis and is likely due to massive melanomatous infiltration (with the poor echo reflectivity of melanin). However, confirmation in larger pathologically proven series is required. PMID- 21795480 TI - Application of endoscopic sonography in preoperative staging of rectal cancer: six-year experience. AB - OBJECTIVES: The aim of this study was to evaluate our experience with the application of endoscopic sonography in preoperative staging of rectal cancer. METHODS: Between April 2004 and May 2010, 192 patients with rectal cancer first underwent endoscopic sonography and then underwent surgery at our hospital. None of the patients in this study received neoadjuvant therapy. The endoscopic sonographic staging results were compared with those of postoperative pathologic staging. RESULTS: The accuracy of overall T staging was 86.5%, and for T1, T2, T3, and T4, the accuracy rates were 86.7%, 94.0%, 86.2%, and 65.5%, respectively. The accuracy of T staging for ulcerated lesions was significantly lower than that for nonulcerated lesions (P = .013). The accuracy of T staging between nontraversable stenotic lesions and traversable lesions was also significantly different (P = .002). The accuracy of N staging was 77.8%, and the specificity and sensitivity were 85.6% and 74.2%, respectively. CONCLUSIONS: Endoscopic sonography is safe and effective for preoperative staging of rectal cancer and should be a routine examination before surgery. As for ulcerated and nontraversable stenotic lesions, however, the results of endoscopic sonographic staging could be doubtful. Moreover, the accuracy of endoscopic sonographic N staging still needs modification by further research. PMID- 21795478 TI - Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. AB - Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment. PMID- 21795481 TI - Usefulness of the twinkling artifact in identifying implanted mesh after inguinal hernia repair. AB - OBJECTIVES: Implanted mesh for inguinal hernia repair is often difficult to visualize with gray scale sonography and may present without the knowledge of the sonographer. We sought to evaluate the utility of the twinkling artifact produced by inguinal mesh to assist in mesh identification. METHODS: Two reviewers evaluated focused sonographic examinations of 44 inguinal regions, 24 of which had implanted inguinal mesh. The sonographic examinations consisted of static gray scale and color Doppler images with both linear and curvilinear array transducers. The presence of the twinkling artifact and visibility of the mesh were graded on a 4-point visibility scale. RESULTS: Inguinal mesh was not easily identified on gray scale imaging using either the curvilinear array (P = .5) or linear array (P = .5) transducer. The mesh was definitely seen in 3 of 24 inguinal regions using the linear array transducer and 2 of 24 inguinal regions using the curvilinear array transducer. In 79% of inguinal regions with mesh, the twinkling artifact was produced with the curvilinear array transducer only. The artifact was not elicited when using the linear array transducer. With the use of the curvilinear array transducer and the presence of the twinkling artifact, there was a significant chance of correctly identifying the presence of mesh (P < .005) in the entire study group. CONCLUSIONS: Standard gray scale imaging alone is not reliable when identifying inguinal mesh. The twinkling artifact was present in 79% of inguinal regions with mesh when evaluated with a low-frequency curvilinear array transducer. PMID- 21795482 TI - Detection of intracranial arterial stenosis using transcranial color-coded duplex sonography, computed tomographic angiography, and digital subtraction angiography. AB - OBJECTIVES: The aim of this retrospective study was to compare intracranial arterial stenosis in patients with stroke using 3 different methods: transcranial color-coded duplex sonography, computed tomographic (CT) angiography, and digital subtraction angiography in a common clinical practice. METHODS: Sixty-seven patients (47 male and 20 female; age range, 23-79 years; mean age +/- SD, 62.0 +/ 9.5 years) were enrolled in this study over 40 months. All patients underwent examinations of the intracranial arteries using transcranial color-coded sonography, CT angiography, and digital subtraction angiography. Findings were divided into 4 groups: normal, mild stenosis (<50%), severe stenosis (50%-99%), and occlusion. RESULTS: Because of technical reasons or an insufficient bone window, 465 of 536 arterial segments in 67 patients were evaluated; 12 stenotic and 15 occluded segments were detected using digital subtraction angiography. The sensitivity, specificity, positive predictive value, and negative predictive value of transcranial color-coded sonography and CT angiography in comparison with digital subtraction angiography as a reference standard were 88.9%, 94.8%, 51.1%, and 99.3% and 81.5%, 98.7%, 78.6%, and 98.6%, respectively. The agreement between transcranial color-coded sonography and CT angiography was 93.8% (kappa = 0.559); between transcranial color-coded sonography and digital subtraction angiography, it was 93.9% (kappa = 0.588); and between CT angiography and digital subtraction angiography, it was 96.6% (kappa = 0.697). CONCLUSIONS: Moderate agreement was found between CT angiography, transcranial color-coded sonography, and digital subtraction angiography in the evaluation of intracranial stenosis. Computed tomographic angiography and digital subtraction angiography are sufficient for assessment of the diagnosis. PMID- 21795483 TI - Enhancing awareness of the diagnostic medical sonography professions: a high school outreach program. AB - OBJECTIVES: The purpose of this project was to develop a presentation that can be used to increase the number of high school students who recognize diagnostic medical sonography (DMS) professions as career alternatives and will consider pursuing DMS careers. METHODS: An interactive program was developed that includes a digital presentation, question-and-answer session, and scanning demonstration. The program was presented to students at their high schools. Handout materials were provided, and a questionnaire was distributed to obtain feedback regarding the program's content and effectiveness. Refinements to the program were made based on feedback. A Student t test was used to determine the statistical significance of changes in students' level of knowledge about DMS and their interest in pursuing a DMS career before and after the program. The student preferred component of the program was assessed by 1-way analysis of variance. RESULTS: Six programs were provided to a total of 148 high school students. Of 120 students who returned questionnaires, 90% indicated that their level of knowledge of DMS increased after the program, and 60% indicated that their level of interest in pursuing a DMS career had increased. The increases in both knowledge and interest were statistically significant (P < .0001). Forty-nine percent of students indicated that the scanning demonstration was the most interesting aspect of the program. CONCLUSIONS: This program was very well received by students and teachers. It significantly improved students' knowledge about DMS and their interest in pursuing a DMS career. Presentation materials used in this program are available to DMS professionals who would like to provide similar programs to students in their geographic areas. The PowerPoint presentation and related documents can be downloaded from the American Institute of Ultrasound in Medicine's website at http://www.aium.org/misc/dms.aspx. PMID- 21795484 TI - In vitro models of the fetal lung: comparison of lung volume measurements with 3 dimensional sonography and magnetic resonance imaging. AB - OBJECTIVES: Three-dimensional (3D) sonography is an established volumetric method in gynecology and obstetrics. The aim of this study was to investigate the variability of 3D sonographic measurements and their accuracy in comparison with magnetic resonance imaging (MRI) for assessing fetal lung volume using in vitro lung models. METHODS: Twenty-three in vitro lung models with randomly defined volumes ranging from 1 to 60 mL were made from gelatin with plastic sheaths, manually molded into the shape of fetal lungs. The models were measured using 3D sonography and MRI. The 3D sonographic volumes were calculated using the rotational technique with angles of 6 degrees and 30 degrees . Multiplanar T2 weighted sequences were used for the MRI measurements. The percentage error and absolute percentage error were calculated for each method, and intraobserver and interobserver variability in 3D sonographic measurements was assessed with intraclass correlation coefficients (ICCs). Agreement between calculated and real volumes using the limits of agreement method was also evaluated. RESULTS: The ICCs for the rotation angles indicated very good intraobserver and interobserver variability (6 degrees , 0.995 and 0.996; 30 degrees , 0.997 and 0.985). No systematic errors were observed in the mean percentage errors for 3D sonographic measurements or MRI volumetry. The lowest median absolute percentage error (1.76) was obtained with MRI volumetry, significantly lower than the values for sonography (6 degrees , 5.00; P < .001; 30 degrees , 5.49; P < .001). There were no significant differences in absolute percentage errors between the rotation angles (P = .82) and no significant differences in limits of agreement between 3D sonography and MRI (6 degrees , P = .76; 30 degrees , P = .39). CONCLUSIONS: Three-dimensional sonographic volumetry was almost as accurate as MRI in this in vitro model and can be regarded as a good alternative method. Further research is needed to confirm these findings in vivo and to assess the prognostic value in fetuses with lung hypoplasia (eg, congenital diaphragmatic hernias). PMID- 21795485 TI - Second-trimester estimated fetal weight and discordance in twin pregnancies: association with fetal growth restriction. AB - OBJECTIVES: The purpose of this study was to estimate the association between second-trimester estimated fetal weight and fetal growth restriction in twin pregnancies. METHODS: A historical cohort of 306 twin pregnancies from a single center was analyzed. Estimated fetal weight and discordance at 18 to 24 weeks were calculated. Patients with a fetus whose second-trimester estimated fetal weight was below the 10th percentile were compared to patients with both fetuses at or above the 10th percentile. Also, patients with second-trimester discordance of 15% or greater were compared to patients with discordance of less than 15%. RESULTS: Second-trimester discordance was significantly smaller than birth weight discordance (mean discordance +/- SD, 7.41% +/- 6.06% versus 11.43% +/- 9.6%, respectively; P < .001). Patients with second-trimester discordance of 15% or greater were significantly more likely to deliver a twin with a birth weight below the 10th percentile for gestational age (67.7% versus 44.1%; P = .012) and below the 5th percentile for gestational age (41.9% versus 22.8%; P = .019). Patients with a second-trimester estimated fetal weight below the 10th percentile were significantly more likely to deliver a twin with a birth weight below the 10th percentile for gestational age (65.5% versus 44.5%; P = .031) and below the 5th percentile for gestational age (55.2% versus 21.5%; P < .001). CONCLUSIONS: In twin pregnancies, second-trimester estimated fetal weight below the 10th percentile and discordance of 15% or greater are associated with fetal growth restriction. PMID- 21795486 TI - Contrast-enhanced sonographic characterization of the vascularity of the repaired rotator cuff: utility of maximum intensity projection imaging. AB - OBJECTIVES: To characterize the distribution of vascularity of the postoperative rotator cuff tendon using a maximum intensity projection technique after contrast enhanced sonography. METHODS: We retrospectively evaluated image data on 23 patients (11 male and 12 female) with intact rotator cuff repairs who had previously undergone contrast-enhanced sonography of their shoulders using lipid microspheres before and after a standardized exercise protocol. The patients were on average 3 months out from their surgery. Using offline image analysis software, a maximum intensity projection image was obtained for each patient, reflecting the regional vascular distribution within the repair and adjacent soft tissue. Subjective analysis was performed in 4 regions of interest: peribursal, articular medial, articular lateral, and suture anchor, independently by 2 musculoskeletal radiologists using a semiquantitative scale ranging from 0 to 4 for each region (0, no enhancement; 1, 1%-25% enhancement; 2, 26%-50%; 3, 51% 75%; and 4, 76%-100%). A combined vascularity score (0-8) was produced for each region and formed the basis for the subjective analysis. RESULTS: Using a Mann Whitney nonparametric test, the data showed significantly higher regional enhancement in the peribursal and suture anchor regions compared to the tendon (P < .001). Exercise resulted in a statistically significant increase in the extent of enhancement in all regions (P < .002). Inter-rater reliability analysis using a weighted kappa statistic showed strong agreement (0.63-0.64) for the suture anchor site and moderate agreement for the others (peribursal, 0.35-0.39; articular medial, 0.45-0.55; and articular lateral 0.32-0.33). CONCLUSIONS: The maximum intensity projection technique after contrast-enhanced sonography provides a topographic map of rotator cuff vascularity; the latter has been implicated as an important factor in promoting bone-tendon healing. Approximately 3 months after rotator cuff repair, the suture anchor and peribursal regions showed the most robust vascularity. Maximum intensity projection imaging further establishes that there is a global increase in vascular response at the repair site after exercise. PMID- 21795487 TI - Sonography of benign palpable masses of the elbow. AB - The purpose of this pictorial essay is to show the sonographic appearances of benign masses found in and around the elbow, including fat-containing tumors, fibrous tumors, vascular lesions, selected skin lesions, and other miscellaneous lesions. Sonographic features, including the use of dynamic and color Doppler imaging, can be helpful in characterizing these masses and in narrowing the differential diagnosis. PMID- 21795488 TI - Statistical analysis and interpretation of prenatal diagnostic imaging studies, Part 1: evaluating the efficiency of screening and diagnostic tests. AB - Screening and diagnostic testing play fundamental roles in all fields of clinical medicine, with obstetric imaging and prenatal diagnosis being no exceptions. With advances in maternal serum screening and ultrasound technology, much research effort in the field of pre-natal diagnosis has actually been dedicated to the development and refinement of screening tests for fetal aneuploidy and other congenital disorders. This article aims to review the differences between screening and diagnostic tests, describe the accepted criteria for an efficient screening test, and provide an overview of the calculation and interpretation of test performance characteristics in relation to prenatal imaging studies. PMID- 21795489 TI - Statistical analysis and interpretation of prenatal diagnostic imaging studies, Part 2: descriptive and inferential statistical methods. AB - The objective of this article is to discuss the rationale for common statistical tests used for the analysis and interpretation of prenatal diagnostic imaging studies. Examples from the literature are used to illustrate descriptive and inferential statistics. The uses and limitations of linear and logistic regression analyses are discussed in detail. PMID- 21795490 TI - Development of a mobile ultrasound-guided peripheral nerve block and catheter service. AB - Ultrasound guidance is associated with improved efficiency and success of peripheral nerve blockade and a decreased incidence of vascular puncture, making these interventions safer. Patients with peripheral nerve blocks report decreased pain and increased satisfaction scores. We present the development of a mobile ultrasound-guided block service that allows for the safe and efficient placement of nerve blocks and perineural catheters at the nontraditional location of the patient's bedside and in the emergency department. PMID- 21795491 TI - The "filarial dance" is not characteristic of filariasis: observations of "dancing megasperm" on high-resolution sonography in patients from nonendemic areas mimicking the filarial dance and a proposed mechanism for this phenomenon. AB - The objective of this series was to show that the sonographic appearance described as the "filarial dance" is not characteristic of filariasis but occurs in nonendemic areas as a manifestation of epididymal obstruction. An experienced observer documented cases after initial observation of the filarial dance in routine clinical practice using high-frequency linear array transducers. The filarial dance was described as excessive to-and-fro movement of echogenic particles within a prominent epididymis and graded 1 to 4 according to the extent and distribution of the abnormality. The country of birth, exposure to filarial infection or travel to a filarial-endemic area, previous scrotal surgery including vasectomy, any previous or current scrotal inflammatory disease, and any congenital testicular abnormalities were recorded. Over a 10-year period, sonographic appearances consistent with the filarial dance were observed in 18 patients (bilateral in 6). The mean patient age was 47.7 (range, 28-91) years. The abnormality was graded in the 24 affected testes as follows: grade 1, n = 3; grade 2, n = 8; grade 3, n = 8; and grade 4, n = 5. No patient had a history of filariasis or travel to an endemic area. Six of 18 patients (33.3%) had bilateral vasectomies; 5 (27.8%) had a history of epididymo-orchitis in the ipsilateral testis; 3 (16.7%) had previous scrotal surgery; and 4 (22.2%) had no relevant urologic history. We have described a sonographic appearance identical to the filarial dance in men with no history of filarial infection. Most had previous scrotal surgery or infection, suggesting that the filarial dance may not always be due to movement of filarial worms. The unifying condition in patients with filariasis and our patients is lymphatic obstruction, likely the underlying cause of the appearance in both groups. PMID- 21795492 TI - Treatment of twin-twin transfusion syndrome with proximate umbilical cord insertions. AB - Laser ablation of anastomosis is one method for treatment of twin-twin transfusion syndrome in monochorionic pregnancies. Sonographic mapping of the umbilical cord insertions is an important aspect of the preoperative workup before laser ablation. Proximate umbilical cord insertions can be potential contraindications to laser ablation. This series discusses 6 such cases. PMID- 21795493 TI - Do not confuse the edge-to-edge technique with mitral valve stenosis: methodological considerations for echocardiography after mitral valve repair. PMID- 21795494 TI - External jugular vein aneurysm: a rare cause of neck swelling. PMID- 21795495 TI - Forehead hemangioma: a rare location for a large vascular tumor in a fetus. PMID- 21795496 TI - Laterally displaced superior vena cava on the fetal 3-vessel view from a right diaphragmatic hernia. PMID- 21795497 TI - The bifurcating distal biceps femoris tendon: potential pitfall in musculoskeletal sonography. PMID- 21795499 TI - Population sciences, translational research, and the opportunities and challenges for genomics to reduce the burden of cancer in the 21st century. AB - Advances in genomics and related fields are promising tools for risk assessment, early detection, and targeted therapies across the entire cancer care continuum. In this commentary, we submit that this promise cannot be fulfilled without an enhanced translational genomics research agenda firmly rooted in the population sciences. Population sciences include multiple disciplines that are needed throughout the translational research continuum. For example, epidemiologic studies are needed not only to accelerate genomic discoveries and new biological insights into cancer etiology and pathogenesis, but to characterize and critically evaluate these discoveries in well-defined populations for their potential for cancer prediction, prevention and response to treatment. Behavioral, social, and communication sciences are needed to explore genomic modulated responses to old and new behavioral interventions, adherence to therapies, decision making across the continuum, and effective use in health care. Implementation science, health services, outcomes research, comparative effectiveness research, and regulatory science are needed for moving validated genomic applications into practice and for measuring their effectiveness, cost effectiveness, and unintended consequences. Knowledge synthesis, evidence reviews, and economic modeling of the effects of promising genomic applications will facilitate policy decisions and evidence-based recommendations. Several independent and multidisciplinary panels have recently made specific recommendations for enhanced research and policy infrastructure to inform clinical and population research for moving genomic innovations into the cancer care continuum. An enhanced translational genomics and population sciences agenda is urgently needed to fulfill the promise of genomics in reducing the burden of cancer. PMID- 21795500 TI - The GISS trial: a phase II prevention trial of screening plus goserelin, ibandronate, versus screening alone in premenopausal women at increased risk of breast cancer. AB - BACKGROUND: Genetic testing for inherited mutations in breast cancer genes provides valuable information for disease prevention. Today, premenopausal women with increased risk for breast cancer have only limited nonsurgical options to reduce their risk. METHODS: The GISS trial, a randomized, multicenter, open-label phase II trial, assessed the feasibility of a preventive treatment with goserelin and ibandronate for premenopausal women at increased risk for breast cancer. The primary endpoints were refusal to undergo randomization and discontinuation of treatment. Safety and quality of life were also evaluated. RESULTS: Between the years 2001 and 2003, 31 of 322 eligible women participated in the trial; 15 received goserelin/ibandronate plus screening, 15 screening only, and 1 withdrew her consent after randomization. The treatment duration was 24 months. Here, mainly the results from the first 12 months were evaluated because of the low compliance thereafter. Hot flushes, headache, and vaginal dryness/discharge occurred more often in the goserelin arm. No difference was observed between the two arms in the agreement to randomization, compliance, or any other endpoints. CONCLUSIONS: Acceptance of chemoprevention with goserelin and ibandronate was low. Premenopausal women at increased risk for breast cancer should be better informed about chemoprevention through physician counseling and a more feasible study design (e.g., oral medication) should be provided. IMPACT: This is the first chemoprevention trial in premenopausal women at increased risk for breast cancer. PMID- 21795498 TI - Confirmation of 5p12 as a susceptibility locus for progesterone-receptor positive, lower grade breast cancer. AB - BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. METHODS: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. RESULTS: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 * 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 * 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 * 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 * 10(-7)]. CONCLUSION: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. IMPACT: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. PMID- 21795502 TI - Novel protective effect of mifepristone on detrimental GABAA receptor activity to immature Purkinje neurons. AB - Immature Purkinje neurons are particularly vulnerable cells. They survive in cerebellar slice cultures under treatment by the synthetic steroid mifepristone (RU486) that depolarizes them at this age. The present study aims at understanding the mechanism underlying this neuroprotective effect. In the developing cerebellum, the role of gamma-aminobutyric acid (GABA) in neuron survival is unknown. In 3-d-old mouse cerebellar slice cultures, we show that GABA(A) receptor activation is depolarizing and excitatory. Antagonists of GABA(A) receptors rescue Purkinje neurons, demonstrating that GABA is endogenously released in this preparation and is toxic. Mifepristone likely protects these neurons by reversing GABA(A) receptor-mediated chloride fluxes and reducing their driving force. Neuroprotection by mifepristone is dose-dependently decreased by the agonist of GABA(A) receptors muscimol and by caffeine, an agonist of internal calcium store release. Moreover, the survival induced by neomycin, an inhibitor of calcium release, is partially reversed by muscimol. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 also rescues Purkinje neurons. In summary, we propose that when GABA is depolarizing, mifepristone protects Purkinje neurons by shunting GABA responses and probably chloride fluxes, by inhibiting p38 MAPK activity and likely internal calcium store release. A new and nonhormonal effect of mifepristone is thus revealed. PMID- 21795501 TI - Replication of breast cancer GWAS susceptibility loci in the Women's Health Initiative African American SHARe Study. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with risk of breast cancer. These studies have primarily been conducted in populations of European descent. To fully understand the impact of these loci, it is important to study groups with other genetic ancestries, including African American women. METHODS: We examined 22 single-nucleotide polymorphisms (SNP), previously identified in GWAS of breast cancer risk in European and Asian descent women (index SNPs), and SNPs in the surrounding regions in a study of 7,800 African American women (including 316 women with incident invasive breast cancer) from the Women's Health Initiative SNP Health Association Resource. RESULTS: Two index SNPs were associated with breast cancer: rs3803662 at 16q12.2/TOX3 (Hazard ratio [HR] for the T allele = 0.79, 95% CI: 0.67-0.92, P = 0.003) and rs10941679 at 5p12 (HR for the G allele = 1.31, 95% CI: 1.06-1.63, P = 0.014). When we expanded to regions, the 3p24.1 region showed an association with breast cancer risk (permutation based P = 0.027) and three regions (10p15.1, 10q26.13/FGFR2, and 16q12.2/TOX3) showed a trend toward association. CONCLUSION: Our findings provide evidence that some breast cancer GWAS regions may be associated with breast cancer in African American women. Larger, more comprehensive studies are needed to fully assess generalizability of published GWAS findings and to identify potential novel associations in African American populations. IMPACT: Both replication and lack of replication of published GWAS findings in other ancestral groups provides important information of the genetic etiology of this disease and may impact translation of GWAS findings to clinical and public health settings. PMID- 21795503 TI - Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample. AB - While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide linkage study of schizophrenia in Arab Israeli families with multiple affected individuals, we previously reported significant evidence for a susceptibility locus at chromosome 6q23.2-q24.1 and suggestive evidence at chromosomes 10q22.3-26.3, 2q36.1-37.3 and 7p21.1-22.3. To identify schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample. We performed genome-wide single nucleotide polymorphism (SNP) genotyping and single SNP transmission disequilibrium test association analysis and found genome-wide significant association (best value of P=1.22*10(-11)) for 8 SNPs within or near highly reasonable functional candidate genes for schizophrenia. Of particular interest are a group of SNPs within and flanking the transcriptional factor LRRFIP1 gene. To determine replicability of the significant associations beyond the Arab-Israeli population, we studied the association of the significant SNPs in a German case-control validation sample and found replication of associations near the UGT1 subfamily and EFHD1 genes. Applying an exploratory homozygosity mapping approach as a complementary strategy to identify schizophrenia susceptibility genes in our Arab Israeli sample, we identified 8 putative disease loci. Overall, this GWAS, which emphasizes the important contribution of family based studies, identifies promising candidate genes for schizophrenia. PMID- 21795504 TI - Epigenetics: DNA demethylation promotes skeletal myotube maturation. AB - Mesenchymal progenitor cells can be differentiated in vitro into myotubes that exhibit many characteristic features of primary mammalian skeletal muscle fibers. However, in general, they do not show the functional excitation-contraction coupling or the striated sarcomere arrangement typical of mature myofibers. Epigenetic modifications have been shown to play a key role in regulating the progressional changes in transcription necessary for muscle differentiation. In this study, we demonstrate that treatment of murine C2C12 mesenchymal progenitor cells with 10 MUM of the DNA methylation inhibitor 5-azacytidine (5AC) promotes myogenesis, resulting in myotubes with enhanced maturity as compared to untreated myotubes. Specifically, 5AC treatment resulted in the up-regulation of muscle genes at the myoblast stage, while at later stages nearly 50% of the 5AC-treated myotubes displayed a mature, well-defined sarcomere organization, as well as spontaneous contractions that coincided with action potentials and intracellular calcium transients. Both the percentage of striated myotubes and their contractile activity could be inhibited by 20 nM TTX, 10 MUM ryanodine, and 100 MUM nifedipine, suggesting that action potential-induced calcium transients are responsible for these characteristics. Our data suggest that genomic demethylation induced by 5AC overcomes an epigenetic barrier that prevents untreated C2C12 myotubes from reaching full maturity. PMID- 21795505 TI - Caveolin-1 deficiency decreases atherosclerosis by hampering leukocyte influx into the arterial wall and generating a regulatory T-cell response. AB - Caveolin-1 plays a crucial role in atherosclerosis, which is mainly attributed to its effects on low-density-lipoprotein (LDL) transcytosis. However, caveolin-1 has also been implicated in the regulation of inflammation. We investigated the effects of caveolin-1 deficiency in atherosclerosis with its accompanying changes in plaque- and lymphoid-related immunology and inflammation. Cav1(-/-)Apoe(-/-) mice exhibited a 15-fold reduction in plaque size with plaques containing fewer macrophages, T cells, and neutrophils. Intravital microscopy revealed 83% less leukocyte adhesion to the vessel wall in Cav1(-/-)Apoe(-/-) mice, which could be attributed to reduced endothelial chemokine ligand-2 (CCL-2/MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Caveolin-1 deficiency resulted in a 57% increase in regulatory T cells and a 4% decrease in CD4(+) effector T cells in lymphoid organs. Bone marrow transplantations revealed that Cav1(-/-)Apoe(-/-) mice receiving Cav1(+/+)Apoe(-/-) or Cav1(-/-)Apoe(-/-) bone marrow presented 4- to 4.5-fold smaller plaques with no additional phenotypic changes. In contrast, atherosclerosis was not affected in Cav1(+/+) Apoe(-/-) recipients receiving Cav1(-/-)Apoe(-/-) or Cav1(+/+) Apoe(-/-) bone marrow. However, the presence of Cav1(-/-) Apoe(-/-) bone marrow was associated with an anti-inflammatory T-cell profile. Our study reveals that nonhematopoietic caveolin-1 determines plaque size, whereas hematopoietic caveolin-1 regulates lymphoid immune-modulation. However, both are required for phenotypic modulation of plaques. PMID- 21795506 TI - Evaluation of quantitative antibiotic susceptibility testing by Vitek 2 as a routine method to predict strain relatedness of coagulase-negative staphylococci isolated from blood cultures. AB - To test the hypothesis that the strain relatedness of coagulase-negative staphylococci (CoNS) recovered from blood cultures can be inferred from automated antibiotic susceptibility testing (AST) results generated by Vitek 2, concordant or discordant AST results were compared with pulsed-field gel electrophoresis (PFGE) typing results for 119 CoNS blood culture isolate pairs. Concordant AST results were highly predictive of the strain relatedness of CoNS isolates. PMID- 21795507 TI - Performance characteristics and comparison of Abbott and artus real-time systems for hepatitis B virus DNA quantification. AB - Virological monitoring of hepatitis B virus (HBV) DNA is critical to the management of HBV infection. With several HBV DNA quantification assays available, it is important to use the most efficient testing system for virological monitoring. In this study, we evaluated the performance characteristics and comparability of three HBV DNA quantification systems: Abbott HBV real-time PCR (Abbott PCR), artus HBV real-time PCR with QIAamp DNA blood kit purification (artus-DB), and artus HBV real-time PCR with the QIAamp DSP virus kit purification (artus-DSP). The lower limits of detection of these systems were established against the WHO international standards for HBV DNA and were found to be 1.43, 82, and 9 IU/ml, respectively. The intra-assay and interassay coefficients of variation of plasma samples (1 to 6 log(10) IU/ml) ranged between 0.05 to 8.34% and 0.16 to 3.48% for the Abbott PCR, 1.53 to 26.85% and 0.50 to 12.89% for artus-DB, and 0.29 to 7.42% and 0.94 to 3.01% for artus-DSP, respectively. Ninety HBV clinical samples were used for comparison of assays, and paired quantitative results showed strong correlation by linear regression analysis (artus-DB with Abbott PCR, r = 0.95; Abbott PCR with artus-DSP, r = 0.97; and artus-DSP with artus-DB, r = 0.94). Bland-Altman analysis showed a good level of agreement for Abbott PCR and artus-DSP, with a mean difference of 0.10 log(10) IU/ml and limits of agreement of -0.91 to 1.11 log(10) IU/ml. No genotype specific bias was seen in all three systems for HBV genotypes A, C, and D, which are predominant in this region. This finding illustrates that the Abbott real time HBV and artus-DSP systems show more comparable performance than the artus-DB system, meeting the current guidelines for assays to be used in the management of hepatitis B. PMID- 21795508 TI - Rapid identification of Staphylococcus aureus and methicillin resistance by flow cytometry using a peptide nucleic acid probe. AB - A total of 56 Staphylococcus aureus isolates incubated for 2 h in the presence or absence of oxacillin were analyzed by flow cytometry after labeling with an S. aureus-specific peptide nucleic acid (PNA) probe. Two defined ratios, the paired signal count ratio (PSCR) and the gate signal count ratio (GSCR), differentiated methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) with sensitivities of 100% each and specificities of 96% and 100%, respectively. PMID- 21795509 TI - Assessment of two new molecular methods for identification of Candida parapsilosis sensu lato species. AB - Candida parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis replaced C. parapsilosis groups I, II, and III in 2005. Since then, an increased interest in studying their epidemiology has arisen based on the observed differences in antifungal susceptibilities and virulence the three species. A strict differentiation of these species cannot be achieved by phenotypic methods. We evaluate two new molecular methodologies to differentiate among these species by the use of a collection of 293 bloodstream infection isolates of C. parapsilosis sensu lato. For the first method, the isolates were studied using PCR amplification of a fragment of the C. parapsilosis sensu lato FKS1 gene and a universal primer pair followed by EcoRI enzyme digestion. The other method used the allele discrimination ability of molecular beacons in a multiplex real-time PCR format. Both methods of identification showed 100% concordance with internal transcribed spacer 1 (ITS1)/ITS2 sequencing and proved to be effective for clinical applications, even with mixed-species DNAs. PMID- 21795510 TI - Genotypic characterization of ureaplasma serovars from clinical isolates by pulsed-field gel electrophoresis. AB - Genetic relationships within ureaplasma serovars were investigated by pulsed field gel electrophoresis (PFGE). One hundred thirteen Ureaplasma parvum isolates and 78 Ureaplasma urealyticum isolates were different from their ATCC serovar type strains and different within the same serovars. The organisms were geographically widespread. No unique patterns were associated with invasive disease. PMID- 21795511 TI - Native valve endocarditis due to a novel strain of Legionella. AB - Legionellae are Gram-negative bacteria which are capable of causing disease, most commonly in the form of pneumonia. We describe a case of native valve endocarditis caused by a Legionella strain which by genotypic (16S rRNA and mip gene sequencing) and phenotypic analyses is unlike previously described strains of Legionella. PMID- 21795512 TI - Sensitivity and specificity of immunocytochemical staining of mycobacterial antigens in the cytoplasm of cerebrospinal fluid macrophages for diagnosing tuberculous meningitis. AB - The sensitivity and specificity of immunocytochemical staining of mycobacterial antigens in the cytoplasm of cerebrospinal fluid (CSF) macrophages for diagnosis of tuberculous meningitis (TBM) was prospectively compared with Ahuja criteria from 393 consecutive CSF specimens. The assay can play an important role for the diagnosis of TBM, with sensitivity of 73.5% and specificity of 90.7%. PMID- 21795513 TI - First report of prosthetic joint infection by Gemella sanguinis and associated "pseudosatelliting" phenomenon on culture. AB - We report the first case of a prosthetic joint infection caused by Gemella sanguinis. This report includes a description of a "pseudosatelliting" phenomenon by G. sanguinis, the use of gene sequencing for pathogen identification, and successful use of debridement, retention, and chronic antibiotic suppression to preserve the prosthesis. PMID- 21795514 TI - Multiple-locus variable-number tandem-repeat analysis genotyping of human Brucella isolates from Turkey. AB - A multiple-locus variable-number tandem-repeat analysis (MLVA) was applied to investigate the epidemiological relationship and genetic diversity among 162 human Brucella isolates collected from all geographic regions of Turkey in an 8 year period (2001 to 2008). The isolates were genotyped by using an MLVA assay developed in Orsay, France (MLVA-16(Orsay)) including eight minisatellite (panel 1) and eight microsatellite (panel 2, subdivided into 2A and 2B) markers. Panels 1 and 2A distinguish 14 genotypes; two of these represented 85% of the strains. Panel 2B displayed a very high discriminatory power. Three loci from panel 2B had diversity index values higher than 0.74. MLVA-16(Orsay) yielded 105 genotypes; 73 were represented by a unique isolate, and 32 included two to eight isolates. The isolates from different patients within the same outbreak or from the same patient before first-line therapy and after relapse showed identical genotypes. A number of MLVA genotypes appeared to be partially restricted to some geographic areas and displayed no annual variation, possibly reflecting persistence of genotypes in certain areas for a time span of at least a decade. This study, representing the first molecular typing results of human Brucella isolates from Turkey, indicated that Turkish human Brucella melitensis isolates were most closely related to the neighboring countries' isolates included in the East Mediterranean group. PMID- 21795515 TI - Using matrix-assisted laser desorption ionization-time of flight mass spectrometry to detect carbapenem resistance within 1 to 2.5 hours. AB - In recent years, the percentage of carbapenem-resistant bacteria has increased at an alarming pace and become a major threat for patient survival. Carbapenemase induced carbapenem resistance can be confirmed through the detection of carbapenem degradation using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). This method works for strains carrying NDM-1, VIM-1, VIM-2, KPC-2, and different IMP enzymes. PMID- 21795516 TI - Clinical and laboratory diagnostic characteristics and cytotoxigenic potential of Hafnia alvei and Hafnia paralvei strains. AB - A collection of 68 Hafnia strains previously identified to the species level by 16S rRNA gene sequencing were investigated for simple phenotypic properties that could aid in their recognition in the clinical laboratory. Four tests, including malonate utilization, fermentation of salicin and d-arabinose, and expression of beta-glucosidase activity, correctly assigned each strain to either Hafnia alvei or H. paralvei. Antibiotic susceptibility profiles were generated for 35 H. alvei and H. paralvei isolates using Etest strips for 24 antibiotics. All strains were susceptible to aminoglycosides, quinolones, carbapenems, and monobactams. Most of the Hafnia isolates had a colistin MIC of >=2 MUg/ml. Sequencing of an internal ampC gene fragment allowed genotypic differentiation of the two Hafnia species. Approximately 70% of the hafniae tested additionally produced a cytolytic toxin active on Vero cells which may play a role in gastroenteritis. PMID- 21795517 TI - Adhesin-encoding genes from shiga toxin-producing Escherichia coli are more prevalent in atypical than in typical enteropathogenic E. coli. AB - Four of six adhesin-encoding genes (lpfA, paa, iha, and toxB) from Shiga toxin producing Escherichia coli strains were detected in typical and atypical enteropathogenic E. coli (EPEC) strains of various serotypes. Although the most prevalent gene was lpfA in both groups, paa was the only potential diarrhea associated gene in atypical EPEC. PMID- 21795518 TI - CyPPA, a positive modulator of small-conductance Ca(2+)-activated K(+) channels, inhibits phasic uterine contractions and delays preterm birth in mice. AB - Organized uterine contractions, including those necessary for parturition, are dependent on calcium entry through voltage-gated calcium channels in myometrial smooth muscle cells. Recent evidence suggests that small-conductance Ca(2+) activated potassium channels (K(Ca)2), specifically isoforms K(Ca)2.2 and 2.3, may control these contractions through negative feedback regulation of Ca(2+) entry. We tested whether selective pharmacologic activation of K(Ca)2.2/2.3 channels might depress uterine contractions, providing a new strategy for preterm labor intervention. Western blot analysis and immunofluorescence microscopy revealed expression of both K(Ca)2.2 and K(Ca)2.3 in the myometrium of nonpregnant (NP) and pregnant (gestation day 10 and 16; D10 and D16, respectively) mice. Spontaneous phasic contractions of isolated NP, D10, and D16 uterine strips were all suppressed by the K(Ca)2.2/2.3-selective activator CyPPA in a concentration-dependent manner. This effect was antagonized by the selective K(Ca)2 inhibitor apamin. Whereas CyPPA sensitivity was reduced in D10 and D16 versus NP strips (pIC(50) 5.33 +/- 0.09, 4.64 +/- 0.03, 4.72 +/- 0.10, respectively), all contractions were abolished between 30 and 60 MUM. Blunted contractions were associated with CyPPA depression of spontaneous Ca(2+) events in myometrial smooth muscle bundles. Augmentation of uterine contractions with oxytocin or prostaglandin F(2alpha) did not reduce CyPPA sensitivity or efficacy. Finally, in an RU486-induced preterm labor model, CyPPA significantly delayed time to delivery by 3.4 h and caused a 2.5-fold increase in pup retention. These data indicate that pharmacologic stimulation of myometrial K(Ca)2.2/2.3 channels effectively suppresses Ca(2+)-mediated uterine contractions and delays preterm birth in mice, supporting the potential utility of this approach in tocolytic therapies. PMID- 21795519 TI - Covalently grafted VEGF(165) in hydrogel models upregulates the cellular pathways associated with angiogenesis. AB - Angiogenesis is an important biological response known to be involved in many physiological and pathophysiological situations. Cellular responses involved in the formation of new blood vessels, such as increases in endothelial cell proliferation, cell migration, and the survival of apoptosis-inducing events, have been associated with vascular endothelial growth factor isoform 165 (VEGF(165)). Current research in the areas of bioengineering and biomedical science has focused on developing polyethylene glycol (PEG)-based systems capable of initiating and sustaining angiogenesis in vitro. However, a thorough understanding of how endothelial cells respond at the molecular level to VEGF(165) incorporated into these systems has not yet been established in the literature. The goal of the current study was to compare the upregulation of key intracellular proteins involved in angiogenesis in human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC) seeded on PEG hydrogels containing grafted VEGF(165) and adhesion peptides Arg-Gly-Asp Ser (RGDS). Our data suggest that the covalent incorporation of VEGF(165) into PEG hydrogels encourages the upregulation of signaling proteins responsible for increases in endothelial cell proliferation, cell migration, and the survival after apoptosis-inducing events. PMID- 21795520 TI - Characterization of FGF receptor expression in human neutrophils and their contribution to chemotaxis. AB - Several members of the fibroblast growth factor (FGF) family are potent endothelial cell (EC) mitogens and angiogenic factors, and their activities can be mediated by four tyrosine kinase receptors (FGFR1-4). In addition, FGFs can induce the release of inflammatory mediators by ECs and the expression of adhesion molecules at their surface, thereby favoring the recruitment and transvascular migration of inflammatory cells such as neutrophils. Neither the expression nor the biological activities that could be mediated by FGFRs have been investigated in human neutrophils. By biochemical and cytological analyses, we observed that purified circulating human neutrophils from healthy individuals expressed varying levels of FGFRs in their cytosol and at their cytoplasmic membrane. FGFR-2 was identified as the sole cell surface receptor, with FGFR-1 and -4 localizing in the cytosol and FGFR-3 being undetectable. We assessed the capacity of FGF-1 and FGF-2 to induce neutrophil chemotaxis in a modified Boyden microchamber and observed that they increase neutrophil transmigration at 10(-10) and 10(-9) M and by 1.77- and 2.34-fold, respectively, as compared with PBS treated cells. Treatment with a selective anti-FGFR-2 antibody reduced FGF-1 mediated chemotaxis by 75% and abrogated the effect of FGF-2, while the blockade of FGFR-1 and -4 partially inhibited (15-40%) FGF-chemotactic activities. In summary, our data are the first to report the expression of FGF receptors in human neutrophils, with FGF-1 and FGF-2 promoting neutrophil chemotaxis mainly through FGFR-2 activation. PMID- 21795521 TI - Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor. AB - Activated G protein-coupled receptors (GPCRs) are phosphorylated and interact with beta-arrestins, which mediate desensitization and endocytosis. Endothelin converting enzyme-1 (ECE-1) degrades neuropeptides in endosomes and can promote recycling. Although endocytosis, dephosphorylation, and recycling are accepted mechanisms of receptor resensitization, a large proportion of desensitized receptors can remain at the cell surface. We investigated whether reactivation of noninternalized, desensitized (phosphorylated) receptors mediates resensitization of the substance P (SP) neurokinin 1 receptor (NK(1)R). Herein, we report a novel mechanism of resensitization by which protein phosphatase 2A (PP2A) is recruited to dephosphorylate noninternalized NK(1)R. A desensitizing concentration of SP reduced cell-surface SP binding sites by only 25%, and SP-induced Ca(2+) signals were fully resensitized before cell-surface binding sites started to recover, suggesting resensitization of cell-surface-retained NK(1)R. SP induced association of beta-arrestin1 and PP2A with noninternalized NK(1)R. beta Arrestin1 small interfering RNA knockdown prevented SP-induced association of cell-surface NK(1)R with PP2A, indicating that beta-arrestin1 mediates this interaction. ECE-1 inhibition, by trapping beta-arrestin1 in endosomes, also impeded SP-induced association of cell-surface NK(1)R with PP2A. Resensitization of NK(1)R signaling required both PP2A and ECE-1 activity. Thus, after stimulation with SP, PP2A interacts with noninternalized NK(1)R and mediates resensitization. PP2A interaction with NK(1)R requires beta-arrestin1. ECE-1 promotes this process by releasing beta-arrestin1 from NK(1)R in endosomes. These findings represent a novel mechanism of PP2A- and ECE-1-dependent resensitization of GPCRs. PMID- 21795522 TI - KCNQ5/K(v)7.5 potassium channel expression and subcellular localization in primate retinal pigment epithelium and neural retina. AB - Previous studies identified in retinal pigment epithelial (RPE) cells an M-type K(+) current, which in many other cell types is mediated by channels encoded by KCNQ genes. The aim of this study was to assess the expression of KCNQ genes in the monkey RPE and neural retina. Application of the specific KCNQ channel blocker XE991 eliminated the M-type current in freshly isolated monkey RPE cells, indicating that KCNQ subunits contribute to the underlying channels. RT-PCR analysis revealed the expression of KCNQ1, KCNQ4, and KCNQ5 transcripts in the RPE and all five KCNQ transcripts in the neural retina. At the protein level, KCNQ5 was detected in the RPE, whereas both KCNQ4 and KCNQ5 were found in neural retina. In situ hybridization in frozen monkey retinal sections revealed KCNQ5 gene expression in the ganglion cell layer and the inner and outer nuclear layers of the neural retina, but results in the RPE were inconclusive due to the presence of melanin. Immunohistochemistry revealed KCNQ5 in the inner and outer plexiform layers, in cone and rod photoreceptor inner segments, and near the basal membrane of the RPE. The data suggest that KCNQ5 channels contribute to the RPE basal membrane K(+) conductance and, thus, likely play an important role in active K(+) absorption. The distribution of KCNQ5 in neural retina suggests that these channels may function in the shaping of the photoresponses of cone and rod photoreceptors and the processing of visual information by retinal neurons. PMID- 21795524 TI - Editor's Note: AJP-Cell and AJP-Renal article series to honor the work of Dale Benos. PMID- 21795523 TI - Matriptase is inhibited by extravascular antithrombin in epithelial cells but not in most carcinoma cells. AB - Antithrombin, a major anticoagulant, is robustly transported into extravascular compartments where its target proteases are largely unknown. This serpin was previously detected in human milk as complexes with matriptase, a membrane-bound serine protease broadly expressed in epithelial and carcinoma cells, and under tight regulation by hepatocyte growth factor activator inhibitor (HAI)-1, a transmembrane Kunitz-type serine protease inhibitor that forms heat-sensitive complexes with active matriptase. In the current study, we detect, in addition to matriptase-HAI-1 complexes, heat-resistant matriptase complexes generated by nontransformed mammary, prostate, and epidermal epithelial cells that we show to be matriptase-antithrombin complexes. These findings suggest that in addition to HAI-1, interstitial antithrombin participates in the regulation of matriptase activity in epithelial cells. This physiological mechanism appears, however, to largely be lost in cancer cells since matriptase-antithrombin complexes were not detected in all but two of a panel of seven breast, prostate, and ovarian cancer cell lines. Using purified active matriptase, we further characterize the formation of matriptase-antithrombin complex and show that heparin can significantly potentiate the inhibitory potency of antithrombin against matriptase. Second-order rate constants for the inhibition were determined to be 3.9 * 10(3) M(-1)s(-1) in the absence of heparin and 1.2 * 10(5) M(-1)s(-1) in the presence of heparin, a 30-fold increase, consistent with the established role of heparin in activating antithrombin function. Taken together these data suggest that normal epithelial cells employ a dual mechanism involving HAI-1 and antithrombin to control matriptase and that the antithrombin-based mechanism appears lost in the majority of carcinoma cells. PMID- 21795525 TI - Tumor necrosis factor-alpha downregulates sodium current in skeletal muscle by protein kinase C activation: involvement in critical illness polyneuromyopathy. AB - Sepsis is involved in the decrease of membrane excitability of skeletal muscle, leading to polyneuromyopathy. This effect is mediated by alterations of the properties of voltage-gated sodium channels (Na(V)), but the exact mechanism is still unknown. The aim of the present study was to check whether tumor necrosis factor (TNF-alpha), a cytokine released during sepsis, exerts a rapid effect on Na(V). Sodium current (I(Na)) was recorded by macropatch clamp in skeletal muscle fibers isolated from rat peroneus longus muscle, in control conditions and after TNF-alpha addition. Analyses of dose-effect and time-effect relationships were carried out. Effect of chelerythrine, a PKC inhibitor, was also studied to determine the way of action of TNF-alpha. TNF-alpha induced a reversible dose- and time-dependent inhibition of I(Na). A maximum inhibition of 75% of the control current was observed. A shift toward more negative potentials of activation and inactivation curves of I(Na) was also noticed. These effects were prevented by chelerythrine pretreatment. TNF-alpha is a cytokine released in the early stages of sepsis. Besides a possible transcriptional role, i.e., modification of the channel type and/or number, we demonstrated the existence of a rapid, posttranscriptional inhibition of Na(V) by TNF-alpha. The downregulation of the sodium current could be mediated by a PKC-induced phosphorylation of the sodium channel, thus leading to a significant decrease in muscle excitability. PMID- 21795526 TI - Building and breaking interfaces: how a receptor takes shape. PMID- 21795527 TI - Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A(1) receptors. AB - Torpor in hibernating mammals defines the nadir in mammalian metabolic demand and body temperature that accommodates seasonal periods of reduced energy availability. The mechanism of metabolic suppression during torpor onset is unknown, although the CNS is a key regulator of torpor. Seasonal hibernators, such as the arctic ground squirrel (AGS), display torpor only during the winter, hibernation season. The seasonal character of hibernation thus provides a clue to its regulation. In the present study, we delivered adenosine receptor agonists and antagonists into the lateral ventricle of AGSs at different times of the year while monitoring the rate of O(2) consumption and core body temperature as indicators of torpor. The A(1) antagonist cyclopentyltheophylline reversed spontaneous entrance into torpor. The adenosine A(1) receptor agonist N(6) cyclohexyladenosine (CHA) induced torpor in six of six AGSs tested during the mid hibernation season, two of six AGSs tested early in the hibernation season, and none of the six AGSs tested during the summer, off-season. CHA-induced torpor within the hibernation season was specific to A(1)AR activation; the A(3)AR agonist 2-Cl-IB MECA failed to induce torpor, and the A(2a)R antagonist MSX-3 failed to reverse spontaneous onset of torpor. CHA-induced torpor was similar to spontaneous entrance into torpor. These results show that metabolic suppression during torpor onset is regulated within the CNS via A(1)AR activation and requires a seasonal switch in the sensitivity of purinergic signaling. PMID- 21795528 TI - Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. AB - The neuronal alpha4beta2 nicotinic acetylcholine receptors exist as two distinct subtypes, (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian alpha4 and beta2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (alpha4)(3)(beta2)(2) receptor. In addition to two high-sensitivity sites at alpha4beta2 interfaces, the (alpha4)(3)(beta2)(2) receptor contains a third low sensitivity agonist binding site in the alpha4alpha4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the alpha4beta2 and alpha4alpha4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes. PMID- 21795529 TI - Synaptogenesis of electrical and GABAergic synapses of fast-spiking inhibitory neurons in the neocortex. AB - Parvalbumin-expressing fast-spiking (FS) cells are interconnected via GABAergic and electrical synapses and represent a major class of inhibitory interneurons in the neocortex. Synaptic connections among FS cells are critical for regulating network oscillations in the mature neocortex. However, it is unclear whether synaptic connections among FS interneurons also play a central role in the generation of patterned neuronal activity in the immature brain, which is thought to underlie the formation of neocortical circuits. Here, we investigated the developmental time course of synaptogenesis of FS cell in mouse visual cortex. In layer 5/6 (L5/6), we recorded from two or three FS and/or pyramidal (PYR) neurons to study the development of electrical and chemical synaptic interactions from postnatal day 3 (P3) to P18. We detected no evidence for functional connectivity for FS-FS or FS-PYR pairs at P3-P4. However, by P5-P6, we found that 20% of FS pairs were electrically coupled, and 24% of pairs were connected via GABAergic synapses; by P15-P18, 42% of FS pairs had established functional electrical synapses, and 47% of FS pairs were connected via GABAergic synapses. FS cell GABAergic inhibition of pyramidal cells showed a similar developmental time line, but no electrical coupling was detected for FS-PYR pairs. We found that synaptogenesis of electrical and GABAergic connections of FS cells takes place in the same period. Together, our results suggest that chemical and electrical connections among FS cells can contribute to patterned neocortical activity only by the end of the first postnatal week. PMID- 21795531 TI - Branch-specific plasticity enables self-organization of nonlinear computation in single neurons. AB - It has been conjectured that nonlinear processing in dendritic branches endows individual neurons with the capability to perform complex computational operations that are needed to solve for example the binding problem. However, it is not clear how single neurons could acquire such functionality in a self organized manner, because most theoretical studies of synaptic plasticity and learning concentrate on neuron models without nonlinear dendritic properties. In the meantime, a complex picture of information processing with dendritic spikes and a variety of plasticity mechanisms in single neurons has emerged from experiments. In particular, new experimental data on dendritic branch strength potentiation in rat hippocampus have not yet been incorporated into such models. In this article, we investigate how experimentally observed plasticity mechanisms, such as depolarization-dependent spike-timing-dependent plasticity and branch-strength potentiation, could be integrated to self-organize nonlinear neural computations with dendritic spikes. We provide a mathematical proof that, in a simplified setup, these plasticity mechanisms induce a competition between dendritic branches, a novel concept in the analysis of single neuron adaptivity. We show via computer simulations that such dendritic competition enables a single neuron to become member of several neuronal ensembles and to acquire nonlinear computational capabilities, such as the capability to bind multiple input features. Hence, our results suggest that nonlinear neural computation may self organize in single neurons through the interaction of local synaptic and dendritic plasticity mechanisms. PMID- 21795530 TI - Multiple types of cerebellar target neurons and their circuitry in the vestibulo ocular reflex. AB - The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells. PMID- 21795532 TI - Neural oscillations associated with item and temporal order maintenance in working memory. AB - The ability to retain information in working memory (WM) requires not only the active maintenance of information about specific items, but also the temporal order in which the items appeared. Although many studies have investigated the neural mechanisms of item maintenance, little is known about the neural mechanisms of temporal order maintenance in WM. Here, we used electroencephalography (EEG) to compare neural oscillations during WM tasks that required maintenance of item or temporal order information. Behavioral results revealed that accuracy and reaction times were comparable between the two conditions, suggesting that task difficulty was matched between the item and temporal order WM tasks. EEG analyses indicated that theta (5-7 Hz) oscillations over prefrontal sites were increased during temporal order maintenance, whereas alpha oscillations (9-12 Hz) over posterior parietal and lateral occipital sites were increased during item maintenance. The frontal theta enhancement was primarily evident in high performers on the order WM task, whereas the posterior alpha enhancement was primarily evident in high performers on the item WM task. These results support the idea that frontal theta and posterior alpha oscillations are differentially related to maintenance of item and temporal order information. PMID- 21795533 TI - Synaptic kainate receptors in interplay with INaP shift the sparse firing of dentate granule cells to a sustained rhythmic mode in temporal lobe epilepsy. AB - Dentate granule cells, at the gate of the hippocampus, use coincidence detection of synaptic inputs to code afferent information under a sparse firing regime. In both human patients and animal models of temporal lobe epilepsy, mossy fibers sprout to form an aberrant glutamatergic network between dentate granule cells. These new synapses operate via long-lasting kainate receptor-mediated events, which are not present in the naive condition. Here, we report that in chronic epileptic rat, aberrant kainate receptors in interplay with the persistent sodium current dramatically expand the temporal window for synaptic integration. This introduces a multiplicative gain change in the input-output operation of dentate granule cells. As a result, their sparse firing is switched to an abnormal sustained and rhythmic mode. We conclude that synaptic kainate receptors dramatically alter the fundamental coding properties of dentate granule cells in temporal lobe epilepsy. PMID- 21795534 TI - Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. AB - Peripheral nerve lesion triggers alterations in the spinal microenvironment that contribute to the pathogenesis of neuropathic pain. While neurons and glia have been implicated in these functional changes, it remains largely underexplored whether the blood-spinal cord barrier (BSCB) is also involved. The BSCB is an important component in the CNS homeostasis, and compromised BSCB has been associated with different pathologies affecting the spinal cord. Here, we demonstrated that a remote injury on the peripheral nerve in rats triggered a leakage of the BSCB, which was independent of spinal microglial activation. The increase of BSCB permeability to different size tracers, such as Evans Blue and sodium fluorescein, was restricted to the lumbar spinal cord and prominent for at least 4 weeks after injury. The spinal inflammatory reaction triggered by nerve injury was a key player in modulating BSCB permeability. We identified MCP-1 as an endogenous trigger for the BSCB leakage. BSCB permeability can also be impaired by circulating IL-1beta. In contrast, antiinflammatory cytokines TGF beta1 and IL-10 were able to shut down the openings of the BSCB following nerve injury. Peripheral nerve injury caused a decrease in tight junction and caveolae associated proteins. Interestingly, ZO-1 and occludin, but not caveolin-1, were rescued by TGF-beta1. Furthermore, our data provide direct evidence that disrupted BSCB following nerve injury contributed to the influx of inflammatory mediators and the recruitment of spinal blood borne monocytes/macrophages, which played a major role in the development of neuropathic pain. These findings highlight the importance of inflammation in BSCB integrity and in spinal cord homeostasis. PMID- 21795535 TI - Optogenetic interrogation of dopaminergic modulation of the multiple phases of reward-seeking behavior. AB - Phasic activation of dopaminergic neurons is associated with reward-predicting cues and supports learning during behavioral adaptation. While noncontingent activation of dopaminergic neurons in the ventral tegmental are (VTA) is sufficient for passive behavioral conditioning, it remains unknown whether the phasic dopaminergic signal is truly reinforcing. In this study, we first targeted the expression of channelrhodopsin-2 to dopaminergic neurons of the VTA and optimized optogenetically evoked dopamine transients. Second, we showed that phasic activation of dopaminergic neurons in freely moving mice causally enhances positive reinforcing actions in a food-seeking operant task. Interestingly, such effect was not found in the absence of food reward. We further found that phasic activation of dopaminergic neurons is sufficient to reactivate previously extinguished food-seeking behavior in the absence of external cues. This was also confirmed using a single-session reversal paradigm. Collectively, these data suggest that activation of dopaminergic neurons facilitates the development of positive reinforcement during reward-seeking and behavioral flexibility. PMID- 21795536 TI - LRAD3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. AB - We have identified a novel low-density lipoprotein (LDL) receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons. The LRAD3 gene encodes an ~50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW-domain-containing proteins. Immunohistochemical analysis of mouse brain reveals LRAD3 expression in the cortex and hippocampus. In the mouse hippocampal-derived cell line HT22, LRAD3 partially colocalizes with amyloid precursor protein (APP) and interacts with APP as revealed by coimmunoprecipitation experiments. To identify the portion of APP that interacts with LRAD3, we used solid-phase binding assays that demonstrated that LRAD3 failed to bind to a soluble APP fragment (sAPPalpha) released after alpha-secretase cleavage. In contrast, C99, the beta-secretase product that remains cell associated, coprecipitated with LRAD3, confirming that regions within this portion of APP are important for associating with LRAD3. The association of LRAD3 with APP increases the amyloidogenic pathway of APP processing, resulting in a decrease in sAPPalpha production and increased Abeta peptide production. Pulse-chase experiments confirm that LRAD3 expression significantly decreases the cellular half-life of mature APP. These results reveal that LRAD3 influences APP processing and raises the possibility that LRAD3 alters APP function in neurons, including its downstream signaling. PMID- 21795537 TI - Dendritic calcium signaling triggered by spontaneous and sensory-evoked climbing fiber input to cerebellar Purkinje cells in vivo. AB - Cerebellar Purkinje cells have one of the most elaborate dendritic trees in the mammalian CNS, receiving excitatory synaptic input from a single climbing fiber (CF) and from ~200,000 parallel fibers. The dendritic Ca(2+) signals triggered by activation of these inputs are crucial for the induction of synaptic plasticity at both of these synaptic connections. We have investigated Ca(2+) signaling in Purkinje cell dendrites in vivo by combining targeted somatic or dendritic patch clamp recording with simultaneous two-photon microscopy. Both spontaneous and sensory-evoked CF inputs triggered widespread Ca(2+) signals throughout the dendritic tree that were detectable even in individual spines of the most distal spiny branchlets receiving parallel fiber input. The amplitude of these Ca(2+) signals depended on dendritic location and could be modulated by membrane potential, reflecting modulation of dendritic spikes triggered by the CF input. Furthermore, the variability of CF-triggered Ca(2+) signals was regulated by GABAergic synaptic input. These results indicate that dendritic Ca(2+) signals triggered by sensory-evoked CF input can act as associative signals for synaptic plasticity in Purkinje cells in vivo and may differentially modulate plasticity at parallel fiber synapses depending on the location of synapses, firing state of the Purkinje cell, and ongoing GABAergic synaptic input. PMID- 21795538 TI - In vivo neuronal subtype-specific targets of Atoh1 (Math1) in dorsal spinal cord. AB - Neural basic helix-loop-helix (bHLH) transcription factors are crucial in regulating the differentiation and neuronal subtype specification of neurons. Precisely how these transcription factors direct such processes is largely unknown due to the lack of bona fide targets in vivo. Genetic evidence suggests that bHLH factors have shared targets in their common differentiation role, but unique targets with respect to their distinct roles in neuronal subtype specification. However, whether neuronal subtype-specific targets exist remains an unsolved question. To address this question, we focused on Atoh1 (Math1), a bHLH transcription factor that specifies distinct neuronal subtypes of the proprioceptive pathway in mammals including the dI1 (dorsal interneuron 1) population of the developing spinal cord. We identified transcripts unique to the Atoh1-derived lineage using microarray analyses of specific bHLH-sorted populations from mouse. Chromatin immunoprecipitation-sequencing experiments followed by enhancer reporter analyses identified five direct neuronal subtype specific targets of Atoh1 in vivo along with their Atoh1-responsive enhancers. These targets, Klf7, Rab15, Rassf4, Selm, and Smad7, have diverse functions that range from transcription factors to regulators of endocytosis and signaling pathways. Only Rab15 and Selm are expressed across several different Atoh1 specified neuronal subtypes including external granule cells (external granule cell layer) in the developing cerebellum, hair cells of the inner ear, and Merkel cells. Our work establishes on a molecular level that neuronal differentiation bHLH transcription factors have distinct lineage-specific targets. PMID- 21795539 TI - Pathways of attention: synaptic relationships of frontal eye field to V4, lateral intraparietal cortex, and area 46 in macaque monkey. AB - The frontal eye field (FEF) of the primate neocortex occupies a pivotal position in the matrix of inter-areal projections. In addition to its role in directing saccadic eye movements, it is the source of an attentional signal that modulates the activity of neurons in extrastriate and parietal cortex. Here, we tested the prediction that FEF preferentially excites inhibitory neurons in target areas during attentional modulation. Using the anterograde tracer biotinylated dextran amine, we found that the projections from FEF terminate in all cortical layers of area 46, lateral intraparietal area (LIP), and visual area V4. Axons in layer 1 spread extensively, those in layer 2/3 were most numerous, individual axons in layer 4 formed sprays of collaterals, and those of the deep layers were the finest caliber and irregular. All labeled synapses were the typical asymmetric morphology of excitatory synapses of pyramidal neurons. Dendritic spines were the most frequent synaptic target in all areas (95% in area 46, 89% in V4, 84% in LIP, 78% intrinsic local FEF). The remaining targets were one soma and dendritic shafts, most of which showed characteristics of inhibitory neurons with smooth dendrites (5% of all targets in area 46, 2% in V4, 9% in LIP, and 13% in FEF). PMID- 21795540 TI - Heritability of working memory brain activation. AB - Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean +/- SD age, 23.6 +/- 1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0 back) were significantly heritable, with the highest estimates (40-65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders. PMID- 21795541 TI - alpha4beta2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief. AB - Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although alpha4 containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of alpha4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the alpha4 subunit from dopaminergic neurons in mice. The loss alpha4 mRNA and alpha4beta2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of alpha4beta2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. alpha4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. alpha4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of alpha4beta2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of alpha4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine related behaviors. PMID- 21795542 TI - Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly. AB - The sense of hearing depends on the faithful transmission of sound information from the ear to the brain by spiral ganglion (SG) neurons. However, how SG neurons develop the connections and properties that underlie auditory processing is largely unknown. We catalogued gene expression in mouse SG neurons from embryonic day 12, when SG neurons first extend projections, up until postnatal day 15, after the onset of hearing. For comparison, we also analyzed the closely related vestibular ganglion (VG). Gene ontology analysis confirmed enriched expression of genes associated with gene regulation and neurite outgrowth at early stages, with the SG and VG often expressing different members of the same gene family. At later stages, the neurons transcribe more genes related to mature function, and exhibit a dramatic increase in immune gene expression. Comparisons of the two populations revealed enhanced expression of TGFbeta pathway components in SG neurons and established new markers that consistently distinguish auditory and vestibular neurons. Unexpectedly, we found that Gata3, a transcription factor commonly associated with auditory development, is also expressed in VG neurons at early stages. We therefore defined new cohorts of transcription factors and axon guidance molecules that are uniquely expressed in SG neurons and may drive auditory-specific aspects of their differentiation and wiring. We show that one of these molecules, the receptor guanylyl cyclase Npr2, is required for bifurcation of the SG central axon. Hence, our dataset provides a useful resource for uncovering the molecular basis of specific auditory circuit assembly events. PMID- 21795543 TI - Dendritic sodium channels promote active decorrelation and reduce phase locking to parkinsonian input oscillations in model globus pallidus neurons. AB - Correlated firing among populations of neurons is present throughout the brain and is often rhythmic in nature, observable as an oscillatory fluctuation in the local field potential. Although rhythmic population activity is believed to be critical for normal function in many brain areas, synchronized neural oscillations are associated with disease states in other cases. In the globus pallidus (GP in rodents, homolog of the primate GPe), pairs of neurons generally have uncorrelated firing in normal animals despite an anatomical organization suggesting that they should receive substantial common input. In contrast, correlated and rhythmic GP firing is observed in animal models of Parkinson's disease (PD). Based in part on these findings, it has been proposed that an important part of basal ganglia function is active decorrelation, whereby redundant information is compressed. Mechanisms that implement active decorrelation, and changes that cause it to fail in PD, are subjects of great interest. Rat GP neurons express fast, transient voltage-dependent sodium channels (NaF channels) in their dendrites, with the expression level being highest near asymmetric synapses. We recently showed that the dendritic NaF density strongly influences the responsiveness of model GP neurons to synchronous excitatory inputs. In the present study, we use rat GP neuron models to show that dendritic NaF channel expression is a potential cellular mechanism of active decorrelation. We further show that model neurons with lower dendritic NaF channel expression have a greater tendency to phase lock with oscillatory synaptic input patterns like those observed in PD. PMID- 21795544 TI - Longitudinal development of human brain wiring continues from childhood into adulthood. AB - Healthy human brain development is a complex process that continues during childhood and adolescence, as demonstrated by many cross-sectional and several longitudinal studies. However, whether these changes end in adolescence is not clear. We examined longitudinal white matter maturation using diffusion tensor tractography in 103 healthy subjects aged 5-32 years; each volunteer was scanned at least twice, with 221 total scans. Fractional anisotropy (FA) and mean diffusivity (MD), parameters indicative of factors including myelination and axon density, were assessed in 10 major white matter tracts. All tracts showed significant nonlinear development trajectories for FA and MD. Significant within subject changes occurred in the vast majority of children and early adolescents, and these changes were mostly complete by late adolescence for projection and commissural tracts. However, association tracts demonstrated postadolescent within-subject maturation of both FA and MD. Diffusion parameter changes were due primarily to decreasing perpendicular diffusivity, although increasing parallel diffusivity contributed to the prolonged increases of FA in association tracts. Volume increased significantly with age for most tracts, and longitudinal measures also demonstrated postadolescent volume increases in several association tracts. As volume increases were not directly associated with either elevated FA or reduced MD between scans, the observed diffusion parameter changes likely reflect microstructural maturation of brain white matter tracts rather than just gross anatomy. PMID- 21795546 TI - Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS. PMID- 21795545 TI - A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity. AB - Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors. However, while studies of the early specification of neocortical interneurons are rapidly advancing, similar lineage analyses of hippocampal interneurons have lagged. A "hippocampocentric" investigation is necessary as several hippocampal interneuron subtypes remain poorly represented in the neocortical literature. Thus, we investigated the spatiotemporal origins of hippocampal interneurons using transgenic mice that specifically report MGE- and CGE-derived interneurons either constitutively or inducibly. We found that hippocampal interneurons are produced in two neurogenic waves between E9-E12 and E12-E16 from MGE and CGE, respectively, and invade the hippocampus by E14. In the mature hippocampus, CGE-derived interneurons primarily localize to superficial layers in strata lacunosum moleculare and deep radiatum, while MGE-derived interneurons readily populate all layers with preference for strata pyramidale and oriens. Combined molecular, anatomical, and electrophysiological interrogation of MGE/CGE-derived interneurons revealed that MGE produces parvalbumin-, somatostatin-, and nitric oxide synthase-expressing interneurons including fast-spiking basket, bistratified, axo-axonic, oriens lacunosum moleculare, neurogliaform, and ivy cells. In contrast, CGE-derived interneurons contain cholecystokinin, calretinin, vasoactive intestinal peptide, and reelin including non-fast-spiking basket, Schaffer collateral-associated, mossy fiber-associated, trilaminar, and additional neurogliaform cells. Our findings provide a basic blueprint of the developmental origins of hippocampal interneuron diversity. PMID- 21795547 TI - Attentional modulation of firing rate varies with burstiness across putative pyramidal neurons in macaque visual area V4. AB - One of the most well established forms of attentional modulation is an increase in firing rate when attention is directed into the receptive field of a neuron. The degree of rate modulation, however, can vary considerably across individual neurons, especially among broad spiking neurons (putative pyramids). We asked whether this heterogeneity might be correlated with a neuronal response property that is used in intracellular recording studies to distinguish among distinct neuronal classes: the burstiness of the neuronal spike train. We first characterized the burst spiking behavior of visual area V4 neurons and found that this varies considerably across the population, but we did not find evidence for distinct classes of burst behavior. Burstiness did, however, vary more widely across the class of neurons that shows the greatest heterogeneity in attentional modulation, and within that class, burstiness helped account for differences in attentional modulation. Among these broad spiking neurons, rate modulation was primarily restricted to bursty neurons, which as a group showed a highly significant increase in firing rate with attention. Furthermore, every bursty broad spiking neuron whose firing rate was significantly modulated by attention exhibited an increase in firing rate. In contrast, non-bursty broad spiking neurons exhibited no net attentional modulation, and, although some individual neurons did show significant rate modulation, these were divided among neurons showing increases and decreases. These findings show that macaque area V4 shows a range of bursting behavior and that the heterogeneity of attentional modulation can be explained, in part, by variation in burstiness. PMID- 21795548 TI - Cell-type-specific CCK2 receptor signaling underlies the cholecystokinin-mediated selective excitation of hippocampal parvalbumin-positive fast-spiking basket cells. AB - Parvalbumin-positive (PV+) fast-spiking basket cells are thought to play key roles in network functions related to precise time keeping during behaviorally relevant hippocampal synchronous oscillations. Although they express relatively few receptors for neuromodulators, the highly abundant and functionally important neuropeptide cholecystokinin (CCK) is able to selectively depolarize PV+ basket cells, making these cells sensitive biosensors for CCK. However, the molecular mechanisms underlying the CCK-induced selective and powerful excitation of PV+ basket cells are not understood. We used single and paired patch-clamp recordings in acute rat hippocampal slices, in combination with post hoc identification of the recorded interneurons, to demonstrate that CCK acts via G-protein-coupled CCK2 receptors to engage sharply divergent intracellular pathways to exert its cell-type-selective effects. In contrast to CCK2 receptors on pyramidal cells that signal through the canonical G(q)-PLC pathway to trigger endocannabinoid mediated signaling events, CCK2 receptors on neighboring PV+ basket cells couple to an unusual, pertussis-toxin-sensitive pathway. The latter pathway involves ryanodine receptors on intracellular calcium stores that ultimately activate a nonselective cationic conductance to depolarize PV+ basket cells. CCK has highly cell-type-selective effects even within the PV+ cell population, as the PV+ dendrite-targeting bistratified cells do not respond to CCK. Together, these results demonstrate that an abundant ligand such as CCK can signal through the same receptor in different neurons to use cell-type-selective signaling pathways to provide divergence and specificity to its effects. PMID- 21795549 TI - A synaptic mechanism for retinal adaptation to luminance and contrast. AB - The gain of signaling in primary sensory circuits is matched to the stimulus intensity by the process of adaptation. Retinal neural circuits adapt to visual scene statistics, including the mean (background adaptation) and the temporal variance (contrast adaptation) of the light stimulus. The intrinsic properties of retinal bipolar cells and synapses contribute to background and contrast adaptation, but it is unclear whether both forms of adaptation depend on the same cellular mechanisms. Studies of bipolar cell synapses identified synaptic mechanisms of gain control, but the relevance of these mechanisms to visual processing is uncertain because of the historical focus on fast, phasic transmission rather than the tonic transmission evoked by ambient light. Here, we studied use-dependent regulation of bipolar cell synaptic transmission evoked by small, ongoing modulations of membrane potential (V(M)) in the physiological range. We made paired whole-cell recordings from rod bipolar (RB) and AII amacrine cells in a mouse retinal slice preparation. Quasi-white noise voltage commands modulated RB V(M) and evoked EPSCs in the AII. We mimicked changes in background luminance or contrast, respectively, by depolarizing the V(M) or increasing its variance. A linear systems analysis of synaptic transmission showed that increasing either the mean or the variance of the presynaptic V(M) reduced gain. Further electrophysiological and computational analyses demonstrated that adaptation to mean potential resulted from both Ca channel inactivation and vesicle depletion, whereas adaptation to variance resulted from vesicle depletion alone. Thus, background and contrast adaptation apparently depend in part on a common synaptic mechanism. PMID- 21795550 TI - How ongoing neuronal oscillations account for evoked fMRI variability. AB - Variability of evoked single-trial responses despite constant input or task is a feature of large-scale brain signals recorded by fMRI. Initial evidence signified relevance of fMRI signal variability for perception and behavior. Yet the underlying intrinsic neuronal sources have not been previously substantiated. Here, we address this issue using simultaneous EEG-fMRI and real-time classification of ongoing alpha-rhythm states triggering visual stimulation in human subjects. We investigated whether spontaneous neuronal oscillations-as reflected in the posterior alpha rhythm-account for variability of evoked fMRI responses. Based on previous work, we specifically hypothesized linear superposition of fMRI activity related to fluctuations of ongoing alpha rhythm and a visually evoked fMRI response. We observed that spontaneous alpha-rhythm power fluctuations largely explain evoked fMRI response variance in extrastriate, thalamic, and cerebellar areas. For extrastriate areas, we confirmed the linear superposition hypothesis. We hence linked evoked fMRI response variability to an intrinsic rhythm's power fluctuations. These findings contribute to our conceptual understanding of how brain rhythms can account for trial-by-trial variability in stimulus processing. PMID- 21795551 TI - Frequency-tuned cerebellar channels and burst-induced LTD lead to the cancellation of redundant sensory inputs. AB - For optimal sensory processing, neural circuits must extract novel, unpredictable signals from the redundant sensory input in which they are embedded, but the detailed cellular and network mechanisms that implement such selective cancellation are presently unknown. Using a combination of modeling and experiment, we characterize in detail a cerebellar circuit in weakly electric fish, showing how it can carry out this computation. We use a model incorporating the wide range of experimentally estimated parallel fiber feedback delays and a burst-induced LTD rule derived from in vitro experiments to explain the precise cancellation of redundant signals observed in vivo. Our model demonstrates how the backpropagation-dependent burst dynamics adjusts the temporal pairing width of the plasticity mechanism to precisely match the frequency of the redundant signal. The model also makes the prediction that this cerebellar feedback pathway must be composed of frequency-tuned channels; this prediction is subsequently verified in vivo, highlighting a novel and general capability of cerebellar circuitry. PMID- 21795552 TI - Effect of holding potential on the dynamics of homosynaptic facilitation. AB - We study a form of short-term synaptic plasticity that was originally described as a graded potentiating effect of holding potential on spike-mediated synaptic transmission (Shimahara and Tauc, 1975). This form of plasticity has recently generated considerable interest, as it has become apparent that it is present in the mammalian brain (Clark and Hausser, 2006; Marder, 2006). It has been suggested that it adds a previously unappreciated analog component to spike mediated synaptic transmission (Alle and Geiger, 2006, 2008). A limitation of most previous research in this area is that effects of holding potential have been studied in relative isolation. Presynaptic neurons are stimulated at low frequencies so that a second form of plasticity (homosynaptic facilitation) is not induced. Under physiological conditions, however, both forms of plasticity are likely to be coinduced. In this report, we study the two types of plasticity together in an experimentally advantageous preparation (the mollusk Aplysia californica). Somewhat surprisingly, we find that effects of holding potential can be relatively modest when presynaptic neurons are activated at low frequencies. Interestingly, however, changes in membrane potential are highly effective when homosynaptic facilitation is induced. In this situation, PSPs facilitate at an increased rate. To summarize, our research suggests a novel view of the effect of holding potential on synaptic transmission. We propose that, under physiological conditions, it modifies the dynamics of homosynaptic facilitation. PMID- 21795553 TI - Repetitive transcranial magnetic stimulation enhances BDNF-TrkB signaling in both brain and lymphocyte. AB - Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B (TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz rTMS for 5 d improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine phosphorylated TrkB, increased recruitment of PLC-gamma1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF-TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB-NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes. PMID- 21795554 TI - Ascl1 genetics reveals insights into cerebellum local circuit assembly. AB - Two recently generated targeted mouse alleles of the neurogenic gene Ascl1 were used to characterize cerebellum circuit formation. First, genetic inducible fate mapping (GIFM) with an Ascl1(CreER) allele was found to specifically mark all glial and neuron cell types that arise from the ventricular zone (vz). Moreover, each cell type has a unique temporal profile of marking with Ascl1(CreER) GIFM. Of great utility, Purkinje cells (Pcs), an early cohort of Bergmann glia, and four classes of GABAergic interneurons can be genetically birth dated during embryogenesis using Ascl1(CreER) GIFM. Astrocytes and oligodendrocytes, in contrast, express Ascl1(CreER) throughout their proliferative phase in the white matter. Interestingly, the final position each neuron type acquires differs depending on when it expresses Ascl1. Interneurons (including candelabrum) attain a more outside position the later they express Ascl1, whereas Pcs have distinct settling patterns each day they express Ascl1. Second, using a conditional Ascl1 allele, we discovered that Ascl1 is differentially required for generation of most vz-derived cells. Mice lacking Ascl1 in the cerebellum have a major decrease in three types of interneurons with a tendency toward a loss of later-born interneurons, as well as an imbalance of oligodendrocytes and astrocytes. Double mutant analysis indicates that a related helix-loop-helix protein, Ptf1a, functions with Ascl1 in generating interneurons and Pcs. By fate mapping vz derived cells in Ascl1 mutants, we further discovered that Ascl1 plays a specific role during the time period when Pcs are generated in restricting vz progenitors from becoming rhombic lip progenitors. PMID- 21795555 TI - Molecular mechanism of species-dependent sweet taste toward artificial sweeteners. AB - The heterodimer of Tas1R2 and Tas1R3 is a broadly acting sweet taste receptor, which mediates mammalian sweet taste toward natural and artificial sweeteners and sweet-tasting proteins. Perception of sweet taste is a species-selective physiological process. For instance, artificial sweeteners aspartame and neotame taste sweet to humans, apes, and Old World monkeys but not to New World monkeys and rodents. Although specific regions determining the activation of the receptors by these sweeteners have been identified, the molecular mechanism of species-dependent sweet taste remains elusive. Using human/squirrel monkey chimeras, mutagenesis, and molecular modeling, we reveal that the different responses of mammalian species toward the artificial sweeteners aspartame and neotame are determined by the steric effect of a combination of a few residues in the ligand binding pocket. Residues S40 and D142 in the human Tas1R2, which correspond to residues T40 and E142 in the squirrel monkey Tas1R2, were found to be the critical residues for the species-dependent difference in sweet taste. In addition, human Tas1R2 residue I67, which corresponds to S67 in squirrel monkey receptor, modulates the higher affinity of neotame than of aspartame. Our studies not only shed light on the molecular mechanism of species-dependent sweet taste toward artificial sweeteners, but also provide guidance for designing novel effective artificial sweet compounds. PMID- 21795556 TI - Focusing attention on the health aspects of foods changes value signals in vmPFC and improves dietary choice. AB - Attention is thought to play a key role in the computation of stimulus values at the time of choice, which suggests that attention manipulations could be used to improve decision-making in domains where self-control lapses are pervasive. We used an fMRI food choice task with non-dieting human subjects to investigate whether exogenous cues that direct attention to the healthiness of foods could improve dietary choices. Behaviorally, we found that subjects made healthier choices in the presence of health cues. In parallel, stimulus value signals in ventromedial prefrontal cortex were more responsive to the healthiness of foods in the presence of health cues, and this effect was modulated by activity in regions of dorsolateral prefrontal cortex. These findings suggest that the neural mechanisms used in successful self-control can be activated by exogenous attention cues, and provide insights into the processes through which behavioral therapies and public policies could facilitate self-control. PMID- 21795557 TI - Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. AB - GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia. PMID- 21795559 TI - High efficiency in human muscle: an anomaly and an opportunity? AB - Can human muscle be highly efficient in vivo? Animal muscles typically show contraction-coupling efficiencies <50% in vitro but a recent study reports that the human first dorsal interosseous (FDI) muscle of the hand has an efficiency value in vivo of 68%. We examine two key factors that could account for this apparently high efficiency value: (1) transfer of cross-bridge work into mechanical work and (2) the use of elastic energy to do external work. Our analysis supports a high contractile efficiency reflective of nearly complete transfer of muscular to mechanical work with no contribution by recycling of elastic energy to mechanical work. Our survey of reported contraction-coupling efficiency values puts the FDI value higher than typical values found in small animals in vitro but within the range of values for human muscle in vivo. These high efficiency values support recent studies that suggest lower Ca(2+) cycling costs in working contractions and a decline in cost during repeated contractions. In the end, our analysis indicates that the FDI muscle may be exceptional in having an efficiency value on the higher end of that reported for human muscle. Thus, the FDI muscle may be an exception both in contraction-coupling efficiency and in Ca(2+) cycling costs, which makes it an ideal muscle model system offering prime conditions for studying the energetics of muscle contraction in vivo. PMID- 21795560 TI - Streamlining behaviour of the red urchin Strongylocentrotus franciscanus in response to flow. AB - This work was motivated by subtidal observations of red urchins (Strongylocentrotus franciscanus) moving their spines into streamlined positions as water current increased in the field. Trials in a flume across flow speeds from 0 to 65 cm s(-1) enabled us to observe the change in overall shape of the urchins and quantify the decrease in spine angle that occurred as flow speeds increased. The effect of this behaviour on drag and lift was measured with physical models made from urchin tests with spines in the 'up' position (typical in stagnant and slow velocities) and in the 'down' position (typical of posture in high velocities). Streamlining spines decreased the drag, but increased the lift experienced by urchin models at flow speeds between 10 and 40 cm s(-1), current velocities that are commonly encountered by these animals in the field in Washington, USA. Total force (combination of drag and lift) was similar for 'up' and 'down' models at all flow speeds, lift comprising the majority of the force for 'down' models, and drag slightly higher for 'up' models. Live urchins in the field routinely adopt a streamlined 'down' posture in flow, suggesting that they may be better able to cope with lift than drag. This behaviour, although affecting hydrodynamic forces and enabling S. franciscanus to remain attached to the substratum in high currents, may lead to reduced capture of drift kelp, which is entrapped on upright spines and then eaten, delivery of which is positively related to flow speed. Urchins living in deep subtidal habitats rely on drift kelp capture but must stay attached to the substratum to be successful in a habitat. Therefore, this streamlining behaviour may be an important factor enabling S. franciscanus to persist in deep, high-current areas. PMID- 21795561 TI - Identification and evolutionary implications of neurotransmitter-ciliary interactions underlying the behavioral response to hypoxia in Lymnaea stagnalis embryos. AB - Acceleration of embryonic rotation is a common response to hypoxia among pond snails. It was first characterized in Helisoma trivolvis embryos, which have a pair of sensorimotor neurons that detect hypoxia and release serotonin onto postsynaptic ciliary cells. The objective of the present study was to determine how the hypoxia response is mediated in Lymnaea stagnalis, which differ from H. trivolvis by having both serotonergic and dopaminergic neurons, and morphologically distinct ciliated structures at comparative stages of embryonic development. Time-lapse video recordings of the rotational behavior in L. stagnalis revealed similar rotational features to those previously observed in H. trivolvis, including rotational surges and rotational responses to hypoxia. Serotonin and dopamine increased the rate of rotation with similar potency. In contrast, serotonin was more potent than dopamine in stimulating the ciliary beat frequency of isolated pedal cilia. Isolated apical plate cilia displayed an irregular pattern of ciliary beating that precluded the measurement of ciliary beat frequency. A qualitative assessment of ciliary beating revealed that both serotonin and dopamine were able to stimulate apical plate cilia. The ciliary responses to dopamine were reversible in both pedal and apical plate cilia, whereas the responses to serotonin were only reversible at concentrations below 100 MUmol l(-1). Mianserin, a serotonin receptor antagonist, and SKF83566, a dopamine receptor antagonist, effectively blocked the rotational responses to serotonin and dopamine, respectively. The rotational response to hypoxia was only partially blocked by mianserin, but was fully blocked by SKF83566. These data suggest that, despite the ability of serotonin to stimulate ciliary beating in L. stagnalis embryos, the rotational response to hypoxia is primarily mediated by the transient apical catecholaminergic neurons that innervate the ciliated apical plate. PMID- 21795562 TI - Growing backwards: an inverted role for the shrimp ortholog of vertebrate myostatin and GDF11. AB - Myostatin (MSTN) and growth differentiation factor-11 (GDF11) are closely related proteins involved in muscle cell growth and differentiation as well as neurogenesis of vertebrates. Both MSTN and GDF11 negatively regulate their functions. Invertebrates possess a single ortholog of the MSTN/GDF11 family. In order to understand the role of MSTN/GDF11 in crustaceans, the gene ortholog was identified and characterized in the penaeid shrimp Penaeus monodon. The overall protein sequence and specific functional sites were highly conserved with other members of the MSTN/GDF11 family. Gene transcripts of pmMstn/Gdf11, assessed by real-time PCR, were detected in a variety of tissue types and were actively regulated in muscle across the moult cycle. To assess phenotypic function in shrimp, pmMstn/Gdf11 gene expression was downregulated by tail-muscle injection of sequence-specific double-stranded RNA. Shrimp with reduced levels of pmMstn/Gdf11 transcripts displayed a dramatic slowing in growth rate compared with control groups. Findings from this study place the MSTN/GDF11 gene at the centre of growth regulation in shrimp, but suggest that, compared with higher vertebrates, this gene has an opposite role in invertebrates such as shrimp, where levels of gene expression may positively regulate growth. PMID- 21795563 TI - Ammonia sensing by neuroepithelial cells and ventilatory responses to ammonia in rainbow trout. AB - Ammonia, the third respiratory gas in teleost fish, acts as an acute stimulant to ventilation in ammoniotelic rainbow trout. We investigated whether this sensitivity is maintained in trout chronically exposed (1+ months) to high environmental ammonia [HEA, 250 MUmol l(-1) (NH(4))(2)SO(4)] in the water, and whether gill neuroepithelial cells (NECs) are involved in ammonia sensing. Hyperventilation was induced both by acute external (NH(4))(2)SO(4) exposure [250 or 500 MUmol l(-1) (NH(4))(2)SO(4)] and by intra-arterial (NH(4))(2)SO(4) injection (580 MUmol kg(-1) of ammonia) in control trout, but these responses were abolished in chronic HEA animals. Hyperventilation in response to acute ammonia exposure persisted after bilateral removal of each of the four gill arch pairs separately or after combined removal of arches III and IV, but was delayed by removal of gill arch I, and eliminated by combined removal of arches I and II. NECs, identified by immunolabeling against 5-HT, were mainly organized in two lines along the filament epithelium in all four gill arches. In control trout, NECs were slightly smaller but more abundant on arches I and II than on arches III and IV. Chronic HEA exposure reduced the density of the NECs on all four arches, and their size on arches I and II only. Fura-2 fluorescence imaging was used to measure intracellular free calcium ion concentration ([Ca(2+)](i)) responses in single NECs in short-term (24-48 h) culture in vitro. [Ca(2+)](i) was elevated to a comparable extent by perfusion of 30 mmol l(-1) KCl and 1 mmol l(-1) NH(4)Cl, and these [Ca(2+)](i) responses presented in two different forms, suggesting that ammonia may be sensed by multiple mechanisms. The [Ca(2+)](i) responses to high ammonia were attenuated in NECs isolated from trout chronically exposed to HEA, especially in ones from gill arch I, but responses to high K(+) were unchanged. We conclude that the hyperventilatory response to ammonia is lost after chronic waterborne HEA exposure, and that NECs, especially the ones located in gill arches I and II, are probably ammonia chemoreceptors that participate in ventilatory modulation in trout. PMID- 21795564 TI - Gliding saves time but not energy in Malayan colugos. AB - Gliding is thought to be an economical form of locomotion. However, few data on the climbing and gliding of free-ranging gliding mammals are available. This study employed an animal-borne three-dimensional acceleration data-logging system to collect continuous data on the climbing and gliding of free-ranging Malayan colugos, Galeopterus variegatus. We combined these movement data with empirical estimates of the metabolic costs to move horizontally or vertically to test this long-standing hypothesis by determining whether the metabolic cost to climb to sufficient height to glide a given distance was less than the cost to move an equivalent distance horizontally through the canopy. On average, colugos climb a short distance to initiate glides. However, due to the high energetic cost of climbing, gliding is more energetically costly to move a given horizontal distance than would be predicted for an animal travelling the same distance through the canopy. Furthermore, because colugos spend a small fraction of their time engaged in locomotor activity, the high costs have little effect on their overall energy budget. As a result, the energetic economy hypothesis for the origins of gliding is not supported. It is likely that other ecologically relevant factors have played a greater role in the origins of gliding in colugos and other mammals. PMID- 21795565 TI - Hearing and morphological specializations of the mojarra (Eucinostomus argenteus). AB - The air-filled swimbladder acts as an acoustic amplifier for some fish by converting sound pressure into particle motion, which is transmitted to the inner ear. Here, we describe in detail the specialized connection between the swimbladder and ear in the mojarra, as well as a modified cone on the anal fin in which the posterior end of the swimbladder sits. Hearing tests show the mojarra has better hearing sensitivity than other species of fish without a connection. However, mojarras do not seem to use this adaptation for communication. Furthermore, the inclined position of the swimbladder may help the fish to catch their prey more easily, as the swimbladder will be horizontal when they are picking up benthic prey. PMID- 21795566 TI - Sound production and mechanism in Heniochus chrysostomus (Chaetodontidae). AB - The diversity in calls and sonic mechanisms appears to be important in Chaetodontidae. Calls in Chaetodon multicinctus seem to include tail slap, jump, pelvic fin flick and dorsal-anal fin erection behaviors. Pulsatile sounds are associated with dorsal elevation of the head, anterior extension of the ventral pectoral girdle and dorsal elevation of the caudal skeleton in Forcipiger flavissiumus. In Hemitaurichthys polylepis, extrinsic swimbladder muscles could be involved in sounds originating from the swimbladder and correspond to the inward buckling of tissues situated dorsally in front of the swimbladder. These examples suggest that this mode of communication could be present in other members of the family. Sounds made by the pennant bannerfish (Heniochus chrysostomus) were recorded for the first time on coral reefs and when fish were hand held. In hand-held fishes, three types of calls were recorded: isolated pulses (51%), trains of four to 11 pulses (19%) and trains preceded by an isolated pulse (29%). Call frequencies were harmonic and had a fundamental frequency between 130 and 180 Hz. The fundamental frequency, sound amplitude and sound duration were not related to fish size. Data from morphology, sound analysis and electromyography recordings highlight that the calls are made by extrinsic sonic drumming muscles in association with the articulated bones of the ribcage. The pennant bannerfish system differs from other Chaetodontidae in terms of sound characteristics, associated body movements and, consequently, mechanism. PMID- 21795567 TI - Endogenous vascular synthesis of B-type and C-type natriuretic peptides in the rainbow trout. AB - In mammals, natriuretic peptides (NPs) lower blood pressure, reduce blood volume and broadly inhibit cardiovascular remodeling. NPs are often referred to as cardiac hormones, though they also have integral roles in regulating vascular tone, endothelial remodeling and inhibiting vascular smooth muscle cell hypertrophy. Two NPs [atrial (ANP) and C-type (CNP)] have been identified as endogenous constituents in the vasculature of mammals, though such a phenomenon has not previously been described in fishes. Here we describe the endogenous production of B-type NP (BNP) and CNP in multiple blood vessels of the rainbow trout. Western blot analysis showed pro-BNP and pro-CNP production in the efferent branchial artery, celiacomesenteric artery, ventral aorta and anterior cardinal vein. The detection of pro-BNP and pro-CNP was also supported by MALDI TOF mass spectrometry analysis of NP-enriched tissue extracts. Although vascular pro-peptide levels of BNP and CNP were quantitatively quite comparable to those found in reference tissues (the atrium for BNP and brain for CNP), mRNA levels of these NPs in the vasculature were greatly reduced as determined by quantitative PCR. When the evolutionarily conserved vascular NP (CNP) was infused into un anesthetized trout, it reduced central venous pressure and mean circulatory filling pressure. CNP also decreased cardiac output via a reduction in preload. The presence of endogenous NP production in the trout vasculature and potent in vivo hypotensive effects further support the numerous functional similarities between teleost and mammalian NP systems. PMID- 21795568 TI - Dominance hierarchy-dependent behavioural plasticity of crayfish avoidance reactions. AB - Crayfish showed avoidance reactions when mechanical stimulation was applied to their tailfan. The response pattern of the avoidance reaction was dependent on crayfish size. Small crayfish showed an escape-like dart response while larger crayfish displayed a defensive-like turn response. We show that the response pattern to the same sensory stimulus changed with social status in the small crayfish. Crayfish are territorial animals and a dominant-subordinate relationship was determined when two previously unacquainted animals were paired. This winner-loser hierarchy was observed in pairs of small crayfish. Before fighting, all crayfish showed a dart response following mechanical stimulation of the tailfan. However, the probability of occurrence of a turn response increased significantly in the crayfish that won a fight. This behavioural transition from dart to turn response occurred immediately and was maintained for at least 3 days even if a dominant crayfish was isolated again with no opponent. PMID- 21795569 TI - Adaptation in the optical properties of the crystalline lens in the eyes of the Lessepsian migrant Siganus rivulatus. AB - Vision is an important source of information for many animals. The crystalline lens plays a central role in the visual pathway and hence the ecology of fishes. In this study, we tested whether the different light regimes in the Mediterranean and Red Seas have an effect on the optical properties of the lenses in the rivulated rabbitfish, Siganus rivulatus. This species has migrated through the Suez Canal from the Red Sea and established a vital population in the Mediterranean Sea. Longitudinal spherical aberration curves and focal lengths of the fish lenses were measured by laser scans and compared between the two populations. In addition, rivulated rabbitfish from the Mediterranean Sea were exposed to colored light (yellow, green and blue) and unfiltered light for periods of 1 or 13 days to test for short-term adjustments. Lens focal length was significantly longer (3%) in the Rea Sea population. The shorter focal length of the Mediterranean population can be explained as an adaptation to the dimmer light environment, as this difference makes the Mediterranean eyes 5% more sensitive than the eyes of the Red Sea population. The difference may be due to genetic differences or, more likely, adaptive developmental plasticity. Short term regulatory mechanisms do not seem to be involved. PMID- 21795570 TI - Different effects of temperature on foraging activity schedules in sympatric Myrmecia ants. AB - Animals avoid temperatures that constrain foraging by restricting activity to specific times of the day or year. However, because temperature alters the availability of food resources, it is difficult to separate temperature-dependent effects on foraging and the occupation of temporal niches. By studying two congeneric, sympatric Myrmecia ants we isolated the effect of temperature and investigated whether temperature affects foraging schedules and causes the two ants to be active at distinct times of the day or year. We monitored foraging activity and identified the ants' temperature tolerance in the laboratory by determining (1) critical thermal minima and maxima (CT(min) and CT(max)) and (2) the relationship between walking speed and temperature. Ants of Myrmecia croslandi were diurnal throughout the year, but ceased above-ground activity during winter. Surface temperature at the onset of foraging was 9.8-30.1 degrees C, while their laboratory CT(min) and CT(max) were 10.4 and 48.5 degrees C, respectively. Time of foraging onset was significantly influenced by surface temperature at time of sunrise and of onset. Ants of Myrmecia pyriformis were nocturnal throughout the year. Surface temperature at the onset of foraging was 5.4-26.2 degrees C, while their laboratory CT(min) and CT(max) were 8.2 and 41.6 degrees C, respectively. Time of foraging onset was not influenced by surface temperature, but solely by sunset time. We conclude that temperature determines the timing of foraging as well as the daily and seasonal foraging activity in M. croslandi, but has less obvious effects on M. pyriformis. In both species, CT(max) was greater than temperatures at the natural foraging times. PMID- 21795571 TI - Do wood ants learn sequences of visual stimuli? AB - The visually guided foraging routes of some formicine ants are individually stereotyped, suggesting the importance of visual learning in maintaining these routes. We ask here whether the wood ant Formica rufa learns a sequence of visual features encountered at different stages along a route, as reported for honeybees. We trained ants in several simple mazes to follow two alternative routes. Along each two-stage route, the ants first encountered one of two priming stimuli. The identity of the priming stimulus determined which of two choice stimuli was rewarded in the second stage of the route. As stimuli we used ultraviolet and yellow/green light panels, and two black-and-white patterns. Did ants learn to pair each colour with the appropriate black-and-white pattern? Ants learnt readily to discriminate between the two coloured stimuli or between the two black-and-white patterns. They could also pair coloured and black-and-white patterns, provided that the two were presented simultaneously. The ants' behaviour with sequential stimuli varied according to whether the priming stimulus was a coloured stimulus or a black-and-white pattern. When the priming stimulus was coloured, ants seemed to learn the two sequences, but tests showed that their success was probably caused by the after-effects of colour adaptation. With a black-and-white priming stimulus and a coloured second stage stimulus, robust sequential learning could not be demonstrated, although under certain experimental conditions a tiny proportion of ants did acquire the sequence. Thus, ants perform conditional discriminations reliably when priming and choice stimuli are simultaneous, but they usually fail when the stimuli are sequential. PMID- 21795572 TI - High phosphate uptake requirements of the scleractinian coral Stylophora pistillata. AB - Several untested aspects of the regulation of inorganic nutrient uptake were examined using nutrient depletion experiments with the symbiotic coral Stylophora pistillata. The total inhibition of phosphate uptake in artificial seawater lacking sodium indicates the involvement of a sodium/phosphate symporter for the uptake of phosphate across host membranes. Addition of ammonium or nitrate (up to 6.0 MUmol l(-1)) did not enhance saturated phosphate uptake rates, thus indicating that corals, or their symbiotic algae, were not, or not sufficiently, nitrogen limited to modify their phosphate needs. Conversely, the saturated uptake rate of ammonium increased by 2.5-fold in the presence of 3.0 MUmol l(-1) of phosphate, thus indicating that the corals or their symbionts were lacking intracellular phosphate to take advantage of the inorganic nitrogen compounds dissolved in their surrounding medium. Overall, these results highlight some greater limitation in phosphate rather than in nitrogen. Finally, the rate of phosphate uptake decreased with particulate feeding of the host (organic phosphate source). Indeed, corals that were fed 1 and 3 days before the uptake experiment took up phosphate 42 and 19% slower, respectively, than corals that were fed 21 days before. This result provides additional evidence of phosphate limitation in S. pistillata. This study therefore brings new insights into the relationships between nutrients and symbiotic corals, and may provide a rapid and effective tool to investigate which nutrient is the most limiting for coral metabolism. PMID- 21795573 TI - Fully reversible phenotypic plasticity of digestive physiology in young house sparrows: lack of long-term effect of early diet composition. AB - Feeding conditions during the nestling period may significantly affect whole-life fitness in altricial birds but little is known about the physiological mechanisms responsible for these effects. Permanent changes (irreversible developmental plasticity) in digestive physiology caused by the neonatal diet may form such a mechanism. We previously showed that the lack of starch in the diet of house sparrow (Passer domesticus) nestlings between 3 and 12 days post-hatching significantly decreased the activity of intestinal maltase, an enzyme essential for starch digestion. To check whether diet-induced variation in maltase activity in young house sparrows is reversible, we raised them under laboratory conditions from 3 until 30 days of age on diets with either 0% starch or 25% starch, with some individuals experiencing a switch in their assigned diet at 12 days of age. We found evidence for the presence of an internal, presumably genetic, program for changes in the activity of maltase and sucrase, which was, however, significantly affected by diet composition (i.e. environmental factor). Digestive enzyme activity in 30 day old birds was not influenced by diet composition prior to day 12 but instead depended only on diet that was fed between days 12 and 30. We conclude that plasticity in the activity of intestinal disaccharidases in house sparrow nestlings represents completely reversible phenotypic flexibility that can help young sparrows to cope with unpredictable variation in food composition during ontogeny without long-term effects on their digestive system. However, comparison with other species suggests that the magnitude of digestive flexibility in young passerines may be evolutionarily matched to species-specific variation in feeding conditions. PMID- 21795574 TI - Early elevation of testosterone advances migratory preparation in a songbird. AB - The timing of events associated with spring migration can be an important determinant of fitness for migratory birds. The need to prepare and maintain physical condition for migration is one demand that must be met for early arrival on breeding areas, and this demand is compounded by the energetic demands of the physiological transition to breeding. Here, we examined whether migratory birds, specifically males, can adequately meet both of these demands by elevating the sex steroid testosterone early during migratory preparation. To test this, we used a captive experiment in which we photostimulated male dark-eyed juncos (Junco hyemalis) and manipulated circulating testosterone. We predicted males with elevated testosterone would prepare to migrate and breed faster than control males or males where the ability of testosterone to bind with receptors, or be converted to estradiol, was inhibited (testosterone inhibited). We measured migratory preparation using mass, food intake, fat deposits and nocturnal activity (Zugunruhe). To estimate breeding preparation, we measured the diameter of the cloacal protuberance (CP). We found that males in the testosterone treatment group began migratory preparation approximately 10 days before controls. There was no difference in the magnitude of peak migratory condition between testosterone-implanted birds and controls. Males implanted with testosterone also reached the onset of breeding preparation faster and had larger peak CP diameter compared with controls. Testosterone-inhibited birds showed no signs of migratory preparation and only a weak increase in CP diameter. These results demonstrate that early elevation of testosterone during migratory preparation could incur benefits for males in terms of the ability to depart earlier from non-breeding areas and arrive in a more advanced breeding condition. This experiment demonstrates that there may be important physiological underpinnings to known winter to breeding season carry-over effects in migratory birds. PMID- 21795575 TI - Physiological trade-offs in self-maintenance: plumage molt and stress physiology in birds. AB - Trade-offs between self-maintenance processes can affect life-history evolution. Integument replacement and the stress response both promote self-maintenance and affect survival in vertebrates. Relationships between the two processes have been studied most extensively in birds, where hormonal stress suppression is down regulated during molt in seasonal species, suggesting a resource-based trade-off between the two processes. The only species found to differ are the rock dove and Eurasian tree sparrow, at least one of which performs a very slow molt that may reduce resource demands during feather growth, permitting investment in the stress response. To test for the presence of a molt-stress response trade-off, we measured hormonal stress responsiveness during and outside molt in two additional species with extended molts, red crossbills (Loxia curvirostra) and zebra finches (Taeniopygia guttata). We found that both species maintain hormonal stress responsiveness during molt. Further, a comparative analysis of all available species revealed a strong relationship between molt duration and degree of hormonal suppression. Though our results support trade-off hypotheses, these data can also be explained by alternative hypotheses that have not been formally addressed in the literature. We found a strong relationship between stress suppression and seasonality of breeding and evidence suggesting that the degree of suppression may be either locally adaptable or plastic and responsive to local environmental conditions. We hypothesize that environmental unpredictability favors extended molt duration, which in turn allows for maintenance of the hormonal stress response, and discuss implications of a possible trade-off for the evolution of molt schedules. PMID- 21795576 TI - Experimentally increased in ovo testosterone leads to increased plasma bactericidal activity and decreased cutaneous immune response in nestling house wrens. AB - Maternally derived testosterone in the eggs of birds may benefit nestlings by increasing various aspects of their growth, condition and behavioral development, but these benefits may come at a cost, including suppression of immune responsiveness. Experiments on a variety of species in which in ovo levels of testosterone have been experimentally increased have produced mixed results; some have found increased growth and suppressed immune function of nestlings whereas others have found the opposite. In an attempt to clarify the relationship between in ovo testosterone and nestling size, mass, health state and immune responsiveness, we experimentally increased levels of testosterone in the eggs of house wrens (Troglodytes aedon). We simultaneously determined the size, mass, hematocrit (a measure of health state), cutaneous immune response to phytohaemagglutinin and plasma bactericidal activity of nestlings near the time of fledging. We predicted that nestlings hatching from testosterone-injected eggs would exhibit lower immune responsiveness, but achieve greater mass, size and condition, than nestlings hatching from vehicle-injected control eggs. Instead, we found that nestlings hatching from testosterone-injected eggs had a weaker cutaneous immune response but greater bactericidal activity than those hatching from control eggs. They did not, however, differ significantly in mass, size or hematocrit from controls. These results suggest that experimentally increased in ovo testosterone induced a trade-off between bactericidal activity and the cutaneous immune response. The opposite responses by two different measures of immune function to experimentally increased in ovo testosterone underscore the importance of including multiple immune assays when investigating the potential for trade-offs with the immune system and other physiological functions. PMID- 21795577 TI - Effects of temperature on the respiration of brooded larvae from tropical reef corals. AB - This study describes the effects of temperature on the respiration of brooded larvae of scleractinian corals, and evaluates the implications of these effects relative to seawater temperature when peak larval release occurs. Respiration rates of larvae from Pocillopora damicornis, Seriatopora hystrix and Stylophora pistillata were quantified in darkness as oxygen uptake during 1-3 h exposures to five temperatures between 26.4 and 29.6 degrees C. To assess the biological significance of these experiments, the temperature of the seawater into which larvae of P. damicornis and S. hystrix were released was measured for 32-34 months over 5 years between 2003 and 2008. Mean respiration varied from 0.029 to 0.116 nmol O(2) larva(-1) min(-1), and was related parabolically to temperature with a positive threshold at 28.0 degrees C. The temperature coefficients (Q(10)) for the ascending portion of these relationships (Q(10)=15-76) indicate that the temperature dependency is stronger than can be explained by kinetics alone, and probably reflects behavioral and developmental effects. Larval release occurred year-round in synchrony with the lunar periodicity when seawater temperature ranged from 21.8 to 30.7 degrees C, and more than half of the sampled larvae were released at 27.5-28.9 degrees C. The coincidence on the temperature scale of peak larval release with the thermal threshold for respiration suggests that high metabolic rates have selective value for pelagic coral larvae. The large and rapid effects of temperature on larval respiration have implications for studies of the effects of climate change on coral reproduction, particularly when seawater temperature exceeds ~28 degrees C, when our results predict that larval respiration will be greatly reduced. PMID- 21795578 TI - The influence of 17beta-estradiol on intestinal calcium carbonate precipitation and osmoregulation in seawater-acclimated rainbow trout (Oncorhynchus mykiss). AB - The intestine of marine teleosts produces carbonate precipitates from ingested calcium as part of their osmoregulatory strategy in seawater. The potential for estrogens to control the production of intestinal calcium carbonate and so influence osmoregulation was investigated in seawater-acclimated rainbow trout following intraperitoneal implantation of 17beta-estradiol (E2) at two doses (0.1 and 10 MUg E2 g(-1)). Levels of plasma vitellogenin provided an indicator of estrogenic effect, increasing significantly by three and four orders of magnitude at the low and high doses, respectively. Plasma osmolality and muscle water content were unaffected, whereas E2-treated fish maintained lower plasma [Na(+)] and [Cl(-)]. Plasma [Ca(2+)] and [Mg(2+)] and muscle [Ca(2+)] increased with vitellogenin induction, whereas the intestinal excretion of calcium carbonate was reduced. This suggests that elevated levels of circulating E2 may enhance Ca(2+) uptake via the gut and simultaneously reduce CaCO(3) formation, which normally limits intestinal availability of Ca(2+). Increasing E2 caused an elevation of [Na(+)] and [Cl(-)] and a reduction of [HCO(3(-))] in intestinal fluid. We speculate that E2 may influence a number of intestinal ion transport processes that ultimately may influence water absorption: (1) reduced NaCl cotransport, (2) reduced Cl(-) uptake via Cl(-)/HCO(3(-)) exchange and (3) reduced precipitation of Ca(2+) and Mg(2+) carbonates. Despite these effects on intestinal ion and water transport, overall osmoregulatory status was not compromised in E2-treated fish, suggesting the possibility of compensation by other organs. PMID- 21795579 TI - A multilevel approach to examining cephalopod growth using Octopus pallidus as a model. AB - Many aspects of octopus growth dynamics are poorly understood, particularly in relation to sub-adult or adult growth, muscle fibre dynamics and repro-somatic investment. The growth of 5 month old Octopus pallidus cultured in the laboratory was investigated under three temperature regimes over a 12 week period: seasonally increasing temperatures (14-18 degrees C); seasonally decreasing temperatures (18-14 degrees C); and a constant temperature mid-way between seasonal peaks (16 degrees C). Differences in somatic growth at the whole-animal level, muscle tissue structure and rate of gonad development were investigated. Continuous exponential growth was observed, both at a group and at an individual level, and there was no detectable effect of temperature on whole-animal growth rate. Juvenile growth rate (from 1 to 156 days) was also monitored prior to the controlled experiment; exponential growth was observed, but at a significantly faster rate than in the older experimental animals, suggesting that O. pallidus exhibit a double-exponential two-phase growth pattern. There was considerable variability in size-at-age even between individuals growing under identical thermal regimes. Animals exposed to seasonally decreasing temperatures exhibited a higher rate of gonad development compared with animals exposed to increasing temperatures; however, this did not coincide with a detectable decline in somatic growth rate or mantle condition. The ongoing production of new mitochondria-poor and mitochondria-rich muscle fibres (hyperplasia) was observed, indicated by a decreased or stable mean muscle fibre diameter concurrent with an increase in whole-body size. Animals from both seasonal temperature regimes demonstrated higher rates of new mitochondria-rich fibre generation relative to those from the constant temperature regime, but this difference was not reflected in a difference in growth rate at the whole-body level. This is the first study to record ongoing hyperplasia in the muscle tissue of an octopus species, and provides further insight into the complex growth dynamics of octopus. PMID- 21795580 TI - Functional and expressional analyses of PmDAM genes associated with endodormancy in Japanese apricot. AB - Bud endodormancy in woody plants plays an important role in their perennial growth cycles. We previously identified a MADS box gene, DORMANCY-ASSOCIATED MADS box6 (PmDAM6), expressed in the endodormant lateral buds of Japanese apricot (Prunus mume), as a candidate for the dormancy-controlling gene. In this study, we demonstrate the growth inhibitory functions of PmDAM6 by overexpressing it in transgenic poplar (Populus tremula * Populus tremuloides). Transgenic poplar plants constitutively expressing PmDAM6 showed growth cessation and terminal bud set under environmental conditions in which control transformants continued shoot tip growth, suggesting the growth inhibitory functions of PmDAM6. In the Japanese apricot genome, we identified six tandemly arrayed PmDAM genes (PmDAM1-PmDAM6) that conserve an amphiphilic repression motif, known to act as a repression domain, at the carboxyl-terminal end, suggesting that they all may act as transcriptional repressors. Seasonal expression analysis and cold treatment in autumn indicated that all PmDAMs were repressed during prolonged cold exposure and maintained at low levels until endodormancy release. Furthermore, PmDAM4 to PmDAM6 responses to a short period of cold exposure appeared to vary between low- and high-chill genotypes. In the high-chill genotype, a short period of cold exposure slightly increased PmDAM4 to PmDAM6 expression, while in the low-chill genotype, the same treatment repressed PmDAM4 to PmDAM6 expression. Furthermore, PmDAM4 to PmDAM6 expression was negatively correlated with endodormancy release. We here discuss the genotype-dependent seasonal expression patterns of PmDAMs in relation to their involvement in endodormancy and variation in chilling requirements. PMID- 21795581 TI - A common genetic determinism for sensitivities to soil water deficit and evaporative demand: meta-analysis of quantitative trait Loci and introgression lines of maize. AB - Evaporative demand and soil water deficit equally contribute to water stress and to its effect on plant growth. We have compared the genetic architectures of the sensitivities of maize (Zea mays) leaf elongation rate with evaporative demand and soil water deficit. The former was measured via the response to leaf-to-air vapor pressure deficit in well-watered plants, the latter via the response to soil water potential in the absence of evaporative demand. Genetic analyses of each sensitivity were performed over 21 independent experiments with (1) three mapping populations, with temperate or tropical materials, (2) one population resulting from the introgression of a tropical drought-tolerant line in a temperate line, and (3) two introgression libraries genetically independent from mapping populations. A very large genetic variability was observed for both sensitivities. Some lines maintained leaf elongation at very high evaporative demand or water deficit, while others stopped elongation in mild conditions. A complex architecture arose from analyses of mapping populations, with 19 major meta-quantitative trait loci involving strong effects and/or more than one mapping population. A total of 68% of those quantitative trait loci affected sensitivities to both evaporative demand and soil water deficit. In introgressed lines, 73% of the tested genomic regions affected both sensitivities. To our knowledge, this study is the first genetic demonstration that hydraulic processes, which drive the response to evaporative demand, also have a large contribution to the genetic variability of plant growth under water deficit in a large range of genetic material. PMID- 21795582 TI - Enhancing Arabidopsis leaf growth by engineering the BRASSINOSTEROID INSENSITIVE1 receptor kinase. AB - The BRASSINOSTEROID INSENSITIVE1 (BRI1) receptor kinase has recently been shown to possess tyrosine kinase activity, and preventing autophosphorylation of the tyrosine-831 regulatory site by site-directed mutagenesis enhances shoot growth. In this study, we characterized the increased leaf growth of Arabidopsis (Arabidopsis thaliana) plants expressing BRI1(Y831F)-Flag compared with BRI1-Flag (both driven by the native promoter and expressed in the bri1-5 weak allele background) and provide insights into the possible mechanisms involved. On average, relative leaf growth rate was increased 16% in the Y831F plants (in the bri1-5 background), and the gain of function of the Y831F-directed mutant was dominant in the wild-type background. Leaves were larger as a result of increased cell numbers and had substantially increased vascularization. Transcriptome analysis indicated that genes associated with brassinolide biosynthesis, secondary cell wall biosynthesis and vascular development, and regulation of growth were altered in expression and may contribute to the observed changes in leaf architecture and whole plant growth. Analysis of gas exchange and chlorophyll fluorescence indicated that Y831F mutant plants had higher rates of photosynthesis, and metabolite analysis documented enhanced accumulation of starch, sucrose, and several amino acids, most prominently glycine and proline. These results demonstrate that mutation of BRI1 can enhance photosynthesis and leaf growth/vascularization and may suggest new approaches to increase whole plant carbon assimilation and growth. PMID- 21795583 TI - Systems biology of tomato fruit development: combined transcript, protein, and metabolite analysis of tomato transcription factor (nor, rin) and ethylene receptor (Nr) mutants reveals novel regulatory interactions. AB - Tomato (Solanum lycopersicum) is an established model to study fleshy fruit development and ripening. Tomato ripening is regulated independently and cooperatively by ethylene and transcription factors, including nonripening (NOR) and ripening-inhibitor (RIN). Mutations of NOR, RIN, and the ethylene receptor Never-ripe (Nr), which block ethylene perception and inhibit ripening, have proven to be great tools for advancing our understanding of the developmental programs regulating ripening. In this study, we present systems analysis of nor, rin, and Nr at the transcriptomic, proteomic, and metabolomic levels during development and ripening. Metabolic profiling marked shifts in the abundance of metabolites of primary metabolism, which lead to decreases in metabolic activity during ripening. When combined with transcriptomic and proteomic data, several aspects of the regulation of metabolism during ripening were revealed. First, correlations between the expression levels of a transcript and the abundance of its corresponding protein were infrequently observed during early ripening, suggesting that posttranscriptional regulatory mechanisms play an important role in these stages; however, this correlation was much greater in later stages. Second, we observed very strong correlation between ripening-associated transcripts and specific metabolite groups, such as organic acids, sugars, and cell wall-related metabolites, underlining the importance of these metabolic pathways during fruit ripening. These results further revealed multiple ethylene associated events during tomato ripening, providing new insights into the molecular biology of ethylene-mediated ripening regulatory networks. PMID- 21795585 TI - Losing the war against obesity: the need for a developmental perspective. AB - Developed countries are struggling to control epidemics of obesity and related chronic diseases; thus, we can expect only limited success from applying the current approaches to the developing world, which is experiencing an alarming increase in such disorders. This failure results in part from the fact that our focus on adult life-styles, although important, ignores data that suggest that biological and cultural factors operating early in life affect adult health status. To stem the rising obesity burden in developing countries, scientists and policy-makers must address obesity-promoting factors from early development to adulthood. PMID- 21795584 TI - Bharangin, a diterpenoid quinonemethide, abolishes constitutive and inducible nuclear factor-kappaB (NF-kappaB) activation by modifying p65 on cysteine 38 residue and reducing inhibitor of nuclear factor-kappaB alpha kinase activation, leading to suppression of NF-kappaB-regulated gene expression and sensitization of tumor cells to chemotherapeutic agents. AB - Although inflammatory pathways have been linked with various chronic diseases including cancer, identification of an agent that can suppress these pathways has therapeutic potential. Herein we describe the identification of a novel compound bharangin, a diterpenoid quinonemethide that can suppress pro-inflammatory pathways specifically. We found that bharangin suppresses nuclear factor (NF) kappaB activation induced by pro-inflammatory cytokine, tumor promoter, cigarette smoke, and endotoxin. Inhibition of NF-kappaB activation was mediated through the suppression of phosphorylation and degradation of inhibitor of nuclear factor kappaB (IkappaBalpha); inhibition of IkappaBalpha kinase activation; and suppression of p65 nuclear translocation, and phosphorylation. The diterpenoid inhibited binding of p65 to DNA. A reducing agent reversed the inhibitory effect, and mutation of the Cys(38) of p65 to serine abrogated the effect of bharangin on p65-DNA binding. Molecular docking revealed strong interaction of the ligand with the p65 via two hydrogen bonds one with Lys(37) (2.204 A) and another with Cys(38) (2.023 A). The inhibitory effect of bharangin on NF-kappaB activation was specific, inasmuch as binding of activator protein-1 and octameric transcription factor 1 to DNA was not affected. Suppression of NF-kappaB activation by this diterpenoid caused the down-regulation of the expression of proteins involved in tumor cell survival, proliferation, invasion, and angiogenesis, leading to potentiation of apoptosis, suppression of proliferation, and invasion of tumor cells. Furthermore, the genetic deletion of p65 and mutation of p65Cys(38) residue to Ser abolished the affect of bharangin. Overall, our results demonstrate that bharangin specifically inhibits the NF-kappaB activation pathway by modifying p65 and inhibiting IkappaBalpha kinase activation and potentiates apoptosis in tumor cells. PMID- 21795586 TI - Antibody repertoire: embracing diversity. AB - In this Perspective, we discuss two papers that show that the breadth of the antibody response to vaccines could be manipulated by the use of particular vaccine adjuvants that stimulate innate immune mechanisms. The ability to increase the repertoire of antibodies induced by a vaccine may help to control variable pathogens that alter their exposed antigens to evade the immune system. PMID- 21795587 TI - Photoactivated composite biomaterial for soft tissue restoration in rodents and in humans. AB - Soft tissue reconstruction often requires multiple surgical procedures that can result in scars and disfiguration. Facial soft tissue reconstruction represents a clinical challenge because even subtle deformities can severely affect an individual's social and psychological function. We therefore developed a biosynthetic soft tissue replacement composed of poly(ethylene glycol) (PEG) and hyaluronic acid (HA) that can be injected and photocrosslinked in situ with transdermal light exposure. Modulating the ratio of synthetic to biological polymer allowed us to tune implant elasticity and volume persistence. In a small animal model, implanted photocrosslinked PEG-HA showed a dose-dependent relationship between increasing PEG concentration and enhanced implant volume persistence. In direct comparison with commercial HA injections, the PEG-HA implants maintained significantly greater average volumes and heights. Reversibility of the implant volume was achieved with hyaluronidase injection. Pilot clinical testing in human patients confirmed the feasibility of the transdermal photocrosslinking approach for implantation in abdomen soft tissue, although an inflammatory response was observed surrounding some of the materials. PMID- 21795589 TI - Targeting TLRs expands the antibody repertoire in response to a malaria vaccine. AB - Vaccination with an isolated antigen is frequently not sufficient to elicit a protective immune response. The addition of adjuvants to the antigen can increase the magnitude and breadth of the response generated, but quantification of this increase as a function of adjuvant has been intractable. We have directly determined the variation of the immunoglobulin G variable-chain repertoire of an entire organism as a function of vaccination. Using the well-established Plasmodium vivax antigen, PvRII, and massively parallel sequencing, we showed that the use of a Toll-like receptor (TLR) agonist in the vaccine formulation increased the diversity of the variable region sequences in comparison to the use of an oil-in-water emulsion adjuvant alone. Moreover, increased variable domain diversity in response to the use of TLR agonist-based adjuvants correlated with improved antigen neutralization. The use of TLR agonists also broadened the range of polymorphic variants against which these antibodies could be effective. In addition, a peptide microarray demonstrated that inclusion of adjuvants changed the profile of linear epitopes from PvRII that were recognized by serum from immunized animals. The results of these studies have broad implications for vaccine design--they may enable tailored adjuvants that elicit the broad spectrum of antibodies required to neutralize drifted and polymorphic pathogen strains as well as provide a method for rapid determination of correlates of adjuvant induced humoral immunity. PMID- 21795588 TI - IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-beta in multiple sclerosis. AB - The interleukin-7 receptor alpha chain (IL-7Ralpha) gene was identified as a top non-major histocompatibility complex-linked risk locus for multiple sclerosis (MS). Recently, we showed that a T helper 1 (T(H)1)-driven, but not a T(H)17 driven, form of MS exhibited a good clinical response to interferon-beta (IFN beta) therapy. We now demonstrate that high serum levels of IL-7, particularly when paired with low levels of IL-17F, predict responsiveness to IFN-beta and hence a T(H)1-driven subtype of MS. We also show that although IL-7 signaling is neither necessary nor sufficient for the induction or expansion of T(H)17 cells, IL-7 can greatly enhance both human and mouse T(H)1 cell differentiation. IL-7 alone is sufficient to induce human T(H)1 differentiation in the absence of IL-12 or other cytokines. Furthermore, targeting IL-7/IL-7Ralpha is beneficial in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Mice treated with IL-7Ralpha-blocking antibodies before or after onset of paralysis exhibited reduced clinical signs of EAE, with reduction in peripheral naive and activated T cells, whereas central memory T, regulatory T, B, and natural killer cell populations were largely spared. IL-7Ralpha antibody treatment markedly reduced lymphocyte infiltration into the central nervous system in mice with EAE. Thus, a serum profile of high IL-7 may signify a T(H)1-driven form of MS and may predict outcome in MS patients undergoing IFN-beta therapy. Blockade of IL-7 and the IL-7Ralpha pathway may have therapeutic potential in MS and other autoimmune diseases. PMID- 21795590 TI - Assessing the safety of adjuvanted vaccines. AB - Despite the very low risk-to-benefit ratio of vaccines, fear of negative side effects has discouraged many people from getting vaccinated, resulting in reemergence of previously controlled diseases such as measles, pertussis, and diphtheria. Part of this fear stems from the lack of public awareness of the many preclinical and clinical safety evaluations that vaccines must undergo before they are available to the general public, as well as from misperceptions of what adjuvants are or why they are used in vaccines. The resultant "black box" leads to a preoccupation with rare side effects (such as autoimmune diseases) that are speculated, but not proven, to be linked to some vaccinations. The focus of this review article is to open this black box and provide a conceptual framework for how vaccine safety is traditionally assessed. We discuss the strengths and shortcomings of tools that can be and are used preclinically (in animal studies), translationally (in biomarker studies with human sera or cells), statistically (for disease epidemiology), and clinically (in the design of human trials) to help ascertain the risk of the infrequent and delayed adverse events that arise in relation to adjuvanted vaccine administration. PMID- 21795591 TI - Phagocytosis, a potential mechanism for myeloid-derived suppressor cell regulation of CD8+ T cell function mediated through programmed cell death-1 and programmed cell death-1 ligand interaction. AB - CD8(+) T cells become exhausted, inducing cell surface protein programmed cell death-1 (PD-1) as chronic virus diseases or tumors progress, but underlying mechanisms of this are unclear. We previously showed that M-CSF is important for developing tolerogenic dendritic cells (DCs) from human CD14(+) monocytes. In this article, we identify M-CSF-derived DCs (M-DCs) after stimulation with IL-10 as myeloid-derived suppressor cells with additional tolerogenic activities to CD8(+) T cells. IL-10 increased PD-1 ligand expression on M-DC, and IL-10 stimulated M-DCs (M-DC/IL-10) induced expression of PD-1 on, and apoptosis of, CD8(+) T cells and phagocytosed CD8(+) T cells. Enhanced phagocytic activity of M DC/IL-10 required IFN-gamma, which further increased PD-1 ligand and PD-2 ligand expression on M-DC/IL-10. IFN-gamma-stimulated M-DC/IL-10 cells were phenotypically macrophage-like cells with little or no expression of CD86, a costimulatory molecule, but with high expression levels of CD14, CD200R, and CD80. No phagocytic activity was detected with GM-CSF-derived DCs. We propose that phagocytosis by IFN-gamma-stimulated M-DC/IL-10 cells, which may be DCs or, alternatively, a unique subset of macrophages, may be a mechanism by which IFN gamma-producing CD8(+) T cells are tolerized after type 1 immune responses to chronic virus or tumor, and that IFN-gamma links effector CD8(+) T cells to their phagocytic clearance. PMID- 21795592 TI - A SOCS-1 promoter variant is associated with total serum IgE levels. AB - SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate Ig H chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that IgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children's Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3' genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G > C; rs33932899) were found to have significantly lower levels of serum IgE compared with those of homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G > C SNP was in complete linkage disequilibrium with an SNP at position SOCS1-820G > T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1-820G > T were also found to be associated with the decreased IgE. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of yin yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production. PMID- 21795593 TI - IL-22-induced regulatory CD11b+ APCs suppress experimental autoimmune uveitis. AB - We have previously reported that IL-17(+) interphotoreceptor retinoid-binding protein (IRBP) 161-180-specific T cells have a strong pathogenic effect in experimental autoimmune uveitis (EAU) induced in B10RIII mice; however, this pathogenic activity is not solely attributable to the major cytokine, IL-17, produced by these cells. To determine whether other cytokines produced by Th17 cells show a stronger association with their pathogenic activity, we studied the role of IL-22 in EAU. IL-22 is one of the major cytokines produced by these cells. Our results showed that administration of small doses of IL-22 to EAU susceptible mice significantly reduced the severity of EAU. In addition, mice treated with IL-22 generated decreased numbers of IFN-gamma(+) and IL-17(+) uveitogenic T cells, but increased numbers of Foxp3(+) regulatory T cells. Mechanistic studies showed that the effect of the injected IL-22 was on CD11b(+) APCs, which expressed increased levels of IL-22R during induction of disease following immunization with uveitogenic Ag. In vitro IL-22 treatment of CD11b(+) APCs collected from Ag-primed mice resulted in increased expression of programmed death ligand-1 and the production of increased amounts of IL-10 and TGF-beta. Moreover, IL-22-treated CD11b(+) APCs caused IRBP161-180-specific T cells to lose their uveitogenic activity and acquire immunosuppressive activity, which suppressed the induction of EAU by additional pathogenic IRBP161-180-specific effector T cells. PMID- 21795594 TI - The novel role of SERPINB9 in cytotoxic protection of human mesenchymal stem cells. AB - Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC based therapies for diseases. PMID- 21795595 TI - Cutting Edge: Regulator of G protein signaling-1 selectively regulates gut T cell trafficking and colitic potential. AB - The RGS1 gene is associated with celiac disease, multiple sclerosis, and type I diabetes, which are all T cell-mediated pathologies, yet there is no reported analysis of regulator of G protein signaling (RGS)1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid homing chemokines, whereas RGS1 depletion selectively enhances such chemotaxis in gut T cells and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease. PMID- 21795596 TI - Fish MITA serves as a mediator for distinct fish IFN gene activation dependent on IRF3 or IRF7. AB - In mammals, cytosolic sensors retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) activate multiple signaling cascades initiating IFN-alpha/beta expression. IFN regulatory factor 3 (IRF3) is required for the activation of IFN beta, which, in turn, primes the expression of most IFN-alpha genes by IFN induced IRF7 through the STAT1 pathway. In fish, RIG-I overexpression inhibits virus infection by induction of IFN response; however, the subtle signaling cascade mechanism remains to be identified. In this study, we clone an ortholog of MITA, a recently identified adaptor responsible for RLR pathway, from crucian carp (Carassius auratus L.), and demonstrate its ability to suppress viral replication through IRF3/7-dependent IFN response. The pivotal signaling molecules of RLR pathway, including RIG-I, melanoma differentiation-associated gene 5, laboratory of genetics and physiology 2, and TANK-binding kinase 1, are also cloned and characterized, confirming that the RLR-mediated IFN activation is conserved from fish to mammals. Further characterization of distinct IFN gene activation reveals that zebrafish IFN1 and IFN3 are induced by the MITA pathway but are dependent on distinct transcription factors. Whereas fish IFN genes cannot be classified into IFN-alpha or IFN-beta, zebrafish IFN1 is primarily regulated by IRF3, thereby resembling that of IFN-beta, and zebrafish IFN3 is regulated by IRF7, thereby resembling of those of IFN-alphas. In contrast with mammalian IFN-alpha/beta, zebrafish IFN1 and IFN3 are induced by the basally expressed IRF3 or IRF7, both of which are upregulated by IFN and virus infection. Collectively, these data suggest that IFN genes in fish and mammals have evolved independently to acquire a similar mechanism triggering their expression. PMID- 21795597 TI - CD8- dendritic cells and macrophages cross-present poly(D,L-lactate-co-glycolate) acid microsphere-encapsulated antigen in vivo. AB - The analysis of cell types involved in cross-priming of particulate Ag is essential to understand and improve immunotherapies using microparticles. In this study, we show that murine splenic dendritic cells (DCs) as well as macrophages (MPhis) are able to efficiently endocytose poly(D,L-lactate-co-glycolate) acid (PLGA) microspheres (MS) and to cross-present encapsulated Ags in the context of MHC class I molecules in vitro. A comparison of purified CD8(+) and CD8(-) DCs indicated that both DC subtypes are able to present OVA-derived epitopes on MHC class I and II in vitro. To determine the contribution of DCs and MPhis to cross priming of PLGA MS in vivo, DCs were depleted in transgenic CD11c-DTR mice, and MPhis were depleted by clodronate liposomes in wild-type mice before immunizing mice with OVA-encapsulated MS. Our results show that the depletion of DCs or MPhis alone only led to minor differences in the OVA-specific immune responses. However, simultaneous depletion of DCs and MPhis caused a strong reduction of primed effector cells, indicating a redundancy of both cell populations for the priming of PLGA MS-encapsulated Ag. Finally, we analyzed PLGA MS trafficking to draining lymph nodes after s.c. injection. It was evident that fluorescent particles accumulated within draining lymph nodes over time. Further analysis of PLGA MS-positive lymphatic cells revealed that mainly CD8(-) DCs and MPhis contained MS. Moreover, immune responses in BATF3 knockout mice lacking CD8(+) DCs were normal. The results presented in this work strongly suggest that in vivo cross-priming of PLGA MS-encapsulated Ag is performed by CD8(-) DCs and MPhis. PMID- 21795598 TI - In vivo analysis of uropod function during physiological T cell trafficking. AB - Migrating lymphocytes acquire a polarized phenotype with a leading and a trailing edge, or uropod. Although in vitro experiments in cell lines or activated primary cell cultures have established that Rho-p160 coiled-coil kinase (ROCK)-myosin II mediated uropod contractility is required for integrin de-adhesion on two dimensional surfaces and nuclear propulsion through narrow pores in three dimensional matrices, less is known about the role of these two events during the recirculation of primary, nonactivated lymphocytes. Using pharmacological antagonists of ROCK and myosin II, we report that inhibition of uropod contractility blocked integrin-independent mouse T cell migration through narrow, but not large, pores in vitro. T cell crawling on chemokine-coated endothelial cells under shear was severely impaired by ROCK inhibition, whereas transendothelial migration was only reduced through endothelial cells with high, but not low, barrier properties. Using three-dimensional thick-tissue imaging and dynamic two-photon microscopy of T cell motility in lymphoid tissue, we demonstrated a significant role for uropod contractility in intraluminal crawling and transendothelial migration through lymph node, but not bone marrow, endothelial cells. Finally, we demonstrated that ICAM-1, but not anatomical constraints or integrin-independent interactions, reduced parenchymal motility of inhibitor-treated T cells within the dense lymphoid microenvironment, thus assigning context-dependent roles for uropod contraction during lymphocyte recirculation. PMID- 21795599 TI - Absence of beta2 integrins impairs regulatory T cells and exacerbates CD4+ T cell dependent autoimmune carditis. AB - The immunopathogenic mechanisms mediating inflammation in multiorgan autoimmune diseases may vary between the different target tissues. We used the K/BxN TCR transgenic mouse model to investigate the contribution of CD4(+) T cells and beta(2) integrins in the pathogenesis of autoimmune arthritis and endocarditis. Depletion of CD4(+) T cells following the onset of arthritis specifically prevented the development of cardiac valve inflammation. Genetic absence of beta(2) integrins had no effect on the severity of arthritis and unexpectedly increased the extent of cardiovascular pathology. The exaggerated cardiac phenotype of the beta(2) integrin-deficient K/BxN mice was accompanied by immune hyperactivation and was linked to a defect in regulatory T cells. These findings are consistent with a model in which the development of arthritis in K/BxN mice relies primarily on autoantibodies, whereas endocarditis depends on an additional contribution of effector T cells. Furthermore, strategies targeting beta(2) integrins for the treatment of systemic autoimmune conditions need to consider not only the role of these molecules in leukocyte recruitment to sites of inflammation, but also their impact on the regulation of immunological tolerance. PMID- 21795600 TI - TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. AB - T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART 1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity. PMID- 21795601 TI - Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase. AB - Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The "LR" peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer. PMID- 21795602 TI - EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structure among helix-turn-helix proteins. AB - EspR is a transcriptional regulator that activates the ESX-1 secretion system during Mycobacterium tuberculosis infection and is critical for pathogenesis. It is unique among DNA-binding proteins as it is secreted as part of a feedback regulatory loop that serves to mitigate transcriptional activity. Here we report the crystal structure of a functional EspR dimer at 2.5-A resolution. The amino terminal half of EspR is a helix-turn-helix (HTH) DNA-binding domain and the carboxy terminus consists of a dimerization domain with similarity to the SinR:SinI sporulation regulator of Bacillus subtilis. Surprisingly, the HTH domains of EspR are arranged in an unusual conformation in which they are splayed at an oblique angle to each other, suggesting that EspR binds DNA in a profoundly different way than most other known HTH regulators. By mapping the EspR binding sites in the espACD promoter, using both in vivo and in vitro binding assays, we show that the EspR operators are located unusually far from the promoter. The EspR dimer binds to these sites cooperatively, but the two "half-sites" contacted by each DNA recognition motif are separated by 177 base pairs. The distinctive structure of EspR and the exceptional arrangement of its operator contacts suggest that it could promote DNA looping in its target promoter. We hypothesize that direct DNA looping mediated by single-site binding of each EspR monomer may facilitate transcriptional control of this important virulence system. PMID- 21795603 TI - Coordinated protein and DNA remodeling by human HLTF on stalled replication fork. AB - Human helicase-like transcription factor (HLTF) exhibits ubiquitin ligase activity for proliferating cell nuclear antigen (PCNA) polyubiquitylation as well as double-stranded DNA translocase activity for remodeling stalled replication fork by fork reversal, which can support damage bypass by template switching. However, a stalled replication fork is surrounded by various DNA-binding proteins which can inhibit the access of damage bypass players, and it is unknown how these proteins become displaced. Here we reveal that HLTF has an ATP hydrolysis dependent protein remodeling activity, by which it can remove proteins bound to the replication fork. Moreover, we demonstrate that HLTF can displace a broad spectrum of proteins such as replication protein A (RPA), PCNA, and replication factor C (RFC), thereby providing the first example for a protein clearing activity at the stalled replication fork. Our findings clarify how remodeling of a stalled replication fork can occur if it is engaged in interactions with masses of proteins. PMID- 21795604 TI - Inferring the structure and dynamics of interactions in schooling fish. AB - Determining individual-level interactions that govern highly coordinated motion in animal groups or cellular aggregates has been a long-standing challenge, central to understanding the mechanisms and evolution of collective behavior. Numerous models have been proposed, many of which display realistic-looking dynamics, but nonetheless rely on untested assumptions about how individuals integrate information to guide movement. Here we infer behavioral rules directly from experimental data. We begin by analyzing trajectories of golden shiners (Notemigonus crysoleucas) swimming in two-fish and three-fish shoals to map the mean effective forces as a function of fish positions and velocities. Speeding and turning responses are dynamically modulated and clearly delineated. Speed regulation is a dominant component of how fish interact, and changes in speed are transmitted to those both behind and ahead. Alignment emerges from attraction and repulsion, and fish tend to copy directional changes made by those ahead. We find no evidence for explicit matching of body orientation. By comparing data from two fish and three-fish shoals, we challenge the standard assumption, ubiquitous in physics-inspired models of collective behavior, that individual motion results from averaging responses to each neighbor considered separately; three-body interactions make a substantial contribution to fish dynamics. However, pairwise interactions qualitatively capture the correct spatial interaction structure in small groups, and this structure persists in larger groups of 10 and 30 fish. The interactions revealed here may help account for the rapid changes in speed and direction that enable real animal groups to stay cohesive and amplify important social information. PMID- 21795605 TI - Comparing the role of absolute sea-level rise and vertical tectonic motions in coastal flooding, Torres Islands (Vanuatu). AB - Since the late 1990s, rising sea levels around the Torres Islands (north Vanuatu, southwest Pacific) have caused strong local and international concern. In 2002 2004, a village was displaced due to increasing sea incursions, and in 2005 a United Nations Environment Programme press release referred to the displaced village as perhaps the world's first climate change "refugees." We show here that vertical motions of the Torres Islands themselves dominate the apparent sea-level rise observed on the islands. From 1997 to 2009, the absolute sea level rose by 150 + /-20 mm. But GPS data reveal that the islands subsided by 117 + /-30 mm over the same time period, almost doubling the apparent gradual sea-level rise. Moreover, large earthquakes that occurred just before and after this period caused several hundreds of mm of sudden vertical motion, generating larger apparent sea-level changes than those observed during the entire intervening period. Our results show that vertical ground motions must be accounted for when evaluating sea-level change hazards in active tectonic regions. These data are needed to help communities and governments understand environmental changes and make the best decisions for their future. PMID- 21795607 TI - Plasticity of local GABAergic interneurons drives olfactory habituation. AB - Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA(A) receptors in odorant selective, glomerulus-specific projection neurons(PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant evoked calcium fluxes in PNs as well as growth of the respective odorant responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems. PMID- 21795608 TI - Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. AB - In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5alpha-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5alpha-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5alpha-reduction of androstenedione by SRD5A1 to 5alpha-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies. PMID- 21795609 TI - The Ataxin-2 protein is required for microRNA function and synapse-specific long term olfactory habituation. AB - Local control of mRNA translation has been proposed as a mechanism for regulating synapse-specific plasticity associated with long-term memory. We show here that glomerulus-selective plasticity of Drosophila multiglomerular local interneurons observed during long-term olfactory habituation (LTH) requires the Ataxin-2 protein (Atx2) to function in uniglomerular projection neurons (PNs) postsynaptic to local interneurons (LNs). PN-selective knockdown of Atx2 selectively blocks LTH to odorants to which the PN responds and in addition selectively blocks LTH associated structural and functional plasticity in odorant-responsive glomeruli. Atx2 has been shown previously to bind DEAD box helicases of the Me31B family, proteins associated with Argonaute (Ago) and microRNA (miRNA) function. Robust transdominant interactions of atx2 with me31B and ago1 indicate that Atx2 functions with miRNA-pathway components for LTH and associated synaptic plasticity. Further direct experiments show that Atx2 is required for miRNA mediated repression of several translational reporters in vivo. Together, these observations (i) show that Atx2 and miRNA components regulate synapse-specific long-term plasticity in vivo; (ii) identify Atx2 as a component of the miRNA pathway; and (iii) provide insight into the biological function of Atx2 that is of potential relevance to spinocerebellar ataxia and neurodegenerative disease. PMID- 21795610 TI - Spatial and temporal second messenger codes for growth cone turning. AB - Cyclic AMP (cAMP) and calcium are ubiquitous, interdependent second messengers that regulate a wide range of cellular processes. During development of neuronal networks they are critical for the first step of circuit formation, transducing signals required for axon pathfinding. Surprisingly, the spatial and temporal cAMP and calcium codes used by axon guidance molecules are unknown. Here, we identify characteristics of cAMP and calcium transients generated in growth cones during Netrin-1-dependent axon guidance. In filopodia, Netrin-1-dependent Deleted in Colorectal Cancer (DCC) receptor activation induces a transient increase in cAMP that causes a brief increase in calcium transient frequency. In contrast, activation of DCC in growth cone centers leads to a transient calcium-dependent cAMP increase and a sustained increase in frequency of calcium transients. We show that filopodial cAMP transients regulate spinal axon guidance in vitro and commissural axon pathfinding in vivo. These growth cone codes provide a basis for selective activation of specific downstream effectors. PMID- 21795612 TI - Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia. AB - The truncated brain-derived neurotrophic factor (BDNF) receptors (truncated TrkB [TrkB-TK-] and sarc homology containing TrkB [TrkB-Shc]) are alternative transcripts of the full-length TrkB receptor (TrkB-TK+) that produce isoforms capable of binding to BDNF but not being able to mediate the classic neurotrophic response via tyrosine kinase signaling. We hypothesized that in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia, truncated TrkB receptors (TK- and Shc) would be altered and may contribute to deficits in BDNF function. Using a large cohort of controls and schizophrenics (n = 72/72), we measured mRNA expression of the full-length TrkB receptor, TrkB-TK+ and the truncated TrkB receptors, TrkB-TK- and TrkB-Shc, by quantitative real-time polymerase chain reaction and protein expression by western blotting. We found highly significant increases in mRNA expression of both truncated TrkB receptor isoforms in people with schizophrenia. When we examined the full-length TrkB-TK+:truncated TrkB ratios, we observed significant decreases in schizophrenia both on the mRNA and protein level. We found a slight reduction in TrkB-TK+ mRNA and a significant reduction in TrkB-TK+ protein expression in schizophrenia, which was evident in females. No gender-specific changes were found for the truncated TrkB receptors. Diagnostic changes in TrkB-TK+ mRNA and protein may be subtle and/or gender specific, whereas changes in TrkB-TK- and TrkB-Shc expression are robust and may generalize to both males and females with schizophrenia. Increased truncated TrkB receptors may contribute to reduced overall BDNF/tyrosine receptor kinase B (TrkB) signaling and lead to reduced neuronal plasticity in the DLPFC in schizophrenia suggesting that therapies aimed at ameliorating neurotrophin deficits may need to consider blocking excessive truncated TrkB function. PMID- 21795613 TI - Peer victimization partially mediates the schizotypy-aggression relationship in children and adolescents. AB - While persuasive evidence has accumulated over the past 15 years documenting an association between schizophrenia and violence, there are 3 unresolved issues. First, does a downward extension of this relationship exist at the nonclinical level with respect to schizotypal personality and aggression in children? Second, is aggression more associated with impulsive reactive aggression or with more planned proactive aggression. Third and importantly, does peer victimization mediate the relationship between schizotypy and aggression? A further aim of this cross-sectional study was to examine the utility of a new child self-report measure of schizotypal personality. These issues were examined in a sample of 3804 schoolchildren assessed on schizotypy using the Schizotypal Personality Questionnaire-Child (SPQ-C), reactive-proactive aggression, and peer victimization. A confirmatory factor analysis confirmed the 3-factor structure (cognitive-perceptual, interpersonal, and disorganized) of the SPQ-C. Schizotypy was positively associated with total aggression and reactive aggression but not with proactive aggression. Peer victimization was found to significantly mediate the schizotypy-aggression relationship, accounting for 58.9% of the association. Results are broadly consistent with the hypothesis that schizotypal features elicit victimization from other children, which in turn predisposes to reactive retaliatory aggression. Findings are to the authors' knowledge the first to document any mediator of the schizotypy-aggression relationship and have potential treatment implications for violence reduction in schizophrenia-spectrum disorders. This study also provides initial evidence for the factorial and discriminant validity of a brief and simple measure of schizotypal personality in children as young as 8 years. PMID- 21795614 TI - Temporal processing in the auditory core: transformation or segregation? AB - Scott et al. (J Neurophysiol 105: 712-730, 2011) examine temporal processing in auditory Core fields AI and R in the macaque, arguing that temporal properties are the most salient functional differences between these areas. How these results imply transformation of information between AI and R or whether these fields may be processing divergent information somewhat separately is discussed. PMID- 21795615 TI - Functional magnetic resonance adaptation reveals the involvement of the dorsomedial stream in hand orientation for grasping. AB - Reach-to-grasp actions require coordination of different segments of the upper limbs. Previous studies have examined the neural substrates of arm transport and hand grip components of such actions; however, a third component has been largely neglected: the orientation of the wrist and hand appropriately for the object. Here we used functional magnetic resonance imaging adaptation (fMRA) to investigate human brain areas involved in processing hand orientation during grasping movements. Participants used the dominant right hand to grasp a rod with the four fingers opposing the thumb or to reach and touch the rod with the knuckles without visual feedback. In a control condition, participants passively viewed the rod. Trials in a slow event-related design consisted of two sequential stimuli in which the rod orientation changed (requiring a change in wrist posture while grasping but not reaching or looking) or remained the same. We found reduced activation, that is, adaptation, in superior parieto-occipital cortex (SPOC) when the object was repeatedly grasped with the same orientation. In contrast, there was no adaptation when reaching or looking at an object in the same orientation, suggesting that hand orientation, rather than object orientation, was the critical factor. These results agree with recent neurophysiological research showing that a parieto-occipital area of macaque (V6A) is modulated by hand orientation during reach-to-grasp movements. We suggest that the human dorsomedial stream, like that in the macaque, plays a key role in processing hand orientation in reach-to-grasp movements. PMID- 21795616 TI - Representation of limb kinematics in Purkinje cell simple spike discharge is conserved across multiple tasks. AB - Encoding of movement kinematics in Purkinje cell simple spike discharge has important implications for hypotheses of cerebellar cortical function. Several outstanding questions remain regarding representation of these kinematic signals. It is uncertain whether kinematic encoding occurs in unpredictable, feedback dependent tasks or kinematic signals are conserved across tasks. Additionally, there is a need to understand the signals encoded in the instantaneous discharge of single cells without averaging across trials or time. To address these questions, this study recorded Purkinje cell firing in monkeys trained to perform a manual random tracking task in addition to circular tracking and center-out reach. Random tracking provides for extensive coverage of kinematic workspaces. Direction and speed errors are significantly greater during random than circular tracking. Cross-correlation analyses comparing hand and target velocity profiles show that hand velocity lags target velocity during random tracking. Correlations between simple spike firing from 120 Purkinje cells and hand position, velocity, and speed were evaluated with linear regression models including a time constant, tau, as a measure of the firing lead/lag relative to the kinematic parameters. Across the population, velocity accounts for the majority of simple spike firing variability (63 +/- 30% of R(adj)(2)), followed by position (28 +/- 24% of R(adj)(2)) and speed (11 +/- 19% of R(adj)(2)). Simple spike firing often leads hand kinematics. Comparison of regression models based on averaged vs. nonaveraged firing and kinematics reveals lower R(adj)(2) values for nonaveraged data; however, regression coefficients and tau values are highly similar. Finally, for most cells, model coefficients generated from random tracking accurately estimate simple spike firing in either circular tracking or center-out reach. These findings imply that the cerebellum controls movement kinematics, consistent with a forward internal model that predicts upcoming limb kinematics. PMID- 21795617 TI - Decorrelation of cortical inputs and motoneuron output. AB - Oscillations in the primary motor cortex are transmitted through the corticospinal tract to the motoneuron pool. This pathway is believed to produce an effective and direct command from the motor cortex to the spinal motoneurons for the modulation of the force output. In this study, we used a computational model of a population of motoneurons to investigate the factors that can influence the transmission of the cortical input to the output of motoneurons, since it can be quantified by coherence analysis. The simulations demonstrated that, despite the nonlinearity of the motoneurons, oscillations present in the cortical input are transmitted to the output of the motoneuron pool at the same frequency. However, the interference introduced by the nonlinearity of the system increases the variability of the oscillations in output, introducing spectral lines whose frequency depends on the input frequencies and the motoneuron discharge rates. Moreover, an additional source of synaptic input common to all motoneurons but independent from the corticospinal component decorrelates the cortical input and motoneuron output and, thus, decreases the magnitude of the estimated coherence, even if the effective cortical drive does not change. These results indicate that the corticospinal input can effectively be sampled by a small population of motoneurons. However, the transmission of a corticospinal drive to the motoneuron pool is influenced by the nonlinearity of the spiking processes of the active motoneurons and by synaptic inputs common to the motoneuron population but independent from the cortical input. PMID- 21795618 TI - Eye position effects in saccadic adaptation. AB - Saccades are used by the visual system to explore visual space with the high accuracy of the fovea. The visual error after the saccade is used to adapt the control of subsequent eye movements of the same amplitude and direction in order to keep saccades accurate. Saccadic adaptation is thus specific to saccade amplitude and direction. In the present study we show that saccadic adaptation is also specific to the initial position of the eye in the orbit. This is useful, because saccades are normally accompanied by head movements and the control of combined head and eye movements depends on eye position. Many parts of the saccadic system contain eye position information. Using the intrasaccadic target step paradigm, we adaptively reduced the amplitude of reactive saccades to a suddenly appearing target at a selective position of the eyes in the orbitae and tested the resulting amplitude changes for the same saccade vector at other starting positions. For central adaptation positions the saccade amplitude reduction transferred completely to eccentric starting positions. However, for adaptation at eccentric starting positions, there was a reduced transfer to saccades from central starting positions or from eccentric starting positions in the opposite hemifield. Thus eye position information modifies the transfer of saccadic amplitude changes in the adaptation of reactive saccades. A gain field mechanism may explain the eye position dependence found. PMID- 21795619 TI - Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA(A) receptors. AB - Extrasynaptic GABA(A) receptors (eGABARs) allow ambient GABA to tonically regulate neuronal excitability and are implicated as targets for ethanol and anesthetics. These receptors are thought to be heteropentameric proteins made up of two alpha subunits-either alpha4 or alpha6-two beta2 or beta3 subunits, and one delta subunit. The GABA analog 4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3( ol) (THIP) has been proposed as a selective ligand for eGABARs. Behavioral and in vitro studies suggest that eGABARs have nanomolar affinity for THIP; however, all published studies on recombinant versions of eGABARs report micromolar affinities. Here, we examine THIP sensitivity of native eGABARs on cerebellar neurons and on reconstituted GABARs in heterologous systems. Concentration response data for THIP, obtained from cerebellar granule cells and molecular layer interneurons in wild-type and delta subunit knockout slices, confirm that submicromolar THIP sensitivity requires delta subunits. In recombinant experiments, we find that delta subunit coexpression leads to receptors activated by nanomolar THIP concentrations (EC(50) of 30-50 nM for alpha4beta3delta and alpha6beta3delta), a sensitivity almost 1,000-fold higher than receptors formed by alpha4/6 and beta3 subunits. In contrast, gamma2 subunit expression significantly reduces THIP sensitivity. Even when delta subunit cDNA or cRNA was supplied in excess, high- and low-sensitivity THIP responses were often apparent, indicative of variable mixtures of low-affinity alphabeta and high-affinity alphabetadelta receptors. We conclude that delta subunit incorporation into GABARs leads to a dramatic increase in THIP sensitivity, a defining feature that accounts for the unique behavioral and neurophysiological properties of THIP. PMID- 21795620 TI - Multiple T-type Ca2+ current subtypes in electrophysiologically characterized hamster dorsal horn neurons: possible role in spinal sensory integration. AB - Whole cell patch-clamp recordings were used to investigate the contribution of transient, low-threshold calcium currents (I(T)) to firing properties of hamster spinal dorsal horn neurons. I(T) was widely, though not uniformly, expressed by cells in Rexed's laminae I-IV and correlated with the pattern of action potential discharge evoked under current-clamp conditions: I(T) in neurons responding to constant membrane depolarization with one or two action potentials was nearly threefold larger than I(T) in cells responding to the same activation with continuous firing. I(T) was evoked by depolarizing voltage ramps exceeding 46 mV/s and increased with ramp slope (240-2,400 mV/s). Bath application of 200 MUM Ni(2+) depressed ramp-activated I(T). Phasic firing recorded in current clamp could only be activated by membrane depolarizations exceeding ~43-46 mV/s and was blocked by Ni(2+) and mibefradil, suggesting I(T) as an underlying mechanism. Two components of I(T), "fast" and "slow," were isolated based on a difference in time constant of inactivation (12 ms and 177 ms, respectively). The amplitude of the fast subtype depended on the slope of membrane depolarization and was twice as great in burst-firing cells than in cells having a tonic discharge. Post hoc single-cell RT-PCR analyses suggested that the fast component is associated with the Ca(V)3.1 channel subtype. I(T) may enhance responses of phasic-firing dorsal horn neurons to rapid membrane depolarizations and contribute to an ability to discriminate between afferent sensory inputs that encode high- and low-frequency stimulus information. PMID- 21795622 TI - A history of low back pain associates with altered electromyographic activation patterns in response to perturbations of standing balance. AB - People with a history of low back pain (LBP) exhibit altered responses to postural perturbations, and the central neural control underlying these changes in postural responses remains unclear. To characterize more thoroughly the change in muscle activation patterns of people with LBP in response to a perturbation of standing balance, and to gain insight into the influence of early- vs. late-phase postural responses (differentiated by estimates of voluntary reaction times), this study evaluated the intermuscular patterns of electromyographic (EMG) activations from 24 people with and 21 people without a history of chronic, recurrent LBP in response to 12 directions of support surface translations. Two factor general linear models examined differences between the 2 subject groups and 12 recorded muscles of the trunk and lower leg in the percentage of trials with bursts of EMG activation as well as the amplitudes of integrated EMG activation for each perturbation direction. The subjects with LBP exhibited 1) higher baseline EMG amplitudes of the erector spinae muscles before perturbation onset, 2) fewer early-phase activations at the internal oblique and gastrocnemius muscles, 3) fewer late-phase activations at the erector spinae, internal and external oblique, rectus abdominae, and tibialis anterior muscles, and 4) higher EMG amplitudes of the gastrocnemius muscle following the perturbation. The results indicate that a history of LBP associates with higher baseline muscle activation and that EMG responses are modulated from this activated state, rather than exhibiting acute burst activity from a quiescent state, perhaps to circumvent trunk displacements. PMID- 21795621 TI - Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control. AB - Motor cortex is a key brain center involved in motor control in rodents and other mammals, but specific intracortical mechanisms at the microcircuit level are largely unknown. Neuronal expression of hyperpolarization-activated current (I(h)) is cell class specific throughout the nervous system, but in neocortex, where pyramidal neurons are classified in various ways, a systematic pattern of expression has not been identified. We tested whether I(h) is differentially expressed among projection classes of pyramidal neurons in mouse motor cortex. I(h) expression was high in corticospinal neurons and low in corticostriatal and corticocortical neurons, a pattern mirrored by mRNA levels for HCN1 and Trip8b subunits. Optical mapping experiments showed that I(h) attenuated glutamatergic responses evoked across the apical and basal dendritic arbors of corticospinal but not corticostriatal neurons. Due to I(h), corticospinal neurons resonated, with a broad peak at ~4 Hz, and were selectively modulated by alpha-adrenergic stimulation. I(h) reduced the summation of short trains of artificial excitatory postsynaptic potentials (EPSPs) injected at the soma, and similar effects were observed for short trains of actual EPSPs evoked from layer 2/3 neurons. I(h) narrowed the coincidence detection window for EPSPs arriving from separate layer 2/3 inputs, indicating that the dampening effect of I(h) extended to spatially disperse inputs. To test the role of corticospinal I(h) in transforming EPSPs into action potentials, we transfected layer 2/3 pyramidal neurons with channelrhodopsin-2 and used rapid photostimulation across multiple sites to synaptically drive spiking activity in postsynaptic neurons. Blocking I(h) increased layer 2/3-driven spiking in corticospinal but not corticostriatal neurons. Our results imply that I(h)-dependent synaptic integration in corticospinal neurons constitutes an intracortical control mechanism, regulating the efficacy with which local activity in motor cortex is transferred to downstream circuits in the spinal cord. We speculate that modulation of I(h) in corticospinal neurons could provide a microcircuit-level mechanism involved in translating action planning into action execution. PMID- 21795623 TI - Cholinergic modulation of working memory activity in primate prefrontal cortex. AB - The prefrontal cortex, a cortical area essential for working memory and higher cognitive functions, is modulated by a number of neurotransmitter systems, including acetylcholine; however, the impact of cholinergic transmission on prefrontal activity is not well understood. We relied on systemic administration of a muscarinic receptor antagonist, scopolamine, to investigate the role of acetylcholine on primate prefrontal neuronal activity during execution of working memory tasks and recorded neuronal activity with chronic electrode arrays and single electrodes. Our results indicated a dose-dependent decrease in behavioral performance after scopolamine administration in all the working memory tasks we tested. The effect could not be accounted for by deficits in visual processing, eye movement responses, or attention, because the animals performed a visually guided saccade task virtually error free, and errors to distracting stimuli were not increased. Performance degradation under scopolamine was accompanied by decreased firing rate of the same cortical sites during the delay period of the task and decreased selectivity for the spatial location of the stimuli. These results demonstrate that muscarinic blockade impairs performance in working memory tasks and prefrontal activity mediating working memory. PMID- 21795625 TI - Target modality determines eye-head coordination in nonhuman primates: implications for gaze control. AB - We have studied eye-head coordination in nonhuman primates with acoustic targets after finding that they are unable to make accurate saccadic eye movements to targets of this type with the head restrained. Three male macaque monkeys with experience in localizing sounds for rewards by pointing their gaze to the perceived location of sources served as subjects. Visual targets were used as controls. The experimental sessions were configured to minimize the chances that the subject would be able to predict the modality of the target as well as its location and time of presentation. The data show that eye and head movements are coordinated differently to generate gaze shifts to acoustic targets. Chiefly, the head invariably started to move before the eye and contributed more to the gaze shift. These differences were more striking for gaze shifts of <20-25 degrees in amplitude, to which the head contributes very little or not at all when the target is visual. Thus acoustic and visual targets trigger gaze shifts with different eye-head coordination. This, coupled to the fact that anatomic evidence involves the superior colliculus as the link between auditory spatial processing and the motor system, suggests that separate signals are likely generated within this midbrain structure. PMID- 21795624 TI - Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia. AB - Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents (I(h)) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage "sag" associated with I(h) activation. These differences became nonsignificant after application of the I(h) blocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting I(h) with ZD7288 increased the half width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that I(h) serves to constrain network activity in addition to its role in regulating cellular excitability. Reduced I(h) may contribute to increased network excitability in cortical dysplasia. PMID- 21795626 TI - Impaired inhibitory control of cortical synchronization in fragile X syndrome. AB - Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5 dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype. PMID- 21795627 TI - The organization of the human cerebellum estimated by intrinsic functional connectivity. AB - The cerebral cortex communicates with the cerebellum via polysynaptic circuits. Separate regions of the cerebellum are connected to distinct cerebral areas, forming a complex topography. In this study we explored the organization of cerebrocerebellar circuits in the human using resting-state functional connectivity MRI (fcMRI). Data from 1,000 subjects were registered using nonlinear deformation of the cerebellum in combination with surface-based alignment of the cerebral cortex. The foot, hand, and tongue representations were localized in subjects performing movements. fcMRI maps derived from seed regions placed in different parts of the motor body representation yielded the expected inverted map of somatomotor topography in the anterior lobe and the upright map in the posterior lobe. Next, we mapped the complete topography of the cerebellum by estimating the principal cerebral target for each point in the cerebellum in a discovery sample of 500 subjects and replicated the topography in 500 independent subjects. The majority of the human cerebellum maps to association areas. Quantitative analysis of 17 distinct cerebral networks revealed that the extent of the cerebellum dedicated to each network is proportional to the network's extent in the cerebrum with a few exceptions, including primary visual cortex, which is not represented in the cerebellum. Like somatomotor representations, cerebellar regions linked to association cortex have separate anterior and posterior representations that are oriented as mirror images of one another. The orderly topography of the representations suggests that the cerebellum possesses at least two large, homotopic maps of the full cerebrum and possibly a smaller third map. PMID- 21795629 TI - Concentration- and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to 12 weeks. AB - Inorganic arsenic (As(i)) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to As(i) in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/l. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to downregulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/l, despite the fact that pathway enrichment was observed at the 0.5 mg As/l exposure concentration. This disparity may result from the nonmonotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/l compared with lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of As(i) in mouse bladder cells in the vicinity of 2 mg As(i)/l. PMID- 21795628 TI - Inhibition to excitation ratio regulates visual system responses and behavior in vivo. AB - The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the gamma2 subunit of the GABA(A) receptors (GABA(A)R) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the gamma2 subunit, called ICL, which interferes with anchoring GABA(A)R at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ~50% decrease in the ratio of I/E synaptic input. ICL expression and gamma2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ~30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, gamma2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate. PMID- 21795630 TI - The PGC-1alpha-related coactivator promotes mitochondrial and myogenic adaptations in C2C12 myotubes. AB - The transcriptional coactivator PGC-1alpha is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1alpha related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 +/- 0.3-fold and protein content by 108 +/- 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 +/- 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 +/ 0.52%) and myosin heavy chain (15.4 +/- 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some-COX4 (2.6 +/- 0.18-fold), ATP5B (2.7 +/- 0.34-fold) cytochrome c (5.1 +/- 0.68-fold)-but not all, MTCO1 (0.61 +/- 0.18 fold) and HAD (0.98 +/- 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome-c (28.7 +/- 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 +/- 0.01-fold) and citrate synthase (2.1 +/- 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 +/- 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 +/- 3.31%) and oxidation (31.1 +/- 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 +/- 0.22-fold) and protein (13.8 +/- 2.08%) and CPT1 protein (28.9 +/- 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 +/- 0.3-fold vs. 4.4 +/- 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC 1alpha. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration. PMID- 21795631 TI - Hypotension in the chronically hypoxic chicken embryo is related to the beta adrenergic response of chorioallantoic and femoral arteries and not to bradycardia. AB - Prolonged fetal hypoxia leads to growth restriction and can cause detrimental prenatal and postnatal alterations. The embryonic chicken is a valuable model to study the effects of prenatal hypoxia, but little is known about its long-term effects on cardiovascular regulation. We hypothesized that chicken embryos incubated under chronic hypoxia would be hypotensive due to bradycardia and betaAR-mediated relaxation of the systemic and/or the chorioallantoic (CA) arteries. We investigated heart rate, blood pressure, and plasma catecholamine levels in 19-day chicken embryos (total incubation 21 days) incubated from day 0 in normoxia or hypoxia (14-15% O(2)). Additionally, we studied alpha-adrenoceptor (alphaAR)-mediated contraction, relaxation to the beta-adrenoceptor (betaAR) agonist isoproterenol, and relaxation to the adenylate cyclase activator forskolin in systemic (femoral) and CA arteries (by wire myography). Arterial pressure showed a trend toward hypotension in embryos incubated under chronic hypoxic conditions compared with the controls (mean arterial pressure 3.19 +/- 0.18 vs. 2.59 +/- 0.13 kPa, normoxia vs. hypoxia, respectively. P = 0.056), without an accompanied bradycardia and elevation in plasma norepinephrine and lactate levels. All vessels relaxed in response to betaAR stimulation with isoproterenol, but the CA arteries completely lacked an alphaAR response. Furthermore, hypoxia increased the sensitivity of femoral arteries (but not CA arteries) to isoproterenol. Hypoxia also increased the responsiveness of femoral arteries to forskolin. In conclusion, we suggest that hypotension in chronic hypoxic chicken embryos is the consequence of elevated levels of circulating catecholamines acting in vascular beds with exclusive (CA arteries) or exacerbated (femoral arteries) betaAR-mediated relaxation, and not a consequence of bradycardia. PMID- 21795632 TI - Role of the alpha-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species. AB - Using an integrative approach at the whole animal, isolated vessels, and molecular levels, we tested the hypothesis that the llama, a species that undergoes pregnancy under the influence of the chronic hypoxia of high altitude, delivers offspring with an increased alpha-adrenergic peripheral vascular reactivity compared with neonates from lowland species. We studied the femoral vascular response to acute hypoxia in vivo, the reactivity of femoral vessels ex vivo, and the expression of femoral alpha(1)-adrenergic receptor subtypes using RT-PCR in vitro. The increase in femoral resistance during hypoxia was 3.6 times greater in newborn llamas than newborn sheep (P < 0.05). The sensitivity of the contractile response to noradrenaline (pD(2) = 5.18 +/- 0.06 vs. 4.84 +/- 0.05, P < 0.05) and the maximal response (R(max) = 101.3 +/- 1.4 vs. 52.4 +/- 1.4% K(+)(max), P < 0.05) and sensitivity (pD(2) = 5.47 +/- 0.03 vs. 4.57 +/- 0.05, P < 0.05) to phenylephrine were higher in femoral vessels from newborn llamas than newborn sheep. Competitive inhibition with prazosin of noradrenaline-induced contraction followed by Schild analysis showed higher affinity in the llama than the sheep (pA(2) = 10.08 +/- 0.093 vs. 8.98 +/- 0.263, respectively, P < 0.05), consistent with greater alpha(1B)-adrenergic receptor transcript expression observed in small femoral arteries from neonatal llama. The llama newborn demonstrates significantly greater alpha-adrenergic peripheral vascular reactivity compared with neonates from lowland species that could be partially explained by preferential expression of alpha(1B)-adrenergic receptor subtype. PMID- 21795633 TI - Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity. AB - We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630-640; 1103-1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (-8%) in both groups, with a fall in blood pressure (-10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control. PMID- 21795634 TI - Persistent detrusor overactivity in rats after relief of partial urethral obstruction. AB - Detrusor overactivity (DO) persists after prostatectomy in 20% to 25% of patients with benign disease. Assuming that nonvoiding contractions (NVCs) can be used as a surrogate for DO in humans, the rat model of obstruction/deobstruction may allow us to study the pathophysiology of persistent DO after deobstruction. We investigated bladder function, with a special focus on NVCs, in rats by use of a new, modified method of obstruction and deobstruction and compared these results with those obtained by use of the conventional method. Seventy female Sprague Dawley rats underwent 1) sham operation (n = 10), 2) obstruction by a modified method (Modif-Obs; n = 12), 3) obstruction/deobstruction by the conventional method (Conv-Obs/Deobs; n = 13), or 4) obstruction/deobstruction by the modified method (Modif-Obs/Deobs; n = 35). The Modif-Obs/Deobs animals were divided into subgroups with (DO+) and without (DO-) NVCs. Two weeks after partial urethral obstruction, the animals were deobstructed, and 1 wk later cystometry was performed with recording of intravesical and intra-abdominal pressures. NVCs were shown in all groups: Modif-Obs (80%), Conv-Obs/Deobs (100%), and Modif-Obs/Deobs (40%). In the Modif-Obs/Deobs group, bladder weight and the muscle-to-collagen ratio were higher in DO+ than in DO- rats. The Modif-Obs/Deobs group showed no mortality compared with 25% mortality in the Conv-Obs/Deobs group. The modified method may be more adequate for studying persistent DO after deobstruction, because it resulted in pressure/volume- and DO-related parameters similar to those found in the clinical situation. The persistence of DO after deobstruction may partly be due to irreversible changes in the bladder caused during the period of obstruction. PMID- 21795635 TI - Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation. AB - Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E(2) (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 <= P <= 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E(2)/T administration potentiated both pulsatile (P = 0.006) and entropic (P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode (P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass (P = 0.005). The composite of gender, body mass index, E(2), IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans. PMID- 21795636 TI - Patterning of somatosympathetic reflexes reveals nonuniform organization of presympathetic drive from C1 and non-C1 RVLM neurons. AB - To determine the organization of presympathetic vasomotor drive by phenotypic populations of rostral ventrolateral medulla (RVLM) neurons, we examined the somatosympathetic reflex (SSR) evoked in four sympathetic nerves together with selective lesions of RVLM presympathetic neurons. Urethane-anesthetized (1.3 g/kg ip), paralyzed, vagotomized and artificially ventilated Sprague-Dawley rats (n = 41) were used. First, we determined the afferent inputs activated by sciatic nerve (SN) stimulation at graded stimulus intensities (50 sweeps at 0.5-1 Hz, 1 80 V). Second, we recorded sympathetic nerve responses (cervical, renal, splanchnic, and lumbar) to intensities of SN stimulation that activated A-fiber afferents (low) or both A- and C-fiber afferents (high). Third, with low intensity SN stimulation, we examined the cervical SSR following RVLM microinjection of somatostatin, and we determined the splanchnic SSR in rats in which presympathetic C1 neurons were lesioned following intraspinal injections of anti-dopamine-beta-hydroxylase-saporin (anti-DbetaH-SAP). Low-intensity SN stimulation activated A-fiber afferents and evoked biphasic responses in the renal, splanchnic, and lumbar nerves and a single peak in the cervical nerve. Depletion of presympathetic C1 neurons (59 +/- 4% tyrosine hydroxylase immunoreactivity profiles lesioned) eliminated peak 2 of the splanchnic SSR and attenuated peak 1, suggesting that only RVLM neurons with fast axonal conduction were spared. RVLM injections of somatostatin abolished the single early peak of cervical SSR confirming that RVLM neurons with fast axonal conduction were inhibited by somatostatin. It is concluded that unmyelinated RVLM presympathetic neurons, presumed to be all C1, innervate splanchnic, renal, and lumbar but not cervical sympathetic outflows, whereas myelinated C1 and non-C1 RVLM neurons innervate all sympathetic outflows examined. These findings suggest that multiple levels of neural control of vasomotor tone exist; myelinated populations may set baseline tone, while unmyelinated neurons may be recruited to provide actions at specific vascular beds in response to distinct stressors. PMID- 21795637 TI - Intrinsic contractile properties of the crucian carp (Carassius carassius) heart during anoxic and acidotic stress. AB - The crucian carp (Carassius carassius) seems unique among vertebrates in its ability to maintain cardiac performance during prolonged anoxia. We investigated whether this phenomenon arises in part from a myocardium tolerant to severe acidosis or because the anoxic crucian carp heart may not experience a severe extracellular acidosis due to the fish's ability to convert lactate to ethanol. Spontaneously contracting heart preparations from cold-acclimated (6-8 degrees C) carp were exposed (at 6.5 degrees C) to graded or ungraded levels of acidosis under normoxic or anoxic conditions and intrinsic contractile performance was assessed. Our results clearly show that the carp heart is tolerant of acidosis as long as oxygen is available. However, heart rate and contraction kinetics of anoxic hearts were severely impaired when extracellular pH was decreased below 7.4. Nevertheless, the crucian carp heart was capable of recovering intrinsic contractile performance upon reoxygenation regardless of the severity of the anoxic + acidotic insult. Finally, we show that increased adrenergic stimulation can ameliorate, to a degree, the negative effects of severe acidosis on the intrinsic contractile properties of the anoxic crucian carp heart. Combined, these findings indicate an avoidance of severe extracellular acidosis and adrenergic stimulation are two important factors protecting the intrinsic contractile properties of the crucian carp heart during prolonged anoxia, and thus likely facilitate the ability of the anoxic crucian carp to maintain cardiac pumping. PMID- 21795638 TI - Atherosclerotic lesion progression is attenuated by reconstitution with bone marrow from macrophage-specific cholesteryl ester hydrolase transgenic mice. AB - Accumulation of cholesteryl ester (CE)-enriched macrophage foam cells is central to the development of atherosclerotic lesions. Intracellular CE hydrolysis is the rate-limiting step in the removal of free cholesterol from macrophage foam cells. Enhancing this process by transgenic overexpression of CE hydrolase (CEH) resulted in a significant decrease in diet-induced atherosclerosis in LDL receptor-deficient (LDLR-/-) mice. However, for development of this step as an antiatherosclerotic target it is imperative to demonstrate that increase in CE hydrolysis after initiation of lesion formation will also attenuate further lesion progression. The objective of the present study was to directly address this issue using an animal model. LDLR-/- mice were fed a high-fat high cholesterol diet (Western Diet) for 8 wk to initiate lesion formation and were then divided into three groups. Group 1 mice were killed to determine baseline lesion development. Mice in groups 2 and 3 were irradiated and transplanted with either LDLR-/- or LDLR-/-CEH transgenic bone marrow and maintained on Western Diet. Atherosclerotic lesion progression was assessed after 12 wk. While a more than fourfold increase in total lesions (compared to group 1) was seen in group 2 receiving LDLR-/- marrow, a significantly lower increase (<2-fold) was noted in mice reconstituted with CEH transgenic marrow (group 3). Lesions in group 3 mice were also more cellular with smaller necrotic cores. Lesion progression is associated with a switch in macrophage phenotype from anti-inflammatory M2 to proinflammatory M1 phenotype and is consistent with reduced lesion progression. Aortas from group 3 mice contained a significantly higher percentage of macrophages in M2 phenotype (Ly6C(lo)). These data demonstrate for the first time that enhancing macrophage CE hydrolysis even after lesion initiation can still attenuate further lesion progression and also switches the phenotype of lesion associated macrophages to anti-inflammatory M2 phenotype establishing intracellular CE hydrolysis as an anti-atherosclerotic as well as anti inflammatory target. PMID- 21795639 TI - Mechanisms mediating sodium-induced pressor responses in the PVN of Dahl rats. AB - Intracerebroventricular infusion of Na(+)-rich artificial cerebrospinal fluid (aCSF) causes larger sympathetic and pressor responses in Dahl salt-sensitive (S) than -resistant (R) or Wistar rats. Enhanced activity of the aldosterone "ouabain" pathway or decreased nitric oxide (NO) release may contribute to this enhanced responsiveness. Where in the brain these mechanisms interact is largely unknown. The present study evaluated whether Na(+) in the paraventricular nucleus (PVN) causes larger pressor responses in Dahl S (SS/Mcw) than R (Dahl SS.BN13) rats and whether mineralocorticoid receptors, benzamil-blockable Na(+) channels, "ouabain," angiotensin type 1 receptors, or NO mediates these enhanced responses. Na(+)-rich aCSF in the PVN caused 30-40% larger increases in blood pressure and heart rate in Dahl S than R or Wistar rats, whereas responses to ouabain, ANG II, or N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME) in the PVN were the same. These responses to Na(+) were not affected by eplerenone, benzamil, or Fab fragments, whereas they were fully blocked by losartan, in Dahl S and R rats. l-NAME enhanced them more in Dahl R than S rats, thereby equalizing the responses in the two strains. Pressor responses to l-NAME in the PVN were attenuated by a high-salt diet in Dahl S, but not R, rats. The results indicate that acute and chronic increases in Na(+) concentration in the PVN inhibit NO release in the PVN of Dahl S, but not R, rats, thereby contributing to the enhanced pressor responses to Na(+) in Dahl S rats. PMID- 21795640 TI - Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats. AB - In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Delta= -23 +/- 3 beats per minute (bpm)] and light/inactive (Delta= -20 +/- 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Delta= -54 +/- 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Delta= -16 +/- 3 bpm, inactive phase Delta= -19 +/- 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent. PMID- 21795641 TI - Inflammatory stress exacerbates lipid-mediated renal injury in ApoE/CD36/SRA triple knockout mice. AB - Both lipids and inflammation play important roles in the progression of kidney disease. This study was designed to investigate whether inflammation exacerbates lipid accumulation via LDL receptors (LDLr), thereby causing renal injury in C57BL/6J mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE/CD36/scavenger receptor A triple KO mice. The mice were given a subcutaneous casein injection to induce inflammatory stress. After 14 wk, terminal blood samples were taken for renal function, lipid profiles, amyloid A (SAA), and IL-6 assays. Lipid accumulation in kidneys was visualized by oil red O staining. Fibrogenic molecule expression in kidneys was examined. There was a significant increase in serum SAA and IL-6 in the all casein-injected mice compared with respective controls. Casein injection reduced serum total cholesterol, LDL cholesterol, and HDL cholesterol and caused lipid accumulation in kidneys from three types of mice. The expression of LDLr and its regulatory proteins sterol responsive element-binding protein (SREBP) 2 and SREBP cleavage-activating protein (SCAP) were upregulated in inflamed mice compared with controls. Casein injection induced renal fibrosis accompanied by increased expression of fibrogenic molecules in the triple KO mice. These data imply that inflammation exacerbates lipid accumulation in the kidney by diverting lipid from the plasma to the kidney via the SCAP-SREBP2-LDLr pathway and causing renal injury. Low blood cholesterol levels, resulting from inflammation, may be associated with high risk for chronic renal fibrosis. PMID- 21795642 TI - Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia reperfusion. AB - Meprins, metalloproteinases abundantly expressed in the brush-border membranes (BBMs) of rodent proximal kidney tubules, have been implicated in the pathology of renal injury induced by ischemia-reperfusion (IR). Disruption of the meprin beta gene and actinonin, a meprin inhibitor, both decrease kidney injury resulting from IR. To date, the in vivo kidney substrates for meprins are unknown. The studies herein implicate villin and actin as meprin substrates. Villin and actin bind to the cytoplasmic tail of meprin beta, and both meprin A and B are capable of degrading villin and actin present in kidney proteins as well as purified recombinant forms of these proteins. The products resulting from degradation of villin and actin were unique to each meprin isoform. The meprin B cleavage site in villin was Glu(744)-Val(745). Recombinant forms of rat meprin B and homomeric mouse meprin A had K(m) values for villin and actin of ~1 MUM (0.6 1.2 MUM). The k(cat) values varied substantially (0.6-128 s(-1)), resulting in different efficiencies for cleavage, with meprin B having the highest k(cat)/K(m) values (128 M(-1).s(-1) * 10(6)). Following IR, meprins and villin redistributed from the BBM to the cytosol. A 37-kDa actin fragment was detected in protein fractions from wild-type, but not in comparable preparations from meprin knockout mice. The levels of the 37-kDa actin fragment were significantly higher in kidneys subjected to IR. The data establish that meprins interact with and cleave villin and actin, and these cytoskeletal proteins are substrates for meprins. PMID- 21795643 TI - Role of AUF1 and HuR in the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in LLC-PK1-F+ cells. AB - Onset of metabolic acidosis leads to a rapid and pronounced increase in expression of phosphoenolpyruvate carboxykinase (PEPCK) in rat renal proximal convoluted tubules. This adaptive response is modeled by treating a clonal line of porcine LLC-PK(1)-F(+) cells with an acidic medium (pH 6.9, 9 mM HCO(3)(-)). Measurement of the half-lives of PEPCK mRNA in cells treated with normal (pH 7.4, 26 mM HCO(3)(-)) and acidic medium established that the observed increase is due in part to stabilization of the PEPCK mRNA. The pH-responsive stabilization was reproduced in a Tet-responsive chimeric reporter mRNA containing the 3'-UTR of PEPCK mRNA. This response was lost by mutation of a highly conserved AU sequence that binds AUF1 and is the primary element that mediates the rapid turnover of PEPCK mRNA. However, siRNA knockdown of AUF1 had little effect on the basal levels and the pH-responsive increases in PEPCK mRNA and protein. Electrophoretic mobility shift assays established that purified recombinant HuR, another AU element binding protein, also binds with high affinity and specificity to multiple sites within the final 92-nucleotides of the 3'-UTR of the PEPCK mRNA, including the highly conserved AU-rich element. siRNA knockdown of HuR caused pronounced decreases in basal expression and the pH-responsive increases in PEPCK mRNA and protein. Therefore, basal expression and the pH-responsive stabilization of PEPCK mRNA in LLC-PK(1)-F(+) cells, and possibly in the renal proximal tubule, may require the remodeling of HuR and AUF1 binding to the elements that mediate the rapid turnover of PEPCK mRNA. PMID- 21795644 TI - Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis. AB - The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-beta1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-beta1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-beta1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential. PMID- 21795646 TI - Cellular and molecular basis of increased ammoniagenesis in potassium deprivation. AB - Hypokalemia is associated with increased ammoniagenesis and stimulation of net acid excretion by the kidney in both humans and experimental animals. The molecular mechanisms underlying these effects remain unknown. Toward this end, rats were placed in metabolic cages and fed a control or K(+)-deficient diet (KD) for up to 6 days. Rats subjected to KD showed normal acid-base status and serum electrolytes composition. Interestingly, urinary NH(4)(+) excretion increased significantly and correlated with a parallel decrease in urine K(+) excretion in KD vs. control animals. Molecular studies showed a specific upregulation of the glutamine transporter SN1, which correlated with the upregulation of glutaminase (GA), glutamate dehydrogenase (GDH), and phosphoenolpyruvate carboxykinase. These effects occurred as early as day 2 of KD. Rats subjected to a combined KD and 280 mM NH(4)Cl loading (to induce metabolic acidosis) for 2 days showed an additive increase in NH(4)(+) excretion along with an additive increment in the expression levels of ammoniagenic enzymes GA and GDH compared with KD or NH(4)Cl loading alone. The incubation of cultured proximal tubule cells NRK 52E or LLC-PK(1) in low-K(+) medium did not affect NH(4)(+) production and did not alter the expression of SN1, GA, or GDH in NRK cells. These results demonstrate that K(+) deprivation stimulates ammoniagenesis through a coordinated upregulation of glutamine transporter SN1 and ammoniagenesis enzymes. This effect is developed before the onset of hypokalemia. The signaling pathway mediating these events is likely independent of KD-induced intracellular acidosis. Finally, the correlation between increased NH(4)(+) production and decreased K(+) excretion indicate that NH(4)(+) synthesis and transport likely play an important role in renal K(+) conservation during hypokalemia. PMID- 21795647 TI - Evaluation of soluble HLA-G as a biomarker for multiple sclerosis. PMID- 21795648 TI - Comment: The new mentoring and team leadership. PMID- 21795649 TI - Effects of beta-blocker selectivity on blood pressure variability and stroke: a systematic review. AB - OBJECTIVES: beta-Blockers increase variability in systolic blood pressure (SBP), which probably explains their lesser effectiveness in preventing stroke vs myocardial infarction compared with other agents. This increase in variability in blood pressure (BP) may be particularly marked on non-cardioselective agents, potentially calling into question the widespread first-line use of propranolol in migraine with aura, elderly patients with essential tremor or anxiety, and other groups at risk of stroke. METHODS: We determined beta-blocker subclass effects on variability in BP and stroke risk in a systematic review of randomized controlled trials (RCTs) comparing different types of beta-blocker with placebo or other agents. We determined pooled estimates of the effect of treatment on group variability in BP (ratio of the variances [VR]) and on the risk of stroke vs myocardial infarction during follow-up. RESULTS: Compared with other antihypertensives, variability in SBP was increased more by nonselective beta blockers (VR=1.34, 1.13-1.59, p =0.002, 25 comparisons, 9,992 patients) than by beta1-selective agents (VR=1.09, 95% confidence interval 1.00-1.19, p =0.053, 68 comparisons, 40,746 patients; difference-p =0.038). In direct comparisons, variability in SBP was also significantly lower with beta1-selective vs nonselective beta-blockers (VR=0.81, 0.68-0.97, p =0.03, 18 comparisons, 954 patients). In comparisons with other antihypertensives, the increase in stroke risk with nonselective beta-blockers ([OR]=2.29, 1.32-3.96, p =0.002) was more marked than with beta1-selective agents (OR=1.24, 1.08-1.42, p =0.003, difference p =0.03), as was the risk of stroke relative to the risk of myocardial infarction: OR=1.50 (0.93-2.42) vs 0.99 (0.82-1.19). CONCLUSION: Use of beta1 selective rather than nonselective agents may be advisable when beta-blockers are indicated for patients at risk of stroke. PMID- 21795650 TI - Pilot trial of IOM duty hour recommendations in neurology residency programs: unintended consequences. AB - OBJECTIVE: To study the potential effect of the 2008 Institute of Medicine (IOM) work duty hour (WDH) recommendations on neurology residency programs. METHODS: This study evaluated resident sleepiness, personal study hours, quality of life, and satisfaction and faculty satisfaction during a control month using the Accreditation Council for Graduate Medical Education WDH requirements and during an intervention month using the IOM WDH recommendations. Resident participation in both schedules was mandatory, but both resident and faculty participation in the outcome measures was voluntary. RESULTS: Thirty-four residents (11 postgraduate year [PGY]-4, 9 PGY-3, and 14 PGY-2) participated. End-of-work shift sleepiness, mean weekly sleep hours, personal study hours, and hours spent in lectures did not differ between the control and intervention months. Resident quality of life measured by the Maslach Burnout Inventory declined for 1 subscore in the intervention month (p = 0.03). Resident education satisfaction declined during the intervention month for issues related to continuity of care, patient hand-offs, and knowledge of their patients. Faculty satisfaction declined during the intervention month, without a decline in quality of life. CONCLUSIONS: The results from 3 residency programs suggest that the IOM WDH recommendations may negatively affect neurology resident education. This study was limited by the short duration of implementation, negative bias against the IOM recommendations, and inability to blind faculty. Additional study of the IOM WDH recommendations is warranted before widespread implementation. PMID- 21795651 TI - Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. AB - OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination. PMID- 21795653 TI - beta-Blockers in neurologic practice: should we be advising caution? PMID- 21795652 TI - Guided self-help for functional (psychogenic) symptoms: a randomized controlled efficacy trial. AB - OBJECTIVES: Functional (psychogenic or somatoform) symptoms are common in neurology clinics. Cognitive-behavioral therapy (CBT) can be an effective treatment, but there are major obstacles to its provision in practice. We tested the hypothesis that adding CBT-based guided self-help (GSH) to the usual care (UC) received by patients improves outcomes. METHODS: We conducted a randomized trial in 2 neurology services in the United Kingdom. Outpatients with functional symptoms (rated by the neurologist as "not at all" or only "somewhat" explained by organic disease) were randomly allocated to UC or UC plus GSH. GSH comprised a self-help manual and 4 half-hour guidance sessions. The primary outcome was self rated health on a 5-point clinical global improvement scale (CGI) at 3 months. Secondary outcomes were measured at 3 and 6 months. RESULTS: In this trial, 127 participants were enrolled, and primary outcome data were collected for 125. Participants allocated to GSH reported greater improvement on the primary outcome (adjusted common odds ratio on the CGI 2.36 [95% confidence interval 1.17-4.74; p = 0.016]). The absolute difference in proportion "better" or "much better" was 13% (number needed to treat was 8). At 6 months the treatment effect was no longer statistically significant on the CGI but was apparent in symptom improvement and in physical functioning. CONCLUSIONS: CBT-based GSH is feasible to implement and efficacious. Further evaluation is indicated. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CBT-based GSH therapy improves self-reported general health, as measured by the CGI, in patients with functional neurologic symptoms. PMID- 21795654 TI - Comment: Career guidelines promote neurologist satisfaction. PMID- 21795655 TI - Synaptic vesicle protein 2A predicts response to levetiracetam in patients with glioma. AB - OBJECTIVES: To correlate SV2A expression in surgically removed tumor and peritumoral tissue of glioma patients with epilepsy with the clinical response to levetiracetam in a prospective cohort. METHODS: Forty glioma patients with epilepsy were recruited. All patients had undergone surgery and were on levetiracetam monotherapy. Clinical characteristics were documented. Follow-up visits were scheduled at 3 and 6 months. Patients who responded to levetiracetam were compared to those who did not respond. Expression of SV2A was determined by means of immunohistochemistry in the surgically removed tumor and peritumoral tissue. Optical density (OD) was used to measure SV2A expression. RESULTS: In total, 34 patients were eligible for analysis. Patients with a good response to treatment had significantly stronger SV2A expression as demonstrated by OD in tumor tissue (mean 44.5, SD 17.3) as well as in peritumoral tissue (mean 67.5, SD 7.8) than patients who did not show such a response (mean 8.1, SD 7.7, p < 0.01 and 45.6, SD 11.2, p < 0.01). SV2A expression predicted efficacy of levetiracetam monotherapy with an accuracy of 91%. CONCLUSIONS: Our results suggest that expression of SV2A in tumor and peritumoral tissue is correlated to the clinical response to levetiracetam and predicts levetiracetam efficacy. PMID- 21795656 TI - Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. AB - OBJECTIVE: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). METHODS: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). RESULTS: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. CONCLUSIONS: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors. PMID- 21795657 TI - Further restrictions on resident duty hours: let's look before we leap. PMID- 21795658 TI - Patient-ventilator asynchrony with nocturnal noninvasive ventilation in ALS. AB - BACKGROUND: American Academy of Neurology (AAN) practice parameters for amyotrophic lateral sclerosis (ALS) include noninvasive positive pressure ventilation (NIV) for a forced vital capacity (FVC) <=50%predicted. Despite the limited ability of NIV systems to deliver adequate ventilation synchronous with patient demand, nocturnal patient-ventilator asynchrony has not been systematically studied in patients with ALS prescribed such NIV. METHODS: Twenty three consecutively recruited patients with ALS reporting consistent use of nocturnal NIV (nNIV) prescribed for FVC <=50% or orthopnea underwent home nocturnal polysomnography (PSG) on their current nNIV regimen (all used bilevel positive airway pressure). PSG recorded airflow, NIV pressures, thoracic and abdominal respiratory effort, and O(2) saturation by pulse oximetry (SpO(2)). Patient-ventilator asynchrony was calculated as an asynchrony index (AI), the number of episodes of asynchrony per hour of nocturnal recording time (RT). RESULTS: Nineteen patients had an adequate PSG. Their mean AI was 69 +/- 46 SD (range 15-146/hour). Mean asynchrony time as a percent of RT was 17% +/- 19%. Mean nadir SpO(2) was 85% +/- 7%. In multiple regression analysis, no demographic, functional severity (including FVC and ALS Revised Functional Rating Scale), or NIV (including pressure levels and duration of NIV prescription) variables were significantly predictive of degree of patient-ventilator asynchrony. CONCLUSIONS: These findings document frequent nocturnal patient ventilator asynchrony in patients with ALS consistently using nNIV prescribed as per current AAN practice parameters, and suggest that use of nNIV per these parameters is unlikely to provide patients with ALS optimal nocturnal ventilatory support. PMID- 21795659 TI - Neurology Academic Advisory Committee: a strategy for faculty retention and advancement. AB - Major effort and expense are devoted to faculty recruitment. Subsequent direction, support, and guidance of faculty members for retention and academic advancement are often inconsistent and ineffective. Individual mentorship is widely endorsed as an important element in advancement but often does not occur or is uneven in its pragmatic benefit. We formed a Departmental Academic Advisory Committee to provide individualized advice and guidance about career development and institutional promotion, retention, and tenure procedures. To assess the effectiveness of this process, a survey was sent to faculty members. A 100% response rate was achieved. The results of the survey demonstrated high levels of acceptance by faculty members and described benefits experienced by faculty, including better understanding of promotion and tenure policies and specific actions taken to achieve professional goals. An academic advisory committee can be a valuable adjunct to individual mentorship and to meetings with department chairs to enhance faculty satisfaction and advancement of neurology faculty members. PMID- 21795660 TI - A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. AB - BACKGROUND: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. OBJECTIVE: To determine if the lipid lowering agent simvastatin slows the progression of symptoms in AD. METHODS: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. RESULTS: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. CONCLUSION: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. PMID- 21795661 TI - Comment: New models of successful academic mentoring. PMID- 21795662 TI - Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. AB - OBJECTIVES: Most patients with anti-NMDA receptor (NMDAR) encephalitis have intrathecal synthesis of antibodies, which cause a decrease of cell surface and synaptic NMDAR. Antibodies are immunoglobulin G (IgG)1 and IgG3 subtypes and can potentially activate complement. We examined whether complement immunoreactivity and antibody-secreting cells (plasma cells/plasmablasts) are present in the brain of these patients. METHODS: Cultured rat hippocampal neurons were used in an immunocytochemical assay to test whether patients' antibodies can fix complement. Using the same reagents (antibodies to C9neo, C(5b-9), C3), complement immunoreactivity was determined in the brain of 5 patients, the teratoma of 21 patients, and appropriate control tissues. A set of markers for B (CD20), T (CD3, CD4, CD8) and antibody-secreting cells (plasma cells/plasmablasts, CD138) were used to examine the brain inflammatory infiltrates. RESULTS: Patients' antibodies were able to bind complement in vitro, but deposits of complement were not detected in patients' brain. Parallel experiments with teratomas showed that in contrast to the brain, the neural tissue of the tumors contained complement. Analysis of the inflammatory infiltrates in brain samples from autopsy or biopsy performed 3-4 weeks after symptom presentation demonstrated numerous antibody secreting cells (CD138+) in perivascular, interstitial, and Virchow-Robin spaces, and B and T cells predominantly located in perivascular regions. CONCLUSIONS: Complement-mediated mechanisms do not appear to play a substantial pathogenic role in anti-NMDAR encephalitis. In contrast, there are copious infiltrates of antibody-secreting cells (plasma cells/plasmablasts) in the CNS of these patients. The demonstration of these cells provides an explanation for the intrathecal synthesis of antibodies and has implications for treatment. PMID- 21795663 TI - Breast density influences tumor subtypes and tumor aggressiveness. PMID- 21795665 TI - Mobile phone use and brain tumors in children and adolescents: a multicenter case control study. AB - BACKGROUND: It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents. METHODS: CEFALO is a multicenter case-control study conducted in Denmark, Sweden, Norway, and Switzerland that includes all children and adolescents aged 7-19 years who were diagnosed with a brain tumor between 2004 and 2008. We conducted interviews, in person, with 352 case patients (participation rate: 83%) and 646 control subjects (participation rate: 71%) and their parents. Control subjects were randomly selected from population registries and matched by age, sex, and geographical region. We asked about mobile phone use and included mobile phone operator records when available. Odds ratios (ORs) for brain tumor risk and 95% confidence intervals (CIs) were calculated using conditional logistic regression models. RESULTS: Regular users of mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors compared with nonusers (OR = 1.36; 95% CI = 0.92 to 2.02). Children who started to use mobile phones at least 5 years ago were not at increased risk compared with those who had never regularly used mobile phones (OR = 1.26, 95% CI = 0.70 to 2.28). In a subset of study participants for whom operator recorded data were available, brain tumor risk was related to the time elapsed since the mobile phone subscription was started but not to amount of use. No increased risk of brain tumors was observed for brain areas receiving the highest amount of exposure. CONCLUSION: The absence of an exposure-response relationship either in terms of the amount of mobile phone use or by localization of the brain tumor argues against a causal association. PMID- 21795666 TI - Computer-assisted detection and screening mammography: where's the beef? PMID- 21795664 TI - Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. AB - BACKGROUND: Few studies that investigated the associations between breast density and subsequent breast cancer according to tumor characteristics have produced inconclusive findings. We aimed to determine whether the associations between breast density and subsequent breast cancer varied by tumor characteristics. METHODS: We included 1042 postmenopausal women diagnosed with breast cancer between June 1, 1989, and June 30, 2004, and 1794 matched control subjects from the Nurses' Health Study, an ongoing prospective cohort study of 121 701 registered female nurses across the United States. Breast density was estimated from digitized images using computerized techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires before the date of cancer diagnosis for case subjects and matched control subjects. Polychotomous logistic regression was used to assess associations of breast density with tumor subtypes based on invasiveness, histology, size, grade, receptor status, and involvement of lymph nodes. All tests of statistical significance were two-sided. RESULTS: The risk of breast cancer increased progressively with increase in percent breast density (P(trend) < .001). Women with higher breast density (>=50%) showed a 3.39-fold (odds ratio = 3.39, 95% confidence interval = 2.46 to 4.68) increased risk of breast cancer compared with women with lower breast density (<10%). The associations between breast density and breast cancer risk were stronger for in situ compared with invasive tumors (P(heterogeneity) < .01), high-grade compared with low-grade tumors (P(heterogeneity) = .02), larger (>2 cm) compared with smaller (<=2 cm) tumors (P(heterogeneity) < .01), and estrogen receptor-negative compared with estrogen receptor-positive tumors (P(heterogeneity) = .04). There were no differences in associations by tumor histology, involvement of lymph nodes, and progesterone receptor and HER2 status (P(heterogeneity) > .05). CONCLUSIONS: The findings suggest that higher mammographic density is associated with more aggressive tumor characteristics and also with in situ tumors. PMID- 21795667 TI - Cell phones, cancer, and children. PMID- 21795668 TI - Effectiveness of computer-aided detection in community mammography practice. AB - BACKGROUND: Computer-aided detection (CAD) is applied during screening mammography for millions of US women annually, although it is uncertain whether CAD improves breast cancer detection when used by community radiologists. METHODS: We investigated the association between CAD use during film-screen screening mammography and specificity, sensitivity, positive predictive value, cancer detection rates, and prognostic characteristics of breast cancers (stage, size, and node involvement). Records from 684 956 women who received more than 1.6 million film-screen mammograms at Breast Cancer Surveillance Consortium facilities in seven states in the United States from 1998 to 2006 were analyzed. We used random-effects logistic regression to estimate associations between CAD and specificity (true-negative examinations among women without breast cancer), sensitivity (true-positive examinations among women with breast cancer diagnosed within 1 year of mammography), and positive predictive value (breast cancer diagnosed after positive mammograms) while adjusting for mammography registry, patient age, time since previous mammography, breast density, use of hormone replacement therapy, and year of examination (1998-2002 vs 2003-2006). All statistical tests were two-sided. RESULTS: Of 90 total facilities, 25 (27.8%) adopted CAD and used it for an average of 27.5 study months. In adjusted analyses, CAD use was associated with statistically significantly lower specificity (OR = 0.87, 95% confidence interval [CI] = 0.85 to 0.89, P < .001) and positive predictive value (OR = 0.89, 95% CI = 0.80 to 0.99, P = .03). A non statistically significant increase in overall sensitivity with CAD (OR = 1.06, 95% CI = 0.84 to 1.33, P = .62) was attributed to increased sensitivity for ductal carcinoma in situ (OR = 1.55, 95% CI = 0.83 to 2.91; P = .17), although sensitivity for invasive cancer was similar with or without CAD (OR = 0.96, 95% CI = 0.75 to 1.24; P = .77). CAD was not associated with higher breast cancer detection rates or more favorable stage, size, or lymph node status of invasive breast cancer. CONCLUSION: CAD use during film-screen screening mammography in the United States is associated with decreased specificity but not with improvement in the detection rate or prognostic characteristics of invasive breast cancer. PMID- 21795669 TI - RNA sequencing reveals novel gene clusters in bovine conceptuses associated with maternal recognition of pregnancy and implantation. AB - Successful establishment and maintenance of pregnancy can be attained only through optimum conceptus-maternal cross talk. Despite significant progress in our understanding of the temporal changes in the transcriptome of the uterine endometrium, we have only a rudimentary knowledge of the genes and pathways governing growth and development of the bovine conceptus. In particular, very little information exists for the posthatching embryo and elongating conceptus. This period of development is arguably the most important, as approximately 40% of all embryonic loss occurs between Days 8 and 17 of pregnancy in cattle. Here, we describe the global transcriptome profile of the bovine conceptus at five key stages of its pre- and peri-implantation growth (Days 7, 10, 13, 16, and 19) using state-of-the-art RNA sequencing techniques. More than 287 million reads were generated at the five stages, and more than 22 700 unique transcripts were detected. Analysis of variance followed by self-organizing maps identified differentially regulated (P < 0.05) genes organized in nine gene clusters forming a sequential transcript dynamics across these developmental stages. Of particular interest, genes in clusters 3 (n = 236) and 6 (n = 1409) were significantly up regulated on Days 16 and 19, suggesting a role in maternal recognition and initiation of implantation. This transcriptome analysis of the bovine conceptus will provide a blueprint of the dynamic changes in gene expression occurring during maternal recognition and implantation and will complement existing knowledge of the temporal changes in the endometrial transcriptome, thus facilitating a better understanding of conceptus-maternal cross talk during the peri-implantation period of pregnancy. PMID- 21795670 TI - The placental response to excess maternal glucocorticoid exposure differs between the male and female conceptus in spiny mice. AB - The placenta is the intermediary between the mother and fetus, and its primary role is to provide for the appropriate growth of the fetus. A suboptimal in utero environment has been shown to differentially affect the health of offspring, depending on their sex. Here we show that excess maternal glucocorticoids administered in midgestation (Day 20, 0.5 gestation in the spiny mouse) for 60 h, have persisting effects on the placenta that differ by fetal sex, placental region, and time after glucocorticoid exposure. Dexamethasone (DEX) exposure altered placental structure and mRNA expression from male and female fetuses both immediately (Day 23) and 2 wk posttreatment (Day 37). The immediate consequences (Day 23) of DEX were similar between males and females, with reductions in the expression of IGF1, IGF1R, and SLC2A1 in the placenta. However, by Day 37, the transcriptional and structural response of the placenta was dependent on the sex of the fetus, with placentas of male fetuses having an increase in GCM1 expression, a decrease in SLC2A1 expression, and an increase in the amount of maternal blood sinusoids in the DEX-exposed placenta. Female placentas, on the other hand, showed increased SLC2A1 and MAP2K1 expression and a decrease in the amount of maternal blood sinusoids in response to DEX exposure. We have shown that the effect of a brief glucocorticoid exposure at midgestation has persisting effects on the placenta, and this is likely to have ongoing and dynamic effects on fetal development that differ for a male and female fetus. PMID- 21795671 TI - The effect of lace-up ankle braces on injury rates in high school basketball players. AB - BACKGROUND: Ankle injuries are the most common injury in basketball players. However, no prospective studies have been performed to determine if wearing lace up ankle braces will reduce the incidence of ankle injuries in high school athletes. PURPOSE: This trial was undertaken to determine if lace-up ankle braces reduce the incidence and severity of acute first-time and recurrent ankle injuries sustained by high school basketball players. DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 1460 male and female basketball players from 46 high schools were randomly assigned to a braced or control group. The braced group players wore lace-up ankle braces during the 2009 2010 basketball season. Athletic trainers recorded brace compliance, athlete exposures, and injuries. Cox proportional hazards models (adjusted for demographic covariates), accounting for intracluster correlation, were utilized to compare time to first acute ankle injury between groups. Injury severity (days lost) was tested with the Wilcoxon rank-sum test. RESULTS: The rate of acute ankle injury (per 1000 exposures) was 0.47 in the braced group and 1.41 in the control group (Cox hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.20, 0.52; P < .001). The median severity of acute ankle injuries was similar (P = .23) in the braced (6 days) and control group (7 days). For players with a previous ankle injury, the incidence of acute ankle injury was 0.83 in the braced group and 1.79 in the control group (Cox HR 0.39; 95% CI 0.17, 0.90; P = .028). For players who did not report a previous ankle injury, the incidence of acute ankle injury was 0.40 in the braced group and 1.35 in the control group (Cox HR 0.30; 95% CI 0.17, 0.52, P < .001). CONCLUSION: Use of lace-up ankle braces reduced the incidence but not the severity of acute ankle injuries in male and female high school basketball athletes both with and without a previous history of an ankle injury. PMID- 21795672 TI - Comprehensive analysis of pathogen-specific antibody response in vivo based on an antigen library displayed on surface of yeast. AB - Host antibody response is a crucial defense against pathogenic infection. Here, we report a novel technique allowing quantitative measurement of polyclonal antibody response in vivo. This involves expression of a combinatorial library of target proteins from a candidate pathogen on the surface of yeast Saccharomyces cerevisiae. After mixing with serum/plasma from infected or immunized subjects, positive yeast clones were isolated via fluorescence-activated cell sorting (FACS). Using this technique, we have studied mouse immunized serum with recombinant hemagglutinin (HA) protein from a human influenza H5N1 strain (A/Anhui/1/2005) and convalescent plasma from an infected human in China. Our technique has identified novel antigenic domains targeted by serum/plasma and allowed calculation of the relative proportion of the antibody response against each domain. We believe such systematic measurement of an antibody response is unprecedented, and applying this method to different pathogens will improve understanding of protective immunity and guide development of vaccines and therapeutics. PMID- 21795673 TI - Structure and function of a "yellow" protein from saliva of the sand fly Lutzomyia longipalpis that confers protective immunity against Leishmania major infection. AB - LJM11, an abundant salivary protein from the sand fly Lutzomyia longipalpis, belongs to the insect "yellow" family of proteins. In this study, we immunized mice with 17 plasmids encoding L. longiplapis salivary proteins and demonstrated that LJM11 confers protective immunity against Leishmania major infection. This protection correlates with a strong induction of a delayed type hypersensitivity (DTH) response following exposure to L. longipalpis saliva. Additionally, splenocytes of exposed mice produce IFN-gamma upon stimulation with LJM11, demonstrating the systemic induction of Th1 immunity by this protein. In contrast to LJM11, LJM111, another yellow protein from L. longipalpis saliva, does not produce a DTH response in these mice, suggesting that structural or functional features specific to LJM11 are important for the induction of a robust DTH response. To examine these features, we used calorimetric analysis to probe a possible ligand binding function for the salivary yellow proteins. LJM11, LJM111, and LJM17 all acted as high affinity binders of prohemostatic and proinflammatory biogenic amines, particularly serotonin, catecholamines, and histamine. We also determined the crystal structure of LJM11, revealing a six-bladed beta-propeller fold with a single ligand binding pocket located in the central part of the propeller structure on one face of the molecule. A hypothetical model of LJM11 suggests a positive electrostatic potential on the face containing entry to the ligand binding pocket, whereas LJM111 is negative to neutral over its entire surface. This may be the reason for differences in antigenicity between the two proteins. PMID- 21795674 TI - The dystrophin-associated protein complex maintains muscle excitability by regulating Ca(2+)-dependent K(+) (BK) channel localization. AB - The dystrophin-associated protein complex (DAPC) consists of several transmembrane and intracellular scaffolding elements that have been implicated in maintaining the structure and morphology of the vertebrate neuromuscular junction (NMJ). Genetic linkage analysis has identified loss-of-function mutations in DAPC genes that give rise to degenerative muscular dystrophies. Although much is known about the involvement of the DAPC in maintaining muscle integrity, less is known about the precise contribution of the DAPC in cell signaling events. To better characterize the functional role of the DAPC at the NMJ, we used electrophysiology, immunohistochemistry, and fluorescent labeling to directly assess cholinergic synaptic transmission, ion channel localization, and muscle excitability in loss-of-function (lf) mutants of Caenorhabditis elegans DAPC homologues. We found that all DAPC mutants consistently display mislocalization of the Ca(2+)-gated K(+) channel, SLO-1, in muscle cells, while ionotropic acetylcholine receptor (AChR) expression and localization at the NMJ remained unaltered. Synaptic cholinergic signaling was also not significantly impacted across DAPC(lf) mutants. Consistent with these findings and the postsynaptic mislocalization of SLO-1, we observed an increase in muscle excitability downstream of cholinergic signaling. Based on our results, we conclude that the DAPC is not involved in regulating AChR architecture at the NMJ, but rather functions to control muscle excitability, in an activity-dependent manner, through the proper localization of SLO-1 channels. PMID- 21795675 TI - Structure-function map of the receptor site for beta-scorpion toxins in domain II of voltage-gated sodium channels. AB - Voltage-gated sodium (Na(v)) channels are the molecular targets of beta-scorpion toxins, which shift the voltage dependence of activation to more negative membrane potentials by a voltage sensor-trapping mechanism. Molecular determinants of beta-scorpion toxin (CssIV) binding and action on rat brain sodium channels are located in the S1-S2 (IIS1-S2) and S3-S4 (IIS3-S4) extracellular linkers of the voltage-sensing module in domain II. In IIS1-S2, mutations of two amino acid residues (Glu(779) and Pro(782)) significantly altered the toxin effect by reducing binding affinity. In IIS3-S4, six positions surrounding the key binding determinant, Gly(845), define a hot spot of high impact residues. Two of these substitutions (A841N and L846A) reduced voltage sensor trapping. The other three substitutions (N842R, V843A, and E844N) increased voltage sensor trapping. These bidirectional effects suggest that the IIS3-S4 loop plays a primary role in determining both toxin affinity and efficacy. A high resolution molecular model constructed with the Rosetta-Membrane modeling system reveals interactions of amino acid residues in sodium channels that are crucial for toxin action with residues in CssIV that are required for its effects. In this model, the wedge-shaped CssIV inserts between the IIS1-S2 and IIS3-S4 loops of the voltage sensor, placing key amino acid residues in position to interact with binding partners in these extracellular loops. These results provide new molecular insights into the voltage sensor-trapping model of toxin action and further define the molecular requirements for the development of antagonists that can prevent or reverse toxicity of scorpion toxins. PMID- 21795676 TI - ClbP is a prototype of a peptidase subgroup involved in biosynthesis of nonribosomal peptides. AB - The pks genomic island of Escherichia coli encodes polyketide (PK) and nonribosomal peptide (NRP) synthases that allow assembly of a putative hybrid PK NRP compound named colibactin that induces DNA double-strand breaks in eukaryotic cells. The pks-encoded machinery harbors an atypical essential protein, ClbP. ClbP crystal structure and mutagenesis experiments revealed a serine-active site and original structural features compatible with peptidase activity, which was detected by biochemical assays. Ten ClbP homologs were identified in silico in NRP genomic islands of closely and distantly related bacterial species. All tested ClbP homologs were able to complement a clbP-deficient E. coli mutant. ClbP is therefore a prototype of a new subfamily of extracytoplasmic peptidases probably involved in the maturation of NRP compounds. Such peptidases will be powerful tools for the manipulation of NRP biosynthetic pathways. PMID- 21795677 TI - Cullin 4B protein ubiquitin ligase targets peroxiredoxin III for degradation. AB - Cullin 4B (CUL4B) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes. Recent studies have revealed that germ-line mutations in CUL4B can cause mental retardation, short stature, and many other abnormalities in humans. Identifying specific CUL4B substrates will help to better understand the physiological functions of CUL4B. Here, we report the identification of peroxiredoxin III (PrxIII) as a novel substrate of the CUL4B ubiquitin ligase complex. Two-dimensional gel electrophoresis coupled with mass spectrometry showed that PrxIII was among the proteins up-regulated in cells after RNAi mediated CUL4B depletion. The impaired degradation of PrxIII observed in CUL4B knockdown cells was confirmed by Western blot. We further demonstrated that DDB1 and ROC1 in the DDB1-CUL4B-ROC1 complex are also indispensable for the proteolysis of PrxIII. In addition, the degradation of PrxIII is independent of CUL4A, a cullin family member closely related to CUL4B. In vitro and in vivo ubiquitination assays revealed that CUL4B promoted the polyubiquitination of PrxIII. Furthermore, we observed a significant decrease in cellular reactive oxygen species (ROS) production in CUL4B-silenced cells, which was associated with increased resistance to hypoxia and H(2)O(2)-induced apoptosis. These findings are discussed with regard to the known function of PrxIII as a ROS scavenger and the high endogenous ROS levels required for neural stem cell proliferation. Together, our study has identified a specific target substrate of CUL4B ubiquitin ligase that may have significant implications for the pathogenesis observed in patients with mutations in CUL4B. PMID- 21795678 TI - Inhibition of matrix metalloproteinase 14 (MMP-14)-mediated cancer cell migration. AB - Matrix metalloproteinases (MMPs) have been shown to be key players in both extracellular matrix remodeling and cell migration during cancer metastasis. MMP 14, a membrane-anchored MMP, in particular, is closely associated with these processes. The hemopexin (PEX) domain of MMP-14 has been proposed as the modulating region involved in the molecular cross-talk that initiates cell migration through homodimerization of MMP-14 as well as heterodimerization with the cell surface adhesion molecule CD44. In this study, minimal regions required for function within the PEX domain were investigated through a series of substitution mutations. Blades I and IV were found to be involved in cell migration. We found that blade IV is necessary for MMP-14 homodimerization and that blade I is required for CD44 MMP-14 heterodimerization. Cross-talk between MMP-14 and CD44 results in phosphorylation of EGF receptor and downstream activation of the MAPK and PI3K signaling pathways involved in cell migration. Based on these mutagenesis analyses, peptides mimicking the essential outermost strand motifs within the PEX domain of MMP-14 were designed. These synthetic peptides inhibit MMP-14-enhanced cell migration in a dose-dependent manner but have no effect on the function of other MMPs. Furthermore, these peptides interfere with cancer metastasis without affecting primary tumor growth. Thus, targeting the MMP-14 hemopexin domain represents a novel approach to inhibit MMP 14-mediated cancer dissemination. PMID- 21795679 TI - Cellular content of UDP-N-acetylhexosamines controls hyaluronan synthase 2 expression and correlates with O-linked N-acetylglucosamine modification of transcription factors YY1 and SP1. AB - Hyaluronan, a high molecular mass polysaccharide on the vertebrate cell surface and extracellular matrix, is produced at the plasma membrane by hyaluronan synthases using UDP-GlcNAc and UDP-GlcUA as substrates. The availability of these UDP-sugar substrates can limit the synthesis rate of hyaluronan. In this study, we show that the cellular level of UDP-HexNAc also controls hyaluronan synthesis by modulating the expression of HAS2 (hyaluronan synthase 2). Increasing UDP HexNAc in HaCaT keratinocytes by adding glucosamine down-regulated HAS2 gene expression, whereas a decrease in UDP-HexNAc, realized by mannose treatment or siRNA for GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1), enhanced expression of the gene. Tracing the UDP-HexNAc-initiated signal to the HAS2 promoter revealed no change in the binding of STAT3, NF-kappaB, and cAMP response element-binding protein, shown previously to mediate growth factor and cytokine signals on HAS2 expression. Instead, altered binding of SP1 and YY1 to the promoter correlated with cellular UDP-HexNAc content and inhibition of HAS2 expression. siRNA silencing of YY1 and SP1 confirmed their inhibitory effects on HAS2 expression. Reduced and increased levels of O-GlcNAc-modified SP1 and YY1 proteins were associated with stimulation or inhibition of HAS2 expression, respectively. Our data are consistent with the hypothesis that, by regulating the level of protein O-GlcNAc modifications, cellular UDP-HexNAc content controls HAS2 transcription and decreases the effects on hyaluronan synthesis that would result from cellular fluctuations of this substrate. PMID- 21795680 TI - Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and Swedish mutant amyloid precursor protein. AB - In Alzheimer disease amyloid-beta (Abeta) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the beta secretase BACE1 is the rate-limiting step in the production of Abeta. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in cellular models and that the levels of endogenous murine Abeta were significantly increased in PrP(C)-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP(C) interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP(WT) but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP(Swe)). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP(Swe,Ind)), PrP(C) deletion had no influence on APP proteolytic processing, Abeta plaque deposition, or levels of soluble Abeta or Abeta oligomers. In cells, although PrP(C) inhibited the action of BACE1 on APP(WT), it did not inhibit BACE1 activity toward APP(Swe). The differential subcellular location of the BACE1 cleavage of APP(Swe) relative to APP(WT) provides an explanation for the failure of PrP(C) deletion to affect Abeta accumulation in APP(Swe,Ind) mice. Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease. PMID- 21795681 TI - Beta-amyloid peptide variants in brains and cerebrospinal fluid from amyloid precursor protein (APP) transgenic mice: comparison with human Alzheimer amyloid. AB - In this study, we report a detailed analysis of the different variants of amyloid beta (Abeta) peptides in the brains and the cerebrospinal fluid from APP23 transgenic mice, expressing amyloid precursor protein with the Swedish familial Alzheimer disease mutation, at different ages. Using one- and two-dimensional gel electrophoresis, immunoblotting, and mass spectrometry, we identified the Abeta peptides Abeta(1-40), -(1-42), -(1-39), -(1-38), -(1-37), -(2-40), and -(3-40) as well as minor amounts of pyroglutamate-modified Abeta (Abeta(N3pE)) and endogenous murine Abeta in brains from 24-month-old mice. Chemical modifications of the N-terminal amino group of Abeta were identified that had clearly been introduced during standard experimental procedures. To address this issue, we additionally applied amyloid extraction in ultrapure water. Clear differences between APP23 mice and Alzheimer disease (AD) brain samples were observed in terms of the relative abundance of specific variants of Abeta peptides, such as Abeta(N3pE), Abeta(1-42), and N-terminally truncated Abeta(2/3-42). These differences to human AD amyloid were also noticed in a related mouse line transgenic for human wild type amyloid precursor protein. Taken together, our findings suggest different underlying molecular mechanisms driving the amyloid deposition in transgenic mice and AD patients. PMID- 21795682 TI - Toward the discovery of effective polycyclic inhibitors of alpha-synuclein amyloid assembly. AB - The fibrillation of amyloidogenic proteins is a critical step in the etiology of neurodegenerative disorders such as Alzheimer and Parkinson diseases. There is major interest in the therapeutic intervention on such aberrant aggregation phenomena, and the utilization of polyaromatic scaffolds has lately received considerable attention. In this regard, the molecular and structural basis of the anti-amyloidogenicity of polyaromatic compounds, required to evolve this molecular scaffold toward therapeutic drugs, is not known in detail. We present here biophysical and biochemical studies that have enabled us to characterize the interaction of metal-substituted, tetrasulfonated phthalocyanines (PcTS) with alpha-synuclein (AS), the major protein component of amyloid-like deposits in Parkinson disease. The inhibitory activity of the assayed compounds on AS amyloid fibril formation decreases in the order PcTS[Ni(II)] ~ PcTS > PcTS[Zn(II)] >> PcTS[Al(III)] ~ 0. Using NMR and electronic absorption spectroscopies we demonstrated conclusively that the differences in binding capacity and anti amyloid activity of phthalocyanines on AS are attributed to their relative ability to self-stack through pi-pi interactions, modulated by the nature of the metal ion bound at the molecule. Low order stacked aggregates of phthalocyanines were identified as the active amyloid inhibitory species, whose effects are mediated by residue specific interactions. Such sequence-specific anti-amyloid behavior of self-stacked phthalocyanines contrasts strongly with promiscuous amyloid inhibitors with self-association capabilities that act via nonspecific sequestration of AS molecules. The new findings reported here constitute an important contribution for future drug discovery efforts targeting amyloid formation. PMID- 21795683 TI - Nucleobase transport by human equilibrative nucleoside transporter 1 (hENT1). AB - The human equilibrative nucleoside transporters hENT1 and hENT2 (each with 456 residues) are 40% identical in amino acid sequence and contain 11 putative transmembrane helices. Both transport purine and pyrimidine nucleosides and are distinguished functionally by a difference in sensitivity to inhibition by nanomolar concentrations of nitrobenzylmercaptopurine ribonucleoside (NBMPR), hENT1 being NBMPR-sensitive. Previously, we used heterologous expression in Xenopus oocytes to demonstrate that recombinant hENT2 and its rat ortholog rENT2 also transport purine and pyrimidine bases, h/rENT2 representing the first identified mammalian nucleobase transporter proteins (Yao, S. Y., Ng, A. M., Vickers, M. F., Sundaram, M., Cass, C. E., Baldwin, S. A., and Young, J. D. (2002) J. Biol. Chem. 277, 24938-24948). The same study also revealed lower, but significant, transport of hypoxanthine by h/rENT1. In the present investigation, we have used the enhanced Xenopus oocyte expression vector pGEMHE to demonstrate that hENT1 additionally transports thymine and adenine and, to a lesser extent, uracil and guanine. Fluxes of hypoxanthine, thymine, and adenine by hENT1 were saturable and inhibited by NBMPR. Ratios of V(max) (pmol/oocyte . min(-1)):K(m) (mm), a measure of transport efficiency, were 86, 177, and 120 for hypoxantine, thymine, and adenine, respectively, compared with 265 for uridine. Hypoxanthine influx was competitively inhibited by uridine, indicating common or overlapping nucleobase and nucleoside permeant binding pockets, and the anticancer nucleobase drugs 5-fluorouracil and 6-mercaptopurine were also transported. Nucleobase transport activity was absent from an engineered cysteine-less version hENT1 (hENT1C-) in which all 10 endogenous cysteine residues were mutated to serine. Site-directed mutagenesis identified Cys-414 in transmembrane helix 10 of hENT1 as the residue conferring nucleobase transport activity to the wild-type transporter. PMID- 21795685 TI - Neutrophil beta2 integrin inhibition by enhanced interactions of vasodilator stimulated phosphoprotein with S-nitrosylated actin. AB - Production of reactive species in neutrophils exposed to hyperoxia causes S nitrosylation of beta-actin, which increases formation of short actin filaments, leading to alterations in the cytoskeletal network that inhibit beta(2) integrin dependent adherence (Thom, S. R., Bhopale, V. M., Mancini, D. J., and Milovanova, T. N. (2008) J. Biol. Chem. 283, 10822-10834). In this study, we found that vasodilator-stimulated protein (VASP) exhibits high affinity for S-nitrosylated short filamentous actin, which increases actin polymerization. VASP bundles Rac1, Rac2, cyclic AMP-dependent, and cyclic GMP-dependent protein kinases in close proximity to short actin filaments, and subsequent Rac activation increases actin free barbed end formation. Using specific chemical inhibitors or reducing cell concentrations of any of these proteins with small inhibitory RNA abrogates enhanced free barbed end formation, increased actin polymerization, and beta(2) integrin inhibition by hyperoxia. Alternatively, incubating neutrophils with formylmethionylleucylphenylalanine or 8-bromo-cyclic GMP activates either cyclic AMP-dependent or cyclic GMP-dependent protein kinase, respectively, outside of the short F-actin pool and phosphorylates VASP on serine 153. Phosphorylated VASP abrogates the augmented polymerization normally observed with S-nitrosylated actin, VASP binding to actin, elevated Rac activity, and elevated formation of actin free barbed ends, thus restoring normal beta(2) integrin function. PMID- 21795684 TI - Mitochondrial calcium uptake regulates rapid calcium transients in skeletal muscle during excitation-contraction (E-C) coupling. AB - Defective coupling between sarcoplasmic reticulum and mitochondria during control of intracellular Ca(2+) signaling has been implicated in the progression of neuromuscular diseases. Our previous study showed that skeletal muscles derived from an amyotrophic lateral sclerosis (ALS) mouse model displayed segmental loss of mitochondrial function that was coupled with elevated and uncontrolled sarcoplasmic reticulum Ca(2+) release activity. The localized mitochondrial defect in the ALS muscle allows for examination of the mitochondrial contribution to Ca(2+) removal during excitation-contraction coupling by comparing Ca(2+) transients in regions with normal and defective mitochondria in the same muscle fiber. Here we show that Ca(2+) transients elicited by membrane depolarization in fiber segments with defective mitochondria display an ~10% increased amplitude. These regional differences in Ca(2+) transients were abolished by the application of 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, a fast Ca(2+) chelator that reduces mitochondrial Ca(2+) uptake. Using a mitochondria-targeted Ca(2+) biosensor (mt11-YC3.6) expressed in ALS muscle fibers, we monitored the dynamic change of mitochondrial Ca(2+) levels during voltage-induced Ca(2+) release and detected a reduced Ca(2+) uptake by mitochondria in the fiber segment with defective mitochondria, which mirrored the elevated Ca(2+) transients in the cytosol. Our study constitutes a direct demonstration of the importance of mitochondria in shaping the cytosolic Ca(2+) signaling in skeletal muscle during excitation-contraction coupling and establishes that malfunction of this mechanism may contribute to neuromuscular degeneration in ALS. PMID- 21795686 TI - Spatiotemporally distinct protein kinase D activation in adult cardiomyocytes in response to phenylephrine and endothelin. AB - Protein kinase D (PKD) is a nodal point in cardiac hypertrophic signaling. It triggers nuclear export of class II histone deacetylase (HDAC) and regulates transcription. Although this pathway is thought to be critical in cardiac hypertrophy and heart failure, little is known about spatiotemporal aspects of PKD activation at the myocyte level. Here, we demonstrate that in adult cardiomyocytes two important neurohumoral stimuli that induce hypertrophy, endothelin-1 (ET1) and phenylephrine (PE), trigger comparable global PKD activation and HDAC5 nuclear export, but via divergent spatiotemporal PKD signals. PE-induced HDAC5 export is entirely PKD-dependent, involving fleeting sarcolemmal PKD translocation (for activation) and very rapid subsequent nuclear import. In contrast, ET1 recruits and activates PKD that remains predominantly sarcolemmal. This explains why PE-induced nuclear HDAC5 export in myocytes is totally PKD-dependent, whereas ET1-induced HDAC5 export depends more prominently on InsP(3) and CaMKII signaling. Thus alpha-adrenergic and ET-1 receptor signaling via PKD in adult myocytes feature dramatic differences in cellular localization and translocation in mediating hypertrophic signaling. This raises new opportunities for targeted therapeutic intervention into distinct limbs of this hypertrophic signaling pathway. PMID- 21795687 TI - CEP70 protein interacts with gamma-tubulin to localize at the centrosome and is critical for mitotic spindle assembly. AB - Deregulation of the mitotic spindle has been implicated in genomic instability, an important aspect of tumorigenesis and malignant transformation. To ensure the fidelity of chromosome transmission, the mitotic spindle is assembled by exquisite mechanisms and orchestrated by centrosomes in animal cells. Centrosomal proteins especially are thought to act coordinately to ensure accurate spindle formation, but the molecular details remain to be investigated. In this study, we report the molecular characterization and functional analysis of a novel centrosomal protein, Cep70. Our data show that Cep70 localizes to the centrosome throughout the cell cycle and binds to the key centrosomal component, gamma tubulin, through the peptide fragments that contain the coiled-coil domains. Our data further reveal that the centrosomal localization pattern of Cep70 is dependent on its interaction with gamma-tubulin. Strikingly, Cep70 plays a significant role in the organization of both preexisting and nascent microtubules in interphase cells. In addition, Cep70 is necessary for the organization and orientation of the bipolar spindle during mitosis. These results thus report for the first time the identification of Cep70 as an important centrosomal protein that interacts with gamma-tubulin and underscore its critical role in the regulation of mitotic spindle assembly. PMID- 21795688 TI - Rapid dephosphorylation of G protein-coupled receptors by protein phosphatase 1beta is required for termination of beta-arrestin-dependent signaling. AB - Termination of signaling of activated G protein-coupled receptors (GPCRs) is essential for maintenance of cellular homeostasis. It is well established that beta-arrestin redistributes to phosphorylated GPCRs and thereby facilitates desensitization of classical G protein-dependent signaling. beta-Arrestin in turn serves as a scaffold to initiate a second wave of signaling. Here, we report a molecular mechanism that regulates the termination of unconventional beta arrestin-dependent GPCR signaling. We identify protein phosphatase 1beta (PP1beta) as a phosphatase for the cluster of phosphorylated threonines ((353)TTETQRT(359)) within the sst(2A) somatostatin receptor carboxyl terminus that mediates beta-arrestin binding using siRNA knock-down screening. We show that PP1beta-mediated sst(2A) dephosphorylation is initiated directly after receptor activation at or near the plasma membrane. As a functional consequence of diminished PP1beta activity, we find that somatostatin- and substance P induced but not epidermal growth factor-induced ERK activation was aberrantly enhanced and prolonged. Thus, we demonstrate a novel mechanism for fine tuning unconventional beta-arrestin-dependent GPCR signaling in that recruitment of PP1beta to activated GPCRs facilitates GPCR dephosphorylation and, hence, leads to disruption of the beta-arrestin-GPCR complex. PMID- 21795689 TI - The novel plasminogen receptor, plasminogen receptor(KT) (Plg-R(KT)), regulates catecholamine release. AB - Neurotransmitter release by catecholaminergic cells is negatively regulated by prohormone cleavage products formed from plasmin-mediated proteolysis. Here, we investigated the expression and subcellular localization of Plg-R(KT), a novel plasminogen receptor, and its role in catecholaminergic cell plasminogen activation and regulation of catecholamine release. Prominent staining with anti Plg-R(KT) mAb was observed in adrenal medullary chromaffin cells in murine and human tissue. In Western blotting, Plg-R(KT) was highly expressed in bovine adrenomedullary chromaffin cells, human pheochromocytoma tissue, PC12 pheochromocytoma cells, and murine hippocampus. Expression of Plg-R(KT) fused in frame to GFP resulted in targeting of the GFP signal to the cell membrane. Phase partitioning, co-immunoprecipitation with urokinase-type plasminogen activator receptor (uPAR), and FACS analysis with antibody directed against the C terminus of Plg-R(KT) were consistent with Plg-R(KT) being an integral plasma membrane protein on the surface of catecholaminergic cells. Cells stably overexpressing Plg-R(KT) exhibited substantial enhancement of plasminogen activation, and antibody blockade of non-transfected PC12 cells suppressed plasminogen activation. In functional secretion assays, nicotine-evoked [(3)H]norepinephrine release from cells overexpressing Plg-R(KT) was markedly decreased (by 51 +/- 2%, p < 0.001) when compared with control transfected cells, and antibody blockade increased [(3)H]norepinephrine release from non-transfected PC12 cells. In summary, Plg-R(KT) is present on the surface of catecholaminergic cells and functions to stimulate plasminogen activation and modulate catecholamine release. Plg-R(KT) thus represents a new mechanism and novel control point for regulating the interface between plasminogen activation and neurosecretory cell function. PMID- 21795690 TI - Role of extracellular matrix renal tubulo-interstitial nephritis antigen (TINag) in cell survival utilizing integrin (alpha)vbeta3/focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B-serine/threonine kinase (AKT) signaling pathway. AB - Tubulo-interstitial nephritis antigen (TINag) is an extracellular matrix protein expressed in tubular basement membranes. Combined mutations in TINag and nephrocystin-1 genes lead to nephronophthisis with reduced cell survival. Because certain extracellular matrix proteins are known to modulate cell survival, studies were initiated in Lewis rats lacking TINag to assess if they are more susceptible to cisplatin-induced injury. Cisplatin induced a higher degree of tubular cell damage and apoptosis in regions where TINag is expressed in a parental Wistar strain. This was accompanied by an accentuated increase in serum creatinine and Kim-1 RNA and renal expression of Bax, p53, and its nuclear accumulation, mtDNA fragmentation, and a decrease of Bcl-2. Cisplatin induced fulminant apoptosis of HK-2 cells with increased caspase3/7 activity, mtDNA fragmentation, and a reduced cell survival. These effects were partially reversed in cells maintained on TINag substratum. Far Western/solid phase assays established TINag binding with integrin alphavbeta3 comparable with vitronectin. Transfection of cells with alphav-siRNA accentuated cisplatin-induced apoptosis, aberrant translocation of cytochrome c and Bax, and reduced cell survival. The alphav-siRNA decreased expression of integrin-recruited focal adhesion kinase (FAK) and p-FAK, while increasing the expression of p53 and p-p53. Similarly, p AKT was reduced although ILK was unaffected. Inhibition of PI3K had similar adverse cellular effects. These effects were ameliorated in cells on TINag substratum. In vivo, a higher degree of decrease in the expression of p-FAK and pAKT was observed in Lewis rats following cisplatin treatment. These in vivo and in vitro studies demonstrate an essential role of TINag in cellular survival to maintain proper tubular homeostasis utilizing integrin alphavbeta3 and downstream effectors. PMID- 21795692 TI - Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. AB - Shank3/PROSAP2 gene mutations are associated with cognitive impairment ranging from mental retardation to autism. Shank3 is a large scaffold postsynaptic density protein implicated in dendritic spines and synapse formation; however, its specific functions have not been clearly demonstrated. We have used RNAi to knockdown Shank3 expression in neuronal cultures and showed that this treatment specifically reduced the synaptic expression of the metabotropic glutamate receptor 5 (mGluR5), but did not affect the expression of other major synaptic proteins. The functional consequence of Shank3 RNAi knockdown was impaired signaling via mGluR5, as shown by reduction in ERK1/2 and CREB phosphorylation induced by stimulation with (S)-3,5-dihydroxyphenylglycine (DHPG) as the agonist of mGluR5 receptors, impaired mGluR5-dependent synaptic plasticity (DHPG-induced long-term depression), and impaired mGluR5-dependent modulation of neural network activity. We also found morphological abnormalities in the structure of synapses (spine number, width, and length) and impaired glutamatergic synaptic transmission, as shown by reduction in the frequency of miniature excitatory postsynaptic currents (mEPSC). Notably, pharmacological augmentation of mGluR5 activity using 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)-benzamide as the positive allosteric modulator of these receptors restored mGluR5-dependent signaling (DHPG induced phosphorylation of ERK1/2) and normalized the frequency of mEPSCs in Shank3-knocked down neurons. These data demonstrate that a deficit in mGluR5 mediated intracellular signaling in Shank3 knockdown neurons can be compensated by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)-benzamide; this raises the possibility that pharmacological augmentation of mGluR5 activity represents a possible new therapeutic approach for patients with Shank3 mutations. PMID- 21795691 TI - Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signaling. AB - Collagen deposition by fibroblasts contributes to scarring in fibrotic diseases. Activation of protein kinase A (PKA) by cAMP represents a pivotal brake on fibroblast activation, and the lipid mediator prostaglandin E(2) (PGE(2)) exerts its well known anti-fibrotic actions through cAMP signaling. However, fibrotic fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis, or of mice with bleomycin-induced fibrosis, are resistant to the normal collagen inhibiting action of PGE(2). In this study, we demonstrate that plasminogen activation to plasmin restores PGE(2) sensitivity in fibrotic lung fibroblasts from human and mouse. This involves amplified PKA signaling resulting from the promotion of new interactions between AKAP9 and PKA regulatory subunit II in the perinuclear region as well as from the inhibition of protein phosphatase 2A. This is the first report to show that an extracellular mediator can dramatically reorganize and amplify the intracellular PKA-A-kinase anchoring protein signaling network and suggests a new strategy to control collagen deposition by fibrotic fibroblasts. PMID- 21795693 TI - Human Siglec-5 inhibitory receptor and immunoglobulin A (IgA) have separate binding sites in streptococcal beta protein. AB - Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors believed to be important for regulation of cellular activation and inflammation. Several pathogenic microbes bind specific Siglecs via sialic acid-containing structures at the microbial surface, interactions that may result in modulation of host responses. Recently, it was shown that the group B Streptococcus (GBS) binds to human Siglec-5 (hSiglec-5), an inhibitory receptor expressed on macrophages and neutrophils, via the IgA-binding surface beta protein, providing the first example of a protein/protein interaction between a pathogenic microbe and a Siglec. Here we show that the hSiglec-5-binding part of beta resides in the N terminal half of the protein, which also harbors the previously determined IgA binding region. We constructed bacterial mutants expressing variants of the beta protein with non-overlapping deletions in the N-terminal half of the protein. Using these mutants and recombinant beta fragments, we showed that the hSiglec-5 binding site is located in the most N-terminal part of beta (B6N region; amino acids 1-152) and that the hSiglec-5- and IgA-binding domains in beta are completely separate. We showed with BIAcore(TM) analysis that tandem variants of the hSiglec-5- and IgA-binding domains bind to their respective ligands with high affinity. Finally, we showed that the B6N region, but not the IgA-binding region of beta, triggers recruitment of the tyrosine phosphatase SHP-2 to hSiglec-5 in U937 monocytes. Taken together, we have identified and isolated the first microbial non-sialic acid Siglec-binding region that can be used as a tool in studies of the beta/hSiglec-5 interaction. PMID- 21795694 TI - Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein. AB - Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy. PMID- 21795695 TI - Calpain protects the heart from hemodynamic stress. AB - Calpains make up a family of Ca(2+)-dependent intracellular cysteine proteases that include ubiquitously expressed MU- and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for MU-calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca(2+) overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload. PMID- 21795696 TI - Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. AB - Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca(2+) rise in response to stimulation of mouse TRPC4beta by MU-opioid receptors. ML204 inhibited TRPC4beta mediated intracellular Ca(2+) rise with an IC(50) value of 0.96 MUm and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4beta currents activated through either MU-opioid receptor stimulation or intracellular dialysis of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 MUm ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPgammaS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4. PMID- 21795697 TI - Calcium occlusion in plasma membrane Ca2+-ATPase. AB - In this work, we set out to identify and characterize the calcium occluded intermediate(s) of the plasma membrane Ca(2+)-ATPase (PMCA) to study the mechanism of calcium transport. To this end, we developed a procedure for measuring the occlusion of Ca(2+) in microsomes containing PMCA. This involves a system for overexpression of the PMCA and the use of a rapid mixing device combined with a filtration chamber, allowing the isolation of the enzyme and quantification of retained calcium. Measurements of retained calcium as a function of the Ca(2+) concentration in steady state showed a hyperbolic dependence with an apparent dissociation constant of 12 +/- 2.2 MUM, which agrees with the value found through measurements of PMCA activity in the absence of calmodulin. When enzyme phosphorylation and the retained calcium were studied as a function of time in the presence of La(III) (inducing accumulation of phosphoenzyme in the E(1)P state), we obtained apparent rate constants not significantly different from each other. Quantification of EP and retained calcium in steady state yield a stoichiometry of one mole of occluded calcium per mole of phosphoenzyme. These results demonstrate for the first time that one calcium ion becomes occluded in the E(1)P-phosphorylated intermediate of the PMCA. PMID- 21795698 TI - Caspase-mediated cleavage of RNA-binding protein HuR regulates c-Myc protein expression after hypoxic stress. AB - Altered expression of RNA-binding proteins modulates gene expression in association with mRNAs encoding many proto-oncogenes, cytokines, chemokines, and proinflammatory factors. Hu antigen R (HuR), a ubiquitously expressed protein, controls a range of cellular functions such as tumor progression, apoptosis, invasion, and metastasis by stabilizing the AU-rich element located at the 3' untranslated region (UTR) of target mRNAs. Although significant progress has been made in understanding HuR regulation in gene expression, little is known about how HuR undergoes post-translational modifications and recruits target mRNAs during hypoxic stress. Here, we report that during CoCl(2)-induced hypoxic stress, HuR is significantly overexpressed and undergoes caspase-dependent cleavage in head and neck squamous cell carcinoma cells. Unexpectedly, the HuR cleavage product 1 (HuR-CP1) was found to strongly associate with the 3'-UTR of c myc mRNA and block mRNA translation. The binding efficiency of HuR to the 3'-UTR of c-myc mRNA was confirmed using ribonucleoprotein immunoprecipitation and site directed mutagenesis at the AU-rich element sequences of the c-myc mRNA. Overexpression of a non-cleavable isoform, HuR-D226A, revealed a potent dominant negative effect, repressing cleavage of endogenous HuR and promoting cell viability. Surprisingly, under hypoxia, siRNA knockdown of HuR elevated c-Myc protein expression. These findings suggest an important role for HuR in hypoxia, and we may have revealed a novel post-transcriptional mechanism that controls c Myc expression in oral cancer progression. PMID- 21795699 TI - Allosteric catch bond properties of the FimH adhesin from Salmonella enterica serovar Typhimurium. AB - Despite sharing the name and the ability to mediate mannose-sensitive adhesion, the type 1 fimbrial FimH adhesins of Salmonella Typhimurium and Escherichia coli share only 15% sequence identity. In the present study, we demonstrate that even with this limited identity in primary sequence, these two proteins share remarkable similarity of complex receptor binding and structural properties. In silico simulations suggest that, like E. coli FimH, Salmonella FimH has a two domain tertiary structure topology, with a mannose-binding pocket located on the apex of a lectin domain. Structural analysis of mutations that enhance S. Typhimurium FimH binding to eukaryotic cells and mannose-BSA demonstrated that they are not located proximal to the predicted mannose-binding pocket but rather occur in the vicinity of the predicted interface between the lectin and pilin domains of the adhesin. This implies that the functional effect of such mutations is indirect and probably allosteric in nature. By analogy with E. coli FimH, we suggest that Salmonella FimH functions as an allosteric catch bond adhesin, where shear-induced separation of the lectin and pilin domains results in a shift from a low affinity to a high affinity binding conformation of the lectin domain. Indeed, we observed shear-enhanced binding of whole bacteria expressing S. Typhimurium type 1 fimbriae. In addition, we observed that anti-FimH antibodies activate rather than inhibit S. Typhimurium FimH mannose binding, consistent with the allosteric catch bond properties of this adhesin. PMID- 21795700 TI - Hydrogen peroxide stimulates the epithelial sodium channel through a phosphatidylinositide 3-kinase-dependent pathway. AB - Recent studies indicate that oxidative stress mediates salt-sensitive hypertension. To test the hypothesis that the renal epithelial sodium channel (ENaC) is a target of oxidative stress, patch clamp techniques were used to determine whether ENaC in A6 distal nephron cells is regulated by hydrogen peroxide (H(2)O(2)). In the cell-attached configuration, H(2)O(2) significantly increased ENaC open probability (P(o)) and single-channel current amplitude but not the unit conductance. High concentrations of exogenous H(2)O(2) are required to elevate intracellular H(2)O(2), probably because catalase, the enzyme that promotes the decomposition of H(2)O(2) to H(2)O and O(2), is highly expressed in A6 cells. The effect of H(2)O(2) on ENaC P(o) was enhanced by 3-aminotriazole, a catalase inhibitor, and abolished by overexpression of catalase, indicating that intracellular H(2)O(2) levels are critical to produce the effect. However, H(2)O(2) did not directly activate ENaC in inside-out patches. The effects of H(2)O(2) on ENaC P(o) and amiloride-sensitive Na(+) current were abolished by inhibition of phosphatidylinositide 3-kinase (PI3K). Confocal microscopy data showed that H(2)O(2) elevated phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3)) in the apical membrane by stimulating PI3K. Because ENaC is stimulated by PI(3,4,5)P(3), these data suggest that H(2)O(2) stimulates ENaC via PI3K-mediated increases in apical PI(3,4,5)P(3). PMID- 21795701 TI - Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein. AB - The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of beta1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration. PMID- 21795702 TI - WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) delays cellular senescence by promoting p27(Kip1) degradation in human diploid fibroblasts. AB - WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) plays an important role in the proliferation of tumor cells and the lifespan of Caenorhabditis elegans. However, the role of WWP1 in cellular senescence is still unknown. Here, we show that the expression patterns of p27(Kip1) and WWP1 are inversely correlated during cellular senescence. Moreover, the overexpression of WWP1 delayed senescence, whereas the knockdown of WWP1 led to premature senescence in human fibroblasts. Furthermore, we demonstrate that WWP1 repressed endogenous p27(Kip1) expression through ubiquitin-proteasome-mediated degradation. Additionally, WWP1 had a strong preference for catalyzing the Lys-48-linked polyubiquitination of p27(Kip1) in vitro. Finally, we demonstrate that WWP1 markedly inhibited the replicative senescence induced by p27(Kip1) by promoting p27(Kip1) degradation. Therefore, our study provides a new molecular mechanism for the regulation of cellular senescence. PMID- 21795703 TI - Role of the transient receptor potential vanilloid 5 (TRPV5) protein N terminus in channel activity, tetramerization, and trafficking. AB - The epithelial Ca(2+) channel transient receptor potential vanilloid 5 (TRPV5) constitutes the apical entry site for active Ca(2+) reabsorption in the kidney. The TRPV5 channel is a member of the TRP family of cation channels, which are composed of four subunits together forming a central pore. Regulation of channel activity is tightly controlled by the intracellular N and C termini. The TRPV5 C terminus regulates channel activity by various mechanisms, but knowledge regarding the role of the N terminus remains scarce. To study the role of the N terminus in TRPV5 regulation, we generated different N-terminal deletion constructs. We found that deletion of the first 32 residues did not affect TRPV5 mediated (45)Ca(2+) uptake, whereas deletion up to residue 34 and 75 abolished channel function. Immunocytochemistry demonstrated that these mutant channels were retained in the endoplasmic reticulum and in contrast to wild-type TRPV5 did not reach the Golgi apparatus, explaining the lack of complex glycosylation of the mutants. A limited amount of mutant channels escaped the endoplasmic reticulum and reached the plasma membrane, as shown by cell surface biotinylation. These channels did not internalize, explaining the reduced but significant amount of these mutant channels at the plasma membrane. Wild-type TRPV5 channels, despite significant plasma membrane internalization, showed higher plasma membrane levels compared with the mutant channels. The assembly into tetramers was not affected by the N-terminal deletions. Thus, the N-terminal residues 34-75 are critical in the formation of a functional TRPV5 channel because the deletion mutants were present at the plasma membrane as tetramers, but lacked channel activity. PMID- 21795704 TI - The assembly of proline-rich membrane anchor (PRiMA)-linked acetylcholinesterase enzyme: glycosylation is required for enzymatic activity but not for oligomerization. AB - Acetylcholinesterase (AChE) anchors onto cell membranes by a transmembrane protein PRiMA (proline-rich membrane anchor) as a tetrameric form in vertebrate brain. The assembly of AChE tetramer with PRiMA requires the C-terminal "t peptide" in AChE catalytic subunit (AChE(T)). Although mature AChE is well known N-glycosylated, the role of glycosylation in forming the physiologically active PRiMA-linked AChE tetramer has not been studied. Here, several lines of evidence indicate that the N-linked glycosylation of AChE(T) plays a major role for acquisition of AChE full enzymatic activity but does not affect its oligomerization. The expression of the AChE(T) mutant, in which all N glycosylation sites were deleted, together with PRiMA in HEK293T cells produced a glycan-depleted PRiMA-linked AChE tetramer but with a much higher K(m) value as compared with the wild type. This glycan-depleted enzyme was assembled in endoplasmic reticulum but was not transported to Golgi apparatus or plasma membrane. PMID- 21795705 TI - Identification of essential cannabinoid-binding domains: structural insights into early dynamic events in receptor activation. AB - The classical cannabinoid agonist HU210, a structural analog of (-)-Delta(9) tetrahydrocannabinol, binds to brain cannabinoid (CB1) receptors and activates signal transduction pathways. To date, an exact molecular description of the CB1 receptor is not yet available. Utilizing the minor binding pocket of the CB1 receptor as the primary ligand interaction site, we explored HU210 binding using lipid bilayer molecular dynamics (MD) simulations. Among the potential ligand contact residues, we identified residues Phe-174(2.61), Phe-177(2.64), Leu 193(3.29), and Met-363(6.55) as being critical for HU210 binding by mutational analysis. Using these residues to guide the simulations, we determined essential cannabinoid-binding domains in the CB1 receptor, including the highly sought after hydrophobic pocket important for the binding of the C3 alkyl chain of classical and nonclassical cannabinoids. Analyzing the simulations of the HU210 CB1 receptor complex, the CP55940-CB1 receptor complex, and the (-)-Delta(9) tetrahydrocannabinol-CB1 receptor complex, we found that the positioning of the C3 alkyl chain and the aromatic stacking between Trp-356(6.48) and Trp-279(5.43) is crucial for the Trp-356(6.48) rotamer change toward receptor activation through the rigid-body movement of H6. The functional data for the mutant receptors demonstrated reductions in potency for G protein activation similar to the reductions seen in ligand binding affinity for HU210. PMID- 21795706 TI - Interleukin-1 activates synthesis of interleukin-6 by interfering with a KH-type splicing regulatory protein (KSRP)-dependent translational silencing mechanism. AB - Post-transcriptional mechanisms play an important role in the control of inflammatory gene expression. The heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) triggers rapid degradation of mRNAs for various cytokines, chemokines, and other inflammation-related proteins by interacting with AU-rich elements (AREs) in the 3'-untranslated mRNA regions. In addition to destabilizing mRNAs, AU-rich elements can restrict their translation. Evidence that KSRP also participates in translational silencing was obtained in a screen comparing the polysome profiles of cells with siRNA-mediated depletion of KSRP with that of control cells. Among the group of mRNAs showing increased polysome association upon KSRP depletion are those of interleukin (IL) 6 and IL-1alpha as well as other ARE-containing transcripts. Redistribution of IL 6 mRNA to polysomes was associated with increased IL-6 protein secretion by the KSRP-depleted cells. Silencing of IL-6 and IL-1alpha mRNAs depended on their 3' untranslated regions. The sequence essential for translational control of IL-6 mRNA and its interaction with KSRP was located to an ARE. KSRP-dependent silencing was reversed by IL-1, a strong inducer of IL-6 mRNA and protein expression. The results identify KSRP as a protein involved in ARE-mediated translational silencing. They suggest that KSRP restricts inflammatory gene expression not only by enhancing degradation of mRNAs but also by inhibiting translation, both functions that are counteracted by the proinflammatory cytokine IL-1. PMID- 21795707 TI - Two distinct aspects of coupling between Galpha(i) protein and G protein activated K+ channel (GIRK) revealed by fluorescently labeled Galpha(i3) protein subunits. AB - G protein-activated K(+) channels (Kir3 or GIRK) are activated by direct interaction with Gbetagamma. Galpha is essential for specific signaling and regulates basal activity of GIRK (I(basal)) and kinetics of the response elicited by activation by G protein-coupled receptors (I(evoked)). These regulations are believed to occur within a GIRK-Galpha-Gbetagamma signaling complex. Fluorescent energy resonance transfer (FRET) studies showed strong GIRK-Gbetagamma interactions but yielded controversial results regarding the GIRK-Galpha(i/o) interaction. We investigated the mechanisms of regulation of GIRK by Galpha(i/o) using wild-type Galpha(i3) (Galpha(i3)WT) and Galpha(i3) labeled at three different positions with fluorescent proteins, CFP or YFP (xFP). Galpha(i3)xFP proteins bound the cytosolic domain of GIRK1 and interacted with Gbetagamma in a guanine nucleotide-dependent manner. However, only an N-terminally labeled, myristoylated Galpha(i3)xFP (Galpha(i3)NT) closely mimicked all aspects of Galpha(i3)WT regulation except for a weaker regulation of I(basal). Galpha(i3) labeled with YFP within the Galpha helical domain preserved regulation of I(basal) but failed to restore fast I(evoked). Titrated expression of Galpha(i3)NT and Galpha(i3)WT confirmed that regulation of I(basal) and of the kinetics of I(evoked) of GIRK1/2 are independent functions of Galpha(i). FRET and direct biochemical measurements indicated much stronger interaction between GIRK1 and Gbetagamma than between GIRK1 and Galpha(i3). Thus, Galpha(i/o)betagamma heterotrimer may be attached to GIRK primarily via Gbetagamma within the signaling complex. Our findings support the notion that Galpha(i/o) actively regulates GIRK. Although regulation of I(basal) is a function of Galpha(i)(GDP), our new findings indicate that regulation of kinetics of I(evoked) is mediated by Galpha(i)(GTP). PMID- 21795708 TI - Structure and activity of Paenibacillus polymyxa xyloglucanase from glycoside hydrolase family 44. AB - The enzymatic degradation of plant polysaccharides is emerging as one of the key environmental goals of the early 21st century, impacting on many processes in the textile and detergent industries as well as biomass conversion to biofuels. One of the well known problems with the use of nonstarch (nonfood)-based substrates such as the plant cell wall is that the cellulose fibers are embedded in a network of diverse polysaccharides, including xyloglucan, that renders access difficult. There is therefore increasing interest in the "accessory enzymes," including xyloglucanases, that may aid biomass degradation through removal of "hemicellulose" polysaccharides. Here, we report the biochemical characterization of the endo-beta-1,4-(xylo)glucan hydrolase from Paenibacillus polymyxa with polymeric, oligomeric, and defined chromogenic aryl-oligosaccharide substrates. The enzyme displays an unusual specificity on defined xyloglucan oligosaccharides, cleaving the XXXG-XXXG repeat into XXX and GXXXG. Kinetic analysis on defined oligosaccharides and on aryl-glycosides suggests that both the -4 and +1 subsites show discrimination against xylose-appended glucosides. The three-dimensional structures of PpXG44 have been solved both in apo-form and as a series of ligand complexes that map the -3 to -1 and +1 to +5 subsites of the extended ligand binding cleft. Complex structures are consistent with partial intolerance of xylosides in the -4' subsites. The atypical specificity of PpXG44 may thus find use in industrial processes involving xyloglucan degradation, such as biomass conversion, or in the emerging exciting applications of defined xyloglucans in food, pharmaceuticals, and cellulose fiber modification. PMID- 21795709 TI - Inhibition of protein-tyrosine phosphatase 1B (PTP1B) mediates ubiquitination and degradation of Bcr-Abl protein. AB - Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-Abl, a chimeric protein with deregulated tyrosine kinase activity. The protein-tyrosine phosphatase 1B (PTP1B) is up-regulated in Bcr-Abl-expressing cells, suggesting a regulatory link between the two proteins. To investigate the interplay between these two proteins, we inhibited the activity of PTP1B in Bcr-Abl-expressing TonB.210 cells by either pharmacological or siRNA means and examined the effects of such inhibition on Bcr Abl expression and function. Herein we describe a novel mechanism by which the phosphatase activity of PTP1B is required for Bcr-Abl protein stability. Inhibition of PTP1B elicits tyrosine phosphorylation of Bcr-Abl that triggers the degradation of Bcr-Abl through ubiquitination via the lysosomal pathway. The degradation of Bcr-Abl consequently inhibits tyrosine phosphorylation of Bcr-Abl substrates and the downstream production of intracellular reactive oxygen species. Furthermore, PTP1B inhibition reduces cell viability and the IC(50) of the Bcr-Abl inhibitor imatinib mesylate. Degradation of Bcr-Abl via PTP1B inhibition is also observed in human CML cell lines K562 and LAMA-84. These results suggest that inhibition of PTP1B may be a useful strategy to explore in the development of novel therapeutic agents for the treatment of CML, particularly because host drugs currently used in CML such as imatinib focus on inhibiting the kinase activity of Bcr-Abl. PMID- 21795710 TI - Conditional expression of the androgen receptor induces oncogenic transformation of the mouse prostate. AB - The androgen signaling pathway, mediated through the androgen receptor (AR), is critical in prostate tumorigenesis. However, the precise role of AR in prostate cancer development and progression still remains largely unknown. Specifically, it is unclear whether overexpression of AR is sufficient to induce prostate tumor formation in vivo. Here, we inserted the human AR transgene with a LoxP-stop-loxP (LSL) cassette into the mouse ROSA26 locus, permitting "conditionally" activated AR transgene expression through Cre recombinase-mediated removal of the LSL cassette. By crossing this AR floxed strain with Osr1-Cre (odd skipped related) mice, in which the Osr1 promoter activates at embryonic day 11.5 in urogenital sinus epithelium, we generated a conditional transgenic line, R26hAR(loxP):Osr1 Cre+. Expression of transgenic AR was detected in both prostatic luminal and basal epithelial cells and is resistant to castration. Approximately one-half of the transgenic mice displayed mouse prostatic intraepithelial neoplasia (mPIN) lesions. Intriguingly, four mice (10%) developed prostatic adenocarcinomas, with two demonstrating invasive diseases. Positive immunostaining of transgenic AR protein was observed in the majority of atypical and tumor cells in the mPIN and prostatic adenocarcinomas, providing a link between transgenic AR expression and oncogenic transformation. An increase in Ki67-positive cells appeared in all mPIN and prostatic adenocarcinoma lesions of the mice. Thus, we demonstrated for the first time that conditional activation of transgenic AR expression by Osr1 promoter induces prostate tumor formation in mice. This new AR transgenic mouse line mimics the human disease and can be used for study of prostate tumorigenesis and drug development. PMID- 21795711 TI - Uptake of dietary retinoids at the maternal-fetal barrier: in vivo evidence for the role of lipoprotein lipase and alternative pathways. AB - Dietary retinoids (vitamin A and its derivatives) contribute to normal embryonic development. However, the mechanism(s) involved in the transfer of recently ingested vitamin A from mother to embryo is not fully understood. We investigated in vivo whether lipoprotein lipase (LPL) facilitates the placental uptake of dietary retinyl ester incorporated in chylomicrons and their remnants and its transfer to the embryo. We examined the effects of both genetic ablation (MCK-L0 mice) and pharmacological inhibition (P-407) of LPL by maintaining wild type and MCK-L0 mice on diets with different vitamin A content or administering them an oral gavage dose of [(3)H]retinol with or without P-407 treatment. We showed that LPL expressed in placenta facilitates uptake of retinoids by this organ and their transfer to the embryo, mainly through its catalytic activity. In addition, through its "bridging function," LPL can mediate the acquisition of nascent chylomicrons by the placenta, although less efficiently. Quantitative real-time PCR and Western blot analysis showed that placental LPL acts in concert with LDL receptor and LRP1. Finally, by knocking out the retinol-binding protein (RBP) gene in the MCK-L0 background (MCK-L0-RBP(-/-) mice) we demonstrated that the placenta acquires dietary retinoids also via the maternal circulating RBP-retinol complex. RBP expressed in the placenta facilitate the transfer of postprandial retinoids across the placental layers toward the embryo. PMID- 21795712 TI - RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity. AB - Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators, of which Smad7, c-Ski, and SnoN play a pivotal role in its negative regulation. Arkadia is a RING-type E3 ubiquitin ligase that targets these negative regulators for degradation to enhance TGF-beta signaling. In the present study we identified a candidate human tumor suppressor gene product RB1CC1/FIP200 as a novel positive regulator of TGF-beta signaling that functions as a substrate-selective cofactor of Arkadia. Overexpression of RB1CC1 enhanced TGF-beta signaling, and knockdown of endogenous RB1CC1 attenuated TGF-beta induced expression of target genes as well as TGF-beta-induced cytostasis. RB1CC1 down-regulated the protein levels of c-Ski but not SnoN by enhancing the activity of Arkadia E3 ligase toward c-Ski. Substrate selectivity is primarily attributable to the physical interaction of RB1CC1 with substrates, suggesting its role as a scaffold protein. RB1CC1 thus appears to play a unique role as a modulator of TGF-beta signaling by restricting substrate specificity of Arkadia. PMID- 21795713 TI - Comparative analysis of Histophilus somni immunoglobulin-binding protein A (IbpA) with other fic domain-containing enzymes reveals differences in substrate and nucleotide specificities. AB - A new family of adenylyltransferases, defined by the presence of a Fic domain, was recently discovered to catalyze the addition of adenosine monophosphate (AMP) to Rho GTPases (Yarbrough, M. L., Li, Y., Kinch, L. N., Grishin, N. V., Ball, H. L., and Orth, K. (2009) Science 323, 269-272; Worby, C. A., Mattoo, S., Kruger, R. P., Corbeil, L. B., Koller, A., Mendez, J. C., Zekarias, B., Lazar, C., and Dixon, J. E. (2009) Mol. Cell 34, 93-103). This adenylylation event inactivates Rho GTPases by preventing them from binding to their downstream effectors. We reported that the Fic domain(s) of the immunoglobulin-binding protein A (IbpA) from the pathogenic bacterium Histophilus somni adenylylates mammalian Rho GTPases, RhoA, Rac1, and Cdc42, thereby inducing host cytoskeletal collapse, which allows H. somni to breach alveolar barriers and cause septicemia. The IbpA mediated adenylylation occurs on a functionally critical tyrosine in the switch 1 region of these GTPases. Here, we conduct a detailed characterization of the IbpA Fic2 domain and compare its activity with other known Fic adenylyltransferases, VopS (Vibrio outer protein S) from the bacterial pathogen Vibrio parahaemolyticus and the human protein HYPE (huntingtin yeast interacting protein E; also called FicD). We also included the Fic domains of the secreted protein, PfhB2, from the opportunistic pathogen Pasteurella multocida, in our analysis. PfhB2 shares a common domain architecture with IbpA and contains two Fic domains. We demonstrate that the PfhB2 Fic domains also possess adenylyltransferase activity that targets the switch 1 tyrosine of Rho GTPases. Comparative kinetic and phylogenetic analyses of IbpA-Fic2 with the Fic domains of PfhB2, VopS, and HYPE reveal important aspects of their specificities for Rho GTPases and nucleotide usage and offer mechanistic insights for determining nucleotide and substrate specificities for these enzymes. Finally, we compare the evolutionary lineages of Fic proteins with those of other known adenylyltransferases. PMID- 21795714 TI - Plant-specific cation/H+ exchanger 17 and its homologs are endomembrane K+ transporters with roles in protein sorting. AB - The complexity of intracellular compartments in eukaryotic cells evolved to provide distinct environments to regulate processes necessary for cell proliferation and survival. A large family of predicted cation/proton exchangers (CHX), represented by 28 genes in Arabidopsis thaliana, are associated with diverse endomembrane compartments and tissues in plants, although their roles are poorly understood. We expressed a phylogenetically related cluster of CHX genes, encoded by CHX15-CHX20, in yeast and bacterial cells engineered to lack multiple cation-handling mechanisms. Of these, CHX16-CHX20 were implicated in pH homeostasis because their expression rescued the alkaline pH-sensitive growth phenotype of the host yeast strain. A smaller subset, CHX17-CHX19, also conferred tolerance to hygromycin B. Further differences were observed in K(+)- and low pH dependent growth phenotypes. Although CHX17 did not alter cytoplasmic or vacuolar pH in yeast, CHX20 elicited acidification and alkalization of the cytosol and vacuole, respectively. Using heterologous expression in Escherichia coli strains lacking K(+) uptake systems, we provide evidence for K(+) ((86)Rb) transport mediated by CHX17 and CHX20. Finally, we show that CHX17 and CHX20 affected protein sorting as measured by carboxypeptidase Y secretion in yeast mutants grown at alkaline pH. In plant cells, CHX20-RFP co-localized with an endoplasmic reticulum marker, whereas RFP-tagged CHX17-CHX19 co-localized with prevacuolar compartment and endosome markers. Together, these results suggest that in response to environmental cues, multiple CHX transporters differentially modulate K(+) and pH homeostasis of distinct intracellular compartments, which alter membrane trafficking events likely to be critical for adaptation and survival. PMID- 21795715 TI - SOX9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. AB - Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1alpha (HIF-1alpha), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF 1alpha, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1alpha and BMP4 in diabetic glomeruli. BMP4 knock in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1alpha and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN. PMID- 21795716 TI - Enhanced autophagy from chronic toxicity of iron and mutant A53T alpha-synuclein: implications for neuronal cell death in Parkinson disease. AB - Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and the presence of alpha-synuclein-enriched Lewy body inclusions in the substantia nigra of the midbrain. Although the etiology of PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral dopaminergic neurons are enriched in iron, the uptake of which is facilitated by the divalent metal ion transporter DMT1. To clarify the role of iron in PD, we generated SH-SY5Y cells stably expressing DMT1 either singly or in combination with wild type or mutant alpha-synuclein. We found that DMT1 overexpression dramatically enhances Fe(2+) uptake, which concomitantly promotes cell death. This Fe(2+)-mediated toxicity is aggravated by the presence of mutant alpha-synuclein expression, resulting in increased oxidative stress and DNA damage. Curiously, Fe(2+)-mediated cell death does not appear to involve apoptosis. Instead, the phenomenon seems to occur as a result of excessive autophagic activity. Accordingly, pharmacological inhibition of autophagy reverses cell death mediated by Fe(2+) overloading. Taken together, our results suggest a role for iron in PD pathogenesis and provide a mechanism underlying Fe(2+)-mediated cell death. PMID- 21795717 TI - Metabolic alterations in highly tumorigenic glioblastoma cells: preference for hypoxia and high dependency on glycolysis. AB - Recent studies suggest that a small subpopulation of malignant cells with stem like properties is resistant to chemotherapy and may be responsible for the existence of residual cancer after treatment. We have isolated highly tumorigenic cancer cells with 100-fold increase in tumor initiating capacity from the tumor xenografts of human glioblastoma U87 cells in mice. These cells exhibit stem-like properties and show unique energy metabolic characteristics including low mitochondrial respiration, increased glycolysis for ATP generation, and preference for hypoxia to maintain their stemness and tumor forming capacity. Mechanistically, mitochondrial depression in the highly tumorigenic cells occurs mainly at complex II of the electron transport chain with a down-regulation of the succinate dehydrogenase subunit B, leading to deregulation of hypoxia inducible factors. Under hypoxia, the stem-like cancer cells are resistant to conventional anticancer agents but are sensitive to glycolytic inhibition. Furthermore, combination of glycolytic inhibition with standard therapeutic agents is effective in killing the tumor-initiating cells in vitro and inhibits tumor formation in vivo. Our study suggests that stem-like cancer cells prefer a low oxygen microenvironment and actively utilize the glycolytic pathway for ATP generation. Inhibition of glycolysis may be an effective strategy to eradicate residual cancer stem cells that are otherwise resistant to chemotherapeutic agents in their hypoxic niches. PMID- 21795724 TI - Strategies for improving antimicrobial use and the role of antimicrobial stewardship programs. PMID- 21795725 TI - Antimicrobial stewardship programs in community hospitals: the evidence base and case studies. AB - By controlling and changing how antimicrobial agents are selected and administered, antimicrobial stewardship programs (ASPs) aim to prevent or slow the emergence of antimicrobial resistance; optimize the selection, dosing, and duration of antimicrobial therapy; reduce the incidence of drug-related adverse events; and lower rates of morbidity and mortality, length of hospitalization, and costs. There is an abundant and growing body of evidence demonstrating that ASPs change the quantity and quality of antimicrobial prescriptions; however, measuring whether, when, and how ASPs improve patient outcomes and change patterns of antimicrobial resistance--which is the ultimate goals of ASPs--has been difficult, but the totality of evidence indicates that ASPs are capable of achieving these goals. In this article, we review the existing data on ASPs and their effects on patient care and antimicrobial resistance, as well as strategies for establishing ASPs in different types of hospitals. PMID- 21795727 TI - A call to arms: the imperative for antimicrobial stewardship. AB - Antimicrobial resistance is a major public health crisis. The prevalence of drug resistant organisms, such as the emerging NAP1 strain of Clostridium difficile, now highly resistant to fluoroquinolones, Acinetobacter species, Klebsiella pneumoniae carbapenemase-producing organisms, and methicillin-resistant Staphylococcus aureus, is increasing nationwide. The sources of antimicrobial resistance are manifold, but there is a well-documented causal relationship between antimicrobial use and misuse and the emergence of antimicrobial-resistant pathogens. As the development of new antimicrobial agents is on the decline, the medical community, across all specialties and in conjunction with public health services, must develop and implement programs and strategies designed to preserve the integrity and effectiveness of the existing antimicrobial armamentarium. Such strategies are collectively known as antimicrobial stewardship programs and have the potential to minimize the emergence of resistant pathogens. PMID- 21795728 TI - Need and potential of antimicrobial stewardship in community hospitals. AB - Preventing, reducing, and controlling the emergence of antimicrobial-resistant organisms is a major public health challenge requiring the participation of the entire medical community and public health agencies. Antimicrobial stewardship programs (ASPs) have the potential to integrate the many and sometimes disparate individuals and organizations that rely on antimicrobial agents in an effort to better control antimicrobial prescribing, possibly minimizing the emergence of resistant organisms. Developing and implementing ASPs can be a major challenge for community-based hospitals. In addition to specific and localized patterns of resistance-a consideration for every hospital-community hospitals must develop strategies that appropriately conform to their size, staffing, personnel, and infrastructure. This article reviews the ASP strategies and resources currently available to community hospitals for improving if, when, and how antimicrobial agents are prescribed and delivered. PMID- 21795729 TI - Isolation and characterization of tetranucleotide microsatellite loci in Pinus massoniana (Pinaceae). AB - PREMISE OF THE STUDY: Tetranucleotide microsatellite markers were developed for the first time in Pinus massoniana Lamb. to facilitate studies of population and conservation biology in this species. METHODS AND RESULTS: Ten tetranucleotide microsatellite primer pairs were developed using dual suppression PCR. Seven, six, and eight of the primer pairs exhibited cross-species transferability to P. thunbergii, P. densiflora, and P. luchuensis, respectively. The number of alleles ranged from 1 to 31 per locus across four pine species. CONCLUSIONS: Considering its advantage over dinucleotide microsatellites in generating fewer artifacts arising from stutter bands, this tetranucleotide microsatellite panel will facilitate future population and conservation biological studies in P. massoniana. Six to eight markers can also be used in studies of three congeneric species. PMID- 21795730 TI - Development of 12 genic microsatellite loci for a biofuel grass, Miscanthus sinensis (Poaceae). AB - PREMISE OF THE STUDY: Miscanthus, a nonfood plant with high potential as a biofuel, has been used in Europe and the United States. The selection of a cultivar with high biomass, photosynthetic efficiency, and stress resistance from wild populations has become an important issue. New genic microsatellite markers will aid the assessment of genetic diversity for different strains. METHODS AND RESULTS: Twelve polymorphic microsatellite markers derived from the transcriptome of Miscanthus sinensis fo. glaber were identified and screened on 80 individuals of M. sinensis. The number of alleles per locus ranged from 6 to 12, and the mean expected heterozygosity was 0.75. Cross-taxa transferability revealed that all loci can be applied to all varieties of M. sinensis, as well as the closely related species M. floridulus. CONCLUSIONS: These new genic microsatellite markers are useful for characterizing different traits in breeding programs or to select genes useful for biofuel. PMID- 21795731 TI - The mechanism for explosive seed dispersal in Cardamine hirsuta (Brassicaceae). AB - PREMISE: Although many highly successful weed species use a ballistic seed dispersal mechanism, little is known about the mechanics of this process. Bittercress (Cardamine hirsuta) siliques are morphologically similar to Arabidopsis siliques, but they can project their seeds up to 5 m, while Arabidopsis seeds are dispersed by gravity. Comparison of these species should enable us to determine which structures might be responsible for ballistic seed dispersal. METHODS: Sections of Arabidopsis and bittercress siliques were immunolabeled with antibodies raised against a variety of polysaccharide epitopes. RESULTS: In bittercress, the second endocarp layer (enB) of the valve had strongly asymmetrical cell wall thickenings, whereas the analogous cells in Arabidopsis were reinforced symmetrically and to a lesser extent. Additionally, an accumulation of mucilaginous pectins was found between the first and second endocarp (enA and enB) layers in the bittercress valve that was not present in Arabidopsis. However, in both species, highly de-esterified homogalacturonan was lost in the dehiscence zone (at the carpel/replum interface) as the siliques matured, thus allowing for separation of the valve at maturity. CONCLUSIONS: Ballistic seed dispersal in bittercress may involve the contraction of the outer pericarp tissue against the highly asymmetrically thickened enB cells, which are hypothesized to bend in one direction preferentially. The stress generated by the differential drying of the inner and outer layers of the valve is released suddenly as the adhesion between the cells of the dehiscence zone is lost, leading to a rapid coiling of the valve and dispersal of the seeds. PMID- 21795732 TI - What can we learn from tobacco and other Solanaceae about horizontal DNA transfer? AB - In eukaryotic organisms, horizontal gene transfer (HGT) is regarded as an important though infrequent source of reticulate evolution. Many confirmed instances of natural HGT involving multicellular eukaryotes come from flowering plants. This review intends to provide a synthesis of present knowledge regarding HGT in higher plants, with an emphasis on tobacco and other species in the Solanaceae family because there are numerous detailed reports concerning natural HGT events, involving various donors, in this family. Moreover, in-depth experimental studies using transgenic tobacco are of great importance for understanding this process. Valuable insights are offered concerning the mechanisms of HGT, the adaptive role and regulation of natural transgenes, and new routes for gene trafficking. With an increasing amount of data on HGT, a synthetic view is beginning to emerge. PMID- 21795733 TI - A 10-gene phylogeny of Solanum section Herpystichum (Solanaceae) and a comparison of phylogenetic methods. AB - PREMISE OF THE STUDY: Solanum section Herpystichum is a lineage that comprises both widespread and very narrowly distributed species. This study investigates the phylogenetic relationships of sect. Herpystichum and evaluates several phylogenetic methods for analysis of multiple sequences. METHODS: Sequence data from seven nuclear (ITS, GBSSI, and five COSII) and three plastid (psbA-trnH, trnT-trnF, and trnS-trnG) regions were concatenated and analyzed under maximum parsimony and Bayesian criteria. In addition, we used two analytical methods that take into account differences in topologies resulting from the analyses of the individual markers: Bayesian Estimation of Species Trees (BEST) and supertree analysis. KEY RESULTS: The monophyletic Solanum sect. Herpystichum was resolved with moderate support in the concatenated maximum parsimony and Bayesian analyses and the supertree analysis, and relationships within the section were well resolved and strongly supported. The BEST topology, however, was poorly resolved. Also, because of how BEST deals with missing sequences, >25% of our accessions, including two species, had to be excluded from the analyses. Our results indicate a progenitor-descendent relationship with two species nested within the widespread S. evolvulifolium. CONCLUSIONS: Analytical methods that consider individual topologies are important for studies based on multiple molecular markers. On the basis of analyses in this study, BEST had the serious shortcoming that taxa with missing sequences must be removed from the analysis or they can produce spurious topologies. Supertree analysis provided a good alternative for our data by allowing the inclusion of all 10 species of sect. Herpystichum. PMID- 21795734 TI - Microsatellites for mahoganies: twelve new loci for Swietenia macrophylla and its high transferability to Khaya senegalensis. AB - PREMISE OF THE STUDY: A new set of 12 microsatellite markers was developed and characterized for big-leaf mahogany (Swietenia macrophylla King, Meliaceae) and its transferability assayed in the African mahogany, Khaya senegalensis (Desr.) A. Juss. (Meliaceae), to study population and conservation genetics of these threatened tropical timber species. METHODS AND RESULTS: Using an enriched library approach twelve novel microsatellite loci were identified for S. macrophylla. The number of alleles per locus ranged from 5 to 14 and mean observed and expected heterozygosities were 0.819 and 0.822, respectively. Twenty microsatellite loci developed for S. macrophylla (12 from this study and eight previously published) were tested for K. senegalensis and 10 polymorphic were characterized. CONCLUSIONS: The results show the highly informative content of the new SSR loci for Swietenia macrophylla and the high effectiveness of these microsatellites for population genetics, gene flow, and mating system studies in Khaya senegalensis. PMID- 21795735 TI - Soil fungal effects on floral signals, rewards, and aboveground interactions in an alpine pollination web. AB - PREMISE OF THE STUDY: Plants interact with above- and belowground organisms; the combined effects of these interactions determine plant fitness and trait evolution. To better understand the ecological and evolutionary implications of multispecies interactions, we explored linkages between soil fungi, pollinators, and floral larcenists in Polemonium viscosum (Polemoniaceae). METHODS: Using a fungicide, we experimentally reduced fungal colonization of krummholz and tundra P. viscosum in 2008-2009. We monitored floral signals and rewards, interactions with pollinators and larcenists, and seed set for fungicide-treated and control plants. KEY RESULTS: Fungicide effects varied among traits, between interactions, and with environmental context. Treatment effects were negligible in 2008, but stronger in 2009, especially in the less-fertile krummholz habitat. There, fungicide increased nectar sugar content and damage by larcenist ants, but did not affect pollination. Surprisingly, fungicide also enhanced seed set, suggesting that direct resource costs of soil fungi exceed indirect benefits from reduced larceny. In the tundra, fungicide effects were negligible in both years. However, pooled across treatments, colonization by mycorrhizal fungi in 2009 correlated negatively with the intensity and diversity of floral volatile organic compounds, suggesting integrated above- and belowground signaling pathways. CONCLUSIONS: Fungicide effects on floral rewards in P. viscosum link soil fungi to ecological costs of pollinator attraction. Trait-specific linkages to soil fungi should decouple expression of sensitive and buffered floral phenotypes in P. viscosum. Overall, this study demonstrates how multitrophic linkages may lead to shifting selection pressures on interaction traits, restricting the evolution of specialization. PMID- 21795737 TI - Sex steroid hormones and reproductive disorders: impact on women's health. AB - The role of sex steroid hormones in reproductive function in women is well established. However, in the last two decades it has been shown that receptors for estrogens, progesterone and androgens are expressed in non reproductive tissue /organs (bone, brain, cardiovascular system) playing a role in their function. Therefore, it is critical to evaluate the impact of sex steroid hormones in the pathophysiology of some diseases (osteoporosis, Alzheimer, atherosclerosis). In particular, women with primary ovarian insufficiency, polycystic ovary syndrome, endometriosis and climacteric syndrome may have more health problems and therefore an hormonal treatment may be crucial for these women. PMID- 21795738 TI - Strong association between angiotensin I-converting enzyme I/D polymorphism and unexplained recurrent miscarriage of Chinese women--a case-control study. AB - The patients with recurrent miscarriage (RM) undergo multiple diagnostic tests to detect parental chromosomal anomalies, maternal thrombophilic, endocrine, or immunological disorders, and over 50% of the cases with RM are classified as idiopathic unexplained RM (URM). Angiotensin I-converting enzyme (ACE) is proposed to be a candidate gene in many common diseases, and the plasma ACE levels was associated with an insertion (I)/deletion (D) polymorphism involving about 287 bp situated in intron 16 of the ACE gene, the so-called ACE/ID polymorphism. In this study, we have estimated the ACE I/D polymorphism within a cohort of Chinese patients with URM. There were significant differences both in allele and genotype distribution between patients with URM and healthy controls. The association to URM reached significant both in dominate (1.63-fold, D allele) and in recessive mode (1.76-fold, DD genotype). To our knowledge, the present study is the first to establish the association between ACE I/D polymorphism and the development of URM and indicates that the D allele of the polymorphism possibly be a risk factor for URM in Chinese population. PMID- 21795740 TI - Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women. AB - Consumption of industrially produced trans fatty acids (IP-TFA) has been positively associated with systemic markers of low-grade inflammation and endothelial dysfunction in cross-sectional studies, but results from intervention studies are inconclusive. Therefore, we conducted a 16 week double-blind parallel intervention study with the objective to examine the effect of IP-TFA intake on biomarkers of inflammation, oxidative stress, and endothelial dysfunction. Fifty two healthy overweight postmenopausal women (49 completers) were randomly assigned to receive either partially hydrogenated soybean oil (15.7 g/day IP-TFA) or control oil without IP-TFA. After 16 weeks, IP-TFA intake increased baseline adjusted serum tumor necrosis factor (TNF) alpha by 12% [95% confidence interval (CI): 5-20; P = 0.002] more in the IP-TFA group compared with controls. Plasma soluble TNF receptors 1 and 2 were also increased by IP-TFA [155 pg/ml (CI: 63 247); P < 0.001 and 480 pg/ml (CI: 72-887); P = 0.02, respectively]. Serum C reactive protein, interleukin (IL) 6 and adiponectin and subcutaneous abdominal adipose tissue mRNA expression of IL6, IL8, TNFalpha, and adiponectin as well as ceramide content were not affected by IP-TFA, nor was urinary 8-iso-prostaglandin F(2alpha). In conclusion, this dietary trial indicates that the mechanisms linking dietary IP-TFA to cardiovascular disease may involve activation of the TNFalpha system. PMID- 21795741 TI - Farming, growing up on a farm, and haematological cancer mortality. AB - OBJECTIVES: Occupation as a farmer has been associated with increased risks of haematological cancers in adults. This study aimed to examine whether farm exposures in childhood contribute to these risks, by using parental occupation in farming as a proxy for growing up on a farm. METHODS: New Zealand death records (1998-2003) of persons aged 35-85 were extracted (n=114 289). For 82.3% usual occupation and the occupation of at least one of the parents could be coded (n=94 054). Unconditional logistic regression analyses included 3119 haematological cancer deaths (cases) and 90 935 deaths from other causes (controls). ORs for farming and growing up on a farm were adjusted for each other, year of birth, age at death, socio-economic status, Maori ethnicity, immigration status and sex. RESULTS: Growing up on a livestock farm was positively associated with haematological cancer (OR 1.22, 95% CI 1.05 to 1.41), particularly for poultry farms (OR 2.99, 95% CI 1.44 to 6.21), while growing up on a crop farm was not (OR 0.81, 95% CI 0.64 to 1.03). Crop farming in adulthood was associated with an increased haematological cancer risk (OR 1.49, 95% CI 1.13 to 1.96), while livestock farming was not (OR 0.80, 95% CI 0.63 to 1.00), except for beef cattle farming (OR 2.99, 95% CI 1.28 to 7.00). These results did not change appreciably when different control groups with different causes of death were used. CONCLUSIONS: These results could suggest a role for early life biological exposures in the development of haematological cancers. PMID- 21795739 TI - Effects of progesterone treatment on expression of genes involved in uterine quiescence. AB - An important action of progesterone during pregnancy is to maintain the uterus in a quiescent state and thereby prevent preterm labor. The causes of preterm labor are not well understood, so progesterone action on the myometrium can provide clues about the processes that keep the uterus from contracting prematurely. Accordingly, we have carried out Affymetrix GeneChip analysis of progesterone effects on gene expression in immortalized human myometrial cells cultured from a patient near the end of pregnancy. Progesterone appears to inhibit uterine excitability by a number of mechanisms, including increased expression of calcium and voltage-operated K(+) channels, which dampens the electrical activity of the myometrial cell, downregulation of agents, and receptors involved in myometrial contraction, reduction in cell signal components that lead to increased intracellular Ca(2+) concentrations in response to contractile stimuli, and downregulation of proteins involved in the cross-linking of actin and myosin filaments to produce uterine contractions. PMID- 21795742 TI - How I treat extramedullary acute myeloid leukemia. AB - Extramedullary (EM) manifestations of acute leukemia include a wide variety of clinically significant phenomena that often pose therapeutic dilemmas. Myeloid sarcoma (MS) and leukemia cutis (LC) represent 2 well-known EM manifestations with a range of clinical presentations. MS (also known as granulocytic sarcoma or chloroma) is a rare EM tumor of immature myeloid cells. LC specifically refers to the infiltration of the epidermis, dermis, or subcutis by neoplastic leukocytes (leukemia cells), resulting in clinically identifiable cutaneous lesions. The molecular mechanisms underlying EM involvement are not well defined, but recent immunophenotyping, cytogenetic, and molecular analysis are beginning to provide some understanding. Certain cytogenetic abnormalities are associated with increased risk of EM involvement, potentially through altering tissue-homing pathways. The prognostic significance of EM involvement is not fully understood. Therefore, it has been difficult to define the optimal treatment of patients with MS or LC. The timing of EM development at presentation versus relapse, involvement of the marrow, and AML risk classification help to determine our approach to treatment of EM disease. PMID- 21795743 TI - Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. AB - Notch is a critical regulator of angiogenesis, vascular differentiation, and vascular integrity. We investigated whether Notch signaling affects macrophage function during retinal angiogenesis in mice. Retinal macrophage recruitment and localization in mice with myeloid-specific loss of Notch1 was altered, as these macrophages failed to localize at the leading edge of the vascular plexus and at vascular branchpoints. Furthermore, these retinas were characterized by elongated endothelial cell sprouts that failed to anastomose with neighboring sprouts. Using Notch reporter mice, we demonstrate that retinal macrophages localize between Dll4-positive tip cells and at vascular branchpoints, and that these macrophages had activated Notch signaling. Taken together, these data demonstrate that Notch signaling in macrophages is important for their localization and interaction with endothelial cells during sprouting angiogenesis. PMID- 21795744 TI - A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies. AB - The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human Fcgamma receptors. The resulting mAb 37.1 showed high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. Furthermore, the Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. In all assays, mAb 37.1 was superior to rituximab in terms of potency and maximal cell lysis. A single dose of mAb CD37.1 administered to human CD37-transgenic mice resulted in a reversible, dose dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC activities very similar to those of mAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys. In conclusion, the remarkable preclinical pharmacodynamic and antitumor effects of mAb 37.1 warrant clinical development for B-cell malignancies. PMID- 21795746 TI - Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS). AB - Using population-based data from Sweden, we identified all multiple myeloma (MM) patients (n = 8740) and 5652 monoclonal gammopathy of undetermined significance (MGUS) patients diagnosed between 1986 and 2005. We calculated standardized incidence rates (SIRs) for all subsequent hematologic and nonhematologic malignancies for MM patients diagnosed before/after 1995 (introduction of high dose melphalan/autologous stem cell transplantation [HDM-ASCT]) and 2000 (introduction of immunomodulatory drugs [IMiDs]), respectively. MM patients had an 11.51-fold (95% confidence interval: 8.19-15.74) increased risk of acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS); risk was very similar before/after 1995 and 2000, respectively. MGUS patients had an 8.01-fold (5.40 11.43) increased risk of AML/MDS. Risk was confined to IgG/IgA, while no IgM MGUS patients developed AML/MDS; patients with monoclonal-protein (M-protein) concentrations > 1.5 g/dL (SIR = 11.12; 3.61-25.96) had higher risk than those < 1.5 g/dL (SIR = 4.67; 1.71-10.16). An excess risk of nonmelanoma skin cancer was observed subsequent to both MM (SIR = 2.22; 1.74-2.80) and MGUS (SIR = 3.30; 2.76 3.90). Our novel observations of an excess risk for AML/MDS following IgG/IgA (but not IgM) MGUS, and the highest risk associated with M-protein concentrations > 1.5 g/dL, support a role for nontreatment-related factors in plasma cell dyscrasias. AML/MDS risk following MM was the same before/after the introduction of HDM-ASCT. Longer follow-up is needed to characterize second tumor risks in the IMiD era. PMID- 21795745 TI - Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of alpha1-antitrypsin. AB - The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ~ 50% of wild-type in Lman1(-/-) mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and alpha1 antitrypsin as additional potential cargoes for LMAN1, no differences were observed between wild-type and Lman1(-/-) mice in the levels of cathepsin C and cathepsin Z in liver lysates or alpha1-antitrypsin levels in plasma. LMAN1 deficiency had no apparent effect on COPII-coated vesicle formation in an in vitro assay. However, the ER in Lman1(-/-) hepatocytes is slightly distended, with significant accumulation of alpha1-antitrypsin and GRP78. An unexpected, partially penetrant, perinatal lethality was observed for Lman1(-/-) mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins. PMID- 21795747 TI - CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling. AB - B cell-specific gene ablation of Notch2 results in the loss of the marginal zone (MZ) B-cell lineage. To analyze the effects of constitutive Notch2 signaling in B cells, we have generated a transgenic mouse strain that allows the conditional expression of a constitutively active, intracellular form of Notch2 (Notch2IC). Expression of Notch2IC at the earliest developmental stages of the B-cell lineage completely abolished B-cell generation and led to the development of ectopic T cells in the bone marrow (BM), showing that Notch2IC is acting redundantly with Notch1IC in driving ectopic T-cell differentiation. In B cells clearly committed to the B-cell lineage induction of Notch2IC drove all cells toward the MZ B-cell compartment at the expense of follicular B cells. Notch2IC-expressing B cells reflected the phenotype of wild-type MZ B cells for their localization in the MZ, the expression of characteristic surface markers, their enhanced proliferation after stimulation, and increased basal activity of Akt, Erk, and Jnk. Notch2IC driven MZ B-cell generation in the spleen was achieved even in the absence of CD19. Our results implicate that a constitutive Notch2 signal in transitional type 1 B cells is sufficient to drive MZ B-cell differentiation. PMID- 21795748 TI - Erythrocyte peripheral type benzodiazepine receptor/voltage-dependent anion channels are upregulated by Plasmodium falciparum. AB - Plasmodium falciparum relies on anion channels activated in the erythrocyte membrane to ensure the transport of nutrients and waste products necessary for its replication and survival after invasion. The molecular identity of these anion channels, termed "new permeability pathways" is unknown, but their currents correspond to up-regulation of endogenous channels displaying complex gating and kinetics similar to those of ligand-gated channels. This report demonstrates that a peripheral-type benzodiazepine receptor, including the voltage dependent anion channel, is present in the human erythrocyte membrane. This receptor mediates the maxi-anion currents previously described in the erythrocyte membrane. Ligands that block this peripheral-type benzodiazepine receptor reduce membrane transport and conductance in P falciparum-infected erythrocytes. These ligands also inhibit in vitro intraerythrocytic growth of P falciparum. These data support the hypothesis that dormant peripheral-type benzodiazepine receptors become the "new permeability pathways" in infected erythrocytes after up-regulation by P falciparum. These channels are obvious targets for selective inhibition in anti malarial therapies, as well as potential routes for drug delivery in pharmacologic applications. PMID- 21795749 TI - Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. AB - Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL), and FISH-based genomic risk classifications are routinely used in clinical decision making in CLL. One of the known limitations of CLL FISH is the inability to comprehensively interrogate the CLL genome for genomic changes. In an effort at overcoming the existing limitations in CLL genome analysis, we have analyzed high-purity DNA isolated from FACS-sorted CD19(+) cells and paired CD3(+) or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays. Overall, >= 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas >= 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. Subsequently, we have correlated genomic lesion loads (genomic complexity) with the clinical outcome measures time to first therapy and overall survival. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array-based genomic lesion loads at various thresholds, we identify elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival. PMID- 21795750 TI - The Anolis lizard genome: an amniote genome without isochores. AB - Isochores are large regions of relatively homogeneous nucleotide composition and are present in the genomes of all mammals and birds that have been sequenced to date. The newly sequenced genome of Anolis carolinensis provides the first opportunity to quantify isochore structure in a nonavian reptile. We find Anolis to have the most compositionally homogeneous genome of all amniotes sequenced thus far, a homogeneity exceeding that for the frog Xenopus. Based on a Bayesian algorithm, Anolis has smaller and less GC-rich isochores compared with human and chicken. Correlates generally associated with GC-rich isochores, including shorter introns and higher gene density, have all but disappeared from the Anolis genome. Using genic GC as a proxy for isochore structure so as to compare with other vertebrates, we found that GC content has substantially decreased in the lineage leading to Anolis since diverging from the common ancestor of Reptilia ~275 Ma, perhaps reflecting weakened or reversed GC-biased gene conversion, a nonadaptive substitution process that is thought to be important in the maintenance and trajectory of isochore evolution. Our results demonstrate that GC composition in Anolis is not associated with important features of genome structure, including gene density and intron size, in contrast to patterns seen in mammal and bird genomes. PMID- 21795751 TI - Genomic species are ecological species as revealed by comparative genomics in Agrobacterium tumefaciens. AB - The definition of bacterial species is based on genomic similarities, giving rise to the operational concept of genomic species, but the reasons of the occurrence of differentiated genomic species remain largely unknown. We used the Agrobacterium tumefaciens species complex and particularly the genomic species presently called genomovar G8, which includes the sequenced strain C58, to test the hypothesis of genomic species having specific ecological adaptations possibly involved in the speciation process. We analyzed the gene repertoire specific to G8 to identify potential adaptive genes. By hybridizing 25 strains of A. tumefaciens on DNA microarrays spanning the C58 genome, we highlighted the presence and absence of genes homologous to C58 in the taxon. We found 196 genes specific to genomovar G8 that were mostly clustered into seven genomic islands on the C58 genome-one on the circular chromosome and six on the linear chromosome suggesting higher plasticity and a major adaptive role of the latter. Clusters encoded putative functional units, four of which had been verified experimentally. The combination of G8-specific functions defines a hypothetical species primary niche for G8 related to commensal interaction with a host plant. This supports that the G8 ancestor was able to exploit a new ecological niche, maybe initiating ecological isolation and thus speciation. Searching genomic data for synapomorphic traits is a powerful way to describe bacterial species. This procedure allowed us to find such phenotypic traits specific to genomovar G8 and thus propose a Latin binomial, Agrobacterium fabrum, for this bona fide genomic species. PMID- 21795752 TI - The human genome retains relics of its prokaryotic ancestry: human genes of archaebacterial and eubacterial origin exhibit remarkable differences. AB - Eukaryotes are generally thought to stem from a fusion event involving an archaebacterium and a eubacterium. As a result of this event, contemporaneous eukaryotic genomes are chimeras of genes inherited from both endosymbiotic partners. These two coexisting gene repertoires have been shown to differ in a number of ways in yeast. Here we combine genomic and functional data in order to determine if and how human genes that have been inherited from both prokaryotic ancestors remain distinguishable. We show that, despite being fewer in number, human genes of archaebacterial origin are more highly and broadly expressed across tissues, are more likely to have lethal mouse orthologs, tend to be involved in informational processes, are more selectively constrained, and encode shorter and more central proteins in the protein-protein interaction network than eubacterium-like genes. Furthermore, consistent with endosymbiotic theory, we show that proteins tend to interact with those encoded by genes of the same ancestry. Most interestingly from a human health perspective, archaebacterial genes are less likely to be involved in heritable human disease. Taken together, these results show that more than 2 billion years after eukaryogenesis, the human genome retains at least two somewhat distinct communities of genes. PMID- 21795753 TI - Three-dimensional quantification of facial symmetry in adolescents using laser surface scanning. AB - Laser scanning is a non-invasive method for three-dimensional assessment of facial morphology and symmetry. The aim of this study was to quantify facial symmetry in healthy adolescents and explore if there is any gender difference. Facial scans of 270 subjects, 123 males and 147 females (aged 15.3 +/- 0.1 years, range 14.6-15.6), were randomly selected from the Avon Longitudinal Study of Parents and Children. Facial scans were processed and analysed using in-house developed subroutines for commercial software. The surface matching between the original face and its mirror image was measured for the whole face, upper, middle, and lower facial thirds. In addition, 3 angular and 14 linear parameters were measured. The percentage of symmetry of the whole face was significantly lower in males (53.49 +/- 10.73 per cent) than in females (58.50 +/- 10.27 per cent; P < 0.01). There was no statistically significant difference in the amount of symmetry among facial thirds within each gender (P > 0.05). Average values of linear parameters were less than 1 mm and did not differ significantly between genders (P > 0.05). One angular parameter showed slight lip line asymmetry in both genders. Faces of male 15-year-old adolescents were less symmetric than those of females, but the difference in the amount of symmetry, albeit statistically significant, may not be clinically relevant. Upper, middle, and lower thirds of the face did not differ in the amount of three-dimensional symmetry. Angular and linear parameters of facial symmetry did not show any gender difference. PMID- 21795754 TI - Pathways between temporomandibular disorders, occlusal characteristics, facial pain, and oral health-related quality of life among patients with severe malocclusion. AB - The aim of this study was to examine the pathways between temporomandibular disorders (TMDs), occlusal characteristics, facial pain, and oral health-related quality of life in patients with severe malocclusion. The study comprised 94 (34 men and 60 women, mean age 38 years) adult patients who were referred for orthodontic or surgical-orthodontic treatment. All the patients had severe malocclusion. Oral health-related quality of life was measured with the Oral Health Impact Profile-14 scale (OHIP-14), the intensity of facial pain using a Visual Analogue Scale (VAS), TMD with Helkimo's clinical dysfunction index (Di), and occlusal characteristics with the Peer Assessment Rating (PAR). A hypothetical model of the interrelationships between these factors was constructed based on the conceptual model of biological, behavioural, and psychosocial consequences of oral diseases. The associations were studied with path analysis. Women reported poorer oral health-related quality of life, higher pain levels, and had more severe TMD than men, but the gender difference was statistically significant only in pain and TMD. In contrast to the hypothetical model, among women the occlusal characteristics were not directly associated with oral health-related quality of life or facial pain. Among men, the occlusal characteristics were directly associated with oral health-related quality of life. In conclusion, patients with severe malocclusion who also have TMD and facial pain more often have impaired oral health-related quality of life. The associations of the occlusal characteristics with oral health-related quality of life differ between genders. Therefore, these associations should be studied separately among genders. PMID- 21795755 TI - Matrix-embedded endothelial cells are protected from the uremic milieu. AB - BACKGROUND: Endothelial cells (ECs) embedded in 3D matrices [matrix-embedded endothelial cells (MEECs)] of denatured collagen implanted around vascular access anastomoses preserve luminal patency. MEEC implant efficacy depends on embedded EC health. As the uremic milieu inhibits proliferation and induces apoptosis of ECs, we examined whether uremia might impact MEECs. METHODS: ECs grown on 2D gelatin-coated polystyrene tissue culture plates (gTCPS) or in MEEC were treated with sera pooled from 20 healthy control or uremic patients with end-stage renal disease. EC viability was examined using 3-(4,5-dimethylthiazole-2-yl)-2,5 diphenyl tetrazolium bromide assay, cell counting and Trypan blue exclusion. Media conditioned (CM) with 2 and 3D-supported ECs were examined for its potential to inhibit vascular smooth muscle cell (vSMC) proliferation using (3)[H] thymidine incorporation and cyclin D1 expression. ECs grown on gTCPS were treated with uremic serum filtered through matrices to examine if matrices retain uremic toxins or whether EC effects were cell mediated. RESULTS: Uremic serum significantly reduced viability and number of live, and increased dead ECs when grown on gTCPS, but not in MEECs. EC survival correlated with vSMC inhibition. While CM from ECs grown in gTCPS with uremic serum inhibited vSMC proliferation no better than uremic serum alone (22 versus 27%), MEEC CM inhibited vSMC proliferation by 47% (P = 0.0004). Cyclin D1 expression tracked with indices of vSMC proliferation. There was no significant difference in EC viability between EC treated with matrix-filtered or unfiltered uremic serum. CONCLUSION: The viability, number and efficacy of MEECs were preserved in uremic serum compared to those of ECs on gTCPS. MEECs are protected from uremic toxicity, not from retention of uremic toxins by matrices, but likely from intrinsic changes in EC sensitivity to uremia. MEECs implanted at vascular access sites should inhibit neointimal hyperplasia in uremia. This study underscores the robustness of matrix embedding as a cell protectant, especially in hostile environments like uremia. PMID- 21795756 TI - Benefits of regular walking exercise in advanced pre-dialysis chronic kidney disease. AB - BACKGROUND: There is increasing evidence of the benefit of regular physical exercise in a number of long-term conditions including chronic kidney disease (CKD). In CKD, this evidence has mostly come from studies in end stage patients receiving regular dialysis. There is little evidence in pre-dialysis patients with CKD Stages 4 and 5. METHODS: A prospective study compared the benefits of 6 months regular walking in 40 pre-dialysis patients with CKD Stages 4 and 5. Twenty of them were the exercising group and were compared to 20 patients who were continuing with usual physical activity. In addition, the 40 patients were randomized to receive additional oral sodium bicarbonate (target venous bicarbonate 29 mmol/L) or continue with previous sodium bicarbonate treatment (target 24 mmol/L). RESULTS: Improvements noted after 1 month were sustained to 6 months in the 18 of 20 who completed the exercise study. These included improvements in exercise tolerance (reduced exertion to achieve the same activity), weight loss, improved cardiovascular reactivity, avoiding an increase in blood pressure medication and improvements in quality of health and life and uraemic symptom scores assessed by questionnaire. Sodium bicarbonate supplementation did not produce any significant alterations. CONCLUSIONS: This study provides further support for the broad benefits of aerobic physical exercise in CKD. More studies are needed to understand the mechanisms of these benefits, to study whether resistance exercise will add to the benefit and to evaluate strategies to promote sustained lifestyle changes, that could ensure continued increase in habitual daily physical activity levels. PMID- 21795757 TI - Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up. AB - The authors assessed changes in the health status of US 1991 Gulf War-era veterans from a 1995 baseline survey to a 2005 follow-up survey, using repeated measurement data from 5,469 deployed Gulf War veterans and 3,353 nondeployed Gulf War-era veterans who participated in both surveys. Prevalence differences in health status between the 2 surveys were estimated for adverse health indices and chronic diseases for each veteran group. Persistence risk ratios and incidence risk ratios were calculated after adjustment for demographic and military service characteristics through Mantel-Haenszel stratified analysis. At 10-year follow up, deployed veterans were more likely to report persistent poor health, as measured by the health indices (functional impairment, limitation of activities, repeated clinic visits, recurrent hospitalizations, perception of health as fair or poor, chronic fatigue syndrome-like illness, and posttraumatic stress disorder), than nondeployed veterans. Additionally, deployed veterans were more likely to experience new onset of adverse health (as measured by the indices) and certain chronic diseases than were nondeployed veterans. During the 10-year period from 1995 to 2005, the health of deployed veterans worsened in comparison with nondeployed veterans because of a higher rate of new onset of various health outcomes and greater persistence of previously reported adverse health on the indices. PMID- 21795758 TI - Impact of subjective sleep quality on glycemic control in type 2 diabetes mellitus. AB - BACKGROUND: Glycaemic control is fundamental to the management of and risk reduction in microvascular complications of diabetes. OBJECTIVES: The aim of this study was to investigate the association of sleep quality with glycaemic control and its impact on type 2 diabetic patients in an Asian population. METHODS: A total of 46 subjects with type 2 diabetes mellitus were enrolled. HbA1C was measured in each patient, and each patient completed the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Good sleep quality was defined as PSQI score <=5. RESULTS: After adjusting for age, gender and body mass index, the total PSQI score and sleep efficiency (P < 0.05) were significantly correlated with the level of HbA1C. Logistic regression analysis showed the adjusted odds ratio (OR) of sleep efficiency for HbA1C level was 6.83 [OR = 6.83, 95% confidence interval (CI) = 2.04-22.8, P = 0.002]. The adjusted ORs of worse glycaemic control for the poor sleep quality group was 6.94 with regard to the group of good sleep quality (OR = 6.94, 95% CI: 1.02-47.16, P < 0.05). CONCLUSIONS: This study demonstrated that both poor sleep quality and less efficient sleep are significantly correlated with worse glycaemic control in patients with type 2 diabetes. These findings are expected to contribute to the prevention and risk reduction of microvascular complications in type 2 diabetes. PMID- 21795759 TI - Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica. AB - In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis. PMID- 21795760 TI - The nuclear lamina as a gene-silencing hub. AB - There is accumulating evidence that the nuclear periphery is a transcriptionally repressive compartment. A surprisingly large fraction of the genome is either in transient or permanent contact with nuclear envelope, where the majority of genes are maintained in a silent state, waiting to be awakened during cell differentiation. The integrity of the nuclear lamina and the histone deacetylase activity appear to be essential for gene repression at the nuclear periphery. However, the molecular mechanisms of silencing, as well as the events that lead to the activation of lamina-tethered genes, require further elucidation. This review summarizes recent advances in understanding of the mechanisms that link nuclear architecture, local chromatin structure, and gene regulation. PMID- 21795761 TI - Paracrystals of STAT proteins and their dissolution by SUMO: how reduced transcription factor solubility increases cytokine signaling. PMID- 21795763 TI - Filtration at the microfluidic level: enrichment of nanoparticles by tunable filters. AB - We present an electrohydrodynamic device for filtration of nanometre-sized particles from suspensions. A high-frequency electric field is locally generated through the action of mutually parallel microelectrodes integrated into a microfluidic channel. Due to the mechanism of ohmic heating, a thermal gradient arises above these electrodes. In conjunction with temperature-sensitive properties of the fluid, an eddy flow behaviour emerges in the laminar environment. This acts as an adjustable filter. For quantification of the filtration efficiency, we tested a wide range of particle concentrations at different electric field strengths and overall external flow velocities. Particles with a diameter of 200 nm were retained in this manner at rates of up to 100%. Numerical simulations of a model taking into account the hydrodynamic as well as electric conditions, but no interactions between the point-shaped particles, yield results that are similar to the experiment in both the flow trajectories and the particle accumulation. Our easy technique could become a valuable tool that complements conventional filtration methods for handling nanometre-scaled particles in medicine and biotechnology, e.g. bacteria and viruses. PMID- 21795764 TI - Origin of the pre-peak features in the oxygen K-edge x-ray absorption spectra of LaFeO3 and LaMnO3 studied by Ga substitution of the transition metal ion. AB - We report on experimental oxygen K-edge x-ray absorption near edge structure (XANES) spectra of the LaFe(1 - x)Ga(x)O(3) and LaMn(1 - x)Ga(x)O(3) series. Transition metal substitution by the 3d full shell Ga atom is mainly reflected in a systematic decrease of the pre-edge structures in the XANES spectra of the two series. This result shows that the associated states originate from the hybridization of oxygen 2p and unoccupied Fe (or Mn) 3d states. In order to gain insight into the states associated with the pre-edge spectral features, we have performed ab initio theoretical calculations based on multiple scattering theory. Simulations with variable cluster size and composition around the absorber oxygen in the LaFeO(3) and LaMnO(3) crystal structures were carried out. We find that the low-energy pre-peak is reproduced once the absorbing oxygen and the two nearest neighbour Fe (or Mn) ions are considered in the cluster. Conversely, higher energy pre-peaks only arise when the full oxygen coordination geometry around the two metal sites is taken into account, implying that their energy distance is a reflection of the strength of the oxygen ligand field. Substitutions of the two nearest neighbours by Ga atoms in the cluster of calculation lead to changes in the theoretical spectra that reasonably agree with the evolution of the pre-peaks in the experimental XANES spectra of both the series. PMID- 21795765 TI - The effect of carbon distribution on the manganese magnetic moment in bcc Fe-Mn alloy. AB - First-principles calculations were performed to study the structural, electronic, and magnetic properties of bcc Fe with C impurities alloyed with 2, 3, and 6 at.% of Mn. Our results reveal that both manganese concentration and carbon location with respect to Mn affect the Fe-Mn magnetic interaction. With an increase in Mn concentration in bcc Fe-Mn alloy, the local magnetic moment of manganese changes sharply from - 2 to 1 u(B) near 3 at.% Mn, while carbon stabilizes the local ferromagnetic interaction between the nearest Mn atom and the Fe matrix. We demonstrate that the Mn-C interaction is attractive and promotes carbon trapping with a low energy defect configuration. Our results indicate that the Mn-C binding energy strongly depends on the magnetism and the formation of Mn(x)C clusters is predicted. PMID- 21795762 TI - Evi1 forms a bridge between the epigenetic machinery and signaling pathways. AB - Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in myeloid malignancies. Evi1-mediated leukemogenic activities include a wide array of functions such as the induction of epigenetic modifications, transcriptional control, and regulation of signaling pathways. We have recently succeeded in comprehensively elucidating the oncogenic function of Evi1 in a model of the polycomb-Evi1-PTEN/AKT/mTOR axis. These results may provide us with novel therapeutic approaches to conquer the poor prognosis associated with Evi1 activated leukemia or other solid tumors with high Evi1 expression. Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling. PMID- 21795766 TI - Pressure effects on the magnetic susceptibility of FeTe(x)(x approximately 1.0). AB - The magnetic susceptibility chi of FeTe(x) compounds (x approximately 1.0) was studied under hydrostatic pressure up to 2 kbar at fixed temperatures of 55, 78 and 300 K. Measurements were taken both for polycrystalline and single crystalline samples. At ambient pressure, with decreasing temperature a drastic drop in chi(T) was confirmed at T approximately 70 K, which appears to be closely related to antiferromagnetic ordering. The obtained results have revealed a puzzling growth of susceptibility under pressure, and this effect is enhanced by lowering the temperature. To shed light on the pressure effects in the magnetic properties of FeTe, ab initio calculations of its volume dependent band structure and the exchange enhanced paramagnetic susceptibility were performed within the local spin density approximation. PMID- 21795767 TI - Nanoscale structures and dynamics of a boundary liquid layer. AB - Our long term scientific interest is the understanding of the interface properties of flowing liquids on a microscopic level. Various mechanisms have been introduced to explain the origin of slip at a solid-liquid interface like the formation of a thin depletion layer or a molecular ordering of the liquid near the interface. Reflectometry (using x-rays or neutrons) is a powerful technique to probe structures in this surface region. However, to date much less attention has been paid to the dynamical properties. In the first part of this paper we show that a different ordering of water exists next to a hydrophobic substrate in comparison to a hydrophilic interface. Furthermore, we find that shear has no effect on the depletion layer on hydrophobic substrates, while no depletion layer exists for hydrophilic surfaces. The second part of the paper addresses the dynamical properties of the boundary layer, and we present a new method which enables the observation of the diffusion dynamics of polymers next to a solid substrate. As a proof of concept, the dynamics of micelles next to the interface has been explored using grazing incidence neutron spin-echo spectroscopy. We were able to verify that investigation of the dynamics of the sample is feasible with this grazing incidence technique and we present data taken near the critical angle of total reflection. It appears that the diffusive motion of micelles at the hydrophobic (repulsive) interface is faster than at a hydrophilic interface or in the bulk. Furthermore, neutron spin-echo spectroscopy was extended to a first evaluation of the Doppler shift which occurs under flow. PMID- 21795768 TI - The fabrication of tunable nanoporous oxide surfaces by block copolymer lithography and atomic layer deposition. AB - Patterned nanoscale materials with controllable characteristic feature sizes and periodicity are of considerable interest in a wide range of fields, with various possible applications ranging from biomedical to nanoelectronic devices. Block copolymer (BC)-based lithography is a powerful tool for the fabrication of uniform, densely spaced nanometer-scale features over large areas. Following this bottom-up approach, nanoporous polymeric films can be deposited on any type of substrate. The nanoporous periodic template can be transferred to the underlying substrate by dry anisotropic etching. Nevertheless the physical sizes of the polymeric mask represent an important limitation in the implementation of suitable lithographic protocols based on BC technology, since the diameter and the center-to-center distance of the pores cannot be varied independently in this class of materials. This problem could be overcome by combining block copolymer technology with atomic layer deposition (ALD): by means of BC-based lithography a nanoporous SiO2 template, with well-reproducible characteristic dimensions, can be fabricated and subsequently used as a backbone for the growth of perfectly conformal thin oxide films by ALD. In this work polystyrene-b poly(methylmethacrylate) (PS-b-PMMA) BC and reactive ion etching are used to fabricate hexagonally packed 23 nm wide nanopores in a 50 nm thick SiO2 matrix. By ALD deposition of Al2O3 thin films onto the nanoporous SiO2 templates, nanostructured Al2O3 surfaces are obtained. By properly adjusting the thickness of the Al2O3 film the dimension of the pores in the oxide films is progressively reduced, with nanometer precision, from the original size down to complete filling of the pores, thus providing a simple and fast strategy for the fabrication of nanoporous Al2O3 surfaces with well-controllable feature size. PMID- 21795769 TI - Submicrometre resolved optical characterization of green nanowire-based light emitting diodes. AB - The electroluminescent properties of InGaN/GaN nanowire-based light emitting diodes (LEDs) are studied at different resolution scales. Axial one-dimensional heterostructures were grown by plasma-assisted molecular beam epitaxy (PAMBE) directly on a silicon (111) substrate and consist of the following sequentially deposited layers: n-type GaN, three undoped InGaN/GaN quantum wells, p-type AlGaN electron blocking layer and p-type GaN. From the macroscopic point of view, the devices emit light in the green spectral range (around 550 nm) under electrical injection. At 100 mA DC current, a 1 mm2 chip that integrates around 10(7) nanowires emits an output power on the order of 10 uW. However, the emission of the nanowire-based LED shows a spotty and polychromatic emission. By using a confocal microscope, we have been able to improve the spatial resolution of the optical characterizations down to the submicrometre scale that can be assessed to a single nanowire. Detailed MU-electroluminescent characterization (emission wavelength and output power) over a representative number of single nanowires provides new insights into the vertically integrated nanowire-based LED operation. By combining both MU-electroluminescent and MU-photoluminescent excitation, we have experimentally shown that electrical injection failure is the major source of losses in these nanowire-based LEDs. PMID- 21795770 TI - Low temperature thermocompression bonding between aligned carbon nanotubes and metallized substrate. AB - Vertically aligned carbon nanotube (VACNT) turf is proposed for use as an electrical and thermal contact material. For these applications, one route for circumventing the high temperatures required for VACNT growth using chemical vapor deposition (CVD) is used to grow firstly VACNTs on one substrate and then transfer them to other substrates. In this work, a nano thermocompression bonding technique between VACNTs and a metallized substrate is developed to allow dry mechanical transfer of the VACNTs. Unlike the diffusion bonding between two bulk materials, nano metal clusters have a high surface energy and the atoms are very active to form alloy with the contacted bulk metal material even at much lower temperatures, so nano thermocompression bonding can decrease the bonding temperature (150 degrees C) and pressure (1 MPa) and greatly shorten the bonding time from hours to 20 min. A debonding experiment shows that the bonding strength between VACNTs and the metallized layer is so high that a break is less likely to occur at the bonding interface. PMID- 21795771 TI - Synthesis of polymer-protected graphene by solvent-assisted thermal reduction process. AB - Polyvinylpyrrolidone-protected (PVP-protected) graphene was synthesized by refluxing graphene oxide (GO) in dimethylformamide (DMF), using PVP as the dispersant. The structure and stability of this composite (DMF-rGO) were characterized using UV-vis spectroscopy, atomic force microscopy (AFM), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), x-ray diffraction (XRD) and thermogravimetric analysis (TGA). The results confirm the presence of a single sheet of DMF-rGO with PVP of 42%. This kind of chemically reduced GO has a greater solubility in water and also is more biocompatible than rGO reduced by hydrazine hydrate. This method is simple, environmentally friendly and the composite has potential applications in biology and polymer nanocomposites. PMID- 21795772 TI - Magnetic nanoparticle biodistribution following intratumoral administration. AB - Recently, heat generated by iron oxide nanoparticles (IONPs) stimulated by an alternating magnetic field (AMF) has shown promise in the treatment of cancer. To determine the mechanism of nanoparticle-induced cytotoxicity, the physical association of the cancer cells and the nanoparticles must be determined. We have used transmission electron microscopy (TEM) to define the time dependent cellular uptake of intratumorally administered dextran-coated, core-shell configuration IONP having a mean hydrodynamic diameter of 100-130 nm in a murine breast adenocarcinoma cell line (MTG-B) in vivo. Tumors averaging volumes of 115 mm3 were injected with iron oxide nanoparticles. The tumors were then excised and fixed for TEM at time 0.1-120 h post-IONP injection. Intracellular uptake of IONPs was 5.0, 48.8 and 91.1% uptake at one, 2 and 4 h post-injection of IONPs, respectively. This information is essential for the effective use of IONP hyperthermia in cancer treatment. PMID- 21795773 TI - Theoretical characterization of the topology of connected carbon nanotubes in random networks. AB - In recent years, a lot of attention has been paid to carbon nanotube (CNT) networks and their applications to electronic devices. Many studies concentrate on the percolation threshold and the characterization of the conduction in such materials. Nevertheless, no theoretical study has yet attempted to characterize the CNT features inside finite size CNT networks. We present a theoretical approach based on geometrical and statistical considerations. We demonstrate the possibility of explicitly determining some relations existing between two neighbor CNTs and their contact efficiency in random networks of identical CNTs. We calculate the contact probability of rigid identical CNTs and we obtain a probability of 0.2027, which turns out to be independent of the CNT density. Based on this probability, we establish also the dependence of the number of contacts per CNT as a function of the CNT density. All the theoretical results are validated by very good agreement with Monte Carlo simulations. PMID- 21795774 TI - Experimental validation of atomic force microscopy-based cell elasticity measurements. AB - Atomic force microscopy (AFM) is widely used for measuring the elasticity of living cells yielding values ranging from 100 Pa to 100 kPa, much larger than those obtained using bead-tracking microrheology or micropipette aspiration (100 500 Pa). AFM elasticity measurements appear dependent on tip geometry with pyramidal tips yielding elasticities 2-3 fold larger than spherical tips, an effect generally attributed to the larger contact area of spherical tips. In AFM elasticity measurements, experimental force-indentation curves are analyzed using contact mechanics models that infer the tip-cell contact area from the tip geometry and indentation depth. The validity of these assumptions has never been verified. Here we utilize combined AFM-confocal microscopy of epithelial cells expressing a GFP-tagged membrane marker to directly characterize the indentation geometry and measure the indentation depth. Comparison with data derived from AFM force-indentation curves showed that the experimentally measured contact area for spherical tips agrees well with predicted values, whereas for pyramidal tips, the contact area can be grossly underestimated at forces larger than ~0.2 nN leading to a greater than two-fold overestimation of elasticity. These data suggest that a re-examination of absolute cellular elasticities reported in the literature may be necessary and we suggest guidelines for avoiding elasticity measurement artefacts introduced by extraneous cantilever-cell contact. PMID- 21795775 TI - Contrast inversion in electrostatic force microscopy imaging of trapped charges: tip-sample distance and dielectric constant dependence. AB - We present a numerical and analytical study of the behavior of both electrostatic force and force gradient created by a charge trapped below the surface of a dielectric on an atomic force microscope tip as a function of the dielectric constant and tip-sample distance. As expected, the force decreases monotonously when the dielectric constant increases. However, a maximum in the dielectric constant dependence of the force gradient is found. This maximum occurs in the typical experimental parameters' range and depends on the tip-sample distance and the sample thickness. The analytical study permits us to understand the physical origin of this phenomenon and is in good agreement with the numerical simulation for small tip-sample distances. We also report a study exemplifying a possible contrast inversion in electrostatic force microscopy (EFM) signals while scanning, at different heights, two charges trapped in a sample having heterogeneous dielectric domains. In addition to this particular contrast inversion effect, this study can be considered as a way to gain insight into the mechanisms of EFM image formation as a function of the dielectric constant and tip-sample. PMID- 21795776 TI - Distribution of cations in nanosize and bulk Co-Zn ferrites. AB - The structural and magnetic properties of Co(1-x)Zn(x)Fe2O4 ferrites (Co-Zn ferrites) are investigated in a narrow compositional range around x = 0.6, which is of interest because of applications in magnetic fluid hyperthermia. The study by x-ray and neutron diffraction, Mossbauer spectroscopy and magnetization measurements is done on nanoparticles prepared by the coprecipitation method and bulk samples sintered at high temperatures. In spite of the known preference of Zn2+ for tetrahedral (A) sites and Co2+ for octahedral [B] sites, the cations are distributed nearly evenly over the two sites of spinel structure and there is also a variable number of [B] site vacancies (see text), making cobalt ions trivalent. In particular for x = 0.6, the cationic distribution is refined to [Formula: see text] and [Formula: see text] for the 13 nm particles (T(C) = 335 K) and bulk sample (T(C) = 351 K), respectively. PMID- 21795777 TI - Magnetization of multicomponent ferrofluids. AB - The solution of the mean spherical approximation (MSA) integral equation for isotropic multicomponent dipolar hard sphere fluids without external fields is used to construct a density functional theory (DFT), which includes external fields, in order to obtain an analytical expression for the external field dependence of the magnetization of ferrofluidic mixtures. This DFT is based on a second-order Taylor series expansion of the free energy density functional of the anisotropic system around the corresponding isotropic MSA reference system. The ensuing results for the magnetic properties are in quantitative agreement with our canonical ensemble Monte Carlo simulation data presented here. PMID- 21795778 TI - A Monte Carlo study of the freezing transition of hard spheres. AB - A simulation method for fluid-solid transitions, which is based on a modification of the constrained cell model of Hoover and Ree, is developed and tested on a system of hard spheres. In the fully occupied constrained cell model, each particle is confined in its own Wigner-Seitz cell. Constant-pressure simulations of the constrained cell model for a system of hard spheres indicate a point of mechanical instability at a density which is about 64% of the density at the close packed limit. Below that point, the solid is mechanically unstable since without the confinement imposed by the cell walls it will disintegrate to a disordered, fluid-like phase. Hoover and Ree proposed a modified cell model by introducing an external field of variable strength. High values of the external field variable favor configurations with one particle per cell and thus stabilize the solid phase. In this work, the modified cell model of a hard-sphere system is simulated under constant-pressure conditions using tempering and histogram reweighting techniques. The simulations indicate that as the strength of the field is reduced, the transition from the solid to the fluid phase is continuous below the mechanical instability point and discontinuous above. The fluid-solid transition of the hard-sphere system is determined by analyzing the field-induced fluid-solid transition of the modified cell model in the limit in which the external field vanishes. The coexistence pressure and densities are obtained through finite-size scaling techniques and are in good accord with previous estimates. PMID- 21795779 TI - Structural investigation of the negative thermal expansion in yttrium and rare earth molybdates. AB - The Sc(2)(WO(4))(3)-type phase (Pbcn) of Y(2)(MoO(4))(3), Er(2)(MoO(4))(3) and Lu(2)(MoO(4))(3) has been prepared by the conventional solid-state synthesis with preheated oxides and the negative thermal expansion (NTE) has been investigated along with an exhaustive structural study, after water loss. Their crystal structures have been refined using the neutron and x-ray powder diffraction data of dehydrated samples from 150 to 400 K. The multi-pattern Rietveld method, using atomic displacements with respect to a known structure as parameters to refine, has been applied to facilitate the interpretation of the NTE behavior. Polyhedral distortions, transverse vibrations of A. . .O-Mo (A = Y and rare earths) binding oxygen atoms, non-bonded distances A. . .Mo and atomic displacements from the high temperature structure, have been evaluated as a function of the temperature and the ionic radii. PMID- 21795780 TI - Fe, Mn, and Cr doped BiCoO3 for magnetoelectric application: a first-principles study. AB - The tetragonal compound BiCoO(3) may play a significant role in magnetoelectric devices if its magnetism can be tuned and its strong ferroelectricity maintained. Here we have studied Fe, Mn, and Cr doped BiCoO(3) with a concentration of 12.5% by density functional theory (DFT) and DFT + U calculations. It is found that all the doped magnetic ions favor ferromagnetic coupling in the C-type antiferromagnetic BiCoO(3) lattice, leading to net magnetic moments of 1, 1, 0 MU(B) for Bi(8)Co(7)XO(24), where X = Fe, Cr, and Mn, respectively. Meanwhile, the Berry phase calculations indicate that the strong ferroelectricity is almost preserved for Fe, Cr, and Mn doped BiCoO(3), with values of 172.7, 152.1, and 169.8 uC cm(-2), respectively, close to the original polarization value of 174.9 uC cm(-2). As a result, Cr or Fe doping may be useful to make the BiCoO(3) system ferrimagnetic while maintaining its excellent ferroelectric performance. PMID- 21795781 TI - Effects of applied electric and magnetic fields on a donor impurity in laterally coupled quantum dots. AB - A theoretical description of the electronic structure, optical spectrum and binding energy of a hydrogenic impurity in laterally coupled quantum discs, under applied electric and magnetic fields, is given within the framework of the effective-mass approach. Calculations are performed using the envelope-function formalism and a variational procedure, with the electric field applied in the coupling direction, the magnetic field along the growth direction, and the impurity at the center of the heterostructure. The results indicate that the anisotropy of the laterally coupled confinement potential leads to interesting relative extrema and anticrossings in the energy spectra, and that the infrared absorption spectrum is sensitive to the type of polarization and magnitude of external fields. PMID- 21795782 TI - Electronic structure interpolation via atomic orbitals. AB - We present an efficient scheme for accurate electronic structure interpolation based on systematically improvable optimized atomic orbitals. The atomic orbitals are generated by minimizing the spillage value between the atomic basis calculations and the converged plane wave basis calculations on some coarse k point grid. They are then used to calculate the band structure of the full Brillouin zone using the linear combination of atomic orbitals algorithms. We find that usually 16-25 orbitals per atom can give an accuracy of about 10 meV compared to the full ab initio calculations, and the accuracy can be systematically improved by using more atomic orbitals. The scheme is easy to implement and robust, and works equally well for metallic systems and systems with complicated band structures. Furthermore, the atomic orbitals have much better transferability than Shirley's basis and Wannier functions, which is very useful for perturbation calculations. PMID- 21795783 TI - High-resolution structure of a new crystal form of BamA POTRA4-5 from Escherichia coli. AB - In Escherichia coli, the BAM complex is employed to mediate correct folding of the outer membrane (OM) proteins into beta-barrels and their insertion into the OM. BamA, which is an essential component of the complex, consists of a C terminal transmembrane region and five N-terminal polypeptide transport associated (POTRA) domains. Although deletion studies have shown that each of the POTRA domains plays an important role in the process of BAM complex formation, only POTRA5 is essential for cell viability. Here, the crystal structure of POTRA4-5 has been determined to 1.50 A resolution with an R factor of 14.7% and an Rfree of 18.9%. PMID- 21795784 TI - Structures of the rat complement regulator CrrY. AB - Complement receptor 1-related protein Y (CrrY) is an important cell-surface regulator of complement that is unique to rodent species. The structure of rat CrrY domains 1-4 has been determined in two distinct crystal forms and reveals a 70 degrees bend between domains 3 and 4. Comparisons of this structure with those of other complement regulators suggests that rearrangement of this interface may occur on forming the regulatory complex with C3b. PMID- 21795785 TI - Structure of the Drosophila melanogaster Rab6 GTPase at 1.4 A resolution. AB - Rab6 is a small GTPase that belongs to the p21 Ras superfamily. It is involved in vesicle trafficking between the Golgi apparatus and endosomes/ER in eukaryotes. The GDP-bound inactive protein undergoes conformational changes when the nucleotide is exchanged to GTP, allowing Rab6 to interact with a variety of different effector proteins. To further understand how these changes affect downstream protein binding, the crystal structure of Rab6 from Drosophila melanogaster has been solved to 1.4 A resolution, the highest resolution for a Rab6 structure to date. The crystals belonged to space group C2, with unit-cell parameters a=116.5, b=42.71, c=86.86 A, alpha=90, beta=133.12, gamma=90 degrees . The model was refined to an R factor of 14.5% and an Rfree of 17.3%. PMID- 21795786 TI - The structure of LpxD from Pseudomonas aeruginosa at 1.3 A resolution. AB - LpxD is a bacterial protein that is part of the biosynthesis pathway of lipid A and is responsible for transferring 3-hydroxymyristic acid from the R-3 hydroxymyristoyl-acyl carrier protein to the 2-OH group of UDP-3-O-(3 hydroxymyristoyl) glucosamine. The crystal structure of LpxD from Pseudomonas aeruginosa has been determined at high resolution (1.3 A). The crystal belonged to space group H3, with unit-cell parameters a=b=106.19, c=93.38 A, and contained one molecule in the asymmetric unit. The structure was solved by molecular replacement using the known structure of LpxD from Escherichia coli (PDB entry 3eh0) as a search model and was refined to Rwork=16.4% (Rfree=18.5%) using 91,655 reflections. The final protein model includes 355 amino-acid residues (including 16 amino acids from a 20 amino-acid N-terminal His tag), one chloride ion and two ethylene glycol molecules. PMID- 21795787 TI - Structure of a multicopper oxidase from the hyperthermophilic archaeon Pyrobaculum aerophilum. AB - The crystal structure of an extremely thermostable multicopper oxidase (McoP) from the hyperthermophilic archaeon Pyrobaculum aerophilum was determined at a resolution of 2.0 A. The overall fold was comprised of three cupredoxin-like domains and the main-chain coordinates of the enzyme were similar to those of multicopper oxidases from Escherichia coli (CueO) and Bacillus subtilis (CotA). However, there were clear topological differences around domain 3 between McoP and the other two enzymes: a methionine-rich helix in CueO and a protruding helix in CotA were not present in McoP. Instead, a large loop (PL-1) covered the T1 copper centre of McoP and a short alpha-helix in domain 3 extended near the N terminal end of PL-1. In addition, the sizes of several surface loops in McoP were markedly smaller than the corresponding loops in CueO and CotA. Structural comparison revealed that the presence of extensive hydrophobic interactions and a smaller cavity volume are likely to be the main factors contributing to the hyperthermostability of McoP. PMID- 21795788 TI - Crystallographic characterization of the DIX domain of the Wnt signalling positive regulator Ccd1. AB - Coiled-coil DIX1 (Ccd1) is a positive regulator that activates the canonical Wnt signalling pathway by inhibiting the degradation of the key signal transducer beta-catenin. The C-terminal DIX domain of Ccd1 plays an important role in the regulation of signal transduction through homo-oligomerization and protein complex formation with other DIX domain-containing proteins, i.e. axin and dishevelled proteins. Here, the expression, purification, crystallization and X ray data collection of the Ccd1 DIX domain are reported. The crystals of the Ccd1 DIX domain belonged to space group P2(1)2(1)2(1), with unit-cell parameters a=72.9, b=75.7, c=125.6 A. An X-ray diffraction data set was collected at 3.0 A resolution. PMID- 21795789 TI - Expression, purification, crystallization and preliminary crystallographic analysis of a putative Clostridium difficile surface protein Cwp19. AB - Cwp19 is a putatively surface-located protein from Clostridium difficile. A recombinant N-terminal protein (residues 27-401) lacking the signal peptide and the C-terminal cell-wall-binding repeats (PFam04122) was crystallized using the sitting-drop vapour-diffusion method and diffracted to 2 A resolution. The crystal appeared to belong to the primitive monoclinic space group P2(1), with unit-cell parameters a=109.1, b=61.2, c=109.2 A, beta=111.85 degrees , and is estimated to contain two molecules of Cwp19 per asymmetric unit. PMID- 21795790 TI - Cloning, purification, crystallization and preliminary X-ray analysis of the catalytic domain of human receptor-like protein tyrosine phosphatase gamma in three different crystal forms. AB - Protein tyrosine phosphatase gamma is a membrane-bound receptor and is designated RPTPgamma. RPTPgamma and two mutants, RPTPgamma(V948I, S970T) and RPTPgamma(C858S, S970T), were recombinantly expressed and purified for X-ray crystallographic studies. The purified enzymes were crystallized using the hanging-drop vapor-diffusion method. Crystallographic data were obtained from several different crystal forms in the absence and the presence of inhibitor. In this paper, a description is given of how three different crystal forms were obtained that were used with various ligands. An orthorhombic crystal form and a trigonal crystal form were obtained both with and without ligand, and a monoclinic crystal form was only obtained in the presence of a particularly elaborated inhibitor. PMID- 21795791 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of a novel plant-type ferredoxin/thioredoxin reductase-like protein from Methanosarcina acetivorans. AB - The genome of Methanosarcina acetivorans contains a gene (ma1659) that is predicted to encode an uncharacterized chimeric protein containing a plant-type ferredoxin/thioredoxin reductase-like catalytic domain in the N-terminal region and a bacterial-like rubredoxin domain in the C-terminal region. To understand the structural and functional properties of the protein, the ma1659 gene was cloned and overexpressed in Escherichia coli. Crystals of the MA1659 protein were grown by the sitting-drop method using 2 M ammonium sulfate, 0.1 M HEPES buffer pH 7.5 and 0.1 M urea. Diffraction data were collected to 2.8 A resolution using the remote data-collection feature of the Advanced Light Source, Lawrence Berkeley National Laboratory. The crystal belonged to the primitive cubic space group P23 or P2(1)3, with unit-cell parameters a=b=c=92.72 A. Assuming the presence of one molecule in the asymmetric unit gave a Matthews coefficient (VM) of 3.55 A3 Da(-1), corresponding to a solvent content of 65%. PMID- 21795792 TI - Expression, crystallization and preliminary X-ray diffraction studies of thermostable beta-1,3-xylanase from Thermotoga neapolitana strain DSM 4359. AB - Crystals of beta-1,3-xylanase (1,3-beta-D-xylan xylanohydrolase; EC 3.2.1.32) from Thermotoga neapolitana strain DSM 4359 with maximum dimensions of 0.2*0.1*0.02 mm were grown using the sitting-drop vapour-diffusion method at 293 K over 24 h. The crystals diffracted to a resolution of 1.82 A, allowing structure determination. The crystals belonged to space group P2(1), with unit cell parameters a=39.061, b=75.828, c=52.140 A; each asymmetric unit cell contained a single molecule. PMID- 21795793 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of the hyperthermophilic nucleotidyltransferase TTHA1015 from Thermus thermophilus HB8. AB - The TTHA1015 gene from Thermus thermophilus HB8 encodes a hyperthermophilic nucleotidyltransferase. TTHA1015 has high homology to proteins belonging to two related families: the nucleotidyltransferase-domain superfamily and the DNA polymerase beta-like family. However, no crystal structures of these proteins have been reported. Determination of the crystal structure of TTHA1015 will help in elucidation of its function and will be useful for understanding the relationship between the structure and the function of these homologous proteins. In this study, TTHA1015 was expressed, purified and crystallized. X-ray diffraction data were collected to 1.70 A resolution. The crystal belonged to the monoclinic space group C2, with unit-cell parameters a=65.5, b=34.7, c=42.4 A, beta=119.1 degrees . There was one molecule per asymmetric unit, giving a Matthews coefficient of 1.86 A3 Da(-1) and an approximate solvent content of 34%. PMID- 21795794 TI - Use of the alpha-mannosidase I inhibitor kifunensine allows the crystallization of apo CTLA-4 homodimer produced in long-term cultures of Chinese hamster ovary cells. AB - Glycoproteins present problems for structural analysis since they often have to be glycosylated in order to fold correctly and because their chemical and conformational heterogeneity generally inhibits crystallization. It is shown that the alpha-mannosidase I inhibitor kifunensine, which has previously been used for the purpose of glycoprotein crystallization in short-term (3-5 d) cultures, is apparently stable enough to be used to produce highly endoglycosidase H-sensitive glycoprotein in long-term (3-4 week) cultures of stably transfected Chinese hamster ovary (CHO) cells. Matrix-assisted laser desorption/ionization time-of flight mass spectrometry-based analysis of the extracellular region of the cytotoxic T-lymphocyte antigen 4 (CTLA-4; CD152) homodimer expressed in long-term CHO cell cultures in the presence of kifunensine revealed that the inhibitor restricted CTLA-4 glycan processing to Man9GlcNAc2 and Man5GlcNAc2 structures. Complex-type glycans were undetectable, suggesting that the inhibitor was active for the entire duration of the cultures. Endoglycosidase treatment of the homodimer yielded protein that readily formed orthorhombic crystals with unit cell parameters a=43.9, b=51.5, c=102.9 A and space group P2(1)2(1)2(1) that diffracted to Bragg spacings of 1.8 A. The results indicate that kifunensine will be effective in most, if not all, transient and long-term mammalian cell-based expression systems. PMID- 21795795 TI - Expression, crystallization and preliminary crystallographic study of the C terminal half of nsp2 from SARS coronavirus. AB - SARS coronavirus (SARS-CoV) is the aetiological agent of the highly infectious severe acute respiratory syndrome (SARS). To gain a better understanding of SARS CoV replication and transcription proteins, a preliminary X-ray crystallographic study of the C-terminal domain of SARS-CoV nonstructural protein 2 (nsp2) is reported here. The C-terminal domain of SARS-CoV nsp2 was cloned, overexpressed, purified and crystallized using polyethylene glycol 5000 monomethyl ether as the precipitant; the crystals diffracted to 2.5 A resolution. The crystals belonged to space group P6(5), with unit-cell parameters a=b=112.8, c=91.1 A, alpha=beta=90, gamma=120 degrees . One molecule is assumed to be present per asymmetric unit, which gives a Matthews coefficient of 2.89 A3 Da(-1) and a solvent content of 56.2%. PMID- 21795796 TI - Crystallization and preliminary crystallographic analysis of the phosphotriesterase-like lactonase from Geobacillus kaustophilus. AB - GK1506 from the thermophilic bacterium Geobacillus kaustophilus is a member of the phosphotriesterase-like lactonases, which can catalyze the hydrolysis of a broad range of compounds with different chemical properties. It is of particular interest because of its high thermostability and its dual activity towards organophosphate compounds and some lactones. These properties make GK1506 an attractive target for future enzyme engineering and use in practical applications. In order to resolve the crystal structure of GK1506 and to gain a better understanding of its biological function, recombinant GK1506 was expressed, purified and crystallized using 0.1 M HEPES pH 7.6, 12%(w/v) PEG 8000, 8%(v/v) ethylene glycol at 291 K. A 2.6 A resolution native data set was collected from a single flash-cooled crystal (100 K) using 10%(v/v) glycerol as a cryoprotectant. These crystals belonged to space group P2(1), with unit-cell parameters a=51.444, b=80.453, c=92.615 A, beta=99.29 degrees . Two molecules were assumed to be present per asymmetric unit, which gives a Matthews coefficient of 2.7 A3 Da(-1). PMID- 21795797 TI - Cloning, overexpression, purification, crystallization, and preliminary X-ray studies of SP_0149, the substrate binding protein of an ABC transporter from Streptococcus pneumoniae. AB - A truncated (29 residues from the N-terminus) and N-terminal His-tagged form of SP_0149 from pneumococcal strain ATCC BAA-334 was overexpressed and purified to homogeneity using affinity and gel-filtration chromatography. Diffraction quality crystals were grown at 293 K using the hanging-drop vapour-diffusion technique. X ray diffraction data were collected to 2.3 A resolution from a single-crystal that belonged to the orthorhombic space group P2(1)2(1)2(1) with the unit-cell parameters a=54.56, b=75.61, c=75.52 A. The calculated values of the Matthews coefficient assuming one molecule (with calculated molecular weight of 30 400 Da) in the crystal asymmetric unit and the corresponding solvent content were 2.56 A3 Da(-1) and 52.0%, respectively. PMID- 21795798 TI - Crystallization and preliminary X-ray crystallographic studies of the ice-binding protein from the Arctic [correction of Aantarctic] yeast Leucosporidium sp. AY30. AB - Freezing is dangerous to cellular organisms because it causes an increase in the concentration of ions and other solutes in the plasma, denatures biomolecules and ruptures cell membranes. Some cold-adapted organisms can survive at subzero temperatures by producing proteins that bind to and inhibit the growth of ice crystals. To better understand the structure and function of these proteins, the ice-binding protein from Leucosporidium sp. AY30 (LeIBP) was overexpressed, purified and crystallized. The native crystal belonged to space group P4(3)2(1)2, with unit-cell parameters a=b=98.05, c=106.13 A. Since LeIBP lacks any cysteine or methionine residues, two leucine residues (Leu69 and Leu155) were substituted by methionine residues in order to obtain selenomethionine-substituted LeIBP for use in multiple-wavelength anomalous diffraction (MAD) phasing. The selenomethionine-substituted mutant crystallized in the same space group as the native protein. PMID- 21795799 TI - Crystallization and preliminary X-ray analysis of a putative sensor histidine kinase domain: the C-terminal domain of HksP4 from Aquifex aeolicus VF5. AB - The histidine kinase domain of the cytoplasmic protein HksP4 from the hyperthermophilic bacterium Aquifex aeolicus VF5, located in the C-terminal half of the protein, was expressed, purified and crystallized. Diffraction-quality crystals were obtained in the presence of adenosine triphosphate (ATP) or adenosine 5'-(beta,gamma-imido)triphosphate (AMPPNP) by the sitting-drop vapour diffusion method using PEG 3350 as the precipitant. The crystals obtained in the presence of ATP and AMPPNP diffracted X-rays to 3.1 and 2.9 A resolution, respectively, on BL-5A at Photon Factory (Ibaraki, Japan) and were found to belong to the same space group P2(1)2(1)2(1), with unit-cell parameters a=80.2, b=105.5, c=122.0 A and a=81.5, b=105.5, c=130.9 A, respectively. Their Matthews coefficients (VM=2.74 and 2.51 A3 Da(-1), respectively) indicated that both crystals contained four protein molecules per asymmetric unit. PMID- 21795800 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of the C-terminal cytoplasmic domain of FlhB from Salmonella typhimurium. AB - FlhB is a key protein in the regulation of protein export by the bacterial flagellar secretion system. It is composed of two domains: an N-terminal transmembrane domain and a C-terminal cytoplasmic domain (FlhBc). FlhBc from Salmonella typhimurium has been successfully crystallized using the vapour diffusion method. The crystals diffracted to 2.45 A resolution and belonged to space group P4(2)2(1)2, with unit-cell parameters a=b=49.06, c=142.94 A. A selenomethionine-containing variant of FlhBc has also been crystallized in the same space group and was used for initial phase calculation by the multiwavelength anomalous dispersion (MAD) method. PMID- 21795801 TI - Cloning, expression, purification, crystallization and preliminary crystallographic analysis of MsDpo4: a Y-family DNA polymerase from Mycobacterium smegmatis. AB - The expression of error-prone DNA polymerases belonging to the Y-family is upregulated in prokaryotes under adverse conditions to facilitate adaptive mutagenesis. However, it has been suggested that representatives of this family in mycobacteria do not participate in adaptive mutagenesis. These studies raise the possibility that mycobacterial representatives might be devoid of biochemical activity. In order to determine whether this possible loss of activity is a consequence of significant changes in the structure of these enzymes, structural studies on a representative enzyme from Mycobacterium smegmatis, MsDpo4, were initiated. The protein crystallized in space group P6(1)22 or P6(5)22. The Matthews coefficient was 4.0 A3 Da(-1) assuming the presence of one molecule in the asymmetric unit; the corresponding solvent content was 69%. X-ray diffraction data were collected to a minimum Bragg spacing of 2.6 A and crystals of selenomethionine-labelled MsDpo4 have been prepared for ab initio phasing. PMID- 21795802 TI - Cloning, expression, purification and preliminary X-ray diffraction studies of a putative Mycobacterium smegmatis thiolase. AB - Thiolases are important in fatty-acid degradation and biosynthetic pathways. Analysis of the genomic sequence of Mycobacterium smegmatis suggests the presence of several putative thiolase genes. One of these genes appears to code for an SCP x protein. Human SCP-x consists of an N-terminal domain (referred to as SCP2 thiolase) and a C-terminal domain (referred as sterol carrier protein 2). Here, the cloning, expression, purification and crystallization of this putative SCP-x protein from M. smegmatis are reported. The crystals diffracted X-rays to 2.5 A resolution and belonged to the triclinic space group P1. Calculation of rotation functions using X-ray diffraction data suggests that the protein is likely to possess a hexameric oligomerization with 32 symmetry which has not been observed in the other six known classes of this enzyme. PMID- 21795803 TI - Crystallization and preliminary X-ray analysis of 4-diphosphocytidyl-2-C-methyl-D erythritol kinase (IspE) from Mycobacterium tuberculosis. AB - The 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis, an enzyme from the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, is crucial and essential for the survival of this pathogenic bacterium. IspE catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP ME) to 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) in an ATP-dependent manner. Solving the crystal structure of M. tuberculosis IspE will shed light on its structural details and mechanism of action and may provide the basis for the future design of drugs for the treatment of multidrug-resistant and extremely drug-resistant M. tuberculosis strains. Recombinant M. tuberculosis IspE was crystallized at 291 K using NaCl or Li2SO4 as a precipitant. A 2.1 A resolution native data set was collected from a single flash-cooled crystal (100 K) belonging to space group P2(1)2(1)2(1), with unit-cell parameters a=52.5, b=72.3, c=107.3 A. One molecule was assumed per asymmetric unit, which gives a Matthews coefficient of 3.4 A3 Da(-1) with 63% solvent content. PMID- 21795804 TI - Overexpression, crystallization, and preliminary X-ray crystallographic analysis of shikimate dehydrogenase from Thermotoga maritima. AB - Shikimate dehydrogenase (SDH), which catalyses the NADPH-dependent reduction of 3 dehydroshikimate to shikimate in the shikimate pathway, is an attractive target for the development of herbicides and antimicrobial agents. Previous structural studies showed that SDH exists in two conformations, an open form and a closed form, and it is believed that the conformational state is crucial to understanding a catalytic mechanism. To facilitate further structural comparisons among SDHs, structural analysis of an SDH from Thermotoga maritima encoded by the Tm0346 gene has been initiated. SDH from T. maritima has been overexpressed in Escherichia coli and crystallized at 296 K using ammonium sulfate as a precipitant. Crystals of T. maritima SDH diffracted to 1.45 A resolution and belonged to orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a=54.21, b=62.45 and c=68.68 A. The asymmetric unit contains a monomer, with a corresponding VM of 2.01 A3 Da(-1) and a solvent content of 38.9% by volume. PMID- 21795805 TI - Crystallization and preliminary X-ray diffraction analysis of membrane-bound respiratory [NiFe] hydrogenase from Hydrogenovibrio marinus. AB - Membrane-bound respiratory [NiFe] hydrogenase is an H2-uptake enzyme found in the periplasmic space of bacteria that plays a crucial role in energy-conservation processes. The heterodimeric unit of the enzyme from Hydrogenovibrio marinus was purified to homogeneity using chromatographic procedures. Crystals were grown using the sitting-drop vapour-diffusion method at room temperature. Preliminary crystallographic analysis revealed that the crystals belonged to space group P2(1), with unit-cell parameters a=75.72, b=116.59, c=113.40 A, beta=91.3 degrees , indicating that two heterodimers were present in the asymmetric unit. PMID- 21795806 TI - Purification, crystallization and X-ray diffraction study of extracellular dermal glycoprotein from carrot and the inhibition complex that it forms with an endo beta-glucanase from Aspergillus aculeatus. AB - Extracellular dermal glycoprotein (EDGP) may play an important role in the plant defence system of the carrot (Daucus carota) as it has inhibitory activity against endo-beta-glucanase produced by invading pathogens. Here, EDGP and the inhibition complex that it forms with FI-CMCase, a carboxyl methyl cellulase from Aspergillus aculeatus, were successfully crystallized. The hexagonal crystal of EDGP belonged to space group P6(2), with unit-cell parameters a=b=130.4, c=44.5 A, gamma=120 degrees . The monoclinic crystal of the complex of EDGP with FI CMCase belonged to space group C2, with unit-cell parameters a=169.5, b=143.0, c=63.0 A, beta=110.9 degrees . PMID- 21795807 TI - Purification, crystallization and preliminary X-ray characterization of the pentamodular arabinoxylanase CtXyl5A from Clostridium thermocellum. AB - The cellulosome, a highly elaborate extracellular multi-enzyme complex of cellulases and hemicellulases, is responsible for the degradation of plant cell walls. The xylanase CtXyl5A (Cthe_2193) is a multimodular arabinoxylanase which is one of the largest components of the Clostridium thermocellum cellulosome. The N-terminal catalytic domain of CtXyl5A, which is a member of glycoside hydrolase family 5 (GH5), is responsible for the hydrolysis of arabinoxylans. Appended after it are three noncatalytic carbohydrate-binding modules (CBMs), which belong to families 6 (CBM6), 13 (CBM13) and 62 (CBM62). In addition, CtXyl5A has a fibronectin type III-like (Fn3) module preceding the CBM62 and a type I dockerin (DOK) module following it which allows the enzyme to be integrated into the cellulosome through binding to a cohesin module of the protein scaffold CipA. Crystals of the pentamodular enzyme without the DOK module at the C-terminus, with the domain architecture CtGH5-CBM6-CBM13-Fn3-CBM62, have been obtained. The structure of this pentamodular xylanase has been determined by molecular replacement to a resolution of 2.64 A using coordinates of CtGH5-CBM6, Fn3 and CBM62 from the PDB as search models. PMID- 21795808 TI - Structural and kinetic insights into the mechanism of 5-hydroxyisourate hydrolase from Klebsiella pneumoniae. AB - The stereospecific oxidative degradation of uric acid to (S)-allantoin has recently been demonstrated to proceed via two unstable intermediates and requires three separate enzymatic reactions. The second step of this reaction, the conversion of 5-hydroxyisourate (HIU) to 2-oxo-4-hydroxy-4-carboxy-5 ureidoimidazoline, is catalyzed by HIU hydrolase (HIUH). The high-resolution crystal structure of HIUH from the opportunistic pathogen Klebsiella pneumoniae (KpHIUH) has been determined. KpHIUH is a homotetrameric protein that, based on sequence and structural similarity, belongs to the transthyretin-related protein family. In addition, the steady-state kinetic parameters for this enzyme and four active-site mutants have been measured. These data provide valuable insight into the functional roles of the active-site residues. Based upon the structural and kinetic data, a mechanism is proposed for the KpHIUH-catalyzed reaction. PMID- 21795810 TI - Structural features of peroxisomal catalase from the yeast Hansenula polymorpha. AB - The reactive oxygen species hydrogen peroxide is a byproduct of the beta oxidation process that occurs in peroxisomes. Since reactive oxygen species can cause serious damage to biomolecules, a number of scavengers control their intracellular levels. One such scavenger that is present in the peroxisome is the oxidoreductase catalase. In this study, the crystal structure of heterologously expressed peroxisomal catalase from the thermotolerant yeast Hansenula polymorpha has been determined at 2.9 A resolution. H. polymorpha catalase is a typical peroxisomal catalase; it is tetrameric and is highly similar to catalases from other organisms. However, its hydrogen peroxide-degrading activity is higher than those of a number of other catalases for which structural data are available. Structural superimpositions indicate that the nature of the major channel, the path for hydrogen peroxide to the active site, varies from those seen in other catalase structures, an observation that may account for the high activity of H. polymorpha catalase. PMID- 21795809 TI - Structure of 2-oxo-3-deoxygalactonate kinase from Klebsiella pneumoniae. AB - In most organisms, efficient D-galactose utilization requires the highly conserved Leloir pathway that converts D-galactose to D-glucose 1-phosphate. However, in some bacterial and fungal species alternative routes of D-galactose assimilation have been identified. In the so-called De Ley-Doudoroff pathway, D galactose is metabolized into pyruvate and D-glyceraldehyde 3-phosphate in five consecutive reactions carried out by specific enzymes. The penultimate step in this pathway involves the phosphorylation of 2-oxo-3-deoxygalactonate to 2-oxo-3 deoxygalactonate 6-phosphate catalyzed by 2-oxo-3-deoxygalactonate kinase, with ATP serving as a phosphoryl-group donor. Here, a crystal structure of 2-oxo-3 deoxygalactonate kinase from Klebsiella pneumoniae determined at 2.1 A resolution is reported, the first structure of an enzyme from the De Ley-Doudoroff pathway. Structural comparison indicates that the enzyme belongs to the ASKHA (acetate and sugar kinases/hsc70/actin) family of phosphotransferases. The protein is composed of two alpha/beta domains, each of which contains a core common to all family members. Additional elements introduced between conserved structural motifs define the unique features of 2-oxo-3-deoxygalactonate kinase and possibly determine the biological function of the protein. PMID- 21795811 TI - A conformation-dependent stereochemical library improves crystallographic refinement even at atomic resolution. AB - To utilize a new conformation-dependent backbone-geometry library (CDL) in protein refinements at atomic resolution, a script was written that creates a restraint file for the SHELXL refinement program. It was found that the use of this library allows models to be created that have a substantially better fit to main-chain bond angles and lengths without degrading their fit to the X-ray data even at resolutions near 1 A. For models at much higher resolution (~0.7 A), the refined model for parts adopting single well occupied positions is largely independent of the restraints used, but these structures still showed much smaller r.m.s.d. residuals when assessed with the CDL. Examination of the refinement tests across a wide resolution range from 2.4 to 0.65 A revealed consistent behavior supporting the use of the CDL as a next-generation restraint library to improve refinement. CDL restraints can be generated using the service at http://pgd.science.oregonstate.edu/cdl_shelxl/. PMID- 21795812 TI - Structural and biochemical characterization of N5-carboxyaminoimidazole ribonucleotide synthetase and N5-carboxyaminoimidazole ribonucleotide mutase from Staphylococcus aureus. AB - With the rapid rise of methicillin-resistant Staphylococcus aureus infections, new strategies against S. aureus are urgently needed. De novo purine biosynthesis is a promising yet unexploited target, insofar as abundant evidence has shown that bacteria with compromised purine biosynthesis are attenuated. Fundamental differences exist within the process by which humans and bacteria convert 5 aminoimidazole ribonucleotide (AIR) to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR). In bacteria, this transformation occurs through a two-step conversion catalyzed by PurK and PurE; in humans, it is mediated by a one-step conversion catalyzed by class II PurE. Thus, these bacterial enzymes are potential targets for selective antibiotic development. Here, the first comprehensive structural and biochemical characterization of PurK and PurE from S. aureus is presented. Structural analysis of S. aureus PurK reveals a nonconserved phenylalanine near the AIR-binding site that occupies the putative position of the imidazole ring of AIR. Mutation of this phenylalanine to isoleucine or tryptophan reduced the enzyme efficiency by around tenfold. The K(m) for bicarbonate was determined for the first time for a PurK enzyme and was found to be ~18.8 mM. The structure of PurE is described in comparison to that of human class II PurE. It is confirmed biochemically that His38 is essential for function. These studies aim to provide foundations for future structure-based drug-discovery efforts against S. aureus purine biosynthesis. PMID- 21795813 TI - A unified convention for biological assemblies with helical symmetry. AB - Assemblies with helical symmetry can be conveniently formulated in many distinct ways. Here, a new convention is presented which unifies the two most commonly used helical systems for generating helical assemblies from asymmetric units determined by X-ray fibre diffraction and EM imaging. A helical assembly is viewed as being composed of identical repetitive units in a one- or two dimensional lattice, named 1-D and 2-D helical systems, respectively. The unification suggests that a new helical description with only four parameters [n(1), n(2), twist, rise], which is called the augmented 1-D helical system, can generate the complete set of helical arrangements, including coverage of helical discontinuities (seams). A unified four-parameter characterization implies similar parameters for similar assemblies, can eliminate errors in reproducing structures of helical assemblies and facilitates the generation of polymorphic ensembles from helical atomic models or EM density maps. Further, guidelines are provided for such a unique description that reflects the structural signature of an assembly, as well as rules for manipulating the helical symmetry presentation. PMID- 21795814 TI - On the routine use of soft X-rays in macromolecular crystallography. Part V. Molecular replacement and anomalous scattering. AB - Currently, about two thirds of all new macromolecular structures are determined by molecular replacement. In general the method works reliably, but it reaches its limits when the search model differs too much from the target structure in terms of coordinate deviations or completeness. Since anomalously scattering substructures are better conserved than the overall structure, these substructures and the corresponding anomalous intensity differences can be utilized to enhance the performance of molecular-replacement approaches. It is demonstrated that the combined and concomitant use of structure-factor amplitudes and anomalous differences constitutes a promising approach to push the limits of molecular replacement and to make more structures amenable to structure solution by this technique. PMID- 21795815 TI - On the application of structure-specific bulk-solvent models. AB - It is often discussed, mainly in connection with the rather high macromolecular R factors, that the treatment of bulk solvent in macromolecular refinement may lack the detail needed for modelling the solvent environment of molecules as complex as proteins and nucleic acids. This line of thought directly leads to the hypothesis that improvements in the modelling of the bulk solvent may substantially improve the agreement between the experimental data and the crystallographic models. Here, part of this hypothesis is being tested through the construction, via molecular-dynamics simulations, of a highly detailed, physics-based, structure-specific and crystallographic data-agnostic model of the bulk solvent of a known crystal structure. The water-distribution map obtained from the simulation is converted (after imposing space-group symmetry) to a constant (but scalable) partial structure factor which is then added in a re refinement of the crystal structure. Compared with the simple Babinet-based correction, a reduction of the totally cross-validated free R value by 0.3% is observed. The implications and possible interpretations of these results are discussed. PMID- 21795816 TI - Distinguishing between Cl- and O2(2-) as the bridging element between Fe3+ and Cu2+ in resting-oxidized cytochrome c oxidase. AB - Fully oxidized cytochrome c oxidase (CcO) under enzymatic turnover is capable of pumping protons, while fully oxidized CcO as isolated is not able to do so upon one-electron reduction. The functional difference is expected to be a consequence of structural differences: [Fe(3+)-OH(-)] under enzymatic turnover versus [Fe(3+) O(2)(2-)-Cu(2+)] for the as-isolated CcO. However, the electron density for O(2)(2-) is equally assignable to Cl(-). An anomalous dispersion analysis was performed in order to conclusively demonstrate the absence of Cl(-) between the Fe(3+) and Cu(2+). Thus, the peroxide moiety receives electron equivalents from cytochrome c without affecting the oxidation states of the metal sites. The metal site reduction is coupled to the proton pump. PMID- 21795818 TI - Characterization of Vibrio parahaemolyticus strains isolated in Chile in 2005 and in 2007. AB - INTRODUCTION: Vibrio (V.) parahaemolyticus has endemically established in Chilean sea shores, causing outbreaks every year, with an important number of cases. In order to know the genetic relationship, genotype dominance and antibiotic resistance of isolates obtained from two outbreaks, this study characterized 110 strains isolated from environmental and clinical samples in years 2005 and 2007 in Chile. METHODOLOGY: Genotyping was performed by determination of PFGE profiles, and pandemic group and integrons were screened by PCR. Antimicrobial susceptibility was studied by the disk diffusion method. RESULTS: High antibiotic susceptibility frequency was found, mainly among 2007 isolates, except to ampicillin, cephalothin, cefoxitin, cefpodoxime, amikacin, streptomycin and kanamycin. Strains belonging to the pandemic group in clinical isolates account for 88% in 2005, decreasing to 66% in 2007 and among environmental isolates were detected in 20% of the strains from 2005, rising to 36% in 2007. In 2005, nine different PFGE profiles were identified, with 78% of the strains corresponding to a single clone. In 2007, sixteen different PFGE profiles were detected, with 61% of the strains included into a sole clone. The same clone was prevalent in both years. None of class 1, 2, 3 and SXT integrases genes was detected; however, the superintegron integrase gene (intIA) was present in almost all strains. CONCLUSIONS: These results suggest the persistence and dominance of a unique PFGE clone of V. parahaemolyticus during 2005 and 2007, and the absence of genetic elements that capture antibiotic resistance genes described in other species of Vibrio. PMID- 21795819 TI - Anti-tuberculosis drug resistance and associated risk factors in a tertiary level TB center in Iran: a retrospective analysis. AB - INTRODUCTION: This study aimed to determine first-line anti-tuberculosis drug resistance rates in new and previously treated cases and to identify risk factors associated with multidrug resistant tuberculosis (MDR-TB) at the National Reference Tuberculosis Laboratory of Iran. METHODOLOGY: This was a retrospective analysis of all confirmed TB patients from December 2000 to June 2005. Drug susceptibility testing to isoniazid, rifampicin, streptomycin, ethambutol and pyrazinamide was performed on Lowenstein-Jensen (LJ) medium according to the proportion method. RESULTS: Mycobacterium tuberculosis strains were isolated from 1,742 patients with TB, of whom 935 (53.7%) were male. The mean age of patients was 44.2 +/- 17.4 years (SD). A total of 1,074 patients were native Iranians while 668 (38.3%) were immigrant patients. Out of 1,139 (65.4%) new cases, 340 (29.9%) had at least one drug resistance. Of 603 (34.6%) previously treated cases, 416 (69.0%) had resistant strains. There were 263 patients (15.1%) with MDR-TB, 72 of whom were new (6.3% of all new cases) and 191 were previously treated (31.7% of all previously treated cases). Factors associated with MDR-TB included age under 45 years, male sex, previous TB treatment, immigration, poor living conditions, and unemployment. CONCLUSIONS: The high rate of initial resistance in MDR-TB cases and the high rate of MDR-TB in a young age group were indicators of recent transmission. Therefore, closer monitoring of transmission trends of drug resistant strains should be considered as priority, to ensure a successful TB control programme. PMID- 21795820 TI - Application of a point-of-care test for the serodiagnosis of typhoid fever in Nigeria and the need for improved diagnostics. AB - INTRODUCTION: There is an urgent need for affordable point-of-care diagnostics for the differentiation of febrile illnesses and the confirmation of typhoid in endemic countries. METHODOLOGY: Blood samples were collected from febrile patients with clinical suspicion of typhoid and screened for typhoid fever using the Widal and Typhi Dri Dot tests, while stool and blood samples were screened for Salmonella Typhi using the culture method as well as PCR as a confirmatory test. RESULTS: A high proportion of febrile patients from Lagos with clinical suspicion of typhoid fever reacted positively in a simple and rapid latex agglutination assay for typhoid fever, indicating that this illness is a common and presumably under-diagnosed health problem in this metropolis. Seropositivity was 19.2% in the rapid test compared with 22.9% in the classical Widal test. The confirmation of typhoid in these seropositive patients appeared cumbersome because of negative blood cultures and low DNA yield in molecular testing. A review of the literature revealed that in Nigeria seroprevalence rates can be high in the normal population and that pathogens other than S. Typhi are often isolated from the blood of seropositive febrile patients. CONCLUSION: The simplicity and the relatively high specificity (97.8%) of the rapid test as determined in a study performed in Indonesia calls for a further validation of this promising test for use in Africa. PMID- 21795821 TI - Intestinal parasites and genotypes of Giardia intestinalis in school children from Berisso, Argentina. AB - INTRODUCTION: Intestinal parasitic infections have been reported in different regions of Argentina. Giardia intestinalis is recognized as "the national parasite". The aim of this work was to determine the prevalence of both intestinal parasites and G. intestinalis genotypes, as well as to analyze the clinical and epidemiological characteristics in schoolchildren from a suburban community. METHODOLOGY: Serial coproparasitological analysis and perianal swab method were performed in 244 schoolchildren. Demographic, sociocultural and environmental variables were registered. The presence of signs/symptoms and risk behaviours were also recorded. Stools with G. intestinalis were selected for genotyping. RESULTS: Out of 244 schoolchildren, 179/244 (73.4%) were infected with intestinal parasites. The presence of intestinal parasitosis was associated only with house flooding. Multivariate analysis identified that use of a latrine is significantly correlated with G. intestinalis and age six to 11 years with E. vermicularis. Signs and symptoms were recorded in 62% of infected children and in 57.9% of those not infected. Genomic amplification was revealed that 65.7% (46/70) of Giardia positive samples corresponded to genotype B, 31.4% (22/70) to genotype AII, and two samples (2.8%) had mixed infection (AII + B). CONCLUSIONS: This study shows a high percentage of infected children living in a suburban community in poor sanitary conditions, and not visiting the doctor in spite of evident signs and symptoms associated a digestive pathology. This situation supports the need for continuing the development of community programs allowing the improvement of quality of life and control of parasitosis in deprived populations. PMID- 21795822 TI - Molecular and serological assessment of parvovirus B19 infections among sickle cell anemia patients. AB - INTRODUCTION: Parvovirus B19 is a cause of hemolysis and red blood cell aplasia in patients with sickle cell anemia. The present study aimed to assess parvovirus B19 infection among sickle cell anemia patients. METHODOLOGY: All patients (n = 138) included in the study were sickle cell anemia patients. Blood donors were used as a control group. Assessment of parvovirus B19 antibodies and viral DNA was performed using established methods of detection and B19 recomBlot assay. RESULTS: Detectable levels of parvovirus B19 IgG were found in 52 samples (37.6%) whereas anti-parvovirus B19 IgM antibodies were detected in four (2.89 %) patients of the sickle-cell anemia group. Anti-B19 IgM-positive samples contained B19-viral DNA. These four patients presented with fever, malaise, pallor and no cutaneous rash. Anti-parvovirus B19 antibodies were detected in 22 (39.3%) of the control blood donors group. Anti-parvovirus B19 IgM antibodies were not detected in the control group. Using the recomBlot assay, 58 test samples (42%) were found to contain detectable levels of Parvovirus B19 antibodies. All the samples that were positive for parvovirus B19 IgG by the ELISA were also positive by the recomBlot assay. Six samples were only positive by the recomBlot assay and not by the ELISA. Two of these six samples were positive for B19 viral DNA. CONCLUSIONS: Establishing the extent of parvovirus B19 infection in sickle cell anemia patients will help in proper management of aplastic crisis in such patients. The B19 recomBlot assay may be suitable as a confirmatory assay. PMID- 21795823 TI - Cytokine levels in bronchoalveolar lavage and serum in 3 patients with 2009 Influenza A(H1N1)v severe pneumonia. AB - INTRODUCTION: Pandemic Influenza A (H1N1)v pneumonia has led to a notable increase of admissions to intensive care units. A cytokine-mediated inflammatory response has been well documented in pneumonia and acute respiratory distress syndrome. However, few studies have focused on the role of these inflammatory mediators in infections caused by the Influenza A (H1N1)v. In this study, we assess the inflammatory response mediated by cytokines at the local and systemic levels in three cases of severe pneumonia caused by Influenza A (H1N1) virus. METHODOLOGY: Serum and bronchoalveolar lavage samples were obtained from three mechanically ventilated patients diagnosed with Influenza A (H1N1) virus pneumonia by bronchoscopic bronchoalveolar lavage. Levels of interleukin 6 (IL 6), interleukin 8 (IL-8), tumour necrosis factor alpha (TNFalpha) and interleukin 1 beta (IL-1beta) were meassured in these samples by enzyme-linked immunosorbent assay (ELISA). RESULTS: High levels of C Reactive Protein, Procalcitonin below 1 ng/ml and absence of leukocytosis were common findings in all patients. TNFalpha and IL-1beta were not detected in the serum. IL-6 levels in serum were (94, pg/ml, 77 pg/ml and 84 pg/ml) respectively in the three patients, while IL-8 levels were (30,2 pg/ml, 128 pg/ml and 40,5 pg/ml). In the BAL samples, only one of the analysed cytokines, IL-1beta was present at detectable levels in two patients (21 pg/ml and 11 pg/ml respectively). CONCLUSIONS: Our results support previous findings which suggest that high levels of IL-6 and IL-8 in serum somehow participate in the inflammatory response in severe cases of pandemic influenza pneumonia. PMID- 21795824 TI - Tubercular spinal epidural abscess involving the dorsal-lumbar-sacral region without osseous involvement. AB - Musculoskeletal tuberculosis is known for its ability to present in various forms and guises at different sites. Tubercular spinal epidural abscess (SEA) is an uncommon infectious entity. Its presence without associated osseous involvement may be considered an extremely rare scenario. We present a rare case of tubercular SEA in an immune-competent 35-year-old male patient. The patient presented with acute cauda equina syndrome and was shown to have multisegmental SEA extending from D5 to S2 vertebral level without any evidence of vertebral involvement on MRI. The patient made an uneventful recovery following surgical decompression and antitubercular chemotherapy. The diagnosis was confirmed by histopathological demonstration of Mycobacterium tuberculosis in drained pus. Such presentation of tubercular SEA has not been reported previously in the English language based medical literature to the best of our knowledge. PMID- 21795825 TI - Membranous glomerulonephritis and tuberculous peritonitis: a rare association. AB - Membranous glomerulonephritis is rarely associated with tuberculosis infection. We report a case of a 24-year-old female with tuberculous peritonitis associated with membranous glomerulonephritis causing subnephrotic range proteinuria. Histological examination confirmed both diagnoses. The patient showed improvement with anti-tubercular drugs over six months of follow-up. PMID- 21795826 TI - Cutaneous Mycobacterium kansasii infection in a patient with AIDS post initiation of antiretroviral therapy. AB - The HIV pandemic has resulted in unique clinical presentations in patients, and their diagnosis and management pose challenges to physicians in the developing world. Due to limited resources and difficulties in laboratory diagnosis, most physicians treat according to the most likely etiological agent that might be causing the disease. In South Africa, when acid-fast bacilli are detected, anti tuberculous treatment is commenced. However, it must be realized that not all acid-fast bacilli are Mycobacterium tuberculosis, and that there are nontuberculous mycobacteria that can cause infections. Clinicians should work closely with the medical microbiologist when unique cases arise to ensure optimal microbial detection, identification, and patient management. This paper describes a very rare case of self-resolving cutaneous Mycobacterium kansasii infection following the initiation of antiretroviral therapy and potentially associated with immune reconstitution inflammatory syndrome. PMID- 21795827 TI - Chromoblastomycosis caused by Cladophialophora carrionii in a child from India. AB - Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissue. It usually occurs following trauma with vegetative matter and mainly affects middle-aged male agricultural workers. Only a few cases have been reported in children. The lesions commonly involve the lower limbs, while the upper limbs and face are only rarely affected. We report a case of cutaneous chromoblastomycosis of the left arm, caused by Cladophialophora carrionii, in a 9 year-old boy from India, who was earlier misdiagnosed as cutaneous tuberculosis. The patient showed a good response to treatment with itraconazole and terbinafine. PMID- 21795828 TI - Isolation of viable Helicobacter pylori in the tonsillar tissues of chronic tonsillitis patients. PMID- 21795830 TI - [Alternative antiandrogen therapy with flutamide in patients with castration resistant prostate cancer : a single center experience]. AB - Alternative Antiandrogen Therapy with Flutamide in Patients with Castration Resistant Prostate Cancer : A Single Center Experience We analyzed the clinical effects of flutamide (FLT) as a second-line agent for maximum androgen blockade (MAB) in patients with castration-resistant prostate cancer who received bicalutamide (BCL) as the first-line MAB agent. This study included 44 cases with progressive prostate cancer who had relapsed after first-line MAB, with BCL at 80 mg/day. After checking for antiandrogen withdrawal syndrome (AWS), they were given FLT at 375 mg/day as second-line MAB. A partial response (prostate-specific antigen [PSA] decline ?50%) and no change (PSA decline of 0-50% or increase <25%) by second-line MAB with FLT were achieved in 34.1% (15/44) and 25.0% (11/44), respectively. The median duration of PSA response was 8.2+/-4.5 months. In multivariate analysis, Gleason score (?7 vs ?8), the first-line response (CR vs PR+NC), and the second-line response (PR+NC vs PD) were significantly predictive of cause-specific survival from first-line hormonal therapy relapse to cancer death. Our results confirm previous findings that alternative antiandrogen therapy is effective as a second-line hormonal therapy. PMID- 21795831 TI - [Optimum initial dose of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia]. AB - We investigated the optimum initial dose and timing of administration of alpha1A adrenoceptor antagonist silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS). Ninety-eight patients were given a 4 mg dose after breakfast (group A), 4 mg after supper (group B), or 4 mg after breakfast and after supper (group C). At baseline, 4, 8 and 12 weeks after treatment, we assessed International Prostate Symptom Score (IPSS) and quality of life (QOL) index. Twenty-five percent or less improvement of total IPSS and no improvement of QOL index compared with baseline were defined as treatment failure at each evaluation point. Otherwise treatment was considered effective. In group A and group B, patients with treatment failure at 4 or 8 weeks after treatment, the dose of silodosin was increased to 8 mg daily. At the end of the study, 83 patients were evaluable. At 12 weeks after treatment, 20 of the 31 patients in group A and 22 of the 29 patients in group B remained on the 4 mg dose ; silodosin was effective in 65 and 76% of the patients, respectively. When patients with dose escalation were included, silodosin was effective in 81 and 90% of the patients, respectively. Silodosin was effective in 18 of the 23(78%) patients in group C, although improvement of total IPSS and voiding symptom score of IPSS at 12 weeks after treatment was better in group C than in group A or group B, the difference was not significant. In patients with IPSS less than 20, the degree of improvement of IPSS was similar among the 3 groups. In contrast, in patients with IPSS of 20 or greater the degree of improvement was better in group C than in group B or group C, but the difference was not significant. Storage symptom score of IPSS was significantly improved in all 3 groups without any significant difference among the 3 groups. Three patients (52, 59 and 76 years old) experienced abnormal ejaculation. In conclusion, 4 mg of silodosin daily showed effectiveness against BPH/LUTS, but 8 mg of silodosin daily might be better for patients with severe LUTS. PMID- 21795829 TI - Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis. AB - Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1beta and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA. PMID- 21795832 TI - [Retroperitoneal extraskeletal Ewing's sarcoma difficult to differentiate from adrenocortical carcinoma : a case report]. AB - A 15-year-old man complained of left upper abdominal distention. Ultrasonography, computed tomography, and magnetic resonance imaging (MRI) revealed a large multilocular tumor measuring 15*10*14 cm in the left retroperitoneal space. MRI showed the high intensity tumor on the T1 and T2 weighted images and enhanced septum above the left kidney. Positron emission tomography revealed high uptake(SUV max 7.9) in the marginal region. Because the left adrenal gland could not be identified on images, we diagnosed the tumor as adrenocortical carcinoma, preoperatively. In February 2010, tumor excision combined with left nephrectomy and adrenalectomy was performed via transperitoneal approach. Left adrenal gland was identified separately from the tumor, but a small tumor was observed in the gland. The pathological specimen showed sheet-like monotonous proliferation of small round cells which had glycogen. Immunostaining technique showed highly positive CD-99 and neuron specific enolase (NSE). Fluorescence in situ hybridization (FISH) showed translocation of EWS gene. Similar pathological findings were observed in the left adrenal tumor. We diagnosed the tumor as retroperitoneal extraskeletal Ewing' s sarcoma with metastasis to the left adrenal gland. Considering it a high risk, we started adjuvant VAIA(vincristine, dactinomycin, ifosfamide, and doxorubicin) chemotherapy soon after the operation. However, there was left retroperitoneal recurrence 9 months after the operation. We changed the chemotherapy regimen to gemcitabine and docetaxel and are continuing chemotherapy. PMID- 21795833 TI - [IgG4-related tubulointerstitial nephritis presented with multiple renal nodular lesions]. AB - A 66-year-old man presented with multiple bilateral renal nodular lesions demonstrated by enhanced computed tomographic scan. He had a history of autoimmune pancreatitis and renal cell carcinoma, which had been treated with partial nephrectomy. We performed renal biopsy under ultrasound guidance. Pathological examination revealed plasma cell infiltration to the renal interstitium. Serum IgG4 level was high and we diagnosed as IgG4-related tubulointerstitial nephritis. After one month of oral steroid therapy the multiple nodular lesions disappeared. PMID- 21795834 TI - [A case of giant hemorrhagic adrenal pseudocystectomy with a flank incision]. AB - The patient was a 43-year-old woman who underwent detailed examinations for a retroperitoneal cystic lesion that was incidentally found during orthopedic treatment. Although the tumor was a non-functioning tumor, and diagnostic imaging was negative for malignancy, the tumor was surgically resected with a flank incision. The histopathological diagnosis was adrenal pseudocyst. PMID- 21795835 TI - [Two cases of bladder cancer with hereditary nonpolyposis colorectal cancer]. AB - Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by an excess of extracolonic malignancies including those of the urinary tract. We report two cases of bladder tumor associated with HNPCC. The reported cases were compatible for Amsterdam criteria II for HNPCC. It is important to obtain a family history of cancer in patients with urothelial carcinoma. A patient with a strongly positive cancer history must be carefully examined for HNPCC and HNPCC associated cancers. PMID- 21795836 TI - [A case of emphysematous cystitis : a case report]. AB - Emphysematous cystitis is a rare lower urinary tract infection. A case of emphysematous cystitis with diabetes mellitus and transverse colon cancer is reported. The patient was an 81-year-old woman complaining of nausea and vomiting. Urinalysis showed hematopyuria. Plain abdominal film and CT scan showed gaseous shadow in the bladder wall. Urine culture contained Escherichia coli. A urethral catheterization and administration of antibiotics resulted in the marked improvement in the clinical course. To our knowledge, 53 cases of emphysematous cystitis have been reported in the Japanese literature including this case and the clinical features are reviewed. PMID- 21795837 TI - [Adenocarcinoma of the sigmoid segment 38 years after sigmoidcystoplasty : a case report]. AB - A 60-year-old woman presented at another hospital with a complaint of voiding difficulty. She had had left nephrectomy and bladder augmentation using the sigmoid colon for treatment of urinary tract tuberculosis 38 years ago. Left ovarian tumor was found by computed tomography and she was referred to our hospital. Another tumor which involved the uterus, bladder, and urethra was revealed by magnetic resonance imaging. An anterior pelvic exenteration was performed with preoperative diagnosis of left ovarian cancer with peritoneal dissemination. Histopathological examination revealed a clear cell adenocarcinoma of the left ovary and a sigmoid cancer arising in the augmented bladder. The sigmoid cancer arose from the anastomotic site between the bladder and sigmoid segment. This is the 34th case of neoplasms following augmentation enterocystoplasty reported in Japan. PMID- 21795838 TI - [A case of prostate cancer with disseminated carcinomatosis of bone marrow which responded to Zoledronic acid]. AB - A 76-year-old man underwent radical prostatectomy under the diagnosis of stage C prostate cancer (cT3bN0M0, Gleason score 3+4) in 1999. Endocrine treatment for postoperative biochemical failure started in 2001. He was admitted to our hospital because of general fatigue and multiple bone pain with a prostate specific antigen (PSA) level of 1,141 ng/ml in August 2009. On admission, no metastasis was detected on bone scintigraphy or computed tomography. Bone marrow biopsy was finally performed for the assessment of bone metastasis after PSA further increased to 8,679 ng/ml with the manifestation of severe anemia and thrombocytopenia. The biopsy findings disclosed disseminated carcinomatosis of bone marrow (DCBM). Treatment with Zoledronic acid (ZA) not only mitigated bone pain, but also rapidly improved of PSA and hematological findings. Although the prognosis of a patient with DCBM is generally considered to be very poor, ZA contributed to the improvement for the survival of the patient in the present case. PMID- 21795839 TI - [Prostatic neuroendocrine carcinoma with priapism : a case report]. AB - An 84-year-old man presented with priapism in May, 2009. At 79 years old, he was diagnosed with stage C prostate cancer and then, was treated with hormonal therapy. The serum level of prostate-specific antigen (PSA) was within the normal range (0.02 ng/ml). Penile caverno-dorsal vein shunt (Barry shunt) and caverno spongiosum shunt (Quackels shunt) were performed for the purpose of managing local symptoms. Following operation, the penile pain was mitigated. Postoperative computed tomography (CT) revealed the enlarged prostate and multiple metastases to lungs and multiple bone metastases. Histological examination of the prostatic needle biopsy revealed poorly differentiated neuroendocrine carcinoma of the prostate. PMID- 21795840 TI - [A cyst arising from tunica vaginalis testis : report of a case]. AB - A 38-year-old man presented with left intrascrotal painless mass. Ultrasound and magnetic resonance imaging (MRI) examinations demonstrated a cystic lesion at the upper side of left testis without enhancement. This mass gradually enlarged in size, and left high orchiectomy was planned. Because intraoperative finding showed a cyst arising from tunica vaginalis testis, excision of the cyst was performed. Histopathological examination showed a cyst with a fibrous wall lined with cuboidal endothelial cells without malignancy. To our knowledge, this is the 15th reported case of a benign cystic lesion in tunica vaginalis testis in Japan. The age distribution of patients showed two peaks ; one from 5 to 8 years old and the other from 30 to 69 years old. Most of the pediatric patients showed acute scrotal swelling with pain. On the other hand, most adult patients demonstrated painless scrotal swelling with slow growth. Operative investigation should be performed in cases with suspicion of malignancy. PMID- 21795841 TI - [A case of carcinosarcoma of the penis]. AB - A 64-year-old man presented with gross hematuria. Physical examination showed a mass under the phimotic foreskin. Circumcision revealed a 2cm polypoid tumor on the inner layer of prepuce. Tumor resection was performed and pathological diagnosis was carcinosarcoma which was composed of squamous cell carcinoma and spindle cell sarcoma. Biopsy of the scar lesions revealed residual squamous cell carcinoma and computed tomographic scan revealed swollen inguinal lymph nodes. Partial penectomy and lymph node biopsy were performed. Pathological examination revealed residual squamous cell carcinoma and no lymph node metastasis. There was no recurrence for one year. We report this very rare case of carcinosarcoma of the penis. PMID- 21795842 TI - Decreased plasma levels of ceruloplasmin after diet-induced weight loss in obese women. AB - BACKGROUND: Plasma ceruloplasmin (Cp) has been shown to be a risk factor for cardiovascular disease and also to be associated with obesity. However, it is not known whether weight loss could decrease the plasma Cp levels. AIM: To investigate the effect of diet-induced weight loss on plasma Cp in obese women. SUBJECTS AND METHODS: Sixty-seven healthy obese women [age =33.4+/-8.7 yr, body mass index (BMI) =36.0+/-4.8 kg/m2] were entered into a medically supervised program aimed at reducing body weight by 10% or more. Weight loss was achieved through a diet providing a daily energy deficit of 500-1000 kcal/day. In addition, all patients were prescribed to use 50 g of a fiber supplement per day. For all subjects, assessment of dietary intake, anthropometric indices, and plasma levels of C-reactive protein and Cp was performed at the first visit and repeated at 12th week of follow-up. RESULTS: By completing the program, weight (Delta=-9.5%, p<0.0001), BMI (Delta=-9.7%, p<0.0001), waist-circumference (Delta= 6.1%, p<0.0001), and triceps skinfold thickness (Delta=-14.9%, p<0.0001) significantly decreased. Plasma Cp significantly decreased after 12 weeks of dietary intervention (33.6+/-5.6 mg/dl vs 25.2+/-5.8 mg/dl, p<0.0001). Percent change in Cp was correlated with percent change in waist-circumference (r=446, p=0.015). CONCLUSION: Our study suggests that an improved body composition induced by restriction of energy intake is associated with decreased serum concentrations of Cp in obese women which in turn might have reduced the subjects' risk of developing cardiovascular disease. PMID- 21795843 TI - Pathogenic mechanism of mutations in the thyroid hormone receptor beta gene. AB - BACKGROUND: Resistance to thyroid hormone (RTH) is characterized by a variable degree of reduced tissue sensitivity to thyroid hormone (TH). It is usually caused by mutations in the TH receptor-beta (TRbeta) gene. AIMS: To characterize clinical and molecular features of a Thai patient with RTH. Functional significance of the identified mutation as well as other uncharacterized TRbeta mutations was also investigated. MATERIALS AND METHODS: Exons 3-10 of the TRbeta gene were assessed by PCR-sequencing. Functional characterization of the mutant TRbeta was determined by the luciferase reporter system. RESULTS: A mutation in exon 9 of the TRbeta gene resulting in a methionine to threonine substitution at codon 313 was identified. The functional consequence of this mutation and other uncharacterized known mutations (p.I276L, p.I280S, p.L330S, p.G344A, p.M442T) was evaluated by transfection studies. Four out of 6 had a significant impairment of T3-dependent transactivation. When co-transfected with the wild-type TRbeta, all exhibited a dominant negative effect. CONCLUSION: A de novo mutation was identified in the patient with clinical diagnosis of RTH. Our findings provide a strong support that interfering with the T3-mediated transcriptional activation of the wild-type TRbeta independent of the ability to activate transcription is a major pathogenic mechanism causing RTH. PMID- 21795844 TI - Increased prevalence of cardiovascular disease in Type 1 diabetic patients with non-alcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of cardiovascular disease (CVD) in both non-diabetic and Type 2 diabetic individuals. We sought to examine whether NAFLD is associated with prevalent CVD in patients with Type 1 diabetes. SUBJECTS AND METHODS: We studied 343 (156 men; mean age ~45 yr) consecutive Type 1 diabetic patients with and without NAFLD, which was diagnosed by ultrasonography. The presence of CVD was diagnosed by patient history, chart review, electrocardiogram, and echo Doppler scanning of carotid and lower limb arteries. RESULTS: Compared with those without steatosis, patients with ultrasound-diagnosed NAFLD (no.=182) had a remarkably greater age- and sex-adjusted prevalence of coronary (15.4 vs 1.2%, p<0.0001), cerebrovascular (41.7 vs 9.3%, p<0.0001) and peripheral (29.7 vs 6.2%, p<0.0001) vascular disease. A multivariable logistic regression analysis revealed that NAFLD was associated with an ~8-fold higher odds of CVD (composite endpoint), independently of age, sex, body mass index, family history of CVD, smoking status, physical activity, alcohol consumption, diabetes duration, glycated hemoglobin, systolic blood pressure, plasma lipids, estimated glomerular filtration rate, albuminuria, and use of anti-hypertensive, lipid-lowering and anti-platelet medications (adjusted odds ratio 7.6, 95% confidence intervals 3.6 24.0, p<0.001). CONCLUSIONS: Our results demonstrate that NAFLD is associated with an increased prevalence of asymptomatic/symptomatic CVD in patients with Type 1 diabetes, independently of several established risk factors, including the components of metabolic syndrome. PMID- 21795845 TI - Rad18 emerges as a critical regulator of the Fanconi anemia pathway. PMID- 21795846 TI - Letter from the editor. PMID- 21795847 TI - From pertussis to meningococcal disease and back. AB - From pertussis to meningococcal disease and back represents nearly 30 years of research at Porton, first at the Centre for Applied Microbiology and Research and latterly as part of the Health Protection Agency. I joined the group lead by Andy Robinson developing an acellular pertussis vaccine and was part of an exciting period that encompassed basic antigen characterisation and pathogenesis studies with the development of an acellular vaccine containing fimbriae. Research then changed to focus on serogroup B meningococcal disease, studying the vaccine potential of iron-regulated proteins and then Neisseria lactamica. The resurgence of pertussis seen in some countries alerted me to the lack of understanding of protective immune responses to Bordetella pertussis infection and disease and this is now an active area of research. PMID- 21795848 TI - Cost impact of complications in meningococcal disease: evidence from a United States managed care population. AB - OBJECTIVES: To compare health care utilization and associated costs among patients with and without invasive meningococcal disease (IMD)-related sequelae. METHODS: A retrospective analysis of an administrative claims database from 1998 2009 was performed. Patients with an IMD-related inpatient admission and continuous health plan enrollment selected and categorized by presence (complicated-IMD) or absence (uncomplicated-IMD) IMD-related sequelae during the follow-up year. Differences in the follow-up year healthcare utilization and costs between the two groups tested using univariate and multivariable analyses. RESULTS: We identified 173 patients; 41% had at least one diagnosis claim for IMD related sequelae. Significantly higher predicted total health care costs for complicated-IMD cases (mean: $72,101), compared with uncomplicated cases (mean: $41,883; P < 0.001). CONCLUSIONS: We observed significantly higher health care costs among complicated-IMD cases, compared with uncomplicated cases. The substantially higher costs observed among patients with IMD-related sequelae warrant inclusion of these costs in studies conducting economic evaluations of meningococcal vaccination programs. PMID- 21795850 TI - The role of Tecpr1 in selective autophagy as a cargo receptor. AB - Bacterial intrusion of host cells can be recognized by the innate immune system, including autophagy, via multiple cellular pathways. We have identified Tecpr1 as an Atg5-binding partner, and found that Tecpr1 interacts with the Atg12-Atg5 Atg16L1 complex via binding to Atg5. In Shigella infected cells, Tecpr1 colocalizes with Atg5 and LC3 at Shigella-containing phagophores. Tecpr1 activity is required for efficient autophagy to target bacteria, but a deficiency of Tecpr1 in host cells does not have a marked effect on canonical autophagy. Tecpr1 plays an important role in promoting selective autophagy via the WIPI-2-Tecpr1 Atg5 pathway in targeting bacteria, protein aggregates and damaged mitochondria. PMID- 21795849 TI - ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. AB - ULK1 (Unc51-like kinase, hATG1) is a Ser/Thr kinase that plays a key role in inducing autophagy in response to starvation. ULK1 is phosphorylated and negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that ULK1 is not only a downstream effector of mTORC1 but also a negative regulator of mTORC1 signaling. ( 1-3) Here, we investigated how ULK1 regulates mTORC1 signaling, and found that ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Deficiency or knockdown of ULK1 or its homolog ULK2 enhanced mTORC1 signaling, cell proliferation rates and accumulation of cell mass, whereas overexpression of ULK1 had the opposite effect. Knockdown of Atg13, the binding partner of ULK1 and ULK2, mimicked the effects of ULK1 or ULK2 deficiency or knockdown. Both insulin and leucine stimulated mTORC1 signaling to a greater extent when ULK1 or ULK2 was deficient or knocked down. In contrast, Atg5 deficiency did not have a significant effect on mTORC1 signaling and cell proliferation. The stimulatory effect of ULK1 knockdown on mTORC1 signaling occurred even in the absence of tuberous sclerosis complex 2 (TSC2), the negative regulator of mTORC1 signaling. In addition, ULK1 was found to bind raptor, induce its phosphorylation, and inhibit the kinase activity of mTORC1. These results demonstrate that ULK1 negatively regulates the kinase activity of mTORC1 and cell proliferation in a manner independent of Atg5 and TSC2. The inhibition of mTORC1 by ULK1 may be important to coordinately regulate cell growth and autophagy with optimized utilization of cellular energy. PMID- 21795852 TI - Reflections on the inhibition of RNAi by cell death signaling. AB - Mutations and most transgenes that induce ectopic cell death in Drosophila will produce an inhibitory effect on RNA interference (RNAi) in adjacent cells. When extensive cell death is sporadically induced using a heat shock promoted-head involution defective (hs-hid) transgene, molecular attributes of this inhibition can be studied. For a Green Fluorescent Protein (GFP) RNAi construct, cell death causes a greater accumulation of the mature mRNA and the double stranded RNA with an accompanying reduction in the homologous siRNAs. Endogenous transposable element expression is increased and there is an overall reduction in their corresponding siRNAs. The implications of this finding for the conduct of RNAi and potential reasons for its existence are discussed. PMID- 21795851 TI - Autophagy induction by tetrahydrobiopterin deficiency. AB - Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr(-/-) mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr(-/-) mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr(-/-) mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr(-/-) mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pah(enu2) mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH4 deficiency. PMID- 21795853 TI - Osteopontin increases breast cancer cell sensitivity to specific signaling pathway inhibitors in preclinical models. AB - Src kinase and Hsp90 play important roles in malignancy-promoting signaling pathways in a variety of cancers and related targeting agents are presently in clinical trials. To help improve the success of Src kinase and Hsp90 inhibitor therapies, identifying sensitive patient populations will be essential. Osteopontin (OPN), a secreted integrin-binding glycophosphoprotein, is associated with progression and metastasis in a variety of cancers and has been studied as a prognostic marker. Previous work of ours and other groups has indicated that OPN induced signal transduction involves activation of both Src and Hsp90-dependent pathways. We thus hypothesized that over-expression of OPN could make tumor cells more vulnerable to these classes of inhibitors. This study used multiple in vitro assays to determine if OPN levels could predict breast cancer cell sensitivity to Hsp90 and/or Src kinase inhibitors. We used multiple derivatives of two unrelated of human breast cancer cell lines, high vs. low levels of OPN, to determine if OPN affects the response to two specific inhibitors, an Hsp90 inhibitor and a Src kinase inhibitor, in in vitro migration and colony formation assays. Cells had greater decreases in migration and colony forming ability after Hsp90 and Src kinase inhibitor treatments when OPN was present (either endogenous or exogenous). Decreasing OPN levels via shRNA knockdown decreased inhibitor effects. In rescue experiments, adding exogenous OPN to non-expressing cells increased inhibitor effects. These results suggest that OPN could potentially be useful clinically as a predictive marker in identifying patients who will benefit from either Hsp90 or Src kinase inhibitor therapy. PMID- 21795854 TI - (Ctm)PrP and ER stress: a neurotoxic mechanism of some special PrP mutants. AB - The pathogenic agent is hypothesized to be PrP(Sc) in prion diseases. However, little accumulation of PrPSc is repeatedly observed in some kinds of natural and experimental prion diseases, including some special genetic human prion diseases. One of the specific topology forms of PrP, (Ctm)PrP, representing a key neurotoxic intermediate in prion disorders, has been testified in cell-free translation systems and transgenic mice models. Recently, some studies have showed that point-mutations within the hydrophobic transmembrane region increase the amount of (Ctm)PrP in cells, such as human homologue A117V which is associated with GSS and G114V associated with gCJD, while the mutations outsides transmembrane region do not. The retention of the CtmPrP in ER subsequently is able to induce ER stress and apoptosis, which is supported by up-regulation of ER chaperone synthesis, such as Grp78, Grp58, Grp94, Bip and the transcription factor CHOP/GADD153. In conclusion, some kinds of intermediate forms of PrP(Sc) , including (Ctm)PrP, may work as the ultimate cause of neurodegeneration. PMID- 21795856 TI - Nicotiana tabacum protoplasts secretome can evidence relations among regulatory elements of exocytosis mechanisms. AB - An alternative study involving proteome analysis of the 24 hour Nicotiana tabacum protoplast culture medium was performed with the aim to confirm relations among regulatory elements of exocytotic processes. Protoplasts present many convenient features to study cellular processes during transient over-expression or suppression of specific gene's products. We performed a proteomic analysis of the culture medium fraction of protoplasts transiently expressing transgenes for 24 hours to characterize the effect of various regulatory proteins dominant negative mutants. A total number of 49 spots were found reproducible in the medium. 24 of these spots were identified with nano RP-HPLC-ESI-MS/MS. Only three and six spots were respectively identified as canonical and non-canonical secreted cell wall proteins. The low number of spots present in the culture medium fraction allowed us the ambitious experiment to analyze the influence of various SNAREs (SYP121, SYP122, SNAP33) and Rab (Rab11) dominant negative mutants. Missing a reasonable number of identified proteins the analyses gave rise to a similarity matrix statistically analyzed considering variation within the presence of 24 spots reproducible in presence of transient over-expression of SNAREs (SYP121 and SYP122) and Rab11 native cDNAs. The similarity confirmed the closer relation between the function of SYP122 and Rab11 as evidenced by the secRGUS based analysis. This analysis included the effect of SNAP33 DN mutant and showed that this Qb-c-SNARE influence both SYP121 and SYP122 SNARE complexes. PMID- 21795855 TI - Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. AB - Poor prognosis cancers, such as pancreatic cancer, represent inherent challenges for ceramide-based nanotherapeutics due to metabolic pathways, which neutralize ceramide to less toxic or pro-oncogenic metabolites. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a bioactive lipid that is pro-apoptotic to many cancer cells, but not to normal cells. In this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide (Lip-C6) with either gemcitabine or an inhibitor of glucosylceramide synthase. We first assessed the biological effect of Lip-C6 in PANC-1 cells, a gemcitabine-resistant human pancreatic cancer cell line, and found that low doses alone did not induce cell toxicity. However, cytotoxicity was achieved by combining Lip-C6 with either non-toxic sub therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Furthermore, these combinations with Lip-C6 cooperatively inhibited PANC-1 tumor growth in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine did not. Furthermore, by including PDMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS3, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we have demonstrated that nanoliposomal ceramide can be an effective anti pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization. PMID- 21795857 TI - Putative molecular mechanisms underlying tandem CCCH zinc finger protein mediated plant growth, stress, and gene expression responses. AB - In animals, Tandem CCCH Zinc Finger (TZF) proteins control a variety of cellular processes via regulation of gene expression at transcriptional and post transcriptional levels. Plant-unique TZF proteins can also affect many aspects of plant growth, development, and stress responses. However, the molecular mechanisms underlying plant TZF function are unknown. The purpose of this short review is to provide an overview of genetic and molecular analyses of plant TZFs, and to speculate on their possible molecular functions. PMID- 21795858 TI - Insulin-like growth factor binding protein 7 exhibits tumor suppressive and vessel stabilization properties in U87MG and T98G glioblastoma cell lines. AB - Insulin-like growth factor binding protein 7 (IGFBP7) is downregulated in several solid cancers. IGFBP7 has been proposed to act as a tumor suppressor gene through mechanisms involving senescence and apoptotic pathways. The tumor suppressor effect of IGFBP7 in glioblastoma multiforme (GBM) was examined in this study using two human GBM cell lines, U87MG and T98G. Exogenously applied IGFBP7 (20 and 100 nM) significantly reduced U87MG (~70 and ~75%, respectively) and T98G (~37 and ~50%, respectively) cell growth in soft agar. IGFBP7 stimulated senescence-associated beta-galactosidase in both U87MG and T98G cells without stimulating apoptosis (annexin V and propidium iodide staining, expression of SMARCB1 or BNIP3L and caspase cleavage) or affecting phosphorylation of p44/42 MAPK. The inhibitory effect of IGFBP7 on U87MG cell growth was further assessed in vivo using U87MG cells grafted on the chick chorioallantoic membrane. In this model, U87MG cells formed solid and highly vascularized tumors that were reduced in size (~40%) when treated with 500 nM IGFBP7 compared with control tumors. Vessels in IGFBP7-treated tumors were clustered, unevenly distributed and associated with higher number of alpha-SMA positive cells compared with those in untreated tumors. IGFBP7 induced both aortic smooth muscle cell (AoSMC) chemoattraction and endothelial cell (EC) transdifferentiation into a SM-like cell phenotype. U87MG conditioned media-induced IGFBP7 expression in ECs was significantly inhibited by the cross-talk/interaction with SMCs. This study indicates that IGFBP7 suppresses U87MG tumor cell growth, induces cell senescence and participates in tumor vessel stabilization by promoting SMC/pericyte recruitment and differentiation. PMID- 21795859 TI - Monitoring transplanted islets by high-frequency ultrasound. AB - Islet transplantation is a cell replacement therapy to improve glycometabolic control in type 1 diabetic patients. Establishing methods to monitor engrafted islets, as well as the islet preparation, is important when performing islet transplantation. Since current imaging techniques are still not available to directly detect transplanted islets, we propose a novel method to visualize transplanted islets using high-frequency ultrasound (HF-US), and to evaluate the correlation between these US findings and metabolic parameters. We transplanted syngeneic (BALB/c mice) and xenogeneic (SD rats) islets into the renal subcapsular space of diabetic mice. The recipient mice were examined by HF-US until post-operative day (POD) 28 and, while syngeneic islets could be detected by HF-US throughout the observational period, the xenogeneic islets had vanished by POD 28. The islet volume calculated by HF-US was correlated with the number of transplanted islets (R(2) = 0.31, p = 0.0003) and the metabolic function of islets (blood glucose: R(2) = 0.15, p < 0.0001, serum insulin: R(2) = 0.22, p < 0.0001). In conclusion, HF-US may be a useful imaging modality for visualizing the islet mass in renal subcapsular transplantation models. It may also be an available modality for clinical settings in the future. PMID- 21795861 TI - Transfer of a motor fascicle from the ulnar nerve to the branch of the radial nerve destined to the long head of the triceps for restoration of elbow extension in brachial plexus surgery: technical case report. AB - BACKGROUND AND IMPORTANCE: Restoration of elbow extension has not been considered of much importance regarding functional outcomes in brachial plexus surgery; however, the flexion of the elbow joint is only fully effective if the motion can be stabilized, what can be achieved solely if the triceps brachii is coactivated. To present a novel nerve transfer of a healthy motor fascicle from the ulnar nerve to the nerve of the long head of the triceps to restore the elbow extension function in brachial plexus injuries involving the upper and middle trunks. CLINICAL PRESENTATION: Case 1 is a 32-year-old man sustaining a right brachial extended upper plexus injury in a motorcycle accident 5 months before admission. The computed tomography myelogram demonstrated avulsion of the C5 and C6 roots. Case 2 is a 24-year-old man who sustained a C5-C7 injury to the left brachial plexus in a traffic accident 4 months before admission. Computed tomography myelogram demonstrated signs of C6 and C7 root avulsion. The technique included an incision at the medial border of the biceps, in the proximal third of the involved arm, followed by identification of the ulnar nerve, the radial nerve, and the branch to the long head of the triceps. The proximal stump of a motor fascicle from the ulnar nerve was sutured directly to the distal stump of the nerve of the long head of the triceps. Techniques to restore elbow flexion and shoulder abduction were applied in both cases. Triceps strength Medical Research Council M4 grade was obtained in both cases. CONCLUSION: The attempted nerve transfer was effective for restoration of elbow extension in primary brachial plexus surgery; however, it should be selected only for cases in which other reliable donor nerves were used to restore elbow flexion. PMID- 21795860 TI - Context effect: microRNA-10b in cancer cell proliferation, spread and death. AB - Single microRNA (miRNA) can regulate expression of several or multiple principal targets in a specific microenvironment. In different cellular contexts, the same miRNA may exhibit diverse functions, depending on the repertoire and stoichiometry of its direct mRNA targets. For instance, in breast cancer, microRNA-10b (miR-10b) promotes invasion and metastasis of tumor cells through post-transcriptional regulation of HOXD10. In contrast, in glioblastoma (GBM), the most common and malignant primary brain tumor, miR-10b promotes proliferation and prevents death of cancer cells by targeting cell cycle inhibitors and pro apoptotic genes. Here, we discuss a unique role of miR-10b in cancer cell survival, in diverse tumor microenvironments. PMID- 21795863 TI - Carotid artery dissection-related intracranial aneurysm development: case report. AB - BACKGROUND AND IMPORTANCE: We analyzed the physiopathology of the association between cervical artery dissections (CADs), intracranial aneurysms (IAs), and aneurysmal subarachnoid hemorrhage. CLINICAL PRESENTATION: A 43-year-old woman presented with diffuse subarachnoid hemorrhage (Fisher 3; Hunt-Hess 1). computed tomography angiography revealed a cervical internal carotid artery dissection and 2 IAs: right paraclinoid and right posterior communicating artery. The patient underwent surgical clipping of the 2 aneurysms. CAD was managed conservatively. Postoperative course was initially uneventful. After 24 hours, digital subtraction angiography (DSA) documented the exclusion of the aneurysms and an improvement of the CAD. After 3 days, the patient's neurological condition suddenly worsened; CT scan documented a subarachnoid rebleeding (Hunt-Hess 4) and DSA revealed the recurrence of CAD and a new right internal carotid artery aneurysm. The patient underwent clipping of the new aneurysm and decompressive craniectomy because of severe brain swelling. Postoperative neurological conditions remained poor. DSA showed the exclusion of the aneurysms and improvement of CAD. Three days later, CT scan performed after a sudden raise in intracranial pressure documented a wide intracerebral hematoma. Computed tomography angiography did not show new vascular malformations. Surgical removal of the hematoma was performed, but poor neurological conditions persisted. CONCLUSION: CAD-related hemodynamic changes may play a role in the development of IAs. The presence of IAs must be screened carefully in case of CAD, because the dynamic behavior of CAD definitively increases the risk of IA formation, enlargement, and rupture. PMID- 21795862 TI - Cervical spine dural arteriovenous fistula with coexisting spinal radiculopial artery aneurysm presenting as subarachnoid hemorrhage: case report. AB - BACKGROUND AND IMPORTANCE: We present a patient with a cervical spine dural arteriovenous fistula associated with a radiculopial artery aneurysm at the same vertebral level presenting with subarachnoid hemorrhage. CLINICAL PRESENTATION: A 45-year-old Native American man presented with sudden-onset severe headache, lethargy, and right hemiparesis. Computed tomography (CT) of the head showed subarachnoid hemorrhage and hydrocephalus. A subsequent CT of the neck showed an anterior spinal subdural hematoma from C2 to C4 causing mild cord compression. Carotid and vertebral angiography failed to demonstrate an intracranial aneurysm, but showed a spinal dural arteriovenous fistula originating from the right vertebral artery at the C5 neuroforamen. The severity of the patient's symptoms, atypical for rupture of a dural arteriovenous fistula, prompted more thorough angiographic evaluation. Thus, injection of the right thyrocervical trunk was performed, demonstrating a 4-mm spinal radiculopial artery aneurysm. Following ventriculostomy, a hemilaminectomy from C4 to C7 was performed with disconnection of the fistula from its drainage system. Subsequent resection of the aneurysm, which was determined to be the cause of the hemorrhage, was accomplished. The patient improved neurologically and was discharged to rehabilitation. CONCLUSION: Spinal cord aneurysms from a separate vascular distribution may coexist with spinal dural arteriovenous fistulas. In the setting of spinal hemorrhage, especially in situations with an atypical clinical presentation, comprehensive imaging is indicated to rule out such lesions. PMID- 21795864 TI - Trapped fourth ventricle phenomenon following aneurysm rupture of the posterior circulation: case reports. AB - BACKGROUND AND IMPORTANCE: Cerebral ventricular noncommunication has been described in the setting of infection and acutely in the setting of intracranial hemorrhage. We describe the first adult case series of individuals who developed delayed isolated fourth ventricles after rupture of intracranial posterior circulation aneurysms and define treatment modality. CLINICAL PRESENTATION: A retrospective review was performed of all patients with aneurysms treated at a single institution from 2005 to 2009. Both microsurgical obliteration and endovascular cases were queried. Of 1044 aneurysms treated in this period, 3 patients were identified who required fourth ventricular shunting, for the treatment of the isolated ventricle. All 3 patients underwent microsurgical clip obliteration of their aneurysms and had subsequent frontal approach ventriculoperitoneal cerebrospinal fluid diversion. These patients had no evidence of infection of the cerebrospinal fluid as measured by serial cultures. Subsequently, all 3 patients presented in a delayed fashion with symptoms attributable to a dilated fourth ventricle and syringomyelia or syringobulbia. Either exploration or percutaneous tapping confirmed the function of the supratentorial shunt. These patients then underwent fourth ventriculoperitoneal cerebrospinal fluid diversion by the use of a low-pressure shunt system. The symptoms attributable to the isolated fourth ventricle resolved rapidly in all 3 patients after shunting. This clinical improvement correlated with the fourth ventricular size. CONCLUSION: Isolated fourth ventricle, in an adult, is a rare phenomenon associated with intracranial posterior circulation aneurysm rupture treated with microsurgical clip obliteration. Fourth ventriculoperitoneal cerebrospinal fluid diversion is effective at resolving the symptoms attributed to the trapped ventricle and associated syrinx. PMID- 21795865 TI - Primary benign brachial plexus tumors: an experience of 115 operated cases. AB - Primary benign brachial plexus tumors are rare. They pose a great challenge to the neurosurgeon, because the majority of patients present with minimal or no neurological deficits. Radical to complete excision of the tumor with preservation of neurological function of the involved nerve is an ideal surgical treatment option with benign primary brachial plexus tumor surgery. We present a review article of our 10-year experience with primary benign brachial plexus tumors surgically treated at King Edward Memorial Hospital and P.D. Hinduja National Hospital from 2000 to 2009. The clinical presentations, radiological features, surgical strategies, and the eventual outcome following surgery are analyzed, discussed, and compared with available series in the world literature. Various difficulties and problems faced in the management of primary benign brachial plexus tumors are analyzed. Irrespective of the tumor size, the indications for surgical intervention are also discussed. The goal of our study was to optimize the treatment of patients with benign brachial plexus tumors with minimal neurological deficits. It is of paramount importance that brachial plexus tumors be managed by a peripheral nerve surgeon with expertise and experience in this field to minimize the neurological insult following surgery. PMID- 21795866 TI - Multicenter analysis of stenting in symptomatic intracranial atherosclerosis. AB - BACKGROUND: Stenting for symptomatic intracranial atherosclerotic disease is a therapeutic option in patients in whom medical therapy fails. OBJECTIVE: To determine the periprocedural complication rates and mid-term restenosis rates in patients treated with balloon-expandable stents (BESs) compared with self expanding stents (SESs). METHODS: A retrospective review of consecutive patients treated with intracranial stents at 5 institutions was performed. Predictors of 30-day stroke and death as well as mid-term restenosis rates were analyzed. RESULTS: A total of 670 lesions were treated in 637 patients with a mean age of 57 +/- 13 years. A total of 454 lesions (68%) were treated with BESs and 216 lesions (32%) with SESs. The overall 30-day periprocedural complication rate was 6.1%, without any difference noted between the 2 groups. Patients treated within 24 hours of the index event were significantly more likely to have experienced a periprocedural complication (odds ratio [OR], 4.0; 95% confidence interval [CI]: 1.7-6.7; P < .007), whereas focal lesions were less likely to have a complication (OR, 0.31; 95% CI: 0.13-0.72; P < .001). Midterm restenosis was less likely in patients with a lower percentage of posttreatment stenosis (OR, 0.97; 95% CI: 0.95-0.99; P < .006), which was more common in BES-treated patients and focal concentric lesions (OR, 0.33; 95% CI: 0.23-0.55; P < .0001). CONCLUSION: BESs have periprocedural complication rates similar to those of SESs. Less posttreatment stenosis was associated with lower rates of mid-term restenosis. Future randomized trials comparing BESs and SESs may help to identify the stent type that is safest and most durable. PMID- 21795867 TI - Prehospital medical documentation in the Joint Theater Trauma Registry: a retrospective study. AB - BACKGROUND: Prehospital care of combat casualties is a critical phase of emergency medical practice on the battlefield. The Joint Theater Trauma Registry (JTTR) was developed to standardize a system of data collection for combat casualty care; however, the degree of population and granularity of prehospital data were unknown. METHODS: This is a retrospective comparative study of all US military personnel who sustained battle injuries in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). The JTTR was queried for all US military battle casualties from OIF and OEF entered between January 2002 and July 2009 containing any data entered into the prefacility fields. Data were separated based on origination, OIF, or OEF. A comparative analysis was performed. RESULTS: During the period studied, 13,080 (66%) entries into the JTTR were recorded in the category of "Battle Injury" and met study inclusion criteria; 3,187 (24%) battle injury entries contained prehospital data (n = 3,187). The percentage of casualty records containing prehospital data were 18.6% for OEF and 25.4% for OIF (p < 0.01). CONCLUSION: Both poor population of data points and poor granularity of prehospital data entered into the JTTR were observed. It appears that the volume and quality of reporting of role-I data were better for OIF than OEF for this study period. Further investigations into the obstacles to free flow of role I casualty clinical data, and the means to mitigate this situation, are warranted. PMID- 21795868 TI - Analysis of life-saving interventions performed by out-of-hospital combat medical personnel. AB - BACKGROUND: To analyze casualties from the Camp Eagle Study, focusing on life saving interventions (LSI) and potentially survivable deaths. METHODS: Retrospective cohort of battle casualties from a forward base engaged in urban combat in Central Iraq. Medical support included emergency medicine practitioners and combat medics with advanced training and protocols. LSI were defined as advanced airway, needle or tube thoracostomy, tourniquet, and hypotensive resuscitation with Hetastarch. Cases were assessed retrospectively for notional application of a Remote Damage Control Resuscitation protocol using blood products. RESULTS: Three hundred eighteen subjects were included. The case fatality rate was 7%. "Urgent" (55) or "priority" (88) medical evacuation was required for 45% of casualties. Sixty-one LSI were performed, in most cases by the physician or PA, with 80% on "urgent" and 9% on "priority" casualties, respectively. Among survivors requiring LSI, the percentage actually performed were airway 100%; thoracostomy 100%; tourniquet 100%; hetastarch 100%. Among nonsurvivors, these percentages were 78%, 50%, 100%, and 56%, respectively. Proximate causes of potentially survivable death were delays in airway placement and ventilation (40%), no thoracostomy (20%), and delayed evacuation resulting in hemorrhagic shock (60%). The notional Remote Damage Control Resuscitation protocol would have been appropriate in 15% of "urgent" survivors and in 26% of nonsurvivors. CONCLUSION: LSI were required by most urgent casualties, and a lack or delay in their performance was associated with increased mortality. Forward deployment of blood components may represent the next addition to LSI if logistical and scope-of-practice issues can be overcome. PMID- 21795869 TI - Use of ultra rapid opioid detoxification in the treatment of US military burn casualties. AB - BACKGROUND: The purpose of this case series was to review the management of burn patients who requested ultrarapid opioid detoxification under anesthesia after extended duration of narcotic use for chronic pain related to burn injury. METHODS: The treatment plan of six opioid-dependent burn patients was analyzed to assess the effectiveness of our detoxification practice to date. Demographic and clinical information was used to characterize the patient population served: age, burn size, injury severity, duration of narcotic use before detoxification intervention, and length of hospitalization stay. Daily narcotic consumption, in morphine equivalent units, was noted both before and after detoxification. RESULTS: Six burn patients (average age, 31 years) underwent detoxification at the Burn Center during a hospitalization lasting between 1 day and 2 days. Average burn size was 38% total body surface area (range, 17-65); average Injury Severity Score was 30 (range, 25-38). Mean duration of narcotic use was 672 days (range, 239-1,156 days); average use of narcotics at time of detoxification was >200 units daily. Mean outpatient consumption for opioids after the intervention was minimal (<25 units/d). No complications were noted during any procedures. CONCLUSIONS: The results of ultrarapid opioid detoxification under anesthesia suggests that it is safe and effective for treating opioid addiction in military burn casualties when a coordinated, multidisciplinary approach is used. Safety and effectiveness to date validate current practice and supports incorporation into clinical practice guidelines. Further clinical research is warranted to identify those patients who may benefit most from detoxification and to determine the timing of such treatment. PMID- 21795870 TI - Return to running and sports participation after limb salvage. AB - BACKGROUND: The ability to return to running and sports participation after lower extremity limb salvage has not been well documented previously. Although the ability to ambulate without pain or assistive devices is generally a criteria for a good limb salvage outcome, many patients at our institution have expressed a desire to return to a more athletic lifestyle to include running and sports participation. The purpose of this study was to investigate the types of athletic endeavors our high-energy lower extremity trauma patients were able to pursue after limb salvage. METHODS: We retrospectively analyzed lower extremity limb salvage patients who were at least 12 weeks status after external fixation removal and participated in our limb salvage return-to-running clinical pathway. Patients were rehabilitated to their highest functional level through a sports medicine-based approach. A custom energy-storing ankle-foot orthosis was implemented to help augment plantarflexion strength in conjunction with running gait retraining. RESULTS: The first 10 patients to complete the clinical pathway were identified. All patients were treated at the same institution by the same orthopedic surgeon and physical therapist. Eight patients have returned to running, and 10 patients have returned to weight-lifting. Seven patients have returned to cycling, three have returned to golf, three to basketball, and two to softball. Two patients have completed a mini-triathlon. CONCLUSION: Aggressive rehabilitation, an energy-storing ankle-foot orthosis, and running gait retraining can restore an active recreational lifestyle to patients who have undergone lower extremity limb salvage. PMID- 21795871 TI - Development of a standard swine hemorrhage model for efficacy assessment of topical hemostatic agents. AB - BACKGROUND: The diverse information of efficacy of hemostatic products, obtained from different military laboratories using different models, has made it difficult to ascertain the true benefit of new hemostatic agents in military medicine. The aim of this study was to recommend a standard hemorrhage model for efficacy testing acceptable by most investigators in the field and avoid contradictory and duplicative efforts by different laboratories. METHODS: The swine femoral artery injury model (6-mm arteriotomy) with some modifications was tested to standardize the model. The suggested modifications included no splenectomy, one-time treatment, 30 seconds free bleeding, and 5 L limit for fluid resuscitation. The model was tested with all or some of these modifications in four experimental conditions (n = 5-6 pigs per condition) using Combat Gauze (CG) as control agent. RESULTS: The primary end points including blood pressure, blood loss, and survival rates were modestly changed in the four conditions. The second experimental condition in which bleeding was treated with a single CG with 3-minute compression produced the most suitable results. The average blood loss was 99 mL/kg, and hemostasis was achieved in one-third of the pigs, which led to matching survival rate. CONCLUSION: A rigorous hemorrhage model was developed for future evaluation of new hemostatic agents and comparison with CG, the current standard of care. This model may not be suitable for testing every agent and some modifications may be necessary for specific applications. Furthermore, laboratory studies using this or similar models must be accompanied by operational testing in the field to confirm the efficacy and practical utility of selected agents when used on the battlefield. PMID- 21795872 TI - Silver dressings augment the ability of negative pressure wound therapy to reduce bacteria in a contaminated open fracture model. AB - BACKGROUND: Despite a lack of evidence supporting their use, silver dressings are often used with negative pressure wound therapy (NPWT). This study investigates the effectiveness of silver dressings to reduce bacteria in contaminated wounds when used with NPWT. METHODS: Complex orthopedic wounds were created on the proximal left legs of anesthetized goats. The wounds were inoculated with either a strain of bioluminescent Pseudomonas aeruginosa or Staphylococcus aureus. These bacteria are genetically modified to emit photons, thereby allowing quantification of bacterial concentration with a photon-counting camera system. The wounds were debrided 6 hours after inoculation and were treated with silver impregnated gauze combined with NPWT. Repeat debridements were performed every 48 hours for 6 days. Imaging was performed pre- and postdebridement. These results were compared with standard NPWT controls that used dressings without silver. RESULTS: There were fewer bacteria in the silver groups than the standard NPWT groups at 6 days. In the groups that were inoculated with P. aeruginosa, wounds in the silver group contained 21% +/- 5% of baseline bacterial load compared with 43% +/- 14% in the standard NPWT group. The addition of the silver dressings has a more pronounced effect on Staphylococcus. Wounds in the silver group contained 25% +/- 8% of baseline bacterial load compared with 115% +/- 19% in the standard NPWT group. CONCLUSIONS: The use of silver dressings with NPWT is a fairly common practice with limited literature to support its use in contaminated wounds. This study demonstrates that the addition of a silver dressing to NPWT effectively reduces bacteria in contaminated wounds and is more beneficial on the gram positive bacteria. These data support the use of silver dressings in contaminated wounds, particularly ones contaminated by S. aureus. PMID- 21795873 TI - A novel multicenter preclinical drug screening and biomarker consortium for experimental traumatic brain injury: operation brain trauma therapy. PMID- 21795874 TI - Decay-accelerating factor mitigates controlled hemorrhage-instigated intestinal and lung tissue damage and hyperkalemia in swine. AB - BACKGROUND: Activation of complement system has been associated with tissue injury after hemorrhage and resuscitation in rats and swine. This study investigated whether administration of human recombinant decay-accelerating factor (DAF; a complement regulatory protein that inhibits classical and alternative pathways) reduces tissue damage in a porcine model of hemorrhagic shock. METHODS: Male Yorkshire swine assigned to four groups were subjected to controlled, isobaric hemorrhage over 15 minutes to a target mean arterial pressure of 35 mm Hg. Hypotension was maintained for 20 minutes followed by a bolus intravenous injection of DAF or vehicle and then animals were observed for 200 minutes. Blood chemistry and physiologic parameters were recorded. Tissue samples from lung and small intestine were subjected to histopathological evaluation and detection of tissue deposition of complement proteins by immunohistochemistry and Western blot analyses. RESULTS: Administration of DAF significantly reduced intestinal and lung tissue damage in a dose-dependent manner (5, 25, and 50 MUg/kg). In addition, DAF treatment improved hemorrhage induced hyperkalemia. The protective effects of DAF appear to be related to its ability to reduce tissue complement activation and deposition on affected tissues. CONCLUSIONS: DAF treatment decreased tissue complement activation and deposition in hemorrhaged animals and attenuated tissue damage at 200 minutes after treatment. The observed beneficial effects of DAF treatment on tissue injury after 20 minutes of severe hypotension presents an attractive model of small volume resuscitation, particularly in situations with a restrictive medical logistical footprint such as far-forward access to first responders in the battlefield or in remote rural or mountainous environments. PMID- 21795876 TI - Died of wounds on the battlefield: causation and implications for improving combat casualty care. AB - BACKGROUND: Understanding the epidemiology of death after battlefield injury is vital to combat casualty care performance improvement. The current analysis was undertaken to develop a comprehensive perspective of deaths that occurred after casualties reached a medical treatment facility. METHODS: Battle injury died of wounds (DOW) deaths that occurred after casualties reached a medical treatment facility from October 2001 to June 2009 were evaluated by reviewing autopsy and other postmortem records at the Office of the Armed Forces Medical Examiners (OAFME). A panel of military trauma experts classified the injuries as nonsurvivable (NS) or potentially survivable (PS), in consultation with an OAFME forensic pathologist. Data including demographics, mechanism of injury, physiologic and laboratory variables, and cause of death were obtained from the Joint Theater Trauma Registry and the OAFME Mortality Trauma Registry. RESULTS: DOW casualties (n = 558) accounted for 4.56% of the nonreturn to duty battle injuries over the study period. DOW casualties were classified as NS in 271 (48.6%) cases and PS in 287 (51.4%) cases. Traumatic brain injury was the predominant injury leading to death in 225 of 271 (83%) NS cases, whereas hemorrhage from major trauma was the predominant mechanism of death in 230 of 287 (80%) PS cases. In the hemorrhage mechanism PS cases, the major body region bleeding focus accounting for mortality were torso (48%), extremity (31%), and junctional (neck, axilla, and groin) (21%). Fifty-one percent of DOW casualties presented in extremis with cardiopulmonary resuscitation upon presentation. CONCLUSIONS: Hemorrhage is a major mechanism of death in PS combat injuries, underscoring the necessity for initiatives to mitigate bleeding, particularly in the prehospital environment. PMID- 21795875 TI - Infection-associated clinical outcomes in hospitalized medical evacuees after traumatic injury: trauma infectious disease outcome study. PMID- 21795877 TI - The severity of oral/facial problems treated in Iraq March 2008 to February 2009. AB - BACKGROUND: The objective of this study was to describe the severity of oral/facial problems occurring in Navy and Marine Corps personnel deployed to Iraq. METHODS: Data documented by Navy Dental Officers deployed to Iraq were used to determine the number and type of oral/facial problems treated and to determine the percentages of severe, moderately severe, and pain/loss of function oral/facial problems treated in Iraq from March 2008 through February 2009. RESULTS: During the year of data collection, a total of 13,933 dental visits were documented for Navy and Marine Corps personnel. Of these, 1,641 were encounters to treat an oral/facial problem in Navy and Marine Corps personnel. In all, 37 (2.2%) of the 1,641 encounters for oral/facial problems were considered severe, 266 (16.2%) moderately severe, and 1,338 (81.5%) were for pain/loss of function. CONCLUSIONS: Although the majority of military personnel with oral/facial problems experience mild to moderate pain or loss of dental function, approximately 20% are of sufficient severity to cause the warfighter to experience a limitation of their operational capability. PMID- 21795878 TI - Infectious complications and soft tissue injury contribute to late amputation after severe lower extremity trauma. AB - BACKGROUND: Although most combat-related amputations occur early for unsalvageable injuries, >15% occur late after reconstructive attempts. Predicting which patients will abandon limb salvage in favor of definitive amputation has not been explored. The purpose of this study was to identify factors contributing to late amputation for type III open tibia fractures sustained in combat. METHODS: Operative databases were reviewed to identify all combat-related type III open diaphyseal tibia fractures from March 2003 to September 2007. Patients were categorized based on their definitive treatment: group I, limb salvage; group II, early amputation (<12 weeks postinjury); group III, late amputation (>= 12 weeks postinjury). Injury, treatment, and complication data were extracted from medical records and compared across groups. RESULTS: We identified 213 consecutive fractures, including 166 (77.9%) treated definitively with limb salvage, 36 (16.9%) with early amputation, and 11 (5.2%) with late amputation. There was no difference in fracture severity among the three groups. Before amputation, group III was more likely to use autograft and bone morphogenic protein (27.3%), compared with group I (4.8%) and group II (0%), and was more likely to undergo rotational flap coverage (45.5%), compared with group II (0%). Group III patients had the highest average number of revision surgeries and rate of deep soft tissue infection and were more likely to have osteomyelitis (54.5%) before amputation compared with group I (13.9%) and group II (16.7%). CONCLUSION: Patients definitively managed with late amputation were more likely to have soft tissue injury requiring flap coverage and have their limb salvage course complicated by infection. PMID- 21795879 TI - Multidrug-resistant bacterial colonization of combat-injured personnel at admission to medical centers after evacuation from Afghanistan and Iraq. AB - BACKGROUND: Multidrug-resistant organism (MDRO) infections, including those secondary to Acinetobacter (ACB) and extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae (Escherichia coli and Klebsiella species) have complicated the care of combat-injured personnel during Operations Iraqi Freedom and Enduring Freedom. Data suggest that the source of these bacterial infections includes nosocomial transmission in both deployed hospitals and receiving military medical centers (MEDCENs). Admission screening for MDRO colonization has been established to monitor this problem and effectiveness of responses to it. METHODS: Admission colonization screening of injured personnel began in 2003 at the three US-based MEDCENs receiving the majority of combat-injured personnel. This was extended to Landstuhl Regional Medical Center (LRMC; Germany) in 2005. Focused on ACB initially, screening was expanded to include all MDROs in 2009 with a standardized screening strategy at LRMC and US-based MEDCENs for patients evacuated from the combat zone. RESULTS: Eighteen thousand five hundred sixty of 21,272 patients admitted to the 4 MEDCENs in calendar years 2005 to 2009 were screened for MDRO colonization. Average admission ACB colonization rates at the US-based MEDCENs declined during this 5-year period from 21% (2005) to 4% (2009); as did rates at LRMC (7-1%). In the first year of screening for all MDROs, 6% (171 of 2,989) of patients were found colonized at admission, only 29% (50) with ACB. Fifty-seven percent of patients (98) were colonized with ESBL-producing E. coli and 11% (18) with ESBL-producing Klebsiella species. CONCLUSIONS: Although colonization with ACB declined during the past 5 years, there seems to be replacement of this pathogen with ESBL-producing Enterobacteriaceae. PMID- 21795880 TI - Infections complicating the care of combat casualties during operations Iraqi Freedom and Enduring Freedom. AB - BACKGROUND: Continued assessment of casualty complications, such as infections, enables the development of evidence-based guidelines to mitigate excess morbidity and mortality. We examine the Joint Theater Trauma Registry (JTTR) for infections and potential risk factors, such as transfusions, among Iraq and Afghanistan trauma patients. METHODS: JTTR entries from deployment-related injuries with completed records between March 19, 2003, and April 13, 2009, were evaluated using International Classification of Diseases-9 codes for infections defined by anatomic/clinical syndromes and/or type of infecting organisms. Risk factors included mechanisms of injury, patient demographics, Injury Severity Score (ISS), and transfusion, including massive transfusions (>= 10 units of packed red blood cells). RESULTS: We reviewed 16,742 patients entries (15,021 from Operation Iraqi Freedom (9,883 battle injuries [BI]) and 1,721 from Operation Enduring Freedom (1,090 BI). A total of 96.6% were men and 77.6% were Army personnel. The majority of BI were due to explosive devices (36.3%). There were 921 patients (5.5%) who had one or more infection codes with only 111 (0.6%) recorded deaths (16 with infections). Infections were commonly gram-negative bacteria (47.6%) involving skin/wound infections (26.7%), and lung infections (14.6%). Risk factors or associations that were most notable in univariate and multivariate analysis were calendar year of trauma, ISS, and pattern of injury. CONCLUSION: The 5.5% infection rate is consistent with previous military and civilian trauma literature; however, with the limitations of the JTTR, the infection rate is likely an underrepresentation due to inadequate level V and long-term infectious complications data. Combat operational trauma is primarily associated with gram negative bacteria typically involving infections of wounds or other skin structures and lung infections such as pneumonia. They are commonly linked with higher ISS and injuries to the head, neck, and face. PMID- 21795881 TI - Mechanism of injury affects acute coagulopathy of trauma in combat casualties. AB - BACKGROUND: Recent evidence suggests trauma involving total body tissue damage increases the acute coagulopathy of trauma (ACOT) by various mechanisms, especially in massive transfusion (MT). Our hypothesis was that MT patients injured by explosion will have a higher international normalization ratio (INR) at admission than MT patients injured by gunshot wound (GSW). METHODS: A retrospective review was performed on US military injured in Operation Iraqi Freedom/Operation Enduring Freedom from March 2003 to September 2008, who received MT (>= 10 red blood cells in 24 hours) and had an INR on admission. Two cohorts were created based on mechanism. Admission vital signs, labs, transfusion, and mortality data were compared. RESULTS: Seven hundred fifty-one MT patients were identified. Four hundred fifty patients had admission INR and were injured by either GSW or explosion. Patients demonstrated similar injury severity scale and Glasgow Coma Scale. Patients injured by explosion presented with higher INR, greater base deficit, and more tachycardic than patients injured by GSW. Transfusion of blood products was similar between both groups. CONCLUSIONS: The primary finding of this study is that patients injured by explosion presented with a higher INR than those injured by GSW, even with similar injury severity scale. In addition, patients injured by explosion presented more tachycardic and with a greater base deficit. These findings support the theory that ACOT is affected by the amount of tissue injured. Further research is needed into the pathophysiology of ACOT because this may impact care of patients with total body tissue damage/hypoxia and improve the treatment of their coagulopathy while minimizing the attendant complications. PMID- 21795882 TI - Severity of head injury is associated with increased risk of coagulopathy in combat casualties. AB - BACKGROUND: Traumatic brain injury (TBI) is believed to cause more profound trauma-induced coagulopathy than other injuries of comparable severity. This has not been reported in a large series of combat casualties in which penetrating injuries predominate. METHODS: Among US combat casualties severely injured in Iraq and Afghanistan who received transfused blood products, isolated TBI patients (head Abbreviated Injury Score [AIS] >= 3 and all other AIS <2) were compared with non-TBI patients (head AIS <= 2 and any other AIS >= 3) to determine the degree to which TBI is associated with coagulopathy as measured by International Normalized Ratio (INR) and to describe characteristics of this population. Stepwise multiple regression analysis was also performed on all US casualties who received transfused blood products to analyze independent predictors of coagulopathy. RESULTS: We compared 117 patients with isolated TBI and 1,492 patients with non-TBI injuries. Admission INR was significantly higher in TBI patients. There were no differences in age, admission base deficit, systolic or diastolic blood pressure, or hemoglobin. On stepwise multiple regression, base deficit, Glasgow Coma Scale, and head AIS score were independently associated with increased coagulopathy as measured by INR. CONCLUSION: Patients with severe combat-related trauma and isolated TBI had worse coagulopathy than non-TBI patients. Base deficit, Glasgow Coma Scale, and severity of head injury, as reflected by head AIS, are independently associated with increased coagulopathy as measured by INR. PMID- 21795883 TI - Impact of improved combat casualty care on combat wounded undergoing exploratory laparotomy and massive transfusion. AB - BACKGROUND: Studies have shown decreased mortality after improvements in combat casualty care, including increased fresh frozen plasma (FFP):red blood cell (RBC) ratios. The objective was to evaluate the evolution and impact of improved combat casualty care at different time periods of combat operations. METHODS: A retrospective review was performed at one combat support hospital in Iraq of patients requiring both massive transfusion (>= 10 units RBC in 24 hours) and exploratory laparotomy. Patients were divided into two cohorts based on year wounded: C1 between December 2003 and June 2004, and C2 between September 2007 and May 2008. Admission data, amount of blood products and fluid transfused, and 48 hour mortality were compared. Statistical significance was set at p < 0.05. RESULTS: There was decreased mortality in C2 (47% vs. 20%). Patients arrived warmer with higher hemoglobin. They were transfused more RBC and FFP in the emergency department (5 units +/- 3 units vs. 2 units +/- 2 units; 3 units +/- 2 units vs. 0 units +/- 1 units, respectively) and received less crystalloid in operating room (3.3 L +/- 2.2 L vs. 8.5 L +/- 4.9 L). The FFP:RBC ratio was also closer to 1:1 in C2 (0.775 +/- 0.32 vs. 0.511 +/- 0.21). CONCLUSIONS: The combination of improved prehospital care, trauma systems approach, performance improvement projects, and improved transfusion or resuscitation practices have led to a 50% decrease in mortality for this critically injured population. We are now transfusing blood products in a ratio more consistent with 1 FFP to 1 RBC. Simultaneously, crystalloid use has decreased by 61%, all of which is consistent with hemostatic resuscitation principles. PMID- 21795884 TI - Tranexamic acid for trauma patients: a critical review of the literature. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot break-down rather than promoting new clot formation. TXA has been used around the world to safely control bleeding since the 1960s. A large randomized trial recently conducted in >20,000 trauma patients adds to the large body of data documenting the usefulness of TXA in promoting hemostasis. METHODS: We reviewed the literature describing use of TXA in a variety of settings including trauma. RESULTS: TXA has been safely used across a wide range of clinical settings to control hemorrhage. The results of a large, randomized, placebo-controlled trial support the use of TXA to treat bleeding trauma patients. CONCLUSIONS: This inexpensive and safe drug should be incorporated into trauma clinical practice guidelines and treatment protocols. Further research on possible alternate mechanisms of action and dosing regimens for TXA should be undertaken. Concurrent to these endeavors, TXA should be adopted for use in bleeding trauma patients because it is the only drug with prospective clinical evidence to support this application. PMID- 21795885 TI - Closing the "care in the air" capability gap for severe lung injury: the Landstuhl Acute Lung Rescue Team and extracorporeal lung support. AB - BACKGROUND: The success of US Air Force Critical Care Air Transport Teams (CCATT) in transporting critically ill and injured patients enabled changes in military medical force deployment and casualty care practice. Even so, a subset of casualties remains who exceed even CCATT capabilities for movement. These patients led to the creation of the Landstuhl Acute Lung Rescue Team (ALeRT) to close the "care in the air" capability gap. METHODS: The ALeRT Registry was queried for the period between November 1, 2005, and June 30, 2010. Additionally, Landstuhl Regional Medical Center critical care patient transfers to host nation medical centers were reviewed for cases using extracorporeal lung support systems. RESULTS: For the review period, US Central Command activated the ALeRT on 40 occasions. The ALeRT successfully evacuated patients on 24 of 27 missions launched (89%). Three patients were too unstable for ALeRT evacuation. Of the 13 remaining activations, four patients died and nine patients improved sufficiently for standard CCATT movement. The ALeRT initiated pumpless extracorporeal lung assistance six times, but only once to facilitate evacuation. Two patients were supported with full extracorporeal membrane oxygenation support after evacuation due to progressive respiratory failure. CONCLUSIONS: ALeRT successfully transported 24 casualties from the combat zones to Germany. Without the ALeRT, these patients would have remained in the combat theater as significant consumers of limited deployed medical resources. Pumpless extracorporeal lung assistance is already within the ALeRT armamentarium, but has only been used for one aeromedical evacuation. Modern extracorporeal membrane oxygenation systems hold promise as a feasible capability for aeromedical evacuation. PMID- 21795886 TI - Rehospitalization after combat injury. AB - BACKGROUND: Frequency of rehospitalization and associated resource requirements are unknown for combat casualties. Differences may also exist in readmission rates for injuries to separate body regions. This study investigates rehospitalization of combat casualties with a hypothesis that extremity injuries cause the greatest number of readmissions and require the greatest resources to treat. METHODS: A Department of Defense database was queried for hospital admissions of a previously published cohort of service members initially wounded in Iraq and Afghanistan between October 2001 and January 2005. Cohort admission data were collected from October 2001 to February 2008. Body region injured was assigned using International Classification of Diseases Ninth Edition primary diagnosis codes. Resource utilization was calculated using the 2008 Department of Defense billing calculator. RESULTS: Our cohort consisted of 1,337 service members with 2,899 admissions. Three hundred forty-one service members had 670 readmissions. Of rehospitalizations, 64% were for extremity injuries making up 66% of all rehospitalization days. Seventy percent of service members injured had at least one admission for extremity injury. Wound debridement made up 12% of all readmissions, and 92% of these were for extremity injuries. The estimated cost of rehospitalization for extremity injuries for this conflict to date is $139 million. CONCLUSIONS: Extremity injuries have been shown to result in the greatest long-term disability and require the greatest resource utilization during initial treatment. This study demonstrates that they also are the most frequent cause of rehospitalization and require the greatest resource utilization during rehospitalization. PMID- 21795887 TI - Exsanguination shock: the next frontier in prevention of battlefield mortality. PMID- 21795888 TI - Virtual reality pain control during burn wound debridement of combat-related burn injuries using robot-like arm mounted VR goggles. AB - BACKGROUND: This is the first controlled study to explore whether adjunctive immersive virtual reality (VR) can reduce excessive pain of soldiers with combat related burn injuries during wound debridement. METHODS: Patients were US soldiers burned in combat attacks involving explosive devices in Iraq or Afghanistan. During the same wound care session using a within-subject experimental design, 12 patients received half of their severe burn wound cleaning procedure (~6 minutes) with standard of care pharmacologies and half while in VR (treatment order randomized). Three 0 to 10 Graphic Rating Scale pain scores for each of the treatment conditions served as the primary variables. RESULTS: Patients reported significantly less pain when distracted with VR. "Worst pain" (pain intensity) dropped from 6.25 of 10 to 4.50 of 10. "Pain unpleasantness" ratings dropped from "moderate" (6.25 of 10) to "mild" (2.83 of 10). "Time spent thinking about pain" dropped from 76% during no VR to 22% during VR. Patients rated "no VR" as "no fun at all" (<1 of 10) and rated VR as "pretty fun" (7.5 of 10). Follow-up analyses showed VR was especially effective for the six patients who scored 7 of 10 or higher (severe to excruciating) on the "worst pain" (pain intensity) ratings. CONCLUSIONS: These preliminary results provide the first evidence from a controlled study that adjunctive immersive VR reduced pain of patients with combat-related burn injuries during severe burn wound debridement. Pain reduction during VR was greatest in patients with the highest pain during no VR. These patients were the first to use a unique custom robot like arm mounted VR goggle system. PMID- 21795889 TI - A porcine model for evaluating the management of noncompressible torso hemorrhage. AB - BACKGROUND: Noncompressible hemorrhage from central vascular injuries remains the leading cause of preventable death in modern combat. This report introduces a large animal model of noncompressible torso hemorrhage, which permits assessment of the various approaches to this problem. METHODS: Yorkshire swine were anesthetized and monitoring devices for central aortic pressure, carotid flow, and intracerebral and transcutaneous brain oximetry were applied. Class IV hemorrhagic shock was induced through an iliac arterial injury and animals were subjected to different vascular control methods including thoracic aortic clamping, supraceliac aortic clamping, direct vascular control, and proximal endovascular balloon occlusion. After vascular control, the injury was shunted, and damage control resuscitation was continued. Serum markers, intravenous fluid volumes, and vasopressor requirements were tracked over a subsequent resuscitation period. Postmortem tissue analysis was performed to compare levels of acute ischemic injury between groups. RESULTS: The protocol for animal preparation, hemorrhage volume, open surgical technique, and posthemorrhage resuscitation was developed using four animals. The endovascular approach was developed using two additional animals. After model development, treatment animals subsequently underwent noncompressible hemorrhage with thoracic aortic clamping, supraceliac aortic clamping, direct vascular control, and endovascular aortic occlusion. Premature death occurred in one animal in the direct vascular control group. CONCLUSION: This study presents a large animal model of class IV hemorrhagic shock from noncompressible hemorrhage, which permits comparison of various vascular control methods to address this challenging problem. Future studies using this model as the standard will allow further development of strategies for the management of noncompressible hemorrhage. PMID- 21795890 TI - Use of advanced machine-learning techniques for noninvasive monitoring of hemorrhage. AB - BACKGROUND: Hemorrhagic shock is a leading cause of death in both civilian and battlefield trauma. Currently available medical monitors provide measures of standard vital signs that are insensitive and nonspecific. More important, hypotension and other signs and symptoms of shock can appear when it may be too late to apply effective life-saving interventions. The resulting challenge is that early diagnosis is difficult because hemorrhagic shock is first recognized by late-responding vital signs and symptoms. The purpose of these experiments was to test the hypothesis that state-of-the-art machine-learning techniques, when integrated with novel non-invasive monitoring technologies, could detect early indicators of blood volume loss and impending circulatory failure in conscious, healthy humans who experience reduced central blood volume. METHODS: Humans were exposed to progressive reductions in central blood volume using lower body negative pressure as a model of hemorrhage until the onset of hemodynamic decompensation. Continuous, noninvasively measured hemodynamic signals were used for the development of machine-learning algorithms. Accuracy estimates were obtained by building models using signals from all but one subject and testing on that subject. This process was repeated, each time using a different subject. RESULTS: The model was 96.5% accurate in predicting the estimated amount of reduced central blood volume, and the correlation between predicted and actual lower body negative pressure level for hemodynamic decompensation was 0.89. CONCLUSIONS: Machine modeling can accurately identify reduced central blood volume and predict impending hemodynamic decompensation (shock onset) in individuals. Such a capability can provide decision support for earlier intervention. PMID- 21795891 TI - Combat-related pelvis fractures in nonsurvivors. AB - BACKGROUND: The purpose of this study was to describe pelvic fractures and their associated injuries in service members who either died of wounds or were killed in action during Operation Iraqi Freedom and Operation Enduring Freedom and define any differences in associated injuries between penetrating versus blunt injury to the pelvis. METHODS: A review of all service members who sustained a pelvis fracture during Operation Iraqi Freedom and Operation Enduring Freedom in the year 2008 was performed. Data were recorded for analysis. RESULTS: One hundred four nonsurvivors were identified with pelvic fractures. Appropriate records, photos, and radiographs were available for 91, 70 were classified as "Not Survivable" (77%) and 21 "Potentially Survivable" (23%). Mechanisms of injury included 69 blast (76%), 14 gunshot wounds (15%), 4 motor vehicle accidents (4.5%), and 4 "other" (4.5%). Direct injury to the pelvis was penetrating in 60 (66%) and blunt in 31 (34%). Large pelvic vessel injury was observed more frequently in penetrating pelvic injuries (27%) than blunt injuries (3%). Hollow viscus abdominal injuries were more common in those with penetrating (57%) than blunt injuries (10%). There was an inverse relationship with intra abdominal, solid organ injuries (blunt, 81%; penetrating, 55%). Head injuries were also more common in blunt pelvic injuries (blunt, 68%; penetrating, 45%), as were cardiopulmonary injuries (blunt, 84%, penetrating injuries, 57%). CONCLUSIONS: Large pelvic vessel and hollow viscus injuries occur more frequently in penetrating combat-related pelvic fractures, whereas intra-abdominal solid organ, head, and cardiopulmonary injuries are more common in blunt pelvic injuries. PMID- 21795892 TI - Relationships between early acute pain scores, autonomic nervous system function, and injury severity in wounded soldiers. AB - BACKGROUND: Acute pain after injury affects the comfort and function of the wounded soldier and the physiology of multiple body systems. In the civilian population, pain alters the function of the autonomic nervous system, causing increased heart rate and blood pressure. However, there are no data regarding the impact of combat-related pain on physiologic responses. This study is a retrospective analysis that examined the relationship of pain and physiologic parameters in injured soldiers. METHODS: After Institutional Review Board approval, the Joint Trauma Theater Registry (JTTR) was queried to identify soldiers who had pain scores recorded in the Emergency Department (ED) in theater. Subject data collected from the JTTR included the following: pain score, Injury Severity Score (ISS), blood pressure, heart rate, and respiratory rate. RESULTS: We identified 2,646 soldiers with pain scores recorded in the ED. The pain score was not related to most physiologic parameters measured in the ED. Pain intensity had no correlation with blood pressure or heart rate. However, there were relationships between the pain score and respiratory rate, with patients reporting a pain score of 10 having a slightly higher respiratory rate. Increasing pain scores were also associated with increased ISS (p < 0.001). CONCLUSIONS: In contrast to data from civilian patients, early pain scores were not related to heart rate or blood pressure. A pain score of 10 corresponded to an increased respiratory rate. Despite little relationship between pain and injury severity in the civilian population, the increasing ISS was proportional to the pain scale in wounded soldiers. PMID- 21795893 TI - Faculty career progression. PMID- 21795894 TI - More about online forums for students and faculty. PMID- 21795895 TI - More about online forums for students and faculty. PMID- 21795896 TI - The tipping point: academic careers of women in medicine today. PMID- 21795897 TI - The need for a standard, systematic oncology curriculum for U.S. medical schools. PMID- 21795900 TI - Commentary: building human capital: discovery, learning, and professional satisfaction. AB - Physician satisfaction is an important contributor to a well-functioning health system. Mohr and Burgess report that physicians in the Veterans Health Administration (VA) who spend time in research have greater overall job satisfaction, that satisfaction tracks with aggregate facility research funding, and that satisfaction is higher among physicians working in VA facilities located on the same campus or within walking distance of an affiliated medical school. An environment conducive to research therefore not only advances science but also seems to be a key element of physician satisfaction. In addition to advancing scientific discovery and promoting greater physician satisfaction, these findings suggest that an environment of discovery and learning may yield benefits beyond specific academic endeavors and contribute more broadly to supporting health system performance. PMID- 21795901 TI - Commentary: to genotype or not to genotype? Addressing the debate through the development of a genomics and personalized medicine curriculum. AB - As technologic innovation helps broaden and refine our knowledge base of genetic associations, a growing interest in translating these genetic discoveries to clinically useful laboratory tests has given rise to the potential of personalized medicine. To fully realize this potential, medical schools must educate trainees on genetic and genomic testing in clinical settings. An emerging debate in academic medical centers is not about the need for this education but, rather, the most effective educational models that should be deployed. At Stanford School of Medicine, several proposals to offer personal genotyping in the educational curriculum argued that learning genetics and the attendant cutting-edge molecular techniques would be more powerful and sustained if students were applying their knowledge to their personal genotypes. Given the complex ethical, legal, and social issues involved in implementing such a program, a schoolwide task force was formed to evaluate the risks and benefits of offering personal genotyping to students and residents. In this commentary, the authors discuss the salient issues raised by the task force and describe the safeguards adopted into the ultimate approval and implementation of the course, which included the opportunity for students to analyze their own genomes. PMID- 21795902 TI - Commentary: the building the next generation of academic physicians initiative: engaging medical students and residents. AB - Data from the 2010 U.S. Census are a reminder of the diverse patient population in the United States and the growing health care needs of Americans. Academic health centers are tasked with reforming the system to expand its capacity for care and with cultivating innovation to generate the teaching, training, and research prowess needed to eliminate health disparities. At the center of this reform is enhancing the system that produces the human capital, including the physicians who care for the patients and the educators who train those physicians. Institutions and foundations have committed to the development of pipeline programs, from kindergarten through college, to create a diverse clinical workforce, but they have limited their direct promotion of diversity in the academic medicine workforce to faculty development programs. Despite faculty efforts, shortcomings in diversity persist, including a paucity of female full professors and deans, an insignificant increase in the proportion of underrepresented racial and ethnic minority faculty, and a lack of knowledge on the cultivation of the lesbian and gay faculty perspective. Furthermore, underrepresented racial and ethnic minority students in particular lose interest in academic medicine careers during medical school, and overall students lose interest in academic medicine careers during residency. The Building the Next Generation of Academic Physicians Initiative is designed to develop interest and promote achievement in pursuing academic medicine careers. This initiative is needed to increase the pool of diverse faculty down the road and elicit their perspectives to more effectively address health care disparities. PMID- 21795905 TI - Medicine and the arts. Infinite jest: [excerpts] by David Foster Wallace. Commentary. PMID- 21795907 TI - AM last page: how to perform an effective database search. PMID- 21795908 TI - Vaccination and 'matters of belief'. PMID- 21795909 TI - Speaking out on social justice. PMID- 21795910 TI - Mutual respect. PMID- 21795911 TI - Human trafficking. PMID- 21795912 TI - Back to basics. PMID- 21795913 TI - Back to basics. PMID- 21795915 TI - Battle over unlicensed volunteers giving insulin in schools. PMID- 21795922 TI - Schools flunk the test on indoor air quality. PMID- 21795929 TI - Adenotonsillectomy for obstructive sleep apnea in children. PMID- 21795930 TI - Prevention and treatment of osteoporosis in postmenopausal women: a review. AB - This article provides an overview of osteoporosis, describes current recommendations for its prevention and treatment, and discusses nursing implications. This is part two of a four-part series on postmenopausal health. PMID- 21795932 TI - From fecal impaction to colon perforation. AB - The authors present the case of an elderly, nonverbal nursing home resident with dementia who developed fecal impaction, despite interventions such as enema. Subsequent stercoral perforation of the sigmoid colon resulted in peritonitis, sepsis, and death. The authors discuss colon perforation as a result of fecal impaction, as well as the difficulties of pain assessment and communication in patients with dementia. PMID- 21795935 TI - Got the picture? Using mobile phone technology to reinforce discharge instructions. PMID- 21795936 TI - Disaster care: children of Hurricane Katrina. PMID- 21795941 TI - Incorporating the WHO FRAX assessment tool into nursing practice. PMID- 21795942 TI - Rocking the night shift. PMID- 21795943 TI - Welcome home. PMID- 21795944 TI - The letter. PMID- 21795948 TI - Presentation of the Southern Society for Clinical Investigation Founders' Medal for 2011 to Michael S. Bronze, MD. PMID- 21795949 TI - Southern Society for Clinical Investigation Founders' Medal acceptance. PMID- 21795957 TI - Oxidative stress and myocardial remodeling in chronic mitral regurgitation. AB - Mechanisms of left ventricular (LV) dysfunction in isolated mitral regurgitation (MR) are not well understood. Vasodilator therapy in other forms of LV dysfunction reduces LV wall stress and improves LV function; however, studies in isolated MR show no beneficial effect on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. Therefore, the search for new therapies that improve LV remodeling and function in isolated MR is clinically significant. Recent work in the authors' laboratory has demonstrated increased oxidants from a number of sources including the enzyme xanthine oxidase (XO) in the LV of patients with isolated MR. In addition to being a major source of reactive oxygen species, XO is linked to bioenergetic dysfunction because its substrates derive from adenosine triphosphate catabolism. Correspondingly, there was also evidence of aggregates of small mitochondria in cardiomyocytes, which is generally considered a response to bioenergetic deficit in cells. Future studies are required to determine whether XO and persistent oxidative stress are causative in maladaptive LV remodeling and offer potential therapeutic targets in ameliorating LV damage in patients with isolated MR. PMID- 21795958 TI - Wrist drop: an atypical presentation of renal cell carcinoma. AB - Renal cell carcinoma (RCC) causing metastasis to the skeletal muscles is extremely rare. The authors describe a patient with history of RCC treated 5 years ago with radical nephrectomy who presented with left arm swelling after receiving seasonal flu shot. He was initially diagnosed with cellulitis, treated with intravenous antibiotics and discharged home. One month later, he presented with persistent left arm swelling accompanied by wrist drop. Subsequently he developed increased swelling, decreased pulse and wrist drop. He was diagnosed with compartment syndrome, for which fasciotomy was performed, and tissue samples were sent for analysis. Histopathological analysis confirmed metastatic clear cell RCC. The authors described a literature review of previously described cases of metastasis of renal cell cancer to the skeletal muscles. The authors also discussed the rarity of muscle metastasis and unpredictable behavior of RCC after being dormant for long periods. PMID- 21795961 TI - Gaps in treatment for anxiety in Parkinson disease. PMID- 21795962 TI - Yokukansan treatment in chronic renal failure patients with dementia receiving hemodialysis: an open label study. PMID- 21795963 TI - Free cortisol and accuracy of total cortisol measurements in the diagnosis of adrenal insufficiency in brain-dead patients. AB - BACKGROUND: After brain death, adrenal insufficiency (AI) is very common and may be one of the mechanisms that contributes to hemodynamic instability and loss of potential organ donors. However, when diagnosed by total cortisol measurement, critically ill patients may be overdiagnosed as having AI. The aims of this study were to assess the prevalence of AI when diagnosed using free cortisol measurement and the accuracy of total cortisol measurement to diagnose AI in brain-dead patients. METHODS: All consecutive brain-dead patients were included in this single-center noninterventional clinical observation study. Assessment of adrenocorticotropin, corticosteroid-binding globulin, baseline and tetracosactin stimulated serum free and total cortisol concentrations were performed. AI was defined as a baseline free cortisol concentration <= 55 nM(-1) and/or Delta free cortisol <= 55 nM(-1). Patients were considered to have a low albumin concentration if less than 25 g . L(-1) and a low corticosteroid-binding globulin concentration if less than 27 mg . L(-1) in men or 31 mg . L(-1) in women. RESULTS: Among the 42 included patients, the incidence of AI was 83% (95% CI, 69 93%). Baseline total cortisol was correlated with baseline free cortisol, whatever the albumin or corticosteroid-binding globulin concentration. The area under the receiver operating characteristic curve of baseline total cortisol measurement to diagnose AI was 0.94 (95% CI, 0.81-0.98). The optimal cutoff was 485 nM(-1), providing a sensitivity and a specificity of 89% and 100%, respectively. CONCLUSION: Total baseline cortisol measurement is accurate and sufficient to diagnose AI in brain-dead patients, even if albumin or corticosteroid-binding globulin concentrations are low. PMID- 21795965 TI - Determining resident clinical performance: getting beyond the noise. AB - BACKGROUND: Valid and reliable (dependable) assessment of resident clinical skills is essential for learning, promotion, and remediation. Competency is defined as what a physician can do, whereas performance is what a physician does in everyday practice. There is an ongoing need for valid and reliable measures of resident clinical performance. METHODS: Anesthesia residents were evaluated confidentially on a weekly basis by faculty members who supervised them. The electronic evaluation form had five sections, including a rating section for absolute and relative-to-peers performance under each of the six Accreditation Council for Graduate Medical Education core competencies, clinical competency committee questions, rater confidence in having the resident perform cases of increasing difficulty, and comment sections. Residents and their faculty mentors were provided with the resident's formative comments on a biweekly basis. RESULTS: From July 2008 to June 2010, 140 faculty members returned 14,469 evaluations on 108 residents. Faculty scores were pervasively positively biased and affected by idiosyncratic score range usage. These effects were eliminated by normalizing each performance score to the unique scoring characteristics of each faculty member (Z-scores). Individual Z-scores had low amounts of performance information, but signal averaging allowed determination of reliable performance scores. Average Z-scores were stable over time, related to external measures of medical knowledge, identified residents referred to the clinical competency committee, and increased when performance improved because of an intervention. CONCLUSIONS: This study demonstrates a reliable and valid clinical performance assessment system for residents at all levels of training. PMID- 21795966 TI - Adherence to CONSORT abstract reporting suggestions in surgical randomized controlled trials published in Annals of Surgery. PMID- 21795964 TI - Effects of glycemic regulation on chronic postischemia pain. AB - BACKGROUND: Ischemia-reperfusion (I/R) injuries consist of enhanced oxidative and inflammatory responses along with microvascular dysfunction after prolonged ischemia and reperfusion. Because I/R injuries induce chronic postischemia pain (CPIP) in laboratory animals, it is possible that surgical procedures using prolonged ischemia may result in chronic postoperative pain. Glycemic modulation during ischemia and reperfusion could affect pain after I/R injury because glucose triggers oxidative, inflammatory, and thrombotic reactions, whereas insulin has antioxidative, antiinflammatory, and vasodilatory properties. METHODS: One hundred ten rats underwent a 3-h period of ischemia followed by reperfusion to produce CPIP. Rats with CPIP had previously been divided into six groups with differing glycemic modulation paradigms: normal feeding; fasting; fasting with normal saline administration; fasting with dextrose administration; normal feeding with insulin administration; and normal feeding with insulin and dextrose administration. Blood glucose concentration was assessed during I/R in these separate groups of rats, and these rats were tested for mechanical and cold allodynia over the 21 days afterward (on days 2, 5, 7, 9, 12, and 21 after I/R injury). RESULTS: I/R injury in rats with normoglycemia or relative hyperglycemia (normal feeding and fasting with dextrose administration groups) led to significant mechanical and cold allodynia; conversely, relative hypoglycemia associated with insulin treatment or fasting (fasting, fasting with normal saline administration, and normal feeding with insulin administration groups) reduced allodynia induced by I/R injury. Importantly, insulin treatment did not reduce allodynia when administered to fed rats given dextrose (normal feeding with dextrose and insulin administration group). CONCLUSION: Study results suggest that glucose levels at the time of I/R injury significantly modulate postinjury pain thresholds in rats with CPIP. Strict glycemic control during I/R injury significantly reduces CPIP and, conversely, hyperglycemia significantly enhances it, which could have potential clinical applications especially in the surgical field. PMID- 21795969 TI - The best laparoscopic hernia repair: TEP or TAPP? PMID- 21795970 TI - Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E selectin. AB - OBJECTIVES: Aggressive human melanomas express, C-X-C chemokine receptor 4 (CXCR4), the receptor for the chemokine, stromal cell-derived factor-1alpha (SDF 1alpha). The CXCR4-SDF-1alpha axis has been postulated to increase melanoma invasiveness. We discovered that SDF-1alpha specifically upregulates E-selectin on endothelial cells, thus tethering circulating endothelial progenitor cells (EPC) and facilitating homing. We investigated the hypothesis that small interfering ribonucleic acid (siRNA)-mediated E-selectin blockade inhibits melanoma angiogenesis and tumor growth. METHODS: Human melanoma cells overexpressing SDF-1alpha were xenografted on severe combined immunodeficiency (SCID) mice. SDF-1alpha expression in cells was measured by enzyme-linked immunosorbent assay (ELISA). In vitro melanoma cell growth was examined by cell proliferation assay. In vivo vascular E-selectin knockdown was achieved by administration of high-volume E-selectin siRNA (100 pmol/180 MUL/week * 3 times) and inhibition was validated by immunostaining (N = 6/group, E-Selectin siRNA vs control siRNA). Tumor angiogenesis was quantified (DiI-perfusion and LASER confocal microscopy). EPC homing to tumor vasculature was detected by immunostaining. Explanted in vivo tumor size and weight were measured. RESULTS: Three melanoma cells tested expressed undetectable levels of SDF-1alpha. Additional enforced overexpression of SDF-1alpha (by Lenti-SDF-1alpha) increased melanoma cell growth both in vitro and in vivo, enhanced EPC homing to tumor tissue, and increased tumor angiogenesis. Knocking-down vascular E-selectin significantly inhibited SDF-1alpha-induced EPC homing, tumor angiogenesis, and decreased melanoma growth in vivo. CONCLUSIONS: Downregulation of vascular E selectin profoundly inhibits EPC homing, tumor angiogenesis, and tumor growth in human melanoma xenograft murine model, potentially by suppression of E-selectin mediated EPC-endothelial cells interactions/homing. These findings identify E selectin as a novel target for inhibition of melanoma angiogenesis and tumor growth. PMID- 21795971 TI - Reply to letter: "Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia". PMID- 21795972 TI - Evaluation of current practice: management of chemotherapy-related toxicities. AB - Adverse effects induced by cytotoxic chemotherapy (CT) have been mostly evaluated in clinical trials. The aim of this study was to assess in a nonselected patients group the incidence of CT-related toxicities and to identify risk factors in daily practice. Patients treated with CT (except cisplatin-based or carboplatin based CT), for a solid tumour, were included in a prospective multicentre observational study. Clinical parameters, renal function and albumin level were assessed at baseline. Multivariate logistic regression was used to identify risk factors of CT-related toxicities. A total of 502 patients were recruited in different types of oncology departments. During CT, 62% of patients experienced grade 2-4 toxicities. Haematological toxicities affected 34% of patients and 20% of patients developed an infection requiring antibiotics. For 55% of patients, toxicities induced dose reduction (59% of cases), CT delay (25%) or discontinuation (16%) according to the management habits in the investigating centre. Performance status>=1, breast cancer, lymphopenia, hypoalbuminaemia and clearance creatinine<60 ml/min were risk factors for haematological toxicity. Performance status>=1, hypoalbuminaemia, proteinuria and clearance creatinine<90 ml/min were risk factors for change of CT schedule. A majority of patients receiving CT experienced significant toxicity leading to change of standard CT protocol. Albumin, creatinine clearance and lymphocyte should be routinely monitored at baseline to manage CT and to prevent their toxicities. PMID- 21795974 TI - Ocular coherence tomography in lymphangiectasia. AB - PURPOSE: To report the aid of ocular coherence tomography (OCT) in diagnosing conjunctival lymphangiectasia and correlate clinical and pathological findings. METHODS: Single interventional case report. A 64-year-old man presented with a 2 year history of ocular discomfort, tearing, and a gradually enlarging lesion on the conjunctiva of his left eye. RESULTS: Slit-lamp biomicroscopy revealed localized conjunctival swelling temporally in the left eye, with the lesion protruding between the upper and lower eyelids. Visante (Carl Zeiss-Meditec, Jena, Germany) OCT revealed clear fluid-filled spaces demarcated by septae within the elevated conjunctiva. The lesion was excised, and histopathology of the specimen showed features consistent with lymphangiectasia. CONCLUSIONS: OCT, a valuable tool in imaging of the anterior segment, is also useful in evaluation of conjunctival pathology. PMID- 21795973 TI - Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status. AB - This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis. PMID- 21795977 TI - Prototheca wickerhamii infection of a corneal graft. AB - Algae are generally noninfectious agents in mammals, with few known pathogenic algae. Prototheca is an achlorophylic nonphotosynthetic algae, globally ubiquitous, and readily isolated from rivers, lakes, ponds, and soil. Although canine and bovine protothecosis have been reported more widely, infections in humans are rare, particularly in patients with an intact immune system. The majority of protothecal infections in humans is associated with Prototheca wickerhamii. We report an unusual case of P. wickerhamii infection in an immunocompetent corneal transplant patient. PMID- 21795976 TI - The role of atopy in corneal graft survival in keratoconus. AB - PURPOSE: To compare the prevalence of endothelial rejection episodes and the probability of graft survival after initial and repeat penetrating keratoplasty (PK) in patients with keratoconus with and without atopy. METHODS: A retrospective review was conducted of all patients receiving PK for keratoconus at the University of Texas Southwestern Medical Center at Dallas from 1988 to 2009. Inclusion criteria involved those with both an International Classification of Diseases-9 code for keratoconus and a Current Procedural Terminology code for PK based on a computer database search. Patients younger than 18 years were excluded. These records were then reviewed for a history of atopic disorders. The main outcome measures included the prevalence of endothelial rejection episodes and the probability of graft survival. The probability of corneal graft survival in patients with and without a history of atopy was compared using the Kaplan Meier method. RESULTS: There were 168 grafts in 122 patients. There were 66 (39.2%) and 102 (60.8%) grafts with and without a history of atopy, respectively. Bilateral first grafts were required in 32 patients, 14 and 18 patients with and without a history of atopy, respectively. The atopic and nonatopic groups had no significant differences with respect to age, preexisting ocular conditions, concomitant surgical procedures, and length of follow-up. Men received first grafts significantly more frequently than women in the nonatopic group (P = 0.029); however, there was no sex difference in repeat grafts. There were no significant differences in the prevalence of endothelial rejection episodes after the first (P = 0.716), second (P > 0.999), and third or further grafts (P > 0.999). Graft survival between the atopic and nonatopic groups did not differ significantly in the first (P = 0.881), second (P = 0.752), or third or further graft (P = 0.157). Among first grafts in the atopic group, no statistically significant difference in survival existed among patients analyzed with different manifestations of atopy (P = 0.061). One episode of allograft endothelial rejection created a statistically significant difference in ultimate graft survival probability in both the atopic (P = 0.003) and nonatopic (P = 0.002) groups. CONCLUSIONS: Among patients with keratoconus receiving PK, there is no statistically significant difference in the prevalence of endothelial graft rejection episodes or probability of graft survival between patients with and without a clinical history of atopy. PMID- 21795978 TI - Gender and hearing aids: patterns of use and determinants of nonregular use. AB - OBJECTIVE: Research addressing gender and hearing has focused mainly on differences in the auditory systems of men and women, communication, and psychological issues. Differences between men and women in the use of hearing aids are less clear. To date, no study has examined the effects of gender on hearing aid use as a primary aim. However, use patterns and underlying reasons for not using hearing aids may differ between men and women, or there might be a gender difference in the impact of some determinants on hearing aid use. A consideration of such factors could increase hearing aid use. Therefore, the aim of the present investigation was to provide information about gender-related influences on hearing aid use by examining differences in usage patterns and determinants of nonregular use. DESIGN: This study used cross-sectional survey data from 4979 adult male and 3410 adult female hearing aid owners in Switzerland in 2005. The survey data, including self-reported hearing aid use, were matched to the hearing loss data and the hearing aid technical information. Descriptive analyses were performed for the use patterns, age at first fitting, and audiogram slope. The determinants of nonregular use were examined using logistic regression models that were stratified by gender. RESULTS: Compared with men, women reported a higher prevalence of daily and regular use and a longer daily duration of use of hearing aids. Men more commonly indicated a limited benefit as a reason for nonregular use. The multivariate analyses showed that nonregular use was significantly less likely in women. The audiogram slope strongly contributed to this difference. Stratified analyses showed that for both men and women, poor handling and low satisfaction were associated with a higher likelihood for nonregular hearing aid use. Associations were discrepant for asymmetric hearing loss, which was a risk factor in women but a protective factor in men. Higher risks of nonregular use were found in men with steeper audiogram slopes and longer durations of ownership of their current aids, in women fitted with their first aid in the previous 2 to 5 yr, and in women older than 65 yr. CONCLUSIONS: Overall, the present study provides evidence of gender-specific factors that influence hearing aid use patterns in men and women and of groups at higher risk for nonregular hearing aid use. Men with steeper audiogram slopes and the other subgroups of men and women with an increased risk for nonregular use should given particular attention when fitting their aids. As common risk factors for nonregular use, poor handling and low satisfaction should be addressed during the fitting process for all users. Further research is needed to clarify the differential influence of asymmetric hearing loss on hearing aid use in men and women. This information could improve hearing aid use and should be incorporated into daily clinical practice. PMID- 21795979 TI - RARbeta2 gene methylation level in the circulating DNA from blood of patients with lung cancer. AB - Alterations in the patterns of DNA methylation are among the earliest and most common events in tumorigenesis. Epigenetic changes were shown to be detectable in DNA, circulating in blood (cirDNA) of cancer patients, indicating the resources to create the minimally invasive diagnostic tests based on tumor-specific DNA markers. RARbeta2 methylation level was significantly increased in plasma cirDNA and cell surface-bound cirDNA (csb-cirDNA) from patients with non-small cell lung cancer compared with healthy individuals (7620 and 1083 copies/ml in the csb fractions, 3589 and 1068 copies/ml in the blood plasma; P=0.003 and 0.001). The cell-bound-to-cell-free RARbeta2 methylation ratio was found to be elevated in patients with non-small cell lung cancer compared with control (2.12 and 1.01, respectively; P=0.023). RARbeta2 methylation level in csb-cirDNA and plasma cirDNA was higher in stage III patients compared with stage I-II patients (P=0.02 and 0.03). In the subgroup of patients with squamous cell carcinoma, RARbeta2 methylation level in the cbs-cirDNA was higher compared with patients with adenocarcinoma (P=0.04). Epigenetic alterations of tumor suppressor gene RARbeta2 in the total cirDNA (plasma cirDNA and csb-cirDNA) were found to be associated with lung cancer progression. The data obtained indicate that cirDNA-based testing provides a valuable source for subsequent verification of methylated DNA markers for lung cancer diagnostics and prognosis. PMID- 21795980 TI - Flexible spectral imaging color enhancement and indigo carmine in neoplasia diagnosis during colonoscopy: a large prospective UK series. AB - OBJECTIVES: At present, all colonic polyps are removed and sent for histopathological evaluation, resulting in laboratory and reporting costs. Recent American Society for Gastrointestinal Endoscopy (ASGE) guidelines have set standards for in-vivo diagnosis in place of conventional histopathology, and all future technologies will have to be tested against these standards. Data on flexible spectral imaging color enhancement (FICE) were very limited. This study aims to evaluate the accuracy of FICE and indigo carmine (IC) for in-vivo histology prediction for polyps of less than 10 mm in size and to assess the economic impact of this strategy. METHODS: In a screening population, polyps of less than 10 mm were assessed using white light (WLI) by FICE, by IC, and the predicted diagnosis was recorded. Polyps were then removed and sent for histological analysis. Accuracy of the predicted rescope interval was calculated using British Society of Gastroenterology and ASGE guidelines. Two models for using in-vivo diagnosis were proposed and savings in terms of histopathology costs calculated. RESULTS: A total of 232 polyps of less than 10 mm were examined. FICE improved the accuracy of in-vivo diagnosis of adenoma to 88% compared with 75% with WLI (P<0.0001). IC after FICE improved this further to 94%. Rescope interval could be set correctly using FICE or IC in 97% of cases by British Society of Gastroenterology guidelines or 97% with FICE and 99% with IC using ASGE guidelines. A saving of L678,253 (?762767) per annum could be made within the UK national screening population. CONCLUSION: FICE and IC significantly improves the in-vivo diagnosis of colonic polyps over WLI and can lead to significant cost savings. PMID- 21795982 TI - Acute pancreatitis during pregnancy. AB - Acute pancreatitis in pregnancy is a rare condition estimated to occur in 1 per 1000 to 1 per 12,000 pregnancies. The most frequent etiology in pregnancy is biliary, followed by hyperlipidemia and/or alcohol abuse. Abdominal ultrasound and endoscopic ultrasound are ideal imaging techniques for diagnosing disease because they have no radiation risk. Computed tomography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography should be used with caution. Treatment could be conservative or surgical, and standard algorithms are slightly modified in pregnant women. In the last decades the outcome of acute pancreatitis in pregnancy is much better, and perinatal mortality is less than 5%. PMID- 21795981 TI - Cannabis use amongst patients with inflammatory bowel disease. AB - BACKGROUND: Experimental evidence suggests the endogenous cannabinoid system may protect against colonic inflammation, leading to the possibility that activation of this system may have a therapeutic role in inflammatory bowel disease (IBD). Medicinal use of cannabis for chronic pain and other symptoms has been reported in a number of medical conditions. We aimed to evaluate cannabis use in patients with IBD. METHODS: One hundred patients with ulcerative colitis (UC) and 191 patients with Crohn's disease (CD) attending a tertiary-care outpatient clinic completed a questionnaire regarding current and previous cannabis use, socioeconomic factors, disease history and medication use, including complimentary alternative medicines. Quality of life was assessed using the short inflammatory bowel disease questionnaire. RESULTS: A comparable proportion of UC and CD patients reported lifetime [48/95 (51%) UC vs. 91/189 (48%) CD] or current [11/95 (12%) UC vs. 30/189 (16%) CD] cannabis use. Of lifetime users, 14/43 (33%) UC and 40/80 (50%) CD patients have used it to relieve IBD-related symptoms, including abdominal pain, diarrhoea and reduced appetite. Patients were more likely to use cannabis for symptom relief if they had a history of abdominal surgery [29/48 (60%) vs. 24/74 (32%); P=0.002], chronic analgesic use [29/41 (71%) vs. 25/81 (31%); P<0.001], complimentary alternative medicine use [36/66 (55%) vs. 18/56 (32%); P=0.01] and a lower short inflammatory bowel disease questionnaire score (45.1+/-2.1 vs. 50.3+/-1.5; P=0.03). Patients who had used cannabis [60/139 (43%)] were more likely than nonusers [13/133 (10%); P<0.001 vs. users] to express an interest in participating in a hypothetical therapeutic trial of cannabis for IBD. CONCLUSION: Cannabis use is common amongst patients with IBD for symptom relief, particularly amongst those with a history of abdominal surgery, chronic abdominal pain and/or a low quality of life index. The therapeutic benefits of cannabinoid derivatives in IBD may warrant further exploration. PMID- 21795983 TI - Personality predictors of antiaggressive response to fluoxetine: inverse association with neuroticism and harm avoidance. AB - Although selective serotonin reuptake inhibitors (SSRI) are generally effective in reducing impulsive aggression in individuals with intermittent explosive disorder, a large proportion of intermittent explosive disorder patients fail to achieve full remission despite adequate dosage and duration of treatment. Temperament, specifically those associated with negative emotionality (neuroticism, harm avoidance) may predict response to SSRI treatment. The objective of this study was to determine whether baseline neuroticism and harm avoidance scores would be associated with reduced aggression (as measured by the Overt Aggression Scale-Modified [OAS-M] aggression scores) after SSRI treatment. Participants participating in a randomized, placebo-controlled clinical trial of fluoxetine completed the Eysenck Personality Questionnaire (n=57) and the Tridimensional Personality Questionnaire (n=38) before entering the treatment trial. Multiple regression analyses (accounting for baseline OAS-M aggression scores) revealed that pretreatment eysenck personality questionnaire neuroticism and tridimensional personality questionnaire harm avoidance independently and uniquely predicted OAS-M aggression scores at endpoint in the fluoxetine, but not placebo, treated group. These preliminary findings are the first from a placebo controlled clinical trial to suggest that temperamental factors such as neuroticism and harm avoidance can partly explain the observed variability in treatment response in SSRI treated individuals with impulsive aggression and prompt future prospective studies examining personality dimensions as predictors of outcomes in clinical trials. PMID- 21795984 TI - Local alpha-tocopherol for acute and short-term vaginal toxicity prevention in patients treated with radiotherapy for gynecologic tumors. AB - INTRODUCTION: Data in literature about the use of adjuvant treatment to reduce acute adverse effects of radiotherapy on the pelvis are scant, with the exception of a few reports on the topical use of estrogen, which promotes proliferation of epithelium. MATERIALS AND METHODS: In this prospective trial, alpha-tocopherol acetate was topically administered to patients affected by endometrial and cervical cancer and undergoing radiation treatment to avoid acute vaginal complications. RESULTS: Vaginal application of alpha-tocopherol reduced vaginal toxicity and pain, although vaginal secretion was not significantly different in the 2 groups studied. The histological scoring system showed a significant reduction of inflammation, no difference in fibrosis, and an increase of acanthosis. CONCLUSIONS: The use of alpha-tocopherol as adjuvant treatment to reduce the acute adverse effects of radiotherapy on the vagina should be considered. PMID- 21795985 TI - Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study. AB - AIMS: This study aimed to investigate the outcome of patients with malignant ovarian germ cell tumors (MOGCTs) and to define the risk factors for recurrence. METHODS: A total of 123 patients with MOGCTs were retrospectively reviewed among MITO centers. Eighty-one patients had primary treatment in a MITO center, whereas the other 42 were referred for adjuvant chemotherapy or recurrence. The clinicopathologic characteristics were evaluated for association with relapse or death. RESULTS: Median age was 24 years (range, 11-76 years). Forty-nine (39.8%) had dysgerminomas, 35 (28.5%) had immature teratomas, 12 (9.8%) had mixed germ cell tumors, 26 (21.1%) had yolk sac tumors, and 1 (0.8%) had embryonal carcinoma. International Federation of Gynecology and Obstetrics stage distribution was as follows: stage I, 87 (70.7%); stage II, 3 (2.4%); stage III, 29 (23.6%); and stage IV, 4 (3.3%). Fertility-sparing surgery was performed in 92 patients, whereas the remaining 31 received radical surgery; 65.8% of patients received adjuvant chemotherapy. Recurrence rate was 17.8% and the median time to recurrence was 9 months. Univariate and multivariate analyses showed that patient age (>45 years) and treatment outside a referral (MITO) center were the most important predictors of recurrence. The 5-year overall survival rate was 88.8%, with a median follow-up of 61 months. Univariate and multivariate analyses demonstrated that stage greater than I and yolk sac tumors were independent poor prognostic indicators. CONCLUSIONS: This study confirms that MOGCTs have excellent prognosis, with 5-year overall survival rates of 95.6% and 73.2% in stage I and advanced stages, respectively. Age older than 45 years and treatment not in a referral center are independent risk factors for recurrence, whereas stage greater than I and yolk sac histology are independent poor prognostic indicators. PMID- 21795986 TI - Fertility outcome after radical vaginal trachelectomy: a prospective study of 212 patients. AB - OBJECTIVE: For treatment in patients with early-stage cervical cancer, radical vaginal trachelectomy (RVT) as a fertility-preserving surgery can be put on a par with radical hysterectomy as to oncologic safety. Our aim was to investigate the fertility concerns and outcome. METHODS: Prospective collection of fertility data of patients treated with RVT. The data were collected on personal communication, by telephone, or e-mail correspondence. Descriptive statistical analysis was performed. RESULTS: Between March 2005 and April 2010, 212 patients were followed up after RVT. Only 76 patients (35.9%) were seeking parenthood currently. Sixty pregnancies occurred in 50 women. Five patients (8.3%) had first-trimester miscarriage, 3 had second-trimester miscarriage (5.0%), 2 patients decided for pregnancy termination (3.3%), and 1 patient (1.7%) had an ectopic pregnancy. Three women (5.0%) delivered prematurely before 28th weeks of gestation, 15 (25.0%) delivered between 28 and 36 weeks, and 27 women (45.0%) reached full term. Four pregnancies are ongoing. CONCLUSIONS: Preservation of childbearing function is a great advantage for patients with early-stage cervical cancer. Many patients do not seek parenthood immediately. We see no impairment of fertility and have solid data on pregnancy outcome. Premature labor is the main problem in pregnancy after RVT. PMID- 21795987 TI - Intraoperative frozen section assessment of myometrial invasion and histology of endometrial cancer using the revised FIGO staging system. AB - OBJECTIVES: The objective of this study was to assess the value of intraoperative frozen section (IFS) diagnosis for myometrial invasion and histology of endometrial cancer using the revised International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS: The medical records of 303 patients with endometrial cancer who underwent surgery with intraoperative diagnosis at the Osaka University Hospital between January 1999 and December 2008 were reviewed. Intraoperative frozen section diagnosis was retrospectively analyzed for the accuracy rates of myometrial invasion and histology compared with the final diagnosis and with preoperative prediction by magnetic resonance imaging (MRI) and endometrial curettage. RESULTS: When using the previous FIGO staging system, the accuracy rate of IFS for the diagnosis of myometrial invasion was 77%, whereas the accuracy rate of preoperative prediction by MRI was 54%. However, using the newly revised FIGO staging system for myometrial invasion, the accuracy rate of IFS was 87% and the preoperative prediction by MRI was 82%. The accuracy rate of IFS for the diagnosis of histology was 71%, whereas the accuracy rate of preoperative prediction by endometrial curettage was 68%. CONCLUSION: Although under the previous FIGO staging system IFS diagnosis was significantly more accurate than preoperative prediction by MRI, when using the newly revised FIGO staging system, there are no significant differences between the values of preoperative and intraoperative diagnoses. The accuracy of IFS, however, trends to be slightly better than the preoperative procedures of MRI and endometrial surface biopsy. Thus, IFS diagnosis is still useful for directing primary operative management. PMID- 21795988 TI - Salvianolic acid A demonstrates cardioprotective effects in rat hearts and cardiomyocytes after ischemia/reperfusion injury. AB - Salvianolic acid A (Sal A), the water-soluble component from the root of the Salvia miltiorrhiza plant, possesses antioxidant, antiproliferative, and antiplatelet properties. However, whether it plays a role in the protection against ischemia-reperfusion (I/R) injury in rat hearts has yet to be elucidated. In the present study, we tested cell viability, shortening amplitude, necrosis, apoptosis, and the expression levels of Akt, phosphorylated Akt, Bcl-2, Bax, and caspase-3 after 3-hour simulated ischemia and 2- or 6-hour simulated reperfusion in cardiomyocytes. We further observed the contractile function and infarct size in isolated hearts after they were subjected to global 30-minute ischemia and 120 minute reperfusion. Pretreatment with Sal A markedly increased cell viability and shortening amplitude while reducing evidence of necrosis and apoptosis in the cells. In addition, the expression of Bcl-2 was upregulated and Bax was downregulated, thereby increasing the Bcl-2/Bax ratio. Sal A inhibited the activation of caspase-3 as well. The results also showed that Sal A significantly increased phosphorylation of Akt and that this phosphorylation can be partially inhibited by phosphoinositide 3-kinase/Akt inhibitor. Furthermore, Sal A improved I/R-induced myocardial contractile function and reduced infarct size. In summary, our results showed that Sal A prevents I/R-induced myocardial damage by reducing necrosis and apoptosis in isolated rat hearts and cardiomyocytes. PMID- 21795989 TI - Hemoglobin vesicle improves recovery of cardiac function after ischemia reperfusion by attenuating oxidative stress in isolated rat hearts. AB - Hemoglobin vesicle (HbV) could be a useful blood substitute in emergency medicine. The aim of this study was to clarify the effects of HbV on cardiac function after ischemia-reperfusion (I/R) ex vivo. Isolated rat hearts were perfused according to the Langendorff method. An ischemia-reperfusion group (n = 6) was subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. HbV (hemoglobin, 0.33 g/dL) was perfused before ischemia-reperfusion for 10 minutes (HbV group, n = 6). Hemodynamics were monitored, and tissue glutathione contents were measured. The redox state of reactive thiols in cardiac tissues was assessed by the biotinylated iodoacetamide labeling method. Left ventricular developed pressure was significantly recovered in the HbV group after 30 minutes of reperfusion (56.3 +/- 2.8 mm Hg vs. ischemia-reperfusion group 27.0 +/- 8.0 mm Hg, P < 0.05). Hemodynamic changes induced by HbV were similar to those observed when N-nitro-L-arginine methyl ester was perfused for 10 minutes before ischemia reperfusion (L-NAME group). The oxidized glutathione contents of cardiac tissues significantly decreased, and biotinylated iodoacetamide labeling of thiols was maintained in both the HbV and the L-NAME groups. HbV improved the recovery of cardiac function after ischemia-reperfusion in isolated rat hearts. This mechanism is dependent on functional protection against thiol oxidation. PMID- 21795991 TI - Thioredoxin reductase inhibition reduces relaxation by increasing oxidative stress and s-nitrosylation in mouse aorta. AB - Oxidative stress is well known to lead to vascular dysfunction. Thioredoxin reductase (TrxR) catalyzes the reduction of oxidized thioredoxin. Reduced thioredoxin plays a role in cellular antioxidative defense and in decreasing S nitrosylation. It is not known whether TrxR affects vascular reactivity. We hypothesized that TrxR inhibition decreases vascular relaxation via increased oxidative stress and S-nitrosylation. Aortic rings from C57BL/6 mice were treated with the TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB), or auranofin for 30 minutes. Vascular relaxation to acetylcholine was measured in the rings contracted with phenylephrine. DNCB and auranofin reduced relaxation compared with vehicle (vehicle Emax = 71 +/- 3%, DNCB Emax = 53 +/- 3%; P < 0.05). The antioxidants, apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), and tempol (superoxide dismutase mimetic) normalized impaired relaxation by DNCB in aorta (DNCB Emax = 53 +/- 3%, DNCB + tempol Emax = 66 +/- 3%; P < 0.05). In addition, DNCB reduced sodium nitroprusside-induced relaxation. DNCB increased soluble guanylyl cyclase (sGC) S-nitrosylation and decreased sGC activity. These data suggest that TrxR regulates vascular relaxation via antioxidant defense and sGC S-nitrosylation. TrxR may be an enzyme to approach for treatment of vascular dysfunction and arterial hypertension. PMID- 21795992 TI - Administration of rosmarinic acid reduces cardiopathology and blood pressure through inhibition of p22phox NADPH oxidase in fructose-fed hypertensive rats. AB - Rosmarinic acid (RA), a caffeic acid ester, has insulin-sensitizing and antioxidant effects in high fructose-fed model of insulin resistance (IR). This study investigated whether RA supplementation prevents cardiac abnormalities and hypertension in fructose-fed rats (FFR). Rats fed with fructose diet (60 g/100 g) for 60 days exhibited metabolic abnormalities and rise in plasma and cardiac lipids and whole body IR. The levels of cardiac antioxidants and plasma ferric reducing antioxidant power were significantly reduced in FFR concomitant with increased levels of lipid peroxidation and protein oxidation products. A significant rise in troponin T, creatine kinase-MB, aspartate transaminase, and lactate dehydrogenase in plasma of FFR was noted. RA supplementation to FFR (10 mg/kg from the 16th day) significantly improved insulin sensitivity, reduced lipid levels, oxidative damage, and the expression of p22phox subunit of nicotinamide adenine dinucleotide phosphate reduced oxidase, and prevented cardiac hypertrophy. Fructose-induced rise in blood pressure was also lowered by RA through decrease in endothelin-1 and angiotensin-converting enzyme activity and increase in nitric oxide levels. Histology revealed a reduction in myocardial damage in RA-supplemented FFR. These findings suggest that RA acts as a vasoactive substance and a cardioprotector through its antioxidant property. Thus, RA may be useful in reducing the cardiovascular risk associated with IR. PMID- 21795993 TI - Automatic tracking of the respiratory motion of lung parenchyma on dynamic magnetic resonance imaging: comparison with pulmonary function tests in patients with chronic obstructive pulmonary disease. AB - PURPOSE: This study evaluated the respiratory motion of the lung parenchyma using dynamic magnetic resonance imaging and clarified differences between healthy individuals and patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: The study comprised 6 healthy volunteers and 42 patients diagnosed with smoking-related COPD. We captured 80 sequential frames from the mid-sagittal portion of the right lung while repeating forced deep breathing using a balanced fast-field echo sequence (repetition time, 2.2 ms; echo time, 1.1 ms; slice thickness, 10 mm; field of view, 450 mm; matrix size, 128 * 256; and acquisition time, 0.28 s/frame). We traced 15 points on pulmonary vessels using a computer-aided system and measured the maximal motion distance of each tracked point. Movement of these points was then compared with spirometric data using the Pearson correlation coefficient. RESULTS: Patients with COPD showed reduced respiratory motion compared with healthy volunteers. Respiratory motion and spirometric data such as forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity showed highly significant positive correlations (correlation between normalized motion distance for the whole lung and FEV1, r = 0.75; P < 0.01). CONCLUSIONS: The respiratory motion of the pulmonary vessels reflects expansion and deflation of the lung parenchyma, and such motion is restricted in patients with COPD due to airflow limitation. PMID- 21795994 TI - Therapy-related noninfectious complications in patients with hematologic malignancies: high-resolution computed tomography findings. AB - Pulmonary complications are a leading source of mortality in patients treated for hematologic malignancies. After hematopoietic stem cell transplantation, treatment-related noninfectious complications constitute more than half of the pulmonary pathology and represent a particular diagnostic challenge. This review illustrates the high-resolution computed tomography findings of common therapy related complications and thereby demonstrates a high degree of overlap between the patterns of various toxicities. Clinical background knowledge of the distinct entities is reviewed and highlighted as an indispensable instrument to narrow the differential diagnosis. PMID- 21795995 TI - Computed tomography and 18F-fluoro-2-deoxyglucose positron emission tomography findings of primary pulmonary follicular dendritic cell sarcoma: case report and a literature review. AB - We report herein computed tomography and F-fluoro-2-deoxyglucose positron emission tomography findings of primary pulmonary follicular dendritic cell sarcoma in a 51-year-old man, which is an extremely rare malignancy originating from follicular dendritic cells. Computed tomography scan revealed a 2.4-cm, well defined solitary pulmonary nodule with delayed contrast enhancement but without regional lymphadenopathy, distant metastasis, or calcification within the nodule. On F-fluoro-2-deoxyglucose positron emission tomography scan, this nodule showed moderate hypermetabolic activity with a maximum standardized uptake value of 3.2. PMID- 21795996 TI - Computed tomography to predict surgical revascularization of a left anterior descending artery occlusion incompletely visualized by conventional angiography. AB - PURPOSE: Previous studies demonstrated that failure to visualize distal chronic total occlusion in conventional coronary angiography (CCA) does not preclude procedural success of coronary artery bypass grafting (CABG). We assessed the utility of computed tomography angiography (CTA) in guiding CABG to the occluded left anterior descending artery (LAD) incompletely visualized by CCA. MATERIALS AND METHODS: Twenty-four symptomatic patients rejected for revascularization of an occluded LAD on the basis of CCA underwent a preoperative CTA before intended transmyocardial laser revascularization. Off-pump CABG to the LAD was attempted in all patients depending on the intraoperative findings. The primary outcome was defined as procedural success of CABG to the LAD. RESULTS: The success rate for CABG was 79.2%. By CCA, Rentrop 0/1 was present in 6 patients (25%), whereas Rentrop 2 was present in 18 patients (75%). By CTA, Rentrop 3 was seen in all patients. Compared with the CABG-failure group, the CABG-success group showed a larger mean distal LAD diameter (1.7 +/- 0.2 mm vs. 1.3 +/- 0.1 mm; P=0.001). By receiver-operating curve analysis, a cutoff value of 1.5 mm for the mean distal LAD diameter predicted CABG availability with 100% specificity and 95% sensitivity. The distal LAD short length and intramyocardial course were other significant correlates of CABG failure compared with CABG success (60% vs. 5.3%, P=0.018; 80% vs. 0%, P<0.001). CONCLUSIONS: Noninvasive CTA is not only superior to CCA in delineating distal coronary occlusion but also very precisely predicts the procedural success of CABG. CTA represents a robust evaluation tool for coronary mapping of chronic total occlusion with doubtful distal anatomy in CCA. PMID- 21795997 TI - Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. AB - INTRODUCTION: Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) (IKK-beta/IKK-2), which activates NF-kappaB, is a substrate of the KEAP1-CUL3-RBX1 E3-ubiquitin ligase complex, implicating this complex in NF-kappaB pathway regulation. We investigated complex component gene disruption as a novel genetic mechanism of NF-kappaB activation in non-small cell lung cancer. METHODS: A total of 644 tumor- and 90 cell-line genomes were analyzed for gene dosage status of the individual complex components and IKBKB. Gene expression of these genes and NF-kappaB target genes were analyzed in 48 tumors. IKBKB protein levels were assessed in tumors with and without complex or IKBKB genetic disruption. Complex component knockdown was performed to assess effects of the E3-ligase complex on IKBKB and NF-kappaB levels, and phenotypic importance of IKBKB expression was measured by pharmacological inhibition. RESULTS: We observed strikingly frequent genetic disruption (42%) and aberrant expression (63%) of the E3-ligase complex and IKBKB in the samples examined. Although both adenocarcinomas and squamous cell carcinomas showed complex disruption, the patterns of gene disruption differed. IKBKB levels were elevated with complex disruption, knockdown of complex components increased activated forms of IKBKB and NF-kappaB proteins, and IKBKB inhibition detriments cell viability, highlighting the biological significance of complex disruption. NF-kappaB target genes were overexpressed in samples with complex disruption, further demonstrating the effect of complex disruption on NF-kappaB activity. CONCLUSIONS: Gene dosage alteration is a prominent mechanism that disrupts each component of the KEAP1-CUL3-RBX1 complex and its NF-kappaB stimulating substrate, IKBKB. Herein, we show that, multiple component disruption of this complex represents a novel mechanism of NF-kappaB activation in non-small cell lung cancer. PMID- 21795998 TI - Exercise-induced pain requires NMDA receptor activation in the medullary raphe nuclei. AB - PURPOSE: Pain in response to physical activity is common in people with chronic musculoskeletal pain and is likely a barrier to regular exercise, which would lead to a sedentary lifestyle. We recently developed a model of exercise-induced pain that is associated with increased activation of neurons in the medullary raphe nuclei, i.e., the nucleus raphe obscurus (NRO) and nucleus raphe pallidus (NRP). Because the NRO and NRP not only modulate motor output but also respond to noxious stimuli, we hypothesized that the NRO and NRP were key nuclei in the interaction between pain and exercise. We tested whether exercise enhances hyperalgesia through activation of N-methyl D-aspartate (NMDA) receptors in the NRO/NRP. METHODS: Muscle insult was induced by two injections of pH 5.0 saline 5 d apart into one gastrocnemius muscle. We initially tested whether hyperalgesia developed in mice injected with acidic saline (pH 5.0) into the gastrocnemius muscle immediately after a 30-min or 2-h exercise task or 2 h after a 2-h exercise task. Next, we tested whether blockade of NMDA receptors in the NRO/NRP during the exercise task prevented the development of exercise-induced hyperalgesia. Finally, we evaluated changes in phosphorylation of the NR1 subunit of the NMDA receptor (pNR1) after the exercise task at times in which muscle insult was given in behavioral experiments, i.e., immediately after a 30-min or 2 h exercise task or 2 h after the 2-h exercise task. RESULTS: All exercise conditions enhanced nociception (hyperalgesia) after combining with two injections of pH 5.0 saline. Microinjection of AP5 (1.0-0.1 nmol; 2-amino-5 phophonopenanoate) dose-dependently prevented the development of exercise-induced hyperalgesia. All exercise conditions increased pNR1 in the NRO and NRP. CONCLUSIONS: Thus, exercise-induced pain in sedentary mice is associated with increased phosphorylation and activation of NMDA receptors in the NRO/NRP, suggesting that changes in central excitability mediate an interaction between unaccustomed exercise and pain. PMID- 21795999 TI - Blood flow restriction exercise in sprinters and endurance runners. AB - PURPOSE: We demonstrated that blood flow restriction (BFR) remarkably enhances muscular metabolic stress in resistance exercise, although there is a wide range of individual differences in the responses. It is possible that these differences could be due to training status and muscular physiological characteristics. We investigated intramuscular metabolic responses during low-intensity resistance exercise with BFR between two different types of track athletes. METHODS: Twelve age-matched male track athletes (sprinter group, n = 6; endurance runner group, n = 6) were recruited and performed unilateral plantarflexion (30 repetitions per minute). The exercise protocols were as follows: low-intensity exercise at 20% of one-repetition maximum (1RM) (L), high-intensity exercise at 65% 1RM without BFR (1.3 times of systolic blood pressure), L with BFR for 2 min (L-BFR), and prolonged exercise time in L-BFR for 3 min (prolonged BFR). Metabolic stress, defined as phosphocreatine and intramuscular pH decrease, and muscle fiber recruitment were evaluated using P magnetic resonance spectroscopy. RESULTS: Endurance runners showed higher peak oxygen uptake and lower muscle strength than sprinters. Phosphocreatine decreases in endurance runners during exercise with BFR protocols were significantly greater than those in sprinters (P < 0.05), although those occurring during L were significantly lower than those in sprinters (P < 0.05). The changes in intramuscular pH and the incidence of fast twitch fiber recruitment did not show a statistical difference between the two groups. Phosphocreatine decreases in L-BFR were significantly correlated with peak oxygen uptake (P < 0.05). CONCLUSIONS: The effects of low-intensity resistance exercise with BFR are greater in endurance runners according to higher aerobic capacity. PMID- 21796001 TI - Outcome of partial contralateral C7 nerve transfer--results of 46 patients. AB - BACKGROUND: : Partial contralateral C7 transfer has been widely used, but outcomes are significantly different. Therefore, the effects of this procedure need to be evaluated. OBJECTIVE: : To evaluate the outcome of patients treated with partial contralateral C7 transfer and to determine the factors affecting the outcome of this procedure. METHODS;: A retrospective review of 46 patients with global root avulsion brachial plexus injuries who underwent contralateral C7 transfer was conducted. All surgeries were performed by two stages and median nerve was the recipient nerve. The contralateral C7 nerve was used in three different ways. The whole C7 root was used in 8 patients; the posterior division together with the lateral part of the anterior division was used in 14 patients; and the anterior or the posterior division alone was used in 24 patients. The mean follow-up period was 6.4 years. RESULTS: : The effective rate of these 46 patients was 47.83% in motor and 56.52% in sensory function. The patients with whole C7 root transfer obtained significantly better recovery than the patients with partial C7 transfer. The best functional recovery was seen if the interval between the two stages was 4 to 8 months. CONCLUSION: : Partial contralateral C7 transfer is an effective procedure in treating global brachial plexus avulsion injury. Using the whole C7 root transfer can obtain better recovery and we emphasize using the whole root as the donor. The optimal interval between the two surgery stages is 4 to 8 months. PMID- 21796000 TI - An optimized system for interventional magnetic resonance imaging-guided stereotactic surgery: preliminary evaluation of targeting accuracy. AB - BACKGROUND: Deep brain stimulation electrode placement with interventional magnetic resonance imaging (MRI) has previously been reported using a commercially available skull-mounted aiming device (Medtronic Nexframe MR) and native MRI scanner software. This first-generation method has technical limitations that are inherent to the hardware and software used. A novel system (SurgiVision ClearPoint) consisting of an aiming device (SMARTFrame) and software has been developed specifically for interventional MRI, including deep brain stimulation. OBJECTIVE: To report a series of phantom and cadaver tests performed to determine the capability, preliminary accuracy, and workflow of the system. METHODS: Eighteen experiments using a water phantom were used to determine the predictive accuracy of the software. Sixteen experiments using a gelatin-filled skull phantom were used to determine targeting accuracy of the aiming device. Six procedures in 3 cadaver heads were performed to compare the workflow and accuracy of ClearPoint with Nexframe MR. RESULTS: Software prediction experiments showed an average error of 0.9 +/- 0.5 mm in magnitude in pitch and roll (mean pitch error, -0.2 +/- 0.7 mm; mean roll error, 0.2 +/- 0.7 mm) and an average error of 0.7 +/- 0.3 mm in X-Y translation with a slight anterior (0.5 +/- 0.3 mm) and lateral (0.4 +/- 0.3 mm) bias. Targeting accuracy experiments showed an average radial error of 0.5 +/- 0.3 mm. Cadaver experiments showed a radial error of 0.2 +/- 0.1 mm with the ClearPoint system (average procedure time, 88 +/- 14 minutes) vs 0.6 +/- 0.2 mm with the Nexframe MR (average procedure time, 92 +/- 12 minutes). CONCLUSION: This novel system provides the submillimetric accuracy required for stereotactic interventions, including deep brain stimulation placement. It also overcomes technical limitations inherent in the first generation interventional MRI system. PMID- 21796002 TI - Evaluation of the antiangiogenic effect of Kringle 1-5 in a rat glioma model. AB - BACKGROUND: Kringle 1-5 (K1-5) is a potent antiangiogenesis factor for treating breast cancer and hepatocellular carcinoma. However, its use in treating brain tumors has not been studied. OBJECTIVE: To evaluate whether K1-5 is effective at treating gliomas. METHODS: The effects of K1-5 on cell morphology and cytotoxicity with or without lipopolysaccharide were tested in primary mixed neuronal-glial cultures. The antiglioma activity of K1-5 was evaluated by intra arterial administration of K1-5 at 4 days after implantation of C6 glioma cells into the rat hippocampus. In 1 group of animals, tumor size, tumor vasculature, and tumor histology were evaluated on day 12. Animal survival was assessed in the other group. RESULTS: In vitro studies showed that K1-5 did not induce cytotoxicity in neurons and glia. In vivo studies demonstrated that K1-5 reduced vessel length and vessel density and inhibited perivascular tumor invasion. In addition, K1-5 normalized vessel morphology, decreased expression of hypoxia inducible factor-1alpha and vascular endothelial growth factor, decreased tumor hypoxia, and decreased pseudopalisading necrosis. The average tumor volume was smaller in the treated than in the untreated group. Furthermore, animals treated with K1-5 survived significantly longer. CONCLUSION: Kringle 1-5 effectively reduces the growth of malignant gliomas in the rat. Although still far from translation in humans, K1-5 might be a possible future alternative treatment option for patients with gliomas. PMID- 21796003 TI - Trigeminal schwannomas: skull base approaches and operative results in 105 patients. AB - BACKGROUND: Trigeminal schwannomas make up 0.8% to 8% of all intracranial schwannomas. OBJECTIVE: To analyze our surgical experience with trigeminal schwannomas. METHODS: We performed 107 operations on 105 patients harboring trigeminal schwannomas over the past 30 years. We classified the tumors as peripheral, ganglion cavernous, posterior fossa root, and dumbbell types according to the portion of the nerve that gave rise to the tumor. RESULTS: Fourteen were peripheral-type tumors (13.1%), 39 (36.4%) were ganglion cavernous type, 22 (20.6%) were posterior fossa root type, and 32 (30.0%) were dumbbell type. Sixty-five tumors were solid, 35 were mixed, and only 7 were cystic. Among solid tumors, 14 were vascular, fibrous, and adherent to adjacent structures. Total or near-total removal was performed in 86 cases (81.9%), and subtotal removal was achieved in 18 (17.1%). The most common symptom was facial hypesthesia, occurring in 69 patients. This symptom improved in 11 patients, persisted in 50 patients, and worsened in 8 patients after surgery. New postoperative hypesthesia was observed in 8 patients. The second most common symptom was facial pain, observed in 24 patients. Facial pain subsided in 22 and persisted in 2 patients after surgery. Diplopia was observed in 21 patients. This symptom improved postoperatively in 14 patients, persisted in 6 patients, and worsened in 1 patient. CONCLUSION: The present series demonstrates acceptable results using microsurgical treatment to remove trigeminal schwannomas. Pain and diplopia may be relieved after surgery; however, hypesthesia frequently remains or may be worsened by surgery. PMID- 21796004 TI - Nerve-muscle-endplate band grafting: a new technique for muscle reinnervation.. AB - BACKGROUND: Because currently existing reinnervation methods result in poor functional recovery, there is a great need to develop new treatment strategies. OBJECTIVE: To investigate the efficacy of our recently developed nerve-muscle endplate band grafting (NMEG) technique for muscle reinnervation. METHODS: Twenty five adult rats were used. Sternohyoid (SH) and sternomastoid (SM) muscles served as donor and recipient muscle, respectively. Neural organization of the SH and SM muscles and surgical feasibility of the NMEG technique were determined. An NMEG contained a muscle block, a nerve branch with nerve terminals, and a motor endplate band with numerous neuromuscular junctions. After a 3-month recovery period, the degree of functional recovery was evaluated with a maximal tetanic force measurement. Retrograde horseradish peroxidase tracing was used to track the origin of the motor innervation of the reinnervated muscles. The reinnervated muscles were examined morphohistologically and immunohistochemically to assess the extent of axonal regeneration. RESULTS: Nerve supply patterns and locations of the motor endplate bands in the SH and SM muscles were documented. The results demonstrated that the reinnervated SM muscles gained motor control from the SH motoneurons. The NMEG technique yielded extensive axonal regeneration and significant recovery of SM muscle force-generating capacity (67% of control). The mean wet weight of the NMEG-reinnervated muscles (87% of control) was greater than that of the denervated SM muscles (36% of control). CONCLUSION: The NMEG technique resulted in successful muscle reinnervation and functional recovery. This technique holds promise in the treatment of muscle paralysis. PMID- 21796007 TI - Keyhole Concept in aneurysm surgery. PMID- 21796006 TI - Cotton-clipping technique: piece of smashed muscle as an alternative. PMID- 21796008 TI - Endovascular treatment of bilateral intracranial vertebral artery dissecting aneurysms presenting with subarachnoid hemorrhage. AB - BACKGROUND: Optimal management of bilateral vertebral artery dissecting aneurysms (bi-VDAs) causing subarachnoid hemorrhage (SAH) remains unclear. OBJECTIVE: To investigate the treatment methods and outcomes of bi-VDA causing SAH. METHODS: Seven patients were treated endovascularly for bi-VDA causing SAH. Treatment methods and outcomes were evaluated retrospectively. RESULTS: Two patients were treated with 2 overlapping stents for both ruptured and unruptured VDAs, 2 with 2 overlapping stents and coiling for ruptured VDA and with conservative treatment for unruptured VDA, 1 with internal trapping (IT) for ruptured VDA and stent assisted coiling for unruptured VDA, 1 with IT for ruptured VDA and 2 overlapping stents for unruptured VDA, and 1 with IT for ruptured VDA and a single stent for unruptured VDA. None had rebleeding during follow-up (range, 15-48 months). All patients had favorable outcomes (modified Rankin Scale score, 0-2). On follow-up angiography at 6 to 36 months, 9 treated and 2 untreated VDAs revealed stable or improved state, whereas 3 VDAs in 2 patients showed regrowth. Of the 3 recurring VDAs, 1 was initially treated with IT but recurred owing to retrograde flow to the ipsilateral posterior inferior cerebellar artery (PICA), the second was treated with single stent but enlarged, and the last was treated with 2 overlapping stents and coiling but recurred from the remnant sac harboring the PICA origin. All 3 recurred VDAs were retreated with coiling with or without stent insertion. CONCLUSION: Bilateral VDAs presenting with SAH were safely treated with endovascular methods. However, endovascular treatment may be limited for VDAs with PICA origin involvement. PMID- 21796009 TI - The use of indocyanine green videoangiography to optimize the dural opening for intracranial parasagittal lesions. AB - BACKGROUND: We describe our clinical experience with the use of indocyanine green (ICG) videoangiography to delineate the locations of the cortical draining veins before dural opening in 3 cases of parasagittal lesions. With this technique, the veins are marked through the dura, and then the dura can be opened precisely to avoid cortical venous injury. OBJECTIVE: To demonstrate in a clinical series the adjunct use of intraoperative ICG angiography to optimize the dural opening for parasagittal lesions. METHODS: We describe 3 cases of parasagittal lesions, 2 meningiomas, and 1 arteriovenous malformation treated using the described technique. RESULTS: Once the dura had been exposed, ICG at a dose of 0.25 mg/kg was injected into the patient's peripheral vein as a bolus. When the dye reached the illuminated field of interest, ICG fluorescence was induced by the use of a light source with a wave-length ICG absorption band. Thereafter, the dural cortical veins were marked through the dura and precisely opened, avoiding cortical venous injury. CONCLUSION: Indocyanine green video angiography is a safe, fast, inexpensive, and accurate investigation that allows the surgeon to strategically plan and protect important parasagittal dural venous drainage during craniotomy. PMID- 21796010 TI - Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage. AB - BACKGROUND: Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role because the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered. OBJECTIVE: To elucidate the mechanism of action of sildenafil against vasospasm and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses. METHODS: SAH was induced via endovascular perforation in male C57BL6 mice. Beginning 2 hours later, mice received sildenafil citrate (0.7, 2 or 5 mg/kg orally twice daily) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure, and intracranial pressure were examined. RESULTS: We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to decrease vasospasm and neuronal cell death and markedly improve neurological outcome without causing significant physiological side effects. CONCLUSION: Sildenafil, a US Food and Drug Administration-approved drug with a proven track record of safety in humans, is a promising new therapy for vasospasm and neurological deficits after SAH. PMID- 21796011 TI - Endovascular treatment of cervical giant perimedullary arteriovenous fistulas. AB - BACKGROUND: Giant perimedullary arteriovenous fistulas (GPMAVFs) located in the cervical region are a rare pathology with distinctive characteristics. OBJECTIVE: To evaluate clinical presentation and different endovascular treatment options of cervical GPMAVFs and review previously published data in the literature regarding cervical GPMAVFs. METHODS: Six patients with cervical GPMAVFs were found in the spinal vascular malformations database of our group collected between 1990 and 2009. Endovascular techniques and treatment outcomes were evaluated and compared with other published series. RESULTS: Clinical presentations were progressive motor deficit (5 patients), hematomyelia (1 patient), meningeal syndrome (1 patient), and respiratory arrest and gait apraxia (1 patient). Three patients were treated by the transarterial approach. One patient was treated by the transvenous approach due to previous embolizations resulting in a proximal occlusion and preventing a safe transarterial approach. A transvenous approach was used in another patient due to complex arterial anatomy. In 1 patient, direct percutaneous puncture of the venous pouch was necessary because of previous proximal occlusion of the arteries. All embolizations resulted in complete occlusions with clinical improvement, and there was no recanalization during a mean follow-up of 21 months. CONCLUSION: Transarterial embolization of cervical GPMAVFs is safe and effective when it is done in highly experienced centers. Cervical GPMAVFs that cannot be accessed by the transarterial technique due to their complex angioarchitecture can be treated by transvenous embolization or direct puncture of the venous pouch. PMID- 21796012 TI - Anterior communicating artery aneurysm rupture after intravenous thrombolysis for acute middle cerebral artery thromboembolism: case report. AB - BACKGROUND AND IMPORTANCE: The use of intravenous recombinant tissue plasminogen activator (IV rtPA) has become an integral part of modern acute ischemic stroke management; however, its use has been associated with the development of intracranial hemorrhage in 6.4% of patients. It is possible that underlying and unsuspected vascular lesions, such as cerebral aneurysms, may lead to intracranial hemorrhage after IV rtPA thrombolysis. CLINICAL PRESENTATION: We present a previously unreported case of a 51-year-old woman who presented with subarachnoid hemorrhage from an acutely ruptured anterior communicating artery aneurysm after IV rtPA treatment for acute left middle cerebral artery thromboembolism. The patient underwent mechanical thromboembolectomy of the left middle cerebral artery occlusion with resultant TIMI (Thrombolysis In Myocardial Infarction) grade I recanalization, followed by coil embolization of the anterior communicating artery aneurysm. The patient never improved neurologically, and she ultimately died. CONCLUSION: Screening to identify patients at risk for development of hemorrhagic complications from underlying structural vascular lesions before the use of IV rtPA with computed tomography angiography should be considered. PMID- 21796013 TI - Rapid enterovirus molecular testing in cerebrospinal fluid reduces length of hospitalization and duration of antibiotic therapy in children with aseptic meningitis. AB - We studied the potential benefits of introducing a rapid enterovirus molecular test in children with enterovirus meningitis. The 2 groups of pediatric patients were comparable with respect to clinical and laboratory data, but differed in availability of enterovirus test results. In the control group, the results were available within 3 to 7 days, whereas in the study group, rapid enterovirus molecular test results were available within 3 to 24 hours. The median duration of hospitalization and the duration of antibiotics were significantly reduced to, respectively, 2 days and 1 day in the study group when compared with the control group (P < 0.001). Mean costs per patient calculation showed an average reduction of more than US $1450 (P < 0.001). PMID- 21796014 TI - Use of urine dipstick evaluating young infants with fever without a source and positive urine culture. AB - We analyzed 239 febrile infants <3 months of age with a positive urine culture to examine their characteristics. Patients with altered urine dipstick showed more commonly alterations of the biologic markers for bacterial infection, and Escherichia coli was more commonly isolated. Febrile young infants with positive urine culture and negative urine dipstick may not have a urinary tract infection and less aggressive management can be considered. PMID- 21796016 TI - Developmental alveologenesis: new roles for ApoE and LDL receptor. AB - Pulmonary developmental alveologenesis occurs, in substantial part, by subdivision (septation) of the gas-exchange saccules of the morphologically immature lung. It determines the starting point of age- and disease-related alveolar loss. Because alveologenesis requires additional cell membranes, we previously asked whether apoE-/-, which delivers lipids to cells, affects pulmonary alveologenesis; male apoE-/- mice had impaired alveologenesis. We now report that, in contrast to male apoE-/- mice, female apoE mice had full developmental alveologenesis. Among mice null for LDL receptor (Ldlr-/-), the receptor for apoE-/-, females had full alveologenesis; by contrast, Ldlr-/- males, as previously shown for apoE males, had impaired alveologenesis. Thus, the absence of apoE and its receptor, Ldlr, results in impaired developmental alveologenesis in males, but their absence does not impair architectural developmental alveologenesis in females. We conclude 1) regulation of alveologenesis is a new function for apoE and Ldlr, 2) one expressed in a sexually dimorphic manner, and 3) females have different molecular requirements for alveologenesis than males, which protects them from its impairment by the absence of apoE and its receptor. PMID- 21796015 TI - Kawasaki disease in monozygotic twins. AB - Multiple lines of evidence suggest that susceptibility to Kawasaki disease (KD) is influenced by host genetics. Subclinical coronary artery vasculitis may be present in monozygotic twins who are discordant for clinical signs of KD. Health care providers should consider laboratory testing and echocardiography in both monozygotic twins when only one twin presents with clinical KD. PMID- 21796017 TI - Risk factors for epilepsy in children with neonatal encephalopathy. AB - We examined neonatal predictors of epilepsy in term newborns with neonatal encephalopathy (NE) by studying children enrolled in a longitudinal, single center cohort study. Clinical data were obtained through chart review, and MRI was performed in the neonatal period. We administered a seizure questionnaire to parents of children aged >= 12 mo (range, 12 mo to 16.5 y) to determine the outcome of epilepsy. The association between clinical predictors and time to onset of epilepsy was assessed using Cox proportional hazards regression. Thirteen of 129 children developed epilepsy: all had neonatal seizures and brain injury on neonatal MRI. Of the newborns with neonatal seizures, 25% (15.8/1000 person-years) developed epilepsy, with the highest hazard ratios (HRs) in the newborns with status epilepticus (HR, 35.8; 95% CI, 6.5-196.5). Children with severe or near-total brain injury were more likely to develop epilepsy compared with those with only mild or moderate injury (HR, 5.5; 95% CI, 1.8-16.8). In a multivariable analysis adjusting for degree of encephalopathy and severe/near total brain injury, status epilepticus was independently associated with epilepsy. These data add to information regarding epilepsy pathogenesis and further aid clinicians to counsel parents regarding the likelihood that a newborn with NE will develop epilepsy. PMID- 21796018 TI - Physiologic brain dysmaturity in late preterm infants. AB - Neonatal EEG sleep was used to determine whether differences are expressed between healthy late preterm and full-term (FT) groups. Twenty-seven 24-channel multihour studies were recorded at similar postmenstrual ages (PMA) and analyzed for eight asymptomatic late preterm infants (LPT) compared with 19 healthy FT infants as a preliminary analysis, followed by a comparison of a subset of eight FT infants, matched for gender, race, and PMA. Z scores were performed on data sets from each group pair comparing each of seven EEG/Sleep measures for entire recordings, active sleep (AS) and quiet sleep (QS) segments and artifact-free intervals. Six of seven measures showed differences between the eight LPT and eight matched FT cohort pair comparisons of >0.3; rapid eye movements, arousals during QS, spectral correlations between homologous centrotemporal regions during QS, spectral beta/alpha power ratios during AS and QS, a spectral measure of respiratory regularity during QS, and sleep cycle length. Quantitative neurophysiologic analyses define differences in brain maturation between LPT and FT infants at similar PMA. Altered EEG/Sleep behaviors in the LPT are biomarkers of developmental neuroplasticity involving interconnected neuronal networks adapting to conditions of prematurity for this largest segment of the preterm neonatal population. PMID- 21796019 TI - Calcium-modulated chloride pathways contribute to chloride flux in murine cystic fibrosis-affected macrophages. AB - Cystic fibrosis (CF), a common lethal inherited disorder defined by ion transport abnormalities, chronic infection, and robust inflammation, is the result of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-activated chloride (Cl-) channel. Macrophages are reported to have impaired activity in CF. Previous studies suggest that Cl- transport is important for macrophage function; therefore, impaired Cl- secretion may underlie CF macrophage dysfunction. To determine whether alterations in Cl- transport exist in CF macrophages, Cl- efflux was measured using N [ethoxycarbonylmethyl]- 6-methoxy-quinolinium bromide (MQAE), a fluorescent indicator dye. The contribution of CFTR was assessed by calculating Cl- flux in the presence and absence of cftr(inh)-172. The contribution of calcium (Ca(2+)) modulated Cl- pathways was assessed by examining Cl- flux with varied extracellular Ca(2+) concentrations or after treatment with carbachol or thapsigargin, agents that increase intracellular Ca(2+) levels. Our data demonstrate that CFTR contributed to Cl- efflux only in WT macrophages, while Ca(2+)-mediated pathways contributed to Cl- transport in CF and WT macrophages. Furthermore, CF macrophages demonstrated augmented Cl- efflux with increases in extracellular Ca(2+). Taken together, this suggests that Ca(2+)-mediated Cl- pathways are enhanced in CF macrophages compared with WT macrophages. PMID- 21796020 TI - Inhibitory effect of 5beta-pregnane-3alpha,20beta-diol on transcriptional activity and enzyme activity of human bilirubin UDP-glucuronosyltransferase. AB - Prolonged unconjugated hyperbilirubinemia in infants associated with breast milk feeding is a common pediatric problem known as breast milk jaundice (BMJ). A polymorphic mutation (G71R) of bilirubin UDP-glucuronosyltransferase (UGT1A1) is a known cause of BMJ on the infantile side, but the responsible components of breast milk are not currently known. We analyzed the inhibitory effect of 5beta pregnane-3alpha,20beta-diol (pregnanediol) on transcriptional activity and enzyme activity of UGT1A1. To this end, we constructed two types of expression vectors. One type comprised vectors including the upstream enhancer-promoter sequence of UGT1A1 for WT and variant type (-3279T>G with A(TA)7TAA), used in studying transcriptional regulation. The other type comprised vectors including cDNA of UGT1A1 for WT and the G71R variant, used in studying enzyme activity. In an in vitro expression study, pregnanediol did not affect the transcriptional activity of UGT1A1 enhancer-promoter complex of WT and variant type, even with coexistence of transcriptional factors such as constitutive androstane receptor or pregnane X receptor. In contrast, in the presence of 100 MUM pregnanediol, bilirubin glucuronidation of G71R-UGT1A1 was reduced to 51% of WT. We suggest that pregnanediol is a cause of breast milk jaundice in carriers of G71R. PMID- 21796021 TI - High cord blood levels of the T-helper 2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of life. AB - Exposure to a strong T-helper 2 (Th2)-like environment during fetal development may promote allergy development. Increased cord blood (CB) levels of the Th2 associated chemokine CCL22 were associated with allergy development during the first 2 y of life. The aim of the present study was to determine whether CB Th1- and Th2-associated chemokine levels are associated with allergy development during the first 6 y of life, allowing assessment of respiratory allergic symptoms usually developing in this period. The CB levels of cytokines, chemokines, and total IgE were determined in 56 children of 20 women with allergic symptoms and 36 women without allergic symptoms. Total IgE and allergen specific IgE antibody levels were quantified at 6, 12, 24 mo, and 6 y of age. Increased CB CCL22 levels were associated with development of allergic sensitization and asthma and increased CCL17 levels with development of allergic symptoms, including asthma. Sensitized children with allergic symptoms showed higher CB CCL17 and CCL22 levels and higher ratios between these Th2-associated chemokines and the Th1-associated chemokine CXCL10 than nonsensitized children without allergic symptoms. A pronounced Th2 deviation at birth, reflected by increased CB CCL17 and CCL22 levels, and increased CCL22/CXCL10 and CCL17/CXCL10 ratios might promote allergy development later in life. PMID- 21796022 TI - Responsiveness and minimal clinically important change of the Pain Disability Index in patients with chronic back pain. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: The objective of this study was to test the responsiveness and minimal clinically important change (MCIC) of the Pain Disability Index (PDI) in patients with chronic back pain (CBP). SUMMARY OF BACKGROUND DATA: Treatment of patients with CBP is primarily focused on reduction of disability. For disability measurement, the PDI is a widely used questionnaire. There are, however, no data available on responsiveness and MCIC. METHODS: Two hundred forty-two patients with CBP were included in this study. Patients filled in the PDI at baseline and at discharge. The PDI consists of 2 subscales: 1 measuring voluntary activities and 1 measuring obligatory activities. PDI was anchored at 2 self-reported global perceived effect (GPE) scales for complaints and self-care, respectively. Responsiveness was considered sufficient when Area Under the Receiver Operating Characteristics (ROC) Curve (AUC) was higher than 0.70. To test interpretability, change scores and MCIC were calculated. MCIC was tested by determination of optimal cut-off point of the ROC curve and determination of specificity and sensitivity of the optimal cut-off point. RESULTS: AUCs were 0.76 and 0.77 depending on the external criterion. The subscale obligatory activities did not meet the criteria for responsiveness (AUC: 0.63-0.69). MCIC of the PDI was 9.5 points for GPE "complaints" and 8.5 for GPE "self-care." CONCLUSION: The total score of the PDI as well as the subscale of voluntary activities is responsive. Partly because of floor effects, the subscale obligatory activities are not sufficiently responsive in patients with CBP. However, the responsiveness of this subscale in other patient groups should be further tested. In patients with CBP, change can be considered clinically important when PDI score has decreased 8.5 to 9.5 points. PMID- 21796024 TI - Predictive value of Tokuhashi scoring systems in spinal metastases, focusing on various primary tumor groups: evaluation of 448 patients in the Aarhus spinal metastases database. AB - STUDY DESIGN: We conducted a prospective cohort study of 448 patients with spinal metastases from a variety of cancer groups. OBJECTIVE: To determine the specific predictive value of the Tokuhashi scoring system (T12) and its revised version (T15) in spinal metastases of various primary tumors. SUMMARY OF BACKGROUND DATA: The life expectancy of patients with spinal metastases is one of the most important factors in selecting the treatment modality. Tokuhashi et al formulated a prognostic scoring system with a total sum of 12 points for preoperative prediction of life expectancy in 1990 and revised it in 2005 to a total sum of 15 points. There is a lack of knowledge about the specific predictive value of those scoring systems in patients with spinal metastases from a variety of cancer groups. METHODS: We included 448 patients with vertebral metastases who underwent surgical treatment during November 1992 to November 2009 in Aarhus University Hospital NBG. Data were retrieved from Aarhus Metastases Database. Scores based on T12 and T15 were calculated prospectively for each patient. We divided all the patients into different groups dictated by the site of their primary tumor. Predictive value and accuracy rate of the 2 scoring systems were compared in each cancer group. RESULTS: Both the T12 and T15 scoring systems showed statistically significant predictive value when the 448 patients were analyzed in total (T12, P < 0.0001; T15, P < 0.0001). The accuracy rate was significantly higher in T15 (P < 0.0001) than in T12. The further analyses by primary cancer groups showed that the predictive value of T12 and T15 was primarily determined by the prostate (P = 0.0003) and breast group (P = 0.0385). Only T12 displayed predictive value in the colon group (P = 0.0011). Neither of the scoring systems showed significant predictive value in the lung (P > 0.05), renal (P > 0.05), or miscellaneous primary tumor groups (P > 0.05). The accuracy rate of prognosis in T15 was significantly improved in the prostate (P = 0.0032) and breast group (P < 0.0001). CONCLUSION: Both T12 and T15 showed significant predictive value in patients with spinal metastases. T15 has a statistically higher accuracy rate than T12. Among the various cancer groups, the 2 scoring systems are especially reliable in prostate and breast metastases groups. T15 is recommended as superior to T12 because of its higher accuracy rate. PMID- 21796025 TI - Stressors of caregivers of school-age children with epilepsy and use of community resources. AB - Childhood epilepsy causes multiple stressors, difficulty in adjustment, and disruptions in family relations. This study sought to identify stressors of caregivers of school-age children and to assess whether use of community resources alleviates or contributes to caregiver stress. Stressors refer to concern about the child, communication with healthcare providers, changes in family relationships, interaction with school, and support within the community. A caregiver refers to the person who had looked after the child for the past 6-12 months. Support groups, religious or worship groups, counseling services, and traditional and spiritual faith healers were the community resources that were addressed. Face-to-face interviews were conducted on a convenience sample of 46 caregivers. A three-part structured interview schedule was used to describe demographic data, stressors of caregivers, and use of community resources. The top 6 stressors were the inability to get antiepileptic drugs, the deep pain or sadness caused by the child's seizures, caregiving (which was predominantly by mothers), limited help from the extended family, inadequate information on side effects of drugs, and inadequate information on seizures. The most commonly used community resource was religious or worship groups, with epilepsy support groups being least used. To alleviate caregiver stress, it is important that healthcare providers routinely assess the effect of seizures on caregivers and refer those requiring counseling, advocate for more male and extended family involvement in caregiving and provide adequate information on side effects of drugs and on seizures as standard practice. Nurses in developed countries should incorporate religious activities among complementary and alternative medicine interventions to reduce caregiver stress. Spiritual faith healers should be encouraged to refer clients with epilepsy for drug therapy and counseling. PMID- 21796026 TI - Sitting without back support position for prolonged consciousness disturbance patients: an intervention program case study. AB - The purpose of this research was to document and compare the before and after levels of consciousness of patients with prolonged consciousness disturbance (PCD) who sat for a specified length of time in a specially designed backless chair (Suwarou-Kun). Three patients were selected as participants using the PCD criteria described by Jennet and Plum in 1972. The Kohnan Vegetative Score (henceforth referred to as the Kohnan PCD Scale) and electroencephalography (EEG) measurements, together with direct observation of subtle changes, were used to record each participant's overt behavior and autonomic responses. A single-case observation/intervention time series design was used in this study. Length of exposure to the intervention and mean exposure time per session were as follows: case 1, 65 days and 30 minutes; case 2, 36 days and 11 minutes; and case 3, 43 days and 36 minutes. The Wilcoxon's rank sum test was used to analyze the pair of Kohnan PCD Scale and EEG scores collected before and at the midway point of each intervention session. Because more than two variables were being measured, the data were reanalyzed using repeated-measure analysis of variance. In cases 2 and 3, there were significant differences in the Kohnan PCD Scale and EEG scores during the "sitting without back support position" (SB) intervention period as well as at the midway point of each session (p < .05) compared with the measurements taken before the intervention. In all three cases, there also were subtle changes during the intervention, for example, eye movement, finger or thumb movement, strength of voice, and salivation. Alpha and beta waves were greater after the introduction of the SB intervention and preceded the behavioral response changes. The SB intervention resulted in at least some improvement in the level of consciousness for each participant. It remains an open question, however, whether longer exposure would have brought about further change. The SB intervention is costly in terms of human time and effort, and its beneficial effects beyond those measured in this study will require additional research. PMID- 21796027 TI - Global health: we are a village. PMID- 21796028 TI - Mild traumatic brain injury: a survey of perceived knowledge and learning preferences of military and civilian nurses. AB - Early case recognition and intervention by nurses for patients with mild traumatic brain injury (mTBI) can significantly improve outcomes for civilian and military patients. The "Concussion/mTBI Learning Needs Assessment for Registered Nurses Survey" was developed to evaluate bedside nurses' knowledge related to the assessment and care of patients with mTBI as well as their preferences for learning in order to develop a targeted curriculum. An anonymous, self administered, Web-based survey was available from February to August 2009. A series of invitational e-mails were sent to nurses at a convenience sample of civilian, federal, and military institutions. A total of 1,224 nurses meeting the inclusion criteria of being bedside care providers and nonadvanced practice responded and were included in the analysis (civilian, n = 731; military, n = 494). Most respondents (91.3%) considered knowledge of mTBI to be important or very important to their practice, and 44.5% saw mTBI patients at least monthly. Despite this perception of importance and exposure to the patients, nurses' self reported knowledge levels were very low. Overall, 39.8% expressed a high knowledge level (score of 4 [a lot] or 5 [expert] on a 1-5 scale) of the causes of mTBI. Fewer than 25% expressed high knowledge level in the skills needed for the identification and assessment of mTBI patients, and less than 15% had high knowledge in the treatment and prognosis of these patients. The nurses' preferred learning method was shadowing another provider (37%), but the most often used method was Internet searches (80.3%). There was minimal difference between military and civilian nurses. Although nurses recognize the importance of familiarity with mTBI for their practice and most clearly self-identify knowledge deficits in all aspects of care of the mTBI patients, a broad but succinct curriculum for the nonadvanced practice bedside nurse could provide a cost effective, quickly accessible way to provide the needed education. PMID- 21796030 TI - Supportive care needs after an acute stroke: a descriptive enquiry of caregivers' perspective. AB - This mixed-methods study explored the use of the Supportive Care Needs Framework (M. Fitch, 1998; M. Fitch, H. B. Porter, & B. D. Page, 2008) as an overall guide to identify the wide spectrum of needs of the family caregivers of patients with stroke. Within this framework, a needs assessment survey developed for a different complex medical population was modified and administered to 10 caregivers of patients recently diagnosed with stroke to identify the specific needs of this population. The applicability of the tool was further evaluated through a focus group of nurses working in acute stroke care. The Supportive Care Needs Framework provides a useful and comprehensive framework for the assessment of caregiver need. Results suggest that although additional validation is needed, the modified survey may aid nurses in early identification of caregiver needs. PMID- 21796031 TI - Reliability of a health questionnaire among women with brain injury. AB - Research with respect to traumatic brain injury (TBI) has identified differential health outcomes by gender. However, despite this, a lack of research exists regarding the impact of TBI on specific health-related issues for women. This study investigated rater agreement of a health questionnaire developed to identify health concerns among women with TBI. Thirteen women with moderate to severe brain injury completed the questionnaire twice (1 week apart) and provided feedback regarding content and ease of use. The questionnaire measures areas of menses, conception, menopause, thyroid function, and change in participation in activities after brain injury. Kappa coefficients and percentage agreement were generated to determine levels of agreement of participant responses between the two sessions. Kappa coefficients ranged from .21 to 1.00, with the highest agreement for items requiring concrete responses (e.g., yes/no) and the lowest with items requiring more subjective answers. Percentage agreement ranged from 58% to 100%. Participants rated the utility of the questionnaire as high (73% 100%). This questionnaire proved to be a reliable and useful method to gather information regarding health in women with TBI. By identifying health issues early, diagnostic and treatment intervention may be delivered in a timelier and effective manner. Further psychometric testing is required to ensure the validity of responses. PMID- 21796032 TI - Updated research priorities for neuroscience nursing. AB - In 2007, the Neuroscience Nursing Foundation (NNF) convened a research panel to update NNF's research priorities used to guide funding. The research panel identified leaders in neuroscience nursing and conducted a review of neuroscience nursing research literature and an American Association of Neuroscience Nurses membership survey on research priorities. A workgroup of leaders in neuroscience nursing was then convened to draft and set priorities on the basis of the review of the literature and the membership survey. The updated priorities were submitted to the NNF Board of Trustees for approval. The revised document reviews the mission of NNF and outlines six strategies and five program areas (including specific subareas) that represent priorities for NNF research funding. The purpose of the updated priority document is to provide guidelines for the systematic development of knowledge in neuroscience nursing through the encouragement of selected neuroscience nursing research activities. PMID- 21796033 TI - The experience of living with a family member with challenging behavior post acquired brain injury. AB - Acquired brain injury (ABI) can be a sudden, dramatic, and, sometimes, fatal event that instantly disrupts the lives of the patients and their families. Healthcare professionals and families are being confronted with the long-term effects of ABI. This article presents a descriptive phenomenological study that aimed to explore the families' meaning of living with the cognitive, emotional, and behavioral sequelae of ABI survivors. In-depth, face-to-face, semistructured interviews were conducted with a purposive sample of five family members of ABI survivors who displayed challenging behavior. Data collected were analyzed using A. Giorgi's (1985) descriptive phenomenological method of data analysis. Analysis and descriptions from the five participants revealed seven interrelated themes; one theme described the challenging behaviors of the people with ABI, and six themes described the experiences of the family members (emotional turmoil that these behaviors engendered, a profound sense of loss, concerns for their future and for the future of the person with ABI, a sense of loneliness, the effect on family functioning, and the family members' coping and adapting to the behaviors). This study contributes to healthcare providers' understanding and knowledge of families' experiences of living with a person with ABI and their cognitive, emotional, and behavioral sequelae and supports the need for continued research in this area. PMID- 21796034 TI - Comparison of outcomes before and after implementation of a water protocol for patients with cerebrovascular accident and dysphagia. AB - The aim of this study was to investigate the impact of a water protocol on the incidence of aspiration pneumonia in persons with cerebrovascular accident and dysphagia admitted to an acute neurologic rehabilitation setting. Retrospective chart review and cohort matching of persons with dysphagia admitted before and after the implementation of a water protocol were carried out. The incidence of aspiration pneumonia was higher in the cohort control group-those patients admitted during the years before the implementation of a water protocol. No persons with dysphagia who received water, even if known aspirators of thin liquids, developed aspiration pneumonia. Our findings support the premise that even in known thin liquid aspirators, offering water does not increase incidence of aspiration pneumonia. PMID- 21796035 TI - A literature review of studies using qualitative research to explore chronic neuromuscular disease. AB - Although most neuromuscular disease research articles reflect traditional quantitative approaches, qualitative methods are becoming more prevalent in the neuromuscular literature. Arguably, qualitative research provides rich data that may be used to generate patient-centered outcome measures or influence current standards of care. The purpose of this article is to explore the qualitative literature pertaining to individuals and families living with chronic neuromuscular disease in order to suggest implications for practice. Fifty-six qualitative articles addressing seven research themes including Illness Experience; Work, Recreation, and Services; Assisted Ventilation; Caregiving; Genetics; Communication and Information Seeking; and Palliative Care were identified. PMID- 21796036 TI - A nursing pilot study on bedside reporting to promote best practice and patient/family-centered care. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of bedside nursing report implementation on a pediatric neuroscience unit. BACKGROUND: The change-of-shift nursing report often involves only nurse-to-nurse communication, occurs far away from the patient's bedside, and includes little or no patient/family involvement. Studies show that the bedside nursing report is a more comprehensive and patient-centered approach (C. D. Anderson & R. R. Mangino, 2006). METHODS: Patient and nurse satisfaction and nursing overtime were measured 6 months before and 6 months after the implementation of bedside reporting. Data were analyzed using paired t test, chi-square test, and Fisher's exact tests to determine significant changes. RESULTS: Patients, families, and nurses reported an increase in satisfaction after the implementation of bedside reporting. Overtime decreased and represented a potential cost savings of nearly $13,000 annually. CONCLUSIONS: Bedside reporting saves money, improves patient and nurse satisfaction, and is a more comprehensive approach to change-of-shift reporting. PMID- 21796037 TI - Craniofacial/Neurosurgery: a multidisciplinary approach to the repair of meningoencephaloceles in a third world country. AB - The repair of meningoencephaloceles in a third world country does not have to be an unrealized goal. Utilizing a team of specialized experienced physicians to provide the treatment, patient selection, comprehensive planning for all surgical variability, and cooperative management of the patients postoperatively with the hosting physicians is essential to the success of these surgeries. In 2007, a team of physicians, including a neurosurgeon, a craniofacial surgeon, a neurosurgical resident, and nursing personnel, traveled for the first time to Davao, in the Philippines, to repair and reconstruct four patients with meningoencephalocele. The planning, surgical approach, and outcome of the repair of this defect are discussed in this article. PMID- 21796038 TI - Nursing's unprecedented opportunity and the courage to lead. PMID- 21796039 TI - Promoting Excellence in End-of-Life Care: lessons learned from a cohort of nursing home residents with advanced Huntington disease. AB - Huntington disease (HD) is a genetic neurodegenerative disorder that progresses over decades and is ultimately terminal. As HD advances, patients are frequently placed in institutional care settings, including nursing homes and hospices where family, nursing staff, and interdisciplinary team members are challenged to help patients live to their highest potential and die with dignity. Edgemoor, a distinct part of the San Diego County Psychiatric Hospital, is a regional referral facility for patients with HD. Over the past 8 years, we have cared for 53 patients with advanced HD and describe our experiences by presenting their demographic characteristics and the lessons we have learned in caring for them. Ultimately, we found that the Robert Wood Johnson Foundation's Promoting Excellence in End-of-Life Care Initiative provided a meaningful framework for setting clinical priorities. This framework is used to summarize the clinical lessons that nursing staff and interdisciplinary team members learned about caring well for institutionalized individuals with advanced HD. PMID- 21796040 TI - Devastating cerebral air embolism after central line removal. AB - BACKGROUND: Air embolism is a well-published complication arising from central venous catheter use. Literature and case studies provide information regarding clinical sequelae. Preventable mistakes still occur despite following what is considered appropriate protocol. This case report describes the neurological complications likely caused by a cerebral air embolism related to central venous catheter removal. CASE: An 84-year-old man was admitted to the neuroscience critical care unit with acute stroke symptoms and seizures after removal of a central venous catheter. CONCLUSION: There is an abundance of literature describing best practice, complications, and treatment of venous air embolism associated with central line catheter use. Utilization of central venous catheters is increasing. With increased utilization comes the responsibility to improve commonplace knowledge and ensure that practice guidelines and protocols are dependable and consistent. PMID- 21796042 TI - A program to improve secondary stroke prevention: the Colorado Neurological Institute stroke preventing recurrence of thromboembolic events through coordinated treatment program. AB - The key to secondary stroke prevention often lies in improved control of traditional stroke risk factors. Studies have shown that there is an evidence practice gap, for both physicians and patients, when it comes to adhering to national stroke prevention guidelines. We developed a program to reinforce stroke prevention messages for 1 year after a patient's ischemic stroke or transient ischemic attack. Our results show encouraging improvement in our patients' adherence to treatment guidelines for 1 year after the event, as well as a reduction in recurrent strokes as compared with the number expected. PMID- 21796043 TI - Clinical recognition and management of amyotrophic lateral sclerosis: the nurse's role. AB - Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes a progressive wasting and loss of the upper and lower motor neurons that facilitate the movement of body parts. At onset, ALS patients may show symptoms such as muscle weakness, atrophy, hyperreflexia, or bulbar symptoms such as dysphagia or dysarthria. Deterioration progresses rapidly, and the later stages of ALS are characterized by severely limited mobility and respiratory failure, which is the primary cause of death. There is no specific diagnostic test for ALS, and there are a number of other conditions that may resemble ALS, making a diagnosis difficult. The variability of the initial presentation combined with the broad differential diagnosis may result in significant delays in diagnosis or, in some cases, misdiagnosis, which in turn have a negative impact on patient outcomes. There is no cure for ALS; however, many of the symptoms are treatable, and the physical and psychological symptoms are best managed through the efforts of a coordinated, multidisciplinary team. Nurses play a critical role in the clinical management of ALS and may be involved in coordinating the activities of the team, facilitating treatment, and helping patients and caregivers in making informed treatment and end-of-life decisions. Drug therapy for ALS is currently limited to riluzole; however, patients may be treated with a number of nonpharmacologic methods on the basis of their symptoms. A number of other treatment modalities, such as stem-cell-based therapy or gene therapy, and an array of neuroprotective clinical trials are currently under development for the treatment of ALS. Nurses may also have a key role in these various ALS studies. PMID- 21796044 TI - Comorbidities and cognitive functioning: implications for nursing research and practice. AB - Optimal cognitive functioning is necessary to successfully negotiate one's environment, yet medical conditions can interfere with brain health, thus negatively impacting cognitive functioning. Such comorbidities include hypertension, heart disease, diabetes, depression, and HIV, as well as others. The physiological properties of these comorbidities can reduce one's cognitive reserve and limit one's cognitive efficiency. This article provides an overview of a few common comorbidities known to affect cognitive functioning and addresses ways in which cognitive functioning may be ameliorated and protected or mitigated in lieu of cognitive declines in such clinical populations. Implications for nursing practice and research are posited. PMID- 21796045 TI - Clinical case study: a 4-year-old boy with posterior fossa syndrome after resection of a medulloblastoma. AB - Posterior fossa syndrome can occur after neurosurgical resections of childhood posterior fossa tumors, such as medulloblastomas. Posterior fossa syndrome is characterized by transient mutism, emotional lability, cognitive deficits, weakness, ataxia, and cranial nerve dysfunction. Symptoms generally appear 1 to 3 days after surgery and persist for months to years. Neuroscience nurses play an integral role in helping affected children and their families through the diagnosis, treatment, and sequelae of this frightening syndrome. PMID- 21796046 TI - Differences among quality improvement, evidence-based practice, and research. AB - All neuroscience nurses must be able to evaluate different avenues to inform their practice and solve clinical problems. The three methodologies discussed in this article have particular strengths in certain situations and require different skill sets, time, and resources. Quality improvement, evidence-based practice, and research are interconnected and inform each other. It can be difficult at times for the practitioners to identify the right method to answer clinical questions. The state of readiness for frontline staff to manage clinical problems with evidence-based practice and research must be advanced for the scientific knowledge employed by our profession to be visible in our clinical care. PMID- 21796047 TI - Clinical practice guideline series update. PMID- 21796049 TI - Pacing strategy in schoolchildren differs with age and cognitive development. AB - PURPOSE: The study's purpose was to examine differences in pacing strategy between schoolchildren of different age, gender, and stage of cognitive development. METHODS: Schoolchildren (n = 106) from four age groups (5-6, 8-9, 11 12, and 14 yr) participated in this study. Each schoolchild completed four conservation tasks to evaluate his or her Piagetian stage of cognitive development. Each schoolchild then performed a best-effort running task on a 150 m running track that was video recorded to analyze pace at 5% increments. The length of the run was varied for each age group to ensure that all schoolchildren were running for approximately 4 min (5-6 yr = 450 m, 8-9 yr = 600 m, 11-12 yr = 750 m, and 14 yr = 900 m). RESULTS: Differences in pacing strategy were found between schoolchildren of different age (P < 0.0001), gender (P < 0.0001), and cognitive development (P < 0.0001). Pacing differences were also found between age groups after controlling for cognitive development (P < 0.001), between cognitive abilities after controlling for age (P < 0.01), and between genders after controlling for both age (P < 0.0001) and cognitive ability (P < 0.0001). CONCLUSIONS: Younger schoolchildren with less advanced cognitive development exhibited a negative pacing strategy indicating an inability to anticipate exercise demand. Older schoolchildren at a more advanced stage of cognitive development exhibited a more conservative U-shaped pacing strategy characterized by faster running speeds during the first 15% and last 20% of the run. Anticipatory pacing strategy seems to be related to both the age and cognitive development of schoolchildren. PMID- 21796048 TI - Cardiorespiratory fitness as a predictor of dementia mortality in men and women. AB - There is evidence that physical activity may reduce the risk of developing Alzheimer disease and dementia. However, few reports have examined the physical activity-dementia association with objective measures of physical activity. Cardiorespiratory fitness (hereafter called fitness) is an objective reproducible measure of recent physical activity habits. PURPOSE: We sought to determine whether fitness is associated with lower risk for dementia mortality in women and men. METHODS: We followed 14,811 women and 45,078 men, age 20-88 yr at baseline, for an average of 17 yr. All participants completed a preventive health examination at the Cooper Clinic in Dallas, TX, during 1970-2001. Fitness was measured with a maximal treadmill exercise test, with results expressed in maximal METs. The National Death Index identified deaths through 2003. Cox proportional hazards models were used to examine the association between baseline fitness and dementia mortality, adjusting for age, sex, examination year, body mass index, smoking, alcohol use, abnormal ECGs, and health status. RESULTS: There were 164 deaths with dementia listed as the cause during 1,012,125 person years of exposure. Each 1-MET increase in fitness was associated with a 14% lower adjusted risk of dementia mortality (95% confidence interval (CI) = 6%-22%). With fitness expressed in tertiles, adjusted hazard ratios (HRs) for those in the middle- and high-fitness groups suggest their risk of dementia mortality was less than half that of those in the lowest fitness group (HR = 0.44, CI = 0.26-0.74 and HR = 0.49, CI = 0.26-0.90, respectively). CONCLUSIONS: Greater fitness was associated with lower risk of mortality from dementia in a large cohort of men and women. PMID- 21796050 TI - A study of exercise modality and physical self-esteem in breast cancer survivors. AB - PURPOSE: This study, theoretically based on the Exercise Self-Esteem Model, EXSEM, examined effects of exercise modality on physical and global self-esteem (PSE, GSE) in breast cancer survivors. The EXSEM posits GSE at the apex with PSE feeding into GSE. PSE has three subdomains: physical condition (PC), attractive body (AB), and physical strength (PS). The goals were to compare the effect of combination modality versus single-modality exercise on PSE and GSE and to explore the relationship between exercise modality and the subdomains of PSE. METHODS: Survivors were randomly allocated to flexibility (F), aerobic (A), resistance (R), or aerobic plus resistance (AR), 12-wk, individualized, home based exercise program. Pre/posttesting included submaximal treadmill test, six repetition maximum chest press and leg press, YMCA bench press, shoulder/hip flexibility, and bioelectric impedance analysis body composition. Esteem measures were the Physical Self-Perception Profile and the Rosenberg Self-Esteem Scale. RESULTS: Forty-two women completed the study (F = 12, A = 10, R = 9, and AR = 11). Fitness improvements congruent with exercise modality were seen in all groups. PSE and GSE outcomes did not reveal a greater effect from the combination modality program, AR, compared with the single-modality programs A and R. The relationships between the single-modality groups and the subdomains of PC, PS, and AB were supported in the R group (PS and AB increased) and were partially supported in the A group (PC, not AB, increased). CONCLUSIONS: A single-modality R program significantly improved all domains of PSE, and participation in the A program improved the PC subdomain. The combination exercise program did not enhance PSE greater than the single-modality programs. EXSEM was a useful framework for exploring esteem in breast cancer survivors. PMID- 21796051 TI - Sweating is greater in NCAA football linemen independently of heat production. AB - PURPOSE: The study's purpose was to investigate whether differences in local sweat rates on the upper body between American football linemen (L) and backs (B) exist independently of differences in metabolic heat production. METHODS: Twelve NCAA Division I American football players (6 linemen (mass = 141.6 +/- 6.5 kg, body surface area (BSA) = 2.67 +/- 0.08 m2) and 6 backs (mass = 88.1 +/- 13.4 kg, BSA = 2.11 +/- 0.19 m2)) cycled at a fixed metabolic heat production per unit BSA of 350 W.m(-2) for 60 min in a climatic chamber (t(db) [dry bulb temperature] = 32.4 degrees C +/- 1.0 degrees C, t(wb) [wet bulb temperature] = 26.3 degrees C +/- 0.6 degrees C, v [air velocity] = 0.9 +/- 0.1 m.s(-1)). Local sweat rates on the head, arm, shoulder, lower back, and chest were measured after 10, 30, and 50 min of exercise. Core temperature, mean skin temperature, and HR were measured throughout exercise. RESULTS: Because metabolic heat production per unit surface area was fixed between participants, the rate of evaporation required for heat balance was similar (L = 261 +/- 35 W.m(-2), B = 294 +/- 30 W.m(-2), P = 0.11). However, local sweat rates on the head, arm, shoulder, and chest were all significantly greater (P < 0.05) in linemen at all time points, and end-exercise core temperature was significantly greater (P = 0.033) in linemen (38.5 degrees C +/- 0.4 degrees C) relative to backs (38.0 degrees C +/- 0.2 degrees C) despite a ~25% lower heat production per unit mass. The change in mean skin temperature from rest was greater in linemen (P < 0.001) after 15, 30, 45, and 60 min, and HR was greater in linemen for the last 30 min of exercise. CONCLUSIONS: Football linemen sweat significantly more on the torso and head than football backs independently of any differences in metabolic heat production per unit BSA and therefore the evaporative requirements for heat balance. Despite greater sweating, linemen demonstrated significantly greater elevations in core temperature suggesting that sweating efficiency (i.e., the proportion of sweat that evaporates) was much lower in linemen. PMID- 21796052 TI - Accelerometer-determined physical activity in adults and older people. AB - PURPOSE: There is a lack of large-scale comparable data on the population levels of physical activity (PA) and sedentary activity. We conducted a cross-sectional population-based multicenter study to describe the levels of PA and sedentary activity and to determine adherence to current national PA recommendations in Norwegian adults and older people. METHODS: In 2008 and 2009, PA was assessed objectively for seven consecutive days using the ActiGraph GT1M accelerometer in 3867 participants age 20-85 yr. A total of 3267 participants provided valid PA assessments that met all inclusion criteria. RESULTS: Women and men did not differ in the overall activity levels (335 and 342 counts per minute, respectively) or in steps per day (8113 and 7951 steps per day, respectively). However, for intensity-specific PA, men accumulated significantly more minutes of sedentary activity and moderate-to-vigorous PA (MVPA) compared with women (557 vs 533 min of sedentary activity, P <= 0.001 and 35 vs 33 min of MVPA, P = 0.01). Both overall activity levels and steps per day remained steady with age, until 65 yr, after which activity levels declined. CONCLUSIONS: Overall, the study sample spent 62% of their time being sedentary, 25% in low-intensity PA, 9% in lifestyle activity, and 4% in MVPA. One in five people met current national PA recommendations. These results suggest that adults and older people spend the majority of their time being sedentary and that adherence to PA recommendations is low. PMID- 21796053 TI - Correlates of heart rate recovery over 20 years in a healthy population sample. AB - INTRODUCTION: Slow HR recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral, or CHD risk factors during young adulthood were associated with the development of slow HRR. METHODS: Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985-1986) and 20-yr follow-up (2005-2006) examinations. HRR was calculated as the difference between peak HR and HR 2 min after cessation of the GXT. Slow HRR was defined as 2-min HRR <22 beats.min(-1). RESULTS: In 2730 participants who did not have slow HRR at baseline, mean +/- SD HRR was 44 +/- 11 beats.min(-1) at baseline and declined to 40 +/- 12 beats.min(-1) in 2005-2006; slow HRR developed in 5% (n = 135) of the sample by 2005-2006. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome, and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model, higher body mass index, larger waist, low education, fasting glucose, and current smoking remained significantly associated with incident slow HRR. Increasing body mass index (per SD higher) during follow-up and incident hypertension, diabetes, and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline) were each associated with significantly elevated odds of incident slow HRR. CONCLUSIONS: On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors. PMID- 21796054 TI - Reliability of cycling gross efficiency using the Douglas bag method. AB - PURPOSE: The aim of this study was to establish the reliability of gross efficiency (GE) measurement (the ratio of mechanical power input to metabolic power output, expressed as a percentage) using the Douglas bag method. METHODS: The experiment was conducted in two parts. Part 1 examined the potential for errors in the Douglas bag method arising from gas concentration analysis, bag residual volume, and bag leakage or gas diffusion rates. Part 2 of this study examined the within-subject day-to-day variability of GE in 10 trained male cyclists using the Douglas bag method. Participants completed three measurements of GE on separate days at work rates of 150, 180, 210, 240, 270, and 300 W. RESULTS: The results demonstrate that the reliability of gas sampling is high with a coefficient of variation (CV) <0.5% for both O2 and CO2. The bag residual volume CV was ~15%, which amounts to +0.4 L. This could cause the largest error, but this can be minimized by collecting large gas sample volumes. For part 2, a mean CV of 1.5% with limits of agreement of +0.6% in GE units, around a mean GE of 20.0%, was found. CONCLUSIONS: The Douglas bag method of measuring expired gases and GE was found to have very high reliability and could be considered the gold-standard approach for evaluating changes in GE. Collecting larger expired gas samples minimizes potential sources of error. PMID- 21796055 TI - Epidural analgesia is associated with improved health outcomes of surgical patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased postoperative morbidity and mortality. Epidural analgesia (EDA) improves postoperative outcome but may worsen postoperative lung function. It is unknown whether patients with COPD benefit from EDA. The objective of this study was to determine whether patients with COPD undergoing major abdominal surgery benefit from EDA in addition to general anesthesia. METHODS: This cohort study included 541 consecutive patients with COPD who underwent major abdominal surgery between 1995 and 2007 at a university medical center. Propensity scores estimating the probability of receiving EDA were used in multivariate correction. The primary outcome was postoperative pneumonia and 30-day mortality. RESULTS: There were 324 patients (60%) who received EDA in addition to general anesthesia. The incidence of postoperative pneumonia (16% vs. 11%; P = 0.08) and 30-day mortality (9% vs. 5%; P = 0.03) was lower in patients who received EDA. After correction EDA was associated with improved outcome for postoperative pneumonia (OR 0.5; 95% CI: 0.3-0.9; P = 0.03). The strongest preventive effect was seen in patients with the most severe type of COPD. CONCLUSION: This study provides evidence that in patients with COPD who are scheduled for major abdominal surgery, epidural analgesia decreases postoperative pulmonary complications. PMID- 21796056 TI - An evaluation of the role of gene expression in the prediction and diagnosis of ventilator-associated pneumonia. AB - BACKGROUND: The SepsiChip project explored transcriptional modulation associated with ventilator-associated pneumonia (VAP) in patients admitted to the intensive care unit for trauma. Genome-wide expression analysis may help to identify potential diagnostic markers for diseases. The current study examined the changes in blood transcriptome during VAP. METHODS: The authors prospectively included 165 trauma patients, and 41 developed VAP. Whole blood samples were collected at admission and at VAP. To predict VAP, the admission samples were compared by microarray in patients who did or did not develop VAP. To identify diagnosis markers, paired samples of 35 patients who developed VAP were analyzed. Using NanoString (Seattle, WA), the results were confirmed in the patients who developed VAP. Trauma patients who did not develop VAP served as controls to eliminate a time effect. RESULTS: The injury severity scores of the patients who did or did not develop VAP were 36 and 29, respectively. No predictive biomarker was identified. For patients who developed VAP, a transcriptional signature was identified between the two sampling times. However, this signature was a generalized pattern related to trauma, independent of the infectious process. Genes involved in the proinflammatory response were down-regulated in the patients who developed VAP, but this difference was not statistically significant. CONCLUSIONS: In contrast to clinical assessment, transcriptional analysis of whole blood samples cannot predict or diagnose VAP in trauma patients. Differentiating infection from inflammation seems challenging. PMID- 21796057 TI - Modality-specific somatosensory changes in a human surrogate model of postoperative pain. AB - BACKGROUND: Postoperative pain remains a challenging problem in part because the underlying mechanisms are still not well understood. There is a compelling need for translational studies in human models of postoperative pain to bridge the gap between animal models und human clinical studies. METHODS: Somatosensory changes using Quantitative Sensory Testing for up to 72 h after an experimental 4-mm incision were characterized in 20 male volunteers. RESULTS: During incision, perceived pain was 29 on a 100-point numeric rating scale and declined rapidly over the next 60 min. After incision, thresholds at the site of incision were lowered to painful heat (primary heat hyperalgesia; P < 0.01, effect size: 0.68) but not to painful cold (P > 0.05, effect size: 0.00). Remote to the incision, mechanical pain thresholds were lowered, pain ratings were increased, and an area of hyperalgesia occurred (P < 0.05, effect size: 0.56; P < 0.01, effect size: 0.70; P < 0.01, respectively; secondary mechanical hyperalgesia). All signs of heat and mechanical hyperalgesia declined until full resolution at 27-72 h after incision. Increased mechanical pain ratings remote to the incision (r = 0.47; P < 0.01) but not the area of hyperalgesia (r = 0.28) or heat hyperalgesia (r = 0.12) correlated with incision-induced pain. CONCLUSIONS: Ongoing activity of nociceptors underlying nonevoked pain after incision in humans may not be explained by sensitization of nociceptors to heat but triggers the increased painfulness of mechanical stimuli in the area of secondary hyperalgesia. However, the spatial expansion of hyperalgesia seems to rely on at least partly different mechanisms. These findings may contribute to the understanding of pain and hyperalgesia after surgery. PMID- 21796059 TI - Dual oral antiplatelet therapy and unplanned surgery: possible role for intravenous platelet glycoprotein receptor inhibitors. PMID- 21796060 TI - Peripheral extracorporeal membrane oxygenation: a useful option to allow recovery in acute cardiogenic shock. PMID- 21796061 TI - Understanding physical activity during home-based cardiac rehabilitation from multiple theoretical perspectives. AB - OBJECTIVE: : Previous studies have shown that moderate-to-vigorous physical activity (MVPA) levels during home-based cardiac rehabilitation (CR) have been problematic. Consequently, the present study examined the utility of the theory of planned behavior, protection motivation theory, and social cognitive theory in explaining physical activity (PA) during a Canadian home-based CR program. METHODS: : Patients (N = 280, mean age 62.8 years; 95.4% white, 72.5% male, 78.9% married, 52.3% retired, 48.0% income more than $60000; and 33.8% postmyocardial infarction) completed a questionnaire at program onset and a MVPA assessment at 3 month followup. RESULTS: : Path analyses showed that each theory accounted for 28% to 34% of the variance in PA. The theory of planned behavior showed that perceived behavior control was the key predictor of 3-month MVPA (beta = .36), whereas protection motivation theory showed that intention (beta = .30) was the key predictor. Finally, barrier self-efficacy (beta = .21) and the availability of home PA equipment (beta = .15) were the key predictors of 3-month MVPA within social cognitive theory. CONCLUSION: : All 3 theories appeared to be viable options to inform the development of a MVPA intervention during home-based CR. However, the key constructs to target within each theory varied, suggesting the need to potentially use multiple theories to inform intervention development. PMID- 21796063 TI - Effect of exercise-based cardiac rehabilitation following coronary artery bypass surgery on ventricular repolarization indices. AB - PURPOSE: Indices of ventricular repolarization heterogeneity are associated with future arrhythmias and sudden cardiac death. We investigated the effect of exercise-based cardiac rehabilitation (CR) on these indices in a sample of Iranian patients. METHODS: Patients (N 122), who had undergone coronary artery bypass surgery (CABGS), were enrolled in this cohort study. Sixty patients attended 15 or more sessions of CR (CR group) and the remaining 62 patients attended 5 or fewer sessions of CR (control group). A standard 12-lead electrocardiogram was recorded for each patient. QT interval dispersion (QTd), RR interval variability (RRV), and heart rate-corrected QTd (QTc-d) were measured 3 times as follow: just before surgery, at the beginning of the first session of the CR program, and at the end of the 15th session for the CR group or the last session for the control group. RESULTS: Following completion of the exercise training program, the CR group showed a significant decrease in QTd (Delta = 49.4%, P < .0001) and QTc-d (Delta = 52.8%, P .0001), but not in the control group (Delta = 13.4% and 17.9%, respectively, P > .05 for both). In both groups, no statistically significant change in RRV was observed. After adjustment for variables such as age, gender, digoxin use, beta-blocker use, and prerehabilitation ejection fraction, CR remained the independent predictor of QTd and QTc-d. CONCLUSION: Results suggest that cardiac rehabilitation and exercise training programs significantly improve the indices of ventricular repolarization heterogeneity in patients with coronary artery disease who received CABGS. PMID- 21796066 TI - Effect of zoledronic acid compared with raloxifene on bone turnover markers in postmenopausal women with low bone density. AB - OBJECTIVE: The aim of this study was to assess the effects of zoledronic acid and raloxifene on bone turnover markers. METHODS: This multicenter, randomized, double-blind study involved 110 postmenopausal women with low bone mineral density who received either a single intravenous infusion of zoledronic acid 5 mg or 6 months of daily oral raloxifene 60 mg. The primary efficacy variable was change from baseline in the bone resorption marker urine N-telopeptide of type I collagen. The secondary efficacy variable was change from baseline in the bone formation marker serum bone-specific alkaline phosphatase. Analysis time points were at 2, 4, and 6 (primary) months. RESULTS: At 6 months, zoledronic acid produced a significantly greater reduction than did raloxifene in urine N telopeptide of type I collagen (P < 0.001). Zoledronic acid also yielded significantly greater decreases in urine N-telopeptide of type I collagen at 2 and 4 months and in serum bone-specific alkaline phosphatase at all time points (P < 0.001 vs raloxifene for all comparisons). Both treatments were well tolerated. More adverse events occurred in the zoledronic acid group; these were primarily transient postdose symptoms that occurred within the first 3 days after the infusion. CONCLUSIONS: Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass. PMID- 21796067 TI - Tandem intercostal thoracic schwannomas resected using a thoracoscopic nerve sparing technique: case report. AB - BACKGROUND AND IMPORTANCE: To describe a novel nerve-sparing technique for the resection of intercostal nerve schwannomas. This case demonstrates that intercostal neuralgia can be caused by intercostal schwannomas and that it can be relieved by their removal. CLINICAL PRESENTATION: A young woman with schwannomatosis had progressively worsening intercostal neuralgia caused by compression of the intercostal nerve against the rib by tandem intercostal schwannomas. After the tumors were removed, her symptoms were completely relieved. A thoracoscopic technique was used to define the involved fascicles and to facilitate removal of the tumors while sparing the uninvolved nerve. CONCLUSION: The patient's radicular pain was relieved completely by the tumor resection. Thoracoscopic surgery offers a safe and minimally invasive technique for removal of intercostal schwannomas and is a valid alternative to open thoracotomy. Removal of thoracic schwannomas can relieve intercostal neuralgia. PMID- 21796069 TI - Brachial plexus reconstruction following resection of a malignant peripheral nerve sheath tumor: case report. AB - BACKGROUND AND IMPORTANCE: The main therapeutic approach for malignant peripheral nerve sheath tumors (MPNSTs) of the brachial plexus is wide local excision. Sacrifice of some--occasionally all--elements of the brachial plexus often is required to obtain complete resection, and therefore can be associated with significant morbidity. While peripheral nerve repair is commonly used in the setting of traumatic nerve injury, little is known about its potential use in the treatment of MPNST. CLINICAL PRESENTATION: We present a patient with an enlarging right neck mass who was diagnosed with MPNST of the brachial plexus. The patient underwent gross total resection of the tumor, requiring sectioning of the upper trunk of the brachial plexus, as well as associated divisions. Following resection, sural nerve grafts were used to connect the C5 nerve root to the anterior division of the upper trunk and the spinal accessory nerve to the suprascapular nerve, whereas a triceps branch of the radial nerve was coapted directly to the anterior division of the axillary nerve. CONCLUSION: By 20 months after surgery, the patient had regained significant strength in her upper trunk distribution and demonstrated no evidence of tumor recurrence. Brachial plexus reconstruction offers a potentially valuable surgical adjunct to MPNST treatment. PMID- 21796068 TI - Osteomalacia caused by skull base tumors: report of 2 cases. AB - BACKGROUND AND IMPORTANCE: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome rarely encountered in neurosurgical practice. We report on 2 cases of TIO caused by skull base tumors. Although the diagnosis of TIO is difficult to make and often is delayed because of the insidious nature of the symptoms, mostly systemic pain and weakness, it is curable once it is diagnosed and properly treated. CLINICAL PRESENTATION: Both patients presented with severe pain developing in the lower extremities and moving out to the entire body, as well as difficulty moving. They were diagnosed with TIO several years after onset. A high level of serum FGF23 was confirmed, and whole-body imaging studies demonstrated tumors in the middle and anterior cranial base, respectively. The patient with the anterior cranial base tumor had a history of hemorrhage into the frontal lobe and partial resection. En bloc resection of tumor with surrounding skull bone was performed. The histological diagnosis for both cases was phosphaturic mesenchymal tumor, mixed connective tissue variant. CONCLUSION: The level of FGF23 normalized immediately after surgery. Both patients experienced a dramatic relief of pain and recovery of muscle power. Although reports of osteomalacia caused by tumors in the neurosurgical field are extremely rare in the literature, its true incidence is unknown. We emphasize the importance of recognition of this syndrome and recommend total resection of tumors when possible. PMID- 21796070 TI - Delayed endovascular revascularization in a patient with progressive neurological deterioration from bilateral intracranial vertebral artery occlusions: case report. AB - BACKGROUND AND IMPORTANCE: This article describes delayed endovascular revascularization in a patient with clinical and radiographic evidence of posterior circulation hemodynamic failure in the setting of intracranial occlusive lesions. CLINICAL PRESENTATION: A 48-year-old man presented with a 6 week history of progressive headache, nausea, and ataxia. Bilateral intracranial vertebral artery occlusions and a left posterior inferior cerebellar artery stroke were diagnosed, and the patient began warfarin therapy. Despite these measures, the patient developed dense lower cranial neuropathies, including severe dysarthria, decreased left-sided hearing acuity, and left facial droop. He presented at this point for endovascular evaluation. The patient underwent successful revascularization with intravascular Wingspan stents (Boston Scientific, Natick, Massachusetts) in a delayed fashion (approximately 6 weeks after his initial stroke presentation). His neurological syndrome stabilized and began to improve slowly. CONCLUSION: Patients with arterial occlusion should be evaluated acutely for potential revascularization. In the posterior circulation, clinical progression may supplant physiological imaging in the assessment of hemodynamic collapse. A subpopulation of patients will present with progressive deficits distinct from extracranial manifestations of vertebrobasilar insufficiency; these patients should be considered for delayed revascularization. PMID- 21796071 TI - Treatment of Harlequin syndrome by costotransversectomy and sympathectomy: case report. AB - BACKGROUND AND IMPORTANCE: Harlequin syndrome is a rare neurological condition involving various degrees of unilateral hyperhidrosis and erythema of the head and neck. We present a clinical presentation and description of curative therapy in a patient with a sudden onset of Harlequin syndrome following a thoracotomy. CLINICAL PRESENTATION: A 42-year-old female with a history of mastectomy for right-sided breast cancer subsequently had a left partial pneumonectomy for a metastasis. Postoperatively, she had onset of contralateral neck and facial flushing and sweating. Flushing was triggered by emotion and exercise, but also occurred spontaneously at random intervals. Magnetic resonance imaging of the brain, cervical spine, and thoracic spine were negative for pathology. Because of the patient's surgical history and negative workup, she was given a diagnosis of Harlequin syndrome. Surgical intervention consisted of a partial right T3 costotransversectomy with T2 sympathectomy. Postoperatively, the patient's symptoms of Harlequin syndrome resolved. The procedure was complicated by T1 radicular pain, which responded well to Gabapentin. CONCLUSION: The diagnosis of Harlequin syndrome is relatively new, and the majority of the scientific literature is concerned with descriptive case presentations. We present a surgical technique for the treatment of Harlequin syndrome. PMID- 21796072 TI - Dizygotic twins with a colloid cyst of the third ventricle: case report. PMID- 21796073 TI - Detection of cerebral compromise with multimodality monitoring in patients with subarachnoid hemorrhage. AB - BACKGROUND: Studies in traumatic brain injury suggest that monitoring techniques such as brain tissue oxygen (P(BTO2)) and cerebral microdialysis may complement conventional intracranial pressure (ICP) and cerebral perfusion pressure (CPP) measurements. OBJECTIVE: In this study of poor-grade (Hunt and Hess grade IV and V) subarachnoid hemorrhage (SAH) patients, we examined the prevalence of brain hypoxia and brain energy dysfunction in the presence of normal and abnormal ICP and CPP. METHODS: SAH patients who underwent multimodal neuromonitoring and cerebral microdialysis were studied. We examined the frequency of brain hypoxia and energy dysfunction in different ICP and CPP ranges and the relationship between P(BTO2) and the lactate/pyruvate ratio (LPR). RESULTS: A total of 2394 samples from 19 patients were analyzed. There were 149 samples with severe brain hypoxia (P(BTO2) <=10 mm Hg) and 347 samples with brain energy dysfunction (LPR >40). The sensitivities of abnormal ICP or CPP for elevated LPR and reduced P(BTO2) were poor (21.2% at best), and the LPR or P(BTO2) was abnormal in many instances when ICP or CPP was normal. Severe brain hypoxia was often associated with an LPR greater than 40 (86% of samples). In contrast, mild brain hypoxia (<=20 mm Hg) and severe brain hypoxia were observed in only 53% and 36% of samples with brain energy dysfunction, respectively. CONCLUSION: Our data demonstrate that ICP and CPP monitoring may not always detect episodes of cerebral compromise in SAH patients. Our data suggest that several complementary monitors may be needed to optimize the care of poor-grade SAH patients. PMID- 21796074 TI - Novel library of selenocompounds as kinase modulators. AB - Although the causes of cancer lie in mutations or epigenic changes at the genetic level, their molecular manifestation is the dysfunction of biochemical pathways at the protein level. The 518 protein kinases encoded by the human genome play a central role in various diseases, a fact that has encouraged extensive investigations on their biological function and three dimensional structures. Selenium (Se) is an important nutritional trace element involved in different physiological functions with antioxidative, antitumoral and chemopreventive properties. The mechanisms of action for selenocompounds as anticancer agents are not fully understood, but kinase modulation seems to be a possible pathway. Various organosulfur compounds have shown antitumoral and kinase inhibition effects but, in many cases, the replacement of sulfur by selenium improves the antitumoral effect of compounds. Although Se atom possesses a larger atomic volume and nucleophilic character than sulfur, Se can also formed interactions with aminoacids of the catalytic centers of proteins. So, we propose a novel chemical library that includes organoselenium compounds as kinase modulators. In this study thirteen selenocompounds have been evaluated at a concentration of 3 or 10 uM in a 24 kinase panel using a Caliper LabChip 3000 Drug Discover Platform. Several receptor (EGFR, IGFR1, FGFR1...) and non-receptor (Abl) kinases have been selected, as well as serine/threonine/lipid kinases (AurA, Akt, CDKs, MAPKs...) implicated in main cancer pathways: cell cycle regulation, signal transduction, angiogenesis regulation among them. The obtained results showed that two compounds presented inhibition values higher than 50% in at least four kinases and seven derivatives selectively inhibited one or two kinases. Furthermore, three compounds selectively activated IGF-1R kinase with values ranging from -98% to -211%. In conclusion, we propose that the replacement of sulfur by selenium seems to be a potential and useful strategy in the search of novel chemical compound libraries against cancer as kinase modulators. PMID- 21796075 TI - Effects of lipoic acid, caffeic acid and a synthesized lipoyl-caffeic conjugate on human hepatoma cell lines. AB - Hepatocellular carcinoma (HCC) is among the most aggressive and fatal cancers. Its treatment with conventional chemotherapeutic agents is inefficient, due to several side effects linked to impaired organ function typical of liver diseases. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies. The use of dietary antioxidants and micronutrients has been proposed for HCC successful management. The aim of this work was to test in vitro the effects of lipoic acid, caffeic acid and a new synthesized lipoyl-caffeic conjugate on human hepatoma cell lines in order to assess their effect on tumor cell growth. The results of cytotoxicity assays at different times showed that the cell viability was directly proportional to the molecule concentrations and incubation times. Moreover, to evaluate the pro- or anti-inflammatory effects of these molecules, the cytokine concentrations were evaluated in treated and untreated cellular supernatants. The obtained cytokine pattern showed that, at the increasing of three molecules concentrations, three pro-inflammatory cytokines such as IL-1beta, IL-8 and TNF-alpha decreased whereas the anti-inflammatory cytokine such as IL-10 increased. PMID- 21796076 TI - Antioxidant capacities and total phenolic contents increase with gamma irradiation in two types of Malaysian honey. AB - Two types of monofloral Malaysian honey (Gelam and Nenas) were analyzed to determine their antioxidant activities and total phenolic and flavonoid contents, with and without gamma irradiation. Our results showed that both types of honey can scavenge free radicals and exhibit high antioxidant-reducing power; however, Gelam honey exhibited higher antioxidant activity (p < 0.05) than Nenas honey, which is in good correlation (r = 0.9899) with its phenolic contents. Interestingly, we also noted that both irradiated honeys have higher antioxidant activities and total phenolic and flavonoid contents compared to nonirradiated honeys by Folin-Ciocalteu and UV-spectrophotometry methods, respectively. However, HPLC analysis for phenolic compounds showed insignificant increase between irradiated and nonirradiated honeys. The phenolic compounds such as: caffeic acid, chlorogenic acid, ellagic acid, p- coumaric acid, quercetin and hesperetin as indicated by HPLC method were found to be higher in Gelam honey versus Nenas honey. In conclusion, irradiation of honey causes enhanced antioxidant activities and flavonoid compounds. PMID- 21796077 TI - 2011 Medicare review of cardiology office visits. PMID- 21796078 TI - Appropriate use criteria: the gold standard, or a mechanism for the derogation of clinical judgment? PMID- 21796079 TI - Our shared cardiology history. PMID- 21796080 TI - Recent advances in cardiovascular magnetic resonance. PMID- 21796081 TI - Non-ST-segment elevation myocardial infarction in the setting of sexual intercourse following the use of cocaine and sildenafil. AB - Acute myocardial infarction (MI) in the setting of sexual intercourse following the concomitant use of cocaine, alcohol, and sildenafil has not been previously reported. We present a case of a middle-aged patient with no previous history of angina pectoris or coronary artery disease who presents with severe ischemic chest pain and an MI induced by cocaine, alcohol, sildenafil, and sexual intercourse. PMID- 21796082 TI - Combination ranolazine and dronedarone to suppress atrial fibrillation. PMID- 21796083 TI - Residual risk and high-density lipoprotein cholesterol levels: is there a relationship? AB - Statins reduce adverse cardiovascular events in both primary and secondary prevention settings. Despite their use, however, a residual burden of cardiovascular events continues to remain; in part this residual risk is related to low high-density lipoprotein (HDL) cholesterol levels. Therefore, HDL-based interventions that either raise HDL cholesterol levels or improve HDL function have become the next target for atherosclerosis management. PMID- 21796084 TI - Emerging practice patterns and outcomes of percutaneous aortic balloon valvuloplasty in patients with severe aortic stenosis. AB - A total of 33 patients with severe aortic stenosis undergoing percutaneous aortic balloon valvuloplasty (PABV) for bridging or palliative therapy were reviewed; the emerging treatment patterns for this procedure are described. Longitudinal data suggest that PABV provides a significant reduction in peak and mean aortic valve gradients with > 12-month survival for more than half of observed patients. This supports the current application of PABV, which is currently limited to palliative care and bridging therapy to more definitive forms of future treatment, including transcatheter aortic valve implantation. PMID- 21796085 TI - Immunology insights into cardiac allograft rejection. AB - Despite long-term complications from chronic immunosuppressive therapy, the phenomenon of chronic rejection is still a limitation in cardiac allograft recipients. In this review, starting from basic immunologic concepts, we analyze the mechanisms involved in rejection following heart transplantation, with particular emphasis on chronic rejection manifested as cardiac allograft vasculopathy (CAV). Etiopathogenesis of CAV and diagnostic imaging studies are also discussed. PMID- 21796086 TI - Treatment options for patients with left main coronary artery disease. AB - Coronary artery bypass grafting (CABG) is the gold standard for the treatment of left main disease, whereas percutaneous coronary intervention is a viable option for patients who are candidates for revascularization but ineligible for CABG. CABG is limited by extended hospital stay followed by rehabilitation and mediocre long-term patency of saphenous vein grafts. Drug-eluting stents decrease the restenosis rates compared with bare metal stents and provide comparable clinical outcomes with those of CABG. Patients with isolated left main disease limited to the ostium or midbody are most likely to have good clinical outcomes with low restenosis and stent thrombosis rates. The results of the ongoing EXCEL trial, which compares left main percutaneous coronary intervention with drug-eluting stents and CABG, will provide insight regarding the ideal revascularization strategy for these patients. PMID- 21796087 TI - Coronary artery disease in women: a review and update. AB - Coronary artery disease is the leading cause of death in women in the United States. In fact, coronary events are responsible for one of every six deaths per year in the United States. Since 1984, more women than men have died of heart disease. Research has shown that there are significant differences in pathophysiology, screening, and treatment between men and women with coronary disease. Future research is needed to explain the sex-specific issues that have led to assumptions about the screening and treatment of coronary artery disease in women, which in turn have led to undertreatment and suboptimal care. PMID- 21796088 TI - Coronary artery calcium scoring. AB - Numerous clinical studies have shown that coronary artery calcium scoring provides substantial incremental risk prediction beyond conventional coronary risk factors for coronary heart disease events. About half of all patients with coronary artery disease (CAD) present initially with unexpected myocardial infarction or sudden death. Early identification of this subgroup of patients is vital for institution of intensive, early preventive measures to decrease morbidity and mortality due to CAD. PMID- 21796089 TI - Effects of myofascial technique in patients with subacute whiplash associated disorders: a pilot study. AB - BACKGROUND: Whiplash associated disorders commonly affect people after a motor vehicle accident, causing a variety of disabling manifestations. Some manual and physical approaches have been proposed to improve myofascial function after traumatic injuries, in order to effectively reduce pain and functional limitation. AIM: To evaluate whether the application of the Fascial Manipulation(c) technique could be more effective than a conventional approach to improve cervical range of motion in patients with subacute whiplash associated disorders. DESIGN: Pilot randomized clinical trial. METHODS: Eighteen patients with subacute whiplash associated disorders were randomized into two groups. Group A (N.=9) received three, 30-minute sessions, (every five days during a two week period) of neck Fascial Manipulation(c). Group B (N.=9) received ten, 30 minute sessions (five days a week for two consecutive weeks) of neck exercises plus mobilization. Patients were evaluated before, immediately after and two weeks post-treatment. PRIMARY OUTCOME MEASURES: cervical active range of motion (flexion, extension, right lateral-flexion, left lateral-flexion, right rotation, and left rotation). RESULTS: A statistically significant improvement in neck flexion was found after treatment in favour of Group A (60.2+/-10.8 degrees ) compared with Group B (46.3+/-15.1 degrees ). No differences were found between groups for the other primary outcomes at post-treatment or follow-up. CONCLUSION: The Fascial Manipulation(c) technique may be a promising method to improve cervical range of motion in patients with subacute whiplash associated disorders. CLINICAL REHABILITATION IMPACT: Myofascial techniques may be useful for improving treatment of subacute whiplash associated disorders also reducing their economic burden. PMID- 21796090 TI - Treatment of penetrating aortic ulcer by endoprosthesis: a single center experience. AB - AIM: This is a retrospective study of a single center experience in the endovascular treatment of penetrating aortic ulcer (PAU). METHODS:Sixteen consecutive patients aged 69.1+/-9.6 years presenting PAU (in the aortic arch in 2, the descending thoracic aorta in 11, and in the abdominal aorta in 3) undergone therapy. Nine patients presented symptomatic, while 7 were asymptomatic. All patients underwent computer tomography angiography (CTA) of the thoracic and the abdominal aorta. Endovascular therapy alone was carried out in 12 patients, while 4 received hybrid therapy. RESULTS:One patient died of multiorgan failure after hybrid procedure. Complications consisted of type II endoleak from lumbar arteries in 1 case of endovascular procedure, and acute respiratory insufficiency in 1 patient treated by endovascular technique on the emergency basis for aortic rupture. CONCLUSION:PAU involves more frequently the descending thoracic aorta. Endovascular treatment (alone or in hybrid therapy) can give good results in patients with severe concomitant diseases. Prognosis of these patients is not favourable in most cases (48-month survival rate 47.9%) due to severe concomitant diseases. PMID- 21796091 TI - Worldwide experience with the Endurant Stent graft: review of the literature. AB - The Endurant Stent-graft System (Medtronic Vascular, Santa Rosa, CA) is a next generation device intended to expand the applicability of endovascular aortic repair (EVAR). To date, the Endurant has been evaluated in 9 short- and intermediate-term studies, several in patients presenting with challenging aneurysm anatomies. Consistently, the device in these studies has been shown to be safe and effective, with an excellent rate of deployment success and with very low rates of type I/III endoleaks and reinterventions. Single center experience with Endurant in challenging anatomies with short kinked necks and calcified angulated iliac arteries in patients unfit for open repair and challenging anatomies show promising early results with no difference in mortality, morbidity and reintervention rates, but need cautious application for EVAR outside of the device-specific IFU. The Endurant Stent-graft Natural Selection Global Postmarket Registry (ENGAGE) is a long-term 1266-patient 80-site worldwide prospective postmarket study initiated to augment the knowledge base (poolable and comparable) about EVAR in a real-world population implanted with the Endurant. Technical and clinical data for ENGAGE patients will be reported through the expected completion of 5-year follow-up for all ENGAGE registry patients in 2018. We discuss the evolving challenges for EVAR that the Endurant and other next generation stent-grafts are designed to address and review outcomes published with the Endurant since the CE marking of the device in July 2008. PMID- 21796092 TI - Percutaneous endovascular abdominal aortic aneurysm repair: methods and initial outcomes from the first prospective, multicenter trial. AB - AIM: A totally percutaneous approach to endovascular abdominal aortic aneurysm repair (PEVAR) has been shown in multiple single center reports to be feasible. Nonetheless, questions regarding the broader applicability of the approach remain due to the lack of a randomized multicenter trial, thus preventing more widespread adoption. We report the methods and outcomes from the roll-in phase of the first prospective, multicenter trial of PEVAR. METHODS: Among 19 institutions participating in the PEVAR Trial (NCT01070069), 38 consecutive patients with abdominal aortic aneurysm were enrolled in a roll-in phase between April 2010 and May 2011. PEVAR procedures with adjunctive "pre-close" of the common femoral arteries (CFAs) targeted for large sheath access using the ProGlide or Prostar XL closure devices were performed using the Endologix IntuiTrak System. All patients were followed periprocedurally and to 30 days for major adverse events and access related vascular complications. RESULTS: Patients presented at a mean age of 71 years with mean aneurysm sac diameter of 5.6cm. Technical success of the pre close procedure was 97% (37/38 patients). In one patient, ProGlide devices failed to achieve ipsilateral CFA hemostasis, leading to bleeding requiring transfusion and surgical vascular repair. All endovascular repairs were successful. No mortality or major adverse events occurred. Other pre-close related complications occurring within 30 days included pseudoaneurysm, lower extremity ischemia, and blood transfusion. CONCLUSION: PEVAR with adjunctive 'pre-close' techniques using the ProGlide or Prostar XL devices is safe and feasible as applied in this multicenter experience. Continued evaluation in the prospective, randomized trial is warranted. PMID- 21796093 TI - Trans-collateral angioplasty for the treatment of long chronic total occlusions of superficial femoral arteries: a novel wiring technique. AB - Endovascular therapy (EVT) utilizing percutaneous transluminal angioplasty has become a standard technique to re-establish sufficient blood flow in ischemic limbs of patients with peripheral arterial disease (PAD). Long chronic total occlusion (CTO) of the superficial femoral artery (SFA) remains one of the challenging lesions in the field of EVT for PAD patients, despite the recent introduction of many dedicated interventional devices such as high-performance guidewires. In this article, we report a novel interventional technique, trans collateral angioplasty (TCA), to improve the initial success rate of EVT for long SFA-CTO lesions. We present one representative case, and describe the technical tips and appropriate device selection criteria for the TCA procedure. The outcomes of TCA for long SFA-CTO performed last year at our institution are also summarized and discussed. PMID- 21796094 TI - Nonfatal sports and recreation heat illness treated in hospital emergency departments--United States, 2001-2009. AB - Although heat illness is recognized as a leading cause of death and disability during participation in U.S. high school and collegiate athletics, the incidence of heat illness among younger children and adults participating in sports and recreational activities is unknown. To examine the incidence and characteristics of nonfatal sports and recreation heat illness among persons of all ages, CDC analyzed 2001-2009 data from the National Electronic Injury Surveillance System- All Injury Program. This report describes the results of that analysis, which found that an estimated 5,946 persons were treated in U.S. emergency departments (EDs) each year for a heat illness sustained while participating in a sport or recreational activity, for an estimated annual rate of 2.0 ED visits per 100,000 population. Incidence was highest among males (72.5%) and among those aged 15-19 years (35.6%), and 7.1% of patients were hospitalized. These findings highlight the need for effective heat illness prevention messages to target all persons who are physically active, including those who participate in unstructured sports and recreational activities. Specific emphasis should be placed on targeting appropriate prevention messages toward those aged 15-19 years, who are at greatest risk, and their coaches and parents. PMID- 21796095 TI - Characteristics associated with seasonal influenza vaccination of preschool children--Oregon, 2006-2008. AB - Starting with the 2010-11 influenza season, the Advisory Committee on Immunization Practices (ACIP) recommended that all children aged >=6 months be vaccinated against influenza annually, and that previously unvaccinated children aged <=8 years be given 2 doses of vaccine. The American Academy of Pediatrics (AAP) also recommends influenza vaccinations for this population. Throughout influenza seasons, preschool children often have higher rates of influenza related hospitalization than any other age group except older adults. To estimate influenza vaccination coverage and identify sociodemographic and health-care usage correlates of influenza vaccination status among children aged 2 years, data from the 2006-2008 Oregon Pregnancy Risk Assessment Monitoring Survey follow back survey (Oregon PRAMS-2) were analyzed. This report summarizes the results. In Oregon, 37.7% of mothers reported that their children had received an influenza vaccination during the most recent influenza season. Factors positively associated with recent influenza vaccination in the multivariable-adjusted model were children's influenza vaccination in the previous year, children's receipt of all recommended immunizations, children's uninterrupted health insurance coverage, and mothers' unmarried status. The only factor negatively associated with vaccination was use of a family doctor rather than a pediatrician for well child visits. The concern about vaccinations most commonly identified by mothers of children who had not received an influenza vaccination during the most recent influenza season (33.9%) was the opinion that too many shots are given at a time. This report highlights the need for health-care provider-based and community based strategies to increase influenza vaccination coverage for children in Oregon. PMID- 21796096 TI - HIV-2 Infection Surveillance--United States, 1987-2009. AB - Human immunodeficiency virus (HIV) is categorized into two types, HIV-1 and HIV 2. Worldwide, most HIV infections are HIV-1, whereas HIV-2 largely has been confined to persons in or from West Africa. HIV-1 and HIV-2 have the same routes of transmission, and both can cause acquired immunodeficiency syndrome (AIDS); however, HIV-2 infections should be differentiated from HIV-1 infections because they are less likely to cause AIDS and their clinical management differs. CDC's current surveillance case definition for HIV infection applies to both variants of HIV but lacks criteria for differentiating between HIV-1 and HIV-2. To enumerate and describe HIV-2 cases reported in the United States, a working case definition was developed. During 1988--June 2010, a total of 242 HIV-2 cases were reported to CDC. Of these, 166 met the working definition. These HIV-2 cases were concentrated in the Northeast (66%, including 46% in New York City) and occurred primarily among persons born in West Africa (81%). Ninety-seven of the HIV-2 cases also had a positive HIV-1 immunoblot antibody test result (e.g., Western blot). Immunoblot antibody tests currently used to confirm HIV reactive screening tests do not contain reagents specific to HIV-2 and thus are not reliable for identification of HIV-2 infections. Additional testing specific to HIV-2 should be considered if HIV-1 test results are atypical or inconsistent with clinical findings, especially for persons from West Africa. If an HIV case is reported to the health department but subsequently identified as HIV-2, health-care providers should update the case report to reflect the correct type. PMID- 21796097 TI - Progress toward elimination of lymphatic filariasis--Togo, 2000--2009. AB - Lymphatic filariasis (LF) is a disabling, mosquito-borne disease of humans caused by the parasitic filarial nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. In 2000, the Global Program to Eliminate LF (GPELF) was established with the objective of eliminating LF as a public health problem by 2020. At that time, 80 countries had ongoing transmission, with an estimated 1.34 billion persons at risk for infection and 120 million infected. This report describes the LF elimination program in Togo, one of the 39 LF-endemic countries in the World Health Organization (WHO) African Region. Togo's approach to interrupt LF transmission included screening for infection to identify LF-endemic districts and mass drug administration (MDA) of ivermectin and albendazole in LF endemic districts. MDA coverage and the impact of MDAs on the prevalence of infection were monitored throughout the program. In 2000, seven of 35 districts were LF-endemic, with baseline prevalence rates ranging from 1% to 22%. By 2009, MDAs had been conducted at least six times in each LF-endemic district. At that time, the decision was made to stop MDAs because reported drug coverage in LF endemic districts exceeded 80% and no microfilaremia was detected in persons tested to monitor impact of MDAs. Togo is the first sub-Saharan country to have stopped MDAs after prevalence data suggested that LF transmission had been interrupted. Post-MDA surveillance is continuing nationally; the next step will be to certify elimination. The successful Togo program demonstrates that LF elimination can be achieved in countries with limited resources. PMID- 21796098 TI - Out-of-hospital cardiac arrest surveillance --- Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005--December 31, 2010. AB - PROBLEM/CONDITION: Each year, approximately 300,000 persons in the United States experience an out-of-hospital cardiac arrest (OHCA); approximately 92% of persons who experience an OHCA event die. An OHCA is defined as cessation of cardiac mechanical activity that occurs outside of the hospital setting and is confirmed by the absence of signs of circulation. Whereas an OHCA can occur from noncardiac causes (i.e., trauma, drowning, overdose, asphyxia, electrocution, primary respiratory arrests, and other noncardiac etiologies), the majority (70%--85%) of such events have a cardiac cause. The majority of persons who experience an OHCA event, irrespective of etiology, do not receive bystander-assisted cardiopulmonary resuscitation (CPR) or other timely interventions that are known to improve the likelihood of survival to hospital discharge (e.g., defibrillation). Because nearly half of cardiac arrest events are witnessed, efforts to increase survival rates should focus on timely and effective delivery of interventions by bystanders and emergency medical services (EMS) personnel. This is the first report to provide summary data from an OHCA surveillance registry in the United States. REPORTING PERIOD: This report summarizes surveillance data collected during October 1, 2005-- December 31, 2010. DESCRIPTION OF THE SYSTEM: In 2004, CDC established the Cardiac Arrest Registry to Enhance Survival (CARES) in collaboration with the Department of Emergency Medicine at the Emory University School of Medicine. This registry evaluates only OHCA events of presumed cardiac etiology that involve persons who received resuscitative efforts, including CPR or defibrillation. Participating sites collect data from three sources that define the continuum of emergency cardiac care: 911 dispatch centers, EMS providers, and receiving hospitals. OHCA is defined in CARES as a cardiac arrest that occurred in the prehospital setting, had a presumed cardiac etiology, and involved a person who received resuscitative efforts, including CPR or defibrillation. RESULTS: During October 1, 2005- December 31, 2010, a total of 40,274 OHCA records were submitted to the CARES registry. After noncardiac etiology arrests and missing hospital outcomes were excluded from the analysis (n = 8,585), 31,689 OHCA events of presumed cardiac etiology (e.g., myocardial infarction or arrhythmia) that received resuscitation efforts in the prehospital setting were analyzed. The mean age at cardiac arrest was 64.0 years (standard deviation [SD]: 18.2); 61.1% of persons who experienced OHCA were male (n = 19,360). According to local EMS agency protocols, 21.6% of patients were pronounced dead after resuscitation efforts were terminated in the prehospital setting. The survival rate to hospital admission was 26.3%, and the overall survival rate to hospital discharge was 9.6%. Approximately 36.7% of OHCA events were witnessed by a bystander. Only 33.3% of all patients received bystander CPR, and only 3.7% were treated by bystanders with an automated external defibrillator (AED) before the arrival of EMS providers. The group most likely to survive an OHCA are persons who are witnessed to collapse by a bystander and found in a shockable rhythm (e.g., ventricular fibrillation or pulseless ventricular tachycardia). Among this group, survival to discharge was 30.1%. A subgroup analysis was performed among persons who experienced OHCA events that were not witnessed by EMS personnel to evaluate rates of bystander CPR for these persons. After exclusion of 3,400 OHCA events that occurred after the arrival of EMS providers, bystander CPR information was analyzed for 28,289 events. In this group, whites were significantly more likely to receive CPR than blacks, Hispanics, or members of other racial/ethnic populations (p<0.001). Overall survival to hospital discharge of patients whose events were not witnessed by EMS personnel was 8.5%. Of these, patients who received bystander CPR had a significantly higher rate of overall survival (11.2%) than those who did not (7.0%) (p<0.001). INTERPRETATION: CARES data have helped identify opportunities for improvement in OHCA care. The registry is being used continually to monitor prehospital performance and selected aspects of hospital care to improve quality of care and increase rates of survival following OHCA. CARES data confirm that patients who receive CPR from bystanders have a greater chance of surviving OHCA than those who do not. PUBLIC HEALTH ACTIONS: Medical directors and public health professionals in participating communities use CARES data to measure and improve the quality of prehospital care for persons experiencing OHCA. Tracking performance longitudinally allows communities to better understand which elements of their care are working well and which elements need improvement. Education of public officials and community members about the importance of increasing rates of bystander CPR and promoting the use of early defibrillation by lay and professional rescuers is critical to increasing survival rates. Reporting at the state and local levels can enable state and local public health and EMS agencies to coordinate their efforts to target improving emergency response for OHCA events, regardless of etiology, which can lead to improvement in OHCA survival rates. PMID- 21796099 TI - The hyperpolarization-activated cyclic nucleotide-gated HCN2 channel transports ammonium in the distal nephron. AB - Recent studies have identified Rhesus proteins as important molecules for ammonia transport in acid-secreting intercalated cells in the distal nephron. Here, we provide evidence for an additional molecule that can mediate NH3/NH4 excretion, the subtype 2 of the hyperpolarization-activated cyclic nucleotide-gated channel family (HCN2), in collecting ducts in rat renal cortex and medulla. Chronic metabolic acidosis in rats did not alter HCN2 protein expression but downregulated the relative abundance of HCN2 mRNA. Its cDNA was identical to the homolog from the brain and the protein was post-translationally modified by N type glycosylation. Electrophysiological recordings in Xenopus oocytes injected with HCN2 cRNA found that potassium was transported better than ammonium, each of which was transported significantly better than sodium, criteria that are compatible with a role for HCN2 in ammonium transport. In microperfused rat outer medullary collecting duct segments, the initial rate of acidification, upon exposure to a basolateral ammonium chloride pulse, was higher in intercalated than in principal cells. A specific inhibitor of HCN2 (ZD7288) decreased acidification only in intercalated cells from control rats. In rats with chronic metabolic acidosis, the rate of acidification doubled in both intercalated and principal cells; however, ZD7288 had no significant inhibitory effect. Thus, HCN2 is a basolateral ammonium transport pathway of intercalated cells and may contribute to the renal regulation of body pH under basal conditions. PMID- 21796100 TI - The neuropeptide galanin and variants in the GalR1 gene are associated with nicotine dependence. AB - The neuropeptide galanin and its receptors are expressed in brain regions implicated in drug dependence. Indeed, several lines of evidence support a role for galanin in modulating the effects of drugs of abuse, including morphine, cocaine, amphetamine, and alcohol. Despite these findings, the role of galanin and its receptors in the effects of nicotine is largely underexplored. Here, using mouse models of nicotine reward and withdrawal, we show that there is a significant correlation between mecamylamine-precipitated nicotine withdrawal somatic signs and basal galanin or galanin receptor 1 (GALR1) expression in mesolimbocortical dopamine regions across the BXD battery of recombinant inbred mouse lines. The non-peptide galanin receptor agonist, galnon, also blocks nicotine rewarding effects and reverses mecamylamine-precipitated nicotine withdrawal signs in ICR mice. Additionally, we conducted a meta-analysis using smoking information from six European-American and African-American data sets. In support of our animal data, results from the association study show that variants in the GALR1 gene are associated with a protective effect in nicotine dependence (ND). Taken together, our data suggest that galanin has a protective role against progression to ND, and these effects may be mediated through GALR1. PMID- 21796101 TI - Cocaine-induced adaptations in cellular redox balance contributes to enduring behavioral plasticity. AB - Impaired glutamate homeostasis in the nucleus accumbens has been linked to cocaine relapse in animal models, and results in part from cocaine-induced downregulation of the cystine-glutamate exchanger. In addition to regulating extracellular glutamate, the uptake of cystine by the exchanger is a rate limiting step in the synthesis of glutathione (GSH). GSH is critical for balancing cellular redox in response to oxidative stress. Cocaine administration induces oxidative stress, and we first determined if downregulated cystine glutamate exchange alters redox homeostasis in rats withdrawn from daily cocaine injections and then challenged with acute cocaine. Among the daily cocaine induced changes in redox homeostasis were an increase in protein S glutathionylation and a decrease in expression of GSH-S-transferase pi (GSTpi). To mimic reduced GSTpi, a genetic mouse model of GSTpi deletion or pharmacological inhibition of GSTpi by administering ketoprofen during daily cocaine administration was used. The capacity of cocaine to induce conditioned place preference or locomotor sensitization was augmented, indicating that reducing GSTpi may contribute to cocaine-induced behavioral neuroplasticity. Conversely, an acute cocaine challenge after withdrawal from daily cocaine elicited a marked increase in accumbens GSTpi, and the expression of behavioral sensitization to a cocaine challenge injection was inhibited by ketoprofen pretreatment; supporting a protective effect by the acute cocaine-induced rise in GSTpi. Together, these data indicate that cocaine-induced oxidative stress induces changes in GSTpi that contribute to cocaine-induced behavioral plasticity. PMID- 21796102 TI - Social interaction promotes nicotine self-administration with olfactogustatory cues in adolescent rats. AB - Cigarette smoking is a social behavior. Smoking is also accompanied by distinctive gustatory and olfactory stimulation. However, none of these factors affecting nicotine intake are modeled in existing preclinical studies. We report a novel model of adolescent nicotine self-administration (SA) in rats where licking on drinking spouts was used as the operant behavior to activate the concurrent delivery of nicotine (i.v.) and an appetitive olfactogustatory (OG) cue, and social interaction was required for stable SA. The operant chamber was divided by a panel that separated the SA rat and another rat serving as the demonstrator, who had free access to the OG cue but did not receive nicotine. Orofacial contacts were permitted by the divider. Conditioned taste aversion prevented solo rats to self-administer nicotine. However, stable nicotine (15-30 MUg/kg, free base) SA was established in the presence of demonstrator rats with free access to the OG cue. Omitting the olfactory component of the cue prevented the acquisition of nicotine SA. Mecamylamine, a nicotinic antagonist, reduced licking behavior. Familiar peers were more effective demonstrators in facilitating the acquisition of nicotine SA than were unfamiliar rats. No sex difference in nicotine intake was found. These data indicate that the contingent OG cue is associated with the aversive property of nicotine that prevents subsequent drug intake. Social information encoded in olfaction not only permits the establishment of stable nicotine SA but also enhances nicotine intake. These findings implicate adolescent social interactions in promoting smoking behavior by surmounting the aversive property of nicotine. PMID- 21796103 TI - The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. AB - Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and IL-1 beta (IL-1beta), are elevated in subjects with major depressive disorder (MDD). The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNFalpha, IL-6, and IL-1beta during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNFalpha, IL-6, and/or IL 1beta were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNFalpha. On the other hand, antidepressant treatment did reduce levels of IL-1beta and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNFalpha. Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain. PMID- 21796104 TI - Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: peripheral vs central administration. AB - Oxytocin is known to have anti-anxiety and anti-stress effects. Using a fear potentiated startle paradigm in rats, we previously demonstrated that subcutaneously administered oxytocin suppressed acoustic startle following fear conditioning compared with startle before fear conditioning (termed background anxiety), but did not have an effect on cue-specific fear-potentiated startle. The findings suggest oxytocin reduces background anxiety, an anxious state not directly related to cue-specific fear, but sustained beyond the immediate threat. The goal of the present study was to compare the effects of centrally and peripherally administered oxytocin on background anxiety and cue-specific fear. Male rats were given oxytocin either subcutaneously (SC) or intracerebroventricularly (ICV) into the lateral ventricles before fear potentiated startle testing. Oxytocin doses of 0.01 and 0.1 MUg/kg SC reduced background anxiety. ICV administration of oxytocin at doses from 0.002 to 20 MUg oxytocin had no effect on background anxiety or cue-specific fear-potentiated startle. The 20 MUg ICV dose of oxytocin did reduce acoustic startle in non-fear conditioned rats. These studies indicate that oxytocin is potent and effective in reducing background anxiety when delivered peripherally, but not when delivered into the cerebroventricular system. Oxytocin given systemically may have anti anxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in many anxiety and mental health disorder patients. PMID- 21796105 TI - Decreased proliferation of adult hippocampal stem cells during cocaine withdrawal: possible role of the cell fate regulator FADD. AB - The current study uses an extended access rat model of cocaine self administration (5-h session per day, 14 days), which elicits several features manifested during the transition to human addiction, to study the neural adaptations associated with cocaine withdrawal. Given that the hippocampus is thought to have an important role in maintaining addictive behavior and appears to be especially relevant to mechanisms associated with withdrawal, this study attempted to understand how extended access to cocaine impacts the hippocampus at the cellular and molecular levels, and how these alterations change over the course of withdrawal (1, 14, and 28 days). Therefore, at the cellular level, we examined the effects of cocaine withdrawal on cell proliferation (Ki-67+ and NeuroD+ cells) in the DG. At the molecular level, we employed a 'discovery' approach with gene expression profiling in the DG to uncover novel molecules possibly implicated in the neural adaptations that take place during cocaine withdrawal. Our results suggest that decreased hippocampal cell proliferation might participate in the adaptations associated with drug removal and identifies 14 days as a critical time-point of cocaine withdrawal. At the 14-day time-point, gene expression profiling of the DG revealed the dysregulation of several genes associated with cell fate regulation, highlighting two new neurobiological correlates (Ascl-1 and Dnmt3b) that accompany cessation of drug exposure. Moreover, the results point to Fas-Associated protein with Death Domain (FADD), a molecular marker previously associated with the propensity to substance abuse and cocaine sensitization, as a key cell fate regulator during cocaine withdrawal. Identifying molecules that may have a role in the restructuring of the hippocampus following substance abuse provides a better understanding of the adaptations associated with cocaine withdrawal and identifies novel targets for therapeutic intervention. PMID- 21796107 TI - Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington's disease. AB - Emerging evidence suggests that the mood stabilizers lithium and valproate (VPA) have broad neuroprotective and neurotrophic properties, and that these occur via inhibition of glycogen synthase kinase 3 (GSK-3) and histone deacetylases (HDACs), respectively. Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by impaired movement, cognitive and psychiatric disturbances, and premature death. We treated N171-82Q and YAC128 mice, two mouse models of HD varying in genetic backgrounds and pathological progressions, with a diet containing therapeutic doses of lithium, VPA, or both. Untreated, these transgenic mice displayed a decrease in levels of GSK-3beta serine 9 phosphorylation and histone H3 acetylation in the striatum and cerebral cortex around the onset of behavioral deficits, indicating a hyperactivity of GSK 3beta and HDACs. Using multiple well-validated behavioral tests, we found that co treatment with lithium and VPA more effectively alleviated spontaneous locomotor deficits and depressive-like behaviors in both models of HD mice. Furthermore, compared with monotherapy with either drug alone, co-treatment more successfully improved motor skill learning and coordination in N171-82Q mice, and suppressed anxiety-like behaviors in YAC128 mice. This combined treatment consistently inhibited GSK-3beta and HDACs, and caused a sustained elevation in striatal as well as cortical brain-derived neurotrophic factor and heat shock protein 70. Importantly, co-treatment markedly prolonged median survival of N171-82Q mice from 31.6 to 41.6 weeks. Given that there is presently no proven treatment for HD, our results suggest that combined treatment with lithium and VPA, two mood stabilizers with a long history of safe use in humans, may have important therapeutic potential for HD patients. PMID- 21796108 TI - Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. AB - Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) and, possibly, the glycine co agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4 (ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 MUl) or ESBA (10 mM, 10 MUl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 MUM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels. PMID- 21796106 TI - Therapeutic strategies in fragile X syndrome: dysregulated mGluR signaling and beyond. AB - Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS. PMID- 21796109 TI - Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system. AB - Rapid tolerance develops to many of nicotine's behavioral and autonomic effects. A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naive, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption. PMID- 21796110 TI - Synaptic and morphological neuroadaptations in the putamen associated with long term, relapsing alcohol drinking in primates. AB - Alcoholism and alcohol use disorders are characterized by several months to decades of heavy and problematic drinking, interspersed with periods of abstinence and relapse to heavy drinking. This alcohol-drinking phenotype was modeled using macaque monkeys to explore neuronal adaptations in the striatum, a brain region controlling habitual behaviors. Prolonged drinking with repeated abstinence narrowed the variability in daily intake, increased the amount of ethanol consumed in bouts, and led to higher blood ethanol concentrations more than twice the legal intoxication limit. After the final abstinence period of this extensive drinking protocol, we found a selective increase in dendritic spine density and enhanced glutamatergic transmission in the putamen, but not in the caudate nucleus. Intrinsic excitability of medium-sized spiny neurons was also enhanced in the putamen of alcohol-drinking monkeys in comparison with non drinkers, and GABAeric transmission was selectively suppressed in the putamen of heavy drinkers. These morphological and physiological changes indicate a shift in the balance of inhibitory/excitatory transmission that biases the circuit toward an enduring increase in synaptic activation of putamen output as a consequence of prolonged heavy drinking/relapse. The resultant potential for increased putamen activation may underlie an alcohol-drinking phenotype of regulated drinking and sustained intoxication. PMID- 21796111 TI - Antidepressant and proneurogenic influence of environmental enrichment in mice: protective effects vs recovery. AB - Physical-cognitive activity has long-lasting beneficial effects on the brain and on behavior. Environmental enrichment (EE) induces brain activity known to influence the behavior of mice, as measured in learned helplessness paradigms (forced swim test), and neurogenic cell populations in the hippocampal dentate gyrus. However, it is not completely clear whether the antidepressant and proneurogenic effects of EE are different in animals that are naive or pre exposed to the stress inducing helplessness, and if this depends on the type of stressor. It also remains unclear whether differential effects are exerted on distinct neurogenic subpopulations. We found that EE has a protective effect in adult female mice (C57BL/6J) when exposed twice to the same stressor (forced swim test) but it has no influence on recovery. The repeated exposure to this stressor was analyzed together with the effects of EE on different neurogenic populations distinguished by age and differentiation state. Younger cells are more sensitive and responsive to the conditions, both the positive and negative effects. These results are relevant to identify the cell populations that are the targets of stress, depression, and enrichment, and that form part of the mechanism responsible for mood dysfunctions. PMID- 21796113 TI - Synergy between intraepithelial lymphocytes and lamina propria T cells drives intestinal inflammation during infection. AB - Oral infection of C57BL/6 mice with Toxoplasma gondii triggers severe necrosis in the ileum within 7-10 days of infection. Lesion development is mediated by Th-1 cytokines, CD4+ T cells, and subepithelial bacterial translocation. As such, these features share similarity to Crohn's disease. Recently, we uncovered a role for intraepithelial lymphocytes (IELs) in mediating pathology after Toxoplasma infection. We show here that alphabeta and not gammadelta T-cell IELs mediate intestinal damage. By adoptive transfer of mucosal T cells into naive Rag1-/- mice, we demonstrate that IELs do not function alone to cause inflammatory lesions, but act with CD4+ T lymphocytes from the lamina propria (LP). Furthermore, recipient mice pretreated with broad-spectrum antibiotics to eliminate intestinal flora resisted intestinal disease after transfer of IELs and LP lymphocytes. Our data provide valuable new insights into the mechanisms of intestinal inflammation, findings that have important implications for understanding human inflammatory bowel disease. PMID- 21796114 TI - Essential pharmacokinetic information for drug dosage decisions: a concise visual presentation in the drug label. PMID- 21796112 TI - Effects of progesterone and testosterone on cocaine self-administration and cocaine discrimination by female rhesus monkeys. AB - The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose-effect curves in female rhesus monkeys. Cocaine self administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose-effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032-0.32 mg/kg, i.m.) and testosterone (0.001 0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse. PMID- 21796115 TI - Cancer pharmacogenomics. PMID- 21796116 TI - Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level. AB - The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU >=6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 umol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 umol/l were required to achieve SU <6 mg/dl. PMID- 21796117 TI - An ancient recipe for flood-basalt genesis. AB - Large outpourings of basaltic lava have punctuated geological time, but the mechanisms responsible for the generation of such extraordinary volumes of melt are not well known. Recent geochemical evidence suggests that an early-formed reservoir may have survived in the Earth's mantle for about 4.5 billion years (ref. 2), and melts of this reservoir contributed to the flood basalt emplaced on Baffin Island about 60 million years ago. However, the volume of this ancient mantle domain and whether it has contributed to other flood basalts is not known. Here we show that basalts from the largest volcanic event in geologic history- the Ontong Java plateau--also exhibit the isotopic and trace element signatures proposed for the early-Earth reservoir. Together with the Ontong Java plateau, we suggest that six of the largest volcanic events that erupted in the past 250 million years derive from the oldest terrestrial mantle reservoir. The association of these large volcanic events with an ancient primitive mantle source suggests that its unique geochemical characteristics--it is both hotter (it has greater abundances of the radioactive heat-producing elements) and more fertile than depleted mantle reservoirs-may strongly affect the generation of flood basalts. PMID- 21796118 TI - Neuronal basis of age-related working memory decline. AB - Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits. PMID- 21796119 TI - Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. AB - Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. PMID- 21796120 TI - Transient dynamics of an altered large marine ecosystem. AB - Overfishing of large-bodied benthic fishes and their subsequent population collapses on the Scotian Shelf of Canada's east coast and elsewhere resulted in restructuring of entire food webs now dominated by planktivorous, forage fish species and macroinvertebrates. Despite the imposition of strict management measures in force since the early 1990s, the Scotian Shelf ecosystem has not reverted back to its former structure. Here we provide evidence of the transient nature of this ecosystem and its current return path towards benthic fish species domination. The prolonged duration of the altered food web, and its current recovery, was and is being governed by the oscillatory, runaway consumption dynamics of the forage fish complex. These erupting forage species, which reached biomass levels 900% greater than those prevalent during the pre-collapse years of large benthic predators, are now in decline, having outstripped their zooplankton food supply. This dampening, and the associated reduction in the intensity of predation, was accompanied by lagged increases in species abundances at both lower and higher trophic levels, first witnessed in zooplankton and then in large bodied predators, all consistent with a return towards the earlier ecosystem structure. We conclude that the reversibility of perturbed ecosystems can occur and that this bodes well for other collapsed fisheries. PMID- 21796122 TI - Measurement of pulse wave velocity in children and young adults: a comparative study using three different devices. AB - To estimate the value of pulse wave velocity (PWV) in pediatric cardiovascular disease, prospective studies are needed. Various instruments based on different measurement principles are proposed for use in children, hence the need to test the comparability of these devices in this younger population. The objective of this study was to compare PWV measured by oscillometry (Vicorder (VIC)) with the gold standard of applanation tonometry (PulsePen (PP), Sphygmocor (SC)). PWV was measured in 98 children and young adults (age: 16.7(6.3-26.6) years (median(range)) with the above three devices at the same visit under standardized conditions. Mean PWV measured by VIC was significantly lower than that measured by SC and PP. There was no difference following path length correction of the VIC measurement (using the distance between the jugular notch and the center of the femoral cuff), (PP: 6.12(1.00), SC: 5.94(0.91), VIC: 6.14(0.75) m s(-1)). Velocities measured by the three devices showed highly significant correlations. Bland-Altman analysis revealed excellent concordance between all three devices, however, there was a small but significant proportional error in the VIC measurements showing a trend toward lower PWV measured by VIC at higher PWV values. Our study provides data on the three most frequently used instruments in pediatrics. Following path length correction of the VIC, all three devices provided comparable results. Thus, our work allows extrapolating data between previously established normal PWV values for children and forthcoming studies using these instruments to assess children at long-term risk of cardiovascular disease. The small proportional error of VIC needs additional technical development to improve the accuracy of the measurements. PMID- 21796121 TI - Neocortical excitation/inhibition balance in information processing and social dysfunction. AB - Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms. PMID- 21796123 TI - Angiotensin II receptor blocker and long-acting calcium channel blocker combination therapy decreases urinary albumin excretion while maintaining glomerular filtration rate. AB - Microalbuminuria is a recognized risk factor and predictor for cardiovascular events in patients with hypertension. We analyzed changes in hypotensive effect, urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) in subjects with hypertension and microalbuminuria as a subanalysis of the results of the Nifedipine and Candesartan Combination (NICE-Combi) Study. A total of 86 subjects with essential hypertension with microalbuminuria (UAE <300 mg g( 1) creatinine) were randomly assigned in a double-blind manner to a combination therapy group (standard-dose candesartan at 8 mg per day plus controlled-release (CR) nifedipine 20 mg per day) (n=42) or an up-titrated monotherapy group (candesartan 12 mg per day) (n=44) for 8 weeks of continuous treatment after initially receiving standard-dose candesartan (8 mg per day) monotherapy for 8 weeks (initial treatment). After 8weeks, blood pressure (BP) was significantly reduced in both groups compared with at the end of initial treatment. UAE also showed a significant decrease in the combination therapy group, while there was no significant change of eGFR in either group. A significant positive correlation was seen between BP reduction and UAE after 8 weeks of double-blind treatment in both groups, whereas no significant association was found between DeltaUAE and DeltaeGFR in either group. These findings show that combination therapy with standard-dose candesartan and nifedipine CR is more effective than up-titrated candesartan monotherapy for reducing BP and improving UAE while maintaining eGFR, and strongly suggest that the combination of an angiotensin II receptor blocker and long-acting calcium channel blocker is beneficial in patients with hypertension and microalbuminuria. PMID- 21796124 TI - Hyperinsulinemia induces hypertension associated with neurogenic vascular dysfunction resulting from abnormal perivascular innervations in rat mesenteric resistance arteries. AB - We previously reported that chronic hyperinsulinemia and insulin resistance induced by fructose-drinking loading elicited hypertension associated with abnormal neuronal regulation of vascular tone in an in vivo study using pithed rats. Therefore, to further clarify the detailed mechanisms of perivascular nervous system malfunction induced by chronic hyperinsulinemia, we investigated the neurogenic vascular responses and distribution of perivascular nerves using mesenteric vascular beds isolated from fructose-loaded rats with hyperinsulinemia. Male Wistar rats (6 weeks old) received 15% fructose solution as drinking fluid for 10 weeks (fructose-drinking rats, FDR), which resulted in significant increases in plasma levels of insulin, the glucose-insulin index, blood norepinephrine (NE) levels and systolic blood pressure, but not blood glucose levels, when compared with normal water-drinking rats (control rats). In perfused mesenteric vascular beds of FDR, enhanced adrenergic nerve-mediated vasoconstriction with no effect on NE-induced vasoconstriction and decreased calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation with no effect on CGRP-induced vasodilation were observed. Immunohistochemistry studies showed increased density of neuropeptide Y immunopositive adrenergic fibers and reduced density of CGRP immunopositive fibers in mesenteric arteries of FDR. Furthermore, FDR showed decreased CGRP content in dorsal root ganglia. These findings suggest that dysfunction of the neuronal vascular control system resulting from abnormal innervation of mesenteric perivascular nerves induced by the hyperinsulinemic state is responsible for the development of hypertension in FDR. PMID- 21796125 TI - Blood pressure levels in patients with subclinical thyroid dysfunction: a meta analysis of cross-sectional data. AB - The relationship between subclinical thyroid dysfunction and blood pressure is controversial and has received insufficient attention. The aim of this study was to assess whether blood pressure levels in patients with subclinical thyroid dysfunction differ from those of euthyroid subjects. A meta-analysis of all cross sectional studies was performed to compare the blood pressure levels in patients with subclinical thyroid dysfunction with those of healthy controls. A computer based online retrieval of databases (MEDLINE and EMBASE) and manual searches were undertaken to identify articles that addressed the association between subclinical thyroid dysfunction and blood pressure levels and were published through 2010, using no language restrictions. The meta-analysis was performed using STATA 11 (Stata). Seven cross-sectional studies were examined. In patients with subclinical hypothyroidism, the pooled estimate of the weighted mean difference (WMD) of increased blood pressure revealed a significant difference in both systolic blood pressure (SBP; WMD with 95% confidence interval (CI) 1.89 mm Hg (0.98-2.80), P<0.05) and diastolic blood pressure (DBP; WMD with 95% CI 0.75 mm Hg (0.24-1.27), P<0.05). However, in patients with subclinical hyperthyroidism, the pooled estimate of the WMD of increased blood pressure revealed no significant difference in SBP (WMD with 95% CI -0.75 mm Hg (-1.81 to 0.31)) or DBP (WMD with 95% CI -0.64 mm Hg (-2.36 to 1.08)). The present meta analysis indicates that subclinical hypothyroidism is associated with increased SBP and DBP, whereas subclinical hyperthyroidism is not. Further investigation is needed to confirm blood pressure levels in patients with subclinical thyroid dysfunction. PMID- 21796126 TI - Roles of central renin-angiotensin system and afferent renal nerve in the control of systemic hemodynamics in rats. AB - Afferent renal nerves (ARNs) convey signals generated by physiological changes in the kidney to the central nervous system. The aim of this study was to determine whether ARNs contribute to cardiovascular regulation through central renin angiotensin system (RAS)-dependent pathways. Blood pressure and renal sympathetic nerve activity (RSNA) were monitored during elevations in pelvic pressure in anesthetized Wistar-Kyoto Izm (WKY) rats and spontaneously hypertensive Izm rats (SHRs). In both groups of rats, blood pressure and RSNA were significantly increased in response to elevations in renal pelvic pressure in a pressure dependent fashion, which were prevented by renal denervation. Injection of an angiotensin II type I receptor blocker (CV-11974, 10 MUg) into the intracerebroventricular region significantly suppressed the vasopressor and sympathoexcitatory responses to the increases in pelvic pressure in both WKY rats and SHRs, although these inhibitory effects of CV-11974 in SHRs appeared to be weaker than in WKY rats. These results indicate that signals transmitted by ARNs have an important role in the control of systemic hemodynamics through regulating central RAS-mediated changes in sympathetic nerve activity. PMID- 21796127 TI - Increased risk of cardiovascular events and mortality among non-diabetic chronic kidney disease patients with hypertensive nephropathy: the Gonryo study. AB - To examine the clinical significance of hypertensive nephropathy (HN) among non diabetic chronic kidney disease (CKD) patients. The study comprised 2692 CKD patients recruited from 11 outpatient nephrology clinics; these included 1306 patients with primary renal disease (PRD), 458 patients with HN, 283 patients with diabetic nephropathy (DN) and 645 patients with other nephropathies (ONs). All patients fulfilled the criteria of CKD, with a persistent low estimated glomerular filtration rate (eGFR) <60 ml min(-1) per 1.73 m(2) or proteinuria as determined by a urine dipstick test. The risk factors for cardiovascular disease (CVD), such as ischemic heart disease, congestive heart failure and stroke; all cause mortality; and progression to end-stage renal failure (dialysis induction) were analyzed using a Cox proportional hazards model in each group. During a mean follow-up period of 22.6 months from recruitment, 100 patients were lost to follow-up and 192 patients began chronic dialysis therapy. A total of 115 CVD events occurred (stroke in 37 cases), and 44 patients died. Regarding CVD events and death, there were significant differences in the hazard ratios (HRs) for the groups of patients with different underlying renal diseases as determined by both univariate and multivariate analysis adjusted for confounding factors including estimated glomerular filtration rate: PRD, 1.0 (reference); HN, 3.33 (95% confidence interval, 1.82-6.09); DN, 5.93 (2.80-12.52); and ON, 2.22 (1.22-4.05). However, there were no differences in the hazard ratio for dialysis induction for the groups of patients with different underlying renal diseases. HN is associated with an increased risk of CVD events and death among non-diabetic CKD patients, which highlights the clinical significance of HN. PMID- 21796128 TI - Effects of telmisartan and losartan on cardiovascular protection in Japanese hypertensive patients. AB - The Telmisartan and Losartan Cardiac Evaluation Trial, a multicenter, prospective, randomized, open-labeled, blinded-endpoint trial, was designed to compare the effects of two angiotensin II receptor blockers (ARBs), telmisartan and losartan, on cardiovascular protection in Japanese patients with mild to moderate essential hypertension. We compared the effects of telmisartan and losartan on left ventricular (LV) hypertrophy, cardiac function, atherosclerosis of carotid arteries and surrogate markers related to the actions of peroxisome proliferator-activated receptor-gamma. A total of 58 patients were enrolled in the present trial and the follow-up period was 1 year. There were no significant differences in blood pressure (BP) levels between the telmisartan group and the losartan group throughout the trial. The percentage of the patients treated with ARB monotherapy was significantly higher in the telmisartan group compared with the losartan group. In addition, the progression of intima-media thickness of common carotid artery was significantly inhibited in the telmisartan group compared with the losartan group. Neither group experienced significant changes in cardiac function and LV mass index. There were no differences between the groups with respect to changes in surrogate markers such as serum adiponectin, creatinine, homeostasis model assessment index, plasminogen activator inhibitor-1 and high sensitivity C-reactive protein. Although BP levels were equal and well controlled in both groups, telmisartan showed more protective vascular effects than losartan. PMID- 21796129 TI - Effect of non-drug interventions on arterial properties determined from 24-h ambulatory blood pressure measurements. AB - Measures derived from the slope of the linear relationship between systolic and diastolic pressures obtained by 24-h ambulatory blood pressure (ABP) measurements incorporate clinical and prognostic information, and are believed to be vascular markers. Using post hoc analysis, we investigated potential changes of these 'slope-related measures' in three different studies conducted in hypertensive patients with before and after 24-h ABP measurements, and also evaluated the sensitivity of the results to the analysis method. Two interventional studies included 8-week device-guided breathing (DGB) exercised by 13 patients with uncontrolled blood pressure (BP), and a 6-month mineral potassium chloride enriched diet administered to 20 elderly patients. One study was observational and involved winter-to-summer change experienced by 13 patients with controlled BP. Slope-related measures included systolic-on-diastolic slope and its equivalent 1-(diastolic-on-systolic slope) called Ambulatory Arterial Stiffness Index, and were determined using three different BP-averaging methods and two types of regression procedures. Results demonstrated sensitivity of slope-related measures to the analysis method, the most significant changes were found when the before and after 24-h ABP profiles included hourly averaged BP further averaged over the patient population, and slope-related measures were determined using symmetric (and not standard) regression. DGB was found to reduce significantly all these measures. The changes in the slope-related variables for individual patients correlated negatively with its baseline value and positively with the observed pulse pressure changes. In conclusion, the study provides evidence that DGB can affect positively vascular markers associated with cardiovascular risk, and suggests improved analysis methods for the determination of slope-related measures in interventional studies. PMID- 21796130 TI - Prediction of pregnancy-induced hypertension by a shift of blood pressure class according to the JSH 2009 guidelines. AB - Elevated blood pressure (BP) at early or mid pregnancy is a known risk factor for pregnancy-induced hypertension (PIH). However, the association between BP changes during the first half of pregnancy and subsequent PIH development is unknown. We used changes in maternal BP between 16 and 20 weeks of gestation to evaluate the risk of PIH. A total of 976 pregnant women with BP estimations recorded before 16 weeks and at 20 weeks of gestation participated in this study. BPs were classified by the Japanese Society of Hypertension 2009 Hypertension Treatment Guidelines (JSH 2009). There was a significant trend for future PIH in women whose JSH 2009 BP class increased between 16 and 20 weeks of gestation, and the risk of PIH was highest among women whose BP was Class IV Hypertension (systolic BP>=140 mm Hg and/or diastolic BP>=90 mm Hg). The risk of PIH increased in women whose BPs shifted from Classes I Optimal (systolic BP<120 mm Hg and diastolic BP<80 mm Hg) and II Normal (systolic BP 120-129 mm Hg and/or diastolic BP 80-84 mm Hg) before 16 weeks to Class III High-Normal (systolic BP 130-139 mm Hg and/or diastolic BP 85-89 mm Hg) at 20 weeks of gestation. These shifts in BP class were significantly correlated with the risk of PIH after adjustments for variables (P value for trend <0.05). Within JSH 2009 Classes I, II and III, a shift in BP from a low to a high class between 16 and 20 weeks of gestation predicts the subsequent development of PIH. PMID- 21796131 TI - Normotension, blood pressure variability and early target organ damage. PMID- 21796132 TI - Blood pressure variability is significantly associated with ECG left ventricular mass in normotensive Africans: the SABPA Study. AB - The prognostic significance of blood pressure (BP) variability has lately enjoyed considerable attention. The need for early markers of cardiovascular dysfunction is imperative in black South Africans who have a significant risk for cardiovascular disease. We therefore compared 24-h BP variability with various traditional and advanced BP measurements, regarding their association with sub clinical organ damage in black and white South Africans. The study included 409 African and Caucasian teachers aged 25-60 yrs. We measured office BP, 1-min continuous (finger) BP, ambulatory BP, BP reactivity and determined weighted 24-h BP variability. Albumin-to-creatinine ratio, Cornell product and carotid cross sectional wall area (CSWA) were measures of organ damage. Africans had higher 24 h BP, BP variability, BP reactivity and sub-clinical organ damage (P<0.001). Correlations of BP variability with organ damage were overall weak when compared with other BP measurements. In normotensive groups, we found an independent association of 24-h systolic BP (SBP) variability with Cornell product only in Africans (r=0.37; P=0.01), confirmed in multiple regression models, with 24-h SBP included in the model. Only in hypertensive Caucasians, a significant correlation between CSWA and 24-h SBP variability was evident (r=0.30; P=0.01), although CSWA indicated stronger correlations with office or 24-h SBP than 24-h SBP variability. To conclude, 24-h SBP variability could potentially be an effective measure for the early detection of normotensive Africans at increased risk for the development of cardiovascular complications. Its usefulness based on associations with target organ damage in hypertensive groups seems to be less than traditional office or 24-h BP measurements. PMID- 21796133 TI - Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders. AB - The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR) bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H(+)-ATPase (v-H(+)-ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H(+)-ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies. PMID- 21796134 TI - Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population. AB - Heart failure with preserved ejection fraction is recently highlighted as a major health problem, and diastolic dysfunction associated with hypertension has a dominant role in the development of heart failure with preserved ejection fraction. Osteopontin (OPN) is a secreted phosphoprotein, which mediates fibrosis. In animal models, OPN is upregulated in response to pressure overload and is thought to be involved in systolic dysfunction. However, the functional role of OPN in diastolic dysfunction is unknown. The guanine base insertion polymorphism at -156 position of the OPN promoter is postulated to upregulate the transcription of OPN in human. To investigate whether -156del/G polymorphism of OPN promoter is associated with diastolic dysfunction in hypertensive hearts, the patients with hypertension have been genotyped for variants of -156del/G polymorphism by genomic sequencing. Diastolic function of the left ventricle was estimated as the ratio of early to atrial filling (E/A ratio), obtained by pulsed Doppler derived transmitral flow in echocardiographic analysis. The patients with -156G allele displayed lower E/A ratio compared with those with -156del/del genotype, suggesting exacerbated diastolic function. Notably, in case of the population with diabetes mellitus, the patients with -156G allele showed significant association with lower E/A ratio, compared with -156del/-156del patients. Multiple linear regression analysis revealed that prevalence of -156G allele was an independent factor for lowering E/A ratio. The -156del/G genetic variants of OPN promoter were associated with decreased E/A ratio in hypertensive patients. These results suggest that OPN has a functional role in the development of diastolic dysfunction in hypertensive hearts. PMID- 21796135 TI - High-normal blood pressure is associated with microalbuminuria in the general population: the Watari study. AB - Microalbuminuria, for which hypertension and diabetes are well-known risk factors, has recently been used to detect individuals at risk for cardiovascular and chronic kidney diseases in the general population. We aimed to determine the thresholds of blood pressure or blood glucose concentration at which the odds ratio of having microalbuminuria begins to increase. An annual public health checkup was conducted on 3166 participants aged 29-84 years (mean, 61+/-11 years; 40% men) living in Watari town, Japan. We studied their demographic data, medical history of hypertension, diabetes, dyslipidemia, sitting blood pressure and fasting blood samples. Urinary albumin excretion was examined in terms of the albumin/creatinine ratio in spot urine samples. Microalbuminuria was defined as 30-299 mg albumin per gram creatinine. Final analyses included 2133 participants under no anti-hypertensive or anti-diabetic medication. Microalbuminuria was detected in 118 subjects (5.5%). We used the adjusted odds ratios for microalbuminuria in different blood pressure and blood glucose groupings as the reference. The adjusted odds ratio increased linearly with increase in systolic blood pressure. A similar trend, although not as linear, was observed with diastolic blood pressure. The odds ratio increased significantly with high-normal levels of both systolic and diastolic blood pressure. For blood glucose, the adjusted odds ratio increased significantly from the impaired fasting glucose level. Therefore, the odds ratio for microalbuminuria begins to increase from high-normal blood pressure and impaired fasting glucose levels in comparison with the reference. Early intervention in such cases may be useful for reducing cardiovascular and renal risks. PMID- 21796137 TI - Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population. AB - Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 * 10( 5)) and rs1421085 (P=7.4 * 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP * SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome. PMID- 21796138 TI - Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population. AB - The beta-hexosaminidase A (HEXA) mutations in the first reported cases of infantile Tay-Sachs disease in the Persian population were identified in two unrelated consanguineous families. The clinical diagnoses of the affected infants were confirmed by their markedly deficient levels of HEXA activity in plasma or peripheral leukocytes. The specific causative mutation in each family was determined by sequencing the HEXA alleles in both sets of related parents. Two mutations were identified: c.1A>G (p.MIV), which obliterated the initiating methionine in codon 1, and c.1177C>T (p.R393X), which predicted a termination codon or nonsense mutation. PMID- 21796139 TI - Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by neurodegeneration, most notably of dopaminergic neurons in the substantia nigra. To date, six causative genes have been identified including LRRK2, whose mutations are the most frequent in autosomal dominant PD (Ad-PD). We conducted a comprehensive mutational analysis of LRRK2 in 30 Ad-PD (11 Japanese and 19 Caucasian) families employing a DNA microarray-based resequencing system and direct nucleotide sequence analysis, and identified 23 variants including two known mutations, p.G2019S and p.I1371V, in three Caucasian families and one Caucasian family, respectively, a novel putative pathogenic mutation, p.N1221K, in one Japanese family, and a known nonsynonymous variant, p.G2385R, in two Japanese families. Detailed analysis of the frequency of p.G2385R among 100 Japanese Ad-PD, 73 sporadic PD (sPD) and 238 controls revealed that the frequency of the p.G2385R variant was significantly higher in Ad-PD than in controls (allele frequency, 9.0 vs 2.1%) (chi(2)=16.32, P=5.34 * 10(-5)). The p.G2385R variant, however, did not show complete cosegregation with PD. In addition, the frequency of p.G2385R was also higher in sPD than in controls, although not significant (allele frequency, 3.4 vs 2.1%) (chi(2)=0.76, P=0.38). These observations support the possibility that p.G2385R is associated with an increased risk of PD. PMID- 21796140 TI - Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes. AB - A growing list of membrane-spanning proteins involved in the transport of a large variety of drugs has been recognized and characterized to include peptide and organic anion/cation transporters. Given such an important role of transporter genes in drug disposition process, the role of single-nucleotide polymorphisms (SNPs) in such transporters as potential determinants of interindividual variability in drug disposition and pharmacological response has been investigated. To define the distribution of transporter gene SNPs across ethnic groups, we screened 450 DNAs in cohorts of 250 Korean, 50 Han Chinese, 50 Japanese, 50 African-American and 50 European-American ancestries for 64 SNPs in four transporter genes encoding proteins of the solute carrier family (SLC15A2, SLC22A1, SLC22A2 and SLC22A6). Of the 64 SNPs, 19 were core pharmacogenetic variants and 45 were HapMap tagging SNPs. Polymorphisms were genotyped using the golden gate genotyping assay. After genetic variability, haplotype structures and ethnic diversity were analyzed, we observed that the distributions of SNPs in a Korean population were similar to other Asian groups (Chinese and Japanese), and significantly different from African-American and European-American cohorts. Findings from this study would be valuable for further researches, including pharmacogenetic studies for drug responses. PMID- 21796141 TI - Computed tomography analysis of the association between the SH2B1 rs7498665 single-nucleotide polymorphism and visceral fat area. AB - Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation. PMID- 21796142 TI - Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline. AB - Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P=0.002-0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P=0.02-0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P>0.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms. PMID- 21796143 TI - Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia: overview of genetic variants of cyclic nucleotide PDEs in human disease. AB - Expression of cyclic adenosine monophosphate-specific phosphodiesterase 7B (PDE7B) mRNA is increased in patients with chronic lymphocytic leukemia (CLL), thus suggesting that variation may occur in the PDE7B gene in CLL. As genetic variation in other PDE family members has been shown to associate with numerous clinical disorders (reviewed in this manuscript), we sought to identify single nucleotide polymorphisms (SNPs) in the PDE7B gene promoter and coding region of 93 control subjects and 154 CLL patients. We found that the PDE7B gene has a 5' non-coding region SNP -347C>T that occurs with similar frequency in CLL patients (1.9%) and controls (2.7%). Tested in vitro, -347C>T has less promoter activity than a wild-type construct. The low frequency of this 5' untranslated region variant indicates that it does not explain the higher PDE7B expression in patients with CLL but it has the potential to influence other settings that involve a role for PDE7B. PMID- 21796144 TI - Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. AB - This study was designed to investigate the molecular basis and the correlation between genotype and phenotype in the southern Chinese patients with Wilson's disease (WD). Genotypes of the ATP7B gene in 73 WD patients were examined by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. A total of 38 different disease-causing mutations were identified, including 10 novel mutations: missense mutations (p.Gln707Arg, p.Cys1079Phe, p.Gly1149Glu, p.Ser855Tyr, p.Ala874Pro and p.Ser921Arg), nonsense mutation (p.Arg1228Stop), splice-site mutations (2121+3A>T and 3244-2A>G) and frameshift mutation (1875_1876insAATT). We found that a pair of siblings carried the same genotype but different clinical type, and two patients were found to have three mutations. In addition, we compared the clinical data for p.Arg778Leu homozygotes and compound heterozygotes. Our research has enriched the mutation spectrum of the ATP7B gene in the Chinese population and can serve as the basis for genetic counseling and clinical/prenatal diagnosis to prevent WD in China. PMID- 21796146 TI - Metrics for NICU antibiotic use: which rate is right? PMID- 21796145 TI - Tracking intracavernously injected adipose-derived stem cells to bone marrow. AB - The intracavernous (i.c.) injection of stem cells (SCs) has been shown to improve erectile function in various erectile dysfunction (ED) animal models. However, the tissue distribution of the injected cells remains unknown. In this study we tracked i.c.-injected adipose-derived stem cells (ADSCs) in various tissues. Rat paratesticular fat was processed for ADSC isolation and culture. The animals were then subject to cavernous nerve (CN) crush injury or sham operation, followed by i.c. injection of 1 million autologous or allogeneic ADSCs that were labeled with 5-ethynyl-2-deoxyuridine (EdU). Another group of rats received i.c. injection of EdU-labeled allogeneic penile smooth muscle cells (PSMCs). At 2 and 7 days post injection, penises and femoral bone marrow were processed for histological analyses. Whole femoral bone marrows were also analyzed for EdU-positive cells by flow cytometry. The results show that ADSCs exited the penis within days of i.c. injection and migrated preferentially to bone marrow. Allogenicity did not affect the bone marrow appearance of ADSCs at either 2 or 7 days, whereas CN injury reduced the number of ADSCs in bone marrow significantly at 7 but not 2 days. The significance of these results in relation to SC therapy for ED is discussed. PMID- 21796147 TI - A pathway to insulin independence in newborns and infants with diabetes. AB - Permanent neonatal diabetes was previously assumed to require insulin injection or infusion for life. Recently, permanent neonatal diabetes resulting from mutations in the two protein subunits of the adenosine triphosphate-sensitive potassium channel (Kir6.2 and SUR1) has proven to be successfully treatable with high doses of sulfonylureas rather than insulin. Many patients with these mutations first develop hyperglycemia in the nursery or intensive care unit. The awareness of the neonatolgist of this entity can have dramatic effects on the long-term care and quality of life of these patients and their families. In this study, we present the experience of our center, highlighting aspects relevant to neonatal diagnosis and treatment. PMID- 21796148 TI - Bochdalek congenital diaphragmatic hernia, severe homolateral limb deficiency with intra-thoracic/abdominal limb remnants. PMID- 21796149 TI - High calcium, ATP, and poly(I:C) augment the immune response to beta-glucan in normal human epidermal keratinocytes. AB - beta-Glucans are pathogen-associated molecular patterns of fungi such as Candida albicans. Here, we studied their effects on normal human epidermal keratinocytes (NHEKs) from neonatal foreskin, and with high calcium to induce keratinocyte differentiation, danger signals, and pathogen-associated compounds such as adenosine 5'-triphosphate (ATP), poly(I:C), and lipopolysaccharide (LPS). beta Glucan stimulation significantly increased IL-8, IL-6, and IL-1alpha production by NHEKs. Well-differentiated NHEKs produced elevated IL-8 levels, whereas ATP, a danger signal, significantly increased IL-8 and IL-6 production, and the pathogen associated compound, poly(I:C), augmented IL-1alpha production by beta-glucan stimulated NHEKs. No response to LPS from Escherichia coli was seen. Dectin-1 is known as the major receptor for beta-glucans on phagocytes and dendritic cells. Dectin-1 mRNA was detected in NHEKs by reverse transcription-PCR. Flow-cytometric analyses confirmed the NHEK cell surface expression of dectin-1. Immunoblotting showed that beta-glucan induced dual phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase (ERK)1/2), and p38 MAPK in NHEKs; these signaling pathways are known to be associated with dectin-1. Treatment with the ERK inhibitor PD98059 and with the p38 kinase inhibitor SB203580 effectively suppressed beta-glucan-induced IL-8 production by NHEKs. Thus, high calcium, ATP, and poly(I:C) augment the cytokine and chemokine production by beta-glucan-stimulated NHEKs. Dectin-1 is present on NHEKs and may have an important role in cell response to beta-glucan. PMID- 21796150 TI - Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. AB - Axl, a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, displays an increasingly important role in carcinogenesis. Analysis of 58 cutaneous melanoma lines indicated that Axl was expressed in 38% of them, with significant overrepresentation in NRAS- compared with BRAF-mutated tumors. Axl activation could be induced by autocrine production of its ligand, Gas6, in a significant fraction of Axl-positive tumors. Pearson's correlation analysis on expression data from five data sets of melanoma lines identified several transcripts correlating positively or negatively with Axl. By functionally grouping genes, those inversely correlated were involved in melanocyte development and pigmentation, whereas those positively correlated were involved in motility, invasion, and microenvironment interactions. Accordingly, Axl positive melanomas did not express microphthalmia transcription factor (MITF) and melanocyte differentiation antigens (MDAs) such as MART-1 and gp100 and possessed a greater in vitro invasive potential compared with Axl-negative ones. Motility, invasivity, and ability to heal a wound or to migrate across an endothelial barrier were inhibited in vitro by Axl knockdown. Pharmacological inhibition of Axl using the selective inhibitor R428 had comparable effects in reducing migration and invasion. These results suggest that targeted inhibition of Axl signaling in the subset of melanomas lacking MITF and MDAs may represent a novel therapeutic strategy. PMID- 21796151 TI - IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. AB - Psoriasis, an immunological skin disease, is characterized by epidermal hyperproliferation, chronic inflammation, and an accumulation of infiltrating T cells. IL-17A is a key cytokine that has a critical role in the pathogenesis of psoriasis. Keratin 17 (K17) is strongly expressed in psoriatic lesions but not in normal skin. Thus, K17 expression is regarded as a hallmark of psoriasis. We previously reported that the K17/T cells/cytokine autoimmune loop was involved in psoriasis. However, the relationship between IL-17A and K17 has yet to be determined. In the present study, IL-17A-induced K17 expression was confirmed in cultured keratinocytes in both mRNA and protein levels. In addition, increased K17 expression was found in the epidermis of IL-17A-injected mouse skin. The regulatory mechanism of K17 expression was further investigated. We found that both the signal transducer and activator of transcription (STAT) 1 and STAT3 pathways were involved in the upregulation of K17 expression induced by IL-17A, and that such regulation could be partially suppressed by STAT1 or STAT3 small interfering RNA and inhibitor. Our data suggest that IL-17A can upregulate K17 expression in keratinocytes in a dose-dependent manner through STAT1- and STAT3 dependent mechanisms. The results indicate that IL-17A might be an important cytokine in the K17/T cells/cytokine autoimmune loop associated with psoriasis. PMID- 21796153 TI - Aggravated TSLP-induced atopic dermatitis in mice lacking Dicer in adult skin keratinocytes. PMID- 21796152 TI - Expression of epidermal CAMP changes in parallel with permeability barrier status. AB - Two critical defensive functions of the outer epidermis, the permeability barrier and antimicrobial defense, share certain structural and biochemical features. Moreover, three antimicrobial peptides (AMPs), i.e., mouse beta-defensin 3 (mBD3), mouse cathelicidin antimicrobial peptide (mCAMP), and the neuroendocrine peptide, catestatin (Cst), all localize to the outer epidermis, and both mBD3 and mCAMP are secreted from the epidermal lamellar bodies with other organelle contents that subserve the permeability barrier. These three AMPs are upregulated in response to acute permeability barrier disruption, whereas conversely, mCAMP-/ mice (unable to combat Gram-positive pathogens) also display abnormal barrier homeostasis. To determine further whether these two functions are co-regulated, we investigated changes in immunostaining for these three AMPs in skin samples in which the permeability barrier function in mice had been either compromised or enhanced. Compromised or enhanced barrier function correlated with reduced or enhanced immunohistochemical expression of mCAMP, respectively, but conversely with Cst expression, likely due to the role of this AMP as an endogenous inhibitor of cathelicidin expression. mBD3 expression correlated with experimental barrier perturbations, but poorly with developmental changes in barrier function. These studies show that changes in cathelicidin and Cst expression parallel changes in permeability barrier status, with a less clear relationship with mBD3 expression. PMID- 21796154 TI - Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze. AB - The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure. PMID- 21796155 TI - Conserved KIR allele-level haplotypes are altered by microvariation in individuals with European ancestry. AB - NK cell immunoglobulin-like receptor (KIR) haplotype-specific DNA fragments were sequenced to identify centromeric and telomeric allele-level haplotype structures and their frequencies from 76 unrelated individuals with European ancestry. Analysis was simplified by redefining the 5' boundary of the centromeric KIR gene cluster to include only exons 7-9 of KIR3DL3. Three consensus allele-level haplotypes were identified for a centromeric gene presence/absence structure designated as Cen-A1. KIR3DL3*00201 (exons 7-9)~KIR2DL3*001~KIR2DL1*00302 was the most frequent (37.5%) centromeric structure. Single consensus haplotypes were observed for haplotype structures Cen-B1 and Cen-B2. Six Tel-A1 and two Tel-B1 consensus haplotypes were observed; the most prevalent (23.0%) was KIR2DL4*00102~KIR3DL1*002~KIR2DS4*00101~KIR3DL2*002. A small number of nucleotide substitutions (<=3) in the coding regions of the functional KIR genes created microvariants of the consensus haplotypes. Eight less common haplotype structures were also detected. Four carried hybrid genes formed during gene deletion events, two carried an insertion with a 2DL5/3DP1 fusion gene and two included a very large insertion. These data show that the KIR gene complex is composed of a limited number of conserved allele-level centromeric and telomeric haplotypes that have diversified by mutation, recombination within a locus and unequal crossing over. PMID- 21796156 TI - Treatment with a BH3 mimetic overcomes the resistance of latency III EBV (+) cells to p53-mediated apoptosis. AB - P53 inactivation is often observed in Burkitt's lymphoma (BL) cells due to mutations in the p53 gene or overexpression of its negative regulator, murine double minute-2 (MDM2). This event is now considered an essential part of the oncogenic process. Epstein-Barr virus (EBV) is strongly associated with BL and is a cofactor in its development. We previously showed that nutlin-3, an antagonist of MDM2, activates the p53 pathway in BL cell lines harboring wild-type p53. However, nutlin-3 strongly induced apoptosis in EBV (-) or latency I EBV (+) cells, whereas latency III EBV (+) cells were much more resistant. We show here that this resistance to apoptosis is also observed in latency III EBV (+) lymphoblastoid cell lines. We also show that, in latency III EBV (+) cells, B cell lymphona 2 (Bcl-2) is selectively overproduced and interacts with Bcl-2 associated X protein (Bax), preventing its activation. The treatment of these cells with the Bcl-2-homology domain 3 mimetic ABT-737 disrupts Bax/Bcl-2 interaction and allows Bax activation by nutlin-3. Furthermore, treatment with these two compounds strongly induces apoptosis. Thus, a combination of Mdm2 and Bcl-2 inhibitors might be a useful anti-cancer strategy for diseases linked to EBV infection. PMID- 21796157 TI - Celecoxib and acetylbritannilactone interact synergistically to suppress breast cancer cell growth via COX-2-dependent and -independent mechanisms. AB - The use of celecoxib is associated with a significant decrease in breast cancer risk. However, the long-term use of high-dose celecoxib might be limited owing to cardiovascular side effects. In this study, we found that acetylbritannilactone (ABL), extract from a Chinese medicinal herb, could reduce celecoxib dose and potentiate the growth-inhibitory effect in breast cancer cells. ABL enhanced the apoptotic effect of celecoxib in COX-2-expressing cells, but had little effect in COX-2-negative cells. The apoptosis induced by the combination treatment disappeared when COX-2 was knocked down, whereas the lack of apoptotic effects in COX-2-negative cells was reversed after COX-2 transfection. However, the combination treatment induced a G(0)/G(1) phase arrest independent of whether or not the cells expressed COX-2. The G(0)/G(1) arrest was attributed to a decreased expression of cyclinD1, cyclinE, CDK2 and CDK6, especially the upregulation of p21. In addition, inhibition of Akt and p38 signaling pathways was required by the synergism, as the constitutively active Akt and p38 protected cells against apoptosis and cell cycle arrest induced by the combination treatment. In vivo, administration of celecoxib and ABL were more effective than the individual agents against xenograft tumor growth. Thus, our data suggested that the combinatorial approach of celecoxib and ABL might be helpful for breast cancer treatment. PMID- 21796159 TI - Heart of the matter. PMID- 21796158 TI - Integrins alpha2beta1 and alpha11beta1 regulate the survival of mesenchymal stem cells on collagen I. AB - Although mesenchymal stem cells (MSCs) are the natural source for bone regeneration, the exact mechanisms governing MSC crosstalk with collagen I have not yet been uncovered. Cell adhesion to collagen I is mostly mediated by three integrin receptors - alpha1beta1, alpha2beta1 and alpha11beta1. Using human MSC (hMSC), we show that alpha11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both alpha2 and alpha11 integrins were significantly upregulated. To elucidate the possible roles of collagen-binding integrins, we applied short hairpin RNA (shRNA)-mediated knockdown in hMSC and found that alpha2 or alpha11 deficiency, but not alpha1, results in a tremendous reduction of hMSC numbers owing to mitochondrial leakage accompanied by Bcl-2 associated X protein upregulation. In order to clarify the signaling conveyed by the collagen-binding integrins in hMSC, we analyzed the activation of focal adhesion kinase, extracellular signal-regulated protein kinase and serine/threonine protein kinase B (PKB/Akt) kinases and detected significantly reduced Akt phosphorylation only in alpha2- and alpha11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of alpha2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of alpha2beta1- or alpha11beta1-mediated interactions to collagen I results in the cell death of MSCs and urges for further investigations examining the impact of MSCs in bone conditions with abnormal collagen I. PMID- 21796160 TI - The legacy of Doctor Moreau. PMID- 21796161 TI - Origin of species. PMID- 21796162 TI - My year as a stem-cell blogger. PMID- 21796174 TI - Human-rights shift under fire. PMID- 21796175 TI - NASA picks Mars landing site. PMID- 21796176 TI - Hint of Higgs, but little more. PMID- 21796178 TI - Physicists count on updated constants. PMID- 21796177 TI - Genome giant offers data service. PMID- 21796179 TI - Regulations proposed for animal-human chimaeras. PMID- 21796181 TI - Climate-change politics: The sceptic meets his match. PMID- 21796182 TI - The search for alien intelligence: SETI is dead--long live SETI. PMID- 21796183 TI - Carbon trading needs a multi-level approach. PMID- 21796184 TI - Regulate research at the animal-human interface. PMID- 21796190 TI - Better provenance for biobank samples. PMID- 21796191 TI - In defence of green economy report. PMID- 21796192 TI - Fishery reform: an economic problem. PMID- 21796193 TI - Fishery reform: ban political haggling. PMID- 21796194 TI - Monitoring ash clouds for aviation. PMID- 21796195 TI - Tweet to collaborate with poorer nations. PMID- 21796196 TI - Humility needed in decision-making. PMID- 21796197 TI - Some more biofuel lessons from Brazil. PMID- 21796198 TI - Palaeontology: An icon knocked from its perch. PMID- 21796199 TI - Precision measurement: Exciting antiprotons. PMID- 21796200 TI - Astronomy: A census of the Carina complex. PMID- 21796201 TI - Immunology: Magnesium in a signalling role. PMID- 21796202 TI - Solar physics: Waves galore. PMID- 21796204 TI - An Archaeopteryx-like theropod from China and the origin of Avialae. AB - Archaeopteryx is widely accepted as being the most basal bird, and accordingly it is regarded as central to understanding avialan origins; however, recent discoveries of derived maniraptorans have weakened the avialan status of Archaeopteryx. Here we report a new Archaeopteryx-like theropod from China. This find further demonstrates that many features formerly regarded as being diagnostic of Avialae, including long and robust forelimbs, actually characterize the more inclusive group Paraves (composed of the avialans and the deinonychosaurs). Notably, adding the new taxon into a comprehensive phylogenetic analysis shifts Archaeopteryx to the Deinonychosauria. Despite only tentative statistical support, this result challenges the centrality of Archaeopteryx in the transition to birds. If this new phylogenetic hypothesis can be confirmed by further investigation, current assumptions regarding the avialan ancestral condition will need to be re-evaluated. PMID- 21796206 TI - Alfvenic waves with sufficient energy to power the quiet solar corona and fast solar wind. AB - Energy is required to heat the outer solar atmosphere to millions of degrees (refs 1, 2) and to accelerate the solar wind to hundreds of kilometres per second (refs 2-6). Alfven waves (travelling oscillations of ions and magnetic field) have been invoked as a possible mechanism to transport magneto-convective energy upwards along the Sun's magnetic field lines into the corona. Previous observations of Alfvenic waves in the corona revealed amplitudes far too small (0.5 km s(-1)) to supply the energy flux (100-200 W m(-2)) required to drive the fast solar wind or balance the radiative losses of the quiet corona. Here we report observations of the transition region (between the chromosphere and the corona) and of the corona that reveal how Alfvenic motions permeate the dynamic and finely structured outer solar atmosphere. The ubiquitous outward-propagating Alfvenic motions observed have amplitudes of the order of 20 km s(-1) and periods of the order of 100-500 s throughout the quiescent atmosphere (compatible with recent investigations), and are energetic enough to accelerate the fast solar wind and heat the quiet corona. PMID- 21796205 TI - Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. AB - The magnesium ion, Mg(2+), is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca(2+) does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg(2+) influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg(2+) influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cgamma1 and a markedly impaired Ca(2+) influx in T cells but not B cells. These observations reveal a role for Mg(2+) as an intracellular second messenger coupling cell surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics. PMID- 21796207 TI - Earth's Trojan asteroid. AB - It was realized in 1772 that small bodies can stably share the same orbit as a planet if they remain near 'triangular points' 60 degrees ahead of or behind it in the orbit. Such 'Trojan asteroids' have been found co-orbiting with Jupiter, Mars and Neptune. They have not hitherto been found associated with Earth, where the viewing geometry poses difficulties for their detection, although other kinds of co-orbital asteroid (horseshoe orbiters and quasi-satellites) have been observed. Here we report an archival search of infrared data for possible Earth Trojans, producing the candidate 2010 TK(7). We subsequently made optical observations which established that 2010 TK(7) is a Trojan companion of Earth, librating around the leading Lagrange triangular point, L(4). Its orbit is stable over at least ten thousand years. PMID- 21796208 TI - Two-photon laser spectroscopy of antiprotonic helium and the antiproton-to electron mass ratio. AB - Physical laws are believed to be invariant under the combined transformations of charge, parity and time reversal (CPT symmetry). This implies that an antimatter particle has exactly the same mass and absolute value of charge as its particle counterpart. Metastable antiprotonic helium (pHe(+)) is a three-body atom consisting of a normal helium nucleus, an electron in its ground state and an antiproton (p) occupying a Rydberg state with high principal and angular momentum quantum numbers, respectively n and l, such that n ~ l + 1 ~ 38. These atoms are amenable to precision laser spectroscopy, the results of which can in principle be used to determine the antiproton-to-electron mass ratio and to constrain the equality between the antiproton and proton charges and masses. Here we report two photon spectroscopy of antiprotonic helium, in which p(3)He(+) and p(4)He(+) isotopes are irradiated by two counter-propagating laser beams. This excites nonlinear, two-photon transitions of the antiproton of the type (n, l) -> (n - 2, l - 2) at deep-ultraviolet wavelengths (lambda = 139.8, 193.0 and 197.0 nm), which partly cancel the Doppler broadening of the laser resonance caused by the thermal motion of the atoms. The resulting narrow spectral lines allowed us to measure three transition frequencies with fractional precisions of 2.3-5 parts in 10(9). By comparing the results with three-body quantum electrodynamics calculations, we derived an antiproton-to-electron mass ratio of 1,836.1526736(23), where the parenthetical error represents one standard deviation. This agrees with the proton-to-electron value known to a similar precision. PMID- 21796209 TI - Carbon loss from an unprecedented Arctic tundra wildfire. AB - Arctic tundra soils store large amounts of carbon (C) in organic soil layers hundreds to thousands of years old that insulate, and in some cases maintain, permafrost soils. Fire has been largely absent from most of this biome since the early Holocene epoch, but its frequency and extent are increasing, probably in response to climate warming. The effect of fires on the C balance of tundra landscapes, however, remains largely unknown. The Anaktuvuk River fire in 2007 burned 1,039 square kilometres of Alaska's Arctic slope, making it the largest fire on record for the tundra biome and doubling the cumulative area burned since 1950 (ref. 5). Here we report that tundra ecosystems lost 2,016 +/- 435 g C m(-2) in the fire, an amount two orders of magnitude larger than annual net C exchange in undisturbed tundra. Sixty per cent of this C loss was from soil organic matter, and radiocarbon dating of residual soil layers revealed that the maximum age of soil C lost was 50 years. Scaled to the entire burned area, the fire released approximately 2.1 teragrams of C to the atmosphere, an amount similar in magnitude to the annual net C sink for the entire Arctic tundra biome averaged over the last quarter of the twentieth century. The magnitude of ecosystem C lost by fire, relative to both ecosystem and biome-scale fluxes, demonstrates that a climate-driven increase in tundra fire disturbance may represent a positive feedback, potentially offsetting Arctic greening and influencing the net C balance of the tundra biome. PMID- 21796210 TI - Transforming binding affinities from three dimensions to two with application to cadherin clustering. AB - Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins. For example, the association of membrane proteins with proteins on different cells (trans-interactions) can drive the oligomerization of proteins on the same cell (cis-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation. A finding of general relevance is that changes in interdomain motion on trans-binding have a crucial role in driving the lateral, cis-, clustering of adhesion receptors. PMID- 21796211 TI - Oxysterols direct B-cell migration through EBI2. AB - EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7alpha,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7alpha,25-OHC stimulated the migration of EBI2 expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7alpha,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7alpha,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7alpha,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules. PMID- 21796214 TI - RNAi-mediated knockdown of HMG CoA reductase enhances gene expression from physiologically regulated low-density lipoprotein receptor therapeutic vectors in vivo. AB - The development of novel strategies to enhance gene expression from therapeutic vectors may prove advantageous for complementation gene therapy. This applies to therapeutic expression of the low-density lipoprotein receptor (LDLR) gene to treat familial hypercholesterolaemia (FH), where appropriate gene regulation could enhance therapeutic effect. We have previously reported that LDLR genomic DNA expression vectors can be regulated in vivo by pravastatin. In the current study, we investigated whether targeted knockdown of the mevalonate pathway in conjunction with LDLR delivery would lead to enhanced LDLR transgene expression and improved phenotype recovery. We demonstrated here that knockdown of HMG CoA reductase (HMGCR) by up to 70% using small interfering RNAs (siRNAs) led to a significant increase in binding and internalisation of LDL particles in vitro in mouse and human cells. In vivo co-injection of LDLR promoter luciferase expression plasmids with siRNAs or microRNA (miRNA) expression vectors targeting mouse Hmgcr led to at least a 10-fold increase in luciferase expression. Injection of Ldlr(-/-) mice with pLDLR-LDLR expression plasmids led to a significant reduction in plasmid LDL cholesterol, which was further enhanced by co-injection with miRNA expression vectors targeted to mouse Hmgcr. Our data suggest that targeted knockdown of HMGCR may enhance gene therapy outcomes for FH. PMID- 21796212 TI - Oxysterols direct immune cell migration via EBI2. AB - Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7alpha,25-dihydroxycholesterol (also called 7alpha,25-OHC or 5-cholesten 3beta,7alpha,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7alpha,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7alpha,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7alpha,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response. PMID- 21796215 TI - Benzoate X receptor zinc-finger gene switches for drug-inducible regulation of transcription. AB - Targeted zinc-finger (ZF) DNA-binding domains in conjunction with nuclear receptor ligand-binding domains (LBDs) produce chemically inducible gene switches that have applications in gene therapy and proteomic and genomic research. The benzoate X receptor-beta (BXRbeta) LBD was used to construct homodimer and single chain ZF transcription factors (ZF(TF)s). These ZF(TF)s specifically regulated the transcription of target genes in response to two ligands, ethyl-4 hydroxybenzoate and propyl-4-hydroxybenzoate, in a dose-dependent manner. The ZF(TF)s also regulated the expression of endogenous intercellular adhesion molecule-1 in response to either ligand. The advantage of BXRbeta-based ZF(TF)s is that the ligands are inexpensive and easily synthetically modified, making the system a base for creation of orthogonal ligand-receptor pairs and expanding the gene-switch toolbox. PMID- 21796216 TI - Spatial distribution of microbial communities in the cystic fibrosis lung. AB - Cystic fibrosis (CF) is a common fatal genetic disorder with mortality most often resulting from microbial infections of the lungs. Culture-independent studies of CF-associated microbial communities have indicated that microbial diversity in the CF airways is much higher than suggested by culturing alone. However, these studies have relied on indirect methods to sample the CF lung such as expectorated sputum and bronchoalveolar lavage (BAL). Here, we characterize the diversity of microbial communities in tissue sections from anatomically distinct regions of the CF lung using barcoded 16S amplicon pyrosequencing. Microbial communities differed significantly between different areas of the lungs, and few taxa were common to microbial communities in all anatomical regions surveyed. Our results indicate that CF lung infections are not only polymicrobial, but also spatially heterogeneous suggesting that treatment regimes tailored to dominant populations in sputum or BAL samples may be ineffective against infections in some areas of the lung. PMID- 21796217 TI - The phylogenetic composition and structure of soil microbial communities shifts in response to elevated carbon dioxide. AB - One of the major factors associated with global change is the ever-increasing concentration of atmospheric CO(2). Although the stimulating effects of elevated CO(2) (eCO(2)) on plant growth and primary productivity have been established, its impacts on the diversity and function of soil microbial communities are poorly understood. In this study, phylogenetic microarrays (PhyloChip) were used to comprehensively survey the richness, composition and structure of soil microbial communities in a grassland experiment subjected to two CO(2) conditions (ambient, 368 p.p.m., versus elevated, 560 p.p.m.) for 10 years. The richness based on the detected number of operational taxonomic units (OTUs) significantly decreased under eCO(2). PhyloChip detected 2269 OTUs derived from 45 phyla (including two from Archaea), 55 classes, 99 orders, 164 families and 190 subfamilies. Also, the signal intensity of five phyla (Crenarchaeota, Chloroflexi, OP10, OP9/JS1, Verrucomicrobia) significantly decreased at eCO(2), and such significant effects of eCO(2) on microbial composition were also observed at the class or lower taxonomic levels for most abundant phyla, such as Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes and Acidobacteria, suggesting a shift in microbial community composition at eCO(2). Additionally, statistical analyses showed that the overall taxonomic structure of soil microbial communities was altered at eCO(2). Mantel tests indicated that such changes in species richness, composition and structure of soil microbial communities were closely correlated with soil and plant properties. This study provides insights into our understanding of shifts in the richness, composition and structure of soil microbial communities under eCO(2) and environmental factors shaping the microbial community structure. PMID- 21796218 TI - Phylodynamics and movement of Phycodnaviruses among aquatic environments. AB - Phycodnaviruses have a significant role in modulating the dynamics of phytoplankton, thereby influencing community structure and succession, nutrient cycles and potentially atmospheric composition because phytoplankton fix about half the carbon dioxide (CO(2)) on the planet, and some algae release dimethylsulphoniopropionate when lysed by viruses. Despite their ecological importance and widespread distribution, relatively little is known about the evolutionary history, phylogenetic relationships and phylodynamics of the Phycodnaviruses from freshwater environments. Herein we provide novel data on Phycodnaviruses from the largest river system on earth--the Amazon Basin--that were compared with samples from different aquatic systems from several places around the world. Based on phylogenetic inference using DNA polymerase (pol) sequences we show the presence of distinct populations of Phycodnaviridae. Preliminary coarse-grained phylodynamics and phylogeographic inferences revealed a complex dynamics characterized by long-term fluctuations in viral population sizes, with a remarkable worldwide reduction of the effective population around 400 thousand years before the present (KYBP), followed by a recovery near to the present time. Moreover, we present evidence for significant viral gene flow between freshwater environments, but crucially almost none between freshwater and marine environments. PMID- 21796219 TI - Hydrocarbon monooxygenase in Mycobacterium: recombinant expression of a member of the ammonia monooxygenase superfamily. AB - The copper membrane monooxygenases (CuMMOs) are an important group of enzymes in environmental science and biotechnology. Areas of relevance include the development of green chemistry for sustainable exploitation of methane (CH(4)) reserves, remediation of chlorinated hydrocarbon contamination and monitoring human impact in the biogeochemical cycles of CH(4) and nitrogen. Challenges for all these applications are that many aspects of the ecology, physiology and structure-function relationships in the CuMMOs are inadequately understood. Here, we describe genetic and physiological characterization of a novel member of the CuMMO family that has an unusual physiological substrate range (C(2)-C(4) alkanes) and a distinctive bacterial host (Mycobacterium). The Mycobacterial CuMMO genes (designated hmoCAB) were amenable to heterologous expression in M. smegmatis-this is the first example of recombinant expression of a complete and highly active CuMMO enzyme. The apparent specific activity of recombinant cells containing hmoCAB ranged from 2 to 3 nmol min(-1) per mg protein on ethane, propane and butane as substrates, and the recombinants could also attack ethene, cis-dichloroethene and 1,2-dichloroethane. No detectable activity of recombinants or wild-type strains was seen with methane. The specific inhibitor allylthiourea strongly inhibited growth of wild-type cells on C(2)-C(4) alkanes, and omission of copper from the medium had a similar effect, confirming the physiological role of the CuMMO for growth on alkanes. The hydrocarbon monooxygenase provides a new model for studying this important enzyme family, and the recombinant expression system will enable biochemical and molecular biological experiments (for example, site-directed mutagenesis) that were previously not possible. PMID- 21796221 TI - Age-dependent association of the polymorphisms in the mitochondria-shaping gene, OPA1, with blood pressure and hypertension in Korean population. AB - BACKGROUND: Essential hypertension is associated with mitochondrial dysfunction. Because mitochondrial dynamics; mitochondrial morphological changes are closely linked with various mitochondrial functions, we aimed to examine whether the genetic variation of the mitochondria-shaping genes influenced the susceptibility to blood pressure (BP) and hypertension. METHODS: The quantitative BP trait analysis and hypertension case-control analysis for the total 52 single nucleotide polymorphisms (SNPs) in the five major mitochondria-shaping genes were performed in the Korean Association Resource (KARE) study cohort (8,512 subjects). RESULTS: In the total subjects of the KARE study cohort, there were no statistically significant associations of the SNPs in the five mitochondria shaping genes with BP or hypertension after adjusting for multiple tests. However, the age group analysis in the 40s, 50s, and 60s age subgroups revealed that 15 SNPs out of 26 SNPs genotyped in the OPA1 gene were significantly associated with BP and/or hypertension in the 60s age subgroup and their association P values satisfied the Bonferroni-corrected significance level (P < 0.00625). Noticeably, nine SNPs were consistently associated with all the three traits; systolic BP (SBP), diastolic BP (DBP), and hypertension. In silico lookup of the associated SNPs in the Southern German population did not reveal associations with BP traits. CONCLUSIONS: Our results indicate that genetic variation of the mitochondrial fusion-regulating gene, OPA1, might be associated with BP and hypertension in an age-dependent and population-specific manner in the Korean study cohort, and suggest that altered mitochondrial dynamics, especially involved in the mitochondrial fusion event, may play an important role in the pathogenesis of hypertension. PMID- 21796222 TI - Association between SLC20A1 and sodium-lithium countertransport. AB - BACKGROUND: Sodium-lithium countertransport (SLC) is a premorbidity marker of essential hypertension. Evidence from linkage analysis and kinetic studies in humans have suggested that SLC20A1 variations may affect SLC activity as measured in erythrocytes and leukocytes. SLC20A1 encodes a sodium-dependent phosphate cotransporter, and is widely expressed on the mammalian plasma membrane. In this study, we investigated the relationship between SLC20A1 and SLC activity. METHODS: By means of gene expression profiling, we studied the expressions of SLC20A1 in individuals with high SLC activity as compared to those with low SLC activity. In order to investigate the allelic association of SLC20A1 with SLC, we genotyped six tag single-nucleotide polymorphisms (tSNPs) in SLC20A1 in subjects from the Rochester Family Heart Study (RFHS) involving 1,815 individuals from 252 pedigrees of mixed European ancestry. The genetic association of SLC20A1 with SLC was assessed by Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS: Expression levels of SLC20A1 were higher in individuals with high SLC activity than in those with low SLC activity. Four SNPs in SLC20A1 were associated with SLC activity after adjusting for age, sex, body mass index, triglycerides, and antihypertensive drug treatment (P <= 0.05). The strongest evidence of association was in respect of rs4849091 (P = 0.001), and this association remained significant even after correction for multiple tests. CONCLUSIONS: Allelic variations in SLC20A1 were associated with the levels of SLC activity, thereby supporting the hypothesis that SLC20A1 is involved in determining SLC activity. PMID- 21796223 TI - The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements. AB - The nature of DNA has captivated scientists for more than fifty years. The discovery of the double-helix model of DNA by Watson and Crick in 1953 not only established the primary structure of DNA, but also provided the mechanism behind DNA function. Since then, researchers have continued to further the understanding of DNA structure and its pivotal role in transcription. The demonstration of DNA secondary structure formation has allowed for the proposal that the dynamics of DNA itself can function to modulate transcription. This review presents evidence that DNA can exist in a dynamic equilibrium between duplex and secondary conformations. In addition, data demonstrating that intracellular proteins as well as small molecules can shift this equilibrium in either direction to alter gene transcription will be discussed, with a focus on the modulation of proto oncogene expression. PMID- 21796224 TI - "Big Events" and Networks. AB - Some, but not all, "big events" such as wars, revolutions, socioeconomic transitions, economic collapses, and ecological disasters in recent years seem to lead to large-scale HIV outbreaks (Friedman et al, in press; Hankins et al 2002). This was true of transitions in the USSR, South Africa and Indonesia, for example, but not those in the Philippines or (so far) in Argentina. It has been hypothesized that whether or not HIV outbreaks occur is shaped in part by the nature and extent of changes in the numbers of voluntary or involuntary risk takers, which itself may be related to the growth of roles such as sex-sellers or drug sellers; the riskiness of the behaviors engaged in by risk-takers; and changes in sexual and injection networks and other "mixing patterns" variables. Each of these potential causal processes, in turn, is shaped by the nature of pre existing social networks and the patterns and content of normative regulation and communication that happen within these social networks-and on how these social networks and their characteristics are changed by the "big event" in question. We will present ideas about what research is needed to help understand these events and to help guide both indigenous community-based efforts to prevent HIV outbreaks and also to guide those who organize external intervention efforts and aid. PMID- 21796226 TI - Active immunotherapy for the Treatment of Cocaine Dependence. AB - Although cocaine is illegal in most countries of the world, addiction is common and increasing in many populations, and the effectiveness of current treatment options for those afflicted has been very limited. The availability of an anti cocaine vaccine could offer help to those who wish to quit their addiction. A number of vaccines differing in their chemical nature have been developed, and one has advanced into clinical trials. This review will discuss the successes and limitations of the various vaccines and the results of clinical trials of the vaccine using succinyl norcocaine conjugated to cholera toxin B. This latter vaccine shows considerable promise for those individuals whose antibody response is adequate.. PMID- 21796227 TI - STUDIES ON THE BIOSYNTHESIS OF THE STEPHACIDINS AND NOTOAMIDES. TOTAL SYNTHESIS OF NOTOAMIDE S. AB - Notoamide S has been suggested to be the final common precursor between two different Aspergillus sp. fungal strains before diverging to form enantiomerically opposite natural products (+)- and (-)-stephacidin A and (+)- and (-)-notoamide B. The synthesis of notoamide S comes from the coupling of N Fmoc proline with a 6-hydroxy-7-prenyl-2-reverse prenyl tryptophan derivative that was synthesized via a late stage Claisen rearrangement from a 6-propargyl-2 reverse prenylated indole. PMID- 21796228 TI - A Comparison of Self-Rated and Objectively Measured Successful Aging Constructs in an Urban Sample of African American Older Adults. AB - Sixty-seven (N = 67) urban African American older adults were divided into successful and nonsuccessful aging groups based on objective MacArthur (i.e., physical and cognitive functioning) and on self-rated health criteria. Only 30% of the sample met objective MacArthur criteria for successful aging compared to 63% who rated themselves as successful. Self-rated successful aging was best predicted by regular exercise, whereas objective successful aging was best predicted by demographic characteristics and cognition. Reading ability mediated the relationship between both education and cognition to objectively defined success. Finally, objective successful aging was related to quantity and quality of education, whereas self-rated successful aging was related to a wider variety of variables. Defining successful aging on objective factors alone may limit our understanding of successful aging in urban African American older adults. PMID- 21796220 TI - Huanglongbing alters the structure and functional diversity of microbial communities associated with citrus rhizosphere. AB - The diversity and stability of bacterial communities present in the rhizosphere heavily influence soil and plant quality and ecosystem sustainability. The goal of this study is to understand how 'Candidatus Liberibacter asiaticus' (known to cause Huanglongbing, HLB) influences the structure and functional potential of microbial communities associated with the citrus rhizosphere. Clone library sequencing and taxon/group-specific quantitative real-time PCR results showed that 'Ca. L. asiaticus' infection restructured the native microbial community associated with citrus rhizosphere. Within the bacterial community, phylum Proteobacteria with various genera typically known as successful rhizosphere colonizers were significantly greater in clone libraries from healthy samples, whereas phylum Acidobacteria, Actinobacteria and Firmicutes, typically more dominant in the bulk soil were higher in 'Ca. L. asiaticus'-infected samples. A comprehensive functional microarray GeoChip 3.0 was used to determine the effects of 'Ca. L. asiaticus' infection on the functional diversity of rhizosphere microbial communities. GeoChip analysis showed that HLB disease has significant effects on various functional guilds of bacteria. Many genes involved in key ecological processes such as nitrogen cycling, carbon fixation, phosphorus utilization, metal homeostasis and resistance were significantly greater in healthy than in the 'Ca. L. asiaticus'-infected citrus rhizosphere. Our results showed that the microbial community of the 'Ca. L. asiaticus'-infected citrus rhizosphere has shifted away from using more easily degraded sources of carbon to the more recalcitrant forms. Overall, our study provides evidence that the change in plant physiology mediated by 'Ca. L. asiaticus' infection could elicit shifts in the composition and functional potential of rhizosphere microbial communities. In the long term, these fluctuations might have important implications for the productivity and sustainability of citrus-producing agro-ecosystems. PMID- 21796229 TI - Effect of Caregiver Family Status on Care Recipient Symptom Severity and Caregiver Stress at Nursing Home Intake. AB - The present research investigates differences between primary informal caregivers who were in the care recipient's immediate family (adult children or spouses) versus those primary caregivers who were outside the immediate family. Measurement occurred at the time of admission of the care recipient to an urban nursing home. We hypothesized that immediate family caregivers would report greater behavioral disturbance among care recipients and increased caregiver depression and stress. Data were collected from 115 consecutive caregiver-elder dyads at nursing home intake. Non-immediate family caregivers comprised 43% of the sample. Consistent with our hypotheses, immediate family caregivers reported significantly greater caregiver depression and caregiver stress. Immediate family care recipients demonstrated greater behavioral disturbance. Implications for policy and caregiver interventions are discussed. PMID- 21796230 TI - Accelerating Advanced MRI Reconstructions on GPUs. AB - Computational acceleration on graphics processing units (GPUs) can make advanced magnetic resonance imaging (MRI) reconstruction algorithms attractive in clinical settings, thereby improving the quality of MR images across a broad spectrum of applications. This paper describes the acceleration of such an algorithm on NVIDIA's Quadro FX 5600. The reconstruction of a 3D image with 128(3) voxels achieves up to 180 GFLOPS and requires just over one minute on the Quadro, while reconstruction on a quad-core CPU is twenty-one times slower. Furthermore, relative to the true image, the error exhibited by the advanced reconstruction is only 12%, while conventional reconstruction techniques incur error of 42%. PMID- 21796231 TI - A rapid and precise procedure for Pb isotopes in whole blood by Fe co precipitation and MC-ICPMS analysis. AB - Elevated Pb levels in humans through environmental exposure are a significant health concern requiring scientific study of the sources of, and physiological response to this toxin. This requires a simple and precise method for measuring radiogenic Pb isotopes and Pb levels in blood. Presented here is a combination of methods for separation and analysis of Pb previously used predominantly for geologic samples. This includes separation of Pb from the complex matrix of blood samples using an Fe co-precipitation method, followed by isotopic analysis by multi-collector inductively coupled plasma mass spectrometry. Evaluation of the efficacy of this procedure shows that the precision of sample preparations as measured by % difference between the (207)Pb/(206)Pb of duplicate analyses averages 0.064% (n = 48). Using the same preparation and analysis techniques to measure Pb concentrations by isotope dilution resulted in a reproducibility of better than 6%. The method was successfully used to measure uptake of ingested soil Pb in a study of the bioavailability of Pb in contaminated soils. PMID- 21796233 TI - Cervical Cancer Tests and Treatment. AB - Advances in screening and treatment of cervical cancer have been made in recent years. Here we discuss tests, stages of disease, and strategies for treatment. PMID- 21796232 TI - Identification of a host 14-3-3 Protein that Interacts with Xanthomonas effector AvrRxv. AB - AvrRxv is a member of a family of pathogen effectors present in pathogens of both plant and mammalian species. Xanthomonas campestris pv. vesicatoria strains carrying AvrRxv induce a hypersensitive response (HR) in the tomato cultivar Hawaii 7998. Using a yeast two-hybrid screen, we identified a 14-3-3 protein from tomato that interacts with AvrRxv called AvrRxv Interactor 1 (ARI1). The interaction was confirmed in vitro with affinity chromatography. Using mutagenesis, we identified a 14-3-3-binding domain in AvrRxv and demonstrated that a mutant in that domain showed concomitant loss of interaction with ARI1 and HR-inducing activity in tomato. These results demonstrate that the AvrRxv bacterial effector recruits 14-3-3 proteins for its function within host cells. AvrRxv homologues YopP and YopJ from Yersinia do not have AvrRxv-specific HR inducing activity when delivered into tomato host cells by Agrobacterium. Although YopP itself cannot induce HR, its C-terminal domain containing the catalytic residues can replace that of AvrRxv in an AvrRxv-YopP chimera for HR inducing activity. Phylogenetic analysis indicates that the sequences encoding the C-termini of family members are evolving independently from those encoding the N-termini. Our results support a model in which there are three functional domains in proteins of the family, translocation, interaction, and catalytic. PMID- 21796235 TI - Methodology development for simultaneous diffuse optical tomography and magnetic resonance imaging in functional human brain mapping. AB - We present an integrated methodology for human brain mapping by simultaneous BOLD fMRI and NIR imaging. This methodology consists of three innovative components: the construction of MRI-compatible optical probes that can be affixed to any part of the human head inside a standard MRI head-coil with minimal MR image distortion, the accurate determination of optode positions on the head from MR images, and the application of a perturbation approach and Monte Carlo method to compute the integral kernel of the Born solution to the diffusion equation for baseline optical properties. This integrated approach has been used to demonstrate promising capabilities for studying functional hemodynamic activation in human visual cortex by simultaneous fMRI and NIR tomography. PMID- 21796236 TI - Plasmon resonant gold-coated liposomes for spectrally controlled content release. AB - We recently demonstrated that liposome-supported plasmon resonant gold nanoshells are degradable into components of a size compatible with renal clearance, potentially enabling their use as multifunctional agents in applications in nanomedicine, including imaging, diagnostics, therapy, and drug delivery (Troutman et al., Adv. Mater. 2008, 20, 2604-2608). When illuminated with laser light at the wavelength matching their plasmon resonance band, gold-coated liposomes rapidly release their encapsulated substances, which can include therapeutic and diagnostic agents. The present research demonstrates that release of encapsulated agents from gold-coated liposomes can be spectrally controlled by varying the location of the plasmon resonance band; this spectral tuning is accomplished by varying the concentration of gold deposited on the surface of liposomes. Furthermore, the amount of laser energy required for release is qualitatively explained using the concept of thermal confinement (Jacques, Appl. Opt. 1993, 32(3), 2447-2454). Overlapping thermal confinement zones can be avoided by minimizing the laser pulse width, resulting in lower energy requirements for liposomal content release and less global heating of the sample. Control of heating is especially important in drug delivery applications, where it enables spatial and spectral control of delivery and prevents thermal damage to tissue. PMID- 21796234 TI - The Small Ribozymes: Common and Diverse Features Observed through the FRET Lens. AB - The hammerhead, hairpin, HDV, VS and glmS ribozymes are the five known, naturally occurring catalytic RNAs classified as the "small ribozymes". They share common reaction chemistry in cleaving their own backbone by phosphodiester transfer, but are diverse in their secondary and tertiary structures, indicating that Nature has found at least five independent solutions to a common chemical task. Fluorescence resonance energy transfer (FRET) has been extensively used to detect conformational changes in these ribozymes and dissect their reaction pathways. Common and diverse features are beginning to emerge that, by extension, highlight general biophysical properties of non-protein coding RNAs. PMID- 21796237 TI - Optimal Time-Resource Allocation for Energy-Efficient Physical Activity Detection. AB - The optimal allocation of samples for physical activity detection in a wireless body area network for health-monitoring is considered. The number of biometric samples collected at the mobile device fusion center, from both device-internal and external Bluetooth heterogeneous sensors, is optimized to minimize the transmission power for a fixed number of samples, and to meet a performance requirement defined using the probability of misclassification between multiple hypotheses. A filter-based feature selection method determines an optimal feature set for classification, and a correlated Gaussian model is considered. Using experimental data from overweight adolescent subjects, it is found that allocating a greater proportion of samples to sensors which better discriminate between certain activity levels can result in either a lower probability of error or energy-savings ranging from 18% to 22%, in comparison to equal allocation of samples. The current activity of the subjects and the performance requirements do not significantly affect the optimal allocation, but employing personalized models results in improved energy-efficiency. As the number of samples is an integer, an exhaustive search to determine the optimal allocation is typical, but computationally expensive. To this end, an alternate, continuous-valued vector optimization is derived which yields approximately optimal allocations and can be implemented on the mobile fusion center due to its significantly lower complexity. PMID- 21796238 TI - Diversifying Biomedical Training: A Synergistic Intervention. AB - For over three decades, the scientific community has expressed concern over the paucity of African American, Latino and Native American researchers in the biomedical training pipeline. Concern has been expressed regarding what is forecasted as a shortage of these underrepresented minority (URM) scientists given the demographic shifts occurring worldwide and particularly in the United States. Increased access to graduate education has made a positive contribution in addressing this disparity. This article describes the multiple pathway approaches that have been employed by a school of medicine at an urban Midwest research institution to increase the number of URM students enrolled in, and graduating from, doctoral programs within basic science departments, through the combination of R25 grants and other grant programs funded by the National Institutes of Health (NIH). This article outlines the process of implementing a strong synergistic approach to the training of URM students through linkages between the NIH-funded "Bridges to the Doctorate (BRIDGES)" and "Initiative for Maximizing Graduate Student Diversity (IMGSD)" programs. The article documents the specific gains witnessed by this particular institution and identifies key components of the interventions that may prove useful for institutions seeking to increment the biomedical pipeline with scientists from diverse backgrounds. PMID- 21796239 TI - Muscle Synergies: Implications for Clinical Evaluation and Rehabilitation of Movement. AB - We present a method called muscle synergy analysis, which can offer clinicians insight into both underlying neural strategies for movement and functional outcomes of muscle activity. Although neural dysfunction is central to many motor deficits, neural activity during movements is not directly measurable. Consequently, the majority of clinical tests focus on evaluating motor outputs at the behavioral and kinematic levels. However, altered behavioral or kinematic outcomes could be the result of multiple distinct neural abnormalities with very different muscle coordination patterns. Because muscle activity reflects motoneuron activity and generates the forces that produce behavioral outcomes, an analysis of muscle activity may provide a better understanding of the functional neural deficits in the impaired nervous system. Unfortunately electromyographic datasets can be large, highly variable, and difficult to interpret, precluding their clinical utility. Computational analyses can be used to extract muscle synergies from such datasets, revealing underlying patterns that may reflect different levels of neural function. These muscle synergies are hypothesized to represent motor modules recruited by the nervous system to flexibly perform biomechanical subtasks necessary for movement. For example, hemiparetic stroke patients exhibit differences in the number of muscle synergies, which may reflect disruptions in descending neural pathways and are correlated to deficits in motor function. Muscle synergy analysis may thus offer the clinician a better view of the neural structure underlying motor behaviors and how they change in motor deficits and rehabilitation. Such information could inform diagnostic tools and evidence-based interventions specifically targeted to a patient's deficits. PMID- 21796240 TI - Suicidal Ideation Among Drug-Dependent Treatment-Seeking Inner-City Pregnant Women. AB - The current retrospective study compared the psychiatric and lifestyle characteristics of two groups of treatment-seeking pregnant, opiate and/or cocaine dependent women admitted to the Center for Addiction and Pregnancy (CAP). Women reporting past and/or current suicidal ideation (SI) (46%; n = 35) were compared to women who did not report thoughts of suicidal ideation (NSI) (54%; n = 41). SI women were more likely to be homeless (p = .020), to report histories of emotional (p = .022), physical (p < 001), sexual abuse (p = .002) and psychiatric treatment (p < .001), and less likely to be married (p = .024) than NSI women. Psychiatrically, SI women were more likely to have co-morbid current and lifetime disorders than NSI women. These findings highlight the need to identify women with histories of suicidal ideation, recognize the potential relapse risk imposed by emotional distress, and confront these issues in treatment. PMID- 21796241 TI - Development of antiproliferative nanohybrid compound with controlled release property using ellagic acid as the active agent. AB - An ellagic acid (EA)-zinc layered hydroxide (ZLH) nanohybrid (EAN) was synthesized under a nonaqueous environment using EA and zinc oxide (ZnO) as the precursors. Powder X-ray diffraction showed that the basal spacing of the nanohybrid was 10.4 A, resulting in the spatial orientation of EA molecules between the interlayers of 22.5 degrees from z-axis with two negative charges at 8,8' position of the molecules pointed toward the ZLH interlayers. FTIR study showed that the intercalated EA spectral feature is generally similar to that of EA, but with bands slightly shifted. This indicates that some chemical bonding of EA presence between the nanohybrid interlayers was slightly changed, due to the formation of host-guest interaction. The nanohybrid is of mesopores type with 58.8% drug loading and enhanced thermal stability. The release of the drug active, EA from the nanohybrid was found to be sustained and therefore has good potential to be used as a drug controlled-release formulation. In vitro bioassay study showed that the EAN has a mild effect on the hepatocytes cells, similar to its counterpart, free EA. PMID- 21796242 TI - Synthesis and characterization of a narrow size distribution of zinc oxide nanoparticles. AB - Zinc oxide nanoparticles (ZnO-NPs) were synthesized via a solvothermal method in triethanolamine (TEA) media. TEA was utilized as a polymer agent to terminate the growth of ZnO-NPs. The ZnO-NPs were characterized by a number of techniques, including X-ray diffraction analysis, transition electron microscopy, and field emission electron microscopy. The ZnO-NPs prepared by the solvothermal process at 150 degrees C for 18 hours exhibited a hexagonal (wurtzite) structure, with a crystalline size of 33 +/- 2 nm, and particle size of 48 +/- 7 nm. The results confirm that TEA is a suitable polymer agent to prepare homogenous ZnO-NPs. PMID- 21796243 TI - Nanoparticles prepared from the water extract of Gusuibu (Drynaria fortunei J. Sm.) protects osteoblasts against insults and promotes cell maturation. AB - Our previous study showed that Gusuibu (Drynaria fortunei J. Sm.) can stimulate osteoblast maturation. This study was further designed to evaluate the effects of nanoparticles prepared from the water extract of Gusuibu (WEG) on osteoblast survival and maturation. Primary osteoblasts were exposed to 1, 10, 100, and 1000 MUg/mL nanoparticles of WEG (nWEG) for 24, 48, and 72 hours did not affect morphologies, viability, or apoptosis of osteoblasts. In comparison, treatment of osteoblasts with 1000 MUg/mL WEG for 72 hours decreased cell viability and induced DNA fragmentation and cell apoptosis. nWEG had better antioxidant bioactivity in protecting osteoblasts from oxidative and nitrosative stress induced apoptosis than WEG. In addition, nWEG stimulated greater osteoblast maturation than did WEG. Therefore, this study shows that WEG nanoparticles are safer to primary osteoblasts than are normal-sized products, and may promote better bone healing by protecting osteoblasts from apoptotic insults, and by promoting osteogenic maturation. PMID- 21796244 TI - Doxorubicin-incorporated polymeric micelles composed of dextran-b-poly(DL-lactide co-glycolide) copolymer. AB - BACKGROUND: Polymeric micelles using amphiphilic macromolecules are promising vehicles for antitumor targeting. In this study, we prepared anticancer agent incorporated polymeric micelles using novel block copolymer. METHODS: We synthesized a block copolymer composed of dextran and poly (DL-lactide-co glycolide) (DexbLG) for antitumor drug delivery. Doxorubicin was selected as the anticancer drug, and was incorporated into polymeric micelles by dialysis. Polymeric micelles were observed by transmission electron microscopy to be spherical and smaller than 100 nm, with a narrow size distribution. The particle size of doxorubicin-incorporated polymeric micelles increased with increasing drug content. Higher initial drug feeding also increased the drug content. RESULTS: During the drug-release study, an initial burst release of doxorubicin was observed for 10 hours, and doxorubicin was continuously released over 4 days. To investigate the in vitro anticancer effects of the polymeric micelles, doxorubicin-resistant HuCC-T1 cells were treated with a very high concentration of doxorubicin. In an antiproliferation study, the polymeric micelles showed higher cytotoxicity to doxorubicin-resistant HuCC-T1 cells than free doxorubicin, indicating that the polymeric micelles were effectively engulfed by tumor cells, while free doxorubicin hardly penetrated the tumor cell membrane. On confocal laser scanning microscopy, free doxorubicin expressed very weak fluorescence intensity, while the polymeric micelles expressed strong red fluorescence. Furthermore, in flow cytometric analysis, fluorescence intensity of polymeric micelles was almost twice as high than with free doxorubicin. CONCLUSION: DexbLG polymeric micelles incorporating doxorubicin are promising vehicles for antitumor drug targeting. PMID- 21796245 TI - Application of supercritical antisolvent method in drug encapsulation: a review. AB - The review focuses on the application of supercritical fluids as antisolvents in the pharmaceutical field and demonstrates the supercritical antisolvent method in the use of drug encapsulation. The main factors for choosing the solvent and biodegradable polymer to produce fine particles to ensure effective drug delivery are emphasized and the effect of polymer structure on drug encapsulation is illustrated. The review also demonstrates the drug release mechanism and polymeric controlled release system, and discusses the effects of the various conditions in the process, such as pressure, temperature, concentration, chemical compositions (organic solvents, drug, and biodegradable polymer), nozzle geometry, CO(2) flow rate, and the liquid phase flow rate on particle size and its distribution. PMID- 21796246 TI - Novel PEG-graft-PLA nanoparticles with the potential for encapsulation and controlled release of hydrophobic and hydrophilic medications in aqueous medium. AB - This study concerns the encapsulation and controlled release of both hydrophobic and hydrophilic medications with one polymer, which are delivered together as a combined therapy to treat diseased tissue. To test our hypothesis that the novel PEG-graft-PLA (PEG, polyethylene glycol; PLA, polylactic acid) can deliver both the hydrophobic and hydrophilic medications on account of its amphiphility, charge, and graft structure, PEG-graft-PLA (molecular weight of PEG = 1900) with very low critical micelle concentration was synthesized. One hydrophilic (insulin) and one hydrophobic (naproxen) model medication were loaded in separately during its self-assembly in aqueous solution. The resulting nanoparticles (NPs) were narrowly distributed and spherical, with average particle size around 200 nm, zeta potential >-10 mV, and encapsulation efficiency >50%. The NPs realized controlled release of insulin and naproxen for over 24 and 160 hours, respectively. Specifically, the bioactivity of the insulin released from the NPs was maintained. Owing to encapsulation, both for hydrophobic and hydrophilic medicines, and NPs obtained with similar size and zeta potential, as well as maintenance of bioactivity of loaded protein, we expect the applications of PEG-graft-PLA NPs in combination therapy. PMID- 21796247 TI - Nano-zinc oxide damages spatial cognition capability via over-enhanced long-term potentiation in hippocampus of Wistar rats. AB - This study focused on the effects of zinc oxide nanoparticles (nano-ZnO) on spatial learning and memory and synaptic plasticity in the hippocampus of young rats, and tried to interpret the underlying mechanism. Rats were randomly divided into four groups. Nano-ZnO and phosphate-buffered saline were administered in 4 week-old rats for 8 weeks. Subsequently, performance in Morris water maze (MWM) was determined, and then long-term potentiation (LTP) and depotentiation were measured in the perforant pathway to dentate gyrus (DG) in anesthetized rats. The data showed that, (1) in MWM, the escape latency was prolonged in the nano-ZnO group and, (2) LTP was significantly enhanced in the nano-ZnO group, while depotentiation was barely influenced in the DG region of the nano-ZnO group. This bidirectional effect on long-term synaptic plasticity broke the balance between stability and flexibility of cognition. The spatial learning and memory ability was attenuated by the alteration of synaptic plasticity in nano-ZnO-treated rats. PMID- 21796248 TI - Reducing infections through nanotechnology and nanoparticles. AB - The expansion of bacterial antibiotic resistance is a growing problem today. When medical devices are inserted into the body, it becomes especially difficult for the body to clear robustly adherent antibiotic-resistant biofilm infections. In addition, concerns about the spread of bacterial genetic tolerance to antibiotics, such as that found in multiple drug-resistant Staphylococcus aureus (MRSA), have significantly increased of late. As a growing direction in biomaterial design, nanomaterials (materials with at least one dimension less than 100 nm) may potentially prevent bacterial functions that lead to infections. As a first step in this direction, various nanoparticles have been explored for improving bacteria and biofilm penetration, generating reactive oxygen species, and killing bacteria, potentially providing a novel method for fighting infections that is nondrug related. This review article will first examine in detail the mechanisms and applications of some of these nanoparticles, then follow with some recent material designs utilizing nanotechnology that are centered on fighting medical device infections. PMID- 21796249 TI - Polyanionic carbohydrate doxorubicin-dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations. AB - This study deals with the preparation and investigation of a nanoscale delivery system for the anticancer drug doxorubicin (DOX) using its complexation with polyanionic carbohydrate dextran sulfate (DS). Dynamic light scattering, SEM, and zeta potential determination were used to characterize nanocomplexes. DOX-DS complexation was studied in the presence of ethanol as a hydrogen-bond disrupting agent, NaCl as an electrostatic shielding agent, and chitosan as a positively charged polymer. Thermodynamics of DOX-DS interaction was studied using isothermal titration calorimetry (ITC). A dialysis method was applied to investigate the release profile of DOX from DOX-DS nanocomplexes. Spherical and smooth-surfaced DOX-DS nanocomplexes (250-500 nm) with negative zeta potential were formed at a DS/DOX (w/w) ratio of 0.4-0.6, with over 90% drug encapsulation efficiency. DOX when complexed with DS showed lower fluorescence emission and 480 nm absorbance plus a 15 nm bathometric shift in its visible absorbance spectrum. Electrostatic hydrogen bonding and pi-pi stacking interactions are the main contributing interactions in DOX-DS complexation. Thermal analysis of DOX-DS complexation by ITC revealed that each DOX molecule binds with 3 DS glycosyl monomers. Drug release profile of nanocomplexes showed a fast DOX release followed by a slow sustained release, leading to release of 32% of entrapped DOX within 15 days. DOX-DS nanocomplexes may serve as a drug delivery system with efficient drug encapsulation and also may be taken into consideration in designing DOX controlled-release systems. PMID- 21796250 TI - Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery. AB - Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 +/- 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)(0-infinity) (20.343 +/- 9.119 MUg . h . mL(-1) vs 5.196 +/- 1.426 MUg . h . mL(-1)), greater clearance (2.050 +/- 0.616 L . kg(-1) . h( 1) vs 0.556 +/- 0.190 L . kg(-1) . h(-1)), and shorter elimination half-life (5.646 +/- 2.941 vs 3.774 +/- 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC(0-infinity) in liver, lung, and spleen (all P < 0.01), but not in heart or kidney. PMID- 21796251 TI - The occurrence of left ventricular hypertrophy in normotensive individuals in a community setting in North-East Trinidad. AB - OBJECTIVE: The purpose of this study is to determine primarily the occurrence of left ventricular hypertrophy (LVH) in normotensive Trinidadians. DESIGN AND METHODS: Enrollment into the study required participants to have normal blood pressure (<= 140/90) using the JNC 7 (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) classification, free of type 2 diabetes, as well as no existing LVH. Upon entry into the study, participants were first screened for LVH using a standard 12-lead electrocardiogram (ECG), using the Sokolow-Lyon index and the Cornell index. ECHO was used to confirm or refute the diagnosis of LVH. RESULTS: A total of 209 patients met the criteria for entry into the study. Of these, 63.6% had LVH using Cornell criteria and 68.2% using LVH by Sokolow-Lyon criteria. Subsequently, ECHO confirmed the diagnosis in 2.9% using American Society of Echocardiography criteria and 1.5% using World Health Organization criteria. Thus the estimated prevalence of LVH in normotensive individuals was approximately 3%. CONCLUSION: The estimated prevalence of LVH in normotensive individuals appears to be relatively high if an ECG is the single investigation performed, which is common in our setting and may also be common in the developing world. However, using ECHO, the prevalence of LVH approaches a value similarly reported in the literature. Therefore, these findings raise two important issues: 1) the use of criteria such as the Cornell and Sokolow-Lyon voltage criteria established in the developed world from populations of vastly different ethnic backgrounds may not be widely applicable, and 2) all individuals suspected of having LVH should have an ECHO. PMID- 21796252 TI - Effects of Azelnidipine plus OlmesaRTAn versus amlodipine plus olmesartan on central blood pressure and left ventricular mass index: the AORTA study. AB - PURPOSE: The aim of this study was to compare the effects of olmesartan combined with either azelnidipine or amlodipine on central blood pressure (CBP) and left ventricular mass index (LVMI) in hypertensive patients. PATIENT AND METHODS: Patients with brachial systolic BP >= 140 mmHg and/or diastolic BP >= 90 mmHg received olmesartan monotherapy (20 mg daily) for 12 weeks. The patients were then randomly assigned to fixed-dose add-on therapy with azelnidipine (16 mg daily) or amlodipine (5 mg daily) (25 patients/group) for a further 24 weeks. CBP and LVMI were measured at baseline and at the end of the study. RESULTS: Baseline characteristics were similar in both groups. The decrease in brachial BP was similar in both groups. CBP and LVMI decreased significantly in both groups (both, P < 0.001). However, the decreases in CBP and LVMI were significantly greater with olmesartan/azelnidipine than with olmesartan/amlodipine (CBP, P < 0.001; LVMI, P = 0.002). CONCLUSIONS: These findings indicate that olmesartan/azelnidipine had greater effects on CBP and LVMI than did olmesartan/amlodipine, even though the reduction in brachial BP was similar in both groups. These differential effects on CBP and LVMI may have important implications for cardiovascular risk reduction. PMID- 21796253 TI - Cardiovascular outcomes with angiotensin II receptor blockers: clinical implications of recent trials. AB - Activation of the renin-angiotensin system plays a major role in cardiovascular morbidity and mortality. Recently, angiotensin II receptor blockers (ARBs) have been the subject of a number of large clinical cardiovascular outcome trials, indicating beneficial effects of ARBs with more than 384,000 patient-years of data in different cardiovascular diseases along the cardiovascular continuum, from patients with risk factors, through high cardiovascular risk, to patients with heart failure. This article reviews the implications of these trials for the optimal management of cardiovascular risk. PMID- 21796254 TI - Effect of proton pump inhibitors on platelet inhibition activity of clopidogrel in Chinese patients with percutaneous coronary intervention. AB - BACKGROUND: The purpose of this study was to examine the effect of proton pump inhibitors (PPI) on the antiplatelet activity of clopidogrel in a consecutive series of Chinese patients after they had received coronary stents. METHODS: A sample of 51 consecutive Chinese patients treated with coronary stents and taking PPI and clopidogrel for more than 30 days were enrolled in this study. Mean values for platelet residual units and percentage inhibition before PPI (+PPI) and 14 days after discontinuation of PPI (-PPI) were compared using the paired t test. RESULTS: There was no effect of concomitant use of esomeprazole and clopidogrel or omeprazole and clopidogrel on the inhibition assay, but platelet residual units and percentage inhibition showed statistically significant improvement after stopping lansoprazole in Chinese patients who were on chronic clopidogrel therapy. Clopidogrel resistance existed more frequently in the Chinese-American population examined, and was as high as 68% (+PPI) to 73% ( PPI). CONCLUSION: The clopidogrel resistance found is cause for concern, although its relationship with clinical events is currently unknown in this population. Further study with other thienopyridines or genetic variant analysis is suggested. PMID- 21796255 TI - Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. AB - Cardiovascular (CV) disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the renin angiotensin-aldosterone system (RAAS) plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs]) may slow inflammatory processes and disease progression. Reduced nitric oxide (NO) bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS). Although CV outcomes were not assessed in these studies, the observed benefits in surrogate endpoints of disease suggest that RAAS suppression with olmesartan medoxomil may potentially have beneficial effects on CV outcomes in these patient populations. PMID- 21796256 TI - Risk factor investigation for cardiovascular health through WHO STEPS approach in Ardabil, Iran. AB - OBJECTIVES: Reliable evidence is the keystone for any noncommunicable disease (NCD) prevention plan to be initiated. In this study we carried out a risk factor investigation based on the WHO Stepwise approach to Surveillance (STEPS). METHODS: The study was conducted on 1000 adults between 15 and 64 years of age living in Ardabil province, north-west Iran during 2006, based on the WHO STEPS approach to surveillance of risk factors for NCD. At this stage only the first and second steps were carried out. Data were collected through standard questionnaires and methods analyzed using STATA version 8 statistical software package. RESULTS: 29.0% of men and 2.6% of women were current daily tobacco smokers. The mean number of manufactured cigarettes smoked per day was 18.9 among current daily smokers. Smoking was most prevalent among men of low-income families and those of lower education. The mean body mass index (BMI) was 26.6 kg/m(2), and was significantly correlated with systolic blood pressure. 58.9% were overweight or obese; 18.0% had raised blood pressure and 3.7% had isolated systolic hypertension. The mean number of servings of fruit consumed per day was 1.1; 33.1% had low levels of activity. Combined risk factor analysis showed that 4.1% of participants were in the low-risk group (up to 5.1% among men and 3.2% among women). Those in the high-risk group comprised 25.6% in the 25- to 44-year age group and 49.7% in the 45- to 64-year age group. Mean BMI increased by age in both sexes at least at the first three decades of adult life. CONCLUSION: Based on observed status of risk for cardiovascular health, burden of cardiovascular diseases is expected to increase if an effective prevention strategy is not undertaken. PMID- 21796257 TI - Racial differences in the responses to shear stress in human umbilical vein endothelial cells. AB - BACKGROUND: African American ethnicity is an independent risk factor for exaggerated oxidative stress, which is related to inflammation, hypertension, and cardiovascular disease. Recently, we reported that in vitro oxidative stress and inflammation levels differ between African American and Caucasian human umbilical vein endothelial cells (HUVECs), African American HUVECs having higher levels of both. However, it remains to be shown whether the cells would respond differently to external stimuli. METHODS: We used a cone and plate viscometer to apply laminar shear stress (LSS) as an aerobic exercise mimetic to compare the responses by race. HUVECs were exposed to static conditions (no LSS), low LSS (5 dyne/cm(2)), and moderate LSS (20 dyne/cm(2)). RESULTS: It was found that African American HUVECs had higher levels of oxidative stress under static conditions, and when LSS was applied protein expression levels (NADPH oxidase NOX2, NOX4 and p47phox subunits, eNOS, SOD2, and catalase) and biomarkers (NO, SOD, and total antioxidant capacity) were modulated to similar levels between race. CONCLUSION: African American HUVECs may be more responsive to LSS stimulus indicating that aerobic exercise prescriptions may be valuable for this population since the potential exists for large in vivo improvements in oxidative stress levels along the endothelial layer in response to increased shear flow. PMID- 21796259 TI - GENOTOXIC MECHANISMS OF ARSENIC TRIOXIDE IN HUMAN JURKAT T-LYMPHOMA CELLS. AB - Arsenic trioxide (As(2)O(3)) has cytotoxic effects on several cancer cell lines. However, the molecular mechanisms of action remain to be elucidated. Hence, the aim of the present study was to evaluate the cytotoxicity and genotoxicity induced by As(2)O(3) in a human Jurkat T-lymphoma cell line using the trypan blue exclusion test and alkaline single cell gel electrophoresis (Comet) assays, respectively. Jurkat T-cells were treated with different doses of As(2)O(3) for 24 and 48 h prior to cytogenetic assessment. Data obtained from the trypan blue exclusion test indicated that As(2)O(3) significantly (p < 0.05) reduced the viability of Jurkat T-cells in a dose and time-dependent manner. Data generated from the comet assay also indicated a significant dose and time-dependent increase in DNA damage in Jurkat T-cells associated with As(2)O(3) exposure. We observed a significant increase (P < 0.05) in comet tail-length, tail arm and tail moment, as well as in percentages of DNA cleavage at all doses tested, showing an evidence As(2)O(3) -induced genotoxic damage in Jurkat T-cells. This study confirms that the comet assay is a sensitive and effective method to detect DNA damage caused by heavy metals such as arsenic. Taken together, our findings suggest that As(2)O(3) exposure significantly (p < 0.05) reduces cellular viability and induces DNA damage in human Jurkat T-lymphoma cells. PMID- 21796260 TI - No consistent effects of prenatal or neonatal exposure to Spanish flu on late life mortality in 24 developed countries. AB - We test the effects of early life exposure to disease on later health by looking for differences in late-life mortality in cohorts born around the 1918-1919 flu pandemic using data from the Human Mortality Database for 24 countries. After controlling for age, period, and sex effects, residual mortality rates did not differ systematically for flu cohorts relative to surrounding cohorts. We calculate at most a 20-day reduction in life expectancy for flu cohorts; likely values are much smaller. Estimates of influenza incidence during the pandemic suggest that exposure was high enough for this to be a robust negative result. PMID- 21796258 TI - Depression in vascular pathologies: the neurologist's point of view. AB - The coexistence of depression and cardiovascular disease (CVD) is regularly discussed, and much debated. There is strong evidence that there are pathophysiological mechanisms, particularly endothelial dysfunction, altered platelet aggregation, and hyperactivation of the thrombosis cascade, which coexist with hypothalamic-pituitary-adrenocortical axis dysfunction, and link depression to CVD. Therefore, depression should not be automatically considered to be a consequence of life impairment due to myocardial infarction or major stroke. Probably, it should be considered as one of the many other stressful events, or "genetic reactions to life", which are risk factors for CVD development. This review will examine the significance of depression in clinical daily practice, its pathophysiology as a determinant in vascular events, and its real importance in, before, and after many CVD events. PMID- 21796261 TI - Using Nonmedically Trained Interviewers to Collect Biomeasures in a National In Home Survey. AB - A key operational component of the National Social Life, Health, and Aging Project (NSHAP) is the use of nonmedically trained interviewers to collect biomeasures in a national in-home interview of health and aging. Few studies have integrated in-home biomeasure collection using nonmedically trained interviewers on a large scale. In this article, we discuss our approach to using nonmedically trained interviewers to collect biomeasures in the home. The article focuses on activities that impact the ability to integrate biomeasures into survey research, including developing field methods, recruiting and training interviewers, and monitoring data collection activities. In addition, cooperation rates and measures of interviewer productivity and data quality are provided to evaluate our approach. PMID- 21796262 TI - Attitudes Toward Adoption of Evidence-Based Practices: A comparison of Autism Early Intervention Providers and Children's Mental Health Providers. AB - Across the country, states are reporting increases in the number of children with autistic spectrum disorders (ASD) served each year in the early intervention system. Research examining factors impacting the successful dissemination and implementation of evidence-based practice (EBPs) into service systems for these children is limited. Preliminary information indicates that adoption of EBPs is variable. Provider attitudes toward the adoption of EBPs may be one factor that limits or facilitates implementation of efficacious treatments and these attitudes vary by organizational context and provider individual differences. The current study examines cross-context differences in provider attitudes toward EBPs by comparing the attitudes of 71 education-based early intervention providers working with children with ASD to the attitudes of 238 mental health providers in the public mental health system. This provides the first examination of ASD early intervention provider attitudes toward EBP. Results indicated that early intervention providers reported significantly more favorable attitudes toward adopting EBPs than did mental health providers. Early intervention providers with extended experience in the field perceived less divergence between their current practice and EBPs. Implications are discussed. PMID- 21796263 TI - DPpackage: Bayesian Non- and Semi-parametric Modelling in R. AB - Data analysis sometimes requires the relaxation of parametric assumptions in order to gain modeling flexibility and robustness against mis-specification of the probability model. In the Bayesian context, this is accomplished by placing a prior distribution on a function space, such as the space of all probability distributions or the space of all regression functions. Unfortunately, posterior distributions ranging over function spaces are highly complex and hence sampling methods play a key role. This paper provides an introduction to a simple, yet comprehensive, set of programs for the implementation of some Bayesian non- and semi-parametric models in R, DPpackage. Currently DPpackage includes models for marginal and conditional density estimation, ROC curve analysis, interval censored data, binary regression data, item response data, longitudinal and clustered data using generalized linear mixed models, and regression data using generalized additive models. The package also contains functions to compute pseudo-Bayes factors for model comparison, and for eliciting the precision parameter of the Dirichlet process prior. To maximize computational efficiency, the actual sampling for each model is carried out using compiled FORTRAN. PMID- 21796264 TI - Determination of problematic ICD-9-CM subcategories for further study of coding performance: Delphi method. AB - In this study, we report on a qualitative method known as the Delphi method, used in the first part of a research study for improving the accuracy and reliability of ICD-9-CM coding. A panel of independent coding experts interacted methodically to determine that the three criteria to identify a problematic ICD-9-CM subcategory for further study were cost, volume, and level of coding confusion caused. The Medicare Provider Analysis and Review (MEDPAR) 2007 fiscal year data set as well as suggestions from the experts were used to identify coding subcategories based on cost and volume data. Next, the panelists performed two rounds of independent ranking before identifying Excisional Debridement as the subcategory that causes the most confusion among coders. As a result, they recommended it for further study aimed at improving coding accuracy and variation. This framework can be adopted at different levels for similar studies in need of a schema for determining problematic subcategories of code sets. PMID- 21796265 TI - Development and testing of a survey instrument to measure benefits of a nursing information system. AB - Information systems (IS) benefits for nurses are outcomes related to the tangible products or improvements that nurses realize from using IS. This study examined the development and psychometric testing of a measure of nurses' benefits from IS. A random sample of 570 nurses working in hospitals, providing direct patient care, and using IS completed the study questionnaire. The internal consistency reliability of the results was .97. Exploratory factor analysis, using principal components extraction and varimax rotation, revealed items loaded on four factors (saving time and efficiency, quality of care, charting, and professional practice) that were confirmed by confirmatory factor analysis. Continued refinement of the instrument is needed with more diverse samples of nurses. PMID- 21796266 TI - Electronic health record adoption and use by Nebraska pharmacists. AB - There is a national focus on electronic health records (EHRs) and health information exchange to improve quality, efficiency, and safety across healthcare settings. The purpose of this study is to describe pharmacists' views and practices about the adoption and use of EHRs and the sharing of health information by pharmacists in the state of Nebraska. A U.S. mail survey of all pharmacists holding a Nebraska license (N = 1,953) was conducted in June-August 2008. Only 12 percent of pharmacists indicated using an EHR. Most pharmacists (63 percent) indicated that their pharmacy had no plans to adopt an EHR system, while 13 percent indicated their pharmacy planned to adopt an EHR system in the future. Only 8 percent of respondents currently had access to EHRs for their patients created by other providers. Despite a national focus on electronic health information exchange, there remains a low uptake of EHRs by pharmacists. PMID- 21796267 TI - Does an education intervention improve physician signature legibility? Pilot study of a prospective chart review. AB - Illegible physician signatures in patient records can lead to inaccurate documentation, improper billing, and potential legal issues. Many studies in the current literature address legibility of prescriptions and medication orders; however, few focus on legibility of physicians' signatures. The purpose of the present quality improvement survey was to evaluate physician signature legibility on patient charts at the University of Mississippi Medical Center's Adult Internal Medicine Clinic. At the time of the study, the clinic was known as the University of Mississippi Medical Center (UMMC) Adult Internal Medicine Clinic. Effective July 1, 2009, UMMC entered into a collaboration with Jackson-Hinds Comprehensive Health Center (JHCHC), a federally qualified health center. The clinic is now known as the Federally Qualified Health Center at the Jackson Medical Mall. In this pilot study, we examined clinic notes and billing sheets for legible physician signatures over a three-month period. Midway through the study, an intervention group was given name stamps and a standardized discussion on the importance of signature legibility and proper name stamp usage. Legibility of resident signatures in the intervention group increased from 26 percent to 60 percent. Legibility of attending signatures in the intervention group increased from 1.4 percent to 86 percent. Results suggest the significant impact of resident education on changing practice behavior. PMID- 21796268 TI - Wavelength-Selective Light-Induced Release from Plasmon Resonant Liposomes. AB - Biodegradable, spectrally tunable plasmon resonant nanocapsules are created via the deposition of gold onto the surface of 100 nm diameter thermosensitive liposomes. These nanocapsules demonstrate selective release of encapsulated contents upon illumination with light of a wavelength matching their distinct resonance bands, which correspond to 760 and 1210 nm in this study. Spectrally selective release is accomplished through the use of multiple, low intensity laser pulses delivered over a period of less than four minutes, ensuring that illumination affects only the gold-coated liposomes and avoids heating the surrounding media. The result of this illumination scheme for selective release using multiple wavelengths of light is a biologically safe mechanism for realizing drug delivery, microfluidic, and sensor applications. PMID- 21796269 TI - Magnetic Resonance Relaxometry at Low and Ultra low Fields. AB - Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are ubiquitous tools in science and medicine. NMR provides powerful probes of local and macromolecular chemical structure and dynamics. Recently it has become possible and practical to perform MR at very low fields (from 1 MUT to 1 mT), the so-called ultra-low field (ULF) regime. Pulsed pre-polarizing fields greatly enhance the signal strength and allow flexibility in signal acquisition sequences. Improvements in SQUID sensor technology allow ultra-sensitive detection in a pulsed field environment.In this regime the proton Larmor frequencies (1 Hz - 100 kHz) of ULF MR overlap (on a time scale of 10 MUs to 100 ms) with "slow" molecular dynamic processes such as diffusion, intra-molecular motion, chemical reactions, and biological processes such as protein folding, catalysis and ligand binding. The frequency dependence of relaxation at ultra-low fields may provide a probe for biomolecular dynamics on the millisecond timescale (protein folding and aggregation, conformational motions of enzymes, binding and structural fluctuations of coupled domains in allosteric mechanisms) relevant to host-pathogen interactions, biofuels, and biomediation. Also this resonance enhanced coupling at ULF can greatly enhance contrast in medical applications of ULF-MRI resulting in better diagnostic techniques.We have developed a number of instruments and techniques to study relaxation vs. frequency at the ULF regime. Details of the techniques and results are presented.Ultra-low field methods are already being applied at LANL in brain imaging, and detection of liquid explosives at airports. However, the potential power of ultra-low field MR remains to be fully exploited. PMID- 21796271 TI - An Experimental Study of Scheduling and Duration of "Tier 2" First-Grade Reading Intervention. AB - This study compared the effects on reading outcomes of delivering supplemental, small-group intervention to first-grade students at risk for reading difficulties randomly assigned to one of three different treatment schedules: extended (4 sessions per week, 16 weeks; n = 66), concentrated (4 sessions per week, 8 weeks; n = 64), or distributed (2 sessions per week, 16 weeks; n = 62) schedules. All at risk readers, identified through screening followed by 8 weeks of oral reading fluency (ORF) progress monitoring, received the same Tier 2 reading intervention in groups of 2 to 4 beginning in January of Grade 1. Group means were higher in word reading and ORF at the final time point relative to pretest; however, the groups did not differ significantly on any reading outcome or on rates of adequate intervention response. Of potential covariates, site, age, free lunch status, program coverage rate, and tutor were significantly related to student outcomes; however, the addition of these variables in multivariate models did not substantially change results. Rates of adequate intervention response were lower than have been reported for some first-grade interventions of longer duration. PMID- 21796270 TI - Health behavior models in the age of mobile interventions: are our theories up to the task? AB - Mobile technologies are being used to deliver health behavior interventions. The study aims to determine how health behavior theories are applied to mobile interventions. This is a review of the theoretical basis and interactivity of mobile health behavior interventions. Many of the mobile health behavior interventions reviewed were predominately one way (i.e., mostly data input or informational output), but some have leveraged mobile technologies to provide just-in-time, interactive, and adaptive interventions. Most smoking and weight loss studies reported a theoretical basis for the mobile intervention, but most of the adherence and disease management studies did not. Mobile health behavior intervention development could benefit from greater application of health behavior theories. Current theories, however, appear inadequate to inform mobile intervention development as these interventions become more interactive and adaptive. Dynamic feedback system theories of health behavior can be developed utilizing longitudinal data from mobile devices and control systems engineering models. PMID- 21796273 TI - Glioblastoma stem-like cells-biology and therapeutic implications. AB - The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells. PMID- 21796272 TI - The cognitive neuroscience toolkit for the neuroeconomist: A functional overview. AB - This article provides the beginning neuroeconomist with an introductory overview to the different methods used in human neuroscience. It describes basic strengths and weaknesses of each technique, points to examples of how each technique has been used in neuroeconomic studies, and provides key tutorial references that contain more detailed information. In addition to this overview, the article presents a framework that organizes human neuroscience methods functionally, according to whether they provide tests of the association between brain activity and cognition or behavior, or whether they test the necessity or the sufficiency of brain activity for cognition and behavior. This framework demonstrates the utility of a multi-method research approach, since converging evidence from tests of association, necessity and sufficiency provides the strongest inference regarding brain-behavior relationships. Set against this goal of converging evidence, human neuroscience studies in neuroeconomics currently rely far too heavily on methods that test association, most notably functional MRI. PMID- 21796274 TI - Akt signaling is required for glioblastoma maintenance in vivo. AB - Glioblastoma multiforme (GBM) can be induced in mice through the combined expression of activated forms of KRas and Akt in glial progenitor cells. We have previously demonstrated that KRas is required for the maintenance of these tumors in vivo as inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. To determine the reliance of these tumors on Akt signaling in vivo, we generated a viral vector that allows the expression of Akt to be controlled post-delivery. Survival rates were compared between those animals with continued Akt expression and animals in which expression of Akt was suppressed. Although a fifth of the tumors were refractory to treatment, inhibition of Akt significantly increased the survival of tumor-bearing mice and nearly a fourth of the mice remained in remission four months after the treatment period. These data suggest that Akt is required for glioblastoma maintenance in the context of activated Ras and that loss of Akt expression results in increased survival; therefore, the PI3K/AKT signaling pathway is a viable therapeutic target in this context. PMID- 21796276 TI - Carbamazepine on a carbamazepine monolayer forms unique 1D supramolecular assemblies. AB - High-resolution STM imaging of the structures formed by carbamazepine molecules adsorbed onto a pseudo-ordered carbamazepine monolayer on Au(111) shows the formation of previously unreported 1-dimensional supramolecular assemblies. PMID- 21796275 TI - MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells. AB - Previous studies have identified several dysregulated microRNAs in esophageal squamous cell carcinoma (ESCC); however, to date there are no ex vivo analyses comparing expression levels of these regulatory molecules in esophageal squamous cell tumors versus patient-matched normal epithelium. We describe here a technical strategy to evaluate microRNAs in normal esophageal basal cells (NB), normal esophageal differentiated cells (ND), and tumor cells (T). Laser capture microdissection was used to procure target populations from five cases and 18 ESCC-associated microRNAs were measured by RT-qPCR. Five microRNAs (miR-25, miR 106b, miR-21, miR-203, and miR-145) demonstrated consistent differential expression in at least one of the three comparisons: T vs. NB, T vs. ND, or NB vs. ND. The potential regulatory role of the microRNAs in ESCC was further evaluated by correlating their expression with a matched mRNA dataset, which included the same five cases and cell populations. In conclusion, the present work demonstrates the feasibility of studying microRNA levels in precisely dissected cell populations from clinical samples, and sheds light on the molecular mechanisms associated with ESCC. PMID- 21796277 TI - Broadening of the derivative discontinuity in density functional theory. AB - We clarify an important aspect of density functional theories, the broadening of the derivative discontinuity (DD) in a quantum system, with fluctuating particle number. Our focus is on a correlated model system, the single level quantum dot in the regime of the Coulomb blockade. We find that the DD-broadening is controlled by the small parameter Gamma/U, where Gamma is the level broadening due to contacting and U is a measure of the charging energy. Our analysis suggests that Kondoesque fluctuations have a tendency to increase the DD broadening in our model by a factor of two. PMID- 21796278 TI - Thermoplastic elastomers for microfluidics: towards a high-throughput fabrication method of multilayered microfluidic devices. AB - Multilayer soft lithography of polydimethylsiloxane (PDMS) is a well-known method for the fabrication of complex fluidic functions. With advantages and drawbacks, this technique allows fabrication of valves, pumps and micro-mixers. However, the process is inadequate for industrial applications. Here, we report a rapid prototyping technique for the fabrication of multilayer microfluidic devices, using a different and promising class of polymers. Using styrenic thermoplastic elastomers (TPE), we demonstrate a rapid technique for the fabrication and assembly of pneumatically driven valves in a multilayer microfluidic device made completely from thermoplastics. This material solution is transparent, biocompatible and as flexible as PDMS, and has high throughput thermoforming processing characteristics. We established a proof of principle for valving and mixing with three different grades of TPE using an SU-8 master mold. Specific viscoelastic properties of each grade allow us to report enhanced bonding capabilities from room temperature bonding to free pressure thermally assisted bonding. In terms of microfabrication, beyond classically embossing means, we demonstrate a high-throughput thermoforming method, where TPE molding experiments have been carried out without applied pressure and vacuum assistance within an overall cycle time of 180 s. The quality of the obtained thermoplastic systems show robust behavior and an opening/closing frequency of 5 Hz. PMID- 21796279 TI - Giant enhancement of photodissociation of polar diatomic molecules in electric fields. AB - We explore the photodissociation of polar diatomic molecules in static electric fields in the rotationally cold regime using the example of the LiCs molecule. A giant enhancement of the differential cross section is found for laboratory electric field strengths, and analyzed with varying rovibrational bound states, continuum energies as well as field strengths. PMID- 21796280 TI - TiO2-ZrO2 affinity chromatography polymeric microchip for phosphopeptide enrichment and separation. AB - We fabricated a TiO(2)-ZrO(2) affinity chromatography micro-column on 2 mm PMMA plates, and demonstrated the enrichment and separation of (a) a standard mono- and tetra-phosphopeptide, and (b) phosphopeptides contained in a tryptic digest of beta-Casein. The chromatography column consisted of 32 parallel microchannels with common input and output ports and was fabricated by lithography directly on the polymeric substrate followed by plasma etching (i.e. standard MEMS processing) and sealed with lamination. The liquid deposited TiO(2)-ZrO(2) stationary phase was characterized by X-ray diffraction and was found to be mostly TiO(2) and ZrO(2) in crystalline phases. Off-chip UV detection and MALDI MS identification of the separated effluents were used. The chip had a capacity of >1.4 MUg (0.7 nmol) of a prototype mono-phosphopeptide and a recovery of 94 +/ 3%, and can be used with small samples (less than 0.1 MUL depending on the syringe pump used). The chip design allows an expansion of its capacity by means of increasing the number of parallel microchannels at a constant sample volume. Our approach provided an alternative to off-line extraction tips (with typical capacities of 1-2 MUg and sample volumes of 1-10 MUL), and to on-chip efforts based on packed bed and frit formats. PMID- 21796281 TI - On the nature and importance of the transition between molecules and nanocrystals: towards a chemistry of "nanoscale perfection". AB - This paper discusses the importance of the transition between molecular compounds and nanocrystals. The boundary between molecular and nanocrystals/nanoclusters can be defined by the emergence of the bulk phase; atoms in the core of the nanoclusters that are not bound to ligands. This transition in dimensions and structural organization is important because it overlaps with the boundary between atomically defined moieties (molecules can be isolated with increasing purity) and mixtures (nanocrystals have a distribution of sizes, shapes, and defects; they cannot be easily separated into batches of structurally identical species). Passing through this boundary, as the size of a structure increases beyond a few nanometres, the information about the position of each atom gradually disappears. This loss of structural information about a chemical structure fundamentally compromises our ability to use it as a part of a complex chemical system. If we are to engineer complex functions encoded in a chemical language, we will need pure batches of atomically defined (truly monodisperse) nanoscale compounds, and we will need to understand how to make them and preserve them over a broad range of length scales, compositions, and timeframes. In this review we survey most classes of monodisperse nanomaterials (mostly nanoclusters) and highlight the recent breakthroughs in this area which might be spearheading the development of a chemistry of "nanoscale perfection". PMID- 21796282 TI - Double emulsions with controlled morphology by microgel scaffolding. AB - Double emulsions are valuable structures that consist of drops nested inside bigger drops; they can be formed with exquisite control through the use of droplet-based microfluidics, allowing their size, composition, and monodispersity to be tailored. However, only little control can be exerted on the morphology of double emulsions in their equilibrium state, because they are deformable and subject to thermal fluctuations. To introduce such control, we use droplet-based microfluidics to form oil-in-water-in-oil double emulsion drops and arrest their shape by loading them with monodisperse microgel particles. These particles push the inner oil drop to the edge of the aqueous shell drop such that the double emulsions adopt a uniform arrested, anisotropic shape. This approach circumvents the need for ultrafast polymerization or geometric confinement to lock such non spherical and anisotropic droplet morphologies. To demonstrate the utility of this technique, we apply it to synthesize anisotropic and non-spherical polyacrylate-polyacrylamide microparticles with controlled size and shape. PMID- 21796283 TI - DPO and POPOP carboxylate-analog sensors by sequential palladium-catalysed direct arylation of oxazole-4-carboxylates. AB - Sequential palladium-catalysed direct (het)arylation of oxazole-4-carboxylates is achieved to give rapid access to DPO and POPOP (di)carboxylate-analogs. Three novel DPO- and POPOP-type sensors with unusual Stokes shifts and high quantum yields are discovered. PMID- 21796287 TI - Development of a lipase-based optical assay for detection of DNA. AB - A lipase-based assay for detection of specific DNA sequences has been developed. Lipase from Candida antarctica was conjugated to DNA and captured on magnetic beads in a sandwich assay, in which the binding was dependent on the presence of a specific target DNA. For amplification and to generate a detectable readout the captured lipase was applied to an optical assay that takes advantage of the enzymatic activity of lipase. The assay applies p-nitrophenol octanoate (NPO) as the substrate and in the presence of lipase the ester is hydrolyzed to p nitrophenolate which has a strong absorbance at 405 nm. The method provides detection a detection limit of 200 fmol target DNA and it was able to distinguish single base mismatches from the fully complementary target. PMID- 21796288 TI - Circular dichroism and UV-Vis absorption spectroscopic monitoring of production of chiral silver nanoparticles templated by guanosine 5'-monophosphate. AB - Herein we report the chemical reduction of silver ions incorporated into chiral supramolecular nanostructures by NaBH(4) in buffered (basic) and unbuffered conditions. In situ self-assembly of guanosine 5'-monophosphate (5'-GMP) templated by Ag(I) and generation of silver nanoparticles (NPs) were continuously monitored by CD and UV-Vis spectroscopy measurements. 5'-GMP has been identified as an efficient chiral organic ligand to complex silver ions into a hierarchical helical nanostructure and is a useful capping agent for stabilizing silver NPs with a size diameter lower than 20 nm. The observation of opposite signed bands in the CD spectra of Ag(I)/5'-GMP complexes at different pH has suggested the existence of opposite-handed supramolecular helical structures depending on pH. Both helical supramolecular structures induce chirality in the silver NPs during their growth of the same handedness as shown by the CD signals in the plasmon resonance band. PMID- 21796289 TI - Under-three minute PCR: probing the limits of fast amplification. AB - Nucleic acid amplification is enormously useful to the biotechnology and clinical diagnostic communities; however, to date point-of-use PCR has been hindered by thermal cycling architectures and protocols that do not allow for near instantaneous results. In this work we demonstrate PCR amplification of synthetic SARS respiratory pathogenic targets and bacterial genomic DNA in less than three minutes in a hardware configuration utilizing convenient sample loading and disposal. Instead of sample miniaturization techniques, near-instantaneous heating and cooling of 5 MUL reaction volumes is enabled by convective heat transfer of a thermal fluid through porous media combined with an integrated electrical heater. This method of rapid heat transfer has enabled 30 cycles of PCR amplification to be completed in as little as two minutes and eighteen seconds. Surprisingly, multiple enzymes have been shown to work at these breakthrough speeds on our system. A tool for measuring enzyme kinetics now exists and can allow polymerase optimization through directed evolution studies. Pairing this instrument technology with modified polymerases should result in a new paradigm for high-throughput, ultra-fast PCR and will hopefully improve our ability to quickly respond to the next viral pandemic. PMID- 21796290 TI - Fluorescent detection of an anthrax biomarker based on PVA film. AB - Due to the dangerous nature of anthrax, the development of a cost-effective, sensitive and field-portable sensor for the anthrax biomarker--calcium dipicolinate (CaDPA)--is of exceptional significance for both military and civilian use. Herein, a flexible polymer-film-based ratiometric sensor for detecting CaDPA was demonstrated. A reference dye and a probe ligand were covalently immobilized onto the film surface through a highly selective and efficient "click chemistry" reaction. The reference dye, whose fluorescence intensity does not change with varying amounts of CaDPA, offers a non-interfering internal calibration. The ethylenediaminetetraacetic acid (EDTA)-based ligand binds with Eu(III) and serves as the probe. In the absence of CaDPA, the film sensor exhibited almost no red fluorescence because the Eu(III) ions themselves give no emission without sensitization by CaDPA owing to the small molar absorption coefficients of Eu(III) ions. The presence of CaDPA induces a significantly enhanced emission intensity of the sensor, and thereby enables the film as a ratiometric sensor for CaDPA. This sensor can selectively detect CaDPA in water with a detection limit of 100 nM. Moreover, this sensor exhibited strong anti-interfering capability, it can not only be used in milieus that contain various amino acids and some biologically-abundant cations, but can also be usable in some biological fluids such as urine and serum. This test-paper-like film sensor is suitable for portable field analysis and needs no extra protective measures during transport due to its flexibility, and it can easily be separated from the analyte solution after the detection. PMID- 21796291 TI - Methylenecyclopropane as C1 synthetic units: [1+4] cycloaddition via a nickel catalyst. AB - Nickel-catalyzed reactions of methylenecyclopropanes and thioanhydrides afford sulfur-containing heterocyclic compounds via [1+4] cycloaddition. The reactions represent a new use for methylenecyclopropane as a possible one-carbon building block to replace carbon monoxide, isocyanides, and Fischer carbene complexes. PMID- 21796292 TI - Emission enhancement of conjugated polymers through self-assembly of unimolecular micelles to multi-micelle aggregates. AB - By using a cosolvent self-assembly approach, the emission of multi-micelle aggregates from star copolymer unimolecular micelles is enhanced greatly through restriction of concentration self-quenching and intermolecular aggregation of a conjugated polymer core, due to the existence of a PEG shell of HCP-star-PEG unimolecular micelles. PMID- 21796293 TI - Pressure-induced pseudorotation in crystalline pyrrolidine. AB - Pressure of 1.14(3) GPa leads to the crystallization of a new beta phase of pyrrolidine, where every second molecule pseudorotates to the CH(2)-off envelope conformation, energetically less favored than the NH-off envelope. The beta phase is triclinic, space group P 1, but it is isostructural with monoclinic phase alpha, where all molecules are in the N-off envelope conformation. The energy associated with the pseudorotation constitutes only about 5% of the total energy change. The energetically unfavorable axial N-H position is retained. PMID- 21796294 TI - A cold and slow molecular beam. AB - Employing a two-stage cryogenic buffer gas cell, we produce a cold, hydrodynamically extracted beam of calcium monohydride molecules with a near effusive velocity distribution. Beam dynamics, thermalization and slowing are studied using laser spectroscopy. The key to this hybrid, effusive-like beam source is a "slowing cell" placed immediately after a hydrodynamic, cryogenic source [Patterson et al., J. Chem. Phys., 2007, 126, 154307]. The resulting CaH beams are created in two regimes. In one regime, a modestly boosted beam has a forward velocity of v(f) = 65 m s(-1), a narrow velocity spread, and a flux of 10(9) molecules per pulse. In the other regime, our slowest beam has a forward velocity of v(f) = 40 m s(-1), a longitudinal temperature of 3.6 K, and a flux of 5 * 10(8) molecules per pulse. PMID- 21796295 TI - Density functional studies of functionalized graphitic materials with late transition metals for Oxygen Reduction Reactions. AB - Low-temperature fuel cells are appealing alternatives to the conventional internal combustion engines for transportation applications. However, in order for them to be commercially viable, effective, stable and low-cost electrocatalysts are needed for the Oxygen Reduction Reaction (ORR) at the cathode. In this contribution, on the basis of Density Functional Theory (DFT) calculations, we show that graphitic materials with active sites composed of 4 nitrogen atoms and transition metal atoms belonging to groups 7 to 9 in the periodic table are active towards ORR, and also towards Oxygen Evolution Reaction (OER). Spin analyses suggest that the oxidation state of those elements in the active sites should in general be +2. Moreover, our results verify that the adsorption behavior of transition metals is not intrinsic, since it can be severely altered by changes in the local geometry of the active site, the chemical nature of the nearest neighbors, and the oxidation states. Nonetheless, we find that these catalysts trend-wise behave as oxides and that their catalytic activity is limited by exactly the same universal scaling relations. PMID- 21796296 TI - Surface basicity on bulk modified phosphorus alumina through different synthesis methods. AB - Bulk modified phosphorus alumina samples were prepared by gel method (GPA) and hydrolysis of phosphide aluminum (HPA). The gamma-Al(2)O(3) impregnated by phosphates precursor (IPA) was also compared. The basicity of the samples has been investigated through the CO(2) adsorption/desorption processes by in situ DRIFT and temperature programmed desorption experiments. It was found that the surface basicity can be adjusted by different location of phosphates species. For the GPA sample, the phosphates species tends to be located in the grain boundaries as they were not stable enough to overcome the structure rearrangement at high temperatures. In contrast, phosphorus was stably anchored in the crystal lattice of HPA sample. Considering the synthesis process of HPA samples, phosphorus changed its valence state from P(-3) to P(+5) and migrated from anion to cation sites. The anion vacancies left in the lattice facilitated the formation of unsaturated oxygen ions and results in the enhanced basicity. PMID- 21796297 TI - Electron transfer-induced fragmentation of thymine and uracil in atom-molecule collisions. AB - Ion-pair formation has been studied in hyperthermal (30-100 eV) neutral potassium collisions with gas phase thymine (C(5)H(6)N(2)O(2)) and uracil (C(4)H(4)N(2)O(2)). Negative ions formed by electron transfer from the alkali atom to the target molecule were analysed by time-of-flight (TOF) mass spectrometry. The most abundant product anions are assigned to CNO(-) and (U-H)( )/(T-H)(-) and the associated electron transfer mechanisms are discussed. Special emphasis is given to the enhancement of ring breaking pathways in the present experiments, notably CNO(-) formation, compared with free electron attachment measurements. PMID- 21796298 TI - Metal-promoted synthesis of amidines containing the model nucleobases 1 methylcytosine and 9-methyladenine. AB - The amidine complexes cis-[L(2)PtNH==C(R){1-MeCy(-2H)}]NO(3) (R = Me, 1a; Ph, 1b, Me(3)C, 1c; Ph(2)(H)C, 1d) and cis-[L(2)PtNH==C(R){9-MeAd(-2H)}]NO(3) (R = Me, 2a; Ph, 2b; Me(3)C, 2c; Ph(2)(H)C, 2d), are formed when cis-[L(2)Pt(MU OH)](2)(NO(3))(2) (L = PPh(3)) reacts with 1-methylcytosine (1-MeCy) and 9 methyladenine (9-MeAd) in solution of MeCN, PhCN, Me(3)CCN and Ph(2)(H)CCN. Reaction of 1a,b and 2a,b with HCl affords the protonated amidines [NH(2)==C(R){1 MeCy(-H)}]NO(3) (R = Me, 3a; Ph, 3b) and [NH(2)==C(R){9-MeAd(-H)}]NO(3) (R = Me, 4a; Ph, 4b) and cis-(PPh(3))(2)PtCl(2) in quantitative yield. Treatment of 3b and 4b with NaOH allows the isolation of the neutral benzimidamides NH(2)-C(Ph){1 MeCy(-2H)} (5b) and NH(2)-C(Ph){9-MeAd(-2H)} (6b). In the solid state 3b shows a planar structure with the hydrogen atom on N(4) cytosine position involved in a strong H-bond with the NO(3)(-) ion. Intermolecular H-bonds between the oxygen of the cytosine ring and one of the H atoms of the amidine-NH(2) group allow the dimerization of the molecule. A detailed analysis of the spectra of 3b in DMF d(7) at -55 degrees C indicates the presence of an equilibrium between the species [NH(2)==C(R){1-MeCy(-H)}]NO(3) and [NH(2)==C(R){1-MeCy( H)}](2)(NO(3))(2), exchanging with trace amounts of water at 25 degrees C. [(15)N,(1)H]-HMBC experiments for 5b and 6b indicate that the amino tautomer H(2)N-C(Ph){nucleobase(-2H)}, is the only detectable in solution and such structure has been confirmed in the solid state. The reaction of 5b and 6b with cis-L(2)Pt(ONO(2))(2) (L = PPh(3)), in chlorinated solvents, determines the immediate appearance of a pale yellow colour due to the coordination of the neutral amidine, likely in its imino form HN==C(Ph){nucleobase(-H)}, to give the adducts cis-[L(2)PtNH==C(Ph){nucleobase(-H)}](2+). In fact, addition of "proton sponge" leads to the immediate deprotonation of the amidine ligand with formation of the starting complexes 1b and 2b. PMID- 21796299 TI - Kinetics and mechanism of the reduction of a macrocyclic Rh(III) complex by chromium(II) ions: pH-controlled selectivity to rhodium(II) vs. rhodium(III) hydride. AB - Aqueous chromium(II) ions reduce a macrocyclic Rh(III) complex L(1)(H(2)O)(2)Rh(3+) (L(1) = 1,4,8,11-tetraazacyclotetradecane) to the hydride L(1)(H(2)O)RhH(2+) in two discrete, one-electron steps. The first step generates L(1)(H(2)O)Rh(2+) with kinetics that are first order in each rhodium(III) complex and Cr(H(2)O)(6)(2+), and inverse in [H(+)], k/M(-1) s(-1) = 0.065/(0.0031 + [H(+)]). Further reduction of L(1)(H(2)O)Rh(2+) to L(1)(H(2)O)RhH(2+) is kinetically independent of [H(+)], k/M(-1) s(-1) = 0.30. The difference in [H(+)] dependence allows relative rates of the two steps to be manipulated to generate either L(1)(H(2)O)Rh(2+) or L(1)(H(2)O)RhH(2+) as the final product. PMID- 21796300 TI - Heterogeneous bilayer molecular structure at a liquid-solid interface. AB - Hexaphenylbenzene (HPB) derivatives, HPB-6a and HPB-6pa, can form a supramolecular network which is stabilized by the intermolecular hydrogen bonding between carboxyl group at an octanoic acid/graphite interface. The observation of the heterogeneous bilayer structure formed exclusively by coronene and HPB-6pa at the octanoic acid/graphite interface is reported. Pronounced selectivity of coronene for the supramolecular networks with different sizes is reflected through the formation of bilayer structure for HPB-6pa network with the introduction of coronene as the guest species, indicating stronger interactions between HPB-6pa and coronene. PMID- 21796301 TI - Structural and biochemical analyses reveal how ornithine acetyl transferase binds acidic and basic amino acid substrates. AB - Structural and biochemical analyses reveal how ornithine acetyl-transferases catalyse the reversible transfer of an acetyl-group from a basic (ornithine) to an acidic (glutamate) amino acid by employing a common mechanism involving an acetyl-enzyme intermediate but using different side chain binding modes. PMID- 21796302 TI - Traditional Chinese medicine, a solution for reducing dual stroke risk factors at once? AB - Based on genome wide association studies (GWAS), the activities of phosphodiesterase 4D (PDE4D) and 5-Lipoxygenase activating protein (ALOX5AP) were suggested as two of the major factors involved in ischemic stroke risks. Uncontrolled PDE4D activities often lead to cAMP-induced stroke and cardiovascular diseases. Overexpression of ALOX5AP, on the other hand, had been shown to play a major role in inflammation pathway that could induce the development of atherosclerosis and stroke. To eliminate the risk factors that lead to stroke, we reported the identification and analysis of dual-targeting compounds that could reduce PDE4D and ALOX5AP activities from traditional Chinese medicine (TCM). We employed world's largest TCM database, TCM Database@Taiwan, for in silico drug identification. We also introduced machine learning predictive models, as well as pharmacophore model, for characterizing the drug-like candidates. Both myristic acid and pentadecanoic acid were identified. The follow up analysis on molecular dynamics simulation further determined the major roles of the carboxyl group for forming stable molecular interactions. Intriguingly, the carboxyl group demonstrated different bonding patterns with PDE4D and ALOX5AP, through electrostatic interaction and hydrogen bonds, respectively. In addition, the large volume occupied by the ligand hydrophobic regions could achieve inhibition through occupying the vacant spaces in the binding site. These pharmacophores held true for both candidates against each protein targets. Hence, we proposed the presence of the carboxyl group and hydrophobic regions as potent dual targeting features that inhibit both PDE4D and ALOX5AP activities. PMID- 21796303 TI - Non-covalent interactions between carbon nanotubes and conjugated polymers. AB - Carbon nanotubes (CNTs) are interest to many different disciplines including chemistry, physics, biology, material science and engineering because of their unique properties and potential applications in various areas spanning from optoelectronics to biotechnology. However, one of the drawbacks associated with these materials is their insolubility which limits their wide accessibility for many applications. Various approaches have been adopted to circumvent this problem including modification of carbon nanotube surfaces by non-covalent and covalent attachments of solubilizing groups. Covalent approach modification may alter the intrinsic properties of carbon nanotubes and, in turn make them undesirable for many applications. On the other hand, a non-covalent approach helps to improve the solubility of CNTs while preserving their intrinsic properties. Among many non-covalent modifiers of CNTs, conjugated polymers are receiving increasing attention and highly appealing because of a number of reasons. To this end, the aim of this feature article is to review the recent results on the conjugated polymer-based non-covalent functionalization of CNTs with an emphasis on the effect of conjugated polymers in the dispersibility/solubility, optical, thermal and mechanical properties of carbon nanotubes as well as their usage in the purification and isolation of a specific single-walled nanotube from the mixture of the various tubes. PMID- 21796304 TI - In situ transmission electron microscopy of solid-liquid phase transition of silica encapsulated bismuth nanoparticles. AB - The solid-liquid phase transition of silica encapsulated bismuth nanoparticles was studied by in situ transmission electron microscopy (TEM). The nanoparticles were prepared by a two-step chemical synthesis process involving thermal decomposition of organometallic precursors for nucleating bismuth and a sol-gel process for growing silica. The microstructural and chemical analyses of the nanoparticles were performed using high-resolution TEM, Z-contrast imaging, focused ion beam milling, and X-ray energy dispersive spectroscopy. Solid-liquid solid phase transitions of the nanoparticles were directly recorded by electron diffractions and TEM images. The silica encapsulation of the nanoparticles prevented agglomeration and allowed particles to preserve their original volume upon melting, which is desirable for applications of phase change nanoparticles with consistently repeatable thermal properties. PMID- 21796305 TI - A thermochemiluminescence array for recognition of protein subtypes and their denatured shapes. AB - Thermochemiluminescence (TCL) of organic compounds or biological substances is an interesting phenomenon and has been applied to polymer analysis and medical diagnostics. We improve traditional TCL assays using the assistance of catalytic nanomaterials and construct a nanomaterials array for the discrimination of three subtypes of proteins (albumin from human serum, bovine serum and porcine serum). With the assistance of catalytic nanomaterials, TCL signals of different protein samples are distinct due to the diverse catalytic activities of the nanomaterials and characteristics of proteins. Using this array-based technology, we obtained unique TCL patterns as 'fingerprints', and then accurately classified these 3 subtypes of serum albumins and the denatured albumins under different heat conditions. In the blind test, 24 unknown samples randomly chosen from these albumins were all assigned to the accurate groups. Moreover, on several nanomaterials, the intensity of TCL could be greatly amplified. For example, on MgO and BaO, albumins in aqueous solutions at 2 MUg mL(-1) (~30 nM) offered robust responses. This improved TCL assay with reversible response and simple instrumentation can offer high differentiability and sensitivity. PMID- 21796307 TI - Molecules for organic electronics studied one by one. AB - The electronic and geometrical structure of single difluoro-bora-1,3,5,7 tetraphenyl-aza-dipyrromethene (aza-BODIPY) molecules adsorbed on the Au(111) surface is investigated by low temperature scanning tunneling microscopy and spectroscopy in conjunction with ab initio density functional theory simulations of the density of states and of the interaction with the substrate. Our DFT calculations indicate that the aza-bodipy molecule forms a chemical bond with the Au(111) substrate, with distortion of the molecular geometry and significant charge transfer between the molecule and the substrate. Nevertheless, most likely due to the low corrugation of the Au(111) surface, diffusion of the molecule is observed for applied bias in excess of 1 V. PMID- 21796308 TI - Ruthenium-catalyzed ring-closing metathesis accelerated by long-range steric effect. AB - Ruthenium-based metathesis catalysts with a N-heterocyclic carbene ligand bearing 2,3,4,5-tetraphenylphenyl moieties (1-TPPh and 1-TPPh*) are developed. The highly active catalyst system has been realized in THF by the combination of 1-TPPh* and CuCl as a phosphine scavenger. PMID- 21796309 TI - Gold-silver bimetallic porous nanowires for surface-enhanced Raman scattering. AB - Highly porous bimetallic nanowires manufactured via a simple galvanic reaction have demonstrated superior activity in surface-enhanced Raman scattering, allowing ultrasensitive chemical detections on isolated porous nanowires in comparison to pristine silver nanowires. PMID- 21796310 TI - Organocatalytic synthesis of carbohydrates. AB - The key role of carbohydrates in biological processes and their visible existence in our everyday life have stimulated the interest of leading research groups on the smart and simple synthesis of common and rare sugar molecules. Now, more than 120 years after Fischer's first synthesis of (D)-glucose (1890), we are witnessing important development in this field of total synthesis. Using modern methods of direct activation of carbonyl compounds chemists can prepare sugars in an elegant and efficient way similar to that of Nature. This tutorial review presents recent impressive progress in the area of de novo synthesis of carbohydrates by using organocatalytic direct aldol reaction as a key step. PMID- 21796311 TI - How molecular oxygen binds to bis[trifluoroacetylacetonato(-1)]cobalt(II)--ab initio and density functional theory studies. AB - Cobalt(II) diketonate complexes, such as bis[trifluoroacetylacetonato( 1)]cobalt(II) [Co(tfa)(2)], catalyze the aerobic oxidation of alkenols into functionalized tetrahydrofurans. To gain insight into activation of triplet dioxygen by Co(tfa)(2) in a protic solvent, as used in oxidation catalysis, the electronic structure of aquabis[trifluoroacetylacetonato(-1)]cobalt(II)- Co(tfa)(2)(H(2)O)--and the derived dioxygen adduct were characterized using ab initio (CASSCF, NEVPT2) and density functional theory (BP86, TPSSh, B3LYP) methods. The ground state of Co(tfa)(2)(H(2)O) is a high-spin, quartet state. As dioxygen approaches the cobalt atom, the quartet state couples with a triplet dioxygen molecule and forms a sextet, a quartet, and a doublet spin state with the high-spin state being the lowest in energy. At the equilibrium Co-O(2) distance of 1.9 A, Co(tfa)(2)(H(2)O)(O(2)) has a doublet superoxo Co(III) ground state with the unpaired electron residing on the oxygen moiety, in a nearly unchanged O(2)pi* orbital. PMID- 21796312 TI - Pseudorotaxane-type n-hydrocarbon container. Metallacyclodimer of ionic palladium(II) complexes containing 1,3-bis(4-pyridyl)tetramethyldisiloxane. AB - An unusual "pseudorotaxaned n-alkane within a metalla-cyclodimer" system, C(n)H(2n+2)@[(Me(4)en)Pd(L)](2)(CF(3)SO(3))(4) (n = 5, 6, 7; Me(4)en = N,N,N',N' tetramethylethylenediamine; L = 1,3-bis(4-pyridyl)tetramethyldisiloxane), was constructed. This system is the first pseudorotaxane-type petroleum container achieved via the appropriate size effect. PMID- 21796313 TI - Copper-catalyzed reductive coupling of tosylhydrazones with amines: a convenient route to alpha-branched amines. AB - A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)(2) and Cs(2)CO(3) has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give alpha-branched amines in good yields. PMID- 21796314 TI - Graphene-based composites. AB - Graphene has attracted tremendous research interest in recent years, owing to its exceptional properties. The scaled-up and reliable production of graphene derivatives, such as graphene oxide (GO) and reduced graphene oxide (rGO), offers a wide range of possibilities to synthesize graphene-based functional materials for various applications. This critical review presents and discusses the current development of graphene-based composites. After introduction of the synthesis methods for graphene and its derivatives as well as their properties, we focus on the description of various methods to synthesize graphene-based composites, especially those with functional polymers and inorganic nanostructures. Particular emphasis is placed on strategies for the optimization of composite properties. Lastly, the advantages of graphene-based composites in applications such as the Li-ion batteries, supercapacitors, fuel cells, photovoltaic devices, photocatalysis, as well as Raman enhancement are described (279 references). PMID- 21796315 TI - Cancer detection using nanoparticle-based sensors. AB - This tutorial review surveys the latest achievements in the use of nanoparticles to detect cancer biomarkers and cancer cells with a focus on optical and electrochemical techniques. Nanoparticle based cancer diagnostics are becoming an increasingly relevant alternative to traditional techniques. Although some drawbacks exist in relation to the obtained sensitivity the use of nanoparticle based sensors in biomarker detection or cancer cell detection offers some advantages in comparison to conventional methods. The developed techniques can be interesting and relevant for their use in point-of-care of cancer diagnostics. The methods can be of low cost and in addition easy to be incorporated into user friendly sensing platforms. PMID- 21796316 TI - Plutonium uptake and behavior in vegetation of the desert southwest: a preliminary assessment. AB - Eight species of desert vegetation and associated soils were collected from the Nevada National Security Site (N2S2) and analyzed for 238Pu and 239 + 240Pu concentrations. Amongst the plant species sampled were: atmospheric elemental accumulators (moss and lichen), the very slow growing, long-lived creosote bush and the rapidly growing, short-lived cheatgrass brome. The diversity of growth strategies provided insight into the geochemical behavior and bio-availability of Pu at the N2S2. The highest concentrations of Pu were measured in the onion moss (24.27 Bq kg-1 238Pu and 52.78 Bq kg-1 239 + 240Pu) followed by the rimmed navel lichen (8.18 Bq kg-1 and 18.4 Bq kg-1 respectively), pointing to the importance of eolian transport of Pu. Brome and desert globemallow accumulated between 3 and 9 times higher concentrations of Pu than creosote and sage brush species. These results support the importance of species specific elemental accumulation strategies rather than exposure duration as the dominant variable influencing Pu concentrations in these plants. Total vegetation elemental concentrations of Ce, Fe, Al, Sm and others were also analyzed. Strong correlations were observed between Fe and Pu. This supports the conclusion that Pu was accumulated as a consequence of the active accumulation of Fe and other plant required nutrients. Cerium and Pu are considered to be chemical analogs. Strong correlations observed in plants support the conclusion that these elements displayed similar geochemical behavior in the environment as it related to the biochemical uptake process of vegetation. Soils were also sampled in association with vegetation samples. This allowed for the calculation of a concentration ratio (CR). The CR values for Pu in plants were highly influenced by the heterogeneity of Pu distribution among sites. Results from the naturally occurring elements of concern were more evenly distributed between sample sites. This allowed for the development of a pattern of plant species that accumulated Ce, Sm, Fe and Al. The highest accumulators of these elements were onion moss, lichen flowed by brome. The lowest accumulators were creosote bush and fourwing saltbush. This ranked order corresponds to plant accumulations of Pu. PMID- 21796317 TI - Visualising gold inside tumour cells following treatment with an antitumour gold(I) complex. AB - Gold(I) phosphine complexes, such as [Au(d2pype)(2)]Cl, (1, where d2pype is 1,2 bis(di-2-pyridyl phosphinoethane)), belong to a class of promising chemotherapeutic candidates that have been shown to be selectively toxic to tumourigenic cells, and may act via uptake into tumour cell mitochondria. For a more holistic understanding of their mechanism of action, a deeper knowledge of their subcellular distribution is required, but to date this has been limited by a lack of suitable imaging techniques. In this study the subcellular distribution of gold was visualised in situ in human breast cancer cells treated with 1, using nano-scale secondary ion mass spectrometry. NanoSIMS ion maps of (12)C(14)N(-), (31)P(-), (34)S(-) and (197)Au(-) allowed, for the first time, visualisation of cellular morphology simultaneously with subcellular distribution of gold. Energy filtered transmission electron microscopy (EFTEM) element maps for gold were also obtained, allowing for observation of nuclear and mitochondrial morphology with excellent spatial resolution, and gold element maps comparable to the data obtained with NanoSIMS. Following 2 h treatment with 1, the subcellular distribution of gold was associated with sulfur-rich regions in the nucleus and cytoplasm, supporting the growing evidence for the the mechanism of action of Au(I) compounds based on inhibition of thiol-containing protein families, such as the thioredoxin system. The combination of NanoSIMS and EFTEM has broader applicability for studying the subcellular distribution of other types of metal based drugs. PMID- 21796318 TI - Theoretical investigation on mechanism of asymmetric Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex. AB - The mechanism of Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex has been investigated by DFT and ONIOM methods. Calculations indicate that the reaction proceeds through a dual activation mechanism, in which Al(III) acts as a Lewis acid to activate the electrophile alpha,beta-unsaturated carbonyl substrate while the tertiary amine in the Cinchona alkaloid works as a Lewis base to promote the activation of the malononitrile and deprotonation. A stepwise pathway involving C-C bond formation followed by proton transfer from the catalyst to the carbonyl substrate is adopted, and latter step is predicted to be the rate-determining-step in the reaction with an energy barrier of 12.4 kcal mol(-1). In the absence of the Al(III)-complex, a Cinchona alkaloid activates the carbonyl substrate by a hydrogen bonding of the hydroxyl group, involving a higher energy barrier of 30.4 kcal mol(-1). The steric repulsion between the phenyl group attached to the carbonyl group in the chalcone and isopropoxyl groups of the Al(III)-complex may play an important role in the control of stereoselectivity. The pi-pi stacking effect between the quinuclidine ring of the quinine and the phenyl group of the chalcones may also help the stabilization of the preferred molecular complex. These results are in agreement with experimental observations. PMID- 21796319 TI - Luminescent bichromophoric spiroindolones--synthesis and electronic properties. AB - Novel bichromophoric spirocyclic indolones have been synthesized by an insertion coupling-isomerization-Diels-Alder domino reaction. The emission colors are strongly affected by the substituents: N-Boc leads to intense blue fluorescence, N-dansyl causes turquoise emission, whereas a 1-anthryl substituent on the butadiene results in yellow luminescence. The latter behavior is rationalized by TDDFT computations as a result of significant geometrical changes. PMID- 21796320 TI - A general phosphoric acid-catalyzed desymmetrization of meso-aziridines with silylated selenium nucleophiles. AB - The first example of meso-aziridine desymmetrization with selenium nucleophiles is reported. The reaction, promoted by VAPOL-hydrogen phosphate using (phenylseleno)trimethylsilane as the nucleophile, proves to be very general and highly enantioselective (84-99% ee). PMID- 21796321 TI - Rewritable multicolor fluorescent patterns for multistate memory devices with high data storage capacity. AB - We report a branched polyethyleneimine (BPEI)-quantum dot (QD) based rewritable fluorescent system with a multicolor recording mode, in which BPEI is both QD multicolor patterning "writer" and data erasing "remover". This method could write distinct colors from size-tailored QDs to represent large numbers of logic states for high data storage capacity. PMID- 21796322 TI - Silver(I) and copper(I) complexes supported by fully fluorinated 1,3,5 triazapentadienyl ligands. AB - Synthesis of the perfluorinated 1,3,5-triazapentadiene [N{(CF(3))C(C(6)F(5))N}(2)]H and the use of its conjugate base as a supporting ligand for the isolation of silver(i) and copper(i) complexes are reported. Some of the related chemistry involving [N{(C(3)F(7))C(C(6)F(5))N}(2)](-) (that has bulkier -C(3)F(7) groups on the 1,3,5-triazapentadienyl ligand backbone) is also presented. X-ray crystallographic data show a wide variety of structures ranging from intermolecular, hydrogen-bonded chain structure for [N{(CF(3))C(C(6)F(5))N}(2)]H with a twisted W-shaped N(3)C(2) core, monomeric [N{(CF(3))C(C(6)F(5))N}(2)]Ag(CN(t)Bu)(2) and [N{(C(3)F(7))C(C(6)F(5))N}(2)]Ag(CN(t)Bu)(2) where the kappa(1)-bonded triazapentadienyl ligand bonding to the metal fragment via the central nitrogen atom, monomeric [N{(CF(3))C(C(6)F(5))N}(2)]Ag(PPh(3))(2) and [N{(C(3)F(7))C(C(6)F(5))N}(2)]Ag(PPh(3))(2) that feature kappa(1)-bonded triazapentadienyl ligand bonding to the metal fragment via one of the terminal nitrogen atoms, to that of the monomeric [N{(CF(3))C(C(6)F(5))N}(2)]Cu(CN(t)Bu)(2) containing a kappa(2)-bonded triazapentadienyl ligand and a U-shaped NCNCN ligand backbone. The isocyanide adducts show relatively high nu(CN) values in the IR spectra. PMID- 21796323 TI - Recent developments in the field of oxa-Michael reactions. AB - Oxa-Michael reactions, i.e. addition reactions of oxygen nucleophiles to conjugated systems, have traditionally received much less attention from the scientific community compared to the addition of carbon nucleophiles to conjugate acceptor systems (Michael reaction). This was mainly due to lack of reactivity and selectivity of these reactions. Within the last few years however, there has been a remarkable increase in publications focussing on method development as well as applications to natural product synthesis. This tutorial review discusses instructive examples that have substantially broadened the scope of oxa-Michael reactions. PMID- 21796324 TI - Fluorescent indicators based on BODIPY. AB - This critical review covers the advances made using the 4-bora-3a,4a-diaza-s indacene (BODIPY) scaffold as a fluorophore in the design, synthesis and application of fluorescent indicators for pH, metal ions, anions, biomolecules, reactive oxygen species, reactive nitrogen species, redox potential, chemical reactions and various physical phenomena. The sections of the review describing the criteria for rational design of fluorescent indicators and the mathematical expressions for analyzing spectrophotometric and fluorometric titrations are applicable to all fluorescent probes (206 references). PMID- 21796325 TI - Interaction of Co(II), Ni(II) and Cu(II) with dibenzo-substituted macrocyclic ligands incorporating both symmetrically and unsymmetrically arranged N, O and S donors. AB - The synthesis and characterisation of four 17-membered, dibenzo-substituted macrocyclic ligands incorporating unsymmetrical arrangements of their N(3)S(2), N(3)O(2) and N(3)OS (two ligands) donor atoms are described; these rings complete the matrix of related macrocyclic systems incorporating both symmetric and unsymmetric donor sets reported previously. The X-ray structures of three of the new macrocycles are reported. In two of the Cu(II) structures only three of the possible five donor atoms present in the corresponding macrocyclic ligand bind to the Cu(II) site, whereas all five donors are coordinated in each of the remaining complexes. The interaction of Co(II), Ni(II) and Cu(II) with the unsymmetric macrocycle series has been investigated by potentiometric (pH) titration in 95% methanol; X-ray structures of two nickel and three copper complexes of these ligands, each exhibiting 1:1 (M:L) ratios, have been obtained. The results are discussed in the context of previous results for these metals with the analogous 17-membered ring systems incorporating symmetrical arrangements of their donor atoms, with emphasis being given to both the influence of the donor atom set, as well as the donor atom sequence, on the nature of the resulting complexes. PMID- 21796326 TI - [Human retrovirus HTLV-1: descriptive and molecular epidemiology, origin, evolution, diagnosis and associated diseases]. AB - Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus discovered in 1980. It is estimated that around 10-20 million people are infected with HTLV-1 worldwide. However, HTLV-1 is not a ubiquitous virus. Indeed, HTLV-1 is present throughout the world with clusters of high endemicity including mainly southern Japan, the Caribbean region, parts of South America and intertropical Africa, with foci in the Middle East and Australia. The origin of this puzzling geographical repartition is probably linked to a founder effect in certain human groups. In the high endemic areas, 0.5 to 50% of the people have antibodies against HTLV-1 antigens. HTLV-1 seroprevalence increases with age, especially in women. HTLV-1 has 3 modes of transmission: mother to child, mainly through prolonged breastfeeding (> 6 months); sexual, mainly but not exclusively occurring from male to female; and by blood products contaminated by infected lymphocytes. HTLV-1 is mainly the etiological agent of two very severe diseases: a malignant T CD4+ cell lymphoproliferation of very poor prognosis, named adult T-cell leukemia/lymphoma (ATLL), and a chronic neuro myelopathy named tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HTLV-1 is also associated with rare anterior uveitis, infective dermatitis and myositis in some high HTLV-1 endemic areas. The repartition of the different molecular subtypes or genotypes is mainly linked to the geographical origin of the infected persons but not to the associated pathology. HTLV-1 possesses a remarkable genetic stability probably linked to viral amplification via clonal expansion of infected cells rather than by reverse transcription. This stability can be used as a molecular tool to gain better insights into the origin, evolution and modes of dissemination of HTLV-1 and infected populations. HTLV-1 originated in humans through interspecies transmission from STLV-1, a very closely related retrovirus, highly endemic in several populations of apes and Old World monkeys. PMID- 21796327 TI - Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. AB - BACKGROUND: Renal sympathetic hyperactivity is associated with hypertension, a leading cause of mortality worldwide. Renal sympathetic denervation via the Symplicity Catheter System has been shown to decrease blood pressure by 33/11 mmHg by 6 months, with no radiofrequency (RF)-related adverse sequelae visible by CT/MR angiography or renal duplex ultrasound 6 months after the procedure. Here, we present preclinical work predating those clinical results. We performed therapeutic renal sympathetic denervation in a swine animal model to characterize the vascular safety and healing response 6 months after renal denervation therapy. METHODS: In December 2007, seven domestic swine received a total of 32 radiofrequency ablations via the Symplicity Catheter System and were euthanatized 6 months later. Renal angiography was done before, immediately after, and 6 months after procedure. The renal vessels were examined histologically with H&E and Movat pentachrome stains to identify evidence of vascular and neural injury. The kidneys and urinary system were also examined for evidence of gross and microscopic abnormalities. RESULTS: Renal nerve injury involved primarily nerve fibrosis, replacement of nerve fascicles with fibrous connective tissue, and thickening of the epineurium and perineurium. Renal arterial findings included fibrosis of 10-25% of the total media and underlying adventitia, with mild disruption of the external elastic lamina. No significant smooth muscle hyperplasia or inflammatory components were observed. There was no renal arterial stenosis or thrombosis observed by angiography or histology. No gross or microscopic device-related abnormalities were noted in the kidney, surrounding stroma, or urinary bladder. CONCLUSIONS: In a swine model, renal denervation via the Symplicity Catheter System resulted in no clinically significant adverse renal artery or renal findings 6 months after the procedure. This is corroborated by the vascular safety profile demonstrated in subsequent human clinical studies. PMID- 21796329 TI - Biological control of Ascaris suum eggs by Pochonia chlamydosporia fungus. AB - Ascaris suum is a gastrointestinal nematode parasite of swines. The aim of this study was to observe Pochonia chlamydosporia fungus on biological control of A. suum eggs after fungus passage through swines gastrointestinal tract. Eighteen pigs, previously dewormed, were randomly divided into three groups: group 1, treated with the fungus isolate VC4; group 2, treated with the fungus isolate VC1 and group 3 did not receive fungus (control). In the treated groups, each animal received a 9 g single dose of mycelium mass containing P. chlamydosporia (VC1 or VC4). Thereafter, animal fecal samples were collected at the following intervals: 8, 12, 24, 36, 48, 72 and 96 h after treatment beginning and these were poured in Petri dishes containing 2% water-agar culture medium. Then, 1,000 A. suum eggs were poured into each dish and kept in an incubator at 26 degrees C and in the dark for 30 days. After this period, approximately 100 eggs were removed from each Petri dish and morphologically analyzed under light microscopy following the ovicidal activity parameters. The higher percentage observed for isolated VC4 eggs destruction was 57.5% (36 h) after fungus administration and for isolate VC1 this percentage was 45.8% (24 h and 72 h) (p > 0.01). P. chlamydosporia remained viable after passing through the gastrointestinal tract of swines, maintaining its ability of destroying A. suum eggs. PMID- 21796330 TI - Malignant Brenner tumor of the ovary: analysis of 13 cases. AB - OBJECTIVE: Most Brenner tumors are benign, with only 1% being malignant. In this study we report on 13 cases with malignant Brenner tumor of the ovary and discuss the clinical, demographic and histologic features. METHOD: Thirteen patients with malignant Brenner tumor of the ovary who were treated at Selcuk University Gynecology Department over a 6-year period from January 2004 to December 2010 were retrospectively analysed from hospital electronic medical records. Clinical and pathologic findings were reported. RESULTS: The median age of the study population was 55.69 +/- 11.81 years (range 43-79 years). Most of the patients presented with abdominal pain (6/13, 46.2%). The mean size of the ovarian tumors was 9.19 +/- 1.34 cm (range 4-16.5 cm). Six patients (46.2%) were in stage III, five (38.5%) in stage I, and two (15.4%) in stage IV. Ten patients (76.9%) received chemotherapy. The mean follow-up was 38.38 +/- 23.25 months (range 5-84 months). During follow-up, recurrence was detected in 7 patients (53.8%). The mean recurrence time was 23.8 +/- 14.46 months (range 11-48 months). CONCLUSION: In our study, we found that diagnosis was at an advanced stage, and recurrence rate was high. The mainstay of treatment is surgical resection, but the exact regimen and benefit of adjuvant therapy remain unknown. PMID- 21796331 TI - Management of advanced colon cancer in a community hospital--impact of age on clinical management and survival. AB - PURPOSE: Colon cancer is more common in the elderly than in younger and middle aged people. Cancer clinical trials focus more on younger patients and the management of elderly patients with advanced disease is still unclear. METHODS: We studied all patients presenting with colon adenocarcinoma metastasis to liver at a community teaching hospital from Dec 2000 through Dec 2007 by a retrospective review of Tumor Registry data and patient chart review with focus on age, clinical management, decision making, and survival. Sixty-seven patients with a median age of 69 and a male to female ratio of 31:36 were identified. RESULTS: The patients with obstructive symptoms and Eastern Cooperative Oncology Group performance status on presentation though varied little by age, smaller proportion of elderly patients underwent resection of the primary bowel tumor in the presence of liver metastases with ten of 16 (63%) aged 80 or greater being managed without surgery. The percentage of patient's preference to physician's preference for patients not undergoing the primary bowel resection increased for older age group. Median survival decreased significantly with age (p < 0.05). CONCLUSIONS: Age-related clinical management, decision-making autonomy, and survival are apparent in this study, and there was an increasing trend of patient's involvement in decision making as the age increases and, thus, affecting the age-related clinical management. PMID- 21796332 TI - Hydrochlorothiazide versus calcium channel blockers: what is the best add-on to a renin-angiotensin system blocker for treating hypertension in patients with renal disease? AB - Hypertension remains an important problem that increases the risk of cardiovascular disease and is a leading cause of mortality worldwide. Achieving long-term control of arterial hypertension, which has an estimated prevalence of 28% in the US adult population, would translate into a significant reduction in cardiovascular events. Specific causes can be identified and treated for certain forms of secondary hypertension, but often it is multifactorial. Therefore, it makes sense to attain blood pressure control by addressing more than one pressor mechanism. Several clinical studies have demonstrated that combination antihypertensive therapy is more effective than monotherapy, and a review of currently published data suggests that approximately 75% of hypertensive individuals will require some form of combination therapy to achieve target blood pressure (BP) goals. To this end, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure (JNC 7) has recommended that antihypertensive therapy should start with two drugs when a patient presents with systolic blood pressure (SBP) more than 20 mm Hg above target levels, diastolic blood pressure (DBP) more than 10 mm Hg above target levels, or both. This review attempts to analyze the current evidence in published medical literature to answer the question of whether hydrochlorothiazide or a calcium channel blocker is a better add-on to a renin angiotensin system blocker for treating hypertension in patients with renal disease. PMID- 21796333 TI - LOX-1 transcription. AB - The importance of the lectin-like oxidized LDL receptor (LOX-1) gene in cardiovascular and other diseases is slowly being revealed. LOX-1 gene expression appears to be a "canary in a coal mine" for atherogenesis, being strongly up regulated early on in a number of cell types when they are activated, and predicting the sites of future disease. From this early time point the LOX-1 protein often participates in the disease process itself. While gene/protein expression can be regulated on a multiplicity of levels, the most basic and important mode of regulation is usually transcriptional. There are very few studies on the transcriptional regulation of the human LOX-1 promoter; fewer still on definitive mapping of the transcription factors involved. It is known that a wide variety of stimuli up-regulate LOX-1, usually/probably on the transcriptional level. Angiotensin II (Ang II) is one important regulator of renin-angiotensin system and stimulator LOX-1. Ang II is known to up-regulate LOX 1 transcription through an NF-kB motif located at nt -2158. Oxidized low density lipoprotein (ox-LDL) is another important cardiovascular regulator, particularly of atherosclerotic disease, and a strong stimulator of LOX-1. Ox-LDL is known to up-regulate LOX-1 transcription through an Oct-1 motif located at nt -1556. The subsequent enhanced LOX-1 receptor numbers and their binding by ox-LDL ligand triggers a positive feedback loop, increasing further LOX-1 expression, with a presently unknown regulatory governor. The Oct-1 gene also has its own Oct-1 driven positive feedback loop, which likely also contributes to LOX-1 up regulation. There is also data which suggests the involvement of the transcription factor AP-1 during stimulation with Phorbol 12-myristate acetate. While the importance of NF-kappaB as a transcriptional regulator of cardiovascular-relevant genes is well known, the importance of Oct-1 is not. Data suggests that Oct-1-mediated up-regulation of transcription is an early event in the stimulation of LOX-1 by ox-LDL. Yet Oct-1 also down-regulates cardiovascular relevant genes by suppressing NF-kappaB transactivation. Thus, Oct-1 is presently somewhat of an enigma, up-regulating and down-regulating genes seemingly at random without an overall theme (with the exception of cell cycle). Yet the up regulation of LOX-1 by ox-LDL is a very important event in atherogenesis (both early and late) and Oct-1 is, therefore, an important transcriptional gatekeeper of this important atherogenic trigger. PMID- 21796334 TI - Custom-made endoprosthetic total humerus reconstruction for musculoskeletal tumours. AB - PURPOSE: We analysed 11 patients with malignant musculoskeletal tumours of the humerus who underwent limb salvage surgery with total humeral custom endoprosthesis from 1990 to 2009. METHODS: There were six male and five female patients, with a mean age of 17 years. The most common diagnosis was osteosarcoma. The average follow-up period was 66 months, with the maximum being 180 months. Functional and oncological outcomes were analysed. RESULTS: The one and five year cumulative survival (Kaplan-Meier method) rates were 90.9% and 77.9 %. The average Musculoskeletal Tumour Society Score (MSTS) was 80%. Two patients died due to metastasis. One patient had a forequarter amputation for local recurrence. The procedure provides fast recovery and relatively good restoration of elbow function, whereas active shoulder movements remain limited CONCLUSION: Total humeral custom endoprosthetic replacement represents a viable treatment option in indicated patients, providing reliable and reasonable function of the upper limb, with a low complication rate. PMID- 21796335 TI - Operative treatment of avascular necrosis of the femoral head after proximal femur fractures in adolescents. AB - PURPOSE: Our aim was to assess operative treatment for post-traumatic avascular necrosis of the femoral head (ANFH) in adolescents. METHODS: Eleven patients with an average age of 17 (range 14-26) years were operated up on for ANFH after proximal femoral fractures. The average interval between injury and reconstructive surgery was four (range two to eight) years. The average follow-up of the entire cohort was 89 (range 48-132) months. Five patients with total ANFH were treated by total hip replacement (THR). Six patients with partial ANFH were treated with valgus intertrochanteric osteotomy (VITO). RESULTS: In all patients, operation improved hip function. The average preoperative Harris Hip Score (HHS) was 70 points and average postoperative HHS was 97 points. Comparison of magnetic resonance imaging (MRI) scans before and after VITO demonstrated resorption of the necrotic segment of the femoral head and its remodelling in all six patients with partial ANFH. A complication was encountered in one patient. CONCLUSION: Patients treated for ANFH had good medium-term outcomes after THR for total necrosis and also after VITO for partial necrosis. PMID- 21796336 TI - Recent advances in the treatment of necrotizing fasciitis. AB - With four types of necrotizing fasciitis (NF) now recognized, the diagnosis and management of NF becomes more challenging as physicians face more unusual pathogenic and atypical presentations. With few published guidelines and little evidence base to justify therapies, much of the literature is pragmatic or provides limited evidence with small underpowered studies and disparate case reports. PMID- 21796337 TI - Salt overload damages the glycocalyx sodium barrier of vascular endothelium. AB - Sodium overload stiffens vascular endothelial cells in vitro and promotes arterial hypertension in vivo. The hypothesis was tested that the endothelial glycocalyx (eGC), a mesh of anionic biopolymers covering the surface of the endothelium, participates in the stiffening process. By using a mechanical nanosensor, mounted on an atomic force microscope, height (~400 nm) and stiffness (~0.25 pN/nm) of the eGC on the luminal endothelial surface of split-open human umbilical arteries were quantified. In presence of aldosterone, the increase of extracellular sodium concentration from 135 to 150 mM over 5 days (sodium overload) led the eGC shrink by ~50% and stiffening by ~130%. Quantitative eGC analyses reveal that sodium overload caused a reduction of heparan sulphate residues by 68% which lead to destabilization and collapse of the eGC. Sodium overload transformed the endothelial cells from a sodium release into a sodium absorbing state. Spironolactone, a specific aldosterone antagonist, prevented these changes. We conclude that the endothelial glycocalyx serves as an effective buffer barrier for sodium. Damaged eGC facilitates sodium entry into the endothelial cells. This could explain endothelial dysfunction and arterial hypertension observed in sodium abuse. PMID- 21796338 TI - Functional arrangement of the 12th transmembrane region in the CFTR chloride channel pore based on functional investigation of a cysteine-less CFTR variant. AB - The membrane-spanning part of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel comprises 12 transmembrane (TM) alpha-helices, arranged into two pseudo-symmetrical groups of six. While TM6 in the N-terminal TMs is known to line the pore and to make an important contribution to channel properties, much less is known about its C-terminal counterpart, TM12. We have used patch clamp recording to investigate the accessibility of cytoplasmically applied cysteine-reactive reagents to cysteines introduced along the length of TM12 in a cysteine-less variant of CFTR. We find that methanethiosulfonate (MTS) reagents irreversibly modify cysteines substituted for TM12 residues N1138, M1140, S1141, T1142, Q1144, W1145, V1147, N1148, and S1149 when applied to the cytoplasmic side of open channels. Cysteines sensitive to internal MTS reagents were not modified by extracellular [2-(trimethylammonium)ethyl] MTS, consistent with MTS reagent impermeability. Both S1141C and T1142C could be modified by intracellular [2-sulfonatoethyl] MTS prior to channel activation; however, N1138C and M1140C, located deeper into the pore from its cytoplasmic end, were modified only after channel activation. Comparison of these results with previous work on CFTR-TM6 allows us to develop a model of the relative positions, functional contributions, and alignment of these two important TMs lining the CFTR pore. We also propose a mechanism by which these seemingly structurally symmetrical TMs make asymmetric contributions to the functional properties of the channel pore. PMID- 21796340 TI - Physiology and cell biology of acupuncture observed in calcium signaling activated by acoustic shear wave. AB - This article presents a novel model of acupuncture physiology based on cellular calcium activation by an acoustic shear wave (ASW) generated by the mechanical movement of the needle. An acupuncture needle was driven by a piezoelectric transducer at 100 Hz or below, and the ASW in human calf was imaged by magnetic resonance elastography. At the cell level, the ASW activated intracellular Ca(2+) transients and oscillations in fibroblasts and endothelial, ventricular myocytes and neuronal PC-12 cells along with frequency-amplitude tuning and memory capabilities. Monitoring in vivo mammalian experiments with ASW, enhancement of endorphin in blood plasma and blocking by Gd(3+) were observed; and increased Ca(2+) fluorescence in mouse hind leg muscle was imaged by two-photon microscopy. In contrast with traditional acupuncture models, the signal source is derived from the total acoustic energy. ASW signaling makes use of the anisotropy of elasticity of tissues as its waveguides for transmission and that cell activation is not based on the nervous system. PMID- 21796341 TI - Significant decline in the erythromycin resistance of group A streptococcus isolates at a German paediatric tertiary care centre. AB - Group A streptococcus (GAS) is considered to be a major pathogen of bacterial tonsillopharyngitis in children. Although GAS is generally susceptible to penicillin, macrolides are often used as the second-line treatment. Over the last several decades, the rising macrolide resistance of GAS has been detected in several countries. With the current study, we aimed to determine the development of macrolide resistance at our paediatric centre. From March 2006 to May 2009, 350 GAS isolates were tested for susceptibility to erythromycin, azithromycin, clindamycin, penicillin and cefotaxime. Macrolide-resistant isolates were screened for the presence of genes related to macrolide resistance (mefA, ermB, ermTR, prtF1). In comparison to a prior study at our hospital, the erythromycin resistance rate decreased significantly from 13.6 to 2.6%. This effect may be attributable to a more restrictive use of macrolides in children in our region. PMID- 21796339 TI - Waking with the hypothalamus. AB - An essential component of the whole-body homoeostasis provided by the hypothalamus is the management of available energy. This includes the regulation of sleeping and waking, feeding and drinking, body temperature and activity, as well as the endocrinium. The waking brain, in particular the cerebral cortex, needs to be activated through neuronal pathways ascending from the brainstem reticular formation (ascending reticular activating system, ARAS) and reaching the cortical structures by a dorsal route through the thalamus and a ventral route, including the hypothalamus and the basal forebrain. This review concentrates on the more recently explored ventral route and the hypothalamus with its different regions involved in the control of the waking state. PMID- 21796342 TI - Comparative evaluation of Vitek 2 identification and susceptibility testing of Gram-negative rods directly and isolated from BacT/ALERT-positive blood culture bottles. AB - The performance of Vitek 2 was evaluated for the identification and susceptibility testing of Gram-negative bacilli directly from positive blood cultures bottles. Direct inoculation of the positive blood cultures with the Vitek cards ID-GN and AST-NO58 was compared with the standard inoculation method based on the sub-culture of the positive blood culture to agar. A total of 142 blood cultures were included in the study; of those, 119 were from patients' clinical samples, while 23 were artificially prepared with strains showing different mechanisms of resistance. A total of 136 (95.8%) strains were correctly identified to the species level, only 2 (1.4%) were mis-identified and 4 (2.8%) were not identified. Susceptibility results were available for all isolates tested against 17 antibiotics, thus, resulting in a total of 2,414 isolate/anti microbial combinations. The error rate was 2.8% (67/2,414) overall; 0.6% (14/2,414) very major errors, 0.1% (3/2,414) major errors and 2.1% (50/2,414) minor errors. The direct method detected 88.5% (22/25) of the strains producing extended-spectrum beta-lactamases (ESBLs). The susceptibility agreement among the added strains with ESBL, AMPc hyperproduction, resistance to ceftazidime, carbapenems and cefepime was very high. Direct identification and susceptibility testing gave rapid and reliable results, reducing by 24 h the turnaround time of the microbiology laboratory. PMID- 21796343 TI - Immunogenicity of a half-dose of adjuvanted 2009 pandemic H1N1 influenza vaccine in adults: a prospective cohort study. AB - We aimed to assess the immunogenicity of a single half-dose of AS03-adjuvanted monovalent 2009 pandemic H1N1 vaccine in healthy adults. Healthy subjects age 20 60 years were prospectively enrolled in a cohort receiving intramuscular administration of a single half-dose (1.875 MUg of hemagglutinin [HA]) of adjuvanted 2009 pandemic H1N1 influenza vaccine. Data from participants enrolled in a concomitant study of immunogenicity following a full-dose (3.75 MUg of HA) are presented concurrently. Sera for assessment of hemagglutination-inhibiting (HAI) antibody to the vaccine strain were obtained before and 14 or 21 days after vaccination. Ninety-seven participants received a half-dose and 50 received a full-dose of vaccine. In the half-dose cohort, Food and Drug Administration criteria for immunogenicity regarding seroprotection and seroconversion rates were met for subjects aged 20-45 years, but not for those aged 46-60 years. There was no statistically significant difference in the proportion of individuals achieving a post-vaccination HAI titre of >=1:40, the geometric mean titres of post-vaccination antibody, or the proportion of individuals with a four-fold or greater increase in antibody levels between the two cohorts. Participants 46-60 years of age were significantly less likely to be seroprotected at day 21 than those 20-45 years old in both cohorts. Immunogenicity of a half dose of adjuvanted pH1N1 influenza vaccine was adequate in subjects aged 20-45 years. Dose reduction is a possible strategy for expanding the availability in the event of vaccine shortage in this age group. PMID- 21796344 TI - Sequence analysis of human rotavirus strains: comparison of clinical isolates from Northern and Southern Italy. AB - The surveillance and monitoring of rotavirus (RV)-related diseases, preferably through the establishment of sentinel surveillance sites, are essential for assessing the need for vaccination and the projected results of the vaccine in terms of reducing the burden of disease. The objective of the present study was to compare RV strains isolated in Northern (Ferrara) and Southern (Galatina-LE) Italy. During 2007-2008, 115 RV-positive stool samples were collected from children with diarrhea admitted to the hospitals of Ferrara and Galatina. The specimens were genotyped for VP7 (G-type) and VP4 (P-type) gene by reverse transcription (RT) and multiplex polymerase chain reaction (PCR). A subset of 21 RV strains was randomly selected and characterized by sequence analysis of the VP7 genes. In total, seven G/P combinations (G1P[8], G2P[4], G4P[8], G9P[8], G2P[8], G1P[9], and G2P[10]) were identified. Phylogenetic comparison of the VP7 encoding gene of selected strains showed that there was similarity among RV strains circulating in Northern and Southern Italy. The observation of nucleotide sequence diversity contributes to a better understanding of RV spreading and helps to characterize the various antigenic shifts that could have an impact on vaccine effectiveness. PMID- 21796345 TI - HBV DNA suppression during entecavir treatment in previously treated children with chronic hepatitis B. AB - The aim of this study was to assess HBV DNA suppression after 24 weeks of treatment with entecavir in previously treated children with CHB. Thirty children aged 5-17 years (25 males and 5 females) with CHB were treated with entecavir 0.5 or 1 mg daily. Twenty-two children were HBeAg-positive, eight were HBeAg negative, and in eight HBV polymerase mutations were detected. After 24 weeks of treatment, mean and median HBV DNA levels and ALT activity were lower versus baseline, overall and in both subgroups. The overall median HBV DNA level decreased from 1.2 x 10(7) IU/mL to 3.3 x 10(2) IU/mL (p < 0.000004), in HBeAg positive from 7.8x10(7) IU/mL to 6.3x10(3) IU/mL (p < 0.00004), and in HBeAg negative from 2.5x10(4) IU/mL to 5.01x10(1) IU/mL (p < 0.03). The serum HBV DNA disappearance was observed in 7/8 (88%) HBeAg-negative and in 5/22 (23%) HBeAg positive patients. The overall mean ALT activity decreased from 164+ 290 U/L to 34.1+ 18.9 U/L (p < 0.000007), in HBeAg-positive from 214+326 U/L to 38.59+19.2 U/L (p < 0.000074), and in HBeAg-negative from 27+14 U/L to 20+8 U/L (p < 0.03). Twenty-four weeks of treatment with entecavir results in suppression of HBV DNA in a substantial proportion of children previously treated ineffectively with CHB. PMID- 21796346 TI - Multi-drug-resistant gram-negative bacterial infection in surgical patients hospitalized in the ICU: a cohort study. AB - We sought to identify risk factors for postoperative infections, caused by multi drug-resistant gram-negative bacteria (MDR-GNB) in surgical patients. This was a retrospective cohort study among patients hospitalized in the intensive care unit (ICU) for more than 5 days, following general surgical operations. Comparison of patients who developed infection caused by MDR-GNB with the remainder of the cohort showed that every minute of operative time, use of special treatments during hospitalization (antineoplastic, immunosuppressive or immunomodulating therapies), every day of metronidazole, and every day of carbapenems use, increased patients' odds to acquire an infection caused by MDR-GNB by 0.7%, 8.9 times, 9%, and 9%, respectively [OR (95% CI): 1.007 (1.003-1.011), p = 0.001; 8.9 (1.8-17.3), p = 0.004; 1.09 (1.04-1.18), p = 0.039; 1.09 (1.01-1.18), p = 0.023, respectively]. The above were adjusted in the multivariable analysis for the confounder of time distribution of infections caused by MDR-GNB. Finally, the secondary comparison, with patients that did not develop any infection, showed that patients who had received antibiotics, within 3 months prior to admission, had 3.8 times higher odds to acquire an infection caused by MDR-GNB [OR (95% CI): 3.8 (1.07-13.2), p = 0.002]. This study depicts certain, potentially modifiable, risk factors for postoperative infections in patients hospitalized in the ICU for more than 5 days. PMID- 21796347 TI - Safety and tolerability of sputum induction in adolescents and adults with suspected pulmonary tuberculosis. AB - Sputum induction by the inhalation of hypertonic saline may increase the yield of microbiological diagnosis of pulmonary tuberculosis (TB). This is particularly relevant in paucibacillary TB, such as in children or human immunodeficiency virus (HIV)-infected patients. Sputum induction must be shown to be safe and tolerable in community settings where invasive diagnostic methods are unavailable. The objective of this study was to describe the changes in physiological parameters and adverse events occurring during sputum induction in ambulatory adult and adolescent TB suspects recruited in community clinics. Sputum induction was performed in HIV-infected (n = 35) and HIV-uninfected (n = 67) TB suspects (n = 102). Oxygen saturation (%), blood pressure (mm Hg), heart rate (/minute), respiratory rate (/minute), and adverse events were monitored at baseline, continuously during the salbutamol pre-treatment and saline nebulization phases, and for 30 min afterwards. During nebulization, there was a statistically significant increase in oxygen saturation (1%, p < 0.0001), systolic BP (7 mm Hg, p < 0.0001), and diastolic BP (2 mm Hg, p = 0.008). Post nebulization decrease in the systolic BP occurred (4 mm Hg, p = 0.016). These changes were not considered to be clinically significant. Eight minor, transitory, self-resolving adverse events occurred (labored breathing, n = 2; chest pain, n = 2; paroxysmal coughing, n = 1; elevated heart rate, n = 1; vomiting, n = 1; hypotension, n = 1), leading to procedure termination in four participants. No serious adverse events occurred. Induced sputum is safe, tolerable, and feasible in adult and adolescent TB suspects in a community healthcare setting. PMID- 21796348 TI - Gender and disease features in Moroccan patients with ankylosing spondylitis. AB - This study was conducted to determine differences in ankylosing spondylitis (AS) between men and women in terms of clinical characteristics, biological features, structural severity and quality of life (QoL). A total of 130 consecutive AS patients fulfilling the modified New York criteria were included. Sociodemographic data were collected. The activity of disease was assessed by the Bath ankylosing spondylitis disease activity index (BASDAI) and the functional disability by the Bath Ankylosing spondylitis functional index (BASFI). Spinal mobility was measured using the occiput-to-wall distance, chest expansion, Schober index and the Bath Ankylosing Spondylitis Metrology Index (BASMI). The Bath Ankylosing Spondylitis Radiologic Index (BASRI) was used to evaluate structural damage. Fatigue was evaluated using a visual analogue scale and the QoL was measured by using the generic instrument SF-36. Laboratory tests included the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP). In our sample, there were 87 (66.9%) men and 43 (33.1%) women. Women had significantly lower educational levels but there were no differences in socioeconomic status, age at onset, diagnosis delay, disease duration or treatments. Also, women had higher clinical disease activity (morning stiffness and BASDAI score), higher number of tender joints, more severe enthesitis and higher scores of fatigue (for all p <= 0.05). Moreover, hip involvement was more prevalent in men and the impairment of spinal mobility was significantly worse compared to women (for all p <= 0.001). Men had worse radiographic damage and lower scores in physical and social domains of QoL, but there were no differences in functional impairment scores. In this study, we noticed that AS presents differently according to gender in our patients. More longitudinal studies seem to be necessary to identify gender-related parameters of disease, thing that may help in diagnosis and therapeutic management of our AS patients. PMID- 21796349 TI - Prevalence, co-occurrence, and predictive factors for musculoskeletal pain among shellfish gatherers. AB - The aims of this study are to determine prevalence and co-occurrence of musculoskeletal pain (MSP) among shellfish gatherers and its consequences for the use of medicine, health care, and sickness leave and to investigate predictive factors (sociodemographic, lifestyle, comorbidity) of MSP in five anatomical areas (neck/shoulder/higher back, lower back, elbow/wrist/hand, hip/knee, and leg/ankle/foot). Nine hundred twenty-nine shellfish gatherers (94% women) voluntarily took part in a physiotherapy workshop. A self-administered questionnaire was used to assess MSP and its consequences. Regression models were performed to determine the factors predicting the presence of MSP. The two most frequently self-reported forms of MSP were neck pain (70.9%) and lower back pain (65.5%). Sixty-four percent of respondents reported contact with their family doctor during the last 12 months due to MSP, and most subjects (88.1%) reported MSP in two or more locations. Hip/knee pain was associated with leg/ankle/foot pain (crude odds ratio = 3.14). Logistic regression analysis showed that being female and young is associated with lumbar pain, and being older is associated with pain in all areas of the lower limbs. The number of pain sites a person reported significantly predicted the presence of pain in all the anatomical areas studied. Prevalence of MSP and musculoskeletal comorbidity were high. The study shows that the presence of pain reported in one body area is highly dependent on the total number of painful areas. These findings are consistent with those of similar studies. PMID- 21796350 TI - Quantitative analysis of vascularization in the finger joints in patients with rheumatoid arthritis using three-dimensional volumetric ultrasonography with power Doppler. AB - This study aimed to compare the intraobserver and interobserver reliability of three-dimensional (3D) and two-dimensional (2D) power Doppler ultrasonography (PDUS) and to assess the relationship between 3D PDUS and clinical parameters in patients with rheumatoid arthritis (RA). Bilateral second/third metacarpophalangeal joints and second/third proximal interphalangeal joints in 33 patients were examined by both 2D and 3D PDUS. Each joint was given a separate 2D PDUS subjective score (range, 0-3) in a standard manner. The 2D PDUS index is the sum of the scores of all eight joints assessed. 3D PDUS voxel signals were quantitatively analyzed by using computerized voxel counts. Intraobserver reliability was high for both examinations (2D PDUS: ICC = 0.957, 95% confidence interval = 0.818-0.999; 3D PDUS: ICC = 0.998, 95% confidence interval = 0.998 1.000). Interobserver reliability was also high (2D PDUS: ICC = 0.993, 95% confidence interval = 0.806-0.988; 3D PDUS: ICC = 0.999, 95% confidence interval = 0.999-1.000). A significant correlation was found between the 2D PDUS index and 3D PDUS voxel count (r = 0.795; p < 0.001). The 3D PDUS voxel count showed significant correlation with 28 joints Disease Activity Score (DAS28)-erythrocyte sedimentation rate (r = 0.448, p < 0.01) and DAS28-C-reactive protein (r = 0.383, p < 0.05). Our study indicates that the measurement of 3D PDUS may be a valuable tool for predicting disease activity. PMID- 21796351 TI - Sympathetic noradrenergic before striatal dopaminergic denervation: relevance to Braak staging of synucleinopathy. AB - Braak's staging concept of Lewy body disease pathogenesis is based on a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-[(18)F]DOPA and myocardial 6-[(18)F]dopamine scanning over 4 years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6 [(18)F]DOPA-derived radioactivity initially was normal, 2 years later was decreased subtly, and by 4 years was clearly decreased, accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation fit with Braak staging. PMID- 21796352 TI - Hemodynamic mechanisms underlying prolonged post-faint hypotension. AB - OBJECTIVE: During hypotension induced by tilt-table testing, low presyncopal blood pressure (BP) usually recovers within 1 min after tilt back. However, in some patients prolonged post faint hypotension (PPFH) is observed. We assessed the hemodynamics underlying PPFH in a retrospective study. METHODS: Seven patients (2 females, aged 31-72 years) experiencing PPFH were studied. PPFH was defined as a systolic BP below 85 mmHg for at least 2 min after tilt back. In 6 out of 7 presyncope was provoked by 0.4 mg sublingual NTG, administered in the 60 degrees head-up tilt position following head-up tilt for 20 min. Continuous BP was monitored and stroke volume (SV) was computed from pressure pulsations. Cardiac output (CO) was calculated from SV * heart rate (HR); and total peripheral resistance (TPR) from mean BP/CO. Left ventricular contractility was estimated by dP/dt (max) of finger pressure pulse. RESULTS: Systolic BP (SYS), diastolic BP (DIAS) and HR during PPFH were lower compared to baseline: SYS 75 +/ 14 versus 121 +/- 18 mmHg, DIAS 49 +/- 9 versus 71 +/- 9 mmHg and HR 52 +/- 14 versus 67 +/- 12 beats/min (p < 0.05). Marked hypotension was associated with a 47% fall in CO 3.1 +/- 0.6 versus 5.9 +/- 1.3 L/min (p < 0.05) and decreases in dP/dt, 277 +/- 77 versus 759 +/- 160 mmHg/s (p < 0.05). The difference in TPR was not significant 1.1 +/- 0.3 versus 1.0 +/- 0.3 MU (p = 0.229). In four patients, we attempted to treat PPFH by 30 degrees head-down tilt. This intervention increased SYS only slightly (to 89 +/- 12 mmHg). INTERPRETATION: PPFH seems to be mediated by severe cardiac depression. PMID- 21796353 TI - Prolonged post-faint hypotension can be reversed by dynamic tension. AB - A severe variant of vasovagal syncope, observed during tilt tests and blood donation has recently been termed "prolonged post-faint hypotension" (PPFH). A 49 year-old male with a life-long history of severe fainting attacks underwent head up tilt for 20 min, and developed syncope 2 min after nitroglycerine spray. He was unconscious for 40 s and asystolic for 22 s. For the first 2 min of recovery, BP and HR remained low (65/45 mmHg and 40 beats/min) despite passive leg-raising. Blood pressure (and symptoms) only improved following active bilateral leg flexion and extension ("dynamic tension"). During PPFH, when vagal activity is extreme, patients may require central stimulation as well as correction of venous return. PMID- 21796354 TI - Severity of autonomic dysfunction in patients with complete spinal cord injury. AB - OBJECTIVE: There is limited information on the relationship between the level and completeness of the spinal cord injury (SCI) lesion and the degree of autonomic dysfunction. We aimed to study the impairment of sympathetic function in chronic SCI patients presenting with a motor and sensory complete lesion above T6. METHOD: 26 consecutive traumatic SCI patients were enrolled (14 tetraplegics and 12 paraplegics). They took a battery of tests that included pressor stimuli above (mental arithmetic, hand cold pressor test, sympathetic skin responses (SSR)) and below the lesion (foot cold pressor test, abdominal electrical stimulation), and Valsalva maneuver. RESULTS: All patients showed abolished plantar SSR, while a significant rise in systolic blood pressure in at least one of the pressor tests below the lesion was seen in all but one paraplegic patient. Palmar SSR and blood pressure overshoot at the end of the Valsalva maneuver were abolished in all tetraplegics, whereas at least one of those responses was seen in each paraplegic. Hand cold pressor test and mental arithmetic induced cardiovascular changes in most patients. CONCLUSION: A complete loss of supraspinal control was observed in all, with a reflex isolated spinal cord in all but one patient. We confirm that in most SCI subjects there is concordance between the impairment of sympathetic function and somatic impairment. To assess autonomic dysfunction, a battery of tests should include SSR, abdominal electrical stimulation and Valsalva maneuver, as they combine pressor stimuli above and below the lesion and assess both cholinergic and sudomotor pathways. PMID- 21796356 TI - Fludrocortisone improves nausea in children with orthostatic intolerance (OI). AB - INTRODUCTION/RESULTS: In 17 patients, chronic idiopathic nausea was associated with orthostatic intolerance (OI) by abnormal tilt table tests (88%) or gastric dysrhythmias (71%). After fludrocortisone treatment, there was >26% nausea improvement in 71%, 1-25% in 6%, and no improvement in 24%. In six subjects, EGGs repeated after >50% nausea improvement all remained to be abnormal, suggesting nausea is independent of gastric dysrhythmias. CONCLUSION: Association of EGG abnormalities and OI in this subset of nausea patients suggests a generalized disturbance of autonomic regulation. PMID- 21796355 TI - Effect of mild hyperglycemia on autonomic function in obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) has been hypothesized to cause a hypersympathetic state, which may be the mechanism for the increased incidence of cardiovascular disease in OSA. However, there is a high prevalence of hyperglycemia in OSA patients, which may also contribute to autonomic dysfunction. METHODS: Thirty-five patients with OSA and 11 controls with average body mass index (BMI) of 32.0 +/- 4.6 underwent polysomnography, glucose tolerance testing, autonomic function tests, lying and standing catecholamines, overnight urine collection, and baseline ECG and continuous blood pressure measurements for spectral analysis. A linear regression model adjusting for age and BMI was used to analyze spectral data, other outcome measures were analyzed with Kruskal-Wallis test. RESULTS: Twenty-three OSA patients and two control patients had hyperglycemia (based on 2001 American Diabetes Association criteria). Apnea-hypopnea index (AHI) correlated with total power and low frequency (LF) power (r = 0.138, 0.177, p = 0.031; and r = 0.013) but not with the LF/high frequency (HF) ratio (p = 0.589). Glucose negatively correlated with LF systolic power (r = -0.171, p = 0.038) but not AHI (p = 0.586) and was marginally associated with pnn50, total power, LF, and HF power (p ranged from 0.07 to 0.08). CONCLUSION: These data suggest that patients with OSA and mild hyperglycemia have a trend towards lower heart rate variability and sympathetic tone. Hyperglycemia is an important confounder and should be evaluated in studies of OSA and autonomic function. PMID- 21796357 TI - Autonomic dysfunction affects cerebral neurovascular coupling. AB - OBJECTIVE: Autonomic failure (AF) affects the peripheral vascular system, but little is known about its influence on cerebrovascular regulation. Patients with familial amyloidotic polyneuropathy (FAP) were studied as a model for AF. METHODS: Ten mild (FAPm), 10 severe (FAPs) autonomic dysfunction FAP patients, and 15 healthy controls were monitored in supine and sitting positions for arterial blood pressure (ABP) and heart rate (HR) with arterial volume clamping, and for blood flow velocity (BFV) in posterior (PCA) and contralateral middle cerebral arteries (MCA) with transcranial Doppler. Analysis included resting BFV, cerebrovascular resistance parameters (cerebrovascular resistance index, CVRi; resistance area product, RAP; and critical closing pressure, CrCP), and neurovascular coupling through visually evoked BFV responses in PCA (gain, rate time, attenuation, and natural frequency). RESULTS: In non-stimulation conditions, in each position, there were no significant differences between the groups, regarding HR, BP, resting BFV, and vascular resistance parameters. Sitting ABP was higher than in supine in the three groups, although only significantly in controls. Mean BFV was lower in sitting in all the groups, lacking statistical significance only in FAPs PCA. CVRi and CrCP increased with sitting in all the groups, while RAP increased in controls but decreased in FAPm and FAPs. In visual stimulation conditions, FAPs comparing to controls had a significant decrease of natural frequency, in supine and sitting, and of rate time and gain in sitting position. INTERPRETATION: These results demonstrate that cerebrovascular regulation is affected in FAP subjects with AF, and that it worsens with orthostasis. PMID- 21796358 TI - Myocardial washout rate of technetium-99m-sestamibi in the chronic phase predicts myocardial damage in patients with previous myocardial infarction. AB - OBJECTIVE: This study aimed to clarify the correlation between the myocardial washout rate (WR) of technetium-99m hexakis 2-methoxy-isobutyl-isonitrile ((99m)Tc-sestamibi) and cardiac enzyme levels in patients with acute myocardial infarction (AMI) 6 months after the onset. METHODS: Sixty-one consecutive AMI patients (mean age, 66.2 +/- 9.7 years) who underwent percutaneous coronary intervention (PCI) on admission were enrolled. Creatinine kinase MB isoenzyme (CK MB) levels were measured every 3 h. (99m)Tc-sestamibi myocardial scintigraphic images were obtained at the early (30 min) and delayed (4 h) phases after tracer injection for calculating heart-to-mediastinum (H/M) ratios and global WRs at 2 weeks (0 M) and 6 months (6 M) after the onset of AMI. Regional WRs in the culprit lesions (culprit WR) and the extent score (ES) and severity score (SS) of myocardial damage were also calculated. RESULTS: PCI was performed 8.3 +/- 7.7 h after AMI onset. At 6 M, the early H/M ratio (p = 0.04), delayed H/M ratio (p = 0.02), global WR (p = 0.01), culprit WR (p = 0.002), and delayed ES (p = 0.008) were alleviated. At 0 M, the peak CK-MB level correlated with the delayed H/M ratio (p = 0.003), global WR (p = 0.003), culprit WR (p < 0.001), early ES (p = 0.03), delayed ES (p = 0.01), early SS (p = 0.001), and delayed SS (p < 0.001). At 6 M, the peak CK-MB level correlated with the delayed H/M ratio (p < 0.001), global WR (p = 0.005), culprit WR (p = 0.001), early ES (p = 0.001), delayed ES (p < 0.001), early SS (p < 0.001), and delayed SS (p < 0.001). CONCLUSIONS: These results demonstrated that (99m)Tc-sestamibi WR in the chronic phase as well as that in the acute phase reflects the extent of initial myocardial damage in AMI patients after PCI. Moreover, it might indicate the myocardial condition in the clinical course. PMID- 21796359 TI - Mobility of selected trace elements in Mediterranean red soil amended with phosphogypsum: experimental study. AB - Soil amendment by phosphogypsum (PG) application becomes of increasing importance in agriculture. This may lead, however, to soil, plant, and groundwater contamination with trace elements (TEs) inherently present in PG. Monitoring of selected TEs (Pb, Zn, Cu, and Cd) distribution and mobility in a Mediterranean red soil profile has been performed in soil parcels applied with PG over a 16 month period. Concentrations were measured in soil and plant samples collected from various depth intervals at different points in time. TEs sequential extraction was performed on soil and PG samples. Results showed soil profile enrichment peaked 5 months after PG application for Cd, and 12 months for Pb, Zn, and Cu. Rainwater, pH, total organic carbon, and cationic exchange capacity were the main controlling factors in TEs accumulation in soils. Cd was transferred to a soil depth of about 20 cm. Zn exhibited mobility towards deeper layers. Pb and Cu were accumulated in around 20-55-cm-deep layers. PG increased the solubility of the studied TEs; PG-applied soils contained TEs bound to exchangeable and acid soluble fractions in higher percentages than reference soil. Pb, Zn, and Cu were sorbed into mineral soil phases, while Cd was mainly found in the exchangeable (bio-available) form. The order of TEs decreasing mobility was Zn > Cd > Pb > Cu. Roots and leaves of existed plants, Cichorium intybus L., accumulated high concentrations of Cd (1-2.4 mg/kg), exceeding recommended tolerable levels, and thus signifying potential health threats through contaminated crops. It was therefore recommended that PG should be applied in carefully established, monitored, and controlled quantities to agricultural soils. PMID- 21796360 TI - Improving Salmonella determination in Sinaloa rivers with ultrafiltration and most probable number methods. AB - Monitoring of waterborne pathogens is improved by using concentration methods prior to detection; however, direct microbial enumeration is desired to study microbial ecology and human health risks. The aim of this work was to determine Salmonella presence in river water with an ultrafiltration system coupled with the ISO 6579:1993 isolation standard method (UFS-ISO). Most probable number (MPN) method was used directly in water samples to estimate Salmonella populations. Additionally, the effect between Salmonella determination and water turbidity was evaluated. Ten liters or three tenfold dilutions (1, 0.1, and 0.01 mL) of water were processed for Salmonella detection and estimation by the UFS-ISO and MPN methods, respectively. A total of 84 water samples were tested, and Salmonella was confirmed in 64/84 (76%) and 38/84 (44%) when UFS-ISO and MPN were used, respectively. Salmonella populations were less than 5 * 10(3) MPN/L in 73/84 of samples evaluated (87%), and only three (3.5%) showed contamination with numbers greater than 4.5 * 10(4) MPN/L. Water turbidity did not affect Salmonella determination regardless of the performed method. These findings suggest that Salmonella abundance in Sinaloa rivers is not a health risk for human infections in spite of its persistence. Thus, choosing the appropriate strategy to study Salmonella in river water samples is necessary to clarify its behavior and transport in the environment. PMID- 21796361 TI - Supratentrial extradural endodermal cyst involving the frontal bone. PMID- 21796362 TI - How did air get into the brain? A case of intracranial air in a patient without skull fracture. PMID- 21796363 TI - Chemoport with a non-collapsible chamber as a replacement for an Ommaya reservoir in the treatment of leptomeningeal carcinomatosis. AB - BACKGROUND: The Ommaya reservoir for intraventricular chemotherapy of leptomeningeal carcinomatosis (LMC) patients has been reported to have some complications. We introduced a Chemoport reservoir, with a solid non-collapsible, high-profile chamber as a the replacement for the Ommaya reservoir in LMC patients. OBJECTIVE: To evaluate the usefulness of Chemoport as an alternative to Ommaya for the intraventricular chemotherapy of LMC. METHODS: The medical records of 155 patients (89 Ommaya and 66 Chemoport) who underwent intraventricular chemotherapy via a subgaleal reservoir were reviewed. Chemoport was secured with engraving of skull. RESULT: Reservoir malfunction, including one intracranial hemorrhage (ICH) under the burr hole occurred, in six patients. During the course of therapy, cerebrospinal fluid (CSF) infection was diagnosed in 19 patients and intraventricular hemorrhage with ICH was evident in three patients of the Ommaya group. Incidence of the above-mentioned complications showed no difference between the two groups. CSF leakage under a galeal flap or through a wound edge occurred more frequently in the Ommaya group (12 patients) than in the Chemoport group (two patients) and the difference was statistically significant (p = 0.03). One-hundred and four patients showed increased intracranial pressure (ICP) and 74 of them received additional CSF drainage to control increased ICP by either intermittent CSF drainage in both groups or continuous extraventricular drainage (EVD) of CSF using designated hooked needle only in the Chemoport group. Among the factors related to the control ICP, the number of chemotherapies, type of reservoir in favor of Chemoport, and EVD showed significantly improved control of ICP (p < 0.05). CONCLUSION: Chemoport, as a reservoir for intraventricular chemotherapy, has superior ICP control at an equal or lower rate of complications compared with the Ommaya reservoir. PMID- 21796364 TI - Decreased cholinergic receptor expression in the striatum: motor function deficit in hypoglycemic and diabetic rats. AB - Hypoglycemic brain injury is a common and serious complication of insulin therapy associated with diabetes. This study evaluated the effect of insulin-induced hypoglycemia and STZ-induced diabetes on striatal cholinergic receptors and enzyme expression and on motor function. Cholinergic enzymes: AChE and ChAT gene expression, radioreceptor binding assay and immunohistochemistry of muscarinic M1, M3 receptors and alpha7nAChR were carried out. Motor performance on grid walk test was analysed. AChE and ChAT expression significantly downregulated in hypoglycemic and diabetic rats. Total muscarinic and Muscarinic M3 receptor binding decreased in hypoglycemic rats compared to diabetic rats whereas muscarinic M1 receptor binding increased in hypoglycemic rats compared to diabetic rats. Real-time PCR analysis and confocal imaging of muscarinic M1, M3 receptors confirmed the changes in muscarinic receptor binding in hypoglycemic and diabetic rats. In hypoglycemic rats, alpha7nAChR expression significantly up regulated compared to diabetic rats. Grid walk test demonstrated the impairment in motor function and coordination in hypoglycemic and hyperglycemic rats. Neurochemical changes along with the behavioral data implicate a role for impaired striatal cholinergic receptor function inducing motor function deficit induced by hypo and hyperglycemia. Hypoglycemia exacerbated the neurobehavioral deficit in diabetes which has clinical significance in the treatment of diabetes. PMID- 21796365 TI - Effect of basic operating parameters on biological phosphorus removal in a continuous-flow anaerobic-anoxic activated sludge system. AB - A continuous-flow anaerobic-anoxic (A2) activated sludge system was operated for efficient enhanced biological phosphorus removal (EBPR). Because of the system configuration with no aeration zones, phosphorus (P) uptake takes place solely under anoxic conditions with simultaneous denitrification. Basic operating conditions, namely biomass concentration, influent carbon to phosphorus ratio and anaerobic retention time were chosen as variables in order to assess their impact on the system performance. The experimental results indicated that maintenance of biomass concentration above 2,500 mg MLVSS/L resulted in the complete phosphate removal from the influent (i.e. 15 mg PO(4) (3-)-P/L) for a mean hydraulic residence time (HRT) of 15 h. Additionally, by increasing the influent COD/P ratio from 10 to 20 g/g, the system P removal efficiency was improved although the experimental results indicated a possible enhancement of the competition between phosphorus accumulating organisms (PAOs) and other microbial populations without phosphorus uptake ability. Moreover, because of the use of acetate (i.e. easily biodegradable substrate) as the sole carbon source in the system feed, application of anaerobic retention times greater than 2 h resulted in no significant release of additional P in the anaerobic zone and no further amelioration of the system P removal efficiency. The application of anoxic P removal resulted in more than 50% reduction of the organic carbon necessitated for nitrogen and phosphorus removal when compared to a conventional EBPR system incorporating aerobic phosphorus removal. PMID- 21796366 TI - Prevalence of child and adolescent psychiatric disorders in Santiago, Chile: a community epidemiological study. AB - PURPOSE: To determine the prevalence of DSM-IV psychiatric disorders in a representative sample of children and adolescents living in Santiago, Chile, as part of a national sample. METHOD: Subjects aged 4-18 were selected using a stratified multistage design. First, ten municipalities/comunas of Santiago were selected; then the blocks, homes, and child or adolescent to be interviewed were chosen. Psychology graduate students administered the Spanish-language, computer assisted version of DISC-IV that estimated DSM-IV 12-month prevalence. RESULTS: A total of 792 children and adolescents were evaluated, with a participation rate of 76.7%. The most stringent impairment DSM-IV DISC algorithm for psychiatric disorders revealed a prevalence of 25.4% (20.7% for boys and 30.3% for girls). The majority of the diagnoses corresponded to anxiety and affective disorders. Prevalence was higher in children aged 4-11 (31.9%) than in adolescents aged 12 18 (18.2%). This difference was mainly accounted for by disruptive disorders in the younger age group. Anxiety disorders had the highest prevalence, although impairment was low. In contrast, most children and adolescents with affective disorders were impaired. CONCLUSIONS: In Santiago, the prevalence of psychiatric disorders in children and adolescents was high. This study helps raise awareness of child and adolescent mental health issues in Spanish-speaking Latin America and serves as a basis for improving mental health services. PMID- 21796367 TI - Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor positive early breast cancer patients. AB - Epithelial mesenchymal transition (EMT) plays an important role in the development of metastases. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by transcription factors, such as SNAIL, SLUG, and TWIST. We examined the prognostic value of these factors as well as E-cadherin and N-cadherin, in a well-described large cohort of breast cancer patients treated with primary surgery. Analyses were stratified by estrogen receptor (ER) status, because of its crucial role in the regulation of these transcription factors. SNAIL, SLUG, and TWIST expression were examined on a TMA containing 575 breast tumors using immunohistochemistry. Nuclear expression was quantified using a weighted histoscore and classified as high versus low expression, based on the median histoscore. High expression of SNAIL, SLUG, and TWIST was seen in 54, 50, and 50% of tumors, respectively. The level of SNAIL (P = 0.014) and TWIST (P = 0.006) expression was associated with a worse patient relapse-free period, specifically in patients with ER-positive tumors (interaction Cox proportional hazards P = 0.039). Combining both factors resulted in an independent prognostic factor with high discriminative power (both low versus either high: HR 1.15; both low versus both high HR 1.84; P = 0.010). Co expression of SNAIL-TWIST was associated with low-E-cadherin and high-N-cadherin expression, especially in ER-positive tumors (P = 0.009), suggesting that, through interactions with ER, SNAIL and TWIST may regulate E- and N-cadherin expression, thereby inducing EMT. Our results are indicative that SNAIL and TWIST play a crucial role in EMT through regulation of E- and N-cadherin expression, exclusively in ER-positive breast cancer patients. PMID- 21796368 TI - Locally advanced breast cancers are more likely to present as Interval Cancers: results from the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657, InterSPORE Trial). AB - Interval cancers (ICs), defined as cancers detected between regular screening mammograms, have been shown to be of higher grade, larger size, and associated with lower survival, compared with screen-detected cancers (SDCs) and comprise 17% of cancers from population-based screening programs. We sought to determine the frequency of ICs in a study of locally advanced breast cancers, the I-SPY 1 TRIAL. Screening was defined as having a mammogram with 2 years, and the proportion of ICs at 1 and 2 years was calculated for screened patients. Differences in clinical characteristics for ICs versus SDCs and screened versus non-screened cancers were assessed. For the 219 evaluable women, mean tumor size was 6.8 cm. Overall, 80% of women were over 40 and eligible for screening; however, only 31% were getting screened. Among women screened, 85% were ICs, with 68% diagnosed within 1 year of a previously normal mammogram. ICs were of higher grade (49% vs. 10%) than SDCs. Among non-screened women, 28% (43/152) were younger than the recommended screening age of 40. Of the entire cohort, 12% of cancers were mammographically occult (MO); the frequency of MO cancers did not differ between screened (11%) and non-screened (15%). ICs were common in the I SPY 1 TRIAL suggesting the potential need for new approaches beyond traditional screening to reduce mortality in women who present with larger palpable cancers. PMID- 21796369 TI - Functional analysis of OsPUT1, a rice polyamine uptake transporter. AB - Polyamines are nitrogenous compounds found in all eukaryotic and prokaryotic cells and absolutely essential for cell viability. In plants, they regulate several growth and developmental processes and the levels of polyamines are also correlated with the plant responses to various biotic and abiotic stresses. In plant cells, polyamines are synthesized in plastids and cytosol. This biosynthetic compartmentation indicates that the specific transporters are essential to transport polyamines between the cellular compartments. In the present study, a phylogenetic analysis was used to identify candidate polyamine transporters in rice. A full-length cDNA rice clone AK068055 was heterologously expressed in the Saccharomyces cerevisiae spermidine uptake mutant, agp2?. Radiological uptake and competitive inhibition studies with putrescine indicated that rice gene encodes a protein that functioned as a spermidine-preferential transporter. In competition experiments with several amino acids at 25-fold higher levels than spermidine, only methionine, asparagine, and glutamine were effective in reducing uptake of spermidine to 60% of control rates. Based on those observations, this rice gene was named polyamine uptake transporter 1 (OsPUT1). Tissue-specific expression of OsPUT1 by semiquantitative RT-PCR showed that the gene was expressed in all tissues except seeds and roots. Transient expression assays in onion epidermal cells and rice protoplasts failed to localize to a cellular compartment. The characterization of the first plant polyamine transporter sets the stage for a systems approach that can be used to build a model to fully define how the biosynthesis, degradation, and transport of polyamines in plants mediate developmental and biotic responses. PMID- 21796370 TI - Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. AB - RATIONALE: Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (Delta(9)-THCV) and cannabigerol (CBG). OBJECTIVES AND METHODS: We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. RESULTS: All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Delta(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. CONCLUSIONS: These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions. PMID- 21796371 TI - Serum NPY and BNDF response to a behavioral stressor in alcohol-dependent and healthy control participants. AB - RATIONALE: Neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) have been implicated in both the stress response and alcohol addiction. However, few studies have assessed the NPY and BDNF response to stress in alcohol-dependent participants and the concurrent measure of NPY and BDNF has not been reported in human participants. OBJECTIVE: The purpose of this study was to concurrently assess serum NPY and BDNF, as well as adrenocorticotropin (ACTH) and cortisol, in control and race- and aged-matched abstinent alcohol-dependent participants in response to a stress-inducing public-speaking task. METHODS: Basal and post stress serum values of NPY and BDNF, as well as ACTH and cortisol, were assessed in 14 abstinent alcohol-dependent and ten healthy control male participants. RESULTS: Basal measures were stable over short periods of time and stress induced a significant increase in both NPY (p = 0.002) and BDNF (p = 0.006) as well as ACTH (p < 0.001) and cortisol (p < 0.007). Alcohol-dependent and control groups did not significantly differ on any basal or stress-induced measure. Basal and delta responses of NPY and BDNF were not significantly correlated, and delta peak responses of NPY and BDNF did not correlate with one another or with their respective ACTH and cortisol responses. CONCLUSIONS: These findings reveal that both serum NPY and BDNF are responsive to behavioral stressors, although their regulatory mechanisms appear to differ from one another and those of the hypothalamic-pituitary-adrenal axis. Differences in basal and stress-induced responses of NPY and BDNF were not supported between control and abstinent alcohol-dependent subjects. PMID- 21796372 TI - Tumor-stromal interactions of the bone microenvironment: in vitro findings and potential in vivo relevance in metastatic lung cancer models. AB - Lung cancer comprises a large variety of histological subtypes with a frequent proclivity to form bone metastasis; a condition associated with dismal prognosis. To identify common mechanisms in the development of osteolytic metastasis, we systematically screened a battery of lung cancer cell lines and developed three models of non-small cell lung cancer (NSCLC) with a common proclivity to form osseous lesions, which represented different histological subtypes. Comparative analysis revealed different incidences and latency times. These differences were correlated with cell-type-specific secretion of osteoclastogenic factors, including macrophage inflammatory protein-1alpha, interleukin-8 and parathyroid hormone-related protein, some of which were exacerbated in conditions that mimicked tumor-stroma interactions. In addition, a distinct signature of matrix metalloproteinase (MMP) activity derived from reciprocal tumor-stroma interactions was detected for each tumor cell line. Thus, these results suggest subtle differences in the mechanisms of bone colonization for each lung cancer subtype, but share, although each to a different degree, dual MMP and osteoclastogenic activities that are differentially enhanced upon tumor-stromal interactions. PMID- 21796373 TI - Return to work after cancer diagnosed in 2002, 2005 and 2008. AB - INTRODUCTION: Improvements in diagnosis and treatment of cancer have increased cancer survival. This study investigated the trends in return to work (RTW) after cancer. METHODS: All employees absent from work due to cancer diagnosed in 2002 (N = 1209), 2005 (N = 1522), and 2008 (N = 1556) were selected from an occupational health service register. Partial RTW was defined as resuming work with 50% of earnings and full RTW as resuming work with 100% of earnings. The percentages of partial and full RTW were determined 2 years after reporting sick and compared with percentages of partial and full RTW after cardiovascular disorders. The time to partial and full RTW after cancer in 2005 and 2008 was compared with the time to RTW in 2002. RESULTS: Partial RTW decreased from 85% 2 years after cancer diagnosis in 2002 to 80% in 2005 and 69% in 2008. Full RTW decreased from 80% 2 years after cancer diagnosis in 2002 to 74% in 2005 and 60% in 2008. RTW after cardiovascular disorders showed similar changes. The time to partial RTW in 2008 was longer than in 2002 after gastrointestinal cancer and lung cancer. The time to full RTW in 2008 was longer than in 2002 after breast cancer, gastrointestinal cancer and lung cancer. CONCLUSIONS: In the past decade, the percentages of employees who resumed work after cancer have decreased in The Netherlands, while the time to RTW increased. Possible explanations include changes in disability policy, economic decline, and resulting decreases in work latitude and workplace accommodations. PMID- 21796374 TI - Absenteeism screening questionnaire (ASQ): a new tool for predicting long-term absenteeism among workers with low back pain. AB - INTRODUCTION: Over the last decades, psychosocial factors were identified by many studies as significant predictive variables in the development of disability related to common low back disorders, which thus contributed to the development of biopsychosocial prevention interventions. Biopsychosocial interventions were supposed to be more effective than usual interventions in improving different outcomes. Unfortunately, most of these interventions show inconclusive results. The use of screening questionnaires was proposed as a solution to improve their efficacy. The aim of this study was to validate a new screening questionnaire to identify workers at risk of being absent from work for more than 182 cumulative days and who are more susceptible to benefit from prevention interventions. METHODS: Injured workers receiving income replacement benefits from the Quebec Compensation Board (n = 535) completed a 67-item questionnaire in the sub-acute stage of pain and provided information about work-related events 6 and 12 months later. Reliability and validity of the 67-item questionnaire were determined respectively by test-retest reliability and internal consistency analysis, as well as by construct validity analyses. The Cox regression model and the maximum likelihood method were used to fix a model allowing calculation of a probability of absence of more than 182 days. Criterion validity and discriminative capacity of this model were calculated. RESULTS: Sub-sections from the 67-item questionnaire were moderately to highly correlated 2 weeks later (r = 0.52-0.80) and showed moderate to good internal consistency (0.70-0.94). Among the 67-item questionnaire, six sub-sections and variables (22 items) were predictive of long term absence from work: fear-avoidance beliefs related to work, return to work expectations, annual family income before-taxes, last level of education attained, work schedule and work concerns. The area under the ROC curve was 73%. CONCLUSIONS: The significant predictive variables of long-term absence from work were dominated by workplace conditions and individual perceptions about work. In association with individual psychosocial variables, these variables could contribute to identify potentially useful prevention interventions and to reduce the significant costs associated with LBP long-term absenteeism. PMID- 21796375 TI - The role of diet on the clinical pharmacology of oral antineoplastic agents. AB - PURPOSE: The number of oral anticancer agents has greatly increased in recent years. It is a well-known fact that food intake can induce significant variations in the bioavailability of these drugs. The aim of this review is to describe the interactions between diet and oral anticancer drugs in terms of the possible effects of such interactions on reducing the antineoplastic activity of the drug or increasing its side effects. METHODS: This was an analytical study of the numerous mechanisms leading to changes in the bioavailability of oral antineoplastic agents due to diet. RESULTS: Food-drug interactions can induce a delay, decrease or increase in the absorption of the oral chemotherapeutic agent. The concomitant intake of food and antineoplastic drugs influence the pharmacokinetic and pharmacodynamic drug processes depending on the composition of the food consumed and the specific interactions of the food with transport mechanisms (p-glycoprotein, multidrug resistance proteins) and intestinal enzymatic systems (cytochrome P450). CONCLUSIONS: In prescribing an oral anticancer agent, clinicians must consider the possibility that the consumption of specific food items has the potential to interfere with the pharmacokinetics and pharmacodynamics of the prescribed drug. PMID- 21796376 TI - Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation. AB - PURPOSE: Garenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens. METHODS: At the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration-time curve divided by the minimum inhibitory concentration (fAUC0-24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases. RESULTS: Logistic regression analysis showed that fAUC0-24/MIC ratio was a significant variable that predicted clinical response (p = 0.0164). Of all subjects, 92.4% reached the target value of fAUC0-24/MIC ratio > 30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC0-24 and maximum concentration) and the incidence of adverse events by the Mann-Whitney test. CONCLUSIONS: The antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations. PMID- 21796377 TI - Behavioural indicators of welfare in farmed fish. AB - Behaviour represents a reaction to the environment as fish perceive it and is therefore a key element of fish welfare. This review summarises the main findings on how behavioural changes have been used to assess welfare in farmed fish, using both functional and feeling-based approaches. Changes in foraging behaviour, ventilatory activity, aggression, individual and group swimming behaviour, stereotypic and abnormal behaviour have been linked with acute and chronic stressors in aquaculture and can therefore be regarded as likely indicators of poor welfare. On the contrary, measurements of exploratory behaviour, feed anticipatory activity and reward-related operant behaviour are beginning to be considered as indicators of positive emotions and welfare in fish. Despite the lack of scientific agreement about the existence of sentience in fish, the possibility that they are capable of both positive and negative emotions may contribute to the development of new strategies (e.g. environmental enrichment) to promote good welfare. Numerous studies that use behavioural indicators of welfare show that behavioural changes can be interpreted as either good or poor welfare depending on the fish species. It is therefore essential to understand the species-specific biology before drawing any conclusions in relation to welfare. In addition, different individuals within the same species may exhibit divergent coping strategies towards stressors, and what is tolerated by some individuals may be detrimental to others. Therefore, the assessment of welfare in a few individuals may not represent the average welfare of a group and vice versa. This underlines the need to develop on-farm, operational behavioural welfare indicators that can be easily used to assess not only the individual welfare but also the welfare of the whole group (e.g. spatial distribution). With the ongoing development of video technology and image processing, the on-farm surveillance of behaviour may in the near future represent a low-cost, noninvasive tool to assess the welfare of farmed fish. PMID- 21796378 TI - Age-related changes in 100-km ultra-marathon running performance. AB - The aims of this study were (1) to investigate the participation and performance trends at the '100 km Lauf Biel' in Switzerland from 1998 to 2010, and (2) to compare the age-related changes in 100-km running performance between males and females. For both sexes, the percent of finishers significantly (P < 0.01) decreased for the 18-29 and the 30-39-year age groups, while it significantly (P < 0.01) increased for the 40-49 and the 50-59-year age groups over the studied period. From 1998 to 2010, the mean age of the top ten finishers increased by 0.4 years per annum for both females (P = 0.02) and males (P = 0.003). The running time for the top ten finishers remained stable for females, while it significantly (P = 0.001) increased by 2.4 min per annum for males. There was a significant (P < 0.001) age effect on running times for both sexes. The best 100 km running times was observed for the age comprised between 30 and 49 years for males, and between 30 and 54 years for females, respectively. The age-related decline in running performance was similar until 60-64 years between males and females, but was greater for females compared to males after 65 years. Future studies should investigate the lifespan from 65 to 75 years to better understand the performance difference between male and female master ultra-marathoners. PMID- 21796379 TI - Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells. AB - Sphingolipid turnover has been shown to be activated at old age and in response to various stress stimuli including oxidative stress. Reduction of vitamin E content in the liver under the pro-oxidant action is associated with enhanced sphingolipid turnover and ceramide accumulation in hepatocytes. In the present paper, the correction of sphingolipid metabolism in the liver cells of old rats and in the palmitate-treated young hepatocytes using alpha-tocopherol has been investigated. 3- and 24-month-old rats, [(14) C]palmitic acid, [methyl-(14) C choline]sphingomyelin (SM), and [(14) C]serine were used. alpha-Tocopherol administration to old rats or addition to the culture medium of old liver slices or hepatocytes prevented age-dependent increase of ceramide synthesis and lipid accumulation, and increased SM content in liver tissue and cells. alpha Tocopherol treatment of old cells decreased the neutral and acid sphingomyelinase (SMase) activities in hepatocytes and serine palmitoyl transferase activity in the liver cell microsomes. Effect of alpha- or gamma-tocopherol, but not of delta tocopherol, on the newly synthesized ceramide content in old cells was correlated with the action of inhibitor of serine palmitoyl transferase (SPT) activity (myriocin) and SMase inhibitors (glutathione, imipramine). Addition of alpha tocopherol as well as myriocin to the culture medium of young hepatocytes, treated by palmitate, abolished ceramide accumulation and synthesis. The data obtained demonstrate that alpha-tocopherol normalized elevated ceramide content in the old liver cells via inhibition of acid and neutral SMase activities and lipid synthesis de novo. alpha-Tocopherol, reducing ceramide synthesis, prevented palmitate-induced aging-like ceramide accumulation in young liver cells. PMID- 21796380 TI - Peptidoglycan turnover and recycling in Gram-positive bacteria. AB - Bacterial cells are protected by an exoskeleton, the stabilizing and shape maintaining cell wall, consisting of the complex macromolecule peptidoglycan. In view of its function, it could be assumed that the cell wall is a static structure. In truth, however, it is steadily broken down by peptidoglycan cleaving enzymes during cell growth. In this process, named cell wall turnover, in one generation up to half of the preexisting peptidoglycan of a bacterial cell is released from the wall. This would result in a massive loss of cell material, if turnover products were not be taken up and recovered. Indeed, in the Gram negative model organism Escherichia coli, peptidoglycan recovery has been recognized as a complex pathway, named cell wall recycling. It involves about a dozen dedicated recycling enzymes that convey cell wall turnover products to peptidoglycan synthesis or energy pathways. Whether Gram-positive bacteria also recover their cell wall is currently questioned. Given the much larger portion of peptidoglycan in the cell wall of Gram-positive bacteria, however, recovery of the wall material would provide an even greater benefit in these organisms compared to Gram-negatives. Consistently, in many Gram-positives, orthologs of recycling enzymes were identified, indicating that the cell wall may also be recycled in these organisms. This mini-review provides a compilation of information about cell wall turnover and recycling in Gram-positive bacteria during cell growth and division, including recent findings relating to muropeptide recovery in Bacillus subtilis and Clostridium acetobutylicum from our group. Furthermore, the impact of cell wall turnover and recycling on biotechnological processes is discussed. PMID- 21796381 TI - Exploration of sulfur metabolism in the yeast Kluyveromyces lactis. AB - Hemiascomycetes are separated by considerable evolutionary distances and, as a consequence, the mechanisms involved in sulfur metabolism in the extensively studied yeast, Saccharomyces cerevisiae, could be different from those of other species of the phylum. This is the first time that a global view of sulfur metabolism is reported in the biotechnological yeast Kluyveromyces lactis. We used combined approaches based on transcriptome analysis, metabolome profiling, and analysis of volatile sulfur compounds (VSCs). A comparison between high and low sulfur source supplies, i.e., sulfate, methionine, or cystine, was carried out in order to identify key steps in the biosynthetic and catabolic pathways of the sulfur metabolism. We found that sulfur metabolism of K. lactis is mainly modulated by methionine. Furthermore, since sulfur assimilation is highly regulated, genes coding for numerous transporters, key enzymes involved in sulfate assimilation and the interconversion of cysteine to methionine pathways are repressed under conditions of high sulfur supply. Consequently, as highlighted by metabolomic results, intracellular pools of homocysteine and cysteine are maintained at very low concentrations, while the cystathionine pool is highly expandable. Moreover, our results suggest a new catabolic pathway for methionine to VSCs in this yeast: methionine is transaminated by the ARO8 gene product into 4-methylthio-oxobutyric acid (KMBA), which could be exported outside of the cell by the transporter encoded by PDR12 and demethiolated by a spontaneous reaction into methanethiol and its derivatives. PMID- 21796382 TI - Amino acid production from rice straw and wheat bran hydrolysates by recombinant pentose-utilizing Corynebacterium glutamicum. AB - Corynebacterium glutamicum wild type lacks the ability to utilize the pentose fractions of lignocellulosic hydrolysates, but it is known that recombinants expressing the araBAD operon and/or the xylA gene from Escherichia coli are able to grow with the pentoses xylose and arabinose as sole carbon sources. Recombinant pentose-utilizing strains derived from C. glutamicum wild type or from the L-lysine-producing C. glutamicum strain DM1729 utilized arabinose and/or xylose when these were added as pure chemicals to glucose-based minimal medium or when they were present in acid hydrolysates of rice straw or wheat bran. The recombinants grew to higher biomass concentrations and produced more L-glutamate and L-lysine, respectively, than the empty vector control strains, which utilized the glucose fraction. Typically, arabinose and xylose were co-utilized by the recombinant strains along with glucose either when acid rice straw and wheat bran hydrolysates were used or when blends of pure arabinose, xylose, and glucose were used. With acid hydrolysates growth, amino acid production and sugar consumption were delayed and slower as compared to media with blends of pure arabinose, xylose, and glucose. The ethambutol-triggered production of up to 93 +/- 4 mM L glutamate by the wild type-derived pentose-utilizing recombinant and the production of up to 42 +/- 2 mM L-lysine by the recombinant pentose-utilizing lysine producer on media containing acid rice straw or wheat bran hydrolysate as carbon and energy source revealed that acid hydrolysates of agricultural waste materials may provide an alternative feedstock for large-scale amino acid production. PMID- 21796383 TI - Challenges of the utilization of wood polymers: how can they be overcome? AB - Diminishing fossil fuel resources as well as growing environmental and energy security concerns, in parallel with growing demands on raw materials and energy, have intensified global efforts to utilize wood biopolymers as a renewable resource to produce biofuels and biomaterials. Wood is one of the most abundant biopolymer composites on earth that can be converted into biofuels as well as used as a platform to produce bio-based materials. The major biopolymers in wood are cellulose, hemicelluloses, and lignin which account for >90% of dry weight. These polymers are generally associated with each other in wood cell walls resulting in an intricate and dynamic cell wall structure. This mini-review provides an overview of major wood biopolymers, their structure, and recent developments in their utilization to develop biofuels. Advances in genetic modifications to overcome the recalcitrance of woody biomass for biofuels are discussed and point to a promising future. PMID- 21796384 TI - Identification and characterization of a new member of the SINE Au retroposon family (GmAu1) in the soybean, Glycine max (L.) Merr., genome and its potential application. AB - A plant short interspersed element (SINE) was identified in Glycine max after re sequencing of the soybean sequence characterized amplified region (SCAR) markers. Detailed analysis revealed that this newly recognized SINE element consisted of a tRNA-related region, a tRNA non-related region, direct flanking repeat sequences, and a short stretch of Ts at the 3'-terminal region. These features are similar to previously characterized SINEs. To investigate the evolution of the SINE retroposon, BLASTN was used to search against genome sequences of other plants. Since it is homologous with the retroposon Au in Aegilops umbellulata (wheat) and its homology in soybean, the SINE is named as GmAu1. Genome analysis of the Glycine max var. Willimas 82 uncovered more than 847 copies of GmAu1 per haploid genome of soybean. Examination of the regions flanking the inserted GmAu1 sequences indicated a preference for introns over exons or other noncoding regions. Considering the flanking insertion sequences, 146 primers were designed in order to detect insertion mutations by a PCR-based method. Seventy-seven primers displayed polymorphism and were used to develop corresponding GmAu1-based SCAR markers. The retroposon GmAu1 and its related SCAR markers identified in this study will prove valuable to future investigations into the genetic mapping, phylogeny, and evolution of the Glycine genus. PMID- 21796385 TI - Sec14l3 is specifically expressed in mouse airway ciliated cells. AB - Airway epithelium is a key component for airway integrity. Previously, we found that expression of the Sec14l3 gene that encodes a 45-kDa secretory protein is inversely associated with the progression of experimentally induced airway inflammation and degeneration/necrosis of alveolar epithelium. In this report, using in situ hybridization we demonstrated that the ciliated cells in mouse lung selectively express Sec14l3 mRNA. In a three-dimensional culture of mouse tracheal epithelial cells, levels of the Sec14l3 mRNA correlated with the differentiation of ciliated cells. Intranasal infection of adult mice with influenza virus resulted in a 20-fold, progressive decrease in Sec14l3 mRNA expression over 10 days post infection. These results enhance the potential value of Sec14l3 as a ciliated epithelial cell-specific biomarker for the progression of airway inflammations such as airway viral infection and asthma. PMID- 21796386 TI - Genetic differentiation of cercariae infrapopulations of the avian schistosome Trichobilharzia szidati based on RAPD markers and mitochondrial cox1 gene. AB - Avian schistosome Trichobilharzia szidati is a member of the largest genus within the family Schistosomatidae (Trematoda). Population genetic structure of Trichobilharzia spp. schistosomes, causative agents of cercarial dermatitis in humans, has not been studied yet. The knowledge of the genetic structure of trichobilharzian populations is essential for understanding the host-parasite coevolutionary dynamics and epidemiology strategies. Here we examined genetic diversity in three geographically isolated local populations of T. szidati cercariae inhabiting Russia based on nuclear (randomly amplified polymorphic DNA, RAPD) and mt (cox1) markers. We analyzed T. szidati cercariae shed from seven naturally infected snails of Lymnaea stagnalis. Using three random primers, we demonstrated genetic variation among populations, thus posing genetic structure across geographic sites. Moreover, T. szidati cercariae have been genetically structured among hosts (infrapopulations). Molecular variance analysis was performed to test the significance of genetic differentiation within and between local populations. Of total parasitic diversity, 18.8% was partitioned between populations, whereas the higher contribution (48.9%) corresponds to the differences among individual cercariae within infrapopulations. In contrast to RAPD markers, a 1,125-bp fragment of cox1 mt gene failed to provide any significant within-species structure. The lack of geographic structuring was detected using unique haplotypes which were determined in the current work for Moscow and Western Siberian local populations as well as obtained previously for European isolates (Czech Republic and Germany). All T. szidati/Trichobilharzia ocellata haplotypes were found to be mixed across their geographical origin. PMID- 21796387 TI - Expression and characterization of Cu/Zn superoxide dismutase from Wuchereria bancrofti. AB - The Cu/Zn superoxide dismutase gene from Wuchereria bancrofti (Cu/Zn WbSOD) was isolated by PCR using degeneracy primers. The complete Cu/Zn WbSOD consisted of 1,032 nucleotides containing 4 exons (477 nucleotides) and 3 introns. The molecular phylogenetic analysis of the Cu/Zn WbSOD gene in comparison with those from other organisms revealed that the gene was classified in the same clade to those of filarial Brugia malayi and Brugia pahangi (bootstrap value at 90). The nucleotide and deduced amino acid sequences of Cu/Zn WbSOD exhibited the similarity to those of intracellular Cu/Zn SOD of B. malayi and B. pahangi. The amino acid comparison of Cu/Zn WbSOD to others revealed that the binding sites and active sites were conserved. The expression of this gene yielded 16.366 kDa in size. After Ni-IDA column purification, the enzyme showed specific activity of 8.5 U/mg and 42.1% yield. The enzyme activity was inhibited when 6 mM KCN was added. PMID- 21796388 TI - Kinetin supplementation modifies chromium (VI) induced alterations in growth and ammonium assimilation in pea seedlings. AB - In the present study, impact of kinetin (KN; 10 and 100 MUM) supplementation on growth, ammonium (NH(4)(+)) assimilation and antioxidant system in pea under hexavalent chromium toxicity (Cr VI; 50, 100 and 250 MUM) was investigated. Chromium decreased growth, protein, and nitrogen, and activity of glutamine synthetase (GS) and glutamate synthase (GOGAT) while it increased NH(4)(+) content and activity of glutamate dehydrogenase (GDH). Kinetin at 100 MUM decreased growth and NH(4)(+) assimilation, and together with Cr, it increased Cr toxicity. Chromium and 100 MUM KN increased superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities while decreasing activities of catalase (CAT), glutathione reductase (GR) and dehydroascorbate reductase (DHAR). Ascorbate and glutathione levels were decreased by Cr and 100 MUM KN. In contrast, supplementation of 10 MUM KN under Cr (VI) toxicity, protected NH(4)(+) assimilation and promoted growth of pea by increasing levels of some of the antioxidants i.e., CAT, GR, DHAR, ascorbate and glutathione. Results showed that 10 MUM KN increases Cr tolerance while 100 MUM KN exhibited opposite responses. These results could contribute to an understanding of the mechanisms of KN mediated dual influence on metal tolerance in crop plants. PMID- 21796389 TI - Purification of cell subpopulations via immiscible filtration assisted by surface tension (IFAST). AB - The selective isolation of a sub-population of cells from a larger, mixed population is a critical preparatory process to many biomedical assays. Here, we present a new cell isolation platform with a unique set of advantages over existing devices. Our technology, termed Immiscible Filtration Assisted by Surface Tension, exploits physical phenomena associated with the microscale to establish fluidic barriers composed of immiscible liquids. By attaching magnetically-responsive particles to a target cell population via immunocapture, we can selectively transport this population across the immiscible barrier and into a separate aqueous solution. The high interfacial energy associated with the immiscible phase / aqueous phase boundaries prevents unwanted cells or other contaminants from inadvertently crossing the immiscible phase. We have demonstrated, using fluorescent particles, stromal cells, and whole blood as "background", that we can successfully isolate ~70% of a target breast cancer cell population with an average purity of >80%. Increased purity was obtained by coupling two immiscible barriers in series, a modification that only slightly increases operational complexity. Furthermore, several samples can be processed in parallel batches in a near-instantaneous manner without the requirement of any washing, which can cause dilution (negative selection) or significant uncontrolled loss (positive selection) of target cells. Finally, cells were observed to remain viable and proliferative following traverse through the immiscible phase, indicating that this process is suitable for a variety of downstream assays, including those requiring intact living cells. PMID- 21796390 TI - A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). AB - Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons. PMID- 21796391 TI - Genetic and phenotypic variation of Fusarium proliferatum isolates from different host species. AB - Fusarium proliferatum (Matsushima) Nirenberg is a common pathogen infecting numerous crop plants and occurring in various climatic zones. It produces large amounts of fumonisins, a group of polyketide-derived mycotoxins. Fumonisin biosynthesis is determined by the presence and activity of the FUM cluster, several co-regulated genes with a common expression pattern. In the present work, we analyzed 38 F. proliferatum isolates from different host plant species, demonstrating host-specific polymorphisms in partial sequences of the key FUM1 gene (encoding polyketide synthase). We also studied growth rates across different temperatures and sample origin and tried to establish the relationships between DNA sequence polymorphism and toxigenic potential. Phylogenetic analysis was conducted based on FUM1 and tef-1alpha sequences for all isolates. The results indicated the greatest variations of both toxigenic potential and growth patterns found across the wide selection of isolates derived from maize. Fumonisin production for maize isolates ranged from 3.74 to 4,500 MUg/g of fumonisin B(1). The most efficient producer isolates obtained from other host plants were only able to synthesize 1,820-2,419 MUg/g of this metabolite. A weak negative rank correlation between fumonisin content and isolate growth rates was observed. All garlic-derived isolates formed a distinct group on a FUM1-based dendrogram. A second clade consisted of tropical and sub-tropical strains (isolated from pineapple and date palm). Interestingly, isolates with the fastest growth patterns were also grouped together and included both isolates originating from rice. The sequence of the FUM1 gene was found to be useful in revealing the intraspecific polymorphism, which is, to some extent, specifically correlated with the host plant. PMID- 21796393 TI - Sagittal balance disorders in severe degenerative spine. Can we identify the compensatory mechanisms? AB - INTRODUCTION: Aging of the spine is characterized by facet joints arthritis, degenerative disc disease and atrophy of extensor muscles resulting in a progressive kyphosis. Recent studies confirmed that patients with lumbar degenerative disease were characterized by an anterior sagittal imbalance, a loss of lumbar lordosis and an increase of pelvis tilt. The aim of this paper was thus to describe the different compensatory mechanisms which are observed in the spine, pelvis and/or lower limbs areas for patients with severe degenerative spine. METHODS: We reviewed all the compensatory mechanisms of sagittal unbalance described in the literature. RESULTS: According to the severity of the imbalance, we could identify three different stages: balanced, balanced with compensatory mechanisms and imbalanced. For the two last stages, the compensatory mechanisms permitted to limit consequences of lumbar kyphosis on the global sagittal alignment. Reduction of thoracic kyphosis, intervertebral hyperextension, retrolisthesis, pelvis backtilt, knee flessum and ankle extension were the main mechanisms described in the literature. The basic concept of these compensatory mechanisms was to extend adjacent segments of the kyphotic spine allowing for compensation of anterior translation of the axis of gravity. CONCLUSIONS: To avoid underestimate the severity of the degenerative spine disorder, it thus seems important to recognize the different compensatory mechanisms from the upper part of the trunk to the lower limbs. We propose a three steps algorithm to analyse the balance status and determine the presence or not of these compensatory mechanisms: measurement of pelvis incidence, assessment of global sagittal alignment and analysis of compensatory mechanisms successively in the spine, pelvis and lower limbs areas. PMID- 21796392 TI - Hip-spine relations and sagittal balance clinical consequences. AB - INTRODUCTION: The role of the pelvic area in sagittal balance is evident for spinal surgeons, but the influence of the coxofemoral joint is underestimated and inadequately explained by conventional imagery. Comprehensive analysis of the pelvic and subpelvic sectors as part of the sagittal, frontal and cross-sectional balance of the trunk sheds new light on some spinal diseases and their relation to the pelvis. METHODS: This analysis, based on innovative radiologic methods as the EOS((r)) technology but also on a new look at conventional imaging makes it possible to better analyze standing lateral images and seated images. RESULTS: Disturbances can come from atypical morphotypes or from unusual postures as in aging spine. The measurement of available extension and the concept of available flexion provide new information regarding individual's adaptation to the imbalance induced by disorders of the spine or lower limbs. CONCLUSION: A comprehensive assessment of each patient and in particular of the complex comprising the spine and the pelvis, is essential for understanding each individual's adaptation to the imbalance induced by disorders of the spine or lower limbs. PMID- 21796394 TI - Sagittal parameters of the spine: biomechanical approach. AB - According to the anatomical segmentation, spine curves are the sacral kyphosis (sacrum), lumbar lordosis (L1 to L5), thoracic kyphosis (T1 to T12) and cervical lordosis (C1 to C7). From the morphological point of view the vertebrae of a curve are not identical: from cranial to caudal and vice versa there is a progressive anatomical modification. Both curves of the thoraco-lumbar spine may be divided at the Inflexion Point where lordosis turns into kyphosis. A geometrical construct of each curve by two tangent arcs of circle allows understanding the reciprocal changes between both curves. Lumbar Lordosis is mainly dependent on SS orientation, and the top of thoracic curve on C7 is very stable over the sacrum. Thoracic curve is dependent on lumbar lordosis orientation and C7 positioning. On a reverse effect, structural changing of thoracic kyphosis may affect the shape of the lumbar lordosis and the orientation of the pelvis. PMID- 21796395 TI - Adjacent-level degeneration after cervical disc arthroplasty versus fusion. AB - INTRODUCTION: The principal objective of this study was to evaluate the incidence of adjacent-segment degeneration (ASD) in patients who underwent cervical disc arthroplasty (CDA) as compared with anterior cervical discectomy and fusion (ACDF). METHODS: It is a prospective cohort study of patients with a single-level cervical degenerative disc disease from C3 to C7 who underwent CDA or ACDF between January 2004 and December 2006, with a minimum follow-up of 3 years. The patients were evaluated pre- and postoperatively with the visual analog scale (VAS), the neck disability index (NDI), and a complete neurological examination. Plain radiographic assessments included sagittal-plane angulation, range of motion (ROM), and radiological signs of ASD. RESULTS: One hundred and five patients underwent ACDF and 85 were treated with CDA. The postoperative VAS and NDI were equivalent in both groups. The ROM was preserved in the CDA group but with a small decreased tendency within the time. Radiographic evidence of ASD was found in 11 (10.5%) patients in the ACDF group and in 7 (8.8%) subjects in the CDA group. The Kaplan-Meier survival analysis for the ASD occurrence did not reach statistically significant differences (log rank, P = 0.72). CONCLUSIONS: Preservation of motion in the CDA patients was not associated with a reduction of the incidence of symptomatic adjacent-segment disease and there may be other factors that influence ASD. PMID- 21796396 TI - Radiographic analysis of type II odontoid fractures in a geriatric patient population: description and pathomechanism of the "Geier"-deformity. AB - INTRODUCTION: Type II odontoid fractures are one among the most common cervical spine fractures in the elders. We reviewed a consecutive series of patients, aged 65 years and older, presenting to our institution with type II odontoid fractures. Our analysis focused on the radiographic outcome, union rate and the development of cervical spine postural deformity. PATIENTS/METHODS: Indications for surgical treatment (OP) included displaced or unstable injuries. Stable, non displaced injuries or patients with significant co-morbidities were treated nonoperatively (non-op). RESULTS: Ninety patients (50 f, 40 m) with an average age of 83 years (65-101) were identified. 31 (34.4%) patients were received OP and 57 (63.3%) were received non-op treatments. The hospital length of stay was significantly longer after OP (mean 10 days vs. 6 days non-op) treatment (p = 0.007). At follow-up, higher union rates were noted in the OP (76.2%) than in the non-op group (58.3%). CONCLUSION: We observed a characteristic cervical spine deformity in geriatric patients with type II odontoid fractures, and have termed this the "Geier-deformity". Clinical findings of the deformity include sagittal imbalance and kyphosis of the lower cervical spine. PMID- 21796397 TI - A traumatic, high-energy and unstable fracture of the C5 vertebra managed with kyphoplasty: a previously unreported case. AB - Unstable cervical fractures commonly require fusion surgery. We present a case of an unstable cervical fracture (AO classification A2.2) affecting the fifth cervical vertebra which was managed by kyphoplasty to achieve a pain-free, functional and stable outcome. The decision to undertake a kyphoplasty procedure was made in the hope of preserving motion and limiting the degree of future adjacent segment disease. We believe this to be the first case of the use of kyphoplasty to be published in the literature in relation to a traumatic cervical fracture. Additionally, at one-year follow-up the patient reports no pain, a near full range of motion in the cervical spine and no neurological deficit. PMID- 21796398 TI - Role of heart rate and stroke volume during muscle metaboreflex-induced cardiac output increase: differences between activation during and after exercise. AB - We hypothesized that the role of stroke volume (SV) in the metaboreflex-induced cardiac output (CO) increase was blunted when the metaboreflex was stimulated by exercise muscle ischemia (EMI) compared with post-exercise muscle ischemia (PEMI), because during EMI heart rate (HR) increases and limits diastolic filling. Twelve healthy volunteers were recruited and their hemodynamic responses to the metaboreflex evoked by EMI, PEMI, and by a control dynamic exercise were assessed. The main finding was that the blood pressure increment was very similar in the EMI and PEMI settings. In both conditions the main mechanism used to raise blood pressure was a CO elevation. However, during the EMI test CO was increased as a result of HR elevation whereas during the PEMI test CO was increased as a result of an increase in SV. These results were explainable on the basis of the different HR behavior between the two settings, which in turn led to different diastolic time and myocardial performance. PMID- 21796399 TI - The possible molecular evolution of sapoviruses by inter- and intra-genogroup recombination. AB - Sapporo virus belongs to the genus Sapovirus (family Caliciviridae) and has a non segmented single-stranded, positive-sense RNA genome. This virus causes acute gastroenteritis in human, porcine and mink hosts. In this study, the complete genome of a Brazilian sapovirus isolate from a child with acute gastroenteritis was determined. A phylogenetic tree was constructed to analyze the genotype of this sapovirus (Sapo_BR-DF01), and possible intra- and inter-genogroups recombination events were evaluated in silico using the RDP3 program. Two inter genogroup and two intra-genogroup recombination events were newly recognized in this study. PMID- 21796400 TI - Complete genome sequences of blueberry red ringspot virus (Caulimoviridae) isolates from the Czech Republic and Slovenia. AB - Genomic DNA of blueberry red ringspot virus (genus Soymovirus, family Caulimoviridae) from highbush blueberry plants growing for years in the Czech Republic and Slovenia was sequenced. The circular dsDNA genomes consist of 8,303 and 8,299 nt, respectively, and contain eight open reading frames (ORFs) longer than 100 amino acids. The European isolates are 90% to 99% identical in aa sequences of distinct proteins. In contrast to the American New Jersey isolate, in-frame initiation codons have been found upstream from AUG codons of ORFs I, IV and V in the European isolates. These and other differences resulted in a longer capsid protein, reverse transcriptase, movement protein and protein the encoded by ORF VII and reduced (75.4% to 93.7%) amino acid identity with corresponding proteins of the New Jersey isolate. PMID- 21796401 TI - Detection of a porcine rotavirus strain with VP4, VP7 and NSP4 genes of different animal origins. AB - A new rotavirus strain, sh0902, was detected in diarrheic piglets on a farm in Shanghai, China, and its genotype was characterized as G1P[7]. Analysis of the VP4, VP7 and NSP4 genes demonstrated VP4 homology to bovine and swine rotavirus strains; the nucleotide (nt) and amino acid (aa) identities were 99.7% and 99.5%, respectively. The VP7 gene was highly homologous to that of a giant panda rotavirus strain, with 98.5% similarity at the nt level and 99% similarity at the aa level. The nucleotide sequence of the NSP4 gene displayed high homology to human rotavirus strain R479, with 99.7% identity at the nt level and 99.3% identity at the aa level. This is the first report of an unusual porcine rotavirus strain with VP4, VP7 and NSP4 genes that are highly homologous to bovine, swine, giant panda and human strains isolated at geographically distant sites (South Korea, China and India). Our data indicate that rotaviruses have circulated among humans and animals and undergone genome reassortment. PMID- 21796402 TI - Cadmium induces alterations in the human spinal cord morphogenesis. AB - The effects of cadmium on the central nervous system are still relatively poorly understood and its role in neurodegenerative diseases has been debated. In our research, cultured explants from 25 human foetal spinal cords (10-11 weeks gestational age) were incubated with 10 and 100 MUM cadmium chloride (CdCl(2)) for 24 h. After treatment, an immunohistochemical study [for Sglial fibrillary acidic protein (GFAP) and choline acetyltransferase (ChAT)], a Western blot analysis (for GFAP, beta-Tubulin III, nerve growth factor receptor, Caspase 8 and poly (ADP-ribose) polymerase), and a terminal deoxynucleotidyl transferase biotin dUTP nick end labelling (TUNEL) assay (for detection of apoptotic bodies) were performed. The treatment with CdCl(2) induced a significant and dose-dependent change in the ratio motor neurons/glial cells in the ventral horns of human foetal spinal cord. The decrease of the choline acetyltransferase-positive cells (motor neurons) and the reduction of beta Tubulin III indicate that CdCl(2) specifically affects motor neurons of the ventral horns. While the number of motor neurons decreased for the activation of apoptotic pathways (as shown by the increased expression of Caspase 8, nerve growth factor receptor, and poly (ADP ribose) polymerase), glial cells, both in the subependymal zone and in the gray matter of the ventral horns, increased (as shown by the increase of GFAP expression). These results provide the evidence that during human spinal cord development, CdCl(2) may affect the fate of neural and glial cells thus, being potentially involved in the etiopathogenesis of neurodegenerative diseases. PMID- 21796403 TI - Delayed feedback control requires an internal forward model. AB - Biological motor control provides highly effective solutions to difficult control problems in spite of the complexity of the plant and the significant delays in sensory feedback. Such delays are expected to lead to non trivial stability issues and lack of robustness of control solutions. However, such difficulties are not observed in biological systems under normal operating conditions. Based on early suggestions in the control literature, a possible solution to this conundrum has been the suggestion that the motor system contains within itself a forward model of the plant (e.g., the arm), which allows the system to 'simulate' and predict the effect of applying a control signal. In this work, we formally define the notion of a forward model for deterministic control problems, and provide simple conditions that imply its existence for tasks involving delayed feedback control. As opposed to previous work which dealt mostly with linear plants and quadratic cost functions, our results apply to rather generic control systems, showing that any controller (biological or otherwise) which solves a set of tasks, must contain within itself a forward plant model. We suggest that our results provide strong theoretical support for the necessity of forward models in many delayed control problems, implying that they are not only useful, but rather, mandatory, under general conditions. PMID- 21796404 TI - N-acetylcysteine offers cardioprotection by decreasing cardiac lipid hydroperoxides and 8-isoprostane level in isoproterenol-induced cardiotoxicity in rats. AB - This study investigated the cardioprotective effect of N-acetylcysteine (NAC) on isoproterenol (ISO)-induced cardiotoxicity in rats. Male Sprague-Dawley rats were divided into control, NAC alone (100 mg/kg BW orally for 14 days), ISO-control (85 mg/kg BW), and ISO with NAC (for 14 days). Serum creatine kinase-MB and Lactate dehydrogenase were measured. From the heart homogenate lipid hydroperoxides (LPO), superoxide dismutase (SOD), total glutathione (GSH), and 8 isoprostane (IP) were measured. Histopathological examination of the heart was also carried out. There was a significant increase (P < 0.05) in LPO and IP levels in ISO-control group and NAC treatment reduced these changes. Antioxidant enzyme, SOD and GSH, level decreased significantly (P < 0.05) in ISO-control group, and treatment with NAC was able to reverse these changes significantly (P < 0.05). Histopathologically, ISO-control group showed morphological changes suggestive of cardiotoxicity with large areas of coagulative necrosis, with diffused interstitial edema. NAC treatment successfully reduced these histopathological changes. In conclusion, the study proves that NAC has a strong cardioprotective effect against isoproterenol-induced cardiac changes. NAC decreases isoproterenol-induced LPO and IP levels in the heart tissue and prevented free radicals-induced damage to the myocardium. PMID- 21796405 TI - Topography of the nasolacrimal duct on the lateral nasal wall in Koreans. AB - PURPOSE: The aim of this study was to describe in detail the gross anatomy of the nasolacrimal apparatus in relation to the lateral nasal wall by the various steps of cadaver dissection and to measure the distances of surgically important landmarks from relevant structures to improve the safety and efficiency of endoscopic surgical procedures. METHODS: Thirty-six half-heads of embalmed Korean adult cadavers were dissected under a surgical microscope. After removal of the nasal septum, the lateral wall of the nasal cavity was examined. RESULTS: The orifice of the nasolacrimal duct (NLD) was most frequently observed in the form of a vertical sulcus in 14 cases (39%) and the lacrimal fold was present in 28 cases (77.8%). A total of 15 morphometric items between the orifice of the NLD and the adjacent anatomical structures were measured. The location of the orifice of the NLD was observed at a mean of 17.5 +/- 3.1 mm from the limen nasi, 22.8 +/ 4.8 mm from the anterior nasal spine, and 21.4 +/- 3.5 mm from the axilla of the middle nasal concha. In the positional relationships, the most frequent finding was that the lacrimal sac was posterior to the axilla of the middle nasal concha in 23 cases (64%), and overlap of the NLD with the maxillary line was observed in 24 cases (67%). CONCLUSIONS: This study was conducted to accumulate anatomic data on the lacrimal sac and duct with regard to the positional relationships among the surrounding structures to establish the information for use in endoscopic dacryocystorhinostomy. PMID- 21796406 TI - The risk of spontaneous rupture of liver hemangiomas: a critical review of the literature. AB - BACKGROUND: The risk of spontaneous bleeding or rupture of liver hemangiomas still remains unknown. The aim of this review was to analyze the problem of spontaneous bleeding or rupture in liver hemangiomas and to identify factors leading to bleeding in these cases. METHODS: A MEDLINE search was undertaken to identify articles in English, French, German, Italian, and Spanish from 1898 to 2010. Basic data such as age and sex of patients were collected. Additional data such as risk factors or causes of rupture were also analyzed. Cases were divided into spontaneous and non-spontaneous ruptures. RESULTS: A total of 97 cases are described. In 51 of the 97 patients (52.6%) a non-spontaneous rupture was identified. Only in 46 out of the 97 cases (47.4%) was a spontaneous rupture found. Non-spontaneous rupture was significantly more frequent in patients aged <40 years than in older ones (p = 0.0099). Mean size of the ruptured lesions was 11.2 cm (range 1-37 cm). Massive bleeding occurred in 88 patients (90.7%). Reported mortality over the past 20 years has been significantly lower than before (p < 0.001). The overall mortality for the period under study was ~35%. CONCLUSIONS: The spontaneous rupture of a hepatic hemangioma is to be considered an exceptional event. Preventive surgery should be considered only for lesions of at least 11-cm size in special cohorts of patients. PMID- 21796407 TI - Larval growth in polyphenic salamanders: making the best of a bad lot. AB - Polyphenisms are excellent models for studying phenotypic variation, yet few studies have focused on natural populations. Facultative paedomorphosis is a polyphenism in which salamanders either metamorphose or retain their larval morphology and eventually become paedomorphic. Paedomorphosis can result from selection for capitalizing on favorable aquatic habitats (paedomorph advantage), but could also be a default strategy under poor aquatic conditions (best of a bad lot). We tested these alternatives by quantifying how the developmental environment influences the ontogeny of wild Arizona tiger salamanders (Ambystoma tigrinum nebulosum). Most paedomorphs in our study population arose from slow growing larvae that developed under high density and size-structured conditions (best of a bad lot), although a few faster-growing larvae also became paedomorphic (paedomorph advantage). Males were more likely to become paedomorphs than females and did so under a greater range of body sizes than females, signifying a critical role for gender in this polyphenism. Our results emphasize that the same phenotype can be adaptive under different environmental and genetic contexts and that studies of phenotypic variation should consider multiple mechanisms of morph production. PMID- 21796408 TI - Atlas of the muscle motor points for the lower limb: implications for electrical stimulation procedures and electrode positioning. AB - The aim of the study was to investigate the uniformity of the muscle motor point location for lower limb muscles in healthy subjects. Fifty-three subjects of both genders (age range: 18-50 years) were recruited. The muscle motor points were identified for the following ten muscles of the lower limb (dominant side): vastus medialis, rectus femoris, and vastus lateralis of the quadriceps femoris, biceps femoris, semitendinosus, and semimembranosus of the hamstring muscles, tibialis anterior, peroneus longus, lateral and medial gastrocnemius. The muscle motor point was identified by scanning the skin surface with a stimulation pen electrode and corresponded to the location of the skin area above the muscle in which an electrical pulse evoked a muscle twitch with the least injected current. For each investigated muscle, 0.15 ms square pulses were delivered through the pen electrode at low current amplitude (<10 mA) and frequency (2 Hz). 16 motor points were identified in the 10 investigated muscles of almost all subjects: 3 motor points for the vastus lateralis, 2 motor points for rectus femoris, vastus medialis, biceps femoris, and tibialis anterior, 1 motor point for the remaining muscles. An important inter-individual variability was observed for the position of the following 4 out of 16 motor points: vastus lateralis (proximal), biceps femoris (short head), semimembranosus, and medial gastrocnemius. Possible implications for electrical stimulation procedures and electrode positioning different from those commonly applied for thigh and leg muscles are discussed. PMID- 21796409 TI - Effects of strength, endurance and combined training on muscle strength, walking speed and dynamic balance in aging men. AB - The aim of this study was to examine effects of 21-week twice weekly strength (ST), endurance (ET) and combined (ST + ET 2 + 2 times a week) (SET) training on neuromuscular, endurance and walking performances as well as balance. 108 healthy men (56.3 +/- 9.9 years) were divided into three training (ST; n = 30, ET; n = 26, SET; n = 31) groups and controls (C n = 21). Dynamic 1RM and explosive leg presses (1RMleg, 50%1RMleg), peak oxygen uptake using a bicycle ergometer (VO(2peak)), 10 m loaded walking time (10WALK) and dynamic balance distance (DYND) were measured. Significant increases were observed in maximal 1RMleg of 21% in ST (p < 0.001) and 22% in SET (p < 0.001) and in explosive 50%1RMleg of 7.5% in ST (p = 0.005) and 10.2% in SET (p < 0.001). VO(2peak) increased by 12.5% in ET (p = 0.001) and 9.8% in SET (p < 0.001). Significant decreases occurred in 10WALK in ST (p < 0.001) and SET (p = 0.003) and also in DYND of -10.3% in ST (p = 0.002) and -8% in SET (p = 0.028). The changes in C remained minor in all variables. In conclusion, ST and SET training produced significant improvements in maximal and explosive strength, walking speed and balance without any interference effect in SET. Significant but moderate relationships were observed between strength and dynamic balance and walking speed, while no corresponding correlations were found in the ET group. PMID- 21796410 TI - Effect of transcutaneous electrical nerve stimulation on muscle metaboreflex in healthy young and older subjects. AB - Transcutaneous electrical nerve stimulation (TENS) increases local blood flow. It is not known whether increase in blood flow may be caused by inhibition of sympathetic activity, mediated by muscle metaboreflex activity. The purpose of this study was to evaluate the effect of TENS on metaboreflex activation and heart rate variability (HRV) in young and older individuals. Eleven healthy young (age 25 +/- 1.3 years) and 11 healthy older (age 63 +/- 4.2 years) were randomized to TENS (30 min, 80 Hz, 150 MUs) or placebo (same protocol without electrical output) applied on the ganglion region. Frequency domain indices of HRV and hemodynamic variables were evaluated during the pressor response to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with (PECO+) or without (PECO-) circulatory occlusion, in a randomized order. At the peak exercise, the increase in mean blood pressure was attenuated by TENS (P < 0.05), which was sustained during PECO+ and PECO-. TENS promoted a higher calf blood flow and lower calf vascular resistance during exercise and recovery. Likewise, TENS induced a reduction in the estimated muscle metaboreflex control both in young (placebo: 28 +/- 4 units vs. TENS: 6 +/- 3, P < 0.01) and in older individuals (placebo: 13 +/- 3 units vs. TENS: 5 +/- 3, P < 0.01). HRV analysis showed similar improvement in sympatho-vagal balance with TENS in young and older individuals. We conclude that application of TENS attenuates blood pressure and vasoconstrictor responses during exercise and metaboreflex activation, associated with improved sympatho-vagal balance in healthy young and older individuals. PMID- 21796412 TI - Inhibitory effect of SJSZ glycoprotein (38 kDa) on expression of heat shock protein 27 and 70 in chromium (VI)-treated hepatocytes. AB - Chromium (VI) is as an extremely toxic chemical substance, and is also an internationally recognized human carcinogen. The principal objective of this study was to determine whether or not Styrax japonica Siebold et al. Zuccarini (SJSZ) glycoprotein prevents hepatocarcinogenesis in chromium-treated BNL CL.2 cells and ICR mice. Firstly, it was evaluated that SJSZ glycoprotein has strong antioxidant character and scavenges radicals. In an effort to assess the chemopreventive effects of SJSZ glycoprotein on hepatocarcinogenesis, ICR mice were intraperitoneally injected with chromium (10 mg/kg, BW) for 8 weeks. After sacrifice, we evaluated indicators of liver tissue damage [the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT), and thiobarbituric acid-reactive substances (TBARS)], antioxidative enzymes [activities of superoxide dismutase (SOD), catalase (CAT) and gluthathione peroxidase (GPx)], and initiating hepatocarcinogenic indicator [heat shock protein (HSP) 27 and 70] and protein kinase C (PKC), p38 MAPK and PCNA via biochemical methods and immunoblot analysis. The results obtained from this study demonstrated that the SJSZ glycoprotein (50 MUg/ml) inhibited the production of intracellular ROS in BNL CL.2 cells. In addition, the SJSZ glycoprotein (10 mg/kg, BW) attenuated the levels of LDH, ALT, and TBARS, whereas it increased antioxidative enzymes in mouse serum. SJSZ glycoprotein attenuated the activity of HSP27, HSP70, PKC, MAPKs, and PCNA in BNL CL.2 cells and liver tissue. Taken together, our results indicate that SJSZ glycoprotein might be have a potent preventive effect against hepatocarcinogenesis induced by oxidative stress. PMID- 21796411 TI - Cardiovascular and hormonal responses to static handgrip in young and older healthy men. AB - The purpose of this study was to investigate the effect of age on cardiovascular changes and plasma concentrations of adrenomedullin (ADM), catecholamines, endothelin-1 (ET-1) and plasma renin activity (PRA) in healthy men. A total of 15 young (21 +/- 0.3 years) and 15 older (64 +/- 0.7 years) healthy men performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. During exercise heart rate (HR), blood pressure (BP), stroke volume (SV) and pre-ejection period (PEP) and left ventricle ejection time (LVET) were measured. Blood samples were taken before exercise, at the end of both exercise bouts and in the fifth minute of the recovery period. The handgrip-induced increases in HR and cardiac output were significantly smaller in older than in young men (p < 0.01). SV decreased only in older men (p < 0.001). There were no differences between groups in BP increases. The baseline plasma ADM and catecholamines were higher in older man compared to young subjects. Handgrip caused increases in plasma ADM, ET-1 and PRA only in older men (p < 0.05). The increases in plasma ADM correlated positively with those of noradrenaline (NA), PRA, ET-1 and LVET and negatively with changes in total peripheral resistance (TPR), SV, PEP and PEP/LVET ratio. The increases in plasma ET-1 correlated positively with those of NA, PRA, TPR, mean BP and SV. These results revealed that ADM, ET-1 and angiotensin II can contribute to maintain vascular tone during static exercise in older but not in younger men. PMID- 21796413 TI - Estimation of tissue contractility from cardiac cine-MRI using a biomechanical heart model. AB - The objective of this paper is to propose and assess an estimation procedure based on data assimilation principles-well suited to obtain some regional values of key biophysical parameters in a beating heart model, using actual Cine-MR images. The motivation is twofold: (1) to provide an automatic tool for personalizing the characteristics of a cardiac model in order to achieve predictivity in patient-specific modeling and (2) to obtain some useful information for diagnosis purposes in the estimated quantities themselves. In order to assess the global methodology, we specifically devised an animal experiment in which a controlled infarct was produced and data acquired before and after infarction, with an estimation of regional tissue contractility-a key parameter directly affected by the pathology-performed for every measured stage. After performing a preliminary assessment of our proposed methodology using synthetic data, we then demonstrate a full-scale application by first estimating contractility values associated with 6 regions based on the AHA subdivision, before running a more detailed estimation using the actual AHA segments. The estimation results are assessed by comparison with the medical knowledge of the specific infarct, and with late enhancement MR images. We discuss their accuracy at the various subdivision levels, in the light of the inherent modeling limitations and of the intrinsic information contents featured in the data. PMID- 21796414 TI - Diagnosis of pure subcortical vascular dementia, hippocampal sclerosis in advanced age and imaging of training-related brain plasticity by fMRI. PMID- 21796415 TI - Chinese guidelines for the diagnosis and comprehensive treatment of hepatic metastasis of colorectal cancer. PMID- 21796416 TI - Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. AB - PURPOSE: Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. METHODS: NSCLC cell lines with EGFR T790M mutation and K ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. RESULTS: Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. CONCLUSIONS: Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. PMID- 21796418 TI - The analysis of association between traits when differences between trait States matter. AB - Because of their elementary significance in almost all fields of science, measures of association between two variables or traits are abundant and multiform. One aspect of association that is of considerable interest, especially in population genetics and ecology, seems to be widely ignored. This aspect concerns association between complex traits that show variable and arbitrarily defined state differences. Among such traits are genetic characters controlled by many and potentially polyploid loci, species characteristics, and environmental variables, all of which may be mutually and asymmetrically associated. A concept of directed association of one trait with another is developed here that relies solely on difference measures between the states of a trait. Associations are considered at three levels: between individual states of two variables, between an individual state of one variable and the totality of the other variable, and between two variables. Relations to known concepts of association are identified. In particular, measures at the latter two levels turn out to be interpretable as measures of differentiation. Examples are given for areas of application (search for functional relationships, distribution of variation over populations, genomic associations, spatiogenetic structure). PMID- 21796417 TI - Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation. AB - Dysregulation of angiogenesis is a common feature of many disease processes. Vascular remodeling is believed to depend on the participation of endothelial progenitor cells, but the identification of endothelial progenitors in postnatal neovascularization remains elusive. Current understanding posits a role for circulating pro-angiogenic hematopoietic cells that interact with local endothelial cells to establish an environment that favors angiogenesis in physiologic and pathophysiologic responses. In the lung, increased and dysregulated angiogenesis is a hallmark of diseases of the bronchial and pulmonary circulations, manifested by asthma and pulmonary arterial hypertension (PAH), respectively. In asthma, T(Helper)-2 immune cells produce angiogenic factors that mobilize and recruit pro-inflammatory and pro-angiogenic precursors from the bone marrow into the airway wall where they induce angiogenesis and fuel inflammation. In contrast, in PAH, upregulation of hypoxia-inducible factor (HIF) in vascular cells leads to the production of bone marrow-mobilizing factors that recruit pro-angiogenic progenitor cells to the pulmonary circulation where they contribute to angiogenic remodeling of the vessel wall. This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH. PMID- 21796419 TI - Selection of confounding variables should not be based on observed associations with exposure. AB - In observational studies, selection of confounding variables for adjustment is often based on observed baseline incomparability. The aim of this study was to evaluate this selection strategy. We used clinical data on the effects of inhaled long-acting beta-agonist (LABA) use on the risk of mortality among patients with obstructive pulmonary disease to illustrate the impact of selection of confounding variables for adjustment based on baseline comparisons. Among 2,394 asthma and COPD patients included in the analyses, the LABA ever-users were considerably older than never-users, but cardiovascular co-morbidity was equally prevalent (19.9% vs. 19.9%). Adjustment for cardiovascular co-morbidity status did not affect the crude risk ratio (RR) for mortality: crude RR 1.19 (95% CI 0.93-1.51) versus RR 1.19 (95% CI 0.94-1.50) after adjustment for cardiovascular co-morbidity. However, after adjustment for age (RR 0.95, 95% CI 0.76-1.19), additional adjustment for cardiovascular co-morbidity status did affect the association between LABA use and mortality (RR 1.01, 95% CI 0.80-1.26). Confounding variables should not be discarded based on balanced distributions among exposure groups, because residual confounding due to the omission of confounding variables from the adjustment model can be relevant. PMID- 21796420 TI - [New tyrosine kinase and EGFR inhibitors in cancer therapy. Cardiac and skin toxicity as relevant side effects. Part B: Skin]. AB - Recently, inhibitors of the epidermal growth factor receptor (EGFR) and multikinase inhibitors have been successfully established in the therapy of various solid tumors. EGFR inhibitors and multikinase inhibitors are specific and selective agents that intervene with the dysfunctional regulatory processes of malignant cells. This results in a favorable safety profile and range of side effects, especially in comparison to conventional chemotherapy. The various cutaneous adverse drug reactions are considered substance class effects and are the most frequent side effects of these targeted therapies. Therapy with EGFR inhibitors is associated with acneiform rash, painful paronychia, xerosis cutis, acral fissures, hair changes, and pruritus. Treatment with tyrosin kinase inhibitors may cause hand-foot syndrome, various types of drug rash, hair loss, xerosis cutis, and pruritus. These side effects may be stigmatizing and place a huge burden on the patient's quality of life. Treatment is a challenge and best performed in interdisciplinary cooperation of dermatologists and oncologists. PMID- 21796421 TI - Single dose 17 alpha-hydroxyprogesterone caproate in preterm labor: a randomized trial. AB - OBJECTIVE: To evaluate the effect of a single 250-mg dose of 17 alpha hydroxyprogesterone caproate (17-OHPC) intramuscularly as adjunct to nifedipine tocolysis in preterm labor. METHOD: Women diagnosed with threatened preterm labor between 22 and 35 weeks' gestation scheduled to receive nifedipine tocolysis and prophylactic antenatal corticosteroid were randomized to a single intramuscular injection of 250 mg of 17-OHPC or placebo saline in a double-blind fashion. Nifedipine tocolysis and corticosteroids were administered to all participants. Further management was otherwise carried out according to providers' discretion. Main outcome measures are delivery within 48 h and 7 days. RESULTS: Data were analyzed for the 56 participants randomized to 17-OHPC and 56 randomized to placebo. Delivery rates within 48 h were 11/54 (20.4%) versus 15/56 (26.8%) RR 0.76 (95% CI 0.38-1.51) and within 7 days were 13/52 (25.0%) versus 19/54 (35.2%) RR 0.71 (95% CI 0.39-1.29) for 17-OHPC and placebo groups, respectively, and were similar. Recruitment to delivery interval, gestation at delivery, delivery rate before 34 weeks' and 37 weeks' gestation, and neonatal outcomes were also similar. CONCLUSION: The results indicated that adjunctive single-dose 17-OHPC in combination with nifedipine tocolysis for threatened preterm labor did not delay delivery. PMID- 21796422 TI - A robotic system to train activities of daily living in a virtual environment. AB - In the past decade, several arm rehabilitation robots have been developed to assist neurological patients during therapy. Early devices were limited in their number of degrees of freedom and range of motion, whereas newer robots such as the ARMin robot can support the entire arm. Often, these devices are combined with virtual environments to integrate motivating game-like scenarios. Several studies have shown a positive effect of game-playing on therapy outcome by increasing motivation. In addition, we assume that practicing highly functional movements can further enhance therapy outcome by facilitating the transfer of motor abilities acquired in therapy to daily life. Therefore, we present a rehabilitation system that enables the training of activities of daily living (ADL) with the support of an assistive robot. Important ADL tasks have been identified and implemented in a virtual environment. A patient-cooperative control strategy with adaptable freedom in timing and space was developed to assist the patient during the task. The technical feasibility and usability of the system was evaluated with seven healthy subjects and three chronic stroke patients. PMID- 21796423 TI - Histological in vitro evaluation of the effects of Er:YAG laser on oral soft tissues. AB - In oral pathology, laser devices can provide important advantages, especially in the treatment of certain lesions. However, there is controversy about the use of some wavelengths in the analysis of suspected dysplastic or neoplastic lesions, raising doubt about the laser's suitability for use in biopsy procedures. In recent studies, the KTP and diode lasers have been used in biopsy procedures without histological artefacts. The aim of this in vitro study was to evaluate the exact extent of peripheral thermal damage to oral soft tissues caused by an Er:YAG laser (lambda 2,940 nm) without water cooling. The study was performed on five swine cadaver tongues. Nine samples from each tongue were taken by the same operator using the Er:YAG laser with increasing energies (from 60 to 150 mJ) and fluencies (from 21 to 53 J/cm(2)). In addition to the laser samples, a specimen obtained using a scalpel was used as control. The samples were placed in 10% formalin solution and were examined by optical microscopy by two blinded pathologists who assigned a thermal damage score (from 0 to 3) to each sample. The Er:YAG laser produced less damage at 80 and 100 mJ and 28 and 35 J/cm(2) (intermediate parameters). Although in some samples thermal damage was minimally visible, in all samples histological evaluation was clearly possible. The study demonstrated that the Er:YAG laser can be safely used in oral biopsy investigations while ensuring a successful histological evaluation, which is fundamental to correct clinical management. PMID- 21796424 TI - Effects of obovatol on GSH depleted glia-mediated neurotoxicity and oxidative damage. AB - Earlier studies indicate that obovatol (OBO), isolated from a medicinal herb Magnolia obovata, has anti-inflammatory and anti-oxidative properties. Depletion of glutathione (GSH) in glial cells with the gamma-glutamylcysteine synthase inhibitor D,L-buthionine-S,R-sulfoximine (BSO) is known to produce oxidative stress which, in turn, induces these cells to secrete inflammatory cytokines and other neurotoxic substances. In the present study, we investigated the ability of OBO to protect SH-SY5Y neuroblastoma cells from this effect. Human microglia, astrocytes and their surrogate THP-1 and U373 cell lines were activated by treatment with BSO. Such treatment depleted their intracellular GSH and increased levels of damage to DNA, lipids and proteins (8-OHdG, lipid peroxide, protein carbonyls and 3-nitrotyrosine), and activated the inflammatory pathways P38 MAP kinase and NFkappaB. These are accompanied by release of proinflammatory factors such as TNFalpha, IL-6 and nitric oxide. Their conditioned media were toxic to SH SY5Y cells. All these effects were attenuated by pre-treatment with OBO. Prior treatment of SH-SY5Y cells with OBO also attenuated THP-1 or U373 conditioned media neurotoxicity and also reduced oxidative damage produced by treatment with hydrogen peroxide or BSO. Prior treatment with OBO potentiated survival of SH SY5Y cells exposed to conditioned medium from BSO-treated THP-1, U373 cells, microglia and astrocytes. The data indicate that OBO could be anti-inflammatory, anti-oxidative and neuroprotective, and be an effective agent for inhibiting pathogenesis in neurological diseases such as Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis in which glial-mediated neuroinflammation and oxidative stress are thought to contribute to disease progression. PMID- 21796425 TI - Production objectives and breeding goals of Sahiwal cattle keepers in Kenya and implications for a breeding programme. AB - The Sahiwal breed has been used for upgrading the East African Zebu (EAZ) for improved milk production and growth performance in the southern rangelands of Kenya. Main users of this breed are Maasai pastoralists. Until now, there has been no deliberate effort to understand why these pastoralists specifically prefer to keep Sahiwal genetic resources as well as which traits are considered important by them and what is the underlying reason for this. However, this information is regarded vital for further development of the breed. A survey was conducted between May and October 2009 among Maasai pastoralists in Kajiado and Narok counties in the Southern part of Kenya, and private ranches and government farms to identify production objectives and breeding goals of Sahiwal cattle producers. Sahiwal genetic resources were mainly kept for domestic milk production and for revenue generation through milk sales and live animals. To a limited extent, they were kept for breeding and also for multiple objectives that included insurance against risks and social functions. Production aims were influenced to varying extents by various household and farmer characteristics. Sahiwal cattle and their crosses were generally perceived to be better with respect to productive traits and fertility traits when compared to the EAZ. However, the EAZ was rated higher with respect to adaptation traits. The breeding objective traits of primary importance were high milk yield and big body size, good reproductive efficiency and relatively good adaptation to local production conditions. Performance and functional traits are important breeding goals that play a major role in fulfilling the multiple production objectives. This forms the basis for the optimisation of a breeding programme for sustainable utilisation to meet the needs of Sahiwal cattle producers. PMID- 21796426 TI - Functional differences in pore properties between wild-type and cysteine-less forms of the CFTR chloride channel. AB - Studies of the structure and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel have been advanced by the development of functional channel variants in which all 18 endogenous cysteine residues have been mutated ("cys-less" CFTR). However, cys-less CFTR has a slightly higher single-channel conductance than wild-type CFTR, raising questions as to the suitability of cys-less as a model of the wild-type CFTR pore. We used site directed mutagenesis and patch-clamp recording to investigate the origin of this conductance difference and to determine the extent of functional differences between wild-type and cys-less CFTR channel permeation properties. Our results suggest that the conductance difference is the result of a single substitution, of C343: the point mutant C343S has a conductance similar to cys-less, whereas the reverse mutation, S343C in a cys-less background, restores wild-type conductance levels. Other cysteine substitutions (C128S, C225S, C376S, C866S) were without effect. Substitution of other residues for C343 suggested that conductance is dependent on amino acid side chain volume at this position. A range of other functional pore properties, including interactions with channel blockers (Au[CN] (2) (-) , 5-nitro-2-[3-phenylpropylamino]benzoic acid, suramin) and anion permeability, were not significantly different between wild-type and cys-less CFTR. Our results suggest that functional differences between these two CFTR constructs are of limited scale and scope and result from a small change in side chain volume at position 343. These results therefore support the use of cys less as a model of the CFTR pore region. PMID- 21796427 TI - Early detection of brain death. PMID- 21796428 TI - Psychotic reaction as a manifestation of multiple sclerosis relapse treated with plasma exchange. AB - We present a patient with a clinically isolated syndrome suggestive of multiple sclerosis, who developed a full-blown picture of paranoid psychosis with suicidal attempt. Four new lesions were observed on brain MRI, one in the left and one in the right temporal lobe, one subcortically in the cingulate gyrus and one centrally in the tegmentum of the midbrain. The patient was treated with plasma exchange and recovered completely. Psychosis is not so rare symptom of multiple sclerosis as previously reported, and poses a major treatment challenge. A combination of lesions at strategic locations was a presumed mechanism of psychosis in this patient. PMID- 21796429 TI - Epilepsy in type 1 Chiari malformation. AB - In patients with Chiari malformation type 1 (CMI), epileptic seizures are occasionally reported both in symptomatic patients candidate to surgery and in patients without symptoms of tonsillar displacement in whom CM1 is often an incidental finding in the diagnostic work up for idiopathic epilepsies. In both groups of patients, the course of epilepsy is almost invariably favorable, with a few seizures easily controlled by treatment. In a subset of CM1 patients, epilepsy occurs in the context of neurodevelopmental disorders that also include mental retardation, autism and somatic dysmorphisms. Epileptic seizures must be accurately differentiated by potentially harmful paroxysmal events due to compression of the medulla, particularly by the cerebellar fits characterized by drop attacks, abnormal extensor posturing and apnea. PMID- 21796430 TI - Scurvy hidden behind neuropsychiatric symptoms. AB - Approaching an uncommon disease may result in diagnostic delay even in patients with typical clinical features. In this respect, diseases related to nutritional deficiencies may represent a diagnostic challenge. We describe a 2.5-year-old child with typical features of scurvy, who was referred for autistic-like behavior and severe muscle weakness and pain in lower limbs. Extensive investigations for non-nutrition-related disorders were first performed, including a muscle biopsy showing a selective type II fibers hypotrophy. Scurvy was eventually considered, after recalling the child's peculiar dietary habits. PMID- 21796431 TI - Asymmetric chorea as presenting symptom in Graves' disease. AB - Chorea is an involuntary movement disorder characterized by irregular, brief movements that flow from one body part to another in a non-stereotyped fashion. In rare instances, chorea is associated with autoimmune thyroid disease. Most of them have been related with Hashimoto's encephalopathy and few cases have been related with Graves' disease. Most reported cases have been in women with Graves' disease. We describe a 16-year-old male patient with asymmetric chorea as presenting symptom in Graves' disease. He had no family history of neurological disease. Brain imaging, laboratory findings and electroencephalogram demonstrated no abnormality except for thyroid dysfunction which was proved by thyroid function test, sonography and radioiodine uptake scan. Asymmetric chorea improved over months after anti-thyroid medications. This asymmetry could be explained by difference in increased hypersensitivity or by the difference in the number of dopamine receptors, and an asymmetrical breakdown of blood-brain barrier due to their genetic differences. PMID- 21796432 TI - Structure and function of polyamine-amino acid antiporters CadB and PotE in Escherichia coli. AB - The structure and function of a cadaverine-lysine antiporter CadB and a putrescine-ornithine antiporter PotE in Escherichia coli were evaluated using model structures based on the crystal structure of AdiC, an agmatine-arginine antiporter, and the activities of various CadB and PotE mutants. The central cavity of CadB, containing the substrate binding site, was wider than that of PotE, mirroring the different sizes of cadaverine and putrescine. The size of the central cavity of CadB and PotE was dependent on the angle of transmembrane helix 6 (TM6) against the periplasm. Tyr(73), Tyr(89), Tyr(90), Glu(204), Tyr(235), Asp(303), and Tyr(423) of CadB, and Cys(62), Trp(201), Glu(207), Trp(292), and Tyr(425) of PotE were strongly involved in the antiport activities. In addition, Trp(43), Tyr(57), Tyr(107), Tyr(366), and Tyr(368) of CadB were involved preferentially in cadaverine uptake at neutral pH, while only Tyr(90) of PotE was involved preferentially in putrescine uptake. The results indicate that the central cavity of CadB consists of TMs 2, 3, 6, 7, 8, and 10, and that of PotE consists of TMs 2, 3, 6, and 8. These results also suggest that several amino acid residues are necessary for recognition of cadaverine in the periplasm because the level of cadaverine is much lower than that of putrescine in the periplasm at neutral pH. All the amino acid residues identified as being strongly involved in both the antiport and uptake activities were located on the surface of the transport path consisting of the central cavity and TM12. PMID- 21796433 TI - Constitutively and highly expressed Oryza sativa polyamine oxidases localize in peroxisomes and catalyze polyamine back conversion. AB - Polyamine oxidases (PAOs) are FAD-dependent enzymes involved in polyamine (PA) catabolism. Recent studies have revealed that plant PAOs are not only active in the terminal catabolism of PAs as demonstrated for maize apoplastic PAO but also in a polyamine back-conversion pathway as shown for most Arabidopsis PAOs. We have characterized Oryza sativa PAOs at molecular and biochemical levels. The rice genome contains 7 PAO isoforms that are termed OsPAO1 to OsPAO7. Of the seven PAOs, OsPAO3, OsPAO4, and OsPAO5 transcripts were most abundant in 2-week old seedlings and mature plants, while OsPAO1, OsPAO2, OsPAO6, and OsPAO7 were expressed at very low levels with different tissue specificities. The more abundantly expressed PAOs--OsPAO3, OsPAO4, and OsPAO5--were cloned, and their gene products were produced in Escherichia coli. The enzymatic activities of the purified OsPAO3 to OsPAO5 proteins were examined. OsPAO3 favored spermidine (Spd) as substrate followed by thermospermine (T-Spm) and spermine (Spm) and showed a full PA back-conversion activity. OsPAO4 substrate specificity was similar to that of OsPAO5 preferring Spm and T-Spm but not Spd. Those enzymes also converted Spm and T-Spm to Spd, again indicative of PA back-conversion activities. Lastly, we show that OsPAO3, OsPAO4, and OsPAO5 are localized in peroxisomes. Together, these data revealed that constitutively and highly expressed O. sativa PAOs are localized in peroxisomes and catalyze PA back-conversion processes. PMID- 21796434 TI - Protein Data Bank Japan (PDBj): an interview with Haruki Nakamura of Osaka University by Wendy A. Warr. PMID- 21796435 TI - Functional characterization of a putative beta-lactamase gene in the genome of Zymomonas mobilis. AB - Zymomonas mobilis ZM4 is resistant to beta-lactam antibiotics but there are no reports of a beta-lactam resistance gene and its regulation. A putative beta lactamase gene sequence (ZMO0103) in the genome of Z. mobilis showed a 55% amino acid sequence identity with class C beta-lactamase genes. qPCR analysis of the beta-lactamase transcript indicated a higher level expression of the beta lactamase compared to the relative transcript quantities in antibiotic susceptible bacteria. The putative beta-lactamase gene was cloned, expressed in Escherichia coli BL21 and the product, AmpC, was purified to homogeneity. Its optimal activity was at pH 6 and 30 degrees C. Further, the beta-lactamase had a higher affinity towards penicillins than cephalosporin antibiotics. PMID- 21796436 TI - Phylogenetic analysis of Rice tungro bacilliform virus ORFs revealed strong correlation between evolution and geographical distribution. AB - A new isolate of Rice tungro bacilliform virus (RTBV) was collected from Chinsura, West Bengal, India. The full genome was sequenced and deposited to GenBank designating the new one as Chinsura isolate. The four open reading frames (ORFs) of the new isolate were compared with those of previously reported 'South east Asian' (SEA) and 'South Asian' (SA) isolates emphasizing the ORF3, which is the largest and functionally most important gene of RTBV. In the ORFs, Chinsura isolate shared 90.0-100.0% identity at amino acid level with SA isolates, but only 58.76-88.63% identity with SEA isolates for the same. Similarly, the amino acid identity of ORFs between SEA and SA isolates ranged from 58.77 to 88.64, whereas within each group the corresponding value was >96.0%. The phylogenetic analysis based on nucleotide and amino acid sequences of each ORF made two broad clusters of SEA- and SA-types including Chinsura isolate within SA cluster. Moreover, the relative positions and length of functional domains corresponding to movement protein (MP), coat protein (CP), aspartate protease (PR) and reverse transcriptase/ribonuclease H (RT/RNase H) of ORF3 of Chinsura isolate were completely identical with SA isolates. The clustering pattern indicated strong influence of geographical habitat on genomic evolution. Comparison of ORF3 among all the isolates revealed major variations at non-functional regions in between the functional domains and at the hypervariable 3'-terminal end of ORF3, while PR appeared to have evolved differentially in SA isolates expecting further characterization. PMID- 21796437 TI - [Advanced therapy strategies in neurological diseases: present and perspectives]. PMID- 21796438 TI - Is health care a luxury or a necessity or both? Evidence from Turkey. AB - This study investigates the effect of per capita income on per capita health expenditures in Turkey over the period 1975-2007 by using ARDL bounds test approach to the cointegration considering both demand and supply side variables. Since we reject the null hypothesis that there is no cointegration among the series, we estimate long run and short run elasticities. The results show that while income has no effect on health expenditures in the long run, it is a necessity good in the short run that is a 1% increase in per capita income creates an 0.75% increase in per capita health expenditures. On the other hand, by examining the coefficient of demand and supply side variables, we found that average length of stay and number of physicians has negative effect, percentage of older people has positive effect and infant mortality rate has no effect on health expenditures in both short and long runs. PMID- 21796439 TI - A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma. AB - BACKGROUND: Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma. METHODS: Two courses of irinotecan [15 mg/m(2)/day (daily *5)*2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought. RESULTS: Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp. CONCLUSIONS: Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials. PMID- 21796440 TI - Isolation and identification of a novel inducible antibacterial peptide from the skin mucus of Japanese eel, Anguilla japonica. AB - In this study, acetone extracts and acidic extracts were prepared from skin mucus, gill, kidney, liver and spleen of the Japanese eel, Anguilla japonica, and they exhibited different levels of antibacterial activities against three strains of Gram-negative bacteria, Edwardsiella tarda, Aeromonas hydrophila, Aeromonas sp. and one Gram-positive bacterium Micrococcus leteus. The mucus was chosen as the source of antibacterial peptide for further purification of antibacterial peptides. Following the intraperitoneal injection of A. hydrophila, one of the main pathogenic bacteria of Japanese eel and many other fish, a peptide was purified from acetic acid extraction of the skin mucus, by using cationic exchange liquid chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC). The isolated antibacterial peptide, named as AJN-10, exhibited antibacterial activity against A. hydrophila. The AJN-10 is a heat tolerant and hydrophilic peptide. The molecular weight of this peptide is 6,044.28 Da, as determined by matrix-assisted laser desorption ionisation time of flight mass spectrometry. The 20 N-terminal amino acid sequences were clarified by Edman degradation, and based on results of homology search by BLAST analysis of the 20 N-terminal sequences, the AJN-10 showed little similarity to other proteins in databases. PMID- 21796441 TI - Psychrophilic yeasts from Antarctica and European glaciers: description of Glaciozyma gen. nov., Glaciozyma martinii sp. nov. and Glaciozyma watsonii sp. nov. AB - Field campaigns in Antarctica, Greenland and the Italian glaciers aiming to explore the biodiversity of these disappearing environments identified several undescribed yeast strains unable to grow at temperature above 20 degrees C and belonging to unknown species. Fourteen of these strains were selected and grouped based on their morphological and physiological characteristics. Sequences of the D1/D2 and ITS regions of the ribosomal RNA demonstrated that the strains belong to unknown species related to Leucosporidium antarcticum. The new genus Glaciozyma is proposed and two new species are described, namely Glaciozyma martinii sp. nov. and Glaciozyma watsonii sp. nov. Additionally, re classification of Leucosporidium antarcticum as Glaciozyma antarctica is proposed. Strains of Glaciozyma form a monophyletic clade and a well separated lineage within class Microbotryomycetes (Pucciniomycotina, Basidiomycota). The description of Glaciozyma genus and the re-classification of L. antarcticum reduce the polyphyletic nature of the genus Leucosporidium. PMID- 21796442 TI - Predictors of consistent condom use among young African American women. AB - The purpose of this study was to determine the predictive value of selected factors to the consistent use of condoms among high-risk young African American women. A clinic-based, prospective, study of 242 young, African-American women (ages 15-21) was conducted. In multivariate analysis, consistent condom use was predicted by having greater perceptions of condom negotiation self-efficacy, lower fear of negotiating condom use, and having communicated with sex partners (during the recall period) about condom use. Relational variables were predictive of consistent condom use among young African American women. STD/HIV preventive interventions should target these factors, perhaps in dyad-level interventions. PMID- 21796443 TI - Commotio Cordis presenting as a temporary complete atrioventricular block in a 2 year-old girl with congenitally corrected transposition of the great arteries. AB - This report describes a 2-year-old girl with congenitally corrected transposition of the great arteries (ccTGA) who presented with transient complete atrioventricular (AV) block after a mild chest blow. Running around the house with her older sister, she fell to the floor. Her sister also fell and landed on her. The girl became cyanotic and pale and experienced a transient loss of consciousness. At arrival to the emergency department, she had regained consciousness, but she remained pale. An electrocardiogram (ECG) demonstrated complete AV block with a heart rate of 78 beats per minute (bpm). The ECG after admission showed a Wenckebach-type second-degree AV block. Day 2 after admission, a 12-lead ECG showed significant ST and T-wave abnormalities in the precordial leads, but the girl had no chest pain and a normal physical examination. Echocardiography demonstrated normal contractility of the systemic right ventricle. The first-degree AV block and the ST and T-wave abnormalities on the 12-lead ECG improved gradually without abnormal Q-waves. This is the first report of ccTGA in which a transient complete AV block naturally recovered after a presentation with commotio cordis. PMID- 21796444 TI - Serum levels after everolimus-stent implantation and paclitaxel-balloon angioplasty in an infant with recurrent pulmonary vein obstruction after repaired total anomalous pulmonary venous connection. AB - Everolimus-eluting stents and paclitaxel-coated balloons are used in the interventional treatment of coronary artery disease in adults to reduce the restenosis rate and in small-vessel disease. Both substances are released into the circulation. We report systemic drug exposure after implantation of one everolimus-eluting stent and dilation with one paclitaxel-coated balloon in an 8 month-old infant, which was used as an innovative therapy for recurrent pulmonary vein stenosis. PMID- 21796445 TI - The two endo-beta-N-acetylglucosaminidase genes from Arabidopsis thaliana encode cytoplasmic enzymes controlling free N-glycan levels. AB - Endo-beta-N-acetylglucosaminidases (ENGases) cleave N-glycans from proteins and/or peptides by hydrolyzing the O-glycosidic linkage between the two core-N acetylglucosamine (GlcNAc) residues. Although, two homologous genes potentially encoding ENGases have been identified in Arabidopsis thaliana, their respective substrate specificity, their subcellular and their organ specific localization was hitherto unknown. In order to investigate the role of ENGases in this model plant species, we transiently expressed the two A. thaliana genes in Nicotiana benthamiana and determined the substrate specificities, as well as the Km values, of the purified recombinant enzymes. The assumed predominantly cytosolic localisation of both enzymes, here referred to as AtENGase85A and AtENGase85B, was determined by confocal microscopy of plant leaves expressing the respective GFP-fusion constructs. For the individual characterization of the two enzymes expression patterns in planta, single knock-out plants were selected for both genes. Although both enzymes are present in most organs, only AtENGase85A (At5g05460) was expressed in stems and no ENGase activity was detected in siliques. A double knock-out was generated by crossing but-like single knock-out plants-no apparent phenotype was observed. In contrast, in this double knock-out, free N-glycans carrying a single GlcNAc at the reducing end are completely absent and their counterparts with two GlcNAc-visible only at a trace level in wild type accumulated dramatically. PMID- 21796446 TI - p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. AB - Medulloblastoma (MB) is the most common malignant primary brain tumour in childhood. Metastatic disease (M+) at diagnosis is the most important negative prognostic clinical marker and, despite craniospinal irradiation and intensive chemotherapy, it remains one of the leading causes of treatment failure. To date, few clinical and biological data have been evaluated to obtain an additional prognostic profile for these high-risk patients. In this study, 169 patients with metastatic MB registered in the multicentre HIT2000 trial of the German Society of Pediatric Oncology and Haematology (GPOH) have been investigated to determine the importance of p53 protein expression in predicting survival. At a median follow-up of 4.1 years, 159 patients with p53-negative tumours had significantly better four-year event-free survival (EFS) and progression-free survival (PFS) (56 +/- 11, 59 +/- 4%) than 10 patients with p53-positive tumours (40 +/- 16, 40 +/- 16%; P = 0.018 for EFS, P = 0.007 for PFS, respectively). Furthermore, four year overall survival (OS) of children with p53-negative tumours was higher than for children with p53-positive tumours (72 +/- 4 vs. 35 +/- 18%, P = 0.05). Three of the p53-positive MBs harbored a point mutation in the TP53 gene. p53 protein assessment by immunohistochemistry may be a useful tool for sub-stratification of metastatic high-risk MB patients. PMID- 21796447 TI - [ProSealTMlaryngeal mask in normal weight and obese patients : oxygenation under pressure-controlled ventilation and different end-expiratory pressures]. AB - BACKGROUND: Most of the data on combining pressure-controlled ventilation (PCV) with positive end-expiratory pressure (PEEP) come from studies with an endotracheal tube (ETT) whereas data on utilization of PEEP with a laryngeal mask airway (LMA) are limited. The LMA-ProSeal(r) (PLMA) forms a more effective seal of the airway than the LMA-ClassicTM (CLMA). The application of PEEP when PCV is used with the PLMA could have an impact on oxygenation in adult patients. METHODS: For this study 148 patients with an mean age of 44 years (range18-65 years) and mean weight of 86 kg (range 49-120 kg) were recruited in 2 groups: group N ((Normal)): body-mass index (BMI) <30 kg/m(2) and group O ((Obesity)) BMI >=30 and <36 kg/m(2). Cardiovascular and pulmonary disease and a history of smoking were exclusion criteria in addition to the usual LMA contraindications. The bispectral index-guided (BIS) anesthesia technique was used with propofol, fentanyl, and remifentanil without muscle relaxants. Measurement of PLMA seal pressure served as recruitment maneuver and PCV was randomly combined with 0 cmH(2)O, 5 cmH(2)O or 8 cmH(2)O PEEP. An arterial blood gas sample was taken 50 min after induction of anesthesia under an inspiratory oxygen fraction (F(I)O(2)) of 0.3. In the first part partial oxygen pressure (p(a)O(2)) under 0 cmH(2)O was compared with p(a)O(2) under 5 cmH(2)O and in the second part p(a)O(2) under 5 cmH(2)O was compared with p(a)O(2) under 8 cmH(2)O. A significant difference was set as p<0.025. RESULTS: The PLMA could be placed after 3 attempts in 147 patients. The mean seal pressure was in the range of 24-30 cm H(2)O. Application of randomized PEEP was possible in all patients and ventilation was comparable between corresponding groups. In group N no differences were found in part 1 (139+/-28 vs. 141+/-28 mmHg, p=0.88) or part 2 (127+/-24 vs. 134+/-26 mmHg, p=0.35). In group O there was a significant difference in p(a)O(2) in part 1 (75+/-12 vs. 94+/-18 mmHg, p=0.02) but not in part 2 (92+/-21 vs. 103+/-18 mmHg, p=0.04). CONCLUSIONS: The application of PEEP when PCV is used with the PLMA results in improved oxygenation in obese patients with a BMI >=30 and <36 kg/m(2) but not in normal weight patients. Alveolar recruitment produced by seal pressure measurements below 30 cm H(2)O was sufficient to produce a clinically significant improvement in oxygenation in most obese patients and there was a significant improvement of oxygenation with PEEP=5 cmH(2)O. Both findings are in contrast to findings of studies using an ETT which suggests that higher pressures (40 cmH(2)O) are needed for recruitment of collapsed alveoli and higher PEEP (10 cmH(2)O) is needed to produce a clinically significant improvement in oxygenation in obese patients. The results of this study support data showing that the consequences of bronchopulmonary airway reactions known to occur with an ETT are less pronounced or absent when an LMA is used. PMID- 21796448 TI - The preeminence of growth pattern and invasiveness and the limited influence of BRAF and RAS mutations in the occurrence of papillary thyroid carcinoma lymph node metastases. AB - Prognostic factors indicative of papillary thyroid carcinoma (PTC) aggressive behaviour remain incompletely established partially due to the different composition of the series on record regarding the relative proportion of classic PTC (CPTC) and follicular variant PTC (FVPTC) subtypes. Several clinico morphological features of PTC, together with the occurrence of BRAF mutations, are still not fully accepted as markers of aggressiveness. In the present clinico pathological study of a series of 75 CPTC and FVPTC cases, we evaluated the relative contribution of the morphological features of the tumours and their BRAF and N-RAS status for the occurrence of nodal metastases. The morphological features most closely related to the occurrence of nodal metastases were extra thyroid extension and poorly circumscribed growth pattern, in both CPTC and FVPTC. Additional features significantly associated to nodal metastases were multicentricity in the CPTC and vascular invasion in the FVPTC group. BRAF V600E mutation was detected in 29% of tumours, 41% of CPTC and 16% of FVPTC; N-RAS Q61R mutation was detected in 6% of tumours, 3% of CPTC and 10% of FVPTC. BRAF mutation was significantly more frequent in the CPTC group and in females, and it was detected only in patients older than 20 years, suggesting a late tumourigenic effect in the development of PTC. BRAF mutation was not significantly associated to any of the other studied features related to aggressiveness or nodal metastases. These results highlight the importance of infiltrative growth pattern and invasiveness over the presence of BRAF mutation in classic and follicular variant PTC for the development of nodal metastases. PMID- 21796449 TI - Prevalence of adult paraumbilical hernia. Assessment by high-resolution sonography: a hospital-based study. AB - BACKGROUND: Abdominal wall hernias are a common imaging finding in the abdomen. Ultrasonography (US) is noninvasive and allows the examination of the patient in a physiological manner. High-frequency annular US probes have become an increasingly important diagnostic tool for detecting pathological lesions in superficial organs. OBJECTIVES: To determine the prevalence of paraumbilical hernias among adult patients by abdominal sonography in a tertiary care hospital and to describe the sonographic technique and findings. MATERIALS AND METHODS: During the 2-year period between January 2008 and December 2009, we performed high-resolution US of the anterior abdominal wall on 302 patients who were referred for different reasons other than the examination of the anterior abdominal wall. The images were taken by a radiologist with 12 years of experience in US, and the images were reviewed by three consultant radiologists with expertise in body imaging. RESULTS: A total of 302 patients [169 females (56.0%) and 133 males (44.0%)], ranging in age from 17 to 85 years, with a mean age of 53.5 years, were enrolled in the study. The number of positive cases among females was 42 (24.9%) and that among males was 31 (23.3%). CONCLUSION: High resolution US is an efficient tool for detecting the presence of paraumbilical hernias and accurately verifying not only their content, but also the possible associated complications. PMID- 21796450 TI - Chromatin affinity-precipitation using a small metabolic molecule: its application to analysis of O-acetyl-ADP-ribose. AB - In the cell, many small endogenous metabolic molecules are involved in distinct cellular functions such as modulation of chromatin structure and regulation of gene expression. O-acetyl-ADP-ribose (AAR) is a small metabolic molecule that is generated during NAD-dependent deacetylation by Sir2. Sir2 regulates gene expression, DNA repair, and genome stability. Here, we developed a novel chromatin affinity-precipitation (ChAP) method to detect the chromatin fragments at which small molecules interact with binding partners. We used this method to demonstrate that AAR associated with heterochromatin. Moreover, we applied the ChAP method to whole genome tiling array chips to compare the association of AAR and Sir2. We found that AAR and Sir2 displayed similar genomic binding patterns. Furthermore, we identified 312 potential association cluster regions of AAR. The ChAP assay may therefore be a generally useful strategy to study the small molecule association with chromosomal regions. Our results further suggest that the small metabolic molecule AAR associates with silent chromatin regions in a Sir2-dependent manner and provide additional support for the role of AAR in assembly of silent chromatin. PMID- 21796451 TI - Synaptic integration by different dendritic compartments of hippocampal CA1 and CA2 pyramidal neurons. AB - Pyramidal neurons have a complex dendritic arbor containing tens of thousands of synapses. In order for the somatic/axonal membrane potential to reach action potential threshold, concurrent activation of multiple excitatory synapses is required. Frequently, instead of a simple algebraic summation of synaptic potentials in the soma, different dendritic compartments contribute to the integration of multiple inputs, thus endowing the neuron with a powerful computational ability. Most pyramidal neurons share common functional properties. However, different and sometimes contrasting dendritic integration rules are also observed. In this review, we focus on the dendritic integration of two neighboring pyramidal neurons in the hippocampus: the well-characterized CA1 and the much less understood CA2. The available data reveal that the dendritic integration of these neurons is markedly different even though they are targeted by common inputs at similar locations along their dendrites. This contrasting dendritic integration results in different routing of information flow and generates different corticohippocampal loops. PMID- 21796452 TI - Right side of heart failure. AB - The function of the right ventricle (RV) in heart failure (HF) has been mostly ignored until recently. A 2006 report of the National Heart, Lung, and Blood Institute identified a gap between RV research efforts and its clinical importance compared with that of the left ventricle. This recent shift in paradigm is fueled by the prognostic value ascribed to RV failure in HF and morbidity/mortality after myocardial infarction and surgery. In this review, we examine the significance of RV failure in the HF setting, its clinical presentation and pathophysiology, and ways to evaluate RV function using echocardiographic measurements. Furthermore, we discuss the medical management of RV failure including traditional therapies like beta-blockers and newer options like nitric oxide, phosphodiesterase inhibitors, and calcium sensitizers. Mechanical support is also examined. Finally, this review places an emphasis on RV failure in the setting of left ventricular assist devices and heart transplantation. PMID- 21796453 TI - Cardiac resynchronization therapy is certainly cardiac therapy, but how much resynchronization and how much atrioventricular delay optimization? AB - Cardiac resynchronization therapy has become a standard therapy for patients who are refractory to optimal medical therapy and fulfill the criteria of QRS >120 ms, ejection fraction <35% and NYHA class II, III or IV. Unless there is some other heretofore unrecognized effect of pacing, the benefits of atrio biventricular pacing on hard outcomes observed in randomized trials can only be attributed to the physiological changes it induces such as increases in cardiac output and/or reduction in myocardial oxygen consumption leading to an improvement in cardiac function efficiency. The term "Cardiac Resynchronization Therapy" for biventricular pacing presupposes that restoration of synchrony (simultaneity of timing) between left and right ventricles and/or between walls of the left ventricle is the mechanism of benefit. But could a substantial proportion of these benefits arise not from ventricular resynchronization but from favorable shortening of AV delay ("AV optimization") which cannot be termed "resynchronization" unless the meaning of the word is stretched to cover any change in timing, thus, rendering the word almost meaningless. Here, we examine the evidence on the relative balance of resynchronization and AV delay shortening as contributors to the undoubted clinical efficacy of CRT. PMID- 21796454 TI - Preoperative radiotherapy combined with capecitabine chemotherapy in Chinese patients with locally advanced rectal cancer. AB - BACKGROUND: This phase II study is performed to evaluate the efficacy and safety of capecitabine combined with preoperative radiotherapy (RT) in Chinese patients with locally advanced rectal cancer (LARC). METHODS: Between February 2007 and December 2008, 62 patients with LARC were treated with capecitabine (825 mg/m(2), twice daily) and concurrent RT (50.4 Gy/28 fractions). Patients underwent surgery after 6-8 weeks of combined therapy, followed by 4 cycles of adjuvant capecitabine (1,250 mg/m(2), twice daily on days 1-14, every 3 weeks). The primary endpoint was the rate of pathologic complete response (pCR). RESULTS: Fifty-eight patients (93.5%) completed the preoperative chemoradiation course as initially planned. The most severe hematologic adverse event was leucopenia, which occurred with grade 2 intensity in 12 (19.7%) patients and grade 3 in 2 (3.3%) patients. Grade 3 diarrhea and hand-foot syndrome (HFS) were observed in one (1.6%) and two (3.3%) patients, respectively. However, no grade 4 toxicity was observed. There were no treatment-related deaths during this study. Of the 59 patients treated with surgery, all had radial margins (R0 resections). Among the 29 patients with the primary tumor <=5 cm from the anal verge, 18 (62.1%) underwent sphincter-preserving surgical resections. pCR was found in eight patients (13.6%). The pathologic stage was lower than the initial clinical stage in 57.6% (34/59), 63.4% (26/41), and 81.4% (48/59) of the resected tumors for the primary tumor (T), lymph node (N), and combined TN categories, respectively. The estimate of disease-free survival and overall survival at 24 months were 80.6% (95% CI, 70.8-90.4%) and 92.5% (95% CI, 85.9-99.1%), respectively. CONCLUSION: Preoperative chemoradiotherapy with capecitabine and RT appears to be a safe, well-tolerated, and effective neoadjuvant treatment modality for LARC. PMID- 21796455 TI - Gastric volvulus associated with a wandering liver: a case report and review of the literature. PMID- 21796456 TI - Silencing of the HCCR2 gene induces apoptosis and suppresses the aggressive phenotype of hepatocellular carcinoma cells in culture. AB - BACKGROUND: The human cervical cancer oncogene HCCR-2 is overexpressed in various malignant tumors and cell lines, and might function as a negative regulator of the p53 tumor suppressor. Here, we used RNA interference strategies to evaluate the role of HCCR-2 in liver cancer, and to explore its potential therapeutic effect. METHODS: Changes of HepG2 cells stably transfected by an HCCR-2 RNA interference vector were detected by real-time PCR, MTT staining, plate colony formation, flow cytometry, and cell migration experiments. Apoptosis-related protein Bcl-2 and Bax levels were measured by Western blot. RESULTS: Our results showed that of the three siRNA-expressing vectors, siRNA-H3 had a suppressive effect on the expression of HCCR-2 mRNA, interfering with proliferation and migration of HCCR-2. Moreover, the apoptotic rate also increased, and cells transfected by siRNA-H3 were blocked in the G0/G1 stage. Plate colony formation experiments demonstrated that the single cell clone formation capacity of HepG2 H3 cells was clearly lower than that of HepG2 and HepG2-N cells. Western blot results indicated that the expression of Bcl-2 was inhibited, and the expression of Bax was increased. CONCLUSIONS: In summary, RNAi targeting HCCR-2 could be an effective means for suppressing malignant features of hepatocellular carcinoma cells. PMID- 21796457 TI - Intravital three-dimensional dynamic pathology of experimental colitis in living mice using two-photon laser scanning microscopy. AB - BACKGROUND: Intravital three-dimensional (3D) visualization of treatment efficacy in experimental colitis in living mice using two-photon laser scanning microscopy (TPLSM) has not been described. METHODS: Colitis was induced with dextran sulfate sodium (DSS) in green fluorescent protein (GFP) transgenic mice. The 3D tomographic image of DSS-induced colitis with or without prednisolone was obtained intravitally using TPLSM. A serosal-approaching method was developed, by which we could observe all layers of the cecum from serosa to luminal mucosa without opening and everting the cecum. The dynamic pathology and treatment efficacy were assessed in the same mouse on several occasions. RESULTS: The time lapse 3D tomographic movie of DSS-induced colitis was obtained in living mice at a magnification of greater than *600, which demonstrated irregularity of crypts, disappearance of crypts, inflammatory cell infiltrates in the lamina propria, and abscess formation at the bottom of crypts. Intravital TPLSM in the same mice demonstrated fewer infiltrating leukocytes and crypt abscesses on day 14 in the steroid group compared with the nonsteroid group. CONCLUSIONS: Intravital 3D tomographic visualization of experimental colitis using TPLSM in combination with the serosal-approaching method can provide dynamic pathology at a high magnification, which may be useful in evaluating treatment efficacy in the same living mice. PMID- 21796458 TI - Utilization and morbidity associated with placement of a feeding jejunostomy at the time of gastroesophageal resection. AB - BACKGROUND: The purpose of the study was to evaluate the utilization and morbidity associated with feeding jejunostomy tubes (JT) placed at the time of gastroesophageal resection (GER). METHODS: Under institutional review board approval, a prospective database of patients undergoing GER from January 2004 to September 2010 was reviewed. Data analyzed included patient demographics, postoperative complications, JT use, and JT specific complications. Fisher's exact tests explored associations with utilization of a JT following resection. RESULTS: Seventy-three patients (51 men, 22 women, median age of 59) underwent placement of a JT at the time of GER (total gastrectomy = 28, Ivor-Lewis = 28, subtotal gastrectomy = 8, proximal gastrectomy = 6, and transhiatal esophagectomy = 3) of both malignant (97%) and benign (3%) disease processes. Twenty-one JT specific complications (11 minor and 10 major) were identified. Reoperation was required in the management of two complications (small bowel obstructions), while all other complications were easily managed by an interventional radiologist (n = 8), bedside procedure (n = 5), or did not require intervention (n = 6). Eighty-six percent of patients were discharged tolerating a postgastrectomy diet, 10% nothing per orem, and 4% a liquid diet. Inpatient enteral nutrition (EN) was initiated in 68%, but continued on discharge in only 54% secondary to failure to thrive (54%), dysphagia (21%), anastomic leak (15%), chyle leak (3%), esophagostomy (3%), and duodenal stump leak (3%). The mean time to discontinuance of EN and removal of the JT was 44 days (range, 4-203) and 71 days (range, 15-337) respectively. Although only 13% (n = 5) of patients requiring adjuvant therapy were utilizing their JT at the commencement of therapy, 75% (n = 21) required EN during its course. The median time to adjuvant therapy was found to be slightly longer in those who required outpatient EN versus those who did not (61 vs. 90 days, p = 0.08). However, the median time to adjuvant therapy did not differ between those who were and were not receiving EN at the time of adjuvant therapy commencement (80 vs. 92 days, p = 0.2). Age (p = 0.4), number of co-morbidities (p = 0.2), preoperative percent body weight loss (p = 0.9), and clinical stage (p = 0.8) were not significantly associated with outpatient JT use. Patients who suffered a postoperative complication were most likely to require EN (p = 0.002), an association that strengthened as the number of complications increased (p = 0.0008). Although not statistically significant, a trend towards increased outpatient EN was noted in patients who underwent transhiatal esophagectomy and total gastrectomy (p = 0.06). CONCLUSIONS: JT placement carries a considerable morbidity in patients undergoing GER. However, because it is difficult to preoperatively ascertain who will need prolonged EN, the routine placement of a JT is recommended, particularly in those who will likely require adjuvant therapy or are at high risk for postoperative complications. Despite patient desires for early removal of an unused JT, caution should be taken if adjuvant therapy is being considered. PMID- 21796459 TI - Single-incision laparoscopic colorectal surgery, experience with 50 consecutive cases. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) is one of the most recent developments in laparoscopic surgery. Having proven its effectiveness in cholecystectomy and appendectomy, the feasibility of SILS in more advanced surgery, such as hemicolectomy and low anterior resection, is now a point of discussion. METHODS: This study reports on the results of the first 50 SILS colorectal operations at our institution. Twenty right hemicolectomies, 16 sigmoid resections, 9 low anterior resections, and 5 total colectomies were performed. Nineteen patients were operated for benign colonic diseases, 31 for malignant disease. RESULTS: Mean operative time was 130 min, and the median duration of postoperative hospital stay was 6 days. None of the procedures needed conversion to a laparotomy, but four patients were converted to a multiport laparoscopy. In one case, an anastomotic leakage occurred, which was treated by creating a diverting ileostomy laparoscopically. Minor complications were four wound infections and two incisional hernias. CONCLUSION: SILS colectomy is a safe and feasible procedure even in more complex cases. Comparative studies are needed to demonstrate advantages over traditional laparoscopic surgery. PMID- 21796460 TI - Predictable factors for lymph node metastasis in early gastric cancer-analysis of single institutional experience. AB - INTRODUCTION: Prediction of lymph node metastasis in early gastric cancer (EGC) is very important to decide treatment strategies preoperatively. The aim of this study was to evaluate factors that predict the presence of lymph node metastasis and to identify the differences between mucosal and submucosal gastric cancers. METHODS: A total of 376 patients with EGC who underwent gastrectomy from March 1999 through December 2007 were retrospectively identified. The clinopathological factors and biological markers (p53, Ki67) were analyzed. RESULTS: The rate of lymph node metastasis was 9.6% (mucosal cancer 2.8%, submucosal cancer 18.4%). Tumor size, depth of invasion, macroscopic type, and lymphovascular invasion were related to lymph node metastasis in EGC. When the carcinomas were confined to the mucosal layer, tumor size and lymphovascular invasion showed significant correlation with lymph node metastasis. On the other side, macroscopic type and lymphovascular invasion were association with lymph node metastasis in submucosal carcinoma. CONCLUSION: The risk factors for lymph node metastasis in EGC are quite different depending on depth of tumor invasion. To predict lymph node metastasis in EGC, it is recommended that distinct assessment according to individual situation should be clearly established. PMID- 21796461 TI - Magnetic resonance enterography for Crohn's disease: what the surgeon can take home. AB - BACKGROUND: Crohn's disease (CD) is a life-long, chronic, relapsing condition requiring often morphological assessment. MR enterography (MRE) offers advantages of not using ionizing radiation and yielding intraluminal and intra-abdominal informations. The aim of our study was to identify how MRE can be useful in planning surgical procedures. PATIENTS AND METHODS: In this retrospective study, 35 patients who underwent MRE and then surgery for CD were enrolled from 2006 to 2010. MRE findings were compared to intraoperative findings. Histology of operative specimens, systemic inflammatory parameters, and fecal lactoferrin were also evaluated. Cohen's kappa agreement test, sensitivity and sensibility, uni /multivariate logistic regression, and non-parametric statistics were performed. RESULTS: MRE identified bowel stenosis with a sensitivity of 0.95 (95% CI 0.76 0.99) and a specificity of 0.72 (95% CI 0.39-0.92). The concordance of MRE findings with intraoperative findings was high [Cohen's kappa = 0.72 (0.16)]. Abscesses were detected at MRE with a sensitivity of 0.92 (95% CI 0.62-0.99) and a specificity of 0.90 (95% CI 0.69-0.98) with a Cohen's kappa = 0.82 (0.16). The grade of proximal bowel dilatation resulted to be a significant predictor of the possibility of using strictureplasty instead of/associated to bowel resection either at univariate or at multivariate analysis. CONCLUSION: Our study confirmed that MRE findings correlate significantly with disease activity. Detailed information about abscess could suggest percutaneous drainage that could ease the following surgery or avoid emergency laparotomy. Proximal bowel dilatation can suggest the possibility to perform bowel sparing surgery such as strictureplasty. PMID- 21796462 TI - Caroli's disease: report of surgical options and long-term outcome of patients treated in Argentina. Multicenter study. AB - BACKGROUND: Caroli's disease (CD) management is still controversial. AIM: The purpose of this study is to report the most frequent clinical features, treatment options, and outcome obtained after surgical management of CD. METHODS: A voluntary survey was conducted. Demographic, clinical, surgical, and pathological variables were analyzed. RESULTS: Six centers included 24 patients having received surgical treatment from 1991 to 2009. Seventeen (70.8%) patients were female, with average age of 48.7 years old (20-71), and 95.5% were symptomatic. There was left hemiliver involvement in 75% of the patients. Surgical procedures included nine left lateral sectionectomies, eight left hepatectomies, and four right hepatectomies for those with hemiliver disease, while for patients with bilateral disease, one right hepatectomy and two Roux-en-Y hepaticojejunostomies were performed. The average length of hospitalization was 7 days. For perioperative complications (25%), three patients presented minor complications (types 1-2), while major complications occurred in three patients (type 3a). No mortality was reported. After a median follow-up of 166 months, all patients are alive and free of symptoms. CD diagnosis was confirmed by histology. Congenital hepatic fibrosis was present in two patients (8.3%) and cholangiocarcinoma in one (4.2%). CONCLUSIONS: CD in Argentina is more common in females with left hemiliver involvement. Surgical resection is the best curative option in unilateral disease, providing long-term survival free of symptoms and complications. In selected cases of bilateral disease without parenchymal involvement, hepaticojejunostomy should be proposed. However, a close follow-up is mandatory because patients might progress and a transplant should be indicated. PMID- 21796463 TI - Small bowel perforation by a clinically unsuspected fish bone: laparoscopic treatment and review of literature. PMID- 21796464 TI - What are the complex operations and why? AB - INTRODUCTION: Surgeons are often judged by their ability to perform complex surgical procedures. DISCUSSION: Data show the number of these procedures as defined by the number of procedures performed during surgical training may be significantly more common than would be expected by their program directors. PMID- 21796465 TI - Excellence in imaging-ASNC's strategic pathway. PMID- 21796466 TI - Disease model discovery and translation. Introduction. PMID- 21796467 TI - Laparoscope-assisted creation of a neovagina using pedicled ileum segment transfer. AB - BACKGROUND: To present our experience of vaginal reconstruction with the use of a pedicled ileum segment and laparoscope assistance, and to analyze its complications and long-term anatomic and functional results. METHODS: The abdominal and perineal approaches were performed simultaneously with the patient in a special position. Under the guidance of laparoscopy, the target ileal segment was harvested and transposed down to the perineum through an artificial tunnel between the bladder and the rectum. A silicon vaginal tutor was introduced into the vaginal cavity and maintained all day long for 2-3 months. The complications and the anatomical and functional results were summarized and analyzed. RESULTS: From February 2002 to June 2010, 82 patients underwent laparoscope-assisted total vaginal reconstruction with a pedicled ileum segment at our department. Complications developed in 16 of 82 patients, including rectum and/or bladder injury during operation, acute renal failure, delayed healing of the ileocutaneous anastomosis, introital stenosis, and partial or complete intestinal obstruction. The abdominal cutaneous scar was acceptable after the surgery. The vulva was not altered, which was especially significant for patients with congenital vaginal atresia. The neovagina was patent, soft, moist, and flexible. The mean width and depth of the neovagina at the latest postoperative visit measured 3.2 and 15 cm, respectively. CONCLUSIONS: The favorable long-term anatomical and functional results demonstrate that our technique is ideal for patients with congenital vaginal atresia or patients who need secondary vaginal reconstruction. For the primary male-to-female transsexuals or hermaphrodites, it can be an alternative method for vaginal construction. PMID- 21796468 TI - Sexual problems in the gynecology clinic: are we making a mountain out of a molehill? AB - INTRODUCTION AND HYPOTHESIS: This study aims to assess the prevalence of sexual problems in general gynecology and urogynecology clinics using a simple screening tool and to compare the prevalence between patients presenting with gynecology or urogynecology complaints. METHODS: Patients attending (uro)gynecology clinics completed three screening questions for sexual problems to be assessed. A fourth question was later introduced to address sexual problems which bother them. Student's t-test, chi-square test, and logistic regression were used. RESULTS: Of 1,194 women, 37% had a sexual complaint. Seventeen percent volunteered this information as part of their main complaint, while the remaining only admitted it on questioning. The last 290 questionnaires included the question on "bother." Of these, 37% had a sexual complaint and only 45% found them bothersome. Multivariate analysis showed that urogynecology complaints were significantly associated with sexual complaints. CONCLUSIONS: As most women only volunteer symptoms when asked directly, clinicians should be vigilant in identifying sexual problems but always establish the question of bother to avoid over-diagnosis. PMID- 21796469 TI - Determining outcomes, adverse events, and predictors of success after sacral neuromodulation for lower urinary disorders in women. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to determine the predictors of successful treatment of lower urinary tract disorders with sacral nerve stimulation (SNS) and the rate of adverse events and reoperations. METHODS: A retrospective case series of patients who underwent SNS at a single institution was analyzed. RESULTS: Seventy-six patients underwent stage I trial of SNS. Fifty eight (76%) patients experienced improvement and underwent placement of an implantable pulse generator with a mean follow-up of 23.7 months (SD +/- 22.3). Surgical revisions occurred in 14/58 (24%) patients and 15/58 (26%) patients had the device explanted after a mean of 2.8 years (SD +/- 1.7). Patients with greater than ten incontinence episodes per day were more likely to have a successful stage I trial compared to those with less than five (OR = 10.3; 95% CI 2.1 to 50.60). CONCLUSIONS: Although SNS is a safe and effective therapy for lower urinary tract disorders, it is associated with a high reoperation rate. PMID- 21796471 TI - The Portuguese validation of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). AB - INTRODUCTION AND HYPOTHESIS: Sexual well-being is an important aspect of women's life. The objective of this study was to validate the Portuguese-translated version of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire--PISQ-12. METHODS: Sixty-four women were enrolled to participate in the process of validating the PISQ-12 (study group). A further 68 subjects were allocated to a control group for comparison between the group of women with pelvic organ prolapse/urinary incontinence and the asymptomatic group. RESULTS: The PISQ-12 presented good internal consistency (Cronbach's alpha of 0.79 for the study group and 0.80 for the control group). The test-retest reliability using the intraclass correlation coefficient was 0.77. Mean score on the PISQ-12 was significantly higher in the control group than in the study group (42.7 +/- 3.9 vs 27.8 +/- 9.3) CONCLUSIONS: The Portuguese version of the PISQ-12 was reliable for the assessment of sexual function in women with pelvic organ prolapse/urinary incontinence. PMID- 21796470 TI - Prevalence of "low-count" bacteriuria in female urinary incontinence versus continent female controls: a cross-sectional study. AB - INTRODUCTION AND HYPOTHESIS: Older studies suggesting an association between detrusor overactivity and bacteriuria used an outdated microbiological threshold. We hypothesised that bacteriuria >=10(3) CFU/ml would be more prevalent in women with urinary incontinence than continent controls. METHODS: A prospective, cross sectional study of prevalence of bacteriuria >=10(3) colony-forming units (CFU)/ml on catheter specimens. Sample estimates suggested 62 women per arm would yield 80% power. Multivariate regression analysis was performed using risk factors including, age, diabetes, menopausal status, sexual activity and cystocele. RESULTS: Among 213 participants, bacteriuria >=10(3) CFU/ml was more prevalent in incontinent women than continent controls (odds ratio [OR] 4.06; p = 0.036). Two thirds of bacteriuric specimens grew "low-count" bacteriuria. On multivariate analysis, only cystocele >= grade II was independently associated with bacteriuria (p = 0.025). On sub-analysis by diagnosis, the only significant finding was with bladder oversensitivity (OR 13.8; p = 0.0017). CONCLUSIONS: Bacteriuria, including "low-count" bacteriuria, is more prevalent in urinary incontinence when compared to continent female controls. PMID- 21796473 TI - My mentors in urogynecology. PMID- 21796472 TI - Urinary incontinence self-report questions: reproducibility and agreement with bladder diary. AB - INTRODUCTION AND HYPOTHESIS: This study aims to measure self-report urinary incontinence questions' reproducibility and agreement with bladder diary. METHODS: Data were analyzed from the Reproductive Risk of Incontinence Study at Kaiser. Participating women reporting at least weekly incontinence completed self report incontinence questions and a 7-day bladder diary. Self-report question reproducibility was assessed and agreement between self-reported and diary recorded voiding and incontinence frequency was measured. Test characteristics and area under the curve were calculated for self-reported incontinence types using diary as the gold standard. RESULTS: Five hundred ninety-one women were included and 425 completed a diary. The self-report questions had moderate reproducibility and self-reported and diary-recorded incontinence and voiding frequencies had moderate to good agreement. Self-reported incontinence types identified stress and urgency incontinence more accurately than mixed incontinence. CONCLUSIONS: Self-report incontinence questions have moderate reproducibility and agreement with diary, and considering their minimal burden, are acceptable research tools in epidemiologic studies. PMID- 21796474 TI - Mentors in urogynecology. PMID- 21796475 TI - Polyethylene quality affects revision knee liner exchange survivorship. AB - BACKGROUND: Options to treat patients with wear or osteolysis include full revision, partial (tibial or femoral) revision, and isolated polyethylene exchange. It is unclear whether one choice is superior to the other. Polyethylene quality reportedly influences the survivorship of primary TKA, but similar reports are not described for revision TKA. QUESTIONS/PURPOSES: We compared the failure rate for the three procedures and the influence of polyethylene quality on failure. PATIENTS AND METHODS: We retrospectively evaluated 123 patients with 135 TKAs in which wear or osteolysis was thought to have contributed to the need for surgery. Twenty-five percent had an isolated polyethylene exchange, 39% a single-component revision, and 36% a full revision. We determined survivorship of the revisions. The mean follow-up for the 123 patients was 6.2 years. Fifteen patients (16 knees, or 12%) were lost before 5-year evaluations leaving 108 patients (119 knees, or 88%) for comparison of rerevision rates. RESULTS: Five year survivorship was similar for all three procedures: 82% +/- 14% for polyethylene exchange, 89% +/- 8% for partial revision, and 88% +/- 10% for a full revision. Polyethylene sterilization had the strongest influence on rerevision. Survivorship was 73% +/- 16% for knees revised with gamma-in-air polyethylene compared to 92% +/- 6% for nongamma or gamma-in-barrier sterilization methods. CONCLUSIONS: The survival rates of isolated polyethylene exchange for wear or osteolysis are similar to those of a single-component or full revision when the components are well aligned and well fixed. Polyethylene sterilization influenced revision TKA survivorship in this study and should be reported in future studies. PMID- 21796476 TI - Surgical technique: Transfer of the anterior portion of the gluteus maximus muscle for abductor deficiency of the hip. AB - BACKGROUND: Loss of the abductor portions of the gluteus medius and gluteus minimus muscles due to THA causes severe limp and often instability. DESCRIPTION OF TECHNIQUE: To minimize the symptoms of limp and instability, the anterior 1/2 of the gluteus maximus was transferred to the greater trochanter and sutured under the vastus lateralis. A separate posterior flap was transferred under the primary flap to substitute for the gluteus minimus and capsule. To ensure tight repair, the flaps were attached and tensioned in abduction. PATIENTS AND METHODS: The technique was performed in 11 patients (11 hips) with complete loss of abductor attachment; the procedure was performed in nine patients during THA and in two later as a secondary procedure. Preoperatively, all patients had abductor lurch, positive Trendelenburg sign, and no abduction of the hip against gravity. Minimum followup was 16 months (mean, 33 months; range, 16-42 months). RESULTS: Postoperatively, nine patients had strong abduction of the hip against gravity, no abductor lurch, and negative Trendelenburg sign. One patient had weak abduction against gravity, negative Trendelenburg sign, and slight abductor lurch. One patient failed to achieve strong abduction, had severe limp after 6 months of protection and physical therapy, and was lost to followup. CONCLUSIONS: Gluteus maximus transfer can restore abductor function in THA with a high success rate. PMID- 21796477 TI - Age and obesity are risk factors for adverse events after total hip arthroplasty. AB - BACKGROUND: Defining the epidemiology of adverse events after THA will aid in the development of strategies to enhance perioperative care. QUESTIONS/PURPOSES: We identified (1) risk factors for adverse events in Medicare beneficiaries while hospitalized after THA and (2) trends in the rates of adverse events. PATIENTS AND METHODS: Data were abstracted from medical records of 1809 Medicare beneficiaries who underwent THA from 2002 to 2007. We used the hierarchical generalized linear modeling approach to assess the odds of change in adverse events over time, the association of adverse events with outcomes, and the relationship of adverse events with patient characteristics by modeling the log odds of adverse events as a function of demographic and clinical variables adjusted for year variable. RESULTS: The overall rate of adverse events was 5.8%; the 30-day mortality rate was 1.00%. Increased age, obesity, and year of procedure were risk factors for experiencing any adverse event. Annual rates of adverse events from 2002 to 2007 were 9.1%, 8.2%, 4.9%, 4.1%, 3.5%, and 3.0%, respectively. Experiencing any adverse event was associated with an increased length of stay and an increased chance of readmission but not with an increased chance of mortality. The annual rate of all adverse events decreased from 2002 2004 to 2005-2007 (odds ratio = 0.83; 95% confidence interval, 0.74-0.92). CONCLUSIONS: Older and obese patients should be counseled regarding their increased risk for the development of adverse events after THA. The cause of the decline in the rate of adverse events between two time periods is unclear and warrants further investigation to confirm and identify the cause. PMID- 21796479 TI - Coexistence of non-alcoholic fatty liver disease with elevated alanine aminotransferase is associated with insulin resistance in young Han males. AB - Elevated alanine aminotransferase (ALT) and non-alcoholic fatty liver disease (NAFLD) have been associated with insulin resistance (IR). The objective of this study was to determine whether elevated ALT and NAFLD were useful for early and definitive determination of IR and to compare their coexistence with conventional risk factors in young Han males. Anthropometric and metabolic measurements were assessed in 216 young Han males (19.3 +/- 0.8 years). NAFLD was diagnosed using ultrasonography, and the homeostasis model assessment of insulin resistance (HOMA IR) served as an index of IR. Subjects in the fourth HOMA-IR quartile had a significantly higher frequency of abdominal obesity, elevated blood pressure and ALT, and NAFLD compared to subjects in quartiles 1-3 (P < 0.05). Using multivariate logistic regression analysis, risk of IR increased by 2.33-fold (95% CI: 1.00-5.42, P = 0.050) in participants with NAFLD. In addition, the coexistence of NAFLD and elevated ALT were significantly associated with HOMA-IR and participants with both elevated ALT and NAFLD had a 4.65-fold (95% CI: 1.55 13.97, P = 0.006) increased risk of IR. Coexistence of NAFLD and elevated ALT are associated with IR in young Han males and might be useful for early detection of IR as compared to conventional risk factors. PMID- 21796478 TI - Identification of miRNAs and their target genes using deep sequencing and degradome analysis in trifoliate orange [Poncirus trifoliata L. Raf] [corrected]. AB - To identify novel as well as conserved miRNAs in citrus, deep sequencing of small RNA library combined with microarray was performed in precocious trifoliate orange (an early flowering mutant of trifoliate orange, Poncirus trifoliata L. Raf.), resulting in the obtainment of a total of 114 conserved miRNAs belonging to 38 families and 155 novel miRNAs. The miRNA star sequences of 39 conserved miRNAs and 27 novel miRNAs were also discovered among newly identified miRNAs, providing additional evidence for the existence of miRNAs. Through degradome sequencing, 172 and 149 genes were identified as targets of conserved miRNAs and novel miRNAs, respectively. GO and KEGG annotation revealed that high ranked miRNA-target genes were those implicated in biological and metabolic processes. To characterize those miRNAs expressed at the juvenile and adult development stages of citrus, further analysis on the expression profiles of these miRNAs through hybridizing the commercial microarray and real-time PCR was performed. The results revealed that some miRNAs were down-regulated at adult stage compared with juvenile stage. Detailed comparison of the expression patterns of some miRNAs and corresponding target genes revealed the negative correlation between them, while few of them are positively correlated. PMID- 21796480 TI - The EIIAPA chimeric promoter for tumor specific gene therapy of hepatoma. AB - PURPOSE: For targeted imaging and therapy of hepatocellular carcinoma (HCC), we established a chimeric promoter (EIIAPA) containing alpha-fetoprotein (AFP) promoter and hepatitis B virus enhancer II (EIIA) to control downstream expression of reporter and therapeutic genes. PROCEDURES: We combined AFP promoter and EIIA to establish a chimeric EIIAPA promoter, then developed a bi cistronic plasmid vector containing HSV1-tk and luciferase genes controlled by EIIAPA to stably transfect HCC cells. The selective transcriptional activity of EIIAPA was assayed by bioluminescence imaging (BLI) and the function of EIIAPA was determined by in vivo microPET and BLI. RESULTS: The luciferase expression driven by EIIAPA was higher than that driven by AFP promoter in HCC cell lines. EIIAPA-tk induced cytotoxicity was observed only in HepG2 cells. Accumulation of 131I-FIAU and bioluminescent signal were detected on HepG2 tumors but not in parental tumors. The HepG2 tumors derived from lentiviral-transduced EIIAPA-tk expressing cells accumulated 124I-FIAU whereas the ARO tumors did not. The transfected HepG2 tumors expressed adequate EIIAPA-controlled HSV1-TK and the tumor regressed after ganciclovir treatment. CONCLUSION: The chimeric EIIAPA is a potential candidate promoter for targeted imaging and gene therapy of HCC. PMID- 21796481 TI - Quantitative assessment of urethral vascularity in nulliparous females using high frequency endovaginal ultrasonography. AB - PURPOSE: To assess the vascular parameters in the urethra of nulliparous females and to compare the vascularity among various parts of the urethra, using high frequency endovaginal ultrasonography (EVUS). METHODS: Twenty-two nulliparous women, mean age 27 years, underwent EVUS using a biplane transducer at 12 MHz frequency. Color Doppler examinations of the urethra were recorded and further evaluated off-line using special software (Pixel Flux) for quantitative assessment of the vascularity. The urethra was divided into four regions of interest (ROIs) in the midsagittal plane and three ROIs in the axial plane. The following parameters were measured: velocity (V), perfused area (A), perfusion intensity (I), pulsatility index (PI), and resistance index (RI). Interobserver and intraobserver reproducibility analysis was also performed. RESULTS: In midsagittal plane, the midurethra presented the highest value of V and lowest value of A. The intramural part showed the lowest value of I and the highest values of RI and PI. In the distal urethra, the highest value of I and the lowest value of RI was seen. In the axial plane, the values of V, A, and I were statistically significantly higher in the external part of the midurethra compared with the internal part. Excellent interobserver and intraobserver reproducibility was shown in the majority of parameters for the entire urethra. CONCLUSIONS: Vascularity differs in different parts of the urethra. Pixel Flux is a valuable tool for providing reproducible quantitative analysis of vascular parameters for the entire urethra. PMID- 21796482 TI - Brain mitochondrial drug delivery: influence of drug physicochemical properties. AB - PURPOSE: To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH. METHODS: The delivery of 8 cationic drugs (beta-blockers), 6 neutral drugs (corticosteroids), and 6 anionic drugs (non-steroidal anti-inflammatory drugs, NSAIDs) to isolated rat brain mitochondria was determined with and without membrane depolarization. Multiple linear regression was used to determine whether lipophilicity (Log D), charge, polarizability, polar surface area (PSA), and molecular weight influence mitochondrial delivery. RESULTS: The Log D for beta-blockers, corticosteroids, and NSAIDs was in the range of -1.41 to 1.37, 0.72 to 2.97, and -0.98 to 2, respectively. The % mitochondrial uptake increased exponentially with an increase in Log D for each class of drugs, with the uptake at a given lipophilicity obeying the rank order cationic>anionic>neutral. Valinomycin reduced membrane potential and the delivery of positively charged propranolol and betaxolol. The best equation for the combined data set was Log % Uptake = 0.333 Log D + 0.157 Charge - 0.887 Log PSA + 2.032 (R(2) = 0.738). CONCLUSIONS: Drug lipopohilicity, charge, and polar surface area and membrane potential influence mitochondrial drug delivery, with the uptake of positively charged, lipophilic molecules being the most efficient. PMID- 21796483 TI - A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). AB - PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer. METHODS: Docetaxel (40 mg/m(2)) and cisplatin (70 or 60 mg/m(2)) were given on day 1 of a 28-day cycle. S-1 (40 mg/m(2)) was given twice daily on days 1-14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1. RESULTS: Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1-25). Because some patients had serious myelosuppression and renal dysfunction with 70 mg/m(2) of cisplatin, dose of cisplatin was reduced to 60 mg/m(2) after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71-91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6-21.5) and 8.7 (95% CI, 6.7-10.7) months, respectively. CONCLUSIONS: Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60 mg/m(2) of cisplatin is as effective as 70 mg/m(2) of cisplatin. PMID- 21796484 TI - Predictors of hooking up sexual behaviors and emotional reactions among U.S. college students. AB - The present study examined factors associated with engaging in oral and vaginal sex and condom use during the most recent hookup, a term that refers to a range of physically intimate behaviors outside of a committed relationship, among college students. In addition, this research aimed to evaluate factors associated with experiencing positive and negative affect resulting from the most recent hookup. A random sample (N = 1,468) of undergraduates (56.4% female) completed a Web-based survey that was comprised of measures of drinking and sexual behavior. Participants (n = 824; 56.1%) who indicated they had ever hooked up were included in data analysis. Findings indicated that sex, partner type, alcohol use, attitudes towards hooking up, and attitudes towards sexual activity during hookups explained significant variance for oral sex, vaginal sex, condom use, and positive and negative affect related to the most recent hookup experience. Clinical implications regarding the role of situational stressors, such as the impact on affect following a hookup, and ways to reduce risks associated with stressors are discussed. PMID- 21796485 TI - Non-erotic cognitive distractions during sexual activity in sexual minority and heterosexual young adults. AB - The present study examined 100 lesbian and gay college students and 100 heterosexual students to determine whether group differences exist in frequency of a range of non-erotic cognitive distractions during sexual activity. Non erotic cognitive distraction is a descriptive term for both self-evaluative cognitions related to physical performance and body image concerns, as well as additional cognitive distractions (e.g., contracting an STI or emotional concerns) during sexual activity. Participants were matched on gender (96 males and 104 females), age, and ethnicity, and completed questionnaires assessing frequency of non-erotic cognitive distractions during sexual activity, as well as measures of additional variables (trait and body image anxiety, attitudes toward sexual minorities, self-esteem, and religiosity). Results indicated that sexual minorities experienced significantly more cognitive distractions related to body image, physical performance, and STIs during sexual activity than heterosexuals. Regarding gender, men reported more distractions related to STIs than women. Interaction effects were observed between sexual orientation and gender for body image-, disease-, and external/emotional-based distractions. Implications of these findings are discussed. PMID- 21796486 TI - Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets. AB - AIMS/HYPOTHESIS: Chronic hyperglycaemia promotes the progressive failure of pancreatic beta cells in patients with type 2 diabetes mellitus, a clinically highly relevant phenomenon known as glucotoxicity. The intracellular metabolic consequences of a chronically high availability of glucose in beta cells are, as yet, poorly understood in its full complexity. METHODS: An unbiased metabolite profiling analysis (GC-time-of-flight-MS) was used to identify the time course of core metabolite patterns in rat beta cell line INS-1E during exposure to high glucose concentrations and its relation to insulin expression. RESULTS: We report here that pentose phosphate pathway (PPP) metabolites accumulate remarkably during chronic but not acute glucose treatment, indicating altered processing of glucose through the pentose phosphate pathway. Subsequent functional studies in INS-1E cells and human islets revealed that a disturbance in this pathway contributes to decreases in insulin gene expression and a lack of glucose stimulated insulin secretion. These effects were found to depend on the activation of extracellular-regulated-kinase (ERK1/2). Long-term inhibition of 6 phosphogluconic acid dehydrogenase resulted in accumulation of PPP metabolites, induced ERK1/2 activation independently of high glucose and impaired beta cell function. In turn, inhibition of ERK1/2 overstimulation during chronic glucose exposure partly inhibited metabolite accumulation and restored beta cell function. CONCLUSIONS/INTERPRETATION: Based on unbiased metabolite analyses, the data presented here provide novel targets, namely the inhibition of PPP metabolite accumulation towards the therapeutic goal to preserve and potentially improve beta cell function in diabetes. PMID- 21796487 TI - The role of sho1 in polarized growth of Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic pathogen that may cause severe invasive disease in immunocompromised patients. The filamentous fungi undergo polarized growth, searching for nutrients in the environment and causing invasive growth in tissue. Sho1 is a sensor of the high osmolarity glycerol pathway, and the sho1 mutant showed a decrease in growth rate. We found that sho1 is involved in the polarized growth of A. fumigatus. The sho1 mutation resulted in extended isotropic growth of germinating conidia followed by multiple germ tubes and wide hyphae with short intercalary cells by calcofluor white staining. The mechanism by which sho1 gene affected polarized growth is investigated. A reduced number of apical vesicles with greater dispersion were observed by transmission electron microscopy in the Spitzenkorper body of the sho1 mutant. Actin patches were distributed randomly at low density at early stages of mutant strain fungal development and reaggregated to the hyphal tip of later stages when long filamentous fungi formed. Actin patches located at the tip of polarized wild-type cells. RNA levels of polarized growth-related genes Rho GTPases were detected by real-time PCR. The sho1 gene did not affect the RNA expression when strains were cultured at 37 degrees C for 6 h. At 17 h, the RNA expression of rho1, rho3 and CDC42 in the sho1 mutant were 0.18-, 0.18- and 0.33-fold of that in the wild type. The sho1 gene affected the polarized growth through affecting the expression of Rho GTPases, the distribution of actin cytoskeleton, vesicle quantity and distribution. PMID- 21796488 TI - A case of Forestier disease with obstructive sleep apnea syndrome. PMID- 21796489 TI - Sleep apnea is a stronger predictor for coronary heart disease than traditional risk factors. AB - BACKGROUND: Sleep apnea (SA) may be linked to coronary artery disease (CAD). Both conditions have similar risk factors, confounding the analyses. Investigation of the lipid profile is routine in the adult population, even without symptoms or suspected cardiac ailment. SA, however, remains underdiagnosed even in the presence of unambiguous clinical manifestations. PURPOSE: The aim of this study was to verify the association between SA and CAD, adjusting for usual CAD risk factors. METHODS: Patients who underwent diagnostic or therapeutic coronariography and portable type III polysomnography were studied. The severity of SA was determined by the apnea-hypopnea index (AHI). We measured classic CAD risk factors: fasting glucose; total, HDL, and LDL cholesterols; triglycerides; uric acid, and high-sensitivity C-reactive protein. We excluded patients older than 65 years, with body mass index higher than 40 kg/m(2), with diabetes, and with history of smoking in the last year. RESULTS: Of 55 included patients, 28 had AHI > 14, showing an odds ratio of 8.7 for CAD. Patients without (n = 29) and with CAD (n = 26), showed AHI of, respectively, 11 +/- 11 and 23 +/- 14 per hour (P = 0.001). In a binary logistic regression to predict CAD, controlling for all the above risk factors, the only variables entered in the stepwise model were AHI (either as continuous or categorical variable) and uric acid. CONCLUSION: In a sample without smokers, morbidly obese, or diabetic patients, AHI is the main predictor of CAD. SA should integrate the set of risk factors routinely assessed in clinical investigation for coronary disease risk stratification. PMID- 21796490 TI - Automatically correlating clinical findings and body locations in radiology reports using MedLEE. AB - In this paper, we describe and evaluate a system that extracts clinical findings and body locations from radiology reports and correlates them. The system uses Medical Language Extraction and Encoding System (MedLEE) to map the reports' free text to structured semantic representations of their content. A lightweight reasoning engine extracts the clinical findings and body locations from MedLEE's semantic representation and correlates them. Our study is illustrative for research in which existing natural language processing software is embedded in a larger system. We manually created a standard reference based on a corpus of neuro and breast radiology reports. The standard reference was used to evaluate the precision and recall of the proposed system and its modules. Our results indicate that the precision of our system is considerably better than its recall (82.32-91.37% vs. 35.67-45.91%). We conducted an error analysis and discuss here the practical usability of the system given its recall and precision performance. PMID- 21796491 TI - An algorithm for intelligent sorting of CT-related dose parameters. AB - Imaging centers nationwide are seeking innovative means to record and monitor computed tomography (CT)-related radiation dose in light of multiple instances of patient overexposure to medical radiation. As a solution, we have developed RADIANCE, an automated pipeline for extraction, archival, and reporting of CT related dose parameters. Estimation of whole-body effective dose from CT dose length product (DLP)--an indirect estimate of radiation dose--requires anatomy specific conversion factors that cannot be applied to total DLP, but instead necessitate individual anatomy-based DLPs. A challenge exists because the total DLP reported on a dose sheet often includes multiple separate examinations (e.g., chest CT followed by abdominopelvic CT). Furthermore, the individual reported series DLPs may not be clearly or consistently labeled. For example, "arterial" could refer to the arterial phase of the triple liver CT or the arterial phase of a CT angiogram. To address this problem, we have designed an intelligent algorithm to parse dose sheets for multi-series CT examinations and correctly separate the total DLP into its anatomic components. The algorithm uses information from the departmental PACS to determine how many distinct CT examinations were concurrently performed. Then, it matches the number of distinct accession numbers to the series that were acquired and anatomically matches individual series DLPs to their appropriate CT examinations. This algorithm allows for more accurate dose analytics, but there remain instances where automatic sorting is not feasible. To ultimately improve radiology patient care, we must standardize series names and exam names to unequivocally sort exams by anatomy and correctly estimate whole-body effective dose. PMID- 21796492 TI - High-intensity focused ultrasound (HIFU)-assisted hepatic resection in an animal model. AB - BACKGROUND: Bleeding is the main cause of postoperative complications of hepatic surgery. To minimize intraoperative bleeding during hepatectomy, resections are generally carried out under hepatic vascular control despite the risk of liver dysfunction in patients with chronic liver disease. This study evaluates the feasibility and safety of high-intensity focused ultrasound (HIFU)-assisted hepatic resection during an open procedure in an animal model. METHODS: Three groups of 12-14-week-old Landrace pigs (n = 7/group) were used to evaluate HIFU assisted liver resection (group A) vs liver resection with or without portal triad clamping (groups B and C). In each pig, liver resection was performed on the right and left paramedian lobes. The following were evaluated and compared in the 3 groups: total blood loss, blood loss/cm(2) of resection area, clip density, procedure duration, morbidity, and mortality. RESULTS: Median blood loss was significantly lower in group A than in group B (P = .02), and group C (P = .007). Median blood loss/cm(2) of resection area was 4.77 mL/cm2 in group A, 11.35 mL/cm2 in group B, 12.22 mL/cm2 in Group C. Precoagulation resulted in sealing blood vessels <5 mm; therefore, median clip density during liver transection was 0.78 clip/cm2 in group A, 1.61 clip/cm(2) in group B, and 1.57 clip/cm(2) in group C. Median duration of the surgical procedure was 12 min in group A, 21 min in group B, and 19 min in group C. CONCLUSIONS: HIFU-assisted hepatic resection during an open procedure in an animal model is safe, reduces bleeding, and allows real-time ultrasound guidance. PMID- 21796493 TI - The critical care research networks experience. AB - Neurocritical care is a subspecialty of critical care medicine, dedicated to the care and the advancement of care of critically ill patients with neurosurgical or neurological diseases. Neurocritical care patients are heterogeneous, in both their disease process and the therapies they receive, however, several studies demonstrate that care of these patients in dedicated NeuroIntensive Care Units (neuroICUs) by neurointensivists, who coordinate their care is associated with reduced mortality and resource utilization. NeuroICUs foster innovation, and yet despite all the recent advances, much research needs to be undertaken in neurocritical care to better understand the disease pathophysiology and to demonstrate improved outcome with the use of goal-directed therapy based on evolving techniques and therapies. PMID- 21796495 TI - Strategy of modern epistaxis management. PMID- 21796496 TI - The interim test effect: testing prior material can facilitate the learning of new material. AB - A wealth of prior research has shown that testing can improve subsequent learning of the initially tested material. In contrast, only one recent study has shown that an interim test over prior material can improve learning of subsequent new material (i.e., an interim-test effect). Five experiments replicated and extended this initial work by exploring the extent to which interim test effects generalize to complex text material. Participants were prompted to recall each section of an expository text before moving on to study the next section, or were only prompted to recall after the final section. In all experiments, recall of the final, target section was greater when prior sections had received interim tests versus no interim tests. Experiment 3 established that the effect was due to interim testing in particular rather than to intervening activity in general. Experiment 4 established that the effect was not due to test expectancy differences. In contrast to prior research, Experiment 4 also provided evidence that the effect is not due to release from proactive interference. We discuss other possible mechanisms underlying interim-test effects with text, including shifting to more effective encoding strategies. PMID- 21796497 TI - Unique system of care issues and challenges in serving children under age 3 and their families. AB - This article addresses the primary modifications necessary for system change to better meet the mental health needs of children under the age of three. The role of risk and resiliency factors in the young child, family and community and the necessity for a comprehensive community infant-family mental health system with a focus on the whole family are addressed. Barriers to care within early childhood systems of care are examined, including stigma, community referral and collaboration, diagnostic concerns during infancy, issues around family engagement, empowerment and partnership, funding of comprehensive and well coordinated infant-family services, workforce capacity and evaluation. Recommendations for implementation of system changes at the community and federal levels are proposed. PMID- 21796494 TI - Research and technology in neurocritical care. AB - The daily practice of neurointensivists focuses on the recognition of subtle changes in the neurological examination, interactions between the brain and systemic derangements, and brain physiology. Common alterations such as fever, hyperglycemia, and hypotension have different consequences in patients with brain insults compared with patients of general medical illness. Various technologies have become available or are currently being developed. The session on "research and technology" of the first neurocritical care research conference held in Houston in September of 2009 was devoted to the discussion of the current status, and the research role of state-of-the art technologies in neurocritical patients including multi-modality neuromonitoring, biomarkers, neuroimaging, and "omics" research (proteomix, genomics, and metabolomics). We have summarized the topics discussed in this session. We have provided a brief overview of the current status of these technologies, and put forward recommendations for future research applications in the field of neurocritical care. PMID- 21796498 TI - Eleven days of moderate exercise and heat exposure induces acclimation without significant HSP70 and apoptosis responses of lymphocytes in college-aged males. AB - The purpose of this study was to assess whether a lymphocyte heat shock response and altered heat tolerance to ex vivo heat shock is evident during acclimation. We aimed to use flow cytometry to assess the CD3(+)CD4(+) T lymphocyte cell subset. We further aimed to induce acclimation using moderately stressful daily exercise-heat exposures to achieve acclimation. Eleven healthy males underwent 11 days of heat acclimation. Subjects walked for 90 min (50 +/- 8% VO(2max)) on a treadmill (3.5 mph, 5% grade), in an environmental chamber (33 degrees C, 30-50% relative humidity). Rectal temperature ( degrees C), heart rate (in beats per minute), rating of perceived exertion , thermal ratings, hydration state, and sweat rate were measured during exercise and recovery. On days 1, 4, 7, 10, and 11, peripheral blood mononuclear cells were isolated from pre- and post-exercise blood samples. Intracellular and surface HSP70 (SPA-820PE, Stressgen, Assay Designs), and annexin V (ab14085, Abcam Inc.), as a marker of early apoptosis, were measured on CD3(+) and CD4(+) (sc-70624, sc-70670, Santa Cruz Biotechnology) gated lymphocytes. On day 10, subjects experienced 28 h of sleep loss. Heat acclimation was verified with decreased post-exercise rectal temperature, heart rate, and increased sweat rate on day 11, versus day 1. Heat acclimation was achieved in the absence of significant changes in intracellular HSP70 mean fluorescence intensity and percent of HSP70(+) lymphocytes during acclimation. Furthermore, there was no increased cellular heat tolerance during secondary ex vivo heat shock of the lymphocytes acquired from subjects during acclimation. There was no effect of a mild sleep loss on any variable. We conclude that our protocol successfully induced physiological acclimation without induction of cellular heat shock responses in lymphocytes and that added mild sleep loss is not sufficient to induce a heat shock response. PMID- 21796499 TI - A method of adjusting SUV for injection-acquisition time differences in (18)F-FDG PET imaging. AB - OBJECTIVE: A time normalisation method of tumour SUVs in (18) F-FDG PET imaging is proposed that has been verified in lung cancer patients. METHODS: A two compartment model analysis showed that, when SUV is not corrected for (18) F physical decay (SUV(uncorr)), its value is within 5% of its peak value (t = 79 min) between 55 and 110 min after injection, in each individual patient. In 10 patients, each with 1 or more malignant lesions (n = 15), two PET acquisitions were performed within this time delay, and the maximal SUV of each lesion, both corrected and uncorrected, was assessed. RESULTS: No significant difference was found between the two uncorrected SUVs, whereas there was a significant difference between the two corrected ones: mean differences were 0.04 +/- 0.22 and 3.24 +/- 0.75 g.ml(-1), respectively (95% confidence intervals). Therefore, a simple normalisation of decay-corrected SUV for time differences after injection is proposed: SUV(N) = 1.66 SUV(uncorr), where the factor 1.66 arises from decay correction at t = 79 min. CONCLUSIONS: When (18) F-FDG PET imaging is performed within the range 55-110 min after injection, a simple SUV normalisation for time differences after injection has been verified in patients with lung cancer, with a +/-2.5% relative measurement uncertainty. PMID- 21796500 TI - Hemoglobin glycation rate constant in non-diabetic Individuals. AB - The objectives were as follows: (1) estimating mean value of the overall hemoglobin glycation rate constant (k); (2) analyzing inter-individual variability of k; (3) verifying ability of the hemoglobin A1c (HbA1c) formation model to predict changes of HbA1c during red blood cells cultivation in vitro and to reproduce the clinical data. The mean k estimated in a group of 10 non diabetic subjects was equal to 1.257 +/- 0.114 * 10(-9) L mmol(-1) s(-1). The mean k was not affected by a way of estimation of glycemia. The mean k differed less than 20% from values reported earlier and it was almost identical to the mean values calculated on basis of the selected published data. Analysis of variability of k suggests that inter-individual heterogeneity of HbA1c formation is limited or rare. The HbA1c mathematical model was able to predict changes of HbA1c in vitro resulting from different glucose levels and to reproduce a linear relationship of HbA1c and average glucose obtained in the A1C-Derived Average Glucose Study. This study demonstrates that the glycation model with the same k value might be used in majority of individuals as a tool supporting interpretation of HbA1c in different clinical situations. PMID- 21796501 TI - Development and validation of a computational model for investigation of wrist biomechanics. AB - In this study, a computational model of the wrist joint complex was developed and validated for investigating the biomechanical function of the joint in clinically representative scenarios. Joint behavior and kinematics were dictated only by osteoarticular contact, ligamentous constraints, and muscle loading. Three dimensional articular surfaces of each bone were generated from CT images, while ligaments and muscles were modeled as linear springs and constant-magnitude force vectors, respectively. Commercially available rigid body dynamics software was to both build the model and simulate joint function. Range of motion model predictions were compared to a cadaveric study analyzing the effects of scaphoid distal pole excision and triquetral excision after radioscapholunate (RSL) fusion for validation. The computational model was able to accurately predict flexion, extension, radial deviation, and ulnar deviation motions in four states: normal (intact), RSL fusion, RSL fusion with the scaphoid distal pole excised, and RSL fusion with both the scaphoid distal pole and triquetrum excised. The model was also able to calculate other parameters of interest that are not easily obtainable experimentally, such as midcarpal forces. This model and modeling approach are anticipated to have value as a predictive clinical tool including effect of injuries or anatomical variations and initial outcome of surgical procedures for patient specific planning and custom implant design. PMID- 21796502 TI - A quantitative real-time PCR approach for the detection and characterization of endothelial cells in whole blood. AB - Pathological inflammation and endothelial dysfunction in atherosclerosis causes endothelial cell detachment from affected vasculature giving rise to circulating endothelial cells (CECs). A blood-based assay that can detect and characterize CECs in atherosclerosis could serve as a valuable diagnostic. Thus, we sought to develop a prototypic assay that detects and characterizes the inflammatory state of endothelial cells present in blood. For this purpose, we spiked resting and inflamed human umbilical vein endothelial cells (HUVEC) into separate samples of whole blood. RNA was harvested and analyzed via quantitative real-time PCR (qPCR) using melanoma cell adhesion molecule (MCAM), as an endothelial marker, and vascular cell adhesion molecule (VCAM-1), which is increased on inflamed endothelium. We found that MCAM mRNA levels correlated with the number of HUVEC spiked into the blood. VCAM-1 mRNA levels were elevated, and correlated with the number of HUVEC, in blood spiked with inflamed HUVEC but not in blood spiked with resting HUVEC. VCAM-1 and MCAM mRNA levels were converted into numerical indices that indicate the inflammatory state of the HUVEC. Combined, the blood spiking studies demonstrate that a VCAM-1/MCAM qPCR assay can successfully detect inflamed endothelial cells in whole blood thus providing proof-of-concept for a diagnostic based on a coupled-phenotypic qPCR assay. PMID- 21796503 TI - CDH13 and FLBN3 gene methylation are associated with poor prognosis in colorectal cancer. AB - The aim of this study was to identify potential epigenetic prognostic biomarkers for colorectal cancer (CRC) in the Chinese population. The methylation status of five tumor suppressor genes (CDH13, DLEC1, FBLN3, hMHL1 and RUNX3) was determined using manual microdissection followed by methylation-specific PCR in 85 paired CRC specimens and adjacent normal tissue. The results showed that methylation frequencies in cancerous tissues were 31.8% for CDH13, 37.6% for DLEC1, 38.8% for FBLN3, 22.4% for hMHL1 and 27.1% for RUNX3, all of which were significantly higher than in corresponding normal tissue. Furthermore, CDH13 methylation was associated with poor differentiation (P = 0.019) and tended to be predominant in advanced stages (P = 0.084); FBLN3 methylation was associated with advanced stages (P = 0.027) and lymph node metastasis (P = 0.029). Accordingly, the methylation status of CDH13 (P = 0.022), FBLN3 (P = 0.008), CDH13 and/or FBLN3 (P = 0.001) predicted adverse overall survival in CRC, while hMHL1 methylation showed a protective role in survival (P = 0.046). Cox proportional hazard models further indicated that CDH13 and/or FBLN3 methylation, but not that of hMHL1, was an independent prognostic factor for CRC. In conclusion, we found CDH13 and FBLN3 gene methylation are potential biomarkers for poor prognosis in CRC. PMID- 21796504 TI - Cardiac autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in Colombia, South America. AB - Several patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre-EPF) have experienced a sudden death syndrome, including persons below the age of 50. El Bagre-EPF patients share several autoantigens with paraneoplastic pemphigus patients, such as reactivity to plakins. Further, paraneoplastic pemphigus patients have autoantibodies to the heart. Therefore, we tested 15 El Bagre-EPF patients and 15 controls from the endemic area for autoreactivity to heart tissue using direct and indirect immunofluorescence, confocal microscopy, immunohistochemistry, immunoblotting, and immunoelectron microscopy utilizing heart extracts as antigens. We found that 7 of 15 El Bagre patients exhibited a polyclonal immune response to several cell junctions of the heart, often colocalizing with known markers. These colocalizing markers included those for the area composita of the heart, such as anti desmoplakins I and II; markers for gap junctions, such as connexin 43; markers for tight junctions, such as ezrin and junctional adhesion molecule A; and adherens junctions, such pan-cadherin. We also detected colocalization of the patient antibodies within blood vessels, Purkinje fibers, and cardiac sarcomeres. We conclude that El Bagre-EPF patients display autoreactivity to multiple cardiac epitopes, that this disease may resemble what is found in patients with rheumatic carditis, and further, that the cardiac pathophysiology of this disorder warrants further evaluation. PMID- 21796506 TI - B3 core biopsies should be assumed as positive findings for accuracy purposes. PMID- 21796505 TI - Mutations in the ELANE gene are associated with development of periodontitis in patients with severe congenital neutropenia. AB - BACKGROUND: Patients with severe congenital neutropenia (SCN) often develop periodontitis despite standard medical and dental care. In light of previous findings that mutations in the neutrophil elastase gene, ELANE, are associated with more severe neutropenic phenotypes, we hypothesized an association between the genotype of SCN and development of periodontitis. METHODS: Fourteen Swedish patients with SCN or cyclic neutropenia harboring different genetic backgrounds were recruited for periodontal examination. Peripheral blood, gingival crevicular fluid (GCF), and subgingival bacterial samples were collected. The levels of cytokines and antibacterial peptides were determined in GCF and plasma by multiplex immunoassay and immunoblotting, respectively. Subgingival bacterial samples were analyzed using 16S rDNA pyrosequencing. RESULTS: ELANE mutations correlated with more severe periodontal status than the HAX1 or unknown mutations in patients with SCN. The subjects with mutant ELANE had higher levels of IL 1beta in GCF. Using principal coordinate analysis of the subgingival microbiota, patients with ELANE mutations and reference subjects with periodontitis tended to cluster differently from patients with HAX1 or unknown mutations and non periodontitis reference subjects. CONCLUSION: This study demonstrates an association between ELANE mutations in SCN and the development of periodontitis with skewed subgingival microbiota, indicating a potential role of ELANE mutations in the pathogenesis of periodontitis. PMID- 21796507 TI - Perioperative management of chronic anticoagulation therapy in urological patients: a cross-sectional survey of practice. AB - BACKGROUND: There has been a significant increase in the volume of urological patients on daily anticoagulation therapy requiring invasive elective urological procedures. AIMS: We sought to assess whether urologists are familiar with appropriate perioperative management strategies in this patient cohort. METHODS: Urologists completed a questionnaire on their current management strategy for warfarin during the perioperative period in patients undergoing elective urological surgery. Eleven urological procedures graded as minor, endoscopic and major were assessed in the study. In addition, respondents were also asked whether they administered bridging therapy with heparin when warfarin was discontinued perioperatively. RESULTS: The response rate was 52.5% (210/400). Procedure grade did not influence the duration warfarin was discontinued preoperatively with respondents discontinuing the agent 4.71 +/- 1.52 days (range 2-10 days) prior to minor procedures, 4.74 +/- 1.43 days (range 2-10 days) prior to endoscopic procedures and 4.88 +/- 1.34 days (range 2-10 days) prior to major procedures (p > 0.05). Postoperatively, procedure grade significantly affected the day to recommencement with respondents recommencing warfarin 2.41 +/- 2.31 days (range 1-14 days) after minor procedures, 3.07 +/- 3.52 days (range 1-28 days) after endoscopic procedures and 4.38 +/- 3.53 days (range 1-14 days) after major procedures (p < 0.0001). In total, 60 +/- 0.52% of the respondents who discontinued warfarin routinely administered bridging therapy with heparin perioperatively. CONCLUSIONS: Our study demonstrates variations in perioperative management practices for patients on chronic anticoagulation therapy undergoing urological procedures. Urologists should familiarise themselves with standardised guidelines if this patient subgroup are to receive optimal perioperative management. PMID- 21796508 TI - Fiberoptic-guided tracheal tube placement through the air-Q(r) Intubating Laryngeal Airway: a performance study in a manikin. AB - PURPOSE: This study characterizes the performance and success rate for fiberoptic guided tracheal tube placement through the air-Q((r)) Intubating Laryngeal Airway (air-Q). METHODS: Using a manikin, anesthesia trainees and staff anesthesiologists, experienced in fiberoptic-guided intubation, performed five consecutive fiberoptic-guided tracheal tube placements via the air-Q. Participant characteristics, procedure segment times, total procedure times, and observed failures were recorded. Linear mixed effect models with random slopes and intercepts were used to assess participant performance. RESULTS: Ten anesthesia trainees and ten staff anesthesiologists participated. Anesthesia trainees were younger and had practiced for fewer years compared to staff anesthesiologists. Gender was equally distributed between the groups. Both segmental and overall procedure times decreased from the first to the fifth trial among all participants, independent of experience level and gender. Overall mean procedure time decreased from 102 +/- 31 to 68 +/- 14 s, representing a relative time reduction of 33% and a mean time difference of 34 s [95% confidence interval (CI) 22-47 s; p < 0.0001]. Tracheal tube placement was successful in all attempts; however, three tracheal tube dislodgements occurred during air-Q removal (overall procedure success 97%). CONCLUSIONS: Fiberoptic-guided tracheal tube placement through the air-Q can be performed in a clinically acceptable period of time with high success by operators skilled in fiberoptic-guided intubation. Tracheal tube dislodgement during air-Q removal remains a potential risk that should be emphasized. PMID- 21796509 TI - [Development of the iridocorneal angle and congenital glaucoma]. AB - The trabecular meshwork originates from cells of the neural crest which migrate to the iridocorneal angle during embryonic and fetal development of the eye. Correct morphogenesis of trabecular outflow pathways requires the differentiation of the cells to a porous and lamellate meshwork as well as the ingrowth of Schlemm's canal and posterior movement of the iris root. A failure in these processes is responsible for primary congenital or infantile glaucoma which presents with increased resistance to aqueous humor outflow resulting in increased intraocular pressure. Most cases appear to be of a sporadic nature but hereditary cases are often caused by mutations in the CYP1B1 gene which encodes for the enzyme cytochrome P450 1B1. Mutations cause a reduction in enzymatic activity which probably leads to diminished turnover of an as yet unidentified metabolite taking part in the signaling processes essential for formation of the trabecular meshwork and Schlemm's canal. More rarely, mutations in latent transforming growth factor beta binding protein 2 (LTBP2) or in the transcription factor FOXC1 have been described as causative for primary congenital glaucoma. PMID- 21796511 TI - [Electronic patient records and teleophthalmology. Part 2: concrete projects in ophthalmology]. AB - Electronic storage of patient-related data will replace paper-based patient records in the near future. Because of the high visualization needed in ophthalmology integrated electronic data storage and usage will be very useful. Chronic diseases like glaucoma, macular degeneration and diabetic retinopathy would benefit from long-term data storage and analysis. Unfortunately there are nearly no widely accepted systems available providing these options. Another important point is the simplification of existing diagnostic procedures and nomenclature on an international level. Increasing mobility of patients requires a better portability of existing medical examination data between different physicians. This is the only way to provide continuously high levels of quality in patient care and to simultaneously reduce costs and prevent unnecessary secondary examinations. PMID- 21796512 TI - [Position on orbitotomy within the scope of ophthalmologic plastic and reconstructive surgical procedures]. PMID- 21796514 TI - Electronic stress as a guiding force for chemical bonding. AB - In the electron-preceding picture of chemical change, the paramount problem is identifying favorable changes in electronic structure. The electronic stress tensor provides this information; its eigenvectors represent electronic normal modes, pointing the way towards energetically favorable (or unfavorable) chemical rearrangements. The resulting method is well founded in both density functional theory and the quantum theory of atoms in molecules (QTAIM). Stress tensor analysis is a natural way to extend the QTAIM to address chemical reactivity. The definition and basic properties of the electronic stress tensor are reviewed and the inherent ambiguity of the stress tensor is discussed. Extending previous work in which the stress tensor was used to analyze hydrogen-bonding patterns, this work focuses on chemical bonding patterns in organic reactions. Other related material (charge-shift bonding, links to the second-density-derivative tensor) is summarized and reviewed. The stress tensor provides a multifaceted characterization of bonding and can be used to predict and describe bond formation and migration. PMID- 21796515 TI - Applications of non-uniform sampling and processing. AB - Modern high-field NMR instruments provide unprecedented resolution. To make use of the resolving power in multidimensional NMR experiment standard linear sampling through the indirect dimensions to the maximum optimal evolution times (~1.2T (2)) is not practical because it would require extremely long measurement times. Thus, alternative sampling methods have been proposed during the past 20 years. Originally, random nonlinear sampling with an exponentially decreasing sampling density was suggested, and data were transformed with a maximum entropy algorithm (Barna et al., J Magn Reson 73:69-77, 1987). Numerous other procedures have been proposed in the meantime. It has become obvious that the quality of spectra depends crucially on the sampling schedules and the algorithms of data reconstruction. Here we use the forward maximum entropy (FM) reconstruction method to evaluate several alternate sampling schedules. At the current stage, multidimensional NMR spectra that do not have a serious dynamic range problem, such as triple resonance experiments used for sequential assignments, are readily recorded and faithfully reconstructed using non-uniform sampling. Thus, these experiments can all be recorded non-uniformly to utilize the power of modern instruments. On the other hand, for spectra with a large dynamic range, such as 3D and 4D NOESYs, choosing optimal sampling schedules and the best reconstruction method is crucial if one wants to recover very weak peaks. Thus, this chapter is focused on selecting the best sampling schedules and processing methods for high dynamic range spectra. PMID- 21796516 TI - Issues and challenges in vapor-deposited top metal contacts for molecule-based electronic devices. AB - Metal vapor deposition to form ohmic contacts is commonly used in the fabrication of organic electronic devices because of significant manufacturability advantages. In the case of single molecular layer devices, however, the extremely small thickness, typically ~1-2nm, presents serious challenges in achieving good contacts and device integrity. This review focuses on recent scientific aspects of metal vapor deposition on monolayer thickness molecular films, particularly self-assembled monolayers, ranging across mechanisms of metal nucleation, metal molecular group interactions and chemical reactions, diffusion of metal atoms within and through organic films, and the correlations of these and other factors with device function. Results for both non-reactive and reactive metal deposition are reviewed. Finally, novel strategies are considered which show promise for providing highly reliable and durable metal/organic top contacts for use in metal molecule-metal junctions for device applications. PMID- 21796513 TI - Editing of neurotransmitter receptor and ion channel RNAs in the nervous system. AB - The central dogma of molecular biology defines the major route for the transfer of genetic information from genomic DNA to messenger RNA to three-dimensional proteins that affect structure and function. Like alternative splicing, the post transcriptional conversion of adenosine to inosine (A-to-I) by RNA editing can dramatically expand the diversity of the transcriptome to generate multiple, functionally distinct protein isoforms from a single genomic locus. While RNA editing has been identified in virtually all tissues, such post-transcriptional modifications have been best characterized in RNAs encoding both ligand- and voltage-gated ion channels and neurotransmitter receptors. These RNA processing events have been shown to play an important role in the function of the encoded protein products and, in several cases, have been shown to be critical for the normal development and function of the nervous system. PMID- 21796517 TI - Molecular mechanisms of androgen action--a historical perspective. AB - Androgens and the androgen receptor (AR) are indispensable for expression of the male phenotype. The two most important androgens are testosterone and 5alpha dihydrotestosterone. The elucidation of the mechanism of androgen action has a long history starting in the 19th century with the classical experiments by Brown Sequard. In the 1960s the steroid hormone receptor concept was established and the AR was identified as a protein entity with a high affinity and specificity for testosterone and 5alpha-dihydrotestosterone. In addition, the enzyme 5alpha reductase type 2 was discovered and found to catalyze the conversion of testosterone to the more active metabolite 5alpha-dihydrotestosterone. In the second half of the 1980s, the cDNA cloning of all steroid hormone receptors, including that of the AR, has been another milestone in the whole field of steroid hormone action. Despite two different ligands (testosterone and 5alpha dihydrotestosterone), only one AR cDNA has been identified and cloned. The AR (NR3C4) is a ligand-dependent transcription factor and belongs to the family of nuclear hormone receptors which has 48 members in human. The current model for androgen action involves a multistep mechanism. Studies have provided insight into AR association with co-regulators involved in transcription initiation and on intramolecular interactions of the AR protein during activation. Knowledge about androgen action in the normal physiology and in disease states has increased tremendously after cloning of the AR cDNA. Several diseases, such as androgen insensitivity syndrome (AIS), prostate cancer and spinal bulbar muscular atrophy (SBMA), have been shown to be associated with alterations in AR function due to mutations in the AR gene or dysregulation of androgen signalling. A historical overview of androgen action and salient features of AR function in normal and disease states are provided herein. PMID- 21796518 TI - Androgen action during prostate carcinogenesis. AB - Androgens are critical for normal prostate development and function, as well as prostate cancer initiation and progression. Androgens function mainly by regulating target gene expression through the androgen receptor (AR). Many studies have shown that androgen-AR signaling exerts actions on key events during prostate carcinogenesis. In this review, androgen action in distinct aspects of prostate carcinogenesis, including (i) cell proliferation, (ii) cell apoptosis, and (iii) prostate cancer metastasis will be discussed. PMID- 21796519 TI - Androgen quantitation in prostate cancer tissue using liquid chromatography tandem mass spectrometry. AB - Prostate cancer that recurs after androgen deprivation therapy is the second leading cause of cancer-related death in North American men. Clinical and experimental evidences indicate that the development of recurrent prostate cancer is dependent on re-activation of the androgen receptor signaling pathway. Androgen is required for androgen receptor translocation to the nucleus, interaction with androgen response elements, expression of target genes, and prostate cancer cell proliferation. The intra-tissue and serum testosterone and dihydrotestosterone levels are important biomarkers to monitor androgen deprivation therapy efficacy in prostate cancer and recurrent prostate cancer. We have measured testosterone and dihydrotestosterone in procured recurrent prostate cancer specimens using liquid chromatography tandem mass spectrometry. The measured androgen levels are sufficient to activate androgen receptor and suggest that the recurrent prostate cancer microenvironment is capable of intracrine androgen biosynthesis. PMID- 21796521 TI - Analysis of androgen receptor activity by reporter gene assays. AB - Androgen receptor (AR) acts as a ligand-regulated transcription factor that conveys the message of both natural and synthetic androgens directly to the level of gene programs. Reporter gene assays provide a convenient and quantitative way to measure the transcriptional activity of AR and the functionality of its binding sites (AREs) in DNA. Many reporter genes and different transfection methods can be used for this purpose. In this chapter, we describe the use of firefly luciferase gene-based reporters and transfection protocols for the measurement of AR activity in heterologous COS-1 cells cotransfected with an AR expression vector and in VCaP prostate cancer cells expressing endogenous AR. We also discuss the suitability of different reporter constructs and transfection methods for different cell types and how reporter gene assays can be employed to complement chromatin immunoprecipitation assays. PMID- 21796520 TI - Ligand competition binding assay for the androgen receptor. AB - Evaluating endocrine activities of environmental chemicals or screening for new small molecule modulators of the androgen receptor (AR) transcription activity requires standardized and reliable assay procedures. Scintillation proximity assays (SPA) are sensitive and reliable techniques that are suitable for ligand competition binding assays. We have utilized a radiolabeled ligand competition binding assay for the androgen receptor (AR) that can be carried out in a 384 well format. This standardized, highly reproducible and low-cost assay has been automated for high-throughput screening (HTS) purposes. PMID- 21796522 TI - Identification and characterization of androgen response elements. AB - The androgen receptor (AR) has a DNA-binding domain that consists of two zinc coordinating modules. While residues of the first module make most of the sequence-specific contacts, the second module functions as a homodimerization interface (1). This explains why the androgen response elements (AREs) are organized as two 5'-AGAACA-3'-like motifs separated by three basepairs (2). AREs can be located near the promoters of androgen-responsive genes, but are also at considerable distances either upstream or downstream, so the initial steps in locating AREs can be challenging. Traditionally, AR-binding sites were identified by DNA cellulose competition assays (3) or by in vitro footprinting (4). However, the advent of the chromatin immunoprecipitation assays made it possible to identify genomic fragments to which the AR binds either directly or indirectly (5). To enable identification of AREs in such genomic fragments, we developed an in silico approach involving a weight matrix based on all known AREs (6). This will point out candidate AREs, which will still need experimental validation involving a direct interaction assay and a transactivation assay. We describe here the methods most fit to describe an ARE: the electrophoretic mobility shift and the transactivation assays. PMID- 21796523 TI - In vitro and in vivo silencing of the androgen receptor. AB - The androgen receptor (AR) plays a pivotal role in the progression of prostate cancer from the androgen-dependent to the castration-resistant state, making it a potential target for therapy. In this chapter, we describe the preparation and use of sublines of LNCaP and C4-2 human prostate cancer cells which have been engineered to stably express a doxycycline (DOX)-inducible AR shRNA in order to study the in vitro and in vivo effects of AR knockdown. PMID- 21796524 TI - Analysis of interdomain interactions of the androgen receptor. AB - High-affinity binding of testosterone or dihydrotestosterone to the androgen receptor (AR) triggers the androgen-dependent AR NH2- and carboxyl-terminal (N/C) interaction between the AR NH2-terminal FXXLF motif and the activation function 2 (AF2) hydrophobic binding surface in the ligand-binding domain. The functional importance of the AR N/C interaction is supported by naturally occurring loss-of function AR AF2 mutations where AR retains high-affinity androgen binding but is defective in AR FXXLF motif binding. Ligands with agonist activity in vivo such as testosterone, dihydrotestosterone, and the synthetic anabolic steroids induce the AR N/C interaction and increase AR transcriptional activity in part by slowing the dissociation rate of bound ligand and stabilizing AR against degradation. AR ligand-binding domain competitive antagonists inhibit the agonist dependent AR N/C interaction. Although the human AR N/C interaction is important for transcriptional activity, it has an inhibitory effect on transcriptional activity from AF2 by competing for p160 coactivator LXXLL motif binding. The primate-specific AR coregulatory protein, melanoma antigen gene protein-A11 (MAGE A11), modulates the AR N/C interaction through a direct interaction with the AR FXXLF motif. Inhibition of AF2 transcriptional activity by the AR N/C interaction is relieved by AR FXXLF motif binding to the F-box region of MAGE-11. Described here are methods to measure the androgen-dependent AR N/C interdomain interaction and the influence of transcriptional coregulators. PMID- 21796525 TI - Methods to study dynamic interaction of androgen receptor with chromatin in living cells. AB - Androgen receptor (AR) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. In the presence of its specific ligands, AR translocates into the nucleus, interacts with chromatin at hormone response elements (HREs) and recruits a variety of coregulators and basal transcription factors to regulate transcription. Using green fluorescent protein (GFP) labelling and the tandem gene array system of mouse mammary tumour virus (MMTV), the interaction of AR with HREs can be visualized and studied in live cells. The MMTV array in nuclei can be specifically detected by DNA fluorescence in situ hybridization (DNA FISH) and thereby specific binding of GFP-AR to the array can be confirmed in the presence of specific ligands. The transcriptional activity of GFP-AR at the MMTV array can be visualized by RNA FISH in combination with interactions of GFP-AR or its cofactors, or different components of the transcriptional initiation complex, by indirect immunofluorescence (IF). Finally, using fluorescence recovery after photobleaching (FRAP), dynamic interactions of GFP-AR with the chromatin template can be studied. Methods to carry out these experiments are described herein. PMID- 21796526 TI - FRET analysis of androgen receptor structure and biochemistry in living cells. AB - The androgen receptor (AR) is the central component of a dynamic conformational and interaction cascade initiated by androgenic hormones. AR function can be modified by cellular inputs not examined in test tube studies of AR action. Thus, there is a need to measure AR conformation and biochemistry directly within the cell where the intracellular locations, levels and availability of the hormone, AR, AR-interacting factors, DNA-binding sites, enzymes that modify those components of AR action, and factors that compete for the formation of functional AR-cofactor complexes may affect AR action. The dynamic nature of the AR functional cycle itself may introduce temporal fluctuations in factor status and location to affect AR output in the intact cell. This chapter focuses on the method of Forster resonance energy transfer which uniquely has the resolving power and ability to directly measure the conformation and biochemistry of AR signaling in living cells. PMID- 21796527 TI - Analysis of nuclear receptor acetylation. AB - Acetylation is an essential post-translational modification in which an acetyl group is covalently conjugated to a protein substrate. Histone acetylation was first proposed nearly half a century ago by Dr. Vincent Allfrey. Subsequent studies have shown that acetylated core histones are often associated with transcriptionally active chromatin. Acetylation at lysine residues of histone tails neutralizes the positive charge, which decreases the binding ability to DNA and increases the accessibility of transcription factors and co-activators to the chromatin template. In addition to histones, a number of non-histone substrates are acetylated. Acetylation of non-histone proteins governs biological processes, including cellular proliferation and survival, transcriptional activity, and intracellular trafficking. We demonstrated that acetylation of transcription factors can regulate cellular growth. Further, we have shown that nuclear receptors are acetylated at a phylogenetically conserved motif. Since our initial observations with the estrogen and androgen receptors, more than a dozen nuclear receptors have been shown to function as substrates for acetyltransferases with a variety of new methods (Fig. 11.1). This chapter focuses on the protocol used in the studies of NR acetylation and de-acetylation. We will discuss the potential pitfalls of each method. PMID- 21796528 TI - Analysis of androgen receptor SUMOylation. AB - Androgen receptor (AR) is a ligand-controlled transcription factor that is deregulated and therefore targeted in prostate cancer. In addition to androgens, AR is regulated by post-translational modifications (PTMs). SUMOylation, conjugation of small ubiquitin-related modifier (SUMO) protein 1, 2, or 3, is a bulky PTM regulating several important physiological processes. We have shown that AR is modified by SUMO-1 at two conserved lysine residues in its N-terminal domain. This agonist-enhanced modification represses the transcriptional activity of the receptor in a reversible and target gene-selective fashion. Acceptor sites for SUMOs are also found in several other nuclear receptors. Since the cellular steady-state level of SUMO modifications of most substrates, including AR, is very low, transfection- and SUMO overexpression-based protocols are often needed to render the modifications clearly detectable. This chapter describes protocols for analyzing AR SUMOylation in cultured cells by immunoblotting, gel mobility shift assays, and immunoprecipitation. These methodologies are generally applicable for determining whether a particular protein is SUMOylated and for identifying the lysine residue(s) modified. PMID- 21796529 TI - Analysis of ligand-specific co-repressor binding to the androgen receptor. AB - The recruitment of co-repressors to the androgen receptor is an important mechanism for reducing androgen-mediated gene activation. Importantly, co repressors play a major role in the treatment of hormone-dependent growing tissue, such as prostate cancer and breast cancer. In line with this, co repressor dysfunction seems to be a major player for development of castration resistant prostate cancer or therapy-resistant breast cancer. The molecular basis of hormone therapy by particular antihormones (antagonists) for the androgen receptor (AR) is mediated by enhanced recruitment and activity of co-repressors that cause repression of AR target genes that regulate proliferation and alteration of cancer cells. Therefore co-repressor recruitment is a crucial molecular mechanism of gene repression as well as inhibition of cancer growth. Here we describe different strategies to investigate co-repressor recruitment to the AR. First, we developed a modified mammalian two-hybrid system to investigate the recruitment of co-repressors to the AR within mammalian cells. This assay is very useful for the identification of the molecular mechanism of new AR antagonists and for molecular analysis of castration-resistant prostate cancer expressing the AR. Second, we describe a technique to analyze the interaction of AR isolated from human prostate cancer cells with a newly generated AR-specific co-repressor peptide, which is bacterially expressed and affinity purified by glutathione-S-transferase affinity precipitation assays in vitro. In summary, these methods can greatly facilitate the study of AR-co-repressor interactions. PMID- 21796530 TI - Detection of ligand-selective interactions of the human androgen receptor by SELDI-MS-TOF. AB - The human androgen receptor (AR) is expressed in nearly all prostate cancers (PCa) and is known to participate in tumor progression through the expression of genes involved in the proliferation and differentiation of PCa. It is suggested that different types of ligands induce a distinct AR conformation that would lead to a specific set of interacting partners for the AR, such as coactivators (CoA) and corepressors (CoR), heat shock proteins (HSP), remodeling factors, kinases, phosphatases, and transcription factors resulting in various degrees of AR activity and stability. The natural ligand of the AR, dihydrotestosterone (DHT), induces a transcriptionally active conformation of the AR while the steroidal antiandrogen cyproterone acetate (CPA) and the nonsteroidal compounds hydroxyflutamide (OHF), bicalutamide (Cas), and atraric acid (AA) prevent acquisition of a transcriptionally active conformation. The AR has, in addition to transactivation, other functional properties. However, the current known interaction partners of AR cannot explain the multitude of AR-mediated functions. Thus, many of the ligand-specific AR-interacting proteins still remain unidentified. Here we provide an assay system to assess AR interactions in LNCaP PCa cells. LNCaP cells were treated with the AR-agonist R1881 or AR-antagonists Cas or AA to induce ligand-specific cofactor (CoF) binding to the AR in vivo. Here we describe a method for the identification of ligand-selective interaction partners of AR combining immunological methods with surface-enhanced laser desorption/ionization (SELDI)--time of flight (TOF)--mass spectrometry (MS). Exemplified here is the interaction of a novel AR-CoF, the cell-cycle regulating protein cell division cycle-associated protein 2 (CDCA2) with AR in the presence of antagonist which is verified by a protein-protein interaction assay in vivo. This scheme can provide further insights into the molecular mechanisms of AR ligand selectivity. PMID- 21796531 TI - Global identification of androgen response elements. AB - Chromatin immunoprecipitation (ChIP) is an invaluable tool in the study of transcriptional regulation. ChIP methods require both a priori knowledge of the transcriptional regulators which are important for a given biological system and high-quality specific antibodies for these targets. The androgen receptor (AR) is known to play essential roles in male sexual development, in prostate cancer and in the function of many other AR-expressing cell types (e.g. neurons and myocytes). As a ligand-activated transcription factor the AR also represents an endogenous, inducible system to study transcriptional biology. Therefore, ChIP studies of the AR can make use of treatment contrast experiments to define its transcriptional targets. To date several studies have mapped AR binding sites using ChIP in combination with genome tiling microarrays (ChIP-chip) or direct sequencing (ChIP-seq), mainly in prostate cancer cell lines and with varying degrees of genomic coverage. These studies have provided new insights into the DNA sequences to which the AR can bind, identified AR cooperating transcription factors, mapped thousands of potential AR regulated genes and provided insights into the biological processes regulated by the AR. However, further ChIP studies will be required to fully characterise the dynamics of the AR-regulated transcriptional programme, to map the occupancy of different AR transcriptional complexes which result in different transcriptional output and to delineate the transcriptional networks downstream of the AR. PMID- 21796532 TI - Tissue-specific knockout of androgen receptor in mice. AB - Androgen acting through the androgen receptor (AR) is known to be essential for male sexual differentiation and development. Using Cre-lox technology, we have generated the floxed AR mice, which have been bred with general or tissue specific Cre expressing transgenic mice to knock out the AR gene in specific target cells. Our findings indicated that AR is required for sexual development and that loss of AR can have significant effects on many aspects of physiological functions and disease progression, such as immune function, metabolism, and tumorigenesis. Furthermore, our strategy can generate AR knockout (ARKO) in female mice, which allows researchers to study the AR function in the female. In brief, our floxed AR mouse model provides a powerful tool to study in vivo AR functions in selective tissues and cell types and has made possible several research breakthroughs in the field of endocrinology. PMID- 21796533 TI - Methodology to investigate androgen-sensitive and castration-resistant human prostate cancer xenografts in preclinical setting. AB - Understanding the biology of prostate cancer and the roles of androgen receptor in prostate cancer progression is essential to the development of novel therapeutic strategies to effectively attack and eradicate this disease. Preclinical, in vivo, studies are critical to further evaluate potential clinical relevance of in vitro findings. Ideally, in vivo studies should employ models that mimic characteristics of prostate cancer from early diagnosis through the period of castration-resistant metastases. In this chapter we describe methodologies used to grow human prostate cancer xenografts in mice. In this setting, roles of androgen receptor signaling in prostate cancer progression and efficacy of novel treatment modalities, including those affecting androgen receptor signaling, can be investigated. PMID- 21796534 TI - Automated microscopy and image analysis for androgen receptor function. AB - Systems-level approaches have emerged that rely on analytical, microscopy-based technology for the discovery of novel drug targets and the mechanisms driving AR signaling, transcriptional activity, and ligand independence. Single cell behavior can be quantified by high-throughput microscopy methods through analysis of endogenous protein levels and localization or creation of biosensor cell lines that can simultaneously detect both acute and latent responses to known and unknown androgenic stimuli. The cell imaging and analytical protocols can be automated to discover agonist/antagonist response windows for nuclear translocation, reporter gene activity, nuclear export, and subnuclear transcription events, facilitating access to a multiplex model system that is inherently unavailable through classic biochemical approaches. In this chapter, we highlight the key steps needed for developing, conducting, and analyzing high throughput screens to identify effectors of AR signaling. PMID- 21796535 TI - Androgen regulation of ETS gene fusion transcripts in prostate cancer. AB - Fusion between androgen-regulated TMPRSS2 and ETS transcription factor gene ERG is the most frequent genetic alteration that occurs in 40-70% of prostate cancers. Not only ERG but also other ETS transcription factor genes are involved in gene fusions. ETV1, ETV4, and ETV5 have all several fusion partners. One common feature shared by the majority of these partners is androgen-regulated expression. Despite its high frequency, the biological and molecular effects of ETS gene fusion in prostate cancer development and progression are unknown. In this chapter quantitative polymerase chain reaction (Q-PCR) is used for detection and further studying the incidence and properties of these fusion transcripts. The focus is on the expression of TMPRSS2-ERG transcripts in clinical prostate samples. Androgen regulation of TMPRSS2 is measured in commonly used LNCaP prostate cancer cells grown with and without the synthetic androgen R1881. Furthermore, combining Q-PCR with 5' RLM-RACE and sequencing are described for the identification of novel ETS fusion partners. PMID- 21796536 TI - Regulation of apoptosis by androgens in prostate cancer cells. AB - The balance between proliferation and cell death is often disrupted in cancer leading to tumor growth. In prostate cancer, these events are regulated, at least in part, through androgen signaling. Prostate cancer is dependent on androgens for growth in the initial stages where apoptosis is simultaneously inhibited. Androgen signaling remains important in later stages of prostate cancer as well. Here, we provide methods to study apoptosis in prostate cancer cells and its regulation by androgens. In prostate cancer cells grown in vitro, apoptosis can be induced by different stimuli, such as the endoplasmic reticulum Ca2+ ATPase inhibitor Thapsigargin (TG) through the intrinsic apoptosis pathway, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plus the inhibition of PI3K, through the extrinsic signaling pathway; both of these apoptotic events can be blocked by androgens. Here, we provide protocols to assess apoptosis triggered by TG or TRAIL plus PI3K inhibitor LY294002, in prostate cancer cells in vitro using nuclear fragmentation and TUNEL assays aided by fluorescence microscopy or flow cytometry. PMID- 21796537 TI - Analysis of androgen receptor rapid actions in cellular signaling pathways: receptor/Src association. AB - Much evidence indicates that, with few exceptions, non-genomic actions of steroids are mediated by receptors universally known as nuclear receptors. Steroid receptors do not exhibit intrinsic tyrosine kinase activity. Nevertheless, they stimulate different signaling pathways in cytoplasm of target cells, including those dependent on Src, a cytoplasmic tyrosine kinase. Steroid induced Src activation regulates cell cycle progression, survival, migration, and associated processes, such as cell growth and differentiation. Androgen stimulation of human prostate cancer-derived LNCaP cells triggers cell cycle progression and proliferation. The key event in this process is the association of androgen receptor (AR) with Src. This association triggers activation of the Src/Ras/Erk pathway and finally impacts cell cycle. Androgen stimulation of fibroblasts also induces AR/Src association, which triggers DNA synthesis. Prevention of this association by a receptor-derived peptide competing for AR interaction with Src specifically inhibits the androgen receptor-dependent proliferative effect in vitro and in vivo. PMID- 21796538 TI - Analysis of androgen-induced increase in lipid accumulation in prostate cancer cells. AB - Increased metabolic activity is a hallmark of proliferating cancer cells. One common deregulated metabolic pathway in prostate cancer is de novo lipogenesis which is highly increased in prostate cancer and is linked to poor prognosis and metastasis. Male sex hormones play an essential role in prostate cancer growth and have been shown to increase the expression and activity of several lipogenic factors, such as fatty acid synthase (FASN) and sterol regulatory element-binding proteins (SREBPs), leading to accumulation of neutral lipids in prostate cancer cells. These factors are being evaluated as potential prognostic markers and therapeutic targets in prostate cancer. Here we describe methods to directly detect and quantify accumulation of neutral lipids and assess concomitant changes in lipogenic gene expression in LNCaP prostate cancer cells. PMID- 21796539 TI - Mortality in a Chinese chrysotile miner cohort. AB - BACKGROUND: Few data were available to address cause-specific mortality in asbestos miners in China. This study observed a cohort of workers from the largest chrysotile asbestos mine to evaluate the association between asbestos exposure and cause-specific mortality. METHODS: The cohort consisting of 1,539 male workers was observed from 1981 to 2006. Information on occupational and smoking history and vital status was obtained through personnel records and individual contact. Causes and dates of deaths were verified from hospitals. Workers were divided into two groups: miners and millers (miner group) and control group (not direct exposed). Recent asbestos dust measurements in the workplaces showed that the concentrations ranged from 12 to 197 mg/m(3). Amphibole contamination was very low. Cox proportional hazard models with competing risks were fit to estimate hazard ratios for cause-specific mortality associated with asbestos exposure (miners vs. controls). In addition, standardized mortality ratios (SMRs) were calculated based on national mortality rates. RESULTS: All mortality rates of selected causes, particularly lung cancer, were substantially higher in the miner group than in the controls. SMRs of lung cancer and nonmalignant respiratory diseases in the miners were 4.71 (95% CI, 3.57, 6.21) and 3.53 (2.78, 4.48), respectively. The controls had similar mortality rates of all causes, lung cancer, all cancers as national rates, but a higher mortality from respiratory diseases. Asbestos exposure was related to a 4.6-fold mortality risk for lung cancer and over threefold risk for all cancers and respiratory diseases, while smoking and age were adjusted. The highest SMR of lung cancer was observed in miners who smoked. CONCLUSION: The results suggested excessive cause-specific mortality, in particular from lung cancer and respiratory diseases, in the cohort, which was associated with exposure to chrysotile asbestos. PMID- 21796540 TI - Prehension synergies during smooth changes of the external torque. AB - We studied characteristics of digit action and their co-variation patterns across trials (prehension synergies) during static holding of an object while the external torque could change slowly and smoothly. The subjects held in the air an instrumented handle with an attachment that allowed a smooth change in the external torque over about 12 s; the load was always kept constant. Series of trials were performed under three conditions: The torque could be zero throughout the trial, or it could change slowly requiring a smooth change of the effort from a non-zero pronation value to zero (PR-0) or from a non-zero supination value to zero (SU-0). The handle was kept vertical at all times. Indices of variance and co-variation of elemental variables (forces and moments of force produced by individual digits) stabilizing such performance variables as total normal force, total tangential force, and total moment of force were computed at two levels of an assumed control hierarchy. At the upper level, the task is shared between the thumb and virtual finger (an imagined digit with the mechanical action equal to that of the four fingers), while at the lower level, the action of the virtual finger is shared among the actual four fingers. We analyzed the total moment of force as the sum of the moments of force produced by the thumb and virtual finger and also as the sum of the moments of force produced by the normal forces and tangential forces. The results showed that the adjustments in the total moment of force were produced primarily with changes in the moment produced by the virtual finger and by changes in the moment produced by the normal forces. The normal force of the thumb at the final state (which was the same across conditions) was larger in the two conditions with changes in the external torque. The safety margin was significantly higher in the PR-0 condition, and it dropped with the decrease in the external torque. A co-contraction index was computed to reflect the moment of force production by the fingers acting against the total moment produced by the virtual finger. It was higher for the SU-0 condition. Most variance indices dropped with a decrease in the external torque. The co-variation indices, however, remained unchanged over the trial duration. They showed signs of a trade-off between the two levels of the assumed hierarchy: larger indices at the higher level corresponded to smaller indices at the lower level. This study and the previous one (Sun et al. in Exp Brain Res 209:571-585, 2011) document several previously unknown features of prehensile tasks. The results show that characteristics of digit action and interaction in such tasks depend not only on the magnitudes of external constraints but also on a variety of other factors including time changes in the constraints and their history. PMID- 21796545 TI - Management of gastrostomy to prevent perforation in acute severe corrosive esophagitis and gastritis: an experimental study. AB - BACKGROUND/AIMS: Symptomatic treatment is still the most commonly preferred treatment modality for acute severe esophagitis and gastritis. Clinical results of this treatment range from pathologies like stricture formation to loss of life. In our study, we aimed to demonstrate the effect of immediate gastrostomy in preventing perforation due to corrosive trauma. METHODS: We used 32 rats in two study groups. In Group I (n: 16 rats), 1 ml of corrosive agent (10% NaOH solution) was administered and immediate gastrostomies were performed within 2 hours. In Group II (n: 16 rats), 1 ml corrosive agent (10% NaOH solution) was administered and the rats were treated symptomatically; no operation was performed. RESULTS: Acute death was observed in 5 rats just after the corrosive agent was administered at the beginning of the study. Three rats from Group II died due to esophageal and gastric perforation within one week (25%). Necrosis was reported in 5 non-gastrostomized rats; however, no necrosis was observed in the gastrostomized group (p=0.037). CONCLUSIONS: Severe acute corrosive esophagitis and gastritis may be fatal. Furthermore, survivors may suffer from lifelong associated problems. From this study, we concluded that immediate gastrostomy in acute corrosive esophagitis and gastritis may play an important role in preventing necrosis and perforation risk. PMID- 21796541 TI - Levodopa medication does not influence motor inhibition or conflict resolution in a conditional stop-signal task in Parkinson's disease. AB - Evidence from animal, clinical, and imaging studies suggests that the basal ganglia and their frontal connections mediate motor inhibition, but the role of dopamine remains unclear. The aim of our study was to investigate, for the first time, whether levodopa medication influences motor inhibition and conflict resolution on the conditional stop-signal reaction time task in patients with Parkinson's disease (PD) tested on or off their medication. Sixteen PD patients and 17 healthy controls performed the conditional stop-signal reaction time (SSRT) task, which requires inhibition of responses when a stop signal is presented on "critical" trials. Additionally, on "non-critical" trials, participants are instructed to ignore the stop signal and respond, thus generating conflict between motor inhibition and initiation; and conflict-induced slowing (CIS) on these "non-critical" trials. Levodopa medication did not significantly influence response initiation, inhibition (SSRT) or the measure of conflict resolution (CIS). Compared to healthy controls, PD patients showed significantly worse response initiation and inhibition both on and off their levodopa medication. Our results suggest that motor inhibition or conflict induced slowing on the conditional stop-signal RT task are not altered by dopamine replacement in PD. This conclusion is consistent with evidence from animal studies and clinical pharmacological investigations suggesting a role for noradrenaline in motor inhibition and impulsivity. PMID- 21796546 TI - Helicobacter pylori and histopathological findings in patients with dyspepsia. AB - BACKGROUND/AIMS: Although Helicobacter pylori infection has been reported to be more frequent in patients with dyspepsia, whether it should be treated in dyspepsia remains controversial. This study was carried out to compare the histopathological changes in Helicobacter pylori-positive and -negative dyspepsia patients. METHODS: A total of 461 patients with Helicobacter pylori-positive dyspepsia seen in our institution were enrolled in the study. The control group was formed from 100 Helicobacter pylori-negative dyspepsia patients. Subjects underwent an upper gastrointestinal endoscopy, and biopsy specimens were taken from the gastric antrum and corpus. All of the cases were evaluated according to the Sydney classification, and the relation of Helicobacter pylori with chronic inflammation, atrophy, intestinal metaplasia, and activity was investigated by two pathologists. RESULTS: Activity, inflammation and intestinal metaplasia were found in 10 (10%), 70 (70%) and 10 (10%) of Helicobacter pylori (-) patients, respectively, and the numbers increased with increasing Helicobacter pylori intensity when compared with Helicobacter pylori (+) patients (p<0.01, p<0.01 and p<0.05, respectively). Atrophy was found in 27 (5.5%) of all cases (in 10 Helicobacter pylori (-) patients and in 17 Helicobacter pylori (+) patients), but no significant relation was found with increasing Helicobacter pylori intensity (p>0.05). There was no significant difference between corpus alone or antrum alone Helicobacter pylori (+) and both corpus/antrum (+) patients in regards to the presence of activity, inflammation, intestinal metaplasia, and atrophy (p>0.05). CONCLUSIONS: Determination of the degree of morphological changes accompanying Helicobacter pylori infection in dyspepsia is important in the follow-up and treatment of patients. As activity, inflammation and intestinal metaplasia increase with increasing Helicobacter pylori intensity in dyspepsia patients, Helicobacter pylori eradication treatment can be recommended in these patients. PMID- 21796547 TI - Acceptability and outcomes of percutaneous endoscopic gastrostomy (PEG) tube placement and patient quality of life. AB - BACKGROUND/AIMS: Since its description in 1980, percutaneous endoscopic gastrostomy has been a widely used method for insertion of a gastrostomy tube in patients who are unable to swallow or maintain adequate nutrition. This study aimed to assess the perspectives of patients/caregivers in our society regarding the acceptability of percutaneous endoscopic gastrostomy tube placement and to evaluate the outcomes. METHODS: One hundred consecutive adults referred to our unit to be considered for primary percutaneous endoscopic gastrostomy feeding at Imam Reza Hospital of Tabriz University of Medical Sciences were evaluated prospectively from October 2007 to June 2009. The nutritional status of patients, complications and quality of life were assessed after percutaneous endoscopic gastrostomy insertion for six months. The data were analyzed using SPSS software. RESULTS: Indications for percutaneous endoscopic gastrostomy were neurologic in 66 patients and recurrent pulmonary aspiration in 14 intensive care unit adult patients. Minor complications included percutaneous endoscopic gastrostomy site infection in 8 patients and tube blockage in 5 patients. Oral feeding was resumed in 27% of the patients and the tube was removed subsequently after 3-6 months; 42 patients died due to primary diseases (in 1-6 months). The Quality of Life Index scores pre-percutaneous endoscopic gastrostomy placement and 6 months after percutaneous endoscopic gastrostomy averaged 19.25+/-11.85 and 30.08+/-27.74, respectively. A similarly significant difference was also found between mean Quality of Life Index scores pre- and post-percutaneous endoscopic gastrostomy placement (p<0.005). CONCLUSIONS: Percutaneous endoscopic gastrostomy is a minimally invasive gastrostomy method with low morbidity and mortality rates, and is easy to follow-up and to replace when blockage occurs. PMID- 21796548 TI - Is there a relationship between Helicobacter pylori and gastric autoimmunity? AB - BACKGROUND/AIMS: Helicobacter pylori-associated corpus atrophy and autoimmune gastric atrophy share similar histopathologic and clinical aspects. In our study, the relation between Helicobacter pylori and autoimmune gastritis was investigated. METHODS: Eighty-two consecutive histologically and serologically Helicobacter pylori-positive and 96 Helicobacter pylori-negative patients were enrolled in the study. All patients underwent diagnostic upper esophagogastroduodenal endoscopy. Three biopsy specimens from the antrum and corpus greater curvature were obtained for histologic evaluation. Serum samples were collected for detection of anti-parietal cell antibody, anti-Helicobacter pylori IgG and vitamin B12. Statistical analyses were determined with Student t test and chi-square test. Statistical significance was determined with a p-value <0.05. RESULTS: Of 82 Helicobacter pylori-positive patients, 45 were female and 36 were male, with a mean age 45.1 +/- 15.1. There was no significant difference in age, gender and corpus atrophy between the Helicobacter pylori-positive and negative groups. Eleven Helicobacter pylori-positive patients (13.4%) and 14 (14.6%) Helicobacter pylori-negative patients were positive for anti-parietal cell antibody; the difference between the two groups was not statistically significant (p>0.05). Differences in esophagogastroduodenal endoscopy findings, antrum and corpus inflammation, antrum and corpus atrophy, and vitamin B12 levels were found to be insignificant between parietal cell antibody-positive and negative groups (p>0.05). CONCLUSIONS: We did not find any relation between Helicobacter pylori infection and anti-parietal cell antibody, a marker of autoimmune gastritis. Long-term follow-up of Helicobacter pylori-infected patients and also determination of the relation between eradication of Helicobacter pylori and autoimmune atrophic gastritis are needed. PMID- 21796549 TI - Analysis of factors related to lymph node metastasis in undifferentiated early gastric cancer. AB - BACKGROUND/AIMS: This study was conducted to analyze the factors related to lymph node metastasis in undifferentiated early gastric cancer and to investigate whether endoscopic resection can be performed. METHODS: Three hundred sixty-two early gastric cancer patients who were diagnosed with undifferentiated early gastric cancer and underwent surgery were divided into groups depending on their age, sex, location of tumor, macroscopic findings, presence of an ulcer, histological type, tumor size, depth of invasion, and lymphatic involvement, and the correlations between clinicopathological characteristics and lymph node metastasis were analyzed. RESULTS: Lymph node metastasis was detected in 31 (8.5%) of the 362 patients. Univariate analysis revealed correlations between lymph node metastasis and various factors ranging from patient age, location of tumor, presence of an ulcer, and depth of invasion to lymphatic involvement. However, in multivariate analysis, presence of an ulcer and lymphatic involvement were found to be independent risk factors. After selecting and analyzing only patients with intramucosal early gastric cancer, we found that lymphatic involvement was the only independent risk factor. CONCLUSIONS: Though presence of an ulcer is an independent predictive factor for lymph node metastasis before operation in patients with undifferentiated early gastric cancer, caution is required in the interpretation. In addition, clinicopathological characteristics such as histological type and tumor size did not have a significant effect on lymph node metastasis. Therefore, we found that the evidence was insufficient to select endoscopic resection even when there is a small lesion, and we believe that the decision on the use of endoscopic resection for patients with undifferentiated early gastric cancer should be made more carefully when there is an ulcer. PMID- 21796550 TI - Differential response of gastric carcinoma MKN-45 and 23132/87 cells to H2O2 exposure. AB - BACKGROUND/AIMS: Reactive oxygen species are involved in tumor progression but how they function is not well understood. In this study, we investigated and compared the effects of hydrogen peroxide on the survival, apoptosis, accumulation of oxidative stress, and matrix metalloprotein-7 gene expression on human gastric carcinoma MKN-45 and 23132/87 cells. METHODS: The cell lines were exposed to hydrogen peroxide in a dose- and time-dependent manner. The surviving cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The oxidative stress was analyzed by an oxidative stress marker, 2,7-dichlorofluorescein diacetate, under fluorescence microscope. The effect of oxidative stress on the apoptotic behavior, caspase-3 activity, and matrix metalloprotein-7 gene expressions of the cell lines were determined, respectively, by TUNEL, caspase-3 activity assay, and quantitative real-time polymerase chain reaction. RESULTS: Exposure of the gastric cancer cells to oxidative stress resulted in dose- and time-dependent decrease in the survival of the cell lines. While MKN-45 cells had oxidative stress, increased apoptosis with no caspase-3 activity, and increased matrix metalloprotein-7 expression following hydrogen peroxide exposure, 23132/87 cells showed none, with internal oxidative stress accumulation prior to hydrogen peroxide exposure. CONCLUSIONS: The two gastric cancer cell lines responded differently to oxidative stress conditions, and unlike in 23132/87 cells, matrix metalloprotein-7 gene expression was shown to be affected by external hydrogen peroxide in MKN-45 cells. PMID- 21796551 TI - Characteristics of patients dying from acute viral hepatitis in Serbia. AB - BACKGROUND/AIMS: Acute viral hepatitis is complicated rarely with severe liver failure due to many factors associated with the etiology, patient age, and time of development of hepatic encephalopathy, etc. The aim of this study was to identify some of the clinical and laboratory features associated with a fatal outcome in patients dying from acute viral hepatitis in Serbia. METHODS: Clinical and laboratory data from 47 patients hospitalized from January 1989 December 2006 were reviewed retrospectively. Serological tests for hepatitis A, B, C, D, and E viruses, herpes simplex viruses, cytomegalovirus, and Epstein-Barr virus were done. Histological features were assessed from 35 liver tissues. The electronic base, SPSS for Windows (version 11.0), was used for statistical analysis. RESULTS: The majority of the patients had alanine aminotransferase (ALT) >20x the normal value, serum bilirubin >300 MUmol/L, prothrombin time >25 seconds (s), and white blood cell count >12 x 10(9)/L. Regression analysis revealed activity of alanine aminotransferase >20x the normal value to be associated with fulminant (p=0.015) and serum bilirubin concentration with subfulminant hepatitis (p=0.008). Hepatitis B virus was the most commonly detected virus (70%). Massive hepatocyte necrosis vs. sub-massive with bridging necrosis were found to be independent of clinical presentation. CONCLUSIONS: Hepatitis B virus infection, severe impairment of liver function tests, and confluent hepatocyte necrosis and infection characterize patients dying from acute viral hepatitis in Serbia. High activity of alanine aminotransferase reflects rapid and extensive acute viral liver injury, while deep jaundice is more common in a protracted course of the disease. PMID- 21796552 TI - MR imaging in diffuse-type hepatocellular carcinoma with synchronous portal vein thrombi. AB - BACKGROUND/AIMS: Diffuse or continuous multifocal tumors with accompanying portal vein thrombosis yield considerable changes in the magnetic resonance imaging findings of hepatocellular carcinoma. The overlapped imaging findings of these two co-existing pathologies may be confusing. We aimed to evaluate the magnetic resonance imaging findings of widespread hepatocellular carcinoma lesions complicated with portal vein thrombosis. METHODS: Twenty-two patients (20 male, 2 female; mean age: 57 years) with portal vein thrombosis and diffuse-type hepatocellular carcinoma who underwent contrast-enhanced hepatic magnetic resonance imaging in our department between August 2001 and November 2008 were evaluated retrospectively. The unenhanced axial T1-weighted, T2-weighted, and post-contrast early- and late-phase images were reviewed in each patient. RESULTS: On T2-weighted magnetic resonance images, tumors were seen mildly hyperintense in 11 patients and heterogeneously hyperintense in 11 patients. Unenhanced T1-weighted images demonstrated homogeneous hypointensity in 15 patients and heterogeneous hypointensity in 7 patients. Post-contrast early-phase magnetic resonance images showed patchy enhancement in 12 patients, moth-eaten enhancement in 6 patients, strong enhancement in 1 patient, and minimal enhancement in 3 patients. Post-contrast late-phase magnetic resonance images demonstrated heterogeneous washout in all patients. Portal vein thrombosis was present in all patients. The mean diameter of main portal vein thrombi was 27 mm (range: 25-30 mm). Serum alpha-fetoprotein levels were elevated in all patients. CONCLUSIONS: In patients with chronic parenchymal liver disease, when portal vein thrombosis and high serum alpha-fetoprotein values co-exist, careful attention must be paid to the hepatic parenchymal changes, especially on contrast-enhanced images, in order to not overlook diffuse-type hepatocellular carcinoma. PMID- 21796553 TI - The impact of hepatitis C virus infection on long-term outcome in renal transplant patients. AB - BACKGROUND/AIMS: The aim of this study was to determine the effect of hepatitis C virus infection on patient and graft survival and liver function in renal transplant patients. METHODS: 1811 renal transplant patients were included in this study. One hundred renal transplant patients (5.5%) were anti-hepatitis C virus-positive. We evaluated demographic, clinical, biochemical, and serological data of patients and compared patient and graft survivals between hepatitis C virus-positive and -negative renal transplant patients. RESULTS: The median follow-up period was 35.7 months. One hundred (5.5%) patients were anti-hepatitis C virus-positive. There were no differences between anti-hepatitis C virus positive and -negative renal transplant patients regarding age, etiology of renal disease, number of pre-transplant blood transfusions, and hepatitis B virus coinfection rate. Rate of graft loss in anti-hepatitis C virus-positive renal transplant patients was significantly higher than in anti-hepatitis C virus negative patients (16.0% vs. 9.2%, p=0.026). Survival analysis revealed that patient survival was similar between anti-hepatitis C virus-positive and negative renal transplant patients. Graft survival was lower in the anti hepatitis C virus-positive group than in anti-hepatitis C virus-negative patients, especially after the fifth year of renal transplant (p<0.001). Thirty three percent of anti-hepatitis C virus-positive patients were positive for hepatitis C virus RNA. Twenty-seven percent of anti-hepatitis C virus-positive patients had persistent alanine aminotransferase elevation. None of the patients developed cirrhosis during the follow-up period. CONCLUSION: Our findings suggest that hepatitis C virus infection in renal transplant patients does not adversely affect patient survival. Long-term graft survival seems to be lower in hepatitis C virus-positive compared to hepatitis C virus-negative renal transplant patients. Nevertheless, renal transplant can be considered as a safe and effective treatment modality in anti-hepatitis C virus-positive patients with end stage renal disease. PMID- 21796555 TI - Gallbladder ascariasis. AB - BACKGROUND/AIMS: Gallbladder ascariasis is rarely encountered. The causative agent is Ascaris lumbricoides. Presence of ascaris inside the gallbladder can incite acalculous cholecystitis. We aimed in this report to study gallbladder ascariasis. METHODS: This is a case study of 28 patients with a diagnosis of gallbladder ascariasis from 2005 to 2010 who were seen in the Department of General Surgery, SMHS Hospital. RESULTS: Three patients with gallbladder ascariasis had associated worms in the common bile duct. On abdominal sonography, all patients showed worms as linear echogenic shadows or the worms showed 'belly dance' of worms when actively moving. Acute acalculous cholecystitis was present in 21 patients, and 7 had biliary colic. Dead worms in the gallbladder were seen in 4 patients, of which, one was fragmented and another had calcified form of parasite. Twenty-two patients had spontaneous exit of worms from the gallbladder with a time interval ranging from 1 hour to 144 hours from the time of a diagnosis. Six patients had cholecystectomy. Two patients were subjected to emergency cholecystectomy due to multiple impacted worms not exiting from the gallbladder after conservative treatment. CONCLUSIONS: Based on our experience, ultrasound diagnosis is advocated as a highly sensitive and noninvasive technique for suspected gallbladder ascariasis and it can be repeated frequently to monitor movement of worms in the gallbladder and common bile ducts. PMID- 21796554 TI - Relationship of CA 19-9 with choledocholithiasis and cholangitis. AB - BACKGROUND/AIMS: It is well known that increased concentrations of CA 19-9 can be found in benign disease of the liver, pancreas and biliary tract, especially in cases with gallstone disease with cholangitis. The aim of this study was to investigate the relation of CA 19-9 with the number and size of the stones, cholangitis and biliary obstruction in patients with choledocholithiasis. METHODS: Seventy patients with radiologically proven choledocholithiasis were studied. Endoscopic retrograde cholangiopancreatography, sphincterotomy and stone extraction were applied to all patients. In each case, the parameters recorded included the levels of CA 19-9 and other laboratory tests before and after endoscopic retrograde cholangiopancreatography and the results of imaging techniques and immunoserologic tests. The correlations of these parameters were determined by SPSS 17 package program for statistical analysis. RESULTS: Elevation of CA 19-9 was found in 32 patients (46%), while 8 patients (11%) had extraordinarily high levels (>1000 U/ml). CA 19-9 levels were correlated with serum alkaline phosphatase (r=0.5, p<0.01), gamma glutamyl transpeptidase (r=0.5, p<0.01) and bilirubin (r=0.4, p<0.01) levels but not with aspartate aminotransferase or alanine aminotransferase levels. There was also no association between serum CA 19-9 levels and the number and size of stones. Six patients had cholangitis. CA 19-9 levels were found higher in patients with cholangitis than others (100% vs. 41%, p<0.01) as well as alkaline phosphatase, gamma glutamyl transpeptidase and bilirubin levels. After stone extraction, CA 19 9 levels started to decrease and reached normal values 1-28 days later. CONCLUSION: In conclusion, CA 19-9 levels are associated with biliary obstruction and cholangitis but not with the number and size of stones in patients with choledocholithiasis. PMID- 21796556 TI - Surgical outcomes of laparoscopic cholecystectomy in scleroatrophic gallbladders. AB - BACKGROUND/AIMS: Macroscopic appearance of the gallbladder is an important factor in laparoscopic cholecystectomy. The aim of this study was to evaluate surgical outcomes in patients with scleroatrophic gallbladders who underwent laparoscopic cholecystectomy. METHODS: From 2002-2007, 295 patients were found to have a scleroatrophic gallbladder during laparoscopic cholecystectomy. The investigated variables included gender, age, body mass index, preoperative ultrasound evidence of gallbladder wall thickening, number of gallstones, diameter of common bile duct, preoperative endoscopic retrograde cholangiopancreatography, surgeon's experience, gallbladder adhesion score, drain use, conversion rate, operative time, intraoperative and postoperative complications, mortality, and length of hospital stay. RESULTS: Most of the patients were male (56.3%). Overall mean age was 55.50+/-13.75 years. Mean body mass index was 27.91+/-4.43 kg/m2. Based on preoperative ultrasound findings, thickened gallbladder wall was present in 30.8% of patients, dilated common bile duct in 30.2% and multiple gallstones in 83.1%. Preoperative endoscopic retrograde cholangiopancreatography was performed in 32.5% of patients. High-grade adhesions (>=III) were encountered in 68.1% of patients. The conversion rate was 23.1%. The overall intraoperative complication rate was 31.5%. Drains were used in 63.7% of patients. Mean operative time was 65.2+/-32.6 minutes. The rate of postoperative complications was 9.5%. Median hospital stay was 1 day (range: 1-31 days). Mortality occurred in 3 patients (1.0%). CONCLUSIONS: This study demonstrates that scleroatrophic gallbladders present more difficulties during laparoscopic cholecystectomy and are associated with a higher conversion rate. Therefore, it is highly important that patients whose preoperative imaging studies suggest a scleroatrophic gallbladder be referred to an experienced center for hepato-biliary surgery. PMID- 21796557 TI - The effect of alpha-lipoic acid in the prevention of peritoneal adhesions. AB - BACKGROUND/AIMS: Peritoneal adhesions, which occur most frequently after abdominal and pelvic operations, may lead to serious complications such as small intestine obstruction. In various studies, it has been shown that oxidative stress may play a role in the development of peritoneal adhesions, and studies carried out with antioxidants reported positive results. In the present study, the probable preventive role of alpha-lipoic acid, a strong antioxidant, in the development of peritoneal adhesions was investigated. METHODS: Sixteen Sprague Dawley male rats weighing 200-250 grams were employed. Under ketamine+xylazine anesthesia, on the antimesenteric aspect of the cecum, an adhesion model was formed with an incision, and half of the experimental animals were administered a daily single dose 100 mg/kg alpha-lipoic acid through orogastric gavage, and the other half formed the control group. Abdomens were opened 15 days later, and after adhesions were scored macroscopically, tissue samples were taken for evaluation of biochemical parameters. RESULTS: In both adhesion scoring methods, a statistically significant decrease was found in the alpha-lipoic acid group compared to the control group (p<0.05). The decrease in adhesions was also confirmed by the significantly lower hydroxyproline levels in the alpha-lipoic acid group (p<0.05). In addition, alpha-lipoic acid decreased malondialdehyde levels in the adhesion region and prevented the increase in superoxide dismutase and glutathione peroxidase activities significantly (p<0.05). CONCLUSIONS: It can be concluded from the findings of our study that alpha-lipoic acid decreased the development of adhesions in a peritoneal adhesion model and increased the quality of healing. These findings suggest that alpha-lipoic acid, already long used in various indications, may be tried clinically in patients about to undergo abdominal operations. PMID- 21796558 TI - Leptomeningeal carcinomatosis of gastric adenocarcinoma. AB - Gastric cancer is the third most common malignancy among gastrointestinal malignancies. With the advance of new treatments, overall survival in gastric cancer is extending, and metastasis to atypical sites is seen more commonly. Leptomeningeal metastasis is one such atypical metastasis for gastric cancer. We report a case of gastric adenocarcinoma with leptomeningeal metastasis as an atypical involvement. A 39-year-old female, presenting with headache, vertigo, horizontal gaze palsy, visual disturbances, and seizures, was admitted to our hospital in August 2009. The funduscopic examination revealed the presence of bilateral papilledema. Magnetic resonance imaging of the brain showed diffuse leptomeningeal enhancement and biventricular dilatation. Cytological examination of the cerebrospinal fluid revealed malignant cells. These findings were consistent with leptomeningeal carcinomatosis. Six months before, she was diagnosed as having gastric cancer by upper gastrointestinal tract endoscopy, which was performed as a part of the diagnostic work-up to clarify the cause of her abdominal ascites. She received six cycles of docetaxel-cisplatin-5 fluorouracil for metastatic gastric cancer, and she developed the above-mentioned symptoms under chemotherapy. She was included in a craniospinal radiotherapy program and received intrathecal methotrexate treatment. We present this case report since leptomeningeal carcinomatosis of gastric cancers is a rare clinical entity, and treatment strategies remain challenging for clinicians. PMID- 21796559 TI - Small bowel obstruction caused by intramural hematoma secondary to warfarin therapy: a report of two cases. AB - BACKGROUND/AIMS: Spontaneous intestinal hematoma is a rare complication of anticoagulant therapy, and small bowel obstruction caused by intramural hematoma secondary to anticoagulant therapy is even rarer. The first symptom is usually abdominal pain, frequently accompanied by nausea and vomiting. A history of anticoagulant use with prolonged international normalized ratios in patients presenting with abdominal pain should alert physicians to search for this entity. Typical findings on abdominal computed tomography yield the diagnosis. Early diagnosis is crucial because most patients are treated non-operatively with a good outcome. Herein, we present the non-enhanced and enhanced computed tomography findings of two cases who were admitted to the emergency clinic with acute abdominal pain and diagnosed as spontaneous intramural ileal hematomas and partial small bowel obstruction secondary to intramural ileal hemorrhage. PMID- 21796560 TI - Ascaris exit through the feeding jejunostomy tract: a rare case report. AB - A 65-year-old male was operated for esophageal carcinoma. Transhiatal esophagogastrectomy with jejunostomy feeding tube was done. Orals were started on the 12th postoperative day. The jejunostomy feeding tube was removed on the 20th postoperative day. Immediately after removal of the feeding tube, a 10-12 cm ascaris was seen emerging through the jejunostomy tract. Ascaris lumbricoides can cause a variety of complications like intestinal obstruction, perforation, biliary obstruction, pancreatitis, liver abscess, cholangiohepatitis, volvulus, and gangrene, etc. Although the above-mentioned complications have been frequently reported, ascaris exit through the feeding jejunostomy tract is very rare. This case is reported here to emphasize the importance of this complication of wandering ascariasis. PMID- 21796561 TI - Ileovesical fistula secondary to chemotherapy for follicular non-Hodgkin lymphoma: a case report and review of the literature. AB - Enterovesical fistulas are rare complications of malignancies, diverticulitis, inflammatory bowel diseases, radiotherapy, and traumas involving the colorectal and pelvic region. In this study, an ileovesical fistula that occurred during chemotherapy for non-Hodgkin lymphoma is presented. The patient had acute abdomen and multiple comorbidities, and ileovesical fistula was diagnosed during the operation. The affected intestinal segment was resected, and an end-to-end anastomosis was performed with a primary bladder repair. This is a reliable treatment method for such cases. PMID- 21796562 TI - A rare perforated gastrointestinal stromal tumor in the jejunum: a case report. AB - We herein report a 45-year-old Chinese male with a perforated jejunal gastrointestinal stromal tumor causing acute diffuse peritonitis and incomplete intestinal obstruction. At urgent laparotomy, a perforated tumor was found in the jejunum about 40 cm from the Treitz's ligament, and the upper small intestine was twisted 1080 degrees . The clinical symptom of this case is extremely rare, and has not been reported in the literature previously. PMID- 21796563 TI - Hematoma of the falciform ligament: a rare cause of acute abdomen. AB - Hematoma or abscess of the liver ligaments is extremely rare, and hematoma of the falciform ligament has been sporadically reported. We report the case of a 70 year-old female who presented with a three-day history of right upper quadrant abdominal pain, fever and nausea. With a preoperative diagnosis of probable perforated acalculous cholecystitis, the patient underwent emergency surgery. Hematoma of the falciform ligament was found. Wide excision of the falciform ligament including the hematoma with abscess was performed. Although pathology of the falciform ligament is rare, it should be included in the differential diagnosis of acute abdomen, especially in the case of antiaggregant drug usage. PMID- 21796564 TI - Gallbladder agenesis with common bile duct stone--a rare case with a brief review of the literature. AB - We present herein the case of a 45-year-old female who presented with obstructive jaundice and was diagnosed as agenesis of the gallbladder with choledocholithiasis. We discuss the radiological and operative features along with a brief literature review of this uncommon entity. PMID- 21796565 TI - Bulky gastrinoma of the common bile duct: unusual localization of extrapancreatic gastrinoma--case report. AB - Zollinger-Ellison syndrome is characterized by elevated levels of serum gastrin associated with increased gastric acid secretion, gastrointestinal ulcerations and diarrhea. Most gastrinomas (75%) occur sporadically and are located within the gastrinoma triangle. Extraduodenal, extrapancreatic and extranodal gastrinomas have been shown in 5.6% of the patients with Zollinger-Ellison syndrome who underwent surgery. We report a 44-year-old female who had been complaining of nausea and diarrhea for 12 years. Abdominal computed tomography and magnetic resonance imaging detected a homogeneous, regular-shaped 6 x 7 cm solid mass, located between the liver, right kidney and inferior vena cava. Somatostatin receptor positive scanning led us to investigate a neuroendocrine tumor. Serum gastrin level was found very high and the patient underwent surgery. Local excision of the tumor was performed, and an 8x6x5 cm, well-capsulated, solitary mass, originating from the common bile duct was removed. The unique feature of our case is the unusual localization, and although the tumor was very large in size, only capsule invasion was observed with no evidence of distant metastasis. PMID- 21796566 TI - Successful endoscopic treatment of huge gastric inflammatory fibroid polyp. PMID- 21796567 TI - A case of atypical celiac hepatitis presenting with hypogonadism, pancytopenia and lymphadenopathy. PMID- 21796568 TI - Endoscopic removal of an iatrogenically induced rectal foreign body. PMID- 21796569 TI - Metastasis of rectal cancer to soft tissue of the hand: an unusual case. PMID- 21796570 TI - Visible common bile duct at the duodenum due to the destructive effect of the tumor. PMID- 21796571 TI - A newly defined biliary anatomic variation. PMID- 21796572 TI - Successful endoscopic removal of fractured basket traction wire during mechanical lithotripsy. PMID- 21796573 TI - Multiorgan involvement in HHV-8-positive multifocal inflammatory myofibroblastic tumor. PMID- 21796574 TI - Incidence of previously unknown cardiac malformations in asymptomatic children after prenatal obstetric ultrasound screening. AB - BACKGROUND: Cardiac murmurs may be frequently found in otherwise asymptomatic children. Obstetric ultrasound screening for congenital heart disease is increasingly used to provide an antenatal diagnosis and an early treatment; thus, the incidence of cardiac anomalies in children has changed. We evaluated cardiac murmurs in otherwise healthy children referred to a level I pediatric cardiology institution. METHODS: Echocardiography data from a cohort of 2045 patients from 2000 to 2009 were evaluated and the incidence and type of a newly diagnosed congenital heart disease have been determined. RESULTS: The majority of the children with a cardiac murmur were found to have an innocent murmur, chordae tendinae, or a minor lesion. Children born after obstetric screening are nevertheless associated with a small risk of severe congenital heart disease. We found 14.9% with a previously unknown congenital cardiac malformation; 1.4% required medical treatment and 0.6% of the patients had either a catheter or a surgical intervention. CONCLUSIONS: This study provides evidence that the use of obstetric screening for congenital heart disease reduces the occurrence of severe heart disease. Otherwise healthy children with murmurs still bear a small risk of having a cardiac defect, even if a prenatal study was negative. Therefore, the evaluation of children with a murmur by a pediatric cardiologist is recommended in an antenatally-screened population. PMID- 21796575 TI - [Myopia update 2011]. AB - This review summarises some recent aspects of myopia research. The following conclusions have been drawn. As long as myopia progression is visually controlled, at least three different interventions are possible: (i) spectacles/contact lenses which correct only the centre of the visual field and leave the periphery somewhat myopic, (ii) outdoor activity or equivalent temporary increase in illuminance, (iii) pharmacological intervention of retinal growth signals that are transmitted to the underlying sclera. Options (i) and (ii) can be used without risks although there is still room for improvement of the variables. Option (iii) has re-entered a new phase of orientation with new searches for candidate targets after previous testing with muskarinic antagonists (pirenzepine) in children did not enter phase 3 level. If myopia is outside the range over which it is visually controlled by emmetropisation (in the case of high and pathological myopias), in principle the possibility exists to improve the mechanical stability of the sclera pharmacologically. However, there is still a need for more research. Up to now, the mechanical weakness of the sclera in highly mopyic eyes is surgically stabilised by "scleral buckling". However, these procedures have found limited acceptance since the effects were not very reliable. In 40 - 50 % of the cases of high myopia, degenerative processes are found in the retina which can be seen as consequence of the mechanical tension in the fundus, but may also be indepedent of this factor (no significant correlation with axial length!). In part they can be slowed down by intravitreal anti-VEGF therapy. A long-term study from Denmark has shown that most patients with myopia of between 6-9 dpt during puberty reach retirement age without disabling visual loss. PMID- 21796576 TI - Biphenyl and biphenyl ether quinolizidine N-oxide alkaloids from Lagerstroemia indica L. AB - Four new biphenyl and biphenyl ether quinolizidine N-oxide alkaloids, 5- EPI dihydrolyfoline N-oxide (1), decamine N-oxide (2), lagerstroemine N-oxide (3), and lagerine N-oxide (4), were isolated from the aerial parts of Lagerstroemia indica, and their structures were established by extensive spectroscopic studies. In addition, the inhibitory effects of isolated compounds on rat lens aldose reductase (RLAR) were examined. PMID- 21796577 TI - Three new phenolic compounds from the lichen Thamnolia vermicularis and their antiproliferative effects in prostate cancer cells. AB - Three new phenolic compounds, thamnoliadepsides A (1), B (2), and thamnolic acid A (3), and seven known compounds, everninic acid (4), baeomycesic acid (5), beta orcinol (6), beta-resorcylic acid (7), ethyl orsellinate (8), squamatic acid (9), and vermicularin (10), were isolated from the lichen Thamnolia vermicularis (Sw.) Ach. ex Schaerer. Their structures were determined based on spectroscopic analysis, including 2D-NMR experiments and HR-MS techniques. Compound 1 inhibited growth of prostate cancer cells and bonded to G-quadruplex DNA based on NMR determination. PMID- 21796578 TI - [Information needs of physicians, professional carers and family carers for an evidence-based dementia website]. AB - OBJECTIVE: Despite the demographically driven rapid growth of the number of persons with dementia, in Germany a website is lacking that provides evidence based information about the disease, its burden and therapeutic options to family and professional carers as well as physicians. A website was developed with the objective to give free access to evidence based information concerning the disease and care for patients with dementia. METHODS: In order to meet the expectations of the user groups an analysis of information needs was performed with 80 physicians, 163 professional carers and 104 family carers. RESULTS: All user groups rated information on symptoms, course and treatment of dementia and support for family carers as important topics. Group differences were found for the need to be informed on financial support, daily care and interaction with patients. CONCLUSIONS: The contents of the website will be accommodated to the specific needs of the user groups. PMID- 21796579 TI - Practice in the perioperative prevention of deep vein thrombosis in german neurosurgical departments: is there a trend towards homogenization? AB - OBJECTIVE: There was no consensus on the most suitable perioperative prophylaxis of deep vein thrombosis (DVT) in neurosurgical patients. The aim of this work was to review the current practice and search for a standard protocol in the prophylaxis of DVT. METHODS AND MATERIAL: Questionnaires addressing the routine prophylaxis of perioperative DVT for 4 groups of neurosurgical procedures and the estimation of risks and benefits of perioperative heparin (unfractionated and/or low-molecular-weight) administration were sent to 130 neurosurgical departments in Germany. RESULTS: 103 of 130 questionnaires were returned and suitable for analysis. The use of heparin (unfractionated and/or low-molecular-weight) is common, with some variation depending on the type of operation (83.5-99%). In spinal procedures, heparin administration is commonly started early, i. e., between the preoperative and first postoperative day (90.3-97.1%). This differs in intracranial procedures. In most neurosurgical departments heparin administration is stopped at the day of discharge (69.6-77.4% depending on procedure). Enoxaparin is the most commonly used heparin. In spinal as well as in cranial procedures, thrombosis risk reduction is unanimously assumed to be lesser the later administration starts. The estimation of the risks related to heparin injection are considered to be higher in cranial than in spinal operation in the early postoperative period. Most departments use antithrombotic stockings (ATS) irrespective of the type of surgery. However, 11% never use ATS. CONCLUSIONS: In spinal surgery, a trend towards homogenization is observed with the early use of heparin. In intracranial procedures, practice is more heterogenous. The heterogeneity is due to the fact that the data available in the literature does not allow for the identification of an optimal protocol. PMID- 21796580 TI - [Treatment of severe chronic constipation: differential roles of conventional laxatives and the prucalopride prokinetic]. PMID- 21796581 TI - Comparisons of outcomes from repair of median nerve and ulnar nerve defect with nerve graft and tubulization: a meta-analysis. AB - In this study, an updated meta-analysis of all published human studies was presented to evaluate the recovery of the median and the ulnar nerves in the forearm after defect repair by nerve conduit and autologous nerve graft. Up to June of 2010, search for English language articles was conducted to collect publications on the outcome of median or ulnar nerve defect repair. A total of 33 studies and 1531 cases were included in this study. Patient information was extracted from these publications and the postoperative outcome was analyzed using meta-analysis. There was no significant difference in the postoperative recovery between the median and the ulnar nerves (odds ratio = 0.98). Sensory nerves were found to achieve a more satisfactory recovery after nerve defect repair than motor nerves (P < 0.05). Median nerve can also achieve more satisfactory recovery in both sensory and motor function than ulnar nerve (P < 0.05). There was no statistical difference between tubulization and autologous nerve graft in repairing defects less than 5 cm. Based on the results of this study, a median nerve with sensory impairment was associated with improved postoperative prognosis, while an ulnar nerve with motor nerve damage was prone to a worse prognosis. Tubulization can be a good alternative in the reconstruction of small defects. PMID- 21796582 TI - Anxiety and trauma perception and quality of life in patients who have undergone replantation. AB - The difficulty in keeping an amputated limb biologically alive is overcome day by day thanks to the successful replantation procedures applied in the early period. However, the reflections of this biological success on patients in functional and psychological terms may not be pleasing all the time. In our study, we aimed to evaluate the perceptual responses of patients to trauma after replantation and their possible effects on clinical results. We conducted a retrospective study of 43 patients who underwent replantation. The average age was 32.4 years and the average follow-up period was 38.6 months. When the results of the Short Form-36 (SF-36), Beck's Depression Inventory, and the assessment scores of the disabilities of the arm, shoulder, and hand survey were evaluated, there was a negative correlation between the patients diagnosed with depression and all SF-36 subunits. A negative correlation between the severity of trauma and the average physical and mental values included in the SF-36 evaluations was observed (R = 0.48, R = 0.51, respectively),. These results revealed that the psychology of the patient was one of the important factors that could not be ignored in the success of replantation. PMID- 21796583 TI - Serratus anterior venous tributary as a second outflow vein in latissimus dorsi free flaps. AB - The latissimus dorsi (LD) flap is a large and reliable myocutaneous flap with a consistently long vascular pedicle. However, the limitation of the thoracodorsal pedicle is that it has only one draining vein for anastomosis. We describe a simple technique of recruiting the tributary vein to the serratus anterior and using it as a second draining vein to alleviate congestion in lower limb reconstruction. The serratus anterior venous tributary segment is cut back to an avalvular segment which averages 5 mm in length. Provision of an additional venous outflow to the flap enabled a second venous anastomosis to the short saphenous vein (N = 1), the long saphenous vein (N = 2), a deep vein (N= 1), and to a deep vein via a vein graft (N = 1), respectively. Five patients with degloving injury of the lower extremity of sizes 150 cm(2) (10 * 15 cm) to 260 cm(2) (10 * 26 cm) underwent successful reconstruction using the LD muscle flap with the serratus anterior tributary vein as a second outflow vein. This serratus anterior venous tributary serves as a useful second outflow channel for alleviating venous congestion during lower limb reconstructive surgery and should be routinely preserved as a lifeboat. PMID- 21796584 TI - Skin perforator flaps: an algorithm for leg reconstruction. AB - The local fasciocutaneous flap has the advantage of low donor site morbidity when used for the coverage of lower limb defects. However, flap reliability remains a major problem with its use. Perforator flaps are indicated for several clinical problems. The versatility of the perforator flap makes it ideal for the reconstruction of extremities. Between September 2007 and November 2010, 34 skin perforator flaps were raised in 33 cases. Flaps which were executed as peroneal artery flaps were 13, 0.16 flaps were raised as posterior tibial artery perforator flaps, and 5 flaps as medial sural medial gastrocnemius muscle perforator skin flap. A segmental perforator was dissected and retained. Thirty two flaps survived completely and none exhibited venous compromise. In one patient, flap was lost completely and the other showed partial tip necrosis. Complicated flaps were responded to conservative treatment. Skin perforator flap represents a technical advancement over conventional lower limb skin flaps because of its improved vascularity. It provides the surgeon with additional reconstructive options in reconstruction of difficult areas and injuries of leg. Clinical judgment is essential to assess the potential vascular territory of the flap. PMID- 21796585 TI - [Intralesional sclerotherapy of venous malformations in the hand with methyl tetradecyl sulfate]. AB - Congenital venous malformations (VM) at the hand are rare. VM consist of dysplastic venous vessels without progressive cellular proliferation. The therapy for VM is considerably different from that for vascular tumours (e. g., haemangiomas). Treatment options for vascular malformations are antithrombotic medication, local compression, resection of the VM, and obliteration of the lumina by percutaneous sclerosation. Here, the percutaneous sclerosation for the treatment of VM with sodium tetradecyl sulfate has been illustrated and discussed on the basis of 2 case reports. PMID- 21796586 TI - [Regional concentration of social disadvantage and of risks for lung cancer and colon cancer: systematic review and recommendations for research]. AB - OBJECTIVES: Individual health status is influenced by individual social characteristics (age, gender, income usw.) and by the social characteristics of the regional environment in which the person lives. This is true also for lung cancer and colon cancer, two of the most common cancer sites in Germany. No systematic review about the social and regional distribution of lung cancer and colon cancer has been published in German-speaking countries yet. However, it could allow us to deepen the discussion regarding explanations of cancer risks and potential interventions. METHODS: Lung cancer and colon cancer have been selected because they are the two most common gender-independent cancer sites in Germany. A systematic literature search has been conducted via the Medline database using PubMed. 2 groups of regional differences have been distinguished, first by socio-economic characteristics (e. g., average household income) and second by urban vs. rural characteristics. The publications have then been analysed in a systematic way. RESULTS: 17 publications could be found, just 2 of them are from a German-speaking country (one each from Germany and Switzerland). The results concerning incidence and mortality can be summarised in the following way: The risks for lung cancer increase with decreasing socio-economic status of the region, but no clear association could be found for colon cancer. Some studies include information on urban-rural differences. They show that the risks for lung cancer are higher in urban as compared to rural areas; for colon cancer, again, no clear associations could be found. CONCLUSION: The review shows that some studies have already looked at social and regional differences in lung cancer and colon cancer, and that these associations have hardly been discussed in German-speaking countries as yet. We still do not know why lung cancer risks are especially high in low status regions, even if individual smoking is accounted for. The answer could probably be provided by risks such as air pollution. Therefore, a balanced strategy for reducing health inequalities should not just focus on improving individual health behaviour, but also on reducing the regional risks factors. PMID- 21796587 TI - [School meals at secondary schools: an analysis in the district of St. Wendel in the Province Saarland, Germany]. AB - INTRODUCTION: This study focuses on the nutrition of young people in schools. The Saarland state government mandates the implementation of the "quality standards for school meals", developed by the Germany Society of Nutrition (Deutschen Gesellschaft fur Ernahrung, DGE) in schools offering school meals. This research evaluates the state of implementation. METHODS: 4-week menu plans were evaluated using a stratified random sample of selected schools (n25%-sample=5, ntotal=23). In addition, all catering services of the district (ncaterer=5) were interviewed by written survey focused on any information on the company, the type of food, the menu design as well as general information. RESULTS: None of the analysed menu plans met the DGE standard. The analysis of the menu plans allows for an assessment of the nutritional quality of food. Interviews with caterers provide background information on menu design. DISCUSSION: The analysis of a randomised 25%-sample shows that the target specifications of the DGE are only implemented by a small number of schools in the exemplary selected district of St. Wendel, Germany. As the German Child and Youth Health Survey (KiGGS), also this evaluation shows that the quality of school meals deviates significantly from the recommendations of the DGE. There is a clear need for action. PMID- 21796588 TI - [Are privately owned hospitals more efficient? Results of a survey of the international literature]. AB - BACKGROUND: In no other European country has the privatisation of hospitals taken such dimensions in the last 15 years as in Germany. Thereby a higher efficiency of private ownership is often assumed as a potential driver. OBJECTIVE: The aim of this study is to analyse the current state of research on the question of whether private hospitals are more efficient, or whether the public ones are just plain worse operators of clinics. METHODS: As a contribution to answering the relevant question, a systematic review of the international literature on benchmarking the performance of hospitals as a function of ownership on the basis of the efficiency measurement using DEA (data envelopment analysis) was conducted. RESULTS: In the closer analysis 8 studies were accepted; of which 3 refer to the U.S.A., 3 to the German and one to the Taiwanese and South Korean health-care sector. These studies compare private hospital operators with other types of ownership, where they differ considerably in their methodological approaches. 5 studies reveal that public and not-for-profit hospitals are more efficient than those in private ownership. One study concludes the opposite, and 2 could not demonstrate any significant differences between the different hospital ownerships. CONCLUSION: This result is a surprise taking into consideration the development and discussion in Germany in recent years and in comparison to studies based on alternative approaches to efficiency measurement. The detailed analysis of the studies shows that because of weaknesses and a variety of differences in the methodological structure of the studies a really convincing answer regarding the first question ultimately cannot be derived from the results. PMID- 21796589 TI - [The Danish debate on priority setting in medicine - characteristics and results]. AB - Priority setting in medicine helps to achieve a fair and transparent distribution of health-care resources. The German discussion about priority setting is still in its infancy and may benefit from other countries' experiences. This paper aims to analyse the Danish priority setting debate in order to stimulate the German discussion. The methods used are a literature analysis and a document analysis as well as expert interviews. The Danish debate about priority setting in medicine began in the 1970s, when a government committee was constituted to evaluate health-care priorities at the national level. In the 1980s a broader debate arose in politics, ethics, medicine and health economy. The discussions reached a climax in the 1990s, when many local activities - always involving the public - were initiated. Some Danish counties tried to implement priority setting in the daily routine of health care. The Council of Ethics was a major player in the debate of the 1990s and published a detailed statement on priority setting in 1996. With the new century the debate about priority setting seemed to have come to an end, but in 2006 the Technology Council and the Danish Regions resumed the discussion. In 2009 the Medical Association called for a broad debate in order to achieve equity among all patients. The long lasting Danish debate on priority setting has entailed only very little practical consequences on health care. The main problems seem to have been the missing effort to bundle the various local initiatives on a national level and the lack of powerful players to put results of the discussion into practice. Nevertheless, today the attitude towards priority setting is predominantly positive and even politicians talk freely about it. PMID- 21796590 TI - [Development, factor-analytical control and psychometric evaluation of a questionnaire on specialty choices among medical students]. AB - AIM OF THE STUDY: A questionnaire was developed and validated which assesses factors influencing career choices of medical students and their perception of possibilities in general practice. METHODS: The first questionnaire version, which was developed based on a systematic literature review, was checked for comprehensibility and redundancy using concurrent think aloud. The revised version was filled out by a pilot sample of medical students and the factor structure was assessed using principal component analysis (PCA). The final version was filled out in an online survey by medical students of all 5 Medical Faculties in the federal state of Baden-Wuerttemberg. The factor structure was validated with a confirmatory factor analysis (CFA). Reliability was assessed as internal consistency using Cronbach's alpha. RESULTS: The questionnaire comprises 2 parts: ratings of (A) the individual importance and of (B) the possibilities in general practice on 5-point scales. The first version comprising 118 items was shortened to 63 items after conducting interviews using concurrent think aloud. A further 3 items giving no information were removed after piloting the questionnaire on 179 students. The 27 items of part A were structured in 7 factors (PCA): image, personal ambition, patient orientation, work-life balance, future perspectives, job-related ambition, and variety in job. This structure had a critical fit in the CFA applied to the final version filled out by 1 299 students. Internal consistency of the factors was satisfactory to very good (Cronbach's alpha=0.55-0.81). CONCLUSION: The questionnaire showed good psychometric properties. Further, not assessed factors influence career choice resulting in unexplained variance in our dataset and the critical fit of the model. PMID- 21796591 TI - [Pathophysiology of abdominal pain]. AB - Abdominal pain can be induced by stimulation of visceral nociceptors. Activation of nociceptors usually requires previous sensitization by pathological events, such as inflammation, ischemia or acidosis. Although abdominal pain can obviously be caused by pathology of a visceral structure, clinicians frequently observe that such a pathology explains only part of the pain complaints. Occasionally, there is lack of objective signs of visceral lesions. There is clear evidence that pain states are associated with profound changes of the central processing of the sensory input. The main consequences of such alterations for patients are twofold: 1) a central sensitization, i.e. an increased excitability of the central nervous system; 2) an alteration of the endogenous pain modulation, which under normal conditions inhibits the processing of nociceptive signals in the central nervous system. Both phenomena lead to a spread of pain to other body regions and an amplification of the pain perception. The interactions between visceral pathology and alterations of the central pain processes represent an at least partial explanation for the discrepancy between objective signs of peripheral lesions and severity of the symptoms. Today, both central hypersensitivity and alteration in endogenous pain modulation can be measured in clinical practice. This information can be used to provide the patients with an explanatory model for their pain. Furthermore, first data suggest that alterations in central pain processing may represent negative prognostic factors. A better understanding of the individual pathophysiology may allow in the future the development of individual therapeutic strategies. PMID- 21796592 TI - [Cultural and migration aspects in functional abdominal pain]. AB - Compared to Europe's mean immigrant contingent of 7.3 to 8.6 % Switzerland holds the highest contingent of foreign population with 23.5 %. Therefore it is of utmost importance that physicians have a knowledge of the specific characteristics of immigrant patients. The influence of personality factors (experience, behavior) is not independent from the influence of culturally related environmental factors (regional differences in diet, pollutants, meanings, etc.). In addition, different cultural groups rate their quality of life differently. Psychological reasons for recurrent abdominal pain are stress (life events), effects of self-medication (laxatives, cocaine) and sexual abuse but also rare infectious diseases are more common among immigrants (e.g. tuberculosis, histoplasmosis, etc.). Migration-specific characteristics are mainly to find in the semiotics of the symptoms: not every abdominal pain is real pain in the abdomen. Finally, it is crucial to make the distinction between organic, functional and psychological-related pain. This can, however, usually only be accomplished in the context of the entire situation of a patient and, depending on the situation, with the support of a colleague from the appropriate cultural group or an experienced interpreter. In this review we limit ourselves to the presentation of the working population of the migrants, because these represent the largest group of all migrants. The specific situation of asylum seekers will also be refrained to where appropriate. PMID- 21796593 TI - [Drug therapy of acute and chronic abdominal pain]. AB - For drug therapy a differentiation of acute and chronic pain is essential. In emergency situations of acute abdominal pain a fast diagnosis is mandatory. Analgesia should be provided as soon as possible. The different groups of analgesics should be used according to their known effects, side effects and contraindications. Postoperative pain after abdominal surgery has to be considered as a special condition of acute abdominal pain. Main treatment options are non opioid analgesics and opioids. Opioids can be administered intravenously via patient controlled analgesia (PCA) devices. In major abdominal surgery neuroaxial analgesia, preferentially administered via an epidural catheter provides excellent pain relief with positive impact on gastrointestinal motility and patients' recovery. Because of difficulties to allocate chronic abdominal pain to a specific organ, causal treatment often turns out to be difficult. Peripheral and central sensitization, as well as an alteration of the endogenous pain modulation comes to the fore in these chronic pain conditions. Co-analgesics like anticonvulsants and antidepressants are utilized to reduce sensitization and improve the endogenous pain modulating system. Non drug approaches and alternative treatment options might be useful. In contrast, orally or transcutaneously administered opioids are the principal corner stone for the treatment of cancer pain. PMID- 21796594 TI - [Abdominal pain in the general doctor's practice]. AB - Abdominal pain is a frequent symptom and in the majority of cases the underlying disease is not life threatening. The general practitioner's first task is to differentiate between inflammatory and other diseases. The patient's history, the clinical examination and laboratory tests form the basis for the differential diagnosis. A sonography is the first additional examination in the vast majority of the cases. Accidentally found gallstones usually do not require surgical intervention. Surgery in asymptomatic patients should be limited to gallbladder polyps and patients with calcifications in their gallbladder wall. PMID- 21796595 TI - [Abdominal pain in children]. AB - A differentiation between chronic relapsing abdominal pain and acute pain is necessary in children. Whilst only 5 - 10 % of the cases of chronic abdominal pain have an organic correlate, such is almost always present in acute abdominal pain. In this chapter we will deal only with the acute abdominal pain in children. It is essential to realize that abdominal pain, especially in small children, can occur even if there is no organic correlate in the abdomen. Pneumonia or even urinary infections may result in acute abdominal pain. The age of the child is crucial in establishing the diagnosis, as typical diseases occur only within a certain age range. In this chapter we present the most typical diseases in children with acute abdominal pain. PMID- 21796596 TI - [Abdominal pain in the geriatric patient]. AB - Abdominal pain is a frequent symptom among elderly hospitalized patients. Taking the patient's history is often difficult because of a cognitive impairment. The objective of the present article is to provide a short summery of important diseases leading to abdominal pain and their special features in the elderly patient population. Especially atypical and less symptomatic courses render establishing the correct diagnosis more difficult. The higher comorbidity, the often more advanced disease stage at the time of seeking medical attention and an delayed accurate diagnosis all contribute to the higher mortality in the elderly patients. PMID- 21796597 TI - [Abdominal pain without any identifiable cause: a guide for the general practitioner]. AB - Abdominal pain without any identifiable cause represents a frequent phenomenon in clinical practice and a challenge for the physician. Prior to establishing the diagnosis of non-specific abdominal pain it is crucial to exclude a variety of potential causes. The differential diagnosis is long and includes functional problems but also extra-intestinal pathologies including thoracic, neurogenic, and metabolic causes as well as intoxications. Moreover, an intra-abdominal pathology, particularly a malignancy, must be ruled out systematically prior to labeling a patient as having "non specific" abdominal pain. PMID- 21796598 TI - [Abdominal pain - differential diagnoses and diagnostic strategies in patients with chronic symptoms]. AB - Abdominal pain is a very common complaint in a primary care consultation. The causes of abdominal pain are extremely diverse and range from conditions that require urgent surgical remedy to those without serious underlying pathology where the problem either settles spontaneously, or becomes chronic without any abnormalities on laboratory or clinical workup. While tests are helpful in confirming diagnoses, clinical judgement based on a careful history and physical examination remains extremely important in choosing from the extremely wide differential diagnoses and in the management of the condition. In this article, we will deal with chronically recurrent intermittent abdominal pain. Our aim is especially to provide guidance on the possibility that abdominal pain is a symptom of chronic inflammatory bowel disease (IBD) or an identifiable functional condition and when the diagnosis of irritable bowel syndrome should be made. PMID- 21796599 TI - [Functional abdominal pain]. AB - Functional abdominal pain is an inhomogeneous group of disorders concerning aetiology and clinical presentation. Support for classification is provided by the ROME-Foundation with its criteria catalogue, ROME-III being the most recent one. However, basic approach consists of exclusion of somatic or psychiatric as well as psychosomatic disorders that are sharply defined and readily diagnosable. This article outlines a pragmatic gastroenterological approach by exemplary means of dyspepsia and irritable bowel syndrome. Dyspepsia includes a broad complex of mainly epigastric located symptoms, whereas irritable bowel syndrome is symptomatic with altered bowel habits and mid-abdominal pain in the majority. Gastreoenterologic therapy modalities are mainly based on empirical and symptomatic grounds, more than on precisely explaining pathophysioligic understanding. PMID- 21796600 TI - [Adhesions and abdominal pain]. AB - Adhesions occur with a high incidence after intra-abdominal surgery but can also develop due to infections, radiation or for idiopathic reasons. The formation of adhesions is initiated by tissue damage and is the result of peritoneal tissue repair involving the activation of the inflammatory system and the coagulation cascade. Acute small bowel obstruction is one of the most common complications and should be diagnosed rapidly using clinical examination and radiological imaging. A complete obstruction is life threatening and in a high percentage of patients requires rapid surgical intervention by laparotomy or laparoscopy depending on the clinical situation and the patients history. Despite numerous investigations, there is no reliable, commonly used method to prevent intra abdominal adhesions. Minimizing tissue damage and foreign body exposure, avoiding spillage of intestinal and biliary contents as well as a laparoscopic approach seem to have a beneficial effect on the formation of intra-abdominal adhesions. PMID- 21796601 TI - [Intra-abdominal inflammation and perforation]. AB - Abdominal pain combined with fever and elevated white blood count as well as c reactive protein are the main features of any intra-abdominal inflammation or perforation. Since these pathologies are commonly encountered, it is of crucial importance for the primary care doctor as well as the specialist to have basic knowledge about clinical symptoms, diagnostic testing and treatment options in patients with intra-abdominal inflammation or perforation. The following article provides a short summary of the most frequent causes of abdominal pain due to inflammation or perforation. PMID- 21796602 TI - [The abdominal catastrophe]. AB - Patients with an abdominal catastrophe are in urgent need of early, interdisciplinary medical help. The treatment plan should be based on medical priorities and clear leadership. First priority should be given to achieve optimal oxygenation of blood and stabilization of circulation during all treatment-phases. The sicker the patient, the less invasive the (surgical) treatment should to be, which means "damage control only". This short article describes 7 important, pragmatic rules that will help to increase the survival of a patient with an abdominal catastrophe. Preexisting morbidity and risk factors must be included in the overall risk-evaluation for every therapeutic intervention. The challenge in patients with an abdominal catastrophe is to carefully balance the therapeutic stress and the existing resistance of the individual patient. The best way to avoid abdominal disaster, however, is its prevention. PMID- 21796603 TI - [Nutrition and attention deficit hyperactivity disorder: developmental follow-up of the anthropometric variables of a group of patients receiving treatment with osmotic controlled-release methylphenidate]. AB - AIM: To perform a developmental analysis of the anthropometric variables of a group of patients diagnosed with attention deficit hyperactivity disorder (ADHD) in order to determine the repercussions of treatment with osmotic controlled release methylphenidate (MTF-OROS). PATIENTS AND METHODS: The medical records of 187 patients with ADHD under treatment with MTF-OROS over a period of 30 months were reviewed. Data collected included weight, height and body mass index at diagnosis (baseline) and at 6, 12, 18, 24 and 30 months' follow-up. RESULTS: The mean age at diagnosis was 8.14 +/- 1.6 years. The dose of MTF-OROS was progressively increased until 36.9 +/- 12.1 mg/day (1.05 mg/kg/day) at day 30 of the follow-up. At diagnosis, 34.9% of patients had a deficient nutritional situation (subnutrition or malnutrition), which affected 50.3% of the patients at 30 months. The baseline value for weight (Z-score) progressively decreased during treatment until values that were significantly lower than the baseline value at 12 months were reached (p < 0.05); these values remained significantly lower until 30 months. The baseline value for height (Z-score) also progressively decreased during treatment until values that were significantly lower than the baseline value at 24 and 30 months were reached (p < 0.05). CONCLUSIONS: At the time they were diagnosed with ADHD, one out of every three patients was in a deficient nutritional situation (subnutrition or malnutrition). Continued treatment with MTF-OROS for 30 months had a negative influence on height, which could perhaps be attenuated by improving the patients' nutrition. PMID- 21796604 TI - [Comparison of the lesion produced by permanent focal cerebral ischaemia in three animal models using magnetic resonance imaging]. AB - INTRODUCTION: Animal models of brain ischemia are essential to reveal the full aspects of cerebrovascular pathologies. The perfect animal model that reflects every aspect of stroke pathophysiology does not exist, hence there is a need for a proper selection of the animal model in order to interpret properly the results from experimental research. AIM: To characterize and compare the temporal evolution of three common models of focal brain ischemia using magnetic resonance imaging (MRI) techniques. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were distributed into three groups, each of them submitted to one of the following surgery procedures: middle cerebral artery (MCA) intracranial suture, MCA electrocoagulation, and MCA intraluminal suture. Each rat was subjected to an MRI study at days 1, 2, 3, 4, 7 and 14 post-surgery. T2 weighted images were obtained in order to calculate both lesion volumes and edema. RESULTS: Infarct volume and edema were maximal for the intraluminal model (peaks of mean 297 +/- 163 mm3 and mean 17 +/- 9%, respectively) compared to intracranial suture (178 +/- 62 mm3 and 9 +/- 6%, respectively) and electrocoagulation (181 +/- 45 mm3 and 9 +/- 6%, respectively) models. DISCUSSION: The intraluminal occlusion of the MCA model, although yields in the highest mortality rate (28%), it is the more suitable for long term studies, mainly because of the absence of craniotomy. In the electrocoagulation model a non ischemic lesion region is observed which leads to an abnormal lesion evolution as compared with the other two models. PMID- 21796605 TI - [Headache and immigration. A study in the outpatient department of the Hospital de la Santa Creu i Sant Pau in Barcelona]. AB - INTRODUCTION: The immigrant population (IP) is visiting neurology departments on an increasingly more frequent basis. Research has still not made it clear whether there are geographical differences in the prevalence of primary headaches and the possible influence of emigration. PATIENTS AND METHODS: We conducted a retrospective (12 months) and prospective study (18 months) of the first visits to the Headache Unit at the Hospital de la Santa Creu i Sant Pau. Data collected included the country of birth, time parameters of the headache and of the immigration, diagnoses according to the criteria of the IHS and treatments that had been used. Related headaches were considered to be those that began within one year of having immigrated. RESULTS: The IP represents 13.6% (n = 142) of the total number of first visits because of headaches (n = 1044). Immigrants came mostly from Latin America (83.9%). Headaches began after immigration in 40.1% of cases without the existence of any temporal relation with immigration. The distribution of the diagnoses of headache is similar to those of the local population, the most frequent being migraine (57.7%) and tension-type headache (15.5%). On comparing treatments prior to and following immigration, we find differences in the use of triptans (2.1% versus 46.2%), ergotamine (9.8% versus 2.1%) and in the use of preventive treatments (2% versus 45%). CONCLUSIONS: The IP accounts for 13% of all first visits due to headaches and their diagnoses are similar to those of the local population. Emigration is neither a precipitating nor an aggravating factor for headaches in our series. There is a significant difference in symptomatic and preventive treatment between the period prior to immigration and afterwards. PMID- 21796606 TI - [Two new cases of sporadic Creutzfeldt-Jakob disease in Madrid, Spain]. AB - INTRODUCTION: Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy, in which there is typically an accumulation of an altered isoform of the prion protein in the brain. The sporadic form is characterised by presenting a rapidly progressive dementia, with signs and symptoms of pyramidal, extrapyramidal, cerebellar and cortical involvement, as well as the presence of myoclonias. Diagnosis is based on the clinical findings in combination with the typical results of an electroencephalogram, cerebrospinal fluid study or neuroimaging. CASE REPORTS: We report two cases detected between the years 2008 and 2010 in the Hospital del Henares, in Coslada, Madrid. Case 1: a female with progressive loss of strength in her limbs, change in her behaviour with mood swings and a tendency towards seeking to isolate herself. Although initially considered a psychiatric patient, in the months that followed she became absolutely immobile with a tendency towards mutism. Death occurred six months after the onset of symptoms. Case 2: a male with a progressive picture of altered vision in the form of right homonymous hemianopia, difficulty in verbally expressing language, dizziness and instability. The patient gradually developed a cerebellar syndrome with generalised myoclonias until his death, 10 weeks after the onset of symptoms. In both cases, the electroencephalogram showed a typical pattern and 14-3-3 protein was positive in the cerebrospinal fluid study. CONCLUSIONS: Such a high incidence over such a short period of time and in a health district of barely 170,000 inhabitants seems rather surprising. PMID- 21796608 TI - [Cerebellar contribution to cognitive process: current advances]. AB - INTRODUCTION: The cerebellum has traditionally been considered a neuronal system which is an essential part of coordination and motor control. However, in recent decades the idea of the cerebellum as an organ related to high level cognitive processes has gained strength, a claim supported by studies carried out on animals and humans with cerebellar lesions such as the contribution of modern neuroimaging techniques. DEVELOPMENT: The contribution of the cerebellum is reviewed in different cognitive functions such as the regulation of motor functions, attention, language, visuoconstructional skills, learning, memory and executive functions. The results of said review produce, as the most clarifying data, the influence of the cerebellum on processes such as attention, working memory (covert articulation) and verbal fluency as well as procedural learning. The results found regarding the cerebellum and the executive functions are not conclusive. CONCLUSIONS: We consider it necessary to systematize the table that has already been outlined. This will enable us to answer not only the question of whether the cerebellum plays a role in human cognition but which is its role. Perhaps the basis for understanding the cognitive functions of the cerebellum are not found in the fact that the cerebellum contains functions but that it relates the intention to the action in the emotional as well as the behavioural cognitive plane although the role of 'interface' is found closer to the output processes than processing of functions with a motor component. PMID- 21796607 TI - [Neurological disorders associated with gluten sensitivity]. AB - Gluten sensitivity is a systemic autoimmune disease that occurs in genetically susceptible individuals on ingesting gluten. It can appear at any age, then becoming a permanent condition. It is more frequent in women, as happens with other autoimmune diseases. Celiac disease is the intestinal form and the most important manifestation among a set of gluten-induced autoimmune pathologies that affect different systems. Neurological manifestations of gluten sensitivity, with or without enteropathy, are also frequent, their pathogenesis including an immunological attack on the central and peripheral nervous tissue accompanied by neurodegenerative changes. The clinical manifestations are varied, but the most common syndromes are cerebellar ataxia and peripheral neuropathy. Finally, gluten sensitivity is associated to a varying degree, with other complex diseases and could influence their evolution. The early detection of cases of gluten sensitivity with neurological manifestations and subsequent treatment with the gluten-free diet could provide remarkable benefits to the patients. PMID- 21796609 TI - [Mesial temporal sclerosis in a case of en coup de sabre linear scleroderma ]. PMID- 21796610 TI - [Spontaneous intracranial hypotension as the cause of persistent headache in a paediatric case]. PMID- 21796611 TI - [Paroxysmal tonic upward gaze deviation triggered by valproic acid within the context of focal epilepsy]. PMID- 21796612 TI - [Neurology, neuropsychology and neurosciences: on the use and abuse of the term 'neuro']. PMID- 21796613 TI - Genetic diversity and evidence for population admixture in Batak Negritos from Palawan. AB - Anthropologists have long been fascinated by the isolated hunter-gatherer populations in Southeast Asia (SEA) collectively known as "Negritos." However, the origins and affinities of these groups remain unresolved. Negritos are characterized by their short stature, dark skin color, and wiry hair, and they inhabit the Philippines, Malay Peninsula, and the Andaman Islands. Among Philippine Negritos, the Batak are of particular interest in understanding population interactions in the region due to their location on Palawan Island, which likely formed a corridor by which human migrations entered the rest of the Philippine archipelago from Island SEA. Here, we extend current understanding of the distribution of genetic diversity in Negritos by presenting the first analysis of mitochondrial DNA and Y-chromosome diversity among the Batak. We show that the Batak are genetically distinct from Negritos of the Andaman Islands and Malay Peninsula and instead bear most resemblance to geographically proximate Philippine Negritos and to non-Negrito populations from the Philippines and Island SEA. An extensive degree of recent admixture between the Batak and their neighbors is indicated by the high frequency of recently coalescing haplogroups in the Batak that are found throughout Island SEA. The comparison of results from these two loci further lends support to the hypothesis that male-biased admixture has, in particular, been a prominent feature of the interactions between the Batak and surrounding non-Negrito populations. PMID- 21796614 TI - Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma. AB - Neuroblastoma (NB) is a paediatric tumour with a remarkable diverse clinical behaviour. Approximately half of the high stage aggressive tumours are characterized by MYCN gene amplification but our understanding of the role of MYCN in NB oncogenesis is incomplete. Previous studies have shown that MYCN expression is inversely correlated with expression of Dickkopf-3 (DKK3), a gene encoding an extracellular protein with presumed tumour suppressor activity, but direct MYCN regulation of DKK3 was excluded leaving the mechanism of regulation unexplained. Given the recently established role of MYCN-regulated miRNAs in downregulation of protein-coding genes and predicted seeds for miR-17-92 cluster members within the DKK3 3'UTR, we hypothesized that this mechanism would act in MYCN regulation of DKK3. To investigate this, we used a validated miR-17-92 inducible cellular system and could demonstrate robust downregulation of DKK3 mRNA and protein levels upon miR-17-92 overexpression. Next, two of the three predicted miRNAs, miR-19b and miR-92a, were shown to lower DKK3 protein levels, in addition to measurable DKK3 mRNA knock-down by miR-92a. Direct interaction between miR-19b or miR-92a and the 3'UTR of DKK3 was validated using luciferase reporter assays. In conclusion, this study demonstrates that the MYCN-induced downregulation of DKK3 results from direct upregulation of miR-17-92 components effecting both DKK3 mRNA stability and translation which further contributes to the pleiotropic oncogenic effect of elevated MYCN levels. The strict MYCN mediated regulation of DKK3 is suggestive for an important downstream function of the MYCN protein and thus warrants further investigations to unravel the role of DKK3 in NB. PMID- 21796615 TI - Development of squamous neoplasia in esophageal iodine-unstained lesions and the alcohol and aldehyde dehydrogenase genotypes of Japanese alcoholic men. AB - We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) >= 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs >= 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79 3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes. PMID- 21796616 TI - Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. AB - T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T cells in PBMC of melanoma patients. Here we analyzed the functionality of these T cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies. PMID- 21796617 TI - Myosin heavy chain is not selectively decreased in murine cancer cachexia. AB - Cachexia is a severe muscle-wasting syndrome associated with several chronic diseases such as cancer and AIDS. Muscle mass loss significantly decreases prognosis and survival. The mechanisms of muscle atrophy and the specific proteins targeted for degradation have been intensely studied and are potential therapeutic targets. Published reports that myosin heavy chain (MyHC), the most abundant protein by mass in skeletal muscle, is selectively targeted for degradation in cancer cachexia remain controversial. Here we show that the results of previous studies showing a selective decrease in MyHC are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. We show that MyHC decreases in parallel with other myofibrillar proteins in cachectic skeletal muscle, which has mechanistic and therapeutic implications. These findings should lead to mechanistic insight into the stoichiometry of sarcomeric disassembly and degradation during cancer cachexia. PMID- 21796618 TI - Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers. AB - The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2'deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitt's lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic based therapy. PMID- 21796620 TI - Leukemia stem cells. AB - Leukemia stem cells (LSCs) might originate from malignant transformation of normal hematopoietic stem cells (HSCs), or alternatively, of progenitors in which the acquired mutations have re-installed a dysregulated self-renewal program. LSCs are on top of a hierarchy and generate leukemia cells with more differentiated characteristics. While most leukemia cells are initially sensitive to chemo- and radiotherapy, LSCs are resistant and are considered to be the basis for disease relapse after initial response. Albeit important knowledge on LSC biology has been gained from xenogeneic transplantation models introducing human leukemia cells into immune deficient mouse models, the prospective identification and isolation of human LSC candidates has remained elusive and their prognostic and therapeutic significance controversial. This review focuses on the identification, enrichment and characterization of human LSC derived from patients with acute myeloid leukemia (AML). Experimental data demonstrating the clinical significance of estimating LSC burden and strategies to eliminate LSC will be summarized. For long-term cure of AML, it is of importance to define LSC candidates and to understand their tumor biology compared to normal HSCs. Such comparative studies might provide novel markers for the identification of LSC and for the development of treatment strategies that might be able to eradicate them. PMID- 21796619 TI - Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas. AB - Neuroblastoma is an aggressive embryonal tumor that accounts for ~15% of childhood cancer deaths. Hitherto, despite the availability of comprehensive genomic data on DNA copy number changes in neuroblastoma, relatively little is known about the genes driving neuroblastoma tumorigenesis. In this study, high resolution array comparative genome hybridization (CGH) was performed on 188 primary neuroblastoma tumors and 33 neuroblastoma cell lines to search for previously undetected recurrent DNA copy number gains and losses. A new recurrent distal chromosome 1q deletion (del(1)(q42.2qter)) was detected in seven cases. Further analysis of available array CGH datasets revealed 13 additional similar distal 1q deletions. The majority of all detected 1q deletions was found in high risk 11q deleted tumors without MYCN amplification (Fisher exact test p = 5.61 * 10(-5) ). Using ultra-high resolution (~115 bp resolution) custom arrays covering the breakpoints on 1q for 11 samples, clustering of nine breakpoints was observed within a 12.5-kb region, of which eight were found in a 7-kb copy number variable region, whereas the remaining two breakpoints were colocated 1.4-Mb proximal. The commonly deleted region contains one miRNA (hsa-mir-1537), four transcribed ultra conserved region elements (uc.43-uc.46) and 130 protein coding genes including at least two bona fide tumor suppressor genes, EGLN1 (or PHD2) and FH. This finding further contributes to the delineation of the genomic profile of aggressive neuroblastoma, offers perspectives for the identification of genes contributing to the disease phenotype and may be relevant in the light of assessment of response to new molecular treatments. PMID- 21796621 TI - PI3K class IB controls the cell cycle checkpoint promoting cell proliferation in hepatocellular carcinoma. AB - Alterations of the cell cycle checkpoint frequently occur during hepatocarcinogenesis. Dysregulation of the phosphatidylinositol-3-kinases (PI3K) signaling pathway is believed to exert a potential oncogenic effect in hepatocellular carcinoma (HCC), ultimately promoting tumor cell proliferation. However, the impact of PI3K on cell cycle regulation remains unclear. We used a combined loss- and gain-of-function approach to address the involvement of p110gamma in HCC cell proliferation, apoptosis and the cell cycle. We also investigated the correlation between p110gamma and Ki-67 in 24 HCC patients. Finally, we analyzed the expression levels of p110gamma and cell cycle regulators in HCC tissues. We found that PI3K class IB, but not class IA, is required for HCC cell proliferation. In particular, we found that knock-down of p110gamma inhibits cell proliferation because of an arrest of the cell cycle in the G0-G1 phase. This effect is associated with an altered expression of proteins regulating the cell cycle progression, including p21, and with an increased apoptosis. By contrast, we found that ectopic expression of p110gamma promotes HCC cell proliferation. Tissues analysis performed in HCC patients showed a positive correlation between the expression of p110gamma and Ki-67, a marker of proliferation, and, even more importantly, that p21 expression is up-regulated in HCC patients with a lower p110gamma expression. Our results emphasize the role of p110gamma as a promoter of HCC proliferation and unveil an important cell cycle regulation function of this molecule. PMID- 21796623 TI - L1-CAM-targeted antibody therapy and (177)Lu-radioimmunotherapy of disseminated ovarian cancer. AB - The L1-cell adhesion molecule (L1-CAM) is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1-CAM and exhibits anti-proliferative effects on L1-CAM-expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel (177)Lu-chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth-inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl, an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10-tetraazacyclododecane-N-N'-N'-N''' tetraacetic acid (DOTA) and labeled with the low-energy beta-emitter (177)Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 MUg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of (177)Lu-chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 +/- 8.1% ID/g at 168 h postinjection. A single treatment with (177)Lu-DOTA-chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted (177)Lu-immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of (177)Lu-DOTA-chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1-CAM. PMID- 21796622 TI - Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. AB - Apoptosis genes, such as TP53 and p16/CDKN2A, that mediate responses to cytotoxic chemotherapy, are frequently nonfunctional in melanoma. Differentiation may be an alternative to apoptosis for inducing melanoma cell cycle exit. Epigenetic mechanisms regulate differentiation, and DNA methylation alterations are associated with the abnormal differentiation of melanoma cells. The effects of the deoxycytidine analogue decitabine (5-aza-2'-deoxycytidine), which depletes DNA methyl transferase 1 (DNMT1), on melanoma differentiation were examined. Treatment of human and murine melanoma cells in vitro with concentrations of decitabine that did not cause apoptosis inhibited proliferation accompanied by cellular differentiation. A decrease in promoter methylation, and increase in expression of the melanocyte late-differentiation driver SOX9, was followed by increases in cyclin-dependent kinase inhibitors (CDKN) p27/CDKN1B and p21/CDKN1A that mediate cell cycle exit with differentiation. Effects were independent of the TP53, p16/CDKN2A and also the BRAF status of the melanoma cells. Resistance, when observed, was pharmacologic, characterized by diminished ability of decitabine to deplete DNMT1. Treatment of murine melanoma models in vivo with intermittent, low-dose decitabine, administered sub-cutaneously to limit high peak drug levels that cause cytotoxicity and increase exposure time for DNMT1 depletion, and with tetrahydrouridine to decrease decitabine metabolism and further increase exposure time, inhibited tumor growth and increased molecular and tumor stromal factors implicated in melanocyte differentiation. Modification of decitabine dose, schedule and formulation for differentiation rather than cytotoxic objectives inhibits the growth of melanoma cells in vitro and in vivo. PMID- 21796624 TI - Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. AB - Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 * 10(-3) vs. 0.13 * 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation. PMID- 21796626 TI - AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B cell lymphomas. AB - Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 MUM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation. PMID- 21796625 TI - Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. AB - Activation of the sonic hedgehog (SHh) pathway is required for the growth of numerous tissues and organs and recent evidence indicates that this pathway is often recruited to stimulate growth of cancer stem cells (CSCs) and to orchestrate the reprogramming of cancer cells via epithelial mesenchymal transition (EMT). The objectives of this study were to examine the molecular mechanisms by which (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, inhibits self-renewal capacity of pancreatic CSCs and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Our data demonstrated that EGCG inhibited the expression of pluripotency maintaining transcription factors (Nanog, c-Myc and Oct-4) and self renewal capacity of pancreatic CSCs. Inhibition of Nanog by shRNA enhanced the inhibitory effects of EGCG on self-renewal capacity of CSCs. EGCG inhibited cell proliferation and induced apoptosis by inhibiting the expression of Bcl-2 and XIAP and activating caspase-3. Interestingly, EGCG also inhibited the components of SHh pathway (smoothened, patched, Gli1 and Gli2) and Gli transcriptional activity. Furthermore, EGCG inhibited EMT by inhibiting the expression of Snail, Slug and ZEB1, and TCF/LEF transcriptional activity, which correlated with significantly reduced CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Furthermore, combination of quercetin with EGCG had synergistic inhibitory effects on self-renewal capacity of CSCs through attenuation of TCF/LEF and Gli activities. Since aberrant SHh signaling occurs in pancreatic tumorigenesis, therapeutics that target SHh pathway may improve the outcomes of patients with pancreatic cancer by targeting CSCs. PMID- 21796627 TI - The lymphangiogenic factor SOX 18: a key indicator to stage gastric tumor progression. AB - SOX group F genes are important regulators of angiogenesis and lymphangiogenesis. The aim of the present study was to examine the relationships between Sox group F expression and clinicopathological factors in gastric cancer. Three hundred and fifteen gastric cancer tissues and the corresponding normal gastric tissue were obtained from the tumor bank at the National Cancer Center, Korea. SOX group F mRNA levels in these tissues were evaluated by reverse transcriptase polymerase chain reaction (RT-PCR). The serum levels of SOX 18 proteins in 219 gastric cancer patients and in 30 healthy volunteers were also measured by enzyme-linked immunosorbent assay. Furthermore, immunohistochemistry (IHC) was performed on 679 gastric cancer tissues and the clinicopathological characteristics, as well as the survival rates of SOX 18 positive and negative gastric cancers were compared. RT-PCR showed that SOX group F mRNA was increased in the gastric cancer tissues compared to the normal gastric tissues (p < 0.001, respectively). The serum levels of SOX 18 protein were also increased in gastric cancer patients compared to healthy volunteers. IHC showed that of the 679 gastric cancer cases, 177 (26.1%) were positive for SOX 18 expression in their tumor stroma, and the frequencies of both lymphovascular invasion and lymph node metastases were higher in the SOX 18 positive than in the negative group. Both the 5-year survival and the recurrence-free survival were shorter for SOX 18 positive tumors (p = 0.023 and 0.012, respectively). SOX 18 expression might be a prognostic tumor marker and a potential therapeutic target in gastric cancer. PMID- 21796628 TI - A four-gene methylation marker panel as triage test in high-risk human papillomavirus positive patients. AB - Cervical neoplasia-specific biomarkers, e.g. DNA methylation markers, with high sensitivity and specificity are urgently needed to improve current population based screening on (pre)malignant cervical neoplasia. We aimed to identify new cervical neoplasia-specific DNA methylation markers and to design and validate a methylation marker panel for triage of high-risk human papillomavirus (hr-HPV) positive patients. First, high-throughput quantitative methylation-specific PCRs (QMSP) on a novel OpenArrayTM platform, representing 424 primers of 213 cancer specific methylated genes, were performed on frozen tissue samples from 84 cervical cancer patients and 106 normal cervices. Second, the top 20 discriminating methylation markers were validated by LightCycler(r) MSP on frozen tissue from 27 cervical cancer patients and 20 normal cervices and ROCs and test characteristics were assessed. Three new methylation markers were identified (JAM3, EPB41L3 and TERT), which were subsequently combined with C13ORF18 in our four-gene methylation panel. In a third step, our methylation panel detected in cervical scrapings 94% (70/74) of cervical cancers, while in a fourth step 82% (32/39) cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and 65% (44/68) CIN2+ were detected, with 21% positive cases for <=CIN1 (16/75). Finally, hypothetical scenario analysis showed that primary hr-HPV testing combined with our four-gene methylation panel as a triage test resulted in a higher identification of CIN3 and cervical cancers and a higher percentage of correct referrals compared to hr-HPV testing in combination with conventional cytology. In conclusion, our four-gene methylation panel might provide an alternative triage test after primary hr-HPV testing. PMID- 21796629 TI - Horizontal transmission and retention of malignancy, as well as functional human genes, after spontaneous fusion of human glioblastoma and hamster host cells in vivo. AB - Cell fusion in vitro has been used to study cancer, gene mapping and regulation, and the production of antibodies via hybridomas. However, in-vivo heterosynkaryon formation by cell-cell fusion has received less attention. This investigation describes the spontaneous fusion of a human glioblastoma with normal hamster cells after xenogeneic transplantation, resulting in malignant cells that express both human and hamster genes and gene products, and retention of glioblastoma traits with an enhanced ability to metastasize. Three of 7 human genes found showed translation of their proteins during serial propagation in vivo or in vitro for years; namely, CD74, CXCR4 and PLAGL2, each implicated with malignancy or glioblastoma. This supports the thesis that genetic hybridization of cancer and normal cells can transmit malignancy and also, as first described herein, regulatory genes involved in the tumor's organotypic morphology. Evidence also is increasing that even cell-free human cancer DNA can induce malignancy and transfer genetic information to normal cells. Hence, we posit that the transfer of genetic information between tumor and stromal cells, whether by cell-cell fusion or other mechanisms, is implicated in the progression of malignancy, and may further define the crosstalk between cancer cells and their stromal neighbors. PMID- 21796630 TI - Dermatopontin: a potential predictor for metastasis of human oral cancer. AB - Dermatopontin (DPT), a component of the extracellular matrix (ECM), is involved in promotion of cellular adhesion and ECM assembly activities. However, the role of DPT in the pathogenesis of carcinoma is unclear. We evaluated DPT expression in human oral cancer and its possible roles including cellular adhesion and invasiveness. We first investigated the DPT mRNA and protein expression status in human oral squamous cell carcinoma (OSCC)-derived cells. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunoblotting analysis detected frequent downregulation of DPT in OSCC-derived cells compared to human normal oral keratinocytes. To assess the epigenetic regulation of DPT, OSCC-derived cells were treated with a histone deacetylase inhibitor, sodium butyrate (NaB). NaB restored the DPT expression in OSCC-derived cells. DPT overexpressed cells were examined whether DPT could contribute to cellular adhesion and invasiveness. Markedly, increased adhesion and decreased invasiveness in DPT-overexpressed cells were found compared to mock-transfected cells. Adhesion of DPT-overexpressed cells was inhibited by alpha3beta1 integrin functional blocking antibody. OSCC-derived cells treated with NaB also decreased invasiveness. The expression status of DPT in primary OSCCs (n = 97) was analyzed and compared to clinicopathological behavior. DPT expression in primary OSCCs was significantly lower (p < 0.05) than in the normal counterparts and was correlated significantly (p < 0.05) with regional lymph node metastasis. Our data provided strong evidence that downregulation of DPT is a characteristic event in OSCCs and that DPT was correlated with cellular adhesion and invasiveness. Therefore, DPT might play an important role in regulating tumor invasion and metastasis. PMID- 21796631 TI - Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. AB - Epithelial-mesenchymal transition (EMT) promotes and facilitates migration and invasion of epithelial tumor cells. EMT is induced by factors such as hepatocyte growth factor (HGF). This study aimed to establish whether the HGF/c-Met pathway is associated with gastric cancer metastasis; especially peritoneal dissemination. HGF and c-Met expression and EMT-related molecules were evaluated using real-time PCR and immunohistochemistry. The role of the HGF/c-Met pathway in EMT and anoikis was determined, and kinase inhibitor SU11274 was tested for its ability to block HGF-induced biological effects. In HGF(-) /c-Met(+) gastric cancer cells, recombinant HGF promoted an EMT phenotype that was characterized by morphology, impaired E-cadherin and induction of vimentin. HGF promoted cell growth, invasiveness and migration and inhibition of anoikis. SU11274 blocked HGF induced EMT and biological effects in vitro. In HGF(+) /c-Met(+) gastric cancer cells, HGF did not affect the biological outcome of EMT and anoikis, but SU11274 exerted the same inhibitory effects as in HGF(-) /c-Met(+) cells. In vivo, HGF(+) /c-Met(+) gastric cancer cells only established peritoneal dissemination and SU11274 inhibited tumor growth. Clinically, HGF expression was significantly correlated with c-Met expression in gastric cancer. Increased HGF and c-Met had a significant association with poor prognosis and predicted peritoneal dissemination. We demonstrated that the HGF/c-Met pathway induces EMT and inhibition of anoikis in gastric cancer cells. Co-expression of HGF and c-Met has the potential to promote peritoneal dissemination in gastric cancer. Blockade of the autocrine HGF/c-Met pathway could be clinically useful for the treatment of peritoneal dissemination in gastric cancer. PMID- 21796632 TI - Knockdown of metallopanstimulin-1 inhibits NF-kappaB signaling at different levels: the role of apoptosis induction of gastric cancer cells. AB - The ribosomal protein S27 (metallopanstimulin-1, MPS-1) has been reported to be a multifunctional protein, with increased expression in a number of cancers. We reported previously that MPS-1 was highly expressed in human gastric cancer. Knockdown of MPS-1 led to spontaneous apoptosis and repressed proliferation of human gastric cancer cells in vitro and in vivo. However, how does MPS-1 regulate these processes is unclear. Here we performed microarray and pathway analyses to investigate possible pathways involved in MPS-1 knockdown-induced apoptosis in gastric cancer cells. Our results showed that knockdown of MPS-1 inhibited NF kappaB activity by reducing phosphorylation of p65 at Ser536 and IkappaBalpha at Ser32, inhibiting NF-kappaB nuclear translocation, and down-regulating its DNA binding activity. Furthermore, data-mining the Gene-Regulatory-Network revealed that growth arrest DNA damage inducible gene 45beta (Gadd45beta), a direct NF kappaB target gene, played a critical role in MPS-1 knockdown-induced apoptosis. Over-expression of Gadd45beta inhibited MPS-1 knockdown-induced apoptosis via inhibition of JNK phosphorylation. Taken together, these data revealed a novel pathway, the MPS-1/NF-kappaB/Gadd45beta signal pathway, played an important role in MPS-1 knockdown-induced apoptosis of gastric cancer cells. This study sheds new light on the role of MPS-1/NF-kappaB in apoptosis and the possible use of MPS 1 targeting strategy in the treatment of gastric cancer. PMID- 21796633 TI - Ten-year survival among HIV-1-infected subjects with AIDS or non-AIDS-defining malignancies. AB - Few data are available regarding the 10-year survival among subjects with HIV and cancer. The aim of this study was to evaluate the 10-year survival of HIV infected subjects with AIDS-defining malignancies (ADM) or non-AIDS-defining malignancies (NADM). This was a single center, retrospective, observational study of subjects with HIV infection and a subsequent cancer diagnosis; the data were collected from January 1991 to April 2010. Malignancies were divided into ADM or NADM on the basis of the Centre of Diseases Control-1993 classification. Survival curves were estimated using Kaplan-Meyer method and compared by the log-rank test. Six hundred and fifteen (9.5%) of the 6,495 subjects recorded in the San Raffaele Infectious Diseases Database developed a malignancy: 431 (70%) an ADM and 184 (30%) a NADM. In the case of ADM, survival was more favorable when cancer was diagnosed during post-highly active antiretroviral therapy (HAART) era (10 year survival: 43.2% +/- 4.4%) than when diagnosed during the pre-HAART era (10 year survival: 16.4% +/- 2.7%; log-rank test: p < 0.001). The same was true in the case of NADM (10-year survival: 44.7% +/- 5.5% vs. 33.3 +/- 9.6%; log-rank test: p = 0.03). An evaluation of survival probability by cancer type showed higher survival rates during the post-HAART era in the case of non-Hodgkin lymphoma (10-year survival: 42.1% +/- 5.3% vs. 11.4% +/- 3.3%; log-rank test: p = <0.001), Kaposi's sarcoma (10-year survival: 44.0% +/- 8.4% vs. 23.5% +/- 3.9%; log-rank test: p < 0.001) and Hodgkin's disease (10-year survival: 49.5% +/- 14.5% vs. 40.0% +/- 12.7%; log-rank test: p = 0.005). Despite the better cancer prognosis during the post-HAART era, the 10-year survival of HIV-infected subjects with an ADM or NADM is poor. PMID- 21796634 TI - A million africans a year dying from cancer by 2030: what can cancer research and control offer to the continent? AB - In Africa, there were an estimated 681,000 new cancer cases and 512,000 deaths in 2008. Projections to 2030 show a startling rise, with corresponding figures of 1.27 million cases and 0.97 million deaths resulting from population growth and aging alone. The figures make no assumptions about incidence rates which may increase due to the further introduction of tobacco and a more westernized lifestyle. The current situation in many parts of Africa with respect to health care systems suggests that improved cancer treatment would be an insufficient response to this increasing burden. Much could be achieved through cancer prevention by applying current knowledge about major risk factors and the natural history of the disease. For example, vaccination against hepatitis B virus and human papilloma viruses would prevent the occurrence of two of the most common cancers in Africa, liver and cervix, respectively, in the long-term. Strong measures to prevent the widespread introduction of tobacco must be a priority. Early detection and treatment of cervical and breast cancers using approaches applicable now in Africa would provide immediate value, as would the management of human immunodeficiency virus (HIV) infection in respect to HIV-associated malignancies. In parallel, further research is needed into the causes of cancer and the barriers to implementation of promising prevention strategies. Underpinning all is the need for African governments to look forward and prioritize cancer through national cancer control plans, to invest in public health infrastructure and to ensure the adequate training and support for people in cancer prevention and control. Given this core commitment from within Africa, international partners can provide complementary support in a cooperation that permits action now to mitigate the impending tragedy of cancer in the continent of Africa. PMID- 21796636 TI - Effectiveness of Zataria multiflora Boiss essential oil and grape seed extract impregnated chitosan film on ready-to-eat mortadella-type sausages during refrigerated storage. AB - BACKGROUND: The effectiveness of chitosan films containing Zataria multiflora Boiss essential oil (ZEO) (5 and 10 g kg(-1) ) and grape seed extract (GSE) (10 g kg(-1) ) on lipid oxidation and microbial (lactic acid bacteria, aerobic mesophiles and inoculated Listeria monocytogenes) characteristics of mortadella sausage at 4 degrees C for 21 days was evaluated. The release of total phenolics (TPs) into sausage was also assessed. RESULTS: All films exhibited antibacterial activity against L. monocytogenes on agar culture media. Chitosan films containing ZEO were the most effective on the growth of bacteria. The growth of L. monocytogenes was significantly inhibited by ZEO-GSE containing films especially during storage of the sausages for 6 days. Aerobic mesophiles and lactic acid bacteria were the most sensitive and resistant groups to films by 0.1 1.1 and 0.1-0.7 log cycles reduction, respectively. Sausages wrapped by 10 g kg( 1) GSE + 10 g kg(-1) ZEO films had the lowest degrees of lipid oxidation, which was 23% lower than the control. The TPs of ZEO films decreased to zero after 6 days, whereas TPs of GSE films followed a slight decrease during the storage. CONCLUSION: Antimicrobial/antioxidant chitosan film could be developed by incorporating GSE and ZEO for extending the shelf life of mortadella sausage. PMID- 21796637 TI - Influence of fertilisation regimes on a nosZ-containing denitrifying community in a rice paddy soil. AB - BACKGROUND: Denitrification is a microbial process that has received considerable attention during the past decade since it can result in losses of added nitrogen fertilisers from agricultural soils. Paddy soil has been known to have strong denitrifying activity, but the denitrifying microorganisms responsible for fertilisers in paddy soil are not well known. The objective of this study was to explore the impacts of 17-year application of inorganic and organic fertiliser (rice straw) on the abundance and composition of a nosZ-denitrifier community in paddy soil. Soil samples were collected from CK plots (no fertiliser), N (nitrogen fertiliser), NPK (nitrogen, phosphorus and potassium fertilisers) and NPK + OM (NPK plus organic matter). The nitrous oxide reductase gene (nosZ) community composition was analysed using terminal restriction fragment length polymorphism, and the abundance was determined by quantitative PCR. RESULTS: Both the largest abundance of nosZ-denitrifier and the highest potential denitrifying activity (PDA) occurred in the NPK + OM treatment with about four times higher than that in the CK and two times higher than that in the N and NPK treatments (no significant difference). Denitrifying community composition differed significantly among fertilisation treatments except for the comparison between CK and N treatments. Of the measured abiotic factors, total organic carbon was significantly correlated with the observed differences in community composition and abundance (P < 0.01 by Monte Carlo permutation). CONCLUSION: This study shows that the addition of different fertilisers affects the size and composition of the nosZ-denitrifier community in paddy soil. PMID- 21796638 TI - Physico-chemical and toxicological assessment of liquid wastes from olive processing-related industries. AB - BACKGROUND: In the last few years, agricultural uses of waste waters from olive processing-related industries have been gaining interest mainly with a view to composting or bio-fertilizers. The present work examines physico-chemical, toxicological and geno-toxicological properties of three liquid wastes, namely olive mill wastewater (OMWW), olive wet husk and olive brine. The effect of OMWW spreading on soil microbial activity and biomass was also evaluated. RESULTS: Data from Artemia salina and Lactuca sativa toxicity tests indicated high levels of lethality, and inhibitory effects on seed germination and seedling growth of all olive wastes. The genotoxicity assays using Allium cepa tests showed contrasting results. At high concentrations, olive wastes caused inhibition or suppression of mitosis. However, they did not produce induced anaphase aberrations. Data on reversion of Salmonella thyphimurium strains using the Ames test indicated that the olive wastes did not present mutagenic activity. Results from the field experiment showed that OMWW at a 500 m(3) ha(-1) had the highest values of both soil microbial activity and biomass after 3 months of the amendment application. CONCLUSION: This work adds new data for environmental risk assessment of olive industrial wastes. Direct use of olive wastes for agricultural purposes should be limited owing to their possible chemotoxic, phytotoxic and antimicrobial effects. PMID- 21796639 TI - Effects of freeze-dried Mitsuokella jalaludinii culture and Natuphos((r)) phytase supplementation on the performance and nutrient utilisation of broiler chickens. AB - BACKGROUND: Phytate-bound phosphorus (P) in poultry diets is poorly available to chickens. Hence exogenous phytase is often added to their diets. Mitsuokella jalaludinii is a rumen bacterial species that produces high phytase activity. In this study the effects of freeze-dried active M. jalaludinii culture (FD-AMJC) and Natuphos((r)) phytase (phytase N) supplementations on the growth performance and nutrient utilisation of broiler chickens fed a low-available P (aP) diet were evaluated. RESULTS: Supplementation of FD-AMJC or phytase N to the low-aP diet improved the feed intake, feed conversion rate, body weight gain, dry matter (DM) digestibility and P, Ca and Mn retention, increased the tibia bone ash content, Ca and P concentrations in tibia DM and P and Zn concentrations in plasma and reduced the P excretion of broiler chickens. However, the feed conversion rate, P and Ca retention, DM digestibility and reduction of P excretion were better with FD-AMJC than phytase N supplementation. Supplementation of FD-AMJC to the low-aP diet also improved the apparent metabolisable energy value of the diet, Cu and Zn retention and crude protein digestibility, but phytase N supplementation did not. CONCLUSION: FD-AMJC supplementation was more efficient in improving nutrient utilisation and reducing P excretion in chickens than phytase N supplementation. PMID- 21796640 TI - Endoscopic maxillary antrostomy: not just a simple procedure. AB - The endoscopic middle meatal maxillary antrostomy is one of the most commonly performed endoscopic procedures. Despite this, at our tertiary institution, we commonly see failed antrostomies requiring revision surgery. Accordingly, we describe in a stepwise fashion strategies helpful in creating a patent and naturally function maxillary antrostomy. PMID- 21796642 TI - No impact of atrial fibrillation on mortality risk in optimally treated heart failure patients. AB - BACKGROUND: Several studies have shown that atrial fibrillation (AF) is associated with increased risk of death in heart failure (HF) patients. However, it is not clear whether this increased risk is independent of other risk factors. HYPOTHESIS: We hypothesized that AF would be an independent risk factor for death in a large cohort of HF patients. METHODS: Patients referred to Norwegian HF outpatient clinics were enrolled between October 2000 and February 2008. Patients with heart rhythm other than AF or sinus rhythm were excluded. Mortality data were obtained from the National Statistics Bureau, Statistics Norway with the last update February 2008. RESULTS: There were 4048 patients included in the analysis, with a median follow-up of 28 months. Adherence to guidelines regarding medical treatment was high. In univariate analysis, AF patients (n = 1391) had a higher risk of death than patients in sinus rhythm (n = 2657) (hazard ratio [HR] 1.181; 95% confidence interval (CI), 1.044-1.336; P = 0.008). However, after adjusting for confounding factors (age, New York Heart Association class, coronary artery disease as the main cause of HF, use of any loop diuretic, hemoglobin level, and serum creatinine), AF was no longer associated with increased risk of death (HR 1.037; 95% CI, 0.901-1.193; P = 0.619). CONCLUSIONS: In this cohort of heart failure patients receiving optimal medical treatment at specialized HF clinics, AF was not associated with increased risk of death after adjusting for confounding factors. PMID- 21796643 TI - AFM detection of mitogen-induced morphological changes in human B lymphocyte. AB - B-lymphocyte activation plays an important role in humoral immune system, and its process has been studied well in vivo and in vitro. However, the ultrastructure and adhesion property changes remain unclear. In this study, changes in the morphology and mechanical properties of human peripheral blood B lymphocytes were first studied by atomic force microscopy (AFM). B lymphocytes were treated with the mitogen, pokeweed mitogen (PWM), and Staphylococcus aureus Cowan strain I (SAC) for 24 hr. After B lymphocyte is stimulated by the mitogen, the cell height, diameter, and volume are changed in different degree. The ultrastructure of the B lymphocytes membrane obviously displayed proteins gathering, corresponding with larger changes of average roughness and mean height of particles on cell membrane. Meanwhile, we detected the adhesion force of B lymphocytes after being stimulated by PWM and SAC. We found that the treated cells had a higher adhesion force of 304.16 +/- 60.30 pN (PWM) and 249.63 +/- 58.03 pN (SAC) than that of control group (104.28 +/- 21.77 pN). Therefore, our results could provide new information to further understand the B-lymphocyte activation process and their structure-function analyses. PMID- 21796644 TI - Investigation of morphological change of green tea polysaccharides by SEM and AFM. AB - The objective of this study is to investigate the morphological structure and its change of green tea polysaccharides (GTPS) before and after enzyme reaction by scanning electron microscope (SEM) and atomic force microscope (AFM). Before enzyme reaction, with the novel sample preparation method SEM images of GTPS have obtained many branches and network structures. After enzyme reaction, the morphological structure of GTPS changed, and surface roughness increased. The microstructure of GTPS from SEM with the novel sample preparation method was in accordance with the results from AFM with the tapping mode. The results indicate that the novel sample preparation of GTPS for SEM is a simple, feasible, and reliable method for observing the surface morphology. PMID- 21796641 TI - MicroRNA expression is differentially altered by xenobiotic drugs in different human cell lines. AB - Several noncoding microRNAs (miR or miRNA) have been shown to regulate the expression of drug-metabolizing enzymes and transporters. Xenobiotic drug-induced changes in enzyme and transporter expression may be associated with the alteration of miRNA expression. Therefore, this study investigated the impact of 19 xenobiotic drugs (e.g. dexamethasone, vinblastine, bilobalide and cocaine) on the expression of ten miRNAs (miR-18a, -27a, -27b, -124a, -148a, -324-3p, -328, 451, -519c and -1291) in MCF-7, Caco-2, SH-SY5Y and BE(2)-M17 cell systems. The data revealed that miRNAs were differentially expressed in human cell lines and the change in miRNA expression was dependent on the drug, as well as the type of cells investigated. Notably, treatment with bilobalide led to a 10-fold increase of miR-27a and a 2-fold decrease of miR-148a in Caco-2 cells, but no change of miR-27a and a 2-fold increase of miR-148a in MCF-7 cells. Neuronal miR-124a was generally down-regulated by psychoactive drugs (e.g. cocaine, methadone and fluoxetine) in BE(2)-M17 and SH-SY5Y cells. Dexamethasone and vinblastine, inducers of drug-metabolizing enzymes and transporters, suppressed the expression of miR-27b, -148a and -451 that down-regulate the enzymes and transporters. These findings should provide increased understanding of the altered gene expression underlying drug disposition, multidrug resistance, drug-drug interactions and neuroplasticity. PMID- 21796645 TI - Real-time in vivo imaging collagen in lymphedematous skin using multiphoton microscopy. AB - Changes of dermal collagen are characteristic for chronic lymphedema. To evaluate these changes, a real-time imaging based on two-photon excited fluorescence and second-harmonic generation was developed for investigating collagen of lymphedematous mouse and rat tail skin in vivo. Our findings showed that the technique could image the morphological changes and distribution of collagen in lymphedematous mouse and rat tail skin in vivo. More importantly, it may allow visualization of dynamic collagen alteration during the progression of lymphedema. Our findings demonstrated that multiphoton microscopy may have potential in a clinical setting as an in vivo diagnostic and monitoring system for therapy in lymphology. PMID- 21796646 TI - Helium ion microscopy of Lepidoptera scales. AB - In this report, helium ion microscopy (HIM) is used to study the micro and nanostructures responsible for structural color in the wings of two species of Lepidotera from the Papilionidae family: Papilio ulysses (Blue Mountain Butterfly) and Parides sesostris (Emerald-patched Cattleheart). Electronic charging of uncoated scales from the wings of these butterflies, due to the incident ion beam, is successfully neutralized, leading to images displaying a large depth-of-field and a high level of surface detail, which would normally be obscured by traditional coating methods used for scanning electron microscopy (SEM). The images are compared with those from variable pressure SEM, demonstrating the superiority of HIM at high magnifications. In addition, the large depth-of-field capabilities of HIM are exploited through the creation of stereo pairs that allows the exploration of the third dimension. Furthermore, the extraction of quantitative height information which matches well with cross sectional transmission electron microscopy measurements from the literature is demonstrated. PMID- 21796647 TI - The prospects of a subnanometer focused neon ion beam. AB - The success of the helium ion microscope has encouraged extensions of this technology to produce beams of other ion species. A review of the various candidate ion beams and their technical prospects suggest that a neon beam might be the most readily achieved. Such a neon beam would provide a sputtering yield that exceeds helium by an order of magnitude while still offering a theoretical probe size less than 1-nm. This article outlines the motivation for a neon gas field ion source, the expected performance through simulations, and provides an update of our experimental progress. PMID- 21796648 TI - N-acetyl-cysteine protects chicken growth plate chondrocytes from T-2 toxin induced oxidative stress. AB - T-2 toxin is now considered to be related to bone malformation such as incomplete ossification, absence of bones and fused bones. In this study, primary cultures of chicken tibial growth plate chondrocytes (GPCs) were treated with various concentrations of T-2 toxin (5, 50, and 500 n m) in the absence and presence of N acetyl-cysteine (NAC) to investigate the effects of the antioxidant NAC on T-2 toxin-induced toxicity. Our results showed that T-2 toxin markedly decreased cell viability, alkaline phosphatase activity and glutathione content (P < 0.05). In addition, T-2 toxin significantly increased reactive oxygen species levels and malondialdehyde in a dose-dependent manner. However, the T-2 toxin-induced cytotoxicity was reversed, in part, by the antioxidant NAC (P < 0.05). These results suggest that T-2 toxin inhibits the proliferation and differentiation of GPCs in vitro by altering cellular homeostasis and NAC can protect GPCs against T 2 toxin cytotoxicity by reducing the T-2 toxin-induced oxidative stress. PMID- 21796649 TI - Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild-type p53 and decrease in p21 and mutant p53 proteins. AB - BACKGROUND: The tumor suppressor gene p53 is implicated in cell cycle control and apoptosis. Antagonists of growth hormone-releasing hormone (GHRH) have been shown to inhibit human experimental prostate cancers. METHODS: We investigated the involvement of p53 apoptotic pathways in this effect. Nude mice bearing xenografted PC-3, DU-145, and MDA-PCa-2b human prostate cancer lines were treated with a new potent GHRH antagonist MZ-J-7-138. To determine whether tumor inhibition by MZ-J-7-138 involves apoptotic mechanisms such as p53 and p21, we evaluated by Western Blot the expression of mutant mt-p53 in PC-3 and DU-145 and of wild type (wt-p53) in MDA-PCa-2b prostate cancers as well as p21. RESULTS: MZ J-7-138 significantly inhibited the growth of PC-3, DU-145, and MDA-PCa-2b xenografts in nude mice. Androgen deprivation with the LHRH antagonist Cetrorelix enhanced the anti-proliferative effect of GHRH antagonist MZ-J-7-138 on MDA-PCa 2b tumors. The expression of mutant (mt-p53) and p21 protein in PC-3 and DU-145 tumors was significantly decreased by treatment with MZ-J-7-138, whereas wild type wt-p53 expression in MDA-PCA-2b tumors was up regulated by treatment with Cetrorelix. All three models investigated expressed specific, high affinity GHRH receptors. CONCLUSIONS: Our findings indicate that the anti-proliferative effects of GHRH antagonist MZ-J-7-138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling. PMID- 21796650 TI - Prostate carcinoma cells LNCaP and glucan cooperate in induction of cytokine synthesis by dendritic cells: effect on natural killer cells and CD4+ lymphocytes activation. AB - BACKGROUND: Glucan is an immunomodulating agent used for cancer therapy. We investigated the effects of glucan on immune cell response to prostate carcinoma. METHODS: Dendritic cells (DC) were co-cultured with prostate carcinoma cells LNCaP and/or glucan, and maturation markers expression, cytokine release, and superoxide anion production were evaluated. Conditioned media from glucan-treated or untreated DC and/or LNCaP cultures were used to stimulate T lymphocytes and natural killer (NK) cells. RESULTS: LNCaP promoted partial DC maturation and scarce IL-12 secretion. Glucan induced DC maturation but no IL-12 production by DC. However, glucan increased IL-12 release by DC co-cultured with LNCaP. Moreover, LNCaP enhanced IL-1beta, IL-23, IL-6, and TNF-alpha secretion, but decreased superoxide anion production in glucan-stimulated DC. The NADPH oxidase inhibitor diphenyliodonium chloride (DPI) and the superoxide anion scavenger superoxide dismutase (SOD) reproduced this effect, but did not affect IL-12 secretion. Conditioned media of glucan-treated DC/LNCaP co-cultures activated IFN gamma production by NK cells and Th1/Th17 generation by CD4(+) lymphocytes, whereas media from DC/LNCaP co-cultured without glucan produced scarce NK and CD4(+) cells responses. Experiments performed with an IL-12-blocking antibody demonstrated that these effects arise from glucan-dependent regulation of IL-12 production by DC. CONCLUSIONS: Glucan and LNCaP cooperate in induction of cytokine synthesis by DC. LNCaP enhance IL-1beta, IL-23, IL-6, and TNF-alpha secretion by decreasing glucan-dependent NADPH oxidase activity, whereas glucan increases IL-12 production through NADPH oxidase-unrelated mechanisms. This cooperation is essential to elicit a substantial NK cells and CD4(+) lymphocytes activity, pointing out a potential relevance of glucan in prostate cancer therapy. PMID- 21796651 TI - PDEF in prostate cancer. AB - Prostate-derived Ets factor (PDEF) is a relatively recently described member of the Ets family of transcription factors. It differs from other family members in its restricted and epithelial-specific expression in normal tissues and its unique DNA-binding motif that together may impart interesting specificity to its function. This communication reviews our current understanding of the expression characteristics of PDEF in normal prostate and in prostate cancer. Also, the biochemical and genetic evidence relating to the role of this transcription factor in prostate cancer is reviewed. Most evidence is consistent with an oncogenic role for PDEF in prostate cancer. Specific observations about the loss of PDEF expression in prostate tumors and its apparent role as a prostate tumor suppressor are also discussed. PDEF is one of the few transcription factors with potential to have a significant impact on the management of prostate cancer. A better understanding of its biology and its role in prostate cancer is urgently needed. PMID- 21796652 TI - Predictive performance of prostate cancer risk in Chinese men using 33 reported prostate cancer risk-associated SNPs. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified more than 30 single nucleotide polymorphisms (SNPs) that were reproducibly associated with prostate cancer (PCa) risk in populations of European descent. In aggregate, these variants have shown potential to predict risk for PCa in European men. However, their utility for PCa risk prediction in Chinese men is unknown. METHODS: We selected 33 PCa risk-related SNPs that were originally identified in populations of European descent. Genetic scores were estimated for subjects in a Chinese case-control study (1,108 cases and 1,525 controls) based on these SNPs. To assess the performance of the genetic score on its ability to predict risk for PCa, we calculated area under the curve (AUC) of the receiver operating characteristic (ROC) in combination with 10-fold cross-validation. RESULTS: The genetic score was significantly higher for cases than controls (P = 5.91 * 10( 20)), and was significantly associated with risk of PCa in a dose-dependent manner (P for trend: 4.78 * 10(-18)). The AUC of the genetic score was 0.604 for risk prediction of PCa in Chinese men. When ORs derived from this Chinese study population were used to calculate genetic score, the AUCs were 0.631 for all 33 SNPs and 0.617 when using only the 11 significant SNPs. CONCLUSION: Our results indicate that genetic variants related to PCa risk may be useful for risk prediction in Chinese men. Prospective studies are warranted to further evaluate these findings. PMID- 21796653 TI - Pathway specific gene expression profiling reveals oxidative stress genes potentially regulated by transcription co-activator LEDGF/p75 in prostate cancer cells. AB - BACKGROUND: Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stress survival transcription co-activator and autoantigen that is overexpressed in tumors, including prostate cancer (PCa). This oncoprotein promotes resistance to cell death induced by oxidative stress and chemotherapy by mechanisms that remain unclear. To get insights into these mechanisms we identified candidate target stress genes of LEDGF/p75 using pathway-specific gene expression profiling in PCa cells. METHODS: A "Human oxidative stress and antioxidant defense" qPCR array was used to identify genes exhibiting significant expression changes in response to knockdown or overexpression of LEDGF/p75 in PC-3 cells. Validation of array results was performed by additional qPCR and immunoblotting. RESULTS: Cytoglobin (CYGB), Phosphoinositide-binding protein PIP3-E/IPCEF-1, superoxidase dismutase 3 (SOD3), thyroid peroxidase (TPO), and albumin (ALB) exhibited significant transcript down- and up-regulation in response to LEDGF/p75 knockdown and overexpression, respectively. CYGB gene was selected for further validation based on its emerging role as a stress oncoprotein in human malignancies. In light of previous reports indicating that LEDGF/p75 regulates peroxiredoxin 6 (PRDX6), and that PRDXs exhibit differential expression in PCa, we also examined the relationship between these proteins in PCa cells. Our validation data revealed that changes in LEDGF/p75 transcript and protein expression in PCa cells closely paralleled those of CYGB, but not those of the PRDXs. CONCLUSIONS: Our study identifies CYGB and other genes as stress genes potentially regulated by LEDGF/p75 in PCa cells, and provides a rationale for investigating their role in PCa and in promoting resistance to chemotherapy- and oxidative stress-induced cell death. PMID- 21796654 TI - The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells. AB - BACKGROUND: The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down-regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down-regulates AR expression in several prostate cancer cell lines. METHODS: ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4-2, and LAPC-4 prostate cancer cells. RESULTS: ca27 induced the down-regulation of AR protein expression in LNCaP, C4-2, and LAPC-4 cells within 12 hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF-E2-related factor 2 (Nrf2) and the induction of the Nrf2 regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27-mediated down regulation of the AR was attenuated by the antioxidant, N-acetyl cysteine. CONCLUSIONS: ca27 induces ROS and mediates AR protein down-regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down-regulation, which could lead to effective new anti-androgenic strategies for the treatment of advanced prostate cancer. PMID- 21796655 TI - Development of a castrate resistant transplant tumor model of prostate cancer. AB - BACKGROUND: Currently, limited mouse models that mimic the clinical course of castrate resistant prostate development currently exist. Such mouse models are urgently required to conduct pre-clinical studies to assist in the understanding of disease progression and the development of rational therapeutic strategies to treat castrate resistant prostate cancer. METHODS: Wild type intact FVB male mice were injected by subcutaneous injection with Myc-CaP cells to establish androgen sensitive Myc-CaP tumors. Tumor bearing mice were castrated and resulting tumors serially passaged in pre-castrated FVB male mice to produce a bone fide Myc-CaP castrate resistant tumor. RESULTS: Immunohistochemical analysis revealed that initial androgen sensitive Myc-CaP tumors had strong nuclear transcriptional active androgen receptor expression, as indicated by marked c-MYC staining and were highly proliferative. Castration of tumor bearing animals resulted in cytoplasmic relocation of androgen receptor concurrent with loss of transcriptional activity and tumor proliferation. Serial passaging of castrate refractory Myc-CaP in pre-castrated male FVB mice resulted in the development of a bona fide castrate resistant Myc-CaP tumor which pheno-copied the original androgen sensitive parental Myc-CaP tumor. CONCLUSIONS: Developing a murine castrate transplant resistant tumor model that mimics the clinical course of human castrate resistant prostate cancer will create better opportunities to understand the development of castrate resistant prostate cancer and also allow for more rapid pre-clinical studies to stratify rational novel therapies for this lethal form of prostate cancer. PMID- 21796657 TI - Acute respiratory distress associated with inhaled hydrocarbon. AB - BACKGROUND: Pneumonitis is a well-known complication following aspiration of ingested liquid hydrocarbons. There are few data about acute pulmonary toxicity from unintentional hydrocarbon inhalation; most human cases involve products containing a fluoropolymer in combination with hydrocarbons. METHODS: Case report of a 45-year-old male who presented with respiratory distress after a 15-min inhalational exposure to a canvas waterproofing spray containing liquefied petroleum gas, ethylene glycol monobutyl ether, and isopropanol. RESULTS: Patients had symptoms, exam findings, and chest X-ray that were consistent with an acute pneumonitis. CONCLUSION: Acute pulmonary injury can occur after a short exposure to an inhaled hydrocarbon and associated symptoms appear to respond to supportive measures, including oxygen, corticosteroids, and bronchodilators. PMID- 21796656 TI - Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity. AB - BACKGROUND: Docetaxel is the mainline treatment approved by the FDA for castration-resistant prostate cancer (CRPC) yet its administration only increases median survival by 2-4 months. Docetaxel is metabolized in the liver by hepatic CYP3A4 activity. Piperine, a major plant alkaloid/amide, has been shown to inhibit the CYP3A4 enzymatic activity in a cell-free system. Thus, we investigated whether the co-administration of piperine and docetaxel could increase docetaxel's pharmacokinetic activity in vitro and in vivo. METHODS: Liver CYP3A4 enzymatic activity was measured by fluorescence. In vivo docetaxel pharmacokinetic activity was analyzed by liquid chromatography. An in vivo xenograft model of human CRPC was utilized to assess the anti-tumor effect of docetaxel when co-administered with piperine. RESULTS: Inhibition of hepatic CYP3A4 activity resulted in an increased area under the curve, half-life and maximum plasma concentration of docetaxel when compared to docetaxel alone administration. The synergistic administration of piperine and docetaxel significantly improved the anti-tumor efficacy of docetaxel in a xenograft model of human CRPC. CONCLUSIONS: Docetaxel is one of the most widely used cytotoxic chemotherapeutic agents and is currently the mainstay treatment for metastatic CRPC. Dietary constituents are important agents modifying drug metabolism and transport. In our studies, dietary consumption of piperine increases the therapeutic efficacy of docetaxel in a xenograft model without inducing more adverse effects on the treated mice. PMID- 21796658 TI - Genotoxicity in vinyl chloride-exposed workers and its implication for occupational exposure limit. AB - BACKGROUND: Vinyl chloride monomer (VCM) is a colorless gas under room temperature and has been mostly used to produce polyvinyl chloride (PVC) since the 1970s. It is classified by the International Agency of Research on Cancer (IARC) as a known human carcinogen (Group 1). In this study, genetic damage in VCM workers was evaluated in relation to their occupational cumulative exposure to VCM. METHODS: Cytokinesis-block micronucleus assay was conducted in 229 VCM workers and 138 controls to detect chromosome damage in peripheral blood lymphocytes. The cumulative exposure dose (CED) of VCM was calculated based on the job type and duration of each worker and the workplace VCM concentration. Dose-response relationships between VCM CED and micronucleus frequency or chromosomal damage were evaluated, and benchmark doses (BMDs) estimated. RESULTS: Dose-response relationships between VCM CED and chromosomal damage were obtained. The 95% lower confidence bound of BMD of VCM CED was 2.86 mg/m(3) -year for both genders combined, leading to an estimated exposure limit of 0.072 mg/m(3) assuming a work life of 40 years. CONCLUSIONS: VCM exposure may induce chromosomal damage at occupational exposure levels below the Chinese national occupational health standard. Further research is needed to better understand micronuclei as biomarker of VCM genotoxicity. Better dose-response assessment and BMD estimation are desirable in order to improve the quantification of occupational exposure limits for VCM with respect to non-cancer risk. PMID- 21796659 TI - Depressive symptoms in women working in a poultry-processing plant: a longitudinal analysis. AB - BACKGROUND: Work in poultry-processing plants is physically demanding, and a number of studies have documented the effects of such work on the physical health of workers. Few studies, however, have examined the potential effects on mental health. METHODS: Longitudinal data were collected on 223 women who worked in two poultry-processing plants in northeastern North Carolina. Effects on depressive symptoms of demographic variables, work tenure at baseline, musculoskeletal pain, psychosocial job characteristics, coping style, and health-related quality of life were examined using mixed models. RESULTS: Psychosocial job characteristics were not associated with depressive symptoms as measured by the Center for Epidemiologic Studies Depression scale (CES-D) in this cohort of workers. CES-D scores decreased with increasing work tenure at the plant, which suggests a healthy worker survivor effect (HWSE). CONCLUSIONS: These exploratory analyses draw attention to the need to more carefully explore the possibility that the HWSE may extend to mental health outcomes as well as physical ones. PMID- 21796660 TI - Factors affecting aggression among females in captive groups of rhesus macaques (Macaca mulatta). AB - Captive groups of primates often exhibit higher rates of aggression than wild, free-ranging groups. It is important to determine which factors influence aggression in captivity because aggression, particularly intense aggression, can be harmful to animal health and well-being. In this study, we investigated the effect of ground substrate as well as season, rank, age, and group size on rates of agonistic interactions per female in seven captive groups of rhesus macaques (n = 70 females, 1,723 focal samples) at the California National Primate Research Center. Agonistic interactions were divided into three categories: displacements, mild aggression, and intense aggression. Females living in enclosures with gravel substrate were 1.7 times more likely to be involved in intense aggression (e.g. chases and physical contact) than females living in enclosures with grass (Poisson regression model: P < 0.001). High-ranking females were at least 1.3 times more likely to be involved in mild (e.g. threats and lunges) aggression than lower-ranking females (low rank: P = 0.03; mid rank: P = 0.001). Females of all ranks were 1.5-1.9 times more likely to be involved in both intense and mild aggression during the breeding season than other seasons. Age and group size did not affect rates of mild or intense aggression. These findings indicate that although some aggression appears to be natural and unavoidable, i.e. aggression during the breeding season, the well-being of captive macaques can be improved by developing grass substrate in outdoor enclosures. PMID- 21796662 TI - Systemic inflammation disrupts the developmental program of white matter. AB - OBJECTIVE: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants. The goal of the present study was to test the hypothesis that moderate systemic inflammation is sufficient to alter white matter development. METHODS: Newborn mice received twice-daily intraperitoneal injections of interleukin-1beta (IL-1beta) over 5 days and were studied for myelination, oligodendrogenesis, and behavior and with magnetic resonance imaging (MRI). RESULTS: Mice exposed to IL 1beta had a long-lasting myelination defect that was characterized by an increased number of nonmyelinated axons. They also displayed a reduction of the diameter of the myelinated axons. In addition, IL-1beta induced a significant reduction of the density of myelinating oligodendrocytes accompanied by an increased density of oligodendrocyte progenitors, suggesting a partial blockade in the oligodendrocyte maturation process. Accordingly, IL-1beta disrupted the coordinated expression of several transcription factors known to control oligodendrocyte maturation. These cellular and molecular abnormalities were correlated with a reduced white matter fractional anisotropy on diffusion tensor imaging and with memory deficits. INTERPRETATION: Moderate perinatal systemic inflammation alters the developmental program of the white matter. This insult induces a long-lasting myelination deficit accompanied by cognitive defects and MRI abnormalities, further supporting the clinical relevance of the present data. PMID- 21796661 TI - Gene therapy for pain: results of a phase I clinical trial. AB - OBJECTIVE: Preclinical evidence indicates that gene transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)-based vectors can reduce pain-related behavior in animal models of pain. This clinical trial was carried out to assess the safety and explore the potential efficacy of this approach in humans. METHODS: We conducted a multicenter, dose-escalation, phase I clinical trial of NP2, a replication-defective HSV-based vector expressing human preproenkephalin (PENK) in subjects with intractable focal pain caused by cancer. NP2 was injected intradermally into the dermatome(s) corresponding to the radicular distribution of pain. The primary outcome was safety. As secondary measures, efficacy of pain relief was assessed using a numeric rating scale (NRS), the Short Form McGill Pain Questionnaire (SF-MPQ), and concurrent opiate usage. RESULTS: Ten subjects with moderate to severe intractable pain despite treatment with >200mg/day of morphine (or equivalent) were enrolled into the study. Treatment was well tolerated with no study agent-related serious adverse events observed at any point in the study. Subjects receiving the low dose of NP2 reported no substantive change in pain. Subjects in the middle- and high-dose cohorts reported pain relief as assessed by NRS and SF-MPQ. INTERPRETATION: Treatment of intractable pain with NP2 was well tolerated. There were no placebo controls in this relatively small study, but the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation. PMID- 21796663 TI - Does achieving an intensive versus usual blood pressure level prevent stroke? AB - OBJECTIVE: The purpose of this study was to compare the impact of achieving tight versus usual systolic blood pressure (SBP) control on stroke prevention through meta-analysis of randomized controlled trials. METHODS: We searched PubMed and bibliographies of recent review articles. Relative risk with 95% confidence interval was used as a measure of the association between an active treatment group with achieved SBP <130 mmHg versus a comparator group with achieved SBP 130 to 139 mmHg, and risk of stroke after pooling data across trials. RESULTS: The search identified 11 studies with 42,572 participants and 794 stroke events. The final SBPs, weighted for trial size, were a mean of 126.5 mmHg in the intensive treatment arms and 132.6 mmHg in the conventional arms (mean SBP reduction, 6.1 mmHg). Achieving a tight SBP level was associated with a lower stroke risk (relative risk, 0.80; 95% confidence interval, 0.70-0.92; p < 0.01) and a lower risk of major vascular events (0.91; 0.86-0.96; p < 0.001). In subgroup analyses, subjects with risk factors but no established cardiovascular disease showed substantial reduction of future stroke risk with tight control (0.49; 0.34-0.69), but those with established cardiovascular disease at entry did not experience stroke risk reduction with tight control (0.92; 0.83-1.03). INTERPRETATION: Achieving an SBP <130 mmHg compared to 130 to 139 mmHg appears to provide additional stroke protection only among people with risk factors but no established cardiovascular disease. PMID- 21796664 TI - Profiles of lacunar and nonlacunar stroke. AB - OBJECTIVE: Determining which small deep infarcts (SDIs) are of lacunar, arterial, or cardioembolic etiology is challenging, but important in delivering optimal stroke prevention therapy. We sought to distinguish lacunar from nonlacunar causes of SDIs using a gene expression profile. METHODS: A total of 184 ischemic strokes were analyzed. Lacunar stroke was defined as a lacunar syndrome with infarction <15mm in a region supplied by penetrating arteries. RNA from blood was processed on whole genome microarrays. Genes differentially expressed between lacunar (n = 30) and nonlacunar strokes (n = 86) were identified (false discovery rate <= 0.05, fold change >|1.5|) and used to develop a prediction model. The model was evaluated by cross-validation and in a second test cohort (n = 36). The etiology of SDIs of unclear cause (SDIs >= 15mm or SDIs with potential embolic source) (n = 32) was predicted using the derived model. RESULTS: A 41-gene profile discriminated lacunar from nonlacunar stroke with >90% sensitivity and specificity. Of the 32 SDIs of unclear cause, 15 were predicted to be lacunar, and 17 were predicted to be nonlacunar. The identified profile represents differences in immune response between lacunar and nonlacunar stroke. INTERPRETATION: Profiles of differentially expressed genes can distinguish lacunar from nonlacunar stroke. SDIs of unclear cause were frequently predicted to be of nonlacunar etiology, suggesting that comprehensive workup of SDIs is important to identify potential cardioembolic and arterial causes. Further study is required to evaluate the gene profile in an independent cohort and determine the clinical and treatment implications of SDIs of predicted nonlacunar etiology. PMID- 21796665 TI - Computed tomography and magnetic resonance perfusion imaging in ischemic stroke: definitions and thresholds. AB - OBJECTIVE: Cerebral perfusion imaging with computed tomography (CT) or magnetic resonance (MR) is widely available. The optimum perfusion values to identify tissue at risk of infarction in acute stroke are unclear. We systematically reviewed CT and MR perfusion imaging in acute ischemic stroke. METHODS: We searched for papers on MR or CT perfusion performed <24 hours after stroke that assessed perfusion thresholds, mean perfusion lesion values, or lesion volumes. We extracted definitions and perfusion values. We compared definitions and evaluated perfusion thresholds for "nonviable"/"at risk" and "at risk"/"not at risk tissue" thresholds. RESULTS: Among 7,152 papers, 69 met inclusion criteria for analysis of definitions (49 MR and 20 CT), 21 MR (n = 551), and 10 CT (n = 266) papers, median sample size 22, provided thresholds. We found multiple definitions for tissue states, eg, tissue at risk, 18; nonviable tissue, 12; 16, no definition. Perfusion parameters varied widely; eg, 9 different MR, 6 different CT parameters for the "at risk"/"not at risk threshold." Median threshold values varied up to 4-fold, eg, for the "at risk"/"not at risk threshold," median cerebral blood flow ranged from 18 to 37ml/100g/min; mean transit time from 1.8 to 8.3 seconds relative to the contralateral side. The influence of reperfusion and duration of ischemia could not be assessed. INTERPRETATION: CT and MR perfusion imaging viability thresholds in stroke are derived from small numbers of patients, variable perfusion analysis methods and definitions of tissue states. Greater consistency of methods would help determine reliable perfusion viability values for wider clinical use of perfusion imaging. PMID- 21796667 TI - DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2 Elk1 pathway in neuroprotection. AB - OBJECTIVE: Loss of function mutations of Park7/DJ-1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ-1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ-1. METHODS: DJ-1 knockdown cells and DJ-1 knockout mice were used to elucidate the mechanisms underlying the antioxidative stress of DJ-1. Preliminary study of the saliva from PD patients and controls was used to confirm our findings obtained from the above studies. RESULTS: Our experiments showed that DJ-1 interacted with Erk1/2 and was required for the nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 were all suppressed in DJ-1 knockdown cells and DJ-1 null mice treated with oxidative insult. Furthermore, reintroduction of SOD1 into DJ-1 knockdown cells protected them against oxidative stress. Finally, in the preliminary study, we found close correlation between the protein levels of DJ-1 and SOD1 in the saliva samples from different stages of PD patients. INTERPRETATION: Our studies suggest that DJ-1 regulates SOD1 expression through Erk1/2-Elk1 pathway in its protective response to oxidative insult. PMID- 21796666 TI - Histopathological correlates of magnetic resonance imaging-defined chronic perinatal white matter injury. AB - OBJECTIVE: Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. METHODS: We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically defined lesions with contrast-weighted and diffusion-weighted high-field ex vivo MRI data. RESULTS: Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined 2 novel hypointense signal abnormalities on T(2) -weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. INTERPRETATION: These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors. PMID- 21796668 TI - Impact of biodegradation on the potential bioaccumulation and toxicity of refinery effluents. AB - Whole effluent assessments (WEA) are being investigated as potential tools for controlling aqueous industrial discharges and minimizing environmental impact. The present study investigated how toxicity and the presence of potentially bioaccumulative substances altered when refinery effluents were subjected to biodegradation tests. Three petrochemical effluents were assessed, two freshwater and one saline, and subjected to two different types of biodegradation tests, resembling either a ready style (dissolved organic carbon (DOC)-die away) or an inherent style (Zahn-Wellens) test and the toxicity and potential to bioaccumulate parameters were re-analysed during and after biodegradation. A high proportion of the potentially bioaccumulative substances (PBS) in these effluents was easily biodegradable. Biodegradation not only lowered the PBS concentration but also toxicity. Appropriate controls are required however, as some increases in toxicity were observed after 4 h. In the present study, six other petrochemical effluents were also assessed for their PBS content and toxicity to increase the understanding of the relationship between PBS and toxicity. The results showed that the PBS concentrations in these samples were lower than the estimated benchmarks of acute toxicity for algae, fish and crustacean, although two samples were above the critical PBS values for chronic narcotic toxicity for Daphnia magna, which support the assumption that narcotic effects are mainly responsible for the observed toxicity in refinery effluents. It can be concluded that for facilities processing petroleum products that the measurement of PBS is a suitable surrogate for toxicity tests at the screening stage. Finally, the combination of persistency, bioaccumulation, and toxicity tests was shown to have additional value compared to an approach using only toxicity tests. PMID- 21796669 TI - Application of an acute biotic ligand model to predict chronic copper toxicity to Daphnia magna in natural waters of Chile and reconstituted synthetic waters. AB - The objective of the present study was to assess the predictive capacity of the acute Cu biotic ligand model (BLM) as applied to chronic Cu toxicity to Daphnia magna in freshwaters from Chile and synthetic laboratory-prepared waters. Samples from 20 freshwater bodies were taken, chemically characterized, and used in the acute Cu BLM to predict the 21-d chronic Cu toxicity for D. magna. The half maximal effective concentration (EC50) values, determined using the Organisation for Economic Co-operation and Development (OECD) 21-d reproduction test (OECD Method 211), were compared with the BLM simulated EC50 values. The same EC50 comparison was performed with the results of 19 chronic tests in synthetic media, with a wide range of hardness and alkalinity and a fixed 2 mg/L dissolved organic carbon (DOC) concentration. The acute BLM was modified only by adjustment of the accumulation associated with 50% of an effect value (EA50). The modified BLM model was able to predict, within a factor of two, 95% of the 21-d EC50 and 89% of the 21-d half-maximal lethal concentrations (LC50) in natural waters, and 100% of the 21-d EC50 and 21-d LC50 in synthetic waters. The regulatory implications of using a slightly modified version of an acute BLM to predict chronic effects are discussed. PMID- 21796670 TI - Equilibrium modeling: a pathway to understanding observed perfluorocarboxylic and perfluorosulfonic acid behavior. AB - Equilibrium distribution models of hydrophobic neutral partitioning of the perfluorinated carboxylic and sulfonic acids were shown, without the need for any physical chemical properties, to successfully predict the sediment-water distribution (D(SW) ) directly from independently measured equilibrium tissue distributions known as the bioconcentration factor (BCF). The constant of proportionality required by the models successfully predicted the correlation between the biotic and abiotic distributions of both sets of chemicals, thus demonstrating the applicability of the assumptions inherent in the models, that is, hydrophobically driven partitioning of the neutral species, and thus the applicability of the models themselves. Colloquially speaking, the models are thus validated as applicable to these chemicals. Subsequent application of the standard equilibrium models showed order of magnitude agreement for 83% of measured BCF values and 88% of measured D(SW) for the perfluorinated carboxylic acids, confirming the physical chemical properties used. The applicability of the models to perfluorooctane sulfonic acid (PFOSA) was shown by the successful prediction of D(SW) from BCF. Therefore, the measured D(SW) and BCF could be used to calculate the octanol-water distribution, D(OW) , and hence the corresponding pK(a):K(OW) solution set, thus providing independent experimentally based estimates of these properties. For both the perfluorinated carboxylic and sulfonic acids, the existing standard equilibrium models are shown to be applicable. PMID- 21796671 TI - Effect of a birth on the behavior of a family group of Asian elephants (Elephas maximus) at Dublin Zoo. AB - Elephants in the wild live in herds of related females from several generations. Zoos, therefore, tend to house elephants in female groups, consisting where possible of related individuals. This type of group structure is very beneficial as it allows group members to experience events such as births in the group, and means that natural social interactions can take place between the group members. The behavior of four related female Asian elephants (Elephas maximus) at Dublin Zoo was recorded before and after the birth of a calf, to examine what effects it would have on the behavior and associations in the elephant group. The mother of the calf significantly decreased the amount of time she spent walking after the birth and the aunt of the calf showed significant decreases in both walking and standing. The mother spent the majority of her time closest to her calf after the birth, but the proportion of time she spent with each of the other individuals in the group did not change. The associations of the aunt also did not change after the birth. The older sister of the newborn calf increased the proportion of time she spent nearest to her mother after the calf was born, and reduced the time she spent close to another young elephant in the group. The new calf seems to have been successfully assimilated into the elephant group. PMID- 21796672 TI - Behavioral responses of maned wolves (Chrysocyon brachyurus, Canidae) to different categories of environmental enrichment stimuli and their implications for successful reintroduction. AB - The maned wolf (Chrysocyon brachyurus, Illiger, 1815, Canidae) is a threatened species that inhabits the cerrados of Brazil, Argentina, Peru, Bolivia, Paraguay, and Uruguay. Captive maned wolves could be potentially used in reintroduction programs for species conservation; however, it is necessary that their behavior and cognitive abilities are conserved. Environmental enrichment is a tool used to stimulate captive animals and maintain a natural behavioral repertoire. To compare the variation of captive maned wolves' behavioral responses to environmental enrichment, we studied three maned wolves held by Belo Horizonte Zoo, Brazil. Foraging, interspecific, and intraspecific stimuli were offered to the animals and their responses were compared with a baseline and postenrichment treatments. The test was used to help in choosing which one of the three individuals would participate in a reintroduction project. The results showed that stimuli type did influence the animal's responses, and that individually wolves responded differently to foraging, interspecific, and intraspecific enrichment items (P80.05 for some behaviors in each enrichment category). The individual's personality seemed to influence their behavioral responses, with animals showing bold and shy responses, and this trait should be considered during decision makings for reintroduction. PMID- 21796673 TI - Sampling Extreme Groups Invalidates Research on the Paraphilias: Implications for DSM-5 and Sex Offender Risk Assessments. AB - Psychiatrist and Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) text editor Michael First has criticized the addition of victim counts to criteria proposed by the Paraphilia Sub-Workgroup for inclusion in DSM 5 because they will increase false-positive diagnoses. Psychologist and Chair of the DSM-5 Paraphilia Sub-Workgroup, Ray Blanchard, responded by publishing a study of pedohebephiles and teleiophiles which seemed to show that victim counts could accurately identify pedohebephiles who were selected per self-report and phallometric testing. His analysis was flawed because it did not conform to conventional clinical practice and because he sampled groups at opposite ends of the clinical spectrum. In an analysis of his full sample, we found the false positive rate for pedohebephilia at the recommended victim count selection points was indeed very large. Why? Because data analyses that eliminate intermediate data points will generate inflated estimates of correlation coefficients, base rates, and the discriminative capacity of predictor variables. This principle is also relevant for understanding the flaws in previous research that led Hanson and Bussiere to conclude that sexual recidivism was correlated with "sexual interest in children as measured by phallometric assessment." The credibility of mental health professionals rests on the reliability of their research. Conducting, publishing, and citing research that reflects PMID- 21796674 TI - Talking about a black man: the influence of defendant and character witness race on jurors' use of character evidence. AB - To determine whether anti-Black bias influences mock jurors' use of character evidence (i.e., information about a defendant's personality), this study manipulated the race (Black, White) of the defendant and character witness and the type of character evidence presented in a fictitious criminal trial. Two hundred six predominantly White participants read a trial transcript, then made verdicts and trial judgments. Results confirm previous findings that positive character evidence has a limited impact on jurors' judgments, but negative character evidence is misused to evaluate the defendant's guilt. However, participants were more influenced by character evidence that was inconsistent with racial stereotypes. Specifically, positive character evidence had a stronger effect for Black defendants, whereas negative rebuttal evidence had a stronger influence for White defendants. The race of the character witness did not affect judgments. Thus, defendant race may provide a framework that influences how mock jurors process character evidence. PMID- 21796675 TI - Resilience and successful community reintegration among female forensic psychiatric patients: a preliminary investigation. AB - Research on resiliency and recovery in forensic psychiatric patients is still limited. Information pertaining to factors associated with successful community reintegration would contribute to a more comprehensive assessment of functioning and informed treatment planning that fits within a recovery approach of service provision. Using a retrospective design involving file reviews and a 3-year follow-up period, the authors investigated the rate of successful/unsuccessful community reintegration (defined by the presence or absence of an absolute discharge/readmission to hospital) in female forensic psychiatric patients (N = 48). The study evaluated the extent to which the risk and protective factors captured in the Short-Term Assessment of Risk and Treatability (START) predicted a range of positive and negative outcomes in the study sample. Results showed that 47.9% of the women qualified as having successfully reintegrated into the community, with the remaining 52.1% qualifying as still being in recovery. Successful individuals possessed significantly more protective factors and significantly fewer risk factors than individuals still in recovery. Furthermore, both the vulnerability and the strength scale of the START demonstrated good predictive validity, however we did not find evidence of incremental validity of the strength scale. PMID- 21796676 TI - Growth potential of different zones of the growth plate-an experimental study in rabbits. AB - Despite clinical efforts to treat growth disturbances only little is known about the growth potential of the different zones of the growth plate. The aim of this study was to investigate the growth potential of different zones of the growth plate. A total of 20 New Zealand White rabbits were used for this experiment. The right and left ulna of each animal were used resulting in a total of 40 ulnae. Animals were assigned into five groups. In groups I and II resection of the metaphyseal (n = 12) or the epiphyseal (n = 6) segment of the growth plate was performed. In group III resection of the growth plate and re-implantation was performed (n = 6). In group IV the growth plate was resected and re-implanted after a 180 degrees rotation (n = 6). Animals in group V served as controls. Histologic and radiologic examinations were performed to evaluate the growth process at 1, 2, 4, and 12 weeks following surgery. In group I, III, and IV temporary growth disturbance which was compensated within a short time was observed. Resection of the epiphyseal part resulted in growth arrest of the distal ulna in combination with normal growth of the radius which led to and valgus deformity of the limb. The results of this study indicate the importance of the reserve zone for the functioning of the growth plate. PMID- 21796678 TI - Organizational analysis of maternal mortality reduction programs in Madagascar. AB - Little is known about the organizational factors involved in policy creation and programs implementation aimed at reducing maternal mortality in Madagascar. A qualitative case study was performed to investigate organizational factors influencing the health system's capacity to elaborate and implement maternal mortality reduction programs. Semi-structured interviews were conducted with 53 participants. A conceptual framework based on Gamson's coalition theory and Hinings and Greenwood's archetypes concept was used. Three major conclusions emerge: the Ministry of Health is a poor leader in the development of national strategies, due to its dependency on external financial resources and expertise, and because of poor transmission of key information from the field; at a meso level (regions and districts), the capacity to adapt programs is highly dependent on the collaboration with NGOs; at the micro level, there are few incentives provided to field workers to participate in a collective effort and little attempt to exploit complementarities between scare resources. The Madagascar health system should consider the need for improvement in data analysis capacity, and implementing behavior-changing tools suitable for stimulating providers who work inside and outside the health care system, to participate to a coordinated collective effort. PMID- 21796679 TI - Public health in Thailand: emerging focus on non-communicable diseases. AB - Over the past three decades, the public health landscape in Thailand has shifted remarkably. Currently chronic non-communicable diseases represent the largest cause of mortality in the Thai population. In light of the current situation, this paper synthesizes what is known about the chronic non-communicable disease situation in Thailand and analyzes current policy responses. Relevant contextual factors such as socio-economic transitions, health systems development, and health workforce capacities are also considered. Primary data for this study were collected by a review of policy documents, government statements, and statistics reported by the Thailand Ministry of Public Health. Secondary data were obtained by a thorough review of the existing literature. The paper finds that while current policy responses to chronic non-communicable diseases in the health sector have focused on improving prevention and control of risk factors, a stronger emphasis on chronic disease treatment and management may be needed in the future. The paper concludes with an exploration of the potential for developing and implementing realistic public health responses to the growing burden of chronic non-communicable diseases in a Southeast Asian country context by utilizing existing capacities in research, policy, and health workforce development. PMID- 21796681 TI - Legitimacy, trustee incentives, and board processes: the case of public and private non-profit nursing homes. AB - Using a unique data set, this study explores how type of ownership (government/private) is related to processes of governance. The findings suggest that the neo-institutional perspective and the self-interest rationale of the agency perspective are helpful in explaining processes of governance in both government- and privately owned non-profit organizations. Due to adverse incentives and the quest for legitimacy, supervising governance bodies within local government-owned non-profit institutions pay relatively less attention to the development of high quality supervising bodies and delegate little to management. Our findings also indicate that governance processes in private institutions are more aligned with the business model and that this alignment is likely driven by a concern to improve decision making. By contrast, our data also suggest that in local government-owned institutions re-election concerns of politicians-trustees are an important force in the governance processes of these institutions. In view of these adverse incentives - in contrast to the case of private organizations - a governance code is unlikely to entail much improvement in government-owned organizations. PMID- 21796682 TI - Dissecting hospital quality. Antecedents of clinical and perceived quality in hospitals. AB - Clinical quality (CQ) and patient satisfaction (PS) are key elements on the agenda of European public healthcare systems. This paper seeks to explore the relationship between CQ and PS, at hospital level, as freedom of hospital choice may lead to a trade-off between them. In addition, the paper studies the influence of some factors--location, size, case-mix, length of stay and occupancy rate (OR)--on hospital clinical and perceived quality. Correlation analyses and the linear mixed-effect methodology are used. The study focuses on the Andalusian Health Service, one of the biggest European public health services, and covers the years from 2002 to 2006. The results indicate that CQ and perceived quality are not related. The 'volume-expertise' effect is not confirmed in our study, but we find a 'complexity-expertise' effect, i.e. attending more complex cases may improve CQ. Shorter hospitalizations and higher ORs might negatively affect CQ. Location, size, case-mix and ORs significantly affect PS. Hospitals with better patient assessments might attract patients without providing a better clinical care. Caution should be taken when evaluating hospital performance and implementing reforms to improve hospital efficiency as quality may be harmed. PMID- 21796684 TI - One-dimensional nanostructures of ferroelectric perovskites. AB - Nanorods, nanowires, and nanotubes of ferroelectric perovskites have recently been studied with increasing intensity due to their potential use in non-volatile ferroelectric random access memory, nano-electromechanical systems, energy harvesting devices, advanced sensors, and in photocatalysis. This Review summarizes the current status of these 1D nanostructures and gives a critical overview of synthesis routes with emphasis on chemical methods. The ferroelectric and piezoelectric properties of the 1D nanostructures are discussed and possible applications are highlighted. Finally, prospects for future research within this field are outlined. PMID- 21796685 TI - The role of the fabrication of anatase-TiO2 chain-networked photoanodes. PMID- 21796686 TI - Rational design and enhanced biocompatibility of a dry adhesive medical skin patch. PMID- 21796687 TI - Permanent polarity and piezoelectricity of electrospun alpha-helical poly(alpha amino acid) fibers. PMID- 21796688 TI - Intrinsically stretchable polymer light-emitting devices using carbon nanotube polymer composite electrodes. PMID- 21796689 TI - Large-scale exfoliation of inorganic layered compounds in aqueous surfactant solutions. PMID- 21796691 TI - Bridging the gap between porphyrins and porphycenes: substituent-position sensitive tautomerism and photophysics in meso-diphenyloctaethylporphyrins. AB - 2,3,7,8,12,13,17,18-Octaethyl-5,15-diphenylporphyrin (1) is characterized by an inner cavity with a rectangular shape and small NH???N distances. It resembles porphycene, which is a constitutional isomer of porphyrin known for its strong intramolecular hydrogen bonds and rapid tautomerization. Such distortion of the porphyrin cavity leads to tautomeric properties of 1 that are intermediate between those of porphyrin and porphycene. In particular, a tautomerization in the lowest excited singlet state of 1 has been discovered, occurring with a rate three orders of magnitude lower than that in porphycene, but three to four orders of magnitude higher than that in porphyrin. An isomer of 1, 2,3,7,8,12,13,17,18 octaethyl-5,10-diphenylporphyrin (2), exhibits a different kind of geometry distortion. This molecule is nonplanar, but the inner cavity shape and dimensions are similar to those of the parent porphyrin. The same hydrogen-bonding strength as that in porphyrin is observed for 2. In contrast, the nonplanarity of 2 significantly influences the photophysics, leading to a decrease in fluorescence quantum yield and lifetime. Absorption, magnetic circular dichroism, and fluorescence spectra are similar for 1 and 2 and resemble those of parent porphyrin. This is a consequence of comparable energy splittings of the frontier orbitals, DeltaHOMO~DeltaLUMO. The results demonstrate that judicious selection of substituents and their position enables a controlled modification of geometry, hydrogen-bonding strength, tautomerization rate, and photophysical and spectral parameters of porphyrinoids. PMID- 21796690 TI - In situ generation and intramolecular Schmidt reaction of keto azides in a microwave-assisted flow format. PMID- 21796692 TI - Porous interpenetrated zirconium-organic frameworks (PIZOFs): a chemically versatile family of metal-organic frameworks. AB - We present the synthesis and characterization of porous interpenetrated zirconium organic frameworks (PIZOFs), a new family of metal-organic frameworks obtained from ZrCl(4) and the rodlike dicarboxylic acids HO(2)C[PE-P(R(1),R(2))-EP]CO(2) H that consist of alternating phenylene (P) and ethynylene (E) units. The substituents R(1),R(2) were broadly varied (alkyl, O-alkyl, oligo(ethylene glycol)), including postsynthetically addressable substituents (amino, alkyne, furan). The PIZOF structure is highly tolerant towards the variation of R(1) and R(2). This together with the modular synthesis of the diacids offers a facile tuning of the chemical environment within the pores. The PIZOF structure was solved from single-crystal X-ray diffraction analysis. The PIZOFs are stable under ambient conditions. PIZOF-2, the PIZOF prepared from HO(2)C[PE-P(OMe,OMe) EP]CO(2)H, served as a prototype to determine thermal stability and porosity. It is stable up to 325 degrees C in air as determined by using thermogravimetry and powder X-ray diffraction. Argon sorption isotherms on PIZOF-2 revealed a Brunauer Emmett-Teller (BET) surface area of 1250 m(2) g(-1) and a total pore volume of 0.68 cm(3) g(-1). PMID- 21796693 TI - Palladium-catalyzed synthesis of 7,9-diaryl-8 H-acenaphtho[1,2-c]pyrroles and their application in explosives detection. PMID- 21796694 TI - Aptamer-based switchable nanovalves for stimuli-responsive drug delivery. PMID- 21796695 TI - N-acetylmethionine and biotin as photocleavable protective groups for ruthenium polypyridyl complexes. PMID- 21796696 TI - Rapid access to alpha-alkoxy and alpha-amino acid derivatives through safe continuous-flow generation of diazoesters. PMID- 21796697 TI - N-heterocyclic carbene-catalyzed hydrosilylation of styryl and propargylic alcohols with dihydrosilanes. PMID- 21796698 TI - Preventive action of Panax ginseng roots in hypercortisolism-induced Impairment of hippocampal neurons in male C57BL/6N mice. AB - An increasing number of people suffering from hypercortisolism are at risk of developing hippocampus impairment and mental disorders. The aim of this study was to investigate whether the water extract of Panax ginseng roots (GWE) could prevent hypercortisolism-induced adverse consequences. Hypercortisolism was experimentally induced by repeated corticosterone injection in male mice. Treatment with corticosterone alone resulted in a significant decrease in hippocampus neurofilament light chain (NF-L) protein expression and induced depression-like behavior. Serum corticosterone was significantly increased in the corticosterone-treated mice. Treatment with GWE (800 and 400 mg/kg) during corticosterone treatment reduced or partially antagonized the effects induced by corticosterone toward the normal values of the controls; however, it failed to normalize increased corticosterone levels in corticosterone-treated mice. Overall, ginseng conclusively exhibited a protective action against hypercortisolism-induced impairment of hippocampal neurons. PMID- 21796699 TI - Antiparasitic activity of C-geranyl flavonoids from Mimulus bigelovii. AB - Bioactivity-directed fractionation of the MeOH fraction of the extract of Mimulus bigelovii by means of an axenic Leishmania amastigote assay and chromatographic techniques resulted in the isolation of four C-geranyl flavanones, diplacone (1), 3'-O-methyldiplacone (2), 4'-O-methyldiplacone (3), 3'-O-methyldiplacol (4), together with a geranylated flavone, cannflavin A (5). These compounds were separated from M. bigelovii for the first time. All compounds showed moderate antileishmanial activity against axenic Leishmania donovani amastigotes with IC(50) values ranging from 4.8 to 14.6 MUg/mL. The compounds were also tested against the related kinetoplastid parasite Trypanosoma brucei brucei and they showed activity with IC(50) values ranging from 1.4 to 7.2 MUg/mL. PMID- 21796700 TI - Effect of Wuzhi tablet (Schisandra sphenanthera extract) on the pharmacokinetics of paclitaxel in rats. AB - Wuzhi tablet (WZ, registration no. in China: Z20025766) is a preparation of an ethanol herb extract of Wuweizi (Schisandra sphenanthera) containing 7.5 mg Schisantherin A per tablet. It was reported recently that WZ could significantly increase the blood concentrations of tacrolimus, which might be due to the inhibitory effect of WZ and its ingredients on P-gp and/or CYP450 activity. Paclitaxel is a substrate of the efflux transporter P-gp, and is mainly metabolized by CYP450 enzymes in the liver. Therefore, the purpose of this study was to investigate whether and how WZ affects the pharmacokinetics of paclitaxel in rats. After pretreatment with WZ, there were significant increases in the AUC(0-24h) of oral paclitaxel (from 280.8 +/- 97.3 to 543.5 +/- 115.2 h ng/mL; p < 0.05) and C(max) (from 44.6 +/- 16.4 to 86.8 +/- 16.1 ng/mL; p < 0.05). The pharmacokinetic data for i.v. paclitaxel with WZ showed a relatively small (when compared against oral paclitaxel) but still significant increase in AUC(0-24h) (from 163.6 +/- 22.1 to 212.7 +/- 17.7 h ng/mL; p < 0.05) and a decrease in clearance (from 3.2 +/- 0.6 to 2.2 +/- 0.3 L/h/kg; p < 0.05). Thus, the presence of WZ improved the systemic exposure of paclitaxel in rats. The herb-drug interaction between WZ and paclitaxel should be taken into consideration in clinical use. PMID- 21796701 TI - Essential oil of clove (Eugenia caryophyllata) augments the humoral immune response but decreases cell mediated immunity. AB - The present study was undertaken to explore the effect of the essential oil isolated from the buds of Eugenia caryophyllata on some immunological parameters. Humoral immunity was assessed by measuring the hemagglutination titre to sheep red blood cells and delayed type hypersensitivity was assessed by measuring foot pad thickness. Clove oil administration produced a significant increase in the primary as well as secondary humoral immune response. In addition, it also produced a significant decrease in foot pad thickness compared with the control group. Thus, these results suggest that clove oil can modulate the immune response by augmenting humoral immunity and decreasing cell mediated immunity. PMID- 21796702 TI - Coriolus versicolor suppresses inflammatory bowel disease by Inhibiting the expression of STAT1 and STAT6 associated with IFN-gamma and IL-4 expression. AB - To investigate the effects of Coriolus versicolor extract (CVE) on infl ammatory bowel disease (IBD), ulcerative colitis was induced in male BALb/c mice by administering drinking water containing dextran-sulfate sodium (DSS). The mice were divided into the following four experimental groups: control, DSS-induced colitis, CVE treatment and CVE treatment + DSS-induced colitis. Mice receiving DSS treatment developed clinical and macroscopic signs of ulcerative colitis. However, treatment with CVE relieved the symptoms of IBD, including the decrease in body and organ weight. The levels of serum, spleen and mesenteric lymph node IgE in the CVE-treated groups was lower compared with the untreated groups. The antiinfl ammatory response upon CVE treatment correlated with the reduced expression of TNF-alpha, IL-1beta and IL-6. Also, there was a significant reduction in the expression of STAT1 and STAT6 molecules, thereby leading to lower IFN-gamma and IL-4 expression. Therefore, the antiinfl ammatory effects of Coriolus versicolor can be explained by its ability to inhibit certain proinflammatory cytokines. PMID- 21796703 TI - Effects of ephedra water decoction and cough tablets containing ephedra and liquorice on CYP1A2 and the pharmacokinetics of theophylline in rats. AB - Ephedra water decoction (EWD) and cough tablets containing ephedra and liquorice (maxing cough tablets, MXCT) have been used widely in the treatment of asthma. In the clinic, EWD and MXCT may be prescribed with theophylline, one of the most popular antiasthmatic drugs and a typical substrate of cytochrome P450 (CYP) 1A2. So in the present study the potential effects of EWD and MXCT on CYP1A2 activity and the pharmacokinetics of theophylline in rats were evaluated. In the in vivo CYP1A2 activity research, the rats were given oral caffeine (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.1, 0.2 or 0.4 g/kg). Then the CYP 1A2 activity was expressed by using the caffeine metabolic ratio (CMR). The results showed that the CMR increased markedly compared with the control groups. In the pharmacokinetics experiment, the rats were given oral theophylline (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.2 g/kg). The results showed that the AUC(0-24 h) and C(max) of theophylline were reduced markedly compared with the control groups. These results demonstrated that EWD or MXCT pretreatment obviously induced CYP1A2 activity, therefore, speeding up the metabolism of theophylline. The concomitant use of EWD or MXCT may decrease the effect of theophylline in rats. PMID- 21796704 TI - Mechanisms of olive leaf extract-ameliorated rat arthritis caused by kaolin and carrageenan. AB - Olive leaf extract (OLE) has antioxidant and antiinflammatory actions. However, the role of OLE in mechanical inflammatory arthritis (osteoarthritis, OA) is unclear. This study investigated the effect of OLE on the development of kaolin and carrageenan-induced arthritis, a murine model of OA. Administration of OLE significantly ameliorated paw swelling, the paw Evans blue content and the histopathological scores. In the human monocyte cell line, THP-1, the OLE reduced the LPS-induced TNF-alpha production and was dose dependent. Croton oil-induced ear edema in mice also revealed that treatment with OLE suppressed ear edema, myeloperoxidase (MPO) production and was dose dependent. These results indicated that OLE is an effective antiarthritis agent through an antiinflammation mechanism. Also OLE may be beneficial for the treatment of OA in humans. PMID- 21796705 TI - Pycnogenol(r) inhibits lipid accumulation in 3T3-L1 adipocytes with the modulation of reactive oxygen species (ROS) production associated with antioxidant enzyme responses. AB - Pycnogenol(r) is a group of flavonoids with antioxidant effects. Adipogenesis is the process of adipocyte differentiation. It causes the increase of lipids as well as ROS (reactive oxygen species). Lipid accumulation and ROS production were determined in 3 T3-L1 adipocyte, and the effect of Pycnogenol(r) was evaluated. Lipid accumulation was elevated in adipocyte treated with hydrogen peroxide, one of the ROS. Pycnogenol(r) showed an inhibitory effect on the lipid accumulation and ROS production during the adipogenesis. We also investigated the molecular events associated with ROS production and lipid accumulation. Our results showed that Pycnogenol(r) inhibited the mRNA expression of pro-oxidant enzymes, such as NOX4 (NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase 4), and the NADPH-producing G6PDH (glucose-6-phosphate dehydrogenase) enzyme. In addition, Pycnogenol(r) suppressed the mRNA abundance of adipogenic transcription factors, PPAR-gamma (peroxisome proliferator-activated receptor gamma) and C/EBP alpha (CCAAT/enhancer binding protein alpha), and their target gene, aP2 (adipocyte protein 2) responsible for fatty acid transportation. On the other hand, Pycnogenol(r) increased the abundance of antioxidant proteins such as Cu/Zn SOD (copper-zinc superoxide dismutase), Mn-SOD (manganese superoxide dismutase), GPx (glutathione peroxidase) and GR (glutathione reductase). Our results suggest that Pycnogenol(r) inhibits lipid accumulation and ROS production by regulating adipogenic gene expression and pro-/antioxidant enzyme responses in adipocytes. PMID- 21796706 TI - Preventative effects of 4,4'-diphenylmethane-bis(methyl) carbamate isolated from cortex mori on human umbilical vein endothelial cell dysfunction induced by advanced glycation end products. AB - Advanced glycation end-products (AGEs) have been regarded as an initial motivating factor in the pathogenesis of endothelial dysfunction in diabetic complications. 4,4'-Diphenylmethane-bis(methyl) carbamate (DMPC), a carbamate compound, was isolated from Cortex Mori and its prevention effects against AGEs induced endothelial dysfunction were studied. 4,4'-Diphenylmethane-bis(methyl) carbamate significantly reduced cell apoptosis to normal level at 10-9 mol/L concentration. Advanced glycation end-products up-regulated the expression of Bad and Bax and down-regulated Bcl-2 proteins, and pretreatment with DMPC significantly down-regulated Bad and Bax while up-regulating Bcl-2 expressions. In addition, ICAM (intercellular adhesion molecule)-1 and TGF (transforming growth factor)-beta1 expressions in human umbilical vein endothelial cell (HUVEC) were significantly enhanced by AGEs. More importantly, these increases of ICAM-1 and TGF-beta1 expressions were reduced meaningfully with the pretreatment of DMPC. All the results showed DMPC had prevention effects against the progression of AGE-induced endothelial dysfunction, and this compound might be a promising agent against endothelial dysfunction in diabetic vascular complications. PMID- 21796707 TI - Effect of different curcuminoid supplement dosages on total in vivo antioxidant capacity and cholesterol levels of healthy human subjects. AB - The impact of consuming curcuminoids containing curcumin at 500 mg/day and 6 g/day for 7 days on plasma antioxidant capacity and serum cholesterol level were determined by using vitamin E 200 IU/day consumption as a comparison. Group A and group B subjects consumed 500 mg and 6 g curcumin, respectively, but group C subjects consumed vitamin E 200 IU. By using the oxygen radical absorbance capacity (ORAC) assay, it was found that plasma antioxidant capacity of group A rose from a baseline of 13% to 24% on day 1 and day 7, as against a 19-20% increase for group B. Serum cholesterol and triglyceride levels were significantly decreased after curcumin treatment at 500 mg/day. By consuming vitamin E, both ORAC values and plasma alpha-tocopherol concentrations were significantly increased, but only very slight responses on serum cholesterol or triglyceride levels were observed. It is therefore suggested that curcumin supplement would not be appropriate for healthy people except for reducing serum cholesterol or triglyceride levels. The dosage of a daily curcumin supplement at 500 mg is more effective than 6 g, although vitamin E is also considered to be an effective antioxidant supplement. PMID- 21796708 TI - Correcting radiofrequency inhomogeneity effects in skeletal muscle magnetisation transfer maps. AB - The potential of MRI to provide quantitative measures of neuromuscular pathology for use in therapeutic trials is being increasingly recognised. Magnetisation transfer (MT) imaging shows particular promise in this context, being sensitive to pathological changes, particularly in skeletal muscle, where measurements correlate with clinically measured muscle strength. Radiofrequency (RF) transmit field (B(1)) inhomogeneities can be particularly problematic in measurements of the MT ratio (MTR) and may obscure genuine muscle MTR changes caused by disease. In this work, we evaluate, for muscle imaging applications, a scheme previously proposed for the correction of RF inhomogeneity artefacts in cerebral MTR maps using B(1) information acquired in the same session. We demonstrate the theoretical applicability of this scheme to skeletal muscle using a two-pool model of pulsed quantitative MT. The correction scheme is evaluated practically in MTR imaging of the lower limbs of 28 healthy individuals and in two groups of patients with representative neuromuscular diseases: Charcot-Marie-Tooth disease type 1A and inclusion body myositis. The correction scheme was observed to reduce both the within-subject and between-subject variability in the calf and thigh muscles of healthy subjects and patient groups in histogram- and region-of interest-based approaches. This method of correcting for RF inhomogeneity effects in MTR maps using B(1) data may markedly improve the sensitivity of MTR mapping indices as measures of pathology in skeletal muscle. PMID- 21796709 TI - Classification of single-voxel 1H spectra of brain tumours using LCModel. AB - This study presents a novel method for the direct classification of (1)H single voxel MR brain tumour spectra using the widespread analysis tool LCModel. LCModel is designed to estimate individual metabolite proportions by fitting a linear combination of in vitro metabolite spectra to an in vivo MR spectrum. In this study, it is used to fit representations of complete tumour spectra and to perform a classification according to the highest estimated tissue proportion. Each tumour type is represented by two spectra, a mean component and a variability term, as calculated using a principal component analysis of a training dataset. In the same manner, a mean component and a variability term for normal white matter are also added into the analysis to allow a mixed tissue approach. An unbiased evaluation of the method is carried out through the automatic selection of training and test sets using the Kennard and Stone algorithm, and a comparison of LCModel classification results with those of the INTERPRET Decision Support System (IDSS) which incorporates an advanced pattern recognition method. In a test set of 46 spectra comprising glioblastoma multiforme, low-grade gliomas and meningiomas, LCModel gives a classification accuracy of 90% compared with an accuracy of 95% by IDSS. PMID- 21796710 TI - Localized 1H NMR spectroscopy in different regions of human brain in vivo at 7 T: T2 relaxation times and concentrations of cerebral metabolites. AB - At the high field strength of 7 T, in vivo spectra of the human brain with exceptional spectral quality sufficient to quantify 16 metabolites have been obtained previously only in the occipital lobe. However, neurochemical abnormalities associated with many brain disorders are expected to occur in brain structures other than the occipital lobe. The purpose of the present study was to obtain high-quality spectra from various brain regions at 7 T and to quantify the concentrations of different metabolites. To obtain concentrations of metabolites within four different regions of the brain, such as the occipital lobe, motor cortex, basal ganglia and cerebellum, the T(2) relaxation times of the singlets and J-coupled metabolites in these regions were measured for the first time at 7 T. Our results demonstrate that high-quality, quantifiable spectra can be obtained in regions other than the occipital lobe at 7 T utilizing a 16-channel transceiver coil and B(1)(+) shimming. PMID- 21796711 TI - Real-time motion and B0 correction for localized adiabatic selective refocusing (LASER) MRSI using echo planar imaging volumetric navigators. AB - A method is presented to correct the effects of motion and motion-related B(0) perturbations on spectroscopic imaging in real time through the use of a volumetric navigator. It is demonstrated that, for an axial slice, lifting the chin significantly disrupts the B(0) homogeneity in the zero-order (frequency), first-order Y (coronal) axis and second-order ZY term. This volumetric navigator is able to measure and correct in real time both head pose and zero- to first order B(0) inhomogeneities. The volumetric navigator was validated in six volunteers who deliberately lifted and then dropped their chin during the scan. These scans show that motion correction alone is not sufficient to recover the spectral quality. By applying real-time shim adjustments, spectral quality was fully recovered to linewidths below 0.08 ppm and the signal-to-noise ratio to within acceptable limits in five of six subjects. In the sixth subject, 83% of the spectra within the volume of interest were recovered, compared with the worst case nonshim-corrected scan, where none of the voxels fell within these quality bounds. It is shown that the use of a volumetric navigator comes at no additional cost to the scan time or spectral signal-to-noise ratio. PMID- 21796712 TI - Manganese kinetics demonstrated double contrast in acute but not in chronic infarction in a mouse model of myocardial occlusion reperfusion. AB - Manganese (Mn(2+)) is considered as a specific MRI contrast agent that enters viable cardiomyocytes through calcium pathways. Compared to extracellular gadolinium based contrast agents, it has the potential to assess cell viability. To date, only information from the washout phase after recirculation has been used for the detection and characterization of myocardial infarct. This study showed for the first time that in a mouse model of coronary occlusion reperfusion, Mn(2+) wash-in kinetics are different at 24 h after surgery (acute infarction) than at eight days after surgery (chronic infarction). A fast but transient entry of Mn(2+) into the acute infarct area led to a double contrast between infarct and remote areas, whereas entry of Mn(2+) into the chronic infarct area remained reduced compared to remote regions during both wash-in and washout phases. The main hypothesis is that extracellular space is largely enhanced in acute infarction due to cell membrane rupture and interstitial edema, whereas scar tissue is densely composed of collagen fibers that reduce the distribution volume of free Mn(2+) ions. In addition to its ability to accurately depict the infarct area during the redistribution phase, Mn(2+) is also able to discriminate acute versus chronic injury by the observation of double-contrast kinetics in a mouse model of ischemia reperfusion. PMID- 21796713 TI - In vivo metabolic profiling of glioma-initiating cells using proton magnetic resonance spectroscopy at 14.1 Tesla. AB - In the last decade, evidence has emerged indicating that the growth of a vast majority of tumors including gliomas is sustained by a subpopulation of cancer cells with stem cell properties called cancer initiating cells. These cells are able to initiate and propagate tumors and constitute only a fraction of all tumor cells. In the present study, we showed that intracerebral injection of cultured glioma-initiating cells into nude mice produced fast growing tumors showing necrosis and gadolinium enhancement in MR images, whereas gliomas produced by injecting freshly purified glioma-initiating cells grew slowly and showed no necrosis and very little gadolinium enhancement. Using proton localized spectroscopy at 14.1 Tesla, decreasing trends of N-acetylaspartate, glutamate and glucose concentrations and an increasing trend of glycine concentration were observed near the injection site after injecting cultured glioma-initiating cells. In contrast to the spectra of tumors grown from fresh cells, those from cultured cells showed intense peaks of lipids, increased absolute concentrations of glycine and choline-containing compounds, and decreased concentrations of glutamine, taurine and total creatine, when compared with a contralateral non tumor-bearing brain tissue. A decrease in concentrations of N-acetylaspartate and gamma-aminobutyrate was found in both tumor phenotypes after solid tumor formation. Further investigation is needed to determine the cause of the dissimilarities between the tumors grown from cultured glioma-initiating cells and those from freshly purified glioma-initiating cells, both derived from human glioblastomas. PMID- 21796714 TI - Structure of a novel thermostable GH51 alpha-L-arabinofuranosidase from Thermotoga petrophila RKU-1. AB - alpha-L-arabinofuranosidases (EC 3.2.1.55) participate in the degradation of a variety of L-arabinose-containing polysaccharides and interact synergistically with other hemicellulases in the production of oligosaccharides and bioconversion of lignocellulosic biomass into biofuels. In this work, the structure of a novel thermostable family 51 (GH51) alpha-L-arabinofuranosidase from Thermotoga petrophila RKU-1 (TpAraF) was determined at 3.1 A resolution. The TpAraF tertiary structure consists of an (alpha/beta)-barrel catalytic core associated with a C terminal beta-sandwich domain, which is stabilized by hydrophobic contacts. In contrast to other structurally characterized GH51 AraFs, the accessory domain of TpAraF is intimately linked to the active site by a long beta-hairpin motif, which modifies the catalytic cavity in shape and volume. Sequence and structural analyses indicate that this motif is unique to Thermotoga AraFs. Small angle X ray scattering investigation showed that TpAraF assembles as a hexamer in solution and is preserved at the optimum catalytic temperature, 65 degrees C, suggesting functional significance. Crystal packing analysis shows that the biological hexamer encompasses a dimer of trimers and the multiple oligomeric interfaces are predominantly fashioned by polar and electrostatic contacts. PMID- 21796715 TI - Identification and characterization of Wfdc gene expression in the male reproductive tract of the rat. AB - WFDC (Whey Acidic Protein Four Disulfide Core)-containing proteins have been reported in many species, yet they remain uncharacterized in the rat. In this study, we report the identification and characterization of four rat Wfdc genes, Wfdc6a, Wfdc8, Wfdc11 and Wfdc16. Their expression profile in a variety of tissues including the male reproductive tract is analyzed. Wfdc8, Wfdc11 and Wfdc16 expression is confined to the epididymis, while Wfdc6a is expressed widely. Since gene expression in the male reproductive tract is largely androgen dependent, Wfdc expression was analyzed in the developing (20-60-day-old) and castrated rats. Their expression pattern in developing rats does not correlate with changes in testosterone. Wfdc genes are, however, down-regulated in castrated adult rats, indicating that their dependence on androgens for expression is more pronounced in the adult than in the developing rat. To test the anti-microbial potential of WFDC8, a recombinant WFDC8 C-terminal protein was produced, which exhibited potent anti-bacterial activity against Eschericia coli. Induction of anti-microbial genes is one of the responses during infections in many organ systems. To determine if WFDCs form the components of male reproductive tract innate immunity, Wfdc8 expression pattern was observed in rats challenged with lipopolysaccharide (LPS). For the first time we report the induction of Wfdc8 gene expression in LPS-treated rats, indicating their contributions to the innate immune functions of the male reproductive tract. PMID- 21796716 TI - Curricular considerations for pharmaceutical comparative effectiveness research. AB - In the U.S. pharmacoepidemiology and related health professions can potentially flourish with the congressional appropriation of $1.1 billion of federal funding for comparative effectiveness research (CER). A direct result of this legislation will be the need for sufficient numbers of trained scientists and decision-makers to address the research and implementation associated with CER. An interdisciplinary expert panel comprised mostly of professionals with pharmaceutical interests was convened to examine the knowledge, skills, and abilities to be considered in the development of a CER curriculum for the health professions focusing predominantly on pharmaceuticals. A limitation of the panel's composition was that it did not represent the breadth of comparative effectiveness research, which additionally includes devices, services, diagnostics, behavioral treatments, and delivery system changes. This bias affects the generalizability of these findings. Notwithstanding, important components of the curriculum identified by the panel included study design considerations and understanding the strengths and limitations of data sources. Important skills and abilities included methods for adjustment of differences in comparator group characteristics to control confounding and bias, data management skills, and clinical skills and insights into the relevance of comparisons. Most of the knowledge, skills, and abilities identified by the panel were consistent with the training of pharmacoepidemiologists. While comparative effectiveness is broader than the pharmaceutical sciences, pharmacoepidemiologists have much to offer academic and professional CER training programs. As such, pharmacoepidemiologists should have a central role in curricular design and provision of the necessary training for needed comparative effectiveness researchers within the realm of pharmaceutical sciences. PMID- 21796717 TI - Trends in emergency department visits attributable to acetaminophen overdoses in the United States: 1993-2007. AB - PURPOSE: With the heightened concern over acetaminophen overdose induced liver toxicity, it is important to track the overdose incidences over time. We estimated the trends in emergency department (ED) visits attributable to acetaminophen overdoses and compared the risk across sociodemographic groups and geographic regions. METHODS: ED visits attributable to acetaminophen overdoses were identified using physician diagnosis codes and cause of injury codes from the National Hospital Ambulatory Medical Care Survey (1993-2007). Annual rates of ED visits for acetaminophen overdoses per 100,000 persons in the U.S. population and by subgroups (age, gender, race, insurance coverage, geographic region, and presence of alcohol abuse and dependence) were calculated. Bivariate analysis and logistic regressions were used to examine the associations of patient demographic characteristics with ED visits for acetaminophen overdoses. Data were analyzed using STATA 9.2 accounting for complex survey design. RESULTS: From 1993 through 2007, an estimated 751,552 ED visits (0.05% of all ED visits) were attributable to acetaminophen overdoses. The annual rate per 100,000 persons was significantly higher prior to 2000 (21.0 visits in 1993-1999 vs. 15.2 visits in 2000-2007, p = 0.017). Rates were particularly high in young children under 5 years (72.4 visits, 95% confidence interval (CI): 49.1-95.8) and for adolescents between 15 17 years (61.8 visits, 95%CI: 35.4-88.3). Rates also varied cross gender, insurance coverage, and geographic regions. CONCLUSIONS: ED visits attributable to acetaminophen overdose decreased in recent years. Children less than 5 years of age, adolescents and young adults account for the overwhelming majority of these visits. PMID- 21796718 TI - Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia. AB - PURPOSE: To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition. METHODS: A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. RESULTS: In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67-0.95) for bupropion, 1.24 (0.93-1.65) for doxepin, 0.79 (0.55 1.15) for lithium, and 1.26 (1.11-1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having nonnull risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition. CONCLUSIONS: Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants. PMID- 21796719 TI - Methodological challenges in the coding and adjudication of sudden deaths in a large simple trial with observational follow-up: the ziprasidone observational study of cardiac outcomes (ZODIAC). AB - PURPOSE: The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death. METHODS: A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions. RESULTS: Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77). CONCLUSIONS: After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data. PMID- 21796720 TI - Variations and determinants of antibiotic consumption in Hungarian adult intensive care units. AB - PURPOSE: The aim of this work was to study the use of systemic antibacterials and its possible determinants in Hungarian intensive care units (ICUs). METHODS: Hospital pharmacy. departments provided package level dispensing data for their corresponding ICU (2006). Data were converted into defined daily doses (DDDs) and expressed as DDD per 100 patient-days and DDD per 100 admissions. Antibiotics were ranked by volume of DDDs, and the agents responsible for 90% of total use (DU90%) were noted. To explore differences and relationships between antibiotic use and antibiotic policy elements/ICU characteristics, the analysis of variances or the Pearson correlation analysis was performed. RESULTS: Valid data were obtained for 44 ICUs. Antibiotic use varied widely (from 27.9 to 167.8 DDD per 100 patient-days and from 104.7 to 1784.6 DDD per 100 admissions). In total, 11 34 different antibacterials per ICUs were used, of which, 5-15 were in the DU90% segment. The proportional use of parenteral agents ranged from 46.2 to 98.3%. The mean of overall antibiotic use was highest for penicillins with beta-lactamase inhibitors, followed by quinolones and third-generation cephalosporins. Of the studied factors, only the ICU category (i.e., level of care) showed significant association with total antibacterial use. CONCLUSIONS: The striking differences in total antibiotic use and the extensive use of the oral agents in some ICUs may indicate room for improvement. As none of the antibiotic policy elements were accompanied by lower antibiotic use in the pooled analysis, it suggests that- beside the ICU category--other unrevealed factors determine antibiotic use. PMID- 21796721 TI - Is less more? Patients' preferences for drug information leaflets. AB - PURPOSE: Present package information leaflets do not fulfil the needs of many patients. The objective of this study was to investigate patients' preferences towards content and presentation of drug information leaflets using prepared medication brochures in a discrete choice experiment. METHODS: 6 binary attributes relating to content and presentation of drug information were used to define and design alternative leaflets. Choice sets between alternative leaflets were created based on an orthogonal design. 1,000 participants aged at least 50 years were presented 8 choice sets of drug information leaflets in a personal interview. The reliability of choices was assessed with a duplicate of one original choice. Regression analysis was used to model the impact of attributes on choices and interactions with responders' age and education. RESULTS: Participants slightly preferred colored over black-white leaflets, no visual presentation of side effects by the use of smilies, the provision of a brief summary, and general health tips, but no information on what-to-do in case of side-effects. All attributes except the " extent of side-effects presented" significantly affected participants' choices. Older and less educated participants preferred less information. Of the repeated (duplicate) choices, 84% were replicates of the original choice. Interrater agreement was moderate (K = 0.67, CI 0.6-0.7). 235 subjects (23.5%) followed an optimization strategy and did not trade attributes, i.e., exhibited dominant preferences. CONCLUSIONS: In general, participants preferred condensed, plain information in a clear and moderately colored design, but preferences towards drug information are affected by age and level of education. PMID- 21796722 TI - Polypharmacy of potentially addictive medication in the older persons- quantifying usage. AB - PURPOSE: The use of restricted medications, for example, opioids, benzodiazepines (BZD), and z-hypnotics, in the older persons continues to increase. Little is known about usage practices or about the extent of polypharmacy within this group. The objectives of this study were (i) to describe polypharmacy and (ii) to develop a medication usage index (MUI) to quantify usage patterns. METHODS: Data for 2008 were obtained from the Norwegian Prescription Database containing all prescriptions filled in Norwegian pharmacies. The study population included people aged 70-89 years who filled prescriptions for weak opioids, strong opioids, anxiolytic BZD, hypnotic BZD, and/or z-hypnotics. A MUI was developed based on Anatomical Therapeutic Chemical codes, defined daily doses, Anatomical Therapeutic Chemical subgroups, and number of prescribers. RESULTS: Forty-two percent of elderly Norwegians filled at least one prescription in one of the medication subgroups in 2008. MUI Level 1 (least) usage was shown by 56.6% of users (23.8% of the general population), Level 2 by 29.7% (12.5%), Level 3 by 11.3% (4.8%), and Level 4 (most) by 2.4% (1.0%). People using strong opioids were the most likely to use other restricted medications. In addition, female participants had a higher MUI than did male participants, and older users higher than younger users. Cancer or palliative care patients attained twice the MUI points than did the others. CONCLUSIONS: Polypharmacy was found to be common within these restricted drug categories for the older persons. MUI provides a convenient approach to summarizing drug usage and will be useful in detecting trends and regional differences and determining the impact of interventions. PMID- 21796724 TI - Perceptions of health risk and smoking decisions of young people. AB - Using the Annenberg Perception of Tobacco Risk Survey 2, this paper finds that perceived risk deters smoking among persons aged 14-22 years who think that it is relatively difficult to quit smoking and that onset of deleterious health effects occurs relatively quickly. Perceived health risk, however, does not affect the smoking status of young people who hold the opposite beliefs. These results are consistent with predictions of rational addiction models and suggest that young people, who view smoking as more addictive and health effects as more immediate, may have greater incentive to consider long-term health effects in their decision to smoke. PMID- 21796723 TI - Surrogates, meta-analysis and cost-effectiveness modelling: a combined analytic approach. AB - Estimates of cost-effectiveness analyses are typically obtained either directly from 'trial' based analyses or indirectly via surrogate endpoints in 'model' based analyses. Data from clinical trials that include both surrogate and final endpoints can be used in a joint analysis that combines these two approaches. This joint approach allows the inclusion of information regarding the effects of treatment on surrogate endpoints while relaxing the strong assumption of 'conditional independence' associated with indirect model-based analyses. An example cost-effectiveness analysis of Chronic Disease Self-Management Programme is used to compare the different approaches. It is shown that despite using a common data set, the different analytic approaches produce differing estimates of the cost-effectiveness of the intervention and the value of future research. The paper concludes by discussing the selection of the appropriate analytic approach. PMID- 21796726 TI - A gain-of-glycosylation mutation associated with myoclonus-dystonia syndrome affects trafficking and processing of mouse epsilon-sarcoglycan in the late secretory pathway. AB - Missense mutations in the SGCE gene encoding epsilon-sarcoglycan account for approximately 15% of SGCE-positive cases of myoclonus-dystonia syndrome (MDS) in humans. In this study, we show that while the majority of MDS-associated missense mutants modeled with a murine epsilon-sarcoglycan cDNA are substrates for endoplasmic reticulum-associated degradation, one mutant, M68T (analogous to human c.275T>C, p.M92T), located in the Ig-like domain of epsilon-sarcoglycan, results in a gain-of-glycosylation mutation producing a protein that is targeted to the plasma membrane, albeit at reduced levels compared to wild-type epsilon sarcoglycan. Removal of the ectopic N-linked glycan failed to restore efficient plasma membrane targeting of M68T demonstrating that the substitution rather than the glycan was responsible for the trafficking defect of this mutant. M68T also colocalized with CD63-positive vesicles in the endosomal-lysosomal system and was found to be more susceptible to lysosomal proteolysis than wild-type epsilon sarcoglycan. Finally, we demonstrate impaired ectodomain shedding of M68T, a process that occurs physiologically for epsilon-sarcoglycan resulting in the lysosomal trafficking of the intracellular C-terminal domain of the protein. Our findings show that functional analysis of rare missense mutations can provide a mechanistic insight into the pathogenesis of MDS and the physiological role of epsilon-sarcoglycan. PMID- 21796725 TI - Prediction of functional regulatory SNPs in monogenic and complex disease. AB - Next-generation sequencing (NGS) technologies are yielding ever higher volumes of human genome sequence data. Given this large amount of data, it has become both a possibility and a priority to determine how disease-causing single nucleotide polymorphisms (SNPs) detected within gene regulatory regions (rSNPs) exert their effects on gene expression. Recently, several studies have explored whether disease-causing polymorphisms have attributes that can distinguish them from those that are neutral, attaining moderate success at discriminating between functional and putatively neutral regulatory SNPs. Here, we have extended this work by assessing the utility of both SNP-based features (those associated only with the polymorphism site and the surrounding DNA) and gene-based features (those derived from the associated gene in whose regulatory region the SNP lies) in the identification of functional regulatory polymorphisms involved in either monogenic or complex disease. Gene-based features were found to be capable of both augmenting and enhancing the utility of SNP-based features in the prediction of known regulatory mutations. Adopting this approach, we achieved an AUC of 0.903 for predicting regulatory SNPs. Finally, our tool predicted 225 new regulatory SNPs with a high degree of confidence, with 105 of the 225 falling into linkage disequilibrium blocks of reported disease-associated genome-wide association studies SNPs. PMID- 21796727 TI - A mutation in SCARB2 is a modifier in Gaucher disease. AB - Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD. PMID- 21796728 TI - Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family. AB - We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation (MR) with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase-activating (GAP) protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology (PH) domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations. PMID- 21796730 TI - Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. AB - Currently, two nomenclature systems are in use to describe sequence variants for cystic fibrosis: the established traditional nomenclature system and the more recent Human Genome Variation Society (HGVS) nomenclature system. We have evaluated the use of both systems in the laboratory reports of 217 participants in the cystic fibrosis external quality assessment scheme of 2009. The mutation c.1521_1523delCTT (p.Phe508del, F508del) was described by traditional and HGVS nomenclature by 32 of 216 (15%) laboratories that correctly identified the mutation, whereas 171 (79%) laboratories used traditional nomenclature only and 13 (6%) laboratories used HGVS nomenclature only. Overall, 29 of 631 (5%) reports used nomenclature that was evaluated as being seriously incorrect and/or misleading and 136 (22%) reports contained attempts at HGVS coding, of which 104 (76%) contained no coding errors; just 33 (24%) mentioned the correct cDNA name and cited the nucleotide reference sequence. We recognized an urgent need for more consistent and correct usage of nomenclature. We recommended that cystic fibrosis transmembrane conductance regulator testing reports should include a description of the identified sequence variants in both HGVS and traditional nomenclature and provided basic recommendations and other guidance. PMID- 21796731 TI - GLI3 is rarely implicated in OFD syndromes with midline abnormalities. PMID- 21796729 TI - Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio facial/DiGeorge/22q11.2 deletion syndrome patients. AB - Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF > 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome. PMID- 21796732 TI - Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses. AB - Bone marrow stromal antigen 2 (BST2)/Tetherin is an antiviral factor that blocks the release of enveloped virions from infected cells. Recent data suggest that efficient BST2 antagonism was a prerequisite for the global spread of HIV/AIDS. Most simian immunodeficiency viruses (SIVs), including the direct precursors of HIV, use their Nef protein to antagonize BST2 of their respective host species. Human BST2, however, contains a five amino acid deletion in its cytoplasmic domain that confers resistance to Nef. Thus, this antiviral factor constitutes a major barrier to effective zoonotic transmissions of SIVs to humans. Here, we show that this protective deletion has already been present in Neanderthal and Denisovan BST2 and thus evolved at least 800,000 years ago. This ancient origin helps to explain why effectively spreading zoonotic transmissions of SIVs to humans have been rare, although SIVs are widespread in African nonhuman primates and humans must have been exposed to these viruses many times. PMID- 21796733 TI - Physical appearance as a measure of social ranking: the role of a new scale to understand the relationship between weight and dieting. AB - This study presents the development of a new self-report instrument to assess how an individual perceives himself as social agent within his group having physical appearance as a reference, the Social Comparison through Physical Appearance Scale (SCPAS). This scale adds to the existent measures by assessing the social ranking based on one's physical appearance, and not the tendency to make comparisons of the general physical appearance or specific body parts. Its psychometric characteristics are investigated in a sample of 828 female participants from normal population. Principal components analysis was conducted for each part of the instrument: the Part A: peers shows a 2-factor structure (Attractiveness/Rank and Group Fit) explaining 72.142% of the variance; the Part B: models presents a one-dimensional structure that explains 69.191% of the variance. Findings show very good internal consistency coefficients and test retest reliability. The two parts of the SCPAS are significantly associated to social comparison and shame measures, to anxiety, depression and stress indicators, and to eating disorders symptomatology. The scale discriminates between a clinical sample of 91 patients with an eating disorder and a non clinical sample of 102 participants. Regression analyses pointed out that social comparison through physical appearance with peers and models partially mediates the effect of the dissatisfaction with current weight on disordered eating, namely drive for thinness. PMID- 21796734 TI - Factors associated with emotional well-being in primary and secondary caregivers of patients with eating disorders. AB - The aim of this study was to examine and identify the psychological, clinical and sociodemographic factors associated with emotional well-being by type of caregiver. A cross-sectional study was conducted among 185 primary caregivers and 92 secondary caregivers of patients with an eating disorder using the Hospital Anxiety and Depression Scale, the Experience of Caregiving Inventory and the Eating Disorders Symptom Impact Scale. According to a multiple regression analysis, a total of four models were obtained accounting for 42%-47% of the variance in emotional well-being. The variable that accounted for most of the variance of emotional well-being in three of the models was the impact of nutrition. Improving aspects of the relationships with the patients reduced anxiety and depression levels in primary caregivers. Similarly, a positive personal experience reduced depression in secondary caregivers. A higher education level was associated with decreased anxiety levels in both types of caregivers. Specific family interventions including both types of caregivers may be useful for providing emotional and adaptive personal coping skills. PMID- 21796735 TI - Binge eating and temperament in morbidly obese prebariatric surgery patients. AB - The objective of this study was to investigate the relationship between binge eating and temperament variables, controlling for depression and adult attention deficit/hyperactivity disorder (ADHD), in 90 extremely obese individuals. The participants completed questionnaires assessing eating pathology, reactive temperament, effortful control, depression and ADHD and were grouped based on the presence of regular binge eating. Patients reporting regular binge eating did not differ from patients not reporting regular binge eating with respect to BMI, age, gender, the occurrence of adult ADHD and reactive temperament. However, individuals with binge eating exhibited more pathological scores with regard to eating pathology, depression and effortful control. A logistic regression analysis revealed that only eating concerns and reduced effortful control remained significantly associated with regular binge eating. Binge eating in morbidly obese individuals appears to be associated with a lack of effortful control. PMID- 21796736 TI - Attention-deficit/hyperactivity disorder in a prebariatric surgery sample. AB - BACKGROUND: Research suggests that obese children, adolescents and adults frequently suffer from attention-deficit/hyperactivity disorder (ADHD). The aim of the current study was to estimate the prevalence of adult ADHD in a group of patients with grade 3 obesity (body mass index >=40 kg/m(2)) prior to bariatric surgery. METHOD: We assessed 116 patients for childhood and adult ADHD, co occurring psychiatric disorders, severity of depression and daytime sleepiness. RESULTS: Fourteen participants (12.1%) screened positive for adult ADHD. Even though this rate is higher compared with prevalence rates in representative population samples, it was not elevated compared with a group of morbidly obese individuals in a German general population sample (14.3%). Adult ADHD was associated with greater severity of depressive symptoms and more psychotherapy contact in the past but not with binge eating disorder or daytime sleepiness. CONCLUSION: As ADHD appears to be a common condition in morbidly obese individuals, the impact of adult ADHD on postsurgical weight loss needs to be examined. Besides, the causal link between obesity and ADHD in adults should be further investigated. PMID- 21796737 TI - Effects of an Internet-based prevention programme for eating disorders in the USA and Germany--a meta-analytic review. AB - A cross-cultural comparison of a cognitive-behavioural, Internet-based, 8-week prevention programme for eating disorders (StudentBodiesTM) evaluated in the USA and in Germany was performed. Six US and four German randomized controlled trials with a total (N) of 990 female high school and college students were included in the review. Two of the US and two of the German trials explicitly addressed high risk samples in a selective prevention approach. Effect sizes for main outcomes (disordered eating, weight and shape concerns) were calculated at postintervention and at follow-up. The intervention was associated with moderate improvements in eating disorder-related attitudes, especially reductions of negative body image and the desire to be thin. The reported effects remained significant at follow-up. No clear differences between US and German samples could be found on any of the outcome measures at postintervention. In conclusion, StudentBodiesTM seems equally suitable and effective for American and German students. PMID- 21796738 TI - The National Network of Depression Centers: progress through partnership. PMID- 21796739 TI - Epidemiology of chronic and nonchronic major depressive disorder: results from the national epidemiologic survey on alcohol and related conditions. AB - BACKGROUND: Burden related to major depressive disorder (MDD) derives mostly from long-term occurrence of symptoms. This study aims to examine the prevalence, sociodemographic correlates, patterns of 12-month and lifetime psychiatric comorbidity, lifetime risk factors, psychosocial functioning, and mental health service utilization of chronic major depressive disorder (CMDD) compared to nonchronic major depressive disorder. METHODS: Face-to-face interviews were conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43,093). RESULTS: The 12-month and lifetime prevalence of CMDD within the population meeting criteria for MDD was 26.5% and 24.0%, respectively. Individuals reporting a chronic course of MDD were socioeconomically and educationally disadvantaged, tended to be older, report loss of spouse or history of divorce, live in rural areas, have public assistance, low self-esteem, worse overall health and more likely to report comorbidities, most importantly dysthymia, generalized anxiety disorder, avoidant, and dependant personality disorder. Individuals with chronic MDD were more likely to report familial but not childhood onset risk factors for MDD. Those suffering CMDD were more likely to seek and receive mental health care than other forms of MDD, even though it took longer to start treatment. CONCLUSION: Chronic course of MDD is related to still worse socioeconomic conditions, educational achievement, more comorbidities, and family risk factors, although other courses of MDD carried greater risk of unmet treatment. PMID- 21796741 TI - Imagining the future in complicated grief. AB - BACKGROUND: Complicated Grief (CG) is a chronic and debilitating consequence of bereavement. Although sharing features with depression and anxiety, CG is associated with independent negative health outcomes. Despite these significant health costs, relatively little is known about the cognitive mechanisms that contribute to the maintenance of CG. The ability to envisage the future is important for adaptive functioning. This study investigates future-related thinking in CG. METHOD: Twenty-one individuals with CG and 24 bereaved individuals without CG were asked to imagine specific events that may take place in their future and recall specific autobiographical memories in response to cue words, and complete a personal goals task. RESULTS: CG participants were less specific in their imagining of future positive events and were more likely to imagine future events relating to their loss. The extent to which individuals were able to imagine a specific future event was significantly correlated with recalling specific memories. The tendency to imagine loss-related events in the future was associated with holding grief-related goals. CONCLUSIONS: These results are consistent with propositions of the self-memory system model of autobiographical memory and shed light on factors that may maintain grieving in people affected by CG. PMID- 21796740 TI - Complicated grief associated with hurricane Katrina. AB - BACKGROUND: Although losses are important consequences of disasters, few epidemiological studies of disasters have assessed complicated grief (CG) and none assessed CG associated with losses other than death of loved one. METHODS: Data come from the baseline survey of the Hurricane Katrina Community Advisory Group, a representative sample of 3,088 residents of the areas directly affected by Hurricane Katrina. A brief screen for CG was included containing four items consistent with the proposed DSM-V criteria for a diagnosis of bereavement related adjustment disorder. RESULTS: Fifty-eight and half percent of respondents reported a significant hurricane-related loss: Most-severe losses were 29.0% tangible, 9.5% interpersonal, 8.1% intangible, 4.2% work/financial, and 3.7% death of loved one. Twenty-six point one percent respondents with significant loss had possible CG and 7.0% moderate-to-severe CG. Death of loved one was associated with the highest conditional probability of moderate-to-severe CG (18.5%, compared to 1.1-10.5% conditional probabilities for other losses), but accounted for only 16.5% of moderate-to-severe CG due to its comparatively low prevalence. Most moderate-to-severe CG was due to tangible (52.9%) or interpersonal (24.0%) losses. Significant predictors of CG were mostly unique to either bereavement (racial-ethnic minority status, social support) or other losses (prehurricane history of psychopathology, social competence.). CONCLUSIONS: Nonbereavement losses accounted for the vast majority of hurricane related possible CG despite risk of CG being much higher in response to bereavement than to other losses. This result argues for expansion of research on CG beyond bereavement and alerts clinicians to the need to address postdisaster grief associated with a wide range of losses. PMID- 21796742 TI - Negative biases and risk for depression; integrating self-report and emotion task markers. AB - BACKGROUND: Negativity biases and their impact on reactivity to negative emotion are implicated in the mechanisms of risk for depression. The aim of this study was to determine whether self-reported negativity bias is related to objective cognitive measures of emotional reactivity. METHODS: A previously established Web self-report measure of negativity bias was used to assess 1,080 volunteers from the Brain Resource International Database (overseen by the nonprofit BRAINnet Foundation). We identified matched subgroups of "High Risk" (n = 216) and "Low Risk" (n = 216) participants using a psychometric high-risk method, which classified High Risk as the sample's top 30% of negativity bias scores and Low Risk as the bottom 30%. These subsamples also completed the WebNeuro cognitive tasks for assessing both conscious and nonconscious reactions to facial emotions. Task performance was quantified by accuracy, reaction time, and misidentification errors. RESULTS: The High Risk (high negativity bias) subgroup was distinguished by greater reactivity to negative emotion in both conscious and nonconscious processing. The High Risk profile was reflected in higher accuracy for sadness (nonconsciously) and disgust (consciously), and more frequent misidentification of neutral as anger (consciously). CONCLUSIONS: These results are consistent with seminal theories that a systematic cognitive negativity bias produces a hyper reactivity to negative emotion, which can impact nonconscious as well as conscious processing. The results provide a step toward objective markers of risk for depression that would help the community act regarding preventative programs. Replication in patient samples is warranted. PMID- 21796743 TI - The position of the AUG start codon in MFG-based gamma-retroviral vectors has a dramatic effect on translation-dependent protein expression. AB - BACKGROUND: In the past three decades, much advancement has been made in gamma retroviral vector mediated gene transfer. One widely used vector design is based on the MFG vector, which uses the Moloney murine leukemia virus (MoMLV) transcriptional unit with extended packaging signals and insertion of the native MoMLV envelope splice acceptor region immediate 5' to the gene of interest inserted at an NcoI restriction site, which contains a translation start codon. Little is known about the impact of variations in start codon location within MFG based vectors on protein expression. METHODS: To evaluate variation in start condo placement, a gene encoding a T-cell receptor (TCR) was cloned into an MFG based vector and site-directed mutagenesis was used to move the gene away from the splice acceptor, as well as alter the frame with respect to the upstream start codon. Kozak consensus sequences were also added to the gene in an attempt to improve translation. RESULTS: Protein expression as measured by TCR surface expression and biological activity was substantially reduced when the gene was placed downstream and out-of-frame with the NcoI start codon. Expression was reestablished by mutation of the upstream start site, although at a reduced level. These findings were repeated with two other genes, a dominant negative TGFbetaRII and the reporter protein dEGFP. CONCLUSIONS: These finding emphasize the scanning rule for translation initiation and stress the importance of cloning genes of interest into or near the native NcoI start site of MFG-based retroviral vectors. PMID- 21796744 TI - Ethics, chemistry, and education for sustainability. PMID- 21796745 TI - Brightly tricolored mechanochromic luminescence from a single-luminophore liquid crystal: reversible writing and erasing of images. PMID- 21796746 TI - Small-molecule-based nanoassemblies as inducible nanoprobes for monitoring dynamic molecular interactions inside live cells. PMID- 21796747 TI - Magneto-chiral dichroism of organic compounds. PMID- 21796748 TI - LFA-1 fine-tuning by cathepsin X. AB - The adhesion molecule lymphocyte function-associated antigen (LFA)-1 plays a key role in immune surveillance and response. Its conformation is spatially and temporally regulated, enabling adhesion and deadhesion during T-cell migration. LFA-1 adhesion to its major ligand intercellular adhesion molecule 1 is controlled by adaptor proteins which bind the cytoplasmic tail of the beta (2) subunit. Cathepsin X, a cysteine carboxypeptidase, promotes T-cell migration and morphological changes by cleaving the beta (2) cytoplasmic tail of LFA-1. In this way, it modulates the affinity of LFA-1 for structural adaptors talin-1 and alpha actinin-1 and enables the stepwise transition between intermediate and high affinity conformations of LFA-1, an event that is necessary for effective T-cell function. Cathepsin X regulation that would allow precise modulation of LFA-1 affinity has a great potential for anti-LFA-1 therapy. PMID- 21796749 TI - Biosynthesis and charging of pyrrolysine, the 22nd genetically encoded amino acid. PMID- 21796750 TI - Identifying protein variants with cross-reactive aptamer arrays. PMID- 21796751 TI - Pmarg-pearlin is a matrix protein involved in nacre framework formation in the pearl oyster Pinctada margaritifera. AB - The shell of pearl oysters is organized in multiple layers of CaCO(3) crystallites packed together in an organic matrix. Relationships between the components of the organic matrix and mechanisms of nacre formation currently constitute the main focus of research into biomineralization. In this study, we characterized the pearlin protein from the oyster Pinctada margaritifera (Pmarg); this shares structural features with other members of a matrix protein family, N14/N16/pearlin. Pmarg pearlin exhibits calcium- and chitin-binding properties. Pmarg pearlin transcripts are distinctively localized in the mineralizing tissue responsible for nacre formation. More specifically, we demonstrate that Pmarg pearlin is localized within the interlamellar matrix of nacre aragonite tablets. Our results support recent models for multidomain matrix protein involvement in nacreous layer formation. We provide evidence here for the existence of a conserved family of nacre-associated proteins in Pteriidae, and reassess the evolutionarily conserved set of biomineralization genes related to nacre formation in this taxa. PMID- 21796752 TI - A "diels-alderase" at last. AB - Diels this Alder your thinking? Electrocyclization reactions are exceedingly rare in metabolic pathways. Why is this so? Recently a [4+2] cycloaddition catalyzed by a monofunctional "Diels-Alderase" has been characterized. How does a 500-fold rate enhancement shown by this enzyme stack up? PMID- 21796753 TI - Simultaneous observation of peptide backbone lipid solvation and alpha-helical structure by deep-UV resonance Raman spectroscopy. PMID- 21796754 TI - Borane derivatives: a new class of super- and hyperhalogens. AB - Super- and hyperhalogens are a class of highly electronegative species whose electron affinities far exceed those of halogen atoms and are important to the chemical industry as oxidizing agents, biocatalysts, and building blocks of salts. Using the well-known Wade-Mingos rule for describing the stability of closo-boranes B(n)H(n)(2-) and state-of-the-art theoretical methods, we show that a new class of super- and hyperhalogens, guided by this rule, can be formed by tailoring the size and composition of borane derivatives. Unlike conventional superhalogens, in which a central metal atom is surrounded by halogen atoms, the superhalogens formed according to the Wade-Mingos rule do not have to have either halogen or metal atoms. We demonstrate this by using B(12)H(13) and its isoelectronic cluster CB(11)H(12) as examples. We also show that while conventional superhalogens containing alkali atoms require at least two halogen atoms, a single borane-like moiety is sufficient to give M(B(12)H(12)) clusters (M=Li, Na, K, Rb, Cs) superhalogen properties. In addition, hyperhalogens can be formed by using the above superhalogens as building blocks. Examples include M(B(12)H(13))(2) and M(CB(11)H(12))(2) (M=Li-Cs). This finding opens the door to an untapped source of superhalogens and weakly coordinating anions with potential applications. PMID- 21796755 TI - Gene expression under laser and light-emitting diodes radiation for modulation of cell adhesion: Possible applications for biotechnology. AB - Experimental data about the modulation of adhesion and proliferation of anchorage dependent HeLa cells with monochromatic or quasimonochromatic radiation in red to near-infrared region are presented. Cell adhesion and proliferation can be increased by irradiation with light of certain wavelengths (maxima in action spectrum are 619, 675, 740, 760, and 820 nm) or decreased when the activity of photoacceptor (cytochrome c oxidase in mitochondrial respiratory chain) is inhibited by chemicals before the irradiation. This modality allows controlling the number of attached and/or proliferating cells. Possible biotechnology applications of this method are outlined. PMID- 21796756 TI - Mating disruption for the control of Aonidiella aurantii Maskell (Hemiptera: Diaspididae) may contribute to increased effectiveness of natural enemies. AB - BACKGROUND: New directives on sustainable use of pesticides have encouraged research on efficient alternative pest control methods. In the case of the California red scale (CRS), Aonidiella aurantii (Maskell), this imperative, along with the many difficulties in controlling this pest, have led to the investigation of new approaches. Previously developed mating disruption (MD) dispensers, together with the augmentative releases of the parasitoid Aphytis melinus DeBach, are here considered as a combined strategy for use against A. aurantii. RESULTS: Efficacy of MD was demonstrated by a mean reduction of 80% in CRS male catches and a mean fruit damage reduction of 83% compared with the control. A delay in the development of A. aurantii instars was observed in the MD plot. This delay increased the period of exposure of the susceptible instars to natural enemies, which resulted in higher predation and parasitism levels in the MD plot. Under laboratory conditions, A. melinus mating behaviour and effects on A. aurantii were not significantly altered in a CRS-pheromone-saturated environment. CONCLUSION: Mating disruption pheromone did not affect the behaviour or level of parasitism by A. melinus or the incidence of other generalist predators. Therefore, A. aurantii pheromone appears to be compatible with augmentative releases and biological control, making its use a good strategy for CRS management. PMID- 21796757 TI - Effects of surface treatments and application shanks on nematode, pathogen and weed control with 1,3-dichloropropene. AB - BACKGROUND: Preplant fumigation with methyl bromide (MeBr) has been used for control of soilborne pests in high-value annual, perennial and nursery crops, but is being phased out. In 2007 and 2008, research trials were conducted to evaluate the effects of surface treatments and two application shanks on pest control with 1,3-dicloropropene (1,3-D) in perennial crop nurseries. RESULTS: All 1,3-D treatments controlled nematodes similarly to MeBr. Application of 1,3-D with virtually impermeable film (VIF) reduced Fusarium oxysporum compared with unfumigated plots, but was not as effective as MeBr. Applications of 1,3-D with VIF or 1,3-D followed by metam sodium reduced Pythium spp., but 1,3-D followed by intermittent water seals was comparable with the untreated plots. When sealed with high-density polyethylene (HDPE) film or VIF, 1,3-D generally was as effective as MeBr for reducing weed density and total weed biomass, but weed control was reduced by intermittent water seals and in unsealed plots subsequently re-treated with additional 1,3-D or metam sodium. CONCLUSION: Applications of 1,3-D sealed with HDPE or VIF film or with intermittent water seals can control nematodes similarly to MeBr. However, additional management practices may be needed for effective pathogen and weed control if plastic film is not used. PMID- 21796758 TI - Site factors and management influence short-term host resistance to spruce budworm, Choristoneura fumiferana (Clem.), in a species-specific manner. AB - BACKGROUND: This study examined the interactions between thinning and soil drainage classes on the resistance of balsam fir, Abies balsamea (L.) Mill, white spruce, Picea glauca (Moench) Voss, and black spruce, P. mariana (Mill.) BSP, to spruce budworm, Choristoneura fumiferana (Clem.), defoliation 1 year after treatment. To estimate host tree resistance, foliage production and larval foliage consumption were determined to generate an index of resistance quantifying the amount of residual foliage available for photosynthesis after insect defoliation. RESULTS: Significant interactions on tree resistance and foliage chemistry were detected between thinning and soil drainage in balsam fir. Drainage class affected spruce budworm performance, foliar chemistry and balsam fir resistance to spruce budworm, whereas no effect was found in white spruce. Thinning had a significant effect on the foliar chemistry of balsam fir and white spruce, but no effect on black spruce. CONCLUSION: Thinning reduced balsam fir resistance to spruce budworm defoliation. This response is due to increased defoliation linked to reduction in concentrations of certain monoterpenes, and a decrease in foliage production, except on hydric drainage, demonstrating the importance of drainage class to tree resistance. The results suggest that the use of Bacillus thuringiensis might be required when conducting stand thinning during spruce budworm outbreaks. PMID- 21796759 TI - Hot-topic debate on kidney function: renal-sparing approaches are beneficial. AB - KEY POINTS: 1. Renal function is frequently compromised in candidates for transplantation with advanced cirrhosis. These patients frequently have chronic and irreversible kidney changes at the time of transplantation. 2. The accumulated incidence of chronic renal failure is high in liver transplant recipients. Chronic renal failure has a deleterious impact on the outcome. 3. Calcineurin inhibitor (CNI)-based immunosuppression is highly effective at preventing rejection. However, CNI nephrotoxicity has a central role in the occurrence of chronic renal failure. 4. Renal function impairment frequently occurs within the first year after transplantation. Once renal function is significantly impaired [glomerular filtration rate (GFR) < 60 mL/minute/1.73 m(2) ], any intervention is unlikely to result in a return to normal renal function. Early interventions are needed to prevent chronic and irreversible kidney injury. 5. De novo CNI minimization has been proven to be effective at reducing the rate of impaired renal function after transplantation. The reduction in the CNI doses should be offset by the addition of mycophenolate mofetil or enteric-coated mycophenolate sodium. 6. Delayed CNI minimization in patients with established renal insufficiency may result in a significant improvement in the GFR, even though the increase in the GFR after minimization is generally modest. 7. Mammalian target of rapamycin (mTOR) inhibitors are considered nonnephrotoxic immunosuppressive agents. They may be an option for improving renal function in liver transplant recipients. However, not all patients with renal dysfunction benefit from a switch to mTOR inhibitors. In addition, the benefits in terms of renal function should be balanced against specific side effects. 8. New immunosuppressive agents without intrinsic nephrotoxicity are currently under development for solid organ transplantation. These agents could help to reduce the burden of impaired renal function in transplantation in the near future. PMID- 21796760 TI - Place of liver transplantation in the treatment of hepatocellular carcinoma in the normal liver. PMID- 21796761 TI - Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database. AB - PURPOSE: To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor. MATERIALS AND METHODS: Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the population-based HIT trials. RESULTS: We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, 0.1-14.0 years). The AT/RT:PNET/MB ratio was 1:12.2 for all children, and 1:1.5 for children younger than 1 year at diagnosis. Three-year overall survival (OS) and event-free survival (EFS) for all patients were 22% and 13%, respectively. Eight patients (14%) are considered long-term event-free survivors (follow-up 1.4-10.6 years). By univariable analyses, younger age, metastatic disease, infratentorial location, and less than complete remission at the end of chemotherapy were identified as negative influencing factors for OS. By multivariable analyses, younger age (OS, EFS) and metastatic disease (OS) were identified as independent risk factors. CONCLUSION: The incidence of AT/RT in children below 1 year is higher than previously reported. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Prospective clinical and biological studies are needed to further define prognostic factors and optimize therapy. PMID- 21796762 TI - Pharmacogenetics, cost of genotyping, and guidelines for individualizing therapy with mercaptopurine in pediatric acute lymphoblastic leukemia. PMID- 21796763 TI - Young adults with SCD in US children's hospitals: are they different from adolescents? AB - BACKGROUND: The period of transition from pediatric to adult care is a vulnerable time for patients with sickle cell disease (SCD). The optimal time for transition is unknown and there is no standard of care regarding this timing in the United States. PROCEDURES: We collected administrative data from the Pediatric Health Information System for all SCD admissions from 2000 to 2009. We compared reasons for hospitalization and resulting charges in adolescents (13-17 years) and young adults (18-21 years). RESULTS: We identified 25,371 admissions of adolescents (n = 18,299) and young adults (n = 7,072) with SCD. Median admissions per patient per year was higher in young adults (0.6) compared to adolescents (0.2, P < 0.001), but reasons for hospitalization were similar between the two age groups. Complications of adult SCD such as nephropathy and pulmonary hypertension were rare (<2.5% of discharges) but more frequent in older patients (P = 0.001). Although length of stay was similar between the two groups (median = 4 days), young adults tended to incur higher charges (median +$1,314, P < 0.001) and were less likely to utilize private insurance (P < 0.001). Deaths (0.2% of admissions) were rare and similar across age groups (P = 0.7). CONCLUSION: In a national sample of US children's hospitals, adolescents (13-17 years) and young adults (18 21 years) with SCD had similar reasons for hospitalization and low mortality. Further studies are needed to investigate whether extending the age of transition to >= 21 years as a national standard may decrease morbidity and mortality, improve health-related quality of life, or increase readiness for transition in patients with SCD. PMID- 21796764 TI - Early diagnosis improves the quality of life in MYH9 disorder. PMID- 21796765 TI - Treatment of relapsed acute lymphoblastic leukemia: approaches used by pediatric oncologists and bone marrow transplant physicians. AB - BACKGROUND: Management of relapsed B-precursor acute lymphoblastic leukemia (ALL) is challenging and varied. We hypothesized that treatment approaches differ between pediatric oncologists and bone marrow transplant (BMT) physicians. PROCEDURE: A survey addressing management of relapsed ALL was sent to pediatric oncologists (n = 883) and BMT (n = 86) physicians across North America. RESULTS: A number of similarities in treatment approaches were identified including: choice of chemotherapy for re-induction/consolidation, preference for unrelated donors (URDs) in very early marrow relapse and the choice to not use URD donors in late marrow relapse. However, differences between the two disciplines were noted. For patients who relapsed 18-36 months from diagnosis, the majority of oncologists (53.7%) would retreat with chemotherapy while a majority BMT physicians (70.3%) recommended URD transplant (P < 0.001). Oncologists were also less likely to use minimal residual disease (MRD) in relapse assessment compared to BMT physicians (52% vs. 67.2%; P = 0.028) and more oncologists believed MRD testing was experimental and/or not proven in relapsed ALL (27.1% vs. 12.3%; P = 0.011). CONCLUSIONS: This study highlights management differences in children with ALL between pediatric oncologists and BMT physicians, identifying opportunities for collaborative clinical trials. PMID- 21796766 TI - Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines. AB - BACKGROUND: HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX-2112 is an orally administered potent HSP90 inhibitor that has demonstrated pre-clinical anti-tumor activity in adult malignancies. As many childhood tumors depend upon HSP90 client proteins, we sought to test the pre-clinical efficacy of SNX-2112 in a panel of pediatric cancer cell lines both as a single-agent and in combination with cisplatin (CP). PROCEDURE: Eight cell lines (from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short- and long-term effects of SNX-2112 were assessed by MTT and clonogenic assays. Cell cycling was measured using flow cytometry. Status of HSC70, HSP72, AKT1, C-Raf, and PARP was assessed by immunoblotting. Efficacy of SNX-2112 in combination with CP was assessed using median-effect analysis. RESULTS: Cell lines studied demonstrated sensitivity to SNX-2112 with IC(50) values ranging from 10-100 nM. Low dose treatments (12 nM) resulted in a cytostatic response with a minimal increase in sub-G1 content. A higher dose (70 nM) exhibited a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of AKT1 and C-Raf were markedly reduced over time along with an increase in PARP cleavage. In concurrently administered combination treatments, SNX-2112 and CP synergistically inhibited cell growth. CONCLUSIONS: SNX-2112 showed marked single-agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX-2112 and CP showed synergistic activity in two cell lines tested. Further studies of HSP90 inhibitors such as SNX-2112 as a single agent or in combination with chemotherapy are warranted in pediatric cancer. PMID- 21796767 TI - Hearing loss among survivors of childhood brain tumors treated with an irradiation-sparing approach. AB - BACKGROUND: Intensive, irradiation-sparing chemotherapy regimens for malignant brain tumors have improved survival and neurocognitive outcomes in very young children. Platinum compounds are pivotal to this approach's success but are associated with hearing loss that markedly reduces quality of life for survivors. The purpose of this study was to determine the prevalence and severity of ototoxicity associated with Head Start and similar irradiation-sparing regimens. PROCEDURE: A retrospective cohort study was conducted of children treated for malignant brain tumors at Children's Hospital Los Angeles using irradiation sparing regimens. Patient and treatment characteristics were ascertained. Primary outcomes were post-treatment hearing status, need for hearing aids, and hearing threshold change. RESULTS: Twenty-nine patients were evaluable. The most common diagnosis was medulloblastoma (n = 14). The median age at diagnosis was 2.0 years (range, 0.2-9.2). Median time from diagnosis to most recent hearing assessment was 1.1 years (mean 2.4; range, 0.2-17.5). Cumulative cisplatin and carboplatin dose was 281 +/- 88 mg/m(2) and 1,205 +/- 277 mg/m(2) , respectively. All patients had aminoglycoside exposure. Following treatment, 18 patients (62.1%) had abnormal hearing and 11 (37.9%) required hearing aids. At 4,000 Hz, statistically significant hearing loss was documented in the range of 30-40 dB. CONCLUSIONS: While eliminating cranial irradiation has dramatically improved survival and neurocognitive and neuroendocrine outcomes in this population, clinically significant hearing loss is now the leading late effect due to the necessity of platinum-based chemotherapy. Our results document the need for audiometric monitoring and developing otoprotective strategies in this vulnerable population. PMID- 21796768 TI - Using MS-MLPA as an efficient screening tool for detecting 9p21 abnormalities in pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Characterization of recurrent genetic lesions in childhood acute lymphoblastic leukemia (ALL) has enabled therapeutic stratification with improved outcomes. The tumor suppressor genes, CDKN2A and CDKN2B, encoding p16(INK4a) , p14(ARF) , and p15(INK4b) have been localized to 9p21. Abnormalities of 9p21 have been reported in 10-30% of childhood ALL using conventional cytogenetics and fluorescence in situ hybridization (FISH). The incidence of 9p21 using more sensitive techniques, such as methylation specific multiplex ligation-dependent probe amplification (MS-MLPA), remains uncertain, and thus also the prognostic significance. PROCEDURE: We investigated the incidence and prognostic importance of 9p21 abnormalities in pediatric ALL patients using MS-MLPA and compared these results to FISH. RESULTS: In total, MS-MLPA or FISH detected aberrations (both dosage and methylation abnormalities) at 9p21 in a remarkable 32/48 (67%) patients in contrast to a much lower rate of only 8% of patients identified to have deletions by standard G banding cytogenetics. MS-MLPA identified five deletions not found by FISH. Aberrant methylation at CDKN2B was found in 19 (46%) patients. 9p21 abnormalities were associated with National Cancer Institute (NCI) high-risk criteria (P = 0.04) and were present in all five patients with T-cell disease. Four pre-B-cell ALL patients relapsed, three of whom had prior 9p21 abnormalities. CONCLUSIONS: MS-MLPA had a higher detection rate for 9p21 abnormalities than previously reported for other techniques. Given the ease of processing, minimal equipment and low cost of MS-MLPA, our results suggest that previous reports may have underestimated the true frequency of 9p21 abnormalities and their potential impact upon ALL outcome. PMID- 21796769 TI - Influence diagrams as decision-making tools for pesticide risk management. AB - The pesticide policy arena is filled with discussion of probabilistic approaches to assess ecological risk, however, similar discussions about implementing formal probabilistic methods in pesticide risk decision making are less common. An influence diagram approach is proposed for ecological risk-based decisions about pesticide usage. Aside from technical data, pesticide risk management relies on diverse sources, such as stakeholder opinions, to make decisions about what, how, where, and when to spray. Bayesian influence diagrams allow multiple lines of evidence, including process related information from existing data and expert judgment, in 1 inclusive decision model. In ecological risk assessments, data informally incorporated for pesticide usage decisions, such as field and laboratory effect studies along with chemical monitoring and modeling data, can be formally incorporated and expressed in linked causal diagrams. A case study is presented from the perspective of an environmental manager wishing to efficiently control pests while minimizing risk to local aquatic receptors. Exposure modeling results and toxicity studies were incorporated, and an ecological risk assessment was carried out but combined with hypothetical information on spraying efficacy and valuation of outcomes that would be necessary for making risk management decisions. The variables and their links in the influence diagram are ones that are important to a manager and can be manipulated to optimally control pests while protecting nontarget resources. PMID- 21796770 TI - Including ecotoxic impacts on warm-blooded predators in life cycle impact assessment. AB - In current life cycle impact assessment, the focus of ecotoxicity is on cold blooded species. We developed a method to calculate characterization factors (CFs) for the impact assessment of chemical emissions on warm-blooded predators in freshwater food chains. The method was applied to 329 organic chemicals. The CF for these predators was defined as a multiplication of the fate factor (FF), exposure factor (XF), bioaccumulation factor (BF), and effect factor (EF). Fate factors and XFs were calculated with the model USES-LCA 2.0. Bioaccumulation factors were calculated with the model OMEGA, for chemical uptake via freshwater, food, and air. Effect factors were calculated based on experimental, median lethal doses (LD50). The concentration buildup (CB) of the chemicals (i.e., FF, XF, and BF over the 3 routes of exposure) showed a range of 7 to 9 orders of magnitude, depending on the emission compartment. Effect factors displayed a range of 7 orders of magnitude. Characterization factors ranged 9 orders of magnitude. After emissions to freshwater, the relative contribution of the uptake routes to CB were 1% (90% confidence interval [CI]: 0%-2%) for uptake from air, 43% (11%-50%) for uptake from water, and 56% (50%-87%) for uptake from food. After an emission to agricultural soil, the contribution was 11% (0%-80%) for uptake from air, 39% (5%-50%) for uptake from water, and 50% (11%-83%) for uptake from food. Uptake from air was mainly relevant for emissions to air (on average 42%, 90% CI: 5%-98%). Characterization factors for cold-blooded species were typically 4 orders of magnitude higher than CFs for warm-blooded predators. The correlation between both types of CFs was low, which means that a high relative impact on cold-blooded species does not necessarily indicate a high relative impact on warm-blooded predators. Depending on the weighing method to be considered, the inclusion of impacts on warm-blooded predators can change the relative ranking of toxic chemicals in a life cycle assessment. PMID- 21796771 TI - Environmental engineering of navigation infrastructure: a survey of existing practices, challenges, and potential opportunities. AB - Navigation infrastructure such as channels, jetties, river training structures, and lock-and-dam facilities are primary components of a safe and efficient water transportation system. Planning for such infrastructure has until recently involved efforts to minimize impacts on the environment through a standardized environmental assessment process. More recently, consistent with environmental sustainability concepts, planners have begun to consider how such projects can also be constructed with environmental enhancements. This study examined the existing institutional conditions within the US Army Corps of Engineers and cooperating federal agencies relative to incorporating environmental enhancements into navigation infrastructure projects. The study sought to (1) investigate institutional attitudes towards the environmental enhancement of navigation infrastructure (EENI) concept, (2) identify potential impediments to implementation and solutions to such impediments, (3) identify existing navigation projects designed with the express intent of enhancing environmental benefit in addition to the primary project purpose, (4) identify innovative ideas for increasing environmental benefits for navigation projects, (5) identify needs for additional technical information or research, and (6) identify laws, regulations, and policies that both support and hinder such design features. The principal investigation tool was an Internet-based survey with 53 questions. The survey captured a wide range of perspectives on the EENI concept including ideas, concerns, research needs, and relevant laws and policies. Study recommendations included further promotion of the concept of EENI to planners and designers, documentation of existing projects, initiation of pilot studies on some of the innovative ideas provided through the survey, and development of national goals and interagency agreements to facilitate implementation. PMID- 21796772 TI - Multiphoton flow cytometry strategies and applications. AB - A handful of research teams around the world have recently begun to utilize multiphoton techniques in cytometry, especially for in vivo applications. These approaches offer similar enhancements to flow cytometry as the multiphoton phenomenon brought to the field of microscopy at the turn of the 20th century, with at least six advantages over single-photon excitation. Here, we review the published literature on multiphoton cytometry in vivo or in vitro from the initial experiments in 1999 to present. Multiphoton cytometry instrumentation set ups vary from adapted multiphoton microscopy to a dedicated system, with laser pulse power and repetition rate serving as important variables. Two-beam geometry enables quantitation of cell size. Labeling strategies include conjugated fluorophore targeting, with folate and/or dendrimer platforms. With two-color measurement, ratiometric labeling is also possible, where one dye serves as a trigger to indicate the amount of excitation a cell receives, and another informs of cellular function. With two-color labeling, geometric fluorophore distribution proves important in theory and experiment for detection sensitivity curves and detected event intensity correlation. The main biological achievements to date using this young technology are reviewed, with emphasis on real-time monitoring of minute-by-minute and long-term cell dynamics as well as the clinically significant surveillance of circulating tumor cells. For this goal, minimally invasive two-photon flow cytometry with a fiber probe may overcome the primary issue of sample volume. The technique of multicolor, multiphoton flow cytometry greatly enhances the capabilities of flow cytometry to investigate the dynamics of circulating cells in cancer and other important diseases, and may in the future benefit from advances in microscopy such as super-resolution imaging, coherent control, and bioluminescence. PMID- 21796774 TI - OMIP-003: phenotypic analysis of human memory B cells. PMID- 21796773 TI - Deep ultraviolet mapping of intracellular protein and nucleic acid in femtograms per pixel. AB - By using imaging spectrophotometry with paired images in the 200- to 280-nm wavelength range, we have directly mapped intracellular nucleic acid and protein distributions across a population of Chinese hamster ovary (CHO-K1) cells. A broadband 100* objective with a numerical aperture of 1.2 NA (glycerin immersion) and a novel laser-induced-plasma point source generated high-contrast images with short (~100 ms) exposures and a lateral resolution nearing 200 nm that easily resolves internal organelles. In a population of 420 CHO-K1 cells and 477 nuclei, we found a G1 whole-cell nucleic acid peak at 26.6 pg, a nuclear-isolated total nucleic acid peak at 11.4 pg, and, as inferred by RNase treatment, a G1 total DNA mass of 7.4 pg. At the G1 peak, we found a whole-cell protein mass of 95.6 pg, and a nuclear-isolated protein mass of 39.3 pg. An algorithm for protein quantification that senses peptide-bond (220-nm) absorbance was found to have a higher signal-to-noise ratio and to provide more reliable nucleic acid and protein determinations when compared to more classical 280/260-nm algorithms when used for intracellular mass mapping. Using simultaneous imaging with common nuclear stains (Hoechst 33342, Syto-14, and Sytox Orange), we have compared staining patterns to deep-UV images of condensed chromatin and have confirmed bias of these common nuclear stains related to nuclear packaging. The approach allows absolute mass measurements with no special sample preparation or staining. It can be used in conjunction with normal fluorescence microscopy and with relatively modest modification of the microscope. PMID- 21796775 TI - Developmental evolution of the insect retina: insights from standardized numbering of homologous photoreceptors. AB - The canonical number of eight photoreceptors and their arrangement in the ommatidia of insect compound eyes is very conserved. However significant variations exist in selective groups, such as the Lepidoptera and Hymenoptera, which independently evolved additional photoreceptors. For this and historical reasons, heterogeneous labeling conventions have been in use for photoreceptor subtypes, despite developmentally and structurally well-defined homologies. Extending earlier efforts, we introduce a universal photoreceptor subtype classification key that relates to the Drosophila numbering system. Its application is demonstrated in major insect orders, with detailed information on the relationship to previous conventions. We then discuss new insights that result from the improved understanding of photoreceptor subtype homologies. This includes evidence of functionally imposed ground rules of differential opsin expression, the underappreciated role of R8 as ancestral color receptor, the causes and consequences of parallel R7 photoreceptor addition in Hymenoptera and Lepidoptera, and the ancestral subfunctionalization of outer photoreceptors cells, which may be only developmentally recapitulated in Drosophila. We conclude with pointing out the need for opsin expression data from a wider range of insect orders. PMID- 21796776 TI - Novelties that change carrying capacity. AB - Comparative developmental studies have revealed a rich array of details about the patterns and processes of morphological change in animals and increasingly in plants. But, applying these insights to the study of major episodes of evolutionary innovation requires understanding how these novel morphologies become established and sufficiently abundant (either as individuals within a species or as a clade of species) to be preserved in the fossil record, and, in many cases, to influence ecological processes. Evolutionary novelties may: (1) disappear without changing the species; (2) be associated with the generation (through selection or drift) of a new species; and if the latter (3) may or may not become ecologically significant. Only the latter are commonly preserved in the fossil record. These alternatives mirror the distinction among historians of technology between innovation and invention. Here, I argue that specific sorts of evolutionary inventions drive ecological transformation, essentially constructing an environment for themselves and ancillary organisms through ecological spillover effects, increasing the "carrying capacity" of an ecosystem. PMID- 21796777 TI - Lessons from probiotic-host interaction studies in murine models of experimental colitis. AB - In inflammatory bowel diseases (IBD), it is known that besides genetic and environmental factors (e.g. diet, drugs, stress), the microbiota play an important role in the pathogenesis. Patients with IBD have an altered microbiota (dysbiosis) and therefore, probiotics, defined as 'live micro-organisms that when administered in adequate amounts can confer a health benefit on the host', have been suggested as nutritional supplements to restore these imbalances. The best response on probiotics among the different types of IBD appears to be in the case of ulcerative colitis. Although probiotics show promise in IBD in both clinical and animal studies, further mechanistic studies are necessary to optimize the use of probiotics as supporting therapy in IBD. Murine models of experimental colitis have been used for decades to study this pathology, and these models have been proven useful to search for new therapeutic approaches. The purpose of this review is to summarize probiotic-host interaction studies in murine models of experimental colitis and to evaluate how these models can further help in understanding these complex interactions. Unraveling the molecular mechanisms behind the beneficial effects will assist in better and possibly more efficient probiotic formulations. PMID- 21796778 TI - Analysis of DNA adducts in human samples: acrolein-derived exocyclic DNA adducts as an example. AB - Acrolein is an environmental pollutant that is also derived endogenously through lipid peroxidation and protein degradation. The reaction of acrolein with 2' deoxyguanosine produces exocyclic 1,N(2) -propano-2'-deoxyguanosine (AdG) adducts, mutagenic lesions that play important roles in multistage carcinogenesis processes. Accurate quantification of acrolein-derived DNA adducts is a critical step toward elucidating the mode of action of acrolein carcinogenicity. Exposure of humans to acrolein can occur through the smoking of tobacco and the dietary consumption of oxidized polyunsaturated fatty acids. This review describes the use of (32) P-postlabeling- and MS-based methods for the analyses of acrolein derived DNA adducts in humans as well as present trends toward improving the sensitivity, specificity, and accuracy of the quantification of trace amounts of DNA adducts in DNA of limited availability. PMID- 21796779 TI - Vitamin C modulates the interaction between adipocytes and macrophages. AB - SCOPE: Increased adiposity is related with monocyte infiltration into the adipose tissue that accentuates inflammation. Antioxidant treatments emerge as approaches to counteract this phenomenon. METHODS AND RESULTS: Cocultures of differentiated 3T3-L1 adipocytes and RAW264.7 macrophages were incubated for 24-72 h with/without 100 nM insulin and/or 200 MUM vitamin C (VC). Nitric oxide (NO) secretion (24 h) was measured. Also, expression (24 h) and secretion (72 h) of MCP-1, leptin and apelin were analyzed. NO secretion was significantly inhibited by insulin and VC only in cocultures. MCP-1 expression/secretion was enhanced in cocultures. Insulin incubation reduced MCP-1 expression in both cultures and VC only in controls. Both treatments inhibited MCP-1 secretion in cocultures. Apelin gene expression was induced in cocultures. Insulin induced apelin mRNA expression, but VC inhibited its expression in cocultures under insulin treatment. Apelin secretion was notably induced by insulin and inhibited by VC in cocultures. Leptin expression was decreased in coculture, while presented no effects by VC. CONCLUSION: VC importantly modulates the established pro inflammatory state in the interaction between adipocytes and macrophages. PMID- 21796782 TI - Creating a human brain proteome atlas--14th HUPO BPP workshop September 20-21, 2010, Sydney, Australia. AB - The HUPO Brain Proteome Project (HUPO BPP) held its 14th workshop during the HUPO 9th Annual World Congress in Sydney, Australia. The principal aim of this project is to discover prognostic and diagnostic biomarkers associated with neurodegenerative diseases and brain aging, with the ultimate objective of obtaining a better understanding of these conditions and creating roads for the development of novel diagnostic techniques and effective treatments. The attendees came together to discuss progress in the human clinical neuroproteomics and to define the needs and guidelines required for more advanced proteomics approaches. PMID- 21796783 TI - Performance evaluation of a rapid-scanning quadrupole mass spectrometer in the comprehensive two-dimensional gas chromatography analysis of pesticides in water. AB - The performance of a novel rapid-scanning (20,000 amu/s) quadrupole mass spectrometer (qMS) has been evaluated in the comprehensive 2-D gas chromatography (GC*GC) analysis of pesticides contained in water. Analyte extraction was performed by using direct solid-phase microextraction (SPME). The MS system was operated using a rather wide m/z 50-450 mass range and a 33 Hz spectral production rate, a frequency which was found sufficient for reliable quantification. The qMS performance was evaluated considering: (i) number of data points per peak, (ii) mass spectral quality, (iii) extent of peak skewing, and (iv) consistency of retention times. Seven-point calibration curves (external calibration) were constructed for 28 pesticides over the limit of quantification range of 100 MUg/L (1, 5, 10, 25, 50, and 100 MUg/L). The solid-phase microextraction-GC*GC-qMS method was validated by calculating limits of detection and quantification, intraday peak area precision, accuracy, and intraday retention-time precision. A series of tap water samples were subjected to analysis, fortunately giving negative results. PMID- 21796784 TI - Monolithic poly(butyl methacrylate-ethylene dimethacrylate-methacrylic acid) column for capillary electrochromatography. AB - A butyl methacrylate-ethylene dimethacrylate-methacrylic acid (MAA) monolithic column was prepared for capillary electrochromatography. The effect of MAA weight percentage on the EOF mobility and column efficiency was studied. BMA-EDMA-MAA monolith with higher content of MAA provided higher EOF mobility as well as higher efficiency. The effect of mobile-phase composition and buffer pH was also investigated. The monolithic columns exhibited a good repeatability and reproducibility of column preparation with relative standard deviation values below 16% in the studied chromatographic parameters. PMID- 21796785 TI - Capacitively coupled contactless conductivity detection as an alternative detection mode in CE for the analysis of kanamycin sulphate and its related substances. AB - A method was developed to determine simultaneously kanamycin, its related substances and sulphate in kanamycin sulphate using capacitively coupled contactless conductivity detection. Kanamycin is an aminoglycoside antibiotic that lacks a strong UV-absorbing chromophore. Due to its physicochemical properties, CE in combination with capacitively coupled contactless conductivity detection was chosen. The separation method uses a BGE composed of 40 mM 2-(N morpholino)ethanesulphonic acid monohydrate and 40 mM L-histidine, pH 6.35. A 0.6 mM N-cetyltrimethyl ammonium bromide (CTAB) solution was added as electroosmotic flow modifier in a concentration below the critical micellar concentration (CMC). Ammonium acetate 50 mg/L was used as internal standard. In total, 30 kV was applied in reverse polarity on a fused-silica capillary (65/41 cm; 75 MUm id). The optimized separation was obtained in less than 6 min with good linearity (R(2)=0.9999) for kanamycin. It shows a good precision expressed as RSD on the relative peak areas equal to 0.3 and 1.1% for intra-day and inter-day precision, respectively. The LOD and LOQ are 0.7 and 2.3 mg/L, respectively. Similarly, for sulphate, a good linearity (R(2)=0.9996) and precision (RSD 0.4 and 0.6% for intra-day and inter-day, respectively) were obtained. PMID- 21796786 TI - Separation and sweeping of metal ions with EDTA in CZE-ESI-MS. AB - Ethylenediaminetetraacetic acid (EDTA) in the background electrolyte (BGE) of capillary zone electrophoresis coupled to an electrospray ionization mass spectrometer is presented as an approach for the determination of metal ions. Significant signals for the metal-ligand complexes were observed even when EDTA was continually eluted from the capillary during the entire electrophoretic run. The signal-to-noise ratio was improved by the addition of ammonia to the sheath liquid and by using an acquisition m/z range above the m/z of EDTA. The LODs for the test metal ions (i.e. calcium(II), manganese(II), and zinc(II)) with conventional injection were around 1-2 mg/L with corrected peak areas that are linear from 8 to 100 mg/L. The presence of EDTA in the BGE was critical not only for the separation but also for sweeping via complexation as an on-line sample concentration technique. The peak height of the test metal ions was improved at least tenfold with sweeping via EDTA complexation and yielded LODs in the MUg/L range. PMID- 21796787 TI - Strong cation exchange monoliths for HPLC by Reactive Gelation. AB - Polymeric monolithic stationary phases for HPLC can be produced by Reactive Gelation. Unlike the conventional method of using porogens, such novel process consists of a number of separate steps, thus enabling a better control of the quality of the final material. A suspension of polymer nanoparticles in water is produced and subsequently swollen with hydrophobic monomers. The particles are then destabilised (usually by salt addition) to make them aggregate into a large percolating structure, the so-called monolith. Finally, the added monomer can then be polymerised to harden the structure. In this work, a polystyrene latex is used as the base material and functionalised by introduction of epoxide groups on the surface and subsequent reaction to sulphonic acid groups, yielding a SO3(-) density of 0.7 mmol/g dry material. Morphological investigations show 54% porosity made of 300 nm large pores. Van Deemter measurements of a large protein show no practical influence of diffusion limitations on the plate number. Finally, a preliminary separation of a test protein mixture is shown, demonstrating the potential of using ion-exchange chromatography on Reactive Gelation monoliths. PMID- 21796788 TI - Simultaneous quantification of three iridoids in rat plasma after oral administration of Zhi-zi-chi decoction using LC-MS. AB - A sensitive and efficient liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the simultaneous determination of geniposide, 6alpha-hydroxygeniposide, and genipin gentiobioside in rat plasma. After the addition of internal standard (I.S.) salidroside and acidification (formic acid, 0.1%), plasma samples were carried out by protein precipitation with acetonitrile and separated on a Kromasil C(18) column (200 mm * 4.6 mm, 5 MUm) within a runtime of 15.0 min. The linear ranges were 2-250 ng/mL for both 6alpha hydroxygeniposide and genipin gentiobioside and 2-2000 ng/mL for geniposide, respectively. The lower limit of quantification (LLOQ) was 2 ng/mL for all the analytes. The validated method was successfully applied to the pharmacokinetics study of geniposide, 6alpha-hydroxygeniposide, and genipin gentiobioside in rats after oral administration of Zhi-zi-chi decoction. PMID- 21796789 TI - Use of tube radial distribution of ternary mixed carrier solvents for introduction of absorption reagent for metal ion separation and online detection into capillary. AB - When ternary mixed solvents consisting of water-hydrophilic/hydrophobic organic solvents are fed into a micro-space under laminar flow conditions, the solvent molecules are radially distributed in the micro-space. The specific fluidic behavior of the solvents is called the "tube radial distribution phenomenon (TRDP)". A novel capillary chromatography method was developed based on the TRDP that creates the inner major and outer minor phases in a tube, where the outer phase acts as a pseudo-stationary phase. This is called "tube radial distribution chromatography (TRDC)". In this study, Chrome Azurol S as an absorption reagent was introduced into the TRDC system for metal ion separation and online detection. The fused-silica capillary tube (75 MUm id and 110 cm length) and water-acetonitrile-ethyl acetate mixture (3:8:4 volume ratio) including 20 mM Chrome Azurol S as a carrier solution were used. Metal ions, i.e. Co(II), Cu(II), Ni(II), Al(III), and Fe(III), as models were injected into the present TRDC system. Characteristic individual absorption characteristics and elution times were obtained as the result of complex formation between the metal ions and Chrome Azurol S in the water-acetonitrile-ethyl acetate mixture solution. The elution times of the metal ions were examined based on their absorption behavior; Co(II), Ni(II), Al(III), Fe(III), and Cu(II) were eluted in this order over the elution times of 4.7-6.8 min. The elution orders were determined from the molar ratios of metal ion to Chrome Azurol S and Irving-Williams series for bivalent metal ions. PMID- 21796790 TI - Size separation and size determination of liposomes. AB - We developed a method for separating liposomes by size and determining their average diameters. Liposomes with different average diameters were separated on a monolithic silica capillary column, and the size of the liposomes corresponding to each peak was determined online with a dynamic light scattering detector coupled to the capillary liquid chromatography system. The calculated diameters for the separated liposomes were similar to the diameter values measured in batch mode. We demonstrate that this combination of a monolithic capillary column and light scattering detection could be used for size separation of liposomes and could provide more details about average diameters than batch-mode analysis. PMID- 21796791 TI - Simultaneous concentration enrichment and electrophoretic separation of weak acids on a microchip, using in situ photopolymerized carboxylate-type polyacrylamide gels as the permselective preconcentrator. AB - A method for the simultaneous concentration and separation of weak acids using an acidic polyacrylamide gel, fabricated in the microfluidic channel of a commercial poly(methyl methacrylate)-made microchip, is reported. This approach is based on simple photochemical copolymerization for the fabrication of a permselective preconcentrator. The intersection of the poly(methyl methacrylate)-made microchip was filled with a gel solution comprising acrylamide, N,N'-methylene-bis acrylamide, and 2-acrylamidoglycolic acid, with riboflavin as a photocatalytic initiator. In situ polymerization, near the cross of the sample outlet channel, was performed by irradiation with an argon ion laser beam that is also used as the light source for fluorimetric detection. The electrokinetic properties, combined with electrostatic repulsion between sample components and the anionic groups on the polyacrylamide gel, enable the entrapment and concentration of weak acids at the interface of the cathodic side of the gel plug. This method displays concentration factors of up to 10(5) within 3 min. The effectiveness of the ionic preconcentrator was demonstrated by the sensitive analysis of fluorescein isothiocyanate-labeled amino acids. PMID- 21796792 TI - Determination of organophosphorous pesticides in the ppq range using a simple solid-phase extraction method combined with dispersive liquid-liquid microextraction. AB - Solid-phase extraction combined with dispersive liquid-liquid microextraction (SPE-DLLME) was applied for the extraction of six organophosphorous pesticides (OPPs) in water samples. The analytes considered in this study were determined by gas chromatography with mass spectrometry and included prophos, diazinon, chlorpyrifos methyl, methyl parathion, fenchlorphos and chlorpyrifos. Several extraction conditions (extraction solvent and elution/dispersion solvents nature, extraction solvent volume, elution solvent volume, water volume and sample volume) were tested for SPE-DLLME with these analytes and the best results were obtained using carbon tetrachloride as the extraction solvent and acetone as the elution/dispersion solvent. Calibration curves for the determination of OPPs in water samples were constructed in the concentration range of 10-100 ng/L. Limits of detection (LODs) ranged from 38 to 230 pg/L values that are below the maximum admissible level for drinking water (100 ng/L). Relative standard deviations (RSD) were between 8.6 and 10.4% for a fortification level of 100 ng/L. At the same fortification level, the relative recoveries (R.R.) of tap, well and irrigation water samples were in the range of 30.2-97.1%. PMID- 21796793 TI - mRNA export and cancer. AB - Studies in the past several years highlight important features of the messenger RNA (mRNA) export process. For instance, groups of mRNAs acting in the same biochemical processes can be retained or exported in a coordinated manner thereby impacting on specific biochemistries and ultimately on cell physiology. mRNAs can be transported by either bulk export pathways involving NXF1/TAP or more specialized pathways involving chromosome region maintenance 1 (CRM1). Studies on primary tumor specimens indicate that many common and specialized mRNA export factors are dysregulated in cancer including CRM1, eukaryotic translation initiation factor 4E (eIF4E), HuR, nucleoporin 88, REF/Aly, and THO. This positions these pathways as potential therapeutic targets. Recently, specific targeting of the eIF4E-dependent mRNA export pathway in a phase II proof-of principle trial with ribavirin led to impaired eIF4E-dependent mRNA export correlating with clinical responses including remissions in leukemia patients. Here, we provide an overview of these mRNA export pathways and highlight their relationship to cancer. PMID- 21796794 TI - Synthesis and anticancer activity of the (R,S)-benzofused 1,5-oxathiepine moiety tethered to purines through alkylidenoxy linkers. AB - Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)-9-[2- or 3-(3,4-dihydro-2H-1,5-benzoxathiepine-3-yloxy)alkyl] 9H-purines. Derivatives with propylenoxy-linked 2',6'-dichloro- and 6' bromopurines are more active than their respective ethylenoxy-linked purine conjugates. On the other hand, the compound with a propylenoxy-linked 6' chloropurine is nearly equipotent to the corresponding ethylenoxy-linked conjugate. Our results show that bromo- and chloropurine-conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF-7 breast cancer cells, indicating that the activation of eIF2alpha, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF-7 cell line; apoptosis was induced in a p53-independent manner. PMID- 21796795 TI - Derivatives of benzimidazol-2-ylquinoline and benzimidazol-2-ylisoquinoline as selective A1 adenosine receptor antagonists with stimulant activity on human colon motility. AB - A number of quinolines and isoquinolines connected in various ways to a substituted benzimidazol-2-yl system were synthesized and evaluated as novel antagonists of adenosine receptors (ARs) by competition experiments using human A(1), A(2A), and A(3) ARs. The new compounds were designed based on derivatives of 2-(benzimidazol-2-yl)quinoxaline, previously reported as potent and selective antagonists of A(1) and A(3) ARs. Among these, 3-[4-(ethylthio)-1H-benzimidazol-2 yl]isoquinoline 4b exhibited the best combination of potency toward the A(1) AR (K(i) =1.4 nM) and selectivity against the A(2A) (K(i) >10 MUM), A(2B) (K(i)>10 MUM), and A(3) ARs (K(i)>1 MUM). Functional experiments in circular smooth muscle preparations of isolated human colon showed that 4b behaves as a potent and selective antagonist of the A(1) AR in the neuromuscular compartment of this intestinal region. Biological and pharmacological data suggest that 4b is a suitable starting point for the development of novel agents endowed with stimulant properties on colonic activity. PMID- 21796796 TI - Solid-state electrochemistry of graphene oxides: absolute quantification of reducible groups using voltammetry. PMID- 21796797 TI - Regulation of cell cycle components during exposure to anoxia or dehydration stress in the wood frog, Rana sylvatica. AB - The wood frog (Rana sylvatica) exhibits a well-developed natural anoxia and dehydration tolerance. The degree of stress tolerance depends on numerous biochemical adaptations, including stress-induced hypometabolism that helps to preserve long-term viability by reducing ATP demand. We hypothesized that the mechanisms involved in cell cycle control could act to aid in the establishment of the hypometabolic state required for stress survival. Selected proteins involved in the proliferation of cells were evaluated using immunoblotting in liver and skeletal muscle of wood frogs comparing controls with animals subjected to either 24-hr anoxia exposure under a nitrogen gas atmosphere or dehydration to 40% of total body water lost (all at 5 degrees C). Levels of cyclins (type A, B, D, and E) decreased significantly under both stresses in liver and skeletal muscle. Similar reductions were seen for Cyclin-dependant kinases (Cdk) types 2, 4, and 6 in both liver and skeletal muscle; however, an increase in the relative amount of phosphorylated inactive p-Cdk (Thr14/Tyr15) was observed in liver under both stresses. Levels of positive regulators of Cdk activity (Cdc25 type A and C) were significantly reduced in both tissues under both stresses, whereas negative regulators of Cdk activity (p16(INK4a) and p27(KIP1) ) increased significantly in liver under both anoxia and dehydration stress (but not in muscle). This study provides the first report of differential regulation of cell cycle components in an anoxia and dehydration tolerant vertebrate, the wood frog, suggesting that cell cycle suppression is an active part of stress resistance and life extension in hypometabolic states. PMID- 21796798 TI - Guidelines for standard photography in gross and clinical anatomy. AB - Photography has a widespread usage in medicine and anatomy. In this review, authors focused on the usage of photography in gross and clinical anatomy. Photography in gross and clinical anatomy is not only essential for accurate documentation of morphological findings but also important in sharing knowledge and experience. Photographs of cadavers are supposed to demonstrate the required information clearly. Thus, photographs should be taken with certain techniques in order to obtain high quality and standardization. Camera, lens, lighting, background, and certain photographic techniques are among the factors to achieve precise images. A set of suggested guidelines for accomplishing these standards are given for anatomists. PMID- 21796799 TI - Learning of musculoskeletal ligament stress testing in a gross anatomy laboratory. AB - Human anatomy in physical therapy programs is a basic science course serving as a foundation for subsequent clinical courses. Integration of anatomy with a clinical emphasis throughout a curriculum provides opportunities for reinforcement of previously learned material. Considering the human cadaver laboratory as a fixed cost to our program, we sought opportunities to add value to the resource via vertical integration into a clinical skills course taught later in the curriculum. We designed an opportunity for second-year physical therapy students to revisit the human anatomy laboratory to study select clinical musculoskeletal tests and the associated anatomy in a clinically relevant context. Students performed select orthopedic ligament test on human cadavers, then incised specific structures and repeated the tests. Students were able to feel and visualize the function of pertinent anatomy associated with the clinical tests. Ninety-five percent of respondents reported that the ligament stress testing experience enhanced their understanding of orthopedic clinical tests with 91% reporting an enhanced understanding of anatomy related to specific clinical tests. Likewise, the experience was perceived as enjoyable and valuable with 86% of respondents reporting the experience as enjoyable and 100% responding the experience should continue as part of the curriculum. PMID- 21796800 TI - Target blood pressure in diabetes patients with hypertension--what is the accumulated evidence in 2011? AB - There is overwhelming evidence that hypertension is an important risk factor for both macrovascular and microvascular complications in patients with diabetes, but the problem remains to identify appropriate goals for preventive therapies. A number of guidelines (the European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) 2007, the Joint National Committee (JNC)-VII 2003, the American Diabetes Association (ADA) 2011) have for example advocated a blood pressure goal of less than 130/80 mmHg, but this suggestion has been challenged by findings in recent trials and meta-analyses (2011). The European Society of Hypertension (ESH) therefore recommends a systolic blood pressure goal of "well below" 140 mmHg. Based on evidence from both randomized controlled trials (hypertension optimal treatment (HOT), action in diabetes and vascular disease: preterax and diamicron MR controlled evaluation (ADVANCE), action to control cardiovascular risk in diabetes (ACCORD)) and observational studies (ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET), international verapamil-trandolapril study (INVEST), treat to new targets (TNT), and the National Diabetes Register (NDR)), it has been shown that the benefit for stroke reduction remains even at lower achieved blood pressure levels, but the risk of coronary events may be uninfluenced or even increased at lower systolic blood pressure levels. In a recent meta analysis, it was therefore concluded that the new recommended goal should be 130 135 mmHg systolic blood pressure for most patients with type 2 diabetes. Other risk factors should also be controlled with a more ambitious strategy applied in the younger patients with shorter diabetes duration, but a more cautious approach in the elderly and frail patients with a number of vascular or non-vascular co morbidities. In patients from East Asia, such as China, the stroke risk is relatively higher than the risk of coronary events. This must also be taken into consideration for individualized goal setting in relation to total risk, for example in patients from stroke-prone families. In conclusion, the current strategy is to have a more individualized approach to risk factor control in patients with type 2 diabetes, also relevant for blood pressure control. PMID- 21796801 TI - Complex pathologies of angiotensin II-induced abdominal aortic aneurysms. AB - Angiotensin II (AngII) is the primary bioactive peptide of the renin angiotensin system that plays a critical role in many cardiovascular diseases. Subcutaneous infusion of AngII into mice induces the development of abdominal aortic aneurysms (AAAs). Like human AAAs, AngII-induced AAA tissues exhibit progressive changes and considerable heterogeneity. This complex pathology provides an impediment to the quantification of aneurysmal tissue composition by biochemical and immunostaining techniques. Therefore, while the mouse model of AngII-induced AAAs provides a salutary approach to studying the mechanisms of the evolution of AAAs in humans, meaningful interpretation of mechanisms requires consideration of the heterogeneous nature of the diseased tissue. PMID- 21796802 TI - Early reperfusion strategy for acute myocardial infarction: a need for clinical implementation. AB - Reperfusion is the key strategy in acute ST-segment elevation myocardial infarction (STEMI) care, and it is time-dependent. Shortening the time from symptom to reperfusion and choosing the optimal reperfusion strategy for STEMI patients are great challenges in practice. We need to improve upon the problems of low reperfusion rate, non-standardized treatment, and economic burden in STEMI care. This article briefly reviews the current status of reperfusion strategy in STEMI care, and also introduces what we will do to bridge the gap between the guidelines and implementation in the clinical setting through the upcoming China STEMI early reperfusion program. PMID- 21796803 TI - MitraClip: a novel percutaneous approach to mitral valve repair. AB - As life expectancy increases, valvular heart disease is becoming more common. Management of heart disease and primarily valvular heart disease is expected to represent a significant proportion of healthcare provided to the elderly population. Recent years have brought a progression of surgical treatments toward less invasive strategies. This has given rise to percutaneous approaches for the correction of valvular heart disease. Percutaneous mitral valve repair using the MitraClip system (Abbott Vascular, Santa Clara, CA, USA) creates a double orifice and has been successfully used in selected patients with mitral regurgitation. We review the rationale, procedural aspects, and clinical data thus far available for the MitraClip approach to mitral regurgitation. PMID- 21796804 TI - Cardioprotective effect of liposomal prostaglandin E1 on a porcine model of myocardial infarction reperfusion no-reflow. AB - OBJECTIVE: To evaluate whether liposomal prostaglandin E1 (lipo-PGE1) can decrease reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). METHODS: Twenty-two male Chinese mini-swines were randomized into three groups: six in a sham-operation group, and eight each in the control and lipo-PGE1 groups. The distal part of the left anterior descending coronary artery (LAD) in the latter two groups was completely occluded for 2 h, and then reperfused for 3 h. Lipo-PGE1 (1 MUg/kg) was injected 10 min before LAD occlusion until reperfusion for 1 h in the lipo-PGE1 group. Hemodynamic data and proinflammatory cytokines were examined before AMI, 2 h after occlusion, and 1, 2, and 3 h after reperfusion. Myocardial contrast echocardiography (MCE) and double staining were performed to evaluate the myocardial no-reflow area (NRA). RESULTS: Left ventricular systolic pressure and end-diastolic pressure significantly improved in the lipo-PGE1 group after reperfusion compared with the control group and also 2 h after AMI (P<0.05 for both). MCE and double staining both showed that lipo-PGE1 decreased reperfusion NRA after AMI (P<0.05, P<0.01). Lipo-PGE1 decreased serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) after myocardial infarction reperfusion (P<0.05 for both). CONCLUSIONS: Lipo-PGE1 is cardioprotective in our porcine model of myocardial infarction reperfusion no-reflow, decreasing NRA and attenuating the inflammatory response. PMID- 21796805 TI - Tongxinluo promotes mesenchymal stem cell tube formation in vitro. AB - OBJECTIVE: To study whether Tongxinluo (TXL) can induce angiogenesis in bone marrow mesenchymal stem cells (MSCs), and to investigate the underlying mechanism. METHODS: Bone marrow MSCs were obtained from male Sprague-Dawley rats. We established an angiogenesis model in vitro via matrigel experiment. MSCs were seeded on matrigel coated 24-well plates, and treated by TXL 50 and 100 mg/L. After 24 h, we observed the tube formations of MSCs in the matrigel. Cell migration ability was examined by wound scratch test and transwell assay. Expressions of vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were analyzed at the protein level by Western blot. Gelatin zymography assay was applied to investigating the MSC paracrine abilities of pro-MMP-2 and activated MMP-2. RESULTS: TXL promoted MSC tube formation in matrigel. The ratio of TXL 100 mg/L treated-MSC tubular length was increased 3.04 fold compared to the control group (P<0.05). Scratch test and transwell assay showed that TXL could improve the cell migration ability of MSCs. Western blot experiments showed that TXL promoted MSC synthesis of MMP-2, but it had no influence on the expressions of MMP-9 and TIMP-2. This effect was confirmed by gelatin zymography assay, which showed that TXL increased MSC secretion of pro MMP-2 and activated MMP-2. VEGF expression of TXL treated-MSCs was increased compared to the control group. The expression of Flk-1 was not different among the groups. CONCLUSIONS: This study demonstrates that TXL can promote the tube formation of MSCs, and the underlying mechanisms are associated with increased migration ability of MSCs and the up-regulation of MMP-2 and VEGF expressions. PMID- 21796807 TI - Association between SNP rs1800875, serum chymase and immunoglobulin E levels in patients with coronary heart disease. AB - OBJECTIVE: The gene for mast cell chymase (CMA1) is an ideal candidate for investigating the genetic predisposition to coronary heart disease (CHD), as activated mast cells have been found to be present in a greater proportion in the shoulder region of atheroma than in normal coronary intimae. Previous studies have indicated that CMA1 promoter polymorphism rs1800875 may be involved in regulating immunoglobulin E (IgE) levels in patients with eczema, and it is associated with the progression of immunoglobulin A nephropathy. METHODS: The association between single nucleotide polymorphism (SNP) rs1800875, serum chymase, and serum IgE levels was examined in 175 CHD subjects and 95 non-CHD subjects. RESULTS: Statistical analysis indicated no significant difference in allele frequency between CHD and non-CHD. However, a significant association was found between CMA1 genotypes and total IgE levels in CHD subjects. Meanwhile, crossover analysis revealed that, in GG homozygotes, CHD risk was nearly six times higher in those with IgE (U/ml) level <2.58 (natural logarithm conversion), while no association was found with chymase level. CONCLUSIONS: Polymorphism rs1800875 of CMA1 may be associated with serum IgE level in CHD subjects, but not with chymase level in both groups. In GG homozygotes, high IgE level is a protective factor against coronary disease. PMID- 21796806 TI - Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats. AB - OBJECTIVE: Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney. METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. CONCLUSIONS: Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney. PMID- 21796808 TI - Midazolam in rabbits terminates dysrhythmias caused by intracerebroventricular ropivacaine. AB - The current study was designed to investigate the mechanisms by which ropivacaine may act within the central nervous system (CNS) to produce cardiotoxicity. Eighty New Zealand rabbits were divided into four groups randomly. In Group 1, 20 rabbits received intracerebroventricular (icv) saline, and then received icv ropivacaine 30 min later. In Group 2, 20 rabbits received icv ropivacaine. Whenever dysrhythmias continued for more than 5 min, 0.1 ml saline was administered into the left cerebral ventricle. Ten minutes later, 0.1 ml midazolam was given into the left lateral ventricle. In Group 3, 20 rabbits received icv ropivacaine, and once the dysrhythmias developed, the inspired isoflurane concentration was increased from 0.75% to 1.50%. In Group 4, 20 animals received an intravenous (iv) phenylephrine infusion until dysrhythmias occurred. In Group 1, the rabbits did not develop dysrhythmias in response to icv saline, whereas dysrhythmias did develop in these animals after icv ropivacaine. In Group 2, icv saline had no effect on the dysrhythmias; however, icv midazolam terminated cardiac dysrhythmias. In Group 3, an increase in the concentration of the inspired isoflurane had no effect on dysrhythmias. In Group 4, icv midazolam had no effect on dysrhythmias in response to iv phenylephrine. Ropivacaine administered directly into the CNS is capable of producing cardiac dysrhythmias; midazolam terminated dysrhythmias presumably by potentiation of gamma aminobutyric acid (GABA) receptor activity. Our results suggest that ropivacaine produces some of its cardiotoxicity not only by the direct cardiotoxicity of the drug, but also by the CNS effects of ropivacaine. PMID- 21796809 TI - Effects of GLUT4 expression on insulin resistance in patients with advanced liver cirrhosis. AB - Decreased glucose tolerance and diabetes are frequently observed in advanced liver cirrhosis patients and may be related to insulin resistance. Glucose transporter-4 (GLUT4), one of the most important glucose transporters, plays a key role in the development of type 2 diabetes. In order to study the mechanism of insulin resistance in liver cirrhosis patients, we measured the insulin sensitivity index and determined the GLUT4 protein and mRNA contents of skeletal muscle by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR), respectively, in normal people and liver cirrhosis patients. The results showed that the levels of glucose, insulin, and C-peptide in two liver cirrhosis groups were higher and the insulin sensitivity index lower than those of the normal control group. The sensitivity of insulin may decrease with the decline of liver function. However, the contents of GLUT4 protein and mRNA in patients with advanced liver cirrhosis were similar to those of normal controls. In conclusion, insulin resistance is observed in patients with advanced liver cirrhosis but may not be correlated with the skeletal contents of GLUT4 protein and mRNA. PMID- 21796810 TI - Correlation between expectations of recovery and injury severity perception in whiplash-associated disorders. AB - OBJECTIVE: To assess the correlation between expectations of recovery and whiplash patients' perceptions of injury severity using a simplified instrument. Expectations of recovery have been shown to predict rate of recovery from whiplash injury in population-based studies. The perception of having more severe pathology or more ominous diagnostic labels has also been associated with a worse prognosis. METHODS: Consecutive patients with whiplash-associated disorder grade 1 or 2, presenting in the acute stage to a primary care centre, were asked "do you think that your injury will..." with response options "get better soon; get better slowly; never get better; don't know." Injury severity perception (ISP) was measured with a numerical rating scale which ranged from 0-10, on which subjects were asked to rate how severe (in terms of damage) they thought their injury was. The anchors were labeled "no damage" (0) and "severe, and maybe permanent damage" (10). The primary outcome measure was the correlation between the subject's ISP score and expectation of recovery. RESULTS: A total of 94 subjects (34 males, 60 females, and mean age (40.6 +/- 10.0) years, range 19-60 years) were included. The initial responses to expectation of recovery were: get better soon (29/94); get better slowly (22/94); never get better (11/94); don't know (32/94). The mean ISP score was 4.9 +/- 1.7 (range 2-9 out of 10). There was a high correlation between expectations and ISP scores (Spearman's rank correlation coefficient 0.68). Those who expected to recover soon and those who expected to get better slowly had the lowest ISP scores. CONCLUSIONS: The more slowly whiplash patients expect to recover, or the less sure they are of recovery, the more severe their initial perceptions of injury. PMID- 21796811 TI - Acupuncture for treating uremic pruritus in patients with end-stage renal disease: a systematic review. AB - Uremic pruritus (UP) is a common and bothersome symptom in end-stage renal disease (ESRD) that does not always respond to conventional care. Acupuncture is frequently used for the treatment of a wide range of conditions, but its effects on UP in ESRD patients are unclear. The objective of this review was to evaluate the effectiveness of acupuncture for UP in patients with ESRD. We searched 16 electronic databases from their inception to November 2009. All prospective clinical studies of needle acupuncture for UP in hemodialysis patients with ESRD were included regardless of their design. Risk of bias of the included studies was assessed using the Cochrane criteria. Three randomized controlled trials and three uncontrolled observational studies were included. All of the included trials reported beneficial effects of acupuncture. However, most of the studies showed high risk of bias, which leaves their reports unconvincing. The current evidence is insufficient to show that acupuncture is an effective treatment for UP inpatients with ESRD because of suboptimal quality and lack of methodological rigor of included studies. Future trials should overcome the limitations of the currently available evidence. J Pain Symptom Manage 2010;40:117e125. 2010 U.S. Cancer Pain Relief Committee. PMID- 21796812 TI - [Eribulin: a new therapeutic option in intensely pretreated metastatic cancer of the breast?]. PMID- 21796813 TI - [Cellular immunotherapy and glioblastoma: a hopeful treatment?]. PMID- 21796814 TI - Bibliography. Sarcomas. Current world literature. PMID- 21796815 TI - Bibliography. Gastrointestinal tract. Current world literature. PMID- 21796816 TI - Bibliography. Pediatric urology. Current world literature. PMID- 21796817 TI - Development of a Forster resonance energy transfer sensor for realtime imaging of intracellular redox dynamics. PMID- 21796818 TI - Bibliography. Corneal and external disorders. Current world literature. PMID- 21796819 TI - Bibliography. Lymphoid biology and diseases. Current world literature. PMID- 21796820 TI - What mergers can do for you. PMID- 21796821 TI - Bibliography. Renal pathophysiology. Current world literature. PMID- 21796823 TI - [Preimplantation diagnosis, twenty years after]. PMID- 21796837 TI - A patient's account. AB - I have wanted to write about this subject for a long time but have held back, fearing it to be not quite socially acceptable. But the bubble inside is ready to burst and I can wait no longer. PMID- 21796838 TI - Chronic heart failure. PMID- 21796839 TI - Patients with Down syndrome. PMID- 21796840 TI - [Expression of HIF-1alpha in serum of primary hepatocellular carcinoma and effects on tumor invasion and metastasis]. AB - AIM: To study the expression of HIF-1alpha in serum of primary hepatocellular carcinoma (PHC) and effects on tumor invasion and metastasis. METHODS: The serum HIF-1alpha level from 60 cases of PHC patients and 60 cases of normal healthy individuals were detected by ELISA. RESULTS: The serum HIF-1alpha level of the PHC group was (161.14+/-80.79) pg/mL, the control group was (22.67+/-8.47) pg/mL, compared the different was significant (P<0.05). The serum HIF-1alpha level of distant metastasis of tumor group was (225.15+/-108.16) pg/mL, the no distant metastasis of tumor group was (101.26+/-55.18) pg/mL, compared the different was significant (P<0.05). The serum HIF-1alpha level of portal vein tumor thrombus group was (255.45+/-122.23) pg/mL. The no portal vein tumor thrombus group was (139.97+/-71.49) pg/mL, compared the different was significant (P<0.05). The serum HIF-1alpha level of tumor capsule group was (99.97+/-55.75) pg/mL. The no tumor capsule group was (187.36+/-91.52) pg/mL, compared the different was significant (P<0.05). The serum HIF-1alpha level was no significantly different among the different age, gender, TNM stage and tumor diameter. CONCLUSION: The serum HIF-1alpha has high expression in PHC. The serum HIF-1alpha expression has close relation with the whether distant metastasis of tumor, portal vein tumor thrombus and tumor capsule. The serum HIF-1alpha level can predict the invasion and metastasis of PHC. PMID- 21796841 TI - [The relationship between the serum ET and resistin concentration and the peripheral neuropathy in type 2 diabetes]. AB - AIM: To study patients with type 2 diabetes, endothelin (ET), resistin level and peripheral neuropathy (DPN) relationship. METHODS: Second affiliated hospital of Zhengzhou university, department of endocrinology hospital of 60 patients with type 2 diabetes, the nerve electrophysiological examination of 20 cases were divided into DM group and 40 patients with DPN, and select the healthy control group of 30 cases. Radioimmunoassay and enzyme-linked immunosorbent assay of serum ET, resistin levels. RESULTS: The DM group and the DPN serum ET, resistin levels were significantly higher (P<0.05), while the DPN group ET, resistin levels were significantly higher than that of DM group (P<0.05). Linear correlation analysis showed that patients with type 2 diabetes serum resistin levels were positively correlated with ET (r=0.436, P<0.01). Logistic regression analysis showed that duration, HbA1c, serum resistin level in ET and be associated with DPN are independent risk factors. CONCLUSION: Patients with type 2 diabetes ET, resistin levels are closely related with the DPN; patients with ET, is the abnormal increase of resistin levels may lead to the risk factors of DPN. PMID- 21796842 TI - [The secreted level of REIC protein in gastric carcinoma and its role of proliferation inhibition]. AB - AIM: To detect secretory REIC content in serum from the patients with gastric carcinoma and cell culture medium of gastric carcinoma cell lines, and determine the effects of recombinant REIC on proliferation of gastric carcinoma cells. METHODS: ELISA was employed to determine REIC content in serum and supernatant, and WST-8 to detect the proliferation of gastric carcinoma cells. RESULTS: The secretion level of REIC was obviously decreased in serum form gastric carcinoma, compared with healthy individuals (P<0.05) and inversely correlated with the tumor size of gastric carcinomas (P<0.05). The REIC content was lower in supernatant from gastric carcinoma cells than that in epithelial cells (P<0.05). After the transfection of REIC-expressing plasmid, the concentration of REIC was increased in supernatant from AGS (P<0.05). The proliferation of AGS and BGC-823 could be inhibited by recombinant REIC (P<0.05). CONCLUSION: REIC expression of secretion type decreased in gastric carcinoma cells, and inhibited the proliferation of gastric carcinoma cells. REIC protein might be employed as a good marker or target for the early diagnosis, biological and gene therapy of gastric carcinoma. PMID- 21796843 TI - [Methodological study on magnetic affinity immunoassay for detecting chloramphenicol]. AB - AIM: To establish a sensitive immunoassay for detection chloramphenicol using magnetic beads as solid phase. METHODS: This assay employs the competitive inhibition, the FITC conjugated with anti-chloramphenicol monoclonal antibodies and the alkaline phosphatase conjugated with chloramphenicol respectively. Magnetic beads were coupled with sheep anti-FITC antibodies as solid phase. And phenolphthalein monophosphate was used as substrate to set up MEIA for detection chloramphenicol. RESULTS: MEIA for detection chloramphenicol was Established, the reaction time is 40 minutes, the sensitivity is 0.03 microg/L, the liner range is 0.1-8.1 microg/L, the intra and inter coefficient variation (CV) was 3.9%-5.3% and 4.8%-8.1% respectively and the recovery is 97%-101.5%. Comparing with national standard method of liquid chromatography-mass spectrometry, the Correlation coefficient of test results is 0.9817 (r=0.9817). CONCLUSION: The chloramphenicol MEIA method is sensitive, accurate, and fast, it provides a new method of immunoassay for the monitoring of chloramphenicol residues in food. PMID- 21796844 TI - Disseminating wound care guidelines: lessons from the literature. AB - The multiplicity of clinical practice guidelines available to the practicing nurse poses considerable challenges in keeping up-to-date not only on their existence but also on their content and implications for practice. The aim of guidelines is to support the clinician in providing up-to-date, evidence -based patient care and to minimize the variations in such care. However, while their development represents and enormous amount of time and expertise, little attention has been given to how to disseminate them and how to implement them. PMID- 21796845 TI - Labeling for bronchodilators to treat asthma; cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Final rule. AB - The Food and Drug Administration (FDA) is amending the final monograph (FM) for over-the-counter (OTC) bronchodilator drug products to add additional warnings (e.g., an "Asthma alert'') and to revise the indications, warnings, and directions in the labeling of products containing the ingredients ephedrine, ephedrine hydrochloride, ephedrine sulfate, epinephrine, epinephrine bitartrate, racephedrine hydrochloride, and racepinephrine hydrochloride. FDA is issuing this final rule after considering data and information submitted in response to the Agency's proposed labeling revisions for these products. This final rule is part of FDA's ongoing review of OTC drug products. PMID- 21796846 TI - Medical devices; neurological devices; classification of repetitive transcranial magnetic stimulation system. Final rule. AB - The Food and Drug Administration (FDA) is classifying the repetitive transcranial magnetic stimulation (rTMS) system into class II (special controls). The Agency is classifying this device type into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of these devices. PMID- 21796847 TI - The U.S. health system in perspective: a comparison of twelve industrialized nations. AB - The Organization for Economic Cooperation and Development (OECD) tracks and reports on more than 1,200 health system measures across 34 industrialized countries. This analysis concentrated on 2010 OECD health data for Australia, Canada, Denmark, France, Germany, Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States. Health care spending in the U.S. towers over the other countries. The U.S. has fewer hospital beds and physicians, and sees fewer hospital and physician visits, than in most other countries. Prescription drug utilization, prices, and spending all appear to be highest in the U.S., as does the supply, utilization, and price of diagnostic imaging. U.S. performance on a limited set of quality measures is variable, ranking highly on five-year cancer survival, middling on in-hospital case specific mortality, and poorly on hospital admissions for chronic conditions and amputations due to diabetes. Findings suggest opportunities for cross-national learning to improve health system performance. PMID- 21796848 TI - It is anticipated that as is usually the case, financial motivation will move TZ from its current status "potential anti-MDR/XDR agent," to one that will cure MDR and XDR TB. Foreword. PMID- 21796849 TI - A proper introduction. PMID- 21796850 TI - A guide to using this guide. PMID- 21796851 TI - The 15th annual HIV drug guide. PMID- 21796852 TI - Do your meds play well with others? A guide to HIV drug interactions. PMID- 21796853 TI - (Unintended) consequences: A guide to side effects that can result from HIV medications. PMID- 21796854 TI - It's in the cards. Where to get help to pay for your meds. PMID- 21796855 TI - Coming into view. Drugs we can look forward to in the future. PMID- 21796856 TI - The rules of the game. Current DHHS treatment guidelines for first time therapy. PMID- 21796857 TI - Ending child abuse, wars and terrorism. PMID- 21796858 TI - Implications of weak father-relationships and anality in the United States. PMID- 21796859 TI - Korean Shamans and childhood trauma. PMID- 21796860 TI - Living same-name siblings and British historical demography. AB - This article examines the extent to which living siblings were given identical first names. Whilst the practice of sibling name-sharing appeared to have died out in England during the eighteenth century, in northern Scotland it persisted at least until the end of the nineteenth century. Previously it has not been possible to provide quantitative evidence of this phenomenon, but an analysis of the rich census and vital registration data for the Isle of Skye reveals that this practice was widespread, with over a third of eligible families recording same-name siblings. Our results suggest that further research should focus on regional variations in sibling name-sharing and the extent to which this northern pattern occurred in other parts of Britain. PMID- 21796861 TI - The workhouse populations of Lancashire in 1881. AB - This article investigates the characteristics of the workhouse populations in Lancashire in 1881. The analysis is based on the snapshot view provided by the 1881 census and, despite the limitations of such an approach, this large-scale survey reveals significant variations in the experience of poverty and local relief policies in a largely industrial region that had been at the forefront of the anti-poor law movement. The workhouse populations are shown to be diverse, and contrast markedly with pauper populations previously studied. Lancashire's Poor Law Unions are divided into three types: conurbation, urban industrial and rural. These three groups appear to represent three different patterns of workhouse residency. The workhouse populations in rural Lancashire are broadly similar to those discussed elsewhere, being dominated by elderly males. However, urban industrial workhouse populations contained large numbers of adults of working age and the absence of children from workhouses in the conurbation is particularly striking. PMID- 21796862 TI - Interpreting seventeenth-century probate documents: John Carter, master carpenter in St Albans. AB - This is a study of a successful seventeenth-century carpenter in St Albans, John Carter, using probate and other documents, assisted by a large-scale computer database of St Albans residents of the period. Sections of the article cover his family, his work and his house and its contents, which have been reconstructed from his probate inventory and from knowledge of the structure of other local houses of the period. Carter's social standing is discussed, both in its local context and in relation to previous probate inventory analyses. This micro-study sheds unusual light upon aspects of the life of a 'middling sort' of person, living in a thriving market town in close proximity to London, at the beginning of the consumer age. PMID- 21796863 TI - The radioguided 111In-pentetreotide surgery in the management of ACTH-secreting bronchial carcinoid. AB - BACKGROUND AND OBJECTIVES: A correct intra-operative detection of the tumour and, therefore, the complete surgical resection is critical to success in ACTH secreting bronchial carcinoids. To date, all available preoperative and intra operative procedures remain not entirely satisfactory. The use of intra-operative 111In-pentetreotide detection could offer a potentially reliable and rapid tool of real time assessment to achieve a radical resection. MATERIALS AND METHODS: In two cases of ACTH-secreting bronchial carcinoids, after a preliminary 111In pentetreotide scan, radio-guided surgery was performed using a hand-held gamma probe 24 h after i.v. administration of the tracer. RESULTS: The 111n pentetreotide radioguided surgery with hand-held gamma probe, if compared with pre-operative 111In-pentetreotide, significantly improved the intra-operative surgical management by detecting a millimetric nodule in one case; detecting mediastinal lymph node metastasis in both cases and ruling out any other disease localization. DISCUSSION: Intra-operative 111In-pentetreotide detection appears to be safe and easy to perform. This technique allowed to achieve a complete resection of all the tumor locations, that would have been impossible to detect with conventional surgical approach. On the basis of these results we advocate for a wider investigation of the potentialities connected with the radioguided surgery coupled with pre-operative 111In-pentetreotide scan as a promising procedure in the management of ACTH-secreting bronchial carcinoids. PMID- 21796864 TI - Seroprevalence of hepatitis B virus markers in individuals for physical examination in West China Hospital, China. AB - BACKGROUND: Hepatitis B virus (HBV) is the major cause of chronic hepatitis,cirrhosis, and hepatocellular carcinoma. The global epidemiological scenario of HBV infection has been changing rapidly over the last two decades due to an effective immunization programme initiated by the World Health Organization. The objective of this study is to estimate the prevalence of HBV in apparently adult people who were taken health examination in our Hospital. METHODS: A cross-sectional seroprevalence analysis of hepatitis B virus infection was performed in 12037 adult residents (aged > or =18 years) in Chengdu, who visited Health Examination Center of West China Hospital of Sichuan University for routine medical check-up during the period from March to December 2008. A structured medical form was used to collect data on demographic characteristics and risk factors. ELISA was used to test sera for HBV markers. Descriptive and logistic regression models were used for analysis. RESULTS: A total of 12,037 urban residents were involved. Prevalence of positive HBsAg was 6.1%, lower than the level of national seroepidemiological survey in (7.18%). Among HBsAg negative people, anti-HBs and anti-HBc was 60.2% and 13.6% respectively. There was a maximum between 18 to 29 years of age (61.8%) in anti-HBs positive people. Multivariate conditional logistic regressive analysis showed that, except for blood and vertical transmission, factors of male gender (OR, 1.876; 95% CI, 1.519 2.316; P < 0.001) and alcohol intake (OR, 0.689; 95% CI, 0.571-0.832; P < 0.001) were associated with a higher risk of positive HBsAg. CONCLUSIONS: Among the medical examination people in Chengdu, HBsAg positive rate was lower than the national general population, the epidemiological characteristics of hepatitis B has been changed, because of vacination policies to the newborn; therefore, the necessity to continue to carry on the vaccination program. PMID- 21796865 TI - Evaluation of in vitro anti-Leishmanial activity of some brown, green and red algae from the Persian Gulf. AB - BACKGROUND AND OBJECTIVES: Leishmaniasis is a protozoan parasitic disease which is transmitted by the female Phlebotomus sand fly and is prevalent in four continents.The first-choice treatment for the leishmaniasis is pentavalent antimonials, which are potentially toxic and often ineffective and use of them exhibit therapeutic failure. These pharmaceutical problems point towards the need to develop novel chemotherapeutic agents. Seaweeds are considered as source of bioactive metabolites characterized by a broad spectrum of biological activities. MATERIALS AND METHODS: In this experimental study, cold and hot water crude extracts of four species of green, brown and red marine algae "Caulerpa sertularioides, Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" collected along the Bushehr coast of the Persian Gulf (southwest of Iran), prepared and their in vitro activities against Leishmania major promastigote were evaluated by using the MTT assay test. RESULTS: The cold and hot water crude extracts of four algae species exhibited different anti Leishmanial activities. The minimum inhibitory concentration of hot water extracts calculated as IC50 was as follows: Caulerpa sertularioides (IC50 < or =85 microg/ml), Gracilaria corticata (IC50 < or =38 microg/ml), Gracillaria salicornia (IC50 < or =46 microg/ml) and Sargassum oligocystum (IC(50)9 < or =78 microg/ml, while these values for cold water extracts were (IC50 >125 microg/ml) for Caulerpa Sertularioides (IC50 >65 microg/ml) for Gracilaria corticata (IC50 >74 microg/ml) for Gracilaria salicornia and (IC50 >105 microg/ml) for Sargassum oligocystum, IC50 values for reference drug (Amphotericin B) was (0.16-0.2 microg/ml). DISCUSSION: According to the results, inhibitory effects of the crude extracts from these four species algae specially hot water crude extracts from "Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" are significant and in accordance with other studies that has been done on different algae species. So these results are sufficiently promising to be followed with further studies on isolation and characterization of pure compounds from these algae species as well as in vivo experiments, a work that is already under way in our laboratory. PMID- 21796866 TI - Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide. AB - The present work on drug-induced ototoxicity, tinnitus and vertigo represents the update and revision of a previous guide to adverse drug reactions for italian physicians (2005). The panorama of drug-induced side effects causing ototoxicity or symptoms such as tinnitus or dizziness and vertigo has enlarged in recent years, thanks to a better knowledge and a more specific attention of pharmaceutical firms and drug-control institutions. In daily clinical practice, there is a need for the family physician and the ENT specialist or audiologist (also in consideration of the possible medico-legal implications) to focus the attention on the possible risk of otological side effects. This would allow a clinical risk-benefit evaluation, weighing the possible clinical advantage in their field of competence against possible otological side-effects. The list of active ingredients and drugs is subdivided in categories based on their audiological and otoneurological side-effects, that have been signaled by the drug companies and/or ministerial notes. Drugs have also been subcategorized with regards to the field in which they are applied, the therapeutic indications and the clinical behaviour. They have also been organized in alphabetical order, for an easier consultation. The guide above, even if initially conceived for being used in Italy, also presents a more general and international interest, expecially as for as the concepts of pharmacology and the features of the active ingredients are concerned. The guide is, therefore, useful as for as we are concerned to any physician, regardless of the country he/she operates in. PMID- 21796868 TI - Incisional hernia surgery: report on 283 cases. AB - BACKGROUND AND OBJECTIVES: Despite the improvement of the surgical technique and several experiences reported in literature about prosthetic incisional hernioplasty, the prevalence rate of recurrence and of the classic complications has not changed over the years. We analyze our caseload, establishing some technical cornerstones in order to reduce their occurrence. PATIENTS AND METHODS: 283 patients underwent incisional hernioplasty in our Department of Surgery in the decade 1999-2008. They were retrospectively divided into four groups (A-D) according to the surgical technique adopted for a comparative analysis: A, 37 primary direct closure; B, 207 Rives-Stoppa procedures; C, 9 Chevrel procedures; D, 30 intraperitoneal repairs. The outcomes were considered in terms of postoperative surgical complications. RESULTS: In total, we observed 11 cases of hernia recurrence (3.9%), 13 cases of infections (4.6%), 7 cases of seroma/hematoma (2.4%) and one case of acute respiratory insufficiency. DISCUSSION: The Rives-Stoppa procedure is, among all those practised, the treatment of choice in incisional hernioplasty. Thanks to the introduction of some simple modifications to this technique and preventing the postoperative infections, we obtained excellent results in terms of recurrence rate (only 1 case on 207 patients, 0.48%) and morbidity. PMID- 21796867 TI - Effect of beta-glucan, inositol and digestive enzymes in GI symptoms of patients with IBS. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a very common functional gastrointestinal (GI). Diagnosis of IBS is based on the fulfilment of the Rome III criteria. Common GI symptoms are lower abdominal pain, bloating and disturbed defecation, such as urgent diarrhoea and/or episodes of chronic constipation. Many agents have been employed in the management of IBS, although only few have been demonstrated to show a relevant efficacy. AIM: To evaluate the effectiveness of the administration of a mixture of beta-glucan, inositol and digestive enzymes (Biointo) in improving GI symptoms in patients affected by IBS. PATIENTS AND METHODS: 50 IBS patients (20 males, 30 females; mean age 51 +/- 19) were treated with Biointo (group A) while another group consisting of 40 IBS patients (15 males, 25 females; mean age 50 +/- 18) did not receive any therapy (group B). RESULTS: Biointol administration improved significantly bloating, flatulence and abdominal pain, with a slight increasing of urgency for bowel movements. On the contrary, Biointol did not show any significant effect on the other IBS symptoms. CONCLUSIONS: Currently, only few agents used in the management of IBS have been proven to be effective. Biointol administration has shown to improve some IBS symptoms, such as bloating, flatulence and abdominal pain, all connected to the presence of gas inside the intestinal lumen. PMID- 21796869 TI - In vitro antimicrobial and antioxidant activity of acetone and methanol extracts from Thymus leucotrichius (Lamiaceae). AB - BACKGROUND AND OBJECTIVES: Thymus species has been used as tonic and herbal tea, antiseptic, antitussive, carminative, antioxidant, anti-inflammatory and antimicrobial activities. The acetone and methanol extracts of Thymus (T.) leucotrichius (Labiatae/Lamiaceae) was examined for antimicrobial and antioxidant properties. MATERIALS AND METHODS: The antioxidant properties of acetone and methanol extracts of Thymus leucotrichius were investigated using 1,1-diphenyl-2 picrylhydrazyl (DPPH)/nitric oxide (NO) radical scavenging activity, reducing power and total phenolic substance analysis. Antibacterial, antiyeast and antifungal activity of the plant extracts were tested using the disc diffusion method. RESULTS AND DISCUSSION: Results showed that IC50 of Thymus leucotrichius acetone and methanol extracts that scavenged 50% of the DPPH radical in the medium was found to be 109.72 microg/ml, 43.53 microg/ml, respectively. It was found that IC50 of Thymus leucotrichius acetone and methanol extracts which scavenged 50% of the NO radical in the medium was 180.56 microg/ml, and 67.34 microg/ml, respectively. In the Thymus leucotrichius acetone and methanol extracts (1 mg), 35.64 microg and 51.78 microg pyrocatechol equivalents of phenols were detected, respectively. Neither acetone nor methanol extract possessed activity towards Proteus vulgaris, Rhodotorula rubra, Candida albicans, Aspergillus parasiticus and Aspergillus niger. Acetone extract was the most active on Bacillus cereus and Bacillus megaterium. The sentivity was also observed against towards Escherichia coli H7:O157, Kluvyeromyces fragilis and Fusarium proliferatum when acetone extract used. The methanol extract also displayed more or less similar inhibitory activity towards the test microorganisms. Kluvyeromyces fragilis was resistant to methanol extract of the species unlike acetone extracts of the species. However, the fungus Fusarium proliferatum was markedly inhibited by the methanol extract of test species at 1000 microg and above. Significant inhibitory activities of the two extracts were based upon the increasing dose-dependent level. PMID- 21796870 TI - Antioxidant activity of hydroalcholic extract of Ferula gummosa Boiss roots. AB - OBJECTIVES: Ferula gummosa Boiss is native to central Asia. This plant has traditionally been used in the treatment of many diseases. The antihypoxic and antioxidant activities of Ferula gummosa roots were investigated. MATERIAL AND METHODS: 1,1-diphenyl-2-picryl hydrazyl radical (DPPH), nitric oxide and hydrogen peroxide scavenging activities, Fe2+ chelating ability, reducing power and hemoglobin-induced linoleic acid peroxidation were used to evaluate antioxidant activities. Antihemolytic activity was evaluated by H2O2 induced hemolysis in rat erythrocytes. The total amount of phenolic compounds was determined as gallic acid equivalents and total flavonoid contents were calculated as quercetin equivalents from a calibration curve. RESULTS: The extracts showed moderate antioxidant activity in some models. IC50 for DPPH radical-scavenging activity was 579.6 +/- 19.4 microg/ml. The extracts showed weak nitric oxide-scavenging activity between 0.1 and 1.6 mg ml(-1) but showed good Fe2+ chelating ability. IC50 was 895.5 +/- 24.1 microg/ml. The extract also exhibited low antioxidant activity in the linoleic acid model but were capable of scavenging hydrogen peroxide in a concentration dependent manner. Tested extract show moderate activity in H2O2 induced hemolysis in rat erythrocytes which was not comparable with vitamin C. CONCLUSIONS: F. gummosa Boiss root showed different level antioxidant and antihemolytic activities. Biological effects may be attributed, at least in part, to the presence of phenols and flavonoids in the extract. PMID- 21796871 TI - Anti-inflammatory and analgesic activities of Tunisian Citrullus colocynthis Schrad. immature fruit and seed organic extracts. AB - BACKGROUND AND OBJECTIVES: Inflammations and immune-related diseases including rheumatoid arthritis are widespread in the entire globe. The treatment of these illnesses is mainly based on the use of synthetic and biotechnological drugs, in recent years. Tunisian traditional medicine is a potential source of new remedies namely Citrullus colocynthis Schrad. (Cucurbitaceae): endemic in southern Tunisia and used in folk medicine to treat many inflammation disorders. Our goal was to assess the in vivo analgesic and anti-inflammatory activities of Tunisian Citrullus colocynthis immature fruit and seed organic extracts (petroleum ether, chloroform, ethyl acetate, acetone and finely methanol extract). MATERIAL AND METHODS: Yields of prepared organic extracts are gravimetrically determined. For the analgesic and anti-inflammatory activities, we have used respectively, the acetic acid writhing test in mice and the carrageenan-induced paw edema assay in rats. RESULTS AND DISCUSSION: All extracts displayed an important analgesic and anti-inflammatory activities at different doses without inducing any side effects. This study has demonstrated the analgesic and anti-inflammatory activities of Citrullus colocynthis immature fruit and seed extracts. Experiment results provide scientific insight into the ancient practice of utilizing Citrullus colocynthis Schrad. as analgesic and as anti-inflammatory agents. PMID- 21796872 TI - Synthesis, antiviral and cytotoxic investigation of 2-phenyl-3-substituted quinazolin-4(3H)-ones. AB - OBJECTIVES: A series of 3(benzylideneamino)-2-phenyl quinazoline-4(3H)-ones was synthesized by reaction of 3-amino-2-phenyl-3H-quinazoline-4-one with various carbonyl compounds. MATERIALS AND METHODS: Chemical structures of the synthesized compounds were confirmed by IR, 1H-NMR and mass spectral analysis. Title compounds were investigated for cytotoxicity and antiviral activity against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK-KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1 N1 subtype, influenza A H3N2 subtype, influenza B and vesicular stomatitis virus. RESULTS AND CONCLUSION: Compound 3d was found inhibit viral replication of para influenza-3virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus in Vero cell cultures. PMID- 21796873 TI - Mesotherapy, definition, rationale and clinical role: a consensus report from the Italian Society of Mesotherapy. AB - OBJECTIVE: Since its introduction in the 1950s, the use of mesotherapy has generated much interest among clinicians and patients. The Italian Society of Mesotherapy (SIM) brought together a panel of experts to review available evidence and to draw up a series of recommendations on the use of intradermal therapy (LIT) in clinical practice. CONSENSUS REPORT: There was overwhelming agreement among Consensus Group members that, when used correctly, LIT is a valuable therapeutic option in the treatment of painful, loco-regional conditions. They also emphasised that the clinical efficacy of LIT has been demonstrated in the management of chronic venous lymphatic insufficiency, oedematous fibrosclerotic panniculopathy and facial skin aging. The experts were unanimous on the use of LIT in vaccination. Mesotherapy is not a substitute for other therapeutic options and should only be used when the patient has been fully informed of its advantages and limitations. Likewise the procedure should only be carried out by an experienced qualified physician. CONCLUSIONS: Although there was widespread agreement among the Consensus Group on the place of LIT in several indications, the Authors reiterated the need for more large-scale clinical trials to determine the specific benefits and limitations in some areas of the application of intradermal therapy. PMID- 21796874 TI - Diagnostic and prognostic significance of high sensitive troponin in chest pain. AB - BACKGROUND AND OBJECTIVES: Chest pain is one of the most frequent presenting complaints among patients arriving to the Emergency Department. In this population, the prevalence of acute coronary syndrome is about 25% instead that of acute myocardial infarction ranges from 5 to 15%. The diagnostic challenge for the emergency physician is the early rule-in or rule out of acute myocardial infarction within first few hours after chest pain presentation, particularly in those patients with normal or not significant electrocardiogram. EVIDENCE AND INFORMATION SOURCES: The current review is based on an analysis of most important clinical trials on this topic. STATE OF THE ART: The universal current guidelines established that the term "myocardial infarction" should be used when there is evidence of myocardial necrosis of ischemic origin, as documented by an increase of myocardial necrosis markers. Actually, cardiac troponins are considered the standard biomarkers for acute myocardial infarction diagnosis, because are more superior in sensitivity and specificity to the other available markers. PERSPECTIVES: More recently, high sensitive troponin assays have been developed, permitting the early measurement of very low concentrations. CONCLUSION: In this review, we analyzed the diagnostic and prognostic significance of these new high sensitive troponins in Emergency Department chest pain management. PMID- 21796875 TI - A critical review of the efficacy and safety in the use of low-molecular-weight heparin in acute ST-elevation myocardial infarction: a Bayesan approach. AB - BACKGROUND: ST segment elevation myocardial infarction (STEMI) is an important risk factor of death worldwide. Significant clinical research has been done to assess ideal reperfusion strategies in the setting of STEMI, including the role of the antithrombin agents: unfractionated heparin (UFH) and low molecular weight heparin (LMWH). Given the evidence that LMWH may be safer than UFH in the treatment of other thrombotic disorders, its role in the management of STEMI needs to be more defined. OBJECTIVE: To assess the safety and efficacy of LMWH compared to UFH and/or placebo for the treatment of STEMI. MATERIALS AND METHODS: The Cochrane Library, MedLine and EMABASE databases were searched for randomized controlled trials pertinent to the study objective. Selection criteria included all randomized controlled trials comparing LMWH to either UFH or placebo in the treatment of STEMI through December 2010. Two Authors performed the search independently.After identifying appropriate studies, a random effect model and Bayesian sensitivity analysis were used to combine results from original trials and assess the consistency of results. RESULTS: We identified 13 studies that met the described selection criteria; 8 comparing LMWH to UFH and 5 to placebo in STEMI patients. The combined Odd's ratio was 0.79 with a 95% confidence interval of 0.67-0.94 for all studies and 0.74 (0.54-1.02) for those comparing LMWH to UFH only. A trend toward more frequent hemorrhagic events was identified in the LMWH group (Odd's ratio 1.40) which did not meet statistical significance (95% confidence interval 0.80-2.47). Sensitivity analysis demonstrated clinical benefits of 6% and 12.5% with probabilities of 99% and 95% respectively. CONCLUSION: Compared to placebo or UFH, LMWH is effective as a first line treatment of STEMI patient with no significant increase in major hemorrhagic events. PMID- 21796876 TI - Acute asthma in children: treatment in emergency. AB - BACKGROUND AND OBJECTIVE: Asthma is one of the most common chronic diseases, leading to an increased rate of hospitalization. MATERIAL AND METHODS: The aim of this report is to review the current concepts and treatment of asthmatic children, focusing our attention on the treatment of children in a Department of Pediatric Emergency. DISCUSSION: Frequent respiratory infections, personal or familial allergy, disease severity and young age are important factors leading to hospitalization. However, regular clinical follow-up and use of inhaled corticosteroids, the IgE levels and O2 saturation may reduce the probability of hospitalization during asthma attacks. The diagnosis of asthma in children is based on recognizing a characteristic pattern of episodic respiratory symptoms and signs, in the absence of an alternative explanation for them. The presence of these factors increases the probability that a child with respiratory symptoms will have asthma. These factors include age at presentation; sex; severity and frequency of previous wheezing episodes; coexistence of atopic disease; family history of atopy; and abnormal lung function. CONCLUSION: Asthma is a chronic condition that often remains uncontrolled for reasons that may be related to the disease process itself, the management decisions of clinicians, the patient's perceptions of disease control or self-management behaviors, the cost of medications, or a combination of all of these factors. To this end, patients with asthma should be educated not to accept a certain level of symptoms or activity limitations as an inevitable consequence of asthma. Both the levels of current impairment and the future risks (of asthma exacerbations or adverse medication effects) should be used to inform decisions about appropriate levels of asthma therapy, and physicians should be aware of the new medication recommendations. PMID- 21796877 TI - Spontaneous closure of bilateral full thickness macular holes without surgery: an eleven-year follow-up. AB - PURPOSE AND METHOD: To present a 60-year-old woman affected by bilateral full thickness macular hole, showing without surgery a spontaneous resolution of the disease in both eyes that remains unchanged during an eleven-year follow-up. To our knowledge, this clinical case is uncommon as no similar reports with such a long follow-up have been published in the scientific literature at this time. RESULTS AND CONCLUSIONS: A spontaneous and bilateral closure of full thickness macular holes was detected, as a consequence of a complete posterior vitreous detachment documented by optical coherence tomography images. An initial reduction up to a complete resolution of the central macular scotoma was also observed by performing scanning laser ophthalmoscope microperimetry. Both these anatomical and functional results did not change during the whole period of follow-up. According to this study, the release or the weakening of the vitreous tractions at the foveal edges seems to play a key role in the spontaneous resolution of macular holes in not surgically treated patients. PMID- 21796878 TI - ECHO and magnetic resonance imaging in a patient with high bleeding risk and ventricular perforation: a case report and literature review. AB - Myocardial perforation is a complication following pacemaker implantation that may cause cardiac tamponade. We present an original case of myocardial lead perforation not complicated by acute cardiac tamponade. The patient with an acute myocardial infarct had a high bleeding risk both in the acute phase of lead insertion (anticoagulant and triple platelet anti-aggregation therapy) and after few days, the percutaneous extraction lead for the double platelet antiaggregant therapy. Torrent-Guasp's theory is considered for explaining the clinical course of patient. Echocardiography and magnetic resonance imaging (MRI) evaluation showed a diffuse pericardial non-hemorrhagic fibrinous effusion and guide the clinical management. PMID- 21796879 TI - Long-term cancer survivorship: a new challenge that requires a new follow-up approach. PMID- 21796880 TI - Survival of occult practices and ideas in modern common sense. AB - For a long time rationalism and materialism were the most important ideological undercurrents of the Western world. Since the Enlightenment, in the eighteenth century, they have influenced the Age of Reason. During the past few decades, the so-called New Age originated strong counter-movements have produced a huge number of different new world-views. They are to be considered as part of the wide field of occultism, and run out in different directions. The belief in angels and in the power of fate, the communication with the dead, and the conviction of a life after death are all expressions of a desire to transcend and of a search for higher powers that watch over each person. Additionally, helpers and healers have created a marketplace to promote esoteric services. Media usage, the need to transcend and this new market interested in the magical signal a new era of consciousness in which reason and technology do not contradict mysticism and the transmission of wisdom: these go, instead, hand in hand. PMID- 21796881 TI - Popular press and forensic genetics in Portugal: expectations and disappointments regarding two cases of missing children. AB - Two cases of missing children in Portugal (Joana and Maddie) have recently highlighted the dilemmas and contingencies associated with the technology of "genetic fingerprinting" for forensic purposes in the context of criminal investigations. The purpose of this article is to analyze the popular press's discourses and representations around forensic genetics in the context of those two highly mediatized criminal investigation cases. The symbolical construction and representation of forensic genetics by the media presents a form of public exposure to beliefs on forensic genetics' characteristics and potential. These are blended with popular cultural contexts that are constructed with reference to images of a super-science which may carry consequences in the public understanding of forensic science. The media coverage of both cases and their actual disclosure resembles the patterns ofa CSI effect, insofar as real science's capabilities and limitations are placed against fictionalized representations of forensic science. PMID- 21796882 TI - Gendered contexts: masculinity, knowledge, and attitudes toward biotechnology. AB - Research into the public understanding of science has revealed that the effect of scientific knowledge on attitudes toward science is contextualized by gender; however there has not yet been an account of how gender contextualizes knowledge. This paper investigates how gender identification affects attitudes toward science, and tempers the effects of scientific knowledge on attitudes toward science. Utilizing data from the Eurobarometer 52.1, it is predicted that when males perceive a threat to their masculinity (as measured by a perceived threat to their financial security) they will become more likely to be aversive to biotechnology, and that increased levels of perceived threat will reduce the effects of knowledge on attitudes toward biotechnology. Moreover, it is predicted that these effects will be smaller than their female counterparts. All predictions are affirmed. PMID- 21796883 TI - Understanding the impact of commercialization on public support for scientific research: is it about the funding source or the organization conducting the research. AB - This research examines the influence of commercialization on support for scientific research. It compares the effects of the funding source with the type of organization on public support for stem cell research. Using a national Australian telephone survey (n = 1000), the results reveal that support drops significantly when scientific research is funded by private rather than public interests, and even more so when it is conducted in a private company rather than a public university. Respondents' preference for university research was enhanced if they trusted universities, distrusted major companies and believed that the research would be beneficial. A preference for public funding was also associated with lower trust in companies and a belief that the research would benefit people. Implications of these results are discussed in relation to the challenge of maintaining public support in an increasingly commercialized research environment. PMID- 21796884 TI - Articulating the signs of danger: lay experiences of post-Chernobyl radiation risks and effects. AB - This essay examines lay experiences of radiation--the hazard imperceptible with unaided senses--and how these experiences are shaped. Analysis is conducted on the basis of participant observation and interviews in Belarusian rural areas affected after the 1986 Chernobyl nuclear accident. I argue that radiation risks and health effects are not always obvious or immediately observable for those experiencing them, and they should be articulated. The paper compares various opportunities for articulation, including the context of radiological testing and administrative contexts, and describes the kinds of articulations they make possible. I conclude that limited opportunities for articulation result in limited lay recognition of radioactive contamination and their own health effects. The analysis implies that affected lay populations cannot always be assumed to be the most risk-conscious and hold special knowledge about radiation effects independently of scientific and administrative definitions of it. PMID- 21796885 TI - Climate change, flooding and the media in Britain. AB - The weather is a preoccupation of the British public, and flooding has become a salient feature of their experience. Climate science also has important things to say about the prevalence, distribution and dangers of rainfall and flooding, and what we should expect from global warming. This paper looks at British press coverage of flooding, and at the connections made between this theme and climate change. It aims to expose longitudinal patterning, and assess how common the connection is. From here the analysis moves to specific cases of high profile flooding events for a detailed exploration of the tone and tenor, and discursive contours of reports. The results suggest the media's contribution to genuine debate is mixed, that the connection between common forms of reportage and our scientific understanding of the phenomena is often tenuous. The paper explores the implications for the way the politics of climate change plays out. PMID- 21796886 TI - Interstitial lung disease in the elderly: pathogenesis, diagnosis and management. AB - Advancing age is associated with increased risk for some forms of interstitial lung disease (ILD), and this risk is especially reflected by the considerably increased incidence of idiopathic pulmonary fibrosis (IPF) in the elderly. Although the causes of this increased risk are not well-defined, both ageing and IPF have been associated with shortening of telomeres due to telomerase deficiency. Thoracic imaging with high-resolution computed tomographic (HRCT) scanning plays a key role in the diagnosis of ILD in the elderly, and a characteristic appearance of the lung parenchymal changes on HRCT may provide a confident diagnosis and obviate the need for invasive testing such as surgical lung biopsy. An effective treatment for IPF remains elusive, but many patients will benefit from supportive care and treatment of various co-morbid conditions that are often found in patients with IPF. PMID- 21796887 TI - The investigation of HLA microsatellites influence in predisposition to sarcoidosis among Croatians. AB - The aim of the present study was to analyze the distribution of HLA alleles (A, B, DRB1, DQB1) and HLA microsatellite alleles (TNFa, TNFb, TNFd, D6S273, D6S1014) in the Croatian patients with acute (N=93), as well as chronic sarcoidosis (N=40), in comparison to healthy controls (N=177), and investigate whether the polymorphism within the HLA region could be associated with different forms of sarcoidosis. Genomic DNA was isolated from peripheral blood. Patients were analyzed for HLA class I loci (A, B) by serology, while PCR-SSP method was used for HLA class II loci (DRB1, DQB1). Five HLA microsatellites were analyzed by PCR and electrophoresis in an automated sequencer. No significant deviation in the distribution of frequencies at HLA class I alleles was observed between the two patients' subgroups and controls. Regarding the HLA class II alleles, a statistically significant increase in frequency of HLA-DRB1*03 and DQB1*0201 allele was found among patients with acute sarcoidosis in comparison to controls as well as in comparison to patients with chronic sarcoidosis. The same finding was observed for HLA-DRB1*03/DQB1*0201 haplotype (Pcorr=0.0168; OR=2.83). In the group of patients with chronic sarcoidosis DRB1*11 (P=0.0219; OR=2.44), DRB1*15 (P=0.0414; OR=2.47) demonstrated statistically significant difference in comparison to controls only, while a lower frequency of DRB1*13 (P=0.0156; OR=0.24) in this group was statistically significant when compared to both patients with acute sarcoidosis and controls. None of the alleles at TNFa microsatellite showed significant difference in distribution among both subgroups of patients and controls. Significant difference between patients with acute form of disease and controls was found for the following alleles: TNFd-2 (Pcorr=0.00007; OR=4.89), D6S273-7 (Pcorr=0.0213; OR=2.96), and D6S1014-7 (Pcorr=0.0028; OR=3.97). On the other hand, patients with chronic sarcoidosis differed from control subjects for D6S1014-8 (Pcorr=0.0296; OR=8.35) allele. This study suggests the existence of an association of non-HLA markers with sarcoidosis and the involvement of the region between HLA-DQB1 and D6S273 loci in its pathophysiology. PMID- 21796888 TI - Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. AB - OBJECTIVE: The aim of this study was to investigate the relationship between SP-D and KL-6 serum concentrations and the extent of interstitial lung involvement, as measured by a quantitative HRCT score and the functional impairment, in patients with systemic sclerosis (SSc). Moreover we analysed the association between these lung-specific biomarkers and skin involvement, anti-Scl-70 antibody titres and an index of disease activity. METHODS: Serum SP-D, KL-6 and anti-Scl-70 concentrations were determined by ELISA in 25 SSc patients. Disease activity and lung function parameters were assessed, and the extent of ILD was measured by a HRCT score. RESULTS: SP-D and KL-6 concentrations were higher in patients with SSc and lung fibrosis than in healthy controls. KL-6 correlated positively with the HRCT-fibrosis score (r=0.68, p<0.001), SP-D showed a weaker correlation (r=0.44, p=0.025). Increased KL-6 concentrations were associated with decreased DLCO and decreased FVC in SSc patients, SP-D showed no association. Furthermore KL-6, but not SP-D, showed a strong association with skin involvement as expressed by the modified Rodnan skin score (r=0.71, p<0.0001) and a disease activity index (r=0.73, p<0.0001). CONCLUSION: KL-6 is more strongly associated than SP-D with the HRCT-fibrosis score, and, different from SP-D, it correlates with skin involvement and disease activity. We suggest that KL-6 may be a useful biomarker in the assessment of scleroderma patients. PMID- 21796889 TI - Factor analysis of sarcoidosis phenotypes at two referral centers in Brazil. AB - BACKGROUND: In sarcoidosis, clinical presentations and outcomes vary widely. OBJECTIVE: To characterize the clinical phenotypes of sarcoidosis, by factor analysis, in a series of cases with long-term follow-up. METHODS: We conducted a retrospective study involving 137 patients with biopsy-confirmed sarcoidosis, recruited from two referral centers in Sao Paulo, Brazil. Organ involvement was evaluated in accordance with a previously established protocol. Sarcoidosis phenotypes were characterized by factor analysis. RESULTS: Follow-up ranged from 6 to 144 months. Four factors (phenotypes) were identified: relevant residual pulmonary fibrosis; relapse; residual airflow limitation; and acute disease. The four factors collectively accounted for 66% of the total variance. Patients with relevant residual pulmonary fibrosis were older and presented with the following: greater symptom duration; skin involvement; low forced vital capacity; low forced expiratory volume in one second/forced vital capacity ratio; and more advanced radiographic stages at baseline. The relapse phenotype was associated with chronic disease, greater dyspnea severity, neurologic involvement, and cardiac involvement. Patients with residual airflow limitation more often had airflow obstruction at baseline, chronic disease, and relevant residual pulmonary fibrosis. Acute disease was associated with being younger, weight loss, scoring lower for dyspnea, and having extensive involvement. Abnormal calcium metabolism was associated with acute disease and with relapse. CONCLUSIONS: Sarcoidosis can be categorized into four different clinical phenotypes: three that are chronic; and one that is acute and self-limiting. In many cases, these phenotypes can be easily recognized. PMID- 21796890 TI - Non-caseating granulomas in patients after the diagnosis of cancer: clinical characteristics and outcome. AB - BACKGROUND: The association between cancer and non-caseating granulomas is controversial. The aim of this study is to describe the clinical characteristics and outcome of a cohort of patients found to have non-caseating granulomas following the diagnosis of cancer. METHODS: Retrospective review of medical records. RESULTS: There were 30 patients with non-caseating granulomas following the diagnosis of cancer. There were 21 females and 14 patients were African Americans. Breast, lung, and head and neck cancers were the most common malignancies. The time between the diagnosis of cancer and non-caseating granulomas was a mean of 27.6 months (range 3 to 245 months). New mediastinal lymphadenopathy were present in 29 patients and pulmonary infiltrates or nodules were detected in 15 patients. All patients who underwent FDG-PET scan (n=18) had FDG avid findings with a mean SUV of 6.8 (range 2.8-19.4). Non-caseating granulomas were diagnosed by mediastinoscopy (12 patients), EBUS-FNA (6 patients), surgical thoracic biopsy (3 patients), transbronchial biopsy (2 patients), and other biopsies (7 patients). Patients were followed for a mean of 32.7 months (range 6-98 months) and 3 patients developed recurrence of the primary cancer. CONCLUSION: Non-caseating granulomas should be considered in patients with cancer who develop lymphadenopathy or pulmonary nodules. Recurrence of cancer should not always be assumed, and tissue diagnosis is essential. PMID- 21796891 TI - Metabolism-perfusion imaging to predict disease activity in cardiac sarcoidosis. AB - FDG-PET is a sensitive but not specific test for myocardial sarcoidosis and its ability to define prognosis remains unclear. Combination with perfusion scanning may improve accuracy by differentiating scar from inflammation. We conducted this retrospective chart review to ascertain the utility of a rubidium -FDG PET scan for assessment of disease activity in patients with cardiac sarcoidosis. The presence of any perfusion-metabolism mismatch or a mismatch of > 6% of the myocardium on the scan were compared with the clinical course. Among 18 subjects, mismatched segments were present in 11 scans, whereas 7 demonstrated mismatch > 6%. There was a suggestion of association between PET scan and active disease using the threshold of any mismatch (p=0.09), with sensitivity of 80% and specificity of 62.5%. The threshold of >6% mismatch improved the specificity to 100% with 70% sensitivity, and the association between PET findings and clinically active disease was highly significant (p=0.0002). Eight patients had follow-up Rb-FDG PET scans, all of which were concordant with the clinical course. The positive predictive value of Rb-FDG PET scan showing >6% mismatch for detecting clinically active cardiac sarcoidosis was 100%. However, the finding of any mismatch still portends a high chance of clinical activity. Further studies to define the utility of Rb-FDG PET scan for management of cardiac sarcoidosis are warranted. PMID- 21796892 TI - Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force. AB - The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis. PMID- 21796893 TI - Type D or 'distressed' personality in sarcoidosis and idiopathic pulmonary fibrosis. AB - BACKGROUND: Personality factors have shown to be related to mortality, morbidity, and psychological aspects in chronic disorders. Little is known about the effect of personality on disease severity in sarcoidosis and idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the prevalence of Type D personality and its relation with relevant clinical characteristics in sarcoidosis and IPF patients. METHODS: The study included 441 sarcoidosis and 49 IPF patients from the outpatient clinic of the ild care team of the MUMC, the Netherlands. They completed the DS14 (Type D questionnaire), the fatigue assessment scale (FAS), the WHO quality of life-BREF (WHOQOL-BREF) and the Centre for Epidemiological Studies-Depression Scale (CES-D). Moreover, relevant clinical data were collected. The control group consisted of 3678 subjects from a general population. RESULTS: Type D personality was found in 25.6% of the sarcoidosis patients compared to 21% in the controls, but only in 18.8% of the IPF patients. No relation with disease severity was found in either of these disorders. Fatigue was a substantial problem in both populations. Depressive symptoms but not Type D personality predicted fatigue and poorer QOL in sarcoidosis and IPF. CONCLUSION: Prevalence of Type D personality is not higher in sarcoidosis and IPF patients than in the general population and does not explain QOL impairment. Depressive symptoms explain QOL impairment and fatigue substantially. Therefore, in the multidisciplinary management of sarcoidosis and IPF psychological screening and psychological counselling concerning adequate coping strategies should be incorporated. PMID- 21796894 TI - An isolated hand tumour as primary manifestation of sarcoidosis. AB - BACKGROUND: Sarcoidosis is a systemic disorder with unknown etiology, characterized by non-caseating granulomas in numerous organs and tissues. In 90% of patients lung and lymph nodes are involved. The incidence of sarcoidal granulomas in the upper extremities is low. Here we present the case of a primary hand manifestation of sarcoidosis without clinical systemic involvement. OBJECTIVES: A young woman presented with a painful swelling in her right hand. There were no signs of inflammation. Normal perfusion, mobility and sensibility were found. Magnetic resonance imaging (MRI) revealed a tumour infiltrating the muscles and flexor tendons of the third digit around the metacarpal bone and with pathological signal enhancement after administration of contrast medium. RESULTS: Intraoperatively, nodular masses and fat tissue were seen. Histological examination after radical tumour resection showed sarcoidal granulomas. Postoperative staging diagnostics with computed tomography (CT) demonstrated multiple thoracic lymph node swellings in the mediastinum and bilateral hill. Follow-up after one year we saw normal scars in the palmar hand. There was no sign of local recurrence. The pulmological care is still going on. CONCLUSIONS: Sarcoidosis is a rare, often asymptomatic disease. Patients present with dyspnoe and cough caused by the inflammation of the lung. The first clinical manifestation of sarcoidosis as a tumor in the palmar hand is unusual. Extrapulmonary systemic or progressive sarcoidosis is regarded as an indication for therapy with glucocorticosteroids. This case demonstrates that surgical excision enabled complete local cure without necessity of systemic and/or local treatment with steroids. PMID- 21796895 TI - Rapid improvement of osseous sarcoidosis after the treatment of pulmonary aspergillosis by itraconazole. AB - Osseous sarcoidosis is relatively uncommon, and treatment with corticosteroids is not always effective. Moreover, patients with an advanced stage of pulmonary sarcoidosis are sometimes infected with aspergillus in the cavities of the pulmonary lesions, and long-term use of corticosteroids should be prohibited to prevent the development of fatal invasive pulmonary aspergillosis. Here, we described a unique case of osseous sarcoidosis with pulmonary aspergillosis, showing a rapid improvement of the osseous symptoms just after the administration of the antifungal agent, itraconazole. Itraconazole is likely to become a candidate among new therapeutic agents for osseous sarcoidosis. PMID- 21796896 TI - Another "chance" for interferon gamma 1b? PMID- 21796897 TI - [Judging reliably. Medical authority and the ability to discriminate between the clean and the unclean]. AB - The article aims to explore the physicians' role at the Nuremberg "Sondersiechenalmosen" in the 15th and 16th centuries. Special attention is given to the question as to how the city's physicians, who claimed expert status superior to other healers and who had special authority to advise the authorities in keeping the city clean and healthy, declared and explained their problems in connection with the "examen leprosorum" on the occasion of the "Sondersiechenschau". From 1394 the city had opened its gates for three days in Holy Week leading up to Easter to offer clerical assistance, food and shelter to foreign lepers. This meant that people were cared for who would not usually have been admitted because they were foreigners as well as being leprous. The physicians' task within that charity was to discriminate between the leprous and foreign beggars, a task which caused serious problems when, in the 16th century, at times two thousand and more foreigners entered the imperial city during Holy Week. When, in 1571, the Nuremberg physician Kammermeister proposed to establish a "Collegium Medicum" in the city of Nuremberg, he described the procedure extensively. The authorities ignored the initial claim to establish a "Collegium Medicum" but requested each academically trained physician of the city to give a personal statement on the physicians' ability to seriously judge the foreigners who claimed to be leprous. Based primarily on these statements, the article hopes to shed some light on the Nuremberg "Sondersiechenalmosen", on the "examen leprosorum", and on the relation between medical judgement and medical authority in general. PMID- 21796898 TI - [Consumption--sickness, health and morals in the early nineteenth century]. AB - At the start of the nineteenth century consumption, also called "phthysis", was one of the most dreaded illnesses along with cancer. The term usually referred to the widespread "pulmonary consumption". Metaphorical descriptions of the disease demonstrate the strong cultural significance attached to this medical, and also lay-medical, concept. Based on handwritten case histories and letters from Kaiserswerth deaconesses in the first half of the nineteenth century the author establishes the cultural implications with which sufferers met in the social practice. Consumption was seen as the visible manifestation of deviance. It was assumed that sufferers were also to blame for contracting the disease due to a lifestyle that was "excessive" in dietetic as well as Christian terms. The paper aims to analyze how the attribution of an "immoral" and "sinful" lifestyle was presented to sufferers by physicians and nurses and how this affected them. The attribution of moral implications to dietetic concepts--as the first thesis of the paper will suggest--originated from demographically motivated health policies prevalent around 1800. The paper will further try to show how, in the early nineteenth century, the idea arose that consumption was the disease of the proletariat suffering from metropolitan life. PMID- 21796899 TI - [The importance of Jewish nursing in World War I as shown by the example of the Jewish nurses' home in Stuttgart]. AB - The history of Jewish nursing in World War I has so far not been central to medical history research. Rosa Bendit's war diary is still the only source available on the voluntary service Jewish nurses provided during World War I. Their number was small compared to that of nurses in general. Jewish nursing in Germany has hardly been researched. Jewish nurses, like their Christian colleagues, took on wartime nursing tasks voluntarily. This paper will focus on the experiences of the nurses who were sent to various locations in East and West by the Stuttgart Jewish Nurses' Home. Based on quotations from the war diary their position within the medical service will be described, compared and analyzed. The paper draws attention to special characteristics in the comparison ofJewish and Christian nurses and explores issues such as religious observance, religious discrimination, patriotism and differences in the evaluation of the nurses' work. A brief outline of the history of the Stuttgart Jewish Nurses' Home illustrates their working conditions. The Jewish nurses applied themselves with as much effort and devotion as their Christian counterparts. Although there were only few of them, the Jewish nurses managed to establish a recognized position for themselves within the medical service. The history of Jewish nursing in Stuttgart ended in 1941 when the Jewish Nurses' Home was dissolved by the Nazis and four nurses were murdered in concentration camps. PMID- 21796900 TI - [A historical perspective on the health of boys and male adolescents (1780 2010)]. AB - In the discourse on health, boys are emerging as a problem group. In contrast to girls who tended to be seen as fragile if not sickly, boys used to be thought of as strong and healthy. Gender-specific concepts stipulated much more exercise for boys, the masturbation discourse prevented a relaxed relationship to the own body. The paper first describes specific problems in the biography (babies, child labour, tuberculosis, school, fitness for military service) and their solutions up to the time of the Weimar Republic. During and after the two world wars school boys tended to be of poorer health than girls. The consequences of war affect the mental health of (half-) orphans gender-non-specifically up to the third generation. After 1945, attention to health concerns is rather restricted to the professional aptitude of mining trainees, health-related risk behaviour tends to be interpreted in terms of gender. Mothers sought medical advice slightly more frequently on behalf of boys up to puberty. Concerning the time between 1780 and 2010 inferior health is often noticeable in boys and male adolescents. This used to, and still does, apply to babies, child labour, industrial work and occupational accidents, conscription and direct consequences of war. It was mostly due to gender-specific separation of labour, but partly also to a higher risk preference. The gender-specific wider scope for exercise and sports up to the 1960s, in contrast, had a health-promoting effect. PMID- 21796901 TI - [The history of ageing in modern times according to current German research]. AB - Historical research into ageing has gained importance since the end of the last century. While in the past ageing used to be mostly the object of historical demographics and historical family research, a number of branches within historical science are now interested in the topic. So far, research has focused on various pension systems, on demographic changes and old age poverty. Other points of interest are the care within or outside of the family and the resulting life conditions, for example in the "sick houses" (Siechenhauser). The construction of age-related images also plays an important part. Medical discourses on the various concepts of age also represent a wide field of historical research. PMID- 21796902 TI - [Samuel Hahnemann and the principle of similars]. AB - The principle of similars (treat likes by likes) is generally considered to be one of the pillars of the homeopathic doctrine established by Samuel Hahnemann (1755-1843). Nevertheless, its status and relevance with regard to the practice of homeopathy can be challenged by semantic, conceptual, and epistemological objections. 1. Contrary to its literal meaning, "similia similibus curentur" is commonly used in the sense of "all diseases should be treated by similar drug diseases", thus transgressing its original field of indication. 2. From 1796, when Hahnemann published his first definition of the principle of similars, he gradually raised his claims from merely suggesting a heuristic principle for finding new curative remedies to insisting on having discovered a law of nature and the only true way of healing, in 1807/1808. To substantiate his ambitious tenets, Hahnemann had to introduce a variety of theories which in turn were to become the main battleground in the ensuing controversy about homeopathy. 3. From the perspective of epistemology of science, science can never consist of a final set of absolute truths or the like but must rather be described as a continuous social process that retains a methodological cycle of abduction, deduction, and induction. From the perspective of theory of medicine, however, medicine is to be considered as a practical rather than a cognitive science in its own right. Its first concern ought to be the development of practical directions for treating patients, while the value of competing theories can only be judged from their usefulness in practice. Hence, even though Hahnemann's theories, including his conception of the principle of similars, may be untenable or outdated, the genuine method of homeopathic treatment he founded remains independent of and unaffected by criticism at the level of theory and concepts. PMID- 21796903 TI - ["At times I had to be an allopathic medical officer and then again I was allowed to be a homoeopathic physician." Homoeopathy and war from the Franco-German War (1870/71) to World War I (1914-1918)]. AB - With its focus on the Franco-German War and World War I the present paper constitutes a first approach to the comprehensive topic of "homoeopathy and war". Sources used include articles from homoeopathic magazines, homoeopathic specialist literature, material from the estate of the homoeopathic lay organization "Hahnemannia" and individual testimonies from non-homoeopaths. The paper begins by examining the importance of the two wars for research into the history of homoeopathy compared to previous conflicts and demonstrates the value of the sources used. A brief outline of homoeopathy and the military forces in the decades before 1870 provides insight into the historical context. This is followed by the investigation of homoeopathic war hospitals at home with an analysis of the attitude of the homoeopathic physicians and lay-healers involved. The paper also describes the difficult relationship between homoeopathy and conventional medicine during the two conflicts. PMID- 21796904 TI - ["And thus there was another pointless thing in the country [...]". The failed homoeopathic training of missionaries at the Basle Mission]. AB - This article deals with the unsuccessful attempts to allow missionaries of the Basle Mission to undergo homoeopathic training. Before the Mission undertook systematic medical missionary work in society in the 1880s, there were various requests and suggestions to train the missionaries in homoeopathy. Here, these attempts are put into a greater context of the research into "Homoeopathy and Mission". It becomes clear that Hahnemann's teachings were certainly used in the Mission, even if finding this out is sometimes arduous. PMID- 21796905 TI - Potency and provenance: an inter-generational study of homeopathic practice in Ontario. PMID- 21796906 TI - Integrating information communication and technology (ICT) in health care. PMID- 21796908 TI - Health information exchange between clinicians and people living with HIV/AIDS on anti retroviral therapy at public health hospitals in Addis Ababa. AB - BACKGROUND: Good quality of clinician-patient health information exchange promotes diagnostic accuracy, patient's knowledge and understanding, health outcomes, clinician and patient satisfaction, adherence to treatment plan, patient's trust in clinicians and reduces medical error. OBJECTIVE: The main objective of this study is to assess health information exchange between clinicians and people living with HIV/AIDS (PLWHA) attending ARTclinics at public hospitals in Addis Ababa. METHODS: A cross-sectional survey was conducted in antiretroviral therapy (ART) clinics of seven public hospitals in Addis Ababa, Ethiopia; during one month period between April and May, 2009. Four hundred ART clients aged 18 years and above in the seven hospitals and 20 clinicians involved in the care of patients constitute the study subjects. Data on patients were collected by an interviewer administered structured Amharic questionnaire. Their perception of the clinical communication was assessed by using a 20 item measure with five point response scale (5=excellent, 4=very good. 3=good, 2=fair and 1=poor). Data on clinicians was collected by a self administered questionnaire. Clinicians' attitude towards information provision was assessed by using a 9 item measure. RESULTS: The mean (SD) scores of patients'perceptions of the communication they had with clinicians during their encounter was 77.1% (14.1%) with median 78.0. ranging from 39 to 100%. Three hundred seventy one (92.8%) study participants reported that they comprehend information that have been provided during their encounter with clinicians while 5 (1.3%) were uncertain of their understanding of the information delivered to them. Likewise 339 (84.8%)) patients have claimed to be satisfied with the information exchange process. CONCLUSION: Current status of relationship building and sharing information in public hospitals in Addis Ababa were rated high by patients on ART We recommend that training institutions and other responsible bodies should work to enhance communication skills of clinicians and all healthcare providers in general, during basic training and/or continuous training programs. PMID- 21796907 TI - The immunological status of newly diagnosed tuberculosis patients co-infected with human immunodeficiency virus-1 in Adama Hospital, Ethiopia. AB - BACKGROUND: Tuberculosis remains a public health problem in patients with human immunodeficiency virus infection in sub-Saharan Africa. Both diseases form a lethal combination, each speeding the progress of the other. OBJECTIVE: The aim of this study was to assess the prevalence of HIV infection in newly diagnosed tuberculosis patients in Adama hospital. METHODS: Blood and sputum samples were collected from adult newly diagnosed tuberculosis patients. Sera were screened for anti-HIV antibody using rapid HIV test kits based on the National testing algorithm. The CD4 and CD8 T-cell subsets were determined using flow cytometry and the ratio of CD4+ and CD8+ were estimated using FACScan. All sputum specimens collected on three consecutive days from patients attending the tuberculosis clinic were screened for acid fast bacilli using smear microscopy. RESULTS: The seroprevalence of HIV among 258 patients with newly diagnosed TB was 26.4%. The median CD4 T cell count of HIV negative and HIV positive TB patients were 702 cells/mm3 and 233 cells/mm3. respectively (P < 0.05). Of the TB patients, 35.7% had extrapulmonary TB and 20% were smear-positive pulmonary TB. The CD4/CD8 ratio in HIV negative patients was 1.33 cells/mm3 compared to the 0.29 cells/mm3 in HIV positive patients. Of the 68 HIV positive TB patients. 58(85.3%) were not aware of their HIV serostatus prior to the screening in the current study. CONCLUSION: In the current study the HIV seroprevalence was 26.4%. The median CD4 count was very low in the TB/HIV co-infected individuals than those infected with TB alone. Majority of the HIV infected individuals were not aware of their serostatus. Provider initiated HIV/AIDS counseling and testing in TB clinics should be strengthened PMID- 21796909 TI - Sexual and reproductive health status and related problems of young people with disabilities in selected associations of people with disability, Addis Ababa, Ethiopia. AB - BACKGROUND: Young people in Ethiopia face many sexual and reproductive health problems. In particular young people with disability are among the most stigmatized, poorest, and least educated. To date, very little is known about the sexuality of disabled youth, in general the reproductive health need and related problems of this group. OBJECTIVE: The aim of this study is to assess the sexual reproductive health status and associated problems of young people with disability at selected associations of people with disability in Addis Ababa. METHOD: A cross-sectional survey was conducted from Feb 11-17, 2008 to assess disabled youth reproductive health status and related problems. Data were collected by trained interviewers using a structured questionnaire and two complementary focus group discussions were also conducted guided by semi structured questions. A total of 384 young people with disability were selected using systematic sampling technique. The sociodemographic and the sexual reproductive health characteristics of the respondents were described and appropriate statistical methods including chi-square test, crude and adjusted odds ratio were used to make comparisons RESULT: A total 174 (45.3%) of respondents in the study ever had sexual intercourse; out of which 100 (57.5%) and 74 (42.5%) were males and females respectively. Seventy three (42.0%) started sex between the age of 15-19 years and only 9.2% were married Only 45.4% of the sexually experienced respondents had used some kind of contraceptive during their first sexual encounter. The prevalence of unintended pregnancy was 62.5% among young disabled females who had ever been pregnant and 50% of them had history of abortion, 87.5% of this abortion was induced type. In this study, 58.6% of the sexually active respondents had multiple life time sexual partners, 20.7% had a casual sex partner and 18.0% of sexually active males had a commercial sex partner in the past 12 months period prior to the survey. The prevalence of history of ever having STI was 25.3% Only 55.5%, 33.1% and 51.8% of respondents had good knowledge on HIV transmission, STI Sign and symptom, HIV Prevention respectively and only 33.3% of respondents had utilized reproductive health services. Adjusting for socio-demographic variables, respondents' educational status, occupation, sex and forms of disability were found to have a significant association with modern contraceptive use (P < 0.05). CONCLUSION & RECOMMENDATIONS: Young People with Disability (YPWD) are at great risk for sexual and reproductive health associated problems. Female young people with disability and the illiterate are the most disadvantaged Awareness of parents, family members and the community about the needs and the capabilities of YPWD should improve and they should work together with the government to provide a safe environment for YPWDs. Organizing programs focused on acquisition of essential skills (communication and negotiation skills) and provision of appropriate for YPWD sexual and reproductive health services deserve due emphasis. PMID- 21796910 TI - Association of dyspepsia symptoms and Helicobacter pylori infections in private higher clinic, Addis Ababa, Ethiopia. AB - BACKGROUND: The discovery of Helicobacter pylori [H. pylori] by Marshall and Warren revealed that, this organism has been implicated as the main etiological agent in the development of acute and chronic active gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue [MALT] lymphoma in humans. Recent estimates suggest that 50% of the world's population is infected with this gastric bacterium. Dyspepsia is a complex set of symptoms, rather than an indication of a specific disease entity and many causes of dyspepsia exist including Helicobacter pylori infections. OBJECTIVE: This study was initiated to determine the association of dyspepsia symptoms and H. pylori infections. DESIGN: A Case control study was conducted to determine the association of dyspepsia symptoms and H. pylori infections using non-invasive tests [Helicobacter pylori stool antigen and Helicobacter pylori rapid antibody] at Noble Higher Clinic, Addis Ababa. Ethiopia, between April 2009 and June 2009. METHODS: A total of 238 informed and consented adult outpatients [n=119 dyspeptic patients and n=119 asymptomatic controls] were investigated for H. pylori infections by Helicobacter pylori stool antigen and Helicobacter pylori rapid antibody tests. RESULTS: The prevalence of H. pylori infection was found in 53% [63/119] dyspeptic patients and 39%[46/119] asymptomatic controls. odds ratio[OR: 1.785:95%, CI, 1.066 to 2.989]. In the asymptomatic controls, the prevalence of H. pylori infection was peak at the age group of 38-45 yrs [61%], followed by 54-61 yrs [60%]. In the dyspeptic patients, the peak prevalence of H. pylori infection was at the age group of 54-61 yrs [75%], followed by 30-37 yrs [72%]. CONCLUSION: There is a statistically significant difference between dyspeptic and non-dyspeptic participant by HpSA test. This demonstrates that H. pylori infection is associated with dyspepsia in this study, even if the causes of dyspepsia were not assessed by the study. Although, this 53 percent prevalence of H. pylori infection in dyspeptic patients seems lower than the previous hospital based studies, further study need to be conducted in the primary health care setup. PMID- 21796911 TI - Bacteriology of ocular infections and antibiotic susceptibility pattern in Gondar University Hospital, north west Ethiopia. AB - BACKGROUND: Ocular infection is a major public health problem particularly in developing countries like Ethiopia. OBJECTIVE: This retrospective study was conducted to identify the causative agents of ocular infection and susceptibility pattern to the commonly prescribed antibiotics in the locality. METHODS: The study was conducted at the University of Gondar Teaching Hospital from September 2004 to August 2008. Culture and antibiotic susceptibility test results of patients who had eye infections were taken for analysis. Eye swab specimens were processed for bacterial culture according the standard procedures. Antimicrobial susceptibility test for isolated organisms was done using Agar disk diffusion method. The data were entered and analyzed using SPSS soft ware version 13 package. RESULTS: Among the 236 eye swabs cultured, 54.2% were positive for different types of bacterial pathogens. Gram negative bacteria accounted for 44.5% and the predominant isolate was E. coli (14.8%). The Gram positive bacteria comprised 55.5% and the predominant isolate was S. aureus (21.1%). Multiple antibiotic resistances were observed in 77.3% of bacterial isolates to the commonly prescribed antibiotics. CONCLUSION: The magnitude of bacterial eye infections in the area was high. Most isolates were resistant to the commonly used antibiotics. We recommend that the findings from this retrospective data will be useful for the selection of effective antibiotics and calls for detailed further study. PMID- 21796912 TI - Throat carriage rate and antimicrobial susceptibility pattern of group A Streptococci (GAS) in healthy Ethiopian school children. AB - BACKGROUND: Group A Streptococci (GAS) or Streptococcus pyogenes are the most frequent cause of pharyngitis and skin infection in children and lead to post infection complications including acute rheumatic fever and glomerulonephritis. Pharyngeal carriage rates of GAS among healthy school children vary with geographical location and seasons. There is not much information on the screening of children for carriage of GAS in Ethiopia. OBJECTIVES: The study aimed at assessing the carriage rate of Group A Streptococci and antimicrobial susceptibility of the isolates in healthy Ethiopian school children. METHODS: A total of 937 children residing in Addis Ababa (n=491), Gondar (n=265) and Dire Dawa (n=181) were investigated during a period between November 2004 and January 2005. Throat specimens were collected and cultured using standard procedure. Beta haemolytic streptococci were serogrouped by agglutination tests using specific antisera. Antimicrobial susceptibility testing of the isolates was performed by diffusion method. RESULTS: The median and the mean ages of the study participants were 11 (range 6-14) years. Girls constituted 52% (486/937) of the study participants. A total of 167 (17.8%) beta haemolytic streptococci were recovered from 937 children investigated GAS accounted for 91/167 (54.5%) of beta hemolytic streptococcal isolates. The carrier rate for GAS was 9.7% (91/937) of the screened children followed by group G with 3.2% (30/937) and group C streptococci with 2.2% (21/937). All GAS isolates were sensitive to oxacillin, penicillin, erythromycin, clindamycin and trimethoprim-sulphamethoxazole. Lower frequency of resistance was observed against tetracycline and vanocmycin. CONCLUSION: The present study revealed that GAS was the most predominant beta-haemolytic streptococcus among healthy Ethiopian school children. Our results showed that pharyngeal carriage of GAS in school children should not be underestimated. Therefore it is recommended to conduct regular screening and GAS surveillance in schools, and maintain rational use of antibiotics to minimize GAS resistance. PMID- 21796913 TI - Validity and reliability of RDT for diagnosis of malaria among febrile children in Jimma Town: southwest Ethiopia. AB - BACKGROUND: Malaria shows variations in its epidemiologic pattern in relation to the local situation. Rapid diagnostic tests (RDTs) have the potential to provide an accurate diagnosis and to determine the prevalence of malaria in ureas. OBJECTIVE: The purpose of the study was to determine the prevalence of malaria and to evaluate the sensitivity and specificity of RDT for diagnosis of malaria. METHODS: A health facility based cross-sectional study was conducted from September to November 2006 among Jebrile children of less than five years of age as part of interventional study to develop and test home management of malaria in Jimma Town. Both thick and thin blood smear microscopy were done by trained laboratory technicians. An RDT was conducted to evaluate its specificity, senstivity and relaibility using blood smear microscopy as a gold standard. Data were analsysed using SPSS12.0.1 and STATA 9.1. RESULTS: A total of 929 febrile children were included in the sunrvey. P. falciparum or/and P. vivax combined together were identified using microscopy in 20.34% offebrile children presented to the health care facility. Forty three (4.63%) febrile children were positive for P. falciparum in their thin blood film microscopy. The sensitivity Iand specificity of RDT was 93.02% and 99.44% where as the positive likelihood ratio was 164.84 and positive predictive value was 88.89%. CONCLUSION: RDT for malaria had high sensitivity and specificity in the group tested. However, the use of RDT in home management of malaria by community workers should be investigated and the validity and reliability of the RDT should he established before recommending using with home management of malaria. PMID- 21796914 TI - Prevalence and determinants of hypertension in rural and urban areas of southern Ethiopia. AB - BACKGROUND: Hypertension is an important public health challenge in both economically developed and developing countries. OBJECTIVE: To asses the magnitude of hypertension in rural and urban southern Ethiopia. PATIENTS AND METHODS: A cross sectional survey was conducted on 979 study participants in Sidama Zone, South Ethiopia from November 1-30, 2008. Data were collected using a structured questionnaire and standardized procedures recommended by the WHO MONICA project for the measurement of the anthopometric variables. Analysis was done using SPSS 15.0 version. RESULTS: Out of 979 participating subjects. 485 were from urban and 494 were from rural. The prevalence of hypertension was 9.9% with 10.1% in urban and 9.7% in rural areas ranging from 4.2% in those below 30 years to 29.4% in those above 60 years. Bivariate analysis showed hypertension was highly occurred more in those above 30 years old, in those with the family history of hypertension, and a BMI > or =25 kg/m2. Hypertension also correlated with, less physical activity, extended family size, personal and family history of diabetes mellitus, measured dysglycemia, excess meat consumption and drinking alcohol. Multivariate analysis showed similar correlation of increased possibility of hypertension with being over 30 years, having a family history of hypertension, a BMI > or =25 kg/m2. and excess meat consumption. Tea drinking was found as a protective factor for hypertension on bivariate and multivariate analysis. CONCLUSIONS: Hypertension has equal public health importance in urban and rural settings of southern Ethiopia. Hypertension is common among those age over 30years. overweight, consume excess meat and have family history of hypertension. Drinking tea may have a protective effect for hypertension. PMID- 21796915 TI - Brown tumor an uncommon and late manifestation of hyperparathyroidism: a case series done at Tikur Anbessa Specialized Hospital, Addis Ababa. AB - Brown tumor of hyperparathyroidism is a non-neoplastic osteoclastic process which results in cystic lesions that are often expansile. It occurs rarely and is often a late manifestation of primary hyperparathyroidism (PHPT). Multiple bone involvement is extremely rare. Because of its resemblance with benign tumors if it occurs as a solitary bone lesion and of metastatic bone lesion when it is multiple, differentiation is often difficult without biochemical analysis. Here we presented eight patients who visited Tikur Anbessa Specialized Hospital for the last 15 years with primary skeletal complaints. Out of these six were females and except one patient all had multiple brown tumors. Based on radiographic features only it is often difficult to diagnose the condition and biochemical tests and anterior neck sonography is usually crucial to reach at a definitive diagnosis. Although the occurrence of more than one separate bone lesion in the skeleton usually suggests metastasis, our cases shows that brown tumors should also be included in the differential diagnosis of such lesions, particularly in patients with hyperparathyroidism. PMID- 21796916 TI - Foreign body in the vagina (FBV) in women of two different age groups. AB - We are presenting two case series of vaginal foreign body (VFB) in patients belonging to two different age groups. The literature review, summary of the two cases, and, the corresponding discussions will be presented. PMID- 21796917 TI - Does preeclampsia/eclampsia pose a higher disease burden to mothers in pastoralist communities in Ethiopia? PMID- 21796918 TI - [Value of the microarray for the study of Laboratory Animal Allergy (LAA)]. AB - Since 1989, the National Institute for Occupational Safety and Health (NIOSH) considers the Laboratory Animal Allergy - LAA a risk for workers and in 1998 the LAA has been recognized as occupational risk in the USA. Rat and mouse are the most source of allergens, not so much for the higher power of allergy respect to the other animals, but because represent the more utilized species in the research. Most of the allergens are members of the lipocalin superfamily, small extracellular proteins represented by at least 50 proteins that mainly bind or carry small hydrophobic molecules. The recent and innovative molecular techniques, as the microarray, have allow the characterization of numerous allergens. The protein microarray gives the possibility to study of IgE profile for each individual, simultaneos analysis of a wide number of parameters concerning the allergy, giving new diagnostic and therapeutic opportunities for the allergies. In the study of occupational allergy--as LAA--the protein microarray could improve: the identification and characterization of new allergens; the individuation of susceptible workers; the study of immunological responses in exposed workers; the strategies of prevention and protection; the environmental and housing conditions. The participation, formation and information of the workers could improve the behavioural and occupational practices, the use of personal and collective protective devices in order to reduce the exposure to LAA in occupational context. PMID- 21796919 TI - [Lesser validity of urinary benzene than S-phenylmercapturic acid for measuring occupational and environmental exposure to very low concentrations of benzene]. AB - AIM: To study the validity of urinary benzene as a biomarker of low and very low exposure to this toxicant, as compared with t,t-muconic acid (t,t-MA) and S phenylmercapturic acid (SPMA), also taking into account the influence of cigarette smoking and co-exposure to toluene on the urinary excretion of benzene. MATERIALS AND METHODS: The results obtained in two different studies were compared: in the first, workers occupationally exposed to low concentrations of benzene (18 fuel tanker drivers and 23 filling station attendants) were compared with 31 controls and in the second, workers exposed to very low concentrations of benzene (the same 23 filling station attendants) were compared with the 31 controls. Exposure to airborne benzene and toluene was monitored with passive personal samplers (Radiello). Then the urine collected at the end of the work shift was analyzed for t,t-MA, SPMA and urinary benzene. All participants also filled out a questionnaire about their lifestyle habits. RESULTS: There were no differences among the three groups in terms of age and smoking habit. Occupational exposure to benzene and toluene and the urinary concentrations of t,t-MA, SPMA and urinary benzene were higher in the fuel tanker drivers than the filling station attendants and higher in the latter than in the controls. Cigarette smoking was found to be associated with urinary excretion of t,t-MA, SPMA and urinary benzene at both low and very low exposure to benzene. The biomarkers t,t-MA, SPMA and urinary benzene were almost always correlated, for both low and very low exposure to benzene. Notably, for low exposure to benzene a dependency relation was found with the levels of t,t-MA, SPMA and urinary benzene on both cigarette smoking and airborne benzene, whereas for very low exposure to benzene there was a dependency relation of SPMA on cigarette smoking and airborne benzene, of urinary benzene only on cigarette smoking and of t,t-MA on none of the variables considered. CONCLUSIONS: For occupational exposure to low concentrations of benzene, urinary benzene and SPMA showed a comparable validity, while for exposure to very low concentrations of this toxicant the validity of SPMA was confirmed while urinary benzene was found to be less useful. Cigarette smoking was the main factor conditioning the excretion of all the biomarkers of benzene in conditions of both low and very low exposure to the toxicant, so for the analysis of occupational exposure to benzene it is best to recommend abstention from smoking at least in the hours immediately before urine collection. PMID- 21796920 TI - [Assessment of fitness to drive in correlation with narcotic and psychotropic drug use. Epidemiologic study in Verona]. AB - Driving under the influence of drugs is a serious problem for road traffic safety. According to the Italian Road Traffic Code, the driving licence must not be issued to anyone who abuses, is addicted to, or suffers for dependence to illicit or psychotropic drugs. The diagnosis of such clinical conditions is performed by Provincial Medical Commissions of the Public Health Service also on the basis of drugs of abuse testing results on urine and/or hair samples. This study aimed at examining test results obtained by the Forensic Toxicology laboratory of the Department of Public Health & Community Medicine, University of Verona, upon request of the local Medical Commission, over the period 2003-2008 with the purposes of (i) defining trends in drug abuse in the examined population (ii) identifying specific risk factors for testing positive and for relapse, (iii) selecting the most effective and efficient analytical strategy to detect illicit drugs use. During the study period, cocaine was the most frequently detected illicit drug. The comparison of results from urine and hair testing confirmed the complementary features of these two biological substrates and the importance to have both data in order to increase the sensitivity in detecting illicit drug use. Moreover, this study showed that testing for driving fitness is an effective deterrent to illicit drug use, as only about one quarter of subjects testing positive at the first testing are still positive at the second testing. PMID- 21796921 TI - [Fitness of workers with particular sensitivity to non-ionizing radiation]. AB - Chapter IV and V of Title VIII of D.Lgs 81/2008, implementing the Directives 2004/40/EC respectively (protection of workers exposed to electromagnetic fields) and 2006/25/EC (protection of workers exposed to artificial optical radiation), make frequent reference to the workers as "at particular risk" namely those workers who, by their biological or pathological characteristics, lifestyles, multiple exposure to other risk factors, may be more susceptible to the effects of electromagnetic fields or optical radiation. The identification of workers with particular sensitivity is essential for health surveillance, in particular regarding the determination of fitness. The operational guidance on Title VIII of D.Lgs 81/2008 drafted by the Italian Technical Coordination for Safety in the workplace of Regions and Autonomous Provinces (Document No. 1-2009), in collaboration with ISPESL and ISS, includes a preliminary identification of the categories of workers considered most susceptible to the risk from exposure to electromagnetic fields and optical radiation. On the basis of this information the authors identified more focused and structured classes of workers to be considered as "particularly sensitive to risk", it is not only related to a specific wavelength, but based on a comprehensive risk assessment in individual exposure situation, with regard to the exposure levels, any multiple exposures, the possibility of adequate personal protection. PMID- 21796922 TI - [The Endocrine Disruptors. Monographies. 6. Chlorpyrifos and chlorpyrifos methyl]. PMID- 21796923 TI - [Polychlorinated dibenzofurans and cancer]. AB - The aim of the present report is to review the main scientific literature about polychlorinated dibenzofurans (PCDFs) and to focus the critical aspects of their identification and assessment of exposure. The 2,3,4,7,8- Pentachlorodibenzofuran (PeCDF) has been classified as carcinogenic to humans and included in Group 1 by IARC, as there is sufficient evidence of carcinogenicity in experimental animals and specific action mechanisms. Experimental studies demonstrated that PeCDF interacts through the binding with the aryl hydrocarbon receptor (AhR) as the 2,3,7,8-tetrachlorodibenzo-para dioxin (TCDD). The epidemiological studies on human exposure are limited to few cohort evaluations like the "Yusho" and "Yucheng" incidents, Swedish fishermen cohorts and workers employed in herbicide production. The PCDF as a group may be therefore classified at limited evidence of carcinogenicity. This paper concludes the cycle of review about other POPs, i.e. dioxins and PCBs. PMID- 21796924 TI - Managing osteoarthritis and joint pain at work: helping the primary care physician educate patients who rely on non-prescription NSAIDs. AB - AIMS: To inform physicians who utilise over-the-counter (OTC) analgesics to treat osteoarthritis (OA) pain on differences among agents and to guide decisions in therapy selection. METHODS: A search of medical literature was conducted to identify articles on the treatment of OA published between 1990 and 2009. MEDLINE, EMBASE and SCISEARCH databases were searched using the terms: OTC NSAIDs, NSAIDs, naproxen, low-dose aspirin, ibuprofen, acetaminophen and COX-2 selective NSAIDs. A total of 396 publications were identified. After a review of the literature, 63 publications were considered sufficiently relevant for inclusion in the manuscript. RESULTS: The majority of working patients with OA pain will require exercise, weight control but above all pharmacotherapy. OTC analgesics, including acetaminophen and NSAIDs, provide an effective option for pain management but vary in regard to their safety and efficacy profiles. Selection of an appropriate agent should be based on an evaluation of pain severity, comorbidities and concomitant medications, as well as efficacy and safety of the individual agents. CONCLUSION: The key to effective OTC therapy for OA pain at work is to suggest exercise and weight control but above all to select an agent that will optimally provide effective clinical benefits with a good safety and tolerability profile. PMID- 21796925 TI - [Disability and occupational therapy in patients with Friedreich's ataxia]. AB - Friedreich ataxia (FA) is a neurodegenerative disease characterized by a progressive course resulting in severe disability. The occupational therapy (OT) is aimed to facilitate task performance by improving relevant performing skills or developing and teaching compensatory strategies to overcome lost performances. This study was aimed to investigate the role of OT in FA subjects carried out with sequential treatments performed during a scheduled time period. Neurological deficits, physical performances, and quality of life were evaluated with appropriate outcome measures in 10 subjects with FA who underwent three different in-hospital rehabilitation periods in one year. The baseline evaluation was performed at the beginning of the rehabilitation treatment and the final one at the end. The observed long-lasting stability of the neurological deficits and the increased functional independence of FA subjects may be considered a remarkable outcome indicating that sequential OT treatments may contribute to limit the progression of disability and maintain the participation in the everyday activities. OT and neuromotor rehabilitation may contribute to recover common abilities of FA patients representing the correct approach to the management of the disease. PMID- 21796926 TI - [The new strategy of the British health system: reflections on the changes in British health care system in the light of the WHO report on the financing of health systems worldwide]. AB - The search for a strategy that can optimise resources far the financing of health systems is currently the subject of numerous worldwide experiments. This interest stems from the fact that in most countries, although having each one different specific characteristics, governments try to improve the efficiency and equity of health care. This worle analyses how innovative financing options at national level can be combined with decision-making processes typical of quality management to devise strategies far funding health services that are oriented towards their continuous improvement. The paper discusses, in particular, the strategy adopted in England, where the new law Equity and Excellence, liberating the NHS radically changes the management of the NHS, giving patients the choice of using different types of structures and therefore the possibility to find the most convenient combination in order to obtain the required service. PMID- 21796927 TI - Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine)--biochemical aspects of anticancer activity. AB - Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine) is a second generation analogue of 2'-deoxyadenosine connecting biochemical activities of its prototypes: cladribine (2-chloro-2'-deoxyadenosine) and fludarabine (2-fluoro arabinosyladenine). This new anticancer drug is more effective (in low doses) and indicates higher oral bioavailability in comparison to its congeners. The studies indicated that the molecular mechanism of clofarabine cytotoxic action includes cell apoptosis, which results from inhibition (by the drug triphosphate nucleotides) of ribonucleotide reductase and DNA polymerases. The most recent research demonstrated also that action of the drug may cause up-expression of some genes on mRNA and protein levels. Clofarabine was synthesized in 1992 and in 2004 was approved for treatment of pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Encouraging results of clinical trials with clofarabine in acute leukemias inclined to present background knowledge about multidirectional biomolecular mechanism of its cytotoxicity. PMID- 21796928 TI - Determination of active substances in binary mixture antiparasitic veterinary formulations by HPLC. AB - The purpose of the study was to develop a simple, versatile HPLC method for the identification and quantification of praziquantel and ivermectin (in Equimax) or praziquantel and abamectin (in Abamitel Plus). A satisfactory separation was obtained using the Supelcosil LC-ABZ+ column in gradient system with a mobile phase A: acetonitrile / water in 40:60 ratio and phase B: acetonitrile. The UV detection was set at 245 nm. The correlation coefficient values (> or = 0,998) for all active substances confirmed that the calibration curves (peak area vs. concentration) are linear. The results of the quantification and the statistical evaluation confirmed that the method is accurate and precise. It can also be applied to confirm the identity of benzyl alcohol, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate in Abamitel Plus formulation. PMID- 21796929 TI - HPLC-UV determination of morphine in human plasma and its application to the clinical study. AB - A sensitive and specific high-performance liquid chromatography method with ultraviolet detection (HPLC-UV) has been developed for the quantification of morphine sulfate [(5alpha,6alpha)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6 diol], (CAS: 52-26-6) in human plasma. The analyte was extracted from plasma samples with chloroform - isopropyl alcohol (90:10, v/v) and analyzed on a Bondapak C18 column. The calibration curves were linear within the range of 10 150 ng/mL. The lower limit of quantitation was 10 ng/mL with 0.5 mL plasma sample. The mean recovery of the drug from plasma samples was 83.39%. The results from analysis of quality-control samples at concentrations of 30, 75, and 150 ng/mL were indicative of good accuracy and precision. This method was successfully used to analyze morphine in plasma samples of patients after abdominal hysterectomy. PMID- 21796930 TI - Applicability of the silver amalgam electrode in voltammetric determination of zinc and copper in gastric juice and gastric mucosa of rats. AB - The aim of the work was to compare two analytical methods of trace analysis in respect to their applicability in heavy metals determination in biological samples. Atomic absorption spectrometry (AAS) may be considered as the method of choice in such analyses due to its accuracy, precision and low detection limit. On the other hand, voltammetric methods seem to be as useful, but rarely applied. Having in mind that there is no universal analytical method, we have compared two AAS and voltammetric methods as the tools for Zn and Cu determination in the samples collected from rat gastric juice and gastric mucosa. Construction of the renewable silver amalgam film electrode (Hg(Ag)FE) for stripping voltammetry was described. Detailed optimization of measurements procedure and sample preparation for differential pulse anodic stripping voltammetry (DP ASV) and AAS were also performed and presented. The obtained results of quantitative analysis of the chosen parameters by means of both methods are discussed. PMID- 21796931 TI - Interaction of amikacin and tobramycin with melanin in the presence of Cu2+ and Zn2+ ions. AB - Aminoglycoside antibiotics such as amikacin and tobramycin are the most commonly used treatment against Gram-negative bacterial infections. The widely used aminoglycosides have the unfortunate side-effect of targeting sensory hair cells of the inner ear, so that treatment often results in permanent hair cell loss. Because melanin can act as an antioxidant as well as drug and metal chelator, evidence for its role in protecting the stria and organ of Corti against noise, ototoxins, and aging has long been sought. Protective properties of melanin may derive from its ability to bind cations and metals and to scavenge free radical. The aim of the presented work was to examine the amikacin and tobramycin binding to melanin in the presence of Cu2+ and Zn2+ ions. It has been demonstrated that amikacin and tobramycin form stable complexes with melanin in the presence of metal ions and the amount of aminoglycoside antibiotics bound to melanin increases with the increasing of initial drugs concentration. For amikacin and tobramycin complexes with [melanin-Cu2+] and [melanin-Zn2+] one class of binding sites with the association constant K 10(3)M(-1) has been found. It has been also shown that Cu2+ and Zn2+ ions administered to melanin before complexing with drugs decrease the amount of aminoglycosides bound to melanin, probably by blocking some active centers in the melanin molecule. PMID- 21796932 TI - Cytotoxic potency and induced biochemical parameters in mice serum of new furan derivatives against liver cancer cell line. AB - On the basis of monitoring the inhibition of the growth of human cancer cells, a series of novel furan derivatives of possessing a broader spectrum of antitumor activity and fewer toxic side effects than traditional anticancer drugs have been studied. Ten selected furan derivatives were subjected to a screening system for investigation of their antitumor potency against liver (HEPG2) cell line. Moreover, the biochemical effects of the selected furan derivatives on some enzymes such as aspartate and a lanine aminotransferases (ASTand ALT) and alkaline phosphatase (ALP), in addition to albumin, globulins, creatinine, total lipids, cholesterol, triglycerides and bilirubin in serum of mice were studied in comparison to 5-fluorouracil and doxorubicin. The antitumor activity results indicated that the selected furan derivatives showed growth of inhibition activity against the tested cell line but with varying intensities extents. Results of the biochemical investigations indicated that 5-fluorouracil and doxorubicin caused significant changes in the level of all parameters tested while treatment with the selected compounds showed slight, moderate or no significant changes. PMID- 21796933 TI - Synthesis of new pyrimidine derivatives with evaluation of their anti inflammatory and analgesic activities. AB - 5-Formyl-6-aminopyrimidine-2,4-(1H, 3H)-dione (2) has been previously prepared fromcompound 1. Cyclocondensation reaction of compound 2 with cyanoacetamide gave substituted pyridopyrimidine 3. Also, compound 2 was condensed with p-amino acetophenone and hydrazine derivatives to give 5-([(4-acetylphenyl)imino]methyl) 6-aminopyrimidine (4) and 5-substituted carboaldehyde-6-amino pyrimidine derivatives (5a-d), respectively. Moreover, cyclocondensation reaction of compound 2 with thiosemcarbazide and semicarbazide hydrochloride gave 5-(5-thioxo or oxo-triazol-3-yl)-6-amino pyrimidine (6) and (7), respectively. Cyclocondensation reaction of compound 2 with thiourea and ethyl acetoacetate led to the formation of substituted ethyl bipyrimidine-5-carboxylate 8. Also, compound 2 was reacted with acetoacetic acid hydrazide and 2-cyanoacetohydrazide to give 5-(acetylpyrazol-6-aminopyrimidine 9 and 3-(6-aminopyrimidine-5-yl) pyrazole-4-carboxamide 10, respectively. Furthermore, compound 1 was diazotized to afford the diazonium salt 11. Its coupling with ethyl acetoacetate, ethyl cyanoacetate, acetylacetone, malononitrile, cyanoacetamide, diethylmalonate, in sodium acetate buffered solution afforded substituted hydrazonopyrimidines: ethylhydrazono-3-oxobutanoate 12, ethylhydrazono-3-oxopropanoate 13, pentane 2,3,4-trione hydrazone 14, cyanohydrazonoacetamide 15, diazenyl malonamide 16 and diethylhydrazonomalonate 17, respectively. Moreover, substituted pyrazolediazenylpyrimidine derivatives 18a,b, 19a,b, 20, 21a-c, 22 were synthesized by the cyclization of substituted hydrazonopyrimidines 12, 17, 15, 14 and 13, respectively. The analgesic and anti-inflammatory activities of some of the synthesized compounds were evaluated. Compounds C18a, C20, C21b and C22 showed the most significant analgesic effects among synthesized moieties. All tested compounds, nonetheless, C18b showed significant anti-inflammatory effect in carrageenan induced paw edema model. PMID- 21796934 TI - Novel benzimidazole derivatives as expected anticancer agents. AB - A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1 methyl analogues 2c-h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, carbon disulfide and/or thiosemicarbazide to yield compounds 11-19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiff's bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly synthesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocytoma of the rat adrenal medulla) cells. Benzimidazole 2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells. PMID- 21796935 TI - Phytochemical and antimicrobial screening of methanol and aqueous extracts of Agave sisalana. AB - The methanol and the aqueous extracts of the plant, Agave sisalana were prepared and evaluated for its phytochemical properties and antimicrobial activities. The phytochemical analysis of the preparation revealed the presence of some secondary metabolites which include: saponins, glycosides, cardiac glycosides, steroids, tannins and flavonoids. The in vitro antimicrobial activity of the crude methanol and aqueous extract of the Agave sisalana were investigated. The extract showed antimicrobial activities against the test organisms with different zones of inhibition ranging from 28-32 mm and 25-29 mm for methanol and aqueous extract, respectively. The minimum inhibitory concentration (MIC) of both the methanol and aqueous extract was between 10-20 mg/mL, and the minimum bactericidal concentration (MBC) was between 20-40 mg/mL for both extracts. The investigation indicated that the methanol extract inhibited the growth of the microbes more than the aqueous extract. The ability of the crude extracts of A. sisalana to inhibit the growth of the microbes is an indication of its antimicrobial potential, which may be employed in the management of microbial infections. PMID- 21796936 TI - Oxytocin inhibiting effect of the aqueous leaf extract of Ficus exasperata (Moraceae) on the isolated rat uterus. AB - The leaves of Ficus exasperata Vahl Enum. Pl. vahl (Moraceae) are used by traditional healers in Southern Nigeria and some parts of Africa to avoid preterm births. However, previous reports showed that the plant also exhibited uterine contractions at specific concentrations. This study is therefore aimed at investigating the purported uterine inhibitory aspect of the plant on the isolated rat uterus. The aqueous extract (AET) was tested on rhythmic spontaneous uterine contractions. Concentration-response relationships were obtained for oxytocin (OT), acetylcholine (ACh) and ergometrine (EGM), in the presence or absence of fixed concentrations of AET. Salbutamol (SBL) and verapamil (VER) were used as positive controls. AET, at 1.0 x 10(-2) mg/mL, significantly increased (p < 0.05) the EC50 of oxytocin-induced contractions but had no significant effect on ACh, EGM and spontaneous uterine contractions. However, SBL and VER significantly increased (p < 0.01) the EC50, of OT, ACh and EGM and significantly inhibited (p < 0.01) the frequency and amplitude of spontaneous uterine contractions. The aqueous leaf extract of F. exasperata inhibits oxytocin-induced uterine contractions at the concentration shown in this study. This observation may explain its folkloric use in counteracting preterm contractions and alleviating dysmenorrhoea. PMID- 21796937 TI - Physical and technological principles of creating biocompatible superparamagnetic particles. AB - Nanodisperse powder of zinc-substituted magnetite has been developed. Functional characteristics (biocompatibility, dispersion, magnetic state) allow to recommend it for approbation in medical and biologic technologies. The character of the temperature dependences of magnetization investigated in the magnetic fields lower than the anisotropy field indicates that transfer from the magnetically stable state into the superparamagnetic state was realized for particles of 3-13 nm in the temperature range of 4.2-150 K. It reflects specificity of small particles magnetism. PMID- 21796938 TI - Stability of cefuroxime in 1% and 5% buffered eye drops determined with HPLC method. AB - The aim of the studies was to develop formulary technologies of 1% and 5% eye drops containing cefuroxime with stability of at least 10-12 days. The stability was defined as the time required to reach the cutoff value of 10% degradation of cefuroxime in the drops, as determined using an HPLC assay. The drops should have such properties as optical clarity, pH in the range of 3.5 to 8.5 and osmotic pressure not lower than 280 mOsm/L. Additionally, drops of enhanced viscosity within the range 7-9 mPaxs were developed. Drops (1% and 5%) were prepared under aseptic conditions by dissolving Biofuroksym (Cefuroxime natricum) IBA Bioton- the form of the drug for dry injections--in citrate buffer of pH 6.05-6.28. Polyvinyl alcohol was used to increase the viscosity of the drops. Phenylmercuric borate at the final concentration of 0.001% was used together with beta phenylethyl alcohol at the final concentration of 0.4% to preserve the drops. The drops were stored for 30 days in tightly closed glass bottles at the temperature of 4 degrees C and 20 degrees C, protected from light. As the course of the infection may differ in intensity, location and the area of the infection in the eye, the composition of the drops was developed at two concentrations (1% and 5%), and five formulary versions for each concentration were prepared. The concentration of cefuroxime in the drops was determined every three days using HPLC. Such properties as pH, osmotic pressure and viscosity were also examined. Additionally, organoleptic analysis (clarity, color, odor) was performed. Physical and chemical properties of all formulations of 1% and 5% drops containing cefuroxime prepared in citrate buffer of pH 6.05-6.28 met the standards set in the objective of the work. The stability of cefuroxime in buffered drops stored at the temperature of 4 degrees C, determined with HPLC as the time of 10% degradation of cefuroxime, was 15 days for 1% and 5% drops. In the drops, which were buffered and of increased viscosity, the times of 10% cefuroxime degradation were 18 days for 1% drops and 30 days for 5% drops. The preservatives added to the buffered drops did not lower their stability. Osmotic pressure, pH and viscosity of the drops during the period of 30-day-storage at the temperature of 4 degrees C met the requirements acceptable for the eye drops. The stability of 1% and 5% buffered drops containing cefuroxime stored at the temperature of 4 degrees C allows preparing the drops in pharmacies on the basis of doctor's prescription. Depending on the character and the course of the infection the drops can be prepared at the concentration of 1% and 5% following the composition of the selected formulation which would meet the individual needs of the patient's therapy. PMID- 21796939 TI - Area under rheogram as multi-point viscosity characteristic of the sterilized hypromellose hydrogels. AB - In this work, the cone and plate rheological viscometry readings of the sterilized hydrogels of hypromellose 4000 (60 g/L) were investigated by using of the three-parameter Herschel a nd Bulkley powerlaw and the new empirical two parameter model. In it, the independent variable of shear rate was transformed by logarithm and the dependent variable of shear stress by square root. The two parameter model showed only non-significantly lower mean value of the coefficient of determination when compared with the results of the three-parameter power law model being of good promise in other investigation of the near pseudoplastic rheograms of hypromellose hydrogels. To express the influence of the addition of the isotonic concentration of sodium chloride and/or pilocarpine hydrochloride, respectively, on the viscosity of sterilized hydrogels of hypromellose, the area under rheogram (AUR) data was employed as a multi-point theological characteristic. No significant differences were noted between AUR calculated using three parameters of the power law model and those calculated using two parameters of the proposed one. The significant increase in viscosity was observed in the presence of the isotonic concentration of sodium chloride in comparison to the hydrogel without additives. In the opposite, the addition of the isotonic concentration of pilocarpine hydrochloride resulted in the significant viscosity decrease. In conclusion, the proposed empirical two parameter model could be used as the rheological model in investigation of the near pseudoplastic rheograms of the sterilized hypromellose hydrogels. PMID- 21796940 TI - Fabrication and optimization of fast disintegrating tablets employing interpolymeric chitosan-alginate complex and chitin as novel superdisintegrants. AB - The objective of the present work was to optimize the formulation of fast disintegrating tablets (FDTs) of ondansetron HCl containing novel superdisintegrants, possessing sufficient mechanical strength and disintegration time comparable to those containing crospovidone or croscarmellose sodium. The FDTs were formulated using a novel superdisintegrant (chitosan-alginate (1:1) interpolymer complex and chitin) to achieve a sweet tasting disintegrating system. The results revealed that chitin (5-20%) increased the porosity and decreased the DT of tablets. At higher concentrations chitin maintained tablet porosity even at 5.5 kg crushing strength. Ondansetron HCl was found to antagonize the wicking action of glycine. Further, evaluation of the mechanism of disintegration revealed that glycine transported the aqueous medium to different parts of the tablets while the chitosan-alginate complex swelled up due to transfer of moisture from glycine. This phenomenon resulted in breakage of the tablet within seconds. For preparing optimized FDTs, the reduced model equations generated from Box-Behnken design (BBD) were solved after substituting the known disintegration time of FDTs containing superdisintegrants in the reduced model equations. The results suggested that excipient system under investigation not only improved the disintegration time but also made it possible to prepare FDTs with higher crushing strength as compared to tablets containing known superdisintegrants. PMID- 21796941 TI - Molecular simulation of hydroxypropyl-beta-cyclodextrin with hydrophobic selective Cox-II chemopreventive agent using host-guest phenomena. AB - The present investigation outlays the host-guest penetration of hydrophobic selective Cox-II chemopreventive agent, celecoxib (CXB), with hydroxypropyl-beta cyclodextrin (HP-beta-CD) using inclusion complexation phenomena. Phase solubility studies conducted at 37 degrees C and 25 degrees C revealed typical A(L)-type curve for the HP-beta-CD indicating the formation of soluble complexes. The inclusion complexes in the molar ratio of 1:1 and 2:1 (CXB-HP-beta-CD) were prepared by kneading technique. The formation of inclusion complexes and the molecular simulation of CXB protons with HP-beta-CD cavity in all samples were testified by 1H-NMR, DSC, powder-XRD, SEM and FTIR and UV/visible spectroscopy. The results of these studies indicated that complex (prepared by kneading method) in molar ratio of 1:1 exhibited better improvement in in vitro dissolution profiles as compared to 1:2 complex. Mean in vitro dissolution time indicated significant difference in the release profiles of CXB from complexes and physical mixtures as compared to pure CXB. PMID- 21796942 TI - Formulation and evaluation of reconstitutable suspensions containing ibuprofen loaded Eudragit microspheres. AB - The objective of this work was to develop and evaluate reconstitutable suspensions of ibuprofen-loaded microspheres prepared with an acrylic polymer (Eudragit RS-PM). The microspheres were prepared by the quasi-emulsion solvent diffusion technique. To prepare reconstitutable suspension formulation, the microspheres used had a mean particle size of 316.6 microm and 99.8% loading efficiency. Xanthan gum was chosen as the suspending agent for the suspension formulations. D-sorbitol was used to impart palatability of suspensions. The amount of D-sorbitol affected sedimentation volume and redispersibility properties of suspensions. The highest improving effect was shown with 20.0% and 25.0% of D-sorbitol concentrations. It was observed that dispersion media of suspensions showed non-Newtonian flow characteristics. To ensure minimum drug leakage from the microspheres into the suspension, the pH was buffered at 3.60 using citrate buffer. The ibuprofen content calculated from the suspended microspheres was consistent with that from microspheres alone. This result indicated that no leakage of drug occurred from the microspheres in the suspension on storage. Moreover, the same release rate of ibuprofen from the microspheres suspension and microspheres alone indicated that the suspension medium studied did not affect the property of drug release. This study suggested that stable suspensions of ibuprofen-loaded microspheres could be formulated with 0.6% w/v xanthan gum by the addition of 20% w/v D-sorbitol. PMID- 21796943 TI - Taste masking of roxithromycin by spray drying technique. AB - The spray drying technique was used to obtain the roxithromycin containing microcapsules with high taste masking efficiency. Eudragit L30D-55 was chosen as a barrier coating. The taste was evaluated by an electronic tongue, and taste masking effect in water lasted at least several dozen hours. PMID- 21796944 TI - A new flavonoid glycoside from the seeds of Cicer arietinum Linn. PMID- 21796945 TI - An update on the effects of conjugated linoleic acid (CLA) in a rodent model of polycystic kidney disease. PMID- 21796946 TI - Evaluation of antioxidant potential of flavonoids: an in vitro study. PMID- 21796947 TI - Normative data and psychometric properties of short form 36 health survey (SF-36, version 1.0) in the population of north Jordan. AB - This study aimed to assess the psychometric properties of the short form 36 health survey (SF-36, version 1.0) and to establish SF-36 population norms among the general population of north Jordan. A systematic sample of 157 households was selected from 6 districts in Irbid governorate in north Jordan. A total of 511 people aged 18 years or more agreed to participate. The reliability of the instrument using the Arabic version of SF-36 was satisfactory: Cronbacha o alphas for all 8 SF-36 scales exceeded 0.70. All items passed the tests for item internal consistency and item discriminant validity. SF-36 population norms amongthe general population of north Jordan were established. The highest mean was for social functioning (66.8) among men and for physical functioning (69.8) among women. The lowest mean was for vitality (55.8) among men and bodily pain (54.6) among women. The SF-36 is a valid and reliable instrument for measuring quality of life among Jordanians. PMID- 21796948 TI - Burden of fall injuries in Pakistan--analysis of the National Injury Survey of Pakistan. AB - There are no reliable estimates of the burden of fall-related injuries in Pakistan. To assess this burden and develop an epidemiologic profile for these injuries data from the National injury Survey of Pakistan, a cross-sectional population-based survey on injuries, were analysed to determine incidence and relative risks for fall injury. The annual incidence of fall-related injuries was 8.85 per 1000 population per year (95% CI: 6.8-11.3). The mean and median age of individuals injured by falls was 19 years and 10.5 years respectively. Children under the age of 15 years were at a substantially higher risk of fall injuries. Being a student and farmer/labourer/vendorwere associated with a higher risk for falls compared with unemployed. Fall-related injuries are a health burden in Pakistan, especially in children under 15 years of age. This represents a significant loss of healthy life and requires policies to curb this burden in the population. PMID- 21796949 TI - Anthropometric characteristics and obesity among adolescents in the United Arab Emirates. AB - Anthropometric measurements and the prevalence of overweight and obesity were studied in 661 adolescents aged 12-17 years from Dubai, United Arab Emirates. Mean values for height and weight increased steadily with age in both sexes. Mean values for waist circumference ranged from 70.8-76.6 cm in males and 64.0-68.8 cm in females. Hip circumference varied from 84.8-91.2 cm in males and 84.9-91.2 cm in females. Body mass index was generally higher in males than in females (range 21.9-23.6 kg/m2 and 19.8-24.1 kg/m2 respectively). The overall prevalence of overweight and obesity was 19.3% and 21.6% in males and 12.3% and 19.5% in females. This study confirms the high incidence of overweight and obesity in Dubai adolescents. PMID- 21796950 TI - Oral hygiene status of Kuwaiti schoolchildren. AB - A national epidemiological survey of children aged 5-14 years was conducted in all 5 governorates of Kuwait in 2001 to determine the oral hygiene status of Kuwait in schoolchildren. Clinical examinations were carried out by calibrated dentists according to World Health Organization criteria. The debris index simplified (DI-S) score was used to assess oral hygiene status. Of the 3294 children, 3.9% were judged to have good oral hygiene (DI-S score: 0.3-0.6), 67% fair (score 0.7-1.8) and 29.1% poor (score 1.9-3.0). The overall level of oral hygiene in the schoolchildren surveyed was fair (mean score 1.5). DI-S scores were significantly higher for boys than girls (mean score 1.6 versus 1.5) but DI S did not vary much by age. There were variations in DI-S scores across different governorates. Oral hygiene measures need to be reinforced for the schoolchildren in Kuwait and should form part of the school curriculum. PMID- 21796951 TI - Public knowledge, beliefs and practices in Greece about cancer etiology and prevention. AB - This questionnaire survey of the parents of elementary schoolchildren in Greece assessed their self-reported knowledge, attitudes and practices towards smoking, diet and exposure to X-radiation. A random sample of 403 household units (379 fathers and 391 mothers) was selected from urban areas of Thessaloniki. Half of the parents who smoked (50.1%) did not ask for permission to smoke from other people and 66.0% regularly smoked in front of their children. On the other hand, 82.6% of smokers recognized the existence of a health risk to children from passive smoking. Parents overestimated the role of nuclear tests and accidents as factors in carcinogenesis. Two-thirds of parents did not know the beneficial role of the Mediterranean diet to health, and dietary intake analysis showed some departure from the traditional Mediterranean diet. A reconsideration of the policy regarding health education programmes concerning cancer prevention in Greece is needed. PMID- 21796952 TI - Association of myocardial infarction with stressful life events and psychiatric symptoms: a population-based survey. AB - Psychosocial factors such as depression, hostility, social isolation are associated with increased risk of coronary heart disease. We aimed to determine the association of psychiatric symptoms and psychosocial factors with myocardial infarction (Ml). We performed a secondary analysis of data from a population based survey of Iranians aged 18-15 years using standardized psychosocial instruments. Of the 2158 participants, 51 had suffered an Ml. In univariate analysis: number of stressful life events, stressfulness, somatization, depression, anxiety, phobic anxiety and psychoticism were significantly associated with Ml(P < 0.05). In multivariate logistic regression, interpersonal sensitivity (P= 0.047), phobic anxiety (P = 0.016) number of stressful life events (P= 0.054), stressfulness (P= 0.057) and age (P = 0.001) remained at significanty associated with Ml. PMID- 21796953 TI - Thalassaemia and glucose-6-phosphate dehydrogenase deficiency in sickle-cell disorder patients in Taiz, Yemen. AB - A pilot study was conducted to determine the prevalence and haematological characteristics of the interaction between thalassaemia or/and glucose-6 phosphate dehydrogenase (G6PD) deficiency in patients with sickle-cell disorder (SCD) in Taiz city, Yemen, where the prevalence of sickle-cell trait (HbAS) is 8.2%. Blood samples were collected from 31 SCD patients. Complete blood count and haemoglobin electrophoresis, G6PD activity and serum ferritin were determined. Thalassaemia was found in 6 patients (19.4%) and G6PD deficiency (6 mild and 1 severe) was detected in 7 patients (22.6%). The frequency ofthalassaemia and/or G6PD deficiency with SCD was high and this may have an effect on the severity of the clinical course of SCD in Taiz. The study should be repeated with DNA analysis to define the nature of the globin gene defect and to clarify its role in the severity of SCD PMID- 21796954 TI - Self-medication practice among patients in a public health care system. AB - A survey of 500 patients attending primary health care centres in Riyadh, Saudi Arabia was carried out to determine the prevalence and factors associated with self-medication practice. The results indicated that 35.4% of the respondents had practised self-medication past 2 weeks. Bivariate and multivariate analyses indicated that respondents who were young, male, having poor health status, reporting inconvenient access or dissatisfied with health care were more likely to practise self-medication. Health education campaigns, strict legislations on dispensing drugs from private pharmacies and increasing the quality of and access to health care are among the important interventions that might be needed in order to change the people's health seeking behaviour and protect them from the potential risks of self-medications. PMID- 21796955 TI - Analysis of surgical emergencies in Benghazi, Libyan Arab Jamahiriya. AB - The increasing incidence of trauma due to road crashes and violence has increased the need for an efficient emergency medical service. This cross-sectional study was based in a surgical emergency care facility in Benghazi city, Libyan Arab Jamahiriya. A representative sample of 391 admissions and 492 deaths was drawn from hospital medical records over a 6-year period (2000-05). A higher proportion of patients were males among both deaths and admissions. Surgical emergencies for females were less serious and less likely to be fatal. The most vulnerable age for admissions was 25-49 years (37.6%) and for deaths was 60+ years (37.0%). Noncommunicable diseases were responsible for 50.0% of deaths and 61.6% of admissions; the remainder were classified as injuries. The causes of surgical emergencies not only highlight priority areas for hospital management but also have relevance for community health management. PMID- 21796956 TI - Susceptibility of Candida species isolated from immunocompromised patients to antifungal agents. AB - This study was carried out from October 2003 to March 2007 to investigated susceptibility patterns ot March 2007 to antifungals of Candida strains isolated from 410 immunocompromised patients in Shiraz, Islamic Republic of Iran. Patients were checked for systemic candidiasis. Fungal colonization was determined and clinical samples collected from those patients with clinical signs of infections were examined. The carbohydrate assimilation patterns of all 354 isolates were studied. Susceptibility of the isolates to antifungal agents was determined using the reference broth microdilution method. Candida albicans was the species most often isolated. Voriconazole was highly active against all the isolates. Major resistance to itraconazole was observed in all Candida spp. Regular investigations into antifungal resistance in medical centres is highly recommended as this will result in more efficient management of invasive candidiasis in immunocompromised patients. PMID- 21796957 TI - [Respiratory morbidity in family practice in the region of Sousse, Tunisia]. AB - We determined the profile of respiratory morbidity in family practice in the region a cross-sectional study in 86 primary health care centres in Souse over 1 year (2002-03). Medical records for 3 weeks per season were randomly selected. The International Classification of Primary Care (ICPC) was used to code recorded data. Respiratory diseases ranked first both for reason for consultation (8397/24 882, 33.7%) and for diagnosis made (7788/18 097, 43.0%). Of the 7715 respiratory complaints, cough was the most common complaint (54.8%). Of respiratory diagnoses, 37.1% were acute tonsillitis, 26.5% acute bronchitis and 21.6% were acute respiratory tract infection. Children under 5 years were most affected by acute upper respiratory tract infections (44.5%). Acute bronchitis was the primary diagnosis for patients aged over 45 years. PMID- 21796958 TI - Ecology of malaria vector Anopheles culicifacies in a malarious area of Sistan va Baluchestan province, south-east Islamic Republic of Iran. AB - A study was done of the bionomics, insecticide susceptibility and irritability status of Anopheles culicifacies in Sistan va Baluchestan province. Sampling was performed to determine the following parameters: species identification, seasonal activity, adult and larval susceptibility tests, irritability tests, anthropophily index and sporozoite rate. An. culicfacies adults were susceptible to all tested pyrethroid insecticides. An. culicfacies started to appear indoors in late May, showing 2 peaks in June and September. Fenitrothion, cyfluthrin and permethrin had the least irritancy effect and DDT the highest. Only 2/860 females tested were infected with Plasmodium spp. (sporozoite rate: 0.25%). ELISA testing of 250 blood meals derived from night-biting collections of female mosquitoes from humans and cows revealed that only 12.5% were human-fed. PMID- 21796959 TI - How successful are women's groups in health promotion and disease prevention? A synthesis of the literature and recommendations for developing countries. AB - There is a general scarcitly of resources for delivery of services to the population in all social welfare and development sectors, with the health sector being no exception. In developing countries, lack of trained manpower, illiteracy and compliance issues make health care interventions even more complex. Various community-based projects have used women as a specific group for delivery of health care interventions. The objective of this paper was to review published studies that evaluated women's groups for the promotion of health and prevention of disease. A total of 8 studies were reviewed. Women's groups have proved to be a convenient and workable option for delivering health care interventions in several developing countries. PMID- 21796960 TI - Implementation of integrated vector management for disease vector control in the Eastern Mediterranean: where are we and where are we going? AB - Integrated vector management (IVM) is an acknowledged strategy of choice for the prevention and control of vector-borne diseases. The paper describes and documents the progress countries of the World Health Organization (WHO) Eastern Mediterranean Region have made in endorsing and translating the strategy into action at the national level. These include increased political commitment; strengthened intersectoral coordination and partnership; strengthened capacity in entomology and vector control; and scaling up of vector control interventions through universal access. These efforts, however, are compromised by inappropriate institutional arrangements in some countries; weak national capacities to address management of pesticides; , development and spread of vector resistance to insecticides, including to pyrethroids; and the expansion of emerging and re-emerging vector-borne diseases. With WHO leadership and support from partners, countries continue to address these challenges head-on. PMID- 21796961 TI - Patients' report of statins use and side-effects in a sample of hospitalized cardiac patients in the Islamic Republic of Iran. AB - We aim to study the prevalence of the side-effects of statins among Iranians patients admitted to a cardiac-specialized hospital and had taken statins prior to hospitalization. Data was collected between September 2007 and March 2008 and 200 patients were enrolled. A questionnaire was completed using the patients' records and by interviewing the patients. The mean age of the participants was 61.5 (SD 12.3) years and 63% were males. The most commonly used statins was atrovastatin (99% of the patients). In all, 63.5% of the participants reported experiencing side-effects due to statins. The reported side-effects were respiratory (18.5%), headache (16.5%), rash (0.5%) and allergic reactions (5%); 9.5% reported (4%) and gastrointestinal effect muscle-related side-effects such as myalgia. Although, the clinical benefits outweigh the small risk of liver failure and myopathy, clinicians should be aware of the side-effects of statins. PMID- 21796962 TI - Climate change and predicted trend of fungal keratitis in Egypt. AB - Rising rates of invasive fungal infections may be linked to global climate change. A study was made of the trend of ophthalmic fungal corneal keratitis in the greater Cairo area of Egypt and its association with climate records during the same period. Data on diagnosed cases of fungal keratitis were collected from records of ophthalmic departments of Cairo University hospital and atmospheric temperature and humidity for the greater Cairo area were obtained from online records. Statistical analysis showed a significant increase in the relative frequency of keratomycosis during 1997-2007. The rise correlated significantly with rises n min,mum temperature and the maximum atmospheric humidity in the greater Cairo area over the same period (after exclusion of the effect of the maximum atmos pheric temperature). The predicted increase in keratomycosis up to the year 2030 corresponds to predicted increases in CO2 emissions and surface temperature from climate change models for Egypt. PMID- 21796963 TI - Hepatitis B virus infection among staff in three hospitals in Khartoum, Sudan, 2006-07. AB - The study was conducted to determine the seropositivity of hepatitis B infection, associated risk factors and history of vaccination among staff in 3 teaching hospitals in Khartoum. The study was carried out from March 2006 to March 2007. Participants comprised 245 randomly selected hospital staff; 12 (4.9%) reacted positively for HBsAg, 6 of whom were nurses, 4 domestic staff and 2 laboratory staff. Only 37 paticipants (15.1%) said that they had attended training courses in biosafety. Just over 50% indicated that they had had needle-stick or sharps injuries during work; 61 (24.9%) indicated that they always followed the bio safety precautions, 52 (21.4%) said that they always wore gloves during their work while 43 (17.6%) said they never wore them. Only 11 (4.5%) of the participants had received the full vaccination dose for hepatitis B. PMID- 21796964 TI - Rising bacterial resistance to common antibiotics in Al Ain, United Arab Emirates. AB - There is a dearth of local information in Al Amin, United Arab Emirates about antibiotic resistance patterns. In this retrospective study in a tertiary referral hospital, antibiotic susceptibility results were analysed over the 5 year period 2004-08 and compared with a previous study in the same hospital during 1999-2002. Staphylococcus aureus showed a significant decrease in sensitivity to oxacillin from 95.0% in the period 1999-2002 to 84.4% in 2008. Sensitivity of Acinetobacter spp. to imipenem dropped from 99.0% in 2004 to only 32.5% in 2008. During the same period, almost half of Escherichia coli isolates developed resistance to cefotoxime. Significant reductions in sensitivity to Pseudomonas aeruginosa between 1999 and 2008 were found for almost all the antibiotics tested. Klebsiella spp. did not show any significant change in resistance to any of the tested antibiotics. Serious efforts are needed to reduce the risk of the spread of resistant strains of bacteria. PMID- 21796965 TI - Epidemiological profile of health-care-associated infections in the central-east area of Tunisia. AB - This study aimed to estimate the prevalence and risk factors for health-care associated infection (HAl) in all 9 hospitals of the central-east area of Tunisia in 2005. Of 1373 patients admitted for more than 48 hours, 74 developed HAI, a prevalence of 5.4% (95% CI: 4.2%-6.6%). The prevalence was significantly higher in the intensive care units (18.4%) and neonatal departments (12.7%). There were 79 infections and the most frequent sites of infection were respiratory tract and urinary tract. Microbiological examination was performed for 25 cases of HAl and Pseudomonas aeruginosa was identified in 8 cases. Multiple logistic regression analysis indicated that HAl was linked to diabetes (OR = 2.0), immunosuppression (OR = 3.3), length of stay (OR = 4.5), central venous catheter (OR = 2.5) and peripheral venous catheter (OR= 10.2). We conclude that HAls are of concern in this area of Tunisia. PMID- 21796966 TI - Assessment of liver function among nickel-plating workers in Egypt. AB - Currently no reports are available from Egypt regarding occupational exposure to nickel and its effects on the liver. The aim of this study was to assess the liver function of workers occupationally exposed to nickel. Standard liver function tests were applied to blood samples from 25 nickel-plating workers in Damietta, Egypt and 30 administrative workers as a reference group. Levels of urine nickel, measured by inductively coupling plasma-emission spectroscopy, were significantly higher in nickel-exposed workers compared with the reference group. The levels of alanine aminotransferase and aspartate aminotransferase were significantly higher in nickel-exposed workers. The level of serum albumin was significantly negatively correlated and the levels of serum aminotransferases, and serum gamma-glutamyl-transpeptidase were significantly positively correlated with urine nickel levels. Liver function is compromised in nickel-plating workers compared with non-exposed administrative workers. PMID- 21796967 TI - Acute kidney injury after cardiac surgery in eastern Saudi Arabia. AB - Acute kidney injury is a serious complication after cardiac surgery. This study was conducted to determine the frequency of acute kidney injury and the associated risk factors following cardiac surgery at Dhahran health centre in eastern Saudi Arabia. All patients who underwent cardiac surgery between June 2005 and December 2008 were included. Of 293 patients who fulfilled the criteria and were included in the final analysis, 85 (29.0%) developed acute kidney injury. Using multivariate analysis, the factors significantly associated with acute kidney injury were age, diabetes, preoperative chronic kidney disease and emergent surgery. Mortality associated with acute kidney injury was 10.5% overall and 42.9% when dialysis was required. Acute kidney injury following cardiac surgery is a serious problem among patients in eastern Saudi Arabia. Measures to prevent this complication are essential. PMID- 21796968 TI - Effect of nutritional intervention on the prevalence of metabolic syndrome and heart disease risk factors in urban Tehran (Tehran lipid and glucose study). AB - In a case-control study a nutritional intervention consisting of an educational program based on the Therapeutic Lifestyle Change diet (TLC) guidelines was implemented in one area of Tehran. Data were collected from subjects in the intervention area (n =133) and controls from another area (n = 183), before and 3.8 years after the intervention. Mean energy and macronutrient intakes and prevalence of risk factors including metabolic syndrome were compared between and within cases and controls. Baseline and follow-up evaluations showed improvement in hypercholesterolemia and high LDL cholesterol levels in cases versus controls. Central obesity and low HDL cholesterol levels increased significantly in controls but not in cases. As there were no significant differences between the 2 groups in energy and macronutrient intakes, it is difficult to claim that nutritional interventions played an important role. PMID- 21796969 TI - Factors associated with breast self-examination among Malaysian women teachers. AB - The purpose of this study was to examine factors related to breast self examination (BSE) among teachers in Selangor, Malaysia. A cross-sectional study was conducted among 425 female teachers in 20 randomly selected secondary schools. A self-administered questionnaire based on the health belief model was randomly selected secondary schools. A self-administered questionnaire based on the health belief model was used, including sociodemographic background and knowledge, beliefs and practices about breast cancer and BSE. Only 19% of the women performed BSE on a regular basis. Higher knowledge about breast cancer, greater confidence in performing BSE and regular visits to a physician were significant predictors for practising BSE. To promote BSE practice among Malaysian women, tailored health education and health promotion programmes should be developed based on a specific understanding of women's health beliefs. PMID- 21796970 TI - Evaluating success of no-scalpel vasectomy by ligation and excision with fascial interposition in a large prospective study in Islamic Republic of Iran. AB - The aims of this prospective, non-comparative study were to determine time to azoospermia and vasectomy success rate based on the results of semen analysis. A total of 334 men seeking vasectomy at a clinic in Urmia city, Islamic Republic of Iran were followed bi-weekly up to 24 weeks after vasectomy or until azoospermia was confirmed via semen analysis. The cumulative life table rate for azoospermia was 93/100 men (95% CI: 88.1 to 97.9). The median time to azoospermia was 10 weeks. By week 24 of follow-up, 3.3% of participants had failed to achieve azoospermia. One pregnancy was reported during the study period and attributed to user failure. The results suggest that men can begin to rely on vasectomy for contraception 12 weeks after no-scalpel vasectomy using fascial interposition performed by an experienced surgeon. PMID- 21796971 TI - Prevalence and predictors of smoking among adolescent schoolchildren in Monastir, Tunisia. AB - A study in Monastir, Tunisia estimated the prevalence of smoking and analysed the determinants of tobacco use among adolescents aged 10-19 years. An observational cross-sectional study was performed in the 8 colleges and high schools of Monastir city in 2004. The mean age of the 900 respondents was 15.8 (SD 2.2) years and 47.7% were aged under 16 years. The overall prevalence of cigarette use during the past year was 16.0% (30.2% among males and 4.6% among females). The first smoking experience was initiated by friends in 45.8% of cases, at a mean age of 13.8 (SD 2.3) years. One-fifth of smokers (21.5%) had used other forms of tobacco. In multivariate analysis, male sex, academic failure, poor family management, antisocial behaviour and addictive behaviour were the main predictors of adolescent smoking status. The prevalence of smoking among adolescents in Monastir is high and requires targeted action. PMID- 21796972 TI - Sociocultural contexts of attempting suicide among Iranian youth: a qualitative study. AB - This paper seeks to illuminate the sociocultural contexts of attempting suicide among Iranian youth. A qualitative approach was employed to uncover the social and cultural dimensions of attempting suicide. In-depth interviews were conducted with 25 participants aged 14-17 years who attempted suicide and were admitted to 2 of the hospitals in Isfahan. A thematic analysis approach was employed. The main themes identified were failure in love, family problems, study, pressure of high expectations and poverty. The findings suggest significant sociocultural influence on attempting suicide in the Islamic Republic of Iran. Exploring sociocultural aspects of suicide is critical in providing effective and culturally-sensitive suicide prevention and care programmes. PMID- 21796973 TI - Public attitude towards biomedical research at outpatient clinics of King Abdulaziz Medical City, Riyadh, Saudi Arabia. AB - The aim of this study was to determine the attitude of Saudi Arabians to research involving storage and use of human tissues from which genetic information may be derived and to assess their willingness to donate tissue samples to biobanks. In a cross-sectional interview study of 1051 outpatients at a hospital in Riyadh city, 68.8% had a positive attitude towards biomedical research and 78.4% were willing to allow use of excess surgical tissues for research purposes. Participants were less willing to allow the use of tissue or organs from a deceased relative. Logistic regression analysis found that predictors for a positive attitude to biomedical research and to use of tissue in research were: female sex, higher level of education, previous experience of blood testing and previous participation in health-related research. The attitudes towards biomedical research among the participants were satisfactory and comparable to findings from other countries. PMID- 21796974 TI - Role of HFE gene mutations on developing iron overload in beta-thalassaemia carriers in Egypt. AB - A case-control study aimed to determine the prevalence of C282Y, H63D and S65C mutations of the HFE gene in beta-thalassaemia carriers and investigate their influence on iron absorption. A total of 41 beta-thalassaemia carriers and 40 control subjects without haemoglobinopathies were screened for the C282Y, H63D and S65C mutations by polymerase chain reaction-restriction fragment-length polymorphism. The iron status in these subjects was studied and correlated with the HFE gene mutations. H63D, S65C and C282Y allele frequencies were 30.5%, 13.4% and 7.3% respectively in beta-thalassaemia carriers and 10.0%, 2.5% and 0.0% respectively in the control group. Compound heterozygosis was found in 10 carriers (24.4%). The transferrin saturation level was high in compound heterozygote cases. Our study has shown that the HFEgene mutations are common in Egypt among beta-thalassaemia carriers compared with normal controls. PMID- 21796975 TI - Social consequences of infected haemophilia cases in the Islamic Republic of Iran. AB - The unintentional contamination of haemophilia patients with HIV in the early 1980s raised serious questions about the safety of blood product supplies worldwide. The events initiated a cascade of consequences for both infected patients and the national health systems of many countries, including the Islamic Republic of Iran. Lawsuits have been filed in the courts mostly in developed countries, leading to the establishment of some kind of reimbursement programme for haemophilia patients who acquired viral infections. In the late 1990s the courts ordered the Iranian Ministry of Health, in addition to providing free care with the latest treatments to pay compensation to the haemophilia patients. The adverse consequences of these events on the equitable distribution of resources in the Iranian health care system are discussed in this paper. PMID- 21796976 TI - [Bioluminescence in-vivo imaging technology and its application in the study of viral infection--a review]. AB - Bioluminescence imaging is one of the bio-optical imaging techniques which report definite biological event in living animals with genetic modification. With high sensitivity, simple operation and high precision, it is particularly applied in observing vital processes like viral infection and tumor growth in vivo. We summarize the principle of bioluminescence imaging, introduce its application in finding virus replication site, study of interferon (IFN) inhibiting-virus effect and real-time visualization of viral latent infection and reactivation, and preview the trend of bioluminescence imaging technological development. PMID- 21796977 TI - [Antimicrobial peptides peptaibols from trichoderma--a review]. AB - Peptaibols are a family of antimicrobial peptides, which are synthesized by non ribosomal peptide synthetases (NRPS) and contain high proportions of alpha aminoisobytyric acid (Aib). Up to now, 317 peptaibols have been identified, and the majority of them are produced by Trichoderma strains. In this review, we described the diversity, fermation, purification, identification and biosynthesis of peptaibols from Trichoderma. PMID- 21796978 TI - [Next-generation sequencing technologies and the application in microbiology--a review]. AB - Since its invention in 1970s, nucleic acid sequencing technology has contributed tremendously to the genomics advances. The next-generation sequencing technologies, represented by HiSeq 2000 from Illumina, SOLiD from Applied Biosystems and 454 from Roche, re-energized the application of genomics. In this review, we first introduced the next-generation sequencing technologies, then, described their potential applications in the field of microbiology. PMID- 21796979 TI - [Co-existence of resistance genes and their association with the genetic marker of integrons among multi-resistant Escherichia coli isolates]. AB - OBJECTIVE: To investigate co-existence of resistance genes (beta-lactamases, BLs, and aminoglycoside-modifying enzymes, AMEs) and their association with the genetic marker genes of Class I, II, III integrons carried by multiresistant Escherichia coli isolates. METHODS: We used VITEK-GNS to determine the susceptibility of 136 isolates to 14 antibiotics, disc agar diffusion test to confirm ESBL-producing isolates, PCR to analyze BLs, AMEs and integrons genes, conjugation and plasmids extraction to locate the methylase genes. RESULTS: We found that 70.59% of the isolates produced ESBLs. They showed stronger resistance against 9 antibiotics than isolates without ESBLs in 14 antibiotics. PCR amplification showed that the positive rate of BLs, AMEs and qacEdelta1-sul1 was 96.32% , 100% and 94.12%, respectively, but Class II, III integrons genes were negative. Only one strain was oprD2 gene negative. 90.44% of the isolates were both positive for BLs and qacEdelta1-sul1 genes, and 94.12% for AMEs and qacEdelta1-sul1 genes, but there was no statistical significance. 90.44% of the isolates were all positive for the 3 genes. 12 strains carried 16S rRNA methylase genes including armA (2.21%), rmtB (7.35%) while rmtA, rmtC, rmtD were negative. The conjugation assay and plasmids mapping results showed that the methylase genes were located on the 23 kb plasmid, and the efficiency of transformation was 83.3%. CONCLUSIONS: The results suggested that there was a tight correlation between the 3 genes (BLs, AMEs and qacEdelta1-sul1) and the incidences of multi resistance of Escherichia coli, but there was no correlation of the incidence of multi-resistance with Class II, III integrons. 16S rRNA methylase genes harboured plasmids of -23 kb which transformed other isolates within the same strains efficiently. PMID- 21796980 TI - [Metabolism of Rhizopus oryzae with xylose or glucose as carbon resource]. AB - OBJECTIVE: As one of the most abandon and cheapest recyclable bio-resources, cellulosic biomass appear to be the promising new energy if the two major components, glucose and xylose, are efficiently used. METHODS: We compared the metabolism of Rhizopus oryzae growing on glucose or xylose. We measured biomass accumulation, intercellular metabolite contents, and organic acids production. RESULTS: When cultured on xylose, the rate of bio-transformation reached 35.2% compared to 24.3% in the glucose. Intercellular contents accumulated much more by using xylose as sole carbon than using glucose. However, the quantity of organic acid was less with xylose than with glucose. In addition, during the coexistence of both substrates, Rhizopus oryzae utilizes glucose first, and xylose later when the glucose is almost exhausted. CONCLUSION: With our data analysis, both the NADH/NAD + and ATP quantity are differed between the utilization of two carbon resources. In xylose, biological macromolecule and biomass accumulation are in advantage, while in glucose, the inorganic acid production is enhanced. PMID- 21796981 TI - [Screening and breeding high 1,3-propanediol producing strains by genome shuffling]. AB - OBJECTIVE: To improve the tolerance of main metabolites, we used genome shuffling to achieve high 1,3-propanediol producing mutants. METHODS: Based on 96 deep-well palates containing prepared ended fed-batch broth as an efficient selection method, genome shuffling has been applied in strain improvement. RESULTS: Five high producers were obtained after genome shuffling (LSG1, LSG2, LSG4, LSG5 and LSG6). During batch fermentation (3 L), the 1, 3-propanediol production of the five mutants were improved 17.0%, 19.0%, 12.9%, 23.9% and 18.0% , compared with the parent strain; the conservations from glycerol were improved 17.7%, 20.0%, 13.3%, 24.4% and 17.7%. CONCLUSION: Genome shuffling was an efficient approach for strain improvement, and 96 deep-well palates containing fed-batch broth has been demonstrated as an efficient selection approach. PMID- 21796982 TI - [Effects of gene pta disruption on L-tryptophan fermentation]. AB - OBJECTIVE: To study the effects of gene pta disruption on biosynthesis of L tryptophan. METHODS: The pta gene of the L-tryptophan producing strain E. coli TRTH was disrupted by Red recombination technology and a pta mutant E. coli TRTHdeltapta was constructed. Fed-batch fermentation of E. coli TRTHdeltapta was carried out in 30-Liter fermentor to investigate the biomass, L-tryptophan production, organic acid content and the concentration of NH4+, lactate, pyruvate and succinate. The metabolic flux balance model of L-tryptophan synthesis by E. coli was established. Based on this model, the practical metabolic flux distribution of E. coli and its pta mutant were determined with the linear program planted in MATLAB software. RESULTS: Compared with E. coli TRTH, the pta mutant was able to maintain higher growth rate at exponential phase, the final biomass and the L-tryptophan production were increased by 52.7% and 46.8% respectively. Meanwhile, the data analysis of organic acids accumulated during fed-batch culture showed that the concentration of acetate was decreased to 2.5 g/L, which was only 19.5% of that of the parental strain; as the decreased concentration of succinate, the accumulation of pyruvate and lactate was increased. The concentration of Na+, K+, PO4(3-) were consistent with E. coli TRTH during the fed-batch culture, the concentration of NH4+ was decreased by 33.2%. The metabolic flux analysis indicated that EMP pathway and TCA cycle were reduced by 7.4% and 32.2% respectively, but PP pathway was increased by 8.4% compared with E. coli TRTH during the middle and late period of the fed-batch culture. CONCLUSION: In the process of L-tryptophan fermentation, pta gene deletion in E. coli TRTH led to change in metabolic flux and acetate content, which derepressed its inhibition on cell growth and production of L-tryptophan and finally made a substantial increase of bacterial biomass and L-tryptophan production. PMID- 21796983 TI - [Screening and identification of a strain with lipolytic activity against Jatropha oil and its catalytic capacity]. AB - OBJECTIVE: To screen lipases applied to biodiesel production, a lipase-producing microorganism was isolated and the enzyme was characterized. METHODS: A strain with lipolytic activity against Jatropha oil was isolated from the soil pretreated by Jatropha curcas L. seed and cultivated on Jatropha oil as sole carbon source. The organic solvent tolerance of the isolated strain and its lipase were measured. The esterification and transesterification catalyzed by the isolated lipase were surveyed. The isolated strain was identified according to the physiological and biochemical characteristics as well as 16S rDNA sequences analysis. RESULTS: The lipolytic activity of the strain LP-2 was 3.03 U/mL. The relative biomass of strain LP-2 in the media containing 5% (v/v) methanol was 87.3%. The residual activity of LP-2 lipase in 10% (v/v) hexane was 80.9%. LP-2 lipase could catalyze esterification between lauric acid or palmitic acid and n butanol, n-octanol, dodecanol or glycerol; stearic acid and n-octanol, dodecanol or glycerol; oleic acid and methanol, n-butanol, n-octanol or dodecanol. The transesterification of Jatropha oil with methanol could be catalyzed by LP-2 lipase. Strain LP-2 was identified as Staphylococcus epidermidis and named Staphylococcus epidermidis LP-2. CONCLUSION: S. epidermidis LP-2 lipase had the ability to catalyze esterification and transesterification reactions, which suggested that it had potential of producing biodiesel. PMID- 21796984 TI - [Purification, characterization of an extracellular dextranase from an isolated Penicillium sp]. AB - OBJECTIVE: To obtain new fungi producing dextranase,we screened and identified a strain F1001 showing high dextranase activities. We provided a new strain with dextranase activity for producing clinical dextran. METHODS: Morphological and ITS rDNA sequences homology analysis were performed to identify the strain F1001. The enzyme was purified to electrophoretic homogeneity by the steps of ammonium sulfate precipitation and Sepharose 6B column chromatography. We studied the catalytic properties and the mechanism of the dextranase, and activities of dextranase were measured with dextran 70 kDa as the substrate. RESULTS: The isolated strain F1001 was identifed as Penicillium aculeatum precisely by ITS rDNA sequences homology analysis. Its molecular mass was estimated to be about 66 kDa by SDS-PAGE. The optimal reaction temperature was 35 degrees C, and the optimum pH was 5.0, it was stable in the condition of pH 4.0 - 7.0 and under the temperature of 50 degrees C. The optimum substrate concentration was 3% (w/v). The final dextranase hydrolysis product was isomaltose, which proved that the enzyme was endodextranase and only had activity with dextran joined mainly by continual alpha, 1-6 glucosidic linkages. The K(m) for dextranase was calculated to be 3.55 x 10(-5) mol/L, and the V(max) was 4.29 x 10(-2) mol (Glu)/min x L. The enzyme activity was enhanced by Zn2+ and Cu2+, and the low concentration of Cu2+ could improve the dextranase activity to 134.7%. However, the enzyme was strongly inhibited by Mn2+. CONCLUSION: We isolated a new strain F1001 producing high dextranase activity and the enzyme was stable. These results may provide an important basis for industrial applications. PMID- 21796985 TI - [Expression of glycerol dehydrogenase gene in Escherichia coli by codon optimization]. AB - OBJECTIVE: To improve expression level of glycerol dehydrogenase gene gldA in Escherichia coli by means of codon optimization. METHODS: For immediately downstream region of initiation codon in gldA, we designed optimized sequence by choosing higher AT-content synonymous, in order that this region's AT-content was increased without changing the corresponding amino acids. Then we had wild gene gldA-WT site-directed mutagenesis depending on mega-primers PCR, so that physically optimized gene gldA-4 was acquired. We cloned gldA-4 into pET-32a(+) to construct expression plasmid pET-gldA4, which was transformed into Escherichia coli BL21 (DE3) for gaining engineering bacteria E. coli-4, by contrast engineering bacteria involved gldA-WT named E. coli-WT. After E. coli-4 and E. coli-WT were fermented in shake flasks,we measured enzyme activities of expression products with glycerol as substrate. RESULTS: Four gldA-4's bases in the second, fifth and sixth codon were different with gldA-WT, so AT-content of the optimized gene was up to 80.0% higher than the wild gene's 53.3%. Furthermore, enzyme activity of E. coli-4's crude extract was 191.3 U/mL more three times than E. coli-WT's 48.3 U/mL. CONCLUSION: This optimization scheme was quick and easy, but indeed increased dehydrogenase's activity. It possible becomes a universal method to improve heterogenous expression level of target genes. PMID- 21796986 TI - [Isolation, identification and characterization of cypermethrin-degrading strain L12]. AB - OBJECTIVE: To isolate and characterize bacteria to degrade cypermethrin (CP). METHODS: We used enrichment culture to isolate and characterize bacterial strains based on the observation of morphological and biochemical characters and analysis of 16S rRNA gene sequences. We determined the concentration of CP, metabolite, densities of strain cells and cell surface hydrophobicity (CSH) in pure culture liquid. RESULTS: We isolated a bacterium able to effectively degrade CP from polluted wastes of pesticide plant and assigned it as strain L12. Phylogenetic analysis based on 16S rRNA gene showed the similarity of 99% between strain L12 and Bacillus cereus. In pure culture with CP as the sole carbon and energy source, 85.6% of CP at initial concentration of 50 mg /L was degraded in 5 days. Thin layer chromatography (TLC) analysis of the culture extracts revealed presence of a metabolite (R(f)0.13), and HPLC analysis confirmed the retention time of the metabolite (2.26 min) corresponded with 3-phenoxybenzoic acid (3-PBA) standard. The method of microorganism adhering to hydrocarbon (MATH) was used to analyze strain L12 of the highest CSH of 68.91%. CONCLUSION: The results showed that strain L12 belonged to Bacillus cereus, which showed CSH and capacity to degrade CP to 3-PBA. PMID- 21796987 TI - [Characterization of Vibrio parahaemolyticus obtained from environment and cases of foodborne disease in Shenzhen, during 2006 - 2008]. AB - OBJECTIVE: To analyze the serological and genetic divergence in the Vibrio parahaemolyticus from environment and cases of foodborne disease, and to compare these two groups in terms of virulence and other biological traits. METHODS: Serotyping, multi-PCR, and pulse-field gel electrophoresis (PFGE) were carried out. RESULTS: The main serotypes of cases isolates were O3:K6 (40.8%), O1: KUT (7.1%), O4:K8 (7.1%), and the main serotypes of environmental isolates were O3:KUT (14.2%), O1: KUT (11.4%) and O2:K3 (11.4%). No O3:K6 strain was isolated from environment. Most cases isolates were tdh positive and trh negative, which account for 83.7%, while most environmental isolates were tdh negative and trh negative, which account for 88.6%. PFGE indicated that Clone P1 was the dominant clone cluster, including serotype O3: K6 (29 isolates), O4: K68 (4 isolates), O11: K36 (3 isolates), O1: K25 (2 isolates), and these strains were all obtained from cases of foodborne disease. No dominant clone cluster was found in environmental isolates. CONCLUSIONS: V. parahaemolyticus from cases of foodborne disease in Shenzhen mostly were hemolytic, tdh positive and trh negative, there were dominant PFGE type in cases isolates, the main serotype was O3:K6, while environmental isolates mostly were non-hemolytic, tdh negative and trh negative, no dominant PFGE type was found. PMID- 21796988 TI - [A series of excellent strategy to analyze environmental sample archaeal diversity]. AB - OBJECTIVE: Finding a series of archaeal 16S rRNA gene universal primer applied strategies to detect complex microbial diversity in environmental samples, especially with rapidly development of next generation sequencing technology challenge. METHODS: We used Oligocheck soft to simulate two pairs of archaeal 16S rRNA gene universal primers with RDP (Ribosomal database project) database 16S rRNA gene sequences matching percentage. In succession, the sediment sample was constructed for two clone libraries by using two pairs of archaeal 16S rRNA gene universal primers. RESULTS: The soft simulation matched percentage result suggests that primer f109/r958 is better than primer f21/r958. This result is consistent with RFLP and diversity index analyses by two clone libraries. CONCLUSION: Multi-primers and properly primer are used to recovery environmental microbiology diversity, which will be advanced in environmental microbial resolution. PMID- 21796989 TI - [Application of a model for gene local shuffling in ubiA mutation]. AB - As a transhydrogen in the mitochondrial respiratory chain, Coenzyme Q (CoQ) has a critical role in the metabolism. 4-hydroxybenzoate polyprenyltransferase (UbiA), which coded by ubiA gene, is the rate-limiting enzyme in the CoQ biosynthesis progress. However, the relationship between structure and function remains unclear. OBJECTIVE: To set up a synthetic oligonucleotide-based shuffling model and apply in the random mutation of DNA sequence of ubiA gene which codes putative active site. METHODS: By using ubiA knockout mutant of E. coli. MC4100 as receptor, we set up a local Shuffling model by replacing target sequence with a random sequence fragment. Sequences of mutants and their function were analyzed. RESULTS: After local Shuffling and two cycle of screening, we gained seven mutants. Compared to the wild type, most of the mutant amino sequences showed obvious change, and had different change trend of CoQ production. Sequencing result showed that three aspartic acid sites may be highly related to UbiA catalyze activity. CONCLUSION: The local Shuffling model we set up is feasible. By applying this model, we preliminary verified several location of key amino acid sites of UbiA. PMID- 21796990 TI - [Development of the soft independent modelling of class analogies model to discrimination Vibrio parahemolyticus by Smartongue]. AB - OBJECTIVE: To explore a new rapid detection method for detecting of Food pathogens. METHOD: We used the Smartongue, to determine the composition informations of the liquid culture samples and combined with soft independent modelling of class analogies (SIMCA) to analyze their respective species, then set up a Smartongue -SIMCA model to discriminate the V. parahaemolyticus. RESULTS: The Smartongue has 6 working electrodes and three frequency segments, we can built 18 discrimination models in one detection. After comparing all the 18 discrimination models, the optimal working electrodes and frequency segments were selected out, they were: palladium electrode in 1 Hz frequency segment, tungsten electrode in 100 Hz and silver electrode in 100 Hz. Then 10 species of pathogenic Vibrio were discriminated by the 3 models. The V. damsela, V. metschnikovii, V. alginalyticus, V. cincinnatiensis, V. metschnikovii and V. cholerae O serogroup samples could be discriminated by the SIMCA model of V. parahaemolyticus with palladium electrode 1 Hz frequency segment; V. mimicus and V. vulnincus samples could be discriminated by the SIMCA model of V. parahaemolyticus with tungsten electrode 100 Hz frequency segment; V. carcariae and V. cholerae non-O serogroup samples could be discriminated with the SIMCA model of V. parahaemolyticus in silver electrode 100 Hz frequency segment. The accurate discrimination of ten species of Vibrio samples is 100%. CONCLUSION: The Smartongue combined with SIMCA can discriminate V. parahaemolyticus with other pathogenic Vibrio effectively. It has a promising future as a new rapid detection method for V. parahaemolyticus. PMID- 21796991 TI - [Identification of yeasts isolated from Chenghai Lake, a plateau lake in Yunnan province]. AB - OBJECTIVE: The aims of this study were to investigate yeast diversity in the plateau lake and to explore the value of these yeasts in such ecological environment. METHODS: Yeasts were isolated from 9 water and 4 soil samples collected in Chenghai lake in Yunnan province. The isolates were identified by using large-subunit (26S) rDNA gene D1/ D2 domain sequence analysis and traditional methods. The ability of the yeast strains to produced various enzymes was tested. RESULTS: In total 64 yeast strains were isolated, these strains were identified as 22 species in 8 genera, including 4 suspected new species or variety. Genera Cryptococcus and Geotrichum were shared in the water and soil samples. Nine strains with secreted enzyme activities were selected. One of them could produce both protease and amylase. CONCLUSION: The preliminary result showed the biodiversity of yeasts in Chenghai lake and the application potential of the yeasts isolated. PMID- 21796992 TI - [Expression of PTX3 gene in Caco-2 cells treated with Lactobacillus acidophilus NCFM]. AB - OBJECTIVE: To study the expression of immunity and inflammatory mediator factor PTX3 in intestinal epithelial cells treated with Lactobacillus acidophilus NCFM and further to reveal the regulatory mechanism. METHODS: Caco-2 cells were cocultured with Lactobacillus acidophilus NCFM for 0, 2, 4, 8, 12 h and 0, 0.5, 1, 2, 4 h respectively, then the total RNA and protein were extracted. The expression of PTX3 gene was analyzed by Real Time RT-PCR. The phosphorylation levels of NF-kappaB was analyzed by Western Blot. Caco-2 cells were pretreated with PDTC for 30 min before cocultured with Lactobacillus acidophilus NCFM for 2 h, then the total RNA was extracted and the expression of PTX3 gene was analyzed by Real Time RT-PCR. RESULTS: Lactobacillus acidophilus NCFM could induce the expression of PTX3 in Caco-2 cells. The PTX3 expression peaked at 4 h after coculture. Then its expression gradually waned out. Lactobacillus acidophilus NCFM could rapidly activate the phosphorylation of NF-kappaB, and the expression of PTX3 was decreased notably after pretreated with PDTC for 30 min. CONCLUSION: Lactobacillus acidophilus NCFM could transiently regulate the immunity and inflammatory mediator factor PTX3 expression through rapidly activating NF-kappaB signaling pathway in Caco-2 cells. PMID- 21796993 TI - [Cholesterol-degrading by Lactobacillus plantarum LpT1 and LpT2 in vitro]. AB - OBJECTIVE: To explore the mechanism of cholesterol-degrading by Lactobacillus plantarum LpT1 and LpT2 in vitro. METHODS: After Lactobacillus plantarum LpT1 and LpT2 being inoculated and cultured in the medium MRS, MRS +CH, MRS + CH + S and MRS + CH + N, the cholesterol content in supernatant, deposit and cells, and the total cholesterol content before and after inoculation were determined and compared to primarily predict the mechanism of cholesterol-degrading by L. plantarum. RESULTS: The mechanism of cholesterol- degrading by L. plantarum LpT1 and LpT2 in vitro involved in metabolic and non-metabolic pathway. Non-metabolic pathway was related to co-precipitation and cell absorption. Metabolic pathway was due to the production of the special enzymes during the growth of L. plantarum which made the cholesterol degrade to be other materials and caused its content reduction. CONCLUSION: L. plantarum has shown its ability to degrade cholesterol in vitro. PMID- 21796994 TI - [Reexaminations of dosages in Shanghanlun: comparison of the dosages among decoctions, pills and powder formulations]. AB - This paper reveals the dosages of decoctions in Shanghanlun in relation of pills and powder formulations, and obtains following results. At the first examination of the system of weight, while Taohongjing shows three kinds of system of weight; [(1)1liang is equivalent to 14 g. (2) 1liang = 7 g (3) 1liang = 1.4 g], he describes the necessity of the corrective system of weight among the decoctions, the pills and the powder formulations. After Song dynasty, Zhusanfa, which is the method of preparing the decoction by placing powder ingredients of prescriptions in water and simmer, have been mainly adopted. In the term of Zhusanfa, although the whole quantities of prescriptions are written with the ancient weight unit, the notation of the dosage is indicated by the current weight unit, Qian. In Shanghanlun, since the dosage form seems to have been changed from the pills or the powders into the decoction, some of decoctions contain impractical dose for decoction. PMID- 21796995 TI - New methods for drug analysis in biological samples and other matrixes. PMID- 21796996 TI - Capillary methods for drug analysis. AB - This review gives an overview of the applicability of capillary electrophoresis, capillary liquid chromatography, capillary electrochromatography, and their derived techniques to analyze drug impurity mixtures, formulations, biological samples, and chiral compounds. For each application type, a few examples are given to illustrate the potential of the capillary technique. Details are provided about the capillaries used, chiral selectors, and stationary and mobile phases. PMID- 21796997 TI - Study and development of reversed-phase HPLC systems for the determination of 2 imidazolines in the presence of preservatives in pharmaceutical preparations. AB - Different HPLC chromatographic systems were investigated on a C18 ACE 5 pm, 150 x 4.6 mm id column for the determination of tymazoline, tramazoline, and antazoline, with either naphazoline or xylometazoline, in commercial preparations. For the development and optimization of the systems, a Response Surface Method (r=0.925-0.980) was used to illustrate the changes in k as a function of pH values and different salt concentrations. The simultaneous separation of 2-imidazolines was accomplished at 40 degrees C with 0.01 M ammonium acetate-methanol (50+50, v/v, pH 6.0) mobile phase at a flow rate of 1.2 mL/min. In order to deal with the usual coexistence of 2-imidazolines with benzethonium and benzalkonium chloride preservatives, it was necessary to use another chromatographic system, 0.01 M ammonium acetate-methanol (50+50, v/v) mobile phase on a cyano ACE 5 pm, 150 x 4.6 mm id column. As part of a more thorough theoretical investigation, a partial least-squares (PLS) technique was used for modeling the RP-HPLC retention data. The model was based on molecular structure descriptors of the analytes' X variables and on their retention time (Log K) Y. The goodness of fit was estimated by the PLS correlation coefficient (r2) and root mean square error of estimation values, which were 0.994 and 0.0479, respectively. PMID- 21796998 TI - Development and validation of an HPLC method for determination of ziprasidone and its impurities in pharmaceutical dosage forms. AB - Ziprasidone is known as a novel "atypical" or "second-generation" antipsychotic drug. A sensitive and reproducible method was developed and validated for determination of ziprasidone and its major impurities, which are significantly different in polarity. The separation is performed on a Waters Spherisorb octadecylsilyl 1 column (5.0 microm particle size, 250 x 4.6 mm id) using a gradient with mobile phase A [buffer-acetonitrile (80+20, v/v)] and mobile phase B [buffer-acetonitrile (10+90, v/v)] at a working temperature of 25 degrees C. The buffer was 0.05 M KH2PO4 solution with an addition of 10 mL triethylamine/L solution, adjusted to pH 2.5 with orthophosphoric acid. The flow rate was 1.5 mL/min, and the eluate was monitored at 250 nm using a diode array detector. Optimization of the experimental conditions was performed using partial least squares regression, for which four factors were selected for optimization: buffer concentration, buffer pH, triethylamine concentration, and temperature. The proposed validated method is convenient and reliable for the assay and purity control in both raw materials and dosage forms. PMID- 21796999 TI - Validation of an oil-in-water microemulsion liquid chromatography method for analysis of perindopril tert-butylamine and its impurities. AB - This paper describes the development and validation of a microemulsion liquid chromatography (MELC) method for simultaneous determination of perindopril tert butylamine and its impurities in bulk active substances and the pharmaceutical dosage form of tablets. An appropriate resolution with reasonable retention times was obtained for a microemulsion containing 0.24% (w/v) butyl acetate, 0.30% (w/v) ethyl acetate, 2% (w/v) sodium dodecyl sulfate, 7.75% (w/v) n-butanol, and 20.0 mM potassium dihydrogen phosphate, the pH of which was adjusted to 3.70 with 85% orthophosphoric acid. Separations were performed on a Nucleosil 120-5 butyl modified (C4), 250 x 4 mm, 5 microm particle size silica column at 40 degrees C, with a mobile phase flow rate of 1.25 mL/min. UV detection was performed at 254 nm. The established method was subjected to method validation, and required validation parameters were defined. Robustness testing, an important part of method validation, was performed as well. Since robustness validation can be conducted using different experimental designs, the Plackett-Burman design was applied due to its possibility of testing many factors at the same time. The validated MELC method was found to be suitable for the simultaneous determination of perindopril tert-butylamine and its impurities in pharmaceuticals. PMID- 21797000 TI - Development and validation of a high-performance thin-layer chromatographic method for determination of ofloxacin residues on pharmaceutical equipment surfaces. AB - An HPTLC method with densitometric quantification using fluorescence at 313 nm was developed and validated for the determination of ofloxacin residue in controlling pharmaceutical equipment cleanliness. Simulated samples at a residue level of 1 mg/m2 were prepared by spreading the calculated amount of ofloxacin solution on 1, 5, and 10 dm2 stainless steel surfaces. After evaporation of the solvent, the residue was removed by two ethanol wetted cotton swabs, which were thereafter extracted with the mixture of ethanol and Na2EDTA-water solution at pH 11 for 15 min with sonication. The extract and standards were applied on HPTLC silica gel 60 plates and then developed in a horizontal developing chamber from both sides using ethanol-conc. ammonia (4+1, v/v) as the mobile phase. The mean recovery (n=6) at 1 mg/m2 from 1, 5, and 10 dm2 was 95.3, 88.6, and 89.7% with the CV values 3.78, 4.41, and 4.97%, respectively. The absolute detection limit was 0.6 ng and the quantitation limit was 2 ng, but it was shown that these can be improved by immersion of the developed plate into a solution of liquid paraffin-n-hexane (1+2, v/v) to approximately 0.25 and 0.9 ng, respectively. The LOD of the method using detection without paraffin-n-hexane was 3, 0.6, and 0.3 microg/m2 by swabbing 1, 5, and 10 dm2, respectively. The method can be applied to routine control of pharmaceutical equipment cleanliness by sampling from stainless steel surface areas of 1 to 10 dm2 with acceptable residue limit/surface of 1 mg/m2. PMID- 21797001 TI - Chemometric detection of acetaminophen in pharmaceuticals by infrared spectroscopy combined with pattern recognition techniques: comparison of attenuated total reflectance-FTIR and Raman spectroscopy. AB - This paper presents and discusses the building of discriminant models from attenuated total reflectance (ATR)-FTIR and Raman spectra that were constructed to detect the presence of acetaminophen in over-the-counter pharmaceutical formulations. The datasets, containing 11 spectra of pure substances and 21 spectra of various formulations, were processed by partial least squares (PLS) discriminant analysis. The models found in the present study coped greatly with the discrimination, and their quality parameters were acceptable. A root mean square error of cross-validation was in the 0.14-0.35 range, while a root mean square error of prediction was in the 0.20-0.56 range. It was found that standard normal variate preprocessing had a negligible influence on the quality of ATR FTIR; in the Raman case, it lowered the prediction error by 2. The influence of variable selection with the uninformative variable elimination by PLS method was studied, and no further model improvement was found. PMID- 21797002 TI - Determination of neomycin and oxytetracycline in the presence of their impurities in veterinary dosage forms by high-performance liquid chromatography/tandem mass spectrometry. AB - Two HPLC/MS/MS methods, one for determination of neomycin sulfate and the other for determination of oxytetracycline hydrochloride in the presence of their impurities, were developed and validated. Separations were achieved with gradient elution on a C18 column. All components were ionized by positive-ion electrospray and detected by multiple reaction monitoring. Calibration curves were linear, with correlation coefficients >0.99. Precision of the methods was confirmed by RSD values of 0.34 and 0.71% for neomycin and oxytetracycline, respectively. Recovery values of 101.5 and 101.0%, respectively, indicated adequate accuracy. Analysis time for neomycin was 24 min, with the retention time of the main compound at 10.1 min; for oxytetracycline, the analysis time was 18 min, with the main peak at 9.95 min. Longer retention times than expected were a consequence of the necessity of chromatographic separation of isomers with the same ion transition. All impurities defined in the pharmacopoeias were determined and their identities confirmed. The methods were tested for QC of veterinary dosage forms (commercial powders and injections containing these antibiotics). PMID- 21797003 TI - Advantages of automation in plasma sample preparation prior to HPLC/MS/MS quantification: application to the determination of cilazapril and cilazaprilat in a bioequivalence study. AB - An HPLC/MS/MS method characterized by complete automation and high throughput was developed for the determination of cilazapril and its active metabolite cilazaprilat in human plasma. All sample preparation and analysis steps were performed by using 2.2 mL 96 deep-well plates, while robotic liquid handling workstations were utilized for all liquid transfer steps, including liquid-liquid extraction. The whole procedure was very fast compared to a manual procedure with vials and no automation. The method also had a very short chromatographic run time of 1.5 min. Sample analysis was performed by RP-HPLC/MS/MS with positive electrospray ionization using multiple reaction monitoring. The calibration curve was linear in the range of 0.500-300 and 0.250-150 ng/mL for cilazapril and cilazaprilat, respectively. The proposed method was fully validated and proved to be selective, accurate, precise, reproducible, and suitable for the determination of cilazapril and cilazaprilat in human plasma. Therefore, it was applied to a bioequivalence study after per os administration of 2.5 mg tablet formulations of cilazapril. PMID- 21797004 TI - Monolithic spin column: a new extraction device for analysis of drugs in urine and serum by GC/MS and HPLC/MS. AB - A monolithic spin column was developed for the extraction of analytes from biological materials. This column was constructed by packing a monolithic silica disk into a spin column. Sample loading, washing, and elution of the target drugs were accomplished simply by centrifugation of the column. Opiates and benzodiazepines are abused throughout the world. Identification and quantification of these drugs is very important to solve crimes or the cause of death. Three opiates (morphine, codeine, and dihydrocodeine) were extracted from urine and serum by using the column. After conversion to trimethylsilyl derivatives of the opiates by vigorous mixing with the derivatizing reagent, the solution was subjected to GC/MS. A linear curve was observed for opiates from 10 to 2500 ng/mL in urine and 5 to 1200 ng/mL in serum, respectively (correlation coefficient > 0.996). For benzodiazepines, the hydroxyl metabolites of triazolam and etizolam were extracted from urine using the column, and the eluate was directly analyzed by HPLC/MS without evaporation. The LOD values were at the ppb level, with RSD values lower than 15%. The proposed methods were successfully applied to clinical and forensic cases, and good agreement of results was obtained compared to conventional methods. PMID- 21797005 TI - Development and validation of micellar liquid chromatographic methods for the determination of antibiotics in different matrixes. AB - Antibiotics are the most important bioactive and chemotherapeutic compounds to be produced by microbiological synthesis, and they have proved their worth in a variety of fields, such as medicinal chemistry, agriculture, and the food industry. Interest in antibiotics has grown in parallel with an increasingly high degree of productivity in the field of analytical applications. Therefore, it is necessary to develop chromatographic procedures capable of determining various drugs simultaneously in the shortest possible time. Micellar liquid chromatography (MLC) is an RP-HPLC technique that offers advantages over conventional HPLC as far as sample preparation, selectivity, and versatility are concerned. Its main advantage is that samples can be injected directly into the chromatographic system with no previous preparation step. This paper mainly focuses on the results of the authors' own recent research and reports the chromatographic conditions for determination of various antibiotics (penicillins, quinolones, and sulfonamides) in different matrixes (pharmaceuticals, biological fluids, and food). The work of other authors on MLC-based antibiotic determination has been included. PMID- 21797006 TI - Development and validation of a UHPLC method for the determination of flavonoids in red wine. AB - A simple and fast ultra-high-performance liquid chromatography (UHPLC) method was developed for the identification and quantification of the following flavonoids in red wine: (+/-)-catechin, (-)-epicatechin, rutin, quercitrin, hesperidin, neohesperidin, (+/-)-naringenin, hesperetin, and chrysin. Chromatographic separation of the flavonoids was performed on a Chromolith Fast Gradient C18e column. A gradient elution was used with mobile phases consisting of 0.1% formic acid in water and acetonitrile. UV detection was performed at 280 nm. A complete separation of flavonoids was possible within 6 min. The calibration curves showed good linearity (R2 > or = 0.9990) in the selected range of each analyte; the LOD ranged between 0.06 and 0.19 microg/mL. An optimized sample preparation method utilized SPE. The Oasis HLB column with the highest recoveries was selected for the preconcentration step. This method was successfully applied to the determination of these flavonoids in the red wine samples with excellent results. PMID- 21797007 TI - Rapid microwave-assisted extraction and HPTLC-photodensitometric method for the quality assessment of Boerhaavia diffusa L. AB - A rapid and cost-effective method for the extraction of rotenoids in Boerhaavia diffusa L., based on the use of microwave-assisted extraction (MAE), is proposed. The conventional reflux, soxhlet, and maceration extraction methods were also conducted to validate the reliability of the new method. Under the optimized conditions, two rotenoids (boeravinone B and E) were extracted and quantified by HPTLC. The yield of boeravinone B and E achieved by MAE was 0.15 and 0.32% (w/w), respectively. The result showed that MAE-HPTLC is a simple, rapid, and solvent sparing method for the extraction and quantitation of boeravinone B and E from B. diffusa L. PMID- 21797008 TI - Dietary supplement laboratory quality assurance program: the first five exercises. AB - The National Institute of Standards and Technology (NIST) has established a Dietary Supplement Laboratory Quality Assurance Program (DSQAP) in collaboration with the National Institutes of Health Office of Dietary Supplements. Program participants measure concentrations of active and/or marker compounds as well as nutritional and toxic elements in food and dietary supplements distributed by NIST. Data are compiled at NIST, where they are analyzed for accuracy relative to reference values and concordance among the participants. Performance reports and certificates of completion are provided to participants, which can be used to demonstrate compliance with current Good Manufacturing Practices as promulgated by the U.S. Food and Drug Administration. The DSQAP has conducted five exercises to date, with total participation including more than 75 different laboratories and many more individual analysts. PMID- 21797009 TI - Determination of fat-soluble vitamins and carotenoids in standard reference material 3280 multivitamin/multielement tablets by liquid chromatography with absorbance detection. AB - The concentrations of selected fat-soluble vitamins and carotenoids in Standard Reference Material (SRM) 3280 Multivitamin/Multielement Tablets have been determined by two independent LC methods, with measurements performed by the National Institute of Standards and Technology (NIST). This SRM has been prepared as part of a collaborative effort between NIST and the National Institutes of Health Office of Dietary Supplements. The SRM is also intended to support the Dietary Supplement Ingredient Database that is being established by the U.S. Department of Agriculture. The methods used at NIST to determine the concentration levels of vitamins A and E, and beta-carotene in the SRM used RPLC with absorbance detection. The relative precision of these methods ranged from 2 to 8% for the analytes measured. SRM 3280 is primarily intended for use in validating analytical methods for the determination of selected vitamins, carotenoids, and elements in multivitamin/multielement tablets and similar matrixes. PMID- 21797010 TI - Liquid chromatographic method for the simultaneous determination of eprosartan and hydrochlorothiazide in tablets and human plasma. AB - A new, specific, and sensitive RP-HPLC method was developed for the simultaneous determination of eprosartan (EPR) and hydrochlorothiazide (HCT). Good chromatographic separation was achieved using a 250 x 4.6 mm id, 5 microm particle size Symmetry C18 column. The mobile phase acetonitrile-0.1 M phosphate buffer (35+65, v/v), pH 4.5, was pumped at a flow rate of 1 mL/min, with UV detection at 275 nm. The method showed good linearity in the ranges of 0.5-50 and 0.1-10 microg/mL, with LOD of 0.06 and 0.02 microg/mL and LOQ of 0.20 and 0.08 microg/mL for EPR and HCT, respectively. The proposed method was successfully applied for the analysis of the studied drugs in their synthetic mixture and co formulated tablets. The method was further extended to the in vitro and in vivo determination of the two drugs in spiked and real human plasma. Interference likely to be encountered from the co-administered drugs was studied. PMID- 21797011 TI - Determination of enantiomers of atenolol and propranolol in pharmaceutical formulations by HPLC. AB - A validated HPLC-UV method was developed for the determination of R(-), S(+) atenolol and R(-), S(+)-propranolol in pharmaceutical formulations. The proposed method required no elaborate sample preparation and was found to be selective, linear, and repeatable within the established ranges. Atenolol and propranolol isomers were separated using a Chirex 3022 (S) column with the mobile phases hexane-dichloromethane-methanol-trifluoroacetic acid (35 + 35 + 5 + 0.25, v/v/v/v) and hexane-dichloromethane-ethanol-trifluoroacetic acid (55 + 40 + 5 + 0.25, v/v/v/v), respectively. The LOD values of R(-) and S(+)-atenolol were 12.3 and 9.86 microg/mL, respectively, and 0.61 and 0.89 microg/mL, respectively, for R(-) and S(+)-propranolol. Retention times of R(-)-propranolol and S(+) propranolol were 12.4 and 14.3 min, respectively, and 29.06 and 32.71 min, respectively, for (R)-atenolol and (S)-atenolol. The proposed method was applied to the determination of enantiomers in pharmaceutical formulations, and no interference from any excipients was found. PMID- 21797012 TI - Simultaneous determination of benzimidazoles and their metabolites in plasma using high-performance liquid chromatography/tandem mass spectrometry: application to pharmacokinetic studies in rabbits. AB - An HPLC/MS/MS method was developed for the simultaneous determination of the following benzimidazole anthelmintics and metabolites in plasma: flubendazole, albendazole, fenbendazole, mebendazole, thiabendazole, hydrolyzed flubendazole, albendazole sulfoxide, albendazole sulfone, albendazole aminosulfone, oxfendazole, fenbendazole sulfone, aminomebendazole, hydroxymebendazole, and 5 hydroxythiabendazole. The sample preparation process involved a pH-dependent extraction of the analytes. Chromatographic separation was performed on a C18 column with a mobile phase gradient starting with methanol-water (20 + 80, v/v) containing 0.1% formic acid. The overall average recoveries of the analytes based on a matrix-matched calibration ranged from 75.0 to 120.0%, with RSD values of <20.0%. The LODs ranged from 0.08 to 2.0 microg/kg and the LOQs from 0.3 to 5.0 microg/kg. The validated method was used in pharmacokinetic studies of benzimidazole compounds in rabbits, and the elimination of the metabolites was measured quantitatively. PMID- 21797013 TI - Robust and sensitive high-performance liquid chromatographic-UV detection technique for the determination of tigecycline in rabbit plasma. AB - An isocratic HPLC method with detection at 248 nm was developed and fully validated for the determination of tigecycline in rabbit plasma. Minocycline was used as an internal standard. A Hypersil BDS RP-C18 column (250 x 4.6 mm, 5 microm particle size) was used with the mobile phase phosphate buffer (pH 7.10, 0.070 M)-acetonitrile (76 + 24, v/v) at a flow rate of 1.0 mL/min. The elution time of tigecycline and minocycline was approximately 8.1 and 9.9 min, respectively. Calibration curves of tigecycline were linear in the concentration range of 0.021-3.15 microg/mL in plasma. The LOD and LOQ in plasma were estimated as 7 and 21 ng/mL, respectively. The intraday and interday precision values of the method were in the range of 5.0-7.1 and 5.6-9.1%, while the corresponding accuracy values were in the ranges of 92.8-111.1 and 97.6-102.3%, respectively. At the LOQ, the intraday precision was 18.7%, while intraday and interday accuracy values were 97.3 and 98.0%, respectively. Robustness of the proposed method was studied using a Plackett-Burman experimental design. A pharmacokinetic profile is presented for confirmation of the applicability of the method to pharmacokinetic studies. PMID- 21797014 TI - Evaluation of TA10 broth for recovery of heat- and freeze-injured Salmonella from beef. AB - The Bacteriological Analytical Manual (BAM) Salmonella pre-enrichment broth [lactose (LAC) broth], buffered peptone water, and universal pre-enrichment (UP) broth were compared with TA10 broth, developed in our laboratory, for recovery of heat- and freeze-injured Salmonella (55 degrees C for 2-20 min and -20 degrees C for 2 months, respectively) from beef. Beef samples were contaminated with single Salmonella serovars, and contamination levels of 0.44 to <0.001 most probable number (MPN)/g and 0.74 to 0.14 MPN/g were used for heat- and freezing-induced injury studies, respectively. Twenty test portions (25 g) of the contaminated beef were pre-enriched in each broth, and the BAM Salmonella culture method was used thereafter. There was a significant difference (chi2 = 7.73) in recovery of heat-injured Salmonella between TA10 broth and LAC broth, 189 (67.5%) versus 156 (55.7%) positive samples, respectively, determined by plating onto selective agars and identification by biochemical tests. For the recovery of freeze-injured Salmonella, there was a significant difference (chi2 = 24.7) between TA10 and LAC broth, 189 (72.7%) versus 133 (51.2%) positive samples, respectively. TA10 broth was more effective than LAC broth and UP broth for recovery of freeze-injured Salmonella. The results indicate that TA10 broth should be used instead of LAC broth for testing of beef that may be contaminated with heat- and freeze-injured Salmonella spp. PMID- 21797015 TI - DuPont Qualicon BAX System assay for genus Listeria 24E. AB - The new BAX System PCR Assay for Genus Listeria 24E was evaluated for detecting Listeria spp. in frankfurters, spinach, cooked shrimp, queso fresco cheese, and on stainless steel surfaces with a single-stage enrichment in BAX System 24 Listeria Enrichment Broth (24 LEB). Method comparison studies performed on samples with low-level inoculates showed that the BAX System demonstrates a sensitivity equivalent or superior to the U.S. Food and Drug Administration's Bacteriological Analytical Manual and the U.S. Department of Agriculture-Food Safety and Inspection Service culture methods, but with a significantly shorter time to result. Tests to evaluate inclusivity and exclusivity returned no false negative and no false-positive results on a diverse panel of isolates, and tests for lot-to-lot variability and tablet stability demonstrated consistent performance. Ruggedness studies determined that none of the factors examined, within the range of deviations from specified parameters examined, affect the performance of the assay. PMID- 21797016 TI - Measurement of aflatoxin M1 in milk by ultra-high-performance liquid chromatography/tandem mass spectrometry. AB - A sensitive method was developed using ultra-high-performance liquid chromatography (UHPLC)/MS/MS with positive electrospray ionization for determining aflatoxin M1 (AFM1) in milk and milk powder. A 50 mL quantity of low fat liquid milk containing 100 ng/L AFM1, was prepared using immunoaffinity columns with a mean recovery rate of 79% (n = 3). UHPLC columns (BEH C18, BEH HILIC, and HSS T3) greatly reduced the chromatographic time and lowered the instrumental detection limits (IDLs) 16 to 58 times compared to an HPLC column (Betabasic C18). The HSS T3 column was chosen because it provided a low IDL (0.11 pg) and the lowest ion suppression of signal intensity (63.4%) among the tested columns. Matrix-fortified calibration curves were used for quantification and showed good linearity (r > 0.997) at 0.05-500 ng/mL. The LOD was 0.18 ng/kg for milk and 2.08 nglkg for milk powder, based on the signal intensity of the confirmatory product ion (m/z 259.1), which was less abundant than the quantitative product ion (m/z 273.1). Certified reference materials of milk powder at three levels (<0.05, 0.111 +/- 0.018, and 0.44 +/- 0.06 microg/kg) were measured within a day and between days; the results were all close to the certified levels with low variations (RSDs < 15%), showing good precision and accuracy. PMID- 21797017 TI - Rapid determination of fumagillin residues in honey by liquid chromatography tandem mass spectrometry using the QuEChERS method. AB - A new, rapid, and efficient method for determining the fumagillin residues in honey was developed. The samples extracted were analyzed using LC/MS/MS. Chromatographic separation of fumagillin was performed in gradient mode on a C8 column (100 x 2.0 mm, 5 microm) at 40 degrees C. The mobile phase consisted of a mixture of 2 mM ammonium formate-0.01% formic acid solution and methanol; the flow rate was set to 0.2 mL/min. Under these conditions, it was possible to measure fumagillin and its isomers as a single peak. The sample preparation procedure used is based on the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method, which is fast (approximately 30 min) and uses less organic solvent. The fumagillin was extracted with acetonitrile containing 0.1% formic acid, then purified using a solid-phase extraction method with an Oasis mixed mode weak anion-exchange cartridge. The overall recovery of fumagillin ranged from 88.1 to 99.4%; the intra- and interassay CVs were <4.5% and <4.9%, respectively. The LOQ was 0.1 microg/kg. LC/MS/MS coupled with the QuEChERS method showed strong potential as a method for determining fumagillin residues in honey. PMID- 21797018 TI - Validation study of a rapid ELISA for detection of histamine in tuna. AB - Neogen Corp. has developed an improved Veratox histamine test kit for the detection of histamine in tuna tissue. The purpose of this study was to validate the method under the requirements of AOAC Research Institute (RI) Performance Tested Methods. Three AOAC Official Methods for histamine (954.04, 957.07, and 977.13) and one ELISA method have been performance tested by the AOAC RI. The most popular is AOAC Official Method 977.13, the fluorometric method, which is considered the reference method, but is complicated and time-consuming. The need for a rapid ELISA test kit to be validated by the AOAC RI exists. PMID- 21797019 TI - Determination of fumonisins B1 and B2 in corn-based foods for infants and young children by LC with immunoaffinity column cleanup: interlaboratory validation study. AB - A liquid chromatographic method for the determination of fumonisins B1 (FB1) and B2 (FB2) in corn-based foods for infants and young children was subjected to an interlaboratory validation study involving 11 laboratories. Five blind duplicate sample pairs of each matrix were analyzed to establish the accuracy, repeatability, and reproducibility of the method. Mass fractions in the baby food samples ranged from 89.1 to 384.4 microg/kg FB1 and from 22.5 to 73.6 microg/kg FB2. The method involved a warm extraction with citrate phosphate buffer-methanol acetonitrile (50 + 25 + 25, v/v/v), a cleanup through an immunoaffinity column, and an end-determination of fumonisins by LC after automated precolumn derivatization with o-phthaldialdehyde reagent. RSDs for within-laboratory repeatability (RSDr) ranged from 6.8 to 23.5% for FB1 and 7.6 to 22.9% for FB2. RSDs for between-laboratory reproducibility (RSDR) ranged from 15.4 to 26.2% for FB1 and 21.6 to 36.3% for FB2. Mean FB1 recoveries from baby foods spiked at 100.0 and 250.0 microg/kg were 89 and 96%, respectively; for FB2 spiked foods at 25.0 and 62.5 microg/kg recoveries were 90 and 85%, respectively. HorRat values ranged from 0.8 to 1.2 for FB1, whereas for FB2 they ranged from 0.9 to 1.4 when calculated according to Horwitz, and from 1.0 to 1.7 when calculated according to Thompson, indicating an acceptable among-laboratory precision for all matrixes (HorRat values <2). PMID- 21797020 TI - Determination of lipophilic toxins by LC/MS/MS: single-laboratory validation. AB - An LC/MS/MS method has been developed, assessed, and intralaboratory-validated for the analysis of the lipophilic toxins currently regulated by European Union legislation: okadaic acid (OA) and dinophysistoxins 1 and 2, including their ester forms; azaspiracids 1, 2, and 3; pectenotoxins 1 and 2; yessotoxin (YTX), and the analogs 45 OH-YTX, Homo YTX, and 45 OH-Homo YTX; as well as for the analysis of 13-desmetil-spirolide C. The method consists of duplicate sample extraction with methanol and direct analysis of the crude extract without further cleanup or concentration. Ester forms of OA and dinophysistoxins are detected as the parent ions after alkaline hydrolysis of the extract. The validation process of this method was performed using both fortified and naturally contaminated samples, and experiments were designed according to International Organization for Standardization, International Union of Pure and Applied Chemistry, and AOAC guidelines. With the exception of YTX in fortified samples, RSDr below 15% and RSDR were below 25%. Recovery values were between 77 and 95%, and LOQs were below 60 microg/kg. These data together with validation experiments for recovery, selectivity, robustness, traceability, and linearity, as well as uncertainty calculations, are presented in this paper. PMID- 21797021 TI - Development of quality assessment method for optically active food flavor chemicals. AB - A quality assessment method for commercially available, optically active flavor compounds, namely, menthol, menthyl acetate, borneol, perillaldehyde, and 1,8 cineol, was developed. A gas chromatograph equipped with a flame ionization detector and a DB-5ms capillary column was used for the chemical purity test. A GC/MS with a beta-DEX cyclodextrin column was used for the optical purity test, by which the enantiomeric separation of each flavor compound was achieved. Enantiomeric excess was calculated as an expression of optical purity. Of the 25 standard samples subjected to the chemical purity test, six were found to have lower purity than the data provided by the manufacturers. When the same samples were subjected to the optical purity test, 11 were found to have lower purity than that indicated on the reagent labels. These results suggest that there is a need to conduct an optical purity test, in addition to a chemical purity test, for the quality assessment of flavor standards. PMID- 21797022 TI - Analysis of pesticides residues in fresh produce using buffered acetonitrile extraction and aminopropyl cleanup with gas chromatography/triple quadrupole mass spectrometry, liquid chromatography/triple quadrupole mass spectrometry, gas chromatography/ion trap detector mass spectrometry, and GC with a halogen specific detector. AB - A rapid and inexpensive multiresidue method for determining pesticides in fruits and vegetables is presented. Extraction of a 15 g sample with 15 mL acetonitrile was followed by buffering with magnesium sulfate, sodium chloride, sodium citrate dihydrate, and disodium citrate. Acidification with formic acid prior to dispersive cleanup with aminopropyl sorbent and magnesium sulfate was used to stabilize base-sensitive pesticides such as chlorothalonil. Extracts were concentrated to 2 g/mL. Analyses were conducted by GC/ion trap detector MS, GC halogen-specific detector, and LC/triple quadrupole MS. Accuracy and repeatability for 166 compounds in tomato, potato, and cabbage were 70-120% and <20% CV in 85% of the compounds, respectively. Reproducibility over a 4 month period in multiple commodities and analytical conditions was 62-124%, with CVs better than 30% for 91% of the compounds. Supply cost/sample was reduced 66%, and time to extract a batch of 24 samples was reduced by half compared to the prior method that used a 50 g sample, 100 mL acetonitrile, multiple SPE columns, and additional instrumentation. Additional extraction studies were conducted in tomatoes, oranges, and green beans at 4 g/mL using a GC/MS triple quadrupole system with a programmable temperature vaporization inlet. Recoveries of 70-120% were achieved in 93% of all compounds in green beans, 95% in tomatoes, and 97% in oranges. PMID- 21797023 TI - Validation of a digestion system using a digester block/cold finger system for the determination of lead in vegetable foods by electrothermal atomic absorption spectrometry. AB - This paper presents the validation of a system for sample digestion using a digester block/cold finger to determine the lead content in vegetables by electrothermal atomic absorption spectrometry (ETAAS). After mineralization, lead contents were determined by ETAAS using a calibration curve based on aqueous standards prepared in 2.60 M nitric acid solutions containing 5 microg ammonium phosphate as chemical modifier. A pyrolysis temperature of 900 degrees C and atomization temperature of 2000 degrees C were used. This method allowed the determination of lead with a characteristic mass of 35 pg; LOD and LOQ of 0.6 and 2 nglg, respectively, were found. The precision was investigated in terms of reproducibility and repeatability. Reproducibility was estimated by analysis of nine different portions of a certified reference material (CRM) of spinach leaves, and the repeatability was determined through the analysis of nine aliquots of the same solution. The reproducibility and repeatability were found to be 4.27 and 2.94% RSD, respectively. The accuracy was confirmed by analysis of whole meal flour, spinach leaves, and orchard leaves CRMs, all furnished by the National Institute of Standards and Technology. Lead contents were measured using the newly developed technique in 11 different potato samples. The lead contents ranged from 12.80 to 69.27 ng/g, with an average value of 28.59 ng/g. These values were in agreement with data reported in the literature. PMID- 21797024 TI - Validation of a method for arsenic speciation in food by ion chromatography inductively coupled plasma/mass spectrometry after ultrasonic-assisted enzymatic extraction. AB - A fully validated and rapid quantitative method is presented for determination of inorganic arsenic [arsenite, As(III) and arsenate, As(V)] and organic arsenic species (methylarsonic acid, dimethylarsinic acid, and arsenobetaine) by ion chromatography paired with inductively coupled plasma/MS after ultrasonic assisted enzymatic extraction (UAEE) in rice- and seafood-based raw materials and finished products. This method gives toxicological meaning to arsenic analysis, since the sum of the toxic chemical forms As(III) and As(V) can be determined. In contrast to classical water-methanol extraction, UAEE enables drastic acceleration of sample extraction (5 min instead of several hours), while total arsenic extraction efficiency is improved without species conversion. Validation was performed to evaluate the method for selectivity, linearity, LOD/LOQ (0.007 0.020 mg/kg), trueness, precision (HorRat values, 0.2-0.6), recovery (93-122%), and uncertainty. The method was also satisfactorily tested using two proficiency tests. Performance characteristics are reported for four certified reference materials, standard reference material (SRM) 1568a (rice flour), Institute for Reference Materials and Measurements 804 (rice flour), SRM 2976 (mussel tissue), certified reference material-627 (tuna fish), and several commercial food samples populating five AOAC triangle food sectors. The results indicated that this speciation method is cost-efficient, time-saving, and accurate, as well as fit for-purpose, according to International Organization for Standardization/International Electrotechnical Commission 17025:2005 standard, and could be used for routine analysis. PMID- 21797025 TI - Flame atomic absorption determination of trace amounts of cadmium after preconcentration using a thiol-containing task-specific ionic liquid. AB - Dispersive liquid-liquid microextraction (DLLME) based on a task-specific ionic liquid (TSIL) was developed for the extraction and preconcentration of trace amounts of cadmium from aqueous samples, followed by flame atomic absorption spectrometry (FAAS) determination. In the proposed approach, cadmium ions are extracted from aqueous samples using small volumes of trioctylmethylammonium thiosalicylate (TOMATS) dissolved in acetone. TOMATS is a thiol-containing TSIL that can form metal thiolate complexes due to the chelating effect of the ortho positioned carboxylate group relative to the thiol functionality. The main parameters affecting the performance of DLLME based on TSIL, such as pH, amount of TOMATS, extraction time, injection volume, salt addition, and centrifugation time, were optimized. Under optimum conditions, an LOD of 1.16 ng/mL and a good RSD of 1.8% at 60.0 ng/mL were obtained (n=7). The proposed method was applied to tap water, wastewater, well water, and milk samples. The results showed that DLLME based on TSIL combined with FAAS is a rapid, simple, sensitive, selective, low cost, volatile organic solvent-free, and efficient analytical method for the separation and determination of trace amounts of cadmium ions. PMID- 21797026 TI - Multiresidue analysis of multiclass plant growth regulators in grapes by liquid chromatography/tandem mass spectrometry. AB - A selective and rapid multiresidue analysis method is presented for simultaneous estimation of 12 plant growth regulators (PGRs), namely, auxins (indol-3-acetic acid, indol-3-butyric acid, and naphthyl acetic acid), cytokinins (kinetin, zeatin, and 6-benzyladenine), gibberellic acid (GA3), abscisic acid, and synthetic compounds, namely, forchlorfenuron, paclobutrazole, isoprothiolane, and 2,4-dichlorophenoxy acetic acid (2,4-D) in bud sprouts and grape berries at the development stages of 2-3 and 6-8 mm diameters, which are the critical phases when exogenous application of PGRs may be necessary to achieve desired grape quality and yield. The sample preparation method involved extraction of plant material with acidified methanol (50%) by homogenization for 2 min at 15000 rpm. The pH of the extract was enhanced up to 6 by adding ammonium acetate, followed by homogenization and centrifugation. The supernatant extract was cleaned by SPE on an Oasis HLB cartridge (200 mg, 6 cc). The final extract was measured directly by LC/MS/MS with electrospray ionization in positive mode, except for 2,4-D, GA3, and abscisic acid extracts, which required analysis in negative mode. Quantification by multiple reaction monitoring (MRM) was supported with full-scan mass spectrometric confirmation using "information-dependent acquisition" triggered with MRM to "enhanced product ionization" mode of the hybrid quadrupole ion trap mass analyzer. The LOQ of the test analytes varied between 1 and 10 ng/g with associated recoveries of 80-120% and precision RSD <25% (n = 8). Significant matrix-induced signal suppression was recorded when the responses for pre- and postextraction spikes of analytes were compared; this could be resolved by using matrix-matched calibration standards. The method could successfully be applied in analyzing incurred residue samples and would, therefore, be useful in precisely deciding the necessity and dose of exogenous applications of PGRs on the basis of measured endogenous levels. PMID- 21797027 TI - Determination of some heavy metals by flame atomic absorption spectrometry before coprecipitation with neodymium hydroxide. AB - A procedure is described for the determination of trace amounts of Cd(II), Ni(II), Cu(II), Pb(II), Fe(III), Co(II), and Mn(II) that combines flame atomic absorption spectrometry with neodymium hydroxide coprecipitation. The influences of analytical parameters (amount of neodymium, pH of the model solutions, etc.) that affect quantitative recoveries of the analyte ions were investigated. The effects of concomitant ions were also examined. The detection limits for analytes were found in the range of 0.2-3.3 microg/L. The validation of the presented procedure was controlled by analysis of certified reference materials (National Institute of Standards and Technology 1570a spinach leaves and TMDA 54.4 fortified lake water). The applications of the procedure were performed by the analysis of water, food, and herbal plants from Turkey. PMID- 21797028 TI - Selective determination of arbutin in cosmetic products through online derivatization followed by disposable electrochemical sensor. AB - An online derivatization followed by a disposable electrochemical sensor was used for the determination of arbutin (AR) in cosmetic products. The AR was chemically oxidized by MnO2 and subsequently reduced at inexpensive screen-printed carbon electrodes using a low detection potential which improved the selectivity of the method. The effects of various parameters, such as solution pH, detection potential, and flow rate of the mobile phase, were studied in detail. Under optimal conditions [pH 1.6 (0.1 M H3PO4), detection potential 0.0 V (versus Ag/AgCl), flow rate 0.6 mL/min], the linear range for AR was 0.1-1500 ppm (r2 = 0.999) with LOD of 30.06 ppb (S/N = 3). The practical application of the proposed method was demonstrated by the determination of arbutin concentration in commercial cosmetic products. PMID- 21797029 TI - Comparison of the effectiveness of recent extraction procedures for antibiotic residues in bovine muscle tissues. AB - Acetonitrile extraction followed by primary-secondary amine dispersive SPE cleanup QuEChERS (quick, easy, cheap, effective, rugged, and safe), was compared to pressurized liquid extraction (PLE) using water at 70 degrees C for 10 min at 1500 psi for the determination of 16 veterinary drugs in bovine muscle tissues by LC/MS/MS. PLE was significantly more effective for the extraction of veterinary drugs (ranging from 69 to 103% with RSD < or = 18%) than QuEChERS (ranging from 19 to 89% with RSD < or = 19%). Linearity of the calibration curves was obtained over the range considered from 10 microg/kg or LOQ to 1000, microg/kg) with r2 > or = 0.99 for all the analytes by both methods. Although an internal standard was used, matrix effects were corrected using matrix- matched standards. LODs were from 5 to 30 microg/kg for PLE and from 10 to 100 microg/kg for QuEChERS. To establish and assess the most efficient conditions for each extraction method, statistical parametric and nonparametric tests were used. PLE with water almost eliminates the use or generation of hazardous wastes. The two methods were applied successfully in a routine analysis during surveys in 2008. PMID- 21797030 TI - Bait and the susceptibility of American lobsters Homarus americanus to epizootic shell disease. AB - Shell disease (SD) has been observed in lobster populations for almost a hundred years, but recently, rates of an epizootic form of shell disease (ESD) have increased in the southern New England (USA) area. A large proportion of fish in the diet of American lobsters Homarus americanus has been linked to increased rates of SD. Therefore, the use of fish as lobster bait may be linked to increased ESD rates in lobsters. Lobsters from the western portion of Martha's Vineyard, MA (41 degrees N, 71 degrees W), were randomly divided into 3 groups of 16 and exposed to dietary treatments (100% herring; 48% crab, 48% blue mussel and 4% plant matter; or 50% herring, 24% crab, 24% mussel, 2% plant matter) to determine if lobster tissue delta15N levels reflected diet. The results of the feeding experiment confirmed that differences in diet are observed in the delta15N levels of lobster muscle tissue. The delta15N levels of tissue samples from 175 wild lobsters with varying degrees of ESD were unrelated to ESD severity but did indicate lobsters were eating large amounts of fish (bait). This result does not support the speculation that fish used as bait is contributing to ESD outbreaks in portions of the southern New England area. PMID- 21797031 TI - Detection and quantification of the crayfish plague agent in natural waters: direct monitoring approach for aquatic environments. AB - Aphanomyces astaci, a specialised parasite of North American freshwater crayfish, is the disease agent of crayfish plague that is lethal to European freshwater crayfish. The life cycle of A. astaci has been inferred from experimental laboratory studies, but less is known about its natural sustainability and ecology. To address such questions, tools for monitoring of A. astaci directly in aquatic environments are needed. Here, we present an approach for detecting and quantifying A. astaci directly from water samples using species-specific TaqMan minor groove binder real-time PCR. Samples of a 10-fold dilution series from approximately 10(4) to approximately 1 spore of A. astaci were repeatedly tested, and reliable detection down to 1 spore was demonstrated. Further, to simulate real-life samples from natural water bodies, water samples from lakes of various water qualities were spiked with spores. The results demonstrated that co extracted humic acids inhibit detection significantly. However, use of bovine serum albumin or the TaqMan Environmental Master Mix largely removes this problem. The practical application of the approach was successfully demonstrated on real-life water samples from crayfish farms in Finland hosting infected North American signal crayfish Pacifastacus leniusculus. Direct monitoring of A. astaci from aquatic environments may find application in the management of wild noble crayfish Astacus astacus stocks, improved aquaculture practices and more targeted conservation actions. The approach will further facilitate studies of A. astaci spore dynamics during plague outbreaks and in carrier crayfish populations, which will broaden our knowledge of the biology of this devastating crayfish pathogen. PMID- 21797032 TI - Penaeus monodon is protected against gill-associated virus by muscle injection but not oral delivery of bacterially expressed dsRNAs. AB - Gill-associated virus (GAV) is a nidovirus that commonly infects Penaeus monodon (black tiger shrimp) in eastern Australia, causing morbidity and mortalities in the acute stage of disease. Here we explored the possibility of inhibiting GAV replication and disease using double-stranded (ds)RNAs expressed in bacteria and delivered either orally or by muscle injection. To enhance potential RNA interference (RNAi) responses, 5 long dsRNAs were used that targeted open reading frame 1a/1b (ORF1a/b) gene regions and thus only the genomic length RNA. To examine oral delivery, P. monodon were fed pellets incorporating a pool of formalin-fixed bacteria containing the 5 GAV-specific dsRNAs before being injected with a minimal lethal GAV dose. Feeding with the pellets continued post challenge but did not reduce mortality accumulation and elevation in GAV loads. In contrast, muscle injection of the dsRNAs purified from bacteria was highly effective at slowing GAV replication and protecting shrimp against acute disease and mortalities. In synergy with these data, dsRNA targeted to P. monodon beta actin mRNA caused 100% mortality following injection, whilst its oral delivery caused no mortality. Findings confirm that injected dsRNA can mount effective RNAi responses in P. monodon to endogenous shrimp mRNA and exogenous viral RNAs, but when delivered orally in bacteria as a feed component, the same dsRNAs are ineffective. The efficacy of the RNAi response against GAV provided by injection of dsRNAs targeted to multiple genome sites suggests that this strategy might have general applicability in enhancing protection against other shrimp single stranded (ss)RNA viruses, particularly in hatcheries or breeding programs where injection-based delivery systems are practical. PMID- 21797033 TI - Temperature, hydric environment, and prior pathogen exposure alter the experimental severity of chytridiomycosis in boreal toads. AB - Prevalence of the pathogen Batrachochytrium dendrobatidis (Bd), implicated in amphibian population declines worldwide, is associated with habitat moisture and temperature, but few studies have varied these factors and measured the response to infection in amphibian hosts. We evaluated how varying humidity, contact with water, and temperature affected the manifestation of chytridiomycosis in boreal toads Anaxyrus (Bufo) boreas boreas and how prior exposure to Bd affects the likelihood of survival after re-exposure, such as may occur seasonally in long lived species. Humidity did not affect survival or the degree of Bd infection, but a longer time in contact with water increased the likelihood of mortality. After exposure to approximately 10(6) Bd zoospores, all toads in continuous contact with water died within 30 d. Moreover, Bd-exposed toads that were disease free after 64 d under dry conditions, developed lethal chytridiomycosis within 70 d of transfer to wet conditions. Toads in unheated aquaria (mean = 15 degrees C) survived less than 48 d, while those in moderately heated aquaria (mean = 18 degrees C) survived 115 d post-exposure and exhibited behavioral fever, selecting warmer sites across a temperature gradient. We also found benefits of prior Bd infection: previously exposed toads survived 3 times longer than Bd-naive toads after re-exposure to 106 zoospores (89 vs. 30 d), but only when dry microenvironments were available. This study illustrates how the outcome of Bd infection in boreal toads is environmentally dependent: when continuously wet, high reinfection rates may overwhelm defenses, but periodic drying, moderate warming, and previous infection may allow infected toads to extend their survival. PMID- 21797034 TI - Biochemical and hematological reference intervals for Krefft's turtles Emydura macquarii krefftii from the Burnett River Catchment, Australia. AB - Biochemical and hematological reference intervals have not previously been reported for Emydura macquarii krefftii. In 2009, 56 E. m. krefftii were captured by hand from the Burnett Catchment, clinically assessed to determine health status and blood sampled. Reference intervals were calculated from the 35 clinically healthy turtles using techniques established in other chelonid species. Aberrant blood results were identified from the 21 clinically unhealthy turtles. Low numbers of observed cases of creatine kinase, glucose, magnesium, phosphorus and uric acid outside of the blood biochemistry reference interval were recorded, as were high numbers of observed cases of estimated eosinophils, thrombocytes and total leukocyte counts outside of the hematological reference interval. Lesions of the shell and plastron (shell rot) were observed in 38% (21/56) of the examined healthy and unhealthy turtles. Microbiological assessment of a subsample (n=7) of these lesions grew Aeromonas veronii 100% (7/7), Aeromonas hydrophila 29% (2/7) and Acinetobacter baumannii 14% (1/7). Of the examined turtles, 13% (7/56) had evidence of opacity of the lens or anterior chamber of the eye and 70% (39/56) had erythema of the neck, axillary and inguinal soft tissues. Not all observed cases of erythema were associated with clinical ill-health. The anomalous blood results and clinical findings identified in this study suggest disease processes which may have resulted from causative agents in the surrounding environment. PMID- 21797035 TI - Lacaziosis and lacaziosis-like prevalence among wild, common bottlenose dolphins Tursiops truncatus from the west coast of Florida, USA. AB - Lacaziosis (lobomycosis; Lacazia loboi) is a fungal skin disease that naturally occurs only in humans and dolphins. The first reported case of lacaziosis in a bottlenose dolphin Tursiops truncatus occurred in 1970 in Sarasota Bay, Florida, USA, and subsequent photo-ID monitoring of the Sarasota Bay dolphin population has revealed persistence of the disease. The objectives of this study were to estimate lacaziosis prevalence (P) in 2 bottlenose dolphin populations on the west coast of Florida (Sarasota Bay and Charlotte Harbor) and compare disease occurrence to other published estimates of lacaziosis in dolphin populations across the globe. Historic photographic records of dolphins captured and released for health assessment purposes (Sarasota Bay) and photo-ID studies (Charlotte Harbor) were screened for evidence of lesions consistent with lacaziosis. Health assessment data revealed a prevalence of lacaziosis in the Sarasota Bay bottlenose dolphin population between 2 and 3%, and analyses of photo-ID data provided a lacaziosis-like prevalence estimate of 2% for Charlotte Harbor dolphins. With the exception of lacaziosis prevalence estimates for dolphins inhabiting the Indian River Lagoon (P = 0.068; P = 0.12), no statistically significant differences were seen among Sarasota Bay, Charlotte Harbor, and other published estimates. Although lacaziosis is a rare disease among these dolphin populations, studies that assess disease burden among different populations can assist with the surveillance of this zoonotic pathogen. PMID- 21797036 TI - Mycobacterium salmoniphilum infection in burbot Lota lota. AB - Burbot Lota lota sampled from lakes Mjosa and Losna in southeastern Norway between 2005 and 2008 were found to be infected with Mycobacterium salmoniphilum at a culture-positive prevalence of 18.6 and 3.3%, respectively. The condition factor (CF) of mycobacteria-affected fish sampled from Mjosa in 2008 was lower than the average CF of total sampled fish the same year. Externally visible pathological changes included skin ulceration, petechiae, exopthalmia and cataract. Internally, the infections were associated with capsulated, centrally necrotic granulomas, containing large numbers of acid-fast bacilli, found mainly in the mesenteries, spleen, heart and swim bladder. Mycobacterial isolates recovered on Middlebrook 7H10 agar were confirmed as M. salmoniphilum by phenotypical investigation and by partial sequencing of the 16S rRNA, rpoB and Hsp65genes as well as the internal transcribed spacer (ITS1) locus. This study adds burbot to the list of fish species susceptible to piscine mycobacteriosis and describes M. salmoniphilum infection in a non-salmonid fish for the first time. PMID- 21797037 TI - Francisella noatunensis subsp. noatunensis is the aetiological agent of visceral granulomatosis in wild Atlantic cod Gadus morhua. AB - During the 1980s and 1990s wild-caught cod displaying visceral granulomatosis were sporadically identified from the southern North Sea. Presumptive diagnoses at the time included mycobacterial infection, although mycobacteria were never cultivated or observed histologically from these fish. Farmed cod in Norway displaying gross pathology similar to that identified previously in cod from the southern North Sea were recently discovered to be infected with the bacterium Francisella noatunensis subsp, noatunensis. Archived formalin-fixed paraffin embedded tissues from the original North Sea cases were investigated for the presence of Mycobacterium spp. and Francisella spp. using real-time polymerase chain reaction, DNA sequencing and immunohistochemistry. Whilst no evidence of mycobacterial infection was found, F. noatunensis subsp. noatunensis was identified in association with pathological changes consistent with Francisella infections described from farmed cod in recent years. This study shows that francisellosis occurred in wild-caught cod in the southern North Sea in the 1980s and 1990s and demonstrates that this disease predates intensive aquaculture of cod. PMID- 21797038 TI - Development and maintenance of a specific pathogen-free (SPF) zebrafish research facility for Pseudoloma neurophilia. AB - Pseudoloma neurophilia (Microsporidia) is very common in zebrafish Danio rerio research facilities. A new zebrafish facility has been established at the Sinnhuber Aquatic Resource Laboratory (SARL), Oregon State University, Corvallis, OR, U.S.A., and this was an opportunity to establish a specific pathogen-free (SPF) colony of zebrafish for this microsporidium. Progeny from 9 zebrafish lines (n=2203) were initially transferred to the SARL facility in 2007 following PCR screening of broodstock and a subpopulation of progeny (258 of 1000 fish from each family). Screening of fish for P. neurophilia within the facility was conducted as follows: (1) Moribund or dead fish were examined by histology. (2) Each line was regenerated on a 4 mo rotation, and a subsample of each of these major propagations (60 fry, in pools of 10) was PCR-screened at 10 d post hatch. (3) Adult fish (approximately 1 yr old) from each line were euthanized; 20 fish were examined by histology and the brains of another 60 fish (in pools of 5) were screened by PCR. (4) This screening was replicated on sentinel fish held in 4 tanks receiving effluent water from all tanks in the facility (20 fish per tank). (5) Four-month old fish (n=760) from a toxicology study conducted within the laboratory were examined by histology. To date, we have evaluated 2800 fish by PCR and 1222 fish by histology without detecting P. neurophilia. Thus, we have established 9 lines of zebrafish SPF for P. neurophilia. However, 26 fish exhibited mycobacteriosis, with acid-fast bacteria present in tissue sections, and 49 other fish had incidental lesions. PMID- 21797039 TI - Detection of VHSV IVb within the gonads of Great Lakes fish using in situ hybridization. AB - Viral haemorrhagic septicaemia virus (VHSV) genotype IVb was recently detected as the cause of numerous mortality events in Great Lakes fish. In situ hybridization was used to examine the gonads from 13 fish, including freshwater drum Aplodinotus grunniens and muskellunge Esox masquinongy that were infected naturally, as well as rainbow trout Oncorhynchus mykiss and fathead minnows Pimphales promelas, which were experimentally infected. Although the ovaries and testes of fish infected by VHSV IVb had few lesions, viral RNA was present in the ovaries of the rainbow trout and fathead minnow and was abundant in the gonads of muskellunge and in the ovaries of freshwater drum. Viral RNA was present mainly surrounding yolk vacuoles/granules or adjacent to the germinal vesicle, with lesser amounts found within the germinal vesicle, in the mesovarium and/or tunica albuginea and blood vessels of the ovary. Viral RNA was also found in and surrounding primary and secondary spermatocytes of the muskellunge. PMID- 21797040 TI - [Permanent education, updating and accreditation in occupational medicine: the contribution of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) in the first decade of the 21st century]. AB - BACKGROUND: Permanent education of health workers is obligatory under Italian legislation and is managed by the Ministry of Health through its Permanent Education Programme. METHODS: In 2000 the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII), set up and implemented a programme of Permanent Education and Accreditation for specialists in occupational medicine, based on participation in "non-mandatory" and "mandatory" educational activities. "Non-mandatory" activities were chosen by the individual physician for education in topics related to occupational medicine. "Mandatory" educational activities, which were organised by the Society, included in-depth analysis of the Society's guidelines related to specific topics in occupational medicine. RESULTS AND DISCUSSION: The Guidelines study course played a pre-eminent role in the Society's permanent education programme and was greatly appreciated by all participants. The Board of the Society has recently approved a new Plan of Permanent Education, identifying the means (Guidelines, Consensus Documents) whereby occupational physicians can improve their professional standards. The Plan's aims are to facilitate accreditation and also to identify and promote high quality updating programmes which will lead to recognition of 'professional excellence". Crucial to its success will be a 3-year on-line learning programme (MeLA) that SIMLII has just implemented, which will enable occupational physicians to acquire credits in "Occupational Medicine and Workplace Safety", as required by current Italian legislation. This article summarizes SIMLII activities over the past ten years in the field of permanent medical education for occupational physicians. PMID- 21797041 TI - [Acute lead poisoning: a singular case of hemolytic anemia and lead colic]. AB - BACKGROUND: Acute lead poisoning due to food intake is exceptional in adults and often associated with mental illness OBJECTIVES: to describe a case report of acute lead intoxication with haemolytic anemia and lead colic. METHODS: A 41-year old male patient was admitted to hospital for abdominal pain and persistent constipation. Abdominal X-ray showed a radiopaque mass in the caecum and progressive anaemia was observed The patient was discharged with a diagnosis of bowel obstruction. Due to persistence of the symptoms he was again hospitalized; abdominal X-ray showed diffuse radiopaque particles in the colon and haemoglobin (hb) had dropped to 8.7 g/dl. Blood levels of lead and zinc protoporphryin were 106.7 microg/dl and 6.6 microg/gHb, respectively. The timely start of chelating therapy led to a rapid return to normal peripheral blood counts and a decline in blood lead levels. RESULTS: Although acute lead poisoning due to intake with food is exceptional in adults and often associated with mental illness, in this case, it was not possible to clarify the route and vehicle of ingestion of the toxic. Lead body burden was shown as a caecal mass, probably as a result of ingesting a single bolus of lead dust which, considering the size and density of the mass, was estimated as weighing several grammes. This acute lead intake induced an acute haemolysis due to enhanced fragility of the erythrocyte membrane. CONCLUSIONS: In the course of acute lead intoxication, the critical organ is not the bone marrow, but rather the red blood cell, leading to haemolysis and anaemia. PMID- 21797042 TI - [Preliminary results of a health survey of muscular-skeletal disorders in a group of 2247 small building trades in the Province of Bergamo]. AB - BACKGROUND: In the past ten years European and Italian statistics reported a significant increase in work-related musculoskeletal disorders, which also covered the construction industry. OBJECTIVES: To verify this issue, the EPM Research Unit, in collaboration with the Small Craft Industries Territorial Joint Committee in Bergamo (CPTA), undertook a research project on muscular-skeletal disorders with special reference to the lumbar spine and upper limbs. METHODS: The health survey was carried out by an ad hoc trained staff RESULTS: Between November 2009 and July 2010, data on 2247 subjects doing a variety of jobs were obtained, more than 50% of whom were masons. The entire sample and the group of masons were investigated and both exhibited a prevalence of upper limb disorders that was definitely higher than in the reference group of non-exposed subjects. Regarding the lumbar spine, the most significant evidence was the high prevalence of degenerative diseases (herniated disc), while subjective disorders appeared to be lower than in the reference groups. These data are influenced by the healthy worker effect, which is extremely marked in this industrial sector, as well as by the economic crisis that led to many workers having to leave. CONCLUSIONS: Active research needs to be included in the protocol of health surveillance (with appropriate clinical protocol), of upper limb and spinal MSDs. The data also highlight the need for biomechanical overload exposure data aimed at reconstructing risk profiles (from biomechanical overload)for each job and at simplifying risk assessment requirements according to present legislation but above all at identifying the technological and organizational solutions to eliminate this particular risk. PMID- 21797043 TI - [Work-related stress in nursery school educators in the Venice and Marghera districts]. AB - BACKGROUND: Based on an investigation on organizational well-being in the Municipality of Venice (2009), we examined 110 public nursery school and preschool teachers working in the Venice and Marghera districts. OBJECTIVES: The aim of this study was to develop and implement a procedure for work-related stress assessment and management in Municipality of Venice, in the light of Law 81/2008. METHODS: Occupational stress and its impact on teachers' well-being and health were assessed by means of self-administered questionnaires and semi structured interviews. Descriptive analyses were conducted to compare teachers' data with those concerning employees operating in other services in the Venice and Marghera districts. RESULTS: According to the results, while nursery school and preschool teachers work with considerable commitment, vigor, dedication and involvement, problems were observed related to: assignment of administrative tasks without appropriate support from the district offices; difficult access to support services; shortage of temporary teachers and auxiliary personnel and, limited to some facilities, lack of adequate physical space devoted to teaching activities. Such adverse conditions result in an increase in vigilance levels required to ensure children's safety. Personnel also suffer from a lack of career prospects, with scarce opportunities for contact with other facilities in the area and inadequate involvement in the decisional processes at Municipality level. CONCLUSIONS: Improving such adverse conditions could solve the current marginalization of public nursery school and preschool teachers and encourage mutual exchange of information, which would in turn favour more appropriate methods of managing each single facility. PMID- 21797044 TI - [Obesity and work: proposal for a multidisciplinary intervention model for prevention and its application in an engineering plant]. AB - INTRODUCTION: Obesity is often particularly burdensome for subjects at work and leads to hypertension and diabetes preceded by a low grade of inflammation. Measures to promote health at the workplace can be achieved through periodic health surveillance. Simple parameters such as height, weight, body mass index (BMI), waist circumference (CV), blood pressure (BP), as well as taking into account the type of work and tasks, shift work and smoking, are in fact sufficient to identify the most significant features of the working population so as to adequately design the type of intervention required. The paper describes how a health promotion programme aimed at preventing overweight and obesity was implemented based on analysis of the health surveillance data routinely collected by the occupational physician in an engineering plant in northern Italy. SUBJECTS AND METHODS: Data on weight, height and BMI were collected for 301 workers with different jobs and shifts in an engineering plant; 32 of these workers, (mean age 44+/-8.4) agreed to undergo a diagnosis and treatment programme at the Obesity and Work Centre of the Clinica del Lavoro in Milan. INTERVENTIONS AND RESULTS: A higher incidence of overweight and obesity was found compared to the national average for similar age classes, therefore meetings were organized at the plant on awareness and information on correct lifestyle and diet targeted for shift workers. The workers who had followed the diagnosis and treatment programme had a mean BMI of 32.6 (SD 2.7) and, considering the parameters investigated, the presence of metabolic syndrome was found in a greater proportion of subjects (62.5%) than the average in our practice (46%) and particularly in workers with three day shifts. CONCLUSIONSThe intervention programme began with assessment of the information obtained in the course of routine periodic health surveillance according to the occupational hazards under study. On the basis of this information it was possible to implement the first awareness campaigns. On completion of the multidisciplinary intervention, which was conducted in collaboration with the occupational physician, two major initiatives were taken: one in the canteen with the aim of improving the nutritional content and type of meals offered to suit the dietary needs of overweight or obese workers, and the other consisted of an agreement with local gyms so as to motivate workers to exercise more. A prerequisitefor this type of initiative is the willingness and understanding of the management to recognize the health of the worker as a priority value. PMID- 21797046 TI - [Risk assessment]. PMID- 21797045 TI - [The effort of being male: a survey on gender and burnout]. AB - INTRODUCTION: Stress at work affects more than 40 million people in the European Union - around 22% of workers - and is the second most reported work-related health problem. Gender does not seem to be a constant predictive factor for burnout: some studies showed that women suffer more from burnout than males, other studies proved that males report higher burnout scores while others did not detect any difference at all. These results may be due to gender-related stereotypes, or could even reiflect the preponderance of a specific gender in some jobs. OBJECTIVES: To determine whether gender might be among the relevant variables in job burnout studies. METHOD: In 2008-2009 a study on burnout was carried out in a Healthcare Trust in northern Italy. The Job Content Questionnaire (JCQ) and the Maslach Burnout Inventory (MBI) were distributed to physicians, administrative staff and auxiliary personnel of hospital departments and local services. RESULTS: A total of l, 604 JCQ's and 1,604 MBI's were analysed, corresponding to 37% of the distributed tests. Results of logistic regression showed that gender, shift work and a low score in relationships with superiors were significantly associated with burnout. Considering the tasks of physicians and nurses, the burnout frequency was 3.78% for physicians and 1.97% for nurses, with higher percentages in males than in females. Women with children reported an average burnout frequency that was lower than the average of the whole population studied while men with children had a double burnout frequency compared to the average. CONCLUSIONS: Male gender is significantly associated with a burnout condition. Moreover, our findings have shown that physicians experience an excess burnout compared to nurses although this excess did not achieve statistical significance when taking into account distribution according to gender in the two professions. PMID- 21797047 TI - [The responsibility of the medical specialist]. PMID- 21797048 TI - [Fourcroy and the "Lycees"]. AB - In XVIIIth century on Encyclopaedists influence, the study of Sciences arouse a real passion. Many courses are proposed. Two private institutions are opened which are called "Lycees": "Lycee de la rue de Valois" and "Lycee des Arts". Fourcroy and Lavoisier have been influential members of these two. Problems come to "Lycee de la rue de Valois", lead to the "purge ballot" and to Lavoisier's eviction. In France, it is the "Terror" and Lavoisier few months after was guillotined as "Fermier general". The historic events exonerate Fourcroy, member of the Convention, to the accusation that he has no made steps to save Lavoisier. This important historic event is a part of this study. As we show in this study "Lycees" are been small universities and have contributed to maintenance bonds between French scientists at the Revolution. The "Musee de Paris" and the "Societe Philomathique de Paris" are also evoked. PMID- 21797049 TI - [Fourcroy and pharmaceutical journals]. AB - Cadet de Gassicourt wrote a brief Eloge of Fourcroy in January 1810 as he died in December of 1809. Fourcroy had a major role concerning the new ideas on the place of pharmacy at the beginning of the 19th century. Fourcroy has had a key influence for the start of several pharmaceutical journals that wanted to emphasize the link between the new chemistry and pharmacy. None of these journals created with him will survive and one has to wait for 1909 to see the creation, without Fourcroy, of a new pharmaceutical journal, the "Journal de Pharmacie" that will become "Journal de Pharmacie et des Sciences accessoires", then "Journal de Pharmacie et de Chimie", before taking the name of"Annales Pharmaceutiques Francaises", the present official journal of the French Academy of Pharmacy. In spite of the essential role of Fourcroy at the start of pharmaceutical journals, Cadet did not even mention it in his Eloge of 1810. PMID- 21797050 TI - [The extractive: life and death of an uncommon product of proximate analysis]. AB - Issued from the pharmaceutical tradition, the "extractive", formerly "extract", is a typical artefact of proximate analysis introduced in the new nomenclature of 1787. After beign one of its most active promotors, Fourcroy published with Vauquelin a posthumous paper in 1810 in which he expressed some doubts about the substance. Theoretically present in almost all vegetable extracts, some chemists, pharmacists and physicians try to isolate the extractive without success and instead accumulated contradictory results. At the end, the eviction of this chimaera held by sceptical chemists such as Chevreul and Braconnot and the conversion of other analysts, dismissed extractive and the name almost gradually disappears at the begining of the 1830s. PMID- 21797051 TI - [Radiated drugs, the way of health]. AB - During the inter-war years, the word "radiated" did not only suggest radioactivity, but it was also used to indicate exposure to others radiations, such as ultraviolets. The actinotherapy, a new therapy in vogue, was applied to many pathologies and tried on many substances. "Radiated drugs" result of those experimentations. Their therapeutical characteristics were found during searches on rickets. Our study relates the story of fight against rickets in France, from the use of cod liver oil to the synthesis of Vitamine D. PMID- 21797053 TI - [Andre Detoeuf (1884-1931): pharmacist, industrialist and chemist]. AB - During the transition between the 19th and 20th century, Auguste Behal (1859 1941), a native of Lens (France, Pas-de-Calais), renewed organic chemistry teaching at the Paris School of Pharmacy by the introduction of atomic notation and pre-electronic mechanisms. This revolution primarily affects the future pharmacists. Thus, Behal becomes the leader of a "School" of thought and directs the work of many students called "Behaliens": Ernest Fourneau (1872-1949), Marc Tiffeneau (1873-1945), Marcel Sommelet (1877-1952), etc. Among these students, three are also from Lens: Amand Valeur (1870-1927), Raymond Delaby (1891-1958) and Andre Detoeuf (1884-1931). The latter, initially, will follow the footsteps of his older siblings (pharmacy studies, writing a thesis under the direction of Behal); however, despite having started a career in academia, he left his post for the industry (Etablissements Kuhlmann and Billault). PMID- 21797052 TI - [Dean Paul Gillot (Magneux 1887-Nancy 1935). A multiform but unfortunately interrupted career. A comparison of past and current practices]. AB - Paul Gillot came in Nancy to study pharmacy. Having obtained his diploma in 1913, one year before First World War, he was enlisted as a soldier then an officer, for five years. During these years, he was wounded and severely ill and he never recovered. In 1919, coming back at the school of pharmacy in Nancy, he began his thesis and his universitary career and became simultaneously hospital pharmacist and inspector of community pharmacies. In 1929 he had the luck of beeing nominated as the professor of materia medica, and in 1935 he was choosed as the dean of the faculty. Unfortunately he died some weeks after his election. The paper describes successively the activities of professor Paul Gillot during all his short life, and closes by some reflections about universitary practices of this period. PMID- 21797054 TI - [Dr. Michiharu Matsuoka, founder of the Department of Orthopaedic Surgery, Kyoto University, and his achievements (Part 6: Studying abroad of Dr. Matsuoka and opening to public, reputation and achievement of the department)]. AB - Dr. Michiharu Matsuoka studied orthopaedic surgery in Germany, Austria and other countries during the period from August, 1902 to May, 1906. He visited many university pathological institutes and surgical and orthopaedic clinics to study pathology and to learn the practice of orthopaedic surgery. After that, he started his practice at the newly established Department of Orthopaedic Surgery in the Medical School of Kyoto Imperial University in June, 1906. The department was opened in 1907 and in 1911 it was opened to all citizens and practical doctors in Kyoto City and exhibited many orthopaedic specimens and instruments. In particular, the x-ray apparatus of the Department was so well equipped that a German radiologist who visited the Department admired it in his article that was published in the journal of radiology in 1911. The Department was not surpassed by others for the number of patients with the dislocation of the hip and tuberculous spondylitis as well as the advanced quality and variety of roentgenological and pathological researches on these diseases. PMID- 21797055 TI - [The evolution of clinical medical books in the 19th century]. AB - Fifty clinical medical books written in the late 18th and the 19th centuries were categorized into four alternating types on the basis of the differences in composition and contents. The nosological type in the first period classified diseases into taxa, and dealt symptoms as diseases. The eclectic type in the second period contained both categories of nosological diseases and those of local diseases. The organ system type in the third period focused on the local diseases arranged in a systematic manner. The infection emphasis type put the infectious diseases at the beginning, followed by the local diseases in a systematic manner. The four types of clinical medical books evolved in accordance with the changes in clinical medicine in the 19th century, exemplified by the activities of the Parisian school, including those regarding pathological anatomy, laboratory medicine in the German universities, and discovery of pathogenic bacteria. When Western medicine was introduced in Japan, different stages of medicine, representing the four types, arrived at different times. PMID- 21797056 TI - [On the "Brain is the House of Yuanshen" in "Bencao Gangmu"; from Li Shizhen to Zhang Xichun]. AB - The phrase the "Brain is the House of Yuanshen" is used in "Bencao Gangmu" in order to explain the reason why magnolia flower is good for sinus problems; however, the ideas on the relationship between the brain and the nose originate from "Huangdi Neijing" and those on the relationship between the brain and Yuanshen come from Taoism. It was "Bencao Beiyao" that combined the theory with the Western idea that "someone's memory is in the brain". The idea of the brain staying on as memory had great impact on "Leizheng Zhicai" and "Yilin Gaicuo", but again in "Yixue Zhongzhong Sanxilu" it claimed that "Yuanshen is in the brain" from Taoism's point of view, and it criticized the theory of the brain derived from the Western world. In this paper, the meaning of "Brain is the House of Yuanshen" in "Bencao Gangmu" is examined, along with the influence this idea had on the subsequent theories of medicine. PMID- 21797057 TI - [Significance of Sijiseiki disease and Henseibyo disease on the Shanghanli chapter in the Shanghanlun]. AB - It seemed that the chapter "Shanghanli" in Shanghaulun had been incorporated into the text of the Shanghanlun by "Wang shuhe". Therefore, the "Shanghanli" wasn't studied as adequately as the original Shanghanlun written by "Zhang Zhongjing. We focused on the significance of "Sijiseiki" disease and "Henseibyo" disease in the chapter "Shanghanli" and revealed their relation to the ideas on pathology in the Shanghanlun. In the theory of "Sijiki", the four seasons each had their own "Qi", called "Sijiki"; the cold belonging to winter, the warm to spring, the hot to summer and the cool to autumn. The influence of "Sijiki" in each season caused the disease of "Sijiseiki". Since "Sijiki" was related to the normal "Qi" for each season, "Sijiseiki" disease was expected to be recovered from in order. When "Sijiseiki" disease had not been cured in each season, it caused a complex disease according to the influence of other seasonal "Sijiki"; "Henseibyo" disease. PMID- 21797058 TI - [Protection of human subjects in medical research: from the viewpoint of historical development of ethical regulations]. AB - Recent clinical research is conducted based on bioethical consideration of human subjects. The Ethical Guidelines for Clinical Studies (EGCS) form the standard for this 'subject protection'. In current clinical research, consideration of subject rights and life is held more important than the scientific and social value of the research. We describe herein the major revisions and history of ethical considerations leading up to implementation of the revised EGCS on April 1, 2009. The obligations of clinical researchers regarding ethical studies and training and enrollment in insurance for subject compensation have been added to these latest guidelines. The role of ethics review boards, which supervise whether clinical researchers are actively performing subject protection, is also becoming extremely important. PMID- 21797059 TI - [Heterogeneity of parasitic contamination of megalopolis soils]. AB - A morphological group ofwhipworm (Trichuris trichiura) eggs, which is detectable in the soil samples from the city's different control lands, shows that their origin is heterogeneous and it is possible to differentiate them by morphometric signs. At the same time is necessary to consider the specific biological factors contributing to soil contamination. Priority in parasitic soil contamination should be given to animals, dogs in particular, which is supported by the fact that the dog walking grounds exhibit the highest contamination rates. PMID- 21797060 TI - [Interaction of plague microbe strains varying in plasmid composition with the fleas Xenopsylla cheopis (Roths. 1903)]. AB - The interaction of two Yersinia pestis strains varying in plasmid composition with the fleas Xenopsylla cheopis was studied. The reference virulent strain I 2638 having four plasmids (pCad, pPst, pFra, and pTP 33) and its selected avirulent strain I-3480 that had lost the plasmids pCad and pPst formed a proventricular block in the fleas with equal frequency. There were no differences in the block-forming capacity of these strains among the infected females; however, the stock strain was more active in blocking the proventriculus in females in spring than was the mutant one. in summer. The fleas infected with a defect strain failed to transmit the pathogen. It follows that the presence of a proventricular block is not an indicator of how effectively the fleas transmit the causative agent of plague. While being in the insect, both strains of plague microbe did not alter their biological properties. In experiments, the death rate for insects infected with different strains was similar, but higher in spring than that in summer. The males naturally died more frequently than the females. PMID- 21797061 TI - [The yeast community associated with the digestive tract of the German cockroach Blattella germanica L]. AB - Data on the yeasts colonizing the digestive tract ofa German cockroach have been first obtained. Cockroach cultures are used in the commercial production of allergy vaccines to treat patients sensitized to cockroach allergens. The enteric microflora of the insects can bring nonshared antigens into the composition of the agents manufactured. An investigation established that out of 10 yeast species isolated from the digestive tract of the cockroaches fed sterile food, 6 species (Candida glabrata, Cryptococcus magnus, Debaryomyces hansenii, Metschikowia pulcherrima, Phodo-torula glutinis, Rhodotorula mucilaginosa) were isolated from both the digestive tract and excrements and 4 (Candida oleophila, Candida shehatae, Cryptococcus albidus, Pichia membmnaefciens) were only from the digestive tract. It seems that the yeast is either digested or inactivated in the digestive tract of the insects and loses their capacity to grow When the cockroaches were fed sterile food for a long time (at least a month), all yeasts virtually disappeared from the digestive tract of the insects except for Candida glabrata, C.shehatae, and Rh.mucilaginosa. However, only C.glabrata achieved a great deal (10(7)-10(8) CFU/g) of cockroaches (both imagoes and larvae of 5-7 ages), which statistically significantly decreased by no less than three orders of magnitude in the excrements after passing through the digestive tract. PMID- 21797062 TI - [Age-related cytokine regulation in children with malaria]. AB - The paper presents data on age-related cytokine dysregulation in children with tertian or tropical malaria infection. Immunological changes depended on the dynamics of the infectious process and the severity of the pathological one. The most pronounced changes were observed in a group of infants probably due to the functional immaturity of immunoregulatory mechanisms appearing as elevated levels of proinflammatory cytokines with a reduction in IFN-gamma, which suggest that Th 1 lymphocyte reactions are inhibited. With age, there is a shift from Th2 towards Th1 immune response, which testifies that the disease runs a favorable course. These findings may be useful in assessing the prognosis of the course and outcome of malaria in children. PMID- 21797063 TI - [Role of cytokines in the clinical course of tropical malaria in children]. AB - The paper gives data on impaired cytokine status in children with tropical malaria. There have been heterodirectional changes in the level ofcytokines during the infectious process and in relation to the severity of the pathological process, which allow prediction of the course of tropical malaria. Correlations were found between the clinical and laboratory parameters and the level of proinflammatory cytokines, which provide evidence for an important role of inflammatory mediators in the clinical course of the disease. The findings suggest that it is expedient to correct immune disorders in the early stages of tropical malaria. PMID- 21797064 TI - [Immunorehabilitation in patients with paecilomycosis-complicated echinococcosis and asthma]. AB - Paecilomycosis is a new type of systemic mycosis caused by different species of fungi of the genus Paecilomyces. Paecilomycosis-complicated echinococcosis and asthma run a severe course. A complication of mycosis is accompanied by secondary immunodeficiency. A good result was obtained in the treatment of ill children by using the fungicide diflucan and the immunomodulator polyoxidonium. In the examinees with paecilomycosis-complicated echinococcosis, secondary immunodeficiency was characterized by a statistical significant reduction in the blood levels of the lymphoid cells CD3+, CD4+, CD8+, CD16+, CD21+, by phagocytosis, a decrease in its quantitative parameters, and an increase in the counts of immunoglobulins and circulating immunocomplexes. To normalize the immune status in patients with paecilomycosis-complicated echinococcosis, it is expedient to postsurgicallyuse fungicides, such as nizoral, diflucan, orungal, mycosyst, and the immunomodulators polyoxidonium and irillen. PMID- 21797065 TI - [Classifications of infectious and parasitic diseases by sociological criteria]. PMID- 21797066 TI - [Experimental data on its toxic and growth--stimulating effects Opisthorhis felineus (Rivolta, 1884)]. PMID- 21797067 TI - [Preparation of a prototype of the anthelmintic nadinate (MCT-02) and evaluation of its therapeutic efficacy in sheep moniesiosis and strongyloidiasis]. PMID- 21797068 TI - [Use of an enzyme immunoassay test system with cystic Echinococcus antigen to diagnose echinococcosis alveolaris (multilocularis) (alveococcosis)]. AB - Twenty-three serum samples from 12 patients with Echinococcus alveolaris collected 1 to 12 years after surgery and 1--13 courses of specific therapy were used to evaluate the diagnostic effectiveness of an enzyme immunoassay (EIA) test system with cystic Echinococcus antigen. The findings enable the EIA test system with cystic Echinococcus antigen to be recommended for the diagnosis of Echinococcosis alveolaris and for the monitoring of its treatment results. PMID- 21797069 TI - [Blastocystis hominis, Brumpt 1912 is a mysterious organism belonging to intestinal protozoa]. PMID- 21797070 TI - [Epizootological assessment of the possibilities of importing plague from Vietnam to Russia]. AB - To assess whether the plague microbe with vectors or carriers can be imported from Vietnam to Russia, the authors consider the specific features of pathogen circulation in this country's biotopes varying in anthropogenic transformation. The idea that there were natural foci of plague in Vietnam dominated until the late 1990s. The small rat Rattus exulans that inhabits open stations and ensures a parasitic contact with the synanthropic representatives of the fauna was considered to be a major carrier. The recent years have provided conclusive proofs that plague foci are absent in Vietnam wild nature. Anthropurgic foci develop in the network of localities whose conditions are favorable to the existence of synanthropic rodents and the fleas Xenopsylla cheopis. Cases of the plague pathogen, FI antigen and its antibodies being detected in wild mammals are due to their parasitic contacts with synanthropic rats in the agrocultural area around the localities with running epizootias. These contacts are provided by X.cheopis only. Since 2003, there have been no reports on the incidence of human plague or its pathogen isolation from environmental objects in Vietnam. However, all conditions and prerequisites for the formation ofanthropurgic plague foci remain in this country. Further epizootological monitoring is required for appropriate services to rapidly and adequately respond if the epizootological or epidemiological situation of this infection changes. PMID- 21797071 TI - [Batai fever]. PMID- 21797072 TI - Margaret Cavendish's materialist critique of van Helmontian chymistry. AB - A striking omission in the scholarship on the reception of the chymical philosophy of Jan Baptista van Helmont in England in the seventeenth century is the work of the mid-seventeenth-century natural philosopher Margaret Cavendish, Duchess of Newcastle. In her Philosophical Letters (1664), Cavendish offers an extended critique of Van Helmont's work (whose Ortus Medicince had recently been translated into English by John Sadler). In this paper, I compare Cavendish's criticisms with those of Robert Boyle in his Sceptical Chymist (1661). Both Boyle and Cavendish attacked Van Helmont for the obscurity of his chymical vocabulary and concepts, and attacked his seminalism. Although their critiques had much in common, they diverged in their attitudes to Van Helmont's experiments. As an opponent of the experimental philosophy, Cavendish had little interest in the quality of Van Helmont's experimental claims, whereas Boyle was critical of their unreplicability. I also try to show that the two writers had very different polemical agendas, with Boyle defending his vision of chymistry based on a corpuscularian natural philosophy, and Cavendish being as much concerned with establishing her religious orthodoxy as with defending the truth claims of her own materialist vitalism. For Cavendish, Van Helmont was an example of the dangers of mingling theology and natural philosophy. PMID- 21797073 TI - Mechanical and chemical explanations in Du Clos' chemistry. AB - Samuel Cottereau Du Clos (1598-1685) appears as the first French chemist to combine in chemistry (for him, the science of substances, the physics of qualities) demonstrations using the laws of motion with demonstrations using the qualities of chemical principles. In this way, he brought to bear two different and complementary orders of explanation. According to Du Clos, the mechanical considerations represent a first approach, a stage towards the knowledge of "the truth of things" (la verite des choses) in natural philosophy. He set out his chemistry at the Academie royale des sciences de Paris, especially through his criticism of Boyle's Certain Physiological Essays in 1668-1669. PMID- 21797074 TI - Private initiatives, public support, and war practices: development of fertilisers in Russia. AB - The scarcity of experiments with fertilisers, the poor domestic industry, and high prices for imported products made Russia lag far behind the leading agrarian countries in the research and use of fertilisers. The first experiments on fertilisers were connected mostly with the private estates of Russian nobility. Things began to change slowly by the turn of the twentieth century, when the Ministry of Agriculture launched a policy of agricultural science promotion, including the development of agricultural chemistry. It was the outbreak of World War I that created a powerful stimulus for fertiliser research in Russia. A specific Russian "symbiosis" emerged between military industry and agricultural chemistry. The numerous factories of explosives set up ad hoc produced vast amounts of waste products; modified, they could serve as fertilisers. In 1915, the Public Committee for Support of Fertilisers was organised. Eventually, this committee gave birth to the Institute of Fertilisers, the first institute founded by the Bolshevik government. Thus, the project of "chemicalisation of agriculture," usually described as a revolutionary endeavour, was firmly rooted in World War I. PMID- 21797075 TI - Alchemical poetry in medieval and early modern Europe: a preliminary survey and synthesis. Part II - Synthesis. AB - This article provides a preliminary description of medieval and early modern alchemical poetry composed in Latin and in the principal vernacular languages of western Europe. It aims to distinguish the various genres in which this poetry flourished, and to identify the most representative aspects of each cultural epoch by considering the medieval and early modern periods in turn. Such a distinction (always somewhat artificial) between two broad historical periods may be justified by the appearance of new cultural phenomena that profoundly modified the character of early modern alchemical poetry: the ever-increasing importance of the prisca theologia, the alchemical interpretation of ancient mythology, and the rise of neo-Latin humanist poetry. Although early modern alchemy was marked by the appearance of new doctrines (notably the alchemical spiritus mundi and Paracelsianism), alchemical poetry was only superficially modified by criteria of a scientific nature, which therefore appear to be of lesser importance. This study falls into two parts. Part I provides a descriptive survey of extant poetry, and in Part II the results of the survey are analysed in order to highlight such distinctive features as the function of alchemical poetry, the influence of the book market on its evolution, its doctrinal content, and the question of whether any theory of alchemical poetry ever emerged. Part II is accompanied by an index of the authors and works cited in both parts. PMID- 21797076 TI - Introduction: lay participation in the history of scientific observation. PMID- 21797077 TI - Clergymen abiding in the fields: the making of the naturalist observer in eighteenth-century Norwegian natural history. AB - By the mid-eighteenth century, governors of the major European states promoted the study of nature as part of natural-resource based schemes for improvement and economic self-sufficiency. Procuring beneficial knowledge about nature, however, required observers, collectors, and compilers who could produce usable and useful descriptions of nature. The ways governments promoted scientific explorations varied according to the form of government, the makeup of the civil society, the state's economic ideologies and practices, and the geographical situation. This article argues that the roots of a major natural history initiative in Denmark Norway were firmly planted in the state-church organization. Through the clergymen and their activities, a bishop, supported by the government in Copenhagen, could gather an impressive collection of natural objects, receive observations and descriptions of natural phenomena, and produce natural historical publications that described for the first time many of the species of the north. Devout naturalists were a common species in the eighteenth century, when clergymen and missionaries involved themselves in the investigation of nature in Europe and far beyond. The specific interest here is in how natural history was supported and enforced as part of clerical practice, how specimen exchange was grafted on to pre-existing institutions of gift exchange, and how this influenced the character of the knowledge produced. PMID- 21797078 TI - Collecting standards: teaching botanical skills in Sweden, 1850-1950. AB - Standards of botanical practice in Sweden between 1850 and 1950 were set, not only in schools and universities, but also in naturalist societies and botanical exchange clubs, and were articulated in handbooks and manuals produced for schoolboys. These standards were maintained among volunteer naturalists in the environmental movement in the 1970s, long after the decline and disappearance of collecting from the curriculum. School science provides a link between the laboratory, the classroom, and the norms and practices of everyday life: between the various insides" and "outsides" of educational and research settings. PMID- 21797079 TI - [Comments of TDP (Treatise on medical Diagnostics and Prognostics) 3-40. First part]. PMID- 21797080 TI - The nature of power: Synthesizing the history of technology and environmental history. PMID- 21797081 TI - Mobile home syndrome. Engineered woods and the making of a new domestic ecology in the post-World War II era. PMID- 21797082 TI - Better look twice--medication errors in anaesthesia and how to avoid them. PMID- 21797083 TI - [Continuous infusion of local anesthetic at the site of the abdominal surgical wound for postoperative analgesia: a systematic review]. AB - OBJECTIVES: We present a systematic review of clinical trials to evaluate the efficacy of infusing local anesthetic through a catheter placed in the abdominal surgical wound. METHODS: The Jadad (Oxford) scoring system was used to select trials. The variables considered in relation to each trial selected were as follows: type of intervention and incision; type, dose, and concentration of local anesthetic; site where the catheter was placed; rescue analgesia required; opioid use; and incidence of adverse events. RESULTS: Fifteen clinical trials with a mean Jadad score of 4.6 were selected. The 1139 patients enrolled in the trials were grouped according to catheter placement: subfascial (6 trials), subcutaneous (8 trials), and both (1 trial). Six additional unpublished trials registered at ClinicalTrials.gov were also located. CONCLUSIONS: Surgical wound analgesia is a safe technique whose effectiveness has been observed in cesarean sections and hysterectomies performed with Pfannenstiel incisions. Outcomes for other types of surgery are inconsistent. There is a lack of studies of the optimal site for catheter placement as well as of adequate anesthetic concentration and volume. PMID- 21797084 TI - [Proposed experimental model to provide training in the management of anesthesia in liver transplantation]. AB - OBJECTIVE: To propose and evaluate the use of a porcine model for training in how to manage and improve the quality of anesthesia during liver transplantation. MATERIAL AND METHODS: Five trained anesthesiologists who had no previous experience in managing anesthesia during liver transplantation and who did not work in hospitals where the procedure was performed volunteered for the training course and evaluated it. Each trainee anesthetized 5 animals. Surgery was performed under total balanced anesthesia with monitoring of hemodynamics, ventilation, biochemistry, arterial blood gases, and coagulation. Previously set criteria were used to evaluate the trainees' skill in maintaining patient stability. Their work was assessed 7 times: at baseline, 15 minutes into the preanhepatic phase, at the end of the preanhepatic stage, 15 minutes into the anhepatic phase, at the end of the anhepatic phase, 15 minutes into the postanhepatic phase, and at the end of the postanhepatic phase. After completing the course, the trainees filled in a questionnaire to evaluate its usefulness. Analysis of variance was applied to score changes in anesthetic quality criteria. RESULTS: After implantation, changes in metabolic (acidosis) and cardiac (hypotension and bradycardia) status were the most critical abnormalities the trainees faced. Their skill in coping with hemodynamic and metabolic changes improved significantly (P<.05). All participants expressed a preference for receiving training in a porcine model before providing anesthesia in this surgical setting. CONCLUSIONS: Under this training model, the anesthesiologists understood and were able to manage the hemodynamic and physiologic changes that develop during a liver transplant procedure. We believe that training using a porcine model allows an anesthesiologist to acquire experience and skill in this setting. PMID- 21797085 TI - [Treating acute postoperative pain: evaluation of results on the surgical ward]. AB - OBJECTIVE: To describe management of acute postoperative pain on the surgical ward. To study the relationship between pain and a variety of surgical procedures and approaches. To determine the level of information patients received, their expectations, and their satisfaction with treatment of postoperative pain. PATIENTS AND METHODS: Cross-sectional observational study by survey and review of patient records. We studied 234 patients, including all who were hospitalized for more than 24 hours after scheduled or emergency operations. The main variables recorded were pain intensity at rest and during movement, including on the day after surgery, and the surgical procedure and approach. RESULTS: The prevalence of pain (>3 on a numerical scale) on the surgical ward was 33% at rest and 66% during movement. The prevalence of intense pain (>6 on the numerical scale) was 1.7% at rest and 7.3% during movement. Factors related to greater pain intensity were timing, that is, the first day after surgery, when 74.4% of patients experienced their most intense pain; type of surgery and approach (P<.004); and expecting to experience moderate or intense pain (P<.001). CONCLUSIONS: Recording the prevalence of postoperative pain on a surgical ward provides information about the real situation of acute postoperative pain control. Pain on movement is a principal indicator for detecting groups of patients for whom analgesic protocols could be improved. Type of surgery and approach is a fundamental factor to consider when comparing the results of analgesic protocols. PMID- 21797086 TI - [Experience with the proseal laryngeal mask in ventriculoperitoneal shunting]. AB - OBJECTIVE: To describe the use, utility, safety, and effectiveness of the Proseal laryngeal mask for airway management in patients undergoing ventriculoperitonea shunting. PATIENTS AND METHODS: We retrospectively reviewed the records of all patients in whom the Proseal laryngeal mask was used during ventriculoperitoneal shunting between January 2006 and October 2009. Patient demographic characteristics, airway assessments, type of anesthesia, quality of ventilation, and perioperative complications were recorded. RESULTS: Of the 43 patients included, 8 (18.6%) had at least 1 difficult airway criterion. We were able to insert the Proseal laryngeal mask in all patients. Ventilation was optimal in 39 (91%) patients, with maintenance of end-expiratory carbon dioxide pressures between 35 and 40 mm Hg and airway pressures above 25 cm H2O throughout the procedures. Air leaks developed in 3 cases (7%) when the patient was placed in a lateral-cervical position for surgery; these patients required orotracheal intubation before surgery could begin. Mean duration of surgery was 53 minutes. Awakening occurred without incident in all cases. CONCLUSIONS: The Proseal laryngeal mask is useful for airway management in patients undergoing ventriculoperitoneal shunting. Due to the forced position of the neck, however, it may be necessary to reposition the mask or even proceed to orotracheal intubation in some cases. As is the case for other advanced uses, experience with the device is necessary. Material for managing a difficult airway should be on hand. PMID- 21797087 TI - [Acute kidney injury]. AB - Acute kidney injury (AKI) is defined as an abrupt decline in the glomerular filtration rate with accumulation of nitrogenous waste products and the inability to maintain fluid and electrolyte homeostasis. Occurring in 7% of all hospitalized patients and 28% to 35% of those in intensive care units, AKI increases hospital mortality. Early evaluation should include differentiating prerenal and postrenal components from intrinsic renal disease. Biological markers can give early warning of AKI and assist with differential diagnosis and assessment of prognosis. The most effective preventive measure is to maintain adequate circulation and cardiac output, avoiding ischemia- or nephrotoxin induced injury. To that end, patients and situations of risk must be identified, hemodynamics and diuresis monitored, hypovolemia reversed, and nephrotoxins avoided. Protective agents such as sodium bicarbonate, mannitol, prostagiandins, calcium channel blockers, N-acetyl-L-cysteine, sodium deoxycholate, allopurinol, and pentoxifylline should be used. Treatment includes the elimination of prerenal and postrenal causes of AKI; adjustment of doses according to renal function; avoidance of both overhydration and low arterial pressure; maintenance of electrolytic balance, avoiding hyperkalemia and correcting hyperglycemia; and nutritional support, assuring adequate protein intake. For severe AKI, several modalities of renal replacement therapy, differentiated by mechanism and duration, are available. Timing--neither the best moment to start dialysis nor the optimal duration--has been not established. Early detection of AKI is necessary for preventing progression and starting renal replacement therapy at adjusted doses that reflect metabolic requirements. PMID- 21797089 TI - [Orotracheal intubation of patients with acromegaly using the AirTraq laryngoscope]. AB - An excess of growth hormone is responsible for the phenotypical characteristics of acromegaly. Tissue hypertrophy and growth also affect the airway, potentially making perioperative management difficult. If tests to foresee the likelihood of difficult airway have limitations affecting their sensitivity, specificity and predictive value even in the normal population, their reliability in patients with acromegaly is still more doubtful. At this time, videoassisted or optical laryngoscopes can offer a way to facilitate intubation in these patients. We report 3 cases in which the AirTraq optical laryngoscope was used to gain a full view of the vocal cords in acromegalic patients scheduled for pituitary surgery by the transsphenoidal route. PMID- 21797088 TI - [Labeling of injectable drugs used in anesthesia]. PMID- 21797090 TI - [Late-onset postpartum sepsis with septic shock and heart dysfunction]. AB - We report a case of late-onset postpartum sepsis from endometritis due to group A streptococci (GAS) in a 37-year-old white woman. The patient developed septic shock, with mitral regurgitation and cardiac dysfunction. Early treatment with broad-spectrum antibiotics and hemodynamic support was essential for a favorable outcome. Because of the resurgence of virulent strains of GAS that can cause fatal infections, these pathogens should be included in the differential diagnosis of postpartum infections in the mother. Although cardiac dysfunction is rare in association with GAS infection, it should be ruled out by echocardiography when the condition of a patient with sepsis does not improve. PMID- 21797091 TI - [Comments on the case report "Use of the flexible laryngeal mask in rheumatoid arthritis with the patient in lateral decubitus position"]. PMID- 21797092 TI - [Epidural fibrin glue injection as a conservative treatment for persistent cerebrospinal fluid leakage after spinal catheterization]. PMID- 21797093 TI - [Non cardiac surgery in a man after a recent coronary angioplasty procedure: intraoperative transesophageal echocardiography is highly useful]. PMID- 21797094 TI - [Lumbar arthrodesis without transfusion in a woman who refused blood products]. PMID- 21797095 TI - [Postdural puncture headache after pediatric inguinal herniotomy]. PMID- 21797096 TI - [Giant pulmonary bulla diagnosed as spontaneous pneumothorax]. PMID- 21797097 TI - [Pneumocephalus after accidental dural puncture during performance of an epidural block for obstetric analgesia]. PMID- 21797098 TI - [Accidental rupture of a caudal catheter in the paravertebral space]. PMID- 21797099 TI - [Double epidural blood patch to treat spontaneous intracranial hypotension syndrome]. PMID- 21797100 TI - [Left ventricle veiled by a giant pulmonary bulla]. PMID- 21797101 TI - Is everything clear about Tako-tsubo syndrome? AB - INTRODUCTION: Tako-tsubo syndrome is a novel cardio-vascular disease affecting predominantly postmenopausal women exposed to unexpected strong emotional or physical stress, in the absence of significant coronary heart disease. It is characterized by acute onset of severe chest pain and/or acute left ventricular failure, ECG-changes, typical left ventricular angiographic findings, good prognosis and positive resolution of the morphological and clinical manifestations. First described in 1990 in Japan by Sato, Tako-tsubo cardiomyopathy is characterized by transient contractile abnormalities of the left ventricle, causing typical left ventricular apical ballooning at end-systole with concomitant compensatory basal hyperkinesia. There are also atypical forms, presenting with left ventricular systolic dysfunction which affects the mid portions of the left ventricle. The etiology of the disease still remains unclear. Many theories have been put forward about the potential underlying pathophysiological mechanisms that may trigger this syndrome among which are the theory of catecholamine excess, the theory of multivessel coronary vasospasm, the ischemic theory, and the theory of microvascular dysfunction and dynamic left ventricular gradient induced by elevated circulating catecholamine levels. Adequate management of Tako-tsubo syndrome demands immediate preparation for coronary angiography. Once the diagnosis is made, treatment is primarily symptomatic and includes monitoring for complications. Patients with Tako-tsubo syndrome most frequently develop acute LV failure, pulmonary edema, rhythm and conductive disturbances and apical thrombosis. Treatment is symptomatic and includes administration of diuretics, vasodilators and mechanical support of circulation with intra-aortic balloon counterpulsation. PMID- 21797102 TI - Effect of moderate and high dose simvastatin on adhesion molecules in severe hypercholesterolemia after targeting the LDL-cholesterol--a randomised, placebo controlled study. AB - INTRODUCTION: The effect of statins on the levels of cell adhesion molecules (CAM) is discussed in the literature as one of the pleiotropic effects of the drugs. This effect is one of the ways that could be used to control the initial stage of atherogenesis. The research in this field is inadequate and controversial. Prevention guidelines recommend that target levels of LDL cholesterol in high-risk patients should be less than 2.6 mmol/l. If the primary target is LDL-cholesterol, it is doubtful if patients can have any significant changes in the levels of the cell adhesion molecules (CAM). AIM: Study the effect of simvastatin administered in a moderate dose of 40 mg and in a high dose of 80 mg on endothelium activation in the context of the plasma levels of soluble cellular adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin) in recently diagnosed untreated severe hypercholesterolemia after reaching target levels for the LDL-cholesterol below 2.6 mmol/1. PATIENTS AND METHODS: One hundred patients (aged > 16 years) were included in the study. Hypercholesterolemia was defined as fasting total serum cholesterol level greater than 7.5 mmol/l and LDL-cholesterol > 4.9 mmol/l. The study was carried out in three phases, the main goal being titration of simvastatin dose from 40 to 80 mg with the purpose of achieving the target LDL level of < 2.6 mmol/l in a randomised placebo-controlled study. RESULTS: There was a statistically significant reduction of sVCAM-1 following the 80-mg simvastatin therapy for one month after reaching target levels of LDL-cholesterol < 2.6 mmol/l in hypercholesterolemic patients in comparison with the moderate dose (40 mg) of simvastatin for one month (p < 0.001). The results of the study demonstrated that simvastatin in a dose of 80 mg exerted an effect on the levels of some CAM, and particularly on VCAM-1 in contrast to the same drug used in a dose of 40 mg. CONCLUSION: As different statins most likely have a distinctly specific effect on different adhesion molecules, this study seeks to establish a suitable panel of such adhesion molecules that may be used in monitoring statin therapy. PMID- 21797103 TI - Serum levels of siCAM-1, sVCAM-1, sE-selectin, sP-selectin in healthy Bulgarian people. AB - BACKGROUND: Endothelial dysfunction is increasingly recognized as an important early feature of vascular disease. As the damage to endothelium is a key underlying factor in the development and progression of atherosclerotic processes, markers of endothelial abnormalities have been sought. Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play a significant role in atherogenesis. Both in vitro and in vivo studies have suggested that different risk factors of atherosclerosis may increase expression of CAMs. The elevated level of soluble forms of CAMs in circulation is associated with a higher risk to future cardiovascular events in subjects predisposed to atherosclerosis OBJECTIVE: To determine the reference range for serum concentration of soluble cell adhesion molecules - slCAM-1, sVCAM 1, sE-selectin, sP-selectin. MATERIAL AND METHODS: We studied 110 healthy people of Bulgarian nationality aged 18-65. The selection criteria for the reference group were made in accordance with the requirements of the International Federation of Clinical Chemistry (IFCC). Serum concentrations of CAMs were analysed by means of ELISA assay. RESULTS: The results are presented as central 95% interval and 0.90 confidence interval of the reference range. Reference ranges were determined for sICAM-1 (128.9 - 347.48 ng/ml), sVCAM-1 (170.42 - 478.36 ng/ml), sE-selectin (9.15 - 65.19 ng/ml) and sP-selectin (101.86 - 209.7 ng/ml). As we found no sex-related differences in the CAMs concentrations (p > 0.05) there needed to be no separate reference intervals for men and women. The single-factor dispersion analysis we used in analysing the effect of age found no age-related dependence (p > 0.05, F = 1.038) for the serum CAM concentrations in the 18-65 age range, which means that it is not necessary to establish reference intervals for smaller age ranges in this age group. CONCLUSION: The reference ranges for slCAM-1, sVCAM-1, sE-selectin, sP-selectin computed in accordance with the results distribution can be used as baseline criteria in clinical laboratory studies. PMID- 21797104 TI - Clinical and laboratory study of pro-inflammatory and antiinflammatory cytokines in women with multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system characterised with a complex system of interactions between proinflammatory and anti-inflammatory cytokines in its course. AIM: The aim of the present study was to investigate the serum levels of cytokines TNF-a, IFN gamma, IL-4 and IL-10 in female patients with MS and healthy individuals, the changes occurring in the relapse and remission phases of the disease and their correlation with the severity of the neurological deficit. PATIENTS AND METHODS: Thirty-five women with relapsing-remitting MS were examined. The patients' age ranged between 18 and 50 years and MS was verified clinically and by magnetic resonance imaging according to the McDonald criteria. Thirteen of the patients were treated with interferon-beta-1b. The serum concentrations of TNF-a, IFN-y, IL-4 and IL-10 were determined twice - in relapse and in remission - using an enzyme-linked immunosorbent assay (ELISA). The control group consisted of 35 age matched healthy females. RESULTS: The comparison of cytokine serum concentrations during the two phases of the disease showed significant elevation of the TNF alpha serum levels in the relapse phase and of IL-4 - in the remission phase. The comparison between the patients and the healthy control subjects demonstrated statistically significant lower concentrations of TNF-a in remission patients and higher concentrations of IL-10 in relapse patients. The patients with interferon beta-lb treatment showed different profile of cytokine secretion from the patients without interferon-beta-1b treatment. Interferon-beta-1b-treated patients showed significantly lower serum levels of TNF-a and IFN-gamma during the relapse phase and higher TNF-a and IL-10 serum levels during the remission phase compared with the untreated patients. CONCLUSIONS: Serum levels of TNF-a and IL-4 objectively reflect the immune response during relapse and remission of the disease. The severity of neurological deficit as estimated with the expanded disability status scale (EDSS) does not depend on the serum levels of TNF-a, IL 10 and IFN-gamma in the two phases of MS. PMID- 21797105 TI - Dynamics in serum cytokine responses during acute and convalescent stages of Mediterranean spotted fever. AB - Mediterranean spotted fever (MSF) is a re-emerging rickettsiosis in Bulgaria after 20 years of absence (1972-1992), and it has since been affecting many people annually in the endemic regions of the country. The role of cytokines in MSF is still in the focus of research due to their complex participation in the immune pathogenesis of the disease. AIM: To study the changes in the serum cytokine concentrations in MSF patients. PATIENDS AND METHODS: Eighty patients with MSF and 20 healthy controls were enrolled in the study. The pro-inflammatory and immunoregulatory cytokines IL-1beta, TNF-a, IL-6, IL-8, IL-12, IFN-gamma, IL 2, and IL-10 were studied in the burst of disease, at clinical recovery stage, and two weeks later. The disease etiology was verified by indirect IFA in the Referral Rickettsiosis Laboratory. The cytokine levels were determined by ELISA (BioSource Europe S.A). RESULTS: In the disease flare up patients showed a manifold increase in the activity of IL-1beta (p < 0.01), TNF-alpha (p < 0.001), IL-6 (p < 0.001), and IL-8 (p < 0.001) compared with the controls. Significant elevation in IFN-gamma and IL-12 values (p < 0.001) was also found. The increase in the immunoregulatory IL-10 also reached statistical significance (p < 0.001), while the rise in IL-2 did not (p > 0.05). Followed in dynamics, only IL-1beta and IL-6 measured up the control levels at the time of clinical recovery. Two weeks later, in the early convalescence IL-12 and TNF-alpha further diminished but did not normalize their values. CONCLUSION: Our findings show that MSF is characterized by a Th1 cytokine profile. The patient's immune system responds by proinflammatory and immunoregulatory cytokine production that accompanies the rickettsial vasculitis and contributes to the healing process. The latter is probably not fully achieved in the early convalescent period, according to our data concerning some pro-inflammatory cytokines' elevation at this period. PMID- 21797106 TI - Serum inflammatory cytokines IL-1beta, IL-6, TNF-alpha and VEGF have influence on the development of diabetic retinopathy. AB - AIM: The aim of this study was to analyze the correlation between serum levels of inflammatory cytokines IL-1beta, IL-6, TNF-alpha and VEGF and the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (DM). PATIENTS AND METHODS: In this prospective study we included 38 healthy volunteers (group 1) and 39 patients with type 2 DM (group 2). All participants underwent routine ophthalmological examination and laboratory analysis of the serum cytokines IL-1beta, IL-6, TNF-alpha and VEGF. Group 2 patients were additionally examined by colour fundus photography and fluorescein angiography to determine the DR stage. We studied the correlation of IL-1beta, IL-6, TNF-alpha and VEGF with the presence of DM, the presence and severity of DR, the duration of DM and DR, the serum levels of glycosylated haemoglobin, as well as with hyperlipidemia and the general indicators of inflammation - erythrocyte sedimentation rate (ESR) and fibrinogen. RESULTS: The group 2 patients had statistically significantly higher levels of IL-1beta (p = 0.01) and IL-6 (p = 0.029) and elevated TNF-alpha and VEGF levels in comparison with group 1 patients. Group 2 patients were divided into 5 subgroups depending on the severity of DR: patients without DR (n = 11), patients with mild non proliferative DR (n = 10), patients with moderate non-proliferative DR (n = 5), and patients with severe non-proliferative DR (n = 2) (total number of non proliferative DR (n = 17)) and patients with proliferative DR (n = 11). The comparative analysis showed statistically significant differences in the serum levels of IL-1beta (p = 0.003), TNF-alpha (p = 0.002) and VEGF (p = 0.005) between the different subgroups. Patients with proliferative DR showed significantly higher values of serum IL-1beta (p < 0.0001), IL-6 (p = 0.007), TNF alpha (p = 0.002) and VEGF (p < 0.0001) compared with the patients with non proliferative DR. The cytokine serum levels did not correlate with the duration of DM, the duration of DR (except for IL-1beta, p = 0.045), and hyperlipidemia (except for TNF-alpha, p = 0.05). TNF-alpha(p = 0.05) and VEGF (p = 0.047) serum levels correlated with the levels of glycosylated hemoglobin, and IL-1beta, TNF alpha and VEGF correlated with the general indicators of inflammation (ESR and fibrinogen). CONCLUSION: Serum concentrations of IL-1beta, TNF-alpha and VEGF have an effect on the development and progression of DR. They correlate with the presence and severity of the disease. Whether serum cytokines can play the role of a prognostic factor or serve as a means to choose a proper therapeutic agent for the treatment of diabetic retinopathy should be analyzed by further more extensive prospective longitudinal studies in future. PMID- 21797107 TI - Reliability and cross-cultural validity of the Bulgarian version of IRES-3. AB - INTRODUCTION: The IRES-3 questionnaire (Indicators of rehabilitation status, version 3) was developed to evaluate the rehabilitation effect in patients with psychosomatic, cardiac, orthopedic, oncologic, neurologic, gastroenterological and other disorders. AIM: The aim of the present study was to validate the Bulgarian version of IRES-3 and assess its reliability and internal consistency. MATERIALS AND METHODS: Validation of the IRES-3 questionnaire was carried out at the Specialized Rehabilitation Hospital, the National Complex PLtd, the Hisar branch. The study included 46 patients: 14 males (30.43%) and 32 females (69.57%). Patients' age ranged between 43 and 75 years (mean age 63.52 +/- 1.27). All participants got preliminary instructions and after that, within a period of one week, they completed the questionnaire two times. To evaluate IRES-3 reliability we used the split-half-reliability model and calculated the Spearman Brown coefficients (rsb) for each of the scales. Internal consistency was estimated using Cronbach's alpha coefficient. We used the mean value of the inter item correlation coefficients as well. RESULTS: The high values of rsb and Cronbach's coefficient alpha as well as the low values of the inter-item correlation coefficient which were obtained in our study demonstrate that the questionnaire under investigation is of high reliability and internal consistency. Our results are very similar to the results of the original German questionnaire which have been reported in literature. CONCLUSION: The Bulgarian version of the IRES-3 questionnaire shows high reliability and cross-cultural validity and can be applied widely for evaluation of the effect of rehabilitation. PMID- 21797108 TI - A study of the effects of lamotrigine on mice using two convulsive tests. AB - The AIM was to study the effects of lamotrigine on bicuculline and pentylenetetrazol models of epilepsy. MATERIAL AND METHODS: Mice divided in 8 groups (n = 6) were pretreated intraperitoneally 30 min before pentylenetetrazol (50 mg/kg) or bicuculline (1 mg/kg) with saline 0.1 ml/10 g body weight or lamotrigine 10 mg/kg, 15 mg/kg or 20 mg/kg, respectively. The seizure intensity and latency to the seizures 60 min after bicuculline or pentylenetetrazol injection were observed. The following scale for seizure intensity was used: 1 - excitation; 2 - body tremor; 3 - clonic seizures of forelimbs; 4 - heavy clonic seizures with rotations; 5 - tonic seizures of forelimbs; 6 - tonic seizures of limbs. RESULTS: The controls showed bicuculline-induced seizure intensity up to 5. Lamotrigine in the higher doses used decreased the seizure intensity (p <0.05). Lamotrigine in all doses studied did not change the latency period of the first bicuculline seizure compared with the control. Controls treated with pentylenetetrazol showed seizure intensity up to 4. Lamotrigine in the highest dose decreased the pentylenetetrazol-induced seizure intensity (p < 0.05). Lamotrigine in all studied doses increased the latency to the first pentylenetetrazol-induced seizure compared with the controls (p < 0.05). Both convulsing drugs influence the brain GABA-ergic transmitter system by competitively blocking GABAA receptors. Lamotrigine inhibits glutamate transmission and sodium channels. Both neurotransmissions - glutamate and GABA are closely related in seizure control. The CONCLUSION is that lamotrigine has an anticonvulsive effect on both bicuculline and pentylenetetrazol seizure models, suppressing seizure intensity and influencing the latency to the first seizure. PMID- 21797109 TI - A model of experimental acute hematogenous pyelonephritis in the rat. AB - The OBJECTIVE of the study was to create a model of acute hematogenous pyelonephritis in the rat without causing urinary retention by ligation of the ureter. Mixed bacterial suspension containing 1.5 x 10(6) colony-forming units (CFU) of S. aureus and 3.0 x 10(6) CFU of E. coli was inoculated in the caudal vein at a dose of 0.5 ml/kg. Control animals received the same amount of saline solution. Pyelonephritis was confirmed by lab urine tests and histopathological study of the kidneys. Infected animals initially developed sepsis with a significant increase of leukocytes and C-reactive protein in the blood. Originally only bacteriuria was found in the urine of experimental animals, but later, in the course of the development of pyelonephritis (12-18 days), leucocyturia and active leukocytes (glitter cells) were also available in urine. The levels of beta-2 microglobulin in the urine of infected animals (4.02 +/- 0.04 mmol/l on day 16 and 4.18 + 0.07 mmol/l on day 18) were significantly highly increased (p <0.0001) in comparison with the value of the control group (0.088 +/ 0.005 mmol/l). In the early days the histopathological examination of the kidneys established erythrocyte stasis. Later leukocyte infiltrates were observed in the interstitial tissue around the kidney tubules, glomeruli and vascular walls, and inflammatory cell infiltration and degenerative changes were present in the epithelium of the canaliculi. Combined hematogenous infection with S. aureus and E. coli led to the development of pyelonephritis in rats. The pathology in the kidney tubules was confirmed by histopathological study and by the elevated levels of beta-2 microglobulin and the presence of active leukocytes in urine. PMID- 21797110 TI - The effects of chronic losartan pretreatment on restraint stress-induced changes in motor activity, nociception and pentylenetetrazol generalized seizures in rats. AB - Accumulated evidence has shown that renin-angiotensin system has a pivotal role in stress responses. AIM: to assess the participation of AT1 receptor in stress induced modulation of motor activity, nociception and seizure susceptibility in male Wistar rats. MATERIAL AND METHODS: AT1 receptor antagonist losartan was administered subcutaneously to rats for 10 days at a dose of 10 mg/kg either alone or as a pretreatment before chronic restraint stress applied for 10 days. Locomotor and exploratory activity (open field test), the nociception (paw pressure test) and the seizure susceptibility (pentylenetetrazol seizure test) were analysed. RESULTS: Chronic restraint stress decreased motor activity and increased anxiety-like behaviour (grooming) while losartan pretreatment alleviated anxiety-like behaviour. Chronic restraint stress had an antinociceptive effect in paw-pressure test and losartan pretreatment abolished stress-induced antinociception. Both chronic restraint stress and losartan showed anticonvulsant activity in pentylenetetrazol seizure test. However, drug pretreatment attenuated this effect in chronically-stressed rats. CONCLUSIONS: Our findings suggest that the AT1 receptor is involved in the mechanism of stress induced changes in anxiety-like behaviour, nociception and seizure susceptibility in rats. PMID- 21797111 TI - A prospective randomised phase II trial of thalidomide with carboplatin compared with carboplatin alone as a first-line therapy in women with ovarian cancer, with evaluation of potential surrogate markers of angiogenesis. AB - OBJECTIVES: To compare the safety and efficacy of thalidomide in combination with carboplatin to carboplatin alone as a first-line therapy in women with ovarian cancer and to evaluate the anti-angiogenic effects of thalidomide by measurement of surrogate markers of angiogenesis. METHODS: Forty patients with Stage IC-IV ovarian cancer were randomly assigned to receive either carboplatin (AUC 7) intravenously every four weeks for up to six doses (n = 20) or carboplatin at the same dose and schedule, plus thalidomide 100 mg orally daily for six months (n = 20). RESULTS: After median follow-up of 1.95 years, there was no difference in the overall response rate (90% in carboplatin arm, 75% in combination arm; p = 0.41). Increased incidence of symptoms of constipation, dizziness, tiredness and peripheral neuropathy was observed in the combination arm. There was a significant fall in CA-125 and E-selectin in both arms after treatment and VCAM-1 in the carboplatin arm. No significant difference between the two arms was observed in any of the markers analysed. CONCLUSIONS: In our trial the addition of thalidomide to carboplatin was well tolerated with no increased efficacy. The fall in some of the angiogenic markers in both groups may reflect tumour response rather than any specific anti-angiogenic effect of thalidomide. PMID- 21797112 TI - Nodal metastasis in endometrial cancer. AB - PURPOSE: Besides hysterectomy and bilateral salpingo-oophorectomy, the goal of surgery in early endometrial cancer is to identify extrauterine disease. The purpose of this study was to evaluate disease characteristics and survival of patients found to have nodal metastasis at staging for endometrial cancer. METHODS: All patients presenting to our practice from January 1993 to July 2009 with a new diagnosis of early endometrial cancer underwent pelvic and paraaortic lymph node sampling at the time of surgery as permitted by the body mass index. Patient and disease characteristics of patients with nodal metastasis were abstracted by retrospective chart review. Factors contributing to disease-free and overall corrected survival were evaluated. RESULTS: Forty-three patients with an early endometrial cancer were found to have pelvic and/or paraaortic nodal metastasis. Thirty-three percent of patients with nodal metastasis had papillary serous or clear cell cancers. Such tumors were often superficially invasive, yet were more likely to demonstrate lymphovascular space involvement as compared to endometrioid cancers. Furthermore, in a global model of disease-free and overall corrected survival, only tumor histology (endometrioid vs non-endometrioid) was a significant prognostic factor. Excluding clear cell and papillary serous tumors, only tumor grade was a significant prognostic factor in disease-free survival and overall corrected survival in patients with endometrioid adenocarcinomas and nodal involvement. Following adjuvant treatment after surgery, the recurrences were nearly evenly divided between pelvic, paraaortic nodal and distant sites. Only four of 33 (12%) patients treated with adjuvant pelvic radiation experienced a failure in the irradiated field. Furthermore, none of the patients experiencing a paraaortic nodal recurrence received adjuvant radiation to this site. CONCLUSIONS: The data suggest a benefit to the use of adjuvant radiation for local control of disease. Furthermore, the use of paclitaxel and carboplatinum chemotherapy also appears a promising adjunct in patients with endometrioid histologies and nodal spread. Papillary serous and clear cell cancers contributed disproportionately to the incidence of nodal metastasis and an adverse prognosis following further adjuvant therapy of patients with nodal disease. Despite taxol/carboplatinum chemotherapy, over half of the patients with non-endometrioid cancers recurred, as opposed to one of 19 endometrioid cancers so treated. The ideal form of adjuvant treatment for such patients remains problematic. PMID- 21797113 TI - Metastasis gene expression analyses of choriocarcinoma and the effect of silencing metastasis-associated genes on metastatic ability of choriocarcinoma cells. AB - OBJECTIVE: Obtaining choriocarcinoma metastasis-associated genes and identifying the role and mechanism of VEGF-B in the progression of human choriocarcinoma. STUDY DESIGN: (1) cDNA microarray technique was used to compare the transcriptional profiles between highly metastatic JEG-3 cells and lowly metastatic JAR cells; (2) An inhibitory effect of VEGF-B shRNA was demonstrated by RT-PCR; (3) The effect of VEGF-B shRNA on invasion of JEG-3 cells in vitro was detected by Matrigel invasion assay. RESULTS: (1) In upregulated genes, 51 genes were correlated with the cell metastasis ability, and FN, MMP-2, uPA, CAV-1 and VEGF-B were the first five genes; (2) Afterwards transfected VEGF-B shRNA, VEGF-B mRNA expression decreased obviously; (3) VEGF-B shRNA transfection significantly downregulated invasion level of JEG-3 cells in vitro (p < 0.05). CONCLUSION: VEGF B plays an important role in the metastatic capability of human choriocarcinoma. Reducing the expression of VEGF-B can help weaken the invasion ability of human choriocarcinoma. PMID- 21797114 TI - Safety and efficacy of a splenectomy during debulking surgery for Mullerian carcinoma. AB - PURPOSE: This study was designed to assess the safety and efficacy of a splenectomy and to analyze the prognostic factors of Mullerian carcinoma with spleen metastasis. METHODS: We reviewed the medical records of 11 patients with Mullerian carcinoma who underwent a splenectomy between 1997 and 2007. The treatment outcome of these patients was examined and the possible prognostic factors were investigated by univariate analysis. RESULTS: Four and seven patients underwent a splenectomy for primary and recurrent disease, respectively. A complete resection was achieved in eight patients. A blood transfusion was not required and only two mild postoperative complications were observed. The median and five-year survivals of all patients following treatment were 39 months and 39%, respectively. Older patients (> or = 60 years old) and patients with a poor performance status (PS2) had a poorer prognosis by univariate analysis. CONCLUSIONS: A splenectomy can be performed safely and effectively during debulking surgery for appropriately selected patients with primary or recurrent Mullerian carcinoma. PMID- 21797115 TI - XRCC1 Arg399Gln polymorphism and risk for cervical cancer development in Argentine women. AB - BACKGROUND: XRCC1 (X-ray repair cross-complementing group 1) plays a central role in the DNA base excision repair mechanism. Single nucleotide polymorphisms (SNPs) in the XRCC1 gene are thought to modulate DNA repair capacity and have been linked to cancer risk in several studies. MATERIALS AND METHODS: We conducted a case-control study comprising 217 cervical samples, including 103 cervical carcinomas and 114 normal tissue samples. Cervical samples were genotyped for two XRCC1 SNPs (Arg194Trp and Arg399Gln) by PCR-RFLPs. RESULTS: Subjects carrying heterozygous Arg399Gln or the combined Gln399Gln + Arg399Gln variant genotypes had a significantly reduced risk for cervical cancer development. In addition, the 194Arg-399Gln haplotype was also found to be associated with a decreased risk for cervical carcinoma. CONCLUSION: Our findings suggest that XRCC1 genotypes and haplotypes contribute in reducing the risk for cervical cancer development. Furthermore, genetic susceptibility conferred by Arg399Gln polymorphism operates independently of human papillomavirus infection of cervical tissue. PMID- 21797116 TI - Compliance to adjuvant therapy in breast cancer patients. AB - During recent years a continuous reduction of mortality from breast cancer has taken place in the Western countries. We wanted to verify whether the actual therapy for our own cases deviates from our recommendations, although the surgeon, radiotherapist and gynaecological oncologist are on the same premises. We sent out questionnaires to all newly diagnosed breast cancer patients in the last seven years regarding their adjuvant therapy. Comparing these answers to our own recommendation showed a very good compliance regarding chemotherapy and radiation therapy. Adjuvant endocrine therapy showed a very poor compliance with an adherence of 77%. Overall we can conclude that endocrine therapy causes many side-effects that seem to burden the patients. In combination with the duration of the therapy this causes a severe reduction in compliance and length of the therapy. PMID- 21797117 TI - Discrepancy of pre- and postoperative grades of patients with endometrial carcinoma. AB - PURPOSE: To investigate the diagnostic accuracy of endometrial curettage in patients with endometrial carcinoma. In this retrospective study, pre- and postoperative histopathologic findings of patients with endometrial cancer were investigated. METHODS: 168 patients with the final diagnosis of endometrial cancer were enrolled in the study. Pre- and postoperative histopathologic diagnoses and grades (according to the 1988 FIGO classification) of the patients were compared retrospectively. RESULTS: 22 patients were diagnosed as having endometrial hyperplasia and the remaining 136 patients had endometrial carcinoma preoperatively. Overall discrepancy rate of grades was 39% (31% upgrade, 8% downgrade; p < 0.05). There was also 9% discrepancy between the pre- and postoperative histopathological types. CONCLUSION: It has been suggested that since endometrial cancer patients with low grades according to the preoperative pathologic diagnosis have a potential to upgrade, the management of these patients if myometrial invasion is less than one-half thickness, simply by hysterectomy plus bilateral salpingo-oophorectomy (without lymph node sampling), might actually miss some patients who actually deserve surgical staging. Further studies are needed to draw a sufficient conclusion. PMID- 21797118 TI - Diagnostic test for ovarian cancer composed of ovarian cancer symptom index, menopausal status and ovarian cancer antigen CA125. AB - The objective of the study was to evaluate accuracy of the diagnostic test composed of the ovarian cancer symptom index, ovarian cancer antigen CA125 and menopausal status. METHODS: A case-control study consisting of 75 women--24 patients with ovarian cancer, 20 patients with benign ovarian diseases, and 31 age-matched healthy controls. RESULTS: Sensitivity and specificity for the ovarian cancer symptom index alone was 83.3% and 48.3%, respectively. Specificity improved up to 70.9% when menopausal status was added. When CA125 (at cut-off level of 21 U/ml) was added to the ovarian cancer symptom index, the highest sensitivity and specificity was achieved resulting in 79.1% and 100.0%, respectively. CONCLUSIONS: The ovarian cancer symptom index could be used as a first-step screening tool in combination with serum biomarkers followed by TVS examination with an acceptable sensitivity and specificity. However, further prospective studies with larger sample size are needed to reach clear conclusions. PMID- 21797119 TI - Ovarian germ cell tumors in children: a 20-year retrospective study in a single institution. AB - PURPOSE: Ovarian germ cell tumors are rare in childhood. The goal of the study is to provide information that may help guide the evaluation and surgical management of future children with ovarian tumors. METHODS: A retrospective review of patients with ovarian germ cell tumors between January 1990 and January 2010 was performed. RESULTS: 137 patients were included with a median age of 9.5 years. Teratomas were found most frequently (mature: 78, immature: 6), followed by yolk sac tumors (n = 51), dysgerminoma (n = 1) and embryonal carcinoma (n = 1). Abdominal pain (81.8%) and abdominal distension (58.4%) were the most common symptoms. Twenty-six infants were found prenatally. Twenty-one patients presented torsion of the ovary. Alpha-feto-protein levels were elevated in all pure yolk sac tumors, two immature teratomas and one embryonal carcinoma. Most patients (84) were Stage I, 16 were Stage II, 23 Stage III, and four Stage IV. All patients with mature and immature teratomas (grade 1) underwent surgery alone. Surgery + chemotherapy were conducted in 55 other patients. The surgical procedures consisted of salpingo-oophorectomy (n = 68), oophorectomy (n = 21) and ovarian-sparing tumorectomy (n = 48). Sixteen patients gave up the treatment and died. Excluding this subset, 5-year relapse-free survival and overall survival was 93.4% and 98.3%, respectively. No recurrences were observed in any patients. CONCLUSION: Ovarian germ cell tumors have an excellent prognosis. With accurate staging, complete resection, and adjuvant chemotherapy, patients should be expected to have excellent survival rates. Preservation of ovarian tissue should be considered whenever safe and feasible, however, this needs to be confirmed by studies on larger numbers of patients. PMID- 21797120 TI - Specific downregulation of death-associated protein kinase enhances Fas-mediated apoptosis in the human differentiated endometrial adenocarcinoma cell line, HHUA. AB - PURPOSE OF INVESTIGATION: Death-associated protein kinase (DAPK) is a serine/threonine kinase that is well-known as a positive mediator of Fas-mediated apoptosis. Previous reports have shown that DAPK and Fas are expressed in human endometrial adenocarcinoma cells. In this study, we examined the effects of specific downregulation of DAPK expression on Fas-mediated apoptosis in the human endometrial adenocarcinoma cell line, HHUA. METHODS AND RESULTS: Transfection of DAPK small-interfering RNAs (siRNAs) into the HHUA cells reduced DAPK protein expression, and enhanced Fas-mediated apoptosis, in a dose-dependent manner. CONCLUSIONS: These results indicate that, in contrast to cases with other malignant tumor cells, DAPK negatively regulates Fas-mediated apoptosis in these human differentiated endometrial adenocarcinoma cells. PMID- 21797121 TI - Immunological evaluation of vaginal secretion in patients with high-grade cervical intraepithelial neoplasia treated with intralesional interferon alpha 2b. AB - INTRODUCTION: Conservative treatment with intralesional interferon (IFN) is a therapeutic option for cervical intraepithelial neoplasia (CIN) patients of childbearing age. MATERIALS AND METHODS: The study group was made up of patients diagnosed with a high-grade lesion and treated with intralesional human recombinant IFNalpha-2b. Vaginal secretion was collected during IFNalpha-2b treatment for analysis of cytokines and viral load. RESULTS: The initial histology diagnostic was 62.5% (n = 5) with CIN 2 and 37.5% (n = 3) with CIN 3. In terms of clinical evaluation and anatomopathology, 6.5% (n = 5) had a good clinical response, while 37.5% (n = 3) had therapeutic failure. All the patients with therapeutic failure were smokers. Interleukin 6 and tumor necrosis factor alpha concentrations were raised at the sixth application for the patient group who failed to respond to therapy compared to the responsive group (p = 0.0357). Patients with a good response exhibited a reduction in human papillomavirus viral load (p = 0.03). CONCLUSIONS: Patients that had a good response had lower concentrations of inflammatory cytokines than did non-responders. PMID- 21797122 TI - Importance of office hysteroscopy screening to diagnose endometrial carcinoma in menopausal women. AB - Uterine cancer is today the upcoming neoplasia in gynaecological oncology. In Western countries endometrial cancer is mostly diagnosed after menopause and often becomes apparent with atypical uterine bleeding. Because of the great importance of such disease a series of accurate diagnostic analyses which require an adequate expenditure by hospital structures become necessary. Transvaginal sonography (TVS) remains the first choice to diagnose atypical bleeding because it is less invasive and highly bearable by the patients. TVS exam allows the selection of all patients who have an endometrial thickness more than 5 mm and/or with an inhomogeneous endometrial line thickness, who would then undergo further analyses. To achieve the diagnosis, office hysteroscopy carried out in an outpatient departments, is the most useful exam. Such exam allows a complete overview of the uterine cavity with possible detection of smaller lesions and a specific sampling of histological material. Hysteroscopy is today an indispensable aid in last resort diagnosis of endometrial cancer and is highly tolerated by patients. PMID- 21797123 TI - Copper and zinc concentrations in Nigerian women with breast cancer. AB - Trace elements are accepted to be involved directly or indirectly in the process of cancer formation. In this study, serum selenium, copper and zinc were measured in three groups of patients using atomic absorption spectrometer. A total of 29 Nigerian women were included: group I consisted of nine age-matched healthy controls without breast problems; group 2 included nine women with benign breast disease; and group 3 was comprised of women with breast cancer. The serum concentration of copper (Cu) was significantly higher in patients with cancer when compared to the control group (1.43 +/- 0.31 microg/ml vs 0.91 +/- 0.18 microg/ul/0.94 +/- 0.10 microg/ml). The zinc (Zn) concentration was significantly lower in the breast cancer group than in the other two groups (0.74 +/- 0.21 microg/ml vs 1.14 +/- 0.31 ug/ml/1.11 +/- 0.29 microg/ml; p < 0.05). The study shows alteration in the concentration of copper and zinc in serum of patients with breast cancer, which may indicate abnormal copper and zinc metabolism in Nigerian females with breast cancer. PMID- 21797124 TI - P16 and retinoblastoma protein expression in endometrial carcinoma and clinical significance. AB - OBJECTIVE: To investigate the clinical significance of p16 expression, a product of the cyclin dependent kinase inhibitor CDKN2 (also known as MTS1, multiple tumor suppressor 1) and assess its relationship with retinoblastoma protein expression in the pathogenesis of endometrial cancer. METHOD: p16 and pRb expression were histochemically evaluated, using p16 and RB polyclonal antibodies on paraffin sections of 27 primary endometrial adenocarcinomas with no therapy prior to surgery, through the streptavidin peroxydase conjugated method. Further analyses were carried out using the polymerase chain reaction for exon 1 gene amplification to investigate the mechanism of abnormal p16 expression. RESULT: p16 expression was detected in 100% of normal endometriums and in 74.04% of endometrial carcinomas (p < 0.05). This was significantly associated with tumor cell grade (p < 0.05). PCR analysis of exon 1 in five cases with no detectable p16 expression revealed four homozygous deletions. Additionally, the inverse correlation between RB and p16 expression was confirmed in this study, with 71.42% of tumors demonstrating inverse expression of p16 and RB (p < .005). CONCLUSION: p16 expression decrease is a significant event in endometrial carcinoma pathogenesis, and it is inversely correlated to tumor cell grade. Exon 1 homozygous deletion might be one of the mechanisms of loss of p16 expression. The p16/pRb growth suppressor pathway is targeted in human endometrial carcinoma. PMID- 21797125 TI - Recombinant human endostatin, Endostar, enhances the effects of chemo radiotherapy in a mouse cervical cancer xenograft model. AB - BACKGROUND: The effects of recombinant human endostatin, Endostar, combined with concurrent chemo-radiotherapy (CCRT) on tumor growth, angiogenesis and lymphangiogenesis in a mouse xenograft model of cervical cancer was investigated. METHODS: HeLa cells were injected subcutaneously to establish mouse xenograft models and mice were treated with normal saline (control), CCRT with cisplatin (CDDP), Endostar, or a combination of Endostar and CCRT. Growth, metastasis, and angiogenesis of tumors was monitored. RESULTS: Tumorogenic activity of tumor cells in the CCRT, Endostar and combination Endostar-CCRT treatment groups was markedly decreased compared with the activity in the NS group (p < 0.05). The most significant inhibition of tumor growth was observed in the Endostar with CCRT group. Lymph node metastases in the Endostar with CCRT group (12.5%) and Endostar alone group (25%) were lower compared to the CCRT group (42.8%) and NS group (66.7%; p < 0.05). Endostar was also found to inhibit tumor angiogenesis. Endostar induced apoptosis of HeLa cells in vivo, and inhibited expression of VEGF and HIF-1alpha in vivo and in vitro. CONCLUSION: Endostar enhanced the anti cancer effect of CCRT in a mouse xenograft model of cervical cancer. These findings thus provide a new strategy to treat cervical cancer. PMID- 21797126 TI - Lymphoepithelial-like carcinoma of the uterine cervix; a case report. AB - Lymphoepithelioma-like carcinoma (LELC) of the uterine cervix is a rare variant of squamous cell carcinoma of the uterine cervix. This tumor is characterized by nests of poorly differentiated epithelial cells surrounded by a prominent lymphocytic infiltration. Despite the poorly differentiated pathological findings, it appears to have a better outcome than the usual squamous cell carcinoma of the uterine cervix. Therefore, it is quite important to differentiate this tumor from poorly differentiated squamous cell carcinoma and lympho-proliferative disorders of the cervix. LELC arising from the nasopharynx has been suggested to be associated with Epstein-Barr virus (EBV), whereas the involvement of EBV in LELC of the uterine cervix is still controversial. In addition, the role of high-risk human papilloma virus (HPV) in this type of tumor remains unknown. We report a case of LELC of the cervix with diagnosis on the basis of histopathology in a 52-year-old Japanese woman who presented with a history of continuous bleeding post menopause. We also examine the association of EBV and HPV in this case. PMID- 21797127 TI - Laparoscopic total fallopian tube removal at the time of bilateral salpingo oophorectomy in BRCA2 positive women. AB - About 10% of all serous ovarian cancer has BRCA1 and/or BRCA2 mutations. Recent data showed that following the SEE FIM protocol it is possible to evidence more fimbriae cancers. Due to those studies, fallopian tube cancer in recent years has become the predominant site of cancer in BRCA1 and/or 2 mutation carriers. The pathological study of the fallopian tube is not complete during salpingo oophorectomy because a small part (intramural site) is situated inside the uterus. In this case report we demonstrate how it is possible to remove the tubes entirely for pathological analysis without hysterectomy by laparoscopic surgery. PMID- 21797128 TI - Virilizing ovarian Krukenberg tumor in a 27-year-old pregnant woman. A case report and literature review. AB - A case is reported of a 27-year-old pregnant woman with ovarian tumors, measuring 12 cm and 11.5 cm in the greatest diameter, discovered during investigation for virilization symptoms. Termination of the pregnancy at the 22nd week of gestation and tumorectomy with both adnexa were performed, with the provisional diagnosis of arrhenoblastoma. Pathological examination of the tumors showed typical Krukenberg neoplasms and subsequent upper GI tract endoscopy revealed a gastric cancer that was excised. The pathological examination revealed a diffuse type gastric adenocarcinoma with signet ring morphology, similar to ovarian tumors. In any case of ovarian tumor with unusual hormonal manifestations, in addition to hormonally active sex cord-stromal neoplasms, metastatic ovarian tumors must be considered as well, especially in cases of bilateral tumors. PMID- 21797130 TI - Leiomyosarcoma of ovarian vein compression as a cause of hydronephrosis. AB - We present a case of leiomyosarcoma of the right ovarian vein with MRI findings. The patient was a 52-year-old woman who had suffered from right flank pain for one week. Abdominal ultrasound and excretory urography revealed hydronephrosis of the right kidney. Ureteroscopy showed external compression at the right upper third of the ureter. CT and MRI of the abdomen revealed a retroperitoneal mass with compression of the right ureter. The retroperitoneal mass proved on histology to be a leiomyosarcoma arising from the right ovarian vein. PMID- 21797129 TI - Unexpected synchronous follicular lymphoma of paraaortic and pelvic lymph nodes in a patient with endometrial carcinoma: a case report. AB - BACKGROUND: Multiple neoplasms in a patient occur rarely. There has only been one case report about synchronous endometrial carcinoma and follicular lymphoma of the paraaortic and pelvic lymph node (LN) until now. CASE REPORT: The patient was 64 years old and had vaginal spotting for four months. She was diagnosed with endometrioid endometrial carcinoma by endometrial biopsy. In intraoperative inspection, the whole paraaortic and pelvic LN had formed into a massive tumor bundle following the aorta and iliac vessels. The diagnosis was endometrial carcinoma FIGO Stage IB with synchronous follicular lymphoma Stage III. We performed adjuvant chemotherapy and radiotherapy. Currently, the patient has no evidence of recurrence for either carcinoma. CONCLUSION: Lymph node dissection was included in the staging and debulking operation of the endometrial carcinoma. An inaccurate result of the frozen section can not rule out metastasis of endometrial carcinoma and surgeons can fall into a dilemma regarding treatment. PMID- 21797131 TI - Proximal-type epithelioid sarcoma of the mons pubis: report of a case. AB - INTRODUCTION: Proximal-type epithelioid sarcoma (PES) represents an extremely rare and aggressive form of soft tissue neoplasm, typically presenting as a painless subcutaneous nodule in the trunk often located in the genital area. CASE REPORT: A 46-year-old female was subjected to the excision of a growing soft tissue mass in the mons pubis that, at histology, was identified as PES. The tumor showed an extreme aggressiveness involving subsequently adjoining structures and lymph nodes despite subsequent wide surgical resections during the following months. DISCUSSION: Gynecologists should pay careful attention to all soft tissue masses of the perineal area or external genitalia. It is important to know the possible genital localization of PES which, although rare, is an aggressive high-grade soft tissue tumor with a deceitful behavior, poorly sensitive to chemotherapy and radiotherapy. Surgery, though wide and demolitive, often fails to obtain the necessary radicality. PMID- 21797132 TI - Off-midline retroperitoneal choriocarcinoma presenting as neurologic symptoms. AB - A 28-year-old woman suffered from frequent headaches. She had a history of a dilatation and curettage for hydatidiform moles. This admission showed markedly elevated levels of human chorionic gonadotropin (hCG) and lactate dehydrogenase. Brain MRI showed a hemorrhagic mass in the left temporal area, with rapid growth. Histology of tumors obtained from multiple areas including retroperitoneum was consistent with choriocarcinoma. PMID- 21797133 TI - Conservative management of decidualized ovarian endometriotic cyst during pregnancy mimicking malignancy: case report and a review of the literature. AB - We report here the case of a 30-year-old woman with a decidualized ovarian endometriotic cyst (DOEC) during pregnancy mimicking malignancy occurring after fertility-preserving surgery for ovarian carcinoma arising from an endometriotic cyst. Intracystic excrescences appeared in the left ovarian endometriotic cyst at five weeks and three days of gestation. The serum CA-125 level rose to 676.7 U/ml (normal, 0-35). Based on these findings, ovarian carcinoma arising from the left ovarian cyst was strongly suspected. Frequent sonographic examinations revealed that the sizes and quality of the intracystic excrescences remained essentially unchanged. The cyst was evaluated for DOEC during pregnancy. The patient eventually delivered a male infant by normal vaginal delivery. After the delivery, the intracystic excrescences in the left ovarian endometriotic cyst disappeared. Close observation may be a reasonable alternative to antepartum surgery in patients with a DOEC during pregnancy. PMID- 21797134 TI - Primary squamous cell carcinoma of the endometrium: a case report. AB - BACKGROUND: Primary endometrial squamous cell carcinoma (PSECC) is a rare neoplasm. Squamous epithelium derived from endometrioid cancer or from cervical squamous cell carcinoma. The prevalence is about 0.1%. The genesis, histogenesis and biological behavior are unknown. CASE PRESENTATION: A 48-year old woman in postmenopause, referring pelvic pain and vaginal bleeding. Transvaginal ultrasound showed a bulky uterus with the endometrium containing an hyperecogenic area. Endometrial biopsy found an epidermoid carcinoma. MRI showed a 4 x 2 x 1.2 cm mass occupying the uterine cavity. The patient underwent radical treatment. Pathological examination showed features of PSECC. The mutation of p53 tumor suppressor protein was disclosed in 15% of neoplastic cells. PCR revealed the absence of HPV DNA. CONCLUSIONS: The findings of our case move us to underline that the pathogenesis of this tumor is still unclear. Moreover, preoperative diagnosis and staging of PESCC is extremely difficult. Most patients do not show characteristic symptoms and predisposing factors, making it almost impossible to diagnose the precise localization of tumor origin. PMID- 21797135 TI - Angiomyofibroblastoma of the vulva: a clinicopathological and immunohistochemical analysis of a rare benign mesenchymal tumor. AB - Angiomyofibroblastoma is a rare benign distinctive mesenchymal tumor that occurs in the genital pelviperineal region, commonly the vulva and vagina. We report a case of angiomyofibroblastoma in a 42-year-old woman, presenting as a "cystic mass" located subcutaneously in the right labial area of the vulva. Recognition of this entity is based on specific histological and immunopathological features, and the correct treatment is important because of the aggressive behavior of other related mesenchymal tumors of the vulva and vagina, such as angiomyxoma and cellular angiofibroma. PMID- 21797136 TI - Krukenberg tumor of gastric origin in pregnancy with dismal outcome. AB - Krukenberg tumors are mostly found as metastatic signet-ring cell adenomucinous carcinomas in young, premenopausal women. They are bilateral in 80% of the cases, and thus can be expected in pregnancy. A 31-year-old female was diagnosed by explorative laparotomy at 27 weeks of gestation with a Krukenberg tumor due to bilateral adnexal masses and a large amount of ascites. At surgery cesarean section with total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy and pelvic lymphadenectomy was performed. The neonate died 24 hours later due to prematurity and respiratory distress syndrome. The primary site of the cancer was detected metachronously two months after surgery and postoperative chemotherapy, as stomach adenomucinous carcinoma. In spite of surgery and postoperative multiagent chemotherapy, the patient died six months from the diagnosis of Krukenberg. PMID- 21797137 TI - Alveolar soft part sarcoma of the uterine cervix in a woman presenting with postmenopausal bleeding: a case report and literature review. AB - INTRODUCTION: Alveolar soft part sarcoma (ASPS) of the uterine cervix is a rare mesenchymal malignancy that occurs in adolescents and young adults. CASE REPORT: A 52-year-old postmenopausal woman presented with profuse vaginal bleeding of one month's duration with severe anemia. The pelvic examination revealed a 3 cm mass on the posterior lip of the uterine cervix. On magnetic resonance imaging, the tumor had high signal intensity on T1- and T2-weighted images. A modified radical hysterectomy and bilateral salpingo-oophorectomy were performed. Immunohistochemical staining for TFE3 and electron microscopic examination revealed an ASPS of the uterine cervix. DISCUSSION: The better prognosis of cervical ASPS, compared to the soft counterparts, may be related to early clinical detection, small size, resectability, and demarcation of the tumor. PMID- 21797138 TI - Tumor dissemination after laparoscopic surgery for an unsuspected endometrial stromal tumor. AB - BACKGROUND: The use of laparoscopic surgery in gynecologic oncology might be complicated by unsuspected side-effects for the patient. Experimental data suggest that the risk of tumor dissemination in the non traumatized peritoneum may be higher after pneumoperitoneum than after laparotomy, and they also show the importance of the surgeon's experience and technique. CASES: We present two cases of uterine endometrial stromal tumors which were laparoscopically excised. In both cases, intraperitoneal tumor seedings were identified shortly after the initial operation. The first patient had a low-grade endometrial stromal sarcoma and succumbed from the disease two years after the initial operation, while the second patient who was diagnosed with endometrial stromal tumor remains disease free two years later. CONCLUSIONS: The laparoscopic excision of an endometrial stromal tumor might result in tumor dissemination into the abdominal cavity. A careful second-look examination of the abdomen or a radical surgical approach is proposed. PMID- 21797139 TI - Teaching anatomical pathology in the undergraduate curriculum in medicine: the experience of 'C Course', Sapienza University, Rome. AB - INTRODUCTION: The aim of the present article is to describe how Anatomical Pathology is taught in 'C Course' undergraduate Curriculum and to outline the benefits of such an organization. SETTING ANALYSIS: 'C Course' is one of the six undergraduate curricula in Medicine within Sapienza University of Rome, focused on integrated teaching and medical education activities. ORIGINAL EXPERIENCE: In 'C Course', the learning objectives of Anatomical Pathology have been subdivided in four areas: i) an 'early contact' aimed to provide a 'clinical trigger' to students learning basic sciences; ii) a methodological background intended to help students understand the role of pathology in the comprehension of disease mechanisms; iii) the full body of systemic pathology, taught within inter disciplinary courses devoted to each apparatus; iv) a latest approach, aimed to explain the role of anatomical pathology in diagnosis, grading and staging of tumours, and in the detection of predictive markers. DISCUSSION: Our teaching organization represents a unusual experience in the Italian setting, allowing students to grasp the concept that anatomical pathology can give many contributions to their overall formation: as a trigger for basic sciences, as a central way of understanding etiology, behavior, and diagnostic pathways, and to predict the outcome of any disease, and as a powerful diagnostic and prognostic means to guide therapy. This approach is well perceived by students, whose questionnaires gave the course an above average score, and offers a valuable output in term of students' knowledge, as assessed by their performance in the area of Anatomical Pathology in the National Progress Test. PMID- 21797140 TI - Cystic sebaceous lymphadenoma of the parotid gland: case report and review of the literature. AB - Sebaceous lymphadenoma (SL) of the salivary glands is a very rare, benign tumour with distinct histopathologic characteristics and uncertain histogenesis. It is almost exclusively confined to the parotid gland where it occurs generally as a slowly growing mass in elderly patients. Several imaging techniques and fine needle aspiration cytology (FNAC) can be used for diagnosis, but definitive diagnosis is usually established only by histopathological examination. Such lesions are composed of a varying admixture of islands, duct-like structures and cysts covered with squamous or cuboid and columnar epithelium intermingled with a background of lymphoid stroma, sometimes with lymph follicles. Accurate diagnosis of SL is important since many salivary masses in adults are malignant. We report a case of cystic sebaceous lymphadenoma of the left parotid gland surgically resected in a 70-year-old woman. Fifteen months after surgery, the patient is well, with no evidence of recurrence. Differential diagnostic problems and histogenetic considerations are provided; a comprehensive review of the literature has also been performed. PMID- 21797141 TI - An unusual case of signet ring cell adenocarcinoma of the prostate. AB - We report the case of a 70-year-old man with symptoms of urinary obstruction and haematuria, with histological diagnosis of primary signet-ring cell carcinoma of the prostate. Almost 90% of the tumour cells contained characteristic intracytoplasmic vacuoles that positively stained with diastase-digested PAS, Alcian blue and mucicarmine. The positive immunostaining for PSA and PSAP confirmed the prostatic origin of the tumour. Although the patient received hormonal therapy, the disease progressed and the patient died 11 months after surgery. PMID- 21797142 TI - Subcutaneous Ewing sarcoma/PNET as a second cancer in a previously irradiated young patient. an uncommon type of post-irradiation soft tissue sarcoma. AB - Soft tissue sarcomas account for a small proportion of second cancers, with an estimated frequency of < 10%. The most common histologic type of soft tissue sarcomas as second cancers include mostly high-grade sarcomas, such as rhabdomyosarcoma, malignant peripheral nerve sheath tumour, fibrosarcoma, leiomyosarcoma, synovial sarcoma, alveolar soft part sarcoma and Ewing sarcoma/primitive neuroectodermal tumour (PNET). We report a case of superficial soft tissue Ewing sarcoma/PNET as a second cancer in a young patient previously treated for Hodgkin's disease (HD). To the best of our knowledge and based on a literature search, this is the first reported case of post-irradiation soft tissue Ewing sarcoma/PNET as a second cancer arising in the same area irradiated for cure of HD. PMID- 21797143 TI - Nodular extramedullary hematopoiesis involving the adrenal gland. An uncommon cause of adrenal "incidentaloma". AB - Adrenal extramedullary hematopoiesis may occur in association with various hematologic diseases. Its identification is invariably incidental, imaging of the lesion is poorly specific and the diagnosis requires the histological examination. We report a case of extramedullary hematopoiesis involving the right adrenal gland in a patient with hereditary spherocytosis. The literature on this entity has been reviewed and the differential with other conditions involving the adrenal gland and showing hematopoietic tissue infiltration is discussed. PMID- 21797144 TI - Ductal carcinoma of the prostate metastatic to the skin. AB - A case of skin metastases of prostatic ductal adenocarcinoma in a 78-year-old patient is reported. This case is characterized by two rare features: uncommon type of prostate carcinoma that metastatized to the skin. PMID- 21797145 TI - Needle core biopsy should replace fine needle aspiration cytology in ultrasound guided sampling of breast lesions. PMID- 21797146 TI - The Royal Society and the decline of magic. AB - Whereas some have asserted that the early Royal Society actively sought to discredit magical beliefs, others have seen ideas of this kind as integral to the Society's 'nature' in its early years. This paper argues that, whatever the magical commitments of individual Fellows, the Society's corporate policy simply sidelined such pursuits. Yet, insofar as the result was that magic was excluded by default from the proper realm of scientific enquiry, this attitude was to prove paradoxically influential (although its roots have been retrospectively misconstrued to an extent that is significant in itself). PMID- 21797147 TI - Currents connecting communities: nearshore community similarity and ocean circulation. AB - Understanding the mechanisms that create spatial heterogeneity in species distributions is fundamental to ecology. For nearshore marine systems, most species have a pelagic larval stage where dispersal is strongly influenced by patterns of ocean circulation. Concomitantly, nearshore habitats and the local environment are also influenced by ocean circulation. Because of the shared dependence on the seascape, distinguishing the relative importance of the local environment from regional patterns of dispersal for community structure remains a challenge. Here, we quantify the "oceanographic distance" and "oceanographic asymmetry" between nearshore sites using ocean circulation modeling results. These novel metrics quantify spatial separation based on realistic patterns of ocean circulation, and we explore their explanatory power for intertidal and subtidal community similarity in the Southern California Bight. We find that these metrics show significant correspondence with patterns of community similarity and that their combined explanatory power exceeds that of the thermal structure of the domain. Our approach identifies the unique influence of ocean circulation on community structure and provides evidence for oceanographically mediated dispersal limitation in nearshore marine communities. PMID- 21797148 TI - Shifting phenology and abundance under experimental warming alters trophic relationships and plant reproductive capacity. AB - Phenological mismatches due to climate change may have important ecological consequences. In a three-year study, phenological shifts due to experimental warming markedly altered trophic relationships between plants and insect herbivores, causing a dramatic decline of reproductive capacity for one of the plant species. In a Tibetan meadow, the gentian (Gentiana formosa) typically flowers after the peak larva density of a noctuid moth (Melanchra pisi) that primarily feeds on a dominant forb (anemone, Anemone trullifolia var. linearis). However, artificial warming of approximately 1.5 degrees C advanced gentian flower phenology and anemone vegetative phenology by a week, but delayed moth larvae emergence by two weeks. The warming increased larval density 10-fold, but decreased anemone density by 30%. The phenological and density shifts under warmed conditions resulted in the insect larvae feeding substantially on the gentian flowers and ovules; there was approximately 100-fold more damage in warmed than in unwarmed chambers. This radically increased trophic connection reduced gentian plant reproduction and likely contributed to its reduced abundance in the warmed chambers. PMID- 21797149 TI - Soil biota drive expression of genetic variation and development of population specific feedbacks in an invasive plant. AB - Invasive plant species alter soils in ways that may affect the success of subsequent generations, creating plant-soil feedbacks. Ailanthus altissima is an invasive tree introduced two centuries ago to North America. We hypothesized that geographically distinct populations of A. altissima have established feedbacks specific to their local environment, due to soil communities cultivated by A. altissima. We collected seeds and soils from three populations in the eastern United States, and in the greenhouse reciprocally planted all families in all collected soils as well as in a control mixed soil, and in soils that had been irradiated for sterilization. There were positive plant-soil feedbacks for two populations in the live field-collected soils, but strong negative feedbacks for the third population. There were no population-level performance differences or feedbacks in the sterilized population locale soils, supporting a soil biotic basis for feedbacks and for the expression of genetic differentiation in A. altissima. If populations of Ailanthus altissima vary in the extent to which they benefit from and promote these plant-soil biota feedbacks, the interaction between invader and invaded community may be more important in determining the course of invasion than are the characteristics of either alone. PMID- 21797150 TI - Quantity and quality: unifying food web and ecosystem perspectives on the role of resource subsidies in freshwaters. AB - Although the study of resource subsidies has emerged as a key topic in both ecosystem and food web ecology, the dialogue over their role has been limited by separate approaches that emphasize either subsidy quantity or quality. Considering quantity and quality together may provide a simple, but previously unexplored, framework for identifying the mechanisms that govern the importance of subsidies for recipient food webs and ecosystems. Using a literature review of > 90 studies of open-water metabolism in lakes and streams, we show that high flux, low-quality subsidies can drive freshwater ecosystem dynamics. Because most of these ecosystems are net heterotrophic, allochthonous inputs must subsidize respiration. Second, using a literature review of subsidy quality and use, we demonstrate that animals select for high-quality food resources in proportions greater than would be predicted based on food quantity, and regardless of allochthonous or autochthonous origin. This finding suggests that low-flux, high quality subsidies may be selected for by animals, and in turn may disproportionately affect food web and ecosystem processes (e.g., animal production, trophic energy or organic matter flow, trophic cascades). We then synthesize and review approaches that evaluate the role of subsidies and explicitly merge ecosystem and food web perspectives by placing food web measurements in the context of ecosystem budgets, by comparing trophic and ecosystem production and fluxes, and by constructing flow food webs. These tools can and should be used to address future questions about subsidies, such as the relative importance of subsidies to different trophic levels and how subsidies may maintain or disrupt ecosystem stability and food web interactions. PMID- 21797151 TI - Variation in resource consumption across a gradient of increasing intra- and interspecific richness. AB - Based on the premise that ecosystems with more species will function at more efficient rates, declining biodiversity is expected to alter important ecosystem functions, goods, and services across the globe. However, applicability of this general hypothesis to genetic or clonal richness in assemblages composed of few species is understudied. This illustrates the need to expand the focus of biodiversity-ecosystem-function experiments across all levels of biological diversity (including genetic). To explore this generality, we manipulated intraspecific (clonal) and interspecific (species) richness of a primary consumer, Daphnia, and measured assemblage feeding rate and total resource consumption. Our results showed that greater clonal richness had no effect on Daphnia feeding, and greater species richness decreased feeding-related effects of Daphnia. This suggests that multiclonal Daphnia assemblages may be no more efficient at consuming resources than monocultures, and that monocultures of Daphnia may consume resources more efficiently than more species-rich assemblages. The inhibitory effect of increasing richness observed in this study resulted from chemical and mechanical interference among some of the Daphnia taxa. This suggests that consumer-mediated ecosystem functions could be reduced when assemblages include taxa equipped with adaptations for interference competition. PMID- 21797152 TI - Life history benefits of residency in a partially migrating pond-breeding amphibian. AB - Species with partial migration, where a portion of a population migrates and the other remains residential, provide the opportunity to evaluate conditions for migration and test mechanisms influencing migratory decisions. We conducted a five-year study of two populations of red-spotted newts (Notophthalmus viridescens), composed of individuals that either remain as residents in the breeding pond over the winter or migrate to the terrestrial habitat. We used multistate mark-recapture methods to (1) test for differences in survival probability between migrants and residents, (2) determine if migrants breed every year or skip opportunities for reproduction, and (3) estimate the frequency of individuals switching migratory tactic. We used estimates of life history parameters from the natural populations in combination with previous experimental work to evaluate processes maintaining partial migration at the population level and to assess mechanisms influencing the decision to migrate. Based on capture recapture information on over 3000 individuals, we found that newts can switch migratory tactics over their lifetime. We conclude that migrants and residents coexist through conditional asymmetries, with residents having higher fitness and inferior individuals adopting the migrant tactic. We found that newts are more likely to switch from residency to migrating than the reverse and males were more likely to remain as residents. Migration differences between the sexes are likely driven by reproduction benefits of residency for males and high energetic costs of breeding resulting in lower breeding frequencies for females. Environmental conditions also influence partial migration within a population; we found support for density-dependent processes in the pond strongly influencing the probability of migrating. Our work illustrates how migration can be influenced by a complex range of individual and environmental factors and enhances our understanding of the conditions necessary for the evolution and maintenance of partial migration within populations. PMID- 21797153 TI - Overturning conclusions of Levy flight movement patterns by fishing boats and foraging animals. AB - A surprisingly diverse variety of foragers have previously been concluded to exhibit movement patterns known as Levy flights, a special type of random walk. These foragers range in size from microzooplankton in experiments to fishermen in the Pacific Ocean and the North Sea. The Levy flight conclusion implies that all the foragers have similar scale-free movement patterns that can be described by a single dimensionless parameter, the exponent micro of a power-law (Pareto) distribution. However, the previous conclusions have been made using methods that have since been shown to be problematic: inaccurate techniques were used to estimate micro, and the power-law distribution was usually assumed to hold without testing any alternative hypotheses. Therefore, I address the open question of whether the previous data still support the Levy flight hypothesis, and thus determine whether Levy flights really are so ubiquitous in ecology. I present a comprehensive reanalysis of 17 data sets from seven previous studies for which Levy flight behavior had been concluded, covering marine, terrestrial, and experimental systems from four continents. I use the modern likelihood and Akaike weights approach to test whether simple alternative models are more supported by the data than Levy flights. The previously estimated values of the power-law exponent micro do not match those calculated here using the accurate likelihood approach, and almost all of them lie outside of the likelihood-based 95% confidence intervals. Furthermore, the original power-law Levy flight model is overwhelmingly rejected for 16 out of the 17 data sets when tested against three other simple models. For one data set, the data are consistent with coming from a bounded power-law distribution (a truncated Levy flight). For three other data sets, an exponential distribution corresponding to a simple Poisson process is suitable. Thus, Levy flight movement patterns are not the common phenomena that was once thought, and are not suitable for use as ecosystem indicators for fisheries management, as has been proposed. PMID- 21797154 TI - In situ measures of foraging success and prey encounter reveal marine habitat dependent search strategies. AB - Predators are thought to reduce travel speed and increase turning rate in areas where resources are relatively more abundant, a behavior termed "area-restricted search." However, evidence for this is rare, and few empirical data exist for large predators. Animals exhibiting foraging site fidelity could also be spatially aware of suitable feeding areas based on prior experience; changes in movement patterns might therefore arise from the anticipation of higher prey density. We tested the hypothesis that regions of area-restricted search were associated with a higher number of daily speed spikes (a proxy for potential prey encounter rate) and foraging success in southern elephant seals (Mirounga leonina), a species exhibiting both area-restricted searches and high interannual foraging site fidelity. We used onshore morphological measurements and diving data from archival tags deployed during winter foraging trips. Foraging success was inferred from in situ changes in relative lipid content derived from measured changes in buoyancy, and first-passage time analysis was used to identify area restricted search behavior. Seals exhibited relatively direct southerly movement on average, with intensive search behavior predominantly located at the distal end of tracks. The probability of being in search mode was positively related to changes in relative lipid content; thus, intensively searched areas were associated with the highest foraging success. However, there was high foraging success during the outward transit even though seals moved through quickly without slowing down and increasing turning rate to exploit these areas. In addition, the probability of being in search mode was negatively related to the number of daily speed spikes. These results suggest that movement patterns represent a response to prior expectation of the location of predictable and profitable resources. Shelf habitat was 4-9 times more profitable than the other habitats, emphasizing the importance of the East Antarctic shelf for this and other predators in the region. We have provided rare empirical data with which to investigate the relationship between predator foraging strategy and prey encounter/ foraging success, underlining the importance of inferring the timing and spatial arrangement of successful food acquisition for interpreting foraging strategies correctly. PMID- 21797155 TI - Pre-reproductive survival in a tropical bird and its implications for avian life histories. AB - The factors that affect survival until reproduction are essential to understanding the organization of life histories within and among species. Theory predicts, for example, that survival until reproduction influences the optimum level of reproductive investment by parents, which might partly explain prolonged parental care in species with high first-year survival. Tests and refinements of life-history theory have been hampered, however, by a lack of field-based estimates of pre-reproductive survival, especially for tropical species, which have been the subject of many comparative analyses. Tropical species are predicted to have higher first-year survival and delayed reproduction compared to Northern Hemisphere species. We estimated survival until reproduction, age at first reproduction, and sources of variation in juvenile survival in a Neotropical passerine, the Western Slaty-Antshrike (Thamnophilus atrinucha), in central Panama. We observed that fledged antshrikes had 76% survival through the dependent period and 48% survival to the age of 1 year; survival rate was lowest during the first week after leaving the nest. Timing of fledging within the breeding season, fledgling mass, and age at dispersal influenced survival, while sex of offspring and year did not. Individuals did not breed until two years of age, and post-fledging pre-reproductive survival was 41% of annual adult survival. High survival until reproduction in antshrikes balanced their low annual productivity, resulting in a stable population. Survival during the post fledging period of dependence and the first year of independence in the Western Slaty-Antshrike exceeded estimates for Northern Hemisphere species. This difference appears to be associated with the extended post-fledging parental care, delayed dispersal, low costs of dispersal, and the less seasonal environment of antshrikes. PMID- 21797156 TI - Spatial variance in abundance and occupancy of corals across broad geographic scales. AB - Species assemblages vary in structure due to a wide variety of processes operating at ecological and much broader biogeographical scales. Cross-scale studies of assemblage structure are necessary to fully understand this variability. Here, we evaluate the abundance and occupancy patterns of hierarchically sampled coral assemblages in three habitats (reef flat, crest, and slope) and five regions (Indonesia, Papua New Guinea, the Solomon Islands, American Samoa, and the Society Islands) across the west-central Pacific Ocean. Specifically, we compare two alternative models that unify spatial variance and occupancy via the negative binomial distribution. The first assumes a power-law scaling between the mean and variance of abundance; the second assumes a quadratic variance-mean relationship and a constant abundance-invariant aggregation parameter. Surprisingly, the well-established power-law model performs worse than the model assuming abundance-invariant aggregation, for both variance-mean and occupancy-abundance relationships. We also find strong evidence for regional and habitat variation in these relationships and in the levels of aggregation estimated by the abundance-invariant aggregation model. Among habitats, corals on reef flats exhibited lower occupancy and higher levels of aggregation compared to reef crests and slopes. Among regions, low occupancy and high aggregation were most pronounced across all habitats in American Samoa. These patterns may be related to habitat and regional differences in disturbance and recovery processes. Our results suggest that the spatial scaling of abundance and occupancy is sensitive to processes operating among these habitats and at regional scales. However, the consistency of these relationships across species within assemblages suggests that a theoretical unification of spatial variance and occupancy patterns is indeed possible. PMID- 21797157 TI - Importance of dispersal and thermal environment for mycorrhizal communities: lessons from Yellowstone National Park. AB - The relative importance of dispersal and niche restrictions remains a controversial topic in community ecology, especially for microorganisms that are often assumed to be ubiquitous. We investigated the impact of these factors for the community assembly of the root-symbiont arbuscular mycorrhizal fungi (AMF) by sampling roots from geothermal and nonthermal grasslands in Yellowstone National Park (YNP), followed by sequencing and RFLP of AMF ribosomal DNA. With the exception of an apparent generalist RFLP type closely related to Glomus intraradices, a distance-based redundancy analysis indicated that the AMF community composition correlated with soil pH or pH-driven changes in soil chemistry. This was unexpected, given the large differences in soil temperature and plant community composition between the geothermal and nonthermal grasslands. RFLP types were found in either the acidic geothermal grasslands or in the neutral to alkaline grasslands, one of which was geothermal. The direct effect of the soil chemical environment on the distribution of two AMF morphospecies isolated from acidic geothermal grasslands was supported in a controlled greenhouse experiment. Paraglomus occultum and Scutellospora pellucida were more beneficial to plants and formed significantly more spores when grown in acidic than in alkaline soil. Distance among grasslands, used as an estimate of dispersal limitations, was not a significant predictor of AMF community similarity within YNP, and most fungal taxa may be part of a metacommunity. The isolation of several viable AMF taxa from bison feces indicates that wide-ranging bison could be a vector for at least some RFLP types among grasslands within YNP. In support of classical niche theory and the Baas-Becking hypothesis, our results suggest that AMF are not limited by dispersal at the scale of YNP, but that the soil environment appears to be the primary factor affecting community composition and distribution. PMID- 21797158 TI - Mycorrhizal fungal identity and diversity relaxes plant-plant competition. AB - There is a great interest in ecology in understanding the role of soil microbial diversity for plant productivity and coexistence. Recent research has shown increases in species richness of mutualistic soil fungi, the arbuscular mycorrhizal fungi (AMF), to be related to increases in aboveground productivity of plant communities. However, the impact of AMF richness on plant-plant interactions has not been determined. Moreover, it is unknown whether species rich AMF communities can act as insurance to maintain productivity in a fluctuating environment (e.g., upon changing soil conditions). We tested the impact of four different AMF taxa and of AMF diversity (no AMF, single AMF taxa, and all four together) on competitive interactions between the legume Trifolium pratense and the grass Lolium multiflorum grown under two different soil conditions of low and high sand content. We hypothesized that more diverse mutualistic interactions (e.g., when four AMF taxa are present) can ease competitive effects between plants, increase plant growth, and maintain plant productivity across different soil environments. We used quantitative PCR to verify that AMF taxa inoculated at the beginning of the experiment were still present at the end. The presence of AMF reduced the competitive inequality between the two plant species by reducing the growth suppression of the legume by the grass. High AMF richness enhanced the combined biomass production of the two plant species and the yield of the legume, particularly in the more productive soil with low sand content. In the less productive (high sand content) soil, the single most effective AMF had an equally beneficial effect on plant productivity as the mixture of four AMF. Since contributions of single AMF to plant productivity varied between both soils, higher AMF richness would be required to maintain plant productivity in heterogeneous environments. Overall this work shows that AMF diversity promotes plant productivity and that AMF diversity can act as insurance to sustain plant productivity under changing environmental conditions. PMID- 21797159 TI - The importance of quantifying propagule pressure to understand invasion: an examination of riparian forest invasibility. AB - The widely held belief that riparian communities are highly invasible to exotic plants is based primarily on comparisons of the extent of invasion in riparian and upland communities. However, because differences in the extent of invasion may simply result from variation in propagule supply among recipient environments, true comparisons of invasibility require that both invasion success and propagule pressure are quantified. In this study, we quantified propagule pressure in order to compare the invasibility of riparian and upland forests and assess the accuracy of using a community's level of invasion as a surrogate for its invasibility. We found the extent of invasion to be a poor proxy for invasibility. The higher level of invasion in the studied riparian forests resulted from greater propagule availability rather than higher invasibility. Furthermore, failure to account for propagule pressure may confound our understanding of general invasion theories. Ecological theory suggests that species-rich communities should be less invasible. However, we found significant relationships between species diversity and invasion extent, but no diversity invasibility relationship was detected for any species. Our results demonstrate that using a community's level of invasion as a surrogate for its invasibility can confound our understanding of invasibility and its determinants. PMID- 21797160 TI - Climate determines upper, but not lower, altitudinal range limits of Pacific Northwest conifers. AB - Does climate determine species' ranges? Rapid rates of anthropogenic warming make this classic ecological question especially relevant. We ask whether climate controls range limits by quantifying relationships between climatic variables (precipitation, temperature) and tree growth across the altitudinal ranges of six Pacific Northwestern conifers on Mt. Rainier, Washington, USA. Results for three species (Abies amabilis, Callitropsis nootkatensis, Tsuga mertensiana) whose upper limits occur at treeline (> 1600 m) imply climatic controls on upper range limits, with low growth in cold and high snowpack years. Annual growth was synchronized among individuals at upper limits for these high-elevation species, further suggesting that stand-level effects such as climate constrain growth more strongly than local processes. By contrast, at lower limits climatic effects on growth were weak for these high-elevation species. Growth-climate relationships for three low-elevation species (Pseudotsuga menziesii, Thuja plicata, Tsuga heterophylla) were not consistent with expectations of climatic controls on upper limits, which are located within closed-canopy forest (< 1200 m). Annual growth of these species was poorly synchronized among individuals. Our results suggest that climate controls altitudinal range limits at treeline, while local drivers (perhaps biotic interactions) influence growth in closed-canopy forests. Climate change-induced range shifts in closed-canopy forests will therefore be difficult to predict accurately. PMID- 21797161 TI - A novel statistical method for classifying habitat generalists and specialists. AB - We develop a novel statistical approach for classifying generalists and specialists in two distinct habitats. Using a multinomial model based on estimated species relative abundance in two habitats, our method minimizes bias due to differences in sampling intensities between two habitat types as well as bias due to insufficient sampling within each habitat. The method permits a robust statistical classification of habitat specialists and generalists, without excluding rare species a priori. Based on a user-defined specialization threshold, the model classifies species into one of four groups: (1) generalist; (2) habitat A specialist; (3) habitat B specialist; and (4) too rare to classify with confidence. We illustrate our multinomial classification method using two contrasting data sets: (1) bird abundance in woodland and heath habitats in southeastern Australia and (2) tree abundance in second-growth (SG) and old growth (OG) rain forests in the Caribbean lowlands of northeastern Costa Rica. We evaluate the multinomial model in detail for the tree data set. Our results for birds were highly concordant with a previous nonstatistical classification, but our method classified a higher fraction (57.7%) of bird species with statistical confidence. Based on a conservative specialization threshold and adjustment for multiple comparisons, 64.4% of tree species in the full sample were too rare to classify with confidence. Among the species classified, OG specialists constituted the largest class (40.6%), followed by generalist tree species (36.7%) and SG specialists (22.7%). The multinomial model was more sensitive than indicator value analysis or abundance-based phi coefficient indices in detecting habitat specialists and also detects generalists statistically. Classification of specialists and generalists based on rarefied subsamples was highly consistent with classification based on the full sample, even for sampling percentages as low as 20%. Major advantages of the new method are (1) its ability to distinguish habitat generalists (species with no significant habitat affinity) from species that are simply too rare to classify and (2) applicability to a single representative sample or a single pooled set of representative samples from each of two habitat types. The method as currently developed can be applied to no more than two habitats at a time. PMID- 21797162 TI - Additive effects of aboveground polyphagous herbivores and soil feedback in native and range-expanding exotic plants. AB - Plant biomass and plant abundance can be controlled by aboveground and belowground natural enemies. However, little is known about how the aboveground and belowground enemy effects may add up. We exposed 15 plant species to aboveground polyphagous insect herbivores and feedback effects from the soil community alone, as well as in combination. We envisaged three possibilities: additive, synergistic, or antagonistic effects of the aboveground and belowground enemies on plant biomass. In our analysis, we included native and phylogenetically related range-expanding exotic plant species, because exotic plants on average are less sensitive to aboveground herbivores and soil feedback than related natives. Thus, we examined if lower sensitivity of exotic plant species to enemies also alters aboveground-belowground interactions. In a greenhouse experiment, we exposed six exotic and nine native plant species to feedback from their own soil communities, aboveground herbivory by polyphagous insects, or a combination of soil feedback and aboveground insects and compared shoot and root biomass to control plants without aboveground and belowground enemies. We observed that for both native and range-expanding exotic plant species effects of insect herbivory aboveground and soil feedback added up linearly, instead of enforcing or counteracting each other. However, there was no correlation between the strength of aboveground herbivory and soil feedback. We conclude that effects of polyphagous aboveground herbivorous insects and soil feedback add up both in the case of native and related range-expanding exotic plant species, but that aboveground herbivory effects may not necessarily predict the strengths of soil feedback effects. PMID- 21797163 TI - Multivariate identification of plant functional response and effect traits in an agricultural landscape. AB - Plant functional traits have been proposed as a linkage between the environmental control of vegetation and ecosystem function. Identification of traits that mediate the response of plant species to the environment is well established, but the identification of effect traits and the linkage between the two sets is less developed. This was attempted for a study of eight contrasting land uses in a marginal agricultural landscape where data on vegetation, management controls of the disturbance regime, and soil characteristics, including nitrogen release, were measured simultaneously with measures of ecosystem function such as litter decomposition rates and primary productivity on 30 sites. Trait data were assembled from databases, and an iterative multivariate approach using the three table (species, trait, environment) method RLQ was employed to identify a parsimonious set of traits that predict plant species responses to the environment and a parsimonious set of traits that link vegetation to ecosystem function. The lists of response and effect traits were similar, and where differences were observed, traits were usually highly correlated with at least one trait in the other list. This approach identified a small number of traits (canopy height, leaf dry matter content, leaf size, and specific leaf area) that provide a means of linking vegetation responses to environmental change with changes in ecosystem function. Other response traits included vegetative spread strategy, start of flowering, and seed terminal velocity, but within the system studied these traits were all significantly correlated to the traits shared between the response and effect lists. PMID- 21797164 TI - Environmental change and declining resource availability for small-mammal communities in the Great Basin. AB - Changes in climate and land use can impact natural systems across all levels of ecological organization. Most documented and anticipated effects consider species' properties, including phenologies, geographic distributions, and abundances. Responses of higher-level aggregate community or ecosystem properties have not been considered as they are assumed to be relatively stable due to compensatory dynamics and diversity-stability relationships. However, this assumption may not be as fundamental as previously thought. Here we assess stability in the aggregate properties of total abundance, biomass, and energy consumption for small-mammal communities in the Great Basin, using paired historical and modern survey data spanning nearly a century of environmental change. Results show marked declines in each aggregate property independent of spatial scale, elevation, or habitat type, and a reallocation of available biomass and energy favoring diet and habitat generalists. Because aggregate properties directly reflect resource availability, our findings indicate a regionwide decline in resources of 50% over the past century, which may signal a resource crisis. This work illustrates the power of using aggregate properties as indicators of ecological conditions and environmental change at broad spatial and temporal scales. PMID- 21797165 TI - Nutrition chemistry in Switzerland. PMID- 21797166 TI - Single-run separation of closely related cationic and anionic compounds by CE-ESI MS: application to the simultaneous analysis of melamine and its analogs in milk. AB - In recent years, two adulteration incidents concerning the addition of melamine, a nitrogen-rich industrial small polar compound, to pet food and infant formula products have occurred in China. These issues prompted laboratories to develop methods for the analysis of melamine and related compounds in a wide variety of food products and ingredients. In this context, a CE-ESI-MS method was developed to simultaneously analyze melamine and its related products (ammeline, ammelide and cyanuric acid) that possess close physico-chemical properties. This method allows the simultaneous analysis of both cations and anions in a single run, using CE to divide the run into two time segments in normal polarity mode. For this purpose, ESI polarity was switched once during the run, increasing sensitivity and data quality. The method was applied to spiked powdered milk and melamine-contaminated powdered milk, with two sample preparation procedures. PMID- 21797167 TI - Nutritional metabonomics: an approach to promote personalized health and wellness. AB - Nutritional research has emerged in the last century from the study of nutrients as a means of nourishment to the general population to the quest for wellness improvement through specific food components. Advances in nutrigenomics technologies have allowed nutrition scientists to be for the first time at the forefront of nutritional research. Such advances have given them the ability to discern new vital scientific discoveries specifically for the development of new tailored dietary patterns. In this, nutritional metabonomics has rapidly evolved into a very powerful bioanalytical tool able to assess multi-parametric metabolic responses of living organisms to specific dietary interventions. Nutritional metabonomics therefore provides a systematic approach through the comprehensive analysis of metabolites aiming today at the quest for homeostatic balance which is dependent not only on the host but also on the crucial metabolic interactions with microbial symbionts. PMID- 21797168 TI - Advanced methods for natural product drug discovery in the field of nutraceuticals. AB - Advances in analytical methods and bioassay development have helped to push forward the research in natural products. In plant extracts and nutraceuticals, bioactive compounds are part of a complex mixture. The development of high resolution methods related to HPLC for both chemical and biological profiling has significantly increased the efficiency of classical bioactivity-guided fractionation procedures. Furthermore, the level of sensitivity obtained by these methods give the possibility to work with few micrograms of compound. This represents a key advantage for rapid localisation of the biological activity and subsequent identification of the compounds of interest. The same methods are also used to study the extracts from a metabolomic view point. The possibility to study them as a whole can highlight synergetic effects, which are likely to occur in plant extracts and nutraceuticals. In this paper, the main trends are summarised and the developments made in our laboratory on profiling crude extracts with UHPLC-TOF-MS, natural product identification at the microgram level using microflow NMR and integration of these methods with biological evaluation are highlighted. PMID- 21797169 TI - Exploring natural products for new taste sensations. AB - This paper discusses the discovery of uncommon taste or trigeminal active compounds and their associated sensory analysis using human tasting panels with the aim of enhancing the overall taste experience whilst reducing where possible the sugar and salt content of foods. The first example outlines the discovery of the sensory quality attributes of (R)-2-(carboxymethylamino)propanoic acid, named (R)-strombine, as assessed by a panel of 47 subjects to confirm its contribution to the typical taste of scallop muscle. The second example discusses the pungency and trigeminal effect of polygodial, which is compared with piperine and capsaicin, as well as the elucidation of a new structure eliciting a trigeminal effect, (+/-)-trans-2,3,3a,7a-tetrahydro-1 H-indene-4-carbaldehyde, discovered in Amomum tsao-ko. Finally, the time intensity trigeminal effect of (-)-menthol is compared with (1R,2RS,4RS)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-2-ol, named dihydroumbellulol, a new cooling compound obtained by hemi-synthesis from umbellulone extracted from Umbellularia californica Nutt. PMID- 21797170 TI - Bioreduction-mediated food-drug interactions: opportunities for oncology nutrition. AB - Chemical and biochemical processes underlying food-drug interactions in cancer therapy have not been well addressed with a systematic focus, even though they offer significant potential for enhancing the efficacy of cancer chemotherapy. Bioreductive anticancer drugs are metabolically activated by reductase enzymes. The levels and activities of relevant metabolic enzymes are regulated by transcription factors, which are under the control of chemical interactions with small molecules, including bioactive food components (BFCs) such as minerals, vitamins, and a variety of phytochemicals. One important and well-established process is the upregulation of enzymes involved in xenobiotic metabolism and redox regulation. Thus, BFCs might help to overcome resistances of some cancer cells towards anticancer agents or to increase efficacy by sensitizing cancer cells towards synergistic drugs. By understanding chemical and biochemical processes involved in food-drug interactions, not only can the risk of harmful food-drug interactions be diminished, but appropriate nutritional recommendations for cancer patients can be made and new functional foods with specific benefits in anticancer therapy may be developed. PMID- 21797171 TI - Out in the green: biologically active metabolites produced by cyanobacteria. AB - Dried cyanobacteria ('Spirulina') are sold as a nutraceutical for their high content of proteins, essential fatty acids and vitamins. Beyond spirulina, other genera of cyanobacteria produce interesting small molecules that could find use in nutraceutical or pharmaceutical applications. This account presents recent research efforts on antimalarial nostocarboline and the aerucyclamides, as well as on potent toxins such as cyanopeptolin 1020 and microcystins. Combinations of spectroscopic, computational, chemical and biological studies investigated the mechanism of action of these compounds. Their application potential with regard to nutraceuticals or pharmaceuticals is discussed. PMID- 21797172 TI - Large-scale production of bioactive ingredients as supplements for healthy human and animal nutrition. AB - In this review, synthetic strategies and the development of environmentally benign methods for the production of economically important vitamins, carotenoids, and nutraceuticals used as food and feed supplements are illustrated by selected examples. The application of efficient catalytic transformations in multi-step chemical syntheses of such natural products enables technically feasible and cost-effective processes. For the preparation of fat-soluble (isoprenoid) vitamins A and E and the water-soluble vitamin (+)-biotin, homogeneous metal catalysis, including enantioselective transformations, heterogeneous and enzymatic catalysis serve as key methodologies. In the area of carotenoids, general building concepts and coupling methods for the total synthesis of beta-carotene and astaxanthin are discussed. Biotechnological methods and isolation from natural sources are also employed successfully, as exemplified for the xanthophyll lutein and the antioxidant (-)-epigallocatechin gallate. Lastly, key steps of the chemical synthesis of the polyphenol resveratrol are highlighted. PMID- 21797173 TI - Vestium or ruthenium--what does a study of the literature tell us? AB - The process of the discovery of the sixth new element and metal present in raw platinum ore granules, and called vestium or ruthenium, took place between 1807 and 1844. The element was first discovered by the Polish chemist and medical doctor, Jedrzej Sniadecki, professor at Vilnius University, presently Lithuania. It took almost 40 years to confirm the discovery by two German chemists working in Russia, Gottfried Osann and Carl Ernst Claus, who had at their disposition platinum ore recently discovered in the Ural Mountains. The discovery work of Jedrzej Sniadecki was supported by his older brother Jan Sniadecki, a noted mathematician and astronomer, who was also the Rector of Vilnius University at the time of the original discovery. Sniadecki brothers were educated in Poland (Poznan and Cracow) and abroad: Jedrzej in Pavia (Italy), Edinburgh (Scotland) and Vienna, and Jan in Gottingen, Leiden, Utrecht and prerevolutionary Paris. PMID- 21797174 TI - The kinship or k-index as an antidote against the toxic effects of h-indices. AB - In a bilingual paper entitled 'Bibliometrics as weapons of mass citation--La bibliometrie comme arme de citation massive', recently translated into English, we have argued that the current fashion of ranking people, papers and journals is anything but harmless. The point was forcefully supported by Richard Ernst in a post-face entitled 'The Follies of Citation Indices and Academic Ranking Lists. We received a surprising number of passionate responses, such as 'It's written out of my heart' (TH); 'Je soutiens cette entreprise courageuse de tout coeur' (VT); 'Impact Faktoren sind ein Marktinstrument gewisser Verlage (FS); 'II y a un combat a mener' (SB). Some thoughtful responses have been incorporated into this Essay, albeit in attenuated form. We suggest that the 'fertility' of individual scientists be appreciated in terms of kinship rather than through personalized indices. PMID- 21797175 TI - Towards Angstrom resolution with dynamic light scattering. PMID- 21797176 TI - "I was always interested in literature, and therefore in clear expression." Interview by Lukas Weber. PMID- 21797177 TI - [Chemistry and the paper industry]. AB - This short paper presents the relationship between the pulp and paper industry and chemistry. The history of this industry is presented including current paper production and consumption statistics. The production of paper pulp is realized by chemically or mechanically separating cellulose fibres from wood and removing the unwanted lignin. This article concludes with an ecological aspect. PMID- 21797178 TI - ["Topliga" as incentive for "2020]. PMID- 21797179 TI - [Proactive shaping the future of nursing]. PMID- 21797180 TI - [Political debate. "Nursing is prepared"]. PMID- 21797181 TI - [An offer from peers for the mentally ill]. PMID- 21797182 TI - [When patients use internet education]. PMID- 21797183 TI - [Getting energy to flow again]. PMID- 21797184 TI - [Bassan Lamboni. Goal: enhancing nursing in Togo]. PMID- 21797185 TI - [Regaining the power source]. PMID- 21797186 TI - [Interpersonal tensions. When two fight together, one must leave]. PMID- 21797187 TI - [Family affairs]. PMID- 21797188 TI - [A dialogue on key issues]. PMID- 21797189 TI - [The patient record as a tool for nursing care]. PMID- 21797190 TI - [Quiet nights]. PMID- 21797191 TI - ["Source of research" colloquium]. PMID- 21797192 TI - [The Valkyrie with feet of clay]. PMID- 21797193 TI - ["Do. it. yourself. hospital"]. PMID- 21797195 TI - Ionic-charge dependence of the intermolecular coulombic decay time scale for aqueous ions probed by the core-hole clock. AB - Auger electron spectroscopy combined with theoretical calculations has been applied to investigate the decay of the Ca 2p core hole of aqueous Ca(2+). Beyond the localized two-hole final states on the calcium ion, originating from a normal Auger process, we have further identified the final states delocalized between the calcium ion and its water surroundings and produced by core level intermolecular Coulombic decay (ICD) processes. By applying the core-hole clock method, the time scale of the core level ICD was determined to be 33 +/- 1 fs for the 2p core hole of the aqueous Ca(2+). The comparison of this time constant to those associated with the aqueous K(+), Na(+), Mg(2+), and Al(3+) ions reveals differences of 1 and up to 2 orders of magnitude. Such large variations in the characteristic time scales of the core level ICD processes is qualitatively explained by different internal decay mechanisms in different ions as well as by different ion-solvent distances and interactions. PMID- 21797194 TI - Amination reaction on copper and germanium beta-nitrocorrolates. AB - Copper and germanium complexes of beta-substituted nitrocorroles were reacted with 4-amino-4H-1,2,4-triazole to give the corresponding beta-amino-beta-nitro derivatives, in moderate to good yields. This is the first successful example of a vicarious nucleophilic substitution performed on corrole derivatives, because the same reaction carried out on silver complexes afforded the corresponding 6 azahemiporphycenes by way of corrole ring expansion. The first step of this work is related to the modification of a synthetic protocol for preparation of the beta-substituted nitro corroles. The nitration reaction was carried out on a copper corrole using NaNO(2) as the primary source of NO(2)(-) coupled with AgNO(2) used as oxidant. By variation of the molar ratio of the reagents it was possible to direct the product distribution toward mono- and dinitro derivatives. The reaction between mono- and dinitro derivatives of (TtBuCorrCu) with 4-amino 4H-1,2,4-triazole gave good results, leading to the isolation of 2-(NH(2))-3 (NO(2))-TtBuCorrCu and 2,18-(NH(2))(2)-3,17-(NO(2))(2)-TtBuCorrCu in moderate yields. To elucidate factors that influence the reaction, and to highlight the different behavior observed for different metal complex substrates, the electrochemistry of three copper complexes, TtBuPCorrCu, (NO(2))TtBuPCorrCu, and (NO(2))(2)TtBuPCorrCu, was studied by cyclic voltammetry and thin-layer UV visible spectroelectrochemistry. The nitro groups on (NO(2))(x)TtBuPCorrCu are highly electron-withdrawing, which leads not only to a substantial positive shift of all redox potentials but also to a unique redox behavior and UV-vis spectrum of the singly reduced product as compared to the parent compound, TtBuPCorrCu. Finally, the amination reaction was carried out on a Ge(IV) nitrocorrolate, giving in good yield the 2-amino-3-nitroderivative, which was structurally characterized by single crystal X-ray crystallography. PMID- 21797196 TI - Weak interactions modulating the dimensionality in supramolecular architectures in three new nickel(II)-hydrazone complexes, magnetostructural correlation, and catalytic potential for epoxidation of alkenes under phase transfer conditions. AB - Three different ONO donor acetyl hydrazone Schiff bases have been synthesized from the condensation of acetic hydrazide with three different carbonyl compounds: salicylaldehyde (HL(1)), 2-hydroxyacetophenone (HL(2)), and 2, 3 dihydroxybenzaldehyde (HL(3)). These tridentate ligands are reacted with Ni(OOCCF(3))(2).xH(2)O to yield three new Ni(II) complexes having distorted octahedral geometry at each Ni center: [Ni(L(1))(OOCCF(3))(CH(3)OH)](2) (1), [Ni(L(2))(OOCCF(3))(H(2)O)](2) (2), and [Ni(L(3))(L(3)H)](OOCCF(3))(H(2)O)(1.65)(CH(3)OH)(0.35) (3). The ligands and the complexes have been characterized by elemental analysis and IR and UV-vis spectroscopy, and the structures of the complexes have been established by single crystal X-ray diffraction (XRD) study. 1 and 2 are centrosymmetric dinuclear complexes and are structural isomers whereas 3 is a bis chelated cationic monomer coordinated by one neutral and one monoanionic ligand. O-H...O hydrogen bonds in 3 lead to the formation of a dimer. Slight steric and electronic modifications in the ligand backbone provoke differences in the supramolecular architectures of the complexes, leading to a variety of one, two, and three-dimensional hydrogen bonded networks in complexes 1-3 respectively. Variable temperature magnetic susceptibility measurements reveal that moderate antiferromagnetic interactions operate between phenoxo bridged Ni(II) dimers in 1 and 2 whereas very weak antiferromagnetic exchange occurs through hydrogen bonding and pi-pi stacking interactions in 3. All complexes are proved to be efficient catalysts for the epoxidation of alkenes by NaOCl under phase transfer condition. The efficiency of alkene epoxidation is dramatically enhanced by lowering the pH, and the reactions are supposed to involve high valent Ni(III)-OCl or Ni(III)-O. intermediates. 3 is the best epoxidation catalyst among the three complexes with 99% conversion and very high turnover number (TON, 396). PMID- 21797197 TI - Ferrocene-conjugated L-tryptophan copper(II) complexes of phenanthroline bases showing DNA photocleavage activity and cytotoxicity. AB - Ferrocene-conjugated L-tryptophan (L-Trp) reduced Schiff base (Fc-TrpH) copper(II) complexes [Cu(Fc-Trp)(L)](ClO(4)) of phenanthroline bases (L), viz. 2,2'-bipyridine (bpy in 1), 1,10-phenanthroline (phen in 2), dipyrido[3,2-d:2',3' f]quinoxaline (dpq in 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 4), were prepared and characterized and their photocytotoxicity studied. Cationic reduced Schiff base (Ph-TrpH) complexes [Cu(Ph-Trp)(L)(H(2)O)](ClO(4)) (L = phen in 5; dppz in 6) having the ferrocenyl moiety replaced by a phenyl group and the Zn(II) analogue (7) of complex 4 were prepared and used as control species. The crystal structures of 1 and 5 with respective square-planar CuN(3)O and square-pyramidal CuN(3)O(2) coordination geometry show significantly different core structures. Complexes 1-4 exhibit a Cu(II)-Cu(I) redox couple near -0.1 V and the Fc(+)-Fc couple at ~0.5 V vs SCE in DMF-0.1 M [Bu(n)(4)N](ClO(4)) (Fc = ferrocenyl moiety). The complexes display a copper(II)-based d-d band near 600 nm and a Fc centered band at ~450 nm in DMF-Tris-HCl buffer. The complexes are efficient binders to calf thymus DNA. They are synthetic chemical nucleases in the presence of thiol or H(2)O(2), forming hydroxyl radicals. The photoactive complexes are cleavers of pUC19 DNA in visible light, forming hydroxyl radicals. Complexes 2-6 show photocytotoxicity in HeLa cancer cells, giving IC(50) values of 4.7, 10.2, 1.3, 4.8, and 4.3 MUM, respectively, in visible light with the appearance of apoptotic bodies. The complexes also show photocytotoxicity in MCF-7 cancer cells. Nuclear chromatin cleavage has been observed with acridine orange/ethidium bromide (AO/EB) dual staining with complex 4 in visible light. The complexes induce caspase-independent apoptosis in the HeLa cells. PMID- 21797198 TI - Greenhouse gas emissions from operating reserves used to backup large-scale wind power. AB - Wind farms provide electricity with no direct emissions. However, their output cannot be forecasted perfectly, even a short time ahead. Consequently, power systems with large amounts of wind power may need to keep extra fossil-fired generators turned on and ready to provide power if wind farm output drops unexpectedly. In this work, I introduce a new model for estimating the uncertainty in short-term wind power forecasts, and how this uncertainty varies as wind power is aggregated over larger regions. I then use this model to estimate the reserve requirements in order to compensate for wind forecast errors to a 99.999% level of reliability, and an upper limit on the amount of carbon dioxide that would be emitted if natural gas power plants are used for this purpose. I find that for regions larger than 500 km across, operating reserves will undo 6% or less of the greenhouse gas emission savings that would otherwise be expected from wind power. PMID- 21797199 TI - Palladium(II)-catalyzed direct intermolecular alkenylation of chromones. AB - A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed C-H functionalization reaction was developed. The use of pivalic acid with Cu(OAc)(3)/Ag(2)CO(3) provided superior reactivity in the cross coupling of chromones with alkene partners. This approach represents a significant advance over the existing two-step method and afforded various 3 vinylchromone derivatives, which are privileged structures in many biologically active compounds and versatile synthetic building blocks. PMID- 21797200 TI - Synthesis of fully substituted polyhydroxylated pyrrolizidines via Cope-House cyclization. AB - Total synthesis of the proposed structure of (-)-hyacinthacine C(5) and its epimers at C6 and C7 is described. A key step of the synthesis was the construction of the bicyclic pyrrolizidine system by means of a nucleophilic addition of a dithiane to a cyclic nitrone followed by a Cope-House cyclization. PMID- 21797201 TI - Speciation analysis of silver nanoparticles and silver ions in antibacterial products and environmental waters via cloud point extraction-based separation. AB - The rapid growth in commercial use of silver nanoparticles (AgNPs) will inevitably increase silver exposure in the environment and the general population. As the fate and toxic effects of AgNPs is related to the Ag(+) released from AgNPs and the transformation of Ag(+) into AgNPs, it is of great importance to develop methods for speciation analysis of AgNPs and Ag(+). This study reports the use of Triton X-114-based cloud point extraction as an efficient separation approach for the speciation analysis of AgNPs and Ag(+) in antibacterial products and environmental waters. AgNPs were quantified by determining the Ag content in the Triton X-114-rich phase with inductively coupled plasma mass spectrometry (ICPMS) after microwave digestion. The concentration of total Ag(+), which consists of the AgNP adsorbed, the matrix associated, and the freely dissolved, was obtained by subtracting the AgNP content from the total silver content that was determined by ICPMS after digestion. The limits of quantification (S/N = 10) for antibacterial products were 0.4 MUg/kg and 0.2 MUg/kg for AgNPs and total silver, respectively. The reliable quantification limit was 3 MUg/kg for total Ag(+). The presence of Ag(+) at concentrations up to 2-fold that of AgNPs caused no effects on the determination of AgNPs. In the cloud point extraction of AgNPs in antibacterial products, the spiked recoveries of AgNPs were in the range of 71.7-103% while the extraction efficiencies of Ag(+) were in the range of 1.2-10%. The possible coextracted other silver containing nanoparticles in the cloud point extraction of AgNPs were distinguished by transmission electron microscopy (TEM), scanning electron microscopy (SEM)- energy dispersive spectroscopy (EDS), and UV-vis spectrum. Real sample analysis indicated that even though the manufacturers claimed nanosilver products, AgNPs were detected only in three of the six tested antibacterial products. PMID- 21797202 TI - Particle formation in ambient MALDI plumes. AB - The ablated particle count and size distribution of four solid matrix materials commonly used for matrix-assisted laser desorption ionization (MALDI) were measured with a scanning mobility particle sizer (SMPS) combined with a light scattering aerodynamic particle sizer (APS). The two particle sizing instruments allowed size measurements in the range from 10 nm to 20 MUm. The four solid matrixes investigated were 2,5-dihydroxybenzoic acid (DHB), 4-nitroaniline (NA), alpha-cyano-4-hydroxycinnamic acid (CHCA), and sinapic acid (SA). A thin film of the matrix was deposited on a stainless steel target using the dried droplet method and was irradiated with a 337 nm nitrogen laser at atmospheric pressure. The target was rotated during the measurement. A large number of nanoparticles were produced, and average particle diameters ranged from 40 to 170 nm depending on the matrix and the laser fluence. These particles are attributed to agglomeration of smaller particles and clusters and/or hydrodynamic sputtering of melted matrix. A coarse particle component of the distribution was observed with diameters between 500 nm and 2 MUm. The coarse particles were significantly lower in number but had a total mass that was comparable to that of the nanoparticles. The coarse particles are attributed to matrix melting and spallation. Two of the compounds, CHCA and SA, had a third particle size distribution component in the range of 10 to 30 nm, which is attributed to the direct ejection of clusters. PMID- 21797203 TI - Atmospheric chemistry of two biodiesel model compounds: methyl propionate and ethyl acetate. AB - The atmospheric chemistry of two C(4)H(8)O(2) isomers (methyl propionate and ethyl acetate) was investigated. With relative rate techniques in 980 mbar of air at 293 K the following rate constants were determined: k(C(2)H(5)C(O)OCH(3) + Cl) = (1.57 +/- 0.23) * 10(-11), k(C(2)H(5)C(O)OCH(3) + OH) = (9.25 +/- 1.27) * 10( 13), k(CH(3)C(O)OC(2)H(5) + Cl) = (1.76 +/- 0.22) * 10(-11), and k(CH(3)C(O)OC(2)H(5) + OH) = (1.54 +/- 0.22) * 10(-12) cm(3) molecule(-1) s(-1). The chlorine atom initiated oxidation of methyl propionate in 930 mbar of N(2)/O(2) diluent (with, and without, NO(x)) gave methyl pyruvate, propionic acid, acetaldehyde, formic acid, and formaldehyde as products. In experiments conducted in N(2) diluent the formation of CH(3)CHClC(O)OCH(3) and CH(3)CCl(2)C(O)OCH(3) was observed. From the observed product yields we conclude that the branching ratios for reaction of chlorine atoms with the CH(3)-, -CH(2) , and -OCH(3) groups are <49 +/- 9%, 42 +/- 7%, and >9 +/- 2%, respectively. The chlorine atom initiated oxidation of ethyl acetate in N(2)/O(2) diluent gave acetic acid, acetic acid anhydride, acetic formic anhydride, formaldehyde, and, in the presence of NO(x), PAN. From the yield of these products we conclude that at least 41 +/- 6% of the reaction of chlorine atoms with ethyl acetate occurs at the -CH(2)- group. The rate constants and branching ratios for reactions of OH radicals with methyl propionate and ethyl acetate were investigated theoretically using transition state theory. The stationary points along the oxidation pathways were optimized at the CCSD(T)/cc-pVTZ//BHandHLYP/aug-cc-pVTZ level of theory. The reaction of OH radicals with ethyl acetate was computed to occur essentially exclusively (~99%) at the -CH(2)- group. In contrast, both methyl groups and the CH(2)- group contribute appreciably in the reaction of OH with methyl propionate. Decomposition via the alpha-ester rearrangement (to give C(2)H(5)C(O)OH and a HCO radical) and reaction with O(2) (to give CH(3)CH(2)C(O)OC(O)H) are competing atmospheric fates of the alkoxy radical CH(3)CH(2)C(O)OCH(2)O. Chemical activation of CH(3)CH(2)C(O)OCH(2)O radicals formed in the reaction of the corresponding peroxy radical with NO favors the alpha-ester rearrangement. PMID- 21797204 TI - Bicyclic 1,2,3-triazolium ionic liquids: synthesis, characterization, and application to rutaecarpine synthesis. AB - Starting with commercial reagents, bicyclic 1,2,3-triazolium ionic liquids [b-3C tr][NTf(2)] (1) and [b-4C-tr][NTf(2)] (2) were synthesized in four steps with high overall isolated yields of 68% and 76%, respectively. Since the C-5 hydrogen is acidic, under basic condition ionic liquids 1 and 2 were readily methylated with methyl iodide to afford chemically stable ionic liquids 7 and 8 at room temperature (88% and 82%, respectively). Ionic liquid 1 was used as the ionic solvent to demonstrate its usefulness for the synthesis of rutaecarpine, a natural product. PMID- 21797205 TI - High-resolution X-ray photoelectron spectroscopy of mixed silane monolayers for DNA attachment. AB - The amine density of 3-aminopropyldimethylethoxysilane (APDMES) films on silica is controlled to determine its effect on DNA probe density and subsequent DNA hybridization. The amine density is tailored by controlling the surface reaction time of (1) APDMES, or (2) n-propyldimethylchlorosilane (PDMCS, which is not amine terminated) and then reacting it with APDMES to form a mixed monolayer. High-resolution X-ray photoelectron spectroscopy (XPS) is used to quantify silane surface coverage of both pure and mixed monolayers on silica; the XPS data demonstrate control of amine density in both pure APDMES and PDMCS/APDMES mixed monolayers. A linear correlation between the atomic concentration of N atoms from the amine and Si atoms from the APDMES in pure APDMES films allows us to calculate the PDMCS/APDMES ratio in the mixed monolayers. Fluorescence from attached DNA probes and from hybridized DNA decreases as the percentage of APDMES in the mixed monolayer is decreased by dilution with PDMCS. PMID- 21797206 TI - The cosolvent-directed Diels-Alder reaction in ionic liquids. AB - The rate constants of a bimolecular Diels-Alder reaction in binary mixtures of ionic liquids prepared in molecular solvents were analyzed to investigate the effect of viscosity of the medium and solvent effect. In this connection, we have carried out the Diels-Alder reaction of anthracene 9-carbinol with N-ethyl maleimide in binary mixtures of pyridinium-based ionic liquids, 1-butyl pyridinium tetrafluoroborate, 1-butyl-3-pyridinium tetrafluoroborate, and 1-butyl 4-methyl pyridinium tetrafluoroborate in water, methanol, and chloroform at 298.15 K. The rates of reaction decreased, caused by gradually increasing the volume fraction of ionic liquids in solvents for all three ionic liquids. The kinetic results demonstrate a successful application of the pairwise interaction model built upon the concept of enforced hydrophobic hydration. A temperature dependent study of kinetics of the Diels-Alder reaction was carried out in the binary mixtures of ionic liquids in water and was explained by the entropy enthalpy compensation effect based upon activation parameters. Kinetics of the Diels-Alder reaction in highly aqueous medium was noted to be entropically driven. PMID- 21797207 TI - Asymmetric cycloaddition reactions of diazoesters with 2-alkenoic acid derivatives catalyzed by binaphthyldiimine-Ni(II) complexes. AB - The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2).6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3 proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2).6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3 pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1 benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5 dimethyl-1-naphthylmethyl-3-pyrazolidinone and an alpha-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid. PMID- 21797208 TI - Multiplexed electrochemical immunoassay of phosphorylated proteins based on enzyme-functionalized gold nanorod labels and electric field-driven acceleration. AB - A multiplexed electrochemical immunoassay integrating enzyme amplification and electric field-driven strategy was developed for fast and sensitive quantification of phosphorylated p53 at Ser392 (phospho-p53(392)), Ser15 (phospho p53(15)), Ser46 (phospho-p53(46)), and total p53 simultaneously. The disposable sensor array has four spatially separated working electrodes, and each of them is modified with different capture antibody, which enables simultaneous immunoassay to be conducted without cross-talk between adjacent electrodes. The enhanced sensitivity was achieved by a multienzyme amplification strategy using gold nanorods (AuNRs) as nanocarrier for coimmobilization of horseradish peroxidase (HRP) and detection antibody (Ab(2)) at a high ratio of HRP/Ab(2), which produced an amplified electrocatalytic response by the reduction of HRP oxidized thionine in the presence of hydrogen peroxide. The immunoreaction processes were accelerated by applying +0.4 V for 3 min and then -0.2 V for 1.5 min; thus, the whole sandwich immunoreactions could be completed in less than 5 min. Under optimal conditions, this method could simultaneously detect phospho-p53(392), phospho-p53(15), phospho-p53(46), and total p53 ranging from 0.01 to 20 nM, 0.05 to 20 nM, 0.1 to 50 nM, and 0.05 to 20 nM with detection limits of 5 pM, 20 pM, 30 pM, and 10 pM, respectively. Accurate determinations of these proteins in human plasma samples were demonstrated by comparison to the standard ELISA method. The disposable immunosensor array shows excellent promise for clinical screening of phosphorylated proteins and convenient point-of-care diagnostics. PMID- 21797209 TI - Self-sorting in rodlike micelles of chiral bisurea bolaamphiphiles. AB - We have demonstrated the formation of segregated enantiomeric dynamic rods in water, from the self-sorting of chiral trans-1,2-bisureido cyclohexane-based bolaamphiphiles. Fluorescence probes have been used to investigate the self sorting through forming exciplex and FRET. PMID- 21797210 TI - Photocontrolled DNA binding of a receptor-targeted organometallic ruthenium(II) complex. AB - A photoactivated ruthenium(II) arene complex has been conjugated to two receptor binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as "tumor-targeting devices" since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV-vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(eta(6)-p-cym)Ru(bpm)(H(2)O)](2+), reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, (5')dCATGGCT and (5')dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide-oligonucleotide hybrid, Phac-His-Gly-Met-linker-p(5')dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids. PMID- 21797211 TI - Impedimetric immobilized DNA-based sensor for simultaneous detection of Pb2+, Ag+, and Hg2+. AB - An unlabeled immobilized DNA-based sensor was reported for simultaneous detection of Pb(2+), Ag(+), and Hg(2+) by electrochemical impedance spectroscopy (EIS) with [Fe(CN)(6)](4-/3-) as redox probe, which consisted of three interaction sections: Pb(2+) interaction with G-rich DNA strands to form G-quadruplex, Ag(+) interaction with C-C mismatch to form C-Ag(+)-C complex, and Hg(2+) interaction with T-T mismatch to form T-Hg(2+)-T complex. Circular dichroism (CD) and UV-vis spectra indicated that the interactions between DNA and Pb(2+), Ag(+), or Hg(2+) occurred. Upon DNA interaction with Pb(2+), Ag(+), and Hg(2+), respectively, a decreased charge transfer resistance (R(CT)) was obtained. Taking advantage of the R(CT) difference (DeltaR(CT)), Pb(2+), Ag(+), and Hg(2+) were selectively detected with the detection limit of 10 pM, 10 nM, and 0.1 nM, respectively. To simultaneously (or parallel) detect the three metal ions coexisting in a sample, EDTA was applied to mask Pb(2+) and Hg(2+) for detecting Ag(+); cysteine was applied to mask Ag(+) and Hg(2+) for detecting Pb(2+), and the mixture of G-rich and C-rich DNA strands were applied to mask Pb(2+) and Ag(+) for detecting Hg(2+). Finally, the simple and cost-effective sensor could be successfully applied for simultaneously detecting Pb(2+), Ag(+), and Hg(2+) in calf serum and lake water. PMID- 21797212 TI - Absolute quantification of the alleles in somatic point mutations by bioluminometric methods based on competitive polymerase chain reaction in the presence of a locked nucleic acid blocker or an allele-specific primer. AB - In somatic (acquired) point mutations, the challenge is to quantify minute amounts of the mutant allele in the presence of a large excess of the normal allele that differs only in a single base pair. We report two bioluminometric methods that enable absolute quantification of the alleles. The first method exploits the ability of a locked nucleic acid (LNA) oligonucleotide to bind to and inhibit effectively the polymerase chain reaction (PCR) amplification of the normal allele while the amplification of the mutant allele remains unaffected. The second method employs allele-specific PCR primers, thereby allowing the amplification of the corresponding allele only. DNA internal standards (competitors) are added to the PCR mixture to compensate for any sample-to-sample variation in the amplification efficiency. The amplification products from the two alleles and the internal standards are quantified by a microtiter well-based bioluminometric hybridization assay using the photoprotein aequorin as a reporter. The methods allow absolute quantification of less than 300 copies of the mutant allele even in samples containing less than 1% of the mutant allele. PMID- 21797213 TI - Effects of milling and baking technologies on levels of deoxynivalenol and its masked form deoxynivalenol-3-glucoside. AB - The co-occurrence of the major Fusarium mycotoxin deoxynivalenol (DON) and its conjugate deoxynivalenol-3-glucoside (DON-3-Glc) has been documented in infected wheat. This study reports on the fate of this masked DON within milling and baking technologies for the first time and compares its levels with those of the free parent toxin. The fractionation of DON-3-Glc and DON in milling fractions was similar, tested white flours contained only approximately 60% of their content in unprocessed wheat grains. No substantial changes of both target analytes occurred during the dough preparation process, i.e. kneading, fermentation, and proofing. However, when bakery improvers enzymes mixtures were employed as a dough ingredient, a distinct increase up to 145% of conjugated DON 3-Glc occurred in fermented dough. Some decrease of both DON-3-Glc and DON (10 and 13%, respectively, compared to fermented dough) took place during baking. Thermal degradation products of DON, namely norDON A, B, C, D, and DON-lactone were detected in roasted wheat samples and baked bread samples by means of UPLC Orbitrap MS. Moreover, thermal degradation products derived from DON-3-Glc were detected and tentatively identified in heat-treated contaminated wheat and bread based on accurate mass measurement performed under the ultrahigh mass resolving power. These products, originating from DON-3-Glc through de-epoxidation and other structural changes in the seskviterpene cycle, were named norDON-3-Glc A, B, C, D, and DON-3-Glc-lactone analogically to DON degradation products. Most of these compounds were located in the crust of experimental breads. PMID- 21797214 TI - Arsenic speciation and phytoavailability in contaminated soils using a sequential extraction procedure and XANES spectroscopy. AB - In this study, a sequential extraction procedure (SEP) and X-ray absorption near edge structure (XANES) spectroscopy were used to determine the solid-phase speciation and phytoavailability of arsenic (As) of historically contaminated soils from As containing pesticides and herbicides and soils spiked with As in the laboratory. Brassica juncea was grown in the contaminated soils to measure plant available As in a glasshouse experiment. Arsenic associated with amorphous Fe oxides was found to be the dominant phase using both SEP and XANES spectroscopy. Arsenic predominantly existed in arsenate (As(V)) form in the soils; in a few samples As was also present in arsenite (As(III)) form or in scorodite mineral. Arsenic concentration in shoots showed significant (p < 0.001 0.05) correlations with the exchangeable As (r = 0.85), and amorphous Fe oxides associated As evaluated by the SEP (r = 0.67), and As associated with amorphous Fe oxides as determined by XANES spectroscopy (r = 0.51). The results show that As in both fractions was readily available for plant uptake and may pose a potential risk to the environment. The combination of SEP and XANES spectroscopy allowed us the quantitative speciation of As in the contaminated soils and the identification of valence and mineral forms of As. Such detailed knowledge on As speciation and availability is vital for management and rehabilitation of As contaminated soils. PMID- 21797215 TI - Dissecting force interactions in cellulose deconstruction reveals the required solvent versatility for overcoming biomass recalcitrance. AB - Pretreatment for deconstructing the multifaceted interaction network in crystalline cellulose is a limiting step in making fuels from lignocellulosic biomass. Not soluble in water and most organic solvents, cellulose was found to dissolve in certain classes of ionic liquids (ILs). To elucidate the underlying mechanisms, we simulated cellulose deconstruction by peeling off an 11-residue glucan chain from a cellulose microfibril and computed the free-energy profile in water and in 1-butyl-3-methylimidazolium chloride (BmimCl) IL. For this deconstruction process, the calculated free-energy cost/reduction in water/BmimCl is ~2 kcal/mol per glucose residue, respectively. To unravel the molecular origin of solvent-induced differences, we devised a coarse graining scheme to dissect force interactions in simulation models by a force-matching method. The results establish that solvent-glucan interactions are dependent on the deconstruction state of cellulose. Water couples to the hydroxyl and side-chain groups of glucose residues more strongly in the peeled-off state but lacks driving forces to interact with sugar rings and linker oxygens. Conversely, BmimCl demonstrates versatility in targeting glucose residues in cellulose. Anions strongly interact with hydroxyl groups, and the coupling of cations to side chains and linker oxygens is stronger in the peeled-off state. Other than enhancing anion-hydroxyl group coupling, coarse-grain analysis of force interactions identifies configuring cations to target side chains and linker oxygens as a useful design strategy for pretreatment ILs. Furthermore, the state dependence of solvent glucan interactions highlights specific stabilization and/or frustration of the different structure states of cellulose as important design parameters for pretreatment solvents. PMID- 21797216 TI - New insight into the mechanism of action of wasp mastoparan peptides: lytic activity and clustering observed with giant vesicles. AB - Antimicrobial peptides of the mastoparans family exert their bactericidal activity by binding to lipid membranes, inducing pores or defects and leaking the internal contents of vesicles and cells. However, this does not seem to be the only mechanism at play, and they might be important in the search for improved peptides with lower undesirable side effects. This work deals with three mastoparans peptides, Polybia-MP-1(MP-1), N2-Polybia-MP-1 (N-MP-1), and Mastoparan X (MPX), which exhibit high sequence homology. They all have three lysine residues and amidated C termini, but because of the presence of two, one, and no aspartic acid residues, respectively, they have +2, +3, and +4 net charges at physiological pH. Here we focus on the effects of these mastoparans peptides on anionic model membranes made of palmitoleyoilphosphatidylcholine (POPC) and palmitoleyoilphosphatidylglycerol (POPG) at 1:1 and 3:1 molar ratios in the presence and in the absence of saline buffer. Zeta potential experiments were carried out to measure the extent of the peptides' binding and accumulation at the vesicle surface, and CD spectra were acquired to quantify the helical structuring of the peptides upon binding. Giant unilamellar vesicles were observed under phase contrast and fluorescence microscopy. We found that the three peptides induced the leakage of GUVs at a gradual rate with many characteristics of the graded mode. This process was faster in the absence of saline buffer. Additionally, we observed that the peptides induced the formation of dense regions of phospholipids and peptides on the GUV surface. This phenomenon was easily observable for the more charged peptides (MPX > N-MP-1 > MP 1) and in the absence of added salt. Our data suggest that these mastoparans accumulate on the bilayer surface and induce a transient interruption to its barrier properties, leaking the vesicle contents. Next, the bilayer recovers its continuity, but this happens in an inhomogeneous way, forming a kind of ply with peptides sandwiched between two juxtaposed membranes. Eventually, a peptide-lipid aggregate forming a lump is formed at high peptide-to-lipid ratios. PMID- 21797217 TI - Synthesis and aggregation behavior of a hexameric quaternary ammonium surfactant. AB - A star-shaped hexameric quaternary ammonium surfactant (PAHB), bearing six hydrophobic chains and six charged hydrophilic headgroups connected by an amide type spacer group, was synthesized. The self-assembly behavior of the surfactant in aqueous solution was studied by surface tension, electrical conductivity, isothermal titration microcalorimetry, dynamic light scattering, cryogenic transmission electron microscopy, and NMR techniques. The results reveal that there are two critical aggregate concentrations during the process of aggregation, namely C(1) and C(2). The aggregate transitions are proved to be caused by the changes of the surfactant configuration through hydrophobic interaction among the hydrocarbon chains. Below C(1), PAHB may present a star shaped molecular configuration due to intramolecular electrostatic repulsion among the charged headgroups, and large aggregates with network-like structure are observed. Between C(1) and C(2), the hydrophobic interaction among the hydrophobic chains may become stronger to make the hydrophobic chains of the PAHB molecules curve back and pack more closely, and then the network-like aggregates transfer to large spherical aggregates of ~100 nm. Beyond C(2), the hydrophobic interaction may become strong enough to cause the PAHB molecular configuration to turn into a pyramid-like shape, resulting in the transition of the spherical large aggregates to spherical micelles of ~10 nm. Interestingly, the PAHB displays high emulsification ability to linear fatty alkyls even at very low concentration. PMID- 21797218 TI - A molecular balance for measuring aliphatic CH-pi interactions. AB - A series of conformationally flexible bicyclic N-arylimides were employed as molecular balances to study the weak aliphatic CH-pi interaction between alkyl and arene groups. The formation of intramolecular CH-pi interactions in the folded conformers was characterized by X-ray crystallography. The strengths of the interactions were characterized in CDCl(3) by the changes in the folded/unfolded ratios, as measured by (1)H NMR. The CH-pi interaction between a methyl group and an aromatic surface was ~1.0 kcal/mol and was easily disrupted or masked by conformational entropy and repulsive steric interactions. PMID- 21797219 TI - Cellulose microfibrils grafted with PBA via surface-initiated atom transfer radical polymerization for biocomposite reinforcement. AB - Immobilizing poly(butyl acrylate) (PBA) on cellulose microfibrils (CMFs) by atom transfer radical polymerization (ATRP) of butyl acrylate (BA) on the surface of 2 bromoisobutyryl-functionalized CMF generated highly hydrophobic microfibrils (CMF PBA) with a hard core and a soft-shell structure. TGA and static water contact angle results suggested that the surfaces of the modified CMF samples were not completely covered by PBA chains until the molecular weight of grafts became sufficiently long. The GPC results indicated that the grafts with low molecular weight showed controlled/"living" characteristics of the surface-initiated ATRP; however, there existed more side reactions with the increase in molecular weights. Biocomposites consisting of polypropylene (PP) and CMF-PBA samples exhibited significantly improved compatibility, interface adhesion, and mechanical properties with the increase in PBA graft length. The findings confirmed that the longer grafts facilitated the better entanglement of PBA grafts with PP macromolecules and thus further improved the mechanical properties. PMID- 21797220 TI - Trimer-based design of pH-responsive protein cage results in soluble disassembled structures. AB - Limited studies have been done on the interactions between subunits of self assembling protein cages. E2 protein cage from Bacillus stearothermophilus was investigated in this work to impart pH-sensitive disassembly profile. Key amino acids were identified at the intratrimer and intertrimer interfaces, and histidine residues were introduced to these key sites to probe for their influences on the E2 assembly. We found that both the intratrimer- and the intertrimer-modified mutant proteins have the same quaternary structures as the wild type (E2-WT) at physiological pH of 7.4. At pH 5.0, the intratrimer-modified protein maintained its spherical structure. In contrast, the intertrimer modified protein lost its integrity, as observed under the electron microscope, whereas it remained soluble and nondenatured. The identified interactions between the intertrimers are critical in the formation of E2 protein cage. The pH-controlled disassembly of E2 protein cage in soluble and nondenatured form make it promising in nanoscale applications, especially for drug delivery and release in the endosomes. PMID- 21797221 TI - Veterinary drug residues in seafood inspected by the European Union, United States, Canada, and Japan from 2000 to 2009. AB - Veterinary drugs are used to treat or prevent a wide array of production-related diseases in aquaculture. Residues of these drugs in seafood products may pose risks to consumers, prompting governments to set drug residue tolerance levels and inspect seafood for violations of these standards. This study characterizes veterinary drug inspection policies and violations among four inspecting bodies (European Union (E.U.), United States (U.S.), Canada, and Japan), using government-collected veterinary drug violation data from 2000 to 2009. Most veterinary drug violations were detected in species that are commonly farm raised. Asian seafood products, including shrimp and prawns, catfish (or fish sold as catfish), crab, tilapia, eel, and Chilean salmon were most frequently in violation of veterinary drug residue standards. Vietnam had the greatest number of violations among exporting countries. Concentrations of most veterinary drugs in seafood found in violation did not differ between inspecting bodies that reported drug concentrations. Transparency in seafood inspection reporting varied widely among inspecting bodies. Estimation of violations in the untested fraction of seafood was precluded by a lack of information from inspecting bodies regarding the distinction between targeted and random sampling. Increased transparency could facilitate a more rigorous characterization of public health risks from consuming imported seafood. PMID- 21797222 TI - Theoretical investigation on reaction of sulbactam with wild-type SHV-1 beta lactamase: acylation, tautomerization, and deacylation. AB - Molecular dynamics (MD) simulation and quantum mechanical (QM) calculations were used to investigate the reaction mechanism of sulbactam with class A wild-type SHV-1 beta-lactamase including acylation, tautomerization, and deacylation. Five different sulbactam-enzyme configurations were investigated by MD simulations. In the acylation step, we found that Glu166 cannot activate Ser70 directly for attacking on the carbonyl carbon, and Lys73 would participate in the reaction acting as a relay. Additionally, we found that sulbactam carboxyl can also act as a general base. QM calculations were performed on the formation mechanism of linear intermediates. We suggest that both imine and trans-enamine intermediates can be obtained in the opening of a five-membered thiazolidine ring. By MD simulation, we found that imine intermediate can exist in two conformations, which can generate subsequent trans- and cis-enamine intermediates, respectively. The QM calculations revealed that trans-enamine intermediate is much more stable than other intermediates. The deacylation mechanism of three linear intermediates (imine, trans-enamine, cis-enamine) was investigated separately. It is remarkably noted that, in cis-enamine intermediate, Glu166 cannot activate water for attacking on the carbonyl carbon directly. This leads to a decreasing of the deacylation rate of cis-enamine. These findings will be potentially useful in the development of new inhibitors. PMID- 21797223 TI - Using atomic layer deposition to hinder solvent decomposition in lithium ion batteries: first-principles modeling and experimental studies. AB - Passivating lithium ion (Li) battery electrode surfaces to prevent electrolyte decomposition is critical for battery operations. Recent work on conformal atomic layer deposition (ALD) coating of anodes and cathodes has shown significant technological promise. ALD further provides well-characterized model platforms for understanding electrolyte decomposition initiated by electron tunneling through a passivating layer. First-principles calculations reveal two regimes of electron transfer to adsorbed ethylene carbonate molecules (EC, a main component of commercial electrolyte), depending on whether the electrode is alumina coated. On bare Li metal electrode surfaces, EC accepts electrons and decomposes within picoseconds. In contrast, constrained density functional theory calculations in an ultrahigh vacuum setting show that, with the oxide coating, e(-) tunneling to the adsorbed EC falls within the nonadiabatic regime. Here the molecular reorganization energy, computed in the harmonic approximation, plays a key role in slowing down electron transfer. Ab initio molecular dynamics simulations conducted at liquid EC electrode interfaces are consistent with the view that reactions and electron transfer occur right at the interface. Microgravimetric measurements demonstrate that the ALD coating decreases electrolyte decomposition and corroborates the theoretical predictions. PMID- 21797224 TI - Synthesis and characterization of three-coordinate Ni(III)-imide complexes. AB - A new family of low-coordinate nickel imides supported by 1,2-bis(di-tert butylphosphino)ethane was synthesized. Oxidation of nickel(II) complexes led to the formation of both aryl- and alkyl-substituted nickel(III)-imides, and examples of both types have been isolated and fully characterized. The aryl substituent that proved most useful in stabilizing the Ni(III)-imide moiety was the bulky 2,6-dimesitylphenyl. The two Ni(III)-imide compounds showed different variable-temperature magnetic properties but analogous EPR spectra at low temperatures. To account for this discrepancy, a low-spin/high-spin equilibrium was proposed to take place for the alkyl-substituted Ni(III)-imide complex. This proposal was supported by DFT calculations. DFT calculations also indicated that the unpaired electron is mostly localized on the imide nitrogen for the Ni(III) complexes. The results of reactions carried out in the presence of hydrogen donors supported the findings from DFT calculations that the adamantyl substituent was a significantly more reactive hydrogen-atom abstractor. Interestingly, the steric properties of the 2,6-dimesitylphenyl substituent are important not only in protecting the Ni?N core but also in favoring one rotamer of the resulting Ni(III)-imide, by locking the phenyl ring in a perpendicular orientation with respect to the NiPP plane. PMID- 21797225 TI - SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1. AB - Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl x(L) and Mfl-1, has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-x(L), and Bcl-w while it is not active against Mcl-1 and Bfl-1. However, early clinical and preclinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL, and possibly all other four antiapoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both Bcl-x(L) and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl 1. PMID- 21797226 TI - Surface-enhanced Raman scattering imaging of a single molecule on urchin-like silver nanowires. AB - Urchin-like silver nanowires are prepared by reacting AgNO(3)(aq) with copper metal in the presence of cetyltrimethylammonium chloride and HNO(3)(aq) on a screen-printed carbon electrode at room temperature. The diameters of the nanowires are about 100 nm, and their lengths are up to 10 MUm. Using Raman spectroscopy, the detection limit of Rhodamine 6G (R6G) on the urchin-like silver nanowire substrate can be as low as 10(-16) M, while the analytical enhancement factor is about 10(13). Raman mapping images confirm that a single R6G molecule on the substrate can be detected. PMID- 21797227 TI - Radiative forcing impacts of boreal forest biofuels: a scenario study for Norway in light of albedo. AB - Radiative forcing impacts due to increased harvesting of boreal forests for use as transportation biofuel in Norway are quantified using simple climate models together with life cycle emission data, MODIS surface albedo data, and a dynamic land use model tracking carbon flux and clear-cut area changes within productive forests over a 100-year management period. We approximate the magnitude of radiative forcing due to albedo changes and compare it to the forcing due to changes in the carbon cycle for purposes of attributing the net result, along with changes in fossil fuel emissions, to the combined anthropogenic land use plus transport fuel system. Depending on albedo uncertainty and uncertainty about the geographic distribution of future logging activity, we report a range of results, thus only general conclusions about the magnitude of the carbon offset potential due to changes in surface albedo can be drawn. Nevertheless, our results have important implications for how forests might be managed for mitigating climate change in light of this additional biophysical criterion, and in particular, on future biofuel policies throughout the region. Future research efforts should be directed at understanding the relationships between the physical properties of managed forests and albedo, and how albedo changes in time as a result of specific management interventions. PMID- 21797228 TI - Fabricating superhydrophobic polymer surfaces with excellent abrasion resistance by a simple lamination templating method. AB - Fabricating robust superhydrophobic surfaces for commercial applications is challenging as the fine-scale surface features, necessary to achieve superhydrophobicity, are susceptible to mechanical damage. Herein, we report a simple and inexpensive lamination templating method to create superhydrophobic polymer surfaces with excellent abrasion resistance and water pressure stability. To fabricate the surfaces, polyethylene films were laminated against woven wire mesh templates. After cooling, the mesh was peeled from the polymer creating a 3D array of ordered polymer microposts on the polymer surface. The resulting texture is monolithic with the polymer film and requires no chemical modification to exhibit superhydrophobicity. By controlling lamination parameters and mesh dimensions, polyethylene surfaces were fabricated that exhibit static contact angles of 160 degrees and slip angles of 5 degrees . Chemical and mechanical stability was evaluated using an array of manual tests as well as a standard reciprocating abraser test. Surfaces remained superhydrophobic after more than 5500 abrasion cycles at a pressure of 32.0 kPa. In addition, the surface remains dry after immersing into water for 5 h at 55 kPa. This method is environmental friendly, as it employs no solvents or harsh chemicals and may provide an economically viable path to manufacture large areas of mechanically robust superhydrophobic surfaces from inexpensive polymers and reusable templates. PMID- 21797229 TI - A comparative study of gold nanocubes, octahedra, and rhombic dodecahedra as highly sensitive SERS substrates. AB - Gold nanocubes, octahedra, and rhombic dodecahedra with roughly two sets of particle sizes have been successfully synthesized via a seed-mediated growth approach. All six samples were analyzed for comparative surface-enhanced Raman scattering (SERS) activity. All of these Au nanostructures were found to yield strong enhancement at a thiophenol concentration of 10(-7) M and are excellent SERS substrates. Rhombic dodecahedra with a rhombus edge length of 32 nm showed significantly better enhancement than the other samples and can reach a detection limit of 10(-8) M. Simulations of the binding energies of thiophenol on the different faces of gold and electric near-field intensities of these nanocrystals have been performed to evaluate the experimental results. Superior SERS activity of these nanocrystals can be expected toward the detection of many other molecules. PMID- 21797231 TI - Separating attoliter-sized compartments using fluid pore-spanning lipid bilayers. AB - Anodic aluminum oxide (AAO) is a porous material having aligned cylindrical compartments with 55-60 nm diameter pores, and being several micrometers deep. A protocol was developed to generate pore-spanning fluid lipid bilayers separating the attoliter-sized compartments of the nanoporous material from the bulk solution, while preserving the optical transparency of the AAO. The AAO was selectively functionalized by silane chemistry to spread giant unilamellar vesicles (GUVs) resulting in large continuous membrane patches covering the pores. Formation of fluid single lipid bilayers through GUV rupture could be readily observed by fluorescence microscopy and further supported by conservation of membrane surface area, before and after GUV rupture. Fluorescence recovery after photobleaching gave low immobile fractions (5-15%) and lipid diffusion coefficients similar to those found for bilayers on silica. The entrapment of molecules within the porous underlying cylindrical compartments, as well as the exclusion of macromolecules from the nanopores, demonstrate the barrier function of the pore-spanning membranes and could be investigated in three-dimensions using confocal laser scanning fluorescence imaging. PMID- 21797230 TI - Evaluating the global CpG methylation status of native DNA utilizing a bipartite split-luciferase sensor. AB - Epigenetic modifications play an essential role in the regulation of gene expression and ultimately cell fate. Methylation of cytosine at CpG dinucleotides (mCpG) is an important epigenetic mark that has been correlated with cancer when present at promoter sites of tumor suppressor genes. To develop a rapid methodology for the direct assessment of global levels of DNA methylation, we first interrogated the methyl-CpG binding domains (MBDs), the Kaiso family of Cys(2)-His(2) zinc fingers, and an SET- and RING-associated domain using a split luciferase reassembly methodology. We identified MBD1 as the most selective domain for the discrimination between mCpG and CpG sites with over 90-fold selectivity. Utilizing a bipartite strategy, we constructed a purely methylation dependent bipartite sensor for the direct detection of global levels of DNA methylation by attaching MBD1 domains to each of the split-luciferase halves. This new sensor was validated for the direct determination of genomic DNA methylation levels in in vitro studies without any intervening chemical or enzymatic processing of DNA. Finally, we demonstrated that this bipartite sensor can be utilized for monitoring dose-dependent changes in global levels of methylation in DNA from HeLa cells challenged with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. PMID- 21797232 TI - Structure-based site of metabolism prediction for cytochrome P450 2D6. AB - Realistic representation of protein flexibility in biomolecular simulations remains an unsolved fundamental problem and is an active area of research. The high flexibility of the cytochrome P450 2D6 (CYP2D6) active site represents a challenge for accurate prediction of the preferred binding mode and site of metabolism (SOM) for compounds metabolized by this important enzyme. To account for this flexibility, we generated a large ensemble of unbiased CYP2D6 conformations, to which small molecule substrates were docked to predict their experimentally observed SOM. SOM predictivity was investigated as a function of the number of protein structures, the scoring function, the SOM-heme cutoff distance used to distinguish metabolic sites, and intrinsic reactivity. Good SOM predictions for CYP2D6 require information from the protein. A critical parameter is the distance between the heme iron and the candidate site of metabolism. The best predictions were achieved with cutoff distances consistent with the chemistry relevant to CYP2D6 metabolism. Combination of the new ensemble-based docking method with estimated intrinsic reactivities of substrate sites considerably improved the predictivity of the model. Testing on an independent set of substrates yielded area under curve values as high as 0.93, validating our new approach. PMID- 21797233 TI - Single-molecule AFM characterization of individual chemically tagged DNA tetrahedra. AB - Single-molecule characterization is essential for ascertaining the structural and functional properties of bottom-up DNA nanostructures. Here we enlist three atomic force microscopy (AFM) techniques to examine tetrahedron-shaped DNA nanostructures that are functionally enhanced with small chemical tags. In line with their application for biomolecule immobilization in biosensing and biophysics, the tetrahedra feature three disulfide-modified vertices to achieve directed attachment to gold surfaces. The remaining corner carries a single bioligand that can capture and present individual cargo biomolecules at defined lateral nanoscale spacing. High-resolution AFM topographic imaging confirmed the directional surface attachment as well as the highly effective binding of individual receptor molecules to the exposed bioligands. Insight into the binding behavior at the single-molecule level was gained using molecular recognition force spectroscopy using an AFM cantilever tip with a tethered molecular receptor. Finally, simultaneous topographic and recognition imaging demonstrated the specific receptor-ligand interactions on individual tetrahedra. In summary, AFM characterization verified that the rationally designed DNA nanostructures feature characteristics to serve as valuable immobilization agents in biosensing, biophysics, and cell biology. PMID- 21797234 TI - Cu(II)-catalyzed olefin migration and Prins cyclization: highly diastereoselective synthesis of substituted tetrahydropyrans. AB - Metal-ligand complexes of Cu(OTf)(2) with an appropriate bisphosphine ligand have been shown to effectively catalyze the formation of substituted tetrahydropyrans via a sequential olefin migration and Prins-type cyclization. This methodology provides convenient access to a variety of functionalized tetrahydropyrans in excellent diastereoselectivities and good to excellent yields. PMID- 21797235 TI - Catalytic enantioselective total synthesis of (+)-torrubiellone C. AB - Silyl-protected (R)-methyl 2-(hydroxymethyl)butanoate was obtained by an enantioselective Ir-catalyzed hydrogenation in high yield and selectivity. Elaboration of this building block via Takai and Stille reactions gave a protected hydroxy polyene chain, which was coupled to a 5-hydroxyphenyl-4-hydroxy 2-pyridone derivative by a modified Horner-Wadsworth-Emmons reaction. Deprotection gave synthetic (+)-torrubiellone C, which led to the assignment of the configuration of the natural product as (R). PMID- 21797239 TI - Trans titanium(IV) complexes of salen ligands exhibit high antitumor activity. AB - Salen-titanium(IV) complexes are introduced as a new family of highly efficient antitumor complexes, being the first cytotoxic titanium(IV) complexes of trans labile ligands, as characterized crystallographically. Four complexes with different aromatic substitutions were analyzed, reveling a meaningful effect of the ligand structure on the complex performance. All complexes exhibit high hydrolytic stability, where the labile OAr ligands hydrolyze in a 10% D(2)O solution with t(1/2) ranging from 2 to 11 h. The IC(50) values obtained for three of the salen complexes studied on HT-29 colon and OVCAR-1 ovarian cells demonstrate activity that exceeds those of the known tianium(IV) complexes Cp(2)TiCl(2) and (bzac)(2)Ti(OiPr)(2) and that of cisplatin, where the most active para-chlorinated complex exhibits activity enhancement relative to cisplatin by 10-fold. PMID- 21797240 TI - Lanthanide-mediated supramolecular cages and host-guest interactions. AB - The structure and thermodynamic properties of lanthanide complexes with a new tripodal ligand L2 have been elucidated using different physicochemical methods. At stoichiometric ratios, the tetrahedral three-dimensional complexes with lanthanide cations are formed in acetonitrile with good stabilities. Despite minor structural changes comparing to previously investigated tripodal ligands, the resulting assembly exhibits different features revealed with the crystal structure of [Eu(4)L2(4)](OH)(ClO(4))(11) (orthorhombic, Pbcn). Interestingly, the highly charged edifice contains an inner cage encapsulating a perchlorate anion. Such lanthanide mediated cage-like assemblies are rare, and may be of interest for different sensing applications. Indeed, the anionic guest can be exchanged with different anions. The related host-guest equilibria were investigated with NMR techniques. Various aspects of these reactions are qualitatively discussed. PMID- 21797241 TI - Multielemental analysis and classification of amaranth seeds according to their botanical origin. AB - The characterization of amaranth seeds (Amaranthus spp.) was developed for Amaranthus hypochondriacus, Amaranthus cruentus, and Amaranthus dubius. The elemental concentrations were determined by inductively coupled plasma optic atomic spectroscopy. Pattern recognition methods were used for the characterization of seed samples: nonsupervised methods included principal components analysis and cluster analysis; supervised methods were linear discriminant analysis and partial least squares discriminant analysis (PLS-DA). Informed are the concentrations of the following elements: Ag, Al, Ba, Ca, Co, Cr, Cu, Fe, K, La, Li, Mg, Mn, Mo, Na, Ni, P, S, Sr, V, Zn, and Zr. The lowest mineral content was found in A. hypochondriacus, and the highest one was found in A. dubius. For the classification, selected variables for all multivariate methods were Ba, Cr, Li, Mn, Ni, S, and Sr. Nonsupervised methods allowed us to distinguish between the three species of amaranth; however, PLS-DA supervised methods showed the best prediction ability. PMID- 21797242 TI - [4]Pseudorotaxanes with remarkable self-sorting selectivities. AB - The synthesis and characterization of several self-assembled [4]pseudorotaxanes is reported, some of which form in a programmed way based on two similar yet orthogonal crown ether/secondary ammonium ion binding motifs. A preference for the formation of a [4]pseudorotaxane with an antiparallel rather than parallel alignment of crown ether building blocks is observed even in the absence of such orthogonal binding sites, when a homodivalent axle is used. PMID- 21797243 TI - Prediction of calcite morphology from computational and experimental studies of mutations of a de novo-designed peptide. AB - Many organisms use macromolecules, often proteins or peptides, to control the growth of inorganic crystals into complex materials. The ability to model peptide mineral interactions accurately could allow for the design of novel peptides to produce materials with desired properties. Here, we tested a computational algorithm developed to predict the structure of peptides on mineral surfaces. Using this algorithm, we analyzed energetic and structural differences between a 16-residue peptide (bap4) designed to interact with a calcite growth plane and single- and double-point mutations of the charged residues. Currently, no experimental method is available to resolve the structures of proteins on solid surfaces, which precludes benchmarking for computational models. Therefore, to test the models, we chemically synthesized each peptide and analyzed its effects on calcite crystal growth. Whereas bap4 affected the crystal growth by producing heavily stepped corners and edges, point mutants had variable influences on morphology. Calculated residue-specific binding energies correlated with experimental observations; point mutations of residues predicted to be crucial to surface interactions produced morphologies most similar to unmodified calcite. These results suggest that peptide conformation plays a role in mineral interactions and that the computational model supplies valid energetic and structural data that can provide information about expected crystal morphology. PMID- 21797244 TI - Infrared spectra of dimethylphenanthrenes in the gas phase. AB - Infrared spectra of atmospherically and astronomically important dimethylphenanthrenes (DMPs), namely 1,9-DMP, 2,4-DMP, and 3,9-DMP, were recorded in the gas phase from 400 to 4000 cm(-1) with a resolution of 0.5 cm(-1) at 110 degrees C using a 7.2 m gas cell. DFT calculations at the B3LYP/6-311G** level were carried out to get the harmonic and anharmonic frequencies and their corresponding intensities for the assignment of the observed bands. However, spectral assignments could not be made unambiguously using anharmonic or selectively scaled harmonic frequencies. Therefore, the scaled quantum mechanical (SQM) force field analysis method was adopted to achieve more accurate assignments. In this method force fields instead of frequencies were scaled. The cartesian force field matrix obtained from the gaussian calculations was converted to a nonredundant local coordinate force field matrix and then the force fields were scaled to match experimental frequencies in a consistent manner using a modified version of the UMAT program of the QCPE package. Potential energy distributions (PEDs) of the normal modes in terms of nonredundant local coordinates obtained from these calculations helped us derive the nature of the vibration at each frequency. The intensity of observed bands in the experimental spectra was calculated using estimated vapor pressures of the DMPs. An error analysis of the mean deviation between experimental and calculated intensities reveal that the observed methyl C-H stretching intensity deviates more compared to the aromatic C-H and non C-H stretching bands. PMID- 21797245 TI - Nanoparticles of the novel coordination polymer KBi(H2O)2[Fe(CN)6].H2O as a potential contrast agent for computed tomography. AB - An aqueous synthetic procedure for preparing nanoparticles of the novel potassium bismuth ferrocyanide coordination polymer KBi(H(2)O)(2)[Fe(CN)(6)].H(2)O is reported. The crystal structure of this coordination polymer is determined through X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, and potential use of such nanoparticles coated with PVP as a CT contrast agent are investigated. PMID- 21797246 TI - Analysis and modeling of airborne BTEX concentrations from the Deepwater Horizon oil spill. AB - Concerns have been raised about whether the Deepwater Horizon oil spill cleanup workers experienced adverse health effects from exposure to airborne benzene, toluene, ethylbenzene, and xylene (BTEX) which volatilized from surfaced oil. Thus, we analyzed the nearly 20 000 BTEX measurements of breathing zone air samples of offshore cleanup workers taken during the six months following the incident (made publicly available by British Petroleum). The measurements indicate that 99% of the measurements taken prior to capping the well were 32-, 510-, 360-, and 77-fold lower than the U.S. Occupational Safety and Health Administration's Permissible Exposure Limits (PELs) for BTEX, respectively. BTEX measurements did not decrease appreciably during the three months after the well was capped. Moreover, the magnitudes of these data were similar to measurements from ships not involved in oil slick remediation, suggesting that the BTEX measurements were primarily due to engine exhaust rather than the oil slick. To supplement the data analysis, two modeling approaches were employed to estimate airborne BTEX concentrations under a variety of conditions (e.g., oil slick thickness, wind velocity). The modeling results corroborated that BTEX concentrations from the oil were well below PELs and that the oil was not the primary contributor to the measured BTEX. PMID- 21797247 TI - Total and inorganic arsenic in marketed food and associated health risks for the Catalan (Spain) population. AB - Inorganic arsenic (iAs) is considered to be a human carcinogen. In this paper, total (As) and iAs contents of 215 food products and drinks (i.e., seafood, fruits and vegetables, meat products, oils and fats, rice and rice products, seasonings, and alcoholic drinks) marketed in Catalonia (Spain) were quantified by inductively coupled plasma-mass spectrometry. The analytical method described was used for different food products, obtaining feasible results without the need to couple LC-ICP-MS for iAs. Daily As and iAs intakes for the average adult Catalan consumer were estimated at 354 and 6.1 MUg/day/person, respectively, using consumption data from the Catalan Nutrition Survey (ENCAT). The highest As content was found in seafood, contributing 96% of dietary As intake, whereas rice presented the highest iAs values, corresponding to 67% of dietary iAs intake. As cooking process may affect iAs content, boiled rice was evaluated, showing an iAs reduction (up to 86%) when using higher water volumes (30:1 water/rice ratio) than those used in previous studies. This iAs exposure was slightly below the exposure risk range stated by the European Food Safety Authority (0.3-8 MUg/kg of body weight/day), although the possibility of a risk to the population with high rice consumption cannot be excluded. PMID- 21797248 TI - Sequence-specific self-stitching motif of short single-stranded DNA on a single walled carbon nanotube. AB - The DNA-single-walled carbon nanotube (SWCNT) hybrid molecule has attracted significant attention recently for its ability to disperse and sort SWCNTs according to their chirality. Key for utilizing their unique properties is an understanding of the structure of DNA adsorbed on the SWCNT surface, which we study here using molecular simulations. Using replica exchange molecular dynamics (REMD), we explore equilibrium structures formed by single strands of 12-mer oligonucleotides, of varying sequence, adsorbed on a (6,5)-SWCNT. We find a consistent motif in which the DNA strand forms a right-handed helical wrap around the SWCNT, stabilized by "stitches" (hydrogen bonding between distant bases) to itself. Variability among equilibrium populations of DNA self-stitched structures was observed and shown to be directly influenced by DNA sequence and composition. Competition between conformational entropy and hydrogen bonding between bases is predicted to be responsible for the formation of random versus stitched configurations. PMID- 21797249 TI - Nanoscale organization in aqueous dicationic ionic liquid solutions. AB - Coarse-grained molecular dynamics simulations have been performed on aqueous solutions of the gemini dicationic ionic liquid 1,5-bis(3-decylimidazolium-1-yl) pentane bromide at room temperature to study the structure and organization in the solution. Several trajectories corresponding to different concentrations of the ionic liquid (IL) in the solution were generated for about a microsecond. The 40% (w/w) aqueous mixture evolves to a hexagonal structure starting from a random distribution of ions. Spontaneous aggregation of cations was observed in solutions at lower concentrations. Unlike the monocationic ILs, which form spherical aggregates, the aggregates observed in the dicationic IL solution displayed a near-hexagonal arrangement of the hydrophobic cores that were connected to each other by hydrophilic head groups. Anions were found to be present close to the polar head groups. The formation of the interlinked aggregates from a random distribution and the organization at the vapor-liquid interface are also discussed. PMID- 21797250 TI - Integrated NMR and computational study of push-pull NLO probes: interplay of solvent and structural effects. AB - In this study we combined QM calculations and NMR measurements to understand at a detailed level the complex interplay of structural/electronic properties with the effects of the solvent in the NLO activity of push-pull systems, quantified in terms of variations of the static hyperpolarizability. Different parameters (bond lengths and bond length alternation, vibrational frequencies, electronic charge distribution) are introduced and tested to rationalize both the solvent sensitivity of three molecular systems (namely, p-nitroaniline, ethyl 4-ammino benzoate, and 5-nitro-1H-indole) and the differences among them. This analysis has finally allowed us to establish a clear correlation between the charge transfer behavior of the systems, their NLO properties, and NMR parameters also validating simplified but effective chemical analyses based on resonance limit forms. PMID- 21797251 TI - PAs3S3 cage as a new building block in copper halide coordination polymers. AB - First examples of the coordination chemistry of the PAs(3)S(3) cage were obtained from solutions of PAs(3)S(3).W(CO)(5) (1) in CH(2)Cl(2) or CH(2)Cl(2)/toluene and CuX (X = Cl, Br, I) in MeCN through interdiffusion techniques. Crystals of [Cu(PAs(3)S(3))(4)]X (2, X = Cl; 3, X = Br) and [(Cu(2)I)(PAs(3)S(3))(3)]I (4) were obtained and characterized by Raman spectroscopy (2) and single-crystal X ray crystallography. The solid-state structures reveal an unexpected coordination versatility of the PAs(3)S(3) ligand: apical phosphorus and bridging sulfur atoms interact with copper, while As...X interactions determine the dimensionality of the frameworks. The structures of 2 and 3 contain tetrahedral [(PAs(3)S(3))(4)Cu](+) cations as secondary building units (SBUs), which are arranged by interactions with Cl(-) or Br(-) anions into two- and three dimensional substructures. These interpenetrate into a (2D + 3D) polycatenane. Compound 4 is built up by a one-dimensional [(Cu(2)I)(PAs(3)S(3))(3)](n)(n+) ribbon with PAs(3)S(3) cages as P,S-linkers. The As atoms of the exo PAs(3)S(4) linkers interact with iodide counterions (3.35 < d(As-I) < 3.59 A). The resulting two-dimensional layer is organized by weak As...I interactions (d(As-I = 3.87 A) into a 3D network. PMID- 21797252 TI - Identifying vulnerable populations through an examination of the association between multipollutant profiles and poverty. AB - Recently, concerns have centered on how to expand knowledge on the limited science related to the cumulative impact of multiple air pollution exposures and the potential vulnerability of poor communities to their toxic effects. The highly intercorrelated nature of exposures makes application of standard regression-based methods to these questions problematic due to well-known issues related to multicollinearity. Our paper addresses these problems by using, as its basic unit of inference, a profile consisting of a pattern of exposure values. These profiles are grouped into clusters and associated with a deprivation outcome. Specifically, we examine how profiles of NO(2)-, PM(2.5)-, and diesel- (road and off-road) based exposures are associated with the number of individuals living under poverty in census tracts (CT's) in Los Angeles County. Results indicate that higher levels of pollutants are generally associated with higher poverty counts, though the association is complex and nonlinear. Our approach is set in the Bayesian framework, and as such the entire model can be fit as a unit using modern Bayesian multilevel modeling techniques via the freely available WinBUGS software package, (1) though we have used custom-written C++ code (validated with WinBUGS) to improve computational speed. The modeling approach proposed thus goes beyond single-pollutant models in that it allows us to determine the association between entire multipollutant profiles of exposures with poverty levels in small geographic areas in Los Angeles County. PMID- 21797253 TI - Selective targeting of disease-relevant protein binding domains by O phosphorylated natural product derivatives. AB - Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains. PMID- 21797254 TI - Homogeneous and heterogeneous tertiary structure ensembles of amyloid-beta peptides. AB - The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides. Amyloid-beta 1 42 (Abeta42), the primary peptide associated with Alzheimer's disease, and fragments such as Abeta21-30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of Abeta42 and Abeta21-30 from the perspective of their classification as IDPs. Unlike the Abeta21-30 fragment that conforms to expectations of an IDP that is primarily extended, we find that Abeta42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble. PMID- 21797255 TI - Total synthesis of the natural product (+/-)-dibromophakellin and analogues. AB - (+/-)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond. PMID- 21797256 TI - Bioorthogonal chemistry: applications in activity-based protein profiling. AB - The close interaction between organic chemistry and biology goes back to the late 18th century, when the modern natural sciences began to take shape. After synthetic organic chemistry arose as a discipline, organic chemists almost immediately began to pursue the synthesis of naturally occurring compounds, thereby contributing to the understanding of their functions in biological processes. Research in those days was often remarkably interdisciplinary; in fact, it constituted chemical biology research before the phrase even existed. For example, histological dyes, both of an organic and inorganic nature, were developed and applied by independent researchers (Gram and Golgi) with the aim of visualizing cellular substructures (the bacterial cell wall and the Golgi apparatus). Over the years, as knowledge within the various fields of the natural sciences deepened, research disciplines drifted apart, becoming rather monodisciplinary. In these years, broadly ranging from the end of World War II to about the 1980s, organic chemistry continued to impact life sciences research, but contributions were of a more indirect nature. As an example, the development of the polymerase chain reaction, from which molecular biology and genetics research have greatly profited, was partly predicated on the availability of synthetic oligonucleotides. These molecules first became available in the late 1960s, the result of organic chemists pursuing the synthesis of DNA oligomers primarily because of the synthetic challenges involved. Today, academic natural sciences research is again becoming more interdisciplinary, and sometimes even multidisciplinary. What was termed "chemical biology" by Stuart Schreiber at the end of the last century can be roughly described as the use of intellectually chemical approaches to shed light on processes that are fundamentally rooted in biology. Chemical tools and techniques that are developed for biological studies in the exciting and rapidly evolving field of chemical biology research include contributions from many areas of the multifaceted discipline of chemistry, and particularly from organic chemistry. Researchers apply knowledge inherent to organic chemistry, such as reactivity and selectivity, to the manipulation of specific biomolecules in biological samples (cell extracts, living cells, and sometimes even animal models) to gain insight into the biological phenomena in which these molecules participate. In this Account, we highlight some of the recent developments in chemical biology research driven by organic chemistry, with a focus on bioorthogonal chemistry in relation to activity-based protein profiling. The rigorous demands of bioorthogonality have not yet been realized in a truly bioorthogonal reagent pair, but remarkable progress has afforded a range of tangible contributions to chemical biology research. Activity-based protein profiling, which aims to obtain information on the workings of a protein (or protein family) within the larger context of the full biological system, has in particular benefited from these advances. Both activity-based protein profiling and bioorthogonal chemistry have been around for approximately 15 years, and about 8 years ago the two fields very profitably intersected. We expect that each discipline, both separately and in concert, will continue to make important contributions to chemical biology research. PMID- 21797257 TI - Stability in the composition equivalence of grain from insect-protected maize and seed from glyphosate-tolerant soybean to conventional counterparts over multiple seasons, locations, and breeding germplasms. AB - Insect-protected maize MON 810 and Roundup Ready soybean 40-3-2 represent major milestones in the adoption of genetically modified (GM) crops to enhance agricultural productivity. This study provides an assessment of the compositional stability of these products over multiple seasons, multiple germplasms, and diverse geographies encompassing North, Central, and South America and Europe. The compositional assessment evaluated levels of proximates in MON 810 and proximates, antinutrients, and isoflavones in 40-3-2. The means and range values for component levels in the GM crops and their conventional comparators were consistently similar to each other within each corresponding year from 2000 to 2009. To our knowledge, this study represents the first meta-analysis of comparative composition assessments of GM products. This approach, combined with graphical approaches, provided an effective summary of the overall data set and confirmed the continued compositional equivalence of these important crops to their conventional counterparts over time. PMID- 21797258 TI - Dansyl labeling to modulate the relative affinity of bile acids for the binding sites of human serum albumin. AB - Binding of natural bile acids to human serum albumin (HSA) is an important step in enterohepatic circulation and provides a measure of liver function. In this article, we report on the use of four dansyl (Dns) derivatives of cholic acid (ChA) to demonstrate a regiodifferentiation in their relative affinity for the two binding sites of HSA. Using both steady-state and time-resolved fluorescence, formation of Dns-ChA@HSA complexes was confirmed; the corresponding binding constants were determined, and their distribution between bulk solution and HSA microenvironment was estimated. By means of energy transfer from Trp to the Dns moiety, donor-acceptor distances were estimated (21-25 A) and found to be compatible with both site 1 and site 2 occupancies. Nevertheless, titration using warfarin and ibuprofen as specific displacement probes clearly indicated that 3alpha- and 3beta-Dns-ChA bind to HSA at site 2, whereas their C-7 regioisomers bind to HSA at site 1. Furthermore, the C-3-labeled compounds are displaced by lithocholic acid, whereas they are insensitive to ChA, confirming the assumption that the former binds to HSA at site 2. Thus, Dns labeling provides a useful tool to modulate the relative affinity of ChA to the major binding sites of HSA and, in combination with other fluorescent ChA analogs, to mimic the binding behavior of natural bile acids. PMID- 21797259 TI - Molecular basis of recognition of antibacterial porphyrins by heme-transporter IsdH-NEAT3 of Staphylococcus aureus. AB - Antibiotic resistance is increasingly seen as a serious problem that threatens public health and erodes our capacity to effectively combat disease. So-called non-iron metalloporhyrins have shown promising antibacterial properties against a number of pathogenic bacteria including Staphylococcus aureus. However, little is known about the molecular mechanism(s) of action of these compounds and in particular how they reach the interior of the bacterial cells. A popular hypothesis indicates that non-iron metalloporphyrins infiltrate into bacterial cells like a "Trojan horse" using heme transport systems. Iron-regulated surface determinant (Isd) is the best characterized heme transport system of S. aureus. Herein we studied the molecular mechanism by which the extracellular heme receptor IsdH-NEAT3 of Isd recognizes antimicrobial metalloporphyrins. We found that potent antibacterial porphyrins Ga(III)-protoporphyrin IX (PPIX) and Mn(III) PPIX closely mimicked the properties of the natural ligand heme, namely (i) stable binding to IsdH-NEAT3 with comparable affinities for the receptor, (ii) nearly undistinghuishable three-dimensional structure when complexed with IsdH NEAT3, and (iii) similar transfer properties to a second receptor IsdA. On the contrary, weaker antibacterial porphyrins Mg(II)-PPIX, Zn(II)-PPIX, and Cu(II) PPIX were not captured effectively by IsdH-NEAT3 under our experimental conditions and displayed lower affinities. Moreover, reduction of Fe(III)-PPIX to Fe(II)-PPIX with dithionite abrogated stable binding to receptor. These data revealed a clear connection between oxidation state of metal and effective attachment to IsdH-NEAT3. Also, the strong correlation between binding affinity and reported antimicrobial potency suggested that the Isd system may be used by these antibacterial compounds to gain access to the interior of the cells. We hope these results will increase our understanding of Isd system of S. aureus and highlight its biomedical potential to deliver new and more efficient antibacterial treatments. PMID- 21797260 TI - Proteins interacting with monoamine transporters: current state and future challenges. AB - Plasma membrane and vesicular transporters for the biogenic amines, dopamine, norepinephrine, and serotonin, represent a group of proteins that play a crucial role in the regulation of neurotransmission. Clinically, mono amine transporters are the primary targets for the actions of many therapeutic agents used to treat mood disorders, as well as the site of action for highly addictive psychostimulants such as cocaine, amphetamine, methamphetamine, and 3,4 methylenedioxymethamphetamine. Over the past decade, the use of approaches such as yeast two-hybrid and proteomics has identified a multitude of transporter interacting proteins, suggesting that the function and regulation of these transporters are more complex than previously anticipated. With the increasing number of interacting proteins, the rules dictating transporter synthesis, assembly, targeting, trafficking, and function are beginning to be deciphered. Although many of these protein interactions have yet to be fully characterized, current knowledge is beginning to shed light on novel transporter mechanisms involved in monoamine homeostasis, the molecular actions of psychostimulants, and potential disease mechanisms. While future studies resolving the spatial and temporal resolution of these, and yet unknown, interactions will be needed, the realization that monoamine transporters do not work alone opens the path to a plethora of possible pharmacological interventions. PMID- 21797261 TI - Rh-doped SrTiO3 photocatalyst electrode showing cathodic photocurrent for water splitting under visible-light irradiation. AB - A Rh-doped SrTiO(3) (SrTiO(3):Rh) photocatalyst electrode that was readily prepared by pasting SrTiO(3):Rh powder onto a transparent indium tin oxide electrode gave a cathodic photocurrent under visible-light irradiation (lambda > 420 nm), indicating that the SrTiO(3):Rh photocatalyst electrode possessed p-type semiconductor character. The cathodic photocurrent increased with an increase in the amount of doped Rh up to 7 atom %. The incident-photon-to-current efficiency at 420 nm was 0.18% under an applied potential of -0.7 V vs Ag/AgCl for the SrTiO(3):Rh(7 atom %) photocatalyst electrode. The photocurrent was confirmed to be due to water splitting by analyzing the evolved H(2) and O(2). The water splitting proceeded with the application of an external bias smaller than 1.23 V versus a Pt counter electrode under visible-light irradiation and also using a solar simulator, suggesting that solar energy conversion should be possible with the present photoelectrochemical water splitting. PMID- 21797262 TI - Quantitative risk-based approach for improving water quality management in mining. AB - The potential environmental threats posed by freshwater withdrawal and mine water discharge are some of the main drivers for the mining industry to improve water management. The use of multiple sources of water supply and introducing water reuse into the mine site water system have been part of the operating philosophies employed by the mining industry to realize these improvements. However, a barrier to implementation of such good water management practices is concomitant water quality variation and the resulting impacts on the efficiency of mineral separation processes, and an increased environmental consequence of noncompliant discharge events. There is an increasing appreciation that conservative water management practices, production efficiency, and environmental consequences are intimately linked through the site water system. It is therefore essential to consider water management decisions and their impacts as an integrated system as opposed to dealing with each impact separately. This paper proposes an approach that could assist mine sites to manage water quality issues in a systematic manner at the system level. This approach can quantitatively forecast the risk related with water quality and evaluate the effectiveness of management strategies in mitigating the risk by quantifying implications for production and hence economic viability. PMID- 21797263 TI - Redox trends in terpyridine nickel complexes. AB - A synthesis has been developed that allows the isolation of four-coordinate [(tpy)Ni-Br] (1, tpy = terpyridine) in high yield. Complex 1 has been structurally characterized, and the X-ray data reveal a square-planar geometry, unlike the known [(tpy')Ni-I] (tpy' = 4,4',4''-tri-tert-butyl-terpyridine) but similar to [(tpy)Ni-CH(3)]. In the solid-state, EPR spectroscopy indicates, however, that unlike [(tpy)Ni-CH(3)], the electronic structure of 1 is a metal centered, not a ligand-centered radical. Density functional theory (DFT) analyses support this assignment. The preparation of 1 also facilitated the analysis of the redox potentials of a series of terpyridine nickel derivatives. It was found that the overall ligand sphere (one vs two coordinated terpyridine ligands) plays more of a role in determining the redox potentials of these derivatives than do the formal oxidation states of the nickel ions in the solution phase. PMID- 21797264 TI - A model of calcium activation of the cardiac thin filament. AB - The cardiac thin filament regulates actomyosin interactions through calcium dependent alterations in the dynamics of cardiac troponin and tropomyosin. Over the past several decades, many details of the structure and function of the cardiac thin filament and its components have been elucidated. We propose a dynamic, complete model of the thin filament that encompasses known structures of cardiac troponin, tropomyosin, and actin and show that it is able to capture key experimental findings. By performing molecular dynamics simulations under two conditions, one with calcium bound and the other without calcium bound to site II of cardiac troponin C (cTnC), we found that subtle changes in structure and protein contacts within cardiac troponin resulted in sweeping changes throughout the complex that alter tropomyosin (Tm) dynamics and cardiac troponin--actin interactions. Significant calcium-dependent changes in dynamics occur throughout the cardiac troponin complex, resulting from the combination of the following: structural changes in the N-lobe of cTnC at and adjacent to sites I and II and the link between them; secondary structural changes of the cardiac troponin I (cTnI) switch peptide, of the mobile domain, and in the vicinity of residue 25 of the N-terminus; secondary structural changes in the cardiac troponin T (cTnT) linker and Tm-binding regions; and small changes in cTnC-cTnI and cTnT-Tm contacts. As a result of these changes, we observe large changes in the dynamics of the following regions: the N-lobe of cTnC, the mobile domain of cTnI, the I-T arm, the cTnT linker, and overlapping Tm. Our model demonstrates a comprehensive mechanism for calcium activation of the cardiac thin filament consistent with previous, independent experimental findings. This model provides a valuable tool for research into the normal physiology of cardiac myofilaments and a template for studying cardiac thin filament mutations that cause human cardiomyopathies. PMID- 21797265 TI - Chiral (acyclic diaminocarbene)gold(I)-catalyzed dynamic kinetic asymmetric transformation of propargyl esters. AB - A highly enantioselective transformation catalyzed by chiral (acyclic diaminocarbene)gold(I) complexes is reported. The enantioselective synthesis of 2 substituted chromenyl pivalates from racemic phenol-substituted propargyl pivalates was developed. Rearrangement of the substrates in the presence of cationic gold gave allene intermediates, whose cyclization resulted in formation of enantioenriched product through a dynamic kinetic asymmetric transformation. PMID- 21797266 TI - Direct elucidation of disulfide bond partners using ultraviolet photodissociation mass spectrometry. AB - Disulfide bonds stabilize the tertiary and quaternary structure of proteins. Identifying the correct disulfide bond pairs can be extremely useful to understand the nature of a protein. However identifying correct disulfide linkages remains a challenge for many proteins. We report the use of ultraviolet photodissociation (UVPD) at 266 nm to selectively cleave disulfide bonds in the gas phase, while leaving all other bonds intact. This methodology can be used to identify disulfide bonded pairs in complex systems with multiple disulfide bond partners. We have explored UVPD chemistry on pairs of model peptides with one disulfide bond to evaluate the importance of various sequence and structural effects. In addition, online experiments were performed on whole protein digests. Bond selective UVPD was able to correctly identify and characterize all known disulfide bonded pairs. The method also proved sufficiently sensitive to identify and characterize several non-native disulfide-bound peptide pairs which were present in trace amounts. Photodissociation at 266 nm can be a valuable tool for disulfide bond identification and pair assignment in high-throughput proteomics studies. PMID- 21797267 TI - Magnetotransport properties of quasi-free-standing epitaxial graphene bilayer on SiC: evidence for Bernal stacking. AB - We investigate the magnetotransport properties of quasi-free-standing epitaxial graphene bilayer on SiC, grown by atmospheric pressure graphitization in Ar, followed by H(2) intercalation. At the charge neutrality point, the longitudinal resistance shows an insulating behavior, which follows a temperature dependence consistent with variable range hopping transport in a gapped state. In a perpendicular magnetic field, we observe quantum Hall states (QHSs) both at filling factors (nu) multiples of four (nu = 4, 8, 12), as well as broken valley symmetry QHSs at nu = 0 and nu = 6. These results unambiguously show that the quasi-free-standing graphene bilayer grown on the Si-face of SiC exhibits Bernal stacking. PMID- 21797268 TI - Stereochemistry of transmetalation of alkylboranes in nickel-catalyzed alkyl alkyl cross-coupling reactions. AB - Deuterium-labeled alkylborane reagents 2a and 2b were prepared and subjected to cross-coupling reactions in the presence of a nickel catalyst. NMR analysis of the products indicates that transmetalation from boron to nickel proceeds with retention of configuration. These results demonstrate that alkylnickel intermediates are configurationally stable under Suzuki cross-coupling conditions. PMID- 21797269 TI - A domino Michael/Dieckmann process as an entry to alpha-(hydroxymethyl)glutamic acid. AB - A domino process that involves a Michael-type addition followed by a Dieckmann reaction mediated by the participation of the cyclic carbamate group is the key step in the synthesis of both enantiomers of alpha-(hydroxymethyl)glutamic acid (HMG). PMID- 21797270 TI - beta-(Trifluoromethyl)vinyl sulfonium salts: preparation and reactions with active methylene and methenyl compounds. AB - Two trifluoromethyl-substituted building blocks beta-(trifluoromethyl)vinyl sulfonium salts 1 and 2 were developed. Reactions of beta-(trifluoromethyl)vinyl sulfonium salt 1 with active methylene compounds containing electron-withdrawing groups using DBU as the base in DMSO occurred to give trifluoromethyl-substituted cyclopropane derivatives 7 as the major products. In contrast, reactions of beta (trifluoromethyl)vinyl sulfonium salt 2 with active methylene compounds occurred with the migration of one of the electron-withdrawing groups to give the products 8 as the major products when NaH was used as the base in DMSO. Moreover, when NaH was used as base in THF/CH(2)Cl(2) at -78 degrees C, reaction of beta (trifluoromethyl)vinyl sulfonium salt 1 gave trifluoromethyl-substituted 2,3 dihydrofuran derivatives 9 as the major products. A working mechanism was proposed to explain the different behaviors of the beta-(trifluoromethyl)vinyl sulfonium salts 1 or 2 with active methylene compounds under these different conditions. PMID- 21797271 TI - Comparison of beta-sheets of capped polyalanine with those of the tau-amyloid structures VQIVYK and VQIINK. A density functional theory study. AB - We present ONIOM calculations using B3LYP/d95(d,p) as the high and AM1 as the low level on parallel beta-sheets containing from two to ten strands of Ac-VQIVYK NHMe and Ac-VQIINK-NHMe, as well as both parallel and antiparallel Ac-AAAAAA NHMe. We find that the first two sequences form more stable sheets due to the additional H-bonding between the Q's in the side chains of both and the N's in the side chain of Ac-VQIINK-NHMe. However, the H-bonds in the amyloid chains are significantly weakened by attractive strain, which prevents all the interstrand H bonds from achieving their optimal geometries simultaneously and requires high distortion energies for the individual strands in the sheets. The antiparallel Ac AAAAAA-NHMe's are generally more stable and more cooperative than the parallel sheets, principally due to the higher distortion energies of the latter. PMID- 21797272 TI - On orthogonal and selective activation of glycosyl thioimidates and thioglycosides: application to oligosaccharide assembly. AB - Discrimination among S-thiazolinyl (STaz), S-benzoxazolyl (SBox), and S-ethyl anomeric leaving groups was achieved by fine-tuning activation conditions. Preferential glycosidation of a certain leaving group is determined neither by the strength of the activating reagent nor by the stability of the leaving group itself; instead, the type of activation plays the key role. The activation conditions established herein were applied to a sequential five-step synthesis of a hexasaccharide using six monosaccharide building blocks equipped with six different leaving groups. PMID- 21797273 TI - Adsorption behavior of hydrophobin and hydrophobin/surfactant mixtures at the solid-solution interface. AB - The adsorption of surface-active protein hydrophobin, HFBII, and HFBII/surfactant mixtures at the solid-solution interface has been studied by neutron reflectivity, NR. At the hydrophilic silicon surface, HFBII adsorbs reversibly in the form of a bilayer at the interface. HFBII adsorption dominates the coadsorption of HFBII with cationic and anionic surfactants hexadecyltrimethyl ammonium bromide, CTAB, and sodium dodecyl sulfate, SDS, at concentrations below the critical micellar concentration, cmc, of conventional cosurfactants. For surfactant concentrations above the cmc, HFBII/surfactant solution complex formation dominates and there is little HFBII adsorption. Above the cmc, CTAB replaces HFBII at the interface, but for SDS, there is no affinity for the anionic silicon surface hence there is no resultant adsorption. HFBII adsorbs onto a hydrophobic surface (established by an octadecyl trimethyl silane, OTS, layer on silicon) irreversibly as a monolayer, similar to what is observed at the air-water interface but with a different orientation at the interface. Below the cmc, SDS and CTAB have little impact upon the adsorbed layer of HFBII. For concentrations above the cmc, conventional surfactants (CTAB and SDS) displace most of the HFBII at the interface. For nonionic surfactant C(12)E(6), the pattern of adsorption is slightly different, and although some coadsorption at the interface takes place, C(12)E(6) has little impact on the HFBII adsorption. PMID- 21797274 TI - Catalytic enantioselective aziridoarylation of aryl cinnamyl ethers toward synthesis of trans-3-amino-4-arylchromans. AB - Catalytic enantioselective one-pot aziridoarylation reaction of aryl cinnamyl ethers has been demonstrated in detail. Combination of suitable copper catalyst and chiral bis-oxazoline ligand was found to be very efficient for asymmetric aziridination followed by intramolecular arylation (Friedel-Crafts) reaction to provide a general and direct method for the synthesis of trans-3-amino-4 arylchromans with high regio-, diastereo- (dr > 99:1), and enantioselectivity (up to 95% ee) with moderate yield. trans-3-Amino-4-arylchroman is an advanced intermediate for the synthesis of chromenoisoquinoline compounds such as doxanthrine, a potent and selective full agonist for the dopamine-D(1) receptor. PMID- 21797275 TI - Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis. AB - Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy. PMID- 21797276 TI - Cloning of a novel L-amino acid oxidase from Trichoderma harzianum ETS 323 and bioactivity analysis of overexpressed L-amino acid oxidase. AB - L-amino acid oxidases (L-AAOs) have been isolated from many organisms, such as snake, and are known to have antibacterial activity. To the best of the authors' knowledge, this is the first report of the cloning of cDNA encoding a novel Trichoderma harzianum ETS 323 L-amino acid oxidase (Th-L-AAO). The protein was overexpressed in Escherichia coli and purified to homogeneity. Comparisons of its deduced amino acid sequence with the sequence of other L-AAOs revealed the similarity to be between 9 and 24%. The molecular mass of the purified protein was 52 kDa, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme substrate specificity was highest for L phenylalanine, and its optimal pH and temperature for activity were 7 and 40 degrees C, respectively; exogenous metal ions had no significant effect on activity. Circular dichroism spectroscopy indicated that the secondary structure of Th-L-AAO is composed of 17% alpha-helices, 28% beta-sheets, and 55% random coils. The bacterially expressed Th-L-AAO also mediated antibacterial activity against both gram-positive and gram-negative food spoilage microorganisms. Furthermore, a three-dimensional protein structure was created to provide more information about the structural composition of Th-L-AAO, suggesting that the N terminal sequence of Th-L-AAO may have contributed to the antibacterial activity of this protein. PMID- 21797277 TI - Ex situ treatment of hydrocarbon-contaminated soil using biosurfactants from Lactobacillus pentosus. AB - The utilization of biosurfactants for the bioremediation of contaminated soil is not yet well established, because of the high production cost of biosurfactants. Consequently, it is interesting to look for new biosurfactants that can be produced at a large scale, and it can be employed for the bioremediation of contaminated sites. In this work, biosurfactants from Lactobacillus pentosus growing in hemicellulosic sugars solutions, with a similar composition of sugars found in trimming vine shoot hydrolysates, were employed in the bioremediation of soil contaminated with octane. It was observed that the presence of biosurfactant from L. pentosus accelerated the biodegradation of octane in soil. After 15 days of treatment, biosurfactants from L. pentosus reduced the concentration of octane in the soil to 58.6 and 62.8%, for soil charged with 700 and 70,000 mg/kg of hydrocarbon, respectively, whereas after 30 days of treatment, 76% of octane in soil was biodegraded in both cases. In the absence of biosurfactant and after 15 days of incubation, only 1.2 and 24% of octane was biodegraded in soil charged with 700 and 70,000 mg/kg of octane, respectively. Thus, the use of biosurfactants from L. pentosus, as part of a well-designed bioremediation process, can provide mechanisms to mobilize the target contaminants from the soil surface to make them more available to the microbial population. PMID- 21797278 TI - Inhibitory effects of muscadine anthocyanins on alpha-glucosidase and pancreatic lipase activities. AB - Inhibitory effects of the Noble muscadine grape extracts and the representative phytochemicals for anthocyanins (i.e., cyanidin and cyanidin-3,5-diglucoside) on two enzymes, that is, alpha-glucosidase and pancreatic lipase, were investigated regarding their antidiabetic activities. The study demonstrated that the anthocyanin extracts and the selected chemicals obeyed the competitive mode against the enzymes. The methanolic extracts of whole fruit and skin of the muscadine showed inhibitory activities against the alpha-glucosidase with their IC(50) values at 1.50 and 2.73 mg/mL, and those against the lipase at 16.90 and 11.15 mg/mL, respectively, which indicated that the muscadine extracts possessed strong antidiabetic activities. Particularly, the ethyl acetate (EtoAc) extract and the butanol (BuOH) extract exhibited much higher inhibitory activities against both enzymes than the CHCl(3) and water extracts, while the majority of anthocyanins existed in the BuOH fractions. Moreover, cyanidin exhibited a much stronger antidiabetic activity than cyanidin-3,5-diglucoside, suggesting that anthocyanins may have higher inhibitory activities after being digested. Further chromatographic analysis by high-performance liquid chromatography-mass spectrometry identified five individual anthocyanins, including cyanidin, delphinidin, petunidin, peonidin, and malvidin glycosides. PMID- 21797279 TI - A new synthetic approach toward bacterial transglycosylase substrates, Lipid II and Lipid IV. AB - A new synthetic approach toward the bacterial transglycosylase substrates, Lipid II (1) and Lipid IV (2), is described. The key disaccharide was synthesized using the concept of relative reactivity value (RRV) and elaborated to Lipid II and Lipid IV by conjugation with the appropriate oligopeptides and pyrophosphate lipids. Interestingly, the results from our HPLC-based functional TGase assay suggested Lipid IV has a higher affinity for the enzyme than Lipid II. PMID- 21797280 TI - Selective cytotoxicity of oxysterols through structural modulation on rings A and B. Synthesis, in vitro evaluation, and SAR. AB - Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A and B was studied. Oxygen functionalities on ring B, such as oxo, oxime, acetamide, acetate, and alkoxy, were evaluated. Most oxysterols were cytotoxic in the low micromolar range, with emphasis to the tetrols 14 and 34, the 6beta methoxy and acetoxy derivatives 21 and 45, and the oxime 28. In general, the oxysterols were more toxic to cancer cells and a set of compounds (9, 14, 21, 28, 45) with very high selectivity was identified. The cytotoxicity of 3beta-acetates was lower than that of the parent alcohols, although incubation for a longer period rendered them equally cytotoxic, pointing them as potential prodrugs of oxysterols. PMID- 21797281 TI - Host-guest interactions between a nonmicellized amphiphilic invertible polymer and insoluble cyclohexasilane in acetonitrile. AB - Host-guest interactions between cyclohexasilane (Si(6)H(12)) and amphiphilic invertible macromolecules based on PEG and sebacic acid in acetonitrile (neither a solvent for cyclohexasilane nor a support for the micellization of amphiphilic invertible macromolecules) have been investigated. Despite the extended conformation of the macromolecules and the absence of self-assembled polymeric domains, a macromolecular amphiphilicity itself contributes to localizing Si(6)H(12) by AIP and thus enables Lewis acid-base interactions between Si(6)H(12) and the AIP carbonyl groups. The obtained results demonstrate an interesting phenomenon in that insoluble Si(6)H(12) can be localized by AIP macromolecules in a medium that does not support the formation of polymeric domains. PMID- 21797282 TI - PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms. AB - The overall goal of this paper was to develop poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) of curcumin (CUR), named CUR-PLGA-NPs, and to study the effect and mechanisms enhancing the oral bioavailability of CUR. CUR-PLGA-NPs were prepared according to a solid-in-oil-in-water (s/o/w) solvent evaporation method and exhibited a smooth and spherical shape with diameters of about 200 nm. Characterization of CUR-PLGA-NPs showed CUR was successfully encapsulated on the PLGA polymer. The entrapment efficiency and loading rate of CUR were 91.96 and 5.75%, respectively. CUR-PLGA-NPs showed about 640-fold in water solubility relative to that of n-CUR. A sustained CUR release to a total of approximately 77% was discovered from CUR-PLGA-NPs in artificial intestinal juice, but only about 48% in artificial gastric juice. After oral administration of CUR-PLGA-NPs, the relative bioavailability was 5.6-fold and had a longer half-life compared with that of native curcumin. The results showed that the effect in improving oral bioavailability of CUR may be associated with improved water solubility, higher release rate in the intestinal juice, enhanced absorption by improved permeability, inhibition of P-glycoprotein (P-gp)-mediated efflux, and increased residence time in the intestinal cavity. Thus, encapsulating hydrophobic drugs on PLGA polymer is a promising method for sustained and controlled drug delivery with improved bioavailability of Biopharmaceutics Classification System (BCS) class IV, such as CUR. PMID- 21797283 TI - Simulation and experimental studies on plasma temperature, flow velocity, and injector diameter effects for an inductively coupled plasma. AB - An inductively coupled plasma (ICP) is analyzed by means of experiments and numerical simulation. Important plasma properties are analyzed, namely, the effective temperature inside the central channel and the mean flow velocity inside the plasma. Furthermore, the effect of torches with different injector diameters is studied by the model. The temperature inside the central channel is determined from the end-on collected line-to-background ratio in dependence of the injector gas flow rates. Within the limits of 3% deviation, the results of the simulation and the experiments are in good agreement in the range of flow rates relevant for the analysis of relatively large droplets, i.e., ~50 MUm. The deviation increases for higher gas flow rates but stays below 6% for all flow rates studied. The velocity of the gas inside the coil region was determined by side-on analyte emission measurements with single monodisperse droplet introduction and by the analysis of the injector gas path lines in the simulation. In the downstream region significantly higher velocities were found than in the upstream region in both the simulation and the experiment. The quantitative values show good agreement in the downstream region. In the upstream region, deviations were found in the absolute values which can be attributed to the flow conditions in that region and because the methods used for velocity determination are not fully consistent. Eddy structures are found in the simulated flow lines. These affect strongly the way taken by the path lines of the injector gas and they can explain the very long analytical signals found in the experiments at low flow rates. Simulations were performed for different injector diameters in order to find conditions where good analyte transport and optimum signals can be expected. The results clearly show the existence of a transition flow rate which marks the lower limit for effective analyte transport conditions through the plasma. A rule-of-thumb equation was extracted from the results from which the transition flow rate can be estimated for different injector diameters and different injector gas compositions. PMID- 21797284 TI - Direct C-N coupling of imidazoles and benzylic compounds via iron-catalyzed oxidative activation of C-H bonds. AB - Iron-catalyzed direct C-N bond formation between imidazoles and benzylic hydrocarbons is described. The reaction utilizes an inexpensive iron catalyst oxidant system that is suitable for the coupling of a range of benzylic C-H bonds with various imidazoles. PMID- 21797285 TI - New Monte Carlo simulation of adsorption of gases on surfaces and in pores: a concept of multibins. AB - We introduce a new and effective Monte Carlo scheme to simulate adsorption on surfaces and in pores. The simulation box is divided into bins to account for the nonuniform distribution of particle density, and the new scheme takes into account the state of each bin and allows the maximum displacement length to vary with the bin density. The probability of acceptance of insertion and deletion from a bin depends on the density of the fluid in that bin, rather than on the average density in the whole simulation box. In other words, our scheme is local. We apply this new scheme to a canonical ensemble and a grand canonical ensemble, and because it is based on exchange of particles between bins of different density, we refer to this new method as Multibin Canonical Monte Carlo (Mu-CMC) and Multibin Grand Canonical Monte Carlo (Mu-GCMC). The process of particle exchange within the canonical ensemble makes the new scheme much more efficient, compared to conventional canonical ensemble simulation. We apply the new scheme to a number of adsorption systems to illustrate its potential. PMID- 21797286 TI - A concise synthetic approach to the sorbicillactones: total synthesis of sorbicillactone A and 9-epi-sorbicillactone A. AB - A concise (12 step) total synthesis of sorbicillactone A and 9-epi sorbicillactone A is reported. Unlike typical routes to the sorbicillinoids, this strategy does not start from sorbicillin and allows for the production of the bicyclic core on a multigram scale. The intramolecular conjugate addition of a tethered malonate serves as an effective means of introducing the lactone ring and provides a synthetic handle for installing the amide nitrogen. PMID- 21797287 TI - Mycobacterium chelonae infection due to black tattoo ink dilution. PMID- 21797288 TI - Does the market share of generic medicines influence the price level?: a European analysis. AB - BACKGROUND: After the expiry of patents for originator medicines, generic medicines can enter the market, and price competition may occur. This process generates savings to the healthcare payer and to patients, but knowledge about the factors affecting price competition in the pharmaceutical market following patent expiry is still limited. OBJECTIVE: This study aimed to investigate the relationship between the market share of generic medicines and the change of the medicine price level in European off-patent markets. METHODS: Data on medicine volumes and values for 35 active substances were purchased from IMS Health. Ex manufacturer prices were used, and the analysis was limited to medicines in immediate-release, oral, solid dosage forms. Countries included were Austria, Belgium, Denmark, Germany, France, Italy, the Netherlands, Spain, Sweden and the UK, which constitute a mix of countries with low and high generic medicines market shares. Data were available from June 2002 until March 2007. RESULTS: Market volume has risen in both high and low generic market share countries (+29.27% and +27.40%, respectively), but the cause of the rise is different for the two markets. In low generic market share countries, the rise was caused by the increased use of generic medicines, while in high market share countries, the rise was driven by the increased use of generic medicines and a shift of use from originator to generic medicines. Market value was substantially decreased in high generic market share countries (-26.6%), while the decrease in low generic market share countries was limited (-0.06%). In high generic market share countries, medicine prices dropped by -43.18% versus -21.56% in low market share countries. CONCLUSIONS: The extent to which price competition from generic medicines leads to price reductions appears to vary according to the market share of generic medicines. High generic market share countries have seen a larger decrease in medicine prices than low market share countries. PMID- 21797289 TI - Effective quantum Brownian dynamics in presence of a rapidly oscillating space dependent time-periodic field. AB - We explore the Brownian dynamics in the quantum regime (by investigating the quantum Langevin and Smoluchowski equations) in terms of an effective time independent Hamiltonian in the presence of a rapidly oscillating field. We achieve this by systematically expanding the time-dependent system-reservoir Hamiltonian in the inverse of driving frequency with a systematic time-scale separation and invoking a quantum gauge transformation within the framework of Floquet theorem. PMID- 21797290 TI - Equilibration of concentrated hard-sphere fluids. AB - We report a systematic molecular dynamics study of the isochoric equilibration of hard-sphere fluids in their metastable regime close to the glass transition. The thermalization process starts with the system prepared in a nonequilibrium state with the desired final volume fraction phi for which we can obtain a well-defined nonequilibrium static structure factor S(0)(k;phi). The evolution of the alpha relaxation time tau(alpha)(k) and long-time self-diffusion coefficient D(L) as a function of the evolution time t(w) is then monitored for an array of volume fractions. For a given waiting time the plot of tau(alpha)(k;phi,t(w)) as a function of phi exhibits two regimes corresponding to samples that have fully equilibrated within this waiting time [phi<=phi(c)(t(w))] and to samples for which equilibration is not yet complete [phi>=phi(c)(t(w))]. The crossover volume fraction phi(c)(t(w)) increases with t(w) but seems to saturate to a value phi(a)=phi(c)(t(w)->infinity)~0.582. We also find that the waiting time t(w)(eq)(phi) required to equilibrate a system grows faster than the corresponding equilibrium relaxation time, t(w)(eq)(phi)~0.27[tau(alpha)(eq)(k;phi)](1.43), and that both characteristic times increase strongly as phi approaches phi(a), thus suggesting that the measurement of equilibrium properties at and above phi(a) is experimentally impossible. PMID- 21797291 TI - Kinetic arrest, dynamical transitions, and activated relaxation in dense fluids of attractive nonspherical colloids. AB - The coupled translation-rotation activated dynamics in dense suspensions of attractive homogeneous and Janus uniaxial dicolloids are studied using microscopic statistical mechanical theory. Multiple kinetic arrest transitions and reentrant phenomena are predicted that are associated with fluid, gel, repulsive glass, attractive glass, plastic glass, and novel glass-gel states. The activated relaxation rate is a nonuniversal nonmonotonic function of attraction strength at high volume fractions due to the consequences of a change of the transient localization mechanism from caging to physical bonding. PMID- 21797292 TI - Effect of enantiomeric excess on the phase behavior of antiferroelectric liquid crystals. AB - Null transmission ellipsometry and resonant x-ray diffraction are employed to study the effect of enantiomeric excess (EE) on the phase behavior of antiferroelectric liquid crystal 10OTBBB1M7. Phase sequence, layer spacing, and pitch of the helical structures of the smectic-C(alpha)* and smectic-C* phases are studied as a function of temperature and EE. Upon reducing EE, a liquid-gas type critical point of the smectic-C(alpha)* to smectic-C* transition is observed, as well as the disappearance of the smectic-C(d4)* and the smectic C(d3)* phases. Results are analyzed in a mean-field model. PMID- 21797293 TI - Surface-induced reduction of twisting power in liquid-crystal films. AB - Null transmission ellipsometry was employed to study the temperature evolution of the helical structure of the smectic-C(alpha)* phase. Free-standing films with thickness ranging from 31 to more than 400 layers were prepared and studied. The experimental results show a reduced twisting power in thin films. A simple model was constructed to explain the results. Surface effects were found to be the key reason for this phenomenon. Our findings are consistent with the theoretical studies of helically ordered magnetic films. PMID- 21797294 TI - Robust network clocks: design of genetic oscillators as a complex combinatorial optimization problem. AB - Complex combinatorial optimization can be used to design network systems having desired dynamics and that are robust against structural perturbations. Here genetic networks exhibiting limit-cycle oscillations with prescribed periods and, furthermore, that are robust against the deletion of links and nodes or the application of noise are constructed. Large ensembles of robust genetic clocks with different periods could thus be obtained, and some of their statistical properties have been investigated. Similar methods can be used to design robust network oscillators of various origins. PMID- 21797295 TI - Hydrodynamics of a microhunter: a chemotactic scenario. AB - Inspired by biological chemotaxis along circular paths, we propose a hydrodynamic molecular scale hunter that can swim and can find its target. The system is essentially a stochastic low-Reynolds-number swimmer with the ability to move in two-dimensional space and to sense the local value of the chemical concentration emitted by a target. We show that, by adjusting the geometrical and dynamical variables of the swimmer, we can always achieve a swimmer that can navigate and can search for the region with a higher concentration of a chemical emitted by a source. PMID- 21797296 TI - Do athermal amorphous solids exist? AB - We study the elastic theory of amorphous solids made of particles with finite range interactions in the thermodynamic limit. For the elastic theory to exist, one requires all the elastic coefficients, linear and nonlinear, to attain a finite thermodynamic limit. We show that for such systems the existence of nonaffine mechanical responses results in anomalous fluctuations of all the nonlinear coefficients of the elastic theory. While the shear modulus exists, the first nonlinear coefficient B(2) has anomalous fluctuations and the second nonlinear coefficient B(3) and all the higher order coefficients (which are nonzero by symmetry) diverge in the thermodynamic limit. These results call into question the existence of elasticity (or solidity) of amorphous solids at finite strains, even at zero temperature. We discuss the physical meaning of these results and propose that in these systems elasticity can never be decoupled from plasticity: the nonlinear response must be very substantially plastic. PMID- 21797297 TI - Kinetics of ring formation. AB - We study reversible polymerization of rings. In this stochastic process, two monomers bond and, as a consequence, two disjoint rings may merge into a compound ring or a single ring may split into two fragment rings. This aggregation fragmentation process exhibits a percolation transition with a finite-ring phase in which all rings have microscopic length and a giant-ring phase where macroscopic rings account for a finite fraction of the entire mass. Interestingly, while the total mass of the giant rings is a deterministic quantity, their total number and their sizes are stochastic quantities. The size distribution of the macroscopic rings is universal, although the span of this distribution increases with time. Moreover, the average number of giant rings scales logarithmically with system size. We introduce a card-shuffling algorithm for efficient simulation of the ring formation process and we present numerical verification of the theoretical predictions. PMID- 21797298 TI - Effective-field-theory analysis of the three-dimensional random-field Ising model on isometric lattices. AB - An Ising model with quenched random magnetic fields is examined for single Gaussian, bimodal, and double-Gaussian random-field distributions by introducing an effective-field approximation that takes into account the correlations between different spins that emerge when expanding the identities. Random-field distribution shape dependencies of the phase diagrams and magnetization curves are investigated for simple cubic, body-centered-cubic, and face-centered-cubic lattices. The conditions for the occurrence of reentrant behavior and tricritical points on the system are also discussed in detail. PMID- 21797299 TI - Critical temperatures of the three- and four-state Potts models on the kagome lattice. AB - The value of the internal energy per spin is independent of the strip width for a certain class of spin systems on two-dimensional infinite strips. It is verified that the Ising model on the kagome lattice belongs to this class through an exact transfer-matrix calculation of the internal energy for the two smallest widths. More generally, one can suggest an upper bound for the critical coupling strength K(c)(q) for the q-state Potts model from exact calculations of the internal energy for the two smallest strip widths. Combining this with the corresponding calculation for the dual lattice and using an exact duality relation enables us to conjecture the critical coupling strengths for the three- and four-state Potts models on the kagome lattice. The values are K(c)(q=3)=1.0565094269290 and K(c)(q=4)=1.1493605872292, and the values can, in principle, be obtained to an arbitrary precision. We discuss the fact that these values are in the middle of earlier approximate results and furthermore differ from earlier conjectures for the exact values. PMID- 21797300 TI - First- and second-order wetting transitions in confined Ising films in the presence of nonmagnetic impurities: a Monte Carlo simulation study. AB - In this work, we present the results of a systematic exploration of the effect caused by the introduction of nonmagnetic impurities (or defects) on the stabilization of the interface between two magnetic domains of opposite magnetic orientation. Those defects are simulated as spin vacancies along the center of confined two-dimensional Ising films, which have competing magnetic fields acting on the confinement walls. The calculations are performed for different L*M film sizes and by using the standard Metropolis dynamics. In the absence of defects, the film is characterized by an interface running along the M direction, which is induced by the competing surface fields. That interface undergoes a localization delocalization transition that is the precursor of a true wetting transition taking place in the thermodynamic limit. When the density of defects is relatively low, our results show that the wetting phase transition is of second order, as in the absence of defects. On the other hand, when the density of nonmagnetic impurities is relatively high, a pinning effect of the interface gives rise to a first-order wetting phase transition. The observed transitions are characterized by measuring relevant properties, such as magnetization profiles, cumulants, magnetization fluctuations, etc., as a function of the density of defects. So, our main finding is that the presence of nonmagnetic impurities introduces a rich physical scenery, such as a line of second-order wetting transitions (observed for low density of defects) that merges into a first-order one just at a tricritical point. Precisely, these two latter findings are the major contributions of our study. PMID- 21797301 TI - Frequency adaptation in controlled stochastic resonance utilizing delayed feedback method: two-pole approximation for response function. AB - Stochastic resonance (SR) enhanced by time-delayed feedback control is studied. The system in the absence of control is described by a Langevin equation for a bistable system, and possesses a usual SR response. The control with the feedback loop, the delay time of which equals to one-half of the period (2pi/Omega) of the input signal, gives rise to a noise-induced oscillatory switching cycle between two states in the output time series, while its average frequency is just smaller than Omega in a small noise regime. As the noise intensity D approaches an appropriate level, the noise constructively works to adapt the frequency of the switching cycle to Omega, and this changes the dynamics into a state wherein the phase of the output signal is entrained to that of the input signal from its phase slipped state. The behavior is characterized by power loss of the external signal or response function. This paper deals with the response function based on a dichotomic model. A method of delay-coordinate series expansion, which reduces a non-Markovian transition probability flux to a series of memory fluxes on a discrete delay-coordinate system, is proposed. Its primitive implementation suggests that the method can be a potential tool for a systematic analysis of SR phenomenon with delayed feedback loop. We show that a D-dependent behavior of poles of a finite Laplace transform of the response function qualitatively characterizes the structure of the power loss, and we also show analytical results for the correlation function and the power spectral density. PMID- 21797302 TI - Forces exerted by a correlated fluid on embedded inclusions. AB - We investigate the forces exerted on embedded inclusions by a fluid medium with long-range correlations, described by an effective scalar field theory. Such forces are the basis for the medium-mediated Casimir-like force. To study these forces beyond thermal average, it is necessary to define them in each microstate of the medium. Two different definitions of these forces are currently used in the literature. We study the assumptions underlying them. We show that only the definition that uses the stress tensor of the medium gives the sought-after force exerted by the medium on an embedded inclusion. If a second inclusion is embedded in the medium, the thermal average of this force gives the usual Casimir-like force between the two inclusions. The other definition can be used in the different physical case of an object that interacts with the medium without being embedded in it. We show in a simple example that the two definitions yield different results for the variance of the Casimir-like force. PMID- 21797303 TI - Quantum Maxwell's demon in thermodynamic cycles. AB - We study the physical mechanism of Maxwell's demon (MD), which helps do extra work in thermodynamic cycles with the heat engine. This is exemplified with one molecule confined in an infinitely deep square potential with a movable solid wall. The MD is modeled as a two-level system (TLS) for measuring and controlling the motion of the molecule. The processes in the cycle are described in a quantum fashion. It is discovered that a MD with quantum coherence or one at a temperature lower than the molecule's heat bath can enhance the ability of the whole working substance, formed by the heat engine plus the MD, to do work outside. This observation reveals that the essential role of the MD is to drive the whole working substance off equilibrium, or equivalently, to work between two heat baths with different effective temperatures. The elaborate studies with this model explicitly reveal the effect of finite size off the classical limit or thermodynamic limit, which contradicts common sense on a Szilard heat engine (SHE). The quantum SHE's efficiency is evaluated in detail to prove the validity of the second law of thermodynamics. PMID- 21797304 TI - Analysis of excitability for the FitzHugh-Nagumo model via a stochastic sensitivity function technique. AB - We study excitability phenomena for the stochastically forced FitzHugh-Nagumo system modeling a neural activity. Noise-induced changes in the dynamics of this model can be explained by the high stochastic sensitivity of its attractors. Computational methods based on the stochastic sensitivity functions technique are suggested for the analysis of these attractors. Our method allows us to construct confidence ellipses and estimate a threshold value of a noise intensity corresponding to the neuron excitement. On the basis of the proposed technique, a supersensitive limit cycle is found for the FitzHugh-Nagumo model. PMID- 21797305 TI - Linear response formula for open systems. AB - An exact expression for the finite frequency response of open classical systems coupled to reservoirs is obtained. The result is valid for any conserved current. No assumption is made about the reservoirs apart from thermodynamic equilibrium. At nonzero frequencies, the expression involves correlation functions of boundary currents and cannot be put in the standard Green-Kubo form involving currents inside the system. PMID- 21797306 TI - Thermodynamic laws and equipartition theorem in relativistic Brownian motion. AB - We extend the stochastic energetics to a relativistic system. The thermodynamic laws and equipartition theorem are discussed for a relativistic Brownian particle and the first and the second law of thermodynamics in this formalism are derived. The relation between the relativistic equipartition relation and the rate of heat transfer is discussed in the relativistic case together with the nature of the noise term. PMID- 21797307 TI - Energy dissipation via coupling with a finite chaotic environment. AB - We study the flow of energy between a harmonic oscillator (HO) and an external environment consisting of N two-degrees-of-freedom nonlinear oscillators, ranging from integrable to chaotic according to a control parameter. The coupling between the HO and the environment is bilinear in the coordinates and scales with system size as 1/?N. We study the conditions for energy dissipation and thermalization as a function of N and of the dynamical regime of the nonlinear oscillators. The study is classical and based on a single realization of the dynamics, as opposed to ensemble averages over many realizations. We find that dissipation occurs in the chaotic regime for fairly small values of N, leading to the thermalization of the HO and the environment in a Boltzmann distribution of energies for a well defined temperature. We develop a simple analytical treatment, based on the linear response theory, that justifies the coupling scaling and reproduces the numerical simulations when the environment is in the chaotic regime. PMID- 21797308 TI - Smoothly varying hopping rates in driven flow with exclusion. AB - We consider the one-dimensional totally asymmetric simple exclusion process (TASEP) with position-dependent hopping rates. The problem is solved, in a mean field adiabatic approximation, for a general (smooth) form of spatial rate variation. Numerical simulations of systems with hopping rates varying linearly against position (constant rate gradient), for both periodic and open-boundary conditions, provide detailed confirmation of theoretical predictions, concerning steady-state average density profiles and currents, as well as open-system phase boundaries, to excellent numerical accuracy. PMID- 21797309 TI - Entropic equation of state and scaling functions near the critical point in uncorrelated scale-free networks. AB - We analyze the entropic equation of state for a many-particle interacting system in a scale-free network. The analysis is performed in terms of scaling functions, which are of fundamental interest in the theory of critical phenomena and have previously been theoretically and experimentally explored in the context of various magnetic, fluid, and superconducting systems in two and three dimensions. Here, we obtain general scaling functions for the entropy, the constant-field heat capacity, and the isothermal magnetocaloric coefficient near the critical point in uncorrelated scale-free networks, where the node-degree distribution exponent lambda appears to be a global variable and plays a crucial role, similar to the dimensionality d for systems on lattices. This extends the principle of universality to systems on scale-free networks and allows quantification of the impact of fluctuations in the network structure on critical behavior. PMID- 21797310 TI - Diffusive behavior of a greedy traveling salesman. AB - Using Monte Carlo simulations we examine the diffusive properties of the greedy algorithm in the d-dimensional traveling salesman problem. Our results show that for d=3 and 4 the average squared distance from the origin (r(2)) is proportional to the number of steps t. In the d=2 case such a scaling is modified with some logarithmic corrections, which might suggest that d=2 is the critical dimension of the problem. The distribution of lengths also shows marked differences between d=2 and d>2 versions. A simple strategy adopted by the salesman might resemble strategies chosen by some foraging and hunting animals, for which anomalous diffusive behavior has recently been reported and interpreted in terms of Levy flights. Our results suggest that broad and Levy-like distributions in such systems might appear due to dimension-dependent properties of a search space. PMID- 21797311 TI - Interference in disordered systems: a particle in a complex random landscape. AB - We consider a particle in one dimension submitted to amplitude and phase disorder. It can be mapped onto the complex Burgers equation, and provides a toy model for problems with interplay of interferences and disorder, such as the Nguyen-Spivak-Shklovskii model of hopping conductivity in disordered insulators and the Chalker-Coddington model for the (spin) quantum Hall effect. We also propose a direct realization in an experiment with cold atoms. The model has three distinct phases: (I) a high-temperature or weak disorder phase, (II) a pinned phase for strong amplitude disorder, and (III) a diffusive phase for strong phase disorder, but weak amplitude disorder. We compute analytically the renormalized disorder correlator, equivalent to the Burgers velocity-velocity correlator at long times. In phase III, it assumes a universal form. For strong phase disorder, interference leads to a logarithmic singularity, related to zeros of the partition sum, or poles of the complex Burgers velocity field. These results are valuable in the search for the adequate field theory for higher dimensional systems. PMID- 21797312 TI - Time-averaged quadratic functionals of a Gaussian process. AB - The characterization of a stochastic process from its single random realization is a challenging problem for most single-particle tracking techniques which survey an individual trajectory of a tracer in a complex or viscoelastic medium. We consider two quadratic functionals of the trajectory: the time-averaged mean square displacement (MSD) and the time-averaged squared root mean-square displacement (SRMS). For a large class of stochastic processes governed by the generalized Langevin equation with arbitrary frictional memory kernel and harmonic potential, the exact formulas for the mean and covariance of these functionals are derived. The formula for the mean value can be directly used for fitting experimental data, e.g., in optical tweezers microrheology. The formula for the variance (and covariance) allows one to estimate the intrinsic fluctuations of measured (or simulated) time-averaged MSD or SRMS for choosing the experimental setup appropriately. We show that the time-averaged SRMS has smaller fluctuations than the time-averaged MSD, in spite of much broader applications of the latter one. The theoretical results are successfully confirmed by Monte Carlo simulations of the Langevin dynamics. We conclude that the use of the time-averaged SRMS would result in a more accurate statistical analysis of individual trajectories and more reliable interpretation of experimental data. PMID- 21797313 TI - Product of Ginibre matrices: Fuss-Catalan and Raney distributions. AB - Squared singular values of a product of s square random Ginibre matrices are asymptotically characterized by probability distributions P(s)(x), such that their moments are equal to the Fuss-Catalan numbers of order s. We find a representation of the Fuss-Catalan distributions P(s)(x) in terms of a combination of s hypergeometric functions of the type (s)F(s-1). The explicit formula derived here is exact for an arbitrary positive integer s, and for s=1 it reduces to the Marchenko-Pastur distribution. Using similar techniques, involving the Mellin transform and the Meijer G function, we find exact expressions for the Raney probability distributions, the moments of which are given by a two parameter generalization of the Fuss-Catalan numbers. These distributions can also be considered as a two-parameter generalization of the Wigner semicircle law. PMID- 21797314 TI - Prescription-induced jump distributions in multiplicative Poisson processes. AB - Generalized Langevin equations (GLE) with multiplicative white Poisson noise pose the usual prescription dilemma leading to different evolution equations (master equations) for the probability distribution. Contrary to the case of multiplicative Gaussian white noise, the Stratonovich prescription does not correspond to the well-known midpoint (or any other intermediate) prescription. By introducing an inertial term in the GLE, we show that the Ito and Stratonovich prescriptions naturally arise depending on two time scales, one induced by the inertial term and the other determined by the jump event. We also show that, when the multiplicative noise is linear in the random variable, one prescription can be made equivalent to the other by a suitable transformation in the jump probability distribution. We apply these results to a recently proposed stochastic model describing the dynamics of primary soil salinization, in which the salt mass balance within the soil root zone requires the analysis of different prescriptions arising from the resulting stochastic differential equation forced by multiplicative white Poisson noise, the features of which are tailored to the characters of the daily precipitation. A method is finally suggested to infer the most appropriate prescription from the data. PMID- 21797315 TI - Modeling Maxwell's demon with a microcanonical Szilard engine. AB - Following recent work by Marathe and Parrondo [Phys. Rev. Lett. 104, 245704 (2010)], we construct a classical Hamiltonian system whose energy is reduced during the adiabatic cycling of external parameters when initial conditions are sampled microcanonically. Combining our system with a device that measures its energy, we propose a cyclic procedure during which energy is extracted from a heat bath and converted to work, in apparent violation of the second law of thermodynamics. This paradox is resolved by deriving an explicit relationship between the average work delivered during one cycle of operation and the average information gained when measuring the system's energy. PMID- 21797316 TI - Stochastic resonance in periodic potentials. AB - The phenomenon of stochastic resonance (SR) is known to occur mostly in bistable systems. However, the question of the occurrence of SR in periodic potential systems has not been resolved conclusively. Our present numerical work shows that the periodic potential system indeed exhibits SR in the high-frequency regime, where the linear-response theory yields maximum frequency-dependent mobility as a function of noise strength. The existence of two (and only two) distinct dynamical states of trajectories in this moderately feebly damped periodically driven noisy periodic potential system plays an important role in the occurrence of SR. PMID- 21797317 TI - Frequency-resonance-enhanced vibrational resonance in bistable systems. AB - The dynamics in an overdamped bistable system subject to the action of two periodic forces (assuming their frequencies are omega and Omega, and amplitudes are A and B, respectively) is studied. For the usual vibrational resonance, the nonmonotonic dependence of signal output of the low frequency omega on the change of B for a fixed Omega, the condition Omega?omega is always assumed in all previous studies. Here, removing this restriction, we find that a resonant behavior can extensively occur with respect to the changes of both the frequency Omega and amplitude B. Especially, the resonance becomes stronger when Omega is chosen such that it is exactly in frequency resonance with omega. This combinative behavior, called frequency-resonance-enhanced vibrational resonance, is of great interest and may shed an improved light on our understanding of the dynamics of nonlinear systems subject to a biharmonic force. PMID- 21797318 TI - Directed excitation transfer in vibrating chains by external fields. AB - We study the coherent dynamics of excitations on vibrating chains. By applying an external field and matching the field strength with the oscillation frequency of the chain it is possible to obtain an (average) transport of an initial Gaussian wave packet. We distinguish between a uniform oscillation of all nodes of the chain and the chain being in its lowest eigenmode. Both cases can lead to directed transport. PMID- 21797319 TI - Critical interfaces and duality in the Ashkin-Teller model. AB - We report on the numerical measures on different spin interfaces and Fortuin Kasteleyn (FK) cluster boundaries in the Askhin-Teller (AT) model. For a general point on the AT critical line, we find that the fractal dimension of a generic spin cluster interface can take one of four different possible values. In particular we found spin interfaces whose fractal dimension is d(f)=3/2 all along the critical line. Furthermore, the fractal dimension of the boundaries of FK clusters was found to satisfy all along the AT critical line a duality relation with the fractal dimension of their outer boundaries. This result provides clear numerical evidence that such duality, which is well known in the case of the O(n) model, exists in an extended conformal field theory. PMID- 21797320 TI - Levy stable two-sided distributions: exact and explicit densities for asymmetric case. AB - We investigate functions g(alpha,beta;x) which are heavy-tailed Levy stable probability distributions of index 0